PMID- 23337547 TI - Early presentation of bilateral gonadoblastoma in Turner syndrome. PMID- 23337548 TI - Neonatal pancytopenia associated with de novo 1q43-44 deletion and 10p15 duplication. AB - Deletion of 1q43-44 has been reported in >50 cases. Phenotype-genotype correlation of this deletion has recently been described based on 20 pure cases. This led to the definition of critical regions and candidate genes for microcephaly, corpus callosum abnormalities, and seizure disorders. Variable penetrance and expressivity are associated with 1q43-44 microdeletion syndrome, explaining the lack of correlation in rare cases. Despite variation in size of the deletion, most cases are characterized by typical dysmorphic features, but none have demonstrated neonatal pancytopenia. We report on a newborn with partial monosomy 1q43-44 and partial trisomy 10p15.1->10pter born with dysmorphic features and neonatal pancytopenia. Array-CGH analysis characterizes the deletion and the duplication as terminal with estimated sizes of 8 to 9 and 5 to 6 Mb, respectively. Conventional cytogenetic analysis showed the 10p duplication as unbalanced and translocated onto 1q. The deletion in the 1q43-44 region is the largest among the 20 cases reported most recently. The 10p partnership with the derivative 1q43-44 region is unique. We discuss the association of neonatal pancytopenia with 1q deletion and 10p duplication, in light of a recent published case of acute lymphoblastic leukemia in a constitutional case of 1q deletion and 1p duplication. PMID- 23337549 TI - FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome in childhood: a case report and review of literature. AB - Hypereosinophilic syndromes in children are rare disorders traditionally characterized by an eosinophil count exceeding 1,500/mm3 on at least 2 occasions or evidence of tissue eosinophilia associated with symptoms and marked blood eosinophilia, lacking any secondary cause (such as infections, allergic disease, chemical-induced eosinophilia, hypoadrenalism, cancer). Until now there have only been 3 reported cases of pediatric FIP1L1-PDGFRalpha-positive hypereosinophilic syndromes. We describe a fourth patient, a white 14-year-old boy, the third treated with imatinib. PMID- 23337550 TI - Rituximab in lymphomatoid granulomatosis. AB - BACKGROUND: Lymphomatoid granulomatosis (LG) is an Epstein-Barr virus-associated, multisystemic disease that combines a granulomatous inflammatory process with lymphoproliferative potential. It is a rare disorder with a variable clinical presentation ranging from an indolent process to an aggressive B-cell lymphoma. Outcome is unpredictable, and a standard treatment has not yet been established. Cases treated with rituximab, an anti-CD20 monoclonal antibody, have been reported with variable results. OBSERVATION: We report on 2 children with LG treated with rituximab and review the literature. The first patient had good response but the second did not. CONCLUSIONS: Rituximab is a treatment option for LG. PMID- 23337551 TI - Childhood, adolescents, and young adults (<=25 y) colorectal cancer: study of Anatolian Society of Medical Oncology. AB - PURPOSE: To evaluate the clinicopathologic characteristics and treatment outcomes of young patients with colorectal cancer (CRC). METHODS: Between May 2003 and June 2010, 76 patients were found eligible for this retrospective study. Age, sex, presenting symptoms, patients with acute presentation, family history, presence of polyps, histologic features, localization and stage of the tumor, treatment outcomes, time and site of recurrence, sites of metastasis, and survival outcomes were recorded from the patient files. RESULTS: Seventy-six patients (55.3% male) with a median age of 23 years were evaluated. Patients were evaluated in 2 groups as follows: child-adolescent (0 to 19 y, n=20) and young adult (20 to 25 y, n=56). Sex and symptoms (abdominal pain and rectal bleeding) were significantly differed between the groups and acute presentation was close to statistical significance. Overall survival significantly increased in patients undergoing curative surgery (P<0.001). Other parameters affecting the survival was stage of disease (P=0.004). Response to palliative chemotherapy in metastatic patients (P=0.042) and postoperative adjuvant chemotherapy had a statistically significant survival advantage (P=0.028). CONCLUSIONS: Diagnosis of CRC should not be excluded solely on the basis of age. CRC features in young-adult patients are more similar to adults compared with that of child-adolescent patients according to the symptoms and presentation. In patients with CRC in this age group, curative surgery, adjuvant chemotherapy, and palliative chemotherapy provide survival advantage. PMID- 23337552 TI - Surveillance of healthcare associated infections in pediatric cancer patients between 2004 and 2009 in a public pediatric hospital in Mexico city, Mexico. AB - Pediatric oncology and hematology patients are at increased risk of developing healthcare associated infections (HAIs). We conducted a prospective surveillance study on children with cancer admitted to the pediatric hematology and oncology units at a public pediatric hospital in Mexico from January 2004 to December 2009. The incidence of HAIs and groups at greatest risk for HAIs were analyzed. The annual HAI incidence rate and incidence density were calculated. Risk factors such as site of infection, HAI types, and cancer diagnosis were studied. A total of 9420 patients participated, and 409 had HAIs (479 episodes). Annual HAI rates were 3.7 to 5.5 per 100 admissions and the incidence density was 5.75 to 6 HAIs per 1000 inpatient days annually. There were 272 (56.8%) bloodstream infections, 45 (9.4%) pneumonia cases, and 44 (9.2%) skin and soft tissue infections. Children with acute lymphoblastic leukemia had 37.2% and those with acute myeloid leukemia had 16.4% of the HAIs. A total of 11.5% of the HAIs were in children with osteosarcoma. The most common pathogens were Gram-negative bacteria. The HAI associated mortality rate was 3.7%. Although the overall HAI rate is in line with published reports, the mortality rate was higher, suggesting the incorporation of more aggressive methods to treat infections at our hospital. PMID- 23337553 TI - Successful unrelated cord blood transplantation for homozygous alpha-thalassemia. AB - A now 10-year-old Laotian female was delivered at 30-week gestation by cesarean section because of severe hydrops. Fetal blood sampling revealed homozygous alpha thalassemia. After immediate resuscitation, the infant was supported with frequent red cell transfusions. At 44 months of age, she received a 5 of 6 human leukocyte antigen-matched unrelated cord blood transplantation. She was treated with phlebotomy and chelation therapy with Deferasirox for correction of hemosiderosis and has been transfusion-independent since 41 days after transplant. She is currently 6 years after transplantation with stable, 100% donor engraftment, resolved iron overload, and normal growth and development. PMID- 23337554 TI - Effect of corneal collagen cross-linking on corneal innervation, corneal sensitivity, and tear function of patients with keratoconus. AB - PURPOSE: To evaluate the effect of corneal collagen cross-linking (CXL) on corneal innervation, corneal sensitivity, and tear function in patients with keratoconus. DESIGN: Prospective, interventional case series. PARTICIPANTS: Twenty-four patients with bilateral keratoconus (30 eyes) who presented to the Institute of Vision and Optics, University of Crete, from May 2008 to October 2008. METHODS: Patients underwent CXL. Confocal microscopic analysis of corneal sub-basal nerve plexus (total nerve length per image), corneal sensitivity (assessed with the Cochet-Bonnet esthesiometer), basic tear secretion (assessed with Schirmer's I test with anesthesia), and tear film stability (evaluated by means of tear film break-up time [TFBUT]) were assessed preoperatively and at 1, 3, 6, 9, 12, 18, and 24 months postoperatively. MAIN OUTCOME MEASURES: Comparisons between preoperative and each postoperative value of total nerve length per image, corneal sensitivity, Schirmer's I test results, and TFBUT. RESULTS: Total nerve length per image and corneal sensitivity were significantly decreased until postoperative month 6 (for both parameters: P<0.05 paired-samples t test at 1, 3, and 6 months postoperatively). Total nerve length per image tended to increase up to 2 years postoperatively, when it reached the preoperative level, but differences with the preoperative values after the sixth post-CXL month were insignificant. The results of Schirmer's I test and TFBUT had no statistically significant difference at any time point. CONCLUSIONS: A transient decrease in corneal innervation and corneal sensitivity can be observed up to 6 months after CXL. No significant effect of CXL could be detected on basic tear secretion and tear film stability in our group of patients. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23337556 TI - Acupuncture and in vitro fertilization: critique of the evidence and application to clinical practice. AB - Women undergoing in vitro fertilization (IVF) commonly use adjunctive therapies to improve IVF outcomes and reduce stress, anxiety and depression. Among these acupuncture is a popular choice. Despite 40 clinical trials and 9 systematic reviews investigating the efficacy of acupuncture for improving IVF outcomes, evidence-based guidelines are difficult to devise. The methodology used in the clinical trials does not closely resemble the use of acupuncture in real world acupuncture clinics, limiting the applicability of this research. Since many women undergoing IVF are currently using acupuncture there is a pressing need for a broader understanding of the use of acupuncture for female infertility. This paper offers a critical examination of the research on acupuncture and IVF and its limitations, details the differences between these studies and real world clinical practice, and discusses Chinese medicine theory for improving fertility and its possible scientific mechanisms within the context of clinical practice. PMID- 23337555 TI - Pharmacogenetics for genes associated with age-related macular degeneration in the Comparison of AMD Treatments Trials (CATT). AB - PURPOSE: To evaluate the pharmacogenetic relationship between genotypes of single nucleotide polymorphisms (SNPs) known to be associated with age-related macular degeneration (AMD) and response to treatment with ranibizumab (Lucentis; Genentech, South San Francisco, CA) or bevacizumab (Avastin; Genentech) for neovascular AMD. DESIGN: Clinical trial. PARTICIPANTS: Eight hundred thirty-four (73%) of 1149 patients participating in the Comparison of AMD Treatments Trials (CATT) were recruited through 43 CATT clinical centers. METHODS: Each patient was genotyped for SNPs rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3), using TaqMan SNP genotyping assays (Applied Biosystems, Foster City, CA). MAIN OUTCOMES MEASURES: Genotypic frequencies were compared with clinical measures of response to therapy at one year, including mean visual acuity (VA), mean change in VA, 15-letter or more increase in VA, retinal thickness, mean change in total foveal thickness, presence of fluid on OCT, presence of leakage on fluorescein angiography (FA), mean change in lesion size, and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. To adjust for multiple comparisons, P<=0.01 was considered statistically significant. RESULTS: No statistically significant differences in response by genotype were identified for any of the clinical measures studied. Specifically, there were no high-risk alleles that predicted final VA or change in VA, the degree of anatomic response (fluid on OCT or FA, retinal thickness, change in total foveal thickness, change in lesion size), or the number of injections. Furthermore, a stepwise analysis failed to show a significant epistatic interaction among the variants analyzed; that is, response did not vary by the number of risk alleles present. The lack of association was similar whether patients were treated with ranibizumab or bevacizumab or whether they received monthly or pro re nata dosing. CONCLUSIONS: Although specific alleles for CFH, ARMS2, HTRA1, and C3 may predict the development of AMD, they did not predict response to anti-vascular endothelial growth factor therapy. PMID- 23337558 TI - Is craniosacral therapy effective for migraine? Tested with HIT-6 Questionnaire. AB - OBJECTIVE: To determine whether or not craniosacral therapy alleviates migraine symptoms. METHODS: A cross-over experimental design was used with twenty participants, aged between 20 and 50 years, who suffered from at least two migraine attacks per month. Participants were randomly assigned to two equal sized groups, A and B. All received six craniosacral treatments over four weeks and the groups answered the "HIT-6" Questionnaire four times; every four weeks (Times 1, 2, 3 and 4). Group A, received treatment after answering the questionnaire the first time, but Group B, answered the questionnaire twice before receiving treatment. RESULTS: Immediately after treatments and one month afterwards there was significant lowering in HIT-6 scorings compared with prior to treatment. There was also significant difference in HIT-6 scorings between Times 1 and 4 (p = 0.004). The effect size was 0.43-0.55. CONCLUSION: The results indicate that craniosacral treatment can alleviate migraine symptoms. Further research is suggested. PMID- 23337557 TI - Tai chi/yoga reduces prenatal depression, anxiety and sleep disturbances. AB - Ninety-two prenatally depressed pregnant women were randomly assigned to a tai chi/yoga or a waitlist control group at an average of 22 weeks gestation. The tai chi/yoga group participated in a 20-min group session per week for 12 weeks. At the end of the treatment period the tai chi/yoga group had lower summary depression (CES-D) scores, as well as lower negative affect and somatic/vegetative symptoms subscale scores on the CES-D, lower anxiety (STAI) scores and lower sleep disturbances scores. PMID- 23337559 TI - Effects of honey, sucrose and glucose on blood glucose and C-peptide in patients with type 1 diabetes mellitus. AB - This study was a case control cross sectional study that was conducted on 50 patients with type 1 diabetes mellitus and 30 controls without diabetes. The mean age of patients was 10.02 years. Oral sugar tolerance tests using glucose, sucrose and honey and measurement of fasting and postprandial serum C-peptide levels were done for all subjects in three separate sittings. The glycemic index (GI) and the peak incremental index (PII) were then calculated for each subject. Honey, compared to sucrose, had lower GI and PII in both patients and controls (P < 0.01). In both patients and controls, the increase in the level of C-peptide after honey was significant when compared with either glucose or sucrose (P < 0.01). CONCLUSION: Because of its possible stimulatory effect on diseased beta cells, honey might be considered in future therapeutic trials targeting beta cells of pancreas. PMID- 23337560 TI - Integrative medicine outcomes: what should we measure? AB - The outcomes of Integrative medicine (IM) that combine biomedicine with traditional, complementary and alternative medicine (TCAM) are broad, reflecting the integration. IM is concerned with acute and chronic diseases, holistic approaches, and health promotion and wellness. Before commencing a research program in a primary care IM clinic, stakeholders were interviewed about IM outcomes. Everyone thought Physical Health and Mental Health were important. Those with a more holistic view of health thought a broader range of topics should be measured. Less important topics were lifestyle; health-related aspects of life satisfaction and quality of life; and healthcare evaluation. However, no one thought these should be excluded. Spirituality was the most contentious. Some commended its inclusion. For others, once religiousness and God were removed, the remaining elements should be relocated to the domains of mental health and life satisfaction. The results highlight the importance of consulting stakeholders before measuring outcomes. PMID- 23337561 TI - Neuromuscular electrical stimulation for muscle strengthening in elderly with knee osteoarthritis - a systematic review. AB - PURPOSE: To identify if there is evidence in favor of the use of NMES to quadriceps muscle strengthening in elderly with knee OA. DATA SOURCES AND STUDY SELECTION: A search of PubMed/Medline, PEDro and Cochrane Library produced a total of 76 relevant trials. Six studies that met the inclusion criteria were selected for this review. DATA EXTRACTION: Trials were addressed by inclusion and exclusion criteria and scoring internal validity using PEDro scale. DATA SYNTHESES: A summary of the sample and design characteristics, and muscle strength results from each study were presented on table. CONCLUSION: The best evidence analysis showed moderate evidence in favor of NMES alone or combined with exercise for isometric quadriceps strengthening in elderly with OA. In addition, for the effects of NMES intervention as an adjunct therapy on isokinetic strength at different angular velocities, there was a limited quality of evidence assessed. PMID- 23337562 TI - A comparison of decision-making processes for conventional and complementary medicine in cancer patients. AB - To understand the decision-making processes involved in conventional medicine and complementary medicine cancer treatment, and the role that information plays, a cross-sectional survey of cancer patients was carried out at 2 Australian cancer centres. Data was obtained from 75 cancer patients. When asked about complementary medicine use, 36 (48%) patients reported using some form of complementary medicine in conjunction with their conventional treatment. In terms of decision-making, our findings suggest that although cancer patients appear to be at different stages of decision-making for complementary medicine compared with conventional medicine, there was no difference between the decision-making process for cancer patients when it comes to utilising conventional medicine or complementary medicine: patients reported comparable high decisional self efficacy and low decisional conflict for both areas of medicine. PMID- 23337563 TI - Complementary and alternative medicine use among Mauritian women. AB - OBJECTIVE: To assess CAM usage among women in Mauritius. METHODS: Cross-sectional survey with a nationally-representative sample (n = 384). Quantitative indices included informant-consensus factor, use-value, fidelity-value and use-mentions were calculated. RESULTS: Thirteen therapies were identified and currently are used to treat or manage 26 ailments. These were phytotherapy (30%); yoga (13%); deep-breathing (12%); massage therapy (11%); ayurvedic medicine (8%); meditation (6%); zootherapy (6%); homeopathy (5%); exercise (3%) and reiki (3%). The most prevalent CAM was phytotherapy. Based on the quantitative ethnobotanical indices, plants commonly used were Acalphya spp., (Copper leaf), Curcuma longa (Tumeric), Cymbopogon citratus (Lemon grass), Erythroxylum hypericifolium (Bois ronde), Lens culinaris (Lentil) and Mentha piperita (Mentha). Interestingly, the present study is the first attempt to record CAM management of women's health in Mauritius. CONCLUSIONS: This study can be considered as a primary information resource recording the current use of CAM by women in Mauritius. PMID- 23337564 TI - A narrative review of maternal physical activity during labour and its effects upon length of first stage. AB - Women in western countries generally lie semi-recumbent during first stage of labour, when perhaps it is more natural to move around. Consequently carers are unaware of what constitutes instinctive behaviours and their outcomes. With this in mind, a structured narrative review of the literature identified what prior research has shown about the impact of maternal movement upon length of first stage; results are ambiguous, with 11 studies reporting no alteration to length and 7 reporting shortening. These studies fail to adequately detail time spent mobilising and what in fact constituted walking, squatting, upright, lying lateral, supine or semi-recumbent, and their direct effects upon progress of first stage. Advancements in knowledge are required to progress understanding about maternal activity during labour and its outcomes. PMID- 23337565 TI - Reiki training for caregivers of hospitalized pediatric patients: a pilot program. AB - To explore the feasibility of a Reiki therapy-training program for the caregivers of pediatric medical or oncology inpatients, at a large pediatric hospital, a series of Reiki training classes were offered by a Reiki Master. At completion of the training, an interview was conducted to elicit participant's feedback regarding the effectiveness and feasibility of the training program. Seventeen of the 18 families agreed to participate. Most families (65%) attended three Reiki training sessions, reporting that Reiki benefitted their child by improving their comfort (76%), providing relaxation (88%), and pain relief (41%). All caregivers identified becoming an active participant in their child's care as a major gain from participation in the Reiki training. A hospital-based Reiki training program for caregivers of hospitalized pediatric patients is feasible and can positively impact patients and their families. More rigorous research regarding the benefits of Reiki in the pediatric population is needed. PMID- 23337566 TI - Metabolic syndrome and antipsychotic monotherapy treatment among schizophrenia patients in Malaysia. AB - OBJECTIVE: The objective of this study is to determine the prevalence of metabolic syndrome among schizophrenia patients receiving antipsychotic monotherapy in Malaysia. METHOD: A cross-sectional study was conducted at multiple centres between June 2008 and September 2011. Two hundred and five patients who fulfilled the DSM IV-TR diagnostic criteria for schizophrenia and who had been on antipsychotic medication for at least one year, were screened for metabolic syndrome. Patients receiving a mood stabilizer were excluded from the study. Metabolic syndrome was defined by using the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Treatment Panel III (ATP III) modified for Asian waist circumference. RESULTS: In the first-generation antipsychotic (FGA) group, the highest prevalence of metabolic syndrome was among patients treated with trifluoperazine and flupenthixol decanoate (66.7% each). For the second generation antipsychotic (SGA) group, the highest prevalence of metabolic syndrome was among patients treated with clozapine (66.7%). The component with the highest prevalence in metabolic syndrome was waist circumference in both FGA and SGA groups except for aripiprazole in SGA. CONCLUSION: The prevalence of metabolic syndrome in schizophrenia patients receiving antipsychotic monotherapy in Malaysia was very high. Intervention measures are urgently needed to combat these problems. PMID- 23337567 TI - Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway. AB - Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, ATO produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive ATO treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases Chk1, Chk2 and p53 levels were increased, as were levels of activated ATM and gamma-H2AX. The cell viability was decreased as an ATM inhibitor was added. Additionally, these effects of ATO on gamma-H2AX, Chk1, Chk2, p53, and p21(waf1/cip1) were reduced by an ATM inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM dependent pathway by which osteoblasts survive. PMID- 23337568 TI - Anti-obesity effects of 3-hydroxychromone derivative, a novel small-molecule inhibitor of glycogen synthase kinase-3. AB - Glycogen synthase kinase 3 (GSK-3) plays a central role in cellular energy metabolism, and dysregulation of GSK-3 activity is implicated in a variety of metabolic disorders, including obesity, type 2 diabetes, and cancer. Hence, GSK-3 has emerged as an attractive target molecule for the treatment of metabolic disorders. Therefore, this research focused on identification and characterization of a novel small-molecule GSK-3 inhibitor. Compound 1a, a structure based on 3-hydroxychromone bearing isothiazolidine-1,1-dione, was identified from chemical library as a highly potent GSK-3 inhibitor. An in vitro kinase assay utilizing a panel of kinases demonstrated that compound 1a strongly inhibits GSK-3beta. The potential effects of compound 1a on the inactivation of GSK-3 were confirmed in human liver HepG2 and human embryonic kidney HEK293 cells. Stabilization of glycogen synthase and beta-catenin, which are direct targets of GSK-3, by compound 1a was assessed in comparison with two other GSK-3 inhibitors: LiCl and SB-415286. In mouse 3T3-L1 preadipocytes, compound 1a markedly blocked adipocyte differentiation. Consistently, intraperitoneal administration of compound 1a to diet-induced obese mice significantly ameliorated their key symptoms such as body weight gain, increased adiposity, dyslipidemia, and hepatic steatosis due to the marked reduction of whole-body lipid level. In vitro and in vivo effects were accompanied by upregulation of beta-catenin stability and downregulation of the expression of several critical genes related to lipid metabolism. From these results, it can be concluded that compound 1a, a novel small-molecule inhibitor of GSK-3, has potential as a new class of therapeutic agent for obesity treatment. PMID- 23337569 TI - Circular dichroism of anthocyanidin 3-glucoside self-aggregates. AB - Self-association constants for the flavylium cations of the six most common anthocyanidin 3-glucosides were determined by circular dichroism (CD) and UV-Vis spectroscopy. Along with previous (1)H NMR results, all measurements were consistent with a monomer-dimer model. The CD spectra of the anthocyanidin 3 glucosides were similar to the analogues 3,5-diglucosides. All dimers of the anthocyanidin 3-glucosides exhibited left-handed CD signals, with petunidin-3 glucoside and myrtillin having the most intense signals. In addition, the magnitude of the molar ellipticity, [theta], was generally higher for the 3 glucosides than for the 3,5-diglucosides. For all six anthocyanins studied, the CD absorption spectra of their dimers showed evidence of the splitting of the monomer absorption into lower (J aggregates) and higher (H aggregates) energy bands. The angle and the distance between the dipolar moments of the two monomers comprising the dimer were obtained from the lower energy absorption band. While the angle was more or less similar in all six dimers, the separation distance between the monomer dipole moments differed dramatically. The intensity of the CD signal displayed a linear dependence with the inverse square of the dipole moment distances. PMID- 23337570 TI - Highly glycosylated flavonols with an O-linked branched pentasaccharide from Iberis saxatilis (Brassicaceae). AB - Four flavonol glycosides isolated from non-flowering leafy shoots of Iberis saxatilis (Brassicaceae) were characterised by spectroscopic and chemical methods as saxatilisins A-D, the 3-O-beta-D-glucopyranosyl-(1->3)-alpha-L-rhamnopyranosyl (1->2)[beta-D-glucopyranosyl-(1->2)-alpha-L-rhamnopyranosyl-(1->6)]-beta-D glucopyranoside, 3-O-beta-D-glucopyranosyl-(1->3)-alpha-L-rhamnopyranosyl-(1 >2)[alpha-L-rhamnopyranosyl-(1->6)]-beta-D-glucopyranoside, 3-O-(6-O-E-sinapoyl) beta-D-glucopyranosyl-(1->3)-alpha-L-rhamnopyranosyl-(1->2)[beta-D-glucopyranosyl (1->2)-alpha-L-rhamnopyranosyl-(1->6)]-beta-D-glucopyranoside, and 3-O-(6-O-E feruloyl)-beta-D-glucopyranosyl-(1->3)-alpha-L-rhamnopyranosyl-(1->2)[beta-D glucopyranosyl-(1->2)-alpha-L-rhamnopyranosyl-(1->6)]-beta-D-glucopyranoside of isorhamnetin (3,5,7,4'-tetrahydroxy-3'-methoxyflavone), respectively. Analysis of (2)J(HC) correlations detected with the H2BC (heteronuclear two-bond correlation) pulse sequence aided the unambiguous assignment of glycosidic resonances in the (1)H and (13)C NMR spectra of these compounds. Saxatilisins A, C, and D, are the first flavonol glycosides to be described with a pentasaccharide chain at a single glycosylation site. Several pentaglycosides of kaempferol and quercetin, tentatively assigned as saxatilisin analogues from LC-MS/MS analyses, were present as minor constituents of the extracts. PMID- 23337571 TI - A mechanistic description of radiation-induced damage to normal tissue and its healing kinetics. AB - We introduce a novel mechanistic model of the yield of tissue damage at the end of radiation treatment and of the subsequent healing kinetics. We find explicit expressions for the total number of functional proliferating cells as well as doomed (functional but non-proliferating) cells as a function of time post treatment. This leads to the possibility of estimating-for any given cohort of patients undergoing radiation therapy-the probability distribution of those kinetic parameters (e.g. proliferation rates) that determine times to injury onset and ensuing resolution. The model is suitable for tissues with simple duplication organization, meaning that functionally competent cells are also responsible for tissue renewal or regeneration following injury. An extension of the model to arbitrary temporal patterns of dose rate is presented. To illustrate the practical utility of the model, as well as its limitations, we apply it to data on the time course of urethral toxicity following fractionated radiation treatment and brachytherapy for prostate cancer. PMID- 23337572 TI - Elucidating the catalytic mechanism of beta-secretase (BACE1): a quantum mechanics/molecular mechanics (QM/MM) approach. AB - In this quantum mechanics/molecular mechanics (QM/MM) study, the mechanisms of the hydrolytic cleavage of the Met2-Asp3 and Leu2-Asp3 peptide bonds of the amyloid precursor protein (WT-substrate) and its Swedish mutant (SW) respectively catalyzed by beta-secretase (BACE1) have been investigated by explicitly including the electrostatic and steric effects of the protein environment in the calculations. BACE1 catalyzes the rate-determining step in the generation of Alzheimer amyloid beta peptides and is widely acknowledged as a promising therapeutic target. The general acid-base mechanism followed by the enzyme proceeds through the following two steps: (1) formation of the gem-diol intermediate and (2) cleavage of the peptide bond. The formation of the gem-diol intermediate occurs with the barriers of 19.6 and 16.1 kcal/mol for the WT- and SW-substrate respectively. The QM/MM energetics predict that with the barriers of 21.9 and 17.2 kcal/mol for the WT- and SW-substrate respectively the cleavage of the peptide bond occurs in the rate-determining step. The computed barriers are in excellent agreement with the measured barrier of ~18.0 kcal/mol for the SW substrate and in line with the experimental observation that the cleavage of this substrate is sixty times more efficient than the WT-substrate. PMID- 23337573 TI - Toward an understanding of the sequence and structural basis of allosteric proteins. AB - Allostery is the most efficient means of regulating protein functions, ranging from the control of metabolic mechanisms to signal transduction pathways. Although allosteric regulation has been recognized for half a century, our knowledge is limited to the characteristics of allosteric proteins and the structural coupling of allosteric sites and modulators. In this paper, we present a comprehensive analysis of allosteric proteins that provides insight into the foundation of allosteric interactions by revealing a series of common features in the allosteric proteins. Allosteric proteins mainly appear in transferases, and phosphorylation is the most common type of modification found in allosteric proteins. Disorders related to allosteric proteins primarily comprise metabolic diseases and cancers. In general, allosteric proteins prefer to exist as monomers or even-numbered multimers. Greater stability and hydrophobicity are observed in allosteric proteins than in general proteins. Further analysis of the allosteric sites reveals a series of buried and compact pockets composed of significantly greater hydrophobic surface area than the corresponding orthosteric sites. The hydrophobicity of the allosteric sites plays a dominant role in the binding of allosteric modulators as observed in the analysis of 106 diverse allosteric protein-modulator pairs. These results may be of great significance in predicting which proteins are allosteric and in designing novel triggers to inhibit or activate proteins of interest. PMID- 23337574 TI - Implementing a collaborative framework for academic support for registered nurses. AB - This paper describes the collaboration between a national health service acute hospital trust and a higher education institution, to implement a framework for academic support for registered nurses undertaking learning beyond registration. A small percentage of the educational budget was utilised to fund two academic staff (0.6 whole time equivalent) to work within the trusts' own learning and development department. The initial aim of the project was to maximise the utilisation of the funding available for learning beyond registration study. The focus of the project was at both a strategic level and with individual staff. Embedding within the culture of the trust was important for the academic staff to understand and gain the service/user perspective to some of the barriers or issues concerning learning beyond registration. Following a scoping exercise, the multiplicity of issues that required action led to the creation of an academic support framework. This framework identified potential for intervention in 4 phases: planning for study, application and access to learning, during study and outcome of study. Interventions were identified that were complimentary and adjuncts to the academic support provided by the higher education institution. New resources and services were also developed such as pathway planning support and study skill workshops. One important resource was a dedicated point of contact for staff. A "live" database also proved useful in tracking and following up students. PMID- 23337576 TI - Degradation of 2,4,6-trichlorophenol by bacteria isolated from secondary sludge of a pulp and paper mill. AB - Bacterial strains capable of degrading trichlorophenol (2,4,6-TCP) were isolated from the secondary sludge of a pulp and paper mill and were characterized. These isolates were identified as Planococcus rifietoensis (CL4) and Bacillus pumilus (CL5), based on their 16S rRNA sequence analysis. These isolates were able to grow and utilize 2,4,6-TCP as their source of carbon as well as energy. HPLC analysis and stoichometric release of chloride in the medium confirmed the degradation ability of these isolates. Removal efficiency of 2,4,6-TCP by these isolates was discovered to be high. They were able to remove 90% of 2,4,6-TCP when grown at a concentration of 600 mg L(-1). Inoculation of these bacteria completely removed 2,4,6-TCP within 2 weeks from the sludge of the pulp and paper mill when supplemented at the rate of 100 mg L(-1). Absorbable Organic Halogen (AOX) and Extractable Organic Halogen (EOX) were significantly reduced by 63% and 70% respectively from the sludge due to inoculation of these bacteria. These isolates have high potential to remove 2,4,6-TCP and may be used for removal of 2,4,6-TCP from pulp paper mill waste. PMID- 23337577 TI - Sphingomonas ginsengisoli sp. nov., isolated from soil of a ginseng field. AB - A Gram-reaction-negative, oxidase- and catalase-positive, non-gliding motile bacteriun, designated DCY58(T), was isolated from a ginseng field in Pocheon Province, South Korea. Colonies of strain DCY58(T) were circular, 0.5-1.5 mm in diameter, yellow, and convex on an R2A agar plate after 2 days. The 16S rRNA gene sequence analysis revealed that strain DCY58(T) belongs to the family of the Sphingomonadaceae and is most closely related to the species of genus Sphingomonas with similarity levels of 95.7-96.4%. Strain DCY58(T) contained Q-10 as the predominant ubiquinone. The major cellular fatty acids included Summed Feature 8 (containing C(18:1omega)6c and/or C(18:1omega)7c), C(14:0) 2-OH and C(16:0). The DNA G+C content was 65.1 mol%. Furthermore, strain DCY58(T) differed from other related Sphingomonas species by a number of phenotypic characteristics. On the basis of the evidence presented in this study, strain DCY58(T) is described as a novel species of genus Sphingomonas, for which the name Sphingomonas ginsengisoli sp. nov., is proposed. The type strain is DCY58(T) (=KCTC 23762(T) =JCM 18016(T)). PMID- 23337578 TI - The FPase properties and morphology changes of a cellulolytic bacterium, Sporocytophaga sp. JL-01, on decomposing filter paper cellulose. AB - Sporocytophaga sp. JL-01 is a sliding cellulose degrading bacterium that can decompose filter paper (FP), carboxymethyl cellulose (CMC) and cellulose CF11. In this paper, the morphological characteristics of S. sp. JL-01 growing in FP liquid medium was studied by Scanning Electron Microscope (SEM), and one of the FPase components of this bacterium was analyzed. The results showed that the cell shapes were variable during the process of filter paper cellulose decomposition and the rod shape might be connected with filter paper decomposing. After incubating for 120 h, the filter paper was decomposed significantly, and it was degraded absolutely within 144 h. An FPase1 was purified from the supernatant and its characteristics were analyzed. The molecular weight of the FPase1 was 55 kDa. The optimum pH was pH 7.2 and optimum temperature was 50 degrees C under experiment conditions. Zn(2+) and Co(2+) enhanced the enzyme activity, but Fe(3+) inhibited it. PMID- 23337579 TI - Geobacillus subterraneus subsp. aromaticivorans subsp. nov., a novel thermophilic and alkaliphilic bacterium isolated from a hot spring in Sirnak, Turkey. AB - A new thermophilic spore-forming strain Ge1(T) was isolated from the Guclukonak hot spring in Sirnak, Turkey. The strain was identified by using a polyphasic taxonomic approach. Strain Ge1(T) was Gram-positive, spore-forming, alkaliphilic rod-shaped, motile, occurring in pairs or filamentous. Growth was observed between 30 and 65 degrees C (optimum 60 degrees C) and at pH 5.5-10.0 (optimum pH 9.0). It was capable of utilizing starch, growth was observed at 0-3% NaCl (w/v) and was positive for catalase and urease. The major cellular fatty acids were iso C(15:0) and iso-C(17:0), and the predominant lipoquinone found was menaquinone MK7 type. The DNA G+C content of the genomic DNA of strain Ge1(T) was 52.0%. Comparative 16S rRNA gene sequence studies showed that the isolate belonged to the genus Geobacillus. The DNA-DNA hybridization mean values between the representative strain Ge1(T) and the closely related species G. subterraneus, G. thermodenitrificans, G. thermocatenulatus, G. vulcani and G. thermoleovorans were 69.3%, 57%, 37%, 27% and 26%, respectively. The results of DNA-DNA hybridization, physiological and biochemical tests allowed genotypic and phenotypic differentiation of strain Ge1(T). Based on these results, we propose assigning a novel subspecies of Geobacillus subterraneus, to be named as Geobacillus subterraneus subsp. aromaticivorans subsp. nov. with the type strain Ge1(T) (DSM 23066 (T)= CIP 110341(T)). PMID- 23337580 TI - Diversity and function of aerobic culturable bacteria in the intestine of the sea cucumber Holothuria leucospilota. AB - Sea cucumbers play an important role in nutrient cycling of marine ecosystems by consuming sediments and moving sand, thus occupying a similar niche to earthworms in terrestrial ecosystems. However, our understanding of microbial diversity and functions associated with sea cucumbers is meager. Here, we isolated 141 bacterial strains under aerobic conditions using various media from the intestine of Holothuria leucospilota, a common sea cucumber in Japanese warm waters. By partial 16S rRNA gene sequences of the isolates, the isolates were tentatively affiliated with 55 described species. Among them, 23 species were common between 2 individuals of H. leucospilota. High diversity was observed in the genera Bacillus and Vibrio, which are often found in marine sediments, marine animals and other various environments. Most isolates showed various polysaccharide degradation activities and were able to grow under or were tolerant of anaerobic condition. We suggest that these aerobically isolated bacteria can play a role in digestion of detritus in aerobic and/or anaerobic regions of the intestine. PMID- 23337575 TI - Anaerocella delicata gen. nov., sp. nov., a strictly anaerobic bacterium in the phylum Bacteroidetes isolated from a methanogenic reactor of cattle farms. AB - A strictly anaerobic bacterial strain (WN081(T)) was isolated from rice-straw residue in a methanogenic reactor treating waste from cattle farms in Japan. Cells were Gram-staining negative, non-motile, non-spore-forming straight rods. The strain grew rather well on PY agar slants supplemented with a B-vitamin mixture as well as sugars (PYV4S medium) and made translucent and glossy colonies. Growth in liquid medium with the same composition, however, was scanty, and growth was not improved in spite of various additives to the medium. Strain WN081(T) produced small amounts of acetate, propionate, isobutyrate, butyrate, isovalerate and H(2) from PYV liquid medium. The strain did not use carbohydrates or organic acids. The pH range for growth was narrow (pH 6.8-8.2), having a pH optimum at 6.8-7.5. The temperature range for growth was 10-37 degrees C, the optimum being 25-30 degrees C. The strain was sensitive to bile, and did not have catalase or oxidase activities. Hydrogen sulfide was produced from L-cysteine and L-methionine as well as peptone. Indole was produced from L-tryptophan and peptone. The strain had iso-C(15:0) as the exclusively predominant cellular fatty acid (70%) together with some branched chain components (such as iso-C(15:0) DMA, iso-C(17:0) 3-OH and iso-C(15:0) aldehyde) as minor components. The genomic DNA G+C content was 32.3 mol%. Phylogenetic analysis based on the 16S rRNA gene sequence placed strain WN081(T) in the phylum Bacteroidetes with rather low sequence similarities with the related species such as Rikenella microfusus (85.7% sequence similarity), Alistipes putredinis (85.5%) and Alistipes finegoldii (85.5%) in the family Rikenellaceae. Based on the phylogenetic, physiological and chemotaxonomic analyses, the novel genus and species Anaerocella delicata gen. nov., sp. nov. is proposed to accommodate the strain. The type strain is WN081(T) (= JCM 17049(T) = DSM 23595(T)). PMID- 23337581 TI - Expression of the serum opacity factor gene and the variation in its upstream region in Streptococcus dysgalactiae isolates from fish. AB - Group C Streptococcus dysgalactiae (GCSD) is a pathogen of farmed fish. Almost all GCSD isolates from Asian countries, including Japan, Taiwan, Malaysia, and China, have a serum opacity factor (SOF-FD). Although the SOF-FD sequences in different GCSD isolates are identical, different opacification activities are observed. Three types of variations were observed in the upstream sequence of the sof-FD gene in GCSD isolates with different SOF-FD activities. Type 1 was characterized by insertion of an IS981-like element into the upstream region of the sof-FD gene. In Type 2, an IS981-like element was inserted into the upstream region in a direction opposite to that in Type 1. In Type 3, no IS element was inserted. Type 1 was predominant among Japanese isolates (129 of 133). Isolates from other Asian countries were generally Type 3 (13 of 16). Except for 1 strain, Type 1 strains exhibited opacification activities with optical densities (ODs)>0.6, while Type 2 and Type 3 strains have low opacification activities (ODs >0.2). Only Type 1 strains have putative -10 and -35 promoter regions upstream of the sof-FD gene, and the expression level of the sof-FD gene was higher in Type 1 strains than in Type 2 and Type 3 strains. PMID- 23337582 TI - Transcriptional factor fur from Thermoplasma volcanium binds its own promoter DNA in a divalent cation-dependent manner. AB - Because archaea possess many respiratory enzymes or radical scavengers with catalytic domains that contain iron, the expression of the genes encoding these enzymes might be regulated by iron acquisition. The genome of an archaeon, Thermoplasma volcanium contains a gene that encodes Fur (TVN0292). The fur gene of T. volcanium was amplified by PCR, and cloned into plasmid pET28a. TvFur (T. volcanium Fur protein) was expressed in E. coli cells and then purified. EMSA revealed that TvFur binds to its own promoter DNA. The binding to its own promoter was in an Mn(2+)-, Zn(2+)-, and Ni(2+)-dependent manner. DNase I footprinting analysis revealed that the binding sequence of tvfur promoter was 5' G TTATTAT G TTTATAT A TTAATTA G-3'. An analysis utilizing oligonucleotides in TvFur-binding sequences revealed that TvFur binds to the TATA-box or regions in the vicinity of the TATA-box in the promoter. These results indicated that TvFur regulates transcription depending on the availability of environmental divalent cations. PMID- 23337584 TI - Unspliced XBP1 controls autophagy through FoxO1. AB - Protein homeostasis in higher eukaryotes is balanced by a dynamic network of adaptive mechanisms, including the unfolded protein response (UPR) and autophagy. In a paper recently published in Cell Research, Zhu and co-workers uncover a novel biological function of the unspliced form of the UPR transcription factor XBP1 in the modulation of autophagy through the control of FoxO1 turnover. PMID- 23337583 TI - Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion. AB - Lysosome is a key subcellular organelle in the execution of the autophagic process and at present little is known whether lysosomal function is controlled in the process of autophagy. In this study, we first found that suppression of mammalian target of rapamycin (mTOR) activity by starvation or two mTOR catalytic inhibitors (PP242 and Torin1), but not by an allosteric inhibitor (rapamycin), leads to activation of lysosomal function. Second, we provided evidence that activation of lysosomal function is associated with the suppression of mTOR complex 1 (mTORC1), but not mTORC2, and the mTORC1 localization to lysosomes is not directly correlated to its regulatory role in lysosomal function. Third, we examined the involvement of transcription factor EB (TFEB) and demonstrated that TFEB activation following mTORC1 suppression is necessary but not sufficient for lysosomal activation. Finally, Atg5 or Atg7 deletion or blockage of the autophagosome-lysosome fusion process effectively diminished lysosomal activation, suggesting that lysosomal activation occurring in the course of autophagy is dependent on autophagosome-lysosome fusion. Taken together, this study demonstrates that in the course of autophagy, lysosomal function is upregulated via a dual mechanism involving mTORC1 suppression and autophagosome lysosome fusion. PMID- 23337585 TI - L-glutamine provides acid resistance for Escherichia coli through enzymatic release of ammonia. AB - Bacteria, exemplified by enteropathogenic Escherichia coli (E. coli), rely on elaborate acid resistance systems to survive acidic environment (such as the stomach). Comprehensive understanding of bacterial acid resistance is important for prevention and clinical treatment. In this study, we report a previously uncharacterized type of acid resistance system in E. coli that relies on L glutamine (Gln), one of the most abundant food-borne free amino acids. Upon uptake into E. coli, Gln is converted to L-glutamate (Glu) by the acid-activated glutaminase YbaS, with concomitant release of gaseous ammonia. The free ammonia neutralizes proton, resulting in elevated intracellular pH under acidic environment. We show that YbaS and the amino acid antiporter GadC, which exchanges extracellular Gln with intracellular Glu, together constitute an acid resistance system that is sufficient for E. coli survival under extremely acidic environment. PMID- 23337586 TI - Trinucleotide repeat expansions catalyzed by human cell-free extracts. AB - Trinucleotide repeat expansions cause 17 heritable human neurological disorders. In some diseases, somatic expansions occur in non-proliferating tissues such as brain where DNA replication is limited. This finding stimulated significant interest in replication-independent expansion mechanisms. Aberrant DNA repair is a likely source, based in part on mouse studies showing that somatic expansions are provoked by the DNA repair protein MutSbeta (Msh2-Msh3 complex). Biochemical studies to date used cell-free extracts or purified DNA repair proteins to yield partial reactions at triplet repeats. The findings included expansions on one strand but not the other, or processing of DNA hairpin structures thought to be important intermediates in the expansion process. However, it has been difficult to recapitulate complete expansions in vitro, and the biochemical role of MutSbeta remains controversial. Here, we use a novel in vitro assay to show that human cell-free extracts catalyze expansions and contractions of trinucleotide repeats without the requirement for DNA replication. The extract promotes a size range of expansions that is similar to certain diseases, and triplet repeat length and sequence govern expansions in vitro as in vivo. MutSbeta stimulates expansions in the extract, consistent with aberrant repair of endogenous DNA damage as a source of expansions. Overall, this biochemical system retains the key characteristics of somatic expansions in humans and mice, suggesting that this important mutagenic process can be restored in the test tube. PMID- 23337588 TI - Lipidomics as an emerging tool to predict endometrial receptivity. AB - From the first histologic dating methods to the new "-omics" technologies, there has been a lot of effort put into understanding and characterizing receptive endometrium. The development of new diagnostic approaches to using biologic fluids has opened up a new field of investigation in noninvasive endometrial diagnosis techniques. Moreover, improvements in the field of mass spectrometry and nuclear magnetic resonance have made the precise detection of lipids possible; these organic molecules are involved in important functions such as modulating energy reserves, forming structural features, and promoting regulatory functions. Developments in endometrial receptivity diagnosis using lipidomics are discussed in this review paper. In summary, the results currently available indicate that prostaglandins E(2) and F(2alpha) are particularly abundant during the window of implantation and that they might serve to nurse the blastocyst at the time of embryo implantation; they may also serve as important biomarkers to define the receptive phase of the endometrium. The importance of understanding the mechanisms that influence the production of these individual prostaglandins in the endometrium is clinically relevant because it may shed light on the sequence of events that leads to successful embryo implantation. PMID- 23337587 TI - Decoding the phosphorylation code in Hedgehog signal transduction. AB - Hedgehog (Hh) signaling plays pivotal roles in embryonic development and adult tissue homeostasis, and its deregulation leads to numerous human disorders including cancer. Binding of Hh to Patched (Ptc), a twelve-transmembrane protein, alleviates its inhibition of Smoothened (Smo), a seven-transmembrane protein related to G-protein-coupled receptors (GPCRs), leading to Smo phosphorylation and activation. Smo acts through intracellular signaling complexes to convert the latent transcription factor Cubitus interruptus (Ci)/Gli from a truncated repressor to a full-length activator, leading to derepression/activation of Hh target genes. Increasing evidence suggests that phosphorylation participates in almost every step in the signal relay from Smo to Ci/Gli, and that differential phosphorylation of several key pathway components may be crucial for translating the Hh morphogen gradient into graded pathway activities. In this review, we focus on the multifaceted roles that phosphorylation plays in Hh signal transduction, and discuss the conservation and difference between Drosophila and mammalian Hh signaling mechanisms. PMID- 23337589 TI - Genetic screening in the American Society for Reproductive Medicine's new guidelines on diagnostic evaluation of the infertile male. PMID- 23337590 TI - Reply of the authors. PMID- 23337591 TI - Neohormones as biomarkers of reproductive health. AB - Neohormone systems are defined as evolutionarily new endocrine or paracrine adaptations that supplement basic physiologic functions and define mammalian success. The relaxin family of peptide hormones are typical neohormones. Because they define the specific mammalian aspects of reproductive physiology, such as viviparity with implantation and placentation, lactation, or in the male the necessary adaptations to sperm needed for successful internal fertilization, they offer excellent biomarkers for characterizing reproductive health and disease. For example, ovarian H2-relaxin aids implantation and the establishment of the placenta, and circulating levels are significantly altered in early miscarriage. In the fetus, testicular INSL3 is responsible for the first phase of testicular descent and may be disrupted in cryptorchidism. In the adult, INSL3 is believed to be involved as an antiapoptotic factor in germ cell survival (male) and follicle selection (female) and acts as an excellent measure of Leydig cell functional capacity, particularly in the aging male. INSL5 and INSL6 appear also to be involved in the maintenance of adequate spermatogenesis. With the development of robust immunoassays for various relaxin family members, we are progressively gathering baseline information about normal biomarker levels as well as their perturbations in a wide range of reproductive pathologies. PMID- 23337592 TI - Unrecognized fine-scale recombination can mimic the effects of adaptive radiation. AB - Gene sequences can undergo accelerated nucleotide changes and rapid diversification. The rapid sequence changes can then potentially lead to phylogenetic incongruence. Recently, Bodilis et al. (2011) observed artificial phylogenetic incongruence using the Pseudomonas surface protein gene oprF, and hypothesized that it was the result of a long-branch attraction artifact ultimately caused by adaptive radiation. In this study, an alternative hypothesis, namely fine-scale recombination, was tested on the same dataset. The results reveal that regions in oprF are of different evolutionary origins, and the mosaic gene structure resulted in confounding phylogenetic signals. These findings demonstrate that unrecognized fine-scale recombination can confound the phylogenetic interpretation and emphasize the limitation of using whole genes as the unit of phylogenetic analysis. PMID- 23337593 TI - Differential gene expression by Osterix knockdown in mouse chondrogenic ATDC5 cells. AB - Osterix (Osx) is a transcription factor required for osteoblast differentiation during intramembranous and endochondral ossification. Recently, several reports have described novel functions of Osx in chondrocyte differentiation. In an in vitro study, in which the effects of Osx gene silencing were examined in mouse chondrogenic ATDC5 cells, chondrocyte marker genes were found to be expressionally downregulated and chondrocyte differentiation reduced. On the other hand, in vivo studies based on chondrocyte-specific Osx knockouts demonstrated impaired endochondral bone formation with delayed chondrocyte differentiation and reduced cartilage matrix ossification. However, little is known about the mechanism or targets of Osx involved in the control of chondrocyte differentiation. Here, we attempted to high-density of Affymetrix GeneChip microarray to investigate global gene expression profile changes caused by Osx knockdown in ATDC5 chondrocytes. The mRNA expressions of 112 genes were significantly modified by Osx knockdown: 68 genes were upregulated and 44 genes downregulated. Functional categories of gene expression classified by gene ontology demonstrated that genes related to cell adhesion, development, and signal transduction were highly affected by Osx knockdown. The expressions of differential genes, such as Sfrp2, Sema3a, Nox4, Rgs4, Zfp521, Has2, Sox6, Scn2a1, Sirpa, and Thbs2, were validated by quantitative real-time PCR. This study shows that expression profiling can be used to identify genes that are transcriptionally modified following Osx knockdown and to reveal the molecular mechanism of chondrocyte differentiation regulated by Osx. PMID- 23337594 TI - Genomic organization and promoter characterization of FcCTL, a C-type lectin-like protein in Fenneropenaeus chinensis. AB - Diseases caused by viruses are the greatest challenge to worldwide shrimp aquaculture. C-type lectins may play an important role in shrimp immunity. The gene encoding FcCTL, a C-type lectin-like protein, was isolated from Fenneropenaeus chinensis and characterized. This gene was composed of five exons spanning 2470 base pairs (bp). Intron 1 contained a possible promoter and many potential transcription factor binding sites, such as those for TATA binding protein, CREB, SRF, Ttk and three sites for HSFs. The 5'-flanking sequences (723 bp) of FcCTL contained typical CTF (CAAT box) and transcriptional regulatory elements, such as CF1, CF2-II and HSEs, observed in immunity-related genes in other arthropods. A series of FcCTL promoter sequences, especially the full length promoter, generated an increase in luciferase expression relative to the promoter-less vector; furthermore, the expression of FcCTL was induced by heat shock and white spot syndrome virus (WSSV) challenge. These results extended our previous findings and provided insights into the molecular regulation of FcCTL gene expression, which would be helpful for shrimp viral disease control. PMID- 23337595 TI - Next generation personalized animals as an enabling technology in personalized vaccinology. PMID- 23337596 TI - Understanding drugs and diseases by systems biology? AB - Systems biology aims to provide a holistic and in many cases dynamic picture of biological function and malfunction, in case of disease. Technology developments in the generation of genome-wide datasets and massive improvements in computer power now allow to obtain new insights into complex biological networks and to copy nature by computing these interactions and their kinetics and by generating in silico models of cells, tissues and organs. The expectations are high that systems biology will pave the way to the identification of novel disease genes, to the selection of successful drug candidates--that do not fail in clinical studies due to toxicity or lack of human efficacy--and finally to a more successful discovery of novel therapeutics. However, further research is necessary to fully unleash the potential of systems biology. Within this review we aim to highlight the most important and promising top-down and bottom-up systems biology applications in drug discovery. PMID- 23337597 TI - Polyoxometalate-biomolecule conjugates: a new approach to create hybrid drugs for cancer therapeutics. AB - Some polyoxometalate (POM) clusters have demonstrated attractive anticancer properties. Unfortunately, their cytotoxicity upon normal cell is one of fateful side effects obstructing their further clinic application as inorganic drugs. In this communication, we report a new approach to create hybrid drugs potentially for cancer therapeutics. At first, the POM cluster bioconjugates were created by attaching the bioactive ligands on an amine grafted POM via simple amidation reaction. The cytotoxicity study with breast cancer cells (MCF-7 and MDA-MB-231) and non-cancerous breast epithelial cell (MCF-10A) showed that rationally selected ligands with cancer-cell targeting ability on POM-biomolecule conjugates can impart enhanced anti-tumor activity and selectivity, thus representing a new concept to develop novel POM-biomolecule hybrid drugs with the potential synergistic effect: increased bioactivity and lower side effect. PMID- 23337598 TI - Novel naphthoquinone derivatives: synthesis and activity against human African trypanosomiasis. AB - A series of naphthoquinone derivatives has been synthesized and tested for its biological activity against human African trypanosomiasis. The use of reverse micellar medium not only enhanced the conversion rate, but also showed selectivity towards mono-coupled product in aryl chloride-aniline coupling reactions. Two derivatives of naphthoquinone (9b and 9c) exhibited potent activity against Trypanosoma brucei in vitro with low cytotoxicity. PMID- 23337599 TI - N-1, C-3 substituted indoles as 5-LOX inhibitors--in vitro enzyme immunoaasay, mass spectral and molecular docking investigations. AB - Based upon the structures of some known 5-LOX inhibitors, a set of five compounds carrying appropriate substituents at N-1 and C-3 of indole were synthesized and investigated for 5-LOX inhibitory activities. Fifty percent inhibitory concn (IC(50)) of these compounds ranges from 0.6 to 5 MUM and found to be comparable to that of clinically used 5-LOX inhibitor, zileuton. The compounds under present investigations exhibited appreciable interactions with 5-LOX as apparent from their association constants calculated from the mass spectral data. Compound 5a with a tosyl group at N-1 and pyrolidinyl-1,2-dione substituent at C-3 of indole, exhibiting IC(50) 0.6 MUM and stoichiometry of 1:7 in the enzyme-compound complex was identified as highly potent 5-LOX inhibitor and seems to be suitable for further investigations. PMID- 23337600 TI - 99mTc-(Me)FGCDEVD, a potential tracer for apoptosis detection. AB - (Me)FGC(Bz)DEVD was radiolabeled with technetium-99m in high yield. This tracer was preferentially accumulated in apoptotic cells in the in vitro studies. Tumor uptake occurred in vivo after cisplatin injection due to the apoptosis induction, which not observed in the untreated tumors. Therefore, (99m)Tc-(Me)FGCDEVD is a potential tracer for apoptosis detection. PMID- 23337601 TI - Discovery of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as potent agonists of TGR5 via sequential combinatorial libraries. AB - Optimization of a high-throughput screening hit led to the discovery of a new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as highly potent agonists of TGR5. This novel chemotype was rapidly developed through iterative combinatorial library synthesis. It was determined that in vitro agonist potency correlated with functional activity data from human peripheral blood monocytes. PMID- 23337602 TI - 3H-1,2,4-Dithiazol-3-one compounds as novel potential affordable antitubercular agents. AB - Small molecules with oxathiazol-2-one moiety were recently reported as potent inhibitors of Mycobacterium bovis var. bacilli Calmette-Guerin (BCG), among which HT1171 was the most potent and selective proteasome inhibitor. Herein we synthesized a series of novel compounds by bioisosteric replacement of the oxathiazol-2-one ring with 3H-1,2,4-dithiazol-3-one, and also fifteen 1,3,4 oxathiazol-2-one molecules in order for potency comparison and structure-activity relationship elucidation since their antibacterial effects on the virulent strains were not evaluated before. All the compounds were assessed for antitubercular activities on the virulent H37Rv strain by a serial dilution method. Among the tested compounds, 3H-1,2,4-dithiazol-3-one compound 4n was found to be the most active with a lowest MIC(90) value of 1 MUg/mL. Furthermore, the cytotoxicities of all the compounds against normal human liver cell line L02 were determined by an MTT method. Compound 4n displayed a lower inhibitory ratio than HT1171 at the concentration of 100 MUM, indicating its better safety profile. PMID- 23337603 TI - Identification of selected organic contaminants in streams associated with agricultural activities and comparison between autosampling and silicone rubber passive sampling. AB - This study evaluates the potential of silicone rubber passive sampling devices (SR-PSDs) as a suitable alternative to automatic water samplers (autosamplers) for the preliminary identification of a wide range of organic contaminants in freshwater systems. The field performance of SR-PSDs deployed at three sites on two streams of an agricultural catchment area in North East (NE) Scotland, United Kingdom (UK) was assessed concurrently with composite water samples collected from two of the sites using autosamplers. The analytical suite consisted of selected plant protection products (PPPs; commonly referred to collectively as 'pesticides'), including 47 pesticides and a separate sub-category of 22 acid/urea herbicides. Of these, a total of 54 substances, comprising 46 pesticides and 8 urea herbicides were detected in at least one of the SR samplers. All but 6 of these SR-PSD detected substances were quantifiable. By comparison, a total of 25 substances comprising 3 pesticides and 22 acid/urea herbicides were detected in the composite water samples, of which only 8 acid/urea herbicides were quantifiable. The larger number and chemical classes of compounds detected and quantified via passive sampling reflect the lower limits of detection achieved by this device when compared to autosamplers. The determination of dissolved concentrations of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) added to the information on contaminant pressures at each site, allowing assessment of the reliability of SR PSDs in freshwater systems and the identification of possible contaminant sources. The study demonstrated the utility of SR-PSDs for detecting and semi quantifying low concentrations of analytes, including those which hitherto have not been measured in the catchment area and also some pesticides that are no longer approved for agricultural use in the UK and EU. The SR-PSD approach can thus provide a better understanding and clearer picture of the use and presence of organic contaminants within catchments. PMID- 23337604 TI - Prenatal and postnatal residential usage of insecticides in a multicenter birth cohort in Spain. AB - This study aimed to describe the residential use of insecticides in a birth cohort in Spain. Study subjects were 2,456 women enrolled into the INMA (Environment and Childhood) birth cohort followed prospectively during pregnancy and in the early postnatal period. The women were recruited at the beginning of their pregnancy between 2003 and 2008 in four regions of Spain. Socio demographic, environmental and lifestyle information was obtained at two interviews during pregnancy, one at the first (mean:13.8+/-2.6 weeks of gestation) and the other at the third trimester (mean: 33.3+/-2.3 weeks of gestation). Information about prenatal use of indoor and outdoor insecticides (type, timing, place of application, place of storage) was obtained from the second interview. In a 3rd interview (mean: 16.2+/-6.9 months of age of children), information about postnatal indoor and outdoor insecticide use was obtained. Regression models examined the association between demographic and lifestyle factors and pesticide use to determine which characteristics predicted use prenatally and postnatally. Fifty-four percent of women reported using indoor insecticides during pregnancy, 45% in their bedroom and 47% elsewhere in the house. Plug-in devices were the most frequent application methods used in the pregnant woman's bedroom and insecticide sprays elsewhere in the house. The maternal factors related to prenatal use of indoor insecticides were parity, country of birth, educational level, region of residence, having a garden or yard with plants, and living near an agricultural area. These products continued to be used postnatally, although 20% of the women stopped using them. Foetuses and children are especially vulnerable to pesticide exposure; thus knowing how pesticides are used during pregnancy and infancy may be a starting point for the study of their potential effects on health as well as useful for designing preventive actions. PMID- 23337605 TI - Removal of cytostatic drugs from aquatic environment: a review. AB - Cytostatic drugs have been widely used for chemotherapy for decades. However, many of them have been categorized as carcinogenic, mutagenic and teratogenic compounds, triggering widespread concerns about their occupational exposure and ecotoxicological risks to the environment. This review focuses on trace presence, fate and ecotoxicity of various cytostatic compounds in the environment, with an emphasis on the major sources contributing to their environmental concentrations. Past records have documented findings mainly on hospital effluents though little effort has been directed to household discharges. There is also a lack in physico chemical data for forecasting the chemodynamics of cytostatics in natural waters along with its human metabolites and environmental transformation products. In this light, obtaining comprehensive ecotoxicity data is becoming pressingly crucial to determine their actual impacts on the ecosystem. Literature review also reveals urinary excretion as a major contributor to various cytostatic residues appeared in the water cycle. As such, engaging urine source-separation as a part of control strategy holds a rosy prospect of addressing the "emerging" contamination issue. State-of-the-art treatment technologies should be incorporated to further remove cytostatic residues from the source-separating urine stream. The benefits, limitations and trends of development in this domain are covered for membrane bio-reactor, reverse/forward osmosis and advanced oxidation processes. Despite the respective seeming advantages of source separation and treatment technology, a combined strategy may cost-effectively prevent the cytostatic residues from seeping into the environment. However, the combination calls for further evaluation on the associated technological, social economic and administrative issues at hand. PMID- 23337606 TI - Impact of entropy monitoring on volatile anesthetic uptake. AB - BACKGROUND: Electroencephalogram-derived monitoring to assess anesthetic depth may allow more accurate hypnotic drug administration, resulting in decreased anesthetic drug consumption. The authors hypothesized that the use of M-Entropy monitoring (Datex-Ohmeda, Helsinki, Finland) is associated with reduced sevoflurane uptake (primary outcome) in patients undergoing major abdominal surgery. METHODS: A total of 50 patients with an American Society of Anesthesiology score of II-III, scheduled for elective laparoscopic rectosigmoidectomy were randomized into two groups in this randomized controlled trial. In the control group, the target expiratory fraction of sevoflurane was adapted according to standard clinical practice. In the study group, the target expiratory fraction of sevoflurane was adapted to maintain state entropy values between 40 and 60. State entropy values were continuously recorded in both groups but were not available to the anesthesiologist in the control group. In both groups, patients were ventilated using the auto-control mode of the Zeus(r) (Drager, Lubeck, Germany) respirator, which allows precise measurements of sevoflurane uptake. Sufentanil was administered using a target-controlled infusion system. RESULTS: Demographics did not differ between groups. During the anesthesia maintenance phase, state entropy values were lower in the control group than the study group (P < 0.0001). Sevoflurane uptake was higher in the control group than the study group (5.2 +/- 1.4 ml/h vs. 3.8 +/- 1.5 ml/h; P = 0.0012). Three patients in the control group developed intraoperative hypotension compared with none in the study group (P = 0.03). CONCLUSIONS: Monitoring the depth of anesthesia using M-Entropy was associated with a significant reduction in sevoflurane uptake. PMID- 23337608 TI - Two-way gastroduodenal artery. PMID- 23337607 TI - Prenatal exposure to bisphenol A impacts midbrain dopamine neurons and hippocampal spine synapses in non-human primates. AB - Prevalent use of bisphenol-A (BPA) in the manufacture of resins, plastics and paper products has led to frequent exposure of most people to this endocrine disruptor. Some rodent studies have suggested that BPA can exert detrimental effects on brain development. However as rodent models cannot be relied on to predict consequences of human exposure to BPA during development, it is important to investigate the effects of BPA on non-human primate brain development. Previous research suggests that BPA preferentially targets dopamine neurons in ventral mesencephalon and glutamatergic neurons in hippocampus, so the present work examined the susceptibility of these systems to low dose BPA exposure at the fetal and juvenile stages of development in non-human primates. Exposure of pregnant rhesus monkeys to relatively low levels of BPA during the final 2 months of gestation, induced abnormalities in fetal ventral mesencephalon and hippocampus. Specifically, light microscopy revealed a decrease in tyrosine hydroxylase-expressing (dopamine) neurons in the midbrain of BPA-exposed fetuses and electron microscopy identified a reduction in spine synapses in the CA1 region of hippocampus. In contrast, administration of BPA to juvenile vervet monkeys (14-18 months of age) was without effect on these indices, or on dopamine and serotonin concentrations in striatum and prefrontal cortex, or on performance of a cognitive task that tests working memory capacity. These data indicate that BPA exerts an age-dependent detrimental impact on primate brain development, at blood levels within the range measured in humans having only environmental contact with BPA. PMID- 23337609 TI - Granular cell tumour of the common bile duct: a condition to be aware of. PMID- 23337610 TI - A case of a suicide attempt associated with hyperthyroidism. AB - Hyperthyroidism has profound effects on mental health. The literature is sparse, however, with regard to suicide attempts related to untreated hyperthyroidism. This case report illustrates the presentation of a patient in the intensive care unit after a life-threatening Tylenol overdose presumed to be secondary to adjustment disorder. During the patient's hospitalization, she experienced anxiety, heart palpitations, tachycardia and diaphoresis. The psychiatric consultant, endocrinology consultant and inpatient psychiatry teams helped to diagnose Graves' disease, significantly changing her treatment and trajectory. PMID- 23337611 TI - Emergence of methicillin-resistant, vancomycin-intermediate Staphylococcus aureus among patients associated with group A Streptococcal pharyngitis infection in southern India. AB - Beyond Staphylococcus aureus being an etiological agent for several serious clinical complications, the foot prints of S. aureus in pharyngitis infection has also been recently recognized. With due response to the fact, a prospective study was conducted between 2009 and 2010 to describe the molecular epidemiology of S. aureus in throat swabs of pharyngitis patients. A total of 63 methicillin resistant S. aureus (MRSA) and 102 methicillin-susceptible S. aureus (MSSA) isolates were recovered from 265 throat swabs, representing a community-acquired outpatient population from Tamil Nadu, India. Molecular characterization of MRSA was done by two conventional multiplex PCR assays including Panton-Valentine leukocidin (PVL), mecA and nuc genes, and staphylococcal cassette chromosome mec (SCCmec) typing. Among 165 S. aureus isolates, methicillin resistance was observed in 38.2% (n=63), in which 69.8% (n=44/63) of the MRSA along with 55.9% (n=57/102) of MSSA harbored PVL toxin genes. SCCmec typing showed 50.8% of isolates as SCCmec V (n=32), 44.4% as SCCmec III (n=28), and 1.6% as SCCmec types I, II and IVa (n=1). Multilocus sequence typing performed for 26 selected MRSA isolates resulted in 12 different sequence types (ST), including a novel ST2129/SCCmec III, PVL-positive. Ten MRSA isolates were categorized as ST772 (38.5%)/SCCmec V, PVL-positive, and three isolates as ST368 (11.5%)/SCCmec III, PVL-negative. Though the prominent clones of ST772/SCCmec V were multidrug susceptible worldwide, they were highly multidrug-resistant in the current study, including four clones intermediate to vancomycin. Totally, 10 (15.9%) out of 63 MRSA isolates were documented as vancomycin-intermediate S. aureus (VISA). Collectively, the present study for the first time portrayed the high prevalence of active MRSA pharyngitis infection and also emphasizes an alarming need for discrimination of pharyngeal-asymptomatic carriers of S. aureus from those with an active S. aureus pharyngitis infection. PMID- 23337612 TI - Polymorphisms in the oligoadenylate synthetase gene cluster and its association with clinical outcomes of dengue virus infection. AB - Oligoadenylate synthetases (OAS) play an important role in the immune response against dengue virus. Single nucleotide polymorphisms (SNPs) in the OAS genes are known to affect OAS activity and are associated with outcome of viral infections. Polymorphisms in the OAS1 (rs1131454 and rs10774671), OAS3 (rs2285932 and rs2072136) and OAS2 (rs15895 and rs1732778) genes were studied using PCR followed by restriction fragment length polymorphism methods in 109 patients hospitalized for dengue (DEN) and 105 healthy controls (HCs) who have no documented evidence of symptomatic dengue. The two locus haplotype of OAS2 G-G was significantly higher in all patient groups [DEN vs. HCs, P=0.0041, P corrected (Pc)=0.012, Odds ratio (OR) 1.73 95% CI 1.16-2.59] while the four locus haplotype of OAS3-OAS2 C-G A-G was significantly lower in all dengue patient groups [DEN vs. HCs, P=0.0054, Pc=0.0486, OR 0.09, 95% CI 0.00-0.64] compared to controls. When the six locus haplotypes involving OAS1, OAS3 and OAS2 polymorphisms were analyzed and compared, the frequency of the haplotype A-A-C-A-G-G was significantly higher [P=0.0267, Pc=0.486, OR 2.34, 95% CI 1.08-4.91] and the frequency of the haplotype A-A-C-G-G-A was significantly lower in DHF cases [P=0.014, Pc=0.252, OR 0.12, 95% CI 0.01-0.85] compared to healthy controls. The results suggest that OAS1-OAS3-OAS2 haplotypes are associated with differential susceptibility to clinical outcomes of dengue infection. PMID- 23337613 TI - Long-term follow-up of congenital distal tibiofibular diastasis: a report of two female patients. AB - Congenital diastasis of the inferior tibiofibular joint is an extremely rare variant of dysplastic tibial anomaly, which is usually associated with significant shortening of the lower leg and ipsilateral foot deformity due to talus incarceration in the distal tibiofibular mortise. The purpose of this study was to present the long-term results of reconstructive treatment and the functional outcome after a follow-up of 11-16 years. The principles of extremity preservation and reconstruction with the Ilizarov frame have shown a stable ankle joint, a plantigrade foot, and fully independent outdoor ambulation in both patients at the final follow-up. We concluded that amputation should not be performed under this condition. PMID- 23337614 TI - Evaluation of 3D fluoroscopic image generation from a single planar treatment image on patient data with a modified XCAT phantom. AB - Accurate understanding and modeling of respiration-induced uncertainties is essential in image-guided radiotherapy. Explicit modeling of the overall lung motion and interaction among different organs promises to be a useful approach. Recently, preliminary studies on 3D fluoroscopic treatment imaging and tumor localization based on principal component analysis motion models and cost function optimization have shown encouraging results. However, the performance of this technique for varying breathing parameters and under realistic conditions remains unclear and thus warrants further investigation. In this work, we present a systematic evaluation of a 3D fluoroscopic image generation algorithm via two different approaches. In the first approach, the model's accuracy is tested for changing parameters for sinusoidal breathing. These parameters include changing respiratory motion amplitude, period and baseline shift. The effects of setup error, imaging noise and different tumor sizes are also examined. In the second approach, we test the model for anthropomorphic images obtained from a modified XCAT phantom. This set of experiments is important as all the underlying breathing parameters are simultaneously tested, as in realistic clinical conditions. Based on our simulation results for more than 250 s of breathing data for eight different lung patients, the overall tumor localization accuracies of the model in left-right, anterior-posterior and superior-inferior directions are 0.1 +/- 0.1, 0.5 +/- 0.5 and 0.8 +/- 0.8 mm, respectively. 3D tumor centroid localization accuracy is 1.0 +/- 0.9 mm. PMID- 23337615 TI - In utero hypertensive diseases and cognition in offspring into old age. PMID- 23337616 TI - Forgetting emotional and neutral words: an ERP study. AB - Previous research has demonstrated that emotional material is more likely to be remembered than neutral material (Hamann, 2001). The present study employed the item-method of directed forgetting in order to examine whether emotionally negative words are not only easier to remember, but also harder to forget. Event related potentials (ERPs) were additionally measured in order to investigate the processes of selective rehearsal and active inhibition in directed forgetting. The results demonstrated directed forgetting effects for both neutral and negative words, with a stronger effect for negative items. Late positive potentials (LPPs) for 'to-be-remembered' (TBR) relative to 'to-be-forgotten' (TBF) cues were enhanced when the cues followed negative in comparison to neutral words, indicating the greater selective rehearsal of TBR negative items. Frontal positivities to TBF relative to TBR cues were not modulated by word valence, indicating that inhibitory processes were unaffected by emotion. Taken together, the present research demonstrates for the first time that, not only are emotionally negative words prone to the same directed forgetting effects as neutral words, but that these effects are in fact enhanced for negative words and due to increased selective rehearsal of TBR negative items. The discrepancies between the present findings and those of previous studies are discussed. PMID- 23337617 TI - Quantitative analysis of astrogliosis in drug-dependent humans. AB - Drug addiction is a chronic, relapsing disease caused by neurochemical and molecular changes in the brain. In this human autopsy study qualitative and quantitative changes of glial fibrillary acidic protein (GFAP)-positive astrocytes in the hippocampus of 26 lethally intoxicated drug addicts and 35 matched controls are described. The morphological characterization of these cells reflected alterations representative for astrogliosis. But, neither quantification of GFAP-positive cells nor the Western blot analysis indicated statistical significant differences between drug fatalities versus controls. However, by semi-quantitative scoring a significant shift towards higher numbers of activated astrocytes in the drug group was detected. To assess morphological changes quantitatively, graph-based representations of astrocyte morphology were obtained from single cell images captured by confocal laser scanning microscopy. Their underlying structures were used to quantify changes in astroglial fibers in an automated fashion. This morphometric analysis yielded significant differences between the investigated groups for four different measures of fiber characteristics (Euclidean distance, graph distance, number of graph elements, fiber skeleton distance), indicating that, e.g., astrocytes in drug addicts on average exhibit significant elongation of fiber structures as well as two-fold increase in GFAP-positive fibers as compared with those in controls. In conclusion, the present data show characteristic differences in morphology of hippocampal astrocytes in drug addicts versus controls and further supports the involvement of astrocytes in human pathophysiology of drug addiction. The automated quantification of astrocyte morphologies provides a novel, testable way to assess the fiber structures in a quantitative manner as opposed to standard, qualitative descriptions. PMID- 23337618 TI - Involvement of the periaqueductal gray in the effect of motor cortex stimulation. AB - Several clinical and animal studies of different pain models reported that motor cortex stimulation (MCS) has an antinociceptive effect. In our previous study, the response of the primary somatosensory cortex (SI) to peripheral stimuli decreased after MCS. The aim of the present study was to investigate involvement of the periaqueductal gray (PAG) in this inhibitory effect of MCS. Responses of the SI to electrical stimuli applied to both forepaws of anesthetized rats were monitored to evaluate the effect of MCS. After sensory-evoked potentials (SEPs) were stable, either saline, opioid, or dopamine receptor antagonists were locally microinjected into the PAG. After drug or saline administration, MCS was applied to the forepaw area of the right motor cortex. SEPs after MCS were compared to those before MCS. In the saline group, SEPs ipsilateral to MCS decreased, but SEPs contralateral to MCS did not. The decrease in SEPs was prevented by pretreatment of the PAG with naloxone. Application of a nonspecific dopamine receptor antagonist (alpha-flupenthixol) to the PAG also blocked the inhibition of SEPs after MCS. Inhibition of SEPs after MCS was blocked by local application of a D1 antagonist (SCH-23390) in the PAG, but not by a D2 antagonist (eticlopride). These results suggest that the PAG participates in the inhibitory effect of MCS, and this effect of MCS may be mediated by opioid and dopamine D1 receptors within thePAG. PMID- 23337619 TI - New tricks for old dogmas: optogenetic and designer receptor insights for Parkinson's disease. AB - Optogenetics and novel designer receptors have revolutionized the way neuroscientists can interrogate neural circuits. These new tools are being rapidly applied to many facets of neuroscience including the study of Parkinson's disease circuitry and therapies. This review highlights how optogenetics and designer receptors can be applied in the study of Parkinsonian dysfunction to understand the mechanisms behind motor and non-motor symptoms. We discuss how these tools have recently advanced our understanding of basal ganglia function and outline how they can be applied in future to refine existing treatments and generate novel therapeutic strategies for Parkinson's disease. This article is part of a Special Issue entitled Optogenetics (7th BRES). PMID- 23337620 TI - Nuclear translocation of alpha-synuclein increases susceptibility of MES23.5 cells to oxidative stress. AB - alpha-Synuclein (alpha-syn) and oxidative stress play pivotal roles in the pathogenesis of Parkinson's disease (PD). However, the mechanisms underlying the interaction between alpha-syn and oxidative stress remain poorly understood. The present study provides evidence to suggest that the nuclear translocation of alpha-syn increases death of dopaminergic neurons in response to oxidative stress. We found that administration of H2O2 induced a rapid cleavage and nuclear translocation of alpha-syn in cultured MES23.5 cells. Inhibition of calpain proteolysis, using a calpain inhibitor (MDL-28170), significantly blocked cleavage and nuclear translocation of alpha-syn and attenuated H2O2-induced cell death in MES23.5 cells. Expression of a truncated fragment of alpha-syn (58-140) significantly increased the cell death induced by H2O2 treatment. These results suggest that calpain proteolysis is involved in the process of nuclear translocation of alpha-syn in MES23.5 dopaminergic cells induced by oxidative stress, and that nuclear translocation of alpha-syn increases susceptibility of these cells to oxidative stress. Taken together, our findings provide new insight into the interaction between alpha-syn and oxidative stress through activation of calpain proteolytic activity. PMID- 23337621 TI - Correlation between micronuclei frequency in peripheral blood lymphocytes and retention of 131-I in thyroid cancer patients. AB - Differentiated thyroid cancers (DTCs) derive from thyroid follicular cells and include papillary and follicular cancers. In patients with DTCs, the initial treatment includes thyroidectomy and radioactive iodine (131-I) therapy. The objective of this study was to examine whether the intensity of DNA damage in peripheral blood lymphocytes (PBLs) of DTC patients depends on the amount of 131 I retained in the selected regions of interest (thyroid and abdominal region) as well as in the whole-body 72 hours after therapy. In addition, the possible influence of other factors that may affect micronuclei (MN) frequency, such as age, gender, smoking habits, and histological type of tumour was analyzed. The study population consisted of 22 DTC patients and 20 healthy donors. Data on the distribution of 131-I were obtained from the whole-body scans. MN frequency and cytokinesis-block proliferation index (CBPI) were measured using cytokinesis block micronucleus assay. 131-I therapy significantly increased the MN frequency (19.50+/-6.90 vs. 27.10+/-19.50 MN) and significantly decreased the CBPI (1.52+/ 0.20 vs. 1.38+/-0.17) in patients' lymphocytes. There was a clear correlation between the increased MN frequency and 131-I accumulation in the thyroid region in patients without metastases. The MN values did not differ in relation to the factors that could affect MN, such as age, gender, smoking habits, and histological type of tumour. In conclusion, the MN frequency in PBLs of DTC patients without metastases depends on the accumulation of 131-I in the thyroid region and does not depend on the other factors examined. PMID- 23337622 TI - Japanese medical students' interest in basic sciences: a questionnaire survey of a medical school in Japan. AB - The number of physicians engaged in basic sciences and teaching is sharply decreasing in Japan. To alleviate this shortage, central government has increased the quota of medical students entering the field. This study investigated medical students' interest in basic sciences in efforts to recruit talent. A questionnaire distributed to 501 medical students in years 2 to 6 of Juntendo University School of Medicine inquired about sex, grade, interest in basic sciences, interest in research, career path as a basic science physician, faculties' efforts to encourage students to conduct research, increases in the number of lectures, and practical training sessions on research. Associations between interest in basic sciences and other variables were examined using chi(2) tests. From among the 269 medical students (171 female) who returned the questionnaire (response rate 53.7%), 24.5% of respondents were interested in basic sciences and half of them considered basic sciences as their future career. Obstacles to this career were their original aim to become a clinician and concerns about salary. Medical students who were likely to be interested in basic sciences were fifth- and sixth-year students, were interested in research, considered basic sciences as their future career, considered faculties were making efforts to encourage medical students to conduct research, and wanted more research-related lectures. Improving physicians' salaries in basic sciences is important for securing talent. Moreover, offering continuous opportunities for medical students to experience research and encouraging advanced-year students during and after bedside learning to engage in basic sciences are important for recruiting talent. PMID- 23337623 TI - Acyclovir reduces the duration of fever in patients with infectious mononucleosis like illness. AB - Acyclovir is known for its antiviral activity against some pathogenic viruses such as the Epstein-Barr virus (EBV) that causes infectious mononucleosis (IM) and IM-like illness. Therefore, we empirically administered acyclovir to patients with suspected EBV-IM and IM like-illness, upon their admission to our hospital. We admitted 25 patients, who were hospitalized for fever and lymphadenopathy, to the Tohoku University Hospital Infectious Disease Ward. As part of treatment, 8 of these patients were given acyclovir (750 mg/day) with their consent and were assigned to the acyclovir group; the remaining 17 patients were assigned to the control group. The mean age of acyclovir patients (all men) was 42+/-5.2 years, and that of control patients (13 men and 4 women) was 31+/-3.0 years. The cause of illness was confirmed as EBV-IM in 6 patients (1, acyclovir; 5, control), and remained unknown for the other 19 IM-like illness patients (7, acyclovir; 12, control). A shorter duration of hospitalization and fever was observed in the acyclovir compared to that in the control patients (hospitalization duration: 16+/-3.7 vs. 27+/-7.7 days, P=0.36; fever duration: 4.5+/-1.8 vs. 18+/-6.5 days, P=0.04). Additionally, serum amyloid A (SAA) levels were lower in acyclovir than that in control patients (98+/-37 vs. 505+/-204 ug/mL, P=0.02). Therefore, we propose that acyclovir is a potential therapeutic agent for both EBV-IM and IM like-illnesses. Future studies should further examine its mechanism of action. PMID- 23337624 TI - Novel cross-linked polymers having pH-responsive amino acid residues for the removal of Cu2+ from aqueous solution at low concentrations. AB - Two novel cross-linked anionic polyelectrolytes (CAPE) I and II containing pH responsive amino acid residues have been synthesized via cycloco- and ter polymerization of a monomer having diallylammonioethanoate motif (90mol%) and a cross-linker 1,1,4,4-tetraallylpiperazinium dichloride (10mol%) in the absence and presence of SO2 (100mol%), respectively. The experimental data for the adsorption of Cu(2+) on the CAPES fitted Lagergren second-order kinetic model thereby indicating the chemical nature of the adsorption process. The fitness order of Freundlich>Langmuir>Temkin for the isotherm models for CAPE I showed the favorability of adsorption on a heterogeneous surface, whereas for CAPE II the fitness order of Langmuir>Freundlich>Temkin certified the favorability toward monolayer adsorption. The adsorption process was spontaneous and endothermic in nature with negative and positive values for DeltaG and DeltaH, respectively. For the sorbents CAPE I and CAPE II, the efficiency of Cu(2+) removal at an initial metal concentration of 200ppb was found to be 77.5 and 99.4%, respectively. Desorption efficiencies were found to be 88 and 93% for CAPE I and CAPE II, respectively. Treatment of real wastewater samples spiked with Cu(2+) ions showed the excellent ability of the resins to adsorb metal ions. PMID- 23337625 TI - Formation of (FexMn(2-x))O3 solid solution and high sulfur capacity properties of Mn-based/M41 sorbents for hot coal gas desulfurization. AB - Several MCM-41 materials were synthesized at different conditions by hydrothermal procedure using cheap and easily available industrial water glass as silica source. Fe doped manganese-based oxide/MCM-41 sorbents were prepared by a sol-gel method. The effects of loadings of metal oxide, Fe/Mn molar ratios over MCM-41 and reaction temperature on the performance of sorbent for hot coal gas desulfurization were investigated. Various techniques such as BET, XRD, XPS, LRS and HRTEM were used to characterize the sorbents. The result indicated Fe(3+) ions could occupy a position of Mn(3+) in cubic lattice of Mn2O3 and the (FexMn2 x)O3 solid solution is mainly active phase of sorbent. Moreover, the result of nine successive sulfurization-regeneration cycles of sorbent showed high sulfur adsorption capacity and endurable stability of FeMn4Ox/MCM-41 for H2S removal. PMID- 23337626 TI - The health risks of ART. PMID- 23337627 TI - Non-autophagic roles of autophagy-related proteins. AB - Autophagy and autophagy-related processes are fundamentally important in human health and disease. These processes are viewed primarily as cellular degradative pathways that recycle macromolecules and dysfunctional or redundant organelles into amino acids, sugars and lipids, especially during starvation. However, the ubiquitin-like autophagy proteins and other components of the autophagic machinery additionally participate in cellular reprogramming. We highlight these non-autophagic roles of autophagy proteins with the aim of drawing attention to this growing, but unexplored, research topic. We focus on the non-autophagic functions of autophagy proteins in cell survival and apoptosis, modulation of cellular traffic, protein secretion, cell signalling, transcription, translation and membrane reorganization. PMID- 23337628 TI - Brk regulates wing disc growth in part via repression of Myc expression. AB - The molecular mechanisms regulating tissue size represent an unsolved puzzle in developmental biology. One signalling pathway controlling growth of the Drosophila wing is Dpp. Dpp promotes growth by repression of the transcription factor Brk. The transcriptional targets of Brk that control cell growth and proliferation, however, are not yet fully elucidated. We report here a genome wide ChIP-Seq of endogenous Brk from wing imaginal discs. We identify the growth regulator Myc as a target of Brk and show that repression of Myc and of the miRNA bantam explains a significant fraction of the growth inhibition caused by Brk. This work sheds light on the effector mechanisms by which Dpp signalling controls tissue growth. PMID- 23337629 TI - Transdermal drug delivery of paroxetine through lipid-vesicular formulation to augment its bioavailability. AB - Paroxetine (PAX) is the most potent serotonin reuptake blocker antidepressant clinically available. This study is aimed to reduce the side effects accompanied with the initial high plasma concentration after oral administration of PAX and fluctuations in plasma levels and also to decrease the broad metabolism of the drug in the liver by developing and optimizing liposomal transdermal formulation of PAX in order to improve its bioavailability. PAX liposomes were prepared by reverse phase evaporation technique using lecithin phosphatidylcholine (LPC), cholesterol (CHOL) and drug in different molar ratios. The prepared liposomes were characterized for size, shape, entrapment efficiency and in vitro drug release. The studies demonstrated successful preparation of PAX liposomes. The effect of using different molar ratios of (LPC:CHOL) on entrapment efficiency and on drug release was studied. Liposomes showed percentage entrapment efficiency (%EE) of 81.22 +/- 3.08% for optimized formula (F5) which composed of (LPC:CHOL, 7:7) and 20mg of PAX, with average vesicle size of 220.53 +/- 0.757 nm. The selected formula F5 (7:7) was incorporated in gel bases of HPMC-E4M (2%, 4%, and 6%). The selected formula of PAX liposomal gel of HPMC-E4M (2% and 4%) were fabricated in the reservoir type of transdermal patches and evaluated through in vitro release. After that the selected formula of PAX liposomal gel transdermal patch was applied to rabbits for in vivo bioavailability study in comparison with oral administration of the marketed PAX tablet. An HPLC method was developed for the determination of PAX in plasma of rabbits after transdermal patch application and oral administration of the marketed PAX tablets of 20mg dose. The intra- and inter-day accuracy and precision were determined as relative error and relative standard deviation, respectively. The linearity was assessed in the range of 5 200 ng/ml. Pharmacokinetic parameters were determined as the C(max) of PAX liposomal transdermal patch was found to be 92.53 ng/ml at t(max) of 12h and AUC(0-48) was 2305.656 ngh/ml and AUC(0-infinity) was 3852.726 ngh/ml, compared to the C(max) of 172.35 ng/ml after oral administration of the marketed PAX tablet with t(max) of 6h and AUC(0-24) was 1206.63 ngh/ml and AUC(0-infinity) was 1322.878 ngh/ml. These results indicate improvement of bioavailability of the PAX after liposomal transdermal patch application and sustaining of the therapeutic effects compared to oral administration. PMID- 23337630 TI - General procedure to aid the development of continuous pharmaceutical processes using multivariate statistical modeling - an industrial case study. AB - Streamlining the manufacturing process has been recognized as a key issue to reduce production costs and improve safety in pharmaceutical manufacturing. Although data available from earlier developmental stages are often sparse and unstructured, they can be very useful to improve the understanding about the process under development. In this paper, a general procedure is proposed for the application of latent variable statistical methods to support the development of new continuous processes in the presence of limited experimental data. The proposed procedure is tested on an industrial case study concerning the development of a continuous line for the manufacturing of paracetamol tablets. The main driving forces acting on the process are identified and ranked according to their importance in explaining the variability in the available data. This improves the understanding about the process by elucidating how different active pharmaceutical ingredient pretreatments, different formulation modes and different settings on the processing units affect the overall operation as well as the properties of the intermediate and final products. The results can be used as a starting point to perform a comprehensive and science-based quality risk assessment that help to define a robust control strategy, possibly enhanced with the integration of a design space for the continuous process at a later stage. PMID- 23337631 TI - Clarithromycin-loaded liposomes offering high drug loading and less irritation. AB - The aim of this study was to develop an efficient method of preparing less irritant clarithromycin-loaded liposomes (CLA-Lip) for injection with a high drug loading and to evaluate their physicochemical characteristics before and after lyophilization. CLA-Lip were prepared using the film-dispersion method with sodium cholesterol sulfate (SCS) and n-hexyl acid as the regulators and then lyophilized. The liposomes were characterized in terms of their size, size distribution, zeta potential, morphology, in vitro release, haemolysis, and lyophilization and irritation testing was carried out. The TEM images revealed that the structure of the CLA-Lip were multilamellar and of a regular size of around 100 nm. In addition, the lyophilized CLA-Lip were characterized by DSC and Infrared spectroscopy to confirm the structure. H-bonding and salt-forming reactions were used to ensure that clarithromycin (CLA) was stably encapsulated in the liposomes. This method provided a 30-fold increase in the concentration of clarithromycin relative to that in aqueous solution. Sucrose was found to be the best protective agent and was added in an amount of 12.5% (w/v). According to the mouse scratch test and the rat paw lick test, the pain of CLA-Lip was significantly reduce by approximately 80% compared with the solution of clarithromycin phosphate. In addition, rabbit ear vein experiments produced similar results. These findings suggested that CLA-Lip was a stable delivery system with less irritation, which should be extremely suitable for clinical application. PMID- 23337632 TI - Self-assembled polymeric nanoparticles for percutaneous co-delivery of hydrocortisone/hydroxytyrosol: an ex vivo and in vivo study using an NC/Nga mouse model. AB - In this study, hydroxytyrosol (HT; a potent antioxidant) was co-administered with hydrocortisone (HC) to mitigate the systemic adverse effects of the latter and to provide additional anti-inflammatory and antioxidant benefits in the treatment of atopic dermatitis (AD). The co-loaded nanoparticles (NPs) prepared had shown different particle sizes, zeta potentials, loading efficiencies, and morphology, when the pH of the chitosan solution was increased from 3.0 to 7.0. Ex vivo permeation data showed that the co-loaded NPs formulation significantly reduced the corresponding flux (17.04MUg/cm(2)/h) and permeation coefficient (3.4*10( 3)cm/h) of HC across full-thickness NC/Nga mouse skin. In addition, the NPs formulation showed higher epidermal (1560+/-31MUg/g of skin) and dermal (880+/ 28MUg/g of skin) accumulation of HC than did a commercial HC formulation. Moreover, an in vivo study using an NC/Nga mouse model revealed that compared to the other treatment groups, the group treated with the NPs formulation efficiently controlled transepidermal water loss (13+/-2g/m(2)/h), intensity of erythema (207+/-12), and dermatitis index (mild). In conclusion, NPs co-loaded with HC/HT is proposed as a promising system for the percutaneous co-delivery of anti-inflammatory and antioxidative agents in the treatment of AD. PMID- 23337633 TI - Utility of prognostic genomic tests in breast cancer practice: The IMPAKT 2012 Working Group Consensus Statement. AB - BACKGROUND: We critically evaluated the available evidence on genomic tests in breast cancer to define their prognostic ability and likelihood to determine treatment benefit. DESIGN: Independent evaluation of six genomic tests [Oncotype DxTM, MammaPrint((r)), Genomic Grade Index, PAM50 (ROR-S), Breast Cancer Index, and EndoPredict] was carried out by a panel of experts in three parameters: analytical validity, clinical validity, and clinical utility based on the principles of the EGAPP criteria. PANEL STATEMENTS: The majority of the working group members found the available evidence on the analytical and clinical validity of Oncotype DxTM and MammaPrint((r)) to be convincing. None of the genomic tests demonstrated robust evidence of clinical utility: it was not clear from the current evidence that modifying treatment decisions based on the results of a given genomic test could result in improving clinical outcome. CONCLUSIONS: The IMPAKT 2012 Working Group proposed the following recommendations: (i) a need to develop models that integrate clinicopathologic factors along with genomic tests; (ii) demonstration of clinical utility should be made in the context of a prospective randomized trial; and (iii) the creation of registries for patients who are subjected to genomic testing in the daily practice. PMID- 23337634 TI - Response to letter from G. McCartney, C. Collins, D. Walsh, G.D. Batty. PMID- 23337635 TI - Early death of Scots: vitamin D and sunlight levels the most compelling hypothesis. PMID- 23337637 TI - Adaptive coupling of inferior olive neurons in cerebellar learning. AB - In the cerebellar learning hypothesis, inferior olive neurons are presumed to transmit high fidelity error signals, despite their low firing rates. The idea of chaotic resonance has been proposed to realize efficient error transmission by desynchronized spiking activities induced by moderate electrical coupling between inferior olive neurons. A recent study suggests that the coupling strength between inferior olive neurons can be adaptive and may decrease during the learning process. We show that such a decrease in coupling strength can be beneficial for motor learning, since efficient coupling strength depends upon the magnitude of the error signals. We introduce a scheme of adaptive coupling that enhances the learning of a neural controller for fast arm movements. Our numerical study supports the view that the controlling strategy of the coupling strength provides an additional degree of freedom to optimize the actual learning in the cerebellum. PMID- 23337636 TI - Short- and long-term risk of colorectal adenoma recurrence among whites and blacks. AB - BACKGROUND: It is unclear whether the higher burden from colorectal cancer among blacks is due to an increased biological susceptibility. OBJECTIVE: To determine whether non-Hispanic blacks (blacks) have a higher risk of adenoma recurrence than non-Hispanic whites (whites) after removal of colorectal adenoma. DESIGN: Secondary analysis of the Polyp Prevention Trial (PPT) data. SETTING: United States. PATIENTS: Patients were 1668 self-identified whites and 153 blacks who completed the 4-year trial. Of these, 688 whites and 55 blacks enrolled in a posttrial, passive Polyp Prevention Trial Continued Follow-up Study (PPT-CFS) and underwent another colonoscopy. MAIN OUTCOME MEASUREMENTS: Recurrence and location of the adenoma and advanced adenoma by race-ethnicity during PPT and cumulative recurrence over a mean follow-up of 8.3 years (range, 4.9-12.4 years) among PPT CFS enrollees. RESULTS: Blacks had similar risk of recurrence of adenoma (39.2% vs 39.4%; incidence risk ratio [RR] = .98; 95% CI, .80-1.20) and advanced adenoma (8.5% vs 6.4%; RR = 1.18; 95% CI, .68-2.05) as whites at the end of PPT. Recurrence risk did not differ by colon subsite. Among PPT-CFS enrollees, the cumulative recurrence rate over a maximal follow-up period of 12 years was similar for blacks and whites for adenoma (67.3% vs 67.0%; RR = 1.01; 95% CI, .84 1.21) and advanced adenoma (14.5% vs 16.9%; RR = 1.03; 95% CI, .60-1.79). LIMITATION: There were few blacks in the long-term follow-up study. CONCLUSIONS: Adenoma and advanced adenoma recurrence did not differ by race. Our study does not support more frequent surveillance colonoscopies for blacks with a personal history of adenoma as an intervention to reduce colorectal cancer disparity. PMID- 23337638 TI - Urea-induced modification of cytochrome c flexibility as probed by cyanide binding. AB - Cyanide binding to cytochrome c was monitored by absorption spectroscopy from neutral to acidic pH in the presence of urea. These results were compared with acid-induced unfolding at corresponding urea concentration monitored by absorption spectroscopy and circular dichroism. The association rate constant ka increased 20-fold when the concentration of urea was raised from 0M to 6M at neutral pH. However, the secondary structure of the protein was not affected, i.e. there was no striking conformational change in these urea concentrations at neutral pH. At the pH that was very close to the pK of acid-induced unfolding, the ka value reached its maximum (ka,max) in all urea concentrations. Interestingly, the ka,max value increased exponentially with increasing urea concentrations. These results are interpreted in terms of a change in the flexibility of the least stable part of the cyt c structure that is responsible for the Fe-S(Met80) bond disruption and for ligand binding to heme iron. PMID- 23337639 TI - Learning through clinical decision support and collaboration. PMID- 23337643 TI - Deep tissue injury: what is it really? PMID- 23337644 TI - 2013 "heads-up": OPPS and ASC medicare payment system changes. PMID- 23337645 TI - Observations of periwound skin protection in venous ulcers: a comparison of treatments. AB - OBJECTIVE: The objective of this study was to examine the effectiveness of 2 products on venous ulcer periwound skin. DESIGN: This was a descriptive comparative study. SETTING: An outpatient wound care clinic in a rural Midwestern area of the United States. PARTICIPANTS: Participants included a retrospective group of 50 patients and a prospective group of 28 patients. INTERVENTION: The intervention compared the experimental product (Remedy Nutrashield; Medline Industries, Mundelein, Illinois) versus Cavilon Moisturizing Lotion (3M, St Paul, Minnesota). OUTCOME MEASURES: The mean outcome measures were a decrease in periwound and ulcer size. MAIN RESULTS: For the periwound size, the estimated rates of change were as follows: 0.092 (SE, 0.021) cm/d and -0.026 (SE, 0.014) cm/d for products B and A groups, respectively. The decrease for the experimental group was significantly greater than the attenuated decrease for the retrospective cases (t297 = -2.57, P = .01), and the decrease for product B group was also significantly different from zero (t76 = -4.34, P < .0001). For the ulcer size model, the estimated rates of change were -0.272 (SE, 0.102) cm/d and 0.130 (SE, 0.067) cm/d for the experimental and retrospective groups, respectively. The rate for the experimental group was significantly less than zero (t76 = -2.67, P = .009), but there was no significant difference between prospective and retrospective cases in the rates of reduction in ulcer size (t308 = -1.16, P = .25). CONCLUSION: The results of this study illustrate how the integrity of the periwound skin may be an important determinant in decreasing periwound and ulcer size. PMID- 23337646 TI - Alginate dressing and polyurethane film versus paraffin gauze in the treatment of split-thickness skin graft donor sites: a randomized controlled pilot study. AB - OBJECTIVES: To compare postoperative healing of split-thickness skin graft (STSG) donor sites using traditional dressings (paraffin gauze) or modern wound dressings (alginate dressing and polyurethane film) in a randomized controlled trial. METHOD: Thirty patients were randomly assigned to treatment of an STSG donor site with an alginate dressing and a polyurethane film or nonadherent paraffin gauze. Outcome variables were pain (measured with a visual analog scale), amount of dressing changes, healing time, cosmetic outcome, treatment costs, and overall satisfaction with the procedure. RESULTS: There was no significant difference in pain (postoperative day 1: 2.1 vs 1.2, P = .26; postoperative days 5-7: 1.0 vs 0.9, P = .47; final removal: 1.9 vs 1.0, P = .19) and time to healing (18.1 vs 15.4 days, P = .29) between alginate/polyurethane film dressing and nonadherent paraffin gauze. The semiocclusive dressings with polyurethane film required multiple dressing changes, whereas the nonadherent paraffin gauze could be left in place until complete epithelialization. Treatment costs were substantially lower for paraffin gauze. CONCLUSIONS: Semiocclusive dressings with alginate dressings and polyurethane film showed no advantages over treatment with paraffin gauze. With lower costs and better patient acceptance, paraffin gauze dressings were the preferred treatment for STSG donor sites. PMID- 23337647 TI - Use of indigenously made negative-pressure wound therapy system for patients with diabetic foot. AB - OBJECTIVE: Negative-pressure wound therapy (NPWT) is a well-known treatment modality for chronic, difficult, nonhealing wounds. Unfortunately, many commercially available negative-pressure therapy systems for wounds are expensive, require hospitalization, and may not be available throughout the world. The authors have designed a less expensive and effective NPWT system from components readily available in the hospital. DESIGN: The system is assembled from ethylene oxide sterilized polyurethane foam, transparent adhesive dressing, and a simple negative suction drain system, which is being routinely used in surgical cases. The multiple holes suction tube is inserted between 2 layers of polyurethane foam and is put on the wound, which is sealed by adhesive dressing. The negative pressure is created using a closed wound suction set. The dressing is changed every third day or as needed. MAIN RESULTS: The authors have used this system in 11 patients with diabetic foot. The mean time for preparation of wound for surgery with this system was 7 days (5-9 days). The raw areas were either secondarily closed or were covered with split-thickness skin graft. The mean hospital stay for debridement and definitive surgical procedure was 11 days (8-15 days). CONCLUSION: In the authors' experience, the NPWT system developed from off the-shelf components reduces the length of hospital stays and therefore cost, without any compromise on quality. It leads to a quicker wound closure and reduces the need for multiple surgeries or flaps. This modification presents a simple, cheap, and effective alternative to commercially available NPWT machines. PMID- 23337648 TI - Telemedicine in wound care: a review. AB - Telemedicine (TM) is a new, rapidly evolving area and can be of great value in the provision of healthcare to remote and rural populations. Wound healing and wound management are prime candidates for TM. The treatment of skin ulcers requires frequent assessments of local wound status and adjustment of therapy. The availability of reasonably priced photographic equipment and quick electronic transfer of high-quality digital images should make the assessment of wound status by remote experts possible. Several studies showing the feasibility and the usefulness of teleconsultations in dermatology have already been described in the literature, and high accordance for diagnosis and treatment between face-to face visits and teleconsultations has been reported. Some used digital photographs and sent the image and clinical data via the Internet to a wound care specialist (store and forward), whereas others used a webcam (televideoconferencing). Tele-wound care offers great potential for the future in chronic wound care. By reducing the need to travel long distances to the hospital or to consult with a physician, TM decreases the costs and improves the quality of life for patients with chronic wounds, while still maintaining high standards of wound care. The intent of TM is to reduce, in a clinically equivalent way, the number of visits to a specialized clinic, but not necessarily to eliminate all visits. Further well-designed research is necessary to understand how best to deploy TM services in healthcare. PMID- 23337649 TI - Exploratory study of nursing home factors associated with successful implementation of clinical decision support tools for pressure ulcer prevention. AB - OBJECTIVES: To determine those factors that are associated with nursing homes' success in implementing the On-Time quality improvement (QI) for pressure ulcer prevention program and integrating health information technology (HIT) tools into practice at the unit level. DESIGN: Observational study with quantitative analysis of nursing home characteristics, team participation levels, and implementation milestones collected as part of a QI program. SETTING: Fourteen nursing homes in Washington, District of Columbia, participating in the On-Time Pressure Ulcer Prevention program. MAIN OUTCOME MEASURES: The nursing home level of implementation was measured by counting the number of implementation milestones achieved after at least 9 months of implementation effort. MAIN RESULTS: After at least 9 months of implementation effort, 36% of the nursing homes achieved level III, a high level of implementation, of the On-Time QI-HIT program. Factors significantly associated with high implementation were high level of involvement from the administrator or director of nursing, high level of nurse manager participation, presence of in-house dietitian, high level of participation of staff educator and QI personnel, presence of an internal champion, and team's openness to redesign. One factor that was identified as a barrier to high level of implementation was higher numbers of health inspection deficiencies per bed. CONCLUSION: The learning from On-Time QI offers several lessons associated with facility factors that contribute to high level of implementation of a QI-HIT program in a nursing home. PMID- 23337651 TI - Clinical pathways integrated with evidence-based decisions: part 1. PMID- 23337652 TI - [Posterior interosseous nerve entrapment syndrome following distal rupture of the biceps tendon: physiopathology and literature review, an unreported case report]. AB - We report a unique and previously unreported case of motor paralysis of the posterior interosseous nerve of rapid onset in a context of hypertrophy of the short supinator muscle, occurring 2 years after a distal rupture of the biceps in a 62 year-old man. The ruptured tendon had received functional treatment due to the patient's age and low functional requirements. Operatively, the deep branch of the radial nerve was released within the arcade of Frohse with complete recovery from symptoms at 5 months. The unrepaired rupture of the distal portion of the biceps could be a risk factor for posterior interosseous nerve compression in active subjects. PMID- 23337653 TI - [Surgical treatment of proximal humeral fractures anatomical plate versus palm tree pinning (26 cases)]. AB - BACKGROUND: The aim of this study is to compare functional and radiological results of two surgical techniques in treatment of proximal humeral fractures. PATIENTS AND METHODS: A prospective study was performed, which included 12 patients operated for a proximal humeral fracture by open reduction and internal fixation using an anatomical humeral plate, and another group of patient (14 patients) treated for the same lesion using a palm tree pinning technique of Kapandji. The comparison of results of the two techniques was based on three parameters: the time of healing, quality of reduction, and the functional result. The global mean age was 48.6 (+/-13,7), and the sex ratio (M/W) was 1. RESULTS: Statistical analysis of functional and radiological results showed no superiority of one technique over another; so the mean time of healing was 6.1 (+/- 0.7) weeks in the group treated by plate, and 6 (+/- 0.7) weeks in the group treated by pinning (P=0.5), the mean absolute Constant score was respectively 86 (+/ 10.4) and 90.92 (+/-2.5) (P=0.09), and the mean measuring of cephalic angle was respectively 46.91 (+/-17.68) and 55.71 (+/-19.48) (P=0.24). CONCLUSION: Univariate analysis showed no statistically significant association between endpoints and the two surgical techniques studied. Therefore the study showed no statistical superiority of one surgical technique over another. PMID- 23337654 TI - Role of childhood adversity in the development of medical co-morbidities associated with bipolar disorder. AB - OBJECTIVE: A role for childhood adversity in the development of numerous medical conditions in adults has been described in the general population, but has not been examined in patients with bipolar disorder who have multiple medical comorbidities which contribute to their premature mortality. METHODS: More than 900 outpatients (average age 41) with bipolar disorder completed questionnaires that included information about the occurrence of verbal, physical, or sexual abuse in childhood and whether their parents had a mood or substance abuse disorder, or a history of suicidality. These factors were combined to form a total childhood adversity score, which was then related to one or more of 30 medical conditions patients rated as present or absent. RESULTS: The child adversity score was significantly related to the total number of medical comorbidities a patient had (p<.001), as well as to 11 specific medical conditions that could be modeled in a logistic regression (p<.03). These included: asthma, arthritis, allergies, chronic fatigue syndrome, chronic menstrual irregularities, fibromyalgia, head injury (without loss of consciousness), hypertension, hypotension, irritable bowel syndrome, and migraine headaches. LIMITATIONS: The contribution of parental diagnosis to childhood adversity is highly inferential. CONCLUSIONS: These data link childhood adversity to the later occurrence of multiple medical conditions in adult outpatients with bipolar disorder. Recognition of these relationships and early treatment intervention may help avert a more severe course of not only bipolar disorder but also of its prominent medical comorbidities and their combined adverse effects on patients'health, wellbeing, and longevity. PMID- 23337655 TI - Laser acupuncture for depression: a randomised double blind controlled trial using low intensity laser intervention. AB - INTRODUCTION: Trials of acupuncture for the treatment of depression have produced mixed results. We examined the effectiveness of laser acupuncture compared with placebo acupuncture for the treatment of major depression. METHODS: A randomised, double blinded, placebo controlled trial was conducted in Sydney, Australia. Participants aged 18-50 years with DSM-IV major depressive disorder were eligible to join the study. Forty-seven participants were randomised to receive laser acupuncture or placebo laser at acupoints LR14, CV14, LR8, HT7 and KI3. The intervention was administered twice a week for 4 weeks and once a week for another four weeks, for a total of 12 sessions. The primary outcome assessed the change in severity of depression using the Hamilton-Depression Rating Scale (HAM D), and secondary outcomes assessed the change in severity of depression using the Quick Inventory for Depression-Self Reporting (QID-SR), the Quick Inventory for Depression-Clinician (QIDS-CL), with outcomes assessed at eight weeks. The treatment response (greater than 50% improvement in HAM-D) and remission (HAM D<8) were analysed. RESULTS: At eight weeks participants showed greater improvement in the active laser group on the primary and clinician-rated secondary outcome measures (HAM-D (mean 9.28 (SD 6.55) vs. mean 14.14 (SD 4.78 p<0.001); QIDS-CL (mean 8.12 (SD 6.61 versus 12.68 (mean SD 3.77)) p<0.001). The self-report QIDS-SR scores improved in both groups but did not differ significantly between the groups. In the active laser group, QIDS-SR scores remained significantly lower than baseline at 3 months follow-up. Response rates (active laser, placebo laser) on ITT (intention to treat) analyses were 72.0% and 18.2% (p<0.001), respectively. Remission rates on ITT analyses (active laser, placebo laser) were 56.0% and 4.5% (p<0.001). Transient fatigue was the only adverse effect reported. LIMITATIONS: There was no follow-up for the placebo group at one and 3 months. CONCLUSION: Laser acupuncture showed a clinically and statistically significant benefit with reducing symptoms of depression on objective measures. PMID- 23337656 TI - Interrogation of sphingosine-1-phosphate receptor 2 function in vivo reveals a prominent role in the recovery from IgE and IgG-mediated anaphylaxis with minimal effect on its onset. AB - Autocrine stimulation of S1PR2, a receptor for the lipid mediator sphingosine-1 phosphate (S1P), has been implicated in mast cell degranulation to IgE/antigen (Ag) although, paradoxically, its ligand cannot trigger substantial degranulation. Additionally, the in vivo role of S1PR2 in the overall allergic responses is unclear since S1PR2 was reported to be required for the onset of systemic anaphylaxis by IgE/Ag but, in apparent contradiction, also for the recovery from histamine-induced anaphylaxis in a mast cell independent manner. Here, we sought to clarify the role of S1PR2 in mast cell degranulation and in IgE and IgG-mediated anaphylaxis. Lack of S1PR2 reduced IgE/Ag-induced degranulation in in vitro experiments with mucosal mast cells, but had no effect on connective tissue type mast cells. This latter response correlated with a lack of involvement of S1PR2 in the onset of non-lethal IgE/Ag-mediated systemic and cutaneous anaphylaxis. However, S1pr2(-/-) mice were slow to recover (or did not recover) from FcERI-mediated anaphylaxis, an outcome that mirrored their known impairment in histamine clearance due to defective vascular tone. A minor role for S1PR2 in mast cell degranulation was uncovered upon engagement of low affinity receptors for IgG and in the onset of IgG-mediated anaphylaxis. Our findings show that S1PR2 is dispensable for initiating IgE/Ag-mediated connective tissue mast cell degranulation and anaphylaxis, but it is required for normal recovery from anaphylaxis. PMID- 23337657 TI - Putting the dietary guidelines for americans into action: behavior-directed messages to motivate parents-phase III quantitative message testing and survey evaluation. PMID- 23337658 TI - Characterization of a SPECT pinhole collimator for optimal detector usage (the lofthole). AB - In single-photon emission computed tomography (SPECT), multi-pinhole collimation is often employed nowadays. Most multi-pinhole collimators avoid overlap (multiplexing) of the projections on the detector. This can be done by using additional shielding or by spacing the pinholes far enough apart. Using additional shielding has the drawback that it increases weight, design complexity and cost. Spacing the pinholes far enough apart results in sub-optimal detector usage, the valuable detector area is not entirely used. This is due to the circular projections of pinholes on the detector; these ellipses can not be tiled with high detector coverage. To overcome this we designed a new pinhole geometry, the lofthole, that has a rectangular projection on the detector. The lofthole has a circular aperture and a rectangular entrance/exit opening. Sensitivity formulae have been derived for pinholes and loftholes. These formulae take the penumbra effect into account; the proposed formulae do not take penetration into account. The derived formulae are valid for geometries where the field-of-view and the sensitivity of the aperture are solely limited by the exit window. A flood map measurement was performed to compare the rectangular projection of a lofthole with the circular projection of a pinhole. Finally, measurements were done to compare the amount of penetration of pinholes with the amount of penetration of a lofthole. A square lofthole collimator has less penetration than a knife-edge pinhole collimator that irradiates the same rectangular detector area with full coverage. A multi-lofthole collimator allows high detector coverage without using additional shielding. An additional advantage is the lower amount of penetration. PMID- 23337659 TI - Maximising the effectiveness of the National Chlamydia Screening Programme in England: should we routinely retest positives? PMID- 23337662 TI - Student narratives and the hidden curriculum in the surgery clerkship. PMID- 23337663 TI - A multi-institutional survey of newer surgery faculty on the impacts of education debt and debt repayment strategies. AB - BACKGROUND: The cost associated with becoming a physician is significant, and studies have shown that surgeons, in particular, accrue higher debts than matched controls from other specialties, and the public. These findings, along with the current era of economic turmoil, prompted our investigation into the effects of educational debt on the career, family and lifestyle choices of recently graduated surgeons. Our goal was to query young surgical faculty about the education debt carried, the burden it presents as they embark on a career, and the financial management strategies employed to pay down their debt. STUDY DESIGN: This study is a one-time, cross-sectional survey of regular and adjunct faculty from the University of Minnesota and the Mayo Clinic-Rochester. Participation was voluntary and responses were collected anonymously via SurveyMonkey. Respondents were sorted into two groups: those with and without education debt at the time of residency graduation. We compared these groups on a number of variables. RESULTS: Of the 111 respondents (111/152, 73% response rate), 69 (62.2%) carried debt at the time of graduation from residency. The median educational debt at graduation was $100,000, and surgeons with educational debt carried a significantly higher burden of consumer and total debt than those without educational debt at graduation (p < 0.001). This continued after graduation with 74% (51/69) of residents with debt at graduation falling below the benchmark 36% debt-to-income ratio, and 45% (17/32) of those without debt at graduation in this same high risk financial situation. CONCLUSIONS: Educational debt places a large financial responsibility on the shoulders of most newer faculty. The debt-to-income ratio demonstrated through our results was considerable for both study groups, and unwise according to financial literature. This is of utmost importance to leaders in academe, as salaries are generally lower than private practice colleagues. This can begin in residency with explicit and practical information on surgeon reimbursement, income ranges, and revenue sources (faculty, clinical), debt repayment strategies, and overall training on financial matters early in their residency. PMID- 23337664 TI - A simple framework for assessing technical skills in a resident observed structured clinical examination (OSCE): vaginal laceration repair. AB - OBJECTIVES: Educators of trainees in procedure-based specialties need focused assessment tools that are valid, objective, and assess technical skills in a realistic context. A framework for hybrid assessment using standardized patient scenarios and bench skills testing might facilitate evaluation of competency. METHODS: Seven PGY-1 obstetrics and gynecology residents participated in a hybrid assessment that used observed structured clinical examination (OSCE) by a standardized patient who had sustained a vaginal laceration during vaginal delivery. The residents elicited a history and counseled the patient, and then completed a laceration repair on a pelvic model. The residents were rated on their performance in the scenario, which included issues of cultural competency, rapport-building, patient counseling. The technical skills were videotaped and rated using a modified global assessment form by 2 faculty members on a 3-point scale from "not done" to "partly done" to "well-done." Residents also completed a subjective assessment of the station. RESULTS: Mean technical performance of the residents on the technical skills was 55% "well-done," with a range of 20%-90%. The assessment identified 3 residents as below the mean, and 1 resident with areas of deficiency. Subjective assessment by the residents was that juggling the technical, cognitive, and affective components of the examination was challenging. CONCLUSIONS: Technical skills can be included in a case-based assessment using scenarios that address a range of cognitive and affective skills required of physicians. Results may help training programs assess individuals' abilities as well as identify program needs for curricular improvement. This framework might be useful in setting standards for competency and identifying poor performers. PMID- 23337665 TI - A survey of study habits of general surgery residents. AB - OBJECTIVE: To understand the study habits of general surgery residents as well as their motivating factors for study. DESIGN: A survey was mailed to general surgical residents. Performance on the American Board of Surgery In-Training Examination (ABSITE) was correlated with reported study habits using the Pearson's correlation coefficient. SETTING: Massachusetts General Hospital and Brigham and Women's Hospital, 2 urban tertiary referral academic training institutions in Boston, Massachusetts. PARTICIPANTS: Fifty-eight general surgical residents of all training levels (including research). RESULTS: On average, surgical residents studied for 3 +/- 1 days per week, the average duration of each study session being 1.3 +/- 0.6 hours. The average total number of study hours per week was 3.4 +/- 2.3. There were strong positive correlations between increased study frequency and high overall ABSITE score (Pearson's r = 0.339; p = 0.02) and between the total number of study hours per week and high overall ABSITE score (Pearson's r = 0.423; p < 0.005). Only 10% and 3% reported complete satisfaction with current study materials and routine, respectively. Most residents (96%) reported a willingness to try a new type of study method and 75% were willing to enroll in a trial comparing study methods. CONCLUSIONS: Increased study frequency and overall increased study duration are positively correlated with ABSITE performance. Dissatisfaction with current study materials and study routine is high, as is willingness to adopt new methods and enroll in investigational trials comparing study methods. PMID- 23337666 TI - A theory-based model for teaching and assessing residents in the operating room. AB - The operating room (OR) remains primarily a master/apprenticeship-based learning environment for surgical residents. Changes in surgical education and health care systems challenge faculty to efficiently and effectively graduate residents truly competent in operations classified by the Surgical Council on Resident Education as "common essential" and "uncommon essential." Program directors are charged with employing resident evaluation systems that yield useful data, yet feasible enough to fit into a busy surgical faculty member's workflow. This paper proposes a simple model for teaching and assessing residents in the operating room to guide faculty and resident interaction in the OR, and designating a resident's earned level of autonomy for a given procedure. The system as proposed is supported by theories associated with motor skill acquisition and learning. PMID- 23337667 TI - An analytic decision support tool for resident allocation. AB - BACKGROUND: Moving residents through an academic residency program is complicated by a number of factors. Across all residency programs the percentage of residents that leave for any reason is between 3.4% and 3.8%.(1) There are a number of residents that participate in research. To avoid discrepancies in the number of residents at the all levels, programs must either limit the number of residents that go into the lab, the number that return to clinical duties, or the number of interns to hire. Traditionally this process consists of random selection and trial and error with names on magnetic strips moved around a board. With the matrix that we have developed this process is optimized and aided by a Microsoft Excel macro (Microsoft Corp, Redmond, Washington). METHODS: We suggest that a residency program would have the same number of residents at each residency stage of clinical practice, as well as a steady number of residents at each research stage. The program consists of 2 phases, in the first phase, an Excel sheet called the "Brain Sheet," there are simple formulas that we have prepared to determine the number of interns to recruit, residents in the research phase, and residents that advance to the next stage of training. The second phase of the program, the macro, then takes the list of current resident names along with the residency level they are in, and according to the formulas allocates them to the relevant stages for future years, creating a resident matrix. RESULTS: Our macro for resident allocation would maximize the time of residency program administrators by simplifying the movement of residents through the program. It would also provide a tool for planning the number of new interns to recruit and program expansion. CONCLUSIONS: The application of our macro illustrates that analytical techniques can be used to minimize the time spent and avoid the trial and error while planning resident movement in a program. PMID- 23337668 TI - Surgical resident allocation: an art or a mathematical formula? PMID- 23337669 TI - Application of the core competencies after unexpected patient death: consolation of the grieved. AB - OBJECTIVES: To review and assess educational strategies and formats regarding communication with families/survivors in the aftermath of unexpected and untimely patient death. To propose an integrated curriculum designed and intended to foster proficiency, competence, confidence, and composure in relaying catastrophic information in the context of the professional experience of a cohort of seasoned surgeons. BACKGROUND: Unexpected and untimely patient death is emotionally and psychologically wrenching for families, surgeons, and healthcare providers. We have previously proffered that 2 distinct, but interactive, phases of response are relevant when communicating with a family before and after the event: a proactive phase intended to establish a positive therapeutic relationship with the family; and a reactive phase intended to respond to the family in a compassionate and respectful manner and to ensure self-care for the physicians and health care providers. STUDY DESIGN: Survey of a cohort of senior surgeons (membership of the Southern Surgical Association) and Surgical Residency Program Directors (membership of the Association of Program Directors in Surgery). RESULTS: Sixty percent of the senior surgeons surveyed had experienced unexpected patient death. They advised strategies to cope with that clinical situation commensurate with the core competencies of the Accreditation Council for Graduate Medical Education: Medical Knowledge: maximize objective information/data and minimize subjective opinion; Patient Care: critique the events and conduct postmortem analyses; Interpersonal and Communication Skills: honesty, empathy, and patience; Professionalism: provide emotional and psychological support to family and personnel with privacy and in a nonaccusatory manner; Practice-Based Learning and Improvement: preoperative discussion and documentation in the context of informed consent and advanced directives vis-a vis risk-benefit, effort-yield, and benefit-burden analyses; and Systems-Based Practice: involve chaplains and hospital personnel. Thirty-six percent of the graduate surgical educational programs surveyed allegedly provided educational venues to enable surgical residents to cope with unexpected patient death, although the formats were not specified. CONCLUSIONS: Graduate, postgraduate, and continuing educational programs aspire to prepare physicians and surgeons for independent professional practice-scientifically, humanistically, and artistically. Incorporating educational strategies to enable graduates to cope with the emotional and psychological turmoil of unexpected patient death is relevant. PMID- 23337670 TI - Assessment of surgical trainees' quality of knot-tying. AB - BACKGROUND: This study aimed to assess surgical trainees' knot tying technique and determine the type and security of knots created. METHODS: Twenty-five participants were requested to tie 40 knots each, using Vicryl 2-0 and Prolene 2 0 sutures. With each suture material, the participants tied: in series 1, 4 knots as they would normally do during surgery; in series 2, 4 knots with 3 throws, 4 knots with 4 throws, 4 knots with 5 throws, and 4 knots with 6 throws. All knots were tested for tensile strength using a tensiometer. Knots with tensile strength of less than 5 N were considered dangerous. RESULTS: Of the 25 participants, 2 created square knots consistently, 2 created a mixture of square and slip knots, and 21 created only slip knots. Square knots accounted for only 12.8% of all the knots. The incidence of knot slipping under tension was significantly lower with square knots (p < 0.001). Square knots had significantly higher tensile strength than slip knots (p < 0.001). For Vicryl, 4-throw square knots were superior to 6 throw slip knots (p < 0.001). For Prolene, 3-throw square knots were superior to 6-throw slip knots (p = 0.035). Some 12.6% of Vicryl knots and 5.6% of Prolene knots were dangerous and all of these were slip knots with up to 6 throws. Three out of 12 participants who thought they had created square knots actually created square knots and the rest produced slip knots. The participants' surgical experience did not have any correlation with their knot security (r = -0.044, p = 0.833). CONCLUSIONS: Knot tying is often executed with technical errors resulting in slip knots with less than optimal security and high incidence of dangerous knots. Tensiometry testing could be used as an objective assessment tool for knot tying competency for surgical trainees. PMID- 23337671 TI - Assessment of the role of a student-led surgical interest group in surgical education. AB - BACKGROUND: We describe the development of a medical student surgical interest group, its initial evaluation, and future plans. The Surgical Students Society of Melbourne was formed in August 2008 by a group of senior medical students from the University of Melbourne. The Surgical Students Society of Melbourne seeks to provide additional surgical teaching and professional development for students interested in a career in surgery. It also aims to provide junior doctors with leadership and teaching opportunities to meet the requirements of the Royal Australasian College of Surgeons for application to the Surgical Education and Training program. Its program also addresses contemporary workforce issues, such as women in surgery and rural surgery. The society runs a weekly teaching program during the semester and procedural and careers workshops throughout the year. METHODS: A survey of students attending the teaching program was conducted by means of written and online questionnaires. RESULTS: The results suggest that the society has been successful in augmenting surgical education and providing opportunities to improve procedural skills, but also highlighted areas of the program that may be improved, including aspects of surgical professional development and role modeling. CONCLUSIONS: The Surgical Students Society initiative was generally very well received by students and shows great potential as a means for augmenting surgical education at the medical student level. PMID- 23337672 TI - British surgeons' experiences of a mandatory online workplace based assessment portfolio resurveyed three years on. AB - INTRODUCTION: An online portfolio, the Intercollegiate Surgical Curriculum Programme (ISCP; http://www.iscp.ac.uk), became mandatory for British surgical trainees 5 years ago, alongside a compulsory L125 (US$200) annual fee. We previously demonstrated widespread dissatisfaction with its 2008 ver. 5. Here we evaluate and contrast user satisfaction with ver. 8. DESIGN, SETTING, AND PARTICIPANTS: A total of 359 users across all surgical specialties and UK regions were randomly sampled and surveyed in 2011 by online questionnaire regarding ISCP, elogbook (http://www.elogbook.org.uk), and results compared with 539 users surveyed in 2008. Likert 5-point rating scales were largely used and data analyzed using chi(2) tests. RESULTS: Seventy-nine percent used ISCP and 38% elogbook (http://www.elogbook.org); 201 responders (56%) evaluated ISCP ver. 8; 31% had registered for at least 1 year, and 59% for 3 years or more. Modal ratings were "average" throughout, with the following percentages of responders rating "poor" or worse vs "good" or better the following domains: registration 12% vs 35%; induction procedure 41% vs. 15%; workplace based assessments 36% vs 22%; peer assessment tool 34% vs 25%; recording meetings 34% vs 19%; Helpdesk 11% vs 40%; user friendliness 29% vs 24%. Trainees were neutral about ISCP's impact upon training and 44% thought that ISCP was needed. Statistically significant (p < 0.05) improvements were seen in user satisfaction with ISCP throughout all domains comparing ver. 8 (2011) to ver. 5 (2008). CONCLUSIONS: The performance of ISCP has improved in the 4 years since its inception with proportionately less negative feedback. British surgeons remain dissatisfied with several of its tools, in particular its workplace-based assessments. Half a decade on, these assessments remain without appropriate evidence of validity despite increasing demands upon trainees to complete quotas of them. With reduced permitted training hours, the growing online bureaucratic burden continues to demoralize busy surgical trainers and trainees. PMID- 23337673 TI - Case based review questions, review sessions, and call schedule type enhance knowledge gains in a surgical clerkship. AB - INTRODUCTION: Medical students in surgical clerkships must gain surgical knowledge while doing clinical rotations. We developed a self-learning program, which is case based, the Case Review Question (CRQ) system. Our hypothesis was that students who used CRQs would score higher on the summative test, Surgery NBME (National Board of Medical Examiners). METHODS: The setting is a surgical clerkship in a Liaison Council for Medical Education (LCME) approved Medical School, with summative examination using the NBME shelf examination in Surgery. Each CRQ document is a series of 20 to 25 questions based on cases. The cases are a paragraph, with pertinent medical facts and extra facts as distracters. The students are encouraged to use these questions to guide study. Students must come to a review session to hear the answers and a discussion. We review the NBME Surgery shelf examination scores taken before and after this program was initiated, along with changes in rotation group size, call schedule type, and other changes. RESULTS: CRQs, review sessions, and call schedule changes improved scores. NBME examination average rose from 77.12 to 82.01 (p = 0.004) after the CRQ program was initiated. Call schedule revision improved scores: intermittent call NBME score was 80.98, whereas night float schedule mean NBME was 84.66 (p < 0.001). During night float call, the CRQ program was already in effect, so that there is no non-CRQ program comparison group. Students scored higher in the second semester, throughout the study. First semester students scored a mean of 79.11, whereas second semester students scored 84.195 (p < 0.001). By the end of the study, there were no failures on the NBME examination, even in the first semester. The factors of presence of the CRQ program, review sessions, call schedule type, and which semester were all significant in a correlation matrix against NBME scores and in a regression analysis (p < 0.001). CONCLUSIONS: The CRQ program of case-based self-study was associated with higher scores on the NBME shelf examination, as a summative test of medical knowledge in surgery. PMID- 23337674 TI - Does orthopedic training compromise the outcome in total hip arthroplasty? AB - BACKGROUND: This study compares the outcomes of total hip arthroplasty surgery performed by a consultant with those performed by supervised and unsupervised orthopedic trainees. METHODS: We reviewed 6 years of patient data from the New Zealand Joint Registry in patients undergoing total hip arthroplasty comparing the outcome measures of revision surgery and Oxford hip score at 6 months with the experience of the primary surgeon. RESULTS: Over the study period 35,415 patients underwent elective total hip arthroplasty; 30,344 performed by a consultant, 2982 by a supervised trainee and 1067 by an unsupervised trainee. There was an overall revision rate of 0.77 per 100 component years. The revision rate was 0.75 (95% confidence interval [CI] 0.68-0.82) for consultants, 0.97 (95% CI, 0.72-1.28) for supervised trainees and 0.70 (95% CI, 0.36-1.22) for unsupervised trainees with no significant differences. There was no significant difference in the reason for revision surgery between the 3 groups. CONCLUSIONS: The mean Oxford hip score was higher for consultants at 40.70 compared with 38.95 and 38.27 for supervised and unsupervised trainees respectively. These results are reassuring and indicate orthopedic training does not adversely compromise arthroplasty patient outcomes. PMID- 23337675 TI - Early intervention to promote medical student interest in surgery and the surgical subspecialties. AB - OBJECTIVE: Concerns about projected workforce shortages are growing, and attrition rates among surgical residents remain high. Early exposure of medical students to the surgical profession may promote interest in surgery and allow students more time to make informed career decisions. The objective of this study was to evaluate the impact of a simple, easily reproducible intervention aimed at increasing first- and second-year medical student interest in surgery. DESIGN: Surgery Saturday (SS) is a student-organized half-day intervention of four faculty-led workshops that introduce suturing, knot tying, open instrument identification, operating room etiquette, and basic laparoscopic skills. Medical students who attended SS were administered pre-/post-surveys that gauged change in surgical interest levels and provided a self-assessment (1-5 Likert-type items) of knowledge and skills acquisition. PARTICIPANTS: First- and second-year medical students. OUTCOME MEASURES: Change in interest in the surgical field as well as perceived knowledge and skills acquisition. RESULTS: Thirty-three first- and second-year medical students attended SS and completed pre-/post-surveys. Before SS, 14 (42%) students planned to pursue a surgical residency, 4 (12%) did not plan to pursue a surgical residency, and 15 (46%) were undecided. At the conclusion, 29 (88%) students indicated an increased interested in surgery, including 87% (13/15) who were initially undecided. Additionally, attendees reported a significantly (p < 0.05) higher comfort level in the following: suturing, knot tying, open instrument identification, operating room etiquette, and laparoscopic instrument identification and manipulation. CONCLUSIONS: SS is a low resource, high impact half-day intervention that can significantly promote early medical student interest in surgery. As it is easily replicable, adoption by other medical schools is encouraged. PMID- 23337676 TI - Effect of surgery resident change of shift on trauma resuscitations and outcomes. AB - INTRODUCTION: The ability of surgery residents to provide continuity of care has come under scrutiny with work hour restrictions. The impact of the surgery resident sign-out period (6-8am and 6-8pm) on trauma outcomes remains unknown. We hypothesize that during shift change, resuscitation times are prolonged with worse outcomes. METHODS: Records of patients treated at a university-based urban trauma center during 2008 and 2009 were reviewed. Patients were separated into a shift change group (6-8am and 6-8pm) and a control group of all other time periods and compared using ANOVA, chi square, and unpaired t-tests. RESULTS: We reviewed the charts of 4361 consecutive trauma patients. There was no difference in gender, acuity, resuscitation times, Glasgow Coma Scale, revised trauma score, injury severity score (ISS), or probability of survival score between patients arriving during shift change compared to other times (p>0.2). There was no difference in total emergency department time for patients arriving during shift change (p = 0.07), even when stratified by ISS (ISS<15, p = 0.09; ISS>15, p = 0.2). Length of stay was increased for patients arriving during shift change compared to other times (5 vs 4 days, p<0.05). This was more pronounced for those with ISS>15 (16 vs 11 days, p = 0.03); however, there was no impact on intensive care unit length of stay, ventilator days, and mortality (p>0.3) regardless of ISS. CONCLUSIONS: Trauma outcomes are generally unaffected by patient arrival during shift change when resident sign-outs occur. Although adaptations are being made to accommodate trauma patient arrival during these times, we need to continue paying close attention, especially to seriously injured patients, to ensure that there are no delays in care that may potentially affect patient outcomes. PMID- 23337677 TI - Evaluation of an interprofessional clinician-patient communication workshop utilizing standardized patient methodology. AB - OBJECTIVE: Communication and interpersonal skills (CIS) are one of the 6 general competencies required by the Accreditation Council for Graduate Medical Education (ACGME). The clinician-patient communication (CPC) workshop, developed by the Institute for Healthcare Communication, provides an interactive opportunity to practice and develop CIS. The objectives of this study were to (1) determine the impact of a CPC workshop on orthopedic surgery residents' CIS (2) determine the impact of physician alone or incorporation of nursing participation in the workshop, and (3) incorporate standardized patients (SPs) in resident training and assessment of CIS. METHODS: Stratified by training year, 18 residents of an Orthopaedic Surgery Residency Program were randomized to a CPC workshop with only residents (group A, n = 9) or a CPC workshop with nurse participants (group B, n = 9). Data included residents' (1) CIS scores as evaluated by SPs and (2) self reports from a 25-question survey on perception of CIS. Data were collected at baseline and 3 weeks following the workshop. RESULTS: Following the workshop, the combined group (group A and B) felt more strongly that the ACGME should require a communication training and evaluation curriculum (post mean = 52.7, post-pre difference = 15.94, p = 0.026). Group A residents felt more strongly that communication is a learned behavior (post mean = 82.7, post-pre difference = 17.67, p = 0.028), and the addition of SPs was a valuable experience (post mean = 59.3, post-pre difference = 16.44, p = 0.038). Group B residents reported less willingness to improve on their communication skills (post-mean = 79.7, post-pre difference = -7.44, p = 0.049) and less improvement in professional satisfaction in effective communication than group A (post mean group A = 81.9, group B = 83.6, post-pre difference group A = 7.11, group B = 1.89, p = 0.047). Few differences between groups regarding CIS scores were detected. CONCLUSIONS: While there was no demonstrable difference regarding CIS, our study indicates that participants valued the importance of communication training and found SPs to be a valuable addition. The addition of interprofessional participation appeared to detract from the experience. Further study is warranted to elucidate the variables associated with interprofessional education within the context of CIS training and assessment using SPs in residency. PMID- 23337678 TI - Evolving trauma and orthopedics training in the UK. AB - The ever-growing population of the UK has resulted in increasing demands on its healthcare service. Changes have been introduced in the UK medical training system to avoid loss of training time and make it more focused and productive. Modernizing medical careers (MMC) was introduced in 2005. This promised to reduce the training period for a safe trauma specialist, in trauma and orthopedics, to 10 years. At around the same time, the European Working Time Directive (EWTD) was introduced to reduce the working hours for junior doctors in training, to improve patient safety and also work-life balance of junior doctors. Introduction of the assessment tools from Orthopedic Competency assessment project (OCAP) will help tailor the training according to the needs of the trainee. The aim of this article is to review the changes in the UK orthopedic surgical training over the past two decades. PMID- 23337679 TI - Implementing a hybrid web-based curriculum for an elective medical student clerkship in a busy surgical intensive care unit (ICU): effect on test and satisfaction scores. AB - OBJECTIVE: To determine whether a hybrid traditional and web-based curriculum improves test scores and enrollment among senior medical students in an elective critical care rotation. DESIGN AND SETTING: Retrospective study in a surgical ICU at a major academic center. SUBJECTS: One hundred twenty-one fourth year medical students completing an elective ICU clerkship between 2007 and 2010. INTERVENTIONS: Pre-test and post-test during a 4-week rotation. METHODS: We implemented a hybrid curriculum that involved both traditional teaching methods and a new online core curriculum that incorporating audio, video, and text using screen capture technology. The curriculum was hosted on a secure online portal called ICON (Desire2Learn Inc., Ontario, Canada). The core curriculum covered topics that were considered essential to meet the didactic objectives of the rotation. MEASUREMENTS AND EVALUATIONS: A pre-test was administered online on day 1 of the rotation. A post-test was administered on the second to last day of the rotation. Both tests were composed of 20 questions randomly chosen from a question bank of 100 questions. The tests are managed (administering, grading, and reporting) exclusively online. RESULTS: One hundred twenty-one medical students have successfully completed the clerkship since implementing the new curriculum. Each group of students showed an improvement in the mean post-test score by at least 17%+ to 10%. The satisfaction scores of the clerkship improved consistently from 2007 and is currently rated at 4.31 +/- 0.85 (on a 5-point scale). The rotation is in the top 25(th) percentile of all clinical clerkships offered at the University of Iowa. CONCLUSION: A systematically implemented hybrid web-based critical care curriculum can improve knowledge based test scores and overall clerkship satisfaction scores in a busy surgical ICU. PMID- 23337680 TI - Isolated congenital agenesis of the gallbladder and cystic duct: report of a case. AB - Congenital agenesis of the gallbladder and cystic duct represents a rare anomaly of the biliary system. It likely results from an embryologic mishap in the development of the hepatobiliary bud and can occur with other associated malformations. We report the case of congenital absence of the gallbladder and cystic duct incidentally found during laparoscopy in a 44-year-old Caucasian female. Based on the clinical presentation and ultrasonography findings, the patient was presumed to have symptomatic cholelithiasis and chronic cholecystitis. A laparoscopic cholecystectomy was planned. After introducing the laparoscope, the gallbladder and cystic duct were absent and the procedure aborted. Gallbladder and cystic duct agenesis was confirmed by magnetic resonance cholangiopancreatography. We describe here the difficulties with diagnosis and pain management, and review the literature of this rare pathology. PMID- 23337681 TI - Medical mentoring via the evolving world wide web. AB - OBJECTIVES: Mentoring, for physicians and surgeons in training, is advocated as an essential adjunct in work-based learning, providing support in career and non career related issues. The World Wide Web (WWW) has evolved, as a technology, to become more interactive and person centric, tailoring itself to the individual needs of the user. This changing technology may open new avenues to foster mentoring in medicine. DESIGN, SYSTEMATIC REVIEW, MAIN OUTCOME MEASURES: A search of the MEDLINE database from 1950 to 2012 using the PubMed interface, combined with manual cross-referencing was performed using the following strategy: ("mentors"[MeSH Terms] OR "mentors"[All Fields] OR "mentor"[All Fields]) AND ("internet"[MeSH Terms] OR "internet"[All Fields]) AND ("medicine"[MeSH Terms] OR "medicine"[All Fields]) AND ("humans"[MeSH Terms] AND English[lang]). Abstracts were screened for relevance (UJ) to the topic; eligibility for inclusion was simply on screening for relevance to online mentoring and web-based technologies. RESULTS: Forty-five papers were found, of which 16 were relevant. All studies were observational in nature. To date, all medical mentoring applications utilizing the World Wide Web have enjoyed some success limited by Web 1.0 and 2.0 technologies. CONCLUSIONS: With the evolution of the WWW through 1.0, 2.0 and 3.0 generations, the potential for meaningful tele- and distance mentoring has greatly improved. Some engagement has been made with these technological advancements, however further work is required to fully realize the potential of these technologies. PMID- 23337682 TI - Open surgical simulation in residency training: a review of its status and a case for its incorporation. AB - BACKGROUND: With the increase in minimally invasive approaches to surgical disease and nonoperative management for solid organ injury, the open operative experience of current surgical residents has decreased significantly. This deficit poses a potentially adverse impact on both surgical training and surgical care. Simulation technology, with the potential to foster the development of technical skills in a safe, nonclinical environment, could be used to remedy this problem. In this study, we systematically review the current status of simulation technology in the training of open surgical skills with the aim of clarifying its role and promise in the education of surgical residents. METHODS: A systematic search of the PubMed database was performed with keywords: "surgical simulation," "skill," "simulat," "surgery," "surgery training," "validity," "surgical trainer," "technical skill," "surgery teach," "skill assessment," and "operative skill." The retrieved studies were screened, and additional studies identified by a manual search of the reference lists of included studies. RESULTS: Thirty-one studies were identified. Most studies used low fidelity bench models designed to train junior residents in more basic surgical skills. Six studies used complex open models to train senior residents in more advanced surgical techniques. "Boot camp" and workshops have been used by some authors for short periods of intense training in a specialized area, with good results. CONCLUSIONS: Despite the increasing use of simulation in the technical training of surgical residents, few studies have focused on the use of simulation in the training of open surgical skills. This is particularly true with regard to skills required to competently perform technically challenging open maneuvers under urgent, life-threatening circumstances. In an era marked by a decline in open operative experience, there is a need for simulation-based studies that not only promote and evaluate the acquisition of such less commonly performed techniques but also determine the efficacy with which they can be transferred from a simulated environment to a patient in an operating room. PMID- 23337683 TI - Predictors of success in a urology residency program. AB - OBJECTIVES: In selecting a medical student for a urology residency, a set of preconceived criteria as to what will predict a successful resident are generally applied. To determine what factors predict an "excellent" clinical resident and a successful in-service test taker, we analyzed 10 years of urology resident files. PARTICIPANTS AND STUDY DESIGN: Retrospective chart review of 29 urology residents at Washington University graduating from July 2000 to July 2009. Medical student applications and interview evaluations were compared with future performance as a general surgical intern and then as a urology resident, in terms of clinical performance and in-service examination scores. RESULTS: Of 29 residents, based on clinical evaluations over 4 years of urology residency, 12 were "excellent," 17 "average and needing improvement." "Excellent" residents had higher applicant rank submitted to the "match" (7.2 vs. 12.1, p = 0.04) and better letters of recommendation (3.0 vs. 2.5, 0.018). "Excellent" residents also had better evaluations as an intern (3.9 vs 2.7, p < 0.001). "Good" urology in-service examination test takers compared with "below average" test takers noted higher rank on the match list (7.8 vs 12.1, p = 0.04), better quality med school (2.6 vs 2.0; p = 0.002), higher USMLE scores (92.5 vs 86.6% tile, p = 0.02), American Board of Surgery in-training examination (ABSITE) score (58.6 vs 37.2% tile, p = 0.04), and were more likely to pass the board examination (100% vs 76.9%, p = 0.03). Residents with higher clinical evaluations were also more likely to go into fellowships (83.3% vs 16.2%, OR = 23.3) and academic careers (41.6 vs 11.1%, OR = 5.71). CONCLUSIONS: Performance as a surgery intern predicts future performance as a GU Resident. "Good" test takers as medical students and as interns continue to test well as GU residents. Early identification, intervention, and mentoring while still an intern are essential. Selection criteria we currently use to select GU residents are surprisingly predictive. PMID- 23337684 TI - Safe laparoscopic colorectal surgery performed by trainees. AB - OBJECTIVES: Laparoscopic surgery for colorectal cancer is safe, but there have been hesitations to implement the technique in all departments. One of the reasons for this may be suboptimal learning possibilities since supervised trainees have not been allowed to do the operations to an adequate extent for the technique to spread. We routinely plan all operations as laparoscopic procedures and most cases are done by supervised trainees. The present study therefore presents the results of operations performed by trainees compared with results obtained by experienced laparoscopic surgeons. DESIGN: Data for all patients who underwent elective colorectal cancer surgery in 2009 were recorded. Surgeries performed by laparoscopic inexperienced surgeons were compared with the outcome of surgery performed by laparoscopic experienced surgeons. These results were also compared with nationwide data extracted from the national database. SETTING: A university teaching department of surgery. PARTICIPANTS: A total of 131 patients underwent colorectal elective surgery in 2009 in the department. RESULTS: Of the 131 operations, 60% were performed by trainees supervised by experienced laparoscopic colorectal surgeons. The trainees performed a total of 70% of all colonic procedures and 43% of all rectal resections. There were no statistically significant differences between the inexperienced and experienced laparoscopic surgeons with regards to short-term outcome other than increased duration of surgery for colonic resections (198 vs 140 min, p = 0.005). Thus, we found no difference regarding length of stay, conversion to laparotomy, intraoperative bleeding or complications, postoperative complications, or 30-day mortality. CONCLUSIONS: Our data suggest that laparoscopic surgery for colorectal cancer can be performed safely by supervised trainees with good short term results. Therefore, a high volume of operations with an educational potential can easily be maintained when going from open to laparoscopic surgery as the standard operative technique for colorectal cancer in a university department of surgery. PMID- 23337685 TI - Surgery clerkship evaluations drive improved professionalism. AB - PURPOSE: To determine whether a brief student survey can differentiate among third-year clerkship student's professionalism experiences and whether sharing specific feedback with surgery faculty and residents can lead to improvements. METHODS: Medical students completed a survey on professionalism at the conclusion of each third-year clerkship specialty rotation during academic years 2007-2010. RESULTS: Comparisons of survey items in 2007-2008 revealed significantly lower ratings for the surgery clerkship on both Excellence (F = 10.75, p < 0.001) and Altruism/Respect (F = 15.59, p < 0.001) subscales. These data were shared with clerkship directors, prompting the surgery department to discuss student perceptions of professionalism with faculty and residents. Postmeeting ratings of surgery professionalism significantly improved on both Excellence and Altruism/Respect dimensions (p < 0.005 for each). CONCLUSIONS: A brief survey can be used to measure student perceptions of professionalism and an intervention as simple as a surgery department openly sharing results and communicating expectations appears to drive positive change in student experiences. PMID- 23337686 TI - Surgical knot integrity: effect of suture type and caliber, and level of residency training. AB - OBJECTIVE: To evaluate if suture type and caliber or level of residency training affects strength and mode of failure of surgical knots. DESIGN: All residents in an obstetrics and gynecology training program were invited to tie knots on a bench model using 2 calibers (0 and 3-0) of 2 types of surgical suture (polyglactin 910 and polydioxanone). The failure load, mode of failure, and loop lengths of the knots were determined. SETTING: University of Texas Southwestern Medical Center, Dallas, Texas. PARTICIPANTS: Physicians enrolled in the University of Texas Southwestern Medical Center Obstetrics and Gynecology residency training program. RESULTS: Seventy-one of 73 residents participated. Knots tied with 0-caliber sutures had a higher mean failure load than those tied with 3-0 caliber sutures. For each type and caliber of suture, there were no differences in failure load between each level of residency training. However, senior residents tied knots with shorter loop lengths and had a lower proportion of knots that unraveled or slipped. CONCLUSIONS: Even though there were no differences in failure loads, senior residents tied tighter and more secure knots than their junior counterparts. PMID- 23337687 TI - Tablet based simulation provides a new solution to accessing laparoscopic skills training. AB - AIM: Access to facilities that allow trainees to develop their laparoscopic skills is very limited in the hospital environment and courses can be very expensive. We set out to build an inexpensive yet effective trainer to allow laparoscopic skill acquisition in the home or classroom environment based on using a tablet as a replacement for the laparoscopic stack and camera. METHODS: The cavity in which to train was made from a cardboard box; we left the sides and back open to allow for natural light to fill the cavity. An iPad 2 (Apple Inc.) was placed over the box to act as our camera and monitor. We provided 10 experienced laparoscopic surgeons with the task of passing a suture needle through 3 hoops; then they filled in a questionnaire to assess Face (training capacity) and Content (performance) validity. RESULTS: On a 5-point Likert scale, the tablet-based laparoscopic trainer scored a mean 4.2 for training capacity (hand eye coordination, development, and maintenance of lap skills) and for performance (graphics, video, and lighting quality) it scored a mean 4.1. CONCLUSIONS: The iPad 2-based laparoscopic trainer was successfully validated for training. It allows students and trainees to practice at their own pace and for inexpensive training on the go. Future "app-"based skills are planned. PMID- 23337688 TI - The value of an annual educational retreat in the orthopedic residency training program. PMID- 23337689 TI - Association of single nucleotide polymorphism rs6903956 on chromosome 6p24.1 with coronary artery disease and lipid levels in different ethnic groups of the Singaporean population. AB - OBJECTIVE: A recent genome wide association study in the Chinese population has implicated rs6903956 within the ADTRP gene on chromosome 6p24.1 as a novel susceptibility locus for coronary artery disease (CAD). In this study, we evaluated the association of rs6903956 with CAD in the different ethnic groups of Singaporean population comprising Chinese, Malays and Asian Indians. DESIGN AND METHODS: The genotypes of the rs6903956 SNP were determined in 645 CAD patients and 755 control group Singaporean subjects by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). We then tested the association of this SNP with CAD and lipid profiles. RESULTS: The risk allele A of rs6903956 was associated significantly only in the Chinese with an odds ratio (OR) of 2.03 (95% CI 1.04-3.96, P=0.037) when analyzed by each ethnic group separately. In a meta-analysis with pooled subjects from all three ethnic groups, rs6903956 showed highly significant association with CAD both before (observed P=1.39e-04; OR=1.66; 95% CI 1.28-2.15) and after adjustment (P=4.63e-03; OR=1.86; 95% CI 1.21-2.87) for conventional risk factors of age, gender, BMI, smoking status and ethnicity. No significant association was observed between rs6903956 genotypes and lipid profiles in Chinese, Malays and Indians, suggesting that the association of this SNP with CAD is not mediated through plasma lipids. CONCLUSION: The SNP rs6903956 within the ADTRP gene on chromosome 6p24.1 is significantly associated with CAD in different ethnic groups of the Singaporean population. PMID- 23337690 TI - A sensitive and rapid mass spectrometric method for the simultaneous measurement of eight steroid hormones and CALIPER pediatric reference intervals. AB - OBJECTIVES: To develop an accurate assay and establish the normal reference intervals for serum cortisol, corticosterone, 11-deoxycortisol, androstenedione, 21-hydroxyprogesterone, testosterone, 17-hydroxyprogesterone, and progesterone. These steroids are commonly used as biomarkers for the diagnosis and monitoring of endocrine diseases such as congenital adrenal hyperplasia. Appropriate age- and gender-stratified reference intervals are essential in accurate interpretation of steroid hormone levels. DESIGN AND METHODS: The samples analyzed in this study were collected from healthy, ethnically diverse children in the Greater Toronto Area as part of the CALIPER program. A total of 337 serum samples from children between the ages of 0 and 18years were analyzed. The concentrations were measured by using an LC-MS/MS method. The data were analyzed for outliers and age- and gender-specific partitions were established prior to establishing the 2.5th and 97.5th percentiles for the reference intervals. RESULTS: Reference intervals for all hormones required significant age-dependent stratification while testosterone and progesterone required additional sex dependent stratification. CONCLUSIONS: We report a sensitive, accurate and relatively fast LC-MS/MS method for the simultaneous measurement of eight steroid hormones. Detailed reference intervals partitioned based on both age and gender were also established for all eight steroid hormones. PMID- 23337691 TI - Deproteination of serum samples for LC-MS/MS analyses by applying magnetic micro particles. AB - OBJECTIVES: Investigation of the practicability and performance of a magnetic micro-particle based method for protein depletion of serum samples, preceding the quantitative analysis of small molecules by LC-MS/MS. DESIGN AND METHODS: A commercially available kit including a protein denaturation reagent and functionalized magnetic particles together with a magnetic separator device was tested by addressing the quantification of amiodarone in serum as an exemplary analyte by LC-MS/MS with on-line SPE. A standard method validation protocol was applied. RESULTS: The sample preparation protocol was found to be convenient, straightforward and robust. Validation data characterized the entire analytical method - combining particle-based protein depletion and two-dimensional chromatography - as compatible with the analytical needs regarding selectivity, accuracy (102-106%), linearity (r(2)>=0.99), reproducibility (CV<7%), and control of ion suppression. CONCLUSIONS: Since this novel approach of sample preparation does neither require centrifugation nor the technically demanding application of positive or negative pressure, as in conventional solid phase extraction protocols, it seems highly attractive for developing fully automatized preparation systems for LC-MS/MS analyzers. PMID- 23337692 TI - Development and psychometric testing of the Antenatal Care Scale within the context of the Theory of Planned Behaviour. AB - OBJECTIVE: To develop an instrument based on the Theory of Planned Behaviour (TPB) to determine the attitudes and intentions of women towards receiving antenatal care. DESIGN: This methodological study was carried out at health centres in Isparta, Turkey. METHODS: 266 pregnant women who were able to communicate, did not have a systemic disease, and who volunteered to participate were included in this study. They were chosen by a random sampling method. A Likert-type scale composed of six subfactors and 26 items was used. RESULTS: Cronbach's alpha for the Antenatal Care Scale (ANCS) was 0.96, and values for the six subfactors were between 0.88 and 0.94. CONCLUSIONS: The ANCS was found to be a valid and reliable instrument to determine the attitudes and intentions of women towards receiving antenatal care. PMID- 23337693 TI - Confirmation of model-based dose selection for a Japanese phase III study of rivaroxaban in non-valvular atrial fibrillation patients. AB - This study was designed to confirm the appropriateness of the dose setting for a Japanese phase III study of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF), which had been based on model simulation employing phase II study data. The previously developed mixed-effects pharmacokinetic/pharmacodynamic (PK-PD) model, which consisted of an oral one compartment model parameterized in terms of clearance, volume and a first-order absorption rate, was rebuilt and optimized using the data for 597 subjects from the Japanese phase III study, J-ROCKET AF. A mixed-effects modeling technique in NONMEM was used to quantify both unexplained inter-individual variability and inter-occasion variability, which are random effect parameters. The final PK and PK-PD models were evaluated to identify influential covariates. The empirical Bayes estimates of AUC and C(max) from the final PK model were consistent with the simulated results from the Japanese phase II study. There was no clear relationship between individual estimated exposures and safety-related events, and the estimated exposure levels were consistent with the global phase III data. Therefore, it was concluded that the dose selected for the phase III study with Japanese NVAF patients by means of model simulation employing phase II study data had been appropriate from the PK-PD perspective. PMID- 23337694 TI - Optimal ossicular site for maximal vibration transmissions to coupled transducers. AB - Totally implantable middle-ear prosthetic devices, such as the Esteem system (Envoy Medical Corporation), detect vibrational motion of the middle-ear ossicles rather than acoustic stimulation to the eardrum. This eliminates the need for a subcutaneous microphone, which is susceptible to interference by ambient noises. Study of the vibrational characteristics of the human ossicles provides valuable information for determining the site of maximum ossicular motion that would be optimal for attachment of the sensor portion of the prosthesis. In this study, vibrational responses at seven locations on the middle-ear ossicles (i.e., the malleus head, 4 different points on the incus body, middle of the incus long process, tip of the incus long process) in human temporal bones (n = 6) were measured using a laser Doppler vibrometer. The measurements were repeated after separating the incudostapedial joint (ISJ). Measured displacement at each location was normalized with the sound pressure level near the tympanic membrane (TM) for representation in the form of a displacement transfer function (DTF). The normalized squared sum of the DTFs (NSSDTF) was then calculated as a measure of vibration motion through a specific frequency range at the considered sites. The relatively large NSSDTF was observed at the sites on the superior part of the malleus head (MH), on the lateral part of the incus body (IBL), and on the superior part of the incus body near the incudomalleal joint (IBS1) for the frequency ranges of 1-4 kHz and 1-9 kHz, regardless of the condition of the ISJ. This indicates that maximum vibrational motion of the middle-ear is deliverable to the piezoelectric transducer of totally implantable devices through these sites. This article is part of a special issue entitled "MEMRO 2012". PMID- 23337695 TI - A comparison of a T1 weighted 3D gradient-echo sequence with three different parallel imaging reduction factors, breath hold and free breathing, using a 32 channel coil at 1.5 T. A preliminary study. AB - PURPOSE: To investigate whether increasing temporal resolution with higher parallel imaging (PI) reduction factors (RF) in both breath-hold and free breathing approaches, using a non-contrast T1-weighted 3D gradient echo (GRE) sequence and a 32-channel phased array coil, permits diagnostic image quality, with potential application in patients unable to cooperate with breath-hold requirements. MATERIALS AND METHODS: The 9 healthy subjects (5 females and 4 males; age range was 20-49, mean 36 yrs) were recruited. A 3D GRE MR imaging of the abdomen was performed on 1.5 T MR system using a 32-element phased-array torso coil with PI RFs of 2, 4 and 6, breath hold and free breathing. Two reviewers retrospectively qualitatively evaluated all sequences for image quality, extent of artifacts, including motion, truncation, aliasing, pixel graininess and signal heterogeneity. The results were compared using Wilcoxon signed rank and a Bonferroni adjustment was applied for multiple comparisons. RESULTS: Image quality and extent of artifacts were better with breath hold than with free breathing acquisitions. The rate of artifacts increased with higher RF. The best quality was acquired with breath hold sequence using RF=2. RF=4 had lower but diagnostic rates (P=.004). The severity of artifacts, mainly pixel graininess (P=.004), rendered sequences with RF=6 non-diagnostic. All sequences were non-diagnostic in free breathing acquisitions. CONCLUSION: Breath hold sequences with RF=2 had excellent quality and RF=4 had good quality and may be potentially used in partially cooperative patients. None of the sequences was considered diagnostic in free breathing acquisitions. PMID- 23337696 TI - [Magnetic resonance imaging in juvenile idiopathic arthritis: peculiarities of imaging children]. AB - The term juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of arthritides with no known cause that begin before the age of 16 years and persist for at least 6 weeks. In recent decades, imaging techniques have acquired a fundamental role in the diagnosis and follow-up of JIA, owing to the unification of the different criteria for classification, which has strengthened the research in this field, and to the development of disease-modifying antirheumatic drugs. In this article, we briefly explain what JIA is. Moreover, we describe the role and limitations of plain-film radiography, ultrasonography, and magnetic resonance imaging (MRI). Finally, we review the MRI protocol and findings, and we comment on the differential diagnosis. PMID- 23337698 TI - Imaging inflammatory leukocyte recruitment in kidney, lung and liver--challenges to the multi-step paradigm. AB - Intravital microscopy has been essential in establishing the multi-step paradigm that describes how leukocytes in the bloodstream interact with the blood vessel wall during the process of leukocyte recruitment. Much of this work has been performed in readily-visualized tissues such as the mesentery and the cremaster muscle, where leukocyte-endothelial cell interactions are restricted to postcapillary venules. However, the microvasculatures of the liver, lung and renal glomerulus differ markedly from these conventionally structured microvascular beds. Moreover, the liver, lung and kidney can be the target of life-threatening leukocyte-mediated inflammation. Therefore, a clear understanding of the mechanisms of leukocyte recruitment to these sites is critical. In this review, we examine the advances made in the understanding of leukocyte recruitment in the liver, lung and glomerulus, as determined using intravital microscopy. We describe how leukocyte recruitment to these sites occurs via mechanisms distinct from the conventional rolling/adhesion/transmigration paradigm, and in some cases involves adhesion molecules with minimal roles in conventional postcapillary venules. In addition, we describe how advanced forms of in vivo imaging in combination with novel approaches for labeling immune cell subsets is revealing new complexities in leukocyte function and immune cell interactions in these specialized microvascular beds. PMID- 23337699 TI - Use of imaging to study leukocyte trafficking in the central nervous system. AB - The migration of leukocytes from the bloodstream into the central nervous system (CNS) is a key event in the pathogenesis of inflammatory neurological diseases and typically involves the movement of cells through the endothelium of post capillary venules, which contains intercellular tight junctions. Leukocyte trafficking has predominantly been studied in animal models of multiple sclerosis, stroke and infection. However, recent evidence suggests that immune cells and inflammation mechanisms play an unexpected role in other neurological diseases, such as epilepsy and Parkinson's disease. Imaging leukocyte trafficking in the CNS can be achieved by epifluorescence intravital microscopy (IVM) and multiphoton microscopy. Epifluorescence IVM is ideal for the investigation of leukocyte-endothelial interactions, particularly tethering and rolling, signal transduction pathways controlling integrin activation, slow rolling, arrest and adhesion strengthening in CNS vessels. Multiphoton microscopy is more suitable for the investigation of intraluminal crawling, transmigration and motility inside CNS parenchyma. The mechanisms of leukocyte trafficking in the CNS are not well understood but the use of in vivo imaging techniques to unravel the underlying regulatory pathways will provide insight into the mechanisms of brain damage and may contribute to the development of novel therapeutic strategies. In this review, we discuss recent work in this field, highlighting the development and use of in vivo imaging to investigate leukocyte recruitment in the CNS. PMID- 23337700 TI - New friendships and old feuds: relationships between innate lymphoid cells and microbial communities. AB - Mammalian barrier surfaces, including the skin, lung and intestine, are constantly exposed to environmental stimuli, including beneficial and pathogenic microbes, dietary substances and non-organic materials. At these anatomical sites it is essential to maintain barrier integrity to promote tissue homeostasis and prevent local and systemic inflammation. As such, changes in the composition and localization of commensal bacteria are closely associated with inflammatory, metabolic and infectious disease in mammals. Cells of the innate and adaptive immune systems have a crucial role in the tight regulation of host-commensal relationships. A recently described family of immune cells, termed innate lymphoid cells (ILCs), contributes to inflammation, modulates adaptive immunity and regulates wound healing and tissue regeneration. ILCs are present at barrier surfaces, and thus are in close proximity to environmental antigens, including commensal bacteria. The composition and localization of microbial communities have a profound impact on immunity at barrier surfaces as well as at distant sites. This review will summarize the phenotypic characteristics of ILC family members and discuss recent findings about the interactions between ILCs and the microbiota in the contexts of homeostasis, immunity, inflammation and tissue organization and repair. PMID- 23337701 TI - Complications of distal radius locking plates. AB - Fixation of distal radius fractures via locking plates is an increasingly popular method. However, these plates include variety of complications, such as flexor and extensor tenosynovitis, tendon injury and intra articular screw or peg penetration. Although they offer superior stability and early mobility, if used improperly; they may cause serious complications related to the implant. Proper use of the implant with strict adherence to the fixation principles and close follow up of patients are very important in order to decrease the rate and severity of complications. PMID- 23337702 TI - Arthroscopic reconstruction of triangular fibrocartilage complex (TFCC) with tendon graft for chronic DRUJ instability. AB - PURPOSE: To report the 10-years' experience of a novel arthroscopic assisted anatomical TFCC reconstruction in treatment of chronic DRUJ instability resulting from irreparable TFCC injuries. MATERIALS AND METHODS: 15 patients (7 males, 8 females) with mean age of 37 (17-49) suffering from irreparable TFCC injuries received arthroscopic assisted reconstruction using palmaris longus graft. Three skin incisions were made with creation of one radial and one ulna tunnel for passage of graft following the path of dorsal and palmar radio-ulnar ligaments under fluoroscopic and arthroscopic guidance. The joint capsule was kept intact. Early mid-range forearm rotation was started since 4th week postoperatively. RESULTS: The mean follow-up was 85.53 months (32-138). Mayo wrist score improved from 62.5 to 88 (p<0.05). Comparing contralateral side, total prono-supination range increased from 76.6% to 92.1% and grip strength increased from 56.1% to 76.9%. Twelve patients resumed previous jobs. No evidence of DRUJ arthritis was noticed. Complications included 2 late graft ruptures and one unexplained dystonia. CONCLUSIONS: Our arthroscopic assisted approach on TFCC reconstruction is safe, produces comparable results as the standard technique and may achieve better range of motion with less soft tissue dissection and earlier mobilization. PMID- 23337703 TI - Chondrogenic differentiation of umbilical cord-derived mesenchymal stem cells in type I collagen-hydrogel for cartilage engineering. AB - INTRODUCTION: A potent mesenchymal stem cell (MSC) population was recently isolated from the Wharton's jelly of human umbilical cord (UC). The aim of the current experiments was to determine the potential of human UC-derived MSC (UC MSC) in cartilage healing. MATERIALS AND METHODS: Chondrogenic differentiation of collagen hydrogel-embedded cells was induced in standard chondrocyte conditioning medium and further detected by real-time PCR, histochemistry and immunohistochemistry analyses. Cell viability and apoptosis of the MSCs in the collagen I hydrogels were monitored using apoptosis detection kit. RESULTS: Cells isolated from UC were positive for MSC biomarkers and negative for haematopoietic lineage and endothelial biomarkers and possess the capacity to differentiate along osteogenic lineage. UC-MSCs embedded in collagen hydrogel can undergo chondrogenesis characterised by significantly increased expressions of collagen II, aggrecan, COMP (cartilage oligomeric matrix protein) and sox9 after exposed cells-embedded hydrogels to chondrogenic factors. The most of cells remained viable throughout the hydrogels after 3 weeks of cultivation in chondrogenic differentiation medium. CONCLUSIONS: Collagen hydrogel can provide an appropriate 3-D environment for the chondrogenesis of UC-MSCs. UC-MSCs embedded in biocompatible scaffold may have great potential for cartilage engineering. PMID- 23337704 TI - Shoulder abduction and external rotation restoration with nerve transfer. AB - INTRODUCTION: In upper brachial plexus palsy patients, loss of shoulder function and elbow flexion is obvious as the result of paralysed muscles innervated by the suprascapular, axillary and musculocutaneus nerve. Shoulder stabilisation, restoration of abduction and external rotation are important as more distal functions will be affected by the shoulder situation. PATIENTS AND METHODS: Between 2005 and 2011, eleven patients with upper type brachial plexus palsy were operated on with triceps nerve branch transfer to anterior axillary nerve branch and spinal accessory nerve transfer to the suprascapular nerve for shoulder abduction and external rotation restoration. Nine patients met the inclusion criteria for the study. All patients were men with ages ranged from 21 to 35 years (average, 27.4 years). The interval between injury and surgery ranged from 4 to 11 months (average, 7.2 months). Atrophy of the supraspinatus, infraspinatus and deltoid muscle and subluxation at the glenohumeral joint was obvious in all patients preoperatively. During the pre-op examination all patients had at least muscle grading 4 on the triceps muscle. RESULTS: The mean post-operative value of shoulder abduction was 112.2 degrees (range: 60-170 degrees ) while preoperatively none of the patients was able for abduction (p<0.001). The mean post-operative value of shoulder external rotation was 66 degrees (range: 35-110 degrees ) while preoperatively none of them was able for external rotation (p<0.001). Postoperative values of shoulder abduction were significantly better that those of external rotation (p=0.0004). The postoperative average muscle grading for shoulder abduction according the MRC scale was 3.6+/-0.5 and for the shoulder external rotation was 3.2+/-0.4. CONCLUSIONS: Combined nerve transfer by using the spinal accessory nerve for suprascapular nerve neurotisation and one of the triceps nerve branches for axillary nerve and teres minor branch neurotisation is an excellent choice for shoulder abduction and external rotation restoration. PMID- 23337705 TI - Micromotion-induced strain fields influence early stages of repair at bone implant interfaces. AB - Implant loading can create micromotion at the bone-implant interface. The interfacial strain associated with implant micromotion could contribute to regulating the tissue healing response. Excessive micromotion can lead to fibrous encapsulation and implant loosening. Our objective was to characterize the influence of interfacial strain on bone regeneration around implants in mouse tibiae. A micromotion system was used to create strain under conditions of (1) no initial contact between implant and bone and (2) direct bone-implant contact. Pin and screw-shaped implants were subjected to displacements of 150 or 300 MUm for 60 cycles per day for 7 days. Pin-shaped implants placed in five animals were subjected to three sessions of 150 MUm displacement per day, with 60 cycles per session. Control implants in both types of interfaces were stabilized throughout the healing period. Experimental strain analyses, microtomography, image-based displacement mapping, and finite element simulations were used to characterize interfacial strain fields. Calcified tissue sections were prepared and Goldner trichrome stained to evaluate the tissue reactions in higher and lower strain regions. In stable implants bone formation occurred consistently around the implants. In implants subjected to micromotion bone regeneration was disrupted in areas of high strain concentrations (e.g. >30%), whereas lower strain values were permissive of bone formation. Increasing implant displacement or number of cycles per day also changed the strain distribution and disturbed bone healing. These results indicate that not only implant micromotion but also the associated interfacial strain field contributes to regulating the interfacial mechanobiology at healing bone-implant interfaces. PMID- 23337706 TI - Development of an equation for calculating vertebral shear failure tolerance without destructive mechanical testing using iterative linear regression. AB - Equations used to determine vertebral failure tolerances without the need for destructive testing are useful for scaling applied sub-maximal forces during in vitro repetitive loading studies. However, existing equations that use vertebral bone density and morphology for calculating compressive failure tolerance are unsuitable for calculating vertebral shear failure tolerance since the primary site of failure is the pars interarticularis and not the vertebral body. Therefore, this investigation developed new equations for non-destructively determining vertebral shear failure tolerance from morphological and/or bone density measures. Shear failure was induced in 40 porcine cervical vertebral joints (20 C3-C4 and 20 C5-C6) by applying a constant posterior displacement to the caudal vertebra at 0.15 mm/s. Prior to destructive testing, morphology and bone density of the posterior elements were made with digital calipers, X-rays, and peripheral quantitative computed tomography. Iterative linear regression identified mathematical relationships between shear failure tolerance, and morphological and bone density measurements. Along with vertebral level, pars interarticularis length and lamina height from the cranial vertebra, and inferior facet height from the caudal vertebra collectively explained 61.8% of shear failure tolerance variance. Accuracy for this relationship, estimated using the same group of specimens, was 211.9 N or 9.8% of the measured shear failure tolerance. PMID- 23337707 TI - The evaluation of protein Z levels of children with acute lymphoblastic leukaemia during induction therapy. AB - The objective of this study was to evaluate the protein Z levels of children with acute lymphoblastic leukaemia (ALL) during induction therapy. Although several studies investigated the association between steroid and L-asparaginase (L-ASP) administration and levels of coagulation proteins such as protein C, protein S and antithrombin in children with ALL, protein Z levels have not been examined in any study yet. Peripheral blood was drawn from the study group before chemotherapy (PZ0) at diagnosis, at 12th day (PZ1), 15th day (PZ2), 18th day (PZ3) and 21st day (PZ4) of treatment wherein L-ASP treatment is given along with steroid administration according to ALL BFM-1995 chemotherapy protocol. Plasma protein Z levels were measured by enzyme immunoassay method. Mean protein Z level at PZ0 was 1.628 +/- 0.485 MUg/ml in the study group and 1.672 +/- 0.662 MUg/ml in the control group. No statistical difference was observed. In the study group, there was a slight increase in protein Z levels between the PZ0 and PZ1 periods in which only steroid therapy was administered. Statistically significant decrease was observed between protein Z levels in PZ0-PZ4, PZ1-PZ2, PZ1-PZ3, PZ1 PZ4 and PZ3-PZ4 periods. During the induction treatment, symptomatic haemorrhage or thrombosis was not followed up in any patients. We demonstrated that children with ALL have similar protein Z values to those of the control group at diagnosis. A significant decrease occurs at the end of the induction treatment with steroid and L-ASP administration. However, this deficiency does not result in development of symptomatic thrombosis or bleeding in these patients. PMID- 23337708 TI - Evaluation of a bedside device to assess the activated partial thromboplastin time for heparin monitoring in infants. AB - To determine the relationship between the activated partial thromboplastin time (aPTT) measured with a standard laboratory assay and the aPTT measured with a bedside device in infants on heparin therapy after cardiothoracic surgery. Twenty infants aged below 1 year who were on heparin therapy were included. Exclusion criteria were prematurity, dysmaturity and the use of anticoagulants other than heparin. Nineteen samples were obtained from four adults in intensive care who were on heparin. The aPTT values were analyzed with the Coaguchek Pro/DM bedside device (aPTTbed) and compared with the aPTT values obtained from the laboratory Electra 1800C coagulation analyzer (aPTTlab). Correlation analysis was performed by linear regression. The agreement was calculated using Bland-Altman analysis. The correlation coefficient of samples obtained from infants was lower (r = 0.48) compared with samples from adults (r = 0.85). A substantial positive bias (27 s) and scatter [95% confidence interval (CI) -11; +65 s) was found. The bias showed a genuine trend to increase at higher aPTT values (r = 0.90; P < 0.001). The bedside device overestimates the aPTT in infants treated with heparin. The disagreement between the bedside device and laboratory increases at higher aPTTs. Bedside devices should not be used to monitor heparin therapy in infants in intensive care. PMID- 23337709 TI - Pseudoaneurysms in haemophilia. AB - The incidence of bleeding as a result of a pseudoaneurysm in haemophilia is very low. The diagnosis should be suspected if the patient has a history of arterial trauma. Pseudoaneurysms can appear anywhere where trauma occurs. This can include arterial access for catheterization, blunt trauma or penetrating trauma. The diagnosis should be confirmed using Duplex ultrasonography, computed tomography (CT) angiogram or conventional angiogram. Many options exist for the treatment of pseudoaneurysms. Although surgery was the gold standard treatment in the past (surgical ligation with or without distal bypass), several less invasive treatment options are popular today. They include covered stent, ultrasound probe compression and ultrasound-guided thrombin injection. So far, only 14 pseudoaneurysms have been reported in patients with haemophilia: nine were located in the musculoskeletal system (four in the hand, four in the knee, one in the ankle), whereas five were non-musculoskeletal. Early diagnosis and treatment of this complication is vital. Endovascular treatment offers a minimally invasive treatment option. If arterial embolization fails to solve the pseudoaneurysm, open vascular surgery with surgical ligation with or without distal bypass should be performed. Whatever the procedure, a correct surgical haemostasis must be achieved by the infusion of factor concentrate (recombinant or plasma-derived) at the right dose and tranexamic acid. The advent of activated prothrombin complex concentrates and recombinant factor VIII (rFVIIa) has made invasive procedures possible in haemophilia patients with high-titre inhibitors. PMID- 23337710 TI - Prediction of ischemic stroke in young Indians: is thrombophilia profiling a way out? AB - Stroke in the young is attributed to the prevalence of thrombophilia, however, reports explaining the cause mechanisms from Indian populations are largely not known. The information about the association of inherited thrombophilia and occurrence of stroke is still missing. Therefore, we describe here 52 cases of young ischemic stroke of which 22 cases were of recurrent stroke and 30 cases of first episode stroke along with an equal number of healthy controls. Imaging techniques (CT/MRI/Doppler studies) were used to identify the type and location of infarcts among various regions of the brain. All the patients and controls were screened for hypercoagulable state by employing Pro C global test. Those tested positive for the latter were evaluated for conventional thrombophilic factors, activity levels of protein C and protein S, antithrombin III levels, plasma homocysteine levels and presence of activated protein C resistance, lupus anticoagulant, methylenetetrahydrofolate reductase (MTHFR C677T) and prothrombin G20210A polymorphisms. Out of 52 cases there were 22 cases of recurrent stroke and 30 cases of first ischemic stroke. Infarcts were single in 39 out of 52 cases and multiple in 13 cases. Among the different regions of brain internal capsule infarcts were seen in 13 of 52 (25%) cases, and cerebellum, basal ganglion and midbrain infarcts were seen in five cases (9.6%) each and remaining infarcts were in other anatomical regions of the brain. Left middle cerebral artery territory was involved in 17 of 52 (32.7%) cases. The prevalence of individual thrombophilia among cases ranged from 28.8% (15/52) for protein S and 11.5% (6/52) for protein C deficiencies respectively. All cases of protein C were protein S deficient. Five cases of protein C deficiency patients were of 25 years and younger as compared with one case in the at least 25 years age group. Plasma homocysteine levels were elevated in three cases (5.7%) as compared with normal levels in controls. Homozygous MTHFR C677T was seen in three cases, whereas heterozygosity for the same was observed in five cases. Out of three homozygous cases for C677T MTHFR polymorphism, two of these patients had hyperhomocysteinemia. None of the five cases of heterozygous C677T MTHFR polymorphism had hyperhomocysteinemia. All patients were found to be negative for prothrombin G20210A mutation. The results of the present study suggest that protein S deficiency alone or protein S deficiency in combination with protein C deficiency as well as hyperhomocysteinemia are significantly associated with ischemic stroke in young Indians. PMID- 23337711 TI - Maternal cerebral venous thrombosis, uncommon but serious disorder, pathologic predictors and contribution of prothrombotic abnormalities. AB - Cerebral venous thrombosis (CVT) is a rare complication during pregnancy or the puerperium. Our aim was to identify thrombotic risk profiles that predispose to maternal CVT.The study comprised 151 individuals. All participants had a thrombotic workup that included the following: genetic markers: factor V Leiden G1691A and G20210A prothrombin mutations, methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms; protein assays: protein C, protein S and antithrombin; other tests: blood typing and screening for hyperhomocysteinemia. Maternal CVT has been associated with factor V Leiden, the prothrombin G20210A mutation, protein C deficiency and hyperhomocysteinemia. We also speculate that non-O blood groups and preeclampsia could be independent risk factors for CVT. PMID- 23337712 TI - Retinal vein occlusion: genetic predisposition and systemic risk factors. AB - The role of systemic risk factors (age, smoking, diabetes, arterial hypertension) in the development of retinal vein occlusion (RVO) is well established. However, the association of RVO with genetic predisposition to thrombosis remains poorly understood. The aim of the study was to assess any possible additional effect of genetic predisposition to the already well known 'classical' risk factors of RVO in a cohort of elderly Greek patients. Fifty-one elderly patients with RVO and 51 healthy individuals matched for age and sex were evaluated for systemic risk factors (smoking, diabetes, dyslipidemia, arterial hypertension) and coagulation defects (lupus anticoagulant, natural inhibitors of coagulation). Additionally, genotyping was performed for mutations/polymorphisms involved in haemostasis such as: FV G1691A, FV G4070A, FIIG 20210A, MTHFR C677T and A1298C, PAI-1-675 4G/5G, F XIII exon 2G/T, EPCR A4600G and G4678C. We identified systemic risk factors in the majority of the patients Hypertension (P=0.001), dyslipidemia (P=0.029) and diabetes (P=0.01) are associated with RVO in the majority of the patients. The prevalence of prothrombotic risk factors was not significantly different in the patients with RVO compared to controls. Apart from systemic risk factors, genetic predisposition to thrombosis does not seem to have an important association with RVO in this group of elderly patients. PMID- 23337713 TI - The clinical impact of uncertainties in the mean excitation energy of human tissues during proton therapy. AB - Uncertainties in the estimated mean excitation energies (I-values) needed for calculating proton stopping powers can be in the order of 10-15%, which introduces a fundamental limitation in the accuracy of proton range determination. Previous efforts have quantified shifts in proton depth dose distributions due to I-value uncertainties in water and homogenous tissue phantoms. This study is the first to quantify the clinical impact of I-value uncertainties on proton dose distributions within patient geometries. A previously developed Geant4 based Monte Carlo code was used to simulate a proton treatment plan for three patients (prostate, pancreases, and liver) with varying tissue I-values. A uniform variation study was conducted in which the tissue I values were varied by +/-5% and +/-10% of the nominal values as well as a probabilistic variation study in which the I-values were randomly sampled according to a normal distribution with the mean equal to the nominal I-value and a standard deviation of 5 and 10% of the nominal values. Modification of tissue I values impacted both the proton range and SOBP width. R(90) range shifts up to 7.7 mm (4.4.%) and R(80) range shifts up to 4.8 mm (1.9%) from the nominal range were recorded. Modulating the tissue I-values by 10% the nominal value resulted in up to a 3.5% difference mean dose in the target volumes and organs at risk compared to the nominal case. The range and dose differences were the largest for the deeper-seated prostate and pancreas cases. The treatments that were simulated with randomly sampled I-values resulted in range and dose differences that were generally within the upper and lower bounds set by the 10% uniform variations. This study demonstrated the impact of I-value uncertainties on patient dose distributions. Clearly, sub-millimeter precision in proton therapy would necessitate a reduction in I-value uncertainties to ensure an efficacious clinical outcome. PMID- 23337714 TI - Contribution of brain-derived neurotrophic factor to mechanical hyperalgesia induced by ventral root transection in rats. AB - It is generally believed that the development of neuropathic pain primarily results from injuries to sensory afferent fibers. Recent studies found that injuries to the motor efferent fibers (e.g. ventral root transection) also contribute to the development of neuropathic pain. Furthermore, an increase in brain-derived neurotrophic factor (BDNF) synthesis has been found in the ventral root transection model, suggesting a possible role of BDNF in this model. To determine the role of BDNF, we observed the effects of intrathecal antibody against BDNF treatment on ventral root transection-induced mechanical hyperalgesia. Paw withdrawal thresholds to mechanical stimuli were measured before and after surgery. The results showed that ventral root transection in rats produced a significant, lasting decrease of mechanical withdrawal thresholds, presenting the development of mechanical hyperalgesia. Intrathecal antibody against BDNF treatment markedly inhibited ventral root transection induced mechanical hyperalgesia in a dose-related manner. The findings suggest that BDNF-mediated signaling pathway within spinal cord may be involved in the development of neuropathic pain involving injuries to motor efferent fibers. PMID- 23337715 TI - Sensitization by ventral pallidal DAMGO: lack of cross-sensitization to morphine. AB - Repeated injections of morphine into the ventral pallidum of laboratory rats results in the development and expression of motor sensitization. Although morphine and [D-Ala, N-MePhe, Gly(ol)]-enkephalin (DAMGO) both activate MU-opioid receptors, their influence on receptor-mediated signaling differs; therefore, we determined if they differentially influenced ventral pallidal-mediated motor sensitization. Repeated intraventral pallidal injections of DAMGO led to the development of motor sensitization and this behavior persisted for at least 18 days. When DAMGO-sensitized rats were challenged with a morphine treatment (either in the ventral pallidum or systemically), the resulting motor response was similar to that seen in rats with a history of intrapallidal saline, that is, cross-sensitization did not occur. As DAMGO and morphine likely activate different arms of the heterologous signal transduction system associated with MU opioid receptors, these observations may reflect behavioral consequences of biased agonism at these receptors. PMID- 23337716 TI - PGE2 differentially regulates monocyte-derived dendritic cell cytokine responses depending on receptor usage (EP2/EP4). AB - Dendritic cells (DCs) are central players in coordinating immune responses, both innate and adaptive. While the role of lipid mediators in the immune response has been the subject of many investigations, the precise role of prostaglandins has often been plagued by contradictory studies. In this study, we examined the role of PGE(2) on human DC function. Although studies have suggested that PGE(2) specifically plays a role in DC motility and cytokine release profile, the precise receptor usage and signaling pathways involved remain unclear. In this report we found that irrespective of the human donor, monocyte-derived dendritic cells (MoDCs) express three of the four PGE(2) receptor subtypes (EP(2-4)), although only EP(2) and EP(4) were active with respect to cytokine production. Using selective EP receptor antagonists and agonists, we demonstrate that PGE(2) coordinates control of IL-23 release (a promoter of Th17, an autoimmune associated T cell subset) in a dose-dependent manner by differential use of EP(2) and EP(4) receptors in LPS-activated MoDCs. This is in contrast to IL-12, which is dose dependently inhibited by PGE(2) through both receptor subtypes. Low concentrations (~1-10nM) of PGE(2) promoted IL-23 production via EP(4) receptors, while at higher (>50 nM), but still physiologically relevant concentrations, IL 23 is suppressed by an EP(2) dependent mechanism. These results can be explained by differential regulation of the common subunit, IL-12p40, and IL-23p19, by EP(2) and EP(4). By these means, PGE(2) can act as a regulatory switch of immune responses depending on its concentration in the microenvironment. In addition, we believe these results may also explain why seemingly conflicting biological functions assigned to PGE(2) have been reported in the literature, as the concentration of ligand (PGE(2)) fundamentally alters the nature of the response. This finding also highlights the potential of designing therapeutics which differentially target these receptors. PMID- 23337717 TI - Therapeutic inhibition of the alternative complement pathway attenuates chronic EAE. AB - Previous studies from our laboratory using complement-mutant mice demonstrated that the alternative pathway is the dominant activation pathway responsible for complement-mediated pathology in demyelinating disease. Using a well characterized inhibitory monoclonal antibody (mAb 1379) directed against mouse factor B, we assessed the therapeutic value of inhibiting the alternative complement pathway in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. Administration of anti-factor B antibody to mice prior to the onset of clinical signs of active EAE had no affect on the onset or acute phase of disease, but significantly attenuated the chronic phase of disease resulting in reduced cellular infiltration, inflammation and demyelination in antibody-treated mice. Attenuation of the chronic phase of disease was long lasting even though antibody administration was terminated shortly after disease onset. Chronic disease was also attenuated in transferred EAE when anti-factor B antibody was administered before or after disease onset. Similar levels of disease attenuation were observed in transferred EAE using MOG-specific encephalitogenic T cells. These studies demonstrate the therapeutic potential for inhibition of factor B in the chronic phase of demyelinating disease, where treatment options are limited. PMID- 23337718 TI - Maternal obesity is associated with the formation of small dense LDL and hypoadiponectinemia in the third trimester. AB - CONTEXT: Maternal obesity is associated with high plasma triglyceride, poor vascular function, and an increased risk for pregnancy complications. In normal weight pregnant women, higher triglyceride is associated with increased small, dense low-density lipoprotein (LDL). HYPOTHESIS: In obese pregnancy, increased plasma triglyceride concentrations result in triglyceride enrichment of very low density lipoprotein-1 particles and formation of small dense LDL via lipoprotein lipase. DESIGN: Women (n = 55) of body mass index of 18-46 kg/m(2) were sampled longitudinally at 12, 26, and 35 weeks' gestation and 4 months postnatally. SETTING: Women were recruited at hospital antenatal appointments, and study visits were in a clinical research suite. OUTCOME MEASURES: Plasma concentrations of lipids, triglyceride-rich lipoproteins, lipoprotein lipase mass, estradiol, steroid hormone binding globulin, insulin, glucose, leptin, and adiponectin were determined. RESULTS: Obese women commenced pregnancy with higher plasma triglyceride, reached the same maximum, and then returned to higher postnatal levels than normal-weight women. Estradiol response to pregnancy (trimester 1-3 incremental area under the curve) was positively associated with plasma triglyceride response (r(2) adjusted 25%, P < .001). In the third trimester, the proportion of small, dense LDL was 2-fold higher in obese women than normal weight women [mean (SD) 40.7 (18.8) vs 21.9 (10.9)%, P = .014], and 35% of obese, 14% of overweight, and none of the normal-weight women displayed an atherogenic LDL subfraction phenotype. The small, dense LDL mass response to pregnancy was inversely associated with adiponectin response (17%, P = .013). CONCLUSIONS: Maternal obesity is associated with an atherogenic LDL subfraction phenotype and may provide a mechanistic link to poor vascular function and adverse pregnancy outcome. PMID- 23337719 TI - Effects of simvastatin on retinoic acid system in primary human endometrial stromal cells and in a chimeric model of human endometriosis. AB - CONTEXT: Retinoic acid (RA) may promote survival or apoptosis of cells, depending on the levels of binding proteins: apoptosis-inducing cellular RA binding protein 2 (CRABP2), and cell survival-promoting fatty acid binding protein 5 (FABP5). Increased cellular uptake of retinol and altered actions of RA related to reduced expression of CRABP2 may contribute to the development of endometriosis. Recently statins have been shown to inhibit growth of human endometrial stromal (HES) cells and to reduce the number and size of endometriotic implants in experimental models of this disorder. OBJECTIVE: The objective of the study was to determine whether effects of simvastatin on HES cells and experimental endometriotic implants are related to the modulation of the RA system. METHODS: Effects of simvastatin and RA on proliferation and apoptosis of HES cells were evaluated. Expression of stimulated by RA 6 (STRA6), CRABP2, and FABP5 was determined by real-time PCR and Western blotting. Effects of simvastatin were also evaluated in a nude mouse model of human endometriosis. RESULTS: Simvastatin potentiated an inhibitory effect of RA on growth of HES cells. In HES cells, simvastatin induced expression of STRA6 and CRABP2 but not FABP5. Similarly, simvastatin treatment of nude mice bearing human endometrial xenografts led to an increased expression of CRABP2 and STRA6 proteins in ectopic lesions. CONCLUSIONS: Simvastatin interacts with the RA system, inducing the expression of the key protein regulating the uptake of retinol (STRA6) and the expression of apoptosis-promoting CRABP2. These effects may contribute to cooperative apoptosis-inducing effects of simvastatin and RA and support the examination of these compounds in the treatment of endometriosis. PMID- 23337720 TI - Hurthle cell neoplasms: a new differential diagnosis for 18F-FDOPA-avid thyroid nodules? PMID- 23337721 TI - Analysis of body composition in individuals with high bone mass reveals a marked increase in fat mass in women but not men. AB - CONTEXT: High bone mass (HBM), detected in 0.2% of dual-energy x-ray absorptiometry (DXA) scans, is characterized by raised body mass index, the basis for which is unclear. OBJECTIVE: To investigate why body mass index is elevated in individuals with HBM, we characterized body composition and examined whether differences could be explained by bone phenotypes, eg, bone mass and/or bone turnover. DESIGN, SETTING, AND PARTICIPANTS: We conducted a case-control study of 153 cases with unexplained HBM recruited from 4 UK centers by screening 219 088 DXA scans. A total of 138 first-degree relatives (of whom 51 had HBM) and 39 spouses were also recruited. Unaffected individuals served as controls. MAIN OUTCOME MEASURES: We measured fat mass, by DXA, and bone turnover markers. RESULTS: Among women, fat mass was inversely related to age in controls (P = .01), but not in HBM cases (P = .96) in whom mean fat mass was 8.9 [95% CI 4.7, 13.0] kg higher compared with controls (fully adjusted mean difference, P < .001). Increased fat mass in male HBM cases was less marked (gender interaction P = .03). Compared with controls, lean mass was also increased in female HBM cases (by 3.3 [1.2, 5.4] kg; P < .002); however, lean mass increases were less marked than fat mass increases, resulting in 4.5% lower percentage lean mass in HBM cases (P < .001). Osteocalcin was also lower in female HBM cases compared with controls (by 2.8 [0.1, 5.5] MUg/L; P = .04). Differences in fat mass were fully attenuated after hip bone mineral density (BMD) adjustment (P = .52) but unchanged after adjustment for bone turnover (P < .001), whereas the greater hip BMD in female HBM cases was minimally attenuated by fat mass adjustment (P < .001). CONCLUSIONS: HBM is characterized by a marked increase in fat mass in females, statistically explained by their greater BMD, but not by markers of bone turnover. PMID- 23337722 TI - Primary hyperparathyroidism: a rare cause of genu valgus in adolescence. PMID- 23337723 TI - Intermedin/adrenomedullin 2 is associated with implantation and placentation via trophoblast invasion in human pregnancy. AB - RATIONALE: Intermedin (IMD) is a novel peptide expressed in trophoblast cells in human placenta and enhances the invasion, migration, and human leukocyte antigen class I, G (HLA-G) expression in first-trimester HTR-8SV/neo cells. We recently reported that infusion of IMD antagonist in pregnant rats is detrimental to pregnancy outcome, resulting in impaired fetoplacental growth and deformed placental vasculature. OBJECTIVE: This study was undertaken to assess expression of IMD and its involvement in human implantation and early placentation and assess whether its expression is altered in spontaneous abortion. FINDINGS AND CONCLUSIONS: We demonstrate for the first time that IMD is present in day 5 embryonic secretome; villous and decidual expression of IMD is higher at 6-8 weeks after a decline as gestation advances toward the second trimester; first trimester spontaneous abortion is associated with a lower expression of IMD in serum, villi, and decidua; IMD stimulates the invasive capacity of first trimester primary Extravillous cytotrophoblast cells; and IMD decreases elevated levels of tumor suppressor Kangia-1 in decidual explants from first-trimester spontaneous abortion. In conclusion, this study is the first to demonstrate a potential involvement of IMD in human embryo implantation and placental development via regulation of trophoblast invasion at the maternal-fetal interface and suggests a physiological role for this novel peptide in establishment of human pregnancy. PMID- 23337724 TI - Evidence for masculinization of adipokine gene expression in visceral and subcutaneous adipose tissue of obese women with polycystic ovary syndrome (PCOS). AB - CONTEXT: Sex hormones, particularly androgens, may influence not only adipose tissue distribution but also its functions. OBJECTIVE: We explored the possibility of sexual dimorphism in adipose tissue and skeletal muscle function. DESIGN: This was a case-control study. SETTING: The setting was an academic hospital. PARTICIPANTS: Participants were severely obese men (n = 7), control women (n = 7), and hyperandrogenic women presenting with polycystic ovary syndrome (PCOS) (n = 7) submitting to bariatric surgery and an independent series of 40 patients with PCOS and 40 control women matched for age and body mass index. INTERVENTIONS: Samples of subcutaneous (SAT) and visceral adipose tissue (VAT) and skeletal muscle were obtained during bariatric surgery in severely obese subjects. MAIN OUTCOME MEASURES: Gene expression of chemerin, lipocalin-2, and omentin-1 in tissue samples was measured. We analyzed the effects of PCOS and obesity on serum concentrations of these adipokines in the larger series of women with PCOS and in control women. RESULTS: Expression of chemerin and lipocalin-2 was higher in VAT than in SAT in men and women with PCOS; the opposite was observed in control women. Omentin-1 expression was higher in VAT than in SAT in the three groups. No differences were observed in the skeletal muscle expression of these adipokines. Obesity increased serum chemerin and lipocalin-2 levels and tended to decrease omentin-1, irrespective of PCOS. CONCLUSIONS: The present results suggest that there is sexual dimorphism in some adipose tissue functions and that this dimorphism may be related to differences in androgen concentrations because women with PCOS show a masculinized pattern of expression of some adipokines. PMID- 23337725 TI - Placental specific mRNA in the maternal circulation are globally dysregulated in pregnancies complicated by fetal growth restriction. AB - CONTEXT: Fetal growth restriction (FGR) is a leading cause of perinatal mortality, yet no reliable screening test exists. Placental specific mRNA in the maternal circulation may reflect changes in the placental transcriptome in FGR and could be a novel biomarker for FGR. OBJECTIVE: The aim of the study was to identify placental specific RNA detectable in the maternal circulation and examine whether they are differentially expressed in severe preterm FGR. DESIGN: In silico screening was used to identify placental specific RNAs. Their expression in cases of severe FGR vs controls was examined in both maternal blood and placenta by microarray, RT-PCR, and in situ hybridization. RESULTS: Via in silico analysis, we identified 137 genes very highly expressed in the placenta relative to other tissues. Using microarray, we found that they were detectable in the maternal blood and were globally dysregulated with preterm FGR; 75 genes (55%) had a >=1.5-fold differential expression compared to controls. Eight genes (ERVWE-1, PSG1, PLAC4, TAC3, PLAC3, CRH, CSH1, and KISS1) were validated by RT PCR to be significantly increased in both maternal blood and placenta in a larger cohort of severe FGR compared to controls. In situ hybridization confirmed PAPPA2 and ERVWE-1 localized to the syncytiotrophoblast. CONCLUSION: There is global differential expression of placental specific mRNA in the maternal blood in pregnancies complicated by severe preterm FGR. Placental specific mRNA in maternal blood may represent a new class of biomarkers for preterm FGR. PMID- 23337726 TI - Treat-to-target for osteoporosis: is now the time? AB - OBJECTIVES: Current clinical practice guidelines identify patients at high risk for fracture who are likely to benefit from pharmacological therapy and suggest ways to monitor for effectiveness of therapy. However, there is no clear guidance on when fracture risk has been reduced to an acceptably low level. As a consequence, some patients at low risk for fracture may be treated for longer than necessary, whereas others at high risk for fracture may have treatment stopped when they might benefit from continuation of the same treatment or a change to a more potent therapeutic agent. The objective of this statement is to describe the potential clinical utility of developing a "treat-to-target" strategy for the management of patients with osteoporosis. PARTICIPANTS: We recommend that a task force of clinicians, clinical investigators, and other stakeholders in the care of osteoporosis explore the options, review the evidence, and identify additional areas for investigation to establish osteoporosis treatment targets. EVIDENCE: Data from large, prospective, randomized, placebo-controlled registration trials for currently available osteoporosis therapies should be analyzed for commonalities of correlations between easily measured endpoints and fracture risk. CONSENSUS PROCESS: Osteoporosis experts, professional organizations, and patient care advocates should be involved in the process of developing consensus on easily measurable osteoporosis treatment targets that are supported by the best available evidence and likely to be accepted by clinicians and patients in the care of osteoporosis. CONCLUSIONS: A treat-to-target strategy for osteoporosis offers the potential of improving osteoporosis care by reducing the burden of osteoporotic fractures and limiting adverse effects of therapy. PMID- 23337727 TI - Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort. AB - CONTEXT: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking. OBJECTIVE: The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH. RESEARCH DESIGN AND METHODS: We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort. RESULTS: CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups. CONCLUSIONS: In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment. PMID- 23337728 TI - Bone density, turnover, and estimated strength in postmenopausal women treated with odanacatib: a randomized trial. AB - CONTEXT: Odanacatib, a cathepsin K inhibitor, increases spine and hip areal bone mineral density (BMD) in postmenopausal women with low BMD and cortical thickness in ovariectomized monkeys. OBJECTIVE: The objective of the study was to examine the impact of odanacatib on the trabecular and cortical bone compartments and estimated strength at the hip and spine. DESIGN: This was a randomized, double blind, 2-year trial. SETTING: The study was conducted at a private or institutional practice. PARTICIPANTS: PARTICIPANTS included 214 postmenopausal women with low areal BMD. INTERVENTION: The intervention included odanacatib 50 mg or placebo weekly. MAIN OUTCOME MEASURES: Changes in areal BMD by dual-energy x-ray absorptiometry (primary end point, 1 year areal BMD change at lumbar spine), bone turnover markers, volumetric BMD by quantitative computed tomography (QCT), and bone strength estimated by finite element analysis were measured. RESULTS: Year 1 lumbar spine areal BMD percent change from baseline was 3.5% greater with odanacatib than placebo (P < .001). Bone-resorption marker C telopeptide of type 1 collagen was significantly lower with odanacatib vs placebo at 6 months and 2 years (P < .001). Bone-formation marker procollagen I N terminal peptide initially decreased with odanacatib but by 2 years did not differ from placebo. After 6 months, odanacatib-treated women had greater increases in trabecular volumetric BMD and estimated compressive strength at the spine and integral and trabecular volumetric BMD and estimated strength at the hip (P < .001). At the cortical envelope of the femoral neck, bone mineral content, thickness, volume, and cross-sectional area also increased from baseline with odanacatib vs placebo (P < .001 at 24 months). Adverse experiences were similar between groups. CONCLUSIONS: Over 2 years, odanacatib decreased bone resorption, maintained bone formation, increased areal and volumetric BMD, and increased estimated bone strength at both the hip and spine. PMID- 23337729 TI - A pilot study of the duodenal-jejunal bypass liner in low body mass index type 2 diabetes. AB - CONTEXT: The duodenal-jejunal bypass liner (DJBL) is a device that mimics the intestinal portion of gastric bypass surgery and has been shown to improve glucose metabolism rapidly in obese subjects with type 2 diabetes (T2DM). OBJECTIVE: To assess the safety of the DJBL and to evaluate its potential to affect glycemic control beneficially in subjects with T2DM who were not morbidly obese. PATIENTS AND DESIGN: Adult men and women with T2DM of <= 10 years' duration with hemoglobin A1c (HbA1c) >= 7.5% and <= 10% and having a body mass index >= 26 to <= 50 kg/m(2) were enrolled in this prospective, 52-week, single center, open-label clinical study. MAIN OUTCOME MEASURES: Adverse events and changes in body weight, fasting plasma glucose (FPG) levels, and HbA1c levels. RESULTS: Sixteen of 20 subjects implanted with the DJBL completed the 1-year study (mean body mass index = 30.0 +/- 3.6, mean +/- SD). Gastrointestinal disorders were reported by 13 subjects, and metabolic or nutritional disorders occurred in 14 subjects. FPG levels dropped from 207 +/- 61 mg/dL at baseline to 139 +/- 37 mg/dL at 1 week and remained low throughout the study. Mean body weight also declined, but the change in body weight was not significantly associated with change in FPG at 52 weeks. HbA1c declined from 8.7 +/- 0.9% at baseline to 7.5 +/- 1.6% at week 52. CONCLUSIONS: The improvements in glycemic status were observed at 1 year in moderately obese subjects with T2DM, suggesting that the DJBL may represent an effective adjuvant to standard medical therapy of T2DM in this population. PMID- 23337730 TI - Varied clinical presentations of seven patients with mutations in CYP11A1 encoding the cholesterol side-chain cleavage enzyme, P450scc. AB - CONTEXT: The cholesterol side-chain cleavage enzyme P450scc, encoded by CYP11A1, converts cholesterol to pregnenolone to initiate steroidogenesis. P450scc deficiency can disrupt adrenal and gonadal steroidogenesis, resembling congenital lipoid adrenal hyperplasia clinically and hormonally; only 12 such patients have been reported previously. OBJECTIVE: We sought to expand clinical and genetic experience with P450scc deficiency. PATIENTS AND METHODS: We sequenced candidate genes in 7 children with adrenal insufficiency who lacked disordered sexual development. P450scc missense mutations were recreated in the F2 vector, which expresses the fusion protein P450scc-Ferredoxin Reductase-Ferredoxin. COS-1 cells were transfected, production of pregnenolone was assayed, and apparent kinetic parameters were calculated. Previously described P450scc mutants were assayed in parallel. RESULTS: Four of five Bedouin children in one kindred were compound heterozygotes for mutations c.694C>T (Arg232Stop) and c.644T>C (Phe215Ser). Single-nucleotide polymorphism analysis confirmed segregation of these mutations. The fifth kindred member and another Bedouin patient presented in infancy and were homozygous for Arg232Stop. A patient from Fiji presenting in infancy was homozygous for c.358T>C (Arg120Stop). All mutations are novel. As assayed in the F2 fusion protein, P450scc Phe215Ser retained 2.5% of wild-type activity; previously described mutants Leu141Trp and Ala269Val had 2.6% and 12% of wild type activity, respectively, and Val415Glu and c.835delA lacked detectable activity. CONCLUSIONS: Although P450scc is required to produce placental progesterone required to maintain pregnancy, severe mutations in P450scc are compatible with term gestation; milder P450scc mutations may present later without disordered sexual development. Enlarged adrenals usually distinguish steroidogenic acute regulatory protein deficiency from P450scc deficiency, but only DNA sequencing is definitive. PMID- 23337731 TI - Control of the motion of the body's center of mass in relation to the center of pressure during high-heeled gait. AB - High-heeled shoes are associated with instability and falling, leading to injuries such as fracture and ankle sprain. Knowledge of the motion of the body's center of mass (COM) with respect to the center of pressure (COP) during high heeled gait may offer insights into the balance control strategies and provide a basis for approaches that minimize the risk of falling and associated adverse effects. The study aimed to investigate the influence of the base and height of the heels on the COM motion in terms of COM-COP inclination angles (IA) and the rate of change of IA (RCIA). Fifteen females who regularly wear high heels walked barefoot and with narrow-heeled shoes with three heel heights (3.9cm, 6.3cm and 7.3cm) while kinematic and ground reaction force data were measured and used to calculate the COM and COP, as well as the temporal-distance parameters. The reduced base of the heels was found to be the primary factor for the reduced normalized walking speed and the reduced frontal IA throughout the gait cycle. This was achieved mainly through the control of the RCIA during double-leg stance (DLS). The heel heights affected mainly the peak RCIA during DLS, which were not big enough to affect the IA. These results suggest young adults adopt a conservative strategy for balance control during narrow-heeled gait. The results will serve as baseline data for future evaluation of patients and/or older adults during narrow-heeled gait with the aim of reducing the risk of falling. PMID- 23337732 TI - Executive function orchestrates regulation of task-relevant gait fluctuations. AB - Humans apply a minimum intervention principle to regulate treadmill walking, rapidly correcting fluctuations in the task-relevant variable (step speed: SS) while ignoring fluctuations in the task-irrelevant variables (step time: ST; step length: SL). We examined whether the regulation of fluctuations in SS and not in ST and SL depends on high-level, executive function, processes. Young adults walked on a treadmill without a cognitive requirement and while performing the cognitive task of dichotic listening. SS fluctuations became less anti-persistent when performing dichotic listening, meaning that taxing executive function impaired the ability to rapidly correct speed deviations on subsequent steps. Conversely, performing dichotic listening had no effect on SL and ST persistent fluctuations. Findings suggest that high-level brain processes are involved only in regulating gait task-relevant variables. PMID- 23337733 TI - Agreement between temporal and spatial gait parameters from an instrumented walkway and treadmill system at matched walking speed. AB - BACKGROUND: Commercially available instrumented treadmill systems that provide continuous measures of temporospatial gait parameters have recently become available for clinical gait analysis. This study evaluated the level of agreement between temporospatial gait parameters derived from a new instrumented treadmill, which incorporated a capacitance-based pressure array, with those measured by a conventional instrumented walkway (criterion standard). METHODS: Temporospatial gait parameters were estimated from 39 healthy adults while walking over an instrumented walkway (GAITRite((r))) and instrumented treadmill system (Zebris) at matched speed. Differences in temporospatial parameters derived from the two systems were evaluated using repeated measures ANOVA models. Pearson-product moment correlations were used to investigate relationships between variables measured by each system. Agreement was assessed by calculating the bias and 95% limits of agreement. RESULTS: All temporospatial parameters measured via the instrumented walkway were significantly different from those obtained from the instrumented treadmill (P<.01). Temporospatial parameters derived from the two systems were highly correlated (r, 0.79-0.95). The 95% limits of agreement for temporal parameters were typically less than +/-2% of gait cycle duration. However, 95% limits of agreement for spatial measures were as much as +/-5cm. CONCLUSIONS: Differences in temporospatial parameters between systems were small but statistically significant and of similar magnitude to changes reported between shod and unshod gait in healthy young adults. Temporospatial parameters derived from an instrumented treadmill, therefore, are not representative of those obtained from an instrumented walkway and should not be interpreted with reference to literature on overground walking. PMID- 23337734 TI - Automated video analysis system reveals distinct diurnal behaviors in C57BL/6 and C3H/HeN mice. AB - Advances in rodent behavior dissection using automated video recording and analysis allows detailed phenotyping. This study compared and contrasted 15 diurnal behaviors recorded continuously using an automated behavioral analysis system for a period of 14 days under a 14/10 light/dark cycle in single housed C3H/HeN (C3H) or C57BL/6 (C57) male mice. Diurnal behaviors, recorded with minimal experimental interference and analyzed using phenotypic array and temporal distribution analysis showed bimodal and unimodal profiles in the C57 and C3H mice, respectively. Phenotypic array analysis revealed distinct behavioral rhythms in Activity-Like Behaviors (i.e. walk, hang, jump, come down) (ALB), Exploration-Like Behaviors (i.e. dig, groom, rear up, sniff, stretch) (ELB), Ingestion-Like Behaviors (i.e. drink, eat) (ILB) and Resting-Like Behaviors (i.e. awake, remain low, rest, twitch) (RLB) of C3H and C57 mice. Temporal distribution analysis demonstrated that strain and time of day affects the magnitude and distribution of the spontaneous homecage behaviors. Wheel running activity, water and food measurements correlated with timing of homecage behaviors. Subcutaneous (3 mg/kg, sc) or oral (0.02 mg/ml, oral) melatonin treatments in C57 mice did not modify either the total 24 h magnitude or temporal distribution of homecage behaviors when compared with vehicle treatments. We conclude that C3H and C57 mice show different spontaneous activity and behavioral rhythms specifically during the night period which are not modulated by melatonin. PMID- 23337735 TI - Effects of aging and body size on proximal and ascending aorta and aortic arch: inner edge-to-inner edge reference values in a large adult population by two dimensional transthoracic echocardiography. AB - BACKGROUND: Aortic size is known to vary significantly by age and body size and to be an important predictor of cardiovascular diseases. The aim of this study was to determine reference values for proximal thoracic aorta diameters, using the inner edge technique and two-dimensional transthoracic echocardiography. METHODS: Diameters of the aortic annulus, sinuses of Valsalva, sinotubular junction, arch, and ascending aorta and the angle of insertion of the aorta were measured in 500 subjects (231 women; mean age, 48 +/- 18 years) with normal echocardiographic findings, retrospectively enrolled. The relations of age and body size with aortic measurements were investigated using bivariate and multiple linear regressions. RESULTS: Measurements were highly feasible (83% for the aortic arch, 100% for the other segments). All aortic diameters significantly related to age, weight and body surface area, while height was correlated only with annular diameter. In predictive models adjusted for gender, older age was associated with increased aortic diameters (R(2) values ranged from 0.36 for the sinotubular junction to 0.52 for the sinuses of Valsalva). Adjustments for height and weight led to significant improvements (R(2) values ranged from 0.43 for the sinotubular junction to 0.58 for the sinuses of Valsalva). Similar correlations were observed for men and women. Angle was found to be dependent only on age and gender. Reproducibility analysis showed good to excellent accordance between repeated measurements. CONCLUSIONS: The results of this study show the effect of aging on the proximal thoracic aorta and emphasize the importance of accounting for gender and body size when assessing aortic size. The obtained reference ranges will help standardize the assessment of aortic dimensions by applying inner edge convention and facilitate comparisons with other imaging techniques. PMID- 23337736 TI - Left-right ventricular interactions in pediatric aortic stenosis: right ventricular myocardial strain before and after aortic valvuloplasty. AB - BACKGROUND: Ventricular-ventricular interactions may affect left ventricular (LV) and right ventricular (RV) function but have not been well characterized in chronic LV afterload in children. The aim of this study was to assess RV myocardial strain in children with aortic stenosis before and after aortic balloon valvuloplasty. METHODS: Two-dimensional echocardiographic images from children aged > 1 month were with aortic stenosis and preserved LV ejection fractions were retrospectively studied using vector velocity imaging. LV and RV strain were compared before and after balloon valvuloplasty and in comparison with normal controls. RESULTS: Twenty-six children were studied. Aortic valve gradient decreased after balloon valvuloplasty. LV ejection fraction, wall thickness, circumferential strain, and basal and mid longitudinal strain were unchanged after valvuloplasty (-18.09 +/- 6.97% vs -16.43 +/- 6.30%, P = .40, and -14.11 +/- 5.011% vs -13.12 +/- 5.52%, P = .50, respectively). LV strain tended to be lower than in controls after valvuloplasty (basal, -16.43 +/- 6.30% vs 19.77 +/- 5.82%, P = .05). RV strain was unchanged at the basal and apical segments but increased at the mid RV segment after valvuloplasty (-21.34 +/- 6.55% vs -24.97 +/- 8.54%, P = .02). Change in RV strain was not correlated with change in aortic gradient or change in LV strain after valvuloplasty (P = .60). LV and RV strain at baseline and their changes after valvuloplasty were variable between patients. CONCLUSIONS: RV strain was normal or reduced in compensated aortic stenosis and was not correlated with LV strain. The change in RV strain was variable among patients after valvuloplasty, with improvement in RV midwall longitudinal strain. PMID- 23337737 TI - Functional maturation of left and right atrial systolic and diastolic performance in infants, children, and adolescents. AB - BACKGROUND: Left atrial (LA) function is an important modulator of left ventricular filling and has a prognostic role in adult heart failure, but pediatric data are limited. The aim of this study was to characterize the normal LA and right atrial (RA) strain (epsilon) and strain rate (SR) in infants and children. METHODS: Atrial epsilon and SR were prospectively investigated in 153 subjects using two-dimensional speckle-tracking echocardiography. High-frame rate, three-beat captures of LA (15-segment model; two-chamber, three-chamber, and four-chamber views) and RA (six-segment model; four-chamber view) were analyzed (Vivid 7, EchoPAC BT11). LA and RA segmental and global peak positive epsilon (epsilonPos) and negative epsilon (epsilonNeg) and peak positive SR, early negative SR, and late negative SR were measured. Linear and nonlinear regressions of epsilon and SR were performed with age and heart rate. Relationships of epsilon and SR with ventricular inflow Doppler and myocardial tissue Doppler indices were explored. RESULTS: The age range was 3 days to 20 years, and body surface area range from 0.17 to 2.3 m(2) for the study cohort. Mean global LA epsilonPos, LA epsilonNeg, RA epsilonPos, and RA epsilonNeg were 28 +/- 9%, -16 +/- 6%, 23 +/- 9%, and -15 +/- 6%, respectively. Positive correlations were found for global atrial epsilonPos and epsilonNeg with age (P < .001). A marked rate of changes in epsilon and SR was seen in the first year of life, reaching normal adult values by adolescence. Peak positive SR had a strong negative correlation with age, and early negative SR had a strong positive correlation with age (P < .001), while late negative SR was correlated nonlinearly. Heart rate and age both influenced all LA and RA epsilon and SR indices. CONCLUSIONS: Maturational changes in LA and RA epsilon and SR occur in normal children and are especially profound in infancy. Consequently, LA and RA performance indices must be interpreted in light of heart rate and age. Normal values and percentiles for atrial epsilon and SR reported here will provide a foundation for the study of pediatric atrial physiology and function in disease states. PMID- 23337738 TI - Measuring the quality of echocardiography using the predictive value of the left ventricular ejection fraction. AB - BACKGROUND: One of the main challenges for imaging laboratories is demonstrating the quality of their studies. The aim of this study was to determine if echocardiographic training and experience are associated with the accuracy of left ventricular ejection fraction (LVEF) reporting using all-cause mortality as the gold standard. METHODS: Survival was determined for consecutive patients undergoing echocardiography at one of four academic facilities. The relationship between LVEF and survival was determined for different groups of physician readers and sonographers on the basis of board certification and experience. Studies of physicians reading <200 studies were excluded. RESULTS: Data from 63,108 patients and 40 physicians were included. There was moderate variation across physicians in the relationship between LVEF and 1-year mortality (area under the receiver operating characteristic curve interquartile range, 0.56 0.64). The relationship between LVEF and 1-year mortality was stronger for physicians board certified in echocardiography (area under the receiver operating characteristic curve, 0.60; 95% confidence interval, 0.59-0.61) compared with those not certified (area under the receiver operating characteristic curve, 0.56; 95% confidence interval, 0.55-0.57; P < .0001). Physician experience, years since training, and sonographer experience and certification were not clearly associated with the predictive value of LVEF. After adjustment for patient characteristics, the LVEF-mortality association of board-certified physicians remained stronger than the LVEF-mortality association of those not certified. CONCLUSIONS: LVEF as determined by physicians board certified in echocardiography was associated with a stronger relationship with mortality than as determined by those not certified. The LVEF-mortality relationship may be useful as one measure of the quality of imaging. PMID- 23337739 TI - Attentional bias for affective visual stimuli in posttraumatic stress disorder and the role of depression. AB - An attentional bias for trauma-related verbal cues was frequently demonstrated in posttraumatic stress disorder (PTSD) using variants of the emotional Stroop task (EST). However, the mechanisms underlying the Stroop-effect are ill-defined and it is yet unclear how the findings apply to different paradigms and stimulus modalities. To address these open questions, for the first time a spatial-cuing task with pictorial cues of different emotional valence was administered to trauma-exposed individuals with and without PTSD, and non-trauma-exposed controls. Groups did not show different response profiles across affective conditions. However, a group effect was evident when comparing depressed with non depressed individuals: Those with depression showed delayed attending towards trauma-related cues and faster attending away from negative cues. In correlational analyses, attentional avoidance was associated with both depression and PTSD symptom severity. These findings highlight the need for research on trauma populations and anxiety in general to pay closer attention to depression as an important confound in the study of emotional information processing. PMID- 23337740 TI - Development of a measure quantifying adverse psychotherapeutic ingredients: the Experiences of Therapy Questionnaire (ETQ). AB - While psychotherapies are of established value, they may, as active treatments, risk adverse outcomes. As there is no validated measure of potentially negative psychotherapeutic ingredients, we sought to develop such a measure for use in psychotherapy evaluation studies. Based on a review of the literature, a 103-item experiential measure was derived. Psychometric properties and scale score correlates were examined in a sample of more than 700 respondents. Principal component analyses revealed a five-factor solution, explaining 53.4% of the variance; namely 'Negative Therapist', 'Pre-occupying Therapy', 'Beneficial Therapy', 'Idealization of Therapist' and 'Passive Therapist' constructs. Derived factors had high internal consistency, and scale scores were correlated with a number of clinically relevant demographic and treatment characteristics. An independent study established high test-retest reliability for the measure. Assessment of any adverse effects of psychotherapy is of clinical and research significance. We report the development of a measure that should allow the impact of such effects to be quantified in treatment studies, and especially in apportioning the contribution of such non-specific therapeutic effects. PMID- 23337741 TI - On-road bicycle facilities and bicycle crashes in Iowa, 2007-2010. AB - PURPOSE: An average of 611 deaths and over 47,000 bicyclists are injured in traffic-related crashes in the United States each year. Efforts to increase bicycle safety are needed to reduce and prevent injuries and fatalities, especially as trends indicate that ridership is increasing rapidly. The objective of this study was to evaluate the effect of bicycle-specific roadway facilities (e.g., signage and bicycle lanes) in reducing bicycle crashes. METHODS: We conducted a case site-control site study of 147 bicycle crash-sites identified from the Iowa Department of Transportation crash database from 2007 to 2010 and 147 matched non-crash sites. Control sites were randomly selected from intersections matched to case sites on neighborhood (census block group) and road classification (arterial, feeder, collector, etc.). We examined crash risk by any on-road bicycle facility present and by facility type (pavement markings--bicycle lanes and shared lane arrows, bicycle-specific signage, and the combination of markings and signage), controlling for bicycle volume, motor vehicle volume, street width, sidewalks, and traffic controls. RESULTS: A total of 11.6% of case sites and 15.0% of controls had an on-road bicycle facility. Case intersections had higher bicycle volume (3.52 vs. 3.34 per 30 min) and motor vehicle volume (248.77 vs. 205.76 per 30 min) than controls. Our results are suggestive that the presence of an on-road bicycle facility decreases crash risk by as much as 60% with a bicycle lane or shared lane arrow (OR=0.40, 95% CI=0.09-1.82) and 38% with bicycle-specific signage (OR=0.62, 95% CI=0.15-2.58). CONCLUSIONS: Investments in bicycle-specific pavement markings and signage have been shown to be beneficial to traffic flow, and our results suggest that they may also reduce the number of bicycle-motor vehicle crashes and subsequent injuries and fatalities. As a relatively low-cost traffic feature, community considerations for further implementation of these facilities are justified. PMID- 23337742 TI - Optimizing gene transfer to conventional outflow cells in living mouse eyes. AB - The mouse eye has physiological and genetic advantages to study conventional outflow function. However, its small size and shallow anterior chamber presents technical challenges to efficient intracameral delivery of genetic material to conventional outflow cells. The goal of this study was to optimize methods to overcome this technical hurdle, without damaging ocular structures or compromising outflow function. Gene targeting was monitored by immunofluorescence microscopy after transduction of adenovirus encoding green fluorescent protein driven by a CMV promoter. Guided by a micromanipulator and stereomicroscope, virus was delivered intracamerally to anesthetized mice by bolus injection using a 33 gauge needle attached to Hamilton syringe or infusion with glass micropipette connected to syringe pump. The total number of particles introduced remained constant, while volume of injected virus solution (3-10 MUl) was varied for each method and time of infusion (3-40 min) tested. Outflow facility and intraocular pressure were monitored invasively using established techniques. Unlike bolus injections or slow infusions, introduction of virus intracamerally during rapid infusions (3 min) at any volume tested preferentially targeted trabecular meshwork and Schlemm's canal cells, with minimal transduction of neighboring cells. While infusions resulted in transient intraocular pressure spikes (commensurate with volume infused, Delta40-70 mmHg), eyes typically recovered within 60 min. Transduced eyes displayed normal outflow facility and tissue morphology 3-6 days after infusions. Taken together, fast infusion of virus solution in small volumes intracamerally is a novel and effective method to selectively deliver agents to conventional outflow cells in living mice. PMID- 23337743 TI - Zanthoxylum capense constituents with antimycobacterial activity against Mycobacterium tuberculosis in vitro and ex vivo within human macrophages. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum capense Thunb. (Rutaceae) is a medicinal plant traditionally used in Mozambique to treat tuberculosis. AIMS OF THE STUDY: The main aim of the study was to find antimycobacterial lead compounds from Zanthoxylum capense. Another goal was to provide scientific validation for the use of this plant in traditional medicine. METHODS AND MATERIALS: By bioassay guided fractionation, 16 compounds were isolated and screened for their in vitro antimycobacterial activity against two different strains of Mycobacterium tuberculosis. Their in vitro cytotoxicity to human THP-1 macrophages was also assessed. The compounds with favourable selectivity index values (SI>10) were further investigated for their ability to inhibit the growth of Mycobacterium tuberculosis H37Rv in an intracellular macrophage model of infection. RESULTS: The best results were obtained for a benzophenanthridine alkaloid, decarine (1), and an N-isobutylamide, N-isobutyl-(2E,4E)-2,4-tetradecadienamide (15), which showed high activity against Mycobacterium tuberculosis H37Rv (MIC of 1.6 MUg/ml), and a low macrophage cytotoxicity (IC50>60 MUg/ml), indicating considerable selective activity. The benzophenanthridine alkaloid 6 acetonyldihydronitidine (6) revealed cytotoxicity (IC50 1.7 MUg/ml), despite the determined MIC of 6.2-12.5 MUg/ml. In infected macrophages, decarine (1) was able to reduce bacterial survival by almost two log units at a concentration of 6.2 MUg/ml 5 days post-drug exposure. Compound 15 exhibited an intermediate activity at drug concentrations ranging from 6.2 to 25 MUg/ml. CONCLUSIONS: The high antimycobacterial activity of decarine found, both in vitro and ex vivo against mycobacteria, and the low cytotoxicity towards human macrophages indicate that it may be valuable as a lead scaffold for the development of anti-TB drugs. PMID- 23337744 TI - Eleutherine indica L. accelerates in vivo cutaneous wound healing by stimulating Smad-mediated collagen production. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Eleutherine indica L. has been used for healing of wound, painful and irregular menstruation, dysentery and lesions, and topically used as antiseptic and antimicrobial agent in folk medicine. In the present study, methanolic extracts of Eleutherine indica was subjected to scientific investigation for in-vivo cutaneous wound healing in wistar rat. MATERIALS AND METHODS: In-vivo wound healing activity of Eleutherine indica was evaluated by using circular excision experimental models, followed by histopathological and western blot analysis. The healing potential was comparatively assessed with a reference gentamicin sulfate hydrogel (0.01% w/w). Wound contraction measurement, hydroxyproline estimation and western blot for COL3A1, bFGF, Smad-2, -3, -4, and -7 were performed. RESULTS: The methanolic extract of Eleutherine indica showed accelerated wound healing activity as evidenced by fast wound contraction rate and higher hydroxyproline content of granulation tissue. Western blot revealed the Smad-mediated collagen production promoting property of Eleutherine indica methanolic extract. Histopathological examinations also supported the experimental findings. CONCLUSION: The study revealed that Eleutherine indica promotes wound healing by augmenting Smad mediated collagen production in wound granulation tissue. PMID- 23337745 TI - Therapeutic effects of extracts from Radix Toddaliae Asiaticae on collagen induced arthritis in Balb/c mice. AB - AIM OF THE STUDY: Radix Toddaliae Asiaticae (RTA), also named "Sanbaibang", is the dry root bark of Toddalia asiatica (L.) Lam. and has long been used as a traditional ethnic Chinese medicine for its considerable activity to alleviate pain and inflammation for patients suffering from rheumatism. It contains coumarin, alkaloids, triterpenes and volatile oils. Information regarding the anti-arthritis activity of RTA in vivo or in vitro is limited yet. In the present study, the aim is to investigate the therapeutic potential and underlying mechanisms of the ethyl alcohol extract (EtOH) and ethyl acetate fraction (EtOAc) from RTA on collagen II-induced arthritis (CIA) in mice. MATERIALS AND METHODS: CIA animal model was performed by subcutaneous injection of type II bovine collagen (CII) on the 1st day and the 14th day of the experiment. Ethyl alcohol extract (542.8, 271.4, 135.7 mg/kg), ethyl acetate fraction (260.8, 130.4, 65.2 mg/kg) was orally administrated from the second antigen immunization for 3 weeks. Progression of edema of paws and knee joints was measured using a vernier caliper every 3 days from the 10th day after the first injection to the end of the experiment. The spleen index was measured and the knee joint changes were observed by pathological sections. ELISA was used to measure cytokines including tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta), interleukin-6 (IL-6) and interleukin-10 (IL-10) in mice serum according to the manufacturer's instructions. RESULTS: Administration of ethyl alcohol extract and ethyl acetate fraction remarkably reduced paws and joints swelling and decreased the spleen indexes. Histopathological examination demonstrated that RTA effectively protected bone and cartilage of knee joint from erosion, lesion and deformation versus those from the control group. Besides, the concentration of cytokines like TNF-alpha, IL-1beta, IL-6 were significantly lower than the ones from the control group respectively, while cytokine like IL-10 was remarkably higher compare with the control group. CONCLUSION: In this present study, it is demonstrated that administration of RTA has potential and therapeutic effect on CIA. The data suggests that RTA could have a contributory ethno-pharmacological role in improved management of RA patients. PMID- 23337746 TI - Baseline survey of animal trypanosomosis in the region of the Boucle du Mouhoun, Burkina Faso. AB - In view of gathering baseline information about the prevalence of animal trypanosomosis, the Pan African Tsetse and Trypanosomiasis Eradication Campaign (PATTEC) funded a cross sectional survey in the region of the Boucle du Mouhoun which constitutes the Northern limit of the tsetse distribution in Burkina. This cross sectional study was carried out in 53 villages located in the six provinces of the region. A total of 2002 cattle, 1466 small ruminants and 481 donkeys were sampled. This survey showed that about 25% of the cattle had been treated with trypanocidal drugs within 3 months before the survey compared to 3% and 0.42% for the small ruminants and donkeys, respectively. Parasitological prevalence in cattle was low: 0.77% (95% C.I. 0.30-1.95%). No goats and three donkeys were found infected with trypanosomes. Infections were mainly due to Trypanosoma vivax (75.0%) with cases of Trypanosoma congolense (25.0%). In cattle, the serological prevalence of trypanosomosis, for the entire region of the Boucle du Mouhoun, was 34.2% (95% C.I. 26.1-43.4%). For sheep, goats and donkeys, the prevalence were of 20.9% (95% C.I. 12.2-33.5%), 8.5% (95% C.I. 5.7-12.5%) and 5.8% (95% C.I. 3.9 8.6%), respectively. The age and distance to the river were the two main risk factors associated with seropositivity. PMID- 23337747 TI - Dynamics and the mesomorphic properties of a novel antiferroelectric liquid crystalline thiobenzoate MHPSBO10: thermal, optical and dielectric spectroscopy study. AB - The complementary studies of the mesomorphic properties of a novel antiferroelectric liquid crystal (AFLC) (S)-2-octile 4-S-(4'decyloxybiphenyl-4 tiocarboxy)benzoate, known under MHPSBO10 acronym have been undertaken. The polymorphism has been complementary studied in details by Differential Scanning Calorimetry (DSC), Transmitted Light Intensity (TLI) and Polarization Microscopy (POM). The switching characteristics along with multiple macroscopic parameters describing the mesomorphic properties were determined by using electro-optic measurements, both upon cooling and heating. Frequency domain dielectric spectroscopy (DS), covering a wide frequency range, has been applied to characterize the molecular motions. Several collective modes, including the low frequency processes in the condensed hexatic phase were detected, analyzed in details and followed with the temperature. The presented studies deliver a wide report of the phase transitions, molecular dynamics and the macroscopic properties of the novel antiferroelectric thiobenzoate. PMID- 23337748 TI - Nickel(II) complexes with methyl(2-pyridyl)ketone oxime: synthesis, crystal structures and DFT calculations. AB - The synthesis and structural characterization of the three novel nickel(II) complexes [Ni(OOCPh)(2)(mpkoH)(2)] (1), [Ni(NO(3))(2)(mpkoH)(2)] (2) and [Ni(mpkoH)(3)](NO(3))(2).1/2H(2)O (3.1/2H(2)O), with mpkoH=methyl(2 pyridyl)ketone oxime is reported. Geometry optimization and population analyses were performed by means of DFT calculations for the previously mentioned compounds as well as for [NiCl(2)(mpkoH)(2)] (4). Electronic UV-vis spectra were also simulated in the TD-DFT framework to assign the origin of the absorption bands and in doing so, to have a clear picture of the absorptive features of the coordination compounds under investigation. PMID- 23337749 TI - Extracting 3D cell parameters from dense tissue environments: application to the development of the mouse heart. AB - MOTIVATION: In developmental biology, quantitative tools to extract features from fluorescence microscopy images are becoming essential to characterize organ morphogenesis at the cellular level. However, automated image analysis in this context is a challenging task, owing to perturbations induced by the acquisition process, especially in organisms where the tissue is dense and opaque. RESULTS: We propose an automated framework for the segmentation of 3D microscopy images of highly cluttered environments such as developing tissues. The approach is based on a partial differential equation framework that jointly takes advantage of the nuclear and cellular membrane information to enable accurate extraction of nuclei and cells in dense tissues. This framework has been used to study the developing mouse heart, allowing the extraction of quantitative information such as the cell cycle duration; the method also provides qualitative information on cell division and cell polarity through the creation of 3D orientation maps that provide novel insight into tissue organization during organogenesis. PMID- 23337750 TI - Quality of cancer survivorship care in the military health system (TRICARE). AB - PURPOSE: Following the acute phase of treatment, national guidelines recommend cancer survivors have routine contact with health care providers and undergo basic ancillary testing while avoiding high-cost imaging (HCI). We conducted this study to determine how frequently breast, prostate, and colorectal cancer survivors received recommended follow-up care and HCI tests during the survivorship period. METHODS: Using administrative data from TRICARE beneficiaries, we identified a cohort of patients who were treated for breast, prostate, or colorectal cancer between October 2005 and March 2007. These patients were then followed through September 2010. During the 3 years after initial treatment, we determined how frequently survivors received all minimum recommended survivorship care as defined by national guidelines and underwent HCI tests and if these outcomes varied by geographic region. RESULTS: Overall, 3148 patients underwent treatment for breast (n = 1630), prostate (n = 1173), or colorectal (n = 345) cancer. Sixty-five percent received all minimum recommended care over 3 years (breast = 74.1%, prostate = 65.3%, colorectal = 25.5%). During the 3-year period, 74.1% of breast cancer survivors received a mammogram each year, whereas 69.1% of colorectal cancer survivors had at least 1 colonoscopy. Sixty-four percent had at least 1 HCI study during the 3-year period (positron emission tomography = 10.9%, computer tomography = 48.8%, magnetic resonance imaging = 36.6%) at a cost of $3.5 million. Substantial state-level variation was noted for both outcomes. DISCUSSION: Some cancer survivors do not receive recommended care following initial treatment while frequently undergoing HCI. The existing geographic variation in quality and imaging utilization suggests that improvements to cancer survivorship care are possible. PMID- 23337752 TI - From the guest editor: progress in the treatment of advanced prostate: new data and horizons. PMID- 23337753 TI - The changing natural history of metastatic prostate cancer. AB - Since 1941, the understanding of prostate cancer pathogenesis and therapy has undergone a significant transformation. Rigorous translational research has identified multiple mechanisms underlying castration resistance, the fatal clinical state of the disease. Therapeutic approaches targeting these mechanisms in metastatic castration-resistant prostate cancer have now been clinically validated in the clinic including high-potency androgen signaling inhibition, novel cytotoxic chemotherapy, and bone-targeted therapies. Despite these advances, cure remains an elusive goal. The natural history of metastatic prostate cancer has evolved particularly in the last 2 decades in step with improved management of age-associated comorbidities, improved imaging, and the expansion of novel therapies, thus providing new opportunities and challenges. It is also important to note that the advent of prostate-specific antigen testing caused a stage shift in the disease spectrum, thus leading to earlier interventions and potentially positively impacting survival. The optimal sequencing and combinations of available therapies, predictive biomarkers, and better understanding of mechanisms of resistance remain high priority. Further refinement of the clinical niche for novel therapies in hormone-sensitive and castration-resistant disease through rationally designed clinical trials incorporating molecular, clinical, and imaging biomarkers and quality-of-life correlatives is of paramount importance. PMID- 23337751 TI - USP-11 as a predictive and prognostic factor following neoadjuvant therapy in women with breast cancer. AB - PURPOSE: USP-11, a member of the ubiquitin-specific protease family, has emerged as an essential regulator of double-strand break repair. Few studies have shown that silencing USP-11 led to hypersensitivity to poly(ADP-ribose) polymerase inhibition, ionizing radiation, and DNA-damaging agents. We sought to examine the predictive and prognostic relevance of USP-11 in patients treated with neoadjuvant systemic therapy (NST) for breast cancer. METHODS: Fifty-six women who were treated with NST for breast cancer between 1999 and 2004 were included in the study. The Kaplan-Meier product-limit method was used to estimate disease free survival and overall survival rates. Logistic regression models were fit to determine the associations between USP-11 status, pathological complete response (pCR), and survival. RESULTS: Sixteen patients (29%) had high-USP-11-expressing tumors, and 40 (71%) patients had low-USP-11-expressing tumors. No significant differences were observed in pCR rates with respect to USP-11 status. At a median follow-up of 7.4 years, 33 patients (59%) experienced a disease recurrence or death. Patients with high-USP-11-expressing tumors had a higher risk of recurrence (odds ratio [OR], 3.87; 95% confidence interval [CI], 1.51-9.93; P = 0.005) and death (OR, 6.03; 95% CI, 2.00-18.17; P = 0.001) than those with low USP-11-expressing tumors. Patients who did not achieve a pCR had an increased risk of recurrence (OR, 5.16; 95% CI, 1.16-23.07; P = 0.03). CONCLUSIONS: Our data indicate that USP-11 is not a predictor of a pCR after anthracycline-taxane containing NST for breast cancer. Low USP-11 expression was independently correlated with better survival outcomes. PMID- 23337754 TI - Potential predictive biomarkers for individualizing treatment for men with castration-resistant prostate cancer. AB - With the surge in therapeutic options for men with castration-resistant prostate cancer (CRPC) comes increasingly complicated treatment decision making, highlighting the need for biomarkers that can identify appropriate patients for specific treatments and accurately assess disease response. Predictive biomarkers are factors related to the disease or the host that are associated with improvements in outcomes, such as survival, due to specific therapies. Such biomarkers have become of paramount importance in oncology to maximize the benefits of novel systemic agents while minimizing harm to individual patients and the costs to society. Given the number of newly approved and expensive systemic therapies, including novel hormonal therapies, chemotherapies, immunotherapies, and bone microenvironment-targeting therapies, predictive biomarkers are needed to give physicians a more rational sense of matching the right patient to the right therapy sequence at a given time. There are currently no validated predictive biomarkers in CRPC. We discuss potential predictive biomarkers in men with CRPC and how these may be developed in the context of therapeutic clinical trials. PMID- 23337755 TI - Agents that target androgen synthesis in castration-resistant prostate cancer. AB - In April 2011, abiraterone acetate (in combination with low-dose steroids) was approved by the US Food and Drug Administration for the treatment of men with metastatic, castration-resistant prostate cancer who have previously been treated with docetaxel-based chemotherapy. The development of abiraterone was the successful result of an improved understanding of the role of the androgen receptor signaling pathway in castration-resistant prostate cancer. Abiraterone is a rationally designed potent inhibitor of cytochrome P450, family 17, subfamily A, polypeptide 1, which is essential for synthesis of testosterone from nongonadal precursors. More recently, other drugs that act along the androgen0synthesis pathway, such as orteronel (TAK-700) and galeterone (TOK-001), have shown promise in early clinical trials. Here, we review the discovery and clinical development of abiraterone and other novel androgen-synthesis inhibitors for the management of advanced prostate cancer. PMID- 23337756 TI - Androgen receptor antagonists in castration-resistant prostate cancer. AB - Persistent androgen receptor (AR) signaling despite low levels of serum androgens has been identified as a critical target for drug discovery in castration resistant prostate cancer (CRPC). As proof of principle that the AR remains relevant in CRPC, 2 AR-targeted agents recently approved by the Food and Drug Administration-abiraterone and enzalutamide-have increased overall survival for patients with CRPC in the setting of prior chemotherapy. This review focuses on the AR and 2 direct antagonists, enzalutamide and ARN-509. These next-generation AR antagonists offer great promise for patients with advanced disease. Relative to conventional antiandrogens such as bicalutamide, they bind to the receptor with higher affinity, prevent nuclear translocation and DNA binding, and induce apoptosis without agonist activity in preclinical models. The success of these AR targeted agents in the clinic has changed the landscape of therapy for patients with CRPC, and further therapeutic options building on this platform are currently in development. PMID- 23337758 TI - Tubulin-targeted agents including docetaxel and cabazitaxel. AB - Microtubules are dynamic filamentous cytoskeletal proteins that are responsible for cellular integrity and architecture, mitosis, intracellular transport, cell signaling, and gene expression. Tubulin exists in the cell as dimers of alpha and beta subunits, which complexes with a variety of regulatory proteins. There is a dynamic equilibrium between free and polymerized tubulin causing a state called "dynamic instability," which is a target of anticancer drugs, which inhibit tubulin through polymerization (taxanes, epothilones) or depolymerization (vinca alkaloids). Docetaxel-based therapy was the first such treatment to demonstrate a survival benefit in men with castration-resistant prostate cancer. Cabazitaxel, an antitubulin agent, which demonstrates activity in multidrug- and docetaxel resistant cancer cell lines, demonstrates a survival benefit over mitoxantrone and prednisone in patients who have failed docetaxel-based chemotherapy. This article reviews the use of antitubulin agents in patients with castration resistant prostate cancer. PMID- 23337757 TI - Demystifying immunotherapy in prostate cancer: understanding current and future treatment strategies. AB - Immunotherapy has emerged as a viable therapeutic option for patients with prostate cancer. There are multiple potential strategies that use the immune system, including therapeutic cancer vaccines that are designed to stimulate immune cells to target antigens expressed by cancer cells. Sipuleucel-T is a vaccine currently approved for the treatment of minimally symptomatic metastatic prostate cancer, whereas the vaccine PSA-TRICOM and the immune-checkpoint inhibitor ipilimumab are in phase III testing. Although there are no short-term changes in disease progression or available biomarkers to assess response, these agents appear to improve survival. One hypothesis suggests that this apparent paradox can be explained by the growth-moderating effects of these treatments, which do not cause tumor size to diminish, but rather stall or slow their growth rate over time. For this reason, the use of immunotherapy earlier in the disease process is being investigated. Another approach is to block immune-regulatory mechanisms mediated by the molecules cytotoxic T lymphocyte antigen 4 and programmed cell death protein 1. Additional future strategies will combine immunotherapy with other standard therapies, potentially enhancing the latter's clinical impact and thereby improving both time to progression and overall survival due to the combined effects of both treatments. Prospective trials are currently evaluating these hypotheses and will ultimately serve to optimize immunotherapy in the treatment of prostate cancer. PMID- 23337759 TI - Bone targeted therapies in metastatic castration-resistant prostate cancer. AB - Prostate cancer is the most common male cancer. About 90% of metastatic patients will develop bone metastases. Bone disease is responsible of pain, deterioration of quality of life and serious bone complications. Proliferation of prostate cancer cells in the bone marrow induces osteoclast activation and osteolysis. Targeting the bone microenvironment reduces morbidity. Relevant preclinical and clinical studies of bone-targeted therapies in castration-resistant prostate cancer were identified in PubMed and clinical trial databases. Different drugs are available or in development that target bone resorption (bisphosphonates, RANK ligand inhibitors), bone formation (endothelin 1 inhibitors), cancer cell migration (SRC-family kinase inhibitors, vascular endothelial growth factor-MET inhibitors), and survival (radiopharmaceuticals). In phase III trials, zoledronic acid, denosumab, and radium-223 were shown to significantly delay skeletal related events. Radium-223 was also shown to improve overall survival. Biomarkers of bone resorption (urinary N-telopeptide) and bone making (alkaline phosphatase) have an independent prognostic impact. Targeting the bone microenvironment is an important component of castration-resistant prostate cancer management to reduce bone complications and improve overall survival. Biomarkers of bone turnover have an independent prognostic impact. PMID- 23337760 TI - Bone-targeting radiopharmaceuticals including radium-223. AB - Bone-seeking radionuclides including samarium-153 ethylene diamine tetramethylene phosphonate and strontium-89 have been used for decades in the palliation of pain from bone metastases especially from prostate cancer. Emerging evidence of improved survival in metastatic castration-resistant prostate cancer (CRPC) with the first-in-class alpha-radionuclide, radium-223 (Ra) has rekindled interest in the role of bone-seeking radionuclide therapy.We review the literature for randomized controlled trials of bone-seeking radionuclides and explore some of the issues regarding the optimal use of these agents. In particular, we discuss dose, dose rate, radiobiology, and quality of radiation and postulate on potential future directions in particular combination schedules. beta-Emitting, bone-seeking radionuclides have proven ability to control pain in prostate cancer metastatic to bone with pain response rates in the order of 60% to 70% when used as single agents. Most of the published trials were underpowered to detect differences in survival; however, there is evidence of the potential for disease modification when these agents are used in combination with chemotherapy or in multiple cycles.Data from the recent phase III ALSYMPCA trial that compared Ra to placebo in symptomatic CRPC demonstrate a significant improvement in median overall survival of 3.6 months for patients with symptomatic CRPC metastatic to bone treated with 6 cycles of the alpha-emitting radionuclide Ra compared with placebo. The success of Ra in improving survival in CRPC will lead this agent to become part of the treatment paradigm for this disease, and with such an excellent safety profile, Ra has huge potential in combination strategies as well as for use earlier in the natural history of metastatic prostate cancer. PMID- 23337761 TI - Targeting the apoptosis pathway in prostate cancer. AB - Important inroads have been made in the understanding and treatment of metastatic prostate cancer in recent years. However, the need for agents targeting novel pathways remains ever present. One such area with promise is through apoptosis or programmed cell death. Many perturbations within the apoptotic process have been associated with treatment resistance and progression in castration-resistant prostate cancer; thus, therapeutic potential exists with agents that can restore an effective apoptotic response to cellular stressors. This article focuses on agents in clinical development targeting apoptosis through the intrinsic and extrinsic pathways. We review the current status of agents that intervene at the Bcl2 checkpoints, humanized antibodies to death receptors, agents that target the inhibitors of apoptosis proteins, mimetics of small mitochondria-derived activator of caspases, and antisense therapies targeting cytoprotective chaperones. Although single-agent activity has been demonstrated with some of these agents, the clinical development path forward will see them coupled with standard hormonal therapy and chemotherapy. OGX-011 (custirsen), which inhibits expression of the cytoprotective chaperone protein clusterin, is the most mature of these agents and is being tested in combination with chemotherapy in phase III clinical trials for castration-resistant prostate cancer, and results are eagerly awaited. PMID- 23337762 TI - Targeting MET and vascular endothelial growth factor receptor signaling in castration-resistant prostate cancer. AB - Effective management of bone metastases in men with castration-resistant prostate cancer (CRPC) remains an important unmet medical need. MET and vascular endothelial growth factor receptor (VEGFR) are rational targets for intervention in CRPC. Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival. Cabozantinib is an oral multitargeted tyrosine kinase inhibitor that inhibits both MET and VEGFR-2. A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans, bone turnover markers, and pain response, but with significant adverse events leading to dose reduction and treatment discontinuation. Lower doses of cabozantinib retain high levels of activity with less toxicity. Ongoing phase III clinical trials will define the role of cabozantinib in CRPC. We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date. PMID- 23337763 TI - From bevacizumab to tasquinimod: angiogenesis as a therapeutic target in prostate cancer. AB - It was first posited in the 1970s that angiogenesis may prove to be a useful target for anticancer therapies. Since then, a number of agents have been developed and tested across a range of tumor types; however, to date, there have unfortunately been more failures than successes. Prostate cancer (PCa) is no exception in this regard, and despite a strong preclinical rationale for targeting angiogenesis in men with PCa, there has yet to be an antiangiogenic therapy proven to prolong survival in this group of patients. Drugs have been developed to target a host of angiogenesis mediators. These include vascular endothelial growth factor (VEGF), the VEGF receptors, antiangiogenic factors (e.g., thrombospondin-1), and downstream mediators of angiogenesis (e.g., hypoxia inducible factor-1alpha and MET). At present, there are 2 drugs being tested in the phase III setting for men with PCa: cabozantinib and tasquinimod. Cabozantinib, a dual VEGF receptor-2/MET inhibitor, has shown dramatic beneficial effects on radiographically evident bone metastases and pain in the phase II setting. There are currently 2 large phase III trials underway to further investigate cabozantinib's role in treating men with PCa. Both trials randomize subjects to cabozantinib versus mitoxantrone: one is designed to evaluate overall survival, and the other, pain response durability. The other drug, tasquinimod, has a somewhat poorly understood mechanism of action. It is thought to exert an antiangiogenic effect through the inhibition of myeloid-derived suppressor cells, key to the support of an angiogenic environment, and down-regulation of hypoxia inducible factor-1alpha. A phase II trial randomizing men to tasquinimod versus placebo revealed a median progression-free survival advantage in the experimental arm (7.6 vs. 3.3 months with placebo; P = 0.0042). Based on these encouraging phase II results, a randomized, double-blind, placebo-controlled trial in men with metastatic castration-resistant PCa was launched. That trial is powered for a primary endpoint of progression-free survival and is expected to enroll 1200 men. PMID- 23337764 TI - The relationship between specific absorption rate and temperature elevation in anatomically based human body models for plane wave exposure from 30 MHz to 6 GHz. AB - According to the international safety guidelines/standard, the whole-body averaged specific absorption rate (Poljak et al 2003 IEEE Trans. Electromagn. Compat. 45 141-5) and the peak spatial average SAR are used as metrics for human protection from whole-body and localized exposures, respectively. The IEEE standard (IEEE 2006 IEEE C95.1) indicates that the upper boundary frequency, over which the whole-body-averaged SAR is deemed to be the basic restriction, has been reduced from 6 to 3 GHz, because radio-wave energy is absorbed around the body surface when the frequency is increased. However, no quantitative discussion has been provided to support this description especially from the standpoint of temperature elevation. It is of interest to investigate the maximum temperature elevation in addition to the core temperature even for a whole-body exposure. In the present study, using anatomically based human models, we computed the SAR and the temperature elevation for a plane-wave exposure from 30 MHz to 6 GHz, taking into account the thermoregulatory response. As the primary result, we found that the ratio of the core temperature elevation to the whole-body-averaged SAR is almost frequency independent for frequencies below a few gigahertz; the ratio decreases above this frequency. At frequencies higher than a few gigahertz, core temperature elevation for the same whole-body averaged SAR becomes lower due to heat convection from the skin to air. This lower core temperature elevation is attributable to skin temperature elevation caused by the power absorption around the body surface. Then, core temperature elevation even for whole-body averaged SAR of 4 W kg(-1) with the duration of 1 h was at most 0.8 degrees C, which is smaller than a threshold considered in the safety guidelines/standard. Further, the peak 10 g averaged SAR is correlated with the maximum body temperature elevations without extremities and pinna over the frequencies considered. These findings were confirmed for seven models, including models of a child and a pregnant female. Thus, the current basic restriction for whole-body exposure in the international guidelines is conservative. Peak spatial-averaged SAR can be used as a metric for estimating local temperature elevation even for whole-body exposure. Our computational results also support the description in the IEEE standard about the reduction of the upper applicable frequency of whole-body averaged SAR from 6 and 3 GHz; the power density reference level is more conservative than the basic restriction limit for the whole-body averaged SAR from the standpoint of temperature elevation. PMID- 23337765 TI - Biomechanical comparison of an angular stable plate with augmented and non augmented screws in a newly developed shoulder test bench. AB - BACKGROUND: The proximal humeral fracture is one of the most common fractures. Although there are a number of treatment options available, the clinical outcomes in geriatric patients are still unsatisfactory. Therefore, the aim of this study was to investigate the biomechanical behaviour of an angular stable plate with either augmented or non-augmented screws using two different fracture models in a shoulder test bench with active muscle forces. METHODS: Six paired fresh-frozen humeri were loaded into a shoulder test bench simulating ab- and adduction between 15 and 45 degrees induced by active muscle forces. The bone mineral density was measured by a quantitative CT. A two-part fracture model (stable and an unstable) was used to investigate the different biomechanical behaviours of the PHILOS plate, either utilising cannulated screws, allowing in situ augmentation, or without utilising augmented screws. Four screws were augmented with 0.5ml PMMA cement. FINDINGS: The in vitro-measured resulting forces in the glenoid fossa were comparable to the in vivo forces generated in shoulder arthroplasties. Under stable conditions, the per cycle motion and varus impaction tilting showed no significant difference. In the unstable state, the augmented group showed a maximum of 0.81 degrees per cycle motion and a maximum varus impaction of -1.46 degrees compared to the non-augmented maximum of 2.31 degrees per cycle motion and maximum varus impaction of -4.26 degrees (P<0.05). INTERPRETATION: In an unstable fracture model under dynamic testing conditions, augmentation leads to a decreased per cycle motion and varus impaction of the humeral head. PMID- 23337766 TI - Temporal structure of variability decreases in upper extremity movements post stroke. AB - BACKGROUND: The objective of this study was to determine movement variability in the more-affected upper-extremity in chronic stroke survivors. We investigated two hypotheses: (1) individuals with stroke will have increased amount of variability and altered structure of variability in upper-extremity joint movement patterns as compared to age-matched controls; and (2) the degree of motor impairment and joint kinematics will be correlated with the temporal structure of variability. METHODS: Sixteen participants with chronic stroke and nine age-matched controls performed three trials of functional reach-to-grasp. The amount of variability was quantified by computing the standard deviation of shoulder, elbow, wrist and index finger flexion/extension joint angles. The temporal structure of variability was determined by calculating approximate entropy in shoulder, elbow, wrist and index finger flexion/extension joint angles. FINDINGS: Individuals with stroke demonstrated greater standard deviations and significantly reduced approximate entropy values as compared to controls. Furthermore, motor impairments and kinematics demonstrated moderate to strong correlations with temporal structure of variability. INTERPRETATION: Changes in the temporal structure of variability in upper-extremity joint angles suggest that movement patterns used by stroke survivors are less adaptable. This knowledge may yield additional insights into the impaired motor system and suggest better interventions that can enhance upper-extremity movement adaptability. PMID- 23337767 TI - In vitro biomechanical study of femoral torsion disorders: effect on moment arms of thigh muscles. AB - BACKGROUND: Lower limb torsion disorders have been considered as a factor inducing gonarthrosis and the three-dimensional effect of the surgical correction is not well reported yet. This paper reports an in vitro study aiming at quantifying the relationships between experimental femoral torsion disorders and moment arms of thigh muscles. METHODS: Five unembalmed lower limbs were used and fixed on an experimental jig. Muscles were loaded and 6 Linear Variable Differential Transformers were used to measure tendon excursions. Experimental osteotomies were performed to simulate torsions by steps of 6 degrees up to 18 degrees . Moment arms of the main thigh muscles were estimated by the tendon excursion method during knee flexion. FINDINGS: Moment arms of the tensor of fascia latae, the gracilis and the semitendinosus were significantly influenced by experimental conditions while the rectus femoris, the biceps femoris and the semimembranosus did not show modifications. Medial femoral torsion decreased the moment arm of both the gracilis and the semimembranosus. Opposite changes were observed during lateral femoral torsion. The moment arm of the tensor of fascia latae decreased significantly after 30 degrees of knee flexion for 18 degrees of medial femoral torsion. INTERPRETATION: Our results showed that medial and lateral femoral torsion disorders induced alterations of the moment arms of the muscles located medially to the knee joint when applied in aligned lower limbs. These results highlight a potential clinical relevance of the effect of femoral torsion alterations on moment arms of muscles of the thigh which may be related, with knee kinematics modifications, to the development of long-term knee disease. PMID- 23337768 TI - A de novo 17q21.2 duplication in a boy with developmental delay and dysmorphic features. AB - We report a boy with severe developmental delay, microcephaly and characteristic facial dysmorphism consisting in round face, hypertelorism, upslanted palpebral fissures, small nose, large mouth, micrognathia, sparse hair and eyelashes. Array CGH revealed a de novo duplication of 103 kb within 17q21.2 not reported to date. The duplication includes 8 genes: DHX58, KAT2A, HSPB9, RAB5C, KCNH4, HCRT, GHDC and STAT5B. Three genes (KATA2, KCNH4, and STAT5B) may contribute to intellectual deficiency. Further observations will be necessary to confirm the specificity of the facial Gestalt. PMID- 23337769 TI - N6-methyl-adenosine modification in messenger and long non-coding RNA. AB - N6-methyl-adenosine (m(6)A) is the most abundant modification in mammalian mRNA and long non-coding RNA. First discovered in the 1970s, m(6)A modification has been proposed to function in mRNA splicing, export, stability, and immune tolerance. Interest and excitement in m(6)A modification has recently been revived based on the discovery of a mammalian enzyme that removes m(6)A and the application of deep sequencing to localize modification sites. The m(6)A demethylase fat mass and obesity associated protein (FTO) controls cellular energy homeostasis and is the first enzyme discovered that reverses an RNA modification. m(6)A Sequencing demonstrates cell-type- and cell-state-dependent m(6)A patterns, indicating that m(6)A modifications are highly regulated. This review describes the current knowledge of mammalian m(6)A modifications and future perspectives on how to push the field forward. PMID- 23337770 TI - Reporting weight change: standardized reporting accounting for baseline weight. AB - BACKGROUND: Although it is recognized that a standardized approach to reporting weight change is essential to meaningful comparisons among cohorts and across studies, consensus is lacking. This study aimed to propose a method of reporting weight change that would allow meaningful comparisons among studies of patients who underwent bariatric surgery and to demonstrate its utility using an example from the Longitudinal Assessment of Bariatric Surgery (LABS). METHODS: Relationships among several measures of weight change are described. Results from an observational, longitudinal cohort study of adults undergoing bariatric surgery and from simulation studies are used to illustrate the proposed method. RESULTS: Baseline weight is a critical parameter when assessing weight change. Men undergoing a bariatric procedure other than gastric bypass or adjustable band tended to have greater weight loss 12 months after surgery than men undergoing gastric bypass when not accounting for baseline weight, but the opposite was found when results were adjusted for baseline weight. Simulation results show that with relatively modest sample sizes, the adjusted weight loss was significantly different between the 2 groups of men. CONCLUSION: A consistent metric for reporting weight loss after bariatric surgery is essential to interpret outcomes across studies and among subgroups. The baseline weight adjusted percent of weight loss (A%WL) uses a standard population (e.g., the LABS cohort) to account for differences between cohorts with respect to baseline weight, and its use can change the interpretation of results compared with an unadjusted measure. PMID- 23337771 TI - A structural perspective of the MAVS-regulatory mechanism on the mitochondrial outer membrane using bioluminescence resonance energy transfer. AB - In most eukaryotic cells, mitochondria have various essential roles for proper cell function, such as energy production, and in mammals mitochondria also act as a platform for antiviral innate immunity. Mitochondrial-mediated antiviral immunity depends on the activation of the cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) signaling pathway, and on the participation of mitochondrial antiviral signaling (MAVS), which is localized on the mitochondrial outer membrane. After RNA virus infection, RLRs translocate to the mitochondrial surface to interact with MAVS, and the adaptor protein undergoes a conformational change that is essential for downstream signaling, although its structural features are poorly understood. Here we examined the MAVS-regulatory mechanism on the mitochondrial outer membrane using bioluminescence resonance energy transfer (BRET) in live cells. Using a combination of BRET and functional analysis, we found that the activated MAVS conformation is a highly ordered oligomer, at least more than three molecules per complex unit on the membrane. Hepatitis C virus NS3/4A protease and mitofusin 2, which are known MAVS inhibitors, interfere with MAVS homotypic oligomerization in a distinct manner, each differentially altering the active conformation of MAVS. Our results reveal structural features underlying the precise regulation of MAVS signaling on the mitochondrial outer membrane, and may provide insight into other signaling systems involving organelles. PMID- 23337772 TI - Glucagon and GLP-1 inhibit food intake and increase c-fos expression in similar appetite regulating centres in the brainstem and amygdala. AB - BACKGROUND: Glucagon and glucagon-like peptide-1 (GLP-1) are evolutionarily related anorectic hormones. Glucagon also increases energy expenditure. The combination of glucagon and GLP-1 could cause weight loss through a simultaneous reduction in food intake and increased energy expenditure. However, the effect of combined administration of glucagon and GLP-1 on food intake and neuronal activation has not previously been studied. Furthermore, the effect of glucagon on neuronal activation in appetite regulating centres has not been assessed. Characterisation of the effects of glucagon when administered singly and in combination with GLP-1 on neuronal activation will be important for determining the mechanism of action of related potential antiobesity therapies. OBJECTIVES: To investigate the effects of peripherally administered GLP-1 and glucagon on food intake, neuronal activation and blood glucose in mice when administered individually and in combination. METHODOLOGY: Food intake, blood glucose and c fos expression in the hypothalamus, amygdala and brainstem were measured in response to GLP-1 and glucagon, alone and in combination. RESULTS: Peripherally administered GLP-1 and glucagon decreased food intake and increased c-fos expression in the brainstem and amygdala. Doses of GLP-1 and glucagon that individually did not significantly affect feeding, in combination were anorectic and stimulated neuronal activation in the area postrema (AP) and central nucleus of the amygdala. Combined administration of GLP-1 and glucagon prevented the acute hyperglycemic effect of glucagon alone. CONCLUSION: Anorectic doses of glucagon and GLP-1 induced similar patterns of c-fos expression. Combined administration of low dose GLP-1 and glucagon inhibited food intake and induced c fos expression in the AP and amygdala. The combination of both hormones may offer the opportunity to utilise the beneficial effects of reduced food intake and increased energy expenditure, and may therefore be a potential treatment for obesity. PMID- 23337773 TI - The Rho-kinase inhibitor fasudil restores normal motor nerve conduction velocity in diabetic rats by assuring the proper localization of adhesion-related molecules in myelinating Schwann cells. AB - The Rho/Rho-kinase signaling pathway has been shown to be involved in the complications of diabetes. In this study, we found that fasudil, a specific Rho kinase inhibitor, had a beneficial effect on the motor nerve conduction velocity (MNCV), which is delayed in rats with streptozotocin (STZ)-induced diabetes. Cadherin-dependent adherens junctions (AJs) in myelinating Schwann cells, necessary for proper myelin formation and rapid propagation of action potentials, are regulated by Rho/Rho-kinase signaling. These AJ structures are maintained by E-cadherin and catenin complexes such as beta-catenin and p120 catenin. To elucidate the mechanism underlying the effect of fasudil on MNCV, we examined alterations in AJ structure in the peripheral nerves of the experimental rats. Our results showed that the activities of Rho and Rho-kinase increased simultaneously in the sciatic nerves of the diabetic rats. Fasudil restored the MNCV by suppressing the up-regulation of the Rho-kinase. In the diabetic state, enhanced Rho and Rho-kinase activity reduced p120 catenin expression and altered the distribution of p120 catenin and E-cadherin, which are normally localized in the paranodal compartment of the nodes of Ranvier and Schmidt-Lanterman incisures where autotypic AJs stabilize myelin structure. Fasudil restored normal p120 catenin expression and the distribution of p120 catenin and E-cadherin in the myelin sheath. In conclusion, reduced expression and altered distribution of the adhesion molecules in the myelin sheath might contribute to the slowing of the MNCV in the diabetic rats. Fasudil, through its effect on the distribution of the adhesion-related molecules, might prevent slowing of the MNCV. PMID- 23337775 TI - Reply by author. PMID- 23337774 TI - Soft templating strategies for the synthesis of mesoporous materials: inorganic, organic-inorganic hybrid and purely organic solids. AB - With the discovery of MCM-41 by Mobil researchers in 1992 the journey of the research on mesoporous materials started and in the 21st century this area of scientific investigation have extended into numerous branches, many of which contribute significantly in emerging areas like catalysis, energy, environment and biomedical research. As a consequence thousands of publications came out in large varieties of national and international journals. In this review, we have tried to summarize the published works on various synthetic pathways and formation mechanisms of different mesoporous materials viz. inorganic, organic inorganic hybrid and purely organic solids via soft templating pathways. Generation of nanoscale porosity in a solid material usually requires participation of organic template (more specifically surfactants and their supramolecular assemblies) called structure-directing agent (SDA) in the bottom up chemical reaction process. Different techniques employed for the syntheses of inorganic mesoporous solids, like silicas, metal doped silicas, transition and non-transition metal oxides, mixed oxides, metallophosphates, organic-inorganic hybrids as well as purely organic mesoporous materials like carbons, polymers etc. using surfactants are depicted schematically and elaborately in this paper. Moreover, some of the frontline applications of these mesoporous solids, which are directly related to their functionality, composition and surface properties are discussed at the appropriate places. PMID- 23337776 TI - Reply by authors. PMID- 23337778 TI - Characteristics of cardiac aging in C57BL/6 mice. AB - The specific processes that cause aging of the cardiac tissue remain elusive. C57BL/6 (B6) mice are commonly used for investigating age-related diseases in mammals. We thus sought to evaluate the cardiac aging process in B6 mice. Cardiac tissues from the newborn (B6 NB), 2month-old (B6 2M) and 21-27month-old B6 mice (B6 aged) were used for the investigation. Several age-related cellular processes were evaluated, including telomere shortening, changes in p53 and p16 expression, changes in mitochondria DNA expression and DNA deletion, and alteration of mitochondria. We found that the aging of the B6 mice cardiac tissue is associated with the maintenance of telomere length, increased expression of p53 and p16, mild changes in mitochondrial DNA expression but widespread DNA deletion, and significant alterations of the mitochondrial ultrastructure within the cardiac tissue. The results of our studies suggest that mitochondrial DNA deletions, which affect the mitochondrial ultrastructure, cytochrome C oxidase activity, and p53 expression, are significantly associated with cardiac aging and may be a source of age-related heart failure. PMID- 23337777 TI - Autophagy and leucine promote chronological longevity and respiration proficiency during calorie restriction in yeast. AB - We have previously shown that autophagy is required for chronological longevity in the budding yeast Saccharomyces cerevisiae. Here we examine the requirements for autophagy during extension of chronological life span (CLS) by calorie restriction (CR). We find that autophagy is upregulated by two CR interventions that extend CLS: water wash CR and low glucose CR. Autophagy is required for full extension of CLS during water wash CR under all growth conditions tested. In contrast, autophagy was not uniformly required for full extension of CLS during low glucose CR, depending on the atg allele and strain genetic background. Leucine status influenced CLS during CR. Eliminating the leucine requirement in yeast strains or adding supplemental leucine to growth media extended CLS during CR. In addition, we observed that both water wash and low glucose CR promote mitochondrial respiration proficiency during aging of autophagy-deficient yeast. In general, the extension of CLS by water wash or low glucose CR was inversely related to respiration deficiency in autophagy-deficient cells. Also, autophagy is required for full extension of CLS under non-CR conditions in buffered media, suggesting that extension of CLS during CR is not solely due to reduced medium acidity. Thus, our findings show that autophagy is: (1) induced by CR, (2) required for full extension of CLS by CR in most cases (depending on atg allele, strain, and leucine availability) and, (3) promotes mitochondrial respiration proficiency during aging under CR conditions. PMID- 23337779 TI - [Anesthesia for craniotomy in the conscious patient]. AB - Craniotomy in the conscious patient (CPC) enables the neurological changes to be assessed during the mapping in epilepsy surgery, the location of the electrodes during deep brain stimulation surgery, and tumor resection in eloquent areas of the brain. CPC is a useful technique for radical surgery in order to minimize the damage to the functional areas of the brain. The anesthesiologist must ensure, adequate patient comfort, analgesia and ensure optimal collaboration. The appropriate selection of potential candidates for CPC should be made jointly with all professionals involved in the case. Knowledge of the different phases of CPC, coordination and communication among specialists, the right management of the pharmacology, and anesthetic techniques specific to CPC, along with the ability of psycho-emotional communication with the patient, determine the success of the procedure to be performed in the culture of patient safety. The aim of this review was to describe the anesthetic management, comprehensive considerations, and intraoperative neurophysiological tests for CPC. PMID- 23337780 TI - Optimal cutoff of polypharmacy and outcomes. PMID- 23337781 TI - Testing a tool for assessing the risk of bias for nonrandomized studies showed moderate reliability and promising validity. AB - OBJECTIVES: To develop and validate a new risk-of-bias tool for nonrandomized studies (NRSs). STUDY DESIGN AND SETTING: We developed the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS). A validation process with 39 NRSs examined the reliability (interrater agreement), validity (the degree of correlation between the overall assessments of RoBANS and Methodological Index for Nonrandomized Studies [MINORS], obtained by plotting the overall risk of bias relative to effect size and funding source), face validity with eight experts, and completion time for the RoBANS approach. RESULTS: RoBANS contains six domains: the selection of participants, confounding variables, the measurement of exposure, the blinding of the outcome assessments, incomplete outcome data, and selective outcome reporting. The interrater agreement of the RoBANS tool except the measurement of exposure and selective outcome reporting domains ranged from fair to substantial. There was a moderate correlation between the overall risks of bias determined using RoBANS and MINORS. The observed differences in effect sizes and funding sources among the assessed studies were not correlated with the overall risk of bias in these studies. The mean time required to complete RoBANS was approximately 10 min. The external experts who were interviewed evaluated RoBANS as a "fair" assessment tool. CONCLUSIONS: RoBANS shows moderate reliability, promising feasibility, and validity. The further refinement of this tool and larger validation studies are required. PMID- 23337782 TI - About half of the noninferiority trials tested superior treatments: a trial register based study. AB - OBJECTIVES: A concern that noninferiority (NI) trials pose a risk of degradation of the treatment effects is prevalent. Thus, we aimed to determine the fraction of positive true effects (superiority rate) and the average true effect of current NI trials based on data from registered NI trials. STUDY DESIGN AND SETTING: All NI trials carried out between 2000 and 2007 analyzing the NI of efficacy as the primary objective and registered in one of the two major clinical trials registers were studied. Having retrieved results from these trials, random effects modeling of the effect estimates was performed to determine the distribution of true effects. RESULTS: Effect estimates were available for 79 of 99 eligible trials identified. For trials with binary outcome, we estimated a superiority rate of 49% (95% confidence interval = 27-70%) and a mean true log odds ratio of -0.005 (-0.112, 0.102). For trials with continuous outcome, the superiority rate was 58% (41-74%) and the mean true effect as Cohen's d of 0.06 ( 0.064, 0.192). CONCLUSIONS: The unanticipated finding of a positive average true effect and superiority of the new treatment in most NI trials suggest that the current practice of choosing NI designs in clinical trials makes degradation on average unlikely. However, the distribution of true treatment effects demonstrates that, in some NI trials, the new treatment is distinctly inferior. PMID- 23337783 TI - Medication initiation rates are not directly comparable across secondary fracture prevention programs: reporting standards based on a systematic review. AB - OBJECTIVE: To examine the methods used to calculate the reported medication initiation rates in secondary fracture prevention programs. STUDY DESIGN AND SETTING: A systematic review was conducted on postfracture interventions that aimed to improve osteoporosis management in an orthopedic environment. Two authors independently reviewed eligible articles to determine the numerator and denominator used to calculate the rates of antiresorptive medication initiation based on author reports. In interventions with numerator and denominator combinations that appeared to be comparable, we examined the inclusion and exclusion criteria to confirm comparability. RESULTS: Fifty-seven articles reporting on 64 interventions were eligible for the review. A total of 28 different combinations of numerators and denominators to calculate rates were reported for medication initiation across 49 of the 64 interventions. After examining the inclusion and exclusion criteria for rates that appeared to be comparable, the highest number of interventions with a comparable rate was 3. CONCLUSION: Reporting processes for antiresorptive medication initiation outcomes in secondary fracture prevention programs used heterogeneous standards that prevented useful comparison of programs. Applying different numerator and denominator combinations meant that the same observed number of patients could have resulted in different reported rates. We propose standards for reporting medication initiation rates in such programs. PMID- 23337784 TI - Optimal cutoff of polypharmacy and outcomes - reply. PMID- 23337785 TI - Many scenarios exist for selective inclusion and reporting of results in randomized trials and systematic reviews. AB - OBJECTIVE: To collate and categorize the ways in which selective inclusion and reporting can occur in randomized controlled trials (RCTs) and systematic reviews. STUDY DESIGN AND SETTING: Searches of the Cochrane Methodology Register, PubMed, and PsycInfo were conducted in April 2011. Methodological reports describing empirically investigated or hypothetical examples of selective inclusion or reporting were eligible for inclusion. Examples were extracted from the reports by one author and categorized by three authors independently. Discrepancies in categorization were resolved via discussion. RESULTS: Two hundred ninety reports were included. The majority were empirical method studies (45.5%) or commentaries (29.3%). Eight categories (30 examples) of selective reporting in RCTs, eight categories (27 examples) of selective inclusion in systematic reviews, and eight categories (33 examples) of selective reporting in systematic reviews were collated. Broadly, these describe scenarios in which multiple outcomes or multiple data for the same outcome are available, yet only a subset is included or reported; outcome data are reported with inadequate detail; or outcome data are given different prominence through its placement across or within reports. CONCLUSION: An extensive list of examples of selective inclusion and reporting was collated. Increasing trialists' and systematic reviewers' awareness of these examples may minimize their occurrence. PMID- 23337787 TI - Quantitative proteomic study identified cathepsin B associated with doxorubicin induced damage in H9c2 cardiomyocytes. AB - The study was performed to analyze the proteomic profiling of doxorubicin-treated H9c2 cardiomyocytes in order to identify novel protein biomarkers associated with doxorubicin-induced cardiomyopathy. The protein profiling of H9c2 cells in response to doxorubicin at an apoptosis-induced concentration of 0.5 MUM were compared using iTRAQ analysis. Western-blot analysis was used to confirm differentially expressed proteins identified in the proteomic study. A total of 22 differently expressed proteins were identified in doxorubicin-treated H9c2 cells including 15 up-regulated and 7 down-regulated proteins. Gene Ontology (GO) analysis revealed that 10 altered proteins were enriched in the process of apoptosis. We further validated the expression of cathepsin B and its possible regulator nuclear factor kappa B (NF-kappaB) in H9c2 cells were increased during doxorubicin treatment using Western-blots. Differentially expressed proteins might provide clues to clarify novel mechanisms underlying doxorubicin-induced cardiomyopathy. Our results also suggest that increased cathepsin B expression might be associated with NF-kappaB up-regulation, and the exact mechanisms need to be clarified. PMID- 23337788 TI - Prevalence and correlates of alcohol use and subsequent sexual activity among adult males in a rural community of ethnic minorities in Yunnan Province, China. AB - This community-based cross-sectional study examined alcohol use and HIV risks among a sample of predominantly ethnic males in Yunnan Province, China. Information about alcohol use, sexual behavior, sex after drinking, and HIV infection was collected using face-to-face interviews and blood testing. Out of 497 potential male participants, 382 males agreed to participate in this study. Of these males, 70% were ethnic minorities, 74.1% were currently married, 95.5% were sexually experienced, 27.5% had used drugs, and 6% were HIV-infected. Over 81% were current drinkers and 55.7% started drinking before the age of 18. Among current drinkers, 44.5% drank daily and 31.9% had drunk heavily in the past 30 days. Baijiu (a Chinese liquor distilled from sorghum with an ethanol content of at least 40%) was the preferred drink of choice. Excessive alcohol use was associated with being an ethnic Jingpo (OR = 1.96), being a smoker (OR = 2.09) and having multiple lifetime sex partners (OR = 1.55). Over 21% reported having ever engaged in sex after drinking. Those who were aged 26 to 35 (OR = 3.80), started drinking before age 18 (OR = 2.14), who were heavy drinkers (OR = 1.99), or who had ever used drugs (OR = 2.00) were more likely to have ever engaged in sex after drinking. Health education programs for alcohol abuse and unwanted outcomes, particularly the risk of HIV, are urgently needed for ethnic males in Yunnan. PMID- 23337789 TI - A cross-sectional study of sputum handling by and supervision of patients with pulmonary tuberculosis treated at home in China. AB - Disposal of sputum from patients with pulmonary tuberculosis (TB) who are treated at home is an important aspect of preventing the spread of TB. However, few studies have examined disposal of sputum by patients with TB who are treated at home. Patients with pulmonary TB who are treated at home were surveyed regarding sputum handling and supervision. A cross-sectional survey of a representative sample of patients with pulmonary TB who are treated at home was conducted in Shandong Province. Participants were individuals with TB who had been registered with a local agency responsible for TB control. Participants completed a questionnaire with both qualitative and quantitative questions. How sputum was handled was determined and factors associated with sputum disposal were analyzed using a non-parametric test, logistic regression, and content analysis. Responses were received from 720 participants. Patients expectorated sputum 4.56 +/- 10.367 times a day, and 68.6% of patients responded that they correctly disposed of their sputum. Supervision as part of TB control focused on the efforts of health agencies and paid little attention to waste management by patients. A non parametric test showed that sputum disposal was significantly associated with gender, age, education, sputum smear results, attitudes toward waste management, and attitudes toward supervision (all p < 0.05). Logistic regression analysis showed that gender (OR = 0.482, 95% CI: 0.329-0.704), sputum smear results (OR = 1.300, 95% CI: 1.037-1.629), and level of education (OR = 0.685, 95% CI: 0.528 0.889) were associated with receipt of TB health education (all p < 0.05). Sputum handling by and supervision of patients with pulmonary TB who are treated at home is severely wanting. From a policy perspective, special attention should be given to the definition, details, and methods of supervision of waste management by patients with TB to give them relevant health education and enhance their willingness to be supervised. A financial incentive should be provided to health workers supervising management of TB-related waste. PMID- 23337786 TI - Substrate specificity and reaction mechanism of purified alkane hydroxylase from the hydrocarbonoclastic bacterium Alcanivorax borkumensis (AbAlkB). AB - An alkane hydroxylase from the marine organism Alcanivorax borkumensis (AbAlkB) was purified. The purified protein retained high activity in an assay with purified rubredoxin (AlkG), purified maize ferredoxin reductase, NADPH, and selected substrates. The reaction mechanism of the purified protein was probed using the radical clock substrates bicyclo[4.1.0]heptane (norcarane), bicyclo[3.1.0]hexane (bicyclohexane), methylphenylcyclopropane and deuterated and non-deuterated cyclohexane. The distribution of products from the radical clock substrates supports the hypothesis that purified AbAlkB hydroxylates substrates by forming a substrate radical. Experiments with deuterated cyclohexane indicate that the rate-determining step has a significant CH bond breaking character. The products formed from a number of differently shaped and sized substrates were characterized to determine the active site constraints of this AlkB. AbAlkB can catalyze the hydroxylation of a large number of aromatic compounds and linear and cyclic alkanes. It does not catalyze the hydroxylation of alkanes with a chain length longer than 15 carbons, nor does it hydroxylate sterically hindered C-H bonds. PMID- 23337790 TI - Effects of two monoclonal antibodies, MLS128 against Tn-antigen and 1H7 against insulin-like growth factor-I receptor, on the growth of colon cancer cells. AB - MLS128 is an anti-carbohydrate monoclonal antibody (mAb) that binds three or two consecutive Tn-antigens. MLS128 bound 110-210 kDa glycoproteins (GPs) and inhibited the growth of LS180 and HT29 colon and MCF-7 breast cancer cells. One possible mechanism of MLS128's inhibition of growth may be via insulin-like growth factor-I receptor (IGF-IR) down-regulation (Morita et al. BioScience Trends. 2009; 3:32-37). The current study examined the role of IGF-IR signaling in the growth of colon cancer cells and its possible interaction with MLS128 induced inhibition of cell growth in LS180, LS174T, and HT29 human colon cancer cells treated with MLS128 or anti-IGF-IR 1H7. Both MLS128 and 1H7 treatment significantly inhibited the growth of colon cancer cells. All three colon cancer cell lines expressed IGF-IR. Their growth was in part IGF-I dependent, but inhibition by MLS128 was independent of IGF-IR signaling. All of the colon cancer cell lines expressed an 110kDa GP for MLS128 binding, but MCF-7 cells expressed MLS128-detectable bands with higher molecular masses. 1H7 treatments caused down regulation of IGF-IR but did not affect 110kDa GP levels. MLS128 treatments resulted in partial disappearance of the 110kDa band but did not affect IGF-IR levels. Western blotting analyses of colon and breast cancer cell lysates revealed that colon and breast cancer cells differed significantly in patterns of expression of growth-related molecules while colon cancer cells were similar but distinctive. In conclusion, MLS128 inhibited the growth of colon cancer cells by binding to the 110kDa GP receptor. Inhibition of growth by MLS128 did not appear to affect IGF-IR signaling and instead only affected other growth signaling pathways. PMID- 23337791 TI - Effect of mild hypothermia on breast cancer cells adhesion and migration. AB - To explore the effect of mild hypothermia (35oC) on breast cancer cells adhesion to vascular endothelial cells, a parallel plant flow chamber was used to observe the adhesion of human breast cancer cells MDA-MB-231 to endothelial cells Eahy926 under physiological flow at 35oC and 37oC, as well as the role of intercellular adhesion molecule 1 (ICAM-1) in this process. Further, the effect of mild hypothermia (35oC) on migration of MDA-MB-231 was also studied. Our results show that mild hypothermia can inhibit the adhesion of tumor cells to endothelial cells and ICAM-1 plays an important role in this process. However, mild hypothermia inhibits breast cancer cell adhesion in a way independent on the change of ICAM-1 expression under our experimental conditions. Mild hypothermia can weaken the chemotaxis of breast cancer cells while it has no obvious effect on unidirectonal migration capacity. These results suggest that mild hypothermia could be used as a potentially adjunct treatment combined with surgery to decrease tumor cell adhesion and migration. PMID- 23337792 TI - Pioglitazone attenuates myocardial ischemia-reperfusion injury via up-regulation of ERK and COX-2. AB - Our previous study demonstrated that the peroxisome proliferator-activated receptor (PPAR) gamma agonist, pioglitazone (PIO), may be cardioprotective against ischemia-reperfusion injury; however, modulation of p42/p44 extracellular signal-regulated kinases (ERK1/2) and cyclooxygenase (COX)-2 by PIO in the myocardium with respect to ischemia-reperfusion (I/R) is only partially understood. We determined if PIO reduces I/R-induced apoptosis in cardiomyocytes, and whether or not this protective effect is due to modulation of ERK1/2 and COX 2. Sixty male Sprague-Dawley rats were randomized and assigned to 1 of 6 groups: I/R; I/R + PIO (5 mg*kg(-1)*day(-1)); I/R + PIO (10 mg*kg(-1)*day(-1)); I/R + PIO (10 mg*kg(-1)*day(-1)) + the ERK1/2 inhibitor, PD98059; I/R + PIO ( 10 mg*kg( 1)*day(-1)) + GW9662;and I/R + PD98059. Rats underwent 30 min of myocardial ischemia and 120 min of reperfusion, and then hearts were harvested for analysis. RT-PCR and Western blotting were performed to detect expression of ERK1/2 and COX 2. The number of TUNEL-positive cardiomyocytes and NEC in the PIO groups (5 and 10 mg*kg(-1)*day(-1)) was much lower than the I/R group. The cardioprotective effect of PIO was abrogated by PD98059 and GW9662. Phosphorylation of ERK1/2 and COX-2 was increased in the PIO-treated group compared with the I/R group. GW9662 reversed the expression of ERK1/2 and COX- 2 phosphorylation induced by PIO. PD98059 reversed the expression of COX-2 induced by PIO. PIO was shown to be cardioprotective in an I/R injury model in rats via inhibition of cardiomyocyte apoptosis. PIO limited the infarct size in a PPAR-gamma-dependent manner. These results show that PIO triggers the MAPK signaling pathway involving ERK1/2 using COX-2 as the downstream target. PMID- 23337793 TI - An eligible biological allograft patch in tension-free herniorrhaphy of swine. AB - Current patches made from macromolecular compounds or composix for tension-free herniorrhaphy are still unsatisfactory in biocompatibility. The ideal patch should be a biological patch with good biocompatibility. Herein allograft patches modified by tissue engineering were used in tension-free herniorrhaphy of swines. Tough membrane tissues from swine were modified with patented tissue engineering techniques to develop allograft patches for tension-free herniorrhaphy. Histological, and physical tests of the allograft patch were performed subsequently, which revealed that the allograft patch was sufficient and satisfactory for tension-free herniorrhaphy. The allograft patches were next used in tension-free herniorrhaphy of abdominal external hernia models of swines and compared to polypropylene patches. Serous CD4+, CD8+ T cells, interleukin-1beta (IL-1beta), and tumor necrosis factor alpha (TNF-alpha) were determined preoperatively and postoperatively. Local pathological changes were recorded postoperatively in swines. In vivo application of the allograft patches revealed that there were no significant serous cellular immune responses in swines, and inflammation induced by allograft patches was significantly lower compared to polypropylene patches, the allograft patches gradually degenerated and new collagen fibers appeared. Abdominal external hernias were cured with allograft patches and without relapse. The modified allograft patch with satisfactory biocompatibility was eligible and sufficient in tension-free herniorrhaphy of swine. Clinical trials should be performed for further evaluation of the allograft patch. PMID- 23337794 TI - Proposed interaction between angiotensinogen and retinoblastoma tumor suppressor protein: Potential molecular origin of hypertension. AB - Hypertension ranks among the most important disease challenges on a global scale. Here, a novel hypothesis is presented which implicates angiotensinogen, i.e. the precursor protein for the hypertensive peptide angiotensin II, as a key culprit in the pathogenesis of hypertension. This hypothesis more precisely entails that intracellular angiotensinogen binds and thereby inactivates the retinoblastoma tumor suppressor protein (RB), consequently leading to an inflammatory and hyperproliferative state that significantly contributes to pathologically increasing blood pressure. Accordingly, a conceivable antihypertensive strategy could comprise RB-derived compounds that neutralize angiotensinogen. PMID- 23337795 TI - [Exercise-induced renal ischemia after kidney transplantation: report of two cases]. AB - INTRODUCTION: Renal transplant patients are high cardiovascular risk patients. Regular ultrasound surveillance of the renal transplant artery and the iliac artery upstream from the anastomosis is required to detect potential arterial stenosis. The purpose of this article was to illustrate the hemodynamic impact of exercise in such patients and the screening efficiency of Doppler ultrasound stress testing. METHODS: Two renal transplant patients were hospitalized in our center for impaired renal function, worsening hypertension, and intermittent claudication. This association of peripheral vascular disease and renal dysfunction led us to perform a Doppler ultrasound stress test to search for vascular stenosis upstream from the graft. Hemodynamic fluctuations in the ipsilateral leg were recorded during flexion-extension exercises. RESULTS: Iliac artery lesions were found in both patients: the Doppler examination showed decreased systolic velocity in the graft artery during exercise, compatible with iliac steal syndrome. Surgical treatment was performed in both patients. After surgery, the control Doppler ultrasound stress test showed that systolic flow did not decline in the graft vessels during exercise. Renal function stabilized in one patient and improved in the other; claudication disappeared after surgery. CONCLUSION: Doppler ultrasound stress testing can be a valuable tool for detecting exercise-induced renal graft ischemia in transplant patients. Its screening performance should be determined in a larger population before routine use. PMID- 23337796 TI - Epidemiology and burden of osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease involving the cartilage and many of its surrounding tissues. Disease progression is usually slow but can ultimately lead to joint failure with pain and disability. OA of the hips and knees tends to cause the greatest burden to the population as pain and stiffness in these large weight-bearing joints often leads to significant disability requiring surgical intervention. SOURCES OF DATA: The article reviews the existing data on epidemiology of osteoarthritis and the burden of the disease. AREAS OF AGREEMENT: Symptoms and radiographic changes are poorly correlated in OA. Established risk factors include obesity, local trauma and occupation. The burden of OA is physical, psychological and socioeconomic. AREAS OF CONTROVERSY: Available data does not allow definite conclusion regarding the roles of nutrition, smoking and sarcopenia as risk factors for developing OA. GROWING POINTS: Variable methods of diagnosing osteoarthritis have significantly influenced the comparability of the available literature. AREAS TIMELY FOR DEVELOPING RESEARCH: Further research is required to fully understand how OA affects an individual physically and psychologically, and to determine their healthcare need. PMID- 23337797 TI - The enigma of adiponectin. PMID- 23337798 TI - The CYP2C19 genotype does not impact the long-term prognosis of patients with coronary artery disease. AB - BACKGROUND: Cytochrome P450 (CYP) 2C19 plays a key role in clopidogrel activation and thus impacts the clinical outcome of patients with coronary artery disease (CAD). However, the majority of patients with CAD gradually discontinue clopidogrel after one year of discharge. This study explored whether the CYP2C19 gene polymorphism was associated with clinical events in patients with CAD after one year of discharge. METHOD: Between July 2008 and July 2009, 506 patients with CAD that was confirmed by coronary angiography were enrolled in this study, and their CYP2C19 genotype was determined. The primary endpoint events included cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. The secondary endpoint events included the components of the primary endpoint events, all-cause mortality and recurrent revascularisation. RESULT: The baseline clinical characteristics of CYP2C19*2-mutation carriers (homozygous *2/*2, n = 49; heterozygous *1/*2, n = 222) and non-carriers (wild-type allele *1/*1, n = 235) were comparable. The follow-up results showed that the incidence of adverse cardiovascular events within one year of discharge was significantly higher in carriers of the CYP2C19*2 homozygous genotype (*2/*2) than non-carriers (12.24% vs. 3.83%, adjusted hazard ratio (HR) 4.651, 95% confidence interval (CI) 1.566 13.814, p = 0.006). However, the follow-up results after one year of discharge showed that the risk of the CYP2C19*2 homozygous genotype were significantly reduced. New primary endpoint events during the second year after discharge had no significant correlation with the CYP2C19 genotype. CONCLUSION: The risk of cardiovascular events in CAD patients with a homozygous CYP2C19*2 mutation was significantly higher than in other patients within the first year after discharge. However, the adverse impact of the CYP2C19*2 polymorphism was significantly reduced after one year of discharge. PMID- 23337799 TI - Within-person variability in kidney measures. AB - BACKGROUND: Our objective was to quantify short-term total within-person variability in standard and nontraditional kidney measures using national data. STUDY DESIGN: Repeated examination study of serum and urine kidney measures. SETTING & PARTICIPANTS: Participants 18 years or older in the Third National Health and Nutrition Examination Survey (NHANES III) who had repeated blood and urine samples collected during visits occurring approximately 18 days apart. MEASUREMENTS: Standardized serum creatinine, standardized cystatin C, beta-trace protein (BTP), beta(2)-microglobulin (B2M), and urine albumin and creatinine. We calculated the within-person coefficient of variation (CV(w)), which includes both biological and analytical variability. We also evaluated the impact of variability on estimates of the prevalence of reduced estimated glomerular filtration rate and albuminuria. RESULTS: Serum cystatin C level demonstrated the lowest short-term within-person variability (CV(w) = 6.8%). Serum creatinine and B2M levels (CV(w) = 7.6% and 8.4%, respectively) also had low variability. BTP level had the most variability of the serum markers (CV(w) = 11.6%). As expected, urine albumin and urine creatinine measurements showed high variability (CV(w) >30% for both); however, albumin-creatinine ratio performed much better than either measure alone, with CV(w) of 11.3%. The effect of short-term variability on the prevalence of reduced estimated glomerular filtration rate was moderate, with an ~20% lower prevalence when defined based on single measurements compared to repeated application of the same test approximately 18 days apart. Repeated testing for albuminuria had a larger effect, showing a 33% lower prevalence of albuminuria when repeated testing was applied. LIMITATIONS: Only 2 measurements available. General population with low prevalence of kidney disease. CONCLUSIONS: Our results suggest that creatinine, cystatin C, and B2M levels have similarly low short-term variability. BTP level was more variable compared with the other serum filtration markers. Urine albumin and creatinine levels were highly variable and may benefit from repeated assessments to reduce the misclassification of albuminuria. PMID- 23337800 TI - Parasitic kidney disease: milestones in the evolution of our knowledge. AB - Of the 342 parasites that infect humans, 20 are associated with kidney disease, yet of these, only schistosomes, plasmodia, filariae, and leishmanias are held responsible for significant clinical or epidemiologic impact. Reviewing the evolution of human knowledge for these parasites discloses a lot of similarities regarding their discovery, patterns of kidney injury, and pathogenic mechanisms. From a historical perspective, our relevant information may be classified into 4 phases: (1) disease documentation in ancient and medieval scripts as far back as 2000-3000 bce; (2) discovery of the parasites, their life cycles, and clinical correlates by European clinicians working in African and Asian colonies during the second half of the 19th century; (3) discovery and characterization of the renal manifestations of monoparasitic infections during the second half of the 20th century; and (4) recognition of the confounding effects of coinfection with bacteria, viruses, or other parasites. The spectrum of respective kidney diseases extends all the way from acute kidney injury to glomerulonephritis, amyloidosis, urologic disorders, and malignancy. Discovery of the common immunopathogenetic host response to parasitic infections has provided a knowledge core that explains the similarities, diversities, and interactions with regard to kidney injury. PMID- 23337802 TI - Synthesis and biological evaluation of novel tryptoline derivatives as indoleamine 2,3-dioxygenase (IDO) inhibitors. AB - Indoleamine 2,3-dioxygenase (IDO) plays a significant role in several disorders such as Alzheimer's disease, age-related cataracts and tumors. A series of novel tryptoline derivatives were synthesized and evaluated for their inhibitory activity against IDO. Substituted tryptoline derivatives (11a, 11c, 11e, 12b and 12c) were demonstrated to be more potent than known inhibitor MTH-Trp. Suzuki Miyaura cross-coupling reaction of 11a-d with phenylboronic acid proceeded in high yields. In most cases, C5 and C6 substitutions on the corresponding indole ring were well tolerated. The tryptoline derivative 11c is a promising chemical lead for the discovery of novel IDO inhibitors. PMID- 23337801 TI - Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein 1 (VAP-1) inhibitors for the treatment of diabetic macular edema. AB - Vascular adhesion protein-1 (VAP-1), an amine oxidase that is also known as a semicarbazide-sensitive amine oxidase (SSAO), is present in particularly high levels in human plasma, and is considered a potential therapeutic target for various inflammatory diseases, including diabetes complications such as macular edema. In our VAP-1 inhibitor program, structural modifications following high throughput screening (HTS) of our compound library resulted in the discovery that thiazole derivative 10, which includes a guanidine group, shows potent human VAP 1 inhibitory activity (IC(50) of 230 nM; rat IC(50) of 14 nM). Moreover, compound 10 exhibited significant inhibitory effects on ocular permeability in STZ-induced diabetic rats. PMID- 23337803 TI - Unintentional extraction of an endothelialized bare metal stent. AB - The extraction of a previously endothelialized stent has been rarely reported in the literature. We report a case of a patient with unstable angina due to in stent restenosis. During percutaneous coronary intervention, a stent was inadvertently dislodged in the ostium of the right coronary artery. Retrieval of the dislodged stent led to unintentional extraction of the previously endothelialized bare metal stent. PMID- 23337804 TI - LC-MS/MS identification of doublecortin as abundant beta cell-selective protein discharged by damaged beta cells in vitro. AB - There is a clinical need for plasma tests that can directly detect injury to pancreatic beta cells in type 1 diabetes. Such tests require biomarkers that are abundantly and selectively released into plasma by damaged beta cells. We combined LC-MS/MS proteomics and tissue-comparative transcriptomics of FACS purified beta cells for bottom-up identification of candidate markers. Less than 10% of 467 proteins detected in beta cells showed endocrine-enriched expression. One surprising candidate was the neuronal migration marker doublecortin: in situ analysis revealed uniform doublecortin expression in the cytoplasm of all beta cells. Western blotting and real-time PCR confirmed its strong beta cell selectivity outside the brain and its high molar abundance, indicating promising biomarker properties in comparison to GAD65, a more established marker of beta cell injury. DCX potential was validated in vitro: chemically-induced necrosis of rat and human beta cells led to a discharge of intracellular doublecortin into the extracellular space, proportionate to the amount of injured cells, and similar to GAD65. In vivo, recombinant DCX showed favorable pharmacokinetic properties, with a half-life in plasma of around 3h. Combined, our findings provide first proof-of-principle for doublecortin as biomarker for beta cell injury in vitro, advocating its further validation as biomarker in vivo. PMID- 23337805 TI - Children's self-reported quality of life after intensive care treatment. AB - OBJECTIVES: A number of studies have reported on parental/clinician reports of children's quality of life after intensive care treatment. The aim of this study was to establish children's own views of their outcome. [corrected]. DESIGN: Prospective cohort study. [corrected]. SETTING: Twenty-one bed PICU in a tertiary Children's Hospital. PATIENTS: Ninety-seven children aged over 7 yr, with no preexisting learning difficulties, consecutively admitted to PICU over an 18 month period INTERVENTIONS: Patients completed the Pediatric Quality of Life Inventory and a post-traumatic stress screener, at 3 months and again at 1 year (n = 72) after discharge from PICU. MEASUREMENTS AND MAIN RESULTS: At 3 months post-discharge, the mean total Pediatric Quality of Life Inventory score reported by the PICU group was lower than that reported in the literature for a non clinical community sample (PICU mean = 79.1 vs community mean = 83.9, p = 0.003), but by 1 year, they were comparable (82.2, p = 0.388). The mean physical functioning subscale score remained lower (PICU mean=81.6 vs. community mean=88.5, p = 0.01), but improved significantly from 73.4 at 3 months (p = 0.001).Sub-group analyses revealed that the elective group reported higher emotional functioning than the community sample (91.0, p=0.005 at 3 months and 88.2, p = 0.038 at 1 year vs community mean=78.5), and made significant gains in social functioning between timepoints (79.1 to 91.4, p = 0.015).Finally, although total PedsQL scores at 1 year were not associated with measures of severity of illness during admission, they were significantly negatively associated with concurrent post-traumatic stress symptom scores (r = -0.40, p = 0.001). CONCLUSIONS: The self-report version of the Pediatric Quality of Life Inventory proved to be a feasible and sensitive tool for assessing health related quality of life in this group of PICU survivors. PMID- 23337806 TI - Are family characteristics associated with attendance at family centered rounds in the PICU?. AB - OBJECTIVE: The objective of this study was to identify if family characteristics or opinions affected participation in family centered rounds. DESIGN: Observational study of 431 patient encounters on daily work rounds, followed by 100 questionnaires completed by family members of patients in the unit during observation. SETTING: PICU at a tertiary care, academic, free-standing children's hospital. SUBJECTS: Patients and families admitted to the PICU during the observation period. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The most frequent family members present for rounds were mothers (40%). Race, educational level, age of the family member, age of the child, whether the admission was expected, and whether the family member was a medical professional had no association with whether the family member attended rounds. Both family members who were present and those who were not present felt being at rounds would improve the care of their child (87% vs. 100%, p = 0.57). A family's response that they preferred to attend rounds was the only factor associated with a higher likelihood of attending rounds (odds ratio 3.4, 95% confidence interval 1.1-10.8, p = 0.03). CONCLUSION: Families feel that participating in family centered rounds improves the care of their children. Those that like attending rounds are more likely to participate in family centered rounds, but family demographic characteristics were not associated with rounds attendance. Future studies are needed to identify barriers to family participation in family centered rounds. PMID- 23337807 TI - Neutrophils control the magnitude and spread of the immune response in a thromboxane A2-mediated process. AB - Neutrophils are obligate cells entering lymph nodes shortly after immunization with protein antigens in adjuvants, starting during the first hour and continuing for several days in two distinct waves. Previously, we demonstrated the strong suppressive effects of neutrophils on CD4 T cell and B cell responses, using either neutrophil-depleting antibodies or genetically neutropenic mice. In this study, we find that neutrophils are the major cells controlling the spread of T cell responses to distal lymph nodes. Although in the presence of neutrophils, ~75% of the response was restricted to the draining node, in their absence, most of the response was found in distal nodes. Prostanoids were responsible for the rapid entry of neutrophils into the draining nodes, as well as for the two distinct neutrophil effects: the modulation of the magnitude of the cellular response, and in its spread outside the draining nodes. Neutrophil-produced thromboxane A(2) was the key eicosanoid controlling both effects. Adoptive transfer of neutrophils into mice genetically deficient in neutrophils indicated their role in both. These functions of neutrophils are important in infections and vaccinations with adjuvants where neutrophils are abundant in the initial stages. PMID- 23337808 TI - Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells. AB - Mutations in Wiskott-Aldrich syndrome (WAS) protein (WASp), a regulator of actin dynamics in hematopoietic cells, cause WAS, an X-linked primary immunodeficiency characterized by recurrent infections and a marked predisposition to develop autoimmune disorders. The mechanisms that link actin alterations to the autoimmune phenotype are still poorly understood. We show that chronic activation of plasmacytoid dendritic cells (pDCs) and elevated type-I interferon (IFN) levels play a role in WAS autoimmunity. WAS patients display increased expression of type-I IFN genes and their inducible targets, alteration in pDCs numbers, and hyperresponsiveness to TLR9. Importantly, ablating IFN-I signaling in WASp null mice rescued chronic activation of conventional DCs, splenomegaly, and colitis. Using WASp-deficient mice, we demonstrated that WASp null pDCs are intrinsically more responsive to multimeric agonist of TLR9 and constitutively secrete type-I IFN but become progressively tolerant to further stimulation. By acute silencing of WASp and actin inhibitors, we show that WASp-mediated actin polymerization controls intracellular trafficking and compartmentalization of TLR9 ligands in pDCs restraining exaggerated activation of the TLR9-IFN-alpha pathway. Together, these data highlight the role of actin dynamics in pDC innate functions and imply the pDC-IFN-alpha axis as a player in the onset of autoimmune phenomena in WAS disease. PMID- 23337809 TI - Helios marks strongly autoreactive CD4+ T cells in two major waves of thymic deletion distinguished by induction of PD-1 or NF-kappaB. AB - Acquisition of self-tolerance in the thymus requires T cells to discriminate strong versus weak T cell receptor binding by self-peptide-MHC complexes. We find this discrimination is reported by expression of the transcription factor Helios, which is induced during negative selection but decreases during positive selection. Helios and the proapoptotic protein Bim were coinduced in 55% of nascent CCR7(-) CD4(+) CD69(+) thymocytes. These were short-lived cells that up regulated PD-1 and down-regulated CD4 and CD8 during Bim-dependent apoptosis. Helios and Bim were also coinduced at the subsequent CCR7(+) CD4(+) CD69(+) CD8( ) stage, and this second wave of Bim-dependent negative selection involved 20% of nascent cells. Unlike CCR7(-) counterparts, Helios(+) CCR7(+) CD4(+) cells mount a concurrent Card11- and c-Rel-dependent activation response that opposes Bim mediated apoptosis. This "hollow" activation response consists of many NF-kappaB target genes but lacks key growth mediators like IL-2 and Myc, and the thymocytes were not induced to proliferate. These findings identify Helios as the first marker known to diverge during positive and negative selection of thymocytes and reveal the extent, stage, and molecular nature of two distinct waves of clonal deletion in the normal thymus. PMID- 23337811 TI - Isolation of clonal cultures of endosymbiotic green algae from their ciliate hosts. AB - Using Paramecium bursaria as a model organism improved protocols have been developed to isolate clonal endosymbiotic algae. This involved micromanipulation of individual protists, rupturing to release endosymbionts followed by enrichment on complex media and a series of plating steps, under low light (PAR ~10MUmol photons m(-2)s(-1)). PMID- 23337810 TI - Target deconvolution techniques in modern phenotypic profiling. AB - The past decade has seen rapid growth in the use of diverse compound libraries in classical phenotypic screens to identify modulators of a given process. The subsequent process of identifying the molecular targets of active hits, also called 'target deconvolution', is an essential step for understanding compound mechanism of action and for using the identified hits as tools for further dissection of a given biological process. Recent advances in 'omics' technologies, coupled with in silico approaches and the reduced cost of whole genome sequencing, have greatly improved the workflow of target deconvolution and have contributed to a renaissance of 'modern' phenotypic profiling. In this review, we will outline how both new and old techniques are being used in the difficult process of target identification and validation as well as discuss some of the ongoing challenges remaining for phenotypic screening. PMID- 23337812 TI - Semi-circular microgrooves to observe active movements of individual Navicula pavillardii cells. AB - We performed a trajectory analysis of movements of Navicula pavillardii diatom cells that were confined to semi-circular microgrooves with several different curvature radii. Using the semi-circular micropattern, we succeeded in observing change of velocity of the same cell before and after the stimulation by N,N dimethyl-p-toluidine (DMT). Because the looped grooves had longer contour length than straight grooves, it was effective to achieve the long term observation of the stimulated active cells. Although average velocity of 150 cells was significantly increased with DMT, the maximum velocity (19 MUm/s) of the cells was not increased after the DMT injection. This may suggest that existence of the mechanical limit of the velocity of the diatom cells. Secondly, trajectories of individual cell movements along the walls of the semi-circular microgrooves were analyzed in detail. As a result, the velocity of the cells was not affected by the curvature radii of the grooves although the trajectories indicated an obvious restriction of area of the cell motion. This suggests that the surface of the diatom is effective in minimizing the frictional force between the cell body and the wall of a groove. Finally, a simple model of cell motion in the semi-circular groove was proposed to clarify the relationships among the forces that determine cell movement. PMID- 23337813 TI - Induction of resistance to Staphylococcus aureus in an environmental marine biofilm. AB - The study of environmental biofilms is complicated by the difficulty of working with them under lab conditions. Nonetheless, knowledge of cellular activity and interactions within environmental biofilms could lead to novel biomedical applications. As a first step in this direction we propose a novel technique for inducing resistance to Staphylococcus aureus (S. aureus) in an intact environmental biofilm. Agar plates were prepared with or without the addition of 20% S. aureus spent culture media and immersed in coastal seawater (Boston Harbor, Massachusetts, USA) for four days to grow up an environmental biofilm. Nucleopore filters inoculated with an overnight culture of S. aureus were then applied to the surface of the agar plates with the environmental biofilms, incubated 4h at 37 degrees C, removed and subsequently stained and analyzed. Marine environmental biofilms grown on agar containing S. aureus spent culture media were significantly more inhibitory of S. aureus growth than were marine environmental biofilms grown on plain agar. PMID- 23337815 TI - Review of drugs for Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia in the elderly. The number of people affected by AD is rapidly increasing. AD is characterized by cerebral atrophy, cerebral senile plaques, intraneuronal neurofibrillary tangles, and neuronal cell loss. Medical treatment of AD has a long history and differing results. We will review the effectiveness and limitations of the drugs used to treat AD. PMID- 23337816 TI - Role of NPxY motif in Draper-mediated apoptotic cell clearance in Drosophila. AB - Draper, a receptor responsible for the phagocytosis of apoptotic cells in Drosophila, possesses atypical epidermal growth factor (EGF)-like sequences in the extracellular region and the two phosphorylatable motifs NPxY and YxxL in the intracellular portion. We previously suggested that Pretaporter, a ligand for Draper, binds to the EGF-like repeat and augments the tyrosine phosphorylation of Draper. In this study, we first tested the binding of Pretaporter to various parts of the extracellular region of Draper and found that a single EGF-like sequence is sufficient for the binding. We next determined roles of the two intracellular motifs by forcedly expressing Draper proteins, in which tyrosine residues within the motifs had been substituted with phenylalanine, in hemocytes of Draper-lacking flies. We found that Draper proteins with Y-to-F substitution in either motif still underwent tyrosine phosphorylation, suggesting the occurrence of phosphorylation at both motifs. The Draper protein with substitution in the YxxL motif rescued a defect of phagocytosis, as did intact Draper, but the Draper protein with substitution in the NPxY motif did not, indicating a role of the motif NPxY, but not YxxL, in Draper-mediated phagocytosis. This coincides with our previous finding that Ced-6, an NPxY binding signaling adaptor, is required for Draper's actions in apoptotic cell clearance. In summary, we demonstrated that Draper binds to its ligand Pretaporter using EGF-like sequences, and that the NPxY motif in the intracellular region of Draper plays an essential role in its actions as an engulfment receptor. PMID- 23337817 TI - In vitro free radical scavenging and anti-hyperglycemic activities of Achyranthes aspera extract in alloxan-induced diabetic mice. AB - Medicinal plants have played an important role in the treatment and prevention of diseases since ancient times. They are also potential sources of nutrients and drugs. This study evaluated Achyranthes aspera ethanolic extracts for their in vitro antioxidant activity and anti-hyperglycemic effects on alloxan-induced diabetic mice. Diabetes was induced in Swiss albino mice through intra-peritoneal administration of alloxan and their blood glucose levels and weight were measured weekly. At the end of the experiment, all animals were sacrificed and tissue samples were collected. A. aspera extracts had potent antioxidant activity compared to reference standard compounds. Treatment with an A. aspera extract at doses of 200 mg/kg and 400 mg/kg significantly reduced blood glucose levels in alloxan-induced diabetic mice. A. aspera extract also prevented lipid peroxidation as gauged by thiobarbituric acid reactive substances (TBARS) and hydroperoxides. Moreover, A. aspera extract increased the activity of catalase and reduced NO levels in alloxan-induced diabetic mice. Results revealed significant anti-hyperglycemic activity of A. aspera extracts in alloxan-treated mice that may be mediated by diminished oxidative stress. PMID- 23337818 TI - Neuroprotective and hepatoprotective effects of micronized purified flavonoid fraction (Daflon(r)) in lipopolysaccharide-treated rats. AB - Micronized purified flavonoid fraction (MPFF, Daflon(r)) is a phlebotonic drug widely used in chronic venous or lymphatic insufficiency. We aimed to investigate the effects of MPFF on hepatic and brain oxidative stress and on liver injury caused by lipopolysaccharide (LPS) in rats. MPFF (4.5, 9, or 18 mg/kg) or saline was administered orally for two days prior to intraperitoneal (i.p.) LPS (300 MUg/kg) and at time of LPS administration. Rats were euthanized 4 h after LPS injection. The administration of LPS increased oxidative stress in brain and liver tissue. Malondialdehyde (MDA) increased by 193.5 and 191.8%, reduced glutathione (GSH) decreased by 73.8 and 70.8% and nitric oxide increased by 118.2 and 151.7% in the brain and liver, respectively. Serum paraoxonase 1 (PON1) activity decreased by 42.6%. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were raised by 101.8, 93.6, and 223.2%, respectively. Rats treated with MPFF at 9 and 18 mg/kg showed decreased brain MDA (27.5-34%), nitrite (25.5-41%) and increased GSH (27.2 74.1%). In the liver, MDA decreased by 16.4-59.8%, nitrite decreased by 54.7 56.7%, and GSH increased by 15.2-70.5% with MPFF at 4.5, 9, or 18 mg/kg, respectively. Serum PON1 activity showed 41-65.9% increments with MPFF. Significant reductions in serum AST, ALT, and ALP were seen after treatment with MPFF. Moreover, the degree of histological damage, expression of the inducible form of nitric oxide synthase and the apoptotic enzyme caspase-3 in the liver were substantially reduced. MPFF thus prevented the increased oxidative stress and inflammation in brain and liver as well as the liver dysfunction caused by endotoxemia in the rat. PMID- 23337819 TI - The synergistic effect of SaOS-2 cell extract and other bone-inducing agents on human bone cell cultivation. AB - Human osteosarcoma cell line SaOS-2 is an osteoblastic cell model that contains factors like bone morphogenetic proteins necessary for initiating bone formation. The cell line also expresses high levels of osteoinductive activity. In contrast to highly complicated and expensive ways to identify, purify, and separate specific bone-inducing agents from SaOS-2 cells, lysate can be used as an alternative to isolated bone-stimulating factors. Lysates of SaOS-2 stimulate the activity of the alkaline phosphatase of human osteoblastic cells HOS 58 in vitro. In other words, they probably possess osteoinductive activity. Different serial concentrations of substances like dexamethasone and insulin were tested with and without a lysate of SaOS-2 cells to assay their synergistic action. Results showed that a lysate of the SaOS-2 cell line acts as a synergistic agent and increases the osteoinductive activity of known bone-inducing agents. SaOS-2 cell lysate could be used in the future as a clinical agent to promote bone repair and possibly enhance osteointegration. Using SaOS-2 total cellular extract offers the possibility of lowering the effective dose of other bone-inducing agents. PMID- 23337820 TI - Separation of the enantiomers of naringenin and eriodictyol by amylose-based chiral reversed-phase high-performance liquid chromatography. AB - Naringenin and eriodictyol are chiral flavanones widely present in citrus fruits and herbal products. Pharmacological interest in the two flavanones is well known. Due to the chiral carbon atom, the compounds always exist in the racemic form. The present study reported a stereospecific HPLC method for the enantioseparation of naringenin and eriodictyol, which was performed on an amylase-based chiral stationary phase (CSP), Chiralpak AD-RH, in the reversed phase mode. The effects of the mobile phase on retention, enantioseparation, and elution order were investigated. The different 3',4' substituent pattern of the two compounds affected the enantioselectivity. An online coupling HPLC-CD method was used for elution order determination. Both the CD sign of the eluted peaks at a single wavelength and complete CD spectra of the eluted enantiomers were obtained by the method. PMID- 23337821 TI - Attenuation of tumor growth by honokiol: an evolving role in oncology. AB - Honokiol may exert significant antineoplastic effects in other systemic tumors besides skin cancers by virtue of modulation of other pathways. For instance, honokiol attenuates tumor growth in mammary malignancies. It mediates its anti neoplastic role in these tumors by accentuating the phosphorylation of AMPK. As a result, honokiol causes significant mitigation of tumor proliferation and growth. PMID- 23337822 TI - Determination of neomycin and related substances in pharmaceutical preparations by reversed-phase high performance liquid chromatography with mass spectrometry and charged aerosol detection. AB - A new, simple and repeatable liquid chromatographic method with charged aerosol detection (LC-CAD) for determination of neomycin and related substances has been developed. Analysis of neomycin or other aminoglycosides is problematic due to a lack of chromophores. Universal response of CAD enables direct quantification of neomycin and related substances, for which no reference standard are available. Separation was performed on C18 Hypersil((r)) Gold aQ column using water, methanol and heptaflurobutyric acid as mobile phase. Under developed chromatographic conditions all impurities were well separated from neomycin B. Peaks identification was evaluated by electrospray ionization mass spectrometry. The proposed method was validated according to ICH guidelines and applied to the content determination of neomycin and related substances in pharmaceutical preparations. PMID- 23337824 TI - Plasmodium relictum (lineages pSGS1 and pGRW11): complete synchronous sporogony in mosquitoes Culex pipiens pipiens. AB - Plasmodium relictum is a widespread invasive agent of avian malaria, responsible for acute, chronic and debilitating diseases in many species of birds. Recent PCR based studies revealed astonishing genetic diversity of avian malaria parasites (genus Plasmodium), with numerous genetic lineages deposited in GenBank. Many studies addressed distribution and evolutionary relationships of avian Plasmodium lineages, but information about patterns of development of different lineages in mosquito vectors remains insufficient. Here we present data on sporogonic development of 2 widespread mitochondrial cytochrome b lineages (cyt b) of P. relictum (pSGS1 and pGRW11) in mosquito Culex pipiens pipiens. Genetic distance between these lineages is 0.2%; they fall in a well-supported clade in the phylogenetic tree. Three P. relictum strains were isolated from common crossbill (Loxia curvirostra, lineage pSGS1), domestic canary (Serinus canaria domestica, pSGS1) and house sparrow (Passer domesticus, pGRW11). These strains were multiplied in domestic canaries and used as donors of malarial gametocytes to infect C. p. pipiens. Mosquitoes were allowed to take blood meal on infected canaries and then dissected on intervals to study development of sporogonic stages. All 3 strains developed synchronously and completed sporogony in this vector, with infective sporozoites reported in the salivary glands on the day 14 after infection. Ookinetes, oocysts and sporozoites of all strains were indistinguishable morphologically. This study shows that patterns of sporogonic development of the closely related lineages pSGS1 and pGRW11 and different strains of the lineage pSGS1 of P. relictum are similar indicating that phylogenetic trees based on the cyt b gene likely can be used for predicting sporogonic development of genetically similar avian malaria lineages in mosquito vectors. PMID- 23337823 TI - Bullous pemphigoid IgG induces BP180 internalization via a macropinocytic pathway. AB - Bullous pemphigoid (BP) is an autoimmune blistering skin disease induced by pathogenic autoantibodies against a type II transmembrane protein (BP180, collagen type XVII, or BPAG2). In animal models, BP180 autoantibody-antigen interaction appears insufficient to develop blisters, but involvement of complement and neutrophils is required. However, cultured keratinocytes treated with BP-IgG exhibit a reduction in the adhesive strength and a loss of expression of BP180, suggesting that the autoantibodies directly affect epidermal cell extracellular matrix integrity. In this study, we explored the consequences of two distinct epithelial cells treated with BP-IgG, particularly the fate of BP180. First, we followed the distribution of green fluorescent protein-tagged BP180 in an epithelial cell line, 804G, and normal human epidermal keratinocytes after autoantibody clustering. After BP-IgG treatment, the adhesive strength of the cells to their substrate was decreased, and BP180 was internalized in both cell types, together with the early endosomal antigen-1. By using various endocytosis inhibitors and a fluid-uptake assay, we demonstrated that BP-IgG induced BP180 internalization is mediated via a macropinocytic pathway. Moreover, a macropinocytosis inhibitor rescued a BP-IgG-induced reduction in the adhesive strength of the cells from their substrate. The results of this study suggest that BP180 internalization induced by BP-IgG plays an important role in the initiation of disease pathogenesis. PMID- 23337825 TI - Impact of protein malnutrition on histological parameters of experimentally infected animals with Giardia lamblia. AB - Giardiasis is one of the most common parasitic diseases worldwide, and the disease is an important cause of diarrhoea and malabsorption in children and immunosuppressed individuals. However, there is no evidence that characterises malnutrition as an aggravating factor for this disease. We evaluated changes in villi structures to examine the association between malnutrition and Giardia lamblia infection. We used 32 gerbils, divided into 4 groups: Control (CT) and Control Infected (CTIn), which each received a 20% protein diet, Malnourished (MN) and Malnourished Infected (MNIn), which each received a 5% protein diet. Groups CTIn and MNIn were inoculated with 1*10(6) trophozoites of G. lamblia, while the remaining groups were mock infected. Seven days post-infection, all groups were sacrificed, and the proximal portions of the small intestines were collected for the analysis of villus height, mucus area and extent of Giardia infection. Gerbils fed with a low-protein diet had significantly lower body weights. Malnourished infected animals presented significantly increased production of mucus, suggesting a synergism occurs between malnutrition and Giardiasis, potentially to control the adhesion of Giardia in the mucosa. Villus height was significantly lower in group MNIn compared to CTIn. This work suggests that malnutrition contributes to severity of Giardiasis by decreasing the intestinal absorption capacity via shortening of the villi. PMID- 23337826 TI - The effect of variation in phased array element performance for Non-Destructive Evaluation (NDE). AB - This paper reports the results of an investigation into the effects of phased array element performance on ultrasonic beam integrity. This investigation has been performed using an array beam model based on Huygens' principle to independently investigate the effects of element sensitivity and phase, and non functioning elements via Monte Carlo simulation. The purpose of this work is to allow a new method of array calibration for Non-Destructive Evaluation (NDE) to be adopted that focuses on probe integrity rather than beam integrity. This approach is better suited to component inspections that utilise Full Matrix Capture (FMC) to record data as the calibration routine is uncoupled from the beams that the array is required to produce. For this approach to be adopted specifications must be placed on element performance that guarantee beam quality without carrying out any beam forming. The principal result of this investigation is that the dominant outcome following variations in array element performance is the introduction of beam artefacts such as main beam broadening, raising of the noise floor of the ultrasonic field, and the enlargement or creation of side lobes. Specifications for practical allowable limits of element sensitivity, element phase, and the number of non-functioning elements have been suggested based on a minimum amplitude difference between beam artefacts and the main beam peak of 8 dB. Simulation at a number of centre frequencies has led to a recommendation that the product of transducer bandwidth and maximum phase error should be kept below 0.051 and 0.035 for focused and plane beams respectively. Element sensitivity should be within 50% of mean value of the aperture, and no more than 9% of the elements should be non-functioning. PMID- 23337827 TI - Higher levels of brain derived neurotrophic factor but similar nerve growth factor in human milk in women with preeclampsia. AB - Children born to mothers with preeclampsia have consistently been suggested to be at risk for cognitive and behavioral disorders in later life. Breastfeeding is said to be associated with better neurodevelopment outcomes. Our earlier studies indicated higher levels of docosahexaenoic acid (DHA) in human milk in women with preeclampsia. DHA is known to regulate the expression of neurotrophins and together they play a vital role in neurodevelopment and cognitive performance. The present study examines the levels of maternal plasma and milk neurotrophins [(nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF)] in women with preeclampsia and compares them with normotensive women who served as controls. Singleton pregnant women diagnosed with preeclampsia (n=72) and controls (n=102) were recruited for this study from Bharati Hospital, Pune. Plasma and milk samples were analyzed for NGF and BDNF levels using the Emax Immuno Assay System using promega kits. Maternal plasma NGF and BDNF levels were lower (p<0.01 for both) in women with preeclampsia as compared to the control women. Milk NGF levels were similar while milk BDNF levels were higher (p<0.05) in the preeclampsia group as compared to controls. Plasma NGF levels were positively correlated with milk NGF levels in the control group. Our results indicate the differential regulation of milk NGF and BDNF levels in women with preeclampsia. The present study suggests a role for both NGF and BDNF in human milk for postnatal brain development. Further studies need to examine the associations of DHA and BDNF in human milk with cognition at later ages. PMID- 23337828 TI - 'Give us the full story': overcoming the challenges to achieving informed choice about fetal anomaly screening in Australian Aboriginal communities. AB - This cross-cultural qualitative study examined the ethical, language and cultural complexities around offering fetal anomaly screening in Australian Aboriginal communities. There were five study sites across the Northern Territory (NT), including urban and remote Aboriginal communities. In-depth interviews were conducted between October 2009 and August 2010, and included 35 interviews with 59 health providers and 33 interviews with 62 Aboriginal women. The findings show that while many providers espoused the importance of achieving equity in access to fetal anomaly screening, their actions were inconsistent with this ideal. Providers reported they often modified their practice depending on the characteristics of their client, including their English skills, the perception of the woman's interest in the tests and assumptions based on their risk profile and cultural background. Health providers were unsure whether it was better to tailor information to the specific needs of their client or to provide the same level of information to all clients. Very few Aboriginal women were aware of fetal anomaly screening. The research revealed they did want to be offered screening and wanted the 'full story' about all aspects of the tests. The communication processes advocated by Aboriginal women to improve understanding about screening included community discussions led by elders and educators. These processes promote culturally defined ways of sharing information, rather than the individualised, biomedical approaches to information-giving in the clinical setting. A different and arguably more ethical approach to introducing fetal anomaly screening would be to initiate dialogue with appropriate groups of women in the community, particularly young women, build relationships and utilise Aboriginal health workers. This could accommodate individual choice and broader cultural values and allow women to discuss the moral and philosophical debates surrounding fetal anomaly screening prior to the clinical encounter and within their own cultural space. PMID- 23337829 TI - McDonaldization or commercial re-stratification: corporatization and the multimodal organisation of English doctors. AB - This paper investigates transitions in the social organisation of medicine found in the extended opportunities for private corporations to own, manage and deliver public healthcare services in the English National Health Service. It follows recent calls to explain the reconstruction of medical work without reducing analysis to either the structures of organisational control or the strategic resistance of doctors. Accordingly, the paper considers how doctors interact, mediate and co-create new organisational environments. Central to our analysis are the variable sources of power that influence whether doctors acquiesce, resist or re-create change. Drawing on ethnographic research carried out between 2006 and 2010 in two Independent Sector Treatment Centres - private providers of public healthcare - the paper shows how doctors' responses to bureaucratic and commercial structures reflect their own structured forms of power, which have variable value within this new commercial environment. These include clinical experience and specialist knowledge, but also social and economic influence. Building on established sociological debates, these divergent sources of power explain how for some doctors the expansion of private healthcare might involve more extreme forms of McDonaldization, while for others it might involve opportunities for Commercial Re-stratification. PMID- 23337830 TI - Social inequalities in adolescent human papillomavirus (HPV) vaccination: a test of fundamental cause theory. AB - A unique contribution of the fundamental cause theory of health disparities is its ability to account for the persistence of disparities in health and mortality, despite changes in the mechanisms that are relevant at any given time. Few studies, however, have investigated how such mechanisms are created or operate. Examining the introduction of the human papillomavirus (HPV) vaccine for adolescents-a treatment aimed at preventing cervical and other cancers that typically emerge in mid- to late-adulthood-we empirically trace such a disparity generating mechanism that is in the process of being latently created, testing whether socioeconomic status (SES) and racial/ethnic disparities exist for several facets of vaccination receipt: knowledge about the vaccine, receipt of a health professional recommendation to vaccinate, and initiation and completion of the three-shot vaccination series. Analyses of 2008, 2009, and 2010 United States National Immunization Survey-Teen data (n = 41,358) reveal disparities consistent with fundamental cause theory, particularly for vaccine knowledge and receipt of a health professional recommendation. While parental knowledge is a prerequisite to adolescent vaccine uptake, low SES and racial/ethnic minority parents have significantly lower odds of knowing about the vaccine. Receipt of a health professional's recommendation to vaccinate is strongly associated with vaccine uptake, however the odds of receiving a recommendation are negatively associated with low SES and black racial/ethnic status. Our findings inform fundamental cause theory by illustrating how disparities in distinct stages of the uptake of new treatments may contribute to reproducing existing health disparities-and, in this case of adolescent HPV vaccination, may maintain future disparities in cervical cancer among adult populations. PMID- 23337831 TI - Political conditions and life expectancy in Europe, 1900-2008. AB - The rise of life expectancy in Europe has been a very uneven process, both in time and space. This paper aims to identify instances in which major political conditions are likely to have influenced the rise of life expectancy, focusing on formation and dissolution of states and supranational blocs and on differences between political regimes (democratic vs. authoritarian non-communist and communist rule). Data on life expectancy, cause-specific mortality and political conditions were compiled from existing data sources. Possible relations between political conditions and life expectancy were studied by direct comparisons of changes in life expectancy in countries with different political conditions but similar starting levels of life expectancy. We found that formation and dissolution of states often went together with convergence and divergence of life expectancy, respectively, and that otherwise similar countries that did or did not become part of the Soviet bloc had distinctly different life expectancy trajectories. Democratically governed states had higher life expectancies than authoritarian states throughout the 20th century. The gap narrowed between 1920 and 1960 due to rapid catching up of infectious disease control in both non communist and communist authoritarian states. It widened again after 1960 due to earlier and more rapid progress in democratic states against cardiovascular disease, breast cancer, motor vehicle accidents and other causes of death that have become amenable to intervention. We conclude that the history of life expectancy in Europe contains many instances in which political conditions are likely to have had a temporary or more lasting impact on population health. This suggests that there is scope for further in-depth studies of the impact of specific political determinants on the development of population health in Europe. PMID- 23337832 TI - How organizational context affects bioethical decision-making: pharmacists' management of gatekeeping processes in retail and hospital settings. AB - Social science studies of bioethics demonstrate that ethics are highly contextual, functioning differently across local settings as actors make daily decisions "on the ground." Sociological studies that demonstrate the key role organizations play in shaping ethical decision-making have disproportionately focused on physicians and nurses working in hospital settings where they contend with life and death issues. This study broadens our understanding of the contexts of ethical decision-making by empirically examining understudied healthcare professionals - pharmacists - working in two organizational settings, retail and hospital, where they act as gatekeepers to regulated goods and services as they contend with ethical issues ranging from the serious to the mundane. This study asks: How do organizations shape pharmacists' identification, negotiation, and resolution of ethical challenges; in other words, how do organizations shape pharmacists' gatekeeping processes? Based on 95 semi-structured interviews with U.S. pharmacists practicing in retail and hospital pharmacies conducted between September 2009 and May 2011, this research finds that organizations influence ethical decision-making by shaping how pharmacists construct four gatekeeping processes: medical, legal, fiscal, and moral. Each gatekeeping process manifests differently across organizations due to how these settings structure inter professional power dynamics, proximity to patients, and means of accessing information. Findings suggest new directions for theorizing about ethical decision-making in medical contexts by drawing attention to new ethical actors, new organizational settings, an expanded definition of ethical challenges, and a broader conceptualization of gatekeeping. PMID- 23337833 TI - Mental health of those directly exposed to the World Trade Center disaster: unmet mental health care need, mental health treatment service use, and quality of life. AB - Mental health service utilization several years following a man-made or natural disaster can be lower than expected, despite a high prevalence of mental health disorders among those exposed. This study focused on factors associated with subjective unmet mental health care need (UMHCN) and its relationship to a combination of diagnostic history and current mental health symptoms, 5-6 years after the 9-11-01 World Trade Center (WTC) disaster in New York City, USA. Two survey waves of the WTC Health Registry, after exclusions, provided a sample of 36,625 enrollees for this analysis. Important differences were found among enrollees who were categorized according to the presence or absence of a self reported mental health diagnosis and symptoms indicative of post-traumatic stress disorder or serious psychological distress. Persons with diagnoses and symptoms had the highest levels of UMHCN, poor mental health days, and mental health service use. Those with symptoms only were a vulnerable group much less likely to use mental health services yet reporting UMHCN and poor mental health days. Implications for delivering mental health services include recognizing that many persons with undiagnosed but symptomatic mental health symptoms are not using mental health services, despite having perceived need for mental health care. PMID- 23337834 TI - Clinical significance of the assessment of the systolic and diastolic myocardial function of the left atrium in patients with paroxysmal atrial fibrillation and low CHADS(2) index treated with catheter ablation therapy. AB - The purpose of this study was to determine the clinical significance of the assessment of the diastolic and systolic myocardial function of the left atrium in patients with paroxysmal atrial fibrillation (AF) and low CHADS(2) scores treated with catheter ablation therapy. In a cohort of 84 symptomatic patients with paroxysmal AF and low CHADS(2) scores (<=1), the clinical significance of the systolic and diastolic myocardial function of the left atrium (assessed using 2-dimensional speckle-tracking echocardiography) were studied to predict the risk for recurrence of AF after catheter ablation therapy in the course of a follow-up period of >=1 year. During a mean follow-up period of 19.2 +/- 5.4 months, patients with left atrial (LA) myocardial diastolic dysfunction (LA strain <18.8%) had a significantly higher rate of recurrence of AF (42.4% vs 9.8%, p <0.05) compared to those without LA diastolic dysfunction. In line with this finding, patients with impaired LA myocardial systolic function (LA strain rate > 0.85 s(-1)) had worse outcomes after catheter ablation therapy than those with normal LA systolic function (rate of recurrence of AF 42.9% vs 12.5%, respectively, p <0.05). In relation to these results, in a logistic regression analysis including co-morbidities, left ventricular dysfunction, LA enlargement, and LA myocardial alterations, diastolic and systolic LA myocardial dysfunction were the principal variable associated with the recurrence of AF (odds ratios 6.8 and 5.2, respectively). In conclusion, in symptomatic patients with paroxysmal AF and low CHADS(2) scores, these findings suggest that the assessment of diastolic and systolic LA myocardial function using 2-dimensional speckle-tracking echocardiography could be of great utility to distinguish those patients with high or low risk for recurrence of AF after catheter ablation therapy. PMID- 23337835 TI - Performance analysis of EuroSCORE II compared to the original logistic EuroSCORE and STS scores for predicting 30-day mortality after transcatheter aortic valve replacement. AB - The original European System for Cardiac Operative Risk Evaluation (EuroSCORE) has been recently updated as EuroSCORE II to optimize its efficacy in cardiac surgery, but its performance has been poorly evaluated for predicting 30-day mortality in patients who undergo transcatheter aortic valve replacement (TAVR). Consecutive patients (n = 250) treated with TAVR were included in this analysis. Transapical access was used in 60 patients, while 190 procedures were performed using a transfemoral approach. Calibration (risk-adjusted mortality ratio) and discrimination (C-statistic and U-statistic) were calculated for the logistic EuroSCORE, EuroSCORE II, and Society of Thoracic Surgeons (STS) scores for predicting 30-day mortality. Observed mortality was 7.6% in the overall population (6.3% and 11.7% for the transfemoral and transapical cohorts, respectively). Predicted mortality was 22.6 +/- 12.8% by logistic EuroSCORE, 7.7 +/- 5.8% by EuroSCORE II, and 7.3 +/- 4.1% by STS score. The risk-adjusted mortality ratio was 0.34 (95% confidence interval [CI] 0.10 to 0.58) for logistic EuroSCORE, 0.99 (95% CI 0.29 to 1.69) for EuroSCORE II, and 1.05 (95% CI 0.30 to 1.79) for STS score. Moderate discrimination was observed with EuroSCORE II (C index 0.66, 95% CI 0.52 to 0.79, p = 0.02) compared to the logistic EuroSCORE (C index 0.63, 95% CI 0.51 to 0.76, p = 0.06) and STS (C-index 0.58, 95% CI 0.43 to 0.73, p = 0.23) score, without a significant difference among the 3 risk scores. Discrimination was slightly better in the transfemoral cohort compared to the transapical cohort with the 3 risk scores. In conclusion, EuroSCORE II and the STS score are better calibrated than the logistic EuroSCORE but have moderate discrimination for predicting 30-day mortality after TAVR. PMID- 23337836 TI - Renal impairment in a "real-life" cohort of anticoagulated patients with atrial fibrillation (implications for thromboembolism and bleeding). AB - Renal dysfunction is highly prevalent among patients with atrial fibrillation (AF) and confers an increased risk of thrombotic and bleeding complications. We evaluated the effect of renal function on prognosis in anticoagulated patients with AF and assessed the changes in renal function during a long-term follow-up period. We recruited 978 consecutive stable anticoagulated patients with AF from our outpatient anticoagulation clinic (international normalized ratio 2.0 to 3.0 within the previous 6 months). The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation at inclusion and 2 years of follow-up. Adverse events were recorded during follow-up (thrombotic/vascular events, major bleeding episodes, and mortality). Longitudinal changes in renal function were analyzed in 886 patients (90.6%). At baseline, the median eGFR using the Modification of Diet in Renal Disease equation was 70.24 ml/min/1.73 m(2) (interquartile range 46.79 to 72.52). During follow-up, a low eGFR was associated with thrombotic/vascular events, with every 30 ml/min/1.73 m(2) eGFR decrease (hazard ratio 1.42, 95% confidence interval [CI] 1.11 to 1.83, p = 0.006), bleeding (hazard ratio 1.44, 95% CI 1.08 to 1.94, p = 0.015), and mortality (hazard ratio 1.47, 95% CI 1.13 to 1.91, p = 0.004). After excluding patients with a baseline eGFR <30 ml/min/1.73 m(2), the mean eGFR in our cohort decreased >10 ml/min/1.73 m(2) in 181 patients (21%) during the follow-up period. The variables associated with severe renal impairment during follow-up were heart failure (odds ratio 3.58, 95% CI 1.36 to 9.42, p = 0.010), basal eGFR (odds ratio 6.34, 95% CI 2.44 to 16.50, p <0.001), and CHADS2 (Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, and previous Stroke or transient ischemic attack [doubled]) score (odds ratio 1.63, 95% CI 1.19 to 2.23, p = 0.003). In conclusion, the presence of impaired renal function was closely related to thrombotic/vascular events, bleeding, and mortality in anticoagulated patients with AF. During follow-up, 1/5 of the patients had significant impairment in renal function. Importantly, normal or mild renal dysfunction at baseline did not exclude the subsequent development of severe renal dysfunction during the follow-up period. PMID- 23337837 TI - Comparison of long-term outcomes between everolimus-eluting and sirolimus-eluting stents in small vessels. AB - Although second-generation everolimus-eluting stents (EESs) have demonstrated superiority over first-generation paclitaxel-eluting stents for a broad subset of patients and lesions, it is unclear whether the same applies to sirolimus-eluting stents (SESs). The present study compared the long-term clinical outcomes between EESs and SESs in patients with small coronary artery disease. A cohort of 643 patients treated with EESs (220 patients with 245 lesions) or SESs (423 patients with 523 lesions) in small vessel lesions (defined as those receiving stents <=2.5 mm) were retrospectively analyzed. The end points included target lesion revascularization, target vessel revascularization, major adverse cardiovascular events (all-cause death, myocardial infarction, or target lesion revascularization), and definite stent thrombosis at 1 year of follow-up. The baseline characteristics were generally similar between the 2 groups, except that more systemic hypertension was seen in the EES group and more patients had a family history of coronary artery disease in the SES group. The 1-year target lesion revascularization (5.6% vs 4.8%, p = 0.68) and target vessel revascularization (5.6% vs 7.6%, p = 0.33) rates showed no significant differences between the EES and SES groups. Overall major adverse cardiovascular events occurred in 9.1% of the EES- and 8.6% of SES-treated patients (p = 0.83). This similar major adverse cardiovascular events rate remained after adjustment. The rate of stent thrombosis was 0% in the EES group and 1.2% in the SES group (p = 0.17). In conclusion, EESs demonstrated comparable clinical outcomes to those of SESs in small vessel interventions. The absence of stent thrombosis among patients treated with EESs suggests a good safety profile for this second generation drug-eluting stent, which should be carefully studied in a larger series of patients with small vessel disease. PMID- 23337838 TI - Comparison of change in coronary atherosclerosis in patients with stable versus unstable angina pectoris receiving statin therapy (from the Treatment With Statin on Atheroma Regression Evaluated by Intravascular Ultrasound With Virtual Histology [TRUTH] study). AB - Although statin-induced regression in coronary atherosclerosis seems to be greater in patients with acute coronary syndrome than in those with stable coronary artery disease, no reports have examined this. The purpose of the present study was to compare the changes in coronary atherosclerosis in patients with stable versus unstable angina pectoris (AP). The effects of 8-month statin therapy on coronary atherosclerosis were evaluated using virtual histology intravascular ultrasound, and analyzable intravascular ultrasound data were obtained from 119 patients (83 patients with stable AP and 36 with unstable AP). A significant decrease in plaque volume was observed in patients with unstable AP (-2.2%, p = 0.02) but not in patients with stable AP. A significant increase in the necrotic-core component (0.30 mm(3)/mm, p = 0.009) was observed only in patients with unstable AP. Significant positive correlations were observed between the percentage of change in platelet-activating factor acetylhydrolase and the percentage of change in plaque volume (r = 0.346, p = 0.05) in patients with unstable AP. No significant correlations were observed in patients with stable AP. Multivariate regression analyses showed that a reduction in platelet activating factor acetylhydrolase was associated with regression in coronary atherosclerosis, particularly of the fibrous component (beta = 0.443, p = 0.003), in patients with unstable AP. In conclusion, regression of the coronary artery plaque volume was greater, although statin therapy did not halt the increases in plaque vulnerability, in patients with unstable AP compared to those with stable AP. A reduction in the serum platelet-activating factor acetylhydrolase level was associated with regression in coronary atherosclerosis, particularly the fibrous plaque volume, in patients with unstable AP. PMID- 23337839 TI - Accuracy of stress myocardial perfusion imaging to diagnose coronary artery disease in end stage liver disease patients. AB - Patients with end-stage liver disease (ESLD) who also have underlying coronary artery disease (CAD) may be at increased risk for undergoing hemodynamically challenging orthotopic liver transplantation. Noninvasive single-photon emission computed tomographic (SPECT) imaging is often used to determine whether a patient with ESLD has unsuspected CAD. The objective of this study was to determine the accuracy of SPECT imaging for detection of CAD in patients with ESLD. Patients with ESLD who underwent coronary angiography and SPECT imaging before orthotopic liver transplantation were analyzed retrospectively. The predictive accuracy of clinical risk factors was calculated and compared to the results of SPECT imaging. There were 473 SPECT imaging studies. Adenosine SPECT imaging had a sensitivity of 62%, specificity of 82%, positive predictive value of 30%, and negative predictive value of 95% for diagnosing severe CAD. Regadenoson SPECT imaging had a sensitivity of 35%, specificity of 88%, positive predictive value of 23%, and negative predictive value of 93% for diagnosing severe CAD. The accuracy of a standard risk factor analysis showed no statistical difference in predicting CAD compared with adenosine (sensitivity McNemar's p = 0.48, specificity McNemar's p = 1.00) or regadenoson (sensitivity McNemar's p = 0.77, specificity McNemar's p = 1.00) SPECT studies. In conclusion, the 2 pharmaceutical agents had low sensitivity but high specificity for diagnosing CAD. However, because the sensitivity of the test is low, the chances of missing patients with ESLD with CAD is high, making SPECT imaging an inaccurate screening test. A standard risk factor analysis as a predictor for CAD in patients with ESLD is less expensive, has no radiation exposure, and is as accurate as SPECT imaging. PMID- 23337840 TI - [Connection between the knowledge of the recommendations of the National Nutrition and Health Program and patterns of eating behaviour and physical activity]. AB - BACKGROUND: Nutrition education is one of the main lines of the French nutrition policy that has been undertaken for several years. The underlying hypothesis of this approach is that knowledge improvement is one of the ways likely to contribute to health-enhancing diet and physical activity. The objective of this paper, based on the 2008 Health and nutrition Barometer, is to examine the associations observed between knowledge and behavior with regard to diet and physical activity. METHODS: The 2008 Health and nutrition Barometer is a nationally representative telephone survey conducted on 4714 individuals aged 12 75 years. For six recommendations of the National Nutrition and Health Program (Programme national nutrition sante [PNNS]), multiple logistic models were used to identify associations between knowledge of these recommendations and behavior, among adults aged 18-75 years. For food consumed on the day before the interview, odds ratios were adjusted for sex, age, education level, agglomeration size and region. As bivariate analysis showed that income level was significant for recommended consumption of fish, this variable was introduced among adjustment variables. Similarly, the variable occupation was introduced for physical activity. RESULTS: A positive association between knowledge of recommendations and nutritional behavior on the day before interview was observed for fruit and vegetables (OR=1.7), dairy products (OR=1.6), and starchy food (OR=1.6). The same was observed for consumption of fish during the 15 days before the interview (OR=5.0) and for physical activity during a usual week (OR=1.5) but not for the "meat, seafood and eggs" food group. CONCLUSION: Eating habits and physical activity are positively associated with knowledge of nutritional recommendations, mainly acquired via nutritional information and educational actions. Nevertheless, the important differences observed for certain dietary groups between knowledge of recommendations and dietary intake emphasizes the need to further support individual-focused initiatives with health-enhancing environmental strategies. PMID- 23337841 TI - [HIV testing among women in delivery rooms in Lubumbashi, Democratic Republic of the Congo: a catch-up strategy for prevention of mother-to-child transmission]. AB - BACKGROUND: Although HIV testing is offered during antenatal care, the proportion of women giving birth without knowing their HIV status is still important in DR Congo. The objective of this study was to determine the acceptability of rapid HIV testing among parturients in labor room, and to identify factors that are associated with the acceptability of HIV testing. METHODS: Intervention including rapid HIV testing among pregnant women in labor rooms in Lubumbashi for 5 months, from September 2010 to February 2011. Pregnant women who tested HIV positive were attended by prevention of mother-to-child transmission service. Descriptive statistical analysis and logistic regression were performed. RESULTS: Among 474 pregnant women who enter the labor room, 433 (91.4%; confidence interval [CI]: 95%: 88.4-93.7%) had voluntary testing for HIV in the labor room after counseling. The acceptance of rapid testing for HIV was significantly higher when the duration of counseling was less or equal to 5 minutes (adjusted Odds ratio [aOR]=5.8; [CI] 95%: 2.6-13); among those who did not report having this screening test during antenatal care (aOR=3.8; [CI] 95%: 2-7.8), among those who were in early labor (aOR=2.3; [CI] 95%: 1.2-4.7) and lower in adolescents than in adults (aOR=0.1; [CI] 95%: 0.0-0.7). CONCLUSION: Counseling and voluntary HIV testing are accepted in our labor rooms. Consistently offering this service in the labor room could be a catch-up strategy to be combined with antenatal care testing. PMID- 23337842 TI - Abnormal cytology in 2012: management of atypical squamous cells, low-grade intraepithelial neoplasia, and high-grade intraepithelial neoplasia. AB - Cervical cancer and human papillomavirus-related diseases continue to cause significant morbidity and mortality in the United States and worldwide. As we begin to understand the natural course of human papillomavirus infection, and the consequences of both its detection and treatment, changes have been made to our clinical approaches. The purpose of this review is to outline the management guidelines for the management of abnormal cytology. Successful triage of abnormal cytology in 2012 will allow for continued detection of precancerous lesions reducing the incidence of cervical cancer and increasing the detection of early stage disease. PMID- 23337843 TI - 2012 cervical cancer screening guidelines and the future role of HPV testing. AB - Persistent high-risk human papillomavirus (HPV) infection is a necessary precursor for the development of cervical cancer. Recent data demonstrating the sensitivity of HPV testing has led to consensus group updates of how to best screen women in the United States. The newest recommendations incorporate HPV testing for women 30 to 65 years of age, but do not yet recommend primary screening with HPV testing alone. With the advent of HPV vaccination and consequent shift in the prevalence of HPV-related disease, the role of cervical cytology as primary testing in national screening programs will be further called into question. PMID- 23337844 TI - Cervical cancer screening and prevention in low-resource settings. AB - Cervical cancer is both preventable and curable, yet it remains one of the leading causes of mortality in women worldwide. Approximately 88% of cervical cancer cases are diagnosed in low-resource countries, yet very few resources are allocated to prevention and treatment programs. In fact, it is estimated that only 5% of women in low-resources countries are screened appropriately for cervical cancer. Cytology-based programs are not feasible because of lack of healthcare infrastructure and cost, thus alternative methods of cancer screening, such as visual inspection with acetic acid and HPV-DNA testing, have been intensively studied and are reviewed in this article. PMID- 23337845 TI - Management of the pregnant substance abusing woman. AB - Operation PAR has been involved in prevention and treatment service development for drug-dependent women for nearly 40 years. Management starts with prevention programs. For opiate-addicted pregnant women, methadone is the treatment of choice and should be maintained throughout pregnancy, despite the manageable problem of neonatal opiate withdrawal. Women are actively engaged in innovative educational and therapeutic activities to help moms build skills to enhance their personal health and develop recovery orientation and drug refusal skills. Specific parenting skills are modeled and taught both on an outpatient and inpatient basis as appropriate. PMID- 23337846 TI - The effect of abused substances on antenatal and intrapartum fetal testing and well-being. AB - Recognition that use and abuse of substances by pregnant patients perpetuates, despite ongoing efforts to educate the public, necessitates clinicians to integrate understanding of potential effects on antepartum and intrapartum fetal testing into their interpretation and implementation of clinical findings. This includes acknowledging some anticipated alterations in results and selecting the appropriate type and frequency of testing methods and interventions. Certain substances are well documented in terms of expected variations in test results; others are not as clearly defined. An overview of information that may be helpful to the clinician is presented to promote understanding of fetal evaluation performed through common tests such as contraction stress test, the nonstress test, the biophysical profile, the modified biophysical profile, fetal movement counting, and Doppler velocimetry. What evidence is available should be used to assist in defining the actual status of the fetus as best as possible, even when the effects of substances may be unknown or have obscure results. PMID- 23337847 TI - Breastfeeding and substance abuse. AB - Breastfeeding is the recommended feeding method for infants. The decision to allow women to breastfeed while consuming alcohol and other drugs postpartum presents a problem for the health care provider. This article discusses the biochemical properties of various drugs as they relate to breastfeeding. Women in a methadone treatment program should be allowed to breast feed; however, more research is needed to determine the efficacy of breastfeeding when women are receiving buprenorphine. Breastfeeding should not be recommended in women who abuse heroin recreationally until more information is known about the actual amount of morphine present in the breast milk. PMID- 23337849 TI - Multiple single nucleotide polymorphism analysis using penalized regression in nonlinear mixed-effect pharmacokinetic models. AB - CONTEXT: Studies on the influence of single nucleotide polymorphisms (SNPs) on drug pharmacokinetics (PK) have usually been limited to the analysis of observed drug concentration or area under the concentration versus time curve. Nonlinear mixed effects models enable analysis of the entire curve, even for sparse data, but until recently, there has been no systematic method to examine the effects of multiple SNPs on the model parameters. OBJECTIVE: The aim of this study was to assess different penalized regression methods for including SNPs in PK analyses. METHODS: A total of 200 data sets were simulated under both the null and an alternative hypothesis. In each data set for each of the 300 participants, a PK profile at six sampling times was simulated and 1227 genotypes were generated through haplotypes. After modelling the PK profiles using an expectation maximization algorithm, genetic association with individual parameters was investigated using the following approaches: (i) a classical stepwise approach, (ii) ridge regression modified to include a test, (iii) Lasso and (iv) a generalization of Lasso, the HyperLasso. RESULTS: Penalized regression approaches are often much faster than the stepwise approach. There are significantly fewer true positives for ridge regression than for the stepwise procedure and HyperLasso. The higher number of true positives in the stepwise procedure was accompanied by a higher count of false positives (not significant). CONCLUSION: We find that all approaches except ridge regression show similar power, but penalized regression can be much less computationally demanding. We conclude that penalized regression should be preferred over stepwise procedures for PK analyses with a large panel of genetic covariates. PMID- 23337848 TI - A polymorphism in the protein kinase C gene PRKCB is associated with alpha2 adrenoceptor-mediated vasoconstriction. AB - OBJECTIVES: alpha2-Adrenoceptors (alpha2-AR) mediate both constriction and dilatation of blood vessels. There is considerable interindividual variability in dorsal hand vein (DHV) constriction responses to alpha2-AR agonist activation. Genetic factors appear to contribute significantly to this variation. The present study was designed to identify the genetic factors contributing toward the interindividual variability in alpha2-AR-mediated vascular constriction induced by the selective alpha2-AR agonist dexmedetomidine. METHODS: DHV constriction responses to a local infusion of dexmedetomidine were assessed by measuring changes in vein diameter with a linear variable differential transformer. The outcome variable for constriction was log-transformed dexmedetomidine ED50. A genome-wide association study (GWAS) of 433 378 single-nucleotide polymorphisms (SNPs) was carried out for determining the sensitivity of DHV responses in 64 healthy Finnish individuals. Twenty SNPs were selected on the basis of the GWAS results and their associations with the ED50 of dexmedetomidine were tested in an independent North American study population of 68 healthy individuals. RESULTS: In both study populations (GWAS and replication samples), the SNP rs9922316 in the gene for protein kinase C type beta was consistently associated with dexmedetomidine ED50 for DHV constriction (unadjusted P=0.00016 for the combined population). CONCLUSION: Genetic variation in protein kinase C type beta may contribute toward the interindividual variation in DHV constriction responses to alpha2-AR activation by the agonist dexmedetomidine. PMID- 23337850 TI - In-vivo analysis of thoracic mechanical response under belt loading: the role of body mass index in thorax stiffness. AB - Thoracic injuries are a major cause of mortality in frontal collisions, especially for elderly and obese people. Car occupant individual characteristics like BMI are known to influence human vulnerability in crashes. In the present study, thoracic mechanical response of volunteers quantified by optical method was linked to individual characteristics. 13 relaxed volunteers of different anthropometries, genders and age were submitted to non-injurious sled tests (4 g, 8 km/h) with a sled buck representing the environment of a front passenger restrained by a 3-point belt. A resulting shoulder belt force was computed using the external and internal shoulder belt loads and considering shoulder belt geometry. The mid sternal deflection was calculated as the distance variation between markers placed at mid-sternum and the 7th vertebra spinous process of the subject. Force-deflection curves were constructed using resulting shoulder belt force and midsternal deflection. Average maximum chest compression was 7.9+/-2.3% and no significant difference was observed between overweight subjects (BMI>=25 kg/m2) and normal subject (BMI<25 kg/m2). The overweight subjects exhibited significantly greater resultant belt forces than normal subjects (715+/-132 N vs. 527+/-111 N, p<0.05), higher effective stiffness (30.9+/-10.6N/mm vs. 19.6+/-8.9 N/mm, p<0.05) and lower dynamic stiffness (42.7+/-8.71 N/mm vs. 61.7+/-15.5 N/mm, p<0.05). PMID- 23337851 TI - The effects of damage accumulation on the tensile strength and toughness of compact bovine bone. AB - Damage accumulation in compact bovine femur subjected to uniaxial tensile loading was examined by strong light illumination effects of microcracking. Imaging was done using a high-speed camera capturing image at 200 to 1500FPS. The tensile tests were performed in a multipurpose tensile testing system with cross-head speeds ranging from 0.5 to 10mm/min which leads to strain rates of 0.0001 to 0.0012s(-1) (physiologically relevant to walking and running Hansen et al., 2008). The post-failure images were then examined in a scanning electron microscopy (SEM) and effects of microstructure, strain rate, and orientation were evaluated. Correlation of the high-speed images with stress-strain curves indicated that optically visible microcracks were most likely initiated at yielding, and the specimens with dispersed microcracks exhibited a higher energy absorption capacity compared to the specimens with coalesced local cracks. It was found that damage accumulation negatively correlates to strain rate and that transverse specimens exhibited a different failure pattern compared to the longitudinal specimens. Strain hardening and softening were found in the longitudinal and transverse specimens respectively. The microcracking in the transverse specimens instantly increased to peak after yielding compared to the gradual growth until failure in the longitudinal specimens. The average Young's modulus (21.5GPa) and ultimate stress (93.5MPa) of the specimens loaded in the longitudinal direction were more than twice that of the specimens (10.9GPa and 36.2MPa respectively) loaded in the transverse direction. The current technique has shown potential in relating damage accumulation real time in bone samples subjected to tensile loading condition. This information will be helpful in relating the role of micro damage accumulation in initiating failure and/or remodeling in bone. PMID- 23337852 TI - Cytoplasmic organelles on the road to mRNA decay. AB - Localization of both mRNAs and mRNA decay factors to internal membranes of eukaryotic cells provides a means of coordinately regulating mRNAs with common functions as well as coupling organelle function to mRNA turnover. The classic mechanism of mRNA localization to membranes is the signal sequence-dependent targeting of mRNAs encoding membrane and secreted proteins to the cytoplasmic surface of the endoplasmic reticulum. More recently, however, mRNAs encoding proteins with cytosolic or nuclear functions have been found associated with various organelles, in many cases through unknown mechanisms. Furthermore, there are several types of RNA granules, many of which are sites of mRNA degradation; these are frequently found associated with membrane-bound organelles such as endosomes and mitochondria. In this review we summarize recent findings that link organelle function and mRNA localization to mRNA decay. This article is part of a Special Issue entitled: RNA Decay mechanisms. PMID- 23337853 TI - The fate of the messenger is pre-determined: a new model for regulation of gene expression. AB - Recent years have seen a rise in publications demonstrating coupling between transcription and mRNA decay. This coupling most often accompanies cellular processes that involve transitions in gene expression patterns, for example during mitotic division and cellular differentiation and in response to cellular stress. Transcription can affect the mRNA fate by multiple mechanisms. The most novel finding is the process of co-transcriptional imprinting of mRNAs with proteins, which in turn regulate cytoplasmic mRNA stability. Transcription therefore is not only a catalyst of mRNA synthesis but also provides a platform that enables imprinting, which coordinates between transcription and mRNA decay. Here we present an overview of the literature, which provides the evidence of coupling between transcription and decay, review the mechanisms and regulators by which the two processes are coupled, discuss why such coupling is beneficial and present a new model for regulation of gene expression. This article is part of a Special Issue entitled: RNA Decay mechanisms. PMID- 23337855 TI - RNA decay machines: deadenylation by the Ccr4-not and Pan2-Pan3 complexes. AB - Shortening and removal of the 3' poly(A) tail of mature mRNA by poly(A)-specific 3' exonucleases (deadenylases) is the initial and often rate-limiting step in mRNA degradation. The majority of cytoplasmic deadenylase activity is associated with the Ccr4-Not and Pan2-Pan3 complexes. Two distinct catalytic subunits, Caf1/Pop2 and Ccr4, are associated with the Ccr4-Not complex, whereas the Pan2 enzymatic subunit forms a stable complex with Pan3. In this review, we discuss the composition and activity of these two deadenylases. In addition, we comment on generic and specific mechanisms of recruitment of Ccr4-Not and Pan2-Pan3 to mRNAs. Finally, we discuss specialised and redundant functions of the deadenylases and review the importance of Ccr4-Not subunits in the regulation of physiological processes. This article is part of a Special Issue entitled: RNA Decay mechanisms. PMID- 23337856 TI - Invited commentary. PMID- 23337854 TI - Roles of helicases in translation initiation: a mechanistic view. AB - The goal of this review is to summarize our current knowledge about the helicases involved in translation initiation and their roles in both general and mRNA specific translation. The main topics covered are the mechanisms of helicase action, with emphasis on the roles of accessory domains and proteins; the functions performed by helicases in translation initiation; and the interplay between direct and indirect effects of helicases that also function in steps preceding translation initiation. Special attention is given to the dynamics of eIF4A binding and dissociation from eIF4F during mRNA unwinding. It is proposed that DHX29, as well as other helicases and translation initiation factors could also cycle on and off the translation initiation complexes, similar to eIF4A. The evidence in favor of this hypothesis and its possible implications for the mechanisms of translation initiation is discussed. This article is part of a Special Issue entitled: The biology of RNA helicases - Modulation for life. PMID- 23337858 TI - Invited commentary. PMID- 23337857 TI - The results of stent graft versus medication therapy for chronic type B dissection. AB - OBJECTIVE: This prospective multicenter comparative study examined early and midterm results of medication and stent-graft therapies on chronic type B aortic dissection in China. METHODS: The study consisted of 303 consecutive patients with chronic type B aortic dissection from four centers in China from January 2007 to December 2010 who were prospectively enrolled and treated by either optimal medical therapy (OMT) or thoracic endovascular aorta repair (TEVAR). Of the patients, 219 were male and 84 were female (average age, 53.6 +/- 20.3 years; range, 29-81 years). Baseline diameter of the thoracic aorta was 41.2 (19.1) mm (mean [standard deviation]), and dissection extended beyond the celiac axis in 87.1% of cases. RESULTS: In total, there were 208 patients in the TEVAR group and 95 patients in the OMT group. Procedural success was 100%, and no deaths occurred during index hospitalization in the two groups. In the TEVAR group, two patients (0.9%) suffered from retrograde type A dissection, and two (0.9%) suffered from paraplegia or paraparesis. For in-hospital outcome, multivariate analysis revealed that age >75 years and American Society of Anesthesiologists class greater than III were independent predictors of major early adverse events. Average follow-up time for hospital survivors was 28.5 +/- 16.3 months (range, 1.0-58 months). In the OMT group, five patients died from rupture of an enlarged false lumen, and six patients died suddenly of unknown reasons. Fourteen cases required crossover to TEVAR (n = 12) or surgical conversion (n = 2). In the TEVAR group, nine patients required reintervention or surgical conversion, and one died of postoperative multi-organ failure. One patient died of delayed retrograde type A dissection, and four died suddenly of unknown reasons. The Kaplan-Meier analysis of survival probability at 2 and 4 years was 87.5% and 82.7% with TEVAR, respectively, and 77.5% and 69.1% with OMT, respectively (P = .0678, log-rank test). The estimated cumulative freedom from aorta-related death at 2 and 4 years was 91.6% and 88.1% with TEVAR, respectively, and 82.8% and 73.8% with OMT, respectively (P = .0392, log-rank test). The thoracic aorta diameter decreased from 42.4 (23.1) mm to 37.3 (12.8) mm in the TEVAR group and increased from 40.7 (18.6) mm to 48.1 (17.3) mm in the OMT group. CONCLUSIONS: This was the first prospective multicenter comparative study on the treatment of type B aortic dissection in China. TEVAR had a significantly lower aorta-related mortality compared with OMT but failed to improve overall survival rate or lower the aorta related adverse event rate. PMID- 23337859 TI - Setting high-impact clinical research priorities for the Society for Vascular Surgery. AB - With the overall goal of enhancing the effectiveness and efficiency of vascular care, the Society for Vascular Surgery (SVS) recently completed a process by which it identified its top clinical research priorities to address critical gaps in knowledge guiding practitioners in prevention and treatment of vascular disease. After a survey of the SVS membership, a panel of SVS committee members and opinion leaders considered 53 distinct research questions through a structured process that resulted in identification of nine clinical issues that were felt to merit immediate attention by vascular investigators and external funding agencies. These are, in order of priority: (1) define optimal management of asymptomatic carotid stenosis, (2) compare the effectiveness of medical vs invasive treatment (open or endovascular) of vasculogenic claudication, (3) compare effectiveness of open vs endovascular infrainguinal revascularization as initial treatment of critical limb ischemia, (4) develop and compare the effectiveness of clinical strategies to reduce cardiovascular and other perioperative complications (eg, wound) after vascular intervention, (5) compare the effectiveness of strategies to enhance arteriovenous fistula maturation and durability, (6) develop best practices for management of chronic venous ulcer, (7) define optimal adjunctive medical therapy to enhance the success of lower extremity revascularization, (8) identify and evaluate medical therapy to prevent abdominal aortic aneurysm growth, and (9) evaluate ultrasound vs computed tomographic angiography surveillance after endovascular aneurysm repair. PMID- 23337860 TI - The Vascular Research Initiatives Conference and over 25 years of conversations on the science of vascular disease. PMID- 23337861 TI - Migration of the ringed ePTFE graft into the small intestine. PMID- 23337862 TI - Management approach to an extracranial internal carotid artery aneurysm. PMID- 23337863 TI - Systematic review and meta-analysis of open surgical and endovascular management of thoracic outlet vascular injuries. AB - BACKGROUND: Junctional vascular trauma such as that at the thoracic outlet poses particular challenges in surgical management. The use of endovascular techniques for such injuries is attractive as repair may be facilitated without the need for thoracotomy; however, the utility of such techniques is currently based on opinion, small retrospective series, and literature reviews of narrative and not systematic quality. The objective of this study is to provide a complete and systematic analysis of the literature pertaining to open surgery (OS) and endovascular management (EM) of thoracic outlet vascular injuries. METHODS: An electronic search using the MEDLINE, Embase, Cochrane Library, Science Citation Index, and LILACS databases was performed for articles published from 1947 to November 2011. The review conformed to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement standards. Prospective studies and retrospective cohorts of more than 10 patients were included. The primary outcome was all-cause mortality. RESULTS: One prospective noncomparative study and 73 retrospective series met the inclusion criteria. There were no randomized studies. All studies were at high risk of bias. Fifteen studies described outcomes for both OS and EM (549 patients). The majority of these studies described EM for traumatic arteriovenous fistulas or false aneurysms in stable patients. Direct comparison between OS and EM was possible in only three studies (comprising 23 OS and 25 EM patients), which showed no difference in all-cause mortality (odds ratio, 0.67; 95% confidence interval [CI], 0.11-4.05), but a shorter operating time with EM (mean difference = 58.34 minutes; 95% CI, 17.82 98.85). These three series included successful EM of unstable patients and those with vessel transection. There were 55 studies describing only OS (2057 patients) with a pooled mortality rate of 12.4% (95% CI, 9.9%-15.2%). Four studies described only EM (101 patients) with a pooled mortality rate of 26% (95% CI, 8% 51%), but these represented a distinct subgroup of cases (mainly iatrogenic injuries in older patients). CONCLUSIONS: The current evidence is weak and fails to show superiority of one modality over the other. EM is currently used primarily in highly selected cases, but there are reports of a broader applicability in trauma. High-quality randomized studies or large-scale registry data are needed to further comment on the relative merits or disadvantages of EM in comparison to OS. PMID- 23337864 TI - Operating one-handed: emergency treatment of Jehovah's Witnesses. AB - An elderly woman was brought to the emergency room (ER) hypotensive in a confused mental state from what turned out at exploration to be a ruptured splenic artery aneurysm. You are in the operating room, and the anesthesiologist has just hung the first unit of blood but has not started infusion when the ER calls. The patient and her husband were visiting their children and live in another state. Her husband, an elder in a Jehovah's Witness congregation, arrived and is adamant that she have no transfusions. Her blood pressure is dangerously low. It is being maintained by a high-dose Levophed (leave-um dead) drip and continues to slip. You have avoided operating on Jehovah's Witness patients because of the added unnecessary risk they pose. Your assistant is of like mind. What is the best ethical course at this time? PMID- 23337865 TI - Endovascular foreign body retrieval. PMID- 23337866 TI - Reply: To PMID 22819304. PMID- 23337867 TI - Regarding "A multilayer stent in the aorta may not seal the aneurysm, thereby leading to rupture". PMID- 23337868 TI - Effects of chronic buspirone treatment on nicotine and concurrent nicotine+cocaine self-administration. AB - Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal pharmacotherapy would reduce both cigarette smoking and cocaine abuse. Buspirone (Buspar) is a clinically available, non-benzodiazepine anxiolytic medication that acts on serotonin and dopamine systems. In preclinical studies, it reduced cocaine self-administration following both acute and chronic treatment in rhesus monkeys. The present study evaluated the effectiveness of chronic buspirone treatment on self-administration of intravenous (IV) nicotine and IV nicotine+cocaine combinations. Five cocaine experienced adult rhesus monkeys (Macaca mulatta) were trained to self-administer nicotine or nicotine+cocaine combinations, and food pellets (1 g) during four 1-h daily sessions under a second-order schedule of reinforcement (FR 2 (VR16:S)). Each nicotine+cocaine combination maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05-0.001). Buspirone (0.032-0.56 mg/kg/h) was administered IV through one lumen of a double-lumen catheter every 20 min for 23 h each day, for 7-10 consecutive days. Each 7-10-day sequence of buspirone treatment was followed by saline-control treatment for at least 3 days until food- and drug-maintained responding returned to baseline. Buspirone dose-dependently reduced responding maintained by nicotine alone (0.001 0.1 mg/kg/inj; P<0.01) and by nicotine (0.001 or 0.0032 mg/kg/inj)+cocaine combinations (0.0032 mg/kg/inj; P<0.05-0.001) with no significant effects on food maintained responding. We conclude that buspirone selectively attenuates the reinforcing effects of nicotine alone and nicotine+cocaine polydrug combinations in a nonhuman primate model of drug self-administration. PMID- 23337869 TI - Lack of association between COMT and working memory in a population-based cohort of healthy young adults. AB - The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is an important regulator of dopamine in the prefrontal cortex, an area critical to working memory. Working memory deficits are present in several psychiatric disorders, and there is wide variation in working memory capacity in the normal population. Association studies of COMT and working memory in healthy volunteers have yielded inconsistent results, possibly because of small sample sizes. Here we examine COMT in relation to N-Back working memory task performance in a large population-based cohort of young adults. We predicted individuals with one or two copies of the Met allele would perform better, and that this relationship would be more evident in males than females. Participants (N=1857-2659) tested at 18 years of age, were enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). We used multiple regression to examine effects of sex and COMT genotype on N-Back hits, false positives, discriminability (d'), and reaction time while controlling for important covariates. COMT genotype did not predict hits or d'. There was a nominally significant interaction between COMT and sex on false positives, but this was not in the predicted direction, and was not significant after controlling for covariates. COMT genotype was not related to working memory in this large population-based cohort. It is possible COMT is not meaningfully associated with working memory in healthy young adults, or that COMT effects are detectable only in assessments reflecting neural processes underlying cognition, such as fMRI, rather than in behavioral performance. PMID- 23337870 TI - Trendspotting in the Protein Data Bank. AB - The Protein Data Bank (PDB) was established in 1971 as a repository for the three dimensional structures of biological macromolecules. Since then, more than 85000 biological macromolecule structures have been determined and made available in the PDB archive. Through analysis of the corpus of data, it is possible to identify trends that can be used to inform us abou the future of structural biology and to plan the best ways to improve the management of the ever-growing amount of PDB data. PMID- 23337871 TI - Identification and characterization of PtDGAT2B, an acyltransferase of the DGAT2 acyl-coenzyme A: diacylglycerol acyltransferase family in the diatom Phaeodactylum tricornutum. AB - Diacylglycerol acyltransferase (DGAT) plays a pivotal role in triacylglycerol (TAG) formation in some oleaginous organisms. We describe here the identification of a type 2 DGAT (PtDGAT2B) in the diatom Phaeodactylum tricornutum that contains four putative type 2 acyl-CoA:DGATs, sharing little sequence similarity with each other. TAG synthesis and lipid body formation could be completely restored in a Saccharomyces cerevisiae TAG-deficient quadruple mutant by expressing PtDGAT2B. Up-regulation of PtDGAT2B precedes the accumulation of TAG. Functional analysis of enzyme activity in vivo demonstrated that expression of PtDGAT2B can increase the proportion of unsaturated C(16) and C(18) fatty acids in yeast TAG. PMID- 23337873 TI - Formation of protein complexes in crowded environments--from in vitro to in vivo. AB - Traditionally, biochemical studies are performed in dilute homogenous solutions, which are very different from the dense mixture of molecules found in cells. Thus, the physiological relevance of these studies is in question. This recognition motivated scientists to formulate the effect of crowded solutions in general, and excluded volume in particular, on biochemical processes. Using polymers or proteins as crowders, it was shown that while crowding tends to significantly enhance the formation of complexes containing many subunits, dimerizations are only mildly affected. Computer simulations, together with experimental evidence, indicate soft interactions and diffusion as critical factors that operate in a concerted manner with excluded volume to modulate protein binding. Yet, these approaches do not truly mimic the cellular environment. In vivo studies may overcome this shortfall. The few studies conducted thus far suggest that in cells, binding and folding occur at rates close to those determined in dilute solutions. Obtaining quantitative biochemical information on reactions inside living cells is currently a main challenge of the field, as the complexity of the intracellular milieu was what motivated crowding research to begin with. PMID- 23337872 TI - Mechanisms of islet amyloidosis toxicity in type 2 diabetes. AB - Amyloid formation by the neuropancreatic hormone, islet amyloid polypeptide (IAPP or amylin), one of the most amyloidogenic sequences known, leads to islet amyloidosis in type 2 diabetes and to islet transplant failure. Under normal conditions, IAPP plays a role in the maintenance of energy homeostasis by regulating several metabolic parameters, such as satiety, blood glucose levels, adiposity and body weight. The mechanisms of IAPP amyloid formation, the nature of IAPP toxic species and the cellular pathways that lead to pancreatic beta-cell toxicity are not well characterized. Several mechanisms of toxicity, including receptor and non-receptor-mediated events, have been proposed. Analogs of IAPP have been approved for the treatment of diabetes and are under investigation for the treatment of obesity. PMID- 23337875 TI - Genome-wide characterization of the relationship between essential and TATA containing genes. AB - Essential genes are involved in most survival-related housekeeping functions. TATA-containing genes encode proteins involved in various stress-response functions. However, because essential and TATA-containing genes have been researched independently, their relationship remains unclear. The present study classified Saccharomyces cerevisiae genes into four groups: non-essential non TATA, non-essential TATA, essential non-TATA, and essential TATA genes. The results showed that essential TATA genes have the most significant codon bias, the highest level of expression, and unique characteristics, including a large number of transcription factor binding sites, a higher degree in protein interaction networks, and significantly different amino acid usage patterns compared with the other gene groups. Notably, essential TATA genes were uniquely involved in functions such as unfolded protein binding, glycolysis, and alcohol and steroid-related processes. PMID- 23337874 TI - Native mass spectrometry of photosynthetic pigment-protein complexes. AB - Native mass spectrometry (MS), or as is sometimes called "native electrospray ionization" allows proteins in their native or near-native states in solution to be introduced into the gas phase and interrogated by mass spectrometry. This approach is now a powerful tool to investigate protein complexes. This article reviews the background of native MS of protein complexes and describes its strengths, taking photosynthetic pigment-protein complexes as examples. Native MS can be utilized in combination with other MS-based approaches to obtain complementary information to that provided by tools such as X-ray crystallography and NMR spectroscopy to understand the structure-function relationships of protein complexes. When additional information beyond that provided by native MS is required, other MS-based strategies can be successfully applied to augment the results of native MS. PMID- 23337876 TI - Differential roles of miR-199a-5p in radiation-induced autophagy in breast cancer cells. AB - Autophagy is a self-degrading process that is triggered by diverse stimuli including ionizing radiation. In this study we show novel phenomena in which transfection of miR-199a-5p mimic significantly suppresses IR-induced autophagy in MCF7 cells, and up-regulates basal and IR-induced autophagy in MDA-MB-231 breast cancer cells. We also identify DRAM1 and Beclin1 as novel target genes for miR-199a-5p. Overexpression of miR-199a-5p inhibits DRAM1 and Beclin1 expression in MCF7 cells, while it enhances expression of these genes in MDA-MB-231 cells. Furthermore, we show that miR-199a-5p sensitizes MDA-MB-231 cells to irradiation. Therefore, our data identify miR-199a-5p as a novel and unique regulator of autophagy, which plays an important role in cancer biology and cancer therapy. PMID- 23337877 TI - A feedback regulation between Kindlin-2 and GLI1 in prostate cancer cells. AB - Kindlin-2 is engaged in tumor progression. However, the mechanism accounting for Kindlin-2 regulation in tumor cells remained largely unknown. Here, we report a regulatory loop between Kindlin-2 and GLI1, an effector of Hedgehog signaling pathway. We show that Kindlin-2 is transcriptionally downregulated via GLI1 occupancy on the Kindlin-2 promoter. Adversely, we found that Kindlin-2 promotes GLI1 expression through a mechanism involving GSK3beta inactivation and is independent of Smoothened. Functionally, knockdown of Kindlin-2 cooperates with cyclopamine, a Smoothened antagonist, to decrease the viability of prostate cancer cells. Taken together, targeting the Kindlin-2-GLI1 feedback loop may facilitate the killing of prostate cancer cells. PMID- 23337878 TI - Recombinant expression of soluble murine prion protein for C-terminal modification. AB - Membrane attachment of prion protein (PrP) via its glycosylphosphatidylinositol (GPI) anchor plays a key role during conversion of cellular PrP(C) into its pathogenic isoform PrP(Sc). Strategies to access homogenous lipidated PrP via expressed protein ligation (EPL) are required to fully decipher the effect of membrane attachment. Such strategies suffer from insoluble expression of PrP intein fusion constructs and low folding efficiencies that severely limit the available amount of homogeneous lipidated PrP. Here, we describe an alternative method for expression of soluble PrP-intein fusion proteins in Escherichia coli that provides access to natively folded PrP ready to use in EPL. PMID- 23337879 TI - MiR-214 reduces cell survival and enhances cisplatin-induced cytotoxicity via down-regulation of Bcl2l2 in cervical cancer cells. AB - MiR-214 has been shown to inhibit cell growth, migration and invasion. Here we demonstrate that ectopic expression of miR-214 reduces cell survival, induces apoptosis and enhances sensitivity to cisplatin through directly inhibiting Bcl2l2 expression in cervical cancer HeLa and C-33A cells. Further analysis reveals that apoptosis induced by miR-214 is correlated with increased expression of Bax, caspase-9, caspase-8 and caspase-3. Moreover, we show that miR-214 is regulated by DNA methylation and histone deacetylation. Taken together, these data suggest that miR-214 might be a candidate target for the development of novel therapeutic strategies to treat cervical cancer. PMID- 23337880 TI - The new view of hydrophobic free energy. AB - In the new view, hydrophobic free energy is measured by the work of solute transfer of hydrocarbon gases from vapor to aqueous solution. Reasons are given for believing that older values, measured by solute transfer from a reference solvent to water, are not quantitatively correct. The hydrophobic free energy from gas-liquid transfer is the sum of two opposing quantities, the cavity work (unfavorable) and the solute-solvent interaction energy (favorable). Values of the interaction energy have been found by simulation for linear alkanes and are used here to find the cavity work, which scales linearly with molar volume, not accessible surface area. The hydrophobic free energy is the dominant factor driving folding as judged by the heat capacity change for transfer, which agrees with values for solvating hydrocarbon gases. There is an apparent conflict with earlier values of hydrophobic free energy from studies of large-to-small mutations and an explanation is given. PMID- 23337881 TI - Augmenter of liver regeneration improves therapeutic effect of hepatocyte homotransplantation in acute liver failure rats. AB - Hepatocyte transplantation (HCT) is an available option on treatment for acute liver failure (ALF). However, short-term survival of engraftment and immunological rejections of recipient are major obstacles. Augmenter of liver regeneration (ALR) has cytoprotective and immunoregulatory effects in liver injury, and has been used in many experimental applications. In the present study, we investigated the potential effect and mechanism of recombinant human ALR (rhALR) on ALF rats treated with intraperitoneal HCT. ALF rats induced by d galactosamine (GalN) were studied in vivo, and were intraperitoneal injected with or without hepatocytes and rhALR 24h after the induction. Animal survival, serum and ascites liver enzymes, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were assessed. Histological examination was performed, and liver regeneration, apoptosis and immunological responses were identified by immunohistochemistry assay. Our results showed that rhALR promoted hepatocytes regeneration, attenuated liver injury and suppressed immunological responses. The ascites liver enzyme, serum and ascites pro-inflammatory cytokines (TNF-alpha, IL-1beta), liver histological injury, apoptotic hepatocytes and activated immunocytes were significantly reduced in ALF rats treated with rhALR and HCT compared with those without rhALR. The proliferative and mitotic hepatocytes were markedly increased, and overall survival improved with rhALR. The administration of rhALR improved survival and promoted liver recovery in HCT treatment for ALF, which was associated with the role of proliferative promoter and immunosuppressor. This study suggests that co-treated with rhALR and HCT can provide a promising strategy for the treatment of ALF. PMID- 23337882 TI - Sorafenib induces autophagy and suppresses activation of human macrophage. AB - BACKGROUND: Sorafenib, a multi-kinase inhibitor approved for treatment of advanced renal cell carcinoma and other malignancies, has been shown as a modulator for dendritic cells. This study was designed to examine the effects of sorafenib on macrophages, the major ontogeny of innate immunity. MATERIALS AND METHODS: Macrophages were derived from sorted CD14(+) monocytes of human peripheral blood mononuclear cells. Cell viability and surface antigens were examined by trypan blue analysis. Autophagy was characterized by light microscopy and transmission electron microscopy for morphology, Western blotting for microtubule associated light chain protein 3B (LC-3B) I lipidation, and acridine orange staining for acidic component vacuoles. Soluble factors contained in culture medium and serum were measured by ELISA. RESULTS: We found that sorafenib inhibited the viability of macrophages accompanied by morphological changes characteristic of autophagy. This autophagy-inducing effect was validated by LC3B I lipidation and autophagosome accumulation. The surface antigen expression and the function of activated macrophages were inhibited by sorafenib, including the expression of co-stimulatory molecule CD80, phagocytosis, and the production of reactive oxygen species. The secretion of IL-10, but not IL-6, TNF-alpha nor TGF beta, was reduced by sorafenib. CONCLUSION: Sorafenib, in addition to being a cancer targeted therapeutic agent, can induce autophagy and modulate the function of human macrophages. PMID- 23337883 TI - Real-time forecasting of Hong Kong beach water quality by 3D deterministic model. AB - Bacterial level (e.g. Escherichia coli) is generally adopted as the key indicator of beach water quality due to its high correlation with swimming associated illnesses. A 3D deterministic hydrodynamic model is developed to provide daily water quality forecasting for eight marine beaches in Tsuen Wan, which are only about 8 km from the Harbour Area Treatment Scheme (HATS) outfall discharging 1.4 million m(3)/d of partially-treated sewage. The fate and transport of the HATS effluent and its impact on the E. coli level at nearby beaches are studied. The model features the seamless coupling of near field jet mixing and the far field transport and dispersion of wastewater discharge from submarine outfalls, and a spatial-temporal dependent E. coli decay rate formulation specifically developed for sub-tropical Hong Kong waters. The model prediction of beach water quality has been extensively validated against field data both before and after disinfection of the HATS effluent. Compared with daily beach E. coli data during August-November 2011, the model achieves an overall accuracy of 81-91% in forecasting compliance/exceedance of beach water quality standard. The 3D deterministic model has been most valuable in the interpretation of the complex variation of beach water quality which depends on tidal level, solar radiation and other hydro-meteorological factors. The model can also be used in optimization of disinfection dosage and in emergency response situations. PMID- 23337884 TI - Catechin inhibits Candida albicans dimorphism by disrupting Cek1 phosphorylation and cAMP synthesis. AB - Candida albicans is a fungal pathogen that undergoes dimorphism (transformation from a yeast form to a hyphal form), wherein, the yeast form is identified as a disseminating form that plays a critical role in the early stages of Candida disease progression, while the hyphal form is found to exert additional pathogenicity by adapting to various environmental conditions. Here, we elucidated the effects of catechin on C. albicans hyphal formation. Flow cytometry analysis showed catechin inhibited FCS-induced hyphal formation. Moreover, hypha-specific gene expression in MAP kinase cascade and cAMP pathway was decreased ascribable to catechin. Furthermore, through Western blotting and cAMP synthesis analysis, we found catechin obstructs Cek1 phosphorylation in MAP kinase cascade and suppresses cAMP synthesis. These results suggest that catechin possesses anti-dimorphism activity by interfering with in vitro signal transduction. Similarly, this highlights the possible application of catechin in clinical therapy for the management and prevention of candidosis. PMID- 23337885 TI - Determination of antibodies against human growth hormone using a direct immunoassay format and different electrochemical methods. AB - A direct immunoassay format with human growth hormone (hGH) immobilized on a self assembled monolayer modified surface plasmon resonance (SPR) chip was chosen to detect specific antibodies (anti-hGH) using different electrochemical techniques. Atomic force microscopy imaging and SPR were used as control methods for the evaluation and confirmation of the antigen-antibody complex formation. The applicability and sensitivity of candidate electrochemical techniques to develop an accurate and sensitive electrochemical immunosensor were investigated. Four electrochemical methods for anti-hGH determination - pulse amperometry (PA), cyclic voltammetry (CV), square wave voltammetry (SWV) and differential pulse voltammetry (DPV), were compared. Higher sensitivity of the developed immunosensor was observed using PA and CV: analytical signal registered using the PA method was 2.50 times higher in comparison with CV, 16.3 times higher in comparison with SWV and 24.5 times higher in comparison with the DPV method. In the case of PA detection method, the limit of detection was lower (75 nM) than that of the CV method (108 nM). PMID- 23337886 TI - Enzymatic regioselective acylation of nucleosides in biomass-derived 2 methyltetrahydrofuran: kinetic study and enzyme substrate recognition. AB - Enzymatic regioselective acylation of pyrimidine nucleosides was mediated by immobilized lipase from Penicillium expansum in 2-methyltetrahydrofuran (MeTHF), a bio-solvent derived from biomass. Despite of the moderate dissolution ability of MeTHF toward nucleosides, the initial enzymatic reaction rate was much higher in this eco-friendly solvent than in other commonly used organic solvents. This could be explained by the lower apparent activation energy of the enzymatic reaction (24.5 vs. 43.3-57.1kJ/mol) and the higher catalytic efficiency of the enzyme (Vmax/Km, 5.8 vs. 1.1-2.9h(-1)) in MeTHF. The enzymatic acylation of a group of ribonucleosides afforded the desirable 5'-esters with the conversions of 96-99% and 5'-regioselectivities of 96 to >99%. In enzymatic acylation of 2' deoxynucleosides, however, 5'-regioselectivities showed a clear dependence on the 5-substituents present in the base moiety although the substrate conversions reached >98% within 1-3h. In the cases of 2',3'-dideoxynucleoside analogs, the reaction rate decreased markedly due to the lack of 3'-hydroxyl. PMID- 23337887 TI - Primary cutaneous CD30-positive T-cell lymphoproliferative disorders with biallelic rearrangements of DUSP22. PMID- 23337888 TI - Constitutive RAC activation is not sufficient to initiate melanocyte neoplasia but accelerates malignant progression. AB - Deregulated Ras signaling initiates and maintains melanocyte neoplasia. The Rho like GTPase Rac has been implicated in Ras-induced neoplastic transformation. Moreover, a recurrent UV-induced mutation activating RAC1 has recently been detected in human melanoma. Here, a role for Rac in melanoma initiation and progression was investigated in human melanomas and zebrafish models of melanocyte neoplasia. Immunohistochemical analysis revealed RAC expression and activity restricted to melanocytes at the junction of the epidermis and dermis in benign neoplasms. Malignant melanocytes displayed elevated RAC activity that extended into the suprabasal epidermis, deeper into the dermis, and was maintained in metastases. Previously, we have used zebrafish transgenic models to demonstrate that deregulated Ras/Raf/mitogen-activated protein kinase signaling can initiate melanocyte neoplasia. Expression of a constitutively active RAC1 mutant (V12RAC1) was not sufficient to initiate melanocyte neoplasia in this organism. Furthermore, we did not detect an additive effect when combined with V600EBRAF, nor could V12RAC1 substitute for suppressed Pi3k signaling to restore melanoma progression. However, coexpression of V12RAC1 and oncogenic RAS accelerated tumor nodule formation. Immunohistochemical analysis revealed that the Rac activator Tiam1 (T-cell lymphoma invasion and metastasis 1) is overexpressed in melanoma tumor nodules in both zebrafish and humans. Thus, our data suggest that Rac contributes to the progression of melanoma and that Tiam1 may activate Rac in nodular presentations. PMID- 23337889 TI - Prolonged activation of ERK contributes to the photorejuvenation effect in photodynamic therapy in human dermal fibroblasts. AB - Photodynamic therapy (PDT) is known to be effective in the photorejuvenation of photoaged skin. However, the molecular mechanisms of rejuvenation by PDT remain elusive. In this study, we aimed to understand the molecular events occurring during the photorejuvenation after PDT in dermal fibroblasts in vitro. First, we found that PDT conditions resulted in an increased fibroblast proliferation and motility in vitro. Under this condition, cells had increased intracellular reactive oxygen species (ROS) production. Importantly, PDT induced a prolonged activation of extracellular signal-regulated kinase (ERK) with a corresponding increase in matrix metalloproteinase (MMP)-3 and collagen type Ialpha messenger RNA and protein. Moreover, inhibition of PDT-induced ERK activation significantly suppressed fibroblast proliferation and expression of MMP-3 and collagen type Ialpha following PDT. In addition, NAC (an antioxidant) inhibited PDT-induced fibroblast proliferation and ERK activation indicating that prolonged ERK activation and intracellular ROS contribute to the proliferation of fibroblasts and the dermal remodeling process for skin rejuvenation. We also identified increased collagen volume and decreased elastotic materials that are used as markers of photoaging in human skin samples using histochemical studies. Results from this study suggest that intracellular ROS stimulated by PDT in dermal fibroblasts lead to prolonged activation of ERK and, eventually, fibroblast proliferation and activation. Our data thus reveal a molecular mechanism underlying the skin rejuvenation effect of PDT. PMID- 23337891 TI - Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell. AB - Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a sebaceous nevus and a speckled lentiginous nevus. The coexistence of an epidermal and a melanocytic nevus has been explained by two homozygous recessive mutations, according to the twin spot hypothesis, of which PPK has become a putative paradigm in humans. However, the underlying gene mutations remained unknown. Multiple tissues of six patients with PPK were analyzed for the presence of RAS, FGFR3, PIK3CA, and BRAF mutations using SNaPshot assays and Sanger sequencing. We identified a heterozygous HRAS c.37G>C (p.Gly13Arg) mutation in four patients and a heterozygous HRAS c.182A>G (p.Gln61Arg) mutation in two patients. In each case, the mutations were present in both the sebaceous and the melanocytic nevus. In the latter lesion, melanocytes were identified to carry the HRAS mutation. Analysis of various nonlesional tissues showed a wild-type sequence of HRAS, consistent with mosaicism. Our data provide no genetic evidence for the previously proposed twin spot hypothesis. In contrast, PPK is best explained by a postzygotic-activating HRAS mutation in a multipotent progenitor cell that gives rise to both a sebaceous and a melanocytic nevus. Therefore, PPK is a mosaic RASopathy. PMID- 23337892 TI - Respiratory syncytial virus infections in infants and children with congenital heart disease: update on the evidence of prevention with palivizumab. AB - PURPOSE OF REVIEW: Lower respiratory tract infections multiply morbidity and mortality within patients with significant congenital heart disease (CHD). For respiratory syncytial virus (RSV), one of the most important pathogens, immunoprophylaxis with palivizumab has successfully been introduced. The question is which patients will benefit most from this costly preventive treatment. RECENT FINDINGS: The era after the introduction of palivizumab has revealed a steep decrease in mortality. The markers of success - hospital stays, admission to the intensive care unit, days on mechanical ventilation, and death - consistently favor immunoprophylaxis. The key point of treatment success remains in all cases a careful patient selection, adherence to a time limit of 30 days between the injections and early use after cardiac surgery with cardiopulmonary bypass, as well as avoidance of nosocomial-acquired infections. Preventive therapy with palivizumab in patients with CHD has been investigated in terms of operating efficiency - with the lowest costs per quality-adjusted life years compared with preterm infants with or without bronchopulmonary dysplasia. SUMMARY: The burden of RSV disease will decline, once a vaccine is available. Meanwhile, immunoprophylaxis with palivizumab is a useful tool for high-risk patients to reduce comorbidity and fatal outcome. Pharmacoeconomic considerations measuring quality-adjusted life years indicate important information about cost effectiveness. PMID- 23337890 TI - Propionibacterium acnes strain populations in the human skin microbiome associated with acne. AB - The human skin microbiome has important roles in skin health and disease. However, bacterial population structure and diversity at the strain level is poorly understood. We compared the skin microbiome at the strain level and genome level of Propionibacterium acnes, a dominant skin commensal, between 49 acne patients and 52 healthy individuals by sampling the pilosebaceous units on their noses. Metagenomic analysis demonstrated that although the relative abundances of P. acnes were similar, the strain population structures were significantly different in the two cohorts. Certain strains were highly associated with acne, and other strains were enriched in healthy skin. By sequencing 66 previously unreported P. acnes strains and comparing 71 P. acnes genomes, we identified potential genetic determinants of various P. acnes strains in association with acne or health. Our analysis suggests that acquired DNA sequences and bacterial immune elements may have roles in determining virulence properties of P. acnes strains, and some could be future targets for therapeutic interventions. This study demonstrates a previously unreported paradigm of commensal strain populations that could explain the pathogenesis of human diseases. It underscores the importance of strain-level analysis of the human microbiome to define the role of commensals in health and disease. PMID- 23337893 TI - Single-ventricle infant home monitoring programs: outcomes and impact. AB - PURPOSE OF REVIEW: Patients with single-ventricle, shunt-dependent physiology are at increased risk for interstage death due to the inherent instability of parallel circulation. Enhanced surveillance and early identification of deteriorating physiology via interstage home monitoring result in significant reduction in mortality. These programs are an important focus of improving outcomes for patients with single-ventricle heart disease. RECENT FINDINGS: In the multi-institutional Pediatric Heart Network Single-Ventricle Reconstruction Trial, interstage mortality was 12%, highlighting the continued opportunity to improve on this metric. A number of single-center series have demonstrated significant benefit of interstage monitoring on survival and growth. The focus on interstage monitoring by the National Pediatric Cardiology Quality Improvement Collaborative of the Joint Council on Congenital Heart Disease should improve our understanding of patients at greatest risk and help establish best practices for interstage care. In addition, a number of pilot projects utilizing newer communication technologies seek to improve the connection between program and patient. SUMMARY: Interstage home monitoring programs are a model of collaborative care that improves outcomes. Continued research in this area will refine the elements of home monitoring programs and continue to guide improved results. In addition, this model may serve as a template for the care of other populations of medically complex infants. PMID- 23337894 TI - Biomarkers for cardiovascular risk in children. AB - PURPOSE OF REVIEW: The magnitude of lifetime risk of cardiovascular disease (CVD) has radically increased along with the high prevalence of obesity in children. The spotlight is now on dysfunctional adiposity as a precursor for the development of premature CVD. As full-blown CVD is not present in childhood, there is a critical need for surrogate markers to best assess, predict, and treat the children who are vulnerable to developing CVD. RECENT FINDINGS: Accumulation of excess fat mass can be conceived as a derangement in the balance between energy intake and expenditure. This appears to provoke various structural and metabolic alterations leading to adipocyte dysfunction, with important cardiovascular health consequences. Subclinical inflammation, insulin resistance, oxidative stress, and endothelial dysfunction appear to play important roles early in the clinical course of obesity. SUMMARY: Associations between biomarkers and noninvasive measures of early atherosclerosis in children continue to emerge and several biomarkers appear to be promising. At present, there are no explicit data to recommend any of these biomarkers as a routine clinical marker of CVD in children. More work is needed to validate these biomarkers and to improve understanding of their role in CVD risk prediction in the pediatric population. PMID- 23337895 TI - Right-ventricular failure following left ventricle assist device implantation. AB - PURPOSE OF REVIEW: To review recent insights on right-ventricular failure (RVF) following left-ventricular assist device (LVAD) implantation. RECENT FINDINGS: Even with the availability of new generation continuous mechanical assist devices, RVF after implantation of LVAD is still associated with high morbidity and mortality. Recent studies have tried to better define the risk of RVF using combined clinical scores and measures of right-ventricular function or strain. Small exploratory studies have also investigated the role of pulmonary vasodilators and phosphodiesterase inhibitors in selected patients receiving LVAD implantation. SUMMARY: Measure of right-ventricular function could improve the risk stratification of RVF following LVAD implantation. Future multicenter studies are needed to validate right-ventricular risk scores and to develop evidence-guided preventive and therapeutic strategies. PMID- 23337896 TI - Add a third hook: S-acetyl protected oligophenylene pyridine dithiols as advanced precursors for self-assembled monolayers. AB - Self-assembled monolayers (SAMs) of thiols on gold substrates are potentially important systems for future technologies such as molecular electronics and sensing. Especially in molecular electronics a strong interaction and coupling between the "device" molecules and substrate is crucial. In this context, we present here two series of novel SAM precursors, viz. bidentate oligophenylenes with either 1,3-phenylenedimethanethiol or pyridine-2,6-diyldimethanethiol anchoring group. Both series are shown to form densely packed monolayers with a low level of contamination and a high orientational order that are additionally promoted by the interaction between the terminal pyridine moiety and the substrate in the second series. At the same time, most of the SAM constituents do not exhibit a strictly bidentate bonding to the substrate - whereas one anchor group has a thiolate-type bonding, the other is weakly coordinated, unbound, or participating in a disulfide bridge with the adjacent molecules. We believe that such a bonding heterogeneity stems from the fundamental problems of molecular self-assembly in the given case. PMID- 23337897 TI - Atrial fibrillation: Proportion of asymptomatic AF increases after catheter ablation. PMID- 23337898 TI - Lipids: Remnant cholesterol is associated with ischaemic heart disease. PMID- 23337899 TI - Kainic acid-induced seizure activity alters the mRNA expression and G-protein activation of the opioid/nociceptin receptors in the rat brain cortex. AB - The opioid/nociceptin receptors are involved in many neurological disorders such as Alzheimer's disease, Parkinson's disease and epilepsy. Kainic acid (KA) is an analog of the excitatory amino acid transmitter glutamate and the systemic administration of KA induces status epilepticus (SE) in rodents. In this study, we examined the alterations in the G-protein activity and the gene expression levels of mu, kappa, delta opioid and nociceptin receptors (MOPr, KOPr, DOPr and NOPr) as well as PNOC, the precursor polypeptide of nociceptin-OFQ (N/OFQ) in KA induced seizures in the rat brain cortex. KA was used to create seizures with the dose of 10 mg/kg body weight i.p. Following the KA administration, the rats were observed for 3 h to assess seizure activity. Seizures occurred approximately 45 min after the KA injection. Only rats exhibiting full limbic seizures, forelimb clonus with rearing, were used in this study. All animals were decapitated 4 h after the administration of KA. Our [(35)S]GTPgammaS binding results showed that there was a significant difference in both the affinity and efficacy particularly one of NOPr stimulation following KA treatment. Slight, but significant increase was observed for MOPr. Moreover PNOC, NOPr and MOPr mRNA levels were increased by KA treatment but there were no significant changes in the levels of DOPr and KOPr mRNAs. These results show that the activities of opioid/nociceptin receptors can be modified by KA-treatment, and MOPr, PNOC and NOPr are the most responsive to KA-induced seizures in the rat brain cortex. PMID- 23337900 TI - Diagnosis and epidemiology of leptospirosis. AB - Leptospirosis is a zoonosis found worldwide, the main reservoir of which is the rat. Human infection generally results from exposure to contaminated river or lake water or animals. Around 600 cases are diagnosed per year in France. Half of these cases occur in French overseas territories, where the incidence can be more than 100 times higher than in mainland France. Leptospirosis has been under diagnosed because of non-specific symptoms, inadequate surveillance system, and lack of readily available quick and simple diagnostic tests. Most cases of leptospirosis are currently detected by PCR amplification of bacterial DNA from the blood during the first week after the onset of symptoms, or by detection of antibodies during the second week of the disease. More than 300 serovars have been identified among leptospires, including serovar Icterohaemorrhagiae, the most frequent in human infections. Leptospirosis remains a major public health issue in many developing countries, one century after discovering the causative agent. Leptospirosis is expected to become more important due to a rapid urbanization in developing countries (slums), global warming, and extreme climatic events (floods). PMID- 23337901 TI - Benefit of conjugate pneumococcal vaccination in preventing influenza hospitalization in children: a case-control study. AB - BACKGROUND: The pneumococcal conjugate vaccine (PCV) might prevent hospitalizations in children because of the role of Streptococcus pneumoniae in the complications of influenza infection. We investigated the benefit of PCV vaccination in preventing influenza hospitalization in children <5 years of age during the 2009 to 2010 pandemic wave and the 2010 to 2011 influenza epidemic in Spain. METHODS: A multicenter matched case-control study was undertaken in 27 hospitals from 7 Spanish regions between July 2009 and April 2011. A case was defined as a hospitalized patient between 6 months and 5 years of age with influenza virus infection confirmed by real-time reverse-transcription polymerase chain reaction. We selected 2 matched controls for each case from patients with unplanned hospital admission for reasons other than acute respiratory infection or influenza-like illness. Cases and controls were matched according to age, date of hospitalization and province of residence. Crude and adjusted odds ratios were calculated for associations between influenza hospitalization and PCV vaccination. RESULTS: One hundred ninety-four cases and 342 controls were included in the study. In the 2009 to 2010 pandemic wave, the adjusted benefit in preventing hospitalization was 48% (95% confidence interval: 1 to 76) in fully vaccinated children compared with -79% (95% confidence interval: -341 to 27) in the 2010 to 2011 influenza season. CONCLUSIONS: The results obtained suggest that, in children <5 years of age, PCV vaccination reduced hospitalization during the 2009 to 2010 pandemic wave. By contrast, there was no observed benefit of vaccination in the 2010 to 2011 influenza season. PMID- 23337902 TI - Evaluation of concordance between the microorganisms detected in the nasopharynx and middle ear of children with otitis media. AB - Studies of microorganisms involved in otitis media in children often use a nasopharyngeal sample as a proxy for the middle ear fluid to test for bacteria and viruses. The question is whether such studies provide an accurate estimate of the prevalence of microorganisms involved in otitis media. We performed a systematic review of the literature reporting on the concordance between test results of nasopharyngeal and middle ear fluid samples for the most prevalent microorganisms in children with otitis media. Our findings show that the concordances vary from 68% to 97% per microorganism. For the most prevalent microbes, positive predictive values are around 50%. Most negative predictive values are moderate to high, with a range from 68% up to 97%. These results indicate that test results from nasopharyngeal samples do not always provide an accurate proxy for those of the middle ear fluid. It is important to interpret and use results of such studies carefully. PMID- 23337903 TI - Severity and outcome associated with human coronavirus OC43 infections among children. AB - BACKGROUND: Human coronaviruses are known causes of the common cold. Subtype OC43 (HCoV-OC43) is the more prevalent human coronavirus in several parts of the world. Recent studies have suggested these viruses can cause severe lower respiratory tract illnesses in children. OBJECTIVE: We sought to determine the epidemiology, clinical characteristics, outcomes and severity of illness associated with HCoV-OC43 infections in a pediatric population. METHODS: We retrospectively identified patients with positive HCoV-OC43 respiratory specimens between December 2009 and December 2010 in a pediatric hospital in Montreal. Each case was compared with 2 controls (tested negative for HCoV-OC43). Clinical characteristics, underlying conditions, outcomes and disease severity were reviewed for both groups. Risk factors and independent predictors of disease severity were also assessed. RESULTS: During the study period, 68 patients were identified as infected with HCoV-OC43 (1.8% of specimens tested, 4.2% of all respiratory viruses identified by reverse transcription polymerase chain reaction). The majority (77%) occurred in November 2010. Chief symptoms of HCoV OC43 infection were fever (in 78% of cases), cough (67%) and upper respiratory tract infection symptoms (57%). HCoV-OC43 infection was not more frequent in children with preexisting conditions. Coinfection with other respiratory viruses was associated with lower respiratory tract infections in HCoV-OC43-infected cases, but did not lead to increased rates of hospitalization, admission to intensive care unit or death. CONCLUSIONS: In our population, HCoV-OC43 infections generally caused upper respiratory tract infection, but can be associated with lower respiratory tract infection especially in those coinfected with other respiratory viruses. PMID- 23337904 TI - Distribution of respiratory syncytial virus subtypes A and B among infants presenting to the emergency department with lower respiratory tract infection or apnea. AB - BACKGROUND: Respiratory syncytial virus (RSV), a leading viral respiratory pathogen worldwide, has 2 major subtypes, A and B. OBJECTIVE: To describe the temporal and geographic distribution and parameters of disease severity associated with RSV A and B in the United States. METHODS: A US multicenter active surveillance study was conducted in emergency departments (EDs) during 2 RSV seasons. Infants <1 year of age presenting to the ED with symptoms of lower respiratory tract infection or apnea were enrolled. RSV subtypes were detected in nasal swabs by reverse transcriptase polymerase chain reaction. RESULTS: Of 4248 patients enrolled, 4172 patients were evaluable; 32.4% of patients were positive for any RSV subtype in season 1 and 29.9% in season 2. RSV A and B were detected in each region studied. More patients presented to the ED with RSV A than with RSV B (853 [20.4%] versus 453 [10.9%], respectively); RSV A-positive patients were more likely to be admitted to the hospital or intensive care unit (47.7%, versus RSV B, 35.8%; P < 0.0001); hospitalized RSV A-positive patients were less likely to be prescribed antibiotics (32.4%, versus RSV B, 47.8%; P < 0.001). CONCLUSIONS: This is the largest epidemiologic study in EDs reporting trends in RSV subtypes. RSV subtypes A and B were documented in both seasons across all US regions studied and detected in September to May. The results of this study support suggestions from smaller studies that RSV A may be more virulent than RSV B; however, more quantitative assessments of disease severity are needed. PMID- 23337905 TI - Metal-free syn-dioxygenation of alkenes. AB - Reactions employing inexpensive reagents from sustainable sources and with low toxicity are becoming increasingly desirable from an academic and industrial perspective. A fascinating example of a synthetic transformation that requires development of alternative procedures is the osmium catalysed dihydroxylation. Recently there has been considerable interest in achieving this reaction through metal-free procedures. This review describes the methods available for metal-free syn-dioxygenation of alkenes. PMID- 23337906 TI - Simultaneous measurement of doxorubicin and reduced metabolite doxorubicinol by UHPLC-MS/MS in human plasma of HCC patients treated with TACE. AB - A sensitive, selective, accurate and precise method for simultaneous quantification of doxorubicin (DOX) and doxorubicinol (DOXol) in human plasma of patients diagnosed as having intermediate stage unresectable hepatocellular carcinoma (HCC) was developed. The method was based on electrospray tandem mass spectrometry in selected reaction monitoring mode. DOX, DOXol and trofosfamide, an internal standard, were extracted from plasma by using a simple solid phase extraction (SPE) procedure after the addition of 0.1 M hydrochloric acid. A 200 MUL aliquot of the extracted sample reconstituted in mobile phase was analyzed on a Zorbax SB-C18 UHPLC column (50 mm * 2.1 mm, 1.8 MUm particle size) in 8 min. The mobile phase consisted of acetonitrile and 0.1% formic acid pH 4.5 (95:05 v/v). Good accuracy and precision of this method were demonstrated by determination of spiked plasma QC samples in four consecutive days. The SPE extraction recoveries ranged from 72.3 to 77.3% and 75.5 to 98.4% for doxorubicin and doxorubicinol, respectively. The intra-day and inter-day precisions were less than 11.4%. The limit of quantitation was 1.0 ng/mL for both compounds. The calibration curves of DOX and DOXol were analyzed by weighted linear regression with 1/x as a weighting factor. They were linear over the concentration range of 1.0-100.0 ng/mL with R(2) greater than 0.99. This developed method was successfully applied to study plasma pharmacokinetics in patients affected by HCC and treated with transarterial chemoemolization practices (TACEs) using HepaSphereTM pre-loaded with DOX in a standardized procedure. PMID- 23337907 TI - A crossover study of noodle soup consumption in melamine bowls and total melamine excretion in urine. PMID- 23337908 TI - Divergent reactivity of nitric oxide with metal-metal quintuple bonds. AB - Reactions of NO with the quintuple bonded chromium and molybdenum amidinate dimers, respectively, gave dichromium nitrosyl nitrito amidinato complexes, and the quadruple bonded dimolybdenum nitrito amidinato species with a paddlewheel configuration. PMID- 23337909 TI - Infant mouse brain passaged Dengue serotype 2 virus induces non-neurological disease with inflammatory spleen collapse in AG129 mice after splenic adaptation. AB - AG129 mice are known to be permissive to infection by multiple serotypes of Dengue virus (DENV). There exists a concern that mouse passaged strains of the virus may induce neurological complications rather than increased vascular permeability in these mice, hence the use of human clinical isolates of the virus to develop the AG129 mouse model of Dengue disease with increased vascular permeability. The present study evaluated four mouse brain passaged DENV strains, each belonging to a different serotype and three of them having an original isolation history in India, for their suitability to serve as candidates to induce rapid lethal disease in AG129 mice. While all the viruses were able to establish a productive infection in the spleen, none of them induced paralysis despite their mouse brain passage history. Only the type-2 virus acquired the ability to induce a lethal disease after a single round of spleen to spleen passage, and became highly virulent after five more rounds. This apparently non neurological lethal disease was characterized by high viral burden, elevated vascular permeability, serum TNF-alpha surge immediately before moribund stage, transient leukocytosis followed by severe leukopenia, lymphopenia throughout the course of the infection, and transient thrombocytopenia. The disease was also characterized by inflammatory splenic collapse during moribund stage, reminiscent of spontaneous splenic rupture reported in rare cases of severe Dengue in humans. PMID- 23337910 TI - EGCG inhibits recepteur d'origine nantais expression by suppressing Egr-1 in gastric cancer cells. AB - Abnormal accumulation and activation of the recepteur d'origine nantais (RON) has been implicated in epithelial tumor carcinogenesis. In the present study, we examined the effect of epigallocatechin-3-gallate (EGCG), the major green tea catechin, on the induction of RON and tumor growth in human gastric cancer. EGCG inhibited phorbol 12-myristate 13-acetate (PMA)-induced RON expression and reduced RON transcriptional activity. However, (-)-epigalloca-techin (EGC), (-) epicatechin gallate (ECG) and (-)-epicatechin (EC) did not affect RON expression. Experiments with deleted and site-directed mutagenesis of the RON promoter indicated that Egr-1 binding sites in the RON promoter may be the EGCG-response element acting as a cis-element in gastric cancer cells. EGCG also inhibited PMA induced Egr-1 expression and DNA binding in a dose-dependent manner. Furthermore, gastric cancer cells pretreated with PMA showed markedly enhanced invasiveness, which was partially abrogated by EGCG and siRNA-targeted RON and Egr-1. EGCG significantly reduced tumor growth in an in vivo tumor model, whereas RON expression was downregulated. These results suggest that EGCG may exert at least part of its anticancer effect by controlling RON expression through suppression of Egr-1 activation. PMID- 23337911 TI - Toxicity assessment on trophoblast cells for some environment polluting chemicals and 17beta-estradiol. AB - The identification of reproductive toxicants is a major scientific challenge for human health. We investigated the effects of a selected group of environmental polluting chemicals mostly provided with estrogenic activity on the human trophoblast cell lines BeWo and HTR-8/SVneo. Cells were exposed for 24h to various concentrations (from 0.1 pM to 1 mM) of atrazine (ATR), diethylstilbestrol (DES), para-nonylphenol (p-NP), resveratrol (RES) and 17 beta estradiol (E2) and assayed for cell viability and human beta-Chorionic Gonadotropin (beta-hCG) secretion. Decrease of cell viability as respect to control, vehicle-treated, cultures was obtained for all chemicals in the concentration range of 1 MUM-1 mM in both cell types. A parallel decrease of beta hCG secretion was observed in BeWo cells, at 1 MUM-1 mM concentrations, with the only exception of ATR which caused an increase at concentrations up to 1mM. beta hCG release was also unexpectedly inhibited by ATR, DES, p-NP and RES at non toxic (pM-nM) concentrations. These findings raise concern about the negative, potential effects of various environmental polluting chemicals on pregnancy success and fetal health. PMID- 23337912 TI - Clearing bloody cerebrospinal fluid: clot lysis, neuroendoscopy and lumbar drainage. AB - PURPOSE OF REVIEW: Bloody cerebrospinal fluid (CSF) is a major cause of morbidity and mortality in intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Different treatment strategies aiming at faster clearance of bloody CSF have emerged. The present review focuses on recent developments in the investigation of those treatments. RECENT FINDINGS: Intraventricular fibrinolysis (IVF) for accelerated IVH-resolution has been clinically tested since the early 1990s. The lately summarized evidence from smaller studies indicates that IVF may result in a benefit in mortality and outcome. Recent investigations have elucidated different aspects of IVF, mainly related to safety. Neuroendoscopy has also emerged as a minimally invasive technique allowing fast removal of IVH. The capability of lumbar drainage to reduce vasospasm after SAH has been tested in a large trial. SUMMARY: IVF is relatively well tolerated and accelerates clot clearance after IVH. The effect of IVF on clinical outcome and mortality is currently being investigated in a large-scale phase III clinical trial. Neuroendoscopy is feasible for the treatment of IVH, however, larger trials are lacking. Lumbar drainage reduces the incidence of vasospasm after SAH. An ongoing phase III trial has been designed to test its influence on outcome. Lumbar drainage may also reduce shunt-dependency after IVH. PMID- 23337913 TI - The expression and role of peroxisome proliferator-activated receptor alpha in atherosclerosis. AB - Peroxisome proliferator-activated receptor alpha (PPAR-alpha) has been detected in the liver, kidney, heart and skeletal muscle. The expression and mechanism of PPAR-alpha in atherosclerosis remains unclear. The present study was undertaken in order to examine the expression and role of PPAR-alpha in programmed atherosclerosis induced by a high-fat diet and balloon-injury in rabbits. Rabbits were randomly divided into 3 groups: control, high-fat diet and high-fat diet+balloon-injury groups. The high-fat diet and high-fat diet+balloon-injury groups were further divided into 6-, 8- and 10-week groups. Real-time quantitative PCR analysis was used to detect PPAR-alpha mRNA and immunohistochemistry (IHC) and western blot analysis were used to examine PPAR alpha protein expression. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-10 and P-selectin levels in the rabbits were measured by enzyme-linked immunosorbent assay (ELISA). In the high-fat or high-fat diet+balloon-injury groups, the vascular thickness was markedly higher than in the control group (P<0.01). PPAR alpha protein and mRNA were significantly increased in the high-fat diet group as compared with the control group (P<0.01). Furthermore, there were marked changes from 6 to 10 weeks in the high-fat diet group (P<0.01). Compared with the control group, PPAR-alpha protein and mRNA were increased in the high-fat diet+balloon injury group (P<0.01). There were significant differences of PPAR-alpha protein and mRNA at various time points in the high-fat diet+balloon-injury group, as shown by real-time quantitative PCR and IHC (P<0.01). As shown by western blotting, there were no differences between the high-fat diet + balloon-injury 8- and 10-week groups (P>0.05). In those arteries that were occluded by >=60%, PPAR alpha expression was lower than that in the arteries which were occluded <60% in the high-fat diet+balloon-injury 10-week group. In the high-fat diet and high-fat diet+balloon-injury groups, the levels of IL-10, TNF-alpha and P-selectin were upregulated compared with the control group. However, from weeks 8 to 10, TNF alpha and P-selectin were decreased and IL-10 was still increased in the high-fat diet+balloon-injury group. The results of this study demonstrate that PPAR-alpha has preventive effects on atherosclerosis, which may be related to the regulation of inflammation. PMID- 23337914 TI - [Qualification concept for delegation of medical tasks to nonmedical professional groups. The "Greifswalder 3-level model"]. AB - To manage the current demographics and the expected medical, nursing, and social care needs of the population, structural changes are needed in the German health care system. On the regional level, there is a shortage of general practitioners in Germany. In the future, the number of affected regions will likely increase. These trends require new support strategies, which include the delegation of medical tasks to nonphysician professionals of which nurses and medical assistants are the primary profession. Thus, they will expand their traditional scope of work. However, their traditional training does not qualify them to perform medical tasks responsibly and with high quality. Hence, there is a need for further development of advanced training programs. The goal is to tailor modular advanced training to the specific support needs of the patients. A recent law (GKV-Versorgungsstrukturgesetz, GKV-VStG, 1 January 2012) was passed that specifies and extends the delegation options of medical tasks beyond the restrictions defined in previous German legislation (S 63, SGB V in 2008). In this article, we present a three-stage model for qualifying nonphysician medical professionals for defined ranges of medical tasks. PMID- 23337915 TI - Palliative care for children with cancer. AB - Over the past two decades, paediatric palliative care has emerged as both a primary approach and as its own medical subspecialty, the overall aim of which is to ease suffering for children with life-threatening illness and their families through a concurrent model of care. However, most discussions have been focused on the transition to palliative care when no realistic hope for cure exists. We believe that, because the course of cancer is so unpredictable, this idea is misleading. Indeed, palliative care is increasingly being recognized as being about not just how to cope with the process of dying, but also about how to engage in living when faced with a life-threatening illness. This article will examine our current understanding of several areas of palliative care, with the ultimate message that palliative care is simply a novel term for the total care of a child and family, an approach that should be applied consistently and concurrently regardless of disease status. By improving familiarity with palliative care and building relationships with palliative care specialists, the paediatric oncology clinician will ensure that the best care possible for children and families is provided, regardless of outcome. PMID- 23337917 TI - Urological cancer: More options for prostate cancer. PMID- 23337918 TI - Pharmacology: Structure-based design for selective inhibition lowers toxicity. PMID- 23337919 TI - Gynaecological cancer: CLOVAR validates prognostic gene-expression signature. PMID- 23337922 TI - Skin cancer: Novel mouse model reveals strategy to delay drug resistance in melanoma. PMID- 23337923 TI - Pulmonary embolism hotline 2012. Recent and expected trials. AB - Management of acute pulmonary embolism (PE) has advanced considerably in the past year, and progress is expected to continue in 2013. To help determine the optimal management strategy for normotensive patients with intermediate-risk PE, the Pulmonary Embolism Thrombolysis (PEITHO) study completed enrolment of 1006 patients with evidence of right ventricular dysfunction (by echocardiography or computed tomography) plus a positive troponin test. Patients have been randomised to thrombolytic treatment with tenecteplase versus placebo, and the effects on clinical end points (death or haemodynamic collapse) assessed at 7 and 30 days. The results are expected in spring 2013; long-term follow-up is also being performed. The results of a randomised trial on ultrasound-enhanced low-dose catheter-delivered thrombolysis will also become available soon. While optimisation of treatment with vitamin K antagonists incorporating pharmacogenetic testing is still being pursued, new oral anticoagulants are entering the field of PE treatment and secondary prophylaxis. Following the successful use of rivaroxaban as single oral drug therapy in the EINSTEIN-PE trial, the approval of this drug has recently been extended to cover, apart from deep vein thrombosis, PE as well. The apixaban (AMPLIFY) and edoxaban (HOKUSAI) trials have finished recruitment of PE patients, and their results will become available shortly. In the meantime, the AMPLIFY-EXT trial showed that both the therapeutic (5 mg twice daily) and the prophylactic dose (2.5 mg twice daily) of apixaban are effective and safe for long-term secondary prophylaxis after PE. For the extended prophylaxis (after the reommended initial anticoagulation period) of the (few) patients who are unable to tolerate any form of anticoagulation, low dose asprin may be a safe albeit moderately efficacious option, as indicated by two recent investigator-initiated trials with a total of 1224 patients. PMID- 23337925 TI - sigma, pi aromaticity and anti-aromaticity as retrieved by the linear response kernel. AB - The chemical importance of the linear response kernel from conceptual Density Functional Theory (DFT) is investigated for some sigma and pi aromatic and anti aromatic systems. The effect of the ring size is studied by looking at some well known aromatic and anti-aromatic molecules of different sizes, showing that the linear response is capable of correctly classifying and quantifying the aromaticity for five- to eight-membered aromatic and anti-aromatic molecules. The splitting of the linear response in sigma and pi contributions is introduced and its significance is illustrated using some sigma-aromatic molecules. The linear response also correctly predicts the aromatic transition states of the Diels Alder reaction and the acetylene trimerisation and shows the expected behavior along the reaction coordinate, proving that the method is accurate not only at the minimum of the potential energy surface, but also in non-equilibrium states. Finally, the reason for the close correlation between the linear response and the Para Delocalisation Index (PDI), found in previous and the present study, is proven mathematically. These results show the linear response to be a reliable DFT-index to probe the sigma and pi aromaticity or anti-aromaticity of a broad range of molecules. PMID- 23337924 TI - Maternal inheritance of mitochondrial genomes and complex inheritance of chloroplast genomes in Actinidia Lind.: evidences from interspecific crosses. AB - The inheritance pattern of chloroplast and mitochondria is a critical determinant in studying plant phylogenetics, biogeography and hybridization. To better understand chloroplast and mitochondrial inheritance patterns in Actinidia (traditionally called kiwifruit), we performed 11 artificial interspecific crosses and studied the ploidy levels, morphology, and sequence polymorphisms of chloroplast DNA (cpDNA) and mitochondrial DNA (mtDNA) of parents and progenies. Sequence analysis showed that the mtDNA haplotypes of F1 hybrids entirely matched those of the female parents, indicating strictly maternal inheritance of Actinidia mtDNA. However, the cpDNA haplotypes of F1 hybrids, which were predominantly derived from the male parent (9 crosses), could also originate from the mother (1 cross) or both parents (1 cross), demonstrating paternal, maternal, and biparental inheritance of Actinidia cpDNA. The inheritance patterns of the cpDNA in Actinidia hybrids differed according to the species and genotypes chosen to be the parents, rather than the ploidy levels of the parent selected. The multiple inheritance modes of Actinidia cpDNA contradicted the strictly paternal inheritance patterns observed in previous studies, and provided new insights into the use of cpDNA markers in studies of phylogenetics, biogeography and introgression in Actinidia and other angiosperms. PMID- 23337926 TI - Low-level laser reduces the production of TNF-alpha, IFN-gamma, and IL-10 induced by OVA. AB - Delayed, or type IV, hypersensitivity reactions are a useful model to study the effects of new substances on the immune system. In this study, the experimental model of the delayed type hypersensitivity (DTH) reaction to ovalbumin (OVA) was used to evaluate the immunomodulating effects of low-level laser therapy (LLLT), which is used as an adjuvant therapy in medicine, dentistry, and physical therapy because of its potential anti-inflammatory and analgesic effects observed in several studies. The effects of LLLT (lambda 780 nm, 0.06 W/cm(2) of radiation, and fluency of 3.8 J/cm(2)) in reaction to ovalbumin in Balb/C mice were examined after the induction phase of the hypersensitivity reaction. The animals treated with azathioprine (AZA), the animals that received a vehicle instead of ovalbumin, and those not immunized served as controls (n = 6 for each group). Footpad thickness measurements and hematoxylin-eosin histopathological exams were performed. Proliferation tests were also performed (spontaneous, in the presence of concanavalin A and ovalbumin) to determine the production in mononuclear cells cultures of tumor necrosis factor-alpha (TNF-alpha), INF-gamma, and IL-10. In the group of animals irradiated with lasers and in the group treated with AZA, footpad thickness measurements were significantly reduced in comparison to the control group (p < 0.05). This reduction was accompanied by a very significant reduction in the density of the inflammatory infiltrate and by a significant reduction in the levels of TNF-alpha, INF-gamma, and IL-10. LLLT radiation was shown to have an immunomodulating effect on DTH to OVA in Balb/C mice. PMID- 23337927 TI - Challenges for community-based forest management in the KoloAla site Manompana. AB - Following the IUCN 5th World Congress on Protected Areas in 2003, the then President of Madagascar decided to increase the area of Madagascar's protected areas from 1.7 to 6 million ha. To combine the aims of protection and timber production, a new concept was developed through the establishment of community based forest management (CBFM) sites, called KoloAla. However, experience shows that similar management transfers to communities in Madagascar have only been successful in a very few cases. We aimed to explore the success to be expected of this new approach in the particular case of the Manompana corridor at Madagascar's eastern coast. In a first step, the readiness of the corridor's resource users for CBFM has been analysed according to the seven resource users' attributes developed by Ostrom that predict an effective self-organized resource management. In a second step, we explored how KoloAla addresses known challenges of Madagascar's CBFM. Analyses lead in a rather sober conclusion. Although KoloAla attempts to address the goals of poverty alleviation, biodiversity conservation and timber production under a single umbrella, it does so in a rather non-innovative way. Challenges with regard to the state's environmental governance, agricultural inefficiency and thus deforestation remain unsolved. PMID- 23337928 TI - Subclonal evolution involving SF3B1 mutations in chronic lymphocytic leukemia. PMID- 23337929 TI - Activation of the mTOR signaling pathway by L-leucine in 5q- syndrome and other RPS14-deficient erythroblasts. PMID- 23337930 TI - JAK2V617F allele burden, JAK2 46/1 haplotype and clinical features of Chinese with myeloproliferative neoplasms. PMID- 23337931 TI - The Wnt5a/Ror2 pathway is associated with determination of the differentiation fate of bone marrow mesenchymal stem cells in vascular calcification. AB - Accumulating evidence have demonstrated that mesenchymal stem cells (MSCs) are involved in the initiation and progression of various vascular diseases. Canonical Wnt signaling controls the fate of MSCs, and plays an important role in vascular calcification. However, vascular calcification can be inhibited by the non-canonical Wnt signaling pathway Wnt5a/Ror2. This study aimed to investigate whether the Wnt5a/Ror2 pathway is associated with determination of the differentiation fate of MSCs in vascular calcification. Direct co-cultures were established by seeding smooth muscle cells (SMCs) or calcified SMCs and MSCs together at ratios of SMCs or calcified SMCs 15x104; SMCs or calcified SMCs 5x104: MSCs 10x104, SMCs or calcified SMCs 10x104: MSCs 5x104. Osteosynthesis inducing medium (OS) was added to the culture medium in the groups of MSCs with non-calcified SMCs. Cells were cultured for nine days. Osteoblastic differentiation was evaluated by cell morphology and the activity of alkaline phosphatase (ALP) in cell lysates and ALP staining. Furthermore, we investigated the inhibition of Wnt signaling, and observed that the members of the non canonical signaling pathway Wnt5a/Ror2 were expressed in each group. Additionally, MSCs cultured in culture media with OS did not differentiate into an osteoblast phenotype when in direct contact with non-calcified SMCs, irrespective of the number of MSCs. However, an osteoblast phenotype was observed when MSCs were cultured in media without OS differentiation towards direct contact with calcified SMCs, and the levels of osteoblastic markers had a direct correlation with the number of MSCs. Of note, the Wnt5a protein was associated with the levels of calcification, thus, although rarely detected in non calcification, Ror2 mRNA in the non-calcified groups was significantly higher compared to that in the calcified groups. Therefore, the Wnt5a/Ror2 pathway is associated with determination of the differentiation fate of bone marrow mesenchymal stem cells in vascular calcification. PMID- 23337932 TI - GNAS is not involved in gastrointestinal tumour formation in Peutz-Jeghers syndrome. AB - Peutz-Jeghers syndrome (PJS), caused by germ-line mutations in LKB1, is characterized by the development of hamartomatous polyps in the gastrointestinal (GI) tract. McCune Albright syndrome (MAS), caused by somatic activating mutations in GNAS, presents with cutaneous, skeletal, and endocrine manifestations. Recently, hamartomatous GI polyps with histological features similar to those in PJS were observed in MAS patients, suggesting a role for GNAS in the pathogenesis of PJS. This study reports the first somatic GNAS mutation analysis in GI tumours of PJS patients. No mutations were observed, suggesting that GNAS is not involved in the pathogenesis of GI tumours in PJS. PMID- 23337933 TI - Locoregional therapy for cholangiocarcinoma. AB - PURPOSE OF REVIEW: Cholangiocarcinoma has a poor prognosis. Surgical resection offers the only curative option and usually requires a major hepatic resection in addition to resection of the cholangiocarcinoma. Unfortunately, curative resection is possible in only about 30% of patients due to locally advanced disease, distant metastases or comorbidity in elderly patients. Even after resection, the recurrence rate is approximately 60%, resulting in a low 5-year overall survival (OS). In unresectable cholangiocarcinoma OS with systemic chemotherapy is less than 1 year. Since most cholangiocarcinoma patients develop distant metastases at late stages only, locoregional therapy is an interesting therapeutic strategy. Here, we review the locoregional concepts of cholangiocarcinoma therapy. RECENT FINDINGS: Locoregional therapy studies in patients with intrahepatic cholangiocarcinoma employing radiofrequency ablation (RFA), transarterial chemoembolization (TACE) or external as well as internal radiation therapy yielded promising results in the last couple of years. SUMMARY: In conclusion, locoregional therapies have been shown to be effective in patients with intrahepatic cholangiocarcinoma. Local tumour control may prolong OS and can be achieved by locoregional interventions applied either sequentially or in combination with systemic chemotherapies. PMID- 23337934 TI - Stories of love and hate: innate immunity and host-microbe crosstalk in the intestine. AB - PURPOSE OF REVIEW: Recent advances in molecular techniques have enabled a deep view into the structure and function of the host's immune system and the stably associated commensal intestinal flora. This review outlines selected aspects of the interplay of innate immune recognition and effectors that shape the ecological niches for the intestinal microbiota. RECENT FINDINGS: Several studies have demonstrated a pivotal role of innate immune receptor pathways (NOD-like receptors and Toll-like receptors) for the maintenance of microbial communities in the gut. Genetic deficiencies in these pathways have been associated with increased susceptibility to inflammation that in animal models can be transmitted via direct contact or by stool transplantation in the absence of abundant pathogens. SUMMARY: The genetic architecture of the human host shapes the diversity and function of its stably associated intestinal microflora. Innate immune receptors such as NOD2 or the inflammasome component NOD-like receptor, pyrin-domain containing 6 play a major role in licensing the microbiota under physiological conditions. Understanding the symbiotic interplay in the intestinal tract should help develop procedures and therapeutic interventions aiming at the identification and restoration of disturbed microbiota states. Indeed, these states may be the missing trigger factor for the manifestation of a multitude of civilization disorders including inflammatory bowel disease and gastrointestinal cancer. PMID- 23337935 TI - Resveratrol facilitates pain attenuation in a rat model of neuropathic pain through the activation of spinal Sirt1. AB - BACKGROUND: Little research has been conducted regarding the implications of Sirt1 (a classic III HDAC) in neuropathic pain. The aim of this study was to investigate the variation in the expressions of spinal Sirt1 and acetyl-histone H3 in a rat model of chronic constriction injury. METHODS: A neuropathic pain model of chronic constriction injury (CCI) was established in a unilateral hind limb in Sprague-Dawley rats. RESULTS: Western blot analysis and immunohistochemistry revealed that Sirt1 (silent information regulator) expression decreased, whereas acetyl-histone H3 increased in the spinal cord following CCI surgery. The intrathecal administration of resveratrol, an activator of Sirt1, attenuated CCI-induced mechanical allodynia and thermal hyperalgesia, increased Sirt1 expression, and decreased acetyl-histone H3 in the spine. Resveratrol induced no obvious histopathological changes in the spinal cord. CONCLUSIONS: Our data provide new evidence for the contribution of spinal Sirt1 to the initiation and maintenance of neuropathic pain. The antinociceptive effects of resveratrol may be mediated through the activation of spinal Sirt1 in CCI rats. PMID- 23337936 TI - Effects of chronic administration of amitriptyline, gabapentin and minocycline on spinal brain-derived neurotrophic factor expression and neuropathic pain behavior in a rat chronic constriction injury model. AB - BACKGROUND: In animal models of neuropathic pain (NP), promising results have been reported with the administration of minocycline, possibly through inhibition of spinal brain-derived neurotrophic factor (BDNF) expression. No data are available on the effect of amitriptyline and gabapentin on spinal BDNF expression. If the mechanism of action of the latter drugs does not involve brain derived NP inhibition, further clinical research in BDNF is warranted. METHODS: In this placebo-controlled study, we investigated the effects of amitriptyline (5 mg/kg), gabapentin (50 mg/kg), and minocycline (25 mg/kg) twice a day on NP behavior in a sciatic chronic constriction injury (CCI) rat model. Drug treatment started 7 days after CCI and lasted 14 days. At postoperative day 21, spinal BDNF expression in laminae I and II was quantified using immunocytochemistry. RESULTS: Sciatic CCI resulted in NP behavior throughout the duration of the experiment in the placebo group. When administered for 2 weeks, minocycline (P <= 0.001) and amitriptyline (P <= 0.05), but not gabapentin, reduced thermal hyperalgesia. None of these drugs reduced mechanical allodynia. As opposed to amitriptyline and gabapentin, 2 weeks of treatment with minocycline reduced brain-derived, neurotrophic factor immunoreactivity (P <= 0.05) in the ipsilateral dorsal horn. CONCLUSIONS: Minocycline and amitriptyline both reduce NP behavior in a sciatic CCI rat model, but only minocycline reduces spinal BDNF, indicating different modes of action of these 2 drugs. The observed actions of minocycline closely fit the clinical needs for the treatment of NP. PMID- 23337937 TI - The association of aspirin use with age-related macular degeneration. AB - OBJECTIVE: To determine whether regular aspirin use is associated with a higher risk for developing age-related macular degeneration (AMD) by using analyzed data from a 15-year prospective cohort. METHODS: A prospective analysis was conducted of data from an Australian population-based cohort with 4 examinations during a 15-year period (1992-1994 to 2007-2009). Participants completed a detailed questionnaire at baseline assessing aspirin use, cardiovascular disease status, and AMD risk factors. Age-related macular degeneration was graded side-by-side from retinal photographs taken at each study visit to assess the incidence of neovascular (wet) AMD and geographic atrophy (dry AMD) according to the international AMD classification. RESULTS: Of 2389 baseline participants with follow-up data available, 257 individuals (10.8%) were regular aspirin users and 63 of the 2389 developed neovascular AMD. Persons who were regular aspirin users were more likely to have incident neovascular AMD: the 15-year cumulative incidence was 9.3% in users and 3.7% in nonusers. After adjustment for age, sex, smoking, history of cardiovascular disease, systolic blood pressure, and body mass index, persons who were regular aspirin users had a higher risk of developing neovascular AMD (odds ratio [OR], 2.46; 95% CI, 1.25-4.83). The association showed a dose-response effect (multivariate-adjusted P = .01 for trend). Aspirin use was not associated with the incidence of geographic atrophy (multivariate-adjusted OR, 0.99; 95% CI, 0.59-1.65). CONCLUSION: Regular aspirin use is associated with increased risk of incident neovascular AMD, independent of a history of cardiovascular disease and smoking. PMID- 23337938 TI - A role for LRIG1 in the regulation of malignant glioma aggressiveness. AB - The molecular mechanisms that drive the development and aggressive progression of malignant astrocytic tumors remain obscure. Recently, in the search for endogenous negative regulators of EGF receptor, LRIG1 was cloned and characterized as a putative tumor suppressor gene often downregulated in various human tumors, including astrocytic tumors. Although several studies have implicated the function of LRIG1 in the inhibition of tumorigenesis, its precise role and potential underlying mechanisms remain obscure. Therefore, we generated a full-length expression vector to overexpress LRIG1 in the U251 malignant glioma cell line. Introduction of exogenous LRIG1 into glioma cells inhibited cell proliferation manifested by MTT and soft agar clone assay in vitro and subcutaneously tumor xenografts. On the other hand, LRIG1 overexpression inhibited glioma growth by significantly changing the expression pattern of cyclins, resulting in delayed cell cycle. Employing transwell invasion and wound scratch assay and gelatin zymography, LRIG1 inhibited U-251 MG cell invasion and migration by attenuating MMP2 and MMP9 production. Under ligand-stimulated conditions, p-ERK levels did not change, whereas p-AKT levels were inhibited in cells with LRIG1 upregulation, indicating that LRIG1 exerts more inhibiting effects on the PI3K/AKT pathway. Our findings suggest that LRIG1 restricted glioma aggressiveness by inhibiting cell proliferation, migration and invasion. Restoration of LRIG1 to glioma cells could offer a novel therapeutic strategy. PMID- 23337939 TI - Antiproliferative activity of daidzein and genistein may be related to ERalpha/c erbB-2 expression in human breast cancer cells. AB - In this study, we investigated the antiproliferative activity of the isoflavones daidzein and genistein in three breast cancer cell lines with different patterns of estrogen receptor (ER) and c-erbB-2 protein expression (ERalpha-positive MCF-7 cells, c-erbB-2-positive SK-BR-3 cells and ERalpha/c-erbB-2-positive ZR-75-1). After treatment at various concentrations (1-200 uM for 72 h), the effect of daidzein and genistein on the proliferation of different cell types varied; these effects were found to be associated with ERalpha and c-erbB-2 expression. Daidzein and genistein exhibited biphasic effects (stimulatory or inhibitory) on proliferation and ERalpha expression in MCF-7 cells. Although 1 uM daidzein significantly stimulated cell growth, ERalpha expression was unaffected. However, genistein showed marked increases in proliferation and ERalpha expression after exposure to <10 uM genistein. Notably, the inhibition of cell proliferation by 200 uM genistein was greater compared to that by daidzein at the same concentration. Daidzein and genistein significantly inhibited proliferation of SK BR-3 and ZR-75-1 cells in a dose-dependent manner. In addition, ERalpha and c erbB-2 expression was reduced by daidzein and genistein in both SK-BR-3 and ZR-75 1 cells in a dose-dependent manner. However, the effect of genistein was greater compared to that of daidzein. In conclusion, the isoflavones daidzein and genistein showed anti-breast cancer activity, which was associated with expression of the ERalpha and c-erbB-2 receptors. PMID- 23337940 TI - Pattern of distribution of serotonergic fibers to the orbitomedial and insular cortex in the rat. AB - As is well recognized, serotonergic (5-HT) fibers distribute widely throughout the brain, including the cerebral cortex. Although some early reports described the 5-HT innervation of the prefrontal cortex (PFC) in rats, the focus was on sensorimotor regions and not on the 'limbic' PFC - or on the medial, orbital and insular cortices. In addition, no reports have described the distribution of 5-HT fibers to PFC in rats using antisera to the serotonin transporter (SERT). Using immunostaining for SERT, we examined the pattern of distribution of 5-HT fibers to the medial, orbital and insular cortices in the rat. We show that 5-HT fibers distribute massively throughout all divisions of the PFC, with distinct laminar variations. Specifically, 5-HT fibers were densely concentrated in superficial (layer 1) and deep (layers 5/6) of the PFC but less heavily so in intermediate layers (layers 2/3). This pattern was most pronounced in the orbital cortex, particularly in the ventral and ventrolateral orbital cortices. With the emergence of granular divisions of the insular cortex, the granular cell layer (layer 4) was readily identifiable by a dense band of labeling confined to it, separating layer 4 from less heavily labeled superficial and deep layers. The pattern of 5-HT innervation of medial, orbital and insular cortices significantly differed from that of sensorimotor regions of the PFC. Serotonergic labeling was much denser overall in limbic compared to non-limbic regions of the PFC, as was striking demonstrated by the generally weaker labeling in layers 1-3 of the primary sensory and motor cortices. The massive serotonergic innervation of the medial, orbital and insular divisions of the PFC likely contributes substantially to well established serotonergic effects on affective and cognitive functions, including a key role in many neurological and psychiatric diseases. PMID- 23337941 TI - Exciton diffusion in near-infrared absorbing solution-processed organic thin films. AB - We report on singlet-singlet annihilation and exciton diffusion in as-prepared p type and annealed n-type thin films of the low-bandgap quinoidal quaterthiophene [QQT(CN)4] using ultrafast transient absorption measurements. The decay dynamics of exciton populations are well described by a one-dimensional diffusion-limited bimolecular recombination, indicating that the singlet excitons migrate preferentially along the stacking direction. Our results show that the exciton diffusion constants in QQT(CN)4 films do not vary significantly upon thermal annealing. Exciton diffusion lengths are measured to be as high as 4 and 5 nm in as-prepared and annealed QQT(CN)4 films, respectively. We also observe an influence of the excitation densities on the singlet exciton diffusion, which is attributed to phonon scattering. Because of the possibility of patterning p-n regions in QQT(CN)4 films by thermal nanolithography techniques, this study provides important insight not only into the photophysical properties of quinoidal oligothiophene derivatives but also for their future integration into high-performance p-n nanostructured near infrared light-sensing devices. PMID- 23337942 TI - Deep brain stimulation of the nucleus accumbens and its usefulness in severe opioid addiction. PMID- 23337943 TI - Expression of the G72/G30 gene in transgenic mice induces behavioral changes. AB - The G72/G30 gene complex is a candidate gene for schizophrenia and bipolar disorder. However, G72 and G30 mRNAs are expressed at very low levels in human brain, with only rare splicing forms observed. We report here G72/G30 expression profiles and behavioral changes in a G72/G30 transgenic mouse model. A human BAC clone containing the G72/G30 genomic region was used to establish the transgenic mouse model, on which gene expression studies, western blot and behavioral tests were performed. Relative to their minimal expression in humans, G72 and G30 mRNAs were highly expressed in the transgenic mice, and had a more complex splicing pattern. The highest G72 transcript levels were found in testis, followed by cerebral cortex, with very low or undetectable levels in other tissues. No LG72 (the long putative isoform of G72) protein was detected in the transgenic mice. Whole-genome expression profiling identified 361 genes differentially expressed in transgenic mice compared with wild-type, including genes previously implicated in neurological and psychological disorders. Relative to wild-type mice, the transgenic mice exhibited fewer stereotypic movements in the open field test, higher baseline startle responses in the course of the prepulse inhibition test, and lower hedonic responses in the sucrose preference test. The transcriptome profile changes and multiple mouse behavioral effects suggest that the G72 gene may play a role in modulating behaviors relevant to psychiatric disorders. PMID- 23337944 TI - Opioid receptor mu 1 gene, fat intake and obesity in adolescence. AB - Dietary preference for fat may increase risk for obesity. It is a complex behavior regulated in part by the amygdala, a brain structure involved in reward processing and food behavior, and modulated by genetic factors. Here, we conducted a genome-wide association study (GWAS) to search for gene loci associated with dietary intake of fat, and we tested whether these loci are also associated with adiposity and amygdala volume. We studied 598 adolescents (12-18 years) recruited from the French-Canadian founder population and genotyped them with 530 011 single-nucleotide polymorphisms. Fat intake was assessed with a 24 hour food recall. Adiposity was examined with anthropometry and bioimpedance. Amygdala volume was measured by magnetic resonance imaging. GWAS identified a locus of fat intake in the MU-opioid receptor gene (OPRM1, rs2281617, P=5.2 * 10( 6)), which encodes a receptor expressed in the brain-reward system and shown previously to modulate fat preference in animals. The minor OPRM1 allele appeared to have a 'protective' effect: it was associated with lower fat intake (by 4%) and lower body-fat mass (by ~2 kg, P=0.02). Consistent with the possible amygdala mediated inhibition of fat preference, this allele was additionally associated with higher amygdala volume (by 69 mm(3), P=0.02) and, in the carriers of this allele, amygdala volume correlated inversely with fat intake (P=0.02). Finally, OPRM1 was associated with fat intake in an independent sample of 490 young adults. In summary, OPRM1 may modulate dietary intake of fat and hence risk for obesity, and this effect may be modulated by subtle variations in the amygdala volume. PMID- 23337945 TI - Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing. AB - Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology. PMID- 23337946 TI - Elevated maternal C-reactive protein and autism in a national birth cohort. AB - Autism is a complex neuropsychiatric syndrome with a largely unknown etiology. Inflammation during pregnancy may represent a common pathway by which infections and other insults increase risk for the disorder. Hence, we investigated the association between early gestational C-reactive protein (CRP), an established inflammatory biomarker, prospectively assayed in maternal sera, and childhood autism in a large national birth cohort with an extensive serum biobank. Other strengths of the cohort included nearly complete ascertainment of pregnancies in Finland (N=1.2 million) over the study period and national psychiatric registries consisting of virtually all treated autism cases in the population. Increasing maternal CRP levels, classified as a continuous variable, were significantly associated with autism in offspring. For maternal CRP levels in the highest quintile, compared with the lowest quintile, there was a significant, 43% elevated risk. This finding suggests that maternal inflammation may have a significant role in autism, with possible implications for identifying preventive strategies and pathogenic mechanisms in autism and other neurodevelopmental disorders. PMID- 23337947 TI - Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. AB - N-methyl-D-aspartate glutamate receptor (NMDA-R) antagonists produce schizophrenia-like positive and negative symptoms in healthy human subjects. Preclinical research suggests that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) neurons and alter the brain oscillations. These changes have been hypothesized to contribute to psychosis. In this investigation, we evaluated the hypothesis that the NMDA-R antagonist ketamine produces alterations in cortical functional connectivity during rest that are related to symptoms. We administered ketamine to a primary sample of 22 subjects and to an additional, partially overlapping, sample of 12 subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Syndrome Scale (PANSS). In the primary sample, functional connectivity was measured via functional magnetic resonance imaging almost immediately after infusion began. In the additional sample, this assessment was repeated after 45 min of continuous ketamine infusion. Global, enhanced functional connectivity was observed at both timepoints, and this hyperconnectivity was related to symptoms in a region specific manner. This study supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of positive and negative symptoms associated with schizophrenia. PMID- 23337948 TI - A mutation in NPAS3 segregates with mental illness in a small family. PMID- 23337949 TI - Achiral endohedral functionality provides stereochemical control in Fe(II)-based self-assemblies. AB - Multicomponent Fe(II)-iminopyridine-based self-assemblies have been synthesized with variably sized internal functionality. Larger internal functions provide increased strain to the complex and confer diastereocontrol upon the assembly process. Complete diastereocontrol is possible upon the introduction of large achiral groups on the cavity interior. PMID- 23337950 TI - When do speakers use gestures to specify who does what to whom? The role of language proficiency and type of gestures in narratives. AB - Previous research has found that iconic gestures (i.e., gestures that depict the actions, motions or shapes of entities) identify referents that are also lexically specified in the co-occurring speech produced by proficient speakers. This study examines whether concrete deictic gestures (i.e., gestures that point to physical entities) bear a different kind of relation to speech, and whether this relation is influenced by the language proficiency of the speakers. Two groups of speakers who had different levels of English proficiency were asked to retell a story in English. Their speech and gestures were transcribed and coded. Our findings showed that proficient speakers produced concrete deictic gestures for referents that were not specified in speech, and iconic gestures for referents that were specified in speech, suggesting that these two types of gestures bear different kinds of semantic relations with speech. In contrast, less proficient speakers produced concrete deictic gestures and iconic gestures whether or not referents were lexically specified in speech. Thus, both type of gesture and proficiency of speaker need to be considered when accounting for how gesture and speech are used in a narrative context. PMID- 23337951 TI - Do you 'see' what I 'see'? Differentiation of visual action words. AB - Dickinson and Szeligo (Can J Exp Psychol 62(4):211-222, 2008) found that processing time for simple visual stimuli was affected by the visual action participants had been instructed to perform on these stimuli (e.g., see, distinguish). It was concluded that these effects reflected the differences in the durations of these various visual actions, and the results were compared to participants' subjective ratings of word meaning but it was also possible that word characteristics like length might have influenced response times. The present study takes advantage of word length differences between French and English visual action words in order to address this issue. The goals of the present study were to provide evidence that (1) the processing time differences previously found were due to differences in the cognitive actions represented by these words (and not due to characteristics to the words themselves), and (2) that individuals subjectively differentiate visual action words in such a way that allows for predictable differences in behaviour. Participants differentiated 14 French visual action words along two dimensions. Four of these words were then used in the instructions for a size-discrimination task. Processing time depended on the visual action word in the instruction to the task and differed in a predictable manner according to word meaning but not word length. PMID- 23337952 TI - The emotional lexicon of individuals diagnosed with antisocial personality disorder. AB - This study investigated the specific emotional lexicons in narratives created by persons diagnosed with antisocial personality disorder (ASPD) to test the hypothesis that individuals with ASPD exhibit deficiencies in emotional language. Study participants consisted of 60 prison inmates with ASPD, 40 prison inmates without ASPD, and 60 men without antisocial tendencies who described situations involving love, hate and anxiety depicted by photographs. The lexical choices made in the narratives were analyzed, and a comparison of the three groups revealed differences between the emotional narratives of inmates with ASPD, inmates without ASPD, and the control group. Although the narratives of the individuals with ASPD included more words describing emotions and higher levels of emotional intensity, the valence of these words was inappropriate. The linguistic characteristics of these narratives were associated with high levels of psychopathy and low emotional reactivity. PMID- 23337954 TI - Height matters-from monogenic disorders to normal variation. AB - Height is a classic polygenic quantitative trait with a high level of heritability. As it is a simple and stable parameter to measure, height is a model for both common, complex disorders and monogenic, Mendelian disease. In this Review, we examine height from the perspective of monogenic and complex genetics and discuss the lessons learned so far. We explore several examples of rare sequence variants with large effects on height and compare these variants to the common variants identified in genome-wide association studies that have small effects on height. We discuss how copy number changes or genetic interactions might contribute to the unidentified aspects of the heritability of height. We also ask whether information derived from genome-wide association studies on specific loci in the vicinity of genes can be used for further research in clinical paediatric endocrinology. Furthermore, we address key challenges that remain for gene discovery and for the transition of moving from genomic localization to mechanistic insights, with an emphasis on using next-generation sequencing to identify causative variants of people at the extremes of height distribution. PMID- 23337953 TI - The role of hepatokines in metabolism. AB - The liver is known to be involved in the natural history of the ongoing epidemics of type 2 diabetes mellitus and cardiovascular disease. In particular, the liver has a role in increased glucose production and dysregulated lipoprotein metabolism, conditions that are often found in patients with nonalcoholic fatty liver disease. Additionally, several proteins that are exclusively or predominantly secreted from the liver are now known to directly affect glucose and lipid metabolism. In analogy to the functional proteins released from adipose tissue and skeletal muscle-adipokines and myokines-these liver-derived proteins are known as hepatokines. The first hepatokine that has been proven to have a major pathogenetic role in metabolic diseases is alpha2-HS-glycoprotein (fetuin A). Production of this glycoprotein is increased in steatotic and inflamed liver, but not in expanded and dysregulated adipose tissue. Thus, research into this molecule and other hepatokines is expected to aid in differentiating between the contribution of liver and those of skeletal muscle and adipose tissue, to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease. PMID- 23337955 TI - Analysis of differentially expressed genes and microRNAs in alcoholic liver disease. AB - The purpose of this study was to screen differentially expressed genes and microRNAs in order to find a new target for the accurate diagnosis and effective therapy of alcoholic liver disease (ALD) at the gene and microRNA levels. The total RNA of liver tissues was extracted from four groups of patients, ten subjects each. Microarrays were utilized to detect differentially expressed genes and microRNAs. According to gene values, significance levels and false discovery rate with a random variance model, gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, node genes and key microRNAs in networks were obtained and analyzed. A total of 878 differentially expressed genes and 26 microRNAs were found. In co-expression genetic networks, node genes modulating the network were Acyl-coenzyme A synthetase-3 (ACSF3), Frizzled-5 (FZD5), LOC727987 and C1orf222. In microRNA-gene networks, the key microRNAs were hsa-miR 570, hsa-miR-122, hsa-miR-34b, hsa-miR-29c, hsa-miR-922 and hsa-miR-185, which negatively regulated approximately 79 downstream target genes. In the course of ALD, we found 4 differentially expressed node genes and analyzed ACSF3 and FZD5. ACSF3 was significantly upregulated, and was involved in fatty acid and lipid metabolism and accelerated liver injury. These two genes were involved in fatty acids and lipid metabolism. FZD5 was downregulated and reduced the synthesis of membrane transport protein in the hepatic membrane and the membrane stability, and accelerated the liver cell apoptosis process. Six key microRNAs regulated numerous biological functions such as the immune response, the inflammatory response and glutathione metabolism. This finding provides valuable insight into the diagnosis and treatment of ALD. PMID- 23337956 TI - The need to reduce cold ischemia time in kidney transplantation. AB - PURPOSE OF REVIEW: Hypothermic preservation is a prerequisite for kidney exchange in transplantation. The severity of tissue damage caused by hypothermic preservation influences the level of ischemia/reperfusion injury and subsequent graft function. With the purpose of reviewing the implications of prolonged cold ischemia time (CIT) in kidney transplantation, its pathophysiology, effects on early and late outcome of transplantation for different types of deceased organ donors, and preservation methods are discussed based on recent literature. RECENT FINDINGS: The main findings are that the consequences of a prolonged CIT are mainly identifiable in the early posttransplant period as delayed graft function, especially in expanded criteria donors, and possibly in an increased acute rejection rate. The preferred method of hypothermic preservation in expanded criteria donors and donors after cardiac death appears to be machine preservation. SUMMARY: The effects of CIT on the long-term outcome of renal transplantation in the form of impaired graft function and graft survival are less evident. PMID- 23337957 TI - Characteristics of cluster randomized trials: are they living up to the randomized trial? PMID- 23337958 TI - Testing pattern synchronization in coupled systems through different entropy based measures. AB - Pattern synchronization (PS) can capture one aspect of the dynamic interactions between bivariate physiological systems. It can be tested by several entropy based measures, e.g., cross sample entropy (X-SampEn), cross fuzzy entropy (X FuzzyEn), multivariate multiscale entropy (MMSE), etc. A comprehensive comparison on their distinguishability is currently missing. Besides, they are highly dependent on several pre-defined parameters, the threshold value r in particular. Thus, their consistency also needs further elucidation. Based on the well accepted assumption that a tight coupling necessarily leads to a high PS, we performed a couple of evaluations over several simulated coupled models in this study. All measures were compared to each other with respect to their consistency and distinguishability, which were quantified by two pre-defined criteria-degree of crossing (DoC) and degree of monotonicity (DoM). Results indicated that X SampEn and X-FuzzyEn could only work well over coupled stochastic systems with meticulously selected r. It is thus not recommended to apply them to the intrinsic complex physiological systems. However, MMSE was suitable for both, indicating by relatively higher DoC and DoM values. Final analysis on the cardiorespiratory coupling validated our results. PMID- 23337959 TI - Hydrophobic flavonoids from Scutellaria baicalensis induce colorectal cancer cell apoptosis through a mitochondrial-mediated pathway. AB - Scutellaria baicalensis extract (SbE) has been shown to exert chemopreventive effects on several types of cancer. Baicalin, a hydrophilic flavonoid found in SbE, may have opposing effects that decrease the antitumor potential of SbE against colorectal cancer. In this study, after removing baicalin, we prepared an aglycone-rich fraction (ARF) of SbE and evaluated its anti-proliferative activity and mechanisms of action. The flavonoids found in ARF, baicalin fraction (BF) and SbE were determined by high-performance liquid chromatography (HPLC). The effects of ARF, BF, SbE and representative flavonoids on the proliferation of HCT-116 and HT-29 human colorectal cancer cells were determined by an MTS assay. The cell cycle, the expression of cyclins A and B1 and cell apoptosis were assayed using flow cytometry. Apoptosis-related gene expression was visualized by quantitative real-time polymerase chain reaction (PCR), and mitochondrial membrane potential was estimated following staining with JC-1. HPLC analysis showed that ARF contained two hydrophobic flavonoids, baicalein and wogonin, and that BF contained only baicalin. SbE had little anti-proliferative effect on the colorectal cancer cells; cancer cell growth was even observed at certain concentrations. ARF exerted potent anti-proliferative effects on the cancer cells. By contrast, BF increased cancer cell growth. ARF arrested cells in the S and G2/M phases, increased the expression of cyclins A and B1, and significantly induced cell apoptosis. Multiple genes in the mitochondrial pathway are involved in ARF-induced apoptosis, and subsequent cellular functional analysis validated the involvement of this pathway. These results suggest that removing baicalin from SbE produces an ARF that significantly inhibits the growth of colorectal cancer cells, and that the mitochondrial apoptotic pathway plays a role in hydrophobic flavonoid-induced apoptosis. PMID- 23337960 TI - Analysis of the effect of integrons on drug-resistant Staphylococcus aureus by multiplex PCR detection. AB - The aim of this study was to detect class I, II and III integrons using multiplex PCR, and to analyze the role that these integrons play in mediating multidrug resistant Staphylococcus aureus (SA). The sensitivity of SA to 20 types of antibiotics was examined using the K-B method. A genomic DNA extraction kit was used for extracting genomic DNA and a high-purity 96 plasmid extraction kit was used for extracting plasmid DNA. Class I, II and III integrons were amplified using multiplex PCR. Agarose gel electrophoresis was used for analysing amplification products. The positive rate of class I and II integrons in the plasmid DNA from SA was higher compared to that of the genomic DNA. The positive rate of class I integrons was highest in the group with multidrug resistance to amoxicillin/clavulanic acid, piperacillin/tazobactam, ciprofloxacin, tetracycline, rifampin, imipenem, cefazolin, cefuroxime, levofloxacin and gentamicin. As regards integron detection in the plasmids from drug-resistant SA strians obtained from sputum, blood, cerebrospinal fluid, drainage fluid, excretion and urine specimens, the difference in the detection rate of class I integrons among the six types of specimens was significant. Multiplex PCR is an effective method to detect class I, II and III integrons. The SA plasmid is the main carrier transferring integrons. Integrons mediate the formation of SA multidrug resistance. PMID- 23337961 TI - [The ichthyoses. Pathophysiological models of epidermal differentiation]. AB - The ichthyoses are a heterogeneous group of monogenetically inherited disorders of cornification, and characterized clinically by scaling or hyperkeratosis. Historically, they were classified by clinical features and inheritance patterns. As a result of the recent molecular biological revolution, the ichthyoses are now recognized as comprising many diverse entities. Importantly, identical phenotypes may be caused by mutations in multiple genes, while mutations in a single gene may result in multiple and sometimes widely divergent phenotypes. The considerable complexity of this clinically and genetically heterogeneous group of disorders has prompted the need for a new classification. A classification that uses terminology based on a combination of the clinical and molecular genetic details, for instance loricrin keratoderma, is desirable. In this chapter we will use in principle the nosology adopted recently by an international group of experts at the First Ichthyosis Consensus Conference in Sorez, France. PMID- 23337962 TI - [Darier disease]. AB - Darier disease (Darier-White disease, dyskeratosis follicularis) is a rare autosomal dominant genodermatosis with regional differences in prevalence. The responsible mutations have been identified on chromosome 12q23-24.1. The gene encodes a calcium-ATPase type 2 in the sarco-/endoplasmic reticulum (SERCA2), which belongs to the large family of P-type cation pumps. This pump couples ATP hydrolysis to the transport of cations across membranes and thus plays a significant role in intracellular calcium signaling. Neuropsychiatric disorders are often associated with Darier disease. However, these diseases are not due to mutations in the gene ATP2A2 but to a susceptibility locus in a 6.5 Mb region near this gene. Currently, the treatment is strictly limited to the relief of symptoms. In severe cases, oral retinoids (acitretin: initial 10-20 mg/Tag and isotretinoin: 0.5-1 mg/kg/day) lead to a response in 90% of cases. However, side effects often prevent long-term use of vitamin A derivatives. PMID- 23337963 TI - [Congenital nevi in childhood]. AB - Nevi represent congenital hamartomatous malformations of various components of the skin. The most common forms are congenital melanocytic nevi (CMN) and nevi of epithelial origin (epidermal and organoid nevi). Large CMN in particular can lead to severe complications and the management of those affected represents a challenge from birth. In contrast to previous assumptions, the risk of malignancy from CMN is considered to be relatively low however, this may be relevantly increased in certain situations. Possible extracutaneous symptoms in cases of central nervous system (CNS) involvement should not be underestimated and early imaging investigations are part of the routine diagnostic procedure. Surgical measures are still very important in the treatment of CMN but the indications must be weighed up for each individual case. Patients often experience marked stigmatization due to disfigurement by their birthmark and this needs to be taken into consideration for their treatment. The most common epithelial nevi are sebaceous nevi. In 2-13 % of cases additional tumors occur within this nevus and early surgical excision is indicated in most cases, not least for aesthetic reasons. If generalized spreading of epidermal nevi occurs, additional investigations are necessary to exclude associated ophthalmological, cardiac or neurological malformations. PMID- 23337964 TI - [Antiinflammatory potential of seven plant extracts in the ultraviolet erythema test. A randomized, placebo-controlled study]. AB - BACKGROUND: Phytotherapeutics are widely used in medicine. The aim of this study was the evaluation of the antiinflammatory potential of seven medical plant extracts using the ultraviolet- (UV)-erythema test. PATIENTS AND METHODS: Randomized, placebo-controlled study on 40 healthy subjects. Test areas on the upper back were irradiated with the 1.5 fold UV-B minimal erythema dose (MED). Formulations of Aloe vera, Chamomilla recutita, Hamamelis virginiana, Melissa officinalis, Mentha arvensis, Melaleuca alternifolia, Coriandrum sativum as well as 1% hydrocortisone acetate and 0.1% betamethasone valerate as positive controls and unguentum leniens as vehicle control were applied under occlusion on the irradiated areas and on non-irradiated area on the contralateral side. Photometric assessment of the erythema was performed before the application of the substances (t0), at 24 h (t1) and at 48 h (t2). RESULTS: Aloe vera, Chamomilla recutita, Melissa officinalis, Melaleuca alternifolia and Coriandrum sativum showed an antiinflammatory effect compared to UV-control and unguentum leniens. However, the results were only statistically significant for Aloe vera. All tested plant extracts were well tolerated. CONCLUSION: Aloe vera possesses an antiinflammatory effect on UV-induced erythemas. PMID- 23337965 TI - 18F-FDG-PET/CT predicts survival in hypopharyngeal squamous cell carcinoma. AB - OBJECTIVES: We investigated the relationship between overall survival of patients and pretreatment [(18)F]-2-fluorodeoxyglucose ((18)F-FDG) uptake, assessed by positron emission tomography combined with computed tomography (PET/CT) in hypopharyngeal squamous cell carcinoma. METHODS: Thirty-one patients who were newly diagnosed as resectable hypopharyngeal squamous cell carcinoma underwent pretreatment (18)F-FDG-PET/CT. We used the maximum standardized uptake value (SUVmax) as (18)F-FDG uptake. Overall survival rate was calculated by the Kaplan Meier method. RESULTS: The median SUVmax was 11.53 (range 2.49-22.33). Patients with SUVmax >= 13 significantly exhibited shorter overall survival in univariate analysis (p < 0.01). Moreover, by Cox proportional hazards model of multivariate analysis, SUVmax >= 13 was a significant prognostic factor independent of clinical T and N classification, and treatment group (p < 0.02). CONCLUSIONS: These results suggested that SUVmax obtained by pretreatment (18)F-FDG PET/CT assessment is an important prognostic factor in patients with hypopharyngeal squamous cell carcinoma. PMID- 23337966 TI - Biological evaluation of 3-[(18)F]fluoro-alpha-methyl-D-tyrosine (D-[(18)F]FAMT) as a novel amino acid tracer for positron emission tomography. AB - OBJECTIVE: 3-[(18)F]Fluoro-alpha-methyl-L-tyrosine (L-[(18)F]FAMT) is a useful amino acid tracer for positron emission tomography (PET) imaging of malignant tumors. Because D-amino acids are not well distributed in non-target organs and are rapidly excreted in urine, the D-isomer of [(18)F]FAMT could allow clear PET imaging of tumors early after administration. In this study, we prepared 3 [(18)F]fluoro-alpha-methyl-D-tyrosine (D-[(18)F]FAMT) and evaluated its usefulness. METHODS: D-[(18)F]FAMT was synthesized according to the method for preparation of L-[(18)F]FAMT. The in vitro and in vivo stability of [(18)F]FAMT were evaluated by high-performance liquid chromatography. Cellular uptake of [(18)F]FAMT was evaluated using LS180 colon adenocarcinoma cells. Biodistribution studies were performed in LS180 tumor-bearing mice, and the tumors were imaged using a small-animal PET scanner. RESULTS: The radiolabeling yield of D [(18)F]FAMT was approximately 10 %, similar to that of L-[(18)F]FAMT. Over 95 % of D-[(18)F]FAMT remained intact in mice until 60 min after administration. D [(18)F]FAMT was gradually taken up by the LS180 cells. Tumor uptake of D [(18)F]FAMT was competitively inhibited by pretreatment with alpha-methyl-L tyrosine, a selective substrate for the system L-amino acid transporter 1 (LAT1), suggesting the involvement of LAT1 in tumor uptake of D-[(18)F]FAMT. In biodistribution studies, D-[(18)F]FAMT showed rapid clearance from the blood, marked accumulation and retention in the tumor, and lower accumulation in non target organs, especially kidney and pancreas, compared to L-[(18)F]FAMT. The amount of D-[(18)F]FAMT in the tumor was also reduced, and tumor-to-blood ratio and tumor-to-muscle ratio of D-[(18)F]FAMT were similar to those of L-[(18)F]FAMT at every time point. PET imaging with D-[(18)F]FAMT did not provide a clear image of the tumor early after administration. However, D-[(18)F]FAMT provided higher tumor-to-background contrast than L-[(18)F]FAMT. CONCLUSIONS: D-[(18)F]FAMT showed rapid blood clearance, low accumulation in non-target organs, and tumor selective imaging compared with L-[(18)F]FAMT. Thus, D-[(18)F]FAMT could potentially serve as a novel PET tracer for imaging malignant tumors. PMID- 23337967 TI - Separating soil CO2 efflux into C-pool-specific decay rates via inverse analysis of soil incubation data. AB - Soil organic matter (SOM) is heterogeneous in structure and has been considered to consist of various pools with different intrinsic turnover rates. Although those pools have been conceptually expressed in models and analyzed according to soil physical and chemical properties, separation of SOM into component pools is still challenging. In this study, we conducted inverse analyses with data from a long-term (385 days) incubation experiment with two types of soil (from plant interspace and from underneath plants) to deconvolute soil carbon (C) efflux into different source pools. We analyzed the two datasets with one-, two- and three pool models and used probability density functions as a criterion to judge the best model to fit the datasets. Our results indicated that soil C release trajectories over the 385 days of the incubation study were best modeled with a two-pool C model. For both soil types, released C within the first 10 days of the incubation study originated from the labile pool. Decomposition of C in the recalcitrant pool was modeled to contribute to the total CO2 efflux by 9-11 % at the beginning of the incubation. At the end of the experiment, 75-85 % of the initial soil organic carbon (SOC) was modeled to be released over the incubation period. Our modeling analysis also indicated that the labile C-pool in the soil underneath plants was larger than that in soil from interspace. This deconvolution analysis was based on information contained in incubation data to separate carbon pools and can facilitate integration of results from incubation experiments into ecosystem models with improved parameterization. PMID- 23337968 TI - Plant species dominance shifts across erosion edge-meadow transects in the Swiss Alps. AB - While exerting no obvious function under "average" environmental conditions, the presence of certain plant specialists becomes crucial in the event of a complete failure of a community due to severe disturbance such as landslides. Plants capable of growing at erosion edges may act as potential edge-engineers by coping with unstable ground and stabilizing the soil with their roots. We hypothesized that life conditions at erosion edges select for a particular set of specialists or species with specific traits, the identification of which was the aim of the study. Across 17 small-scale transects (0.40 * 1.60 m) from intact meadows to landslide edges (Ursern Valley, Swiss Alps, c. 1,600 m a.s.l.), we quantified plant species abundance by the point intercept method and characterized growth conditions based on Landolt's indicator values, leaf delta(13)C, and volumetric soil moisture in the uppermost soil layers. We observed a clear change of plant species composition and relative abundance from the meadow to the edge, presumably induced by the 25 % lower soil moisture and microclimatic exposure. Species richness at the edge was two-thirds of that in the meadow, but was positively correlated with species richness of the adjacent meadow. Species with "edge-preference" had either (1) rolled or festucoid leaves like Festuca spp., Avenella flexuosa and Nardus stricta, or (2) small, scleromorphic leaves like Vaccinium vitis-idaea, Calluna vulgaris and Thymus ssp. Graminoids with rolled/festucoid leaves were found to be the most dominant edge-specialists. The grass Festuca valesiaca s.l. emerged as the most dominant plant species at the edge, having an 11-times higher cover at the edge than in the meadow. In this montane grassland, a single species contributes to the stabilization of erosion edges and may be regarded as a potential keystone species for slope stability and regeneration after landslides even its role has not so far been established. PMID- 23337969 TI - Hand-assisted laparoscopic colorectal surgery. AB - The use of laparoscopic techniques in the treatment of colorectal diseases was first described in the early 1990s. Even though its clinical benefits have been well documented, laparoscopic colorectal surgery has been slow to gain adoption in the surgical community, given its technical demands. To help overcome these challenges while preserving the clinical benefits derived from a minimally invasive approach, hand-assisted laparoscopic surgery (HALS) was proposed. HALS can decrease the learning curve by restoring tactile sensation and improving proprioception, and it may be more accessible for surgeons already in practice. A meta-analysis of the 3 published RCTs comparing hand-assisted laparoscopic to conventional laparoscopic colorectal resection showed a significantly lower rate of conversion in the hand-assist patients, while morbidity rates were equivalent. The meta-analysis further indicated that short-term postoperative benefits of conventional laparoscopic colectomies were preserved and costs were likely to be offset by reduced operative time and specific need of laparoscopic equipment. HALS represents a valuable option for performing colorectal resections. PMID- 23337970 TI - Gene polymorphisms that can predict response to anti-TNF therapy in patients with psoriasis and related autoimmune diseases. AB - Psoriasis (Ps) is a chronic inflammatory disease with an important genetic component. It shares pathophysiological mechanisms with other autoimmune diseases such as psoriatic arthritis (PsA), rheumatoid arthritis (RA) and Crohn's disease (CD). These conditions can be treated using biological drugs such as infliximab, adalimumab and etanercept, which selectively block the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. Although these agents have greatly improved the prognosis of Ps, PsA, RA and CD, they do not cure the disease and are expensive; in addition, significant proportions of patients do not respond or develop serious adverse effects. Therefore, it is important to investigate biomarkers, such as gene polymorphisms, that can predict which patients will respond best to a specific drug. Some polymorphisms in genes TNF, TNF receptor superfamily 1B (TNFR1B) and TNFalpha-induced protein 3 gene (TNFAIP3) have been associated with response to anti-TNF therapy in patients with Ps. The present article reviews other polymorphisms that could also play a role in prediction of response to these treatments. PMID- 23337971 TI - Antibody orientation on biosensor surfaces: a minireview. AB - Detection elements play a key role in analyte recognition in biosensors. Therefore, detection elements with high analyte specificity and binding strength are required. While antibodies (Abs) have been increasingly used as detection elements in biosensors, a key challenge remains - the immobilization on the biosensor surface. This minireview highlights recent approaches to immobilize and study Abs on surfaces. We first introduce Ab species used as detection elements, and discuss techniques recently used to elucidate Ab orientation by determination of layer thickness or surface topology. Then, several immobilization methods will be presented: non-covalent and covalent surface attachment, yielding oriented or random coupled Abs. Finally, protein modification methods applicable for oriented Ab immobilization are reviewed with an eye to future application. PMID- 23337972 TI - Evolutionary rate of human tissue-specific genes are related with transposable element insertions. AB - The influence of transposable elements (TEs) on genome evolution has been widely studied. However, it remains unclear whether TE insertions also impact on evolutionary rate of human genes. In this study, we have compared the differences in TEs and evolutionary rates between human tissue-specific genes. Our results showed that various functional categories of human tissue-specific genes contained different TE numbers and divergent values of Ka/Ks, with human nucleic acid binding transcription factor activity genes having the fewest TE density and Ka/Ks value. Interestingly, we also found that human tissue-specific genes with TEs have also undergone faster evolution than those without TEs. Therefore, TEs have significant impact on the evolutionary rates of human tissue-specific genes. Furthermore, local genomic properties such as gene length, GC content and recombination rate may reflect a true transpositional bias for the particular TEs. Our results may provide important insights for further elucidating the evolution of human tissue-specific genes. PMID- 23337973 TI - Mechanobiology: a new frontier for human pluripotent stem cells. AB - Research on human pluripotent stem cells (hPSCs) has expanded rapidly over the last two decades, owing to the promises of hPSCs for applications in regenerative medicine, disease modeling, and developmental biology studies. While most studies of hPSCs have so far focused on identifying extrinsic soluble factors, intracellular signaling pathways, and transcriptional networks that are involved in regulating hPSC self-renewal and differentiation, a few promising studies have emerged in recent years to reveal some unique mechano-sensitive and -responsive properties of hPSCs and the effect of the physical aspects of the local cellular microenvironment on regulating hPSC behaviors. This Frontier Review is to highlight these recent studies of mechanobiology in hPSCs and to discuss the impact of advancing our understanding of mechanoregulation of hPSC behaviors on improving survival, self-renewal and differentiation of hPSCs using well controlled synthetic micro/nanoscale cell culture tools. PMID- 23337974 TI - Association studies indicate that protein disulfide isomerase is a risk factor in amyotrophic lateral sclerosis. AB - Protein disulfide isomerase (PDI) plays an important role in the endoplasmic reticulum (ER) by facilitating the exchange of disulfide bonds and, together with other ER stress proteins, is induced in amyotrophic lateral sclerosis (ALS). However, genetic polymorphisms in the P4HB gene, which encodes PDI, have not been thoroughly investigated in ALS cases. In this study, we determined whether single nucleotide polymorphisms (SNPs) in the P4HB gene were associated with familial ALS (FALS) and sporadic ALS (SALS). We report significant genotypic associations for two SNPs in P4HB with FALS, rs876016 (P=0.0198) and rs2070872 (P=0.0046), all values being FDR corrected. Significant allelic associations were also obtained for rs876016 with FALS (P=0.0155) and ALS (FALS and SALS) (P=0.0148). Four SNP haplotypes, which included two additional flanking SNPs, rs876017 and rs8324, were examined and rare haplotypes were found to be more common in ALS cases compared to controls. Seven haplotypes were significantly associated with FALS and one haplotype was significantly associated with SALS. One rare haplotype, which was present in controls, was overrepresented in a group of SOD1-positive FALS cases. Reduced survival was observed in FALS cases possessing at least one copy of the minor allele of rs2070872 (P=0.0059) and rs8324 (P=0.0167) and in individuals lacking the homozygous AAAC/AAAC diplotype (P=0.011). The results suggest that P4HB is a modifier gene in ALS susceptibility and may represent a potential therapeutic target for ALS. PMID- 23337975 TI - Psychotherapy and the Mormon faith. AB - The Church of Jesus Christ of Latter-day Saints, also known as the Mormon Church, is a Christian faith with a large presence across the globe. Although Mormon doctrine suggests that faith in Jesus allows people to overcome weakness and heal from pain, Mormon people are not immune from experiencing periods of mental and emotional suffering. The deeply held religious beliefs of Mormons can influence the nature of the psychological difficulties a Mormon individual is prone to experiencing, how and when they choose to seek treatment, as well as the types of treatment that may be most beneficial. PMID- 23337976 TI - Delta-like 3 is silenced by methylation and induces apoptosis in human hepatocellular carcinoma. AB - The genetic and epigenetic events of hepato-carcinogenesis are relatively poorly understood. By analyzing genes from human hepatocellular carcinoma (HCC) with restriction landmark genomic scanning, several aberrantly methylated genes, including Delta-like 3 (DLL3), have been isolated. In this study, we investigated the function of DLL3 in hepatocarcinogenesis. Methylation of the DLL3 gene in HCC cell lines was investigated with methylation-specific PCR and expression of DLL3 mRNA in HCC cells was examined by RT-PCR. Reactivation of DLL3 expression by treatment with a demethylating agent was examined in methylation-silenced HuH2 cells. Human DLL3 cDNA was cloned and DLL3 function was examined by restoring DLL3 expression in HuH2 cells. The effects of DLL3 on cell growth were evaluated by colony formation assay. Induction of cell death by overexpression of DLL3 was examined by flow cytometric assay using Annexin V and PI. Apoptotic cells were detected by TUNEL staining and the amount of single-stranded DNA was measured by ELISA. As a result, the promoter region of the DLL3 gene was methylated in four of ten HCC cell lines. This aberrant methyl-ation correlated well with the suppression of RNA expression and a demethylating agent reactivated DLL3 expression in methylation-silenced HCC cells. Interestingly, the restoration of DLL3 in the methylation-silenced HuH2 cells led to growth suppression on colony formation assay. Flow cytometric assay with Annexin V and PI showed that this growth suppression by DLL3 expression is associated with the induction of apoptosis. Furthermore, these apoptotic effects were confirmed by TUNEL staining and measurement of single-stranded DNA. These results suggest that DLL3 was silenced by methylation in human HCC and that it negatively regulates the growth of HCC cells. PMID- 23337977 TI - (Oxy)nitrides with d0-electronic configuration as photocatalysts and photoanodes that operate under a wide range of visible light for overall water splitting. AB - Water splitting to form H2 and O2 using semiconductor photocatalysts under sunlight is a possible means of clean energy production from renewable resources. (Oxy)nitrides are regarded as suitable candidates for the application, because of their suitable band edge positions, small band gaps (<3 eV), and stability under irradiation. Since early reports published in 2002 by Domen et al., it has been demonstrated that several (oxy)nitrides are active photocatalysts capable of reducing and oxidizing water in the presence of suitable electron donors and acceptors, respectively, under visible light (lambda > 400 nm). Some have achieved direct water splitting into H2 and O2 with good reproducibility. (Oxy)nitrides are also attractive as water-splitting photoelectrodes, and highly efficient photoelectrochemical water splitting has been accomplished using tantalum-based (oxy)nitrides under visible light with good stability. However, there still remain a lot of challenges that have to be addressed in this research field. This perspective highlights recent progress in the development of (oxy)nitride materials for application in photocatalytic and photoelectrochemical water splitting made by the author and his colleagues, especially in the last 5 years. PMID- 23337978 TI - Hearing loss and cognitive decline in older adults. AB - BACKGROUND Whether hearing loss is independently associated with accelerated cognitive decline in older adults is unknown. METHODS We studied 1984 older adults (mean age, 77.4 years) enrolled in the Health ABC Study, a prospective observational study begun in 1997-1998. Our baseline cohort consisted of participants without prevalent cognitive impairment (Modified Mini-Mental State Examination [3MS] score, >=80) who underwent audiometric testing in year 5. Participants were followed up for 6 years. Hearing was defined at baseline using a pure-tone average of thresholds at 0.5 to 4 kHz in the better-hearing ear. Cognitive testing was performed in years 5, 8, 10, and 11 and consisted of the 3MS (measuring global function) and the Digit Symbol Substitution test (measuring executive function). Incident cognitive impairment was defined as a 3MS score of less than 80 or a decline in 3MS score of more than 5 points from baseline. Mixed effects regression and Cox proportional hazards regression models were adjusted for demographic and cardiovascular risk factors. RESULTS In total, 1162 individuals with baseline hearing loss (pure-tone average >25 dB) had annual rates of decline in 3MS and Digit Symbol Substitution test scores that were 41% and 32% greater, respectively, than those among individuals with normal hearing. On the 3MS, the annual score changes were -0.65 (95% CI, -0.73 to -0.56) vs -0.46 (95% CI, -0.55 to -0.36) points per year (P = .004). On the Digit Symbol Substitution test, the annual score changes were -0.83 (95% CI, -0.94 to -0.73) vs -0.63 (95% CI, -0.75 to -0.51) points per year (P = .02). Compared to those with normal hearing, individuals with hearing loss at baseline had a 24% (hazard ratio, 1.24; 95% CI, 1.05-1.48) increased risk for incident cognitive impairment. Rates of cognitive decline and the risk for incident cognitive impairment were linearly associated with the severity of an individual's baseline hearing loss. CONCLUSIONS Hearing loss is independently associated with accelerated cognitive decline and incident cognitive impairment in community-dwelling older adults. Further studies are needed to investigate what the mechanistic basis of this association is and whether hearing rehabilitative interventions could affect cognitive decline. PMID- 23337979 TI - Newcastle disease virus Malaysian strain AF2240 induces apoptosis in MCF-7 human breast carcinoma cells at an early stage of the virus life cycle. AB - Newcastle disease virus (NDV) AF2240 Malaysian strain is a very virulent avian virus. NDV strain AF2240 was previously demonstrated to induce apoptosis in human breast carcinoma MCF-7 cells. However, at which stage of the NDV life cycle apoptosis is induced and whether NDV replication and protein synthesis are involved in apoptosis induction have yet to be determined. In the present study, we investigated the time course of NDV strain AF2240 nucleoprotein (NP) gene expression and the early apoptotic signs in the form of activation of caspase-8 and mitochondrial transition pore opening. In addition, the induction of apoptosis by both ultraviolet-inactivated and cycloheximide-treated NDV-infected MCF-7 cells were examined. Our findings showed that NDV strain AF2240 induced apoptosis at 1 h post-infection (pi) through activation of mitochondrial transition pore opening and at 2 h through activation of caspase-8, while the NP gene was expressed at 6 h pi. The induced apoptosis was independent of both virus replication and protein synthesis. In conclusion, NDV strain AF2240 induces apoptosis at an early stage of its life cycle, possibly during virus binding or fusion with the cell membrane. The mitochondrial-related pathway may be the central activator in NDV strain AF2240-induced apoptosis. PMID- 23337980 TI - Clinical significance of altered S100A2 expression in gastric cancer. AB - The S100A2 gene has been reported to be a putative tumor-suppressor gene. Nevertheless, overexpression of S100A2 has been found in certain types of cancer. This study investigated S100A2 expression in tissue specimens of gastritis, intestinal metaplasia, adenomatous dysplasia and gastric cancer to determine its association with clinical features. A serial of tissue samples (gastritis, intestinal metaplasia, adenomatous dysplasia and gastric cancer samples) were used for quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), western blotting and immunohistochemical analyses of S100A2 expression. The data revealed that there was a gradual loss of S100A2 expression from gastritis, intestinal metaplasia and dysplasia to cancer tissue specimens (p<0.001). In gastric cancer samples, loss of S100A2 expression was associated with increased tumor size, depth of invasion, lymph node metastasis and a poor prognosis (p<0.001). However, the intestinal type of gastric cancer expressed more S100A2 protein than the diffuse type (p<0.001). In conclusion, data from the present study demonstrated that loss of S100A2 expression contributes to gastric cancer development and progression; therefore, the determination of S100A2 expression levels may help to predict the carcinogenesis and aggressiveness of gastric cancer as well as patient survival. PMID- 23337981 TI - Targeting and killing of metastatic cells in the transgenic adenocarcinoma of mouse prostate model with vesicular stomatitis virus. AB - Vesicular stomatitis virus (VSV) is an oncolytic virus which selectively infects and kills cancer cells. The goal of the present study was to determine whether VSV is capable of targeting metastatic lesions that arise in situ in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The interferon (IFN)-responsive luciferase containing VSV(AV3) strain was injected intraprostatically into both control and TRAMP mice. Distribution, infectivity, apoptosis, and status of the IFN response were evaluated at the site of viral injection (prostate), as well as in metastatic lesions (lymph nodes), through plaque, polymerase chain reaction (PCR), and immunohistochemical analysis. Bioluminescence analyses demonstrated that VSV(AV3) persisted at high levels in the prostate region of TRAMP mice for up to 96 hours, but at relatively low levels and for only 48 hours in control mice. Live virus was discovered in the lymph nodes of TRAMP mice, but not in control mice. TUNEL staining revealed increased cell death in VSV(AV3) infected metastatic cells present in the lymph nodes of TRAMP mice. There was an evidence of IFN activation in lymph nodes containing metastatic cells. Our results indicate that intraprostatic injections of VSV(AV3) can be used as a means to infect and kill metastatic lesions associated with advanced prostate cancer. PMID- 23337982 TI - Triplex-forming peptide nucleic acids induce heritable elevations in gamma-globin expression in hematopoietic progenitor cells. AB - Potentiating homologous recombination using triplex-forming peptide nucleic acids (PNAs) can be used to mediate targeted sequence editing by donor DNAs and thereby induce functional gene expression to supplant non-functional counterparts. Mutations that disrupt the normal function of the beta-globin subunit cause hemoglobinopathies such as sickle cell disease and beta-thalassemias. However, expression of the functional gamma-globin subunit in adults, a benign condition called hereditary persistence of fetal hemoglobin (HPFH), can ameliorate the severity of these disorders, but this expression is normally silenced. Here, we harness triplex-forming PNA-induced donor DNA recombination to create HPFH mutations that increase the expression of gamma-globin in adult mammalian cells, including beta-yeast artificial chromosome (YAC) bone marrow and hematopoietic progenitor cells (HPCs). Transfection of human cells led to site-specific modification frequencies of 1.63% using triplex-forming PNA gamma-194-3K in conjunction with donor DNAs, compared with 0.29% using donor DNAs alone. We also concurrently modified the gamma-globin promoter to insert both HPFH-associated point mutations and a hypoxia-responsive element (HRE), conferring increased expression that was also regulated by oxygen tension. This work demonstrates application of oligonucleotide-based gene therapy to induce a quiescent gene promoter in mammalian cells and regulate its expression via an introduced HRE transcription factor binding site for potential therapeutic purposes. PMID- 23337983 TI - A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 gangliosidosis. AB - Lysosomal beta-galactosidase (beta-Gal) deficiency causes a group of disorders that include neuronopathic GM1 gangliosidosis and non-neuronopathic Morquio B disease. We have previously proposed the use of small molecule ligands of beta Gal as pharmacological chaperones (PCs) for the treatment of GM1 gangliosidosis brain pathology. Although it is still under development, PC therapy has yielded promising preclinical results in several lysosomal diseases. In this study, we evaluated the effect of bicyclic 1-deoxygalactonojirimycin (DGJ) derivative of the sp(2)-iminosugar type, namely 5N,6S-(N'-butyliminomethylidene)-6-thio-1- deoxygalactonojirimycin (6S-NBI-DGJ), as a novel PC for human mutant beta-Gal. In vitro, 6S-NBI-DGJ had the ability to inhibit the activity of human beta-Gal in a competitive manner and was able to protect this enzyme from heat-induced degradation. Computational analysis supported that the rigid glycone bicyclic core of 6S-NBI-DGJ binds to the active site of the enzyme, with the aglycone N' butyl substituent, in a precise E-orientation, located at a hydrophobic region nearby. Chaperone potential profiling indicated significant increases of enzyme activity in 24 of 88 beta-Gal mutants, including four common mutations. Finally, oral administration of 6S-NBI-DGJ ameliorated the brain pathology of GM1 gangliosidosis model mice. These results suggest that 6S-NBI-DGJ is a novel PC that may be effective on a broad range of beta-Gal mutants. PMID- 23337984 TI - Adenovirus expressing both thymidine kinase and soluble PD1 enhances antitumor immunity by strengthening CD8 T-cell response. AB - Adenoviruses harboring the herpes simplex virus thymidine kinase (HSVtk) gene under the regulation of a trans-splicing ribozyme targeting human telomerase reverse transcriptase (hTERT-TR) show marked and specific antitumor activity. In addition to inducing tumor cell death by direct cytotoxicity, it is becoming clear that HSVtk also induces antitumor immunity. Programmed death ligand 1 (PD L1) expressed on tumor cell surfaces mediates tumor-induced immunoresistance by inhibiting PD1-expressing tumor-infiltrating T cells. Here, we explored whether a soluble form of PD1 (sPD1-Ig), which blocks PD-L1, could synergize with TERT-TR regulated HSVtk to enhance the adenoviral therapeutic efficacy by boosting antitumor immunity. Tumor antigen released by HSVtk-transduced tumors successfully primed tumor antigen-specific CD8 T cells via dendritic cells (DC). Regression of murine tumors was markedly enhanced when sPD1-Ig was incorporated into the adenovirus as compared with a single-module adenovirus expressing only HSVtk. This effect was abolished by CD8 T-cell depletion. Consistent with this, following adoptive transfer of tumor antigen-specific CD8 T cells into tumor bearing Rag1(-/-) mice, dual-module adenovirus significantly enhanced CD8 T cell mediated tumor rejection. In addition, secondary tumor challenge at a distal site was completely suppressed in mice treated with a dual-module adenovirus. These results suggest that a dual-targeting strategy to elicit both tumor antigen priming and tumor-induced immunoresistance enhances CD8 T cell-mediated antitumor immunity. PMID- 23337985 TI - Gene therapy researchers' assessments of risks and perceptions of risk acceptability in clinical trials. AB - Although recent clinical trials have demonstrated the increasing promise of gene therapy, they have also illustrated the difficulties of assessing risks, given the inherent uncertainty of trial outcomes. An international survey was conducted to investigate gene therapy researchers' perceptions and assessments of risks in clinical trials. Data from respondents (n = 156) demonstrated researchers' perceptions of clinical context and the strength of preclinical evidence strongly influenced risk assessments and judgments of acceptable risk levels. Professional experience in clinical care, and particularly care of children, predicted favorable attitudes toward nonanimal preclinical models and trial initiation when sub-optimal treatments were available. The potential for adverse events to impact negatively on the gene therapy field and on public trust were relevant considerations when planning a trial. Decisions about clinical trials appear to be influenced not only by the clinical context and preclinical evidence, but also subjective factors reflecting the experience of researchers, value-judgments about risk and benefit, and attitudes toward preclinical models, uncertainty, adverse events, and the perceived needs of patients. It is clear that risk assessment in clinical research involves moral and scientific judgment. Identifying moral assumptions and qualitative assessments underpinning the design and conduct of research may facilitate future decision-making in clinical trials. PMID- 23337986 TI - New perspectives in the treatment of cardiac arrhythmias and their application in Brazil. PMID- 23337987 TI - Research training program: Duke University and Brazilian Society of Cardiology. AB - BACKGROUND: Research coaching program focuses on the development of abilities and scientific reasoning. For health professionals, it may be useful to increase both the number and quality of projects and manuscripts. OBJECTIVE: To evaluate the initial results and implementation methodology of the Research and Innovation Coaching Program of the Research on Research group of Duke University in the Brazilian Society of Cardiology. METHODS: The program works on two bases: training and coaching. Training is done online and addresses contents on research ideas, literature search, scientific writing and statistics. After training, coaching favors the establishment of a collaboration between researchers and centers by means of a network of contacts. The present study describes the implementation and initial results in reference to the years 2011-2012. RESULTS: In 2011, 24 centers received training, which consisted of online meetings, study and practice of the contents addressed. In January 2012, a new format was implemented with the objective of reaching more researchers. In six months, 52 researchers were allocated. In all, 20 manuscripts were published and 49 more were written and await submission and/or publication. Additionally, five research funding proposals have been elaborated. CONCLUSION: The number of manuscripts and funding proposals achieved the objectives initially proposed. However, the main results of this type of initiative should be measured in the long term, because the consolidation of the national production of high-quality research is a virtuous cycle that feeds itself back and expands over time. PMID- 23337988 TI - Sleep duration and body mass index among southern Brazilian preschoolers. AB - Prevention and treatment of overweight are particularly complex, reinforcing the importance of studies aimed at clarifying their range of causes and effects. Thus, the objective of this study was to evaluate the relationship between night sleep duration and anthropometric measurements. A cross-sectional analysis was performed from data from 348 children aged 3 and 4 years in Sao Leopoldo/RS. Night sleep duration was reported by their mothers and body mass index, waist circumference and skinfold thickness were measured according to standard protocol. The analyses were adjusted for energy intake and hours of television watching. Overweight children had, on average, 0.39 hours less sleep than those with normal weight (9.77 +/- 1.44 versus 10.17 +/- 1.34; 95% CI 0.03 to 0, 76). We observed an inverse association between night sleep duration and z score values of body mass index for age (B = -0.12 95% CI -0.22 - -0.02). Waist circumference and skinfold thickness showed an inverse relationship with sleep duration, but without any statistic differences. Among preschool children in southern Brazil, smaller night sleep duration was associated with higher body mass index. PMID- 23337989 TI - Living wills. PMID- 23337990 TI - Case 6: late cardiogenic shock after myocardial infarction in a 50 year-old hypertensive and diabetic man. PMID- 23337991 TI - Multidisciplinary interaction in invasive cardiology: septal alcoholization. PMID- 23337992 TI - Surgical repair of aortopulmonary window in twins: a case report. PMID- 23337993 TI - Needs and preferences of the patient with valvular heart disease. PMID- 23337994 TI - Smoking: what has been addressed in Brazilian journals. AB - The topic of tobacco smoking, in its several aspects, has been receiving increasing attention among researchers over the past few years, which has been reflected in more data and more solid scientific literature on the subject in national journals. This article aims to review the studies that focused on smoking published between January 2010 and June 2012, in Arquivos Brasileiros de Cardiologia (Brazilian Archives of Cardiology), Brazilian Journal of Medical and Biological Research, Clinics (Sao Paulo), Jornal Brasileiro de Pneumologia (Brazilian Journal of Pulmonology), Revista da Associacao Medica Brasileira (Journal of the Brazilian Medical Association) and Revista Brasileira de Cirurgia Cardiovascular (Brazilian Journal of Cardiovascular Surgery). During the aforementioned period 58 articles were published, 52 of which were original ones, addressing several aspects of smoking, such as effects on health, epidemiology, cessation and experimental studies. PMID- 23337995 TI - The LiverSurgeryTrainer: training of computer-based planning in liver resection surgery. AB - PURPOSE: The training of liver surgeons depends on local conditions such as the specialization of the clinic, the spectrum of cases, and the instructing surgeons. We present the LiverSurgeryTrainer a software application to support the training of prospective surgeons in preoperative decision making. METHODS: The LiverSurgeryTrainer visualizes radiological images, volumetric information, and interactive 3D models of patients' liver anatomy. In addition, it provides special interaction techniques and tools to perform individual resections on the training data. To assess the correctness of decisions made by the learner, comments and decisions from experienced liver surgeons are provided for each case. To complete the case, additional material concerning the actual surgery (e.g., videos, reports) is presented. The application workflow is derived from a scenario-based design process and is based on an instructional design model. RESULTS: The LiverSurgeryTrainer was evaluated in several steps. A formative usability evaluation identified workflow and user interface flaws that were resolved in further development process. A summative evaluation shows the improvement of the LiverSurgeryTrainer in nearly all analyzed aspects. First results of a learning success evaluation show that learners experience a learning effect. CONCLUSION: Our training system allows surgeons to train procedures and interaction techniques for computer-based planning of liver interventions. The evaluations showed acceptance and usability. PMID- 23337996 TI - Bilaterally absent posterior inferior cerebellar artery: case report. AB - Posterior inferior cerebellar artery (PICA) is one of the cerebellar arteries which originates from the vertebral artery and has the most complex and variable course. The PICA usually originates from the vertebral artery intracranially as a single trunk, however, absent, double trunk, extracranial, and extradural PICA may also exist. In a collection of 50 cerebellar specimens (100 hemispheres) injected with colored gelatin, one case of bilaterally absent PICA was encountered, male aged 59 (causes of the death was not taken into consideration). PMID- 23337997 TI - The effect of low-pass filtering on identification of nonsense syllables in quiet by school-age children with and without cochlear dead regions. AB - OBJECTIVES: The presence of cochlear dead regions (DRs) can have a significant effect on speech perception. Some studies have reported that adults do not benefit from amplification of frequencies well inside an extensive DR. However, the importance of high-frequency amplification for hearing-impaired children has been emphasized by many researchers. This study investigates the benefit of high frequency amplification for children with various degrees of high-frequency hearing impairment, with and without DRs. DESIGN: The children, aged 8 to 13 years, were divided into two groups according to the severity of their hearing impairment. Group MS had moderate to severe impairment (9 ears without DRs and 3 ears with restricted DRs). Group SP had severe to profound hearing impairment (7 ears with DRs and 1 ear without a DR). The vowel-consonant-vowel stimuli were subjected to the frequency-gain characteristics prescribed by the desired sensation level fitting method and presented via headphones broadband and under various low-pass filtering conditions. RESULTS: Group MS benefited from high frequency amplification whether or not a restricted DR was present. In contrast, ears in group SP with continuous extensive DRs showed limited benefit from high frequency amplification. For the latter, performance improved with increasing cutoff frequency up to approximately 1 octave above the edge frequency of the DR and generally stayed the same, or deteriorated, with further increases in bandwidth. In one case of severe to profound hearing impairment without evidence of DRs, performance increased with increasing cutoff frequency up to 2 kHz and remained almost constant with further increases in bandwidth. CONCLUSIONS: For children with severe to profound hearing impairment and continuous high-frequency DRs commencing from approximately 1 kHz, applying amplification only for frequencies up to approximately 1 octave above the edge frequency of the DR may be of benefit. Tests with more participants are needed to confirm this finding. PMID- 23337998 TI - A charge-polarized porous metal-organic framework for gas chromatographic separation of alcohols from water. AB - A bipyridinium ligand with a charge separated skeleton has been introduced into a metal-organic framework to yield a porous material with charge-polarized pore space, which exhibits selective adsorption for polar guest molecules and can be further used in gas chromatography for the separation of alcohol-water mixtures. PMID- 23338002 TI - Microorganism viability influences internal phase droplet size changes during storage in water-in-oil emulsions. AB - Water-in-oil emulsions provide an alternative for long-term stabilization of microorganisms. Maintaining physical stability of the emulsion and cell viability is critical for large-scale application. Water-in-oil (W/O) emulsions were prepared with the biolarvacide Lagenidium giganteum and the green alga Chlorella vulgaris. Physical stability was measured via light scattering measurements of the internal phase droplets and cell viability was measured by plating and enumerating colony forming units. Emulsions were demonstrated to stabilize L. giganteum and C. vulgaris for more than 4 months without refrigeration. Introducing nutrients into the internal phase of W/O emulsions without cells had no significant effect on changes in aqueous phase droplet size dynamics. Internal phase droplet size changes that occurred over time were greater in the presence of cells. Increases in droplet size were correlated with cell death indicating measurement of internal phase droplet size changes may be an approach for monitoring declines in cell viability during storage. PMID- 23338003 TI - A two-step fermentation of distillers' grains using Trichoderma viride and Rhodopseudomonas palustris for fish feed. AB - It is important to provide added value or to make full use of the co-product of grains from ethanol production. In order to convert distillers' grains into a high-quality feed, the Trichoderma viride and Rhodopseudomonas palustris fermentation were combined and investigated in this study. The T. viride fermentation was carried out in an aerobic fermentation installation in favoring of the growth of the fungi and the degradation of the cellulose, and then the fermentation of R. palustris was performed to increase the content of protein with an anaerobic installation. After the two step fermentations, the true protein content of dried distiller' grains increased from 11.4 to 33.6 % (w/w) (the content of crude protein from 14.5 to 39.7 %), the crude fiber content decreased from 21.3 to 7.6 % (w/w), the crude fat content increased from 5.5 to 7.9 % (w/w), the crude ash decreased from 14.6 to 10.2 % (w/w), the total phosphorus content increased from 0.4 to 1.2 % (w/w), and the water content was 11.8 % (w/w). The dried and fermented grains contain the R. palustris viable count of 5.3 * 1011 CFU/g dry matter. The results may support a new application of an active photosynthetic bacteria fish feed in fisheries industry and offer a reference for the further study of lignocellulosic materials as raw materials converting into high-quality feed. PMID- 23338004 TI - Differential dropout and bias in randomised controlled trials: when it matters and when it may not. PMID- 23338005 TI - Discrepancies in predicted fracture risk in elderly people. PMID- 23338006 TI - Commentary: Opportunities to prevent fracture are being missed. PMID- 23338007 TI - Research versus the patient. PMID- 23338008 TI - Are Darzi-style clinics set to make a comeback? PMID- 23338009 TI - Beneath the surface. PMID- 23338010 TI - HMRC closes loophole that allowed tax relief on funding medical research. PMID- 23338011 TI - Cortisol as a biomarker of stress in term human labor: physiological and methodological issues. AB - Literature on the use of plasma cortisol to quantify psychophysiological stress in humans is extensive. However, in parturition at term gestation, the use of cortisol as a biomarker of stress is particularly complex. Plasma cortisol levels increase as labor progresses. This increase seems to be important for maintenance of maternal/fetal well-being and facilitation of normal labor progress. Unique physiological and methodological issues involved in the use of cortisol as a biomarker of stress in labor present challenges for researchers. This review examines these issues, suggests mixed methods and within-subject repeated measures designs, and offers recommendations for assay procedures for parturient sampling. Documentation of clinical interventions and delivery outcomes may elucidate relationships among psychophysiological stressors, cortisol, and normal labor progress. With attention to these methodological issues, analysis of plasma cortisol may lead to clinical interventions that support normal labor physiology. PMID- 23338012 TI - PCR-based detection of resistance genes in anaerobic bacteria isolated from intra abdominal infections. AB - Little information is available on the distribution of antimicrobial resistance genes in anaerobes in Japan. To understand the background of antimicrobial resistance in anaerobes involved in intra-abdominal infections, we investigated the distribution of eight antimicrobial resistance genes (cepA, cfiA, cfxA, ermF, ermB, mefA, tetQ, and nim) and a mutation in the gyrA gene in a total of 152 organisms (Bacteroides spp., Prevotella spp., Fusobacterium spp., Porphyromonas spp., Bilophila wadsworthia, Desulfovibrio desulfuricans, Veillonella spp., gram positive cocci, and non-spore-forming gram-positive bacilli) isolated between 2003 and 2004 in Japan. The cepA gene was distributed primarily in Bacteroides fragilis. Gene cfxA was detected in about 9 % of the Bacteroides isolates and 75 % of the Prevotella spp. isolates and did not appear to contribute to cephamycin resistance. Two strains of B. fragilis contained the metallo-beta-lactamase gene cfiA, but they did not produce the protein product. Gene tetQ was detected in about 81, 44, and 63 % of B. fragilis isolates, other Bacteroides spp., and Prevotella spp. isolates, respectively. The ermF gene was detected in 25, 13, 56, 64, and 16 % of Bacteroides spp., Prevotella spp., Fusobacterium spp., B. wadsworthia, and anaerobic cocci, respectively. Gene mefA was found in only 10 % of the B. fragilis strains and 3 % of the non-B. fragilis strains. Genes nim and ermB were not detected in any isolate. Substitution at position 82 (Ser to Phe) in gyrA was detected in B. fragilis isolates that were less susceptible or resistant to moxifloxacin. This study is the first report on the distribution of resistance genes in anaerobes isolated from intra-abdominal infections in Japan. We expect that the results might help in understanding the resistance mechanisms of specific anaerobes. PMID- 23338014 TI - Vertebral osteomyelitis caused by non-tuberculous mycobacteria: case reports and review. AB - There are currently few reports of vertebral osteomyelitis caused by non tuberculous mycobacteria. To date, only 38 cases, excluding human immunodeficiency virus patients, have been reported. We describe 3 patients with vertebral osteomyelitis caused by Mycobacterium avium-intracellulare complex or Mycobacterium kansasii, and review previous reports of vertebral osteomyelitis caused by non-tuberculous mycobacteria. Case 1 is a 50-year-old man who presented with lower back pain. Radiologic examination revealed L1-L5 enhancement and paravertebral abscess. The surgical specimen was positive for Mycobacterium avium intracellulare complex. The patient was successfully treated by surgical excision and antibiotic administration. Case 2 is a 68-year-old woman who presented with upper back pain. Spine MRI revealed multiple lesions at T9-T12, L2, L4, and L5. Her back pain worsened, and repeated MRI revealed extensive bone lesions. Mycobacterium kansasii was isolated from a T5 vertebral body specimen. Surgery was not performed. Case 3 is a 38-year-old woman who had been taking prednisolone for systemic lupus erythematosus. We diagnosed her condition as suppurative knee arthritis caused by M. avium-intracellulare complex. Vertebral MRI revealed T9 vertebral body enhancement and a paravertebral abscess at T8-T9. Tissue culture of a T9 specimen yielded M. avium-intracellulare complex. Her clinical condition improved following posterior thoracic spinal fusion. In conclusion, vertebral osteomyelitis caused by non-tuberculous mycobacteria should be included in the differential diagnosis, even in immunocompetent patients. PMID- 23338015 TI - Antimicrobial susceptibilities of Clostridium difficile isolated in Japan. AB - Clostridium difficile is a common causative organism of antimicrobial-associated diarrhea and is often responsible for nosocomial infection. C. difficile infection has traditionally been treated with metronidazole (MNZ) or vancomycin (VCM); however, MNZ-resistant strains have reported in some countries. In this study the broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of 15 drugs against 157 clinical isolates of C. difficile in Japan. All C. difficile isolates tested were susceptible to MNZ; MIC50 was 0.25 MUg/ml, MIC90 was 0.5 MUg/ml, and MIC range was 0.06-1 MUg/ml. C. difficile isolates were also susceptible to VCM; MIC50 was 0.5 MUg/ml, MIC90 was 1 MUg/ml, and MIC range was 0.12-2 MUg/ml. Susceptibility to teicoplanin was also similar: MIC50 was 0.12 MUg/ml, MIC90 was 0.12 MUg/ml, and MIC range was 0.03-0.25 MUg/ml. The susceptibility of C. difficile isolates must be monitored continuously because a strain with reduced susceptibility to MNZ or VCM might emerge in the future. PMID- 23338016 TI - Circadian genetics: Translation gets timely. PMID- 23338017 TI - A considerable responsibility. PMID- 23338018 TI - [Treatment of chronic non-malignant pain]. PMID- 23338022 TI - [Troublesome dose limits]. PMID- 23338023 TI - [Research on cell lines]. PMID- 23338027 TI - [Stereotactic irradiation in spinal metastases]. PMID- 23338029 TI - Reimbursement of analgesics for chronic pain. AB - BACKGROUND: The prevalence of chronic non-malignant pain in Norway is between 24% and 30%. The proportion of the population using opioids for non-malignant pain on a long-term basis is around 1%. The purpose of our study was to investigate how many were prescribed analgesics on reimbursable prescription under reimbursement code -71 (chronic non-malignant pain) in 2009 and 2010, which analgesics were prescribed and whether prescribing practices were in accordance with national guidelines. MATERIAL AND METHOD: We retrieved pseudonymised data from the National Prescription Database on all those who received drugs with reimbursement code -71 in 2009 and 2010. The data contain information on drug, dosage, formulation, reimbursement code and date of issue. RESULTS: 90,731 patients received reimbursement for drugs indicated for chronic non-malignant pain in 2010. Of these, 6,875 were given opioids, 33,242 received paracetamol, 25,865 non steroid inflammatory drugs (NSAIDs), 20,654 amitryptiline and 16,507 gabapentin. Oxycodone was the most frequently prescribed opioid, followed by buprenorphine, tramadol and codeine/paracetamol. Of those who were prescribed opioids, 4,047 (59%) received mainly slow-release opioids, 2,631 (38%) also received benzodiazepines and 2,418 (35%) received benzodiazepine-like sleep medications. CONCLUSION: The number of patients who received analgesics and opioids on reimbursable prescriptions was low compared to the proportion of the population with chronic pain and the proportion using opioids long-term. 38% of those reimbursed for opioids also used benzodiazepines, which is contrary to official Norwegian guidelines. PMID- 23338030 TI - Infertility treatment and the risk of cancer. AB - BACKGROUND: A possible correlation between hormonal stimulation during treatment of infertility and the risk of cancer of the breast, the ovaries, the cervix or the uterus has been investigated in a number of epidemiological studies. The purpose of this article is to review the relevant literature and summarise the findings. KNOWLEDGE BASE: This review article is based on literature searches in the databases MEDLINE, Cochrane and EMBASE. RESULTS: No studies showed a specific general correlation between hormonal ovulatory stimulation used as pre-treatment to assisted fertilisation and an increased risk of cancer of the breast, the ovaries, the cervix or the uterus. Most studies detected no increased risk. Some studies, however, showed an increased risk of cancer among certain sub-groups, such as women who have received repeated treatment with clomiphene citrate. INTERPRETATION: On the basis of the studies reviewed, the conclusions are ambiguous. It is therefore necessary to monitor the long-term effects of infertility treatment on women's health. Further good-quality large-scale population studies are necessary, with longer follow-up periods and better adjustment for confounding factors. PMID- 23338031 TI - The ocular fundus in cerebral vasculitis. PMID- 23338032 TI - An elderly man with heart failure. PMID- 23338033 TI - Assessment of heart failure--not always easy. PMID- 23338034 TI - Is Norway heading for a blood-supply crisis? PMID- 23338035 TI - ["Peak level" and "through level"]. PMID- 23338038 TI - The clinical anatomy and pathology of the human atrioventricular valves: implications for repair or replacement. AB - A critical understanding of cardiac anatomy is essential for design engineers and clinicians with the intent of developing and/or employing improved or novel technologies or therapies for treating an impaired atrioventricular valve. Likewise, such knowledge is required for directing translational research, including initiating preclinical research, assessing the feasibility of clinical trials, and performing first-in-man procedures. There are two atrioventricular valves in the human heart, namely the tricuspid and mitral valves. Both are complex structures whose normal anatomies can vary greatly amongst individuals, and also become modified by disease processes. In this review, we discuss the anatomy, pathology, and issues related to surgical and transcatheter repair of the atrioventricular valves in a translational manner. This article is part of a JCTR special issue on Cardiac Anatomy. PMID- 23338039 TI - Label-free DNA quantification via a 'pipette, aggregate and blot' (PAB) approach with magnetic silica particles on filter paper. AB - Reliable measurement of DNA concentration is essential for a broad range of applications in biology and molecular biology, and for many of these, quantifying the nucleic acid content is inextricably linked to obtaining optimal results. In its most simplistic form, quantitative analysis of nucleic acids can be accomplished by UV-Vis absorbance and, in more sophisticated format, by fluorimetry. A recently reported new concept, the 'pinwheel assay', involves a label-free approach for quantifying DNA through aggregation of paramagnetic beads in a rotating magnetic field. Here, we describe a simplified version of that assay adapted for execution using only a pipet and filter paper. The 'pipette, aggregate, and blot' (PAB) approach allows DNA to induce bead aggregation in a pipette tip through exposure to a magnetic field, followed by dispensing (blotting) onto filter paper. The filter paper immortalises the extent of aggregation, and digital images of the immortalized bead conformation, acquired with either a document scanner or a cell phone camera, allows for DNA quantification using a noncomplex algorithm. Human genomic DNA samples extracted from blood are quantified with the PAB approach and the results utilized to define the volume of sample used in a PCR reaction that is sensitive to input mass of template DNA. Integrating the PAB assay with paper-based DNA extraction and detection modalities has the potential to yield 'DNA quant-on-paper' devices that may be useful for point-of-care testing. PMID- 23338040 TI - Use of model organisms for the study of neuronal ceroid lipofuscinosis. AB - Neuronal ceroid lipofuscinoses are a group of fatal progressive neurodegenerative diseases predominantly affecting children. Identification of mutations that cause neuronal ceroid lipofuscinosis, and subsequent functional and pathological studies of the affected genes, underpins efforts to investigate disease mechanisms and identify and test potential therapeutic strategies. These functional studies and pre-clinical trials necessitate the use of model organisms in addition to cell and tissue culture models as they enable the study of protein function within a complex organ such as the brain and the testing of therapies on a whole organism. To this end, a large number of disease models and genetic tools have been identified or created in a variety of model organisms. In this review, we will discuss the ethical issues associated with experiments using model organisms, the factors underlying the choice of model organism, the disease models and genetic tools available, and the contributions of those disease models and tools to neuronal ceroid lipofuscinosis research. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease. PMID- 23338041 TI - How can one be both a philosophical ethicist and a democrat? AB - How can one be both a philosophical ethicist and a democrat? In this article I conclude that it can be difficult to reconcile the two roles. One involves understanding, and reconciling, the conflicting views of citizens, and the other requires the pursuit of truth through reason. Nevertheless, an important function of philosophy and ethics is to inform and improve policy. If done effectively, we could expect better, and more just, laws and policies, thereby benefiting many lives. So applying philosophical thinking to policy is an important job. However, it comes with substantial difficulties, not least in reconciling, or choosing between, competing philosophical theories. Despite the importance of the task, and the apparent obstacles, there is relatively little literature on how to apply ethics to real-world policy-making. Democracies need ethicists who can engage in democratic debate and bridge the gap between philosophy and public policy. I offer some tactics here. PMID- 23338042 TI - The prevalence of concurrent hearing and vision impairment in the United States. PMID- 23338043 TI - Total alkaloids of Rubus aleaefolius Poir inhibit hepatocellular carcinoma growth in vivo and in vitro via activation of mitochondrial-dependent apoptosis. AB - The aim of this study was to evaluate the therapeutic efficacy of Rubus aleaefolius Poir total alkaloids (TARAP) against hepatocellular carcinoma growth in vivo and in vitro, and to investigate the possible molecular mechanisms mediating its biological activity. Nude mice were implanted with HepG2 human hepatocellular carcinoma cells and fed with vehicle (physiological saline) or 3 g/kg/d dose of TARAP, 5 days per week, for 21 days. The in vivo efficacy of TARAP against tumor growth was investigated by evaluating its effect on tumor volume and tumor weight in mice with HCC xenografts and its adverse effect was determined by measuring the body weight gain. The in vitro effect of TARAP on the viability of HepG2 cells was determined by MTT assay. HepG2 cell morphology was observed via phase-contrast microscopy. Apoptosis in tumor tissues or in HepG2 cells was analyzed by TUNEL assay or FACS analysis with Annexin V/PI, respectively. The loss of mitochondrial membrane potential in HepG2 cells was determined via JC-1 staining followed by FACS analysis. Activation of caspase-9 and -3 in HepG2 cells was examined by a colorimetric assay. The mRNA and protein expression of Bcl-2 and Bax in tumor tissues were measured by RT-PCR and immunohistochemistry. TARAP reduced tumor volume and tumor weight, but had no effect on the body weight gain in HCC mice. TARAP decreased the viability of HepG2 cells and induced cell morphological changes in vitro in a dose- and time dependent manner. In addition, TARAP induced apoptosis both in tumor tissues and in HepG2 cells. Moreover, TARAP treatment resulted in the collapse of mitochondrial membrane potential in HepG2 cells, as well as the activation of caspase-9 and -3. Furthermore, administration of TARAP increased the pro apoptotic Bax/Bcl-2 ratio in HCC mouse tumors, at both transcriptional and translational levels. TARAP inhibits hepatocellular carcinoma growth both in vivo and in vitro probably through the activation of mitochondrial-dependent apoptosis, which may, in part, explain its anticancer activity. These results suggest that total alkaloids in Rubus aleaefolius Poir may be a potential novel therapeutic agent for the treatment of hepatocellular carcinoma and other cancers. PMID- 23338044 TI - Electronic and EPR spectra of the species involved in [W10O32]4- photocatalysis. A relativistic DFT investigation. AB - The decatungstate anion [W(10)O(32)](4-) is widely used as a photocatalyst in different transformations, during which it undergoes one-electron reduction to [W(10)O(32)](5-), possibly protonated; the bi-reduced species [W(10)O(32)](6-) is obtained by ensuing disproportionation. Relativistic DFT calculations were used to predict the UV-VIS spectra and EPR parameters of all such species. PMID- 23338046 TI - Pyrrolopyrrole aza-BODIPY analogues: a facile synthesis and intense fluorescence. AB - Pyrrolopyrrole aza-BODIPY analogues were synthesized from diketopyrrolopyrrole and heteroaromatic amines in the presence of titanium tetrachloride. These novel compounds exhibit intense absorption in the visible region and strong emission with high fluorescence quantum yields greater than 0.8. PMID- 23338045 TI - Non-conventional apoptotic response to ionising radiation mediated by N-methyl D aspartate receptors in immature neuronal cells. AB - During cortical development, N-methyl D-aspartate (NMDA) receptors are highly involved in neuronal maturation and synapse establishment. Their implication in the phenomenon of excitotoxicity has been extensively described in several neurodegenerative diseases due to the permissive entry of Ca2+ ions and massive accumulation in the intracellular compartment, which is highly toxic to cells. Ionising radiation is also a source of stress to the cells, particularly immature neurons. Their capacity to induce cell death has been described for various cell types either by directly damaging the DNA or indirectly through the generation of reactive oxygen species responsible for the activation of a battery of stress response effectors leading in certain cases, to cell death. In this study, in order to determine whether a link exists between NMDA receptors-mediated excitotoxicity and radiation-induced cell death, we evaluated radiation-induced cell death in vitro and in vivo in maturing neurons during the fetal period. Cell death induction was assessed by TUNEL, caspase-3 activity and DNA ladder assays, with or without the administration of dizocilpine (MK-801), a non-competitive NMDA receptor antagonist which blocks neuronal Ca2+ influx. To further investigate the possible involvement of Ca2+-dependent enzyme activation, known to occur at high Ca2+ concentrations, we examined the protective effect of a calpain inhibitor on cell death induced by radiation. Doses ranging from 0.2 to 0.6 Gy of X-rays elicited a clear apoptotic response that was prevented by the injection of dizocilpine (MK-801) or calpain inhibitor. These data demonstrate the involvement of NMDA receptors in radiation-induced neuronal death by the activation of downstream effectors, including calpain-related pathways. An increased apoptotic process elicited by radiation, occurring independently of the normal developmental scheme, may eliminate post-mitotic but immature neuronal cells and deeply impair the establishment of the neuronal network, which in the case of cortical development is critical for cognitive capacities. PMID- 23338047 TI - Overexpression of p21-activated kinase 1 promotes endometrial cancer progression. AB - Endometrial cancer (EC) is the most common gynecologic malignancy, but the molecular events involved in the development and progression of EC remain unclear. P21-activated kinase 1 (Pak1) plays important roles in cell motility and survival. This study investigated the clinical significance of Pak1 expression and its functional roles in EC. The expression of Pak1 in clinical samples and EC cell lines was evaluated. The effects of Pak1 on EC cell functions were determined by either overexpressing it via plasmid transfection or depleting its expression using short hairpin RNA (shRNA) in human EC cell lines. Pak1 was overexpressed in clinical samples of EC compared with normal endometrium. High Pak1 expression in EC was positively correlated with lymph node metastasis, advanced disease stage and poor histological differentiation. Pak1 over expression was also observed in multiple human EC cell lines. In EC cell lines, Pak1 overexpression promoted cell proliferation, migration, invasion and anchorage-independent growth in vitro. Conversely, shRNA-mediated stable knockdown of Pak1 reduced cell proliferation, migration, invasion and anchorage independent growth. In addition, ectopic Pak1 overexpression protected EC cells from apoptosis, along with decreased caspase-3 activation. These results suggest that Pak1 plays important roles at multiple stages of EC progression. PMID- 23338048 TI - Quality of life and body image after circumferential body lifting of the lower trunk: a prospective clinical trial. AB - BACKGROUND: Plastic surgery after massive weight loss remains a fast growing subspecialty. However, very few studies exist that investigate the quality of life and psychological outcome after body lift surgery. METHODS: Twenty-seven patients (25 females and 2 males) who had undergone bariatric surgery were scheduled for circumferential body lifting of the lower trunk. The patients, aged 21-58 years (mean = 39.9, SD = 10.9), underwent surgery in our department of plastic and reconstructive surgery between 2008 and 2010. All participants took part in two psychological examinations on a voluntary basis and completed the prospective pre-post study. RESULTS: Post-weight loss surgery improves the quality of life and body image. CONCLUSIONS: It is therefore an important part in the interdisciplinary treatment of the massive weight loss patient. PMID- 23338049 TI - Metabolic/bariatric surgery worldwide 2011. AB - BACKGROUND: Metabolic/bariatric procedures for the treatment of morbid obesity, as well as for type 2 diabetes, are among the most commonly performed gastrointestinal operations today, justifying periodic assessment of the numerical status of metabolic/bariatric surgery and its relative distribution of procedures. METHODS: An email questionnaire was sent to the leadership of the 50 nations or national groupings in the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO). Outcome measurements were numbers of metabolic/bariatric operations and surgeons, types of procedures performed, and trends from 2003 to 2008 to 2011 worldwide and in the regional groupings of Europe, USA/Canada, Latin/South America, and Asia/Pacific. RESULTS: Response rate was 84%. The global total number of procedures in 2011 was 340,768; the global total number of metabolic/bariatric surgeons was 6,705. The most commonly performed procedures were Roux-en-Y gastric bypass (RYGB) 46.6%; sleeve gastrectomy (SG) 27.8%; adjustable gastric banding (AGB) 17.8%; and biliopancreatic diversion/duodenal switch (BPD/DS) 2.2%. The global trends from 2003 to 2008 to 2011 showed a decrease in RYGB: 65.1 to 49.0 to 46.6%; an increase, followed by a steep decline, in AGB: 24.4 to 42.3 to 17.8%; and a marked increase in SG: 0.0 to 5.3 to 27.89%. BPD/DS declined: 6.1 to 4.9 to 2.1%. The trends from the four IFSO regions differed, except for the universal increase in SG. CONCLUSIONS: Periodic metabolic/bariatric surgery surveys add to the knowledge and understanding of all physicians caring for morbidly obese patients. The salient message of the 2011 assessment is that SG (0.0% in 2008) has markedly increased in prevalence. PMID- 23338050 TI - Docetaxel plus cisplatin and bevacizumab for untreated patients with advanced/metastatic non-squamous non-small-cell lung cancer: a multicenter phase II study of the Hellenic Oncology Research Group. AB - BACKGROUND: The docetaxel/cisplatin (DC) combination is an active regimen against advanced/metastatic non-small-cell lung cancer (NSCLC), and bevacizumab (B) improves the efficacy of frontline chemotherapy. This phase II study was designed in order to explore the efficacy and safety of DCB regiment in this setting. METHODS: Chemotherapy-naive patients (n = 48) with measurable, histologically confirmed non-squamous, IIIB (wet)/IV NSCLC, and PS 0-2 were eligible. Patients received D (75 mg/m(2) IV), C (80 mg/m(2) IV), and B (15 mg/kg IV) every 3 weeks. Maintenance of bevacizumab was not mandatory. RESULTS: Complete and partial responses were achieved in two (4.2%) and 14 (29.2%) patients, respectively [overall response rate: 33.3%; 95% CI = 20.0-46.7%], whereas stable disease was documented in 14 [disease control rate = 62.5%; 95% CI = 48.8-76.2%]. The median progression-free survival was 4.4 months and the median overall survival 13.3 months. Treatment-related grade 3 or 4 hematologic adverse events were leukopenia, neutropenia, and anemia in 8.4, 18.7, and 2.1% of the patients, respectively. Febrile neutropenia occurred in three (6.3%) patients. Bleeding was documented in 4% of the patients, thrombotic episodes in 8%, and proteinuria in 3%. There was one treatment-related death. CONCLUSIONS: Frontline DCB in patients with advanced non-squamous NSCLC is an active regimen with manageable toxicity and merits to be further investigated. PMID- 23338051 TI - A phase II study of neoadjuvant combination chemotherapy with docetaxel, cisplatin, and S-1 for locally advanced resectable gastric cancer: nucleotide excision repair (NER) as potential chemoresistance marker. AB - PURPOSE: The combination of docetaxel, cisplatin, and S-1 (DCS) chemotherapy is expected to be a promising regimen for advanced gastric cancer. This study was performed to evaluate the efficacy and safety of neoadjuvant DCS chemotherapy for locally advanced resectable gastric cancer. METHODS: Patients with locally advanced gastric cancer received 2 courses of preoperative chemotherapy with S-1 (40 mg/m(2) b.i.d.) on days 1-14 and docetaxel (60 mg/m(2)) plus cisplatin (60 mg/m(2)) on day 8 every 3 weeks, followed by standard curative surgery within 4-8 weeks. The primary endpoint was R0 resectability. Expression of damage DNA binding protein complex subunit 2 (DDB2)/excision repair cross-complementing 1 (ERCC1) in the pretreated tumor tissues was examined by immunohistochemistry. RESULTS: A total of 43 patients received neoadjuvant chemotherapy. The response rate was 74.4%, and disease control ratio was 100%. Grade 4 neutropenia developed in 53.5% of patients and febrile neutropenia in 16.3%. Non-hematological grade 3/4 adverse events were anorexia (23.3%), nausea (14.0%), and diarrhea (23.3%), but these were generally transient and manageable. The proportion of R0 resections in the 43 eligible patients was 90.7%, and a pathological response was found in 65.9% of patients. There were no treatment-related deaths and no major surgical complications. The accuracy of the combination of DDB2 and ERCC1 expression for predicting chemoresistance was 82.5%. CONCLUSIONS: Preoperative treatment with DCS combination for locally advanced gastric cancer demonstrated a sufficient R0 resection rate and a good pathological response with manageable toxicities. The DDB2/ERCC1-high phenotype, as determined by immunohistochemistry, may be useful predictor of resistance to DCS chemotherapy. PMID- 23338052 TI - Encapsulation of Mo2C in MoS2 inorganic fullerene-like nanoparticles and nanotubes. AB - Mo(2)C nanoparticles encapsulated within MoS(2) inorganic fullerene-like nanoparticles and nanotubes were produced by carbothermal reaction at 1200-1300 degrees C inside a vertical induction furnace. The particles were analyzed using various electron microscopy techniques and complementary methods. PMID- 23338053 TI - Is high-dose cholecalciferol justified in children with chronic kidney disease who failed low-dose maintenance therapy? AB - BACKGROUND: We aimed to investigate the effect of single, high-dose intramuscular cholecalciferol on vitamin D3 and intact parathyroid hormone (iPTH) levels in children with chronic kidney disease (CKD). METHODS: Between January 2012 and June 2012, we conducted a prospective, uncontrolled study at the Pediatric Nephrology Unit of King Abdulaziz University Hospital, Jeddah, to investigate the effect of single, high-dose intramuscular vitamin D3 on 25(OH)D3 and iPTH levels in vitamin D insufficient/deficient children with CKD. Serum vitamin D3, iPTH, calcium, phosphate, alkaline phosphatase (ALP), and creatinine levels were measured before intramuscular vitamin D3 (300,000 IU) administration, and these were subsequently repeated at 1 and 3 months after treatment. Statistical analysis was performed with the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA). RESULTS: Nineteen children fulfilled the criteria. At 3 months after treatment, vitamin D3 levels were significantly higher than at baseline (p < 0.001) but lower than the levels at 1 month. iPTH levels decreased significantly at 3 months (p = 0.01); however, the drop in iPTH levels was not significant at 1 month (p = 0.447). There were no changes in calcium, phosphate, ALP, or creatinine levels after treatment. CONCLUSIONS: Single-dose intramuscular vitamin D3 (300,000 IU) resulted in significant improvement of vitamin D3 and iPTH levels in children with CKD. PMID- 23338054 TI - Therapeutic plasma exchange in the treatment of exertional heat stroke and multiorgan failure. AB - BACKGROUND: Exertional heat stroke (EHS) results in a constellation of systemic inflammatory responses resulting in multiorgan failure and an extremely high mortality. CASE DIAGNOSIS AND TREATMENTS: We present the case of an 11-year-old obese male who suffered EHS with rhabdomyolysis and concurrent renal, pulmonary, and hepatic failure. Conventional therapies including continuous veno-venous hemodiafiltration (CVVHDF) were ineffective in preventing ongoing deterioration in clinical status. Liver biopsy was reported as "extensive hepatocyte ballooning" and liver-kidney transplantation was tentatively planned. CONCLUSIONS: The addition of therapeutic plasma exchange using the Prismaflex(r) system (Gambro, Lakewood, CO, USA) resulted in a reversal of the inflammatory process and recovery from multiorgan failure. Liver biopsy was not a reliable indicator of irreversible hepatic injury. PMID- 23338055 TI - Associations between neck and shoulder discomfort (Katakori) and job demand, job control, and worksite support. AB - OBJECTIVES: To examine the association of neck and shoulder discomfort (Katakori) with somatization and work-related factors (job demand, job control, and worksite support) in Japanese workers. METHODS: Cross-sectional data from 2,022 Japanese workers were analyzed using a logistic regression model to examine the association between Katakori and somatization. A multiple logistic regression model was used to examine the association between Katakori and work-related factors (long working hours, job control, and support from colleagues and supervisors) after adjusting for possible confounding factors. RESULTS: The odds of Katakori were higher among respondents with somatic symptoms than among those without (OR = 2.81 and 95% CI 2.10-3.75 for 1 symptom vs. no symptoms; OR = 3.86 and 95% CI 2.92-5.12 for 2+ symptoms vs. no symptoms). Lack of worksite support was significantly associated with Katakori (adjusted OR = 2.62; 95% CI 1.79 3.83). Long working hours and a lack of job control were not significantly associated with Katakori. CONCLUSIONS: Katakori may be a form of somatization. A significant association was observed between Katakori and lack of worksite support from colleagues or supervisors. An increase in the social support provided at work may decrease the prevalence of this condition and improve workers' well-being, but more research is needed to substantiate this hypothesis. PMID- 23338056 TI - Ultrasound-guided transversus abdominis plane block in children: a randomised comparison with wound infiltration. AB - CONTEXT: The transversus abdominis plane (TAP) block is a new regional anaesthesia technique applicable to infants and children. OBJECTIVE(S): The present study was designed to evaluate the analgesic efficacy of ultrasound guided TAP block with high volume local anaesthetic (0.5 ml kg) during the first 24 h after surgery in children undergoing inguinal hernia repair. DESIGN: Randomised comparative study. SETTING: Gaziantep University Hospital between December 2010 and May 2011. PATIENTS OR OTHER PARTICIPANTS: Fifty-seven children between 2 and 8 years of age undergoing unilateral inguinal hernia repair were randomised to TAP block (group T, n = 29) or to wound infiltration (group C, n = 28). INTERVENTION(S): A TAP block using ultrasound guidance with 0.25% levobupivacaine 0.5 ml kg(-1) or wound infiltration with 0.2 ml kg(-1) 0.25% levobupivacaine, was performed on the same side as the hernia under general anaesthesia. MAIN OUTCOME MEASURES: Time to first analgesic, cumulative number of doses of analgesic, pain scores and adverse effects were assessed over the course of 24 h. RESULTS: The time to first analgesic (mean +/- SD) was significantly longer in group T than in group C (17 +/- 6.8 vs. 4.7 +/- 1.6 h, respectively; P < 0.001). Thirteen (45%) patients in group T did not require any analgesic within the first 24 h. The cumulative number of doses of analgesic was significantly lower in group T than in group C (1.3 +/- 1.2 vs. 3.6 +/- 0.7, respectively, P < 0.001). Pain scores were significantly different between the groups at all time points except at 1, 20 and 24 h (P < 0.001). CONCLUSION: Ultrasound-guided TAP block with high volume (0.5 ml kg) 0.25% levobupivacaine provides prolonged postoperative analgesia and reduced analgesic use without any clinical side effects after unilateral hernia repair in children. TRIAL REGISTRATION: ACTRN12611000585921 (7/06/2011) from Australian New Zealand Clinical Trials Registry. PMID- 23338057 TI - Neuromuscular junction abnormalities in DNM2-related centronuclear myopathy. AB - Dynamin-2-related centronuclear myopathy (DNM2-CNM) is a clinically heterogeneous muscle disorder characterized by muscle weakness and centralized nuclei on biopsy. There is little known about the muscle dysfunction underlying this disorder, and there are currently no treatments. In this study, we establish a novel zebrafish model for DNM2-CNM by transiently overexpressing a mutant version of DNM2 (DNM2-S619L) during development. We show that overexpression of DNM2 S619L leads to pathological changes in muscle and a severe motor phenotype. We further demonstrate that the muscle weakness seen in these animals can be significantly alleviated by treatment with an acetylcholinesterase inhibitor. Based on these results, we reviewed the clinical history of five patients with two different DNM2-CNM mutations (S619L and E368K) and found electrophysiological evidence of abnormal neuromuscular transmission in two of the individuals. All five patients showed improved muscle strength and motor function, and/or reduced fatigability following acetylcholinesterase inhibitor treatment. Together, our results suggest that deficits at the neuromuscular junction may play an important role in the pathogenesis of DNM2-CNM and that treatments targeting this dysfunction can provide an effective therapy for patients with this disorder. PMID- 23338059 TI - Neurogastroenterology: Colonic motor neurotransmission--is beta-NAD+ in control? PMID- 23338058 TI - Extracellular adenosine signaling in molecular medicine. PMID- 23338060 TI - Liver: Fgf15 maintains bile acid homeostasis and is a key mediator of liver regeneration in mice. PMID- 23338061 TI - Hepatitis: New gene IFNL4 is associated with impaired clearance of HCV. PMID- 23338062 TI - Augmented chondroprotective effect of coadministration of celecoxib and rebamipide in the monosodium iodoacetate rat model of osteoarthritis. AB - Osteoarthritis (OA) is a degenerative joint disease characterized by the progressive loss of articular cartilage and chronic pain. Although cyclooxygenase 2 (COX-2) inhibitors such as celecoxib are recommended to patients at high risk of gastrointestinal (GI) adverse events, COX-2 inhibitors do not completely prevent GI adverse events. Rebamipide, a gastroprotective agent, has anti inflammatory properties and acts as an oxygen radical scavenger. The aim of this study was to investigate the in vivo effects of coadministration of rebamipide and celecoxib in an OA rat model. OA was induced by intra-articular injection of monosodium iodoacetate. Oral administration of rebamipide was initiated on the day of OA induction. In this study, rebamipide showed antinociceptive properties and attenuated cartilage degeneration. Rebamipide reduced the expression of matrix metalloproteinase 13, interleukin-1beta, inducible nitric oxide synthase, and nitrotyrosine in OA cartilage. OA rats treated with celecoxib in combination with rebamipide demonstrated a higher pain threshold than those treated with monotherapy. Histological examination also showed that the joints from OA animals treated with combination therapy demonstrated less cartilage damage than those of animals treated with monotherapy. We showed that the potential benefit of combination therapy with celecoxib and rebamipide on pain and cartilage degeneration in OA. PMID- 23338063 TI - Editors as midwifes. PMID- 23338064 TI - [Is the elderly explosion on its' way to the hospitals?]. PMID- 23338065 TI - [Is the warfarin era over?]. PMID- 23338066 TI - [Stem cell research--new hope?]. PMID- 23338067 TI - [The ubiquitous receptors]. PMID- 23338068 TI - [Hypnosis--entertainment or treatment?]. PMID- 23338069 TI - [Too many first names]. PMID- 23338070 TI - [More than courtesy]. PMID- 23338071 TI - [Unprofessional students?]. PMID- 23338072 TI - [The recommendation is rock solid]. PMID- 23338073 TI - [First name--courtesy]. PMID- 23338074 TI - [On first name?]. PMID- 23338075 TI - [Respect for the patient]. PMID- 23338076 TI - [MD]. PMID- 23338077 TI - [Disagreement between generations?]. PMID- 23338079 TI - [Essential medicines missing]. PMID- 23338081 TI - [The chicken or the egg?]. PMID- 23338083 TI - [Evolutionary adaptation and chronic fatigue syndrome]. PMID- 23338084 TI - [What can physicians learn from Jesus?]. PMID- 23338085 TI - [MRSA infection and close caregivers]. PMID- 23338086 TI - [Persistent consciousness disorders after brain injury--need for specialized assessment]. PMID- 23338087 TI - [Cannabis medicines in Norway--the basis for approval]. PMID- 23338089 TI - [Wrong about fat]. PMID- 23338092 TI - [Anaesthesia for the elderly at Nordland Hospital Bodo 1993-2009]. AB - BACKGROUND: We investigated the development in the number of anaesthetised patients >= 67 years at Nordland Hospital Bodo and whether the age group >= 80 years had more problems under anaesthesia. MATERIAL AND METHOD: We used anonymised information on anaesthesia from the DIPS patient data system at Nordland Hospital in Bodo from 1993-2009 and population data from Statistics Norway. RESULTS: The total number of registered anaesthesias increased by 26.8%, from 6,770 in 1993 to 8,584 in 2009. 25,259 (92.7%) of anaesthesias for patients >= 67 years were in connection with surgery. The number, and the percentage of the total number, of anaesthesias for patients aged 67-79 years increased from 931 (13.8%) to 1,337 (15.6%). The percentage therefore increased by 13.0%, while the percentage of the population represented by this age group decreased by 10.7%. For patients >= 80 years the number and percentage increased from 341 (5.0%) to 696 (8.1%) anaesthesias, i.e. a percentage increase of 62.0%. At the same time the percentage of northern Norwegians >= 80 years increased by 30.6%. 4,490 (53.1%) of patients >= 80 years had an ASA classification of 3-5 compared to 6,745 (35.9%) in the age group 67-79 years (p < 0.001). Anaesthesia problems were recorded in 1,044 (12.3%) of patients >= 80 years and 2,349 (12.5%) of patients aged 67-79 years respectively (p = 0.73). INTERPRETATION: The increase in anaesthesias for elderly patients at Nordland Hospital Bodo cannot be explained by population changes alone. That patients >= 80 years do not have more problems during anaesthesia than patients aged 67-79 years may be attributed to better surveillance and use of different methods of anaesthesia, but also to imprecise and deficient registration. PMID- 23338093 TI - [Invasive fungal infection]. PMID- 23338095 TI - Teleradiology--opportunities and challenges. PMID- 23338096 TI - [The neuro literary heritage of Arthur Koestler]. PMID- 23338097 TI - [A description of early hydrocephalus with macrocephaly, cerebral palsy, epilepsy, intellectual disability, and growth retardation by Norwegian novelist Amalie Skram (1846-1905)]. AB - In her novel "S.G. Myre" written in 1890, Norwegian author Amalie Skram describes Hans (Hansemann) Tonnesen, a 16-year-old boy with an enormous head, convulsions, and a rudimentary command of language. He is bullied by children in the street and is held in low esteem by his mother, who refers to him as a beast, crazy, or "a cross". Presumably, the boy has hydrocephalus with macrocephaly, epilepsy, and mental retardation. His retarded growth, small teeth and cracked skin suggest growth hormone deficiency resulting from his hydrocephalus. A couple of interesting details, such as his "splaying his fingers and moving them in various directions to make himself understood" and his "becoming red with exertion and grimacing terribly" when trying to speak, suggest extrapyramidal, dyskinetic cerebral palsy. He may also be deaf. A cousin of Skram's shared several of these traits and is a likely model for Hansemann. A question that occurs to a modern reader is to what degree Hansemann is mentally retarded, or whether he is wrongly perceived as such because of his physical challenges and his communication problems. PMID- 23338098 TI - Regulations with plenty of loopholes--the doctors' prescription rights during the era of prohibition 1916-1926. AB - BACKGROUND: In Norway, the sale of distilled spirits was prohibited from 1916 to 1926, and fortified wines were banned from 1917 to 1923. This period is often referred to as The Prohibition. The consumption of alcohol declined somewhat, but at a high price: Increased smuggling, moonshining and abuse of prescriptions. The latter was caused by the doctors' exclusive right to prescribe alcohol, which some doctors abused for the sake of personal gain. KNOWLEDGE BASIS: The article is based on a review of the records of the Storting's deliberations concerning prescription practices in the period 1916-1926, as well as articles on alcohol issues in the Journal of the Norwegian Medical Association from the same period. RESULTS: With the aid of increasingly strict regulations, the authorities sought to stem the activities of the so-called "whisky doctors". The restrictions and controls imposed on their prescribing rights turned out not to be very effective, however, since the doctors' rights were firmly established. In combination with weaknesses in the legislative base, this hampered the criminal prosecution of doctors who wrote prescriptions in a big way. The abuse reached its climax in 1923. It was only with the enactment of the Prescription Act which came into force on 1 March 1924 that the authorities finally succeeded in gaining control of the abuse of prescriptions. The sale of spirits on prescription subsequently dropped sharply. INTERPRETATION: The prescription of spirits had gradually spiralled out of control, and the repeated control measures enacted by the authorities proved insufficient. When the Prescription Act was finally adopted after three attempts in the Storting, time was in reality up for the prohibition. PMID- 23338099 TI - "Would a doctor really endeavour to refuse a patient his cognac?!"--doctors' prescription practices in the prohibition era 1916-1926. AB - BACKGROUND: In Norway, all sales of distilled spirits were prohibited from 1916 to 1926 and fortified wine was also banned from 1917 to 1923, a period of history called The Prohibition. During this time, the doctors served as gatekeepers who regulated the population's access to alcohol, since a prescription was the only legal way of obtaining fortified wine and distilled spirits. Many have claimed that the doctors failed in this role and undermined Norwegian prohibition policy. KNOWLEDGE BASE: The article is based on a review of articles on the alcohol issue published in the Journal of the Norwegian Medical Association. RESULTS: Many doctors were of the opinion that alcohol had beneficial health effects, for prevention and alleviation as well as to provide a cure. Moreover, few doctors were temperance advocates and many of them were opposed to the prohibition, including the Director of Health. Over time, many doctors prescribed large amounts of spirits and fortified wine. However, there were few real whisky doctors. The medical community was strongly in favour of rationing, i.e. letting people acquire a certain amount of alcohol without any medical supervision, but this proposal never gained political acceptance. INTERPRETATION: The doctors had a certain responsibility for this erosion of the prohibition, and thereby also for its final demise. The whisky doctors were a threat to the profession's reputation, and the most unscrupulous were excluded from the Norwegian Medical Association. The main responsibility for the situation with regard to prescriptions, however, fell on the health authorities and politicians, who delayed the introduction of effective regulations for far too long. PMID- 23338100 TI - [The leprosy colony at Spinalonga]. PMID- 23338101 TI - ["...and we were going to get married!"]. PMID- 23338102 TI - [112 days during spring]. PMID- 23338103 TI - [Cleanup in the terminology jungle]. PMID- 23338107 TI - The effect of 6% Hydroxyethyl starch vs. Ringer's lactate on acute kidney injury after renal ischemia in rats. AB - PURPOSE: To compare fluid replacement therapy with Hydroxyethyl starch 6% (HES) versus Ringer's lactate (RL) in a rodent model of non-septic renal ischemia. METHODS: Forty male Wistar rats were randomized to receive HES 2 ml.kg(-1).hr(-1) or RL 5 ml.kg(-1).hr(-1) that underwent 30 minutes of renal ischemia followed by reperfusion. Twelve hours after kidney ischemia, the kidneys were evaluated for histological changes. Serum NGAL levels were obtained at different times of the experimental protocol. RESULTS: Rodents in the HES group had a median (IQR) grade of renal injury 3 (3 to 5) compared to 2 (2 to 4) in the RL group (p=0.03). NGAL levels were not associated with the severity of kidney injury. CONCLUSION: Hydroxyethyl starch administration caused more kidney injury than Ringer's lactate in a non-infectious model of renal hypoperfusion. PMID- 23338108 TI - Biocompatibility of a new device of self-expandable covered and non-covered tracheal stent: comparative study in rats. AB - PURPOSE: To investigate the compatibility of a new model of self-expandable tracheal stent in rats. METHODS: A new device of polyurethane covered and non - covered stent was placed in the trachea of Wistar rats. Animals were distributed in two groups: the polyurethane covered and non-covered group. Macroscopic parameters included position within the tracheal lumen, adherence to the mucosa, degree of dilatation, permeability and internal diameter. Microscopic findings evaluated were: incorporation, inflammatory activity, granulation tissue and epithelial revetment injuries. The observation follow-up was six weeks. All parameters were quantified based on determined score values. Incorporation of the stents was evaluated based on the observation if the stent was fixed into the trachea or if it could be removed. Degree of dilatation was performed by external diameter measurements. Granulation tissue was evaluated by measurements of height of the tissue growing into the tracheal lumen. RESULTS: 100% of non-covered stents had total attachment to mucosa and 100% of polyurethane covered type had adherence only. Regarding dilatation, granulation tissue, inflammatory activity and internal diameter measurements, there were no significant differences between the groups. Pathological tracheal wall injuries were present in both groups. CONCLUSION: Both models of stent demonstrated biocompatibility with the trachea. Rats are suitable for an experimental model of tracheal stent study. PMID- 23338109 TI - The analgesic effect of nitroglycerin added to lidocaine on quality of intravenous regional anesthesia in patients undergoing elective forearm and hand surgery. AB - PURPOSE: To evaluate the effect of nitroglycerine (NTG) on sensory and motor block onset and recovery time as well as the quality of tourniquet pain relief, when added to lidocaine (LID) for intravenous regional anesthesia in elective forearm and hand surgery. METHODS: A randomized double-blinded clinical trial was performed on 40 patients that were randomly allocated into two groups received lidocaine 3 mg/kg with NTG 200 ug or received only lidocaine 3 mg/kg as the control. RESULTS: There was no difference between the two study groups in hemodynamic parameters before tourniquet inflation, at any time after inflation and after its deflation. There was no difference in the mean of pain score over time between the two groups. The onset time of sensory and motor blockades was shorter in the group received both LID and NTG. The mean recovery time of sensory blockade was longer in the former group. The frequency of opioid injections was significantly lower in those who administered LID and NTG. CONCLUSION: The adjuvant drug of NTG when added to LID is effective in improving the overall quality of anesthesia, shortening onset time of both sensory and motor blockades, and stabling homodynamic parameters in hand and forearm surgery. PMID- 23338110 TI - Spinal anesthesia for elective ceasarean section: use of different doses of hyperbaric bupivacaine associated with morphine and clonidine. AB - PURPOSE: To comparatively study the efficacy and maternal and fetal side-effects of two doses of bupivacaine associated with morphine and clonidine, administered by the subarachnoid route for cesarean section. METHODS: The study included 66 pregnant women at term, distributed into two groups. GI: bupivacaine 8.0 mg (1.6 mL) + clonidine 75 ug (0.5 mL) + morphine 100 ug (1.0 mL) and GII: bupivacaine 10 mg (2.0 mL) + clonidine 75 ug (0.5 mL) + morphine 100 ug (1.0 mL). The following parameters were assessed: onset and maximum level of sensory block; quality of intraoperative and postoperative analgesia; degree and duration of motor block; maternal repercussions and Apgar score. RESULTS: The onset of sensory block, quality of intraoperative analgesia and total duration of analgesia were similar in both groups; maximum extent of sensory block predominated in T4; maximum degree of motor block (Bromage 3); time motor block regression was significantly longer in GII; Hemodynamic, respiratory repercussions, adverse maternal effects and Apgar scores were similar between groups. In both groups, there was a predominance of drowsy or sleeping patients. CONCLUSION: The addition of morphine and clonidine to low doses of hyperbaric bupivacaine produced adequate anesthesia for cesarean section and good postoperative analgesia, without any maternal and fetal repercussions. PMID- 23338111 TI - Unripe Musa sapientum peel in the healing of surgical wounds in rats. AB - PURPOSE: To assess the effects of unripe Musa sapientum peel on the healing of surgical wounds in rats. METHODS: One hundred and twenty Wistar rats were divided into two treatment groups of 60 animals each: the control group (gel without the active ingredient) and experimental group (4% Musa sapientum peel gel). A 4 x 4 cm surgical wound was created on the back of each animal. The wound was cleaned daily with 0.9% saline, treated with 4% gel or natrosol gel (control), and covered with gauze. Animals from both groups were sacrificed after seven, 14 and 21 days of treatment; the tissue from the wound site was removed together with a margin of normal skin for histological analysis. RESULTS: No significant differences in wound contraction rates (p=0.982) were found between time points (seven, 14 and 21 days of treatment) in both groups. However, a significantly higher wound contraction rate was observed in the control group on day 21 compared with the experimental group (p=0.029). There were no significant differences in histomorphological features between groups. The experimental group showed an increased number of polymorphonuclear cells on day 7, with a significant reduction on day 21 (p=0.026). CONCLUSION: The use of 4% unripe Musa sapientum peel gel on surgical wounds in rats resulted in an increased number of polymorphonuclear cells on day 7, reduced wound contraction, reduced vascular proliferation and increased concentration of collagen fibers on day 21. PMID- 23338112 TI - Effect of electrical stimulation of the cranial tibial muscle after end-to-side neurorrhaphy of the peroneal nerve in rats. AB - PURPOSE: To investigate the efficiency of electrical stimulation in the muscle maintenance and nerve regeneration after end-to-side neurorrhaphy (ESN). METHODS: Sixty male Wistar rats (Rattus norvegicus) were divided into four experimental groups. Control group (Control), Denervated Group (Denervated); Group with End-to side neurorrhaphy (ESN); Group with End-to-side neurorrhaphy and electrical stimulation (ESN + ES). We perform electrical stimulation in rats after they had undergone muscle reinnervation by ESN. We collected morphometric and functional data. RESULTS: When comparing the mass of the treated side of cranial tibial muscle (CTM) and that of normal side of CTM, the group ESN + ES (26.12%) exhibited lower mass loss than that of group ESN (37.23%). The peroneal functional index showed that group ESN + ES equaled that of the Control group and showed an evolution of 60.5% while group ESN showed an evolution of 9.5%. In measuring maximum strength of CTM, the group ES + ESN outperformed group ESN. The muscle and nerve morphometry showed superiority of group ES+ESN over ESN group in all parameters. CONCLUSION: Electrical stimulation is an effective means of maintaining functional muscle and nerve regeneration after end-to-side neurorrhaphy. PMID- 23338113 TI - Vascular endothelial growth factor and KIT expression in relation with microvascular density and tumor grade in supratentorial astrocytic tumors. AB - PURPOSE: To evaluate the relationship between microvascular density and the expression of vascular endothelial growth factor (VEGF) and KIT as possible markers of angiogenic stimulus in astrocytic tumors and correlate it with histopathological grading. METHODS: We enrolled 99 surgical specimens of supratentorial astrocytic tumors for analysis of VEGF and KIT and subsequent correlation with MVD and grading. RESULTS: KIT and VEGF expression correlated with microvascular density (p<0.005) and both VEGF and microvascular density correlated with grading (p<0.005). KIT had no significant relationship with grading (p=0.657). CONCLUSION: KIT and VEGF constitute important pathways in the angiogenesis of astrocytomas and therefore are promising prognostic tools and options for therapeutic intervention. PMID- 23338114 TI - Prospective analysis of 44 consecutive liver transplants performed at a university hospital. AB - PURPOSE: To analyze the intraoperative and immediate postoperative biochemical parameters of patients submitted to orthotopic liver transplantation. METHODS: Forty four consecutive orthotopic liver transplants performed from October 2009 to December 2010 were analyzed. The patients (38 male and eight female) were divided into two groups: group A, survivors, and group B, non-survivors. Fifty percent of group A patients were Chid-Pugh C, 40% Chid-Pugh B and 10% Chid-Pugh A. In group B, 52% of the patients were Chid-Pugh C, 41% Chid-Pugh B, and 17% Chid-Pugh A. All orthotopic liver transplants were performed by the piggy-back technique without a portacaval shunt in an anhepatic phase. ALT, AST, LDH and lactate levels were determined preoperatively, at five, 60 minutes after arterial revascularization of the graft and 24 and 48 hours after the end of the surgery.( or: after the surgery was finished). RESULTS: There were no preoperative clinical differences (Child and Meld) between the two groups. The times of warm and hypothermal ischemia were similar for both groups (p>0.05). Serum aminotransferases levels at five and 60 minutes after arterial revascularization of the graft were similar (p>0.05) for both groups, as also were lactate levels at the time points studied. There was no significant difference in Delta lactate between groups at any time point studied (p>0.05). No significant difference was observed between groups during the first 24 and 48 hours after surgery (p>0.05). CONCLUSION: No significant difference in any of the parameters studied was observed between groups. Under the conditions of the present study and considering the parameters evaluated, no direct relationship was detected between the intraoperative situation and the type of evolution of the patients of the two groups studied. PMID- 23338115 TI - Autologous and allogeneic ovarian orthotopic transplantation: morphologic, endocrinologic and natural pregnancy assessment. AB - PURPOSE: To assess pregnancy of rabbits submitted to bilateral ovariectomy and orthotopic allogeneic or autologous intact and sliced ovarian transplantation without a vascular pedicle and to determine the morphofunctional aspects of the transplanted ovaries. METHODS: Fifty-six female rabbits were studied. The ovaries were removed and orthotopically transplanted or replaced without vascular anastomoses: Group 1 (n=8), only laparotomy and laparorrhaphy, Group 2A (n=8) intact ovaries were transplanted on both sides, Group 2B (n=8) both ovaries were sliced and orthotopically transplanted, Group 2C (n=8), an intact ovary was transplanted on one side and a sliced ovary on the other side. In Group 3 the ovaries were reimplanted according to the procedure and subgroups described for Group 2. Three months later, the animals were paired with males for copulation. Estradiol, progesterone, FSH and LH hormone levels were assessed. A histologic study was carried out, and the number of pregnancies and litters were also determined. Chi-square test compared the number of pregnancies and litters. One way ANOVA and the Tukey-Kramer tests compared the hormonal dosages. RESULTS: Pregnancies occurred in seven (87.5%) rabbits of Group 1, in three rabbits (37.5%) of Groups 2A and 3A, in four rabbits (50%) of groups 2B, 3B and 3C, and in five (62.5%) of group 2C. Normal hormone serum levels and histology confirmed the vitality of all ovaries. CONCLUSION: Orthotopic allogeneic and autologous ovarian transplantation without a vascular pedicle is viable in rabbits, and preserves their hormonal levels and fertile functions. PMID- 23338116 TI - Comparative study and histomorphometric analysis of bone allografts lyophilized and sterilized by autoclaving, gamma irradiation and ethylene oxide in rats. AB - PURPOSE: To compare three sterilization methods (autoclave, gamma irradiation and ethylene oxide) over non demineralized lyophilized bone allografts. METHODS: Bone allografts were implanted on paravertebral muscles of 21 rats. After 30 days animals were sacrificed and grafts underwent comparative analysis regarding histomorphometric and macroscopic parameters. RESULTS: Allografts that underwent the three sterilization methods presents similar weight gain, cortical thickness similar to control group, and less fibrosis than the control group. Grafts that underwent sterilization in autoclave presented less presence of multinucleated giant cells, although not statistically significant. There was also no statistically significant difference regarding mineralization on the three groups. CONCLUSION: The three sterilization methods cause similar effects on bone allografts regarding macroscopic and histomorphometric parameters. PMID- 23338117 TI - Effects of preoperative irradiation using fractioned electron beam on the healing process of colocolonic anastomosis in rats undergoing early and late surgical intervention. AB - PURPOSE: To investigate the effects of preoperative fractioned irradiation using an electron beam on the healing process of colocolonic anastomoses in rats that underwent early and late surgical intervention. METHODS: Thirty Wistar rats, distributed as follows: group A (surgery only), group B (fractionated irradiation for 30 days (if), surgery seven days after the end of it), group C (if for 30 days, and surgery after 30 days of termination). On the seventh postoperative day the anastomotic segment analysis was taken, using tension tests, histology and collagen deposition evaluation by computerized analysis. RESULTS: Regarding the tension resistance of the anastomosis, there were no statistical differences (p=0.42). However, a significant increase in cells number in the inflammatory infiltrate in the group with a longer interval between surgery and pre op radiation (p<0.05). The collagen concentration had no significant variance. CONCLUSION: The irradiation in divided doses increased local inflammatory cellularity when the surgery was performed later. This result did not affect the increase of complications, nor on the local concentration of collagen, achieving similar clinical outcomes. PMID- 23338118 TI - Local hemostatic measures in anticoagulated patients undergoing oral surgery: a systematized literature review. AB - PURPOSE: To conduct a systematized review of the literature about the main local hemostatic measures to control postoperative bleeding in anticoagulated patients. METHODS: A systematized review of literature was performed in the electronic database Medline (PubMed) without restriction of the publication date. The eligibility criteria were studies involving maintenance of the anticoagulant therapy, prospective studies, retrospective studies, randomized clinical trials, controlled clinical studies, comparative studies, multicentric studies or case control studies. Studies discontinuing anticoagulant therapy, case reports, literature reviews, in vitro studies, animal experiments and articles written in language not compatible with the search strategy adopted in this work were excluded. RESULTS: Twenty-four articles that met the adopted eligibility criteria were selected, enrolling 3891 subjects under anticoagulant therapy. A total of 171 cases of hemorrhage was observed. Tranexamic acid was the main local hemostatic measure used to controlling of postoperative bleeding. CONCLUSION: The local hemostatic measures proved to be effective according to previously published studies. Nevertheless, further clinical studies should be conducted to confirm this effectiveness. PMID- 23338119 TI - Brazilian Scientific Journals in Surgery: quality control in the abstract structure of non-experimental articles. AB - PURPOSE: To evaluate the quality of abstracts of original non-experimental research articles in Brazilian Journals in Surgery. METHODS: Convenience sample of 471 abstracts of original research articles from six Brazilian surgical journals indexed in Thomson Reuters (ISI) Web of Knowledge. The quality of abstracts was measured against a checklist of eight evaluation criteria, which were divided into 32 categories. The total score for each abstract was obtained by summing the score of all criteria present. The overall mean score was also determined. RESULTS: The overall mean score of abstract quality was that of a good abstract. Most of the abstracts contained some information from each of the eight basic categories of an abstract. All abstracts were structured ones. CONCLUSION: The overall quality, for abstracts of original articles of six Brazilian non-experimental journals in surgery, was classified as good. PMID- 23338120 TI - Voluntary euthanasia, physician-assisted suicide, and the right to do wrong. AB - It has been argued that voluntary euthanasia (VE) and physician-assisted suicide (PAS) are morally wrong. Yet, a gravely suffering patient might insist that he has a moral right to the procedures even if they were morally wrong. There are also philosophers who maintain that an agent can have a moral right to do something that is morally wrong. In this article, I assess the view that a suffering patient can have a moral right to VE and PAS despite the moral wrongness of the procedures in light of the main argument for a moral right to do wrong found in recent philosophical literature. I maintain that the argument does not provide adequate support for such a right to VE and PAS. PMID- 23338121 TI - Electrostatic charging and control of droplets in microfluidic devices. AB - Precharged droplets can facilitate manipulation and control of low-volume liquids in droplet-based microfluidics. In this paper, we demonstrate non-contact electrostatic charging of droplets by polarizing a neutral droplet and splitting it into two oppositely charged daughter droplets in a T-junction microchannel. We performed numerical simulation to analyze the non-contact charging process and proposed a new design with a notch at the T-junction in aid of droplet splitting for more efficient charging. We experimentally characterized the induced charge in droplets in microfabricated devices. The experimental results agreed well with the simulation. Finally, we demonstrated highly effective droplet manipulation in a path selection unit appending to the droplet charging. We expect our work could enable precision manipulation of droplets for more complex liquid handling in microfluidics and promote electric-force based manipulation in 'lab-on-a-chip' systems. PMID- 23338122 TI - New studies about everyday types of chemical exposures: what readers should consider: comment on "A crossover study of noodle soup consumption in melamine bowls and total melamine excretion in urine". PMID- 23338124 TI - Hybrid dithiazolothiadiazinyl radicals; versatile building blocks for magnetic and conductive materials. AB - Resonance stabilized dithiazolothiadiazinyl radicals possess highly delocalized and easily tuned spin distributions; their structural features and transport properties augur well for their use in the design of magnetic and conductive materials. PMID- 23338125 TI - Hydrogen spillover mechanism on covalent organic frameworks as investigated by ab initio density functional calculation. AB - The hydrogen spillover mechanism, including the H chemisorption, diffusion, and H(2) associative desorption on the surface of COFs and H atoms migration from metal catalyst to COFs, have been studied via density functional theory (DFT) calculation. The results described herein show that each sp(2) C atom on COFs' surface can adsorb one H atom with the bond length d(C-H) between 1.11 and 1.14 A, and the up-down arrangement of the adsorbed H atoms is the most stable configuration. By counting the chemisorption binding sites for these COFs, we can predict the saturation storage densities. High hydrogen storage densities show that the gravimetric uptakes of COFs are in the range of 5.13-6.06 wt%. The CI NEB calculations reveal that one H atom diffusing along the C-C path on HHTP surface should overcome the 1.41-2.16 eV energy barrier. We chose tetrahedral Pt(4) cluster and HHTP as the representative catalyst and substrate, respectively, to study the H migration from metal cluster to COFs. At most, two H atoms can migrate from Pt(4) cluster to HHTP substrate. The migration reaction is an endothermic process, undergoing an activation barrier of 1.87 eV and 0.57 eV for the first and second H migration process, respectively. Three types of H(2) associative desorption from hydrogenated COFs were studied: (I) the two H adatoms recombining to one H(2) molecule with a recombination barrier of 4.28 eV, (II) the abstraction of adsorbed H atoms by gas-phase hydrogen atoms through ER type recombination reactions with a recombination barrier of 1.05 eV, (III) the H(2) desorption through the reverse spillover mechanism with an energy barrier of 2.90 eV. PMID- 23338123 TI - Highly lymphatic metastatic pancreatic cancer cells possess stem cell-like properties. AB - Cancer stem cells are thought to be the origin of tumor metastasis. However, evidence of cancer stem cells as the source of lymphatic metastasis in pancreatic cancer is not clear. In this study, we examined the stem cell-like properties of the highly lymphatic metastatic pancreatic cancer cells BxPC-3-LN. Compared with the parental BxPC-3 cells, the BxPC-3-LN cells showed stem cell-like properties, including high lymphatic metastasis potential, self-renewal ability and chemoresistance. In addition, the BxPC-3-LN cells also expressed higher levels of sonic hedgehog and migrating cancer stem cell surface markers (CD133 and CXCR4) compared to the parental BxPC-3 cells. The growth of BxPC-3-LN cells was significantly inhibited by gemcitabine combined with the sonic hedgehog inhibitor cyclopamine. The BxPC-3-LN cells expressed lower levels of let-7, miR-34, miR 107, miR-125, miR-128, miR-130, miR-132 and miR-141 than the parental BxPC-3 cells detected by microRNA PCR array, which were reported to have close relation to stem cell factors. This study provides evidence that cancer stem cells are the major sources of pancreatic cancer lymphatic metastasis, and microRNAs may regulate lymphatic metastasis in pancreatic cancer through modulating cancer stem cells. PMID- 23338126 TI - Hydrogen sulfide attenuates doxorubicin-induced cardiotoxicity by inhibition of the p38 MAPK pathway in H9c2 cells. AB - We previously demonstrated the protective effect of hydrogen sulfide (H2S) against doxorubicin (DOX)-induced cardiotoxicity through inhibition of endoplasmic reticulum stress. The aim of the present study was to explore the role of p38 mitogen-activated protein kinase (MAPK) in DOX-induced cardiotoxicity and ascertain whether exogenous H2S protects DOX-induced injury by inhibiting p38 MAPK in cardiomyoblasts (H9c2). We observed that exposure of H9c2 cells to 5 uM DOX not only markedly induced injuries, including cytotoxicity, apoptosis, overproduction of reactive oxygen species (ROS) and dissipation of mitochondrial membrane potential (MMP), but also enhanced the expression level of phosphorylated (p)-p38 MAPK. The DOX-induced increase in expression of p-p38 MAPK was significantly attenuated by pretreatment of H9c2 cells with either 400 uM sodium hydrogen sulfide (NaHS) (a donor of H2S) or 1,000 uM N-acetyl-L-cysteine (NAC, an ROS scavenger) prior to exposure to DOX. Pretreatment with either 400 uM NaHS or 3 uM SB203580, a selective inhibitor of p38 MAPK, ameliorated DOX-induced cardiomyocyte injuries, as evidenced by an increase in cell viability, and decreases in the number of apoptotic cells, ROS generation as well as dissipation of MMP. In conclusion, the findings of the present study demonstrated that the activation of p38 MAPK contributes to DOX-induced injuries, including cytotoxicity, apoptosis, mitochondrial damage and oxidative stress in H9c2 cells. We also provide novel evidence that exogenous H2S protects H9c2 cells against DOX induced cardiotoxicity by inhibition of the p38 MAPK pathway. PMID- 23338127 TI - Maternal infection in pregnancy and risk of asthma in offspring. AB - This study estimates the effect of maternal infections during pregnancy on childhood asthma. One-thousand four-hundred and twenty-eight pregnant women were prospectively followed using structured interviews and chart review until their child's 6th year of life. Infections were identified from outpatient and hospital visits. Childhood asthma was defined as physician diagnosis with symptoms at age six. Adjusted odds ratios were calculated from multivariable logistic regression models. Six-hundred and thirty-five women experienced an infection during pregnancy. Among antepartum infections, maternal urinary tract infections were significantly associated with childhood asthma (aOR 1.60, 95 % CI 1.12-2.29). Chorioamnionitis and maternal group beta streptococcus colonization were not significantly associated with an increased risk in childhood asthma. This study found an increased risk of asthma in children of women diagnosed with urinary tract infections during pregnancy, while other maternal infections did not increase the risk. PMID- 23338128 TI - Galanthamine in Alzheimer's disease : a new alternative to tacrine? AB - Galanthamine (galantamine), a tertiary alkaloid derived from the bulbs of the snowdrop and various Narcissus species, is a selective, centrally active and reversible inhibitor of acetylcholinesterase that is suitable for oral therapy. After a long period during which the investigational and clinical use of the drug was limited to anaesthesia and the treatment of peripheral paralysis syndromes in Eastern Europe, the molecule has now emerged as a promising lead substance for the treatment of cognitive decline in Alzheimer's disease.Galanthamine has similar therapeutic potential to tacrine, but has a significantly more favourable pharmacokinetic and toxicity profile. A chemical synthesis process on the required industrial scale of several tons per year has become available, removing a major obstacle to the development of the drug. Clinical trials published so far are, however, rather limited in terms of both design and patient number. The main reason for this is that there has been a lack of strong support for the drug within the pharmaceutical industry. However, the available data support the notion that this molecule, if properly developed, could be a peer for any second generation cholinergic drug currently in clinical trials for the symptomatic treatment of Alzheimer's disease. PMID- 23338130 TI - Subacute sclerosing panencephalitis : diagnosis and drug treatment options. AB - Subacute sclerosing panencephalitis (SSPE) is a chronic progressive, usually fatal disease of uncertain pathogenesis that is associated with the presence of mutant measles virus in the CNS. The diagnosis is based on clinical criteria and an elevated titre of measles antibodies in the CSF. Electroencephalography, imaging studies and measles antibody synthesis rate in the CSF provide supportive laboratory data. When CSF studies are negative, a brain biopsy is indicated to assess the presence of inclusion bodies, measles virus antigens or viral RNA.Among the many drugs and methods tried in the treatment of SSPE, the highest rate of stabilisation or improvement has been obtained with intraventricular interferon-alpha (interferon-alfa) and oral inosine pranobex. Further research, including multicentre clinical trials, is warranted to identify more efficient therapeutic regimens. PMID- 23338129 TI - Trigeminal neuralgia : a guide to drug choice. AB - Trigeminal neuralgia, also known as tic douloureux, is an idiopathic condition of severe, unilateral, paroxysmal facial pain. The abrupt nature of the painful attacks (a temporal profile that is similar to that of seizures) led to the discovery that some anticonvulsant drugs are effective against neuralgia.Carbamazepine is the drug of choice, and treatment requires careful dosage titration. Baclofen, phenytoin and sodium valproate are also effective. Transient relief is sometimes possible with local anaesthetics. Limited data suggest that topical capsaicin, and tizanidine, lamotrigine, oxcarbazepine, pyridostigmine and enalapril have helped some patients. While effective, other drugs are limited by their adverse effects; for example, clonazepam is too sedating, pimozide induces extrapyramidal adverse effects, and tocainide and felbamate can cause aplastic anaemia. Phenobarbital (phenobarbitone), opioids, mexiletine, tricyclic antidepressants, corticosteroids, nonsteroidal anti inflammatory drugs and sympatholytics are ineffective.The antineuralgic effect of any drug may eventually wear off. If this occurs, combination therapy can restore pain relief, as can the reintroduction of a previously effective drug following a drug-free interval.Similar pharmacological strategies potentially apply to other paroxysmal pain syndromes such as vagoglossopharyngeal neuralgia. Clinical overlap with multiple sclerosis or cluster headache suggests additional drugs that may be useful in specific patients. Effective neurosurgical procedures exist for patients with trigeminal neuralgia that is refractory to medications. PMID- 23338133 TI - Levetiracetam. AB - [Symbol: see text] Levetiracetam is an ethyl analogue of the nootropic agent piracetam.[Symbol: see text] Results from rodent studies indicate that the drug may offer protection against absence, generalised and partial seizures.[Symbol: see text] Levetiracetam exhibits linear pharmacokinetics and has a wide therapeutic index. Its potential to interact with other anticonvulsants appears to be low.[Symbol: see text] Initial findings from a total of 29 patients with treatment-refractory epilepsy suggest that levetiracetam may be beneficial in patients with partial seizures. These results require confirmation.[Symbol: see text] Somnolence and asthenia were the most common adverse events reported in patients receiving levetiracetam 1000 to 4000 mg/day; these appeared to be dose related. PMID- 23338131 TI - Polydipsia-hyponatraemia syndrome : epidemiology, clinical features and treatment. AB - The polydipsia-hyponatraemia syndrome (PHS) occurs in about 5 to 10% of institutionalised, chronically psychotic patients, 80% of whom have schizophrenia. Major clinical features are polydipsia and dilutional hyponatraemia. Complications of PHS include delirium, generalised seizures, coma and death.Nonpharmacological interventions are fluid restriction, diurnal bodyweight monitoring, behavioural approaches, and supplemental oral sodium chloride administration. These interventions require an experienced and dedicated multidisciplinary staff.A number of pharmacological treatments have been assessed for PHS including the combination of lithium and phenytoin, demeclocycline, propranolol, ACE inhibitors, selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors, typical antipsychotic drugs, clozapine and risperidone. Of these agents, the most promising are the combination of lithium and phenytoin, and clozapine.Integrated treatment requires a highly informed multidisciplinary staff, meticulous monitoring of diurnal weight gain and serum sodium level, and careful record keeping. Acute interventions of observation by trained staff, fluid restriction, water-free areas and supplemental sodium chloride administration are based on diurnal weight gain employing a monthly weight chart and a base weight method. Intravenous hypertonic saline is used briefly and administered in a highly controlled manner when patients with PHS present with generalised seizures and coma. Long term strategies include behavioural interventions and the combination of lithium and phenytoin, and clozapine. PMID- 23338134 TI - Levetiracetam : a viewpoint by philip N. Patsalos. PMID- 23338132 TI - Mechanism of clozapine-induced agranulocytosis : current status of research and implications for drug development. AB - Clozapine is an atypical antipsychotic agent that has several advantages over conventional antipsychotics, not least of which is its superior efficacy. However, the high risk of agranulocytosis (0.8% of patients) associated with clozapine therapy has resulted in restricted indications for its use.The mechanism of clozapine-induced agranulocytosis is not clear. The target cells affected are the myeloid precursors, although the mature neutrophil may also be targeted simultaneously. There is no convincing evidence of direct toxicity of the parent compound or its stable metabolites (demethyl-clozapine and clozapine N oxide). Clozapine is also metabolised by liver microsomes, peripheral blood neutrophils and their bone marrow precursors to a chemically reactive intermediate that has been postulated to be a nitrenium ion. This toxic metabolite has been shown to covalently bind to neutrophil proteins, suggesting that it may be involved in the pathogenesis of the toxicity. However, it is not clear how toxicity is mediated. The nitrenium ion may bind to essential cellular proteins and disrupt neutrophil function or, alternatively, it may act as a hapten and initiate an immune reaction resulting in immune-mediated destruction of the neutrophil. Indirect evidence exists to support both mechanisms, although clear direct evidence is still lacking. The role of cytokines and apoptosis in the pathogenesis of the agranulocytosis is unclear.The reason why only approximately 1% of individuals who are treated with clozapine are affected by agranulocytosis has not been elucidated. Evidence exists to implicate both the major histocompatibility complex antigens and heat shock protein variants in determining individual susceptibility, although more patients of different ethnic backgrounds need to be studied.The ultimate aim of research into clozapine induced agranulocytosis should be to either prospectively predict which individuals are going to develop agranulocytosis and/or to develop analogues that retain efficacy but are not toxic. The former is complicated by the fact that predisposition may be multifactorial, and thus prediction may require multiple tests that may be of statistical but not absolute validity. The latter depends on identifying the mechanism of toxicity and the chemical characteristics of clozapine that are responsible for the toxicity. This knowledge may allow rational design of new analogues that do not cause agranulocytosis. PMID- 23338135 TI - Levetiracetam : a viewpoint by wolfgang loscher. PMID- 23338136 TI - Glycoproteins in bacterial membranes. In vivo labeling of the sugar portion of energy-transducing ATPase and a low-molecular-weight fraction fromMicrococcus lysodeikticus membranes. AB - The energy-transducing ATPase and a low-molecular-weight fraction ofMicrococcus lysodeikticus membranes incorporated(14)C label fromD-[U-(14)C]glucose fed to the bacteria in synthetic medium. The specific radioactivity of the sugar portion of the ATPase and low-molecular-weight fraction was, respectively, 2.65 and 2.88 times that of their amino acids. Glucose and mannose in approximately equimolar amounts were identified as the main sugars of the glycoprotein ATPase, thus confirming previous structural studies. Glucose, galactose, and mannose (1:1:2) were identified as the main sugars of the low-molecular-weight glycopeptides. These results confirm and extend the notion that glycoprotein are constituents of prokaryotic membranes. PMID- 23338137 TI - Immuno-identification of cultures of fungi pathogenic to man. AB - Because isolates of the fungal pathogensBlastomyces dermatitidis. Coccidioides immitis, Histoplasma capsulatum, andParacoccidioides brasiliensis frequently vary widely in gross and microscopic features and are often difficult or impossible to convert to their tissue forms, a simple diagnostic procedure not dependent upon sporulation is needed to identify them specifically and rapidly. The exoantigen technique has been found to meet this need effectively. On the basis of studies with 166Histoplasma spp. isolates, 128C. immitis isolates, 59B. dermatitidis isolates, 30P. brasiliensis isolates, and 181 saprophytes, we determined that the exoantigen test is valuable for the presumptive identification of the four fungal pathogens studied. All of the positive reactions have correlated with the cultural, histologic, or other available laboratory data, and we are unaware of any false positive or flase negative reactions. PMID- 23338138 TI - Evidence for plasmid-associated lactose metabolism inLactobacillus casei subsp.casei. AB - Lac variants ofLactobacillus casei subsp.casei DR1002 (formerly 64H) have been produced using acriflavin, ethidium bromide, mitomycin C, or combinations of these agents. Two successive transfers in the presence of acriflavin and mitomycin C or ethidium bromide and mitomycin C resulted in nearly a 100% loss of lactose fermentation. Cesium chloride-ethidium bromide isopycnic gradient ultracentrifugal analysis of purified lysates demonstrated that the 23-mdal plasmid (pDR101) found inL. casei DR1002 was consistently absent in Lac(-) clones. We concluded that, as in lactic streptococci, lactose metablism is a plasmid-mediated train inL. casei DR1002. PMID- 23338139 TI - Further evidence for entry of infectious bovine rhinotracheitis virus into bovine kidney cells. AB - The penetration of bovine kidney cells by infectious bovine rhinotracheitis virus, a member of the herpesvirus group, was investigated using the direct immunoferritin labeling technique. Electron microscopic examination of infected cells after 10 min at 37 degrees C revealed fusion between viral envelope and cell membrane; the former reacted with the ferritin particles conjugated with antiviral antibody. However, shortly after penetration of the nucleocapsid, viral specific antigenic sites on the plasma membrane were not detected by the immunoferritin technique. Antigenically reactive structures in a disorganized array were frequently detected extracellularly, situated above the penetration sites as indicated by the internalized nucleocapsids. PMID- 23338140 TI - Cell division and trichome breakage inBeggiatoa. AB - The process ofBeggiatoa trichome division was elucidated through phase-contrast microscopy and transmission and scanning electron microscopy. Trichome breakage and dispersion is accomplished by the formation of sacrificial cells (necridia) at various points within the trichome. Upon dying, the sacrificial cells lyse, dividing the trichome into two daughter trichomes. This process is identical with that found in many oscillatorian blue-green bacteria, but differs from the mechanism of trichome division in most of the other flexuous gliding bacteria. Cellular division within the trichome occurs by septation, involving the cytoplasmic membrane and the electron-dense L2 (peptidoglycan) layer. The outer envelope layers do not take part in division. PMID- 23338141 TI - Viruses detected in cells explanted into tissue culture from naturally occurring malignant lymphoma in rhesus monkeys. AB - During a 4-year period 43 cases of spontaneous lymphoma occurred in macaques at the California Primate Research Center. In an attempt to determine if there might be a common viral etiology to the outbreak, lymphoma tissues from 10 rhesus monkeys were explanted into tissue culture and examined for the presence of virus. Electron microscopic studies of the cultured lymphoma cells revealed viruses morphologically characteristics of adenovirus, reovirus, foamy virus, and herpesvirus. Cell-free filtrates from tissue cultures possessing the latter three viruses produced cytopathology in virus-free indicator cells. Virus particles typical of the explant culture were demonstrable in the infected indicator cells. Type-C RNA tumor virus particles were not observed electron microscopically in any of the lymphoma tissues or lymphoma cell cultures examined. PMID- 23338142 TI - A gene,imz, affecting the pH sensitivity of zygote formation inPhysarum polycephalum. AB - Mating inPhysarum polycephalum involves the fusion of two haploid amoebae and the differentiation of the resulting diploid zygote into a multinucleate plasmodium. Mating proceeds optimally with amoebae growing on an agar medium at pH 5.0. At pH 6.2, the amoebae still grow normally, but mating is completely blocked. The barrier at pH 6.2 is not in the differentiation step, since preformed diploids readily convert to plasmodia at this pH. The barrier can be overcome by raising the ionic strength of the agar medium; the effect, moreover, is not ion-specific. We have discovered a genetic locus,imz (ionicmodulation of zygote formation), that affects the upper pH limit for mating; the respective limits associated with the two known alleles,imz-1 andimz-2, are pH 5.6 and pH 6.0 at low ionic strength. Animz-1*imz-2 mating displays the pH 6.0 limit;imz-2 is therefore "dominant". We suggest that this new gene affects a cell component that is exposed to the exterior of the amoeba and is involved in the fusion step of mating. PMID- 23338143 TI - Ultraviolet sensitivity ofBacillus subtilis citD mutants. AB - Cells ofBacillus subtilis 168 with deletions in thecitD locus were found to be sensitive to irradiation with ultraviolet light and to mitomycin C but were able to repair DNA damage induced by methyl methanesulfonate. The recombination abilities of these cells, as determined by transformation and PBS1-mediated transduction experiments, were unaffected by the deletion. These phenotypic characteristics do not result from a metabolic imbalance caused by the deficiency of a functional alpha-ketoglutarate dehydrogenase complex, but most likely are a consequence of a genetic locus involved in ultraviolet repair, which is deleted together with thecitK gene when the deletion is formed. PMID- 23338144 TI - Continuity of the dsRNA genome of bluetongue virus. AB - The duplex RNA genome of bluetongue virus, extracted under acidic conditions with sodium dodecyl sulfate and phenol, is an unfragmented continuous structure. Most genomes appeared as a rosette with 10 loops (genes) emanating from a central crescent- or doughnutshaped area. The genome has a mean length of ca. 10 MUm which corresponds to a molecular weight of ca. 23 million. PMID- 23338145 TI - Pathogenicity ofAeromonas hydrophila in red leg disease in frogs. AB - Endotoxin and hemolysin fromAeromonas hydrophila A(3) were studied to understand the pathogenicity of the organism. Neither the endotoxin nor the hemolysin alone produced typical red leg disease symptoms or death in frogs, even at a very high dosage of 8,000 MUg; however, endotoxin and hemolysin together did. Further, histamine-stressed frogs died from hemolysin but not endotoxin. Hemolytic activity of hemolysin increased in cells that were preincubated with endotoxin. Results point to the conclusion that red leg disease in frogs represents a complex interaction between endotoxin and hemolysin and that stress-producing factors other than the endotoxin might trigger disease production. PMID- 23338146 TI - A thermophilic glucoamylase fromCephalosporium eichhorniae. AB - A novel exocellular glucoamylase produced by a thermophilic fungus,Cephalosporium eichhorniae, was purified by a combination of membrane filtration and Sephadex chromatography. The enzyme was a glycoprotein, 28% carbohydrate by weight. It was composed of a single polypeptide chain with a molecular weight of 26,850. The enzyme was thermostable with optimum activity between 45 and 62 degrees C. It had a substrate preference of amylose>amylopectin. Analysis by thin-layer and gas liquid chromatography showed the major hydrolytic product of starch was glucose, classifying this enzyme as a thermophilic glucoamylase. PMID- 23338147 TI - Substrate specificity of thePenicillium lilacinum enzyme lytic to the cell wall ofRhodotorula glutinis and the structure of theRhodotorula cell wall glucomannan. AB - The lytic enzyme active on cell walls ofRhodotorula, which was produced byPenicillium lilacinum ATCC 36010, decomposed an extracellular mannan fromRhodotorula glutinis IFO 0695 and was confined to the beta-1,3-mannoside bond on the reducing side of the beta-1,4-linkedD-mannopyranose. Based on these results, the structure of the glucomannan, which was a major component ofRhodotorula cell walls, was proposed. PMID- 23338148 TI - Susceptibility tests for sulfamethoxazole-trimethoprim by a broth microdilution procedure. AB - Most media used for susceptibility testing contain sulfonamide inhibitors that make them unacceptable for testing sulfonamides. The major substance that inhibits sulfonamides has been identified as thymidine, and recent efforts to remove it from Mueller-Hinton medium have made it possible to perform susceptibility tests with sulfamethoxazole-trimethoprim by broth microdilution. Some lots of Mueller-Hinton broth are thymidine free, but some contain small amounts of thymidine and require the addition of thymidine phosphorylase or lysed horse blood which contains thymidine phosphorylase. Some lots may contain too much thymidine so that its activity cannot be reversed by adding the recommended amont of thymidine phosphorylase. Therefore the suitability of a medium must be determined by testing with control strains. Some organism, for example enterococci, cannot be tested in thymidine phosphorylase-treated media because thymine works in the same way thymidine does to inhibit the action of sulfamethoxazole-trimethoprim. PMID- 23338149 TI - Guidelines enforcement and clinical outcome. PMID- 23338150 TI - Alternative lengthening of telomeres is induced by telomerase inhibitors in Barrett's esophageal cells. AB - A crucial step in the path to the malignant transformation of cells and tumor formation is immortalization, which essentially depends on telomere maintenance. The aim of this study was to investigate the role of telomerase in the progression of Barrett's esophagus. Telomerase activity was measured in Barrett's cells using terminal restriction fragment (TRF) analysis. Telomere length was measured using Q-FISH analysis. Furthermore, the telomere recombination events were detected between sister chromatids using chromosome orientation FISH (CO FISH). There was a reduction in telomerase activity in the CP-A cells transduced with MT-hTER/47A+siRNA, which led to an almost complete disappearance of telomerase activity. The telomere length of the CP-A cells transduced with MT hTER/47A+siRNA was slightly shorter compared to that of the untransduced cells. The telomerase-inhibited cells were morphologically indistinguishable from those untransduced and WT-hter-transduced cells. In the control cells, the growth rate was between 0.9 to 1.1 with the population doubling per day. Although the transduction of the telomerase inhibitors in the CP-A cells did not cause a significant reduction in cell growth, these transduced cells grew generally slower compared with the control cells. The heterogeneous telomere length was also be detected in the telomerase-inhibited CP-A cells. However, the telomere length remained homogeneous in the control cells. The metaphase of the CP-A cells transduced with MT-hTER/47A+siRNA demonstrated 70% heterogeneous telomeres. In addition, no increased recombination was observed between sister chromatids in the transduced CP-A cells compared with the control cells. Our findings suggest that an alternative lengthening of telomeres (ALT) may be induced by telomerase inhibitors in CP-A cells. Therefore, telomerase inhibitors may exhibit high potency in the treatment of esophageal adenocarcinoma arising from Barrett's esophagus. PMID- 23338151 TI - Effect of irrigation systems on temporal distribution of malaria vectors in semi arid regions. AB - Previous research models have used climate data to explain habitat conditions of Anopheles mosquitoes transmitting malaria parasites. Although they can estimate mosquito populations with sufficient accuracy in many areas, observational data show that there is a tendency to underestimate the active growth and reproduction period of mosquitoes in semi-arid agricultural regions. In this study, a new, modified model that includes irrigation as a factor was developed to predict the active growing period of mosquitoes more precisely than the base model for ecophysiological and climatological distribution of mosquito generations (ECD mg). Five sites with complete sets of observational data were selected in semi arid regions of India for the comparison. The active growing period of mosquitoes determined from the modified ECD-mg model that incorporated the irrigation factor was in agreement with the observational data, whereas the active growing period was underestimated by the previous ECD-mg model that did not incorporate irrigation. This suggests that anthropogenic changes in the water supply due to extensive irrigation can encourage the growth of Anopheles mosquitoes through the alteration of the natural water balance in their habitat. In addition, it was found that the irrigation systems not only enable the active growth of mosquitoes in dry seasons but also play an important role in stabilizing the growth in rainy seasons. Consequently, the irrigation systems could lengthen the annual growing period of Anopheles mosquitoes and increase the maximum generation number of mosquitoes in semi-arid subtropical regions. PMID- 23338152 TI - [The genetics of spinocerebellar ataxias]. AB - Spinocerebellar ataxias are genetically heterogeneous autosomal dominant ataxia disorders. To date more than 30 different subtypes are known. In Germany particularly SCA1, SCA2, SCA3 and SCA6 are prevalent, as well as the less frequent subtypes SCA5, SCA14, SCA15, SCA17 and SCA28. Genetic causes range from coding repeat expansions (polyglutamine diseases), to non-coding expansions as well as conventional mutations. In some subtypes the genetic background is currently unknown. Age of onset, typical clinical findings and geographic distribution may help to reach a correct diagnosis; however a definitive diagnosis requires molecular genetic testing. PMID- 23338153 TI - Gene delivery of cyclin-dependent kinase inhibitors p21Waf1 and p27Kip1 suppresses proliferation of MCF-7 breast cancer cells in vitro. AB - BACKGROUND: Because tumorigenesis depends on a variety of oncogenes, symphyseal study of combined genes may lead to more significant knowledge about tumorigenesis and progression. Combined deficiency of p21 and p27 proteins in mice is linked to more aggressive spontaneous tumorigenesis. We investigated the effect of the transfected p21 (Waf1) -p27 (Kip1) gene on centrosome duplication, cell proliferation, and apoptosis of MCF-7, a breast cancer cell line. METHODS: The pIRES-p21 (Waf1) , pIRES-p27 (Kip1) , and pIRES-p21 (Waf1) -p27 (Kip1) genes were transfected into MCF-7 cells by lipofection. The effect on proliferation was evaluated by MTT assay and clone-formation assay. Cell cycle and apoptosis were analyzed by flow cytometry. Apoptosis was tested by flow cytometry and TUNEL assay. Centrosome duplication was detected by use of indirect immunofluorescence microscopy. RESULTS: The results showed that the pIRES-p21 (Waf1) , pIRES-p27 (Kip1) , and pIRES-p21 (Waf1) -p27 (Kip1) significantly inhibited proliferation of MCF-7 cells, followed by accumulation of MCF-7 cells in cycle G1, induced apoptosis, and a decrease in the proportion of MCF-7 cells which contained abnormal centrosomes. Compared with p21 (Waf1) or p27 (Kip1) alone, combination of p21 (Waf1) and p27 (Kip1) had a much more significant effect (P < 0.05). CONCLUSION: Altogether, these results indicate that the p21 (Waf1) -p27 (Kip1) gene combination has a more obvious antitumor effect than p21 (Waf1) or p27 (Kip1) alone. This study provides preclinical evidence that combination of p21 (Waf1) and p27 (Kip1) could be a novel and promising therapeutic approach to treatment of breast cancer with suppressed p21 (Waf1) and p27 (Kip1) expression. PMID- 23338154 TI - The discordance between primary breast cancer lesions and pulmonary metastatic lesions in expression of aldehyde dehydrogenase 1-positive cancer cells. AB - BACKGROUND: We evaluated the expression of aldehyde dehydrogenase 1 (ALDH1) between primary breast lesions and pulmonary metastatic (PM) lesions in breast cancer patients. METHODS: We retrospectively analyzed the clinicopathological features and the expression statuses of ER, PR, HER2, Ki-67 and ALDH-1 in both primary and metastatic breast cancer lesions and evaluated the discordance rates in the expressions of these markers between the primary and metastatic lesions, and also the prognostic value of these factors. RESULTS: None of the PM patients had metastases at any other sites, and all had undergone curative breast cancer surgery. The pulmonary operation was partial resection in 15 (88 %) patients and lobectomy in 2 (12 %) patients. The median overall survival (OS) after resection of the PNs (OS) was 48 months. The discordance rates in the expressions of ER, PR, HER2, Ki67 and ALDH-1 between the primary and metastatic lesions were 0, 29, 21, 43 and 50 %, respectively. CONCLUSION: There was significant discordance in the biomarkers between the primary tumors and the metastatic lesions. PMID- 23338156 TI - A facile and versatile approach to design self-assembled monolayers on glass using thiol-ene chemistry. AB - This work describes an integrated approach for designing on demand Self-Assembled Monolayers (SAMs) on silicon oxides and particularly glass substrates for cell biology applications. Starting from commercially available compounds, the strategy relies on thiol-ene reaction and provides high quality SAMs exhibiting adhesive and anti-adhesive patterns. PMID- 23338155 TI - Interaction between oral lichen planus and chronic periodontitis with Th17 associated cytokines in serum. AB - The objective of this study was to compare the expression levels of interleukin (IL)-17 IL-17 and IL-23 in serum from patients with both oral lichen planus and chronic periodontitis (OLP-CP), patients only with oral lichen planus (OLP), patients only with chronic periodontitis (CP), and healthy controls (HC). The serum samples were collected from 35 OLP-CP patients, 35 OLP patients, 30 CP patients, and 30 healthy controls. ELISA test was used to detect expression levels of IL-17 and IL-23 in serum from these four groups. ELISA analysis showed significantly elevated levels of serum IL-17 in OLP-CP group compared with OLP group (P < 0.05) and HC group (P < 0.01). Serum IL-23 result showed that there was an increased expression level in OLP-CP compared with HC group (P < 0.01). Additionally, female OLP-CP group showed elevated level of serum IL-17 compared with female OLP group, and also erosive OLP-CP group demonstrated increased serum IL-17 level compared with erosive OLP group. Moreover, analysis showed positive significant correlations of serum IL-17 level with probing depth (P < 0.05) and plaque index (P < 0.05) in erosive OLP-CP patients. This study indicates that OLP CP patients get higher expression level of serum IL-17 and had susceptibility to erosive or female subtype, which indicated that IL-17 may participate in the disease immunopathogenesis of both common oral diseases. PMID- 23338157 TI - 2-carbomethoxy-3-hydroxyquinoxaline-di-N-oxide as a novel ligand for the copper catalyzed coupling reaction of phenols and aryl halides. AB - 2-Carbomethoxy-3-hydroxyquinoxaline-di-N-oxide was identified as an efficient novel ligand for the copper-catalyzed coupling of aryl halides with various phenols under mild conditions. The catalytic system shows great functional-group tolerance and excellent reactive selectivity. PMID- 23338158 TI - Risk of fall in the elderly: how to evaluate. PMID- 23338159 TI - Clinical, histological and imaging aspects of pleomorphic xanthoastrocytomas: the key is in the name. PMID- 23338160 TI - The functional assessment Berg Balance Scale is better capable of estimating fall risk in the elderly than the posturographic Balance Stability System. AB - The purpose of this study was to verify which instrument better identifies recurrent falls in the elderly. Ninety-eight old people, with an average age of 80 +/- 4 years, were submitted to an assessment of balance and fall risk by means of the Berg Balance Scale (BBS) and the posturographic Balance Stability System (BSS). The BBS was correlated with the BSS (r=-0.27; p=0.008), age (r=-0.38; p<0.001) and number of falls (r=-0.25; p=0.013) and the analysis of logistical regression showed that the elderly classified with fall risk on the BBS presented 2.5 (95%CI 1.08-5.78) more chance of identifying who had two falls or more over the last year. The BBS identified that the greater the age the worse the functional balance and demonstrated a greater capacity to identify falls risk suffered over the last year when compared with the BSS. PMID- 23338161 TI - Obstructive sleep apnea prevents the expected difference in craniofacial growth of boys and girls. AB - OBJECTIVES: It was to compare cephalometric measures of mouth-breather boys and girls and with the cephalometric pattern observed in obstructive sleep apnea syndrome (OSAS) patients. METHODS: Craniofacial measurements of lateral cephalometric radiographs obtained from 144 children aged 7-14 years were compared between boys and girls, and both were compared to cephalometric pattern of OSAS patients. RESULTS: Mouth-breather boys and girls had no gender differences regarding to craniofacial morphology while nose-breather boys and girls showed those expected differences. Nose-breather boys presented a more retruded mandible and proinclined upper incisor when compared to nose-breather girls, but mouth-breather boys and girls had no differences. The measure NS.GoGn was the only variable with an interaction with gender and breathing. CONCLUSIONS: There were no cephalometric difference in mouth breather-boys and girls related to normal growth, suggesting that oral breathing make the same craniofacial morphology and both have craniofacial morphology close to that of OSAS patients. PMID- 23338162 TI - Vagus nerve stimulation may be a sound therapeutic option in the treatment of refractory epilepsy. AB - INTRODUCTION: Refractory epilepsy accounts for 20 to 30% of epilepsy cases and remains a challenge for neurologists. Vagus nerve stimulation (VNS) is an option for palliative treatment. OBJECTIVE: It was to study the efficacy and tolerability of VNS in patients implanted with a stimulator at the Curitiba Institute of Neurology (INC). METHODS: A case study of six patients with refractory epilepsy submitted to a VNS procedure at the INC in the last four years was described and discussed. RESULTS: Mean age at time of implantation was 29 years. Mean follow-up was 26.6 months. Seizure frequency decreased in all patients (40-50% (n=2) and >=80% (n=4)). Three patients no longer required frequent hospitalizations. Two patients previously restricted to wheelchairs started to walk, probably because of improved mood. CONCLUSION: In this population, VNS proved to be a sound therapeutic option for treating refractory epilepsy. PMID- 23338163 TI - MacDonald Critchley. AB - The authors presented a historical review on Professor MacDonald Critchley, 15 years after his death. PMID- 23338164 TI - The Brazilian Neurology centenary (1912-2012) and the common origin of the fields of Neurology and Psychiatry. AB - It is reported the Brazilian Neurology birth (1912), that has as the hallmark its first Neurology Cathedra of Rio de Janeiro, and the links between Neurology and Psychiatry, besides the main medical protagonists at that time in Rio de Janeiro: Joao Carlos Teixeira Brandao (1854-1921), first professor of the cathedra of Clinical Psychiatry and Nervous Diseases (1883-1921); Juliano Moreira (1873 1933), the founder of the Brazilian scientific Psychiatry and director of the Hospicio Nacional de Alienados (National Hospice for the Insane) (1903-1930); Antonio Austregesilo Rodrigues de Lima (1876-1960), first professor of the cathedra of Neurology, considered the father of the Brazilian Neurology. Aloysio de Castro (1881-1959) was a great Brazilian neurosemiologist at that time. Austregesilo practiced both disciplines, Neurology and Psychiatry, and like Jean Martin-Charcot, he was very interested in a typically psychiatric disorder, the hysteria. It is also considered in this paper the first Brazilian authors of Neurology and/or Psychiatric texts and the places where Neurology was initially developed by the main founders: Hospicio Nacional de Alienados, Santa Casa de Misericordia do Rio de Janeiro and Policlinica Geral do Rio de Janeiro. PMID- 23338166 TI - Total lesion of the radial nerve in the arm with preservation of the superficial radial nerve sensory action potential. PMID- 23338165 TI - Acute onset of cerebellar ataxia in a spinocerebellar ataxia type 10 patient after use of steroids. PMID- 23338167 TI - Marfanoid features and X-linked mental retardation associated with craniofacial abnormalities: the Lujan-Fryns syndrome. PMID- 23338171 TI - Quebec defies federal government to consider allowing assisted dying in certain circumstances. PMID- 23338172 TI - FDA warns about metal-on-metal hip replacements. PMID- 23338173 TI - Experts question size of savings from NHS going "paperless". PMID- 23338174 TI - From laboratory to pilot plant E. coli fed-batch cultures: optimizing the cellular environment for protein maximization. AB - For recombinant protein production in E. coli fed-batch cultures, post-induction conditions have great influence in the quantity and quality of the product. The present paper covers the effect of different factors affecting the cellular environment in recombinant aldolase (rhamnulose-1-phosphate aldolase, RhuA) production. An operational mode employing an exponential addition profile for constant specific growth rate has been analyzed, in order to understand and define possible modifications with influence on post-induction cellular behavior. A constant addition profile has been demonstrated to render higher specific aldolase production than the exponential addition profile, probably due to a more constant environment for the cells. On the other hand, amino acid (leucine) supplementation has proven to increase protein quality in terms of activity units (U) per unit mass of RhuA (U mg(-1) RhuA), alleviating metabolic overload. Based on the above, a production process was set up and scaled up to pilot plant. Resulting production was double that of a standard laboratory operation, 45,000 U L(-1), and almost all the protein retained the 6xHis-tag with the highest quality, 11.3 U mg(-1) RhuA. PMID- 23338176 TI - Lens wavefront compensation for 3D photomask effects in subwavelength optical lithography. AB - As semiconductor optical lithography is pushed to smaller dimensions, resolution enhancement techniques have been required to maintain process yields. For some time, the customization of illumination coherence at the source plane has allowed for the control of diffraction order distribution across the projection lens pupil. Phase shifting at the photomask plane has allowed for some phase control as well. Geometries smaller than the imaging wavelength introduce complex wavefront effects that cannot be corrected at source or mask planes. Three dimensional photomask topography effects can cause a loss of both focal depth and exposure latitude across geometry of varying density. Wavefront manipulation at the lens pupil plane becomes necessary to provide the degrees of freedom needed to correct for such effects. The focus of this research is the compensation of the wavefront phase error introduced by the topographical photomask structures of high resolution phase shift masking combined with off-axis illumination. The compensation is realized through phase manipulation of the lens pupil plane, specifically in the form of spherical aberration. Subwavelength resolution optimization and imaging is presented showing how phase pupil filtering can measurably improve the depth of focus for several photomask structures and types. PMID- 23338177 TI - In situ calibration of an extreme ultraviolet spectrometer for attosecond transient absorption experiments. AB - We report a method for calibrating an extreme ultraviolet spectrometer based on a flat-field grazing incidence spherical grating in the energy range of 20-30 eV. By measuring absorption lines corresponding to singly excited states in helium atoms and autoionizing states in argon atoms, the photon energy of the detected light was determined. The spectral resolution of the spectrometer, 60 meV, was obtained by deconvolving the Fano resonance profile of argon autoionizing states from the measured absorption line profiles. PMID- 23338175 TI - Biological characteristics of intratumoral [F-18]-fluoromisonidazole distribution in a rodent model of glioma. AB - Accurate imaging to identify hypoxic regions in tumors is key for radiotherapy planning. [F-18]-fluoro-misonidazole ([F-18]-FMISO) is widely used for tumor hypoxia imaging and has the potential to optimize radiotherapy planning. However, the biological characteristics of intratumoral [F-18]-FMISO distribution have not yet been fully investigated. In hypoxic cells, the hypoxia-inducible factor-1 (HIF-1) target proteins that induce cellular proliferation and glucose metabolism, glucose transporter-1 (Glut-1) and hexokinase-II (HK-II), are upregulated. In this study, we determined the intratumoral distribution of [F-18] FMISO by autoradiography (ARG) and compared it with pimonidazole uptake, expression of Glut-1, tumor proliferative activity (Ki-67 index) and glucose metabolism ([C-14]2-fluoro-2-deoxy-D-glucose uptake; [C-14]-FDG) in a glioma rat model. Five C6 glioma-bearing rats were injected with [F-18]-FMISO and [C-14] FDG. After 90 min, the rats were injected with pimonidazole and 60 min later, the rats were sacrificed and tumor tissues were sectioned into slices. The adjacent slices were used for ARG and immunohistochemical (IHC) analyses of pimonidazole, Glut-1 and Ki-67. [F-18]-FMISO ARG images were divided into regions of high [F 18]-FMISO uptake (FMISO+) and low [F-18]-FMISO uptake (FMISO-). Pimonidazole and Glut-1 expression levels, Ki-67 index and [C-14]-FDG distribution were evaluated in the regions of interest (ROIs) placed on FMISO+ and FMISO-. [F-18]-FMISO distribution was generally consistent with pimonidazole distribution. The percentage of positively stained areas (% positive) of Glut-1 in FMISO+ was significantly higher compared to FMISO- (24 +/- 8% in FMISO+ and 9 +/- 4% in FMISO-; P<0.05). There were no significant differences in Ki-67 index and [C-14] FDG uptake between FMISO+ and FMISO- (for Ki-67, 10 +/- 5% in FMISO+ and 12 +/- 5% in FMISO-, P=ns; for [C-14]-FDG, 1.4 +/- 0.3% ID/g/kg in FMISO+ and 1.3 +/- 0.3% ID/g/kg in FMISO-, P = ns). Intratumoral [F-18]-FMISO distribution reflected tumor hypoxia and expression of the hypoxia-related gene product Glut-1; it did not, however, reflect tumor proliferation or glucose metabolism. Our findings help elucidate the biological characteristics of intratumoral [F-18]-FMISO distribution that are relevant to radiotherapy planning. PMID- 23338178 TI - Analysis of the shape of a subwavelength focal spot for the linearly polarized light. AB - By decomposing a linearly polarized light field in terms of plane waves, the elliptic intensity distribution across the focal spot is shown to be determined by the E-vector's longitudinal component. Considering that the Poynting vector's projection onto the optical axis (power flux) is independent of the E-vector's longitudinal component, the power flux cross section has a circular form. Using a near-field scanning optical microscope (NSOM) with a small-aperture metal tip, we show that a glass zone plate (ZP) having a focal length of one wavelength focuses a linearly polarized Gaussian beam into a weak ellipse with the Cartesian axis diameters FWHM(x)=(0.44+/-0.02)lambda and FWHM(y)=(0.52+/-0.02)lambda and the (depth of focus) DOF=(0.75+/-0.02)lambda, where lambda is the incident wavelength. The comparison of the experimental and simulation results suggests that NSOM with a hollow pyramidal aluminum-coated tip (with 70 degrees apex and 100 nm diameter aperture) measures the transverse intensity, rather than the power flux or the total intensity. The conclusion that the small-aperture metal tip measures the transverse intensity can be inferred from the Bethe-Bouwkamp theory. PMID- 23338180 TI - Frequency-division multiplexing for multicomponent shearography. AB - A new method of multiplexing the speckle patterns needed in multicomponent digital shearography systems is presented. Frequency-division multiplexing (FDM) of the measurement channels is achieved by recording speckle patterns from objects illuminated by intensity-modulated sources. Each source is modulated at a discrete frequency, which is less than half of the camera frame rate, and a bank of images of the modulated speckle patterns is captured. This allows for pixel-by pixel Fourier-based extraction of the individual speckle patterns from peaks in the power spectra. The approach is demonstrated with a two-component in-plane shearography instrument. PMID- 23338179 TI - Resonant absorption of a chemically sensitive layer based on waveguide gratings. AB - A colorimetric sensor providing a direct visual indication of chemical contamination was developed. The sensor is a combination of a chemically sensitive dye layer and a resonant waveguide grating. Enhancement of the light absorption by the photonic structure can be clearly seen. The detection is based on the color change of the reflected light after exposure to a gas or a liquid. Low-cost fabrication and compatibility with environments where electricity cannot be used make this device very attractive for applications in hospitals, industries, with explosives, and in traffic. PMID- 23338181 TI - Modeling the effects of near-surface plumes of suspended particulate matter on remote-sensing reflectance of coastal waters. AB - A radiative transfer model was applied to examine the effects of vertically stratified inherent optical properties of the water column associated with near surface plumes of suspended particulate matter on spectral remote-sensing reflectance, R(rs)(lambda), of coastal marine environments. The simulations for nonuniform ocean consisting of two layers with different concentrations of suspended particulate matter (SPM) are compared with simulations for a reference homogeneous ocean whose SPM is identical to the surface SPM of the two-layer cases. The near-surface plumes of particles are shown to exert significant influence on R(rs)(lambda). The sensitivity of R(rs)(lambda) to vertical profile of SPM is dependent on the optical beam attenuation coefficient within the top layer, c(1)(lambda), thickness of the top layer, z(1), and the ratio of SPM in the underlying layer to that in the top layer, SPM(2)/SPM(1), as well as the wavelength of light, lambda. We defined a dimensionless spectral parameter, P(lambda)=c(1)(lambda)*z(1)*(SPM(2)/SPM(1)), to quantify and examine the effects of these characteristics of the two-layer profile of SPM on the magnitude and spectral shape of R(rs)(lambda). In general, the difference of R(rs)(lambda) between the two-layer and uniform ocean decreases to zero with an increase in P(lambda). For the interpretation of ocean color measurements of water column influenced by near-surface plumes of particles, another dimensionless parameter P'(lambda) was introduced, which is a product of terms representing homogenous ocean and a change caused by the two-layer structure of SPM. Based on the analysis of this parameter, we found that for the two-layer ocean there is a good relationship between R(rs)(lambda) in the red and near-infrared spectral regions and the parameters describing the SPM(z) profile, i.e., SPM(1), SPM(2), and z(1). PMID- 23338182 TI - Beating the wavelength limit: three-dimensional imaging of buried subwavelength fractures in sculpture and construction materials by terahertz time-domain reflection spectroscopy. AB - We use reflection terahertz spectroscopy to locate and produce three-dimensional images of air gaps between stones that resemble fractures, even of subwavelength thicknesses. This technique is found to be promising tool for sculpture and building damage evaluation as well as structural quality control in other dielectric materials. PMID- 23338183 TI - Liquid-crystal microlens with focus swing and low driving voltage. AB - A focus-swing liquid-crystal (LC) microlens with two patterned electrodes and filled in nematic liquid crystal is proposed. In order to lower the level of the applied voltage signal and effectively increase the focus-swing range, the bottom electrode is designed as a circular patterned structure. The top electrode is composed of four stripe-patterned subelectrodes, which are powered, respectively to generate expecting potential and drive the focus swing in the focal plane of the microlens. The common optical properties of the LC microlens and the swing behavior of the formed focus in the focal plane are demonstrated experimentally. PMID- 23338184 TI - Development and characterization of optoelectronic circuit boards produced by two photon polymerization using a polysiloxane containing acrylate functional groups. AB - Research into the integration of optical interconnects in printed circuit boards (PCBs) is rapidly gaining interest due to the increase in data transfer speeds now required along with the need for miniaturized devices with increased complexity and functionality. We present a method that involves embedding optoelectronic components in a polymeric material and fabricating optical waveguides in one step. A silanol-terminated polysiloxane cross-linked with an acryloxy functional silane is utilized as a matrix material into which the 3D optical waveguides are inscribed by two-photon-induced polymerization. A pulsed femtosecond laser is used to directly write optical waveguides into the material, forming an optical link between lasers and photodiodes that are directly mounted on a specially designed PCB. The boards produced were characterized by monitoring the transmitted photocurrent as well as temperature-dependent data transmission properties. Data rates exceeding 4 Gbit/s were achieved. PMID- 23338185 TI - Design of ultrahigh energy laser amplifier system with high storage energy extraction. AB - A design concept of realizing high storage energy extraction efficiency is presented for an ultrahigh energy laser system, stressing the advantage of variable-diameter aperture structure for the multistage amplifier system over the constant-aperture design. Based on the established modeling, the conceptual schematic of an amplifier system with optimized high storage energy extraction is developed, which is expected to produce 15 kJ output energy from three stages, with an extremely high storage extraction efficiency of 50.3%. PMID- 23338186 TI - Influence investigation of a void region on modeling light propagation in a heterogeneous medium. AB - A void region exists in some biological tissues, and previous studies have shown that inaccurate images would be obtained if it were not processed. A hybrid radiosity-diffusion method (HRDM) that couples the radiosity theory and the diffusion equation has been proposed to deal with the void problem and has been well demonstrated in two-dimensional and three-dimensional (3D) simple models. However, the extent of the impact of the void region on the accuracy of modeling light propagation has not been investigated. In this paper, we first implemented and verified the HRDM in 3D models, including both the regular geometries and a digital mouse model, and then investigated the influences of the void region on modeling light propagation in a heterogeneous medium. Our investigation results show that the influence of the region can be neglected when the size of the void is less than a certain range, and other cases must be taken into account. PMID- 23338187 TI - Pump-signal combiner with large-core signal fiber feed-through for fiber lasers and amplifiers. AB - A pump-signal combiner with a new processing method is reported in this paper. The core deformation of the signal fiber can be avoided by this method, and an 8+1 to 1 pump-signal combiner with 100 MUm core-signal fiber feed-through is fabricated. The pump and signal coupling efficiencies are 96.8% and 98.0%, respectively. Furthermore, this pump-signal combiner is applied to a CW large mode area fiber laser with a counter pump configuration. The output power of the laser is 87 W. PMID- 23338188 TI - Laser focus positioning method with submicrometer accuracy. AB - Accurate positioning of a sample is one of the primary challenges in laser micromanufacturing. There are a number of methods that allow detection of the surface position; however, only a few of them use the beam of the processing laser as a basis for the measurement. Those methods have an advantage that any changes in the processing laser beam can be inherently accommodated. This work describes a direct, contact-free method to accurately determine workpiece position with respect to the structuring laser beam focal plane based on nonlinear harmonic generation. The method makes workpiece alignment precise and time efficient due to ease of automation and provides the repeatability and accuracy of the surface detection of less than 1 MUm. PMID- 23338189 TI - Effect of substrate overetching and heat treatment of titanium oxide waveguide gratings and thin films on their optical properties. AB - We investigate subwavelength titanium oxide (TiO2) resonance waveguide gratings (RWGs) and TiO2 thin films of thicknesses ~200 nm fabricated by atomic layer deposition (ALD), in both amorphous and crystalline phases on fused silica substrates. The TiO2 RWGs are fabricated by electron beam lithography, reactive ion etching, and ALD. The thin films and RWGs are characterized structurally by x ray diffraction and scanning electron microscopy. The optical characterization of RWGs and optical constants of TiO2 films are studied by an ellipsometer. RWGs are designed for TE and TM modes in such a way that an overetch effect of the fused silica substrate can be investigated. Various RWG samples are prepared by gradually increasing the overetch depth and subsequently measuring the performance of the RWGs. A close agreement between the calculated and experimentally measured resonance wavelength spectral shifts is obtained; however, the magnitudes of the measured shifts are greater than calculated ones. A parallel study related to the measurement of the refractive indices and remeasuring the optical shifts of RWGs is carried out after a heat treatment of all the samples under study. The RWGs do not reveal significant spectral changes after the heat treatment; this is primarily due to a change in the surface chemistry by the redeposition of the reaction byproducts on the grating lines. PMID- 23338190 TI - Narrowband reflective generation of higher-order optical vortices in Bragg spun optical fibers. AB - We have studied theoretically reflecting and transmitting properties of Bragg multihelicoidal spun fibers, in which refractive index distribution features l helical branches and possesses an l-fold symmetry in the transverse cross section. It is shown that for a special choice of the profile function modulation, such fibers in certain spectral ranges have the property to change the topological charge of the incoming Gaussian beam in the reflected field by l units. This property could be used for narrowband generation of optical vortices (OVs) from Gaussian beams and for changing the topological charge of incoming OVs. PMID- 23338191 TI - Adaptation of the Fourier-Hankel method for deflection tomographic reconstruction of axisymmetric field. AB - In this work, we describe an adaptation of Fourier-Hankel method to Abel inversion for the deflection tomographic reconstruction of axisymmetric temperature field. This technique is compared with existing methods to test the accuracy and error propagation using simulated Moire stripes of natural convection flow above a heated horizontal disk in air. Simpson's 1/3rd rule and one-point and two-point formulas are used in this comparison. The results showed that the proposed technique for Abel inversion is accurate and has the powerful capacity to control the smoothing degree of noise in the inversion process. PMID- 23338192 TI - Ultrabroadband polarization splitter based on three-core photonic crystal fibers. AB - An ultrabroadband polarization splitter based on three-core photonic crystal fiber (PCF) is proposed. Two fluorine-doped cores and an elliptical modulation core are introduced to achieve an excellent performance and an ultrawide bandwidth. Numerical results demonstrate that the polarization splitter based on three-core PCF has an extinction ratio as low as -20 dB bandwidth as great as 400 nm covering almost all communication bands (O, E, S, C, and L bands). Its Gaussian-like mode-field distributions and suitable effective mode areas make it highly compatible with the standard single-mode fibers. Due to using a uniform size of circular air holes and only one elliptical central air hole, the difficulty of fabrication can be decreased to some extent. PMID- 23338193 TI - Frequency stabilization of an internal mirror He-Ne laser with a high frequency reproducibility. AB - A method has been developed for the stabilization of an internal mirror He-Ne laser to achieve a high frequency reproducibility that is mainly influenced by the temperature of the stabilized laser. However, it is difficult to achieve a reproducible temperature in a short time under different ambient temperatures. In this paper, the He-Ne laser is stabilized based on the relationship between the laser mode number and the laser cavity temperature where a reproducible temperature can be rapidly achieved under different ambient temperatures, resulting in a high frequency reproducibility. Experiments have demonstrated that the He-Ne laser used can be stabilized in approximately 10 min, typically 6 min; the frequency stability is less than 2*10(-10); the frequency reproducibility is less than 1*10(-9). PMID- 23338194 TI - Design of fixed correctors used in conformal optical system based on diffractive optical elements. AB - A conformal dome was designed and the aberration characteristics of the dome were analyzed using Zernike aberration theory. By deriving the equation used to correct Zernike aberrations, the phase coefficients and the phase orders of diffractive optical elements (DOEs) used to correct primary Zernike aberrations were obtained. DOEs were simulated to correct the aberrations of the conformal dome by using optical design software, and the aberrations of the conformal dome decreased dramatically. Finally, a complete cooled conformal optical system was designed. The results show that the number of the fixed corrector's elements decreases by using DOEs, and the optical system has better imaging quality. PMID- 23338195 TI - Security improvement for asymmetric cryptosystem based on spherical wave illumination. AB - We propose an improvement method for an asymmetric cryptosystem based on spherical wave illumination. Compared with the phase-truncated Fourier transform based cryptosystem and the reported improving methods, the encryption process uses a spherical wave to illuminate the encryption system, rather than a uniform plane wave. As a result, the proposed method can avoid various types of the currently existing attacks and maintain the asymmetric characteristic of the cryptosystem. Moreover, due to only changing the illuminating mode, the proposed method can be easily implemented in optics compared with the reported improving methods. Simulation results are presented to demonstrate the feasibility and the security performance of the proposed method. PMID- 23338196 TI - Analysis of defect layers' insertion effect on optical transmission properties of multilayer structures based on one-dimensional photonic crystals. AB - In this paper, we are interested in the analysis of the transmission spectrum of several multilayer structures based on one-dimensional photonic crystals (1D PCs) infiltrated with different kinds of defect materials, such as bismuth oxide (Bi2O3), lithium niobate (LiNbO3), and E7 liquid crystal (LC). A 1D PC acting as a multichannel filter is constructed by inserting multiple Bi2O3 defect layers, while a localized mode is moved by applying various electric fields on a LiNbO3 defect layer inserted in the middle of a 1D PC structure used as a tunable device. A localized mode is also tuned by applying different magnetic fields on an E7 LC phase shifter inserted between SiO2/TiO2 alternative layers. PMID- 23338197 TI - Analysis of subwavelength bandpass plasmonic filters based on single and coupled slot nanocavities. AB - Subwavelength surface plasmon polariton optical filters based on metal-insulator metal slot nanocavites are proposed and analyzed by using coupled mode theory and a finite element method. Simulation results reveal that a single slot cavity coupled with two access waveguides possesses a bandpass-filtering characteristic with its performance affected by its geometric parameters. To further improve the filtering performance, we explore coupled slot cavities as high-order plasmonic filters. When the slot cavities are side-coupled, the bandpass filtering spectrum is dependent on the positions of the access waveguides. The two slot cavities can also be set orthogonal, leading to strong mutual coupling. With careful tuning of the relative length between the two cavities, improved filtering spectrum can be obtained. Given the subwavelength footprint of the proposed plasmonic filters, they can be used in an ultradense plasmonic integrated circuit for optical signal processing. PMID- 23338198 TI - Effect of glycerol on a diacetone acrylamide-based holographic photopolymer material. AB - The composition of the low-toxicity, environmentally compatible diacetone acrylamide (DA) photopolymer has been modified with the inclusion of different additives. The addition of glycerol to the photopolymer composition is described. Results show that the incorporation of glycerol results in a uniform maximum refractive-index modulation for recording intensities in the range of 1-20 mW/cm(2). This may be attributed to glycerol's nature as a plasticizer, which allows for faster diffusion of an unreacted monomer within the grating during holographic recording. An optimum recording intensity of 0.5 mW/cm(2) is observed for exposure energies of 20-60 mW/cm(2). The modified photopolymer achieves a refractive-index modulation of 2.2*10(-3), with diffraction efficiencies up to 90% in 100 MUm layers. Glycerol has also shown to reduce the rate of photobleaching of the DA photopolymer. This is possibly due to more prevalent inhibition effects caused by increased oxygenation of the photopolymer layers. The stability of the photopolymer samples is also improved with the addition of glycerol. PMID- 23338199 TI - Spectrometer and scanner with optofluidic configuration. AB - We present a spectrometer and scanner based on optofluidic configurations. The main optical component of the spectrometer is a compound optical element consisting of an optofluidic lens and standard blazed diffraction grating. The spectrum size can be changed by filling the lens cavity with different liquids. The scanner comprises two hollow 45 degrees angle prisms oriented at 90 degrees to each other. By changing the liquid inside the prisms, two-dimensional light beam scanning can be performed. PMID- 23338200 TI - Errors from Rayleigh-Jeans approximation in satellite microwave radiometer calibration systems. AB - The advanced technology microwave sounder (ATMS) onboard the Suomi National Polar orbiting Partnership (SNPP) satellite is a total power radiometer and scans across the track within a range of +/-52.77 degrees from nadir. It has 22 channels and measures the microwave radiation at either quasi-vertical or quasi horizontal polarization from the Earth's atmosphere. The ATMS sensor data record algorithm employed a commonly used two-point calibration equation that derives the earth-view brightness temperature directly from the counts and temperatures of warm target and cold space, and the earth-scene count. This equation is only valid under Rayleigh-Jeans (RJ) approximation. Impacts of RJ approximation on ATMS calibration biases are evaluated in this study. It is shown that the RJ approximation used in ATMS radiometric calibration results in errors on the order of 1-2 K. The error is also scene count dependent and increases with frequency. PMID- 23338201 TI - Soft x-ray free-electron laser imaging by LiF crystal and film detectors over a wide range of fluences. AB - LiF crystal and film detectors were used to measure the far-field fluence profile of a self-amplified spontaneous-emission free-electron laser beam and diffraction imaging with high spatial resolution. In these measurements the photoluminescence (PL) response of LiF crystal and film was compared over a wide range of soft x ray fluences. It was found that the soft x-ray fluence dependences of LiF crystal and film differ. At low fluence, the LiF crystal shows higher PL response compared to LiF film, while this comparison is the opposite at higher fluence. Accurate measurement of LiF crystal and film PL response is important for precise characterization of the spatial, spectral, and coherence features of x-ray beams across the full profile and in localized areas. For such measurements, crucial LiF detector attributes are high spatial resolution and high dynamic range. PMID- 23338202 TI - Depth estimation for speckle projection system using progressive reliable points growing matching. AB - In this paper, we propose a progressive reliable points growing matching scheme to estimate the depth from the speckle projection image. First a self-adapting binarization is introduced to reduce the influence of inconsistent intensity. Then we apply local window-based correlation matching to get the initial disparity map. After the initialization, we formulate a progressive updating scheme to update the disparity estimation. There are two main steps in each round of updation. At first new reliable points are progressively selected based on three aspects of criterion including matching degree, confidence, and left-right consistency; then prediction-based growing matching is adopted to recalculate the disparity map from the reliable points. Finally, the more accurate depth map can be obtained by subpixel interpolation and transformation. The experimental results well demonstrate the effectiveness and low computational cost of our scheme. PMID- 23338203 TI - Numerical modeling of mid-infrared fiber optical parametric oscillator based on the degenerated FWM of tellurite photonic crystal fiber. AB - Mid-infrared fiber optical parametric oscillators (MIR FOPOs) based on the degenerate four-wave mixing (DFWM) of tellurite photonic crystal fibers (PCFs) are proposed and modeled for the first time. Using the DFWM coupled-wave equations, numerical simulations are performed to analyze the effects of tellurite PCFs, single-resonant cavity, and pump source on the MIR FOPO performances. The numerical results show that: (1) although a longer tellurite PCF can decrease the pump threshold of MIR FOPOs to a few watts only, the high conversion-efficiency of MIR idler usually requires a short-length optimum PCF with low loss; (2) compared with the single-pass DFWM configurations of the MIR fiber sources published previously, the stable oscillation of signal light in single-resonant cavity can significantly promote the MIR idler output efficiency. With a suggested tellurite PCF as parametric gain medium, the theoretical prediction indicates that such a MIR FOPO could obtain a wide MIR-tunable range and a high conversion efficiency of more than 10%. PMID- 23338204 TI - Coupled-mode equation of polarization modes of twisted birefringent fibers in a unified coordinate. AB - A coupled-mode equation (CME) of twisted birefringent fiber is presented in this paper, which uses the degenerate polarization modes of single-mode fibers as eigenmodes in a unified coordinate. The inconsistency between the coordinate and the rotating principal axis, existing in the previous CME, is solved by conversion to the lab coordinate. The CME gives self-consistent results for fibers with high birefringence or low birefringence and for single-mode fibers as well. Analyses and simulations show the CME gives characteristics of twisted birefringent fiber coincident with the property of polarization-maintaining fibers. PMID- 23338205 TI - Firearm injuries as a public health issue. PMID- 23338207 TI - Transplantation: Pancreas-kidney transplantation may reduce fracture risk in men with type 1 diabetes mellitus. PMID- 23338206 TI - Electric-field induced mutation of DNA: a theoretical investigation of the GC base pair. AB - It is known that intense external electric fields affect the proton transfer (PT) reactions in simple chemical systems, such as hydrated chlorhydric acid or formic acid dimer. Accordingly, electric fields might be used to modulate the PT reactions responsible for the spontaneous mutation mechanism in DNA. In this contribution, we investigate the effect of these fields on the tautomeric equilibria of the guanine-cytosine (GC) base pair in order to gain further insight into this hypothesis. This task is performed with both density functional theory (DFT) and second-order Moller-Plesset (MP2) approaches. Our results demonstrate that electric fields not only drastically alter the rate constants of PT but also tune the mechanism of the PT reactions in the GC base pair. PMID- 23338208 TI - Chronic kidney disease: ESRD risk in CKD patients with incident atrial fibrillation. PMID- 23338209 TI - Renal progenitors: an evolutionary conserved strategy for kidney regeneration. AB - Following kidney injury, repair can result in functional tissue becoming a patch of cells and disorganized extracellular matrix--a scar--or it can recapitulate the original tissue architecture through the process of regeneration. Regeneration can potentially occur in all animal species and humans. Indeed, the repair of portions of the existing nephron after tubular damage, a response that has been designated classically as cellular regeneration, is conserved in all animal species from the ancestral phases of evolution. By contrast, another type of regenerative response--nephron neogenesis--has been described in lower branches of the animal kingdom, but does not occur in adult mammals. Converging evidence suggests that a renal progenitor system is present in the adult kidney across different stages of evolution, with renal progenitors having been identified as the main drivers of kidney regenerative responses in fish, insects, rodents and humans. In this Review, we describe similarities and differences between the renal progenitor systems through evolution, and propose explanations for how progressive kidney adaptation to environmental changes both required and permitted neonephrogenesis to be given up and for cellular regeneration to be retained as the main regenerative strategy. Understanding the mechanisms that drive renal progenitor growth and differentiation represent the key step for modulating this potential for therapeutic purposes. PMID- 23338212 TI - Transplantation: Prolonged cold ischaemic time reduces graft survival in kidneys from controlled-circulatory-death donors. PMID- 23338210 TI - Rituximab therapy in nephrotic syndrome: implications for patients' management. AB - Rituximab offers an alternative to current immunosuppressive therapies for difficult-to-treat nephrotic syndrome. The best outcomes are seen in patients with steroid-dependent nephrotic syndrome who have failed to respond to multiple therapies. By contrast, the benefits of rituximab therapy are limited in patients with steroid-resistant nephrotic syndrome, particularly those with focal segmental glomerulosclerosis (FSGS). Therapy with plasma exchange and one or two doses of rituximab has shown success in patients with recurrent FSGS. Young patients and those with normal serum albumin at recurrence of nephrotic syndrome are most likely to respond to rituximab therapy. A substantial proportion of rituximab-treated patients with idiopathic membranous nephropathy show complete or partial remission of proteinuria, and reduced levels of phospholipase A(2) receptor autoantibodies, which are implicated in the pathogenesis of this disorder. Successful rituximab therapy induces prolonged remission and enables discontinuation of other medications without substantially increasing the risk of infections and other serious adverse events. However, the available evidence of efficacy of rituximab therapy is derived chiefly from small case series and requires confirmation in prospective, randomized, controlled studies that define the indications for use and predictors of response to this therapy. PMID- 23338213 TI - TokyoGreen derivatives as specific and practical fluorescent probes for UDP glucuronosyltransferase (UGT) 1A1. AB - TokyoGreen (TG) derivatives were found to be efficient and specific substrates of an important drug-metabolizing enzyme, UDP-glucuronosyltransferase (UGT) 1A1. A rapid, specific, and sensitive assay of the enzyme was achieved simply by monitoring the change in fluorescence intensity. We also designed and developed the first "turn-on" fluorescent probes for UGTs. PMID- 23338214 TI - Benzodiazepine-like substances and hepatic encephalopathy : implications for treatment. AB - Hepatic encephalopathy is a neuropsychiatric syndrome that can complicate acute and chronic liver disease. Recent research has focused on the role benzodiazepine like substances play in the pathogenesis of this disorder. It has been proposed that potentiation of the action of the neuroinhibitory transmitter gammar aminobutyric acid (GABA) through the binding of endogenous benzodiazepine agonists to the benzodiazepine receptor binding site accounts for the clinical and biochemical features of this condition.Increased levels of endogenous benzodiazepine-like substances have been noted in animal models of hepatic encephalopathy. In human studies, levels of these substances of up to 10 times those found in the body fluids of nonencephalopathic controls have been reported. The existence of such markedly elevated levels cannot be satisfactorily explained with reference to possible pharmaceutical or dietary origins.Further support for the role of benzodiazepines in the mediation of hepatic encephalopathy comes from the therapeutic effect reported after administration of the benzodiazepine receptor antagonist flumazenil. Improvements in the severity of hepatic encephalopathy have been documented in rats with fulminant hepatic failure given flumazenil, although results have been inconsistent according to the dose of flumazenil used and the procedure employed to induce the encephalopathy. Transient, but distinct, improvements in the grade of hepatic encephalopathy have also been documented in several human studies. In a placebo-controlled study involving patients with mild hepatic encephalopathy, a low dose of flumazenil (0.2 mg/kg) resulted in a significant improvement in reaction time.Research now needs to identify whether the beneficial effect of flumazenil is due to its antagonistic or inverse agonistic properties, and also to clarify the mechanisms by which the differential response to the drug in animal models of fulminant hepatic failure is mediated. PMID- 23338211 TI - Cell-matrix adhesion of podocytes in physiology and disease. AB - Cell-matrix adhesion is crucial for maintaining the mechanical integrity of epithelial tissues. Podocytes--a key component of the glomerular filtration barrier--are exposed to permanent transcapillary filtration pressure and must therefore adhere tightly to the underlying glomerular basement membrane (GBM). The major cell-matrix adhesion receptor in podocytes is the integrin alpha3beta1, which connects laminin 521 in the GBM through various adaptor proteins to the intracellular actin cytoskeleton. Other cell-matrix adhesion receptors expressed by podocytes include the integrins alpha2beta1 and alphavbeta3, alpha dystroglycan, syndecan-4 and type XVII collagen. Mutations in genes encoding any of the components critical for podocyte adhesion cause glomerular disease. This Review highlights recent advances in our understanding of the cell biology and genetics of podocyte adhesion with special emphasis on glomerular disease. PMID- 23338215 TI - Prescribing recommendations for interferon-Beta in multiple sclerosis. AB - Multiple sclerosis (MS) is the most common cause of nontraumatic disability affecting young adults in temperate climates. Based on the concept of MS as a tissue-specific autoimmune disease, immunosuppression and immunomodulation have been the mainstays of therapeutic strategies. The rationale for using interferons (IFNs) to treat MS relies primarily on their immunoregulatory effects. Two phase III randomised, placebo-controlled clinical trials independently documented clinical and magnetic resonance imaging (MRI) evidence for the efficacy of IFNbeta using similar but distinct products. As a result of these clinical studies, the US Food and Drug Administration (FDA) approved recombinant IFNbeta 1b and, subsequently, recombinant IFNbeta-1a for relapsing-remitting MS. IFNbeta 1b is currently approved for use in almost all countries around the world, while IFNbeta-1a has gained approval in Europe and Israel.IFNbeta-1b is a nonglycosylated recombinant IFNbeta expressed by Escherichia coli cells. It differs from the native human IFNbeta by having a serine for cysteine substitution at position 17. IFNbeta-1a is identical in terms of amino acid composition to native human IFNbeta, is glycosylated, and is expressed by a mammalian cell line. IFNbeta represents the first treatment approved by the US FDA to modify the natural course of MS. Ongoing studies of IFNbeta for patients at first presentation with MS, and in chronic progressive MS, will clarify the role of IFNbeta in the near future.Despite demonstrable efficacy in the setting of controlled clinical trials, important practice issues that require clarification include the magnitude of long term clinical benefits, toxicity of long term therapy, cost, and the relative value of therapy compared with symptomatic treatment, rehabilitation, education and support services. Because only partial therapeutic benefits have been demonstrated in short term clinical trials, long-range benefits and toxicities of IFNbeta are largely undefined.Since the cost of therapy is high, it seems prudent to restrict the use of IFNbeta to MS patients who are likely to benefit. This requires selection of patients based not only on their past and current disease type, but also on a determination of the likelihood of subsequent disease progression. Selection of patients for IFNbeta therapy should therefore be performed by neurologists based on explicit criteria. Once selected, patients require adequate education about the goals, expectations and method of treatment, and support during the early months of treatment. These critical factors are important elements that promote patient compliance. Recommendations to deviate from the recommended dose usually relate to adverse effects, and many important MS-related issues must be managed during chronic IFNbeta therapy. Therefore, periodic neurological reassessment is essential for appropriate management. PMID- 23338216 TI - Postpartum psychiatric disorders : guidelines for management. AB - Psychiatric disorders, in particular depression, are common Postpartum and have potential long term implications for the woman and her family. Critical to management is identification and early intervention. Management needs to be multifaceted, including hospitalisation in severe cases, psychotherapy (supportive at least) and organisation of community support. A number of factors need to be considered with respect to medication, in particular if the woman is breastfeeding. Women with puerperal psychosis may require antipsychotics, antidepressants and mood stabilisers; ECT achieves good results when available and acceptable. Women with postpartum depression can generally be managed with antidepressants alone. Management needs to take into account that these disorders may be long lasting, with risk of recurrence after subsequent childbirth, and may have significant effects on child development. PMID- 23338218 TI - Erratum to trigeminal neuralgia: a guide to drug choice. PMID- 23338217 TI - Impact of generic substitution of anticonvulsants on the treatment of epilepsy. AB - Two anticonvulsants, namely phenytoin and carbamazepine, are susceptible to bioavailability problems as a result of very low water solubility and a low therapeutic ratio. In addition, phenytoin has nonlinear pharmacokinetics that exaggerate the effects of changes in the fraction of the dose absorbed. There are many published reports of bioinequivalence with different formulations of phenytoin, but fewer with carbamazepine. However, regulatory bodies have developed criteria that have to be satisfied before a new formulation is licensed, and it is therefore considered unlikely that important incidents of bioinequivalence following generic substitution will occur with these drugs in the future. As an overall source of variation in therapeutic response, bioinequivalence is negligible.However, generic substitution may cause confusion and anxiety in patients' minds when it occurs without prior warning. These effects can be allayed by information given by prescribing physicians, pharmacists and patient organisations.Given a positive approach to the issues that arise, the financial benefits of generic prescribing can be enjoyed by patients and by healthcare systems. The pharmaceutical industry should be expected to meet the challenge of fair competition in trading. PMID- 23338220 TI - Ziprasidone. AB - ? Ziprasidone is a novel antipsychotic drug. It has high affinity for serotonin 5 HT(2) and dopamine D(2) receptors in vitro, with an 11-fold higher affinity for 5 HT(2) than for D(2) receptors, suggestive of a low potential for inducing motor disturbance [including extrapyramidal symptoms (EPS)].? The effects of ziprasidone in receptor binding studies reflected its in vitro pharmacology, with more potent effects against 5-HT(2) receptor- than against D(2) receptor-mediated behaviour.? Because ziprasidone inhibits serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine) reuptake, it may have anxiolytic and antidepressant effects.? Data from phase II and III clinical trials have shown ziprasidone to be effective in reducing the positive and negative symptoms of, and depression associated with, schizophrenia, and in reducing anxiety in patients about to undergo dental surgery.? Ziprasidone was generally well tolerated in phase II and III clinical trials, with somnolence and nausea being the most frequently reported adverse events in placebo-controlled studies. Motor disturbances, including EPS, were infrequently observed. PMID- 23338221 TI - Ziprasidone : a viewpoint by robert kerwin. PMID- 23338219 TI - Cholecystokinin and psychiatric disorders : role in aetiology and potential of receptor antagonists in therapy. AB - Cholecystokinin (CCK) is one of the most abundant neuropeptides in the brain. It is found in the highest levels in cortical and limbic structures and also in the basal ganglia. Two subtypes of CCK receptors have been described in the brain and gastrointestinal tissues. CCK(A) (alimentary subtype) receptors are mainly located in the gastrointestinal tract, regulating secretion of enzymes from the pancreas and emptying of the gallbladder. However, CCK(A) receptors are also found in several brain regions, with the highest densities in structures poorly protected by the haematoencephalic barrier (the area postrema, nucleus tractus solitarius and hypothalamus). The distribution of CCK(B) (brain subtype) receptors overlaps with the localisation of CCK and its mRNA in different brain areas, with the highest densities in the cerebral cortex, basal ganglia, nucleus accumbens and forebrain limbic structures.Both subtype of CCK receptor belong to the guanine nucleotide-binding protein-(G protein)-linked receptor superfamily containing 7 transmembrane domains. Signal transduction at CCK receptors is mediated via G(q) protein-related activation of phospholipase C and the formation of inositol 1,4,5-triphosphate (IP(3)) and 1,2-diacylglycerol (DAG). Recent cloning of CCK(A) and CCK(B) receptors has shown that mRNA for both receptors is distributed in the same tissues as established in radioligand binding and receptor autoradiography studies, with few exceptions.The existence of multiple CCK receptors has fuelled the development of selective CCK(A) and CCK(B) receptor antagonists. These antagonists belong to distinct chemical groups, including dibutyryl derivatives of cyclic nucleotides, amino acid derivatives, partial sequences and derivatives of the -COOH terminal sequence heptapeptides of CCK, benzodiazepine derivatives, 'peptoids' based on fragments of the CCK molecule, and pyrazolidinones. At the present time, the compounds of choice for blockade of the CCK(A) receptor are lorglumide, devazepide and lintitript (SR27897). L 365,260, CI-988, L-740,093 and LY288513 are the drugs most widely used to block CCK(B) receptors.Studies with CCK antagonists (and agonists) in animals and humans suggest a role for CCK in the regulation of anxiety and panic. The administration of CCK agonists [ceruletide (caerulein), CCK-4, pentagastrin] has an anxiogenic action in various animal models and in different animal species. However, the anxiogenic action of CCK agonists is restricted to nonconditioned (ethological) models of anxiety, with very limited activity in the 'classical' conditioned models. Pharmacological studies have revealed that CCK(B) receptors are the key targets in the anxiogenic action of CCK agonists. Nevertheless, CCK(B) antagonists displayed very little activity, if any at all, in these models, but strongly antagonised the effects of CCK(B) agonists. The anxiogenic/panicogenic action of CCK(B) agonists (CCK-4, pentagastrin) is even more pronounced in human studies, but the effectiveness of CCK(B) antagonists as anxiolytics remains unclear. Clinical trials performed to date have provided inconclusive data about the anxiolytic potential of CCK(B) receptor antagonists, probably because of limiting pharmacokinetic factors.The results of some animal experiments suggest a role for CCK in depression. The administration of CCK(B) antagonists causes antidepressant-like action in mouse models of depression. However, human studies replicating this result have yet to be carried out.A prominent biochemical alteration in schizophrenia is a reduction of CCK levels in the cerebral cortex. This change may be related to the loss of cortical neurons, due to the schizophrenic process itself. In animal studies (mainly in mice), administration of CCK agonists and antagonists has been shown to be effective in several models, reflecting a possible antipsychotic activity of these drugs. However, the data obtained in human studies suggest that CCK agonists and antagonists do not improve the symptoms of schizophrenia. Taking into account the reduced levels of CCK and its receptors found in schizophrenia, treatments increasing, but not blocking, brain CCK activity may be more appropriate. PMID- 23338223 TI - Ziprasidone : a viewpoint by christopher bench. PMID- 23338222 TI - Ziprasidone : a viewpoint by herbert y. Meltzer. PMID- 23338225 TI - p53 protein subcellular localization and apoptosis in rodent corneal epithelium cell culture following ultraviolet irradiation. AB - The tumor-suppressor gene p53 encodes a phosphoprotein involved in the control of cell growth. p53 expression and function have been documented in malignancy, apoptosis and the aging processes. Recently, p53 has been mapped and characterized in the normal cornea across different species. In the present study, high levels of cytoplasmic p53 protein were noted in normal primary corneal epithelium cultures by immunohistochemistry and western blot analysis. Following ultraviolet (UV) irradiation, the level of cytoplasmic p53 protein expression was increased beginning from 30 min and lasting until 6 h post irradiation and then returned close to control levels by 24 h. Cytoplasmic p53 phosphorylation was detected from 30 min following UV treatment until 6 h post irradiation. p53 protein became apparent in the nucleus in a fraction of these cultured cells beginning 30 min following UV irradiation and was still present 24 h later. We also found that p53 colocalized with mitochondria 2 h following UV irradiation in some of the cells and remained there up to 24 h. As the expression levels of p53 transcription following UV irradiation were not significantly altered, the increase in cytoplasmic p53 protein expression may be conditional only upon post-translational stabilization. We also observed that the apoptotic index increased following UV irradiation in the same time frame as the p53 nuclear transfer and was partially suppressed by pifithrin-alpha, which is a reversible inhibitor of p53-mediated apoptosis and p53-dependent gene transcription. The present study offers new evidence suggesting that cytoplasmic p53 in rodent corneal epithelium is functionally active. PMID- 23338224 TI - Paroxetine : a review of its pharmacology and therapeutic potential in the management of panic disorder. AB - SYNOPSIS: Paroxetine is the first selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) to be approved for the treatment of patients with panic disorder with or without agoraphobia. It is a highly selective inhibitor of presynaptic serotonin reuptake and does not interact with adrenergic, dopaminergic, histaminergic or serotonergic receptors to any significant extent. Oral paroxetine 10 to 60 mg/day is significantly more effective than placebo in reducing the frequency of panic attacks and improving associated symptoms, as shown in short term trials in patients with panic disorder with or without agoraphobia. The efficacy of the drug was maintained during up to 6 months'; treatment, and continued therapy reduced the risk of relapse. Oral paroxetine 10 to 60 mg/day was at least as effective as clomipramine 10 to 150 mg/day, but appeared to have a more rapid onset of effect, in a placebo-controlled trial. The tolerability profile of paroxetine is similar to that established for other SSRIs and is characterised by adverse events such as nausea, headache, somnolence, dry mouth, tremor, insomnia, asthenia, sweating, constipation, dizziness and sexual dysfunction. Paroxetine was better tolerated overall than clomipramine and was associated with a lower incidence of certain anticholinergic events (such as dry mouth and constipation) in a comparative trial. It is not associated with the type of dependence seen with benzodiazepines, and it appears to be safer in overdose than the tricyclic antidepressants. Paroxetine 20 or 30mg does not significantly impair psychomotor function or interact with alcohol (ethanol). In conclusion, the good tolerability profile of paroxetine, including lack of dependence potential and relative safety in overdose, makes it attractive for the treatment of patients with panic disorder. It appears to be at least as effective as clomipramine in reducing panic attacks and associated symptoms. Although further trials to compare the efficacy and tolerability of paroxetine with that of other tricyclic agents (especially Imipramine), high-potency benzodiazepines and monoamine oxidase inhibitors are needed, the drug appears to have the potential to become a first-line treatment for panic disorder. PHARMACODYNAMIC PROPERTIES: Paroxetine increases serotonergic neurotransmission by inhibiting presynaptic reuptake of serotonin (5-hydroxytryptamine; 5-HT) and thereby increasing the level of the neurotransmitter at the synaptic cleft. In vitro, it is a more potent inhibitor of serotonin uptake than the selective serotonin reuptake inhibitors (SSRIs) Citalopram, fluvoxamine and fluoxetine. Paroxetine was more potent than sertraline in one study that compared mean inhibition constants for serotonin uptake, but not in another study that compared the concentrations required to inhibit serotonin uptake by 50%. In contrast to the tricyclic antidepressants, paroxetine has little effect on the uptake of dopamine or noradrenaline (norepinephrine) in vitro. It has negligible affinity for alphar(1-), alphar(2-) and betar-adrenoceptors, dopamine D(1) and D(2) receptors, hi starnine H(1) receptors and serotonin 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors. However, paroxetine does have weak affinity for muscarinic cholinergic receptors. As shown in rats, paroxetine appears to indirectly activate somatodendritic 5-HT(1A) autoreceptors when initially administered, thereby inhibiting firing of 5-HT neurons and release of serotonin. This may explain why the onset of therapeutic effect of paroxetine is delayed. However, repeated administration of paroxetine causes adaptive changes in synaptic serotonergic receptors, including a decrease in the responsiveness of somatodendritic and terminal serotonin autoreceptors. Central betar-adrenoceptors are not down regulated by administration of paroxetine to rats. Various studies in healthy volunteers without sleep disorders or volunteers reporting poor sleep have indicated that paroxetine disturbs normal sleep patterns by reducing rapid eye movement (REM) sleep time and lengthening REM latency. The effect of paroxetine on sleep in patients with panic disorder has not been determined, but in patients with depression the drug improves subjective quality of sleep. In electroencephalographic studies in healthy volunteers, administration of a single dose of paroxetine 30mg produced changes indicative of a sedative profile, whereas administration of 70mg produced changes indicative of activating properties. No significant impairment of psychomotor function was observed after administration of single or multiple doses of paroxetine 20 or 30mg to healthy volunteers or patients with depression. The sedation and impairment of psychomotor function caused by haloperidol, amobarbital, oxazepam or alcohol (ethanol) were not potentiated by the administration of paroxetine 30mg. In contrast to amitriptyline 150 mg/day or doxepin 150 mg/day, 2 to 6 weeks' treatment with paroxetine 20 or 30 mg/day did not produce clinically significant haemodynamic or electrophysiological effects on cardiac function in healthy volunteers or patients with depression. Fewer adverse cardiac effects were reported by paroxetine than nortriptyline recipients in a study in patients with depression and ischaemic heart disease. The anxiolytic activity of paroxetine has been demonstrated after 7 or 21 days' administration in several rodent models. PHARMACOKINETIC PROPERTIES: Paroxetine is well absorbed after oral administration. It undergoes extensive first-pass metabolism and is rapidly distributed into tissue. Only about 1% of the paroxetine dose remains in the systemic circulation. Approximately 95% of paroxetine is protein bound in the plasma. Steady-state concentrations are reached after 7 to 14 days of oral administration and the terminal elimination half-life (t1/2betar) is approximately 24 hours. However, there is a great deal of interindividual variation in the pharmacokinetics of paroxetine. Paroxetine is metabolised by at least 2 enzymes of the cytochrome P450 (CYP) system, one of which is CYP2D6. This enzyme is subject to genetic polymorphism, and thus the pharmacokinetics of paroxetine differ between individuals who have the enzyme (extensive metabolisers) and those who do not (poor metabolisers). The metabolites of paroxetine are essentially inactive. Metabolism of paroxetine by CYP2D6 is saturable. Consequently, with repeated administration, bioavailability of paroxetine increases and pharmacokinetics may become nonlinear in some patients, especially when the dosage of paroxetine is increased. Approximately two-thirds of a paroxetine dose is eliminated in the urine and the remainder is excreted in faeces. Almost all of the dose is eliminated as metabolites; lt3% is excreted as unchanged drug. The plasma concentration and area under the plasma concentration time curve of paroxetine are greater, and the t1/2betar prolonged, in elderly patients and those with hepatic or severe renal impairment compared with the general population. Paroxetine distributes into breast milk to produce concentrations similar to those in plasma. THERAPEUTIC POTENTIAL: As shown in 3 short term placebo-controlled trials in patients with panic disorder with or without agoraphobia, oral paroxetine 10 to 60 mg/day is significantly more effective than placebo for most variables measuring reduction in panic attack frequency. The drug also produced significantly greater improvements in various anxiety and depression scales than placebo. An extension phase of one of the placebo-controlled studies showed that the efficacy of paroxetine in reducing panic attack frequency is maintained during up to 6 months' treatment and that the drug reduces the risk of relapse. Oral paroxetine 10 to 60 mg/day was at least as effective as clomipramine 10 to 150 mg/day in a comparative study. During weeks 7 to 9 of treatment, 51% of paroxetine recipients had no full panic attacks, compared with 37% of clomipramine recipients. The onset of action appeared to be more rapid for paroxetine than for clomipramine. The 2 drugs were equally effective in improving generalised anxiety, phobic avoidance and social, family and work interactions. In patients who elected to continue treatment for a further 36 weeks in an extension phase of the above study, response rates increased further in all groups, including the placebo group. During weeks 34 to 36 of extended treatment, 85% of paroxetine recipients, 72% of clomipramine recipients and 59% of placebo recipients had no panic attacks. The difference between paroxetine and placebo was statistically significant at this time point; however, there was no significant difference between groups at the primary efficacy endpoint (weeks 22 to 24). TOLERABILITY: Paroxetine is generally well tolerated by both younger and older individuals and its adverse event profile is consistent with that expected for an SSRI. The tolerability profile of paroxetine in patients with panic disorder appears to resemble that in patients with depression. Headache, nausea, somnolence, dry mouth and insomnia were the most common adverse events among 469 patients with panic disorder who received paroxetine 10 to 60 mg/day in short term clinical trials. The individual incidences for these events ranged from 18 to 25%; however, the incidence of headache in paroxetine-treated patients was the same as that in placebo recipients. (ABSTRACT TRUNCATED) PMID- 23338226 TI - CD14 overexpression upregulates TNF-alpha-mediated inflammatory responses and suppresses the malignancy of gastric carcinoma cells. AB - CD14 mediates the inflammatory response via recognition of lipopolysaccharide, which has been implicated in Helicobacter pylori (H. pylori) infections. Increasing evidence has suggested that CD14 status significantly influences the clinical outcome of H. pylori infection, which can result in gastric carcinoma. However, there is little evidence regarding the cellular impact and associated molecular basis of CD14 on gastric carcinoma cells. To address this question, we generated a CD14-overexpressing SGC-7901 gastric carcinoma cell line and analyzed the impact of CD14 expression. Our results revealed that cells overexpressing CD14 exhibited antitumor potential, including significantly decreased clonogenic ability, proliferation, metastatic invasion, as well as enhanced apoptosis, suggesting a tumor-suppressive role of CD14 in the cells. Intriguingly, we further discovered that CD14 overexpression activated NF-kappaB via upregulating its expression and simultaneously stimulating DNA binding activity. Upregulated NF-kappaB transcriptionally elevated a series of pro-inflammatory cytokines, including TNF-alpha, IL-1beta, IL-6, and IL-12. Together, the current study utilized a CD14-overexpressing gastric cell model to determine the impacts of CD14 upregulation on cell viability, apoptosis, and migration and NF-kappaB mediated inflammation. PMID- 23338227 TI - The association of serum prolidase activity with developmental dysplasia of the hip. AB - The purpose of this study was to evaluate serum prolidase activity in patients with developmental dysplasia of the hip (DDH). Prolidase enzyme activity was measured spectrophotometrically to pointing out the collagen metabolism. The prolidase activity in patients with DDH was significantly higher than that in the control group (p = 0.002). Furthermore, there was positive correlation between prolidase activity and dysplasia level. Increased serum prolidase activity may have played a role in the presence of DDH. We therefore hypothesized that the increased prolidase activity related to collagen turnover may be associated with etiopathogenesis and/or the progression of the disease. PMID- 23338228 TI - The impact of chemotherapy-induced side effects on medical care usage and cost in German hospital care--an observational analysis on non-small-cell lung cancer patients. AB - PURPOSE: To evaluate frequency and severity of adverse drug reactions (ADRs) and its economic consequences after standard dose (immuno-)chemotherapy (CT) of non small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Subanalysis of a prospective, multicentre, longitudinal, observational cohort study; data were collected from patient interviews and pre-planned chart reviews. Costs were aggregated per CT line and presented from provider perspective. RESULTS: A total of 120 consecutive NSCLC patients (mean age, 63.0 +/- 8.4 (SD) years; men, 64.2%; ECOG (Eastern Cooperative Oncology Group) performance status <2, 84.3%; tumour stage III/IV, 85%; history of comorbidity, 93.3%) receiving 130 CT lines were evaluated. 80% of CT lines were associated with grade 3 or 4 ADRs, 22.3% developed potential life-threatening complications, 77.7% were associated with at least one hospital stay (inpatient, 63.9%; outpatient/day clinic 39.2%, ICU 6.9%), with a mean cumulative number of 12.8 (+/-14.0 SD) hospital days. Mean (median) toxicity management costs per CT line (TMC-TL) amounted to ?3,366 (?1,406) and were found to be higher for first-line compared to second-line treatment: ?3,677 (?1,599) vs. ?2,475 (?518). TMC-TL were particularly high in CT lines with ICU care ?12,207 (?9,960). Eight out of 11 ICU stays were associated with grade 3 or 4 infections. Nine CT lines with ICU care accounted for 25% of total expenses (?109,861 out of ?437,580). CONCLUSIONS: In first-line NSCLC treatment, in particular, CT toxicity management is expensive. Asymmetric cost distribution seems to be triggered by infection associated ICU care. Its avoidance should reduce patients' clinical burden and have considerable economic implications. Nevertheless, comparative observational studies have to confirm estimated savings. PMID- 23338229 TI - Predictive factors for overall quality of life in patients with advanced cancer. AB - OBJECTIVE: This study examined which domains/symptoms from the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 15 Palliative (QLQ-C15-PAL), an abbreviated version of the health-related EORTC QLQ-C30 questionnaire designed for palliative cancer patients, were predictive of overall quality of life (QOL) in advanced cancer patients. METHODS: Patients with advanced cancer from six countries completed the QLQ-C15-PAL at consultation and at one follow-up point. Univariate and multivariate regression analyses were conducted to determine the predictive value of the EORTC QLQ-C15-PAL functional/symptom scores for global QOL (question 15). RESULTS: Three hundred forty-nine patients completed the EORTC QLQ-C15-PAL at baseline. In the total patient sample, worse emotional functioning, pain, and appetite loss were the most significant predictive factors for worse QOL. In the subgroup of patients with bone metastases (n = 240), the domains mentioned above were also the most significant predictors, whereas in patients with brain metastases (n = 109), worse physical and emotional functioning most significantly predicted worse QOL. One-month follow-up in 267 patients revealed that the significant predictors changed somewhat over time. For example, in the total patient sample, physical functioning, fatigue, and appetite loss were significant predictors at the follow-up point. A sub-analysis of predictive factors affecting QOL by primary cancer (lung, breast, and prostate) was also conducted for the total patient sample. CONCLUSION: Deterioration of certain EORTC QLQ-C15-PAL functional/symptom scores significantly contributes to worse overall QOL. Special attention should be directed to managing factors most influential on overall QOL to ensure optimal management of advanced cancer patients. PMID- 23338230 TI - Randomized controlled trial of standardized education and telemonitoring for pain in outpatients with advanced solid tumors. AB - PURPOSE: Previous studies have not defined the role of telemonitoring with educational tools in outpatients with advanced cancers. We tested the effectiveness of standardized education and telemonitoring for improving pain, distress, anxiety, depression, quality of life (QoL), and performance in outpatients with advanced cancers. METHODS: A total of 108 patients were randomly assigned to receive pain education alone (control arm) or pain education plus telemonitoring (experimental arm). Nursing specialists provided video-assisted educational material in both arms and daily telemonitoring for the first week in the experimental arm. Assessment was performed at baseline and 1 week and included evaluations of pain (Brief Pain Inventory, BPI), distress (Distress Thermometer, DT), anxiety, and depression (Hospital Anxiety and Depression Scale, HADS), QoL (QLQ-C30), and a Karnofsky score. RESULTS: Overall (n = 108), pain intensity was significantly improved at 1 week, including worst pain (7.3 to 5.7, P < 0.01) and average pain (4.6 to 3.8, P < 0.01). Additionally, anxiety (HADS score >= 11, 75% to 56%, P < 0.01), depression (HADS score >= 11, 73% to 51%, P < 0.01), QoL (fatigue and insomnia), and the Karnofsky score (32 to 66, P < 0.01) were also significantly improved at 1 week. However, the level of distress did not improve. The telemonitoring plus standardized education group showed more significant improvement in portion of pain >4 on VAS scale (35% vs. 19%, P = 0.02). CONCLUSIONS: Standardized pain education using nursing specialists is an efficient way to improve not only pain itself but also anxiety, depression, performance, and QoL. The addition of telemonitoring helps to improve pain management in the outpatient setting. PMID- 23338231 TI - Hair mass index obtained by cross-section trichometry: an objective and clinically useful parameter to quantify hair in chemotherapy-induced alopecia. AB - PURPOSE: In order to evaluate the efficacy of scalp cooling for the prevention of chemotherapy-induced alopecia (CIA), it is essential to precisely quantify the amount of hair mass that is present. We wanted to determine if the hair mass index (HMI), obtained by cross-section trichometry (CST), was a suitable parameter for hair mass measurement, and whether or not marking the measurement site on the scalp was necessary. METHODS: Ten patients receiving chemotherapy were sequentially measured using CST during their treatment. At the same time, they were asked to report severity of hair loss via three subjective parameters: World Health Organization (WHO) grade, visual analog scale (VAS) score, and patients' need to wear wig or head cover. To investigate the need of marking of the measurement area, differences in HMI between a random 2 * 2-cm site (HMI-C) and four surrounding areas (HMI-S4) on the scalp of eight volunteers and eight chemotherapy patients were calculated and compared. RESULTS: Using CTS, hair loss due to CIA was quite measurable and ranged from 13 to 82 %. Reported VAS scores and WHO grades showed an increase in patients in time; 50 % of patients reported the need to wear a wig or head cover. The difference between HMI-S4 and the HMI-C values in all subjects of the marking group was homogeneously distributed between -11 and +10 and was not statistically different between the volunteer and the patient groups (p = 0.465). CONCLUSIONS: CST for HMI measurement is a useful mechanical modality for assessing hair loss in CIA patients. It is quantitatively more precise than existing non-mechanical measuring methods. It is recommended when detection of minor changes in hair quantity is required. Marking a fixed sampling area to ensure return to the exact same site is only required when a minor change in pre- and posttreatment HMI values is anticipated and the mid-line locating device is not/cannot be used. PMID- 23338232 TI - Controversies in ocular trauma classification and management: review. AB - Ocular trauma is a topic of unresolved controversies and there are continuous controversial and debatable management strategies for open-globe injuries (OGIs). International classification of ocular trauma proposed almost 15 years ago needs to be reviewed and to be more robust in predicting the outcome in the setting of OGIs. Anterior segment trauma involves controversies related to patching for corneal abrasion, corneal laceration repair, and medical management of hyphema. Timing of cataract surgery and intraocular lens implantation in the setting of trauma is still debated worldwide. There are unresolved issues regarding the management of OGIs involving the posterior segment. Timing of vitrectomy has been and will continue to be debated by proponents of early versus delayed intervention. The use of prophylactic cryotherapy and scleral buckle is still practiced differently throughout the world. The role of intravitreal antibiotics in posterior segment trauma in the absence of infection is still debated. Similarly, the use of vitrectomy versus vitreous tap in the setting of traumatic endophthalmitis is not fully resolved. In optic neuropathy, the role of intravenous methylprednisolone versus conservative management is always debated and still there are no evidence-based guidelines about the beneficial role of pulse steroid therapy. The role of optic canal decompression in the setting of acute traumatic optic neuropathy is also not conclusive. Orbital and adnexal trauma has been shown to adversely affect the outcome of OGI patients but both lids and orbital injury are not taken as preoperative variables in international ocular trauma classification. The timing of intervention in blow-out fracture is still debated. The pediatric age group, owing to the high risk of amblyopia and intraocular inflammation as well as strong vitreoretinal adhesions, has to be managed by different principles. Although the risk of sympathetic ophthalmia is very rare, it is always one of the key debated issues while managing traumatized eyes with no light perception vision. Prospective, controlled clinical studies are not possible in the OGI setting and this article reviews pertinent data regarding these management issues and controversies, and provides recommendations for treatment based on the available published data and the authors' personal experience. PMID- 23338233 TI - Retinal nerve fiber layer and ganglion cell layer thickness in patients receiving systemic isotretinoin therapy. AB - To evaluate the effect of oral isotretinoin therapy on retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness by spectral domain optical coherence tomography (OCT). This prospective study included newly diagnosed nodulocystic acne patients about to receive isotretinoin treatment. Macular average GCL thickness and peripapillary average, temporal, nasal, inferior, and superior quadrant RNFL thickness were measured by OCT before and after isotretinoin treatment. Pre- and post-treatment measurements were compared with paired t test. Fifty-six eyes of 28 patients were included. The mean duration of the treatment was 6.5 +/- 1.3 months. The mean average GCL thickness was 90.04 +/ 5.87 (80-96) MUm at baseline and 90.75 +/- 6.34 (81-96) MUm after treatment. The mean average RNFL thickness was 93.25 +/- 6.06 MUm (84-107) before treatment and 93.05 +/- 5.54 MUm (82-106) after treatment. There were no statistically significant differences between pre- and post-treatment values (all p > 0.05). A 6-month course of systemic isotretinoin therapy seems to have no unfavorable effect on retinal ganglion cells; however, larger studies with longer follow-up periods are needed to be conclusive. PMID- 23338234 TI - Temporal dynamics of the primary human T cell response to yellow fever virus 17D as it matures from an effector- to a memory-type response. AB - The live attenuated yellow fever virus (YFV) 17D vaccine provides a good model to study immune responses to an acute viral infection in humans. We studied the temporal dynamics, composition, and character of the primary human T cell response to YFV. The acute YFV-specific effector CD8 T cell response was broad and complex; it was composed of dominant responses that persisted into the memory population, as well as of transient subdominant responses that were not detected at the memory stage. Furthermore, HLA-A2- and HLA-B7-restricted YFV epitope specific effector cells predominantly displayed a CD45RA(-)CCR7(-)PD 1(+)CD27(high) phenotype, which transitioned into a CD45RA(+)CCR7(-)PD-1( )CD27(low) memory population phenotype. The functional profile of the YFV specific CD8 T cell response changed in composition as it matured from an effector- to a memory-type response, and it tended to become less polyfunctional during the course of this transition. Interestingly, activation of CD4 T cells, as well as FOXP3(+) T regulatory cells, in response to YFV vaccination preceded the kinetics of the CD8 T cell response. The present results contribute to our understanding of how immunodominance patterns develop, as well as the phenotypic and functional characteristics of the primary human T cell response to a viral infection as it evolves and matures into memory. PMID- 23338235 TI - Virus-encoded TLR ligands reveal divergent functional responses of mononuclear phagocytes in pathogenic simian immunodeficiency virus infection. AB - The role of mononuclear phagocytes in the pathogenesis or control of HIV infection is unclear. In this study, we monitored the dynamics and function of dendritic cells (DC) and monocytes/macrophages in rhesus macaques acutely infected with pathogenic SIVmac251 with and without antiretroviral therapy (ART). SIV infection was associated with monocyte mobilization and recruitment of plasmacytoid DC (pDC) and macrophages to lymph nodes, which did not occur with ART treatment. SIVmac251 single-stranded RNA encoded several uridine-rich sequences that were potent TLR7/8 ligands in mononuclear phagocytes of naive animals, stimulating myeloid DC (mDC) and monocytes to produce TNF-alpha and pDC and macrophages to produce both TNF-alpha and IFN-alpha. Following SIV infection, pDC and monocytes/macrophages rapidly became hyporesponsive to stimulation with SIV-encoded TLR ligands and influenza virus, a condition that was reversed by ART. The loss of pDC and macrophage function was associated with a profound but transient block in the capacity of lymph node cells to secrete IFN-alpha upon stimulation. In contrast to pDC and monocytes/macrophages, mDC increased TNF alpha production in response to stimulation following acute infection. Moreover, SIV-infected rhesus macaques with stable infection had increased mDC responsiveness to SIV-encoded TLR ligands and influenza virus at set point, whereas animals that progressed rapidly to AIDS had reduced mDC responsiveness. These findings indicate that SIV encodes immunostimulatory TLR ligands and that pDC, mDC, and monocytes/macrophages respond to these ligands differently as a function of SIV infection. The data also suggest that increased responsiveness of mDC to stimulation following SIV infection may be beneficial to the host. PMID- 23338236 TI - Distinct populations of innate CD8+ T cells revealed in a CXCR3 reporter mouse. AB - CXCR3, expressed mainly on activated T and NK cells, is implicated in a host of immunological conditions and can contribute either to disease resolution or pathology. We report the generation and characterization of a novel CXCR3 internal ribosome entry site bicistronic enhanced GFP reporter (CIBER) mouse in which enhanced GFP expression correlates with surface levels of CXCR3. Using CIBER mice, we identified two distinct populations of innate CD8(+) T cells based on constitutive expression of CXCR3. We demonstrate that CXCR3(+) innate CD8(+) T cells preferentially express higher levels of Ly6C and CD122, but lower levels of CCR9 compared with CXCR3(-) innate CD8(+) T cells. Furthermore, we show that CXCR3(+) innate CD8(+) T cells express higher transcript levels of antiapoptotic but lower levels of proapoptotic factors, respond more robustly to IL-2 and IL 15, and produce significantly more IFN-gamma and granzyme B. Interestingly, CXCR3(+) innate CD8(+) T cells do not respond to IL-12 or IL-18 alone, but produce significant amounts of IFN-gamma on stimulation with a combination of these cytokines. Taken together, these findings demonstrate that CXCR3(+) and CXCR3(-) innate CD8(+) T cells are phenotypically and functionally distinct. These newly generated CIBER mice provide a novel tool for studying the role of CXCR3 and CXCR3-expressing cells in vivo. PMID- 23338237 TI - Critical role for all-trans retinoic acid for optimal effector and effector memory CD8 T cell differentiation. AB - A plethora of work implicates important effects of the vitamin A derivative retinoic acid (RA) in myeloid differentiation, whereas fewer studies explore the role of RA in lymphoid cells. Most work on lymphoid cells has focused on the influence of RA on CD4 T cells. Little information about the role of RA in CD8 T cell differentiation is available, and even less on cell-intrinsic effects in the CD8 T cell. This study explores the role of RA in effector and memory differentiation in a cell-intrinsic manner in the context of vaccinia virus infection. We observed the loss of the short-lived effector cell phenotype (reduced KLRG1(+), T-bet(hi), granzyme B(hi)), accompanied by an enhanced memory precursor phenotype at the effector (increased CD127(hi), IL-2(+)) and contraction phases (increased CD127(hi), IL-2(+), eomesodermin(hi)) of the CD8 response in the absence of RA signaling. The lack of RA also increased the proportion of central memory CD8s. Collectively, these results introduce a new role for RA in CD8 T cell activation and differentiation. This new role may have significant implications for optimal vaccine design in which vitamin A supplementation is used to augment effector responses, but it may be to the detriment of the long-term central memory response. PMID- 23338239 TI - Differential Ly49e expression pathways in resting versus TCR-activated intraepithelial gammadelta T cells. AB - The Ly49 NK receptor family in mice is composed of several members that recognize MHC class I (MHC-I) or MHC-I-related molecules. We and others have shown before that Ly49E is a unique member, with a different expression pattern on NK cells and being triggered by the non-MHC-I-related protein urokinase plasminogen activator. Among the entire Ly49 receptor family, Ly49E is the only Ly49 member expressed by epidermal-localized gammadelta T cells and their fetal thymic TCRgammadelta precursors, and it is the most abundantly expressed member on intestinal intraepithelial gammadelta T cell lymphocytes. In this study, we provide mechanistic insights into the regulation of Ly49e expression in gammadelta T cells. First, we demonstrate that TCR-mediated activation of intraepithelial gammadelta T cells significantly increases Ly49E expression. This results from de novo Ly49E expression and is highly selective, because no other Ly49 family members are induced. TCR-mediated Ly49E induction is a conserved feature of skin- and gut-residing intraepithelial-localized gammadelta T cell subsets, whereas it is not observed in spleen gammadelta T cells. By investigating Ly49e promoter activities and lymphotoxin (LT) alphabeta dependency in resting versus TCR-activated intraepithelial gammadelta T cells, we reveal two separate regulatory pathways for Ly49E expression, as follows: a LTalphabeta dependent pathway leading to basal Ly49E expression in resting cells that is induced by Pro2-mediated Ly49e transcription, and a LTalphabeta-independent pathway leading to elevated, Pro3-driven Ly49E expression in TCR-stimulated cells. PMID- 23338238 TI - Spatial coupling of JNK activation to the B cell antigen receptor by tyrosine phosphorylated ezrin. AB - The ezrin-radixin-moesin proteins regulate B lymphocyte activation via their effect on BCR diffusion and microclustering. This relies on their ability to dynamically tether the plasma membrane with actin filaments that is in turn facilitated by phosphorylation of the conserved threonine residue in the actin binding domain. In this study, we describe a novel function of ezrin in regulating JNK activation that is mediated by phosphorylation of a tyrosine (Y353) residue that is unconserved with moesin and radixin. BCR, but not CD40, TLR4, or CXCR5 stimulation, induced phosphorylation of ezrin at Y353 in mouse splenic B cells. Ezrin existed in a preformed complex with Syk in unstimulated B cells and underwent Syk-dependent phosphorylation upon anti-IgM stimulation. Y353 phosphorylated ezrin colocalized with the BCR within minutes of stimulation and cotrafficked with the endocytosed BCRs through the early and late endosomes. The T567 residue of ezrin was rephosphorylated in late endosomes and at the plasma membrane at later times of BCR stimulation. Expression of a nonphosphorylatable Y353F mutant of ezrin specifically impaired JNK activation. BCR crosslinking induced the association of Y353-phosphorylated ezrin with JNK and its kinase MAPKK7, as well as spatial colocalization with phosphorylated JNK in the endosomes. The yellow fluorescent protein-tagged Y353F mutant displayed reduced colocalization with the endocytosed BCR as compared with wild-type ezrin-yellow fluorescent protein. Taken together, our data identify a novel role for ezrin as a spatial adaptor that couples JNK signaling components to the BCR signalosome, thus facilitating JNK activation. PMID- 23338241 TI - Sacsin-related spastic ataxia caused by a novel missense mutation p.Arg272His in a patient from Sicily, southern Italy. PMID- 23338240 TI - Live attenuated Leishmania donovani p27 gene knockout parasites are nonpathogenic and elicit long-term protective immunity in BALB/c mice. AB - Leishmaniasis causes significant morbidity and mortality worldwide, and no vaccines against this disease are available. Previously, we had shown that the amastigote-specific protein p27 (Ldp27) is a component of an active cytochrome c oxidase complex in Leishmania donovani and that upon deletion of its gene the parasite had reduced virulence in vivo. In this study, we have shown that Ldp27( /-) parasites do not survive beyond 20 wk in BALB/c mice and hence are safe as an immunogen. Upon virulent challenge, mice 12 wk postimmunization showed significantly lower parasite burden in the liver and spleen. When mice were challenged 20 wk postimmunization, a significant reduction in parasite burden was still noted, suggesting long-term protection by Ldp27(-/-) immunization. Immunization with Ldp27(-/-) induced both pro- and anti-inflammatory cytokine responses and activated splenocytes for enhanced leishmanicidal activity in association with NO production. Protection in both short- and long-term immunized mice after challenge with the wild-type parasite correlated with the stimulation of multifunctional Th1-type CD4 and CD8 T cells. Adoptive transfer of T cells from long-term immunized mice conferred protection against virulent challenge in naive recipient mice, suggesting involvement of memory T cell response in protection against Leishmania infection. Immunization of mice with Ldp27(-/-)also demonstrated cross-protection against Leishmania major and Leishmania braziliensis infection. Our data show that genetically modified live attenuated Ldp27(-/-) parasites are safe, induce protective immunity even in the absence of parasites, and can provide protection against homologous and heterologous Leishmania species. PMID- 23338242 TI - Theoretical study of the proton transfer wires influence on the one- and two photon absorption properties of green fluorescent protein chromophore. AB - The excited-state proton transfer (ESPT) via proton transfer wires in green fluorescent protein (GFP) plays an important role on the spectroscopic of GFP. In this work, we use the proton transfer wires and the chromophore complex to simulate the tautomer structures of neutral state and the intermediate state in wt-GFP. And we employ the time-dependent density functional theory combined with the sum-over-states method to calculate the one- and two-photon absorption properties of these complexes in GFP. We obtain the large stokes shift from 383 nm to 500 nm in GFP when simulating the ESPT process by these isomerous H-bonding complexes. We find that the TPA spectrum of the H-bonding complex of the intermediate state agrees more with experimental measurement than that of the H bonding complex of the neutral state. The TPA spectrum of GFP might be mainly dominated by the structure which is similar to the H-bonding complex of intermediate state. Further, we simulate another kind of complex which possess short-strong hydrogen bonds in proton transfer wires, and find that TPA properties of these complexes are much stronger than that of the complexes with the long distance proton wires from GFP. PMID- 23338243 TI - Use of surgical-site infection rates to rank hospital performance across several types of surgery. AB - BACKGROUND: Comparing and ranking hospitals based on health outcomes is becoming increasingly popular, although case-mix differences between hospitals and random variation are known to distort interpretation. The aim of this study was to explore whether surgical-site infection (SSI) rates are suitable for comparing hospitals, taking into account case-mix differences and random variation. METHODS: Data from the national surveillance network in the Netherlands, on the eight most frequently registered types of surgery for the year 2009, were used to calculate SSI rates. The variation in SSI rate between hospitals was estimated with multivariable fixed- and random-effects logistic regression models to account for random variation and case mix. 'Rankability' (as the reliability of ranking) of the SSI rates was calculated by relating within-hospital variation to between-hospital variation. RESULTS: Thirty-four hospitals reported on 13 629 patients, with overall SSI rates per surgical procedure varying between 0 and 15.1 per cent. Statistically significant differences in SSI rate between hospitals were found for colonic resection, caesarean section and for all operations combined. Rankability was 80 per cent for colonic resection but 0 per cent for caesarean section. Rankability was 8 per cent in all operations combined, as the differences in SSI rates were explained mainly by case mix. CONCLUSION: When comparing SSI rates in all operations, differences between hospitals were explained by case mix. For individual types of surgery, case mix varied less between hospitals, and differences were explained largely by random variation. Although SSI rates may be used for monitoring quality improvement within hospitals, they should not be used for ranking hospitals. PMID- 23338244 TI - [Alpha angle 2.0! Is an update for the diagnosis of cam impingement necessary?]. PMID- 23338245 TI - [Magnetic resonance imaging of hypertrophic cardiomyopathy : evaluation of diastolic function]. AB - Hypertrophic cardiomyopathy (HCM) has a prevalence of approximately 0.2% and is clinically asymptomatic in many patients or presents with unspecific symptoms. This explains the importance of imaging for the diagnosis of HCM as well as for the assessment of the clinical course. The definitive finding in HCM is myocardial hypertrophy with thickening of the ventricular wall >= 15 mm. While echocardiography is an excellent screening tool magnetic resonance imaging (MRI) allows a comprehensive analysis of the heart in HCM. This includes a detailed analysis of the distribution and extent of myocardial hypertrophy, a thorough evaluation of systolic and diastolic cardiac function, the assessment of the presence and extent of dynamic outflow tract obstruction as well as the description of the systolic anterior motion (SAM) phenomenon of the mitral valve with secondary mitral insufficiency. When contrast material is administered, additional information about myocardial perfusion as well as the presence and extent of myocardial fibrosis can be obtained. This study compared systolic functional parameters as well as end systolic and end diastolic wall thickness of patients with and without diastolic dysfunction. PMID- 23338246 TI - [Magnetic resonance imaging of dilated cardiomyopathy]. AB - Dilated cardiomyopathy (DCM) is the most common type of cardiomyopathy with a prevalence of 1 out of 2,500 in adults. Due to mild clinical symptoms in the early phase of the disease, the true prevalence is probably even much higher. Patients present with variable clinical symptoms ranging from mild systolic impairment of left ventricular function to congestive heart failure. Even sudden cardiac death may be the first clinical symptom of DCM. The severity of the disease is defined by the degree of impairment of global left ventricular function. Arrhythmias, such as ventricular or supraventricular tachycardia, atrioventricular (AV) block, ventricular extrasystole and atrial fibrillation are common cardiac manifestations of DCM. Magnetic resonance imaging (MRI) plays an important role in the exact quantification of functional impairment of both ventricles and in the evaluation of regional wall motion abnormalities. With its excellent ability for the assessment of myocardial structure, it is becoming increasingly more important for risk stratification and therapy guidance. PMID- 23338247 TI - [MRI for myocarditis]. AB - Cardiovascular magnetic resonance imaging (CMRI) has become the primary tool for the non-invasive assessment in patients with suspected myocarditis, especially after exclusion of acute coronary syndrome (ACS) for the differential diagnosis. Various MRI parameters are available which have different accuracies. Volumetric and functional ventricular assessment and the occurrence of pericardial effusion alone demonstrate only a poor sensitivity and specificity. The calculation of the T2-ratio (edema assessment), the early or global relative myocardial enhancement (gRE) and the late gadolinium enhancement (LGE), which represents irreversibly injured myocardium, are more specific parameters. All MRI parameters demonstrate the best accuracy in infarct-like acute myocarditis, whereas in chronic myocarditis sensitivity and specificity are less accurate. Therefore, a multisequential (at least two out of three parameters are positive) approach is recommended. The assessment of the value of newer, more quantitative MRI sequences, such as T1 and T2-mapping is still under investigation. PMID- 23338248 TI - [MRI for arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)]. AB - Arrhythmogenic right ventricular dysplasia/cardiomyopathy is a congenital disease that may present with sudden cardiac death as the first manifestation. Standards for the difficult clinical diagnosis are the so-called modified Task Force criteria that incorporate imaging-based, electrocardiographic and anamnestic information. Cardiac magnetic resonance imaging (MRI) is the standard technique for imaging of the right ventricle and can compliment the recent ARVD/C diagnosis criteria by providing exact information on right ventricular size and function. It is the most reliable modality available for the detection of right ventricular aneurysms and the quantification of ventricular size. Furthermore, MRI is able to identify areas of fatty or fibrous replacement within the right ventricular myocardium in a non-invasive way. However, a suspicion of ARVD/C cannot be confirmed or excluded based on MRI findings alone. In clinical routine cardiac MRI is an enormously important component in the ARVD/C diagnostic toolbox; however, MRI can only act as one part of the diagnostic puzzle and should exclusively be performed by experienced centers using specifically tailored protocols. PMID- 23338249 TI - [Internet resources for radiologists : a positive selection]. AB - In radiology the use of internet resources is part of the daily routine. The critical selection of but not the access to radiologically relevant information is the key topic in internet use. We offer a selection of reviewed internet sources for radiologists. We present sources that offer guidance in decision making in daily routine as well as internet sources on technical topics in radiology. Case selection and radiological search engines are helpful sites to begin an internet research. Online anatomy sites can be of assistance for interpretation of findings in radiology. Writing and publishing scientific works in radiology requires access to numerous internet services, a positive selection of which are reviewed in the present article. A variety of freeware is available on the internet, some of which may be a substantial benefit to projects in radiology. PMID- 23338250 TI - [Radiology and pregnancy : Part 2: clinical recommendations]. AB - In spite of a growing number of radiological scans in pregnant women there is still a high level of uncertainty concerning radiation exposure to the fetus. At the same time, the risk of fetal radiation injury is frequently overestimated. This entails an avoidable fear in the pregnant patient and may delay urgently required imaging and thus lead to an increased risk for maternal and fetal health. As a consequence, radiological scans in pregnant patients do not only require a thorough medical check but also a careful estimate of the specific radiation exposure to the fetus. The previous first part of the article described the legal requirements in Germany, the technical exposure and pharmacological risks for the pregnant woman and the fetus. The current second article focuses on the risk analysis for examinations with ionizing radiation and will provide recommendations for typical indications for maternal and fetal imaging. PMID- 23338252 TI - Steroidal and non-steroidal cyclooxygenase-2 inhibitor anti-inflammatory drugs as pre-emptive medication in patients undergoing periodontal surgery. AB - The aim of the present study was to compare the pre-emptive use of a cyclooxygenase-2 (COX-2) inhibitor with a well established steroidal anti inflammatory drug for pain and edema relief following periodontal surgery for crown lengthening. Thirty patients requiring periodontal surgery were randomly assigned to receive one of the following medications: selective COX-2 inhibitor or steroidal anti-inflammatory drug, 60 min before the surgical procedure. To examine patient anxiety, a Corah's dental anxiety scale was applied before surgery. Using a visual analog scale, the extent of pain/discomfort during the trans-operative period and immediately after the surgery was measured. Additionally, intensity of pain/discomfort and edema were examined 4, 8, 12 and 24 h postoperatively. With regard to anxiety, no statistical differences between the groups were observed (p>0.05). With respect to the extent of pain/discomfort during the trans-operative, immediate and late postoperative period, data demonstrated no significant differences (p>0.05) between the COX-2 inhibitor and steroidal groups. With regard to edema, intragroup analysis did not reveal any statistically significant difference (p>0.05) during the 24 h following surgery in either group. In conclusion, both anti-inflammatory drugs presented a similar potential for pain and edema relief following periodontal surgery. PMID- 23338253 TI - Fluoride modulates preosteoblasts viability and matrix metalloproteinases-2 and 9 activities. AB - This study evaluated the influence of fluoride on cell viability and activity of matrix metalloproteinases (MMP) -2 and -9 secreted by preosteoblasts. Preosteoblasts (MC3T3-E1 murine cell line) were cultured in MEM medium supplement with 10% Fetal Bovine Serum (FBS) and nucleosides/ribonucleosides without ascorbic acid. Adherent cells were treated with different concentrations of F (as sodium fluoride-NaF) in medium (5 x 10(-6) M, 10(-5) M, 10(-4) M and 10(-3) M) for 24, 48, 72 and 96 h at 37oC, 5% CO(2). Control cells were cultivated in MEM only. After each period, preosteoblast viability was assessed by MTT assay. MMP-2 and -9 activities were performed by gel zymography. Also, alkaline phosphatase (ALP) activity was quantified by colorimetry in all experimental groups. It was shown that cultured cells with the highest dose of F (10(-3) M) for 96 h decreased preosteoblast viability while lower doses of F did not alter it, when compared to untreated cells. No differences were observed in ALP activity among groups. Moreover, compared to control, the treatment of cells with F at low dose slightly increased MMP-2 and -9 activities after 24 h. It was concluded that F modulates preosteoblast viability in a dose-dependent manner and also may regulate extracellular matrix remodeling. PMID- 23338254 TI - Histological evaluation of bone response to pediatric endodontic pastes: an experimental study in guinea pig. AB - This study aimed to evaluate by the intra-osseous implant technique the most commonly used materials for pulp therapy in pediatric dentistry: calcium hydroxide (CH), Guedes Pinto paste and CTZ paste, according to FDI (1980) and ANSI/ADA (1982) recommendations. Thirty guinea pigs, 10 for each material, divided into experimental periods of 4 and 12 weeks received one implant on each side of the lower jaw symphysis. The external lateral tube wall served as control for the technique. At the end of the observation periods, the animals were euthanized and specimens were prepared for routine histological examination. It was observed that CH and CTZ paste induced severe inflammation, a large amount of necrotic tissue, lymphocytes, foreign body cells and bone resorption, while Guedes Pinto Paste induced little or no inflammation in the 4-week observation period. After 12 weeks, the reactions to CH and Guedes Pinto paste were also absent/mild, presenting a general pattern of replacement by recently formed bone tissue while a moderate to severe inflammatory response was observed with CTZ paste. Guedes Pinto paste presented acceptable biocompatibility levels in both analyzed periods; CH only showed acceptable biocompatibility in the 12-week period while CTZ paste showed no biocompatibility in both periods. Among the tested materials, only Guedes Pinto paste presented an acceptable biocompatibility. PMID- 23338255 TI - A preliminary study of the antibacterial potential of cetylpyridinium chloride in root canals infected by E. faecalis. AB - The aim of this preliminary study was to verify the antibacterial potential of cetylpyridinium chloride (CPC) in root canals infected by Enterococcus faecalis. Forty human maxillary anterior teeth were prepared and inoculated with E. faecalis for 60 days. The teeth were randomly assigned to the following groups: 1: Root canal preparation (RCP) + 0.1% CPC with positive-pressure irrigation (PPI, Conventional, NaviTip((r))); 2: RCP + 0.2% CPC PPI; 3: RCP + 2.5% NaOCl PPI; 4: RCP + 2.5% NaOCl with negative-pressure irrigation system (NPI, EndoVac((r))); 5: Positive control; and 6: Negative control. Four teeth of each experimental group were evaluated by culture and 4 by scanning electron microscopy (SEM). In all teeth, the root canals were dried and filled with 17% EDTA (pH 7.2) for 3 min for smear layer removal. Samples from the infected root canals were collected and immersed in 7 mL of Letheen Broth (LB), followed by incubation at 37 degrees C for 48 h. Bacterial growth was analyzed by turbidity of culture medium and then observed with a UV spectrophotometer. The irrigating solutions were further evaluated for antimicrobial effect by an agar diffusion test.The statistical data were treated by means, standard deviation, Kruskal Wallis test and analysis of variance. Significance level was set at 5%. The results showed the presence of E. faecalis after root canal sanitization. The number of bacteria decreased after the use of CPC. In the agar diffusion test, CPC induced large microbial inhibition zones, similar to 2% chlorhexidine and large than 2.5% NaOCl. In conclusion, cetylpyridinium chloride showed antibacterial potential in endodontic infection with E. faecalis. PMID- 23338256 TI - Effect of sodium hypochlorite and EDTA irrigation, individually and in alternation, on dentin microhardness at the furcation area of mandibular molars. AB - The aim of this study was to evaluate the effect of irrigation regimens on dentin microhardness at the furcation area of mandibular molars, using sodium hypochlorite and ethylenediaminetetraacetic acid (EDTA), individually and in alternation. The occlusal surface and the roots of 20 non-carious extracted human permanent mandibular molars were cut transversally and discarded. The tooth blocks were embedded in acrylic resin and randomly assigned to 4 groups (n=5) according to the irrigating regimens: 1% NaOCl solution, 17% EDTA solution, 1% NaOCl and 17% EDTA and distilled water (control). Knoop microhardness of dentin at the furcation area was evaluated. Data were analyzed using one-way ANOVA and Tukey's multiple comparison tests (alpha=0.05). The results of this study indicated that all irrigation solutions, except for distilled water (control), decreased dentin microhardness. EDTA did not show a significant difference with NaOCl/EDTA (p>0.05), but showed a significant difference with NaOCl (p<0.01). EDTA and NaOCl/EDTA showed a maximum decrease in microhardness. The 17% EDTA solution, either alone or in combination with 1% NaOCl reduced significantly dentin microhardness at the furcation area of mandibular molars. PMID- 23338257 TI - Changes in surface roughness and color stability of two composites caused by different bleaching agents. AB - The objective of this study was to evaluate the effect of two bleaching agents (10% and 35% hydrogen peroxide) on the color stability and surface roughness of two composites, one nanohybrid and one nanoparticle. Specimens were polished, aged, stained, bleached and polished again. The action of the bleaching agents on the composites was analyzed using a profilometer (surface roughness) and a spectrophotometer (color stability). The effect of polishing the composites on the surface roughness and the resumption of the composite color was also evaluated. The results were analyzed statistically by ANOVA and Tukey's test at 5% significance level. The analysis indicated that the nanohybrid composite was more affected by staining. The bleaching agents were not able to promote bleaching of either composite over the evaluation period. Surface polishing returned nanohybrid composite to its original color condition, which did not occur for the nanoparticle composite. Additionally, polishing did not return the surface roughness of either composite to its original value. It may be concluded that polishing surface after bleaching should not be the treatment of choice, as it was not possible to reverse the roughness of the composites to their original values, suggesting that a more extensive and irreversible degradation might have occurred. PMID- 23338258 TI - Effect of acid fruit juices combined with electric or sonic toothbrushing on root dentin permeability--an in vitro study. AB - The purpose of this in vitro study was to quantify the alterations on human root dentin permeability after exposure to different acid fruit juices and to evaluate the effect of toothbrushing with electric or sonic toothbrush after acid exposure. The root dentin of 50 extracted third molars was exposed with a high speed bur. Crowns were sectioned above the cementoenamel junction and root fragments were used to prepare dentin specimens. Specimens were randomly assigned to 5 groups according to the fruit juice (kiwifruit, starfruit, green apple, pineapple and acerolla). Each specimen was connected to a hydraulic pressure apparatus to measure root dentin permeability using fluid filtration method after the following sequential steps: I) conditioning with 37% phosphoric acid for 30 s, II) root scaling, III) exposure to acid fruit juices for 5 min and IV) electric or sonic toothbrushing without dentifrice for 3 min. Data were analyzed statistically by the Wilcoxon and Mann-Whitney tests at 5% significance level. All fruit juices promoted a significant increase of dentin permeability while toothbrushing decreased it significantly (p<0.05). It may be concluded that all acid fruit juices increased root dentin permeability, while toothbrushing without dentifrice after acid exposure decreased the permeability. The toothbrush mechanism (electric or sonic) had no influence on the decrease of root dentin permeability. PMID- 23338259 TI - Marginal adaptation of indirect restorations using different resin coating protocols. AB - This study evaluated the influence of material combinations used in the resin coating technique (RCT) on the marginal adaptation of indirect restorations with gingival margins in enamel (EM) and cement (CM). Eighty third-molars were used. Two cavities were prepared in each tooth. The cavities were distributed into 16 groups. Cavities with EM were filled with the following material combinations: G1: Single-Bond 2 (Sb2), G2: Sb2 + Bond/Scotchbond-Multipurpose (Sb2B), G3: Sb2 + Filtek-Flow Z350 (Sb2Fl), G4: Scotchbond-Multipurpose (SBMP), G5: Clearfil-S3 (CS3), G6: CS3 + Bond/Clearfil-SE Bond (CSE3B), G7: CS3 + Protect Liner F (CS3PL) and G8: Clearfil SE Bond + Protect Liner F (CSEBPL). The same combinations were applied to the cavities in CM: G9, G10, G11, G12, G13, G14, G15, G16, respectively. The fillings were performed with the Sinfony-System (3M/ESPE). After 24 h, the teeth were submitted to thermocycling (2,000 cycles, 5 degrees to 55 degrees C) and load-cycling (50,000 cycles, 50 N). Next, the Caries Detector (Kuraray) was applied to the restoration margins. Images from the proximal margin were evaluated using the Image-Tool 3.0 software. The results were submitted to ANOVA and Tukey's test (alpha=0.05). The mean values (%) for the groups were: EM: G1=46.68, G2=15.53, G3=19.83, G4=27.53; G5=59.49, G6=25.13, G7=34.37, G8=15.20; CM: G9=38.38, G10=23.25, G11=26.97, G12=25.85, G13=37.81, G14=30.62, G15=29.17, G16=20.31. The highest percentages of marginal gap on EM or CM were found in the groups that did not use a liner. It can be concluded that the most appropriate RCT combinations were the groups that used a liner. PMID- 23338261 TI - Effect of plasma welding parameters on the flexural strength of Ti-6Al-4V alloy. AB - The aim of this study was to assess the effect of different plasma arc welding parameters on the flexural strength of titanium alloy beams (Ti-6Al-4V). Forty Ti 6Al-4V and 10 NiCr alloy beam specimens (40 mm long and 3.18 mm diameter) were prepared and divided into 5 groups (n=10). The titanium alloy beams for the control group were not sectioned or subjected to welding. Groups PL10, PL12, and PL14 contained titanium beams sectioned and welded at current 3 A for 10, 12 or 14 ms, respectively. Group NCB consisted of NiCr alloy beams welded using conventional torch brazing. After, the beams were subjected to a three-point bending test and the values obtained were analyzed to assess the flexural strength (MPa). Statistical analysis was carried out by one-way ANOVA and Tukey's HSD test at 0.05 confidence level. Significant difference was verified among the evaluated groups (p<0.001), with higher flexural strength for the control group (p<0.05). No significant differences was observed among the plasma welded groups (p>0.05). The NCB group showed the lowest flexural strength, although it was statistically similar to the PL 14 group (p>0.05). The weld depth penetration was not significantly different among the plasma welded groups (p=0.05). Three representative specimens were randomly selected to be evaluated under scanning electron microcopy. The composition of the welded regions was analyzed by energy dispersive X-ray spectroscopy. This study provides an initial set of parameters supporting the use of plasma welding during fabrication of titanium alloy dental frameworks. PMID- 23338260 TI - Flexural properties, morphology and bond strength of fiber-reinforced posts: influence of post pretreatment. AB - The aim of this study was to assess the influence of surface pretreatments of fiber-reinforced posts on flexural strength (FS), modulus of elasticity (ME) and morphology of these posts, as well as the bond strength (BS) between posts and core material. Fifty-two fiber posts (smooth and serrated) were assigned to 4 groups (n=13): no treatment (control), 10% hydrogen peroxide (HP) for 10 min (HP 10), 24% HP for 1 min (HP-24) and airborne-particle abrasion (Al(2)O(3)). To evaluate FS and ME, a 3-point bending test was performed. Three posts of each group were examined by scanning electron microscopy. Composite resin was used as the core build-up and samples were sectioned to obtain microtensile sticks. Data were analyzed by ANOVA and Tukey's test (alpha=0.05). For FS, significant differences were observed between posts type and surface pretreatment (p<0.05), with the highest means for the smooth posts. Al2O3 provided higher FS than HP-24. Al(2)O(3) promoted higher ME than HP-24 and control. SEM images revealed partial dissolution of the resin matrix in all treated groups. The smooth posts had higher BS and FS than serrated posts (p<0.05). Mechanical properties of the glass fiber posts and the bond strength between posts and composite material were not altered by the surface treatments, except for airborne-particle abrasion that increased the post elastic modulus. PMID- 23338262 TI - Effect of different surface penetrating sealants on the roughness of a nanofiller composite resin. AB - This study evaluated the effectiveness of different sealants applied to a nanofiller composite resin. Forty specimens of Filtek Z-350 were obtained after inserting the material in a 6x3 mm stainless steel mold followed by light activation for 20 s. The groups were divided (n=10) according to the surface treatment applied: Control group (no surface treatment), Fortify, Fortify Plus and Biscover LV. The specimens were subjected to simulated toothbrushing using a 200 g load and 250 strokes/min to simulate 1 week, 1, 3 and 6 months and 1 and 3 years in the mouth, considering 10,000 cycles equivalent to 1 year of toothbrushing. Oral-B soft-bristle-tip toothbrush heads and Colgate Total dentifrice at a 1:2 water-dilution were used. After each simulated time, surface roughness was assessed in random triplicate readings. The data were submitted to two-way ANOVA and Tukey's test at a 95% confidence level. The specimens were observed under scanning electron microscopy (SEM) after each toothbrushing cycle. The control group was not significantly different (p>0.05) from the other groups, except for Fortify Plus (p<0.05), which was rougher. No significant differences (p>0.05) were observed at the 1-month assessment between the experimental and control groups. Fortify and Fortify Plus presented a rougher surface over time, differing from the baseline (p<0.05). Biscover LV did not differ (p>0.05) from the baseline at any time. None of the experimental groups showed a significantly better performance (p>0.05) than the control group at any time. SEM confirmed the differences found during the roughness testing. Surface penetrating sealants did not improve the roughness of nanofiller composite resin. PMID- 23338263 TI - Effect of fluoride solutions on the shear bond strength of orthodontic brackets. AB - The aim of this in vitro study was to evaluate the shear bond strength of brackets after pre-treatment with different fluoride solutions. This study used 48 freshly extracted sound bovine incisors that were randomly assigned to 4 experimental groups (n=12). CG: (control) without treatment; NF: 4 min application of neutral fluoride; APF: application of 1.23% acidulated phosphate fluoride (APF) for 4 min; and SFV: application of 5% sodium fluoride varnish for 6 h. For each group, after surface treatment, prophylaxis of enamel and bracket bonding with Transbond XT composite resin (3M) were performed following the manufacturer's specifications. The shear bond strength was performed with a universal testing machine 24 h after fixing the brackets. The tooth surfaces were analyzed to verify the adhesive remnant index (ARI). Data were analyzed statistically by ANOVA and Tukey's test (alpha=0.05). There was statistically significant difference among the groups (p<0.0001). CG and NF groups presented significantly higher bond strength than APF and SFV. There was no significant difference between CG and NF or between APF and SFV (p>0.05). The analysis of ARI scores revealed that most failures occurred at the enamel-resin interface. It may be concluded that the pre-treatment of enamel with 1.23% APF and 5% SFV prior to fixing orthodontic brackets reduces shear bond strength values. PMID- 23338264 TI - Gray scale inversion in digital image for measurement of tooth length. AB - The aim of this study was to assess the applicability of gray scale inversion in performing digital linear endodontic measurements. Standardized digital images were taken of 40 extracted human permanent single-rooted teeth with K-files size 15 placed at different lengths in the root canal, using the CDR Wireless((r)) digital system. All images were treated with Positive, a digital tool that inverts the grayscale value. Eight radiologists measured the distance between the lower limit of the rubber stop and the tip of the file on both original and positive images. After 15 days, they repeated this procedure in 50% of the image samples. The intra- and inter-examiner agreement was analyzed by intraclass correlation test, and the comparison between the two image groups and the actual lengths by the Student's t-test (alpha=0.05). Intra- and inter-examiner evaluation showed high reproducibility (r>0.95) of both original and positive images. No statistically significant differences (p>0.05) were found between measurements performed on original and positive images, but both differed significantly from the actual lengths (p<0.05). Gray scale inversion has low applicability in measuring endodontic files, since it did not improve the accuracy of measurements. PMID- 23338265 TI - Wilms Tumor 1 protein is not expressed in oral lymphangiomas. AB - Lymphangiomas are benign hamartomatous lesions of lymphatic vessels. Wilms Tumor 1 (WT1) is a transcription factor that is activated in some human neoplasias. WT1 protein expression is observed in endothelial cells during angiogenesis and is a useful marker to distinguish between vascular proliferations and vascular malformations. The purpose of the present study is to report a case series of oral lymphangiomas together with an immunohistochemical investigation of WT1. Seventeen cases of oral lymphangioma were retrieved and reviewed. Immunohistochemical analysis of WT1 protein was performed and pyogenic granuloma samples were used as positive controls. The male/female ratio was 1.125 and most of the lesions occurred in young subjects. While pyogenic granuloma showed positive staining for WT1, the endothelial cells lining the thin-walled dilated lymphatic vessels of lymphangiomas were negative for this protein. The findings strengthen the idea that oral lymphangioma is a vascular malformation characterized by lymphatic dilatation without significant endothelial proliferation. PMID- 23338266 TI - Isolated relapse in the oral cavity of a child with T-lineage acute lymphoblastic leukemia. AB - Despite high cure rates, approximately 20% of patients with acute lymphoblastic leukemia (ALL) have disease relapse. Isolated recurrence in oral cavity is extremely unusual. The aim of this paper is to report a case of an isolated relapse occurred in a child with T-lineage ALL. Clinical picture included swelling and pain in the right upper gingiva of the oral cavity, with no other clinical or hematological alterations. Diagnosis was confirmed by biopsy and immunohistochemical staining. Bone marrow aspiration was normal. Five months later leukemic infiltration of the bone marrow was detected and systemic chemotherapy was reintroduced. This case report highlights the relevance of dental care during and after chemotherapy, not only to treat lesions in the oral cavity resulting from the disease itself or from treatment side effects, but also to detect unusual sites of ALL relapse. PMID- 23338267 TI - Exopolysaccharide matrix of developed Candida albicans biofilms after exposure to antifungal agents. AB - This study aimed to evaluate the effects of fluconazole or nystatin exposure on developed Candida albicans biofilms regarding their exopolysaccharide matrix. The minimal inhibitory concentration (MIC) against fluconazole or nystatin was determined for C. albicans reference strain (ATCC 90028). Poly(methlymethacrylate) resin (PMMA) specimens were fabricated according to the manufacturer's instructions and had their surface roughness measured. Biofilms were developed on specimens surfaces for 48 h and after that were exposed during 24 h to fluconazole or nystatin prepared in a medium at MIC, 10 x MIC or 100 x MIC. Metabolic activity was evaluated using an XTT assay. Production of soluble and insoluble exopolysaccharide and intracellular polysaccharides was evaluated by the phenol-sulfuric method. Confocal laser scanning microscope was used to evaluate biofilm architecture and percentage of dead/live cells. Data were analyzed statistically by ANOVA and Tukey's test at 5% significance level. The presence of fluconazole or nystatin at concentrations higher than MIC results in a great reduction of metabolic activity (p<0.001). At MIC or 10 x MIC, fluconazole showed high amounts of intracellular polysaccharides (p<0.05), but did not affect the exopolysaccharide matrix (p>0.05). The exposure to nystatin also did not alter the exopolysaccharide matrix at all the tested concentrations (p>0.05). Biofilm architecture was not affected by either of the antifungal agents (p>0.05). Nystatin promoted higher proportion of dead cells (p<0.05). It may be concluded that fluconazole and nystatin above the MIC concentration reduced the metabolic activity of C. albicans biofilms; however, they were not able to alter the exopolysaccharide matrix and biofilm architecture. PMID- 23338268 TI - Radioprotective effect of sodium selenite on bone repair in the tibia of ovariectomized rats. AB - This study evaluated protection by selenium (Se) in the bone repair process in ovariectomized rats after irradiation. For such purpose, 80 ovariectomized female Wistar rats were randomly divided into 4 experimental groups: ovariectomized (Ov), Ov/Se, Ov/irradiated (Irr) and Ov/ Se/Irr. A bone defect was created on the tibia of all animals 40 days after ovariectomy. Two days after surgery, only the Ov/Se and Ov/Se/Irr rats received 0.8 mg Se/kg. Three days after surgery, only the Ov/Irr and Ov/Se/Irr rats received 10 Gy of x-rays on the lower limb region. The animals were euthanized at 7, 14, 21 and 28 days after surgery to assess the repair process, which was evaluated by analysis of trabecular bone number (Masson Trichrome) and birefringence analysis (Picrosirius). It was possible to observe a delay in the bone repair process in the ovariectomized/irradiated group and similarity between the ovariectomized, Ov/Se and Ov/Se/Irr groups. In conclusion, sodium selenite exerted a radioprotective effect in the bone repair of tibia of ovariectomized rats without toxicity. PMID- 23338269 TI - Dental students' perceptions about the endodontic treatments performed using NiTi rotary instruments and hand stainless steel files. AB - This study evaluated the perceptions of Brazilian undergraduate dental students about the endodontic treatments performed using NiTi rotary instruments and hand stainless steel. Data were collected using a questionnaire administered to undergraduate dental students enrolled in endodontic disciplines. The students were divided into 3 groups: G1, students who had treated straight canals with SS hand instruments; G2, students who had treated curved canals with SS hand instruments; and G3, students who had treated both straight and curved canals with NiTi rotary instruments. The number of endodontic treatments performed, types of treated teeth, students' learning, time spent, encountered difficulties, quality of endodontic treatment and characteristics of the employed technique were analyzed. There was a 91.3% rate of return for the questionnaires. Mandibular molars were the most frequently treated teeth, followed by maxillary incisors. The Kruskal-Wallis test showed no differences in learning (p=0.528) or in the characteristics of the technique employed (p=0.560) among the three groups. G3 students performed a greater number of endodontic treatments (p<0.001) in a smaller time (p<0.001) than did G1 and G2 students. Difficulties were reported primarily by students in G2 and G3 compared with G1 (p=0.048). The quality of endodontic treatments differed only between G1 and G2 (p=0.045). The use of NiTi rotary instruments should be included in undergraduate dental curriculum, contributing to the increase of patients assisted and consequently to improve the clinical experience of the students. PMID- 23338270 TI - Factors associated with changes in self-reported dentifrice consumption in a Brazilian group from 1996 and 2009. AB - The aim of the study was to determine factors associated with changes in self reported dentifrice consumption in an urban population group over 13 years. This study evaluated two surveys of 671 and 688 households sampled in the urban area of a city from Southern Brazil in 1996 and 2009, respectively. The mother of the family was asked to answer a structured questionnaire about demographics, socioeconomic and behavioral variables. The primary outcome was obtained by questioning "how long does a dentifrice tube last in your house?" The cut-off point of duration was less than 1 month. It was used to determine high consumption of dentifrice (HCD). Associations between HCD and independent variables were evaluated by multivariable Poisson regression. There was a significant decrease of 20% (81.2% to 61.2%) in the prevalence of HCD between 1996 and 2009, resulting in a crude annual decrease of 1.54%. Mother's age, family income, dental assistance, mother's brushing frequency and number of household members that use a toothbrush were significantly associated with HCD independent from the year of survey. The prevalence ratio (PR) of HCD for the year of survey was 0.75, indicating an overall decrease of 25% in the probability of HCD from 1996 to 2009. Probabilities of HCD also decreased over the 13 years among the strata of education, number of household members and reason for choice of dentifrice. It may be concluded that the factors associated with the observed decrease were higher educational levels, larger number of household members and reasons for choosing a dentifrice related to preventive/therapeutic effects. PMID- 23338271 TI - Signs, symptoms, parafunctions and associated factors of parent-reported sleep bruxism in children: a case-control study. AB - Bruxism is the non-functional clenching or grinding of the teeth that may occur during sleep or less commonly in daytime. The aim of this study was to investigate the association between clinical signs and symptoms, parafunctions and associated factors of sleep bruxism in children. A population-based case control study was carried out involving 120 children, 8 years of age, with sleep bruxism and 240 children without sleep bruxism. The sample was randomly selected from public and private schools in the city of Belo Horizonte, MG, Brazil. Groups were matched by gender and social class. The Social Vulnerability Index (SVI) drawn up by the city of Belo Horizonte was employed for social classification. Data collection instruments included clinical forms and pre-tested questionnaires. The diagnosis of sleep bruxism was supported by the American Association of Sleep Medicine (AASM) criteria. The McNemar test, binary and multivariate logistic regression models were used for statistical analysis. The risk factors associated with sleep bruxism included: primary canine wear (OR=2.3 IC 95% 1.2-4.3), biting of objects like pencils or pens (OR=2.0 IC 95% 1.2-3.3) and wake-time bruxism (tooth clenching) (OR=2.3 IC 95% 1.2-4.3). Children that present the parafunctions of object biting and wake-time bruxism were more susceptible to sleep bruxism. PMID- 23338272 TI - A retrospective study of oral manifestations in patients with paracoccidioidomycosis. AB - South American blastomycosis, paracoccidioidomycosis (Pb mycosis) or Lutz disease is an endemically fungal infection in Latin America. It is caused by the dimorphic fungus Paracoccidioides brasiliensis and may cause oral mucosal lesions. The incidence of Pb mycosis oral lesions was evaluated in patients assisted at a Brazilian Dental School's Specialized Oral Diagnosis Service with special focus on the different clinical forms of these lesions, its location, patients' occupation, deleterious habits, and diagnosis methodology. Students' and professionals' initial diagnoses were compared with the definitive diagnosis. Lesions were detected 31 cases (18 patients). The results show that 88.8% of the patients were male with a mean age of 50 years and 39% work(ed) with activities related to agriculture. As much as 88.9% were smokers and 72.2% were alcohol users. Exfoliative cytology was performed in 66.6% of the patients. Oral mucosa (30%), gingiva (16.6%) and lips 16.6% were the most common sites of Pb mycosis oral lesions. Comparing the initial with the definitive diagnosis made by the professionals their accuracy was 33% (6 out of 18 patients). Students' diagnosis was more accurate demonstrating 72.5% of initial correct diagnosis (13 out of 18). Statistical analysis by ANOVA (alpha=0.05, SPSS WIN) demonstrated a significant difference between the diagnosis of Pb mycosis made by students and professionals when considering initial diagnosis and final diagnosis (after histopathological analysis) (p=0.25). Incisional biopsy and exfoliate cytology are efficient for an early diagnosis of this disease in mouth. Students' training in diagnosis of oral pathologies to recognize lesions is urgent to improve public health. PMID- 23338273 TI - Combination of orthodontic movement and periodontal therapy for full root coverage in a Miller class III recession: a case report with 12 years of follow up. AB - One of the main purposes of mucogingival therapy is to obtain full root coverage. Several treatment modalities have been developed, but few techniques can provide complete root coverage in a class III Miller recession. Thus, the aim of this case report is to present a successful clinical case of a Miller class III gingival recession in which complete root coverage was obtained by means of a multidisciplinary approach. A 17-year-old Caucasian female was referred for treatment of a gingival recession on the mandibular left central incisor. The following procedures were planned for root coverage in this case: free gingival graft, orthodontic movement by means of alignment and leveling and coronally advanced flap (CAF). The case has been followed up for 12 years and the patient presents no recession, no abnormal probing depth and no bleeding on probing, with a wide attached gingiva band. A compromised tooth with poor prognosis, which would be indicated for extraction, can be treated by orthodontic movement and periodontal therapy, with possibility of 100% root coverage in some class III recessions. PMID- 23338274 TI - Eruption sequestrum--case report and histopathological findings. AB - Eruption sequestrum is an uncommon disturbance in eruption and consists of small fragments of calcified tissue overlying the crowns of erupting permanent molar teeth, especially at the time of eruption of the mandibular first molars. This paper reports a case of unilateral eruption sequestrum in a 7-year-old Brazilian boy and describes its histopathological findings. A white small fragment, 0.5 cm in diameter, with hard consistency, irregular shape and located on the occlusal surface of the erupting mandibular left first molar was excised. Microscopic examination revealed large trabeculae with empty lacunae and a minimal amount of existing spongy bone consisting of acute inflammatory cells (neutrophils). Signs of necrosis were found on the periphery. The histological analysis was consistent with non-vital bone and the diagnosis of eruption sequestrum was established. Clinical and radiographic follow-up visits scheduled at short intervals and then every 6 months revealed normal postoperative conditions. PMID- 23338275 TI - Open bite: diagnosis, treatment and stability. AB - Open bite has fascinated Orthodontics due to the difficulties regarding its treatment and maintenance of results. This anomaly has distinct characteristics that, in addition to the complexity of multiple etiological factors, have aesthetic and functional consequences. Within this etiological context, several types of mechanics have been used in open bite treatment, such as palatal crib, orthopedic forces, occlusal adjustment, orthodontic camouflage with or without extraction, orthodontic intervention using mini-implants or mini-plates, and even orthognathic surgery. An accurate diagnosis and etiological determination are always the best guides to establish the objectives and the ideal treatment plan for such a malocclusion. This report describes two cases of open bite. At the end of the treatment, both patients had their canines and molars in Class I occlusion, normal overjet and overbite, and stability during the posttreatment period. PMID- 23338276 TI - Bilateral asymptomatic fibrous-ankylosis of the temporomandibular joint associated with rheumatoid arthritis: a case report. AB - The American Academy of Orofacial Pain (AAOP) defines ankylosis of the temporomandibular joint (TMJ) as a restriction of movements due to intracapsular fibrous adhesions, fibrous changes in capsular ligaments (fibrous-ankylosis) and osseous mass formation resulting in the fusion of the articular components (osseous-ankylosis). The clinical features of the fibrous-ankylosis are severely limited mouth-opening capacity (limited range of motion during the opening), usually no pain and no joint sounds, marked deflection to the affected side and marked limitation of movement to the contralateral side. A variety of factors may cause TMJ ankylosis, such as trauma, local and systemic inflammatory conditions, neoplasms and TMJ infection. Rheumatoid arthritis (RA) is one of the systemic inflammatory conditions that affect the TMJ and can cause ankylosis. The aim of this study is to present a case of a female patient diagnosed with bilateral asymptomatic fibrous-ankylosis of the TMJ associated with asymptomatic rheumatoid arthritis. This case illustrates the importance of a comprehensive clinical examination and correct diagnosis of an unusual condition causing severe mouth opening limitation. PMID- 23338277 TI - Prostaglandin E2 promotes liver cancer cell growth by the upregulation of FUSE binding protein 1 expression. AB - Liver cancer is a common human cancer with a high mortality rate and currently there is no effective chemoprevention or systematic treatment. Recent evidence suggests that prostaglandin E(2) (PGE(2)) plays an important role in the occurrence and development of liver cancer. However, the mechanisms through which PGE(2) promotes liver cancer cell growth are not yet fully understood. It has been reported that the increased expression of FUSE-binding protein 1 (FBP1) significantly induces the proliferation of liver cancer cells. In this study, we report that PGE(2) promotes liver cancer cell growth by the upregulation of FBP1 protein expression. Treatment with PGE2 and the E prostanoid 3 (EP3) receptor agonist, sulprostone, resulted in the time-dependent increase in FBP1 protein expression; sulprostone increased the viability of the liver cancer cells. The protein kinase A (PKA) inhibitor, H89, and the adenylate cyclase (AC) inhibitor, SQ22536, inhibited the cell viability accelerated by sulprostone. By contrast, the Gi subunit inhibitor, pertussis toxin (PTX), exhibited no significant effect. Treatment with PGE(2) and sulprostone caused a decrease in JTV1 protein expression, blocked the binding of JTV1 with FBP1, which served as a mechanism for FBP1 degradation, leading to the decreased ubiquitination of FBP1 and the increase in FBP1 protein expression. Furthermore, H89 and SQ22536 prevented the above effects of JTV1 and FBP1 induced by PGE(2) and sulprostone. These findings indicate that the EP3 receptor activated by PGE(2) may couple to Gs protein and activate cyclic AMP (cAMP)-PKA, downregulating the levels of JTV1 protein, consequently inhibiting the ubiquitination of FBP1 and increasing FBP1 protein expression, thus promoting liver cancer cell growth. These observations provide new insights into the mechanisms through which PGE(2) promotes cancer cell growth. PMID- 23338278 TI - Lentiviral-mediated RNA interference of lipoprotein-associated phospholipase A2 ameliorates inflammation and atherosclerosis in apolipoprotein E-deficient mice. AB - Lipoprotein associated phospholipase A2 (Lp-PLA2) overexpression is implicated in athero-sclerosis. In the present study, we evaluated the effects of lentiviral mediated RNA interference (RNAi) of Lp-PLA2 on inflammation and atherosclerosis in apolipoprotein E-deficient mice. Apolipoprotein E-deficient mice were randomly allocated to control and experimental groups, and constrictive collars were used to induce plaque formation. Eight weeks after surgery, the lentiviral-mediated RNAi construct was used to silence expression of Lp-PLA2. Control and experimental lentivirus was transfected directly into carotid plaques or administered systemically. Tissues were collected for analysis 7 weeks after transfection. Inflammatory gene expression in the plasma and atherosclerotic lesions was then determined at the mRNA and protein levels. We observed no differences in body weight and plasma lipid levels at the end of the investigation. However, the expression levels of Lp-PLA2 and pro-inflammatory cytokines were significantly reduced in the RNAi groups, compared to the controls, whereas the plasma concentration of anti-inflammatory cytokines was markedly increased. Moreover, our results demonstrated a significant reduction in plaque area and lipid content, as well as a rise in collagen content following RNAi treatment. Importantly, when comparing the two methods of viral delivery, we found that transluminal local transfection exhibited enhanced improvement of plaque stability as compared to systemic administration. Inhibition of Lp-PLA2 by lentiviral-mediated RNAi ameliorates inflammation and atherosclerosis in apolipoprotein E-deficient mice. In addition, transluminal local delivery of Lp PLA2 shRNA is superior to systemic administration for stabilizing atherosclerotic plaques. PMID- 23338281 TI - Analysis of oncology research from 2001 to 2010: a scientometric perspective. AB - Over the past half-century, the incidence of tumours has increased, resulting in cancer becoming one of the most lethal diseases in humans. In the present study, we elucidated the status of oncology research from 2001 to 2010. Studies published in 30 representative oncology journals were retrieved from the Web of Science (2001-2010) to compose our dataset. Knowledge domain visualisation, co citation analysis and social network analysis methods were used. By mapping the oncology research performed from 2001 to 2010, we identified the primary research centres, including the top 20 institutions and countries and the 4 major oncology research fronts: i) the mechanism of abnormal oncogene expression; ii) tumour metastasis and angiogenesis; iii) the relationship between cancer cells and apoptosis; and iv) tumour vaccines. We also identified the 36 most collaborative academic communities, and multiple myeloma, angiogenesis and acute lymphocytic leukaemia were found to be the focuses of collaborative research in oncology from 2001 to 2010. Over the past 10 years, America has led oncology research, while China is the sole developing country to be ranked in the top 10. Analyses of the main research centres and forefronts may assist researchers in addressing these forefronts and ascertaining the developing trends in oncology. Analysis of the academic communities performing oncology research may provide scientific evidence and suggestions for policymakers to select the most prolific academic groups and leaders and to effectively manage and finance future oncology research. These selected groups and individuals will carry out additional joint undertakings and solve complex problems encountered in oncology research. PMID- 23338282 TI - Multiple sclerosis in 2012: Novel therapeutic options and drug targets in MS. AB - 2012 witnessed important developments for multiple sclerosis, including successful phase III trials of novel oral therapeutics and identification of the potassium channel KIR4.1 as an autoimmune target. Additionally, the lung was highlighted as an important site for immune-cell programming, and the relevance of a TNF receptor variant was clarified. PMID- 23338285 TI - Dementia in 2012: Further insights into Alzheimer disease pathogenesis. AB - In 2012, studies of autosomal dominant Alzheimer disease (AD), late-onset AD, and a rare genetic mutation of amyloid precursor protein provided support for the critical role of amyloid in AD pathogenesis. Increasing evidence implicated cell to-cell transmission in the spread of tau and amyloid, highlighting novel targets for therapeutic intervention. PMID- 23338289 TI - E-care as craftsmanship: virtuous work, skilled engagement, and information technology in health care. AB - Contemporary health care relies on electronic devices. These technologies are not ethically neutral but change the practice of care. In light of Sennett's work and that of other thinkers (Dewey, Dreyfus, Borgmann) one worry is that "e-care"- care by means of new information and communication technologies--does not promote skilful and careful engagement with patients and hence is neither conducive to the quality of care nor to the virtues of the care worker. Attending to the kinds of knowledge involved in care work and their moral significance, this paper explores what "craftsmanship" means in the context of medicine and health care and discusses whether today the care giver's craftsmanship is eroded. It is argued that this is a real danger, especially under modern conditions and in the case of telecare, but that whether it happens, and to what extent it happens, depends on whether in a specific practice and given a specific technology e carers can develop the know-how and skill to engage more intensely with those under their care and to cooperate with their co-workers. PMID- 23338283 TI - Eye movements in patients with neurodegenerative disorders. AB - The neural pathways and brain regions involved in eye movements during ocular fixation and gaze control include the cerebrum, brainstem and cerebellum, and abnormal eye movements can indicate the presence of neurodegeneration. In some patients, oculomotor signs are key to making a diagnosis. Careful clinical examination of eye movements in patients with neurodegenerative disorders is, therefore, an invaluable adjunct to neurological and cognitive assessments. Eye movement recordings in the laboratory are generally not necessary for diagnostic purposes, but can be a useful addition to the clinical examination. Laboratory recordings of eye movements can provide valuable information about disease severity, progression or regression in neurodegenerative disease, and hold particular promise for objective evaluation of the efficacy of putative neuroprotective and neurorestorative therapies. For example, aspects of saccade performance can be tested to probe both motor and cognitive aspects of oculomotor behaviour. This Review describes the oculomotor features of the major age-related movement disorders, including Parkinson disease, Huntington disease, dementia and other neurodegenerative disorders. Findings in presymptomatic individuals and changes associated with disease progression are discussed. PMID- 23338290 TI - Relationship of aspirin use with age-related macular degeneration: association or causation?: comment on "The association of aspirin use with age-related macular degeneration". PMID- 23338291 TI - RuO2/TiSi2/graphene composite for enhanced photocatalytic hydrogen generation under visible light irradiation. AB - A novel composite composed of TiSi(2), graphene and RuO(2) nanoparticles was fabricated by a one-pot deposition method using reduced graphene oxide (RGO) as a supporting matrix and RuCl(3) as the RuO(2) precursor. The resulting RuO(2)/TiSi(2)/RGO composite was characterized by scanning electron microscopy, X ray diffraction, Fourier transform infrared spectra, X-ray photoelectron spectroscopy, UV-vis diffuse reflectance spectra, photoelectrical response and electrochemical impedance spectra. The results indicated that the three components in the composite were effectively contacted, thus facilitating the photogenerated charges transfer and separation through multiple routes. By using the composite as a photocatalyst for visible-light water splitting the average hydrogen production rate could reach 97.5 MUmol h(-1) g(-1), which is higher than that from RuO(2)/TiSi(2) and pure TiSi(2) systems under the same conditions. PMID- 23338476 TI - S genotyping in Japanese plum and sweet cherry by allele-specific hybridization using streptavidin-coated magnetic beads. AB - KEY MESSAGE: We report a rapid and reliable method for S genotyping of Rosaceae fruit trees, which would to be useful for successful planting of cross-compatible cultivars in orchards. Japanese plum (Prunus salicina) and sweet cherry (Prunus avium), belonging to the family Rosaceae, possess gametophytic self incompatibility controlled by a single polymorphic locus containing at least two linked genes, S-RNase and SFB (S-haplotype-specific F-box gene). For successful planting of cross-compatible cultivars of Rosaceae fruit trees in commercial orchards, it is necessary to obtain information on S genotypes of cultivars. Recently, a method of dot-blot analysis utilizing allele-specific oligonucleotides having sequences of SFB-HVa region has been developed for identification of S haplotypes in Japanese plum and sweet cherry. However, dot blot hybridization requires considerable time and skill for analysis even of a small number of plant samples. Thus, a quick and efficient method for S genotyping was developed in this study. In this method, instead of a nylon membrane used for dot-blot hybridization, streptavidin-coated magnetic beads are used to immobilize PCR products, which are hybridized with allele-specific oligonucleotide probes. Our improved method allowed us to identify 10 S haplotypes (S-a, S-b, S-c, S-d, S-e, S-f, S-h, S-k, S-7 and S-10) of 13 Japanese plum cultivars and 10 S haplotypes (S-1, S-2, S-3, S-4, S-4', S-5, S-6, S-7, S-9 and S-16) of 13 sweet cherry cultivars utilizing SFB or S-RNase gene polymorphism. This method would be suitable for identification of S genotypes of a small number of plant samples. PMID- 23338477 TI - Rewriting the bacterial glycocalyx via Suzuki-Miyaura cross-coupling. AB - Suzuki-Miyaura cross-coupling has been used to couple novel carbohydrate-based boronic acids, site-selectively, to the surface of E. coli at an unnatural amino acid. In this way, benign metal-catalyzed cellular switching allowed modulation of interactions with biomolecular partners via prokaryotic O-glycosylation mimics. PMID- 23338479 TI - Asymmetric Michael/cyclization tandem reaction of 4-hydroxycoumarin with beta nitroalkenes catalyzed by chiral bifunctional thioureas. AB - The first asymmetric Michael/cyclization tandem reaction of 4-hydroxycoumarin with nitroolefins catalyzed by chiral bifunctional thioureas was reported and 2,3 dihydrofuro[3,2-c]-coumarin adducts have been obtained in moderate yields (53 75%) and good enantioselectivities (64-90% ee). PMID- 23338480 TI - Development of Proteasome Inhibitors as Therapeutic Drugs. AB - The proteasome is a multi-unit enzyme complex found in the cytoplasm and nucleus of all eukaryotic cells and is responsible for degradation of unneeded or damaged intracellular proteins by proteolysis, a chemical reaction that breaks peptide bonds. Proteasome inhibition presents a promising approach to cancer therapy by targeting the proteasome function in tumor cells. Delineating the success of bortezomib in the treatment of multiple myeloma and mantle cell lymphoma, this review explores various proteasome inhibitors, currently in development, as molecular targeting agents in the fight against cancer. Proteasome inhibitors can be used alone or in combination with other conventional cancer therapies to sensitize tumor cells to cell death by various mechanisms and improve therapeutic benefits. PMID- 23338478 TI - Gender specific effect of psychological stress and cortisol reactivity on adolescent risk taking. AB - The purpose of this study was to evaluate how psychological stress, gender and cortisol response to stress relate to risk behavior among 132 14-18 year old adolescents. Participants completed a laboratory based risk task prior to and immediately after a computerized psychological stress task, and salivary cortisol was collected from pre-stress to 60 min following initial stress exposure. Results indicate that adolescent boys (n = 59) and girls (n = 73) demonstrate different patterns of risk taking (RT) in response to stress, such that boys evidenced an increase in RT following stress exposure, whereas girls evidenced a decrease in RT. In addition, a gender by cortisol interaction demonstrated that for boys, both a smaller total cortisol output (AUCg) and peak cortisol response to stress (PC) was associated with greater stress-induced RT. Both cortisol measures were unrelated to stress-induced RT among girls. Taken together, data suggest that among boys, a blunted cortisol response to stress underlies an increase in risk taking in the context of psychological stress. Further research with an additional behavioral stress task is needed prior to drawing conclusions regarding the relation between female gender, cortisol response to stress, and risk taking in the context of psychological stress. PMID- 23338481 TI - Clinical implementations of preoperative computed tomography lymphography in gastric cancer: a comparison with dual tracer methods in sentinel node navigation surgery. AB - BACKGROUND: Current sentinel node (SN) detection techniques require a learning period and tracers have many disadvantages for practical use. The purpose of this study was to evaluate the feasibility of preoperative computed tomography (CT) lymphography using lipiodol for detecting SNs in gastric cancer. METHODS: A total of 24 patients who underwent laparoscopic surgery for early gastric cancer were enrolled in this study. Noncontrast CT images were obtained 1-2 h after endoscopic submucosal peritumoral injection of 1 mL of lipiodol the day before surgery. The final sentinel basins (SBs) were decided by the dual tracer method (indocyanine green plus (99m)Tc-antimony sulfur colloid) during laparoscopic gastrectomy. SN detection rate by preoperative CT lymphography using lipiodol and agreement between CT lymphography versus dual tracer method were evaluated. The agreement was confirmed with soft X-ray radiography of detected SBs. RESULTS: Technical failure of endoscopic lipiodol injection occurred in one patient. SNs were successfully detected in the remaining 23 patients (95.8 %), whereas the intraoperative SB detection rate using the dual method was 100 %. The agreement rate, defined as the concordance between two methods or inclusion of SNs detected by CT lymphography in SBs by the dual tracer method, was 87 %. CONCLUSIONS: Our initial experience of CT lymphography using lipiodol shows good potential in predicting SBs of gastric cancer preoperatively. However, SN detection by CT lymphography and the dual method should be applied complementarily in gastric cancer because discrepancies between these methods occur. PMID- 23338482 TI - Wound complications after inguinal lymph node dissection for melanoma: is ACS NSQIP adequate? AB - BACKGROUND: In the treatment of melanoma, inguinal lymph node dissection (ILND) is the standard of care for palpable or biopsy-proven lymph node metastases. Wound complications occur frequently after ILND. In the current study, the multicenter American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) was utilized to examine the frequency and predictors of wound complications after ILND. METHODS: Patients with cutaneous melanoma who underwent superficial and superficial with deep ILND from 2005-2010 were selected from the ACS NSQIP database. Standard ACS NSQIP 30-day outcome variables for wound occurrences-superficial surgical site infection (SSI), deep SSI, organ space SSI, and disruption-were defined as wound complications. RESULTS: Of 281 total patients, only 14 % of patients had wound complications, a rate much lower than those reported in previous single institution studies. In a multivariable model, superficial with deep ILND, obesity, and diabetes were significantly associated with wound complications. There was no difference in the rate of reoperation in patients with and without wound complications. CONCLUSIONS: ACS NSQIP appears to markedly underreport the actual incidence of wound complications after ILND. This may reflect the program's narrow definition of wound occurrences, which does not include seroma, hematoma, lymph leak, and skin necrosis. Future iterations of the ACS NSQIP for Oncology and procedure-specific modules should expand the definition of wound occurrences to incorporate these clinically relevant complications. PMID- 23338483 TI - Infection with hepatitis C virus is an adverse prognostic factor after liver resection for early-stage hepatocellular carcinoma: implications for the management of hepatocellular carcinoma eligible for liver transplantation. AB - INTRODUCTION: Recent data support liver resection (LR) as first-line approach in patients with preserved liver function who have resectable/transplantable hepatocellular carcinoma (HCC). This study was designed to evaluate the outcome of LR in patients with transplantable HCC. METHODS: Between 1998 and 2009, 75 patients (65 men, mean age 61 +/- 11 years) with HCC eligible for liver transplantation (LT) underwent LR. The underlying hepatic disease was related to hepatitis C (HCV) in 30 (40 %) patients, hepatitis B (HBV) in 15 (20 %) patients, alcohol abuse in 26 patients (36 %) and other in 10 patients (13 %). Fifty-five (73 %) patients had cirrhosis. Intermittent clamping of the hepatic pedicle was used in 41 (55 %) patients. Treatment of recurrence by salvage LT was performed in 6 (8 %) patients. RESULTS: Operative morbidity and mortality rates were 37 and 5 % respectively. At 1, 3, and 5 years, overall (OS) and disease-free (DFS) survival rates were 81, 69,55 and 56, 31, and 21 %, respectively. On multivariate analysis, HCV infection was the only independent factor associated with decreased OS (p = 0.02). On multivariate analysis, HCV infection (p = 0.05) and intermittent hepatic pedicle clamping (p = 0.003) were associated with decreased DFS. The 1-, 3-, and 5-year OS and DFS rates in patients with HCV-related HCC were 69, 53, 38 and 50, 18, and 9% respectively. CONCLUSIONS: Overall and disease free survival after liver resection in patients with HCV-related HCC and preserved liver function is poor. Primary LT should be offered to these patients. PMID- 23338484 TI - The bone tissue compatibility of a new Ti35Nb2Ta3Zr alloy with a low Young's modulus. AB - Titanium (Ti) alloys of the beta-type are highly attractive metallic materials for biomedical applications due to their low elastic modulus, high corrosion resistance and notable biocompatibility. A new beta-type Ti35Nb2Ta3Zr alloy with a low Young's modulus of approximately 48 GPa was previously fabricated. In the present study, the biocompatibility of this alloy was evaluated. In an in vitro assay, the Ti35Nb2Ta3Zr alloy did not markedly affect the adhesion of MG63 osteoblast cells, but it increased their proliferation, alkaline phosphatase (ALP) activity, calcium deposition and mRNA expression of osteogenic genes (i.e., ALP, osteocalcin, osteopontin). In an in vivo study, no marked histological differences were observed between the new bone formed on the surface of Ti35Nb2Ta3Zr and that formed on the surface of control Ti6Al4V rods placed in the medullary canal of rabbit femurs. Additionally, no significant differences were observed in the failure load of Ti35Nb2Ta3Zr and Ti6Al4V in pull-out tests. In conclusion, the Ti35Nb2Ta3Zr alloy with a lower elastic modulus closer to that of human bone has significant bone tissue compatibility equal to that of Ti6Al4V, which has been widely used in orthopedic applications. PMID- 23338485 TI - Overexpressed miR-301a promotes cell proliferation and invasion by targeting RUNX3 in gastric cancer. AB - BACKGROUND: MicroRNAs can promote or suppress the evolution of malignant behaviors by regulating multiple targets. We aimed to determine the expression of miR-301a recently screened in gastric cancer, to investigate the biological effects of miR-301a and to identify the specific miR-301a target gene. METHODS: Quantitative real-time RT-PCR was used to test miR-301a expression. Functional effects were explored by a water-soluble tetrazolium salt assay, a colony formation assay in soft agar, a migration assay, an invasion assay and cytometry used to determine apoptosis and cell cycle. Nude mice were inoculated subcutaneously by retrovirus-mediated stably expressed SGC-7901 cells. The target gene was determined by bioinformatic algorithms, dual luciferase reporter assay and Western blot. RESULTS: Firstly, we found that miR-301a was significantly upregulated both in cells and tissues of gastric cancer. The expression level of miR-301a was inversely correlated with tumor differentiation of gastric cancer tissues. Secondly, miR-301a promoted cell growth, soft agar clonogenicity, migration, invasion, and decreased cell apoptosis induced by cisplatin in vitro, while blockage of miR-301a reduced the percentage of G2/M phase cells via flow cytometry in gastric cancer cells. Ectopic expression of miR-301a enhanced the subcutaneous tumorigenesis in vivo. Finally, miR-301a directly downregulated RUNX3 expression post-transcriptionally in gastric cancer. CONCLUSION: Our results demonstrate that miR-301a plays important roles in the development of gastric cancer. PMID- 23338486 TI - Combination therapy with a nucleos(t)ide analogue and interferon for chronic hepatitis B: simultaneous or sequential. AB - Currently available antiviral treatment for chronic hepatitis B virus infection can be divided into two classes of therapeutic agents: nucleos(t)ide analogues (NAs) and interferon (IFN). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy; the advantages of IFN include a finite course of treatment, absence of drug resistance, and an opportunity to obtain a post-treatment durable response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment. Here, we have reviewed previous reports of either simultaneous or sequential combination therapy with NA and IFN for chronic hepatitis B patients. In previous studies comparing the lamivudine/IFN combination and lamivudine monotherapy in a finite course, combination therapy was associated with higher rates of sustained post-treatment response and lower rates of drug resistance than lamivudine monotherapy. However, NAs such as lamivudine are generally administered indefinitely because of high rates of post-treatment relapse. In addition, concern for drug resistance has decreased significantly with newer, high-potency NAs even when administered alone. In previous studies comparing the lamivudine/IFN combination and IFN monotherapy, the combination therapy showed greater on-treatment viral suppression, but no difference was observed in the post-treatment sustained response. Thus, whether combination therapy confers an additional benefit compared to monotherapy for treating chronic hepatitis B remains unclear. The efficacy of IFN in combination with a more potent NA, such as entecavir or tenofovir, remains to be comprehensively evaluated. PMID- 23338487 TI - Aprepitant plus granisetron and dexamethasone for prevention of chemotherapy induced nausea and vomiting in patients with gastric cancer treated with S-1 plus cisplatin. AB - BACKGROUND: We aimed to evaluate the efficacy of a new combination antiemetic therapy comprising aprepitant, granisetron, and dexamethasone in gastric cancer patients undergoing chemotherapy with cisplatin and S-1. METHODS: Gastric cancer patients scheduled to receive their first course of chemotherapy with cisplatin (60 mg/m(2)) and S-1 (80 mg/m(2)) were treated with a new combination antiemetic therapy aprepitant, granisetron, and dexamethasone on day 1; aprepitant and dexamethasone on days 2 and 3; and dexamethasone on day 4. The patients reported vomiting, nausea, use of rescue therapy, and change in the amount of diet intake, and completed the Functional Living Index-Emesis (FLIE) questionnaire. The primary endpoint was complete response (CR; no emesis and use of no rescue antiemetics) during the overall study phase (0-120 h after cisplatin administration). The secondary endpoints included complete protection (CP; CR plus no significant nausea); change in the amount of diet intake; and the impact of chemotherapy-induced nausea and vomiting (CINV) on daily life during the overall, acute (0-24 h), and delayed (24-120 h) phases. RESULTS: Fifty-three patients were included. CR was achieved in 88.7, 98.1, and 88.7% of patients in the overall, acute, and delayed phases, respectively. The corresponding rates of CP were 67.9, 96.2, and 67.9%. Approximately half of the patients had some degree of anorexia. FLIE results indicated that 79.5% of patients reported "minimal or no impact of CINV on daily life". CONCLUSIONS: Addition of aprepitant to standard antiemetic therapy was effective in gastric cancer patients undergoing treatment with cisplatin and S-1. PMID- 23338488 TI - Ablative margin states by magnetic resonance imaging with ferucarbotran in radiofrequency ablation for hepatocellular carcinoma can predict local tumor progression. AB - BACKGROUND: Our aim was to determine how well ablative margin (AM) grading assessed by magnetic resonance imaging (MRI) with ferucarbotran administered prior to radiofrequency ablation (RFA) predicts local tumor progression in comparison with enhanced computed tomography (CT). METHODS: 101 hepatocellular carcinomas were treated by RFA after ferucarbotran administration. We performed T2*-weighted MRI after 1 week and enhanced CT after 1 month. The assessment was categorized in three grades: AM(+): high-intensity area with continuous low intensity rim; AM zero: high-intensity area with discontinuous low-intensity rim; and AM(-): high-intensity area extending beyond the low-intensity rim. RESULTS: AM(+), AM zero, AM(-) and indeterminable were found in 47, 36, 8 and 10 nodules, respectively. The overall agreement rate between MRI and enhanced CT for the diagnosis of AM was 71.3%. The kappa coefficient was 0.523 (p < 0.001), indicating moderate agreement. Multivariate logistic regression showed that a significant factor for the achievement of AM(+) on MRI was only segment location (odds ratio 5.9, non-segment 4 + 8 vs. segment 4 + 8). The cumulative local tumor progression rates (4.4, 7.6, and 7.6% in 1, 2, and 3 years) in 47 AM(+) nodules were significantly lower than those (13.9, 33.4, and 41.8% in 1, 2, and 3 years) in 36 AM zero nodules. A multivariate Cox proportional hazards model identified contiguous vessels (odds ratio 12.0) and AM(+) on MRI (odds ratio 0.19) as independent factors for local tumor progression. CONCLUSION: AM assessment by MRI using ferucarbotran can predict local tumor progression after RFA and enable early and less invasive diagnosis. PMID- 23338489 TI - Potent growth-inhibitory effect of a dual cancer-specific oncolytic adenovirus expressing apoptin on prostate carcinoma. AB - Apoptin is a chicken anemia virus-derived, p53-independent, bcl-2-insensitive apoptotic protein with the ability to specifically induce apoptosis in various human tumor cells, but not in normal cells. To explore the use of apoptin in tumor gene therapy, we assessed a recombinant adenovirus expressing the apoptin protein (Ad-hTERTp-E1a-Apoptin) in order to determine its lethal and growth inhibitory effects on PC-3 and RM-1 cells in vitro and its antitumor effect on solid tumors in vivo. 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), acridine orange (AO)/ethidium bromide (EB), 4'-6-diamidino-2 phenylindole (DAPI), and Annexin V assays showed that Ad-hTERTp-E1a-Apoptin inhibited the proliferation of PC-3 and RM-1 cells in vitro by inducing apoptosis of prostate cancer cells, and that this inhibitory effect was dose and time dependent. In the animal models, Ad-hTERTp-E1a-Apoptin significantly inhibited tumor growth and extended the lifespan of animals. Experimental results indicate that Ad-hTERTp-E1a-Apoptin has a potential application in tumor gene therapy. PMID- 23338491 TI - [Participatory potential and deliberative function: a debate on broadening the scope of democracy through the health councils]. AB - This article reflects upon the relation between democracy and health councils. It seeks to analyze the councils as a space for broadening the scope of democracy. First, some characteristics and principles of the liberal democratic regime are presented, with an emphasis on the minimalist and procedural approach of decision making. The fragilities of the representative model and the establishment of new relations between the Government and society are then discussed in light of the new social grammar and the complexity of the division between governmental and societal responsibilities. The principles of deliberative democracy and the idea of substantive democracy are subsequently presented. Broadening the scope of democracy is understood not only as the guarantee of civil and political rights, but also especially, of social rights. Lastly, based on discussion of the participation and deliberation categories, the health councils are analyzed as potential mechanisms for broadening the scope of democracy. PMID- 23338492 TI - [Is a second reform of primary health care in Spain necessary?]. AB - Created in 1986, the Spanish National Health System adopted Primary Health Care (PHC) as one of its building blocks. Since the beginning, the Spanish PHC model has been the subject of both praise and criticism. Nowadays, a crisis in public policy funding--including health funding policies--is resurrecting old debates and raising new ones. This paper analyzes the data available about the degree of acceptance of PHC from the perspective of Spanish citizens as well as data about the debate produced in the last five years by politicians, patients and health workers. At the end of the paper the authors seek to draw some conclusions based on the commonly acknowledged strengths and weakness of the PHC model, which decision-makers ought to take into consideration in order to avoid mistakes caused by improvised decisions elicited by the requirements of the moment. PMID- 23338490 TI - Investigating efficacy of two brief mind-body intervention programs for managing sleep disturbance in cancer survivors: a pilot randomized controlled trial. AB - PURPOSE: After completing treatment, cancer survivors may suffer from a multitude of physical and mental health impairments, resulting in compromised quality of life. This exploratory study investigated whether two mind-body interventions, i.e., Mind-Body Bridging (MBB) and Mindfulness Meditation (MM), could improve posttreatment cancer survivors' self-reported sleep disturbance and comorbid symptoms, as compared to sleep hygiene education (SHE) as an active control. METHODS: This randomized controlled trial examined 57 cancer survivors with clinically significant self-reported sleep disturbance, randomly assigned to receive MBB, MM, or SHE. All interventions were conducted in three sessions, once per week. Patient-reported outcomes were assessed via the Medical Outcomes Study Sleep Scale and other indicators of psychosocial functioning relevant to quality of life, stress, depression, mindfulness, self-compassion, and well-being. RESULTS: Mixed effects model analysis revealed that mean sleep disturbance symptoms in the MBB (p = .0029) and MM (p = .0499) groups were lower than in the SHE group, indicating that both mind-body interventions improved sleep. In addition, compared with the SHE group, the MBB group showed reductions in self reported depression symptoms (p = .040) and improvements in overall levels of mindfulness (p = .018), self-compassion (p = .028), and well-being (p = .019) at postintervention. CONCLUSIONS: This study provides preliminary evidence that brief sleep-focused MBB and MM are promising interventions for sleep disturbance in cancer survivors. Integrating MBB or MM into posttreatment supportive plans should enhance care of cancer survivors with sleep disturbance. Because MBB produced additional secondary benefits, MBB may serve as a promising multipurpose intervention for posttreatment cancer survivors suffering from sleep disturbance and other comorbid symptoms. IMPLICATIONS FOR CANCER SURVIVORS: Two brief sleep focused mind-body interventions investigated in the study were effective in reducing sleep disturbance and one of them further improved other psychosocial aspects of the cancer survivors' life. Management of sleep problems in survivors is a high priority issue that demands more attention in cancer survivorship. PMID- 23338493 TI - [Making progress in the use of health policies and practices informed by evidence: the Piripiri-Piaui experience]. AB - Evidence-informed decision making (EIDM) can optimize health services and systems. EIDM involves defining problems, identifying measures to tackle them, assessing the quality of global and local evidence and translating it for the main stakeholders in line with social values and laws. Brazil encourages the use of EIDM in health policy in Piripiri, a municipality of 61,840 inhabitants in the country's poorest region, and launched Brazil's first Evidence Use in Health Care (NEv) center in 2010. The development and preliminary results of the NEv center are reported and its vision, composition, mandate, and activities are presented. The NEv center experience has the support of the Evidence-Informed Policy Network, the Latin American and Caribbean Center of Information on Health Sciences and federal and municipal governments. The decentralization of financing and the provision of healthcare services, the expansion of EIDM in management, and the local political context illustrate the progress of the experiment. Its activities include the production and dissemination of deliberative briefs and dialogues with opinion shapers, workers and health service users. Monitoring and evaluation are underway and the results will help to broaden the scale of activities in Brazil and abroad. PMID- 23338494 TI - [Quality of care in the family healthcare units in the city of Recife: user perception]. AB - This study seeks to assess user perception regarding the quality of care in Family Health Units in Recife. It is a descriptive cross-sectional study adopting a quantitative approach. The survey was conducted in Recife and 939 users were interviewed, being predominantly young adults, female, married, housewives with low levels of education. They have strong links with the units, taking it as a benchmark for their care. The results show care in accordance with scheduled demand and users manifest marked satisfaction with the work of the professionals and less satisfaction with the conditions offered at the units. The younger and more educated the users are, the less satisfied they are with the conditions offered. There is considerable dissatisfaction with delays in attendance, in accessibility and the lack of educational and community activities, the latter two dimensions being related to the core principles of this strategy. The marked satisfaction with clinical care, confidentiality and right to information, which are dimensions related to user-professional relationship are fundamental to the quality of care. This evaluation focused on each aspect of the service provided and makes an important contribution with the critical appraisal reported by users. PMID- 23338495 TI - [The experiment of participatory mapping in order to construct a cartographical alternative to the FHS]. AB - Maps and mapping procedures are useful tools for systematic interpretation and evaluation and for reporting of results to management. Applied to the Family Health Strategy (FHS), these maps permit the demarcation of the territory and the establishment of links between the territory, its population and health services. In this paper the use of maps by the FHS in 17 municipalities in northern and northeastern Brazil is studied and the process of demarcation and digitization of areas with the participation of teams is described. The survey conducted using questionnaires and discussion workshops showed that difficulties still prevail in reconciling the map (drawing) produced at the local level with maps produced by other government sectors. In general, the maps used at local level employ their own references, which prevent the interplay of information with other cartographic documents and their full use as a tool for evaluation and management. The combination of participatory mapping tools, associated with Geographic Information Systems (GIS) applications proposed in this paper, represents an alternative to mapping the territory of operations of FHS teams, as well as a reflection on the concept of territory and operation by the FHS. PMID- 23338496 TI - [Users and the technological transition in the supplemental health sector: case study of a health insurance plan company]. AB - This paper presents the results obtained from qualitative research conducted with a group of users involved in Case Management, a program which was developed by a company of a medical group to provide healthcare for patients in situations of high vulnerability. The study sought to create a perspective in which the experience of the user, instead of representing merely additional or superimposed information upon the quality of services, is considered an inherent part of the arrangement under scrutiny, with the ability to highlight its internal qualities and contradictions. The results show how patients attribute high value to the healthcare they receive, with special emphasis on the bond that is created with the health team in charge, even when contact is only by telephone. Simultaneously, they are able to perceive the double-sided aspect presented by the regulation/assistance model found in the technological arrangement at issue, notably in relation to the prominent role played by the economic bias towards cost reduction--which lies in the forefront of its operationalization--and the final impact it has upon the final quality of healthcare. PMID- 23338497 TI - [Hospital treatment: right or concession to the hospitalized user?]. AB - The study sought to understand--from the viewpoint of the hospitalized user--the perception and the difficulties involved in administering hospital attendance in surgical inpatient units at a public hospital in the city of Niteroi, R.J., and discuss them in light of the concepts of Institutional Analysis (IA). Maintaining the emotional and social bonds of the hospitalized individual is essential and is encouraged by public health policies. However, discussions are needed about how to take maximum advantage of this possibility. In the descriptive research using a qualitative approach, the techniques of semi-structured interviews and field observations were used and the resulting data were classified using Content Analysis. Three thematic areas were identified for discussion, namely the presence of nurses for care requests, interference in communication between the companions and nurses, and the conditions of comfort afforded to the companion. The conclusions drawn from the studies relating to the presence of the companion together with the hospitalized user are that it is indispensable to include companions and the nursing team in the discussions and the creation of strategies to make this user right a reality. PMID- 23338498 TI - [The social-political-environmental and health reality of families belonging to a vulnerable community]. AB - The scope of this paper is to ascertain the perception of community leadership, health professionals and users regarding citizenship status and the enhancement of the healthcare conditions of families belonging to a vulnerable community. This is an exploratory study of a qualitative nature, guided by theory based on data. Data were collected between July and December 2009, by means of interviews with four community health leaders, a team of eight family health team professionals and twelve health users. The codification of the data resulted in the following categories: Understanding the social conditions, the political conditions, the environmental conditions and the health conditions of families in a vulnerable community. The conclusions reached were, that if on the one hand the social security and health policies made it possible to reduce poverty and local inequalities, on the other hand they do not ensure the requisite enhancement of citizenship or even the improvement of health conditions. PMID- 23338499 TI - [Vulnerability and health problems while traveling: the viewpoint of the tourist in the city of Rio de Janeiro]. AB - This article examines how a group of tourists perceives health issues related to safety, prevention and health care during their travels. Interviews were conducted with Brazilian tourists visiting the city of Rio de Janeiro, as well as local residents leaving the city on trips. The interviews were analyzed in accordance with the dimensions of vulnerability, information, prevention and health care, from which vulnerability emerged as a category of analysis. The reports of the trajectory of the tourists made it possible to identify problems and opportunities that could be used by the health sector for actions of prevention and promotion. The means of transport determines the trajectory of tourists and their security alternatives. Traveling in groups and visiting tourist attractions are seen as protective factors, which reinforces the role of information and social support networks as resources used by tourists in the absence of specific policies geared to this highly mobile and vulnerable population group. PMID- 23338500 TI - [City Academy: a health promotion service in the healthcare network of the Unified Health System]. AB - This is an analysis of the health and nutritional profile of users of the Unified Health System admitted to a City Academy in Belo Horizonte, Minas Gerais during a triennium. It is a cross-sectional study with users> 20 years and socio demographic characteristics, health habits, food intake and anthropometrics were gathered. Kolmogorov-Smirnov tests, ANOVA, Kruskal-Wallis test, chi-square and Fisher exact test were applied. There was a high prevalence of hypertensive subjects (41.6%), overweight (70.6%) and metabolic risks associated with obesity (67.6%). About 40% of entrants had 1-3 chronic diseases and over 65% used medication daily. There was an imbalance in daily consumption of fruits and vegetables (75.3%), fatty meat (72.4%) and sweetened drinks (54.2%). They had low education and income, and inadequate eating habits and high prevalence of hypertension, overweight and metabolic risks associated with obesity, which suggests users seeking health care services for treatment of diseases. This illustrates the perceived quest for cure, further demonstrating the lack of healthcare initiatives in the population. This reveals the need to review the actions at different levels of health care, to promote greater comprehensiveness of care provided. PMID- 23338501 TI - [Evaluation of primary care from the perspective of users: adaptation of the EUROPEP instrument for major Brazilian urban centers]. AB - Satisfaction with health care is a multidimensional concept that considers aspects such as access, organization and professional-user interaction. The aim of this study was to adapt and apply an instrument in the Family Health Strategy (FHS) to assess user satisfaction with Primary Health Care (PHC) based on the European Task Force on Patient Evaluation of General Practice Care (EUROPEP), which refers to user satisfaction wth general and family medicine services. The instrument consists of five dimensions of satisfaction: relationship and communication, medical care, information and support, continuity and cooperation, and organization of services. The study was divided into phases: review and adjustment of the instrument and application to a representative sample of users of the FHS in Rio de Janeiro. The averages of the proportions of answers for each indicator were calculated to analyze the results. Relationship and communication between professionals and users received the best evaluation and Organization of Services eceived the worst appraisal. Regarding education level, good self perceived health and more elderly were more satisfied. The instrument proved to be easy to apply, can be routinely used for monitoring of the FHS, and is a tool for the institutionalization of evaluation. PMID- 23338502 TI - [Healthcare expenses of Brazilian families living in metropolitan areas: composition and trends during the period from 1995 to 2009]. AB - Private health insurance plans represent a significant proportion of total health spending in Brazil. In order to establish the evolution and composition of spending on health among families living in metropolitan areas, Family Budget Research findings conducted in 1995-1996, 2002-2003, and 2008-2009 were studied. The categories of spending were standardized and values were adjusted by the Broad Consumer Price Index in order to compare the findings. In the period from 1995 to 2009, average family spending on health fell from R$ 194.68 to R$ 179.01. The components that most contributed to the reduction were dental care, medical consultations and other spending on health. Private health insurance was the component with the greatest increase in participation in relation to total spending - from 29% to 44% - and the highest increase in average spending, from R$ 56.50 to R$ 78.62. The reduction of average spending on health occurred mainly among lower income families, whereas these figures remained stable among families with higher incomes. Family health spending became less regressive, since lower income families began to commit a lower proportion of their income for these expenses, while the opposite was observed in families with higher incomes. PMID- 23338503 TI - [Cooperation in health from the bioethical perspective]. AB - This study considers the scenario of international relations in the transition to the twenty-first century as a backdrop for reflection on the bioethical perspective of international cooperation in health. It presents an exploratory analysis of the interdisciplinary scientific production in bioethics and public health in the international context, revealing that the focus and confluence of both issues has scant coverage in terms of diplomatic relations. It describes the methodology used to select publications cataloged in this interdisciplinary area from two bibliographic sources available on the web (93 articles in BVS/BIREME and 161 in PubMed), pointing to difficulties in locating this literature. The potential of the epistemological approach that flourished in Latin America under the guise of the Bioethics of Intervention in addressing the challenges that confront the international cooperation system, identified as the benchmark for analysis of South-South cooperation in health, is recommended. It concludes by proposing systematization and broadening of knowledge at the intersection of bioethics, public health and diplomacy, whose projection in the political and institutional field can contribute to reducing inequalities in health conditions among nations. PMID- 23338504 TI - [Episodes of care: a concept in public health]. AB - This paper presents a revision of the literature on the definition of episodes of care, which emerged as a concept in health services research during the 1960s. Episodes of care have been described from three different perspectives: that of the patient (episode of indisposition); the care provider (episode of illness); and the financial sponsor (episode of care). The main scope of this study is to present a review of the literature on the operational definition of episode of care. A computerized bibliographical review was conducted for the period between 1950 and 2007 in the MEDLINE database and 54 articles met the criteria for evaluation. The definition of episode of care differs widely in the literature. The operational definition of the episode of care to be applied should be determined by the overall goals of the study, as well as the relative advantages and limitations of the methodology used. PMID- 23338505 TI - [Provision of building maintenance services in healthcare facilities]. AB - The scope of this paper was to evaluate the provision of building maintenance services in health units, by means of a descriptive, quantitative and cross sectional study, considering the five types of facilities (Primary Health, Emergency, Specialty, Hospital and Mental Health Units). The research was approved by the Research Ethics Comittee of FHEMIG with the Terms of Agreement signed with the Unified Health System of Betim. Comparative analysis was conducted by checking the requirements of "Physical-Functional Structure Management" of the "Brazilian Hospital Accreditation Manual" of the National Accreditation Organization. Nonconformities were noted in the physical-functional management of the health centers, especially the primary health units. The assessment was important, considering that compliance with formal, technical and structural requirements, welfare activities, according to the service organization and appropriate to the profile and complexity, can collaborate to minimize the risks of users. To improve the quality of health care establishments, it is essential that managers, backed by "top management," prioritize financial, human and material resources in planning to ensure compliance with security requirements of users in buildings. PMID- 23338506 TI - [Education and competences for the Brazilian Unified Health System (SUS): is it possible to find alternatives to the logic of late capitalism?]. AB - The transformations that have revolutionized the labor market in contemporary society make it necessary to think of new alternatives for training health care professionals, thereby establishing a new approach to the health problems of individuals and collectives. Based on these considerations, this paper sets out to discuss training in health--based on the concept of competence--with a focus on education for the Brazilian Unified Health System (SUS), using attempts to analyze and propose an alternative to the system entrenched in the logic of late capitalism as a theoretical benchmark. It is thus a reflection on the subject, correlating theory and praxis, in constant and relentless movement of construction, deconstruction and (re)construction of propositions. PMID- 23338507 TI - [Current debates on humanization and health: who are we?]. AB - Bearing in mind that the Brazilian Unified Health System (SUS) is a social process in construction, and as health professionals are important individuals in this process, the role of permanent education as an important instrument to ensure humanized care is highlighted. The scope of this paper is to discuss the experience of the training course for health professionals of a public health outpatient unit, based on the prospect of humanized treatment, seeking the implementation of a sanitary model committed to the formal values contained in the SUS ideals. The teaching-learning methodology used is based on problem solving, derived from the processing of a problem situation taken from the experience of teachers. The professionals identified that the standard established in the way of thinking and acting in health is unsatisfactory to meet the challenges faced in the sector. The strategies used contributed to systematize the content through reflection on the theoretical benchmarks submitted, by eliciting reflective and critical thought, which are fundamental aspects for broadening and increasing the process of empowerment of professionals. The course stimulated group action, placing the discussion on the humanization of health actions on the agenda. PMID- 23338508 TI - [The Brazilian Unified Health System (SUS) is universal, but quotas are the norm]. AB - In the context of the Unified Health System (SUS), health actions and services constitute a social right to be guaranteed by the State and managed under the responsibility of three autonomous spheres of government. This is a holistic multiple case study with a qualitative approach based on the assumptions of Comprehensive Everyday Sociology, which originated from a PhD thesis. It sought to understand the construction of comprehensive health practices in the daily work of family health teams and managers of the cities in Vale do Jequitinhonha - Minas Gerais, Brazil. The individuals studied were professionals from the Family Health Teams, support staff and managers with a total of 48 participants. In order to reveal the construction of the whole, the data show that "SUS is universal, but quotas are the norm." Bearing in mind its limitations, it is difficult to ensure that SUS is a right for all. Thus, regulation is essential to order, guide, define and optimize the use of resources available for comprehensive care and also guarantee public access to actions and services in a timely and equitable manner. PMID- 23338509 TI - [Challenges for the discussion of a complex institutional mission: the case of a health research institute]. AB - This study is based on an adaptation of the Strategic Demarche Approach applied to the Evandro Chagas Institute of Clinical Research (IPEC) in Brazil, from April to July 2009. The results are related to the experience of the Leishmaniasis Laboratory. A strategic analysis of four homogeneous segments was performed, considering the administration of care and specific teaching and research indicators. In both portfolios, all segments showed competitiveness and an appropriate response to mission goals. However, the second portfolio (teaching/research) showed a greater concentration of production in one segment. A highlight was the presence in the work team of cultural traits consistent with the objectives of cultural change. This experience, by operating indirectly in furtherance of the features of the new culture that emerges, revealed the potential of the method in question, to effect policies, processes and resources in a democratic and communicative way, which contributes to the operationalization of the guidelines of the Brazilian Unified Health System. PMID- 23338510 TI - [Research program for the Brazilian Unified Health System (SUS): the contribution to health management and services in Paraiba State, Brazil]. AB - The shared management in health of the Research Program for the Unified Health System (PPSUS) has the purpose of funding research in priority areas for the health of the Brazilian population. The scope of this qualitative study is to understand the researchers' perception of the contribution of research funded by the PPSUS invitations to bid in the State of Paraiba, for resolving the priority health problems of the Paraiba population, for reducing regional inequalities in health and for bolstering the management of SUS. A documentary survey of the bids and final reports of research and a semi-structured interview with 28 coordinators of these studies was conducted. Triangulation strategy of data was used and subsequently subjected to content analysis, which converged with the categories: solving the health problems; reducing regional inequalities; contribution to management. Paraiba state needs adjustments such that the PPSUS can be fully implemented, ensuring that the knowledge generated can be converted into health policies and actions, since the research funded respond to the health needs of the population and difficulties in SUS management. PMID- 23338511 TI - [Knowledge of the municipal health managers about the National Policy on Integrative and Complementary Practices and its influence on the provision of homeopathy in the Local Unified Health System]. AB - The social determinants of the health-disease process and the challenge of comprehensive care have led the World Health Organization to propose Complementary and Alternative Medicines to be included in health policies. In Brazil in 2006 the National Policy on Integrative and Complementary Practices (PNPIC) was published. It is a tool for the institutionalization of homeopathy in the Unified Health System (SUS). This paper analyzes the knowledge of health managers of municipalities of Sao Paulo on PNPIC, and its influence on homeopathic care. In 2008, the municipalities that performed homeopathic consultations from 2000 to 2007 were identified in DATASUS, managers were interviewed and the results were analyzed quantitatively and qualitatively: of the 645 municipalities, 47 had offered homeopathy and 42 of them were interviewed. Of these, 26% knew about PNPIC, 31% knew little, 41% were unaware of it. It should be stressed that those aware of it stated that they use PNPIC to: instruct the local government about homeopathy; the construction of specific legislation and the increase in homeopathic services. The conclusion is that PNPIC is unknown by health managers and those that know it use it to make known the homeopathic medical rationale and justify its application in the SUS. PMID- 23338512 TI - [Brazilian scientific production on the Family Health Strategy and the change in the model of care]. AB - The variety of existing studies addressing the Family Health Strategy (ESF) and its role in the reorientation of the model of care in the country has motivated the systematization of the advances and limitations described in these studies. Thus, this study, from a review of the scientific production on this theme, analyzed if the ESF has been able to modify the model of care. Forty-one articles from the Scielo database published between 2002 and 2010 that fulfilled the inclusion criteria were analyzed. They were fully analyzed in terms of political institutional, organizational or technical-care dimensions. The results show that despite the improvement in the work process in primary care, its replacement aspect was not seen in the majority of the studies. Universal expansion of access to the health services, extension of coverage and focus were predominant. The changes are observed when analyzed in light of the demand, with better attendance and connectivity. The most evident limits are in the lack of focus on health needs, as in the territorial issue, community participation and the social determinants addressed in an intersectoral way. Different degrees of the implementation of strategy were identified, though they have not yet resulted in system reorganization at local level. PMID- 23338513 TI - [Co-occurrence of physical and psychological violence among dating adolescents in Recife, Brazil: prevalence and associated factors]. AB - The scope of this study was to assess the prevalence of physical and psychological violence among dating adolescents from Recife, Brazil, to identify associated factors and the co-occurrence of both types of violence. 302 adolescents aged between 15 and 19 years in public and private schools who were in a relationship in the last year filled out the questionnaire. Univariate and multivariate logistic regression statistical analysis were performed and the sample weight and the complex sample design were entered. The prevalence was 19.9% of physical violence 82.8% of psychological violence and 18.9% for the co occurrence of both. Adolescents who have experienced violence in the community and who were in dating relationships of more than one year duration were more likely to perpetrate psychological violence. For the co-occurrence of physical and psychological violence, the variables that increased the chance of perpetration were suffering physical violence from the father, violence among siblings, physical violence and the perpetration of verbal violence in previous relationships. The conclusion reached is that psychological violence and the co occurrence of physical and psychological violence have a distinct dynamics from physical violence in dating relationships. PMID- 23338514 TI - [The image in qualitative research in health]. AB - This paper explores the use of the image as a methodological instrument in qualitative research in health. It is divided into two parts. The first part, which is theoretical in perspective, deals with aspects of anthropological fieldwork in which different views interact in the interpretation, either in the speech of the social actor or in the image that is produced. The second part describes two empirical studies on the image as a methodological instrument to obtain qualitative data, presenting research with images recorded on DVD and photographs of garbage pickers and garbage collectors, respectively. The conclusion reached is that the image can be used both as a complementary example, and as an instrument in qualitative research. Participant observation and interviews can be supplemented with the image but the image itself generates an accumulation of information, stimulating the viewer's ability to comprehend. PMID- 23338515 TI - [The prevalence of abstinence from tobacco in patients treated in health units and related factors]. AB - The scope of this study is to discover the prevalence and identify the variables related to tobacco abstinence in patients treated for quitting smoking through group therapy or support groups in primary health care units of the municipality of Vitoria, State of Espirito Santo, in the year of 2009. A cross-sectional study was performed with 160 participants of the support groups who participated in 75% of the sessions. Telephone interviews were conducted 9 to 20 months after treatment and secondary data from the text of the initial interview were used. Chi-square and Fischer tests were used in statistical analysis and the statistical significance was 5%. It was found that 28.7% were abstainers, 51.9% had relapsed and 19.4% never stopped smoking. There was a statistical difference between the groups in the variables of marital status (0.039), previous attempts to stop smoking (0.029), amount of cigarettes smoked per day (0.019), use of medication (0.001) and reported anxiety/mood disorders (0.040). The abstaining group included more married people, people who had tried to quit smoking several times, smoked fewer cigarettes/day, showed less anxiety/mood change. The incidence of abstinence was similar to other studies and the highest percentage of subjects relapsed. PMID- 23338516 TI - [Family Health Strategy in tuberculosis control in Curitiba, State of Parana]. AB - Tuberculosis defined by some as the 'neglected calamity' is still an important public health problem. To try to improve results in tackling the disease, actions have been decentralized to the level of Primary Health Care (PHC), which has been demanding a new direction in the Family Health Strategy (FHS). This research sought to analyze the evolution of the FHS in the municipality of Curitiba between the years 2000 and 2009 and its impact on incidence rates of tuberculosis. The aggregate-type ecological study with a longitudinal territorial time-series base was the methodology used. Data collection was conducted from October 2010 to July 2011. The main results revealed a marked increase of 127.63% in the number of Family Health Teams, with a 76.28% increase of coverage. There was also concern about the ongoing training of these teams, which reflected positively in increasing the number of diagnostic tests performed, reducing the number of new cases, the proportion of individuals abandoning treatment and the mortality rate related to tuberculosis. From the research conducted it can be seen that there has been a correction in the direction of actions to control the incidence of tuberculosis in the municipality of Curitiba. PMID- 23338517 TI - [The Brazilian Unified Health System (SUS), State Public Policy: its institutionalized and future development and the search for solutions]. AB - This paper redeems the significance of the health reform movement and the municipal healthcare movement in the context of the 1970s and 1980s, and its social, politic and innovative power in the democratic reconstruction of the day. It then notes that the implementation of the constitutional guidelines, regulated in 1990 by Laws 8080/90 and 8142/90, has been characterized in the last 22 years by four major and mounting obstacles imposed by State policy on all governments: federal underfunding; federal subsidies to the private health plan market; resistance to reform of the State management structure of service provision; and the handing over of administration of public facilities to private entities. The Brazilian Unified Health System (SUS) included half the population that was once excluded in the public health system, though these obstacles keep the coverage of primary care focused below the poverty line and with poor resolution. The conclusion drawn is that the real policy of the state for healthcare in the past 22 years has prioritized the creation and expansion of the private health plan market for consumer rights, and relegated the effectiveness of constitutional guidelines for civic human rights to second place. PMID- 23338519 TI - I know it when I quantify it: ecological momentary assessment and recurrence quantification analysis of emotion dysregulation in children with ADHD. AB - Two studies examined the feasibility, utility, and validity of Ecological Momentary Assessment (EMA) and Recurrence Quantification Analysis (RQA) in assessing emotion dysregulation in children with Attention-Deficit/Hyperactivity Disorder (ADHD). In Study 1, 11 parents of children with ADHD ages 8-11 completed EMA-based ratings of their children's mood three times daily for 28 days (84 ratings total) and questionnaires regarding their children's emotion dysregulation. RQA was used to quantify the temporal patterning of dysregulation of the children's mood. In Study 2, five children ages 8-11 completed EMA-based ratings of their mood three times daily for 28 days. Results supported the feasibility and validity of the parent report EMA protocol, with greater intensity, variability, and persistent patterning of variability associated with greater emotion dysregulation. Results did not support the validity of the child report protocol, as children were less likely to complete ratings when emotionally distressed and demonstrated substantial response bias. PMID- 23338521 TI - Prostate cancer: Benefit and safety of adjuvant radiation therapy. PMID- 23338522 TI - De novo next-generation sequencing, assembling and annotation of Arachis hypogaea L. Spanish botanical type whole plant transcriptome. AB - Peanut is a major agronomic crop within the legume family and an important source of plant oil, proteins, vitamins, and minerals for human consumption, as well as animal feed, bioenergy, and health products. Peanut genomic research effort lags that of other legumes of economic importance, mainly due to the shortage of essential genomic infrastructure, tools, resources, and the complexity of the peanut genome. This is a pioneering study that explored the peanut Spanish Group whole plant transcriptome and culminated in developing unigenes database. The study applied modern technologies, such as, normalization and next-generation sequencing. It overall sequenced 8,308,655,800 nucleotides and generated 26,048 unigenes amongst which 12,302 were annotated and 8,817 were characterized. The remainder, 13,746 (52.77 %) unigenes, had unknown functions. These results will be applied as the reference transcriptome sequences for expanded transcriptome sequencing of the remaining three peanut botanical types (Valencia, Runner, and Virginia), which is currently in progress, RNA-seq, exome identification, and genomic markers development. It will also provide important tools and resources for other legumes and plant species genomic research. PMID- 23338520 TI - Multiparametric ultrasonography of the testicles. AB - Ultrasonography is the standard modality to image the scrotum because it can provide information about volume, echo texture, tissue stiffness and functional information that includes macrovascularization and microvascularization. Indeed, ultrasound imaging is indicated in the presentation of acute scrotal pain and swelling to differentiate between testicular torsion, infarction and inflammation, as well as being the modality of choice when an intrascrotal mass is suspected. Advances in ultrasonography technology have produced new innovative techniques for imaging the scrotum, including grey-scale ultrasound, Doppler ultrasonography, contrast-enhanced ultrasonography and real-time sonoelastography. Each of these techniques provides information that can be useful when diagnosing diseases and disorders of the testicles. Consequently, the standard approach to accurate diagnosis should rely on multiparametric ultrasonography techniques, rather than just one or two techniques in isolation. PMID- 23338524 TI - The incremental nature of clinical research: comment on "The association of aspirin use with age-related macular degeneration". PMID- 23338523 TI - High-throughput virtual screening of phloroglucinol derivatives against HIV reverse transcriptase. AB - Therapeutic agents exert their pharmacological and adverse effects by interacting with molecular targets. Even if drug molecules are intended to interact with specific targets in a desirable manner, they are often found to bind to other targets. Nowadays, research is focused on a single molecule that simultaneously targets multiple disease-causing proteins. Therefore, off-target identification of existing chemical space can be a valuable tool to find safe and effective multi-targeted therapeutic agents at a significantly lower cost to patients. Phloroglucinols represent a class of compounds, which exhibits a diverse range of biological activities, such as anti-HIV, antimalarial, antileishmanial, antituberculosis, antibacterial, and antifungal. The aim of the current study is to explore untapped potential of various series of phloroglucinols against HIV reverse transcriptase (HIV-RTase). A series of filtering parameters was applied in search of viable phloroglucinol derivatives against HIV-RTase. A library of phloroglucinol derivatives was screened based on their toxicity potential followed by predicted ADME parameters. The filtered compounds were then carried forward for docking analysis against HIV-RTase. A set of 37 phloroglucinol compounds with diverse pharmacological profile was found to have good binding affinity towards HIV-RTase. These molecules formed hydrogen bonds with Lys101, Lys103, Val106, and Leu234 residues and pi-pi stacking interaction with Tyr318 residue of the protein. Here, we propose potential phloroglucinol derivatives with different known biological activity that can be repurposed as potential hits against HIV. PMID- 23338525 TI - Highly effective Ir(x)Sn(1-x)O2 electrocatalysts for oxygen evolution reaction in the solid polymer electrolyte water electrolyser. AB - We developed an advanced surfactant-assistant method for the Ir(x)Sn(1-x)O(2) (0 < x <= 1) nanoparticle (NP) preparation, and examined the OER performances by a series of half-cell and full-cell tests. In contrast to the commercial Ir black, the collective data confirmed the outstanding activity and stability of the fabricated Ir(x)Sn(1-x)O(2) (x = 1, 0.67 and 0.52) NPs, which could be ascribed to the amorphous structure, good dispersion, high pore volume, solid-solution state and Ir-rich surface for bi-metal oxides, and relatively large size (10-11 nm), while Ir(0.31)Sn(0.69) exhibited poor electro-catalytic activity because of the separated two phases, a SnO(2)-rich phase and an IrO(2)-rich phase. Furthermore, compared with highly active IrO(2), the improved durability, precious-metal Ir utilization efficiency and correspondingly reduced Ir loading were realized by the addition of Sn component. When the Ir(0.52)Sn(0.48)O(2) cell operated at 80 degrees C using Nafion(r) 115 membrane and less than 0.8 mg cm( 2) of the noble-metal Ir loading, the cell voltages we achieved were 1.631 V at 1000 mA cm(-2), and 1.821 V at 2000 mA cm(-2). The IR-free voltage at the studied current density was very close to the onset voltage of oxygen evolution. The only 50 MUV h(-1) of voltage increased for the 500 h durability test at 500 mA cm(-2). In fact, these results are exceptional compared to the performances for OER in SPEWE cells known so far. This work highlights the potential of using highly active and stable IrO(2)-SnO(2) amorphous NPs to enhance the electrolysis efficiency, reduce the noble-metal Ir loading and thus the cost of hydrogen production from the solid polymer electrolyte water electrolysis. PMID- 23338526 TI - Downregulation of Src enhances the cytotoxic effect of temozolomide through AKT in glioma. AB - Src is an attractive target since it is overexpressed in a number of malignancies, including glioma. However, the mechanism of Src signaling as well as its silencing effect on temozolomide in glioma is not well known. We hypothesized that downregulation of Src may enhance the cytotoxic effect of temozolomide on glioma. As expected, Src was overexpressed in glioblastoma multiforme (GBM) compared with normal brain tissues. Src silencing suppressed tumor proliferation and induced apoptosis in glioma. In addition, Src silencing combined with temozolomide treatment resulted in significant inhibition of tumor growth. These effects may be mediated by AKT which is a downstream effector of Src, since downregulation of AKT exhibited a similar effect as Src siRNA when combined with temozolomide. Finally, we demonstrated that overexpression of AKT suppressed the enhanced cytotoxic effect of temozolomide mediated by Src silencing. Thus, the present study demonstrated that Src plays a biologically significant role in tumor proliferation and apoptosis and enhances the cytotoxic effect of temozolomide through AKT supression in glioma. PMID- 23338527 TI - Migration of methylethynyl group in a long-lived carbocation. AB - Degenerate 1,2-shift of methylethynyl group in long-lived 9,10-dimethyl-9 methylethynyl-phenanthrenium ion has been detected by NMR. This is the first example of ethynyl migration in a long-lived carbocation. PMID- 23338528 TI - [Sensitivity and specificity of flicker perimetry with Pulsar. Comparison with achromatic (white-on-white) perimetry in glaucoma patients]. AB - The early detection of functional glaucoma damage plays an increasingly more central role in the diagnosis and treatment of glaucoma disease. Using selective perimetry detection of early glaucomatous defects is more likely and one of these methods is flicker perimetry with Pulsar. Flicker perimetry is used to analyze the temporal visual function in combination with spatial resolution and contrast sensitivity as opposed to standard automated perimetry which measures the differential light sensitivity with a non-specific stimulus. This study showed a higher sensitivity and specificity of Pulsar perimetry in comparison to achromatic perimetry in glaucoma patients. PMID- 23338529 TI - [Managing complications in intraoperative floppy iris syndrome]. AB - The intraoperative floppy iris syndrome (IFIS) describes an ophthalmologically relevant phenomenon which is observed after systemic intake of alpha blockers for treatment of benign prostate hyperplasia. This leads to an increase in intraoperative complications in cataract surgery characterized by a flaccid iris which billows in response to currents with a tendency to prolapse towards the area of surgery. This results in damage to the iris by the instruments used or posterior capsule rupture with loss of lens material. We describe the preoperative and intraoperative measures and techniques to deal with this challenging situation in order to minimize development of IFIS and reduce the complication rate. PMID- 23338530 TI - [Functional results after bilateral intrastromal femtosecond laser correction of presbyopia]. AB - PURPOSE: The purpose of this study was to evaluate the results of bilateral intrastromal femtosecond laser correction of presbyopia (INTRACOR). METHODS: In a prospective study 17 patients were enrolled who had previously received binocular treatment in a two-step approach. Postoperative (4-8 months) outcomes were compared with a matched control group who had undergone only unilateral surgery of the non-dominant eye (n = 17 patients, 24 months after surgery). RESULTS: The binocular distance corrected near visual acuity (DCNVA) showed the same median but lower scattering of values after bilateral treatment: 0.10 (median in logMAR) (0.30/- 0.10 min/max) (study) versus 0.10 (0.50/- 0.10) (control). In the study group, however, a higher loss of binocular corrected distance visual acuity (CDVA) was found: 23.5 %, 70.6 %, 5.9 % (0, - 1, - 2 lines) (study) versus 35.3 %, 64.7 % and 0 %, respectively (control). CONCLUSIONS: Regarding the reduced CDVA INTRACOR should initially only be performed in the non-dominant eye. In selected cases binocular treatment can improve DCNVA; however, careful risk benefit assessment and informed consent are necessary. PMID- 23338531 TI - [Leopard-spot pattern in fluorescein angiography]. AB - The uveal effusion syndrome is a rare disease characterized by serous choroidal detachment. The pathogenesis of idiopathic uveal effusion syndrome has not yet been conclusively established. One hypothesis is an abnormality of diffusion of extravascular proteins in the choroid leading to decompensation of the pigment epithelium pumping capacity. Fluid then accumulates in the subretinal space leading to retinal detachment which results in loss of visual acuity. It typically affects males and hypermetropia is another risk factor. When looking at the fundus a circular serous detachment of the choroid and choroidal puckering is typical. The fluorescein angiography shows hyperfluorescence in the form of a leopard-spot pattern. Space-occupying lesions have to be excluded with the help of ultrasound or magnetic resonance tomography. The uveal effusion syndrome is a diagnosis by exclusion. Treatment varies because of the different hypotheses for the pathogenesis. An intraocular tamponade in combination with laser coagulation may for example be an effective treatment. PMID- 23338532 TI - Brief report: examining driving behavior in young adults with high functioning autism spectrum disorders: a pilot study using a driving simulation paradigm. AB - Although it is speculated that impairments associated with autism spectrum disorder (ASD) will adversely affect driving performance, little is known about the actual extent and nature of the presumed deficits. Ten males (18-24 years of age) with a diagnosis of high functioning autism and 10 age matched community controls were recruited for a driving simulation experiment. Driving behavior, skin conductance, heart rate, and eye tracking measurements were collected. The high functioning ASD participants displayed a nominally higher and unvaried heart rate compared to controls. With added cognitive demand, they also showed a gaze pattern suggestive of a diversion of visual attention away from high stimulus areas of the roadway. This pattern deviates from what is presumed to be optimal safe driving behavior and appears worthy of further study. PMID- 23338533 TI - Apolipoprotein A-IV as a novel gene associated with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder, affecting 6-10% of women of reproductive age. The etiology remains poorly understood. To investigate the differentially expressed proteins from PCOS patients versus healthy women, the protein expression in follicular fluid was analyzed using two-dimensional electrophoresis (2-DE). Since follicular fluid contains a number of secretory proteins required for oocyte fertilization and follicle maturation, it is possible that follicular fluid can be used as a provisional source for identifying pivotal proteins associated with PCOS. In this study, six overexpressed proteins [kininogen 1, cytokeratin 9, antithrombin, fibrinogen gamma-chain, apolipoprotein A-IV (apoA-IV) precursor and alpha-1-B glycoprotein (A1BG)] in follicular fluids from PCOS patients were identified with matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) and nano LC-MS/MS. Western blot analysis confirmed that the protein expression levels of apoA-IV precursor and A1BG were increased in follicular fluid from PCOS patients compared with those from normal controls. The analysis of protein expression for other proteins revealed individual variation. These results facilitate the understanding of the molecular mechanisms of PCOS and provide candidate biomarkers for the development of diagnostic and therapeutic tools. PMID- 23338534 TI - A bowl-shaped organic host using bispyridine ligands: selective encapsulation of carbonyl guests in water. AB - A bowl-shaped organic host was prepared by linking two anthracene-embedded bispyridine ligands with two methylene spacers. The water-soluble host has a hemispherical hydrophobic cavity (~1 nm in diameter) with two cationic methylenebispyridinyl (Lewis acidic) moieties and shows the selective recognition and encapsulation of aromatic guest molecules containing carbonyl groups in water. PMID- 23338535 TI - Ten things I learned when writing a book of medical education quotations. AB - Medical education has had a long history. Much of that history can be captured in quotations from the many people who have made medical education what it is today. Even though newcomers to the field often see and approach problems as if they were the first to discover them, examining quotations makes us realise that ideas of reform in medical education have been around a long time. Despite the longevity of ideas however, the pace of change has sometimes been slow. Quotations can help us realise the myriad of reasons that have contributed to this slow pace-sometimes a fear of change, sometimes an ill-conceived desire to develop innovations that will be proved to work for all learners in all circumstances. Even though quotations can show where medical education in the past has at times gone wrong, they can also point to a bright future-where intelligent and passionate people reflect and debate on the directions that our important specialty should take. PMID- 23338537 TI - Intracameral cefuroxime: prophylaxis of postoperative endophthalmitis after cataract surgery. AB - Results of the landmark European Society of Cataract and Refractive Surgeons trial and additional prospective and retrospective studies support the use of intracameral cefuroxime in the prophylaxis of endophthalmitis following cataract surgery. Prophylaxis with intracameral cefuroxime at the recommended dose appears to be well tolerated in patients undergoing cataract surgery. However, off-label use of intracameral cefuroxime usually requires a two-step dilution process with the potential for dilution errors, and there are also concerns regarding the risk of contamination. Aprokam(r) (intracameral cefuroxime) has been approved in the EU for the prophylaxis of postoperative endophthalmitis after cataract surgery. After reconstitution of Aprokam(r), no further dilution is required and each vial is only indicated for single-patient use; this has the potential to reduce the risk of both dilution errors and contamination. PMID- 23338539 TI - Subcutaneous bortezomib: in multiple myeloma. AB - A subcutaneous formulation of bortezomib is now indicated in the EU and the US for the treatment of patients with multiple myeloma. This article reviews pharmacological, therapeutic efficacy and tolerability data relevant to the utilization of subcutaneous bortezomib (Velcade((r))) in the treatment of patients with multiple myeloma. In a randomized, nonblind, phase III study, subcutaneous bortezomib was noninferior to intravenous bortezomib in the treatment of adults with relapsed multiple myeloma, as determined by the overall response rate after four cycles of therapy (primary endpoint). No significant differences between the subcutaneous and intravenous bortezomib formulations were observed in the median time to first response, median progression-free survival, median time to progression and 1-year overall survival. Compared with intravenous bortezomib, subcutaneous bortezomib confers a significant advantage with respect to the incidence of peripheral neuropathy (all grades, grade >=2 and grade >=3). As a consequence, it provides a new treatment option for patients with multiple myeloma, particularly those with pre-existing neuropathy or at a high risk of developing peripheral neuropathy. PMID- 23338536 TI - Differentiating factors between erythropoiesis-stimulating agents: an update to selection for anaemia of chronic kidney disease. AB - Erythropoiesis-stimulating agents (ESAs) have become a hallmark of anaemia therapy in patients with chronic kidney disease (CKD). Although different ESAs are available for the treatment of renal anaemia, each nephrologist should select a single ESA for an individual patient. Epoetin alfa and epoetin beta have been used 1-3 times weekly but extended-interval dosing up to every 4 weeks is also effective in a substantial majority of CKD patients. However, the epoetin dose necessary to achieve or maintain target haemoglobin (Hb) levels increases substantially as the dosing interval increases. Subcutaneous administration of short-acting ESAs is more effective than the intravenous route of administration. Darbepoetin alfa and the continuous erythropoietin receptor activator (CERA) have been developed as a treatment for anaemia with extended administration intervals (every 2 weeks and every 4 weeks, respectively). Dose requirements for these long acting ESAs are independent of the route of administration. Patents of short acting ESAs have expired, which has opened the field for biosimilars. Epoetin biosimilars approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) have been shown to have a comparable efficacy and safety profile to their originators. An alarming increase in pure red cell aplasia (PRCA) in Thailand with follow-on epoetins manufactured in Asia (but also those manufactured in Latin America) indicates that stringent country-specific approval and pharmacovigilance protocols for ESAs manufactured in non-North American and non-EU European countries are urgently needed. Two PRCA cases occurring with subcutaneous HX575 (one certain, one likely) indicate that chances of inducing a more immunogenic product are unpredictable, even with a biosimilar epoetin approved under the EMA biosimilar approval pathway. Phase III clinical trials with peginesatide, a pegylated synthetic peptide-based ESA without any homology to erythropoietin raised safety concerns in non-dialysis CKD patients but not in dialysis patients. PMID- 23338540 TI - Certolizumab pegol: a review of its use in the management of rheumatoid arthritis. AB - Certolizumab pegol (Cimzia((r))) is a recombinant, polyethylene glycolylated, antigen-binding fragment of a humanized monoclonal antibody that selectively targets and neutralizes tumour necrosis factor (TNF)-alpha. The drug is indicated for subcutaneous use every 2 or 4 weeks (q2w or q4w) for the treatment of adults with moderate to severe active rheumatoid arthritis (RA). The efficacy of subcutaneous certolizumab pegol in adults with active RA has been investigated in several well designed, placebo-controlled trials. In four pivotal studies of <=52 weeks duration, patients with moderate to severe disease receiving recommended dosages of certolizumab pegol (200 mg q2w or 400 mg q4w), either as monotherapy (after failing prior disease-modifying anti-rheumatic drug [DMARD] therapy) or in combination with methotrexate (after responding inadequately to methotrexate alone), experienced rapid clinical improvement, with some combination trials also demonstrating inhibition of radiographic progression. The beneficial effects of certolizumab pegol therapy were generally maintained for up to ~5 years in clinical trial extensions in which the drug was administered at dosages of 400 mg q4w or q2w. Additional studies suggest certolizumab pegol is also effective in patients who are Asian or have low to moderate disease activity, as well as more clinically representative patient populations. The tolerability profile of certolizumab pegol was acceptable, with infections/infestations the most common adverse events. Thus, certolizumab pegol is an effective option for the management of active RA in adults, although additional long-term and comparative efficacy and tolerability data are needed to help definitively position certolizumab pegol relative to other biological DMARDs, particularly other anti TNF agents. PMID- 23338541 TI - The effect of simulated knee flexion on sagittal spinal alignment: novel interpretation of spinopelvic alignment. AB - INTRODUCTION: Many studies regarding spinal sagittal alignment were focused mainly on above-hip structures, not considering the knee joint. Knee-spine syndrome was proposed earlier, but the mechanism of this phenomenon has not been revealed. The aim of the study was to demonstrate how spinopelvic alignment and sagittal balance change in response to simulated knee flexion in normal non diseased population. METHODS: Thirty young male were enrolled in the study cohort. Two motion-controlled knee braces were used to simulate knee flexion of 0 degrees , 15 degrees , and 30 degrees settings. Whole spine and lower extremity lateral radiographs were taken at each knee setting of 0 degrees , 15 degrees , and 30 degrees flexion. Spinal and pelvic parameters were measured, including two angular parameters, femoropelvic angle (FPA) and femoral tilt angle (FTA). RESULTS: The following equation can be made; PT (pelvic tilt) = FPA + FTA. The mean values of FPA and lumbar lordosis decreased significantly at 15 degrees and 30 degrees knee settings compared to the parameters at the 0 degrees knee setting, while the mean values of pelvic tilt and sacral slope rarely changed. Results also showed FTA was not correlated with PT, but strongly correlated with FPA (R = -0.83, p < 0.01). CONCLUSIONS: The knee flexion resulted in decrease of lumbar lordosis without a significant change of pelvic posture in non-diseased population group. PMID- 23338542 TI - Utilization of physical rehabilitation among people with multiple sclerosis. AB - BACKGROUND: The goal in rehabilitating patients with multiple sclerosis (MS) is to minimize their physical and mental impairments and keep them integrated into their social environment. However, rehabilitation is not systematically utilized in MS patients. OBJECTIVES: This study aimed to determine how many patients diagnosed with MS use rehabilitation as a way of treatment and to evaluate correlation between use of rehabilitation and level of impairment. METHODS: We analyzed data regarding the use of rehabilitation in the last 2 years in 63 MS patients. Data were gathered using questionnaires during regular visits to neurological outpatient clinic from October to December 2011. Expanded Disability Status Scale (EDSS) was determined for all patients. RESULTS: One or more types of rehabilitation were used in 41.3% of questioned patients: inpatient, outpatient and home-based rehabilitation were used in 28.5, 17.4 and 4.7% of patients, respectively. Average EDSS in group with inpatient rehabilitation was 2.9, in group with outpatient rehabilitation 3.0 and in group without rehabilitation 1.0. We found that patients who used inpatient, outpatient and home-based rehabilitation had higher level of impairment comparing to patients who were not rehabilitated (p=0.002, p=0.004 and p=0.021, respectively). CONCLUSION: Rehabilitation of MS patients is not systematically provided, especially in early stages of disease when best results can be achieved. PMID- 23338543 TI - Life after the cancer strategy: analysis of surgical workload in the general hospital setting. AB - BACKGROUND: The National Cancer Strategy heralded a major reorganisation of the delivery of cancer services in Ireland. As a result of this policy, cancer care was centralised to eight centres. The impact of this strategy on hospitals no longer providing cancer services has not been analysed to date. AIM: The aim of this study was to examine the impact of centralisation of cancer services on surgical workload at Mayo General Hospital. METHODS: Data pertaining to all surgical procedures performed in 2007 (prior to the introduction of the National Cancer Strategy) and 2011 were obtained using the Hospital Inpatient Enquiry system. Histopathology reports and theatre registers were also analysed to ensure accuracy of the data. RESULTS: The numbers of elective and emergency surgical admissions during 2007 and 2011 were broadly similar (2,581 vs. 2,662). One hundred and thirty-five oncological procedures (colorectal and breast) were carried out in 2007 compared with 50 (colorectal) in 2011. This represents a 63% reduction in cancer surgery workload following the implementation of the National Cancer Strategy. There was a concomitant increase in surgery performed for benign conditions (laparoscopic cholecystectomy and hernia repair), which coincided with the innovative introduction of 43 ring-fenced surgical in-patient beds in June 2010. CONCLUSION: This study demonstrates the impact of the centralisation of cancer services on surgical workload in a non-cancer centre. Our results show that there continues to be a role for general hospitals in the provision of elective surgical services. Hospital network arrangements have the potential to facilitate such developments. PMID- 23338544 TI - Proteomic (antibody microarray) exploration of the molecular mechanism of action of the specific COX-2 inhibitor DuP 697. AB - We have previously shown that specific COX-2 inhibitors, including DuP 697, have anti-proliferative effects on mesothelioma cells and potentiate the cytotoxicity of pemetrexed. Here, we used a novel proteomic approach to explore the mechanism of action of this agent. COX-2-positive cell lines MSTO-211H (mesothelioma) and A549 (lung cancer) were exposed to DuP 697 for 72 h. Drug carrier only was added to control cells. Extracted proteins from treated and control cells were analysed using a comparative proteomic platform. Differentially expressed proteins, identified by the Panorama Xpress Profiler725 antibody microarray were submitted to Ingenuity Pathway Analysis. A total of 32 unique differentially expressed proteins were identified with a significant (>1.8-fold) difference in expression between treated and untreated cells in at least one cell line. Five molecules, BCL2L1 (Bcl-xL), BID, CHUK (IKK), FASLG and RAF1, were mapped to the Apoptosis Signaling pathway following Ingenuity Pathway Analysis. BCL2L1 (Bcl-xL) and BID were analysed using immuno-blotting and differential expression was confirmed. Proteomic (antibody microarray) analysis suggests that the mechanism of action of DuP 697 may be exerted via the induction of apoptosis. The antibody microarray platform can be utilised to explore the molecular mechanism of action of novel anticancer agents. PMID- 23338545 TI - [Again the issue of abortion in Brazil: winds of change?]. PMID- 23338546 TI - Can endometrial arylsulfatase A activity predict the onset of endometrial polyps over the years? AB - PURPOSE: To assess if arylsulfatase A activity (ASA) and sulfatide (SL) concentration in the human endometrium can be predictive of the development of endometrial polyps over the years, since ASA activity reflects the endometrial sensitivity to hormones. METHODS: ASA activity and SL concentration were determined by biochemical procedures on endometrial samples collected between 1990 and 1994 in non-menopausal women. These women underwent a new endometrial sampling following the clinical indication some years after the first endometrial sampling. The histological assessment of the second endometrial specimens found four patients with normal endometrial pattern and 10 patients with one or more endometrial polyps. ASA activity/years elapsed and SL concentration/years elapsed were compared using two tailed Mann-Whitney test for unpaired data between patients with normal pattern and patients with endometrial polyps. RESULTS: Median ASA activities were 2.62 (normal pattern) versus 1.85 (endometrial polyps) nmol hydrolized substrate/min. Median activity/years elapsed is higher in patients with second endometrial sample presenting normal pattern (p=0.006) and median SL concentration/years elapsed does not differ significantly among groups, even if median SL concentration seems to be higher in patients who subsequently developed polyps (1031 ug/g of fresh tissue versus 341,5 ug/g of fresh tissue). CONCLUSIONS: ASA activity can predict the onset of endometrial polyps over the years. PMID- 23338547 TI - [The effect of an exercise program to strengthen pelvic floor muscles in multiparous women]. AB - PURPOSES: To investigate the effect of an individualized and supervised exercise program for the pelvic floor muscles (PFM) in the postpartum period of multiparous women, and to verify the correlation between two methods used to assess PFM strength. METHODS: An open clinical trial was performed with puerperal, multiparous women aged 18 to 35 years. The sample consisted of 23 puerperal women divided into two groups: Intervention Group (IG, n=11) and Control Group (CG, n=12). The puerperal women in IG participated in an eight-week PFM exercise program, twice a week. The puerperal women in CG did not receive any recommendations regarding exercise. PFM strength was assessed using digital vaginal palpation and a perineometer. The statistical analysis was performed using the following tests: Fisher's exact, chi(2), Student's t, Kolmogorov Smirnov for two samples, and Pearson's correlation coefficient. Significance was defined as p<0.05. RESULTS: The participants' mean age was 24 +/- 4.5 years in IG and 25.3 +/- 4 years in CG (p=0.4). After the exercise program, a significant difference was found between the groups in both modalities of muscle strength assessment (p<0.001). The two muscle strength assessment methods showed a significant correlation in both assessments (1(st) assessment: r=0.889, p<0.001; 2(nd) assessment: r=0.925, p<0.001). CONCLUSIONS: The exercise program promoted a significant improvement in PFM strength. Good correlation was observed between digital vaginal palpation and a perineometer, which indicates that vaginal palpation can be used in clinical practice, since it is an inexpensive method that demonstrated significant correlation with an objective method, i.e. the use of a perioneometer. PMID- 23338548 TI - [Correlation of the International Consultation on Incontinence Questionaire: Urinary Incontinence/Short Form to Urodynamic diagnosis in women with urinary incontinence]. AB - PURPOSE: To evaluate the correlation between the International Consultation on Incontinence Questionnaire - Urinary Incontinence/Short Form (ICIQ-UI/SF) and Urodynamic evaluation (UE) in women with urinary incontinence (UI). METHODS: Clinical data, UE and ICIQ-UI/SF scores for 358 patients from private health service were analyzed retrospectively . The correlation between ICIQ-UI/SF and urodynamic parameters was determined by Spearman's test. A ROC curve with the sensitivity and specificity of the ICIQ-UI/SF scores was utilized to establish the value of the questionnaire that would predict an altered urodynamic parameter. The chi(2) test or Fisher's exact test was used to calculate the p value. The level of significance was 5% and the software used was SAS 9.2. RESULTS: Sixty-seven point three percent of the patients presented Stress UI (SUI) according to the UE (urodynamic SUI); those with SUI and Detrusor overactivity (DO) at UE represented 16.2% of the women (SUI+DO), and those with only DO at UE (DO) represented 7.3% of the women. Patients with normal UE represented 9.2% of the women. There was a significant association between ICIQ UI/SF scores >=14 and patients with urodynamic SUI, with or without DO. Patients with Valsava Leak Point Pressure (VLPP)<=90 cmH2O presented ICIQ-UI/SF>=15. Spearman's test showed a weak inverse correlation between ICIQ-UI/SF score and VLPP, although it did not show any correlation with maximum cystometric capacity or with bladder volume on first desire to void. CONCLUSION: There was an association between ICIQ-UI/SF score and patients with SUI, with or without DO, but no association between the score and patients with DO alone. The lower the VLPP value, the higher the ICIQ-UI/SF score. The ICIQ-UI/SF was not able to distinguish the different types of UI in the studied population. PMID- 23338549 TI - Arterial hypertension and metabolic profile in patients with polycystic ovary syndrome. AB - PURPOSE: To evaluate parameters related with arterial pressure and metabolic profile in women with polycystic ovary syndrome (POS). METHODS: This monocentric study at the University Hospital Endocrinology Section included 60 women aged 18 45 years, 42 being diagnosed with POS and acting as 18 controls. All women were subjected to transvaginal ultrasound and monitored for arterial pressure for 24 h in the ambulatory (MAP). Venous blood samples were taken between 07.00 and 09.00, after 12 h fasting. Basal (BG) and fasting glucose concentrations, total cholesterol and its fractions, triglycerides and insulin (to calculate the homeostatic assay insulin-resistance, HOMA-IR) were measured. Collected data were the mean arterial blood pressure (24-h awake/sleep cycle), arterial pressure nocturnal descensus, glycemia and fasting glucose for HOMA-IR, and lipid profile. The Student's t test was used to compare homogeneous variables; the Mann-Whitney test was used to compare non-homogeneous variables; the Pearson's correlation coefficient was used to search for correlation between the variables. The chi(2) test was used for comparison of the absence of nocturnal descensus. Significance was taken as p<0.05. RESULTS: The mean age of the patients with POS was 27.4 +/- 5.5 (18-45 years, n=42) and the body mass index (BMI) was 30.2 +/- 6.5 kg/m(2) (18.3-54.9). In the Control Group, the mean age was 31.4 +/- 6.1 (18-45 years) and the BMI was 27.1 +/- 6.2 kg/m(2) (18.3-54.9, n=18). No difference in the metabolic parameters and insulin resistance was observed between the two groups. Comparison between these parameters and MAP showed that the only parameter with a correlation was the BMI, independent of the POS diagnosis. This was not seen in nocturnal descensus, which was uncorrelated with POS and any of the other studied parameters. CONCLUSION: POS women do not show higher arterial blood pressure, glycemia, HDL-col, TG, HOMA-IR and BMI compared to non-POS women. However, POS patients showed correlation between arterial pressure and BMI, suggesting that obesity is a primary factor involved in arterial pressure changes in these patients. PMID- 23338550 TI - [Abortion in women living in the outskirts of Sao Paulo: experience and socioeconomic aspects]. AB - PURPOSE: To compare and analyze socioeconomic aspects and the emotional experience of women with spontaneous or induced abortion and in women living in the outskirts of Sao Paulo. METHODS: A prospective case-control study carried out from July 2008 to March 2010, involving semi-structured interviews with women who presented a previous diagnosis of abortion and who had been admitted to two public hospitals in the outskirts of Sao Paulo. The study included 100 women with diagnosis of abortion and were hospitalized for curettage. Eleven women who reported induced abortion (11%) represented the case group. The control group (n=22) was selected at a 2:1 ratio according to the following procedure: for every case of induced abortion, the next two cases of spontaneous abortion at the same hospital. A semistructured interview was conducted with questions regarding emotional aspects and family, social and economic context. RESULTS: The women with induced abortion compared to the group with spontaneous abortion had lower educational level, with more frequent elementary level (82 versus 36%, p=0.04), lower income (median, R$ 1,000.00 versus R$ 1,400.00, p=0.04), lower personal income (median, R$ 200.00 versus R$ 333.00, p=0.04), higher frequency of negative feelings upon suspicion (82 versus 22%, p=0.004) and confirmation (72 versus 22%, p=0.03) of pregnancy. CONCLUSION: Among women looking for health care in hospitals in the outskirts of Sao Paulo, induced abortion is related to unfavorable socioeconomic conditions, which affects the emotional experiences of suspicion and confirmation of pregnancy. PMID- 23338551 TI - [Longitudinal reference intervals of maternal-fetal Doppler parameters]. AB - PURPOSE: To create longitudinal reference intervals for pulsatility index (PI) of the umbilical (UA), middle cerebral (MCA), uterine (UtA) arteries and ductus venosus (DV) in a Brazilian cohort. METHODS: A longitudinal observational study performed from February 2010 to May 2012. Low risk pregnancies were scanned fortnightly from 18 to 40 weeks for the measurements of PI of the UA, MCA, DV and UtA. Linear mixed models were used for the elaboration of longitudinal reference intervals (5th, 50th and 95th percentiles) of these measurements. PI obtained for the placental and abdominal portions of the umbilical artery were compared by the t-test for independent samples. Two-sided p values of less than 0.05 were considered statistically significant. RESULTS: A total of 164 patients underwent 1,242 scans. There was significant decrease in PI values of all vessels studied with gestational age (GA). From the 18(th) to the 40(th) week of pregnancy, the median PI values of UA (abdominal and placental ends of the cord), MCA, DV and the mean PI of the UtA ranged from 1.19 to 0.74, 1.33 to 0.78, 1.56 to 1.39, 0.58 to 0.41, and 0.98 to 0.66, respectively. The following equations were obtained for the prediction of the medians: PI-UA=1.5602786 - (0.020623 x GA); Logarithm of the PI-MCA=0.8149111 - (0.004168 x GA) - [0.02543 x (GA - 28.7756)2]; Logarithm of the PI-DV=-0.26691- (0.015414 x GA); PI-UtA = 1.2362403 - (0.014392 x GA). There was a significant difference between the PI-UA obtained at the abdominal and placental ends of the umbilical cord (p<0.001). CONCLUSIONS: Longitudinal reference intervals for the main gestational Doppler parameters were obtained in a Brazilian cohort. These intervals could be more adequate for the follow-up of maternal-fetal hemodynamic modifications in normal and abnormal pregnancies, a fact that still requires further validation. PMID- 23338552 TI - Complete mole in a dichorionic twin pregnancy after intracytoplasmic sperm injection. AB - A dichorionic twin pregnancy with complete hydatidiform mole and coexistent fetus is a rare and challenging situation, whose pathogenesis has not been yet fully understood. We present a case of a 39-year-old woman who underwent intracytoplasmic sperm injection with two embryos transfer. The 12-week gestation ultrasound examination revealed normal fetus and placenta with features of hydatidiform mole, leading to pregnancy termination. Autopsy and histological examinations diagnosed a complete mole coexisting with a normal fetus, and the genetic analysis showed a diploid fetus with biparental genome and molar tissue with paternal diploidy. This case highlighted that complete molar pregnancies may still occur even though pregnancy is achieved after intracytoplasmic sperm injection. A review of the literature was performed by collecting data from the few similar reported cases and by commenting on the pathogenesis of this rare condition. PMID- 23338553 TI - Exercise training programs in Dutch cardiac rehabilitation centres. AB - PURPOSE: To assess methods for determination of exercise intensity, and to investigate practice variation with respect to the contents, volume and intensity of exercise training programs in Dutch cardiac rehabilitation (CR) centres. METHODS: A paper questionnaire was sent to all Dutch CR centres, consisting of 85 questions for patients with an acute coronary syndrome (ACS) or after coronary revascularisation (Group 1) and for patients with chronic heart failure (CHF, Group 2). RESULTS: CR professionals from 45 centres completed the questionnaires (58 %). Symptom-limited exercise testing was used to determine exercise capacity in 76 % and 64 % of the CR centres in group 1 and group 2, respectively; in these centres, a percentage of the maximum heart rate was the most frequently used exercise parameter (65 % and 56 %, respectively). All CR centres applied aerobic training and the majority applied strength training (64 % in group 1 and 92 % in group 2, respectively). There was a considerable variation in training intensity for both aerobic and strength training, as well as in training volume (1-20 h and 1-18 h respectively). CONCLUSION: Among Dutch CR centres, considerable variation exists in methods for determination of exercise intensity. In addition, there is no uniformity in training volume and intensity. PMID- 23338555 TI - Prostate cancer disease severity and country of origin among black men in the United States. AB - BACKGROUND: Previous studies have reported higher rates of advanced Gleason score among black versus white men with prostate cancer in the United States. However, few studies have examined if elevated Gleason scores among black men vary by country of birth. We examined differences in prostate cancer disease severity among US black men born in the United States and in Jamaica, West Africa and other sub-Saharan Africa countries. METHODS: Our study included 19 798 US-born, 267 Jamaican-born, and 246 West African-born black men diagnosed with prostate cancer during 2004-2009 in the 18 Surveillance Epidemiology and End Results population-based cancer registries. We evaluated the association of advanced Gleason score (7-10), as well as PSA levels and stage by country of origin adjusting for age, and county-level income. RESULTS: Among men with known Gleason score, the percentage of advanced Gleason score (scores 7-10) was 61.11% in Jamaican-born, 60.99% in West African-born and 58.26% in US-born black men (P value=0.49). In a multivariable analysis among black men, there were no differences in advanced Gleason score (scores 7-10 versus 2-6) by country of origin. Mean PSA level (range 12.8-13.1 ng ml(-1)) did not vary among black men (P-value=0.94) in unadjusted and adjusted results. CONCLUSIONS: Similar Gleason score among US-born, African and Caribbean-born black men were observed. Future more detailed studies are needed to elucidate if these similarities are a result of similar early detection practices or shared risk factors. PMID- 23338554 TI - miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models. AB - AIMS/HYPOTHESIS: The loss of beta cell function is a critical factor in the development of type 2 diabetes. Glucotoxicity plays a major role in the progressive deterioration of beta cell function and development of type 2 diabetes mellitus. Here we demonstrate that microRNA (miR)-30a-5p is a key player in early-stage glucotoxicity-induced beta cell dysfunction. METHODS: We performed northern blots, RT-PCR and western blots in glucotoxicity-exposed primary rat islets and INS-1 cells. We also measured glucose-stimulated insulin secretion and insulin content. In vivo approaches were used to evaluate the role of miR-30a-5p in beta cell dysfunction. RESULTS: miR-30a-5p expression was increased in beta cells after exposure to glucotoxic conditions, and exogenous miR-30a-5p overexpression also induced beta cell dysfunction in vitro. miR-30a-5p directly suppressed expression of Beta2/NeuroD (also known as Neurod1) by binding to a specific binding site in its 3'-untranslated region. After restoration of Beta2/NeuroD expression by knockdown miR-30a-5p or transfection of the Beta2/NeuroD gene, beta cell dysfunction, including decreased insulin content, gene expression and glucose-stimulated insulin secretion, recovered. Glucose tolerance and beta cell dysfunction improved on direct injection of Ad-si30a-5p into the pancreas of diabetic mice. CONCLUSIONS/INTERPRETATION: Our data demonstrate that miR-30a-5p-mediated direct suppression of Beta2/NeuroD gene expression is an important initiation step of glucotoxicity-induced beta cell dysfunction. PMID- 23338556 TI - High Nr-CAM expression is associated with favorable phenotype and late PSA recurrence in prostate cancer treated by prostatectomy. AB - BACKGROUND: Neuron-glia-related cell-adhesion molecule (Nr-CAM) is another potential membrane-bound target molecule for specific prostate cancer therapy. The role of Nr-CAM in normal and neoplastic prostate tissue has not been extensively studied. The aim of our study is to evaluate the prevalence of Nr-CAM expression in prostate cancer and to explore its association with phenotype and clinical disease course. METHODS: A preexisting tissue microarray including more than 3000 prostate cancers that underwent prostatectomy at our center with clinical follow-up data was used. The tissue microarray (TMA) was immunhistochemically stained for Nr-CAM. RESULTS: A total of 2883 (88.4%) of tumor samples were interpretable in our TMA analysis. Membranous Nr-CAM staining was seen in 1418 (49.2%) of 2883 analyzable cases. According to predefined criteria, staining was considered weak in 778 (27.0%), moderate in 412 (14.3%) and strong in 228 (7.9%) cancers. Significant associations were found with pathological tumor stage (P=0.0015), Gleason grade (P=0.0003), nodal stage (P=0.0061), preoperative PSA (P=0.0138) and prolonged PSA recurrence-free survival (P<0.0001). CONCLUSIONS: Nr-CAM expression is frequent in prostate cancer. High level of Nr-CAM expression is associated with favorable tumor phenotype and reduced risk of PSA recurrence. The abundant presence of Nr-CAM in prostate cancer epithelium makes Nr-CAM a potential target of therapy. PMID- 23338557 TI - Low-cost industrially available molybdenum boride and carbide as "platinum-like" catalysts for the hydrogen evolution reaction in biphasic liquid systems. AB - Rarely reported low-cost molybdenum boride and carbide microparticles, both of which are available in abundant quantities due to their widespread use in industry, adsorb at aqueous acid-1,2-dichloroethane interfaces and efficiently catalyse the hydrogen evolution reaction in the presence of the organic electron donor - decamethylferrocene. Kinetic studies monitoring biphasic reactions by UV/vis spectroscopy, and further evidence provided by gas chromatography, highlight (a) their superior rates of catalysis relative to other industrially significant transition metal carbides and silicides, as well as a main group refractory compound, and (b) their highly comparable rates of catalysis to Pt microparticles of similar dimensions. Insight into the catalytic processes occurring for each adsorbed microparticle was obtained by voltammetry at the liquid-liquid interface. PMID- 23338558 TI - Direct arylation of phenanthroline derivatives via oxidative C-H/C-H cross coupling: synthesis and discovery of excellent ligands. AB - A concise synthetic protocol for aryl functionalized phenanthrolines has been developed. It was demonstrated that 3,8-diphenyl-1,10-phenanthroline (7a) is competent in promoting transition-metal-free direct arylation and 2,3,8,9 tetraphenyl-1,10-phenanthroline (8a) is a highly efficient ligand in the in situ Pd-catalysed Heck reaction. PMID- 23338559 TI - Clinical relevance of plasma miR-106b levels in patients with chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is characterized by both chronic inflammation in the airway and systemic inflammation; however, the molecular mechanism of COPD has not been fully elucidated. By measuring microRNA (miRNA) expression in the plasma of COPD subjects, we aimed to identify the clinical relevance of plasma miRNA levels in these patients. Blood samples were obtained from COPD patients and age-matched normal controls. We initially produced plasma miRNA expression profiles using TaqMan low-density array screening. For further validation, individual qRT-PCRs were performed in 40 COPD patients and 20 healthy subjects. TaqMan low-density array screening showed that 9 miRNAs (miR-29b, miR 483-5p, miR-152, miR-629, miR-26b, miR-101, miR-106b, miR-532-5p and miR-133b) were significantly downregulated in the plasma from COPD patients when compared with normal smokers. Among these miRNAs, we focused on miR-106b. A reduction in the plasma miR-106b levels was evident in COPD ex-smokers and COPD current smokers compared with levels in smokers. There was a negative correlation between the plasma miR-106b level and the duration of disease since diagnosis in COPD ex smokers and the duration of smoking in COPD current smokers. These findings support the concept that progressive reduction in the plasma miR-106b level may reflect persistent and systemic changes even after the discontinuation of smoking in COPD patients. miR-106b may therefore play an important role in the pathogenesis of COPD. PMID- 23338560 TI - Why longer song elements are easier to detect: threshold level-duration functions in the Great Tit and comparison with human data. AB - Our study estimates detection thresholds for tones of different durations and frequencies in Great Tits (Parus major) with operant procedures. We employ signals covering the duration and frequency range of communication signals of this species (40-1,010 ms; 2, 4, 6.3 kHz), and we measure threshold level duration (TLD) function (relating threshold level to signal duration) in silence as well as under behaviorally relevant environmental noise conditions (urban noise, woodland noise). Detection thresholds decreased with increasing signal duration. Thresholds at any given duration were a function of signal frequency and were elevated in background noise, but the shape of Great Tit TLD functions was independent of signal frequency and background condition. To enable comparisons of our Great Tit data to those from other species, TLD functions were first fitted with a traditional leaky-integrator model. We then applied a probabilistic model to interpret the trade-off between signal amplitude and duration at threshold. Great Tit TLD functions exhibit features that are similar across species. The current results, however, cannot explain why Great Tits in noisy urban environments produce shorter song elements or faster songs than those in quieter woodland environments, as detection thresholds are lower for longer elements also under noisy conditions. PMID- 23338561 TI - Antitumor properties of salinomycin on cisplatin-resistant human ovarian cancer cells in vitro and in vivo: involvement of p38 MAPK activation. AB - In order to search for alternative agents to overcome chemoresistance during the treatment of ovarian cancer, this study aimed to examine the anticancer effects and action mechanism of salinomycin, a selective inhibitor of cancer stem cells, on cisplatin-resistant human ovarian cancer cell lines in vitro and in vivo. The concentration- (0.01-200 uM) and time-dependent (24-72 h) growth inhibitory effects of salinomycin were observed in the ovarian cancer cell lines OV2008, C13, A2780, A2780-cp, SKOV3 and OVCAR3, by measuring cell viability using the resazurin reduction assay. The IC50 (24 h) range of salinomycin on the six cell lines was found to be 1.7-7.4 uM. After cisplatin-resistant C13 cells were treated with salinomycin, the percentage of apoptotic cells determined by flow cytometry was significantly increased, in a concentration- and time-dependent manner. However, no cell cycle arrest was detected in the G1/G0, S and G2/M phases in the salinomycin-treated and control cells. The Bio-Plex phosphoprotein 5-plex assay (Akt, IkappaB-alpha, ERK1/2, JNK and p38 MAPK) demonstrated a marked time- and concentration-dependent increase in the phosphorylation of p38 MAPK, subsequent to salinomycin treatment. Moreover, salinomycin significantly suppressed tumor growth in a tumor xenograft model. These findings suggested that salinomycin efficiently inhibits the cisplatin-resistant human ovarian cancer cell line growth through the induction of apoptosis, potentially associated with the p38 MAPK activation. PMID- 23338562 TI - In support of more clustered randomized trials. PMID- 23338563 TI - Depression, substance abuse and other contextual predictors of adherence to antiretroviral therapy (ART) among Haitians. AB - Haiti has the highest number of individuals living with HIV in the Caribbean. Due to Haiti's resource-poor environment and inadequate mental health and substance abuse services, adherence to antiretroviral therapy (ART) may be especially difficult. This study examined associations among demographics, maladaptive coping, partner conflict, alcohol problems, depression, and negative attitudes about medications and their impact on adherence among 194 HIV-positive Haitians. In a mediated directional structural equation model, depression and negative attitudes about ART directly predicted poorer adherence. Greater partner conflict, maladaptive coping and alcohol problems predicted more depression. Maladaptive coping predicted a negative attitude about ART. Alcohol problems predicted partner conflict and maladaptive coping. Significant indirect effects on adherence mediated through both depression and negative attitudes about ART include negative effects of female gender, alcohol problems and maladaptive coping. Results highlight the importance of integrated care for depression, alcohol use and other psychosocial problems to increase ART adherence. PMID- 23338564 TI - Charges for criminal exposure to HIV and aggravated prostitution filed in the Nashville, Tennessee Prosecutorial Region 2000-2010. AB - This paper examines comprehensive data on arrests for HIV-specific crimes within a single jurisdiction, the Nashville Tennessee prosecutorial region, over 11 years. There were 25 arrests for HIV exposure and 27 for aggravated prostitution. Eleven of the arrests for HIV exposure involved nonsexual behaviors; none alleged transmission. Sixteen of the arrests for HIV exposure involved sexual behavior; three alleged transmission. Aggravated prostitution cases (i.e. prostitution while knowing one has HIV) often involved solicitation of oral sex; none alleged transmission. Maximum sentences for HIV-specific crimes ranged from 5 to 8 years. We conclude that enforcement of US HIV-specific laws is underestimated. Fifty-two arrests over 11 years were recorded in one jurisdiction. Over half of the arrests involved behaviors posing minimal or no HIV transmission risk. Despite concerns about malicious, intentional HIV transmission, no cases alleged malice or intention. PMID- 23338565 TI - HIV and men who have sex with men in South Africa. PMID- 23338568 TI - Tat-SmacN7 induces radiosensitization in cancer cells through the activation of caspases and induction of apoptosis. AB - A major concern in cancer therapy is resistance of tumors such as human non-small cell lung cancer and esophageal cancer to radiotherapy. Intrinsic radioresistance of these cancer cells limits therapeutic efficiency. Here, we determined in two cancer cell lines the potential radiosensitizing activity of Tat-SmacN7, a small molecule compound, which mimics the activity of Smac, a mitochondrial protein released during apoptosis. We found that Tat-SmacN7 can enter the cells and promote RNA expression and the activity of caspase-3, -8 and -9 and sensitized the cancer cells to radiation with a sensitization enhancement ratio (SER) of 1.5 1.6. Tat-SmacN7 radiosensitization was mediated by both extrinsic and intrinsic apoptosis pathways through activation of caspases. Consistently, blockage of caspase activation, through treatment with a caspase inhibitor, z-VAD-fmk, inhibited apoptosis and abrogated Tat-SmacN7 radiosensitization. Our study demonstrates that Tat-SmacN7 also has radiosensitization effects in vivo, so it could be further developed as a novel class of radiosensitizers for the treatment of radioresistant human non-small cell lung cancer and esophageal cancer. PMID- 23338569 TI - Evaluation of fully automated ventilation: a randomized controlled study in post cardiac surgery patients. AB - PURPOSE: Discrepancies between the demand and availability of clinicians to care for mechanically ventilated patients can be anticipated due to an aging population and to increasing severity of illness. The use of closed-loop ventilation provides a potential solution. The aim of the study was to evaluate the safety of a fully automated ventilator. METHODS: We conducted a randomized controlled trial comparing automated ventilation (AV) and protocolized ventilation (PV) in 60 ICU patients after cardiac surgery. In the PV group, tidal volume, respiratory rate, FiO(2) and positive end-expiratory pressure (PEEP) were set according to the local hospital protocol based on currently available guidelines. In the AV group, only sex, patient height and a maximum PEEP level of 10 cmH(2)O were set. The primary endpoint was the duration of ventilation within a "not acceptable" range of tidal volume. Zones of optimal, acceptable and not acceptable ventilation were based on several respiratory parameters and defined a priori. RESULTS: The patients were assigned equally to each group, 30 to PV and 30 to AV. The percentage of time within the predefined zones of optimal, acceptable and not acceptable ventilation were 12 %, 81 %, and 7 % respectively with PV, and 89.5 %, 10 % and 0.5 % with AV (P < 0.001). There were 148 interventions required during PV compared to only 5 interventions with AV (P < 0.001). CONCLUSION: Fully AV was safe in hemodynamically stable patients immediately following cardiac surgery. In addition to a reduction in the number of interventions, the AV system maintained patients within a predefined target range of optimal ventilation. PMID- 23338571 TI - Invasive pulmonary aspergillosis in the ICU: an emerging disease? PMID- 23338572 TI - Invasive pulmonary aspergillosis in the ICU: reply to Wichmann et al. PMID- 23338570 TI - Year in review in Intensive Care Medicine 2012: III. Noninvasive ventilation, monitoring and patient-ventilator interactions, acute respiratory distress syndrome, sedation, paediatrics and miscellanea. PMID- 23338573 TI - Nursing and care for the elderly at home. PMID- 23338574 TI - [The interface of nursing care with the aged attention policies]. AB - The objective was to make an explanation on the interface of nursing care with the elder care policies. It is presented the aging phenomenon as a global reality and a victory of modern society; the situation of elderly people and the social consequences of aging in Spain; the dependence and assistance needs; the situation of elderly people in Brazil; comparison between Spain and Brazil; dependency levels; and the solutions that nurses provide and home care as a basis for a better future. The considerations given are: meeting the dependency must be addressed immediately, considering the failures in other countries, to avoid the same mistakes, and to urge the elder population to maintain their independence with health promotion. PMID- 23338575 TI - [Caregivers of dependent elderly at home: changes in family relationships]. AB - The study aimed to identify, in the view of the caretaker, the changes that happened in the family relationships after a dependence generator event on aged person, and the factors that provoked it. It is a field study with a qualitative approach. It was carried out recorded interviews with eight family caregivers, during home visits, with guiding questions and observations being recorded in a field diary. The content analysis of Bardin was applied, being constructed categories and subcategories. The familiar union preexisting to the dependence situation predisposes positive changes, favored with formal and informal support. The family caregiver burden due to lack of support, age and activities of caregiving, leads to negative situations in the family. The effectiveness of public policies to provide formal support for the elderly and their caregivers, and the creation of support groups, may contribute to the family wellbeing. PMID- 23338576 TI - [Drug use by elderly residents in long-stay institutions, Brasilia-DF, Brazil]. AB - The aim of this study is to describe the drug utilization by 154 elderly from five long-stay institutions of Brasilia-DF, Brazil, through a questionnaire adapted from the Dader Method. The sample is characterized mostly of men, age of 74.6 years, with preserved cognition, low income and low education level and in use of four to five medications. The adherence to pharmacotherapy is compromised by low knowledge about current medical prescription, difficulty of access and refusal to use medicines. Results suggest the need for investment in human resources training and research in the area to provide better quality of life and to reduce costs with the assistance health. PMID- 23338577 TI - [Prevention of sexually transmitted diseases in the point of view of elderly clients of a Family Health Strategy]. AB - The aim of this study was to assess the knowledge of elderly people on preventive actions to sexually transmitted diseases (STDs) in the context of the Family Health Strategy (FHS). This is a cross-sectional study, involving 94 elderly, aged >= 60 years, attached to the ESF in Serra Gaucha (a region at Rio Grande do Sul, Brazil). The results indicate parity in the sample for sexual activity and prevalence of sexual activity with the same partner. Older people have knowledge of how to prevent STDs, mostly by the use of condoms. Most interviewees reported they received no information from FHS team. Those who received orientation related that the focus was on the usage of condoms. It is necessary to intensify the actions and discussions of sexuality and STDs, aimed at healthy aging. PMID- 23338578 TI - [Construction and validation of an instrument to assess the Reception with Risk Rating]. AB - Methodological study, carried out between April to December 2010, which aimed to describe the criteria for construction, appearance and content validation of an instrument to assess the Reception with Risk Rating (RRR). The strategies of Content Validation through Delphi technique and Appearance Validation were used. The appreciation of the instrument was made by a panel of judges, consisting of ten nurses, teachers with titration of specialists, teachers and/or doctors with experience in RRR. We conclude that the instrument has content and appearance validity to assess the RRR because the indices of reliability and agreement in all three dimensions of health evaluation Donabedian reached values above the established standard, ie 80%. PMID- 23338579 TI - [User embracement and attachment in the humanization of nursing care for people with diabetes mellitus]. AB - It is a qualitative research, which aimed to evaluate the user embracement and attachment in the humanization of nursing care for people with Diabetes Mellitus in a public specialized outpatient service. The theoretical support was the National Policy of Humanization of the Health Ministry / Brazil. Data was collected through semi-structured interviews with twenty people with type 1 or type 2 diabetes, between 2010 March and May. The analysis resulted in four categories that explore listening and dialogue, relationships, problem solving and access. People with diabetes recognize the user embracement and attachment as part of humanized attention given, which is highlighted by the appreciation of the patients' subjective dimension. PMID- 23338580 TI - [History of care to women in the Maternity Carmela Dutra, Florianopolis-SC, Brazil (1956-2001)]. AB - This study examines the practices of care developed by nurses to women at Maternity Carmela Dutra, Florianopolis, Santa Catarina state, Brazil, in the period 1956 to 2001. It is a qualitative research with socio-historical approach. Nine nurses were interviewed using the technique of thematic oral history. The data were categorized using thematic content analysis and based on the foulcaultian theoretical framework. Four categories emerged: Context of Motherhood; care practices to women on admission; care practices to women on childbirth and care practices to women on puerperium. It was concluded that the care provided to women at the Maternity has been exercised by religious and midwives, nurses and lay nurse midwives, a path that goes from laic to professional care, intercalated with knowledge-power relationships marked by struggles and resistances to doctor's hegemony of that time. PMID- 23338581 TI - [Effectiveness of a training course on the measure of uterine height for nurses and nursing students]. AB - A prospective, longitudinal study sought to quantify the intra and inter-observer variability of the uterine height (UH) measurement and verify the contribution of a training course for nurses and nursing students in measurement bias. We selected two participants who performed two measurements in 20 pregnant women before and after the course. We calculated the intra and inter-observer variability, the coefficient of intraclass correlation, the absolute and relative technical error of measurement and the measure reliability. The paired t test showed a statistically significant reduce (p = 0.0396) in the measurement bias. We conclude that the training of nurses and nursing students in the technical measurement of UH significantly reduces intra and inter-observer variability. PMID- 23338582 TI - [Reinterpretation of the potentiality of Critical-emancipative Workshops]. AB - This qualitative study aims to discuss the potential of Critical-emancipative Workshops utilizing the Tree of Knowledge as a facilitator strategy. The theoretical basis that constitutes this workshop was: the critical-emancipative education and empowerment; emotions as constructors of knowledge; the dialectical approach to transform reality and awareness; participation and shared responsibility. The study was conducted with 95 professionals working in 12 Family Health Staff in a city in the province of Sao Paulo, Brazil. The results indicate that the potential of the Critical-emancipatory Workshops relate directly to theoretical basis. The dynamics Tree of Knowledge used in the evaluation was powerful to reveal them. Thus, the workshops constitute an important tool for nursing in terms of their educational dimension, particularly, to face gender-based violence against women. PMID- 23338583 TI - [Fathers' experiences during the hospitalization of the premature newborn in the Neonatal Intensive Care Unit]. AB - This study aimed to understand the fathers' experiences during the hospitalization of premature newborn in the Neonatal Intensive Care Unit at a public hospital in Feira de Santana, Bahia. This is a qualitative descriptive exploratory study that was approved by the Ethics Committee of the Faculty of Technology and Sciences, and carried out in a public hospital in Bahia, with nine fathers who accompanied their children hospitalized in the Neonatal Intensive Care Unit. The data were analyzed through content analysis. The results showed that premature births cause feelings of surprise, anxiety and fear in the fathers. It is needed rethink how does the inclusion of premature infants' fathers in the hospitalization process and about the changes in established routines for the visit and paternal participation in the context of premature care. PMID- 23338584 TI - [Qualifying child care in primary health care]. AB - Child care is supported by a shared action enriched by subjectivities of professionals and family in order to meet peculiar characteristics of child growth and development. This study aimed to understand modes of child care in Primary Health Care, supported by the Grounded Theory. Twenty-nine subjects participated in the research, including managers, coordinators of nursing and medicine courses, doctors, nurses and mothers of children assisted by the Family Health Strategy in Sao Luis-MA, Brazil. To collect data it was used a semi structured interview. The category Qualifying child care at PHC and its respective subcategories recognize that care has different meanings based on the value of life and human dignity and that the value of care is built by efforts, collaboration, communication, complementarity and in the actions of professionals, families, services and managers. PMID- 23338585 TI - [The presence of family members in the pediatric chemotherapy room]. AB - The purpose was to analyze the needs of the family companion that follows the child in the chemotherapy unit from the standpoint of the child in treatment. It was a qualitative study. We used the adaptation of drawing-story with themes for the production of empirical data from seven children with cancer. The analysis was done using a thematic interpretation. For children, the family needs are: to incentive to change among family members as caregivers of the child; counseling and training for all family members who accompany the children; comfort for the family to remain with the child; autonomy for the family; take care the healthy sibling; environment that provides closeness between unmarried parents to support the child in treatment. It is essential to expand the focus of care restricted to children with cancer, broadening also the attention of nursing's team to family. PMID- 23338586 TI - [The concept of risk and its symbolic effects in accidents with sharp instruments]. AB - The study aims to understand the occupational risks as symbolic processes that shapes the daily activities of health professionals that manipulate sharps objects. Descriptive research was conducted at a university hospital, with information collected through the survey on the accidents at work in Intensive Care and hospital laundry, with the application of 105 questionnaires. The information was analyzed through an interdisciplinary perspective, and enabled the conciliation of quantitative and qualitative analysis. The results revealed that although the number of accidents is low, it is still necessary to improve the instruments such as the risk map, the use of safety equipment and staff training. PMID- 23338587 TI - [Education and professional experience in the context of a Regional Management Board]. AB - This study aimed to analyze the nurses' role in a Regional Management Board - COGERE from their academic formation and understand the technologies used by them in their work process. It is a case study with twelve administrators from COGERE. Data were collected through interviews and analyzed using thematic analysis. The nursing academic formation was grounded in the biomedical model, which mobilizes hard and light-hard technologies, but not enough to hard technologies. The role of nurses in the field of health management requires a greater incorporation of the concept of co-responsibility between the educational system and health services, with a reciprocal implication among teaching, management, attention, and social participation. PMID- 23338588 TI - [Meaning given by health workers of Belo Horizonte-MG to the principle of resolvability in everyday actions]. AB - This is a qualitative study, based on comprehensive sociology, which aimed to understand the meaning assigned by health professionals of Belo Horizonte-MG, Brazil, to the principle of resolvability in the everyday actions of health. Thirty-two workers were the informants of this research. We used a semi structured interview technique and content analysis. Professionals describe what is the solution and the factors that hinder their achievement. They realize, too, that patients do not always leave the Units with the response they want; and that the service is resolute in that matches your level of attention, although for some people and managers is the reverse. We conclude that it becomes urgent to reorganize aspects of this doctrinal principle of SUS. PMID- 23338589 TI - [National studies on family caregivers of older persons: integrative review]. AB - It is an integrative literature review of Brazilian scientific production on elderly family caregivers, which sought to highlight the profile of papers published in national and international, from January 2005 to September 2010, indexed in MEDLINE, CINAHL and LILACS. It was found 76 studies, published in Portuguese, Spanish or English. Twenty five were selected; most of them were published in 2009 in nursing and public health journals. The sample was divided into the following topics, according to the theme: "building the caregiver's role", "caregivers' quality of life and burden", "caregiver's knowledge about the issues involved in care". The authors found high levels of burden, significant worsening of caregivers' quality of life, lack of support for caregivers, lack of information and preparation for care and lack of instrumentation and studies within this theme. PMID- 23338590 TI - [Scales for evaluation of the overload of caregivers of patients with stroke]. AB - The objective of the study was to evaluate the available productions in literature about scales to measure the overload of caregivers of patients with stroke. It was carried out a bibliographical revision in three databases: LILACS, CINAHL and SCOPUS. In 23 works, 24 different scales were identified, and the most cited were: the Caregiver Strain Index, the Caregiver Burden Scale, the Caregiver Reaction Assessment, the Sense of Competence Questionnaire, the Relatives Stress Scale and the Zarit Burden Interview. The use of scales to measure the overload is an important tool to evaluate the context in which the caregiver is inserted, but is more trustworthy to use more than one measure instrument than use only one. Therefore, the validation of scales becomes important for this population. PMID- 23338591 TI - [Elderly human being with ostomy and environments of care: reflection on the perspective of complexity]. AB - This is discussion about the relationship between elderly human beings with ostomy and their environments care, under the perspective of Complexity Edgar Morin. An axis holds the reflection: environments of care for elderly humans with ostomy. In this sense, we present three types of environment that surround the context of elderly humans with ostomy: home environment, group environment and hospital environment. This brings, as a social contribution, a new look about resizing caring of elderly humans with ostomy in their environment. It is considered that the environment hosting this human being contains a diversity of feelings, emotions, experiences; it binds multiple meanings, from the Complexity perspective, about the relationship between the environment and the caring process. PMID- 23338592 TI - [Competency to provide cross-cultural nursing care for people with disability: a self-assessment instrument]. AB - This study addresses the Cross-Cultural Nursing Theory, which develops foundations for care delivery, as the essence of nursing work, based on anthropology, which supports and explains culture and care aspects. This reflexive study was based on the Theory Analysis method to study the concepts aimed at constructing a Self-Assessment Instrument of Competencies for Cross Cultural Care to Disabled People. After analyzing the main concepts, Culturally Competent Care and Cultural Communication, were analyzed, as well as the sub concepts: assessment, values, bio-cultural diversity, skill, knowledge, identity, code and cultural empathy. The analysis cycle of cultural values supporting self assessment was summarized. The Self-Assessment Instrument of Competencies for Cross-Cultural Nursing Care to Disabled People was constructed, specifically deafness, blindness or low sight, physical impairment and mental impairment, regarding greeting, accepting, helping, knowing and advocating. It is concluded that the theory joins characteristics for care delivery to disabled people. PMID- 23338593 TI - [Educational Mercosur in the Nursing career]. AB - The Mercosul, established with the objective of integrate economics, political, social and cultural differences among member countries, currently is highlighted by its strategies of educational framework. This article discusses the movement on the academic background of the Nursing career and the history of educational integration, presenting the accreditation system for university courses of Mercosul, the Arcu-Sul, and also the sectors responsible for this process and the prospects for Nursing in Mercosul. We believe that for the development of a critic, reflective and social-political committed professional is essential to invest in training and in the quality of education centers in Nursing. PMID- 23338594 TI - [Virtual learning environment in nursing education: an experience report]. AB - New Technologies of Information / Communication offer the option of using a virtual learning environment (VLE), which allows for greater interactivity in daily nursing education urging educators to rethink their teaching practices. The aim of this study was to report the experience of the use of virtual environment in nursing education from the perspective of students. The discipline "Nursing Education: Trends and Challenges" was given to 78 students from the 4th semester of undergraduate nursing, from which 48 answered a questionnaire with closed and, among these, 33 answered an open question about the use of AVA. Students considered the AVA a facilitating tool of learning, the process of knowledge construction and interaction between students, teachers and tutors enriching thus the sharing of ideas and allowing a meaningful and collaborative learning. The study revealed the need for enhancement of use of VLE in teaching undergraduate nursing. PMID- 23338595 TI - Bilateral variations of musculocutaneous nerves with rare pattern in a Korean female cadaver. AB - Bilateral variations in the formation and branching of brachial plexus are rare. Variations between median and musculocutaneous nerves were observed on both sides during the dissection of an 87-year-old Korean female cadaver, whose cause of death was cholangiocarcinoma. The variations found were bilateral, in which each musculocutaneous nerve did not pierce the coracobrachialis muscle. The musculocutaneous nerve was rudimentary in the right arm and all branches arose from the median nerve separately, which corresponds to previous classification type 0-2. In the case of the left arm, the musculocutaneous nerve originated from the lateral cord, but had connections between median and musculocutaneous nerves below the coracobrachialis muscle, which corresponds to previous classification type 1-B-2. To the best of our knowledge, the bilateral variations between median and musculocutaneous nerves in this case have different features from other previous reports. Awareness of the possible variations between median and musculocutaneous nerves is important to both anatomists and clinicians. PMID- 23338596 TI - Management of traumatic aortic rupture. AB - A traumatic thoracic aortic injury is a severe and life-threatening clinical entity. Although largely fatal; if untreated, these injuries are amenable to surgical repair if appropriately diagnosed. Therefore, early triage of this condition is critically important. Unfortunately, aortic injuries rarely occur in isolation, and there has been no good cutoff value to help select the appropriate surgical strategy. Algorithms for the both diagnosis and treatment of traumatic thoracic aortic injury have undergone changes in recent years. There have been several case reports, retrospective series and registry data describing the treatment of patients with traumatic thoracic aortic rupture using endovascular treatment. Endovascular treatment is a less-invasive management option for polytraumatized patients. Because it is less invasive, without the need for thoracotomy or the use of heparin, endovascular repair can be performed even in acutely injured patients, without the risk of destabilizing pulmonary, head or abdominal traumatic lesions. Long-term follow-up especially in young patients is necessary after endovascular treatment. PMID- 23338597 TI - Gallbladder herniation into the lesser sac through the foramen of Winslow: report of a case. AB - We report a case of gallbladder hernia into the lesser sac through the foramen of Winslow. The patient was a 90-year-old woman, admitted to hospital with obstructive jaundice. Computed tomography (CT) showed a left-deviated and remarkably enlarged gallbladder dragging the liver, and a dilated intrahepatic bile duct. The deviated gallbladder was thought to compress the common bile duct, causing the obstruction. Laparoscopic examination revealed gallbladder herniation into the lesser sac without a floating gallbladder; thus, we performed laparoscopic cholecystectomy. Herniation of the gallbladder is the rarest of all internal hernias and most reported cases have involved a floating gallbladder. The case we report here is therefore considered especially unusual. PMID- 23338598 TI - Surgical ethics. PMID- 23338599 TI - Folic acid uptake by the human syncytiotrophoblast is affected by gestational diabetes, hyperleptinemia, and TNF-alpha. AB - BACKGROUND: The mechanisms whereby gestational diabetes mellitus (GDM) increases the risk of fetal overgrowth and development of metabolic diseases later in life are likely to involve changes in nutrient supply to the fetus. Hence, in this work, we hypothesize that GDM may affect folic acid (FA) supply to the placenta and fetus. METHODS: We compared (3)H-FA uptake by human cytotrophoblasts isolated from normal pregnancies (normal trophoblasts; NTB cells) and GDM pregnancies (diabetic trophoblasts; DTB cells) and investigated the effect of GDM hallmarks on (3)H-FA uptake by BeWo cells. RESULTS: (3)H-FA uptake by NTB and DTB cells was time dependent and acidic pH stimulated. When compared with NTB, (3)H-FA uptake by DTB cells was more sensitive to acidic pH changes and to 5 methyltetrahydrofolate and pemetrexed (PTX) inhibition, indicating a proportionally greater involvement of the proton-coupled folate transporter (PCFT). A 4-h exposure of BeWo cells to lipopolysaccharide (LPS, 1-10 MUg/ml) or to high levels of tumor necrosis factor-alpha (TNF-alpha, 300 ng/l) significantly reduced (3)H-FA uptake. Moreover, hyperleptinemic conditions (100 ng/ml leptin) decreased (3)H-FA uptake by BeWo cells in a time-dependent manner when compared with normoleptinemic conditions (1 ng/ml leptin). CONCLUSION: GDM modulates (3)H FA uptake by the syncytiotrophoblast, and leptin as well as TNF-alpha downregulate it. PMID- 23338600 TI - Molecular characterization and evolution of haemocyanin from the two freshwater shrimps Caridina multidentata (Stimpson, 1860) and Atyopsis moluccensis (De Haan, 1849). AB - Haemocyanin (Hc) is a copper-containing respiratory protein, floating freely dissolved in the hemolymph of many arthropod species. A typical haemocyanin is a hexamer or oligohexamer of six identical or similar subunits, with a molecular mass around 75 kDa each. In the crustaceans, the haemocyanins appear to be restricted to the remipedes and the malacostracans. We have investigated the haemocyanins of two freshwater shrimps, the Amano shrimp Caridina multidentata and the bamboo shrimp Atyopsis moluccensis. We obtained three full-length and one partial cDNA sequences of haemocyanin subunits from the Amano shrimp, which were assigned to the alpha- and gamma-types of decapod haemocyanin subunits. Three complete and two partial haemocyanin cDNA sequences were obtained from the bamboo shrimp, which represent subunit types alpha, beta and gamma. This is the first time that sequences of all three subunit types of the decapod haemocyanins were obtained from a single species. However, mass spectrometry analyses identified only alpha- and gamma-type subunits, suggesting that a beta-subunit is not a major component of the native haemocyanin of the bamboo shrimp. Phylogenetic and molecular clock analyses showed that malacostracan haemocyanins commenced to diversify into distinct subunit types already ~515 million years ago. beta subunits diverged first, followed by alpha- and gamma-type subunits ~396 million years ago. The haemocyanins of phyllocarids and peracarids form distinct clades within the alpha/gamma-cluster. Within the Caridea, an early divergence of distinct alpha-type subunits occurred ~200 MYA. The tree of the gamma-subunits suggests a common clade of the Caridea (shrimps) and Penaeidae (prawns). PMID- 23338601 TI - Essentiality of respiratory activity for pentose utilization in thermotolerant yeast Kluyveromyces marxianus DMKU 3-1042. AB - By random integrative mutagenesis with a kanMX4 cassette in Kluyveromyces marxianus DMKU 3-1042, we obtained three mutants of COX15, ATP25 and CYC3 encoding a cytochrome oxidase assembly factor (singleton), a transcription factor required for assembly of the Atp9p subunit of mitochondrial ATP synthase and cytochrome c heme lyase, respectively, as mutants lacking growth capability on xylose and/or arabinose. They exhibited incapability of growth on non-fermentable carbon sources, such as acetate or glycerol, and thermosensitiveness. Their biomass formation in glucose medium was reduced, but ethanol yields were increased with a high ethanol level in the medium, compared to those of the parental strain. Experiments with respiratory inhibitors showed that cox15 and cyc3, but not atp25, were able to grow in glucose medium containing antimycin A and that the atp25 mutant was KCN-resistant. Activities of NADH and ubiquinol oxidases in membrane fractions of each mutant became a half of that of the parent and negligible, respectively, and their remaining NADH oxidase activities were found to be resistant to KCN. Absolute absorption spectral analysis revealed that the peak corresponding to a + a 3 was very small in atp25 and negligible in cox15 and cyc3. These findings suggest that the K. marxianus strain possesses an alternative KCN-resistant oxidase that is located between primary dehydrogenases and the ubiquinone pool and that the respiratory activity is essential for utilization of pentoses. PMID- 23338602 TI - Vibrio zhuhaiensis sp. nov., isolated from a Japanese prawn (Marsupenaeus japonicus). AB - A Gram-negative, oxidase-positive, facultatively anaerobic bacterium, designated strain E20121, was isolated from the digestive tract of a Japanese prawn (Marsupenaeus japonicus) collected from the coastal sea water area of Zhuhai, Guangdong province, China. The new isolate was determined to be closely related to Vibrio ponticus DSM 16217(T), having 97.6 % 16S rRNA gene sequence similarity. Phylogenetic analysis based on recA, pyrH and rpoA also showed low levels of sequence similarities (72.6-96.6 %) with all species of the genus Vibrio. A multigene phylogenetic tree using concatenated sequences of the four genes (16S rRNA, rpoA, recA and pyrH) clearly showed that the new isolate is different from the currently known Vibrio species. DNA-DNA hybridization experiments revealed similarity values below 70 % with the closest related species V. ponticus DSM 16217(T). Several phenotypic traits enabled the differentiation of strain E20121 from the closest phylogenetic neighbours. The DNA G+C content of strain E20121 was determined to be 47.6 mol % and the major fatty acid components identified were C16:1omega7c and/or C16:1omega6c (39.8 %), C18:1omega7c (13.6 %) and C16:0 (9.6 %). Based on genotypic, phenotypic, chemotaxonomic, phylogenetic and DNA-DNA hybridization analyses, strain E20121 is proposed to represent a novel species of the genus Vibrio for which the name Vibrio zhuhaiensis sp. nov. is proposed. The type strain is E20121(T)(=DSM 25602(T) = CCTCC AB 2011174(T)). PMID- 23338603 TI - Halalkalicoccus paucihalophilus sp. nov., a halophilic archaeon from Lop Nur region in Xinjiang, northwest of China. AB - Two extremely halophilic archaea, designated YIM 93701(T) and YIM 93664, were isolated from Lop Nur region in Xinjiang Province, northwest of China. The cells of the two strains were observed to be cocci, non-motile and Gram-negative. The organisms were determined to be aerobic and required at least 6 % NaCl for growth (optimum 20-25 % and maximum 35 %). Growth was found to occur in the ranges of 16 50 degrees C (optimum 37 degrees C) and pH 6.0-8.5 (optimum 6.5-7.5). Cells did not lyse in distilled water. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the two strains belongs to the genus Halalkalicoccus and possessed 99.3 and 99.5 % similarities with their closest phylogenetic relative Halalkalicoccus tibetensis JCM 11890(T). Major polar lipids of the two strains were determined to be phosphatidylglycerol(PG),phosphatidylglycerol phosphate methyl ester (PGP-Me), phosphatidylglycerol sulfate (PGS) and three unidentified glycolipids. The DNA G+C contents were determined to be 60.0-60.4 mol%. The DNA hybridization between the two strains was 92.0 %. In addition, the hybridizations of both strains to H. tibetensis were 49 and 52 %, respectively, and to Halalkalicoccus jeotali were 38 and 33 %, respectively. On the basis of physiological, biochemical tests and phylogenetic differentiations, strains YIM 93701(T) and YIM 93664 were classified as the same species which represent a novel species in the genus Halalkalicoccus, for which the name Halalkalicoccus paucihalophilus sp. nov. is proposed. The type strain is YIM 93701(T) (=JCM 17505(T) = CCTCC 2012803(T)). PMID- 23338604 TI - Oceanospirillum nioense sp. nov., a marine bacterium isolated from sediment sample of Palk bay, India. AB - A novel Gram-negative, spiral shaped, motile bacterium, designated strain NIO S6(T), was isolated from a sediment sample collected from Off-shore Rameswaram, Tamilnadu, India. Strain NIO-S6(T) was found to be positive for oxidase, DNase and lysine decarboxylase activities and negative for catalase, gelatinase, lipase, ornithine decarboxylase, nitrate reductase, aesculinase, amylase and urease activities. The fatty acids were determined to be dominated by C10:0 3OH, C16:0, C16:1 and C18:1. Strain NIO-S6(T) contains Q-8 as the major respiratory quinone. The DNA G+C content of the strain NIO-S6(T) was determined to be 49.5 +/ 0.6 mol %. Phylogenetic analysis based on 16S rRNA gene sequence of strain NIO S6(T) indicated Oceanospirillum linum and Oceanospirillum maris of the family Oceanospirillaceae (phylum Proteobacteria) are the closest related species with sequence similarities of 98.4 and 97.8 % respectively. Other members of the family showed sequence similarities <96.4 %. However, DNA-DNA hybridization with Oceanospirillum linum LMG 5214(T) and Oceanospirillum maris LMG 5213(T) showed a relatedness of 31.5 and 46.9 % with respect to strain NIO-S6(T). Based on the phenotypic characteristics and on phylogenetic inference, strain NIO-S6(T) is proposed as a novel species of the genus Oceanospirillum as Oceanospirillum nioense sp. nov. and the type strain is NIO-S6(T) (=MTCC 11154(T) = KCTC 32008(T)). PMID- 23338605 TI - MiRNA-mediated tumor specific delivery of TRAIL reduced glioma growth. AB - As an aggressive cancer with high morbidity, malignant glioma always has a poor prognosis even after surgery, chemotherapy and radiotherapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows a strong apoptosis inducing effect on a variety of cancer cells including glioma. However so far, TRAIL delivery mediated by adenoviral vectors lacks tumor specificity and thus has cytotoxicity to normal cells. To improve the tumor-specificity of adenovirus mediated TRAIL delivery, we utilized miR-124, miR-128, miR-146b and miR-218 to restrict its expression to within glioma cells. qPCR assay showed that expression of these four miRNAs was greatly downregulated in glioma in comparison with normal brain tissue. Luciferase reporter assay confirmed that miR-124, miR-128, miR-146b and miR-218 conferred exogenous gene expression with glioma-specificity. By inserting miRNA response elements (MREs) of these miRNAs into the downstream of TRAIL on adenoviral vectors, TRAIL was highly expressed in glioma cells, but not in normal brain cells. Cell viability and immunoblotting assays and FACS analysis showed that cytotoxicity and apoptosis elicited by TRAIL was only observed in glioma cells, rather than normal brain cells. Animal experiments also showed that MREs-regulated TRAIL delivery reduced the growth of glioma xenograft. In this study, we proved that miRNA-mediated tumor specific delivery of TRAIL was able to inhibit the survival of glioma cells and reduce the growth of glioma in vivo. PMID- 23338607 TI - Long-term successes of various sinus surgeries: a comprehensive analysis. AB - Outcome studies often examine the efficacy of sinus surgery with 1 year of follow up data, while longer-term postoperative data is less easily available. This article reviews long-term outcomes of various endoscopic techniques to further delineate risk factors for surgical failure. A systematic review of the literature was performed and studies were stratified based on surgical technique and recognized risk factors of postoperative failure. A total of 126 abstracts were identified, 82 articles were retrieved for full review, and 56 were included in this report. A total of 30 studies had longer than 1 year of follow-up data and the longest follow-up period was 10 years. Based on the available evidence, endoscopic sinus surgery has a high success rate, but with well-recognized risk factors for failure. Aggressive postoperative local care and medical therapy should be tailored to each patient's particular disease process, and form an integral part of surgical management. PMID- 23338608 TI - Distinct effects of ligand-induced PDGFRalpha and PDGFRbeta signaling in the human rhabdomyosarcoma tumor cell and stroma cell compartments. AB - Platelet-derived growth factor receptors (PDGFR) alpha and beta have been suggested as potential targets for treatment of rhabdomyosarcoma, the most common soft tissue sarcoma in children. This study identifies biologic activities linked to PDGF signaling in rhabdomyosarcoma models and human sample collections. Analysis of gene expression profiles of 101 primary human rhabdomyosarcomas revealed elevated PDGF-C and -D expression in all subtypes, with PDGF-D as the solely overexpressed PDGFRbeta ligand. By immunohistochemistry, PDGF-CC, PDGF-DD, and PDGFRalpha were found in tumor cells, whereas PDGFRbeta was primarily detected in vascular stroma. These results are concordant with the biologic processes and pathways identified by data mining. While PDGF-CC/PDGFRalpha signaling associated with genes involved in the reactivation of developmental programs, PDGF-DD/PDGFRbeta signaling related to wound healing and leukocyte differentiation. Clinicopathologic correlations further identified associations between PDGFRbeta in vascular stroma and the alveolar subtype and with presence of metastases. Functional validation of our findings was carried out in molecularly distinct model systems, where therapeutic targeting reduced tumor burden in a PDGFR-dependent manner with effects on cell proliferation, vessel density, and macrophage infiltration. The PDGFR-selective inhibitor CP-673,451 regulated cell proliferation through mechanisms involving reduced phosphorylation of GSK-3alpha and GSK-3beta. Additional tissue culture studies showed a PDGFR dependent regulation of rhabdosphere formation/cancer cell stemness, differentiation, senescence, and apoptosis. In summary, the study shows a clinically relevant distinction in PDGF signaling in human rhabdomyosarcoma and also suggests continued exploration of the influence of stromal PDGFRs on sarcoma progression. PMID- 23338609 TI - The planar cell polarity pathway drives pathogenesis of chronic lymphocytic leukemia by the regulation of B-lymphocyte migration. AB - The planar cell polarity (PCP) pathway is a conserved pathway that regulates cell migration and polarity in various contexts. Here we show that key PCP pathway components such as Vangl2, Celsr1, Prickle1, FZD3, FZD7, Dvl2, Dvl3, and casein kinase 1 (CK1)-epsilon are upregulated in B lymphocytes of patients with chronic lymphocytic leukemia (CLL). Elevated levels of PCP proteins accumulate in advanced stages of the disease. Here, we show that PCP pathway is required for the migration and transendothelial invasion of CLL cells and that patients with high expression of PCP genes, FZD3, FZD7, and PRICKLE1, have a less favorable clinical prognosis. Our findings establish that the PCP pathway acts as an important regulator of CLL cell migration and invasion. PCP proteins represent an important class of molecules regulating pathogenic interaction of CLL cells with their microenvironment. PMID- 23338610 TI - Prooncogenic factors miR-23b and miR-27b are regulated by Her2/Neu, EGF, and TNF alpha in breast cancer. AB - miRNAs (miR) are a critical class of small (21-25 nucleotides) noncoding endogenous RNAs implicated in gene expression regulation. We identified miR-23b and miR-27b as miRNAs that are highly upregulated in human breast cancer. We found that engineered knockdown of miR-23b and miR-27b substantially repressed breast cancer growth. Nischarin (NISCH) expression was augmented by knockdown of miR-23b as well as miR-27b. Notably, these miRNAs and Nischarin were inversely expressed in human breast cancers, underscoring their biologic relevance. We showed the clinical relevance of the expression of these miRNAs and showed that high expression of miR-23b and miR-27b correlates with poor outcome in breast cancer. Moreover, intraperitoneally delivered anti-miR-27b restored Nischarin expression and decreased tumor burden in a mouse xenograft model of human mammary tumor. Also, we report for the first time that HER2/neu (ERBB2), EGF, and TNF alpha promote miR-23b/27b expression through the AKT/NF-kappaB signaling cascade. Nischarin was found to regulate miR-27b/23b expression through a feedback loop mechanism by suppressing NF-kappaB phosphorylation. Because anti-miR-27b compounds that suppress miR-27b inhibit tumor growth, the anti-miR-27b seems to be a good candidate for the development of new antitumor therapies. PMID- 23338611 TI - Therapeutic efficacy of bifunctional siRNA combining TGF-beta1 silencing with RIG I activation in pancreatic cancer. AB - Deregulated TGF-beta signaling in pancreatic cancer promotes tumor growth, invasion, metastasis, and a potent immunosuppressive network. A strategy for disrupting this tumor-promoting pathway is silencing TGF-beta by siRNA. By introducing a triphosphate group at the 5' end of siRNA (ppp-siRNA), gene silencing can be combined with immune activation via the cytosolic helicase retinoic acid-inducible gene I (RIG-I), a ubiquitously expressed receptor recognizing viral RNA. We validated RIG-I as a therapeutic target by showing that activation of RIG-I in pancreatic carcinoma cells induced IRF-3 phosphorylation, production of type I IFN, the chemokine CXCL10, as well as caspase-9-mediated tumor cell apoptosis. Next, we generated a bifunctional ppp-siRNA that combines RIG-I activation with gene silencing of TGF-beta1 (ppp-TGF-beta) and studied its therapeutic efficacy in the orthotopic Panc02 mouse model of pancreatic cancer. Intravenous injection of ppp-TGF-beta reduced systemic and tumor-associated TGF beta levels. In addition, it induced high levels of type I IFN and CXCL10 in serum and tumor tissue, systemic immune cell activation, and profound tumor cell apoptosis in vivo. Treatment of mice with established tumors with ppp-TGF-beta significantly prolonged survival as compared with ppp-RNA or TGF-beta siRNA alone. Furthermore, we observed the recruitment of activated CD8(+) T cells to the tumor and a reduced frequency of CD11b(+) Gr-1(+) myeloid cells. Therapeutic efficacy was dependent on CD8(+) T cells, whereas natural killer cells were dispensable. In conclusion, combing TGF-beta gene silencing with RIG-I signaling confers potent antitumor efficacy against pancreatic cancer by breaking tumor induced CD8(+) T cell suppression. PMID- 23338612 TI - Collections of simultaneously altered genes as biomarkers of cancer cell drug response. AB - Computational analysis of cancer pharmacogenomics data has resulted in biomarkers predictive of drug response, but the majority of response is not captured by current methods. Methods typically select single biomarkers or groups of related biomarkers but do not account for response that is strictly dependent on many simultaneous genetic alterations. This shortcoming reflects the combinatorics and multiple-testing problem associated with many-body biologic interactions. We developed a novel approach, Multivariate Organization of Combinatorial Alterations (MOCA), to partially address these challenges. Extending on previous work that accounts for pairwise interactions, the approach rapidly combines many genomic alterations into biomarkers of drug response, using Boolean set operations coupled with optimization; in this framework, the union, intersection, and difference Boolean set operations are proxies of molecular redundancy, synergy, and resistance, respectively. The algorithm is fast, broadly applicable to cancer genomics data, is of immediate use for prioritizing cancer pharmacogenomics experiments, and recovers known clinical findings without bias. Furthermore, the results presented here connect many important, previously isolated observations. PMID- 23338614 TI - Unprecedented combination of regioselective hydrodefluorination and ligand exchange reaction during the syntheses of tris-cyclometalated iridium(III) complexes. AB - The first reported combination of regioselective hydro-defluorination and a ligand exchange reaction during the syntheses of neutral iridium(III) complexes is presented. Surprisingly, loss of one fluorine atom per ligand combined with a complete ligand exchange reaction on the transition metal were jointly observed during a bridge-splitting and substitution reaction of two different dimeric iridium(III) precursor complexes with two different ancillary ligands. The regioselectivity of defluorination was evidenced in both cases. The reaction time was identified as a factor strongly impacting the kinetics of the thermally induced reaction. PMID- 23338613 TI - G-protein inactivator RGS6 mediates myocardial cell apoptosis and cardiomyopathy caused by doxorubicin. AB - Clinical use of the widely used chemotherapeutic agent doxorubicin is limited by life-threatening cardiotoxicity. The mechanisms underlying doxorubicin-induced cardiomyopathy and heart failure remain unclear but are thought to involve p53 mediated myocardial cell apoptosis. The tripartite G-protein inactivating protein RGS6 has been implicated in reactive oxygen species (ROS) generation, ATM/p53 activation, and apoptosis in doxorubicin-treated cells. Thus, we hypothesized that RGS6, the expression of which is enriched in cardiac tissue, might also be responsible for the pathologic effects of doxorubicin treatment in heart. In this study, we show that RGS6 expression is induced strongly by doxorubicin in the ventricles of mice and isolated ventricular myocytes via a posttranscriptional mechanism. While doxorubicin-treated wild-type (WT) mice manifested severe left ventricular dysfunction, loss of heart and body mass, along with decreased survival 5 days after doxorubicin administration, mice lacking RGS6 were completely protected against these pathogenic responses. Activation of ATM/p53 apoptosis signaling by doxorubicin in ventricles of WT mice was also absent in their RGS6(-/-) counterparts. Doxorubicin-induced ROS generation was dramatically impaired in both the ventricles and ventricular myocytes isolated from RGS6(-/-) mice, and the apoptotic response to doxorubicin in ventricular myocytes required RGS6-dependent ROS production. These results identify RGS6 as an essential mediator of the pathogenic responses to doxorubicin in heart, and they argue that RGS6 inhibition offers a rational means to circumvent doxorubicin cardiotoxicity in human patients with cancer. PMID- 23338615 TI - Evolving insights about the impact of sensory deficits in the elderly: comment on "The prevalence of concurrent hearing and vision impairment in the United states" and "Hearing loss and cognitive decline in older adults". PMID- 23338617 TI - Introductory paragraph - Volume 27, Issue 2. PMID- 23338618 TI - Harmol induces autophagy and subsequent apoptosis in U251MG human glioma cells through the downregulation of survivin. AB - The beta-carboline alkaloids are plant substances that exhibit a wide spectrum of neuropharmacological, psychopharma-cological and antitumor effects. In the present study, we found that harmol, a beta-carboline alkaloid, induced autophagy and suppression of survivin expression, and subsequently induced apoptotic cell death in U251MG human glioma cells. Autophagy was induced within 12 h by treatment with harmol. When treated for over 36 h, however, apoptotic cell death was induced. Harmol treatment also reduced survivin protein expression. Small interfering RNA (siRNA)-mediated knockdown of survivin enhanced the harmol induced apoptosis. Knockdown of survivin by siRNA also induced autophagy. Therefore, harmol-induced apoptosis is a result of the reduction in survivin protein expression. Treatment with 3-methyladenine (3-MA) in the presence of harmol did not affect the expression of survivin and diminished harmol-induced cell death. Treatment with chloroquine in the presence of harmol did not suppress the reduction of survivin expression and increased harmol-induced cell death. From these results, harmol-induced reduction of survivin expression was closely related to autophagy. It is assumed that when isolation membrane formation is inhibited by treatment with 3-MA, reduction of survivin protein expression and apoptotic cell death were not induced. However, when isolation membrane formation is started and an autophagosome is formed, survivin expression is suppressed and apoptosis is executed. Harmol treatment reduced phosphorylation of Akt, mammalian target of rapamycin (mTOR) and its downstream targets p70-ribosomal protein S6 kinase and 4E-binding protein 1, resulting in induction of autophagy. Conversely, activation of the Akt/mTOR pathway inhibited harmol-induced autophagy and cell death. These findings indicate that harmol-induced autophagy involves the Akt/mTOR pathway. Taken together, autophagy induced by harmol represented a pro apoptotic mechanism, and harmol suppressed the expression of survivin and subsequently induced apoptosis. PMID- 23338616 TI - Impact of a brief intervention on physical activity and social cognitive determinants among working mothers: a randomized trial. AB - Working mothers exhibit high levels of inactivity, and theory-based interventions to bolster physical activity within this population are needed. This study examined the effectiveness of a brief social cognitive theory-based intervention designed to increase physical activity among working mothers. Participants (N = 141) were randomly assigned to an intervention only, intervention plus follow-up support, or waitlist control condition. The intervention consisted of two group based workshop sessions designed to teach behavior modification strategies using social cognitive theory. Data were collected at baseline, immediately post intervention, and 6-month follow-up. Results showed intervention participants exhibited short-term increases in physical activity, which were partially maintained 6 months later. Improvements in physical activity were mediated by increases in self-regulation and self-efficacy. This study provides some support for the effectiveness of a brief intervention to increase physical activity among working mothers. Future programs should explore alternative support mechanisms which may lead to more effective maintenance of initial behavior changes. PMID- 23338619 TI - Biospectroscopy insights into the multi-stage process of cervical cancer development: probing for spectral biomarkers in cytology to distinguish grades. AB - Cervical cancer screening programmes have greatly reduced the burden associated with this disease. However, conventional cervical cytology screening still lacks sensitivity and specificity. There is an urgent need for the development of a low cost robust screening technique. By generating a spectral "biochemical-cell fingerprint", Fourier-transform infrared (FTIR) spectroscopy has been touted as a tool capable of segregating grades of dysplasia. A total of 529 specimens were collected over a period of one year at two colposcopy centres in Dublin, Ireland. Of these, n = 128 were conventionally classed as high-grade, n = 186 as low-grade and n = 215 as normal. Following FTIR spectroscopy, derived spectra were examined for segregation between classes in scores plots generated with subsequent multivariate analysis. A degree of crossover between classes was noted and this could be associated with imperfect conventional screening resulting in an inaccurate diagnosis or an incomplete transition between classes. Maximal crossover associated with n = 102 of 390 specimens analyzed was found between normal and low-grade specimens. However, robust spectral differences (P<= 0.0001) were still observed at 1512 cm(-1), 1331 cm(-1) and 937 cm(-1). For high-grade vs. low-grade specimens, spectral differences (P<= 0.0001) were observed at Amide I (1624 cm(-1)), Amide II (1551 cm(-1)) and asymmetric phosphate stretching vibrations (nuasPO2(-); 1215 cm(-1)). Least crossover (n = 50 of 343 specimens analyzed) was seen when comparing high-grade vs. normal specimens; significant inter-class spectral differences (P<= 0.0001) were noted at Amide II (1547 cm( 1)), 1400 cm(-1) and 995 cm(-1). Deeper understanding of the underlying changes in the transition between cervical cytology classes (normal vs. low-grade vs. high-grade) is required in order to develop biospectroscopy tools as a screening approach. This will then allow for the development of blind classification algorithms. PMID- 23338620 TI - Prospective clinical study of endoscopic ultrasound-guided choledochoduodenostomy with direct metallic stent placement using a forward-viewing echoendoscope. AB - A prospective clinical study was conducted to evaluate the safety, feasibility, and efficacy of endoscopic ultrasound (EUS)-guided choledochoduodenostomy (CDS) with direct metallic stent placement using a prototype forward-viewing echoendoscope. The indication for EUS - CDS in this study was lower biliary obstruction only, and not failed endoscopic biliary drainage, because the aim was to evaluate EUS - CDS for first-line biliary drainage therapy. The technical and functional success rates were 94 % (17 /18) and 94 % (16 /17), respectively. Early complications (focal peritonitis) were encountered in two patients (11 %). No patients developed late complications. EUS - CDS with direct metallic stent placement using a forward-viewing echoendoscope was generally feasible and effective for malignant distal biliary tract obstruction. The forward-viewing echoendoscope was useful, especially for deploying the metallic stent. PMID- 23338621 TI - Recombinant hemangiopoietin promotes cell adhesion and binds heparin in its multimeric form. AB - Hemangiopoietin (HAPO) is a novel growth factor stimulating the proliferation of hematopoietic and endothelial progenitor cells in vitro and in vivo. The native protein is a 294-amino acid multimodular protein. The N-terminus constitutes of two somatomedin B (SMB) homology domains that contain 14 cysteines. The central region is a putative heparin-binding domain (pHBD) and the C-terminus contains mucin-like repeats. In the present study, we demonstrated that prokaryotic recombinant human HAPO (rhHAPO) self-associates into a multimeric form with a mass weight of ~129 kDa, suggesting a homologous tetramer. rhHAPO in its multimeric form was found to be more stable and more potent in promoting HESS-5 cell adhesion. Multimeric rhHAPO had a higher affinity to heparin compared with its dimeric form, although there was no significant conformational change. C terminal repeats-truncated rhHAPO (rhHAPODeltamucin) was also found to be assembled into a multimer, while deletion of pHBD (rhHAPODeltamucin-pHBD) caused the protein to remain in a dimeric form, demonstrating that SMB domains participate in self-aggregation of the molecule and that the pHBD region promotes the tetramerization. PMID- 23338623 TI - Role of glucagon-like peptide-1 in the pathogenesis of experimental irritable bowel syndrome rat models. AB - Alterations in gut motility and visceral hypersensitivity are two major features of irritable bowel syndrome (IBS). The aim of this study was to investigate the roles of glucagon-like peptide-1 (GLP-1) in the pathogenesis of experimental IBS. Rat models of constipation-predominant IBS (IBS-C) and diarrhea-predominant IBS (IBS-D) were established. Fecal water content and behavioral responses to colorectal distention (CRD), using electromyography (EMG), were measured. The expression of glucagon-like peptide-1 receptor (GLP-1R) in the colon was detected by immunohistochemistry, and the serum concentration of GLP-1 was measured by ELISA assay. The movement of circular and longitudinal colonic muscle was detected using an organ bath recording technique. Compared to controls, the fecal water contents were lower in the IBS-C group, while they were higher in the IBS-D group (P<0.05). EMG response to CRD in the experimental IBS groups was increased compared with their respective controls (P<0.05). GLP-1R was localized in the mucosa layer, circular muscle and myenteric nerve plexus of the colon. Notably, the expression of GLP-1R in the IBS-C group was higher, but in the IBS-D group, it was lower compared with controls. The serum levels of GLP-1 in the IBS-C group were higher compared to those in the IBS-D group (P<0.05). In addition, administration of exogenous GLP-1 and exendin-4 inhibited colonic circular muscle contraction, particularly in the IBS-C group, while there was no significant effect on longitudinal muscle contraction. In conclusion, these results indicated that GLP-1 and GLP-1R are implicated in the pathogenesis of IBS-C and IBS-D. PMID- 23338624 TI - [Current situation of clinical trials in Peru]. PMID- 23338625 TI - [Clinical trials and public health in Peru: reconciling an unnecessary divorce]. PMID- 23338626 TI - [Characteristics of clinical trials authorized in Peru: 1995-2012]. AB - OBJECTIVE: To identify main characteristics of clinical trials (CT) authorized by the National Institute of Health (INS) of Peru from 1995 to August 2012. MATERIAL AND METHODS: Cross-sectional study, which reviewed all records of CT submitted for review and possible approval by INS, whose data are part of the Peruvian Registry of Clinical Trials. We performed a descriptive analysis of the states of the CT approval and other characteristics. RESULTS: 1475 clinical trials were assessed, of which 1255 (85.1%) were authorized. From 1 clinical trial officially registered in 1995, its quantity increased to 176 trials submitted in 2008, and then, declined to 128 in 2011. Among the approved CT, 64.1% was in Phase III. Oncology (22.4%), infectious diseases (15.5%) and endocrinology (12.7%) were the most studied specialties and a only 1.2% were for neglected tropical diseases. The oral hypoglycemic drugs, systemic antiviral and antineoplastic agents were the most studied investigational products. The transnational pharmaceutical industry was the main sponsor (87.1%) and executors (62.3%) of clinical trials were mostly in Lima. CONCLUSIONS: Clinical trials in Peru mainly focus on noncommunicable diseases and phase III studies. The pharmaceutical industry is the main sponsor. A very small number of authorized clinical trials in Peru were for neglected tropical diseases that shows little attention to the health problems in vulnerable populations. PMID- 23338627 TI - [Evaluation of the seroprotection against measles, rubella and hepatitis B in children under 5 years of age in Peru, 2011]. AB - OBJECTIVES: To estimate the prevalence of antibodies against measles, rubella and hepatitis B in children aged between 1 and 4 years in Peru. MATERIALS AND METHODS: A national survey was conducted based on a questionnaire and capillary blood sample taken on filter paper in order to study antibodies against measles, rubella and hepatitis B in children from 1 to 4 years of age. A stratified, multistage, probability sampling design was used to be representative at the national level and at level of seven ambits, including the Metropolitan Lima Area, the rest of the urban coast, the rural coast, the urban highlands, the rural highlands, the urban jungle and the rural jungle. The capillary blood samples were processed according to the standardized protocols for detection of antibodies using the ELISA technique and commercial reagents. RESULTS: The survey showed a national prevalence of antibodies against measles, rubella and hepatitis B of 91.6% (CI 95%: 90.6%; 92.7%), 91.3% (CI 95%: 90.3%; 92.4%) and 95.9% (CI 95%: 95.0%; 96.8%) respectively. There was no evidence of significant differences in the prevalence among the ambits of study or among the socioeconomic strata of the conglomerates for any of the three types of antibodies. CONCLUSIONS: In children from 1 to 4 years of age, the national prevalence of antibodies against measles and Rubella was between 90-93%, while the prevalence of antibodies against Hepatitis B (anti-HBsAg) was between 95-97%. PMID- 23338628 TI - [Association between HIV infection status and infectious complications after an elective C-section]. AB - OBJECTIVES: To determine the connection between HIV and infectious complications (IC) after an elective C-section. MATERIALS AND METHODS: A non-concurrent cohort study was conducted, in which the clinical records of 237 elective C-sections on HIV-positive pregnant women who gave birth at the Instituto Nacional Materno Perinatal (National Maternal Perinatal Institute) between 2004 and 2012 were revised. The records were matched by surgeon and C-section date, with 237 HIV negative pregnant women. Socio-demographic and clinical data were collected, along with characteristics of the C-section and data related to the HIV infection. IC were evaluated according to the NIH Consensus Development Task Force. The descriptive analysis and the bivariate analysis were carried out with a significance level of 5% for the hypothesis tests and the calculation of the Odds Ratio (OR) with a confidence interval (CI) at 95%. A conditional logistic regression model was built. RESULTS: IC were present in 13.9% of HIV-positive women and 9.7% of the control group (OR: 1.5 CI95% [0.9-2.7]); those who were exposed (women with HIV) were more likely to have a urinary tract infection (UTI) than those who were not exposed (ORa: 4.5 CI95% [1.4-14.5]). A connection was found between the IC and the type of incision (ORa: 2.3 CI95% [1.1-4.5]) and time of hospitalization (6 versus 3 days, p<0.001). CONCLUSIONS: Exposed women did not register a greater global risk of IC after an elective C-section; however, they were, indeed, more likely to get a UTI. Those HIV-positive women who were not receiving antiretroviral treatment were in greater risk of IC. The main risk factors associated with a post C-section IC in HIV-positive women were the type of incision, as well as the surgery time with the UTI. PMID- 23338629 TI - [Estimation and analysis of HIV incidence in the adult population in Peru: results of application of the MoT mathematical model]. AB - OBJECTIVES: To estimate HIV incidence in the adult population of Peru, 2010, and analyze its distribution based on risk behavior. MATERIALS AND METHODS: The UNAIDS model was applied based on the modes of transmission (MoT). The information was obtained from the review detailed in 59 documents (1984 - 2008). National databases were also analyzed to obtain specific data. Final selection of data was validated by the technical group and a group of experts. After consultation with experts, values were corrected and an uncertainty analysis was conducted. The model was adjusted to 2009 national prevalence (0.45%). RESULTS: Incidence estimated for 2010 was 0.03%, (4346 new infections). 84% of new infections concentrate on higher risk groups: men who have sex with men (55%) and people who have casual sex with heterosexuals (6.2%). The remaining 16% corresponds to low-risk heterosexual population. Heterosexual transmission accounts for 43% of new cases, 18% of which corresponds to female partners of high risk individuals. Only 2.2% of cases is related to female sexual work and 1.0% to injection drug users. CONCLUSIONS: The model provides an estimation of the incidence and its distribution among risk groups according to the mode of transmission, consistent with the HIV case reporting. The model creates scenarios to help decision making and policy formulation, as well as surveillance and planning of prevention and control. PMID- 23338630 TI - [Publication of summaries presented at the scientific congresses of medical students, Peru 2002-2009: characteristics and related factors]. AB - OBJECTIVES: To determine the publication rate of abstracts submitted at the national scientific meetings of medical students in Peru between 2002 and 2009, and associated factors. MATERIALS AND METHODS: A retrospective cohort was performed; the characteristics of overall abstract submitted were assessed. In addition, whether they were published in scientific journals was determined by way of a search strategy validated using Google Scholar. Crude and adjusted relative risks (RR) were calculated using Poisson regression with robust variance to assess association with the analyzed factors. RESULTS: 532 abstracts were analyzed, 52 (9.8%) of which were published in scientific journals after their presentation at a scientific meeting. All of them were published in Peruvian journals written in Spanish. The most important journal in which they were published was Ciencia e Investigacion Medica Estudiantil Latinoamericana (CIMEL) (13/52). The median of publication time was 13 months (range: 0-75). The fact that a student from the Universidad Nacional Mayor de San Marcos (RR: 5.18; CI95%:2.3-11.6) is the author of the abstract and that the abstract was collaboratively written by students from two universities (RR: 3.64; CI95%:1.1 11.7) are associated factors in the multivariate analysis. CONCLUSIONS: The publication rate of abstract submitted at national scientific meetings of medical students in Peru is low. New strategies should be taken, and the existing ones should be reinforced in order to increase the publication rate of the abstract submitted. PMID- 23338631 TI - [Genetic diversity of Peruvian isolates of Leptospira spp. through pulsed field gel electrophoresis]. AB - OBJECTIVES: Determine the genetic diversity of Peruvian isolations of Leptospira spp. through Pulsed Field Gel Electrophoresis (PFGE). MATERIALS AND METHODS: The PFGE methodology proposed by Galloway and Levett (2008) was standardized. A database including the PFGE profiles of 65 reference strains was prepared, and the technique was applied in 111 isolates of Leptospira spp. obtained in Peru between 2002 and 2010. RESULTS: A great generic diversity of serovars of circulating Leptospira spp. was determined in our country. 57 serovars were identified, 47 out of 97 pathogen isolates. Most frequent serovars were Icterohaemorrhagiae/Copenhageni (n=24) and Canicola (n=7). The most frequent species were L. santarosai (49,5%) and L. interrogans (37,1%). The distribution of species, clusters and serovars changed according to the source of isolate, the environmental context and the origin. CONCLUSIONS: There is great diversity of circulating serovars in Peru. There are genetic and epidemiological relations among isolates of different sources, and this is related to species, reservoir, environmental context and the origin of the isolate. PMID- 23338632 TI - [Assessment of body adiposity in school students in Arequipa, Peru]. AB - OBJECTIVES: To assess the relation between the percentage of body fat, the Body Mass Index and the abdominal perimeter in a population of school students who live at a moderate altitude. MATERIALS AND METHODS: A cross-sectional study was conducted, for which 394 boys and 405 girls between 6 and 11 years of age were selected using a probabilistic method. All the school students chosen were middle class children who lived in the urban area of Arequipa, Peru, located at a moderate altitude (2320m above sea level). The percentage of fat, the Body Mass Index and the abdominal perimeter were assessed. RESULTS: There was a moderate correlation between the percentage of fat and the abdominal perimeter in boys (0.59) and girls (0.68). Lower figures were obtained between the percentage of fat and the Body Mass Index in boys (0.56) and girls (0.66). A connection among the categories of fat percentage (%F) and the abdominal perimeter (p<0.05) was observed; yet, there was no connection between the %F and the Body Mass Index (p>0.05). CONCLUSIONS: The abdominal perimeter has a moderate correlation with the percentage of body fat and can be used as an indicator of adiposity in the mid-section of the body of children who live in Arequipa (Peru) at a moderate altitude. PMID- 23338633 TI - [Levels of dissatisfaction of external users of the Instituto Nacional de Salud del Nino (National Institute of Child Health) in Lima, Peru]. AB - OBJECTIVES: To determine the changes in the levels of dissatisfaction of the external users of the Instituto Nacional de Salud del Nino, in Lima, Peru. MATERIALS AND METHODS: Observational study based on a software to evaluate surveys completed by health care users (Software de Evaluacion de Encuestas de Usuarios en Salud - SEEUS). The population consisted of every person accompanying external users to outpatient visits, inpatient visits or emergency treatment in the years 2008, 2009 and 2010. To calculate the sample size, last year's proportion of users dissatisfied with each service was used, with an estimated error of 5% at a 95% confidence level. RESULTS: A sample of 2051 people was obtained, which revealed a decreasing trend in the levels of dissatisfaction with outpatient visits, and an increased dissatisfaction in the medical capabilities dimension for hospitalization and emergency services. In addition, a dissatisfaction index lower than 0.20 was registered in the medical capabilities dimension for outpatient visits. In contrast, the highest dissatisfaction indexes were registered in the hygiene dimension for 2009 (0.25) and 2010 (0.25), and in the others dimension for emergency services in 2009 (0.25). CONCLUSIONS: The dimensions showing an increase in the dissatisfaction index were tangible aspects, hygiene and others for hospitalization and emergency services. On the other hand, the medical capabilities dimension for outpatient visits showed a decrease in the level of dissatisfaction over the evaluated period. PMID- 23338634 TI - [Effects of spironolactone administration on the podocytes loss and progression of experimental diabetic nephropathy]. AB - OBJECTIVES: Evaluate the effect of spironolactone (SPL) on the loss of podocytes during the progression of experimental diabetic nephropathy (DN). MATERIALS AND METHODS: A group of male Holtzman rats randomly received streptozotocin (diabetic group) or a buffer citrate (control group). Diabetic rats were treated with SPL (50 mg/kg/day). The glomerular area and the cellularity were evaluated by histomorphometric methods. The injury and loss of podocytes was assessed by desmin expression and Wt-1, respectively. The gene expression of TGF-beta1 was assessed by RT-PCR. RESULTS: Glucose levels, the glomerular area, the mesangial expansion and collagen content increased significantly in diabetic rats. The administration of SPL prevented these changes without changing glucose levels. Immunostain for Wt-1 decreased significantly while immunostain for desmin increased dramatically in diabetic rats. Treatment with SPL prevented the increase of desmin expression and the loss of Wt-1 expression. Furthermore, the administration of SPL prevented the increase of TGF-beta1 mRNA expression in diabetic rats. CONCLUSIONS: Treatment with SPL, through independent glucose effects, reduces the loss of podocytes and the progression of DN morphological changes. These results suggest that these effects are mediated, at least in part, by the inhibition of TGF-beta1 mRNA expression. PMID- 23338635 TI - [Immune reconstitution syndrome due to BCG in HIV-treated children]. AB - The objective of this study is to describe the clinical profile of the immune reconstitution syndrome due to Mycobacterium bovis Bacillus Calmette-Guerin (IRS BCG) in children with HIV infection who receive highly active antiretroviral treatment (HAART) at Instituto Nacional de Salud del Nino de Lima (National Children's Health Institute of Lima), Peru. A case study was conducted, including 8 children with IRS-BCG, defined as the presence of regional lymphadenopathy or inflammation on the BCG vaccination site with at least one less logarithm in the viral load or immune improvement. All patients had AIDS (C3). The starting median age in HAART was 7.2 months and the event occurred 3 to 11 weeks after the treatment was started. 7 cases showed axillary adenitis. When compared with the Non IRS-BCG group, a significant association between the age at which HAART was started at one year, severe immunodepression, and increased viral load was found. It is concluded that IRS-BCG was related to a rapid clinical progression of the mother-to-child transmitted HIV/AIDS infection, severe immunosuppression and high viral load when the HAART began. PMID- 23338636 TI - [Diversity of phlebotominae in an endemic zone of american visceral leishmaniasis in Venezuela]. AB - In order to study the ecology of phlebotominae in the population of La Rinconada, in the state of Lara, Venezuela, endemic zone of Leishmaniasis, where cases of American Visceral Leshmaniasis (AVL) have been described, a longitudinal study was conducted during five months, and the presence of phlebotominae was identified one night per month in the surrounding areas of a home where an AVL case had been reported. Six species were found, of which only two were anthropophilic. The most abundant species was Lutzomyia pseudolongipalpis (90%), the abundance peak was observed in July - a dry month preceding the rainiest months of the year. Although in our sample we have not found any evidence that phlebotominae were infected by Leishmania; evidence presented is important for a better understanding of a vector that participates in AVL transmission. PMID- 23338637 TI - [Role of government in clinical trials]. AB - The regulation of clinical trials by the Government is a process of continuous change and adaptation, current challenge is to ensure the safety of participants and get balance of administrative procedures. Development and regulation of clinical trials in different countries vary according to the situation, context national or international execution, determining the insufficiency of national regulation requiring review of international regulation. The aim of this publication is to present a comprehensive overview of the role of Government in the regulation of clinical trials in different realities. It includes a review of the regulation in The European Union, The United States and some Latin American countries and finally the regulation in Peru. Contemporary trends in the regulation of clinical trials, are characterized by increasing standards of quality, ensuring the safety of the participants, promote transparency, lower bureaucratic processes and strengthening ethics IRB committees in the framework of open democratic processes, involving all stakeholders in dynamic processes based on current knowledge and changing tendencies. The challenge is to promote the development of clinical trials from the government institutions (universities, research centers, institutes, hospitals, etc.) priorizing local needs including orphan drugs, prevalent and neglected diseases, and therapeutic use of active components of local native plants. PMID- 23338638 TI - [Role of the state as regulatory authority of clinical trials in Peru]. AB - This article sheds the light on historical review of the clinical trials regulatory process to the publication of the Clinical Trials Regulation in Peru, by Supreme Decree 017-2006-SA. In this context, that Regulation was amended within one year, with many critics including from the Ombudsman. It also considers the achievements as a regulatory authority that has strengthened its steering and its main objective of protecting the rights, safety and welfare of human subjects in clinical trials. Those achievements are: the internal register of clinical trials, strengthening inspections on all stakeholders that take part in research, the Notification System of Serious Adverse Events (REAS-NET), the publication of the Guideline: "Ethical, Legal and methodology in clinical trials for use of the Ethical Review Board" which won an international award; the 1st prize in the category of fizcalization and accomplishment of the law by the Good Practice of Public Management: "Protecting the rights of human subjects in experimental studies", the publication of the new Manual of Procedures for Clinical Trials and the implementation Plan of the National Bioethics Network in Peru. PMID- 23338639 TI - [Development of new drugs: opportunities and benefits for Peru]. AB - The development of innovative drugs allows coming up with new medicines to prevent and better treat illnesses. This improves people's quality of life and makes it more productive. Therefore, the mission of pharmaceutical research is to develop safe and effective drugs. Clinical trials allow the evaluation of the safety and efficacy profiles of new medicines, medical devices and diagnostic tests. Research and development (R&D) of new drugs is a long and costly process, where out of every 5000 to 10000 new components that enter preclinical testing, only one is approved. Compared to 2011, drug development has increased by 7.6%. According to ClinicalTrials.gov, 5% of the trials take place in Latin America, and Peru is in the fifth position. On the other hand, according to the Global Competitiveness Report issued by the World Economic Forum, Peru ranks 61st, its biggest challenges being the functioning of its public institutions, investment in R&D and technological capacity. The complexity of drug R&D results in a search for competitive places to develop clinical trials. Clinical Research is a humanized industry due to its ethical platform, stated in the guidelines of good clinical practices. This industry demands our country to develop a differentiating value that contributes to the development of knowledge and its competitiveness. PMID- 23338640 TI - [Do clinical trials contribute to research development in Peru? How can that be achieved?]. AB - The participation of the National Institute of Health as a leader in ethical and methodological assessment and its responsibility to approve the implementation of studies dates back to 1995. Since then, clinical trials have increased significantly until 2009; for this reason, a preliminary analysis was made to assess whether this increase has had an impact in the production of clinical trials on endemic topics or disease burden problems that must be researched and resolved by Peruvian people. For this purpose, a search in SCOPUS and MEDLINE was conducted, with 102 clinical trials in humans found, all of them designed, implemented and carried out in Peru on endemic or domestic health issues. Observation over time does not reveal any parallel increase or the inclusion of new research groups or researchers, no research on endemic problems has been carried out in our country; for example, clinical trials on the "Carrion's Disease" have not been conducted. Very few clinical trials have been promoted during this period by academic institutions and the civil society. Taking this into consideration, we can affirm that there is no positive influence in the generation of native clinical trials on local problems that Peruvian people need to resolve. PMID- 23338642 TI - [Metastatic prostate cancer associated with low levels of prostate-specific antigen]. AB - A case was reported of a 67-year-old patient with right buttock pain radiating to the thighs and affecting his bipedalism and gait. With four months into the disease and a weight loss of 15 kilos, the patient underwent imaging tests which showed sacrum infiltration. The biopsy diagnosis was injury of bone tissue infiltrated by poorly differentiated adenocarcinoma. The rectal examination performed as part of the clinical urologic examination revealed a nodular lesion of less than one centimeter, despite the level of prostate-specific antigen (total PSA: 4.62 mg/dL). The prostate biopsy evidenced a poorly differentiated adenocarcinoma (Gleason score: 8). The bone scan showed active lesions associated with metastasis in the middle third of the right clavicle, the sacrum and the right pubic region. PMID- 23338641 TI - [Ethical challenges of genetic manipulation and research with animals]. AB - Research with animals presents ethical questions both for being used as models of human diseases and for being a prerequisite for trials in humans, as in the introduction of genetic modifications. Some of these questions refer to the fact that, as models, they do not fully represent the human condition; that conducting toxicity tests causes great harm to animals; that their nature is altered by genetic modifications and that introducing genetically modified organisms is a risk. The use of animals in research for the benefit of humans imposes the moral responsibility to respect them, not making them suffer unnecessarily, since they are living beings capable of feeling. PMID- 23338643 TI - [Efficacy and safety in the new regulation of pharmaceutical products in Peru]. AB - Internationally, pharmaceutical products (FP) are authorized after their risk benefit profile has been assessed, taking into account efficacy, safety and quality parameters. In 2009, it was established in Peru that all pharmaceutical products to be commercialized should show proof of their efficacy and safety. According to the new regulation, in effect as of 2012, the pharmaceutical specialties (FS) have been grouped into three categories: category 1, if included in the National List of Essential Medicines; category 2, if authorized in countries with high health surveillance; and category 3, if not included in categories 1 or 2. The scientific documentation to be submitted for the registration or re-registration of the product in the regulatory entity will depend on its FS category. PMID- 23338644 TI - [Strategy to strengthen health research capabilities in regional public universities: the role of the Mining Canon and the Instituto Nacional de Salud]. AB - The development of scientific health research requires a sustained and articulated research system that is consistent with the research priorities, as well as both internal and external funding, and availability of competent human resources. The Mining Canon, a constitutional right, has been partly used to foster applied scientific research in public universities (PU). In addition, the National Health Institute (INSTITUTO NACIONAL DE SALUD - INS) is devoted, among others, to promoting, managing and disseminating health research development at a national level. As part of these activities, a technical team was created to provide technical assistance to PU for research development using Mining Canon funds by making local adjustments to research protocols promoted by the INS and assumed by the professors-researchers at the Universities. This article aims at describing the reality of research at Peruvian public universities that have access to Mining Canon funds, as well as to elaborate on the work the INS is carrying out in order to strengthen research capabilities, starting with the development of research proposals that could potentially be funded by the Mining Canon. PMID- 23338645 TI - [Phenomenology of multiculturalism and intercultural pluralism]. AB - Multiculturalism is defined as the combination, within a given territory, of a social unit and a cultural plurality by way of exchanges and communications among actors who use different categories of expression, analysis and interpretation. A multiculturalist project should not promote a society that is split up into closed groups; on the contrary, it should set forth policies based on communication and cooperation processes among the cultural communities. To understand this concept, we will present the ontological basis of this phenomenonin the search for a communicational solution, with our startpoint being a phenomenological description of the way in which multiculturalism manifests to us in life; to later deepen into the meaning of the phenomenon,and finally offer a pluralist solution to the problems and challenges cultural differences bring about. PMID- 23338646 TI - [Reflections for having bioethics involved in the human rights culture]. AB - Bioethics can be interpreted as a critical reflection on life and health, a new way to make decisions in these fields, a social reform movement, and an academic discipline. In any case, Bioethics implies an interdisciplinary and intercultural dialogue. At the same time, human rights, as universal moral guidelines, provide a plausible basis for this intercultural dialogue, for they enable the identification of a core of transcultural values that can work as "moral minima" in the dialogue among different cultures and the search for international consensuses. This article sets forth the triple connection (historical genealogical, conceptual and practical) between bioethics and human rights, and reflects on some of the conditions that should be taken into account for bioethics to be involved in the human rights culture. PMID- 23338647 TI - [Reasons for an intercultural perspective of bioethics]. AB - Bioethics must have an intercultural perspective. This is based on three facts: The principles and values around which reflection is made are related to world views and traditions, human beings are cultural beings, and current societies are considerably diverse. Based on this, bioethics will seek an adequate balance between ethical universalism and contextualism. This is a fundamental step for unconditional respect for human dignity and mutual recognition, dialogue, correlation and complementarity among diverse cultures. PMID- 23338648 TI - [Mother's hemoglobin in perinatal and mother health in the highlands: implications in the Andean Region]. AB - This review analyzes the importance of hemoglobin levels in pregnant women and its implications in pregnancy. It discuss the use of biomass fuel for cooking and the impact on birthweight, maternal hemoglobin levels and the risk of late fetal death, pre-term delivery, and small for gestational age. Furthermore, the need to correct the cut-off points of hemoglobin level to define anemia at high altitudes is addressed. Current evidence suggests that corrections should not be made and iron supplements should be given to pregnant mothers with moderate or severe anemia. It is discussed whether iron supplementation should change its target population from pregnant women to infants aged 6 to 36 months. PMID- 23338649 TI - [Blood sample collection in native populations in Peru]. PMID- 23338650 TI - [Validation of the Peruvian version of the PHQ-9 for diagnosing depression]. PMID- 23338651 TI - [A need to monitor P. falciparum resistance to artesunate in Peru]. PMID- 23338652 TI - [Obesity in Peru: recommendations for a surveillance system]. PMID- 23338653 TI - [Practices of the health care personnel in relation to tuberculosis prevention measures]. PMID- 23338654 TI - [Participative budget, do the most vulnerable regions invest it in health care?]. PMID- 23338655 TI - [Reactivity to Treponema pallidum in blood donors, Ibague, Colombia, 2011]. PMID- 23338656 TI - Immediate effects of obstacle crossing training in independent ambulatory patients with spinal cord injury. AB - STUDY DESIGN: A 2 * 2 cross-over design. OBJECTIVES: To compare immediate effects of obstacle crossing training and conventional overground walking training on functional ability among independent ambulatory patients with spinal cord injury (SCI). SETTING: A tertiary rehabilitation center, Thailand. METHODS: Twenty independent ambulatory participants with SCI received a 1-day overground walking training and a 1-day obstacle crossing training program in a randomized cross over design with a 2-day washout period. Immediately prior and after each training program, the functional ability of all participants was measured using the timed up and go test (TUGT), five times sit-to-stand test (FTSST) and 10-m walk test (10MWT). RESULTS: The TUGT, FTSST and 10MWT data were significantly better after obstacle crossing training (P<0.001) but not after the overground walking training (P>0.05). The improvement following obstacle crossing training was also significantly different from that of the overground walking training (P<0.05). CONCLUSION: Obstacle crossing training immediately enhanced functional ability related to walking of ambulatory participants with SCI. However, a further longitudinal study using a randomized controlled trial is needed to support benefits of incorporation of obstacle crossing training into rehabilitation practice. PMID- 23338657 TI - Efficacy and tolerability of propiverine hydrochloride extended-release compared with immediate-release in patients with neurogenic detrusor overactivity. AB - STUDY DESIGN: Double-blind, randomised, multicentre study. OBJECTIVES: Efficacy and tolerability of propiverine extended-release (ER) compared with immediate release (IR) were evaluated in patients with proven neurogenic detrusor overactivity (NDO). SETTING: Six Spinal Cord Injury Units located in Austria, Germany and Romania. METHODS: Propiverine ER 45 mg s.i.d. or IR 15 mg t.i.d. were administered in patients with proven NDO. Outcomes were assessed at baseline (V1), and after 21 days of treatment (V2): Reflex volume served as primary, leak point volume and maximum detrusor pressure as secondary efficacy outcomes, treatment-related adverse events as tolerability outcomes. RESULTS: Sixty-six patients with proven NDO were enrolled. Reflex volume (ml) increased significantly in the IR (V1: 100.9, V2: 202.9) and in the ER (V1: 89.8, V2: 180.3) group, no significant intergroup difference. Leak point volume increased, and maximum detrusor pressure decreased significantly in both groups, no significant intergroup differences. The percentage of patients presenting with incontinence was reduced by 14% in the IR and by 39% in the ER group, the difference is significant. Treatment-related adverse events manifested in 42 and 36% following propiverine IR and ER, respectively. CONCLUSION: The urodynamic efficacy outcomes demonstrated both galenic formulations to be equieffective. However, following propiverine ER 45 mg s.i.d. higher continence rates compared with propiverine IR 15 mg t.i.d. were achieved, possibly indicative of more balanced plasma-levels. A slight tendency for superior tolerability outcomes of propiverine ER compared with IR was demonstrated. PMID- 23338658 TI - Computed tomographic angiography of anterior spinal artery in acute cervical spinal cord injury. AB - BACKGROUND: In addition to spinal fracture and/or dislocation, acute traumatic spinal cord injury (SCI) includes neural tissue and vascular damage at the site of contusion. Vascular damage results in spinal cord ischemia, which is a key factor that contributes to secondary pathogenesis. There is a need to identify spinal cord ischemia secondary to anterior spinal artery (ASA) rupture in acute cervical SCI. METHODS: After admission, 20 patients with cervical SCI, including 10 cases of central cord syndrome (CCS), four cases of brown-sequard syndrome (BSS) and six cases of tetraplegia (ASIA A), had computed tomographic angiography (CTA) of ASA performed on them. ASA rupture or occlusion was observed. RESULTS: The ASA was visualized in all 20 patients. No ASA rupture was found in CCS and BSS patients, even for sever blunt cervical fracture and dislocation tetraplegia patients, except one stab-wound patient. CONCLUSION: CTA provides the most detailed, highest resolution imaging of ASA in acute cervical SCI. ASA rupture is not commonly seen in acute blunt cervical SCI. PMID- 23338659 TI - National risk prediction model for elective abdominal aortic aneurysm repair. AB - BACKGROUND: Mortality results for elective abdominal aortic aneurysm (AAA) repair are published by the Vascular Society of Great Britain and Ireland. These mortality results are not currently risk-adjusted. The objective of this study was to develop a national risk prediction model for elective AAA repair. METHODS: Data for consecutive patients undergoing elective AAA repair from the National Vascular Database between April 2008 and March 2011 were analysed. Multiple logistic regression and backwards model selection were used for model development. The study outcome measure was in-hospital mortality. Model calibration and discrimination were assessed for all AAA repairs, and separately for open repair and endovascular aneurysm repair (EVAR) subgroups. RESULTS: There were 312 in-hospital deaths among 11,423 AAA repairs (2.7 (95 per cent confidence interval (c.i.) 2.4 to 3.0) per cent): 230 after 4940 open AAA repairs (4.7 (4.1 to 5.3) per cent) and 82 after 6483 EVARs (1.3 (1.0 to 1.6) per cent). Variables associated with in-hospital death included in the final model were: open repair, increasing age, female sex, serum creatinine level over 120 umol/l, cardiac disease, abnormal electrocardiogram, previous aortic surgery or stent, abnormal white cell count, abnormal serum sodium level, AAA diameter and American Society of Anesthesiologists fitness grade. The area under the receiver operating characteristic (ROC) curve was 0.781 (95 per cent c.i. 0.756 to 0.806) with a bias-corrected value of 0.774. Model calibration was good (P = 0.963) based on the Hosmer-Lemeshow goodness-of-fit test, (bias-corrected) calibration curves, risk group assessment and recalibration regression. CONCLUSION: This multivariable model for elective AAA repair can be used to risk-adjust outcome analyses and provide patient-specific estimates of in-hospital mortality risk for open AAA repair or EVAR. PMID- 23338660 TI - High Stokes shift perylene dyes for luminescent solar concentrators. AB - Highly efficient plastic based single layer Luminescent Solar Concentrators (LSCs) require the design of luminophores having complete spectral separation between absorption and emission spectra (large Stokes shift). We describe the design, synthesis and characterization of a new perylene dye possessing Stokes shift as high as 300 meV, fluorescent quantum yield in the LSC slab of 70% and high chemical and photochemical stability. PMID- 23338661 TI - Arthroscopic labral repair concomitantly performed with curved periacetabular osteotomy. AB - A 23-year-old female presented with pain in the left hip. Radiological examination showed developmental dysplasia of the hip (DDH) combined with acetabular retroversion and posterior wall deficiency. Findings in the physical examination were coincident with femoroacetabular impingement. At surgery, we performed curved periacetabular osteotomy concomitant with arthroscopic labral repair and osteochondroplasty, simultaneously addressing dysplastic acetabulum and femoroacetabular impingement. The final follow-up examination at 18 months showed satisfactory outcome with the D'Aubigne and Postel hip score of 17/18. In addition to accurate diagnosis, the arthroscopic procedure for associated intra- and peri-articular problems seems to help improve the surgical outcome of periacetabular osteotomy performed for patients with DDH. PMID- 23338662 TI - Comparison of magnetic resonance imaging findings with arthroscopic findings in discoid meniscus. AB - PURPOSE: It is widely accepted that although valuable in the diagnosis of the discoid meniscus and tears, magnetic resonance imaging (MRI) can be insufficient in determining the type of the tear. This study calculates the sensitivity and specificity of MRI in determining the presence and absence of tears and how these values differ for different types of tears. METHODS: This study is a retrospective review of 10 years of our experience with arthroscopic discoid meniscus treatment between 1999 and 2009. MRI findings were compared with the intraoperative arthroscopic findings in 52 patients with 50 lateral and two medial discoid menisci of which 24 were complete and 28 were incomplete. Tears were classified into six groups: (1) no tear, (2) simple horizontal tear, (3) radial tear, (4) combined horizontal tear, (5) complex tear and (6) longitudinal tear. Sensitivity, specificity, positive and negative predictive values of MRI were calculated for each group separately and for the presence and absence of tears in general. In addition, the effect of age, type of discoid meniscus, and presence and absence of shift on the distribution of tear types were analysed. RESULTS: MRI was found to be 100 % specific and 97.8 % sensitive for determining the presence or absence of a tear with a negative predictive value of 85.7 % and a positive predictive value of 100 %. The specificities were 80 % for simple horizontal, 50 % for radial, 66.7 % for combined horizontal, 55.6 % for complex and 14.3 % for longitudinal tears, whereas the sensitivities were 66.7 % for simple horizontal, 96.9 % for radial, 87.5 % for combined horizontal, 94.6 % for complex and 100 % for longitudinal tears. The presence and absence of shift and type of the discoid were found to affect the distribution of the tear type. CONCLUSIONS: MRI is successful in determining the presence or absence of tears in discoid menisci; however, its ability to determine the tear type is questionable. Complete discoid menisci were found to have tendency towards having a simple horizontal or longitudinal tear, whereas incomplete discoid menisci tend to have radial or combined horizontal tears. Determination of the shift prior to surgery is important since it alters the surgical technique. PMID- 23338663 TI - Validity of GNRB(r) arthrometer compared to TelosTM in the assessment of partial anterior cruciate ligament tears. AB - PURPOSE: The main goal of this study was to compare the results of the GNRB((r)) arthrometer to those of TelosTM in the diagnosis of partial thickness tears of the anterior cruciate ligament (ACL). METHODS: A prospective study performed January-December 2011 included all patients presenting with a partial or full thickness ACL tears without ACL reconstruction and with a healthy contralateral knee. Anterior laxity was measured in all patients by the TelosTM and GNRB((r)) devices. This series included 139 patients, mean age 30.7 +/- 9.3 years. Arthroscopic reconstruction was performed in 109 patients, 97 for complete tears and 12 single bundle reconstructions for partial thickness tears. Conservative treatment was proposed in 30 patients with a partial thickness tear. The correlation between the two devices was evaluated by the Spearman coefficient. The optimal laxity thresholds were determined with ROC curves, and the diagnostic value of the tests was assessed by the area under the curve (AUC). RESULTS: The differential laxities of full and partial thickness tears were significantly different with the two tests. The correlation between the results of laxity measurement with the two devices was fair, with the strongest correlation between TelosTM 250 N and GNRB((r)) 250 N (r = 0.46, p = 0.00001). Evaluation of the AUC showed that the informative value of all tests was fair with the best results with the GNRB((r)) 250 N: AUC = 0.89 [95 % CI 0.83-0.94]. The optimal differential laxity threshold with the GNRB((r)) 250 N was 2.5 mm (Se = 84 %, Sp = 81 %). CONCLUSION: The diagnostic value of GNRB((r)) was better than TelosTM for ACL partial thickness tears. PMID- 23338664 TI - Can a tibial tunnel in ACL surgery be placed anatomically without impinging on the femoral notch? A risk factor analysis. AB - PURPOSE: To analyze anatomical risk factors and surgical technique dependent variables, which determine the risk for femoral notch impingement in anatomically correct placed tibial tunnels for anterior cruciate ligament (ACL) surgery. METHODS: Twenty fresh frozen adult human knee specimens under the age of 65 years were used. Digital templates mimicking a tibial tunnel aperture at the tibia plateau were designed for different tibial tunnel diameters and different drill guide angles. The centres of these templates were placed over the geometric centre of the native tibial ACL footprint. The distances between the anterior borders of the templates and the anterior borders of the footprints (graft free zone) were measured and compared. Furthermore, anatomic risk factors for femoral notch impingement were determined. RESULTS: The graft free zone was statistically significantly longer for larger drill-guide angles compared to smaller drill guide angles (p < 0.00001). Furthermore, 8 mm diameter tibial tunnels had a statistically significant larger graft free zone compared to 10-mm-diameter tibial tunnels (p < 0.00001). For the 10 mm diameter tibial tunnels with drill guide angle of 45 degrees , 9 out of 20 knees (45 %) were "at risk" for notching and 4 out of 20 knees (20 %) had "definite" notching. For 10-mm tunnels with drill-guide angle of 45 degrees , a risk for notching was associated with smaller tibial ACL footprint (p < 0.05). CONCLUSION: If a perfect centrally positioned tibial tunnel is drilled, a real risk for femoral notch impingement exists depending on the size of the tibial ACL footprint and surgery-related factors. Therefore, in anatomical tibial tunnel placement in single bundle ACL reconstruction surgery, particular attention should be paid to size of the tunnel and drill-guide angle to minimize the risk of femoral notch impingement. PMID- 23338665 TI - Prospective randomized comparison of anatomic single- and double-bundle anterior cruciate ligament reconstruction. AB - PURPOSE: To determine if anatomic double-bundle anterior cruciate ligament (ACL) reconstruction is superior to anatomic single-bundle reconstruction in restoring the stabilities and functions of the knee joint. METHODS: A prospective randomized clinical study was done to compare the results of 32 cases of anatomic single-bundle ACL reconstruction and 34 cases of anatomic double-bundle ACL reconstruction with average follow-up of 16.3 +/- 3.1 months. Tunnel placements of all the cases were measured on 3D CT. Clinical results were collected after reconstruction; graft's appearance, meniscus status and cartilage state under arthroscopy were compared and analysed too. RESULTS: Tunnel placements, confirmed with 3D CT, were in the anatomic positions as described in literature both in SB and DB group. No differences were found between SB and DB groups in clinical outcome scores, pivot shift test and KT 1000 measurements (average side-to-side difference for anterior tibial translation was 0.7 mm in SB group and 1.0 mm in DB group). More than 70 % of the single-bundle graft and AM bundle graft in DB group appeared excellent, but only 44.1 % of PL bundle grafts in DB group were excellent and 11.8 % were in poor state. No new menisci tear was found either in SB or DB group, however, in DB group cartilage damages in medial patella-femoral joint occurred in 38.2 % cases. This rate was significantly higher than in the SB group which is only 9.3 %. CONCLUSION: Both single- and double-bundle anatomic ACL reconstruction can restore the knee's stability and functions very well. However, more incidences of poor PL status and medial patellar-femoral cartilage damage may occur in double-bundle ACL reconstruction. PMID- 23338666 TI - Local infiltration analgesia is comparable to femoral nerve block after anterior cruciate ligament reconstruction with hamstring tendon graft: a randomised controlled trial. AB - PURPOSE: Arthroscopic anterior cruciate ligament (ACL) reconstruction is a painful procedure requiring intensive postoperative pain management. Femoral nerve block is widely used in ACL surgery. However, femoral nerve block does not cover the donor site of the hamstring tendons. Local infiltration analgesia is a simple technique that has proven effective in postoperative pain management after total knee arthroplasty. Further, local infiltration analgesia covers the donor site and is associated with few complications. It was hypothesised that local infiltration analgesia at the donor site and wounds would decrease pain and opioid consumption after ACL reconstruction with hamstring tendon graft. METHODS: Sixty patients undergoing primary ACL surgery with hamstring tendon graft were randomised to receive either local infiltration analgesia or femoral nerve block. Pain was scored on the numeric rating scale, and use of opioid, range of motion and adverse effects were assessed at the postoperative recovery unit (0 h), 3, 24 and 48 h, postoperatively. RESULTS: There were no significant differences between the groups in pain intensity or total opioid consumption at any of the follow-up points. Further, there were no differences between groups concerning side effects and range of motion. CONCLUSIONS: Local infiltration analgesia and femoral nerve block are similar in the management of postoperative pain after ACL reconstruction with hamstring tendon graft. Until randomised studies have investigated femoral nerve block combined with infiltration at the donor site, we recommend local infiltration analgesia in ACL reconstruction with hamstring tendon graft. PMID- 23338667 TI - Correlation of WOMAC and KOOS scores to tibiofemoral cartilage loss on plain radiography and 3 Tesla MRI: data from the osteoarthritis initiative. AB - PURPOSE: The purpose of this study was to determine the correlation between the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) and Knee Injury Osteoarthritis Outcomes scores (KOOS) and the degree of tibiofemoral cartilage loss on plain radiography and 3T magnetic resonance imaging (MRI). We hypothesize that these subjective outcome scores will have a significant correlation to quantitative joint space loss. METHODS: Data used in the preparation of this article were obtained from the osteoarthritis initiative (OAI) database (OAI public use data sets kMRI_QCart_Eckstein18 and kXR_QJSW_Duryea16). Four hundred and forty-five patients had WOMAC/KOOS scores, quantitative tibiofemoral joints space width on plain radiographs and quantitative tibiofemoral cartilage thickness and per cent full thickness cartilage loss on 3T MRI. Joint space width on plain radiographs was correlated to cartilage thickness on MRI, and WOMAC/KOOS scores were correlated to the degree of cartilage loss using Pearson correlation coefficients. RESULTS: There was a statistically significant correlation between medial and lateral compartment cartilage thickness on MRI and medial and lateral joint space width on plain radiography (r = 0.86, r = 0.80) (p < 0.001). KOOS knee pain score was significantly correlated to increasing per cent full thickness cartilage loss in the medial femoral compartment (r = 0.34) (p < 0.001). KOOS symptom score was significantly correlated to decreasing joint space width in the medial (r = 0.16) and lateral (r = 0.15) compartment and increasing per cent full thickness cartilage loss in the medial femoral compartment (r = 0.36) (p < 0.001). No WOMAC score was correlated to degree of joint space width, cartilage thickness or per cent full thickness cartilage loss (n.s). CONCLUSION: The WOMAC and KOOS scores are poor indicators of tibiofemoral cartilage loss, with only the KOOS symptom and knee pain score being weakly correlated. Osteoarthritis is a multifactorial process and the need to treat patients based off their symptoms and rely on radiographs as confirmatory modalities, and not diagnostic modalities, when talking about OA and medical intervention. PMID- 23338668 TI - Penetration of topical diclofenac sodium 4 % spray gel into the synovial tissue and synovial fluid of the knee: a randomised clinical trial. AB - PURPOSE: The present study was designed to evaluate the penetration of diclofenac sodium 4 % spray gel in synovial tissue, synovial fluid and blood plasma after topical application in subjects with joint effusions and planned total knee arthroplasty (TKA) due to osteoarthritis. METHODS: A total of 39 patients were randomised to two- or three-times daily application of diclofenac sodium 4 % spray gel to knees requiring surgery over a treatment period of 3 days. Within 8 h after the last application, TKA was conducted, and the diclofenac concentrations in synovial tissue, synovial fluid and blood plasma were measured by liquid chromatography. RESULTS: The median diclofenac concentration was approximately 10-20-fold higher in synovial tissue (36.2 and 42.8 ng/g) than in synovial fluid (2.6 and 2.8 ng/mL) or plasma (3.9 and 4.1 ng/mL) in both treatment groups. Dose proportionality for any compartment or treatment groups could not be detected. Treatment-related adverse events were noted in two cases and limited to skin reactions. CONCLUSION: Diclofenac sodium 4 % spray gel was found to penetrate the skin locally in substantial amounts and thus reach the desired target tissue. Concentrations were not dose-dependent, and application was well tolerated by 97.4 % of patients. Topical application of diclofenac should be considered a valuable alternative to systemic NSAID therapy in the initial treatment of osteoarthritis. PMID- 23338669 TI - CID: a valid incentive delay paradigm for children. AB - Despite several modifications and the wide use of the monetary incentive delay paradigm (MID; Knutson et al. in J Neurosci 21(16):RC159, 2001a) for assessing reward processing, evidence concerning its application in children is scarce. A first child-friendly MID modification has been introduced by Gotlib et al. (Arch Gen Psychiatry 67(4): 380-387, 2010); however, comparability in the results of different tasks and validity across different age groups remains unclear. We investigated the validity of a newly modified MID task for children (CID) using functional magnetic resonance imaging. The CID comprises the integration of a more age appropriate feedback phase. We focused on reward anticipation and their neural correlates. Twenty healthy young adults completed the MID and the CID. Additionally, 10 healthy children completed the CID. As expected, both paradigms elicited significant ventral and dorsal striatal activity in young adults during reward anticipation. No differential effects of the tasks on reaction times, accuracy rates or on the total amount of gain were observed. Furthermore, the CID elicited significant ventral striatal activity in healthy children. In conclusion, these findings demonstrate evidence for the validity of the CID paradigm. The CID can be recommended for the application in future studies on reward processing in children, adolescents, and in adults. PMID- 23338670 TI - From bench to bed: putative animal models of REM sleep behavior disorder (RBD). AB - REM behavior disorder (RBD) is a parasomnia characterized by REM sleep without atonia, leading to abnormal and potentially injurious behavior during REM sleep. It is considered one of the most specific predictors of neurodegenerative disorders, such as Parkinson's disease. In this paper, we provide an overview of animal models contributing to our current understanding of REM-associated atonia, and, as a consequence, the pathophysiology of RBD. The generator of REM associated atonia is located in glutamatergic neurons of the pontine sublaterodorsal nucleus (SLD), as shown in cats, rats and mice. These findings are supported by clinical cases of patients with lesions of the homologous structure in humans. Glutamatergic SLD neurons, presumably in conjunction with others, project to (a) the ventromedial medulla, where they either directly target inhibitory interneurons to alpha motor neurons or are relayed, and (b) the spinal cord directly. At the spinal level, alpha motor neurons are inhibited by GABAergic and glycinergic interneurons. Our current understanding is that lesions of the glutamatergic SLD are the key factor for REM sleep behavior disorder. However, open questions remain, e.g. other features of RBD (such as the typically aggressive dream content) or the frequent progression from idiopathic RBD to neurodegenerative disorders, to name only a few. In order to elucidate these questions, a constant interaction between basic and clinical researchers is required, which might, ultimately, create an early therapeutic window for neurodegenerative disorders. PMID- 23338671 TI - Sleep and non-motor symptoms in Parkinson's disease. AB - Beyond the cardinal motor symptoms, bradykinesia, rigidity, tremor and postural instability, defining the diagnosis of Parkinson's disease, there is a big spectrum of non-motor features that patients may suffer from and that may reduce their quality of life. Non-motor symptoms are not only frequent but also often under-reported by patients and caregivers. As they are frequently under recognized by clinicians, they remain consequently under-treated. This review wants to give a short overview of the importance of non-motor symptoms on patients' quality of life and helpful assessment tools that might facilitate recognition of non-motor features during clinical setting. Given the wide range of non-motor symptoms in Parkinson's disease, we concentrate on common issues such as depression and sleep disorders like sleep-onset insomnia or sleep maintenance insomnia and restless legs syndrome. Thereby, we present some recent studies that have investigated the efficacy of dopaminergic drugs, especially dopamine agonists, revealing possible treatment strategies and thus improving disease management. PMID- 23338672 TI - Fractionated stereotactic radiotherapy using Novalis for confined intra-orbital optic nerve glioma in pediatric patient. AB - INTRODUCTION: Optic gliomas are the most common tumors in the optic pathways during childhood. Among them, about 10 % are located within intra-orbital cavity. However, the optimal management for intra-orbital optic nerve gliomas remains controversial. An 11-year-old male complained about progressive decline of vision in his right eye. Brain MRI revealed a fusiform enlargement of right optic nerve within intra-orbital cavity. MATERIALS AND METHODS: A presumptive diagnosis of optic nerve glioma was made. Therefore, we performed fractionated stereotactic radiotherapy (FSRT) using Novalis. DISCUSSION: Five years after FSRT treatment, follow-up MRI revealed size reduction of tumor and visual acuity improvement without radiation-related complications. PMID- 23338673 TI - Molecular cloning and evolutionary analysis of the HOG-signaling pathway genes from Saccharomyces cerevisiae rice wine isolates. AB - The high osmolarity glycerol (HOG) signaling pathway is crucial for yeast to cope with high osmolarity. Here, we showed that Saccharomyces cerevisiae rice wine isolates exhibited higher tolerance to osmotic stress, which was associated with the evolution of HOG pathway genes. Phylogenetic analysis of HOG genes revealed that Chinese rice wine strains were closely related to sake strains, indicating a common origin of rice wine strains. The DNA sequence diversity analysis showed that higher levels of polymorphism tended to accumulate on the osmosensor genes (MSB2 and SLN1), suggesting that most changes in a signaling transduction pathway were concentrated in the receptors. Moreover, the rapid evolution of osmosensors (Sln1/Msb2) and transcription factor (Msn4) might experience positive selection. Our results imply that the evolution of HOG pathway genes in S. cerevisiae rice wine strains is associated with their adaptation to high osmotic environments. PMID- 23338674 TI - Racial and Ethnic Health Disparities in Incarcerated Populations. AB - Alarming disparities in population health and wellness in the United States have led to multidisciplinary research efforts to create health equity. Identifying disparities, elucidating the etiological bases of disparities, and implementing solutions to eliminate disparities are part of the U.S. national health agenda. Racial and ethnic disparities have been identified throughout the cancer control continuum, in cardiovascular disease, diabetes and a multitude of other conditions. The causes of disparities are complex, condition specific, and conjectured to result from combinations of biological and socio-behavioral factors. Racial and ethnic health disparities within the vast incarcerated communities have been excluded from most studies, yet are of significant ethical and fiscal concern to inmates, governing bodies, and non-incarcerated communities into which inmates return. Importantly, research on racial and ethnic disparities in this unique population may shed light on the relative etiologies of health disparities and solutions for creating health equity throughout the general population in the United States. PMID- 23338675 TI - Prevention of coronary artery disease: recent advances in the management of hypertension. AB - As coronary artery disease (CAD) still represents the leading cause of death worldwide, more efforts should be made to improve CAD prevention with both lifestyle changes and medical treatment. Elevated blood pressure has been identified as a risk factor for CAD; however, recent evidence suggests that lowering blood pressure too much could be harmful in patients at high cardiovascular risk. Despite the availability of a wide selection of antihypertensive drugs, new strategies and treatments are needed to improve blood pressure control and reduce cardiovascular risk factors associated with elevated blood pressure. New fixed-dose combinations have been recently approved; they usually contain an inhibitor of the renin-angiotensin system, a calcium antagonist and/or a diuretic. Although research and development related to new antihypertensive drugs has slowed in recent years, some new antihypertensive compounds with novel mechanisms of action or dual activity are currently in clinical development. PMID- 23338676 TI - A case of successful use of microsnare to hold and pull the retrograde guidewire for the intervention to peripheral chronic total occlusion. AB - A basket-shaped microsnare has various uses such as the pull through technique during coronary intervention to chronic total occlusion (CTO). A 79-year-old man underwent angioplasty for the femoral artery occlusion. We performed a controlled antegrade and retrograde tracking (CART) with dilatation of a balloon on the antegrade guidewire. The retrograde guidewire partly ran in the true lumen but could not pass through the CTO lesion because of inadequate CART. Eventually, we successfully gripped the top of the retrograde guidewire in the CTO lesion using the basket-shaped microsnare (Soutenir((r))). The microsnare may be useful for bidirectional approach in peripheral CTO lesions. PMID- 23338677 TI - Early detection of ischemia by implantable cardioverter defibrillator capable of intracardiac electrogram monitoring in a case of old myocardial infarction. AB - A 72-year-old man received an implantation of implantable cardioverter defibrillator with intracardiac electrogram (ICEG) monitoring because ventricular fibrillation occurred in a case of old myocardial infarction with reduced left ventricular function. A year later, he came to our hospital for a regular checkup. Unexpectedly, ST depression was recorded by ICEG monitoring. He had no significant symptoms at the time, but had had exertional chest discomfort about 3 or 4 weeks before. The patient subsequently underwent successful revascularization, which potentially prevented the recurrence of acute myocardial infarction. ST depression has not been recorded by ICEG monitoring since the revascularization. PMID- 23338679 TI - Synthesis, photophysics and reverse saturable absorption of bipyridyl platinum(II) bis(arylfluorenylacetylide) complexes. AB - A series of Pt(II) bipyridyl complexes with different aryl substituents (Ar = naphthyl (1a), anthryl (1b), pyrenyl (1c) and phenothiazyl (1d)) on the fluorenylacetylide ligands are synthesized and investigated. The influence of the aryl substituent on the photophysics of these complexes is systematically investigated by spectroscopic methods and simulated by time dependent density functional theory (TD-DFT). All complexes exhibit ligand-centered (1)pi,pi* transitions significantly admixed with the metal-to-ligand charge transfer ((1)MLCT)/ligand-to-ligand charge transfer ((1)LLCT) transitions in the UV and blue spectral region, and broad, structureless (1)MLCT/(1)LLCT absorption bands in the visible spectral region. All complexes are emissive in solution at room temperature, with the fluorescence originating predominantly from the (1)MLCT/(1)LLCT states. The triplet emitting state is dominated by the (3)pi,pi* state localized on the fluorenylacetylide motif and mixed with some (3)ML'CT character (metal-to-fluorenylacetylide ligand charge transfer) for 1a, 1b and 1d. For 1c, the phosphorescence predominantly originates from the pyrene localized (3)pi,pi* state. The variation in the photophysical properties is related to the twisting angle of the aryl substituent from the fluorenyl plane, which defines the conjugation between the substituents and fluorenylacetylide ligands and, consequently, alters the energy and intensity of absorption and emission in these complexes. also exhibit broadband triplet excited-state absorption in the visible spectral region. Therefore, they show strong reverse saturable absorption at 532 nm for nanosecond laser pulses as demonstrated by the nonlinear transmission experiment. PMID- 23338678 TI - The pro-inflammatory cytokine TNF-alpha regulates the activity and expression of the serotonin transporter (SERT) in astrocytes. AB - Pro-inflammatory cytokines have been implicated in the precipitation of depression and related disorders, and the antidepressant sensitive serotonin transporter (SERT) may be a major target for immune regulation in these disorders. Here, we focus on astrocytes, a major class of immune competent cells in the brain, to examine the effects of pro-longed treatment with tumor necrosis factor-alpha (TNF-alpha) on SERT activity. We first established that high affinity serotonin uptake into C6 glioma cells occurs through a SERT-dependent mechanism. Functional SERT expression is also confirmed for primary astrocytes. In both cell types, exposure to TNF-alpha resulted in a dose- and time-dependent increase in SERT-mediated 5-HT uptake, which was sustained for at least 48 h post stimulation. Further analysis in primary astrocytes revealed that TNF-alpha enhanced the transport capacity (Vmax) of SERT-specific 5-HT uptake, suggesting enhanced transporter expression, consistent with our observation of an increase in SERT mRNA levels. We confirmed that in both, primary astrocytes and C6 glioma cells, treatment with TNF-alpha activates the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Pre-treatment with the p38 MAPK inhibitor SB203580 attenuated the TNF-alpha mediated stimulation of 5-HT transport in both, C6 glioma and primary astrocytes. In summary, we show that SERT gene expression and activity in astrocytes is subject to regulation by TNF-alpha, an effect that is at least in part dependent on p38 MAPK activation. PMID- 23338680 TI - Tetraarsenic oxide and cisplatin induce apoptotic synergism in cervical cancer. AB - Tetraarsenic oxide (As4O6, TAO) is a new arsenic compound that inhibits cell growth and induces apoptosis in human cervical cancer cell lines. In the present study, we report that the growth of tumor cells (CaSki) was inhibited by treatment with TAO alone or in combination with cisplatin or paclitaxel in vitro and in vivo. Proliferation was assessed by WST-1 assay, and apoptosis was assessed by Annexin-V/PI FACS analysis in the CaSki cell line treated with a single agent or with the combinations of two agents. Expression of apoptosis related proteins was analyzed by western blot analysis. A mouse xenograft model using CaSki cells was used to determine the in vivo activity of tetraarsenic oxide alone and in combination with cisplatin or paclitaxel by estimation of tumor size. At the end of the experiment, tumor tissue from each mouse was removed and processed for TUNEL analysis for confirmation of apoptotic cells. TAO was able to inhibit cell proliferation in a time- and dose-dependent manner. A combination of TAO and cisplatin effectively induced apoptosis by activating caspase-3. Using a mouse xenograft model, the sizes of tumors which were treated with a single agent and with a combination of agents decreased in a time dependent manner. A combination of TAO and cisplatin resulted in a significantly reduced tumor size (P<0.05). The data for the histochemical staining of TUNEL positive cells showed that the number of apoptotic cells was significantly increased by the combination of TAO and cisplatin. Thus, TAO is a good candidate for use in a combined regimen with cisplatin for patients with cervical cancer. PMID- 23338682 TI - Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort. AB - OBJECTIVE: To characterize patients with frontotemporal lobar degeneration (FTLD) with a repeat expansion mutation in the gene C9orf72, and to determine whether there are differences in the clinical presentation compared with FTLD carriers of a mutation in GRN or MAPT or with patients with FTLD without mutation. DESIGN: Patient series. SETTING: Dementia clinics in Flanders, Belgium. PATIENTS: Two hundred seventy-five genetically and phenotypically thoroughly characterized patients with FTLD. MAIN OUTCOME MEASURES: Clinical and demographic characteristics of 26 C9orf72 expansion carriers compared with patients with a GRN or MAPT mutation, as well as patients with familial and sporadic FTLD without mutation. RESULTS: C9orf72 expansion carriers developed FTLD at an early age (average, 55.3 years; range, 42-69 years), significantly earlier than in GRN mutation carriers or patients with FTLD without mutation. Mean survival (6.2 years; range, 1.5-17.0 years) was similar to other patient groups. Most developed behavioral variant frontotemporal dementia (85%), with disinhibited behavior as the prominent feature. Concomitant amyotrophic lateral sclerosis is a strong distinguishing feature for C9orf72 -associated FTLD. However, in most patients (73%), amyotrophic lateral sclerosis symptoms were absent. Compared with C9orf72 expansion carriers, nonfluent aphasia and limb apraxia were significantly more common in GRN mutation carriers. CONCLUSIONS: C9orf72 -associated FTLD most often presents with early-onset behavioral variant frontotemporal dementia with disinhibition as the prominent feature, with or without amyotrophic lateral sclerosis. Based on the observed genotype-phenotype correlations between the different FTLD syndromes and different genetic causes, we propose a decision tree to guide clinical genetic testing in patients clinically diagnosed as having FTLD. PMID- 23338683 TI - Effects of 1.8 GHz radiofrequency radiation on protein expression in human lens epithelial cells. AB - OBJECTIVE: The aim of the present study was to observe the effects of 1.8 GHz radiofrequency (RF) radiation on the protein expression of human lens epithelial cells (hLECs) in vitro. METHODS: The hLECs were exposed and sham-exposed to 1.8 GHz RF radiation (specific absorption rate (SAR) of 4 W/kg) for 2 h. After exposure, the proteins extracted from LECs were loaded on the Ettan MDLC system connected to the LTQ-Orbitrap MS for screening the candidate protein biomarkers induced by RF. The quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the levels of messenger RNA of candidate biomarkers. After the hLECs were exposed to 1.8 GHz RF (SAR of 2, 3 and 4 W/kg) for 2 h, the Western blot assay was utilized to measure the expression levels of the above-screened candidate protein biomarkers. RESULTS: The results of shotgun proteomic analysis indicated that there were eight proteins with differential expression between exposure and sham exposure groups. The results of qRT-PCR showed that there were three genes with expressional differences (valosin containing protein (VCP), ubiquitin specific peptidase 35 (USP35) and signal recognition particle 68 kDa (SRP68)) between exposure and sham exposure groups. The results of Western blot assay exhibited that the expressional levels of VCP and USP35 proteins significantly increased and the expressional level of protein SRP68 significantly decreased in hLECs exposed to 1.8 GHz RF radiation (SAR of 3 and 4 W/kg) for 2 h when compared with the corresponding sham groups (p < 0.05). CONCLUSION: The shotgun proteomics technique can be applied to screen the proteins with differential expression between hLECs exposed to 1.8 GHz RF and hLECs sham exposed to 1.8 GHz RF, and three protein biomarkers associated with RF radiation were validated by Western blot assay. PMID- 23338685 TI - Systematic review and meta-analysis of triclosan-coated sutures for the prevention of surgical-site infection. AB - BACKGROUND: Surgical-site infections (SSIs) increase morbidity and mortality in surgical patients and represent an economic burden to healthcare systems. Experiments have shown that triclosan-coated sutures (TCS) are beneficial in the prevention of SSI, although the results from individual randomized controlled trials (RCTs) are inconclusive. A meta-analysis of available RCTs was performed to evaluate the efficacy of TCS in the prevention of SSI. METHODS: A systematic search of PubMed, Embase, MEDLINE, Web of Science((r)), the Cochrane Central Register of Controlled Trials and internet-based trial registries for RCTs comparing the effect of TCS and conventional uncoated sutures on SSIs was conducted until June 2012. The primary outcome investigated was the incidence of SSI. Pooled relative risks with 95 per cent confidence interval (c.i.) were estimated with RevMan 5.1.6. RESULTS: Seventeen RCTs involving 3720 participants were included. No heterogeneity of statistical significance across studies was observed. TCS showed a significant advantage in reducing the rate of SSI by 30 per cent (relative risk 0.70, 95 per cent c.i. 0.57 to 0.85; P < 0.001). Subgroup analyses revealed consistent results in favour of TCS in adult patients, abdominal procedures, and clean or clean-contaminated surgical wounds. CONCLUSION: TCS demonstrated a significant beneficial effect in the prevention of SSI after surgery. PMID- 23338687 TI - Silencing of the human SET gene in vitro with lentivirus-mediated RNA interference. AB - In our previous study, SET was identified as one of the differentially expressed proteins that was associated with tetra-arsenic tetra-sulfide (As4S4)-induced NB4 R1 [retinoic acid-resistant acute promyelocytic leukemia (APL) cell line] apoptosis. However, the mechanism through which SET regulates pathways during this process remains unclear. The aim of this study was to construct lentivirus mediated short hairpin RNA (shRNA) against SET and investigate the effect of SET on As4S4-induced retinoic acid-resistant APL cell apoptosis. In the present study, 4 different oligonucleotides targeting the human SET gene were synthesized and cloned into the eukaryotic expression plasmid pGCSIL-GFP. The recombinant vectors were introduced into NB4-R1 cells. The silencing efficiency was measured by real-time quantitative PCR (RT-qPCR) and western blotting. Our results showed that the 4 recombinant RNA interference (RNAi) vectors were constructed successfully. Fluorescence microscopy demonstrated that infection efficiency ranged from 70 to 90%. Infection with the 4 different RNAi vectors significantly knocked down the expression of SET by 52.8, 69.1, 48.9 and 90.3% at the mRNA level, and 92.5, 96.3, 91.7 and 98.4% at the protein level, respectively. We attempt to clarify the mechanism of As4S4 treatment on retinoic acid-resistant APL. PMID- 23338686 TI - The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin: in vitro and in vivo studies. AB - We have synthesized a novel derivative of indomethacin, phospho-tyrosol indomethacin (PTI; MPI-621), and evaluated its anticancer efficacy in vitro and in vivo. PTI inhibited the growth of human colon, breast and lung cancer cell lines 6-30-fold more potently than indomethacin. In vivo, in contrast to indomethacin that was unable to inhibit colon cancer xenograft growth, PTI inhibited the growth of colon (69% at 10mg/kg/day, P < 0.01) and lung (91% at 15mg/kg/day, P < 0.01) subcutaneous cancer xenografts in immunodeficient mice, suppressing cell proliferation by 33% and inducing apoptosis by 75% (P < 0.05, for both). Regarding its pharmacokinetics in mice, after a single intraperitoneal injection of PTI, its plasma levels reached the maximum concentration (Cmax = 46 MUM) at 2h (Tmax) and became undetectable at 4h. Indomethacin is the major metabolite of PTI, with plasma Cmax = 378 MUM and Tmax = 2.5h; it became undetectable 24h postadministration. The cellular uptake of PTI (50-200 MUM) at 6h was about 200-fold greater than that of indomethacin. Regarding its safety, PTI had no significant genotoxicity, showed less gastrointestinal toxicity than indomethacin and presented no cardiac toxicity. Mechanistically, PTI suppressed prostaglandin E2 production in A549 human lung cancer cells and strongly inhibited nuclear factor-kappaB activation in A549 xenografts. These findings indicate that PTI merits further evaluation as an anticancer agent. PMID- 23338688 TI - Geographic distribution of risk of death due to homicide in Puerto Rico, 2001 2010. AB - OBJECTIVE: To raise awareness of the impact of homicides in Puerto Rico based on the findings of the spatial and temporal distribution of homicides and the use of firearms, by age and gender, using reports of interpersonal violent deaths from the Institute of Forensic Science (IFS) headquartered in San Juan, Puerto Rico. METHODS: This was a descriptive study of all homicide incidents in Puerto Rico reported by the IFS for the period 2001-2010. For each of the 8 542 cases, data analyzed included age, sex, municipality of incident, date of death, and mechanism. Crude sex- and age-specific mortality rates for Puerto Rico and for each municipality per year and for the 10-year period were calculated. Cumulative rate and cumulative risks were estimated and defined as lifetime risk. The relative distribution of cumulative rates for each municipality was categorized into quartiles of highest to lowest risk and displayed as a map. RESULTS: The risk of homicide death among males is 13 times greater than among females. The highest rates were observed among males 20-24 years of age (198.4 homicides per 100 000). In any given year, firearms were used in at least 80% of homicides. The average lifetime risk of homicide death for males is 1 in 34. CONCLUSIONS: Young adult males with access to firearms are at greatest risk of homicide in Puerto Rico. Also, highly urbanized municipalities are at highest risk; however, certain non-urban municipalities along the coast also have a very high homicide risk. Top priorities should be applying the WHO "ecological model" for violent injury prevention and establishing a surveillance system that will assist in identifying the role that socioeconomics, illegal firearms trade, and drug trafficking are playing. PMID- 23338689 TI - Prevalence and correlates of preterm labor among young parturient women attending public hospitals in Brazil. AB - OBJECTIVE: To determine the prevalence of and risk factors for preterm labor (< 37 weeks of gestation) among young pregnant women in Brazil. METHODS: A national cross-sectional study was conducted among parturient women aged 15-24 years attending Brazilian public maternities in 2009. Questionnaires were administered by interviewers during parturient admission to the maternity clinic (or soon after delivery, if survey participants were in too much pain to respond during labor). The questionnaires collected demographic, behavioral, and clinical data. RESULTS: A total of 2 071 (86.3%) of the 2 400 parturient women invited to participate were included in the study. Mean age was 20.2 years (standard deviation [SD]: 2.7) and mean years of formal education was 8 (SD: 2.4). Preterm labor occurred in 450 women (21.7%). The highest proportion of premature labor (36.1%) was found in the North region and the lowest proportion (6.9%) was found in the South region. In the final multivariate logistic regression model, living in the North region (odds ratio [OR]: 1.43, 95% confidence interval [CI]: 1.28 1.59); having monthly income less than twice the Brazilian minimum wage (OR: 1.27, 95% CI: 1.01-1.60); having suffered domestic violence (OR: 2.27, 95% CI: 1.23-4.18); and having had inadequate prenatal care (OR: 3.17, 95% CI: 2.54-3.97) remained significant correlates of preterm labor in this population. CONCLUSIONS: Results show a high prevalence of preterm labor among young women in Brazil. Preterm labor has multifactorial etiologies. More public health resources must be directed toward accelerating understanding of this complex process. PMID- 23338690 TI - [Impact of homicide on male life expectancy in Mexico]. AB - OBJECTIVE: To determine the impact of homicide on male life expectancy in Mexico and its 32 states during the three-year periods 1998-2000 and 2008-2010 and the weight of the different age groups in years of life expectancy lost (YLEL) due to this cause. METHODS: Based on official death and population data, abridged tables for male mortality in Mexico as a whole and its states were created for the three year periods studied. Health-adjusted life expectancy and YLEL for men aged 15 to 75 were calculated by selected causes (homicide, diabetes mellitus, and traffic accidents) and age groups in each three-year period. RESULTS: In the years between the 1998-2000 and 2008-2010 periods, YLEL due to homicide increased both nationally and in 19 states. In four states, the YLEL in 2008-2010 exceeded two, with the state of Chihuahua standing out at 5.2 years. In 14 of the 18 states where health-adjusted life expectancy among men declined between the two three year periods, the YLEL due to homicide increased. From 2008 to 2010, homicides were the leading cause of YLEL among men aged 20-44. YLEL due to homicide among those aged 15-44 increased between the two three-year periods. CONCLUSIONS: The increase in the rate of homicidal violence, especially among young people, is impeding an increase in male life expectancy in Mexico. In several states, such as Chihuahua and Durango, this violence appears to be the main reason for the decline in life expectancy among men aged 15 to 75. PMID- 23338692 TI - Suicide in Brazil, 2004-2010: the importance of small counties. AB - OBJECTIVE: To describe suicide rates by county size in the five geopolitical areas of Brazil. METHODS: This was an ecological, descriptive study of suicide deaths in Brazil that occurred among the population 10 years of age and older in 2004-2010. Data were obtained from the National Mortality Information System of Brazil. Counties were defined by size as: very large (200,000+), large (< 200,000 100,000), medium (< 100,000-50,000), small (< 50,000-20,000), very small (< 20,000-10,000, and micro (< 10,000). Age-adjusted suicide rates were calculated for all counties and for population-size groups in each geopolitical area. Rate ratio and 95% confidence interval were used to compare suicide risk between groups and the reference. RESULTS: The national, average suicide mortality rate was 5.7 deaths/100,000 inhabitants. Except in the North and North-East, suicide mortality rates increased from the very large (> 200,000) to the micro counties (< 10,000 population). Very high rates were scattered in the North and Mid-West among the indigenous peoples (> 30 deaths per 100,000). At highest risk were micro counties in the South (13.6 deaths per 100,000), with elderly males (60+ years, 31.4) and males 40-59 years (31.3) being the sex/age group with the highest rates. CONCLUSIONS: To reduce suicide mortality in Brazil, public health authorities must support mental health training in small cities and multi professional interventions among the indigenous peoples. In addition, the causes behind underreporting of suicide deaths must be resolved in several areas. PMID- 23338691 TI - Mortality among critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia: a multicenter cohort study in Colombia. AB - OBJECTIVE: To evaluate risk factors associated with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia emergence, its prognosis, and mortality determining factors in critically ill patients in Colombia. METHODS: A multicenter, retrospective cohort study conducted in 2005-2008 at 16 public and private reference health care institutions in Bogota, Colombia, that form part of a national epidemiological surveillance network and a hospital network with 4 469 beds. Methicillin-resistant emergence and mortality were analyzed using descriptive and time-to-event analysis; a multivariate Cox proportional hazard regression model was built to test the association between methicillin resistance and mortality. RESULTS: A total of 372 patients were studied: 186 with MRSA bacteremia, randomly matched with 186 with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. Previous surgery, antibiotic exposure, and hospital acquired infections were independently associated with methicillin resistance. MRSA caused longer hospital stays among survivors (median 24 versus 18 days, P = 0.014). Mortality predictors were: patient age, creatinine level over 1.21 mg/dl at ICU admission, severe sepsis, and inotropic requirement. Appropriate antimicrobial therapy and antimicrobial therapy change were independent protective factors, as was male gender. CONCLUSIONS: Methicillin resistance per se was not a mortality-independent prognostic factor. Previous conditions, such as age, baseline renal impairment, severe sepsis, and inotropy demand explained the observed mortality. Appropriate antimicrobial therapy remained a protective factor. A call to improve infection control measures in Colombia is mandatory. PMID- 23338693 TI - Effectiveness of antiretroviral treatment in Colombia. AB - OBJECTIVE: To evaluate the effectiveness of antiretroviral therapies and factors associated with HIV/AIDS control in a population of patients treated by the Colombian Social Security Health System (SGSSS). METHODS: This was a descriptive study of 510 HIV/AIDS patients treated with antiretroviral therapies in 19 cities in Colombia from June 1992-April 2011. Factors assessed from each patient's clinical history were: viral load, CD4 count, antiretroviral treatment regimens, prescribed daily doses of medications, length of disease evolution, duration of therapy, history of opportunistic diseases, and drug costs. RESULTS: Patients were predominantly male (75.1% males versus 24.9% women), with a mean age of 41.0 +/- 11.4 years and an average length of disease progression of 72 months. All recommended treatment regimens were prescribed at the defined daily dose. Treatment was effective in 65.3% of patients (viral load < 50 copies per mL). Non adherence to treatment, treatment failure, the presence of anxiety or depression, and treatment in the city of Barranquilla were associated with an increased risk of uncontrolled HIV infection. The mean annual cost of drugs per patient was US$ 2,736. CONCLUSIONS: Factors associated with uncontrolled HIV infection, especially regarding treatment adherence, must be identified to promote solutions for health care programs treating patients with HIV/AIDS. PMID- 23338694 TI - Regional integration and south-south cooperation in health in Latin America and the Caribbean. AB - This paper analyzes whether south-south cooperation is legitimately a recent practice or merely an improved version of previous regional integration processes in Latin America and the Caribbean. The authors reviewed and systematized the historic development of subregional integration processes in Latin America and the Caribbean and focused on health cooperation in the following contexts: the Central American Integration System, the Andean Community of Nations, the Caribbean Community, the Amazon Cooperation Treaty Organization, the Southern Common Market, and the Union of South American Nations. The study concludes that the conceptual and methodologic foundations of south-south cooperation in health were born from and nurtured by the processes of regional integration in Latin America and the Caribbean. This paper posits that regional political and economic integration initiatives bring potential benefits to the health sector and act as an important mechanism to develop south-south cooperation in this domain. The study recommends furthering this type of research to provide information that will allow national and multilateral agencies, or other stakeholders, to formulate and implement better policies for international health cooperation that target reducing inequities and promoting health and well-being for all people. PMID- 23338695 TI - [Educational status and patterns of weight gain in adulthood in Brazil: Estudo Pro-Saude]. AB - The aim of the present study was to investigate the association between participant and parental educational status (considered as an indicator of socioeconomic status) and participant pattern of weight gain in adulthood. We analyzed data from 2 582 baseline participants (1999) of Estudo Pro-Saude (Pro Health Study), a longitudinal investigation of civil servants from a public university in Rio de Janeiro, Brazil. Self-administered questionnaires were used to identify patterns of weight gain in adulthood. Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated for the association between parental and participant educational status and steady weight gain or weight cycling, with stable weight as a reference, using multinomial logistic regression models. For males, lower paternal educational level entailed a chance about 55% lower of weight cycling as compared to stable weight (OR = 0.45; IC95% = 0.26-0.78), whereas lower maternal schooling was related to increased risk of weight cycling, although without reaching statistical significance (OR = 1.68; IC95% = 0.94 3.00). The association between participant educational status and weight history was not statistically significant among men. In women, lower educational status entailed a chance 94% higher of self-reported weight cycling (OR = 1.94; 95% CI = 1.17-3.23), and there was no association between parental educational level and history of weight gain. In this study, changes in weight throughout life, both steady and cyclic, were associated with parental and participant educational status, with major differences between genders. PMID- 23338696 TI - [Surveillance of antimicrobial drug use in Mexican hospitals: current situation and practical guidelines for its implementation]. AB - Antibiotic use in Mexico is characterized by high levels of consumption, irrational use in primary care services, and high rates of bacterial resistance that cause hospital infections. Changes are needed in the recommended method for reporting antimicrobial drug use, so that quantification can be carried out through drug utilization studies. Such studies, which make it possible to know which drugs are used in hospitals, require an accessible source of data on antimicrobial drug use with the least risk of biases, a single drug identification system, and the adoption of units of measure that can be extrapolated. The methodology developed by the WHO Collaborating Centre for Drug Statistics Methodology, based on the anatomical, therapeutic, and chemical classification (ATC) system and the daily defined dosage (DDD), is proposed. Despite its limitations, employing this methodology to monitor local antimicrobial drug use will make it possible to detect differences in usage patterns among institutions, and, especially, trends within a given institution. This would facilitate timely alerts about potential problems related to the use of antimicrobial drugs and the need for specific interventions. PMID- 23338697 TI - Redistributing health through public health policies in Latin America: fair to whom and fair how? PMID- 23338698 TI - [Teaching autonomy in order to optimize drug therapy outcomes]. PMID- 23338699 TI - Luminescent silver nanoclusters anchored by oligonucleotides detect human telomerase ribonucleic acid template. AB - Luminescent silver nanoclusters were anchored by designed oligonucleotides. After hybridizing with human telomerase RNA template, the luminescence of the cluster decreased linearly with respect to the concentration of the complementary strand (25-250 nM). The cluster is therefore a potential candidate for human telomerase detection. PMID- 23338700 TI - Cloning, expression and characterization of phenylalanine ammonia-lyase from Rhodotorula glutinis. AB - The industrial-scale production of phenylalanine ammonia-lyase (PAL) mainly uses strains of Rhodotorula. However, the PAL gene from Rhodotorula has not been cloned. Here, the full-length gene of PAL from Rhodotorula glutinis was isolated. It was 2,121 bp, encoding a polypeptide with 706 amino acids and a calculated MW of 75.5 kDa. Though R. glutinis is an anamorph of Rhodosporium toruloides, the amino acid sequences of PALs them are not the same (about 74 % identity). PAL was expressed in E. coli and characterized. Its specific activity was 4.2 U mg(-1) and the k cat/K m was 1.9 * 10(4) mM(-1) s(-1), exhibiting the highest catalytic ability among the reported PALs. The genetic and biochemical information reported here should facilitate future application in industry. PMID- 23338701 TI - Characterization of an aldo-keto reductase from Thermotoga maritima with high thermostability and a broad substrate spectrum. AB - A novel aldo-keto reductase gene, Tm1743, from Thermotoga maritima was overexpressed in Escherichia coli. The enzyme displayed the highest activity at 90 degrees C and at pH 9. It retained 63 % of its activity after 15 h at 85 degrees C. The enzyme also could tolerate (up to 10 % v/v) acetonitrile, ethanol and 2-propanol with slightly increased activities. Methanol, DMSO and acetone decreased activity slightly. Furthermore, Tm1743 exhibited broad substrate specificity towards various keto esters, ketones and aldehydes, with relative activities ranging from 2 to 460 % compared to the control. Its optimum substrate, 2,2,2-trifluoroacetophenone, was asymmetrically reduced in a coupled NADPH-regeneration system with an enantioselectivity of 99.8 % and a conversion of 98 %. PMID- 23338702 TI - Cloning of two 5-aminolevulinic acid synthase isozymes HemA and HemO from Rhodopseudomonas palustris with favorable characteristics for 5-aminolevulinic acid production. AB - 5-Aminolevulinic acid (ALA) synthase (ALAS) HemA from non-sulfur photosynthetic bacteria has been used for the ALA bioproduction, whereas the isoenzyme HemT/HemO is less studied and not used for ALA production. Two ALAS-encoding genes, hemA and hemO from Rhodopseudomonas palustris were cloned, purified and characterized. The ALASs had very high specific activity, 3.6 and 2.7 U/mg, respectively, and strong affinity for one of its substrates, succinyl-CoA, K m with values of 11 and 4.4 MUM, respectively. HemO retained up to 60 % maximum activity within a broad range of concentrations of hemin, while HemA kept only 20 % at 10 MUM hemin. Escherichia coli overexpressing HemA or HemO produced 5.7 and 6.3 g ALA/l, respectively, in a 5 l bioreactor. PMID- 23338703 TI - Selection and characterization of colorectal cancer cell-specific peptides. AB - To develop a novel peptide probe for imaging detection of colorectal cancer, a 12 mer phage display library was used to select peptides that bind specifically to the human colorectal cancer cell line Caco-2. After four rounds of panning, four phage clones that bound specifically to the Caco-2 cells were selected. The phage clone SP-2 had a particularly high affinity and specificity for Caco-2 cells. This clone was identified using a series of methods. The peptide SP-2 that was displayed on phage SP-2 exhibited a high specificity to Caco-2 cells. Thus, the peptide SP-2 could be a candidate probe for the detection of colorectal cancer. PMID- 23338704 TI - [ASAS recommendations on the use of TNF inhibitors for patients with axial spondyloarthritis : evaluation of the 2010 update in the German-speaking area]. AB - The ASAS recommendations on the use of tumor necrosis factor (TNF) inhibitors for patients with axial spondyloarthritis were amended in 2010. Essential new aspects have been included in the update. The diagnosis is extended from patients with ankylosing spondlitis (AS) to all patient groups of axial spondyloarthritis. Pretreatment with at least two non-steroidal anti-rheumatic drugs (NSARD) for 4 weeks is recommended. The success of therapy with TNF inhibitors is to be compiled after at least 12 weeks.This article presents the results of the evaluation of the German translation of these recommendations. A total of 25 experts from Germany, Austria and Switzerland have scored the translation on a scale between 0 (no agreement) and 10 (full agreement) with respect to the recommendation grade. The agreement on the recommendations between the experts was very high (8.98 +/- 1.25). PMID- 23338705 TI - Analysis of porcine parvoviruses in tonsils and hearts from healthy pigs reveals high prevalence and genetic diversity in Germany. AB - In the present study, tonsils and hearts from 100 pigs were collected in a German slaughterhouse in 2010 and tested for porcine parvoviruses (PPV, PPV2, PPV3 and PPV4). PPV was observed in 60 of 100 hearts and 61 of 100 tonsils, and PPV2 was observed in 55 of 100 hearts and 78 of 100 tonsils. PPV3 and PPV4 were found in 20 and 7, respectively, of the 100 tonsils tested, but not in the heart samples. Positive samples of PPV, PPV2 and PPV3 were analyzed by nucleotide sequencing, and phylogenetic analysis revealed at least two distinct lineages for each virus in the German samples. The high detection rate of PPV, PPV2 and PPV3 in healthy animals and their genetic diversity highlights the importance of continuous monitoring of these viruses and their zoonotic potential. PMID- 23338706 TI - Simultaneous detection and identification of four viruses infecting pepino by multiplex RT-PCR. AB - Potato virus M (PVM), pepino mosaic virus (PepMV), tomato mosaic virus (ToMV), and potato virus S (PVS) infect pepino and cause serious crop losses. In this study, a multiplex RT-PCR method was developed for simultaneous detection and differentiation of PVS, ToMV, PepMV and PVM. The method was highly reliable and sensitive; validation was accomplished by testing pepino samples collected from different regions of China. In this survey, PVM, ToMV and PVS were detected in 37.0 %, 31.0 % and 5.5 % of samples tested, respectively, confirming the widespread occurrence of these three viruses in China. PepMV was not detected in any of the samples, which indicated that this virus may not be prevalent in China. The results suggest that the new multiplex RT-PCR method has potential to be used routinely for surveys of pepino for virus infection. PMID- 23338707 TI - Thrombin-induced TGF-beta1 pathway: a cause of communicating hydrocephalus post subarachnoid hemorrhage. AB - The mechanism of communicating hydrocephalus after subarachnoid hemorrhage (SAH) remains unclear. Revealing a signaling cascade may provide significant insights into the molecular etiology of the accumulation of cerebrospinal fluid (CSF) in cerebral compartments during SAH. To investigate the mechanism of the communicating hydrocephalus following SAH, we infused CSF with thrombin (TH), resulting in proinflammatory and proliferative responses in rat meninges of SAH. The effect of TH could be completely blocked by a transforming growth factor beta1 (TGF-beta1) inhibitor, SB-431542, suggesting that TH-stimulated proliferation of meninges is through the TGF-beta1 signaling pathway. The cascade of TGF beta1-Smad3 was significantly upregulated by TH, which, in turn, stimulated the proliferation of subarachnoid meninges. TH-induced overexpression of TGF-beta1 and activation of its downstream factors might be a mechanism of communicating hydrocephalus after SAH. PMID- 23338708 TI - Editorial: antibody validation requirements for articles published in endocrinology. PMID- 23338709 TI - Understanding the direct synaptic effects of estradiol. PMID- 23338710 TI - Mammalian labor: variations on a theme by amniota. PMID- 23338711 TI - NDP-MSH inhibits neutrophil migration through nicotinic and adrenergic receptors in experimental peritonitis. AB - Melanocortin is a potent anti-inflammatory molecule. However, little is known about the effect of melanocortin on acute inflammatory processes such as neutrophil migration. In the present study, we investigated the ability of [Nle4, D-Phe7]-melanocyte-stimulating hormone (NDP-MSH), a semisynthetic melanocortin compound, in the inhibition of neutrophil migration in carrageenin-induced peritonitis model. Herein, subcutaneous pretreatment with NDP-MSH decreased neutrophil trafficking in the peritoneal cavity in a dose-dependent manner. NDP MSH inhibited vascular leakage, leukocyte rolling, and adhesion and reduced peritoneal macrophage inflammatory protein 2, but not TNF-alpha, IL-1beta, IL-10, and keratinocyte-derived chemokine production. In addition, the effect on neutrophil migration was reverted by the pretreatment with both propranolol (a nonselective beta-adrenergic antagonist) and mecamylamine (a nonselective nicotinic antagonist) but not by splenectomy surgery. Moreover, NDP-MSH intracerebroventricular administration inhibited neutrophil migration, indicating participation of the central nervous system. Our results propose that the NDP-MSH effect may be due to a spleen-independent neuro-immune pathway that efficiently regulates excessive neutrophil recruitment to tissues. PMID- 23338712 TI - Vocal cord paralysis during the treatment of mantle cell lymphoma with vincristine. AB - CASE DESCRIPTION: We present a case of a seventy-eight year-old man who developed vocal cord paralysis without any sign of peripheral neuropathy during the treatment of Mantle Cell Lymphoma. He first presented in 2008 with a few bilateral small inguinal lymph nodes. Inguinal lymph node biopsy demonstrated Mantle Cell Lymphoma. Flow cytometry studies of peripheral blood and bone marrow cells were compatible with Mantle Cell Lymphoma. R-CHOP chemotherapy triweekly (Rituximab; Cyclophosphamide; Adriamycin; Vincristine; and Methylprednisolone) was planned. At the end of the second cycle, the patient complained of hoarseness without any symptoms of dysphagia or odynophagia. Direct flexible laryngoscopy showed bilateral vocal cord paralysis. Vincristine was discontinued and the patient's voice gradually resolved in about 4 months. CONCLUSION: Vincristine may cause peripheral, autonomic and cranial neuropathies. However cranial nerve involvement is quite uncommon. PMID- 23338716 TI - Significant correlation of TLR4 expression with the clinicopathological features of invasive ductal carcinoma of the breast. AB - Toll-like receptor 4 belongs to the family of pattern recognition receptors and is therefore an important part of innate immunity. Since the last decade, Toll like receptors (TLRs) have gained much interest in cancer research due to their role in tumor progression. However, there is scarcity of data evaluating TLR4 expression in different cell populations of tumor in relation to clinicopathological parameters of invasive ductal carcinoma of the breast. Therefore, we investigated TLR4 expression in 50 primary invasive ductal carcinoma and 17 lymph node sections through immunohistochemistry. Significant association of TLR4 expression with local metastasis and absence of necrosis was observed. The incidence of lymph node metastasis was higher in patients with high TLR4 expression in the tumor cells. We also observed an interesting inverse relationship of TLR4 with necrosis. In endothelial and lymphocytic population constituting breast tumors, a significant association of TLR4 expression was seen with the tumor grade. Therefore, we conclude that TLR4 expression is of biological interest both as a prognostic marker as well as a possible therapeutic target. PMID- 23338717 TI - Correlation between Rho-kinase pathway gene expressions and development and progression of glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the most common and the most aggressive primary malignant tumor of the brain. Prognostic factors in GBM can be sorted as age, tumor localization, tumor diameter, symptom period and type, the extent of surgery, postoperative tumor volume, and adjuvant radiotherapy and/or chemotherapy status. Besides the interactions between actin microfilaments, microtubules, and intermediate filaments, environmental factors and intracellular signals which regulate them affect the cell invasion. Rho proteins and therefore Rho-kinase activation play important role at these changes. The aim of this study is to evaluate the relationship between the Rho-kinase pathway gene expressions and prognosis in GBM. Ninety-eight patients diagnosed as GBM between 2001 and 2010 were enrolled into the study. RNA was obtained from the paraffinized tumor tissue of the patients with formalin-fixed, paraffin-embedded RNA isolation kit and the mRNA expressions of 26 genes were investigated. There was a statistically significant negative correlation between the ages at the diagnosis and survival. There was a significant relationship between the overexpression of Rho-kinase pathway-related genes LIMK1, CFL1, CFL2, and BCL2 and low expression of MAPK1 gene and the survival of the patients. These results demonstrate for the first time that there is a marked contribution of Rho-kinase pathway-related genes to the progression and survival of the GBM. The expression of these genes may be related to response of multimodal therapy or these parameters could be used to determine possible unresponsive patients before treatment. PMID- 23338718 TI - Zebularine-induced apoptosis in Calu-6 lung cancer cells is influenced by ROS and GSH level changes. AB - Zebularine (Zeb) is a DNA methyltransferase (DNMT) inhibitor that has various biological properties including anti-cancer effect. In the present study, we evaluated the effects of Zeb on the growth and death of Calu-6 lung cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. Zeb inhibited the growth of Calu-6 cells with an IC50 of approximately 150 MUM at 72 h in a dose-dependent manner. Zeb induced an S phase arrest of the cell cycle and apoptosis in Calu-6 cells. Pan-caspase inhibitor (Z-VAD) and caspase-8 inhibitor (Z-IETD) significantly rescued some cells from Zeb-induced Calu-6 cell death. In relation to ROS and GSH levels, O2 (*-) level was significantly increased in Zeb treated Calu-6 cells and caspase inhibitors reduced O2 (*-) level in these cells. Zeb induced GSH depletion in HeLa cells, which was attenuated by caspase inhibitors. L-buthionine sulfoximine (BSO), a GSH synthesis inhibitor, intensified the apoptotic cell death, ROS level, and GSH depletion in Zeb-treated Calu-6 cells. In addition, BSO increased Bax protein and decreased Bcl-2 protein in Zeb-treated Calu-6 cells. In conclusion, Zeb inhibited the growth of Calu-6 lung cancer cells via cell cycle arrest and caspase-dependent apoptosis and its cell death was influenced by ROS and GSH level changes. PMID- 23338719 TI - PET and SPECT in heart failure. AB - Heart failure is a serious condition with poor prognosis, which imposes an ever increasing burden on healthcare systems due to its rising prevalence. Nonetheless, physiological processes underlying heart failure remain poorly understood. In recent years, functional imaging such as gated CT has become available for routine clinical cardiology investigations. However, a maturation of nuclear imaging techniques such as PET and SPECT is now yielding new insights into the pathophysiological changes underlying heart failure, based on non invasive measurements of myocardial blood flow, myocardial viability, sympathetic innervation, neoangiogenesis and matrix metalloproteinases activity. Investigations of these biomarkers have the potential to reveal early aspects of left ventricle remodeling; diagnosis at an earlier stage of heart failure promises to facilitate improved intervention and therapy guidance. Furthermore, nuclear imaging techniques are being developed to monitor and predict outcome of novel cell-based approaches for restorative therapy of heart failure. PMID- 23338720 TI - Interventional echocardiography in structural heart disease. AB - Over the past decade, catheter based treatments of an increasing variety of cardiac diseases have expanded dramatically. These advancements became available through new developments and improvements in available devices, as well as increasing expertise of operators. However, arguably it is the innovation and progress in imaging techniques, and in particular in echocardiography, that allowed for such a surge in available percutaneous procedures. In this paper, current echocardiographic techniques, imaging protocols and recommendations will be reviewed and clinical examples will be shown to illustrate the use and importance of echocardiographic imaging in catheter based procedures for structural heart disease. PMID- 23338721 TI - Longitudinal and circumferential strain in patients with regional LV dysfunction. AB - The multilayer, helical arrangement of myofibers within the left ventricular myocardium forms the fundamental basis of the complex, multidimensional deformation of the left ventricle during the cardiac cycle. Echocardiographic characterization of the different components of this dynamic process not only provides a means to quantify the myocardial contractile function but also facilitates improved understanding of the pathophysiological mechanisms. Longitudinal deformation, which is more sensitive to the cardiac pathologies and is also easier to measure, has emerged as a reliable measure of the extent of the myocardial damage and may be helpful in the diagnosis and management of the patients with regional left ventricular dysfunction. Circumferential deformation, on the other hand, is affected relatively late in the disease process and therefore serves mainly as a marker of the transmural extent of the damage. PMID- 23338722 TI - Chronic kidney disease as a coronary artery disease risk equivalent. AB - Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease (CVD) risk and a higher CVD event rate. Substantial data from prospective cohort studies support the concept that dialysis patients as well as those with advanced stage (stages 3-5) CKD are associated with an increased risk for all cause and cardiovascular mortality. The risk for coronary artery disease (CAD) increases exponentially with declining kidney function, i.e., stage 3 or higher CKD. Indeed, CVD accounts for more than 50 % of deaths in patients with CKD. CKD patients are more likely to die of CVD than to progress to end stage kidney disease. This increase in CV risk is commonly attributed to co-existence of numerous traditional and nontraditional risk factors for the development of CVD that frequently accompany reduced kidney function. Therefore, CKD itself is now considered an independent CVD risk factor and a coronary artery disease (CAD) equivalent for all-cause mortality. All patients at risk for CAD should be evaluated for kidney disease. Treatments used for management of established CAD might have similar benefits for patients with concomitant CKD. PMID- 23338723 TI - Transcatheter valve-in-valve therapies: patient selection, prosthesis assessment and selection, results, and future directions. AB - The development of transcatheter valve implantations (TAVI) has induced profound changes in the treatment of valvular heart disease over the past decade. At the same time, due to excellent clinical results, bioprostheses continuously outperformed mechanical prostheses. The increasing number of elderly patients has led to numerous patients presenting with deteriorated bioprostheses needing reoperation. In selected high-risk patients or patients with unreasonable surgical risk, valve-in-valve TAVI has advanced to a viable alternative to conventional redo surgery. High procedural success, good hemodynamics and acceptable clinical results were reported up until now. Valve-in-valve TAVI seems to be safe and effective in treatment of deteriorated valve prostheses in high risk patients. The valve-in-valve concept presents the next step toward an individual treatment strategy for patients at prohibitive risk for conventional surgery. Present studies were reviewed with special concern to patient selection, prosthesis assessment, device selection, clinical outcome and technical challenging aspects as well. PMID- 23338724 TI - Percutaneous mitral and aortic paravalvular leak repair: indications, current application, and future directions. AB - Paravalvular regurgitation (PVR) is a symptomatic or asymptomatic complication after surgical valve replacement. It may be related to calcification, infection or tissue friability and occurs in 5 % to 17 % of surgical implanted heart valves. Reoperation is associated with a higher morbidity and mortality than the index procedure. Percutaneous closure of PVR can be an effective and lower risk alternative to reoperation. However, feasibility for percutaneous closure has to be assessed by defining the shape, size and location of the defect. Echocardiography with three-dimensional defect reconstruction is a cornerstone for guiding percutaneous PVR closure. Access for aortic PVR is usually retrograde via the femoral artery and access to mitral PVR either retrograde from the aorta, transvenous-transseptal or transapical. Meticulous planning and prudent procedural execution by experienced operators ensuring no impingement of the prosthetic leaflets leads to a high success rate of percutaneous PVR repair. PMID- 23338725 TI - Echocardiographic screening for subclinical rheumatic heart disease remains a research tool pending studies of impact on prognosis. AB - The application of portable echocardiography to the screening of asymptomatic children and young adults for rheumatic heart disease (RHD) in developing countries indicates that the disease may affect 62 million to 78 million individuals worldwide, which could potentially result in 1.4 million deaths per year from RHD and its complications. The World Heart Federation has developed a guideline for the echocardiographic diagnosis of RHD in asymptomatic individuals without a history of acute rheumatic fever (ARF) in order to ensure the reliability, comparability, and reproducibility of findings of the echocardiographic screening studies. Early studies suggest that a third of individuals with asymptomatic subclinical RHD revert to normal echocardiographic findings on repeat testing after 6-12 months, suggesting that repeat echocardiography may be necessary to confirm the findings prior to consideration of interventions such as antibiotic prophylaxis. It is not known, however, whether echocardiographic screening for asymptomatic subclinical RHD or the introduction of antibiotic prophylaxis for affected individuals improves the prognosis of RHD. Furthermore, the cost-effectiveness of this screening method has not been established in the vast majority of affected countries. Therefore, echocardiographic screening for asymptomatic subclinical RHD remains a research tool until studies of impact on prognosis and cost-effectiveness are conducted. PMID- 23338727 TI - The zinc-binding fragment of HypA from Helicobacter pylori: a tempting site also for nickel ions. AB - HypA, a nickel accessory protein from H. pylori, binds a zinc ion in it's structural site, a loop with two conserved CXXC motifs (Ac ELECKDCSHVFKPNALDYGVCEKCHS-NH(2)). There are at least three hypotheses on the binding mode of this ion. In this paper, we try to understand how Zn(2+) binds to this fragment and why Ni(2+), a metal with quite a high affinity towards thiolic sites, doesn't compete with zinc in the binding to this motif. Potentiometric titrations, mass spectrometry, NMR, UV-Vis and CD spectroscopy help us to compare the coordination modes in both metal complexes and discuss their thermodynamic stabilities. PMID- 23338726 TI - PCSK9 Inhibitors: potential in cardiovascular therapeutics. AB - Despite the efficacy of statin therapy, patients treated with these agents face substantial residual risk that is associated with achieved levels of LDL cholesterol (LDL-C). These observations suggest a potential benefit of additional strategies to promote further LDL-C reduction. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an attractive target in this regard. Abrogation of PCSK9 function prevents PCSK9-mediated catabolism of LDL receptors, increases cell surface LDL receptor density, and promotes clearance of LDL and other atherogenic lipoproteins from the circulation. Thus far, the most advanced approaches to block PCSK9 action are monoclonal antibodies and anti sense oligonucleotides. Among statin-treated patients, these agents may produce additional LDL-C lowering exceeding 50 %. In rare genetic experiments of nature, individuals with dominant negative or dual loss of function mutations of PCSK9 appear to have no adverse health effects resulting from lifelong, very low levels of LDL-C. In short-term trials, PCSK9 antibodies have been generally well tolerated. However, evidence to support long-term safety and efficacy of PCSK9 therapy to reduce cardiovascular risk awaits the results of large cardiovascular outcome trials. PMID- 23338728 TI - Folic acid supplementation and cancer risk: a meta-analysis of randomized controlled trials. AB - There are growing data and a continuing controversy over the effect of folic acid supplementation on cancer risk. We conducted a meta-analysis based on up-to-date published relevant randomized trials to further examine this issue. Relative risk (RR) was used to measure the effect of folic acid supplementation on risk of cancer using a random-effects model. Overall, folic acid supplementation had no significant effect on total cancer incidence (13 trials, n = 49,406, RR = 1.05; 95% CI: 0.99-1.11, p = 0.13), colorectal cancer (seven trials, n = 33,824, 1.01; 0.82-1.23, p = 0.95), other gastrointestinal cancer (two trials, n = 20,228, 1.00; 0.75-1.33, p = 0.99), prostate cancer (five trials, n = 27,065, 1.17; 0.84 1.62, p = 0.35), other genitourinary cancer (two trials, n = 20,228, 0.97; 0.75 1.27, p = 0.84), lung cancer (five trials, n = 31,864, 1.00; 0.84-1.21, p = 0.97), breast cancer (four trials, n = 19,800, 0.82; 0.63-1.07, p = 0.15), hematological malignancy (three trials, n = 25,670, 0.87; 0.64-1.17, p = 0.35) and total cancer mortality (six trials, n = 31,930, 1.02; 0.90-1.15, p = 0.81). However, a significantly reduced risk was observed for melanoma (three trials, n = 19,128, 0.47; 0.23-0.94, p = 0.03). Furthermore, higher total cancer incidence risk was observed among those trials with a higher percent use of lipid-lowering drugs (>60%, 1.10; 1.00-1.20, p = 0.04), or with lower percent baseline hypertension (<=70%, 1.08; 1.00-1.16, p = 0.057).Consistently, meta-regression analyses suggested that the similar trend between percent use of lipid-lowering drugs (p = 0.084) or percent baseline hypertension (p = 0.056) and log-RR for total cancer incidence associated with folic acid supplementation. Our findings indicate that folic acid supplementation has no significant effect on total cancer incidence, colorectal cancer, prostate cancer, lung cancer, breast cancer or hematological malignancy, but reduces the risk of melanoma. PMID- 23338729 TI - Lessons learned from fatal progressive multifocal leukoencephalopathy in a patient with multiple sclerosis treated with natalizumab. AB - OBJECTIVE: To describe the clinical, radiological, and histopathological features of a fatal case of progressive multifocal leukoencephalopathy (PML) in a patient with multiple sclerosis treated with natalizumab. We will use this case to review PML risk stratification and diagnosis. DESIGN: Case report. SETTING: Tertiary referral center hospitalized care. PATIENT: A 55-year-old, JC virus (JCV) antibody-positive patient with multiple sclerosis who died of PML after receiving 45 infusions of natalizumab. MAIN OUTCOME MEASURES: Brain magnetic resonance imaging and cerebrospinal fluid JCV DNA polymerase chain reaction results. RESULTS: The patient developed subacute onset of bilateral blindness following his 44th dose of natalizumab. Ophthalmologic examination was normal, the brain magnetic resonance imaging was not suggestive of PML, and cerebrospinal fluid analysis did not reveal the presence of JCV DNA. The patient was subsequently treated for a presumed multiple sclerosis relapse with high-dose corticosteroids. Two weeks after his 45th dose of natalizumab, he developed hemiplegia that evolved into quadriparesis. Repeated magnetic resonance imaging and cerebrospinal fluid studies were diagnostic for PML. Postmortem histopathological analysis demonstrated PML-associated white matter and cortical demyelination. CONCLUSIONS: The risks and benefits of natalizumab must be reassessed with continued therapy duration. When there is high clinical suspicion for PML in the setting of negative test results, close clinical vigilance is indicated, natalizumab treatment should be suspended, and JCV polymerase chain reaction testing and brain magnetic resonance imaging scans should be repeated. PMID- 23338730 TI - Changing smokers' risk perceptions--for better or worse? AB - This study investigated the effect of a smoking health message on smokers' comparative optimism. Two groups watched an anti-smoking scenario, with one group imagining being part of the scenario. Participants, including controls, completed comparative optimism ratings for four smoking-related illnesses. The intervention had negative consequences with both intervention groups reporting significantly higher comparative optimism versus the control group for all four smoking-related illnesses. It is concluded that media health messages can be powerful tools in changing comparative optimism but are influenced by peoples' prior perceptions. Health messages need to be systematically assessed to understand prior beliefs of the target audience. PMID- 23338731 TI - E-Learning: from useful to indispensable tool. PMID- 23338732 TI - Changes in mastectomy rates at a Brazilian public hospital over 20 years (1989 to 2008). AB - CONTEXT AND OBJECTIVE: Recently, breast-conserving surgery (BCS) has been replacing mastectomy for breast cancer treatment. The aim of this study was to evaluate the changes in mastectomy and BCS rates and the factors relating to these shifts. DESIGN AND SETTING: A retrospective study in a Brazilian public hospital. METHODS: Pathological records from female patients who underwent surgery for breast cancer at Hospital das Clinicas, Universidade Federal de Minas Gerais (HC-UFMG), between 1989 and 2008 were reviewed. The mastectomy and BCS rates were calculated. The chi-square test was used to assess factors associated with type of surgical treatment and to compare trends in treatment type over the years. Logistic regression was used for multivariate analysis. RESULTS: From 1989 to 2008, 2050 breast cancer surgical specimens were received in our service, corresponding to 1973 patients; 1324 (64.6%) of them were from mastectomy and 726 (35.4%) from BCS. A shift from mastectomy towards BCS was observed (P < 0.001). In multivariate analysis, earlier year of surgery (P < 0.001), larger tumor size (P < 0.001), having at least one positive axillary lymph node (P < 0.001) and patients' age greater than 68 years (P = 0.007) were predictors of mastectomy. CONCLUSIONS: There was a shift from mastectomy towards BCS in our institution over the years. This may reflect consolidation of BCS (plus radiotherapy) as an equivalent treatment to mastectomy in terms of survival and a shift to earlier diagnosis for the disease. PMID- 23338733 TI - Effectiveness of intra-articular lidocaine injection for reduction of anterior shoulder dislocation: randomized clinical trial. AB - CONTEXT AND OBJECTIVE: Shoulder dislocation is the most common dislocation among the large joints. The aim here was to compare the effectiveness of reduction of acute anterior shoulder dislocation with or without articular anesthesia. DESIGN AND SETTING: Prospective randomized trial conducted in Escola Paulista de Medicina, Universidade Federal de Sao Paulo (EPM-Unifesp). METHODS: From March 2008 to December 2009, 42 patients with shoulder dislocation were recruited. Reductions using traction-countertraction for acute anterior shoulder dislocation with and without lidocaine articular anesthesia were compared. As the primary outcome, pain was assessed through application of a visual analogue scale before reduction, and one and five minutes after the reduction maneuver was performed. Complications were also assessed. RESULTS: Forty-two patients were included: 20 in the group without analgesia (control group) and 22 in the group that received intra-articular lidocaine injection. The group that received intra-articular lidocaine had a statistically greater decrease in pain over time than shown by the control group, both in the first minute (respectively: mean 2.1 (0 to 5.0), standard deviation, SD 1.3, versus mean 4.9 (2.0 to 7.0, SD 1.5; P < 0.001) and the fifth minute (respectively: mean 1.0; 0 to 3.0; SD = 1.0 versus mean 4.0; 1.0 to 6.0; SD = 1.4; P < 0.001). There was one failure in the control group. There were no other complications in either group. CONCLUSION: Reduction of anterior shoulder dislocation using intra-articular lidocaine injection is effective, since it is safe and diminishes the pain. CLINICAL TRIAL REGISTRATION: ISRCTN27127703. PMID- 23338734 TI - Double muscle innervation using end-to-side neurorrhaphy in rats. AB - CONTEXT AND OBJECTIVE: One of the techniques used for treating facial paralysis is double muscle innervation using end-to-end neurorrhaphy with sectioning of healthy nerves. The aim of this study was to evaluate whether double muscle innervation by means of end-to-side neurorrhaphy could occur, with maintenance of muscle innervation. DESIGN AND SETTING: Experimental study developed at the Experimental Research Center, Faculdade de Medicina de Botucatu, Unesp. METHODS: One hundred rats were allocated to five groups as follows: G1, control group; G2, the peroneal nerve was sectioned; G3, the tibial nerve was transected and the proximal stump was end-to-side sutured to the intact peroneal nerve; G4, 120 days after the G3 surgery, the peroneal nerve was sectioned proximally to the neurorrhaphy; G5, 120 days after the G3 surgery, the peroneal and tibial nerves were sectioned proximally to the neurorrhaphy. RESULTS: One hundred and fifty days after the surgery, G3 did not show any change in tibial muscle weight or muscle fiber diameter, but the axonal fiber diameter in the peroneal nerve distal to the neurorrhaphy had decreased. Although G4 showed atrophy of the cranial tibial muscle 30 days after sectioning the peroneal nerve, the electrophysiological test results and axonal diameter measurement confirmed that muscle reinnervation had occurred. CONCLUSION: These findings suggest that double muscle innervation did not occur through end-to-side neurorrhaphy; the tibial nerve was not able to maintain muscle innervation after the peroneal nerve had been sectioned, although muscle reinnervation was found to have occurred, 30 days after the peroneal nerve had been sectioned. PMID- 23338735 TI - Using selected scenes from Brazilian films to teach about substance use disorders, within medical education. AB - CONTEXT AND OBJECTIVES: Themes like alcohol and drug abuse, relationship difficulties, psychoses, autism and personality dissociation disorders have been widely used in films. Psychiatry and psychiatric conditions in various cultural settings are increasingly taught using films. Many articles on cinema and psychiatry have been published but none have presented any methodology on how to select material. Here, the authors look at the portrayal of abusive use of alcohol and drugs during the Brazilian cinema revival period (1994 to 2008). DESIGN AND SETTING: Qualitative study at two universities in the state of Sao Paulo. METHODS: Scenes were selected from films available at rental stores and were analyzed using a specifically designed protocol. We assessed how realistic these scenes were and their applicability for teaching. One author selected 70 scenes from 50 films (graded for realism and teaching applicability > 8). These were then rated by another two judges. Rating differences among the three judges were assessed using nonparametric tests (P < 0.001). Scenes with high scores (> 8) were defined as "quality scenes". RESULTS: Thirty-nine scenes from 27 films were identified as "quality scenes". Alcohol, cannabis, cocaine, hallucinogens and inhalants were included in these. Signs and symptoms of intoxication, abusive/harmful use and dependence were shown. CONCLUSIONS: We have produced rich teaching material for discussing psychopathology relating to alcohol and drug use that can be used both at undergraduate and at postgraduate level. Moreover, it could be seen that certain drug use behavioral patterns are deeply rooted in some Brazilian films and groups. PMID- 23338736 TI - Nutritional evaluation of stage 5 chronic kidney disease patients on dialysis. AB - CONTEXT AND OBJECTIVE: Patients with chronic kidney failure undergoing dialysis have high prevalence of protein-energy malnutrition. There is still no uniform method for assessing these patients' nutritional status. It is recommended that a set of subjective and objective methods should be applied so that an adequate nutritional diagnosis can be reached. The aim of this study was to evaluate the nutritional profile of patients undergoing hemodialysis. DESIGN AND SETTING: Cross-sectional study conducted in the Dialysis Treatment Unit, Araraquara, Sao Paulo, Brazil, in 2008. METHODS: Anthropometric and biochemical indicators were characterized for 48 patients who also gave responses to the modified Subjective Global Assessment questionnaire (SGAm), and possible correlations between these indicators were investigated. RESULTS: The frequency of moderate or severe malnutrition ranged from 22% to 54%, according to the parameter used. Regarding the patients' conformity with the ideal weight, 29% of them weighed less than 75% of the ideal, and thus were classified as having moderate or severe malnutrition. The most significant correlations were observed between body mass index (BMI) and the idealness of triceps skinfold (TSF), upper arm circumference (UAC) and upper arm muscle circumference (UAMC); and between SGAm and the idealness of UAC and UAMC. CONCLUSION: The frequency of malnutrition showed great variability among the patients, according to the evaluation criterion chosen. Routine nutritional monitoring and validation of methods for assessing body composition among such patients are extremely important for diagnosing malnutrition early on, thus preventing complications and reducing the morbidity and mortality rates in this population. PMID- 23338737 TI - Overview of systematic reviews - a new type of study: part I: why and for whom? AB - CONTEXT AND OBJECTIVE: Healthcare decision-making is complex and should involve healthcare professionals, patients and the best level of evidence. The speed of information production creates barriers against keeping up to date. In this light, methodologists have proposed a new type of study: overviews of systematic reviews (OoRs). The aim here was to introduce and demonstrate the role of OoRs in information synthesis for healthcare professionals, managers, researchers and patients. DESIGN AND SETTING: Time-series study conducted at the Brazilian Cochrane Center, jointly with the Postgraduate Program on Internal Medicine and Therapeutics, Discipline of Emergency Medicine and Evidence-Based Medicine, Department of Medicine, Federal University of Sao Paulo. METHODS: To show the growth in the numbers of published papers that provide high-level evidence and thus demonstrate the importance of OoRs for synthesis and integration of information, three filters for study designs were applied to two databases. An equation for predicting the expected number of published papers was developed and applied. RESULTS: Over the present decade, the number of randomized controlled trials in Medline might reach 2,863,203 and the number of systematic reviews might reach 174,262. Nine OoRs and 15 OoRs protocols have been published in the Cochrane Library. CONCLUSIONS: With the exponential growth of published papers, as shown in this study, a new type of study directed especially towards healthcare decision-makers was proposed, named "overview of systematic reviews". This could reduce the uncertainties in decision-making and generate a new hierarchy in the pyramid of evidence. PMID- 23338738 TI - Erythema induratum of Bazin associated with Addison's disease: first description. AB - CONTEXT: Erythema induratum of Bazin (EIB) is considered to be a tuberculid reaction and consists of recurrent painful nodules. The differential diagnosis includes diseases like nodular vasculitis, perniosis, polyarteritis nodosa and erythema nodosum. CASE REPORT: We report the case of a woman with EIB who developed Addison's disease during treatment with anti-tuberculosis drugs with good response to glucocorticoid replacement. The diagnosis was obtained through the clinical picture, positive tuberculin test and positive BCG (bacillus Calmette-Guerin) test on the histological sample. Anti-tuberculosis drugs and glucocorticoid replacement led to disappearance of the signs and symptoms. CONCLUSIONS: This is the first description of an association between EIB and Addison's disease. It should be borne in mind that tuberculosis is an important etiological factor for Addison's disease. PMID- 23338739 TI - Chin tremor in full-term neonate after hypoxia. AB - CONTEXT: Newborns may present a range of motor phenomena that are not epileptic in nature. Chin tremor is an unusual movement disorder that typically starts in early childhood and may be precipitated by stress and emotion. Its pathophysiology has not been fully elucidated. CASE REPORT: We describe a full term newborn that, immediately after neonatal anoxia, presented body and chin tremors that were unresponsive to anti-epileptic drugs. Subsequent neurological evaluation revealed signs of pyramidal tract damage and chin tremor triggered by percussion and crying. We discuss the hypothesis that the anatomopathological abnormality may lie at the level of the higher cortical centers or midbrain. CONCLUSIONS: Further studies are needed in order to gain greater comprehension of neonatal tremors. Recognition of the various etiological possibilities and consequent management of treatable causes is essential for care optimization. PMID- 23338741 TI - Back to EGF+61 genetic polymorphisms and lung cancer risk: looking to the future! PMID- 23338742 TI - Pharmacotherapy for mild hypertension. PMID- 23338743 TI - Omega 3 fatty acid for the prevention of cognitive decline and dementia. PMID- 23338744 TI - Cardiac risk in patients with treatment naive, first-line medically controlled and first-line surgically cured acromegaly in comparison to matched data from the general population. AB - INTRODUCTION: Coronary risk factors in patients with acromegaly after first-line transsphenoidal surgery (TSS) or first-line somatostatine analogue (SSA) treatment have rarely been examined. Aim of this study was an evaluation of cardiovascular risk factors and left ventricular hypertrophy (LVH) in 3 different patient groups with treatment naive, active (ACT), first-line medically controlled (MED) and first-line surgically treated (SUR) acromegaly and a calculation of the Framingham Weibull Risk Score (FS). DESIGN: Retrospective comparative matched case-control study. PATIENTS & METHODS: 40 acromegalic patients (cases aged 45-74 years, 23 men) were matched with respect to age and gender to 200 controls from the general population. 13 patients had treatment naive acromegaly (ACT), 12 patients were SSA treated (MED) and 15 patients were operated by TSS (SUR). Coronary risk factors were assessed after 12 months of treatment by interviews and direct laboratory measurements. Only patients normalized for IGF-I in MED and SUR group were included. FS and odds ratios (OR) from multiple conditional logistic regression (matched for age and gender, adjusted for BMI) were calculated. RESULTS: Compared to matched controls ACT patients had higher HbA1c levels (6.9+/-1.4 vs. 5.5+/-0.7% (p<0.0001)) and an increased prevalence of left ventricular hypertrophy (LVH) (30.8 vs. 3.2% (p=0.007). MED and SUR groups were similar for gender, age, disease duration and IGF-I levels at diagnosis. Compared to matched controls, MED patients had a significantly increased diastolic blood pressure (89+/-9 vs. 79+/-11 mmHg (p=0.001), prevalence of LVH (41.7 vs. 1.7% (p<0.0001), prevalence of diabetes mellitus (33.3 vs. 10.0% (p=0.03)), higher HbA1c levels (6.8+/-1.3 vs. 5.5+/-0.7% (p=0.0005)) and a higher FS (21.2+/-9.7 vs. 12.4+/-7.7% (p=0.002), OR 1.11 [1.02 1.21] (p=0.01)) while in the SUR group only higher prevalences of LVH (40.0 vs. 4.1% (p<0.0001)) and HbA1c levels (6.4+/-1.2 vs. 5.5+/-0.8% (p=0.006)) were found compared to controls. CONCLUSION: When comparing treatment naive, medically treated and surgically cured patients with acromegaly to age- and gender-matched subjects from the general population, we have found an increased cardiovascular risk in patients at 12 months after first-line SSA treatment but not in patients after first-line surgery. PMID- 23338745 TI - Quality of life in patients with non-CAD chest pain: associations to fear of pain and psychiatric disorder severity. AB - Chest pain in the absence of identified cardiac cause, or non-cardiac chest pain (NCCP), is a common condition that may result in impaired quality of life. Theories of NCCP put forward that patients who react to cardiopulmonary sensations with fear may avoid activities that elicit cardiac sensations. Co morbid psychiatric disorders, which are prevalent in this population, may predispose individuals to be more vigilant to physiological sensations, including cardiac-related symptoms. The daily impact of avoiding cardiopulmonary cues may limit quality of life. This study examined psychiatric disorders, fear of pain, and quality of life in 30 non-coronary artery disease (CAD) chest pain patients. Psychiatric disorder severity was independently associated with mental health related quality of life and fear of pain was independently associated with physical health related quality of life. This research adds understanding to contributory factors to impaired quality of life among patients with non-CAD chest pain. PMID- 23338746 TI - Generation of Mycobacterium tuberculosis-specific recombinant antigens and evaluation of the clinical value of antibody detection for serological diagnosis of pulmonary tuberculosis. AB - Rapid diagnosis of pulmonary tuberculosis (TB) infection is critical in clinical practice. To establish an effective serological diagnostic technique, we generated the several Mycobacterium tuberculosis (MTB)-specific immunogenic antigens and evaluated the clinical benefits of detection of immunoglobulin G (IgG) and IgM antibodies raised against these target antigens for the diagnosis of patients with active TB. The genes encoding the MTB-specific antigens 6-kDa early secretory antigenic target of MTB (ESAT-6), 10-kDa culture filtrate protein (CFP-10), ESX-1 substrate protein C (ESPC), 14KD/38KD and ESAT-6/14KD/38KD, were amplified from the MTB genome by PCR. Prokaryotic vectors were constructed for the expression of the individual MTB antigens. The target recombinant protein was expressed in Escherichia coli (BL21/DE3) and purified using immobilized metal affinity chromatography (IMAC). An ELISA based immunoassay was set up using these target antigens for the diagnosis of active TB. The detection samples included 98 patients with active TB and 102 healthy control volunteers. The cutoff OD value for IgG and IgM antibodies was selected according to a receiver operating characteristic (ROC) analysis. The sensitivity, specificity and positive likelihood ratio were also determined. We successfully cloned, expressed and purified the ESAT-6, CFP-10, ESPC, 14KD/38KD and ESAT-6/14KD/38KD recombinant antigens of MTB. The mean levels of IgG antibodies were significantly higher in patients with pulmonary TB compared with control groups. The target MTB-specific antigens can distinguish a TB infection from a non-TB infection, showing significant difference in statistics (P<0.001). The sensitivity of the IgG test ranged from 69.4% (ESAT-6) to 77.6% (ESAT-6/14KD/38KD) in the active TB patients; the specificity of assays varied from 78.4% (CFP-10) to 90.2% (14KD+38KD) in the healthy control groups. The IgM antibody test can not distinguish a TB infection from a non-TB healthy control. In conclusion, clinical use of the ESAT-6, CFP-10, ESPC, 14KD/38KD and ESAT-6/14KD/38KD antigens based on serodiagnostic IgG assay is of significant value for the rapid diagnosis of TB and for the discrimination between active TB patients and healthy controls. PMID- 23338747 TI - Palmitate induces H9c2 cell apoptosis by increasing reactive oxygen species generation and activation of the ERK1/2 signaling pathway. AB - Cardiac myocytes undergo apoptosis under conditions of high free fatty acid concentrations, including palmitate, which is implicated in lipotoxic cardiomyopathy. However, the underlying mechanisms remain unknown. The aim of the present study was to understand the role of reactive oxygen species (ROS) production and the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway in palmitate-induced apoptosis in H9c2 cells. H9c2 cells were exposed to palmitate for 12 h. The effect on the cell viability of H9c2 cells was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell apoptosis was determined by Hoechst 33342 staining. Levels of intracellular ROS were determined using a peroxide-sensitive fluorescent probe, 2',7'-dichlorofluorescein diacetate. Protein expression was measured by western blot analysis. Following treatment with palmitate for 12 h, H9c2 cells apoptosis was demonstrated as increased brightly condensed chromatin or unclear fragments by staining with Hoechst 33342, which was associated with increasing levels of active caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP). In this model of treatment with palmitate, H9c2 cell apoptosis correlated with increased levels of p53 and Bax expression and reduced levels of Bcl-2 expression. Palmitate induced apoptosis was observed to increase levels of intracellular ROS production and p-ERK1/2 and decrease p-Akt significantly. Consistent with these results, palmitate-induced apoptosis was attenuated by the ERK1/2 inhibitor, U0126, through partial reduction of intracellular ROS generation. Collectively, these results indicate that palmitate-induced apoptosis in H9c2 cells is mediated by activation of the ERK1/2 signaling pathway and increased ROS generation. PMID- 23338748 TI - Improving the Odds Through the Collaboration Success Wizard. AB - Collaboration has become a dominant mode of scientific inquiry, and good collaborative processes are important for ensuring scientific quality and productivity. Often the participants in these collaborations are not collocated, yet distance introduces challenges. There remains a need for evaluative tools that can identify potential collaboration problems early and provide strategies for managing and addressing collaboration issues. This paper introduces a new research and diagnostic tool, the Collaboration Success Wizard (CSW), and provides two case studies of its use in evaluating ongoing collaborative projects in the health sciences. The CSW is designed both to validate and refine existing theory about the factors that encourage successful collaboration and to promote good collaborative practices in geographically distributed team-based scientific projects. These cases demonstrate that the CSW can promote reflection and positive change in collaborative science. PMID- 23338749 TI - Effect of an overproduction of accessory Gvp proteins on gas vesicle formation in Haloferax volcanii. AB - Gas vesicle formation in haloarchaea requires the expression of the p-vac region consisting of 14 genes, gvpACNO and gvpDEFGHIJKLM. Expression of gvpFGHIJKLM leads to essential accessory proteins formed in minor amounts. An overexpression of gvpG, gvpH or gvpM in addition to p-vac inhibited gas vesicle formation, whereas large amounts of all other Gvp proteins did not disturb the synthesis. The unbalanced expression and in particular an aggregation of the overproduced Gvp with other accessory Gvp derived from p-vac could be a reason for the inhibition. Western analyses demonstrated that the hydrophobic GvpM (and GvpJ) indeed form multimers. Fluorescent dots of GvpM-GFP were seen in cells in vivo underlining an aggregation of GvpM. In search for proteins neutralizing the inhibitory effect in case of GvpM, p-vac +pGM(ex), +pHM(ex), +pJM(ex), and +pLM(ex) transformants were constructed. The inhibitory effect of GvpM on gas vesicle formation was suppressed by GvpH, GvpJ or GvpL, but not by GvpG. Western analyses demonstrated that pHM(ex) and pJM(ex) transformants contained additional larger protein bands when probed with an antiserum raised against GvpH or GvpJ, implying interactions. The balanced amount of GvpM-GvpH and GvpM-GvpJ appears to be important during gas vesicle genesis. PMID- 23338750 TI - Frontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1-q12.2: genetic, clinical and neuropathological analysis. AB - Numerous families exhibiting both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been described, and although many of these have been shown to harbour a repeat expansion in C9ORF72, several C9ORF72-negative FTD-ALS families remain. We performed neuropathological and genetic analysis of a large European Australian kindred (Aus-12) with autosomal dominant inheritance of dementia and/or ALS. Affected Aus-12 members developed either ALS or dementia; some of those with dementia also had ALS and/or extrapyramidal features. Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration. Aus-12 DNA samples were negative for mutations in all known dementia and ALS genes, including C9ORF72 and FUS. Genome-wide linkage analysis provided highly suggestive evidence (maximum multipoint LOD score of 2.9) of a locus on chromosome 16p12.1-16q12.2. Affected individuals shared a chromosome 16 haplotype flanked by D16S3103 and D16S489, spanning 37.9 Mb, with a smaller suggestive disease haplotype spanning 24.4 Mb defined by recombination in an elderly unaffected individual. Importantly, this smaller region does not overlap with FUS. Whole-exome sequencing identified four variants present in the maximal critical region that segregate with disease. Linkage analysis incorporating these variants generated a maximum multipoint LOD score of 3.0. These results support the identification of a locus on chromosome 16p12.1-16q12.2 responsible for an unusual cluster of neurodegenerative phenotypes. This region overlaps with a separate locus on 16q12.1-q12.2 reported in an independent ALS family, indicating that this region may harbour a second major locus for FTD-ALS. PMID- 23338752 TI - Offline and online capillary electrophoresis enzyme assays of beta-N acetylhexosaminidase. AB - Enzyme assays of beta-N-acetylhexosaminidase from Aspergillus oryzae using capillary electrophoresis in the offline and online setup have been developed. The pH value and concentration of the borate-based background electrolyte were optimized in order to achieve baseline separation of N,N',N" triacetylchitotriose, N,N'-diacetylchitobiose, and N-acetyl-D-glucosamine. The optimized method using 25 mM tetraborate buffer, pH 10.0, was evaluated in terms of repeatability, limits of detection, quantification, and linearity. The method was successfully applied to the offline enzyme assay of beta-N acetylhexosaminidase, which was demonstrated by monitoring the hydrolysis of N,N',N"-triacetylchitotriose. The presented method was also utilized to study the pH dependence of enzyme activity. An online assay with N,N'-diacetylchitobiose as a substrate was developed using the Transverse Diffusion of Laminar Flow Profiles model to optimize the injection sequence and in-capillary mixing of substrate and enzyme plugs. The experimental results were in good agreement with predictions of the model. The online assay was successfully used to observe the inhibition effect of N,N'-dimethylformamide on the activity of beta-N-acetylhexosaminidase with nanoliter volumes of reagents used per run and a high degree of automation. After adjustment of background electrolyte pH, an online assay with N,N',N" triacetylchitotriose as a substrate was also performed. PMID- 23338753 TI - Real-time size discrimination and elemental analysis of gold nanoparticles using ES-DMA coupled to ICP-MS. AB - We report the development of a hyphenated instrument with the capacity to quantitatively characterize aqueous suspended gold nanoparticles (AuNPs) based on a combination of gas-phase size separation, particle counting, and elemental analysis. A customized electrospray-differential mobility analyzer (ES-DMA) was used to achieve real-time upstream size discrimination. A condensation particle counter and inductively coupled plasma mass spectrometer (ICP-MS) were employed as downstream detectors, providing information on number density and elemental composition, respectively, of aerosolized AuNPs versus the upstream size selected by ES-DMA. A gas-exchange device was designed and optimized to improve the conversion of air flow (from the electrospray) to argon flow required to sustain the ICP-MS plasma, the key compatibility issue for instrumental hyphenation. Our work provides the proof of concept and a working prototype for utilizing this construct to successfully measure (1) number- and mass-based distributions; (2) elemental compositions of nanoparticles classified by size, where the size classification and elemental analysis are performed within a single experiment; (3) particle concentrations in both solution (before size discrimination) and aerosol (after size discrimination) phases; and (4) the number of atoms per nanoparticle or the nanoparticle density. PMID- 23338754 TI - In vivo and in vitro metabolism of a novel beta2-adrenoceptor agonist, trantinterol: metabolites isolation and identification by LC-MS/MS and NMR. AB - Trantinterol is a novel beta(2)-adrenoceptor agonist used for the treatment of asthma. The aim of this study is to identify the metabolites of trantinterol using liquid chromatography tandem mass spectrometry (LC-MS/MS), to isolate the main metabolites, and confirm their structures by nuclear magnetic resonance (NMR). Urine, feces, bile, and blood samples of rats were obtained and analyzed. Reference standards of six metabolites were achieved with the combination of chemical synthesis, microbial transformation, and the model systems of rats. Moreover, in order to investigate the phase I metabolism of trantinterol in humans and to study the species differences between rats and humans, incubations with liver microsomes were performed. The biotransformation by a microbial model Cunninghamella blakesleana AS 3.970 was also studied. A total of 18 metabolites were identified in vivo and in vitro together, 13 of which were newly detected. Three phase I metabolites were detected in vivo and in vitro as well as in the microbial model, including the arylhydroxylamine (M1), the tert-butyl hydroxylated trantinterol (M2) and the 1-carbonyltrantinterol (M3). Another important pathway in rats is glutathione conjugation and further catabolism and oxidation to form consecutive derivatives (M4 through M10). Other metabolites include glucuronide, glucoside, and sulfate conjugates. The results of in vitro experiments indicate no species difference exists among rats, humans, and C. blakesleana AS 3.970 on the phase I metabolism of trantinterol. Our study provided the most comprehensive picture for trantinterol in vivo and in vitro metabolism to this day, and may predict its metabolism in humans. PMID- 23338755 TI - Concentration measurements and isotopic composition of airborne molybdenum collected in an urban environment. AB - Here, we report the first measurements of the molybdenum (Mo) isotopic composition of aerosols collected on Teflon air filters. Mo concentrations and isotopic compositions were measured at selected locations in the city of Calgary, Canada, including a residence, the isotope laboratory at the University of Calgary, the University of Calgary weather station, and the City of Calgary Transit bus garage. Concentrations ranged from 0.07 ng/m(3) in the laboratory to 19.0 ng/m(3) in the bus garage. The concentrations of Mo in the air samples collected in the bus garage were the highest measured in this study. To date, there are no reported data for the Mo isotopic composition of airborne Mo. In this study, the delta(98/95)Mo values measured for the different urban sampling sites and reported relative to SRM 3134, ranged from -0.18 to +0.94 0/00. The results of this investigation suggest that measurements of Mo concentrations and isotopic compositions have the potential to trace anthropogenic emissions in an urban environment. PMID- 23338756 TI - Analysis of the evolution of the detection limits of electrochemical DNA biosensors. AB - In this paper we critically review detection limits of electrochemical DNA biosensors enabling DNA detection without target labelling. The review includes transduction principles and latest breakthroughs. To compare the efficiency of each type of electrochemical DNA biosensor, a simple DNA biosensors classification is established on the basis of the nature of the bio electrochemical transduction. PMID- 23338757 TI - An evaluation of the capability of a biolayer interferometry biosensor to detect low-molecular-weight food contaminants. AB - The safety of our food is an essential requirement of society. One well recognised threat is that of chemical contamination of our food, where low molecular-weight compounds such as biotoxins, drug residues and pesticides are present. Low-cost, rapid screening procedures are sought to discriminate the suspect samples from the population, thus selecting only these to be forwarded for confirmatory analysis. Many biosensor assays have been developed as screening tools in food contaminant analysis, but these tend to be electrochemical, fluorescence or surface plasmon resonance based. An alternative approach is the use of biolayer interferometry, which has become established in drug discovery and life science studies but is only now emerging as a potential tool in the analysis of food contaminants. A biolayer interferometry biosensor was assessed using domoic acid as a model compound. Instrument repeatability was tested by simultaneously producing six calibration curves showing replicate repeatability (n = 2) ranging from 0.1 to 6.5 % CV with individual concentration measurements (n = 12) ranging from 4.3 to 9.3 % CV, giving a calibration curve midpoint of 7.5 ng/ml (2.3 % CV (n = 6)). Reproducibility was assessed by producing three calibration curves on different days, giving a midpoint of 7.5 ng/ml (3.4 %CV (n = 3)). It was further shown, using assay development techniques, that the calibration curve midpoint could be adjusted from 10.4 to 1.9 ng/ml by varying assay parameters before the simultaneous construction of three calibration curves in matrix and buffer. Sensitivity of the assay compared favourably with previously published biosensor data for domoic acid. PMID- 23338758 TI - Effect of shRNA targeting mouse CD99L2 gene in a murine B cell lymphoma in vitro and in vivo. AB - Mouse CD99 antigen-like 2 (mCD99L2) has previously been confirmed to be expressed in murine B lymphoma (A20) cells by our group. The present study aimed to establish a mCD99L2-downregulated A20 cell line and to investigate the effect of shRNA targeting mCD99L2 in A20 cells in vitro and in vivo. Four pLenti6/mCD99L2 expression vectors containing the mCD99L2 shRNA-expressing cassette were constructed, transfected into A20 cells and stable mCD99L2-downregulated A20 subclones, termed A20-mCD99L2- cells, were established and identified by quantitative PCR and western blot analysis. Light and transmission electron microscopy, MTT assay, flow cytometry and immunofluorenscence labeling were used to observe the morphological, biological and phenotypic characteristics in vitro. Some of the A20-mCD99L2- cells exhibited H/RS-cell like morphology, a decreased proliferative ability, a prolonged G2 phase and increased CD30 and CD15 expression. Upon injecting cells into nude or immunocompetent BALB/c mice, tumorigenesis, tumor growth, morphology and phenotypes in vivo were observed. A20 mCD99L2- cells induced tumors in nude and BALB/c mice, but with less potency in the latter compared with the controls. Similar morphological, biological and phenotypic characteristics were observed in the A20-mCD99L2- cell-induced tumors as those in vitro. Several cytokines including CD30T, IL-12p40/p70, IL-3, IFN gamma, CXCL16, MIP-1alpha and CD40 were upregulated following mCD99L2 downregulation when detected using antibody arrays. The results from western blot analysis indicated that the regulation of mCD99L2 expression may involve the activated nuclear factor-kappaB pathway in the murine B lymphoma cells. The present study provides data for further investigation into the mCD99L2 gene in tumor cells. PMID- 23338759 TI - Highly efficient ionization of phosphopeptides at low pH by desorption electrospray ionization mass spectrometry. AB - A fast and novel strategy for efficient ionization of phosphopeptides in mixtures is reported, in which the sample is acidified to low pH to suppress the deprotonation of phosphate groups and then followed by direct analysis using liquid sample desorption electrospray ionization mass spectrometry (DESI-MS). PMID- 23338760 TI - Involvement of early growth response factors in TNFalpha-induced aromatase expression in breast adipose. AB - Expression of the oestrogen producing enzyme, aromatase, is regulated in a tissue specific manner by its encoding gene CYP19A1. In post-menopausal women, the major site for oestrogen production in the breast is the adipose, where CYP19A1 transcription is driven by the distal promoter I.4 (PI.4). Transcripts via this promoter are also elevated in breast adipose fibroblasts (BAFs) adjacent to a tumour. PI.4 expression is stimulated by a number of cytokines, and TNFalpha is one such factor. The transcriptional mechanisms induced by TNFalpha to stimulate PI.4 are poorly characterised. We show that the early growth response (Egr) transcription factors play an important role in the TNFalpha-induced signalling pathway resulting in elevated PI.4 transcription. TNFalpha treatment of BAFs increases mRNA levels of all four Egr family members, with EGR2 being the most highly expressed. Overexpression of EGR2 causes an increase in endogenous CYP19A1 expression in preadipocyte Simpson-Golabi-Behmel syndrome cells, driven by increases in PI.4-specific transcripts. PI.4 luciferase reporter activity is increased in a dose-dependent manner by EGR2, EGR3 and EGR4, with EGR2 showing the most potent activation of promoter activity. Deletion analysis indicates that this promoter activity is being indirectly mediated by a short region of the promoter not containing any previously characterised binding sites, and we further show that EGR2 does not bind directly or indirectly to this promoter region. However, siRNA knockdown of the Egrs reduces the total and PI.4-derived CYP19A1 transcription in BAFs. These studies unveil a novel component of the aromatase gene regulatory network and further enhance the complexity of oestrogen production in the breast. PMID- 23338761 TI - Loss of E-cadherin is not a necessity for epithelial to mesenchymal transition in human breast cancer. AB - Epithelial to mesenchymal transition (EMT) is typically defined by the acquisition of a spindle cell morphology in combination with loss of E-cadherin and upregulation of mesenchymal markers. However, by studying E-cadherin inactivation in 38 human breast cancer cell lines, we noted that not all cell lines that had undergone EMT had concomitantly lost E-cadherin expression. We further investigated this discrepancy functionally and in clinical breast cancer specimens. Interestingly, reconstitution of wild-type E-cadherin cDNA in a E cadherin negative cell line that had undergone EMT (MDA-MB-231) did not revert the spindle morphology back to an epithelial morphology. Neither were changes observed in the expression of several markers known to be involved in the EMT process. Similarly, upregulation of E-cadherin via global DNA demethylation in eleven cell lines that had undergone EMT did not induce a change in cell morphology, nor did it alter the expression of EMT markers in these cells. Next, we extracted genes differentially expressed between cell lines that had undergone EMT versus cell lines that had not undergone EMT. Caveolin-1 was identified to be an excellent marker for EMT, irrespective of E-cadherin status (specificity and sensitivity of 100 %). Consistent with our observations in the breast cancer cell lines, expression of Caveolin-1 identified a subset of basal breast cancers, particularly of metaplastic pathology, and only 50 % of these lacked E-cadherin expression. The discrepancy between E-cadherin loss and EMT was thus reproduced in clinical samples. Together, these results indicate that in human breast cancer loss of E-cadherin is not causal for EMT and even not a necessity. PMID- 23338762 TI - Trade-offs associated with axillary lymph node dissection with breast irradiation versus breast irradiation alone in patients with a positive sentinel node in relation to the risk of non-sentinel node involvement: implications of ACOSOG Z0011. AB - Recent data suggest that axillary lymph node dissection (ALND) may be unnecessary for patients with positive sentinel lymph node biopsy (SLNB) receiving whole breast irradiation (ACOSOG Z0011). The purpose of this study was to use decision analysis with simulated patients to determine subgroups with positive SLNB who may still benefit from ALND. We performed a decision analysis simulating axillary recurrence (ALR) risk, lymphedema, and quality of life following breast conserving surgery (BCS) with positive SLNB and either completion ALND and whole breast radiation (ALND + BRT) or breast radiation (BRT) alone. Simulated patients were divided into two risk groups based on the likelihood of disease in non sentinel axillary nodes after positive SLNB: those with risk 30-60 % ("high risk") and those with risk under 30 % ("low-risk," similar to average Z0011 patients). In simulated patients aged 55, BRT alone resulted in 1 month of additional QALE in the low-risk group versus ALND + BRT, while ALND + BRT resulted in 9.7 months of additional QALE in the high-risk group versus BRT alone. Overall survival was similar at 5 years in this simulation with either treatment in both groups, but ALND + BRT was superior to BRT alone at 20 years in the high-risk group (42 vs. 38 %). In the low-risk group, BRT alone is preferable unless ALR risk with BRT is greater than 1.6 % or lymphedema risk with ALND is under 10 %. Patients eligible for Z0011 but at a higher risk of residual nodal disease following BCS and positive SLNB may benefit from ALND + BRT, rather than BRT alone. PMID- 23338763 TI - Comparative estimation of percentage breast tissue density for digital mammography, digital breast tomosynthesis, and magnetic resonance imaging. AB - Given the increasingly important role of breast density as an independent risk factor for breast cancer, and the variable breast imaging tests that potentially provide measures for density. We compared breast tissue density on digital mammography (FFDM), digital breast tomosynthesis (DBT), and magnetic resonance imaging (MRI) using semi-automated automated software. These three imaging modalities have not been previously directly compared for estimating breast tissue density. Following informed consent from all participating women, FFDM, DBT, and MRI were performed. Breast percentage density was calculated with semi automated software, and compared, for all three imaging modalities. 48 patients (mean age, 41 years; range, 35-67 years) underwent FFDM, DBT, and MRI. Percent FFDM, DBT, and MRI breast density measures showed a positive linear correlation, (r = 0.95 for MRI and DBT, P < 0.0001; r = 0.97, P < 0.0001 for FFDM and DBT; r = 0.87 for FFDM and MRI). Linear regression analysis related to MRI and DBT had a high r (2) = 0.89 (95 % CI = 0.88-0.99, P < 0.001). FFDM overestimated breast density in 15.1 % in comparison to DBT and in 16.2 % in comparison to MRI, or conversely each of DBT and MRI underestimated density (relative to FFDM) by 15.1 or 16.2 %, respectively. Differences in percentage breast density between FFDM and DBT, and between FFDM and MRI, were highly significant (P < 0.0001). Differences in percentage breast density between DBT and MRI were not significant (P > 0.05). Breast density measures using FFDM, DBT, or MRI were generally well correlated, although differences were noted between estimates when comparing FFDM and DBT, and for estimates comparing FFDM and MRI. No signficant differences in percentage density were observed when comparing DBT and MRI. Our work highlight that differences between FFDM, DBT, and MRI should be considered when measuring percentage breast density. PMID- 23338764 TI - Synthesis and characterization of heterocyclic disilylchalcogenides. AB - The reaction of a dipotassium silyl dianion (1) with chalcogenide elements (E) does not afford the corresponding silylchalcogenolates, but allows the generation of a series of heterocyclic disilylchalcogenides (E = S (2), Se (3), Te (4)). Under high temperature, compound 4 can be converted into compound 5, a Te analog of compounds 2 and 3. The compounds were characterized by (1)H, (13)C and (29)Si NMR spectroscopy and high resolution mass spectrometry (HRMS). In addition, X-ray structure analyses were carried out on compounds 2-5. A DFT calculation was also performed. PMID- 23338765 TI - Author's reply to: Estimating net survival in population-based cancer studies. PMID- 23338766 TI - The impact of drug transporters on adverse drug reaction. AB - In this review, we have highlighted the adverse drug reaction mediated by transporters from two aspects: (1) competitive interactions between drug and drug/metabolite/endogenous substance mediated by transporters; (2) the expression/function change of transporter due to physiologic factors, disease, and drugs induction. It indicated that transporters exhibited a broad substrate specificity with a degree of overlap, which could change the pharmacokinetics of drugs and cause toxicity due to competition interactions among substrates. In addition, the expression and function of transporters were regulated by physiological conditions, pathological conditions, and drugs induction, which could cause adverse drug reaction and interindividual differences. Furthermore, one substrate was always medicated by several transporters and often subjected to metabolism by CYP enzymes, so we should be more aware of the increased plasma concentration of drugs caused by drug transporters as well as drug metabolizing enzymes synergistically, especially for drugs with narrow therapeutic window. In addition, the weightiness for one transporter to induce drugs plasma/tissue concentration change could be different in different condition. On the whole, transporters were corresponding with systemic/organs exposure of drug/metabolites/endogenous compounds. So understanding the expression and function in drug transporters will result in better strategies for optimal dosage regimen and reduce the risk for drug adverse reaction as well as adverse drug drug interactions. PMID- 23338767 TI - Diaschisis as the presenting feature in sporadic Creutzfeldt-Jakob disease. PMID- 23338768 TI - Disposition and adjustment to chronic pain. AB - Several empirical studies have shown that personal characteristics act as differential variables, which determine how pain is experienced and how the chronic pain patient adjusts to pain. The main aim of the present research is to review the relationships between some dispositional characteristics and pain adjustment. Taking into account the empirical literature, 6 personality traits that are relevant to the pain experience have been selected: neuroticism, anxiety sensitivity, and experiential avoidance as risk factors that increase the probability of patients experiencing a disability; and extraversion, optimism, and resilience as personal resources that increase their capacity to manage pain effectively. The results suggest that it would be useful to include an assessment of normal personality structure during the multi-dimensional evaluation of a person with chronic pain. Understanding these individual personality characteristics will aid in designing pain intervention programs and help predict possible treatment outcomes. PMID- 23338769 TI - Psychological resilience, pain catastrophizing, and positive emotions: perspectives on comprehensive modeling of individual pain adaptation. AB - Pain is a complex construct that contributes to profound physical and psychological dysfunction, particularly in individuals coping with chronic pain. The current paper builds upon previous research, describes a balanced conceptual model that integrates aspects of both psychological vulnerability and resilience to pain, and reviews protective and exacerbating psychosocial factors to the process of adaptation to chronic pain, including pain catastrophizing, pain acceptance, and positive psychological resources predictive of enhanced pain coping. The current paper identifies future directions for research that will further enrich the understanding of pain adaptation and espouses an approach that will enhance the ecological validity of psychological pain coping models, including introduction of advanced statistical and conceptual models that integrate behavioral, cognitive, information processing, motivational and affective theories of pain. PMID- 23338770 TI - Temperament, character, and personality disorders in chronic pain. AB - In the past decades investigators have used personality inventories to help explain the relationship between personality and pain experience. This article reviews empirical research, which has examined temperament and character features in chronic pain patients. Robert Cloninger's temperament and character model of personality based on a bio-psychosocial approach to personality and psychopathology has been used in multiple studies investigating the temperament and character profile of chronic pain patients. According to Cloninger's model, research portrayed a common personality profile of chronic pain patients characterized by prevailing harm avoidance and lower self-directedness, which has been shown to predict the presence of a personality disorder. Pain-prone patients could benefit from the measurement of personality by the temperament and character inventory with improved treatment response. PMID- 23338771 TI - Peripheral nerve stimulation for the treatment of primary headache. AB - A headache is a common neurological disorder, and large numbers of patients suffer from intractable headaches including migraine, tension headache and cluster headache, etc., with no clear therapeutic options. Despite the advances made in the treatment of headaches over the last few decades, subsets of patients either do not achieve adequate pain relief or cannot tolerate the side effects of typical migraine medications. An electrical stimulation of the peripheral nerves via an implantable pulse generator appears to be good alternative option for patients with treatment-refractory headaches. A number of clinical trials show considerable evidence supporting the use of peripheral nerve stimulator (PNS) for headaches not responding to conservative therapies. However, the mechanism by which PNS improves headaches or predicts who will benefit from PNS remains uncertain. The decision to use PNS should be individualized based on patient suffering and disability. Hence, further work is imperative. Here, we discuss the mechanism, indication, efficacy, implant technique, and complications of PNS. PMID- 23338772 TI - Headache and vasculitis. AB - Although headaches are common in the general population and have many causes, headaches secondary to inflammatory processes in the blood vessels in the Central Nervous System (CNS) are not so common. The most common types of vasculitis that are associated with headaches include primary CNS vasculitis, systemic necrotizing arteritis, granulomatous vasculitis, and systemic collagen diseases. It is important to differentiate between "true" vasculitides and a condition known and reversible cerebral vasoconstriction syndrome (RCVS). While treatment for many of the vasculitides consists of anti-inflammatory medications, this approach may produce significant complications in RCVS. It is up to the clinician to judiciously use imaging and laboratory data to reach the proper diagnosis and therefore offer the correct treatment to these patients. PMID- 23338773 TI - Acupuncture for cancer pain and related symptoms. AB - Cancer pain is one of most prevalent symptoms in patients with cancer. Acupuncture and related techniques have been suggested for the management of cancer pain. The National Comprehensive Cancer Network guidelines for adult cancer pain recommends acupuncture, as one of several integrative interventions, in conjunction with pharmacologic intervention as needed. This review presents the latest available evidence regarding the use of acupuncture for cancer pain. It also provides "actionable" acupuncture protocols for specific cancer pain conditions and related symptoms in order to provide more clinically relevant solutions for clinicians and cancer patients with pain. These conditions include postoperative cancer pain, postoperative nausea and vomiting, postsurgical gastroparesis syndrome, opioid-induced constipation, opioid-induced pruritus, chemotherapy-induced neuropathy, aromatase inhibitor-associated joint pain, and neck dissection-related pain and dysfunction. PMID- 23338774 TI - Extent of resection and radiotherapy in GBM: A 1973 to 2007 surveillance, epidemiology and end results analysis of 21,783 patients. AB - Surgery, radiation and chemotherapy are the standard of care for GBM patients, however, the impact of extent of resection (EOR) and radiotherapy (RT) on patient survival across age groups has not been established. Therefore, we present the current largest study on EOR and RT in GBM over the past three decades. Using the population based Surveillance, Epidemiology and End Results (SEER) registry, we identified a total of 21,783 GBM patients (1973-2007). Survival analysis based on EOR and RT was performed by means of factor analysis, Kaplan-Meier survival and Cox proportional hazard's ratio. Age, RT and EOR were highly prognostic (p<0.00001). Combined gross total resection (GTR) and RT showed the longest median survival (11 months) compared to subtotal resection (STR) and RT (9 months). Survival times after monotherapy with RT, GTR and STR were 5, 3 and 2 months, respectively. Patients without therapy showed a median survival of 1 month. RT and GTR demonstrated highest median survival. Interestingly, survival advantage of GTR versus STR amounted to only 1-2 months. Monotherapy (GTR, STR or RT) showed a significantly lower survival rate compared to combination therapies. RT alone yielded significantly better survival compared to any resective approach. Relative to overall age-specific median survival, elderly patients still reasonably benefit from RT alone. However, across all age groups multimodality treatment with surgery and RT continues to provide the largest survival benefit compared to either treatment alone and, thus, should be pursued whenever feasible. PMID- 23338775 TI - Behavioral interventions and counseling to prevent child abuse and neglect: a systematic review to update the US Preventive services task force recommendation. AB - BACKGROUND: In 2004, the U.S. Preventive Services Task Force determined that evidence was insufficient to recommend behavioral interventions and counseling to prevent child abuse and neglect. PURPOSE: To review new evidence on the effectiveness of behavioral interventions and counseling in health care settings for reducing child abuse and neglect and related health outcomes, as well as adverse effects of interventions. DATA SOURCES: MEDLINE and PsycINFO (January 2002 to June 2012), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the second quarter of 2012), Scopus, and reference lists. STUDY SELECTION: English-language trials of the effectiveness of behavioral interventions and counseling and studies of any design about adverse effects. DATA EXTRACTION: Investigators extracted data about study populations, designs, and outcomes and rated study quality using established criteria. DATA SYNTHESIS: Eleven fair-quality randomized trials of interventions and no studies of adverse effects met inclusion criteria. A trial of risk assessment and interventions for abuse and neglect in pediatric clinics for families with children aged 5 years or younger indicated reduced physical assault, Child Protective Services (CPS) reports, nonadherence to medical care, and immunization delay among screened children. Ten trials of early childhood home visitation reported reduced CPS reports, emergency department visits, hospitalizations, and self-reports of abuse and improved adherence to immunizations and well-child care, although results were inconsistent. LIMITATION: Trials were limited by heterogeneity, low adherence, high loss to follow-up, and lack of standardized measures. CONCLUSION: Risk assessment and behavioral interventions in pediatric clinics reduced abuse and neglect outcomes for young children. Early childhood home visitation also reduced abuse and neglect, but results were inconsistent. Additional research on interventions to prevent child abuse and neglect is needed. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 23338776 TI - An assessment of the feasibility and acceptability of a friendship-based social network recruitment strategy to screen at-risk African American and Hispanic/Latina young women for HIV infection. AB - OBJECTIVES To examine the feasibility and acceptability of a friendship-based network recruitment strategy for identifying undiagnosed human immunodeficiency virus (HIV) infection within young women's same-sex friendship networks and to determine factors that facilitated and hindered index recruiters (IRs) in recruiting female friendship network members (FNMs) as well as factors that facilitated and hindered FNMs in undergoing HIV screening. DESIGN A cross sectional study design that incorporated dual incentives for IRs and their female FNMs. SETTING The IRs were recruited through 3 Adolescent Trials Network for HIV/AIDS Interventions sites within their Adolescent Medicine Trials Units. Data were collected from January 1, 2009, through June 30, 2010. PARTICIPANTS The IRs self-identifying as HIV positive, negative, or status unknown were enrolled to recruit FNMs to undergo HIV screening. MAIN OUTCOME MEASURES Self-reports of HIV risk and facilitators and barriers to network recruitment and HIV screening were assessed using an audio-computer-assisted self-interview. Participants were identified as HIV negative or positive on the basis of an OraQuick HIV test with confirmatory enzyme-linked immunosorbent assay and/or Western blot tests. RESULTS Nearly all (156 [98.1%]) eligible IRs agreed to participate and most (78.4%) recruited 1 or more FNMs. Of the 381 FNMs, most (342 [89.8%]) agreed to HIV screening. Although a high acceptance of HIV screening was achieved, the HIV prevalence was low (0.26%). CONCLUSION Our findings provide compelling evidence to suggest that use of a female friendship network approach is a feasible and acceptable means for engaging at-risk young women in HIV screening, as shown by their high rates of agreement to undergo HIV screening. PMID- 23338777 TI - Different conformation of thiol protease inhibitor during amyloid formation: inhibition by curcumin and quercetin. AB - Cystatins are thiol proteinase inhibitors ubiquitously present in mammalian body and serve various important physiological functions. In the present study, we examined the effects of acid denaturation on newly identified thiol protease inhibitors from the lungs of Capra hircus (Goat) with a focus on protein conformational changes and amyloid fibril formation. Acid denaturation as studied by CD (Circular Dichroism) and fluorescence spectroscopy showed that purified inhibitor named GLC (Goat Lung Cystatin) populates three partly unfolded species, a native like state at pH 3.0, a partly unfolded intermediate at pH2.0, and unstructured unfolded state at pH 1.0, from each of which amyloid like fibrils grow as assessed by thioflavin T (ThT) spectroscopy. The result showed, native like structure formed at pH 3.0 is more responsive towards amyloid formation when compare to other conformation of proteins. Morphology of the protein species incubated for amyloid process was observed using transmission electron microscopy (TEM). Moreover, anti-fibrillogenic effects of curcumin and quercetin were analysed using ThT binding assay. Curcumin and quercetin produced a concentration dependent decline inThT fluorescence suggesting deaggregation of the fibrils. When added prior to amyloid fibril initiation 50 MUM curcumin inhibited amyloid aggregation. However, more quercetin is needed to prevent the same extent of fibrillation. Implications for therapeutics in view of polyphenols as essential nutrients are suggested in lung diseases. PMID- 23338778 TI - Chromophobe renal cell carcinoma, oncocytic variant: a proposal of a new variant giving a critical diagnostic pitfall in diagnosing renal oncocytic tumors. AB - In chromophobe renal cell carcinoma (RCC), two forms of typical and eosinophilic variants have been reported to date. We have previously reported a new variant of chromophobe RCC, namely an oncocytic variant. However, little is known on the histological features of this variant. In this article, we report such five cases. Macroscopically, the tumor was well demarcated, but unencapsulated. The cut surface of the tumor showed brown in color, but neither hemorrhage nor necrosis was seen. Microscopically, the tumor consisted of predominant tubular configuration with or without various proportion of solid-sheet pattern. In one tumor, tumor cells microscopically invaded branches of renal vein. In addition, the constituting cells were characterized by the oncocytic cytoplasm, trivial to minimal variation in tumor size, indistinct to slightly distinct cell border, centrally located round nuclei and the absence of perinuclear halo. These characteristics entirely resembled renal oncocytoma. However, neoplastic cells immunohistochemically showed the diffuse and strong labeling for cytokeratin 7 and mitochondrial antigen in all cases. In addition, in fluorescence in situ hybridization (FISH) study the loss of more than four chromosomes among chromosomes 7, 10, 13, 17 and 21 was confirmed in all tumors and the diagnosis of chromophobe RCC was rendered. In conclusion, we propose a new variant, namely an oncocytic variant, of chromophobe RCC morphologically resembling renal oncocytoma and biologically showing characteristics of chromophobe RCC, and this recognition is practically crucial in the differential diagnosis from renal oncocytoma. PMID- 23338779 TI - Effects of a water-soluble extract of Ganoderma lucidum mycelia on aberrant crypt foci induced by azoxymethane and small-intestinal injury by 5-FU in F344 rats. AB - The present study investigated whether a water-soluble extract from the culture medium of Ganoderma lucidum mycelia (Japanese: Reishi or Mannentake) (designated as MAK) exerted a protective effect against induction of aberrant crypt foci (ACF) by azoxymethane (AOM) and small-intestinal damage induced by the anticancer drug 5-FU. Six-week-old male F344 rats were fed a basic diet (MF), either alone or containing 2.5 % MAK, beginning 1 week before treatment with AOM. The rats were then given subcutaneous injections of AOM (15 mg/kg body weight) once in a week for 3 weeks. Next, beginning 1 day after the final AOM treatment, 25 or 80 mg/kg 5-FU was injected intraperitoneally three times at 5-day intervals. Finally, the rats were killed 3.5 days after the last injection of 5-FU. The large and small intestines were removed, and tissue specimens were examined for both ACF in the large intestine and regeneration of small-intestinal crypts. The number of ACF was significantly decreased by treatment with 25 mg 5-FU and further decreased by 25 mg 5-FU + MAK in comparison with 5-FU alone. Moreover, there was a greater degree of recovery from small-intestinal damage in the 5-FU + MAK groups than in rats that had received 5-FU alone. The present results indicate that MAK ameliorates the colon precancerous lesions induced by AOM and the small-intestinal injury caused by 5-FU, suggesting that MAK could have potential as a preventive agent against colonic precancer, which is a common adverse effect of chemotherapy. PMID- 23338780 TI - Various copper and iron overload patterns in the livers of patients with Wilson disease and idiopathic copper toxicosis. AB - Wilson disease (WD) is a major type of primary copper toxicosis associated with hypoceruloplasminemia, while idiopathic copper toxicosis (ICT) is a minor type characterized by normoceruloplasminemia. Because ceruloplasmin is the major circulating ferroxidase, iron metabolism may be affected in patients with WD. Biopsied liver specimens obtained from patients with primary copper toxicosis were fixed with glutaraldehyde solution and embedded in epoxy resin. Ultrathin sections that had or had not been stained with uranyl acetate solution were examined under an electron microscope equipped with an energy dispersive X-ray analyzer. A 7-year-old boy with WD was free from any metal overloading at the pre treatment stage. Pre-treatment liver specimens of another 16 patients showed a variety of copper and iron overload patterns, from isolated copper to evenly distributed combined overloading. A 19-year-old female patient was free from any metal overloading after 7 years of treatment. Post-treatment overloading in another 6 patients ranged between evenly distributed combined patterns and isolated iron patterns. All patients had hypoceruloplasminemia throughout treatment periods. A patient with normoceruloplasminemic ICT continued to display isolated copper overloading after 2.5 years of treatment. In conclusion, these observations support the hypothesis that iron accumulates in patients with hypoceruloplasminemia. PMID- 23338781 TI - Ultrastructural cell wall characteristics of clinical gentamycin-resistant Staphylococcus aureus isolates. AB - The frequent use of gentamycin (GM) ointment for the treatment of skin infections has led to an increase in the number of GM-resistant clinical isolates of Staphylococcus aureus. We examined the ultrastructural characteristics of 14 clinical strains of S. aureus by transmission electron microscopy. Seven of these isolates were GM-resistant, and seven isolates were GM-sensitive. We found that the cell wall of GM-resistant strains (32.24 +/- 5.99 nm) was significantly thicker than that of GM-sensitive strains (19.02 +/- 2.72 nm). We genetically characterized these isolates by polymerase chain reaction, targeting the genes for three aminoglycoside-modifying enzymes, aac(6')-aph(2''), aph(3')-III, and ant(4')-I. All GM-resistant strains tested carried the gene encoding aac(6') aph(2''). However, we were unable to establish a link between a specific gene and cell wall thickening, because one GM-resistant strain was also positive for aph(3')-III. We also demonstrated that a GM-resistant mutant strain, derived in vitro from a GM-sensitive S. aureus parent strain (209P), also exhibited a thickened cell wall. These results strongly suggest that a thickened cell wall is a common ultrastructural characteristic of GM-resistant S. aureus clinical strains. PMID- 23338783 TI - The four P's that make a microsurgeon: perfectionist, pragmatist, persistent, and paranoid. PMID- 23338782 TI - Dose-dependent effect of tamoxifen in tamoxifen-resistant breast cancer cells via stimulation by the ERK1/2 and AKT signaling pathways. AB - The majority of breast cancers undergo progression from an initially endocrine responsive phenotype to an endocrine therapy-resistant phenotype, and acquired resistance to tamoxifen (Tam) is a major clinical problem. In the present study, we aimed to identify the function and mechanism of Tam at different concentrations in cells with acquired Tam resistance. Estrogen-dependent MCF-7 cells were cultured with Tam to generate Tam-resistant (TAM-R) breast cancer cells or in estrogen-free medium to mimic the effects of clinical treatment. In addition, we analyzed the effects of different concentrations of Tam on TAM-R cells by cell counting. Furthermore, the crosstalk between the stimulatory G protein alpha subunit (Galphas) and the activation of ERK1/2 and AKT in TAM-R cells was examined by small interfering RNA (siRNA) and immunoblotting methods. Low-dose Tam was found to act as an estrogen agonist via stimulation of the ERK1/2 signaling pathway, resulting in acquired resistance to Tam, whereas high dose Tam inhibited TAM-R cell growth by blocking the activation of ERK1/2 and AKT. Moreover, Galphas was involved in Tam resistance in breast cancer cells. Taken together, our study demonstrated a dose-dependent growth response to Tam in TAM-R cells, which will promote the understanding of the importance of the appropriate use and dosage of Tam in the clinic. PMID- 23338784 TI - Perforator flap from proximal lateral leg for head and neck reconstruction. AB - INTRODUCTION: Perforator flap transfer has the benefits of minimal donor site morbidity and customization in design. This study reports on the proximal lateral leg perforator (PLLP) flap transfer for head and neck reconstruction. MATERIALS AND METHODS: From January 2000 through December 2009, 18 patients underwent head and neck reconstruction with the PLLP flap, including 16 males and 2 females ranging in age between 32 and 80 years old. The mean follow-up time was 9.8 months. RESULTS: Mother vessels of PLLP flaps can arise 77.8% (14/18) from the peroneal system, 11.1% (2/18) from the posterior tibial system, or 11.1% (2/18) from the common popliteal system. The skin dimension ranges from 4 cm * 7 cm to 6.5 cm * 18 cm. The mean of the perforator size is 1.96 mm (1.5 mm to 2.3 mm). The mean of the pedicle length is 6.96 cm (4.5 cm to 10 cm). All flaps survived completely except one flap that had partial necrosis. CONCLUSIONS: The PLLP flap for head and neck reconstruction offers versatility in design, diverse tissues for composition, a two-team approach, and negligible donor site morbidity, and it spares major vessels. The unpredictable pedicle length and the feasibility for microvascular anastomosis in the perforator level can be adapted with further experience and refining techniques. PMID- 23338785 TI - Factors affecting pregnancy rates after microsurgical reversal of tubal sterilization. AB - The aim of this study was to determine the prognostic factors and pregnancy rates after microsurgical reversal of tubal sterilization. Patients undergoing tubal anastomosis from 2001 to 2008 were included. Relevant data were extracted from their medical records. Pregnancy outcomes were ascertained by responses to mailed questionnaires and telephone contact. A total of 98 patients were identified. We found that the mean duration of follow-up was 67 +/- 28 months. Fifty-five patients conceived (pregnancy rate 62.5%; 95% confidence interval [CI] 52 to 72.8%). Of these, 50 were intrauterine and 5 were tubal pregnancies. Life-table analysis estimated cumulative pregnancy rates to be 30.7%, 39.8%, 49%, and 53.7% at 6, 12, 18, and 24 months after reversal, respectively. Age at the time of reversal was the only significant prognostic factor multivariate model. We concluded that age of the patient at the operation is the most important prognostic factor. PMID- 23338786 TI - Vision impairment among older adults residing in assisted living. AB - OBJECTIVE: To examine rates of visual impairment of older adults in assisted living facilities (ALFs). METHODS: Vision screening events were held at 12 ALFs in Jefferson County, Alabama, for residents above 60 years of age. Visual acuity, cognitive status, and presence of eye conditions were assessed. RESULTS: A total of 144 residents were screened. Of these 67.8% failed distance screening, 70.9% failed near screening, and 89.3% failed contrast sensitivity screening. A total of 40.4% of residents had cognitive impairment and 89% had a least one diagnosed eye condition. Visual acuities did not differ significantly between cognitive status groups or with greater numbers of eye conditions. DISCUSSION: This study is the first to provide information about vision impairment in the assisted living population. Of those screened, 70% had visual acuity worse than 20/40 for distance or near vision, and 90% had impaired contrast sensitivity. Cognitive impairment accounted for a small percentage of the variance in near vision and contrast sensitivity. PMID- 23338787 TI - Bioelectrocatalytic oxidation of glucose with antibiotic channel-containing liposomes. AB - We developed an efficient bioelectrocatalytic system for glucose oxidation by introducing hydrophilic glucose-permeable antibiotic channels into liposomes. PMID- 23338788 TI - Exploring the association between genetic variation in the SUMO isopeptidase gene USPL1 and breast cancer through integration of data from the population-based GENICA study and external genetic databases. AB - Small ubiquitin-like modifier (SUMO) proteins are covalently attached to target proteins to modify their function. SUMO conjugation participates in processes tightly linked to tumorigenesis. Recently USPL1 (ubiquitin-specific peptidase like (1) was identified as a SUMO isopeptidase. We report here on the first exploratory study investigating the relationship between genetic variability in USPL1 and breast cancer. Three potentially functional nonsynonymous coding SNPs (rs3742303, rs17609459, rs7984952) were genotyped in 1,021 breast cancer cases and 1,015 controls from the population-based GENICA study. We took advantage of multiple genotype imputation based on HapMap and the 1000 Genomes Project data to refine the association screening in the investigated region. Public genetic databases were also used to investigate the relationship with USPL1 expression in lymphoblastoid cell lines and breast tissue. Women homozygous for the minor C allele of rs7984952 showed a lower risk of Grade 3 breast tumors compared to TT homozygotes (OR 0.50, 95% CI 0.30-0.81). Case-only analyses confirmed the association between rs7984952 and tumor grade (OR 0.60, 95% CI 0.39-0.93). Imputation results in a 238 kb region around rs7984952 based on HapMap and the 1000 Genomes Project data were similar. No imputed variant showed an association signal stronger than rs7984952. USPL1 expression in tumor breast tissue increased with the number of C alleles. The present study illustrates the contribution of multiple imputation of genotypes using public data repositories to standard genotyping laboratory. The provided information may facilitate the design of independent studies to validate the association between USPL1 rs7984952 and risk of Grade 3 breast tumors. PMID- 23338790 TI - Clinical and molecular genetic analysis of a new mutation in children with Wolfram syndrome: a case report. AB - A 12-year-old Chinese girl presented with gradual vision loss and insulin dependent diabetes mellitus and was suspected to suffer from Wolfram syndrome (WFS). A series of clinical examinations were performed, as well as direct DNA sequencing to screen the entire coding region of the WFS1 gene in the patient's family, including her parents and a brother. Ophthalmological examination revealed counting fingers/10 cm in the right eye and hand motions/10 cm in the left eye. Ophthalmoscopical examination identified bilateral optic atrophy without any signs of diabetic retinopathy. A hearing test was performed and revealed that the hearing ability for high frequency sounds was decreased. Urinary output in 24 h was >5,000 ml. In addition, a base substitution at c.2411T>C (Leu804Pro) in exon 8 was identified which was homozygous with the patient and heterozygous with the healthy parents and the brother. In the present case, a neuroophthalmology consult performed in the early stages of the disease was crucial for early diagnosis. In addition, this case study highlights the importance of performing a hearing test as well as collecting and analyzing 24-h urine output in patients presenting with juvenile diabetes mellitus patients and optic atrophy without any signs of diabetic retinopathy. PMID- 23338791 TI - Experimental investigation and modeling of the kinetics of CCl4 pyrolysis behind reflected shock waves using high-repetition-rate time-of-flight mass spectrometry. AB - The pyrolysis kinetics of CCl(4) behind reflected shock waves was studied with high-repetition-rate time-of-flight mass spectrometry. For modeling, quantum mechanical calculations were performed to evaluate the dissociation energies of CCl bonds for the different CCl(x) (x = 1 to 4) radicals. Good agreement with the JANAF thermochemical table was found. With the reaction mechanism developed for CCl(4) decomposition satisfactory agreement with experimental results was obtained. The investigations show the importance of C(2)Cl(2) formation for understanding the processes of carbon cluster growth leading to carbonaceous particle formation. PMID- 23338789 TI - Co-expression of two fibrolytic enzyme genes in CHO cells and transgenic mice. AB - Cellulose is the main non-starch polysaccharides (NSP) in plant cell walls and acts as anti-nutritional factor in animal feed. However, monogastric animals do not synthesize enzymes that cleave such plant structural polysaccharides and thus waste of resources and pollute the environment. We described the vectors construction and co-expressions of a multi-functional cellulase EGX (with the activities of exo-beta-1,4-glucanase, endo-beta-1,4-glucanase, and endo-beta-1,4 xylanase activities) from mollusca, Ampullaria crossean and a beta-glucosidase BGL1 from Asperjillus niger in CHO cells and the transgenic mice. The recombinant enzymes were synthesised, secreted by the direction of pig PSP signal peptide and functionally active in the eukaryote systems including both of CHO cells and transgenic mice by RT-PCR analysis, western blot analysis and cellulolytic enzymes activities assays. Expressions were salivary glands-specific dependent under the control of pig PSP promoter in transgenic mice. 2A peptide was used as the self-cleaving sequence to mediate co-expression of the fusion genes and the cleavage efficiency was very high both in vitro and in vivo according to the western blot analysis. In summary, we have demonstrated that the single ORF containing EGX and BGL1 were co-expressed by 2A peptide in CHO cells and transgenic mice. It presents a viable technology for efficient disruption of plant cell wall and liberation of nutrients. To our knowledge, this is the first report using 2A sequence to produce multiple cellulases in mammalian cells and transgenic animals. PMID- 23338792 TI - Surfactant-free sacrificial template synthesis of submicrometer-sized YVO4:Eu3+ hierarchical hollow spheres with tunable textual parameters and luminescent properties. AB - For the first time, well-dispersed submicrometer-sized YVO(4):Eu(3+) hollow spheres were successfully synthesized though a surfactant-free method by employing Y(OH)CO(3):Eu(3+) colloidal spheres as a sacrificial template and NH(4)VO(3) as a vanadium source. The synthetic process mainly consists of two steps, i.e., hydrothermal reaction and acid erosion. By simply changing the amount of NH(4)VO(3) added, the textural parameters of the as-obtained hollow spheres, such as the inner diameter and shell-thickness, can be easily tuned. Moreover, double-shelled hollow spheres could also be obtained when the amount of NH(4)VO(3) was increased to a certain extent. Particularly, the amorphous colloidal spheres of the template could be completely consumed when the amount of NH(4)VO(3) was in large excess, giving rise to the direct formation of uniform hollow spheres without acid erosion. The possible formation process is discussed in detail. Under ultraviolet excitation, the obtained hollow YVO(4):Eu(3+) phosphors showed strong red emissions, and the Commission Internationale d'Eclairage (CIE) coordinates of the YVO(4):Eu(3+) phosphors were closely related with the textural parameters such as the inner diameter, shell-thickness and number of shells, indicating a size-dependent characteristic. PMID- 23338793 TI - The importance of formative assessment in science and engineering ethics education: some evidence and practical advice. AB - Recent research in ethics education shows a potentially problematic variation in content, curricular materials, and instruction. While ethics instruction is now widespread, studies have identified significant variation in both the goals and methods of ethics education, leaving researchers to conclude that many approaches may be inappropriately paired with goals that are unachievable. This paper speaks to these concerns by demonstrating the importance of aligning classroom-based assessments to clear ethical learning objectives in order to help students and instructors track their progress toward meeting those objectives. Two studies at two different universities demonstrate the usefulness of classroom-based, formative assessments for improving the quality of students' case responses in computational modeling and research ethics. PMID- 23338794 TI - Improving epistemological beliefs and moral judgment through an STS-based science ethics education program. AB - This study develops a Science-Technology-Society (STS)-based science ethics education program for high school students majoring in or planning to major in science and engineering. Our education program includes the fields of philosophy, history, sociology and ethics of science and technology, and other STS-related theories. We expected our STS-based science ethics education program to promote students' epistemological beliefs and moral judgment development. These psychological constructs are needed to properly solve complicated moral and social dilemmas in the fields of science and engineering. We applied this program to a group of Korean high school science students gifted in science and engineering. To measure the effects of this program, we used an essay-based qualitative measurement. The results indicate that there was significant development in both epistemological beliefs and moral judgment. In closing, we briefly discuss the need to develop epistemological beliefs and moral judgment using an STS-based science ethics education program. PMID- 23338795 TI - Adjuvant pharmacotherapy in the management of elderly patients with pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is the fourth or fifth leading cause of death from cancer in Western industrialized countries. Surgical resection is the only chance of cure, but only 15-20 % of cases are potentially resectable at presentation, and despite complete resection, the overall prognosis remains relatively poor. Adjuvant therapy has modestly improved cure rates. The majority of patients with pancreatic cancer are over the age of 65 years. But this age group is underrepresented within clinical trials, and it is unknown whether older patients achieve similar results to younger ones in terms of survival and treatment tolerance. In addition, there are no clinical trials dedicated to the elderly. Retrospective studies coming from the non-resectable setting provide some understanding on outcomes in older patients with PDAC. To date, we can reasonably argue that selected elderly patients with PDAC can benefit from curative surgery and postoperative chemotherapy as do their younger counterparts, without a significant increase in morbidity and mortality. Gemcitabine should be preferred to 5-fluorouracil on the basis of a better risk-benefit balance. PMID- 23338797 TI - Summaries for patients. Screening for intimate partner violence and abuse of vulnerable adults: U.S. Preventive Services Task Force recommendation. PMID- 23338796 TI - Safety and efficacy of thrombolysis with intravenous alteplase in older stroke patients. AB - Stroke is a common cause of death and persisting disability worldwide, and thrombolysis with intravenous alteplase is the only approved treatment for acute ischaemic stroke. Older age is the most important non-modifiable risk factor for stroke, and demographic changes are also resulting in an increasingly ageing population. However, clinical trial evidence for the use of intravenous alteplase is limited for the older age group where stroke incidence is highest. In this article, the current evidence regarding the safety and efficacy of intravenous thrombolytic therapy in stroke patients aged >=80 years is critically analysed and the gap in current knowledge highlighted. In summary, intravenous thrombolysis in stroke patients aged >=80 years seems to be associated with less favourable clinical outcomes and higher mortality than in younger patients, which is consistent with the natural course in untreated patients. The risk of symptomatic intracranial haemorrhage does not appear to be significantly higher in the elderly group, suggesting that intracranial bleeding complications are unlikely to outweigh the potential benefit in this age group. Overall, withholding thrombolytic treatment in ischaemic stroke on the basis of advanced age alone is no longer justifiable. PMID- 23338798 TI - Inhibition of repair-related DNA polymerases by vitamin Ks, their related quinone derivatives and associated inflammatory activity (Review). AB - Vitamin Ks (VKs) are fat-soluble quinone compounds known to have various bioactivities. This review describes the inflammatory effects of VKs and their related quinone derivatives based on DNA polymerase (pol) inhibition. VK3, but not VK1 or VK2 (=MK-4), inhibited the activity of human pol gamma, which is the DNA replicative pol in mitochondria. Of the intermediate compounds between VK2 and VK3 (namely MK-3, MK-2 and MK-1), MK-2 was the strongest inhibitor of mammalian pols alpha, kappa and lambda, which belong to the B-, Y- and X-families of pols, respectively. Among the VK3 based quinone derivatives, such as 1,4 naphthoquinone (NQ), 2-dimethyl-1,4-naphthoquinone (1,2-dimethyl-NQ), 1,4 benzoquinone (BQ), 9,10-anthraquinone (AQ) and 5,12-naphthacenequinone (NCQ), NQ was the strongest inhibitor of mammalian pols alpha and lambda, in particular, DNA repair-related pol lambda. Among the all compounds tested, NQ displayed the strongest suppression of tumor necrosis factor (TNF)-alpha production induced by lipopolysaccharide (LPS) in a cell culture system using RAW264.7 mouse macrophages. NQ also suppressed the expression of pol lambda protein in these cells, after LPS-treated RAW264.7 cells were stimulated to induce pol lambda expression. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of NQ into mice suppressed TNF-alpha production in peritoneal macrophages and serum. In an in vivo colitis mouse model induced using dextran sulfate sodium (DSS), NQ markedly suppressed DSS-evoked colitis. The promising anti-inflammatory candidates based on the inhibition of DNA repair related pols, such as pol lambda, by VKs quinone derivatives, such as NQ, are discussed. PMID- 23338799 TI - Recent trends in childhood attention-deficit/hyperactivity disorder. AB - OBJECTIVE To examine trends in attention-deficit/hyperactivity disorder (ADHD) by race/ethnicity, age, sex, and median household income. DESIGN An ecologic study of trends in the diagnosis of ADHD using the Kaiser Permanente Southern California (KPSC) health plan medical records. Rates of ADHD diagnosis were derived using Poisson regression analyses after adjustments for potential confounders. SETTING Kaiser Permanente Southern California, Pasadena. PARTICIPANTS All children who received care at the KPSC from January 1, 2001, through December 31, 2010 (n = 842 830). MAIN EXPOSURE Period of ADHD diagnosis (in years). MAIN OUTCOME MEASURES Incidence of physician-diagnosed ADHD in children aged 5 to 11 years. RESULTS Rates of ADHD diagnosis were 2.5% in 2001 and 3.1% in 2010, a relative increase of 24%. From 2001 to 2010, the rate increased among whites (4.7%-5.6%; relative risk [RR] = 1.3; 95% CI, 1.2-1.4), blacks (2.6%- 4.1%; RR = 1.7; 95% CI, 1.5-1.9), and Hispanics (1.7%-2.5%; RR = 1.6; 95% CI, 1.5-1.7). Rates for Asian/Pacific Islander and other racial groups remained unchanged over time. The increase in ADHD diagnosis among blacks was largely driven by an increase in females (RR = 1.9; 95% CI, 1.5-2.3). Although boys were more likely to be diagnosed as having ADHD than girls, results suggest the sex gap for blacks may be closing over time. Children living in high-income households were at increased risk of diagnosis. CONCLUSIONS The findings suggest that the rate of ADHD diagnosis among children in the health plan notably has increased over time. We observed disproportionately high ADHD diagnosis rates among white children and notable increases among black girls. PMID- 23338800 TI - Clinical management of the most common group A beta-hemolytic streptococcal infections. AB - Group A streptococcal (Streptococcus pyogenes) infections remain important causes of medical and public health morbidity and mortality even during the early twenty first century. Although most often concentrated in socially/economically disadvantaged populations, the problems remain significant in both industrializing and industrialized countries. The many M/emm types of GAS contribute to herd immunity in populations and also affect the control of streptococcal infections in these populations. Although this bacterium remains among the most susceptible to most antibiotics, it is evident that antibiotics alone have not solved the group A streptococcal medical and public health problems, even in those places where access to medical care is readily available. It is likely that the current streptococcal problems will remain difficult to manage and will remain essentially unchanged until the broad implementation of a cost-effective group A streptococcal vaccine, likely some years in the future. PMID- 23338801 TI - What would you say? Genetic counseling graduate students' and counselors' hypothetical responses to patient requested self-disclosure. AB - Genetic counselor self-disclosure is a complex behavior that lacks extensive characterization. In particular, data are limited about genetic counselors' responses when patients ask them to self-disclose. Accordingly, this study investigated genetic counseling students' (n = 114) and practicing genetic counselors' (n = 123) responses to two hypothetical scenarios in which a female prenatal patient requests self-disclosure. Scenarios were identical except for a final patient question: "Have you ever had an amniocentesis?" or "What would you do if you were me?" Imagining themselves as the counselor, participants wrote a response for each scenario and then explained their response. Differences in disclosure frequency for students vs. counselors and disclosure question were assessed, and themes in participant responses and explanations were extracted via content and thematic analysis methods. Chi-square analyses indicated no significant differences in frequency of student versus counselor disclosure. Self disclosure was significantly higher for, "Have you ever had an amniocentesis?" (78.5 %) than for, "What would you do if you were me?" (53.2 %) (p < .001). Types of self-disclosures included personal, professional, and mixed disclosures. Prevalent explanations for disclosure and non-disclosure responses included: remain patient focused and support/empower the patient. Additional findings, practice and training implications, and research recommendations are presented. PMID- 23338802 TI - Delivering genetic education and genetic counseling for rare diseases in rural Brazil. AB - Brazil is the largest country in Latin America, with an ethnically diverse, Portuguese-speaking and predominantly Roman Catholic population of some 194 million. Universal health care is provided under the Federal Unified Health System (Sistema Unico de Saude) but, as in many other middle and low income countries, access to medical genetics services is limited in rural and remote regions of the country. Since there is no formally recognized Genetic Counseling profession, genetic counseling is provided by physicians, trained either in medical genetics or a related clinical discipline. A comprehensive medical genetics program has been established in Monte Santo, an inland rural community located in the state of Bahia in Northeast Brazil, with high prevalences of a number of autosomal recessive genetic disorders, including non-syndromic deafness, phenyketonuria, congenital hypothyroidism and mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Genetic education, counseling and treatment are locally provided, with a neonatal screening program for MPSVI currently under trial. PMID- 23338804 TI - Using toxicological evidence from QSAR models in practice. AB - Leading QSAR models provide supporting documentation in addition to a predicted toxicological value. Such information enables the toxicologist to explore the properties of chemical substances as well as to review and to increase the reliability of toxicity predictions. This article focuses on the use of this information in practice. We explore the supporting documentation provided by the EPISuite, T.E.S.T. and VEGA platforms when evaluating the bioconcentration factor (BCF) of three example compounds. Each compound presents a different challenge: to recognize high reliability, analyze complex evidence of reliability, and recognize uncertainty. In each case, we first describe and discuss the supporting documentation provided by the QSAR platforms. We then discuss the judgments on reliability across sectors from 28 toxicologists who used this supporting information and commented on the process. The article demonstrates both the use of QSAR models as tools to reduce or replace in vivo testing, and the need for scientific expertise and rigor in their use. PMID- 23338803 TI - Integrated testing strategies for safety assessments. AB - Despite the fact that toxicology uses many stand-alone tests, a systematic combination of several information sources very often is required: Examples include: when not all possible outcomes of interest (e.g., modes of action), classes of test substances (applicability domains), or severity classes of effect are covered in a single test; when the positive test result is rare (low prevalence leading to excessive false-positive results); when the gold standard test is too costly or uses too many animals, creating a need for prioritization by screening. Similarly, tests are combined when the human predictivity of a single test is not satisfactory or when existing data and evidence from various tests will be integrated. Increasingly, kinetic information also will be integrated to make an in vivo extrapolation from in vitro data. Integrated Testing Strategies (ITS) offer the solution to these problems. ITS have been discussed for more than a decade, and some attempts have been made in test guidance for regulations. Despite their obvious potential for revamping regulatory toxicology, however, we still have little guidance on the composition, validation, and adaptation of ITS for different purposes. Similarly, Weight of Evidence and Evidence-based Toxicology approaches require different pieces of evidence and test data to be weighed and combined. ITS also represent the logical way of combining pathway-based tests, as suggested in Toxicology for the 21st Century. This paper describes the state of the art of ITS and makes suggestions as to the definition, systematic combination, and quality assurance of ITS. PMID- 23338805 TI - Ocular cytotoxicity evaluation of medical devices such as contact lens solutions and benefits of a rinse step in cleaning procedure. AB - Contact lens care solutions are known to have toxic effects on the ocular surface. The ISO 10993-5 standard describes test methods to assess the cytotoxicity of medical devices, but it needs some improvements to discriminate contact lens care multipurpose solutions. First we evaluated the biological hazards associated with the use of ophthalmic solutions, running a collaborative study with the French medical agency to propose adapted tools to study contact lens care solutions' ocular cytotoxicity (human cell line, short incubation times, and no dilution of solutions to test). Then we took into account the potential risk of these ophthalmic solutions adsorbed on contact lenses and released on the ocular surface, highlighting the addition of a rinse step with unpreserved marine solution in the contact lens cleaning procedure to avoid side effects of contact lens care solutions. PMID- 23338807 TI - Evidence-based toxicology: strait is the gate, but the road is worth taking. AB - The concept of evidence-based toxicology (EBT) was proposed in 2006, but progress since that time has been impeded by differing definitions and goals. This paper describes the parallels and discontinuities between the approach and methods of evidence-based medicine and health care and those proposed for toxicology. The critical element of an evidence-based approach for either discipline is the adoption of unbiased, transparent methodologies during the collection, appraisal, and pooling of evidence. This approach, implemented during the conduct of a systematic review, allows evaluation of the breadth and quality of available evidence. At present, systematic reviews are rarely done in toxicology by regulatory agencies, international organizations, or academic scientists. Adopting an EBT approach will necessitate significant changes in practice as well as attention to distinctive characteristics of toxicological studies, notably their emphasis on identifying harms and their reliance on experimental animal studies. An evidence-based approach does not obviate the role of judgment and values in decision making; its goal is to ensure provision of all available information in a transparent and unbiased manner. PMID- 23338806 TI - Perspectives on validation of high-throughput assays supporting 21st century toxicity testing. AB - In vitro high-throughput screening (HTS) assays are seeing increasing use in toxicity testing. HTS assays can simultaneously test many chemicals but have seen limited use in the regulatory arena, in part because of the need to undergo rigorous, time-consuming formal validation. Here we discuss streamlining the validation process, specifically for prioritization applications. By prioritization, we mean a process in which less complex, less expensive, and faster assays are used to prioritize which chemicals are subjected first to more complex, expensive, and slower guideline assays. Data from the HTS prioritization assays is intended to provide a priori evidence that certain chemicals have the potential to lead to the types of adverse effects that the guideline tests are assessing. The need for such prioritization approaches is driven by the fact that there are tens of thousands of chemicals to which people are exposed, but the yearly throughput of most guideline assays is small in comparison. The streamlined validation process would continue to ensure the reliability and relevance of assays for this application. We discuss the following practical guidelines: (1) follow current validation practice to the extent possible and practical; (2) make increased use of reference compounds to better demonstrate assay reliability and relevance; (3) de-emphasize the need for cross-laboratory testing; and (4) implement a web-based, transparent, and expedited peer review process. PMID- 23338808 TI - Evidence-based toxicology for the 21st century: opportunities and challenges. AB - The Evidence-based Toxicology Collaboration (EBTC) was established recently to translate evidence-based approaches from medicine and health care to toxicology in an organized and sustained effort. The EBTC held a workshop on "Evidence-based Toxicology for the 21st Century: Opportunities and Challenges" in Research Triangle Park, North Carolina, USA on January 24-25, 2012. The presentations largely reflected two EBTC priorities: to apply evidence-based methods to assessing the performance of emerging pathway-based testing methods consistent with the 2007 National Research Council report on "Toxicity Testing in the 21st Century" as well as to adopt a governance structure and work processes to move that effort forward. The workshop served to clarify evidence-based approaches and to provide food for thought on substantive and administrative activities for the EBTC. Priority activities include conducting pilot studies to demonstrate the value of evidence-based approaches to toxicology, as well as conducting educational outreach on these approaches. PMID- 23338809 TI - [Future psychosomatic medicine, revisited]. PMID- 23338810 TI - [Evaluation of single case change in continuous variables]. PMID- 23338811 TI - Traumatic abdominal wall hernia, easily missed. AB - A 30-year-old male was diagnosed with a disruption of the musculofibrotic abdominal wall as a result of a blunt trauma 3 years after the injury. His traumatic abdominal wall hernia (TAWH) was initially missed on physical examination and computed tomography. The patient presented now with a lump in the left flank after a period of intended weight loss. Laparoscopic repair of the hernia resulted in being asymptomatic ever since. Missing a TAWH might have major consequences, such as incarceration and strangulation. Therefore, it is important to consider a TAWH after blunt abdominal trauma. PMID- 23338812 TI - Mexican American 7(th) Graders' Future Work and Family Plans: Associations with Cultural Experiences and Adjustment. AB - We describe Mexican American 7(th) graders' expectations for future work and family roles and investigate links between patterns of future expectations and adolescents' cultural experiences and adjustment. Adolescents participated in home interviews and a series of seven nightly phone calls. Five unique patterns of adolescents' future expectations were identified (N = 246): Career Oriented, Independent, Family Oriented, Early, and Inconsistent. Career Oriented adolescents had the highest socioeconomic status and contact with the U.S. (e.g., generation status) whereas Family Oriented adolescents had the lowest. Cultural orientations, values, and involvement also varied across groups. For example, Career Oriented adolescents reported significantly higher familism values compared to Inconsistent adolescents. Clusters also differed on adjustment: Career Oriented and Family Oriented adolescents reported higher parental warmth and less risky behavior compared to Independent and Inconsistent adolescents. Findings underscore the multi-faceted nature of adolescents' future expectations and the diversity in cultural experiences among Mexican origin youth. PMID- 23338813 TI - New insights into the initial stages of Ta oxide nanotube formation on polycrystalline Ta electrodes. AB - Ta oxide nanotubes (NTs) were formed by the anodization of Ta at 15 V in a solution of concentrated sulfuric acid containing 0.8-1.0 M hydrofluoric acid. To study the initial stages of NT formation, FESEM images of samples anodized for very short times were obtained. The results contradict the existing explanation of the current-time data collected during anodization, which has persisted in the literature for more than two decades. In addition to providing a first-time morphological study of Ta oxide NT formation at very early stages of anodization, we also propose a new interpretation of the i-t response, showing that pores are already present in the first few milliseconds of anodization and that NTs are formed well before present models predict. This behaviour may also extend to the anodization of other valve metals, such as Al, Ti, Zr, W, and Nb. PMID- 23338814 TI - Lack of effect of nitrates on exercise stress test results in patients with microvascular angina. AB - PURPOSE: To assess the effects of short-acting nitrates on exercise stress test (EST) results and the relation between EST results and coronary blood flow (CBF) response to nitrates in patients with microvascular angina (MVA). METHODS: We completed 2 symptom/sign limited ESTs on 2 separate days, in a random sequence and in pharmacological washout, in 29 MVA patients and in 24 patients with obstructive coronary artery disease (CAD): one EST was performed without any intervention (control EST, C-EST), and the other after sublingual isosorbide dinitrate, 5 mg (nitrate EST, N-EST). CBF response to nitroglycerin (25 MUg) was assessed in the left anterior descending coronary artery by transthoracic Doppler echocardiography. RESULTS: At C-EST. ST-segment depression >=1 mm (STD) was induced in 26 (90 %) and 23 (96 %) MVA and CAD patients, respectively (p=0.42), whereas at N-EST, STD was induced in 25 (86 %) and 14 (56 %) MVA and CAD patients, respectively (p=0.01). Time and rate pressure product at 1 mm STD increased during N-EST, compared to C-EST, in CAD patients (475+/-115 vs. 365+/ 146 s, p<0.001; and 23511+/-4352 vs. 20583+/-6234 bpm?mmHg, respectively, p=0.01), but not in MVA patients (308+/-160 vs. 284+/-136 s; p=0.19; and 21290+/ 5438 vs. 20818+/-4286 bpm?mmHg, respectively, p=0.35). In MVA patients, a significant correlation was found between heart rate at STD during N-EST and CBF response to nitroglycerin (r=0.40, p=0.04). CONCLUSIONS: Short-acting nitrates improve EST results in CAD, but not in MVA patients. In MVA patients a lower nitrate-dependent coronary microvascular dilation may contribute to the lack of effects of nitrates on EST results. PMID- 23338815 TI - A 5-year exercise program in pre- and peripubertal children improves bone mass and bone size without affecting fracture risk. AB - We studied the effect in children of an exercise intervention program on fracture rates and skeletal traits. Fractures were registered for 5 years in a population based prospective controlled exercise intervention study that included children aged 6-9 years at study start, 446 boys and 362 girls in the intervention group and 807 boys and 780 girls in the control group. Intervention subjects received 40 min/school day of physical education and controls, 60 min/week. In 73 boys and 48 girls in the intervention group and 52 boys and 48 girls in the control group, bone mineral density (BMD, g/cm(2)) and bone area (mm(2)) were followed annually by dual-energy X-ray absorptiometry, after which annual changes were calculated. At follow-up we also assessed trabecular and cortical volumetric BMD (g/cm(3)) and bone structure by peripheral computed tomography in the tibia and radius. There were 20.0 fractures/1,000 person-years in the intervention group and 18.5 fractures/1,000 person-years in the control group, resulting in a rate ratio of 1.08 (0.79-1.47) (mean and 95 % CI). The gain in spine BMD was higher in both girls (difference 0.01 g/cm(2), 0.005-0.019) and boys (difference 0.01 g/cm(2), 0.001-0.008) in the intervention group. Intervention girls also had higher gain in femoral neck area (difference 0.04 mm(2), 0.005-0.083) and at follow-up larger tibial bone mineral content (difference 0.18 g, 0.015-0.35), larger tibial cortical area (difference 17 mm(2), 2.4-31.3), and larger radial cross-sectional area (difference 11.0 mm(2), 0.63-21.40). As increased exercise improves bone mass and in girls bone size without affecting fracture risk, society ought to encourage exercise during growth. PMID- 23338817 TI - Estimating net survival in population-based cancer studies. PMID- 23338818 TI - Prevalence and significant geospatial clusters of bovine tuberculosis infection at livestock-wildlife interface ecosystem in Eastern Tanzania. AB - Bovine tuberculosis (BTB) is an important neglected zoonosis that affects livestock, wildlife and human. A study to determine prevalence and geospatial clusters for BTB was conducted from June 2010 to March 2012 at livestock-wildlife interface areas (LWIA). A total of 1,288 cattle located in vicinity of Mikumi Selous ecosystem Tanzania were tested. Single Intradermal Comparative Tuberculin Test and spatial scan statistic analysis were applied to establish the status of the disease and identify significant spatial BTB clusters. Overall individual prevalence was 3.7 % (n=1,288) (95 % CI=2.8-4.9) and 7.8 % (95 % CI=6.4-9.4) with cut-off of >4 and >2 mm, respectively. Villages with at least one reactor were 55.8 % (n=43). Reactivity was significantly higher in Mvomero and Kilosa districts compared with Kilombero and Ulanga districts (chi (2) =15.9; P<0.001). Significant spatial BTB clusters were revealed at 11 villages. BTB clustering was significant in Kilosa and Mvomero districts compared with Kilombero and Ulanga districts. There was overlap and aggregation of BTB clusters covering south and south-east of Kilosa district bordering Mikumi National Park (MNP) and Mvomero. Generally, clustering occurred around major rivers. The current study provides useful information on the dynamics and epidemiological status of BTB around the wildlife-livestock-human interface, it reveals that the wildlife are at risk of BTB from infected livestock. The study revealed hotspots for BTB that can be applied to guide implementation of participatory intervention at LWIA and control strategies in marginalised pastoralist communities. This study calls for similar studies in other Tanzania's LWIA for efficient intervention of BTB countrywide. PMID- 23338819 TI - Seroprevalence of bovine tuberculosis infection in yaks (Bos grunniens) on the Qinghai-Tibetan Plateau of China. AB - Bovine tuberculosis (BTB), a chronic disease caused by Mycobacterium bovis, has been widely reported in bovines in developing countries, but there is little information on this infection in domestic yaks. Seroprevalence of antibodies to M. bovis in yaks from six and three regions of Tibet and Qinghai plateau, China, respectively, was investigated in 2011 by enzyme-linked immunosorbent assay kits. A total of 1,244 (Tibet 938, Qinghai 306) blood samples was collected and the results showed that 24 (2.6%) of Tibetan samples and 3 (1%) of Qinghai's samples were positive for BTB. The findings of the present study indicated that M. bovis infection is prevalent in Chinese yaks in Qinghai and Tibet. These observations should raise a serious public health concern considering the extent to which the herdsmen of the study areas are in contact with their animals and the levels at which they use untreated livestock products. This is the first study showing the infection of M. bovis in domestic yaks. PMID- 23338820 TI - Novel amelogenin-releasing hydrogel for remineralization of enamel artificial caries. AB - Recently, the use of recombinant full-length amelogenin protein in combination with fluoride has shown promising results in the formation of densely packed enamel-like structures. In this study, amelogenin (rP172)-releasing hydrogels containing calcium, phosphate, and fluoride were investigated for remineralization efficacy using in vitro early enamel caries models. The hydrogels were applied to artificial caries lesions on extracted human third molars, and the remineralization efficacy was tested in different models: static gel remineralization in the presence of artificial saliva, pH cyclic treatment at pH 5.4 acetic buffer and pH 7.3 gel remineralization, and treatment with multispecies oral biofilms grown in a continuous flowing constant-depth film fermenter. The surface microhardness of remineralized enamel increased significantly when amelogenin was released from hydrogel. No cytotoxicity was observed when periodontal ligament cells were cultured with the mineralized hydrogels. PMID- 23338822 TI - Suppression of cell proliferation and collagen production in cultured human hypertrophic scar fibroblasts by Sp1 decoy oligodeoxynucleotide. AB - Hypertrophic scars are characterized by the abnormal proliferation of fibroblasts and an overproduction of collagen. The Sp1 transcription factor is involved in the stimulation of collagen synthesis. A decoy oligonucleotide (ODN) targeting Sp1 was designed and transfected into hypertrophic scar fibroblasts (HSFs) cells using cationic liposomes. The transfection efficiency was determined by flow cytometry and was observed to be 85+/-7% (n=5). Specific binding of the Sp1 decoy ODN was monitored with an electrophoretic mobility shift assay (EMSA). Following transfection with the decoy ODN to Sp1, cell viability and cell proliferation, which were examined by the cell counting kit WST-8, were decreased by 80% compared with untreated cells. Transforming growth factor-beta (TGF-beta) mRNA and collagen mRNA expression were also reduced by 48% in the transfection decoy ODN group. The cell viability of HSFs after 48 h of transfection with 25, 50, 100 and 150 nM Sp1 decoy ODN was 0.9331+/-0.0203, 0.7479+/-0.0868, 0.577+/-0.0347 and 0.4703+/-0.0147, respectively. The 100 nM dose of the Sp1 decoy ODN inhibited the expression of types I and III collagen by 32 and 28%, respectively (both P<0.01). TGF-beta mRNA expression was also effectively suppressed by the 100 nM Sp1 decoy ODN (P<0.01). The Sp1 decoy ODN inhibited cell proliferation and the expression of types I and III collagen. Therefore, Sp1 decoy ODNs may be a promising tool for developing and testing novel therapeutic applications for treating hypertrophic scars. PMID- 23338821 TI - miRNAs in head and neck cancer revisited. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer mortality in the world and the 5th most commonly occurring cancer. Tobacco smoking, alcohol consumption and human papilloma virus (HPV) infections have been associated with the occurrence of HNSCC. Despite advances that have been made in HNSCC treatment, smoking-associated HNSCC patients still exhibit a poor 5 year survival rate (30-50 %) and a concomitant poor quality of life. The major clinical challenge to date lies in the early detection of dysplastic lesions,which can progress to malignancy. In addition, there are currently no tools available to monitor HNSCC patients for early stages of local recurrences or distant metastases. In the recent past, micro-RNAs (miRNA) have been assessed for their role in cancer initiation and progression, including HNSCC. It is now well-established that deregulation of these single stranded, small non-coding, 19-25 nt RNAs can e.g. enhance the expression of oncogenes or subdue the expression of tumor suppressor genes. The aims of this review are three-fold: first to retrieve from the literature miRNAs that have specifically been associated with HNSCC, second to group these miRNAs into those regulating tumor initiation, progression and metastasis, and third to discern miRNAs related to smoking-associated HNSCC versus HPV-associated HNSCC development. CONCLUSIONS: This review gives an overview on the miRNAs regulating the development of head and neck cancers. The ultimate establishment of miRNA expression profiles that are HNSCC specific, and miRNAs that orchestrate altered gene and protein expression levels in HNSCC, could pave the way for a better understanding of the mechanism underlying its pathogenesis and the development of novel, targeted therapies. PMID- 23338824 TI - Crystalline xylitol production by a novel yeast, Pichia caribbica (HQ222812), and its application for quorum sensing inhibition in gram-negative marker strain Chromobacterium violaceum CV026. AB - Xylitol, a sugar alcohol, is fast gaining ground over other artificial sugar substitutes owing to its advantageous properties. Xylitol is a safer alternative for diabetics because of insulin-independent metabolism. It has beneficial properties suitable to form an important part of odontological formulations. Conventional commercial production of xylitol involves harsh chemical method operating at high temperature and pressure. Thus, microbial production of xylitol is preferred over chemical method, and yeasts have been extensively exploited for this purpose. In the present manuscript, quantitative production of xylitol from D-xylose with the yield of 0.852 gm/gm and volumetric productivity of 1.83 gm/l/h in crystalline form, using novel yeast Pichia caribbica is reported. Also, a mild, safe procedure for product extraction is described. The ability of xylitol to act as a quorum sensing antagonist in gram-negative marker strain Chromobacterium violaceum CV026 has been demonstrated for the first time. PMID- 23338823 TI - Effects of TRAIL and taurolidine on apoptosis and proliferation in human rhabdomyosarcoma, leiomyosarcoma and epithelioid cell sarcoma. AB - Soft tissue sarcomas (STS) are a heterogeneous group of malignant tumours representing 1% of all malignancies in adults. Therapy for STS should be individualised and multimodal, but complete surgical resection with clear margins remains the mainstay of therapy. Disseminated soft tissue sarcoma still represents a therapeutic dilemma. Commonly used chemotherapeutic agents such as doxorubicin and ifosfamide have proven to be effective in fewer than 30% in these cases. Therefore, we tested the apoptotic and anti-proliferative in vitro effects of TNF-related apoptosis-inducing ligand (TRAIL) and taurolidine (TRD) on rhabdomyosarcoma (A-204), leiomyosarcoma (SK-LMS-1) and epithelioid cell sarcoma (VA-ES-BJ) cell lines. Viability, apoptosis and necrosis were quantified by FACS analysis (propidium iodide/Annexin V staining). Gene expression was analysed by DNA microarrays and the results validated for selected genes by rtPCR. Protein level changes were documented by western blot analysis. Cell proliferation was analysed by BrdU ELISA assay. The single substances TRAIL and TRD significantly induced apoptotic cell death and decreased proliferation in rhabdomyosarcoma and epithelioid cell sarcoma cells. The combined use of TRAIL and TRD resulted in a synergistic apoptotic effect in all three cell lines, especially in rhabdomyosarcoma cells leaving 18% viable cells after 48 h of incubation (p<0.05). Analysis of the differentially regulated genes revealed that TRD and TRAIL influence apoptotic pathways, including the TNF-receptor associated and the mitochondrial pathway. Microarray analysis revealed remarkable expression changes in a variety of genes, which are involved in different apoptotic pathways and cross talk to other pathways at multiple levels. This in vitro study demonstrates that TRAIL and TRD synergise in inducing apoptosis and inhibiting proliferation in different human STS cell lines. Effects on gene expression differ relevantly in the sarcoma entities. These results provide experimental support for in vivo trials assessing the effect of TRAIL and TRD in STS and sustain the approach of individualized therapy. PMID- 23338825 TI - Dehydrogenation and demethanation of 2-methylpropane and propane in the gas-phase by the 16-electron complex [Ru(bipy)2(CO)]2+* chemically activated by the association of [Ru(bipy)2]2+ and CO. AB - The reactions of [Ru(bipy)(2)](2+) with 2-methylpropane, propane, and propene have been investigated in the ICR cell of a mass spectrometer. In these reactions, the association of one molecule of each hydrocarbon was observed. When [Ru(bipy)(2)](2+) was ligated with CO, and the newly formed [Ru(bipy)(2)(CO)](2+) was allowed to react with 2-methylpropane and propane both dehydrogenation and demethanation were observed among association and substitution products. Density functional calculations were used to help elucidate the mechanism and the energy requirement for the dehydrogenation and demethanation reactions of 2 methylpropane mediated by [Ru(bipy)(2)(CO)](2+)*. These very interesting elimination reactions of [Ru(bipy)(2)(CO)](2+) are attributed to a hot 16 electron intermediate, [Ru(bipy)(2)(CO)](2+)*, formed upon ligation of [Ru(bipy)(2)](2+) with CO which has no efficient means of dissipating its internal energy in the low-pressure confines of the ICR cell. The reactions were concluded to occur via a concerted elimination mechanism rather than by oxidative addition/reductive elimination following the dissociation of one Ru-N bond. PMID- 23338826 TI - Error Estimates for Generalized Barycentric Interpolation. AB - We prove the optimal convergence estimate for first order interpolants used in finite element methods based on three major approaches for generalizing barycentric interpolation functions to convex planar polygonal domains. The Wachspress approach explicitly constructs rational functions, the Sibson approach uses Voronoi diagrams on the vertices of the polygon to define the functions, and the Harmonic approach defines the functions as the solution of a PDE. We show that given certain conditions on the geometry of the polygon, each of these constructions can obtain the optimal convergence estimate. In particular, we show that the well-known maximum interior angle condition required for interpolants over triangles is still required for Wachspress functions but not for Sibson functions. PMID- 23338827 TI - 2D and 3D characterization of a surfactant-synthesized TiO2-SiO2 mesoporous photocatalyst obtained at ambient temperature. AB - A mesoporous TiO(2)-SiO(2) nanocomposite photocatalyst has been prepared from TiO(2) nanoparticles and ethoxysilane oligomers in the presence of a non-ionic surfactant (n-octylamine). The 2D and 3D structure properties of the resulting nanomaterial are described. The use of 3D techniques, particularly HAADF-STEM electron tomography, together with 3D reconstructions and atomic force microscopy, provides insight into the fine structure of these materials. We find that n-octylamine creates a mesoporous silica structure in which titania nanoparticles are embedded, and that some of the titania is retained on the outer surface of the material. Rapid photodegradation of methylene blue dye is facilitated, due to the synergistic effect of: (1) its adsorption into the composite mesoporous structure, and (2) its photodegradation by the superficial TiO(2). PMID- 23338828 TI - Screening for intimate partner violence and abuse of elderly and vulnerable adults: U.S. preventive services task force recommendation statement. AB - DESCRIPTION: Update of the 2004 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for family and intimate partner violence (IPV). METHODS: The USPSTF commissioned a systematic evidence review on screening women for IPV and elderly and vulnerable adults for abuse and neglect. This review examined the accuracy of screening tools for identifying IPV and the benefits and harms of screening women of childbearing age and elderly and vulnerable adults. POPULATION: These recommendations apply to asymptomatic women (women who do not have signs or symptoms of abuse) of reproductive age and elderly and vulnerable adults. RECOMMENDATION: The USPSTF recommends that clinicians screen women of childbearing age for IPV, such as domestic violence, and provide or refer women who screen positive to intervention services (B recommendation).The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening all elderly or vulnerable adults (physically or mentally dysfunctional) for abuse and neglect (I statement). PMID- 23338829 TI - A population-based cohort study of undervaccination in 8 managed care organizations across the United States. AB - OBJECTIVES To examine patterns and trends of undervaccination in children aged 2 to 24 months and to compare health care utilization rates between undervaccinated and age-appropriately vaccinated children. DESIGN Retrospective matched cohort study. SETTING Eight managed care organizations of the Vaccine Safety Datalink. PARTICIPANTS Children born between 2004 and 2008. MAIN EXPOSURE Immunization records were used to calculate the average number of days undervaccinated. Two matched cohorts were created: 1 with children who were undervaccinated for any reason and 1 with children who were undervaccinated because of parental choice. For both cohorts, undervaccinated children were matched to age-appropriately vaccinated children by birth date, managed care organization, and sex. MAIN OUTCOME MEASURES Rates of undervaccination, specific patterns of undervaccination, and health care utilization rates. RESULTS Of 323 247 children born between 2004 and 2008, 48.7% were undervaccinated for at least 1 day before age 24 months. The prevalence of undervaccination and specific patterns of undervaccination increased over time (P < .001). In a matched cohort analysis, undervaccinated children had lower outpatient visit rates compared with children who were age-appropriately vaccinated (incidence rate ratio [IRR], 0.89; 95% CI, 0.89- 0.90). In contrast, undervaccinated children had increased inpatient admission rates compared with age-appropriately vaccinated children (IRR, 1.21; 95% CI, 1.18-1.23). In a second matched cohort analysis, children who were undervaccinated because of parental choice had lower rates of outpatient visits (IRR, 0.94; 95% CI, 0.93-0.95) and emergency department encounters (IRR, 0.91; 95% CI, 0.88-0.94) than age-appropriately vaccinated children. CONCLUSIONS Undervaccination appears to be an increasing trend. Undervaccinated children appear to have different health care utilization patterns compared with age appropriately vaccinated children. PMID- 23338830 TI - The gambling behavior of indigenous Australians. AB - The gambling activities of minority groups such as Indigenous peoples are usually culturally complex and poorly understood. To redress the scarcity of information and contribute to a better understanding of gambling by Indigenous people, this paper presents quantitative evidence gathered at three Australian Indigenous festivals, online and in several Indigenous communities. With support from Indigenous communities, the study collected and analyzed surveys from 1,259 self selected Indigenous adults. Approximately 33 % of respondents gambled on card games while 80 % gambled on commercial gambling forms in the previous year. Gambling participation and involvement are high, particularly on electronic gaming machines (EGMs), the favorite and most regular form of gambling. Men are significantly more likely to participate in gambling and to gamble more frequently on EGMs, horse/dog races, sports betting and instant scratch tickets. This elevated participation and frequency of gambling on continuous forms would appear to heighten gambling risks for Indigenous men. This is particularly the case for younger Indigenous men, who are more likely than their older counterparts to gamble on EGMs, table games and poker. While distinct differences between the gambling behaviors of our Indigenous sample and non-Indigenous Australians are apparent, Australian Indigenous behavior appears similar to that of some Indigenous and First Nations populations in other countries. Although this study represents the largest survey of Indigenous Australian gambling ever conducted in New South Wales and Queensland, further research is needed to extend our knowledge of Indigenous gambling and to limit the risks from gambling for Indigenous peoples. PMID- 23338831 TI - Review of self-exclusion from gambling venues as an intervention for problem gambling. AB - Self-exclusion programs are required to be provided by gambling operators in many international jurisdictions in an attempt to provide an option for those who have gambling problems to avoid further gambling. However, minimal robust and comprehensive research has been conducted to evaluate the effectiveness of self exclusion programs. There is much scope for reform and greater cohesion between jurisdictions, particularly neighbouring jurisdictions that would offer greater protection to individuals and industry bodies. This review outlines the evidence surrounding existing self-exclusion strategies, the benefits and limitations of such programs, and provides potential recommendations for an effective intervention program. Research suggests that self-exclusion programs are under utilised by problem gamblers and are not completely effective in preventing individuals from gambling in venues from which they have excluded, or on other forms. Nonetheless, self-report indicates that self-excluders generally experience benefits from programs, including decreased gambling and increased psychological wellbeing and overall functioning. There are many areas in which existing programs could be improved, such as providing more resources for excluded individuals and reducing barriers to program entry, and more research is needed. However, self-exclusion programs are an important component of any public health strategy that aims to minimise gambling-related harms and these should be based as far as possible on empirical evidence for effective program components. PMID- 23338833 TI - Recurrent spontaneous ovarian hyperstimulation secondary to hypothyroidism in an adolescent girl. PMID- 23338832 TI - Large protein complexes retained in the ER are dislocated by non-COPII vesicles and degraded by selective autophagy. AB - Multisubunit protein complexes are assembled in the endoplasmic reticulum (ER). Existing pools of single subunits and assembly intermediates ensure the efficient and rapid formation of complete complexes. While being kinetically beneficial, surplus components must be eliminated to prevent potentially harmful accumulation in the ER. Surplus single chains are cleared by the ubiquitin-proteasome system. However, the fate of not secreted assembly intermediates of multisubunit proteins remains elusive. Here we show by high-resolution double-label confocal immunofluorescence and immunogold electron microscopy that naturally occurring surplus fibrinogen Aalpha-gamma assembly intermediates in HepG2 cells are dislocated together with EDEM1 from the ER to the cytoplasm in ER-derived vesicles not corresponding to COPII-coated vesicles originating from the transitional ER. This route corresponds to the novel ER exit path we have previously identified for EDEM1 (Zuber et al. Proc Natl Acad Sci USA 104:4407 4412, 2007). In the cytoplasm, detergent-insoluble aggregates of fibrinogen Aalpha-gamma dimers develop that are targeted by the selective autophagy cargo receptors p62/SQSTM1 and NBR1. These aggregates are degraded by selective autophagy as directly demonstrated by high-resolution microscopy as well as biochemical analysis and inhibition of autophagy by siRNA and kinase inhibitors. Our findings demonstrate that different pathways exist in parallel for ER-to cytoplasm dislocation and subsequent proteolytic degradation of large luminal protein complexes and of surplus luminal single-chain proteins. This implies that ER-associated protein degradation (ERAD) has a broader function in ER proteostasis and is not limited to the elimination of misfolded glycoproteins. PMID- 23338834 TI - A community engaged curriculum for public service psychiatry fellowship training. AB - Transforming the mental health system into a recovery oriented, integrated system of care requires a psychiatric work force that understands the relationship between recovery processes and community living. Fellowship programs in public and community psychiatry contribute to this transformation by educating psychiatrists about recovery, system dynamics, leadership, effective administration and community involvement. This paper describes a novel approach to fellowship programming that accomplishes these aims through an organizational strategy that emphasizes community engagement. After describing the administrative background for the program, we describe how the content curriculum and teaching process focus on the engagement of community members-both service users and service providers-as participating faculty. The faculty includes over 100 consumers, family members, advocacy group representatives, clinicians, and administrators. We present evaluation data obtained from 45 of the 100 community and university faculty who participated in the first 2 years' of the fellowship and conclude with a critique and recommendations for further progress in community engaged fellowship training. PMID- 23338835 TI - Who cares for former child soldiers? Mental health systems of care in sierra leone. AB - While numerous studies on former child soldiers (FCS) have shown mental health needs, adequate services are a challenge. This study aimed to identify priorities, barriers and facilitators of mental health care for Sierra Leonean FCS. Thematic analysis was done on 24 qualitative interviews with participants from diverse sectors. Priorities of mental distress, substance abuse, and gender based violence were common among FCS clients. Barriers were governmental support and communication with other providers. Perceived facilitators of care were primary- and secondary-level interventions. A public mental health model would feasibly build upon local, culturally embraced interventions, targeting local priorities and reducing barriers to care. PMID- 23338837 TI - Computational design of glutamate dehydrogenase in Bacillus subtilis natto. AB - Bacillus subtilis natto is widely used in industry to produce natto, a traditional and popular Japanese soybean food. However, during its secondary fermentation, high amounts of ammonia are released to give a negative influence on the flavor of natto. Glutamate dehydrogenase (GDH) is a key enzyme for the ammonia produced and released, because it catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate using NAD(+) or NADP(+) as co-factor during carbon and nitrogen metabolism processes. To solve this problem, we employed multiple computational methods model and re-design GDH from Bacillus subtilis natto. Firstly, a structure model of GDH with cofactor NADP(+) was constructed by threading and ab initio modeling. Then the substrate glutamate were flexibly docked into the structure model to form the substrate-binding mode. According to the structural analysis of the substrate-binding mode, Lys80, Lys116, Arg196, Thr200, and Ser351 in the active site were found could form a significant hydrogen bonding network with the substrate, which was thought to play a crucial role in the substrate recognition and position. Thus, these residues were then mutated into other amino acids, and the substrate binding affinities for each mutant were calculated. Finally, three single mutants (K80A, K116Q, and S351A) were found to have significant decrease in the substrate binding affinities, which was further supported by our biochemical experiments. PMID- 23338838 TI - Desmoid-type fibromatosis in the head and neck: CT and MR imaging characteristics. AB - INTRODUCTION: In the head and neck region, desmoid-type fibromatosis is an uncommon tumor, and the imaging features have not been well described. The purpose of this study was to describe imaging features with their pathologic correlation of desmoid-type fibromatosis in this region. METHODS: Computed tomographic (CT) and magnetic resonance (MR) images of nine consecutive patients (five women and four men; age range, 2-72 years; mean age, 28 years) with desmoid type fibromatosis in the head and neck were retrospectively evaluated, focusing on lesion location, size, shape, presence of a rim of surrounding fat, CT attenuation, signal intensity, and enhancement characteristics on MR with pathologic correlation. RESULTS: Desmoid-type fibromatosis involved perivertebral space (n = 5) and carotid space (n = 1) in six adult patients. In three pediatric patients, the fibromatosis primarily involved submandibular space (n = 2) and masticator space (n = 1) with frequent invasion to the adjacent spaces (3/3). A mean greatest dimension of 5.8 cm, elongated shape (7/9), and rim of surrounding fat (8/9) were the common features of the desmoid-type fibromatosis. Tumors often showed iso (3/7) or high attenuation (3/7) on postcontrast CT, high signal intensity (6/9) on T2-weighted image, iso signal intensity (8/9) on T1-weighted image, and strong MR enhancement (8/9). Characteristic nonenhancing low signal intensity bands (8/9) on all MR sequences were well correlated with dense collagenous stroma. CONCLUSIONS: Desmoid-type fibromatosis in the head and neck of adults frequently involves perivertebral space. Along with various common imaging features, desmoid-type fibromatosis shows characteristic nonenhancing low signal intensity bands on MR images. PMID- 23338840 TI - The VHL tumor suppressor protein regulates tumorigenicity of U87-derived glioma stem-like cells by inhibiting the JAK/STAT signaling pathway. AB - The signal transducer and activator of transcription 3 (STAT3) factor plays an important role in the tumorigenicity of cancer stem cells. The purpose of this study was to investigate the inhibitory mechanism of this pathway acting through the tumor suppressor von Hippel-Lindau (VHL) protein in glioma cancer stem cells. We isolated floating neurosphere-forming CD133+ cells as glioma stem-like cells (GSLCs) by the MACS method. Furthermore, we examined these cells for their growth rate, ability to form colonies and neurospheres in soft agar, capacity for implantation into SCID mice and expression of CD133, STAT3, JAK2, Elongin A, PTEN and VHL. Furthermore, we transferred the VHL gene, an inhibitor of STAT3, into GSLCs using an adenovirus vector and compared these transfectants with control vector-transfected GSLCs. GSLCs proved to be implantable and formed a tumor in the subcutaneous tissue of SCID mice, the histology of which was similar to that of human glioblastomas. In addition, GSLCs exhibited a high capacity for soft agar colony and neurosphere formation, nearly all of which were CD133 positive. The majority of GSLCs were immunopositive for STAT3, JAK2 and Elongin A, but immunonegative for PTEN and VHL. When the VHL gene was transferred to GSLCs and these cells were transplanted into SCID mice, they did not result in tumor formation. Their capacity for soft agar colony and neurosphere formation was significantly inhibited, although their proliferation was only moderately inhibited. Regarding the expression of various factors, that of CD133 was decreased in the VHL transfectants and those of STAT3, JAK2 and Elongin A were eliminated. However, the expression of PTEN and of VHL was upregulated. These findings suggest that VHL regulated the tumorigenicity and self-renewal ability of glioma cancer stem cells by inhibiting the JAK/STAT signaling pathway. PMID- 23338841 TI - Tspan8, CD44v6 and alpha6beta4 are biomarkers of migrating pancreatic cancer initiating cells. AB - Pancreatic adenocarcinoma (PaCa) being the deadliest cancer is partly due to early metastatic spread. Thus, we searched for PaCa-initiating cell (PaCIC) markers with emphasis on markers contributing to metastatic progression. PaCIC were enriched from long-term and freshly established lines by repeated selection for spheroid or holoclone growth in advance of evaluating PaCIC markers. Sphere and holoclone formation steeply increased by recloning and remained stable thereafter. Cells not forming spheres or holoclones died on recloning. PaCIC enrichment in spheres and holoclones was accompanied by increased motility, anchorage independence and upregulated CXCR4 expression. After subcutaneous injection in NOD/SCID mice tumorigenicity and, impressively, recovery of metastasizing tumor cells in peripheral blood, spleen, bone marrow, lung and pancreas was strongly increased in spheres and holoclones. PaCIC enrichment in spheres and holoclones was accompanied, besides CXCR4, by upregulated CD44v6, alpha6beta4, weakly CD133 and tetraspanin Tspan8 expression. Notably, CD44v6, alpha6beta4, CXCR4 and Tspan8 expressing PaCa cells had a growth advantage in vivo and became dominating in migrating and in distant organs settled tumor cells. This is the first report showing that CD44v6, alpha6beta4, Tspan8 and CXCR4 are biomarkers in PaCIC allowing for long-term survival, expansion and migration in immunocompromised mice. The stability of the percentage of PaCIC in long-term and freshly established lines after a roughly 8-fold enrichment by cloning indicates PaCIC, though required for long-term survival, concomitantly depending on support by non-CIC. PMID- 23338843 TI - Local deposition of anisotropic nanoparticles using scanning electrochemical microscopy (SECM). AB - We demonstrate localized electrodeposition of anisotropic metal nanoobjects, namely Au nanorods (GNR), on indium tin oxide (ITO) using scanning electrochemical microscopy (SECM). A gold microelectrode was the source of the gold ions whereby double pulse chronoamperometry was employed to generate initially Au seeds which were further grown under controlled conditions. The distance between the microelectrode and the ITO surface as well as the different experimental parameters (electrodeposition regime, solution composition and temperature) were optimized to produce faceted gold seeds with the required characteristics (size and distribution). Colloidal chemical synthesis was successfully exploited for better understanding the role of the surfactant and different additives in breaking the crystallographic symmetry and anisotropic growth of GNR. Experiments performed in a conventional three-electrode cell revealed the most appropriate electrochemical conditions allowing high yield synthesis of nanorods with well-defined shape as well as nanocubes and bipyramids. PMID- 23338839 TI - Towards automated detection of depression from brain structural magnetic resonance images. AB - INTRODUCTION: Depression is a major issue worldwide and is seen as a significant health problem. Stigma and patient denial, clinical experience, time limitations, and reliability of psychometrics are barriers to the clinical diagnoses of depression. Thus, the establishment of an automated system that could detect such abnormalities would assist medical experts in their decision-making process. This paper reviews existing methods for the automated detection of depression from brain structural magnetic resonance images (sMRI). METHODS: Relevant sources were identified from various databases and online sites using a combination of keywords and terms including depression, major depressive disorder, detection, classification, and MRI databases. Reference lists of chosen articles were further reviewed for associated publications. RESULTS: The paper introduces a generic structure for representing and describing the methods developed for the detection of depression from sMRI of the brain. It consists of a number of components including acquisition and preprocessing, feature extraction, feature selection, and classification. CONCLUSION: Automated sMRI-based detection methods have the potential to provide an objective measure of depression, hence improving the confidence level in the diagnosis and prognosis of depression. PMID- 23338845 TI - Overexpression of GPC3 inhibits hepatocellular carcinoma cell proliferation and invasion through induction of apoptosis. AB - Glypican-3 (GPC3) is a membrane heparan sulfate proteoglycan involved in cell proliferation, differentiation, adhesion, migration and the development of the majority of mesodermal tissues and organs. GPC3 has been found to be important for the occurrence and development of hepatocellular carcinoma (HCC). Therefore, it may be suitable for use as a novel molecular marker for the diagnosis of primary liver cancer. In the present study, the role of GPC3 in the occurrence and development of HCC was determined. GPC3 recombinant vector was transfected into two HCC cell lines, Huh7 and SK-HEP-1, to upregulate the expression of GPC3 and examine changes in the biological behavior of the cells. Results indicate that overexpression of GPC3 in Huh7 and SK-HEP-1 cells effectively inhibited cell proliferation and cell invasion through induction of apoptosis. However, cotreatment of the cells with insulin-like growth factor 2 (IGF2) and fibroblast growth factor 2 (FGF2) was found by Annexin V-PI flow cytometric analysis to significantly inhibit the apoptotic cell death induced by GPC3 overexpression. These observations indicate that GPC3 may act as a negative regulator of IGF2 and FGF2 pathways. Taken together, these results demonstrate that overexpression of GPC3 inhibits the occurrence and development of HCC. PMID- 23338846 TI - Comparison of microscopic (pT3a) and gross extravesical extension (pT3b) in pathological staging of bladder cancer: analysis of patient outcomes. AB - OBJECTIVE: To determine the prognostic value of pT3 bladder urothelial carcinoma substaging in patients without lymphatic involvement. PATIENTS AND METHODS: Pathologic and clinical data were reviewed on patients who underwent radical cystectomy for urothelial carcinoma between 1991 and 2010. Of the 460 reviewed patients, 74 patients were diagnosed with pathologic T3No urothelial carcinoma of the bladder. The impact of pathologic substaging (pT3a vs. pT3b) was examined to determine the effect on overall and disease-specific survival. RESULTS: Five years disease-specific and overall survival rates were 46.9 % and 39.6 % for patients with pT3aNo tumor, whereas these ratios were 34.4 and 30.3 %, respectively, for patients with pT3bNo tumor (p > 0.05). Mean disease-specific survival time was 43.94 +/- 6.50 months for pT3aNo, while it was 39.01 +/- 7.19 months for pT3bNo (p = 0.539). In multivariate cox regression analysis, age (p = 0.459), gender (p = 0.710), urinary diversion type (p = 0.088), and pT3 substaging (p = 0.554) were not noticed as an independent predictive factor for survival. CONCLUSION: Macroscopic extravesical extension (pT3b) is not associated with a worse outcome than pT3a disease in lymph node-negative cases of bladder urothelial carcinoma. PMID- 23338847 TI - Metal ions directing the geometry and nuclearity of azido-metal(II) complexes derived from bis(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)amine. AB - The reaction of a methanolic solution containing M(ClO(4))(2).nH(2)O (M = Cu, Ni, Zn or Cd) or CoCl(2).6H(2)O with bis(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)amine (bedmpza) in the presence of NaN(3) afforded the complexes [Cu(bedmpza)(MU(1,1) N(3))](2)(ClO(4))(2) (1), [Ni(bedmpza)(N(3))(MU(1,1)-N(3))](2).1.5H(2)O (2), [Co(bedmpza)(N(3))(2)] (3), [Zn(bedmpza)(N(3))]ClO(4) (4) and [Cd(bedmpza)(N(3))(MU(1,1)-N(3))](2).1.5H(2)O (5). The five complexes were characterized by spectroscopic techniques and their molecular structures were determined by single crystal X-ray crystallography. The two mononuclear complexes 3 and 4 display distorted TBP and tetrahedral geometry, respectively with the azide ions acting as monodentate ligands. Doubly bridged end-on-azido dinuclear complexes were obtained in the remaining compounds. Compounds 2 and 5 are isomorphic with distorted octahedral geometry, whereas distorted square pyramidal geometry was determined in the Cu(II) complex 1. The magnetic properties for complexes 1 and 2 were investigated by measuring the magnetic susceptibilities at variable temperatures (300-2 K). The Ni(II) complex exhibits moderate ferromagnetic coupling, whereas [Cu(bedmpza)(MU(1,1)-N(3))](2)(ClO(4))(2) (1) which contains two crystallographic independent dinuclear subunits in the unit cell, with different Cu-N(N3)-Cu bond angles, reveals different signs in the magnetic coupling. The complex represents the first example in the literature that has simultaneously two moieties with ferro- (J = 15.4 cm(-1)) and antiferromagnetic (J = -18.9 cm(-1)) interactions. PMID- 23338848 TI - The Road to Health Reform: What Can Physicians Expect Over the Next 4 Years? PMID- 23338849 TI - Lakota elders' views on traditional versus commercial/addictive tobacco use; oral history depicting a fundamental distinction. AB - This qualitative study is intended to elucidate Lakota elders' views on traditional tobacco and commercial/addictive tobacco use, capturing the oral history that depict the cultural protocol regarding traditional tobacco, called Cansasa. Commercial tobacco use has significantly impacted the Northern Plains Indians. National surveillance systems report that tobacco use is more prevalent among American Indian/Alaska Natives than any other population, and is notably higher than the national average. Lung cancer among Native Americans is highest in the Northern Plains and Alaska, where smoking prevalence is also the highest, and smoking is responsible for nearly 90 % of all lung cancer cases. Yet, the use of traditional tobacco is largely ignored by surveillance and seems to have a distinct, positive role. Using a community-based participatory research approach, semi-structured interviews, and qualitative analysis tools, the research team, including 2 Lakota tribe elders, Lakota speaking tribal college students, and university faculty, sought to discern tribal elders' distinctions between traditional and the addictive commercial tobacco. The team interviewed thirty Lakota elders, transcribed the interviews and field notes, and analyzed them using immersion/crystallization organizing framework. The research design engaged the Lakota tribal community in all stages, from planning to publication. Analysis revealed a clear distinction between traditional and commercial tobacco: tribal elders conveyed strong positive messages connected to traditional tobacco use (i.e., spirituality, respect, health and wellness, humility, and thoughtfulness) versus strong negative messages linked to addictive tobacco (i.e., crime, loss of control and self-esteem, lack of respect to self and others, sickness and death). These messages, along with stories in the Lakota language that were told and recorded during the interviews, can guide new ways to address addictive tobacco prevention in this community, to enhance cultural pride, and to serve as a cross generation bridge regarding tobacco use. PMID- 23338851 TI - Nandrolone attenuates aortic adaptation to exercise in rats. AB - AIMS: In this study, we investigated the interaction between exercise-induced mitochondrial adaptation of large vessels and the effects of chronic anabolic androgenic steroids (AASs). METHODS AND RESULTS: Four groups of Sprague-Dawley rats were studied: (i) sedentary, (ii) sedentary + nandrolone-treated, (iii) aerobic exercise trained, and (iv) trained + nandrolone-treated. Aerobic training increased the levels of aortic endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1) in accordance with improved acetylcholine-induced vascular relaxation. These beneficial effects were associated with induction of mitochondrial complexes I and V, increased mitochondrial DNA copy number, and greater expression of transcription factors involved in mitochondrial biogenesis/fusion. We also observed enhanced mitochondrial autophagy pathway activity, including increased conversion of LC3-I to LC3-II and greater expression of beclin1 and autophagy-related protein-7 (ATG7). The levels of thiobarbituric acid-reactive substances and protein carbonyls remained unchanged, whereas significant increases in catalase and mitochondrial manganese superoxide dismutase (MnSOD) levels were observed in the aortas of trained animals, when compared with sedentary controls. Nandrolone increased oxidative stress biomarkers and inhibited exercise-induced increases of eNOS, HO-1, catalase, and MnSOD expression. In addition, it also attenuated elevated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) and mitofusin-2 expression, and further up-regulated LC3II conversion, beclin1, ATG7, and dynamin-related protein-1 expression. CONCLUSION: These results demonstrate that nandrolone attenuates aortic adaptations to exercise by regulating mitochondrial dynamic remodelling, including down-regulation of mitochondrial biogenesis and intensive autophagy. PMID- 23338852 TI - The enigma of alternative childhood immunization schedules: what are the questions? PMID- 23338853 TI - Lanthanum induced primary neuronal apoptosis through mitochondrial dysfunction modulated by Ca2+ and Bcl-2 family. AB - As a representative element of lanthanide, lanthanum has been widely used in various fields and eventually entered environment and accumulated in human body. Epidemiological and experimental evidences indicated that lanthanum has neurotoxicity; however, the detailed mechanism is still elusive. Here, we chose primary cerebral cortical neurons as model in vitro to investigate the mechanism underlying the toxic effects of lanthanum chloride (LaCl3). This study revealed the following findings: (1) LaCl3 treatment (0.01, 0.1, and 1.0 mM for 24 h) reduced the viability of cortical neurons and elevated apoptotic rate significantly in a dose-dependent manner. (2) LaCl3 triggered mitochondrial apoptotic pathway in cortical neurons, characterized with collapsed mitochondrial membrane potential, release of cytochrome c into cytosol, and increasing expression of activated caspase-3. (3) LaCl3 elevated intracellular Ca(2+) concentration, promoted reactive oxygen species generation, and upregulated pro apoptotic Bax, whereas it downregulated anti-apoptotic Bcl-2 expression and consequently altered Bax/Bcl-2 ratio, which ultimately lead to neuronal mitochondrial apoptosis. Our results demonstrated that toxicity of lanthanum in cortical neurons perhaps partly attributed to enhanced mitochondrial apoptosis due to mitochondrial dysfunction modulated by Ca(2+) and Bcl-2 family. PMID- 23338854 TI - Efficient light trapping in inverted polymer solar cells by a randomly nanostructured electrode using monodispersed polymer nanoparticles. AB - The randomly nanotextured back electrode provides a simple and efficient route for enhancing photocurrent in polymer solar cells (PSCs) by light trapping, which can increase light absorption within a finite thickness of the active layer. In this study, we incorporated mono-disperse 60 nm polystyrene nanoparticles (PS NPs) into a 50 nm thick poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) anode buffer layer (ABL) to create a randomly nanotextured back electrode with 10 nm height variations in inverted-type PSCs. The roughened interface between the PS NP-PEDOT:PSS ABL and the Ag electrode scatters light in the visible range, leading to efficient light trapping within the device and enhanced light absorption in the active layer. Inverted PSCs with randomly nanotextured electrodes (phi(NP) = 0.31) showed short-circuit current density (J(SC)) and power conversion efficiency (PCE) values that were 15% higher than those of control devices with flat electrodes. External quantum efficiency, reflectance, and optical light scattering as a function of phi(NP) were examined to determine the origin of the enhancement in J(SC) and PCE. PMID- 23338855 TI - N-terminal B-type natriuretic peptide and the association with left ventricular diastolic function in a population at high risk of incident heart failure: results of the SCReening Evaluationof the Evolution of New-Heart Failure Study (SCREEN-HF). AB - AIMS: Impaired diastolic function is associated with increased morbidity and mortality, but antecedents and predictors of progression to heart failure (HF) are not well understood. We examined associations between NT-proBNP, HF risk factors, and diastolic function in a population at high risk for incident HF. METHODS AND RESULTS: A total of 3550 subjects at high risk for incident HF (>=60 years plus >=1 HF risk factor), but without pre-existing HF or LV dysfunction were recruited. Participants at highest risk (n = 664) (NT-proBNP in the highest quintile >254 pg/mL) underwent echocardiography. Moderate or severe diastolic dysfunction was observed in 25% [95% confidence interval (CI) 21-29%] of participants. Age (P = 0.001), male gender (P = 0.03), diabetes (P = 0.03), and NT-proBNP (P = 0.002) were associated with severity of diastolic dysfunction after adjustment for HF risk factors and LVEF. In regression analysis, log transformed NT-proBNP was also associated with LV mass index (P = 0.05), left atrial size (P < 0.0001), and Doppler ratio of the mitral valve E/e' (P = 0.001). Multiple HF risk factors were present in the majority of participants (>70%), but no association was observed between diastolic dysfunction and the number of risk factors reported (P = 0.3). CONCLUSION: Diastolic dysfunction was observed in one in four of these high risk subjects (>= 60 years, HF risk factor, NT-proBNP >254 pg/mL). NT-proBNP, age and diabetes were strongly associated with severity of diastolic dysfunction, whereas other HF risk factors and LVEF were not. More targeted surveillance using a combination of risk factors and biomarkers may improve identification of those at great risk of incident HF. PMID- 23338856 TI - Erratum to: Nucleofection of whole murine retinas. PMID- 23338857 TI - Effects of Lonomia obliqua caterpillar venom upon the proliferation and viability of cell lines. AB - Many active principles produced by animals, plants and microorganisms have been employed in the development of new drugs for the treatment of human diseases. Among animals known to produce pharmacologically active molecules that interfere in human cell physiology, the caterpillar Lonomia obliqua has become the focus of toxicological studies due to recent findings about its venom constituents. The objective of this study was to investigate the effects of L. obliqua venom upon the viability and the proliferation of different cell lineages and to propose mechanisms for the herein observed induction of cell proliferation in glioma cell lines. MTT analyses indicate that L. obliqua venom increases the viability of tumor cell lines U138-MG and HT-29; on the other hand, it inhibits the viability of V-79 nontumor cells. Cell count based on the trypan blue exclusion method suggests a proliferating activity of the venom upon U138-MG cells. Exposure of U138-MG to crude venom extract led to a decrease in the production of nitric oxide, and activation of the cAMP signaling pathway inhibited the effects of the venom, indicating that these mechanisms may influence cell proliferation triggered by the venom. Despite the proliferative effects of crude venom on U138 MG and HT-29 cell cultures, a protein purified from L. obliqua hemolymph previously shown to have cytoprotective activity had no effect on U138-MG and HT 29; however, this same protein increased the viability of V-79 cells that had previously been exposed to the cytotoxic activity of the crude venom extract. This study indicates that the venom and the antiapoptotic protein act differently and have different effects on cell cultures, depending on the cell line analyzed. Biomolecules displaying either mitogenic or cytotoxic activities are of great biotechnological interest. Further studies encompassing the purification of active principles from L. obliqua venom are necessary to further elucidate its effects on different cell types. PMID- 23338859 TI - Theoretical predictions for hexagonal BN based nanomaterials as electrocatalysts for the oxygen reduction reaction. AB - The catalytic activity for the oxygen reduction reaction (ORR) of both the pristine and defect-possessing hexagonal boron nitride (h-BN) monolayer and H terminated nanoribbon have been studied theoretically using density functional theory. It is demonstrated that an inert h-BN monolayer can be functionalized and become catalytically active by nitrogen doping. It is shown that the energetics of adsorption of O(2), O, OH, OOH, and H(2)O on N atom impurities in the h-BN monolayer (N(B)@h-BN) is quite similar to that known for a Pt(111) surface. The specific mechanism of destructive and cooperative adsorption of ORR intermediates on the surface point defects is discussed. It is demonstrated that accounting for entropy and zero-point energy (ZPE) corrections results in destabilization of the ORR intermediates adsorbed on N(B)@h-BN, while solvent effects lead to their stabilization. Therefore, entropy, ZPE and solvent effects partly cancel each other and have to be taken into account simultaneously. Analysis of the free energy changes along the ORR pathway allows us to suggest that a N-doped h-BN monolayer can demonstrate catalytic properties for the ORR under the condition that electron transport to the catalytically active center is provided. PMID- 23338860 TI - Picosecond pulsed electric fields induce apoptosis in HeLa cells via the endoplasmic reticulum stress and caspase-dependent signaling pathways. AB - The non-invasive treatment of tumors with preserved fertility holds great promise. The application of pulsed electric field (PEF) is a new biomedical engineering technique for tumor therapy. Picosecond pulsed electric fields (psPEF) can be transferred to target deep tissue non-invasively and precisely; however, research of the biological effects of psPEF on cells is limited. Electric theory predicts that when the pulse duration decreases to nanoseconds and picoseconds, it will mainly affect organelles and lead to intracellular electromanipulations. Previous studies have shown that psPEF targets the mitochondria and induces apoptosis through a mitochondrial-mediated pathway in HeLa cells. The endoplasmic reticulum is also involved in the intrinsic pathways of apoptosis. In the present study, HeLa cells were exposed to psPEF to investigate the underlying mechanisms of apoptosis. MTT assay demonstrated that psPEF displayed strong growth inhibitory effects on HeLa cells. Treatment with psPEF led to marked cell apoptosis and cell cycle arrest at the G2/M phase. In addition, psPEF affected the phosphorylation levels of endoplasmic reticulum sensors and upregulated the expression of glucose-regulated protein 78 (GRP78), glucose-regulated protein 94 (GRP94) and CCAAT enhancer-binding protein (C/EBP) homologous protein (CHOP). These changes were accompanied by the elevation of intracellular Ca2+ concentrations. Furthermore, the activation of caspase-12, -9 and -3, led to the release of cytochrome c, as well as the upregulation of Bax and the downregulation of Bcl-2, as observed in the HeLa cells. Taken together, these data suggest that psPEF is an efficient apoptosis-inducing agent for HeLa cells, which exerts its effects, at least partially, via the endoplasmic reticulum stress and caspase-dependent signaling pathways. PMID- 23338862 TI - Pivoted composite nasal septal flap for reconstruction of the nose. AB - Reconstruction of nasal tip support and internal lining after excision of nasal carcinoma is challenging. Since its original description by Menick in 1989, the outcomes of bipedicled septal pivot flap are rarely reported in the literature. Objective of this work is to review our results using the Septal pivoted flap in nasal reconstruction. It is a retrospective case series, Dalhousie University, Halifax, Nova Scotia. We studied six patients who underwent significant resection of the tip and dorsum of the nose for squamous or basal cell carcinoma. All involved nasal subunits were removed. Nasal reconstruction was subsequently performed using an inferiorly bipedicled pivoted composite nasal septal flap combined with a regional flap for skin coverage. The bipedicled SPF provided excellent support of the nasal tip in all six cases. All flaps in the cohort survived. Five patients had good mucosal lining from the septal flap alone and only one patient required a concurrent pericranial flap. Three patients experienced bleeding and required additional nasal packing. A bipedicled septal pivoted flap is exceptionally useful in providing a good tip support and well vascularized nasal lining for reconstruction after major resection of the nasal tip. Bleeding is common and should be anticipated in the majority of patients. PMID- 23338863 TI - Residents as teachers. PMID- 23338865 TI - Evaluating psychiatry residents as physician-managers: development of an assessment tool. AB - OBJECTIVES: With the emergence of physician-manager (PM) curricula in medical education, more effective assessment tools are needed to evaluate psychiatry trainees in this role. The aim of this study was to determine psychiatry residents', program directors', and PM educators' perceptions about PM role assessment. METHODS: Psychiatry residents at two Canadian programs were given a survey on PM assessment and the use of portfolios to assess PM competency. Qualitative interviews of Canadian psychiatry educators and program directors were used to determine faculty perceptions on PM assessment. Authors analyzed survey data with descriptive statistics, and qualitative interviews were analyzed using a grounded theory approach. RESULTS: Nearly 55% of psychiatry residents responded to the survey; 47% of residents did not want to change the way they were assessed by the PM role. Residents identified an array of assessment methods for each of the specific PM domains. Educator interview themes included supervisor and resident barriers to assessment, the need for new PM assessment approaches integrating multiple assessment methods, and a role for the use of portfolios if sufficient infrastructure was available. CONCLUSION: The data supported a preference for a multimodal approach to assessment of the PM role. Future research should examine the implementation of the proposed PM assessment tool. PMID- 23338864 TI - Physiological and neurobiological aspects of stress and their relevance for residency training. PMID- 23338866 TI - A curriculum to address issues and challenges of the professional developmental stage of chief residency. PMID- 23338868 TI - Teaching psychiatry residents to teach: a national survey. AB - OBJECTIVE: Because there have been no previously published national surveys on teaching psychiatry residents about how to teach, the authors surveyed United States psychiatry program directors on what and how residents are taught about teaching. METHODS: All psychiatry training programs across the United States were mailed a semistructured questionnaire; 95 responded (response rate: 53%). The survey included questions on what, if anything, was provided in the way of formal instruction; the number of seminars offered each year; texts and other materials that were used for teaching; and how seminars were evaluated. RESULTS: The majority (N=69, 73%) of all responding programs provided formal instruction to residents about how to teach. Topics most commonly taught included evaluation and feedback (N=57; 60%), lecturing skills (N=43; 45%), small-group skills (N=40; 42%), learning theory (N=37; 39%), and problem-based learning (N=36; 38%). Instructional methods used were predominantly group discussion (N=62; 65%), lecturing (N=59; 62%), reading of relevant literature (N=35; 37%), role-playing (N=33; 35%), and audiovisual instruction (N=32; 34%). There was a heterogeneity of texts and materials used for teaching. Few of the programs utilized formal validated and reliable tools for evaluating their teaching. CONCLUSION: Although most programs provided formal teaching, there remains a need to further develop teaching programs and to create model ones. PMID- 23338869 TI - Training in a clozapine clinic for psychiatry residents: a plea and suggestions for implementation. AB - OBJECTIVE: The authors sought to develop a model educational clinic and curriculum for psychiatric residents, to increase knowledge and comfort about clozapine prescribing. This matters because clozapine is an important evidence based treatment for refractory schizophrenia that remains underutilized in clinical practice. METHOD: This is a description of how the Clozapine Clinic of the Massachusetts General Hospital (MGH) Schizophrenia Program was integrated into the curriculum of the MGH-McLean Adult Psychiatric Residency. RESULTS: PGY II residents participated in a weekly clozapine clinic with direct patient contact and accompanying curriculum-based instruction for a 6-week period. The method of teaching by participating in a dedicated Clozapine Clinic received favorable feedback. Residents' knowledge about clozapine increased. CONCLUSION: Residency programs should determine whether their trainees receive sufficient training in the use of clozapine and consider setting up clozapine clinics where feasible. PMID- 23338870 TI - Survey of sensitive information written in patient notes by psychiatry trainees. AB - OBJECTIVE: Allowing psychiatric patients access to their electronic medical record (EMR) may cause difficulty related to the sensitivity of the note content. The authors investigated whether notes written by psychiatry trainees were ready for release to patients. METHODS: Authors conducted a review of 128 PGY-3 to PGY 5 outpatient notes not explicitly marked as "highly confidential." One psychiatrist and one non-psychiatrist read each note from the patient's perspective. Reviewers assigned a score of 0-2 (0: No Concern; 1: Some Concern; 2: Major Concern) for each note. RESULTS: Eighty-nine notes (70%) were assessed as "No Concern" by both reviewers; 30 (23%) were of "Some Concern;" and 9 (7%) were of "Major Concern;" 92 (72%) were deemed of "No Concern" by a psychiatrist, as compared with 120 (94%) by the non-psychiatrist. CONCLUSIONS: Trainee EMR outpatient notes are not likely to cause major concerns for patients who read them. Psychiatrist-reviewers identified more concerns than non-psychiatrist reviewers. PMID- 23338871 TI - Integrating systems-based practice, community psychiatry, and recovery into residency training. AB - BACKGROUND: Behavioral health services involving multiple systems of care are increasingly being provided in community as well as hospital settings. Residents therefore should be familiar with multiple systems and the role of the psychiatrist in these systems. The authors describe a curriculum incorporating principles of systems-based practice (SBP), community psychiatry, and recovery. METHODS: This curriculum was designed to include lectures, clinical rotations, specialized written/oral presentations, and supervision focused on SBP and recovery principles. Residents also participate in home and site visits for further immersion into the multiple systems that their patients have to navigate. RESULTS/CONCLUSION: The essential elements of this curriculum are the 1) consistent review and emphasis on the four researched-based SBP roles of the psychiatrist; 2) recovery principles of person-centered care and shared decision making; 3) requirement that residents interact with patients in community and home settings; 4) integration of didactic courses and clinical rotations; and 5) focus on the supervisor/supervisee relationship. PMID- 23338872 TI - Using simulation to train junior psychiatry residents to work with agitated patients: a pilot study. AB - OBJECTIVE: This article examines the benefit and feasibility of introducing a new, simulation-based learning intervention for junior psychiatry residents. METHOD: Junior psychiatry residents were invited to participate in a new simulation-based learning intervention focusing on agitated patients. Questionnaires were used to explore the success of the intervention. RESULTS: Participants (N=12) reported increases in self-assessed knowledge. Pre/post comparison of ratings indicated increases in comfort and perceived competence both in evaluating and managing agitated patients after the intervention. Participants reported improvements in knowledge and skills and appreciated feedback. Some indicated the need for continued practice and suggested that their anxiety was still prominent. Overall, the intervention was well received and seen as useful. CONCLUSIONS: Simulation may be well suited to teaching residents to work with agitated patients. More research is needed to determine whether this kind of educational intervention leads to changes in patient care. PMID- 23338873 TI - Training psychiatry residents in quality improvement: an integrated, year-long curriculum. AB - OBJECTIVE The authors describe a curriculum for psychiatry residents in Quality Improvement (QI) methodology. METHODS All PGY3 residents (N=12) participated in a QI curriculum that included a year-long group project. Knowledge and attitudes were assessed before and after the curriculum, using a modified Quality Improvement Knowledge Assessment Tool (QIKAT) and a QI Self-Assessment survey. RESULTS QIKAT scores were significantly higher for residents after participating in the curriculum when compared with pretest scores. Self-efficacy ratings in QI improved after the course for each item. Residents demonstrated gains in QI skills through participation in the group projects in which they increased rates of depression-screening and monitoring in an outpatient clinic. CONCLUSIONS Combining didactic and experiential learning can be an effective means for training psychiatry residents in QI. PMID- 23338874 TI - "Culture and psychiatry": a course for second-year psychiatry residents. PMID- 23338876 TI - Psychotherapy Training e-Resources (PTeR): on-line psychotherapy education. PMID- 23338877 TI - (Honest) letters of recommendation. PMID- 23338878 TI - Teaching Housestaff to Enhance Student Education with the Use of Fantasy Sports (THESEUS). PMID- 23338879 TI - A resident rotation in collaborative care: learning to deliver primary care-based psychiatric services. PMID- 23338880 TI - Web-based involuntary-commitment educational project for emergency medicine residents: an interdepartmental quality initiative. PMID- 23338881 TI - Disclosure of competing interests. PMID- 23338900 TI - Effects of cyclin E gene silencing on the proliferation of esophageal cancer cell lines, EC9706, Eca109 and KYSE30. AB - In order to observe the effects of cyclin E gene silencing by small interfering RNA (siRNA) on the growth, proliferation, invasion and apoptosis of esophageal cancer cell lines, including EC9706, Eca109 and KYSE30, siRNA vectors targeting cyclin E gene were constructed and then transfected into the EC9706, Eca109 and KYSE30 human esophageal cancer cell lines. Cyclin E mRNA and protein expression were determined by RT-PCR and western blotting. Cell proliferation and clonality were detected using a CCK-8 test and soft agar colony formation assay. Cell cycle distribution, apoptosis and invasion of EC9706, Eca109 and KYSE30 cells were evaluated with flow cytometry and a transwell culture system. After siRNA vectors targeting the cyclin E gene were transfected into EC9706, Eca109 and KYSE30 cell lines, compared with blank and negative control groups, the expression of cyclin E mRNA and protein (P<0.01), colony-forming units and the number of cells penetrating the transwell membrane (P<0.05) were significantly decreased, the cells in the S and G2/M phase were reduced, the cells in the G0/G1 phase were increased and the apoptosis rate was increased (P<0.01) in the experimental groups. Cyclin E gene silencing effectively inhibits growth, proliferation and invasion of esophageal cancer cells. PMID- 23338901 TI - Kinetic insights into the reactivity of the intermediates generated from hydrogen peroxide and diiron(III) complex with tris(picolyl)amine (TPA). AB - Two intermediates (2 and 3) are formed consecutively in the reaction of a diiron(III) complex [Fe(III)(2)(MU-O)(OH)(H(2)O)(TPA)(2)](ClO(4))(3) (TPA = tris(2-pyridylmethyl)amine, tris(picolyl)amine) with H(2)O(2) in CH(3)CN at -40 degrees C. Low-temperature stopped-flow studies showed that both species are kinetically competent in oxidation of phosphines and phenols. The first intermediate (2) reacts with substrates very rapidly (second-order rate constants reach 10(5)-10(6) M(-1) s(-1) for substituted triarylphosphines and 10(3)-10(5) M(-1) s(-1) for substituted phenols), in keeping with a diiron(IV)-oxo formulation. The second intermediate (3), a mixed-valent Fe(III)Fe(IV) species, is more stable than 2, and reacts with substrates more slowly (second-order rate constants range from 150 to 550 M(-1) s(-1) for triaryl phosphine oxidation, and from 18 to 790 M(-1) s(-1) for phenol oxidation). Reaction rates increase with increasing electron donating abilities of substituents, indicating that both 2 and 3 act as electrophilic oxidants. PMID- 23338902 TI - Novel oral anticoagulants in atrial fibrillation: a meta-analysis of large, randomized, controlled trials vs warfarin. AB - BACKGROUND: Warfarin reduces ischemic stroke in atrial fibrillation, but has numerous limitations. Novel oral anticoagulants provide more predictable anticoagulation with fewer shortcomings. HYPOTHESIS: Novel oral anticoagulants are superior to warfarin to prevent stroke or systemic embolism. METHODS: Phase III randomized warfarin-controlled trials enrolling >3000 patients that reported clinical efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation were identified from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through October 2012. Two reviewers extracted data; differences were resolved by consensus. The end points analyzed were stroke or systemic embolism (primary efficacy composite); all-cause mortality, ischemic stroke, systemic embolism (individually, secondary efficacy); and hemorrhagic stroke, major bleeding (individually, safety). The Mantel-Haenszel method was used to calculate pooled relative risk (RR) and 95% confidence intervals (CI) from fixed-effects (if homogenous) or random-effects models (if heterogeneous). RESULTS: In 5 studies of 51895 patients, the composite of stroke or systemic embolism (RR: 0.82; 95% CI: 0.69-0.98; P = 0.03) and all-cause mortality (RR: 0.91; 95% CI: 0.85-0.96; P = 0.0026, respectively) were reduced with the novel agents. Factor Xa inhibitors significantly reduced the primary composite (RR: 0.84; 95% CI: 0.74-0.94; P = 0.004) and all-cause mortality (RR: 0.91; 95% CI: 0.84 - 0.98; P = 0.01). Direct thrombin inhibitor achieved results similar to the overall meta-analysis (drug class-outcome interactions P = 0.47 for primary outcome, P = 1.00 for mortality). Compared with warfarin, novel anticoagulants markedly reduced hemorrhagic stroke (RR: 0.51; 95% CI: 0.41-0.64; P < 0.0001). CONCLUSIONS: Novel oral anticoagulants may be superior to warfarin in patients with atrial fibrillation, reducing the composite of stroke or systemic embolism and lowering all-cause mortality. The benefit is largely due to fewer hemorrhagic strokes. PMID- 23338903 TI - Body mass index, smoking, and risk of death between 40 and 70 years of age in a Norwegian cohort of 32,727 women and 33,475 men. AB - Overweight-obesity and smoking are two main preventable causes of premature death. Because the relationship between smoking and body mass index (BMI) complicates the interpretation of associations between BMI and death risks, direct estimates of risks associated with joint exposures are helpful. We have studied the relationships of BMI and smoking to middle age (40-69 years) death risk-overall and by causes-in a Norwegian cohort of 32,727 women and 33,475 men who were 35-49 years old when baseline measurements and lifestyle information were collected in 1974-1988. Individuals with a history of cancer, cardiovascular disease or diabetes at baseline were excluded. Mortality follow-up was through 2009. The relationship between BMI and middle age death risk was U-shaped. Overall middle age death risks were 11% in women and 21 % in men. The combination of obesity and heavy smoking resulted in fivefold increase in middle age death risks in both women and men: For women middle age death risk ranged from 6 % among never smokers in the 22.5-24.9 BMI group to 31% (adjusted 28%) in obese (BMI > 30 kg/m(2)) heavy smokers (>=20 cigarettes/day). The corresponding figures in men were 10% and 53% (adjusted 45%). Obese never smokers and light (1-9 cigarettes/day) smokers in the 22.5-24.9 BMI groups both experienced a twofold increase in middle age risks of death. For women, cancer (56%) was the most common cause of death followed by cardiovascular disease (22%). In men, cardiovascular disease was most common (41%) followed by cancer (34%). Cardiovascular disease deaths were more strongly related to BMI than were cancer deaths. PMID- 23338904 TI - Depressive symptoms, antidepressants and disability and future coronary heart disease and stroke events in older adults: the Three City Study. AB - To investigate the association between baseline depressive symptoms and first fatal and non fatal coronary heart disease (CHD) and stroke in older adults, taking antidepressants and disability into account. In the Three City Study, a community-based prospective multicentric observational study cohort, 7,308 non institutionalized men and women aged >=65 years with no reported history of CHD, stroke or dementia, completed the 20-item Center for Epidemiologic Studies depression scale (CESD) questionnaire. First CHD and stroke events during follow up were adjudicated by an independent expert committee. Hazard ratios (HRs) were estimated by Cox proportional hazard model. After a median follow-up of 5.3 years, 338 subjects had suffered a first non-fatal CHD or stroke event, and 82 had died from a CHD or stroke. After adjustment for study center, baseline socio demographic characteristics, and conventional risk factors, depressive symptoms (CESD >= 16) were associated with fatal events only: fatal CHD plus stroke (HR = 2.50; 95% CI 1.57-3.97), fatal CHD alone (n = 57; HR = 2.21 ; 95%CI 1.27-3.87), and fatal stroke alone (n = 25; HR = 3.27; 95% CI 1.42-7.52). These associations were even stronger in depressed subjects receiving antidepressants (HR = 4.17; 95% CI 1.84-9.46) and in depressed subjects with impaired Instrumental Activities of Daily Living (HR = 8.93; 95% CI 4.60-17.34). By contrast, there was no significant association with non fatal events (HR for non-fatal CHD or stroke = 0.94; 95% CI 0.66-1.33). In non-institutionalized elderly subjects without overt CHD, stroke or dementia, depressive symptoms were selectively and robustly associated with first fatal CHD or stroke events. PMID- 23338905 TI - Osteoporosis and milk intake among Korean women in California: relationship with acculturation to U.S. lifestyle. AB - The Korean population in the US increased by a third between 2000 and 2010. Korean women in the US report low calcium intake and relatively high rate of fractures. However, little is known about the prevalence of osteoporosis among Korean American women. This paper examined the relationship between prevalence of osteoporosis and milk consumption, and their relationship with acculturation among a representative sample of immigrant California women of Korean descent. Bilingual telephone surveys were conducted from a probability sample (N = 590) in 2007. Lower acculturation significantly related to lower milk consumption for women during the age periods of 12-18 and 19-34 years. Acculturation was related to higher prevalence of osteoporosis among post-menopausal, but not pre menopausal Korean women in California. Future research should include larger cohorts, objective measures of osteoporosis, other sources of calcium specific to Korean cuisine, and assessment of bone-loading physical activity. PMID- 23338906 TI - Strategies to recruit minority persons: a systematic review. AB - To identify and describe strategies used to recruit persons of ethnically and culturally diverse backgrounds and to examine their reported effectiveness. Studies (n = 26) reporting on recruitment of persons of different cultural and ethnic backgrounds, published in English between 1995 and 2012, were included in this systematic review. Data on the type of recruitment strategies and overall reported effectiveness of the strategy in recruiting participants were extracted. The vote counting method was used to synthesize the findings on effectiveness. Both proactive (face-to-face) and reactive recruitment strategies (collaboration with key leaders, snowball and word of mouth, printed material, and broadcast media) and providing compensation, being flexible, building rapport and trust, and employing ethnically and culturally diverse research staff were effective in recruiting participants. A list of strategies that are effective in recruiting persons of diverse ethnic and cultural backgrounds were generated. Researchers can select the evidence-based strategies that are most applicable in the context of their study. PMID- 23338907 TI - Peripartum cardiomyopathy: when labour turns to heartbreak. PMID- 23338908 TI - ECG P wave abnormalities. AB - P wave abnormalities are commonly found on ECG. However, they are seldom discussed and may also be neglected during ECG interpretion. In this article, we discuss two common types of P wave abnormalities, 'P mitrale' and 'P pulmonale'. The former was found in a patient with mitral valve stenosis, while the latter was from a patient with pulmonary hypertension. Echocardiography is important in evaluating the causes of P wave abnormalities. PMID- 23338909 TI - Sun Yat-sen (1866-1925): physician revolutionist. PMID- 23338910 TI - Doctor, my dentist wants your opinion. AB - Dental surgery is very common, and it is important for our dental colleagues to understand the medical history and chronic medications of our co-managed patients. Antibiotic prophylaxis is currently recommended only for patients at high risk for infective endocarditis when undergoing high-risk dental procedures. Good dental hygiene can prevent more infective endocarditis than prophylactic antibiotic therapy, as transient bacteraemia is common in daily activities such as the brushing and flossing of teeth. Most dental surgeries can generally be performed on patients taking a daily dose of aspirin, but the dentist must be able to assess the risk-benefit ratio of employing local measures of haemostasis versus stopping the antiplatelet therapy. Patients on antiplatelet with recent coronary artery stenting should be referred to their primary cardiologist regarding the cessation of these agents before any surgery. PMID- 23338911 TI - Coronary computed tomography angiography with prospective electrocardiography triggering: a systematic review of image quality and radiation dose. AB - The purpose of this study was to perform a systematic review of the diagnostic accuracy, image quality and radiation dose of prospective electrocardiography (ECG)-triggered coronary computed tomography angiography (CCTA). We searched databases containing studies of CCTA that used prospective ECG-triggering between 2008 and 2011. The effective dose and image quality reported in each study were analysed and compared between the types of multislice CT scanners. We identified 23 studies through this search, with mean assessable coronary segments and effective dose at 96.8% (95% confidence level [CI] 83%, 100%) and 3.6 mSv (95% CI 2.9, 4.3 mSv), respectively. Both quantitative and qualitative assessments of image quality indicated that image quality was achieved in studies using prospective ECG-triggered CCTA, regardless of the type of CT scanners. The pooled estimates of diagnostic values were more than 90% for patient-, vessel- and segment-based assessments. Prospective ECG-triggered CCTA results in high diagnostic accuracy and image quality, with a significantly low radiation dose. PMID- 23338912 TI - Peripartum cardiomyopathy: experience in an Asian tertiary centre. AB - INTRODUCTION: Peripartum cardiomyopathy (PPCM) is a rare but life-threatening condition. We report 11 patients admitted to the National Heart Centre Singapore with a diagnosis of PPCM over a period of 14 months. METHODS: Baseline demographics, pregnancy history, haematology, serum biochemistry and echocardiographic findings of women admitted with a diagnosis of PPCM were analysed. RESULTS: The incidence of PPCM was 0.89 per 1,000 live births in our cohort. 63.6% of the patients were Malay and 27.3% were Chinese. 45.5% of the patients were smokers and 45.5% had a history of pregnancy-induced hypertension or preeclampsia. There was no maternal mortality. Mean left ventricular ejection fractions at diagnosis and at six months were 26.9% +/- 9.1% and 51.9% +/- 10.6%, respectively. Mean left ventricular internal diameters in end-diastole at diagnosis and at six months were 5.5 +/- 0.5 cm and 5.1 +/- 0.6 cm, respectively. All patients were treated successfully for the acute episode and all but one patient had returned to New York Heart Association functional class I status at six months. CONCLUSION: PPCM remains a rare condition and appears to occur more commonly in Malay patients. Smoking and pregnancy-induced hypertension appear to be significant risk factors. While short-term outcome remains excellent, collaborative studies with other tertiary centres will help enhance our understanding of the long-term management of and clinical outcomes in these patients. PMID- 23338913 TI - Favourable outcome after peripartum cardiomyopathy: a ten-year study on peripartum cardiomyopathy in a university hospital. AB - INTRODUCTION: Peripartum cardiomyopathy (PPCM) is an uncommon form of congestive heart failure, affecting obstetric patients around the time of delivery. The epidemiology of PPCM is infrequently reported. This study was undertaken to define the prevalence, presentation and outcome of PPCM among women giving birth in a teaching hospital in Malaysia. METHODS: A retrospective case record analysis was conducted on all patients admitted and diagnosed with PPCM at the University Malaya Medical Centre, Kuala Lumpur, Malaysia, from 1 January 2000 to 31 December 2009. All deliveries were undertaken in the same hospital. RESULTS: A total of 12 patients were diagnosed with PPCM during the ten-year study period. The prevalence of PPCM was 2.48 in 100,000 (1 in 40,322) live births. Nine women were diagnosed with PPCM within five months of delivery. Three women had twin pregnancies. There was one death in the group (mortality rate 8.3%). The mean left ventricular ejection fraction at the time of diagnosis was 28.9% +/- 8.5% (range 15%-40%). Following the index event, left ventricular function normalised in six of the nine patients (66.7%) who underwent subsequent echocardiography one year later. All patients were treated with standard heart failure therapy. Two patients with normalised left ventricular function had subsequent pregnancies - one pregnancy was terminated at seven weeks and the other patient delivered uneventfully at full term. CONCLUSION: PPCM is uncommon. The outcome in our series was favourable, with 66.7% of patients with PPCM recovering their left ventricular function. The mortality rate was 8.3%. PMID- 23338914 TI - Public perceptions, knowledge and awareness of cholesterol management in Singapore: a prospective pilot study. AB - INTRODUCTION: Hyperlipidaemia is a major risk factor for coronary artery disease (CAD). Its effective treatment has been shown to reduce the incidence of cardiovascular events, both in secondary and primary prevention. An essential component of risk factor management at the community level is public awareness and knowledge of treatment benefits. However, this data is limited in Singapore. METHODS: A cross-sectional survey questionnaire of public perception and knowledge on cholesterol treatment among adult Singaporeans aged 30-69 years was commissioned by the Singapore Heart Foundation and conducted by a professional market survey company. Regional quota sampling was performed to ensure that the sample was representative of the Singapore population. This was followed by random sampling of households and respondents. RESULTS: Of the 365 respondents, 40.9% were male, 70.3% were Chinese, 18.8% Malay and 10.9% Indian. The mean age was 47.5 years. Although 81.9% of respondents had medical check-ups involving blood tests, only 11.0% knew their actual cholesterol levels. A third of the respondents saw herbal medicine as healthier and safer than Western medication. More than 80% of respondents believed that diet and exercise were equally effective at lowering cholesterol as medication. About half of the respondents associated long-term use of statins with damage to the liver and kidney, while a third associated chronic statin use with the development of cancer. CONCLUSION: There are gaps in the level of public awareness and understanding of cholesterol treatment in Singapore. Common misconceptions should be addressed, as they could potentially impair effective management or treatment compliance. PMID- 23338915 TI - Demographics of severe valvular aortic stenosis in Singapore. AB - INTRODUCTION: The treatment of aortic valve stenosis (AS) is seeing renewed interest mainly due to the availability of transcatheter therapies. However, the number of epidemiological studies of this disease in Singapore is limited. We aimed to describe the aetiology and clinical presentation of AS in Singapore, as well as patients' attitudes toward it. Our findings may facilitate the future planning and utilisation of resources to better manage these patients. METHODS: 249 consecutive patients who underwent transthoracic echocardiography (from April 1999 to April 2008) and diagnosed with severe AS were assessed. Demographic and clinical data were collected, and patients' decisions on surgery were determined. RESULTS: The mean patient age was 71 (range 23-98) years. 50.2% of patients were male. The commonest presenting symptom was dyspnoea, and 40 (16.0%) patients had coexistent atrial fibrillation. The aetiology of AS was degenerative in 216 (86.7%), rheumatic in 11 (4.4%) and related to a bicuspid valve in 22 (8.9%) patients. The average peak velocity across the aortic valve was 4.2 +/- 0.8 m/s and the mean aortic valve area was 0.76 +/- 0.13 cm2. The overall mean logistic EuroSCORE was 10.7 +/- 12.3. 105 (42.2%) patients who were offered surgery refused. 87 (35%) deaths were seen during the follow-up period (mean duration 14.5 months), which also saw 68 (27%) patients undergo surgery and 86 (34%) patients hospitalised for heart failure. CONCLUSION: Degenerative AS was the commonest aetiology in this contemporary cohort of patients. Despite the known benefits of surgery, the refusal rate for surgery remained high. PMID- 23338916 TI - Relationship between leucocytosis and left ventricular ejection fraction in patients with acute myocardial infarction. AB - INTRODUCTION: Myocardial infarction (MI) is common and affects a significant number of people annually. Death occurs due to either arrhythmia or heart failure. As leucocytosis, especially elevated neutrophil count, is a hallmark of inflammatory reactions in patients with MI, we investigated the relationship between leucocytosis on admission and left ventricular ejection fraction (LVEF) in patients with acute MI (AMI). METHODS: Patients with AMI were enrolled in a case-control study. Blood samples obtained in the first 24 hours after the onset of pain were analysed for cardiac enzyme levels and cell count. Echocardiography was performed on Days 3-5. Patients with LVEF < 45% were assigned to the left ventricular (LV) systolic dysfunction group (n = 69) and those with LVEF >= 45% were taken as controls (n = 69). All patients were matched for variables such as hypertension, diabetes mellitus, hyperlipidaemia, family history of cardiac disease, age and gender. RESULTS: Leucocytosis was higher in patients with systolic dysfunction (47.8%) when compared with the controls (20.3%), and was significantly associated with the development of LV systolic dysfunction (p = 0.001). Similarly, neutrophilia was more common in patients with systolic dysfunction than the controls (6.6% vs. 34.8%), and was significantly associated with LV systolic dysfunction (p < 0.001). Monocytosis was higher in the controls than the systolic dysfunction group (40.6% vs. 33.3%; p = 0.378). CONCLUSION: Leucocytosis and neutrophilia in the acute phase of MI are important predictive factors for the development of LV systolic dysfunction. Leucocytosis can be used for risk stratification of such patients. PMID- 23338917 TI - Morphological variations of papillary muscles in the mitral valve complex in human cadaveric hearts. AB - INTRODUCTION: Papillary muscle rupture and dysfunction can lead to complications of prolapsed mitral valve and mitral regurgitation. Multiple operative procedures of the papillary muscles, such as resection, repositioning and realignment, are carried out to restore normal physiological function. Therefore, it is important to know both the variations and the normal anatomy of papillary muscles. METHODS: This study was carried out on 116 human cadaveric hearts. The left ventricles were opened along the left border in order to view the papillary muscles. The number, shape, position and pattern of the papillary muscles were observed. RESULTS: In this series, the papillary muscles were mostly found in groups instead of in twos, as is described in standard textbooks. Four different shapes of papillary muscles were identified - conical, broad-apexed, pyramidal and fan shaped. We also discovered various patterns of papillary muscles. CONCLUSION: No two mitral valve complexes have the same architectural arrangement. Each case seems to be unique. Therefore, it is important for scientists worldwide to study the variations in the mitral valve complex in order to ascertain the reason behind each specific architectural arrangement. This will enable cardiothoracic surgeons to tailor the surgical procedures according to the individual papillary muscle pattern. PMID- 23338918 TI - Anatomical variations in the left coronary artery and its branches. AB - INTRODUCTION: Proficiency in the anatomy of coronary arteries and their variations is important for proper interpretation of coronary angiographies. The left coronary artery (LCA) commonly originates at the level of the left posterior aortic sinus and normally bifurcates into the anterior interventricular artery and circumflex artery. This study aimed to determine the variations in the LCA and its branches. METHODS: The study was conducted on 30 heart specimens. We observed the origin, length and branching pattern of the LCA and its coronary dominance. RESULTS: We found a short main LCA trunk in three specimens and a long main LCA trunk in one specimen. In two specimens, the division of the LCA led to three branches. With regard to 'dominance', one specimen showed left dominance while another showed codominance. CONCLUSION: Variations of the LCA are clinically relevant, especially when a perioperative coronary perfusion or coronary arteriography is performed. PMID- 23338919 TI - Comment on: efficacy of omega-3 fatty acid supplementation on serum levels of tumour necrosis factor-alpha, C-reactive protein and interleukin-2 in type 2 diabetes mellitus patients. PMID- 23338920 TI - I speak, therefore I am. PMID- 23338923 TI - Catheter ablation of ventricular fibrillation storm in a long QT syndrome genotype carrier with normal QT interval. AB - Patients with long QT syndrome can sometimes present with a ventricular fibrillation (VF) storm. Catheter ablation of culprit premature ventricular complexes responsible for the triggering of the VF episodes may be required in rare cases of electrical storm that do not respond to conventional measures, and this can be life-saving. We describe a case of emergency catheter ablation in a young woman with a normal corrected QT interval, who presented with malignant VF storm for the first time. We also discuss the diagnostic and management challenges involved, as well as the value of genetic testing in refining the diagnosis. PMID- 23338924 TI - Churg-Strauss syndrome presenting with focal segmental glomerulosclerosis without proteinuria: response to unconventional therapy. AB - Churg-Strauss syndrome (CSS), or allergic granulomatosis, is a rare disease manifested by tissue infiltration, hypereosinophilia and vasculitis. Renal involvement may be seen in up to 50% of cases. We report the case of a 25-year old man who presented with a history of fever for two months, tingling, numbness, and paraesthesia of the upper limbs and left lower limb, along with diarrhoea for one month and an inability to walk for the past seven days. Serial laboratory investigations helped to reach the final diagnosis of CSS with mononeuritis multiplex, and skin, pulmonary and gastrointestinal involvement with hypertension. This is due to renal involvement in the form of focal segmental glomerulosclerosis without any nephrotic range proteinuria, which is a very rare clinical entity. The patient's symptoms were relieved after the administration of an unconventional mode of therapy. PMID- 23338925 TI - Do intercultural factors play a role in exacerbating psychiatric symptoms? AB - We report the case of a 29-year-old mixed-race woman suffering from recurrent major depressive episodes, with suicidal ideation and risk, involving several inpatient admissions. A comorbid diagnosis of borderline personality disorder was also recorded in one of her previous inpatient admissions. During her last inpatient admission, a multidisciplinary case discussion and review of the patient's life highlighted several possible intercultural trigger factors that could have contributed to the exacerbation of her psychiatric illness. We emphasise the need to explore intercultural predisposing and precipitating factors for a more complete psychodynamic understanding of psychiatric illnesses among the multiracial population of Singapore. This also adds to the discussion on the management of such patients with the option of formal in-depth psychotherapy in adjunct to medication. This may prevent recurrent relapses, modify suicide intent and reduce the necessity for inpatient treatment, which will be cost-effective and result in efficacious treatment. PMID- 23338926 TI - A case of Gitelman syndrome with severe hyponatraemia and hypophosphataemia. AB - Gitelman syndrome (GS) is a renal tubular disorder of the thiazide-sensitive sodium chloride cotransporter, which is located in the distal tubule of the loop of Henle. We present a rare case of GS complicated by severe hyponatraemia and hypophosphataemia. A 17-year-old boy was admitted to our institution with fever and lethargy. The workup revealed typical features of GS, i.e. hypokalaemia, hypomagnesaemia and metabolic alkalosis. In this report, we discuss the differential diagnoses and rationale for accepting GS as the most likely diagnosis. This case was complicated by severe hyponatraemia (115 mmol/L) and hypophosphataemia (0.32 mmol/L). We concluded that the syndrome of inappropriate secretion of antidiuretic hormones could not be ruled out and that respiratory alkalosis was the most likely aetiology of hypophosphataemia. This case report also generates an interesting discussion on water and electrolyte metabolism. PMID- 23338927 TI - Strumal carcinoid tumour of the ovary presenting with severe constipation. AB - A 30-year-old single woman presented with an incidental finding of abdominal mass associated with severe constipation. Her cancer antigen-25, alpha-foetoprotein and beta human chorionic gonadotropin levels were normal, but her carcinoembryonic antigen level was raised at 7.6 g/dL. Magnetic resonance imaging showed a 11.4 cm * 8.6 cm * 9.5 cm right ovarian mass with solid and cystic areas. An open right cystectomy was performed. Intraoperatively, she was found to have hirsutism and clitoromegaly. During the operation, there was a right ovarian 10-cm mass, with faecal loading from the caecum to the transverse colon. The uterus, fallopian tubes, left ovary and intraperitoneal survey were normal. Final histology confirmed strumal carcinoid tumour Stage 1A. This case report shows that a strumal carcinoid tumour can present with longstanding constipation as a patient's main complaint and may also be associated with hirsutism. PMID- 23338928 TI - Challenges in the management of aortic coarctation in the elderly: native coarctation complicated by severe calcification. AB - Although the treatment of aortic coarctation in adults with the use of stents has shown favourable results and reduced complications, there have been few studies involving elderly patients. We highlight the clinical challenges faced in the management of such patients, with attention to severe calcification at the coarctation site. The midterm results were good in our patient, showing an improvement in blood pressure control and maintenance of stent patency. PMID- 23338929 TI - Percutaneous mitral valve repair with MitraClip for severe functional mitral regurgitation. AB - A 67-year-old Chinese woman with comorbidities of chronic obstructive lung disease, hypertension and prior coronary artery bypass surgery presented with severe functional mitral regurgitation (MR) and severely depressed left ventricular function. She was in New York Heart Association (NYHA) Class II-III. Due to high surgical risk, she was referred for percutaneous treatment with the MitraClip valve repair system. This procedure is typically performed via the femoral venous system and involves a transseptal puncture. A clip is delivered to grasp the regurgitant mitral valve leaflets and reduce MR. This was performed uneventfully in our patient, with reduction of MR from 4+ to 1+. She was discharged on post-procedure Day 2 and her NYHA class improved to Class I. This was the first successful MitraClip procedure performed in Asia and represents a valuable treatment option in patients with severe MR, especially those with functional MR or those at high surgical risk. PMID- 23338931 TI - Detection of African swine fever virus-like sequences in ponds in the Mississippi Delta through metagenomic sequencing. AB - Metagenomic characterization of water virome was performed in four Mississippi catfish ponds. Although differing considerably from African swine fever virus (ASFV), 48 of 446,100 sequences from 12 samples were similar enough to indicate that they represent new members in the family Asfarviridae. At present, ASFV is the only member of Asfarviridae, and this study presents the first indication of a similar virus in North America. At this point, there is no indication that the identified virus(es) pose a threat to human or animal health, and further study is needed to characterize their potential risks to both public health and agricultural development. PMID- 23338932 TI - DTaP-IPV-Hep B-Hib vaccine (Hexaxim(r)) : a review of its use in primary and booster vaccination. AB - Hexaxim((r)) (DTaP-IPV-Hep B-Hib) is a new, thiomersal-free, fully liquid, hexavalent combination pediatric vaccine containing diphtheria and tetanus toxoids, acellular pertussis, inactivated poliovirus, recombinant hepatitis B virus surface antigen produced in the yeast Hansenula polymorpha, and Haemophilus influenzae type b polysaccharide (polyribosylribitol phosphate) conjugated to tetanus toxoid. It is currently registered in markets outside of the EU for primary vaccination of infants from 6 weeks of age and for booster vaccination up to 24 months of age. In randomized controlled trials, primary vaccination of infants with Hexaxim((r)) using various immunization schedules was highly immunogenic for all vaccine component antigens regardless of the administration schedule, producing high levels of seroprotection or seroconversion for each antigen. Hexaxim((r)) was as immunogenic as the comparator DTwP- or DTaP-based vaccines in these studies. The serological responses were generally sustained at high levels over a follow-up of ~1 year, and booster vaccination at 15-18 months further enhanced the immune response. Hexaxim((r)) was less reactogenic than a DTwP-based combination vaccine, and displayed a tolerability profile similar to those of the comparator DTaP-based combination vaccines. Thus, Hexaxim((r)) provides effective seroprotection or seroconversion against six major childhood diseases simultaneously, both as primary and booster vaccination, and offers the benefits and convenience of a fully liquid, ready-to-use vaccine. PMID- 23338935 TI - Bayes and base rates: what is an informative prior for actuarial violence risk assessment? AB - Bayes' theorem describes an axiomatic relationship among marginal and conditional proportions within a single "experiment." In many ways, it has been fruitful to greatly extend this idea to the task of drawing inferences from data much more generally. Commonly, what matters is how all prior knowledge is revised (or not) by new findings resulting in posterior (sometimes "subjective") probabilities. And, to address many important problems, it is sensible to conceive of probability in such subjective terms. However, some commentators in the domain of violence risk assessment have assumed an analogous axiomatic relationship among marginals (i.e., priors in the form of base rates) observed in one study and conditionals (i.e., posteriors in the form of revised rates) expected in a separate study or assessment context. We present examples from our own research to suggest this assumption is generally unwarranted and ultimately an unaddressed empirical matter. PMID- 23338936 TI - Influence of edentulism on human orbit and zygomatic arch shape. AB - Edentulism, or tooth loss, seriously alters the appearance of the lower facial skeleton. The aim of this study was to determine if complete maxillary edentulism also impacts the curvature shape of the orbits and zygomatic arches in elderly adults. The study was conducted on 80 crania comprising two cross-sectional populations of elderly African- and European-Americans (60-80 years old). Forty of the crania possessed intact dentition; the remaining 40 exhibited complete edentulism with tooth socket resorption. Three-dimensional semilandmarks representing the curvature of the orbits and zygomatic arches were collected using a hand-held digitizer. Each craniofacial region's semilandmarks were aligned into a common coordinate system via generalized Procrustes superimposition. Regional variation in shape was explored via principal component analysis, multivariate analysis of variance, discriminant function analysis, cross-validation, and vector plots. Shape differences between the edentulous and dentate groups were detected in both the orbits (P = 0.0022) and zygomatic arches (P = 0.0026). Ancestry and sex differences were also identified in both regions. Orbit data correctly classified dentate crania 65% of the time and edentulous crania 72.5% of the time. Zygomatic arch data correctly classified 75% dentate and 60% of edentulous crania. The individual curves constituting each region also exhibited shape alteration with tooth loss, with the exception of the inferior zygomatic curve. Vector plots revealed patterns of superoinferior expansion, and medial and lateral recession depending on the region examined. These results suggest a relationship exists between maxillary edentulism and changes in the surrounding craniofacial structures. PMID- 23338938 TI - In vivo confocal microscopy in dermatology: from research to clinical application. AB - Confocal laser scanning microscopy (CLSM) represents an emerging technique for the noninvasive histomorphological analysis of skin in vivo and has shown its applicability for dermatological research as well as its value as an adjunct tool in the clinical management of skin cancer patients. Herein, we aim to give an overview on the current clinical indications for CLSM in dermatology and also highlight the diverse applications of CLSM in dermatological research. PMID- 23338937 TI - Differentiation of human endometrial stromal cells into oligodendrocyte progenitor cells (OPCs). AB - Oligodendrocytes are myelinating cells in the central nervous system that form the myelin sheath of axons to support rapid nerve conduction. Human endometrial stromal cells (EnSCs) are the abundant and easy available source for cell replacement therapy. In the present study, the EnSCs were coaxed to oligodendrocyte progenitor programming by induction of neuronal condition media, including bFGF, epidermal growth factor, and platelet-derived growth factor (PDGF)-AA signaling molecules as well as triiodothyronine. Differentiated cells were analyzed for expression of oligodendrocytic markers by quantitative reverse transcription PCR and immunocytochemistry. The results showed the expression of oligodendrocyte lineage markers such as nestin, PDGF receptor alpha (PDGFRalpha), Sox10, and Olig2 in the level of mRNAs. The expression of nestin and PDGFRalpha increased after 8 days posttreatment. Interestingly, the expression of nestin and PDGFRalpha genes at the levels of mRNA and proteins decreased 24 days after induction. The expression of A2B5, O4, and Olig2 proteins in EnSCs was confirmed using immunocytochemistry. The results confirmed that EnSCs could response to the signaling molecules which routinely applied for oligodendrocyte differentiation. Here for the first time, we demonstrated that EnSCs could be programmed into oligodendrocyte progenitor cells and may convince to consider these cells as suitable source for cell therapy of neurodegenerative diseases. PMID- 23338939 TI - Jahn-Teller instability in cationic boron and carbon buckyballs B80+ and C60+: a comparative study. AB - This paper investigates the Jahn-Teller effect in the icosahedral cation B(80)(+) and compares the descent in symmetry with that in C(60)(+). For both cations the icosahedral ground state is a (2)H(u) state, which exhibits a H ? (g ? 2h) Jahn Teller instability. A detailed construction of the potential energy surface of B(80)(+) using different DFT methods including B3LYP/6-31G(d), VWN/6-31G(d), PBE/TZP and PBE/6-31G(d) shows that, contrary to C(60)(+), which prefers D(5d) symmetry, the ground state of B(80)(+) adopts S(6) point group symmetry. A D(3d) structure is identified as a saddle point among the S(6) minima of B(80)(+). The distortion of D(3d) to S(6) in B(80)(+) is attributed to a superposition of Jahn Teller and pseudo-Jahn-Teller effects. Imaginary modes, transforming as the g(g) representation, which are present in neutral icosahedral B(80), form the dominant symmetry breaking active modes. The pronounced difference between the JT effects in the boron and carbon buckyball cations is due to the plasticity of the boron caps. The calculated Jahn-Teller stabilization of B(80)(+) is nearly 1549 cm(-1) (PBE/TZP), which exceeds the stabilization of 596 cm(-1) computed for C(60)(+) at the same level. PMID- 23338940 TI - Truncation of murine CaV1.2 at Asp 1904 increases CaV1.3 expression in embryonic atrial cardiomyocytes. AB - Cardiac CaV1.2 channels play a critical role in cardiac function. It has been proposed that the carboxyl-terminal intracellular tail of the CaV1.2 channel is the target of Ca(2+)-dependent and Ca(2+)-independent regulation of the channel. Recent studies on C-terminal truncated forms of the CaV1.2 channel reported neonatal death, reduced CaV1.2 current, and failure of beta-adrenergic stimulation of these channels in ventricular cardiomyocytes (CMs). Here, we used atrial CMs at embryonic day 18.5 that expressed a C-terminal truncated form of the CaV1.2 channel (Stop/Stop). Surprisingly, the atrial CMs showed robust L-type Ca(2+) currents which could be stimulated by forskolin, an activator of adenylyl cyclase. These currents exhibited a left-ward shift in the voltage-dependent activation curve and a reduced sensitivity to the Ca(2+) channel blocker isradipine as compared to currents in wild-type atrial CMs. RT-PCR analysis revealed normal levels of mRNA for the CaV1.2 channel but a twofold increase in the level of mRNA for the CaV1.3 channel in the Stop/Stop atrium as compared to wild-type atrium. A Western blot analysis indicated an increase of CaV1.3 protein in the Stop/Stop atrium. We suggest that, in contrast to Stop/Stop ventricular CMs, Stop/Stop atrial CMs can compensate the functional loss of the truncated CaV1.2 channel with an upregulation of the CaV1.3 channel. PMID- 23338941 TI - The IGF-1 receptor and regulation of nitric oxide bioavailability and insulin signalling in the endothelium. AB - The insulin-like growth factor-1 receptor (IGF-1R), like the insulin receptor (IR), plays a significant role in determining bioavailability of the critical signalling molecule nitric oxide (NO) and hence, modulates endothelial cell function, particularly in response to stimulation with insulin. In particular, the ability of the IGF-1R to form hybrid receptors with the IR appears to be highly significant in determining the sensitivity of the endothelial cell to insulin. This review will examine the structure of the IGF-1R and how this, with particular reference to the ability of the IGF-1R and the IR to form hybrid receptors, may have an effect both on endothelial cell function and the development of cardiovascular disease. PMID- 23338942 TI - Intracellular distribution of the DeltaNp73 protein isoform in medulloblastoma cells: a study with newly generated rabbit polyclonal antibodies. AB - The p73 protein is a member of the p53 family of transcription factors that has two N-terminal isoforms: the TAp73 isoform is reported to have a tumor suppressor function, whereas the DeltaNp73 isoform likely has oncogenic potential. The expression of these isoforms and the differences in their intracellular distribution have been described in many cancer types; however, little is known about the p73 isoforms in brain tumors. Our study is focused on the intracellular localization of DeltaNp73 in medulloblastoma cell lines. Due to a lack of suitable anti-DeltaNp73 antibodies, we developed two new rabbit polyclonal antibodies, DeltaNp73-26 and DeltaNp73-27, with sufficient specificity, as demonstrated by immunodetection methods using transiently transfected cell lines. Both of these new antibodies were subsequently used for analysis of the DeltaNp73 distribution in medulloblastoma cells using immunofluorescence, immunoblotting and immunogold labeling for transmission electron microscopy. We found a nuclear localization of the DeltaNp73 isoform in all of the medulloblastoma cell lines included in this study. Furthermore, a non-random accumulation of the DeltaNp73 isoform near the cell nuclei was observable in all of these cell lines. By double labeling with DeltaNp73 and golgin-97, we showed the co-localization of the DeltaNp73 isoform with the Golgi apparatus. Nevertheless, further detailed analyses of possible interactions of DeltaNp73 with the proteins accumulated in the Golgi apparatus should be performed to explain the dynamics of DeltaNp73 outside the cell nucleus. PMID- 23338943 TI - Effects of dronedarone started rapidly after amiodarone discontinuation. AB - BACKGROUND: Multiple studies have shown that amiodarone is effective in treating atrial fibrillation (AF), but is associated with a relatively high incidence of side effects; however, due to amiodarone's long elimination half-life (20-100 days), physicians may hesitate to start other drugs until it has fully cleared. HYPOTHESIS: A rapid switch from amiodarone to dronedarone is feasible. METHODS: EURIDIS and ADONIS were double-blind, multinational, parallel-group trials comparing the efficacy and safety of dronedarone with placebo over 12 months. This retrospective subanalysis of EURIDIS/ADONIS compared the effects of dronedarone in patients discontinuing amiodarone within 2 days before randomization ("rapid switch") with results in patients who had received no amiodarone during the 2 months preceding randomization. RESULTS: In total, 1237 patients were enrolled ("rapid switch", n = 154; "no amiodarone", n = 1014). In both the "rapid switch" and the "no amiodarone" groups, dronedarone users had significantly lower AF recurrence than patients receiving placebo (HR = 0.64, 95% CI, 0.44-0.95; P = 0.0224 and HR = 0.79, 95% CI, 0.67-0.92; P = 0.0027, respectively). Dronedarone users had a higher incidence of bradyarrhythmic events than placebo-treated patients. A "rapid switch" from amiodarone to dronedarone was associated with a higher incidence of serious heart failure events and heart failure hospitalizations versus all other groups. Overall event rates were low and there was no significant difference in total adverse event rates or deaths between groups. CONCLUSION: In this patient population, a switch from amiodarone to dronedarone within a 2-day time frame might be feasible in certain patient categories, but further investigation is warranted. PMID- 23338944 TI - A cyclopalladated complex of corannulene with a pyridine pendant and its columnar self-assembly. AB - Bowl-shaped corannulene provides various metal binding modes with its curved pi surfaces and rim. Herein, we report the syntheses of 2-pyridylcorannulene and its cyclopalladated complex. Its expanded pi-system and columnar self-assembly in the crystal state were revealed by NMR and UV-vis spectroscopies, ESI-TOF mass spectrometry and single-crystal X-ray analysis. PMID- 23338945 TI - Transcriptional profiling of human endogenous retrovirus group HERV-K(HML-2) loci in melanoma. AB - Recent studies suggested a role for the human endogenous retrovirus (HERV) group HERV-K(HML-2) in melanoma because of upregulated transcription and expression of HERV-K(HML-2)-encoded proteins. Very little is known about which HML-2 loci are transcribed in melanoma. We assigned >1,400 HML-2 cDNA sequences generated from various melanoma and related samples to genomic HML-2 loci, identifying a total of 23 loci as transcribed. Transcription profiles of loci differed significantly between samples. One locus was found transcribed only in melanoma-derived samples but not in melanocytes and might represent a marker for melanoma. Several of the transcribed loci harbor ORFs for retroviral Gag and/or Env proteins. Env-encoding loci were transcribed only in melanoma. Specific investigation of rec and np9 transcripts indicated transcription of protein encoding loci in melanoma and melanocytes hinting at the relevance of Rec and Np9 in melanoma. UVB irradiation changed transcription profiles of loci and overall transcript levels decreased in melanoma and melanocytes. We further identified transcribed HML-2 loci formed by reverse transcription of spliced HML-2 transcripts by L1 machinery or in a retroviral fashion, with loci potentially encoding HML-2-like proteins. We reveal complex, sample-specific transcription of HML-2 loci in melanoma and related samples. Identified HML-2 loci and proteins encoded by those loci are particularly relevant for further studying the role of HML-2 in melanoma. Transcription of HERVs appears as a complex mechanism requiring specific studies to elucidate which HERV loci are transcribed and how transcribed HERVs may be involved in disease. PMID- 23338946 TI - G-Protein coupled receptor 64 promotes invasiveness and metastasis in Ewing sarcomas through PGF and MMP1. AB - Metastatic spread in Ewing sarcomas (ES) is frequent and haematogenous. G-protein coupled receptor 64 (GPR64), an orphan receptor with normal expression restricted to human epididymis is specifically over-expressed in ES among sarcoma, but also up-regulated in a number of carcinomas derived from prostate, kidney or lung. Inhibition of GPR64 expression in ES by RNA interference impaired colony formation in vitro and suppressed local tumour growth and metastasis in Rag2(-/-) gammaC (-/-) mice. Microarray analysis after GPR64 knock down revealed a GPR64 mediated repression of genes involved in neuronal development like SLIT, drosophila, homolog of, 2 (SLIT2), and genes regulating transcription including pre-B cell leukemia homeobox 2 (PBX2). Concurrently, the suppression of GPR64 increased ES susceptibility to TRAIL induced apoptosis. Moreover, a GPR64 mediated induction of placental growth factor (PGF) in ES was observed. PGF suppression by RNA interference resulted in a reduction of metastatic growth similar to that observed after GPR64 knock down. Importantly, inhibition of GPR64 as well as PGF expression was associated with a reduced expression of matrix metalloproteinase (MMP) 1 and invasiveness in vitro. Furthermore, MMP1 knock down abrogated lung metastasis in Rag2(-/-) gammaC (-/-) mice. Thus, GPR64 expression in ES maintains an immature phenotype that is less sensitive to TRAIL-induced apoptosis and via its up-regulation of PGF and MMP1 orchestrates and promotes invasiveness and metastatic spread. PMID- 23338947 TI - Infantile hemangiomas: an update. AB - Infantile hemangioma (IH) is a common vascular tumor of infancy. Although benign, infants with IH can experience complications including ulceration, visual and airway impairment, and residual scarring and disfigurement. It is often challenging for clinicians to predict which tumors are in need of systemic treatment. However, data from various demographic and other studies have revealed further insights into this tumor. This article reviews the identification, evaluation, and management of high-risk IHs, including the indications for treatment and the use of systemic treatments such as corticosteroids, beta blockers, and vincristine. PMID- 23338948 TI - Hippocampal damage and alterations of inflammatory cytokine expression in mice caused by exposure to cerium chloride. AB - Rare earth element (REE) exposure has been shown to induce central nerve system intoxication, but the molecular mechanisms by which this occurs are poorly understood. In this study, cerium (Ce), in the form of CeCl3, was administered by way of gavage to mice for 90 consecutive days, and cytokine expression, associated with neuroinflammation of hippocampus, as well as spatial memory were increased in mice. Significant Ce accumulation in hippocampus, which led to neuroinflammation and decreased spatial memory of mice, was observed. Furthermore, CeCl3 remarkably increased levels of Toll-like receptors 2 and 4, tumor necrosis factor-alpha, nucleic IkappaB kinase, factor-kappaB-inducible kinase, nucleic factor-kappaB, and p52 and p65 expression as well as significantly decreased levels of IkappaB and interleukin-2 expression. These results showed that neuroinflammation and damaged hippocampal function may be associated with CeCl3-induced neuerotoxicity. Our findings suggest the need for workers and consumers to exercise caution when handling REEs. PMID- 23338950 TI - Recombinant Ganoderma lucidum immunomodulatory protein modified with polyethylene glycol. AB - Recombinant Ganoderma lucidum immunomodu-latory protein (rLZ-8) expressed using the Pichia yeast eukaryotic expression system is a potential new drug for cancer therapy; however, it has a short half-life in the body. In order to optimize the potency and stability of rLZ-8, we modified the recombinant protein chemically using methoxy-PEG-succinimidyl propionate (mPEG-SPA). The results indicated that several parameters, including pH, the molar ratio of rLZ-8 to mPEG-SPA and time, played crucial roles in the modification process. In particular, when the molar ratio of rLZ-8 to mPEG-SPA was 1:1, rLZ-8 was modified by a single mPEG-SPA moiety. In addition, MALDI-TOF/TOF and ESI Q-Trap results revealed that the difference in molecular weight (MW) between the peptide-linked mPEG-SPA and the mPEG-SPA closely matched the MW of a methionine amino acid. Taken together, these data suggest that modification of mPEG-SPA occurred on the N-terminal helix of rLZ-8. This modification method has laid a foundation for the development of long acting formulations of rLZ-8. PMID- 23338949 TI - Metals and breast cancer. AB - Metalloestrogens are metals that activate the estrogen receptor in the absence of estradiol. The metalloestrogens fall into two subclasses: metal/metalloid anions and bivalent cationic metals. The metal/metalloid anions include compounds such as arsenite, nitrite, selenite, and vanadate while the bivalent cations include metals such as cadmium, calcium, cobalt, copper, nickel, chromium, lead, mercury, and tin. The best studied metalloestrogen is cadmium. It is a heavy metal and a prevalent environmental contaminant with no known physiological function. This review addresses our current understanding of the mechanism by which cadmium and the bivalent cationic metals activate estrogen receptor-alpha. The review also summarizes the in vitro and in vivo evidence that cadmium functions as an estrogen and the potential role of cadmium in breast cancer. PMID- 23338951 TI - The effects of low frequency noise on mental performance and annoyance. AB - Low frequency noise (LFN) as background noise in urban and work environments is emitted from many artificial sources such as road vehicles, aircraft, and air movement machinery including wind turbines, compressors, and ventilation or air conditioning units. In addition to objective effects, LFN could also cause noise annoyance and influence mental performance; however, there are no homogenous findings regarding this issue. The purpose of this research was to study the effects of LFN on mental performance and annoyance, as well as to consider the role of extraversion and neuroticism on the issue. This study was conducted on 90 students of Iran University of Medical Sciences (54 males and 36 females). The mean age of the students was 23.46 years (SD = 1.97). Personality traits and noise annoyance were measured by using Eysenck Personality Inventory and a 12 scale self-reported questionnaire, respectively. Stroop and Cognitrone computerized tests measured mental performance of participants each exposed to 50 and 70 dBA of LFN and silence. LFNs were produced by Cool Edit Pro 2.1 software. There was no significant difference between mental performance parameters under 50 and 70 dBA of LFN, whereas there were significant differences between most mental performance parameters in quiet and under LFN (50 and 70 dBA). This research showed that LFN, compared to silence, increased the accuracy and the test performance speed (p < 0.01). There was no association between LFN and noise annoyance (p > 0.01). Introverts conducted the tests faster than extraverts (p < 0.05). This research showed that neuroticism does not influence mental performance. It seems that LFN has increased arousal level of participants, and extraversion has a considerable impact on mental performance. PMID- 23338952 TI - Accounting for misalignments and thermal fluctuations in fluorescence correlation spectroscopy experiments on membranes. AB - Several authors have exploited the ability of the fluorescence correlation spectroscopy to probe motion at the molecular level. In a couple of decades, all their efforts have allowed the application of this technique even to the diffusion measurement of cellular components. Nowadays, the fluorescence correlation spectroscopy is considered a standard tool to measure diffusion in cells both in vivo and in vitro. Unfortunately, while the interpretation and the set-up have been consolidated for 3D diffusion measurements (i.e. diffusion in an aqueous solution), the experiments carried out on flat elements, such as membranes, show unusually high relative errors. Furthermore, long tail correlations are generally detected and ascribed to diffusion anomalies. The 2D fluorescence correlation measurements have been interpreted under certain hypotheses, whereby the membrane is assumed to be perfectly flat, motionless and aligned with the optical axes. Here, we investigated the robustness of these hypotheses, trying to understand, in an elementary but not trivial way, how misalignments and thermal fluctuations affect the temporal correlation of the intensity fluctuation collected during measurements on membranes. PMID- 23338953 TI - Season of birth bias and bulimia nervosa--results from a multi-centre collaboration. AB - BACKGROUND: Season of birth bias has been observed for people with a number of disorders, including women with bulimia nervosa. However, inconsistent results and methodological weaknesses render previous conclusions about such bias uncertain. With an enhanced methodology, this study aims to test whether there is a season of birth bias for women with bulimia nervosa. METHOD: Women with bulimia nervosa at five secondary and tertiary services in Norway, born between 1966 and 1988 (n = 549), were compared with women in the general population in a chi square test for contingency tables, with known population parameters testing monthly deviations. RESULTS: There was no statistically significant association between month of birth and the distribution of births in the two groups (Cramer's V = .09). CONCLUSION: There appears not to be any season of birth bias in women with bulimia nervosa in Norway. PMID- 23338955 TI - How to distinguish between inconsistencies in CTA results and DSA findings: interobserver variability cannot be ignored. AB - Renovascular hypertension (RVH) is a common cause of secondary hypertension. Noninvasive tests such as computed tomography angiography (CTA) or magnetic resonance angiography have a high specificity and sensitivity for the diagnosis. Digital subtraction angiography (DSA) is, however, the gold standard with which RVH can be reliably diagnosed. We report the case of a 30-year-old Chinese man with right ureter malformation and stenosis of the entire right renal artery. We discuss how to distinguish between inconsistencies in CTA results and DSA findings. Interobserver variability is an important factor that leads to such inconsistencies and cannot be ignored. Importantly, clinicians should combine imaging findings with the patient's medical history and clinical manifestations rather than blindly believing the DSA results so as to avoid unnecessary medical disputes. PMID- 23338956 TI - Severe bradycardia and syncope due to topical ophthalmic timolol. PMID- 23338957 TI - Non-ECG-gated MDCTA of infracardiac total anomalous pulmonary venous connection in neonates and young infants. AB - OBJECTIVE: To compare the diagnostic accuracy of non-electrocardiogram-gated (non ECG-gated) multidetector computed tomography angiography (MDCTA) with transthoracic echocardiography (TTE) in the evaluation of infracardiac total anomalous pulmonary venous connection (TAPVC) in neonate and infant patients. METHODS: Nine patients aged from 2 days to 3 months were included in this study. All clinical and imaging data were reviewed. Compared with findings from surgery, the diagnostic accuracy of MDCTA and TTE was calculated in three respects: the path of the drainage vein, the drainage site, and the stenosis of the vein. RESULTS: Images acquired from all patients were eligible for diagnosis and reconstruction. The sites of the drainage point were all clarified and the drainage vessels were oriented by axial and reconstructed images. Stenosis was found at 13 sites, including mild stenosis at the diaphragmatic level (n = 3), distortion or stenosis at the drainage site (n = 5), and hypogenesis of the pulmonary vein branch (n = 5). TTE misdiagnosed the upward-flowing collateral vessels as the drainage veins in 2 patients and misidentified the drainage site in 7 patients, yielding an accuracy of 77.8% and 22.9%, respectively. It identified stenosis at four sites at the drainage site in concordance with MDCTA. The hypogenesis of the pulmonary vein branch was not detected and the stenosis at the diaphragmatic level was not suggested by TTE. CONCLUSION: For infracardiac TAPVC, non-ECG-gated MDCTA is superior to TTE and can facilitate the preoperative evaluation when combined with TTE. PMID- 23338958 TI - Serum uric acid and slow coronary flow in cardiac syndrome X. AB - OBJECTIVE: It has been recently shown that cardiac syndrome X (CSX) patients with slow coronary flow (SCF) have a worse long-term prognosis than those with normal coronary flow. Increased uric acid levels were shown to be associated with atherosclerosis, oxidative stress, and endothelial dysfunction. The purpose of the study was to investigate the relationship between coronary flow assessed with TIMI frame count (TFC) and serum uric acid (SUA) levels in patients with CSX. METHODS: The study population consisted of 113 consecutive patients with typical cardiac CSX and 41 controls without cardiac CSX. Frequencies of risk factors as well as biochemical and hematological data were recorded for all participants. Coronary blood flow was evaluated by TFC. All patients with a TFC greater than two standard deviations from the published normal range for any one of the three vessels were accepted as having slow coronary flow (SCF group), while those whose TFC values fell within the standard deviation of the published normal range for all of the three vessels were considered to have normal coronary flow. RESULTS: Of the 113 CSX patients enrolled, 40 (35.4%) had SCF. The mean TFC value was strongly positively correlated with SUA level, but weakly correlated with male sex, hypertension, diabetes, smoking, serum creatinine level, and hemoglobin. Multivariate regression analysis showed that only the SUA level was independently associated with SCF. The cut-off value for uric acid obtained by the ROC curve analysis was 4.55 mg/dl for the prediction of SCF (sensitivity, 77.5%; specificity, 73.6%). CONCLUSION: The SUA level is independently associated with SCF in patients with CSX. PMID- 23338959 TI - Saphenous vein graft aneurysm in a young patient with familial dyslipidemia. PMID- 23338960 TI - Evaluating risk assessments using receiver operating characteristic analysis: rationale, advantages, insights, and limitations. AB - The last two decades have witnessed major changes in the way that mental health professionals assess, describe, and think about persons' risk for future violence. Psychiatrists and psychologists have gone from believing that they could not predict violence to feeling certain they can assess violence risk with well-above-chance accuracy. Receiver operating characteristic (ROC) analysis has played a central role in changing this view. This article reviews the key concepts underlying ROC methods, the meaning of the area under the ROC curve (AUC), the relationship between AUC and effect size d, and what these two indices tell us about evaluations of violence risk. The area under the ROC curve and d provide succinct but incomplete descriptions of discrimination capacity. These indices do not provide details about sensitivity-specificity trade-offs; they do not tell us how to balance false-positive and false-negative errors; and they do not determine whether a diagnostic system is accurate enough to make practically useful distinctions between violent and non-violent subject groups. Justifying choices or clinical practices requires a contextual investigation of outcomes, a process that takes us beyond simply knowing global indices of accuracy. PMID- 23338961 TI - Residues Asn214, Gln211, Glu219 and Gln221 contained in the subfamily 3 catalytic signature of the isocitrate lyase from Pseudomonas aeruginosa are involved in its catalytic and thermal properties. AB - Isocitrate lyase, encoded by the aceA gene, plays an important role in the ability of Pseudomonas aeruginosa to grow on fatty acids, acetate, acyclic terpenes, and amino acids. Phylogenetic analysis indicated that the ICL superfamily is divided in two families: the ICL family, which includes five subfamilies, and the 2-methylisocitrate lyase (MICL) family. ICL from P. aeruginosa (ICL-Pa) was identified in a different ICL node (subfamily 3) than other Pseudomonas ICL enzymes (grouped in subfamily 1). Analysis also showed that psychrophilic bacteria are mainly grouped in ICL subfamily 3, whose ICL proteins contain the highly conserved catalytic pattern QIENQVSDEKQCGHQD. We performed site-directed mutagenesis, enzymatic activity, and structure modeling of conserved residues in mutated ICLs by using ICL-Pa as a model. Our results indicated that the N214 residue is essential for catalytic function, while mutating the Q211, E219, and Q221 residues impairs its catalytic and thermostability properties. Our findings suggest that conserved residues in the subfamily 3 signature of ICL-Pa play important roles in catalysis and thermostability and are likely associated with the catalytic loop structural conformation. PMID- 23338962 TI - Microbial transformation of ginsenoside Rb1 to compound K by Lactobacillus paralimentarius. AB - In this study, the major ginsenoside Rb1 was transformed into the more pharmacologically active minor compound K by food grade Lactobacillus paralimentarius LH4, which was isolated from kimchi, a traditional Korean fermented food. The enzymatic reaction was analyzed by TLC, HPLC, and NMR. Using the cell-free enzyme of Lactobacillus paralimentarius LH4 at optimal conditions for 30 degrees C at pH 6.0, 1.0 mg ml(-1) ginsenoside Rb1 was transformed into 0.52 mg ml(-1) compound K within 72 h, with a corresponding molar conversion yield of 88 %. The cell-free enzyme hydrolyzed the two glucose moieties attached to the C-3 position and the outer glucose moiety attached to the C-20 position of the ginsenoside Rb1. The cell-free enzyme hydrolyzed the ginsenoside Rb1 along the following pathway: ginsenoside Rb1 -> gypenoside XVII and ginsenoside Rd -> ginsenoside F2 -> compound K. Our results indicate that Lactobacillus paralimentarius LH4 has the potential to be applied for the preparation of compound K in the food industry. PMID- 23338964 TI - Improving confidence in observational studies : should statistical analysis plans be made publicly available? PMID- 23338965 TI - High quality NMP exfoliated graphene nanosheet-SnO2 composite anode material for lithium ion battery. AB - A graphene nanosheet-SnO(2) (GNS-SnO(2)) composite is prepared using N methylpyrrolidone as a solvent to exfoliate graphene from graphite bar with the aid of CTAB by single phase co-precipitation method. The synthesized composites has been characterised physically by powder XRD which confirms the formation of the composite tetragonal SnO(2) crystal system with the low intense broad 002 plane for GNS. The sandwiched morphology of GNS-SnO(2) and the formation of nanosized particles (around 20 nm) have been confirmed by SEM and TEM images. The presence of sp(2) carbon in the GNS is clear by the highly intense G than D band in laser Raman spectroscopy analysis; furthermore, a single chemical shift has been observed at 132.14 ppm from solid-state (13)C NMR analysis. The synthesized composite has been electrochemically characterized using charge-discharge and EIS analysis. The capacity retentions at the end of the first 10 cycles is 57% (100 mA g(-1) rate), the second 10 cycles is 77.83% (200 mA g(-1)), and the final 10 cycles (300 mA g(-1)) is 81.5%. Moreover the impedance analysis clearly explains the low resistance pathway for Li(+) insertion after 30 cycles when compared with the initial cycle. This superior characteristic of GNS-SnO(2) composite suggests that it is a promising candidate for lithium ion battery anode. PMID- 23338963 TI - Influence of pharmacogenomic profiling prior to pharmaceutical treatment in metastatic colorectal cancer on cost effectiveness : a systematic review. AB - BACKGROUND: Metastatic colorectal cancer (mCRC) imposes a substantial health burden on individual patients and society. Furthermore, rising costs in oncology cause a growing concern about reimbursement for innovations in this sector. The promise of pharmacogenomic profiling and related stratified therapies in mCRC is to improve treatment efficacy and potentially save costs. Among other examples, the commonly used epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab are only effective in patients with kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type cancers. Hence, the adaptation of predictive biomarker testing might be a valid strategy for healthcare systems worldwide. OBJECTIVE: This study aims to review the clinical and economic evidence supporting pharmacogenomic profiling prior to the administration of pharmaceutical treatment in mCRC. Moreover, key drivers and areas of uncertainty in cost-effectiveness evaluations are analysed. METHODS: A systematic literature review was conducted to identify studies evaluating the cost effectiveness of predictive biomarkers and the result dependent usage of pharmaceutical agents in mCRC. RESULTS: The application of predictive biomarkers to detect KRAS mutations prior to the administration of EGFR antibodies saved treatment costs and was cost effective in all identified evaluations. However, because of the lack of data regarding cost-effectiveness analyses for predictive biomarker testing, e.g. for first-line treatment, definitive conclusions cannot be stated. Key drivers and areas of uncertainty in current cost-effectiveness analyses are, among others, the consideration of predictive biomarker costs, the characteristics of single predictive biomarkers and the availability of clinical data for the respective pharmaceutical intervention. Especially the cost effectiveness of uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1) mutation analysis prior to irinotecan-based chemotherapy remains unclear. CONCLUSION: Pharmacogenomic profiling has the potential to improve the cost effectiveness of pharmaceutical treatment in mCRC. Hence, quantification of the economic impact of stratified medicine as well as cost-effectiveness analyses of pharmacogenomic profiling are becoming more important. Nevertheless, the methods applied in cost-effectiveness evaluations for the usage of predictive biomarkers for patient selection as well as the level of evidence required to determine clinical effectiveness are areas for further research. However, mCRC is one of the first indications in which stratified therapies are used in clinical practice. Thus, clinical and economic experiences could be helpful when adopting pharmacogenomic profiling into clinical practice for other indications. PMID- 23338966 TI - Hemorrhagic cystic lesion of the median nerve: An unusual complication of venipuncture. PMID- 23338967 TI - Severe bronchiolitis in infants born very preterm and neurodevelopmental outcome at 2 years. AB - Preterm infants are at greater risk of bronchopulmonary dysplasia, which is associated with neurodevelopmental impairment. These infants are also more likely to develop severe bronchiolitis, which can contribute to neurodevelopmental impairment. The aim of this study was to determine whether severe bronchiolitis in very preterm infants (born before 33 weeks of gestation) was associated with an increased risk of neurodevelopmental impairment at 2 years of age. We analyzed a population-based cohort of infants (the Loire Infant Follow-up Team cohort) born between 1 January 2003 and 31 December 2009. Severe bronchiolitis was defined as hospitalization due to bronchiolitis during the first year of life. Neurodevelopmental outcome was assessed at 2 years of corrected age. A total of 2,405 infants were included in this analysis and categorized based on neonatal respiratory status: 1,308 (54.4 %) received no respiratory assistance, 864(35.9 %) received oxygen for <28 days, and 167 (6.9 %) had mild and 66 (2.7) moderate or severe bronchopulmonary dysplasia. At 2 years, 502 children displayed non optimal neurodevelopmental outcome (20.9 %). Moderate or severe bronchopulmonary dysplasia was significantly associated with non-optimal neurodevelopmental outcome at 2 years (adjusted odds ratios (OR) = 2.3 [95 % confidence interval (CI): 1.3-3.9], p = 0.003). In the first year, 318 infants acquired severe bronchiolitis (13.2 %), which was not associated with non-optimal neurodevelopmental outcome (adjusted OR = 1.0 [95 % CI: 0.8-1.4]; p = 0.88). In conclusion, respiratory status in the neonatal period was significantly associated with non-optimal neurodevelopmental outcome at 2 years, while severe bronchiolitis was not. PMID- 23338970 TI - Tests of inferential reasoning by exclusion in Clark's nutcrackers (Nucifraga columbiana). AB - We examined inferential reasoning by exclusion in the Clark's nutcracker (Nucifraga columbiana) using two-way object-choice procedures. While other social scatter-hoarding corvids appear capable of engaging in inferential reasoning, it remains unclear if the relatively less social nutcracker is able to do so. In an initial experiment, food was hidden in one of two opaque containers. All of the birds immediately selected the baited container when shown only the empty container during testing. We subsequently examined the nutcrackers in two follow up experiments using a task that may have been less likely to be solved by associative processes. The birds were trained that two distinctive objects were always found hidden in opaque containers that were always positioned at the same two locations. During testing, one of the two objects was found in a transparent "trash bin" and was unavailable. The birds were required to infer that if one of the objects was in the "trash," then the other object should still be available in its hidden location. Five out of six birds were unable to make this inference, suggesting that associative mechanisms likely accounted for our earlier results. However, one bird consistently chose the object that was not seen in the "trash," demonstrating that nutcrackers may have the ability to use inferential reasoning by exclusion to solve inference tasks. The role of scatter hoarding and social organization is discussed as factors in the ability of corvid birds to reason. PMID- 23338968 TI - Soluble FAS in the prediction of benefit from cetuximab and irinotecan for patients with advanced colorectal cancer. AB - The FAS/FASL system, comprising membrane-bound (mFAS and mFASL) and soluble forms (sFAS and sFASL), has been related to apoptosis driven by chemotherapy administration. In vitro experiments show chemotherapy upregulating membrane bound forms, leading to an increase of receptor availability (at 24-72 h) and favoring apoptosis. The regulatory effect of chemotherapy on sFAS in patients has never been explored prospectively in advanced colorectal cancer (ACRC). We performed a pharmacodynamic study to address sFAS/sFASL variation. A prospective phase II translational multicenter study was designed to evaluate progression free rate (PFR) in patients with ACRC treated with irinotecan and cetuximab in third-line therapy. The effect of sFAS was studied in vitro in colorectal cancer cell lines. Our results showed that statistically significant changes were observed in sFAS at 24-72 h compared to baseline levels in the pharmacodynamic study. Of the 93 patients enrolled in the prospective study in third-line therapy with cetuximab-irinotecan, 85 were evaluated for sFAS/sFASL changes at 48 h. There was no difference in PFR at 4 months between patients with sFAS and sFASL changes. In vitro analysis showed that although LoVo cell lines were sensitive to oxaliplatin and fluorouracil due to modulation of sFAS and FAS, HT29 lines were not. In summary, chemotherapy regulates FAS soluble fractions in vitro and in vivo, but does not predict PFR in ACRC patients undergoing third-line therapy with the combination of cetuximab and irinotecan. PMID- 23338971 TI - Balloon-assisted techniques for advancing long sheaths through difficult anatomy. AB - We describe two balloon-assisted techniques to facilitate the advancement of large, long sheaths through freshly placed stents or tortuous anatomy. The first technique uses a balloon inflated while partially housed within the sheath to help clear an edge, thus offering resistance. The second uses an angioplasty balloon inflated in a distal pulmonary artery branch to better anchor the wire while advancing the sheath through a tortuous path. The techniques are illustrated by the cases of four patients, including two undergoing Melody valve (Medtronic, Minneapolis, MN) implantation. PMID- 23338972 TI - NPM-ALK up-regulates iNOS expression through a STAT3/microRNA-26a-dependent mechanism. AB - NPM-ALK chimeric oncogene is aberrantly expressed in an aggressive subset of T cell lymphomas that frequently occurs in children and young adults. The mechanisms underlying the oncogenic effects of NPM-ALK are not completely elucidated. Inducible nitric oxide synthase (iNOS) promotes the survival and maintains the malignant phenotype of cancer cells by generating NO, a highly active free radical. We tested the hypothesis that iNOS is deregulated in NPM ALK(+) T-cell lymphoma and promotes the survival of this lymphoma. In line with this possibility, an iNOS inhibitor and NO scavenger decreased the viability, adhesion, and migration of NPM-ALK(+) T-cell lymphoma cells, and an NO donor reversed these effects. Moreover, the NO donor salvaged the viability of lymphoma cells treated with ALK inhibitors. In further support of an important role of iNOS, we found iNOS protein to be highly expressed in NPM-ALK(+) T-cell lymphoma cell lines and in 79% of primary tumours but not in human T lymphocytes. Although expression of iNOS mRNA was identified in NPM-ALK(+) T-cell lymphoma cell lines and tumours, iNOS mRNA was remarkably elevated in T lymphocytes, suggesting post transcriptional regulation. Consistently, we found that miR-26a contains potential binding sites and interacts with the 3'-UTR of iNOS. In addition, miR 26a was significantly decreased in NPM-ALK(+) T-cell lymphoma cell lines and tumours compared with T lymphocytes and reactive lymph nodes. Restoration of miR 26a in lymphoma cells abrogated iNOS protein expression and decreased NO production and cell viability, adhesion, and migration. Importantly, the effects of miR-26a were substantially attenuated when the NO donor was simultaneously used to treat lymphoma cells. Our investigation of the mechanisms underlying the decrease in miR-26a in this lymphoma revealed novel evidence that STAT3, a major downstream substrate of NPM-ALK tyrosine kinase activity, suppresses MIR26A1 gene expression. PMID- 23338973 TI - Women at risk for cardiovascular disease lack knowledge of heart attack symptoms. AB - BACKGROUND: It is not known whether cardiovascular disease (CVD) risk level is related to knowledge of the leading cause of death of women or heart attack symptoms. HYPOTHESIS: Women with higher CVD risk estimated by Framingham Risk Score (FRS) or metabolic syndrome (MS) have lower CVD knowledge. METHODS: Women visiting primary care clinics completed a standardized behavioral risk questionnaire. Blood pressure, weight, height, waist size, fasting glucose, and lipid profile were assessed. Women were queried regarding CVD knowledge. RESULTS: Participants (N = 823) were Hispanic women (46%), non-Hispanic white (37%), and non-Hispanic black (8%). FRS was determined in 278: low (63%), moderate (29%), and high (8%); 24% had >=3 components of MS. The leading cause of death was answered correctly by 54%, heart attack symptoms by 67%. Knowledge was lowest among racial/ethnic minorities and those with less education (both P< 0.001). Increasing FRS was inversely associated with knowing the leading cause of death (low 72%, moderate 68%, high 45%, P = 0.045). After multivariable adjustment, moderate/high FRS was inversely associated with knowing symptoms (moderate odds ratio [OR] 0.52, 95% confidence interval [CI]: 0.28-0.98; high OR 0.29, 95% CI: 0.11-0.81), but not the leading cause of death. MS was inversely associated with knowing the leading cause of death (P< 0.001) or heart attack symptoms (P = 0.018), but not after multivariable adjustment. CONCLUSIONS: Women with higher FRS were less likely to know heart attack symptoms. Efforts to target those at higher CVD risk must persist, or the most vulnerable may suffer disproportionately, not only because of risk factors but also inadequate knowledge. PMID- 23338974 TI - Relative cardiovascular and gastrointestinal safety of non-selective non steroidal anti-inflammatory drugs versus cyclo-oxygenase-2 inhibitors: implications for clinical practice. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used in clinical practice, and are considered a first-line option for pain management. However, non-selective NSAIDs (nsNSAIDs) and new generation NSAIDs named cyclo-oxygenase-2 inhibitors (coxibs) are very different from one another and their cardiovascular and gastrointestinal safety profiles may influence prescribing. This article resulted from a search of MEDLINE/Pubmed, Cochrane Library, Bandolier, Medscape and Trip database, up to June 2011. Key words included non-steroidal anti inflammatory, coxib and safety, with the purpose of reviewing the gastrointestinal and cardiovascular safety issues of NSAIDS and the main aspects that differentiate both classes. Selective coxibs are associated with a more favourable gastrointestinal safety profile than nsNSAIDs. In terms of the risk of cardiovascular events, there seems to be a class effect for all NSAIDs with the possible exception of naproxen. The proper usage guidelines for NSAIDs detail the importance of risk factors for each patient in addition to the differences between classes. Patients with high cardiovascular or gastrointestinal risk should avoid using NSAIDs. These medications should be used at the minimum effective dose and for the shortest time possible in all patients. PMID- 23338975 TI - Nateglinide in combination with metformin in Chinese patients with type 2 diabetes mellitus: a post-marketing surveillance study. AB - BACKGROUND AND OBJECTIVE: Diabetes mellitus has become a major public health problem in China. This open-label, prospective, multicentre, post-marketing surveillance study was conducted to investigate the efficacy and safety of nateglinide in combination with metformin in Chinese patients with type 2 diabetes (T2DM). PATIENTS AND METHODS: A total of 892 patients with T2DM were included in the study, of whom 361 subjects had been pretreated with metformin and 531 subjects had not previously been treated with any oral antihyperglycaemic agent. All enrolled patients received 120 mg of nateglinide three times daily within 15 minutes before meals together with metformin (with no restrictions on dosage or frequency of administration) for 12 weeks. Physical examination, laboratory tests and relevant tests in terms of efficacy were performed, and adverse events and subject compliance were documented and monitored. RESULTS: From baseline to week 12, glycosylated haemoglobin (HbA1c) was reduced by 1.52 % +/- 1.25 % (mean +/- SD), fasting plasma glucose (FPG) by 1.92 +/- 1.78 mmol/L, and 2-h post-prandial plasma glucose (2-h PPG) by 4.55 +/- 2.93 mmol/L (all p < 0.01); 61.66 % of subjects achieved the HbA1c goals of <7 %. A total adverse events incidence of 2.47 % was observed, including an incidence of 1.68 % treatment-emergent adverse events. The incidence of hypoglycaemia was 1.57 %. Other nateglinide-related adverse events (including gastrointestinal disorders, rash and allergic dermatitis) were also reported. There were no serious adverse effects. CONCLUSION: The combination of nateglinide and metformin is a safe and effective means of achieving glycaemic target in Chinese patients with T2DM. PMID- 23338976 TI - Contributions of syntactic awareness to reading in Chinese-speaking adolescent readers with and without dyslexia. AB - This study investigated the relative contribution of syntactic awareness to Chinese reading among Chinese-speaking adolescent readers with and without dyslexia. A total of 78 junior high school students in Hong Kong, 26 dyslexic adolescent readers, 26 average adolescent readers of the same age (chronological age control group) and 26 younger readers matched with the same reading level (reading-level group) participated and were administered measures of IQ, syntactic awareness, morphological awareness, vocabulary knowledge, working memory, word reading, and reading comprehension. Results showed that dyslexic readers scored significantly lower than chronological age but similarly to reading level control groups in most measures, especially in the areas of syntactic skills. Analyses of individual data also revealed that over half of the dyslexic readers exhibited certain aspects of deficits in syntactic skills. In regression analyses, syntactic skills were the strongest predictors of ability in word reading and reading comprehension measures. This study highlights the uniquely important correlates of syntactic skills in Chinese reading acquisition and impairment. PMID- 23338977 TI - Computer-assisted interventions targeting reading skills of children with reading disabilities - a longitudinal study. AB - The purpose of the present study was to examine the effects of three computerized interventions on the reading skills of children with reading disabilities in Grade 2. This longitudinal intervention study included five test sessions over 1 year. Two test points occur before the intervention, and three afterwards. The last follow-up was conducted 1 year after the first measurement. One hundred thirty children in Grade 2 participated in the study. Three groups of children with reading difficulties received computerized training programmes: one aimed at improving word decoding skills and phonological abilities, the second focused on word and sentence levels and the third was a combination of these two training programmes. A fourth group received ordinary special instruction. In addition, there was one comparison group with age-matched typical readers. All groups improved their reading skills. The group that received combined training showed greater improvement than the one with ordinary special instruction and the group of typical readers at two follow-ups. The longitudinal results indicate additional positive results for the group that received the combined training, the majority of students from that group being no longer judged to be needing special education 1 year after the intervention. PMID- 23338978 TI - Fabrication, characterization and mosquito larvicidal bioassay of silver nanoparticles synthesized from aqueous fruit extract of putranjiva, Drypetes roxburghii (Wall.). AB - Highly stable nanoparticles of metallic silver with average dimension of 26.6 nm were synthesized by a simple, cost-effective, reproducible and previously unexploited biogenic source viz. dried green fruits of Drypetes roxburghii (Wall.) (common name putranjiva). The as-synthesized silver nanoparticles (Ag NP) were characterized by their characteristic surface plasmon resonance absorption spectra, X-ray diffraction analysis, energy dispersive X-ray analysis and selected area electron diffraction study. The morphology of the particles was determined by high-resolution transmission electron microscopy. Fourier transform infrared analysis focuses some light on the chemical framework that stabilizes the nanoparticles. The analyses of the phytochemicals present in the fruit extract of the plant were also performed following standard protocol. Mosquito larvicidal bioassay with the Ag NPs was carried out with two mosquitoes, namely Anopheles stephensi Liston and Culex quinquefasciatus Say. The results show impressive mortality rate even at too low concentration of nanoparticle. Toxicity test on non-target organism shows no harmful effect during the study period. PMID- 23338979 TI - Biological assay of a novel quinoxalinone with antimalarial efficacy on Plasmodium yoelii yoelii. AB - Compound 1-methyl-7-nitro-4-(5-(piperidin-1-yl)pentyl)-3,4-dihydroquinoxalin 2(1H)-one (VAM2-6) was evaluated against a blood-induced infection with chloroquine-sensitive Plasmodium yoelii yoelii lethal strain in CD1 mice in a 4 day test scheme. LD50 of the compound was 56.51 mg/kg and LD10 was 20.58 mg/kg (taken as the highest dose). Animals were treated by oral gavage of 20, 10, and 5 mg/kg. Mice in the untreated control group showed a progressively increasing parasitemia leading to mouse death on 6 days post-infection; in this group, all mice showed parasites in the blood on the fifth day of sampling; the mean parasitemia on that day was 19.4%. A 4-day dosage of 20 mg/kg of VAM2-6 showed a 97% chemosuppression of total parasitemia on the fifth day, a 28 days survival time, and 20% of cured animals. A 4-day dosage of 10 and 5 mg/kg showed 85 and 37%, respectively, chemosuppression of total parasitemia on the fifth day; but all mice died from days 6 to 9 post-infection with increasing parasitemia. Mice treated with chloroquine at 5 mg/kg survived during the experiment. The results obtained in this study showed that the infection outcome of P. yoelii yoelii infected mice is affected by VAM2-6 compound by slowing down the parasite replication, retarding the patency time, and increasing their survival time. Although compound VAM2-6 was active at higher doses than chloroquine, these results leaves a door open to the study of its structure in order to improve its antimalarial activity. PMID- 23338980 TI - Quantitative systems pharmacology as an extension of PK/PD modeling in CNS research and development. AB - Quantitative systems pharmacology (QSP) is a recent addition to the modeling and simulation toolbox for drug discovery and development and is based upon mathematical modeling of biophysical realistic biological processes in the disease area of interest. The combination of preclinical neurophysiology information with clinical data on pathology, imaging and clinical scales makes it a real translational tool. We will discuss the specific characteristics of QSP and where it differs from PK/PD modeling, such as the ability to provide support in target validation, clinical candidate selection and multi-target MedChem projects. In clinical development the approach can provide additional and unique evaluation of the effect of comedications, genotypes and disease states (patient populations) even before the initiation of actual trials. A powerful property is the ability to perform failure analysis. By giving examples from the CNS R&D field in schizophrenia and Alzheimer's disease, we will illustrate how this approach can make a difference for CNS R&D projects. PMID- 23338982 TI - Characterization of Squalene synthase gene from Chlorophytum borivilianum (Sant. and Fernand.). AB - Saponins are important group of secondary metabolites known for their pharmacological properties. Chlorophytum borivilianum contains high amount of saponins and is thus, recognized as an important medicinal plant with aphrodisiac properties. Though the plant is well known for its pharmaceutical properties, there is meager information available about the genes and enzymes responsible for biosynthesis of saponins from this plant. Squalene synthase (SqS) is the key enzyme of saponin biosynthesis pathway and here, we report cloning and characterization of SqS gene from C. borivilianum. A full-length CbSqS cDNA consisting of 1,760 bp was cloned which contained an open reading frame (ORF) of 1,233 bp, encoding a protein of 411 amino acids. Analysis of deduced amino acid sequence of CbSqS predicted the presence of conserved isoprenoid family domain and catalytic sites. Phylogenetic analysis revealed that CbSqS is closer to Glycine max and monocotyledonous plants. 3D structure prediction using various programs showed CbSqS structure to be similar to SqS from other species. C terminus truncated recombinant squalene synthase (TruncCbSqS) was expressed in E. coli M15 cells with optimum expression induced with 1 mM IPTG at 37 degrees C. The gene expression level was analyzed through semi-quantitative RT-PCR and was found to be higher in leaves as compared to the roots. PMID- 23338983 TI - Improvement of cyclodextrin glycosyltransferase gene expression in Escherichia coli by insertion of regulatory sequences involved in the promotion of RNA transcription. AB - Regulation of RNA transcription in controlling the expression of genes at promoter and terminator regions is crucial as the interaction of RNA polymerase occurred at both sites. Gene encoding cyclodextrin glycosyltransferase (CGTase) from Bacillus sp. NR5 UPM isolated in the previous study was used for further construction of pTZCGT-SS, pTZCGT-BS and pTZCGT-BT expression systems for enhancement of CGTase production. The putative promoter regions, -35 and -10 sequences were found in the upstream of the mature gene start codon. Whereas, long inverted repeats sequences which can form a stable stem and loop structure was found downstream of the open reading frame (ORF) of Bacillus sp. NR5 UPM CGTase. The construction of E. coli strain harbouring pTZCGT-BS showed increment of 3.2-fold in CGTase activity compared to the wild type producer. However, insertion of terminator downstream of CGTase gene in E. coli strain harbouring pTZCGT-BT only resulted in 4.42 % increment of CGTase production compared to E. coli strain containing pTZCGT-BS, perhaps due to low intrinsic termination efficiency. Thus, it is suggested that the insertion of the putative promoter regions upstream of the coding sequence for the construction of CGTase expression system will further enhance in the recombinant enzyme production. PMID- 23338984 TI - Monitoring drug residues in donor blood/plasma samples using LC-(MS)/MS--a pilot study. AB - Quality assurance of pharmaceutical products is of particular importance and thoroughly controlled. Among these, the preparation of human plasma follows strict guidelines from the point of donor selection to product processing. While various precautions particularly concerning antiviral treatment as well as quality assessment are standard procedure, tests for drug residues are rarely, if at all, conducted with fresh frozen plasma products. With the constantly increasing sensitivity and specificity of modern analytical instruments, the detection of trace amounts of therapeutics in plasma is feasible and can be applied to blood products where considered appropriate. To estimate the prevalence of a selection of commonly prescribed and over-the-counter drugs (including diuretics, beta-receptor blocking agents, contraceptives, beta2 agonists, antibiotics, antidepressants, analgesics, opioids, glucocorticosteroids, benzodiazepines, stimulants, and oral anti-diabetics) as well as cannabinoids in human donor plasma, a total of 100 specimens (61 female, 39 male) collected at the German Red Cross Organization in 2012 was subjected to an established analytical approach. The methodology was based on protein precipitation followed by liquid chromatographic-high resolution/high accuracy mass spectrometric analysis. Following initial test results, confirmatory analyses were conducted with respective reference substances employing a conventional liquid chromatography-triple-quadrupole mass spectrometer (LC-MS/MS) apparatus. Out of one hundred samples, five were found to contain diuretics (four hydrochlorothiazide and one torasemide), five contained beta-receptor blocking agents (four bisoprolol and one metoprolol), one was found with residues of pseudoephedrine (stimulant) and one with drosperinone (contraceptive). Overall, 12% of samples yielded detectable amounts of drug residues at concentrations estimated to levels common to individuals under therapeutic treatment. In addition, six aliquots of different lots of commercially available plasma preparations with solvent-detergent processing were tested. Here, no drug residues of the targeted therapeutics were detected. PMID- 23338988 TI - N-N migration of a carbamoyl group in a pyrazole derivative revealed by NMR. AB - During a synthesis of 5-amino-4-(6-methoxy-2-methylpyridin-3-yl)-3-methyl-1H pyrazole-1-carboxamide (see Scheme 1), a side-reaction produced 3-amino-4-(6 methoxy-2-methylpyridin-3-yl)-5-methyl-1H-pyrazole-1-carboxamide as a by-product that forms an equilibrium with the target-compound. The structure of the by product was elucidated by the interpretation of 1D and 2D (HMQC, HMBC) NMR data where (1)H-(15)N HMBC correlations revealed the position of carbamoyl group attachment on the pyrazole. Comparison of structures of the target-compound and the by-product showed that the latter resulted from N-N migration of the carbamoyl group in the target-compound. PMID- 23338989 TI - Hypoplastic occipital condyle and third occipital condyle: review of their dysembryology. AB - Disruption or embryologic derailment of the normal bony architecture of the craniovertebral junction (CVJ) may result in symptoms. As studies of the embryology and pathology of hypoplasia of the occipital condyles and third occipital condyles are lacking in the literature, the present review was performed. Standard search engines were accessed and queried for publications regarding hypoplastic occipital condyles and third occipital condyles. The literature supports the notion that occipital condyle hypoplasia and a third occipital condyle are due to malformation or persistence of the proatlas, respectively. The Pax-1 gene is most likely involved in this process. Clinically, condylar hypoplasia may narrow the foramen magnum and lead to lateral medullary compression. Additionally, this maldevelopment can result in transient vertebral artery compression secondary to posterior subluxation of the occiput. Third occipital condyles have been associated with cervical canal stenosis, hypoplasia of the dens, transverse ligament laxity, and atlanto-axial instability causing acute and chronic spinal cord compression. Treatment goals are focused on craniovertebral stability. A better understanding of the embryology and pathology related to CVJ anomalies is useful to the clinician treating patients presenting with these entities. PMID- 23338987 TI - Potential mechanisms for a role of metabolic stress in hypertrophic adaptations to resistance training. AB - It is well established that regimented resistance training can promote increases in muscle hypertrophy. The prevailing body of research indicates that mechanical stress is the primary impetus for this adaptive response and studies show that mechanical stress alone can initiate anabolic signalling. Given the dominant role of mechanical stress in muscle growth, the question arises as to whether other factors may enhance the post-exercise hypertrophic response. Several researchers have proposed that exercise-induced metabolic stress may in fact confer such an anabolic effect and some have even suggested that metabolite accumulation may be more important than high force development in optimizing muscle growth. Metabolic stress pursuant to traditional resistance training manifests as a result of exercise that relies on anaerobic glycolysis for adenosine triphosphate production. This, in turn, causes the subsequent accumulation of metabolites, particularly lactate and H(+). Acute muscle hypoxia associated with such training methods may further heighten metabolic buildup. Therefore, the purpose of this paper will be to review the emerging body of research suggesting a role for exercise-induced metabolic stress in maximizing muscle development and present insights as to the potential mechanisms by which these hypertrophic adaptations may occur. These mechanisms include increased fibre recruitment, elevated systemic hormonal production, alterations in local myokines, heightened production of reactive oxygen species and cell swelling. Recommendations are provided for potential areas of future research on the subject. PMID- 23338991 TI - Spatial distribution of polycyclic aromatic hydrocarbons in soil, sediment, and combusted residue at an e-waste processing site in southeast China. AB - The environmental pollution and health impacts caused by the primitive and crude recycling of e-waste have become urgent global issues. Guiyu, China is a major hotspot of e-waste recycling. In this study, the levels and distribution of polycyclic aromatic hydrocarbons in soil in Guiyu were determined to investigate the effect of e-waste activities on the environment and to identify possible sources of these pollutants. Sediment samples from a local duck pond, water gullies, a river tributary, and combusted residue from e-waste burning sites were also investigated. The general trend found in soil (Sigma16 PAHs) was acid leaching site > duck pond > rice field > printer roller dump site > reservoir (control site) and ranged from 95.2 +/- 54.2 to 5,210 +/- 89.6 ng/g (dry wt). The highest average total PAH concentrations were found in combusted residues of wires, cables, and other computer electrical components located at two e-waste open burning sites (18,600 and 10,800 +/- 3,940 ng/g). These were 195- and 113 fold higher than the PAH concentrations of soil at the control site. Sediment PAH concentrations ranged from 37.2 +/- 6 to 534 +/- 271 ng/g. Results of this study provide further evidence of significant input of PAHs to the environment attributed to crude e-waste recycling. PMID- 23338990 TI - Degradation of dyes from aqueous solution by Fenton processes: a review. AB - Several industries are using dyes as coloring agents. The effluents from these industries are increasingly becoming an environmental problem. The removal of dyes from aqueous solution has a great potential in the field of environmental engineering. This paper reviews the classification, characteristics, and problems of dyes in detail. Advantages and disadvantages of different methods used for dye removal are also analyzed. Among these methods, Fenton process-based advanced oxidation processes are an emerging prospect in the field of dye removal. Fenton processes have been classified and represented as "Fenton circle". This paper analyzes the recent studies on Fenton processes. The studies include analyzing different configurations of reactors used for dye removal, its efficiency, and the effects of various operating parameters such as pH, catalyst concentration, H2O2 concentration, initial dye concentration, and temperature of Fenton processes. From the present study, it can be conclude that Fenton processes are very effective and environmentally friendly methods for dye removal. PMID- 23338992 TI - Metal fractionation in soils and assessment of environmental contamination in Vallecamonica, Italy. AB - Metal contamination was investigated in soils of the Vallecamonica, an area in the northern part of the Brescia province (Italy), where ferroalloy industries were active for a century until 2001. The extent in which emissions from ferroalloy plants affected metal concentration in soils is not known in this area. In this study, the geogenic and/or anthropogenic origin of metals in soils were estimated. A modified Community Bureau of Reference sequential chemical extraction method followed by inductively coupled plasma optical emission spectroscopy (ICP-OES) analyses were employed to evaluate the potential bioavailability of Al, Cd, Mn, Fe, Cr, Zn, and Pb in soils. Principal component analysis (PCA) was used to assess the relationships among metal sources in soil samples from different locations. This approach allowed distinguishing of different loadings and mobility of metals in soils collected in different areas. Results showed high concentrations and readily extractability of Mn in the Vallecamonica soils, which may suggest potential bioavailability for organisms and may create an environmental risk and potential health risk of human exposure. PMID- 23338993 TI - Concentrations of organochlorine pesticides and polychlorinated biphenyls in human serum and their relation with age, gender, and BMI for the general population of Bizerte, Tunisia. AB - Human serum samples (n = 113) from Bizerte, northern Tunisia, collected between 2011 and 2012 were analyzed for 8 organochlorine pesticides (OCPs) including p,p' dichlorodiphenyltrichloroethane (DDT) and its metabolites, hexachlorobenzene (HCB), hexachlorocyclohexane isomers, dieldrin, and heptachlor and 12 polychlorinated biphenyls (PCBs) congeners. Concentrations of these residues in serum were determined by gas chromatography with electron capture detector and total cholesterol (CHOL) and triglycerides (TG) levels were evaluated by enzymatic colorimetric method. HCB, p,p'-DDE, PCB-138, PCB-153, and PCB-180, were the most abundant organochlorine compounds (OCs) detected in >95 % of the study subjects. The mean levels of p,p'-DDE and HCB in serum were 168.8 and 49.1 ng g( 1) lipid, respectively. The sum PCBs concentrations ranged from 37.5 to 284.6 ng g(-1) lipid in the samples, with mean and median value of 136.1 and 123.2 ng g( 1) lipid, respectively. The PCB profile consisted of persistent congeners, such as PCB-138, PCB-153, and PCB-180 which contributed for approximately 82.7 % to the ?PCBs. Statistical analysis showed that most OCs correlated significantly with age, considering all samples together or with gender differentiation. The present study shows that the levels of p,p'-DDE and ?DDTs were significantly higher in females than in males (p < 0.05), while PCBs levels were significantly higher in male (p < 0.05) than in females. No statistically significant association was found between body mass index and concentration of any organochlorine pesticide or PCB congeners 153, 138, 180, or ?PCBs. PMID- 23338994 TI - Assessment of ozone variations and meteorological influences in a tourist and health resort area on the island of Mali Losinj (Croatia). AB - The purpose of this study was to investigate ozone, variations, and its correlation with meteorological parameters at a remote location on the Mali Losinj Island, which has been a tourist and health resort area in the northern Adriatic. The measured data are discussed in relation to the EU guidelines (Directive 2002/3/EC; Directive 2008/50/EC). In order to characterize ambient air with respect to ozone vegetation injury and photochemical pollution, we calculated accumulated dose over a threshold of 40 parts per billion index and two photochemical pollution indicators. The influence of local meteorological parameters on the measured ozone volume fractions was also investigated. We used the multivariate technique principal component analysis to trace correlations between measured ozone concentration and meteorological parameters. PMID- 23338996 TI - Editorial. PMID- 23338997 TI - Determinants of atherosclerosis in children and adolescents with diabetes type 1. AB - INTRODUCTION: To evaluate the degree of atherosclerosis in children and adolescents with type 1 diabetes and its correlation with risk factors, traditional and other, such as anti-oxidative capacity of circulating blood and level of lipid peroxidation. MATERIAL AND METHODS: Forty children and adolescents with type 1 diabetes with mean age 13.7 years were compared with 20 age- and sex matched healthy control subjects. Association of carotid artery intima-media thickness (cIMT) with different risk factors measured in children with type 1 diabetes was evaluated. RESULTS: Mean carotid IMT was higher in subjects with diabetes (p < 0.01) and was strongly associated with total cholesterol with an odds ratio of 4.08 (p = 0.016), LDL-cholesterol with an odds ratio of 2.78 (p = 0.037), length of disease with an odds ratio of 1.87 (p = 0.007) and positive family history (first- and second-degree relatives) of diabetes and early CVD (heart attack and/or stroke before the age of 60 years) with an odds ratio of 6.8 (p = 0.007). CONCLUSIONS: We found significantly increased cIMT in the diabetic patients compared to the healthy control subjects. Risk factors for the development of atherosclerosis included higher total and LDL-cholesterol, higher systolic blood pressure, positive family history of diabetes and early CVD and longer diabetes duration. In spite of the documented increased oxidative stress, we failed to establish a correlation between the oxidative stress parameters and cIMT values. PMID- 23338995 TI - Lead tolerance in plants: strategies for phytoremediation. AB - Lead (Pb) is naturally occurring element whose distribution in the environment occurs because of its extensive use in paints, petrol, explosives, sludge, and industrial wastes. In plants, Pb uptake and translocation occurs, causing toxic effects resulting in decrease of biomass production. Commonly plants may prevent the toxic effect of heavy metals by induction of various celular mechanisms such as adsorption to the cell wall, compartmentation in vacuoles, enhancement of the active efflux, or induction of higher levels of metal chelates like a protein complex (metallothioneins and phytochelatins), organic (citrates), and inorganic (sulphides) complexes. Phyotochelains (PC) are synthesized from glutathione (GSH) and such synthesis is due to transpeptidation of gamma-glutamyl cysteinyl dipeptides from GSH by the action of a constitutively present enzyme, PC synthase. Phytochelatin binds to Pb ions leading to sequestration of Pb ions in plants and thus serves as an important component of the detoxification mechanism in plants. At cellular level, Pb induces accumulation of reactive oxygen species (ROS), as a result of imbalanced ROS production and ROS scavenging processes by imposing oxidative stress. ROS include superoxide radical (O2(.-)), hydrogen peroxide (H2O2) and hydroxyl radical ((.)OH), which are necessary for the correct functioning of plants; however, in excess they caused damage to biomolecules, such as membrane lipids, proteins, and nucleic acids among others. To limit the detrimental impact of Pb, efficient strategies like phytoremediation are required. In this review, it will discuss recent advancement and potential application of plants for lead removal from the environment. PMID- 23338998 TI - Genetic predispositions and the short- and long-term effects of hormonal therapy on bone mineral density in girls with functional hypothalamic amenorrhoea. AB - INTRODUCTION: The aim of this study was to verify if genetic factors influence the short- and long-term therapeutic responses to oestroprogestagen (OP) therapy, implemented in girls with functional hypothalamic amenorrhoea (FHA) in order to improve their bone mineral density (BMD). MATERIAL AND METHODS: The study included 78 FHA girls who underwent a four-year sequential OP therapy with 17 beta oestradiol and didrogesterone. Changes in the lumbar spine BMD were determined at the end of the therapy and six years after its discontinuation, and analysed in regards to PvuII and XbaI polymorphisms of oestrogen receptor-alpha gene, BsmI polymorphism of vitamin D3 receptor gene, and Sp1 polymorphism of the type-1 collagen gene. RESULTS: After four years of OP therapy, a significant increase in BMD was documented in the studied group. Follow-up densitometry performed six years after completing the therapy revealed a significant decrease in BMD level; nonetheless, the values of this parameter were still significantly higher compared to pretreatment level. Neither the particular polymorphisms nor their combinations influenced the relative change in BMD at the end of the therapy and after a six-year follow-up. CONCLUSIONS: Variability of genes involved in oestrogen, vitamin D3 and collagen metabolism does not influence the short- and long-term results of OP therapy in girls with FHA. PMID- 23338999 TI - Adiponectin and resistin in relationship with skeletal status in women from the RAC-OST-POL study. AB - INTRODUCTION: The aim of this study was to establish adiponectin and resistin serum levels and their relationship with skeletal status in women from the RAC OST-POL study. MATERIAL AND METHODS: 40 women with the lowest and 40 women with the highest value of bone mineral density (BMD) measured at the femoral neck (FN) were selected from a total of 625 women after dividing them into six age categories. Mean age in the whole group of 80 women was 66.1 +/- 8.0 years. 22 women had osteoporotic fractures. Adiponectin and resistin were measured, and skeletal assessment included measurements of BMD of FN and total hip (TH) using Lunar DPX (USA) and quantitative ultrasound (QUS) of hand phalanges by means of DBM Sonic 1200 (IGEA, Italy). RESULTS: Mean age did not differ between the subgroups, whereas height, weight, BMI and BMD were significantly higher in women with high BMD values. In women with high and low BMD, adiponectin concentration [MUg/mL] was 24.81 +/- 12.7 and 31.04 +/- 12.64 respectively, and differed significantly (p < 0.05). Respective values for resistin concentration [ng/mL] were 3.29 +/- 1.37 and 3.62 +/- 1.45, and did not differ. Adiponectin negatively correlated with weight (r = -0.34, p < 0.01), BMI (r = -0.37, p < 0.01), FN BMD (r = -0.26, p < 0.05), TH BMD (r = -0.33, p < 0.01), and did not correlate with QUS result. Stepwise multiple regression analysis showed that TH BMD was negatively influenced by age and adiponectin and positively by weight, and that FN BMD was dependent on age and weight only. CONCLUSIONS: Our results suggest that adiponectin may be an independent factor influencing skeletal status in women aged over 55 years. PMID- 23339000 TI - Changes of systemic microinflammation after weight loss and regain - a five-year follow up study. AB - INTRODUCTION: The aim of this study was to evaluate the influence of body mass changes on plasma concentrations of proinflammatory cytokines in obese women after the initially obtained weight reduction in a five-year follow-up period. MATERIAL AND METHODS: Thirty out of 42 women with simple obesity (age 41.8 +/- 11.9 years; BMI 36.5 +/- 4.6 kg/m2) who achieved a greater than 5% weight loss at the end of a three-month weight loss programme were re-examined after five years. In addition to anthropometric and body composition measurements, plasma concentrations of TNF-alpha, sTNFRs and IL-6 were determined. RESULTS: The mean weight loss after the three-month weight loss programme was 7.9 +/- 4.4 kg. After five years, body mass was still lower than initially in 14 women, while in 16 it was higher (the so-called 'yo-yo effect'). A significant decrease of plasma TNF alpha and IL-6 and increase of sTNFR1 and sTNFR2 levels obtained after weight loss therapy were maintained after five years, including in the subgroup with the yo-yo effect. During the follow-up period, the increase of body fat mass was similar in the subgroup that maintained reduced weight (+4.4 +/- 10.7 kg) and in the subgroup with the yo-yo effect (+4.1 +/- 7.1 kg), while a significant difference was found in changes of body free fat mass (-7.1 +/- 7.1 v. -0.7 +/- 4.5 kg, respectively). CONCLUSIONS: The yo-yo effect has a modest influence on systemic microinflammation and seems not to abolish the benefit achieved via a weight loss programme. This may suggest that the persistence of changes in lifestyle implemented during the programme such as regular physical activity and diet composition may have a significant impact on the level of systemic microinflammation in the obese. (Endokrynol Pol 2012; 63 (6): 432-438). PMID- 23339001 TI - Total and high molecular weight adiponectin and level-modifying polymorphisms of ADIPOQ in centenarians. AB - INTRODUCTION: Adiponectin demonstrates a protective role against the development of obesity, type 2 diabetes mellitus, and cardiovascular disease. The -11377C > G, -11391G > A, and -11426A > G promoter polymorphisms of ADIPOQ gene influence the level of circulating adiponectin. We examined the level of total and high molecular weight (HMW) adiponectin in centenarians and associated it with biochemical parameters. We checked if the expression and concentration-modifying polymorphisms of ADIPOQ are associated with extreme longevity. MATERIAL AND METHODS: Total and HMW adiponectin were examined using ELISA in 40 female centenarians. The frequencies of the ADIPOQ polymorphisms were tested by restriction fragment length polymorphism in 148 centenarians, 414 young controls, in 207 myocardial infarction patients, and in 190 type 2 diabetes mellitus patients. RESULTS: The mean concentration of total adiponectin in centenarians was 13.19 +/- 1.37 mg/mL and of HMW adiponectin it was 9.17 +/- 1.15 mg/mL. They were positively correlated with HDL (r = 0.4696, p = 0.0025 and r = 0.3912, p = 0.015, respectively), and negatively with BMI (r = -0.3702, p = 0.034 and r = 0.3963, p = 0.025) and triglycerides (r = -0.346, p = 0.028 and r = -0.3227, p = 0.045). A very rare AA genotype of the -11391G > A polymorphism was significantly more common in centenarians than in young controls (p = 0.026) and, while compared to the GG genotype, it was associated with a 2.4-fold higher mean concentration of total adiponectin (26.53 +/- 13.29 mg/ mL v. 10.97 +/- 4.28 mg/mL) and with an almost 3-fold higher mean HMW adiponectin (20.65 +/- 12.72 mg/mL v. 7.36 +/- 3.35 mg/mL). CONCLUSIONS: Serum adiponectin concentration in female centenarians is associated with biochemical parameters that are favourable for cardiovascular risk. We suggest that adiponectin might be of importance for extreme longevity. PMID- 23339002 TI - Evaluation of the prevalence of metabolic obesity and normal weight among the Polish population. AB - INTRODUCTION: In the 1980s, the idea evolved that some individuals with normal weight (Metabolically Obese, Normal-Weight), who probably have increased abdominal fat, have metabolic disturbances related to obesity. This observation initiated the concept of the metabolically obese but normal-weight syndrome (MONW). Since then, there have been only a few studies in non-obese subjects. MONW men and women should be regarded as at high risk for cardiovascular disease. MATERIAL AND METHOD: A group of 854 randomly chosen non-obese men and women, 20 40 years of age, was selected from three different areas of Poland - Szczecin, Krakow and Wroclaw. All subjects were interviewed and underwent physical examination, anthropometric measurements (waist circumference, hip circumference, BMI and WHR) as well as densitometry (total body DPX, total fat, android/gynoid deposit). Serum level of fasting glucose and insulin, indices of insulin sensibility (QUICKI) and insulin resistance (HOMA, FIRI), total cholesterol, triglycerides and HDL-C were measured using commercially available kits. LDL-C level was calculated using Friedewald's formula. RESULTS: The total amassed fatty tissue and its android deposit was found to be significantly greater in MONW men and women. MONW women were found to exhibit increased levels of triglycerides and LDL-C but lower levels of HDL-C. In women with excess abdominal fat (EAF), fasting glucose and insulin levels, HOMA and FIRI were considerably higher, while QUICKI was lower. Triglyceride and LDL-C levels were also higher while HDL-C levels were lower. In men with EAF, increased levels of total cholesterol and LDL C were confirmed. CONCLUSIONS: The occurrence of MONW is contingent upon the diagnosis criterion and increases when the criterion represents the value of HOMA - 21.76% in women and 31.42% in men. The frequency of MONW occurrence is lower when the criterion for abdominal fat content limit is used, amounting to 15.78% in women and 7.83% in men. PMID- 23339003 TI - Ghrelin and obestatin in thyroid dysfunction. AB - INTRODUCTION: Ghrelin and obestatin derive from the same precursor. Ghrelin is an energy balance regulator and obestatin's role in metabolic processes cannot be excluded. The aim of this study was to assess plasma ghrelin and obestatin changes in thyroid disorders. MATERIAL AND METHODS: We evaluated plasma ghrelin and obestatin levels in severe hypothyroidism, hypothyroidism after thyreoidectomy and 4-weeks L-thyroxine withdrawal, and in hyperthyroidism. We also re-evaluated plasma ghrelin and obestatin levels in patients with severe hypothyroidism and hyperthyroidism after treatment. RESULTS: Severe hypothyroidism was associated with a reasonably high ghrelin level (p = 0.055) and hyperthyroidism with a significantly lower ghrelin level (p = 0.01) compared to healthy subjects. Ghrelin in hypothyroid patients after L-thyroxine withdrawal did not differ from the control group (p = 0.3). Compared to healthy subjects, obestatin level in hyperthyroidism was decreased (p = 0.03) and did not differ in severe hypothyroidism due to thyroiditis (p = 1) or after L-thyroxine withdrawal (p = 0.6). Ghrelin and obestatin levels correlated positively. Both peptides levels correlated positively with TSH and negatively with free thyroid hormones. In patients with severe hypothyroidism, ghrelin level significantly decreased after treatment (p < 0.01) and in hyperthyroid patients significantly increased after treatment (p = 0.04). There were no significant changes in obestatin levels in hypo- or hyperthyroid patients after treatment. CONCLUSIONS: Plasma ghrelin changes and its correlation with TSH and thyroid hormones may indicate a compensatory role of ghrelin in metabolic disturbances associated with thyroid dysfunction. The positive correlation between ghrelin and obestatin levels may suggest a modulatory role of obestatin in these processes. PMID- 23339004 TI - The role of orexin A in metabolic disturbances in patients with acromegaly. AB - INTRODUCTION: It has been reported that orexins may play an important role in GH regulation. Orexins participate in the regulation of pituitary hormones secretion, food intake regulation, and the sleep-wake cycle. It has been suggested that a defect of orexin A synthesis could be responsible for disturbances in GH synthesis in patients with acromegaly, and consequently aggravate metabolic disturbances caused by high levels of IGF1. THE AIM OF THIS STUDY: THE AIM OF THIS STUDY was to assess orexin A levels in relation to the activity of the disease and the influence on metabolic profile in patients with acromegaly. MATERIAL AND METHODS: The subjects were 55 acromegalic patients divided into three main groups: a surgically cured acromegalic group (SCA); a well-controlled acromegalic group (WCA); an active acromegalic group (AA); and 29 healthy controls. In all subjects, blood samples were taken to assess the concentration of orexin A, lipids, glucose, insulin and hormones of the pituitary and peripheral glands. RESULTS: The concentration of orexin A was highest in the control group (CG) and lowest in the WCA group. The differences of orexin A concentration were statistically significant when each group of acromegalics were compared to the CG. There were no significant differences in orexin A concentration among the studied groups of patients with acromegaly. The metabolic disturbances were more often observed in the groups of acromegaly patients. In the AA group, orexin A concentrations correlated negatively with plasma lipids. CONCLUSIONS: The concentration of orexin A is reduced in acromegaly compared to healthy subjects. PMID- 23339005 TI - Is determination of matrix metalloproteinases and their tissue inhibitors serum concentrations useful in patients with gastroenteropancreatic and bronchopulmonary neuroendocrine neoplasms? AB - INTRODUCTION: Gastroenteropancreatic (GEP) and bronchopulmonary (BP) neurendocrine neoplasms (NENs) are rare and slowly growing tumours. Matrix metalloproteinases (MMPs) degrade extracellular matrix and are responsible for invasion and metastasis. Tissue inhibitors of matrix metalloproteinases (TIMPs) affect the invasiveness of tumour cells and the formation of distant metastases. The aim of this study was to evaluate selected MMPs (MMP2 and MMP9) and their tissue inhibitors (TIMP1 and TIMP2) depending on the pTNM classification, grading, and the occurrence of metastases. MATERIAL AND METHODS: The study group consisted of 86 patients with GEP NENs. The control group consisted of 31 healthy volunteers. Serum levels of TIMP1, TIMP2, MMP2 and MMP9 were determined by ELISA (R&D Systems) in all the study subjects. The statistical calculations were performed using MedCalc. RESULTS: We observed significant differences in MMP2 and TIMP1 levels between the study group with NENs and the control group. TIMP1 levels were significantly higher in patients with high-grade NEN (NEC, neuroendocrine carcinoma) compared to patients with low-grade tumour (NET G1, neuroendocrine tumours G1) (p < 0.017). We also observed a significant correlation between TIMP1 levels and the presence of metastases in the group of patients with GEP NENs, and also higher TIMP1 levels than those in the patients without metastases (p < 0.05). We also found a higher likelihood of metastases in patients with GEP NENs with TIMP1 levels exceeding 206.4 ng/mL. CONCLUSIONS: Patients with NENs secreted larger quantities of MMP2 and TIMP1. TIMP1 may be considered a marker of metastases in patients with GEP NENs. PMID- 23339006 TI - Selected neuroendocrine tumour markers, growth factors and their receptors in typical and atypical bronchopulmonary carcinoids. AB - INTRODUCTION: Bronchopulmonary neuroendocrine tumours (BP NET) cause many diagnostic and therapeutic problems. There is an ongoing search for biochemical markers of activity of these tumours. The use of polypeptide growth factors seems potentially feasible in establishing the diagnosis, prognosis and treatment of these tumours. MATERIAL AND METHODS: We included 41 patients aged 25 to 78 years with histopathologically confirmed typical and atypical bronchopulmonary carcinoid tumours and 20 healthy volunteers. We assessed the levels of specific and non-specific markers of these tumours and of selected growth factors relative to TNM classification. RESULTS: The levels of specific markers (serotonin and its metabolite, 5-hydroxyindoleacetic acid [5HIAA]) and non-specific markers (chromogranin A [CgA]) were significantly higher in patients with atypical carcinoid tumours. The serum levels of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and VEGF receptor-1 (VEGFR-1) were significantly higher in patients with carcinoid tumours versus the control group. The levels of VEGFR-1 closely correlated with TNM classification. No such correlation could, however, be confirmed for the levels of HGF, VEGF or VEGFR-2. CONCLUSIONS: Determination of CgA, serotonin and 5HIAA may be useful in the diagnosis of BP NET, particularly in atypical carcinoid tumours, and their levels depend on the presence of distant metastases. Determination of growth factors (VEGF and its receptor, VEGFR-1, and HGF) may prove useful in the clinical diagnosis of these tumours, while the assessment of VEGFR-1 expression may be helpful in tumour staging. PMID- 23339007 TI - Screening to detect carbohydrate disturbances in welfare home residents in Rzeszow. AB - INTRODUCTION: To screen for undiagnosed type 2 diabetes and other disturbances of the glucose metabolism in welfare home residents in Rzeszow. MATERIAL AND METHODS: 478 residents of four randomly selected welfare homes in Rzeszow were initially enrolled in the study. Among them were 66 residents with previously diagnosed diabetes. Of the remaining 412 adults, 191 (39 males) aged 66.0 +/- 17.7 years were enrolled in the study having completed informed consent. All subjects underwent measurements of fasting glucose levels using a glucose meter (Roche Accu-Chek Active, Mannheim, Germany). In participants whose glucose levels exceeded 99 mg/dL, an oral glucose tolerance test (OGTT) was performed. The results of OGTT were qualified as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or diabetes mellitus (DM). RESULTS: Among the 191 participants, we found 26 cases of IFG (13.6%), 25 of IGT (13.1%), and ten (5.2%) cases of newly diagnosed T2DM. CONCLUSIONS: This study highlights that in Polish welfare homes greater medical vigilance is needed in order to optimise the health of residents. PMID- 23339008 TI - Psychiatric disorders related to polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The psychiatric disorders accompanying the clinical symptoms and hormonal abnormalities are important, but underestimated, aspects in PCOS. Obesity, hirsutism, acne, menstrual disturbances and infertility play important roles in lowering the quality of life in women with PCOS. Depression and anxiety are more often observed in patients with PCOS than in healthy women. Some authors consider that there is a relationship between valproic acid treatment of bipolar disease and PCOS. There have been reports that in women with PCOS anorexia nervosa, bulimia nervosa and other unspecified eating disorders are found more often than in the general population. PMID- 23339009 TI - Hypercalcaemic crisis due to primary hyperparathyroidism - a systematic literature review and case report. AB - Hypercalcaemic crisis is an uncommon and potentially life-threatening manifestation of primary hyperparathyroidism, and it is associated with rapid deterioration of the central nervous system, and cardiac, gastrointestinal, and renal function. We present the case of a 76 year-old man in a sudden coma due to hypercalcaemic crisis as a first manifestation of primary hyperparathyroidism. At first, the patient was treated conservatively, his mental status gradually improved in the next three days. On the ninth day after the initiation of therapy, a minimally invasive radio-guided parathyroidectomy was performed. Histologically, the tumour consisted of densely arranged chief cells immunohistochemically positive for PTH antigens, suggesting adenoma. Calcaemia level and PTH were normalised in the immediate postoperative period. A systematic review was performed by consulting PubMed MEDLINE for publications from 1958 to 2011. This review found a total of 499 reported cases of hypercalcaemic crisis due to primary hyperparathyroidism. Manifestations are neurological alterations, and cardiac, renal and gastrointestinal dysfunctions associated with markedly elevated serum calcium and parathyroid hormone levels. The most frequent histology is the parathyroid adenoma. In untreated cases, mortality is 100%. Despite advances in its management, the mortality rate is still 93.5% in patients treated only conservatively. Medical therapy followed by expeditious parathyroidectomy should be considered as the treatment of choice for patients affected by hypercalcaemic crisis due to a primary hyperparathyroidism. PMID- 23339010 TI - Mnemonics for endocrinologists - hyperparathyroidism. PMID- 23339011 TI - Two-phase electromembrane extraction followed by gas chromatography-mass spectrometry analysis. AB - A two-phase electromembrane extraction (EME) was developed and directly coupled with gas chromatography mass spectrometry (GC-MS) analysis. The proposed method was successfully applied to the simultaneous determination of imipramine, desipramine, citalopram and sertraline. The model compounds were extracted from neutral aqueous sample solutions into the organic phase filled in the lumen of the hollow fiber. This method was accomplished with 1-heptanol as organic phase, by means of 60 V applied voltage and with the extraction time of 15 min. Experiments reported recoveries in the range of 69-87% from 1.2 mL neutral sample solution. The compounds were quantified by GC-MS instrument, with acceptable linearity ranging from 1 to 500 ng mL(-1) (R(2) in the range of 0.989 to 0.998), and repeatability (RSD) ranging between 7.5 and 11.5% (n = 5). The estimated detection limits (S/N ratio of 3:1) were less than 0.25 ng mL(-1). This novel approach based on two-phase EME brought advantages such as simplicity, low costing, low detection limit and fast extraction with a total analysis time less than 25 min. These experimental findings were highly interesting and demonstrated the possibility of solving ionic species in the organic phase at the presence of electrical potential. PMID- 23339012 TI - Enzymatic degradation of polyester films by a cutinase-like enzyme from Pseudozyma antarctica: surface plasmon resonance and atomic force microscopy study. AB - Enzymatic degradation of polyester films by a cutinase-like enzyme from Pseudozyma antarctica JCM10317 (PaE) was analyzed by surface plasmon resonance (SPR). The adsorption of PaE and the degradation rate for polyester films were quantitatively monitored by a positive and negative SPR signal shifts, respectively. The decrease in SPR signal and the erosion depth of amorphous poly(L-lactide) (a-PLLA) film measured by atomic force microscopy (AFM) had a linear relationship, and the weight loss was estimated from the AFM data combined with a density of a-PLLA film. Furthermore, SPR sensorgrams for various polyester films showed that degradation rate of poly(epsilon-caprolactone) and poly(butylene succinate-co-adipate) which contain C6 units was higher than that of other polyesters such as poly(butylene succinate) and a-PLLA. These results suggest that C6 is the preferred chain length as substrates for PaE. PMID- 23339013 TI - Variovorax sp.-mediated biodegradation of the phenyl urea herbicide linuron at micropollutant concentrations and effects of natural dissolved organic matter as supplementary carbon source. AB - In nature, pesticides are often present as micropollutants with concentrations too low for efficient biodegradation and growth of heterotrophic pollutant degrading bacteria. Instead, organic carbon present in environmental dissolved organic matter (eDOM) constitutes the main carbon source in nature. Information on how natural organic carbon affects degradation of pollutants and micropollutants, in particular, is however poor. Linuron-degrading Variovorax sp. strains SRS16, WDL1, and PBLH6 and a triple-species bacterial consortium, from which WDL1 originated, were examined for their ability to degrade linuron at micropollutant concentrations and the effect hereon of different eDOM formulations of varying biodegradability as supplementary C-source was explored. Individual strains and the consortium degraded linuron at initial concentrations as low as 1 MUg L(-1) till concentrations below 4 ng L(-1). Degradation kinetics differed among strains with rates that differed up to 70-fold at the lowest linuron concentrations and with lag phases ranging from 0 to 7 days. Linuron biodegradation by the individual strains was inhibited by an easily biodegradable compound such as citrate but stimulated by eDOM at a linuron concentration of 10 mg L(-1). Effects were strongly reduced or became non-existent at micropollutant linuron concentrations. Effects of eDOM on degradation at 10 mg L(-1) linuron by WDL1 were reduced when WDL1 was incubated together with its original consortium members. This is the first report on eDOM effects on degradation of pesticides at micropollutant concentrations and indicates these effects are limited and depend on linuron and eDOM concentrations, eDOM quality, and the bacterial culture. PMID- 23339014 TI - Purification and characterization of a glutaminase enzyme accounting for the majority of glutaminase activity in Aspergillus sojae under solid-state culture. AB - Glutaminase, an enzyme that hydrolyzes L-glutamine to L-glutamate, plays an important role in the production of fermented foods by enhancing the umami taste. In this study, we found ten glutaminase genes in the Aspergillus sojae genome by conducting a BLAST search of the characterized glutaminase sequence. We subsequently constructed glutaminase gene disruptants. The glutaminase activity of the gahB disruptant was decreased by approximately 90 % in A. sojae and Aspergillus oryzae, indicating that this enzyme (GahB) accounted for the majority of the glutaminase activity in Aspergillus species. Subsequently, GahB protein was purified from the AsgahB-overexpressing transformant and characterized. The molecular mass was estimated to be approximately 110 and 259 kDa by SDS-PAGE and gel filtration chromatography, respectively, indicating that the native form of AsGahB was a dimer. The optimal pH was 9.0, and the optimal temperature was 50 degrees C. Analysis of substrate specificity revealed that AsGahB had peptidoglutaminase-asparaginase activity, similar to AsGahA, but preferred free L glutamine to free L-asparagine, C-terminal glutaminyl, and asparaginyl residues in peptides. PMID- 23339015 TI - Metabolic reconstruction and flux analysis of industrial Pichia yeasts. AB - Pichia yeasts have been recognized as important microbial cell factories in the biotechnological industry. Notably, the Pichia pastoris and Pichia stipitis species have attracted much research interest due to their unique cellular physiology and metabolic capability: P. pastoris has the ability to utilize methanol for cell growth and recombinant protein production, while P. stipitis is capable of assimilating xylose to produce ethanol under oxygen-limited conditions. To harness these characteristics for biotechnological applications, it is highly required to characterize their metabolic behavior. Recently, following the genome sequencing of these two Pichia species, genome-scale metabolic networks have been reconstructed to model the yeasts' metabolism from a systems perspective. To date, there are three genome-scale models available for each of P. pastoris and P. stipitis. In this mini-review, we provide an overview of the models, discuss certain limitations of previous studies, and propose potential future works that can be conducted to better understand and engineer Pichia yeasts for industrial applications. PMID- 23339017 TI - Separation of nadolol stereoisomers by chiral liquid chromatography at analytical and preparative scales. AB - The separation of the four nadolol stereoisomers on Chiralpak(r) AD by chiral liquid chromatography was carried out at both analytical and preparative scales. A screening of possible mobile-phase compositions was performed using different alcohol-hydrocarbon mixtures. The results obtained confirm the use of 20:80:0.3 ethanol-hexane-diethylamine reported by McCarthy (1994) but introduce other possibilities for the complete resolution of the four nadolol stereoisomers at analytical scale, namely, the mixtures 30-40:70-60:0.3 ethanol-heptane diethylamine. Additionally, this work describes how retention and resolution depend on the ethanol content in hexane and heptane mixtures. The separation of nadolol stereoisomers is also carried out at preparative scale and different alcohol-hydrocarbon compositions are proposed, depending on the target component to be obtained. Particularly, this work presents the experimental separation of the more retained nadolol stereoisomer (RSR-nadolol) by simulated moving bed (SMB) chromatography using an 80:20:0.3 ethanol-heptane-diethylamine mobile phase. For a 2 g/l feed concentration, RSR-nadolol is 100% recovered at the extract outlet stream, 100% pure, and with a system productivity of 0.65 g(RSR nadolol)/(l(bed)(.)h) and a solvent consumption of 9.6 l(solvent)/g(RSR-nadolol). PMID- 23339016 TI - Recent advances in molecular medicine techniques for the diagnosis, prevention, and control of infectious diseases. AB - In recent years we have observed great advances in our ability to combat infectious diseases. Through the development of novel genetic methodologies, including a better understanding of pathogen biology, pathogenic mechanisms, advances in vaccine development, designing new therapeutic drugs, and optimization of diagnostic tools, significant infectious diseases are now better controlled. Here, we briefly describe recent reports in the literature concentrating on infectious disease control. The focus of this review is to describe the molecular methods widely used in the diagnosis, prevention, and control of infectious diseases with regard to the innovation of molecular techniques. Since the list of pathogenic microorganisms is extensive, we emphasize some of the major human infectious diseases (AIDS, tuberculosis, malaria, rotavirus, herpes virus, viral hepatitis, and dengue fever). As a consequence of these developments, infectious diseases will be more accurately and effectively treated; safe and effective vaccines are being developed and rapid detection of infectious agents now permits countermeasures to avoid potential outbreaks and epidemics. But, despite considerable progress, infectious diseases remain a strong challenge to human survival. PMID- 23339018 TI - Erectile dysfunction in heart failure patients: a critical reappraisal. AB - Heart failure (HF) is a complex clinical syndrome with a constantly increasing incidence and prevalence in western countries. Total absence of sexual activity is registered in 30% of HF patients. Moreover, HF-induced reduction in exercise tolerance, side effects of HF medications and the coexistence of shared risk factors between HF and sexual dysfunction may further aggravate the sexual health of HF patients. The purpose of this review is to examine the pathophysiological mechanisms behind the association of erectile dysfunction (ED) and HF, the potential therapeutic approaches and the eventual indications for sexual activity in HF patients. Medline and Cochrane Library search was performed from January 1970 through October 2012 to retrieve relevant papers outlining the association between ED and HF. Many evidences have outlined a tight association between ED and HF pathophysiological standpoint. Shared risk factors, common pathogenic traits and epidemiologic association represent some of the links between these conditions. Erectile dysfunction has been recognized as an earlier predictor of cardiovascular events; moreover, HF itself may cause and/or worsen ED because of its particular feature and co-morbidities. Furthermore, some cardiovascular drugs may contribute to impaired erectile function. In stable patients with stable HF, sexual activity is generally not contraindicated but it should be encouraged, as a form of moderate-intensity physical exertion. An effective treatment of ED in HF patients should be founded on the correction of reversible risk factors, on the choice of cardiovascular drugs with the lowest effect upon patient's erectile function, and on the use of phosphodiesterase-5-inhibitors. Physicians should be aware of the close relation between HF and ED and of the related clinical and therapeutic implications, in order to improve patients quality of life and clinical outcome. PMID- 23339019 TI - Vitamin D-binding protein in cerebrospinal fluid is associated with multiple sclerosis progression. AB - Multiple sclerosis is a neurological disorder that presents with symptoms including inflammation, neurodegeneration, and demyelination of the central nervous system (CNS). Secondary progressive multiple sclerosis (SPMS) manifests with serious physical disability. To quantitatively analyze differential protein expression in patients with SPMS, we performed two-dimensional fluorescence difference in-gel electrophoresis, followed by mass spectrometry on the cerebrospinal fluid of these patients and patients with other neurological diseases. Vitamin D-binding protein (DBP), gelsolin, albumin, etc. showed more than a 1.5-fold difference between the two groups. Based on these results, an experimental allergic encephalomyelitis (EAE) model of multiple sclerosis in Lewis rats was used to investigate DBP's role in the disease. Protein levels, mRNA transcripts, and ligands of DBP in different regions of the CNS were evaluated under various vitamin D intake levels. Here, DBP levels increased in the experimental rat groups compared to the control groups regardless of vitamin D intake. Moreover, DBP mRNA levels varied in different parts of the CNS including spinal cords in the experimental groups. The observed differences between DBP protein and mRNA levels in the experimental groups' spinal cords could be derived from the disruption of the blood-brain barrier. Furthermore, an interaction between DBP and actin was confirmed using coimmunoprecipitation and western blot. These results indicate a role for DBP in the actin scavenge system. Moreover, in the experimental group that received oral vitamin D3 supplement, we observed both delayed onset and diminished severity of the disease. When DBP was upregulated, however, the benefits from the vitamin D3 supplements were lost. Thus, we inferred that high levels of DBP were adverse to recovery. In conclusion, here we observed upregulated DBP in the cerebrospinal fluid could serve as a specific diagnostic biomarker for the progression of multiple sclerosis. Next, we demonstrate the vital function of increased levels of free vitamin D metabolites for multiple sclerosis treatment. Finally, vitamin D supplements may be particularly beneficial for SPMS patients. PMID- 23339021 TI - Light-emitting diode therapy induces analgesia and decreases spinal cord and sciatic nerve tumour necrosis factor-alpha levels after sciatic nerve crush in mice. AB - BACKGROUND: Neuropathic pain is severely debilitating and resistant to pharmacological approaches; therefore, the study of therapies to complement its treatment is especially relevant. In a case report study, light-emitting diode therapy (LEDT) has shown analgesic activity as well as reduced the expression of pro-inflammatory cytokines in a rabbit osteoarthritis model and in calcaneal tendinitis in rats. Although LEDT stimulated morphofunctional recovery after nerve injury in rats, its effect against neuropathic pain has not been tested. METHODS: To that purpose, mice under anaesthesia were subjected to the sciatic nerve crush (SNC) model. On the seventh post-operative day, after determining analgesic dose (energy density in joules), LEDT (950 nm, 80 mW/cm2, 2.5 J/cm2 ) was irradiated, daily for a period of 15 days, on the skin over the crush site. RESULTS: Compared with the SNC group, LEDT reduced mechanical hypersensitivity but not cold hypersensitivity which is induced by SNC, decreased spinal cord and sciatic nerve levels of tumour necrosis factor alpha (TNF-alpha) but did not alter interleukin (IL)-1beta and IL-10 levels, and finally, failed to accelerate motor functional recovery and morphological nerve regeneration. CONCLUSION: Taken together, these data provide first-hand evidence of LEDT effectiveness against neuropathic pain induced by SNC, with corresponding decrease of pro-inflammatory cytokine levels, both in the sciatic nerve and in the spinal cord, although at a small analgesic dose, LEDT failed to accelerate nerve regeneration. PMID- 23339022 TI - Cellular-signaling pathways unveil the carcinogenic potential of chemicals. AB - Most of the current in vitro carcinogenicity assays assess the potential carcinogenic properties of chemicals through the detection of inflicted DNA damage or subsequent chromosome damage and gene mutations. Unfortunately, these assays generally do not provide mechanistic insight into the reactive properties of a chemical. Upon chemical-induced damage of biomolecules, molecular sensors will activate general and damage-specific cellular response pathways that provide protection against the (geno)toxic and potential carcinogenic properties of chemicals. These cellular defense mechanisms include activation of cell-cycle checkpoints, DNA repair systems and induction of apoptosis or necrosis. Visualization of activated cellular-signaling pathways forms a powerful means to readily detect the genotoxic potential of chemical compounds and simultaneously gain insight into their reactive properties. Over the past years, various in vitro reporter assays have been developed that monitor activation of general and more specific cellular-signaling pathways, including the GreenScreen HC and ToxTracker assays. In this review we provide a perspective on how we can exploit activation of cellular signaling pathways to shed light on the mode of action of the chemical exposure and to develop sophisticated mechanism-based in vitro assays for cancer risk assessment. PMID- 23339023 TI - Ammonium as sole N source improves grain quality in wheat. AB - BACKGROUND: The skilful handling of N fertilizer, including N source type and its timing, is necessary to obtain maximum profitability in wheat crops in terms of production and quality. Studies on grain yield and quality with ammonium as sole N source have not yet been conducted. The aim of this study was to evaluate the effect of N source management (nitrate vs. ammonium), and splitting it into two or three amendments during the wheat life cycle, on grain yield and quality under irrigated conditions. RESULTS: This experiment demonstrates that Cezanne wheat plants growing with ammonium as exclusive N source are able to achieve the same yield as plants growing with nitrate and that individual wheat plants grown in irrigated pots can efficiently use late N applied in GS37. Ammonium nutrition increased both types of grain reserve proteins (gliadins and glutenins) and also increased the ratio gli/glu with respect to nitrate nutrition. The splitting of the N rate enhanced the ammonium effect on grain protein composition. CONCLUSIONS: The application of ammonium N source, especially when split into three amendments, has an analogous effect on grain protein content and composition to applications at a higher N rate, leading to higher N use efficiency. PMID- 23339024 TI - The sedative effect of inhaled terpinolene in mice and its structure-activity relationships. AB - Terpinolene is a cyclic monoterpene compound found in some Labiatae herbs. In our previous study, we evaluated the sedative effect of inhaled essential oils of Microtoena patchoulii leaves in mice and isolated terpinolene as an active ingredient. We investigated the structure-activity relationships of terpinolene to identify the structural part essential to its sedative effect. Comparison of terpinolene analog activities showed that a double bond in the side-chain or pi bonds in the six-membered ring play important roles in the sedative effect. In another experiment using olfactory impaired mice, we further revealed that inhaled terpinolene exerted the effect after nasal absorption into the body. PMID- 23339020 TI - The ubiquitin-proteasome system in retinal health and disease. AB - The ubiquitin-proteasome system (UPS) is the main intracellular pathway for modulated protein turnover, playing an important role in the maintenance of cellular homeostasis. It also exerts a protein quality control through degradation of oxidized, mutant, denatured, or misfolded proteins and is involved in many biological processes where protein level regulation is necessary. This system allows the cell to modulate its protein expression pattern in response to changing physiological conditions and provides a critical protective role in health and disease. Impairments of UPS function in the central nervous system (CNS) underlie an increasing number of genetic and idiopathic diseases, many of which affect the retina. Current knowledge on the UPS composition and function in this tissue, however, is scarce and dispersed. This review focuses on UPS elements reported in the retina, including ubiquitinating and deubiquitinating enzymes (DUBs), and alternative proteasome assemblies. Known and inferred roles of protein ubiquitination, and of the related, SUMO conjugation (SUMOylation) process, in normal retinal development and adult homeostasis are addressed, including modulation of the visual cycle and response to retinal stress and injury. Additionally, the relationship between UPS dysfunction and human neurodegenerative disorders affecting the retina, including Alzheimer's, Parkinson's, and Huntington's diseases, are dealt with, together with numerous instances of retina-specific illnesses with UPS involvement, such as retinitis pigmentosa, macular degenerations, glaucoma, diabetic retinopathy (DR), and aging related impairments. This information, though still basic and limited, constitutes a suitable framework to be expanded in incoming years and should prove orientative toward future therapy design targeting sight-affecting diseases with a UPS underlying basis. PMID- 23339027 TI - A study on the system of nonaqueous microchip electrophoresis with on-line peroxyoxalate chemiluminescence detection. AB - This article describes a further development of our previously reported miniaturized analysis system of microchip electrophoresis with on-line chemiluminescence detection. The system, developed first time for nonaqueous microchip electrophoresis with peroxyoxalate chemiluminescence detection, consists of a suction pressure device for sample or reagent introduction, a constant voltage supplied for electrophoretic separation, an either hydrophilic or hydrophobic porous polymer plug for preventing chemiluminescence reagent flowing upstream and a spiral detection channel for enhancement of both detection sensitivity and reproducibility. Especially, by using organic solvent as BGE medium, the developed system avoided the interface problem between aqueous running buffer and low-water-content chemiluminescence solvent in previous reports. The influencing factors on chemiluminescence signal were optimized using rhodamine 6G as model molecule. The system performance was further investigated in the experiment of separation of hydrophilic rhodamine dyes and analysis of hydrophobic polycyclic aromatic hydrocarbon, providing the detection limit (S/N = 3) of 3.5 nmol/L for rhodamine 123, 6.8 nmol/L for rhodamine 6G, and 60 nmol/L for 1-aminopyrene, respectively. The experimental results showed the system offered a number of benefits, including compact structure, high sensitivity, good reproducibility, and a wide range of application prospect. PMID- 23339025 TI - Antinociceptive and wound healing activities of Croton adamantinus Mull. Arg. essential oil. AB - Leaves of Croton adamantinus have been used to treat inflammation and skin wounds in the semi-arid area of the Northeast of Brazil. In order to evaluate if the essential oil (EO) was responsible for the claimed activities; antinociceptive, wound healing and antimicrobial tests were carried out. Twenty constituents were identified in C. adamantinus EO by GC-MS, 1H-NMR and 13C-NMR, the major compounds being methyl-eugenol (14.81%) and 1,8-cineol (13.74%). Antinociceptive activity was evaluated by the formalin test and the abdominal contortion assay in mice. The EO (50 and 100 mg/kg) decreased the licking time of both phases of the formalin test when compared to the vehicle, but not to morphine (7.5 mg/kg). In the abdominal contortion assay, the EO (50 and 100 mg/kg) reduced the number of contortions compared to the vehicle and to indometacin (10 mg/kg). The wound healing activity was verified also using two experimental models: excisional wound and dead space. Topical treatment with the EO (1%) increased the wound contraction from the third day of treatment (compared with nitrofurazone 0.2%), while systemic treatment (50 mg/kg/day) increased granulation tissue formation and reduced the water content. C. adamantinus EO also showed antimicrobial activity against Staphylococcus aureus in disk diffusion method. These results corroborate the ethnobotanical use of this specie by Brazilian population. PMID- 23339028 TI - Inhibiting roles of berberine in gut movement of rodents are related to activation of the endogenous opioid system. AB - Although Berberine (BER) is popular in treating gastrointestinal (GI) disorders, its mechanisms are not clear yet. In order to investigate the effects and possible mechanism of BER on GI motility in rodents, we first explored GI motility by recording the myoelectrical activity of jejunum and colon in rats, and upper GI transit with a charcoal marker in mice. Then, the plasma levels of gastrin, motilin, somatostatin and glucagon-like-peptide-1 (Glp-1) were measured by ELISA or radioimmunoassay (RIA). Furthermore, endogenous opioid-peptides (beta endorphin, dynorphin-A, met-enkephalin) were detected by RIA after treatment with BER. Our results showed that BER concentration-dependently inhibited myoelectrical activity and GI transit, which can be antagonized by opioid receptor antagonists to different extents. The elevated somatostatin and Glp-1, and decreased gastrin and motilin in plasma, which were caused by BER application, also could be antagonized by the opioid-receptor antagonists. Additionally, plasma level of beta-endorphin, but not dynorphin-A and met enkephalin, was increased by applying BER. Taken together, these studies show that BER plays inhibiting roles on GI motility and up-regulating roles on somatostatin, Glp-1 and down-regulating roles on gastrin, motilin. The pharmacological mechanisms of BER on GI motility and plasma levels of GI hormones were discovered to be closely related to endogenous opioid system. PMID- 23339029 TI - Benefits of using algae as natural sources of functional ingredients. AB - Algae have been suggested as a potential source of bioactive compounds to be used in the food and pharmaceutical industries. With the strong development of functional foods as a method to improve or maintain health, the exploration of new compounds with real health effects is now an intense field of research. The potential use of algae as source of functional food ingredients, such as lipids, proteins, polysaccharides, phenolics, carotenoids, etc., is presented, together with the different possibilities of improving valuable metabolites production either using the tools and the knowledge provided by marine biotechnology or improving the different factors involved in the production on a large scale of such metabolites. The bio-refinery concept is also presented as a way to improve the efficient use of algae biomass while favouring process sustainability. PMID- 23339030 TI - Neuropathic pain needs systematic classification. PMID- 23339031 TI - Assignments of human integrin alpha1I domain in the apo and Mg2+ bound states. AB - The alpha1beta1 integrin receptor binds to its main extracellular ligand, collagen, through an inserted domain in its alpha-subunit called the alphaI domain (alphaI). alphaI contains a metal binding site that allows collagen to coordinate to the domain through a divalent metal ion. Here we report the backbone assignments of the apo and Mg(2+) bound state of the isolated human alpha1I and the chemical shift changes resulting from metal coordination. PMID- 23339032 TI - Backbone and partial side chain assignment of the microtubule binding domain of the MAP1B light chain. AB - Microtubule-associated protein 1B (MAP1B) is a classical high molecular mass microtubule-associated protein expressed at high levels in the brain. It confers specific properties to neuronal microtubules and is essential for neuronal differentiation, brain development and synapse maturation. Misexpression of the protein contributes to the development of brain disorders in humans. However, despite numerous reports demonstrating the importance of MAP1B in regulation of the neuronal cytoskeleton during neurite extension and axon guidance, its mechanism of action is still elusive. Here we focus on the intrinsically disordered microtubule binding domain of the light chain of MAP1B. In order to obtain more detailed structural information about this domain we assigned NMR chemical shifts of backbone and aliphatic side chain atoms. PMID- 23339033 TI - Involvement of geranylgeranylation of Rho and Rac GTPases in adipogenic and RANKL expression, which was inhibited by simvastatin. AB - Simvastatin suppresses myoblast differentiation via inhibition of Rac GTPase, which is involved in the mevalonic acid pathway that produces cholesterol. Statins also inhibit adipogenic differentiation and receptor activator of NFkappaB ligand (RANKL) expression, possibly through the mevalonic acid pathway, although the involvement of that pathway and effector proteins in these cellular events has not been fully clarified. In the present study, we aimed to elucidate the mechanism of the effects of simvastatin on adipogenic differentiation and calcitriol-induced RANKL expression in bone marrow stromal ST2 cells. Adipogenesis and mRNA up-regulation of peroxisome proliferator-activated receptor gamma and adipocyte fatty acid-binding protein were induced by troglitazone, and those events were efficiently inhibited by simvastatin. In addition, RANKL expression induced by calcitriol was abrogated by simvastatin in ST2 cells. The inhibitory effects of simvastatin were adequately compensated by the addition of either mevalonic acid or an intermediate of the mevalonic acid pathway, geranylgeranyl pyrophosphate, but not by another intermediate, farnesyl pyrophosphate. These findings suggest that protein geranylgeranylation is related to cellular differentiation in those two directions. Furthermore, inhibitor analysis demonstrated that Rac GTPase is involved in adipogenic differentiation, whereas Rho GTPase was found to be involved in RANKL expression. Taken together, the present findings suggest that geranylgeranylation of Rho family GTPase is involved in both adipogenesis and RANKL expression of stromal cells, while Rac GTPase is involved in adipogenesis and Rho GTPase in RANKL expression. PMID- 23339034 TI - Microwave-assisted extraction combined with on-line solid phase extraction followed by ultra-high-performance liquid chromatography with tandem mass spectrometric determination of benzotriazole UV stabilizers in marine sediments and sewage sludges. AB - Benzotriazole ultra-violet stabilisers are compounds widely used in personal care products, which can reach the environment after passing through wastewater treatment plants. In this work, we develop a novel method to evaluate the presence of seven compounds in marine sediments and sewage sludges using microwave-assisted extraction followed by a clean-up step based in on-line solid phase extraction coupled to ultra-high-performance liquid chromatography with MS/MS detection. This method allows for fast and efficient extraction from the solid matrix, subsequent automatic on-line purification and preconcentration, and analysis. For the optimised method, LOD were from 53.3 to 146 ng/kg and LOQ were in the range of 176-486 ng/kg. The method was validated for different environmental solid samples with satisfactory recoveries and relative standard deviations, between 46.1 and 83.9 and 7.8 and 15.5% (sludges) and 50.1 and 87.1% and 8.83 and 16.3% (sediments), respectively. Finally, the studied analytes were quantified in concentrations between 0.18 and 24.0 ng/g in real samples of marine sediments and sewage sludges from Gran Canaria Island (Spain). PMID- 23339035 TI - Comparison of laparoscopic and open intraoperative ultrasonography for staging liver tumours. AB - BACKGROUND: Laparoscopic liver surgery must reproduce open surgical steps. Intraoperative ultrasonography (IOUS) is mandatory, but reliability of laparoscopic IOUS has been poorly evaluated. The aim of this study was to compare laparoscopic versus open IOUS in staging liver tumours. METHODS: All patients scheduled for liver resection between September 2009 and March 2011 were considered. Inclusion criteria were primary and metastatic tumours. Exclusion criteria were: hilar/gallbladder cholangiocarcinoma, ten or more lesions, repeat resection, laparoscopic hepatectomy, adhesions and unresectability. Following percutaneous ultrasonography and thoracoabdominal computed tomography (CT), and on indication contrast-enhanced (CE) liver magnetic resonance imaging (MRI) and/or positron emission tomography (PET)-CT, patients were scheduled for laparoscopy, laparoscopic IOUS, then laparotomy, open IOUS and Partial hepatectomy. Data were collected prospectively. Reference standards were final pathology and 6-month follow-up results. RESULTS: Sixty-five patients were included, who had a median of 3 preoperative imaging studies (ultrasonography/CT 100 per cent, CE-MRI 67 per cent, PET-CT 54 per cent). A total of 119 lesions were diagnosed. Laparoscopic IOUS detected 22 additional lesions (+18.5 per cent) in 14 patients. Open IOUS detected two additional lesions, but did not confirm four lesions; overall 20 additional lesions (+16.8 per cent) were detected in ten patients. Pathology confirmed 14 newly detected malignant nodules (+11.8 per cent) in eight patients. After 6 months ten new nodules were identified in six patients. The sensitivity of preoperative imaging, laparoscopic IOUS and open IOUS was 83.1, 92.3 and 93.0 per cent respectively; accuracy was 79, 82 and 88 per cent. In comparison with open IOUS, the sensitivity and accuracy of laparoscopic IOUS were 98.6 and 94 per cent. CONCLUSION: Laparoscopic IOUS is a reliable tool for staging liver tumours with a performance similar to that of open IOUS in detecting new nodules. PMID- 23339036 TI - The inhibitory effects of the standardized extracts of Ginkgo biloba on Aromatase activity in JEG-3 human choriocarcinoma cells. AB - Breast cancer is the most common cancer in women worldwide. There are many endocrine adjuvant therapies for breast cancer patients that are categorized according to their mechanisms. Among them, aromatase inhibitors (AIs) that block the synthesis of estrogens have proven superiority compared with tamoxifen and have replaced it as a first-line hormonal therapy. However, AIs also have limitations due to their side effects - increased rate of bone loss and musculoskeletal complaints. We therefore need new candidate AIs with fewer side effects. The extracts of Ginkgo biloba (EGb), which contain phytochemicals from the tree, had biphasic effects for estrogens and osteoporosis-inhibiting activities in our previous experiments. In this study, we explored the possibility of EGb as an AI and their mechanisms. Aromatase activities were inhibited by EGb both in JEG-3 cells and in recombinant CYP19 microsomes. The results of polymerase chain reaction for aromatase from a coding sequence and specific promoter sequences (exon I.a, exon I.c) in JEG-3 cells as well as the results of reporter gene assays showed that EGb dose-dependently decreased the aromatase gene expression. The decreased protein levels were demonstrated by Western blotting. From these results, we concluded that EGb could act as an AI at both the enzyme and transcriptional levels. PMID- 23339037 TI - What helps can also hinder: a dissociation in the acute effect of levodopa treatment on motor and cognitive functions. PMID- 23339038 TI - Residue depletion of nifuroxazide in broiler chicken. AB - BACKGROUND: Several nitrofuran drugs have been prohibited for use in food producing animals due to their carcinogenic and mutagenic effects. However, one of the nitrofurans, nifuroxazide, is still used as a veterinary drug in some countries. This study was conducted to investigate the residue depletion of nifuroxazide in broiler chicken. Chickens were fed with dietary feeds containing 50 mg kg-1 of nifuroxazide for seven consecutive days. Liver, kidney, muscle and plasma samples were collected at different withdrawal periods, and the residues of parent nifuroxazide and its acid-hydrolysable side chain, 4 hydroxybenzhydrazide (HBH), in these samples were determined. RESULTS: Nifuroxazide was metabolised in vivo and its metabolite HBH was formed. Parent nifuroxazide was not detectable in these samples after 14 days of cessation. HBH was detectable in these samples even after 28 days of cessation and the total HBH residues were higher than 1.0 ng g-1. Furthermore, the residue level of tissue bound HBH was much higher than that of free HBH. CONCLUSION: The tissue-bound HBH could be used as a marker to monitor the residue of nifuroxazide in chicken and the best target tissue should be liver. This is the first paper reporting the residue depletion of nifuroxazide in chicken. PMID- 23339039 TI - Study of adsorption and preconcentration by using a new silica organomodified with [3-(2,2'-dipyridylamine)propyl] groups. AB - In this work, a silica surface chemically modified with [3-(2,2' dipyridylamine)propyl] groups, named [3-(2,2'-dipyridylamine)propyl]silica (Si-Pr DPA) was prepared, characterized, and evaluated for its heavy metal adsorption characteristics from aqueous solution. To our knowledge, we are the first authors who have reported the present modification. The material was characterized using infrared spectroscopy, SEM, and NMR (29) Si and (13) C solid state. Batch and column experiments were conducted to investigate for heavy metal removal from dilute aqueous solution by sorption onto Si-Pr-DPA. From a number of studies the affinity of various metal ions for the Si-Pr-DPA sorbent was determined to follow the order Fe(III) > Cr(III) >> Cu(II) > Cd(II) > Pb(II) > Ni(II). Two standard reference materials were used for checking the accuracy and precision of the method. The proposed method was successfully applied to the analysis of environmental samples. This ligand material has great advantage for adsorption of transition-metal ions from aqueous medium due to its high degree of organofunctionalization associated with the large adsorption capacity, reutilization possibility, and rapidity in reaching the equilibrium. PMID- 23339040 TI - Randomized clinical trial of enhanced recovery versus standard care after laparoscopic sleeve gastrectomy. AB - BACKGROUND: Optimized perioperative care within an enhanced recovery after surgery (ERAS) protocol is designed to reduce morbidity after surgery, resulting in a shorter hospital stay. The present study evaluated this approach in the context of sleeve gastrectomy for patients with morbid obesity. METHODS: Patients were allocated to perioperative care according to a bariatric ERAS protocol or a control group that received standard care. These groups were also compared with a historical group of patients who underwent laparoscopic sleeve gastrectomy at the same institution between 2006 and 2010, selected using matched propensity scores. The primary outcome was median length of hospital stay. Secondary outcomes included readmission rates, postoperative morbidity, postoperative fatigue and mean cost per patient. RESULTS: Of 116 patients included in the analysis, 78 were allocated to the ERAS (40) or control (38) group and there were 38 in the historical group. There were no differences in baseline characteristics between groups. Median hospital stay was significantly shorter in the ERAS group (1 day) than in the control (2 days; P < 0.001) and historical (3 days; P < 0.001) groups. It was also shorter in the control group than in the historical group (P = 0.010). There was no difference in readmission rates, postoperative complications or postoperative fatigue. The mean cost per patient was significantly higher in the historical group than in the ERAS (P = 0.010) and control (P = 0.018) groups. CONCLUSION: The ERAS protocol in the setting of bariatric surgery shortened hospital stay and was cost-effective. There was no increase in perioperative morbidity. REGISTRATION NUMBER: NCT01303809 (http://www.clinicaltrials.gov). PMID- 23339041 TI - A rapid and sensitive LC-MS/MS method for the determination of osthole in rat plasma: application to pharmacokinetic study. AB - Osthole, a major component isolated from the fruit of Cnidium monnieri (L.) Cusson, has been widely used in traditional Chinese medicine. We developed and validated a rapid and sensitive LC-MS/MS method for the quantification of osthole in rat plasma. Sample preparation involved simple liquid-liquid extraction by ethyl acetate after addition of imperatorin as internal standard (IS). The analyte was separated using a C(18) column with the mobile phase of methanol-0.1% formic acid (80:20, v/v) at a flow rate of 0.4 mL/min. The elutes were detected under positive electrospray ionization in multiple reaction monitoring mode. The method was sensitive with 0.5 ng/mL as the lower limit of detection. Good linearity was obtained over the range of 1.0-500.0 ng/mL. The intra and inter batch accuracy for osthole in rat plasma samples ranged from 99.5 to 108.1% and the variation was <8.9%. The stability, extraction efficiency and matrix effect were also acceptable. This method was successfully applied to the pharmacokinetic study of osthole in rat after intravenous and oral administration. PMID- 23339042 TI - Molecular mechanisms of hypolipidemic effects of curcumin. AB - Recent evidence suggests potential benefits from phytochemicals and micronutrients in reducing the elevated oxidative and lipid-mediated stress associated with inflammation, obesity, and atherosclerosis. These compounds may either directly scavenge reactive oxygen or nitrogen species or they may modulate the activity of signal transduction enzymes leading to changes in the expression of antioxidant genes. Alternatively, they may reduce plasma lipid levels by modulating lipid metabolic genes in tissues and thus reduce indirectly lipid mediated oxidative and endoplasmic reticulum stress through their hypolipidemic effect. Here we review the proposed molecular mechanisms by which curcumin, a polyphenol present in the rhizomes of turmeric (Curcuma longa) spice, influences oxidative and lipid-mediated stress in the vascular system. At the molecular level, mounting experimental evidence suggests that curcumin may act chemically as scavenger of free radicals and/or influences signal transduction (e.g., Akt, AMPK) and modulates the activity of specific transcription factors (e.g., FOXO1/3a, NRF2, SREBP1/2, CREB, CREBH, PPARgamma, and LXRalpha) that regulate the expression of genes involved in free radicals scavenging (e.g., catalase, MnSOD, and heme oxygenase-1) and lipid homeostasis (e.g., aP2/FABP4, CD36, HMG-CoA reductase, and carnitine palmitoyltransferase-I (CPT-1)). At the cellular level, curcumin may induce a mild oxidative and lipid-metabolic stress leading to an adaptive cellular stress response by hormetic stimulation of these cellular antioxidant defense systems and lipid metabolic enzymes. The resulting lower oxidative and lipid-mediated stress may not only explain the beneficial effects of curcumin on inflammation, cardiovascular, and neurodegenerative disease, but may also contribute to the increase in maximum life-span observed in animal models. PMID- 23339043 TI - Prevalence and impact of restless legs syndrome in university students. PMID- 23339044 TI - Changes in reactive oxygen species production and antioxidant enzyme activity of Agaricus bisporus harvested at different stages of maturity. AB - BACKGROUND: The edible mushroom Agaricus bisporus is more prone to senescence than most other vegetables. However, the senescence of A. bisporus before harvesting is often ignored. In this study the changes in reactive oxygen species (ROS) production and antioxidant enzyme activity of A. bisporus harvested at four different stages of maturity were investigated. RESULTS: The firmness of A. bisporus decreased from 6.22 to 5.12 N. Respiration rate increased from 540.65 to 609.82 mg CO2 kg-1 fresh weight (FW) h-1. Browning degree increased from 0.42 to 0.71, showing a positive correlation with polyphenol oxidase activity. For ROS production, superoxide radical production rate increased from 0.51 to 1.16 nmol g 1 FW s-1. Hydrogen peroxide content increased from 0.81 to 1.39 nmol g-1 FW and then decreased rapidly to 0.68 nmol g-1 FW. Malondialdehyde content increased from 1.58 to 2.64 nmol g-1 FW. For antioxidant enzymes, superoxide dismutase and peroxidase activities decreased significantly at stage 4, whereas a significant increase in catalase activity was found at stages 3 and 4. CONCLUSIONS: The balance between ROS and antioxidants was destroyed at stage 4, causing extensive senescence of mushroom tissues. Thus A. bisporus should be harvested at stage 3. PMID- 23339045 TI - Quantification of 5-aminolevulinic acid by CE using dynamic pH junction technique. AB - An online dynamic pH junction preconcentration method was developed for quantification of 5-aminolevulinic acid (ALA) by CE with the separation time less than 6 min. The optimal dynamic pH junction of ALA was carried out between pH 9.3 borate buffer (BGE, 40 mM) and pH 2.5 phosphate buffer (sample matrix, 40 mM) when 4.1 cm of sample plug was hydrodynamically injected into an uncoated fused silica capillary (48.5 cm in length, id of 50 MUm). If a 24 kV separation voltage was applied, the calibration curve of ALA peak area (200 nm) showed good linearity (R(2) = 0.9991) ranging from 0.01 to 6.5 mg/mL. The reproducibility of this system was excellent with RSDs (n = 10) of 2.5% for peak area response and 0.6% for migration time at ALA concentration of 0.5 mg/mL. The LOD was evaluated as 1.0 MUg/mL (S/N > 3). Compared to conventional CE procedure, the sensitivity was successfully improved over 50-fold. The analytical results of pharmaceutical formulations show a good agreement with those by HPLC (r = 0.94). PMID- 23339046 TI - A new approach for pharmacokinetic studies of natural products: measurement of isoliquiritigenin levels in mice plasma, urine and feces using modified automated dosing/blood sampling system. AB - The present study was undertaken to investigate the pharmacokinetics of isoliquiritigenin (isoLQ) as determined by the automated dosing/blood sampling (ABS) and traditional manual blood sampling techniques in awake and freely moving mice using combined liquid chromatography tandem mass spectrometry. Pharmacokinetic comparison was conducted by allocating mice into two groups; an ABS group (intravenous study and oral studies, n = 5 each) and a manual group (intravenous and oral studies; n = 5 each). Significant differences in pharmacokinetic parameters (area under the curve and clearances) were observed between ABS and manual groups. This could be mainly due to the blood sampling site difference (via heart puncture in traditional manual group and via carotid artery in ABS groups). The low F of isoLQ could be mainly due to a considerable gastrointestinal and/or hepatic first-pass effect and not to incomplete absorption. The driving force for distribution and elimination of drugs is its concentration in the arterial blood. Therefore, the ABS method was found to be a useful drug development tool for accelerating the process of preclinical in vivo studies and for obtaining reliable and accurate pharmacokinetic parameters in mice. PMID- 23339047 TI - Randomized clinical trial of the impact of insulin therapy on liver function in patients undergoing major liver resection. AB - BACKGROUND: Postoperative liver dysfunction is the major source of morbidity and mortality in patients undergoing partial hepatectomy. This study tested the benefits of a metabolic support protocol based on insulin infusion, for reducing liver dysfunction following hepatic resection. METHODS: Consecutive consenting patients scheduled for liver resection were randomized to receive preoperative dextrose infusion followed by insulin therapy using the hyperinsulinaemic normoglycaemic clamp protocol (n = 29) or standard therapy (control group, n = 27). Patients in the insulin therapy group followed a strict dietary regimen for 24 h before surgery. Intravenous dextrose was started at 2 mg per kg per min the night before and continued until surgery. Hyperinsulinaemic therapy for a total of 24 h was initiated at 2 munits per kg per min at induction of anaesthesia, and continued at 1 munit per kg per min after surgery. Normoglycaemia was maintained (3.5-6.0 mmol/l). Control subjects received no additional dietary supplement and a conventional insulin sliding scale during fasting. All patients were tested serially to evaluate liver function using the Schindl score. Liver tissue samples were collected at two time points during surgery to measure glycogen levels. RESULTS: Demographics were similar in the two groups. More liver dysfunction occurred in the control cohort (liver dysfunction score range 0-8 versus 0-4 with insulin therapy; P = 0.031). Median (interquartile range) liver glycogen content was 278 (153-312) and 431 (334-459) umol/g respectively (P = 0.011). The number of complications rose with increasing severity of postoperative liver dysfunction (P = 0.032) CONCLUSION: The glucose-insulin protocol reduced postoperative liver dysfunction and improved liver glycogen content. REGISTRATION NUMBER: NCT00774098 (http://www.clinicaltrials.gov). PMID- 23339048 TI - Benign tremulous Parkinson's disease: a misnomer? PMID- 23339049 TI - Curcumin and obesity. AB - Turmeric has been long recognized for its anti-inflammatory and health-promoting properties. Curcumin is one of the principal anti-inflammatory and healthful components of turmeric comprising 2-8% of most turmeric preparations. Experimental evidence supports the activity of curcumin in promoting weight loss and reducing the incidence of obesity-related diseases. With the discovery that obesity is characterized by chronic low-grade metabolic inflammation, phytochemicals like curcumin which have anti-inflammatory activity are being intensely investigated. Recent scientific research reveals that curcumin directly interacts with white adipose tissue to suppress chronic inflammation. In adipose tissue, curcumin inhibits macrophage infiltration and nuclear factor kappaB (NF kappaB) activation induced by inflammatory agents. Curcumin reduces the expression of the potent proinflammatory adipokines tumor necrosis factor-alpha (TNFalpha), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor type-1 (PAI-1), and it induces the expression of adiponectin, the principal anti-inflammatory agent secreted by adipocytes. Curcumin also has effects to inhibit adipocyte differentiation and to promote antioxidant activities. Through these diverse mechanisms curcumin reduces obesity and curtails the adverse health effects of obesity. PMID- 23339050 TI - Effects of the NYU caregiver intervention-adult child on residential care placement. AB - PURPOSE: This study determined whether the NYU Caregiver Intervention, adapted in Minnesota for adult child caregivers (NYUCI-AC), prevented or delayed residential care placement for persons with dementia. DESIGN AND METHODS: A single-blinded randomized controlled trial design was used. One hundred and seven adult child caregivers of persons with dementia were randomly assigned to the NYUCI-AC treatment group who received individual and family counseling, support group referral, and ad hoc consultation or a contact control group. Participants were asked to complete structured assessments quarterly during Year 1 and every 6 months thereafter for a minimum of 2 years. RESULTS: Two thirds (66%) of adult child caregivers in the control condition admitted their parent to a residential care setting compared with 37% in the treatment condition. Logistic regression and Cox proportional hazards models found that NYUCI-AC participants were significantly less likely (p < .05) to admit their parents to a residential care setting and delayed their parents' time to admission significantly longer (228.36 days longer on average) than those in the control group. IMPLICATIONS: The multicomponent NYUCI-AC offered adult children the psychosocial support required to continue providing care to cognitively impaired parents at home. PMID- 23339051 TI - Sonographic findings in acute uterine inversion. AB - We present a case of acute uterine inversion in the third stage of labor in which critical management decisions were facilitated by ultrasound imaging in the operating room. Identification of the ovary and adnexa pulled into the indentation of the inversion allowed the successful diagnosis and guidance for uterine replacement. PMID- 23339052 TI - Synthesis of long-circulating, backbone degradable HPMA copolymer-doxorubicin conjugates and evaluation of molecular-weight-dependent antitumor efficacy. AB - Backbone degradable, linear, multiblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (DOX) conjugates are synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization followed by chain extension via thiol-ene click reaction. The examination of molecular-weight-dependent antitumor activity toward human ovarian A2780/AD carcinoma in nude mice reveals enhanced activity of multiblock, second-generation, higher molecular weight conjugates when compared with traditional HPMA copolymer-DOX conjugates. The examination of body weight changes during treatment indicates the absence of non specific adverse effects. PMID- 23339053 TI - Liquid chromatography-tandem mass spectrometric assay for the determination of tetrabenazine and its active metabolites in human plasma: a pharmacokinetic study. AB - A simple, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC MS/MS) assay method has been developed and fully validated for the simultaneous quantification of tetrabenazine and its active metabolites alpha dihydrotetrabenazine and beta-dihydrotetrabenazine in human plasma. Tetrabenazine d7 was used as internal standard (IS). The analytes were extracted from 200 MUL aliquots of human plasma via solid-phase extraction using C18 solid-phase extraction cartridges. The reconstituted samples were chromatographed on a Zorbax SB C18 column using a 60:40 (v/v) mixture of acetonitrile and 5 mm ammonium acetate as the mobile phase at a flow rate of 0.8 mL/min. The API-4000 LC-MS/MS in multiple reaction-monitoring mode was used for detection. The calibration curves obtained were linear (r(2) >= 0.99) over the concentration range of 0.01 5.03 ng/mL for tetrabenazine and 0.50-100 ng/mL for alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine. Method validation was performed as per Food and Drug Administration guidelines and the results met the acceptance criteria. The method is precise and sensitive enough for its intended purpose. A run time of 2.5 min for each sample made it possible to analyze more than 300 plasma samples per day. The proposed method was found to be applicable to clinical studies. PMID- 23339054 TI - Caffeine consumption and risk of dyskinesia in CALM-PD. AB - BACKGROUND: Adenosine A2A receptor antagonists reduce or prevent the development of dyskinesia in animal models of levodopa-induced dyskinesia. METHODS: We examined the association between self-reported intake of the A2A receptor antagonist caffeine and time to dyskinesia in the Comparison of the Agonist Pramipexole with Levodopa on Motor Complications of Parkinson's Disease (CALM-PD) and CALM Cohort extension studies, using a Cox proportional hazards model adjusting for age, baseline Parkinson's severity, site, and initial treatment with pramipexole or levodopa. RESULTS: For subjects who consumed >12 ounces of coffee/day, the adjusted hazard ratio for the development of dyskinesia was 0.61 (95% CI, 0.37-1.01) compared with subjects who consumed <4 ounces/day. For subjects who consumed between 4 and 12 ounces/day, the adjusted hazard ratio was 0.73 (95% CI, 0.46-1.15; test for trend, P = .05). CONCLUSIONS: These results support the possibility that caffeine may reduce the likelihood of developing dyskinesia. PMID- 23339055 TI - Curcumin, a component of turmeric: from farm to pharmacy. AB - Curcumin, an active polyphenol of the golden spice turmeric, is a highly pleiotropic molecule with the potential to modulate the biological activity of a number of signaling molecules. Traditionally, this polyphenol has been used in Asian countries to treat such human ailments as acne, psoriasis, dermatitis, and rash. Recent studies have indicated that curcumin can target newly identified signaling pathways including those associated with microRNA, cancer stem cells, and autophagy. Extensive research from preclinical and clinical studies has delineated the molecular basis for the pharmaceutical uses of this polyphenol against cancer, pulmonary diseases, neurological diseases, liver diseases, metabolic diseases, autoimmune diseases, cardiovascular diseases, and numerous other chronic diseases. Multiple studies have indicated the safety and efficacy of curcumin in numerous animals including rodents, monkeys, horses, rabbits, and cats and have provided a solid basis for evaluating its safety and efficacy in humans. To date, more than 65 human clinical trials of curcumin, which included more than 1000 patients, have been completed, and as many as 35 clinical trials are underway. Curcumin is now used as a supplement in several countries including the United States, India, Japan, Korea, Thailand, China, Turkey, South Africa, Nepal, and Pakistan. In this review, we provide evidence for the pharmaceutical uses of curcumin for various diseases. PMID- 23339056 TI - Systematic review and meta-analysis of the effect of perioperative steroids on ischaemia-reperfusion injury and surgical stress response in patients undergoing liver resection. AB - BACKGROUND: Several therapeutic strategies, such as ischaemic preconditioning, intermittent or selective pedicle clamping and pharmacological interventions, have been explored to reduce morbidity caused by hepatic ischaemia-reperfusion injury and the surgical stress response. The role of steroids in this setting remains controversial. METHODS: A comprehensive literature search in MEDLINE, Embase and the Cochrane Register of Clinical Trials (CENTRAL) was conducted (1966 onwards), identifying studies comparing perioperative administration of intravenous steroids with standard care or placebo, in the setting of liver surgery. Randomized Controlled trials (RCTs) and non-RCTs were included. Critical appraisal and meta-analysis were carried out according to the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) statement. RESULTS: Six articles were included; five were RCTs. Pooling the results revealed that patients receiving intravenous glucocorticoids were 24 per cent less likely to suffer postoperative morbidity compared with controls (risk ratio 0.76, 95 per cent confidence interval 0.57 to 0.99; P = 0.047). The treated group experienced a significantly greater rise in early postoperative interleukin (IL) 10 levels compared with controls. In addition, steroids significantly reduced postoperative blood levels of bilirubin, and of inflammatory markers such as IL-6 and C reactive protein. There was no evidence supporting a risk difference in infectious complications and wound healing between study groups. CONCLUSION: Perioperative steroids have a favourable impact on postoperative outcomes after liver resection. PMID- 23339063 TI - Spleen stiffness: toward a noninvasive portal sphygmomanometer? PMID- 23339064 TI - Cholinergic neurons: an unexpected source of striatal dopamine release. PMID- 23339067 TI - Hepatocyte caspase-8 is an essential modulator of steatohepatitis in rodents. AB - In human and murine models of nonalcoholic steatohepatitis (NASH), increased hepatocyte apoptosis is a critical mechanism contributing to inflammation and fibrogenesis. Caspase 8 (Casp8) is essential for death-receptor-mediated apoptosis activity and therefore its modulation might be critical for the pathogenesis of NASH. The aim was to dissect the role of hepatocyte Casp8 in a murine model of steatohepatitis. We generated hepatocyte-specific Casp8 knockout (Casp8(Deltahep) ) mice. Animals were fed with a methionine-choline-deficient (MCD) diet. Liver injury was assessed by histopathological analysis, apoptotic death, serum alanine aminotransferase (ALT), fluorescent-activated cell sorter (FACS), analysis of liver infiltration and inflammation, reactive oxygen species (ROS), and liver fibrosis. MCD feeding triggered steatosis, hepatic lipid storage, and accumulation of free fatty acid (FFA) in wildtype (WT) livers, which were significantly reduced in Casp8(Deltahep) animals. Additionally, lack of Casp8 expression in hepatocytes reduced the MCD-dependent increase in apoptosis and decreased expression of proinflammatory cytokines as well as hepatic infiltration. As a consequence, ROS production was lower, leading to a reduction in the progression of liver fibrosis in Casp8(Deltahep) livers. CONCLUSION: Selective ablation of Casp8 in hepatocytes ameliorates development of NASH by modulating liver injury. Casp8-directed therapy might be a plausible treatment for patients with steatohepatitis. (HEPATOLOGY 2013;57:2189-2201). PMID- 23339066 TI - MicroRNAs in age-related diseases. AB - Aging is a complex process that is linked to an increased incidence of major diseases such as cardiovascular and neurodegenerative disease, but also cancer and immune disorders. MicroRNAs (miRNAs) are small non-coding RNAs, which post transcriptionally control gene expression by inhibiting translation or inducing degradation of targeted mRNAs. MiRNAs target up to hundreds of mRNAs, thereby modulating gene expression patterns. Many miRNAs appear to be dysregulated during cellular senescence, aging and disease. However, only few miRNAs have been so far linked to age-related changes in cellular and organ functions. The present article will discuss these findings, specifically focusing on the cardiovascular and neurological systems. PMID- 23339068 TI - The use of spin desalting columns in DMSO-quenched H/D-exchange NMR experiments. AB - Dimethylsulfoxide (DMSO)-quenched hydrogen/deuterium (H/D)-exchange is a powerful method to characterize the H/D-exchange behaviors of proteins and protein assemblies, and it is potentially useful for investigating non-protected fast exchanging amide protons in the unfolded state. However, the method has not been used for studies on fully unfolded proteins in a concentrated denaturant or protein solutions at high salt concentrations. In all of the current DMSO quenched H/D-exchange studies of proteins so far reported, lyophilization was used to remove D2 O from the protein solution, and the lyophilized protein was dissolved in the DMSO solution to quench the H/D exchange reactions and to measure the amide proton signals by two-dimensional nuclear magnetic resonance (2D NMR) spectra. The denaturants or salts remaining after lyophilization thus prevent the measurement of good NMR spectra. In this article, we report that the use of spin desalting columns is a very effective alternative to lyophilization for the medium exchange from the D2 O buffer to the DMSO solution. We show that the medium exchange by a spin desalting column takes only about 10 min in contrast to an overnight length of time required for lyophilization, and that the use of spin desalting columns has made it possible to monitor the H/D-exchange behavior of a fully unfolded protein in a concentrated denaturant. We report the results of unfolded ubiquitin in 6.0M guanidinium chloride. PMID- 23339069 TI - From channelrhodopsins to optogenetics. PMID- 23339070 TI - Reducing cost in sequential testing: a limit of indifference approach. AB - In noninferiority studies, a limit of indifference is used to express a tolerance in results such that the clinician would regard such results as being acceptable or 'not worse'. We applied this concept to a measure of accuracy, the Receiver Operating Characteristic (ROC) curve, for a sequence of tests. We expressed a limit of indifference for the range of acceptable sensitivity values and examined the associated cost of testing within this range. In doing so, we generated the minimum cost maximum ROC (MCMROC) curve, which reflects the reduced sensitivity and cost of testing. We compared the MCMROC and its associated cost curve between limits of indifference set to 0.999 [a 0.1% reduction in true positive rate (TPR)], 0.95 (a 5% reduction in TPR), and 1 (no reduction in TPR). The limit of indifference tended to have less of an effect on the MCMROC curves than on the associated cost curves that were greatly affected. Cost was reduced at high false positive rates (FPRs) at higher limit of indifference (0.999) and at small FPRs as the limit of indifference decreased (0.95). These patterns were also observed as applied to sequential strategies used to diagnose diabetes in the Pima Indians. PMID- 23339072 TI - Journeys into the genome of cancer cells. PMID- 23339071 TI - Open and shut: crystal structures of the dodecylmaltoside solubilized mechanosensitive channel of small conductance from Escherichia coli and Helicobacter pylori at 4.4 A and 4.1 A resolutions. AB - The mechanosensitive channel of small conductance (MscS) contributes to the survival of bacteria during osmotic downshock by transiently opening large diameter pores for the efflux of cellular contents before the membrane ruptures. Two crystal structures of the Escherichia coli MscS are currently available, the wild type protein in a nonconducting state at 3.7 A resolution (Bass et al., Science 2002; 298:1582-1587) and the Ala106Val variant in an open state at 3.45 A resolution (Wang et al., Science 2008; 321:1179-1183). Both structures used protein solubilized in the detergent fos-choline-14. We report here crystal structures of MscS from E. coli and Helicobacter pylori solubilized in the detergent beta-dodecylmaltoside at resolutions of 4.4 and 4.2 A, respectively. While the cytoplasmic domains are unchanged in these structures, distinct conformations of the transmembrane domains are observed. Intriguingly, beta dodecylmaltoside solubilized wild type E. coli MscS adopts the open state structure of A106V E. coli MscS, while H. pylori MscS resembles the nonconducting state structure observed for fos-choline-14 solubilized E. coli MscS. These results highlight the sensitivity of membrane protein conformational equilibria to variations in detergent, crystallization conditions, and protein sequence. PMID- 23339073 TI - Olfactory ensheathing cells: the primary innate immunocytes in the olfactory pathway to engulf apoptotic olfactory nerve debris. AB - The olfactory system is an unusual tissue in which olfactory receptor neurons (ORNs) are continuously replaced throughout the life of mammals. Clearance of the apoptotic ORNs corpses is a fundamental process serving important functions in the regulation of olfactory nerve turnover and regeneration. However, little is known about the underlying mechanisms. Olfactory ensheathing cells (OECs) are a unique type of glial cells that wrap olfactory axons and support their continual regeneration from the olfactory epithelium to the bulb. In the present study, OECs were identified to exist in two different states, resting and reactive, in which resting OECs could be activated by LPS stimulation and functioned as phagocytes for cleaning apoptotic ORNs corpses. Confocal analysis revealed that dead ORNs debris were engulfed by OECs and co-localized with lysosome associated membrane protein 1. Moreover, phosphatidylserine (PS) receptor was identified to express on OECs, which allowed OECs to recognize apoptotic ORNs by binding to PS. Importantly, engulfment of olfactory nerve debris by OECs was found in olfactory mucosa under normal turnover and was significantly increased in the animal model of olfactory bulbectomy, while little phagocytosis by Iba-1-positive microglia/macrophages was observed. Together, these results implicate OEC as a primary innate immunocyte in the olfactory pathway, and suggest a cellular and molecular mechanism by which ORNs corpses are removed during olfactory nerve turnover and regeneration. PMID- 23339074 TI - Rapid expression screening of eukaryotic membrane proteins in Pichia pastoris. AB - The overexpression of milligram quantities of protein remains a key bottleneck in membrane protein structural biology. A challenge of particular difficulty has been the overproduction of eukaryotic membrane proteins. In order to cope with the frequently poor expression levels associated with these challenging proteins, it is often necessary to screen a large number of homologues to find a well expressing clone. To facilitate this process using the heterologous, eukaryotic expression host Pichia pastoris, we have developed a simple fluorescent induction plate-screening assay that allows for the rapid detection of well expressing clones of eukaryotic membrane proteins that have been fused to GFP. Using a eukaryotic membrane protein known to express well in P. pastoris (human aquaporin 4) and homologues of the ER associated membrane protein phosphatidylethanolamine N-methyltransferase (PEMT), we demonstrate that when a large number of clones are screened, a small number of highly expressing "jackpot" clones can be isolated. A jackpot PEMT clone resulted in 5 mg/L yield after purification. The method allows for the facile simultaneous screening of hundreds of clones providing an alternate to in-culture screening and will greatly accelerate the search for overexpressing eukaryotic membrane proteins. PMID- 23339075 TI - Differences in birth weight by sex using adjusted quantile distance functions. AB - Herein, we report results from a study of birth weight distribution among boys and girls born in Norway in 2008. As our primary interest was to detect differences in the variability between the two sexes, we used the quantile distance function to describe the difference between two distribution functions. We used an adjusted version of the quantile function to look into the relation of sex differences in birth weight conditioned on maternal age, gestational age, preeclampsia, maternal diabetes type 1, maternal smoking status, and parity. At term (?37 weeks of gestation), boys showed a greater variability in birth weight than did girls, and these differences were maintained in the adjusted model. We also found that maternal age and maternal smoking habits influenced both sexes equally, whereas gestational age, preeclampsia, maternal diabetes type 1, and parity influenced one sex more than the other. The adjusted quantile distance function proved efficient in analyzing and demonstrating how covariates influence sex differences in birth weight. PMID- 23339076 TI - Structure prediction of binary pernitride MN2 compounds (M=Ca, Sr, Ba, La, and Ti). AB - Metal-pernitride compounds belong to a class of chemical systems in which both the complex ions and the non-bonding electrons may play roles in the formation of their modified crystalline structures. To investigate this issue, the energy landscapes of pernitrides of metals with different maximum valence (M=Ca, Sr, Ba, La, and Ti) were globally explored on the ab initio level at standard and high pressures, thereby yielding possible (meta)stable modifications in these systems together with information on how the landscape changed as function of the valence of the metal cation. For all of the systems in which no compounds had been synthesized so far, we predicted the existence of kinetically stable modifications that should, in principle, be experimentally accessible. In particular, TiN2 should crystallize in a new structure type, TiN2-I. PMID- 23339077 TI - Somatotopic astrocytic activity in the somatosensory cortex. AB - Astrocytes play a crucial role in maintaining neuronal function and monitoring their activity. According to neuronal activity maps, the body is represented topographically in the somatosensory cortex. In rats, neighboring cortical areas receive forelimb (FL) and hindlimb (HL) sensory inputs. Whether astrocytic activity is also restricted to the cortical area receiving the respective peripheral sensory inputs is not known. Using wide field optical imaging we measured changes in the concentration of astrocytic calcium within the FL and HL sensorimotor cortex in response to peripheral sensory inputs. Mapping the calcium signals upon electrical stimulation of the forepaw and hindpaw we found activity largely restricted to the FL and HL area, respectively. In comparison to neuronal activity the time course of the astrocytic calcium activity was considerably slower. The signal took 6 s to peak after the onset of a 2 Hz and 2 s long electrical stimulation of the hindpaw and 8 s for a 4 s stimulation. The astrocytic signals were delayed relative to cerebral blood flow measured using laser speckle imaging. The intensity of both the astrocytic and neuronal signals in the HL sensorimotor cortex declined with increase in stimulation frequency. Moreover, blocking neuronal input by tetrodotoxin abolished astrocytic calcium signals. We suggest that the topographical representation of the body is not only true for cortical neurons but also for astrocytes. The maps and the frequency dependent activations reflect strong reciprocal neuroglial communication and provide a new experimental approach to explore the role of astrocytes in health and disease. PMID- 23339078 TI - Sequence motifs of myelin membrane proteins: towards the molecular basis of diseases. AB - The shortest sequence of amino acids in protein containing functional and structural information is a "motif." To understand myelin protein functions, we intensively searched for motifs that can be found in myelin proteins. Some myelin proteins had several different motifs or repetition of the same motif. The most abundant motif found among myelin proteins was a myristoylation motif. Bovine MAG held 11 myristoylation motifs and human myelin basic protein held as many as eight such motifs. PMP22 had the fewest myristoylation motifs, which was only one; rat PMP22 contained no such motifs. Cholesterol recognition/interaction amino-acid consensus (CRAC) motif was not found in myelin basic protein. P2 protein of different species contained only one CRAC motif, except for P2 of horse, which had no such motifs. MAG, MOG, and P0 were very rich in CRAC, three to eight motifs per protein. The analysis of motifs in myelin proteins is expected to provide structural insight and refinement of predicted 3D models for which structures are as yet unknown. Analysis of motifs in mutant proteins associated with neurological diseases uncovered that some motifs disappeared in P0 with mutation found in neurological diseases. There are 2,500 motifs deposited in a databank, but 21 were found in myelin proteins, which is only 1% of the total known motifs. There was great variability in the number of motifs among proteins from different species. The appearance or disappearance of protein motifs after gaining point mutation in the protein related to neurological diseases was very interesting. PMID- 23339080 TI - Iodine-initiated domino reaction of hepta-1,2-dien-6-yn-4-ols and Bronsted acid promoted cyclization of hepta-1,2,6-trien-4-ols leading to functionalized benzenes. PMID- 23339079 TI - Fetal health shocks and early inequalities in health capital accumulation. AB - Several studies report socioeconomic inequalities in child health and consequences of early disease. However, not much is known about inequalities in health capital accumulation in the womb in response to fetal health shocks, which is essential for finding the earliest sensitive periods for interventions to reduce inequalities. We identify inequalities in birth weight accumulation as a result of fetal health shocks from the occurrence of one of the most common birth defects, oral clefts, within the first 9 weeks of pregnancy, using quantile regression and two datasets from South America and the USA. Infants born at lower birth weight quantiles are significantly more adversely affected by the health shock compared with those born at higher birth weight quantiles, with overall comparable results between the South American and US samples. These results suggest that fetal health shocks increase child health disparities by widening the spread of the birth weight distribution and that health inequalities begin in the womb, requiring interventions before pregnancy. PMID- 23339081 TI - Astrocytes are a neural target of morphine action via glucocorticoid receptor dependent signaling. AB - Chronic opioid use leads to the structural reorganization of neuronal networks, involving genetic reprogramming in neurons and glial cells. Our previous in vivo studies have revealed that a significant fraction of the morphine-induced alterations to the striatal transcriptome included glucocorticoid (GC) receptor (GR)-dependent genes. Additional analyses suggested glial cells to be the locus of these changes. In the current study, we aimed to differentiate the direct transcriptional effects of morphine and a GR agonist on primary striatal neurons and astrocytes. Whole-genome transcriptional profiling revealed that while morphine had no significant effect on gene expression in both cell types, dexamethasone significantly altered the transcriptional profile in astrocytes but not neurons. We obtained a complete dataset of genes undergoing the regulation, which includes genes related to glucose metabolism (Pdk4), circadian activity (Per1) and cell differentiation (Sox2). There was also an overlap between morphine-induced transcripts in striatum and GR-dependent transcripts in cultured astrocytes. We further analyzed the regulation of expression of one gene belonging to both groups, serum and GC regulated kinase 1 (Sgk1). We identified two transcriptional variants of Sgk1 that displayed selective GR-dependent upregulation in cultured astrocytes but not neurons. Moreover, these variants were the only two that were found to be upregulated in vivo by morphine in a GR dependent fashion. Our data suggest that the morphine-induced, GR-dependent component of transcriptome alterations in the striatum is confined to astrocytes. Identification of this mechanism opens new directions for research on the role of astrocytes in the central effects of opioids. PMID- 23339082 TI - Exercise performance in thalassemia major: correlation with cardiac iron burden. AB - Exercise performance is decreased in patients with Thalassemia major (TM), but the relative impact of anemia and iron overload on exercise capacity is unknown. We assessed the cardiopulmonary function of 71, well-transfused TM patients via graded treadmill exercise stress test. All patients underwent MRI of the heart, pancreas, and liver and diagnostic phlebotomy. Patients ranged in age from 13 to 46 years of age. Fifteen patients were excluded from analysis due to submaximal effort. Mean Vo2 max was 83.0% of predicted and was limited by abnormal cardiovascular mechanisms, consisting of a decreased O2 pulse (86.6% of predicted) in men and decreased maximum heart rate (HR) response (85% of predicted) in women. Patients with hemoglobin less than 12 g/dL had lower O2 pulse and Vo2 max, regardless of sex. Cardiac iron was negatively associated with maximum HR response and Vo2 max (r2 = 0.10 and 0.08, respectively, P < 0.05). Vo2 max was correlated with cardiac R2*, hs-CRP, sex and hemoglobin in decreasing strength of association. In thalassemia, exercise performance is limited by impaired stroke-volume reserve in men and blunted HR response in women. Iron toxicity may be mediated through vascular inflammation and direct modulation of HR response to exercise. PMID- 23339083 TI - Price controls for medical innovations in a life cycle perspective. AB - We study the market for new medical technologies from a life cycle perspective, incorporating the fact that healthcare utilization is biased towards old age. Contrary to conventional wisdom, we find that price controls on medical innovations can expand investment in medical R&D and results in Pareto superior social outcomes, a consequence of the price controls' ability to increase saving. Importantly, this finding occurs only when the price cap regime is extensive: selective regulation on few technologies - such as pharmaceuticals alone - have the conventional negative effect on innovation. PMID- 23339084 TI - Microproteomics by liquid extraction surface analysis: application to FFPE tissue to study the fimbria region of tubo-ovarian cancer. AB - PURPOSE: We have developed a new method for rapid analysis of a specific region on formalin fixed and paraffin embedded (FFPE) tissue sections. This method combines advantages of direct tissue MS analysis keeping histological information and conventional proteomics approaches for confident identification of proteins in complex sample. EXPERIMENTAL DESIGN: After histological annotation, heat induced antigen retrieval is performed on FFPE tissue. Using a chemical inkjet printer, trypsin is deposited on discrete regions of less than 1 mm2. After protein digestion, a liquid extraction is performed to retrieve all the peptides. Data coming from identification of proteins in cancer and benign region are compared. RESULTS: In total, 3649 unique peptides were identified (with a peptide strict false discovery rate less than 1%) corresponding to 983 and 792 nonredundant protein groups identified in benign and cancer region, respectively. A total of 123 protein groups are found only in cancer region and 315 are specific to the benign part. From these data, it has been possible to obtain different important signaling pathways involved in cancer processes and some proteins already known as biomarkers. CONCLUSIONS AND CLINICAL RELEVANCE: This new approach using a combination of localized on-tissue protein digestion and liquid microextraction followed by LC-MS/MS analysis is useful for advancing our understanding of cancer biology. It is a rapid and innovative technique that will contribute positively to clinical proteomics. PMID- 23339085 TI - Three-dimensional demonstration of the lymphatic system in the lower extremities with multi-detector-row computed tomography: a study in a cadaver model. AB - Sentinel lymph node biopsy (SLNB) has had a great impact on the staging and treatment of cancer. The purpose of this study was to study the lymphatic anatomy of the lower extremities by constructing three-dimensional images using multi detector-row computed tomography (MDCT). To select appropriate contrast media for MDCT lymphatic imaging in a cadaver, we tested four kinds of contrast media by injecting them into fresh swine kidneys. After the suitable contrast medium was selected, 10 lower extremities from 5 fresh cadavers were studied. After injection of the contrast medium, each lower extremity was scanned with high spatial-resolution MDCT. The zinc oxide mixture was found to be the most appropriate contrast formula for MDCT imaging of cadaver lymphatics in terms of CT value and no extravasation. The high-resolution MDCT imaging revealed two different superficial lymphatic pathways in the legs. One lymphatic pathway accompanying the great saphenous vein had a constant course and was connected to the superficial inguinal lymph nodes. However, another pathway, along the small saphenous vein, was variable. Some of the deep lymphatic vessels bypassed the inguinal lymph nodes. Using a new protocol, we were able to construct three dimensional images of the lower extremity lymphatics in a cadaver model. MDCT imaging provided novel information about two different superficial lymphatic pathways in the lower extremities. PMID- 23339086 TI - SIE, SIES, GITMO revised guidelines for the management of follicular lymphoma. AB - By using the GRADE system, we updated the guidelines for management of follicular cell lymphoma issued in 2006 from SIE, SIES, and GITMO group. We confirmed our recommendation to frontline chemoimmunotherapy in patients with Stage III-IV disease and/or high tumor burden. Maintenance rituximab was also recommended in responding patients. In patients relapsing after an interval longer than 12 months from frontline therapy, we recommended chemoimmunotherapy with non cross resistant regimens followed by rituximab maintenance. High dose chemotherapy followed by hematopoietic stem cell transplant was recommended for young fit patients who achieve a response after salvage chemoimmunotherapy. PMID- 23339087 TI - Frequency of palmaris longus absence and its association with other anatomical variations in the Egyptian population. AB - The palmaris longus (PL) is one of the most variable muscles in the human body. Racial differences in its variation have been documented. Several studies have attempted to correlate PL absence with other anatomical variations. This study was conducted to determine the prevalence of absence of PL, correlate it with gender and body side and to determine its association with other anatomical variations in the Egyptian population. The presence of PL was clinically determined in 386 Egyptians using the standard technique. All subjects were examined for the presence of the flexor digitorum superficialis (FDS) to the fifth finger. Allen's test was done to assess the completeness of the superficial palmar arch (SPA). The overall prevalence of absence of the PL in Egyptian subjects was 50.8%. There was no significant difference in PL absence with regard to the body side but a significant difference was seen as regards gender and when bilateral absence of PL was compared to its unilateral absence. Absence of FDS tendon to the fifth finger was seen in 1.3% subjects. There was no association between the absence of the FDS tendon to the fifth finger and either presence or absence of PL and also between the absence of PL and the incompleteness of SPA in both genders. In conclusion, the prevalence of absence of PL in the Egyptian population represents one of the highest rates of absence to be reported for this muscle, which is significantly different from that in other ethnic groups. PMID- 23339088 TI - Improved protein extraction and protein identification from archival formalin fixed paraffin-embedded human aortas. AB - PURPOSE: Evaluate combination of heat and elevated pressure to enhance protein extraction and quality of formalin-fixed (FF), and FF paraffin-embedded (FFPE) aorta for proteomics. EXPERIMENT DESIGN: Proteins were extracted from fresh frozen aorta at room temperature (RT). FF and FFPE aortas (3 months and 15 years) were extracted at RT, heat alone, or a combination of heat and high pressure. Protein yields were compared, and digested peptides from the extracts were analyzed with MS. RESULTS: Combined heat and elevated pressure increased protein yield from human FF or FFPE aorta compared to matched tissues with heat alone (1.5-fold) or at RT (8.3-fold), resulting in more proteins identified and with more sequence coverage. The length of storage did adversely affect the quality of proteins from FF tissue. For long-term storage, aorta was preserved better with FFPE than FF alone. Periostin and MGF-E8 were demonstrated suitable for MRM assays from FFPE aorta. CONCLUSIONS AND CLINICAL RELEVANCE: Combination of heat and high pressure is an effective method to extract proteins from FFPE aorta for downstream proteomics. This method opens the possibility for use of archival and often rare FFPE aortas and possibly other tissues available to proteomics for biomarker discovery and quantification. PMID- 23339089 TI - Pdx1 protein induces human embryonic stem cells into the pancreatic endocrine lineage. AB - Success in generating insulin-producing cells (IPCs) from human embryonic stem (hES) cells by genetic manipulation has recently revealed a new therapeutic potential for diabetes. However, clinical application has been hampered by the viral genome integration and the risk of insertion mutagenesis that are entailed. Herein, we report the induction of hEC into IPCs by direct delivery of human Pdx1 proteins per se. Recombinant human Pdx1 proteins (hPdx1), which have an Antennapedia-like protein transduction domain sequence in their structure, can be efficiently translocated into hES cells and function as pancreatic transcription factor. hPdx1 protein activates a group of genes related to pancreatic beta-cell lineage development in hES cells, including NeuroD1, Nkx2.2, Pax4, Pax6, Nkx6.1 and Isl-1. hPdx1-treated hES cells synthesise and release insulin in response to glucose challenge. Therefore, this study constitutes a proof-of-concept demonstration of protein-mediated pancreatic specific differentiation of the hES cells by exploiting specific intrinsic properties of the hPdx1 protein. PMID- 23339090 TI - Role of 14-3-3sigma in resistance to cisplatin in non-small cell lung cancer cells. AB - The efficacies of chemotherapeutic agents are often limited by side effects and acquired drug resistance. We have investigated whether the differential expression pattern of 14-3-3sigma affects cisplatin response in non-small cell lung cancer cell lines. Two pairs of parental/cisplatin resistant cell lines (A549/CRA549 and Calu1/CR-Calu1) and clinical lung cancer biopsy samples were analysed for 14-3-3sigma expression. Cell viability was assessed by WST assay; and 14-3-3sigma expression was suppressed by siRNA transfection. 14-3-3sigma mRNA expression increased in CR-A549 and CR-Calu1 compared with their cisplatin sensitive parental A549 and Calu1 cell lines. But when 14-3-3sigma expression was suppressed, elevated cisplatin response was seen in A549 and CR-Calu1 cell lines. Increased 14-3-3sigma expression might also account for reduced cisplatin response in vivo, since, 14-3-3sigma expression in clinical biopsy samples obtained from lung cancer patients undergoing cisplatin-based chemotherapy significantly higher in the non-responder compared with the responder group. We therefore propose that increased 14-3-3sigma expression is correlated with cisplatin response in non-small cell lung cancer cells; monitoring its expression might become useful in the future in predicting poor outcome to cisplatin treatment and/or the verification of acquired cisplatin resistance in lung cancer patients. PMID- 23339091 TI - Differentiation of mouse induced pluripotent stem cells into corneal epithelial like cells. AB - Somatic cells can be reprogrammed into a pluripotent ES-cell-like state (termed induced pluripotent stem cells, iPS) by transcription factors, which have enormous therapeutic potential for regenerative medicine. We have investigated whether iPS can directly differentiate into corneal epithelium-like cells. Mouse iPS cells were co-cultured with corneal limbal stroma. RT-PCR, immunohistochemistry and scanning electron microscopy analysis were used to detect differentiated iPS. Undifferentiated iPS cells expressed ES cells related genes. Co-culture with corneal limbal stroma, in the presence of additional factors bFGF, EGF and NGF, activated keratin expression 12 (K12, a marker of corneal epithelial cells) and downregulated Nanog. These data suggest that mouse iPS cells can differentiate into corneal epithelial-like cells by replication of a corneal epithelial stem cell niche. PMID- 23339092 TI - The role of automated analyzers in detecting abnormal granulation of leucocytes in lysosomal storage diseases: Maroteaux-Lamy disease. PMID- 23339093 TI - Direct oxidation of cycloalkanes to cycloalkanones with oxygen in water. PMID- 23339094 TI - Paravalvular aortic leak after transcatheter aortic valve replacement: current knowledge. PMID- 23339095 TI - Atrial fibrillation through the years: contemporary evaluation and management. PMID- 23339096 TI - Pneumoabdomen with abdominal compartment and aortic collapse due to gastric bursting acute release by trocar insertion. PMID- 23339097 TI - Traumatic coronary artery dissection: potential cause of sudden death in soccer. PMID- 23339098 TI - Letter by Lippi and Cervellin regarding article, "High-sensitivity cardiac troponin in the distinction of acute myocardial infarction from acute cardiac noncoronary artery disease". PMID- 23339099 TI - Letter by Carmo et al regarding article, "High-sensitivity cardiac troponin in the distinction of acute myocardial infarction from acute cardiac noncoronary artery disease". PMID- 23339101 TI - A benign psoas teratoma of the non-pelvic retroperitoneal space: A case report. AB - This case report is of a benign retroperitoneal teratoma which was adherent to the psoas muscle of a 53-year-old female cadaver with a history of metastatic bladder cancer as a cause of death. Teratomas possess derivatives of all three germ cell layers and are usually seen either in children or in the lower pelvic region of adults. The finding of this mass deep to the inferior pole of the kidney is quite unusual. Few studies mention a possible association between metastatic cancer and teratoma growth in extrapelvic locations. The following report is a detailed account of this unusual finding and a summary of the literature on growths of this kind. PMID- 23339100 TI - Complete solubilization of formalin-fixed, paraffin-embedded tissue may improve proteomic studies. AB - Tissue-based proteomic approaches (tissue proteomics) are essential for discovering and evaluating biomarkers for personalized medicine. In any proteomics study, the most critical issue is sample extraction and preparation. This problem is especially difficult when recovering proteins from formalin fixed, paraffin-embedded (FFPE) tissue sections. However, improving and standardizing protein extraction from FFPE tissue is a critical need because of the millions of archival FFPE tissues available in tissue banks worldwide. Recent progress in the application of heat-induced antigen retrieval principles for protein extraction from FFPE tissue has resulted in a number of published FFPE tissue proteomics studies. However, there is currently no consensus on the optimal protocol for protein extraction from FFPE tissue or accepted standards for quantitative evaluation of the extracts. Standardization is critical to ensure the accurate evaluation of FFPE protein extracts by proteomic methods such as reverse phase protein arrays, which is now in clinical use. In our view, complete solubilization of FFPE tissue samples is the best way to achieve the goal of standardizing the recovery of proteins from FFPE tissues. However, further studies are recommended to develop standardized protein extraction methods to ensure quantitative and qualitative reproducibility in the recovery of proteins from FFPE tissues. PMID- 23339102 TI - Mucins 1-shRNA inhibit the proliferation and HIF-1alpha protein expression on human cholangiocarcinoma cells. AB - To explore the effects of Mucins (MUC)1-shRNA on the proliferation and hypoxia inducible factor (HIF)-1alpha expression of human cholangiocarcinoma (CCA) QBC939 cells in vitro. MUC1-shRNA was constructed and transfected with LipofectamineTM 2000 into cultured CCA cells. MUC1 mRNA and protein expression levels were determined by RT-PCR and Western blot, respectively. The cellular proliferation and HIF-1alpha expression of QBC939 cells were evaluated by the MTT assay and Western blot, respectively. After transfection, the expression levels of MUC1 mRNA and protein in the experimental group decreased significantly in QBC939 (P < 0.01). The proliferation of MUC1 shRNA-transfected group was 0.30 +/- 0.05, 38.32 +/- 1.43%, 15.18 +/- 1.32%, and there were remarkable differences when compared with the control groups (P < 0.05). Significant inhibition of HIF-1alpha protein expression in MUC1 shRNA-transfected group was also discovered (P < 0.05). MUC1 shRNA could inhibit proliferation and significantly weaken HIF-1alpha protein expression of QBC939 cells, suggesting its potential as a therapeutic target of CCA. PMID- 23339103 TI - Capping protein beta is required for actin cytoskeleton organisation and cell migration during Drosophila oogenesis. AB - Capping protein (CP) is a well-characterised actin-binding protein important for regulation of actin filament (AF) assembly. CP caps the barbed end of AFs, inhibiting the addition and loss of actin monomers. In Drosophila melanogaster, the gene encoding CP beta-subunit is named capping protein beta (cpb; see Hopmann et al. [1996] J Cell Biol 133: 1293-305). The cpb level is reduced in the Drosophila bristle actin cytoskeleton and becomes disorganised with abnormal morphology. A reduced level of the CP protein in ovary results in disruption of oocyte determination, and disturbance of nurse cell (NC) cortical integrity and dumping. We describe novel defects appearing in cpb mutants during oogenesis, in which cpb plays an important role in border and centripetal follicle cell migration, ring canal development and cytoplasmic AF formation. The number of long cytoplasmic AFs was dramatically reduced in cpb hypomorphs and abnormal actin aggregates was seen on the inner side of NC membranes. A hypothesis to explain the formation of abnormal short-cut cytoplasmic AFs and actin aggregates in the cpb mutant NCs was proffered, along with a discussion of the reasons for 'dumpless' phenotype formation in the mutants. PMID- 23339104 TI - Adventitial fibroblasts from apoE(-/-) mice exhibit the characteristics of transdifferentiation into myofibroblasts. AB - Adventitial fibroblasts (AFs) are the main cell type in the adventitia, however, their role in atherosclerosis remains unclear. We have investigate the role of AFs in atherosclerotic lesion formation by comparing the characteristics of AFs from apoE(-/-) to C57BL/6 mice. A minority of AFs from apoE(-/-) mice expressed alpha-SM-actin, but no alpha-SM-actin-positive cells were found in AFs from C57BL/6 mice. The content of total collagens, and the mRNA levels of collagen I and collagen III in AFs of apoE(-/-) mice, were higher than in C57BL/6 mice. AFs from apoE(-/-) mice proliferate and migrate faster, and synthesized more TGF beta(1) , MCP-1, and PDGF-b AFs from apoE(-/-) mice have the characteristics of transdifferentiation into myofibroblasts, including enhanced proliferation and migration, along with synthesis of collagens and cytokines compared to AFs from C57BL/6 mice. The histological and functional characteristics of AFs may contribute to early atherosclerotic lesion formation. PMID- 23339105 TI - Dopaminergic cells, derived from a high efficiency differentiation protocol from umbilical cord derived mesenchymal stem cells, alleviate symptoms in a Parkinson's disease rodent model. AB - Mesenchymal stem cells (MSCs) could be an alternative to foetal cells in the treatment of several neurodegenerative diseases, especially Parkinson's disease (PD). We have previously demonstrated the functional efficacy of the undifferentiated bone marrow MSCs (BMMSCs) cultured in a xenofree conditions in PD animal models. We now demonstrate isolation of MSCs from the umbilical cord matrix tissue and assess their safety and efficacy to improve Parkinsonian symptoms in an in vivo animal model. The efficacy of MSCs from BM and umbilical cord in the PD animal mode has also been studied, and more importantly the efficacy of using differentiated UCMSC (D-UCMSCs) to dopaminergic phenotype. Phenotypically, UCMSCs expressed higher levels of SSEA4 compared to BMMSCs. Analysis of differentiated cells showed that D-UCMSCs expressed significant levels of Tyrosine Hydroxyalse and Nurr1 compared to D-BMMSCs. The in vivo efficacy of the differentiated and undifferentiated cell types in the Parkinsonian rats showed that D-UCMSCs improved the symptoms throughout a year of study. Differentiated cell types are potentially better for clinical use than the undifferentiated type, provided they are made available at the site of action in adequate numbers. MSCs are less immunogenic and immunomodulatory, which opens up the further possibility of using these cells in allogeneic settings. This could be a novel cell therapy application, especially when getting autochthonous cells is difficult. PMID- 23339106 TI - Engineering hierarchical nanostructures by elastocapillary self-assembly. AB - Surfaces coated with nanoscale filaments such as silicon nanowires and carbon nanotubes are potentially compelling for high-performance battery and capacitor electrodes, photovoltaics, electrical interconnects, substrates for engineered cell growth, dry adhesives, and other smart materials. However, many of these applications require a wet environment or involve wet processing during their synthesis. The capillary forces introduced by these wet environments can lead to undesirable aggregation of nanoscale filaments, but control of capillary forces can enable manipulation of the filaments into discrete aggregates and novel hierarchical structures. Recent studies suggest that the elastocapillary self assembly of nanofilaments can be a versatile and scalable means to build complex and robust surface architectures. To enable a wider understanding and use of elastocapillary self-assembly as a fabrication technology, we give an overview of the underlying fundamentals and classify typical implementations and surface designs for nanowires, nanotubes, and nanopillars made from a wide variety of materials. Finally, we discuss exemplary applications and future opportunities to realize new engineered surfaces by the elastocapillary self-assembly of nanofilaments. PMID- 23339107 TI - South-East Asian ovalocytosis. PMID- 23339108 TI - Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families. AB - BACKGROUND: Asphyxiating Thoracic Dysplasia (ATD) belongs to the short rib polydactyly group and is characterized by a narrow thorax, short long bones and trident acetabular roof. Other reported features include polydactyly, renal, liver and retinal involvement. To date, mutations in IFT80, DYNC2H1, TTC21B and WDR19 have been reported in ATD. The clinical and molecular heterogeneity leads to difficulties in the evaluation of the long-term prognosis. METHODS: We investigated 53 ATD cases (23 living cases and 30 fetuses) from 39 families. They benefited from a combined approach of deep phenotyping and IFT80 and DYNC2H1 molecular screening. RESULTS: Among the 23 postnatal cases, pulmonary insufficiency was noted in 60% of cases, with tracheotomy requirement in five cases. Renal and liver diseases occurred respectively in 17% and 22% of cases, whereas retinal alteration was present in 50% of cases aged more than 5 years. We identified DYNC2H1 mutations in 23 families (59%) and IFT80 mutations in two families (5%). However, in six families, only one heterozygote mutation in either IFT80 or DYNC2H1 was identified. Finally, the two genes were excluded in 14 families (36%). CONCLUSIONS: We conclude that DYNC2H1 is a major gene responsible for ATD, while IFT80 is rarely involved. The presence of only one mutation in six families and the exclusion of the two genes in 14 families support the involvement of other causal cilia genes. The long-term follow up emphasizes that the pulmonary prognosis is probably less pejorative and retinal involvement more frequent than previously thought. PMID- 23339109 TI - Skewed X-inactivation patterns in ageing healthy and myelodysplastic haematopoiesis determined by a pyrosequencing based transcriptional clonality assay. AB - BACKGROUND: Investigation of X-chromosome inactivation patterns (XCIP) by determination of differential CpG-methylation has been widely applied for investigation of female cell clonality. Using this approach the clonal origin of various tumours has been corroborated. Controversially, strong age-related increase of peripheral blood (PB) cell clonality in haematologically healthy female subjects was reported. Recently, transcriptional XCIP ratio analysis challenged these results and questioned the suitability of methylation based clonality assays. METHODS: To reinvestigate XCIP-skewing in CD34, low-density mononuclear bone marrow (BM) as well as PB cells from healthy female subjects and patients with myelodysplastic syndromes (MDS), we established a transcriptional assay using pyrosequencing technique for quantification of single nucleotide polymorphism allele frequencies, representative for XCIP ratios. RESULTS: Our assay provides high sensitivity for XCIP ratio assessment as determined by standard curves, reproducibility, inter-marker correlation as well as correlation with the DNA-methylation based human androgen receptor (HUMARA) assay. Notably, in agreement with most studies investigating this issue, significant age-related increase of XCIP skewing in PB cells from healthy elderly female subjects was confirmed. Moreover, XCIP ratio analysis suggests even stronger clonal manifestation in BM and CD34 cells. In MDS, XCIP skewing levels were distinctively elevated as compared with controls of similar age and higher degrees were associated with poor clinical outcome. CONCLUSIONS: Transcriptional clonal profiling via pyrosequencing allows accurate assessment of XCIP ratios, confirms the validity of the DNA-methylation based HUMARA assay and reveals important insights into ageing healthy and myelodysplastic haematopoiesis. PMID- 23339110 TI - Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy. AB - BACKGROUND: Early infantile epileptic encephalopathies usually manifest as severely impaired cognitive and motor development and often result in a devastating permanent global developmental delay and intellectual disability. A large set of genes has been implicated in the aetiology of this heterogeneous group of disorders. Among these, the ion channelopathies play a prominent role. In this study, we investigated the genetic cause of infantile epilepsy in three affected siblings. METHODS AND RESULTS: Homozygosity mapping in DNA samples followed by exome analysis in one of the patients resulted in the identification of a homozygous mutation, p.L1040P, in the CACNA2D2 gene. This gene encodes the auxiliary alpha(2)delta2 subunit of high voltage gated calcium channels. The expression of the alpha(2)delta2-L1040P mutant instead of alpha(2)delta2 wild type (WT) in Xenopus laevis oocytes was associated with a notable reduction of current density of both N (Ca(V)2.2) and L (Ca(V)1.2) type calcium channels. Western blot and confocal imaging analyses showed that the alpha(2)delta2-L1040P mutant was synthesised normally in oocyte but only the alpha(2)delta2-WT, and not the alpha(2)delta2-L1040P mutant, increased the expression of alpha(1B), the pore forming subunit of Ca(V)2.2, at the plasma membrane. The expression of alpha(2)delta2-WT with Ca(V)2.2 increased the surface expression of alpha(1B) 2.5 3 fold and accelerated current inactivation, whereas alpha(2)delta2-L1040P did not produce any of these effects. CONCLUSIONS: L1040P mutation in the CACNA2D2 gene is associated with dysfunction of alpha(2)delta2, resulting in reduced current density and slow inactivation in neuronal calcium channels. The prolonged calcium entry during depolarisation and changes in surface density of calcium channels caused by deficient alpha(2)delta2 could underlie the epileptic phenotype. This is the first report of an encephalopathy caused by mutation in the auxiliary alpha(2)delta subunit of high voltage gated calcium channels in humans, illustrating the importance of this subunit in normal physiology of the human brain. PMID- 23339111 TI - Preimplantation genetic diagnosis in mitochondrial DNA disorders: challenge and success. AB - BACKGROUND: Mitochondrial or oxidative phosphorylation diseases are relatively frequent, multisystem disorders; in about 15% of cases they are caused by maternally inherited mitochondrial DNA (mtDNA) mutations. Because of the possible severity of the phenotype, the lack of effective treatment, and the high recurrence risk for offspring of carrier females, couples wish to prevent the transmission of these mtDNA disorders to their offspring. Prenatal diagnosis is problematic for several reasons, and concern the often poor correlation between mutation percentages and disease severity and the uncertainties about the representativeness of a fetal sample. A new option for preventing transmission of mtDNA disorders is preimplantation genetic diagnosis (PGD), which circumvents these problems by transferring an embryo below the threshold of clinical expression. METHODS: We present the data on nine PGD cycles in four female carriers of mitochondrial diseases: three mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) (m.3243A>G), and one Leigh (m.8993T>G). Our threshold for transfer after PGD is 15% for the m.3243A>G mutation and 30% for the m.8993T>G mutation. RESULTS: All four female carriers produced embryos eligible for transfer. The m.8993T>G mutation in oocytes/embryos showed more skewing than the m.3243A>G. In about 80% of the embryos the mutation load in the individual blastomeres was fairly constant (interblastomere differences <10%). However, in around 11% (in embryos with the m.3243A>G mutation only), the mutation load differed substantially (>15%) between blastomeres of a single embryo, mostly as a result of one outlier. The m.8993T>G carrier became pregnant and gave birth to a healthy son. CONCLUSIONS: PGD provides carriers of mtDNA mutations the opportunity to conceive healthy offspring. PMID- 23339112 TI - Anatomical basis of laparoscopic medial-to-lateral mobilization of the descending colon. AB - In laparoscopic colorectal resection, the medial-to-lateral approach has been largely adopted. This approach can be initiated by the division of either the inferior mesenteric artery (IMA) or the inferior mesenteric vein (IMV). This cadaveric study aimed to establish the feasibility of IMV dissection as the initial landmark of medial-to-lateral left colonic mobilization for evaluating the size of the peritoneal window between the IMV at the lower part of the pancreas and the origin of the IMA (IMA-IMV distance) and the point of origin of the IMA compared to the lower edge of the third part of the duodenum (IMA-D3 distance). These distances were recorded on 30 fresh cadavers. The IMA-D3 distance was 0.4 +/- 2.2 cm (mean +/- SD). The IMA originated from the aorta at the level of or below the D3 in 21 cases (70%). The IMA-IMV distance was 5.5 +/- 1.8 cm and was greater or equal to 5 cm (large window) in 21 cases (70%). IMA-IMV distance was correlated with IMA-D3 showing that a large window was inversely correlated with a low IMA origin (P < 0.001). IMA-D3 distance was not correlated with weight, height and sex. IMA-IMV distance was largerin male (6.7 +/- 0.9 vs. 4.9 +/- 1.8, P = 0.001) and correlated with weight, (r = 0.60, 95%CI = 0.03-0.10, P < 0.001) and height (r = 0.54, 95%CI = 0.05-0.21, P = 0.002). IMV can be used as the initial landmark for laparoscopic medial-to-lateral dissection in two thirds of cases. A too-small window can require first IMA division. The choice between the two different medial-to-lateral approaches could be made by evaluating the anatomical relationship between IMA, IMV, and D3. PMID- 23339113 TI - Metabolic studies of formestane in horses. AB - Formestane (4-hydroxyandrost-4-ene-3,17-dione) is an irreversible steroidal aromatase inhibitor with reported abuse in human sports. In 2011, our laboratory identified the presence of formestane in a horse urine sample from an overseas jurisdiction. This was the first reported case of formestane in a racehorse. The metabolism of formestane in humans has been reported previously; however, little is known about its metabolic fate in horses. This paper describes the in vitro and in vivo metabolic studies of formestane in horses, with the objective of identifying the target metabolite with the longest detection time for controlling formestane abuse. In vitro metabolic studies of formestane were performed using homogenized horse liver. Seven in vitro metabolites, namely 4-hydroxytestosterone (M1), 3beta,4alpha-dihydroxy-5beta-androstan-17-one (M2a), 3beta,4beta-dihydroxy 5beta-androstan-17-one (M2b), 3beta,4alpha-dihydroxy-5alpha-androstan-17-one (M2c), androst-4-ene-3alpha,4,17beta-triol (M3a), androst-4-ene-3beta,4,17beta triol (M3b), and 5beta-androstane-3beta,4beta,17beta-triol (M4) were identified. For the in vivo studies, two thoroughbred geldings were each administered with 800 mg of formestane (32 capsules of Formadex) by stomach tubing. The results revealed that the parent drug and seven metabolites were detected in post administration urine. The six in vitro metabolites (M1, M2a, M2b, M2c, M3a, and M3b) identified earlier were all detected in post-administration urine samples. In addition, 3alpha,4alpha-dihydroxy-5alpha-androstan-17-one (M2d), a stereoisomer of M2a/M2b/M2c, was also identified. This study has shown that the detection of formestane administration would be best achieved by monitoring 4 hydroxytestosterone (M1) in the glucuronide-conjugated fraction. M1 could be detected for up to 34 h post-administration. In blood samples, the parent drug could be detected for up to 34 h post administration. PMID- 23339115 TI - Elucidating the biosynthetic pathway for vibralactone: a pancreatic lipase inhibitor with a fused bicyclic beta-lactone. PMID- 23339114 TI - Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner. AB - Accumulated evidence suggests that glioma stem cells (GSCs) may contribute to therapy resistance in high-grade glioma (HGG). Although recent studies have shown that the serine/threonine kinase maternal embryonic leucine-zipper kinase (MELK) is abundantly expressed in various cancers, the function and mechanism of MELK remain elusive. Here, we demonstrate that MELK depletion by shRNA diminishes the growth of GSC-derived mouse intracranial tumors in vivo, induces glial fibrillary acidic protein (+) glial differentiation of GSCs leading to decreased malignancy of the resulting tumors, and prolongs survival periods of tumor-bearing mice. Tissue microarray analysis with 91 HGG tumors demonstrates that the proportion of MELK (+) cells is a statistically significant indicator of postsurgical survival periods. Mechanistically, MELK is regulated by the c-Jun NH(2)-terminal kinase (JNK) signaling and forms a complex with the oncoprotein c-JUN in GSCs but not in normal progenitors. MELK silencing induces p53 expression, whereas p53 inhibition induces MELK expression, indicating that MELK and p53 expression are mutually exclusive. Additionally, MELK silencing-mediated GSC apoptosis is partially rescued by both pharmacological p53 inhibition and p53 gene silencing, indicating that MELK action in GSCs is p53 dependent. Furthermore, irradiation of GSCs markedly elevates MELK mRNA and protein expression both in vitro and in vivo. Clinically, recurrent HGG tumors following the failure of radiation and chemotherapy exhibit a statistically significant elevation of MELK protein compared with untreated newly diagnosed HGG tumors. Together, our data indicate that GSCs, but not normal cells, depend on JNK-driven MELK/c-JUN signaling to regulate their survival, maintain GSCs in an immature state, and facilitate tumor radioresistance in a p53-dependent manner. PMID- 23339117 TI - Does engagement in meaningful occupation reduce challenging behaviour in people with intellectual disabilities? A systematic review of the literature. AB - Over several years, there has been much debate about the best way to manage challenging behaviour. Although national guidance highlights the importance of meaningful occupation, it is unclear to what extent this helps. This systematic review of the literature aimed to answer the question, 'does engagement in meaningful occupation reduce challenging behaviour in people with intellectual disability?' By searching a range of databases, electronic resources and web pages, 13 relevant articles were identified. Additionally, experts in the field were contacted, hand searches were performed and citation searches were carried out. These 13 articles were critically appraised and analysed using narrative synthesis. Although the amount of research identified was limited and the methodological quality was variable, some broad themes arose. A skilled and structured approach for carrying out occupation may be effective in reducing challenging behaviour; however, more robust research is needed before definitive conclusions can be drawn. PMID- 23339116 TI - Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase. AB - Velaglucerase alfa is a glucocerebrosidase produced by gene activation technology in a human fibroblast cell line (HT-1080), and it is indicated as an enzyme replacement therapy (ERT) for the treatment of Gaucher disease type 1 (GD1). This multicenter, open-label, 12-month study examined the safety and efficacy of velaglucerase alfa in patients with GD1 previously receiving imiglucerase. Eligible patients, >=2 years old and clinically stable on imiglucerase therapy, were switched to velaglucerase alfa at a dose equal to their prior imiglucerase dose. Infusion durations were 1 hr every other week. Forty patients received velaglucerase alfa (18 male, 22 female; four previously splenectomized; age range 9-71 years). Velaglucerase alfa was generally well tolerated with most adverse events (AEs) of mild or moderate severity. The three most frequently reported AEs were headache (12 of 40 patients), arthralgia (9 of 40 patients), and nasopharyngitis (8 of 40 patients). No patients developed antibodies to velaglucerase alfa. There was one serious AE considered treatment-related: a grade 2 anaphylactoid reaction within 30 min of the first infusion. The patient withdrew; this was the only AE-related withdrawal. Hemoglobin concentrations, platelet counts, and spleen and liver volumes remained stable through 12 months. In conclusion, adult and pediatric patients with GD1, previously treated with imiglucerase, successfully transitioned to velaglucerase alfa, which was generally well tolerated and demonstrated efficacy over 12 months' treatment consistent with that observed in the velaglucerase alfa phase 3 clinical trial program. PMID- 23339118 TI - One is the loneliest number: a review of the ganglion impar and its relation to pelvic pain syndromes. AB - The ganglion impar is often overlooked as a component of the sympathetic nervous system. Despite its obscurity, this ganglion provides a pathway for neurons by accommodating postganglionic sympathetics, visceral afferents, and somatic fibers traveling to and from the pelvis. Its classic anatomic location as described in the 1720's held up until recently, with the current literature now revealing a great deal of anatomical variability. This variation becomes important when the ganglion impar is used as a treatment target for patients with chronic pelvic pain - its primary clinical implication. The aim of this review was to provide a better understanding of the anatomy of ganglion impar, accounting for variation in size, shape, and location. In addition, the clinical importance and treatment modalities associated with the ganglion impar are outlined. PMID- 23339119 TI - Reference ranges for the urinary steroid profile in a Latin-American population. AB - The urinary steroid profile has been used in clinical endocrinology for the early detection of enzyme deficiencies. In the field of doping, its evaluation in urine samples is used to diagnose the abuse of substances prohibited in sport. This profile is influenced by sex, age, exercise, diet, and ethnicity, among others; laboratories own reference ranges might compensate for ethnic differences among population and inter-laboratory biases. This paper shows the reference ranges obtained in the Antidoping Laboratory of Havana for the following steroid profile parameters: ten androgens (testosterone, epitestosterone, androsterone, etiocholanolone, 5alpha-androstan-3alpha,17beta-diol, 5beta-androstan 3alpha,17beta-diol, dehydroepiandrosterone, epiandrosterone, 11beta hydroxyandrosterone and 11beta-hydroxyetiocholanolone), three estrogens (estradiol, estriol and estrone), two pregnanes (pregnanediol and pregnanetriol) and two corticosteroids (cortisol and tetrahydrocortisol). The urine samples (male: n = 2454 and female: n = 1181) and data obtained are representative of population from Latin-American countries like Cuba, Venezuela, Mexico, Dominican Republic, Guatemala and Chile. Urine samples were prepared by solid-phase extraction followed by enzymatic hydrolysis and liquid-liquid extraction with an organic solvent in basic conditions. Trimethylsilyl derivatives were analyzed by gas chromatography coupled to mass spectrometry. Reference ranges were established for each sex, allowing the determination of abnormal profiles as a first diagnostic tool for the detection of the abuse of androgenic anabolic steroids. The comparison with the Caucasian population confirms that the urinary steroid profile is influenced by ethnicity. PMID- 23339120 TI - Human all too human reasoning: comparing clinical and phenomenological intuition. AB - This paper compares clinical intuition and phenomenological intuition. I begin with a brief analysis of Husserl's conception of intuition. Second, I review the attitude toward clinical intuition by physicians and philosophers. Third, I discuss the Aristotelian conception of intellectual intuition or nous and its relation to phronesis. Phronesis provides a philosophical ground for clinical intuition by linking medicine as both a techne and praxis. Considering medicine as a techne, Pellegrino and Thomasma exclude clinical intuitions from their philosophy of medicine. However, in modeling clinical reasoning on phronesis, they link Aristotelian nous with clinical reasoning. While supporting the application of phronesis to clinical reasoning, I consider Pellegrino and Thomasma's model deficient for eliminating intuition as an inalienable element of clinical reasoning. Rather, clinical intuitions are necessary in linking medicine as both art and practice. This becomes more obvious through the phenomenological analysis of clinical intuitions. Clinical reasoning and phenomenological intuitions are similar in joining the perceptual and intellectual aspects of human judgment. Furthermore, clinical intuitions can be extended to become phenomenological intuitions through phenomenological reflection. Clinical intuitions may be examined phenomenologically for their originary foundations. In this way, medicine acts as a phenomenological clue. Phenomenology provides a method to restore the Hippocratic synthesis of empirical observation and wholism associated with clinical intuitions. PMID- 23339121 TI - Valuing structured professional judgment: predictive validity, decision-making, and the clinical-actuarial conflict. AB - Structured professional judgment (SPJ) has received considerable attention as an alternative to unstructured clinical judgment and actuarial assessment, and as a means of resolving their ongoing conflict. However, predictive validity studies have typically relied on receiver operating characteristic (ROC) analysis, the same technique commonly used to validate actuarial assessment tools. This paper presents SPJ as distinct from both unstructured clinical judgment and actuarial assessment. A key distinguishing feature of SPJ is the contribution of modifiable factors, either dynamic or protective, to summary risk ratings. With modifiable factors, the summary rating scheme serves as a prognostic model rather than a classification procedure. However, prognostic models require more extensive and thorough predictive validity testing than can be provided by ROC analysis. It is proposed that validation should include calibration and reclassification techniques, as well as additional measures of discrimination. Several techniques and measures are described and illustrated. The paper concludes by tracing the limitations of ROC analysis to its philosophical foundation and its origin as a statistical theory of decision-making. This foundation inhibits the performance of crucial tasks, such as determining the sufficiency of a risk assessment and examining the evidentiary value of statistical findings. The paper closes by noting a current effort to establish a viable and complementary relationship between SPJ and decision-making theory. PMID- 23339122 TI - Syntheses and structural studies of tris(N-phenothiazinyl)borane and its radical cation. AB - A radical comparison: The neutral (1) and radical cation (1(.+)) forms of tris(N phenothiazinyl)borane were prepared and their molecular structures and spectral properties investigated. The results established that 1(.+) possessed a localized radical cation on one of the phenothiazine (PTZ) rings. The crystal structure of 1(.+) showed elongation of the B=N bond bound to the PTZ(.+) ring (B=N1: 1.53 A). PMID- 23339123 TI - Monitoring of protein arginine deiminase activity by using fluorescence quenching: multicolor visualization of citrullination. PMID- 23339124 TI - Phase I study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma. AB - PURPOSE: Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial. EXPERIMENTAL DESIGN: Patients with advanced or metastatic renal cell carcinoma (RCC) with predominant clear cell histology were treated with oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule). RESULTS: Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having previously received at least 1: VEGFR inhibitor, mTOR inhibitor, and immunotherapy, respectively. Fifteen and 5 patients were treated in 500- and 600-mg cohorts, respectively. Three patients experienced dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events 5% or less (except asthenia, 15%) and only one grade 4 event (hypertensive crisis). Two patients achieved a partial response (500 mg), and 12 patients had stable disease, including 2 patients with long lasting disease stabilizations (>1 year) in the 500-mg cohort. CONCLUSIONS: Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500 mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients. PMID- 23339126 TI - Diffuse large B-cell lymphoma in the elderly: a review of potential difficulties. AB - Half of patients with diffuse large B-cell lymphoma (DLBCL) are more than 65 years old. These elderly patients frequently have other diseases, some of them severe, which may alter their ability to receive standard curative therapy. However, these associated diseases are heterogeneous and only a few contraindicate chemotherapy treatments. We reviewed all potential difficulties, such as the evaluation of comorbidities, the heterogeneous functional status of this population, and the consequences of the aging process that might be associated with treating these patients, and now propose solutions. As standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy may cure the majority of patients, it must always be the first proposed option. With this approach, elderly patients with DLBCL treated with a curative intent can reach a complete remission and have a similar outcome as younger patients. Reduced dose intensity must be applied for very elderly patients or those unfit for full-dose anthracycline. The critical question for a physician is why these patients cannot be treated with the standard regimen, namely R-CHOP. PMID- 23339125 TI - Murine microenvironment metaprofiles associate with human cancer etiology and intrinsic subtypes. AB - PURPOSE: Ionizing radiation is a well-established carcinogen in rodent models and a risk factor associated with human cancer. We developed a mouse model that captures radiation effects on host biology by transplanting unirradiated Trp53 null mammary tissue to sham or irradiated hosts. Gene expression profiles of tumors that arose in irradiated mice are distinct from those that arose in naive hosts. We asked whether expression metaprofiles could discern radiation-preceded human cancer or be informative in sporadic breast cancers. EXPERIMENTAL DESIGN: Affymetrix microarray gene expression data from 56 Trp53-null mammary tumors were used to define gene profiles and a centroid that discriminates tumors arising in irradiated hosts. These were applied to publicly available human cancer datasets. RESULTS: Host irradiation induces a metaprofile consisting of gene modules representing stem cells, cell motility, macrophages, and autophagy. Human orthologs of the host irradiation metaprofile discriminated between radiation preceded and sporadic human thyroid cancers. An irradiated host centroid was strongly associated with estrogen receptor-negative breast cancer. When applied to sporadic human breast cancers, the irradiated host metaprofile strongly associated with basal-like and claudin-low breast cancer intrinsic subtypes. Comparing host irradiation in the context of TGF-beta levels showed that inflammation was robustly associated with claudin-low tumors. CONCLUSIONS: Detection of radiation-preceded human cancer by the irradiated host metaprofile raises possibilities of assessing human cancer etiology. Moreover, the association of the irradiated host metaprofiles with estrogen receptor-negative status and claudin-low subtype suggests that host processes similar to those induced by radiation underlie sporadic cancers. PMID- 23339127 TI - Measles virus vaccine-infected tumor cells induce tumor antigen cross presentation by human plasmacytoid dendritic cells. AB - PURPOSE: Plasmacytoid dendritic cells (pDC) are antigen-presenting cells specialized in antiviral response. The measles virus vaccine is proposed as an antitumor agent to target and specifically kill tumor cells without infecting healthy cells. EXPERIMENTAL DESIGN: Here, we investigated, in vitro, the effects of measles virus vaccine-infected tumor cells on the phenotype and functions of human pDC. We studied maturation and tumor antigen cross-presentation by pDC, exposed either to the virus alone, or to measles virus vaccine-infected or UV irradiated tumor cells. RESULTS: We found that only measles virus vaccine infected cells induced pDC maturation with a strong production of IFN-alpha, whereas UV-irradiated tumor cells were unable to activate pDC. This IFN-alpha production was triggered by the interaction of measles virus vaccine single stranded RNA (ssRNA) with TLR7. We observed that measles virus vaccine-infected tumor cells were phagocytosed by pDC. Interestingly, we showed cross-presentation of the tumor antigen NYESO-1 to a specific CD8(+) T-cell clone when pDC were cocultured with measles virus vaccine-infected tumor cells, whereas pDC were unable to cross-present NYESO-1 after coculture with UV-irradiated tumor cells. CONCLUSIONS: Altogether, our results suggest that the use of measles virus vaccine in antitumor virotherapy induces immunogenic tumor cell death, allowing pDC to mature, produce high amounts of IFN-alpha, and cross-present tumor antigen, thus representing a mode of recruiting these antigen-presenting cells in the immune response. Clin Cancer Res; 19(5); 1147-58. (c)2012 AACR. PMID- 23339128 TI - Gold nanorods: controlling their surface chemistry and complete detoxification by a two-step place exchange. PMID- 23339129 TI - Voices from a minority: experiences of chinese male nursing students in clinical practice. AB - In Hong Kong, males constituted only about 10.2% of the nursing workforce in 2010. The learning experiences of male nursing students in Hong Kong during their clinical practicum have rarely been explored. If these students cannot maintain their psychological well-being and psychological health in formal education and clinical placements, then their physical health will also suffer. This ethnographic qualitative study gave male nursing students in Hong Kong a chance to voice their experiences during their clinical practicum. Selected through snowball sampling, 18 male nursing students from a local university participated in individual face-to-face semistructured interviews. The data were processed with content analysis. The findings indicated that male students not only received more support and understanding from male rather than female members of staff but endured a certain amount of oppression while working in female wards. According to the students' comments on nursing culture, the work climate of male nursing students could be improved by reorganizing the clinical placements and providing extra support to male nursing students. PMID- 23339130 TI - Racial disparities in survival after diagnosis of prostate cancer in Kentucky, 2001-2010. AB - Whether the African American race remains a significant predictor of poorer prostate cancer survival after adjusting for other sociodemographic and treatment related factors remains unclear. We examined whether disparities in survival among 18,900 African American and Caucasian men diagnosed with prostate cancer in Kentucky remained after adjusting for health insurance (payor source), cancer treatment, cancer stage at diagnosis, prostate-specific antigen (PSA) level, smoking status, and Appalachian region. After adjusting for these predictors, African American men living in Kentucky had poorer prostate cancer survival after 5 years (hazard ratio [HR] = 1.33; 95% confidence interval = 1.11, 1.59) and 10 years (HR = 1.39; 95% CI = 1.18, 1.28) of follow-up, and for the entire follow-up period (HR = 1.41; 95% CI = 1.26, 1.65) compared to their Caucasian counterparts. Thus, health insurance status, cancer treatment, cancer stage at diagnosis, PSA level at diagnosis, smoking status, and geographic location did not explain the racial gap in survival in Kentucky. PMID- 23339131 TI - What do we know about older abusers? a typology of violent husbands dwelling in lifelong intimate violence relationships. AB - Most research on intimate partner violence to date has focused on young men. Although interest and research regarding older abused women has increased in recent years, research on the voices and experiences of older abusive men is still scarce. The purpose of this article is to present a typology of older battering men dwelling in lifelong intimate violence relationships. Fifteen older Israeli abusive men, aged 65 to 84 years, were interviewed in depth. Four types were identified: the "Non-quitter," the "Cover-up"-er, the "In-between"-er, and the "Normalizer." These types were constructed based on four dimensions: the construction of violence over the years, the perception of the spouse over the years, losses accompanying the violent relationship, and the meaning of violence in old age. The four types enable an in-depth look at the experiential world of older abusers and paint a complex picture of various ways in which abusive men live with violence over time. PMID- 23339132 TI - Catalytic asymmetric C-N bond formation: phosphine-catalyzed intra- and intermolecular gamma-addition of nitrogen nucleophiles to allenoates and alkynoates. AB - Pin the amine on the gamma: A new method has been developed for the gamma addition of nitrogen nucleophiles to gamma-substituted alkynoates or allenoates through intra- and intermolecular processes that are catalyzed by spirophosphine 1. An asymmetric version of this reaction affords enantioenriched pyrrolidines, indolines, and gamma-amino-alpha,beta-unsaturated carbonyl compounds. PMID- 23339133 TI - Enantioselective synthesis of epoxides having a tetrasubstituted trifluoromethylated carbon center: methylhydrazine-induced aerobic epoxidation of beta,beta-disubstituted enones. PMID- 23339134 TI - The power of fluorogenic probes. AB - A definite turn-on: Turning on fluorescence only where successful labeling is happening sounds as desirable as delivering a drug only where the drug target resides. New fluorogenic xanthene derivatives from the Bertozzi research group are getting us closer to "magic bullet" dyes. PMID- 23339135 TI - Imatinib-induced amelioration of neurologic deficits in a rare case of simultaneous association of missed multiple sclerosis and chronic myeloblastic leukemia. PMID- 23339136 TI - Renal deterioration in multiple sclerosis patients with neurovesical dysfunction. AB - OBJECTIVES: Our aims were to determine the prevalence of renal ultrasound (RUS) abnormalities over time in multiple sclerosis (MS) patients with lower urinary tract symptoms (LUTS). METHODS: Data were examined retrospectively from MS patients with LUTS, from 2000-2009. Study inclusion requirements were both baseline urodynamics (UD) and RUS data, with followup RUS at >= 12 months. Age, time since diagnosis (TSD), MS subtype and the UD/RUS results were evaluated for associations. RESULTS: At presentation, 173 subjects underwent UD and RUS, but only 89 had a repeat RUS at >= 12 months. Median followup was 61 months. Initial RUS abnormalities were found in 10 (5.8%) subjects. At followup, upper urinary tract (UUT) abnormalities were seen in 11 (12.4%) subjects. Patients > 49 years old were more likely to have an abnormality (OR 0.181, 95% CI 0.037-0.892, p = 0.04). Patients with abnormal compliance were also more likely to have an abnormal followup RUS (OR 0.185, 95% CI 0.037-0.924, p = 0.04). No other demographic or UD factor was associated with RUS abnormalities. CONCLUSIONS: The development of structural UUT changes is low in MS patients. Urodynamic studies are useful for LUTS treatment strategies in complicated patients, but UD does not appear to have much impact with regard to upper tract changes. PMID- 23339137 TI - An "ex vivo" model to evaluate toxicological responses to mixtures of contaminants in cetaceans: integumentum biopsy slices. AB - The need for powerful new tools to detect the effects of chemical pollution, in particular of persistent organic pollutants (POPs) and polycyclic aromatic hydrocarbons (PAHs) on Mediterranean cetaceans led us to develop and apply a suite of sensitive biomarkers for integument biopsies of stranded and free ranging animals. This multi-response ex vivo method has the aim to detect toxicological effects of contaminant mixtures. In the present study, we applied an ex vivo assay using skin biopsy and liver slices, combining molecular biomarkers [Western blot of Cytochrome P450 1A1 (CYP1A1) and Cytochrome P450 2B (CYP2B)] and gene expression biomarkers (Quantitative real-time PCR of CYP1A1, heat shock protein 70, estrogen receptor alpha and E2F transcription factor) in response to chemical exposure [organochlorines compounds (OCs), polybrominated diphenyl ethers (PBDEs), and PAHs] for stranded Mediterranean Stenella coeruleoalba. The main goal of this experiment was to identify the biomarker and/or a suite of biomarkers that could best detect the presence of a specific class of pollutants (OCs, PBDEs, and PAHs) or a mixture of them. This multi response biomarker methodology revealed an high sensitivity and selectivity of responses (such as CYP1A and ER alpha mRNA variations after OCs and PAHs exposure) and could represent a valid future approach for the study of inter- and intra-species sensitivities to various classes of environmental contaminants. PMID- 23339138 TI - Side-effects of thiamethoxam on the brain andmidgut of the africanized honeybee Apis mellifera (Hymenopptera: Apidae). AB - The development of agricultural activities coincides with the increased use of pesticides to control pests, which can also be harmful to nontarget insects such as bees. Thus, the goal of this work was assess the toxic effects of thiamethoxam on newly emerged worker bees of Apis mellifera (africanized honeybee-AHB). Initially, we determined that the lethal concentration 50 (LC50 ) of thiamethoxam was 4.28 ng a.i./MUL of diet. To determine the lethal time 50 (LT50 ), a survival assay was conducted using diets containing sublethal doses of thiamethoxam equal to 1/10 and 1/100 of the LC50. The group of bees exposed to 1/10 of the LC50 had a 41.2% reduction of lifespan. When AHB samples were analyzed by morphological technique we found the presence of condensed cells in the mushroom bodies and optical lobes in exposed honeybees. Through Xylidine Ponceau technique, we found cells which stained more intensely in groups exposed to thiamethoxam. The digestive and regenerative cells of the midgut from exposed bees also showed morphological and histochemical alterations, like cytoplasm vacuolization, increased apocrine secretion and increased cell elimination. Thus, intoxication with a sublethal doses of thiamethoxam can cause impairment in the brain and midgut of AHB and contribute to the honeybee lifespan reduction. PMID- 23339144 TI - Protective role of silymarin against manganese-induced nephrotoxicity and oxidative stress in rat. AB - Metal toxicity may occur after exposure from many sources. Oxidative stress is thought to be involved in manganese-induced toxicity and leads to various health disorders. Silymarin (SIL), a natural flavonoid, has been reported to have many benefits and medicinal properties. The aim of this study was to assess the toxicity of manganese (Mn) on oxidative stress and DNA damage in the kidney of rats and its alleviation by SIL. Manganese was given orally in drinking water (20 mg MnCl2 /mL) with or without SIL administration (100 mg /kg intraperitoneally) for 30 days. Our data showed that SIL significantly prevented Mn induced nephrotoxicity, indicated by both diagnostic indicators of kidney injury like plasma urea, uric acid and creatinine and urinary electrolyte levels and by histopathological analysis. Moreover, Mn-induced profound elevation of the production of reactive oxygen species (ROS) and altered the levels of oxidative stress related biomarkers in kidney tissue. This is evidenced by the increase of lipid peroxidation, protein carbonylation, DNA fragmentation and urinary hydrogen peroxide, while, the activities of enzymatic antioxidant and glutathione level were decreased. Treatment with SIL reduced the alterations in the renal and urine markers, decreasing lipid peroxidation markers, increasing the antioxidant cascade and decreasing the Mn-induced damage. All these changes were supported by histopathological observations. These findings suggested that the inhibition of Mn-induced damage by SIL was due at least in part to its antioxidant activity and its capacity to modulate the oxidative damage. PMID- 23339145 TI - Nerve-sparing minilaparoscopic versus conventional laparoscopic radical hysterectomy plus systematic pelvic lymphadenectomy in cervical cancer patients. AB - AIM: To present our preliminary experience with nerve-sparing minilaparoscopic radical hysterectomy plus pelvic lymphadenectomy for the surgical treatment of cervical cancer and to compare outcomes with those of the conventional laparoscopic approach. METHODS: Data of 87 consecutive women who underwent minimally invasive surgery for early and locally advanced stage cervical cancer were prospectively collected. Ten women who underwent laparoscopic surgery using a nerve-sparing technique performed through 3-mm ancillary ports were compared with the 77 patients who had standard laparoscopic surgery previously with 3 sovrapubic 5-mm trocars. RESULTS: Minilaparoscopic radical hysterectomy was successfully accomplished in every case with no conversion to standard laparoscopy or open surgery. Two (2.6%) conversions to open surgery occurred in the conventional laparoscopy group. Surgical characteristics (operative time, estimated blood loss, and length of stay) and complication rate were similar between the 2 groups. No differences in the amount of parametrial and vaginal tissue removed were observed. The number of lymph nodes retrieved through minilaparoscopy was higher than conventional laparoscopy (30 [range = 26-38] vs 22 [range = 8-49]; P = .002). However, no difference was observed when the analysis was restricted to the last 10 conventional procedures (30 [range = 26 38] vs 29 [range = 24-49]; P = .81). CONCLUSIONS: Our data show that minilaparoscopic radical hysterectomy with pelvic lymphadenectomy is a feasible procedure if performed by skilled surgeons. PMID- 23339146 TI - IDEAL in meshes for prolapse, urinary incontinence, and hernia repair. AB - PURPOSE: Mesh surgeries are counted among the most frequently applied surgical procedures. Despite global spread of mesh applying surgeries, there is no current systematic analysis of incidence and possible prevention of adverse events after mesh implantation. MATERIALS AND METHODS: Based on the recommendations of IDEAL an in vitro test system for biocompatibility of surgical meshes has been generated (Innovation). Coating strategies for biocompatibility optimization have been developed (Development). The native and modified alloplastic materials have been tested in an animal model over 2 years (Exploration and Assessment and Long term study). RESULTS: In 3 meshes, implanted in sheep and explanted at 4 different time points (a, 3 months; b, 6 months; c, 12 months; and d, 24 months) over 24 months, thickness of inflammatory tissue (TVT a, 35 um; b, 32 um; c, 33 um; d, 28 um; UltraPro, a, 25 um; b, 24 um; c, 21 um; d, 22 um; PVDF a, 20 um; b, 21 um; c, 14 um; d, 15um), connective tissue (TVT a, 37 um; b, 36 um; c, 43 um; d, 41 um; UltraPro a, 33 um; b, 32 um; c, 40 um; d, 38 um; PVDF a, 25 um; b, 22 um; c, 22 um; d, 24 um), and macrophage infiltration (TVT a, 36%; b, 33%; c, 23%; d, 20%; UltraPro a, 34%; b, 28%; c, 25%; d, 22%; PVDF a, 24%; b, 18%; c, 18%; d, 16%) revealed comparable ranking characteristics at every time point after explantation. The in vivo performance of these meshes in a sheep model was predictable with a previously developed in vitro test system. Coating of meshes with autologous plasma prior to implantation seems to have a positive effect on the meshes biocompatibility. CONCLUSION: We have applied IDEAL criteria on a new innovation for surgical meshes. The results permit the generation of a ranking of currently available meshes with potential to optimize future meshes. PMID- 23339147 TI - Double PPH technique for hemorrhoidal prolapse: a multicentric, prospective, and nonrandomized trial. AB - INTRODUCTION: Longo's technique (or PPH technique) is well known worldwide. Meta analysis suggests that the failure due to persistence or recurrence is close to 7.7%. One of the reasons for the recurrence is the treatment of the advanced hemorrhoidal prolapse with a single stapling device, which is not enough to resect the appropriate amount of prolapse. MATERIALS AND METHODS: We describe the application of "Double PPH Technique" (D-PPH) to treat large hemorrhoidal prolapses. We performed a multicentric, prospective, and nonrandomized trial from July 2008 to July 2009, wherein 2 groups of patients with prolapse and hemorrhoids were treated with a single PPH or a D-PPH. Results were compared. The primary outcome was evaluation of safety and efficacy of the D-PPH procedure in selected patients with large hemorrhoidal prolapse. RESULTS: In all, 281 consecutive patients suffering from hemorrhoidal prolapse underwent surgery, of whom 74 were assigned intraoperatively to D-PPH, whereas 207 underwent single PPH. Postoperative complications were 5% in both groups (P = .32), in particular: postoperative major bleeding 3.0% in PPH versus 4.1% D-PPH (P = .59); pain 37.9 % PPH versus 27.3% D-PPH (mean visual analog scale [VAS] = 2.5 vs 2.9, respectively; P = .72); and fecal urgency 2.1% PPH versus 5.7% D-PPH (P = .8). Persistence of hemorrhoidal prolapse at 12-month follow-up was 3.7% in the PPH group versus 5.9% in the D-PPH group (P = .5). CONCLUSIONS: Our data support the hypothesis that an accurate intraoperative patient selection for single (PPH) or double (D-PPH) stapled technique will lower in a significant way the incidence of recurrence after Longo's procedure for hemorrhoidal prolapse. PMID- 23339148 TI - Investigation on 1O2 generation ability of di-sulfonic phthalocyanine zinc isomers using an HPLC-CL system. AB - An HPLC system combining a chemiluminescence detector was applied to estimate the singlet oxygen ((1)O2) generation ability of di-sulfonic phthalocyanine zinc (ZnPcS2 ) isomers. As photosensitizers, ZnPcS2 produces (1)O2 in air-saturated solutions under photoirradiation. The latter reacts with methyl Cypridina luciferin analogue (MCLA) to initiate chemiluminescence. This photoinduced chemiluminescence (PCL) of MCLA provides an easy method for evaluating the isomers' (1)O2 generation ability during a simultaneous HPLC separation procedure. The cis-isomers and trans-isomers of ZnPcS2 show different (1)O2 generation abilities, which are in accordance with differences in their absorption spectra. PMID- 23339149 TI - Combined multispectroscopic and molecular docking investigation on the interaction between strictosamide and human serum albumin. AB - The interaction between strictosamide (STM) and human serum albumin (HSA) was investigated by fluorescence spectroscopy, synchronous fluorescence spectroscopy, three-dimensional fluorescence spectroscopy, ultraviolet-visible absorption spectroscopy, circular dichroism spectroscopy and molecular modeling under physiological pH 7.4. STM effectively quenched the intrinsic fluorescence of HSA via static quenching. The binding site number n and apparent binding constant K(a) were determined at different temperatures by fluorescence quenching. The thermodynamic parameters, enthalpy change (DeltaH) and entropy change (DeltaS) for the reaction were calculated as -3.01 kJ/mol and 77.75 J/mol per K, respectively, which suggested that the hydrophobic force played major roles in stabilizing the HSA-STM complex. The distance r between donor and acceptor was obtained to be 4.10 nm according to Forster's theory. After the addition of STM, the synchronous fluorescence and three-dimensional fluorescence spectral results showed that the hydrophobicity of amino acid residues increased and the circular dichroism spectral results showed that the alpha-helix content of HSA decreased (from 61.48% to 57.73%). These revealed that the microenvironment and conformation of HSA were changed in the binding reaction. Furthermore, the study of molecular modeling indicated that STM could bind to site I of HSA and the hydrophobic interaction was the major acting force, which was in agreement with the binding mode study. PMID- 23339150 TI - No increased risk of spinal cord ischemia in delayed AAA repair following thoracic aortic surgery. AB - OBJECTIVE: To examine the results of open or endovascular abdominal aortic aneurysm (AAA) repair following prior open or endovascular thoracic aortic surgery. METHODS: A retrospective review of all patients who underwent AAA repair in a delayed fashion following prior thoracic aortic surgery at a single university hospital between 1999 and 2011 was performed. RESULTS: Thirteen patients underwent AAA repair following prior thoracic aortic repair. Mean age was 68.9 +/- 6.9 years and 77% (n = 10) were male. Three patients experienced transient delayed-onset spinal cord ischemia (SCI) following initial thoracic surgery. Mean time interval between initial thoracic aortic surgery and subsequent AAA repair was 2.0 +/- 1.8 years. Overall rate of SCI and 30-day mortality after delayed AAA repair was 0%. CONCLUSIONS: This series does not demonstrate any evidence of increased risk of perioperative mortality or SCI in patients undergoing delayed AAA repair after prior thoracic aortic surgery. PMID- 23339151 TI - Balloon-assisted N-butyl-2-cyanoacrylate closure of an iatrogenic femoral arteriovenous fistula. AB - Femoral arteriovenous fistula (AVF) is an abnormal communication between femoral artery and vein, which is frequently caused by an iatrogenic or traumatic event. Surgery and endovascular approach with coil and stent graft placement are the most frequent choices of treatment. Herein, we present 2 cases of iatrogenic superficial femoral AVF, which were treated with percutaneous balloon-assisted N butyl-2-cyanoacrylate glue (N-BCA). Both fistulae had a short tract, and 1 of the patients had previously undergone a failed coil embolization. The occlusions with N-BCA were achieved immediately, and both fistulae remained obliterated at 1 and 12 months of follow-up. PMID- 23339152 TI - The impact of endograft surveillance on a vascular imaging service. AB - BACKGROUND: Surveillance is considered mandatory after endovascular repair (EVR), but its impact on imaging services remains unreported. This study reports the effect of EVR surveillance on imaging resources. METHODS: A single-center's duplex database was interrogated from January 1, 2004 to January 1, 2012. All examinations requested by a vascular surgeon were reported, including preoperative abdominal aortic aneurysms, surveillance after EVR, lower limb arterial and venous duplex, and arteriovenous fistulae. RESULTS: A total of 24 309 patients underwent duplex. The EVR surveillance increased from 192 scans in 2004 to 1325 scans in 2011, 9.5% (192 of 2030) and 34.4% (1325 of 3850) of each year's examinations. By 2011, EVR surveillance was the most common indication for duplex. CONCLUSION: Lifelong EVR surveillance creates a rapidly increasing workload for imaging services. Further research should aim to reduce the burden of EVR surveillance. Targeting surveillance to the minority of patients at greatest risk of endograft failure might optimize the usage of imaging resources. PMID- 23339153 TI - Can we protect the kidneys after hypertensive pregnancy? PMID- 23339154 TI - Threshold. PMID- 23339155 TI - Unexpected predictor-outcome associations in clinical prediction research: causes and solutions. PMID- 23339156 TI - Association between hypertensive disorders during pregnancy and end-stage renal disease: a population-based study. AB - BACKGROUND: Studies into the association between hypertensive disorders during pregnancy and end-stage renal disease are limited. We investigated the risk of end-stage renal disease after delivery among women with hypertensive disorders during pregnancy. METHODS: We used insurance claims data from 1998 to 2009 to identify 26,651 women aged 19-40 years old who experienced hypertensive disorders during pregnancy; these women had no history of hypertension, diabetes, kidney disease or lupus. We also randomly selected 213,397 women without hypertensive disorders during pregnancy as a comparison cohort; the frequency was matched by age and index year of pregnancy. We compared the incidence of end-stage renal disease in the 2 cohorts. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) after controlling for demographic and clinical factors. RESULTS: Women with hypertensive disorders during pregnancy had a greater risk of chronic kidney disease and end-stage renal disease, with adjusted HRs of 9.38 (95% CI 7.09-12.4) and 12.4 (95% CI 8.54-18.0), respectively, after controlling for urban status, coronary artery disease, congestive heart failure, hyperlipidemia and abruption. The HR for end-stage renal disease was 2.72 (95% CI 1.76-4.22) after we also controlled for hypertension and diabetes. Women with preeclampsia or eclampsia had a higher risk of end-stage renal disease (adjusted HR 14.0, 95% CI 9.43-20.7) than women who had gestational hypertension only (adjusted HR 9.03, 95% CI 5.20-15.7). INTERPRETATION: Women with hypertensive disorders during pregnancy were at a high risk of end-stage renal disease. The risk was much greater for women who had preeclampsia or eclampsia than those who had gestational hypertension only. PMID- 23339157 TI - Imprisoning the mentally ill. PMID- 23339159 TI - Trauma and posttraumatic stress disorder in older adults. PMID- 23339160 TI - Black eyes and barriers. PMID- 23339162 TI - Agony behind bars. PMID- 23339163 TI - Health and hard time. PMID- 23339164 TI - Asthma and occupation in the 1958 birth cohort. AB - OBJECTIVE: To examine the association of adult onset asthma with lifetime exposure to occupations and occupational exposures. METHODS: We generated lifetime occupational histories for 9488 members of the British 1958 birth cohort up to age 42 years. Blind to asthma status, jobs were coded to the International Standard Classification of Occupations 1988 and an Asthma Specific Job Exposure Matrix (ASJEM) with an expert re-evaluation step. Associations of jobs and ASJEM exposures with adult onset asthma were assessed in logistic regression models adjusting for sex, smoking, social class at birth and childhood hay fever. RESULTS: Of the 7406 cohort members with no asthma or wheezy bronchitis in childhood, 639 (9%) reported asthma by age 42 years. Adult onset asthma was associated with 18 occupations, many previously identified as risks for asthma (eg, farmers: OR 4.26, 95% CI 2.06 to 8.80; hairdressers: OR 1.88, 95% CI 1.24 to 2.85; printing workers: OR 3.04, 95% CI 1.49 to 6.18). Four were cleaning occupations and a further three occupations were likely to use cleaning agents. Adult onset asthma was associated with five of the 18 high-risk specific ASJEM exposures (flour exposure: OR 2.12, 95% CI 1.17 to 3.85; enzyme exposure: OR 2.32, 95% CI 1.22 to 4.42; cleaning/disinfecting products: OR 1.67, 95% CI 1.26 to 2.22; metal and metal fumes: OR 1.45, 95% CI 1.02 to 2.07; textile production: OR 1.71, 95% CI 1.12 to 2.61). Approximately 16% (95% CI 3.8% to 27.1%) of adult onset asthma was associated with known asthmagenic occupational exposures. CONCLUSIONS: This study suggests that about 16% of adult onset asthma in British adults born in the late 1950s could be due to occupational exposures, mainly recognised high-risk exposures. PMID- 23339165 TI - Sex-specific mTOR signaling determines sexual dimorphism in myocardial adaptation in normotensive DOCA-salt model. AB - The deoxycorticosterone acetate (DOCA)-salt mouse model exhibits adverse cardiac remodeling in male mice and cardiac protection in female mice, even when blood pressure is normalized. We hypothesized that intact mammalian target of rapamycin (mTOR) signaling is necessary for cardiac protection in females. We first tested sex differences and intracellular signaling after mTOR targeting with rapamycin in wild-type mice. Radio-telemetric blood pressure was maintained at normal for 6 weeks. Rapamycin significantly reduced left ventricular hypertrophy, preserved ejection fraction, inhibited fibrosis, and maintained capillary structure in male mice. Decreased mTORC1 and increased mTORC2 activity were detected in rapamycin treated male mice compared with vehicle controls. In contrast, female mice developed dilative left ventricular hypertrophy, cardiac fibrosis, and capillary loss similar to DOCA-salt females lacking the estrogen receptor beta (ERbeta(-/ )) that we described earlier. Because rapamycin downregulated ERbeta in female mice, we next studied ERbeta(-/-) normotensive DOCA-salt females. Vehicle-treated wild-type females maintained their high constitutive mTORC1 and mTORC2 in response to DOCA-salt. In contrast to males, both mTORCs were decreased by rapamycin, in particular mTORC2 by 60%. ERbeta(-/-) DOCA-salt females showed similar mTORC1 and mTORC2 response patterns. We suggest that ERbeta-dependent regulation involves sex-specific use of mTOR signaling branches. Maintenance of both mTORC1 and mTORC2 signaling seems to be essential for adaptive cardiac remodeling in females and supports a rationale for sex-specific therapeutic strategies in left ventricular hypertrophy. PMID- 23339166 TI - Multimodality imaging of subclinical aortic atherosclerosis: relation of aortic stiffness to calcification and plaque in female twins. AB - Aortic stiffness, an important predictor of cardiovascular events, may relate to aortic calcification rather than noncalcified atherosclerotic plaque. The aim of this study was to determine the relation of aortic stiffness to aortic plaque and aortic calcification in asymptomatic postmenopausal women. One hundred female twins (mean age+/-standard deviation 64+/-7 years) underwent computed tomography and magnetic resonance imaging (black-blood sequence) of the aorta. The topographical relation of plaque on magnetic resonance images and calcification on computed tomography images was assessed on magnetic resonance/computed tomography fused images. Carotid-femoral pulse wave velocity was used as a measure of aortic stiffness. Aortic plaque was identified in 87% and calcification in 65% of subjects, both increased with age and were higher in the abdominal compared with thoracic aorta (P<0.0001). Plaque correlated with calcification (R=0.68; P<0.0001), but was also detected in 58% of women who had no calcification. Pulse wave velocity (adjusted for age and blood pressure) increased across quartiles of calcification (P<0.01) but not plaque score (P=0.56). Shared genetic factors accounted for >99% of the correlation (0.35) between PWV and calcification. In conclusion, there is a high prevalence of subclinical atherosclerosis within the aorta in asymptomatic middle-aged women. Aortic stiffening relates to aortic calcification, but not to atherosclerotic plaque burden, and the association of aortic stiffness with calcification is driven by common genes. PMID- 23339167 TI - Single nucleotide polymorphisms in G protein signaling pathway genes in preeclampsia. AB - Preeclampsia is a pregnancy specific disorder and a risk factor for later cardiovascular disease. The cause and detailed pathophysiology remains unknown. G protein signaling is involved in a variety of physiological processes, including blood pressure regulation. We assessed whether distributions of 3 single nucleotide polymorphisms in genes coding for components of G protein signaling pathways that have been associated with hypertension differ between women with preeclampsia and normotensive pregnant women; the G protein beta3 subunit gene (GNB3) C825T polymorphism (rs5443), the angiotensin II type 1 receptor gene (AGTR1) 3'UTR A1166C polymorphism (rs5186), and the regulator of G protein signaling 2 gene (RGS2) 3'UTR C1114G polymorphism (rs4606). Two separate Norwegian study populations were used; a large population based study and a smaller, but clinically well-described pregnancy biobank. A descriptive study of 43 women with eclampsia was additionally included. In the population-based study, an increased odds of preeclampsia (odds ratio, 1.21; [95% confidence interval, 1.05-1.40]; P=0.009) and recurrent preeclampsia (odds ratio, 1.43; [95% confidence interval, 1.06-1.92];, P=0.017) was found in women carrying the rs4606 CG or GG genotype. In early-onset preeclamptic patients with decidual spiral artery biopsies available (n=24), the rs4606 CG or GG genotype was more frequent in those with acute atherosis (resembling early stage of atherosclerosis) compared with those without: odds ratio, 15.0; (95% confidence interval, 2.02 111.2); P=0.004. No association was found between preeclampsia and the rs5443 or the rs5186. The genotype distribution in eclamptic women was not different from preeclamptic women. In conclusion, RGS2 rs4606 may affect the risk and progression of preeclampsia. PMID- 23339168 TI - Pulmonary hypertension secondary to left-heart failure involves peroxynitrite induced downregulation of PTEN in the lung. AB - Pulmonary hypertension (PH) that occurs after left-heart failure (LHF), classified as Group 2 PH, involves progressive pulmonary vascular remodeling induced by smooth muscle cell (SMC) proliferation. However, mechanisms involved in the activation of SMCs remain unknown. The objective of this study was to determine the involvement of peroxynitrite and phosphatase-and-tensin homolog on chromosome 10 (PTEN) in vascular SMC proliferation and remodeling in the LHF induced PH (LHF-PH). LHF was induced by permanent ligation of left anterior descending coronary artery in rats for 4 weeks. MRI, ultrasound, and hemodynamic measurements were performed to confirm LHF and PH. Histopathology, Western blot, and real-time polymerase chain reaction analyses were used to identify key molecular signatures. Therapeutic intervention was demonstrated using an antiproliferative compound, HO-3867. LHF-PH was confirmed by significant elevation of pulmonary artery pressure (mean pulmonary artery pressure/mm Hg: 35.9+/-1.8 versus 14.8+/-2.0, control; P<0.001) and vascular remodeling. HO-3867 treatment decreased mean pulmonary artery pressure to 22.6+/-0.8 mm Hg (P<0.001). Substantially higher levels of peroxynitrite and significant loss of PTEN expression were observed in the lungs of LHF rats when compared with control. In vitro studies using human pulmonary artery SMCs implicated peroxynitrite-mediated downregulation of PTEN expression as a key mechanism of SMC proliferation. The results further established that HO-3867 attenuated LHF-PH by decreasing oxidative stress and increasing PTEN expression in the lung. In conclusion, peroxynitrite and peroxynitrite-mediated PTEN inactivation seem to be key mediators of lung microvascular remodeling associated with PH secondary to LHF. PMID- 23339169 TI - 23Na magnetic resonance imaging-determined tissue sodium in healthy subjects and hypertensive patients. AB - High dietary salt intake is associated with hypertension; the prevalence of salt sensitive hypertension increases with age. We hypothesized that tissue Na(+) might accumulate in hypertensive patients and that aging might be accompanied by Na(+) deposition in tissue. We implemented (23)Na magnetic resonance imaging to measure Na(+) content of soft tissues in vivo earlier, but had not studied essential hypertension. We report on a cohort of 56 healthy control men and women, and 57 men and women with essential hypertension. The ages ranged from 22 to 90 years. (23)Na magnetic resonance imaging measurements were made at the level of the calf. We observed age-dependent increases in Na(+) content in muscle in men, whereas muscle Na(+) content did not change with age in women. We estimated water content with conventional MRI and found no age-related increases in muscle water in men, despite remarkable Na(+) accumulation, indicating water free Na(+) storage in muscle. With increasing age, there was Na(+) deposition in the skin in both women and men; however, skin Na(+) content remained lower in women. Similarly, this sex difference was found in skin water content, which was lower in women than in men. In contrast to muscle, increasing Na(+) content was paralleled with increasing skin water content. When controlled for age, we found that patients with refractory hypertension had increased tissue Na(+) content, compared with normotensive controls. These observations suggest that (23)Na magnetic resonance imaging could have utility in assessing the role of tissue Na(+) storage for cardiovascular morbidity and mortality in longitudinal studies. PMID- 23339171 TI - Obesity-related hypertension and the role of insulin and leptin in high-fat-fed rabbits. AB - Feeding a high-fat diet (HFD) to rabbits results in increased blood pressure and renal sympathetic nerve activity (RSNA) and marked increases in plasma leptin and insulin. We determined the contribution of insulin and leptin signaling in the central nervous system to the increased blood pressure and RSNA during a HFD using specific antagonists. New Zealand White rabbits were implanted with an intracerebroventricular (ICV) catheter and RSNA electrode and placed on a normal or 13.5% HFD for 1 or 3 weeks. Blood pressure, heart rate, and RSNA were recorded before and for 90 minutes after ICV administration of a leptin antagonist (100 ug), insulin antagonist (0.5 U), or vehicle (50 uL) on separate days. Rabbits had higher blood pressure (+8%, +17%) and RSNA (+55%, +71%), at 1 and 3 weeks, respectively, of HFD compared with controls (n=7-11). ICV leptin antagonist reduced blood pressure by 9% and RSNA by 17% (P<0.001) after 3 weeks of HFD but had no effect at week 1. ICV administration of the insulin antagonist reduced blood pressure by ~5% at both times (P<0.05) but there was no effect on RSNA. Leptin and insulin antagonist doses were confirmed to effectively block the pressor responses to ICV leptin and insulin, respectively. The elevation of blood pressure and RSNA induced by a HFD is predominantly mediated by central actions of leptin. Central actions of insulin contribute a smaller proportion of the hypertension but independently of RSNA. PMID- 23339170 TI - Testosterone alters maternal vascular adaptations: role of the endothelial NO system. AB - Sex steroid hormones estradiol and progesterone play an important role in vascular adaptations during pregnancy. However, little is known about the role of androgens. Plasma testosterone (T) levels are elevated in preeclampsia, mothers with polycystic ovary, and pregnant African American women, who have endothelial dysfunction and develop gestational hypertension. We tested whether increased T alters vascular adaptations during pregnancy and whether these alterations depend on endothelium-derived factors, such as prostacyclin, endothelium-derived hyperpolarizing factor, and NO. Pregnant Sprague Dawley rats were injected with vehicle (n=12) or T propionate [0.5 mg/Kg per day from gestation day 15-19; n=12] to increase plasma T levels 2-fold, similar to that observed in preeclampsia. Telemetric blood pressures and endothelium-dependent vascular reactivity were assessed with wire-myograph system. Phospho-endothelial NO synthase and total endothelial NO synthase were examined in mesenteric arteries. Mean arterial pressures were significantly higher starting from gestation day19 until delivery in T-treated dams. Endothelium-dependent relaxation responses to acetylcholine were significantly lower in mesenteric arteries of T-treated dams (pD(2) [-log EC(50)]=7.05+/-0.06; E(max)=89.4+/-1.89) compared with controls (pD(2)=7.38+/ 0.04; E(max)=99.9+/-0.97). Further assessment of endothelial factors showed NO mediated relaxations were blunted in T-treated mesenteric arteries (E(max)=42.26+/-5.95) compared with controls (E(max)=76.49+/-5.06); however, prostacyclin- and endothelium-derived hyperpolarizing factor-mediated relaxations were unaffected. Relaxation to sodium nitroprusside was unaffected with T treatment. Phosphorylations of endothelial NO synthase at Ser(1177) were decreased and at Thr(495) increased in T-treated mesenteric arteries without changes in total endothelial NO synthase levels. In conclusion, increased maternal T, at concentrations relevant to abnormal clinical conditions, cause hypertension associated with blunting of NO-mediated vasodilation. T may induce the increased vascular resistance associated with pregnancy-induced hypertension. PMID- 23339172 TI - Input-specific learning rules at excitatory synapses onto hippocampal parvalbumin expressing interneurons. AB - Hippocampal parvalbumin-expressing interneurons (PV INs) provide fast and reliable GABAergic signalling to principal cells and orchestrate hippocampal ensemble activities. Precise coordination of principal cell activity by PV INs relies in part on the efficacy of excitatory afferents that recruit them in the hippocampal network. Feed-forward (FF) inputs in particular from Schaffer collaterals influence spike timing precision in CA1 principal cells whereas local feedback (FB) inputs may contribute to pacemaker activities. Although PV INs have been shown to undergo activity-dependent long term plasticity, how both inputs are modulated during principal cell firing is unknown. Here we show that FF and FB synapses onto PV INs are endowed with distinct postsynaptic glutamate receptors which set opposing long-term plasticity rules. Inward-rectifying AMPA receptors (AMPARs) expressed at both FF and FB inputs mediate a form of anti Hebbian long term potentiation (LTP), relying on coincident membrane hyperpolarization and synaptic activation. In contrast, FF inputs are largely devoid of NMDA receptors (NMDARs) which are more abundant at FB afferents and confer on them an additional form of LTP with Hebbian properties. Both forms of LTP are expressed with no apparent change in presynaptic function. The specific endowment of FF and FB inputs with distinct coincidence detectors allow them to be differentially tuned upon high frequency afferent activity. Thus, high frequency (>20 Hz) stimulation specifically potentiates FB, but not FF afferents. We propose that these differential, input-specific learning rules may allow PV INs to adapt to changes in hippocampal activity while preserving their precisely timed, clockwork operation. PMID- 23339173 TI - Increased activity of pre-motor network does not change the excitability of motoneurons during protracted scratch initiation. AB - Intrinsic response properties of neurons change during network activity. These changes may reinforce the initiation of particular forms of network activity. If so, the involvement of neurons in particular behaviours in multifunctional networks could be determined by up- or down-regulation of their intrinsic excitability. Here we employed an experimental paradigm of protracted scratch initiation in the integrated carapace-spinal cord preparation of adult turtles (Chrysemys scripta elegans). The protracted initiation of scratch network activity allows us to investigate the excitability of motoneurons and pre-motor network activity in the time interval from the start of sensory stimulation until the onset of scratch activity. Our results suggest that increased activity in the pre-motor network facilitates the onset of scratch episodes but does not change the excitability of motoneurons at the onset of scratching. PMID- 23339174 TI - Lack of cholinergic innervation in gastric mucosa does not affect gastrin secretion or basal acid output in neurturin receptor GFRalpha2 deficient mice. AB - Efferent signals from the vagus nerve are thought to mediate both basal and meal induced gastric acid secretion, and provide trophic support of the mucosa. However, the underlying mechanisms are incompletely understood. Neurturin, signalling via glial cell line-derived neurotrophic factor (GDNF)-family receptor alpha2 (GFRalpha2), is essential for parasympathetic innervation of many target tissues but its role in gastric innervation is unknown. Here we show that most nerve fibres in wild-type mouse gastric mucosa, including all positive for gastrin-releasing peptide, are cholinergic. GFRalpha2-deficient (KO) mice lacked virtually all cholinergic nerve fibres and associated glial cells in the gastric (oxyntic and pyloric) mucosa but not in the smooth muscle, consistent with the selective expression of neurturin mRNA in the gastric mucosa. 2-Deoxyglucose and hexamethonium failed to affect acid secretion in the GFRalpha2-KO mice indicating the lack of functional innervation in gastric mucosa. Interestingly, basal and maximal histamine-induced acid secretion did not differ between wild-type and GFRalpha2-KO mice. Moreover, circulating gastrin levels in both fasted and fed animals, thickness of gastric mucosa, and density of parietal and different endocrine cells were similar. Carbachol-stimulated acid secretion was higher in GFRalpha2-KO mice, while atropine reduced basal secretion similarly in both genotypes. We conclude that cholinergic innervation of gastric mucosa depends on neurturin-GFRalpha2 signalling but is dispensable for gastrin secretion and for basal and maximal acid output. Basal acid secretion in the KO mice appears to be, at least partly, facilitated by constitutive activity of muscarinic receptors. PMID- 23339175 TI - Functional role of vasoactive intestinal polypeptide in inhibitory motor innervation in the mouse internal anal sphincter. AB - There is evidence that vasoactive intestinal polypeptide (VIP) participates in inhibitory neuromuscular transmission (NMT) in the internal anal sphincter (IAS). However, specific details concerning VIP-ergic NMT are limited, largely because of difficulties in selectively blocking other inhibitory neural pathways. The present study used the selective P2Y1 receptor antagonist MRS2500 (1 MUm) and the nitric oxide synthase inhibitor N(G)-nitro-l-arginine (l-NNA; 100 MUm) to block purinergic and nitrergic NMT to characterize non-purinergic, non-nitrergic (NNNP) inhibitory NMT and the role of VIP in this response. Nerves were stimulated with electrical field stimulation (0.1-20 Hz, 4-60 s) and the associated changes in contractile and electrical activity measured in non-adrenergic, non-cholinergic conditions in the IAS of wild-type and VIP(-/-) mice. Electrical field stimulation gave rise to frequency-dependent relaxation and hyperpolarization that was blocked by tetrodotoxin. Responses during brief trains of stimuli (4 s) were mediated by purinergic and nitrergic NMT. During longer stimulus trains, an NNNP relaxation and hyperpolarization developed slowly and persisted for several minutes beyond the end of the stimulus train. The NNNP NMT was abolished by VIP6 28 (30 MUm), absent in the VIP(-/-) mouse and mimicked by exogenous VIP (1-100 nm). Immunoreactivity for VIP was co-localized with neuronal nitric oxide synthase in varicose intramuscular fibres but was not detected in the VIP(-/-) mouse IAS. In conclusion, this study identified an ultraslow component of inhibitory NMT in the IAS mediated by VIP. In vivo, this pathway may be activated with larger rectal distensions, leading to a more prolonged period of anal relaxation. PMID- 23339176 TI - Construction of a polarized neuron. AB - Aside from rare counterexamples (e.g. the starburst amacrine cell in retina), neurons are polarized into two compartments, dendrites and axon, which are linked at the cell body. This structural polarization carries an underlying molecular definition and maps into a general functional polarization whereby inputs are collected by the dendrites and cell body, and output is distributed via the axon. Explanations of how the polarized structure arises invariably coalesce around somatic polarity, defined by the roving location of the microtubule organizing centre, or centrosome, the Golgi apparatus, associated endosomes and the nucleus during early development. In some neurons, proper positioning of these structures can determine the sites for axon and dendrite elongation, and support processes that underlie cell migration. We briefly review these events as a basis to propose a new role for polarized arrangement of somatic organelles as a potential determinant for patterned innervation of the cell body membrane. We cite an example from preliminary studies of synaptogenesis at the calyx of Held, a large nerve terminal that selectively innervates the cell body of its postsynaptic partner, and suggest other neural systems in which polarity mechanisms may guide initial synapse formation onto the somatic surface. PMID- 23339177 TI - Interactions between spinal interneurons and ventral spinocerebellar tract neurons. AB - Recent evidence indicates that ventral spinocerebellar tract (VSCT) neurons do not merely receive information provided by spinal interneurons but may also modulate the activity of these interneurons. Hence, interactions between them may be mutual. However, while it is well established that spinal interneurons may provide both excitatory and inhibitory input to ascending tract neurons, the functional consequences of the almost exclusively inhibitory input from premotor interneurons to subpopulations of VSCT neurons were only recently addressed. These are discussed in the first part of this review. The second part of the review summarizes evidence that some VSCT neurons may operate both as projection neurons and as spinal interneurons and play a role in spinal circuitry. It outlines the evidence that initial axon collaterals of VSCT neurons target premotor inhibitory interneurons in disynaptic reflex pathways from tendon organs and muscle spindles (group Ia, Ib and/or II muscle afferents) to motoneurons. By activating these interneurons VSCT neurons may evoke disynaptic IPSPs in motoneurons and thus facilitate inhibitory actions of contralateral muscle afferents on motoneurons. In this way they may contribute to the coordination between neuronal networks on both sides of the spinal cord in advance of modulatory actions evoked via the cerebellar control systems. PMID- 23339178 TI - Taste responses in mice lacking taste receptor subunit T1R1. AB - The T1R1 receptor subunit acts as an umami taste receptor in combination with its partner, T1R3. In addition, metabotropic glutamate receptors (brain and taste variants of mGluR1 and mGluR4) are thought to function as umami taste receptors. To elucidate the function of T1R1 and the contribution of mGluRs to umami taste detection in vivo, we used newly developed knock-out (T1R1(-/-)) mice, which lack the entire coding region of the Tas1r1 gene and express mCherry in T1R1 expressing cells. Gustatory nerve recordings demonstrated that T1R1(-/-) mice exhibited a serious deficit in inosine monophosphate-elicited synergy but substantial residual responses to glutamate alone in both chorda tympani and glossopharyngeal nerves. Interestingly, chorda tympani nerve responses to sweeteners were smaller in T1R1(-/-) mice. Taste cell recordings demonstrated that many mCherry-expressing taste cells in T1R1(+/-) mice responded to sweet and umami compounds, whereas those in T1R1(-/-) mice responded to sweet stimuli. The proportion of sweet-responsive cells was smaller in T1R1(-/-) than in T1R1(+/-) mice. Single-cell RT-PCR demonstrated that some single mCherry-expressing cells expressed all three T1R subunits. Chorda tympani and glossopharyngeal nerve responses to glutamate were significantly inhibited by addition of mGluR antagonists in both T1R1(-/-) and T1R1(+/-) mice. Conditioned taste aversion tests demonstrated that both T1R1(-/-) and T1R1(+/-) mice were equally capable of discriminating glutamate from other basic taste stimuli. Avoidance conditioned to glutamate was significantly reduced by addition of mGluR antagonists. These results suggest that T1R1-expressing cells mainly contribute to umami taste synergism and partly to sweet sensitivity and that mGluRs are involved in the detection of umami compounds. PMID- 23339179 TI - Pan-junctional sarcoplasmic reticulum in vascular smooth muscle: nanospace Ca2+ transport for site- and function-specific Ca2+ signalling. AB - This review focuses on how smooth muscle sarcoplasmic reticulum (SR), the major releasable Ca(2+) store in these cells, performs its many functions by communicating with the plasma membrane (PM) and other organelles across cytoplasmic nanospaces, defined by membrane-membrane junctions less than 50 nm across. In spite of accumulating evidence in favour of the view that cytoplasmic nanospaces are a prerequisite for effective control of diverse cellular functions, our current understanding of how smooth muscle cells accomplish site- and function-specific Ca(2+) signalling remains in its infancy. We first present evidence in support of the view that effective Ca(2+) signalling depends on the restricted diffusion of Ca(2+) within cytoplasmic nanospaces. We then develop an evidence-based model of the smooth muscle SR - the 'pan-junctional SR' model - that incorporates a network of tubules and quilts that are capable of auto regulating their Ca(2+) content and determining junctional [Ca(2+)]i through loading and unloading at membrane-membrane nanojunctions. Thereby, we provide a novel working hypothesis in order to inform future investigation into the control of a variety of cellular functions by local Ca(2+) signals at junctional nanospaces, from contraction and energy metabolism to nuclear transcription. Based on the current literature, we discuss the molecular mechanisms whereby the SR mediates these multiple functions through the interaction of ion channels and pumps embedded in apposing membranes within inter-organellar junctions. We finally highlight the fact that although most current hypotheses are qualitatively supported by experimental data, solid quantitative simulations are seriously lacking. Considering that at physiological concentrations the number of calcium ions in a typical junctional nanospace between the PM and SR is of the order of 1, ion concentration variability plays a major role as the currency of information transfer and stochastic quantitative modelling will be required to both test and develop working hypotheses. PMID- 23339180 TI - Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans. AB - Transcranial direct current stimulation (tDCS) of the human motor cortex at an intensity of 1 mA with an electrode size of 35 cm(2) has been shown to induce shifts of cortical excitability during and after stimulation. These shifts are polarity-specific with cathodal tDCS resulting in a decrease and anodal stimulation in an increase of cortical excitability. In clinical and cognitive studies, stronger stimulation intensities are used frequently, but their physiological effects on cortical excitability have not yet been explored. Therefore, here we aimed to explore the effects of 2 mA tDCS on cortical excitability. We applied 2 mA anodal or cathodal tDCS for 20 min on the left primary motor cortex of 14 healthy subjects. Cathodal tDCS at 1 mA and sham tDCS for 20 min was administered as control session in nine and eight healthy subjects, respectively. Motor cortical excitability was monitored by transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) from the right first dorsal interosseous muscle. Global corticospinal excitability was explored via single TMS pulse-elicited MEP amplitudes, and motor thresholds. Intracortical effects of stimulation were obtained by cortical silent period (CSP), short latency intracortical inhibition (SICI) and facilitation (ICF), and I wave facilitation. The above-mentioned protocols were recorded both before and immediately after tDCS in randomized order. Additionally, single-pulse MEPs, motor thresholds, SICI and ICF were recorded every 30 min up to 2 h after stimulation end, evening of the same day, next morning, next noon and next evening. Anodal as well as cathodal tDCS at 2 mA resulted in a significant increase of MEP amplitudes, whereas 1 mA cathodal tDCS decreased corticospinal excitability. A significant shift of SICI and ICF towards excitability enhancement after both 2 mA cathodal and anodal tDCS was observed. At 1 mA, cathodal tDCS reduced single-pulse TMS-elicited MEP amplitudes and shifted SICI and ICF towards inhibition. No significant changes were observed in the other protocols. Sham tDCS did not induce significant MEP alterations. These results suggest that an enhancement of tDCS intensity does not necessarily increase efficacy of stimulation, but might also shift the direction of excitability alterations. This should be taken into account for applications of the stimulation technique using different intensities and durations in order to achieve stronger or longer lasting after-effects. PMID- 23339181 TI - Assessment of emerging biomarkers of liver injury in human subjects. AB - Hepatotoxicity remains a major challenge in drug development. Although alanine aminotransferase (ALT) remains the gold standard biomarker of liver injury, alternative biomarker strategies to better predict the potential for severe drug induced liver injury (DILI) are essential. In this study, we evaluated the utility of glutamate dehydrogenase (GLDH), purine nucleoside phosphorylase (PNP), malate dehydrogenase (MDH), and paraxonase 1 (PON1) as indicators of liver injury in cohorts of human subjects, including healthy subjects across age and gender, subjects with a variety of liver impairments, and several cases of acetaminophen poisoning. In the healthy subjects, levels of GLDH and MDH were not affected by age or gender. Reference ranges for GLDH and MDH in healthy subjects were 1-10 and 79-176U/L, respectively. In contrast, the levels of PON1 and PNP were not consistent across cohorts of healthy subjects. Furthermore, GLDH and MDH had a strong correlation with elevated ALT levels and possessed a high predictive power for liver injury, as determined by ROC analysis. In contrast, PON1 and PNP did not detect liver injury in our study. Finally, evaluation of patients with acetaminophen-induced liver injury provided evidence that both GLDH and MDH might have utility as biomarkers of DILI in humans. This study is the first to evaluate GLDH, MDH, PON1, and PNP in a large number of human subjects and, and it provides an impetus for prospective clinical studies to fully evaluate the diagnostic value of GLDH and MDH for detection of liver injury. PMID- 23339182 TI - Propiconazole inhibits steroidogenesis and reproduction in the fathead minnow (Pimephales promelas). AB - Conazoles are designed to inhibit cytochrome P450 (CYP) 14alpha-demethylase, an enzyme key to fungal cell wall formation. In vertebrates, conazoles may inhibit other CYPs, potentially disrupting processes like sex steroid synthesis. Propiconazole is a current-use pesticide that is among the first chemicals being tested in the U.S. Environmental Protection Agency endocrine disruptor screening program. Fathead minnows (Pimephales promelas) were exposed to 0, 5, 50, 500, or 1000 ug propiconazole/l in a 21-day study that evaluated apical reproductive endpoints (fecundity, fertility, hatch); measures of endocrine function and steroid synthesis, such as cholesterol, vitellogenin (VTG), and sex steroid (testosterone [T], 17beta-estradiol [E2]) concentrations in the plasma; and changes in gonadal expression of steroidogenic genes. Plasma E2 and VTG concentrations in females were reduced by exposure to propiconazole, and egg production was decreased in the 500 and 1000 ug/l treatment groups. These in vivo effects coincided with inhibition of E2 synthesis by ovary explants exposed to propiconazole in vitro. We also observed a compensatory response in females exposed to propiconazole, manifested as increased gonad weight and upregulation of genes coding for key steriodogenic proteins, including CYP19 (aromatase), CYP17 (hydroxylase/lyase), CYP11A (cholesterol side-chain-cleavage), and steroidogenic acute regulatory protein. Other than an increase in relative testis weight, effects on endocrine function in males were less pronounced than in females. This study provides important data relative to the potential endocrine activity of propiconazole in fish and, more generally, to the further delineation of pathways for the reproductive effects of steroid synthesis inhibitors in fish. PMID- 23339183 TI - Molecular evolution of alpha-latrotoxin, the exceptionally potent vertebrate neurotoxin in black widow spider venom. AB - Black widow spiders (members of the genus Latrodectus) are widely feared because of their potent neurotoxic venom. alpha-Latrotoxin is the vertebrate-specific toxin responsible for the dramatic effects of black widow envenomation. The evolution of this toxin is enigmatic because only two alpha-latrotoxin sequences are known. In this study, ~4 kb alpha-latrotoxin sequences and their homologs were characterized from a diversity of Latrodectus species, and representatives of Steatoda and Parasteatoda, establishing the wide distribution of latrotoxins across the mega-diverse spider family Theridiidae. Across black widow species, alpha-latrotoxin shows >= 94% nucleotide identity and variability consistent with purifying selection. Multiple codon and branch-specific estimates of the nonsynonymous/synonymous substitution rate ratio also suggest a long history of purifying selection has acted on alpha-latrotoxin across Latrodectus and Steatoda. However, alpha-latrotoxin is highly divergent in amino acid sequence between these genera, with 68.7% of protein differences involving non conservative substitutions, evidence for positive selection on its physiochemical properties and particular codons, and an elevated rate of nonsynonymous substitutions along alpha-latrotoxin's Latrodectus branch. Such variation likely explains the efficacy of red-back spider, L. hasselti, antivenom in treating bites from other Latrodectus species, and the weaker neurotoxic symptoms associated with Steatoda and Parasteatoda bites. Long-term purifying selection on alpha-latrotoxin indicates its functional importance in black widow venom, even though vertebrates are a small fraction of their diet. The greater differences between Latrodectus and Steatoda alpha-latrotoxin, and their relationships to invertebrate-specific latrotoxins, suggest a shift in alpha-latrotoxin toward increased vertebrate toxicity coincident with the evolution of widow spiders. PMID- 23339184 TI - Microenvironmental regulation of BRCA1 gene expression by c-Jun and Fra2 in premalignant human ovarian surface epithelial cells. AB - Reduced BRCA1 gene expression is common in the sporadic form of ovarian carcinoma. The spread of this highly lethal cancer often begins when tumor cell clusters are shed into the fluid of the abdominopelvic cavity such that they can float freely before seeding distant sites on the peritoneal walls and organs. Thus, the microenvironment that tumor cells find themselves in changes dramatically during these early shedding and floating stages of transperitoneal metastasis. To mimic this microenvironmental change in vitro, we released premalignant human ovarian surface epithelial cells from the substratum and forced them to cluster in suspension. Under these conditions, steady state levels of BRCA1 mRNA and protein fell significantly and the transcriptional activation state of the BRCA1 promoter was suppressed. Analysis of the promoter indicated that the previously identified "CRE" element located within the "positive regulatory region" (PRR) contributed to this suppression. More specifically, we show that the suppression was mediated, at least in part, by a suspension culture driven decrease in the levels of two members of the AP1 transcription factor complex, c-Jun and Fra2, that bind to the CRE element. Therefore, a microenvironmental change that is manifested during the initial stages of ovarian carcinoma dissemination may, potentially, help suppress BRCA1 expression in sporadic tumors and thus promote their progression. PMID- 23339185 TI - Targeting constitutively activated beta1 integrins inhibits prostate cancer metastasis. AB - Disseminated prostate cancer cells must survive in circulation for metastasis to occur. Mechanisms by which these cells survive are not well understood. By immunohistochemistry of human tissues, we found that levels of beta1 integrins and integrin-induced autophosphorylation of FAK (pFAK-Y397) are increased in prostate cancer cells in primary prostate cancer and lymph node metastases, suggesting that beta1 integrin activation occurs in metastatic progression of prostate cancer. A conformation-sensitive antibody, 9EG7, was used to examine beta1 integrin activation. We found that beta1 integrins are constitutively activated in highly metastatic PC3 and PC3-mm2 cells, with less activation in low metastatic LNCaP and C4-2B4 cells. Increased beta1 integrin activation as well as the anoikis resistance in prostate cancer cells correlated with metastatic potential in vivo. Knockdown of beta1 integrin abrogated anoikis resistance in PC3-mm2 cells. In agreement with beta1 integrin activation, PC3-mm2 cells strongly adhered to type I collagen and fibronectin, a process inhibited by the beta1 integrin-neutralizing antibody mAb 33B6. mAb 33B6 also inhibited the phosphorylation of beta1 integrin downstream effectors, focal adhesion kinase (FAK) and AKT, leading to a 3-fold increase in PC3-mm2 apoptosis. Systemic delivery of mAb 33B6 suppressed spontaneous metastasis of PC3-mm2 from the prostate to distant lymph nodes following intraprostatic injection and suppressed metastasis of PC3-mm2 to multiple organs following intracardiac injection. Thus, constitutively activated beta1 integrins play a role in survival of PC3-mm2 cells in circulation and represent a potential target for metastasis prevention. PMID- 23339186 TI - Nuclear expression of beta-catenin promotes RB stability and resistance to TNF induced apoptosis in colon cancer cells. AB - Tumor necrosis factor (TNF)-alpha promotes tumor development under chronic inflammation. Because TNF also activates caspase-8, selective inhibition of TNF induced extrinsic apoptosis would be required for inflammation-associated tumor growth. In a mouse model of inflammation-associated colon carcinogenesis, we found nuclear expression of beta-catenin in tumors of wild-type, but not mutant, mice that were made resistant to TNF-induced apoptosis by a germline mutation blocking caspase cleavage of the retinoblastoma (RB) protein, despite similar frequencies of beta-catenin exon-3 mutations in these two genetic backgrounds. TNF-induced apoptosis was also attenuated in human colon cancer cell lines with genetically activated beta-catenin. However, we found that HCT116 cells, which contain an activated allele of beta-catenin but do not express nuclear beta catenin, were sensitive to TNF-induced apoptosis. In HCT116 cells, TNF stimulated efficient RB cleavage that preceded chromatin condensation. In contrast, TNF did not induce RB cleavage in colon cancer cells expressing nuclear beta-catenin and these cells could be sensitized to basal and/or TNF-induced apoptosis by the knockdown of beta-catenin or RB. In the apoptosis-resistant colon cancer cells, knockdown of beta-catenin led to a reduction in the RB protein without affecting RB mRNA. Furthermore, ectopic expression of the caspase-resistant, but not the wild-type, RB re-established resistance to TNF-induced caspase activation in colon cancer cells without beta-catenin. Together, these results suggest that nuclear beta-catenin-dependent RB stabilization suppresses TNF-induced apoptosis in caspase-8-positive colon cancer cells. PMID- 23339188 TI - Identification and structural elucidation of four cannabimimetic compounds (RCS 4, AM-2201, JWH-203 and JWH-210) in seized products. AB - Since 2008, herbal mixtures with synthetic cannabinoid compounds have been sold as incense throughout the world. Although these new drugs are labeled as not for human consumption, these products are smoked for their cannabis-like effects. This study reports the structural and spectral elucidation of four cannabimimetic compounds seized in Belgium: (4-methoxyphenyl)-1-(pentyl-1H-indol-3-yl)methanone (RCS-4), 1-(5-fluoropentyl)-3-(1-naphtoyl)indole (AM-2201), 2-(2-chlorophenyl)-1 (1-pentylindol-3-yl)ethanone (JWH-203) and 4-ethylnaphthalen-1-yl-(1-pentylindol 3-yl)methanone (JWH-210). Laboratory investigations were conducted by liquid chromatography (LC)-ultraviolet spectroscopy, high-resolution accurate mass detection and nuclear magnetic resonance (NMR) analysis. This combined analytical approach allowed the detection of illicit compounds for which reference materials were not available. To facilitate identification and to complete existing databases, ultraviolet spectra and NMR data of all seized products are presented. Additionally, LC-quadrupole time-of-flight data were recorded to provide absolute identification. PMID- 23339187 TI - The heterochronic microRNA let-7 inhibits cell motility by regulating the genes in the actin cytoskeleton pathway in breast cancer. AB - The heterochronic gene let-7 serves as a tumor suppressor microRNA by targeting various oncogenic pathways in cancer cells. Considerable evidence indicates that reduced expression of let-7 might be associated with poor clinical outcome in patients with cancer. Here, we report that the expression levels of three let-7 family members, let-7a, let-7b, and let-7g, were significantly decreased in the patients with breast cancer with lymph node metastasis compared with those without lymph node metastasis. Enforced expression of let-7b significantly inhibits breast cancer cell motility and affects actin dynamics. Using bioinformatic and experimental approaches, four genes in the actin cytoskeleton pathway, including PAK1, DIAPH2, RDX, and ITGB8, were identified as let-7 direct targets. Blocking the expression of PAK1, DIAPH2, and RDX significantly inhibits breast cancer cell migration induced by let-7b repression. Our results indicate that reconstitution of let-7 expression in tumor cells could provide a novel therapeutic strategy for the treatment of metastatic disease. PMID- 23339189 TI - Antitumor effect of SIRT1 inhibition in human HCC tumor models in vitro and in vivo. AB - Sirtuins (SIRT1-7) are a highly conserved family of NAD(+)-dependent enzymes that control the activity of histone and nonhistone regulatory proteins. SIRT1 is purposed to promote longevity and to suppress the initiation of some cancers. Nevertheless, SIRT1 is reported to function as a tumor suppressor as well as an oncogenic protein. Our data show that compared with normal liver or surrounding tumor tissue, SIRT1 is strongly overexpressed in human hepatocellular carcinoma (HCC). In addition, human HCC cell lines (Hep3B, HepG2, HuH7, HLE, HLF, HepKK1, skHep1) were screened for the expression of the sirtuin family members and only SIRT1 was consistently overexpressed compared with normal hepatocytes. To determine its effect on HCC growth, SIRT1 activity was inhibited either with lentiviruses expressing short hairpin RNAs or with the small molecule inhibitor, cambinol. Knockdown or inhibition of SIRT1 activity had a cytostatic effect, characterized by an altered morphology, impaired proliferation, an increased expression of differentiation markers, and cellular senescence. In an orthotopic xenograft model, knockdown of SIRT1 resulted in 50% fewer animals developing tumors and cambinol treatment resulted in an overall lower tumor burden. Taken together, our data show that inhibition of SIRT1 in HCC cells impairs their proliferation in vitro and tumor formation in vivo. These data suggest that SIRT1 expression positively influences the growth of HCC and support further studies aimed to block its activity alone or in combination as a novel treatment strategy. PMID- 23339190 TI - Novel inhibitors of Rad6 ubiquitin conjugating enzyme: design, synthesis, identification, and functional characterization. AB - Protein ubiquitination is important for cell signaling, DNA repair, and proteasomal degradation, and it is not surprising that alterations in ubiquitination occur frequently in cancer. Ubiquitin-conjugating enzymes (E2) mediate ubiquitination by selective interactions with ubiquitin-activating (E1) and ubiquitin ligase (E3) enzymes, and thus selective E2 small molecule inhibitor (SMI) will provide specificity unattainable with proteasome inhibitors. Here we describe synthesis and functional characterization of the first SMIs of human E2 Rad6B, a fundamental component of translesion synthesis DNA repair. A pharmacophore model for consensus E2 ubiquitin-binding sites was generated for virtual screening to identify E2 inhibitor candidates. Twelve triazine (TZ) analogs screened in silico by molecular docking to the Rad6B X-ray structure were verified by their effect on Rad6B ubiquitination of histone H2A. TZs #8 and 9 docked to the Rad6B catalytic site with highest complementarity. TZs #1, 2, 8, and 9 inhibited Rad6B-ubiquitin thioester formation and subsequent ubiquitin transfer to histone H2A. SMI #9 inhibition of Rad6 was selective as BCA2 ubiquitination by E2 UbcH5 was unaffected by SMI #9. SMI #9 more potently inhibited proliferation, colony formation, and migration than SMI #8, and induced MDA-MB-231 breast cancer cell G2-M arrest and apoptosis. Ubiquitination assays using Rad6 immunoprecipitated from SMI #8- or 9-treated cells confirmed inhibition of endogenous Rad6 activity. Consistent with our previous data showing Rad6B-mediated polyubiquitination stabilizes beta-catenin, MDA-MB-231 treatment with SMIs #8 or 9 decreased beta-catenin protein levels. Together these results describe identification of the first Rad6 SMIs. PMID- 23339191 TI - Solute accumulation and elastic modulus changes in six radiata pine breeds exposed to drought. AB - Drought is one of the main abiotic factors that determine forest species growth, survival and productivity. For this reason, knowledge of plant drought response and the identification of physiological traits involved in stress tolerance will be of interest to breeding programs. In this work, several Pinus radiata D. Don breeds from different geographical origins were evaluated along a water stress period (4 weeks) and subsequent rewatering (1 week), showing different responses among them. Leaf water potential (Psi(leaf)) and osmotic potential decreases were accompanied by a variation in the total relative water content (RWC, %). The most tolerant breeds presented the lowest leaf water potential and RWC at turgor loss point, and showed the lowest elastic modulus (epsilon) values. A high epsilon value was a characteristic of a less-drought-tolerant plant and was related to membrane alterations (high electrolyte leakage percentages) that could favor cell water loss. Of the group of solutes that contributed to osmotic adjustment, soluble carbohydrates were the most abundant, although stressed plants also increased their content of free amino acids [mainly proline (Pro) and glutamic acid (Glu), and gamma-aminobutyric acid (GABA)] and free polyamines. In addition, the most sensitive breeds had a higher GABA/Glu ratio. After rewatering, Pro and GABA were higher in rehydrated plants than in controls. PMID- 23339192 TI - Regulation of microRNAs by Brahma-related gene 1 (Brg1) in smooth muscle cells. AB - MicroRNAs are involved in phenotypic switching of smooth muscle cells (SMCs). Brg1-containing SWI/SNF chromatin-remodeling complexes also play an important role in controlling the phenotype of SMCs. We thus determined whether Brg1 influences the transcription of microRNAs in SMCs. Microarray and quantitative RT PCR analysis of smooth muscle from mice harboring smooth muscle-specific deletion of Brg1 revealed altered expression of several microRNAs, including miRs-143/145 and miR-133. Ablation of Brg1 in SMCs in vitro either by expression of dominant negative Brg1 or Brg1 knock-out attenuated miRs-143/145 expression. Knockdown of serum response factor (SRF) in SMCs significantly reduced the expression levels of miRs-143/145 and miR-133, whereas knockdown of myocardin only attenuated miRs 143/145 expression. Myocardin induced expression of miRs-143/145 and miR-133a and increased SRF binding to these genes in 10T1/2 cells. This myocardin-mediated induction was attenuated by dominant negative Brg1. In Brg1-null SW13 cells, miRs 143/145 were dramatically induced by myocardin only in the presence of Brg1, whereas miR-133 was not induced by myocardin in a Brg1-dependent manner. Chromatin immunoprecipitation assays demonstrated that in the presence of Brg1, myocardin increased SRF binding to both the miRs-143/145 and miR-133a loci. Together, these data suggest a mechanism in which Brg1-containing SWI/SNF complexes are required for myocardin to induce expression of miRs-143/145 in smooth muscle cells. In contrast, miR-133 expression appears to be regulated by Brg1-containing chromatin remodeling complexes in a partially SRF-dependent, although largely myocardin-independent manner. SWI/SNF-mediated chromatin remodeling thus regulates the phenotype of smooth muscle by affecting expression of protein-coding genes and microRNAs. PMID- 23339193 TI - Molecular basis for Jagged-1/Serrate ligand recognition by the Notch receptor. AB - We have mapped a Jagged/Serrate-binding site to specific residues within the 12th EGF domain of human and Drosophila Notch. Two critical residues, involved in a hydrophobic interaction, provide a ligand-binding platform and are adjacent to a Fringe-sensitive residue that modulates Notch activity. Our data suggest that small variations within the binding site fine-tune ligand specificity, which may explain the observed sequence heterogeneity in mammalian Notch paralogues, and should allow the development of paralogue-specific ligand-blocking antibodies. As a proof of principle, we have generated a Notch-1-specific monoclonal antibody that blocks binding, thus paving the way for antibody tools for research and therapeutic applications. PMID- 23339194 TI - Kir2.4 surface expression and basal current are affected by heterotrimeric G proteins. AB - Kir2.4, a strongly rectifying potassium channel that is localized to neurons and is especially abundant in retina, was fished with yeast two-hybrid screen using a constitutively active Galphao1. Here, we wished to determine whether and how Galphao affects this channel. Using transfected HEK 293 cells and retinal tissue, we showed that Kir2.4 interacts with Galphao, and this interaction is stronger with the GDP-bound form of Galphao. Using two-electrode voltage clamp, we recorded from oocytes that were injected with Kir2.4 mRNA and a combination of G protein subunit mRNAs. We found that the wild type and the inactive mutant of Galphao reduce the Kir2.4 basal current, whereas the active mutant has little effect. Other pertussis-sensitive Galpha subunits also reduce this current, whereas Galphas increases it. Gbetagamma increases the current, whereas m phosducin, which binds Gbetagamma without affecting the state of Galpha, reduces it. We then tested the effect of G-protein subunits on the surface expression of the channel fused to cerulean by imaging the plasma membranes of the oocytes. We found that the surface expression is affected, with effects paralleling those seen with the basal current. This suggests that the observed effects on the current are mainly indirect and are due to surface expression. Similar results were obtained in transfected HEK cells. Moreover, we show that in retinal ON bipolar cells lacking Gbeta3, localization of Kir2.4 in the dendritic tips is reduced. We conclude that Gbetagamma targets Kir2.4 to the plasma membrane, and Galphao slows this down by binding Gbetagamma. PMID- 23339195 TI - The role of Drosophila heparan sulfate 6-O-endosulfatase in sulfation compensation. AB - The biosynthesis of heparan sulfate proteoglycans is tightly regulated by multiple feedback mechanisms, which support robust developmental systems. One of the regulatory network systems controlling heparan sulfate (HS) biosynthesis is sulfation compensation. A previous study using Drosophila HS 2-O- and 6-O sulfotransferase (Hs2st and Hs6st) mutants showed that loss of sulfation at one position is compensated by increased sulfation at other positions, supporting normal FGF signaling. Here, we show that HS sulfation compensation rescues both Decapentaplegic and Wingless signaling, suggesting a universal role of this regulatory system in multiple pathways in Drosophila. Furthermore, we identified Sulf1, extracellular HS 6-O-endosulfatase, as a novel component of HS sulfation compensation. Simultaneous loss of Hs2st and Sulf1 led to 6-O-oversulfation, leading to patterning defects, overgrowth, and lethality. These phenotypes are caused at least partly by abnormal up-regulation of Hedgehog signaling. Thus, sulfation compensation depends on the coordinated activities of Hs2st, Hs6st, and Sulf1. PMID- 23339196 TI - Urinary levels of thymine dimer as a biomarker of exposure to ultraviolet radiation in humans during outdoor activities in the summer. AB - The incidence of skin cancer is rising rapidly in many countries, presumably due to increased leisure time exposure to solar ultraviolet radiation (UVR). UVR causes DNA lesions, such as the thymine dimer (T=T), which have been causatively linked to the development of skin cancer. T=T is clearly detectable in urine and may, thereby, be a potentially valuable biomarker of UVR exposure. The objective of this study was to evaluate the relationship between UVR exposure and urinary levels of T=T in a field study involving outdoor workers. Daily ambient and personal exposure of 52 beach lifeguards and agricultural workers to UVR were determined (employing 656 personal polysulphone dosimeters). In 22 of these subjects, daily urinary T=T levels (120 samples) were measured, the area of skin exposed calculated and associations assessed utilizing mixed statistical models. The average daily UVR dose was approximately 600 J/m(2) (7.7 standard erythemal doses), i.e. about 20% of ambient UVR. T=T levels were correlated to UVR dose, increasing by about 6 fmol/umol creatinine for each 100 J/m(2) increase in dose (average of the three preceding days). This is the first demonstration of a relationship between occupational UVR exposure and urinary levels of a biomarker of DNA damage. On a population level, urinary levels of T=T can be used as a biomarker for UVR exposure in the field. PMID- 23339197 TI - Clinical and epidemiological study on severe fever with thrombocytopenia syndrome in Yiyuan County, Shandong Province, China. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in China. Polymerase chain reaction and enzyme-linked immunosorbent assay were used to detect SFTS virus (SFTSV) and Anaplasma phagocytophilum in previous clinically diagnosed human anaplasmosis patients and SFTS patients. A serosurvey for SFTSV infection was also conducted on healthy persons and animals in Yiyuan County in Shandong Province of China. Among 21 patients SFTSV was detected in 17 (81%) however A. phagocytophilum was not detected in any of the patients. The seroprevalence rate of IgG antibody to SFTSV antigens was 1.3% (1 of 78) in healthy persons, 95% (19 of 20) in goats, 50% (1 of 2) in dogs, 0% in cattle (0 of 21), and rats (Rattus norvegicus) (0 of 35). The conclusion of this study was that co-infection of SFTSV and A. phagocytophilum are rare in SFTS patients and goats might play an important role in transmission of SFTSV. PMID- 23339198 TI - A five-country evaluation of a point-of-care circulating cathodic antigen urine assay for the prevalence of Schistosoma mansoni. AB - We evaluated a commercial point-of-care circulating cathodic antigen (POC-CCA) test for assessing Schistosoma mansoni infection prevalence in areas at risk. Overall, 4,405 school-age children in Cameroon, Cote d'Ivoire, Ethiopia, Kenya, and Uganda provided urine for POC-CCA testing and stool for Kato-Katz assays. By latent class analysis, one POC-CCA test was more sensitive (86% versus 62%) but less specific (72% versus ~100%) than multiple Kato-Katz smears from one stool. However, only 1% of POC-CCA tests in a non-endemic area were false positives, suggesting the latent class analysis underestimated the POC-CCA specificity. Multivariable modeling estimated POC-CCA as significantly more sensitive than Kato-Katz at low infection intensities (< 100 eggs/gram stool). By linear regression, 72% prevalence among 9-12 year olds by POC-CCA corresponded to 50% prevalence by Kato-Katz, whereas 46% POC-CCA prevalence corresponded to 10% Kato Katz prevalence. We conclude that one urine POC-CCA test can replace Kato-Katz testing for community-level S. mansoni prevalence mapping. PMID- 23339199 TI - Disseminated Mycobacterium tuberculosis infection in a dog. AB - An uncommon disseminated Mycobacterium tuberculosis infection is described in a 12-year-old female dog presenting with fever, dyspnea, cough, weight loss, lymphadenopathy, melena, epistaxis, and emesis. The dog had a history of close contact with its owner, who died of pulmonary tuberculosis. Radiographic examination revealed diffuse radio-opaque images in both lung lobes, diffuse visible masses in abdominal organs, and hilar and mesenteric lymphadenopathy. Bronchial washing samples and feces were negative for acid-fast organisms. Polymerase chain reaction (PCR)-based species identification of bronchial washing samples, feces, and urine revealed M. tuberculosis using PCR-restriction enzyme pattern analysis-PRA. Because of public health concerns, which were worsened by the physical condition of the dog, euthanasia of the animal was recommended. Rough and tough colonies suggestive of M. tuberculosis were observed after microbiological culture of lung, liver, spleen, heart, and lymph node fragments in Lowenstein-Jensen and Stonebrink media. The PRA analysis enabled diagnosis of M. tuberculosis strains isolated from organs. PMID- 23339200 TI - Restricted outbreak of American tegumentary leishmaniasis with high microfocal transmission. AB - Cutaneous leishmaniasis is endemic in Salta, the northwestern province of Argentina. We describe an outbreak involving five recreational hunters whose exposure was limited to several hours in a residual patch of primary forest. All patients presented with typical cutaneous lesions after a mean incubation period of 59 days (range 15-78), and one developed simultaneous mucosal involvement. Polymerase chain reaction analysis of lesions confirmed Leishmania (V.) braziliensis as the etiologic agent in three cases. All patients were cured with anti-Leishmania treatment. Entomologic surveys in the transmission area revealed a predominance of Lutzomyia neivai. This outbreak report confirms a microfocal transmission pattern of tegumentary leishmaniasis in the Americas and based on a well-determined exposure, allows the determination of incubation times for leishmaniasis caused by Leishmania braziliensis. PMID- 23339201 TI - Hepatitis B, C, and D and HIV infections among immigrants from Equatorial Guinea living in Spain. AB - A total of 1,220 subjects from Equatorial Guinea living in Spain (median age = 41 years; 453 male and 767 female) was examined for antibodies to human immunodeficiency virus (HIV) and Hepatitis B (HBV), C (HCV), and D (HDV) viruses. Extracted RNA and DNA from the positive samples were used to quantify viral load. The prevalence of HIV antibodies, HCV RNA, and HBV surface antigen (HBsAg) was 10.8% (N = 132), 11.6% (N = 141), and 7.9% (N = 96), respectively. The most prevalent HIV variant was CRF02_AG (38.5%; N = 40). HCV genotype 4 (60%; N = 36) and HBV genotype A3 (32%; N = 8) were the hepatitis variants most frequently found. Superinfection with HDV was seen in 20.9% (N = 24) of HBsAg carriers. A control group of 276 immigrants from other sub-Saharan countries showed similar rates of HIV and HBsAg, although no HCV cases were found. Immigrants constitute a major source of HIV and hepatitis viruses in Spain; therefore, it is important that control measures are intensified. PMID- 23339202 TI - Clinical cutaneous leishmaniasis rates are associated with household Lutzomyia gomezi, Lu. Panamensis, and Lu. trapidoi abundance in Trinidad de Las Minas, western Panama. AB - American cutaneous leishmaniasis (ACL) transmission patterns have been increasingly associated with domestic and peridomestic environments. Here, we present results from an epidemiological survey of 94 people from 24 households in Trinidad de Las Minas, western Panama. We studied the role of sand fly abundance, housing quality, peridomicile landscape matrix, and vegetation structure on shaping household clinical ACL rate patterns at Trinidad de Las Minas. We found that sand fly abundance was significantly associated with household clinical ACL rates, with a 6% rate increase for each additional Lutzomyia gomezi sand fly found inside a domicile. PMID- 23339203 TI - Determination of viremia and concentration of circulating nonstructural protein 1 in patients infected with dengue virus in Mexico. AB - Higher levels of viremia and circulating nonstructural protein 1 (NS1) have been associated with dengue disease severity. In this study, viremia and circulating NS1 levels were determined in 225 serum samples collected from patients in Mexico infected with dengue virus serotypes 1 and 2 (DENV-1 and DENV-2). Patients with dengue hemorrhagic fever (DHF) who were infected with DENV-1 showed higher levels of circulating NS1 than patients with dengue fever (DF) (P = 0.0175). Moreover, NS1 levels were higher in patients with primary infections with DENV-1 than in patient infected with DENV-2 (P < 0.0001) and in patients with primary infections with DENV-2 than in patients with secondary infections with DENV-2 (P = 0.0051). Unexpectedly, viremia levels were higher in patients with DF than in those with DHF infected with either DENV-1 or DENV-2 (P = 0.0019 and P = 0.001, respectively) and in patients with primary infections than those with secondary DENV-2 infections (P < 0.0001). Results indicate that levels of circulating NS1 vary according to the infecting serotype, immunologic status (primary or secondary infection), and dengue disease severity. PMID- 23339204 TI - MRI findings in a cohort of brain injured survivors of pediatric cerebral malaria. AB - Abstract. A prospective cohort study of retinopathy-confirmed cerebral malaria (CM) survivors identified 42 of 132 with neurologic sequelae. The 38 survivors with sequelae who were alive when magnetic resonance imaging (MRI) technology became available underwent brain MRIs. Common MRI abnormalities included periventricular T2 signal changes (53%), atrophy (47%), subcortical T2 signal changes (18%), and focal cortical defects (16%). The chi(2) tests assessed the relationship between chronic MRI findings, acute clinical and demographic data, and outcomes. Children who were older at the time of CM infection (P = 0.01) and those with isolated behavioral problems (P = 0.02) were more likely to have a normal MRI. Acute focal seizures were associated with atrophy (P = 0.05). Acute papilledema was associated with subcortical T2 signal changes (P = 0.02). Peripheral retinal whitening (P = 0.007) and a higher admission white blood cell count (P = 0.02) were associated with periventricular T2 signal changes. Chronic MRI findings suggest seizures, increased intracranial pressure, and microvascular ischemia contribute to clinically relevant structural brain injury in CM. PMID- 23339205 TI - Resolution of hypercalcemia and acute kidney injury after treatment for pulmonary tuberculosis without the use of corticosteroids. AB - Abstract. Hypercalcemia caused by tuberculosis is rare and it is usually asymptomatic. Tuberculosis (TB) -related hypercalcemia associated with acute kidney injury (AKI) is rarely reported. We report a case of a 22-year-old immunocompetent man with 1-month history of daily fever, asthenia and weight loss. Laboratory findings on admission included serum calcium 14.9 mg/dL, urinary Ca(2+) 569.6 mg/24 hours, low level of parathyroid hormone, serum creatinine = 2.2 mg/dL and sodium fractional excretion (FeNa) 2.73%. The result of the tuberculin skin test was 17 mm. A chest X-ray revealed micronodular pulmonary infiltrate in the apex of the right lung, which was confirmed by computed tomography scan. The patient was diagnosed with hypercalcemia associated with pulmonary TB and AKI. A general improvement of the hypercalcemia and renal function was observed in the first 2 weeks after effective hydration and treatment of TB without corticosteroids. The patient was discharged with normal calcium levels and renal function. PMID- 23339206 TI - Neurology in Canada: history of the Canadian Neurological Society. PMID- 23339208 TI - Shadow sign in a T2* brain image in spontaneous middle cerebral artery dissection. PMID- 23339209 TI - Teaching NeuroImages: differential diagnosis of scapular winging. PMID- 23339207 TI - Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy. AB - Fatigue is commonly reported in many neurologic illnesses, including multiple sclerosis, Parkinson disease, myasthenia gravis, traumatic brain injury, and stroke. Fatigue contributes substantially to decrements in quality of life and disability in these illnesses. Despite the clear impact of fatigue as a disabling symptom, our understanding of fatigue pathophysiology is limited and current treatment options rarely lead to meaningful improvements in fatigue. Progress continues to be hampered by issues related to terminology and assessment. In this article, we propose a unified taxonomy and a novel assessment approach to addressing distinct aspects of fatigue and fatigability in clinical and research settings. This taxonomy is based on our current knowledge of the pathophysiology and phenomenology of fatigue and fatigability. Application of our approach indicates that the assessment and reporting of fatigue can be clarified and improved by utilizing this taxonomy and creating measures to address distinct aspects of fatigue and fatigability. We review the strengths and weaknesses of several common measures of fatigue and suggest, based on our model, that many research questions may be better addressed by using multiple measures. We also provide examples of how to apply and validate the taxonomy and suggest directions for future research. PMID- 23339210 TI - Comorbidity of migraine in children presenting with epilepsy to a tertiary care center. PMID- 23339211 TI - Teaching Video NeuroImages: periodic alternating nystagmus evident only in darkness. PMID- 23339212 TI - Emerging subspecialties in Neurology: transcranial stimulation. PMID- 23339213 TI - Pearls and oy-sters: tuberculous meningitis: not a diagnosis of exclusion. AB - A 21-year-old man presented to his local emergency department with 5 days of headache, which was dull, occipital, bilateral, nonthrobbing, and progressively worsening. It was associated with mild fever, photophobia, and neck pain and stiffness. He had no history of headache, chronic illness, recent vaccinations, cutaneous rash, cough, diarrhea, arthralgia, or myalgia. He was from Ecuador and had been living in the United States for less than 1 year. He had been incarcerated while in Ecuador. Sublingual temperature on admission was 102.6 degrees F. Other vital signs were within normal limits. On physical examination, he appeared thin but not cachectic. He had meningismus and photophobia, but no papilledema and his mental status was alert and attentive. There were no focal neurologic deficits. CSF contained red blood cells: 24 * 10(3)/MUL; white blood cells: 85/MUL (lymphocytic predominant); protein: 128 mg/dL; and glucose: 48 mg/dL (CSF/serum glucose ratio = 0.53). CSF Gram stain and cultures, PPD test, and blood and urine cultures were all negative. CT scan of the head on day of admission was entirely normal. MRI without gadolinium contrast showed a single punctate T2 hyperintensity in the left frontal periventricular white matter. Chest radiograph was clear. He received empiric vancomycin, ceftriaxone, and acyclovir. Corticosteroids were not given. The patient did not improve with antibiotics and continued to be intermittently febrile. On day 5, he became abruptly more somnolent, then comatose, opening eyes only to pain, his pupils were 5 mm and reactive, he had intact brainstem reflexes, withdrawing both arms and legs. Emergent head CT showed development of hydrocephalus and a ventriculoperitoneal shunt was emergently placed. The neurologic examination did not improve after shunt placement, and repeat head CT showed increased hydrocephalus with bilateral cerebral infarcts. On day 11, he was transferred to Columbia University Medical Center for intensive care. He was febrile and comatose. He did not open his eyes to pain, pupils were 7 mm minimally reactive, brainstem reflexes were intact, and he exhibited extensor posturing to pain. Mannitol was given, corticosteroid therapy was started, and an extraventricular drain was placed. The next day, his right pupil was 8 mm and nonreactive. MRI showed diffuse contrast enhancement of the arachnoid, extensive infarction of basal ganglia, midbrain, and pons, and small ring-enhancing lesions in the cerebellum (figure 1, A-D). Repeat lumbar puncture showed red blood cells: 550 * 10(3)/MUL; white blood cells: 250/MUL (14% neutrophils, 80% lymphocytes, 6% monocytes); protein: 65 mg/dL; and glucose: <10 mg/dL (CSF/serum glucose ratio = 0.08). CSF testing for Cryptococcus and toxoplasmosis was negative. CSF acid fast bacilli (AFB) smear was negative *2, and CSF nucleic acid amplification test was also negative for tuberculosis. Serum HIV test was negative. Not until 14 days after initial presentation and 3 days after transfer to the intensive care unit was antituberculosis therapy finally started, because the pattern of infarcts on the MRI suggested basilar meningitis and he had not improved on broad-spectrum antibiotics. That same day, the first sputum AFB smear was positive, as were all succeeding daily sputum AFB smears. Tuberculosis nucleic acid amplification was positive from the sputum, but persistently negative from the CSF. Daily portable chest radiographs had been normal (read as likely atelectasis), but chest CT showed dense consolidations in the left lung and diffuse micronodular opacities throughout both lungs. Two days later, only 21 days after the onset of his headache, the patient died of cardiopulmonary arrest secondary to transtentorial cerebral herniation. Thirteen days later, the CSF culture became positive for Mycobacterium tuberculosis sensitive to streptomycin, isoniazid, ethambutol, rifampin, and pyrazinamide. PMID- 23339214 TI - Teaching NeuroImages: multifocal neurologic involvement as the only manifestation of IgG4-related disease. PMID- 23339215 TI - Stillbirth and newborn mortality in India after helping babies breathe training. AB - OBJECTIVE: This study evaluated the effectiveness of Helping Babies Breathe (HBB) newborn care and resuscitation training for birth attendants in reducing stillbirth (SB), and predischarge and neonatal mortality (NMR). India contributes to a large proportion of the worlds annual 3.1 million neonatal deaths and 2.6 million SBs. METHODS: This prospective study included 4187 births at >28 weeks' gestation before and 5411 births after HBB training in Karnataka. A total of 599 birth attendants from rural primary health centers and district and urban hospitals received HBB training developed by the American Academy of Pediatrics, using a train-the-trainer cascade. Pre-post written trainee knowledge, posttraining provider performance and skills, SB, predischarge mortality, and NMR before and after HBB training were assessed by using chi(2) and t-tests for categorical and continuous variables, respectively. Backward stepwise logistic regression analysis adjusted for potential confounding. RESULTS: Provider knowledge and performance systematically improved with HBB training. HBB training reduced resuscitation but increased assisted bag and mask ventilation incidence. SB declined from 3.0% to 2.3% (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.59-0.98) and fresh SB from 1.7% to 0.9% (OR 0.54, 95% CI 0.37-0.78) after HBB training. Predischarge mortality was 0.1% in both periods. NMR was 1.8% before and 1.9% after HBB training (OR 1.09, 95% CI 0.80-1.47, P = .59) but unknown status at 28 days was 2% greater after HBB training (P = .007). CONCLUSIONS: HBB training reduced SB without increasing NMR, indicating that resuscitated infants survived the neonatal period. Monitoring and community-based assessment are recommended. PMID- 23339217 TI - Promoting child health equity: family-centered care coordination is just one piece of the puzzle. PMID- 23339216 TI - Hospital admissions for childhood asthma after smoke-free legislation in England. AB - OBJECTIVE: To assess whether the implementation of English smoke-free legislation in July 2007 was associated with a reduction in hospital admissions for childhood asthma. METHODS: Interrupted time series study using Hospital Episodes Statistics data from April 2002 to November 2010. Sample consisted of all children (aged <=14 years) having an emergency hospital admission with a principle diagnosis of asthma. RESULTS: Before the implementation of the legislation, the admission rate for childhood asthma was increasing by 2.2% per year (adjusted rate ratio 1.02; 95% confidence interval [CI]: 1.02-1.03). After implementation of the legislation, there was a significant immediate change in the admission rate of 8.9% (adjusted rate ratio 0.91; 95% CI: 0.89-0.93) and change in time trend of 3.4% per year (adjusted rate ratio 0.97; 95% CI: 0.96-0.98). This change was equivalent to 6802 fewer hospital admissions in the first 3 years after implementation. There were similar reductions in asthma admission rates among children from different age, gender, and socioeconomic status groups and among those residing in urban and rural locations. CONCLUSIONS: These findings confirm those from a small number of previous studies suggesting that the well-documented population health benefits of comprehensive smoke-free legislation appear to extend to reducing hospital admissions for childhood asthma. PMID- 23339218 TI - A quality improvement intervention to increase access to pediatric subspecialty practice. AB - OBJECTIVE: To improve access to new pediatric endocrinology appointments in an urban academic hospital faculty-based practice. METHODS: Three strategies were implemented to increase the number of appointment slots: new patient appointments were protected from conversion to follow-up appointments; all physicians, including senior faculty, were scheduled to see 3 to 4 new patients per session; and sessions devoted exclusively to follow-up appointments were added based on demand. The main outcomes for this quality improvement activity were waiting times for new and follow-up appointments, monthly visit volume, the per-provider visit volume, differences in the proportion of new visits, and clinic arrival rates pre- and postintervention. RESULTS: Thirteen months after the intervention, average wait for a new patient appointment decreased from 11.4 to 1.7 weeks (P < .001) and follow-up appointment wait time decreased from 8.2 to 2.9 weeks (P < .001). Mean monthly total visit volume increased from 284 to 366 patient visits (P < .01) and mean monthly visit volume per provider increased from 36.8 to 41.0 patients (P = .08). New patients were 27% of the visit volume and 35% after the intervention. CONCLUSIONS: Access to our pediatric specialty care clinic was improved without increasing the number of providers by improved scheduling. PMID- 23339219 TI - Paucity of clinical trials in iron deficiency: lessons learned from study of VLBW infants. PMID- 23339220 TI - RVUs and DRGs: do they fairly reimburse physicians and hospitals and incentivize improved care? PMID- 23339221 TI - Playground safety and quality in chicago. AB - OBJECTIVES: To assess playground safety and quality in Chicago, Illinois, identify disparities in access, and use the data to inform collaborative improvement. METHODS: A cross-sectional survey of public park playgrounds in Chicago, Illinois, was conducted in 2009, 2010, and 2011 by using the National Program for Playground Safety Standardized Survey. All playgrounds were surveyed in 2009 and 2010; those that failed in 2010 were resurveyed in 2011. Playgrounds were assessed in 4 main categories: age-appropriate design, fall surfacing, equipment maintenance, and physical environment. Safety scores were generated from the assessment. Geographic information system mapping provided a visual description of the playground pass/fail rate based on neighborhood, child population, race/ethnicity, and poverty level. RESULTS: Of the ~500 playgrounds, 467 were assessed in 2009, and 459 were assessed in 2010. In 2009, half of all playgrounds (55%) and in 2010, nearly two-thirds (61%) earned scores consistent with safe playgrounds (P < .001). Playgrounds scored poorest in fall surfacing and equipment maintenance. Geographic information system mapping showed neighborhoods with a higher percentage of children and impoverished families had fewer playgrounds and more failing playgrounds. In 2011, 154 (85%) of the playgrounds that failed in 2010 were surveyed. The mean playground score among failing playgrounds improved significantly between 2010 (61%) and 2011 (67%, P < .001). CONCLUSIONS: Since the playground improvement initiative began in 2009, considerable progress has been made in the safety scores, although access to high quality playgrounds varies by neighborhood. Many failing playgrounds can be brought up to standard with improvement in fall surfacing and equipment maintenance. PMID- 23339222 TI - A model of community pediatrics: improving access to safe play environments. PMID- 23339223 TI - Newborn mortality and fresh stillbirth rates in Tanzania after helping babies breathe training. AB - BACKGROUND: Early neonatal mortality has remained high and unchanged for many years in Tanzania, a resource-limited country. Helping Babies Breathe (HBB), a novel educational program using basic interventions to enhance delivery room stabilization/resuscitation, has been developed to reduce the number of these deaths. METHODS: Master trainers from the 3 major referral hospitals, 4 associated regional hospitals, and 1 district hospital were trained in the HBB program to serve as trainers for national dissemination. A before (n = 8124) and after (n = 78 500) design was used for implementation. The primary outcomes were a reduction in early neonatal deaths within 24 hours and rates of fresh stillbirths (FSB). RESULTS: Implementation was associated with a significant reduction in neonatal deaths (relative risk [RR] with training 0.53; 95% confidence interval [CI] 0.43-0.65; P <= .0001) and rates of FSB (RR with training 0.76; 95% CI 0.64-0.90; P = .001). The use of stimulation increased from 47% to 88% (RR 1.87; 95% CI 1.82-1.90; P <= .0001) and suctioning from 15% to 22% (RR 1.40; 95% CI 1.33-1.46; P <= .0001) whereas face mask ventilation decreased from 8.2% to 5.2% (RR 0.65; 95% CI 0.60-0.72; P <= .0001). CONCLUSIONS: HBB implementation was associated with a significant reduction in both early neonatal deaths within 24 hours and rates of FSB. HBB uses a basic intervention approach readily applicable at all deliveries. These findings should serve as a call to action for other resource-limited countries striving to meet Millennium Development Goal 4. PMID- 23339224 TI - The science of early life toxic stress for pediatric practice and advocacy. AB - Young children who experience toxic stress are at high risk for a number of health outcomes in adulthood, including cardiovascular disease, cancers, asthma, and depression. The American Academy of Pediatrics has recently called on pediatricians, informed by research from molecular biology, genomics, immunology, and neuroscience, to become leaders in science-based strategies to build strong foundations for children's life-long health. In this report, we provide an overview of the science of toxic stress. We summarize the development of the neuroendocrine-immune network, how its function is altered by early life adversity, and how these alterations then increase vulnerability to disease. The fact that early environments shape and calibrate the functioning of biological systems very early in life is both a cautionary tale about overlooking critical periods in development and reason for optimism about the promise of intervention. Even in the most extreme cases of adversity, well-timed changes to children's environments can improve outcomes. Pediatricians are in a unique position to contribute to the public discourse on health and social welfare by explaining how factors that seem distal to child health may be the key to some of the most intractable public health problems of our generation. We consider the challenges and opportunities for preventing toxic stress in the context of contemporary pediatric practice. PMID- 23339225 TI - Randomized trial of iron supplementation versus routine iron intake in VLBW infants. AB - OBJECTIVE: To determine if iron supplementation of 2 mg/kg per day, in addition to routine iron-fortified formula or mother's milk, increased the hematocrit (Hct) at 36 weeks' postmenstrual age (PMA). METHODS: : Infants with a birth weight <1500 g who reached 120 mL/kg per day of feedings before 32 weeks' PMA were randomly assigned to iron (multivitamin with iron) or control (multivitamin) from enrollment until 36 weeks' PMA (or discharge, if sooner). Investigators and caregivers were masked. Transfusion guidelines were used. The primary outcome was Hct at 36 weeks' PMA. A nonparametric rank sum analysis was performed so that infants who died before 36 weeks and infants who were transfused could be included in an intention-to-treat analysis. Infants were ranked by death (lowest rank) then by number of transfusions (next lowest ranks). For infants who survived and were not transfused, the 36-week PMA Hct was used for the rank. RESULTS: One hundred fifty infants were enrolled (76 iron, 74 controls). There were 2 deaths (1 in each group). One hundred other infants (47 iron, 53 controls) received transfusion(s). There was no significant difference in the primary outcome ranking (P = .59), in the number of transfusions per subject (P = .64), or in 36-week Hct (iron mean +/- SD, 29.2% +/- 4.0%; control, 28.3% +/- 4.5%; mean difference and 95% confidence interval 0.9 [-0.5 to 2.3]; P = .21) or reticulocyte count among survivors. No short-term adverse effects of iron supplementation were observed. CONCLUSIONS: Among infants <1500 g birth weight, iron supplementation, in addition to routine iron intake, did not significantly increase the 36-week Hct or the decrease number of transfusions. PMID- 23339226 TI - Promoting excellence in the care of pediatric endocrine diseases in the developing world. AB - On behalf of the Global Pediatric Endocrinology and Diabetes group, the authors provide a perspective on the rights of a child as enshrined in the United Nations Convention on the Rights of the Child (1989) concerning the care of pediatric endocrine disorders and diabetes mellitus, throughout the world, with particular reference to care in resource-constrained settings. In this article, we define the spectrum of health care needs of the child with an endocrine disorder and how they may be addressed, in terms of education, research, and development of sustainable programs for improved health outcomes. We emphasize the responsibilities of medical communities, the pharmaceutical industry, and relevant governments in promoting and supporting such concepts. PMID- 23339227 TI - Stimulating reflective practice among your learners. PMID- 23339228 TI - Disparities in unmet need for care coordination: the national survey of children's health. AB - OBJECTIVE: To determine (1) the proportion of parents who report a need for and receipt of effective care coordination for their child, (2) whether unmet care coordination needs differ by children with special health care needs (CSHCN) status and sociodemographic characteristics, and (3) whether having a personal provider or family-centered care mitigates disparities. METHODS: This study was a cross-sectional analysis of the 2007 National Survey for Children's Health, a nationally representative survey of 91 642 parents. Outcome measures were parent report of need for and lack of effective care coordination. We also examined the effect of parent report of having a personal provider and family-centered care. We conducted weighted bivariate and multivariate analyses. RESULTS: Forty-one percent of parents reported that their child needed care coordination. Among those who needed care coordination, 31% did not receive effective coordination. CSHCN (41%) were more likely than children without special health care needs (26%; P < .001) to have unmet care coordination needs. Latino (40%) and black (37%) children were more likely to have unmet needs than white (27%; P < .001) children. These patterns remained in multivariate analysis. Having a personal provider decreased the odds of having unmet need for care coordination but did not attenuate disparities. Receiving family-centered care mitigated disparities associated with race/ethnicity but not with health status or health insurance. CONCLUSIONS: A considerable proportion of parents reported their child needed more care coordination than they received. This was especially true for parents of CSHCN and parents of black and Latino children. Interventions that enhance family-centered care might particularly contribute to reducing racial/ethnic disparities. PMID- 23339229 TI - Capture of complexity of specialty care in pediatric cardiology by work RVU measures. AB - OBJECTIVE: We sought to determine the relationship between relative value units (RVUs) and intended measures of work in catheterization for congenital heart disease. METHODS: RVU was determined by matching RVU values to Current Procedural Terminology codes generated for cases performed at a single institution. Differences in median case duration, radiation exposure, adverse events, and RVU values by risk category and cases were assessed. Interventional case types were ranked from lowest to highest median RVU value, and correlations with case duration, radiation dose, and a cases-predicted probability of an adverse event were quantified with the Spearman rank correlation coefficient. RESULTS: Between January 2008 and December 2010, 3557 of 4011 cases were identified with an RVU and risk category designation, of which 2982 were assigned a case type. Median RVU values, radiation dose, and case duration increased with procedure risk category. Although all diagnostic cases had similar RVU values (median 10), adverse event rates ranged from 6% to 21% by age group (P < .001). Median RVU values ranged from 9 to 54 with the lowest in diagnostic and biopsy cases and increasing with isolated and then multiple interventions. Among interventional cases, no correlation existed between ranked RVU value and case duration, radiation dose, or adverse event probability (P = .13, P = .62, and P = .43, respectively). CONCLUSIONS: Time, skill, and stress inherent to performing catheterization procedures for congenital heart disease are not captured by measurement of RVU alone. PMID- 23339230 TI - Reshaping pediatric practice. PMID- 23339231 TI - Addressing high infant mortality in the developing world: a glimmer of hope. PMID- 23339232 TI - The relationship between EQ-5D, HAQ and pain in patients with rheumatoid arthritis. AB - OBJECTIVE: This study aims to provide robust estimates of EQ-5D as a function of the HAQ and pain in patients with RA. METHOD: Repeated observations were made of patients diagnosed with RA in a US observational cohort (n = 100 398 observations) who provided data on HAQ, pain on a visual analogue scale and the EQ-5D questionnaire. We used a bespoke statistical method based on mixture modelling to appropriately reflect the characteristics of the EQ-5D instrument and to compare this with results from standard multiple regression. RESULTS: EQ 5D can be predicted from summary HAQ and pain scores. We identify four different classes of respondents who differ in terms of disease severity. Unlike the multiple regression, the mixture model exhibits very good fit to the data and does not suffer from problems of bias or predict values outside the feasible range. CONCLUSION: It is appropriate to model the relationship between HAQ and EQ 5D but only if suitable statistical methods are applied. Linear models underestimate the quality-adjusted life year benefits, and therefore the cost effectiveness, of therapies. The bespoke mixture model approach outlined here overcomes this problem. The addition of pain as an explanatory variable greatly improves the estimates. Reimbursement agencies rely on these types of analyses when formulating policy on the use of new drug therapies. Clinicians as well as economists should be concerned with these issues. PMID- 23339233 TI - The polyandry revolution. PMID- 23339235 TI - Selection on female remating interval is influenced by male sperm competition strategies and ejaculate characteristics. AB - Female remating rate dictates the level of sperm competition in a population, and extensive research has focused on how sperm competition generates selection on male ejaculate allocation. Yet the way ejaculate allocation strategies in turn generate selection on female remating rates, which ultimately influence levels of sperm competition, has received much less consideration despite increasing evidence that both mating itself and ejaculate traits affect multiple components of female fitness. Here, we develop theory to examine how the effects of mating on female fertility, fecundity and mortality interact to generate selection on female remating rate. When males produce more fertile ejaculates, females are selected to mate less frequently, thus decreasing levels of sperm competition. This could in turn favour decreased male ejaculate allocation, which could subsequently lead to higher female remating. When remating simultaneously increases female fecundity and mortality, females are selected to mate more frequently, thus exacerbating sperm competition and favouring male traits that convey a competitive advantage even when harmful to female survival. While intuitive when considered separately, these predictions demonstrate the potential for complex coevolutionary dynamics between male ejaculate expenditure and female remating rate, and the correlated evolution of multiple male and female reproductive traits affecting mating, fertility and fecundity. PMID- 23339234 TI - Polyandry as a mediator of sexual selection before and after mating. AB - The Darwin-Bateman paradigm recognizes competition among males for access to multiple mates as the main driver of sexual selection. Increasingly, however, females are also being found to benefit from multiple mating so that polyandry can generate competition among females for access to multiple males, and impose sexual selection on female traits that influence their mating success. Polyandry can reduce a male's ability to monopolize females, and thus weaken male focused sexual selection. Perhaps the most important effect of polyandry on males arises because of sperm competition and cryptic female choice. Polyandry favours increased male ejaculate expenditure that can affect sexual selection on males by reducing their potential reproductive rate. Moreover, sexual selection after mating can ameliorate or exaggerate sexual selection before mating. Currently, estimates of sexual selection intensity rely heavily on measures of male mating success, but polyandry now raises serious questions over the validity of such approaches. Future work must take into account both pre- and post-copulatory episodes of selection. A change in focus from the products of sexual selection expected in males, to less obvious traits in females, such as sensory perception, is likely to reveal a greater role of sexual selection in female evolution. PMID- 23339236 TI - Polyandry and alternative mating tactics. AB - Many species in the animal kingdom are characterized by alternative mating tactics (AMTs) within a sex. In males, such tactics include mate guarding versus sneaking behaviours, or territorial versus female mimicry. Although AMTs can occur in either sex, they have been most commonly described in males. This sex bias may, in part, reflect the increased opportunity for sexual selection that typically exists in males, which can result in a higher probability that AMTs evolve in that sex. Consequently, females and polyandry can play a pivotal role in governing the reproductive success associated with male AMTs and in the evolutionary dynamics of the tactics. In this review, we discuss polyandry and the evolution of AMTs. First, we define AMTs and review game theoretical and quantitative genetic approaches used to model their evolution. Second, we review several examples of AMTs, highlighting the roles that genes and environment play in phenotype expression and development of the tactics, as well as empirical approaches to differentiating among the mechanisms. Third, ecological and genetic constraints to the evolution of AMTs are discussed. Fourth, we speculate on why female AMTs are less reported on in the literature than male tactics. Fifth, we examine the effects of AMTs on breeding outcomes and female fitness, and as a source, and possibly also a consequence, of sexual conflict. We conclude by suggesting a new model for the evolution of AMTs that incorporates both environmental and genetic effects, and discuss some future avenues of research. PMID- 23339237 TI - How multiple mating by females affects sexual selection. AB - Multiple mating by females is widely thought to encourage post-mating sexual selection and enhance female fitness. We show that whether polyandrous mating has these effects depends on two conditions. Condition 1 is the pattern of sperm utilization by females; specifically, whether, among females, male mating number, m (i.e. the number of times a male mates with one or more females) covaries with male offspring number, o. Polyandrous mating enhances sexual selection only when males who are successful at multiple mating also sire most or all of each of their mates' offspring, i.e. only when Cov(?)(m,o), is positive. Condition 2 is the pattern of female reproductive life-history; specifically, whether female mating number, m, covaries with female offspring number, o. Only semelparity does not erode sexual selection, whereas iteroparity (i.e. when Cov(?)(m,o), is positive) always increases the variance in offspring numbers among females, which always decreases the intensity of sexual selection on males. To document the covariance between mating number and offspring number for each sex, it is necessary to assign progeny to all parents, as well as identify mating and non mating individuals. To document significant fitness gains by females through iteroparity, it is necessary to determine the relative magnitudes of male as well as female contributions to the total variance in relative fitness. We show how such data can be collected, how often they are collected, and we explain the circumstances in which selection favouring multiple mating by females can be strong or weak. PMID- 23339239 TI - Sexually transmitted infections in polygamous mating systems. AB - Sexually transmitted infections (STIs) are often associated with chronic diseases and can have severe impacts on host reproductive success. For airborne or socially transmitted pathogens, patterns of contact by which the infection spreads tend to be dispersed and each contact may be of very short duration. By contrast, the transmission pathways for STIs are usually characterized by repeated contacts with a small subset of the population. Here we review how heterogeneity in sexual contact patterns can influence epidemiological dynamics, and present a simple model of polygyny/polyandry to illustrate the impact of biased mating systems on disease incidence and pathogen virulence. PMID- 23339238 TI - Polyandry and sex-specific gene expression. AB - Polyandry is widespread in nature, and has important evolutionary consequences for the evolution of sexual dimorphism and sexual conflict. Although many of the phenotypic consequences of polyandry have been elucidated, our understanding of the impacts of polyandry and mating systems on the genome is in its infancy. Polyandry can intensify selection on sexual characters and generate more intense sexual conflict. This has consequences for sequence evolution, but also for sex biased gene expression, which acts as a link between mating systems, sex-specific selection and the evolution of sexual dimorphism. We discuss this and the remarkable confluence of sexual-conflict theory and patterns of gene expression, while also making predictions about transcription patterns, mating systems and sexual conflict. Gene expression is a key link in the genotype-phenotype chain, and although in its early stages, understanding the sexual selection transcription relationship will provide significant insights into this critical association. PMID- 23339240 TI - The dynamic relationship between polyandry and selfish genetic elements. AB - Selfish genetic elements (SGEs) are ubiquitous in eukaryotes and bacteria, and make up a large part of the genome. They frequently target sperm to increase their transmission success, but these manipulations are often associated with reduced male fertility. Low fertility of SGE-carrying males is suggested to promote polyandry as a female strategy to bias paternity against male carriers. Support for this hypothesis is found in several taxa, where SGE-carrying males have reduced sperm competitive ability. In contrast, when SGEs give rise to reproductive incompatibilities between SGE-carrying males and females, polyandry is not necessarily favoured, irrespective of the detrimental impact on male fertility. This is due to the frequency-dependent nature of these incompatibilities, because they will decrease in the population as the frequency of SGEs increases. However, reduced fertility of SGE-carrying males can prevent the successful population invasion of SGEs. In addition, SGEs can directly influence male and female mating behaviour, mating rates and reproductive traits (e.g. female reproductive tract length and male sperm). This reveals a potent and dynamic interaction between SGEs and polyandry highlighting the potential to generate sexual selection and conflict, but also indicates that polyandry can promote harmony within the genome by undermining the spread of SGEs. PMID- 23339242 TI - The incidence and selection of multiple mating in plants. AB - Mating with more than one pollen donor, or polyandry, is common in land plants. In flowering plants, polyandry occurs when the pollen from different potential sires is distributed among the fruits of a single individual, or when pollen from more than one donor is deposited on the same stigma. Because polyandry typically leads to multiple paternity among or within fruits, it can be indirectly inferred on the basis of paternity analysis using molecular markers. A review of the literature indicates that polyandry is probably ubiquitous in plants except those that habitually self-fertilize, or that disperse their pollen in pollen packages, such as polyads or pollinia. Multiple mating may increase plants' female component by alleviating pollen limitation or by promoting competition among pollen grains from different potential sires. Accordingly, a number of traits have evolved that should promote polyandry at the flower level from the female's point of view, e.g. the prolongation of stigma receptivity or increases in stigma size. However, many floral traits, such as attractiveness, the physical manipulation of pollinators and pollen-dispensing mechanisms that lead to polyandrous pollination, have probably evolved in response to selection to promote male siring success in general, so that polyandry might often best be seen as a by-product of selection to enhance outcross siring success. In this sense, polyandry in plants is similar to geitonogamy (selfing caused by pollen transfer among flowers of the same plant), because both polyandry and geitonogamy probably result from selection to promote outcross siring success, although geitonogamy is almost always deleterious while polyandry in plants will seldom be so. PMID- 23339241 TI - Beyond promiscuity: mate-choice commitments in social breeding. AB - Obligate eusociality with distinct caste phenotypes has evolved from strictly monogamous sub-social ancestors in ants, some bees, some wasps and some termites. This implies that no lineage reached the most advanced form of social breeding, unless helpers at the nest gained indirect fitness values via siblings that were identical to direct fitness via offspring. The complete lack of re-mating promiscuity equalizes sex-specific variances in reproductive success. Later, evolutionary developments towards multiple queen-mating retained lifetime commitment between sexual partners, but reduced male variance in reproductive success relative to female's, similar to the most advanced vertebrate cooperative breeders. Here, I (i) discuss some of the unique and highly peculiar mating system adaptations of eusocial insects; (ii) address ambiguities that remained after earlier reviews and extend the monogamy logic to the evolution of soldier castes; (iii) evaluate the evidence for indirect fitness benefits driving the dynamics of (in)vertebrate cooperative breeding, while emphasizing the fundamental differences between obligate eusociality and cooperative breeding; (iv) infer that lifetime commitment is a major driver towards higher levels of organization in bodies, colonies and mutualisms. I argue that evolutionary informative definitions of social systems that separate direct and indirect fitness benefits facilitate transparency when testing inclusive fitness theory. PMID- 23339243 TI - Sex allocation and investment into pre- and post-copulatory traits in simultaneous hermaphrodites: the role of polyandry and local sperm competition. AB - Sex allocation theory predicts the optimal allocation to male and female reproduction in sexual organisms. In animals, most work on sex allocation has focused on species with separate sexes and our understanding of simultaneous hermaphrodites is patchier. Recent theory predicts that sex allocation in simultaneous hermaphrodites should strongly be affected by post-copulatory sexual selection, while the role of pre-copulatory sexual selection is much less clear. Here, we review sex allocation and sexual selection theory for simultaneous hermaphrodites, and identify several strong and potentially unwarranted assumptions. We then present a model that treats allocation to sexually selected traits as components of sex allocation and explore patterns of allocation when some of these assumptions are relaxed. For example, when investment into a male sexually selected trait leads to skews in sperm competition, causing local sperm competition, this is expected to lead to a reduced allocation to sperm production. We conclude that understanding the evolution of sex allocation in simultaneous hermaphrodites requires detailed knowledge of the different sexual selection processes and their relative importance. However, little is currently known quantitatively about sexual selection in simultaneous hermaphrodites, about what the underlying traits are, and about what drives and constrains their evolution. Future work should therefore aim at quantifying sexual selection and identifying the underlying traits along the pre- to post-copulatory axis. PMID- 23339245 TI - Polyandry: the history of a revolution. AB - We give a historic overview and critical perspective of polyandry in the context of sexual selection. Early approaches tended to obfuscate the fact that the total matings (copulations) by the two sexes is equal, neglecting female interests and that females often mate with (or receive ejaculates from) more than one male (polyandry). In recent years, we have gained much more insight into adaptive reasons for polyandry, particularly from the female perspective. However, costs and benefits of multiple mating are unlikely to be equal for males and females. These must be assessed for each partner at each potential mating between male i and female j, and will often be highly asymmetric. Interests of i and j may be in conflict, with (typically, ultimately because of primordial sex differences) i benefitting and j losing from mating, although theoretically the reverse can also obtain. Polyandry reduces the sex difference in Bateman gradients, and the probability of sexual conflict over mating by: (i) reducing the potential expected value of each mating to males in inverse proportion to the number of mates per female per clutch, and also often by (ii) increasing ejaculate costs through increased sperm allocation. It can nevertheless create conflict over fertilization and increase conflict over parental investment. The observed mean mating frequency for the population (and hence the degree of polyandry) is likely, at least in part, to reflect a resolution of sexual conflict. Immense diversity exists across and within taxa in the extent of polyandry, and views on its significance have changed radically, as we illustrate using avian polyandry as a case study. Despite recent criticisms, the contribution of the early pioneers of sexual selection, Darwin and Bateman, remains generally valid, and should not, therefore, be negated; as with much in science, pioneering advances are more often amplified and refined, rather than replaced with entirely new paradigms. PMID- 23339244 TI - The consequences of polyandry for population viability, extinction risk and conservation. AB - Polyandry, by elevating sexual conflict and selecting for reduced male care relative to monandry, may exacerbate the cost of sex and thereby seriously impact population fitness. On the other hand, polyandry has a number of possible population-level benefits over monandry, such as increased sexual selection leading to faster adaptation and a reduced mutation load. Here, we review existing information on how female fitness evolves under polyandry and how this influences population dynamics. In balance, it is far from clear whether polyandry has a net positive or negative effect on female fitness, but we also stress that its effects on individuals may not have visible demographic consequences. In populations that produce many more offspring than can possibly survive and breed, offspring gained or lost as a result of polyandry may not affect population size. Such ecological 'masking' of changes in population fitness could hide a response that only manifests under adverse environmental conditions (e.g. anthropogenic change). Surprisingly few studies have attempted to link mating system variation to population dynamics, and in general we urge researchers to consider the ecological consequences of evolutionary processes. PMID- 23339246 TI - Sexual networks: measuring sexual selection in structured, polyandrous populations. AB - Sexual selection is traditionally measured at the population level, assuming that populations lack structure. However, increasing evidence undermines this approach, indicating that intrasexual competition in natural populations often displays complex patterns of spatial and temporal structure. This complexity is due in part to the degree and mechanisms of polyandry within a population, which can influence the intensity and scale of both pre- and post-copulatory sexual competition. Attempts to measure selection at the local and global scale have been made through multi-level selection approaches. However, definitions of local scale are often based on physical proximity, providing a rather coarse measure of local competition, particularly in polyandrous populations where the local scale of pre- and post-copulatory competition may differ drastically from each other. These limitations can be solved by social network analysis, which allows us to define a unique sexual environment for each member of a population: 'local scale' competition, therefore, becomes an emergent property of a sexual network. Here, we first propose a novel quantitative approach to measure pre- and post copulatory sexual selection, which integrates multi-level selection with information on local scale competition derived as an emergent property of networks of sexual interactions. We then use simple simulations to illustrate the ways in which polyandry can impact estimates of sexual selection. We show that for intermediate levels of polyandry, the proposed network-based approach provides substantially more accurate measures of sexual selection than the more traditional population-level approach. We argue that the increasing availability of fine-grained behavioural datasets provides exciting new opportunities to develop network approaches to study sexual selection in complex societies. PMID- 23339247 TI - Primary cancellous bone formation with BMP and micro-chambered beads: experimental study on sheep. AB - PROBLEM: The physiological reconstruction of cancellous bone defects in surgery of the locomotor system is an unsatisfactorily solved problem. AIMS: The aims of this study are to examine whether micro-chambered beta-tricalcium-phosphate (beta TCP) beads provide a certain capillary force suctioning in blood and bone marrow thus forming a stable "negative"-replica of the bone marrow spaces. If so, a new approach for osteoconduction would yield primarily a scaffold of lamellar cancellous bone under load without a long-lasting remodeling process. Recombinant human bone morphogenetic protein (rhBMP) might even enhance all processes of defect healing, remodeling and beta-TCP resorption; gentamicin-loaded epsilon caprolactone might protect the implant. MATERIAL AND METHODS: Ten sheep were operated on; the patella-groove model and the tibial head were used. A defect of 9.4 * 20 mm was created using wet-grinding-diamond instruments. Micro-chambered beta-TCP-beads of 4-6 mm with 0.35 mg rhBMP-7 + 0.1 g collagen per animal, or 1.5 g demineralized bone matrix (DBM) paste on the contra-lateral side were implanted. Both osteoinduction groups were compared with the defect in the tibial heads where plain micro-chambered ceramic beads were inserted. Added to the beads was 12.5 mg gentamicin sulphate in 12.5 mg epsilon-caprolactone-carrier. Outward diffusion was prevented using a 1-mm-thick press-fit inserted ceramic lid. The bone healing, remodeling and resorption of the ceramic in a right-left comparison of the patella groove and the tibial head was examined at 6 weeks, 2 and 3 months; one animal in reserve was followed for 14 months. The animals were perfusion-fixed, the vasculature micro-casted with an acrylate and nondemineralized processed, and with MU-CT and microscopically documented. RESULTS: A primary load-bearing spongiosa had developed around the beads, which shortened the remodeling process. The strong micro-chambered, resorbable beta-TCP beads demonstrate high capillary strength, resorb blood and bone marrow, and represent a stable formative material which, as a carrier for the controlled local release of BMP, that accelerates bone healing, shortens resorption and remodeling compared with plain and DBM loaded implants. CONCLUSION: Micro chambered beads represent the bone-forming element, BMP yields a fast defect healing and enhanced remodeling of bone and resorption of beta-TCP compared to delayed and incomplete reconstruction and resorption of beta-TCP on the DBM-side, the plain implants reached nearly the same reconstruction, but far later compared with the BMP loaded implants. PMID- 23339248 TI - Retraction notice to "Spectroscopic investigation of collagen scaffolds impregnated with AgNPs coated by PEG/TX-100 mixed systems" [Int. J. Biol. Macromol. 50 (3) (2012) 603-612]. PMID- 23339249 TI - Revisiting the concept of vulnerability:recognising strength and resilience in the context of risk and susceptibility. PMID- 23339250 TI - The three developmental phases of addressing sexuality in nursing care:where do we go from here? PMID- 23339251 TI - Creating culturally relevant and sustainable research strategies to meet the needs of vulnerable populations. PMID- 23339252 TI - Children out of place: vulnerability and risk in the countryside? PMID- 23339253 TI - Strong inhibition of deoxyschizandrin and schisantherin A toward UDP glucuronosyltransferase (UGT) 1A3 indicating UGT inhibition-based herb-drug interaction. AB - Deoxyschizandrin and schisantherin A are major bioactive lignans isolated from Fructusschisandrae which has been widely used as a tonic in traditional Chinese medicine for manyyears. Inhibition of UDP-glucuronosyltransferases (UGTs) by herbal components might be animportant reason for clinical herb-drug interaction. The aim of the present study is toinvestigate the inhibitory effect of deoxyschizandrin and schisantherin A on major UGTisoforms. Recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate4 methylumbelliferone (4-MU) was utilized as substrate. The results showed that 100 MUM ofdeoxyschizandrin and schisantherin A exhibited strong inhibition on UGT1A3, and negligibleinhibition on other tested UGT isoforms. Furthermore, deoxyschizandrin and schisantherin Awere demonstrated to inhibit UGT1A3 in a concentration-dependent manner, with IC50 valueof 10.8+/-0.4 MUM and 12.5+/-0.5 MUM, respectively. Dixon and Lineweaver-Burk plots showedthat inhibition of UGT1A3 by deoxyschizandrin was best fit to competitive inhibition type, andinhibition kinetic parameter (Ki) was calculated to be 0.48 MUM. Inhibition of UGT1A3 byschisantherin A gave the best fit for types of noncompetitive inhibition, and the results showedKi to be 11.3 MUM. All these experimental data suggested that herb-drug interaction might occurwhen deoxyschizandrin or schisantherin A containing herbs were co-administered with drugswhich mainly undergo UGT1A3-mediated metabolism. However, given that many in vivofactors could influence the in vitro-in vivo extrapolation (IVIVE), these in vitro inhibitoryparameters should be considered with caution. PMID- 23339254 TI - Occurrence of stilbene oligomers in Cyperus rhizomes. AB - Investigation of the chemical constituents of Rhizoma Cyperi (Cyperus rotundus Linneus)resulted in the isolation of novel enantiomeric andmeso-stilbene trimers [i.e., (+)- and (-)-(E)-cyperusphenol A (1, 2 respectively) and (E) mesocyperusphenol A (3)], a trimer bearing a novelhexacyclic ring system [cyperusphenol B (5)], aswell as knownstilbenoids (cyperusphenols C (4)and D (6), scirpusins A (7) and B (8), and piceid (9)) and luteolin. HPLC was used for the opticalresolution of 1 and 2 as well as for the identification of cooccurrence of enantiomers of 7. Thestructures of the isolates were established by spectroscopic analyses, including a detailed NMRspectroscopic investigation. The isolates were evaluated in terms of their antiproliferative activityemploying the Jurkat cell line (human T-cell leukemia cells), while the IC50 potencies of aracemate of 1 and 2, 3, 5, and 6 were estimated as 27.4, 40.5, 26.4, and 26.3 MUM, respectively. Thesuppression of cell growth by 6 was due to the induction of apoptosis,whichwas characterized bynuclear changes and PARP-1 cleavage determined bywestern blotting.We also evaluated the freeradical scavenging activity of the isolates. PMID- 23339255 TI - Antibacterial dihydrobenzopyran and xanthone derivatives from Garcinia cowa stem barks. AB - Two new compounds, garciniacowol (1) and garciniacowone (2) along with 15 knowncompounds were isolated from the stem barks of Garcinia cowa. Their structures weredetermined by intensive spectroscopic methods. The structure of 1 was a symmetrical dimericdihydrobenzopyran derivative, whereas the framework of 2 was a triprenyl caged-xanthoneprecursor. The antibacterial activities against Escherichia coli TISTR 780, Salmonellatyphimurium TISTR 292, Staphylococcus aureus TISTR 1466, and methicillin-resistant S. aureus(MRSA) SK1 of the isolated compounds were also evaluated. Compounds 2 and 9 exhibitedgood antibacterial activity against MRSA SK1 with the same minimum inhibitory concentration(MIC) value of 2 MUg/mL. Moreover, compound 2 also showed good antibacterial activityagainst S. aureus with an MIC value of 2 MUg/mL. PMID- 23339256 TI - Comparative pharmacokinetics of baicalin in normal and the type 2 diabetic rats after oral administration of the Radix scutellariae extract. AB - Radix scutellariaewas used alone or in combinationwith othermedicinal herbs in the treatment oftype 2 diabetes mellitus in China. At present, the pharmacokinetics of baicalin in type 2 diabeticrats following oral administration of Radix scutellariae extract was investigated. The resultsshowed that the pharmacokinetics (especially AUC) of baicalin in type 2 diabetic rats after oraladministration of Radix scutellariae extract was remarkably different from that in normal rats.Then the mechanism which resulted in the increased AUC of baicalin in diabetic rats wasinvestigated from system clearance and presystemic metabolism. And it was found that theincreased AUC of baicalin in diabetic rats at least partly resulted from higher production ofbaicalein in the intestinal tract of type 2 diabetic rats.Moreover, the activity of beta-glucuronidase inintestinal mucosa of type 2 diabetic rats was demonstrated to be higher than that in normal rats,which confirmed the results above. In conclusion, the pharmacokinetic behavior of baicalin wassignificantly altered in type 2 diabetic rats after orally administrated Radix scutellariae extract,which may partly result from the increased activity of intestinal beta-glucuronidase under thepathological state of type 2 diabetes mellitus. PMID- 23339257 TI - [Semi-closed endarterectomy from the aortic-iliac-femoral segment]. AB - Presented herein is a review of the literature dedicated to extended semi-closed endarterectomy from the aortoiliac segment. Considered in the article are historical data concerning the development of semi-closed loop endarterectomy, also showing present-day approaches to revascularization of the arteries of the aortofemoral zone. Also given are indications/or and contraindications to surgical management and the data on immediate and remote outcomes of semi-closed endarterectomy, which are not inferior to the classical aortofemoral reconstructions. The advantages of this method are as follows: a minimally traumatic nature, a possibility to be performed in patients presenting with severe concomitant pathology, and no use of synthetic materials. PMID- 23339258 TI - [Primary aorto-intestinal fistulas (review of the literature and description of clinical case reports)]. AB - The article contains a review of the literature dedicated to a rare complication of an abdominal aortic aneurysm, i.e., an aortic-intestinal fistula, and a report of two clinical cases illustrating different tactical approaches to management of this pathology in the settings of a referral department. PMID- 23339259 TI - [Overactive bladder--posterior tibial nerve stimulation helps]. PMID- 23339260 TI - Chest x-ray quiz. PMID- 23339261 TI - [Southwest Clinic defends its education in the intensive care nursing specialty. "Occupational political concerns will not help us in clinical practice"]. PMID- 23339262 TI - Ethics: treatment claims must match reality, says CEO. PMID- 23339263 TI - Weighing cost, liability in delivering recommended addiction treatment. PMID- 23339264 TI - Seeing synergy: aligning meaningful use measures with accreditation standards. PMID- 23339265 TI - Knowledge platform envisions better clinical, operational decisions. PMID- 23339266 TI - What CIOs want for the holidays. PMID- 23339267 TI - Challenge in stage 2: involve the patient. PMID- 23339268 TI - Temporomandibular disorders and occlusion. AB - Occlusion has an important place within the multifactorial concept of the temporomandibular disorder (TMD) etiopathogenesis as well as in every form of dental treatment. The modern concept of treatment of these disorders differentiates initial and definitive forms of treatment. The aim of this paper is to analyze recent viewpoints on the role of occlusion in the etiopathogenesis and treatment ofTMDs. Masticatory muscles and temporomandibular joints are directly connected with occlusal relations and TMDs are traditionally linked with occlusal disorders. The initial occlusal treatment can be applied to all TMD patients, regardless of their having intact teeth with respect to physiological occlusal relations and in patients in need of orthodontic or prosthodontic treatment or an oral surgical procedure. On managing TMD patients, there are doubts about the indications for definitive treatment and whether there has been a possibility of treating a painful TMD by reversible treatment modalities, that is, by initial treatment. Other types of orofacial pain such as trigeminal neuralgia can be comorbid with TMDs but also result in unnecessary procedures on the teeth and prosthodontic work if they are not recognized. Although dental profession mainly recognizes the importance of occlusal treatment of TMD problems, their relationship is controversial because it is not strictly demonstrated in numerous scientific studies. Occlusion is not the dominant cause of TMD problems. PMID- 23339269 TI - Hospital industry pushes back against the RACs. AB - Groups ranging from the American Hospital Association to the U.S. Congress have taken up the issues posed by the Recovery Audit Contractors and other Medicare and Medicaid auditors. The high percentage of denials overturned upon appeal and large number of records requests are getting attention. Hospitals may get relief, but it's not likely to be immediate so they should continue preparing for the audits. Meanwhile, in addition to the Recovery Audit Contractors (RACs), hospitals are facing scrutiny from the Zoned Program Integrity Contractors (ZPICs), Medicare Prepayment Reviews, and Medicare Administrative Contractor (MAC) on-site audits. PMID- 23339271 TI - Nurses scrutinize records before bill drops. PMID- 23339270 TI - ZPICs focus on hospital staff credentials. PMID- 23339272 TI - CMs work overtime in Sandy's wake. AB - When Hurricane Sandy devastated parts of Manhattan, Lutheran Medical Center in Brooklyn prepared in advance to handle an influx of patients evacuated from nursing homes and hospitals. Case management staff worked overtime in advance to discharge appropriate patients and free up beds. When evacuated patients came into the emergency department, the staff transferred stable patients to the hospital's own nursing homes and others with available beds, and admitted patients who met inpatient criteria. After the storm passed, case managers worked to discharge more patients to free up beds for injured patients and find placement for patients who presented to the emergency department but didn't meet admission criteria. PMID- 23339273 TI - Culture change improves ED throughput. AB - Following a revamp of emergency department procedures, wait time for patients to see a provider dropped to 20 minutes and patients are typically triaged into a bed in three to four minutes at Bronson Methodist Hospital in Kalamazoo, MI. A dedicated team of providers is responsible for a particular set of beds and specific kinds of patients. A triage nurse evaluates patients and assigns them to a team. Case managers work with physicians on medical necessity 24-7. PMID- 23339274 TI - Hospital flu shot rates entering the public realm. PMID- 23339275 TI - CMs more appreciated but budgets are tight. PMID- 23339276 TI - ASCs seek dialog on drug shortages, single-use vials. PMID- 23339277 TI - Examining chemical compound biodegradation at low concentrations through bacterial cell proliferation. AB - We show proof of principle for assessing compound biodegradation at 1-2 mg C per L by measuring microbial community growth over time with direct cell counting by flow cytometry. The concept is based on the assumption that the microbial community will increase in cell number through incorporation of carbon from the added test compound into new cells in the absence of (as much as possible) other assimilable carbon. We show on pure cultures of the bacterium Pseudomonas azelaica that specific population growth can be measured with as low as 0.1 mg 2 hydroxybiphenyl per L, whereas in mixed community 1 mg 2-hydroxybiphenyl per L still supported growth. Growth was also detected with a set of fragrance compounds dosed at 1-2 mg C per L into diluted activated sludge and freshwater lake communities at starting densities of 10(4) cells per ml. Yield approximations from the observed community growth was to some extent in agreement with standard OECD biodegradation test results for all, except one of the examined compounds. PMID- 23339278 TI - Different nature of the interactions between anions and HAT(CN)6: from reversible anion-pi complexes to irreversible electron-transfer processes (HAT(CN)6 = 1,4,5,8,9,12-hexaazatriphenylene). AB - We report experimental evidence indicating that the nature of the interaction established between HAT(CN)(6), a well-known strong electron acceptor aromatic compound, with mono- or polyatomic anions switches from the almost exclusive formation of reversible anion-pi complexes, featuring a markedly charge transfer (CT) or formal electron-transfer (ET) character, to the quantitative and irreversible net production of the anion radical [HAT(CN)(6)](*-) and the dianion [HAT(CN)(6)](2-) species. The preferred mode of interaction is dictated by the electron donor abilities of the interacting anion. Thus, weaker Lewis basic anions such as Br(-) or I(-) are prone to form mainly anion-pi complexes. On the contrary, stronger Lewis basic F(-) or (-)OH anions display a net ET process. The ET process can be either thermal or photoinduced depending on the HOMO/LUMO energy difference between the electron donor (anion) and the electron acceptor (HAT(CN)(6)). These ET processes possibly involve the intermediacy of anion-pi complexes having strong ET character and producing an ion-pair radical complex. We hypothesize that the irreversible dissociation of the pair of radicals forming the solvent-caged complex is caused by the reduced stability (high reactivity) of the radical resulting from the anion. PMID- 23339279 TI - Development of rapid determination of 18 phthalate esters in edible vegetable oils by gas chromatography tandem mass spectrometry. AB - A simultaneous and fast determination of 18 phthalic acid esters (PAEs) in edible vegetable oils was developed. After solvent extraction, the PAEs in the oil sample were further cleaned up by solid-phase extraction. After concentration, the extract was directly injected into gas chromatography tandem mass spectrometry (GC-MS/MS) in positive-ion electron impact (EI) mode. Method quantification limits of 18 PAEs were between 0.01 and 0.1 mg/kg. Quantitative recoveries ranging from 63.9 to 115.3% were obtained by analysis of spiked oil. The relative standard deviations were less than 15% (n = 6). The method could potentially overcome the interference from large amounts of lipids and pigment. It was applied to real sample and shown to be a rapid and reliable alternative for determination and confirmation of PAEs in routine analysis. PMID- 23339281 TI - Systemic lupus erythematosus: an update on current pharmacotherapy and future directions. AB - INTRODUCTION: In the last decade, the development of a number of potential drugs for lupus that target the pathogenesis of the disease at different levels has been witnessed. Despite a number of negative trials during this period, belimumab was recently approved for the treatment of adult seropositive lupus patients with mild-to-moderate disease activity. AREAS COVERED: This review summarizes the results of the most recent drug trials in lupus and highlights the aspects that require further refinement and modification in order to facilitate positive results in new drug trials for lupus. EXPERT OPINION: The success of a clinical trial depends on the efficacy of the study drug and its appropriate dosing. Several other factors play a major role in the success of trials, including the patient inclusion criteria, the choice of evidence-based study outcomes and endpoints and other aspects of study design that are described in this review. PMID- 23339280 TI - Interconverting conformations of slipped-DNA junctions formed by trinucleotide repeats affect repair outcome. AB - Expansions of (CTG).(CAG) repeated DNAs are the mutagenic cause of 14 neurological diseases, likely arising through the formation and processing of slipped-strand DNAs. These transient intermediates of repeat length mutations are formed by out-of-register mispairing of repeat units on complementary strands. The three-way slipped-DNA junction, at which the excess repeats slip out from the duplex, is a poorly understood feature common to these mutagenic intermediates. Here, we reveal that slipped junctions can assume a surprising number of interconverting conformations where the strand opposite the slip-out either is fully base paired or has one or two unpaired nucleotides. These unpaired nucleotides can also arise opposite either of the nonslipped junction arms. Junction conformation can affect binding by various structure-specific DNA repair proteins and can also alter correct nick-directed repair levels. Junctions that have the potential to contain unpaired nucleotides are repaired with a significantly higher efficiency than constrained fully paired junctions. Surprisingly, certain junction conformations are aberrantly repaired to expansion mutations: misdirection of repair to the non-nicked strand opposite the slip-out leads to integration of the excess slipped-out repeats rather than their excision. Thus, slipped-junction structure can determine whether repair attempts lead to correction or expansion mutations. PMID- 23339282 TI - Rhodium-catalyzed enantioselective hydrogenation of oxime acetates. AB - Rh-catalyzed enantioselective hydrogenation of oxime acetates was first reported, which afforded a new approach for chiral amine synthesis. PMID- 23339283 TI - Gene therapy briefs. PMID- 23339284 TI - A historical view on the creation of the European society for cell and gene therapy. PMID- 23339285 TI - A comprehensive resource on EU regulatory information for investigators in gene therapy clinical research and advanced therapy medicinal products. PMID- 23339286 TI - 3-Hydroxybutyric acid interacts with lipid monolayers at concentrations that impair consciousness. AB - 3-Hydroxybutyric acid (also referred to as beta-hydroxybutyric acid or BHB), a small molecule metabolite whose concentration is elevated in type I diabetes and diabetic coma, was found to modulate the properties of 1,2-dipalmitoyl-sn-glycero 3-phosphocholine (DPPC) monolayers when added to the subphase at clinical concentrations. This is a key piece of evidence supporting the hypothesis that the anesthetic actions of BHB are due to the metabolite's abilities to alter physical properties of cell membranes, leading to indirect effects on membrane protein function. Pressure-area isotherms show that BHB changes the compressibility of the monolayer and decrease the size of the two-phase coexistence region. Epi-fluorescent microscopy further reveals that the reduction of the coexistence region is due to the significant reduction in morphology of the liquid condensed domains in the two-phase coexistence region. These changes in monolayer morphology are associated with the diminished interfacial viscosity of the monolayers (measured using an interfacial stress rheometer), which gives insight as to how changes in phase and structure may contribute to membrane function. PMID- 23339287 TI - Neuroinflammation in ageing and in neurodegenerative disease. PMID- 23339288 TI - Review: microglia in protein aggregation disorders: friend or foe? AB - Microglia cells have been implicated, to some extent, in the pathogenesis of all of the common neurodegenerative disorders involving protein aggregation such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. However, the precise role they play in the development of the pathologies remains unclear and it seems that they contribute to the pathological process in different ways depending on the specific disorder. A better understanding of their varied roles is essential if they are to be the target for novel therapeutic strategies. PMID- 23339290 TI - An approximation of herd effect due to vaccinating children against seasonal influenza - a potential solution to the incorporation of indirect effects into static models. AB - BACKGROUND: Indirect herd effect from vaccination of children offers potential for improving the effectiveness of influenza prevention in the remaining unvaccinated population. Static models used in cost-effectiveness analyses cannot dynamically capture herd effects. The objective of this study was to develop a methodology to allow herd effect associated with vaccinating children against seasonal influenza to be incorporated into static models evaluating the cost effectiveness of influenza vaccination. METHODS: Two previously published linear equations for approximation of herd effects in general were compared with the results of a structured literature review undertaken using PubMed searches to identify data on herd effects specific to influenza vaccination. A linear function was fitted to point estimates from the literature using the sum of squared residuals. RESULTS: The literature review identified 21 publications on 20 studies for inclusion. Six studies provided data on a mathematical relationship between effective vaccine coverage in subgroups and reduction of influenza infection in a larger unvaccinated population. These supported a linear relationship when effective vaccine coverage in a subgroup population was between 20% and 80%. Three studies evaluating herd effect at a community level, specifically induced by vaccinating children, provided point estimates for fitting linear equations. The fitted linear equation for herd protection in the target population for vaccination (children) was slightly less conservative than a previously published equation for herd effects in general. The fitted linear equation for herd protection in the non-target population was considerably less conservative than the previously published equation. CONCLUSIONS: This method of approximating herd effect requires simple adjustments to the annual baseline risk of influenza in static models: (1) for the age group targeted by the childhood vaccination strategy (i.e. children); and (2) for other age groups not targeted (e.g. adults and/or elderly). Two approximations provide a linear relationship between effective coverage and reduction in the risk of infection. The first is a conservative approximation, recommended as a base-case for cost-effectiveness evaluations. The second, fitted to data extracted from a structured literature review, provides a less conservative estimate of herd effect, recommended for sensitivity analyses. PMID- 23339289 TI - Activation/Inhibition of mast cells by supra-optimal antigen concentrations. AB - Mast cells (MCs) are tissue resident cells of hemopoietic origin and are critically involved in allergic diseases. MCs bind IgE by means of their high affinity receptor for IgE (FcepsilonRI). The FcepsilonRI belongs to a family of multi-chain immune recognition receptors and is activated by cross-linking in response to multivalent antigens (Ags)/allergens. Activation of the FcepsilonRI results in immediate release of preformed granular substances (e.g. histamine, heparin, and proteases), generation of arachidonic acid metabolites, and production of pro-inflammatory cytokines. The FcepsilonRI shows a remarkable, bell-shaped dose-response behavior with weak induction of effector responses at both low and high (so-called supra-optimal) Ag concentrations. This is significantly different from many other receptors, which reach a plateau phase in response to high ligand concentrations. To explain this unusual dose-response behavior of the FcepsilonRI, scientists in the past have drawn parallels to so called precipitin curves resulting from titration of Ag against a fixed concentration of antibody (Ab) in solution (a.k.a. Heidelberger curves). Thus, for high, supra-optimal Ag concentrations one could assume that every IgE-bound FcepsilonRI formed a monovalent complex with "its own Ag", thus resulting in marginal induction of effector functions due to absence of receptor cross linking. However, this was never proven to be the case. More recently, careful studies of FcepsilonRI activation and signaling events in MCs in response to supra-optimal Ag concentrations have suggested a molecular explanation for the descending part of this bell-shaped curve. It is obvious now that extensive FcepsilonRI/IgE/Ag clusters are formed and inhibitory molecules and signalosomes are engaged in response to supra-optimal cross-linking (amongst them the Src family kinase Lyn and the inositol-5'-phosphatase SHIP1) and they actively down regulate MC effector responses. Thus, the analysis of MC signaling triggered by supra-optimal crosslinking holds great potential for identifying novel targets for pharmacologic therapeutic intervention to benefit patients with acute and chronic allergic diseases. PMID- 23339291 TI - Senescence in amniocytes and placentas from trisomy 21 pregnancies. AB - OBJECTIVE: Senescence has been described as a stable cell proliferation arrest resulting from the progression of primary human fibroblasts through a finite number of population doublings in vitro. Accelerated telomere shortening was observed in pregnancies complicated by intrauterine growth restriction, in placentas of diabetic mothers and trisomy 21 amniocytes. We hypothesized that under conditions of stress, telomeres in placentas will be shorter and there will be more cells with the senescence phenotype. METHODS: The two study groups included placental biopsies from 7 cases of trisomy 21 and amniocytes from 10 cases of trisomy 21. The control groups consisted of placental biopsies from 6 cases and amniocytes from 10 pregnancies with a normal karyotype. The samples were analyzed for the presence of senescent cells based on the number of fragments in each cell. RESULTS: A significantly higher percentage of cells in the senescent state, based on a higher percentage of cells with more fragmentations, were found in the amniocytes (20.8%) and in trophoblasts (94.3%) from placentas with trisomy 21 compared to the control groups. CONCLUSION: Among other genetic instability parameters, trisomy 21 amniocytes and trophoblasts express a higher prevalence of senescent cells than were previously reported. PMID- 23339292 TI - Associations among measures of sequential processing in motor and linguistics tasks in adults with and without a family history of childhood apraxia of speech: a replication study. AB - The purpose of this study was to address the hypothesis that childhood apraxia of speech (CAS) is influenced by an underlying deficit in sequential processing that is also expressed in other modalities. In a sample of 21 adults from five multigenerational families, 11 with histories of various familial speech sound disorders, 3 biologically related adults from a family with familial CAS showed motor sequencing deficits in an alternating motor speech task. Compared with the other adults, these three participants showed deficits in tasks requiring high loads of sequential processing, including nonword imitation, nonword reading and spelling. Qualitative error analyses in real word and nonword imitations revealed group differences in phoneme sequencing errors. Motor sequencing ability was correlated with phoneme sequencing errors during real word and nonword imitation, reading and spelling. Correlations were characterized by extremely high scores in one family and extremely low scores in another. Results are consistent with a central deficit in sequential processing in CAS of familial origin. PMID- 23339294 TI - Long-term results of cemented total hip arthroplasty in patients younger than 30 years and the outcome of subsequent revisions. AB - BACKGROUND: The number of total hip arthroplasties in patients under 30 years is increasing over the years. Almost all of them will face at least one or more future revisions in their life. Therefore, the implant used should have a high survival rate, and needs to be easily revisable resulting in a low re-revision rate. Several studies have evaluated the outcome of total hip arthroplasties in patients under 30 years. However, only a few reported on the follow-up outcome of 10 years or more. In addition, none of these reports published data of the subsequent revisions of these implants within their original report. METHODS: We studied historically prospective collected data of 48 consecutive patients (69 hips) younger than 30 years, treated with a cemented primary total hip prosthesis between 1988 and 2004. Since the last evaluation of this cohort, two patients were lost to follow-up. For all hip revisions in this cohort, again cemented implants were used, mostly in combination with bone impaction grafting. Kaplan Meier survival curves at 10- and 15 years for the primary total hip arthroplasties and revisions were determined. RESULTS: The mean age at time of primary surgery was 25 years (range, 16 to 29 years). Mean follow-up of the primary hips was 11.5 years (range, 7 to 23 years). During follow-up 13 revisions were performed; in 3 cases a two-stage total revision was performed for septic loosening and 9 cups were revised for aseptic loosening. There were no aseptic stem revisions. The 10 and 15-year survival rates with endpoint revision for aseptic loosening of the primary total hip were 90% (95% CI: 79 to 96) and 82% (95% CI: 65 to 92) respectively. None of our 13 subsequent revisions needed a re revision within 10 years after re-implantation. CONCLUSIONS: Cemented total hip implants in patients under 30 years have an encouraging outcome at 10 and 15 years after surgery in these young patients. The 13 revised hips, treated with bone grafting and the third generation cement technique, were performing well with no re-revisions within ten years after surgery. PMID- 23339295 TI - Evaluating the implementation of health and safety innovations under a regulatory context: a collective case study of Ontario's safer needle regulation. AB - BACKGROUND: Implementation effectiveness models have identified important factors that can promote the successful implementation of an innovation; however, these models have been examined within contexts where innovations are adopted voluntarily and often ignore the socio-political and environmental context. In the field of occupational health and safety, there are circumstances where organizations must adopt innovations to comply with a regulatory standard. Examining how the external environment can facilitate or challenge an organization's change process may add to our understanding of implementation effectiveness. The objective of this study is to describe implementation facilitators and barriers in the context of a regulation designed to promote the uptake of safer engineered medical devices in healthcare. METHODS: The proposed study will focus on Ontario's safer needle regulation (2007) which requires healthcare organizations to transition to the use of safer engineered medical devices for the prevention of needlestick injuries. A collective case study design will be used to learn from the experiences of three acute care hospitals in the province of Ontario, Canada. Interviews with management and front-line healthcare workers and analysis of supporting documents will be used to describe the implementation experience and examine issues associated with the integration of these devices. The data collection and analysis process will be influenced by a conceptual framework that draws from implementation science and the occupational health and safety literature. DISCUSSION: The focus of this study in addition to the methodology creates a unique opportunity to contribute to the field of implementation science. First, the study will explore implementation experiences under circumstances where regulatory pressures are influencing the organization's change process. Second, the timing of this study provides an opportunity to focus on issues that arise during later stages of implementation, a phase during the implementation cycle that has been understudied. This study also provides the opportunity to examine the relevance and utility of current implementation science models in the field of occupational health where the adoption of an innovation is meant to enhance the health and safety of workers. Previous work has tended to focus almost exclusively on innovations that are designed to enhance an organization's productivity or competitive advantage. PMID- 23339297 TI - Relationship between the surface chemical composition of implants and contact with the substrate. AB - The purpose of the study was to use scanning electron microscopy and energy dispersive x-ray spectrometry to assess possible morphologic and chemical changes after performing double-insertion and pullout tests of implants of different shapes and surface treatments. Four different types of implants were used cylindrical machined-surface implants, cylindrical double-surface-treated porous implants, cylindrical surface-treated porous implants, and tapered surface treated porous implants-representing a total of 32 screws. The implants were inserted into synthetic bone femurs, totaling 8 samples, before performing each insertion with standardized torque. After each pullout the implants were analyzed by scanning electron microscopy and energy dispersive x-ray spectrometry using a universal testing machine and magnified 35 times. No structural changes were detected on morphological surface characterization, only substrate accumulation. As for composition, there were concentration differences in the titanium, oxygen, and carbon elements. Implants with surface acid treatment undergo greater superficial changes in chemical composition than machined implants, that is, the greater the contact area of the implant with the substrate, the greater the oxide layer change. In addition, prior manipulation can alter the chemical composition of implants, typically to a greater degree in surface-treated implants. PMID- 23339296 TI - Anti-cyclic citrullinated peptide antibody titer predicts time to rheumatoid arthritis onset in patients with undifferentiated arthritis: results from a 2 year prospective study. AB - INTRODUCTION: The diagnostic, predictive and prognostic role of anti-cyclic citrullinated peptide (CCP) antibodies in rheumatoid arthritis (RA) patients is widely accepted. Moreover, detection of these antibodies in subjects presenting with undifferentiated arthritis (UA) is associated with a significant risk to develop the disease. On the other hand, clinical and prognostic significance of evaluating anti-CCP levels in subjects with inflammatory arthritis at disease onset has not been fully clarified. The goal of this prospective study is to analyze the value and prognostic significance of anti-CCP titer quantification in UA subjects. METHODS: Serial anti-CCP assays were measured in 192 consecutive patients presenting with UA lasting less than 12 weeks. Clinical and serological data and arthritis outcome were evaluated every 6 months until two years of follow-up. RESULTS: Anti-CCP positivity, at both low and high titer, and arthritis of hand joints significantly predicted RA at two years, risk increasing in subjects with high anti-CCP titers at baseline. Moreover, time to RA diagnosis was shorter in patients with high anti-CCP2 titers at enrollment with respect to those with low antibody concentration. CONCLUSIONS: Presence of anti-CCP antibodies, at both low and high concentration, is significantly associated with RA development in subjects with recent onset UA. However, time interval from the onset of the first symptoms to the fulfilment of the classification criteria appears to be directly related to the initial anti-CCP level. PMID- 23339299 TI - Protein misfolding in conformational disorders. PMID- 23339300 TI - Protein misfolding in disease and small molecule therapies. AB - A large number of human disorders are caused by defects in protein folding resulting from genetic mutations or adverse physiological conditions, and these are collectively referred to protein misfolding diseases. Such disorders imply dysfunction of a cellular process either as a result of a toxic gain of function due to protein aggregation, or loss of function due to protein instability, inefficient folding or defective trafficking. For a number of cases, drugs acting directly on the affected protein have been found to prevent misfolding and rescue function. This brief review will illustrate molecular mechanisms through which small molecules acting as folding correctors can prevent excessive protein buildup or recover faulty protein conformers, thus acting as effective therapeutic pharmacological chaperones. As background, the principles underlying the thermodynamics and kinetics of the protein folding reaction will be overviewed, as well as pathways leading to the formation of misfolding. The mechanism of action of small molecule correctors will then be discussed in light of these basic principles using illustrative examples referring to drugs that are effective over proteins involved in trafficking and folding diseases, amyloid aggregation disorders and metabolic deficiencies. An outlook on synergistic effects between different folding correctors and their combination with proteostasis regulators will also be addressed, as a relevant strategy towards the design of more effective therapies against protein folding diseases. PMID- 23339301 TI - Aggregation prone regions and gatekeeping residues in protein sequences. AB - Most protein sequences contain one or several short aggregation prone regions (APR) that can nucleate protein aggregation. Under normal conditions these APRs are protected from aggregation by protein interactions or because they are buried in the hydrophobic core of native protein domains. However, mutation, physiological stress or age-related disregulation of protein homeostasis increases the probability that aggregation-nucleating regions become solvent exposed. Aggregation then results from the self-assembly of APRs into beta structured agglomerates that vary from small soluble oligomeric assemblies to large insoluble inclusions containing thousands of molecules. The functional effects of APR-driven aggregation are diverse and protein-specific leading to distinct disease phenotypes ranging from neurodegeneration to cancer. On a cellular and physiological level both wild type loss-of-function as well as aggregation-dependent gain-of-function effects have been shown to contribute to disease. Several molecular mechanism have been proposed to contribute to gain-of function activity of protein aggregates including cellular membrane disregulation, saturation of the protein quality control machinery or the ability of aggregates to engage non-native interactions with proteins and nucleic acids. These different mechanisms will all, to some extent, contribute to gain-of function as in essence they all contribute to the rewiring of the cellular interactome by aggregation-specific interactions, resulting for instance in the pronounced neurotoxicity of TDP43 aggregates by the sequestration of RNA molecules or the promotion of cell proliferation by the entrapment of homologous tumor suppressor proteins in p53 aggregates in cancer. In this review we discuss the mechanism of APR driven aggregation and how APRs contribute to modifying the cellular interactome by recruiting both misfolded as well as active proteins thereby inhibiting or activating specific cellular functions. Finally, we discuss the ubiquity of APRs in protein sequences and how selective pressure shaped protein sequences to minimize APR aggregation. PMID- 23339302 TI - DNAJ proteins and protein aggregation diseases. AB - Many neurodegenerative diseases are late onset diseases, associated with aggregation of proteins, implying that aged cells are more susceptible to proteotoxic stress. It is known that with aging, there is a decline in the functionality of chaperone networks and on the other hand, accumulation of damaged proteins occurs. Together, this has a cumulative effects on cellular protein homeostasis. Several studies have revealed that availability of DNAJ proteins, the co-chaperones to the Hsp70 machine, could be a rate-limiting factor in handling diseased proteins within the cell. In this review,we highlight how DNAJ proteins can affect aggregation of disease-causing proteins, if and how this depends on their function as Hsp70 co-chaperones, and how much this depends on the type of protein causing the disease. Finally, we will discuss the five known degenerative diseases that are linked to mutations in individual DNAJ members and what mechanism may underlie these DNAJ chaperonopathies. PMID- 23339303 TI - Molecular chaperone disorders: defective Hsp60 in neurodegeneration. AB - Chaperonins, a subgroup of molecular chaperones, form ring-shaped structures and assist folding of proteins by enclosing them in their inner cavity. The mitochondrial Hsp60/Hsp10 chaperonin system is essential for cell viability and only a very small number of mutations causing human disease have so far been found that appear to selectively affect neuronal tissues. We here review the knowledge on the mammalian Hsp60/Hsp10 system and discuss evidence and observations, which may explain why this is the case. The Hsp60 mutations shown to be associated with neurodegenerative diseases mildly affect the protein and leave residual function. We present arguments for the notion that the neuron/glia specificity may be due to an effect of Hsp60 deficiency on myelination, a neuron specific property. The substrates of the Hsp60/Hsp10 system are only poorly defined, but the combination of deficiency of a number of mitochondrial enzymes and proteins that are highly dependent on this system for folding is the likely trigger for deficient myelination. However, a number of experimental observations indicate that Hsp60 may also have roles outside mitochondria and deficiency of Hsp60 due to mutation may also affect myelination via these signaling pathways. Taken together, it appears that mild Hsp60 deficiency primarily affects neuronal and/or glia cells whereas more severe deficiency of Hsp60 would affect all tissues and not be compatible with life. We discuss in the end what approaches may lead to a further understanding of the functions of the Hsp60/Hsp10 system in mammalian cells and thus its role in disease conditions. PMID- 23339304 TI - On the design of broad based screening assays to identify potential pharmacological chaperones of protein misfolding diseases. AB - Correcting aberrant folds that develop during protein folding disease states is now an active research endeavor that is attracting increasing attention from both academic and industrial circles. One particular approach focuses on developing or identifying small molecule correctors or pharmacological chaperones that specifically stabilize the native fold. Unfortunately, the limited screening platforms available to rapidly identify or validate potential drug candidates are usually inadequate or slow because the folding disease proteins in question are often transiently folded and/or aggregation-prone, complicating and/or interfering with the assay outcomes. In this review, we outline and discuss the numerous platform options currently being employed to identify small molecule therapeutics for folding diseases. Finally, we describe a new stability screening approach that is broad based and is easily applicable toward a very large number of both common and rare protein folding diseases. The label free screening method described herein couples the promiscuity of the GroEL binding to transient aggregation-prone hydrophobic folds with surface plasmon resonance enabling one to rapidly identify potential small molecule pharmacological chaperones. PMID- 23339305 TI - Amyloid formation in light chain amyloidosis. AB - Light chain amyloidosis is one of the unique examples within amyloid diseases where the amyloidogenic precursor is a protein that escapes the quality control machinery and is secreted from the cells to be circulated in the bloodstream. The immunoglobulin light chains are produced by an abnormally proliferative monoclonal population of plasma cells that under normal conditions produce immunoglobulin molecules such as IgG, IgM or IgA. Once the light chains are in circulation, the proteins misfold and deposit as amyloid fibrils in numerous tissues and organs, causing organ failure and death. While there is a correlation between the thermodynamic stability of the protein and the kinetics of amyloid formation, we have recently found that this correlation applies within a thermodynamic range, and it is only a helpful correlation when comparing mutants from the same protein. Light chain amyloidosis poses unique challenges because each patient has a unique protein sequence as a result of the selection of a germline gene and the incorporation of somatic mutations. The exact location of the misfolding process is unknown as well as the full characterization of all of the toxic species populated during the amyloid formation process in light chain amyloidosis. PMID- 23339307 TI - Cofactors and metabolites as protein folding helpers in metabolic diseases. AB - In the past few decades, improved early diagnosis methods, technological developments and an increasing crosstalk between clinicians and researchers has led to the identification of an increasing number of inborn metabolic diseases. In these disorders, missense mutations are the most frequent type of genetic defects, frequently resulting in defective protein folding. A better understanding at the molecular level of protein misfolding and its role in disease has prompted the emergence of therapies based in the use of small molecules that have the ability to correct protein folding defects. Well-known cases are reported for phenylketonuria and Gaucher's disease. Most of these compounds have a specific mechanism of action interacting directly with a particular protein, the so called pharmacological chaperones. Among such small molecules are protein ligands, either natural substrates or synthetic derivatives, cofactors, competitive inhibitors, and agonist/antagonists. In this review we will start by briefly overviewing the mechanisms through which such ligands exert a stabilizing action, and then move on to an extended discussion on therapeutic approaches and use of vitamins and substrates to correct protein misfolding in metabolic disorders. Examples of vitamins that have been successfully prescribed to rescue some cases of inborn errors of metabolism will be presented. In particular, the role of riboflavin supplementation in the treatment of fatty acid beta-oxidation disorders will be thoroughly analyzed, focusing on recent reports that shed light on the molecular basis of vitamin responsiveness. Moreover, we will highlight the latest studies that point to a synergistic effect of cofactors and metabolites in the rescue of defective fatty acid beta-oxidation enzymes. The synergism of multiple small molecules may underlie a promising general pharmacological strategy for the treatment of metabolic diseases in general. PMID- 23339306 TI - Phenylalanine hydroxylase misfolding and pharmacological chaperones. AB - Phenylketonuria (PKU) is a loss-of-function inborn error of metabolism. As many other inherited diseases the main pathologic mechanism in PKU is an enhanced tendency of the mutant phenylalanine hydroxylase (PAH) to misfold and undergo ubiquitin-dependent degradation. Recent alternative approaches with therapeutic potential for PKU aim at correcting the PAH misfolding, and in this respect pharmacological chaperones are the focus of increasing interest. These compounds, which often resemble the natural ligands and show mild competitive inhibition, can rescue the misfolded proteins by stimulating their renaturation in vivo. For PKU, a few studies have proven the stabilization of PKU-mutants in vitro, in cells, and in mice by pharmacological chaperones, which have been found either by using the tetrahydrobiopterin (BH(4)) cofactor as query structure for shape focused virtual screening or by high-throughput screening of small compound libraries. Both approaches have revealed a number of compounds, most of which bind at the iron-binding site, competitively with respect to BH(4). Furthermore, PAH shares a number of ligands, such as BH(4), amino acid substrates and inhibitors, with the other aromatic amino acid hydroxylases: the neuronal/neuroendocrine enzymes tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPHs). Recent results indicate that the PAH-targeted pharmacological chaperones should also be tested on TH and the TPHs, and eventually be derivatized to avoid unwanted interactions with these other enzymes. After derivatization and validation in animal models, the PAH chaperoning compounds represent novel possibilities in the treatment of PKU. PMID- 23339308 TI - SOD1 aggregation and ALS: role of metallation states and disulfide status. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons. About 10% of ALS cases are inherited (familial), and a large subset of them are caused by mutations in the gene encoding the copper-zinc superoxide dismutase (SOD1). The detection of SOD1 positive inclusions in familial ALS patients suggests the role of SOD1 aggregation underlying the pathology of familial ALS. Although SOD1 mutant proteins are different in structure, stability and activity, they all exhibit a higher aggregation propensity than wild-type SOD1. We here review the recent studies on the role of metallation states and disulfide status in the unfolding, misfolding, and aggregation of SOD1. Investigations of the mechanism of SOD1 aggregation enhance our understanding of onset and progression of ALS and have implications for therapeutic approaches for treating ALS. PMID- 23339309 TI - Copper and heme-mediated Abeta toxicity: redox chemistry, Abeta oxidations and anti-ROS compounds. AB - Oxidative stress mediated by reactive oxygen or nitrogen species (ROS/RNS) seems to be implicated in several diseases including neurodegenerative ones. In one of them, namely Alzheimer's disease, there is a large body of evidence that the aggregation of the peptide amyloid-beta (Abeta) is implicated in the generation of the oxidative stress. Redox active metal ions play a key role in oxidative stress, either in the production of ROS/RNS by enzymes or loosely bound metals or in the protection against ROS, mostly as catalytic centers in enzymes. In Alzheimer's disease, it is thought that metals (mostly Cu, Fe and heme) can bind to amyloid-beta and that such systems are involved in the generation of oxidative stress. In the present article, we review the role of ROS/RNS produced by redox active Cu ions and heme compounds in the context of the amyloid cascade. We focus on (i) the coordination chemistry of Cu and heme to Abeta; (ii) the role of the corresponding Abeta adducts in the (catalytic) production of ROS/RNS; (iii) the subsequent degradation of Abeta by these reactive species and (iv) the use of antioxidants, in particular metal sequestering compounds and direct antioxidants like polyphenols as a therapeutic strategies. PMID- 23339310 TI - Insights into Abeta aggregation: a molecular dynamics perspective. AB - This article reviews recent molecular dynamics simulations of the Alzheimer's amyloid-beta protein, the primary component of the amyloid plaques found in the brain of Alzheimer's patients. Different simulation techniques, and their application to the study of monomeric, oligomeric, and fibrillar species is discussed. This review highlights how simulations have acted as an invaluable complement to experiment, providing atomistically detailed structural information about monomer, oligomer, and fibrillar structures, as well as mechanistic insights into the aggregation process of amyloid-beta protein in the absence and presence of toxicity and aggregation inhibitors. PMID- 23339311 TI - Putting huntingtin "aggregation" in view with windows into the cellular milieu. AB - Huntington's disease arises from CAG codon-repeat expansions in the Htt gene, which leads to a Htt gene product with an expanded polyglutamine (polyQ) sequence. The length of the polyQ expansion correlates with an increased tendency to form aggregates and clustering into micrometer-plus sized inclusion bodies in neurons and other cell types. Yet after nearly 20 years since the genetic basis for HD was identified, our knowledge of how polyQ-expanded Htt fragment aggregation relates to disease mechanisms remains fragmentary and controversial. Challenges remain in defining the aggregation process at the molecular level and how this process is influenced by, or influences cellular activities. Insight is further confounded by the term "aggregation" being used to describe a composite of distinct processes that may have opposing consequences to cell health and survival. This review discusses these issues in light of a historic summary of Htt aggregation in the cellular milieu and the intrinsic attributes of polyQ expanded Htt that lead to aggregation. Finally, discussion centers on strategies forward to improve our knowledge for how aggregation relates to cellular dysfunction. PMID- 23339313 TI - Response shifts in mental health interventions: an illustration of longitudinal measurement invariance. AB - The efficacy of treatments for depression is often measured by comparing observed total scores on self-report inventories, in both clinical practice and research. However, the occurrence of response shifts (changes in subjects' values, or their standards for measurement) may limit the validity of such comparisons. As most psychological treatments for depression are aimed at changing patients' values and frame of reference, response shifts are likely to occur over the course of such treatments. In this article, we tested whether response shifts occurred over the course of treatment in an influential randomized clinical trial. Using confirmatory factor analysis, measurement models underlying item scores on the Beck Depression Inventory (Beck & Beamesderfer, 1974) of the National Institute of Mental Health Treatment of Depression Collaborative Research Program (Elkin, Parloff, Hadley, & Autry, 1985) were analyzed. Compared with before treatment, after-treatment item scores appeared to overestimate depressive symptomatology, measurement errors were smaller, and correlations between constructs were stronger. These findings indicate a response shift, in the sense that participants seem to get better at assessing their level of depressive symptomatology. Comparing measurement models of patients receiving psychotherapy and medication suggested that the aforementioned effects were more apparent in the psychotherapy groups. Consequently, comparisons of observed total scores on self-report inventories may yield confounded measures of treatment efficacy. PMID- 23339314 TI - Pictorial Representation of Self and Illness Measure (PRISM): a graphic instrument to assess suffering in fatigued cancer survivors. AB - OBJECTIVE: The Pictorial Representation of Self and Illness Measure (PRISM) measures in a simple, graphic way the burden of suffering due to illness. The question addressed in this study is whether the PRISM is a valid instrument to measure suffering in cancer survivors experiencing severe fatigue. METHOD: Quantitative and qualitative data of a previous randomized controlled trial demonstrating the efficacy of cognitive behavior therapy (CBT) especially designed for postcancer fatigue was used to assess convergent validity and sensitivity to change in a sample of 83 cancer survivors. MEASURES: The PRISM, yielding self-illness separation (SIS-fatigue = suffering due to fatigue; SIS cancer = suffering due to cancer), fatigue severity (Checklist Individual Strength; CIS-fatigue), functional impairment, psychological well-being, quality of life, and coping with the experience of cancer (Impact of Event Scale; IES). RESULTS: Moderate significant correlations were found with the PRISM and the above-mentioned measures. On the basis of SIS scores, the sample was divided into two separate groups: cancer survivors who suffered more because of fatigue and cancer survivors who suffered more because they had cancer in the past. The two groups had different scores on CIS-fatigue and IES, in line with that aspect that caused them the most suffering. The qualitative data confirmed this finding. Participants in the CBT condition demonstrated a significant difference between SIS-fatigue at baseline versus 6 months later compared with those in the waiting list condition. No change of SIS-cancer was found. CONCLUSION: The PRISM seems to be a valuable tool in fatigue research and clinical practice. PMID- 23339315 TI - Understanding the Psychopathic Personality Inventory (PPI) in terms of the unidimensionality, orthogonality, and construct validity of PPI-I and -II. AB - Comments on an article by Marcus et al. (see record 2011-23134-001). Marcus et al. (this issue) hold that PPI-I and PPI-II are generally orthogonal (uncorrelated). Examination of the primary PPI scales calls this into question. Specifically, the scales that make up Psychopathic Personality Inventory (PPI)-I and PPI-II are differentially correlated in offenders (Neumann et al., 2008) and college students (as reported in Lilienfeld, 1990, final sample). This pattern of correlations indicates that the socalled orthogonal association between PPI-I and PPI-II may be attributable to a statistical "washout" effect, rather than zero correlations across scales. The scales that make up PPI-I and PPI-II may also be correlated differentially with external correlates, rendering interpretation of PPI-I and PPI-II associations with such correlates ambiguous. The overlap of PPI scale scores among forensic and nonforensic samples also is problematic, particularly for the PPI-I scales. PMID- 23339312 TI - Protein homeostasis as a therapeutic target for diseases of protein conformation. AB - Protein misfolding and aggregation are widely implicated in an increasing number of human diseases providing for new therapeutic opportunities targeting protein homeostasis (proteostasis). The cellular response to proteotoxicity is highly regulated by stress signaling pathways, molecular chaperones, transport and clearance machineries that function as a proteostasis network (PN) to protect the stability and functional properties of the proteome. Consequently, the PN is essential at the cellular and organismal level for development and lifespan. However, when challenged during aging, stress, and disease, the folding and clearance machineries can become compromised leading to both gain-of-function and loss-of-function proteinopathies. Here, we assess the role of small molecules that activate the heat shock response, the unfolded protein response, and clearance mechanisms to increase PN capacity and protect cellular proteostasis against proteotoxicity. We propose that this strategy to enhance cell stress pathways and chaperone activity establishes a cytoprotective state against misfolding and/or aggregation and represents a promising therapeutic avenue to prevent the cellular damage associated with the variety of protein conformational diseases. PMID- 23339316 TI - The role of fearless dominance in differentiating psychopathy from antisocial personality disorder: comment on Marcus, Fulton, and Edens. AB - Comments on the original article by Marcus et al. (see record 2011-23134-001). Based on their meta-analytic review of the correlates of the two factors of the Psychopathic Personality Inventory (PPI), Fearless Dominance (FD) and Self Centered Impulsivity (SCI), Marcus, Fulton, and Edens (this issue, pp. 70-79) raise important questions about the role of FD in diagnostic conceptualizations of psychopathy. In considering their findings, general limitations of metaanalyses (e.g., Ioannidis & Lau, 1999) should be borne in mind, along with specific limitations of their analysis. These limitations are discussed here. PMID- 23339317 TI - Heterogeneity in content and psychopathies: comment on Marcus et al. AB - Comments on the original article by Marcus et al. (see record 2011-23134-001). Marcus et al. report a fascinating set of meta-analyses examining the correlations of fearless dominance (FD), self-centered impulsivity (SCI), and coldheartedness (CH) with each other, other psychopathy factors, and personality variables from four important higher-order domains. Across these studies, the factors of the Psychopathic Personality Inventory (PPI; Lilienfeld & Widows, 2005) were essentially uncorrelated, raising questions about the precise nature of psychopathy. Their meta-analyses also demonstrated that there was significant heterogeneity of effect sizes across analyses. The form of the PPI and the nature of the populations from which the samples were drawn often explained the heterogeneity in the relationships between the PPI factors and criterion-related variables. However, in a point raised by the authors, the content of the measures subsumed within the personality analyses in particular might also account for some of the unexplained heterogeneity. In this commentary, I will focus first on potential facets of the higher-order factors of personality and psychopathy that might explain conceptually the heterogeneity of effect sizes. PMID- 23339318 TI - Is psychopathy a syndrome? Commentary on Marcus, Fulton, and Edens. AB - Comments on the original article by Marcus, Fulton, and Edens (see record 2011 23134-001). The term "syndrome" derives from the Greek, meaning to "run together." Accordingly, in organic medicine, syndromes are traditionally conceptualized as conditions marked by constellations of signs (observable indicators) and symptoms (subjective indicators) that covary across individuals (Kazdin, 1983; Lilienfeld, Waldman, & Israel, 1994). For example, panic disorder is a classical syndrome because it consists of signs (e.g., sweating and difficulty breathing) and symptoms (e.g., intense fear and fears of dying or losing control) that are positively correlated. In rare cases, syndromes also comprise constellations of largely uncorrelated traits that point to an underlying pathology. For example, Gerstmann's syndrome in neurology is marked by four indicators: dysgraphia/ agraphia, dyscalculia/acalculia, left-right disorientation, and finger agnosia (Benton, 1992). Across the general population, these four indicators are essentially uncorrelated. Nevertheless, when observed together, this constellation of four signs generally indicates a lesion in the left hemisphere near the angular gyrus. PMID- 23339319 TI - Is fearless dominance relevant to the construct of psychopathy? Reconciling the dual roles of theory and clinical utility. AB - Comments on the original article by Marcus et al. (see record 2011-23134-001). Since its introduction to the field, the Psychopathic Personality Inventory (PPI; Lilienfeld & Andrews, 1996)-particularly its two-factor model (Benning, Patrick, Hicks, Blonigen, & Krueger, 2003)-has captured much attention among scholars and generated considerable debate over a number of fundamental issues pertaining to this construct. The present meta-analytic review is therefore quite timely and should provide a valuable contribution to the literature and further constructive debate. In their work, Marcus et al. provide a thoughtful and balanced discussion regarding the evidence for the construct validity of fearless dominance (FD) and self-centered impulsivity (SCI), and they suggest a number of implications of these findings for our conceptualization of psychopathy. A key question highlighted by the authors, which lies at the heart of many of the issues they raise, is whether or not FD should be considered a central (or even relevant) component of psychopathy. Addressing this question will ultimately require a reconciliation of two issues: (1) FD is aligned with many classic clinical conceptions of the disorder, particularly primary psychopathy; (2) As a standalone construct, FD is not especially maladaptive and is weakly related to overt forms of deviance. PMID- 23339320 TI - Is it the inventory, the meta-analysis, or the construct? Reply to the comments on Marcus, Fulton, and Edens. AB - Replies to comments by Neumann et al. (see record 2013-01797-001), Patrick et al. (see record 2013-01797-002), Benning (see record 2013-01797-003), Lilienfeld (see record 2013-01797-004), and Blonigen (see record 2013-01797-005) on the original article by Marcus, Fulton, and Edens (see record 2011-23134-001). We wish to thank all of the authors for their thought-provoking and insightful comments about our meta-analysis. All of the comments addressed two of the major findings from our meta-analysis: (a) that the two factors of the Psychopathic Personality Inventory (PPI; Lilienfeld & Andrews, 1996; Lilienfeld & Widows, 2005), Fearless Dominance (FD) and Self-Centered Impulsivity (SCI), are orthogonal or weakly correlated; and (b) that FD was positively correlated with desirable traits indicative of psychological health (i.e., positive emotionality) and negatively associated with traits indicative of distress and psychopathology (i.e., negative emotionality; NEM). Where the commentators differed was in the meaning that they ascribed to this pattern of results. PMID- 23339321 TI - The evaluation of multivariate adaptive regression splines for the prediction of antitumor activity of acridinone derivatives. AB - Multivariate adaptive regression splines (MARSplines) have been applied for the quantitative structure-activity relationships (QSAR) studies of antitumor activity of acridinone derivatives. Molecular modeling studies were performed with the use of HyperChem and Dragon software. The structures of the compounds were firstly pre-optimized with the MM+ mechanics and semi-empirical AM1 method procedure included in the HyperChem and resulting geometrical structures were studied with the use of Dragon software, and several molecular descriptors of acridinones were calculated and used as predictor (independent) variables in the MARS model building. Principal component analysis (PCA) was used to select the training and test sets. The optimal MARS model uses 28 basis functions to describe acridinones' antitumor activity and characterized high correlation between predicted antitumor activity and that one from biological experiments for the data used in the training and testing sets of acridinones with correlation coefficients on the level of 0.9477 and 0.9660, respectively. Generally, results showed that MARS model provided powerful capacity of prediction of antitumor activity of acridinone derivatives. Moreover, a physicochemical explanation of the descriptors selected by MARSplines analysis is also given, and indicated that molecular parameters describing 3-D properties as well as lipophilicity of acridinone derivative molecule are important for acridinones antitumor activity. PMID- 23339322 TI - Synthesis and in vitro antibacterial activity of 5-halogenomethylsulfonyl- benzimidazole and benzotriazole derivatives. AB - A series of 5-halogenomethylsulfonylbenzimidazole and benzotriazole derivatives was synthesized as potential antibacterial agents. A new method of synthesis of benzimidazoles was developed. The antimicrobial activities of these compounds were tested against a series of reference and clinical strains. The reference strains include Gram-positive bacteria (S. aureus, S. epidermidis, B. subtilis, B. cereus, E. hirae, M. luteus) and Gram-negative rods (E. coli, P. vulgaris, P. aeruginosa, B. bronchiseptica). The clinical strains include six methicillin resistant (MRSA) and two methicillin-sensitive (MSSA) S. aureus strains, one methicillin-resistant S. epidermidis, three E. faecalis and two E. faecium strains. Compound with trifluoromethyl- substituent at C-2 position (4) displayed significant antibacterial activities comparable with nitrofurantoin against four strains, and higher against Micrococcus luteus. MIC values for clinical Staphylococci strains (MRSA) were 12.5-25 MUg/mL; for Enterococcus strains these values were 50-100 MUg/mL. MIC values for reference and clinical strains of Staphylococcus and Enterococcus group were similar, respectively. PMID- 23339323 TI - An examination of factors influencing responses to requests for disability accommodations. AB - PURPOSE/OBJECTIVE: The purpose of this study was to examine the influences of responses to reasonable accommodation requests for an individual with a disability. RESEARCH METHOD/DESIGN: Two-hundred-forty individuals participated in a vignette-based experiment in which aspects of the requestor's disability and the accommodation request were manipulated. RESULTS: The results showed that intentions to grant an accommodation were predicted by a number of factors, including emotional responses toward the requestor, characteristics of the impairment causing the disability, characteristics of the accommodation, and perceptions of fairness. CONCLUSIONS/IMPLICATIONS: The Americans with Disabilities Amendments Act (ADAAA) mandates organizations to provide reasonable accommodations to qualified employees with impairments that are disabling, yet discrimination in the form of the unfair rejections of these requests still persists. Altogether, this study provides evidence that decisions regarding reasonable accommodations requests are likely influenced by a number of factors, none of which constitute legal reasons for denying a request. PMID- 23339326 TI - Reactive template-induced self-assembly to ordered mesoporous polymeric and carbonaceous materials. AB - As an important method for preparing ordered mesoporous polymeric and carbonaceous materials, the organic template directed self-assembly is facing challenges because of the weak noncovalent interactions between the organic templates and the building blocks. Herein we develop a novel reactive template induced self-assembly procedure for fabrication of ordered mesoporous polymer and carbon materials. In our approach, the aldehyde end-group of reactive F127 template can react with the resol building block to in-situ form a stable covalent bond during the self-assembly process. This is essential for an enhanced interaction between the resol and the template, thus leading to the formation of an ordered body-centered cubic mesostructure. We also show that the ordered mesoporous carbon product exhibits superior capacitive performance, presenting an attractive potential candidate for high performance supercapacitor electrodes. PMID- 23339324 TI - Deficits in sequential processing manifest in motor and linguistic tasks in a multigenerational family with childhood apraxia of speech. AB - The purpose of this study was to evaluate a global deficit in sequential processing as candidate endophenotypein a family with familial childhood apraxia of speech (CAS). Of 10 adults and 13 children in a three-generational family with speech sound disorder (SSD) consistent with CAS, 3 adults and 6 children had past or present SSD diagnoses. Two preschoolers with unremediated CAS showed a high number of sequencing errors during single-word production. Performance on tasks with high sequential processing loads differentiated between the affected and unaffected family members, whereas there were no group differences in tasks with low processing loads. Adults with a history of SSD produced more sequencing errors during nonword and multisyllabic real word imitation, compared to those without such a history. Results are consistent with a global deficit in sequential processing that influences speech development as well as cognitive and linguistic processing. PMID- 23339327 TI - Effects of aquarium-related stressors on the zebrafish: a comparison of behavioral, physiological, and biochemical indicators. AB - Fishes in aquaria and aquaculture settings may experience a variety of stressors including crowding, different lighting, periods of food deprivation, and vibrations from sources including pumps and tapping of tank sides. The effects of such low-level chronic stress are poorly explored. We used replicate sets of six Zebrafish Danio rerio in four series of experiments to compare the effects of (1) stocking densities ranging from 0.13 to 1.2 fish/L, (2) cool white (6,500 K), warm white (4,100 K), and ultraviolet-enhanced (420 actinic) fluorescent lighting, (3) food deprivation for up to 9 d, and (4) random mechanical tapping on the tank side sufficient to induce a startle response on specific behaviors (fin display, body fluttering, aggression, mouth gaping, and chattering), dissolved cortisol released into aquarium water (collected on a chromatography column and analyzed with an immunoassay), and heat-shock proteins (HSPs 27, 40, 60, and 70) detected immunochemically in western blots of muscle tissue. Of all the treatments, only food deprivation resulted in significant differences between control and treatment fish; dissolved cortisol declined after 120 h of starvation and HSP40 and HSP60 in muscle tissue increased significantly after 216 h. High variability in behaviors and HSP measurements was noted within all controls and treatments, suggesting that effects of treatments were experienced unequally by individuals within a treatment. Social stressors resulting from dominance hierarchies may play a critical role in modifying the effects of aquarium and aquaculture stressors on captive fish. PMID- 23339328 TI - Report on the 10th anniversary of international drug discovery science and technology conference, 8 - 10 november 2012, nanjing, china. AB - The 10th Anniversary of International Drug Discovery Science and Technology (IDDST) Conference was held in Nanjing, China from 8 to 10 November 2012. The conference ran in parallel with the 2nd Annual Symposium of Drug Delivery Systems. Over 400 delegates from both conferences came together for the Opening Ceremony and Keynote Addresses but otherwise pursued separate paths in the huge facilities of the Nanjing International Expo Centre. The IDDST was arranged into 19 separate Chapters covering drug discovery biology, target validation, chemistry, rational drug design, pharmacology and toxicology, drug screening technology, 'omics' technologies, analytical, automation and enabling technologies, informatics, stem cells and regenerative medicine, bioprocessing, generics, biosimilars and biologicals and seven disease areas: cancer, CNS, respiratory and inflammation, autoimmune, emerging infectious, bone and orphan diseases. There were also two sessions of a 'Bench to Bedside to Business' Program and a Chinese Scientist programme. In each period of the IDDST conference, up to seven sessions were running in parallel. This Meeting Highlight samples just a fraction of the content of this large meeting. The talks included have as a link, the use of new approaches to drug discovery. Many other excellent talks could have been highlighted and the author has necessarily had to be selective. PMID- 23339329 TI - Stereoselective synthesis of anti-1,3-aminoalcohols via reductive opening of 4 amidotetrahydropyrans derived from the Prins/Ritter sequence. AB - A novel method has been devised for anti-1,3-aminoalcohols through reductive elimination of iodomethyltetrahydropyrans which are in turn derived from a Prins/Ritter reaction sequence. The synthetic versatility of this method has been explored in the total synthesis of piperidine alkaloids and beta-amino acids. PMID- 23339330 TI - Anionic and cationic Hofmeister effects on hydrophobic and hydrophilic surfaces. AB - Using a two-step modeling approach, we address the full spectrum of direct, reversed, and altered ionic sequences as the charge of the ion, the charge of the surface, and the surface polarity are varied. From solvent-explicit molecular dynamics simulations, we extract single-ion surface interaction potentials for halide and alkali ions at hydrophilic and hydrophobic surfaces. These are used within Poisson-Boltzmann theory to calculate ion density and electrostatic potential distributions at mixed polar/unpolar surfaces for varying surface charge. The resulting interfacial tension increments agree quantitatively with experimental data and capture the Hofmeister series, especially the anomaly of lithium, which is difficult to obtain using continuum theory. Phase diagrams that feature different Hofmeister series as a function of surface charge, salt concentration, and surface polarity are constructed from the long-range force between two surfaces interacting across electrolyte solutions. Large anions such as iodide have a high hydrophobic surface affinity and increase the effective charge magnitude on negatively charged unpolar surfaces. Large cations such as cesium also have a large hydrophobic surface affinity and thereby compensate an external negative charge surface charge most efficiently, which explains the well known asymmetry between cations and anions. On the hydrophilic surface, the size dependence of the ion surface affinity is reversed, explaining the Hofmeister series reversal when comparing hydrophobic with hydrophilic surfaces. PMID- 23339331 TI - Effects of a new implant abutment design on peri-implant soft tissues. AB - The purpose of this study was to assess the effects of a modified implant abutment design on peri-implant soft and hard tissues in dogs. Three months after extraction of mandibular premolar teeth, 3 dental implants were placed in each side of the jaw using a 1-stage approach. Implants on one side of the mandible received standard abutments (control), and implants on the contralateral side received modified, patented, grooved abutments (test). Two months after implant placement, animals were euthanized and specimens were prepared for histologic and histomorphometric assessment. The linear distance (in micrometers) was measured from the implant shoulder (IS) to the following landmarks: gingival margin (GM; distance IS-GM), most apical position of the junctional epithelium (JE; distance IS-JE), and bone crest (BC; distance IS-BC). Percent of bone-to-implant contact was also measured. Histologic assessment revealed that all implants were osseointegrated and that interimplant gingival fibers between test abutments appeared to be more numerous and organized than control abutments. The IS-GM and IS-JE distances in test implants were greater than the corresponding distances in control implants (P = .024 and P = .015, respectively), whereas crestal bone loss (IS-BC) was greater for control implants than test implants (P = .037). There were no differences between control and test implants in bone-to-implant contact (P = .69), which averaged close to 50%. These results suggest that the modified groove design incorporated in standard abutments confers both soft and hard tissue benefits. PMID- 23339332 TI - Thermodynamic effects of the alteration of the axial ligand on the unfolding of thermostable cytochrome C. AB - The role the axial methionine plays in the conformational properties and thermostability of the heme active site has been investigated with the help of site-specific mutations at the axial Met69 position with His (M69H) and Ala (M69A) in thermostable cytochrome c(552) from Thermus thermophilus. Detailed circular dichroism, direct electrochemistry, and other spectroscopic studies have been employed to investigate the thermally induced and GdnHCl-induced unfolding properties of the heme active site of the wild type and the mutants of cytochrome c(552). We observed an unusually high thermodynamic and thermal stability of the M69A mutant compared to that of wild-type cytochrome c(552). However, the M69H mutant exhibited a slightly lower unfolding free energy compared to that of the wild-type protein. The high conformational stability of the M69A mutant was attributed to the presence of residual structure in the unfolded state as well as to the altered conformation in the folded state of this mutant of cytochrome c(552). This study thus supports the view that apart from the folded state, the unfolded state of a protein may also make a significant contribution to the stability of a protein. PMID- 23339333 TI - A dual contribution to the involuntary semantic processing of unexpected spoken words. AB - Sounds are a major cause of distraction. Unexpected to-be-ignored auditory stimuli presented in the context of an otherwise repetitive acoustic background ineluctably break through selective attention and distract people from an unrelated visual task (deviance distraction). This involuntary capture of attention by deviant sounds has been hypothesized to trigger their semantic appraisal and, in some circumstances, interfere with ongoing performance, but it remains unclear how such processing compares with the automatic processing of distractors in classic interference tasks (e.g., Stroop, flanker, Simon tasks). Using a cross-modal oddball task, we assessed the involuntary semantic processing of deviant sounds in the presence and absence of deviance distraction. The results revealed that some involuntary semantic analysis of spoken distractors occurs in the absence of deviance distraction but that this processing is significantly greater in its presence. We conclude that the automatic processing of spoken distractors reflects 2 contributions, one that is contingent upon deviance distraction and one that is independent from it. PMID- 23339334 TI - Learning from social rewards predicts individual differences in self-reported social ability. AB - The ability to adapt face-to-face social behavior in response to an interaction's changing contingencies is an important aspect of social skill. Individual differences in social ability may depend on how well people learn from social rewards and punishments. Here we relate people's social aptitude to their ability to learn from differences in the reward values of two common social reinforcers, genuine and polite smiles. In a series of experiments, participants experienced a hidden social contingency in which they either learned to repeat actions that received genuine smile feedback and switch after polite smiles or the reverse. A condition with nonsocial feedback served as a comparison measure. Participants showed better ability to repeat actions reinforced with genuine smile feedback than with nonsocial feedback. When participants were required to switch actions following genuine smiles, performance was inhibited relative to nonsocial reinforcement. The ability to detect task contingencies and learn from social rewards predicted self-reported social ability. These novel results suggest that individual differences in reinforcement learning, and particularly in people's motivation to receive social rewards, may relate to social ability in face-to face interactions. This finding has important implications for understanding the social difficulties that characterize disorders such as autism, depression, and schizophrenia, in which the ability to learn from rewards may be compromised. PMID- 23339335 TI - Antidepressant effects of citalopram on treatment of alopecia areata in patients with major depressive disorder. AB - OBJECTIVE: The authors sought to determine whether antidepressant therapy could enhance the efficacy of dermatological treatment in alopecia areata patients who suffer from major depressive disorder. METHODS: Sixty patients were enrolled in the study. Thirty patients with alopecia who were diagnosed with major depressive disorder received 20 mg/day citalopram and 5 mg/mL triamcinolone injection every 4 weeks, up to six injections, and 30 patients received only triamcinolone injection each month for 6 months using a simple random method. RESULTS: The mean diameter of the alopecic patches in the triamcinolone injection only group as against the combined treatment group (psychiatric [citalopram] plus dermatologic treatment) before treatment was 2.7 +/- 0.7 (mean +/- SD) and 2.5 +/- 1.8, respectively, with no statistically significant differences (Mann-Whitney, p = 0.08). After 6 months of therapy, the mean diameter of patches reached 1.6 +/- 1 and 0.54 +/- 0.97 in the triamcinolone injection only group and the combined treatment groups, respectively (Mann-Whitney, p < 0.0001). DISCUSSION: The results of this study showed that antidepressant treatment might help in improving alopecia areata in patients with major depressive disorder. PMID- 23339336 TI - Effects of tungsten and titanium oxide nanoparticles on the diazotrophic growth and metals acquisition by Azotobacter vinelandii under molybdenum limiting condition. AB - The acquisition of essential metals, such as the metal cofactors (molybdenum (Mo) and iron (Fe)) of the nitrogenase, the enzyme responsible for the reduction of dinitrogen (N(2)) to ammonium, is critical to N(2) fixing bacteria in soil. The release of metal nanoparticles (MNPs) to the environment could be detrimental to N(2) fixing bacteria by introducing a new source of toxic metals and by interfering with the acquisition of essential metals such as Mo. Since Mo has been reported to limit nonsymbiotic N(2) fixation in many ecosystems from tropical to cold temperate, this question is particularly acute in the context of Mo limitation. Using a combination of microbiology and analytical chemistry techniques, we have evaluated the effect of titanium (Ti) and tungsten (W) oxide nanoparticles on the diazotrophic growth and metals acquisition in pure culture of the ubiquitous N(2) fixing bacterium Azotobacter vinelandii under Mo replete and Mo limiting conditions. We report that under our conditions (<=10 mg.L(-1)) TiO(2) NPs have no effects on the diazotrophic growth of A. vinelandii while WO(3) NPs are highly detrimental to the growth especially under Mo limiting conditions. Our results show that the toxicity of WO(3) NPs to A. vinelandii is due to an interference with the catechol-metalophores assisted uptake of Mo. PMID- 23339337 TI - Clinical linguistics: conversational reflections. AB - This is a report of the main points I made in an informal "conversation" with Paul Fletcher and the audience at the 14th ICPLA conference in Cork. The observations arose randomly, as part of an unstructured 1-h Q&A, so they do not provide a systematic account of the subject, but simply reflect the issues which were raised by the conference participants during that time. PMID- 23339338 TI - Pseudo Jahn-Teller effect and natural bond orbital analysis of structural properties of tetrahydridodimetallenes M2H4, (M = Si, Ge, and Sn). AB - The structural properties of ethene (1) and tetrahydridodimetallenes M(2)H(4) [M = Si (2), Ge (3), and Sn (4)] have been examined by means of CCSD(T)/Def2-TZVPP, MP4(SDTQ)/Def2-TZVPP, and B3LYP/Def2-TZVPP levels of theory and natural bond orbital analysis (NBO) interpretations. The results obtained showed the expected planar ground state structure for compound 1 (D(2h) symmetry) but trans-bent ground state structures for compounds 2-4 (C(2h) symmetry). The distortions of the high-symmetry configurations of compounds 2-4 are due to the pseudo Jahn Teller effect (PJTE), which is the only source of instability of high-symmetry configurations in nondegenerate states. The distortions are due to the mixing of the ground A(g) and excited B(2g) states [i.e., HOMO(B(3u)) -> LUMO + 3(B(1u)) for compound 1, HOMO(B(3u)) -> LUMO + 2(B(1u)) for compound 2, and HOMO(B(3u)) -> LUMO + 1(B(1u)) for compounds 3 and 4]. Importantly, the higher-lying B(1g), B(2u), and B(2g) states are not involved in the PJT interactions. The energy gaps between reference states (Delta) in the undistorted configurations decrease from compound 1 to compound 4, and the PJT stabilization energies increase. Therefore, the primary force constant of the ground state in the Q((b2g)) direction (K(0)) decreases from compound 1 to compound 4. This fact can be justified by the valence isoelectronic systems of these compounds (having similar vibronic coupling constants, F). For the purpose of more chemical transparency, the NBO results were analyzed, and their relation to the PJT interactions has been revealed. The NBO analysis showed that stabilization energy associated with pi(M H) (b(u)) -> sigma*(M?M) (b(u)) electron delocalization (i.e., the mixing of the distorted b(u) molecular orbitals along the b(2g) bending distortions) increases from compound 1 to compound 4. Also, by using the hybridized orbitals obtained, an n parameter is defined. The NBO results revealed that the n values in the mean hybrid orbitals (sp(n)) increase from compound 1 to 4. The correlations between the PJT stabilization energies, bond orders, n values, pi(M-M) -> sigma*(M?M) electron delocalizations, and structural parameters of compounds 1-4 have been investigated. PMID- 23339339 TI - Graphene nanoribbons as an advanced precursor for making carbon fiber. AB - Graphene oxide nanoribbons (GONRs) and chemically reduced graphene nanoribbons (crGNRs) were dispersed at high concentrations in chlorosulfonic acid to form anisotropic liquid crystal phases. The liquid crystal solutions were spun directly into hundreds of meters of continuous macroscopic fibers. The relationship of fiber morphology to coagulation bath conditions was studied. The effects of colloid concentration, annealing temperature, spinning air gap, and pretension during annealing on the fibers' performance were also investigated. Heat treatment of the as-spun GONR fibers at 1500 degrees C produced thermally reduced graphene nanoribbon (trGNR) fibers with a tensile strength of 378 MPa, Young's modulus of 36.2 GPa, and electrical conductivity of 285 S/cm, which is considerably higher than that in other reported graphene-derived fibers. This better trGNR fiber performance was due to the air gap spinning and annealing with pretension that produced higher molecular alignment within the fibers, as determined by X-ray diffraction and scanning electron microscopy. The specific modulus of trGNR fibers is higher than that of the commercial general purpose carbon fibers and commonly used metals such as Al, Cu, and steel. The properties of trGNR fibers can be further improved by optimizing the spinning conditions with higher draw ratio, annealing conditions with higher pretensions, and using longer flake GONRs. This technique is a new high-carbon-yield approach to make the next generation carbon fibers based on solution-based liquid crystal phase spinning. PMID- 23339340 TI - Experimental infection of Australian freshwater fish with epizootic haematopoietic necrosis virus (EHNV). AB - The ranavirus, epizootic hematopoietic necrosis virus (EHNV), is endemic to southern Australia with natural outbreaks resulting in mass mortality events in wild Redfin Perch Perca fluviatilis (also known as Eurasian Perch) and less severe disease in farmed Rainbow Trout Oncorhynchus mykiss. To further investigate the host range for EHNV, 12 ecologically or economically important freshwater fish species from southeastern Australia were exposed experimentally to the virus. A bath-challenge model at 18 +/- 3 degrees C was employed with limited use of intraperitoneal inoculation to determine if a species was likely to be susceptible to EHNV. Of the species tested, Murray-Darling Rainbowfish Melanotaenia fluviatilis and Dewfish Tandanus tandanus (also known as Freshwater Catfish) were considered to be potentially susceptible species. EHNV was isolated from approximately 7% of surviving Eastern Mosquitofish Gambusia holbrooki, indicating this widespread alien fish species is a potential carrier. The infection of Silver Perch Bidyanus bidyanus and Macquarie Perch Macquaria australasica and the lack of infection in Murray Cod Maccullochella peelii peelii and Golden Perch Macquaria ambigua ambigua after exposure to EHNV via water confirmed earlier data from Langdon (1989). Five other species of native fish were potentially not susceptible to the virus or the fish were able to recover during the standard 35-d postchallenge observation period. Overall, it appeared that EHNV was less virulent in the present experimental model than in previous studies, but the reasons for this were not identified. Received May 21, 2012; accepted November 1, 2012. PMID- 23339341 TI - Investigation of the fate of trifluralin in shrimp. AB - Juvenile Pacific white shrimp (Litopenaeus vannamei) were exposed to trifluralin at 0.1 and 0.01 mg L(-1) for 72 h under controlled conditions. Samples of shrimp and tank water were collected at intervals up to 48 days after exposure. Analysis of the shrimp tissues by gas chromatography-mass spectrometry (GC-MS) and ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-qToF-MS) in combination with profiling and metabolite identification software (Agilent MET-ID and Mass Profiler Professional) detected the presence of parent trifluralin together with two main transformation products (TPs), 2-ethyl-7-nitro-5-(trifluoromethyl)benzimidazole (TP1) and 2-amino-6-nitro 4-(trifluoromethyl)phenyl)propylamine (TP2). The highest concentration of trifluralin, determined by GC-MS, was 120 MUg kg(-1) at 0 day withdrawal. Residues of trifluralin (CCalpha = 0.25 MUg kg(-1), CCbeta = 0.42 MUg kg(-1)) were detectable for up to 7 days after exposure. Similarly, the highest concentrations of TP1 and TP 2, determined by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), were 14 and 18 MUg kg(-1), respectively. Residues of TP1 (CCalpha = 0.05 MUg kg(-1), CCbeta = 0.09 MUg kg( 1)) and TP2 (CCalpha = 0.1 MUg kg(-1), CCbeta = 0.17 MUg kg(-1)) were detectable for up to 4 and 24 withdrawal days, respectively. PMID- 23339342 TI - An update on pharmaceutical film coating for drug delivery. AB - INTRODUCTION: Pharmaceutical coating processes have generally been transformed from what was essentially an art form in the mid-twentieth century to a much more technology-driven process. AREAS COVERED: This review article provides a basic overview of current film coating processes, including a discussion on polymer selection, coating formulation additives and processing equipment. Substrate considerations for pharmaceutical coating processes are also presented. EXPERT OPINION: While polymeric coating operations are commonplace in the pharmaceutical industry, film coating processes are still not fully understood, which presents serious challenges with current regulatory requirements. Novel analytical technologies and various modeling techniques that are being used to better understand film coating processes are discussed. This review article also examines the challenges of implementing process analytical technologies in coating operations, active pharmaceutical ingredients in polymer film coatings, the use of high-solids coating systems and continuous coating and other novel coating application methods. PMID- 23339343 TI - Nanoscale origin of defects at metal/molecule engineered interfaces. AB - The control and repair of defects at metal/molecule interfaces is central to the realization of molecular electronic circuits with reproducible performance. The fundamental mechanism governing defect (pore) evolution on mica-supported metal surfaces, its propagation in self-assembled molecular layers, and its implications for molecular junction devices are discussed. Pore eradication by replacing mica with halide platforms coupled with elevated substrate temperature during metal deposition yields exceptionally ultraflat metal landscapes. In situ scanning tunneling microscopy further substantiates molecular locking at defect sites and upon defect healing; the emergence of a closely packed 2-D molecular architecture is demonstrated with nanometer-scale spatial resolution in liquids. PMID- 23339344 TI - Single-dose metronidazole clears Opalina sp. from juvenile Bufo woodhousii. AB - Protozoans of the family Opalinidae are intestinal commensals in amphibians. To test the hypothesis that these organisms are susceptible to the antiprotozoal antibiotic metronidazole, we randomly assigned 60 juvenile Woodhouse's toads ( Bufo woodhousii ) to receive a single oral dose of metronidazole or water. In pilot trials, the prevalence of opalinids in untreated members of this population was over 70%. One-third of the study population was dissected at each of 3 time points: 18 hr, 1 wk, and 2 wk post-treatment. An examiner blinded to the toad's treatment history determined the presence or absence of opalinids using a dissecting microscope. Opalinids were found in 3/10 toads in the treatment group and 9/10 in the control group after 18 hr (P < 0.02), in none of the treatment group and 8/10 in the control group after 1 wk (P < 0.001), and in none of the treatment group and 10/10 in the control group after 2 wk (P < 0.0001). These results suggest that a single-dose of metronidazole quickly and reliably clears opalinids from juvenile Woodhouse's toads with no evidence of short-term recurrence. The treatment was well tolerated, with no apparent morbidity and no mortality in either group. Future exploration of opalinid-related host fitness consequences may be facilitated by this simple method of developing a protozoan free host population. PMID- 23339345 TI - Association between periodontal disease and chronic obstructive pulmonary disease: a reality or just a dogma? AB - BACKGROUND: In the past few years, the association between chronic obstructive pulmonary disease (COPD) and periodontal disease has been promulgated. The present study is aimed at determining the association between these two diseases. METHODS: This observational study includes 501 individuals consisting of 102 patients (case group) having COPD and 399 individuals as controls. Individuals in the case group were well-functioning and ambulatory patients having COPD as determined by their history and their values of forced expiratory volume in 1 second (FEV1) and forced vital capacity. Periodontal status was evaluated by the following five indices: 1) plaque index; 2) oral hygiene index (OHI); 3) gingival index (GI); 4) probing depth (PD); and 5) clinical attachment level (CAL). Lung function test was performed by all the patients (case group), who were then graded into mild, moderate, severe, and very severe. RESULTS: Preliminary analysis was performed to identify the covariates in this study. Individuals in the case group had significantly higher CAL, PD, and OHI (P <0.0001) compared with the control group after adjusting for covariates. A significant negative correlation was observed between FEV1 values and CAL, PD, and GI, thus indicating a trend in which severity of lung obstruction increased as these periodontal indices worsened. CONCLUSION: Although the present study cannot ascertain causal association, it provides substantial evidence that poor periodontal health is associated with obstructive lung disease. PMID- 23339346 TI - The (not so) social Simon effect: a referential coding account. AB - The joint go-nogo Simon effect (social Simon effect, or joint cSE) has been considered as an index of automatic action/task co-representation. Recent findings, however, challenge extreme versions of this social co-representation account by suggesting that the (joint) cSE results from any sufficiently salient event that provides a reference for spatially coding one's own action. By manipulating the salient nature of reference-providing events in an auditory go nogo Simon task, the present study indeed demonstrates that spatial reference events do not necessarily require social (Experiment 1) or movement features (Experiment 2) to induce action coding. As long as events attract attention in a bottom-up fashion (e.g., auditory rhythmic features; Experiment 3 and 4), events in an auditory go-nogo Simon task seem to be co-represented irrespective of the agent or object producing these events. This suggests that the cSE does not necessarily imply the co-representation of tasks. The theory of event coding provides a comprehensive account of the available evidence on the cSE: the presence of another salient event requires distinguishing the cognitive representation of one's own action from the representation of other events, which can be achieved by referential coding-the spatial coding of one's action relative to the other events. PMID- 23339347 TI - Temporal position priming: memory traces of recent experience bias the allocation of attention in time. AB - Explicit expectations can guide attention toward the time at which an upcoming target is likely to appear. However, in real-life situations, explicit preknowledge of upcoming events' temporal occurrence is rarely provided. We investigated whether implicit memory traces can guide attention in time, as they guide attention to recently attended features and locations (priming of pop-out and priming of location; V. Maljkovic & K. Nakayama, 1994, Priming of pop-out: I. Role of features, Memory & Cognition, Vol. 22, pp. 657-672; V. Maljkovic & K. Nakayama, 1996, Priming of pop-out: II. The role of position, Perception & Psychophysics, Vol. 58, pp. 977-991). Using a rapid serial visual presentation task, we show a temporal position priming (TPP) effect by which search performance is speeded when the target temporal position within the visual stream happens to repeat on consecutive trials. We show that such repetition priming is one of the mechanisms that underlie the much-studied sequential effect of the foreperiod. We further demonstrate that the learned association that gives rise to TPP does not require the selection or execution of a motor response and that it affects perceptual stages of visual processing. The relations between these findings and existing accounts of the sequential effect as well as with other intertrial priming effects in visual search are discussed. PMID- 23339348 TI - Urbanization decreases attentional engagement. AB - Exposure to the urban environment has been shown dramatically to increase the tendency to process contextual information. To further our understanding of this effect of urbanization, we compared performance on a local-selection task of a remote people, the Himba, living traditionally or relocated to town. We showed that (a) spatial attention was defocused in urbanized Himba but focused in traditional Himba (Experiment 1), despite urbanized Himba performing better on a working memory task (Experiment 3); (b) imposing a cognitive load made attention as defocused in traditional as in urbanized Himba (Experiment 2); and (c) using engaging stimuli/tasks made attention as focused in urbanized Himba, and British, as in traditional Himba (Experiments 4 and 5). We propose that urban environments prioritize exploration at the expense of attentional engagement and cognitive control of attentional selection. PMID- 23339349 TI - The functional role of working memory in the (re-)planning and execution of grasping movements. AB - Three experiments were conducted to dissociate movement planning costs and movement execution costs in working memory (WM). The aim of the study was to clarify what kind of WM processes (verbal, spatial, or both) are recruited during movement planning and movement execution. Therefore, a WM task (verbal and spatial versions) was combined with a high-precision manual action. Participants initially planned a placing movement toward 1 of 2 targets, subsequently encoded verbal or spatial information in WM, and then executed the movement during the retention phase. We tested the impact of movement execution on memory performance (Experiment 1), the role of WM task difficulty as a moderating variable in motor memory interactions (Experiment 2), and the impact of implementing a new motor plan during memory retention (Experiment 3). Our results show that movement execution disrupted spatial more than verbal memory (Experiment 1) and that this domain-specific interference pattern was independent of WM task difficulty (Experiment 2). Hence, the results of Experiments 1 and 2 demonstrate that executing a prepared movement recruits domain-specific visuospatial memory resources. Experiment 3 involved trials that required the implementation of a new motor plan. The additional planning requirement during the retention phase reduced performance in both WM tasks in equal measure beyond the relative movement execution costs observed in Experiments 1 and 2. These results provide evidence for distinct roles of WM in manual actions, with action execution requiring principally modality-specific capacities and (re-)planning engaging modality-general WM resources. PMID- 23339350 TI - Perseveration in barrier crossing. AB - The phenomenon of response perseveration has captivated psychologists for years, with the majority of theories of this effect focusing primarily on the cognitive, spatially oriented nature of this behavior. The current project examined whether response perseveration would also occur within a task requiring little cognitive spatial resources--barrier crossing. Across three experiments, significant response perseveration was observed in toddlers' choices of which side of a barrier to cross. Specifically, Experiment 1 demonstrated the basic effect of response perseveration in barrier crossing, Experiment 2 showed that perseveration would continue even when the chosen side was more difficult to cross than the nonchosen side, and Experiment 3 demonstrated that perseverations were based on an environment-centered reference frame, as opposed to a body centered reference frame. These findings are discussed in terms of their implications for theoretical accounts of response perseveration specifically, and with regard to perceptual-motor relations more generally. PMID- 23339351 TI - Off to a bad start: uncertainty about the number of targets at the onset of multiple object tracking. AB - Visual tracking abilities are limited to only a few objects at a time. When do errors arise? We hypothesized that some errors arise prior to tracking; specifically, during the first moments of a trial because of an inability to correctly perceive the number of targets in a display. To test this hypothesis, we modified a basic multiple object tracking (MOT) task in two ways: (1) we distilled the first moments of MOT into a static working memory task, requiring participants to remember and then identify targets among nontargets in displays without motion; (2) we unconstrained the number of responses a participant could make, asking them to terminate each trial when they felt that they had made an adequate number of responses. In Experiment 1, participants made the wrong number of responses in a considerable number of trials, and they tendered the wrong number of responses more frequently with larger loads. Comparisons across different delay durations demonstrated that these results were not caused by temporal decay. Follow-up experiments produced similar results when participants stated the cardinal number of targets perceived in a static trial (Experiment 2), and when they reported whether or not a test display included the same number of targets as a memory display (Experiment 3). Finally, with a typical tracking duration, participants also produced the wrong number of responses frequently (Experiment 4). Thus, some of the difficulty associated with MOT originates from uncertainty about the number of targets at the start of an episode. PMID- 23339353 TI - Self-assembled growth of MnSi~1.7 nanowires with a single orientation and a large aspect ratio on Si(110) surfaces. AB - MnSi~1.7 nanowires (NWs) with a single orientation and a large aspect ratio have been formed on a Si(110) surface with the molecular beam epitaxy method by a delicate control of growth parameters, such as temperature, deposition rate, and deposition time. Scanning tunneling microscopy (STM) was employed to study the influence of these parameters on the growth of NWs. The supply of free Si atoms per unit time during the silicide reaction plays a critical role in the growth kinetics of the NWs. High growth temperature and low deposition rate are favorable for the formation of NWs with a large aspect ratio. The orientation relationship between the NWs and the reconstruction rows of the Si(110) surface suggests that the NWs grow along the 11-0 direction of the silicon substrate. High-resolution STM and backscattered electron scanning electron microscopy images indicate that the NWs are composed of MnSi~1.7. PMID- 23339352 TI - Reassessing word frequency as a determinant of word recognition for skilled and unskilled readers. AB - The importance of vocabulary in reading comprehension emphasizes the need to accurately assess an individual's familiarity with words. The present article highlights problems with using occurrence counts in corpora as an index of word familiarity, especially when studying individuals varying in reading experience. We demonstrate via computational simulations and norming studies that corpus based word frequencies systematically overestimate strengths of word representations, especially in the low-frequency range and in smaller-size vocabularies. Experience-driven differences in word familiarity prove to be faithfully captured by the subjective frequency ratings collected from responders at different experience levels. When matched on those levels, this lexical measure explains more variance than corpus-based frequencies in eye-movement and lexical decision latencies to English words, attested in populations with varied reading experience and skill. Furthermore, the use of subjective frequencies removes the widely reported (corpus) Frequency * Skill interaction, showing that more skilled readers are equally faster in processing any word than the less skilled readers, not disproportionally faster in processing lower frequency words. This finding challenges the view that the more skilled an individual is in generic mechanisms of word processing, the less reliant he or she will be on the actual lexical characteristics of that word. PMID- 23339354 TI - Ruthenium-catalyzed C-H oxygenation on aryl Weinreb amides. AB - Versatile ruthenium catalysts enabled unprecedented C-H bond oxygenations of aryl Weinreb amides with ample scope under exceedingly mild reaction conditions, thereby also giving access to valuable ortho-hydroxylated aldehydes. Mechanistic studies provided strong support for a kinetically relevant C-H bond activation. PMID- 23339355 TI - Accuracy of real-time PCR, Gram stain and culture for Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae meningitis diagnosis. AB - BACKGROUND: Although cerebrospinal fluid (CSF) culture is the diagnostic reference standard for bacterial meningitis, its sensitivity is limited, particularly when antibiotics were previously administered. CSF Gram staining and real-time PCR are theoretically less affected by antibiotics; however, it is difficult to evaluate these tests with an imperfect reference standard. METHODS AND FINDINGS: CSF from patients with suspected meningitis from Salvador, Brazil were tested with culture, Gram stain, and real-time PCR using S. pneumoniae, N. meningitidis, and H. influenzae specific primers and probes. An antibiotic detection disk bioassay was used to test for the presence of antibiotic activity in CSF. The diagnostic accuracy of tests were evaluated using multiple methods, including direct evaluation of Gram stain and real-time PCR against CSF culture, evaluation of real-time PCR against a composite reference standard, and latent class analysis modeling to evaluate all three tests simultaneously. RESULTS: Among 451 CSF specimens, 80 (17.7%) had culture isolation of one of the three pathogens (40 S. pneumoniae, 36 N. meningitidis, and 4 H. influenzae), and 113 (25.1%) were real-time PCR positive (51 S. pneumoniae, 57 N. meningitidis, and 5 H. influenzae). Compared to culture, real-time PCR sensitivity and specificity were 95.0% and 90.0%, respectively. In a latent class analysis model, the sensitivity and specificity estimates were: culture, 81.3% and 99.7%; Gram stain, 98.2% and 98.7%; and real-time PCR, 95.7% and 94.3%, respectively. Gram stain and real-time PCR sensitivity did not change significantly when there was antibiotic activity in the CSF. CONCLUSION: Real-time PCR and Gram stain were highly accurate in diagnosing meningitis caused by S. pneumoniae, N. meningitidis, and H. influenzae, though there were few cases of H. influenzae. Furthermore, real time PCR and Gram staining were less affected by antibiotic presence and might be useful when antibiotics were previously administered. Gram staining, which is inexpensive and commonly available, should be encouraged in all clinical settings. PMID- 23339356 TI - Impaired beta cell function is present in nondiabetic rheumatoid arthritis patients. AB - INTRODUCTION: To investigate how markers of beta-cell secretion (proinsulin processing metabolites) are expressed in rheumatoid arthritis (RA) patients and their potential relation with the insulin resistance (IR) observed in these patients. METHODS: The 101 RA patients and 99 nondiabetic sex- and age-matched controls were included. IR by homeostatic model assessment (HOMA2), and beta-cell secretion, as measured by insulin, split and intact proinsulin, and C-peptide levels were determined for both groups. Multiple regression analysis was performed to compare IR between groups and to explore the interrelations between RA features, proinsulin metabolites, and IR. Data were adjusted for glucocorticoids intake and for IR classic risk factors. RESULTS: Compared with controls, RA patients showed higher HOMA-IR (beta coef., 0.40 (95% CI, 0.20 to 0.59); P=0.00). When data were adjusted for glucocorticoids intake, noncorticosteroid patients maintained a higher IR index (beta, 0.14 (0.05 to 0.24); P=0.00). Impaired insulin processing in RA patients was detected by the onset of elevated split proinsulin levels (beta, 0.70 pmol/L (0.38 to 1.02); P=0.00). These data remained significant also when adjusted for prednisone intake (beta, 0.19 (0.00 to 0.36) pmol/L; P=0.04). Split proinsulin-to-C-peptide ratios were higher in RA patients undergoing corticosteroid therapy (beta, 0.25 (0.12 to 0.38); P=0.03) and were nearly significant in comparison between noncorticosteroids patients and controls (beta, 0.16 (-0.02 to 0.34); P=0.08). Interestingly, the impact of HOMA-IR on the ratio of intact proinsulin to C peptide was higher in controls compared with patients (beta, 6.23 (1.41 to 11.06) versus 0.43 (-0.86 to 1.71); P=0.03). CONCLUSIONS: beta-Cell function is impaired in nondiabetic and in RA patients not taking corticoids by a mechanism that seems to be, at least in part, independent of IR. PMID- 23339357 TI - A route to metal-organic frameworks through framework templating. AB - A microporous metal-organic framework (MOF), PCN-922 [Cu(4)(ETTB)], containing a dendritic octatopic organic linker and a Cu(2)-paddlewheel structural motif, has been synthesized by using a Zn(2)-paddlewheel-based MOF as a template to prearrange the linkers for the Cu(2)-based MOF target. PCN-922 shows permanent porosity and excellent gas adsorption capacity. PMID- 23339358 TI - Monotrimethylene-bridged bis-p-phenylenediamine radical cations and dications: spin states, conformations, and dynamics. AB - The properties of p-phenylenediamine- (PD-) based systems substantially depend on the molecular topology. The singly bridged PD analogues HMPD and OMPD in which the PD rings are connected by a flexible linker reveal particular electronic properties in their radical cations and dications. The EPR and UV-vis spectra of HMPD(2+**) were found to be exceptionally temperature-sensitive, following a change from the extended conformation (doublet-doublet state) predominant at room temperature to the pi-stacked conformation (singlet state) prevailing at dry-ice temperature. Changing the single bridge from (CH(2))(3) to dimethylated CH(2)CMe(2)CH(2) in OMPD(2+**) causes considerably less of the pi-stacked conformation to be present at low temperature as a result of the steric interactions with the methyl groups of the bridge. In contrast to HMPD(2+**) and OMPD(2+**), in which the positive charges are localized separately in each PD(+*) ring, in the extended conformation, exchange of the electron ("hole hopping") between the two PD units (fast at the time scale of EPR experiments) was observed for HMPD(+*) and OMPD(+*). This process slows in a reversible manner with decreasing temperature, thus forming the radical cation with the unpaired electron spin density predominantly on one PD core, at low temperatures. Accordingly, a subtle balance between conformational changes, electron delocalization, and spin states could be established. PMID- 23339359 TI - Effects of temporary vascular occluder poloxamer 407 gel on the endothelium. AB - BACKGROUND: Coronary occlusion techniques during OPCAB may lead to an endothelial damage to the target vessel. The adverse effects of these techniques are well known, and researches have been trying to find out new materials to occlude the coronary artery without an endothelial damage. In the present study, we investigate to the endothelial damage in the rat aorta which is occluded by Poloxamer 407 gel. METHODS: Forty-five rats were randomized in three groups: (1) segment of the aorta was occluded with Poloxamer 407 gel in P 407 group; (2) segment of the aorta was occluded with microvascular clamp in MV clamp group; and (3) no onclusion was available in the Control group. The rats were sacrificed of observation, and a 15mm segment of the aorta was obtained as a specimen. Integrity of the endothelial lining was observed with a scanning electron microscopy. RESULTS: Scanning electron microscopy revealed a statistically significant difference among the 3 groups (p<0,001) using the SPSS 13.0 test. No difference was found between the Control group and the P 407 group (p=0,059). The differences between MV clamp-Control group (p<0,001) and MV clamp-P 407 group were statistically significant (p<0,002). CONCLUSIONS: We suggest that Poloxamer 407 gel occlusion may be a safer and more effective method compared to the microvascular clamp occlusion. PMID- 23339361 TI - Concerning HB-EGF brain levels in schizophrenia: cellular distribution of putative sheddases may matter. PMID- 23339360 TI - Comparing radiation exposure during percutaneous vertebroplasty using one- vs. two-fluoroscopic technique. AB - BACKGROUND: Percutaneous vertebroplasty (PV) requires relatively lengthy fluoroscopic guidance, which might lead to substantial radiation exposure to patients or operators. The two-fluoroscopic technique (two-plane radiographs obtained using two fluoroscopes) during PV can provide simultaneous two-planar projections with reducing operative time. However, the two-fluoroscopic technique may expose the operator or patient to increased radiation dose. The aim of this study was to quantify the amount of radiation exposure to the patient or operator that occurs during PV using one- vs. two-fluoroscopic technique. METHODS: Two radiation dosimeters were placed on the right flank of each patient and on the upper sternum of each operator during 26 single-level PV procedures by one senior surgeon. The use of two-fluoroscopic technique (13 patients) and one-fluoroscopic technique (13 patients) were allocated in a consecutive and alternative manner. The operative time and mean radiation dose to each patient and operator were monitored and compared between groups. RESULTS: Mean radiation dose to the patient was 1.97+/-1.20 mSv (95% CI, 0.71 to 3.23) for the one-fluoroscopic technique group vs. 0.95+/-0.34 mSv (95% CI, 0.85 to 1.23) for the two fluoroscopic technique group (P=0.031). Mean radiation dose to the operator was 0.27+/-0.12 mSv (95% CI, 0.17-0.56) for the one-fluoroscopic technique group vs. 0.25+/-0.14 mSv (95% CI, 0.06-0.44) for the two-fluoroscopic technique group (P=0.653). The operative time was significantly different between groups: 47.15+/ 13.48 min (range, 20-75) for the one-fluoroscopic technique group vs. 36.62+/ 8.42 min (range, 21-50) for the two-fluoroscopic technique group (P=0.019). CONCLUSION: Compared to the one-fluoroscopic technique, the two-fluoroscopic technique used during PV provides not only shorter operative times but also reduces the radiation exposure to the patient. There was no significant difference between the two techniques with regards to radiation exposure to the operator. PMID- 23339362 TI - Preschool children's performance on Profiling Elements of Prosody in Speech Communication (PEPS-C). AB - Profiling Elements of Prosody in Speech-Communication (PEPS-C) has not been used widely to assess prosodic abilities of preschool children. This study was therefore aimed at investigating typically developing 4-year-olds' performance on PEPS-C. PEPS-C was presented to 30 typically developing 4-year-olds recruited in southern Ireland. Children were judged to have completed the test if they produced analysable responses to >95% of the items. The children's scores were compared with data from typically developing 5-6-year-olds. The majority (83%) of 4-year-olds were able to complete the test. The children scored at chance or weak ability levels on all subtests. The 4-year-olds had lower scores than 5-6-year olds in all subtests, apart from one, with the difference reaching statistical significance in 8 out of 12 subtests. The results indicate that PEPS-C could be a valuable tool for assessing prosody in young children with typical development and some groups of young children with communication disorders. PMID- 23339363 TI - The serrated pathway to colorectal carcinoma: current concepts and challenges. AB - Approximately 30% of colorectal carcinomas develop via a serrated neoplasia pathway, named for the pattern of crypts in the precursor polyps. Molecular abnormalities consistently involve methylation of CpG islands [CpG island methylator phenotype (CIMP)] of low degree (CIMP-L) or high degree (CIMP-H), and activating mutations of the mitogen-activated protein kinase pathway components BRAF or KRAS. Microsatellite instability (MSI) of a high level (MSI-H) is often present, allowing for a molecular classification of serrated pathway carcinoma as: (i) BRAF mutant/CIMP-H with either a) MSI-H or b) microsatellite stable (MSS); and (ii) KRAS mutant/CIMP-L/MSS. Precursor polyps include sessile serrated adenoma (SSA), characterized by proximal location, crypt architectural disturbance, and BRAF mutation. Microvesicular hyperplasic polyp (MVHP) probably precedes the development of SSA, and borderline lesions between MVHP and SSA occur. Cytological dysplasia in SSA portends advanced genetic abnormality and a high risk of progression to carcinoma. The traditional serrated adenoma has a predilection for the left colon, tubulovillous architecture, eosinophilic cytoplasm, and frequent KRAS mutation. Serrated morphology carcinoma is a new World Health Organization subtype with well-differentiated, mucinous or trabecular patterns. It has frequent KRAS or BRAF mutations and a poor prognosis. This review provides an insight into the histology and molecular mechanisms driving these serrated pathway lesions. PMID- 23339364 TI - Expression of multidrug resistance 1 gene in B-cell lymphomas: association with follicular dendritic cells. AB - AIMS: Multidrug resistance (MDR) in B-cell lymphomas still constitutes a major obstacle to the effectiveness of chemotherapy even in the anti-CD20 antibody therapy era. The aim of this study was to investigate the expression of MDR associated molecules in reactive lymphadenopathy (RL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). METHODS AND RESULTS: The expression of mRNA for ABC-transporter family genes was determined by real-time RT-PCR in lymph nodes from RL, FL, and DLBCL cases. MDR1 exhibited significantly stronger expression in RL, FL, and DLBCL than Raji B-cell lymphoma cells. RL and FL showed significantly higher expression than DLBCL. Immunohistochemically, MDR1 positive cells were localized in the germinal centers of RL and center of the nodular lesions of FL showing associations with CD21 positive follicular dendritic cells (FDCs). Raji cells were co-cultured with FDC sarcoma-derived cells and the expression of MDR1 and drug resistance were analyzed. The co-culture of Raji cells with FDCs induced strong expression of MDR1 and introduced resistance to doxorubicin-induced apoptosis. CONCLUSIONS: These results suggest that FDCs induce MDR1 expression in reactive as well as neoplastic B-cells. Inhibition of the interaction of FDCs with B-cells may provide a novel strategy for treating the chemotherapy resistant fraction. PMID- 23339365 TI - Salivary gland-type renal carcinoma, a subset of collecting duct carcinoma: case report and meta-analysis of the entity. PMID- 23339366 TI - Ectopic hamartomatous thymoma is distinct from lipomatous pleomorphic adenoma in lacking PLAG1 aberration. PMID- 23339367 TI - Renal cell carcinoma with clear cells, smooth muscle stroma, and negative for 3p deletion: a variant of renal angiomyoadenomatous tumour? A case report. PMID- 23339368 TI - Dr Robert E. Scully--obituary. PMID- 23339369 TI - New approach to study starch gelatinization applying a combination of hot-stage light microscopy and differential scanning calorimetry. AB - To overcome the difficulty of the original polarizing microscope-based method in monitoring the gelatinization of starch, a new method for dynamically monitoring the gelatinization process, integral optical density (IOD), which was based on the digital image analysis technique, was proposed. Hot-stage light microscopy and differential scanning calorimetry (DSC) techniques were coupled to study the dynamic changes of three types of starches: type A (corn starch), type B (potato starch), and type C (pea starch), during the gelatinization process in an excess water system. A model of response difference change of crystallite could represent the responding intensity of crystallization changes in the process of starch gelatinization. Results demonstrated that three crystalline types of starch underwent a process of swelling, accompanied with gradual disappearing of the crystallite. This difference was mainly associated with the diversity and composition of the starch structure. The IOD method was of advantage compared to the previous traditional methods that are based on a polarization microscope, such as counting the particle number and calculating polarization area methods, because it was the product of two parameters: optical density and area, which would be a response of both light intensity and area of birefringence light. The single peak in DSC corresponded to the combination of crystalline helix-helix dissociation and the reduction of the molecule helix-coil transition, while the gelatinization degree measured by the IOD method mainly corresponded to the helix helix dissociation. The gelatinization mechanism could be revealed clearer in this study. PMID- 23339371 TI - Improving adherence to injectable disease-modifying drugs in multiple sclerosis. AB - Multiple sclerosis (MS) is the most common neurological disorder leading to permanent disability in early adulthood and premature pension. Prophylactic treatment should be initiated early in the disease process to prevent permanent disability at best. Injectable drugs, i.e., interferon beta preparations and glatiramer acetate, belong to the first-line therapeutics in MS. Autoinjection devices, available for all disease-modifying drugs, can improve injection tolerability and patient's satisfaction compared with manual injection. In one study, the use of an autoinjector has been found to be the strongest predictor of adherence at 24 months. Nevertheless, long-term adherence to injectable MS therapies is generally suboptimal for various barriers with an impact on efficacy of these treatments. Improvements concerning drug delivery by innovative features could be achieved by the first electronic autoinjector RebiSmart(TM) and may help to increase adherence. Patients' rating of the new electronic device and short term adherence data convey some evidence that patients' treatment satisfaction and adherence may increase by its use. Long-term studies, already under way, are awaited to show, if long-term adherence will be positively influenced. A further achievement of the new electronic device is the possibility to monitor adherence objectively allowing a discussion between the patient and health care provider about nonadherence reasons. The necessity of improving adherence to injectable disease-modifying drugs within the growing field of oral MS therapeutics will also be discussed. PMID- 23339372 TI - MSi20H20 aggregates: from simple building blocks to highly magnetic functionalized materials. AB - Density-functional theory based global geometry optimization is used to scrutinize the possibility of using endohedrally doped hydrogenated Si clusters as building blocks for constructing highly magnetic materials. In contrast to the known clathrate-type facet-sharing, the clusters exhibit a predisposition to aggregation through double Si-Si bridge bonds. For the prototypical CrSi20H20 cluster we show that reducing the degree of hydrogenation may be used to control the number of reactive sites to which other cages can be attached, while still preserving the structural integrity of the building block itself. This leads to a toolbox of CrSi20H(20-2n) monomers with different number of double "docking sites", that allows building network architectures of any morphology. For (CrSi20H18)2 dimer and [CrSi20H16](CrSi20H18)2 trimer structures we illustrate that such aggregates conserve the high spin moments of the dopant atoms and are therefore most attractive candidates for cluster-assembled materials with unique magnetic properties. The study suggests that the structural completion of the individual endohedral cages within the doubly bridge bonded structures and the high thermodynamic stability of the obtained aggregates are crucial for potential synthetic polimerization routes via controlled dehydrogenation. PMID- 23339370 TI - The structural dynamics of actin during active interaction with myosin depends on the isoform of the essential light chain. AB - We have used time-resolved phosphorescence anisotropy to investigate the effects of essential light chain (ELC) isoforms (A1 and A2) on the interaction of skeletal muscle myosin with actin, to relate structural dynamics to previously reported functional effects. Actin was labeled with a phosphorescent probe at C374, and the myosin head (S1) was separated into isoenzymes S1A1 and S1A2 by ion exchange chromatography. As previously reported, S1A1 exhibited substantially lower ATPase activity at saturating actin concentrations but substantially higher apparent actin affinity, resulting in a higher catalytic efficiency. In the absence of ATP, each isoenzyme increased actin's final anisotropy cooperatively and to a similar extent, indicating a similar restriction of the amplitude of intrafilament rotational motions in the strong-binding (S) state of actomyosin. In contrast, in the presence of a saturating level of ATP, S1A1 increased actin anisotropy much more than S1A2 and with greater cooperativity, indicating that S1A1 was more effective in restricting actin dynamics during the active interaction of actin and myosin. We conclude that during the active interaction of actin and ATP with myosin, S1A1 is more effective at stabilizing the S state (probably the force-generating state) of actomyosin, while S1A2 tends to stabilize the weak-binding (non-force-generating) W state. When a mixture of isoenzymes is present, S1A1 is dominant in its effects on actin dynamics. We conclude that ELC of skeletal muscle myosin modulates strong-to-weak structural transitions during the actomyosin ATPase cycle in an isoform-dependent manner, with significant implications for the contractile function of actomyosin. PMID- 23339373 TI - Reliability and validity of the psoriasis symptom inventory in patients with moderate-to-severe psoriasis. AB - OBJECTIVES: The psoriasis symptom inventory (PSI) is a patient-reported outcome measure for assessing symptom severity in patients with moderate-to-severe psoriasis. The primary objective of this study was to evaluate the measurement properties of the PSI. MATERIALS AND METHODS: Analyses of psychometric characteristics (reliability, convergent and known-groups validity,responsiveness, item performance, and dimensionality) were conducted using data from a Phase II trail to evaluate efficacy of brodalumab in subjects with moderate-to-severe psoriasis. RESULTS: The PSI had excellent internal consistency (alpha = 0.93-0.98) and good test-retest reliability (ICCs = 0.77 0.87). Convergent and discriminant validity was indicated by moderate-to-strong correlations between the PSI and Dermatology Life Quality Index scores, and small correlations between PSI total scores and ShortfFrm-36 Health Survey mental health, role emotional, and role physical scales. Known groups validity was shown as mean PSI total scores varied by Psoriasis Area and Severity Index (PASI) and Static Physician's Global Assessment (sPGA) defined groups (p < 0.001). PSI total scores were responsive to changes in clinical status as assessed by PASI (p < 0.001) and sPGA (p < 0.001). Unidimensionality of the PSI was supported. CONCLUSIONS: The PSI is a short and valid unidimensional measure of psoriasis symptom severity that is well suited for use in clinical trials. PMID- 23339375 TI - Still no evidence for the encoding variability hypothesis: a reply to Jang, Mickes, and Wixted (2012) and Starns, Rotello, and Ratcliff (2012). AB - Koen and Yonelinas (2010) contrasted the recollection and encoding variability accounts of the finding that old items are associated with more variable memory strength than new items. The study indicated that (a) increasing encoding variability did not lead to increased measures of old item variance, and (b) old item variance was directly related to the contribution of recollection. Jang, Mickes, and Wixted (2012) and Starns, Rotello, and Ratcliff (2012) wrote responses that, on the surface, appear to challenge those results. However, the issues raised about our first finding turn out to have no theoretical or empirical support. In addition, although Jang et al. replicated our second finding, they contested our conclusions on the basis of a perceived problem with the analyses (i.e., we used 5 rather than 2 points to calculate predicted zROC slopes). However, their concern was misplaced because the pattern of results is the same regardless of the number of points used in the analysis. They also conducted a simulation that, at first glance, appeared to suggest that our second finding was biased to favor the recollection account of the dual process model. We show that this conclusion arose because Jang et al. mistakenly built the contested correlation pattern into the simulated data. Overall, the 2 response articles serve to strengthen the main conclusions of our initial article by reiterating that there is no evidence in support of the encoding variability account, and the replication study by Jang et al. adds to the evidence favoring the recollection account. PMID- 23339376 TI - Distractor exclusion is not an early process: a reply to Roelofs, Piai, and Schriefers (2011). AB - In their comment, Roelofs, Piai, and Schriefers (2011) argue against our interpretation of the distractor frequency effect in terms of a late blocking mechanism. They state that the experiments reported by Dhooge and Hartsuiker (2010) can be incorporated in WEAVER++ when assuming an early input blocking mechanism. We first rectify a misunderstanding regarding the claim of the target article. Next, we show that Roelofs et al. provide no evidence that allows differentiating between early and late blocking accounts. We end by providing evidence in favor of our claim that distractor blocking occurs late and specify our blocking account in terms of verbal self-monitoring. PMID- 23339377 TI - Women experience a better long-term immune recovery and a better survival on HAART in Lao People's Democratic Republic. AB - BACKGROUND: In April 2003, Medecins Sans Frontieres launched an HIV/AIDS programme to provide free HAART to HIV-infected patients in Laos. Although HIV prevalence is estimated as low in this country, it has been increasing in the last years. This work reports the first results of an observational cohort study and it aims to identify the principal determinants of the CD4 cells evolution and to assess mortality among patients on HAART. METHODS: We performed a retrospective database analysis on patients initiated on HAART between 2003 and 2009 (CD4<200cells/MUL or WHO stage 4). We excluded from the analysis patients who were less than 16 years old and pregnant women. To explore the determinants of the CD4 reconstitution, a linear mixed model was adjusted. To identify typical trajectories of the CD4 cells, a latent trajectory analysis was carried out. Finally, a Cox proportional-hazards model was used to reveal predictors of mortality on HAART including appointment delay greater than 1 day. RESULTS: A total of 1365 patients entered the programme and 913 (66.9%) received an HAART with a median CD4 of 49 cells/MUL [IQR 15-148]. High baseline CD4 cell count and female gender were associated with a higher CD4 level over time. In addition, this gender difference increased over time. Two typical latent CD4 trajectories were revealed showing that 31% of women against 22% of men followed a high CD4 trajectory. In the long-term, women were more likely to attend appointments without delay. Mortality reached 6.2% (95% CI 4.8-8.0%) at 4 months and 9.1% (95% CI 7.3-11.3%) at 1 year. Female gender (HR=0.17, 95% CI 0.07-0.44) and high CD4 trajectory (HR=0.19, 95% CI 0.08-0.47) were independently associated with a lower death rate. CONCLUSIONS: Patients who initiated HAART were severely immunocompromised yielding to a high early mortality. In the long-term on HAART, women achieved a better CD4 cells reconstitution than men and were less likely to die. This study highlights important differences between men and women regarding response to HAART and medical care, and questions men's compliance to treatment. PMID- 23339378 TI - Ridge preservation comparing socket allograft alone to socket allograft plus facial overlay xenograft: a clinical and histologic study in humans. AB - BACKGROUND: Previous studies of ridge preservation showed a loss of ~18% or 1.5 mm of crestal ridge width in spite of treatment. The primary aim of this randomized, controlled, masked clinical trial is to compare a socket graft to the same treatment plus a buccal overlay graft, both with a polylactide membrane, to determine if loss of ridge width can be prevented by use of an overlay graft. METHODS: Twelve patients who served as positive controls received an intrasocket mineralized cancellous allograft (socket group), and 12 patients received the same socket graft procedure plus buccal overlay cancellous xenograft (overlay group). Horizontal ridge dimensions were measured with a digital caliper, and vertical ridge changes were measured from a stent. Before implant placement, at 4 months, a trephine core was obtained for histologic analysis. RESULTS: The mean horizontal ridge width at the crest for the socket group decreased from 8.7 +/- 1.0 to 7.1 +/- 1.5 mm for a mean loss of 1.6 +/- 0.8 mm (P <0.05), whereas the same measurement for the overlay group decreased from 8.4 +/- 1.4 to 8.1 +/- 1.4 mm for a mean loss of 0.3 +/- 0.9 mm (P >0.05). The overlay group was significantly different from the socket group (P <0.05). Histologic analysis revealed that the socket group had 35% +/- 16% vital bone, and the overlay group had 40% +/- 16% (P >0.05). CONCLUSIONS: The overlay treatment significantly prevented loss of ridge width and preserved or augmented the buccal contour. The socket and overlay groups healed with a high percentage of vital bone. PMID- 23339379 TI - Firefighter noise exposure during training activities and general equipment use. AB - Multiple noise measurements were taken on 6 types of fire station equipment and 15 types of emergency response vehicle-related equipment used by firefighters during routine and emergency operations at 10 fire stations. Five of the six types of fire station equipment, when measured at a distance of one meter and ear level, emitted noise equal to or greater than 85 dBA, including lawn maintenance equipment, snow blowers, compressors, and emergency alarms. Thirteen of 15 types of equipment located on the fire engines emitted noise levels equal to or greater than 85 dBA, including fans, saws, alarms, and extrication equipment. In addition, noise measurements were taken during fire engine operations, including the idling vehicle, vehicle sirens, and water pumps. Results indicated that idling fire-engine noise levels were below 85 dBA; however, during water pump and siren use, noise levels exceeded 85 dBA, in some instances, at different locations around the trucks where firefighters would be stationed during emergency operations. To determine if the duration and use of fire fighting equipment was sufficient to result in overexposures to noise during routine training activities, 93 firefighter personal noise dosimetry samples were taken during 10 firefighter training activities. Two training activities per sampling day were monitored during each sampling event, for a mean exposure time of 70 min per day. The noise dosimetry samples were grouped based on job description to compare noise exposures between the different categories of job tasks commonly associated with fire fighting. The three job categories were interior, exterior, and engineering. Mean personal dosimetry results indicated that the average noise exposure was 78 dBA during the training activities that lasted 70 min on average. There was no significant difference in noise exposure between each of the three job categories. Although firefighters routinely use equipment and emergency response vehicles that can produce hazardous levels of noise, this study showed that the average noise levels experienced by firefighters was below generally accepted guidelines. PMID- 23339380 TI - Edible Bird's nest extract as a chondro-protective agent for human chondrocytes isolated from osteoarthritic knee: in vitro study. AB - BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease that results in the destruction of cartilage. Edible Bird's Nest (EBN) extract contains important components, which can reduce the progression of osteoarthritis and helps in the regeneration of the cartilage. The present study aimed to investigate the effect of EBN extract on the catabolic and anabolic activities of the human articular chondrocytes (HACs) isolated from the knee joint of patients with OA. METHODS: A single batch of EBN extract was prepared with hot-water extraction and coded as HMG. HACs were isolated from the knee joint cartilage removed during surgery. The optimum concentration of HMG for HAC cultures was determined using MTT assay. The effect of HMG on the catabolic and anabolic genes' expression in HACs was measured by real-time PCR. The total amount of prostaglandin E2 (PGE2) production was determined by ELISA method, and the total sulphated glycosaminoglycan (GAGs) production was quantified by 1,9-dimethylmethylene blue (DMMB) assay. RESULTS: MTT assay showed 0.50% - 1.00% HMG supplementation promoted HACs proliferation. HMG supplementation was able to reduce the catabolic genes' expression in cultured HACs such as matrix metalloproteinases (MMP1 & MMP3), Interleukin 1, 6 and 8 (IL-1, IL-6 & IL-8), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Prostaglandin E2 (PGE2) production was significantly reduced in HAC cultures supplemented with HMG. With regard to anabolic activity assessment, type II collagen, Aggrecan and SOX-9 gene expression as well as sGAG production was increased in the HMG supplemented groups. CONCLUSION: Edible Bird's Nest extract coded as HMG demonstrated chondro-protection ability on human articular chondrocytes in vitro. It reduced catabolic activities and increased cartilage extracellular matrix synthesis. It is concluded that HMG is a potential agent in the treatment of osteoarthritis. PMID- 23339381 TI - Application of hand-held and portable infrared spectrometers in bovine milk analysis. AB - A simple and fast method for the detection and quantification of milk adulteration was developed using portable and hand-held infrared (IR) spectrometers. Milk samples were purchased from local supermarkets (Columbus, OH, USA) and spiked with tap water, whey, hydrogen peroxide, synthetic urine, urea, and synthetic milk in different concentrations. Spectral data were collected using mid-infrared (MIR) and near-infrared (NIR) spectrometers. Soft independent modeling of class analogy (SIMCA) classification models exhibited tight and well separated clusters allowing the discrimination of control from adulterated milk samples. Partial least-squares regression (PLSR) was used to estimate adulteration levels, and results showed high coefficients of determination (R(2)) and low standard errors of prediction (SEP). Classification and quantification models indicated that the tested MIR systems were superior to NIR systems in monitoring milk adulteration. This method can be potentially used as an alternative to traditional methods due to their simplicity, sensitivity, low energy cost, and portability. PMID- 23339382 TI - A fluorescent ratiometric chemodosimeter for Cu2+ based on TBET and its application in living cells. AB - Based on a through bond energy transfer (TBET) between Rhodamine and a naphthalimide fluorophore, a fluorescent ratiometric chemodosimeter RN1 was designed and prepared for single selective detection of Cu(2+) in aqueous solution and in living cells, as Cu(2+) acts as not only a selective recognizing guest but also a hydrolytic promoter. PMID- 23339384 TI - Correcting thrombocytopenia in patients with liver diseases: a difficult hurdle. PMID- 23339383 TI - Patient-derived breast tumor xenografts facilitating personalized cancer therapy. AB - Despite improved detection and reduction of breast cancer-related deaths over the recent decade, breast cancer remains the second leading cause of cancer death for women in the US, with 39,510 women expected to succumb to metastatic disease in 2012 alone (American Cancer Society, Cancer Facts &Figures 2012. Atlanta: American Cancer Society; 2012). Continued efforts in classification of breast cancers based on gene expression profiling and genomic sequencing have revealed an underlying complexity and molecular heterogeneity within the disease that continues to challenge therapeutic interventions. To successfully identify and translate new treatment regimens to the clinic, it is imperative that our preclinical models recapitulate this complexity and heterogeneity. In this review article, we discuss the recent advances in development and classification of patient-derived human breast tumor xenograft models that have the potential to facilitate the next phase of drug discovery for personalized cancer therapy based on the unique driver signaling pathways in breast tumor subtypes. PMID- 23339385 TI - Functional gastrointestinal diseases in children: facing the rising tide. PMID- 23339386 TI - Development of biliary malignancy after cyst excision for congenital choledochal cysts: what should we do? PMID- 23339387 TI - Factors affecting short- and long-term effects of leukocyte removal therapy in active ulcerative colitis. AB - BACKGROUND AND AIM: Leukocyte removal therapy (LRT) is recognized as an effective treatment for active ulcerative colitis (UC). In this study, factors associated with the efficacy and long-term effects of LRT were evaluated. METHODS: From April 1998 to March 2010, 98 patients with moderate to severe UC were randomly assigned to granulocyte and monocyte/macrophage adsorptive apheresis (GMA) (n = 47) or leukocytapheresis (LCAP) (n = 51) treatment. Patients received two sessions of LRT in the first week, followed by three weekly administrations. All patients were treated with 5-aminosalicylic acid and corticosteroid. Steroid doses were tapered if patients achieved clinical improvement. Clinical remission was defined as a decrease in clinical activity index to < 4 and endoscopic findings to Matts' grade 1 or 2. When clinical activity index decreased but still remained >= 5 and Matts' grading was 1 or 2, the patient was considered to have improved. Patients were observed for at least 1 year and diagnosed as relapsed when additional treatment was required. RESULTS: Seventy-one (73%) patients achieved clinical remission or improvement. No significant difference was found between LCAP and GMA. Increased age, >= 3 attacks of UC, and >= 2 sessions of LRT were indicative of refractoriness to LRT. During 1 year observation, 28 patients were relapsed. Duration of UC, >= 3 attacks of UC, and >= 2 sessions of LRT were indicative of refractoriness to the long-term effects of LRT. CONCLUSION: Both GMA and LCAP were effective to treat active UC. However, long duration of UC, multiple UC attacks, and past history of LRT reduce the efficacy. PMID- 23339388 TI - Expression of argininosuccinate synthetase in patients with hepatocellular carcinoma. AB - BACKGROUND AND AIM: Arginine is a nonessential amino acid for humans and mice because it can be synthesized from citrulline by argininosuccinate synthetase (ASS) and argininosuccinate lyase. Hepatocellular carcinoma (HCC) is believed to be auxotrophic for arginine through the lack of expression of ASS. However, there are also some ASS-positive HCC cells. Therefore, the aim of this article was to study the levels of arginine and the expression of ASS in patients with HCC. METHODS: Thirty patients with HCC who had undergone HCC surgery were enrolled in the study. Serum arginine levels were determined with an automatic amino acid analyzer. ASS expression was examined by Western blot and immunohistochemistry. Methylation specific polymerase chain reaction and methylation sequencing were performed to detect the methylation of DNA encoding ASS. RESULTS: There was a decrease of arginine in HCC patients compared with that of healthy control. High expression of ASS was found in the adjacent tissues by Western blot and immunohistochemistry. Little ASS expression was found in most HCC tissues, but there were also some HCC tissues that expressed low levels of ASS. Methylation of the DNA encoding ASS was obviously higher in HCC tissues than that in paired adjacent tissues. CONCLUSIONS: ASS expression is decreased significantly in HCC tissues. The downregulation of arginine and ASS expression may be a self-defense action of the body against malignant tumors, and the decreased arginine and ASS levels in HCC patients are an advantage for the arginine deiminase treatment. PMID- 23339389 TI - Education and imaging: gastrointestinal: cholecystoduodenal fistula with gallstone-induced intestinal obstruction. PMID- 23339390 TI - Education and imaging: gastrointestinal: omental infarction. PMID- 23339392 TI - Education and imaging: hepatobiliary and pancreatic: fatal tumor embolism caused by hepatocellular carcinoma. PMID- 23339391 TI - Education and imaging: gastrointestinal: villous adenoma of the ampulla of Vater causing acute pancreatitis. PMID- 23339393 TI - Education and imaging: hepatobiliary and pancreatic: clear cell myomelanotic tumor of ligamentum teres. PMID- 23339394 TI - The posterior surgical approach to robot-assisted radical prostatectomy facilitates dissection of large glands. AB - INTRODUCTION: Despite the abundant data on outcomes after robot-assisted radical prostatectomy (RARP), no study has compared outcomes between an anterior vs a posterior approach. We postulated that a posterior approach may facilitate dissection and lead to improved outcomes in patients with larger prostate glands. PATIENTS AND METHODS: After Institutional Review Board approval, 404 patients underwent RARP between 2007 and 2011 by two surgeons at our institution. Of these, 187 patients underwent RARP using a posterior surgical approach while 217 patients were approached anteriorly. Retrospective review of preoperative, intraoperative, and perioperative characteristics and outcomes were compared between the two cohorts using two sample t tests and two proportion z tests to calculate statistical significance. RESULTS: There were no significant differences in age, body mass index, prostate volume, or prostate-specific antigen of the two cohorts. Pathology was similar, although there was a significantly increased proportion of Gleason 9 disease in the anterior approach group. Intraoperative and perioperative outcomes including console time, transfusion rate, positive margins, and complication rates were compared. There was no difference observed in outcomes or console time between the two approaches. When console time was stratified for prostate volume, however, a shorter operative time was seen in the two highest quartiles for prostate volume with the posterior approach (163.8 vs 145.9 min and 183.8 vs 166.2 min, P=0.02, P=0.04). CONCLUSIONS: Despite the widespread application of RARP, there is no literature that addresses which surgical approach is most advantageous. Our data suggest that the posterior approach offers shorter operative times in patients with large prostate glands while overall outcomes remain the same between the two approaches. PMID- 23339395 TI - Mitochondrial DNA and Y-chromosomal diversity in ancient populations of domestic sheep (Ovis aries) in Finland: comparison with contemporary sheep breeds. AB - BACKGROUND: Several molecular and population genetic studies have focused on the native sheep breeds of Finland. In this work, we investigated their ancestral sheep populations from Iron Age, Medieval and Post-Medieval periods by sequencing a partial mitochondrial DNA D-loop and the 5'-promoter region of the SRY gene. We compared the maternal (mitochondrial DNA haplotypes) and paternal (SNP oY1) genetic diversity of ancient sheep in Finland with modern domestic sheep populations in Europe and Asia to study temporal changes in genetic variation and affinities between ancient and modern populations. RESULTS: A 523-bp mitochondrial DNA sequence was successfully amplified for 26 of 36 sheep ancient samples i.e. five, seven and 14 samples representative of Iron Age, Medieval and Post-Medieval sheep, respectively. Genetic diversity was analyzed within the cohorts. This ancient dataset was compared with present-day data consisting of 94 animals from 10 contemporary European breeds and with GenBank DNA sequence data to carry out a haplotype sharing analysis. Among the 18 ancient mitochondrial DNA haplotypes identified, 14 were present in the modern breeds. Ancient haplotypes were assigned to the highly divergent ovine haplogroups A and B, haplogroup B being the major lineage within the cohorts. Only two haplotypes were detected in the Iron Age samples, while the genetic diversity of the Medieval and Post Medieval cohorts was higher. For three of the ancient DNA samples, Y-chromosome SRY gene sequences were amplified indicating that they originated from rams. The SRY gene of these three ancient ram samples contained SNP G-oY1, which is frequent in modern north-European sheep breeds. CONCLUSIONS: Our study did not reveal any sign of major population replacement of native sheep in Finland since the Iron Age. Variations in the availability of archaeological remains may explain differences in genetic diversity estimates and patterns within the cohorts rather than demographic events that occurred in the past. Our ancient DNA results fit well with the genetic context of domestic sheep as determined by analyses of modern north-European sheep breeds. PMID- 23339396 TI - Why reference to the past is difficult for agrammatic speakers. AB - Many studies have shown that verb inflections are difficult to produce for agrammatic aphasic speakers: they are frequently omitted and substituted. The present article gives an overview of our search to understanding why this is the case. The hypothesis is that grammatical morphology referring to the past is selectively impaired in agrammatic aphasia. That is, verb inflections for past tense and perfect aspect are hard to produce. Furthermore, verb clusters that refer to the past will be affected as well, even if the auxiliary is in present tense, as in he has been writing a letter. It will be argued that all these verb forms referring to the past require discourse linking [Zagona, K. (2003). Tense and anaphora: Is there a tense-specific theory of coreference. In A. Barrs (Ed.), Anaphora: A reference guide (pp. 140-171). Oxford: Blackwell Publishing] and discourse linking is affected in agrammatic aphasia [Avrutin, S. (2006). Weak syntax. In K. Amunts, & Y. Grodzinsky (Eds.), Broca's region (pp. 49-62). New York: Oxford Press]. This hypothesis has been coined the PAst DIscourse LInking Hypothesis (PADILIH) [Bastiaanse, R., Bamyaci, E., Hsu, C.-J., Lee, J., Yarbay Duman, T., & Thompson, C.K. (2011). Time reference in agrammatic aphasia: A cross linguistic study. Journal of Neurolinguistics, 24, 652-673]. The PADILIH has been tested in several languages and populations that have hardly been studied before in aphasiology: languages such as Turkish, Swahili and Indonesian were included, as well as monolingual and bilingual populations. In all these populations, the same test has been used: the Test for Assessing Reference of Time [Bastiaanse, R., Jonkers, R., & Thompson, C.K. (2008). Test for assessing reference of time (TART). Groningen: University of Groningen] to enable reliable comparisons between the languages. The results show that the PADILIH predicts the performance of agrammatic speakers very well: discourse-linked grammatical morphemes expressing time reference to the past are hard to produce for agrammatic speakers, whereas non-discourse-linked verb inflections (for present and future) are relatively spared. In languages that use aspectual adverbs (free-standing and optional time reference markers), such as Chinese and Indonesian, time reference to all time frames is impaired, since all aspectual adverbs, regardless of the time frame they refer to, require discourse linking. Remarkably, the problems are not restricted to grammatical morphemes: the production of temporal lexical adverbs is impaired as well. PMID- 23339397 TI - Catalyst-free direct vapor-phase growth of Zn1-xCuxO micro-cross structures and their optical properties. AB - We report a simple catalyst-free vapor-phase method to fabricate Zn1-xCuxO micro cross structures. Through a series of controlled experiments by changing the location of the substrate and reaction time, we have realized the continuous evolution of product morphology from nanorods into brush-like structures and micro-cross structures at different positions, together with the epitaxial growth of branched nanorods from the central stem with the time extended. The growth mechanism of the Zn1-xCuxO micro-cross structures has been proposed to involve the synthesis of Cu/Zn square-like core, surface oxidation, and the secondary growth of nanorod arrays. By the detailed structural analysis of the yielded Zn1 xCuxO samples at different locations, we have shown that the CuO phases were gradually formed in Zn1-xCuxO, which is significant to induce the usual ZnO hexagonal structures changing into four-folded symmetrical hierarchical micro cross structures. Furthermore, the visible luminescence can be greatly enhanced by the introduction of Cu, and the observed inhomogeneous cathode luminescence in an individual micro-cross structure is caused by the different distributions of Cu. PMID- 23339398 TI - Lanthanide dinuclear complexes involving tetrathiafulvalene-3-pyridine-N-oxide ligand: semiconductor radical salt, magnetic, and photophysical studies. AB - Centro-symmetric dinuclear complexes of formula [Ln(tta)(3)(L)](2).xCH(2)Cl(2), (tta(-) = 2-thenoyltrifluoroacetonate anion, x = 0.5 for Ln = Eu (1a), Tb (3), and Dy (4) and x = 0 for Ln = Eu (1b) and Nd (2)) have been synthesized using the tetrathiafulvalene-3-pyridine-N-oxide as a bridging ligand (L). X-ray structures have shown the formation of channels with CH(2)Cl(2) solvent inside. 1 is stable with both filled channels (at 150 K) and empty channels (at room temperature). The Dy(III) analogue displays a complex butterfly like hysteresis loop at 1.5 K. Photophysical properties of the coordination complexes have been studied by solution and solid-state absorption spectroscopy. Time-dependent density functional theory (TD-DFT) calculations have been carried out on the diamagnetic Y(III) derivative to shed light on the absorption spectrum. For 2, the excitation of the charge transfer transitions induces line shape emission in the near infrared spectral range assigned to (4)F(3/2) -> (4)I(9/2), (4)F(3/2) -> (4)I(11/2), and (4)F(3/2) -> (4)I(13/2) neodymium centered transitions. The reversible redox-activity of the ligand L makes possible an original sensitization process involving a ligand centered charge separation followed by energy transfer to the Nd(III) ion upon recombination. PMID- 23339400 TI - Semiconductor@metal-organic framework core-shell heterostructures: a case of ZnO@ZIF-8 nanorods with selective photoelectrochemical response. AB - Metal-organic frameworks (MOFs) and related material classes are attracting considerable attention for their applications in gas storage/separation as well as catalysis. In contrast, research concerning potential uses in electronic devices (such as sensors) is in its infancy, which might be due to a great challenge in the fabrication of MOFs and semiconductor composites with well designed structures. In this paper, we proposed a simple self-template strategy to fabricate metal oxide semiconductor@MOF core-shell heterostructures, and successfully obtained freestanding ZnO@ZIF-8 nanorods as well as vertically standing arrays (including nanorod arrays and nanotube arrays). In this synthetic process, ZnO nanorods not only act as the template but also provide Zn(2+) ions for the formation of ZIF-8. In addition, we have demonstrated that solvent composition and reaction temperature are two crucial factors for successfully fabricating well-defined ZnO@ZIF-8 heterostructures. As we expect, the as prepared ZnO@ZIF-8 nanorod arrays display distinct photoelectrochemical response to hole scavengers with different molecule sizes (e.g., H(2)O(2) and ascorbic acid) owing to the limitation of the aperture of the ZIF-8 shell. Excitingly, such ZnO@ZIF-8 nanorod arrays were successfully applied to the detection of H(2)O(2) in the presence of serous buffer solution. Therefore, it is reasonable to believe that the semiconductor@MOFs heterostructure potentially has promising applications in many electronic devices including sensors. PMID- 23339399 TI - Aggregation and neurotoxicity of recombinant alpha-synuclein aggregates initiated by dimerization. AB - BACKGROUND: Aggregation of the alpha-Synuclein (alpha-Syn) protein, amyloid fibril formation and progressive neurodegeneration are the neuropathological hallmarks of Parkinson's Disease (PD). However, a detailed mechanism of alpha-Syn aggregation/fibrillogenesis and the exact nature of toxic oligomeric species produced during amyloid formation process are still unknown. RESULTS: In this study, the rates of alpha-Syn aggregation were compared for the recombinant wild type (WT) alpha-Syn and a structurally relevant chimeric homologous protein containing an inducible Fv dimerizing domain (alpha-SynFv), capable to form dimers in the presence of a divalent ligand (AP20187). In the presence of AP20187, we report a rapid random coil into beta-sheet conformational transformation of alpha-SynFv within 24 h, whereas WT alpha-Syn showed 24 h delay to achieve beta-sheet structure after 48 h. Fluorescence ANS and ThT binding experiments demonstrate an accelerated oligomer/amyloid formation of dimerized alpha-SynFv, compared to the slower oligomerization and amyloidogenesis of WT alpha-Syn or alpha-SynFv without dimerizer AP20187. Both alpha-SynFv and alpha Syn pre-fibrillar aggregates internalized cells and induced neurotoxicity when injected into the hippocampus of wild-type mice. These recombinant toxic aggregates further converted into non-toxic amyloids which were successfully amplified by protein misfolding cyclic amplification method, providing the first evidence for the in vitro propagation of synthetic alpha-Syn aggregates. CONCLUSIONS: Together, we show that dimerization is important for alpha-Syn conformational transition and aggregation. In addition, alpha-Syn dimerization can accelerate the formation of neurotoxic aggregates and amyloid fibrils which can be amplified in vitro. A detailed characterization of the mechanism of alpha Syn aggregation/amyloidogenesis and toxicity is crucial to comprehend Parkinson's disease pathology at the molecular level. PMID- 23339401 TI - Seeds of Peganum Harmala L. chemical analysis, antimalarial and antioxidant activities, and cytotoxicity against human breast cancer cells. AB - The present study evaluated the levels of total phenolics, flavonoids, tannins and anthocyanins from Peganum harmala L. seeds and determined their antioxidant, antiplasmodial and anticancer potentials. Antioxidant activity was determined by DPPH and ABTS assays. Extracts of P. harmala seeds from Oudref and Djerba (two places in Tunisia) were obtained by successive extraction solvents: petroleum ether, chloroform, ethyl acetate, ethanol and water. Their composition was evaluated for phenolics (gallic acid equivalent 2.48 to 72.52 g/kg), tannins (catechin equivalent 0 to 25.27 g/kg), anthocyanins (cyanidin equivalent 0 to 20.56 mg/kg) and flavonoids (quercetin equivalent 0 to 3.12 g/kg). Ethanolic extract exerted the highest activities against a chloroquine-resistant strain of Plasmodium falciparum (IC50=23 mg/L), against human breast cancer cells MCF7 (IC50=32 mg/L) and against free radical (IC50=19.09+/-3.07 mg/L). Correlations were studied between each chemical family and the three activities. Total phenolics content exhibited the highest correlation with antiplasmodial activity (R2=0.92) and with anticancer activity (R2=0.86), respectively. PMID- 23339403 TI - Towards plug-and-play integration of archetypes into legacy electronic health record systems: the ArchiMed experience. AB - BACKGROUND: The dual model approach represents a promising solution for achieving semantically interoperable standardized electronic health record (EHR) exchange. Its acceptance, however, will depend on the effort required for integrating archetypes into legacy EHR systems. METHODS: We propose a corresponding approach that: (a) automatically generates entry forms in legacy EHR systems from archetypes; and (b) allows the immediate export of EHR documents that are recorded via the generated forms and stored in the EHR systems' internal format as standardized and archetype-compliant EHR extracts. As a prerequisite for applying our approach, we define a set of basic requirements for the EHR systems. RESULTS: We tested our approach with an EHR system called ArchiMed and were able to successfully integrate 15 archetypes from a test set of 27. For 12 archetypes, the form generation failed owing to a particular type of complex structure (multiple repeating subnodes), which was prescribed by the archetypes but not supported by ArchiMed's data model. CONCLUSIONS: Our experiences show that archetypes should be customized based on the planned application scenario before their integration. This would allow problematic structures to be dissolved and irrelevant optional archetype nodes to be removed. For customization of archetypes, openEHR templates or specialized archetypes may be employed. Gaps in the data types or terminological features supported by an EHR system will often not preclude integration of the relevant archetypes. More work needs to be done on the usability of the generated forms. PMID- 23339402 TI - Evolution of an amino acid based prodrug approach: stay tuned. AB - Certain acyclic nucleoside phosphonates (ANPs) such as (S)-HPMPC (cidofovir, Vistide) and (S)-HPMPA have been shown to be active against a broad spectrum of DNA and retroviruses. However, their poor absorption as well as their toxicity limit the utilization of these therapeutics in the clinic. Nucleoside phosphonates are poorly absorbed primarily due to the presence of the phosphonic acid group, which ionizes at physiological pH. When dosed intravenously they display dose-limiting nephrotoxicity due to their accumulation in the kidney. To overcome these limitations, nucleoside phosphonate prodrug strategies have taken center stage in the development pathway and a number of different approaches are at various stages of development. Our efforts have focused on the development of ANP prodrugs in which a benign amino acid promoiety masks a phosphonate P-OH via a hydroxyl side chain. The design of these prodrugs incorporates multiple chemical groups (the P-X-C linkage, the amino acid stereochemistry, the C terminal and N-terminal functional groups) that can be tuned to modify absorption, pharmacokinetic and efficacy properties with the goal of improving overall prodrug performance. PMID- 23339404 TI - Cellular intermingling between adrenal gland and liver: an infrequent cause of incomplete resection at right adrenalectomy. AB - PURPOSE: To assess the incidence of difficulty in complete dissection between the right adrenal gland and the liver at the time of laparoscopic surgery for adrenal tumor and to elucidate its cause histopathologically. PATIENTS AND METHODS: Thirty-six patients underwent laparoscopic right adrenalectomy between 2004 and 2011 at our institution. Two reviewers independently assessed difficulty in dissection for the 36 nonedited video records of laparoscopic right adrenalectomy in blinded fashion. Twenty-seven records were evaluable for the judgment of difficulty in dissection between the lower surface of the liver and the right adrenal gland. On the other hand, the gross and microscopic relationship between the right adrenal gland and the surface of the liver was investigated in 32 cadavers. RESULTS: Incomplete resection of the adrenal gland was found in 11 of 27 (40.7%) patients. Difficulties in dissection because of adhesions between the liver and the adrenal gland were apparently recognized in 5 of 27 (18.5%) patients. Pathologic assessment for cadavers revealed that capsules between these two organs are partially fused in 10 of 32 (31.3%) cases. Histopathologically, intermingling of parenchymal cells (infiltration through the fibrous capsules) was observed in nine (28.1%) cases. CONCLUSIONS: The tight adhesion between the lower surface of the liver and the adrenal gland because of intermingling of parenchymal cells of both organs is a major cause of incomplete resection of right adrenalectomy. Surgeons have to keep this fact in mind during right adrenalectomy to avoid unnecessary adverse events. PMID- 23339405 TI - Editorial: Proceeding for Chinese-Canada symposium in atherosclerosis and cardiovascular disease. September 23-25, Beijing. PMID- 23339406 TI - Abstracts from the Chinese-Canada Symposium in Atherosclerosis and Cardiovascular Disease Conference, September 23-25, 2012, Beijing, China.. PMID- 23339407 TI - RhoB modifies estrogen responses in breast cancer cells by influencing expression of the estrogen receptor. AB - INTRODUCTION: RhoB has been reported to exert positive and negative effects on cancer pathophysiology but an understanding of its role in breast cancer remains incomplete. Analysis of data from the Oncomine database showed a positive correlation between RhoB expression and positivity for both estrogen receptor alpha (ERalpha) and progesterone receptor (PR). METHODS: This finding was validated by our analysis of a tissue microarray constructed from a cohort of 113 patients and then investigated in human cell models. RESULTS: We found that RhoB expression in tissue was strongly correlated with ERalpha and PR expression and inversely correlated with tumor grade, tumor size and count of mitosis. In human breast cancer cell lines, RhoB attenuation was associated with reduced expression of both ERalpha and PR, whereas elevation of RhoB was found to be associated with ERalpha overexpression. Mechanistic investigations suggested that RhoB modulates ERalpha expression, controlling both its protein and mRNA levels, and that RhoB modulates PR expression by accentuating the recruitment of ERalpha and other major co-regulators to the promoter of PR gene. A major consequence of RhoB modulation was that RhoB differentially regulated the proliferation of breast cancer cell lines. Interestingly, we documented crosstalk between RhoB and ERalpha, with estrogen treatment leading to RhoB activation. CONCLUSION: Taken together, our findings offer evidence that in human breast cancer RhoB acts as a positive function to promote expression of ERalpha and PR in a manner correlated with cell proliferation. PMID- 23339409 TI - Reduced genetic influence on childhood obesity in small for gestational age children. AB - BACKGROUND: Children born small-for-gestational-age (SGA) are at increased risk of developing obesity and metabolic diseases later in life, a risk which is magnified if followed by accelerated postnatal growth. We investigated whether common gene variants associated with adult obesity were associated with increased postnatal growth, as measured by BMI z-score, in children born SGA and appropriate for gestational age (AGA) in the Auckland Birthweight Collaborative. METHODS: A total of 37 candidate SNPs were genotyped on 547 European children (228 SGA and 319 AGA). Repeated measures of BMI (z-score) were used for assessing obesity status, and results were corrected for multiple testing using the false discovery rate. RESULTS: SGA children had a lower BMI z-score than non-SGA children at assessment age 3.5, 7 and 11 years. We confirmed 27 variants within 14 obesity risk genes to be individually associated with increasing early childhood BMI, predominantly in those born AGA. CONCLUSIONS: Genetic risk variants are less important in influencing early childhood BMI in those born SGA than in those born AGA, suggesting that non-genetic or environmental factors may be more important in influencing childhood BMI in those born SGA. PMID- 23339410 TI - Comparing effects of tobacco use prevention modalities: need for complex system models. AB - Many modalities of tobacco use prevention programming have been implemented including various policy regulations (tax increases, warning labels, limits on access, smoke-free policies, and restrictions on marketing), mass media programming, school-based classroom education, family involvement, and involvement of community agents (i.e., medical, social, political). The present manuscript provides a glance at these modalities to compare relative and combined impact of them on youth tobacco use. In a majority of trials, community-wide programming, which includes multiple modalities, has not been found to achieve impacts greater than single modality programming. Possibly, the most effective means of prevention involves a careful selection of program type combinations. Also, it is likely that a mechanism for coordinating maximally across program types (e.g., staging of programming) is needed to encourage a synergistic impact. Studying tobacco use prevention as a complex system is considered as a means to maximize effects from combinations of prevention types. Future studies will need to more systematically consider the role of combined programming. PMID- 23339412 TI - Introduction. PMID- 23339411 TI - Construction of a green fluorescent protein (GFP)-marked multifunctional pesticide-degrading bacterium for simultaneous degradation of organophosphates and gamma-hexachlorocyclohexane. AB - An autofluorescent whole-cell biocatalyst capable of simultaneously degrading organophosphates (OPs) and gamma-hexachlorocyclohexane (gamma-HCH) was constructed by display of organophosphorus hydrolase (OPH) and green fluorescent protein (GFP) fusion on the cell surface of a gamma-HCH-degrading Sphingobium japonicum UT26 using the truncated ice nucleation protein (INPNC) as an anchoring motif. The surface localization of INPNC-OPH-GFP fusion was verified by cell fractionation, Western blot, proteinase accessibility, and immunofluorescence microscopy. Surface display of macromolecular OPH-GFP fusion (63 kDa) neither inhibits cell growth nor affects cell viability. In sterile and nonsterile soil samples, a mixture of parathion (100 mg kg(-1)) and gamma-HCH (10 mg kg(-1)) could be degraded completely within 15 days when inoculated with the engineered UT26, and the strain could be easily monitored by fluorescence during bioremediation. These results indicate that the engineered UT26 is a promising multifunctional bacterium that could be used for the bioremediation of environments contaminated with multiple pesticides. PMID- 23339413 TI - Evaluation of attitude survey translations an investigation using item response theory. AB - Abstract The fidelity of a translated survey instrument used to measure attitudes toward mental health was evaluated using statistical methods based on item response theory. Data from French and German versions of the attitude survey wm analyzed, and items that displayed differential item functioning (dif) were identified. Item characteristic curves (ICCs) were examined to determine whether the source of dif could be attributed to errors in translation or differences in cultural experiences or knowledge. The proposal by Humphreys and Hulin for using ICCs to determine the source of dif is evaluated. PMID- 23339414 TI - Equivalence of cross-cultural data: an overview of basic issues. AB - Abstract The logic of comparison is taken as a starting point. It is argued that any cross-cultural comparison presupposes a comparison scale, i.e. a scale that is identical across the populations included in a study. Scale identity can be Specified for various levels of measurement. In the second section a simple classification is presented for inferences about cross-cultural differences derived from psychological measurements. Two questions are asked for various categories of inferences, viz., whether they are logically feasible and whether they can be validated empirically. In the third section the statistical analysis of psychometric conditions for equivalence is discussed. The fourth section deals with the problem what alternatives for meaningful interpretation a researcher has if data turn out to be lacking in equivalence. In the fifth section a conceptual problem is raised. namely whether the basic assumption of this article is realistic that psychological concepts are identical across cultures. PMID- 23339416 TI - Base-induced dehydrogenation of ruthenium hydrazine complexes. AB - Treatment of [RuCl(PP(3)(iPr))](+)Cl(-) (PP(3)(iPr) = P(CH(2)CH(2)P(i)Pr(2))(3)) with hydrazine, phenylhydrazine, and methylhydrazine afforded side-on bound hydrazine complexes [RuCl(eta(2)-H(2)N-NH(2))(eta(3)-PP(3)(iPr))](+), [RuCl(eta(2)-H(2)N-NHPh)(eta(3)-PP(3)(iPr))](+), and [RuCl(eta(2)-H(2)N NHMe)(eta(3)-PP(3)(iPr))](+). The analogous reactions of [RuCl(2)(PP(3)(Ph))] (PP(3)(Ph) = P(CH(2)CH(2)PPh(2))(3)) with hydrazine, phenylhydrazine, and methylhydrazine afforded end-on bound hydrazine complexes [RuCl(eta(1)-H(2)N NH(2))(PP(3)(Ph))](+), [RuCl(eta(1)-H(2)N-NHPh)(PP(3)(Ph))](+), and [RuCl(eta(1) H(2)N-NHMe)(PP(3)(Ph))](+). Treatment of parent hydrazine complex [RuCl(N(2)H(4))(PP(3)(iPr))](+) with strong base afforded the dinitrogen and dihydride complexes [Ru(N(2))(PP(3)(iPr))] and [RuH(2)(PP(3)(iPr))]. Treatment of phenylhydrazine complex [RuCl(NH(2)NHPh)(PP(3)(iPr))](+) with strong base afforded the hydrido ruthenaindazole complex [RuH(eta(2)-NH?NC(6)H(4))(eta(3) PP(3)(iPr))] while similar treatment of methylhydrazine complex [RuCl(NH(2)NHMe)(PP(3)(iPr))](+) afforded the hydrido methylenehydrazide complex [RuH(NHN?CH(2))(PP(3)(iPr))]. Treatment of the hydrazine complexes [RuCl(NH(2)NHR)(PP(3)(Ph))](+) (R = H, Ph, Me) with strong base afforded the dinitrogen complex [Ru(N(2))(PP(3)(Ph))]. PMID- 23339417 TI - Imageability of Norwegian nouns, verbs and adjectives in a cross-linguistic perspective. AB - In this article, we present a study of imageability ratings for a set of 1599 Norwegian words (896 nouns, 483 verbs and 220 adjectives) from a web-based survey. To a large extent, the results are in accordance with previous studies of other languages: high imageability scores in general, higher imageability scores for nouns than for verbs, and an inverse relation between frequency and imageability. A more surprising finding is the low imageability of low-frequency verbs. Also, imageability ratings increase systematically and significantly with informant age, reminding us that conceptual learning continues and changes throughout life. This has consequences for our expectations of different linguistic skills in a life span perspective. These findings have an obvious clinical relevance both for choice of items in test construction, for evaluation of performance in clinical groups and for development of therapy material. PMID- 23339418 TI - Closed-face filter cassette (CFC) sampling-guidance on procedures for inclusion of material adhering to internal sampler surfaces. PMID- 23339419 TI - Changes in FDA enforcement activities following changes in federal administration: the case of regulatory letters released to pharmaceutical companies. AB - BACKGROUND: The United States (US) Food and Drug Administration (FDA) is responsible for the protection of the public health by assuring the safety, effectiveness and security of human drugs and biological products through the enforcement of the Federal Food, Drug and Cosmetic Act (FDCA) and related regulations. These enforcement activities include regulatory letters (i.e. warning letters and notice of violation) to pharmaceutical companies. A regulatory letter represents the FDA's first official notification to a pharmaceutical company that the FDA has discovered a product or activity in violation of the FDCA.This study analyzed trends in the pharmaceutical-related regulatory letters released by the FDA during the period 1997-2011 and assessed differences in the average number and type of regulatory letters released during the last four federal administrations. METHODS: Data derived from the FDA webpage. Information about the FDA office releasing the letter, date, company, and drug-related violation was collected. Regulatory letters were classified by federal administration. Descriptive statistics were performed for the analysis. RESULTS: Between 1997 and 2011 the FDA released 2,467 regulatory letters related to pharmaceuticals. FDA headquarters offices released 50.6% and district offices 49.4% of the regulatory letters. The Office of Prescription Drug Promotion released the largest number of regulatory letters (850; 34.5% of the total), followed by the Office of Scientific Investigations (131; 5.3%), and the Office of Compliance (105; 4.3%). During the 2nd Clinton Administration (1997-2000) the average number of regulatory letters per year was 242.8 +/- 45.6, during the Bush Administration (2001-2008) it was 120.4 +/- 33.7, and during the first three years of the Obama administration (2009-2011) it was 177.7.0 +/- 17.0. The average number of regulatory letters released by the Office of Prescription Drug Promotion also varied by administration: Clinton (122.3 +/- 36.4), Bush (29.5 +/- 16.2) and Obama (41.7 +/- 11.1). CONCLUSIONS: Most regulatory letters released by FDA headquarters were related to marketing and advertising activities of pharmaceutical companies. The number of regulatory letters was highest during the second Clinton administration, diminished during the Bush administrations, and increased again during the Obama administration. A further assessment of the impact of changes in federal administration on the enforcement activities of the FDA is required. PMID- 23339420 TI - IAPP aggregation and cellular toxicity are inhibited by 1,2,3,4,6-penta-O-galloyl beta-D-glucose. AB - The polyphenol, 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) has been found to exhibit a host of positive pharmacologic activities, including anti-cancer and anti-diabetic. Little is known about the mode of action of PGG in yielding these positive activities. We show here that PGG is a potent inhibitor of IAPP (islet amyloid polypeptide, amylin) aggregation. Preventing the initial aggregation event of IAPP is one strategy for slowing, and possibly preventing, the toxic effects of IAPP oligomeric intermediates. Equal molar ratios of PGG to IAPP substantially reduced the ability of IAPP to bind thioflavin T. Atomic force microscopy revealed that PGG prevented amyloid-based fiber formation under rigorous conditions conducive to forming IAPP aggregates. PGG was also found to protect PC12 rat cells from toxic IAPP. PGG was compared to the known amyloid inhibitors (and structural relatives); tannic acid and gallic acid. In every test, PGG was far superior to tannic and gallic acids at inhibiting amyloid aggregation. These results indicate that PGG is a potent inhibitor of IAPP amyloid aggregation and a potential lead molecule for development of an amyloid inhibiting therapeutic. PMID- 23339421 TI - Evaluation of patients with cardiac amyloidosis using echocardiography, ECG and right heart catheterization. AB - AIMS: To characterize patients with cardiac amyloidosis using echocardiography, electrocardiogram (ECG) and right heart catheterization (RHC). METHODS AND RESULTS: Fourteen patients with biopsy verified light chain or transthyretin cardiac amyloidosis were included. All patients had heart failure with markedly elevated NT-proBNP. Echocardiography demonstrated biventricular hypertrophy, left atrial enlargement and normal to slightly reduced left ventricular ejection fraction. Tissue Doppler septal e was low and median E/e was high. Within 6 months RHC was performed in eight of the patients. The restrictive filling pattern demonstrated by echocardiography corresponded well to median pulmonary wedge pressure (21 mmHg). Systolic pulmonary artery pressure (SPAP) was increased, whereas cardiac output and stroke volume were seen to be decreased with both methods. ECG demonstrated: low voltage (36%), abnormal R-progression (65%), ST-T abnormalities (71%) and high incidence of fibrillation (36%). In addition, a case report following the treatment of melphalan and dexamethasone is presented with improvement of hypertrophy, SPAP, left ventricular mass and e. CONCLUSION: These findings should lead to a suspicion of cardiac amyloidosis and suggest further investigation. PMID- 23339423 TI - From desk to bed: computational simulations provide indication for rheumatoid arthritis clinical trials. AB - BACKGROUND: Rheumatoid arthritis (RA) is among the most common human systemic autoimmune diseases, affecting approximately 1% of the population worldwide. To date, there is no cure for the disease and current treatments show undesirable side effects. As the disease affects a growing number of individuals, and during their working age, the gathering of all information able to improve therapies--by understanding their and the disease mechanisms of action--represents an important area of research, benefiting not only patients but also societies. In this direction, network analysis methods have been used in previous work to further our understanding of this complex disease, leading to the identification of CRKL as a potential drug target for treatment of RA. Here, we use computational methods to expand on this work, testing the hypothesis in silico. RESULTS: Analysis of the CRKL network--available at http://www.picb.ac.cn/ClinicalGenomicNTW/software.html--allows for investigation of the potential effect of perturbing genes of interest. Within the group of genes that are significantly affected by simulated perturbation of CRKL, we are lead to further investigate the importance of PXN. Our results allow us to (1) refine the hypothesis on CRKL as a novel drug target (2) indicate potential causes of side effects in on-going trials and (3) importantly, provide recommendations with impact on on-going clinical studies. CONCLUSIONS: Based on a virtual network that collects and connects a large number of the molecules known to be involved in a disease, one can simulate the effects of controlling molecules, allowing for the observation of how this affects the rest of the network. This is important to mimic the effect of a drug, but also to be aware of -and possibly control- its side effects. Using this approach in RA research we have been able to contribute to the field by suggesting molecules to be targeted in new therapies and more importantly, to warrant efficacy, to hypothesise novel recommendations on existing drugs currently under test. PMID- 23339424 TI - Tris(azidoethyl)amine hydrochloride; a versatile reagent for synthesis of functionalized dumbbell oligodeoxynucleotides. AB - Triazole-cross-linked oligodeoxynucleotides were synthesized using the Cu(I) catalyzed alkyne-azide cycloaddition with tris(azidoethyl)amine hydrochloride and oligodeoxynucleotides possessing N-3-(propargyl)thymidine at both the 3'- and 5' termini. Further installation of a functional molecule to the dumbbell oligodeoxynucleotides was achieved by utilizing the remaining azide group. PMID- 23339426 TI - In vitro inhibition effect and structure-activity relationships of some saccharin derivatives on erythrocyte carbonic anhydrase I and II. AB - In this study, in vitro inhibitory effects of some saccharin derivatives on purified carbonic anhydrase I and II were investigated using CO2 as a substrate. The results showed that all compounds inhibited the hCA I and hCA II enzyme activities. Among the compounds, 6-(p-tolylthiourenyl) saccharin (6m) was found to be the most active one for hCA I activity (IC50=13.67 MUM) and 6-(m methoxyphenylurenyl) saccharin (6b) was found to be the most active one for hCA II activity (IC50=6.54 MUM). Structure-activity relationships (SARs) study showed that, generally, thiourea derivatives (6l--v) inhibited more hCA I and hCA II than urea derivatives (6a-k). All compounds (excluding 6c and 6r) have higher inhibitory activity on hCA II than on hCA I. PMID- 23339425 TI - Serological profiles in nursery piglets colonized with Staphylococcus aureus. AB - At present, the immune response of pigs in relation to Staphylococcus aureus carriage is poorly understood. This study was aimed at investigating the dynamics of the anti-staphylococcal humoral immune response in methicillin-susceptible S. aureus (MSSA)-positive piglets and at assessing the effect of the experimental introduction of a methicillin-resistant S. aureus (MRSA) Sequence Type (ST) 398 strain. Therefore, serum samples were collected at different times from 31 weaned piglets originating from four different sows. Twenty-four out of the 31 piglets were challenged with MRSA ST398. The serum samples were analyzed for IgG antibodies to 39 S. aureus antigens, using a multiplex bead-based assay (xMAP technology, Luminex Corporation). Though antibody responses showed broad inter individual variability, serological results appeared to be clustered by litter of origin. For most antigens, an age-related response was observed with an apparent increase in antibody titers directed against staphylococcal microbial surface components recognizing adhesive matrix molecules (MSCRAMM), which have been shown to play a role in S. aureus colonization. In most animals, antibody titers directed against staphylococcal toxins or immune-modulating proteins decreased with age, possibly reflecting the absence of bacterial invasion. The introduction of MRSA ST398 did not elicit a significant humoral immune reaction.This study describes, for the first time, the humoral immune response in weaned pigs colonized with S. aureus. PMID- 23339427 TI - Synthesis and activity of proteasome inhibitors. AB - Among its various catalytic activities, "chymotrypsin-like" activity of proteasome, a large multicatalytic proteinase complex has emerged as the focus of drug discovery efforts in cancer therapy. Herein, we report results from our investigation on a series of peptidomimetic inhibitors. PMID- 23339428 TI - Synthesis and biological evaluation of modified purine homo-N-nucleosides containing pyrazole or 2-pyrazoline moiety. AB - 9-Substituted (pyrazol-5-yl)methyl- or (2-pyrazolin-5-yl)methyl-9H-purines were synthesized from 9-allyl-6-chloro-9H-purine through the 1,3-dipolar cycloaddition reaction with nitrile imines, prepared in situ from the corresponding hydrazone and NBS/Et3N under MW or from hydrazinoylchloride and Et3N under reflux. The coupling of new 6-chloropurines with amines in H2O under microwaves resulted quantitatively to modified pyrazol-5-yl- or 2-pyrazolin-5-yl adenine homo-N nucleosides. The new compounds were tested in vitro for their ability to: (i) interact with 1,1-diphenyl-2-picryl-hydrazyl (DPPH), (ii) inhibit lipid peroxidation, (iii) inhibit the activity of soybean lipoxygenase, (iv) inhibit in vitro thrombin and for (v) their antiproliferative and cytotoxic activity. Pyrazolines were found to be more potent in vitro. Compound 7a exhibited satisfactory combined antioxidant and anti-lipid peroxidation activity, inhibition of lipoxygenase (89%) and thrombin inhibitory ability, whereas compound 7b exhibited high lipoxygenase inhibitory activity in combination to significant anti-thrombin activity. No compound exhibited a significant cytotoxic activity, while all showed moderate antiproliferative activity. PMID- 23339429 TI - Ringing the changes at the Journal of Human Nutrition and Dietetics. PMID- 23339430 TI - Cluster analysis of fruit and vegetable-related perceptions: an alternative approach of consumer segmentation. AB - BACKGROUND: Audience segmentation optimises health communication aimed to promote healthy dietary habits, such as fruit and vegetable (F&V) consumption. The present study aimed to segment respondents into clusters based on F&V-related perceptions, and to describe these clusters with respect to F&V consumption and sex. METHODS: The cross-sectional study was conducted using a semi-structured questionnaire. The respondents were randomly selected among Swedish adults (n = 1304; response rate 51%; 56% women). A two-step cluster analysis was conducted followed by a binary logistic regression with cluster membership as a dependent variable. The clusters were compared using t-tests and chi-squared tests. P < 0.05 (two-sided) was considered statistically significant. The respondents' open ended answers of determinants of F&V consumption were used as a descriptive support for the conducted multivariate analysis. RESULTS: Of the two identified clusters, the Positive cluster (n = 476) was older and consumed more vegetables (both sexes) and fruit (women only), whereas men in the Indifferent cluster (n = 715) consumed more juice. Indifferent cluster reported more F&V consumption preventing factors, such as storage and preparation difficulties and low satisfaction with F&V selection and price. Not liking or not having a habit of F&V consumption, laziness, forgetting and a lack of time were mentioned as main barriers to F&V consumption. CONCLUSIONS: The Indifferent cluster reports more practical and life-style related difficulties. The Positive cluster consumes more vegetables, perceives fewer F&V-related difficulties, and looks for more dietary information. The findings confirm that cluster analysis is an appropriate way of identifying consumer subgroups for targeted health and nutrition communication. PMID- 23339433 TI - Fibroblast growth factor 23 is associated with carotid artery calcification in chronic kidney disease patients not undergoing dialysis: a cross-sectional study. AB - BACKGROUND: Fibroblast growth factor 23 (FGF23) is an important hormone in the regulation of phosphate metabolism. It is unclear whether FGF23 is associated with carotid artery calcification (CAAC) in predialysis patients. The present study aimed to clarify the relationship between FGF23 and CAAC in patients with chronic kidney disease (CKD) who were not on dialysis. METHODS: One-hundred ninety-five predialysis CKD patients were enrolled in this cross-sectional study. CAAC was assessed using multidetector computed tomography, and the prevalence of CAAC was examined. Intact FGF23 was measured in each patient. The risk factors for CAAC were evaluated using a logistic regression model. RESULTS: We found CAAC in 66% of the patients. The prevalence of CAAC significantly increased across CKD stages: it was 37% in CKD stages 1-2, 58% in stage 3; 75% in stage 4, and 77% in stage 5 (p < 0.01). In multivariate analysis, smoking, diabetes mellitus and log FGF23 were each identified as risk factors for CAAC. The study population was divided in quartiles of FGF23 levels. Compared with the lowest FGF23 quartile, each subsequent quartile had a progressively higher odds ratio (OR) for CAAC, adjusted for confounders (ORs [95% confidence interval] of 2.34 [0.78 to 7.31], 5.28 [1.56 to 19.5], and 13.6 [2.92 to 74.6] for the second, third, and fourth quartiles, respectively. CONCLUSIONS: The prevalence of CAAC is increased with the decline in the kidney function. FGF23 is independently related to CAAC in patients with CKD who are not on dialysis. PMID- 23339434 TI - Matching-adjusted indirect comparison of adalimumab vs etanercept and infliximab for the treatment of psoriatic arthritis. AB - OBJECTIVES: No head-to-head trial has compared the efficacy of adalimumab vs etanercept and infliximab for psoriatic arthritis (PsA). This study implements a matching-adjusted indirect comparison technique to address that gap. METHODS: Patient-level data from a placebo-controlled trial of adalimumab (ADEPT) were re weighted to match average baseline characteristics from pivotal published trials of etanercept and infliximab. ADEPT patients were re-weighted by odds of enrollment in comparator trials, estimated using logistic regression. Matched-on characteristics included PsA duration, age, gender, severity, active psoriasis, and concomitant treatment. After matching, placebo-adjusted treatment arms were compared at weeks 12 (or 14) and 24. Outcomes included ACR20/50/70, PsARC, HAQ, and modified TSS. PASI50/75/90 were compared for patients with active psoriasis. Cost per responder (CPR) was assessed in the US and Germany using matching adjusted end-points and drug list prices. Statistical significance was assessed using weighted t-tests. RESULTS: After matching, adalimumab-treated patients had greater placebo-adjusted rates of ACR70 and PASI50/75/90 at week 24 compared with etanercept (all p < 0.05). Adalimumab patients had a higher placebo-adjusted rate of ACR70 than infliximab at week 14 (p = 0.034). Adalimumab treatment had lower CPR for ACR70 and PASI50/75/90 compared with etanercept at week 24, in both the US and Germany (all p < 0.02). Adalimumab had lower CPR than infliximab for all outcomes at week 24 (all p < 0.05). CONCLUSION: Adalimumab is associated with higher ACR70 and PASI50/75/90 response rates than etanercept at week 24 and a higher ACR70 response rate than infliximab at week 14. Adalimumab has significant advantages over etanercept and infliximab in CPR across multiple end-points. KEY LIMITATIONS: The matching-adjusted indirect comparison method cannot account for unobserved differences in patient characteristics across trials, and only a head to-head randomized clinical trial can fully avoid the limitations of indirect comparisons. CPR findings are limited to the US and German markets, and may not be generalizable to other markets with different relative pricing. PMID- 23339435 TI - p-terphenyl derivatives from the mushroom Thelephora aurantiotincta suppress the proliferation of human hepatocellular carcinoma cells via iron chelation. AB - A novel 2',3'-dihydroxy-p-terphenyl derivative, thelephantin O (TO), which has cancer-selective cytotoxicity, was isolated. This study investigated the underlying basis of the cytotoxicity of 2',3'-dihydroxy-p-terphenyl compounds in view of their ability to chelate metal ions. FeCl(2) significantly reduced TO induced cytotoxicity, whereas several other salts of transition metals and alkaline-earth metals did not. A structure-activity relationship study using newly synthesized p-terphenyl derivatives revealed that o-dihydroxy substitution of the central benzene ring was necessary for both the cytotoxicity and Fe(2+) chelation of the compounds. Real-time PCR array and cell cycle analysis revealed that the TO-induced cytotoxicity was attributed to cell cycle arrest at the G1 phase via well-known cell cycle-mediated genes. The TO-induced changes in the cell cycle and gene expression were completely reversed by the addition of FeCl(2). Thus, it was concluded that Fe(2+) chelation occurs upstream in the pivotal pathway of 2',3'-dihydroxy-p-terphenyl-induced inhibition of cancer cell proliferation. PMID- 23339436 TI - Mammographic density as a predictor of breast cancer survival: the Multiethnic Cohort. AB - INTRODUCTION: Mammographic density, a strong predictor for breast cancer incidence, may also worsen prognosis in women with breast cancer. This prospective analysis explored the effect of prediagnostic mammographic density among 607 breast cancer cases diagnosed within the Hawaii component of the Multiethnic Cohort (MEC). METHODS: Female MEC participants, aged >= 50 years at cohort entry, diagnosed with primary invasive breast cancer, and enrolled in a mammographic density case-control study were part of this analysis. At cohort entry, anthropometric and demographic information was collected by questionnaire. Tumor characteristics and vital status were available through linkage with the Hawaii Tumor Registry. Multiple digitized prediagnostic mammograms were assessed for mammographic density using a computer-assisted method. Cox proportional hazards regression was applied to examine the effect of mammographic density on breast cancer survival while adjusting for relevant covariates. RESULTS: Of the 607 cases, 125 were diagnosed as in situ, 380 as localized, and 100 as regional/distant stage. After a mean follow-up time of 12.9 years, 27 deaths from breast cancer and 100 deaths from other causes had occurred; 71 second breast cancer primaries were diagnosed. In an overall model, mammographic density was not associated with breast cancer-specific survival (HR = 0.95 per 10%; 95%CI: 0.79-1.15), but the interaction with radiotherapy was highly significant (p = 0.006). In stratified models, percent density was associated with a reduced risk of dying from breast cancer (HR = 0.77; 95%CI: 0.60-0.99; p = 0.04) in women who had received radiation, but with an elevated risk (HR = 1.46; 95% CI: 1.00-2.14; p = 0.05) in patients who had not received radiation. High breast density predicted a borderline increase in risk for a second primary (HR = 1.72; 95% CI: 0.88-2.55; p = 0.15). CONCLUSIONS: Assessing mammographic density in women with breast cancer may identify women with a poorer prognosis and provide them with radiotherapy to improve outcomes. PMID- 23339437 TI - Penetration of fiber versus spherical particles through filter media and faceseal leakage of N95 filtering facepiece respirators with cyclic flow. AB - This study investigated differences in penetration between fibers and spherical particles through faceseal leakage of an N95 filtering facepiece respirator. Three cyclic breathing flows were generated corresponding to mean inspiratory flow rates (MIF) of 15, 30, and 85 L/min. Fibers had a mean diameter of 1 MUm and a median length of 4.9 MUm (calculated aerodynamic diameter, d(ae) = 1.73 MUm). Monodisperse polystyrene spheres with a mean physical diameter of 1.01 MUm (PSI) and 1.54 MUm (PSII) were used for comparison (calculated d(ae) = 1.05 and 1.58 MUm, respectively). Two optical particle counters simultaneously determined concentrations inside and outside the respirator. Geometric means (GMs) for filter penetration of the fibers were 0.06, 0.09, and 0.08% at MIF of 15, 30, and 85 L/min, respectively. Corresponding values for PSI were 0.07, 0.12, and 0.12%. GMs for faceseal penetration of fibers were 0.40, 0.14, and 0.09% at MIF of 15, 30, and 85 L/min, respectively. Corresponding values for PSI were 0.96, 0.41, and 0.17%. Faceseal penetration decreased with increased breathing rate for both types of particles (p <= 0.001). GMs of filter and faceseal penetration of PSII at an MIF of 30 L/min were 0.14% and 0.36%, respectively. Filter penetration and faceseal penetration of fibers were significantly lower than those of PSI (p < 0.001) and PSII (p < 0.003). This confirmed that higher penetration of PSI was not due to slightly smaller aerodynamic diameter, indicating that the shape of fibers rather than their calculated mean aerodynamic diameter is a prevailing factor on deposition mechanisms through the tested respirator. In conclusion, faceseal penetration of fibers and spherical particles decreased with increasing breathing rate, which can be explained by increased capture by impaction. Spherical particles had 2.0-2.8 times higher penetration through faceseal leaks and 1.1-1.5 higher penetration through filter media than fibers, which can be attributed to differences in interception losses. PMID- 23339438 TI - Protein network-based Lasso regression model for the construction of disease miRNA functional interactions. AB - BACKGROUND: There is a growing body of evidence associating microRNAs (miRNAs) with human diseases. MiRNAs are new key players in the disease paradigm demonstrating roles in several human diseases. The functional association between miRNAs and diseases remains largely unclear and far from complete. With the advent of high-throughput functional genomics techniques that infer genes and biological pathways dysregulted in diseases, it is now possible to infer functional association between diseases and biological molecules by integrating disparate biological information. RESULTS: Here, we first used Lasso regression model to identify miRNAs associated with disease signature as a proof of concept. Then we proposed an integrated approach that uses disease-gene associations from microarray experiments and text mining, and miRNA-gene association from computational predictions and protein networks to build functional associations network between miRNAs and diseases. The findings of the proposed model were validated against gold standard datasets using ROC analysis and results were promising (AUC=0.81). Our protein network-based approach discovered 19 new functional associations between prostate cancer and miRNAs. The new 19 associations were validated using miRNA expression data and clinical profiles and showed to act as diagnostic and prognostic prostate biomarkers. The proposed integrated approach allowed us to reconstruct functional associations between miRNAs and human diseases and uncovered functional roles of newly discovered miRNAs. CONCLUSIONS: Lasso regression was used to find associations between diseases and miRNAs using their gene signature. Defining miRNA gene signature by integrating the downstream effect of miRNAs demonstrated better performance than the miRNA signature alone. Integrating biological networks and multiple data to define miRNA and disease gene signature demonstrated high performance to uncover new functional associations between miRNAs and diseases. PMID- 23339439 TI - Competing causes of chronic ill health: what do we do and what should we do? PMID- 23339440 TI - The contribution of atom accessibility to site of metabolism models for cytochromes P450. AB - Three different types of atom accessibility descriptors are investigated in relation to site of metabolism predictions. To enable the integration of local accessibility we have constructed 2DSASA, a method for the calculation of the atomic solvent accessible surface area that is independent of 3D coordinates. The method was implemented in the SMARTCyp site of metabolism prediction models and improved the results by up to 4 percentage points for nine cytochrome P450 isoforms. The final models are made available at http://www.farma.ku.dk/smartcyp. PMID- 23339441 TI - Learning strengths from cultural differences: a comparative study of maternal health-related behaviors and infant care among Southern Asian immigrants and Taiwanese women. AB - BACKGROUND: Many studies have indicated that most immigrant women come from underdeveloped countries, and this can have negative effects on their lives, children's adaptation to school, and medical care utilization. However, there is insufficient literature about differences in infant caretaking, pre-postpartum health care, and health outcome between immigrant and native Taiwanese populations. The aim of this study was to investigate the differences between Southern Asia immigrants and Taiwanese women in their access to medical care, postnatal growth, and infant care throughout the first six months postpartum. METHODS: Comparative and descriptive designs were applied. Immigrant women were eligible if they visited three suburban settings of the Outpatient Department of Obstetrics and Gynecology and the Outpatient Department of Pediatrics in Northern Taiwan during the period up to six months postpartum. RESULTS: Immigrant women appeared to have a lower frequency of antenatal examinations and obtained less health information from health care providers. However, they did not differ significantly from native Taiwanese women in maternal body size, postnatal growth curves, exclusive breastfeeding rates or vaccination awareness at the 6th month postpartum. CONCLUSIONS: Learning strengths from cultural differences between immigrant and native women and closing the gaps in health inequality are important issues. Despite the limitation of small sample size, the present findings can be used as references to help health care providers to develop further health policies in Taiwan. PMID- 23339442 TI - Iron-catalyzed allylic arylation of olefins via C(sp3)-H activation under mild conditions. AB - An aryl Grignard reagent in the presence of mesityl iodide converts an allylic C H bond of a cycloalkene or an allylbenzene derivative into a C-C bond in the presence of a catalytic amount of Fe(acac)(3) and a diphosphine ligand at 0 degrees C. The stereo- and regioselectivity of the reaction, together with deuterium labeling experiments, suggest that C-H bond activation is the slow step in the catalytic cycle preceding the formation of an allyliron intermediate. PMID- 23339443 TI - Isolable, copper(I) dicarbonyl complexes supported by N-heterocyclic carbenes. AB - Cationic copper(I) dicarbonyl complexes supported by N-heterocyclic carbene ligands, SIPr and IPr*, have been synthesized. [(SIPr)Cu(CO)(2)][SbF(6)] and [(IPr*)Cu(CO)(2)][SbF(6)] have a trigonal planar, three-coordinate copper atom with an average Cu-CO distance of 1.915 A and display C-O stretching frequencies higher than that of the free CO (2143 cm(-1)). The high CO stretching frequencies suggest that the Cu(I)-CO interaction in these cationic adducts is dominated by electrostatic and OC -> Cu sigma-donor components. [(SIPr)Cu(CO)(2)][SbF(6)] and [(IPr*)Cu(CO)(2)][SbF(6)] readily form the corresponding [(SIPr)Cu(CO)(H(2)O)][SbF(6)] and [(IPr*)Cu(CO)(H(2)O)][SbF(6)] with loss of a CO even with traces of water, but they can be converted back to the dicarbonyl adducts using excess CO. The synthesis and structure of [(IPr*)Cu(H(2)O)][SbF(6)] are also reported. It is a two-coordinate copper adduct with a Cu-O distance of 1.874(2) A. It reacts with excess CO to form [(IPr*)Cu(CO)(2)][SbF(6)]. PMID- 23339445 TI - MYC addiction in chronic lymphocytic leukemia. PMID- 23339444 TI - Signaling dynamics of palmitate-induced ER stress responses mediated by ATF4 in HepG2 cells. AB - BACKGROUND: Palmitic acid, the most common saturated free fatty acid, has been implicated in ER (endoplasmic reticulum) stress-mediated apoptosis. This lipoapotosis is dependent, in part, on the upregulation of the activating transcription factor-4 (ATF4). To better understand the mechanisms by which palmitate upregulates the expression level of ATF4, we integrated literature information on palmitate-induced ER stress signaling into a discrete dynamic model. The model provides an in silico framework that enables simulations and predictions. The model predictions were confirmed through further experiments in human hepatocellular carcinoma (HepG2) cells and the results were used to update the model and our current understanding of the signaling induced by palmitate. RESULTS: The three key things from the in silico simulation and experimental results are: 1) palmitate induces different signaling pathways (PKR (double stranded RNA-activated protein kinase), PERK (PKR-like ER kinase), PKA (cyclic AMP (cAMP)-dependent protein kinase A) in a time dependent-manner, 2) both ATF4 and CREB1 (cAMP-responsive element-binding protein 1) interact with the Atf4 promoter to contribute to a prolonged accumulation of ATF4, and 3) CREB1 is involved in ER-stress induced apoptosis upon palmitate treatment, by regulating ATF4 expression and possibly Ca2+ dependent-CaM (calmodulin) signaling pathway. CONCLUSION: The in silico model helped to delineate the essential signaling pathways in palmitate-mediated apoptosis. PMID- 23339446 TI - BH3 mimetic therapy: an emerging and promising approach to treating chronic lymphocytic leukemia. PMID- 23339447 TI - MicroRNAs in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin lymphoma. New treatment modalities, including intensive induction regimens with immunochemotherapy and autologous stem cell transplant, have improved survival. However, many patients still relapse, and there is a need for novel therapeutic strategies. Recent progress has been made in the understanding of the role of microRNAs (miRNAs) in MCL. Comparisons of tumor samples from patients with MCL with their normal counterparts (naive B-cells) have identified differentially expressed miRNAs with roles in cellular growth and survival pathways, as demonstrated in various biological model systems. In addition, MCL clinico pathological and prognostic subtypes can be identified using individual miRNAs or miRNA classifiers. miRNA based therapies have now shown efficacy in animal models, and many efforts are currently being made to further develop these drugs for use in patients. Thus, there is hope that specific targeting of pathogenic miRNAs may be used in cases of MCL when conventional therapies fail. Here, we review the current knowledge about the role of miRNAs in MCL, and highlight the perspectives for clinical use. PMID- 23339448 TI - Role of serum high mobility group box 1 in hematological malignancies complicated with systemic inflammatory response syndrome and effect of recombinant thrombomodulin. AB - High mobility group box 1 (HMGB1) mediates inflammation. We investigated the role of serum HMGB1 in 54 patients with hematological malignancies with and without systemic inflammatory response syndrome (SIRS). There was no difference between groups 1 (complete remission of hematological disease: n = 13) and 2 (no remission: n = 16) in serum HMGB1 levels. However, those of group 3 (complicated by SIRS: n = 25) were significantly higher (vs. group 1: p < 0.001 and vs. group 2: p = 0.008, respectively). Seventeen patients in group 3 also developed disseminated intravascular coagulation and received recombinant human thrombomodulin (rhTM). Thirteen of those with SIRS improved, and serum HMGB1 levels significantly decreased (p = 0.047). Seven patients in group 3 who died within 28 days of SIRS onset had significantly higher serum HMGB1 levels than the survivors (p = 0.016). The anti-HMGB1 properties of rhTM might be useful therapy if serum HMGB1 is associated with the development of SIRS in the presence of hematological malignancies. PMID- 23339449 TI - Risk factors of central nervous system relapse in mantle cell lymphoma. AB - Central nervous system (CNS) relapse has not been extensively studied in mantle cell lymphoma (MCL). We retrospectively analyzed the risk factors and pattern of CNS relapse in consecutive patients with MCL. We identified 142 cases of MCL treated from 1980 to 2011. Median age at diagnosis was 68 years; 82% of patients had advanced stage; extranodal disease was reported in 89% of cases and high serum lactate dehydrogenase (LDH) in 40%. Fourteen patients (10%) did not receive treatment at diagnosis. Chemotherapy was administered to 125 patients (88%), in 21 cases (15%) including drugs penetrating into the CNS or given intrathecally; 49 patients (35%) had rituximab. Ten patients had front-line autologous transplant. After a median follow-up of 7.9 years, CNS relapse occurred in 11 cases (7.8%) at a median of 13.8 months. Actuarial risk of CNS relapse was higher in patients with elevated LDH (p = 0.002), higher International Prognostic Index (IPI) score (p = 0.018) and blastoid histology (p < 0.0001). Blastoid histology retained significance at multivariate analysis. Median survival after CNS relapse was 6.3 months. No front-line treatment reduced the risk of CNS relapse. Our analysis confirms the poor outcome of MCL after CNS relapse and may allow the identification of patients needing prophylaxis of CNS relapse. PMID- 23339450 TI - Immunogenic potential of irradiated lymphoma cells is enhanced by adjuvant immunotherapy and modulation of local macrophage populations. AB - The aim of this study was to assess the immunogenic potential of irradiated lymphoma cells in vivo and determine whether immunogenicity can be enhanced by modulation of the host immune system. Syngeneic murine lymphoma models irradiated ex vivo were used as an orthotopic cellular vaccination prior to challenge with viable tumor cells. We demonstrate that irradiated lymphoma cells are poorly immunogenic and that protective anti-tumor CD8 T-cell responses require the addition of immunostimulatory monoclonal antibody as an immune adjuvant, and increased frequency of antigen exposure by multiple vaccinations. Furthermore, we show the potential importance of macrophages in regulating immunogenicity of irradiated lymphoma cells and demonstrate that depletion of macrophages using clodronate-encapsulated liposomes considerably enhances primary vaccination efficacy in the presence of adjuvant anti-CD40 antibody. Our results demonstrate that the immunogenic potential of poorly immunogenic lymphoma cells dying after radiation therapy can be improved by modulation of the host immune system. PMID- 23339451 TI - Lexical and child-related factors in word variability and accuracy in infants. AB - The present study investigated the effects of lexical age of acquisition (AoA), phonological complexity, age and expressive vocabulary on spoken word variability and accuracy in typically developing infants, aged 1;9-3;1. It was hypothesized that later-acquired words and those with more complex speech sounds would be produced more variably and less accurately than earlier-acquired words and those with less complex speech sounds. It was also hypothesized that word variability would decrease and word accuracy would increase with increasing age and vocabulary knowledge. Participants' productions of 20 target words, experimentally controlled for AoA and phonological complexity, were audio recorded during a play session. Results revealed a nonsignificant effect of AoA on variability and accuracy, a significant effect of phonological complexity on variability and accuracy, a significant effect of age on variability and accuracy and a significant effect of vocabulary on variability. Theoretical and clinical implications are discussed. PMID- 23339453 TI - Organophophorous ester degradation by chromium(III) terephthalate metal-organic framework (MIL-101) chelated to N,N-dimethylaminopyridine and related aminopyridines. AB - Porous materials based on chromium(III) terephthalate metal organic frameworks (MOF) MIL-101(Cr) and their complexes with dialkylaminopyridines (DAAP) were synthesized via a DAAP-MOF complexation, and tested for hydrolytic degradation of organophosphorous esters such as diethyl 4-nitrophenyl phosphate (paraoxon). Elemental analysis, TGA, XRD, FT-IR, TEM, SEM, and nitrogen adsorption measurements indicated that the DAAP units were incorporated into MIL-101 pores by complexation, keeping the parent framework intact. The DAAP-MOF enabled facile paraoxon hydrolysis in water/acetonitrile mixtures under ambient conditions (100% conversion after 24 h at pH 10). The MOF-DAAP complexes showed synergistic effects, being 7-fold and 47-fold more active than the parent MIL-101 or DAAP materials, respectively. The high hydrolysis reaction turnover was realized by simultaneous action of the Lewis acid Cr(III) center of the MOF as well as the electron-rich nucleophile, DAAP. This study demonstrates a simple and efficient method of generating catalytically active MOF materials for environmental detoxification as well as defensive applications. PMID- 23339454 TI - Structural topology and activation of an initial adenylate kinase-substrate complex. AB - Enzymatic activity is ultimately defined by the structure, chemistry, and dynamics of the Michaelis complex. A large number of experimentally determined structures between enzymes and substrates, substrate analogues, or inhibitors exist. However, transient, short-lived encounter and equilibrium structures also play fundamental roles during enzymatic reaction cycles. Such structures are inherently difficult to study with conventional experimental techniques. The enzyme adenylate kinase undergoes major conformational rearrangements in response to binding of its substrates, ATP and AMP. ATP is sandwiched between two binding surfaces in the closed and active enzyme conformation. Thus, adenylate kinase harbors two spatially distant surfaces in the substrate free open conformation, of which one is responsible for the initial interaction with ATP. Here, we have performed primarily nuclear magnetic resonance experiments on Escherichia coli adenylate kinase (AK(eco)) variants that allowed identification of the site responsible for the initial ATP interaction. This allowed a characterization of the structural topology of an initial equilibrium complex between AK(eco) and ATP. On the basis of the results, we suggest that the ATP binding mechanism for AK(eco) is a mixture between "induced fit" and "conformational selection" models. It is shown that ATP is activated in the initial enzyme-bound complex because it displays an appreciable rate of nonproductive ATP hydrolysis. In summary, our results provide novel structural and functional insights into adenylate kinase catalysis. PMID- 23339452 TI - Redox regulation of thylakoid protein kinases and photosynthetic gene expression. AB - SIGNIFICANCE: Photosynthetic organisms are subjected to frequent changes in their environment that include fluctuations in light quality and quantity, temperature, CO(2) concentration, and nutrient availability. They have evolved complex responses to these changes that allow them to protect themselves against photo oxidative damage and to optimize their growth under these adverse conditions. In the case of light changes, these acclimatory processes can occur in either the short or the long term and are mainly mediated through the redox state of the plastoquinone pool and the ferredoxin/thioredoxin system. RECENT ADVANCES: Short term responses involve a dynamic reorganization of photosynthetic complexes, and long-term responses (LTRs) modulate the chloroplast and nuclear gene expression in such a way that the levels of the photosystems and their antennae are rebalanced for an optimal photosynthetic performance. These changes are mediated through a complex signaling network with several protein kinases and phosphatases that are conserved in land plants and algae. The phosphorylation status of the light-harvesting proteins of photosystem II and its core proteins is mainly determined by two complementary kinase-phosphatase pairs corresponding to STN7/PPH1 and STN8/PBCP, respectively. CRITICAL ISSUES: The activity of the Stt7 kinase is principally regulated by the redox state of the plastoquinone pool, which in turn depends on the light irradiance, ambient CO(2) concentration, and cellular energy status. In addition, this kinase is also involved in the LTR. FUTURE DIRECTIONS: Other chloroplast kinases modulate the activity of the plastid transcriptional machinery, but the global signaling network that connects all of the identified kinases and phosphatases is still largely unknown. PMID- 23339455 TI - ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours. AB - The PTF1 (pancreas transcription factor 1) complex is a master regulator of differentiation of acinar cells, responsible for the production of digestive enzymes. In the adult pancreas, PTF1 contains two pancreas-restricted transcription factors: Ptf1a and Rbpjl. PTF1 recruits P/CAF [p300/CREB (cAMP response-element-binding protein)-binding protein-associated factor] which acetylates Ptf1a and enhances its transcriptional activity. Using yeast two hybrid screening, we identified ICAT (inhibitor of beta-catenin and Tcf4) as a novel Ptf1a interactor. ICAT regulates the Wnt pathway and cell proliferation. We validated and mapped the ICAT-Ptf1a interaction in vitro and in vivo. We demonstrated that, following its overexpression in acinar tumour cells, ICAT regulates negatively PTF1 activity in vitro and in vivo. This effect was independent of beta-catenin and was mediated by direct binding to Ptf1a and displacement of P/CAF. ICAT also modulated the expression of Pdx1 and Sox9 in acinar tumour cells. ICAT overexpression reduced the interaction of Ptf1a with Rbpjl and P/CAF and impaired Ptf1a acetylation by P/CAF. ICAT did not affect the subcellular localization of Ptf1a. In human pancreas, ICAT displayed a cell-type specific distribution; in acinar and endocrine cells, it was nuclear, whereas in ductal cells, it was cytoplasmic. In ductal adenocarcinomas, ICAT displayed mainly a nuclear or mixed distribution and the former was an independent marker of survival. ICAT regulates acinar differentiation and it does so through a novel Wnt pathway-independent mechanism that may contribute to pancreatic disease. PMID- 23339457 TI - mGlu5 negative allosteric modulators: a patent review (2010-2012). AB - INTRODUCTION: The design and development of small molecule negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGlu5) has been an area of intense interest for over a decade. Potential roles have been established for mGlu5 NAMs in the treatment of diseases such as pain, anxiety, gastroesophageal reflux disease (GERD), Parkinson's disease levodopa-induced dyskinesia (PD-LID), fragile X syndrome (FXS), autism, addiction, and depression. AREAS COVERED: This review begins with an update of the clinical trial efforts with mGlu5 NAMs. Following that update, the review summarizes small molecule mGlu5 NAM patent applications published between 2010 and 2012. These summaries are subdivided into three separate groups: inventions related to improvements in drug properties and/or developability, new chemical entities that contain a disubstituted alkyne, and new chemical entities that do not contain a disubstituted alkyne. EXPERT OPINION: Given the abundant promise found within the mGlu5 NAM field, optimism remains that a drug will emerge from this therapeutic class. Still, the launch of a new drug is far from a certainty. It is encouraging to observe the ever-increasing chemical diversity among mGlu5 NAMs. Finally, in spite of the mature nature of this field, room remains for new advancements. PMID- 23339456 TI - Loss of alveolar membrane diffusing capacity and pulmonary capillary blood volume in pulmonary arterial hypertension. AB - BACKGROUND: Reduced gas transfer in patients with pulmonary arterial hypertension (PAH) is traditionally attributed to remodeling and progressive loss of pulmonary arterial vasculature that results in decreased capillary blood volume available for gas exchange. METHODS: We tested this hypothesis by determination of lung diffusing capacity (DL) and its components, the alveolar capillary membrane diffusing capacity (D(m)) and lung capillary blood volume (V(c)) in 28 individuals with PAH in comparison to 41 healthy individuals, and in 19 PAH patients over time. Using single breath simultaneous measure of diffusion of carbon monoxide (DL(CO)) and nitric oxide (DL(NO)), DL and D(m) were respectively determined, and V(c) calculated. D(m) and V(c) were evaluated over time in relation to standard clinical indicators of disease severity, including brain natriuretic peptide (BNP), 6-minute walk distance (6MWD) and right ventricular systolic pressure (RVSP) by echocardiography. RESULTS: Both DL(CO) and DL(NO) were reduced in PAH as compared to controls and the lower DL in PAH was due to loss of both D(m) and V(c) (all p < 0.01). While DL(CO) of PAH patients did not change over time, DL(NO) decreased by 24 ml/min/mmHg/year (p = 0.01). Consequently, D(m) decreased and V(c) tended to increase over time, which led to deterioration of the D(m)/V(c) ratio, a measure of alveolar-capillary membrane functional efficiency without changes in clinical markers. CONCLUSIONS: The findings indicate that lower than normal gas transfer in PAH is due to loss of both D(m) and V(c), but that deterioration of D(m)/V(c) over time is related to worsening membrane diffusion. PMID- 23339458 TI - Pre-transfusion compatibility guidelines: a new edition. PMID- 23339459 TI - Antenatal monitoring of anti-D and anti-c: could titre scores determined by column agglutination technology replace continuous flow analyser quantification? AB - OBJECTIVE: To determine if column agglutination technology (CAT) for titration of anti-D and anti-c concentrations produces comparable results to those obtained by continuous flow analyser (CFA). BACKGROUND: Anti-D and anti-c are the two commonest antibodies that contribute to serious haemolytic disease of the foetus and neonate (HDFN). Current practice in the UK is to monitor these antibodies by CFA quantification, which is considered more reproducible and less subjective than manual titration by tube IAT (indirect antiglobulin test). CAT is widely used in transfusion laboratory practice and provides a more objective endpoint than tube technique. MATERIALS AND METHODS: Antenatal samples were (i) quantified using CFA and (ii) titrated using CAT with the reaction strength recorded by a card reader and expressed as a titre score (TS). RESULTS: The TS rose in accordance with levels measured by quantification and was able to distinguish antibody levels above and below the threshold of clinical significance. CONCLUSION: CAT titre scores provided a simple and reproducible method to monitor anti-D and anti-c levels. The method was sensitive to a wide range of antibody levels as determined by quantification. This technique may have the potential to replace CFA quantification by identifying those cases that require closer monitoring for potential HDFN. PMID- 23339460 TI - Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease. AB - BACKGROUND: Galectin-9 (Gal-9) induces apoptosis in activated T helper 1 (TH1) cells as a ligand for T cell immunoglobulin mucin-3 (Tim-3). Gal-9 also inhibits the G1 phase cell cycle arrest and hypertrophy in db/db mice, the hallmark of early diabetic nephropathy, by reversing the high glucose-induced up-regulation of cyclin dependent kinase inhibitors such as p27(Kip1) and p21(Cip1). METHODS: We investigated the serum levels of Gal-9 in the patients with type 2 diabetes and various stages of chronic kidney disease (CKD) (n=182). RESULTS: Serum Gal-9 levels in the patients with type 2 diabetes were 131.9 +/- 105.4 pg/ml and Log(10)Gal-9 levels significantly and positively correlated with age (r=0.227, p=0.002), creatinine (r=0.175, p=0.018), urea nitrogen (r=0.162, p=0.028) and osmotic pressure (r=0.187, p=0.014) and negatively correlated with estimated glomerular filtration rate (eGFR) (r=-0.188, p=0.011). Log(10)Gal-9 levels increased along with the progression of GFR categories of G1 to G4, and they were statistically significant by Jonckheere-Terpstra test (p=0.012). Log(10)Gal-9 levels remained similar levels in albuminuria stages of A1 to A3. CONCLUSION: The elevation of serum Gal-9 in the patients with type 2 diabetes is closely linked to GFR and they may be related to the alteration of the immune response and inflammation of the patients with type 2 diabetes and CKD. PMID- 23339461 TI - Foodomics platform for the assay of thiols in wines with fluorescence derivatization and ultra performance liquid chromatography mass spectrometry using multivariate statistical analysis. AB - The presence of specific volatile and aminothiols in wine is associated with quality, worth, price, and taste. The identification of specific thiol-containing compounds in various wines has been reported in many valuable and interesting works. In this study, a novel foodomics assay of thiol-containing compounds, such as free aminothiols and related conjugates, was developed using ultra performance liquid chromatography (UPLC) with fluorescence (FL) and electrospray (ESI) time of-flight mass spectrometric (TOF/MS) detections. FL specific derivatization was applied along with multivariate statistical analysis. First, the optimal experimental conditions were studied using representative thiols, such as l cysteine, N-acetyl-l-cysteine, cysteamine, and l-glutathione, and then the UPLC FL derivatization and separation steps were fixed for the subsequent screening of unknown thiol-containing compounds. The screening assay consisted of monitoring the UPLC-TOF/MS peaks of unknown thiols, which decreased due to the derivatization as compared to the nonderivatized thiols. The principal component analysis of the UPLC-TOF/MS data could be well-differentiated and categorized into two groups. The orthogonal signal correction partial least-squares discriminant analysis, the so-called S-plot, showed that the quality differentiation is directly related to the decrease of native thiols and increase of derivatized thiols. With this strategy, the mass difference from the derivatization reagent (+m/z 198) could be utilized for the identification of these thiols using the FL peaks retention time and metabolomics-databases. The presence of l-glutathione in rice wine was for the first time reported on the basis of the available metabolomics-databases and standard matching. This novel concept based on foodomics could be applied in food analysis for the ready screening of specific functional compounds by exploiting the various derivatization modes available. PMID- 23339463 TI - High levels of mortality, malnutrition, and measles, among recently-displaced Somali refugees in Dagahaley camp, Dadaab refugee camp complex, Kenya, 2011. AB - BACKGROUND: Following a rapid influx of over 200,000 displaced Somalis into the Dadaab refugee camp complex in Kenya, Medecins Sans Frontieres conducted a mortality and nutrition survey of the population living in Bulo Bacte, a self settled area surrounding Dagahaley camp (part of this complex). METHODS: The survey was conducted between 31st July and 10th August 2011. We exhaustively interviewed representatives from all households in Bulo Bacte, collecting information on deaths, births, and population movements during the recall period (15th February 2011 to survey date), in order to provide estimates of retrospective death rates. We recorded the mid-upper arm circumference and presence or absence of bipedal oedema of all children of height 67-<110 cm to provide estimates of global and severe acute malnutrition. RESULTS: The surveyed population included 26,583 individuals, of whom 6,488 (24.4%) were children aged under 5 years. There were 360 deaths reported during the 177 days of the recall period, of which 186 (52%) were among children aged under 5 years. The crude death rate for the entire recall period was 0.8 per 10,000 person-days. The under 5 death rate was 1.8 per 10,000 person-days. More than two-thirds of all deaths were reported to have been associated with diarrhoea (25%), cough or other breathing difficulties (24%), or with fever (19%). Measles accounted for a reported 17% of all deaths; this was due to a measles outbreak that occurred between June and October 2011.Global acute malnutrition was observed in 13.4%, and severe acute malnutrition in 3.0%, of children measuring 67-<110 cm. Among children measuring 110-< 140 cm, 9.8% met the admission criteria for entry into the nutritional programme. Trends of decreasing death rates and malnutrition prevalence with length of stay in Bulo Bacte were observed. CONCLUSIONS: We report high death rates and prevalence of malnutrition among this population, reflecting at least a partial failure of the various humanitarian and governmental actors to adequately safeguard the welfare of this population. An outbreak of measles and long delays before registration should not have occurred. The recommendations for measles vaccination among crisis-affected populations should be revised to take into account the epidemiologic context. Organisations must be sensitive and reactive to changes in the health status of the populations they assist. PMID- 23339462 TI - MicroRNA paraffin-based studies in osteosarcoma reveal reproducible independent prognostic profiles at 14q32. AB - BACKGROUND: Although microRNAs (miRNAs) are implicated in osteosarcoma biology and chemoresponse, miRNA prognostic models are still needed, particularly because prognosis is imperfectly correlated with chemoresponse. Formalin-fixed, paraffin embedded tissue is a necessary resource for biomarker studies in this malignancy with limited frozen tissue availability. METHODS: We performed miRNA and mRNA microarray formalin-fixed, paraffin-embedded assays in 65 osteosarcoma biopsy and 26 paired post-chemotherapy resection specimens and used the only publicly available miRNA dataset, generated independently by another group, to externally validate our strongest findings (n = 29). We used supervised principal components analysis and logistic regression for survival and chemoresponse, and miRNA activity and target gene set analysis to study miRNA regulatory activity. RESULTS: Several miRNA-based models with as few as five miRNAs were prognostic independently of pathologically assessed chemoresponse (median recurrence-free survival: 59 months versus not-yet-reached; adjusted hazards ratio = 2.90; P = 0.036). The independent dataset supported the reproducibility of recurrence and survival findings. The prognostic value of the profile was independent of confounding by known prognostic variables, including chemoresponse, tumor location and metastasis at diagnosis. Model performance improved when chemoresponse was added as a covariate (median recurrence-free survival: 59 months versus not-yet-reached; hazard ratio = 3.91; P = 0.002). Most prognostic miRNAs were located at 14q32 - a locus already linked to osteosarcoma - and their gene targets display deregulation patterns associated with outcome. We also identified miRNA profiles predictive of chemoresponse (75% to 80% accuracy), which did not overlap with prognostic profiles. CONCLUSIONS: Formalin-fixed, paraffin-embedded tissue-derived miRNA patterns are a powerful prognostic tool for risk-stratified osteosarcoma management strategies. Combined miRNA and mRNA analysis supports a possible role of the 14q32 locus in osteosarcoma progression and outcome. Our study creates a paradigm for formalin-fixed, paraffin-embedded based miRNA biomarker studies in cancer. PMID- 23339464 TI - Prasugrel vs clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a model-based cost-effectiveness analysis for Germany, Sweden, the Netherlands, and Turkey. AB - OBJECTIVE: To evaluate the long-term cost-effectiveness of 12-months treatment with prasugrel vs clopidogrel from four European healthcare systems' perspectives (Germany, Sweden, the Netherlands, and Turkey). METHODS: In the TRITON-TIMI 38 trial, patients with an acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) were treated with prasugrel or clopidogrel. Prasugrel reduced the composite end-point (cardiovascular death, MI, or stroke), but increased TIMI major bleeding. A Markov model was constructed to facilitate a lifetime horizon for the analysis. A series of risk equations constructed using individual patient data from TRITON-TIMI 38 was used to estimate risks of clinical events. Quality-adjusted life-years (QALYs) were derived by weighting survival time by estimates of health-related quality-of-life. Incremental cost effectiveness is presented based on differences in treatments' mean costs and QALYs for the licensed population in TRITON-TIMI 38, and the sub-groups of UA NSTEMI, STEMI, diabetes, and the 'core clinical cohort' (<75 years, >=60 kg, no history of stroke or TIA). RESULTS: Mean cost of study drug was ?364 (Turkey) to ?818 (Germany) higher for prasugrel vs clopidogrel. Rehospitalization costs at 12 months were lower for prasugrel due to reduced rates of revascularization, although hospitalization costs beyond 12 months were higher due to longer life expectancy associated with lower rates of non-fatal MI in the prasugrel group. The incremental cost per QALY saved with prasugrel in the licensed population ranged from ?6520 (for Sweden) to ?14,350 for (Germany). Prasugrel's cost per QALY was more favourable still in the STEMI and diabetes sub-groups of the licensed population. LIMITATIONS: Probabilistic analyses of the whole trial population is impractical due to the number of individual patient profiles over which population level results are calculated. CONCLUSION: Among patients undergoing PCI for ACS, treatment with prasugrel compared with clopidogrel resulted in favourable cost-effectiveness profiles from these healthcare systems' perspectives. PMID- 23339465 TI - Healthcare resource utilization and economic impact of a >=2 g/dL decrease in hemoglobin in osteoarthritis patients. AB - OBJECTIVE: In non-steroidal anti-inflammatory drug (NSAID) users, chronic occult blood loss may lead to decreases in hemoglobin, which may lead to increased healthcare expenditures. This study, therefore, sought to quantify healthcare resource utilization of >=2 g/dL hemoglobin decrease in osteoarthritis patients. METHODS: Using a large US managed care database, osteoarthritis patients aged >=18 years who had exposure to >=90 days of non-selective or selective COX-2 NSAID use, a hemoglobin value within 6 months before index NSAID, and at least one hemoglobin value 24 months after were evaluated. Resource utilization was evaluated in those with >=2 g/dL hemoglobin drop vs patients with <=0.5 g/dL hemoglobin drop (control). RESULTS: Of 1800 NSAID users meeting inclusion criteria, 228 patients [mean (SD) = 59.8 (9.3) years] had >=2 g/dL hemoglobin drop vs 1572 controls [mean (SD) = 58.3 (8.0) years]. Despite relatively low absolute rates, endoscopic procedures were more commonly observed in the >=2 g/dL hemoglobin drop group [endoscopy: 37/228 (16.2%) vs 65/1572 (4.1%); adjusted odds ratio (AOR) 3.5, (95% confidence interval [CI] = 2.1-6.0); colonoscopy: 36/228 (15.8%) vs 137/1572 (8.7%); AOR 2.0 (95% CI 1.2-3.2)]. During the 12-month follow up, patients with >=2 g/dL hemoglobin drop utilized significantly more healthcare resources [adjusted relative risk (95% CI) for hospitalization, 2.1 (1.5-2.9); outpatient visits, 1.4 (1.3-1.5); physician visits, 1.3 (1.1-1.4)] and charges (total adjusted charges $47,766 vs $23,342) across major categories of healthcare services. LIMITATIONS: This was a retrospective analysis with baseline demographic differences. The source or cause of the hemoglobin drops could not be verified; and it is assumed that they are related to occult gastrointestinal loss. Differences with healthcare utilization and charges were not linked to hemoglobin-associated complications. CONCLUSION: In patients exposed to NSAIDs, those with significant hemoglobin drops experienced higher subsequent healthcare utilization and charges than controls who did not have a significant hemoglobin drop. PMID- 23339466 TI - Chromium(IV) siloxide. AB - The reaction of Na(OSi(t)Bu(2)Me) with CrCl(3) yields solid [Cr(OSi(t)Bu(2)Me)(3)](n) (1), which can be crystallized in the presence of excess Na(OSi(t)Bu(2)Me) to yield [Na(THF)][Cr(OSi(t)Bu(2)Me)(4)] (2). This complex is oxidized to yield Cr(OSi(t)Bu(2)Me)(4) (3), a crystalline chromium(IV) siloxide complex that is air- and moisture-stable. Electronic spectroscopic analysis of the absorption spectrum of 3 indicates a particularly weak ligand field (Delta(T) = 7940 cm(-1)) and covalent Cr-O bonding. 3 provides the first structural and spectroscopic characterization of a homoleptic chromium(IV) siloxide complex and provides a benchmark for tetrahedral chromium(IV) ions residing in solid oxide lattices. PMID- 23339467 TI - Relative timing of hydrogen and proton transfers in the reaction of flavin oxidation catalyzed by choline oxidase. AB - The oxidation of the reduced flavin in choline oxidase was investigated with pH, solvent viscosity, and kinetic isotope effects (KIEs) in steady-state kinetics and time-resolved absorbance spectroscopy of the oxidative half-reaction in a stopped-flow spectrophotometer. Both the effects of isotopic substitution on the KIEs and the multiple KIEs suggest a mechanism for flavin oxidation in which the H atom from the reduced flavin and a H(+) from the solvent or a solvent exchangeable site are transferred in the same kinetic step. Stopped-flow kinetic data demonstrate flavin oxidation without stabilization of flavin-derived species. Solvent viscosity effects establish an isomerization of the reduced enzyme. These results allow us to rule out mechanisms for flavin oxidation in which C4a-peroxy and -hydroperoxy flavin intermediates accumulate to detectable levels in the reaction of flavin oxidation catalyzed by choline oxidase. A mechanism of flavin oxidation that directly results in the formation of oxidized flavin and hydrogen peroxide without stabilization of reaction intermediates is consistent with the data presented. PMID- 23339469 TI - Polarization-sensitive linear plasmonic nanostructures via colloidal lithography with uniaxial colloidal arrays. AB - The ability of metallic nanostructures to support surface plasmon excitations is widely exploited nowadays for developing new technologies and applications in many fields, like communications, medicine or environment. It is known that the plasmonic response of a nanostructure is strongly dependent on its size and shape, and thus a fine control of these features is required for developing applications. In this paper uniaxial colloidal crystal arrays are prepared by convective self-assembly on DVD surfaces. These are then used as template/mask for metal film deposition, in order to obtain two original kinds of metallic nanostructures with controllable morphology: (i) linear arrays of metal half shells (LAMHSs) and (ii) arrays of periodically serrated plasmonic strips (PSPSs). Angle-resolved optical transmittance measurements reveal the presence of several surface plasmon resonances, while polarized light transmission demonstrates the anisotropic plasmonic response of both LAMHSs and PSPSs. FDTD simulations support the experimental observations and help in the assignments of observed plasmon modes. The proposed linear metallic nanostructures can prove useful for the design of plasmonic components. PMID- 23339468 TI - Cadmium induces neuronal cell death through reactive oxygen species activated by GADD153. AB - BACKGROUND: Cadmium(Cd), a heavy metal, which has a potent harmful effects, is a highly stress-inducible material that is robustly expressed following disruption of homeostasis in the endoplasmic reticulum (ER) (so-called ER stress). The mechanism Cd induced cell death of neuroblastoma cells complex, involving cellular signaling pathways as yet incompletely defined but, in part, involving the generation of reactive oxygen species (ROS). Several studies have correlated GADD153 expression with cell death, but a mechanistic link between GADD153 and apoptosis has never been demonstrated. RESULTS: SH-SY5Y cells were treated Cd led to increase in intracellular ROS levels. ROS generation is not consistent with intracellular [Ca2+]. The exposure of neuroblastoma cells to Cd led to increase in intracellular GADD153 and Bak levels in a doses and time dependent manner. The induction of these genes by Cd was attenuated by NAC. Cd-induced apoptosis is decreased in GADD153 knockdown cells compared with normal cells. The effect of GADD153 on the binding of C/EBP to the Bak promoters were analyzed ChIP assay. Basal constitutive GADD153 recruitment to the -3,398/-3,380 region of the Bak promoter is observed in SH-SY5Y cells. CONCLUSIONS: The exposure of SH-SY5Y cells to Cd led to increase in intracellular ROS levels in a doses and time dependent manner. The generation of ROS result in the induction of GADD153 is causative of cadmium-induced apoptosis. GADD153 regulates Bak expression by its binding to promoter region (between -3,398 and -3,380). Therefore, we conclude that GADD153 sensitizes cells to ROS through mechanisms that involve up-regulation of BAK and enhanced oxidant injury. PMID- 23339470 TI - Molecular dynamics of drug crystal dissolution: simulation of acetaminophen form I in water. AB - In order to gain molecular level understanding of drug dissolution into aqueous media, we report the first molecular dynamics (MD) simulation of a drug crystal dissolving. The simulation was performed for acetaminophen crystal Form I dissolving in 0.15 M aqueous NaCl solution at 37 degrees C. The 10 ns simulation revealed interesting details of the dissolution process. Dissolution of the molecules from the crystal surface is far from a random process. On the contrary, the order in which molecules enter the solution depends on their initial positions in or on the crystal. Molecules located on the corners and edges dissolved first followed by those located on {100}, {010}, and {001) surfaces with slight variation. This corner and edge effect that has been observed in our real dissolution experiment conducted under polarized light microscope was successfully predicted at molecular scale by the MD simulation. Further analyses identified the underlying mechanism: the differences in the molecular interaction energetics between the drug and water molecules. The molecules located on corners and edges of the parallelepiped crystal are not as tightly bound to their surrounding neighbors as those located in other positions, but they are more strongly interacting with the surrounding water molecules. The extent of molecular release is strongly correlated with the interplay between interaction forces with solvent molecules and with other drug molecules in the crystal lattice. These findings, especially the significant "corner and edge effect", will help us gain additional fundamental understanding in the relationship between dissolution rate and particle size and morphology and, thus, are very relevant in the context of particle size reduction in delivering poorly water soluble compounds. This study has also demonstrated that MD simulation is a powerful tool in studying dissolution phenomena. PMID- 23339472 TI - Foreword for EDICT special edition, volume 2. PMID- 23339471 TI - Enhanced 5-methylcytosine detection in single-molecule, real-time sequencing via Tet1 oxidation. AB - BACKGROUND: DNA methylation serves as an important epigenetic mark in both eukaryotic and prokaryotic organisms. In eukaryotes, the most common epigenetic mark is 5-methylcytosine, whereas prokaryotes can have 6-methyladenine, 4 methylcytosine, or 5-methylcytosine. Single-molecule, real-time sequencing is capable of directly detecting all three types of modified bases. However, the kinetic signature of 5-methylcytosine is subtle, which presents a challenge for detection. We investigated whether conversion of 5-methylcytosine to 5 carboxylcytosine using the enzyme Tet1 would enhance the kinetic signature, thereby improving detection. RESULTS: We characterized the kinetic signatures of various cytosine modifications, demonstrating that 5-carboxylcytosine has a larger impact on the local polymerase rate than 5-methylcytosine. Using Tet1 mediated conversion, we show improved detection of 5-methylcytosine using in vitro methylated templates and apply the method to the characterization of 5 methylcytosine sites in the genomes of Escherichia coli MG1655 and Bacillus halodurans C-125. CONCLUSIONS: We have developed a method for the enhancement of directly detecting 5-methylcytosine during single-molecule, real-time sequencing. Using Tet1 to convert 5-methylcytosine to 5-carboxylcytosine improves the detection rate of this important epigenetic marker, thereby complementing the set of readily detectable microbial base modifications, and enhancing the ability to interrogate eukaryotic epigenetic markers. PMID- 23339474 TI - Asphyxiation fatality exposure from chlorodifluoromethane. PMID- 23339473 TI - 20/(fasting C-peptide * fasting plasma glucose) is a simple and effective index of insulin resistance in patients with type 2 diabetes mellitus: a preliminary report. AB - BACKGROUND: We developed a simple and new insulin resistance index derived from a glucose clamp and a meal tolerance test (MTT) in Japanese patients with type 2 diabetes mellitus. METHODS: Fifteen patients [mean age: 53 years, fasting plasma glucose (FPG) 7.7 mmol/L, HbA1c 7.1% (54 mmol/mol), body mass index 26.8 kg/m(2)] underwent a MTT and a glucose clamp. Participants were given a test meal (450 kcal). Plasma glucose and insulin were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum C-peptide immunoreactivity (CPR) was measured at 0 (fasting; F CPR) and 120 min. Homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity indices (ISI) were calculated from the MTT results. The glucose infusion rate (GIR) was measured during hyperinsulinemic-euglycemic glucose clamps. RESULTS: The mean GIR in all patients was 5.8 mg.kg(-1).min(-1). The index 20/(F-CPR * FPG) was correlated strongly with GIR (r = 0.83, P < 0.0005). HOMA-IR (r = -0.74, P < 0.005) and ISI (r = 0.66, P < 0.01) were also correlated with GIR. In 10 patients with mild insulin resistance (GIR 5.0-10.0 mg.kg(-1).min(-1)), 20/(F-CPR * FPG) was very strongly correlated with GIR (r = 0.90, P < 0.0005), but not with HOMA-IR and ISI (r = -0.49, P = 0.15; r = 0.20, P = 0.56, respectively). In patients with mild insulin resistance, plasma adiponectin (r = 0.65, P < 0.05), but not BMI or waist circumstance, was correlated with GIR. CONCLUSIONS: 20/(F-CPR * FPG) is a simple and effective index of insulin resistance, and performs better than HOMA-IR and ISI in Japanese patients with type 2 diabetes mellitus. Our results suggest that 20/(F-CPR * FPG) is a more effective index than HOMA-IR in Japanese patients with mild insulin resistance. PMID- 23339475 TI - The DNA methylome as a biomarker for epigenetic instability and human aging. AB - Methylation of DNA is intimately involved in control of mammalian/vertebrate gene expression as part of a complex epigenetic regulatory system. We hypothesize that DNA methylation at cytosine-phosphate-guanine sites (CpGs), the "DNA methylome," evolved to increase stability of the differentiated state in somatic vertebrate cells, especially post-mitotic cells, which may have helped to increase longevity. Therefore, the DNA methylome may play a key role in human aging and be an ideal source of biomarkers aging. A new model that links the methylome to chronological age has been reported by Hannum et al.( 1 ) that accurately predicts age and rate of aging from the DNA methylation state of 71 markers in human blood samples. This model may make possible the development of new anti aging therapeutics as well as more accurately assess the impact of anti-aging regimens, such as caloric restriction and drugs such as rapamycin. Furthermore, the model reveals information loss with increased age consistent with noise/unstable diffentiation-based models of aging. The model may eventually lead to experiments to differentiate the contributions of biomolecular damage and noise/incomplete structural replication during aging. PMID- 23339476 TI - Hydrogen-free alkene reduction in continuous flow. AB - The first continuous hydrogenation that requires neither H(2) nor metal catalysis generates diimide by a novel reagent combination. The simple flow reactor employed minimizes residence time by enabling safe operation at elevated temperature. PMID- 23339477 TI - Accent identification by adults with aphasia. AB - The UK is a diverse society where individuals regularly interact with speakers with different accents. Whilst there is a growing body of research on the impact of speaker accent on comprehension in people with aphasia, there is none which explores their ability to identify accents. This study investigated the ability of this group to identify the geographical origins of a speaker. Age-matched participants with and without aphasia listened to 120 audio recordings of five speakers each of six accents, reading aloud four sentences each. Listeners were asked to make a forced-choice decision about the geographical origin of the speaker. Adults with aphasia were significantly less accurate than control participants at identifying accents but both groups made the same pattern of errors. Adults with aphasia who are able to identify a new speaker as being from a particular place may draw on this information to help them "tune in" to the accent. PMID- 23339478 TI - Ambulatory systolic-diastolic pressure regression index predicts acute coronary syndromes. AB - OBJECTIVES: Ambulatory systolic-diastolic pressure regression index (ASDPRI) is a composite marker of cardiovascular properties. The study was conducted to investigate the relationship between ASDPRI and cardiovascular events in patients with significant coronary atherosclerosis confirmed in angiography. METHODS: Associations between ASDPRI and cardiovascular events were examined in 891 subjects referred for diagnostic coronary angiography. ASDPRI was calculated as 1 minus the slope of the linear relation between 24-h DBP and 24-h SBP. RESULTS: During follow-up (median 6.7 years), 135 acute coronary syndromes (ACS), including five deaths and 55 strokes occurred in the studied group. There was a higher 24-h ASDPRI in patients with ACS than in patients with no ACS (0.35 +/- 01 vs 0.30 +/- 0.1, p < 0.01); 24-h ASDPRI was the independent predictor for ACS (OR = 4.0; 95% CI 1.3-12.0). CONCLUSIONS: ASDPRI has an important role as a risk factor of ACS in patients with coronary atherosclerosis. PMID- 23339479 TI - Structural equation modeling of factors contributing to quality of life in Japanese patients with multiple sclerosis. AB - BACKGROUND: To improve quality of life (QOL) in patients with multiple sclerosis (MS), it is important to decrease disability and prevent relapse. The aim of this study was to examine the causal and mutual relationships contributing to QOL in Japanese patients with MS, develop path diagrams, and explore interventions with the potential to improve patient QOL. METHODS: Data of 163 Japanese MS patients were obtained using the Functional Assessment of MS (FAMS) and Nottingham Adjustment Scale-Japanese version (NAS-J) tests, as well as four additional factors that affect QOL (employment status, change of income, availability of disease information, and communication with medical staff). Data were then used in structural equation modeling to develop path diagrams for factors contributing to QOL. RESULTS: The Expanded Disability Status Scale (EDSS) score had a significant effect on the total FAMS score. Although EDSS negatively affected the FAMS symptom score, NAS-J subscale scores of anxiety/depression and acceptance were positively related to the FAMS symptom score. Changes in employment status after MS onset negatively affected all NAS-J scores. Knowledge of disease information improved the total NAS-J score, which in turn improved many FAMS subscale scores. Communication with doctors and nurses directly and positively affected some FAMS subscale scores. CONCLUSIONS: Disability and change in employment status decrease patient QOL. However, the present findings suggest that other factors, such as acquiring information on MS and communicating with medical staff, can compensate for the worsening of QOL. PMID- 23339480 TI - Dendrimer and cancer: a patent review (2006-present). AB - INTRODUCTION: Dendrimers were widely used in cancer diagnosis and therapy during the past decade. The surface functionalities allow bioactive molecules such as imaging probes, therapeutic compounds, targeting ligands to be present on dendrimer surface in a multivalent fashion. In addition, the interior pockets as well as the charged surface of dendrimer can be encapsulated/bound with anti cancer drugs or therapeutic DNAs/siRNAs. AREAS COVERED: The combination of dendrimer chemistry and new cancer therapy techniques such as radiotherapy, photodynamic therapy, neuron capture therapy, and photothermal therapy provides promising strategies in future cancer therapy. Here, we focused on recent advances on this topic in the patents (2006 - present) and discussed the advantages of dendrimer technology in these inventions. EXPERT OPINION: The challenges and perspectives of dendrimer-based theranostics for cancer diagnosis and therapy are discussed. Future efforts in this area should be focused on designing materials to solve problems such as cancer metastasis, multidrug resistance (MDR) in cancer cells, and early-stage cancer diagnosis. PMID- 23339481 TI - Fungicides and the effects of mycotoxins on milling fractions of irrigated rice. AB - This study aimed to evaluate the effect of fungicides on rice cultivation, regarding the occurrence and the distribution of mycotoxins in fractions of the processed grain, by a validated chromatographic method. A method based on extraction with acetonitrile:water, determination by HPLC-DAD, and confirmation by LC-MS was validated before the mycotoxin evaluation. Control samples and samples to which triazole fungicides had been applied were collected from experimental fields for four years. Results showed that 87% of the samples were contaminated with deoxynivalenol or zearalenone, and that all samples treated with fungicide were contaminated with some of these mycotoxins. Aflatoxin B(1) and ochratoxin A were found in 37% of the samples; half of them had been treated with fungicide. Therefore, fungicides tend to be stressors for toxigenic fungi found in the fields. PMID- 23339482 TI - Mortality from the influenza pandemic of 1918-19 in Indonesia. AB - The influenza pandemic of 1918-19 was the single most lethal short-term epidemic of the twentieth century. For Indonesia, the world's fourth most populous country, the most widely used estimate of mortality from that pandemic is 1.5 million. We estimated mortality from the influenza pandemic in Java and Madura, home to the majority of Indonesia's population, using panel data methods and data from multiple quinquennial population counts and two decennial censuses. The new estimates suggest that, for Java alone, population loss was in the range of 4.26 4.37 million, or more than twice the established estimate for mortality for all of Indonesia. We conclude that the standing estimates of mortality from influenza in Java and Indonesia need to be revised upward significantly. We also present new findings on geographic patterns of population loss across Java, and pre pandemic and post-pandemic population growth rates. PMID- 23339483 TI - Mechanisms for the reactions of group 10 transition metal complexes with metal group 14 element bonds, Bbt(Br)E?M(PCy3)2 (E = C, Si, Ge, Sn, Pb; M = Pd and Pt). AB - The electronic structures of the Bbt(Br)E?M(PCy(3))(2) (E = C, Si, Ge, Sn, Pb and M = Pt, Pd) complexes and their potential energy surfaces for the formation and water addition reactions were studied using density functional theory (B3LYP/LANL2DZ). The theoretical evidence suggests that the bonding character of the E?M double bond between the six valence-electron Bbt(Br)E: species and the 14 valence-electron (PCy(3))(2)M complexes has a predominantly high s-character. That is, on the basis of the NBO, this theoretical study indicates that the sigma donation from the E element to the M atom prevails. Also, theoretical computations suggest that the relative reactivity decreases in the order: Bbt(Br)C?M(PCy(3))(2) > Bbt(Br)Si?M(PCy(3))(2) > Bbt(Br)Ge?M(PCy(3))(2) > Bbt(Br)Sn?M(PCy(3))(2) > Bbt(Br)Pb?M(PCy(3))(2), irrespective of whether M = Pt or M = Pd is chosen. Namely, the greater the atomic weight of the group 14 atom (E), the larger is the atomic radius of E and the more stable is its Bbt(Br)E?M(PCy(3))(2) doubly bonded species toward chemical reactions. The computational results show good agreement with the available experimental observations. The theoretical results obtained in this work allow a number of predictions to be made. PMID- 23339485 TI - Women in the limelight: a varied issue. PMID- 23339484 TI - Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP). AB - The hepatic bile acid uptake transporter sodium taurocholate cotransporting polypeptide (NTCP) is less well characterized than its ileal paralog, the apical sodium dependent bile acid transporter (ASBT), in terms of drug inhibition requirements. The objectives of this study were (a) to identify FDA approved drugs that inhibit human NTCP, (b) to develop pharmacophore and Bayesian computational models for NTCP inhibition, and (c) to compare NTCP and ASBT transport inhibition requirements. A series of NTCP inhibition studies were performed using FDA approved drugs, in concert with iterative computational model development. Screening studies identified 27 drugs as novel NTCP inhibitors, including irbesartan (Ki = 11.9 MUM) and ezetimibe (Ki = 25.0 MUM). The common feature pharmacophore indicated that two hydrophobes and one hydrogen bond acceptor were important for inhibition of NTCP. From 72 drugs screened in vitro, a total of 31 drugs inhibited NTCP, while 51 drugs (i.e., more than half) inhibited ASBT. Hence, while there was inhibitor overlap, ASBT unexpectedly was more permissive to drug inhibition than was NTCP, and this may be related to NTCP possessing fewer pharmacophore features. Findings reflected that a combination of computational and in vitro approaches enriched the understanding of these poorly characterized transporters and yielded additional chemical probes for possible drug-transporter interaction determinations. PMID- 23339486 TI - Using a model filamentous fungus to unravel mechanisms of lignocellulose deconstruction. AB - Filamentous fungi are the main source of enzymes used to degrade lignocellulose to fermentable sugars for the production of biofuels. While the most commonly used organism for the production of cellulases in an industrial setting is Trichoderma reesei (Hypocrea jecorina), recent work in the model filamentous fungus Neurospora crassa has shown that the variety of molecular, genetic and biochemical techniques developed for this organism can expedite analyses of the complexities involved in the utilization of lignocellulose as a source of carbon. These include elucidating regulatory networks associated with plant cell wall deconstruction, the identification of signaling molecules necessary for induction of the expression of genes encoding lignocellulolytic enzymes and the characterization of new cellulolytic enzymatic activities. In particular, the availability of a full genome deletion strain set for N. crassa has expedited high throughput screening for mutants that display a cellulolytic phenotype. This review summarizes the key findings of several recent studies using N. crassa to further understanding the mechanisms of plant cell wall deconstruction by filamentous fungi. PMID- 23339487 TI - Engineering a cyanobacterium as the catalyst for the photosynthetic conversion of CO2 to 1,2-propanediol. AB - BACKGROUND: The modern society primarily relies on petroleum and natural gas for the production of fuels and chemicals. One of the major commodity chemicals 1,2 propanediol (1,2-PDO), which has an annual production of more than 0.5 million tons in the United States, is currently produced by chemical processes from petroleum derived propylene oxide, which is energy intensive and not sustainable. In this study, we sought to achieve photosynthetic production of 1,2-PDO from CO2 using a genetically engineered cyanobacterium Synechococcus elongatus PCC 7942. Compared to the previously reported biological 1,2-PDO production processes which used sugar or glycerol as the substrates, direct chemical production from CO2 in photosynthetic organisms recycles the atmospheric CO2 and will not compete with food crops for arable land. RESULTS: In this study, we reported photosynthetic production of 1,2-PDO from CO2 using a genetically engineered cyanobacterium Synechococcus elongatus PCC 7942. Introduction of the genes encoding methylglyoxal synthase (mgsA), glycerol dehydrogenase (gldA), and aldehyde reductase (yqhD) resulted in the production of ~22 mg/L 1,2-PDO from CO2. However, a comparable amount of the pathway intermediate acetol was also produced, especially during the stationary phase. The production of 1,2-PDO requires a robust input of reducing equivalents from cellular metabolism. To take advantage of cyanobacteria's NADPH pool, the synthetic pathway of 1,2-PDO was engineered to be NADPH-dependent by exploiting the NADPH-specific secondary alcohol dehydrogenases which have not been reported for 1,2-PDO production previously. This optimization strategy resulted in the production of ~150 mg/L 1,2-PDO and minimized the accumulation of the incomplete reduction product, acetol. CONCLUSION: This work demonstrated that cyanobacteria can be engineered as a catalyst for the photosynthetic conversion of CO2 to 1,2-PDO. This work also characterized two NADPH-dependent sADHs for their catalytic capacity in 1,2-PDO formation, and suggested that they may be useful tools for renewable production of reduced chemicals in photosynthetic organisms. PMID- 23339488 TI - Physiological implications of arteriovenous anastomoses and venous hemodynamic dysfunction in early gestational uterine circulation: a review. AB - This review summarizes current information on anatomical and physiological properties of the early gestational uteroplacental circulation, and implications of normal or abnormal functioning of the venous compartment. It is illustrated that these properties serve intra-uterine redistribution of blood flow, which is a crucial activity during different stages of trophoblastic remodelling of spiral arteries. Maintaining conditions of pressure and flow constant in the developing intervillous space is important towards normal functioning of the placenta in advanced pregnancy. Failure of this process predisposes to damage of trophoblastic villi, which is commonly seen in preeclampsia and/or fetal growth restriction. Basic principles of vascular physiology allow linking venous hemodynamic dysfunction to increased intervillous pressure. From this, it is concluded that current methods to explore the uteroplacental circulation in normal pregnancy and preeclampsia should be expanded with integrative methods focussing on each site of the microvascular network, the arterial and the venous compartment. PMID- 23339489 TI - The association of apathy with central fatigue perception in patients with Parkinson's disease. AB - This study was designed to evaluate the association of different apathy conceptual domains with central fatigue perception in Parkinson's disease (PD), taking into consideration other nonmotor symptoms. To this end, 90 consecutive PD patients (66.7% men, mean age 61.44 +/- 13.2 years) underwent a comprehensive neurological and psychiatric examination, including the Structured Clinical Interview for DSM-IV, Parkinson Fatigue Scale, Lille Apathy Rating Scale, Hamilton Depression Scale, and State-Trait Anxiety Inventory. A linear regression model was applied to analyze the relationship between apathy and its different conceptual domains with fatigue severity. Thirty-seven (41.1%) patients presented fatigue. Its presence was associated with higher apathy total scores and with 2 of the 4 apathy conceptual domains (less intellectual curiosity and action initiation) with no associations in the emotion and self-awareness apathy domains. Patients with fatigue scored higher in depression (p < .001), anxiety trait (p < .001), and anxiety state (p = .006). Regression analysis identified that Lille Apathy Rating Scale total score (p = .008), intellectual curiosity and action initiation apathy subscores (p = .001 and p = .003) were associated with fatigue severity in patients with right predominant motor symptoms. Sex, age, disease duration, clinical stage, motor complications, prior psychiatric disorders, and treatment were not significantly associated with presence of fatigue. The findings suggest that some apathy-related domains are more frequent in fatigued PD and may be related with fatigue severity. PMID- 23339490 TI - Promoting excellence--evidence-based practice at the bedside and beyond. PMID- 23339491 TI - Evidence-based practice: collaboration between education and nursing management. AB - AIM: To examine practicing nurses' attitudes and knowledge of evidence-based practice. BACKGROUND: Health care providers acknowledge that health care decisions should be grounded in current evidence. Limited evidence documents practicing nurses' attitudes and knowledge regarding evidence-based practice. METHODS: A descriptive survey was administered to 286 practicing nurses. Demographics of educational preparation, area of practice, years in practice, age and gender were collected. RESULTS: The largest number of respondents held an associate degree (30.6%) or baccalaureate degree (29.5%). Thirty-seven per cent reported over 15 years experience in nursing. Forty-three percent reported 61 100% of their practice was evidence based. Fifty percent reported an ability to determine the validity of evidence, and 58% rated an ability to apply findings to individual cases positively. Administrative support of evidence-based practice was reported by only 5.5%. CONCLUSIONS: Nurses voiced agreement that their practice was evidence-based; however, they reported only an average ability to retrieve or critically analyse evidence. IMPLICATIONS FOR NURSING MANAGEMENT: The findings support the need for an educational intervention for practicing nurses regarding evidence-based practice. Role modelling and collaboration of nurse managers and educators will promote transition of evidence into clinical practice. PMID- 23339492 TI - Nurse manager cognitive decision-making amidst stress and work complexity. AB - AIM: The present study provides insight into nurse manager cognitive decision making amidst stress and work complexity. BACKGROUND: Little is known about nurse manager decision-making amidst stress and work complexity. Because nurse manager decisions have the potential to impact patient care quality and safety, understanding their decision-making processes is useful for designing supportive interventions. METHODS: This qualitative descriptive study interviewed 21 nurse managers from three hospitals to answer the research question: What decision making processes do nurse managers utilize to address stressful situations in their nurse manager role? Face-to-face interviews incorporating components of the Critical Decision Method illuminated expert-novice practice differences. Content analysis identified one major theme and three sub-themes. RESULTS: The present study produced a cognitive model that guides nurse manager decision-making related to stressful situations. Experience in the role, organizational context and situation factors influenced nurse manager cognitive decision-making processes. CONCLUSIONS: Study findings suggest that chronic exposure to stress and work complexity negatively affects nurse manager health and their decision making processes potentially threatening individual, patient and organizational outcomes. IMPLICATIONS FOR NURSING MANAGEMENT: Cognitive decision-making varies based on nurse manager experience and these differences have coaching and mentoring implications. This present study contributes a current understanding of nurse manager decision-making amidst stress and work complexity. PMID- 23339493 TI - Investigating factors that have an impact on nurses' performance of patients' conscious level assessment: a systematic review. AB - AIM: To identify factors that have an impact on nurses' performance of patients' conscious level assessment. BACKGROUND: There is a need for nurses to accurately assess a patient's conscious level to detect neurological changes and initiate prompt action. METHODS: Nine databases were systematically searched (1990-February 2010) to review experimental, cohort, case control, cross sectional and descriptive studies that addressed factors which affected nurses' performance of patient conscious level assessment. Participants in the studies reviewed were nursing staff. The Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument was used for quality assessment. RESULTS: Eleven studies were analysed in this review. Knowledge and experience were found to be the most significant factors in determining nurses' performance of patient conscious level assessment. Formal training was found to be effective in improving assessment skills and experience greatly affected the accuracy of assessment. CONCLUSION: Knowledge and experience are the most significant factors on nurses' performance of consciousness level assessment. Implications for nursing management Formal training is needed on a continual basis to maintain skills in consciousness level assessment, and nurses who are more experienced in the use of assessment should mentor those that are less experienced. PMID- 23339494 TI - End-of-life care pathways and nursing: a literature review. AB - AIM: To identify and discuss the current state of knowledge about end-of-life care (EOLC) pathways in relation to nursing. BACKGROUND: Enhancing EOLC has become a central concern in governments' health policies worldwide. End-of-life care pathways have been championed as complex interventions to enhance the quality of end-of-life care. However, concerns have been expressed regarding their purpose, initiation and use. EVALUATION: A range of published literature was used to examine EOLC pathways in relation to nursing. KEY ISSUES: Three main themes emerged: nursing's contribution to the evolution of EOLC pathways, implementing EOLC pathways and the influence of EOLC pathways on nursing practice. CONCLUSIONS: End-of-life care pathways are to be welcomed as a means by which the quality of EOLC might be enhanced. However, the state of knowledge about EOLC pathways, their development, implementation and influence on families and professional practice is in its infancy. IMPLICATIONS FOR NURSING MANAGEMENT: End-of-life care pathways are championed as a means by which the quality of EOLC, for dying people and their families might be enhanced. However, as concerns regarding the quality of EOLC persist, nursing management has a crucial role in driving forward and supporting EOLC pathway development, implementation and evaluation. PMID- 23339495 TI - Determinants of postpartum physical activity, dietary habits and weight loss after gestational diabetes mellitus. AB - AIM: To describe the most significant findings of the studies that examined the prevalence and determinants of postpartum health behaviours (physical activity, dietary habits and/or weight loss) in patients with gestational diabetes mellitus (GDM). BACKGROUND: Patients with gestational diabetes have a high risk of developing type 2 diabetes in the months after delivery. For this reason, GDM patients are encouraged to practice specific health behaviours during the postpartum period. It is important to identify the factors that may impact the adherence to these behaviours. EVALUATION: Eighteen published research articles that examined postpartum health behaviours and/or their potential determinants in women diagnosed with GDM were selected from electronic databases. KEY ISSUES: Physical activity and diet rarely meet the recommendations. Risk perception, health beliefs, social support and self-efficacy are the main factors identified as having an impact on the adoption of health behaviours. However, the cross sectional nature of the studies and the lack of social, geographical and/or ethnic variety in the populations studied do not allow us to generalize the conclusions. IMPLICATIONS FOR NURSING MANAGEMENT: This literature review reports all the information currently available that can enable nurses and midwives to engage in the evaluation and optimization of their interventions in GDM patients. Motivational interventions based on Social Cognitive Theory are proposed. PMID- 23339496 TI - Applying the plan-do-study-act model to increase the use of kangaroo care. AB - AIM: To increase the rate of participation in kangaroo care within a level III neonatal intensive care unit. BACKGROUND: Preterm birth typically results in initial separation of mother and infant which may disrupt the bonding process. Nurses within the neonatal intensive care unit can introduce strategies that will assist parents in overcoming fears and developing relationships with their infants. Kangaroo care is a method of skin-to-skin holding that has been shown to enhance the mother-infant relationship while also improving infant outcomes. However, kangaroo care has been used inconsistently within neonatal intensive care unit settings. METHODS: The Plan-Do-Study-Act Model was used as a framework for this project. Plan-Do-Study-Act Model uses four cyclical steps for continuous quality improvement. Based upon Plan-Do-Study-Act Model, education was planned, surveys were developed and strategies implemented to overcome barriers. RESULTS: Four months post-implementation, the use of kangaroo care increased by 31%. CONCLUSIONS: Staff surveys demonstrated a decrease in the perceived barriers to kangaroo care as well as an increase in kangaroo care. Application of Plan-Do Study-Act Model was successful in meeting the goal of increasing the use of kangaroo care. IMPLICATIONS FOR NURSING MANAGEMENT: The use of the Plan-Do-Study Act Model framework encourages learning, reflection and validation throughout implementation. Plan-Do-Study-Act Model is a strategy that can promote the effective use of innovative practices in nursing. PMID- 23339497 TI - The person-centred care of older people with cognitive impairment in acute care scale (POPAC). AB - AIM: To construct and evaluate psychometric properties of the person-centred care of older people with cognitive impairment in acute care settings (POPAC) scale. BACKGROUND: Older people with cognitive impairment are admitted frequently to acute care, with needs not always met through standard practice. Best practice models have been suggested, but few assessment scales exist. METHODS: Psychometric evaluation using statistical estimates of validity and reliability based on an Australian sample of acute care nursing staff (n = 212). RESULTS: The final 15-item questionnaire consists of three subscales, 'using cognitive assessments and care interventions', 'using evidence and cognitive expertise' and 'individualizing care'. Estimates of validity and reliability were highly satisfactory. CONCLUSION: The POPAC scale makes a valuable contribution by providing valid and reliable measures of the extent to which acute nursing staff report using best practice care processes to identify and consider cognitive impairment and to employ nursing interventions to meet the needs associated with old age and cognitive impairment. IMPLICATIONS FOR NURSING MANAGEMENT: The POPAC scale is short, easy to administer and not time consuming to complete, but still provides clinically relevant information. It can be used as a conceptual fundament in developing best practice nursing care in the acute clinical setting, as well as for nursing research. PMID- 23339498 TI - Perceptions of nursing care quality, in acute hospital settings measured by the Karen instruments. AB - AIMS: The objectives of this study were to measure the quality of nursing care from the perspectives of patients and personnel and to compare these perspectives. BACKGROUND: The perception of quality in nursing care is affected by patient needs and it is common that patients and personnel disagree on the nature of the quality. Thus, it is important to measure the quality from both perspectives. METHOD: A total of 95 patients and 120 personnel from surgical and medical wards at a hospital in Sweden participated. The Karen instruments were used for data collection. A scale index was used for comparison of the perspectives. RESULTS: The patients and personnel were satisfied with the quality of care and there were no obvious differences in the total index. The different subscales indicated areas of lower care quality in need of improvement. CONCLUSION: The quality of the care seemed to be satisfactory from the perspectives of both the patients and the personal. Further analysis from the subscale or a variable level is needed to define areas of lower care quality. IMPLICATIONS FOR NURSING MANAGEMENT: Measurements have to be carried out continuously to guarantee care quality over time, as a result of organisational changes and financial cutbacks. PMID- 23339499 TI - Assessment of the elderly: it's worth covering the risks. AB - BACKGROUND: Comprehensive assessments provide an invaluable opportunity to identify those at risk of adverse health events, enabling timely access to appropriate health care. AIMS: This study aimed to evaluate the effectiveness of a comprehensive assessment tool, the Adult Patient Assessment Tool (APAT), particularly in relation to early identification of older people at risk of falls, pressure areas, cognitive impairment or delirium, or patients with mental illness or substance abuse. METHODS: Concurrent mixed methods including an initial retrospective medical record audit and focus groups were used. RESULTS: With the introduction of the APAT, assessment of falls risk and mental illness increased. The number of nursing actions relating to pressure areas and falls also increased, indicating a greater awareness of patients' individual needs. Non clinical information gathered through the APAT enabled a more holistic approach to patient care. CONCLUSION: The use of electronic medical records would alleviate pressures on nurses' time, providing an opportunity to store and retrieve comprehensive nursing assessment and benefit patient health care. IMPLICATIONS FOR NURSING MANAGEMENT: Early assessment results in an increased number of nursing activities related to patient care. Further education relating to mental health and substance abuse screening and cognitive assessment may enhance the completion of these tools. PMID- 23339500 TI - Improving patient safety using the sterile cockpit principle during medication administration: a collaborative, unit-based project. AB - AIM: To implement the sterile cockpit principle to decrease interruptions and distractions during high volume medication administration and reduce the number of medication errors. BACKGROUND: While some studies have described the importance of reducing interruptions as a tactic to reduce medication errors, work is needed to assess the impact on patient outcomes. METHODS: Data regarding the type and frequency of distractions were collected during the first 11 weeks of implementation. Medication error rates were tracked 1 year before and after 1 year implementation. RESULTS: Simple regression analysis showed a decrease in the mean number of distractions, (beta = -0.193, P = 0.02) over time. The medication error rate decreased by 42.78% (P = 0.04) after implementation of the sterile cockpit principle. CONCLUSIONS: The use of crew resource management techniques, including the sterile cockpit principle, applied to medication administration has a significant impact on patient safety. IMPLICATIONS FOR NURSING MANAGEMENT: Applying the sterile cockpit principle to inpatient medical units is a feasible approach to reduce the number of distractions during the administration of medication, thus, reducing the likelihood of medication error. 'Do Not Disturb' signs and vests are inexpensive, simple interventions that can be used as reminders to decrease distractions. PMID- 23339501 TI - Health-care professionals' documentation of wellbeing in patients following open heart surgery: a content analysis of medical records. AB - AIM: To explore health-care professionals' documentation of patient wellbeing in the first five months after open heart surgery. BACKGROUND: Open heart surgery (coronary artery bypass grafting or heart valve replacement) is an intervention aimed at relief of symptoms and increased wellbeing. It is a complex procedure with deep experiences encompassing physiological, psychological and social aspects. Health-care professionals' documentation of expressions of decreased wellbeing related to open heart surgery is an important basis for decisions and for the understanding of patients' overall health situation. METHOD: Eighty medical records were examined by means of qualitative and quantitative methods in order to explore documentation of patient wellbeing at four points in time. The analysis was performed by content analysis and descriptive statistics. RESULTS: Documentation of physical wellbeing was dominant on all occasions, while psychological wellbeing was moderately well documented and social aspects of wellbeing were rarely documented. CONCLUSION: The medical records did not adequately reflect the complexity of undergoing open heart surgery. Hence the holistic approach was not confirmed in health-care professionals' documentation. IMPLICATIONS FOR NURSING MANAGEMENT: Managers need to support and work for a patient-centred approach in cardiac care, resulting in patient documentation that reflects patient wellbeing as a whole. PMID- 23339502 TI - Nurses discuss bedside handover and using written handover sheets. AB - BACKGROUND: The analysis of nursing errors in clinical management highlighted that clinical handover plays a pivotal role in patient safety. Changes to handover including conducting handover at the bedside and the use of written handover summary sheets were subsequently implemented. AIM: The aim of the study was to explore nurses' perspectives on the introduction of bedside handover and the use of written handover sheets. METHOD: Using a qualitative approach, data were obtained from six focus groups containing 30 registered and enrolled (licensed practical) nurses. Thematic analysis revealed several major themes. FINDINGS: Themes identified included: bedside handover and the strengths and weaknesses; patient involvement in handover, and good communication is about good communicators. Finally, three sources of patient information and other issues were also identified as key aspects. CONCLUSIONS: How bedside handover is delivered should be considered in relation to specific patient caseloads (patients with cognitive impairments), the shift (day, evening or night shift) and the model of service delivery (team versus patient allocation). IMPLICATIONS FOR NURSING MANAGEMENT: Flexible handover methods are implicit within clinical setting issues especially in consideration to nursing teamwork. Good communication processes continue to be fundamental for successful handover processes. PMID- 23339503 TI - The influence of the learning climate on learning outcomes from Marte Meo counselling in dementia care. AB - AIM: To identify factors that affected the learning outcomes from Marte Meo counselling (MMC). BACKGROUND: Although MMC has shown promising results regarding learning outcomes for staff working in dementia-specific care units, the outcomes differ. METHOD: Twelve individual interviews and four focus group interviews with staff who had participated in MMC were analysed through a qualitative content analysis. RESULTS: The learning climate has considerable significance for the experienced benefit of MMC and indicate that this learning climate depends on three conditions: establishing a common understanding of the content and form of MMC, ensuring staff's willingness to participate and the opportunity to do so, and securing an arena in the unit for discussion and interactions. CONCLUSION: Learning outcomes from MMC in dementia-specific care units appear to depend on the learning climate in the unit. Implication for nursing management The learning climate needs attention from the nursing management when establishing Marte Meo intervention in nursing homes. The learning climate can be facilitated through building common understandings in the units regarding why and how this intervention should take place, and by ensuring clarity in the relationship between the intervention and the organization's objectives. PMID- 23339504 TI - How is nursing care for stroke patients organised? Nurses' views on best practices. AB - AIM: To describe staff nurses' and charge nurses' perceptions of how to organise stroke care. BACKGROUND: Many elements are important for high quality care and stroke patients' ability to regain pre-stroke capacities. Among them is how nursing care is organised. Research on the organisation of nursing care in stroke units is sparse. METHOD: A qualitative descriptive study was conducted in four inpatient stroke units in Denmark using semi-structured interviews with charge nurses and focus groups with staff nurses. Data were analysed using conventional content analysis. Data from the two groups were analysed 8 months apart. RESULTS: Five themes emerged: nursing staff competencies focused on high quality care (29%); focus on organising continuity of care (26%); strong culture of collaboration no matter the work environment (19%); staff committed to their patients (13%); continuity of care maintained during hospital discharge transitions (13%). CONCLUSION: Organisation of care to maintain continuity is important for high quality care and includes assigning patients permanent designated nurses who are responsible for interdisciplinary care coordination. Other important elements include nurses' competencies, collaboration, commitment and resources. IMPLICATIONS FOR NURSING MANAGEMENT: To improve quality care, the nurse managers should implement processes that strengthen continuity across the care spectrum and among all disciplines. PMID- 23339505 TI - How magnetic are Finnish hospitals measured by transformational leadership and empirical quality outcomes? AB - AIM: The overall aim of this study was to examine nurses' and patients' perceptions of the Magnet model components of transformational leadership and empirical quality outcomes in four Finnish hospitals and to determine if the evidence for transformational leadership and empirical quality outcomes is the same or different in the four hospitals. BACKGROUND: This report presents baseline measurements for a longitudinal study of the adaptation of the Magnet model in Finnish hospitals. METHODS: Web-based surveys and mailed questionnaires were used in 2008-2009 to collect data from patients (n = 2566) about their satisfaction with care, and from nursing staff about transformational leadership (n = 1151), job satisfaction (n = 2707) and patient safety culture (n = 925) in the selected hospitals. RESULTS: Awareness of the work of nursing leaders was low. Nurses reported a high level of job satisfaction. Patient safety culture varied considerably between the four hospitals. Patients believed they generally received excellent quality care. CONCLUSIONS: Leadership systems are in transition at the hospitals. Patient safety culture is a complex phenomenon that may be unfamiliar to respondents. The results of the study provide a baseline description to guide the journey toward development of Magnet standards. IMPLICATIONS FOR NURSING MANAGEMENT: Finnish nursing leaders, especially nursing directors, should increase their visibility by working more closely with their staff. They should also pay attention to giving direct feedback about work generally and patient safety issues in particular. PMID- 23339506 TI - Interdisciplinary collaboration: the role of the clinical nurse leader. AB - AIMS: To explore the feasibility and acceptability of a clinical nurse leader (CNL) role to improve interdisciplinary collaboration (IC) within a fragmented acute-care microsystem. BACKGROUND: Fragmented patient care is associated with preventable adverse healthcare outcomes. IC decreases fragmentation and improves patient care quality. The CNL role is theorized to provide the necessary leadership and competency skill base to impact IC at the optimal organizational level, the point of care where most healthcare decisions are made. METHODS: This study used a descriptive non-experimental design. CNL daily workflow was developed to target empirical determinants of IC. Descriptive data were collected from multiple stakeholders using an investigator-developed survey. RESULTS: Findings indicate the integration of the role is feasible and acceptable to the microsystem healthcare team. CONCLUSIONS: Preliminary evidence suggests the CNL role may be an effective intervention to facilitate IC. More research is needed to support the CNL role's association with microsystem IC. IMPLICATIONS FOR NURSING MANAGEMENT: The CNL role presents an innovative opportunity for clinical and administrative leadership to partner together to redesign a healthcare delivery system and improve patient care quality. PMID- 23339507 TI - Evolution of an innovative role: the clinical nurse leader. AB - AIMS: This study describes the evolution of the clinical nurse leader (CNL((r)) ) role and its utility in a tertiary care and community hospital. BACKGROUND: In the US, quality and safety metrics are being publically reported and healthcare organizations are just beginning to experience pay-for-performance and its impact. The American Association of the Colleges of Nursing (AACN) developed the role of the CNL to address the complexities and challenges of providing high quality care in the current environment. EVALUATION: Since 2007, a cohort of CNLs in practice has evaluated the effectiveness of the role with measures of clinical outcomes, financial savings and case studies. KEY ISSUES: Having CNLs with a strategic perspective acting as facilitators and integrators of care has proven invaluable. Leadership support has been critical and commitment to maintaining the integrity of the role has ensured its success and sustainability. CONCLUSIONS: This role has established its value in risk assessment, strategic quality improvement, interdisciplinary collaboration and the implementation of evidence-based solutions. IMPLICATIONS FOR NURSING MANAGEMENT: The flexibility and broad scope of this role allows for its use across practice settings and represents an exciting opportunity for nursing to drive quality of care to new levels while managing costs. PMID- 23339508 TI - Continuity of care in home health-care practice: two management paradoxes. AB - AIM: To explore continuity of care from a manager's perspective: How do managers understand the concept of continuity of care and how do they assess continuity of care in home health-care? How do managers work to ensure continuity of care when managing care provision for patients in their homes? BACKGROUND: Continuity of care is considered a prerequisite for service quality. Managers can influence continuity of care through managing day-to-day work. METHODS: Semi structured interviews of a purposive sample of 16 managers from 12 municipal units. Theory-driven and data-driven analysis was applied. RESULTS: Ideally, to promote continuity of care, the number of carers should be limited. Yet, in practice, discontinuity of care was accepted as a working compromise. The managers faced two paradoxes: the continuity ideal vs. the practicalities of home health-care, and caring for patients vs. caring for staff. CONCLUSIONS: The managers were forced to prioritize, in conflict with ideals or professional standards, patients' wellbeing or the wellbeing of the staff. Ensuring continuity of care for all patients did not seem feasible. IMPLICATIONS FOR NURSING MANAGEMENT: The study highlights management paradoxes: possible unintended consequences of prioritizing needs for continuity of care should be objects of reflection in care management. PMID- 23339510 TI - Letter to the Editor: Organizational vision: experience in the unit level. PMID- 23339509 TI - Nurse-led case management for community dwelling older people: an explorative study of models and costs. AB - AIM: To compare community matrons with other nurses carrying out case management for impact on service use and costs. BACKGROUND: In England, nurses working in general practice, as district nurses and disease-specific nurses, undertake use case management. Community matrons were introduced to case management to reduce unplanned hospitalizations of people with complex conditions. METHODS: Managers in three Primary Care Trusts (PCTs) identified four nurses/matrons engaged in case management. Nurses/matrons recruited five community-dwelling patients referred to them for case management. Patients reported use of health/social services for 9 months, 2008 to 2009. Nurses/matrons completed activity diaries. RESULTS: Service use data were available for 33 patients. Compared with other nurse case managers, community matrons had: smaller caseloads; more patient contact time (mean 364 vs. 80 minutes per patient per month); and older patients (mean age 81 vs. 75 years, P = 0.03) taking more medications (mean 8.9 vs. 5.6, P = 0.014). Monthly costs were significantly higher for patients managed by community matrons (add L861), and who lived alone (add L696). Hospitalizations were not associated with patient or service delivery factors. CONCLUSION: Further research on cost-effectiveness of case management models is required. IMPLICATIONS FOR NURSING MANAGEMENT: The case for continued investment in community matrons remains to be proven. PMID- 23339511 TI - Ultrafast spectral migration of photoluminescence in graphene oxide. AB - We use subpicosecond time-resolved photoluminescence measurements to study the nature of photoluminescence in graphene oxide and reduced graphene oxide. Our data indicate that, in contrast to prior suggestions, the photoluminescence spectra of graphene oxide and reduced graphene oxide are inhomogeneously broadened. We observe substantial energy redistribution and relaxation among the emitting states within the first few picoseconds, leading to a progressive red shift of the emission spectrum. Blue shifts that arise in time-integrated spectra upon photothermal reduction are easily understood within this dynamical context without invoking a modified distribution of dipole-coupled states. Rather, reduction increases the nonradiative electron-hole recombination rate and curtails the red-shifting process, which is consistent with an increase in quenching through the introduction of larger and/or more numerous sp(2) clusters. Polarization memory measurements show energetic signatures of electron-hole correlations, established on a subpicosecond time scale and developing little thereafter. PMID- 23339512 TI - Sensitization to pets is a major determinant of persistent asthma and new asthma onset in Sweden. AB - INTRODUCTION: Our knowledge about atopy as a longitudinal predictor of asthma is limited. The purpose of this study was to investigate the prognosis of asthma and risk factors for asthma onset, especially sensitization of specific allergens in a population sample. MATERIAL AND METHODS: A cohort responded to a respiratory questionnaire in 1990 and 2003. At baseline, 2,060 subjects who, in the screening questionnaire, reported respiratory symptoms and 482 controls were investigated with interviews, spirometry, and skin-prick test. A total of 721 asthmatics and 976 subjects without respiratory disease were clinically verified. At follow-up in 2003, 340 subjects with persistent asthma and 186 subjects with asthma remission were identified, while 76 subjects reported new asthma onset. RESULTS: Sensitization to pets and a high symptom score were significant determinants of persistent asthma (odds ratio (OR) 3.2 (95% CI 1.9-5.6) and 5.7 (2.5-13.3), respectively) and onset of asthma (OR 2.6 (1.1-6.0), and 1.7 (1.2-2.3)). A high self-reported responsiveness to airway irritants (OR 1.6 (1.1-2.2)), and more asthma medications (OR 2.0 (1.3-2.9)) were additional indicators of persistent asthma at the follow-up. Belonging to the older age group decreased the risk both of having persistent asthma and asthma onset. DISCUSSION: Asthmatics sensitized to pets have a more severe outcome than asthmatics not sensitized to pets. Sensitization to pets was also a strong predictor for onset of asthma. Special attention should be given to asthmatics who report having severe symptoms and problems with airway irritants as such patients are more likely to have persistent problems. PMID- 23339514 TI - The development of falling intonation in young children with cochlear implants: a 2-year longitudinal study. AB - This article describes the development of intonation in 12 cochlear implant (CI) recipients. In a previously reported study of the first year of CI use, children who were implanted late (after 24 months) acquired intonation more rapidly than the younger participants. The older children's advantage is plausibly owing to their greater maturity. However, children who were implanted early (before 25 months) did not have an advantage over the still younger control group of infants with normal hearing (NH), suggesting that the advantage requires a critical age of about 30 months. The younger CI-users reached this age in the second year of CI use. The results confirmed our expectation that even the younger CI recipients would acquire intonation more rapidly than infants with NH who had the same amount of robust hearing experience. Clinical implications are discussed in relation to the question of early versus late implantation. PMID- 23339513 TI - Systematic review and meta-analysis: influence of smoking cessation on incidence of pneumonia in HIV. AB - BACKGROUND: Smoking is common in people infected with HIV but cessation support is not a routine part of clinical care. The aim was to assess whether smoking is a risk factor for pneumonia in people with HIV and whether smoking cessation ameliorates excess risk. METHODS: We performed MEDLINE and Embase database searches and included cohort or case-control studies conducted in adult patients infected with HIV extracting a hazard ratio (HR) or odds ratio (OR) that compared the incidence of bacterial pneumonia or pneumonia caused by Pneumocystis jiroveci (PCP) between two smoking categories. Studies were appraised for quality and combined using inverse variance meta-analysis. RESULTS: Fourteen cohort and case control studies were included. Assessment of outcome was good, but assessment of exposure status was poor. Current smokers were at higher risk of bacterial pneumonia than former smokers: HR 1.37 (95% confidence interval (CI): 1.06, 1.78). There was no evidence that former smokers were at higher risk than never smokers: HR 1.24 (95%CI: 0.96, 1.60). Current smokers were at higher risk of bacterial pneumonia than current non-smokers: HR of 1.73 (95%CI: 1.44, 2.06). There was no evidence that smoking increased the incidence of PCP. The HR for current versus non-smokers was 0.94 (95%CI: 0.79, 1.12), but from case-control studies the OR was 1.76 (95%CI: 1.25, 2.48) with heterogeneity. Confined to higher quality studies, the OR was 0.97 (95%CI: 0.81, 1.16). Residual confounding is possible, but available data suggest this is not an adequate explanation. CONCLUSIONS: Smoking is a risk factor for bacterial pneumonia but not PCP and smoking cessation reduces this risk.See related article: http://www.biomedcentral.com/1741-7015/11/16. PMID- 23339515 TI - The effect of health facility delivery on neonatal mortality: systematic review and meta-analysis. AB - BACKGROUND: Though promising progress has been made towards achieving the Millennium Development Goal four through substantial reduction in under-five mortality, the decline in neonatal mortality remains stagnant, mainly in the middle and low-income countries. As an option, health facility delivery is assumed to reduce this problem significantly. However, the existing evidences show contradicting conclusions about this fact, particularly in areas where enabling environments are constraint. Thus, this review was conducted with the aim of determining the pooled effect of health facility delivery on neonatal mortality. METHODS: The reviewed studies were accessed through electronic web based search strategy from PUBMED, Cochrane Library and Advanced Google Scholar by using combination key terms. The analysis was done by using STATA-11. I(2) test statistic was used to assess heterogeneity. Funnel plot, Begg's test and Egger's test were used to check for publication bias. Pooled effect size was determined in the form of relative risk in the random-effects model using DerSimonian and Laird's estimator. RESULTS: A total of 2,216 studies conducted on the review topic were identified. During screening, 37 studies found to be relevant for data abstraction. From these, only 19 studies fulfilled the preset criteria and included in the analysis. In 10 of the 19 studies included in the analysis, facility delivery had significant association with neonatal mortality; while in 9 studies the association was not significant. Based on the random effects model, the final pooled effect size in the form of relative risk was 0.71 (95% CI: 0.54, 0.87) for health facility delivery as compared to home delivery. CONCLUSION: Health facility delivery is found to reduce the risk of neonatal mortality by 29% in low and middle income countries. Expansion of health facilities, fulfilling the enabling environments and promoting their utilization during childbirth are essential in areas where home delivery is a common practice. PMID- 23339516 TI - Relationship of serum magnesium concentration to risk of short-term outcome of acute ischemic stroke. AB - OBJECTIVE: To assess whether serum magnesium concentration can predict risk of short-term outcome of acute ischemic stroke. METHODS: Between January 1, 2006 and December 31, 2008, 1493 patients with acute ischemic stroke were recruited from four hospitals in Shandong province, P.R China. Data on demographic characteristics, life style risk factors, history of cardiovascular disease, admission blood pressure and other clinical characteristics were collected from all subjects. The short-term outcome was defined as neurological deficiency NIHSS >= 10 or death (NIHSS >= 10/death). The Cox proportion hazard regression model was used to evaluate the association between serum magnesium concentration and risk of short-term outcome of acute ischemic stroke. RESULTS: Serum magnesium concentration in subjects with NIHSS >= 10/death was lower than those with NIHSS < 10 (p < 0.05). When comparing the highest quartile of serum magnesium concentration with the lowest quartile in an unadjusted model, there was a decreased risk of NIHSS >= 10/death in individuals with the highest quartile; the risk ratio (RR) was 0.47 (p < 0.05). However, after adjustment for age, sex, serum calcium concentration, serum potassium concentration and other covariates, the fourth and the third quartiles of serum magnesium concentration were associated with decreased risks of NIHSS >= 10/death; the RRs were 0.40 and 0.56 (all p < 0.05), respectively. The dose-response relationship between serum magnesium concentration and risk of NIHSS >= 10/death was not materially altered after adjustment for other covariates (p-value for trend = 0.002). CONCLUSION: Higher serum magnesium concentration was associated with lower risk of NIHSS >= 10/death; there was a dose-response relationship between serum magnesium concentration and risk of NIHSS >= 10/death. PMID- 23339517 TI - Exploration of lagged associations using longitudinal data. AB - Several statistical approaches for the analysis of longitudinal data require that models be correctly specified for the association between a current outcome and the full history of past outcomes and time-dependent exposures. It is empirically challenging to determine the specific aspects of the outcome and/or exposure history that are predictive of a current outcome because the potential number of variables representing the history can be quite large. The purpose of this article is to outline statistical methods that can characterize lagged effects and to provide a structured approach for data analysis with the goal of appropriate model development. One of the main contributions of the article is to emphasize the possibility that in practice transition models may frequently require more than simple additive and linear models for the predictors representing the history of the outcome and covariate processes. We illustrate the concepts using an example from anemia treatment for dialysis patients and show how linear models can be specified with flexible dependence on exposure and/or outcome histories. PMID- 23339518 TI - Structural transformations and disordering in zirconolite (CaZrTi2O7) at high pressure. AB - There is interest in identifying novel materials for use in radioactive waste applications and studying their behavior under high pressure conditions. The mineral zirconolite (CaZrTi(2)O(7)) exists naturally in trace amounts in diamond bearing deep-seated metamorphic/igneous environments, and it is also identified as a potential ceramic phase for radionuclide sequestration. However, it has been shown to undergo radiation-induced metamictization resulting in amorphous forms. In this study we probed the high pressure structural properties of this pyrochlore-like structure to study its phase transformations and possible amorphization behavior. Combined synchrotron X-ray diffraction and Raman spectroscopy studies reveal a series of high pressure phase transformations. Starting from the ambient pressure monoclinic structure, an intermediate phase with P2(1)/m symmetry is produced above 15.6 GPa via a first order transformation resulting in a wide coexistence range. Upon compression to above 56 GPa a disordered metastable phase III with a cotunnite-related structure appears that is recoverable to ambient conditions. We examine the similarity between the zirconolite behavior and the structural evolution of analogous pyrochlore systems under pressure. PMID- 23339519 TI - Maximizing the concentrations of wheat grain fructans in bread by exploring strategies to prevent their yeast ( Saccharomyces cerevisiae )-mediated degradation. AB - The degradation of endogenous wheat grain fructans, oligosaccharides with possible health-promoting potential, during wheat whole meal bread making was investigated, and several strategies to prevent their degradation were evaluated. Up to 78.4 +/- 5.2% of the fructans initially present in wheat whole meal were degraded during bread making by the action of yeast ( Saccharomyces cerevisiae ) invertase. The addition of sucrose to dough delayed fructan degradation but had no effect on final fructan concentrations. However, yeast growth conditions and yeast genotype did have a clear impact. A 3-fold reduction of fructan degradation could be achieved when the commercial bread yeast strain was replaced by yeast strains with lower sucrose degradation activity. Finally, fructan degradation during bread making could be prevented completely by the use of a yeast strain lacking invertase. These results show that the nutritional profile of bread can be enhanced through appropriate yeast technology. PMID- 23339520 TI - Propylene glycol-linked amino acid/dipeptide diester prodrugs of oleanolic acid for PepT1-mediated transport: synthesis, intestinal permeability, and pharmacokinetics. AB - In our previous studies, ethylene glycol-linked amino acid diester prodrugs of oleanolic acid (OA), a Biopharmaceutics Classification System (BCS) class IV drug, designed to target peptide transporter 1 (PepT1) have been synthesized and evaluated. Unlike ethylene glycol, propylene glycol is of very low toxicity in vivo. In this study, propylene glycol was used as a linker to further compare the effect of the type of linker on the stability, permeability, affinity, and bioavailability of the prodrugs of OA. Seven diester prodrugs with amino acid/dipeptide promoieties containing L-Val ester (7a), L-Phe ester (7b), L-Ile ester (7c), D-Val-L-Val ester (9a), L-Val-L-Val ester (9b), L-Ala-L-Val ester (9c), and L-Ala-L-Ile ester (9d) were designed and successfully synthesized. In situ rat single-pass intestinal perfusion (SPIP) model was performed to screen the effective permeability (P(eff)) of the prodrugs. P(eff) of 7a, 7b, 7c, 9a, 9b, 9c, and 9d (6.7-fold, 2.4-fold, 1.24-fold, 1.22-fold, 4.15-fold, 2.2-fold, and 1.4-fold, respectively) in 2-(N-morpholino)ethanesulfonic acid buffer (MES) with pH 6.0 showed significant increase compared to that of OA (p < 0.01). In hydroxyethyl piperazine ethanesulfonic acid buffer (HEPES) of pH 7.4, except for 7c, 9a, and 9d, P(eff) of the other prodrugs containing 7a (5.2-fold), 7b (2.0 fold), 9b (3.1-fold), and 9c (1.7-fold) exhibited significantly higher values than that of OA (p < 0.01). In inhibition studies with glycyl-sarcosine (Gly-Sar, a typical substrate of PepT1), P(eff) of 7a (5.2-fold), 7b (2.0-fold), 9b (3.1 fold), and 9c (2.3-fold) had significantly reduced values (p < 0.01). Compared to the apparent permeability coefficient (P(app)) of OA with Caco-2 cell monolayer, significant enhancement of the P(app) of 7a (5.27-fold), 9b (3.31-fold), 9a (2.26 fold), 7b (2.10-fold), 7c (2.03-fold), 9c (1.87-fold), and 9d (1.39-fold) was also observed (p < 0.01). Inhibition studies with Gly-Sar (1 mM) showed that P(app) of 7a, 9b, and 9c significantly reduced by 1.3-fold, 1.6-fold, and 1.4 fold (p < 0.01), respectively. These results may be attributed to PepT1-mediated transport and their differential affinity toward PepT1. According to the permeability and affinity, 7a and 9b were selected in the pharmacokinetic studies in rats. Compared with group OA, C(max) for group 7a and 9b was enhanced to 3.04 fold (p < 0.01) and 2.62-fold (p < 0.01), respectively. AUC(0->24) was improved to 3.55-fold (p < 0.01) and 3.39-fold (p < 0.01), respectively. Compared to the ethylene glycol-linked amino acid diester prodrugs of OA in our previous work, results from this study revealed that part of the propylene glycol-linked amino acid/dipeptide diester prodrugs showed better stability, permeability, affinity, and bioavailability. In conclusion, propylene glycol-linked amino acid/dipeptide diester prodrugs of OA may be suitable for PepT1-targeted prodrugs of OA to improve the oral bioavailability of OA. PMID- 23339521 TI - How and when do personal values guide our attitudes and sociality? Explaining cross-cultural variability in attitude-value linkages. AB - This article examines how and when personal values relate to social attitudes. Considering values as motivational orientations, we propose an attitude-value taxonomy based on Moral Foundation Theory (Haidt & Joseph, 2007) and Schwartz's (1992) basic human values theory allowing predictions of (a) how social attitudes are related to personal values, and (b) when macro-contextual factors have an impact on attitude-value links. In a meta-analysis based on the Schwartz Value Survey (Schwartz, 1992) and the Portrait Value Questionnaire (Schwartz et al., 2001; k = 91, N = 30,357 from 31 countries), we found that self-transcendence (vs. self-enhancement) values relate positively to fairness/proenvironmental and care/prosocial attitudes, and conservation (vs. openness-to-change) values relate to purity/religious and authority/political attitudes, whereas ingroup/identity attitudes are not consistently associated with value dimensions. Additionally, we hypothesize that the ecological, economic, and cultural context moderates the extent to which values guide social attitudes. Results of the multi-level meta analysis show that ecological and cultural factors inhibit or foster attitude value associations: Disease stress is associated with lower attitude-value associations for conservation (vs. openness-to-change) values; collectivism is associated with stronger attitude-value links for conservation values; individualism is associated with stronger attitude-value links for self transcendence (vs. self-enhancement) values; and uncertainty avoidance is associated with stronger attitude-values links, particularly for conservation values. These findings challenge universalistic claims about context-independent attitude-value relations and contribute to refined future value and social attitude theories. PMID- 23339522 TI - On the automatic activation of attitudes: a quarter century of evaluative priming research. AB - Evaluation is a fundamental concept in psychological science. Limitations of self report measures of evaluation led to an explosion of research on implicit measures of evaluation. One of the oldest and most frequently used implicit measurement paradigms is the evaluative priming paradigm developed by Fazio, Sanbonmatsu, Powell, and Kardes (1986). This paradigm has received extensive attention in psychology and is used to investigate numerous phenomena ranging from prejudice to depression. The current review provides a meta-analysis of a quarter century of evaluative priming research: 73 studies yielding 125 independent effect sizes from 5,367 participants. Because judgments people make in evaluative priming paradigms can be used to tease apart underlying processes, this meta-analysis examined the impact of different judgments to test the classic encoding and response perspectives of evaluative priming. As expected, evidence for automatic evaluation was found, but the results did not exclusively support either of the classic perspectives. Results suggest that both encoding and response processes likely contribute to evaluative priming but are more nuanced than initially conceptualized by the classic perspectives. Additionally, there were a number of unexpected findings that influenced evaluative priming such as segmenting trials into discrete blocks. We argue that many of the findings of this meta-analysis can be explained with 2 recent evaluative priming perspectives: the attentional sensitization/feature-specific attention allocation and evaluation window perspectives. PMID- 23339524 TI - Chorioamnionitis without foetal inflammatory response is associated with stillbirth in early preterm pregnancies. AB - OBJECTIVE: The aim of this study was to compare placental findings from early preterm stillbirths with gestational week-matched liveborn infants. The main focus was to investigate the differences in the presence and distribution of inflammatory signs in the placentas of these two groups, especially referring to histological acute chorioamnionitis (CAM). METHODS: A case-control study of preterm stillbirths, between 22 and 32 weeks gestation, here referred to as early preterm, (cases, n = 112) and gestational week-matched liveborn infants (references, n = 166) in Stockholm. Relevant clinical data were collected from a web-based database (for cases) and delivery records (for references). Macroscopic and histological examinations of placentas were performed according to a structured protocol (placental weight relative to gestational age, accelerated villous maturation, infarction, intervillous thrombosis, foetal thrombosis, chronic villitis and CAM (polymorphonuclear leucocytes in the chorion/amnion), with and without foetal inflammatory responses (FIRs) (vasculitis in placental and/or cord vessels and funisitis). Statistical analyses were performed using a multivariable logistic regression. RESULTS: Small for gestational age (AOR: 2.13, CI: 1.26-3.62) and CAM without a FIR (AOR: 2.44, CI: 1.10-5.41) were associated with an elevated risk of preterm stillbirth. CONCLUSIONS: Histological acute CAM without a FIR is associated with a higher risk for stillbirth in early preterm pregnancies. PMID- 23339523 TI - Declining malaria parasite prevalence and trends of asymptomatic parasitaemia in a seasonal transmission setting in North-Western Burkina Faso between 2000 and 2009-2012. AB - BACKGROUND: Malaria transmission was reported to have declined in some East African countries. However, a comparable trend has not been confirmed for West Africa. This study aims to assess the dynamics of parasite prevalence and malaria species distribution over time in an area of highly seasonal transmission in Burkina Faso. The aim was also to compare frequency of asymptomatic parasitaemia between wet and dry season by parasite density status and age group. METHODS: During the years 2009-2012, six cross-sectional studies were performed in the rural village Bourasso in the Nouna Health District in north-west Burkina Faso. In subsequent rainy and dry seasons blood samples were collected to assess the parasite prevalence, species, density and clinical parameters. In total, 1,767 children and adults were examined and compared to a baseline collected in 2000. RESULTS: The microscopical parasite prevalence (mainly P. falciparum) measured over the rainy seasons decreased significantly from 78.9% (2000) to 58.4%, 55.9% and 49.3%, respectively (2009-2011; p <0.001). The frequency of Plasmodium malariae infections (mono- and co-infections) decreased parallel to the overall parasite prevalence from 13.4% in 2000 to 2.1%, 4.1% and 4.7% in 2009-2011 (p <0.001). Comparing parasite-positive subjects from the rainy season versus dry season, the risk of fever was significantly reduced in the dry season adjusting for parasite density (grouped) and age group. CONCLUSIONS: The results of this study suggest a decline of malaria transmission over the rainy seasons between 2000 and 2009-2011 in the region of Nouna, Burkina Faso. The decreased transmission intensity was associated with lower prevalence of P. malariae infections (both mono-infections and co-infections). Asymptomatic parasitaemia was more frequent in the dry season even adjusting for parasite density and age group in a multivariate regression. Possible reasons for this observation include the existence of less pathogenic Plasmodium falciparum genotypes prevailing in the dry season, or the effect of a reduced incidence density during the dry season. PMID- 23339525 TI - Synthesis of cationic polylactides with tunable charge densities as nanocarriers for effective gene delivery. AB - Well-defined cationic polylactides (CPLAs) with tertiary amine groups were synthesized by thiol-ene click functionalization of an allyl-functionalized polylactide to yield polymers with tunable charge densities. CPLAs have not previously been utilized in the context of DNA delivery. Thus, plasmid DNA (pDNA) encoding luciferase was delivered to two physiologically distinct cell lines (macrophage and fibroblast) via formation of CPLA/pDNA polyplexes by electrostatic interaction. The formulated polyplexes demonstrated high levels of transfection with low levels of cytotoxicity when compared to a positive control. Biophysical characterization of charge densities at various CPLA/pDNA weight ratios revealed a positive correlation between surface charge and gene delivery. Overall, these results help to elucidate the influence of polyplex charge and size upon the delivery of nucleic acid and support future gene delivery applications using this next-generation biomaterial. PMID- 23339526 TI - Empirical assessment of sequencing errors for high throughput pyrosequencing data. AB - BACKGROUND: Sequencing-by-synthesis technologies significantly improve over the Sanger method in terms of speed and cost per base. However, they still usually fail to compete in terms of read length and quality. Current high-throughput implementations of the pyrosequencing technique yield reads whose length approach those of the capillary electrophoresis method. A less obvious question is whether their quality is affected by platform-specific sequencing errors. RESULTS: We present an empirical study aimed at assessing the quality and characterising sequencing errors for high throughput pyrosequencing data. We have developed a procedure for extracting sequencing error data from genome assemblies and study their characteristics, in particular the length distribution of indel gaps and their relation to the sequence contexts where they occur. We used this procedure to analyse data from three prokaryotic genomes sequenced with the GS FLX technology. We also compared two models previously employed with success for peptide sequence alignment. CONCLUSIONS: We observed an overall very low error rate in the analysed data, with indel errors being much more abundant than substitutions. We also observed a dependence between the length of the gaps and that of the homopolymer context where they occur. As with protein alignments, a power-law model seems to approximate the indel errors more accurately, although the results are not so conclusive as to justify a depart from the commonly used affine gap penalty scheme. In whichever case, however, our procedure can be used to estimate more realistic error model parameters. PMID- 23339527 TI - Chemical vapor sensing with monolayer MoS2. AB - Two-dimensional materials such as graphene show great potential for future nanoscale electronic devices. The high surface-to-volume ratio is a natural asset for applications such as chemical sensing, where perturbations to the surface resulting in charge redistribution are readily manifested in the transport characteristics. Here we show that single monolayer MoS(2) functions effectively as a chemical sensor, exhibiting highly selective reactivity to a range of analytes and providing sensitive transduction of transient surface physisorption events to the conductance of the monolayer channel. We find strong response upon exposure to triethylamine, a decomposition product of the V-series nerve gas agents. We discuss these results in the context of analyte/sensor interaction in which the analyte serves as either an electron donor or acceptor, producing a temporary charge perturbation of the sensor material. We find highly selective response to electron donors and little response to electron acceptors, consistent with the weak n-type character of our MoS(2). The MoS(2) sensor exhibits a much higher selectivity than carbon nanotube-based sensors. PMID- 23339528 TI - Spectral analysis of word-initial alveolar and velar plosives produced by Iranian children with cleft lip and palate. AB - Spectral moment analysis (SMA) was used to describe voiceless alveolar and velar stop-plosive production in Persian-speaking children with repaired cleft lip and palate (CLP). Participants included 11 children with bilateral CLP who were undergoing maxillary expansion and 20 children without any type of orofacial clefts. Four of the children with CLP also exhibited backed (palatal) placement for alveolar stops. All children produced consonant-vowel-consonant nonsense words that targeted the plosives /t/ and /k/. SMA revealed that children with CLP had significantly reduced first spectral moment of /t/ and /t/-/k/ difference. Children with CLP who produced palatal stops for alveolar targets also had lower but non-significant first spectral moments for /t/ as compared with children with CLP who did not produce palatal stops. The results are consistent with previously reported findings for English-speaking children with repaired CLP and further suggest that maxillary arch constriction may be a contributing factor for (a) reduced spectral distinction of alveolar targets and/or (b) palatal substitutions for alveolar targets. PMID- 23339529 TI - Overexpression of microRNA-145 in atherosclerotic plaques from hypertensive patients. AB - BACKGROUND: MicroRNAs (miRNAs) are endogenous, non-coding, short, single-stranded RNAs and represent a new class of gene regulators. Recent evidence supports a role for miRNAs in cardiovascular pathophysiology and atherosclerosis development. We have previously demonstrated that miR-145 is widely expressed in human atherosclerotic lesions and its downregulation has been correlated with vascular smooth muscle cell dedifferentiation, a cardinal step in the development of atherosclerosis. However, no evidences are available at this time about modulation of miR-145 in the setting of hypertension. Thus, the aim of this study was to investigate the expression of miR-145 in complicated hypertension. MATERIALS AND METHODS: Atherosclerotic plaques were obtained from 22 patients undergoing carotid endarterectomy for high-grade internal carotid artery stenosis. Plaques were subdivided into hypertension (n = 15) and control (n = 7) groups according to the presence or absence of hypertension (as defined by blood pressure > 140/90 mmHg or current antihypertensive treatment). In study plaques, miR-145 values were evaluated using real-time PCR. The level of induction has been tested by using DeltaDelta cycle threshold method. RESULTS: We found that miR-145 was significantly more expressed in atherosclerotic plaques of hypertensive patients than in control plaques (1.201 +/- 0.260 vs 0.483 +/- 0.148 fold induction +/- SE; p = 0.026). Moreover, a post-hoc analysis showed that treatment with angiotensin receptor blockers may be associated with the maximum increase in miR-145 levels, although these data did not show any statistical significance probably due to the limited sample size. CONCLUSIONS: To the best of our knowledge, this study is the first demonstration that hypertension may upregulate miR-145 expression in human atherosclerotic plaques. Future investigations will be necessary to establish the molecular readout of miR-145 upregulation in atherosclerotic lesions in hypertension. PMID- 23339530 TI - Pharmacases.de - a student-centered e-learning project of clinical pharmacology. AB - AIM: The aim of the project Pharmacases.de was to develop an innovative concept for creating high-quality e-learning content which integrates and promotes the theoretical and cooperative skills of final-year medical students and is easily adoptable by cooperating institutes and hospitals. METHODS AND RESULTS: A peer teaching concept was developed in which final-year medical students with the elective pharmacology independently researched and wrote e-learning cases of clinical pharmacology ("pharmacases"). Subject-specific expertise was acquired by consulting a peer network of elective students of other disciplines. The created material was subjected to a multi-step peer review and published on the open access internet platform http://www.pharmacases.de . At present, the website contains 45 e-learning cases, 27 quizzes, and a student-managed discussion forum. Each month, approximately 1200 students access the e-learning content on the website with above-average evaluation results. SUMMARY AND CONCLUSION: The didactic concept of Pharmacases.de enabled the efficient generation of high quality e-learning content in a student-centered and interdisciplinary manner and was well received by the students. It will likely facilitate the transfer of theoretical pharmacological knowledge into clinical practice. PMID- 23339532 TI - The atrial fibrillation ablation theory of relativity. PMID- 23339531 TI - Clinical-grade mesenchymal stromal cells produced under various good manufacturing practice processes differ in their immunomodulatory properties: standardization of immune quality controls. AB - Clinical-grade mesenchymal stromal cells (MSCs) are usually expanded from bone marrow (BMMSCs) or adipose tissue (ADSCs) using processes mainly differing in the use of fetal calf serum (FCS) or human platelet lysate (PL). We aimed to compare immune modulatory properties of clinical-grade MSCs using a combination of fully standardized in vitro assays. BMMSCs expanded with FCS (BMMSC-FCS) or PL (BMMSC PL), and ADSC-PL were analyzed in quantitative phenotypic and functional experiments, including their capacity to inhibit the proliferation of T, B, and NK cells. The molecular mechanisms supporting T-cell inhibition were investigated. These parameters were also evaluated after pre-stimulation of MSCs with inflammatory cytokines. BMMSC-FCS, BMMSC-PL, and ADSC-PL displayed significant differences in expression of immunosuppressive and adhesion molecules. Standardized functional assays revealed that resting MSCs inhibited proliferation of T and NK cells, but not B cells. ADSC-PL were the most potent in inhibiting T-cell growth, a property ascribed to interferon-gamma-dependent indoleamine 2,3-dioxygenase activity. MSCs did not stimulate allogeneic T cell proliferation but were efficiently lysed by activated NK cells. The systematic use of quantitative and reproducible validation techniques highlights differences in immunological properties of MSCs produced using various clinical-grade processes. ADSC-PL emerge as a promising candidate for future clinical trials. PMID- 23339533 TI - Weight stigma in maternity care: women's experiences and care providers' attitudes. AB - BACKGROUND: Weight stigma is pervasive in Western society and in healthcare settings, and has a negative impact on victims' psychological and physical health. In the context of an increasing focus on the management of overweight and obese women during and after pregnancy in research and clinical practice, the current studies aimed to examine the presence of weight stigma in maternity care. Addressing previous limitations in the weight stigma literature, this paper quantitatively explores the presence of weight stigma from both patient and care provider perspectives. METHODS: Study One investigated associations between pre pregnancy body mass index (BMI) and experiences of maternity care from a state wide, self-reported survey of 627 Australian women who gave birth in 2009. Study Two involved administration of an online survey to 248 Australian pre-service medical and maternity care providers, to investigate their perceptions of, and attitudes towards, providing care for pregnant patients of differing body sizes. Both studies used linear regression analyses. RESULTS: Women with a higher BMI were more likely to report negative experiences of care during pregnancy and after birth, compared to lower weight women. Pre-service maternity care providers perceived overweight and obese women as having poorer self-management behaviours, and reported less positive attitudes towards caring for overweight or obese pregnant women, than normal-weight pregnant women. Even care providers who reported few weight stigmatising attitudes responded less positively to overweight and obese pregnant women. CONCLUSIONS: Overall, these results provide preliminary evidence that weight stigma is present in maternity care settings in Australia. They suggest a need for further research into the nature and consequences of weight stigma in maternity care, and for the inclusion of strategies to recognise and combat weight stigma in maternity care professionals' training. PMID- 23339534 TI - Semiparametric Bayesian inference for phage display data. AB - We discuss inference for a human phage display experiment with three stages. The data are tripeptide counts by tissue and stage. The primary aim of the experiment is to identify ligands that bind with high affinity to a given tissue. We formalize the research question as inference about the monotonicity of mean counts over stages. The inference goal is then to identify a list of peptide tissue pairs with significant increase over stages. We use a semiparametric Dirichlet process mixture of Poisson model. The posterior distribution under this model allows the desired inference about the monotonicity of mean counts. However, the desired inference summary as a list of peptide-tissue pairs with significant increase involves a massive multiplicity problem. We consider two alternative approaches to address this multiplicity issue. First we propose an approach based on the control of the posterior expected false discovery rate. We notice that the implied solution ignores the relative size of the increase. This motivates a second approach based on a utility function that includes explicit weights for the size of the increase. PMID- 23339535 TI - Meta-analysis of dropout in treatments for posttraumatic stress disorder. AB - OBJECTIVE: Many patients drop out of treatments for posttraumatic stress disorder (PTSD); some clinicians believe that trauma-focused treatments increase dropout. METHOD: We conducted a meta-analysis of dropout among active treatments in clinical trials for PTSD (42 studies; 17 direct comparisons). RESULTS: The average dropout rate was 18%, but it varied significantly across studies. Group modality and greater number of sessions, but not trauma focus, predicted increased dropout. When the meta-analysis was restricted to direct comparisons of active treatments, there were no differences in dropout. Differences in trauma focus between treatments in the same study did not predict dropout. However, trauma-focused treatments resulted in higher dropout compared with present centered therapy (PCT), a treatment originally designed as a control but now listed as a research-supported intervention for PTSD. CONCLUSION: Dropout varies between active interventions for PTSD across studies, but variability is primarily driven by differences between studies. There do not appear to be systematic differences across active interventions when they are directly compared in the same study. The degree of clinical attention placed on the traumatic event does not appear to be a primary cause of dropout from active treatments. However, comparisons of PCT may be an exception to this general pattern, perhaps because of a restriction of variability in trauma focus among comparisons of active treatments. More research is needed comparing trauma focused interventions to trauma-avoidant treatments such as PCT. PMID- 23339536 TI - The relationship between the therapeutic alliance and treatment outcome in two distinct psychotherapies for chronic depression. AB - OBJECTIVE: This study tested whether the quality of the patient-rated working alliance, measured early in treatment, predicted subsequent symptom reduction in chronically depressed patients. Secondarily, the study assessed whether the relationship between early alliance and response to treatment differed between patients receiving cognitive behavioral analysis system of psychotherapy (CBASP) vs. brief supportive psychotherapy (BSP). METHOD: 395 adults (57% female; Mage = 46; 91% Caucasian) who met criteria for chronic depression and did not fully remit during a 12-week algorithm-based, open-label pharmacotherapy trial were randomized to receive either 16-20 sessions of CBASP or BSP in addition to continued, algorithm-based antidepressant medication. Of these, 224 patients completed the Working Alliance Inventory-Short Form at Weeks 2 or 4 of treatment. Blind raters assessed depressive symptoms at 2-week intervals across treatment using the Hamilton Rating Scale for Depression. Linear mixed models tested the association between early alliance and subsequent symptom ratings while accounting for early symptom change. RESULTS: A more positive early working alliance was associated with lower subsequent symptom ratings in both the CBASP and BSP, F(1, 1236) = 62.48, p < .001. In addition, the interaction between alliance and psychotherapy type was significant, such that alliance quality was more strongly associated with symptom ratings among those in the CBASP treatment group, F(1, 1234) = 8.31, p = .004. CONCLUSIONS: The results support the role of the therapeutic alliance as a predictor of outcome across dissimilar treatments for chronic depression. Contrary to expectations, the therapeutic alliance was more strongly related to outcome in CBASP, the more directive of the 2 therapies. PMID- 23339537 TI - Patient characteristics and variability in adherence and competence in cognitive behavioral therapy for panic disorder. AB - Although associations with outcome have been inconsistent, therapist adherence and competence continues to garner attention, particularly within the context of increasing interest in the dissemination, implementation, and sustainability of evidence-based treatments. To date, research on therapist adherence and competence has focused on average levels across therapists. With a few exceptions, research has failed to address multiple sources of variability in adherence and competence, identify important factors that might account for variability, or take these sources of variability into account when examining associations with symptom change. OBJECTIVE: (a) statistically demonstrate between- and within-therapist variability in adherence and competence ratings and examine patient characteristics as predictors of this variability and (b) examine the relationship between adherence/competence and symptom change. METHOD: Randomly selected audiotaped sessions from a randomized controlled trial of cognitive-behavioral therapy for panic disorder were rated for therapist adherence and competence. Patients completed a self-report measure of panic symptom severity prior to each session and the Inventory of Interpersonal Problems-Personality Disorder Scale prior to the start of treatment. RESULTS: Significant between- and within-therapist variability in adherence and competence were observed. Adherence and competence deteriorated significantly over the course of treatment. Higher patient interpersonal aggression was associated with decrements in both adherence and competence. Neither adherence nor competence predicted subsequent panic severity. CONCLUSIONS: Variability and "drift" in adherence and competence can be observed in controlled trials. Training and implementation efforts should involve continued consultation over multiple cases in order to account for relevant patient factors and promote sustainability across sessions and patients. PMID- 23339538 TI - The relationship between posttraumatic and depressive symptoms during prolonged exposure with and without cognitive restructuring for the treatment of posttraumatic stress disorder. AB - OBJECTIVE: In the present study, we examined the relationship between posttraumatic and depressive symptoms during prolonged exposure (PE) treatment with and without cognitive restructuring (CR) for the treatment of posttraumatic stress disorder (PTSD). METHOD: Female assault survivors (N = 153) with PTSD were randomized to either PE alone or PE with added CR (PE/CR). During treatment, bi weekly self-report measures of posttraumatic and depressive symptoms were administered. RESULTS: Multilevel mediational analyses indicated that during PE, changes in posttraumatic symptoms accounted for 80.3% of changes in depressive symptoms, whereas changes in depressive symptoms accounted for 45.0% of changes in posttraumatic symptoms. During PE/CR, changes in posttraumatic symptoms accounted for 59.6% of changes in depressive symptoms, and changes in depressive symptoms accounted for 50.7% of changes in posttraumatic symptoms. CONCLUSIONS: This pattern of results suggests that PE primarily affects posttraumatic symptoms, which in turn affect depressive symptoms. In contrast, PE/CR results in a more reciprocal relationship between posttraumatic and depressive symptoms. PMID- 23339539 TI - Smoking and HIV: time for a change? AB - Cigarette smoking is one of the most important causes of morbidity and mortality in the general population, and is a well-recognized risk factor for a variety of serious clinical conditions, including cardiovascular diseases, pulmonary diseases and cancers. Smoking-related morbidity and mortality are of particular concern in patients with HIV infection, as the prevalence of current cigarette smoking is higher among HIV-positive patients than among the general population. In a study by De et al., it has been evidenced that smoking is a risk factor for bacterial pneumonia in HIV-positive patients and smoking cessation reduces this risk. HIV-positive patients who smoke have significantly increased mortality compared to those who have never smoked, indicating that smoking confers different mortality risk in HIV-positive as compared to HIV-negative patients, and lifestyle-related factors may pose a greater hazard to long-term survival of HIV-positive patients than those related to the HIV infection per se. The high prevalence of smoking among HIV population, the many health risks that can result from this behavior, and the proven efficacy of cessation interventions in HIV positive patients should encourage HIV care providers to make smoking cessation a high priority. PMID- 23339540 TI - Improved sugar beet pectin-stabilized emulsions through complexation with sodium caseinate. AB - The study investigates the complexes formed between sodium caseinate (SC) and sugar beet pectin (SBP) and to harness them to stabilize SBP emulsions. We find that both hydrophobic and electrostatic interactions are involved in the complexation. In SC/SBP mixed solution, soluble SC/SBP complexes first form on acidification and then aggregate into insoluble complexes, which disassociate into soluble polymers upon further decreasing pH. The critical pH's for the formation of soluble and insoluble complexes and disappearance of insoluble complexes are designated as pH(c), pH(phi), and pH(d), respectively. These critical pH values define four regions in the phase diagram of complexation, and SC/SBP emulsions were prepared in these regions. The results show that the stability of SBP-stabilized emulsion is greatly improved at low SC/SBP ratios and acidic pH's. This enhancement can be attributed to an increase in the amount of adsorbed SBP as a result of cooperative adsorption to sodium caseinate. Using a low ratio of SC/SBP ensured that all caseinate molecules are completely covered by adsorbed SBP chains, which eliminates possible instability induced by thermal aggregation of caseinate molecules resulting from stress acceleration at elevated temperatures. A mechanistic model for the behavior is proposed. PMID- 23339541 TI - Phenylcyanamidoruthenium scorpionate complexes. AB - Nine [Ru(Tp)(dppe)L] complexes, where Tp is hydrotris(pyrazol-1-yl)borate, dppe is ethylenebis(diphenylphosphine), and L is (4-nitrophenyl)cyanamide (NO(2)pcyd( )), (2-chlorophenyl)cyanamide (2-Clpcyd(-)), (3-chlorophenyl)cyanamide (3-Clpcyd( )), (2,4-dichlorophenyl)cyanamide (2,4-Cl(2)pcyd(-)), (2,3 dichlorophenyl)cyanamide (2,3-Cl(2)pcyd(-)), (2,5-dichlorophenyl)cyanamide (2,5 Cl(2)pcyd(-)), (2,4,5-trichlorophenyl)cyanamide (2,4,5-Cl(3)pcyd(-)), (2,3,5,6 tetrachlorophenyl)cyanamide (2,3,5,6-Cl(4)pcyd(-)), and (pentachlorophenyl)cyanamide (Cl(5)pcyd(-)), and the dinuclear complex [{Ru(Tp)(dppe)}(2)(MU-adpc)], where adpc(2-) is azo-4,4-diphenylcyanamide, have been prepared and characterized. The crystal structures of [Ru(Tp)(dppe)(Cl(5)pcyd)] and [{Ru(Tp)(dppe)}(2)(MU-adpc)] reveal the Ru(II) ion to occupy a pseudooctahedral coordination sphere in which the cyanamide ligand coordinates to Ru(II) by its terminal nitrogen atom. For both complexes, the cyanamide ligands are planar, indicating significant pi mixing between the cyanamide and phenyl moieties as well as the azo group in the case of adpc(2-). The optical spectra of the nominally ruthenium(III) species [Ru(Tp)(dppe)L](+) were obtained through spectroelectrochemistry measurements and showed an intense near-IR absorption band. Time-dependent density functional theory calculations of these species revealed that oxidation of the ruthenium(II) species led to species where partial oxidation of the cyanamide ligand had occurred, indicative of noninnocent character for these ligands. The spin densities reveal that while the 3-Clpycd species has substantial Ru(II)(3-Clpycd(0)) character, the Cl(5)pycd species is a much more localized ruthenium(III) complex of the Cl(5)pycd monoanion. Some bond order and charge distribution data are derived for these ruthenium(III) species. The near-IR band is assigned as a quite complex mixture of d-d, 4d(pi) to L(NCN) MLCT, and L(NCN) to Ru 4d LMCT with even a scorpionate ligand component. Spectroelectrochemistry was also performed on [{Ru(Tp)(dppe)}(2)(MU-adpc)] to generate the mixed-valence state. The intense intervalence transition that is observed in the near-IR is very similar to that previously reported for [{Ru(trpy)(bpy)}(2)(MU-adpc)](2+), where trpy is 2,2':6',2"-terpyridine and bpy is 2,2'-bipyridine, and by analogy identifies [{Ru(Tp)(dppe)}(2)(MU-adpc)](+) as a delocalized mixed-valence complex. PMID- 23339543 TI - Comparison of nanocomplexes with branched and linear peptides for siRNA delivery. AB - Efficient delivery of small interfering RNA (siRNA) remains the greatest technological barrier to the clinical implementation of RNA interference strategies. We are investigating the relationship between the biophysical properties of siRNA nanocomplexes and their transfection efficiency as an approach to the generation of improved formulations. Peptide-based formulations are of great interest, and so in this study we have compared nanocomplex formulations for siRNA delivery containing linear and branched oligolysine or oligoarginine peptides. Peptides were combined with cationic liposomes in siRNA formulations and compared for transfection efficiency, siRNA packaging efficiency, biophysical properties, and particle stability. Nanocomplexes containing linear peptides were more condensed and stable than branched peptide formulations; however, their silencing activity was lower, suggesting that their greater stability might limit siRNA release within the cell. Thus, differences in transfection appeared to be associated with differences in packaging and stability, indicating the importance of optimizing this feature in siRNA nanocomplexes. PMID- 23339545 TI - Single-step process for the deposition of high water contact angle and high water sliding angle surfaces by atmospheric pressure dielectric barrier discharge. AB - Fluorine-free surfaces with high water contact angle (WCA) and high adhesion force to water are prepared by the atmospheric pressure dielectric barrier discharge (AP-DBD) of hexamethyldisiloxane on cold rolled aluminum foil. Water droplets, which remained on the plasma-polymerized hexamethyldisiloxane (ppHMDSO) surface with contact angle of 155 degrees , do not slide even when the surface is tilted vertically or turned upside down. Scanning electron microscopy, atomic force microscopy and confocal microscopy highlight the importance of the dual scale roughness of the ppHMDSO surface. The "sticky" high WCA property is achieved only when the nanometer scale particles generated during the AP-DBD process are present at the surface of the film and combine to the micrometer scale rolling lines of the aluminum substrate. PMID- 23339544 TI - Automatic thickness estimation for skeletal muscle in ultrasonography: evaluation of two enhancement methods. AB - BACKGROUND: Ultrasonography is a convenient technique to investigate muscle properties and has been widely used to look into muscle functions since it is non invasive and real-time. Muscle thickness, a quantification which can effectively reflect the muscle activities during muscle contraction, is an important measure for musculoskeletal studies using ultrasonography. The traditional manual operation to read muscle thickness is subjective and time-consuming, therefore a number of studies have focused on the automatic estimation of muscle fascicle orientation and muscle thickness, to which the speckle noises in ultrasound images could be the major obstacle. There have been two popular methods proposed to enhance the hyperechoic regions over the speckles in ultrasonography, namely Gabor Filtering and Multiscale Vessel Enhancement Filtering (MVEF). METHODS: A study on gastrocnemius muscle is conducted to quantitatively evaluate whether and how these two methods could help the automatic estimation of the muscle thickness based on Revoting Hough Transform (RVHT). The muscle thickness results obtained from each of the two methods are compared with the results from manual measurement, respectively. Data from an aged subject with cerebral infarction is also studied. RESULTS: It's shown in the experiments that, Gabor Filtering and MVEF can both enable RVHT to generate comparable results of muscle thickness to those by manual drawing (mean +/- SD, 1.45 +/- 0.48 and 1.38 +/- 0.56 mm respectively). However, the MVEF method requires much less computation than Gabor Filtering. CONCLUSIONS: Both methods, as preprocessing procedure can enable RVHT the automatic estimation of muscle thickness and MVEF is believed to be a better choice for real-time applications. PMID- 23339546 TI - Investigation of the serum glucocorticoid kinase 1 gene in patients with transient tachypnea of the newborn. AB - OBJECTIVE: The aim of this study was to investigate whether there is a role of the serum glucocorticoid kinase (SGK) 1 gene, which has an effect on the control of the epithelial sodium channels. MATERIALS AND METHOD: This study included patients who were diagnosed with transient tachypnea of the newborn (TTN) with more than 37 weeks of gestation. As the control group, healthy newborns of the same gestational age were included. From each group, within the first 5 d of their lives, 2 cc of whole blood was taken in EDTA tubes, and stored at -80 degrees C. The DNA extraction was performed. RESULTS: There were 32 patients in the TTN, and also 32 patients in the control group. The heterozygous allele rs1057293 (3/28) and rs1743966 (8/28) were located in the encoder region of the SGK 1 gene. In addition, in encoding region of the SGK 1 gene, the Arg97Ile (1/28), which causes the amino acid changes, had a genotype frequency of 0.0357, and a mutation was identified in Arg97Ile. DISCUSSION: We have defined polymorphisms rs1057293 and rs1743966 in the SGK 1 gene, and the Arg97Ile mutation, for the first time in patients with TTN. This pilot study gave us some clues about a genetic basis of TTN phenotype, next to the lack of the pulmonary maturation. PMID- 23339547 TI - Comparative single-dose pharmacokinetics of rasagiline in minipigs after oral dosing or transdermal administration via a newly developed patch. AB - 1. A rasagiline transdermal patch was developed for the treatment of early and advanced Parkinson's disease. Relevant pharmacokinetic parameters of rasagiline obtained after transdermal administration to minipigs were compared with those of rasagiline after oral administration. 2. A total of 18 minipigs were randomly divided into three groups (six animals for each group). A single dose of 1 mg rasagiline tablet was orally administrated to one group. Meanwhile, single dose of 1.25 and 2.5 mg (2 and 4 cm(2)) rasagiline patches were given (at the postauricular skin) to the other two groups, respectively. The pharmacokinetic parameters such as plasma half-life (t1/2), time to peak plasma-concentration (Tmax), mean residence time (MRT), area under the curve (AUC(0-t)) were significantly (p < 0.05) different between transdermal and oral administrations. 3. The plasma half-life (t1/2) of rasagiline (1.25 mg patch: 11.8 +/- 6.5 h, 2.5 mg patch: 12.5 +/- 4.7 h) in minipig following transdermal administration was significantly prolonged as compared with that following the oral administration (1 mg tablet: 4.7 +/- 2.5 h). The dose-normalized relative bioavailability of rasagiline patch in minipig were 178.5% and 156.4%, respectively, for 1.25 and 2.5 mg patches compared with 1 mg rasagiline tablet. The prolonged t1/2 and increased bioavailability of rasagiline patch suggested a possible longer dosing interval compared with oral tablet. PMID- 23339542 TI - Regulation of actin dynamics and protein trafficking during spermatogenesis- insights into a complex process. AB - In the mammalian testis, extensive restructuring takes place across the seminiferous epithelium at the Sertoli-Sertoli and Sertoli-germ cell interface during the epithelial cycle of spermatogenesis, which is important to facilitate changes in the cell shape and morphology of developing germ cells. However, precise communications also take place at the cell junctions to coordinate the discrete events pertinent to spermatogenesis, namely spermatogonial renewal via mitosis, cell cycle progression and meiosis, spermiogenesis and spermiation. It is obvious that these cellular events are intimately related to the underlying actin-based cytoskeleton which is being used by different cell junctions for their attachment. However, little is known on the biology and regulation of this cytoskeleton, in particular its possible involvement in endocytic vesicle mediated trafficking during spermatogenesis, which in turn affects cell adhesive function and communication at the cell-cell interface. Studies in other epithelia in recent years have shed insightful information on the intimate involvement of actin dynamics and protein trafficking in regulating cell adhesion and communications. The goal of this critical review is to provide an updated assessment of the latest findings in the field on how these complex processes are being regulated during spermatogenesis. We also provide a working model based on the latest findings in the field including our laboratory to provide our thoughts on an apparent complicated subject, which also serves as the framework for investigators in the field. It is obvious that this model will be rapidly updated when more data are available in future years. PMID- 23339548 TI - Liquid-liquid miscibility gaps in drug-water binary systems: crystal structure and thermodynamic properties of prilocaine and the temperature-composition phase diagram of the prilocaine-water system. AB - EMLA cream, a "eutectic mixture of local anesthetics", was developed in the early 1980s by Astra Pharmaceutical Production. The mixture of anesthetics containing lidocaine, prilocaine, and water is liquid at room temperature, which is partly due to the eutectic equilibrium between prilocaine and lidocaine at 293 K, as was clear from the start. However, the full thermodynamic background for the stability of the liquid and its emulsion-like appearance has never been elucidated. In the present study of the binary system prilocaine-water, a region of liquid-liquid demixing has been observed, linked to a monotectic equilibrium at 302.4 K. It results in a prilocaine-rich liquid containing approximately 0.7 mol fraction of anesthetic. Similar behavior has been reported for the binary system lidocaine-water (Ceolin, R.; et al. J. Pharm. Sci. 2010, 99 (6), 2756 2765). In the ternary mixture, the combination of the monotectic equilibrium and the above-mentioned eutectic equilibrium between prilocaine and lidocaine results in an anesthetic-rich liquid that remains stable below room temperature. This liquid forms an emulsion-like mixture in the presence of an aqueous solution saturated with anesthetics. Physical properties and the crystal structure of prilocaine are also reported. PMID- 23339549 TI - Ability to cause erythema migrans differs between Borrelia burgdorferi sensu lato isolates. AB - BACKGROUND: Lyme borreliosis is a tick-borne disease caused by Borrelia burgdorferi sensu lato. The variety of characteristic and non-specific clinical manifestations is partially explained by its genetic diversity. We investigated the ability of B. burgdorferi sl isolates to cause erythema migrans. METHODS: The genetic constellation of isolates from ticks was compared to isolates found in erythema migrans. PCR and sequence analysis was performed on the plasmid-encoded ospC and the chromosomal 5S-23S rDNA spacer region (IGS). RESULTS: Seven different B. burgdorferi sl genospecies were identified in 152 borrelia isolates from ticks and erythema migrans biopsies. B afzelii (51%) and B. garinii (27%) were the most common in ticks. From the 44 sequences obtained from erythema migrans samples 42 were B. afzelii, one B. garinii and one B. bavariensis. Significant associations with erythema migrans formation were found for four IGS and two ospC types. Five from 45 ospC types were associated with more than one genospecies. CONCLUSIONS: B. burgdorferi sl isolates differ in their propensity to cause erythema migrans. These differences were also found within genospecies. In other words, although B. afzelii was mostly associated with erythema migrans, some B. afzelii isolates had a low ability to cause erythema migrans. Our data further support the occurrence of plasmid exchange between borrelia genospecies under natural conditions. PMID- 23339551 TI - Activation timing of soleus and tibialis anterior muscles during sit-to-stand and stand-to-sit in post-stroke vs. healthy subjects. AB - INTRODUCTION: Sit-to-stand (SitTS) and stand-to-sit (StandTS) are very important functional tasks that become compromised in stroke patients. As in other voluntary movements, they require an adequate postural control (PC) involving the generation of anticipatory postural adjustments (APAs). In order to give clues for more efficient and directed rehabilitation programs, a deeper knowledge about APAs during challenging and daily life movements is essential. PURPOSE: To analyze the activation timing of tibialis anterior (TA) and soleus (SOL) muscles during SitTS and StandTS in healthy subjects and in post-stroke patients. METHODS: Two groups participated in this study: one composed of ten healthy subjects and the other by ten subjects with a history of stroke and increased H reflex. Electromyographic activity (EMGa) of SOL and TA was analyzed during SitTS and StandTS in the ipsilateral (IPSI) and the contralateral (CONTRA) limb to the side lesion in stroke subjects, and in one limb in healthy subjects. A force plate was used to identify the movement onset. RESULTS: In both sequences, in the stroke group SOL activation timing occurred prior to movement onset, contrary to the pattern observed in the healthy subjects. Statistically significant differences were found in SOL activation timings between each lower limb of the stroke and healthy groups, but no significant differences were found between the IPSI and the CONTRA limb. The TA activation timing seems to be delayed in the CONTRA limb when compared to the healthy subjects and showed a better organization of TA timing activation in StandTS when compared to SitTS. CONCLUSION: Compared to healthy subjects, APAs seem to be altered in both limbs of the post-stroke subjects, with the SOL activation timing being anticipated in both SitTS and StandTS. PMID- 23339550 TI - The gain and loss of chromosomal integron systems in the Treponema species. AB - BACKGROUND: Integron systems are now recognized as important agents of bacterial evolution and are prevalent in most environments. One of the human pathogens known to harbor chromosomal integrons, the Treponema spirochetes are the only clade among spirochete species found to carry integrons. With the recent release of many new Treponema genomes, we were able to study the distribution of chromosomal integrons in this genus. RESULTS: We find that the Treponema spirochetes implicated in human periodontal diseases and those isolated from cow and swine intestines contain chromosomal integrons, but not the Treponema species isolated from termite guts. By examining the species tree of selected spirochetes (based on 31 phylogenetic marker genes) and the phylogenetic tree of predicted integron integrases, and assisted by our analysis of predicted integron recombination sites, we found that all integron systems identified in Treponema spirochetes are likely to have evolved from a common ancestor--a horizontal gain into the clade. Subsequent to this event, the integron system was lost in the branch leading to the speciation of T. pallidum and T. phagedenis (the Treponema sps. implicated in sexually transmitted diseases). We also find that the lengths of the integron attC sites shortened through Treponema speciation, and that the integron gene cassettes of T. denticola are highly strain specific. CONCLUSIONS: This is the first comprehensive study to characterize the chromosomal integron systems in Treponema species. By characterizing integron distribution and cassette contents in the Treponema sps., we link the integrons to the speciation of the various species, especially to the pathogens T. pallidum and T. phagedenis. PMID- 23339552 TI - Automatic design of decision-tree algorithms with evolutionary algorithms. AB - This study reports the empirical analysis of a hyper-heuristic evolutionary algorithm that is capable of automatically designing top-down decision-tree induction algorithms. Top-down decision-tree algorithms are of great importance, considering their ability to provide an intuitive and accurate knowledge representation for classification problems. The automatic design of these algorithms seems timely, given the large literature accumulated over more than 40 years of research in the manual design of decision-tree induction algorithms. The proposed hyper-heuristic evolutionary algorithm, HEAD-DT, is extensively tested using 20 public UCI datasets and 10 microarray gene expression datasets. The algorithms automatically designed by HEAD-DT are compared with traditional decision-tree induction algorithms, such as C4.5 and CART. Experimental results show that HEAD-DT is capable of generating algorithms which are significantly more accurate than C4.5 and CART. PMID- 23339553 TI - Exciton localization and optical properties improvement in nanocrystal-embedded ZnO core-shell nanowires. AB - We present a comparative investigation of the morphological, structural, and optical properties of vertically aligned ZnO nanowires (NWs) before and after high energy argon ion (Ar(+)) milling. It is found that the outer regions of the as-grown sample change from crystalline to amorphous, and ZnO core-shell NWs with ZnO nanocrystals embedded are formed after Ar(+) milling. Optical properties of the ZnO NWs have been investigated systematically through power and temperature dependent photoluminescence measurements, and the phenomenon of exciton localization as well as the relevant favorable photoluminescence characteristics is elucidated. Interestingly, under high density optical pumping at room temperature, coherent random lasing action is observed, which is ascribed to exciton localization and strong scattering. Our results on the unique optical properties of localized exciton in ZnO core-shell nanostructures shed light on developing stable and high-efficiency excitonic optoelectronic devices such as light-emitting diodes and lasers. PMID- 23339554 TI - Dynamics of decanethiol self-assembled monolayers on Au(111) studied by time resolved scanning tunneling microscopy. AB - We investigated the dynamics of decanethiol self-assembled monolayers on Au(111) surfaces using time-resolved scanning tunneling microscopy at room temperature. The expected ordered phases (beta, delta, chi*, and phi) and a disordered phase (epsilon) were observed. Current-time traces with the feedback loop disabled were recorded at different locations on the surface. The sulfur end group of the decanethiolate molecule exhibits a stochastic two-level switching process when the molecule is adsorbed in a (local) beta phase registry. This two-level process is attributed to the diffusion of the Au-thiolate complex between two adjacent adsorption sites. The irregular current jumps in the current-time traces recorded on the tails of decanethiolate molecules in the ordered beta, delta, and chi* phases are ascribed to wagging of the alkyl tails. Finally, the disordered phase is characterized by even larger current jumps, which indicates that the tail of the decanethiolate flips up occasionally and makes contact with the tip. Our experiments reveal that the massive dynamics of the self-assembled monolayer is due to diffusion of decanethiol-Au complexes, rather than the diffusion of decanethiolate molecules. PMID- 23339555 TI - Postoperative performance of the Quartet(r) left ventricular heart lead. AB - INTRODUCTION: The Quartet((r)) left ventricular (LV) lead is the first with 4 pacing electrodes (tip and 3 rings) that enables pacing from 10 different pacing vectors. Postoperative performance of this lead was evaluated in a prospective, nonrandomized, multicenter IDE study. METHODS: Patients with standard indications for CRT-D were enrolled. Electrical performance and presence of phrenic nerve stimulation (PNS) were assessed during pacing from each of 10 vectors at predischarge (within 7 days), 1 month, and 3 months postimplant. RESULTS: The Quartet LV lead was implanted successfully in 170 patients (95.5% implant success rate, 68 +/- 11 years, 68.5% male, LVEF: 25 +/- 7%, NYHA class III: 98.3% and class IV: 1.7%). Mean follow-up was 4.7 +/- 1.9 months. Capture threshold and impedance for each of the 10 LV lead pacing vectors remained stable during follow up. LV lead dislodgement occurred in 6 (3.5%) patients and PNS was observed in 23 (13.5%) patients. PNS was resolved noninvasively in all 23 (100%) patients, either by reprogramming to pace from the additional LV lead pacing vectors alone (13 pts, 56.5%), reprogramming to pace from the additional LV lead pacing vectors and reprogramming pacing output (4 pts, 17.4%), or by reprogramming pacing output alone (6 pts, 26.1%). CONCLUSIONS: The Quartet LV lead electrical performance was stable and was associated with a high implant success and low dislodgement rate during 3-month follow-up. In all patients with PNS, the 10 pacing vectors combined with reduced output programming enabled the elimination of PNS noninvasively. PMID- 23339556 TI - Spanish-English speech perception in children and adults: developmental trends. AB - This study explored the developmental trends and phonetic category formation in bilingual children and adults. Participants included 30 fluent Spanish-English bilingual children, aged 8-11, and bilingual adults, aged 18-40. All completed gating tasks that incorporated code-mixed Spanish-English stimuli. There were significant differences in performance according to phonotactic construction of the stimuli, with fastest word recognition on words with voiceless initial consonants. Analysis of developmental trends revealed significant differences in children's performance by grade level and fastest recognition on English voiceless initial consonants than Spanish voiceless initial consonants. Differences in voice onset time between English and Spanish may have contributed to quicker recognition of English voiceless consonants than Spanish voiceless consonants. It is also possible that increased exposure to both spoken and written English may account for faster recognition of English voiceless words than Spanish voiceless words. In conclusion, multiple factors may influence perception of a second language. PMID- 23339557 TI - Cognitive reserve preserves cognitive function in obese individuals. AB - Obesity is an established risk factor for cognitive impairment. Theories of cognitive reserve suggest that premorbid factors, such as intellectual ability, may attenuate the expression of cognitive impairment due to age or disease. The current study examined whether cognitive reserve, defined as estimated premorbid intellectual ability, moderates the relationship between obesity and cognitive function in obese adults. Participants without major medical or psychological conditions completed a computerized battery of neuropsychological tests. Hierarchical regression models found a significant interaction between BMI and cognitive reserve for attention/executive function and memory, suggesting that cognitive reserve attenuates the expression of obesity-related cognitive impairment. PMID- 23339558 TI - Competitive coordination of Cu2+ between cysteine and pyrophosphate ion: toward sensitive and selective sensing of pyrophosphate ion in synovial fluid of arthritis patients. AB - Direct selective and sensitive sensing of pyrophosphate ion (PPi) in synovial fluid of arthritis patients is of great importance because of its crucial roles in the diagnosis and therapy of arthritic diseases. In this study, we demonstrate a sensitive and selective method for PPi sensing in synovial fluid of arthritis patients with gold nanoparticles (Au-NPs) as the signal readout based on the competitive coordination chemistry of Cu(2+) between cysteine and PPi. Initially, Au-NPs stabilized with cysteine are red in color and exhibit absorption at 519 nm in the UV-vis spectrum. The addition of an aqueous solution of Cu(2+) to the Au NPs dispersion containing cysteine causes the aggregation of Au-NPs, resulting in the wine red-to-blue color change and the appearance of a new absorption at 650 nm in the UV-vis spectrum of the Au-NPs dispersion. The subsequent addition of PPi to the Au-NPs aggregation well solubilizes the aggregated Au-NPs with the changes in both the color and the UV-vis spectrum of the Au-NPs dispersion. These changes are ascribed to the higher coordination reactivity between Cu(2+) and PPi than that between Cu(2+) and cysteine. On the basis of this, the concentration of PPi can be visualized with the naked eyes through the blue-to-wine red color change of the Au-NPs dispersion and quantitatively determined by UV-vis spectroscopy. Under the optimized conditions, the ratio of the absorbance at 650 nm (A(650)) to that at 519 nm (A(519)) shows a linear relationship with PPi concentration within a concentration range from 130 nM to 1.3 mM. The method demonstrated here is highly sensitive, free from the interference from other species in the synovial fluid, and is thus particularly useful for fast and simple clinic diagnosis of arthritic diseases. PMID- 23339559 TI - Relational responding by eastern box turtles (Terrapene carolina) in a series of color discrimination tasks. AB - Prior work with chelonians has demonstrated their capacity for successful performance in cognitive tasks, including those requiring color discrimination. Here, we sought to expand on historical research and determine whether eastern box turtles (Terrapene carolina) are capable of not only making simple color discriminations but also whether they can demonstrate abstract concept formation evidenced by using a relational response rule in their discrimination performance. Two eastern box turtles were rapidly and successfully trained on a black-and-white two-choice discrimination task using painted paddles and food reinforcement. After mastery, a medium gray paddle was added as a choice stimulus and turtle "Flippy" was reinforced for selecting the darker of the 2 stimuli presented in each trial, and turtle "Mario" was reinforced for selecting the lighter of the paddles presented. Nonreinforced probe trials incorporating light and dark gray stimuli paired with all other color options were then added to each session to test the turtles' ability to use the relationship between choice stimuli to guide responding. The turtles successfully selected the paddles corresponding to their assigned relational response rule of "darker" or "lighter" at a level significantly above that predicted by chance. The turtles then demonstrated immediate generalization of their relational rule in testing with a novel array of blue paddles. Finally, the turtles continued to use their relational rule when presented with a novel array of green paddles in a traditional transposition task. Together, these findings support the capacity for higher order cognitive functioning in chelonians beyond that previously described. PMID- 23339560 TI - Spontaneous triadic engagement in bonobos (Pan paniscus) and chimpanzees (Pan troglodytes). AB - Humans are believed to have evolved a unique motivation to participate in joint activities that first develops during infancy and supports the development of shared intentionality. We conducted five experiments with bonobos (Pan paniscus) and chimpanzees (Pan troglodytes) (Total n = 119) to assess their motivation to spontaneously participate in joint activities with a conspecific or a human. We found that even the youngest subjects preferred to interact together with a human and a toy rather than engaging in an identical game alone. In addition, we found that subjects could spontaneously interact with a human in a turn-taking game involving passing a ball back and forth and used behaviors to elicit additional interaction when the game was disrupted. However, when paired with a conspecific, subjects preferred to interact with an object individually rather than together. Our results indicate that nonhuman apes are motivated to engage in triadic activities if they occur spontaneously with humans and require a minimum amount of coordination. These findings leave open the question of whether these activities are coordinated through shared intentions. PMID- 23339561 TI - Personality structure, sex differences, and temporal change and stability in wild white-faced capuchins (Cebus capucinus). AB - Research on nonhuman primate personality dimensions has focused on a small number of taxa, and little of this work has focused on wild populations. We used ratings to assess personality structure in wild white-faced capuchins (Cebus capucinus) over a 9-year period, using a capuchin-specific rating instrument based partly on existing instruments. Adequate levels of interrater reliability were found for 24 of 26 items. A longitudinal analysis found that 15 of these items showed significant rank-order stability from adolescence through early adulthood. Principal components analysis revealed 5 components. Four of these components were recognizable "Big Five" dimensions: Extraversion (E), Openness (O), Neuroticism (N), and Agreeableness (A). A dimension incorporating aspects of high O and high Conscientiousness (C) was labeled Eccentricity. Every dimension except for N showed significant rank-order stability from adolescence through early adulthood. Males were more extraverted, open, neurotic, and eccentric than females, whereas females were more agreeable than males. A cross-sectional analysis revealed that openness and agreeableness declined, whereas eccentricity increased, during adulthood. The item content of capuchin Extraversion and Openness, and the existence of a distinctive Eccentricity dimension, are consistent with known characteristics of capuchin social and ecological adaptations, specifically the central roles of alliances, behavioral innovation, and social learning. PMID- 23339563 TI - Clinical and research markers of oxidative stress in chronic kidney disease. AB - CONTEXT: Kidney-related pathologies have increasing prevalence rates, produce a considerable financial burden, and are characterized by elevated levels of oxidative stress (OS). OBJECTIVE: This review examines relationships between chronic kidney disease (CKD) and markers of OS and antioxidant status (AS). METHODS: A systematic review of MEDLINE-indexed clinical trials, randomized controlled trials and comparative studies that examined OS and AS was performed. RESULTS AND CONCLUSION: Several markers emerged as well-suited indicators of OS and AS in CKD: malondialdehyde, F2-isoprostanes, lipid hydroperoxides, asymmetric dimethylarginine, 8-oxo-7,8-dihydro-2'-deoxyguanosine, protein carbonyls, advanced oxidation protein products and glutathione-related activity. PMID- 23339562 TI - Recent alcohol consumption and risk of incident ovarian carcinoma: a pooled analysis of 5,342 cases and 10,358 controls from the Ovarian Cancer Association Consortium. AB - BACKGROUND: Studies evaluating the association between alcohol intake and ovarian carcinoma (OC) are inconsistent. Because OC and ovarian borderline tumor histologic types differ genetically, molecularly and clinically, large numbers are needed to estimate risk associations. METHODS: We pooled data from 12 case control studies in the Ovarian Cancer Association Consortium comprising 5,342 OC cases, 1,455 borderline tumors and 10,358 controls with quantitative information on recent alcohol intake to estimate odds ratios (OR) and 95% confidence intervals (CI) according to frequencies of average daily intakes of beer, wine, liquor and total alcohol. RESULTS: Total alcohol intake was not associated with all OC: consumption of >3 drinks per day compared to none, OR=0.92, 95% CI=0.76 1.10, P trend=0.27. Among beverage types, a statistically non-significant decreased risk was observed among women who consumed >8 oz/d of wine compared to none (OR=0.83, 95% CI=0.68-1.01, P trend=0.08). This association was more apparent among women with clear cell OC (OR, 0.43; 95% CI, 0.22-0.83; P trend=0.02), although based on only 10 cases and not statistically different from the other histologic types (P value for statistical heterogeneity between histologic types = 0.09). Statistical heterogeneity of the alcohol- and wine-OC associations was seen among three European studies, but not among eight North American studies. No statistically significant associations were observed in separate analyses evaluating risk with borderline tumors of serous or mucinous histology. Smoking status did not significantly modify any of the associations. CONCLUSIONS: We found no evidence that recent moderate alcohol drinking is associated with increased risk for overall OC, or that variation in risk is associated strongly with specific histologic types. Understanding modifiable causes of these elusive and deadly cancers remains a priority for the research community. PMID- 23339565 TI - Preservation of superhydrophobic and superoleophobic properties upon wear damage. AB - Superhydrophobicity and self-cleaning require a combination of surface topography and low-energy surfaces, where mechanical damage of the topography or contamination with oils lead to loss of the nonwetting properties. We show that such vulnerability can be solved by superamphiphobic (i.e., both superhydrophobic and superoleophobic) surfactant-coated aerogel surfaces. Using silica aerogels as model materials, the self-similar network structure allows fresh re-entrant surface topographies even after removal of the uppermost layer upon mechanical abrasion, and superoleophobicity suppresses oil contamination. Given the recent progress toward mechanically strong aerogels, we foresee that the concept can open routes for robust self-cleaning coating technologies. PMID- 23339564 TI - Asymmetric ligand binding facilitates conformational transitions in pentameric ligand-gated ion channels. AB - The anesthetic propofol inhibits the currents of the homopentameric ligand-gated ion channel GLIC, yet the crystal structure of GLIC with five propofol molecules bound symmetrically shows an open-channel conformation. To address this dilemma and determine if the symmetry of propofol binding sites affects the channel conformational transition, we performed a total of 1.5 MUs of molecular dynamics simulations for different GLIC systems with propofol occupancies of 0, 1, 2, 3, and 5. GLIC without propofol binding or with five propofol molecules bound symmetrically, showed similar channel conformation and hydration status over multiple replicates of 100-ns simulations. In contrast, asymmetric binding to one, two or three equivalent sites in different subunits accelerated the channel dehydration, increased the conformational heterogeneity of the pore-lining TM2 helices, and shifted the lateral and radial tilting angles of TM2 toward a closed channel conformation. The results differentiate two groups of systems based on the propofol binding symmetry. The difference between symmetric and asymmetric groups is correlated with the variance in the propofol-binding cavity adjacent to the hydrophobic gate and the force imposed by the bound propofol. Asymmetrically bound propofol produced greater variance in the cavity size that could further elevate the conformation heterogeneity. The force trajectory generated by propofol in each subunit over the course of a simulation exhibits an ellipsoidal shape, which has the larger component tangential to the pore. Asymmetric propofol binding creates an unbalanced force that expedites the channel conformation transitions. The findings from this study not only suggest that asymmetric binding underlies the propofol functional inhibition of GLIC, but also advocate for the role of symmetry breaking in facilitating channel conformational transitions. PMID- 23339566 TI - Trends in racial/ethnic disparities in medical and oral health, access to care, and use of services in US children: has anything changed over the years? AB - INTRODUCTION: The 2010 Census revealed the population of Latino and Asian children grew by 5.5 million, while the population of white children declined by 4.3 million from 2000-2010, and minority children will outnumber white children by 2020. No prior analyses, however, have examined time trends in racial/ethnic disparities in children's health and healthcare. The study objectives were to identify racial/ethnic disparities in medical and oral health, access to care, and use of services in US children, and determine whether these disparities have changed over time. METHODS: The 2003 and 2007 National Surveys of Children's Health were nationally representative telephone surveys of parents of 193,995 children 0-17 years old (N = 102,353 in 2003 and N = 91,642 in 2007). Thirty-four disparities indicators were examined for white, African-American, Latino, Asian/Pacific-Islander, American Indian/Alaskan Native, and multiracial children. Multivariable analyses were performed to adjust for nine relevant covariates, and Z-scores to examine time trends. RESULTS: Eighteen disparities occurred in 2007 for >=1 minority group. The number of indicators for which at least one racial/ethnic group experienced disparities did not significantly change between 2003-2007, nor did the total number of specific disparities (46 in 2007). The disparities for one subcategory (use of services), however, did decrease (by 82%). Although 15 disparities decreased over time, two worsened, and 10 new disparities arose. CONCLUSIONS: Minority children continue to experience multiple disparities in medical and oral health and healthcare. Most disparities persisted over time. Although disparities in use of services decreased, 10 new disparities arose in 2007. Study findings suggest that urgent policy solutions are needed to eliminate these disparities, including collecting racial/ethnic and language data on all patients, monitoring and publicly disclosing disparities data annually, providing health-insurance coverage and medical and dental homes for all children, making disparities part of the national healthcare quality discussion, ensuring all children receive needed pediatric specialty care, and more research and innovative solutions. PMID- 23339568 TI - DC voltammetry of electro-deoxidation of solid oxides. PMID- 23339567 TI - Monocyte chemoattractant protein-1 affects migration of hippocampal neural progenitors following status epilepticus in rats. AB - BACKGROUND: Epilepsy is a common brain disorder characterized by a chronic predisposition to generate spontaneous seizures. The mechanisms for epilepsy formation remain unknown. A growing body of evidence suggests the involvement of inflammatory processes in epileptogenesis. In the present study, we investigated the involvement of monocyte chemoattractant protein-1 (MCP-1) in aberrant migration of hippocampal progenitors in rats after the insult of status epilepticus (SE). METHODS: SE was induced with pilocarpine in Sprague-Dawley rats. Transcriptional expression of MCP-1 in the dentate gyrus (DG) was measured using quantitative real-time PCR. From 1 to 28 days after SE, the temporal profiles of MCP-1 protein expression in DG were evaluated using enzyme-linked immunosorbent assay. Chemokine (C-C motif) receptor 2 (CCR2) expression in doublecortin-positive neuronal progenitors was examined using double-labeling immunohistochemistry. The involvement of MCP-1/CCR2 signaling in aberrant neuronal progenitor migration in the epileptic hippocampus was assessed in the SE rats using a CCR2 antagonist, RS102895, and the ectopic migration of neuronal progenitors was determined using Prox1/doublecortin double immunostaining. RESULTS: After SE, MCP-1 gene was significantly upregulated and its corresponding protein expression in the DG was significantly increased on days 1 and 3. Some hilar ectopic progenitor cells of SE rats expressed the MCP-1 receptor, CCR2. Notably, the ectopic migration of neuronal progenitors into hilus was attenuated by a blockade of the MCP-1/CCR2 interaction with a selective CCR2 inhibitor, RS102895. CONCLUSIONS: An increase in dentate MCP-1 is associated with seizure induced aberrant migration of neuronal progenitors through the interaction with CCR2. The upregulation of MCP-1 after an insult of SE may play a role in the generation of epilepsy. PMID- 23339569 TI - Quantitative analysis of fetal DNA in maternal plasma in gestational diabetes mellitus, iron deficiency anemia and gestational hypertension pregnancies. AB - OBJECTIVE: To quantify circulating fetal DNA (fDNA) levels in the second and third trimesters of normal healthy pregnant individuals and pregnant women with the following clinical conditions: gestational diabetes mellitus (GDM), iron deficiency anemia and gestational hypertension (GHT). METHODS: The SRY gene located on the Y chromosome was used as a unique fetal marker. The fDNA was extracted from maternal plasma and the SRY gene concentrations were measured by quantitative real-time polymerase chain reaction (PCR) amplification using TaqMan dual labeled probe system. RESULTS: No significant differences were observed in the mean fDNA concentration between normal and GDM pregnancy samples (p > 0.05) and also between normal and anemic pregnancy samples (p > 0.05) in both trimesters, but significant differences were observed between the third trimester normal and GHT pregnancy samples (p = 0.001). GDM and iron deficiency anemia do not affect the levels of fDNA in maternal plasma while GHT significantly elevates the levels of fDNA in maternal plasma. CONCLUSIONS: Increased amount of circulating fDNA in maternal plasma could be used for early identification of adverse pregnancies. GDM and anemia do not affect the levels of fDNA in maternal plasma while GHT significantly elevates the levels of fDNA in maternal plasma. Hence, the elevated fDNA values could be used as a potential screening marker in pregnancies complicated with GHT but not with GDM and iron deficiency anemia. PMID- 23339570 TI - Ultrasonic relaxation measurements in aqueous solution and molecular orbital calculation on imipramine. AB - Ultrasonic absorption coefficients have been measured in aqueous solution of imipramine {3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1 amine} in the frequency range of 0.8-220 MHz at 25 degrees C. The frequency dependences of the observed absorption was characterized by a Debye-type relaxational equation with two relaxation frequencies, although only one relaxation had been observed in aqueous solutions of the related molecule amitriptyline. Both of the relaxation frequencies in imipramine solutions were found to be independent of the solute concentration and the amplitudes of the relaxational absorptions increase linearly with increasing solute concentration. It was therefore concluded that these two relaxations are associated with unimolecular reactions, such as a structural change due to rotational motions of the bond in the specified group in the imipramine molecule. To analyze quantitatively the source of the relaxations, semiempirical molecular orbital methods have been applied to determine the standard enthalpy of formation of the imipramine molecule at various dihedral angles around the bonds in the alkylamine side chain. According to the results, only one rotational motion of carbon-carbon bond in the side chain was found to be appropriate and the three minima of the standard enthalpy of formation was obtained as a function of the rotational angle. At the three minimum positions, the values of the standard enthalpy of formation are almost the same. With the assumptions (a) that rotational motion is not accompanied by a volume change of the reaction and (b) that the standard free energy change is close to the difference in the values between the standard enthalpies of formation, the equilibrium constants for the rotational isomerization have been calculated to be near unity. Hence, the forward and backward rate constants of the isomerization reactions are nearly the same. If one assumes that there are two kinds of rotational motions in one bond of the molecule, one proceeds with a rate constant on the order of 10(8) s(-1), whereas the other with a rate constant on the order of 10(6) s(-1). The faster and slower processes are also distinguished by the height of the standard enthalpy of formation. PMID- 23339571 TI - Phage-induced diversification improves host evolvability. AB - BACKGROUND: Bacteriophage (viruses that infect bacteria) are of key importance in ecological processes at scales from biofilms to biogeochemical cycles. Close interaction can lead to antagonistic coevolution of phage and their hosts. Selection pressures imposed by phage are often frequency-dependent, such that rare phenotypes are favoured; this occurs when infection depends on some form of genetic matching. Also, resistance to phage often affects host fitness by pleiotropy (whereby mutations conferring resistance affect the function of other traits) and/or direct costs of resistance mechanisms. RESULTS: Here a simple model of bacteria and bacteriophage coevolving in a resource-limited chemostat is used to study the effect of coevolving phage on the evolution of bacterial hosts. Density-dependent mortality from phage predation limits the density of any single bacterial strain, preventing competitive exclusion by faster-growing strains. Thus multiple strains can coexist by partitioning resources and stable high diversity is created by negative frequency-dependent selection from phage. Standing bacterial diversity promotes adaptation in dynamic environments, since it increases the likelihood of a pre-existing genotype being suited to altered conditions. In addition, frequency-dependent selection for resistance creates transient local trade-offs between growth rate and resistance that allow bacterial strains to adapt across fitness valleys. Thus bacterial populations that (in the absence of phage) would have been trapped at sub-optimal local peaks in the adaptive landscape are able (in the presence of phage) to reach alternate higher peaks than could have been reached by mutation alone. CONCLUSIONS: This study shows that reasonable assumptions for coevolution of bacteria and phage create conditions in which phage increase the evolutionary potential of their hosts. Thus phage, in contrast to their deleterious effects on individual host cells, can confer an evolutionary benefit to bacterial populations. These findings have implications for the role of phage in ecosystem processes, where they have mainly been considered as a mortality factor; these results suggest that on long timescales phage may actually increase bacterial productivity by aiding the evolution of faster-growing strains. Furthermore, these results suggest that the therapeutic use of phage to treat bacterial infections (phage therapy) could have unintended negative side-effects. PMID- 23339572 TI - Chemical reactivity and biological activity of chalcones and other alpha,beta unsaturated carbonyl compounds. AB - Abstract 1. Chalcones are structural analogues of benzalacetophenone (BAP). Several derivatives have been identified in plants and anticarcinogenic and anti inflammatory properties were attributed to the compounds, probably related to their direct antioxidant activity or stimulatory effects on the expression of endogenous defence enzymes like hemeoxygenase-1 (HO-1). HO-1 expression is triggered by the Nrf2-Keap1 signalling pathway, initiated by the addition of chalcones to thiol groups of Keap1 via Michael-type reaction. 2. The present study used a model system estimating the reactivity of different synthetic chalcones and other alpha,beta-unsaturated carbonyl compounds with thiols and compared the chemical reactivity with the biological activity, measured by HO-1 expression in human dermal fibroblasts. 3. Chemical reactivity with the thiol group of N-acetylcysteine was determined with 5,5'-dithiobis-(2-nitrobenzoic acid) and followed chemical principles of structure-reactivity relationship. Most reactive were sulforaphane, dimethylfumarate, chalcone 3 ((2E)-1-phenyl-3 pyrimidin-2-ylprop-2-en-1-one) and chalcone 7 (1,3-diphenylprop-2-yn-1-one). This result demonstrates that alpha,beta-unsaturated carbonyl derivatives react with thiols differently. All compounds were also biologically active; however, expression of HO-1 was not only related to the chemical reactivity but also to the lipophilicity of the molecules which likely affected transmembrane uptake. Most efficient inducers of HO-1 expression were BAP, 4-hydroxynonenal and chalcone 1 (4-[(1E)-3-oxo-3-phenylprop-1-en-1-yl]benzonitrile), chalcone 5 ((2E) 1-phenyl-3-[4-(trifluoromethyl)-phenyl]prop-2-en-1-one) and chalcone 7. PMID- 23339573 TI - Largely enhanced efficiency in ZnO nanowire/p-polymer hybridized inorganic/organic ultraviolet light-emitting diode by piezo-phototronic effect. AB - ZnO nanowire inorganic/organic hybrid ultraviolet (UV) light-emitting diodes (LEDs) have attracted considerable attention as they not only combine the high flexibility of polymers with the structural and chemical stability of inorganic nanostructures but also have a higher light extraction efficiency than thin film structures. However, up to date, the external quantum efficiency of UV LED based on ZnO nanostructures has been limited by a lack of efficient methods to achieve a balance between electron contributed current and hole contributed current that reduces the nonradiative recombination at interface. Here we demonstrate that the piezo-phototronic effect can largely enhance the efficiency of a hybridized inorganic/organic LED made of a ZnO nanowire/p-polymer structure, by trimming the electron current to match the hole current and increasing the localized hole density near the interface through a carrier channel created by piezoelectric polarization charges on the ZnO side. The external efficiency of the hybrid LED was enhanced by at least a factor of 2 after applying a proper strain, reaching 5.92%. This study offers a new concept for increasing organic LED efficiency and has a great potential for a wide variety of high-performance flexible optoelectronic devices. PMID- 23339574 TI - Editorial: separation surgery. PMID- 23339576 TI - Pericardial pouch: a cause of low voltage during epicardial mapping and ablation of ventricular tachycardia. PMID- 23339577 TI - Redox-active pi-conjugated organometallic monolayers: pronounced Coulomb blockade characteristic at room temperature. AB - We report the electrical transport characteristics of a series of molecular wires, fc-C=C-C6H4-SAc (fc = ferrocenyl; Ac = acetyl) and AcS-C6H4-C=C-(fc)n-C=C C6H4-SAc (n = 2, 3), consisting of multiple redox-active ferrocenyl centers. The self-assembled monolayers of these molecular wires on Au surfaces were comprehensively characterized by electrochemistry and conductive atomic force microscopy techniques. Characterization of the wires revealed that electron transport is made extremely efficient by the organometallic redox states. There is a strong electronic coupling between ferrocenyl moieties, and superior electron-transport ability exists through these semirigid molecular wires. Standard rate constants for the electron transfer between the electrode and the ferrocenyl moieties were measured for the monolayers by a potential-step chronoamperometry technique. The electron conduction through the molecular wires was estimated using the monolayers as a bridge from the Au(111) metal surface to the gold tip of a conductive atomic force microscope (CAFM). Using the CAFM, Coulomb blockade behavior arising from the capacitive charging of the multinuclear redox-active molecules was observed at room temperature. The conductance switching was mediated by the presence of various ferrocenyl redox states and each current step corresponded to a specific redox state. PMID- 23339575 TI - Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide. AB - A consensus has famously yet to emerge on the locus and mechanisms underlying the expression of the canonical NMDA receptor-dependent form of LTP. An objective assessment of the evidence leads us to conclude that both presynaptic and postsynaptic expression mechanisms contribute to this type of synaptic plasticity. PMID- 23339578 TI - Larch arabinogalactan effects on reducing incidence of upper respiratory infections. AB - OBJECTIVE: Larch arabinogalactan (ResistAid * ) may prevent cold infections due to its immune-stimulatory properties. In a placebo-controlled, double-blind, randomized clinical trial, the effect of a proprietary larch arabinogalactan preparation on the incidences of common colds and its effect on cold symptoms, as a well established model for immune function, was compared to placebo. RESEARCH DESIGN AND METHODS: A total of 199 healthy participants who had a self reported cold infection rate of three in 6 months were randomly assigned to receive a total of either 4.5 g of an arabinogalactan preparation (n = 101) or placebo (n = 98) over a period of 12 weeks. MAIN OUTCOME MEASURES: The participants documented each common cold episode in a diary, and rated 10 predefined infection symptoms on a 4 point rating scale during an infection period, resulting in an infection score. The common cold episodes were confirmed by medical doctors. CLINICAL TRIAL REGISTRATION: ISRCTN41183655. RESULTS: In the full analysis set (FAS), arabinogalactan tended to decrease the incidence of common cold (p = 0.055). The number of participants affected by a cold was significantly reduced by arabinogalactan supplementation (p = 0.038). Concerning the per protocol (PP) collective, the incidences of common cold (p = 0.040) and the number of participants affected by the infection (p = 0.033) were significantly fewer after arabinogalactan compared to placebo consumption. The severity of symptoms at episode start as experienced by the participants was significantly higher after arabinogalactan supplementation (p = 0.028). The treatment was well tolerated with no significant differences between the study groups. CONCLUSION: The present study demonstrated that larch arabinogalactan increased the body's potential to defend against common cold infection. While the immunomodulatory effect of arabinogalactan can be assumed, its mechanism of action remains to be elucidated. PMID- 23339579 TI - NASR: an effective approach for simultaneous noise and artifact suppression in NMR spectroscopy. AB - As a powerful tool for biological analysis, especially protein structure and dynamic studies, nuclear magnetic resonance (NMR) spectroscopy suffers from intrinsic low signal to nose ratio (SNR) and long acquisition time required for multidimensional (nD) experiments. Nonuniform sampling (NUS) can effectively speed up the experiment but often introduces artifacts into the spectrum. In addition to the development of highly sensitive hardware and NMR pulse sequences, data postprocessing is a relative simple and cost-effective method to improve the SNR and suppress the artifacts. In this work, we propose an effective approach for simultaneously suppressing noise and artifacts based on the resampling principle. The method is named NASR for short and tested using one-, two-, and three-dimensional (1D, 2D, and 3D) NMR spectra that were acquired using ether conventional or NUS (spiral and random, for 3D) approaches. The results reveal that the NASR is fast and applicable for improving the quality of 1D to nD NMR spectra with all kinds of sampling schemes. PMID- 23339580 TI - Psychosocial risk factors for HIV sexual risk among Indian men who have sex with men. AB - Indian men who have sex with men (MSM) are at increased risk for HIV compared to the general Indian population. Psychosocial factors may be uniquely associated with HIV risk among Indian MSM and may moderate the beneficial impact of standard HIV prevention approaches. Psychiatric diagnostic interviews and psychosocial and sexual risk assessments were conducted among 150 MSM in Mumbai, India. Logistic regression was employed to examine the association of psychiatric disorders and psychosocial problems to recent sexual risk behavior. Twenty-five percent of participants reported engaging in unprotected anal sex (UAS) during their last sexual contact with a man. Men who were married to a woman were more likely to have engaged in UAS during their last sexual contact with a man (35% vs. 17%, p=0.018). In multivariable models, significant predictors of engaging in UAS were current major depression (adjusted odds ratio [AOR]=2.61; 95% confidence interval [CI] 1.07, 6.39) and number of stressful life events (AOR=0.91; 95% CI 0.83, 0.99). Alcohol dependence, anxiety, and self-esteem were not associated with engaging in UAS. Indian MSM with depression are at higher odds of engaging in UAS compared to MSM without depression. HIV prevention programs for Indian MSM may benefit from incorporating treatment or triage for mental health problems. PMID- 23339581 TI - The relationship between alcohol and cognitive functioning following traumatic brain injury. AB - The present study aimed to examine the association between frequency and quantity of alcohol consumption and cognitive functioning following traumatic brain injury (TBI). Sixty moderately to severely injured individuals had completed the Alcohol Use Disorders Identification Test (AUDIT) to measure preinjury alcohol use soon after injury and were recruited and assessed with AUDIT and Time Line Follow-Back (TLFB), as a measure of frequency and quantity of alcohol consumption at 6-9 months post injury. Fifty participants completed both AUDIT and TLFB at a follow up assessment at 12-15 months post injury. Measures of processing speed/attention, memory, and executive function were also administered. Regression analyses were used to examine the relationships between alcohol use and cognition at the two occasions of measurement. Harmful or hazardous alcohol use pre injury was associated with poorer memory performance on the California Verbal Learning Test (CVLT-II) and slower processing speed on Symbol Digit Modalities Test on average across postinjury measurement occasions, but not with executive functioning, measured by the Modified Six Elements Test (MSET) at 6-9 months post injury. On the other hand, executive functioning on MSET 6-9 months post injury was significantly poorer in participants who were consuming any alcohol at all in the month prior to follow-up assessment. The current study provides evidence showing that pre- and postinjury alcohol use is negatively associated with different aspects of cognitive functioning following TBI. In addition to providing some support for the provision of advice to abstain from alcohol after injury, these findings suggest that interventions to reduce postinjury alcohol use may be useful. PMID- 23339582 TI - High-resolution insight into G-overhang architecture. AB - NMR and fluorescence spectroscopy were used to address the effect of intracellular molecular crowding and related hydration on a model telomeric G quadruplex (G4) DNA structure (d(AG(3)(TTAGGG)(3))). d(AG(3)(TTAGGG)(3)) prevalently adopted the hybrid-1 conformation in vivo, ex vivo, and in dilute potassium-based solution, while it formed the parallel propeller fold in water depleted potassium-based solution, a commonly used model system for studying intracellular molecular crowding. The dilute potassium-based solution appeared to imitate the properties of the cellular environment required for d(AG(3)(TTAGGG)(3)) folding under in vivo and ex vivo conditions. High-resolution NMR investigations of site-specifically (15)N-labeled G4 units in native-like single-stranded telomeric DNA revealed that the 3'-terminal and internal G4 unit predominantly coexist in 2-tetrad antiparallel basket and hybrid-2 structures that are arranged in "beads-on-a-string"-like fashion. Our data provide the first high-resolution insight into the telomeric G-overhang architecture under essentially physiological conditions and identify the 2-tetrad antiparallel basket and hybrid-2 topologies as the structural targets for the development of telomere-specific G4 ligands. PMID- 23339583 TI - Low heart-type fatty acid binding protein level during aging may protect down syndrome people against atherosclerosis. AB - BACKGROUND: Aging is considered an important independent risk factor for atherosclerosis. Down syndrome people (DS) display an accelerated aging process compared to healthy subjects, anyway they are relatively resistant to developing atherosclerosis. The mechanisms involved in such protective effect are not well known. Since heart-type fatty acid binding protein (H-FABP) is a protein involved in the transport of fatty acids and it has been recently correlated with the presence of atherosclerosis, we aimed to measure H-FABP level both in DS and in healthy subjects during aging to evaluate the association between this molecule, aging and atherosclerosis. FINDINGS: We quantified plasmatic H-FABP level in three groups of male DS and age-matched healthy subjects (children, age 2-14 years; adults, age 20-50 years; elderly, > 60 years) using a biochip array analyzer. We observed that aging is associated with increased H-FABP level in healthy subjects but not in DS which display both the same protein level in the different ages of life and have also lower level compared to their age-matched healthy subjects. CONCLUSION: Reduced H-FABP level during aging in DS may play a protective role against atherosclerosis. The potential involvement of H-FABP in the relationship between aging, atherosclerosis and development of coronary artery disease needs further investigations. PMID- 23339585 TI - A method for estimating the fibre length in fibre-PLA composites. AB - Wood pulp fibres are an important component of environmentally sound and renewable fibre-reinforced composite materials. The high aspect ratio of pulp fibres is an essential property with respect to the mechanical properties a given composite material can achieve. The length of pulp fibres is affected by composite processing operations. This thus emphasizes the importance of assessing the pulp fibre length and how this may be affected by a given process for manufacturing composites. In this work a new method for measuring the length distribution of fibres and fibre fragments has been developed. The method is based on; (i) dissolving the composites, (ii) preparing the fibres for image acquisition and (iii) image analysis of the resulting fibre structures. The image analysis part is relatively simple to implement and is based on images acquired with a desktop scanner and a new ImageJ plugin. The quantification of fibre length has demonstrated the fibre shortening effect because of an extrusion process and subsequent injection moulding. Fibres with original lengths of >1 mm where shortened to fibre fragments with length of <200 MUm. The shortening seems to be affected by the number of times the fibres have passed through the extruder, the amount of chain extender and the fraction of fibres in the polymer matrix. PMID- 23339584 TI - A pilot randomised controlled trial of cognitive behavioural therapy for antenatal depression. AB - BACKGROUND: Few trials have evaluated the effectiveness of psychological treatment in improving depression by the end of pregnancy. This is the first pilot randomised controlled trial (RCT) of individual cognitive behavioural therapy (CBT) looking at treating depression by the end of pregnancy. Our aim was to assess the feasibility of delivering a CBT intervention modified for antenatal depression during pregnancy. METHODS: Women in North Bristol, UK between 8-18 weeks pregnant were recruited through routine contact with midwives and randomised to receive up to 12 sessions of individual CBT in addition to usual care or to continue with usual care only. Women were eligible for randomisation if they screened positive on a 3-question depression screen used routinely by midwives and met ICD-10 criteria for depression assessed using the clinical interview schedule - revised version (CIS-R). Two CBT therapists delivered the intervention. Follow-up was at 15 and 33 weeks post-randomisation when assessments of mental health were made using measures which included the CIS-R. RESULTS: Of the 50 women assessed for the trial, 36 met ICD-10 depression criteria and were randomised: 18 to the intervention and 18 to usual care. Thirteen of the 18 (72%) women who were allocated to receive the intervention completed 9 or more sessions of CBT before the end of pregnancy. Follow-up rates at 15 and 33 weeks post-randomisation were higher in the group who received the intervention (89% vs. 72% at 15 weeks and 89% vs. 61% at 33 weeks post randomisation). At 15 weeks post-randomisation (the end of pregnancy), there were more women in the intervention group (11/16; 68.7%) who recovered (i.e. no longer met ICD-10 criteria for depression), than those receiving only usual care (5/13; 38.5%). CONCLUSIONS: This pilot trial shows the feasibility of conducting a large RCT to assess the effectiveness of CBT for treating antenatal depression before the end of pregnancy. The intervention could be delivered during the antenatal period and there was some evidence to suggest that it could be effective. TRIAL REGISTRATION: ISRCTN44902048. PMID- 23339586 TI - Improvement of photoluminescence of graphene quantum dots with a biocompatible photochemical reduction pathway and its bioimaging application. AB - As a rising star in the family of fluorescent material, graphene quantum dots (GQDs) have attracted great attention because of their excellent properties such as high photostability against photobleaching and blinking, biocompatibility, and low toxicity. Herein, blue luminescent GQDs were prepared by photo-reducing GQDs with isopropanol. After photochemical reduction, the increasing of sp(2) domains and the formed hydroxyl in pGQDs can enhance the photoluminescence of GQDs. The quantum yield of the photo-reduced GQDs (pGQDs) was increased 3.7 fold. Because of its less negative surface charges and lower cytotoxicity than chemical reduced GQDs (cGQDs), the pGQDs were more easily uptaken by cells. This work may provide a simple and green pathway to enhance the QY of GQDs with satisfactory biocompatibility as fluorescent nanoprobes. PMID- 23339587 TI - Keep going in adversity - using a resilience perspective to understand the narratives of long-term social assistance recipients in Sweden. AB - INTRODUCTION: In Sweden, means-tested social assistance serves as a temporary, last resort safety net. However, increasing numbers of people are receiving it for longer periods and about a third has assistance for more than a year. The aim of this study was to explore the ways social assistance recipients manage long lasting adversity and their roles as active, rather than passive, agents in this process, using a resilience perspective. METHOD: The study is based on thirteen in-depth interviews with long-term social assistance recipients from diverse areas in Stockholm County. The interviews were guided by narrative inquiry to interpret and construct stories of experiences and are part of a larger qualitative study exploring experiences of living on social assistance in Sweden. RESULTS: Experiences of cumulative adversity during many years compounded recipients' difficulties in finding ways out of hardship. They had different strategies to deal with adversities, and many had underlying "core problems", including mental health problems, which had not been properly resolved. Recipients' showed resistance in adverse situations. Some made attempts to find ways out of hardship, whereas others struggled mainly to achieve a sense of mastering life. They received important support from individual professionals in different authorities, but mostly the help from the welfare system was fragmented. CONCLUSIONS: Social assistance recipients in this study demonstrated agency in ways of managing long lasting difficulties, sometimes caused by "core problems", which were often accumulated into complex difficulties. Resilience was about keeping going and resisting these difficulties. To find ways out of social assistance required help from different welfare agencies and professionals and was hindered by the fragmentation of services. This study shows that there is a need for more long-term personalised, comprehensive support, including interventions both to increase individual well-being and self-esteem and to open up opportunities for education and employment. Adequate benefit levels and overall quality of welfare services such as health and social care, day care and schools, are of major importance for those in greatest need. PMID- 23339588 TI - Does warmth moderate longitudinal associations between maternal spanking and child aggression in early childhood? AB - This study examines whether maternal warmth moderates the association between maternal use of spanking and increased child aggression between ages 1 and 5. Participants were 3,279 pairs of mothers and their children from a cohort study of urban families from 20 U.S. cities. Maternal spanking was assessed when the child was 1 year, 3 years, and 5 years of age. Maternal warmth and child aggressive behavior were measured at 3 years and 5 years of age. Models controlled for demographic characteristics (measured at the child's birth), child emotionality (measured at age 1), and maternal psychosocial risk factors (measured when children were 3 years old). Cross-lagged path models examined the within-time and longitudinal associations between spanking and child aggression. Results indicated that maternal spanking at age 1 was associated with higher levels of child aggression at age 3; similarly, maternal spanking at age 3 predicted increases in child aggression by age 5. Maternal warmth when children were 3 years old did not predict changes in child aggression between 3 and 5 years old. Furthermore, maternal warmth did not moderate the association between spanking and increased child aggression over time. Beginning as early as age 1, maternal spanking is predictive of child behavior problems, and maternal warmth does not counteract the negative consequences of the use of spanking. PMID- 23339589 TI - Selective trust: children's use of intention and outcome of past testimony. AB - Children's epistemic vigilance was examined for their reasoning about the intentions and outcomes of informants' past testimony. In a 2 * 2 factorial design, 5- and 6-year-olds witnessed informants offering advice based on the intent to help or deceive others about the location of hidden prizes, with the advice leading to positive or negative outcomes. Informants then suggested to the children where to search for hidden prizes. Children trusted informants who had previously tried to help others more than informants who had previously tried to deceive others, regardless of past outcome. In addition, children trusted informants with positive past outcomes more than informants with negative past outcomes, regardless of intention. By varying intention and outcome independently, this study revealed that when children are deciding whether to trust testimony, they take into account the informant's mental states but also give slightly greater weight to the informants' past outputs. PMID- 23339590 TI - "Who can help me fix this toy?" The distinction between causal knowledge and word knowledge guides preschoolers' selective requests for information. AB - Preschoolers use outcomes of actions to infer causal properties of objects. We asked whether they also use them to infer others' causal abilities and knowledge. In Experiment 1, preschoolers saw 2 informants, 2 tools, and 2 broken toys. One informant (the labeler) knew the names of the tools, but his actions failed to activate the toys. The other (the fixer) was ignorant about the names of the tools, but his actions succeeded in activating the toys. Four-year-olds (and to a lesser extent, 3-year-olds) selectively directed requests for new labels to the labeler and directed requests to fix new broken toys to the fixer. In a second experiment, 4-year-olds also endorsed a fixer's (over a nonfixer's) causal explanations for mechanical failures. They did not, however, ask the fixer about new words (Experiments 1 and 2) or artifact functions (Experiment 1). Thus, preschoolers take demonstrated causal ability as a sign of specialized causal knowledge, which suggests a basis for developing ideas about causal expertise. PMID- 23339591 TI - Comparison between emergent and elective delivery in women with placenta accreta. AB - OBJECTIVE: To identify possible predictive factors associated with emergent delivery of antenatally diagnosed placenta accreta and to estimate association between emergent delivery and adverse maternal outcomes in comparison to elective delivery. METHODS: A retrospective study of all patients with placenta accreta diagnosed antenatally and confirmed pathologically, who were delivered between 2000 and 2010. Baseline characteristics and outcomes of emergent deliveries were compared with elective deliveries. RESULTS: A total of 48 women met inclusion criteria, of which 24 (50%) were delivered emergently. 79.2% of emergent deliveries were preceded by antenatal bleeding (p = 0.0005), and 62.5% were preceded by recurrent bleeding (p = 0.001). Comparison of elective and emergent deliveries revealed no clinical significant difference in maternal outcome. CONCLUSIONS: Antenatal bleeding is associated with an increased risk of emergent delivery. Emergent delivery in a tertiary care facility with immediate access to blood bank and ICU capabilities does not appear to be associated with an increased risk of adverse maternal outcomes. Consequently, some patients may be candidates for delivery later than 34 weeks of gestation. PMID- 23339592 TI - Genotoxic properties of cyclopentenone prostaglandins and the onset of glutathione depletion. AB - Prostaglandins are endogenous mediators formed from arachidonic acid by cyclooxygenases and prostaglandin synthases during inflammatory processes. The five-membered ring can be dehydrated, and alpha,beta-unsaturated cyclopentenone PGs (cyPGs) are generated. Recent studies have been focused on their potential pharmacological use against inflammation and cancer. However, little is known so far about possible adverse health effects of cyPGs. We addressed the question whether selected cyPGs at a concentration range of 0.1-10 MUM exhibit mutagenic and genotoxic properties in the hamster lung fibroblast V79 cell line and whether these effects are accompanied by a depletion of intracellular glutathione (GSH). The cyPGs 15-deoxy-Delta12,14-prostaglandin J2 (15dPGJ2) and prostaglandin A2 (PGA2) significantly induced DNA damage in V79 cells after 1 h of incubation. Furthermore, a more pronounced increase in formamidopyrimidine-DNA glycosylase (FPG) sensitive sites, indicative of oxidative DNA-damage, was observed. The findings on DNA-damaging properties were supported by our results that 15dPGJ(2) acts as an aneugenic agent which induces the amount of kinetochore positive micronuclei associated with an increase of apoptosis. The strong potency of cyPGs to rapidly bind GSH measured in a chemical assay and to significantly reduce the GSH level after only 1 h of incubation may contribute to the observed oxidative DNA strand breaks, whereas directly induced oxidative stress via reactive oxygen species could be excluded. However, after an extended incubation time of 24 h no genotoxicity could be measured, this may contribute to the lack of mutagenicity in the hypoxanthine phosphorybosyltransferase (HPRT) assay. In conclusion, potential in vitro genotoxicity of cyPG and a strong impact on GSH homeostasis have been demonstrated, which may be involved in carcinogenesis mediated by chronic inflammation. PMID- 23339593 TI - Local disease control for spinal metastases following "separation surgery" and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients. AB - OBJECT: Decompression surgery followed by adjuvant radiotherapy is an effective therapy for preservation or recovery of neurological function and achieving durable local disease control in patients suffering from metastatic epidural spinal cord compression (ESCC). The authors examine the outcomes of postoperative image-guided intensity-modulated radiation therapy delivered as single-fraction or hypofractionated stereotactic radiosurgery (SRS) for achieving long-term local tumor control. METHODS: A retrospective chart review identified 186 patients with ESCC from spinal metastases who were treated with surgical decompression, instrumentation, and postoperative radiation delivered as either single-fraction SRS (24 Gy) in 40 patients (21.5%), high-dose hypofractionated SRS (24-30 Gy in 3 fractions) in 37 patients (19.9%), or low-dose hypofractionated SRS (18-36 Gy in 5 or 6 fractions) in 109 patients (58.6%). The relationships between postoperative adjuvant SRS dosing and fractionation, patient characteristics, tumor histology-specific radiosensitivity, grade of ESCC, extent of surgical decompression, response to preoperative radiotherapy, and local tumor control were evaluated by competing risks analysis. RESULTS: The total cumulative incidence of local progression was 16.4% 1 year after SRS. Multivariate Gray competing risks analysis revealed a significant improvement in local control with high-dose hypofractionated SRS (4.1% cumulative incidence of local progression at 1 year, HR 0.12, p = 0.04) as compared with low-dose hypofractionated SRS (22.6% local progression at 1 year, HR 1). Although univariate analysis demonstrated a trend toward greater risk of local progression for patients in whom preoperative conventional external beam radiation therapy failed (22.2% local progression at 1 year, HR 1.96, p = 0.07) compared with patients who did not receive any preoperative radiotherapy (11.2% local progression at 1 year, HR 1), this association was not confirmed with multivariate analysis. No other variable significantly correlated with progression-free survival, including radiation sensitivity of tumor histology, grade of ESCC, extent of surgical decompression, or patient sex. CONCLUSIONS: Postoperative adjuvant SRS following epidural spinal cord decompression and instrumentation is a safe and effective strategy for establishing durable local tumor control regardless of tumor histology-specific radiosensitivity. Patients who received high-dose hypofractionated SRS demonstrated 1-year local progression rates of less than 5% (95% CI 0%-12.2%), which were superior to the results of low-dose hypofractionated SRS. The local progression rate after single-fraction SRS was less than 10% (95% CI 0%-19.0%). PMID- 23339594 TI - Differential gene expression in the endometrium on gestation day 12 provides insight into sow prolificacy. AB - BACKGROUND: Erhualian pigs, one of Chinese Taihu pig breeds, are known to have the largest recorded litter size in the world. A lower prenatal death rate is the major contributing factor to the prolificacy of Taihu pigs. Cross-breeding experiments have demonstrated that Taihu sows exhibit a strong maternal effect and that their large litter sizes are mainly caused by maternal genes. The growth and development of porcine embryos on gestation day (GD) 12 are dependent on histotroph secreted by endometrium. Embryonic loss of Taihu pigs on GD12 is lower than that of Western pigs. Here, endometrial samples were collected from pregnant Erhualian sows (parity 3) and Landrace * Large White (LL) sows (parity 3) on GD12. Digital gene expression profiling (DGE) was used to measure the gene expression in the endometrium of the two breeds. RESULTS: A total of 13,612 genes were differentially expressed between the two breeds (P < 0.001, FDR < 0.001). Gene Ontology (GO) analysis showed that the differential genes involved in reproduction and growth. Pathway analysis revealed that the differentially expressed genes significantly enriched in 24 KEGG pathways. Quantitative real time RT-PCR confirmed the differential expression of eight genes. Analyses of the differentially expressed genes suggested possible reasons for the difference in embryonic survival ratio between the two breeds. Specifically, these findings point to a higher ratio of PGE2:PGF2alpha in the endometrium of Erhualian pigs, which facilitates the establishment and maintenance of pregnancy. We also suggest that the differences in the uterine environment lead to higher uterine capacity in Erhualian pigs. CONCLUSIONS: The DGE expression profiles of Erhualian and LL endometrium demonstrated differential expression of genes. Our results will increase understanding of the molecular mechanisms of the low rate of embryonic loss in Chinese Taihu pigs, facilitate the identification of major genes that affect litter size, and be valuable for porcine transcriptomic studies. PMID- 23339595 TI - DNA repair gene variants are associated with an increased risk of myelodysplastic syndromes in a Czech population. AB - BACKGROUND: Interactions between genetic variants and risk factors in myelodysplastic syndromes are poorly understood. In this case-control study, we analyzed 1 421 single nucleotide polymorphisms in 408 genes involved in cancer related pathways in 198 patients and 292 controls. METHODS: The Illumina SNP Cancer Panel was used for genotyping of samples. The chi-squared, p-values, odds ratios and upper and lower limits of the 95% confidence interval were calculated for all the SNPs that passed the quality control filtering. RESULTS: Gene-based analysis showed nine candidate single nucleotide polymorphisms significantly associated with the disease susceptibility (q-value<0.05). Four of these polymorphisms were located in oxidative damage/DNA repair genes (LIG1, RAD52, MSH3 and GPX3), which may play important roles in the pathobiology of myelodysplastic syndromes. Two of nine candidate polymorphisms were located in transmembrane transporters (ABCB1 and SLC4A2), contributing to individual variability in drug responses and patient prognoses. Moreover, the variations in the ROS1 and STK6 genes were associated with the overall survival of patients. CONCLUSIONS: Our association study identified genetic variants in Czech population that may serve as potential markers for myelodysplastic syndromes. PMID- 23339596 TI - Need for tailored strategies to diagnose venous thrombo-embolism in older primary care patients. Extension of a keynote presentation at the 2012 Wonca Europe conference. AB - Venous thrombo-embolism (VTE, pulmonary embolism and deep vein thrombosis) is common in the elderly and short-term mortality risk increases with age. Hence, notably in older patients, accurately diagnosing VTE can be lifesaving. However, most clinically suspected individuals turn out to have no VTE after imaging examination. Therefore, many physicians would feel reluctant to refer older patients as this can be very burdensome for these patients. Consequently, it is possible that elderly patients are often not referred for diagnostic work-up (risk of under diagnosis), or that treatment for VTE is initiated without confirmation by further testing (risk of overtreatment). Moreover, anticoagulation treatment of VTE is associated with a higher bleeding risk in the elderly. This bleeding risk might even outweigh the potential benefits in some of these patients. Therefore, availability of an accurate diagnostic strategy to safely exclude, and timely diagnose VTE without the need of burdening referrals in many patients might better serve the needs of older patients. Such strategies have been derived and validated in both primary and secondary care patients suspected of VTE. However, the generalizability of these strategies to older patients may be hampered, and their accuracy has never been tested in elderly populations; this in spite of the high prevalence of VTE and the potential for misdiagnosis and thus mistreatment in these patients. Therefore, we advocate validation and adaptation of current diagnostic strategies for VTE for application in elderly patients. PMID- 23339597 TI - Evolutionary kinetics of graphene formation on copper. AB - It has been claimed that graphene growth on copper by chemical vapor deposition is dominated by crystallization from the surface initially supersaturated with carbon adatoms, which implies that the growth is independent of hydrocarbon addition after the nucleation phase. Here, we present an alternative growth model based on our observations that oppose this claim. Our Gompertzian sigmoidal growth kinetics and secondary nucleation behavior support the postulate that the growth can be controlled by adsorption-desorption dynamics and the dispersive kinetic processes of catalytic dissociation and dehydrogenation of carbon precursors on copper. PMID- 23339600 TI - Usefulness of the Geriatric Depression Scale 15-item version among very old people with and without cognitive impairment. AB - OBJECTIVES: The aim of this population-based study was to investigate the usefulness of the Geriatric Depression Scale 15-item version (GDS-15) to assess depressive symptoms among very old people with differing levels of cognitive function. METHODS: The 834 participants were aged 85 and over. Feasibility of GDS 15 was evaluated as the proportion of people who completed the scale. Concurrent criterion validity was evaluated by calculating correlations between GDS-15 and Philadelphia Geriatric Center Morale Scale (PGCMS). PGCMS measures psychological wellbeing which is closely related with depressive symptoms. Correlations were calculated within groups according to cognitive function assessed with Mini Mental State Examination (MMSE); 0-4, 5-9, 10-14, 15-19, 20-24, 25-27, and 28-30, using Pearson's two-sided correlation and compared using Fisher r-to-z transformation. Internal consistency of the GDS-15 was evaluated by calculating Cronbach's alpha in each group. RESULTS: In total, 651 (78%) of the 834 participants completed the GDS-15. For the two MMSE-groups with scores of <10, the proportion who completed GDS-15 were 1% and 42%, respectively, compared to 65 95% in the MMSE-groups with scores of >=10. Cronbach's alpha in each MMSE-group ranged from 0.636 (MMSE 28-30) to 0.821 (MMSE 5-9). The level of correlation between GDS-15 and PGCMS did not significantly differ between MMSE-groups with scores of 5-27 compared to the MMSE-group with scores of 28-30. CONCLUSIONS: The GDS-15 seems to have an overall usefulness to assess depressive symptoms among very old people with an MMSE score of 10 or more. More studies are needed to strengthen the validity of GDS-15 among older people with MMSE scores of 10-14. For older people with MMSE scores lower than 10, there is a need to develop and validate other measurements. PMID- 23339601 TI - Systematic review and meta-analysis of application of fibrin sealant after liver resection. AB - BACKGROUND: Fibrin sealant (FS) has been increasingly used on the raw surface after liver resection but its clinical value has not been established to date. The aim of this study was to evaluate the efficacy and safety of the employment of FS after liver resection. METHODS: PubMed, Cochrane Library, Embase, CNKI, CBM and VIP were searched for randomized trials comparing the effect of FS with no FS or any other intervention for patients undergoing liver resection. Primary outcomes included time to hemostasis, hemostatic success, amount of drainage and drainage duration. RESULTS: Eleven randomized controlled trials were included. Meta-analysis suggested that the amount of drainage (standard mean difference 0.30; 95% confidence interval [CI] -0.82 to 0.23) and drainage duration (mean difference [MD] -0.46, 95% CI -0.61 to -1.53) were similar between FS group and no FS group. Compared with topical hemostatic agents, FS could significantly reduce time to hemostasis (MD -208.46, 95% CI -228.22 to -188.70) and increase hemostasis success rate (relative risk 1.35, 95% CI 1.17 to 1.57). Two trials compared FS with argon beam coagulation (ABC), which both suggested that FS could significantly decrease the time to hemostasis. CONCLUSIONS: This study demonstrated a modest benefit of FS over no FS, topical hemostatic agents and ABC in controlling intraoperative bleeding from the raw liver surface after liver resection. But there is no evidence that FS is beneficial to patients in reducing amount of drainage and drainage duration. PMID- 23339602 TI - Quantum mechanical interpretation of intermolecular vibrational modes of crystalline poly-(R)-3-hydroxybutyrate observed in low-frequency Raman and terahertz spectra. AB - Low-frequency vibrational bands observed in the Raman and terahertz (THz) spectra in the region of 50-150 cm(-1) of crystalline powder poly-(R)-3-hydroxybutyrate (PHB) were assigned based on comparisons of the Raman and THz spectra, polarization directions of THz absorption spectra, and their congruities to quantum mechanically (QM) calculated spectra. This combination, Raman and THz spectroscopies and the QM simulations, has been rarely adopted in spite of its potential of reliable assignments of the vibrational bands. The QM simulation of a spectrum has already been popular in vibrational spectroscopies, but for low frequency bands of polymers it is still a difficult task due to its large scales of systems and a fact that interactions among polymer chains should be considered in the calculation. In this study, the spectral calculations with the aid of the Cartesian-coordinate tensor transfer (CCT) method were applied successfully to the crystalline PHB, which include the explicit consideration of an intermolecular interaction among helical polymer chains. The agreements between the calculations and the experiments are good in both the Raman and THz spectra in terms of spectral shapes, frequencies, and intensities. A Raman active band at 79 cm(-1) was assigned to the intermolecular vibrational mode of the out-of-plane C?O + CH(3) vibration. A polarization state of the corresponding far-infrared absorption band at ~82 cm(-1), perpendicular to the helix-elongation direction of PHB, was reproduced only under the explicit correction, which indicates that this polarized band originates from the interaction among the polymer chains. The calculation explored that the polarization direction of this band was along the a axis, which is consistent with the direction in which weak intermolecular hydrogen bonds are suggested between the C?O and CH(3) groups of two parallel polymer chains. The results obtained here have confirmed sensitivity of the low frequency vibrational bands to the weak hydrogen bonds among the polymer chains. PMID- 23339603 TI - High-throughput secretomic analysis of single cells to assess functional cellular heterogeneity. AB - Secreted proteins dictate a range of cellular functions in human health and disease. Because of the high degree of cellular heterogeneity and, more importantly, polyfunctionality of individual cells, there is an unmet need to simultaneously measure an array of proteins from single cells and to rapidly assay a large number of single cells (more than 1000) in parallel. We describe a simple bioanalytical assay platform consisting of a large array of subnanoliter microchambers integrated with high-density antibody barcode microarrays for highly multiplexed protein detection from over a thousand single cells in parallel. This platform has been tested for both cell lines and complex biological samples such as primary cells from patients. We observed distinct heterogeneity among the single cell secretomic signatures that, for the first time, can be directly correlated to the cells' physical behavior such as migration. Compared to the state-of-the-art protein secretion assay such as ELISpot and emerging microtechnology-enabled assays, our approach offers both high throughput and high multiplicity. It also has a number of clinician-friendly features such as ease of operation, low sample consumption, and standardized data analysis, representing a potentially transformative tool for informative monitoring of cellular function and immunity in patients. PMID- 23339604 TI - Supramolecular organization and magnetic properties of mesogen-hybridized mixed valent manganese single molecule magnets [Mn(III)8Mn(IV)4O12(L(x,y,z CB))16(H2O)4]. AB - Single molecule magnets (SMM) may be considered for the construction of future integrated nanodevices, provided however that some degree of ordering is imparted to these molecules (surfaces nanostructuration). Combining such nanoobjects with liquid-crystalline orderings to control their assembly and to potentially address them individually therefore appears as one promising strategy. Four mesomorphic, mixed-valent [Mn(III)(8)Mn(IV)(4)O(12)(L(x,y,z-CB))(16)(H(2)O)(4)] SMM, differing in the number of liquid-crystalline promoters, (L(x,y,z-CB)), were synthesized, and their self-organizing and magnetic properties were investigated. The influence of the peripheral modifications, and precisely how supramolecular ordering and magnetic properties may be affected by the evolution of the proto mesogenic cyanobiphenyl-based ligands substitution pattern, was explored. Small angle X-ray scattering studies revealed that all of the hybridized clusters self organize into room-temperature bilayer smectic phases, mandated by the specific mesogenic functionalization and that the polymetallic cores are further organized according to a short-range pseudo-2D lattice with hexagonal and/or square symmetry. All mesomorphous hybridized dodecamanganese complexes still behave as SMM: they exhibit blocking of the magnetization at about 2.6 K as evidenced by the occurrence of frequency-dependent out-of-phase ac susceptibility signals as well as an opening of the hysteresis cycle with coercive fields varying between 0.13 and 0.6 T, depending on the surface ligands topology. Comparison of the magnetic properties within this series reveals intricate correlations between the structural features of the mesomorphous molecule magnet (i.e., symmetry of the ligands substitution patterns, molecular conformation, average intercluster distances, and respective inclination) with respect to the relative proportion of slow- and fast-relaxing species and the absolute values of the coercive fields. PMID- 23339605 TI - Strategies to develop antivirals against enterovirus 71. AB - Enterovirus 71 (EV71) is an important human pathogen which may cause severe neurological complications and death in children. The virus caused several outbreaks in the Asia-Pacific region during the past two decades and has been considered a significant public health problem in the post-poliovirus eradication era. Unlike poliovirus, there is no effective vaccine or approved antivirals against EV71. To explore anti-EV71 agents therefore is of vital importance. Several strategies have been employed to develop antivirals based on the molecular characteristics of the virus. Among these, some small molecules that were developed against human rhinoviruses and poliovirus are under evaluation. In this review, we discuss the recent development of such small molecules against EV71, known drug resistance and possible solutions to it, and animal models for evaluating the efficacy of these antivirals. Although further investigation is required for clinical applications of the existing candidates, the molecular mechanisms revealed for the inhibition of EV71 replication can be used for designing new molecules against this virus in the future. PMID- 23339607 TI - Weight gain regardless of pre-pregnancy BMI and influence of fetal gender in response to labor induction in postdate pregnancy. AB - OBJECTIVE: To evaluate whether maternal weight and body mass index (BMI) and their increase throughout pregnancy are associated with the response to labor induction in postdate pregnancies. METHODS: A total of 376 nulliparous women carrying singleton postdate pregnancies with unfavorable cervix were enrolled. We considered as primary outcome vaginal delivery within 24 h after induction, and outcomes were divided into responders (n = 258) and non-responders (n = 107) to the induction of labor to perform the statistical analyses. RESULTS: In the total population of study, women who successfully delivered within 24 h differed significantly from the remaining patients in terms of maternal weight gain (p = 0.009) and BMI increase (p = 0.02) during pregnancy. In addition, males were significantly more (p = 0.005) than females among newborns of women not responding to induction of labor. In the multivariate analysis, maternal weight gain and fetal sex significantly influenced the induction response. The occurrence of a failed induction of labor was more likely in patients presenting a greater maternal weight gain (cut-off 12 kg) and male fetus. CONCLUSION: Weight gain over 12 kg regardless of pre-pregnancy weight and male fetal gender are two novel potential risk factors for the prediction of failure to induction of labor in postdate pregnancy. PMID- 23339606 TI - Assessing equity in health care through the national health insurance schemes of Nigeria and Ghana: a review-based comparative analysis. AB - BACKGROUND: Nigeria and Ghana have recently introduced a National Health Insurance Scheme (NHIS) with the aim of moving towards universal health care using more equitable financing mechanisms. This study compares health and economic indicators, describes the structure of each country's NHIS within the wider healthcare system, and analyses impacts on equity in financing and access to health care. METHODS: The World Bank and other sources were used to provide comparative health and economic data. Pubmed, Embase and EconLit were searched to locate studies providing descriptions of each NHIS and empirical evidence regarding equity in financing and access to health care. A diagrammatical representation of revenue-raising, pooling, purchasing and provision was produced in order to analyse the two countries' systems. RESULTS: Over the period 2000 2010, Ghana maintained a marked advantage in life expectancy, infant mortality, under-5 year mortality, and has a lower burden of major diseases. Health care expenditure is about 5% of GDP in both countries but public expenditure in 2010 was 38% of total expenditure in Nigeria and 60% in Ghana. Financing and access are less equitable in Nigeria as, inter alia, private out-of-pocket expenditure has fallen from 80% to 66% of total spending in Ghana since the introduction of its NHIS but has remained at over 90% in Nigeria; NHIS membership in Nigeria and Ghana is approximately 3.5% and 65%, respectively; Nigeria offers a variable benefits package depending on membership category while Ghana has uniform benefits across all beneficiaries. Both countries exhibit improvements in equity but there is a pro-rich and pro-urban bias in membership. CONCLUSIONS: Major health indicators are more favourable in Ghana and overall equity in financing and access are weaker in Nigeria. Nigeria is taking steps to expand NHIS membership and has potential to expand its public spending to achieve greater equity. However, heavy burdens of poverty, disease and remote settings make this a substantial challenge. Ghana's relative success has to be tempered by the high number of exemptions through taxation and the threat of moral hazard. The results and methods are anticipated to be informative for policy makers and researchers in both countries and other developing countries more widely. PMID- 23339608 TI - Modular encoding and decoding models derived from bayesian canonical correlation analysis. AB - Neural encoding and decoding provide perspectives for understanding neural representations of sensory inputs. Recent functional magnetic resonance imaging (fMRI) studies have succeeded in building prediction models for encoding and decoding numerous stimuli by representing a complex stimulus as a combination of simple elements. While arbitrary visual images were reconstructed using a modular model that combined the outputs of decoder modules for multiscale local image bases (elements), the shapes of the image bases were heuristically determined. In this work, we propose a method to establish mappings between the stimulus and the brain by automatically extracting modules from measured data. We develop a model based on Bayesian canonical correlation analysis, in which each module is modeled by a latent variable that relates a set of pixels in a visual image to a set of voxels in an fMRI activity pattern. The estimated mapping from a latent variable to pixels can be regarded as an image basis. We show that the model estimates a modular representation with spatially localized multiscale image bases. Further, using the estimated mappings, we derive encoding and decoding models that produce accurate predictions for brain activity and stimulus images. Our approach thus provides a novel means of revealing neural representations of stimuli by automatically extracting modules, which can be used to generate effective prediction models for encoding and decoding. PMID- 23339609 TI - Continuation-based numerical detection of after-depolarization and spike-adding thresholds. AB - The changes in neuronal firing pattern are signatures of brain function, and it is of interest to understand how such changes evolve as a function of neuronal biophysical properties. We address this important problem by the analysis and numerical investigation of a class of mechanistic mathematical models. We focus on a hippocampal pyramidal neuron model and study the occurrence of bursting related to the after-depolarization (ADP) that follows a brief current injection. This type of burst is a transient phenomenon that is not amenable to the classical bifurcation analysis done, for example, for periodic bursting oscillators. In this letter, we show how to formulate such transient behavior as a two-point boundary value problem (2PBVP), which can be solved using well-known continuation methods. The 2PBVP is formulated such that the transient response is represented by a finite orbit segment for which onsets of ADP and additional spikes in a burst can be detected as bifurcations during a one-parameter continuation. This in turn provides us with a direct method to approximate the boundaries of regions in a two-parameter plane where certain model behavior of interest occurs. More precisely, we use two-parameter continuation of the detected onset points to identify the boundaries between regions with and without ADP and bursts with different numbers of spikes. Our 2PBVP formulation is a novel approach to parameter sensitivity analysis that can be applied to a wide range of problems. PMID- 23339610 TI - Some sampling properties of common phase estimators. AB - The instantaneous phase of neural rhythms is important to many neuroscience related studies. In this letter, we show that the statistical sampling properties of three instantaneous phase estimators commonly employed to analyze neuroscience data share common features, allowing an analytical investigation into their behavior. These three phase estimators-the Hilbert, complex Morlet, and discrete Fourier transform-are each shown to maximize the likelihood of the data, assuming the observation of different neural signals. This connection, explored with the use of a geometric argument, is used to describe the bias and variance properties of each of the phase estimators, their temporal dependence, and the effect of model misspecification. This analysis suggests how prior knowledge about a rhythmic signal can be used to improve the accuracy of phase estimates. PMID- 23339611 TI - A self-organized neural comparator. AB - Learning algorithms need generally the ability to compare several streams of information. Neural learning architectures hence need a unit, a comparator, able to compare several inputs encoding either internal or external information, for instance, predictions and sensory readings. Without the possibility of comparing the values of predictions to actual sensory inputs, reward evaluation and supervised learning would not be possible. Comparators are usually not implemented explicitly. Necessary comparisons are commonly performed by directly comparing the respective activities one-to-one. This implies that the characteristics of the two input streams (like size and encoding) must be provided at the time of designing the system. It is, however, plausible that biological comparators emerge from self-organizing, genetically encoded principles, which allow the system to adapt to the changes in the input and the organism. We propose an unsupervised neural circuitry, where the function of input comparison emerges via self-organization only from the interaction of the system with the respective inputs, without external influence or supervision. The proposed neural comparator adapts in an unsupervised form according to the correlations present in the input streams. The system consists of a multilayer feedforward neural network, which follows a local output minimization (anti Hebbian) rule for adaptation of the synaptic weights. The local output minimization allows the circuit to autonomously acquire the capability of comparing the neural activities received from different neural populations, which may differ in population size and the neural encoding used. The comparator is able to compare objects never encountered before in the sensory input streams and evaluate a measure of their similarity even when differently encoded. PMID- 23339612 TI - Error analysis of coefficient-based regularized algorithm for density-level detection. AB - In this letter, we consider a density-level detection (DLD) problem by a coefficient-based classification framework with [Formula: see text]-regularizer and data-dependent hypothesis spaces. Although the data-dependent characteristic of the algorithm provides flexibility and adaptivity for DLD, it leads to difficulty in generalization error analysis. To overcome this difficulty, an error decomposition is introduced from an established classification framework. On the basis of this decomposition, the estimate of the learning rate is obtained by using Rademacher average and stepping-stone techniques. In particular, the estimate is independent of the capacity assumption used in the previous literature. PMID- 23339613 TI - Information transmission using non-poisson regular firing. AB - In many cortical areas, neural spike trains do not follow a Poisson process. In this study, we investigate a possible benefit of non-Poisson spiking for information transmission by studying the minimal rate fluctuation that can be detected by a Bayesian estimator. The idea is that an inhomogeneous Poisson process may make it difficult for downstream decoders to resolve subtle changes in rate fluctuation, but by using a more regular non-Poisson process, the nervous system can make rate fluctuations easier to detect. We evaluate the degree to which regular firing reduces the rate fluctuation detection threshold. We find that the threshold for detection is reduced in proportion to the coefficient of variation of interspike intervals. PMID- 23339614 TI - Optimality and saturation in axonal chemotaxis. AB - Chemotaxis (detecting and following chemical gradients) plays a crucial role in the function of many biological systems. In particular, gradient following by neuronal growth cones is important for the correct wiring of the nervous system. There is increasing interest in the constraints that determine how small chemotacting devices respond to gradients, but little quantitative information is available in this regard for neuronal growth cones. Mortimer et al. ( 2009 ) and Mortimer, Dayan, Burrage, and Goodhill ( 2011 ) proposed a Bayesian ideal observer model that predicts chemotactic performance for shallow gradients. Here we investigated two important aspects of this model. First, we found by numerical simulation that although the analytical predictions of the model assume shallow gradients, these predictions remain remarkably robust to large deviations in gradient steepness. Second, we found experimentally that the chemotactic response increased linearly with gradient steepness for very shallow gradients as predicted by the model; however, the response saturated for steeper gradients. This saturation could be reproduced in simulations of a growth rate modulation response mechanism. Together these results illuminate the domain of validity of the Bayesian model and give further insight into the biological mechanisms of axonal chemotaxis. PMID- 23339615 TI - Solving the distal reward problem with rare correlations. AB - In the course of trial-and-error learning, the results of actions, manifested as rewards or punishments, occur often seconds after the actions that caused them. How can a reward be associated with an earlier action when the neural activity that caused that action is no longer present in the network? This problem is referred to as the distal reward problem. A recent computational study proposes a solution using modulated plasticity with spiking neurons and argues that precise firing patterns in the millisecond range are essential for such a solution. In contrast, the study reported in this letter shows that it is the rarity of correlating neural activity, and not the spike timing, that allows the network to solve the distal reward problem. In this study, rare correlations are detected in a standard rate-based computational model by means of a threshold-augmented Hebbian rule. The novel modulated plasticity rule allows a randomly connected network to learn in classical and instrumental conditioning scenarios with delayed rewards. The rarity of correlations is shown to be a pivotal factor in the learning and in handling various delays of the reward. This study additionally suggests the hypothesis that short-term synaptic plasticity may implement eligibility traces and thereby serve as a selection mechanism in promoting candidate synapses for long-term storage. PMID- 23339616 TI - Learning with boundary conditions. AB - Kernel machines traditionally arise from an elegant formulation based on measuring the smoothness of the admissible solutions by the norm in the reproducing kernel Hilbert space (RKHS) generated by the chosen kernel. It was pointed out that they can be formulated in a related functional framework, in which the Green's function of suitable differential operators is thought of as a kernel. In this letter, our own picture of this intriguing connection is given by emphasizing some relevant distinctions between these different ways of measuring the smoothness of admissible solutions. In particular, we show that for some kernels, there is no associated differential operator. The crucial relevance of boundary conditions is especially emphasized, which is in fact the truly distinguishing feature of the approach based on differential operators. We provide a general solution to the problem of learning from data and boundary conditions and illustrate the significant role played by boundary conditions with examples. It turns out that the degree of freedom that arises in the traditional formulation of kernel machines is indeed a limitation, which is partly overcome when incorporating the boundary conditions. This likely holds true in many real world applications in which there is prior knowledge about the expected behavior of classifiers and regressors on the boundary. PMID- 23339617 TI - Double-gabor filters are independent components of small translation-invariant image patches. AB - The analysis of natural images with independent component analysis (ICA) yields localized bandpass Gabor-type filters similar to receptive fields of simple cells in visual cortex. We applied ICA on a subset of patches called position-centered patches, selected for forming a translation-invariant representation of small patches. The resulting filters were qualitatively different in two respects. One novel feature was the emergence of filters we call double-Gabor filters. In contrast to Gabor functions that are modulated in one direction, double-Gabor filters are sinusoidally modulated in two orthogonal directions. In addition the filters were more extended in space and frequency compared to standard ICA filters and better matched the distribution in experimental recordings from neurons in primary visual cortex. We further found a dual role for double-Gabor filters as edge and texture detectors, which could have engineering applications. PMID- 23339618 TI - Charge transport properties in TiO2 network with different particle sizes for dye sensitized solar cells. AB - The charge transport properties in the TiO(2) nanoparticle networks with the different TiO(2) nanoparticle sizes were investigated by means of electrochemical impedance spectroscopy (EIS) with consideration of morphological aspects of mesoporous TiO(2) network including particle size (d(p)), coordination number (N(n)), neck diameter (d(n)), and effective surface area (S(e)). The morphological analysis of the network revealed that the particle size and surface area would be factors exerting an impact on the charge transport properties, while the coordination number and neck diameter seemed to be consistent with the nanoparticle size. As a result, the electron transport along with the TiO(2) network was predominantly affected by the particle size in terms of the mean free path; the bigger particle size provides both long travel distance and less collision chance with the boundary. Surface area seems to exert a strong influence on the recombination when it is in contact with an electrolyte, suggesting that pore size distribution determining penetration of an electrolyte has to be considered in terms of the effective surface area (S(e)). Due to the low transport resistance, high recombination resistance, and low chemical capacitance, the largest particle showed the longest diffusion length (L(n)). However, the highest efficiency observed in 15 nm TiO(2) nanoparticle photoanode indicated that the compensating characteristics of the morphological factors of the network for light harvesting efficiency (LHE) (surface area) and charge collection efficiency (eta(c), particle size) should be balanced in designing a nanostructured network for high performance DSCs. PMID- 23339619 TI - Systematic identification of scaffolds representing compounds active against individual targets and single or multiple target families. AB - Given the enormous growth of compound activity data we currently observe, we have revisited the previously introduced concepts of privileged substructures and community-selective scaffolds and systematically searched for molecular scaffolds representing compounds active against single targets, multiple targets belonging to the same target family, or targets belonging to different families. The influence of different types of activity measurements on scaffold assignments has been determined. Furthermore, scaffold assignments have also been carried out after applying a potency threshold to exclude weakly active compounds from the comparison and address the issue of molecular selectivity. In both instances, the results were very similar indicating that single-target and single-family scaffolds display target- and family-selective tendencies, respectively. Unexpectedly large numbers of 630 unique single-target, 489 single-family, and 336 multi-family scaffolds have been identified in public domain compound data that represented relatively large numbers of compounds. Other important findings are that most of the growth in high-confidence compound activity data has been due to the evaluation of new compounds, rather than additional measurements for previously tested compounds or analog series for previously explored scaffolds. The majority of scaffolds have remained in the same category over time. Activity measurement type-dependent sets of single-target, single-family, and multi-family scaffolds are also provided as an up-to-date scaffold knowledge base. PMID- 23339620 TI - Calculation of noncontact forces between silica nanospheres. AB - Quantification of the interactions between nanoparticles is important in understanding their dynamic behaviors and many related phenomena. In this study, molecular dynamics simulation is used to calculate the interaction potentials (i.e., van der Waals attraction, Born repulsion, and electrostatic interaction) between two silica nanospheres of equal radius in the range of 0.975 to 5.137 nm. The results are compared with those obtained from the conventional Hamaker approach, leading to the development of modified formulas to calculate the van der Waals attraction and Born repulsion between nanospheres, respectively. Moreover, Coulomb's law is found to be valid for calculating the electrostatic potential between nanospheres. The developed formulas should be useful in the study of the dynamic behaviors of nanoparticle systems under different conditions. PMID- 23339621 TI - Positive and negative emotion prospectively predict trajectories of resilience and distress among high-exposure police officers. AB - Responses to both potentially traumatic events and other significant life stressors have been shown to conform to discrete patterns of response such as resilience, anticipatory stress, initial distress with gradual recovery, and chronic distress. The etiology of these trajectories is still unclear. Individual differences in levels of negative and positive emotion are believed to play a role in determining risk and resilience following traumatic exposure. In the current investigation, we followed police officers prospectively from academy training through 48 months of active duty, assessing levels of distress every 12 months. Using latent class growth analysis, we identified 4 trajectories closely conforming to prototypical patterns. Furthermore, we found that lower levels of self-reported negative emotion during academy training prospectively predicted membership in the resilient trajectory compared with the more symptomatic trajectories following the initiation of active duty, whereas higher levels of positive emotion during academy training differentiated resilience from a trajectory that was equivalently low on distress during academy training but consistently grew in distress through 4 years of active duty. These findings emerging from a prospective longitudinal design provide evidence that resilience is predicted by both lower levels of negative emotion and higher levels of positive emotion prior to active duty stressor exposure. PMID- 23339622 TI - Three new steroid glycosides from the starfish Asterina pectinifera. AB - Three new steroid glycosides, pectiniosides H-J (1-3), were isolated along with three known compounds (4-6) including a steroid glycoside and two polyhydroxysteroids, from the alcoholic extract of the starfish Asterina pectinifera. The structures of 1-3 were determined by extensive NMR and HR-ESI-MS experiments. Compounds 1-4 did not show cytostatic activity on HL-60 cells below 100 MUM, while compounds 5-6 showed moderate cytostatic activity, with IG50 values of 80.3 and 40.5 MUM, respectively. PMID- 23339623 TI - Enhancing Buruli ulcer control in Ghana through social interventions: a case study from the Obom sub-district. AB - BACKGROUND: Buruli ulcer is considered a re-emerging disease in West Africa where it has suffered neglect over the years, though children below the age of 16 years are the worst affected in most endemic regions. Due to delayed health seeking, the disease leads to disabilities resulting from amputation and loss of vital organs like the eye leading to school dropout and other social and economic consequences for the affected family. Early treatment with antibiotics is effective; however, this involves daily oral and intramuscular injection at distant health facilities for 56 days making it a challenge among poor rural folks living on daily subsistence work. The mode of transmission of Buruli ulcer is not known and there is no effective preventive vaccine for Buruli ulcer. Thus the only effective control tool is early case detection and treatment to reduce morbidity and associated disabilities that occurs as a result of late treatment. It is therefore essential to implement interventions that remove impediments that limit early case detection; access to early effective treatment and this paper reports one such effort where the feasibility of social interventions to enhance Buruli ulcer control was assessed. METHODS: This was a qualitative study using in depth interviews to generate information to ascertain the benefit or otherwise of the intervention implemented. Clinical records of patients to generate data to determine the feasibility and effectiveness of social interventions in the fight against Buruli ulcer was examined. In all, 56 in-depth interviews (28 at baseline and 28 at evaluation) were conducted for this report. RESULTS: At full implementation, treatment default and dropout reduced significantly from 58.8% and 52.9% at baseline to 1.5% and 1.5% respectively. The number of early case detection went up significantly. Affected families were happy with social interventions such as provision of transportation and breakfast to patients on daily basis. Families were happy with the outpatient services provided under the intervention where no patient was admitted into the hospital. CONCLUSION: The study showed that with a little more investment in early case detection, diagnosis and treatment, coupled with free transportation and breakfast for patients, most of the cases could be treated effectively with the available antibiotics to avoid disability and complications from the disease. PMID- 23339624 TI - Systems infection biology: a compartmentalized immune network of pig spleen challenged with Haemophilus parasuis. AB - BACKGROUND: Network biology (systems biology) approaches are useful tools for elucidating the host infection processes that often accompany complex immune networks. Although many studies have recently focused on Haemophilus parasuis, a model of Gram-negative bacterium, little attention has been paid to the host's immune response to infection. In this article, we use network biology to investigate infection with Haemophilus parasuis in an in vivo pig model. RESULTS: By targeting the spleen immunogenome, we established an expression signature indicative of H. parasuis infection using a PCA/GSEA combined method. We reconstructed the immune network and estimated the network topology parameters that characterize the immunogene expressions in response to H. parasuis infection. The results showed that the immune network of H. parasuis infection is compartmentalized (not globally linked). Statistical analysis revealed that the reconstructed network is scale-free but not small-world. Based on the quantitative topological prioritization, we inferred that the C1R-centered clique might play a vital role in responding to H. parasuis infection. CONCLUSIONS: Here, we provide the first report of reconstruction of the immune network in H. parasuis-infected porcine spleen. The distinguishing feature of our work is the focus on utilizing the immunogenome for a network biology-oriented analysis. Our findings complement and extend the frontiers of knowledge of host infection biology for H. parasuis and also provide a new clue for systems infection biology of Gram-negative bacilli in mammals. PMID- 23339625 TI - Time-dependent changes in hepatic and intestinal induction of cytochrome P450 3A after administration of dexamethasone to rats. AB - We investigated the effects of the dose of and the number of times an inducer was administered and the duration of induction of hepatic and intestinal cytochrome P450 3A (CYP3A) in rats using dexamethasone 21-phosphate (DEX-P) and midazolam (MDZ) as an inducer and a substrate to CYP3A, respectively. The number of times DEX-P was administered was not a significant factor in the induction of either hepatic or intestinal CYP3A; however, administration of DEX-P multiple times markedly decreased the bioavailability of DEX-P by self-induction of CYP3A. CYP3A induction in the liver increased depending on the dose of DEX-P, whereas that in intestine showed a mild increase, but the induction level was almost constant regardless of the dose of DEX-P. Administration of a single dose of DEX-P showed a temporal increase in CYP3A activity in both tissues and the induction ratios reached maximum values at 12 h after DEX-P administration. On the other hand, a mild increase of CYP3A activity, which lasted for at least 48 h, was observed in both tissues after administration of multiple doses. Some physiological compounds such as cytokines might be involved in decreasing the CYP3A activity to maintain homeostasis of the body. PMID- 23339626 TI - The pharmacokinetic interaction between mycophenolic acid and cyclosporine revisited: a commentary on "Mycophenolic acid glucuronide is transported by multidrug resistance-associated protein 2 and this transport is not inhibited by cyclosporine, tacrolimus or sirolimus". PMID- 23339627 TI - Where on earth to publish? A sample survey comparing traditional and open access publishing in the oncological field. AB - BACKGROUND: The paper intends to help scientific authors to make the best choice of journals in which to publish, by describing and comparing journal features in the area of oncology. For this purpose, the authors identified impact factor (IF) ranking, cost options and copyright conditions offered to authors wishing to publish in full open access (OA), subscription-based or hybrid journals. METHODS: Data referring to articles published in 2010 by three Italian research institutions (National Institute of Health - Rome (ISS), Regina Elena National Cancer Institute - Rome (IRE), National Cancer Institute - Milan (INT) in journals (78) managed according to different business models, all listed in the Journal Citation Reports, subject category Oncology, were collected and analysed. The journals surveyed were ranked according to IF, position in quartiles, publication charges, usage rights in published articles, self-archiving conditions in OAI-compliant repositories digital archives. RESULTS: Almost half (34) the journals surveyed were included in the first quartile, thus revealing authors' preference for journals with a high IF. The prevalent journal business model was the hybrid formula (based on subscriptions but also offering a paid OA option) with 51 journals, followed by subscription-based only journals accounting for 22, while just 5 full OA journals were identified. In general, no relationship was found between IF and article publication charges, in terms of correspondence between more expensive fees and higher IF. CONCLUSIONS: The issue of OA journals as compared with traditional subscription-based journals is highly debated among stakeholders: library administrators facing financial restrictions, authors seeking to locate the best outlet for their research, publishers wishing to increase their revenues by offering journals with wider appeal. Against this background, factors such as the quest for alternatives to high-cost business models, investments in setting up institutional repositories hosting the published versions of articles and efforts to overcome copyright barriers and gain free access to scientific literature are all crucial. PMID- 23339629 TI - Photoinduced formation mechanism of the thymine-thymine (6-4) adduct. AB - The photoinduced mechanism leading to the formation of the thymine-thymine (6-4) photolesion has been studied by using the CASPT2//CASSCF approach over a dinucleotide model in vacuo. Following light absorption, localization of the excitation on a single thymine leads to fast singlet-triplet crossing that populates the triplet (3)(npi*) state of thymine. This state, displaying an elongated C(4)?O bond, triggers (6-4) dimer formation by reaction with the C(5)?C(6) double bond of the adjacent thymine, followed by a second intersystem crossing, which acts as a gate between the excited state of the reactant and the ground state of the photoproduct. The requirement of localized excitation on just one thymine, whose main decay channel (by radiationless repopulation of its ground state) is nonphotochemical, can rationalize the experimentally observed low quantum yield of formation for the thymine-thymine (6-4) adduct. PMID- 23339630 TI - Response to the letter "Risk assessment of methanol poisoning in outbreaks not applicable to isolated cases". PMID- 23339631 TI - Characterization of HIV-1 gag and nef in Cameroon: further evidence of extreme diversity at the origin of the HIV-1 group M epidemic. AB - BACKGROUND: Cameroon, in west central Africa, has an extraordinary degree of HIV diversity, presenting a major challenge for the development of an effective HIV vaccine. Given the continuing need to closely monitor the emergence of new HIV variants in the country, we analyzed HIV-1 genetic diversity in 59 plasma samples from HIV-infected Cameroonian blood donors. Full length HIV gag and nef sequences were generated and phylogenetic analyses were performed. FINDINGS: All gag and nef sequences clustered within HIV-1M. Circulating recombinant form CRF02_AG predominated, accounting for 50% of the studied infections, followed by clade G (11%), clade D and CRF37_cpx (4% each), and clades A, F, CRF01_AE and CRF36_cpx (2% each). In addition, 22% of the studied viruses apparently had nef and gag genes from viruses belonging to different clades, with the majority (8/10) having either a nef or gag gene derived from CRF02_AG. Interestingly, five gag sequences (10%) and three (5%) nef sequences were neither obviously recombinant nor easily classifiable into any of the known HIV-1M clades. CONCLUSION: This suggests the widespread existence of highly divergent HIV lineages in Cameroon. While the genetic complexity of the Cameroonian HIV-1 epidemic has potentially serious implications for the design of biomedical interventions, detailed analyses of divergent Cameroonian HIV-1M lineages could be crucial for dissecting the earliest evolutionary steps in the emergence of HIV-1M. PMID- 23339632 TI - Real time monitoring of on-chip coenzyme regeneration with SPR and DPI. AB - We report in this work real time characterization of enzyme-coenzyme binding by using surface plasmon resonance (SPR) and dual polarization interferometry (DPI) analyses. Results showed that diaphorase (DP) and lactate dehydrogenases (LDH) had distinct binding selectivity and preference over reduced and oxidized states of coenzyme NAD(H). On the basis of that, DP and LDH were chosen as indicator enzymes to distinguish the specific state of surface-bound NAD(H). The transformation between NADH and NAD(+) during enzyme-catalyzed redox reactions was therefore transduced into variation in interaction signals as indicated via the binding status of the indicator enzymes as detected with both SPR and DPI. This real time molecule-specific detection strategy revealed quick and direct reflection of the state and reactivity of the coenzyme, promising a unique way of precise molecular interaction analysis. PMID- 23339633 TI - Toxicity of CuO nanoparticles to yeast Saccharomyces cerevisiae BY4741 wild-type and its nine isogenic single-gene deletion mutants. AB - A suite of eight tentatively oxidative stress response-deficient Saccharomyces cerevisiae BY4741 single-gene mutants (sod1Delta, sod2Delta, yap1Delta, cta1Delta, ctt1Delta, gsh1Delta, glr1Delta, and ccs1Delta) and one copper vulnerable mutant (cup2Delta) was used to elucidate weather the toxicity of CuO nanoparticles to S. cerevisiae is mediated by oxidative stress (OS). Specifically, sensitivity profiles of mutants' phenotypes and wild-type (wt) upon exposure to nano-CuO were compared. As controls, CuSO4 (solubility), bulk-CuO (size), H2O2, and menadione (OS) were used. Growth inhibition of wt and mutant strains was studied in rich YPD medium and cell viability in deionized water (DI). Dissolved Cu-ions were quantified by recombinant metal-sensing bacteria and chemical analysis. To wt strain nano-CuO was 32-fold more toxic than bulk-CuO: 24 h IC50 4.8 and 155 mg/L in DI and 643 and >20000 mg/L in YPD, respectively. In toxicant-free YPD medium, all mutants had practically similar growth patterns as wt. However, the mutant strains sod1Delta, sod2Delta, ccs1Delta, and yap1Delta showed up to 12-fold elevated sensitivity toward OS standard chemicals menadione and H2O2 but not to nano-CuO, indicating that CuO nanoparticles exerted toxicity to yeast cells via different mechanisms. The most vulnerable strain to all studied Cu compounds was the copper stress response-deficient strain cup2Delta (~16-fold difference with wt), indicating that the toxic effect of CuO (nano)particles proceeds via dissolved Cu-ions. The dissolved copper solely explained the toxicity of nano-CuO in DI but not in YPD. Assumingly, in YPD nano CuO acquired a coating of peptides/proteins and sorbed onto the yeast's outer surface, resulting in their increased solubility in the close vicinity of yeast cells and increased uptake of Cu-ions that was not registered by the assays used for the analysis of dissolved Cu-ions in the test medium. Lastly, as yeast retained its viability in DI even by 24th hour of incubation, the profiling of the acute basal toxicity of chemicals toward yeasts may be conducted in DI. PMID- 23339634 TI - Askin's tumor: a case report and literature review. AB - Askin's tumor is a primitive neuroectodermal tumor developing from the soft tissues of the chest wall. Its diagnosis approach is complex and requires a multidisciplinary team. Given the rarity of this entity, no regimen has been validated in the literature. We report two cases of Askin's tumor with a major response to polychemotherapy and surgical resection in one case. These cases show that treatment of Askin's tumor should be multimodal, requiring discussion in multidisciplinary tumor working groups. PMID- 23339635 TI - Size-dependent dissociation of carbon monoxide on cobalt nanoparticles. AB - In situ soft X-ray absorption spectroscopy (XAS) was employed to study the adsorption and dissociation of carbon monoxide molecules on cobalt nanoparticles with sizes ranging from 4 to 15 nm. The majority of CO molecules adsorb molecularly on the surface of the nanoparticles, but some undergo dissociative adsorption, leading to oxide species on the surface of the nanoparticles. We found that the tendency of CO to undergo dissociation depends critically on the size of the Co nanoparticles. Indeed, CO molecules dissociate much more efficiently on the larger nanoparticles (15 nm) than on the smaller particles (4 nm). We further observed a strong increase in the dissociation rate of adsorbed CO upon exposure to hydrogen, clearly demonstrating that the CO dissociation on cobalt nanoparticles is assisted by hydrogen. Our results suggest that the ability of cobalt nanoparticles to dissociate hydrogen is the main parameter determining the reactivity of cobalt nanoparticles in Fischer-Tropsch synthesis. PMID- 23339636 TI - The role of VEGF and its soluble receptor VEGFR-1 in preterm newborns of preeclamptic mothers with RDS. AB - OBJECTIVE: We measured vascular endothelial growth factor (VEGF) and soluble VEGF receptor 1(sVEGFR-1) concentrations in cord blood and tracheal aspirate fluid (TAF) in order to investigate the role of them in lung maturation and the severity of respiratory distress syndrome (RDS) in preterm newborns, born to preeclamptic mothers. METHODS: Newborns were divided into two groups as preterms born to preeclamptic mothers and preterms born to healthy mothers. They were also divided into two groups as severe RDS (sRDS) and mild RDS (mRDS) according to the need of surfactant and extent or type of ventilatory support. The concentrations of VEGF and sVEGFR-1 in cord blood and TAF (only in preterms with sRDS) were assayed by standardized enzyme-linked immunosorbent assay. RESULTS: When the patients were evaluated as sRDS and mRDS, cord blood VEGF and VEGF/sVEGFR-1 concentrations of preterms with sRDS were significantly lower than the concentrations of preterms with mRDS. Conversely, cord blood sVEGFR-1 concentrations of preterms with sRDS were significantly higher than the concentrations of preterms with mRDS. VEGF and sVEGFR-1 concentrations in TAF could be compared only between sRDS preterms, born to preeclampsia (+) and (-) mothers. No statistical significance was detected between the two groups when sVEGFR-1, VEGF and VEGF/sVEGFR-1 concentrations in TAF were compared. CONCLUSION: Preeclampsia seems not to have an important effect on VEGF and sVEGFR-1 concentrations of preterm newborns both in cord blood and in TAF. Low VEGF and high sVEGFR-1 concentrations seem to be associated with the severity of RDS irrespective of preeclampsia, suggesting that VEGF may be one of the main components of lung maturation. PMID- 23339637 TI - Electric-field dependence of the effective dielectric constant in graphene. AB - The dielectric constant of a material is one of the fundamental features used to characterize its electrostatic properties such as capacitance, charge screening, and energy storage capability. Graphene is a material with unique behavior due to its gapless electronic structure and linear dispersion near the Fermi level, which can lead to a tunable band gap in bilayer and trilayer graphene, a superconducting-insulating transition in hybrid systems driven by electric fields, and gate-controlled surface plasmons. All of these results suggest a strong interplay between graphene properties and external electric fields. Here we address the issue of the effective dielectric constant (epsilon) in N-layer graphene subjected to out-of-plane (E(ext)(?)) and in-plane (E(ext)(||)) external electric fields. The value of epsilon has attracted interest due to contradictory reports from theoretical and experimental studies. Through extensive first principles electronic structure calculations, including van der Waals interactions, we show that both the out-of-plane (epsilon(?)) and the in-plane (epsilon(||)) dielectric constants depend on the value of applied field. For example, epsilon(?) and epsilon(||) are nearly constant (~3 and ~1.8, respectively) at low fields (E(ext) < 0.01 V/A) but increase at higher fields to values that are dependent on the system size. The increase of the external field perpendicular to the graphene layers beyond a critical value can drive the system to a unstable state where the graphene layers are decoupled and can be easily separated. The observed dependence of epsilon(?) and epsilon(||) on the external field is due to charge polarization driven by the bias. Our results point to a promising way of understanding and controlling the screening properties of few layer graphene through external electric fields. PMID- 23339638 TI - High-frequency oscillation for acute respiratory distress syndrome. AB - BACKGROUND: Patients with the acute respiratory distress syndrome (ARDS) require mechanical ventilation to maintain arterial oxygenation, but this treatment may produce secondary lung injury. High-frequency oscillatory ventilation (HFOV) may reduce this secondary damage. METHODS: In a multicenter study, we randomly assigned adults requiring mechanical ventilation for ARDS to undergo either HFOV with a Novalung R100 ventilator (Metran) or usual ventilatory care. All the patients had a ratio of the partial pressure of arterial oxygen (PaO) to the fraction of inspired oxygen (FiO) of 200 mm Hg (26.7 kPa) or less and an expected duration of ventilation of at least 2 days. The primary outcome was all-cause mortality 30 days after randomization. RESULTS: There was no significant between group difference in the primary outcome, which occurred in 166 of 398 patients (41.7%) in the HFOV group and 163 of 397 patients (41.1%) in the conventional ventilation group (P=0.85 by the chi-square test). After adjustment for study center, sex, score on the Acute Physiology and Chronic Health Evaluation (APACHE) II, and the initial PaO:FiO ratio, the odds ratio for survival in the conventional-ventilation group was 1.03 (95% confidence interval, 0.75 to 1.40; P=0.87 by logistic regression). CONCLUSIONS: The use of HFOV had no significant effect on 30-day mortality in patients undergoing mechanical ventilation for ARDS. (Funded by the National Institute for Health Research Health Technology Assessment Programme; OSCAR Current Controlled Trials number, ISRCTN10416500.). PMID- 23339640 TI - High-frequency oscillatory ventilation on shaky ground. PMID- 23339641 TI - Risk Analysis. From the editors. PMID- 23339643 TI - Remembering Jim Flynn. PMID- 23339639 TI - High-frequency oscillation in early acute respiratory distress syndrome. AB - BACKGROUND: Previous trials suggesting that high-frequency oscillatory ventilation (HFOV) reduced mortality among adults with the acute respiratory distress syndrome (ARDS) were limited by the use of outdated comparator ventilation strategies and small sample sizes. METHODS: In a multicenter, randomized, controlled trial conducted at 39 intensive care units in five countries, we randomly assigned adults with new-onset, moderate-to-severe ARDS to HFOV targeting lung recruitment or to a control ventilation strategy targeting lung recruitment with the use of low tidal volumes and high positive end expiratory pressure. The primary outcome was the rate of in-hospital death from any cause. RESULTS: On the recommendation of the data monitoring committee, we stopped the trial after 548 of a planned 1200 patients had undergone randomization. The two study groups were well matched at baseline. The HFOV group underwent HFOV for a median of 3 days (interquartile range, 2 to 8); in addition, 34 of 273 patients (12%) in the control group received HFOV for refractory hypoxemia. In-hospital mortality was 47% in the HFOV group, as compared with 35% in the control group (relative risk of death with HFOV, 1.33; 95% confidence interval, 1.09 to 1.64; P=0.005). This finding was independent of baseline abnormalities in oxygenation or respiratory compliance. Patients in the HFOV group received higher doses of midazolam than did patients in the control group (199 mg per day [interquartile range, 100 to 382] vs. 141 mg per day [interquartile range, 68 to 240], P<0.001), and more patients in the HFOV group than in the control group received neuromuscular blockers (83% vs. 68%, P<0.001). In addition, more patients in the HFOV group received vasoactive drugs (91% vs. 84%, P=0.01) and received them for a longer period than did patients in the control group (5 days vs. 3 days, P=0.01). CONCLUSIONS: In adults with moderate to-severe ARDS, early application of HFOV, as compared with a ventilation strategy of low tidal volume and high positive end-expiratory pressure, does not reduce, and may increase, in-hospital mortality. (Funded by the Canadian Institutes of Health Research; Current Controlled Trials numbers, ISRCTN42992782 and ISRCTN87124254, and ClinicalTrials.gov numbers, NCT00474656 and NCT01506401.). PMID- 23339645 TI - Psychosocial and cultural reasons for delay in seeking help and nonadherence to treatment in Indonesian women with breast cancer: a qualitative study. AB - OBJECTIVE: The aim of this study was to explore reasons for delay in seeking medical help and nonadherence to treatment in Indonesian women with breast cancer. METHOD: Semistructured interviews were conducted by purposive sampling, using a consecutive sample of 50 breast cancer patients who were treated at the Outpatient Surgical Oncology Clinic of Hasan Sadikin Hospital in Bandung, Indonesia. Interviews were recorded, transcribed verbatim, and coded using qualitative software. Codes were merged into main themes that were subsequently mapped onto the study's aim. RESULTS: Eight main themes concerning reasons for delay in seeking medical help and treatment nonadherence emerged, namely: lack of awareness and knowledge, cancer beliefs, treatment beliefs, financial problems, emotional burden, severe side effects, paternalistic style of communication, and unmet information needs. CONCLUSION: This study has identified several modifiable psychosocial and cultural factors related to delay in seeking help and nonadherence to treatment in breast cancer patients. We suggest that the provision of extensive information through media campaigns, treatment decision aids, and caregiver and patient education are needed to change the illness behaviors of Indonesian breast cancer patients. PMID- 23339644 TI - Characterization of host-cell line specific glycosylation profiles of early transmitted/founder HIV-1 gp120 envelope proteins. AB - Glycosylation plays an essential role in regulating protein function by modulating biological, structural, and therapeutic properties. However, due to its inherent heterogeneity and diversity, the comprehensive analysis of protein glycosylation remains a challenge. As part of our continuing effort in the analysis of glycosylation profiles of recombinant HIV-1 envelope-based immunogens, we evaluated and compared the host-cell specific glycosylation pattern of recombinant HIV-1 surface glycoprotein, gp120, derived from clade C transmitted/founder virus 1086.C expressed in Chinese hamster ovary (CHO) and human embryonic kidney containing T antigen (293T) cell lines. We used an integrated glycopeptide-based mass mapping workflow that includes a partial deglycosylation step described in our previous study with the inclusion of a fragmentation technique, electron transfer dissociation (ETD), to complement collision-induced dissociation. The inclusion of ETD facilitated the analysis by providing additional validation for glycopeptide identification and expanding the identified glycopeptides to include coverage of O-linked glycosylation. The site specific glycosylation analysis shows that the transmitted/founder 1086.C gp120 expressed in CHO and 293T displayed distinct similarities and differences. For N linked glycosylation, two sites (N386 and N392) in the V4 region were populated with high mannose glycans in the CHO cell-derived 1086.C gp120, while these sites had a mixture of high mannose and processed glycans in the 293T cell-derived 1086.C gp120. Compositional analysis of O-linked glycans revealed that 293T cell derived 1086.C gp120 consisted of core 1, 2, and 4 type O-linked glycans, while CHO cell-derived 1086.C exclusively consisted of core 1 type O-linked glycans. Overall, glycosylation site occupancy of the CHO and 293T cell-derived 1086.C gp120 showed a high degree of similarity except for one site at N88 in the C1 region. This site was partially occupied in 293T-gp120 but fully occupied in CHO gp120. Site-specific glycopeptide analysis of transmitted/founder 1086.C gp120 expressed in CHO cells revealed the presence of phosphorylated glycans, while 293T cell-produced 1086.C gp120 glycans were not phosphorylated. While the influence of phosphorylated glycans on immunogenicity is unclear, distinguishing host-cell specific variations in glycosylation profiles provide insights into the similarity (or difference) in recombinant vaccine products. While these differences had minimal effect on envelope antigenicity, they may be important in considering immunogenicity and functional capacities of recombinant envelope proteins produced in different expression systems. PMID- 23339646 TI - Sexual compulsivity and interpersonal functioning: sexual relationship quality and sexual health in gay relationships. AB - OBJECTIVE: The present study examined the role of sexual compulsivity (SC) in four aspects of interpersonal functioning relevant to main partnerships-sexual satisfaction, sexual communication, the presence of weekly sexual activity with main partner, and the number of recent casual male sex partners (i.e., outside of the relationship) with whom participants had unprotected anal intercourse (UAI). METHOD: Data were collected using a street-intercept strategy from both members of 172 gay male couples (N = 344 individuals) attending gay-community events together. SC was measured using the Sexual Compulsivity Scale; sexual satisfaction using a modified version of the Sexual Functioning Inventory (SFI); and sexual communication using a shortened version of the Dyadic Sexual Communication (DSC) Scale. RESULTS: Men high on SC were as likely to be partnered with men low on SC as they were to be partnered with others having high levels of SC. SC was negatively associated with sexual satisfaction and sexual communication. Individuals with higher SC scores and those whose partners had higher SC scores engaged in UAI with a greater number of male partners outside their relationship. SC was unrelated to frequency of sex with main partners. CONCLUSION: SC was associated with lower sexual relationship quality and increased potential for human immunodeficiency virus (HIV) transmission from a casual partner and subsequent transmission to (or reinfection with) a primary partner. Couples interventions for SC may be relevant to individual and public health. They provide a platform to practice communication skills, identify preferred sexual activities, and negotiate sexual safety. PMID- 23339647 TI - Local perceptions of cholera and anticipated vaccine acceptance in Katanga province, Democratic Republic of Congo. AB - BACKGROUND: In regions where access to clean water and the provision of a sanitary infrastructure has not been sustainable, cholera continues to pose an important public health burden. Although oral cholera vaccines (OCV) are effective means to complement classical cholera control efforts, still relatively little is known about their acceptability in targeted communities. Clarification of vaccine acceptability prior to the introduction of a new vaccine provides important information for future policy and planning. METHODS: In a cross sectional study in Katanga province, Democratic Republic of Congo (DRC), local perceptions of cholera and anticipated acceptance of an OCV were investigated. A random sample of 360 unaffected adults from a rural town and a remote fishing island was interviewed in 2010. In-depth interviews with a purposive sample of key informants and focus-group discussions provided contextual information. Socio cultural determinants of anticipated OCV acceptance were assessed with logistic regression. RESULTS: Most respondents perceived contaminated water (63%) and food (61%) as main causes of cholera. Vaccines (28%), health education (18%) and the provision of clean water (15%) were considered the most effective measures of cholera control. Anticipated vaccine acceptance reached 97% if an OCV would be provided for free. Cholera-specific knowledge of hygiene and self-help in form of praying for healing were positively associated with anticipated OCV acceptance if costs of USD 5 were assumed. Conversely, respondents who feared negative social implications of cholera were less likely to anticipate acceptance of OCVs. These fears were especially prominent among respondents who generated their income through fishing. With an increase of assumed costs to USD 10.5, fear of financial constraints was negatively associated with anticipated vaccine acceptance as well. CONCLUSIONS: Results suggest a high motivation to use an OCV as long as it seems affordable. The needs of socially marginalized groups such as fishermen may have to be explicitly addressed when preparing for a mass vaccination campaign. PMID- 23339649 TI - Magnetic resonance imaging in clinical cardiac electrophysiology. AB - Radiofrequency ablation is routinely used to treat numerous cardiac arrhythmias originating in the atrium and the ventricle. The process of ablation was pioneered to treat supraventricular tachycardias originating from fixed electrical circuits. These circuits could be identified using innovative electrophysiological maneuvers, which have been refined over the years to achieve excellent cure rates using fluoroscopy. More recently, electrophysiology ablation procedures have been greatly expanded to treat more diffuse arrhythmias like atrial fibrillation and ventricular tachycardia that are sustained by a remodeled myocardium or scar tissue. Given that there is no fixed circuit to target during most of these ablations, especially atrial fibrillation, there is a need to better visualize the substrate or the remodeling in the myocardium. Currently, when ablating atrial fibrillation or ventricular tachycardias, it is routine to use a cardiac CT or intra-cardiac echocardiogram to provide a three-dimensional anatomical structural map of the heart. This approach does not provide any substrate information like fibrosis or scar tissue in the myocardium. MRI has excellent soft-tissue visualization characteristics and has been used extensively to characterize the myocardial tissue as scar or fibrosis. This structural remodeling information of the myocardium is increasingly being used, along with the three-dimensional structural information in the ablation procedures, with the goal of improving the outcome. In addition MRI can also be used to visualize radiofrequency ablation lesions, potentially leading to significant improvement in procedural outcomes. PMID- 23339650 TI - Red blood cell flow in the cardiovascular system: a fluid dynamics perspective. AB - The dynamics of red blood cells (RBCs) is one of the major aspects of the cardiovascular system that has been studied intensively in the past few decades. The dynamics of biconcave RBCs are thought to have major influences in cardiovascular diseases, the problems associated with cardiovascular assistive devices, and the determination of blood rheology and properties. This article provides an overview of the works that have been accomplished in the past few decades and aim to study the dynamics of RBCs under different flow conditions. While significant progress has been made in both experimental and numerical studies, a detailed understanding of the behavior of RBCs is still faced with many challenges. Experimentally, the size of RBCs is considered to be a major limitation that allows measurements to be performed under conditions similar to physiological conditions. In numerical computations, researchers still are working to develop a model that can cover the details of the RBC mechanics as it deforms and moves in the bloodstream. Moreover, most of reported computational models have been confined to the behavior of a single RBC in 2-dimensional domains. Advanced models are yet to be developed for accurate description of RBC dynamics under physiological flow conditions in 3-dimensional regimes. PMID- 23339651 TI - Next generation long-term mechanical circulatory support systems: are pulsatile pumps extinct? Challenges, goals, and opportunities. AB - The therapeutic value of mechanically assisted circulation in the management of end-stage congestive heart failure has been shown. However, the ideal mechanical circulatory support device has not been introduced, especially for long-term or permanent use. Such a device should be durable, completely implantable, autonomous, small in size, and easy to use; it should provide a physiologic perfusion pattern. Current trends have favored non-pulsatile or continuous-flow devices over the older pulsatile devices. There has been no significant innovation in pulsatile devices for over 10 years. There is an ongoing debate about the physiologic impact of non-pulsatile flow. We explore the physiologic impact, biocompatibility issues, challenges in energy management, mechanical efficiency, and implantable power sources that exist in developing new classes of pulsatile devices for long-term mechanical circulatory support. PMID- 23339653 TI - Serum under-carboxylated osteocalcin levels in women with polycystic ovary syndrome: weight-dependent relationships with endocrine and metabolic traits. AB - BACKGROUND: Under-carboxylated osteocalcin (ucOC), the precursor substrate of bone biomarker OC is a potent regulator of energy metabolism by promoting insulin production and adiponectin synthesis and decreasing fat stores. The aim of the present study was to point out the potential role of ucOC in the physiopathology of polycystic ovary syndrome (PCOS), a common disorder defined by the constellation of anovulation, insulinresistance, hyperinsulinemia, obesity and androgen excess. METHODS: In this prospective case-control investigation, 78 young premenopausal women, i.e. 52 PCOS patients and 26 age- and body mass index (BMI)-matched healthy controls, were successively enrolled. Recruitment of PCOS patients was performed according to Androgen Excess-Polycystic Ovary Syndrome (AE PCOS) Society 2006 criteria. All study participants were subjected to clinical examination, whole-body composition assessment and measurements of serum ucOC, OC (1-49), glucose and lipids, insulin, total testosterone (TT), estradiol, sex hormone binding globulin (SHBG), high-sensitivity C-reactive protein (Hs-CRP) and beta-CrossLaps. RESULTS: BMI-stratified multivariate analysis revealed significantly higher ucOC levels in PCOS vs. controls in lean (p = 0.001) but not overweight and obese study participants (p = 0.456). Notably, a positive correlation between ucOC and TT (p = 0.018), calculated free testosterone (cFT, p = 0.028) and serum insulin (p = 0.036), respectively, was found to be confined to the lean analysis subgroup. Furthermore, in stepwise multiple regression models, beta-CrossLaps and cFT were able to predict 46.71% of serum ucOC variability. (1 43/49)OC failed to be significantly associated to any PCOS trait. CONCLUSIONS: Circulating ucOC concentration is related to key endocrine PCOS characteristics in a weight-dependent manner. Within the bone-pancreas loop, high ucOC may favor insulin release in lean hyperandrogenic women to compensate for impaired insulin sensitivity. PMID- 23339652 TI - Specific and efficient N-propionylation of histones with propionic acid N hydroxysuccinimide ester for histone marks characterization by LC-MS. AB - Histones participate in epigenetic regulation via a variety of dynamic posttranslational modifications (PTMs) on them. Mass spectrometry (MS) has become a powerful tool to investigate histone PTMs. With the bottom-up mass spectrometry approach, chemical derivatization of histones with propionic anhydride or deuterated acetic anhydride followed by trypsin digestion was widely used to block the hydrophilic lysine residues and generate compatible peptides for LC-MS analysis. However, certain severe side reactions (such as acylation on tyrosine or serine) caused by acid anhydrides will lead to a number of analytical issues such as reducing results accuracy and impairing the reproducibility and sensitivity of MS analysis. As an alternative approach, we report a novel derivatization method that utilizes N-hydroxysuccinimide ester to specifically and efficiently derivatize both free and monomethylated amine groups in histones. A competitive inhibiting strategy was implemented in our method to effectively prevent the side reactions. We demonstrated that our method can achieve excellent specificity and efficiency for histones derivatization in a reproducible manner. Using this derivatization method, we succeeded to quantitatively profile the histone PTMs in KMS11 cell line with selective knock out of translocated NSD2 allele (TKO) and the original parental KMS11 cell lines (PAR) (NSD2, a histone methyltransferase that catalyzes the histone H3 K36 methylation), which revealed a significant crosstalk between H3 protein K27 methylation and adjacent K36 methylation. PMID- 23339654 TI - Type I collagen self-assembly: the roles of substrate and concentration. AB - Collagen molecules, self-assembled into macroscopic hierarchical tissue networks, are the main organic building block of many biological tissues. A particularly common and important form of this self-assembly consists of type I collagen fibrils, which exhibit a nanoscopic signature, D-periodic gap/overlap spacing, with a distribution of values centered at approximately 67 nm. In order to better understand the relationship between type I collagen self-assembly and D-spacing distribution, we investigated surface-mediated collagen self-assembly as a function of substrate and incubation concentration. Collagen fibril assembly on phlogopite and muscovite mica as well as fibrillar gel coextrusion in glass capillary tubes all exhibited D-spacing distributions similar to those commonly observed in biological tissues. The observation of D-spacing distribution by self assembly of type I collagen alone is significant as it eliminates the necessity to invoke other preassembly or postassembly hypotheses, such as variation in the content of collagen types, enzymatic cross-linking, or other post-translational modifications, as mechanistic origins of D-spacing distribution. The D-spacing distribution on phlogopite mica is independent of type I collagen concentration, but on muscovite mica D-spacing distributions showed increased negative skewness at 20 MUg/mL and higher concentrations. Tilted D-spacing angles were found to correlate with decreased D-spacing measurements, an effect that can be removed with a tilt angle correction, resulting in no concentration dependence of D spacing distribution on muscovite mica. We then demonstrated that tilted D spacing is uncommon in biological tissues and it does not explain previous observations of low D-spacing values in ovariectomized dermis and bone. PMID- 23339648 TI - Bone tissue engineering: recent advances and challenges. AB - The worldwide incidence of bone disorders and conditions has trended steeply upward and is expected to double by 2020, especially in populations where aging is coupled with increased obesity and poor physical activity. Engineered bone tissue has been viewed as a potential alternative to the conventional use of bone grafts, due to their limitless supply and no disease transmission. However, bone tissue engineering practices have not proceeded to clinical practice due to several limitations or challenges. Bone tissue engineering aims to induce new functional bone regeneration via the synergistic combination of biomaterials, cells, and factor therapy. In this review, we discuss the fundamentals of bone tissue engineering, highlighting the current state of this field. Further, we review the recent advances of biomaterial and cell-based research, as well as approaches used to enhance bone regeneration. Specifically, we discuss widely investigated biomaterial scaffolds, micro- and nano-structural properties of these scaffolds, and the incorporation of biomimetic properties and/or growth factors. In addition, we examine various cellular approaches, including the use of mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), adult stem cells, induced pluripotent stem cells (iPSCs), and platelet-rich plasma (PRP), and their clinical application strengths and limitations. We conclude by overviewing the challenges that face the bone tissue engineering field, such as the lack of sufficient vascularization at the defect site, and the research aimed at functional bone tissue engineering. These challenges will drive future research in the field. PMID- 23339655 TI - Total synthesis of (-)-isoavenaciolide. AB - An enantioselective approach to (-)-isoavenaciolide was achieved starting from 1 undecyn-3-ol. The synthesis relied upon the preparation of a chiral 4-silyloxy-2 alkenylborane by hydroboration of a protected 2,3-allenol and subsequent stereoselective addition to 2-thiophenecarboxaldehyde. PMID- 23339656 TI - Commentary on: "Further studies are necessary in order to conclude a causal association between the consumption of monosodium L-glutamate (MSG) and the prevalence of the metabolic syndrome in the rural Thai population". AB - : See related article: http://www.nutritionandmetabolism.com/content/10/1/14. PMID- 23339657 TI - Influence of various tubal surgeries to serum antimullerian hormone level and outcome of the subsequent IVF-ET treatment. AB - OBJECTIVE: To compare the influence of various tubal surgeries to ovarian reserve via serum level of antimullerian hormone (AMH) and the subsequent in vitro fertilization and embryo transplantation (IVF-ET) outcome in patients with simple tubal infertility. STUDY DESIGN: A prospective cohort study was conducted on 134 IVF cycles undegone by 26 and 34 cases with bilateral and unilateral salpingectomy, respectively, 23 cases with bilateral oviducts interrupted in the proximal and 51 cases with bilateral oviducts obstruction without intervention as controls. RESULTS: Serum AMH displayed its great superiority to traditional markers of ovarian reserve in correspondence with antral follicles count and decisive effect for the number of oocytes retrieved after stimulation in each group. No significant differences on ovarian reserve and responsiveness or IVF-ET outcome existed among four groups comparable on essential characteristics, except for numerically higher clinical pregnancy rate and live birth rate after various tubal surgeries versus no intervention for bilateral oviducts obstruction. Especially, bilateral salpingectomy precursed the statistically highest implantation rate (51.0% versus 28.0%, 39.1%, 30.4%) and numerically best IVF outcome. CONCLUSION: Tubal surgical procedures have some beneficial effect for improving IVF outcome without significant impact on ovarian reserve or responsiveness. Bilateral salpingectomy appears to be an appropriate procedure before IVF treatment for bilateral salpingitis, especially hydrosalpinx. PMID- 23339659 TI - Evaluation of chemosensitivity prediction using quantitative dose-response curve classification for highly advanced/relapsed gastric cancer. AB - BACKGROUND: The use of standard chemotherapy regimens has changed the application of chemosensitivity tests from all chemotherapy-eligible patients to those who have failed standard chemotherapy, which includes patients with highly advanced, relapsed, or chemoresistant tumors. METHODS: We evaluated a total of 43 advanced primary and relapsed gastric cancers for chemosensitivity based on drug dose response curves to improve the objectivity and quality of quantitative measurements. The dose response curves were classified based on seven expected patterns. Instead of a binary chemosensitivity evaluation, we ranked drug sensitivity according to curve shapes and comparison with the peak plasma concentration (ppc) of each drug. RESULTS: A total of 193 dose response curves were obtained. The overall informative rate was 67.4%, and 85.3% for cases that had a sufficient number of cells. Paclitaxel (PXL)and docetaxel tended to show a higher rank, while cisplatin (CIS) and 5-fluorouracil (5-FU) tended to show resistance, particularly among the 20 cases (46.5%) that had recurrent disease after receiving chemotherapy with CIS and S-1 (5-FU). As such, we speculate that the resistant pattern of the chemosensitivity test suggests that cells with acquired drug resistance were selected by chemotherapy. Indeed, we observed a change in the chemosensitivity pattern of a sample before and after chemotherapy in terms of PXL sensitivity, which was used after primary chemotherapy. CONCLUSIONS: These results suggest that: (i) the dose-response pattern provides objective information for predicting chemosensitivity; and (ii) chemotherapy may select resistant cancer cell populations as a result of the therapy. PMID- 23339660 TI - The association between prenatal maternal objective stress, perceived stress, preterm birth and low birthweight. AB - OBJECTIVE: To evaluate the association between prenatal maternal stress, preterm birth (PTB) and low birthweight (LBW). METHODS: Forty-seven women exposed to life threatening rocket attacks during pregnancy were compared to 78 unexposed women. Women were interviewed within 9 months of delivery regarding socio-demographic background, smoking and perceived level of stress prenatally. Clinical data was obtained from hospital records and information regarding rocket attacks was obtained from official local authorities. RESULTS: Women exposed to rocket attacks during the second trimester of pregnancy were more likely to deliver LBW infants than were unexposed women (14.9% versus 3.3%, p = 0.03). No association was found between stress exposure and PTB. A multivariate logistic regression revealed that every 100 alarm increment increased the risk of LBW by 1.97 (adj.OR = 1.97, 95%CI 1.05-3.7). Perceived stress was not associated with LBW. CONCLUSIONS: Exposure to rocket attacks during the second trimester of pregnancy was associated with LBW. Objective stress can be used as an indicator of stress. Further studies are required to understand the underlying mechanism. PMID- 23339658 TI - Reassessment of the Listeria monocytogenes pan-genome reveals dynamic integration hotspots and mobile genetic elements as major components of the accessory genome. AB - BACKGROUND: Listeria monocytogenes is an important food-borne pathogen and model organism for host-pathogen interaction, thus representing an invaluable target considering research on the forces governing the evolution of such microbes. The diversity of this species has not been exhaustively explored yet, as previous efforts have focused on analyses of serotypes primarily implicated in human listeriosis. We conducted complete genome sequencing of 11 strains employing 454 GS FLX technology, thereby achieving full coverage of all serotypes including the first complete strains of serotypes 1/2b, 3c, 3b, 4c, 4d, and 4e. These were comparatively analyzed in conjunction with publicly available data and assessed for pathogenicity in the Galleria mellonella insect model. RESULTS: The species pan-genome of L. monocytogenes is highly stable but open, suggesting an ability to adapt to new niches by generating or including new genetic information. The majority of gene-scale differences represented by the accessory genome resulted from nine hyper variable hotspots, a similar number of different prophages, three transposons (Tn916, Tn554, IS3-like), and two mobilizable islands. Only a subset of strains showed CRISPR/Cas bacteriophage resistance systems of different subtypes, suggesting a supplementary function in maintenance of chromosomal stability. Multiple phylogenetic branches of the genus Listeria imply long common histories of strains of each lineage as revealed by a SNP-based core genome tree highlighting the impact of small mutations for the evolution of species L. monocytogenes. Frequent loss or truncation of genes described to be vital for virulence or pathogenicity was confirmed as a recurring pattern, especially for strains belonging to lineages III and II. New candidate genes implicated in virulence function were predicted based on functional domains and phylogenetic distribution. A comparative analysis of small regulatory RNA candidates supports observations of a differential distribution of trans-encoded RNA, hinting at a diverse range of adaptations and regulatory impact. CONCLUSIONS: This study determined commonly occurring hyper variable hotspots and mobile elements as primary effectors of quantitative gene-scale evolution of species L. monocytogenes, while gene decay and SNPs seem to represent major factors influencing long-term evolution. The discovery of common and disparately distributed genes considering lineages, serogroups, serotypes and strains of species L. monocytogenes will assist in diagnostic, phylogenetic and functional research, supported by the comparative genomic GECO-LisDB analysis server (http://bioinfo.mikrobio.med.uni-giessen.de/geco2lisdb). PMID- 23339661 TI - Nanophotonics and nanochemistry: controlling the excitation dynamics for frequency up- and down-conversion in lanthanide-doped nanoparticles. AB - Nanophotonics is an emerging science dealing with the interaction of light and matter on a nanometer scale and holds promise to produce new generation nanophosphors with highly efficient frequency conversion of infrared (IR) light. Scientists can control the excitation dynamics by using nanochemistry to produce hierarchically built nanostructures and tailor their interfaces. These nanophosphors can either perform frequency up-conversion from IR to visible or ultraviolet (UV) or down-conversion, which results in the IR light being further red shifted. Nanophotonics and nanochemistry open up numerous opportunities for these photon converters, including in high contrast bioimaging, photodynamic therapy, drug release and gene delivery, nanothermometry, and solar cells. Applications of these nanophosphors in these directions derive from three main stimuli. Light excitation and emission within the near-infrared (NIR) "optical transparency window" of tissues is ideal for high contrast in vitro and in vivo imaging. This is due to low natural florescence, reduced scattering background, and deep penetration in tissues. Secondly, the naked eye is highly sensitive in the visible range, but it has no response to IR light. Therefore, many scientists have interest in the frequency up-conversion of IR wavelengths for security and display applications. Lastly, frequency up-conversion can convert IR photons to higher energy photons, which can then readily be absorbed by solar materials. Current solar devices do not use abundant IR light that comprises almost half of solar energy. In this Account, we present our recent work on nanophotonic control of frequency up- and down-conversion in fluoride nanophosphors, and their biophotonic and nanophotonic applications. Through nanoscopic control of phonon dynamics, electronic energy transfer, local crystal field, and surface-induced non-radiative processes, we were able to produce new generation nanophosphors with highly efficient frequency conversion of IR light. We show that nanochemistry plays a vital role in the design and interface engineering of nanophosphors, providing pathways to expand their range of applications. High contrast in vitro and in vivo NIR-to-NIR up- and down-conversion bioimaging were successfully demonstrated by our group, evoking wide interests along this line. We introduced trivalent gadolinium ions into the lattice of the nanophosphors or into the shell layer of nanophosphors in a core/shell configuration to produce novel nanophosphors for multimodal (MRI and optical) imaging. We also demonstrate the security and display applications using photopatternable NIR-to-NIR and NIR to-visible frequency up-conversion nanophosphors with appropriately engineered surface chemistry. In addition, we present preliminary results on dye-sensitized solar cells using up-conversion in fluoride lattice-based nanophosphors for IR photon harvesting. PMID- 23339662 TI - Target-responsive "sweet" hydrogel with glucometer readout for portable and quantitative detection of non-glucose targets. AB - Portable devices with the advantages of rapid, on-site, user-friendly, and cost effective assessment are widely applied in daily life. However, only a limited number of quantitative portable devices are commercially available, among which the personal glucose meter (PGM) is the most successful example and has been the most widely used. However, PGMs can detect only blood glucose as the unique target. Here we describe a novel design that combines a glucoamylase-trapped aptamer-cross-linked hydrogel with a PGM for portable and quantitative detection of non-glucose targets. Upon target introduction, the hydrogel collapses to release glucoamylase, which catalyzes the hydrolysis of amylose to produce a large amount of glucose for quantitative readout by the PGM. With the advantages of low cost, rapidity, portability, and ease of use, the method reported here has the potential to be used by the public for portable and quantitative detection of a wide range of non-glucose targets. PMID- 23339663 TI - Inhibition pathways of the potent organophosphate CBDP with cholinesterases revealed by X-ray crystallographic snapshots and mass spectrometry. AB - Tri-o-cresyl-phosphate (TOCP) is a common additive in jet engine lubricants and hydraulic fluids suspected to have a role in aerotoxic syndrome in humans. TOCP is metabolized to cresyl saligenin phosphate (CBDP), a potent irreversible inhibitor of butyrylcholinesterase (BChE), a natural bioscavenger present in the bloodstream, and acetylcholinesterase (AChE), the off-switch at cholinergic synapses. Mechanistic details of cholinesterase (ChE) inhibition have, however, remained elusive. Also, the inhibition of AChE by CBDP is unexpected, from a structural standpoint, i.e., considering the narrowness of AChE active site and the bulkiness of CBDP. In the following, we report on kinetic X-ray crystallography experiments that provided 2.7-3.3 A snapshots of the reaction of CBDP with mouse AChE and human BChE. The series of crystallographic snapshots reveals that AChE and BChE react with the opposite enantiomers and that an induced-fit rearrangement of Phe297 enlarges the active site of AChE upon CBDP binding. Mass spectrometry analysis of aging in either H(2)(16)O or H(2)(18)O furthermore allowed us to identify the inhibition steps, in which water molecules are involved, thus providing insights into the mechanistic details of inhibition. X-ray crystallography and mass spectrometry show the formation of an aged end product formed in both AChE and BChE that cannot be reactivated by current oxime based therapeutics. Our study thus shows that only prophylactic and symptomatic treatments are viable to counter the inhibition of AChE and BChE by CBDP. PMID- 23339664 TI - From isolated metaatoms to photonic metamaterials: evolution of the plasmonic near-field. AB - Metamaterials are artificial media which can provide optical properties not available from natural materials. These properties often result from the resonant excitation of plasmonic modes in the metallic building blocks ("metaatoms") of the metamaterial. Electromagnetic interactions between the metaatoms significantly modify the resonances of the individual metaatoms and influence the optical properties of the whole metamaterial. To better understand these interactions, we study in this Letter the evolution of the plasmonic near-field in the course of the transition from an isolated metaatom, in our case a split ring resonator (SRR), to a photonic metamaterial via electron energy-loss spectroscopy. For small SRR ensembles, we observe the formation of discrete optical bright and dark modes due to coupling of the metaatoms. Large SRR arrays reveal a quasi-continuum of modes in the interior and distinct edge modes at the boundaries of the array. Our experimental results are in excellent agreement with numerical calculations. PMID- 23339665 TI - A Kampo formula, saikokaryukotsuboreito, improves serum testosterone levels of castrated mice and its possible mechanism. AB - The term "late-onset hypogonadism (LOH)" is recommended to express the symptoms in middle-aged males with decreased testosterone. Although androgen replacement therapy (ART) might be an effective way to manage LOH, the risk of testosterone supplementation in elderly men is still concerned. On the other hand, to avoid adverse effects of ART, Kampo medicine (traditional Chinese-Japanese medicine) is often a first choice to treat LOH in Japan. However, their pharmacological studies are few. In this study, castrated mice was used as an LOH animal model for examining the pharmacological effects of a Kampo formula, saikokaryukotsuboreito (shortly SKRBT) on serum testosterone levels and seminal vesicles weights. Furthermore, an attempt to elucidate its pharmacological mechanism, inhibition of SKRBT and its components against aromatase were also examined with the enzyme-based assay. As a result, SKRBT improved significantly both the decline of serum testosterone levels and decrease of seminal vesicles weight of castrated mice at a dose of 125 mg/kg with a non dose-dependent manner. SKRBT and two components Scutellariae radix and Rhei rhizoma exhibited inhibitory activities with the IC(50) values of 145, 29.2 and 29.7 ug/ml, respectively. These results suggested that the aromatase inhibitory activity of SKRBT may contribute, to a different extent, to the improvement of serum testosterone levels. PMID- 23339666 TI - Nonparametric Bayesian methods for benchmark dose estimation. AB - The article proposes and investigates the performance of two Bayesian nonparametric estimation procedures in the context of benchmark dose estimation in toxicological animal experiments. The methodology is illustrated using several existing animal dose-response data sets and is compared with traditional parametric methods available in standard benchmark dose estimation software (BMDS), as well as with a published model-averaging approach and a frequentist nonparametric approach. These comparisons together with simulation studies suggest that the nonparametric methods provide a lot of flexibility in terms of model fit and can be a very useful tool in benchmark dose estimation studies, especially when standard parametric models fail to fit to the data adequately. PMID- 23339667 TI - False alibi corroboration: witnesses lie for suspects who seem innocent, whether they like them or not. AB - To test the commonly held assumption that individuals who share a personal relationship are more likely to lie for one another than are strangers, 81 undergraduate students were given the opportunity to either corroborate or refute a confederate's alibi. In either a "friendship-enhancing" or a "stranger maintaining" condition, confederate-participant pairs completed tasks under the pretext of a problem-solving study. During the experimental session, the confederate briefly left the testing room; upon her return she either came back empty handed (evidence absent) or with money in her hands (evidence present). Later, both the confederate and participant were questioned about a purported theft in an adjacent room. When questioned by the experimenter in the presence of the participant, the confederate provided a false alibi that she was in the testing room with the participant the entire time. The experimenter later questioned the participant alone and asked whether the confederate's statement was in fact true. Although we hypothesized that participants in the friendship enhancing condition would corroborate the false alibi more often than those in the stranger-maintaining condition, participants in both conditions were as likely to support the alibi. In the "evidence-present" condition, however, participants were much less likely to corroborate the false alibi than in the "evidence-absent" condition. The results call into question our belief that closeness and affinity toward a suspect is important in judging the truthfulness of witness statements and emphasize the need for further empirical research on alibi corroboration. The research described also introduces a new and effective paradigm to directly measure false alibi corroboration. PMID- 23339668 TI - PfHPRT: a new biomarker candidate of acute Plasmodium falciparum infection. AB - Plasmodium falciparum is a protozoan parasite that causes human malaria. This parasitic infection accounts for approximately 655,000 deaths each year worldwide. Most deaths could be prevented by diagnosing and treating malaria promptly. To date, few parasite proteins have been developed into rapid diagnostic tools. We have combined a shotgun and a targeted proteomic strategy to characterize the plasma proteome of Gambian children with severe malaria (SM), mild malaria, and convalescent controls in search of new candidate biomarkers. Here we report four P. falciparum proteins with a high level of confidence in SM patients, namely, PF10_0121 (hypoxanthine phosphoribosyltransferase, pHPRT), PF11_0208 (phosphoglycerate mutase, pPGM), PF13_0141 (lactate dehydrogenase, pLDH), and PF14_0425 (fructose bisphosphate aldolase, pFBPA). We have optimized selected reaction monitoring (SRM) assays to quantify these proteins in individual patients. All P. falciparum proteins were higher in SM compared with mild cases or control subjects. SRM-based measurements correlated markedly with clinical anemia (low blood hemoglobin concentration), and pLDH and pFBPA were significantly correlated with higher P. falciparum parasitemia. These findings suggest that pHPRT is a promising biomarker to diagnose P. falciparum malaria infection. The diagnostic performance of this marker should be validated prospectively. PMID- 23339669 TI - Investigation of human cationic antimicrobial protein-18 (hCAP-18), lactoferrin and CD163 as potential biomarkers for ovarian cancer. AB - BACKGROUND: Epithelial ovarian cancer is one of the leading causes of gynaecological cancer morbidity and mortality in women. Early stage ovarian cancer is usually asymptomatic, therefore, is often first diagnosed when it is widely disseminated. Currently available diagnostics lack the requisite sensitivity and specificity to be implemented as community-based screening tests. The identification of additional biomarkers may improve the diagnostic efficiency of multivariate index assays. The aims of this study were to characterise and compare the ovarian tissue immunohistochemical localisation and plasma concentrations of three putative ovarian cancer biomarkers: human cationic antimicrobial protein-18 (hCAP-18); lactoferrin; and CD163 in normal healthy women and women with ovarian cancer. METHODS: In this case-control cohort study, ovarian tissue and blood samples were obtained from 164 women (73 controls, including 28 women with benign pelvic masses; 91 cancer, including 21 women with borderline tumours). Localisation of each antigen within the ovary was assessed by immunohistochemistry and serum concentrations determined by ELISA assays. RESULTS: Immunoreactive (ir) hCAP-18 and lactoferrin were identified in epithelial cells, while CD163 was predominately localised in stromal cells. Tissue ir CD163 increased significantly (P<0.05) with disease grade. Median plasma concentrations of soluble (s)CD163 were significantly greater in the cases (3220 ng/ml) than in controls (2488 ng/ml) (P< 0.01). Median plasma concentrations of hCAP-18 and lactoferrin were not significantly different between cases and controls. The classification efficiency of each biomarker (as determined by the area under the receiver operator characteristic curve; AUC) was: 0.67+/- 0.04; 0.62 +/- 0.08 and 0.51 +/- 0.07 for sCD163, hCAP-18 and lactoferrin, respectively. When the 3 biomarkers were modelled using stochastic gradient boosted logistic regression, the AUC increased to 0.95 +/- 0.03. CONCLUSIONS: The data obtained in this study establishes the localisation and concentrations of CD163, hCAP-18, and lactoferrin in ovarian tumours and peripheral blood. Individually, the 3 biomarkers display only modest diagnostic efficiency as assessed by AUC. When combined in a multivariate index assay, however, diagnostic efficiency increases significantly. As such, the utility of the biomarker panel, as an aid in the diagnosis of cancer in symptomatic women, is worthy of further investigation in a larger phase 2 biomarker trial. PMID- 23339670 TI - Proton MR spectroscopy correlates diffuse axonal abnormalities with post concussive symptoms in mild traumatic brain injury. AB - There are no established biomarkers for mild traumatic brain injury (mTBI), in part because post-concussive symptoms (PCS) are subjective and conventional imaging is typically unremarkable. To test whether diffuse axonal abnormalities quantified with three-dimensional (3D) proton magnetic resonance spectroscopic imaging (1H-MRSI) correlated with patients' PCS, we retrospectively studied 26 mTBI patients (mean Glasgow Coma Scale [GCS] score of 14.7), 18- to 56-year-olds and 13 controls three to 55 days post-injury. All were scanned at 3 Tesla with T1 and T2-weighted MRI and 3D 1H-MRSI (480 voxels over 360 cm3, ~30% of the brain). On scan day, patients completed a symptom questionnaire, and those who indicated at least one of the most common subacute mTBI symptoms (headache, dizziness, sleep disturbance, memory deficits, blurred vision) were grouped as PCS-positive. Global gray matter and white matter (GM/WM) absolute concentrations of N acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI) in PCS positive and PCS-negative patients were compared to age- and gender-matched controls using two-way analysis of variance. The results showed that the PCS negative group (n=11) and controls (n=8) did not differ in any GM or WM metabolite level. The PCS-positive patients (n=15) had lower WM NAA than the controls (n=12; 7.0 +/- 0.6 versus 7.9 +/- 0.5mM; p=0.0007). Global WM NAA, therefore, showed sensitivity to the TBI sequelae associated with common PCS in patients with mostly normal neuroimaging, as well as GCS scores. This suggests a potential biomarker role in a patient population in which objective measures of injury and symptomatology are currently lacking. PMID- 23339672 TI - The inflammatory process underlying atherosclerosis. AB - Atherosclerosis is considered an inflammatory disease that starts and evolves in response to cholesterol accumulation in the arterial intima of the large and medium arteries. In recent years, new insights into innate immunity have changed our understanding of the events that initiate and drive inflammation, changing many concepts about pathogenesis of inflammatory disorders and on the susceptibility to infections. This review summarizes some of the current concepts on innate immunity and rearranges old and new data on pathogenesis in atherosclerosis to shed light on the disease with a new inflammatory view. PMID- 23339671 TI - Rice-eating pattern and the risk of metabolic syndrome especially waist circumference in Korean Genome and Epidemiology Study (KoGES). AB - BACKGROUND: Metabolic syndrome poses a serious health threat in Asian countries. Rice is a staple food in Korea, and carbohydrate intake is associated with the risk of MetS. We hypothesized that various rice-eating patterns in a carbohydrate based diet would have different effects on the risk of MetS. METHODS: Participants were 26,006 subjects enrolled in the Korean Genome and Epidemiology Study between 2004 and 2006. They were classified into four dietary patterns - white rice, rice with beans, rice with multi-grains, and mixed based on their food frequency questionnaire responses. We compared metabolic risk traits according to the rice-eating patterns. RESULTS: Nutrients consumption and the presence of MetS risk factors differed according to rice-eating patterns. In men odds ratio(OR) for central obesity was slightly elevated in mixed group(1.18). In women, the risk for central obesity and abnormal fasting glucose were lower in the rice with beans group (adjusted OR =0.79, 0.83 respectively) and central obesity in rice with multi-grains(adjusted OR=0.91) than the white rice group. In postmenopausal women, ORs for central obesity (0.78) and abnormal fasting glucose (0.75) in the rice with beans group and ORs for central obesity (0.83), abnormal HDL-cholesterol (0.87) and MetS(0.85) in the rice with multi-grains group was lower than those in white rice group. In premenopausal women, the risk for central obesity (OR=0.77) was reduced in the rice with beans group. CONCLUSION: The risk for MetS was lower in the rice with beans and rice with multi-grains groups compared with the white rice group, particularly in postmenopausal women. PMID- 23339673 TI - CANMAT Guidelines commentary: where does the evidence come from, and how can we use it for our patients? PMID- 23339674 TI - Raising the bar for the evidence in evidence-based guidelines. PMID- 23339675 TI - Have the CANMAT bipolar guidelines transmogrified from do matter to can matter? PMID- 23339676 TI - The evolution of CANMAT Bipolar Disorder Guidelines: past, present, and future. PMID- 23339677 TI - Prenatal stress and affective disorders in a population birth cohort. AB - OBJECTIVES: Pregnant women exposed to an acute traumatic event are thought to produce offspring with an increased incidence of affective disorders. It is not known whether there are specific times in pregnancy which confer increased vulnerability, or if psychosocial stress alone can increase the incidence of affective disorders in offspring. We examined the relationship of the timing of an acute psychosocial threat during pregnancy to the incidence of affective disorders in offspring using data from a large birth cohort. METHODS: Using data on 90079 offspring born in Jerusalem in 1964-1976 and linked to Israel's psychiatric registry, we constructed proportional hazards models to evaluate the link between gestational age during the Arab-Israeli war of June 1967 and incidence of mood disorders. RESULTS: Those in their first trimester of fetal development during the war were more likely to be admitted to hospitals for any mood disorders [relative risk (RR) = 3.01, 95% confidence interval (CI): 1.68 5.39, p = 0.0002]; for bipolar disorder the risk was doubled (RR = 2.44, 95% CI: 0.996-5.99, p = 0.054) and for all 'other' mood disorders the risk was tripled (RR = 3.61, 95% CI: 1.68-7.80, p = 0.001). Mood disorders were also increased in offspring whose mothers had been in the third month of pregnancy in June of 1967 (RR = 5.54, 95% CI: 2.73-11.24, p < 0.0001). CONCLUSIONS: A time-limited exposure to a severe threat during early gestation may be associated with an increased incidence of affective disorders in offspring. The third month of fetal development was a moment of special vulnerability. PMID- 23339678 TI - Impact of ketorolac administration around ovarian stimulation on in vivo and in vitro fertilization and subsequent embryo development. AB - We performed this study to investigate the effect of ketorolac (a non-steroidal anti-inflammatory drug) administration around ovarian stimulation on in vivo and in vitro fertilization process. Sixty-four female mice (ICR) were injected with ketorolac (0, 7.5, 15 and 30 ug/d) for 3 d starting from the day of eCG treatment. In experiment 1, 41 mice were triggered by hCG and then mated; two cell embryos were obtained and in vitro development up to blastocyst was observed. In experiment 2, 23 mice were triggered by hCG and mature oocytes were collected; in vitro fertilization rate and subsequent embryo development up to blastocyst was recorded. In experiment 1, the blastocyst-forming rates per in vivo fertilized two-cell embryo showed an inverse relationship with a dosage of ketorolac (97.6%, 64.2%, 35.4% and 25.9%). In experiment 2, degenerated oocytes were frequently observed in a dose-dependent manner (4.3%, 22.9%, 22.4% and 75.0%). Lower fertilization rates were noted in all the three ketorolac-treating groups; blastocyst-forming rate was significantly lower in 30-ug-treating group when compared with the control group. Administration of ketorolac around ovarian stimulation significantly affects the development of in vivo fertilized embryo in a dose-dependent manner. High-dose ketorolac could result in a poor oocyte quality and decreased embryo developmental competence. PMID- 23339679 TI - Quantification of iron in seawater at the low picomolar range based on optimization of bromate/ammonia/dihydroxynaphtalene system by catalytic adsorptive cathodic stripping voltammetry. AB - A new analytical protocol for the challenging analysis of total dissolved iron at the low picomolar level in oceanic waters suitable for onboard analysis is presented. The method is based on the revision of the adsorptive properties of the iron/2,3-dihydroxynaphthalene (Fe/DHN) complexes on the hanging mercury drop electrode with catalytic enhancement by bromate ions. Although it was based on a previously proposed reagent combination, we show here that the addition of an acidification/alkalinization step is essential in order to cancel any organic complexation, and that an extra increment of the pH to 8.6-8.8 leads to the definition of a preconcentration-free procedure with the lowest detection limit described up to now. For total dissolved iron analysis, samples were acidified to pH 2.0 in the presence of 30 MUM DHN and left to equilibrate overnight. A 10 mL sample was subsequently buffered to a pH of ~8.7 in the presence of 20 mM bromate: a 60 s deposition at 0 V led to a sensitivity of 34 nA nM(-1) min(-1), a 4-fold improvement over previous methods, that translated in a limit of detection of 5 pM (2-20 fold improvement). Several tests proved that a nonreversible reaction in the time scale of the analysis, triggered by the acidification/alkalinization step, was behind the signal magnification. The new method was validated onboard via the analysis of reference material and via intercalibration against flow injection analysis-chemiluminescence on Southern Ocean surface samples. PMID- 23339680 TI - SLUG is activated by nuclear factor kappa B and confers human alveolar epithelial A549 cells resistance to tumor necrosis factor-alpha-induced apoptosis. AB - BACKGROUND: The role of tumor necrosis factor alpha (TNF-alpha) in cancer is complex with both apoptotic and anti-apoptotic roles proposed. However the mechanism is not clear. In the study, we designed to investigate the effect of TNF-alpha on the activation and expression of nuclear factor kappa B (NF kappaB)/p65/SLUG/PUMA/Bcl-2 levels in human lung cancer A549 cell line, and in conditions of TNF-alpha-induced apoptosis. METHODS: We have engineered three A549 cell lines that were transiently transfected with PUMA siRNA, SLUG siRNA and Bcl 2 siRNA, respectively. We have measured the in vitro effects of siRNA on apoptosis, and sensitivity to 20 ng/ml of TNF-alpha treatment for 24-48 h. RESULTS: We found the NF-kappaB activity and PUMA mRNA/protein was significantly increased after treatment of TNF-alpha for 24 h in untreated A549 cells, and led to a significant increase in TNF-alpha-induced apoptosis, no significant increase of SLUG and Bcl-2 level was shown. However, after treatment of TNF-alpha for 48 h in untreated A549 cells, SLUG and Bcl-2 level was significant increased, and PUMA level was significant decreased, and TNF-alpha-induced apoptosis was significantly decreased compared to the apoptosis level after treatment of TNF alpha for 24 h. Inhibition of the NF-kappaB activity could effectively decrease the PUMA level and increase the SLUG and Bcl-2 level. PUMA silencing by siRNA led to a significant decrease in TNF-alpha-induced apoptosis after treatment of TNF alpha for 24 h. Bcl-2 and SLUG silencing by siRNA led to a significant increase in TNF-alpha-induced apoptosis for 48 h. Furthermore, SLUG silencing increased PUMA level and decreased Bcl-2 level. CONCLUSIONS: The findings suggested that TNF-alpha treatment promoted apoptosis via the NF-kappaB-dependent PUMA pathway. The anti-apoptotic role of TNF-alpha was via NF-kappaB-dependent SLUG and Bcl-2 pathway at a later time. PMID- 23339681 TI - Brazil-Africa technical cooperation in health: what's its relevance to the post Busan debate on 'aid effectiveness'? AB - BACKGROUND: Brazil is rapidly becoming an influential player in development cooperation, also thanks to its high-visibility health projects in Africa and Latin America. The 4th High-level Forum on Aid Effectiveness held in Busan in late 2011 marked a change in the way development cooperation is conceptualised. The present paper explores the issue of emerging donors' contribution to the post Busan debate on aid effectiveness by looking at Brazil's health cooperation projects in Portuguese-speaking Africa. DEBATE: We first consider Brazil's health technical cooperation within the country's wider cooperation programme, aiming to identify its key characteristics, claimed principles and values, and analysing how these translate into concrete projects in Portuguese-speaking African countries. Then we discuss the extent to which the Busan conference has changed the way development cooperation is conceptualised, and how Brazil's technical cooperation health projects fit within the new framework. SUMMARY: We conclude that, by adopting new concepts on health cooperation and challenging established paradigms--in particular on health systems and HIV/AIDS fight--the Brazilian health experience has already contributed to shape the emerging consensus on development effectiveness. However, its impact on the field is still largely unscrutinised, and its projects seem to only selectively comply with some of the shared principles agreed upon in Busan. Although Brazilian cooperation is still a model in the making, not immune from contradictions and shortcomings, it should be seen as enriching the debate on development principles, thus offering alternative solutions to advance the discourse on cooperation effectiveness in health. PMID- 23339682 TI - Assessment of effects of IR and IPC on activities of cytochrome P450 isozymes in rats by a five-drug cocktail approach. AB - BACKGROUND AND OBJECTIVE: To evaluate the effects of ischemia and reperfusion (IR) and ischemic preconditioning (IPC) on the metabolic activities of cytochrome P450 (CYP) isozymes in rats by a five-drug cocktail approach. METHODS: Cocktail approach was used to evaluate the influence of IR and IPC on the activities of CYP1A2, CYP2C9, CYP2E1, CYP2D6 and CYP3A4, which were reflected by the changes of pharmacokinetic parameters of five specific probe drugs: caffeine, chlorzoxazone, tolbutamide, metoprolol and midazolam, respectively. Rats were randomly divided into IR, IPC and sham groups, and then injected the mixture of five probe drugs. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by a HPLC method with UV detection. The pharmacokinetic parameters were calculated by the software of DAS 2.0. RESULTS: The parameters including t(1/2beta), CLs, AUC, MRT and K10 exhibited a similar tendency for both IR and IPC groups. Compared with sham group, CLs and K10 of five probe drugs were significantly lower (p < 0.05), AUC and t(1/2beta) of five or some probe drugs were significantly increased in IR and IPC groups (p < 0.05). Compared with IPC group, CLs of five probe drugs were decreased and AUC were significantly increased in the IR group (p < 0.05). CONCLUSION: IR can variably decrease the activities of CYP isozymes in rats and this decrease can be attenuated by IPC. PMID- 23339683 TI - The relationship between amniotic and newborn gastric fluid inflammatory mediators. AB - To determine whether the levels of inflammatory mediators in gastric fluid (GF) of a premature newborn are associated with those in amniotic fluid (AF) of the newborn's mother. PATIENTS: Twenty-three pairs of pregnant women and their premature newborns <35 weeks gestation, born by Cesarean sections. METHODS: Amniotic fluids and newborn gastric fluids were obtained from women during Cesarean section procedure. The mother-premature newborn dyads were retrospectively assessed to analyze the clinical and laboratory data. Concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and mannose-binding lectin (MBL) were compared between amniotic and newborn gastric fluids in each dyad. RESULTS: Premature newborns and their mothers with funisitis had significantly higher median AF IL-6, TNF-alpha and GF IL-8 concentrations than those without funisitis (p = 0.022 for AF IL-6; p = 0.023 for AF TNF-alpha; p = 0.022 for GF IL-8). The concentrations of IL-6, IL 8, TNF-alpha and MBL in newborn GF were significantly correlated with those in AF in each dyad (p < 0.001, r = 0.872 for IL-6; p < 0.001, r = 0.851 for IL-8; p < 0.001, r = 0.768 for TNF-alpha; p < 0.001, r = 0.845 for MBL, respectively). CONCLUSION: The levels of inflammatory mediators in GF of a premature newborn immediately after birth are strongly associated with those in AF of the newborn's mother. PMID- 23339686 TI - Investigating heterogeneity in the characterization of risks using best worst scaling. AB - This research proposes and implements a new approach to the elicitation and analysis of perceptions of risk. We use best worst scaling (BWS) to elicit the levels of control respondents believe they have over risks and the level of concern those risks prompt. The approach seeks perceptions of control and concern over a large risk set and the elicitation method is structured so as to reduce the cognitive burden typically associated with ranking over large sets. The BWS approach is designed to yield strong discrimination over items. Further, the approach permits derivation of individual-level values, in this case of perceptions of control and worry, and analysis of how these vary over observable characteristics, through estimation of random parameter logit models. The approach is implemented for a set of 20 food and nonfood risks. The results show considerable heterogeneity in perceptions of control and worry, that the degree of heterogeneity varies across the risks, and that women systematically consider themselves to have less control over the risks than men. PMID- 23339685 TI - Strongly coupled inorganic/nanocarbon hybrid materials for advanced electrocatalysis. AB - Electrochemical systems, such as fuel cell and water splitting devices, represent some of the most efficient and environmentally friendly technologies for energy conversion and storage. Electrocatalysts play key roles in the chemical processes but often limit the performance of the entire systems due to insufficient activity, lifetime, or high cost. It has been a long-standing challenge to develop efficient and durable electrocatalysts at low cost. In this Perspective, we present our recent efforts in developing strongly coupled inorganic/nanocarbon hybrid materials to improve the electrocatalytic activities and stability of inorganic metal oxides, hydroxides, sulfides, and metal-nitrogen complexes. The hybrid materials are synthesized by direct nucleation, growth, and anchoring of inorganic nanomaterials on the functional groups of oxidized nanocarbon substrates including graphene and carbon nanotubes. This approach affords strong chemical attachment and electrical coupling between the electrocatalytic nanoparticles and nanocarbon, leading to nonprecious metal-based electrocatalysts with improved activity and durability for the oxygen reduction reaction for fuel cells and chlor-alkali catalysis, oxygen evolution reaction, and hydrogen evolution reaction. X-ray absorption near-edge structure and scanning transmission electron microscopy are employed to characterize the hybrids materials and reveal the coupling effects between inorganic nanomaterials and nanocarbon substrates. Z-contrast imaging and electron energy loss spectroscopy at single atom level are performed to investigate the nature of catalytic sites on ultrathin graphene sheets. Nanocarbon-based hybrid materials may present new opportunities for the development of electrocatalysts meeting the requirements of activity, durability, and cost for large-scale electrochemical applications. PMID- 23339684 TI - Genomic variations associated with attenuation in Mycobacterium avium subsp. paratuberculosis vaccine strains. AB - BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) whole cell vaccines have been widely used tools in the control of Johne's disease in animals despite being unable to provide complete protection. Current vaccine strains derive from stocks created many decades ago; however their genotypes, underlying mechanisms and relative degree of their attenuation are largely unknown. RESULTS: Using mouse virulence studies we confirm that MAP vaccine strains 316 F, II and 2e have diverse but clearly attenuated survival and persistence characteristics compared with wild type strains. Using a pan genomic microarray we characterise the genomic variations in a panel of vaccine strains sourced from stocks spanning over 40 years of maintenance. We describe multiple genomic variations specific for individual vaccine stocks in both deletion (26-32 Kbp) and tandem duplicated (11-40 Kbp) large variable genomic islands and insertion sequence copy numbers. We show individual differences suitable for diagnostic differentiation between vaccine and wild type genotypes and provide evidence for functionality of some of the deleted MAP-specific genes and their possible relation to attenuation. CONCLUSIONS: This study shows how culture environments have influenced MAP genome diversity resulting in large tandem genomic duplications, deletions and transposable element activity. In combination with classical selective systematic subculture this has led to fixation of specific MAP genomic alterations in some vaccine strain lineages which link the resulting attenuated phenotypes with deficiencies in high reactive oxygen species handling. PMID- 23339687 TI - Induction of amphiphilicity in polymer@silica particles: ceramic surfactants. AB - It is shown that, in general, when submicrometer hybrid particles of polymer@silica are subjected to thermal treatment, phase-separated hydrophobicity emerges at particles surface; and that the triggering of hydrophobicity results in particles which show amphiphilic behavior, arranging themselves at water interfaces and stabilizing W/O and O/W emulsions. Many polymer@silica particles show this behavior, and the entrapped polymers include polyethylene Engage, poly(dimethylsiloxane), poly-l-lactic acid, poly(ethylene-block-ethyleneglycol), poly(styrene-co-allyl-achohol), and poly(dimethylesiloxane-block-ethyleneoxide-co propyleneoxide). The concept is attractive because, by doping the particles with functional molecules, one can get various surfactants from the same treated particle; this is demonstrated with fluorescent probes. It is proposed that the amphiphilic activity is due to Janus heterogeneous distribution of the hydrophobic moieties on the surface. PMID- 23339688 TI - Chemical and stereochemical actions of UDP-galactose 4-epimerase. AB - Uridine(5')diphospho(1)alpha-D-galactose (UDP-gal) provides all galactosyl units in biologically synthesized carbohydrates. All healthy cells produce UDP-gal from uridine(5')diphospho(1)alpha-D-glucose (UDP-glc) by the action of UDP-galactose 4 epimerase (GalE). This Account provides our recent results describing unusual mechanistic features of this enzyme. Fully active GalE is dimeric and contains one tightly bound nicotinamide adenine dinucleotide (NAD) per subunit. The NAD undergoes reversible reduction to NADH in the chemical mechanism. GalE displays unusual enzymological, chemical, and stereochemical properties. These include practically irreversible binding of NAD, nonstereospecific hydride transfer, uridine nucleotide-induced activation of NAD, Tyr149 as a base catalyst, and [GalE-NADH]-oxidation in one-electron steps by one-electron acceptors. Early studies revealed that uridine(5')diphospho(1)alpha-D-4-ketopyranose (UDP-4 ketopyranose) and NADH are reaction intermediates. Weak binding of the 4 ketopyranosyl moiety and strong binding of the UDP-moiety allowed either face of the 4-ketopyranosyl moiety to accept hydride from NADH. In crystal structures of GalE, NAD bound within a Rossmann-type fold and uridine nucleotides within a substrate domain. Structures of [GalE-NADH] in complex with UDP-glc show Lys153, Tyr149, and Ser124 in contact with NAD or glucosyl-C4(OH). Lys153 forms hydrogen bonds to the ribosyl-OH groups of NAD. The phenolate of Tyr149 is associated with both the nicotinamide ring of NAD and glucosyl-C4(OH). Ser124 is hydrogen-bonded to glucosyl-C4(OH). Spectrophotometry studies show a pH-dependent charge transfer (CT) complex between Tyr149 and NAD. The CT-complex has a pKa of 6.1, which results in bleaching of the CT-band. The CT-band also bleaches upon binding of a uridine nucleotide. Kinetic experiments with wild-type GalE and Ser124Ala-GalE show the same kinetic pKa values as the corresponding CT-band pKa, which point to Tyr149 as the base catalyst for hydride transfer. We used NMR studies to verify that uridine nucleotide binding polarizes nicotinamide pi-electrons. The binding of uridine(5')-diphosphate (UDP) to GalE-[nicotinamide-1-15N]NAD shifts the 15N signal upfield 3 ppm, whereas UDP-binding to GalE-[nicotinamide-4-13C]NAD shifts the 13C-signal downfield by 3.4 ppm. Electrochemical and 13C NMR data for a series of N-alkylnicotinamides show that the 3.4 ppm downfield 13C-perturbation in GalE corresponds to an elevation of the NAD reduction potential by 150 mV. These results account for the uridine nucleotide-dependence in the reduction of [GalE-NAD] by glucose or NaBH3CN. Kinetics in the reduction of Tyr149Phe- and Lys153Met-GalE-NAD implicate Tyr149 and Lys153 in the nucleotide-dependent reduction of NAD. They further implicate electrostatic repulsion between N1 of NAD and the epsilon-aminium group of Lys153 in nucleotide-induced activation of NAD. In an O2-dependent reaction, [GalE-NADH] reduces the stable radical UDP TEMPO with production of superoxide radical. The reaction must proceed by way of a NAD-pyridinyl radical intermediate. PMID- 23339689 TI - Effects of natalizumab treatment on the cerebrospinal fluid proteome of multiple sclerosis patients. AB - Natalizumab is a very effective, relatively new drug for the treatment of relapsing remitting multiple sclerosis. Inflammatory and neurodegenerative processes in the central nervous system are presumed to cause adverse effects during the course of this disease. To monitor the effects of natalizumab treatment on the cerebrospinal fluid (CSF) proteome of patients, CSF samples were taken from patients before commencing treatment as well as after 1 year of treatment. Profiling proteomics experiments using electrospray Orbitrap mass spectrometry and pair wise comparison of patients before and after 1 year of natalizumab treatment revealed a number of candidate biomarkers that were significantly differentially abundant between the before and after treatment groups. Three proteins were subsequently validated using selected reaction monitoring (SRM) in a new, independent sample set. All three proteins, Ig mu chain C region and haptoglobin, both known inflammation-related proteins, as well as Chitinase-3-like protein 1, were confirmed by SRM to be significantly lower abundant in CSF of multiple sclerosis patients after 1 year of natalizumab treatment. The findings for Chitinase-3-like protein 1, a presumed biomarker for more rapid progression from a first clinically isolated syndrome to clinically definite multiple sclerosis, was further confirmed by ELISA measurements. PMID- 23339690 TI - Functional tissue engineering in articular cartilage repair: is there a role for electromagnetic biophysical stimulation? AB - Hyaline cartilage lesions represent an important global health problem. Several approaches have been developed in the last decades to resolve this disability cause, including tissue engineering, but to date, there is not a definitive procedure that is able to promote a repair tissue with the same mechanical and functional characteristics of native cartilage, and to obtain its integration in the subchondral bone. The need of resolutive technologies to obtain a "more effective" tissue substitutes has led Butler to propose the "Functional Tissue Engineering" (FTE) paradigm, whose principles are outlined in a so-called FTE road map. It consists of a two-phase strategy: in vitro tissue engineering and clinically surgery evaluation. The first phase, based on construct development, should take into account not only the chondrocyte biology, as their sensitivity to biochemical and physical stimuli, the risk of dedifferentiation in culture, and the ability to produce extracellular matrix, but also the features of suitable scaffolds. The in vivo phase analyzes the inflammatory microenvironment where the construct will be placed, because the cytokines released by synoviocytes and chondrocytes could affect the construct integrity, and, in particular, cause matrix degradation. The use of pulsed electromagnetic fields (PEMFs) represents an innovative therapeutic approach, because it is demonstrated that this physical stimulus increases the anabolic activity of chondrocytes and cartilage explants with consequent increase of matrix synthesis, but, at the same time, PEMFs limit the catabolic effects of inflammatory cytokines, reducing the construct degradation inside the surgical microenvironment. PEMFs mediate an up regulation of A2A adenosine receptors and a potentiation of their anti inflammatory effects. PMID- 23339691 TI - Postdoctoral recruitment in neuropsychology: a review and call for inter organizational action. AB - The history of centralized matches for postgraduate selection is briefly discussed with a focus on the match instituted by the Association of Postdoctoral Programs in Clinical Neuropsychology (APPCN) in 2001] Survey data, conducted both by APPCN and independently, are summarized. In general, despite incomplete participation and an estimated 30% rate of "exploding offers", applicants are somewhat satisfied with the match according to recent surveys (although satisfaction varies depending on whether an applicant matched). Given the high rate of withdrawal, the history of other specialties with suboptimal participation, and the concerns most commonly expressed by participants about this issue in survey data, there is cause for concern. We assert that incomplete participation in the match hurts applicants and programs. We propose that focused efforts are needed involving multiple organizations to enhance the match, including the Clinical Neuropsychology Synarchy (CNS) as our specialty council and the multiple organizations represented on the CNS. PMID- 23339692 TI - Optical nanoantennas with tunable radiation patterns. AB - We address new optical nanoantenna systems with tunable highly directional radiation patterns. The antenna comprises a regular linear array of metal nanoparticles in the proximity of an interface with high dielectric contrast. We show that the radiation pattern of the system can be controlled by changing parameters of the excitation, such as the polarization and/or incidence angles. In the case of excitation under the total reflection condition, the system operates as a nanoscopic source of radiation, converting the macroscopic incident plane wavefront into a narrow beam of light with adjustable characteristics. We derive also simple analytical formulas which give an excellent description of the radiation pattern and provide a useful tool for analysis and antenna design. PMID- 23339694 TI - Therapeutic efficacy of Rosa damascena Mill. on acetaminophen-induced oxidative stress in albino rats. AB - Rosa damascena (RD) is a widely cultivated ornamental plant. It acts as an astringent, aperients, carminative, and refrigerant and is used in respiratory disorders, tonsillitis, eye disorders, migraines, gynecological disorders, and menopausal symptoms. The aim of this study is to investigate the hepatoprotective activity of the aqueous extract of RD flowers at different oral dose levels (250, 500, and 1000 mg/kg body weight) on acetaminophen (2 g/kg oral N-acetyl-p aminophenol [APAP])-induced toxicity in rats. APAP administration altered various biochemical parameters, including serum transaminases, serum alkaline phosphatase, lactate dehydrogenase, albumin, bilirubin, urea and creatinine, hepatic lipid peroxidation, and reduced glutathione levels. Adenosine triphosphatase and glucose-6-phosphatase activity in the liver was decreased significantly in animals treated with APAP. These values are retrieved significantly by treatment with RD extract at all 3 doses in dose-dependant manner. Apart from these, histopathological changes also reveal the protective nature of the RD extract against acetaminophen-induced necrotic damage of hepatic tissues. In conclusion, these data suggest that the aqueous extract of RD may prevent hepatic damage from APAP-induced toxicity in rats and is likely to be mediated through its antioxidant activities. PMID- 23339695 TI - CD10 and E-cad expression in urinary bladder urothelial and squamous cell carcinoma. AB - Identification of prognostic markers in bladder carcinoma comprises a major clinical issue and therapeutic target. CD10 and the adhesion molecule E-cadherin (E-cad) are expressed in a variety of normal tissues and their neoplasms. CD10 is able to degrade extracellular matrix and other proteins, including adhesion molecules. The roles of CD10 and E-cad and their relationship in the development and progression of bladder carcinoma are poorly understood. The aim of this study was to investigate the expression of CD10 and E-cad in bladder carcinomas and relate the results to the established prognostic factors. This study included 144 patients with bladder carcinoma, including 72 with transitional cell carcinoma (TCC; 30 bilharzial and 42 nonbilharzial) and 72 with squamous cell carcinoma (SCC; 38 bilharzial and 34 nonbilharzial). Immunohistochemical analysis for both CD10 and E-cad were carried out on paraffin-fixed sections of neoplastic bladder tissues. CD10 tumor cells, CD10 stromal cells, and E-cad were expressed in 56%, 58%, and 51% of cancer bladder cases, respectively. There was a statistically significant correlation between percentage of tumor cells positively stained by CD10 and each of the tumor grade, clinical stage, and lymph node metastasis of both TCC and SCC. There was a significant statistical correlation between immunostaining by E-cad marker and each of the tumor grade, clinical stage, and lymph node metastasis of TCC, but no such association with SCC. The frequency of stromal expression of CD10 was higher in bilharzial-associated bladder carcinomas than in nonbilharzial ones, and these results were statistically significant. In conclusion, increased expression of CD10 in the tumor and stromal cells of both TCC and SCC and decreased expression of E-cad in the tumor cells of only TCC are strongly correlated with tumor progression, invasion, and metastasis in human bladder cancer. PMID- 23339696 TI - Restoration of brain antioxidant status by hydroalcoholic extract of Mimusops elengi flowers in rats treated with monosodium glutamate. AB - Monosodium glutamate (MSG) is commonly used as a flavor enhancer in many countries. However, overconsumption of MSG has been reported to produce detrimental effects on several organs. It mainly affects the normal physiology and function of the brain and causes severe oxidative stress. Mimusops elengi Linn. traditionally is used in many countries as a brain tonic and to calm anxiety and panic attacks. The effect of standardized hydroalcoholic extract of M. elengi flowers (ME) was evaluated against MSG-induced oxidative stress and excitotoxicity in Wistar rats. Excitotoxicity was induced by intraperitoneal administration of MSG (2 g/kg) for 7 days, and ME (100 and 200 mg/kg) was administered for 3 days before and for 7 days with administration of MSG. Animals were evaluated for locomotor activity, and brain homogenates were estimated for the levels of antioxidants and nitrite. In animals treated with MSG, pretreatment with ME improved ambulatory behavior, reduced lipid peroxidation and nitrite levels, and restored the enzymatic and nonenzymatic antioxidant (glutathione, total thiols, glutathione-S-transferase and catalase) status to near-normal levels; these were altered in the MSG control animals. Altogether, this investigation demonstrates the neuroprotective effect of ME against excitotoxicity and oxidative stress induced by MSG, and the observed protective effect might be attributed to the potential antioxidant property of ME. PMID- 23339697 TI - Antitumor activity of a polysaccharide-protein complex isolated from a wood rotting polypore macro fungus Phellinus rimosus (Berk) Pilat. AB - A protein-bound, water-soluble polysaccharide-protein complex was isolated from a medicinal mushroom, Phellinus rimosus (Berk) Pilat (PPC-Pr). The isolation was achieved by hot water extraction, filtration, solvent precipitation, dialysis, and freeze-drying. The proximate analysis showed that PPC-Pr comprised 54.8% polysaccharide and 28.6% protein. The molecular weight of the compound was determined by gel filtration using a Sephadex G 100. The molecular weight of PPC Pr was approximately 1,200,000 D. The thin-layer chromatography analysis of PPC Pr after acid hydrolysis with trifluroacetic acid showed that it was composed of glucose as the only monosaccharide unit. The amino acid profile analysis of PPC Pr revealed that it contained large amounts of aspartic acid, glutamic acid, alanine, glycine, and serine. Thus, the results indicated that PPC-Pr is a glucan protein complex. The PPC-Pr did not show in vitro cytotoxic activity against Dalton's lymphoma ascites and Ehrlich's ascites carcinoma cell lines. The PPC-Pr was found to be effective in increasing the life span of ascites tumors induced by Ehrlich's ascites carcinoma cell line in mice. PPC-Pr also was found to have significant preventive and curative effects on solid tumors induced by the Dalton's lymphoma ascites cell line. The experimental results thus indicated that protein-bound polysaccharide (PPC-Pr) isolated from P. rimosus possessed profound antitumor activity. The findings suggest the potential therapeutic use of this compound as an antitumor agent. PMID- 23339698 TI - Photochemoprotective effect of Calluna vulgaris extract on skin exposed to multiple doses of ultraviolet B in SKH-1 hairless mice. AB - UVB is a major cause of nonmelanoma skin cancer in humans. Photochemoprevention represents an important strategy in protecting the skin against the detrimental effects of ultraviolet B (UVB). We investigated the activity of Calluna vulgaris (Cv) delivered via a hydrogel on 3 main pathways (oxidative stress, inflammation, DNA damage) on skin exposed to multiple doses of UVB in SKH-1 mice. Fifty female mice were divided randomly into 5 groups: control, vehicle, UVB irradiated, Cv + UVB irradiated, and Cv + vehicle + UVB irradiated. The extract was applied topically on the skin in a dose of 4 mg polyphenols/cm2 30 minutes before each UVB (240 mJ/cm2) exposure over 10 consecutive days. Malondialdehyde, reduced glutathione, tumor necrosis factor-alpha, interleukin-6, cyclobutane pyrimidine dimer (CPD) levels, sunburn cell formation and epidermal thickness, and the number of epidermal cell layers in skin were evaluated 24 hours after the last treatment. UVB increased cytokine levels (P < 0.001), formation of CPDs (P < 0.001) and sunburn cells (P < 0.001), and the epidermal thickness and number of epidermal cell layers (P < 0.001) compared with the control group. The topical application of Cv protected the skin against inflammation and DNA damage, as shown by a decreased number of CPDs (P < 0.001) and sunburn cells (P < 0.001). The administration of Cv via hydrogel may be a viable method for chemoprevention.. PMID- 23339699 TI - Cancer stem cells in the mechanism of metal carcinogenesis. AB - Environmental metal carcinogenesis is a major public health concern. The mechanism underlying metal-induced carcinogenesis remains unclear. The concept of cancer stem cell recently has drawn considerable attention. Various studies indicate that the generation of cancer stem cells might contribute to the overall mechanism of development of metal-induced cancer. It is believed that oxidative stress and abnormal signaling caused by metals lead to the enrichment of cancer stem cells and eventually initiate cancer. In addition, metal-induced angiogenesis may also contribute to the generation of cancer stem cells. Studies using animal models further suggest that metals could induce the production of cancer stem cells and thus cause the development of cancer. This review summarizes recent studies of oxidative stress and cancer stem cells in relation to the mechanism of metal carcinogenesis. PMID- 23339700 TI - Nephroprotective effect of jaggery against acute and subchronic toxicity of acetaminophen in Wistar rats. AB - The present investigation was planned to evaluate the nephroprotective activity of jaggery against acetaminophen (APAP)-induced renal damage in rats. The protective activity of jaggery at different doses (250, 500, and 750 mg/kg, orally) was evaluated against oxidative damage induced by APAP administration (2 g/kg, once orally in acute exposure; 20 mg/kg, orally for 21 days in subchronic exposure) in rats. APAP administration significantly increased the levels of serum urea, creatinine, and renal lipid peroxidation (LPO), whereas substantial decreases were observed in levels of glutathione (GSH), adenosine triphosphatase (ATPase), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) enzymatic activities after APAP administration. Administration of jaggery significantly moved the studied parameters toward normal levels and also reversed the histopathologic alterations. Thus, jaggery can be used to reduce renal damage and may serve as an alternative medicine in the treatment of renal etiologies. PMID- 23339701 TI - Angiogenesis modulation: the "spice effect". AB - Spices have been used as flavoring agents since antiquity. Extensive research throughout the world has indicated that various phytochemicals present in spices play a critical role in the prevention and/or cure of several chronic diseases. Angiogenesis, the formation of new blood vessels, is regulated by a finely balanced equilibrium between pro- and anti-angiogenic factors. Any shift in this balance is linked to a wide range of human disorders. Experimental evidences suggest that anti- or pro-angiogenic strategies can contribute to the therapy of such disorders. The clinical benefits of the U.S. FDA-approved drugs that target angiogenesis are relatively modest due to their high toxicity and exorbitant cost. Therefore, there has been a renewed interest in identifying natural food sources for the development of novel and safer angiogenesis targeting agents. In this article, we discuss those dietary spices and their phytochemicals that have been experimentally found to target the angiogenic pathway. PMID- 23339702 TI - Calcium ameliorates renal cyst growth in metanephric organ culture: a morphological study. AB - Polycystic kidney disease (PKD) is associated with alterations in developmental processes that severely affect kidney integrity, often leading to fatal consequences. It has been suggested that dysfunctional calcium (Ca2+) regulation associated with the PKD phenotype is consequent to mutations affecting the pkd1 gene. Previously, it has been observed that blocking calcium along with cAMP allowed tubular epithelial cells to enter the proliferative phase that culminated in a cyst-like phenotype. In this regard, mouse metanephroi, (embryonic day 13.5, E13.5) were used to study morphological and ultrastructural effects of calcium replenishment on 8-bromocyclic 3'5'cyclic adenosine monophosphate (8-Br-cAMP) induced cyst-like tubular dilations. Phase contrast microscopy of 8-Br-cAMP treated metanephroi exhibited numerous dilated tubules that continued to increase in size for 4 days in culture. The effects of 8-Br-cAMP on renal tubular epithelia were assessed by histopathological and electron microscopic analyses. Transmission electron microscopy revealed changes such as increased vacuolation, swollen mitochondria, chromatin condensation, and disrupted cell membrane in tubular epithelia of 8-Br-cAMP-treated metanephroi. Concurrent treatments with calcium-channel agonists (calcium ionophore A23187 and phorbol-12-myristate-13 acetate) and 8-Br-cAMP abolished cAMP-induced morphometric and ultrastructural alterations. Calcium replenishment rescued tubular epithelial cells from mitogenic effects of cAMP and restored normal morphology at cellular and sub cellular levels as verified by histopathological and ultrastructural examinations. PMID- 23339703 TI - alpha-Diketone formation accompanied by oxidation of sulfur functional group by the reaction of o-alkynylarenesulfoxide with iodine. AB - The reaction of o-alkynylarenesulfoxide with iodine was investigated in detail, revealing functionalities of the formation of alpha-diketones with sulfenyl, sulfinyl, and sulfonyl. Additives can change the ratio of products to give medium to-excellent yields. Results show that water is taken into only sulfonyl compound and that other oxygen atoms constructed in the products are presumably derived from sulfoxide of the starting material and molecular oxygen. PMID- 23339704 TI - Endometrial injury in the menstrual cycle prior to assisted reproduction techniques to improve reproductive outcomes. PMID- 23339705 TI - Bead injection extraction chromatography using high-capacity lab-on-valve as a front end to inductively coupled plasma mass spectrometry for urine radiobioassay. AB - A novel bead injection (BI) extraction chromatographic microflow system exploiting a high-capacity lab-on-valve (LOV) platform coupled with inductively coupled plasma mass spectrometric detection is developed for rapid and automated determination of plutonium in human urine. A column attached to the LOV processing unit is loaded online with a metered amount of disposable extraction chromatographic resin (up to 330 mg of TEVA (abbreviation for tetravalent actinides)) through programmable beads transport. Selective capture and purification of plutonium onto the resin beads is then performed by pressure driven flow after preliminary sample pretreatment. The analytical results demonstrate the large capacity of bead surfaces for uptake of Pu within the tailor-made LOV platform that fosters processing of large-sized biological samples, e.g., 1 L of human urine, along with good reproducibility for automatic column renewal (0.319 +/- 0.004 g, n = 5). The chemical yields of plutonium were averagely better than 90% under the optimal experimental conditions, and the entire analytical procedure could be accomplished within a short time frame (<3 h) as compared to manual counterparts (1-2 days). Therefore, the developed system is well suited for expedient analysis of low-level plutonium in urine of exposed individuals as required in emergency situations. PMID- 23339706 TI - Local level epidemiological analysis of TB in people from a high incidence country of birth. AB - BACKGROUND: The setting for this analysis is the low tuberculosis (TB) incidence state of New South Wales (NSW), Australia. Local level analysis of TB epidemiology in people from high incidence countries-of-birth (HIC) in a low incidence setting has not been conducted in Australia and has not been widely reported. Local level analysis could inform measures such as active case finding and targeted earlier diagnosis. The aim of this study was to use a novel approach to identify local areas in an Australian state that have higher TB rates given the local areas' country of birth profiles. METHODS: TB notification data for the three year period 2006-2008 were analysed by grouping the population into those from a high-incidence country-of-birth and the remainder. RESULTS: During the study period there were 1401 notified TB cases in the state of NSW. Of these TB cases 76.5% were born in a high-incidence country. The annualised TB notification rate for the high-incidence country-of-birth group was 61.2/100,000 population and for the remainder of the population was 1.8/100,000. Of the 152 Local Government Areas (LGA) in NSW, nine had higher and four had lower TB notification rates in their high-incidence country-of-birth populations when compared with the high-incidence country-of-birth population for the rest of NSW. The nine areas had a higher proportion of the population with a country of birth where TB notification rates are >100/100,000. Those notified with TB in the nine areas also had a shorter length of stay in Australia than the rest of the state. The areas with higher TB notification rates were all in the capital city, Sydney. Among LGAs with higher TB notification rates, four had higher rates in both people with a high-incidence country of birth and people not born in a high incidence country. The age distribution of the HIC population was similar across all areas, and the highest differential in TB rates across areas was in the 5-19 years age group. CONCLUSIONS: Analysing local area TB rates and possible explanatory variables can provide useful insights into the epidemiology of TB. TB notification rates that take country of birth in local areas into account could enable health services to strategically target TB control measures. PMID- 23339707 TI - Next-generation phylogenomics. AB - Thanks to advances in next-generation technologies, genome sequences are now being generated at breadth (e.g. across environments) and depth (thousands of closely related strains, individuals or samples) unimaginable only a few years ago. Phylogenomics--the study of evolutionary relationships based on comparative analysis of genome-scale data--has so far been developed as industrial-scale molecular phylogenetics, proceeding in the two classical steps: multiple alignment of homologous sequences, followed by inference of a tree (or multiple trees). However, the algorithms typically employed for these steps scale poorly with number of sequences, such that for an increasing number of problems, high quality phylogenomic analysis is (or soon will be) computationally infeasible. Moreover, next-generation data are often incomplete and error-prone, and analysis may be further complicated by genome rearrangement, gene fusion and deletion, lateral genetic transfer, and transcript variation. Here we argue that next generation data require next-generation phylogenomics, including so-called alignment-free approaches. PMID- 23339708 TI - Microarray analysis reveals marked intestinal microbiota aberrancy in infants having eczema compared to healthy children in at-risk for atopic disease. AB - BACKGROUND: Deviations in composition and diversity of intestinal microbiota in infancy have been associated with both the development and recurrence of atopic eczema. Thus, we decided to use a deep and global microarray-based method to characterize the diversity and temporal changes of the intestinal microbiota in infancy and to define specific bacterial signatures associated with eczema. Faecal microbiota at 6 and 18 months of age were analysed from 34 infants (15 with eczema and 19 healthy controls) selected from a prospective follow-up study based on the availability of faecal samples. The infants were originally randomized to receive either Lactobacillus rhamnosus GG or placebo. RESULTS: Children with eczema harboured a more diverse total microbiota than control subjects as assessed by the Simpson's reciprocal diversity index of the microarray profiles. Composition of the microbiota did not differ between study groups at age of 6 months, but was significantly different at age of 18 months as assessed by MCPP (p=0.01). At this age healthy children harboured 3 -fold greater amount of members of the Bacteroidetes (p=0.01). Microbiota of children suffering from eczema had increased abundance of the Clostridium clusters IV and XIVa, which are typically abundant in adults. Probiotic Lactobacillus rhamnosus GG supplementation in early infancy was observed to have minor long-term effects on the microbiota composition. CONCLUSION: A diverse and adult-type microbiota in early childhood is associated with eczema and it may contribute to the perpetuation of eczema. PMID- 23339709 TI - Outcomes of pregnancy following postpartum haemorrhage. AB - OBJECTIVE: To assess the outcomes of pregnancy following postpartum haemorrhage (PPH) in the first pregnancy. DESIGN: Cohort study. SETTING: Aberdeen Maternity Hospital, Scotland, UK. POPULATION: All women with first deliveries recorded in the Aberdeen Maternity and Neonatal Databank (AMND) between 1986 and 2005. METHODS: All women identified from the AMND were classified into exposed and unexposed cohorts, according to whether or not they had PPH in their first delivery. They were then linked to any records of a second pregnancy. MAIN OUTCOME MEASURES: Any second pregnancy, time to second pregnancy, early or late pregnancy loss, and prevalence of PPH in the second pregnancy. RESULTS: Out of 34 334 women, 10% had a PPH in their first pregnancy. There was no statistically significant difference in the time to a second pregnancy, nor in the outcome of that second pregnancy, between women who had experienced a PPH in their first pregnancy and women who had not. For women with a caesarean delivery, there was a significant reduction in the proportion conceiving again, comparing the exposed and unexposed cohorts. CONCLUSIONS: From this cohort study we can conclude that if a PPH occurs in a first pregnancy, there is no delay in achieving a second pregnancy, and no detrimental effect on the outcome of that pregnancy. Significantly fewer women conceive a second pregnancy if they have a caesarean section in their first pregnancy that is complicated by PPH. PMID- 23339710 TI - Massive idiopathic feto-maternal transfusion associated with dilatation of umbilical vein: case report and review of literature. AB - Feto-maternal transfusion (FMT) or haemorrhage occurs when there is an entry of fetal blood into the maternal circulation in pregnancy or during delivery. It has been stated that very small amount of fetal red cells are normally detectable in maternal circulation in all pregnancies. However, massive FMT is rare and even rarer is the resultant severe anaemia which may cause severe fetal morbidity or early neonatal death in apparently uneventful normal pregnancy. Massive FMT is regarded as a pathological condition with a variety of clinical presentations essentially secondary to the fetal anaemia. We present a case of FMT associated with umbilical vein dilation and speculate whether this finding is of prognostic value. PMID- 23339711 TI - Molecular effects of baicalein in Hct116 cells and Caenorhabditis elegans : activation of the Nrf2 signaling pathway and prolongation of lifespan. AB - Baicalein is a major compound of extracts derived from Scutellaria baicalensis Lamiaceae, which are used as food supplements. Baicalein possesses a high radical scavenging activity and decreases intracellular reactive oxygen species in Hct116 human colon carcinoma cells and in Caenorhabditis elegans . It activates Nrf2, a key transcription factor that binds to the antioxidant responsive element (ARE): Baicalein causes a nuclear accumulation of Nrf2, increases ARE-dependent luciferase activity, and enhances the expression of heme oxygenase-1 in Hct116 cells. Additionally, accumulation of the Nrf2 homologue SKN-1 in nuclei of intestinal cells of C. elegans was observed. Lifespan analysis revealed that baicalein extends the mean, median, and maximum lifespans of the nematode by 45, 57 and 24%, respectively. Because SKN-1 activation is associated with prolongation of lifespan, the results suggest that baicalein increases the lifespan of C. elegans by activation of the Nrf2/SKN-1 signaling pathway. PMID- 23339713 TI - Her-2/neu expression is a negative prognosticator in ovarian cancer cases that do not express the follicle stimulating hormone receptor (FSHR). AB - BACKGROUND: Anti-Her-2 treatment is successfully administered to Her-2 overexpressing breast cancer patients and significantly implicates upon their survival. Building on these promising results, anti-Her-2 treatment protocols were tested as an option for epithelial ovarian cancer (EOC) as well. However Her 2 signalling is known to be modulated by G-protein coupled receptors (GPCR). Since a common GPCR in ovarian cancer is the FSH receptor (FSHR), we investigated the prognostic significance of Her-2 in patients that had been stratified according to their FSHR status. FINDINGS: A total number of 153 EOC patients were included in this study. Her-2 positivity was assessed using a standard protocol. Intriguingly Her-2 turned out to be an independent prognostic marker for poor overall survival only in those patients that did not express FSHR. This did neither apply for the whole panel nor in case of FSHR co-expression. CONCLUSIONS: We thus conclude that Her-2 can be a negative prognosticator only in FSHR negative EOC cases. Hence by stratifying EOC patients according to their FSHR expression status, we introduce a diagnostic protocol to effectively select EOC patients that would most probably respond to anti-Her-2 treatment. This observation could be of clinical importance in terms of selecting the patient that would most likely benefit from anti-Her-2 treatment. PMID- 23339712 TI - Utero-placental expression of angiotensin-(1-7) and ACE2 in the pregnant guinea pig. AB - BACKGROUND: In humans, trophoblast invasion, vascular remodeling and placental development are critical to determine the fate of pregnancy. Since guinea-pigs (GP) and humans share common pregnancy features including extensive trophoblast invasion, transformation of the uterine spiral arteries and a haemomonochorial placenta, the GP animal model was deemed suitable to extend our knowledge on the spatio-temporal immunoreactive expression of the vasodilator arpeptide of the renin-angiotensin system, angiotensin-(1-7) [Ang-(1-7)] and its main generating enzyme, angiotensin converting enzyme 2 (ACE2). METHODS: Utero-placental units were collected in days 15, 20, 40 and 60 of a 64-67 day long pregnancy in 25 Pirbright GP. Ang-(1-7) and ACE2 expression in utero-placental units were evaluated by immunohistochemistry. RESULTS: Ang-(1-7) and ACE2 were detected in the endothelium and syncytiotrophoblast of the labyrinthine placenta, interlobium, subplacenta, giant cells, syncytial sprouts, syncytial streamers, and myometrium throughout pregnancy. In late pregnancy, perivascular or intramural trophoblasts in spiral and mesometrial arteries expressed both factors. Immunoreactive Ang-(1-7) and ACE2 were present in decidua and in the vascular smooth muscle of spiral, myometrial and mesometrial arteries, which also express kallikrein (Kal), the bradykinin receptor 2 (B2R), vascular endothelial growth factor (VEGF) and its type 2 receptor (KDR), but no endothelial nitric oxide synthase (eNOS). In addition, the signal of Ang-(1-7) and ACE2 was especially remarkable in giant cells, which also show Kal, B2R. eNOS, VEGF and KDR. CONCLUSIONS: The spatio-temporal expression of Ang-(1-7) and ACE2 in GP, similar to that of humans, supports a relevant evolutionary conserved function of Ang-(1-7) and ACE2 in decidualization, trophoblast invasion, vascular remodeling and placental flow regulation, as well as the validity of the GP model to understand the local adaptations of pregnancy. It also integrates Ang-(1-7) to the utero-placental vasodilatory network. However, its antiangiogenic effect may counterbalance the proangiogenic activity of some of the other vasodilator components. PMID- 23339714 TI - Oxidation of adenosine and inosine: the chemistry of 8-oxo-7,8-dihydropurines, purine iminoquinones, and purine quinones as observed by ultrafast spectroscopy. AB - Oxidative damage to purine nucleic acid bases proceeds through quinoidal intermediates derived from their corresponding 8-oxo-7,8-dihydropurine bases. Oxidation studies of 8-oxo-7,8-dihyroadenosine and 8-oxo-7,8-dihydroinosine indicate that these quinoidal species can produce stable cross-links with a wide variety of nucleophiles in the 2-positions of the purines. An azide precursor for the adenosine iminoquinone has been synthesized and applied in ultrafast transient absorption spectroscopic studies. Thus, the adenosine iminoquinone can be observed directly, and its susceptibility to nucleophilic attack with various nucleophiles as well as the stability of the resulting cross-linked species have been evaluated. Finally, these observations indicate that this azide might be a very useful photoaffinity labeling agent, because the reactive intermediate, adenosine iminoquinone, is such a good mimic for the universal purine base adenosine. PMID- 23339715 TI - Polycyclic aromatic hydrocarbons and halogenated persistent organic pollutants in canned fish and seafood products: smoked versus non-smoked products. AB - In this study, levels of several groups of environmental contaminants represented by PAHs, PCBs, organochlorine pesticides and polybrominated diphenyl ethers were determined in various types of canned smoked and non-smoked fish and seafood products (54 samples) obtained from the Czech market. PAHs were detected in all of the studied samples, and at least one of the target halogenated persistent organic pollutants was present above the LOQ in 85% of the samples. The levels of PAHs, PCBs, organochlorine pesticides (mainly DDTs) and polybrominated diphenyl ethers found in the canned products varied in the range of 1.4-116 ug kg(-1), 0.6 59.6 ug kg(-1), 0.6-82.7 ug kg(-1) and 0.1-2.1 ug kg(-1) can content, respectively. Smoked sprats were the most contaminated fish product (n = 12) in which the highest levels of both PAHs and persistent organic pollutants were found. In 67% of the samples of smoked sprats in oil, the level of benzo[a]pyrene exceeded the maximum level of 5 ug kg(-1) established for smoked fish by European Union legislation. The distribution of target analytes between oil and fish fractions was also assessed. Significantly higher levels of PAHs were measured in the oil fraction. PMID- 23339716 TI - A new multicriteria risk mapping approach based on a multiattribute frontier concept. AB - Invasive species risk maps provide broad guidance on where to allocate resources for pest monitoring and regulation, but they often present individual risk components (such as climatic suitability, host abundance, or introduction potential) as independent entities. These independent risk components are integrated using various multicriteria analysis techniques that typically require prior knowledge of the risk components' importance. Such information is often nonexistent for many invasive pests. This study proposes a new approach for building integrated risk maps using the principle of a multiattribute efficient frontier and analyzing the partial order of elements of a risk map as distributed in multidimensional criteria space. The integrated risks are estimated as subsequent multiattribute frontiers in dimensions of individual risk criteria. We demonstrate the approach with the example of Agrilus biguttatus Fabricius, a high risk pest that may threaten North American oak forests in the near future. Drawing on U.S. and Canadian data, we compare the performance of the multiattribute ranking against a multicriteria linear weighted averaging technique in the presence of uncertainties, using the concept of robustness from info-gap decision theory. The results show major geographic hotspots where the consideration of tradeoffs between multiple risk components changes integrated risk rankings. Both methods delineate similar geographical regions of high and low risks. Overall, aggregation based on a delineation of multiattribute efficient frontiers can be a useful tool to prioritize risks for anticipated invasive pests, which usually have an extremely poor prior knowledge base. PMID- 23339717 TI - Chronic ventilation and social participation: experiences of men with neuromuscular disorders. AB - OBJECTIVE: The purpose of this study was to investigate how mechanical ventilation-dependent adults with neuromuscular disorders experience their occupational and social participation. METHODS: Data were collected through two successive focus-group discussions with six men (aged 23-40 years) living in the same specialized nursing home in the Netherlands. RESULTS: The results showed that the participants wanted to be involved in activities that provide interaction with others in society or community; they desired social participation. Thematic analysis brought out that the participants wanted to be taken seriously in all aspects of life. Four themes emerged: "Responsibility for risk-taking", "The influence of dependency", "Being treated as an employee", and "Maintaining optimism". These men appreciated good information from health care providers, wanted to have more autonomy in decision-making and risk-taking - and did not wish to be patronized. They wanted to have a social network to help them suction their tracheal cannula. Also, they would like activities at the activity centre to be more contributing to society and wished to be treated as employees rather than as clients. In view of their short life expectancy, they would also welcome discussions of end-of-life issues in group sessions led by a professional. Facilitating aspects of social participation, i.e. the experience of meaningful occupations in connection with autonomy and self-determination, would provide a more client-centred approach. PMID- 23339718 TI - Knowledge translation in physical therapy: from theory to practice. AB - PURPOSE: Knowledge translation (KT) has emerged as a concept that can lead to a greater utilization of evidence-based research in systems of care. Despite a rise in KT research, the literature on KT in relation to physical therapy practice is scarce. This article provides physical therapists (PTs) with recommendations that can support the effective implementation of new knowledge and scientific evidence in clinical practice. METHOD: Recommendations are grounded in the Ottawa Model of Research Use and in the literature in KT in the health professions. RESULTS: A well-established KT process, which is supported by a planning model, is essential to guide the implementation of scientific evidence. Consensus among all stakeholders about what evidence will be implemented must be reached. Context related barriers and facilitators should be assessed and tailored active and multi-component interventions should be considered. Participation from individuals in intermediary positions (e.g. opinion leaders) supports implementation of KT interventions. Monitoring of the process and assessment of intended outcomes should be performed in order to assess the success of the implementation. CONCLUSION: Five major recommendations grounded in the Ottawa model are provided that can assist PTs with the complex task of implementing new knowledge in their clinical practice. IMPLICATIONS FOR REHABILITATION: In order to support EBP, knowledge translation interventions can be used to support best practice. Implementation of new knowledge should be guided by a framework or a conceptual model. Consensus on the evidence must be reached and assessment of context-related factors should be done prior to the implementation of any KT intervention. Intervention strategies should be active, multi-component and include individuals with intermediary positions that can facilitate the KT process. PMID- 23339719 TI - Predictors of attendance and barriers to cataract surgery in Kenya, Bangladesh and the Philippines. AB - PURPOSE: Cataract is the leading cause of blindness worldwide, and is particularly common in low- and middle-income countries. Our study aims to identify the predictors for and barriers to acceptance of cataract surgery in Kenya, Bangladesh and the Philippines. METHODS: Cases were individuals aged >=50 years and with best corrected VA of <6/24 in the better eye due to cataract who were identified through population-based surveys and community-based case detection. Cases were asked why they had not attended for surgery. They were offered free cataract surgery and followed-up at one year. Non-acceptors were interviewed to identify barriers to accepting surgery. RESULTS: Of all participants, 58.6% attended for cataract surgery in Kenya, 53.9% Bangladesh and 47.1% the Philippines. Younger age was a predictor for attendance for surgery in all three countries. In Bangladesh and Kenya, male gender and psychosocial score were predictors. At baseline "cost" and "unaware of cataract" were most frequently reported barriers to uptake of surgery in the three settings. At follow-up, "surgical services inaccessible" was one of the two most frequently reported barriers in Kenya and the Philippines while "fear" was most frequently reported in Bangladesh and the Philippines. There were no consistent predictors of the most frequently reported barriers across the different settings. CONCLUSIONS: Future services need to focus on increasing uptake among older people and women. Cost is often reported as a barrier but this may conceal more complicated underlying barriers which need to be explored through in-depth qualitative research. IMPLICATIONS FOR REHABILITATION: Cataract is the leading cause of blindness worldwide, and is particularly common in low- and middle income countries. Evidence suggests that even when surgical services are available, there can be a lack of demand and low utilization resulting from barriers to uptake. Older cataract patients, females and especially older females are least likely to attend for surgery. Future cataract surgical programmes should put special emphasis on targeting and increasing uptake in these groups. PMID- 23339720 TI - Capacity to work while depressed and anxious--a phenomenological study. AB - PURPOSE: The aim was to explore experiences of capacity to work in persons working while depressed and anxious in order to identify the essence of the phenomenon capacity to work. METHOD: Four focus groups were conducted with 17 participants employed within the regular job market. Illness experiences ranged from symptoms to clinical diagnoses. A phenomenological approach was employed. RESULTS: The phenomenon of capacity to work was distinguished by nine constituents related to task, time, context and social interactions. The phenomenon encompassed a lost familiarity with one's ordinary work performance, the use of a working facade and adoption of new time-consuming work practices. Feelings of exposure in interpersonal encounters, disruption of work place order, lost "refueling" and a trade-off of between work capacity and leisure-time activities was also identified. The reduced capacity was pointed out as invisible, this invisibility was considered troublesome. CONCLUSIONS: A complex and comprehensive concept emerged, not earlier described in work capacity studies. Rehabilitation processes would benefit from deeper knowledge of the individual's capacity to work in order to make efficient adjustments at work. Results can have particular relevance both in clinical and occupational health practice, as well as in the workplaces, in supporting re-entering workers after sickness absence. Implications for Rehabilitation The reduced capacity to work due to depression and anxiety is not always understandable or observable for others, therefore, the rehabilitation process would benefit from increased knowledge and understanding of the difficulties afflicted individuals experience at work. Identifying tasks that contribute to "refueling" at work might enhance the success of the rehabilitation. Rehabilitation programs could be tailored to better address the inabilities that impact on the capacity to work when depressed and anxious. PMID- 23339721 TI - The effect of thoracic spine manipulation on pain and disability in patients with non-specific neck pain: a systematic review. AB - PURPOSE: The aim of this systematic review was to determine the efficacy of thoracic spine manipulation (TSM) in reducing pain and disability in patients diagnosed with non-specific neck pain. METHODS: An extensive literature search of PubMed, The Cochrane Library, CINAHL and EMBASE was conducted in February 2012. Randomized controlled trials (RCTs) or controlled clinical trials evaluating the effect of TSM in patients aged 18 to 65 years with non-specific neck pain were eligible. Methodological quality of the studies was assessed according to the Physiotherapy Evidence Database scale (PEDro). Qualitative analyses were conducted by means of the best evidence synthesis of van Peppen et al. RESULTS: The methodological quality of the 10 included RCTs (677 patients) varied between four and eight points. Eight studies reported significant reduction in pain and/or disability by TSM. Overall, according to the best evidence synthesis, there is insufficient evidence that TSM is more effective than control interventions in reducing pain and disability in patients with non-specific neck pain. CONCLUSIONS: TSM has a therapeutic benefit to some patients with neck pain, when compared to the effect of interventions such as electrotherapy/thermal programme, infrared radiation therapy, spinal mobilization and exercises. However, in comparison to cervical spine manipulation, no evidence is found that TSM is more effective in reducing pain and disability. Implications for Rehabilitation TSM is often used in the treatment of non-specific neck pain, which is a major health problem in the Western society. There is insufficient evidence that TSM is more effective in reducing pain and disability than control treatments in patients with non-specific neck pain. Despite the insufficient evidence that TSM is more effective than control treatments, TSM has a therapeutic benefit to some patients with neck pain. Therefore, TSM alone or in combination with other interventions is a suitable intervention to use in the treatment of non-specific neck pain. PMID- 23339722 TI - A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice. AB - In the search for the most efficacious antisense oligonucleotides (AOs) aimed at inducing SMN2 exon 7 inclusion, we systematically assessed three AOs, PMO25 (-10, -34), PMO18 (-10, -27), and PMO20 (-10, -29), complementary to the SMN2 intron 7 splicing silencer (ISS-N1). PMO25 was the most efficacious in augmenting exon 7 inclusion in vitro in spinal muscular atrophy (SMA) patient fibroblasts and in vitro splicing assays. PMO25 and PMO18 were compared further in a mouse model of severe SMA. After a single intracerebroventricular (ICV) injection in neonatal mice, PMO25 increased the life span of severe SMA mice up to 30-fold, with average survival greater by 3-fold compared with PMO18 at a dose of 20 MUg/g and 2-fold at 40 MUg/g. Exon 7 inclusion was increased in the CNS but not in peripheral tissues. Systemic delivery of PMO25 at birth achieved a similar outcome and produced increased exon 7 inclusion both in the CNS and peripherally. Systemic administration of a 10-MUg/g concentration of PMO25 conjugated to an octaguanidine dendrimer (VMO25) increased the life span only 2-fold in neonatal type I SMA mice, although it prevented tail necrosis in mild SMA mice. Higher doses and ICV injection of VMO25 were associated with toxicity. We conclude that (1) the 25-mer AO is more efficient than the 18-mer and 20-mer in modifying SMN2 splicing in vitro; (2) it is more efficient in prolonging survival in SMA mice; and (3) naked Morpholino oligomers are more efficient and safer than the Vivo Morpholino and have potential for future SMA clinical applications. PMID- 23339723 TI - Community-level risk factors for notifiable gastrointestinal illness in the Northwest Territories, Canada, 1991-2008. AB - BACKGROUND: Enteric pathogens are an important cause of illness, however, little is known about their community-level risk factors (e.g., socioeconomic, cultural and physical environmental conditions) in the Northwest Territories (NWT) of Canada. The objective of this study was to undertake ecological (group-level) analyses by combining two existing data sources to examine potential community level risk factors for campylobacteriosis, giardiasis and salmonellosis, which are three notifiable (mandatory reporting to public health authorities at the time of diagnosis) enteric infections. METHODS: The rate of campylobacteriosis was modeled using a Poisson distribution while rates of giardiasis and salmonellosis were modeled using a Negative Binomial distribution. Rate ratios (the ratio of the incidence of disease in the exposed group to the incidence of disease in the non-exposed group) were estimated for infections by the three major pathogens with potential community-level risk factors. RESULTS: Significant (p<=0.05) associations varied by etiology. There was increased risk of infection with Salmonella for communities with higher proportions of 'households in core need' (unsuitable, inadequate, and/or unaffordable housing) up to 42% after which the rate started to decrease with increasing core need. The risk of giardiasis was significantly higher both with increased 'internal mobility' (population moving between communities), and also where the community's primary health facility was a health center rather than a full-service hospital. Communities with higher health expenditures had a significantly decreased risk of giardiasis. Results of modeling that focused on each of Giardia and Salmonella infections separately supported and expanded upon previous research outcomes that suggested health disparities are often associated with socioeconomic status, geographical and social mobility, as well as access to health care (e.g. facilities, services and professionals). In the campylobacteriosis model, a negative association was found between food prices in communities and risk of infection. There was also a significant interaction between trapping and consumption of traditional foods in communities. Higher rates of community participation in both activities appeared to have a protective effect against campylobacteriosis. CONCLUSIONS: These results raise very interesting questions about the role that traditional activities might play in infectious enteric disease incidence in the NWT, but should be interpreted with caution, recognizing database limitations in collection of case data and risk factor information (e.g. missing data). Given the cultural, socioeconomic, and nutritional benefits associated with traditional food practices, targeted community-based collaborative research is necessary to more fully investigate the statistical correlations identified in this exploratory research. This study demonstrates the value of examining the role of social determinants in the transmission and risk of infectious diseases. PMID- 23339724 TI - Analysis of recent papers in hypertension: Treatment of obstructive sleep apnea with continuous positive airway pressure appears to decrease the incidence of incident hypertension. PMID- 23339725 TI - The treatment of hypertension: a remarkable success story. AB - One of the most successful public health programs in the past century provides an example of what can be accomplished when the government, the private sector, academia, and community organizations work together. The results of 4 decades of activities of the National High Blood Pressure Education Program (NHBPEP) can be measured in several ways. The publics' awareness, treatment, and control have increased remarkably. Hypertension is the primary reason adults visit physicians. Age-adjusted mortality for heart disease and stroke has declined by 70% and 80%, respectively, since the beginning of the program. The decline in heart and stroke deaths is seen in both sexes and blacks and whites, and is particularly evident in people who reside in the southeastern portion of the United States, which once had the highest mortality rates of stroke in the United States. This dramatic decrease in strokes and heart disease has occurred despite the substantial increase in obesity and diabetes in the United States. PMID- 23339726 TI - Randomized study of antihypertensive efficacy and safety of combination aliskiren/valsartan vs valsartan monotherapy in hypertensive participants with type 2 diabetes mellitus. AB - In this double-blind study, 1143 hypertensive participants with type 2 diabetes and stage 1 or 2 chronic kidney disease (CKD) were randomized to receive combination aliskiren/valsartan 150/160 mg or valsartan 160 mg monotherapy for 2 weeks, with force-titration to 300/320 mg and 320 mg, respectively, for another 6 weeks. Ambulatory blood pressure (ABP), the primary outcome, was available for 665 participants. Reductions from baseline to week 8 in 24-hour ABP were -14.1/ 8.7 mm Hg with aliskiren/valsartan vs -10.2/-6.3 mm Hg with valsartan (P<.001). Adverse events were reported in 202 participants (35.2%) taking aliskiren/valsartan and 182 participants (32.2%) taking valsartan. No participant had blood urea nitrogen values>40 mg/dL or serum creatinine values>2.0 mg/dL. There were no confirmed cases of serum potassium values>=6.0 mEq/L. Combination aliskiren/valsartan has additive effects on blood pressure reduction and tolerability similar to valsartan in hypertensive/diabetic participants with early-stage (stages 1 and 2) CKD. PMID- 23339727 TI - Low nadir CD4 cell count predicts sustained hypertension in HIV-infected individuals. AB - Hypertension is associated with cardiovascular disease in the human immunodeficiency virus (HIV)-infected population. The authors aimed to test the hypothesis whether advanced immunosuppression with low nadir CD4 lymphocyte cell count is a predictor of sustained hypertension in HIV-infected individuals. In a longitudinal study of an HIV cohort of 434 patients (43+/-11 years, 72% men, 71% Caucasians), standardized blood pressure was measured in duplicate during 3 clinical visits both at baseline and after 3.4+/-0.8 years. The lowest CD4 cell count in the individual history was recorded as nadir CD4. Both nadir CD4 cell count<50 cells/MUL and duration of antiretroviral therapy (ART) were associated with sustained hypertension, and the highest proportion of hypertensive patients was observed in those who had both nadir CD4 cell count<50 cells/MUL and prolonged ART duration. Nadir CD4 cell-count<50 cells/MUL was an independent predictor of hypertension (adjusted odds ratio [OR], 2.48; 95% confidence interval [CI], 1.27-4.83), as was ART duration (adjusted OR, 1.13; 95% CI, 1.03 1.24). The predictive power of ART duration was more pronounced in patients with nadir CD4 cell count<50 cells/MUL. Delaying ART initiation until a state of advanced immunosuppression might add to and even fuel the cardiovascular risk associated with ART. PMID- 23339728 TI - Patterns of nonadherence to antihypertensive therapy in primary care. AB - Nonadherence to medications is an important cause of poor blood pressure control. Long-acting antihypertensive agents could theoretically be beneficial in partially adherent patients, who are commonly seen in contemporary practice. Little has been reported about the duration of drug holidays (DHs) in treated hypertensives outside of generally compliant patients in phase 4 clinical trials. The authors described patterns of nonadherence to single and multiple antihypertensives in a random sample of 120 primary care patients with uncontrolled hypertension. Adherence to up to 3 antihypertensives was measured by electronic monitoring. Frequencies of single-day omissions and DHs of 2 consecutive days (DH2), 3 days (DH3), or >=4 days (DH>=4) for each drug were calculated. Overall, 89 (74%) of patients had at least a 1-day omission. A single day omission was found in 61.4% of the patients taking 1 drug, followed by DH>=4 (28.1%), DH2 (26.3%), and DH3 (8.8%). In patients using multiple drugs, single day omissions were also most common, followed by DH>=4, DH2, and DH3. Omissions of <=3 days comprise on average 74% of all omissions. Although encouraging full adherence remains important, it may be prudent to prescribe long-acting antihypertensive agents, which can compensate for the majority of dose omissions. PMID- 23339729 TI - Association between antihypertensive medication adherence and visit-to-visit variability of blood pressure. AB - It has been hypothesized that high visit-to-visit variability (VVV) of systolic blood pressure (SBP) may be the result of poor antihypertensive medication adherence. The authors studied this association using data from 1391 individuals taking antihypertensive medication selected from a large managed care organization. The 8-item Morisky Medication Adherence Scale, administered during 3 annual surveys, captured self-report adherence, with scores<6, 6 to <8, and 8 representing low, medium. and high adherence, respectively. The mean (standard deviation [SD]) for SD of SBP across study visits was 12.9 (4.4), 13.5 (4.8), and 14.1 (4.5) mm Hg in participants with high, medium, and low self-reported adherence, respectively. After multivariable adjustment and compared with those with high self-report adherence, SD of SBP was 0.60 (95% confidence interval, 0.13-1.07) and 1.08 (95% confidence interval, 0.29-1.87) mm Hg higher among participants with medium and low self-report adherence, respectively. Results were consistent when pharmacy fill was used to define adherence. These data suggest that low antihypertensive medication adherence explains only a small proportion of VVV of SBP. PMID- 23339730 TI - Association of arterial stiffness with obesity in Australian women: a pilot study. AB - This study investigated the arterial stiffness status in overweight/obese Australian women compared with their lean counterparts. Twenty-six Caucasian women were designated into one of two groups: overweight/obese (body mass index [BMI] 25-34.9 kg/m2 [ n=12]) and lean (BMI 18.5-24.9 kg/m2 [n=14]) groups. Participants were assessed for clinical, anthropometric, metabolic, and augmentation index (AIx) measurements. Age was similar between groups (P=.482). BMI was significantly higher in overweight/obese compared with lean participants (30.26+/-1.09 vs 21.62+/-0.52 kg/m2, P=.001) as well as the percentage of body fat (40.60+/-2.43 vs 21.57+/-1.13, P=.001), waist circumference (91.47+/-2.77 vs 70.67+/-1.60, P=.001), and waist/hip ratio (0.81+/-0.04 vs 0.71+/-0.03, P=.036). Overweight/obese group showed higher total cholesterol, triglyceride, low-density lipoprotein cholesterol, and fasting glucose levels compared with the lean group (all P<.05). Both systolic (122.92+/-3.18 mm Hg vs 108.14+/-2.42 mm Hg, P=.001) and diastolic (83.58+/-2.43 mm Hg vs 72.43+/-1.29 mm Hg, P=.0001) blood pressures, as well as AIx (50.08+/-4.7 vs 120.79+/-2.17, P=.001) were significantly higher in the overweight/obese group compared with the lean group. AIx was positively associated with measurements of body composition (P<.05), triglycerides (r=0.361, P=.035) and glucose levels (r=0.371, P=.031), and systolic and diastolic blood pressure (r=0.793 and r=0.718, respectively; P=.0001). This data suggests that arterial stiffness is associated with obesity, along with other metabolic abnormalities in Australian women. PMID- 23339731 TI - Risk of methylphenidate-induced prehypertension in normotensive adult smokers with attention deficit hyperactivity disorder. AB - The authors studied predictors of methylphenidate-induced increases in blood pressure (BP). In this secondary analysis of a randomized, double-blind, placebo controlled smoking cessation trial, nonhypertensive adult smokers with attention deficit hyperactivity disorder randomized to osmotic-release oral system methylphenidate (OROS-MPH) (n=115) were matched one-to-one on baseline systolic BP (SBP) (+/-5 mm Hg) with participants randomized to placebo (n=115) and followed for 10 weeks. In adjusted mixed linear models of SBP and diastolic BP (DBP), baseline normal SBP (P<.0001) and DBP (P<.0001) were associated with significant OROS-MPH-induced increases compared with placebo, whereas significant increases were not observed in participants with baseline prehypertensive SBP (P=.27) and DBP (P=.79). Participants randomized to OROS-MPH with baseline normal BP had increased odds of developing either systolic (odds ratio [OR], 3.32; 95% confidence interval [CI], 1.41-8.37; P=.006) or diastolic prehypertension (OR, 4.32; 95% CI, 1.56-14.0; P=.004) compared with placebo using simple logistic regression. The authors demonstrated an augmented OROS-MPH-induced BP elevation and risk of prehypertension in adults with baseline normal BP. Significantly increased BP was not observed in adults with baseline prehypertension. PMID- 23339732 TI - The effects of the L/N-type calcium channel blocker (cilnidipine) on sympathetic hyperactive morning hypertension: results from ACHIEVE-ONE. AB - The Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering By N-Channel Blocker Cilnidipine (ACHIEVE-ONE) trial is a large scale clinical study on blood pressure (BP) and pulse rate (PR) in the real world with use of cilnidipine, a unique L/N-type Ca channel blocker, possessing a suppressive action on increased sympathetic activity in patients with essential hypertension. The effects of cilnidipine on morning hypertension were examined. The authors examined 2319 patients treated with cilnidipine for 12 weeks. Clinic systolic BP (SBP) decreased by 19.6 mm Hg from 155.0 mm Hg, whereas morning SBP decreased by 17.0 mm Hg from 152.9 mm Hg after 12-week cilnidipine treatment. Cilnidipine reduced both morning SBP and PR more markedly in patients with higher baseline morning SBP (-3.2 mm Hg and -1.3 beats per minute in the first quartile of morning SBP, -30.9 mm Hg and -3.2 beats per minute in the fourth quartile), and also reduced both morning PR and SBP more markedly in patients with higher baseline morning PR (0.6 beats per minute and -15.6 mm Hg in <70 beats per minute, and -9.7 beats per minute and -20.2 mm Hg in >=85 beats per minute). Cilnidipine significantly reduced BP and PR in hypertensive patients at the clinic and at home, especially with higher BP and PR in the morning. PMID- 23339733 TI - Development of genomic SSR markers for fingerprinting lettuce (Lactuca sativa L.) cultivars and mapping genes. AB - BACKGROUND: Lettuce (Lactuca sativa L.) is the major crop from the group of leafy vegetables. Several types of molecular markers were developed that are effectively used in lettuce breeding and genetic studies. However only a very limited number of microsattelite-based markers are publicly available. We have employed the method of enriched microsatellite libraries to develop 97 genomic SSR markers. RESULTS: Testing of newly developed markers on a set of 36 Lactuca accession (33 L. sativa, and one of each L. serriola L., L. saligna L., and L. virosa L.) revealed that both the genetic heterozygosity (UHe = 0.56) and the number of loci per SSR (Na = 5.50) are significantly higher for genomic SSR markers than for previously developed EST-based SSR markers (UHe = 0.32, Na = 3.56). Fifty-four genomic SSR markers were placed on the molecular linkage map of lettuce. Distribution of markers in the genome appeared to be random, with the exception of possible cluster on linkage group 6. Any combination of 32 genomic SSRs was able to distinguish genotypes of all 36 accessions. Fourteen of newly developed SSR markers originate from fragments with high sequence similarity to resistance gene candidates (RGCs) and RGC pseudogenes. Analysis of molecular variance (AMOVA) of L. sativa accessions showed that approximately 3% of genetic diversity was within accessions, 79% among accessions, and 18% among horticultural types. CONCLUSIONS: The newly developed genomic SSR markers were added to the pool of previously developed EST-SSRs markers. These two types of SSR-based markers provide useful tools for lettuce cultivar fingerprinting, development of integrated molecular linkage maps, and mapping of genes. PMID- 23339734 TI - Design, synthesis, and functional evaluation of leukocyte function associated antigen-1 antagonists in early and late stages of cancer development. AB - The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its alpha(L)-chain inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report the structure-based design, small-scale synthesis, and biological activity evaluation of a novel family of LFA-1 antagonists. The design led to the synthesis of a family of highly substituted homochiral pyrrolidines with antiproliferative and antimetastatic activity in a murine model of colon carcinoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. NMR analysis of their binding to the isolated I domain shows that they bind to the I-domain allosteric site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled. PMID- 23339735 TI - Sensitive monitoring of volatile chemical warfare agents in air by atmospheric pressure chemical ionization mass spectrometry with counter-flow introduction. AB - A new method for sensitively and selectively detecting chemical warfare agents (CWAs) in air was developed using counter-flow introduction atmospheric pressure chemical ionization mass spectrometry (MS). Four volatile and highly toxic CWAs were examined, including the nerve gases sarin and tabun, and the blister agents mustard gas (HD) and Lewisite 1 (L1). Soft ionization was performed using corona discharge to form reactant ions, and the ions were sent in the direction opposite to the airflow by an electric field to eliminate the interfering neutral molecules such as ozone and nitrogen oxide. This resulted in efficient ionization of the target CWAs, especially in the negative ionization mode. Quadrupole MS (QMS) and ion trap tandem MS (ITMS) instruments were developed and investigated, which were movable on the building floor. For sarin, tabun, and HD, the protonated molecular ions and their fragment ions were observed in the positive ion mode. For L1, the chloride adduct ions of L1 hydrolysis products were observed in negative ion mode. The limit of detection (LOD) values in real-time or for a 1 s measurement monitoring the characteristic ions were between 1 and 8 MUg/m(3) in QMS instrument. Collision-induced fragmentation patterns for the CWAs were observed in an ITMS instrument, and optimized combinations of the parent and daughter ion pairs were selected to achieve real-time detection with LOD values of around 1 MUg/m(3). This is a first demonstration of sensitive and specific real-time detection of both positively and negatively ionizable CWAs by MS instruments used for field monitoring. PMID- 23339736 TI - Early treatment of posterior crossbite--a randomised clinical trial. AB - BACKGROUND: The aim of this randomised clinical trial was to assess the effect of early orthodontic treatment in contrast to normal growth effects for functional unilateral posterior crossbite in the late deciduous and early mixed dentition by means of three-dimensional digital model analysis. METHODS: This randomised clinical trial was assessed to analyse the orthodontic treatment effects for patients with functional unilateral posterior crossbite in the late deciduous and early mixed dentition using a two-step procedure: initial maxillary expansion followed by a U-bow activator therapy. In the treatment group 31 patients and in the control group 35 patients with a mean age of 7.3 years (SD 2.1) were monitored. The time between the initial assessment (T1) and the follow-up (T2) was one year. The orthodontic analysis was done by a three-dimensional digital model analysis. Using the 'Digimodel' software, the orthodontic measurements in the maxilla and mandible and for the midline deviation, the overjet and overbite were recorded. RESULTS: Significant differences between the control and the therapy group at T2 were detected for the anterior, median and posterior transversal dimensions of the maxilla, the palatal depth, the palatal base arch length, the maxillary arch length and inclination, the midline deviation, the overjet and the overbite. CONCLUSIONS: Orthodontic treatment of a functional unilateral posterior crossbite with a bonded maxillary expansion device followed by U-bow activator therapy in the late deciduous and early mixed dentition is an effective therapeutic method, as evidenced by the results of this RCT. It leads to three-dimensional therapeutically induced maxillary growth effects. Dental occlusion is significantly improved, and the prognosis for normal craniofacial growth is enhanced. TRIAL REGISTRATION: Registration trial DRKS00003497 on DRKS. PMID- 23339737 TI - Distinct dedifferentiation processes affect caveolin-1 expression in hepatocytes. AB - BACKGROUND: Dedifferentiation and loss of hepatocyte polarity during primary culture of hepatocytes are major drawbacks for metabolic analyses. As a prominent profibrotic cytokine and potent inducer of epithelial mesenchymal transition (EMT), TGF-beta contributes to these processes in liver epithelial cells. Yet, a distinction between culture dependent and TGF-beta driven hepatocyte dedifferentiation has not been shown to date. RESULTS: Here, we show that in both settings, mesenchymal markers are induced. However, upregulation of Snai1 and downregulation of E-Cadherin are restricted to TGF-beta effects, neglecting a full EMT of culture dependent hepatocyte dedifferentiation. Mechanistically, the latter is mediated via FAK/Src/ERK/AKT pathways leading to the induction of the oncogene caveolin-1 (Cav1). Cav1 was recently proposed as a new EMT marker, but our results demonstrate Cav1 is not up-regulated in TGF-beta mediated hepatocyte EMT, thus limiting validity of its use for this purpose. Importantly, marking differences on Cav1 expression exist in HCC cell lines. Whereas well differentiated HCC cell lines exhibit low and inducible Cav1 protein levels - by TGF-beta in a FAK/Src dependent manner, poorly differentiated cell lines display high Cav1 expression levels which are not further modulated by TGF-beta. CONCLUSIONS: This study draws a detailed distinction between intrinsic and TGF beta mediated hepatocyte dedifferentiation and elucidates cellular pathways involved. Additionally, by evaluating the regulation of the oncogene Cav1, we provide evidence to argue against Cav1 as a reliable EMT marker. PMID- 23339738 TI - Direct visualization of single ions in the Stern layer of calcite. AB - Calcite is among the most abundant minerals on earth and plays a central role in many environmental and geochemical processes. Here we used amplitude modulation atomic force microscopy (AFM) operated in a particular regime to visualize single ions close to the (1014) surface of calcite in solution. The results were acquired at equilibrium, in aqueous solution containing different concentrations of NaCl, RbCl, and CaCl(2). The AFM images provide a direct and atomic-level picture of the different cations adsorbed preferentially at certain locations of the calcite-water interface. Highly ordered water layers at the calcite surface prevent the hydrated ions from directly interacting with calcite due to the energy penalty incurred by the necessary restructuring of the ions' solvation shells. Controlled removal of the adsorbed ions from the interface by the AFM tip provides indications about the stability of the adsorption site. The AFM results show the familiar "row pairing" of the carbonate oxygen atoms, with the adsorbed monovalent cations located adjacent to the most prominent oxygen atoms. The location of adsorbed cations near the surface appears better defined for monovalent ions than for Ca(2+), consistent with the idea that Ca(2+) ions remain further away from the surface of calcite due to their larger hydration shell. The precise distance between the different hydrated ions and the surface of calcite is quantified using MD simulation. The preferential adsorption sites found by MD as well as the ion residence times close to the surface support the AFM findings, with Na(+) ions dwelling substantially longer and closer to the calcite surface than Ca(2+). The results also bring new insights into the problem of the Stern and electrostatic double layer at the surface of calcite, showing that parameters such as the thickness of the Stern layer can be highly ion dependent. PMID- 23339739 TI - Probes for non-invasive matrix metalloproteinase-targeted imaging with PET and SPECT. AB - Dysregulation of matrix metalloproteinase (MMP) activity can lead to a wide range of disease states such as atherosclerosis, inflammation or cancer. The ability to image MMP activity non-invasively in vivo, by radiolabelled synthetic inhibitors, would allow the characterization of atherosclerotic plaques, inflammatory lesions or tumors. Here we present an overview of radiolabelled MMP inhibitors (MMPIs) and MMP peptides for positron emission tomography (PET) and single photon emission computed tomography (SPECT) for the detection of proteolytic activity of MMPs. So far, most studies are at a preliminary stage; however, some hydroxamate based tracers such as the peptidomimetics [111In]-DTPA-RP782, [99mTc]-(HYNIC RP805)(tricine)(TPPTS), or Marimastat-ArB[18F]F3 and the picolyl- benzenesulfonamide [123I]I-HO-CGS 27023A identified specifically the enzymatic action of MMPs in animal models of various pathologies. The development of new compounds that may lead to novel tracers (e.g. modification of zinc-binding group, variation of substituents attached to the S1', S2' and S3' pockets of the MMP inhibitors) and the use of antibodies and cell penetrating peptides are also discussed. In general, preclinical studies with atherosclerosis models proved to be more successful than those with oncological models. PMID- 23339740 TI - Ultrafast strong-field photoemission from plasmonic nanoparticles. AB - We demonstrate the ultrafast generation of electrons from tailored metallic nanoparticles and unravel the role of plasmonic field enhancement in this process by comparing resonant and off-resonant particles, as well as different particle geometries. We find that electrons become strongly accelerated within the evanescent fields of the plasmonic nanoparticles and escape along straight trajectories with orientations governed by the particle geometry. These results establish plasmonic nanoparticles as versatile ultrafast, nanoscopic sources of electrons. PMID- 23339741 TI - Salient beliefs about earthquake hazards and household preparedness. AB - Prior research has found little or no direct link between beliefs about earthquake risk and household preparedness. Furthermore, only limited work has been conducted on how people's beliefs influence the nature and number of preparedness measures adopted. To address this gap, 48 qualitative interviews were undertaken with residents in three urban locations in New Zealand subject to seismic risk. The study aimed to identify the diverse hazard and preparedness related beliefs people hold and to articulate how these are influenced by public education to encourage preparedness. The study also explored how beliefs and competencies at personal, social, and environmental levels interact to influence people's risk management choices. Three main categories of beliefs were found: hazard beliefs; preparedness beliefs; and personal beliefs. Several salient beliefs found previously to influence the preparedness process were confirmed by this study, including beliefs related to earthquakes being an inevitable and imminent threat, self-efficacy, outcome expectancy, personal responsibility, responsibility for others, and beliefs related to denial, fatalism, normalization bias, and optimistic bias. New salient beliefs were also identified (e.g., preparedness being a "way of life"), as well as insight into how some of these beliefs interact within the wider informational and societal context. PMID- 23339742 TI - Single molecule characterization of the interactions between amyloid-beta peptides and the membranes of hippocampal cells. AB - Oligomers of the 40 and 42 residue amyloid-beta peptides (Abeta40 and Abeta42) have been implicated in the neuronal damage and impaired cognitive function associated with Alzheimer's disease. However, little is known about the specific mechanisms by which these misfolded species induce such detrimental effects on cells. In this work, we use single-molecule imaging techniques to examine the initial interactions between Abeta monomers and oligomers and the membranes of live cells. This highly sensitive method enables the visualization of individual Abeta species on the cell surface and characterization of their oligomerization state, all at biologically relevant, nanomolar concentrations. The results indicate that oligomers preferentially interact with cell membranes, relative to monomers and that the oligomers become immobilized on the cell surface. Additionally, we observe that the interaction of Abeta species with the cell membrane is inhibited by the presence of ATP-independent molecular chaperones. This study demonstrates the power of this methodology for characterizing the interactions between protein aggregates and the membranes of live neuronal cells at physiologically relevant concentrations and opens the door to quantitative studies of the cellular responses to potentially pathogenic oligomers. PMID- 23339743 TI - Post-mortem high-field magnetic resonance imaging: effect or various factors. AB - PURPOSE: To evaluate image quality and diagnostic accuracy of high-field post mortem (PM) magnetic resonance imaging (MRI) on fetuses below 20 weeks of gestation before and after the freeze-thaw process. MATERIALS AND METHODS: Nine fetuses were scanned with three different scanning procedures: "fresh", just after termination of pregnancy (TOP), "non-fresh short scan" and "non-fresh long scan" after being kept at -20 degrees C, followed by a conventional autopsy. The brain, thorax except the heart, heart and abdomen were studied. The qualities of the images for the four different fetal regions and for the three different scanning procedures were reported. Regression analysis was used to investigate the effect on image quality of different factors. Additionally, the diagnostic accuracy was also evaluated. RESULTS: Fetuses at 12.0-19.6 weeks were included. Regression analysis showed that better image quality was correlated to advanced gestation at TOP and scan on fresh fetuses. PM-MRI on fresh fetuses was always diagnostic for the brain and in more than half of cases on non-fresh fetuses and was nearly equally diagnostic for thoracic and abdominal structures. CONCLUSION: High-field PM-MRI seems to offer a quite reliable alternative to the parents declining conventional PM for fetuses before 20 weeks whether these fetuses are freshly scanned or after being frozen. PMID- 23339744 TI - Thyroid hormone levels within reference range are associated with heart rate, cardiac structure, and function in middle-aged men and women. AB - BACKGROUND: Triiodothyronine (T3) has many effects on the heart, and marked changes in cardiac function and structure occur in patients with (subclinical) thyroid disease. We investigated whether between-subject variation in thyroid hormone levels within the euthyroid range is also associated with heart rate and echocardiographic heart function and structure. METHODS: Subjects were selected from the Asklepios study (n=2524), a population-representative random sample of patients aged between 35 and 55 years, free from overt cardiovascular disease at baseline. Analyses were restricted to 2078 subjects (1013 women and 1065 men), not using antihypertensive or thyroid medication nor having antithyroperoxidase antibody levels above clinical cut-off or thyrotropin (TSH) levels outside the reference range. All subjects were phenotyped in-depth and underwent comprehensive echocardiography, including diastolic evaluation. Thyroid function parameters were determined by automated electrochemiluminescence. RESULTS: Heart rate was robustly positively associated with (quartiles of) free T3 (FT3) and T3, both in subjects with TSH levels within reference (0.27-4.2 MUU/L) and in narrow TSH range (0.5-2.5 MUU/L; p<0.0001). FT3 and T3 were negatively associated with left ventricular (LV) end-diastolic volume but positively associated with relative wall thickness. Total T3 (TT3) was associated with enhanced ventricular contraction (as assessed by tissue Doppler imaging). Free thyroxine, FT3, and TT3 were positively associated with late ventricular filling, and TT3 was associated with early ventricular filling. CONCLUSION: We have demonstrated a strong positive association between thyroid hormone levels within the euthyroid range and heart rate, and more subtle effects on cardiac function and structure. More specifically, we suggest a smaller LV cavity size (with increased relative wall thickness), an enhanced atrial and ventricular contraction, and LV relaxation with higher circulating thyroid hormones. These results illustrate that variation in thyroid hormone levels, even within the reference range, exerts effects on the heart. PMID- 23339745 TI - Manufacturing and banking of mesenchymal stem cells. AB - INTRODUCTION: Mesenchymal stem cells (MSC) and MSC-like cells hold great promise and offer many advantages for developing effective cellular therapeutics. Current trends indicate that the clinical application of MSC will continue to increase markedly. For clinical applications, large numbers of MSC are usually required, ideally in an off-the-shelf format, thus requiring extensive MSC expansion ex vivo and subsequent cryopreservation and banking. AREAS COVERED: To exploit the full potential of MSC for cell-based therapies requires overcoming significant cell-manufacturing, banking and regulatory challenges. The current review will focus on the identification of optimal cell source for MSC, the techniques for production scale-up, cryopreservation and banking and the regulatory challenges involved. EXPERT OPINION: There has been considerable success manufacturing and cryopreserving MSC at laboratory scale. Surprisingly little attention, however, has been given to translate these technologies to an industrial scale. The development of cost-effective advanced technologies for producing and cryopreserving commercial-scale MSC is important for successful clinical cell therapy. PMID- 23339746 TI - Shear bond strength of an autopolymerizing repair resin to injection-molded thermoplastic denture base resins. AB - OBJECTIVE: This study investigated the shear bond strength of an autopolymerizing repair resin to injection-molded thermoplastic denture base resins. MATERIALS AND METHODS: Four injection-molded thermoplastic resins (two polyamides, a polyethylene terephthalate copolymer and a polycarbonate) were used in this study. The specimens were divided into eight groups according to the type of surface treatment given: (1) no treatment, (2) air abrasion with alumina, (3) dichloromethane, (4) ethyl acetate, (5) 4-META/MMA-TBB resin, (6) alumina and 4 META/MMA-TBB resin, (7) tribochemical silica coating or (8) tribochemical silica coating and 4-META/MMA-TBB resin. Half of the specimens in groups 1, 5, 6 and 8 were thermocycled for 10,000 cycles in water between 5-55 degrees C with a dwell time of 1 min at each temperature. The shear bond strengths were determined. RESULTS: The shear bond strengths to the two polyamides treated with alumina, dichloromethane and ethyl acetate and no treatment were very low. The greatest post-thermocycling bond strengths to polyamides were recorded for the specimens treated with tribochemical silica coating and 4-META/MMA-TBB resin (PA12: 16.4 MPa, PACM12: 17.5 MPa). The greatest post-thermocycling bond strengths to polyethylene terephthalate copolymer and polycarbonate were recorded for the treatment with alumina and 4-META/MMA-TBB resin (22.7 MPa, 20.8 MPa). CONCLUSION: Polyamide was exceedingly difficult to bond to an autopolymerizing repair resin; the shear bond strength improved using tribochemical silica coating followed by the application of 4-META/MMA-TBB resin. Both polyethylene terephthalate copolymer and polycarbonate were originally easy to bond to an autopolymerizing repair resin. However, with 4-META/MMA-TBB resin, the bond was more secure. PMID- 23339747 TI - Demands, control, and support: a meta-analytic review of work characteristics interrelationships. AB - The job demands-control-support model (DCS; Karasek, 1979) is an influential theory for understanding how work characteristics relate to employee well-being, health, and performance. However, previous research has largely neglected theory building regarding the interrelationships between job demands, control, and support. We remedy such theoretical underdevelopment by reviewing and integrating theory on the relationships between demands, control, and support to develop five hypotheses. We test our hypotheses within a meta-analytic framework using a set of 106 studies. Our results show negative demands-supervisor support and demands coworker support relationships, but no significant demand-control relationship. Our findings also indicate positive control-supervisor support and control coworker support relationships. Using the meta-analytic effect sizes, we also estimate two competing structural equation models intended to discern which theoretical model using DCS work characteristics to predict occupational strain and well-being is more consistent with our data. Our results suggest that job control and both sources of social support should be treated independently, as opposed to indicators of a shared latent factor, in terms of their prediction of well-being and job demands. Our study offers support for the usefulness of the DCS and more modern conceptualizations of the working environment in understanding the employee work experience and for predicting important work outcomes. ( PMID- 23339748 TI - The role of appraisals and emotions in understanding experiences of workplace incivility. AB - Theoretically grounded in both the cognitive-motivational-relational theory of emotions and affect events theory, the present research used multiple analytic techniques and positioned appraisals and emotions as key variables in understanding the experience of incivility at work. Data consisted of survey responses from a stratified random sample of 522 U.S. working adults. K-means cluster analyses revealed interindividual differences in cognitive/emotional responding to workplace incivility experiences. In addition, multiple mediation analyses revealed that optimism and emotionality may play important roles in showing why the experience of incivility is related to job-related outcomes. The results help to advance workplace mistreatment research and suggest possible strategies for organizations to maintain civil working environments. PMID- 23339749 TI - The impact of fluctuating workloads on well-being and the mediating role of work nonwork interference in this relationship. AB - Heavy workloads have been central to the discussion of well-being. However, fluctuations in workloads have received sparse attention, even though transient and routine levels of workloads may have independent effects on well-being. The article assesses this, particularly focusing on the effort-recovery model of the workload/well-being relationship in which work-nonwork interference mediates this relationship. Using data from a weekly diary study of freelance or portfolio workers, multilevel analyses showed that both routine and transient levels of work to nonwork interference mediated the job demands-calmness relationship. Work to nonwork interference also negatively mediated the hours worked-calmness relationship, but the direct relationship between hours worked and calmness was a positive one so the mediating effect reduced this positive effect. In the case of enthusiasm, which was a second measure of well-being, there were no mediating effects but both routine and nonroutine levels of job demands and transient levels of hours worked were related to it. The study highlights the value of introducing the temporal dimension into the study of the work-nonwork interface, and the diversity of relationships that occur across different dimensions of workload and well-being. PMID- 23339751 TI - Can a core outcome set improve the quality of systematic reviews?--a survey of the Co-ordinating Editors of Cochrane Review Groups. AB - BACKGROUND: Missing outcome data or the inconsistent reporting of outcome data in clinical research can affect the quality of evidence within a systematic review. A potential solution is an agreed standardized set of outcomes known as a core outcome set (COS) to be measured in all studies for a specific condition. We investigated the amount of missing patient data for primary outcomes in Cochrane systematic reviews, and surveyed the Co-ordinating Editors of Cochrane Review Groups (CRGs) on issues related to the standardization of outcomes in their CRG's reviews. These groups are responsible for the more than 7,000 protocols and full versions of Cochrane Reviews that are currently available, and the several hundred new reviews published each year, presenting the world's largest collection of standardized systematic reviews in health care. METHODS: Using an unselected cohort of Cochrane Reviews, we calculated and presented the percentage of missing patient data for the primary outcome measure chosen for each review published by each CRG. We also surveyed the CRG Co-ordinating Editors to see what their policies are with regards to outcome selection and outcomes to include in the Summary of Finding (SoF) tables in their Cochrane Reviews. They were also asked to list the main advantages and challenges of standardizing outcomes across all reviews within their CRG. RESULTS: In one fifth of the 283 reviews in the sample, more than 50% of the patient data for the primary outcome was missing. Responses to the survey were received from 90% of Co-ordinating Editors. Thirty six percent of CRGs have a centralized policy regarding which outcomes to include in the SoF table and 73% of Co-ordinating Editors thought that a COS for effectiveness trials should be used routinely for a SoF table. CONCLUSIONS: The reliability of systematic reviews, in particular meta-analyses they contain, can be improved if more attention is paid to missing outcome data. The availability of COSs for specific health conditions might help with this and the concept has support from the majority of Co-ordinating Editors in CRGs. PMID- 23339750 TI - Multi-parameter systematic strategies for predictive, preventive and personalised medicine in cancer. AB - Cancer is a complex disease that causes the alterations in the levels of gene, RNA, protein and metabolite. With the development of genomics, transcriptomics, proteomics and metabolomic techniques, the characterisation of key mutations and molecular pathways responsible for tumour progression has led to the identification of a large number of potential targets. The increasing understanding of molecular carcinogenesis has begun to change paradigms in oncology from traditional single-factor strategy to multi-parameter systematic strategy. The therapeutic model of cancer has changed from adopting the general radiotherapy and chemotherapy to personalised strategy. The development of predictive, preventive and personalised medicine (PPPM) will allow prediction of response with substantially increased accuracy, stratification of particular patient groups and eventual personalisation of medicine. The PPPM will change the approach to tumour diseases from a systematic and comprehensive point of view in the future. Patients will be treated according to the specific molecular profiles that are found in the individual tumour tissue and preferentially with targeted substances, if available. PMID- 23339752 TI - Selecting optimal screening items for delirium: an application of item response theory. AB - BACKGROUND: Delirium (acute confusion), is a common, morbid, and costly complication of acute illness in older adults. Yet, researchers and clinicians lack short, efficient, and sensitive case identification tools for delirium. Though the Confusion Assessment Method (CAM) is the most widely used algorithm for delirium, the existing assessments that operationalize the CAM algorithm may be too long or complicated for routine clinical use. Item response theory (IRT) models help facilitate the development of short screening tools for use in clinical applications or research studies. This study utilizes IRT to identify a reduced set of optimally performing screening indicators for the four CAM features of delirium. METHODS: Older adults were screened for enrollment in a large scale delirium study conducted in Boston-area post-acute facilities (n = 4,598). Trained interviewers conducted a structured delirium assessment that culminated in rating the presence or absence of four features of delirium based on the CAM. A pool of 135 indicators from established cognitive testing and delirium assessment tools were assigned by an expert panel into two indicator sets per CAM feature representing (a) direct interview questions, including cognitive testing, and (b) interviewer observations. We used IRT models to identify the best items to screen for each feature of delirium. RESULTS: We identified 10 dimensions and chose up to five indicators per dimension. Preference was given to items with peak psychometric information in the latent trait region relevant for screening for delirium. The final set of 48 indicators, derived from 39 items, maintains fidelity to clinical constructs of delirium and maximizes psychometric information relevant for screening. CONCLUSIONS: We identified optimal indicators from a large item pool to screen for delirium. The selected indicators maintain fidelity to clinical constructs of delirium while maximizing psychometric information important for screening. This reduced item set facilitates development of short screening tools suitable for use in clinical applications or research studies. This study represents the first step in the establishment of an item bank for delirium screening with potential questions for clinical researchers to select from and tailor according to their research objectives. PMID- 23339753 TI - Fluorescence detection and imaging of biomolecules using the micropatterned nanostructured aluminum oxide. AB - Micropatterns of the nanostructured aluminum oxide (NAO) with sizes from 5 to 200 MUm have been successfully fabricated on the indium tin oxide (ITO) glass substrate by simply combining a lift-off process and a one-step anodization process for the first time. The detection of fluorescent dyes and biomolecules tagged with fluorescent dyes on the NAO has been investigated and demonstrated successfully. Experiments reveal that the micropatterned NAO substrates can increase the fluorescence signals up to 2 or 3 orders of magnitude compared to the glass substrate, suggesting a possibility to significantly reduce the consumption of the biosamples for fluorescence-based sensing, imaging, and analysis. The stability of the NAO substrates for fluorescence enhancement has also been evaluated by monitoring the fluorescence signals after the fluorophores applied on the substrates for a period of time and reusing the same NAO substrates many times. It was found that this type of substrate has very good stability. Because the micropatterned NAO can be easily integrated with microsensors or microfluidic chips, a simple and inexpensive fluorescence enhancement platform can be developed for a variety of applications, such as microarray technology and single-cell imaging, facilitating the construction of the on-chip fluorescence-based micro- or nanosystems. PMID- 23339754 TI - Terahertz bandwidth all-optical modulation and logic using multiexcitons in semiconductor nanocrystals. AB - Optical pumping of semiconductor nanocrystals with femtosecond pulse sequences was performed in order to modulate multiexciton populations. We show for the first time that control of multiexciton populations produces high speed modulation of stimulated emission. Upon the basis of the speed of multiexcitonic processes in nanocrystals, we show modulation rates approaching 1 THz by virtue of strong quantum confinement effects. Employing femtosecond optical pulse sequences, we demonstrate all-optical logic using these nanocrystals in two forms: an AND gate, and an inverter, a key step toward all optical signal processing. PMID- 23339755 TI - International approaches to measuring the quality of mental health care. AB - The importance of measuring the quality of mental health care is widely recognized. A number of factors should be considered when constructing mental health quality indicators including the aspects of care to be measured; translation of quality measurement concepts into indicators that can be measured; pilot-testing, analysis and display of measures; and maintaining effectiveness of performance measures and policies over time. The impetus to measure quality in mental health care may be dampened by the innumerable challenges inherent in this worthwhile endeavour. In particular, many countries lack adequate quality measurement infrastructure. Challenges may be overcome to a certain extent by international collaboration. While cross-country co-operation can also introduce additional complexities; its benefits usually outweigh the costs. Quality indicators can have many uses but of utmost importance is that quality measurement in mental health care subsequently results in quality improvements. PMID- 23339756 TI - Tobacco control in the Russian Federation--a policy analysis. AB - BACKGROUND: The Russian Federation (Russia) has one of the highest smoking rates in the world. The purpose of this study is to analyze past and current trends of the tobacco epidemic in the Russian Federation, review current tobacco control policy responses, and identify areas of opportunity for policy priorities. METHODS: We used a policy triangle as analytical framework to examine content, context, and processes of Russian tobacco control policy. The analysis was based on secondary data on supply and demand sides of the Russian tobacco epidemic, tobacco-related economic and health effects during Russia's economic transition, and compliance of Russian tobacco policy with international standards and regulations. RESULTS: Tobacco-promoting strategies have specifically targeted women and youth. Russia's approval of a "National Tobacco Control Concept" and draft for a comprehensive tobacco control bill increasingly align national legislature with the WHO Framework Convention on Tobacco Control (FCTC). However, several structural and cultural factors represent substantial barriers to the policy process. The influence of transnational tobacco companies on policy processes in Russia has so far impeded a full implementation of the FCTC mandates. CONCLUSIONS: Several strategies have been identified as having the potential to reduce the prevalence of tobacco use in Russia and decrease tobacco related national health and economic burden: adjusting national tobacco policy by raising tobacco tax from the current lowest level in Europe to at least 70%; consequent enforcement of a complete smoking ban in public places; marketing restrictions; and smoking cessation interventions integrated into primary care. Russia's tobacco control efforts need to target women and youths specifically to efficiently counter industry efforts. PMID- 23339758 TI - The effect of varying implant position in immediately loaded implant-supported mandibular overdentures. AB - This study was carried out to evaluate the effect of varying implant position in immediately loaded implant-supported mandibular overdentures on peri-implant bone density, muscle activity, and patient satisfaction. Fourteen completely edentulous patients were selected for the study. After complete denture construction, patients were divided into 2 equal groups. Four dental implants were installed bilaterally in the interforaminal region in the first group, while in the second group, 4 dental implants were inserted bilaterally: 2 in the interforaminal region and 2 in the first molar area. Immediately after suturing, telescopic abutments were screwed to the implants, and the retaining caps were picked up into the fitting surface of the lower denture, which was delivered to the patient. Patients were recalled for radiographic bone density evaluation just after denture delivery and then at 3, 6, and 12 months thereafter. Muscle activities of masseter and temporalis muscles as well as patient satisfaction were also evaluated. The results of the study showed a high success rate approximating 98.2% of the immediately loaded implants. The electromyographic (EMG) records of both muscles in group 1 were significantly higher during chewing hard food after 3 months compared with group 2 (P < .05). Bone density changes were comparable in the 2 groups except at the end of the follow-up period, when group 2 showed a significant increase in peri-implant bone density values of the posteriorly placed implants compared with group 1 (P < .05). From the results of this study, it may be concluded that wide distribution of immediately loaded implants used for supporting mandibular overdentures through posterior placement beyond the interforaminal area results in a favorable response in terms of increased peri-implant bone density as well as decreased EMG activity of masseter and temporalis muscles. PMID- 23339757 TI - Cross-sectional and longitudinal relationships of body mass index with glycemic control in children and adolescents with type 1 diabetes mellitus. AB - AIMS: Weight gain is an oft-cited outcome of improved glycemic control in adults with type 1 diabetes, though few studies have investigated this in youth. The purpose of this paper was to examine cross-sectional and longitudinal associations of body mass index (BMI, kg/m(2)) with glycemic control in youth with type 1 diabetes (n=340, 12.5 +/- 1.7 year, 49% female, duration >= 1 year) participating in a 2-year multi-center intervention study targeting family diabetes management. METHODS: BMI was calculated from height and weight measured at clinic visits. Glycohemoglobin (HbA1c) at each visit was assayed centrally. Cross-sectional associations of baseline BMI with glycemic control, and of change in BMI and HbA1c with baseline values, were examined. Longitudinal associations of time-varying BMI and HbA1c were examined using a multilevel linear mixed effects model controlling for time-varying time (months), insulin dose (units/kg/day), regimen, Tanner stage, and time invariant baseline diabetes duration, BMI, treatment group and sociodemographic characteristics. RESULTS: Baseline HbA1c was unrelated to baseline BMI, but was related positively to subsequent BMI change (p=0.04) and inversely to HbA1c change (p=0.002). Baseline BMI was inversely related to BMI change (p=0.01) and unrelated to HbA1c change. In multilevel regression, BMI was related inversely to HbA1c (%) (beta +/- SE= 0.11 +/- 0.02, p<0.001) and positively to insulin dose (0.23 +/- 0.07, p=0.001). In the treatment group only, BMI was positively related to pump regimen (0.18 +/- 0.08, p=0.02). CONCLUSIONS: Increased insulin administered to improve glycemic control may contribute to increased BMI in youth with type 1 diabetes, indicating the importance of determining ways to minimize weight gain while optimizing glycemic control. PMID- 23339759 TI - Molecular imaging and therapy in nuclear medicine. PMID- 23339760 TI - Alpha-emitters for immuno-therapy: a review of recent developments from chemistry to clinics. AB - Alpha-particles are of considerable growing interest for Targeted Alpha Therapy (TAT). TAT gains more attention as new targets, chemical labeling techniques and alpha-particle emitters are developed but translation of TAT into the clinic has been slow, in part because of the limited availability and the short physical half-lives of some of the available alpha-particle emitters. This article is an up-to-date overview of the literature concerning alpha-emitters used for TAT of cancer. It briefly describes the nuclear characteristics, the production parameters (targets, extraction and purification), the complexation properties of these radionuclides to chelates and biological vectors and finally draws-upon the preclinical and clinical studies that have been performed over the past two decades. Radiobiology and dosimetry aspects are also presented in this paper. PMID- 23339761 TI - Tetraamine-coupled peptides and resulting (99m)Tc-radioligands: an effective route for receptor-targeted diagnostic imaging of human tumors. AB - The successful application of OctreoScan((r)) ([(111)In-DTPA]octreotide) in the diagnosis of sst(2)-expressing neuroendocrine tumors (NETs), on one hand, and the manifestation of peptide receptor targets in a wide range of human cancers, on the other, have synergistically induced a booming emergence of numerous radiolabeled peptide (radiopeptide) probes for tumor diagnosis and therapy in man. Definition of molecular targets and their relation to neoplastic disease has preceded peptide-based radiopharmaceutical design and development. New criteria have been set to safeguard efficient localization of radionuclides on tumor associated high affinity - low capacity peptide receptor systems. New technical and biological terms, such as specific activity or receptor affinity and internalization, have invaded the Radiopharmacy domain and have irrevocably altered our concept of radiopharmaceutical design. Nonetheless, (99m)Tc remains the gold standard of diagnostic nuclear medicine as a result of ideal nuclear characteristics, cost-effectiveness and wide availability in high purity and high specific activity by means of commercial (99)Mo/(99m)Tc-generators. The evolution of conventional (99m)Tc-perfusion agents into modern state-of-the-art molecular radiopharmaceuticals has been a challenge addressed by several researchers. The present review summarizes recent advances in the development of (99m)Tc-labeled peptides for in vivo targeting of neoplastic disease, and, in particular, those functionalized with acyclic tetraamines. Conclusions on their applicability in non-invasive diagnosis and staging of cancer patients are drawn. PMID- 23339762 TI - Iodination and stability of somatostatin analogues: comparison of iodination techniques. A practical overview. AB - For iodination ((125/127)I) of tyrosine-containing peptides, chloramin-T, Pre Coated Iodo-Gen((r)) tubes and Iodo-Beads((r)) (Pierce) are commonly used for in vitro radioligand investigations and there have been reliant vendors hereof for decades. However, commercial availability of these radio-iodinated peptides is decreasing. For continuation of our research in this field we investigated and optimized (radio-)iodination of somatostatin analogues. In literature, radioiodination using here described somatostatin analogues and iodination techniques are described separately. Here we present an overview, including High Performance Liquid Chromatography (HPLC) separation and characterisation by mass spectrometry, to obtain mono- and di-iodinated analogues. Reaction kinetics of (125/127)I iodinated somatostatin analogues were investigated as function of reaction time and concentration of reactants, including somatostatin analogues, iodine and oxidizing agent. To our knowledge, for the here described somatostatin analogues, no (127)I iodination and optimization are described. (Radio-)iodinated somatostatin analogues could be preserved with a >90% radiochemical purity for 1 month after reversed phase HPLC-purification. PMID- 23339763 TI - Effectiveness of quenchers to reduce radiolysis of (111)In- or (177)Lu-labelled methionine-containing regulatory peptides. Maintaining radiochemical purity as measured by HPLC. AB - An overview how to measure and to quantify radiolysis by the addition of quenchers and to maintain Radio-Chemical Purity (RCP) of vulnerable methionine containing regulatory peptides is presented. High RCP was only achieved with a combination of quenchers. However, quantification of RCP is not standardized, and therefore comparison of radiolabelling and RCP of regulatory peptides between different HPLC-systems and between laboratories is cumbersome. Therefore we suggest a set of standardized requirements to quantify RCP by HPLC for radiolabelled DTPA- or DOTA-peptides. Moreover, a dosimetry model was developed to calculate the doses in the reaction vials during radiolabelling and storage of the radiopeptides, and to predict RCP in the presence and absence of quenchers. RCP was measured by HPLC, and a relation between radiation dose and radiolysis of RCP was established. The here described quenchers are tested individually as f(concentration) to investigate efficacy to reduce radiolysis of radiolabelled methionine-containing regulatory peptides. PMID- 23339764 TI - Beta-emitting radionuclides for peptide receptor radionuclide therapy. AB - The paper focuses on the beta-emitting radionuclides which might be useful for peptide receptor radionuclide therapy, PRRT. For the effective design of the radiopharmaceutical, the choice of radionuclide will depend on the purpose for which the radioligand is being used and on the physicochemical properties of the radionuclide. The important factor is also the availability and the cost of production. The physical characteristics of several radionuclides which are currently used or can be considered as potential candidates for PRRT is provided, followed by short description of production methods and chemical aspects of their use in preparation of peptide-based radiopharmaceuticals. Somatostatin analogues labeled with radionuclides have been a successful example of PRRT. For treatment of patients with inoperable or metastasized neuroendocrine tumors, somatostatin analogues labeled with the radioisotopes (111)In, (90)Y and (177)Lu have been used so far. Labeling with (111)In, mainly an Auger electron emitter, resulted in no reduction of tumor size while somatostatin analogues labeled with (90)Y and (177)Lu gave overall positive response and improved the patients' quality of life. These promising results together with the increasing availability of other beta-emitting radionuclides are a good basis for further studies. PMID- 23339765 TI - Radiolabeled iron oxide nanoparticles as dual-modality SPECT/MRI and PET/MRI agents. AB - Dual-modality contrast agents, such as radiolabeled nanoparticles, are promising candidates for a number of diagnostic applications, since they combine the advantages of two different imaging modalities, namely SPECT or PET imaging with MR imaging. The benefit of such a combination is to more accurately interpret disease and abnormalities in vivo, by exploiting the advantages of each imaging technique, i.e. high sensitivity for SPECT/PET, high resolution anatomical information for MRI. In this review article, we provide an overview of recent findings in the synthesis, evaluation and application of radiolabeled iron oxide nanoparticles as dual-modality SPECT/MRI and PET/MRI imaging probes. PMID- 23339766 TI - Comparison between hepatic and renal effects in rats treated with arsenic and/or antioxidants during gestation and lactation. AB - The aim of this study was to determine whether biochemical changes occurred in the liver and kidney of arsenic (As) exposed pups during gestation and lactation, and investigate the potential beneficial role of antioxidants against arsenic exposure damage. Pregnant wistar rats received the following treatments as drinking water: (1) distilled water; (2) arsenic (50 mg/L); (3) antioxidants: zinc (20 mg/L)+vitamin C (2 g/L)+vitamin E (500 mg/L); (4) arsenic (50 mg/L)+antioxidants. As- intoxicated pups showed significant decreases in liver cholesterol and triglyceride concentration, whereas Aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities were increased. Treatment with antioxidants returns these values to control ones. TBARS production in both organs and liver glutathione peroxidase (GPx) activity also increased whereas catalase (CAT) activity in both organs decreased in arsenic-exposed pups; the antioxidant administration only recover TBARS concentration to control values. Our findings suggest that administration of antioxidants during gestation and lactation could prevent some of the negative effects of arsenic. PMID- 23339767 TI - Psychiatric symptoms in adults with phenylketonuria. AB - BACKGROUND: The objective of this study was to identify psychiatric symptom patterns reported by individuals with phenylketonuria (PKU) in the outpatient clinic setting. METHODS: Brief Symptom Inventory (BSI) results, phenylalanine (phe) levels, and demographic information were collected through a retrospective chart review on 64 participants in the study, "A Diversified Approach for PKU Treatment" (ADAPT). RESULTS: The number of BSI scores meeting clinical threshold was significantly elevated for all global indexes and 6 out of 7 symptom subscales in patients with PKU. Recent and mean phe levels were correlated with age at the time of screening (R(2)=0.10, R(2)=0.10, respectively; p<0.05). Psychoticism and the Positive Symptom Distress Index (PSDI) scores were associated with metabolic control. CONCLUSIONS: The results of this study demonstrate a positive correlation between phe levels and psychiatric symptom severity in individuals with PKU. PMID- 23339768 TI - Ternary interpolyelectrolyte complexes insulin-poly(methylaminophosphazene) dextran sulfate for oral delivery of insulin. AB - Ternary interpolyelectrolyte complexes of insulin with biodegradable synthetic cationic polymer, poly(methylaminophosphazene) hydrochloride (PMAP), and dextran sulfate (DS) were investigated by means of turbidimetry, dynamic light scattering, phase analysis, and high-sensitivity differential scanning calorimetry. Formation of ternary insoluble stoichiometric Insulin-PMAP-DS complexes was detected under conditions imitating the human gastric environment (pH 2, 0.15 M NaCl). A complete immobilization of insulin in the complexes was observed in a wide range of the reaction mixture compositions. The ternary complexes were shown to dissolve and dissociate under conditions imitating the human intestinal environment (pH 8.3, 0.15 M NaCl). The products of the complex dissociation were free insulin and soluble binary Insulin-PMAP complexes. The conformational stability of insulin in the soluble complexes of various compositions was investigated by high-sensitivity differential scanning calorimetry. The dependence of the excess denaturation free energy of insulin in these complexes on the PMAP content was obtained. The binding constants of the folded and unfolded forms of insulin to the PMAP polycation were estimated. Proteolysis of insulin involved in the insoluble ternary complexes by pepsin was investigated under physiological conditions. It was found that the complexes ensure an almost 100% protection of insulin against proteolytic degradation. The obtained results provide a perspective basis for development of oral insulin preparations. PMID- 23339769 TI - The incidence of feline injection site sarcomas in the United Kingdom. AB - BACKGROUND: Feline injection site sarcomas (FISS) are aggressive neoplasms that have been associated with vaccination. In North America the incidence estimates have varied from 1 case of FISS per 1,000-10,000 cats vaccinated. The aim of this study was to estimate the incidence of FISS in the United Kingdom (UK) in 2007. The ratio of FISS to vaccines sold in the UK was also estimated.Fourteen FISS were diagnosed by a convenience sample of 34 small animal veterinary practices in the United Kingdom in 2007 and were used as the numerator for the incidence estimates. Denominator data was obtained from the computer systems of each practice. Considering that a single cause relationship with vaccination is not proven, three different denominators (number of cats registered, the number of cat consultations undertaken and the number of vaccination visits for cats at the practices) were used to express the potential variation in risk. RESULTS: The incidence risk of FISS per year was estimated to be 1/16,000 -50,000 cats registered by practices, 1/10,000-20,000 cat consultations and 1/5,000-12,500 vaccination visits. CONCLUSION: When interpreting these findings, it needs to be taken into consideration that this sample of practices and their cats may not be representative of veterinary practices and cats at risk of FISS in the UK. However it can still be concluded with reasonable certainty that the incidence of FISS in the UK is very low. PMID- 23339770 TI - Living with severe allergy: an Anaphylaxis Campaign national survey of young people. AB - BACKGROUND: The transition to adulthood can be particularly challenging for young people with severe allergies, who must learn to balance personal safety with independent living. Information and support for young people and their families are crucial to successfully managing this transition. We sought to: gather insights into the impact of severe allergies on the lives of young people; explore where young people go for information about anaphylaxis and what information they want and need; identify areas where further support is needed. METHODS: An online questionnaire survey of young people aged 15-25 years with severe allergies in the United Kingdom (UK) was conducted on behalf of the Anaphylaxis Campaign, the main patient support organisation. Participants were recruited mainly from the Anaphylaxis Campaign membership database and also via allergy clinics and social media. The study was funded by the Anaphylaxis Campaign's In Memoriam Fund. RESULTS: A total of 520 young people responded to the survey. The majority had lived with severe allergies since they were young children; 59% reported having attended Accident and Emergency units as a consequence of their allergies. Only 66% of respondents reported always carrying their epinephrine auto-injectors; only 23% had ever used these. Few were currently receiving specialist allergy care; younger respondents were more likely to be under specialist care (34%) than those 18 years and above (23%). Respondents wanted more information about eating out (56%), travelling (54%) and food labelling (43%). Almost a quarter of respondents (23%) reported needing more information on managing their allergies independently without parental help. Managing allergies in the context of social relationships was a concern for 22% of respondents. CONCLUSIONS: This survey has identified the information and support needs and gaps in service provision for young people with severe allergies. Healthcare professionals and patient support organisations, with the support of the food industry, can help to meet these needs. PMID- 23339771 TI - Transmission of fish-borne zoonotic trematodes (Heterophyidae) to common carp (Cyprinus carpio) is independent of density of fish and trematodes. AB - Fish-borne zoonotic trematodes (FZTs) can cause major human health problems. The aim of this study was to quantify the transmission of parapleurolophocercous cercariae to common carp (Cyprinus carpio) and to study the effect of the density of cercariae and the density of fish on transmission with respect to the volume of water and surface area of the bottom. Fish were kept individually either as controls (n= 91) or were exposed to 250 cercariae in tubes with a volume of 25, 50, 100, 250 or 500 ml water (n= 190) with a surface area of 4, 12, 21, 30 or 49 cm2 (n= 195). The dose to which the fish were exposed was kept constant. Infection occurred in 94-100% of fish, with a mean of 15-18 metacercariae per fish and the proportion of FZTs established at 0.06-0.07 metacercariae per cercariae per fish. Neither the prevalence of infection with FZTs nor the number of metacercariae per fish nor the proportion of FZTs established were significantly associated with differences in the density of cercariae or the density of fish per ml water or per cm2 surface area. Thus, it was concluded that the transmission of cercariae to fish is independent of density. PMID- 23339772 TI - Fine needle sclerotherapy as a new effective therapeutic approach for nonparasitic splenic cysts: a case series. AB - BACKGROUND: Nonparasitic splenic cysts are rare. Until now, surgical intervention has been the standard therapy of symptomatic splenic cysts. AIMS: We herein present a retrospective analysis of an approach using percutaneous ultrasound guided fine needle aspiration and sclerotherapy. METHODS: Out of 88,151 ultrasound reports, we identified 138 patients who presented with splenic cysts. A single splenic cyst was found in 88% (mean size 28.9 mm). Twelve patients underwent percutaneous therapy of symptomatic splenic cysts. They were younger, had larger splenic cysts and more often cyst internal echoes than the 126 untreated patients (all p < 0.0001). RESULTS: Initial sclerotherapy was performed with polidocanol 1% in 9 patients and with NaCl 10% in 2 patients. One hemorrhagic cyst was only purged. Serious adverse events were not noted. Eight patients had to undergo 1-11 further percutaneous cyst therapies. 15 of these 30 reinterventions were cyst aspiration therapies, only, and 11 of them were sclerotherapies with NaCl 10%. Four patients were readmitted to hospital for cyst retreatment. After 57 +/- 43 months of follow-up, cyst size significantly decreased (p < 0.0001). Only two patients had a complicated course of cyst therapy. CONCLUSIONS: Percutaneous ultrasound-guided sclerotherapy is a new approach for symptomatic splenic cysts. In most patients, cyst size and symptoms can be significantly reduced during one hospital stay. PMID- 23339774 TI - Engineering plasmon-enhanced Au light emission with planar arrays of nanoparticles. AB - By systematically investigating the light emission and scattering properties of arrays of Au nanoparticles with varying size and separation, we demonstrate tunability and control of metal photoluminescence and unveil the critical role of near-field plasmonic coupling for the engineering of active metal nanostructures. We show that the decay of photoexcited electron-hole pairs into localized surface plasmons (LSPs) dramatically modifies the Au emission wavelength, line shape, and quantum efficiency depending both on particles size and separation. In particular, in arrays with near-field coupled nanoparticles we demonstrate broad light scattering and emission spectra that scale differently with respect to nanoparticle size due to the enhanced LSP nonradiative decay caused by near-field interparticle coupling. Our experimental results are fully supported by semianalytical extinction simulations based on rigorous coupled wave analysis, which demonstrate the importance of tuning plasmonic near-field coupling for the engineering of active devices based on light emitting arrays of metallic nanoparticles. PMID- 23339773 TI - In-vivo-validation of a cardiovascular risk prediction tool: the arriba-pro study. AB - BACKGROUND: Calculation of individual risk is the cornerstone of effective cardiovascular prevention. arriba is a software to estimate the individual risk to suffer a cardiovascular event in 10 years. Prognosis and the absolute effects of pharmacological and lifestyle interventions help the patient make a well informed decision. The risk calculation algorithm currently used in arriba is based on the Framingham risk algorithm calibrated to the German setting. The objective of this study is to evaluate and adapt the algorithm for the target population in primary care in Germany. METHODS/DESIGN: arriba-pro will be conducted within the primary care scheme provided by a large health care insurer in Baden-Wurttemberg, Germany. Patients who are counseled with arriba by their general practitioners (GPs) will be included in the arriba-pro cohort. Exposure data from the consultation with arriba such as demographic data and risk factors will be recorded automatically by the practice software and transferred to the study centre. Information on relevant prescription drugs (effect modifiers) and cardiovascular events (outcomes) will be derived from administrative sources. DISCUSSION: The study is unique in simulating a therapy naive cohort, matching exactly research and application setting, using a robust administrative data base, and, finally, including patients with known cardiovascular disease who have been excluded from previous studies. TRIAL REGISTRATION: The study is registered with Deutsches Register Klinischer Studien (DRKS00004633). PMID- 23339775 TI - Integration of genomic and non-genomic steroid receptor actions. PMID- 23339776 TI - Does neighbourhood social capital aid in levelling the social gradient in the health and well-being of children and adolescents? A literature review. AB - BACKGROUND: Although most countries in the European Union are richer and healthier than ever, health inequalities remain an important public health challenge. Health-related problems and premature death have disproportionately been reported in disadvantaged neighbourhoods. Neighbourhood social capital is believed to influence the association between neighbourhood deprivation and health in children and adolescents, making it a potentially interesting concept for policymakers. METHODS: This study aims to review the role of social capital in health inequalities and the social gradient in health and well-being of children and adolescents. A systematic review of published quantitative literature was conducted, focussing on (1) the mediating role of neighbourhood social capital in the relationship between socio-economic status (SES) and health related outcomes in children and adolescents and (2) the interaction between neighbourhood social capital and socio-economic characteristics in relation to health-related outcomes in children and adolescents. Three electronic databases were searched. Studies executed between 1 January 1990 and 1 September 2011 in Western countries (USA, New Zealand, Australia and Europe) that included a health related outcome in children or adolescents and a variable that measured neighbourhood social capital were included. RESULTS: Eight studies met the inclusion criteria for the review. The findings are mixed. Only two of five studies confirmed that neighbourhood social capital mediates the association between neighbourhood deprivation and health and well-being in adolescents. Furthermore, two studies found a significant interaction between neighbourhood socio-economic factors and neighbourhood social capital, which indicates that neighbourhood social capital is especially beneficial for children who reside in deprived neighbourhoods. However, two other studies did not find a significant interaction between SES and neighbourhood social capital. Due to the broad range of studied health-related outcomes, the different operationalisations of neighbourhood social capital and the conceptual overlap between measures of SES and social capital in some studies, the factors that explain these differences in findings remain unclear. CONCLUSIONS: Although the findings of this study should be interpreted with caution, the results suggest that neighbourhood social capital might play a role in the health gradient among children and adolescents. However, only two of the included studies were conducted in Europe. Furthermore, some studies focussed on specific populations and minority groups. To formulate relevant European policy recommendations, further European-focussed research on this issue is needed. PMID- 23339777 TI - In vitro toxicity of camalexin derivatives in human cancer and non-cancer cells. AB - The aim of the study was to investigate the cytotoxic activity of camalexin and its five synthetic derivatives in cancer and non-cancer cells. In cancer cells the benzocamalexin (BC) displayed the most potent activity with an IC value of 23.3-30.1 MUmol/L. On the other hand, minimal toxicity (IC>100.0 MUmol/L) in non cancer cells was observed. Based on these results, BC was selected for further studies. Flow cytometric analysis revealed a BC-induced arrest of the cell cycle in the G2 phase associated with downregulation of alpha-tubulin, alpha1-tubulin, beta5-tubulin expression. These findings suggest that the inhibitory effect of BC is mediated via inhibition of microtubule formation. Moreover, BC downregulated the expression of microtubule-related protein indicating the effect of this compound on microtubule assembly. After treatment with BC increase of the sub-G DNA content fraction was noted which is considered to be a marker of apoptotic cell death. Apoptosis was also confirmed by DNA fragmentation assay. Moreover, quantitative real-time PCR showed that BC downregulated the expression of antiapoptotic genes Bcl-2 and Bcl-xL and upregulated the expression of proapoptotic Bax. Taken together, our study suggests that the blockade of cell cycle progression and initiation of apoptosis may play an important role in the antiproliferative activity of BC in human cancer cells. PMID- 23339778 TI - Environmental and economic trade-offs in a watershed when using corn stover for bioenergy. AB - There is an abundant supply of corn stover in the United States that remains after grain is harvested which could be used to produce cellulosic biofuels mandated by the current Renewable Fuel Standard (RFS). This research integrates the Soil Water Assessment Tool (SWAT) watershed model and the DayCent biogeochemical model to investigate water quality and soil greenhouse gas flux that results when corn stover is collected at two different rates from corn soybean and continuous corn crop rotations with and without tillage. Multiobjective watershed-scale optimizations are performed for individual pollutant-cost minimization criteria based on the economic cost of each cropping practice and (individually) the effect on nitrate, total phosphorus, sediment, or global warming potential. We compare these results with a purely economic optimization that maximizes stover production at the lowest cost without taking environmental impacts into account. We illustrate trade-offs between cost and different environmental performance criteria, assuming that nutrients contained in any stover collected must be replaced. The key finding is that stover collection using the practices modeled results in increased contributions to atmospheric greenhouse gases while reducing nitrate and total phosphorus loading to the watershed relative to the status quo without stover collection. Stover collection increases sediment loading to waterways relative to when no stover is removed for each crop rotation-tillage practice combination considered; no-till in combination with stover collection reduced sediment loading below baseline conditions without stover collection. Our results suggest that additional information is needed about (i) the level of nutrient replacement required to maintain grain yields and (ii) cost-effective management practices capable of reducing soil erosion when crop residues are removed in order to avoid contributions to climate change and water quality impairments as a result of using corn stover to satisfy the RFS. PMID- 23339779 TI - The impact of compulsory helmet legislation on cyclist head injuries in New South Wales, Australia: a response. AB - This article responds to criticisms made in a rejoinder (Accident Analysis and Prevention 2012, 45: 107-109) questioning the validity of a study on the impact of mandatory helmet legislation (MHL) for cyclists in New South Wales, Australia. We systematically address the criticisms through clarification of our methods, extension of the original analysis and discussion of new evidence on the population-level effects of MHL. Extensions of our analysis confirm the original conclusions that MHL had a beneficial effect on head injury rates over and above background trends and changes in cycling participation. The ongoing debate around MHL draws attention away from important ways in which both safety and participation can be improved through investment in well-connected cycling infrastructure, fostering consideration between road users, and adequate legal protection for vulnerable road users. These are the essential elements for providing a cycling environment that encourages participation, with all its health, economic and environmental benefits, while maximising safety. PMID- 23339780 TI - Development of the teneral adult Anoplophora glabripennis (Coleoptera: Cerambycidae): time to initiate and completely bore out of maple wood. AB - Anoplophora glabripennis (Motschulsky) is an introduced invasive pest with the potential to devastate hardwood forests in North America. Using artificial pupal chambers, we documented the time required by teneral adults at three temperatures (20, 25, and 30 degrees C), 60-80% RH, and a photoperiod of 16:8 (L:D) h to initiate boring after eclosion and subsequently bore completely through a 7-mm (range, 3-11 mm) layer of Norway maple wood (Acer platanoides L.). In total, 218 laboratory-reared pupae from the Chicago, IL, or Inner Mongolia, China, populations were used in the study. Females (1.54 +/- 0.03 g) weighed significantly more than males (1.12 +/- 0.03 g), but the average weights of the beetles emerging in each temperature did not differ. Adult weight was positively correlated with exit hole diameter (diameter [mm] = 2.2 * weight [g] + 7.9). The rate at which beetles bored through the wood (136, 178, and 168 mm(3)/d at 20, 25 and 30 degrees C, respectively) significantly differed between temperatures but did not differ with beetle weight. Temperature had a significant effect on the time it took adults to initiate boring (7, 5, and 4 d at 20, 25, and 30 degrees C, respectively) and subsequently to complete boring to emerge (5, 4, and 4 d at 20, 25, and 30 degrees C, respectively). This suggests that beetles require more than a week to progress from eclosion to emergence in wood, even at summer temperatures. This information on A. glabripennis basic biology is critical for developing phenology models that are used to time exclusion and eradication methodologies. PMID- 23339781 TI - Effects of reforestation practices on Staphylinid beetles (Coleoptera: Staphylinidae) in Southwestern China forests. AB - In 2004, Staphylinid beetle (Coleoptera) assemblages were studied via pitfall trapping to examine the effects of reforestation in southwestern China forests. Sites included two 100-yr-old mature forest types (hemlock-spruce forest and birch forest), and three 40-yr-old forest types established after harvesting (spruce plantation, larch plantation, and natural broad-leaved forest). Staphylinid species richness was greater in natural broad-leaved forests than those in hemlock-spruce forests and spruce plantations, but no significant difference was found in abundance among the five forest types. Beetle assemblages from young forest stands were significantly different from those in older forest stands, and some environmental characteristics, i.e., elevation, proportion of broad-leaved trees, and coarse woody debris, significantly affected species abundances. Moreover, some staphylinid species predominantly found only in older forest stands indicate that mature forest specialists might be threatened by loss of habitat. So it is necessary to retain adequate patches of older successional stages for conserving these beetle assemblages. PMID- 23339782 TI - Distribution patterns of three long-horned beetles (Coleoptera: Cerambycidae) shortly after fire in boreal forest: adults colonizing stands versus progeny emerging from trees. AB - We identified the factors that affect the early colonization of burned stands by adults and the progeny surviving in fire-killed black spruce trees for three cerambycid beetles: Acmaeops proteus proteus (Kirby), Acmaeops pratensis (Laicharting), and Monochamus scutellatus scutellatus (Say) (Coleoptera: Cerambycidae) in the northern Canadian boreal forest. Furthermore, we measured if progeny emerging from burned trees was related to patterns of adults captured in traps the same year as the fire. Fire severity at the stand and landscape scales were the most important predictors for colonizing adults. Except for A. pratensis, thick-barked and lightly burned trees positively influenced the occurrence of surviving progeny at the tree level. Last-instar larvae of A. pratensis emerged from burned trees more often in severely burned landscapes. This may result from biotic interactions with intraguild species or predators. With the exception of A. pratensis, variables affecting the postfire abundance and occurrence pattern of adults were strikingly different from progeny emerging after fire. Progeny emerging from burned trees was almost exclusively related to tree- or stand level characteristics, whereas colonizing adults were correlated with variables measured at various spatial scales, and most often at the landscape scale. Moreover, A. proteus proteus and M. scutellatus scutellatus adults were more common in severely burned landscapes, although their progeny emerged more often in lightly or moderately burned trees. Host selection behavior within stands (e.g., host acceptance) by colonizing adults or host suitability for the larvae might have caused this discrepancy. PMID- 23339783 TI - Phenological variation in the composition of a temperate forest leaf tie community. AB - Arthropod communities in an array of temperate ecosystems follow similar phenological patterns of distinct compositional turnovers during the course of a season. The arthropod community inhabiting leaf ties is no exception. Many caterpillars build leaf ties, shelters between overlapping leaves attached together with silk, which are colonized secondarily by a variety of arthropods. We created experimental leaf ties by clipping overlapping leaves together with metal clips. We censused the arthropod community within experimental ties on two host plants, American beech (Fagus grandifolia Ehrhart), and white oak (Quercus alba L.), weekly for 10 wk during the summer of 2009. Diversity measures for leaf tying caterpillars and the entire arthropod community within ties varied little between tree species and sampling periods, but caterpillar and arthropod density per tie was significantly higher on white oak than beech and abundance increased on both tree species as the season progressed. The composition (i.e., species presence and abundance) of the leaf-tying caterpillar community and the arthropod community as a whole differed between host-tree species and sampling periods. Although the arthropod communities on American beech and white oak differed, they showed similar patterns of compositional turnover, with distinct communities in early and late summer and a transitional community midsummer. PMID- 23339784 TI - Ant assemblage on a coffee farm: spatial mosaic versus shifting patchwork. AB - Competition has been recognized as a major organizing process in ant communities, with ant communities frequently forming spatial mosaics of dominant species associated with subdominants. Often, species exhibit tradeoffs in their ability to discover versus dominate resources, suggesting a mechanism for coexistence. Here we describe spatial patterns of dominant ants in two sites within a coffee plantation. Ants were sampled for three consecutive years by using tuna baits set on a grid on the ground and on coffee bushes. In addition, so as to determine which species discovered baits first and which species dominated baits, a separate experiment was set up where baits were observed every minute for 2 hr. The relative abundance of species followed a power law, with coefficients of determination ranging from 92 to 97% explanation. At site I the terrestrial community is dominated by two species, Pheidole synanthropica Longino and Pheidole protensa Wilson, whereas at site II the community exhibits codominance of four species: P. synanthropica, P. protensa, Solenopsis geminata F., and Pheidole 1 group. The spatial pattern formed by these species is distinct for each of the sites, both in terms of generalized appearance and dynamic stability. The terrestrial foraging ants at site I do not maintain a fixed mosaic over time. In contrast, at site II ants maintain a fixed mosaic. The arboreally foraging ants reflect, to some extent, the pattern of the terrestrial foragers. A possible interpretation of these results is that dominant ants at site I contain competitive intransitivities that generate a changing mosaic, whereas dominant ants in site II are organized in a competitive hierarchy that generates a fixed mosaic. PMID- 23339785 TI - Stable fly phenology in a mixed agricultural--wildlife ecosystem in northeast Montana. AB - The stable fly, Stomoxys calcitrans (L.), is a cosmopolitan species of blood feeding Muscidae and an important pest of cattle. Although the cattle industry is the largest commodity in Montana, no research has been conducted on the abundance, distribution, or impact of stable flies in the state. Observations of stable flies attacking West Nile virus (family Flaviviridae, genus Flavivirus, WNV) -infected pelicans on a refuge in close proximity to pastured and confined cattle provided an opportunity to describe stable fly phenology in a mixed agricultural-wildlife ecosystem. Coroplast cards used to monitor and compare adult populations in three habitats (peninsula, pasture, confinement lot) located within 1.5-4.5 km of each other revealed that temporal dynamics differed by site. Adult abundance was generally lowest at the confinement lot, the only location where larval development was identified. Stable flies were collected on all traps placed in pasture, with traps adjacent to pastured cattle consistently collecting the most. Adults also were collected on the peninsula supporting the pelicans' nesting site, but whether the potential hosts or physical landscape served as an attractant is unclear. At all three sites, data indicated that overwintering was not successful and that a transition occurred from early season immigrating adults that used suitable local larval development substrates to subsequent autochthonous populations. PMID- 23339786 TI - Shifts in composition of monthly invertebrate assemblages in Moorland differed between lowland and montane locations but not fire-ages. AB - Understanding seasonal changes in invertebrate populations is important for understanding ecosystem processes and for conservation of invertebrate communities. Few studies have investigated variation in seasonal responses of multiorder and multispecies invertebrate assemblages. To determine whether temporal patterns in invertebrate assemblages and taxa vary between locations and vegetation age since burning, patterns of invertebrate occurrence were investigated monthly for 12 mo in cool temperate buttongrass moorlands at two locations (lowland and montane) containing paired plots with different fire history (young and old regrowth). For both locations and fire-ages, invertebrate taxon richness and abundance were generally higher during the warmer months than during the winter months. At the lowland location, foliage dwelling invertebrates were caught in greater numbers during winter than during summer owing to large numbers of Collembola. Each season had a distinct invertebrate assemblage. The invertebrate assemblages did not differ between young and old regrowth. The shifts in composition of monthly invertebrate assemblages between winter and summer differed between locations with assemblages in cooler months more dissimilar from warmer months at the montane location than the lowland location. Most taxa common to both locations had similar patterns of monthly occurrence but some taxa showed markedly different patterns. Mid- to late summer is the optimum time to conduct short-term surveys in buttongrass moorland to maximize species richness and abundance but short-term studies will miss significant components of the invertebrate community. PMID- 23339787 TI - Relative amount of symbionts in insect hosts changes with host-plant adaptation and insecticide resistance. AB - The impact of symbionts on their hosts depends on their infection density. In the current study, we investigated the effects of host plant and insecticide resistance on the relative amount of symbionts Portiera, Hamiltonella, Rickettsia, and Cardinium in the whitefly Bemisia tabaci (Gennadius) B biotype. The relative amount of symbionts in three host plant-adapted subpopulations (cucumber, Cucumis sativus L.; cabbage, Brassica oleracea L.; and cotton, Gossypium herbaceum L.) with the same genetic background and insecticide (thiamethoxam)-resistant and -susceptible subpopulations with the same genetic background were measured by quantitative polymerase chain reaction. The results showed that the cucumber population harbored more Portiera than the cabbage and cotton populations, the cabbage population harbored more Hamiltonella than the cucumber population, Hamiltonella amount did not statistically differ between the cotton and cucumber or the cotton and cabbage populations, and the cabbage population harbored more Rickettsia and Cardinium than the cucumber and cotton populations. In addition, the thiamethoxam-susceptible population harbored more Portiera and Hamiltonella than the thiamethoxam-resistant population, whereas the thiamethoxam-resistant population harbored more Rickettsia than the thiamethoxam susceptible population. These results indicated that relative amounts of symbionts were affected significantly by host plant-adaption and insecticide resistance, and the response to host plant and insecticide differed among the symbionts. PMID- 23339788 TI - Nematodes associated with Dryocoetes uniseriatus (Coleoptera: Scolytidae). AB - We examined the nematode fauna associated with a species of bark beetle, Dryocoetes uniseriatus Eggers, as part of a biodiversity survey of forest beetle associated nematodes. Collections were made in a pine stand at an experimental forest station in Ibaraki, Japan, from April to July of 2011; we examined the nematode association in 273 insects collected during this time. In total, 68% of the insects were associated with at least one species of nematode. Six species of nematodes, including two phoretic microbe feeders (Bursaphelenchus rainulfi Braasch & Burgermeister and Micoletzkya sp.), one insect parasite and nematode predator (Devibursaphelenchus cf. eproctatus), one insect parasite (Contortylenchus sp.), one insect parasite and potential microbe feeder (unidentified rhabditid parasite), and one potential insect parasite and fungal feeder (B. sinensis) were recovered from the beetles. D. cf. eproctatus was enclosed in nematangia on the backsides of the elytra, B. rainulfi was isolated from the backsides of the elytra or enclosed in nematangia, Micoletzkya sp. was isolated from under the elytra, Contortylenchus sp. and a rhabditid parasite parasitized the body cavity, and B. sinensis was found in the digestive tract of the insect. The association patterns of the nematode species varied seasonally, although definitive interactions among species (e.g., segregation, competition) were not observed. PMID- 23339789 TI - A multi-approach study to delineate interactions between carabid beetles and soybean aphids. AB - In recent years, the soybean aphid, Aphis glycines Matsumura, has become the most important exotic pest of soybean, Glycine max (L.) Merrill, in North America. Given the significant yield losses that are reported, considerable effort has been expended to characterize the natural enemy community associated with this pest. Several indigenous and naturalized predators have been identified as potential biological control agents, and these include carabid beetles, an abundant and important family of aphid predators. The objectives of this study were to assess the incidence of field predation by Pterostichus melanarius (Illiger), the most common carabid species in Quebec soybeans, using molecular gut-content analysis, and to quantify its impact on A. glycines populations through laboratory and field cage experiments. Throughout the growing season between 16.8% (during low aphid density) and 33.7% (at times of high aphid density) of P. melanarius tested positive for aphid DNA. Furthermore, although laboratory feeding trials confirmed that P. melanarius prey on A. glycines, short term field cage experiments failed to demonstrate a significant reduction of A. glycines populations by carabid beetles. These results suggest a relatively weak interaction between P. melanarius and A. glycines when pest densities are high, but the high predation rate when aphid densities are particularly low suggests these natural enemies may function as important early-season predators. PMID- 23339790 TI - Agricultural management systems affect the green lacewing community (Neuroptera: Chrysopidae) in olive orchards in southern Spain. AB - Green lacewings are generalist predators whose conservation is important for pest control in olive orchards (Olea europaea L.) Sustainable farming practices, as opposed to conventional management techniques, are believed to foster the presence of natural enemies. This study therefore aims to analyze the effect of 1) herbicidal weed cover removal and insecticide applications, and 2) the general management systems used in the olive orchards of southern Spain on chrysopid assemblages and abundance. Green lacewing adults and larvae were collected from olive orchards under conventional, integrated, and organic management systems. In addition, chemical analyses of residues were carried out to determine the presence of insecticidal and herbicidal residues. Eight adult species and three genera of larvae were identified. No rare species were captured from the most intensively farmed orchard, which therefore recorded the most limited chrysopid diversity with a very marked dominance of Chrysoperla carnea s.l.. No effect of dimethoate treatments on Chrysoperla larvae or C. carnea s.l. adults was observed. However, the presence of insecticide residues was associated with the depletion of Dichochrysa larvae. The absence of herbicide treatments favored C. carnea s.l. adult presence on olive trees while larval abundance decreased. Dichochrysa larvae were more abundant when weed cover received no treatment. In relation to the management systems studied, no difference in Chrysoperla larval abundance was observed between conventional and organic orchards. However, Dichochrysa larvae were more abundant in orchards under organic management. PMID- 23339791 TI - Biology of Habrobracon gelechiae (Hymenoptera: Braconidae), as a parasitoid of the obliquebanded leafroller (Lepidoptera: Tortricidae). AB - Habrobracon gelechiae Ashmead (Hymenoptera: Braconidae) was studied as a parasitoid of the obliquebanded leafroller, Choristoneura rosaceana (Harris) (Lepidoptera: Tortricidae) in California pistachio (Pistacia vera L.) orchards. Ovipositional behavior, adult longevity and fecundity, and the effects of temperature on developmental time and survival were determined. Habrobracon gelechiae develops as a gregarious, ectoparasitic idiobiont on late-instar C. rosaceana larvae. At 25 degrees C, adult female wasps survived longer when provided honey and water (35.4 +/- 4.9 d) or honey, water, and host larvae (34.4 +/- 2.4 d) than when provided water (8.9 +/- 1.1 d) or no food (5.9 +/- 0.8 d). Over the adult lifespan, females parasitized 20.6 +/- 2.1 hosts and deposited 228.8 +/- 24.6 eggs. The intrinsic rate of increase was 0.24, the mean generation time was 18.15 d, and the double time 2.88 d. At constant temperatures, H. gelechiae successfully developed (egg to adult) from 15 to 35 degrees C. The developmental rate was fit to a nonlinear model, providing estimates of the parasitoid's lower (10.5 degrees C), upper (36.0 degrees C), and optimal (33.3 degrees C) development temperatures. Based on a linear model, 155 degree days were estimated for egg to adult eclosion. Temperature-dependent nonlinear model of survival showed similar shape with the model of development rate. The wasp developed under two diurnal temperature regimes, with 31.0 +/- 13.3% survival at low (4-15 degrees C) and 63.0 +/- 11.4% survival at high (15-35 degrees C) temperature regimes. The results are discussed with respect to H. gelechiae potential as a parasitoid of C. rosaceana in California's San Joaquin Valley. PMID- 23339792 TI - Host density drives spatial variation in parasitism of the alfalfa weevil, Hypera postica, across dryland and irrigated alfalfa cropping systems. AB - Classical biological control against the alfalfa weevil, Hypera postica (Gyllenhal), a destructive pest of alfalfa (Medicago sativa L.), has resulted in the establishment of nine parasitoid species in the United States. Despite widespread redistribution of a number of species, there remains little postrelease data on their establishment and potential effectiveness in many regions. I surveyed parasitoids associated with alfalfa weevil larvae across 30 or more sites in eastern Montana and western North Dakota over 2 yr. Replicate sites were sampled in two habitat types that differ in their physical characteristics, flood-irrigated and dryland alfalfa fields. Irrigated systems are more productive but also more intensively disturbed habitats because of increased harvest frequency and repeated flooding. Given evidence that both habitat disturbance and herbivore density, which often increases with productivity, can influence parasitoid dynamics, I predicted that parasitism levels, the relative importance of different species, or both, would differ across these two system types. Of four larval parasitoid species released previously or recovered in the region, two were found in this study, Bathyplectes curculionis (Thomson) and Oomyzus incertus (Ratzenberg), with average levels of parasitism across habitat types and years of 37.2 and 3.5%, respectively. Parasitism levels differed between habitat types, but the effect was driven by concomitant differences in host densities that were higher in irrigated than dryland fields. Parasitoid responses to host density varied across years and species. B. curculionis exhibited positive density dependence in parasitism across sites in 2009 and negative density dependence in 2010 when host densities were higher regionally. In contrast, O. incertus exhibited positive density dependence in 2010. Our results suggest that these species may be differentially effective at different host densities. Thus, variation in host density could represent an important axis along which parasitoids exhibit spatial complementarity in function. PMID- 23339793 TI - Why oviposit there? Fitness consequences of a gall midge choosing the plant's youngest leaf. AB - For animals that lay eggs, a longstanding question is, why do females choose particular oviposition sites? For insects that lay eggs on plants there are three hypotheses: maximizing suitable habitat for juveniles, maximizing female lifespan, and maximizing egg survival. We investigated the function of the oviposition-site choice behavior of a gall midge, the Hessian fly, Mayetiola destructor (Say). In spite of living less than a day and having hundreds of eggs, the ovipositing female is choosy about the placement of eggs. Choosiness makes sense. The tiny gall-making neonate larva has limited movement and strict requirements for colonization. We examined whether offspring benefit from the Hessian fly female's preference for the plant's youngest leaf. To do this we restricted the female's access to the first, second, or third leaf of a seedling (wheat Triticum aestivum L.) plant. Being placed on older leaves did not impact egg survival or larval survival during migration to attack sites at the base of the plant, but did have negative impacts on egg-to-adult survival (reduced by 48%) and reproductive potential (reduced by 30-45%). These negative impacts appear to come from larvae having to search harder to find the limited number of reactive plant cells that can be reprogrammed to form the gall nutritive tissue. We propose that the ability of larvae to find these reactive cells in spite of being placed on an older leaf is important because it creates leeway for female behavior to evolve in the face of other selection pressures, e.g., attack by egg parasitoids. PMID- 23339794 TI - Spider fauna of semiarid eastern Colorado agroecosystems: diversity, abundance, and effects of crop intensification. AB - Spiders are critical predators in agroecosystems. Crop management practices can influence predator density and diversity, which, in turn, can influence pest management strategies. Crop intensification is a sustainable agricultural technique that can enhance crop production although optimizing soil moisture. To date, there is no information on how crop intensification affects natural enemy populations, particularly spiders. This study had two objectives: to characterize the abundance and diversity of spiders in eastern Colorado agroecosystems, and to test the hypothesis that spider diversity and density would be higher in wheat (Triticum aestivum L.) in crop-intensified rotations compared with wheat in conventional rotations. We collected spiders through pitfall, vacuum, and lookdown sampling from 2002 to 2007 to test these objectives. Over 11,000 spiders in 19 families from 119 species were captured from all sampling techniques. Interestingly, the hunting spider guild represented 89% of the spider fauna captured from all sites with the families Gnaphosidae and Lycosidae representing 75% of these spiders. Compared with European agroecosystems, these agroecosystems had greater diversity, which can be beneficial for the biological control of pests. Overall, spider densities were low in these semiarid cropping systems, and crop intensification effects on spider densities were not evident at this scale. PMID- 23339795 TI - Effect of abundance of the navel orangeworm on sampling range and interference between pheromone traps. AB - The sampling range of pheromone traps for the navel orangeworm Amyelois transitella (Walker) (Lepidoptera: Pyralidae) and its association with abundance was investigated by examining mutual interference within cross-shaped arrays of nine wing traps baited with virgin females and placed at 400-m intervals in three 256-ha blocks of almonds (Prunus dulcis [Miller] D. A. Webb), and three of pistachios (Pistacia vera L.). The proportions of males captured in the different positions were compared with the mean males for all traps, used as an index for abundance. For means between zero and 50 males per trap per week, the distribution was unequal between trap positions and the greatest proportion of males were captured in the northern-most trap (i.e., the within-row direction). Between 50 and 100 males per trap per week, most males were captured in the western-most traps and fewest in the center, and proportions were equal in other trap positions. Above 100 males per trap per week, the proportion of males captured was more nearly equal for all trap positions. These results demonstrate that the sampling range of pheromone traps for navel orangeworm is density dependent and, at low densities, is >400 m. They also indicate that abundance affects the impact of direction (orientation) of trap interference. At low density, female-strength pheromone traps sample males from beyond the block in which they are placed for orchard blocks of <50 ha. PMID- 23339796 TI - Influence of trap design on upwind flight behavior and capture of female grape berry moth (Lepidoptera: Tortricidae) with a kairomone lure. AB - Oil-coated clear panel traps baited with a host plant-based kairomone lure have successfully been used for monitoring female grape berry moth, Paralobesia viteana (Clemens) (Lepidoptera: Tortricidae), but low capture rates as well as difficulty in servicing these traps makes them unsuitable for commercial use. We compared the performance of different trap designs in a flight tunnel and in a vineyard by using a 7-component synthetic kairomone blend, with a focus on trap visual cues. In flight tunnel experiments, a clear delta trap performed better than other traps. When we tested clear delta, green delta, or clear wing traps baited with a cut grape shoot, >50% of female grape berry moths made complete upwind flights. However, the clear delta trap was the only design that resulted in female moths entering the trap. Similar results were observed when females were tested with different traps (clear delta, green delta, white delta, clear wing, or green wing traps) baited with the kairomone lure. Adding a visual pattern that mimicked grape shoots to the outside surface of the clear delta trap resulted in 66% of the females that made upwind flights entering the trap. However, the positive effect of adding a visual pattern to the trap was not observed in a vineyard setting, where clear delta traps with or without a visual pattern caught similar numbers of females. Still, the number of male and female grape berry moths captured in clear delta traps with or without a visual pattern was not significantly different from the number of male and female grape berry moths captured in panel traps, suggesting that the use of these delta traps could be a less cumbersome alternative to oil-coated panel traps for monitoring female grape berry moth. PMID- 23339797 TI - An attempt to increase efficacy of moth mating disruption by co-releasing pheromones with kairomones and to understand possible underlying mechanisms of this technique. AB - Pheromone-based mating disruption is used worldwide for management of the internal fruit feeding codling moth, Cydia pomonella (L.). There has been recent interest in the potential of improving mating disruption of C. pomonella, and potentially other insect species in general, by broadcasting combinations of pheromone and attractive host-plant kairomones. Given that such kairomones are attractive by themselves (often to both sexes), and also enhance male moth response to their pheromone, it is possible that the effects of competitive attraction and potentially other mechanisms of disruption might be increased. Herein, we tested the hypothesis that mating disruption of C. pomonella could be enhanced by co-deploying pheromone with either of two kairomones: (2E, 4Z)-2, 4 decadienoate (pear ester), or (E)-beta-farnesene, as compared with various pheromone blend components alone. When deployed individually, each kairomone caused a low level of synthetic lure trap disruption and (E)-beta-farnesene also caused disruption of mating as measured by tethering virgin females. However, combined release of either pear ester or (E)-beta-farnesene with pheromone within the same dispenser or as a co-deployed dispenser treatment, respectively, did not increase the level of mating disruption as compared with deploying pheromone alone. Disruption efficacy did not decline when reducing the amount of (E,E)-8,10-dodecadien-1-ol (codlemone) in dispensers by fourfold, when combined with pear ester. C. pomonella readily were observed briefly approaching all dispenser types (with and without pheromone) in the field. Exposure of male C. pomonella to pear ester alone in a manner mimicking observed field exposures did not reduce the number of males able to contact a female-mimic pheromone lure in flight tunnel assays. Also, reduction of male moth behavioral response to pheromone was similar after exposure to codlemone alone, and codlemone and pear ester after exposures that mimicked those observed in the field and none of the main treatments tested (pheromone versus pheromone and either kairomone) affected male moth antennal response seconds after exposure as measured by electroantenogram assays. Collectively, our data indicate that disruption of C. pomonella was not improved by co-releasing pheromone with either kairomone tested from point source devices as compared with pheromone alone at the relatively high loading dosages and associated release rates tested. PMID- 23339798 TI - Effect of fluctuating temperatures on the development of a forensically important blow fly, Protophormia terraenovae (Diptera: Calliphoridae). AB - Experiments were conducted to compare the immature development of Protophormia terraenovae (Robineau-Desvoidy) at fluctuating temperatures of 4-28 and 9-23 degrees C to their mean constant temperature, 16 degrees C. Overall development was fastest at the greater fluctuation and slowest at the constant temperature but showed similar percentages of development time in each stage. The rate summation effect is suspected to have caused this difference in development rate because fluctuations above the mean increase the rate relatively more than temperatures below the mean can lower the rate. PMID- 23339799 TI - Impact of six transgenic Bacillus thuringiensis rice lines on four nontarget thrips species attacking rice panicles in the paddy field. AB - As a key component of ecological risk assessments, nontarget effects of Bacillus thuringiensis (Bt) rice have been tested under laboratory and field conditions for various organisms. A 2-yr field experiment was conducted to observe the nontarget effects of six transgenic rice lines (expressing the Cry1Ab or fused protein of Cry1Ab and Cry1Ac) on four nontarget thrips species including Frankliniella intonsa (Trybom), F. tenuicornis (Uzel), Haplothrips aculeatus (F.), and H. tritici (Kurd), as compared with their rice parental control lines. Two sampling methods including the beat plate and plastic bag method were used to monitor the population densities of the four thrips species for 2 yr. The results showed that the seasonal average densities of four tested thrips species in Bt rice plots were significantly lower than or very similar to those in the non-Bt rice plots depending on rice genotypes, sampling methods, and years. Among all six tested Bt rice lines, transgenic B1 and KMD2 lines suppressed the population of these tested thrips species the most. Our results indicate that the tested Bt rice lines are unlikely to result in high population pressure of thrips species in comparison with non-Bt rice. In some cases, Bt rice lines could significantly suppress thrips populations in the rice ecosystem. In addition, compatibility of Bt rice, with rice host plant resistance to nontarget sucking pests is also discussed within an overall integrated pest management program for rice. PMID- 23339800 TI - Simazine transport in undisturbed soils from a vineyard at the Casablanca valley, Chile. AB - Simazine is a soil-active herbicide that has been applied worldwide in agricultural soils, being the second most commonly detected herbicide in groundwater and surface waters. Although its use has been restricted in many countries of Europe, it is still applied in many locations around the world in orchards, vineyards and forestry. Therefore, it is important to study its fate and transport in the environment. This paper investigates simazine transport in undisturbed bare soils from a vineyard at the Casablanca valley, Chile. In the study site, shallow groundwater tables (<1.0 m depth) and high simazine levels (>15 MUg L(-1)) in the groundwater were observed and thus, there is potential for simazine to be transported further away through the saturated zone. The soils from the study site were characterized and the hydrodynamic transport parameters were determined. Column leaching experiments showed that the two-site chemical non-equilibrium model correctly represented simazine transport. It was found that 36.3% of the adsorption sites achieve instantaneous equilibrium and that the first-order kinetic rate of the non-equilibrium sites was 6.2 * 10(-3) h(-1). Hydrus 2D was used to predict the transport of simazine in the study site under natural field conditions. Simulation results showed that simazine concentrations at depths shallower than 2.1 m are above the maximum contaminant level of 4 MUg L(-1) (defined by the U.S. Environmental Protection Agency). The timing of herbicide application was found to be important on simazine leaching and the main processes involved in simazine transport were degradation and adsorption, which accounted for 95.78 and 4.19% of the simulated mass of pesticide, respectively. A qualitative agreement in the timing and magnitude of simazine concentration was obtained between the simulations and the field data. Therefore, the model utilized in this investigation can be used to predict simazine transport and is a valuable tool to assess agricultural practices to minimize environmental impacts of simazine. PMID- 23339801 TI - Integrating spatial and temporal oxygen data to improve the quantification of in situ petroleum biodegradation rates. AB - Accurate estimation of biodegradation rates during remediation of petroleum impacted soil and groundwater is critical to avoid excessive costs and to ensure remedial effectiveness. Oxygen depth profiles or oxygen consumption over time are often used separately to estimate the magnitude and timeframe for biodegradation of petroleum hydrocarbons in soil and subsurface environments. Each method has limitations. Here we integrate spatial and temporal oxygen concentration data from a field experiment to develop better estimates and more reliably quantify biodegradation rates. During a nine-month bioremediation trial, 84 sets of respiration rate data (where aeration was halted and oxygen consumption was measured over time) were collected from in situ oxygen sensors at multiple locations and depths across a diesel non-aqueous phase liquid (NAPL) contaminated subsurface. Additionally, detailed vertical soil moisture (air-filled porosity) and NAPL content profiles were determined. The spatial and temporal oxygen concentration (respiration) data were modeled assuming one-dimensional diffusion of oxygen through the soil profile which was open to the atmosphere. Point and vertically averaged biodegradation rates were determined, and compared to modeled data from a previous field trial. Point estimates of biodegradation rates assuming no diffusion ranged up to 58 mg kg(-1) day(-1) while rates accounting for diffusion ranged up to 87 mg kg(-1) day(-1). Typically, accounting for diffusion increased point biodegradation rate estimates by 15-75% and vertically averaged rates by 60-80% depending on the averaging method adopted. Importantly, ignoring diffusion led to overestimation of biodegradation rates where the location of measurement was outside the zone of NAPL contamination. Over or underestimation of biodegradation rate estimates leads to cost implications for successful remediation of petroleum impacted sites. PMID- 23339802 TI - The authors' challenge. PMID- 23339803 TI - First-in-man, last in evidence? PMID- 23339804 TI - Innovation in education: what's new in 2013? PMID- 23339805 TI - Clinical and angiographic experience with a third-generation drug-eluting Orsiro stent in the treatment of single de novo coronary artery lesions (BIOFLOW-I): a prospective, first-in-man study. AB - AIMS: To report the four-month and nine-month angiographic results as well as one year clinical follow-up from the first-in-man study with the silicon carbide and sirolimus-eluting bioabsorbable polymer (poly-L-lactic acid (PLLA) polymer) coated cobalt-chromium Orsiro stent. METHODS AND RESULTS: A group of 30 patients with documented myocardial ischaemia related to a single de novo coronary stenosis up to 22 mm in length, in vessels with a 2.5 to 3.5 mm reference diameter, and between >50% and <90% diameter stenosis were enrolled at two sites. The primary endpoint of the study was in-stent late lumen loss at nine months. The secondary endpoints included major adverse cardiac events (MACE) at one year defined as the composite of cardiac death, ischaemia-driven target lesion revascularisation (TLR) and target vessel myocardial infarction (MI). Procedural success was 100%. Angiographic late lumen loss was 0.12+/-0.19 mm and 0.05+/-0.22 mm at four and nine months respectively. At one-year clinical follow-up, the composite MACE was 10% with one patient who died from cardiac death and two patients who had ischaemia-driven target lesion revascularisation. There was no report of MI or stent thrombosis. CONCLUSIONS: The Orsiro drug-eluting stent demonstrated potency with low rates of in-stent neointimal hyperplasia and cardiovascular events but warrants further evaluation in a larger population cohort with longer follow-up time points. PMID- 23339807 TI - First-in-man assessment of a dedicated guidewire for transcatheter aortic valve implantation. AB - AIMS: The aim of this study was to evaluate the safety and performance of a specifically designed, dedicated TAVI guidewire. METHODS AND RESULTS: From May 2011 to August 2012, 39 consecutive patients referred for TAVI were prospectively enrolled in a first-in-man, open label, non-randomised feasibility study to evaluate the safety and performance of a specifically designed, dedicated TAVI guidewire in our institution (mean age 80.4+/-5.1 years, mean logistic EuroSCORE 26.8+/-11.7%, n=29 CoreValve transfemoral, n=8 CoreValve direct aortic, n=1 Edwards SAPIEN valve direct aortic, n=1 CoreValve subclavian). The primary safety endpoint was reached successfully with the dedicated TAVI guidewire in all 39 cases with no cases of guidewire displacement from the left ventricle during the procedure. In three cases the wire was repositioned to optimise loop position using a pigtail catheter prior to valve implantation. There were no cases of guidewire-related procedural complications. The mean delivery system tracking time using the guidewire was 1.4+/-0.6 minutes and the mean deployment time for TAVI was 13.8+/-7.8 minutes. CONCLUSIONS: This represents the first recorded use of a dedicated TAVI guidewire to treat patients with a transcatheter aortic valve. The wire is easy to place, safe to adjust within the ventricle, and the stiffness of the wire facilitates valve tracking through tortuous anatomy. In this study there were no pericardial complications with the use of this dedicated TAVI guidewire. PMID- 23339806 TI - First-in-man evaluation of the MOMO cobalt-chromium carbon-coated stent. AB - AIMS: Bare metal stents continue to be used for the interventional treatment of coronary artery disease. We report the clinical and angiographic results of a multicentre, single-arm evaluation of safety and feasibility of the MOMO stent (Japan Stent Technology Co., Ltd, Okayama Research Park Incubation Centre, Okayama, Japan). METHODS AND RESULTS: The MOMO stent is a novel thin-strut cobalt chromium carbon-coated stent for the treatment of de novo coronary artery disease (CAD). In this prospective, non-randomised, single-arm study, 40 patients (stable and unstable angina) with single-vessel CAD were recruited into the study from three centres. Patients with lesions <=15 mm in length and with a target vessel diameter of >=3 mm were eligible. Angiographic follow-up was performed at six months. Quantitative coronary angiography (QCA) was used to measure acute gain and late luminal loss (LLL). Intravascular ultrasound (IVUS) was performed in 15 consecutive patients from two centres to assess the degree of neointimal proliferation within the stented segment at six-month follow-up. The MOMO stent performed well without any procedural complications with an acute procedure and technical success rate of 100%. Repeat revascularisation was performed in six patients (15%) during the six-month follow-up. Ischaemia-driven revascularisation was documented in three patients (7.5%). No myocardial infarction, stent thrombosis or cardiac death was observed. One non-cardiac death was reported secondary to lung cancer. Binary restenosis was 12.5% (n=5), and the LLL was 0.54+/-0.3 mm. CONCLUSIONS: This first-in-man experience demonstrates proof of concept of the safety and feasibility of the MOMO cobalt-chromium carbon-coated stent for patients with single focal de novo lesions presenting with stable and unstable CAD. PMID- 23339808 TI - First clinical experience with the GARDEX EPD: a novel embolic protection device for carotid artery stenting. AB - AIMS: Carotid artery stenting (CAS) has become an alternative to carotid endarterectomy in the treatment of carotid artery disease. The use of an embolic protection device (EPD) can reduce the frequency of embolic events during CAS. Difficult vascular anatomy may complicate current generation EPD placement. This problem is addressed by a new EPD, the GARDEX System. The aim of this study was to assess the safety and performance of the GARDEX EPD during CAS. METHODS AND RESULTS: Thirty-eight patients underwent CAS with the GARDEX EPD in two medical centres. All patients were prospectively followed up for 30 days. Device performance and procedural details were collected and analysed prospectively. Vessel anatomy and lesion morphology were evaluated and stratified into a scoring system for anatomic difficulty. More than a third of the patients were considered to have difficult vascular anatomy for CAS. All enrolled patients were successfully treated. There was one (2.6%) minor periprocedural stroke and there were two (5.3%) periprocedural TIAs which resolved within 24 hours. No additional complications were noted during the 30-day follow-up period. CONCLUSIONS: In this first experience, CAS under cerebral protection with the GARDEX EPD was safe and feasible. Our data suggest that the use of the GARDEX EPD is simple and shows high success rates even in challenging anatomies. The role of this new device in CAS needs to be further confirmed in a larger patient population. PMID- 23339809 TI - Stent thrombosis after primary angioplasty for STEMI in relation to non-adherence to dual antiplatelet therapy over time: results of the HORIZONS-AMI trial. AB - AIMS: Rates of stent thrombosis (ST) after ST-elevation myocardial infarction (STEMI) may vary over time and the relationship of this complication with non adherence to dual antiplatelet therapy (DAPT) during long-term follow-up remains unclear. METHODS AND RESULTS: We analysed 2,997 patients who were treated with at least one stent and in whom a non-target vessel ST did not occur during follow-up from the large-scale Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial of patients with STEMI undergoing primary percutaneous coronary intervention (PCI). Aspirin was prescribed indefinitely, and a thienopyridine for at least six months. DAPT usage was evaluated according to the development of ST in four time periods (<1 month, 1-6 months, 6-12 months and >1 year from index stent implantation). DAPT non usage was lowest within the first month, but was strongly associated with ST. During the 1-6 month period the relationship remained strong, but was absent in the 6-12 month period. Beyond one year, ST was associated with non-usage of aspirin but was paradoxically more common in patients taking a thienopyridine. CONCLUSIONS: The relationship between stent thrombosis and non-adherence to DAPT varies over time. It is strong within the first month, remains important until six-month follow-up but fades afterwards. Very late ST is associated with both DAPT and aspirin alone but not with thienopyridine non-adherence. PMID- 23339810 TI - An intravascular ultrasound comparison of left anterior descending artery/first diagonal branch versus distal left main coronary artery bifurcation lesions. AB - AIMS: We report the intravascular ultrasound (IVUS) analysis of plaque distribution in left anterior descending (LAD) artery/first diagonal (D1) and distal left main coronary artery (LMCA) bifurcation lesion location. METHODS AND RESULTS: We reviewed 58 angiograms of LAD/D1 bifurcation lesions with pre intervention IVUS of both the LAD and D1 and compared these data to a corresponding cohort (n=81) of LMCA bifurcations, dividing each bifurcation into three segments: MV (main vessel), MB (main branch distal to the carina), and SB (side branch). In the LAD/D1 cohort, D1 (SB) had less calcium and a smaller plaque burden compared to the other two segments. Continuous plaque from the LAD proximal to the carina (MV) into the LAD distal to the carina (MB) was seen in 90%, from the MV into the SB in 72%, and from the MV into both the MB and SB in 62%. In the LMCA cohort, ostial left circumflex (LCX) (SB) had less calcium and a smaller plaque burden compared to the distal LMCA (MV) and ostial LAD (MB). Continuous plaque from MV to MB was seen in 96%, from MV to the SB in 78%, and from MV to both branches in 74%. CONCLUSIONS: The IVUS analysis of the LAD/D1 and LMCA bifurcations revealed that most lesions had diffuse plaques extending from the MV into the MB with the SB having the least amount of calcium and the smallest plaque burden, regardless of location. PMID- 23339811 TI - Five-year long-term clinical follow-up of the XIENCE V everolimus-eluting coronary stent system in the treatment of patients with de novo coronary artery disease: the SPIRIT II trial. AB - AIMS: To assess the safety and performance of the XIENCE V everolimus-eluting stent (EES) versus the TAXUS paclitaxel-eluting stent (PES) in the treatment of patients with de novo coronary artery lesions after a five-year follow-up period. Second-generation drug-eluting stents (DES) were developed with the aim of improving the safety profile of DES, after reports of stent thrombosis (ST) with first-generation devices. However, long-term follow-up data are scarce. METHODS AND RESULTS: SPIRIT II was a multicentre, prospective, single-blind, clinical trial, randomising 300 patients with up to two de novo coronary artery lesions in a ratio of 3:1 to either a EES or a PES. The five-year clinical follow-up was completed in 244 patients (81%). At five-year follow-up, 19.5% of patients were on thienopyridine in the EES arm, while 30.5% were on the same therapy in the PES arm. Cardiac mortality was significantly lower in EES than in PES (1.5% vs. 7.3%, p=0.015). There was a trend towards lower cardiac death and MI (4.8% vs. 11.4%) and lower ID-TLR (4.7% vs. 9.4%) in EES than in PES. As a result, there was a consistent reduction in ID-MACE for EES vs. PES (ID-MACE 8.0% vs. 18.1%, p=0.018). In addition, the ARC-defined stent thrombosis rate was numerically lower in EES compared to PES (0.9% vs. 2.8%). No definite stent thrombosis events were observed after two years in the EES arm. CONCLUSIONS: Five-year clinical follow-up of the SPIRIT II trial demonstrated the continuing long-term safety and efficacy of EES. PMID- 23339812 TI - Impact of atrial fibrillation on clinical outcomes among patients with coronary artery disease undergoing revascularisation with drug-eluting stents. AB - AIMS: Coronary artery disease (CAD) and atrial fibrillation (AF) are major determinants of morbidity and mortality. A combined treatment with antiplatelet agents and vitamin K antagonists limits the risk of stent thrombosis and stroke while increasing the rate of bleeding. The objective of this study was to investigate the impact of atrial fibrillation (AF) on long-term clinical outcomes in patients with CAD undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). METHODS AND RESULTS: Among 6,308 consecutive patients undergoing PCI with DES between 2002 and 2009, 323 (5.3%) patients were diagnosed with AF. We compared clinical outcomes between patients with and those without AF throughout four years. The primary endpoint was a composite of all-cause mortality, myocardial infarction (MI), ischaemic stroke, and BARC bleeding type 3b/3c/5a/5b. In adjusted analyses, the primary composite endpoint was more frequent among patients with AF (HR 1.59, 95% CI 1.26-2.00; p<0.001). Differences were driven by an increased risk of all-cause mortality (HR 1.67, 95% CI 1.27 2.20; p=0.003), ischaemic stroke (HR 3.09, 95% CI 1.45-6.56; p=0.003), and intracranial bleeding (HR 4.28, 95% CI 1.36-13.48; p=0.013). We observed a gradient of risk among patients with higher CHA2DS2-VASc scores and modified outpatient bleeding risk index. CONCLUSIONS: Among patients with CAD undergoing revascularisation with DES, AF confers an increased risk of all-cause mortality, ischaemic stroke, and intracranial bleeding. The hazard imposed by AF correlates with the CHA2DS2-VASc score. PMID- 23339813 TI - Therapeutic angiogenesis with VEGF164 for facilitation of guidewire crossing in experimental arterial chronic total occlusions. AB - AIMS: Percutaneous revascularisation of chronic total occlusions (CTO) is limited by failure of guidewire crossing. Neovascularisation within the proximal CTO segment may be important for guidewire crossing and dramatically declines in CTO beyond six weeks of age. The aims of the current study were to determine whether local delivery of a pro-angiogenic growth factor increases neovascularisation in mature CTO and facilitates guidewire crossings. METHODS AND RESULTS: CTO (n=51) were created in the femoral arteries of 44 New Zealand white rabbits using the thrombin injection model. At 12 weeks, CTO were treated with poly-lactic-glycolic acid (PLGA) microspheres containing either bovine serum albumin (BSA) (n=15) or recombinant mouse VEGF164 (n=14), or received no intervention (controls, n=12). Contrast-enhanced magnetic resonance angiography (CEMRA) was performed prior to treatment and at three weeks post treatment. Animals were sacrificed at three weeks post treatment and arterial samples were excised for micro-computed tomography imaging (uCT) and histologic morphometric analysis. Guidewire crossing was assessed at three weeks post treatment in an additional 10 VEGF164-treated CTO. In comparison to BSA-treated and control non-intervened CTO, VEGF164-treated CTO showed a significant increase in relative blood volume index in the proximal segment of the CTO lesion as determined by CEMRA and by uCT. Histologic measurements of microvessel area were also higher in VEGF164-treated CTO. Guidewire crossing across the proximal fibrous cap was successful in eight out of 10 VEGF164-treated CTO. CONCLUSIONS: Angiogenic therapy appears to be a promising strategy to improve neovascularisation and guidewire crossing rates in CTO. PMID- 23339814 TI - First-in-human use of the OneShotTM renal denervation system from Covidien. AB - Percutaneous transcatheter renal sympathetic denervation (RDN) is a promising treatment for refractory hypertension (HT). RDN was found in one series of clinical studies to reduce systolic blood pressure (SBP) by as much as a mean of 30 mmHg with 85% of subjects experiencing sustained reductions of 10 mm or more out to two years after RDN. This degree of blood pressure reduction may reduce stroke and myocardial infarction rates and is anticipated to translate into improved life expectancy. The lowering of blood pressure by RDN has been shown to improve glycaemic control and reverse left ventricular hypertrophy. Beneficial effects on renal function, sleep apnoea and heart failure are suggested as well. This report describes the first patient treated using the OneShotTM Renal Denervation System (formerly Maya Medical now Covidien, Campbell, CA, USA). PMID- 23339815 TI - The AmplatzerTM Cardiac Plug 2 for left atrial appendage occlusion: novel features and first-in-man experience. AB - Percutaneous left atrial appendage (LAA) closure is becoming a frequently performed procedure for patients with atrial fibrillation and high haemorrhagic risk. The AmplatzerTM Cardiac Plug (ACP) is one of the most commonly used devices for this purpose. Despite high success rate and low procedure risk associated with the ACP, a second generation of the device is now available. The new ACP has been designed to facilitate the implantation process, improve sealing performance and further reduce the risk of complications. The present report focuses on the novel features of the second generation of the AmplatzerTM Cardiac Plug (ACP 2 or AmuletTM) and describes the first-in-man experience. PMID- 23339816 TI - A modified technique of balloon anchoring for tricky stent delivery. PMID- 23339817 TI - How should I treat acute aortic annulus rupture during transcatheter aortic valve implantation? PMID- 23339818 TI - First-in-human experience: percutaneous renal denervation through a false lumen fenestration in aortic dissection type B. PMID- 23339819 TI - Catheter-based renal denervation: a word of caution. PMID- 23339820 TI - Farmers' self-reported perceptions and behavioural impacts of a welfare scheme for suckler beef cattle in Ireland. AB - BACKGROUND: To date, there have been a limited number of studies on the impact of government-incentivised farm animal welfare programmes or 'schemes', and on farmers' attitudes regarding such schemes. In this study, focus groups were used to gain insight into Irish farmers' perceptions of such a scheme for suckler cattle and its behavioural impacts on farmers. RESULTS: The findings were categorised into 46 codes and ultimately yielded two Global themes: 1) Beliefs and Evidence and 2) Logic and Logistics. The former theme covered farmers' attitudes and observations regarding the Scheme. The latter dealt with factors such as workload and costs. The Global themes allowed for comprehensive reporting of the strongest messages from focus groups. There was consensus that Scheme measures for the minimum calving age and for weaning had a positive impact on welfare. Two aspects criticized by participants were firstly disbudding, due to the logistics for anaesthetic application, and secondly the administrative workload associated with data capture and utilisation. The majority anticipated that data being collected via the Scheme would help to inform farm management decisions in future. CONCLUSIONS: Farm animal welfare schemes, which incentivise participants to implement certain practices, aspire to long-term behavioural change after scheme conclusion. Our research showed that this Scheme increased farmer awareness of the benefits of certain practices. It also demonstrated the importance of stakeholder participation in the design stages of welfare initiatives to ensure scheme measures are practical and relevant, to address any perceived controversial measures, and to plan for training and adding value to schemes. PMID- 23339821 TI - Tunable localized surface plasmon-enabled broadband light-harvesting enhancement for high-efficiency panchromatic dye-sensitized solar cells. AB - In photovoltaic devices, light harvesting (LH) and carrier collection have opposite relations with the thickness of the photoactive layer, which imposes a fundamental compromise for the power conversion efficiency (PCE). Unbalanced LH at different wavelengths further reduces the achievable PCE. Here, we report a novel approach to broadband balanced LH and panchromatic solar energy conversion using multiple-core-shell structured oxide-metal-oxide plasmonic nanoparticles. These nanoparticles feature tunable localized surface plasmon resonance frequencies and the required thermal stability during device fabrication. By simply blending the plasmonic nanoparticles with available photoactive materials, the broadband LH of practical photovoltaic devices can be significantly enhanced. We demonstrate a panchromatic dye-sensitized solar cell with an increased PCE from 8.3% to 10.8%, mainly through plasmon-enhanced photoabsorption in the otherwise less harvested region of solar spectrum. This general and simple strategy also highlights easy fabrication, and may benefit solar cells using other photoabsorbers or other types of solar-harvesting devices. PMID- 23339822 TI - Finding common ground to achieve a "good death": family physicians working with substitute decision-makers of dying patients. A qualitative grounded theory study. AB - BACKGROUND: Substitute decision-makers are integral to the care of dying patients and make many healthcare decisions for patients. Unfortunately, conflict between physicians and surrogate decision-makers is not uncommon in end-of-life care and this could contribute to a "bad death" experience for the patient and family. We aim to describe Canadian family physicians' experiences of conflict with substitute decision-makers of dying patients to identify factors that may facilitate or hinder the end-of-life decision-making process. This insight will help determine how to best manage these complex situations, ultimately improving the overall care of dying patients. METHODS: Grounded Theory methodology was used with semi-structured interviews of family physicians in Edmonton, Canada, who experienced conflict with substitute decision-makers of dying patients. Purposeful sampling included maximum variation and theoretical sampling strategies. Interviews were audio-taped, and transcribed verbatim. Transcripts, field notes and memos were coded using the constant-comparative method to identify key concepts until saturation was achieved and a theoretical framework emerged. RESULTS: Eleven family physicians with a range of 3 to 40 years in clinical practice participated.The family physicians expressed a desire to achieve a "good death" and described their role in positively influencing the experience of death.Finding Common Ground to Achieve a "Good Death" for the Patient emerged as an important process which includes 1) Building Mutual Trust and Rapport through identifying key players and delivering manageable amounts of information, 2) Understanding One Another through active listening and ultimately, and 3) Making Informed, Shared Decisions. Facilitators and barriers to achieving Common Ground were identified. Barriers were linked to conflict. The inability to resolve an overt conflict may lead to an impasse at any point. A process for Resolving an Impasse is described. CONCLUSIONS: A novel framework for developing Common Ground to manage conflicts during end-of-life decision-making discussions may assist in achieving a "good death". These results could aid in educating physicians, learners, and the public on how to achieve productive collaborative relationships during end-of-life decision-making for dying patients, and ultimately improve their deaths. PMID- 23339823 TI - Sandwich ELISA assay for the quantitation of palytoxin and its analogs in natural samples. AB - Palytoxins are potent marine biotoxins that have recently become endemic to the Mediterranean Sea, and are becoming more frequently associated with seafood. Due to their high toxicity, suitable methods to quantify palytoxins are needed. Thus, we developed an indirect sandwich ELISA for palytoxin and 42-hydroxy-palytoxin. An intralaboratory study demonstrated sensitivity (limit of detection, LOD = 1.1 ng/mL; limit of quantitation, LOQ = 2.2 ng/mL), accuracy (bias of 2.1%), repeatability (RSDr = 6% and 9% for intra- and interassay variability, respectively) and specificity: other common marine toxins (okadaic acid, domoic acid, saxitoxin, brevetoxin-3, and yessotoxin) do not cross-react in this assay. It performed well in three different matrices: observed LOQs were 11.0, 9.6, and 2.4 ng/mL for mussel extracts, algal net samples and seawater, respectively, with good accuracy and precision. The LOQ in seafood is 11 MUg palytoxin/kg mussel meat, lower than that of the most common detection technique, LC-MS/MS. PMID- 23339824 TI - Diffuse lipomatosis of the thyroid with amyloid deposition. AB - BACKGROUND: The authors present a case of diffuse fatty infiltration of the thyroid gland with coexistent deposition of amyloid protein. METHOD: A case history and brief literature review concerning amyloid goitre and fatty infiltration of the thyroid are presented, and the relationship between these two phenomena is discussed. RESULTS: A patient with AA amyloidosis presented with a slowly enlarging goitre, which on histological examination was extensively infiltrated with adipose tissue. Amyloid protein was found on Congo red staining. CONCLUSION: To our best knowledge, this patient represents the first reported case of diffuse lipomatosis of the thyroid gland causing goitre in a patient with AA amyloidosis. The presence of amyloid protein within the thyroid was not sufficient to cause enlargement per se, and was therefore of unclear significance. Together with previous reports of the concurrent deposition of amyloid and fat, this case raises questions as to the relationship between these two phenomena. PMID- 23339825 TI - Three-component domino reactions for regioselective formation of bis-indole derivatives. AB - A microwave-assisted regioselective reaction dealing with arylglyoxal monohydrate, diverse N-aryl enaminones, and indoles to achieve 3,2'- and 3,3'-bis indoles by varying a substituted indole substrate is reported. The 2 unsubstituted indoles resulted in the 3,2'-bis-indole skeleton, whereas indoles bearing a methyl or phenyl group at C2 led to the 3,3'-bis-indoles with simultaneous formation of three sigma-bonds. The procedures feature excellent regioselectivity, short reaction times, convenient one-pot manner, and operational simplicity. PMID- 23339826 TI - A validation study of the 2003 American College of Cardiology/European Society of Cardiology and 2011 American College of Cardiology Foundation/American Heart Association risk stratification and treatment algorithms for sudden cardiac death in patients with hypertrophic cardiomyopathy. AB - AIMS: Sudden cardiac death (SCD) is a common mode of death in hypertrophic cardiomyopathy (HCM), but identification of patients who are at a high risk of SCD is challenging as current risk stratification guidelines have never been formally validated. The objective of this study was to assess the power of the 2003 American College of Cardiology (ACC)/European Society of Cardiology (ESC) and 2011 ACC Foundation (ACCF)/American Heart Association (AHA) SCD risk stratification algorithms to distinguish high risk patients who might be eligible for an implantable cardioverter defibrillator (ICD) from low risk individuals. METHODS AND RESULTS: We studied 1606 consecutively evaluated HCM patients in an observational, retrospective cohort study. Five risk factors (RF) for SCD were assessed: non-sustained ventricular tachycardia, severe left ventricular hypertrophy, family history of SCD, unexplained syncope and abnormal blood pressure response to exercise. During a follow-up period of 11 712 patient years (median 6.6 years), SCD/appropriate ICD shock occurred in 20 (3%) of 660 patients without RF (annual rate 0.45%), 31 (4.8%) of 636 patients with 1 RF (annual rate 0.65%), 27 (10.8%) of 249 patients with 2 RF (annual rate 1.3%), 7 (13.7%) of 51 patients with 3 RF (annual rate 1.9%) and 4 (40%) of 10 patients with >=4 RF (annual rate 5.0%). The risk of SCD increased with multiple RF (2 RF: HR 2.87, p<=0.001; 3 RF: HR 4.32, p=0.001; >=4 RF: HR 11.37, p<0.0001), but not with a single RF (HR 1.43 p=0.21). The area under time-dependent receiver operating characteristic curves (representing the probability of correctly identifying a patient at risk of SCD on the basis of RF profile) was 0.63 at 1 year and 0.64 at 5 years for the 2003 ACC/ESC algorithm and 0.61 at 1 year and 0.63 at 5 years for the 2011 ACCF/AHA algorithm. CONCLUSIONS: The risk of SCD increases with the aggregation of RF. The 2003 ACC/ESC and 2011 ACCF/AHA guidelines distinguish high from low risk individuals with limited power. PMID- 23339827 TI - [Prognostic factors for patients with brain metastases]. AB - Approximately 20 to 40 % of patients with metastatic cancer will develop brain metastases (BM) during the disease course. Whole-brain radiation therapy (WBRT) is considered the standard treatment for most patients, particularly those with extensive intracranial disease, providing symptom relief and increasing median and overall survival. Despite WBRT, the prognosis for the general population of patients with BM remains poor, with a median survival time of approximately five months. Several studies have examined the relative contribution of patient characteristics to survival and have attempted to identify subgroups of patients with substantially different outcomes in order to tailor therapy and to influence the design, stratification and interpretation of future clinical trials. Here, we review the main prognostic factors and prognostic scores in patients with BM and the value and limits of these prognostic scores in clinical practice. PMID- 23339828 TI - Retraction statement: Performance of three culture media commonly used for detecting Listeria monocytogenes. PMID- 23339830 TI - Disorder imposed limits of mono- and bilayer graphene electronic modification using covalent chemistry. AB - A central question in graphene chemistry is to what extent chemical modification can control an electronically accessible band gap in monolayer and bilayer graphene (MLG and BLG). Density functional theory predicts gaps in covalently functionalized graphene as high as 2 eV, while this approach neglects the fact that lattice symmetry breaking occurs over only a prescribed radius of nanometer dimension, which we label the S-region. Therefore, high chemical conversion is central to observing this band gap in transport. We use an electrochemical approach involving phenyl-diazonium salts to systematically probe electronic modification in MLG and BLG with increasing functionalization for the first time, obtaining the highest conversion values to date. We find that both MLG and BLG retain their relatively high conductivity after functionalization even at high conversion, as mobility losses are offset by increases in carrier concentration. For MLG, we find that band gap opening as measured during transport is linearly increased with respect to the I(D)/I(G) ratio but remains below 0.1 meV in magnitude for SiO(2) supported graphene. The largest transport band gap obtained in a suspended, highly functionalized (I(D)/I(G) = 4.5) graphene is about 1 meV, lower than our theoretical predictions considering the quantum interference effect between two neighboring S-regions and attributed to its population with midgap states. On the other hand, heavily functionalized BLG (I(D)/I(G) = 1.8) still retains its signature dual-gated band gap opening due to electric-field symmetry breaking. We find a notable asymmetric deflection of the charge neutrality point (CNP) under positive bias which increases the apparent on/off current ratio by 50%, suggesting that synergy between symmetry breaking, disorder, and quantum interference may allow the observation of new transistor phenomena. These important observations set definitive limits on the extent to which chemical modification can control graphene electronically. PMID- 23339829 TI - Physiologic and laboratory correlates of depression, anxiety, and poor sleep in liver cirrhosis. AB - BACKGROUND: Studies have shown psychological distress in patients with cirrhosis, yet no studies have evaluated the laboratory and physiologic correlates of psychological symptoms in cirrhosis. This study therefore measured both biochemistry data and heart rate variability (HRV) analyses, and aimed to identify the physiologic correlates of depression, anxiety, and poor sleep in cirrhosis. METHODS: A total of 125 patients with cirrhosis and 55 healthy subjects were recruited. Each subject was assessed through routine biochemistry, 5-minutes ECG monitoring, and psychological ratings of depression, anxiety, and sleep. HRV analysis were used to evaluate autonomic functions. The relationship between depression, sleep, and physiologic correlates was assessed using a multiple regression analysis and stepwise method, controlling for age, duration of illness, and severity of cirrhosis. RESULTS: Reduced vagal-related HRV was found in patients with severe liver cirrhosis. Severity of cirrhosis measured by the Child-Pugh score was not correlated with depression or anxiety, and only had a weak correlation with poor sleep. The psychological distress in cirrhosis such as depression, anxiety, and insomnia were correlated specifically to increased levels of aspartate aminotransferase (AST), increased ratios of low frequency to high frequency power, or reduced nonlinear properties of HRV (alpha1 exponent of detrended fluctuation analysis). CONCLUSIONS: Increased serum AST and abnormal autonomic nervous activities by HRV analysis were associated with psychological distress in cirrhosis. Because AST is an important mediator of inflammatory process, further research is needed to delineate the role of inflammation in the cirrhosis comorbid with depression. PMID- 23339831 TI - Role of spirometry in detection of nasal obstruction. AB - BACKGROUND: A subjective feeling of nasal airflow obstruction is a common symptom. An objective method for quantitative measurement of nasal airflow has long been desired. Rhinomanometry and acoustic rhinometry have been developed for anatomical and physiological evaluation of nasal obstruction. This study was designed to determine the usefulness of a portable spirometer in assessing upper airway obstruction. METHODS: One hundred and ninety-six patients were assessed with nasal inspiratory spirometry to determine nasal airflow. All patients also underwent paranasal sinus computed tomography to determine anatomical abnormalities. Spirometry was performed on each nostril separately. RESULTS: Sensitivity and specificity levels were high. This portable and easy to use device may be useful in respiratory assessment. Correlation between anatomical obstructions and subjects' complaints was statistically significant (p < 0.001), but no definite correlation between septal deviation severity and spirometric values was found. CONCLUSION: Portable spirometry is an objective and useful method of evaluating nasal obstruction, but needs more investigation to establish a standardised test. PMID- 23339832 TI - Illustrations of mathematical modeling in biology: epigenetics, meiosis, and an outlook. AB - In the past few years, mathematical modeling approaches in biology have begun to fulfill their promise by assisting in the dissection of complex biological systems. Here, we review two recent examples of predictive mathematical modeling in plant biology. The first involves the quantitative epigenetic silencing of the floral repressor gene FLC in Arabidopsis, mediated by a Polycomb-based system. The second involves the spatiotemporal dynamics of telomere bouquet formation in wheat-rye meiosis. Although both the biology and the modeling framework of the two systems are different, both exemplify how mathematical modeling can help to accelerate discovery of the underlying mechanisms in complex biological systems. In both cases, the models that developed were relatively minimal, including only essential features, but both nevertheless yielded fundamental insights. We also briefly review the current state of mathematical modeling in biology, difficulties inherent in its application, and its potential future development. PMID- 23339833 TI - Magnetic dynamic properties of electron-doped La(0.23)Ca(0.77)MnO3 nanoparticles. AB - Magnetic properties of basically antiferromagnetic La(0.23)Ca(0.77)MnO(3) particles with average sizes of 12 and 60 nm have been investigated in a wide range of magnetic fields and temperature. Particular attention has been paid to magnetization dynamics through measurements of the temperature dependence of ac susceptibility at various frequencies, the temperature and field dependence of thermoremanent and isothermoremanent magnetization originating from nanoparticles shells, and the time decay of the remanent magnetization. Experimental results and their analysis reveal the major role in magnetic behaviour of investigated antiferromagnetic nanoparticles played by the glassy component, associated mainly with the formation of the collective state formed by ferromagnetic clusters in frustrated coordination at the surfaces of interacting antiferromagnetic nanoparticles. Magnetic behaviour of nanoparticles has been ascribed to a core shell scenario. Magnetic transitions have been found to play an important role in determining the dynamic properties of the phase separated state of coexisting different magnetic phases. PMID- 23339834 TI - Surface-enhanced Raman scattering with Ag nanoparticles optically trapped by a photonic crystal cavity. AB - We demonstrate a reusable and reconfigurable surface enhanced Raman scattering (SERS) platform by optically trapping Ag nanoparticles with a photonic crystal cavity integrated with a microfluidic chip. High-performance SERS is performed in a very reproducible manner, owing to the fact that Ag aggregates are produced by optical trapping in a controllable process that is monitored in real-time by the cavity resonance shift that occurs with the trapping of each additional nanoparticle. PMID- 23339835 TI - Simple method of glenoid bone loss calculation using ipsilateral magnetic resonance imaging. AB - BACKGROUND: Current methods for estimating glenoid bone loss in patients with chronic shoulder instability include computed tomography imaging with 3 dimensional reconstruction, specialized computer software, and imaging of the contralateral shoulder. An ideal method of glenoid measurement would require only magnetic resonance imaging (MRI) of the injured shoulder. PURPOSE: To determine whether MRI measurement of glenoid height, as well as sex, could be used to estimate glenoid width in healthy subjects with no history of shoulder instability. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Bilateral shoulder MRIs were obtained in a healthy cohort of young athletes as part of the baseline assessment in a prospective cohort study. A musculoskeletal radiologist measured glenoid height and width using the sagittal MRI cuts. Univariate and multivariate regression analyses were performed to determine whether demographic and MRI measurements of the glenoid could be used to estimate glenoid width. RESULTS: Of the 1264 shoulder MRIs evaluated, the mean glenoid width was 26.67 mm (+/-2.49 mm), and the mean glenoid height was 42.15 mm (+/ 3.00 mm). There were significant differences between the 129 female glenoids and the 1035 male glenoids for both width (23.1 mm, 27.1 mm, respectively, P < .0001) and height (37.9 mm, 42.7 mm, respectively, P < .0001); however, the relationship between glenoid height and width was similar for both men and women. The glenoid width was found to correlate with the height measurement (r = 0.56) for the entire cohort. Based on the results of linear regression analysis, controlling for the influence of sex, a formula was created that represents the relationship between these variables for male subjects: Glenoid Width = (1/3 Height) + 15 mm. Female patients are estimated with a formula that represents the same slope but a different intercept: W = 1/3 H + 13 mm. CONCLUSION: Significant differences in glenoid height and width were found by sex; however, the relationship between height and width was similar. These variables are correlated, and the resultant formula can be used to estimate the expected glenoid width in a patient with bone loss. This formula allows for easy calculation of the amount of glenoid bone loss with only a ruler and an MRI of the injured shoulder. PMID- 23339836 TI - Differences in knee joint stabilization between children and adults and between the sexes. AB - BACKGROUND: Differences in knee joint stabilization between children and adults and between the sexes are not fully understood. PURPOSE: To compare the knee laxity and the dynamic tibial translation between (1) children and adults, (2) girls and boys, and (3) women and men. STUDY DESIGN: Controlled laboratory study. METHODS: Sixty-seven children (aged 8-13 years) and 63 adults (aged 18-30 years) without previous knee injuries participated. Sagittal tibial translation was measured during the instrumented Lachman test at 90 N and 134 N (knee laxity) and during gait (dynamic translation). Tibial translation was recorded with an electrogoniometer. RESULTS: Knee laxity was greater in children than in adults (Lachman test at 90 N: 9.1 +/- 2.9 vs 7.3 +/- 2.7, respectively; P < .001). In contrast, dynamic tibial translation during gait did not differ between children and adults. Girls and boys did not differ in knee laxity or maximum anterior tibial translation during gait, and men and women did not differ in knee laxity. Women had greater dynamic tibial translation during gait than men (7.8 +/- 2.7 vs 5.7 +/- 3.0, respectively; P = .004). CONCLUSION: Children had greater knee laxity than adults, whereas the dynamic tibial translation did not differ. In adults, knee laxity did not differ between the sexes, but dynamic tibial translation was greater in women. CLINICAL RELEVANCE: Children and men had less dynamic tibial translation during gait in proportion to their maximum knee laxity. The observed less dynamic tibial translation in children and adult men might be related to their reduced risk of sustaining an anterior cruciate ligament injury. PMID- 23339837 TI - Results of arthroscopic repair of partial- or full-thickness longitudinal medial meniscal tears by single or double vertical sutures using the inside-out technique. AB - BACKGROUND: Although numerous studies have assessed arthroscopic repair of meniscal tears, no study has described the repair of partial- or full-thickness longitudinal medial meniscal tears using single or double vertical sutures. PURPOSE: To present the intermediate-term results of medial meniscal tears repaired with single or double vertical sutures. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The authors evaluated the results of 112 longitudinal medial meniscal tears treated with inside-out single or double vertical sutures, with or without anterior cruciate ligament (ACL) reconstruction, based on the clinical resolution of symptoms, the Lysholm knee scoring scale, and the Tegner activity scale. Re-examination was also performed by magnetic resonance imaging after the repair. The length of the tears was evaluated arthroscopically. Eighty five tears of 112 were >2 cm in length, and 27 were tears <=2 cm. Eighty-nine (79.4%) of the 112 repairs were performed in conjunction with ACL reconstructions, and the remaining 23 (20.6%) repairs were performed in ACL intact knees. The tear type of the menisci in our study was full thickness in 66 (58.9%) cases and partial thickness in 46 (41.1%) cases. Double vertical sutures were used for full-thickness tears, and single vertical sutures were used for partial-thickness tears. RESULTS: The cases were evaluated after a mean follow-up duration of 49.3 months (range, 12-88 months). Clinical and radiological examination results determined that 99 (88.4%) meniscal repairs had healed, and the remaining 13 cases (10.6%) were considered to be failures. The healing rate of the full-thickness group was 80.3%, while in the partial-thickness group, the rate was 100%. The mean Lysholm score improved significantly from a preoperative value of 63.8 to a postoperative value of 89.5 (P < .001). The mean Tegner activity score was 3.3 preoperatively and 6.7 postoperatively (P < .001). Logistic regression analysis found that concurrent ACL reconstruction, tear length, and smoking as factors had a significant effect on meniscal healing. CONCLUSION: Single or double vertical sutures using the inside-out technique provide a high rate of healing in longitudinal medial meniscal tears. PMID- 23339838 TI - Predictors of recurrent instability after acute patellofemoral dislocation in pediatric and adolescent patients. AB - BACKGROUND: Patellofemoral instability is common in the pediatric and adolescent population, yet prognosis after the first dislocation has been difficult to determine. PURPOSE: To describe the demographics of pediatric and adolescent patients with a first-time patellofemoral dislocation and to determine predictors of recurrent instability. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A search of the Mayo Medical Index database between 1998 to 2010 was performed, and 2039 patients were identified. Inclusion criteria were (1) age 18 years or younger, (2) no history of patellofemoral subluxation/dislocation of the affected knee, (3) radiographs within 4 weeks of the initial instability episode, and (4) a dislocated patella requiring reduction or convincing history/findings suggestive of acute patellar dislocation (effusion/hemarthrosis, tenderness along medial parapatellar structures, and apprehension with lateral patellar translation). Radiographs were evaluated for trochlear dysplasia (Dejour classification) and patella alta (Caton-Deschamps and Insall-Salvati indices). Skeletal maturity was graded based on the distal femoral and proximal tibial physes (open, closing, or closed). RESULTS: A total of 222 knees (120 male [54.1%] and 102 female [45.9%]) in 210 patients with an average age of 14.9 years (range, 9-18 years), met the inclusion criteria. Twenty-four patients (10.8%) underwent early surgery. All others were initially treated nonoperatively. Of the 198 patients in this group, 76 (38.4%) had recurrent instability, and 39 (51.3%) of these required surgical treatment. Recurrent instability was associated with trochlear dysplasia (P < .01). Patients with both immature physes and trochlear dysplasia had a recurrence rate of 69% (33/48), with a hazard ratio of 3.3. Age, sex, body mass index, and patella alta were not statistically associated with recurrent instability. CONCLUSION: Nonoperative treatment for first-time patellofemoral dislocation resulted in a 62% success rate. However, skeletally immature patients with trochlear dysplasia had only a 31% success rate with nonoperative management. Nearly half of patients with recurrent instability required surgical intervention to gain stability. PMID- 23339839 TI - Transcatheter closure of post-myocardial infarction ventricular septal rupture. AB - BACKGROUND: Ventricular septal rupture (VSR) after acute myocardial infarction (AMI) is a potentially lethal mechanical complication of acute coronary syndromes. Given high surgical mortality, transcatheter closure has emerged as a potential strategy in selected cases. We report our single-center experience with double-umbrella device percutaneous closure of post-AMI VSR. METHODS AND RESULTS: In this single-center, retrospective, cohort study, patients who underwent transcatheter closure of post-AMI VSR between 1988 and 2008 at Boston Children's Hospital were included. Data were analysed according to whether the patients underwent direct percutaneous VSR closure or closure of a residual VSR after a previous surgical approach. Primary outcome was mortality rate at 30 days. Clinical predictors of primary outcome were investigated using univariate logistic regression. Thirty patients were included in the study (mean age, 67+/-8 years). A total of 40 closure devices were implanted. Major periprocedural complications occurred in 4 (13%) patients. Cardiogenic shock, increasing pulmonary/systemic flow ratio, and the use of the new generation (6-arm) STARFlex device all were associated with higher risk of mortality. The Model for End-Stage Liver Disease Excluding international normalized ratio (MELD-XI) score at the time of VSR closure seemed to be most strongly associated with death (odds ratio, 1.6; confidence interval, 1.1-2.2; P<0.001). CONCLUSIONS: Transcatheter closure of post-AMI VSR using CardioSEAL or STARFlex devices is feasible and effective. The MELD-XI score, a marker of multiorgan dysfunction, is a promising risk stratifier in this population of patients. Early closure of post-AMI VSR is advisable before establishment of multiorgan failure. PMID- 23339840 TI - Preinfarction angina reduces infarct size in ST-elevation myocardial infarction treated with percutaneous coronary intervention. AB - BACKGROUND: Preinfarction angina may act as a clinical surrogate of ischemic preconditioning that may reduce infarct size and improve mortality in the setting of thrombolytic therapy for ST-elevation myocardial infarction. However, the benefits of preinfarction angina in the setting of primary percutaneous coronary intervention with stenting is inconclusive because of the greater achievement of infarct artery patency and speed of reperfusion. METHODS AND RESULTS: To identify a homogeneous population, we performed a retrospective analysis of 1031 patients admitted with a first ST-elevation myocardial infarction with ischemic times between 1 and 6 hours who received primary percutaneous coronary intervention. We identified 245 patients who had occluded arteries on presentation, of which 79 patients had documented preinfarction angina defined as chest pain within 24 hours of infarction. Infarct size was measured as the peak creatine kinase level, a metric supported in a subgroup by late enhancement on cardiac magnetic resonance imaging. Patients with preinfarction angina (n=79) had a 50% reduction in infarct size compared with those patients without preinfarction angina (n=166) by both peak creatine kinase (1094+/-75 IU/L versus 2270+/-102 IU/L; P<0.0001) and creatine kinase area under curve (18 420+/-18 941 versus 36 810+/-21 741 IU/h per liter; P<0.0001) despite having identical ischemic times (185+/-8 minutes versus 181+/-5 minutes; P=0.67) and angiographic area at risk (24.1+/-1.2% versus 25.3+/-0.9%; P=0.43). There was an absolute 4% improvement in left ventricular ejection fraction before discharge in those patients with preinfarction angina (P<0.02). CONCLUSIONS: The occurrence of preinfarction angina is associated with significant myocardial protection in the setting of primary percutaneous coronary intervention with stenting during ST-elevation myocardial infarction. Because preinfarction angina is relatively common, it is important that these patients be identified in clinical trials investigating therapies designed to reduce reperfusion injury and infarct size. PMID- 23339841 TI - Efficacy and safety of postdilatation to reduce paravalvular regurgitation during balloon-expandable transcatheter aortic valve replacement. AB - BACKGROUND: Paravalvular regurgitation (PVR) is common after transcatheter aortic valve replacement (TAVR) and may be associated with adverse outcomes. Postdilatation (PD) has been proposed to treat PVR without being formally studied. We performed a study to evaluate the safety and efficacy of PD after balloon expandable TAVR. METHODS AND RESULTS: Consecutive cases of TAVR were reviewed for clinical outcomes. Procedural transesophageal echocardiography imaging was reviewed for a subgroup of consecutive patients. PVR areas seen on a short-axis view were measured immediately after deployment, after PD, and at the completion of the study. Stent dimensions measured using angiography and the Paieon's C-THV system pre- and post-PD were compared. Between May 2007 and November 2011, 259 patients underwent TAVR at our institution. PD was performed in 106 patients (41%). These patients had larger annulus, lower cover-index; more often had transfemoral access and implantation of a 26 mm valve. There was a nonsignificant greater rate of cerebrovascular events in PD patients. There was no significant difference in major aortic injury and permanent pacemaker implantation rates between groups. TTE studies were reviewed in 58 patients (35 with PD and 23 without PD). PD patients had larger PVR areas immediately after deployment (40.3+/-17.1 versus 15.4+/-14.2 mm(2); P<0.0001). There was significant reduction in PVR area attributable to PD (21.7+/-9.3 mm(2); P<0.0001). Spontaneous regression of PVR was seen in both groups. PD increased stent dimensions. CONCLUSIONS: This study demonstrates the efficacy of PD at reducing PVR in patients with greater than mild PVR after balloon-expandable TAVR. PMID- 23339842 TI - A mechanism to pin skyrmions in chiral magnets. AB - We propose a mechanism to pin skyrmions in chiral magnetic thin films by introducing local maxima of magnetic exchange strength as pinning centers. The local maxima can be realized by engineering the local density of itinerant electrons. The stationary properties and the dynamical pinning and depinning processes of an isolated skyrmion around a pinning center are studied. We carry out numerical simulations of the Landau-Lifshitz-Gilbert (LLG) equation and find a way to control the position of an isolated skyrmion in a pinning center lattice using electric current pulses. The results are verified by a Thiele equation analysis. We also find that the critical current to depin a skyrmion, which is estimated to have order of magnitude 10(7)-10(8) A m(-2), has linear dependence on the pinning strength. PMID- 23339843 TI - Screening medical patients for distress and depression: does measurement in the clinic prior to the consultation overestimate distress measured at home? AB - BACKGROUND: Medical patients are often screened for distress in the clinic using a questionnaire such as the Hospital Anxiety and Depression Scale (HADS) while awaiting their consultation. However, might the context of the clinic artificially inflate the distress score ? To address this question we aimed to determine whether those who scored high on the HADS in the clinic remained high scorers when reassessed later at home. METHOD: We analysed data collected by a distress and depression screening service for cancer out-patients. All patients had completed the HADS in the clinic (on computer or on paper) prior to their consultation. For a period, patients with a high score (total of > or = 15) also completed the HADS again at home (over the telephone) 1 week later. We used these data to determine what proportion remained high scorers and the mean change in their scores. We estimated the effect of ' regression to the mean' on the observed change. RESULTS: Of the 218 high scorers in the clinic, most [158 (72.5 %), 95% confidence interval (CI) 66.6-78.4] scored high at reassessment. The mean fall in the HADS total score was 1.74 (95% CI 1.09-2.39), much of which could be attributed to the estimated change over time (regression to the mean) rather than the context. CONCLUSIONS: Pre-consultation distress screening in clinic is widely used. Reassuringly, it only modestly overestimates distress measured later at home and consequently would result in a small proportion of unnecessary further assessments. We conclude it is a reasonable and convenient strategy. PMID- 23339844 TI - [Brain metastasis: clinical and cognitive assessments]. AB - The incidence of brain metastases (BM) has increased due to the improvement of therapeutics and diagnostic imaging, but also to an aging population. The initial symptoms may develop suddenly or insidiously over weeks or months. The symptoms depend on the location of the BM and related complications (hydrocephalus, tumor hemorrhage, cerebral herniation). Headaches are the most frequent symptoms (50%); they are related to intracranial hypertension. Cognitive deficits are commonly described at diagnosis (67 to 90.5%). Cognitive assessment is essential because of its impact on patients' prognosis and quality of life. Nevertheless, these deficits remain underestimated. The Karnofsky Perfomance Scale and the Mini Mental State Examination (MMSE) seem inadequate. A short battery was proposed and internationally validated, assessing seven domains: attention (Digit Symbol Test WAIS-III), episodic memory (Hopkins Verbal Learning Test [HVLT]), working memory (Digit Span Test WAIS-III), verbal fluency (Controlled Oral Word Association Test [COWA]), fine motor dexterity (Grooved Pegboard Test), information processing speed (Trail Making Test [TMT] A) and executive functions (TMT B). This battery is relevant, feasible and associated with a good compliance. These cognitive tests are currently recommended to assess cognitive functions in patients with BM. PMID- 23339846 TI - Baylisascariosis--infections of animals and humans with 'unusual' roundworms. AB - The nematode genus Baylisascaris (order Ascaridida, superfamily Ascaridoidea) contains nine relatively host-specific, parasite species of carnivores, omnivores, herbivores, carnivorous marsupials or rodents. They have a facultative heteroxenous life cycle, at least under experimental conditions. Eggs passed in faeces embryonate in the environment and the second-stage larva infective for both definitive and intermediate hosts develops. In intermediate hosts larvae migrate extensively through tissues, where they grow and moult to the third stage, causing extensive damage. All Baylisascaris spp. are considered a potential cause of visceral, ocular and/or neural larval migrans in mammals including humans and in birds. This paper summarises our current knowledge on the prevalence, biology, pathogenicity and zoonotic significance of three Baylisascaris species: B. transfuga, B. schroederi and B. procyonis which have as definitive hosts bears, giant pandas and raccoons (occasionally dogs), respectively. PMID- 23339845 TI - Lymphotoxin network pathways shape the tumor microenvironment. AB - Accumulating evidence indicates that Lymphotoxin (LT)-beta related cytokines directly contribute to the phenotype of cancer cells and alter the tumor microenvironment. Lymphotoxins are part of a cytokine network well known in controlling the development and homeostasis of secondary lymphoid organs. In the adult, the LT network takes on the responsibility of generating inflammatory microenvironments that control innate and adaptive immune responses involved in host defense. This review provides a perspective of the emerging evidence implicating the LT Network in the development and progression of various cancers including lymphoma. Redirecting the LT Network to alter tumor microenvironments may provide a specific approach to therapeutically target tumor-permissive microenvironments and cancer progression. PMID- 23339847 TI - Latitudinal variability in the seroprevalence of antibodies against Toxoplasma gondii in non-migrant and Arctic migratory geese. AB - Toxoplasma gondii is an intracellular coccidian parasite found worldwide and is known to infect virtually all warm-blooded animals. It requires a cat (family Felidae) to complete its full life cycle. Despite the absence of wild felids on the Arctic archipelago of Svalbard, T. gondii has been found in resident predators such as the arctic fox and polar bear. It has therefore been suggested that T. gondii may enter this ecosystem via migratory birds. The objective of this study was to identify locations where goose populations may become infected with T. gondii, and to investigate the dynamics of T. gondii specific antibodies. Single blood samples of both adults and juveniles were collected from selected goose species (Anser anser, A. brachyrhynchus, Branta canadensis, B. leucopsis) at Arctic brood-rearing areas in Russia and on Svalbard, and temperate wintering grounds in the Netherlands and Denmark (migratory populations) as well as temperate brood-rearing grounds (the Netherlands, non-migratory populations). A modified agglutination test was used on serum, for detection of antibodies against T. gondii. Occasional repeated annual sampling of individual adults was performed to determine the antibody dynamics. Adults were found seropositive at all locations (Arctic and temperate, brood-rearing and wintering grounds) with low seroprevalence in brood-rearing birds on temperate grounds. As no juvenile geese were found seropositive at any brood-rearing location, but nine month old geese were found seropositive during spring migration we conclude that geese, irrespective of species and migration, encounter T. gondii infection in wintering areas. In re-sampled birds on Svalbard significant seroreversion was observed, with 42% of seropositive adults showing no detectable antibodies after 12 months, while the proportion of seroconversion was only 3%. Modelled variation of seroprevalence with field data on antibody longevity and parasite transmission suggests seroprevalence of a population within a range of 5.2-19.9%, in line with measured values. The high occurrence of seroreversion compared to the low occurrence of seroconversion hampers analysis of species- or site-specific patterns, but explains the absence of an increase in seroprevalence with age and the observed variation in antibody titre. These findings imply that even though infection rate is low, adults introduce T. gondii to the high Arctic ecosystem following infection in temperate regions. PMID- 23339848 TI - Gadolinium-153 as a brachytherapy isotope. AB - The purpose of this work was to present the fundamental dosimetric characteristics of a hypothetical (153)Gd brachytherapy source using the AAPM TG 43U1 dose-calculation formalism. Gadolinium-153 is an intermediate-energy isotope that emits 40-100 keV photons with a half-life of 242 days. The rationale for considering (153)Gd as a brachytherapy source is for its potential of patient specific shielding and to enable reduced personnel shielding requirements relative to (192)Ir, and as an isotope for interstitial rotating shield brachytherapy (I-RSBT). A hypothetical (153)Gd brachytherapy source with an active core of 0.84 mm diameter, 10 mm length and specific activity of 5.55 TBq of (153)Gd per gram of Gd was simulated with Geant4. The encapsulation material was stainless steel with a thickness of 0.08 mm. The radial dose function, anisotropy function and photon spectrum in water were calculated for the (153)Gd source. The simulated (153)Gd source had an activity of 242 GBq and a dose rate in water 1 cm off axis of 13.12 Gy h(-1), indicating that it would be suitable as a low-dose-rate or pulsed-dose-rate brachytherapy source. The beta particles emitted have low enough energies to be absorbed in the source encapsulation. Gadolinium-153 has an increasing radial dose function due to multiple scatter of low-energy photons. Scattered photon dose takes over with distance from the source and contributes to the majority of the absorbed dose. The anisotropy function of the (153)Gd source decreases at low polar angles, as a result of the long active core. The source is less anisotropic at polar angles away from the longitudinal axes. The anisotropy function increases with increasing distance. The (153)Gd source considered would be suitable as an intermediate-energy low dose-rate or pulsed-dose-rate brachytherapy source. The source could provide a means for I-RSBT delivery and enable brachytherapy treatments with patient specific shielding and reduced personnel shielding requirements relative to (192)Ir. PMID- 23339849 TI - Radicicol, a Hsp90 inhibitor, inhibits intestinal inflammation and leakage in abdominal sepsis. PMID- 23339850 TI - Redox-regulating sirtuins in aging, caloric restriction, and exercise. AB - The consequence of decreased nicotinamide adenine dinucleotide (NAD(+)) levels as a result of oxidative challenge is altered activity of sirtuins, which, in turn, brings about a wide range of modifications in mammalian cellular metabolism. Sirtuins, especially SIRT1, deacetylate important transcription factors such as p53, forkhead homeobox type O proteins, nuclear factor kappaB, or peroxisome proliferator-activated receptor gamma coactivator 1alpha (which controls the transcription of pro- and antioxidant enzymes, by which the cellular redox state is affected). The role of SIRT1 in DNA repair is enigmatic, because it activates Ku70 to cope with double-strand breaks, but deacetylation of apurinic/apyrimidinic endonuclease 1 and probably of 8-oxoguanine-DNA glycosylase 1 decreases the activity of these DNA repair enzymes. The protein-stabilizing effects of the NAD+-dependent lysine deacetylases are readily related to housekeeping and redox regulation. The role of sirtuins in caloric restriction (CR)-related longevity in yeast is currently under debate. However, in mammals, it seems certain that sirtuins are involved in many cellular processes that mediate longevity and disease prevention via the effects of CR through the vascular, neuronal, and muscular systems. Regular physical exercise-mediated health promotion also involves sirtuin-regulated pathways including the antioxidant-, macromolecular damage repair-, energy-, mitochondrial function-, and neuronal plasticity-associated pathways. This review critically evaluates these findings and points out the age-associated role of sirtuins. PMID- 23339851 TI - Action, prediction, and temporal awareness. AB - The brain needs to track changes in the relation between action and effect. In two experiments, participants made voluntary keypress actions. In an adaptation phase, these actions were followed after a fixed interval by a tone. During a subsequent test phase, the duration of the interval was unexpectedly changed. We used time perception as an implicit marker of the experience of participants' control over the effect, and confirmed a temporal binding between actions and effects. On test trials, participants perceived tones to occur as shifted towards their time of occurrence in the preceding adaptation phase. Therefore, the perceived time of a tone was partly based on learning of an internal prediction, rather than on the time of actual sensory input. This predictive model is rapidly updated over a few trials (Experiment 1), and requires attention to the tones (Experiment 2). The brain learns action-effect relations. This predictive learning influences the perception of effects, and underlies some temporal illusions associated with action. PMID- 23339852 TI - Corticosteroids for neurocysticercosis: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Neurocysticercosis is an infection of the central nervous system by the larval stage of Taenia solium. It is a major cause of epileptic seizures in low- and middle-income countries. Corticosteroids are frequently used to reduce inflammation and perilesional edema. We aimed to evaluate their efficacy for reducing the rate of seizures and lesion persistence in imaging studies. METHODS: We searched randomized controlled trials in Medline, Central, EMBASE, LILACS, and the gray literature without language restrictions. We assessed eligibility, extracted data, and assessed the risk of bias in the included studies. The main outcomes included seizure recurrence and lesion persistence on imaging studies at 6-12 months of follow-up. Risk ratios (RR) were used for evaluating the main outcomes. RESULTS: Thirteen studies involving 1373 participants were included. The quality of the evidence was deemed low to very low. Corticosteroids alone versus placebo/no drug (five trials) reduced the rate of seizure recurrence at 6 12 months (RR 0.46, 95% confidence interval (CI) 0.27-0.77; 426 participants) and the persistence of lesions in imaging studies (RR 0.63, 95% CI 0.43-0.92; 417 participants). No differences were noted in other comparisons, including the use of corticosteroids and albendazole combined. Corticosteroids plus albendazole increased the risk of abdominal pain, rash, and headaches (odds ratio 8.73, 95% CI 2.09-36.5; 116 participants, one trial). CONCLUSIONS: Although the evidence suggest corticosteroids can reduce the rate of seizure recurrence and speed up resolution of lesions at 6-12 months of follow-up, there remains uncertainty on the effect estimate due to a high risk of methodological and publication bias. More adequately performed randomized trials that evaluate the use of anthelmintics, corticosteroids, and both combined against placebo are needed. PMID- 23339853 TI - Antivenom therapy of carpet viper (Echis ocellatus) envenoming: effectiveness and strategies for delivery in West Africa. AB - In West Africa, response to specific, geographically appropriate, antivenom is often dramatic following carpet viper (Echis ocellatus) envenoming with rapid restoration of blood coagulability and resolution of spontaneous haemorrhage. Envenoming from Australasian snakes causing similar coagulopathies may respond less dramatically and the effectiveness of antivenom is being questioned. Here we have reviewed and re-analysed all published preclinical and clinical studies on envenoming and antivenom therapy conducted in West Africa to determine the effectiveness of antivenom. 22 studies provided relevant information: 12 observational studies, 4 RCTs and 6 preclinical studies. Four comparative studies confirmed statistically significant protection against mortality ranging from 57 to 87% using specific antivenoms compared to non-specific or no antivenoms. Meta analysis estimated combined Odds Ratio (95% CI) of 0.25 (0.14-0.45) of dying among those treated with specific antivenom or 75% (95% CI: 55-86%) protection against death. Mortality more than doubled during times when stocks of reliable antivenoms ran out, with Relative Risk (95% CI)] of 2.33 (1.26-4.06). Serum kinetics of venom antigen/antivenom levels also confirmed that decline of venom antigen levels coincided with resolution of coagulopathy while decline of antivenom levels was associated with venom antigen reappearance and recurrence of coagulopathy. Preclinical and antivenomics analysis confirmed efficacy of regionally appropriate antivenoms against E. ocellatus and related species' venoms in Sub-Saharan Africa but not against Asian Echis carinatus venom. Antivenoms raised against E. carinatus were ineffective in human studies. In West Africa, specific antivenom is effective in managing carpet viper envenoming. A centralized hub-and-spoke strategy is suggested for broadening antivenom access to endemic rural areas together with instituting quality assurance, standardization and manpower training. Benefits, risks, cost-effectiveness and feasibility of the approach should be formally assessed. PMID- 23339854 TI - Comparative analysis of proteases in the injected and dissected venom of cone snail species. AB - The venom of cone snails has been the subject of intense studies because it contains small neuroactive peptides of therapeutic value. However, much less is known about their larger proteins counterparts and their role in prey envenomation. Here, we analyzed the proteolytic enzymes in the injected venom of Conus purpurascens and Conus ermineus (piscivorous), and the dissected venom of C. purpurascens, Conus marmoreus (molluscivorous) and Conus virgo (vermivorous). Zymograms show that all venom samples displayed proteolytic activity on gelatin. However, the electrophoresis patterns and sizes of the proteases varied considerably among these four species. The protease distribution also varied dramatically between the injected and dissected venom of C. purpurascens. Protease inhibitors demonstrated that serine and metalloproteases are responsible for the gelatinolytic activity. We found fibrinogenolytic activity in the injected venom of C. ermineus suggesting that this venom might have effects on the hemostatic system of the prey. Remarkable differences in protein and protease expression were found in different sections of the venom duct, indicating that these components are related to the storage granules and that they participate in venom biosynthesis. Consequently, different conoproteases play major roles in venom processing and prey envenomation. PMID- 23339855 TI - Medical aspects of bio-terrorism. AB - INTRODUCTION: Bioterrorism is a terrorist action involving the intentional release or dissemination of a biological warfare agent (BWA), which includes some bacteria, viruses, rickettsiae, fungi or biological toxins. BWA is a naturally occurring or human-modified form that may kill or incapacitate humans, animals or plants as an act of war or terrorism. BWA is a weapon of choice for mass destruction and terrorism, because of the incubation period, less effective amount than chemical warfare agents, easily distribution, odorless, colorless, difficult to detect, no need of specialized equipment for production and naturally distribution which can easily be obtained. BWA may be disseminating as an aerosol, spray, explosive device, and by food or water. CLASSIFICATION: Based on the risk for human health, BWAs have been prioritized into three categories of A, B and C. Category A includes microorganisms or toxins that easily spread, leading to intoxication with high death rates such as Anthrax, Botulism, Plague, Smallpox, Tularemia and Viral hemorrhagic fevers. Category B has lower toxicity with wider range, including Staphylococcal Entrotoxin type B (SEB), Epsilon toxin of Clostridium perfringens, Ricin, Saxotoxins, Abrin and Trichothecene mycotoxins. The C category includes emerging pathogens that could also be engineered for mass spread such as Hanta viruses, multidrug-resistant tuberculosis, Nipah virus, the tick-borne encephalitis viruses, hemorrhagic fever viruses and yellow fever. CLINICAL MANIFESTATIONS OF BIOTOXINS IN HUMAN: Clinical features and severity of intoxication depend on the agent and exposed dose, route of entry, individual variation and environmental factors. Onset of symptoms varies from 2-24 h in Ricin to 24-96 h in Botulism. Clinical manifestations also vary from irritation of the eyes, skin and mucus membranes in T2 toxin to an acute flaccid paralysis of bilateral cranial nerve impairment of descending manner in botulism. Most of the pyrogenic toxins such as SEB produce the same signs and symptoms as toxic shock syndrome including a rapid drop in blood pressure, elevated temperature, and multiple organ failure. MANAGEMENT: There is no specific antidote or effective treatment for most of the biotoxins. The clinical management is thus more supportive and symptomatic. Fortunately vaccines are now available for most of BWA. Therefore, immunization of personnel at risk of exposure is recommended. CONCLUSION: Biotoxins are very wide and bioterrorism is a heath and security threat that may induce national and international problems. Therefore, the security authorities, health professional and even public should be aware of bioterrorism. PMID- 23339856 TI - Body satisfaction is associated with Transtheoretical Model constructs for physical activity behavior change. AB - Despite advancements in health behavior theory and practice, less than half of the United States population meets physical activity recommendations. Two cross sectional studies (n=432; n=1455) were conducted to explore associations between body satisfaction and Transtheoretical Model (TTM) constructs proposed to explain the physical activity behavior change process. A series of regression analyses were conducted, controlling for demographic and TTM variables, as appropriate. Results indicate that body satisfaction significantly explains 2-8% of variance in the TTM constructs responsible for promoting stage movement. Furthermore, body satisfaction was significantly associated with stages of change representing short (>6 months) and long-term (>5 years) maintenance of physical activity. Future research should continue to examine these construct relationships using more rigorous research designs, with the ultimate goal of implementing body satisfaction components alongside traditionally effective TTM interventions to improve physical activity maintenance. PMID- 23339857 TI - Reflection impulsivity and response inhibition in first-episode psychosis: relationship to cannabis use. AB - BACKGROUND: People with psychosis demonstrate impaired response inhibition on the Stop Signal Task (SST). It is less clear if this impairment extends to reflection impulsivity, a form of impulsivity that has been linked to substance use in non psychotic samples. METHOD: We compared 49 patients with first-episode psychosis (FEP) and 30 healthy control participants on two forms of impulsivity measured using the Information Sampling Test (IST) and the SST, along with clinical and IQ assessments. We also compared those patients who used cannabis with those who had either given up or never used. RESULTS: Patients with FEP had significantly greater impairment in response inhibition but not in reflection impulsivity compared with healthy controls. By contrast, patients who reported current cannabis use demonstrated greater reflection impulsivity than those that had either given up or never used, whereas there were no differences in response inhibition. CONCLUSIONS: These data suggest that abnormal reflection impulsivity is associated with substance use in psychosis but not psychosis itself ; the opposite relationship may hold for response inhibition. PMID- 23339858 TI - Research on shaky ground. PMID- 23339859 TI - Rational design of a secreted enzymatically inactive mutant of extracellular superoxide dismutase. AB - Extracellular superoxide dismutase (SOD3) is a secreted enzyme that regulates levels of extracellular superoxide and protects the extracellular matrix from degradation by reactive species. The SOD3 protein contains a heparin-binding domain and resides in a microenvironment rich in other heparin-bound growth factors, raising the possibility that SOD3 may have some biological role independent of its catalytic activity. To begin to address this, we designed and created enzymatically inactive mutant constructs targeting either the copper coordinating (i.e. H96 and H98) or superoxide channeling (i.e. N180 and R186) amino acid residues of SOD3. All constructs expressed equal quantities of immature intracellular SOD proteins, but only the N180A, R186A, and combination N180A/R186A mutants produced fully processed and secreted extracellular protein. Furthermore, while SOD activity was significantly inhibited in the single N180A and R186A mutants, the activity was completely abrogated in the N180A/R186A double mutant. Overall, the use of this novel tool may have broad reaching impacts into various fields of biology and medicine, and will aid in the delineation of cellular processes that are regulated by solely the SOD3 protein, its reactive oxygen species substrates and products, or the combination of both. PMID- 23339860 TI - Clonidine pre-treatment prevents hemorrhagic shock-induced endotoxemia and oxidative stress in the gut, liver, and lungs of the rat. AB - OBJECTIVES: To study the effect of clonidine pre-treatment on hemorrhagic shock (H/S)-induced endotoxemia and oxidative stress (OS) in three vital organs of the rat. METHODS: The study protocol consisted of two arms: one for the measurement of organic hydroperoxide (LOOH) and superoxide radical (O(2)(-.)) production in the gut, liver, and lungs (n = 32 rats) and one for the measurement of endotoxin in portal and systemic circulation (n = 32 rats). Four animal groups (sham, clonidine, H/S, and clonidine-H/S group) were used in each arm. Three hours after H/S and concominant blood resuscitation, tissues were collected for LOOHs and O(2)(-.) measurement and blood samples were obtained for endotoxin determination. RESULTS: Clonidine pre-treatment prior to H/S resulted in a significant reduction of LOOHs and O(2)(-.) production in all vital organs (P < 0.05-0.001), while additionally, clonidine reduced H/S-induced endotoxemia in portal (P < 0.05) and systemic circulation as well (P < 0.01). DISCUSSION: Clonidine pre-treatment prevents endotoxemia and OS in the gut, liver, and lungs of rats subjected to severe H/S. The improved intestinal barrier function probably stems from the antioxidant effect of clonidine on the intestinal epithelium, whereas the reduced endotoxemia may contribute to a decreased OS observed in the liver and lungs. PMID- 23339861 TI - Computation of the bond dissociation enthalpies and free energies of hydroxylic antioxidants using the ab initio Hartree-Fock method. AB - INTRODUCTION: A new method for calculating theoretical bond dissociation enthalpy (BDE) and bond dissociation free energy (BDFE) of hydroxylic antioxidants is forwarded. BDE and BDFE may be understood as activation energies accompanying the formation of transition states, which may undergo downhill homolytic dissociation. The new method does not involve the complete fission of O-H bonds. METHOD: Theoretical gas phase BDE values were calculated with the ab initio unrestricted Hartree-Fock (UHF) method, as changes in enthalpy between ground singlet states (GS) and triplet dissociative states (DS). Similarly, gas phase BDFEs were estimated from the corresponding changes in Gibbs free energy. The results were then compared with reliable experimental reports. RESULTS: The proposed theoretical approach of BDE and BDFE determination was tested using 10 simple phenols, 5 flavonoids, and l-ascorbic acid derivatives. The agreement between our calculated gas phase results and the adopted experimental values were generally within 0.5 kcal mol(-1), with a very few exceptions. DISCUSSION: Generally, steric interactions as well as intramolecular hydrogen bonding involving the dissociating OH group should be minimized in the GS. The DS are both electronically and vibrationally exited transition states. They have one unpaired electron on the carbon atom, which bears the homolytically dissociating OH group and are second order saddle points with a fixed 20 minutes has been considered futile after pediatric in-hospital cardiac arrests. This concept has recently been questioned, although the effect of CPR duration on outcomes has not recently been described. Our objective was to determine the relationship between CPR duration and outcomes after pediatric in-hospital cardiac arrests. METHODS AND RESULTS: We examined the effect of CPR duration for pediatric in hospital cardiac arrests from the Get With The Guidelines-Resuscitation prospective, multicenter registry of in-hospital cardiac arrests. We included 3419 children from 328 U.S. and Canadian Get With The Guidelines-Resuscitation sites with an in-hospital cardiac arrest between January 2000 and December 2009. Patients were stratified into 5 patient illness categories: surgical cardiac, medical cardiac, general medical, general surgical, and trauma. Survival to discharge was 27.9%, but only 19.0% of all cardiac arrest patients had favorable neurological outcomes. Between 1 and 15 minutes of CPR, survival decreased linearly by 2.1% per minute, and rates of favorable neurological outcome decreased by 1.2% per minute. Adjusted probability of survival was 41% for CPR duration of 1 to 15 minutes and 12% for >35 minutes. Among survivors, favorable neurological outcome occurred in 70% undergoing <15 minutes of CPR and 60% undergoing CPR >35 minutes. Compared with general medical patients, surgical cardiac patients had the highest adjusted odds ratios for survival and favorable neurological outcomes, 2.5 (95% confidence interval, 1.8-3.4) and 2.7 (95% confidence interval, 2.0-3.9), respectively. CONCLUSIONS: CPR duration was independently associated with survival to hospital discharge and neurological outcome. Among survivors, neurological outcome was favorable for the majority of patients. Performing CPR for >20 minutes is not futile in some patient illness categories. PMID- 23339875 TI - Endogenous opioids and nonsuicidal self-injury: a mechanism of affect regulation. AB - Nonsuicidal self-injury (NSSI), or the purposeful destruction of body tissue occurring without suicidal intent, is a perplexing behavior as it goes against the natural instinct to maximize pleasure and minimize pain. One possible reason that people engage in NSSI is to regulate affect. However, the exact mechanisms that cause NSSI to lead to reduced feelings of negative affect remain unclear. Due to its involvement in the regulation of pain and emotion, the endogenous opioid system has been proposed to mediate the affect regulation effects of NSSI. The authors review evidence from multiple literatures to support this claim. Based on the current research, it is proposed that (1) individuals who engage in NSSI have lower baseline levels of endogenous opioids, (2) NSSI releases endogenous opioids, and (3) opioids released during NSSI regulate affect. These predictions are discussed in terms of previous models and other functions of NSSI. PMID- 23339876 TI - Structural changes in the German pharmaceutical market: price setting mechanisms based on the early benefit evaluation. AB - In the past, free price setting mechanisms in Germany led to high prices of patented pharmaceuticals and to increasing expenditures in the pharmaceutical sector. In order to control patented pharmaceutical prices and to curb increasing pharmaceutical spending, the Act for Restructuring the Pharmaceutical Market in Statutory Health Insurance (AMNOG) came into effect on 1st January 2011. In a structured dossier, pharmaceutical manufacturers have to demonstrate the additional therapeutic benefit of the newly approved pharmaceutical compared to its appropriate comparator. According to the level of additional benefit, pharmaceuticals will be subject to price negotiations between the Federal Association of Statutory Health Insurance Funds and the pharmaceutical company concerned (or assigned to a reference price group in case of no additional benefit). Therefore, the health care reform is a first step to decision making based on "value for money". The process of price setting based on early benefit evaluation has an impact on the German as well as the European pharmaceutical markets. Therefore, these structural changes in Germany are of importance for pricing decisions in many European countries both from a political point of view and for strategic planning for pharmaceutical manufacturers, which may have an effect on insured patients' access to pharmaceuticals. PMID- 23339877 TI - Organochlorine pesticides and chlorobiphenyls in the blubber of bycaught female common dolphins from England and Wales from 1992-2006. AB - We report concentrations of organochlorine pesticides (HCB, HCHs, DDTs, dieldrin) and PCBs in the blubber of 43 common dolphins bycaught in fisheries operating off the SW coast of the UK from 1992 to 2006. Concentrations of SigmaDDT (summed p,p' DDT and its metabolites, p,p'-DDE and p,p'-TDE) and of 25 summed CB congeners ranged from 0.2 to 16.1 and 2.1 to 62.4 mg kg(-1) lipid weight, respectively. Concentrations of sum HCH, HCB and dieldrin were lower, ranging from not detected to 0.14, 0.01 to 0.27 and 0.01 to 0.73 mg kg(-1) lipid weight, respectively. All contaminants studied showed a downward time trend but only that for HCHs was statistically significant. Overall, 72% of the dolphins analysed had blubber PCB concentrations above an established toxicity threshold value. PMID- 23339878 TI - Influence of size and density on filtration rate modeling and nutrient uptake by green mussel (Perna viridis). AB - This study investigates green mussel filtration rates based on variation of the mussel size and density, and attempts to correlate these with the amount of Chaetoceros calcitrans consumed by kinetic modeling. The filtration rates were found to be more effective in small mussels and with greater volumes of seawater/mussel which represent low mussel densities in the mussel farms. Under field condition, the first order kinetic model is useful for evaluation of mussel filtration rate. However, the composite exponential kinetic model was determined to better describe filtration rates in a close system. Higher ratios of seawater volume L/g DW mussel tissue, resulted in an increasing filtration rate until a maximum plateau was reached at 10.37 L/h/g DW tissue as determined by first order kinetics. Based on the filtration rate, carbon, nitrogen, and phosphorus uptake by green mussels were found to be 2128.72, 265.41, and 66.67 mg/year/indv, respectively. PMID- 23339880 TI - Person-centered care training in long-term care settings: usefulness and facility of transfer into practice. AB - The person-centered approach is increasingly recommended in long-term care facilities to increase quality of care. In Quebec, Canada,. caregivers were specifically trained in "relationship-based care. "This study analyzed caregivers' assessment of this approach's usefulness and their capacity, after training, to apply it to care practices. Questionnaires with open-ended questions were administered to caregivers (n= 392) one month after training. Caregivers' answers were categorized using a qualitative approach. Respondents perceive some features of this approach are beyond their reach or in opposition to their beliefs. They reported feeling pressure related to time constraints, their peers and the families of residents. These results indicate that training itself is insufficient to transform practice. Institutions wishing to implement such an approach must also act upon the beliefs of individuals, as well as upon work situations. PMID- 23339879 TI - Working memory in bisphenol-A treated middle-aged ovariectomized rats. AB - Over 90% of the U.S. population has detectable bisphenol-A (BPA) in their urine according to recent biomonitoring data. BPA is best known for its estrogenic properties, and most rodent research on the nervous system effects of BPA has focused on determining if chronic exposures during pre- and perinatal development have organizational effects on brain development and behavior. Estrogens also have important impacts on brain and behavior during adulthood, particularly in females during aging, but the impact of BPA on the adult brain is less studied. We have published a series of studies documenting that chronic exposure to various estrogens including 17beta-estradiol, ERbeta selective SERMs and soy phytoestrogens impairs performance of middle-aged female rats on an operant working memory task. The purpose of this study was to determine if chronic oral exposure to BPA would alter working memory on this same task. Ovariectomized (OVX) middle-aged Long Evans rats were tested on an operant delayed spatial alternation (DSA) task. Rats were treated for 8-10 weeks with either a 0 (vehicle control), 5 or 50 MUg/kg bw/day oral bolus of BPA. A subset of the vehicle control rats was implanted with a Silastic implant containing 17beta-estradiol (low physiological range) to serve as a positive control. All rats were tested for 25 sessions on the DSA task. BPA treatment did not influence performance accuracy on the DSA task, whereas 17beta-estradiol significantly impaired performance, as previously reported. The results of this study suggest that chronic oral exposure to BPA does not alter working memory processes of middle aged OVX rats assessed by this operant DSA task. PMID- 23339881 TI - Immobilisation of lead smelting slag within spent aluminate-fly ash based geopolymers. AB - This study presents the solidification/stabilisation and immobilisation of lead smelting slag (LSS) by its incorporation in coal fly ash - blast furnace slag based geopolymers. It also explores the use of a spent aluminium etching solution (AES) as geopolymer activator instead of the commonly used silicate solutions. The compressive strength of the geopolymers produced with the AES was lower than when applying a K-silicate solution as activator (100MPa versus 80MPa after 28 days). Compressive strength was not affected when up to 10% of the FA was replaced by LSS. NEN 12457-4, TCLP, SPLP and NEN 7375 leaching tests indicated that mobile Pb from LSS was highly immobilised. The diffusion leaching test NEN 7375 revealed exceeding of the Dutch Soil Quality Regulation threshold limits only for Se and Sb. On the condition that the remaining excess leaching can be reduced by further refinement of the mixture recipes, the proposed process will have the potential of producing waste-based construction materials that may be applied under controlled conditions in specific situations. PMID- 23339882 TI - Removal of Cr(VI) from aqueous solution by flocculant with the capacity of reduction and chelation. AB - A novel agent polyethyleneimine-sodium xanthogenate (PEX) with the multifunction of reduction, chelation, flocculation and precipitation was synthesized by using polyethyleneimine (PEI), carbon disulfide (CS2), and sodium hydroxide (NaOH). The effects of different important parameters, such as pH value, initial Cr(VI) concentration, coexisting ions and turbidity etc., on the removal of chromium from aqueous solution by PEX were investigated in flocculation experiments. The experiments results demonstrated that PEX could efficiently remove Cr(VI) and total Cr (Cr(VI)+Cr(III)) in strongly acidic media. It was proved that the presence of coexisting ions (Na(+), Ca(2+), F(-), Cl(-), and SO4(2-)) in the solution had a little influence on the removal of chromium. Furthermore, it was conformed that Cr(VI) ions and turbidity could be simultaneously removed when water samples contained both Cr(VI) ions and turbidity. Finally, the mechanism of interaction between chromium and PEX was further confirmed by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The results reveal that dithiocarboxylic acid groups on PEX macromolecule play a major role in Cr(VI) reduction and Cr(III) chelation, and the flocs formation is attributed to the interparticle bridging mechanism of PEX. PMID- 23339883 TI - Occurrence of phthalate esters in sediments in Qiantang River, China and inference with urbanization and river flow regime. AB - Phthalate esters (PAEs), a group of emerging organic contaminants, have become a serious issue arousing much attention for their ubiquitous presence and hazardous impact on the environment. This study provides the first data on distribution of PAEs in the sediments in the Qiantang River, Zhejiang Province, China, and the inference with urbanization and river flow regime. PAEs were detected in all 23 sediment samples analyzed, and the total concentrations of their 16 congeners in sediments ranged from 0.59 to 6.74MUg/g dry weight (dw), with the geometric mean value of 2.03MUg/g dw. Of the 16 PAE congeners, di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), and di(2-ethylhexyl) phthalate (DEHP) were present in all sediment samples. The PAEs concentrations in urban regions were higher than those in rural regions because of higher discharge of PAEs from plastic materials in urbanized areas. Concentrations of PAEs were positively correlated with sediment organic matter (fOM) and negatively correlated with logistic value of annual average flow volume at sample sites. River flow regime modified by man made dams significantly affected the distribution of PAEs. Analysis of congener composition of PAEs indicated that the DEHP was predominant congener in the Qiantang River. The normalized concentration of DEHP exceeded recommended environmental risk limit (ERL). PMID- 23339884 TI - Sonochemical effects on free phenolic acids under ultrasound treatment in a model system. AB - Sonochemical effects on seven free phenolic acids under ultrasound treatment in a model system have been investigated. The degradation products have also been tentatively identified by FTIR and HPLC-UV-ESIMS. Five phenolic acids (protocatechuic acid, p-hydroxybenzoic acid, vanillic acid, p-coumaric acid, and ferulic acid) proved to be stable, while two others (caffeic acid and sinapic acid) were degraded under ultrasound treatment. The nature of the solvent and the temperature has been identified as important factors in determining the degradation reaction. Liquid height, ultrasonic intensity, and duty cycle of the ultrasound exposure affected only the degradation rate and did not change the nature of the degradation. The degradation rates of caffeic acid and sinapic acid decreased with increasing temperature. The degradation kinetics of these two acids under ultrasound conformed to zeroth-order reactions at -5 to 25 degrees C. Both decomposition and polymerization reactions occurred when caffeic acid and sinapic acid were subjected to ultrasound. Degradation products, such as the corresponding decarboxylation products and their dimers, have been tentatively identified. PMID- 23339885 TI - On-substrate fabrication of a bio-conjugated Au nanoring solution for photothermal therapy application. AB - The on-substrate fabrication of a bio-conjugated Au nanoring (NRI) solution with the localized surface plasmon (LSP) resonance wavelength in the 1200-1300 nm range is demonstrated. Also, the effects of photothermal therapy through LSP resonance-induced absorption enhancement are illustrated by applying the bio conjugated Au NRIs to human liver cancer cells and illuminating the cells with a laser of 1315 nm in wavelength. The Au NRI fabrication is based on the techniques of nano-imprint lithography and metal secondary sputtering. The procedure for on substrate surface modification of Au NRIs leads to a high production yield of bio conjugated NRIs. The threshold levels of the local laser intensity for injuring cancer cells based on the LSP resonances of Au NRIs of two different samples are determined. PMID- 23339886 TI - [Desensitization versus clinical tolerance]. PMID- 23339887 TI - [Elephantiasis nostras verrucosa]. PMID- 23339888 TI - [Analysis of discordance between tuberculin test and QuantiFERON-TB(r) Gold In Tube in studies of contacts]. AB - BACKGROUND AND OBJECTIVES: Our objective is to compare the tuberculin skin test (TST) and the QuantiFERON-TB((r)) Gold In-Tube (QFT) in the diagnosis of latent tuberculosis infection (LTI) in a population of contacts of patients with pulmonary tuberculosis, and to analyze the influence of different variables in the discordance. PATIENTS AND METHOD: From March 2008 to September 2010, among a population of 300,000 inhabitants of the Basque Country, we analyzed all contacts of patients with pulmonary tuberculosis. All patients underwent the TST and the value of QFT was measured. Sociodemographic variables and vaccination were examined and we analyzed the discordance between the 2 tests. RESULTS: Seven hundred and four were included in the study, with a mean age of 27 years. Of these, 397 were vaccinated, with similar proportion between native and foreign. Increasing the age to 59 years (odds ratio [OR] 10.53, P<.001), being foreign (OR 2.71, P=.02) and vaccination (OR 4.22, P<.001) were predictors of the discordance between a positive TST and negative QFT. CONCLUSIONS: It seems that the QFT, alone or combined with the TST, is a safe method for the diagnosis of LTI and its use would contribute to a more specific selection of individuals who would need preventive treatment. PMID- 23339889 TI - [Natural history of moderate-degree carotid stenosis in patients with peripheral artery disease]. AB - BACKGROUND AND OBJECTIVE: To understand the evolution of moderate asymptomatic carotid stenosis, the factors that influence its progression and the related morbimortality. PATIENTS AND METHODS: Retrospective observational study of 133 patients with asymptomatic carotid stenosis between 50-69% in one or both carotids between 2002 and 2009. Included patients were subjected to screening for peripheral arterial disease (PAD), aneurysmal disease or carotid bruit. The monitoring was carried out using an annual duplex scan. The rate of progression, the variables related to this, the appearance of neurological events, and global and cardiovascular mortality were evaluated. Descriptive studies, univariate analysis (chi-squared test and Student's t-test), multivariate analysis (logistic regression), and survival curves (Log-Rank test) were carried out. RESULTS: With an average time of monitoring: 30.8 +/- 1.7 months, stenosis progression was observed in 33% of the patients, with an average progression time of 31.3 +/- 2.7 months. Greater progression was observed in the subgroup of patients with PAD and ischemic heart disease (odds ratio [OR] 2.84, confidence interval [CI] 95% 1.14 7.03). In the multivariate analysis only the PAD was identified as a risk factor for progression (P=.043). The group of patients with progression showed greater rates of neurological events: 15 vs. 1.6% (P=.01), greater global mortality: 15 vs. 3% (P=.04), and greater cardiovascular mortality: 12.1 vs. 1.5% (P=.03). CONCLUSIONS: The progression of asymptomatic carotid stenosis between 50-69% is common in patients subjected to screening, especially in those with a history of ischaemic heart disease and/or PAD. This progression is associated with an increased rate of cardiovascular complications. For this reason, we recommend clinical and echographic follow-up of these patients. PMID- 23339891 TI - Persistent problems with persistent disease: minimal residual disease in acute myelogenous leukemia. PMID- 23339890 TI - No evidence for an effect of testosterone administration on delay discounting in male university students. AB - Intertemporal choices between a smaller sooner and a larger delayed reward are one of the most important types of decisions humans face in their everyday life. The degree to which individuals discount delayed rewards correlates with impulsiveness. Steep delay discounting has been associated with negative outcomes over a wide range of behaviors such as addiction. However, little is known about the biological foundations of delay discounting. Here, we examine a potential causal link between delay discounting and testosterone, a hormone which has been associated with other types of impulsive behavior. In our double-blind placebo controlled study 91 healthy young men either received a topical gel containing 50 mg of testosterone (N=46) or a placebo (N=45) before participating in a delay discounting task with real incentives. Our main finding is that a single dose administration of testosterone did not lead to significant differences in discount rates between the placebo and the testosterone group. Within groups and in the pooled sample, no significant relationship between testosterone and discount rates was observed. At the same time, we do replicate standard findings from the delay discounting literature such as a magnitude-of-rewards effect on discount rates. In sum, our findings suggest that circulating testosterone does not have a significant effect on delay discounting in young men. PMID- 23339892 TI - Plasmonic layers based on Au-nanoparticle-doped TiO2 for optoelectronics: structural and optical properties. AB - The anti-reflective effect of dielectric coatings used in silicon solar cells has traditionally been the subject of intensive studies and practical applications. In recent years the interest has permanently grown in plasmonic layers based on metal nanoparticles, which are shown to increase light trapping in the underlying silicon. In the present work we have combined these two concepts by means of in situ synthesis of Au nanoparticles in a dielectric matrix (TiO2), which is commonly used as an anti-reflective coating in silicon solar cells, and added the third element: a 10-20% porosity in the matrix. The porosity is formed by means of a controllable wet etching by low concentration HF. As a consequence, the experimentally measured reflectance of silicon coated by such a plasmonic layer decreases to practically zero in a broad wavelength region around the localized surface plasmon resonance. Furthermore, we demonstrate that extinction and reflectance spectra of silicon coated by the plasmonic films can be successfully accounted for by means of Fresnel formulae, in which a double refractive index of the metal-dielectric material is used. This double refractive index cannot be explained by effective medium theory (Maxwell-Garnett, for example) and appears when the contribution of Au nanoparticles located at the TiO2/Si interface is high enough to result in formation of interface surface plasmon modes. PMID- 23339893 TI - [Diagnosis of hematochezia in Abidjan Cocody University Hospital (Ivory Coast)]. AB - AIM: To determine the prevalence of endoscopic lesions, according to age and location, in patients with rectal bleeding who underwent total colonoscopy. METHODS: Retrospective observational study examining records from the hepatogastroenterology department at the Cocody University Hospital (Abidjan) of colonoscopies for rectal examination from September 1, 1991, through August 15, 2007. The data collected and analyzed from the records included age, sex and colonoscopy results. A p value less than 0.05 was considered statistically significant. RESULTS: Of 1,158 colonoscopies, 270 (23.3%) were performed for hematochezia: 105 women (mean age: 48.8 years +/- 19.9 years, range: 10-96 years) and 165 men (mean age: 46 +/- 14.2, range: 21-83 years) with a sex-ratio (M/F) of 1.57. Because colorectal cancer seems to occur at a younger age in Africa, patients were divided into two groups (aged 45 years: 139 [51.5%] and above 45 years: 131 [48.5%]). The abnormalities found were consistent with anal pathologies (16.3%), polyps (10.4%), diverticular disease (11.1%), colorectal inflammatory lesions (21.5%) and carcinoma (7%). Diverticula were significantly more common in those older than 45 years and inflammatory lesions in the younger group (p < 10(-3)). More than two thirds of the significant lesions were found in the distal colon (p < 10(-3)). CONCLUSION: The predominance of distal colon lesions suggests that exploration by flexible sigmoidoscopy can be performed in patients with low to moderate risk of colorectal cancer, with total colonoscopy reserved for the population at high risk. PMID- 23339894 TI - Commanding a robotic wheelchair with a high-frequency steady-state visual evoked potential based brain-computer interface. AB - This work presents a brain-computer interface (BCI) used to operate a robotic wheelchair. The experiments were performed on 15 subjects (13 of them healthy). The BCI is based on steady-state visual-evoked potentials (SSVEP) and the stimuli flickering are performed at high frequency (37, 38, 39 and 40 Hz). This high frequency stimulation scheme can reduce or even eliminate visual fatigue, allowing the user to achieve a stable performance for long term BCI operation. The BCI system uses power-spectral density analysis associated to three bipolar electroencephalographic channels. As the results show, 2 subjects were reported as SSVEP-BCI illiterates (not able to use the BCI), and, consequently, 13 subjects (12 of them healthy) could navigate the wheelchair in a room with obstacles arranged in four distinct configurations. Volunteers expressed neither discomfort nor fatigue due to flickering stimulation. A transmission rate of up to 72.5 bits/min was obtained, with an average of 44.6 bits/min in four trials. These results show that people could effectively navigate a robotic wheelchair using a SSVEP-based BCI with high frequency flickering stimulation. PMID- 23339895 TI - Epidemiology of syndesmosis injuries in intercollegiate football: incidence and risk factors from National Collegiate Athletic Association injury surveillance system data from 2004-2005 to 2008-2009. AB - OBJECTIVE: To describe the incidence and risk factors for high ankle sprains (ie, syndesmosis injuries) among National Collegiate Athletic Association (NCAA) football players. DESIGN: Descriptive epidemiologic study. SETTING: Data were examined from the NCAA's Injury Surveillance System (ISS) for 5 football seasons (from 2004-2005 to 2008-2009). PARTICIPANTS: All NCAA men's football programs participating in the ISS. ASSESSMENT OF RISK FACTORS: No additional risk factors were introduced as a result of this analysis. MAIN OUTCOME MEASURES: For partial and complete syndesmosis injuries, outcome measures included incidence, time lost from participation, and requirement for surgical repair. RESULTS: The overall incidence of high ankle sprains in NCAA football players was 0.24 per 1000 athlete exposures, accounting for 24.6% of all ankle sprains. Athletes were nearly 14 times more likely to sustain the injury during games compared with practice; complete syndesmosis injuries resulted in significantly greater time lost compared with partial injuries (31.3 vs 15.8 days). Less than 3% of syndesmosis injuries required surgical intervention. There was a significantly higher injury incidence on artificial surfaces compared with natural grass. The majority of injuries (75.2%) occurred during contact with another player. CONCLUSIONS: Our data suggest a significantly higher incidence of syndesmosis injuries during games, during running plays, and to running backs and interior defensive linemen. The wide range in time lost from participation for complete syndesmosis injuries underscores the need for improved understanding of injury mechanism and classification of injury severity such that prevention, safe return to play protocols, and outcomes can be further improved. PMID- 23339897 TI - Genetic heterogeneity and subtyping of human Hepatitis E virus isolates from Uruguay. AB - Hepatitis E virus (HEV) infection is an important public health concern in many developing countries causing waterborne outbreaks, as well as sporadic autochthonous hepatitis. It is transmitted primarily by the fecal-oral route. However, zoonotic transmission from animal reservoirs to human has also been suggested. Genotype 3 is the most frequent genotype found in South America and the HEV epidemiology in this region seems to be very complex. However, data about the molecular characterization of HEV isolates of the region is still lacking and further investigation is needed. Our study characterized human HEV strains detected in a 1-year period in Uruguay, by extensive sequence analysis of three regions of the HEV genome. Uruguayan strains were closely related to a set of European strains and in turn, were dissimilar to Brazilian, Argentinean and Bolivian isolates. Additionally, the co-circulation of viral subtypes 3i and 3h was observed. Circulation of subtype 3i had been reported in Argentina and Bolivia whereas sequences of subtype 3h are rare and had never been reported in Latin America. In order to contribute to shedding light over the molecular epidemiology of this emergent infection in the region, we thoroughly analyzed the genetic variability of HEV strains detected in Uruguay, providing the largest dataset of sequences of HEV ever reported in a country in South America. PMID- 23339896 TI - Synovial perlecan is required for osteophyte formation in knee osteoarthritis. AB - The osteophyte associated with osteoarthritis (OA) is a bony outgrowth formed at the margins of the affected joint through endochondral ossification-like processes. However, the mechanism of osteophyte formation and its pathogenesis are unclear. Perlecan (Hspg2), a heparan sulfate proteoglycan, is expressed in many extracellular tissues and plays critical roles in skeletal development and diseases. The aim of the present study is to identify the role of synovial perlecan in osteophyte formation using perinatal lethality rescued perlecan knockout mice (Hspg2(-/-)-Tg) wherein perlecan expression is lacking in the synovial and other tissues, except for cartilage. We analyzed the development of osteophytes in joints of Hspg2(-/-)-Tg mice in two different animal models: the surgical OA model, in which the medial collateral ligament was transected and the medial meniscus was resected, and the TGF-beta-induced osteophyte formation model. In the surgical OA model, the osteophyte size and maturation were significantly reduced in the OA joints of Hspg2(-/-)-Tg mice compared with control mice, while OA developed on the medial side of the knee joints with no differences in the cartilage degradation score or synovitis score between control and Hspg2(-/-)-Tg mice. The reduced osteophyte formation in Hspg2(-/-)-Tg mice was associated with reduced cell proliferation and chondrogenesis. In the TGF beta model, the osteophyte size and maturation were also significantly reduced in Hspg2(-/-)-Tg mice compared with control mice. Our findings suggest that synovial perlecan plays an important role in osteophyte development in OA, and they provide insights that may facilitate the development of OA therapy. PMID- 23339899 TI - Evaluating targets for control of plasmid-mediated antimicrobial resistance in enteric commensals of beef cattle: a modelling approach. AB - Enteric commensal bacteria of food animals may serve as a reservoir of genes encoding antimicrobial resistance (AMR). The genes are often plasmidic. Different aspects of bacterial ecology can be targeted by interventions to control plasmid mediated AMR. The field efficacy of interventions remains unclear. We developed a deterministic mathematical model of commensal Escherichia coli in its animate and non-animate habitats within a beef feedlot's pen, with some E. coli having plasmid-mediated resistance to the cephalosporin ceftiofur. We evaluated relative potential efficacy of within- or outside-host biological interventions delivered throughout rearing depending on the targeted parameter of bacterial ecology. Most instrumental in reducing the fraction of resistant enteric E. coli at steer slaughter age were interventions acting on the enteric E. coli and capable of either 'plasmid curing' E. coli, or lowering maximum E. coli numbers or the rate of plasmid transfer in this habitat. Also efficient was to increase the regular replacement of enteric E. coli. Lowering replication rate of resistant E. coli alone was not an efficient intervention target. PMID- 23339898 TI - HSV-1 strain McKrae is more neuroinvasive than HSV-1 KOS after corneal or vaginal inoculation in mice. AB - Strains of HSV-1 have been noted to vary in their pathogenesis. We compared the replication of strains KOS and McKrae in mice by two routes of infection, ocular and vaginal. Peripheral replication of KOS was similar (cornea) or attenuated over time (vagina) compared with McKrae; however, McKrae replicated in the nervous system to significantly higher levels than KOS after inoculation by either route. Host genetic background strongly influenced the capacity for virus entry into the nervous system from the vagina. KOS and McKrae replicated equivalently after intracranial inoculation, indicating that McKrae's pathogenic phenotype is linked to neuroinvasiveness rather than neurovirulence. PMID- 23339900 TI - Multi-atlas based segmentation using probabilistic label fusion with adaptive weighting of image similarity measures. AB - Label fusion multi-atlas approaches for image segmentation can give better segmentation results than single atlas methods. We present a multi-atlas label fusion strategy based on probabilistic weighting of distance maps. Relationships between image similarities and segmentation similarities are estimated in a learning phase and used to derive fusion weights that are proportional to the probability for each atlas to improve the segmentation result. The method was tested using a leave-one-out strategy on a database of 21 pre-segmented prostate patients for different image registrations combined with different image similarity scorings. The probabilistic weighting yields results that are equal or better compared to both fusion with equal weights and results using the STAPLE algorithm. Results from the experiments demonstrate that label fusion by weighted distance maps is feasible, and that probabilistic weighted fusion improves segmentation quality more the stronger the individual atlas segmentation quality depends on the corresponding registered image similarity. The regions used for evaluation of the image similarity measures were found to be more important than the choice of similarity measure. PMID- 23339901 TI - Performance comparison of machine learning methods for prognosis of hormone receptor status in breast cancer tissue samples. AB - We examined the classification and prognostic scoring performances of several computer methods on different feature sets to obtain objective and reproducible analysis of estrogen receptor status in breast cancer tissue samples. Radial basis function network, k-nearest neighborhood search, support vector machines, naive bayes, functional trees, and k-means clustering algorithm were applied to the test datasets. Several features were employed and the classification accuracies of each method for these features were examined. The assessment results of the methods on test images were also experimentally compared with those of two experts. According to the results of our experimental work, a combination of functional trees and the naive bayes classifier gave the best prognostic scores indicating very good kappa agreement values (kappa=0.899 and kappa=0.949, p<0.001) with the experts. This combination also gave the best dichotomization rate (96.3%) for assessment of estrogen receptor status. Wavelet color features provided better classification accuracy than Laws texture energy and co-occurrence matrix features. PMID- 23339902 TI - Modeling complicated rheological behaviors in encapsulating shells of lipid coated microbubbles accounting for nonlinear changes of both shell viscosity and elasticity. AB - It has been accepted that the dynamic responses of ultrasound contrast agent (UCA) microbubbles will be significantly affected by the encapsulating shell properties (e.g., shell elasticity and viscosity). In this work, a new model is proposed to describe the complicated rheological behaviors in an encapsulating shell of UCA microbubbles by applying the nonlinear 'Cross law' to the shell viscous term in the Marmottant model. The proposed new model was verified by fitting the dynamic responses of UCAs measured with either a high-speed optical imaging system or a light scattering system. The comparison results between the measured radius-time curves and the numerical simulations demonstrate that the 'compression-only' behavior of UCAs can be successfully simulated with the new model. Then, the shell elastic and viscous coefficients of SonoVue microbubbles were evaluated based on the new model simulations, and compared to the results obtained from some existing UCA models. The results confirm the capability of the current model for reducing the dependence of bubble shell parameters on the initial bubble radius, which indicates that the current model might be more comprehensive to describe the complex rheological nature (e.g., 'shear-thinning' and 'strain-softening') in encapsulating shells of UCA microbubbles by taking into account the nonlinear changes of both shell elasticity and shell viscosity. PMID- 23339903 TI - Biological upgrading of volatile fatty acids, key intermediates for the valorization of biowaste through dark anaerobic fermentation. AB - VFAs can be obtained from lignocellulosic agro-industrial wastes, sludge, and various biodegradable organic wastes as key intermediates through dark fermentation processes and synthesized through chemical route also. They are building blocks of several organic compounds viz. alcohol, aldehyde, ketones, esters and olefins. These can serve as alternate carbon source for microbial biolipid, biohydrogen, microbial fuel cells productions, methanisation, and for denitrification. Organic wastes are the substrate for VFA platform that is of zero or even negative cost, giving VFA as intermediate product but their separation from the fermentation broth is still a challenge; however, several separation technologies have been developed, membrane separation being the most suitable one. These aspects will be reviewed and results obtained during anaerobic treatment of slaughterhouse wastes with further utilisation of volatile fatty acids for yeast cultivation have been discussed. PMID- 23339904 TI - Biodiesel production with continuous supercritical process: non-catalytic transesterification and esterification with or without carbon dioxide. AB - The non-catalytic transesterification of refined sunflower oil with supercritical methanol, in the presence of carbon dioxide, was conducted in a tubular reactor at temperatures from 553.2 to 593.2K and pressures up to 25.0 MPa. The FAME yield can be achieved up to about 0.70 at 593.2 K and 10.0 MPa in 23 min with methanol:oil of 25:1 in molar ratio. The effect of adding CO2 on the FAME yield is insignificant. The kinetic behavior of the non-catalytic esterification and transesterification of oleic acid or waste cooking oil (WCO) with supercritical methanol was also investigated. By using the supercritical process, the presence of free fatty acid (FFA) in WCO gives positive contribution to FAME production. The FAME yield of 0.90 from WCO can be achieved in 13 min at 573.2K. The kinetic data of supercritical transesterification and esterifaication were correlated well with a power-law model. PMID- 23339906 TI - A survey investigation of UK physiotherapists' use of online search engines for continuing professional development. AB - OBJECTIVES: The purpose of this study was to discover the frequency and type of use of online resources for continuing professional development displayed by physiotherapists in the UK. Therapists' skills, needs and frustrations using these resources were explored. With the relatively recent release and saturated use of the internet the potential presence of a skills gap between therapists at different stages of their career was also investigated. DESIGN: National online survey study. SETTING: The online survey was carried out using the international online service 'Survey Monkey'. PARTICIPANTS: 774 physiotherapists from students to band 8c completed the survey. INTERVENTIONS: The online survey was advertised through Frontline, the Interactive Chartered Society of Physiotherapy, Journal of Physiotherapy Pain Association and cascade email through research and other networks. RESULTS: Most physiotherapists reported using the internet for professional purposes daily (40%) or 2 to 4 times a week (37%), with only 8% of respondents using it less than once a week. Overall the results suggest band 6 and 7 physiotherapists had the least skills and most frustrations when using online search engines. CONCLUSIONS: History and the nature of rapid technological advancement, specifically of the internet, appears to have created a generational skills gap within the largest group of the physiotherapy workforce band 6 and 7 therapists. Students, band 5 and band 8a therapists appear to most successfully use online resources and the reasons for this are explored. PMID- 23339905 TI - Membrane glucocorticoid receptor activation induces proteomic changes aligning with classical glucocorticoid effects. AB - Glucocorticoids exert rapid nongenomic effects by several mechanisms including the activation of a membrane-bound glucocorticoid receptor (mGR). Here, we report the first proteomic study on the effects of mGR activation by BSA-conjugated cortisol (Cort-BSA). A subset of target proteins in the proteomic data set was validated by Western blot and we found them responding to mGR activation by BSA conjugated cortisol in three additional cell lines, indicating a conserved effect in cells originating from different tissues. Changes in the proteome of BSA conjugated cortisol treated CCRF-CEM leukemia cells were associated with early and rapid pro-apoptotic, immune-modulatory and metabolic effects aligning with and possibly "priming" classical activities of the cytosolic glucocorticoid receptor (cGR). PCR arrays investigating target genes of the major signaling pathways indicated that the mGR does not exert its effects through the transcriptional activity of any of the most common kinases in these leukemic cells, but RhoA signaling emerged from our pathway analysis. All cell lines tested displayed very low levels of mGR on their surface. Highly sensitive and specific in situ proximity ligation assay visualized low numbers of mGR even in cells previously thought to be mGR negative. We obtained similar results when using three distinct anti-GR monoclonal antibodies directed against the N terminal half of the cGR. This strongly suggests that the mGR and the cGR have a high sequence homology and most probably originate from the same gene. Furthermore, the mGR appears to reside in caveolae and its association with caveolin-1 (Cav-1) was clearly detected in two of the four cell lines investigated using double recognition proximity ligation assay. Our results indicate however that Cav-1 is not necessary for membrane localization of the GR since CCRF-CEM and Jurkat cells have a functional mGR, but did not express this caveolar protein. However, if expressed, this membrane protein dimerizes with the mGR modulating its function. PMID- 23339907 TI - Usage evaluation of a resource to support evidence-based physiotherapy: the Physiotherapy Evidence Database (PEDro). AB - OBJECTIVES: The Physiotherapy Evidence Database (PEDro) is a free, web-based database of reports of randomised controlled trials, systematic reviews and evidence-based clinical practice guidelines in physiotherapy. The objective of this study was to describe the usage of PEDro over a 2-year period, including the number of visits and searches performed, the number of countries and territories from which users accessed PEDro, and amount of usage from each country. DESIGN: Survey of web-site and database log files. MAIN OUTCOME MEASURES: Usage of the PEDro home-page (www.pedro.org.au) and the search function were logged for a 2 year period. Visit and search data were used to calculate the number of visits and searches each month. Domain data were used to calculate the total number of countries accessing PEDro and the amount of usage from each country and territory. RESULTS: The PEDro home-page received 921,181 visits from 205 countries and territories in 2010 and 2011, with 3,350,740 new searches performed. On average, a new search was initiated every 19seconds. The highest usage was from the United States of America (15%), Australia (13%) and Brasil (8%). Highest normalised usage was from Peru (255 searches/physiotherapist), Chile (154) and Columbia (90), and from Australia (19,883 searches/million population), New Zealand (13,267) and Switzerland (11,361). CONCLUSIONS: There was substantial use of the PEDro resource by the global physiotherapy community during 2010 and 2011. The provision of the PEDro search function in languages other than English may enhance accessibility. PMID- 23339908 TI - Eradication of malaria through genetic engineering: the current situation. AB - Malaria is an intra-cellular parasitic protozoon responsible for millions of deaths annually. Host and parasite genetic factors are crucial in affecting susceptibility to malaria and progression of the disease. Recent increased deployment of vector controls and new artemisinin combination therapies have dramatically reduced the mortality and morbidity of malaria worldwide. However, the gradual emergence of parasite and mosquito resistance has raised alarm regarding the effectiveness of current artemisinin-based therapies. In this review, mechanisms of anti-malarial drug resistance in the Plasmodium parasite and new genetically engineered tools of research priorities are discussed. The complexity of the parasite lifecycle demands novel interventions to achieve global eradication. However, turning laboratory discovered transgenic interventions into functional products entails multiple experimental phases in addition to ethical and safety hurdles. Uncertainty over the regulatory status and public acceptance further discourage the implementation of genetically modified organisms. PMID- 23339909 TI - Larvicidal activity of green synthesized silver nanoparticles using bark aqueous extract of Ficus racemosa against Culex quinquefasciatus and Culex gelidus. AB - OBJECTIVE: To investigate the larvicidal activity of synthesized silver nanoparticles (Ag NPs) utilizing aqueous bark extract of Ficus racemosa (F. racemosa) was tested against fourth instar larvae of filariasis vector, Culex quinquefasciatus (Cx. quinquefasciatus) and japanese encephalitis vectors, Culex gelidus (Cx. gelidus). METHODS: The synthesized Ag NPs was characterized by UV vis spectrum, X-ray diffraction (XRD), Scanning electron microscopy (SEM) and Fourier transform infrared (FTIR). The larvicidal activities were assessed for 24 h against the larvae of Cx. quinquefasciatus and Cx. gelidus with varying concentrations of aqueous bark extract of F. racemosa and synthesized Ag NPs. LC(50) and r(2) values were calculated. RESULTS: The maximum efficacy was observed in crude aqueous extract of F. racemosa against the larvae of Cx. quinquefasciatus and Cx. gelidus (LC(50)=67.72 and 63.70 mg/L; r(2)=0.995 and 0.985) and the synthesized Ag NPs (LC(50)=12.00 and 11.21 mg/L; r(2)=0.997 and 0.990), respectively. Synthesized Ag NPs showed the XRD peaks at 2 theta values of 27.61, 29.60, 35.48, 43.48 and 79.68 were identified as (210), (121), (220), (200) and (311) reflections, respectively. The FTIR spectra of Ag NPs exhibited prominent peaks at 3,425, 2,878, 1,627 and 1,382 in the region 500-3,000 cm(-1). The peaks correspond to the presence of a stretching vibration of (NH) C=O group. SEM analysis showed shape in cylindrical, uniform and rod with the average size of 250.60 nm. CONCLUSIONS: The biosynthesis of silver nanoparticles using bark aqueous extract of F. racemosa and its larvicidal activity against the larvae of disease spreading vectors. The maximum larvicidal efficacy was observed in the synthesized Ag NPs. PMID- 23339910 TI - Mosquito larvicidal and pupicidal activity of Euphorbia hirta Linn. (Family: Euphorbiaceae) and Bacillus sphaericus against Anopheles stephensi Liston. (Diptera: Culicidae). AB - OBJECTIVE: To explore the larvicidal and pupicidal activity of Euphorbia hirta (E. hirta) leaf extract and Bacillus sphaericus (B. sphaericus) against the malarial vector, Anopheles stephensi (An. stephensi). METHODS: The larvicidal and pupicidal activity was assayed against An. stephensi at various concentrations ranging from (75-375 ppm) under the laboratory as well as field conditions. The LC(50) and LC(90) value of the E. hirta leaf extract was determined by probit analysis. RESULTS: The plant extract showed larvicidal effects after 24 h of exposure; however, the highest larval mortality was found in the methanol extract of E. hirta against the first to fourth instars larvae and pupae of values LC(50)= 137.40, 172.65, 217.81, 269.37 and 332.39 ppm; B. sphaericus against the first to fourth instars larvae and pupae of values LC(50)= 44.29, 55.83, 68.51, 82.19 and 95.55 ppm, respectively. Moreover, combined treatment of values of LC(50)= 79.13, 80.42, 86.01, 93.00 and 98.12 ppm, respectively. No mortality was observed in the control. CONCLUSIONS: These results suggest methanol leaf extracts of E. hirta and B. sphaericus have potential to be used as an ideal eco friendly approach for the control of the malarial vector, An. stephensi as target species of vector control programs. This study provides the first report on the combined mosquito larvicidal and pupicidal activity of this plant crude extract and bacterial toxin against An. stephensi mosquitoes. PMID- 23339911 TI - Adhesion and cellsurface properties of wild species of spore formers against enteric pathogens. AB - OBJECTIVE: To investigate the adhesion potential and cell surface properties against enteric pathogens Salmonella typhi, Salmonella para typhi A and Vibrio cholera. METHODS: Adhesion potentials of spore and vegetative phase were studied separately for the isolates. Hydrophobic nature was measured on the basis of affinity towards the xylene. Autoaggregation and coaggregation were studied on the basis of clumping of cells. In vitro adhesion studies were done on mucous which were prepared from infant child faeces. Biofilm production of superior adhesive isolate was confirmed by SEM analysis. RESULTS: Spore and vegetative phases of isolates possessed a different rate of adhesion potentials on intestinal mucous, which indicated that cell surface properties were involved in adhesion process. Spores showed a higher hydrophobicity than their vegetative cells which remained less or non hydrophobic. Vegetative phases showed capabilities for autoaggregation and coaggregation. Spores were found to be more adhesive on intestinal mucous than vegetative phase. Among enteric pathogens Vibrio cholera registered higher adhesion potentials with supporting cell surface properties. Among the five sporeforming isolates, isolate BM-3 possess superior adhesion than enteric pathogens and also exhibited biofilm formation which enhances colonization potential. CONCLUSIONS: Spore and vegetative cell phases shows differences in adhesion potentials. Cell surface properties and adhesion studies reveals that isolate BM-3 can be selected as superior isolate which is capable for biofilm production. In short, isolate BM-3 possesses an enhanced adhesion potential than enteric pathogens towards intestinal mucous which is a desirable probiotic character. PMID- 23339912 TI - Design of a multiplex PCR method for detection of toxigenic-pathogenic in Vibrio cholerae. AB - OBJECTIVE: To study virulence and regulatory genes (hlyA, ctxB, tcpI) in clinical strains of Vibrio cholerae (V. cholerae), simultaneously. METHODS: Three important genes, tcpI, hlyA and ctxB were used for detection of toxigenic and pathogenic V. cholera by chain reaction assay method. RESULTS: According to the results of the PCR, the incidence of hlyA, tcpI, and ctxB genes in clinical isolates was obtained as 94.7% (72 sample), 90.8% (69 sample), and 92.1% (70 sample), respectively. Five strains possessed all genes except ctxB, six strains possessed all genes except tcpI, four strains possessed all genes except hlyA, one strain possessed only hlyA and 60 strains contained a combination of three genes, Including hlyA, ctxB and tcpI. CONCLUSIONS: Result show that this method could be reliable to detect toxigenic-pathogenic strains of V. cholerae in Iran. PMID- 23339913 TI - Epidemiology of schistosomiasis in Gezira area Central Sudan and analysis of cytokine profiles. AB - OBJECTIVE: To determine and compare anti-schistosoma IgG, interleukin-10 (IL-10) and interferon-gamma(IFN-gamma) levels in the serum of patients and endemic controls and to investigate the epidemiological situation of Al-Hebaika village in the northern part of Gezira Agricultural Irrigation Scheme in 2005. METHODS: During 2005 survey, serum were collected from 118 villagers. Sixty eight were parasitological positive (patients), and 50 were negative (endemic controls). Indirect ELISA was used to measure and compare the levels of immunoglobulin G (IgG) against Schistsoma mansoni (S. mansoni) soluble worm antigen (SWA) in the patients and endemic control groups from the village and compared with 20 healthy non endemic controls. Sandwich ELISA was also used to measure and compare IL-10 and IFN-gamma in the serum of the selected groups. RESULTS: The overall prevalence of S. haematobium was 20.0% and 0.9% in the first and the second surveys respectively, while the intensity of infection was the same in the two surveys 1.38 [geometric mean egg count (GMFC)]. The overall prevalence of S. mansoni infection was 68.5% and 15.4%, while the intensity of infection was 2.75 (GMEC) and 1.70 (GMEC) in the two surveys respectively. IgG reactivity against SWA showed no significant difference between Schistosoma positive patients and endemic controls. However, there were high significant differences between each of these two groups and the non endemic control group (P= 0,000). Schistosoma patients and exposed controls had significantly higher IL-10 concentration compared with non endemic controls. While endemic controls showed significantly higher IFN-gamma concentration than patients (P = 0.000). Also there was very significant difference between IFN-gamma levels of each of patients endemic controls and that of the non endemic controls (P = 0.003). CONCLUSIONS: The study concluded that IFN-gamma has a role in the natural resistant to schistosoma mansoni infection. The prevalence and intensity of S. mansoni in the Gezira Irrigation Scheme was greatly reduced. S. haematobium has disappeared from the area. PMID- 23339914 TI - Prevalence of parasitemia and associated immunodeficiency among HIV-malaria co infected adult patients with highly active antiretroviral therapy. AB - OBJECTIVE: To investigate the malaria parasitemia, CD4(+) cell counts and some haematological indices among HIV-malaria co-infected adult patients with highly active antiretroviral therapy (HAART). METHODS: A total of 342 adult HIV positive subjects were recruited at the consultant outpatient HIV/AIDS clinic, University of Benin Teaching Hospital, Benin City, Nigeria between June 2011 to November 2011. Blood samples were taken for malaria parasite count, CD4(+) cell count and other haematological counts. RESULTS: Out of the 342 adult HIV positive subjects a total of 254 patients (74.3%) were found to have malaria parasitemia. The incidence of malaria parasitemia increased with advancing clinical stage of HIV infection and this was statistically significant (P=0.002). There was no statistical significance when gender was compared with the HIV-malaria status (P >0.05). Of the 254 co-infected patients, 134 (52.8%) had high parasitemia (>1.25 * 10(9)/L). Sixty patients were found to be hyperparasitemic (>2.5 parasites/L). There was a significant association between CD4(+) cell count and having significant parasitemia (P < 0.000 1). About half (50.8%) of co-infected patients had CD4(+) cell count <= 200/MUL, and majority (44.9%) of this population also had significant parasitemia. Anaemia and thrombocytopenia were not significantly associated with HIV-malaria co-infection (P > 0.05). CONCLUSIONS: The prevalence of parasitemia is high among the HIV/AIDS infected patients. PMID- 23339915 TI - Representativeness of suspected measles cases reported in a southern district of Nigeria. AB - OBJECTIVE: To compare the characteristics of suspected measles cases at the health facilities and to determine the representativeness of the data. METHODS: We visited 25 hospitals in the Aniocha Local Government Area (LGA) of Delta State, Nigeria, from which information on reportable diseases was collected. In particular, the suspected measles cases in their registries between January 1, 2007, and June 30, 2008, were reviewed. We compared the characteristics, including age, sex, location, and month of reporting, of the suspected cases with the LGA surveillance records. RESULTS: In the LGA records, 10% cases involved individuals older than 14 years, compared with 20% in the same age group in the health facility records. Based on geographic location, 53% of the measles cases among the hospital records came from a single location, in contrast to only 30% of the cases among the LGA records. An analysis considering time revealed that 30% of the cases in the LGA records occurred in August 2007, whereas 20% of hospital cases were reported in February and May 2008 combined. CONCLUSIONS: The two record types differed considerably in all of the characteristics used in this comparison. PMID- 23339916 TI - Interferon gamma in patients with HIV/AIDS and suspicion or latent tuberculosis infection. AB - OBJECTIVE: To assess the usefulness of IGRA test (QuantiFERON((r))-Cell mediated immune) compared with the tuberculin skin test. METHODS: A cross-sectional study was carried out in Mexico, 25 infected patients with HIV-AIDS and the suspicion or with latent tuberculous infection (LTBI) who were >18 years of age and without treatment for tuberculosis (TB), were enrolled in the study. RESULTS: Median cluster of differentiation (CD4) count was 364 cells/MU L and median HIV viral load was 50 copies/mL. Overall, 20 patients (80%) had at least one positive diagnostic test for LTBI: four (16%) had a positive tuberculin skin test and 19 (76%), a positive QuantiFERON((r))-tuberculosis. CONCLUSIONS: No agreement is found between the two diagnostic tests: k = -0.004, 95% confidence interval ( 0.2219, 0.2210). Additional longitudinal studies among HIV-infected populations with high prevalence of TB are needed to further assess the usefulness of IGRAs in this patient population. PMID- 23339917 TI - Prevalence and haemato-biochemical profile of Anaplasma marginale infection in dairy animals of Punjab (India). AB - OBJECTIVE: To do the systematic comparison of prevalence of anaplasmosis by PCR and Giemsa stained thin blood smear (GSTBS) based parasitological assays in dairy cattle of Punjab, which has not been reported yet. To analyse the haematobiochemical alterations in infected animals to arrive at the conclusion regarding the pathogenicity induced by Anaplasma marginale (A. marginale) in latent and patent infection. METHODS: Study was conducted on 320 animals (236 cows, 62 calves and 22 buffaloes) of Punjab, India. PCR on genome of A. marginale was performed by targeting msp1 beta gene using specific primers BAP-2/AL34S, amplifies products of size 407 bp. Questionnaires based data on the characteristics of the infected animals and management strategies of the farm were collected and correlated. RESULTS: Higher prevalence and more significant association was observed in the PCR based molecular diagnosis (P=0.00012) as compared to that in GSTBS (P=0.028 8) based diagnosis with various regions under study. With respect to the regions, highest prevalence was recorded in Ferozepur by PCR based diagnosis, while that in Jalandhar by GSTBS examination. Similar marked significant association of the PCR based diagnosis with the age of the animals under study (P=0.00013) was observed elucidating no inverse age resistance to A. marginale in cow calves. Haematobiochemical profile of infected animals revealed marked anemia, liver dysfunction and increase globulin concentrate indicating rise in immunoglobulin level to counteract infection. CONCLUSIONS: PCR is far more sensitive in detecting the disease even in latent infection which may act as nidus for spread of anaplasmosis to susceptible animals in endemic areas. Severity of anaemia and liver dysfunction were comparable both in patent as well as latent infection indicating pathogenicity of both. PMID- 23339918 TI - Effect of Salvia miltiorrhiza on retinopathy. AB - OBJECTIVE: To explore the effect of Salvia miltiorrhiza on diabetic retinopathy (DR). METHODS: Diabetic mice of natural incidence type with monogenic inheritance were selected. Alloxan was injected into the caudal vein of mice once to induce DR. The structural changes of retina tissue in normal mice, DR mice and mice with high, medium and low dose of Salvia miltiorrhiza injection were observed under microscope. Then the blood glucose concentration and malonaldehyde (MDA) content were detected. RESULTS: There were some microaneurysms in retina of DR group, number of gangliocyte was decreased significantly, and cells were sparse and in disorder. After modeling, the blood glucose level of high-dose Salvia miltiorrhiza group (SM III group) was significantly different from DR group (P<0.01). Till the tenth week, the blood glucose level of all SM groups was decreased significantly compared with DR group (P<0.01). The effective rates of three SM groups were 93.8%, 76.4% and 50.3%, respectively. After ten weeks, MDA content of DR group was significantly higher than those of the normal control group and SM group (P<0.01), and medium and low dose SM groups had significantly higher MDA than that of normal control group (P<0.01). CONCLUSIONS: Salvia miltiorrhiza had certain protective effect on DR mice through the blood-ocular barrier. PMID- 23339919 TI - Expression and function of Annexin II in lung cancer tissue. AB - OBJECTIVE: To explore the expression of Annexin II and its relationship with the cell differentiation, proliferation in lung cancer. METHODS: RT-PCR and Western blot assays were used to detect the expression of Annexin II in lung cancer tissues and cell lines. RESULTS: Annexin II was significantly up-regulated in lung cancer tissues, and in lung cancer cell lines, Annexin II had higher mRNA and protein expressions. CONCLUSIONS: Annexin II is up-regulated in lung cancer, suggesting that the Annexin II has a potential value in the human lung cancer. PMID- 23339920 TI - Ultrastructural observation on pulmonary fibrosis in E9 rats treated with compound Carapax trionycis formula. AB - OBJECTIVE: To investigate ultrastructural changes in pulmonary tissue of a rat model of pulmonary fibrosis following treatment with compound Carapax trionycis (C. trionycis; Biejia in Chinese) formula. METHODS: Sixty male Sprague-Dawley rats were randomly divided into four groups (n=15): compound C. trionycis formula high-, middle-, and low-dose groups as well as model group. Pulmonary fibrosis was induced by bleomycin. Five rats from each group were sacrificed on day 7, 14 and 28 of the drug treatment, respectively. The pulmonary tissue was harvested followed by hematoxylin-eosin staining and subsequent transmission electron microscopy. The Szapiel's method was used to assess the degree of alveolitis and pulmonary fibrosis. RESULTS: Compared with the model group, the compound C. trionycis formula groups had slighter pulmonary alveolitis after the 7-day treatment and also had alleviated alveolar inflammation and pulmonary fibrosis after the 14-day treatment. After the 28-day treatment, the compound C. trionycis formula groups showed deposition of a small amount of fibrous tissue and lesions occupying less than 21% of the whole lung area, while the model group showed focal or diffuse fibrous deposition, narrow alveolar cavity, disordered lung structure, and lesions in larger than 51% of the whole lung area. CONCLUSIONS: The compound C. trionycis formula can inhibit the proliferation of collagen fibers and resist pulmonary fibrosis. PMID- 23339921 TI - Effects of salidroside pretreatment on expression of tumor necrosis factor-alpha and permeability of blood brain barrier in rat model of focal cerebralischemia reperfusion injury. AB - OBJECTIVE: To observe changes in expression of tumor necrosis factor (TNF)-alpha and permeability of blood brain barrier after salidroside pretreatment in rats with injury induced by focal cerebralischemia-reperfusion. METHODS: Forty-five male SD rats were randomly divided into three groups (n=15): control group, ischemia-reperfusion (IR) model group, and salidroside pretreatment group. Before the IR model establishment, the rats in the salidroside pretreatment group were intraperitoneally administered with salidroside at a dose of 24 mg/(kg.d) for 7 d. After 30 min post the last administration, the IR model was induced by occlusion of middle cerebral artery with a filament. After 24 h post the operation, the water content and Evens blue content in the ischemia cerebral hemisphere were determined, and the level of TNF-alpha mRNA was detected by the semi-quantitative RT-PCR. RESULTS: Compared with the IR model group, the salidroside pretreatment group had significantly lower (P<0.05) water content and Evens blue content in the ischemia cerebral hemisphere and also had significantly lower (P<0.05) level of TNF-alpha in the ischemic cerebral cortex tissue. CONCLUSIONS: The salidroside pretreatment alleviated the focal cerebralischemia reperfusion injury in the rat model, possibly by decreasing the permeability of blood brain barrier, attenuating brain edema and reducing TNF-alpha expression. PMID- 23339922 TI - High-resolution MRI of cranial nerves in posterior fossa at 3.0 T. AB - OBJECTIVE: To evaluate the influence of high-resolution imaging obtainable with the higher field strength of 3.0 T on the visualization of the brain nerves in the posterior fossa. METHODS: In total, 20 nerves were investigated on MRI of 12 volunteers each and selected for comparison, respectively, with the FSE sequences with 5 mm and 2 mm section thicknesses and gradient recalled echo (GRE) sequences acquired with a 3.0-T scanner. The MR images were evaluated by three independent readers who rated image quality according to depiction of anatomic detail and contrast with use of a rating scale. RESULTS: In general, decrease of the slice thickness showed a significant increase in the detection of nerves as well as in the image quality characteristics. Comparing FSE and GRE imaging, the course of brain nerves and brainstem vessels was visualized best with use of the three dimensional (3D) pulse sequence. CONCLUSIONS: The comparison revealed the clear advantage of a thin section. The increased resolution enabled immediate identification of all brainstem nerves. GRE sequence most distinctly and confidently depicted pertinent structures and enables 3D reconstruction to illustrate complex relations of the brainstem. PMID- 23339923 TI - Behavioral pattern in Chinese school-aged children with cleft lip and palate. AB - OBJECTIVE: To obtain descriptive information of behavioral pattern in Chinese school-aged children with cleft lip and palate. METHODS: A total of 93 cleft lip and palate patients between the age of 6-11 year-old and treated at West China Stomatology Hospital were selected. And another 100 unaffected controls, matched for age and gender, were recruited randomly from a common primary school in Chengdu. Chart review of medical records was used to obtain psychosocial checklists. Scores were compared with published norms and controls to evaluate the risk of problems, separately for three diagnostic groups. RESULTS: The patients group had lower scores of social and academic competencies, especially those with facial deformity or speech problem. No difference was found in the aspect of activity competency. All patients showed elevations in behavior problems. But the type of behavior problems varied in different genders. CONCLUSIONS: Chinese school-aged children with cleft lip and palate are at raised risk for social and academic difficulties. Specific pattern of behavior problems displays differently depending on gender of the patient. PMID- 23339924 TI - Outbreak of Salmonella Typhi enteric fever in sub-urban area of North India: a public health perspective. AB - Outbreaks of enteric fever are a major health concern not only due to significant human morbidity and mortality but also fear of spread of multidrug resistant strains. We report an outbreak of enteric fever caused by Salmonella enterica serotype Typhi in a suburban area, in city Chandigarh of North India. Twenty seven strains of S. typhi were isolated from blood cultures over a period of two weeks with 18 of these 27 patients residing in the same area. Maximum cases were in the age group 5-14 years (10 patients, 55.5%) while 4 (22.2%) cases were children under 5 years. All the strains showed similar resistogram being resistant to ampicillin and nalidixic acid, intermediate to ciprofloxacin and sensitive to chloramphenicol, ceftriaxone, cefotaxime, cotrimoxazole and azithromycin on disc diffusion testing. Minimum inhibitory concentration of ciprofloxacin was determined by agar dilution method and was found to be raised (>= 2 MU g/mL). This nalidixic acid resistant S. typhi outbreak report warrants the necessity of implementing stringent sanitation practices in public health interest. PMID- 23339925 TI - A functional copy number variation in the WWOX gene is associated with lung cancer risk in Chinese. AB - WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that has been reported to lose function due to genetic alterations in several cancers. WWOX maps to the common chromosomal fragile site FRA16D and several copy number variations (CNVs) were found within this gene. In this study, we investigated the association between the CNVs of WWOX and lung cancer risk in four independent case-control studies, which are on 2942 lung cancer cases and 3074 cancer-free controls of southern, eastern and northern Chinese. A common CNV-67048 was genotyped by the Taqman real-time PCR, and its biological effect was accessed with protein expression and sequencing assays. We found that in comparison with the common 2-copy genotype, the carriers of loss variant genotypes (1-copy or 0 copy) had a significantly increased risk of lung cancer (adjusted OR = 1.39, 95% CI = 1.24-1.55, P = 9.01*10(-9)) in a dose-response manner (Ptrend = 1.12 * 10( 10)), and the WWOX protein expressions in lung cancer tissues were significantly lower (P = 0.036), accompanying a higher rate of exons absence (P = 0.021) in subjects with loss genotypes of CNV-67048. Our data suggest that the loss genotypes of CNV-67048 in WWOX predispose their carriers to lung cancer; this might be related with altered WWOX gene expression and exons absence in them. PMID- 23339926 TI - Identification of a synthetic muramyl peptide derivative with enhanced Nod2 stimulatory capacity. AB - Muramyl peptides (MPs) represent the building blocks of bacterial peptidoglycan, a critical component of bacterial cell walls. MPs are well characterized for their immunomodulatory properties, and numerous studies have delineated the role of MPs or synthetic MP analogs in host defense, adjuvanticity and inflammation. More recently, Nod1 and Nod2 have been identified as the host sensors for specific MPs, and, in particular, Nod2 was shown to detect muramyl dipeptide (MDP), a MP found in both Gram-positive and Gram-negative bacterial cell walls. Because mutations in Nod2 are associated with the etiology of Crohn's disease, there is a need to identify synthetic MP analogs that could potentiate Nod2 dependent immunity. Here, we analyzed the Nod2-activating property of 36 MP analogs that had been tested previously for their adjuvanticity and anti infectious activity. Using a luciferase-based screen, we demonstrate that addition of a methyl group to the second amino acid of MDP generates a MDP derivative with enhanced Nod2-activating capacity. We further validated these results in murine macrophages, human dendritic cells and in vivo. These results offer a basis for the rational development of synthetic MPs that could be used in the treatment of inflammatory disorders that have been associated with Nod2 dysfunction, such as Crohn's disease. PMID- 23339927 TI - Fish oil attenuates liver injury caused by LPS in weaned pigs associated with inhibition of TLR4 and nucleotide-binding oligomerization domain protein signaling pathways. AB - This study evaluated whether fish oil exerted a hepatoprotective effect in a LPS induced liver injury model via regulation of TLR4 and nucleotide-binding oligomerization domain protein (NOD) signaling pathways. Twenty-four piglets were used in a 2 * 2 factorial design, and the main factors included diet (5% corn oil or 5% fish oil) and immunological challenge (LPS or saline). Fish oil resulted in enrichment of eicosapentaenoic acid, docosahexaenoic acid and total (n-3) polyunsaturated fatty acids in liver. Less severe liver injury was observed in pigs fed fish oil, as evidenced by improved serum biochemical parameters and less severe histological liver damage. In addition, higher expression of liver tight junction proteins, and lower hepatocyte proliferation and higher hepatocyte apoptosis were observed in pigs fed fish oil. The improved liver integrity in pigs fed fish oil was concurrent with reduced hepatic mRNA expression of TLR4, myeloid differentiation factor 88, IL-1 receptor-associated kinase 1 and TNF alpha receptor-associated factor 6, and NOD1, NOD2 and receptor-interacting serine/threonine-protein kinase 2, as well as reduced hepatic protein expression of NF-kappaB p65, leading to reduced hepatic pro-inflammatory mediators. These results indicate that fish oil improves liver integrity partially via inhibition of TLR4 and NOD signaling pathways under an inflammatory condition. PMID- 23339928 TI - Inflammation in dry eye associated with rheumatoid arthritis: cytokine and in vivo confocal microscopy study. AB - The purpose of this research was to study ocular surface inflammation in relation to systemic disease activity in rheumatoid arthritis (RA) patients with or without secondary Sjogren's syndrome (SSII and non-SSII respectively). The study was conducted in two phases. In phase I, 12 patients with active RA SSII and 12 with active RA non-SSII were consecutively enrolled. Each completed an Ocular Surface Disease Index (OSDI) questionnaire and underwent a full eye exam and in vivo confocal microscopy examination of the cornea. Tear fluid samples were collected in sponges and analyzed for IL-1alpha, -6, and -8, and TNF-alpha. When RA activity was suppressed by systemic treatment the patients entered phase II of the study in which all of the phase I examinations were repeated. In RA SSII patients, OSDI, fluorescein staining dendritic cell density, and concentrations of IL-1alpha and IL-6 decreased significantly (P < 0.01) between phases I and II. Tear breakup time scores increased significantly. For RA non-SSII patients, there were no significant differences between phases I and II. Differences in the clinical, cellular and cytokine responsiveness to systemic RA treatments show that the ocular surface pathology is dissimilar for RA SSII and RA non-SSII patients. PMID- 23339929 TI - A route for fabricating printable photonic devices with sub-10 nm resolution. AB - A novel and robust route for high-throughput, high-performance nanophotonics based direct imprint of high refractive index and low visible wavelength absorption materials is presented. Sub-10 nm TiO2 nanostructures are fabricated by low-pressure UV-imprinting of an organic-inorganic resist material. Post imprint thermal annealing allows optical property tuning over a wide range of values. For instance, a refractive index higher than 2.0 and an extinction coefficient close to zero can be achieved in the visible wavelength range. Furthermore, the imprint resist material permits fabrication of crack-free nanopatterned films over large areas and is compatible for fabricating printable photonic structures. PMID- 23339930 TI - Altered gene expression profiles associated with enhanced skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate in streptozotocin-diabetic mice. AB - To examine the mechanisms of diabetes-enhanced inflammation, ear inflammation was induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in streptozotocin (STZ) injected diabetic and control mice. The inflammatory response was determined from ear thickness and histology. The mRNA expression of several inflammation-related genes 8, 24 and 32 h after TPA treatment was determined by quantitative real-time RT-PCR. Ear thickness did not differ between the two groups at 8 h, but was greater in the diabetic mice than control mice at 24 and 32 h (late phase). STZ diabetic conditions variously affected TPA-induced gene expression. The changes 8 h after TPA treatment probably reflected transcriptional regulation, and the genes were divided into three groups, up-regulated (IL-6, MCP-1, HO-1 and SOCS3), unregulated (IL-1beta, TNF-alpha and IL-10) and down-regulated (RANTES) genes. TPA-induced gene expression of cytokines, except for RANTES, peaked at 8 h and significantly declined in the late phase in control mice, while the expression of IL-1beta and TNF-alpha did not decline in the late phase in the diabetic mice. This result indicated the destabilization process for these mRNA, a type of post transcriptional regulation, to be impaired under STZ-induced diabetic conditions; however, TPA-induced gene and protein expression of TTP, an RNA-binding protein involved in mRNA decay, were adversely enhanced in the diabetic mice. These findings suggested that STZ-induced diabetes affected the transcriptional and post-transcriptional control of TPA-induced inflammation, and greater mRNA levels of IL-1beta and TNF-alpha in the late phase were probably responsible for the diabetes-enhanced inflammation. PMID- 23339931 TI - Hypokalemic myopathy in inflammatory bowel diseases. PMID- 23339932 TI - Interleukin-6 is associated with steroid resistance and reflects disease activity in severe pediatric ulcerative colitis. AB - BACKGROUND AND AIM: Approximately one third of patients with acute severe ulcerative colitis (ASC) will fail intravenous corticosteroids (IVCS). Predicting response to IVCS to initiate early salvage therapy remains challenging. The aim of this study was to evaluate the role of serum inflammatory cytokines in ASC and determine their predictive utility with IVCS treatment failure. METHODS: This preplanned ancillary study, part of the prospective multicenter OSCI study, evaluated pediatric ASC in North America. Serum samples were obtained from 79 children admitted for ASC on the third day of IVCS treatment. Twenty-three (29%) patients required second-line therapy. ELISA-based cytokine arrays were used [TNF alpha, IFN-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL 12, IL-13, and IL-17], selected based on a systematic literature search. RESULTS: In univariate analysis, only IL-6 was significantly different between responders and non-responders (P=0.003). The risk for IVCS failure increased by 40% per each pg/mL increase in IL-6 level. Factor analysis found IL-6 to be associated with IL 17, suggesting involvement of the T-helper (TH)17 pathway. In a multivariate analysis, disease activity [judged by the Pediatric UC Activity Index (PUCAI)] assumed all the association with the treatment outcome while IL-6 was no longer significant (P=0.32; PUCAI score P<0.001). CONCLUSIONS: While IL-6 strongly predicted IVCS failure, it likely reflects disease activity and not direct interference with corticosteroid pathway. Nonetheless, IL-6 levels may have a role in predicting IVCS response in severe pediatric UC for treatment decision making or potentially in medical intervention by virtue of anti-IL-6 antibodies in severe UC. PMID- 23339933 TI - Nutrition economics - food as an ally of public health. AB - Non-communicable diseases (NCD) are a major and increasing contributor to morbidity and mortality in developed and developing countries. Much of the chronic disease burden is preventable through modification of lifestyle behaviours, and increased attention is being focused on identifying and implementing effective preventative health strategies. Nutrition has been identified as a major modifiable determinant of NCD. The recent merging of health economics and nutritional sciences to form the nascent discipline of nutrition economics aims to assess the impact of diet on health and disease prevention, and to evaluate options for changing dietary choices, while incorporating an understanding of the immediate impacts and downstream consequences. In short, nutrition economics allows for generation of policy-relevant evidence, and as such the discipline is a crucial partner in achieving better population nutritional status and improvements in public health and wellness. The objective of the present paper is to summarise presentations made at a satellite symposium held during the 11th European Nutrition Conference, 28 October 2011, where the role of nutrition and its potential to reduce the public health burden through alleviating undernutrition and nutrition deficiencies, promoting better-quality diets and incorporating a role for functional foods were discussed. PMID- 23339934 TI - Intracrine oestrogen production and action in breast cancer: an epigenetic focus. AB - Epigenome changes have been widely demonstrated to contribute to the initiation and progression of a vast array of cancers including breast cancer. The reversible process of many epigenetic modifications is thus an attractive feature for the development of novel therapeutic measures. In oestrogen receptor alpha (hereinafter referred to as ER) positive tumours, endocrine therapies have proven beneficial in patient care, particularly in postmenopausal women where two-thirds of tumours are oestrogen dependent. However, resistance to such therapies is a common feature amongst individuals. In the current review, we discuss the influence that epigenetics has on oestrogen dependent breast cancers, in particular (i) the production of intracrine oestrogen in postmenopausal women, (ii) the action of oestrogen on epigenetic processes, and (iii) the links between epigenetics and endocrine resistance and the current advancements in epigenetic therapy that target this process. This article is part of a Special Issue entitled 'CSR 2013'. PMID- 23339935 TI - Medical surveillance for prevention of occupational asthma. AB - PURPOSE OF REVIEW: Because there is sufficient knowledge of its environmental determinants, occupational asthma is a disease that ought to be largely preventable; yet its incidence in many settings remains unacceptably high. Here we review one approach to prevention: the routine use of health surveillance in exposed workforces. RECENT FINDINGS: Health surveillance is widely practised but there is little evidence that it is used strategically to reduce disease incidence. There are several barriers to the effective use of its various components, chiefly symptoms questionnaires and spirometry. Cost-benefit analyses may help to increase the uptake of industry-wide workplace interventions. SUMMARY: The effective use of health surveillance for occupational asthma continues to be challenging and there remains relatively little published evidence that will encourage those involved to use it more efficiently. Useful advances could be made by greater collaboration between employers, employee organizations, legislators and researchers. PMID- 23339936 TI - Remodeling, inflammation and airway responsiveness in early childhood asthma. AB - PURPOSE OF REVIEW: Remodeling and inflammation together with airway hyperresponsiveness are essential components of asthma but their role in development of the disease is still obscure. RECENT FINDINGS: Recent data imply that remodeling can occur early in childhood, not necessarily subsequent to but rather, in parallel with inflammation. The assumption of thickening of the reticular basement membrane being a prerequirement for chronic asthma is questioned but development of airway responsiveness is a significant factor. Airway responsiveness is at least partially linked to bronchial inflammation but there are several other genes and pathways regulating airway responsiveness. Increased airway smooth muscle in early childhood is associated with later development of asthma and may be one link between inflammation and airway responsiveness. Novel findings on genetic variation in genes regulating lung growth and remodeling in early childhood shed light on the pathophysiological mechanisms leading to chronic asthma. SUMMARY: Even young children with chronic asthma have detectable elements of airway remodeling, inflammation and increased airway responsiveness, which all contribute to impaired lung function. PMID- 23339937 TI - The cytopathic effects of Trichomonas vaginalis on fibroblast cell culture alone and with C. albicans and E. coli. AB - OBJECTIVE: In this study, the cytopathic effects of Trichomonas vaginalis were investigated in L929 mouse fibroblast cell cultures (FCC) under different conditions: only parasite, or coexistence with Candida albicans and Escherichia coli. METHODS: The parasite was isolated from a symptomatic patient and cultured in Cysteine-Peptone-Liver infusion Maltose medium (CPLM). C. albicans strain 10235 and E. coli strain 25922 were used in the experiments. Five groups were created and inoculated on FCC. The groups were as follows; only T. vaginalis, C. albicans, E. coli, T. vaginalis+C. albicans and T. vaginalis+E. coli. The plates were incubated for 24 hours and cell viability was examined under an inverted microscope. Each experiment was repeated 11 times. RESULTS: The fibroblast death rate was 19.1%, 21%, 40.9%, 96.5% and 89.6% in the five groups, respectively. CONCLUSION: All fibroblasts were alive in the control group. T. vaginalis showed almost 100% cytopathic effects on FCC with C. albicans and parasites were very motile in this coexistence. PMID- 23339938 TI - The prevalence, isolation and morphotyping of potentially pathogenic free-living amoebae from tap water and environmental water sources in Sivas. AB - OBJECTIVE: To our knowledge, there is no study dealing with the prevalence of free-living amoebas (FLA) in water sources in Turkey, previous studies were mostly case presentations. The aim of the present study was to investigate the prevalence of FLA from tap water and natural water sources in different parts of the city. METHODS: In the study, 250 samples were collected from the city centre, districts and villages. Two litres of water was collected from each source and filtered through a vacuum filtration system. The filter papers were washed in "Page's Amoeba Saline (PAS)" solution and incubated overnight. Filter papers were removed from the tubes and centrifuged; the final pellet was inoculated on non nutrient agar (NNA) plates. The growth rate of FLA was checked after three days of inoculation and the flagellation test was performed to determine the presence of Naegleria spp. Heat tolerance of isolated strains was checked at 37, 42 and 52 degrees C for the presence of pathogenic Acanthamoeba species. The cyst and trophozoite morphology of amoebas were examined under a light microscope and the genera was identified according to morphotyping keys. RESULTS: FLA were found in 75 (30.0%) of examined water samples. Eleven (4.4%) were identified as Acanthamoeba spp., 25 (10.0%) as Naegleria spp. and 39 (15.6%) as Hartmannella spp. after microscopic examination. CONCLUSION: Our study revealed that FLA are common inhabitants of household water as they are in the environment, so their own potential risks as well as transferring bacteria as other pathogens is important for human health. PMID- 23339939 TI - [Malaria cases detected by active and passive surveillance in Adiyaman between 2000-2008]. AB - OBJECTIVE: In this study, malaria cases were determined in Adiyaman with active and passive surveillance studies by Local Health Authority, Centre for Struggle against malaria between the years 2000-2011. METHODS: In 312.125 blood samples, obtained with the method of active and passive surveillance from the region where malaria is common, malarial parasite was investigated by the method of thin and thick blood smears. RESULTS: In the observed samples, 184 malaria cases were determined; 38 (21.1%) with active, 145 (78.8%) of them with passive surveillance method. The rate of positive cases among all the observations was 0.05%. 108 (58.6%) of the cases were male, 76 (41.3%) of the cases were female. It was stated that 3 of the cases were provincial cases and 181 of them originated from extra-provincial sources. It was observed that, apart from one Plasmodium falciparum case which was from a foreign-source; all of the cases were plasmodium vivax positive. there were no cases of malaria between 2008 and 2011 years. CONCLUSION: The fact that there are many farming workers in Adiyaman and that these workers work in regions where malaria is endemic, threatens the population in the region with malarial infection . It was considered important for the Centre for the Struggle against Malaria and Adiyaman University, Medical Faculty to cooperate in the struggle against malaria by offering planned training programs in public health. PMID- 23339940 TI - [Investigating Demodex folliculorum in patients with urological cancer]. AB - OBJECTIVE: In this study, it was aimed to determine frequency of Demodex folliculorum infestation in patients with urological cancers. METHODS: This study evaluated 49 patients with urological cancers; 31 sex-matched healthy individuals as a control group were included in the study between March 2011 and April 2012 at the Hospital of Mustafa Kemal University, School of Medicine, Urology Clinic. The demographic characteristics of the patients were recorded. Samples from the perineal region of the subjects were taken by standard method of superficial skin biopsy and evaluated by microscopy. Presence of five or more Demodex sp. in a cm < sup > 2 < /sup > was considered as positive. RESULTS: Mean age was found to be 60.2+/-18.6 years. D. folliculorum was found to be positive in 11 (22.4%) of the patients with cancer and in 1 (3.2%) of the subjects in the control group. It was found that D. folliculorum frequency was significantly higher in the cancer group compared to the control group. No significant difference was found among the cancer groups in terms of D. folliculorum detection. In the cancer group, mean age was significantly higher in D. folliculorum positive patients than negative ones. CONCLUSION: It should be kept in mind that D. folliculorum incidence may increase in immunosuppressive states, such as cancer. PMID- 23339941 TI - [Comparison of individual differences in the direct microscopic examination in the diagnosis of intestinal parasites]. AB - OBJECTIVE: The aim is to emphasise the importance for intestinal parasites' diagnosis by direct microscopic examination and the discrepancies among results from different microscopists. METHODS: Stool specimens were obtained from 225 children with diarrhoea after the macroscopic examination, prepared by formalineether sedimentation methods and included in microscopically examination by three different independent investigators (parasitologist, microbiologist, research assistant). Furthermore, specimens were stained with the modified Ehrlich Ziehl Neelsen method and evaluated for Cryptosporidium and Cyclospora. RESULTS: A total 161 specimens were evaluated as negative by all investigators. The number of specimens containing parasites detected by at least one investigator was 64; Cryptosporidium parvum 30, Blastocytis hominis 16, Endolimax nana 5, Giardia intestinalis 4, Dientamoeba fragilis 3, Ascaris lumbricoides 3, Entamoeba histolytica/dispar 2, Cyclospora cayetanensis 1. The concordance among investigators was observed for 21 (33%) specimens; when specimens were evaluated for the presence of leukocytes and/or parasites, concordance was detected for 58 (91%) of the 64 specimens. In particular, significant differences were observed for the species level identification. CONCLUSION: Different results can be obtained by microscopic examination according to the experience and educational level of microscopists. Therefore, we think that these tests should be performed by persons who have sufficient education and experience, if possible, combined with at least two different methods. PMID- 23339942 TI - Larval hook length measurement for differentiating G1 and G6 genotypes of Echinococcus granulosus sensu lato. AB - OBJECTIVE: Echinococcus granulosus is a globally important cestode parasite causing remarkable medical and economical losses in the world. Ten genotypes (G1 G10) have been identified within this complex species. Protoscoleces rostellar hook characters e.g. total large and small hook lengths may be useful to differentiate genotypes. This study investigates the value of rostellar hook morphometry on genetically identified isolates of E. granulosus using mitochondrial cox1 and nad1 sequencing. METHODS: In total, 24 hydatid cyst samples of livestock and human origin were collected. The isolates were then sequenced for the mitochondrial cox1 and nad1 genes and total large and small rostellar hook lengths of protoscoleces were measured. RESULTS: Total large and small hook lengths could differentiate between G1 and G6 genotypes; however, G1 and G3 were not distinguishable by hook morphometry. Only large hook length was significantly different between the G3 and G6 isolates. CONCLUSION: The G6 genotype is readily distinguishable from G1 by using both small and large hook lengths; however, only total large hook length was significantly different between the G3 and G6 genotypes. PMID- 23339943 TI - [Retrospective evaluation of patients with probable cystic echinococcosis to the central laboratory of the Kocaeli Derince education and research hospital between 2009 and 2011]. AB - OBJECTIVE: Cystic echinococcosis (CE) is caused by metacestodes of Echinococcus granulosus, which is one of the most widespread zoonotic diseases in humans in both developing and developed countries, and also in Turkey. The aim of this retrospective study was to evaluate the situation of hydatid disease in Kocaeli. METHODS: The specific anti-Echinococcus granulosus indirect haemagglutination test results of 225 patients, who were referred with probable CE to the Centre Laboratory of the Kocaeli Derince Education and Research Hospital during December 2009-May 2011 was assessed retrospectively. Positive cases were also reassessed clinically. RESULTS: Of the total, 151 (67.1%) were female and 74 (32.8%) were male. The seropositivity ratio of IHA test was found to be 8% (18 patients), borderline ratio as 2.2% (5 patients), and seronegative ratio as 89.8% (202 patients). In 15 of the 23 seropositive and borderline patients, CE compatible radiological lesions were determined, while 4 of the remaining patients showed no lesion and the other 4 had no radiological data. CONCLUSION: Considering that hospital records can represent only a small part of the CE cases, it can be said that CE still subsists and retains its importance in our city. Essential precautions should be taken for the prevention and protection for this disease. PMID- 23339944 TI - [Helminths of pheasant (Phasianus colchicus) detected by necropsy and faecal examination in Samsun, Turkey]. AB - OBJECTIVE: This study was performed at the Gelemen Pheasant Procreation Farm affiliated to the General Directorate of Nature Conservation and National Parks, Ministry of Forest and Water Affairs. METHODS: A total of 203 faecal samples and 17 necropsies were examined. RESULTS: In the faecal examination, Capillaria spp. accounted for 28.6% and Heterakis spp. for 17.2% of eggs; in necropsy, Capillaria annulata (17.6%), C. bursata (35.3%), C. caudinflata (23.5%), C. contorta (64.7%), C. obsignata (5.9%) and Heterakis gallinarum (58.8%) were detected. DISCUSSION: Syngamus trachea, often reported in helminths in pheasant, could be found neither upon faecal examination nor on necropsy. CONCLUSION: This study is the first extensive research to identify helminths of pheasants in Turkey. Capillaria bursata, C. caudinflata, C. contorta, C. obsignata and H. gallinarum are the first reports from pheasants in Turkey. PMID- 23339945 TI - [About ciliates Entodinium palmare and E. okoppensis (Ciliophora: Ophryoscolecidae) in the rumen of domestic cattles (Bos taurus taurus) in the vicinity of Kastamonu]. AB - OBJECTIVE: The aim of this study was to determine the cytological features of the rumen ciliates Entodinium palmare and E. okoppensis living in the rumen of domestic cattle in the vicinity of Kastamonu, compare the morphological characters of species with their original descriptions and discuss the similarities and differences. METHODS: The specimens were obtained from 24 cattle, fixed with 10% formalin and stained with methylgreen formalin saline (MFS) solution. RESULTS: Specimens were measured from cattle in our country, and were found to be similar to the original description on the basis of morphological characteristics and biometric data. CONCLUSION: With this investigation, E. palmare and E. okoppensis were firstly detected from our cattle and were secondly detected from cattle throughout the world. E. palmare and E. okoppensis have low frequency appearance and percentage composition in our cattle. This study concluded that the feeding habits and feeding frequencies of cattle, the physiological conditions of rumen or competition between species can be important reasons for this situation. PMID- 23339946 TI - The parasitic communities of the rock pigeon Columba livia from Iraq: component and importance. AB - OBJECTIVE: The main objectives of the present study were to investigate the rock pigeon parasitic communities from Iraq as well as reporting on the prevalence and intensity of various infections from both sexes. METHODS: An examination of 128 specimens of the live rock pigeon Columba livia from Iraq was undertaken. The samples were obtained from several localities of Iraq. Blood samples were examined for haemoprotozoa, carcasses were investigated for the ectoparasites throughout their body skins and feathers, and the alimentary canal was examined for protozoans and helminths. RESULTS: Twenty-seven species of parasites were identified. They comprised 1 Fungi, Candida sp.; 4 Protozoa, Eimeria labbeana, Trichomonas gallinae, Haemoproteus columbae and Plasmodium sp.; 8 Cestoda, 4 of each of the genera Cotugnia and Raillietina; 4 Nematoda, Ascaridia columbae, A. galli, Capillaria obsignata and Synhimantus spiralis; and 10 Arthropoda, the commonest of which were the wing and tail feather louse Columbicola sp. and the pigeon louse fly Pseudolinchia canariensis. Infection indices are provided for each species and in respect to both sexes of the host. CONCLUSION: The issue of zoonosis is raised, so is the role of the rock pigeons in acting as a reservoir and spreading some of the disease agents associated with other avian populations including poultry. Seven of the species are newly introduced to the parasitological list of Iraq and for this country the rock pigeon is a new host record for another 9 of the endoparasites that were diagnosed. PMID- 23339947 TI - Parasitosis of the chukar partridge, Alectoris chukar in North Iraq. AB - OBJECTIVE: The aim of this study was to establish the identity of the parasitic communities of the chukar partridge from Iraq as well as reporting on the prevalence and intensity of various infections from several localities and comprising both sexes. METHODS: Twenty-nine live adult chukar partridge (Alectoris chukar) were obtained from several localities across the northern provinces of Iraq. Blood samples were examined for haemoprotozoa, carcasses were assessed for the ectoparasites throughout the body skins and feathers, and the alimentary canal was examined for protozoans and helminths. RESULTS: All of the examined animals were infected with the 18 different endo- and ectoparasite species identified. These include 2 protozoans, 3 cestodes, 2 nematodes, and 11 arthropods. The overall figures suggest no significant differences in infection indices in terms of the host's sexuality. Pathogenicity of the parasites involved is briefly emphasised. Furthermore, the role of the chukar in the dissemination of these disease agents among populations of other avian species is discussed. CONCLUSION: With the exception of C. latiproglottina, all of the species differentiated represent new records for chukar from Iraq, and the 2 coccidians are new addenda to the country parasitological list. PMID- 23339948 TI - Isospora belli in a patient with liver transplantation. AB - Isospora belli is an opportunistic protozoon which should be monitored in patients with gastrointestinal complaints such as abdominal pain, nausea and diarrhoea, in both immune-compromised and immune-competent patients. Our case was a 35 year-old male patient who had received a liver transplant because of cirrhosis and hepatic fibrosis. A diarrhoeic stool sample of the patient was sent to the laboratory for microbiological and parasitological analyses. Faecal occult blood was positive and bacteriological analysis was negative. Isospora belli infection was diagnosed by detection of the oocysts in stool samples. Per oral trimethoprim-sulphamethoxazole treatment was given in 500 mg bid dose for 10 days. At the end of the treatment, no oocyst of Isospora belli was seen but non pathogenic cysts of Entamoeba coli and vacuolar forms of Blastocystis hominis were observed. Two months later the patient had abdominal pain, fatigue and diarrhoea again and parasitological re-evaluation showed oocysts of Isospora belli. PMID- 23339949 TI - [Hydatid acute pancreatitis]. AB - Liver hydatid cysts are known to rupture into the biliary tree, but acute pancreatitis is a rare complication of intra-biliary rupture. Intra-biliary rupture was first reported in 1928 by Dew. Intra-biliary rupture is a serious complication of hepatic hydatid cysts. The incidence varies from 1% to 25% in adult patients. In our case, we aimed to show the migration of the material of a hepatic hydatid cyst to the common bile duct and the impaction of hydatid membrane in the papillary orifice, which may cause acute pancreatitis. Parasitic infections should be considered as a differential diagnosis in patients with acute biliary pancreatitis. PMID- 23339950 TI - Facial nerve paralysis due to intra-aural Hyalomma tick infestation. AB - We present the case of a 33 year-old man from a village of the north-eastern part of central Anatolia admitted to the otolaryngology department of Yeditepe University Hospital with right facial asymmetry and pain on the right ear. A tick of the genus Hyalomma was observed in the external auditory canal of the right ear and it was removed with fine cup forceps under otomicroscopy. We are of the opinion that in patients presenting with sudden acute ear pain and facial palsy, the ear canal should be examined to exclude an infestation by ticks. PMID- 23339951 TI - Eosinophilic pneumonia due to toxocariasis: an adult case report. AB - Toxocara is a roundworm, a common parasite of dogs (T. canis) and cats (T. cati). Toxocariasis or Visceral larva migrans (VLM) are diseases caused by the larvae of Toxocara sp., which may involve many organs, but pulmonary symptoms such as coughing and wheezing and allergic symptoms are seen in more than 80% of patients. It is known that, although the risk of infection is present, the worldwide diagnosis of toxocariasis is difficult since clinical and laboratory data provide insufficient evidence for the diagnosis. Nowadays, the diagnosis of toxocariasis is performed by serologic methods. We describe herein a case of toxocariasis with eosinophilic pneumonia that was diagnosed using serologic methods. PMID- 23339952 TI - Haemodipsus leporis Blagoveshtchensky, 1966 (Phthiraptera: Anoplura: Polyplacidae) on a Hare (Lepus europaeus, L.): new record for Turkish Phthiraptera fauna. AB - This study was carried out to detect lice species found on hares (L. europaeus, L.) in the Konya province. Several lice individuals were collected on a hare and were kept in 70% alcohol. Then, they were cleaned in 10% KOH for 24 hours, washed in distilled water, stored in 70%, 80%, 90% and 96% alcohol for 24 hours for each step. They were mounted on the slides in Canada balsam and examined under a binocular light microscope. Two of the species were identified as Haemodipsus leporis Blagoveshtchensky, 1966, while the others were H. lyriocephalus (Burmeister, 1839). H. leporis was found on L. europaeus for the first time in Turkey, and it was also detected on this host species for the first time throughout the world. The morphological characteristics of this species are given in this paper. PMID- 23339953 TI - Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. AB - BACKGROUND & AIMS: Pharmacological approaches can potentially improve fatty liver condition in alcoholic and non-alcoholic fatty liver diseases. The salutary effects of reducing lipid synthesis or promoting lipid oxidation have been well reported, but the benefits of increasing lipid degradation have yet to be well explored. Macroautophagy is a cellular degradation process that can remove subcellular organelles including lipid droplets. We thus investigated whether pharmacological modulation of macroautophagy could be an effective approach to alleviate fatty liver condition and liver injury. METHODS: C57BL/6 mice were given ethanol via intraperitoneal injection (acute) or by a 4-week oral feeding regime (chronic), or high fat diet for 12 weeks. An autophagy enhancer, carbamazepine or rapamycin, or an autophagy inhibitor, chloroquine, was given before sacrifice. Activation of autophagy, level of hepatic steatosis, and blood levels of triglycerides, liver enzyme, glucose and insulin were measured. RESULTS: In both acute and chronic ethanol condition, macroautophagy was activated. Carbamazepine, as well as rapamycin, enhanced ethanol-induced macroautophagy in hepatocytes in vitro and in vivo. Hepatic steatosis and liver injury were exacerbated by chloroquine, but alleviated by carbamazepine. The protective effects of carbamazepine and rapamycin in reducing steatosis and in improving insulin sensitivity were also demonstrated in high fat diet-induced non alcoholic fatty liver condition. CONCLUSIONS: These findings indicate that pharmacological modulation of macroautophagy in the liver can be an effective strategy for reducing fatty liver condition and liver injury. PMID- 23339954 TI - Regional metabolic liver function measured in patients with cirrhosis by 2 [18F]fluoro-2-deoxy-D-galactose PET/CT. AB - BACKGROUND & AIMS: There is a clinical need for methods that can quantify regional hepatic function non-invasively in patients with cirrhosis. Here we validate the use of 2-[(18)F]fluoro-2-deoxy-d-galactose (FDGal) PET/CT for measuring regional metabolic function to this purpose, and apply the method to test the hypothesis of increased intrahepatic metabolic heterogeneity in cirrhosis. METHODS: Nine cirrhotic patients underwent dynamic liver FDGal PET/CT with blood samples from a radial artery and a liver vein. Hepatic blood flow was measured by indocyanine green infusion/Fick's principle. From blood measurements, hepatic systemic clearance (Ksyst, Lblood/min) and hepatic intrinsic clearance (Vmax/Km, Lblood/min) of FDGal were calculated. From PET data, hepatic systemic clearance of FDGal in liver parenchyma (Kmet, mL blood/mL liver tissue/min) was calculated. Intrahepatic metabolic heterogeneity was evaluated in terms of coefficient-of-variation (CoV, %) using parametric images of Kmet. RESULTS: Mean approximation of Ksyst to Vmax/Km was 86% which validates the use of FDGal as PET tracer of hepatic metabolic function. Mean Kmet was 0.157 mL blood/mL liver tissue/min, which was lower than 0.274 mL blood/mL liver tissue/min, previously found in healthy subjects (p<0.001), in accordance with decreased metabolic function in cirrhotic livers. Mean CoV for Kmet in liver tissue was 24.4% in patients and 14.4% in healthy subjects (p<0.0001). The degree of intrahepatic metabolic heterogeneity correlated positively with HVPG (p<0.05). CONCLUSIONS: A 20-min dynamic FDGal PET/CT with arterial sampling provides an accurate measure of regional hepatic metabolic function in patients with cirrhosis. This is likely to have clinical implications for the assessment of patients with liver disease as well as treatment planning and monitoring. PMID- 23339955 TI - New onset diabetes after transplantation: a type 1.5 diabetes or latent autoimmune diabetes of adults? PMID- 23339956 TI - Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. AB - BACKGROUND AND PURPOSE: Rivaroxaban has recently been approved for stroke prevention in atrial fibrillation. However, lack of an effective antidote represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with rivaroxaban, and to examine the effectiveness of different hemostatic factors in preventing excess hematoma expansion. METHODS: In C57BL/6 mice receiving 10 or 30 mg/kg rivaroxaban by gastric gavage, plasma concentration, prothrombin time, and coagulation factor activities were measured repeatedly. Thirty minutes after inducing ICH by intrastriatal collagenase-injection, mice received an intravenous injection of either saline, prothrombin complex concentrate (100 U/kg), murine fresh frozen plasma (200 MUL), or recombinant human Factor VIIa (1 mg/kg). ICH volume was quantified on brain cryosections and using hemoglobin spectrophotometry 24 hours later. RESULTS: Rivaroxaban in 30 mg/kg dose substantially increased the hematoma volume in ICH induced by 0.060 U collagenase. Prothrombin complex concentrate, fresh frozen plasma, or Factor VIIa prevented excess hematoma expansion caused by anticoagulation. Prevention of hematoma expansion by prothrombin complex concentrate was dose-dependent. None of the 3 agents completely corrected the prolonged prothrombin time, although they restored the activities of deficient FII and X. CONCLUSIONS: Prothrombin complex concentrate, Factor VIIa, and fresh frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with rivaroxaban. The efficacy and safety of this reversal strategy must be further evaluated in clinical studies. PMID- 23339957 TI - Neuroimaging findings in cryptogenic stroke patients with and without patent foramen ovale. AB - BACKGROUND AND PURPOSE: Patent foramen ovale (PFO) and cryptogenic stroke are commonly associated but some PFOs are incidental. Specific radiological findings associated with PFO may be more likely to indicate a PFO-related cause. We examined whether specific radiological findings are associated with PFO among subjects with cryptogenic stroke and known PFO status. METHODS: We analyzed the Risk of Paradoxical Embolism(RoPE) Study database of subjects with cryptogenic stroke and known PFO status, for associations between PFO and: (1) index stroke seen on imaging, (2) index stroke size, (3) index stroke location, (4) multiple index strokes, and (5) prior stroke on baseline imaging. We also compared imaging with purported high-risk echocardiographic features. RESULTS: Subjects (N=2680) were significantly more likely to have a PFO if their index stroke was large (odds ratio [OR], 1.36; P=0.0025), seen on index imaging (OR, 1.53; P=0.003), and superficially located (OR, 1.54; P<0.0001). A prior stroke on baseline imaging was associated with not having a PFO (OR, 0.66; P<0.0001). Finding multiple index strokes was unrelated to PFO status (OR, 1.21; P=0.161). No echocardiographic variables were related to PFO status. CONCLUSIONS: This is the largest study to report the radiological characteristics of patients with cryptogenic stroke and known PFO status. Strokes that were large, radiologically apparent, superficially located, or unassociated with prior radiological infarcts were more likely to be PFO-associated than were unapparent, smaller, or deep strokes, and those accompanied by chronic infarcts. There was no association between PFO and multiple acute strokes nor between specific echocardiographic PFO features with neuroimaging findings. PMID- 23339960 TI - Clopidogrel added to aspirin adds no benefit but bleeding risk in patients with recent lacunar stroke. PMID- 23339959 TI - Induction of cooling with a passive head and neck cooling device: effects on brain temperature after stroke. AB - BACKGROUND AND PURPOSE: Therapeutic hypothermia improves clinical outcome after cardiac arrest and appears beneficial in other cerebrovascular diseases. We conducted this study to investigate the relationship between surface head/neck cooling and brain temperature. METHODS: Prospective observational study enrolling consecutive patients with severe ischemic or hemorrhagic stroke undergoing intracranial pressure (ICP) and brain temperature monitoring. Arterial pressure, ICP, cerebral perfusion pressure, heart rate, brain, tympanic, and bladder temperature were continuously registered. Fifty-one applications of the Sovika cooling device were analyzed in 11 individual patients. RESULTS: Sovika application led to a significant decrease of brain temperature compared with baseline with a maximum of -0.36 degrees C (SD, 0.22) after 49 minutes (SD, 17). During cooling, dynamics of brain temperature differed significantly from bladder (-0.25 degrees C [SD, 0.15] after 48 minutes [SD, 19]) and tympanic temperature ( 1.79 degrees C [SD, 1.19] after 37 minutes [SD, 16]). Treatment led to an increase in systolic arterial pressure by >20 mm Hg in 14 applications (n=7 patients) resulting in severe hypertension (>180 mm Hg) in 4 applications (n=3). ICP increased by >10 mm Hg in 7 applications (n=3), led to ICP crisis >20 mm Hg in 6 applications (n=3), and a drop of cerebral perfusion pressure <50 mm Hg in 1 application. CONCLUSIONS: Although the decrease of brain temperature after Sovika cooling device application was statistically significant, we doubt clinical relevance of this rather limited effect (-0.36 degrees C). Moreover, the transient increases of blood pressure and ICP warrant caution. PMID- 23339958 TI - Amino terminal pro-B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy. AB - BACKGROUND AND PURPOSE: Because of its association with atrial fibrillation and heart failure, we hypothesized that amino terminal pro-B-type natriuretic peptide (NT-proBNP) would identify a subgroup of patients from the Warfarin-Aspirin Recurrent Stroke Study, diagnosed with inferred noncardioembolic ischemic strokes, where anticoagulation would be more effective than antiplatelet agents in reducing risk of subsequent events. METHODS: NT-proBNP was measured in stored serum collected at baseline from participants enrolled in Warfarin-Aspirin Recurrent Stroke Study, a previously reported randomized trial. Relative effectiveness of warfarin and aspirin in preventing recurrent ischemic stroke or death over 2 years was compared based on NT-proBNP concentrations. RESULTS: About 95% of 1028 patients with assays had NT-proBNP below 750 pg/mL, and among them, no evidence for treatment effect modification was evident. For 49 patients with NT-proBNP >750 pg/mL, the 2-year rate of events per 100 person-years was 45.9 for the aspirin group and 16.6 for the warfarin group, whereas for 979 patients with NT-proBNP <=750 pg/mL, rates were similar for both treatments. For those with NT proBNP >750 pg/mL, the hazard ratio was 0.30 (95% confidence interval: 0.12-0.84; P=0.021) significantly favoring warfarin over aspirin. A formal test for interaction of NT-proBNP with treatment was significant (P=0.01). CONCLUSIONS: For secondary stroke prevention, elevated NT-proBNP concentrations may identify a subgroup of ischemic stroke patients without known atrial fibrillation, about 5% based on the current study, who may benefit more from anticoagulants than antiplatelet agents. Clinical Trial Registration- This trial was not registered because enrollment began before 2005. PMID- 23339961 TI - Remote limb perconditioning [corrected] and postconditioning: will it translate into a promising treatment for acute stroke? PMID- 23339962 TI - Letter by Mead et al regarding article, "Selective serotonin reuptake inhibitors for stroke: more trials are needed". PMID- 23339963 TI - Defining intravenous recombinant tissue plasminogen activator failure. PMID- 23339964 TI - Convergent validity and interrater reliability of estimating the ABCD2 score from medical records. AB - BACKGROUND AND PURPOSE: The ABCD(2) score is increasingly used for risk stratification of transient ischemic attack patients. We sought to determine the reliability and convergent validity of retrospective ABCD(2) score estimation from medical records. METHODS: We compared ABCD(2) scores that were prospectively determined by a vascular neurology attending to scores determined retrospectively from medical record review. Emergency department records and neurology consult notes for patients with acute transient ischemic attack were abstracted with explicit ABCD(2) scoring redacted. Scores were estimated by 2 independent raters using these records. Estimated ABCD(2) component scores, total scores, and risk category were compared both between retrospective raters and with prospectively obtained scores. Reliability was assessed using unweighted kappa statistics. RESULTS: Interrater reliability was substantial with 72% exact agreement in total score between retrospective raters (kappa=0.64) and nearly perfect with 82% agreement for ABCD(2) category (kappa=0.71). Interrater agreement was best for age and diabetes mellitus and poorest for clinical features and duration. Agreement between the retrospective raters and prospectively obtained score was >90% for age, blood pressure, and diabetes mellitus, but only ~70% for clinical features and duration. Retrospectively, estimated total ABCD(2) score exactly matched the prospective score in 58% of patients for rater 1 and 44% of patients for rater 2. Retrospectively, estimated ABCD(2) category matched the prospectively scored category in 67% of patients for rater 1 and 71% of patients for rater 2. CONCLUSIONS: The ABCD(2) score can be abstracted from medical records with substantial interrater reliability but limited convergent validity. This may lead to misclassification of risk category in more than one third of patients. PMID- 23339965 TI - A novel approach to assess the probability of disease eradication from a wild animal reservoir host. AB - Surveying and declaring disease freedom in wildlife is difficult because information on population size and spatial distribution is often inadequate. We describe and demonstrate a novel spatial model of wildlife disease-surveillance data for predicting the probability of freedom of bovine tuberculosis (caused by Mycobacterium bovis) in New Zealand, in which the introduced brushtail possum (Trichosurus vulpecula) is the primary wildlife reservoir. Using parameters governing home-range size, probability of capture, probability of infection and spatial relative risks of infection we employed survey data on reservoir hosts and spillover sentinels to make inference on the probability of eradication. Our analysis revealed high sensitivity of model predictions to parameter values, which demonstrated important differences in the information contained in survey data of host-reservoir and spillover-sentinel species. The modelling can increase cost efficiency by reducing the likelihood of prematurely declaring success due to insufficient control, and avoiding unnecessary costs due to excessive control and monitoring. PMID- 23339966 TI - 5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones as potential anticancer agents with anti-inflammatory properties. AB - A series of novel 5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine 4,6(1H,5H)-diones (3a-z) have been evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells (GI(50)=850 nM), against leukemia SR cancer cells (GI(50)=1.45 MUM), and OVCAR-3 (GI(50)=1.26 MUM) ovarian cancer cell lines. The structurally related compound 3s had a GI(50) value of 1.77 MUM against MDA-MB-435 cells. The N-naphthoyl analogue 3t had GI(50) values of 1.30 and 1.91 MUM against HOP-92 non-small cell lung cancer and MDA-MB-435 melanoma cell lines, respectively. The related analogue 3w had GI(50) values of 1.09 MUM against HOP-92 non-small cell lung cancer cell lines. Interestingly, docking of the two active molecules 3k and 3w into the active site of COX-2 indicates that these compounds are COX-2 ligands with strong hydrophobic and hydrogen bonding interactions. Thus, compounds 3k, 3t, 3s, and 3w constitute a new class of anticancer/anti-inflammatory agents that may have unique potential for cancer therapy. PMID- 23339967 TI - Characterization of a key aminoglycoside phosphotransferase in gentamicin biosynthesis. AB - Gentamicin is an aminoglycoside antibiotic obtained from cultures of Micromonospora as the important anti-infective agents. Gentamicin which lacks 3' hydroxyl group can avoid the attack from the modification enzymes of antibiotic resistant bacteria in clinic. Consequently, C-3' dehydroxylation is the key step in gentamicins biosynthesis. We suppose that there are some enzymes responsible for converting intermediate JI-20A to 3',4'-bisdehydroxylated final product gentamicin C(1a), while phosphorylation of 3'-OH is possibly the first step for C 3' dehydroxylation. The gentamicin biosynthetic gene gntI, encoding an aminoglycoside phosphotransferase, was cloned from Micromonospora echinospora ATCC15835 and overexpressed in Escherichia coli. The resulting phosphotransferase was purified, and the kinetic parameters for Kanamycin A, Kanamycin B, Neomycin B and Amikacin were determined. Elucidation of NMR data of phosphorylated kanamycin B has unambiguously demonstrated a regiospecific phosphorylation of 3'-hydroxyl of the 6-aminohexose ring. The results described here partly confirm that the 3' dehydroxylation step is preceded by a 3' phosphorylation step. It is predicted that GntI belongs to a new aminoglycoside phosphotransferase group involved with aminoglycoside antibiotics biosynthesis pathway. PMID- 23339968 TI - Impact of inhomogeneous optical scattering coefficient distribution on recovery of optical absorption coefficient maps using tomographic photoacoustic data. AB - We present a study through extensive simulation that considers the impact of inhomogeneous optical scattering coefficient distribution on recovery of optical absorption coefficient maps using tomographic photoacoustic data collected from media mimicking breast tissue. We found that while the impact of scattering heterogeneities/targets is modest on photoacoustic recovery of optical absorption coefficients, the impact of scattering contrast caused by adipose tissue, a layer of normal tissue along the boundary of the breast, is dramatic on reconstruction of optical absorption coefficients using photoacoustic data-up to 25.8% relative error in recovering the absorption coefficient is estimated in such cases. To overcome this problem, we propose a new method to enhance photoacoustic recovery of the optical absorption coefficient in heterogeneous media by considering inhomogeneous scattering coefficient distribution provided by diffuse optical tomography (DOT). Results from extensive simulations show that photoacoustic recovery of absorption coefficient maps can be improved considerably with a priori scattering information from DOT. PMID- 23339969 TI - Validity and reliability of the nicotine and marijuana interaction expectancy (NAMIE) questionnaire. AB - BACKGROUND: The co-occurring use of tobacco and marijuana among young people is a concern, yet little research has examined processes of co-use. Understanding expectancies around use of the two substances will help identify intervention targets. This study examined psychometric properties of the Nicotine and Marijuana Interaction Expectancy (NAMIE) questionnaire based on three modified scales of the Nicotine and Other Substance Interaction Expectancy (NOSIE) questionnaire. METHOD: An anonymous online survey recruited participants (N=1152) age 18-25 (mean age 20 years, 67% male, 72% Caucasian) who reported use of cigarettes and marijuana in the past 30 days. Analyses examined reliability and validity of the NAMIE. RESULTS: A confirmatory factor analysis indicated good model fit for a 3-factor model. Scales were marijuana increases tobacco use and urges, tobacco increases marijuana use and urges, and smoking to cope with marijuana urges. Subscales correlated significantly with measures of cigarette smoking (r=.08 to .27, p<.01) and nicotine dependence (r=-.07 to -.20, p<.01), marijuana use (r=.08 to .29, p<.01) and dependence (r=.27 to .42, p<.01), percent of days using both cigarettes and marijuana in the past 30 days (r=.15 to .30, p<.01), thoughts about tobacco and marijuana abstinence (r=-.09 to .44, p<.01), and motivation to quit using marijuana (F=9.43, p<.001). When entered into a regression model, variables of use and thoughts about use remained significant. CONCLUSIONS: The NAMIE was well-adapted for use with a marijuana-using community sample of young adult smokers. PMID- 23339970 TI - Northern white-breasted hedgehogs Erinaceus roumanicus as hosts for ticks infected with Borrelia burgdorferi sensu lato and Anaplasma phagocytophilum in Romania. AB - Borrelia burgdorferi sensu lato and Anaplasma phagocytophilum are two tick-borne pathogens of medical and/or veterinary importance which are distributed worldwide. Erinaceus roumanicus, the Northern white-breasted hedgehog, is a common synanthropic species that is known to carry not only the hedgehog tick, Ixodes hexagonus, but also I. ricinus, the most common European tick species. I. ricinus is the main vector of both mentioned pathogens. Within this framework and because only limited information is available on the role of E. roumanicus in the ecology of B. burgdorferi s.l. and Anaplasma phagocytophilum in Europe, we carried out an epidemiological surveillance on this species in Romania. From the 57 examined hedgehogs collected in 12 different counties, 24 presented tick infestation. Most ticks (n=959) were morphologically identified as larvae, nymphs, or adults of I. ricinus. The prevalence of B. burgdorferi s.l. was 0.4%, and that of A. phagocytophilum 12%. In all positive cases for B. burgdorferi s.l., restriction fragment length polymorphism revealed the genospecies B. afzelii. In Romania, only limited information is available on the epidemiology of B. burgdorferi s.l. and A. phagocytophilum. As hedgehogs commonly share the same environment with humans and other potential reservoir hosts for tick-borne pathogens, our study provides new epidemiological data of public health importance. PMID- 23339971 TI - Efficacy testing of several Ixodes ricinus tick repellents: different results with different assays. AB - In the European Union (EU), tick repellents for humans need to be registered and approved by the authorities in order to be marketed. As there are currently no specific technical guidelines for product evaluation, we compared 3 different test methods: the mechanical moving object bioassay (MOB), and 2 assays involving human volunteers. For the latter, procedures according to the U.S. Environmental Protection Agency (EPA) and the Stiftung Warentest (StiWa), a German consumer care organization, were used. Two repellents, Autan((r)) (AU), based on 20% Picaridin [2-(2-hydroxyethyl)-1-piperidinecarboxylic acid-1-methylpropyl ester], and ZeckWeck (ZW), based on 12.5g/100g CitriodiolTM (main compound: p-menthane 3,8-diol) were tested with all 3 assays. Three repellents, Anti Brumm((r)) naturelle, based on 20% CitriodiolTM (main compound: p-menthane-3,8-diol), G090141, based on 20% EBAAP (ethyl buthyl acetyl aminopropionate), and G090152, based on 10% decanoic acid (capric acid), which is contained in Zanzarin((r)), were tested according to the EPA and the StiWa procedures. The EPA assay indicated a significantly higher repellency of the products AU and G090141 than the StiWa test, but no difference between assays could be detected for the remaining 3 products. Also the corresponding protection times were significantly longer (approximately 4h) when determined according to EPA versus to StiWa for 3 of the products, whilst the difference was insignificant for ZW and G090152. Additionally, significantly lower numbers of ticks initially walked onto the repellent-treated skin when tested according to EPA versus to StiWa in all products except ZW and G090152. Thus, the StiWa protocol appears to pose higher demands on a repellent than the EPA method. Contrary to expectation, the MOB showed the same or even lower product efficacy when compared to the EPA and StiWa tests. Particularly, the percentage of ticks clinging to repellent-treated filter paper was significantly higher than the proportion of ticks walking onto treated skin in the other assays. This could mean that in nature more ticks may probably cling to a human protected by a given repellent than the EPA or the StiWa assay might suggest. Nevertheless, the MOB produced results that are quite similar to the tests involving human volunteers. PMID- 23339972 TI - Molecular properties and immune defense of two ferritin subunits from freshwater pearl mussel, Hyriopsis schlegelii. AB - Ferritin is a conserved iron-binding protein involved in cellular iron metabolism and host defense. In the present study, two distinct cDNAs for ferritins in the freshwater pearl mussel Hyriopsis schlegelii were identified (designated as HsFer 1 and HsFer-2) by SMART RACE approach and expressed sequence tag (EST) analysis. The full-length cDNAs of HsFer-1 and HsFer-2 were of 760 and 877 bp, respectively. Both of the two cDNAs contained an open reading frame (ORF) of 522 bp encoding for 174 amino acid residues. Sequence characterization and homology alignment indicated that HsFer-1 and HsFer-2 had higher similarity to H-type subunit of vertebrate ferritins than L-type subunit. Analysis of the HsFer-1 and HsFer-2 untranslated regions (UTR) showed that both of them had an iron response element (IRE) in the 5'-UTR, which was considered to be the binding site for iron regulatory protein (IRP). Quantitative real-time PCR (qPCR) assays were employed to examine the mRNA expression profiles. Under normal physiological conditions, the expression level of both HsFer-1 and HsFer-2 mRNA were the highest in hepatopancreas, moderate in gonad, axe foot, intestine, kidney, heart, gill, adductor muscle and mantle, the lowest in hemocytes. After stimulation with bacteria Aeromonas hydrophila, HsFer-1 mRNA experienced a different degree of increase in the tissues of hepatopancreas, gonad and hemocytes, the peak level was 2.47-fold, 9.59-fold and 1.37-fold, respectively. Comparatively, HsFer-2 showed up-regulation in gonad but down-regulation in hepatopancreas and hemocytes. Varying expression patterns indicate that two types of ferritins in H. schlegelii might play different roles in response to bacterial challenge. Further bacteriostatic analysis showed that both the purified recombinant ferritins inhibited the growth of A. hydrophila to a certain degree. Collectively, our results suggest that HsFer-1 and HsFer-2 are likely to be functional proteins involved in immune defense against bacterial infection. PMID- 23339973 TI - Modelling vitamin D status due to oral intake and sun exposure in an adult British population. AB - A mathematical model is described for estimating changes in plasma 25 hydroxyvitamin D (25(OH)D) levels throughout the year as a consequence of varying the oral intake of vitamin D and the behaviour outdoors of white British adults resident in different regions of the UK. The model yields seasonal and geographical patterns of 25(OH)D concentrations that agree closely with observational studies. Use of the model allows estimates to be easily made of the sun exposure and oral intake necessary to avoid vitamin D deficiency in defined proportions of the population, as well as strategies that would lead to vitamin D sufficiency throughout the year. The analysis demonstrates that addressing concerns about insufficient vitamin D levels, especially during the winter, may be achieved by modifying oral vitamin D intake over the winter, increasing summer sun exposure or a combination of both. PMID- 23339974 TI - Ubiquitin - omics reveals novel networks and associations with human disease. AB - Human neurodegenerative and infectious diseases and tumorigenesis are associated with alterations in ubiquitin pathways. Over 10% of the genome encode for genes that either bind or manipulate ubiquitin to affect a large proportion of biological processes. This has been the basis for the development of approaches allowing the enrichment of ubiquitinated proteins for comparisons using proteomics and mass spectrometry. Tools such as tagged tandem ubiquitin binding domains, chemically derivatized ubiquitin or anti-gly-gly-lys antibodies combined with mass spectrometry have contributed to surveys of poly-ubiquitinated proteins, poly-ubiquitin linkage diversity and protein ubiquitination sites and their relation to other posttranslational modifications at a proteome wide level, providing insights in to how dynamic alterations in ubiquitination and deubiquitination steps are associated with normal physiology and pathogenesis. PMID- 23339975 TI - Does training with human patient simulation translate to improved patient safety and outcome? AB - PURPOSE OF REVIEW: In this review, we evaluate several articles in an attempt to qualify the effect of human patient simulation in anaesthesia on patient outcome. The recognition of medical error as a significant cause of patient morbidity and mortality has sparked an increased focus on improving healthcare quality and patient safety. Simulation in anaesthesia is a potential tool to help achieve this goal by allowing anaesthesia providers to learn, practice and perfect their craft without a potential harm to patients. It has gained growing traction in the field and is recently a required element in the American Board of Anesthesiology's Maintenance of Certification in Anesthesia programme. RECENT FINDINGS: Very few studies have evaluated the effect of simulation on patient outcome. To date, one study has demonstrated improved individual clinical performance in anaesthesia after simulation training. Research suggests that simulation-based team training can reduce patient mortality and improve the quality of care as measured by surgical quality improvement measures. Simulation may improve healthcare systems by serving as a tool to detect latent error and drive process improvement. SUMMARY: Despite the adoption of simulation, further study is needed to better qualify its effect on patient safety and outcome. PMID- 23339976 TI - Dosimetric consideration of transient volume enlargement induced by edema in prostate brachytherapy seed implants. AB - PURPOSE: To investigate enlargement of prostate volume by edema during brachytherapy seed implantation and develop a nomogram model to calculate air kerma strength (AKS) required for implantation of the enlarged transient prostatic volume. MATERIALS AND METHODS: The prostate volume was measured prior and after seed implantation using trans-rectal ultrasound imaging in the operating room to obtain volume enlargement. A nomogram model was developed that calculates AKS required for implantation of the enlarged transient prostate volume with optimal dose coverage. RESULTS: The measured prostate enlargement in this study was up to 60% of the initial volume. The effective prostatic volume enlargement was calculated for three isotopes: 125I, 103Pd and 131Cs. The effective volume enlargement for 125I implants was relatively small (< 10%) because of its long half-life. For 103Pd and 131Cs with short half-lives, additional AKS up to 20% and 30%, respectively, might be required to provide appropriate dose coverage of possible enlarged prostatic volumes. CONCLUSIONS: Prostate volume enlargement should be considered to obtain optimal dose coverage particularly for short half-life isotopes such as 131Cs and 103Pd. The nomogram model developed in this work provides the AKS required for implants with a wide range of prostatic volume enlargements (5-100%) for three isotopes. KEYWORDS: prostate brachytherapy; nomogram; air-kerma strength; edema; volume enlargement. PMID- 23339977 TI - Assessment of an existing and modified model for predicting non sentinel lymph node metastasis in breast cancer patients with positive sentinel node biopsy. AB - SUMMARY: The Memorial Sloan Kettering Cancer Center (MSKCC) breast nomogram has been validated in different populations. In this study, the nomogram was validated for the first time in a Middle East population sample. Although our sample was found to have significant differences from the dataset from which the model was derived, the nomogram proved to be accurate in predicting non sentinel axillary lymph node metastasis. An attempt to use the proportions of involved sentinel lymph nodes instead of absolute numbers of positive and negative sentinel lymph nodes, yet using the same online calculator to predict the probability of non sentinel axillary lymph node metastasis, improved the accuracy, specificity, negative predictive value, and false negative rate. BACKGROUND: Axillary clearance is the standard of care in patients with invasive breast cancer and positive sentinel lymph node biopsy. However, in 40-60% of patients, the sentinel lymph nodes are the only involved lymph nodes in the axilla. The Memorial Sloan Kettering Cancer Center (MSKCC) breast nomogram serves to identify a subgroup of patients with low risk of non sentinel lymph node (NSLN) metastasis, in whom axillary lymph node dissection (ALND) could be spared, and thereby, preventing the unwarranted associated morbidity. METHODS: The MSKCC nomogram was applied on 91 patients who met the criteria. A modified predictive model was developed by substituting proportions of positive and negative SLN for their absolute numbers. The accuracy was assessed by calculating the area under the receiver-operator characteristic (ROC) curve. RESULTS: The MSKCC nomogram achieved an area under the ROC curve of 0.76. The area under the curve for the modified predictive model was 0.81. The specificity, negative predictive value, and false negative were 30%, 71%, 20% (MSKCC model) and 55%, 84%, 17% (modified model) at 20% predicted probability cut-off values. CONCLUSION: Although differences existed in characteristics of our breast cancer population, and in the methods of sentinel lymph node metastasis detection, the MSKCC model proved to be accurate. An attempt to replace the number of positive and negative SLNs with proportions in the MSKCC model raised the accuracy but did not achieve statistical significance (p = 0.09). KEYWORDS: Breast cancer, Sentinel lymph node, Non sentinel lymph node, Axillary clearance, Predictive model. PMID- 23339978 TI - Docetaxel in advanced or metastatic endometrial cancer: Clinical Outcome (Mansoura University). AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the efficacy, safety and toxicity of docetaxel as first line chemotherapy or previously treated patients (one regimen) in patients with recurrent or metastatic endometrial cancer. PATIENTS AND METHODS: Prospective phase II, in patients referred to the Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, Egypt.. Fifty patients with advanced or metastatic endometrial cancer were enrolled to receive docetaxel 70 mg/m2 administered intravenously on day 1 of a 3-week cycle. If patients responded well to docetaxel, additional cycles were administered until progressive disease or unacceptable toxicity occurred. Therapy response was evaluated every 6-week. RESULTS: Fifty patients with a median age of 60 years (range, 40-70 years) who entered the study, 17 patients (34%) had received one prior chemotherapy regimen. All patients were evaluable for efficacy, yielding an overall response rate of 34% (95% confidence interval, 14.8-55.6%); complete response and partial response (PR) were 4 and 30%, respectively. Of 17 pretreated patients, five (29%) had a PR. The median duration of response was 2 months. The median time to progression was 4 months and the median survival time was 18 months . The predominant toxicity was grade 3-4 neutropenia, occurring in 92% of the patients, although febrile neutropenia arose in 10% of the patients. Oedema was mild and infrequent. CONCLUSION: This prospective phase II trial, clearly demonstrated that docetaxel is active in the treatment of endometrial cancer. Toxicity was manageable and predominantly haematologic. KEYWORDS: docetaxel; advanced or metastatic endometrial cancer; phase II. PMID- 23339979 TI - Dosimetric comparison between bone marrow sparing intensity-modulated radiation therapy and conventional techniques in the treatment of cervical cancer: a retrospective study. AB - PURPOSE: To investigate enlargement of prostate volume by edema during brachytherapy seed implantation and develop a nomogram model to calculate air kerma strength (AKS) required for implantation of the enlarged transient prostatic volume. MATERIALS AND METHODS: The prostate volume was measured prior and after seed implantation using trans-rectal ultrasound imaging in the operating room to obtain volume enlargement. A nomogram model was developed that calculates AKS required for implantation of the enlarged transient prostate volume with optimal dose coverage. RESULTS: The measured prostate enlargement in this study was up to 60% of the initial volume. The effective prostatic volume enlargement was calculated for three isotopes: 125I, 103Pd and 131Cs. The effective volume enlargement for 125I implants was relatively small (< 10%) because of its long half-life. For 103Pd and 131Cs with short half-lives, additional AKS up to 20% and 30%, respectively, might be required to provide appropriate dose coverage of possible enlarged prostatic volumes. CONCLUSIONS: Prostate volume enlargement should be considered to obtain optimal dose coverage particularly for short half-life isotopes such as 131Cs and 103Pd. The nomogram model developed in this work provides the AKS required for implants with a wide range of prostatic volume enlargements (5-100%) for three isotopes. KEYWORDS: prostate brachytherapy, nomogram, airkerma strength, edema, volume enlargement. PMID- 23339980 TI - Trends in oesophagus and Stomach cancer incidence in Bangalore, India. AB - BACKGROUND: During recent decades, an increase in the incidence of certain oesophago-gastric cancer has been reported in some countries and in India. This study sought to analyze oesophageal and gastric cancer incidence trends in Bangalore by sex and morphology for the period 1982-2007. PATIENTS AND METHODS: Oesophageal and gastric cancer cases were drawn from Bangalore population-based cancer registry locating in Kidwai memorial Institute of Oncology started in 1982 under national cancer Registry Programme funded by Indian Council of Medical Research. Time trends in sex- and age-standardized cancer incidence rates were analyzed by site and histology over the study period, using relative change. RESULTS: Age-standardised oesophageal cancer incidence rates increased in males, in females failed to register a significant trend over the study period. Overall, gastric cancer decreased from 9.81 and 5.48 rates per 100 000 person-years in 1982-86 to 9.45 and 5.25 in 2002-07, among men and women, respectively. Where as oesophageal adenocarcinomas increased sharply in both sex, among men, oesophageal squamous cell cancer rates increased steadily from the mid-1982s onwards a bit decline was observed from 1997, the same trend observed in females. The gastric cancer decreased over the study period. There was a marked decrease in the incidence of oesophago-gastric cancer presenting with unknown and unspecified morphology reported. KEYWORDS: adenocarcinoma, Oesophageal and stomach, incidence, age specific rate, age adjusted rate, population-based registry, trends. PMID- 23339981 TI - Clinical significance of telomerase genes (hTERC and hTERT) amplification in patients with acute myeloid leukemia. AB - Acute myeloid leukemia (AML) describes a heterogenous group of hematological disorders. Cytogenetic and molecular assays have allowed patients' follow up aiming for detection of minimal residual disease, prediction of patients' outcome, in addition to providing the rationale for designing novel molecular targeted therapeutic strategies. Human telomerase reverse transcriptase (hTERT), encoded by the hTERT gene and the telomerase RNA component (hTERC) genes are frequently amplified in human tumors, which may indicate that the hTERT and the hTERC genes may be target for amplification during the transformation of human malignancies including hematological malignancies. This genetic event has implications in diagnosis, prognosis and therapeutics of cancer. To evaluate the hTERC and hTERT genes as a prognostic marker in patients with AML, hTERC and hTERT gene amplification was studied in 20 adult AML patients using a commercial FISH probes (Kreatech) designated to detect the copy numbers of the genes. They were 12 males and 8 females. Their ages ranged from 16 to 67 years. The patients were further divided into two groups; group I (12 patients) includes newly diagnosed AML patients and group II (8 patients) includes patients taken at 28th day of chemotherapy. The hTERC amplification was detected in 19/21 cases (90.5%). The copy number of the gene ranged from 2-5 copies per interphase cell. For the hTERT gene, the amplification was found in the same percent of the patients. The copy number of the gene ranged from 2-9 copies per interphase cell. On comparing the group I with group II there was a highly statistical significant difference regarding the percent of amplification of both genes. The percent of amplification of hTERT gene was found to be higher among patients with poor outcome of the disease than in patients with good outcome. On the contrary the hTERC gene amplification did not exhibit such a correlation. In conclusion, hTERT and hTERC genes amplification were detected in patients with AML; therefore telomerase can be a good cancer marker which may be involved in carcinogenesis of leukemia. Higher amplification was found in de novo cases than cases in remission which emphasize its role in clinical analysis, disease monitoring and detection of minimal residual disease. KEYWORDS: Acute Myeloid leukemia, telomerase amplification, hTERC gene, hTERT gene. PMID- 23339982 TI - Management Of Metastatic Breast Cancer (MBC). AB - Chemotherapy of metastatic breast carcinoma so far, is not curative using the currently available chemotherapeutic, hormonal or biologic agents. The treatment of metastatic breast cancer is aimed mainly at alleviation of symptoms rather than cure. The first choice of therapy is dependent on patient age, performance status, hormone receptor status, human epidermal growth factor receptor-2 (HER 2), involvement of the viscera, or enrollment of patients in investigational trials. Combination of chemotherapeutic drugs showed an advantage for survival, tumor response and time to progression with adverse effects of these agents. It is very important, therefore, to balance between the benefits of treatment and the adverse effects and complication of therapy. KEYWORDS: chemotherapy, metastatic, HER-2, breast, combination. PMID- 23339983 TI - Extensive review in the detection of the malignant transformation of pleomorphic adenoma. AB - BACKGROUND AND OBJECTIVES: There is an increasing likelihood of malignant change in pleomorphic adenoma (PA) with time. This extensive review aims to highlight the current areas of difficulty or controversy in the diagnosis of malignant transformation of pleomorphic adenoma - a subject of most interest and challenge to a pathologist. It is also the objective of this review to compare the clinical and pathological points-of-view on the diagnosis of malignant transformation of pleomorphic adenoma. METHODS: A literature search using MEDLINE, accessed through the National Library of Medicine PubMed interface, for articles relating to malignant transformation of pleomorphic salivary adenoma written in the English language. RESULTS: The updated literature indicates that carcinomas in pleomorphic adenoma may arise in an older age group than benign lesions and are usually larger and longer standing lesions. The use of molecular changes to study malignant transformation of pleomorphic adenoma, unfortunately, have no specific expression on the tumor suppressor genes to detect the malignant transformation of pleomorphic adenoma from pathological point view. CONCLUSION: The use of combined clinical evidence and pathological evidence are very important in the detection of the malignant transformation of pleomorphic adenoma. KEYWORDS: pleomorphic adenoma, malignant transformation of pleomorphic adenoma. PMID- 23339984 TI - Primary adenoid cystic carcinoma of the breast: Case report and review of the literature. AB - Adenoid cystic carcinoma of the breast is a very rare neoplasm. We report a case of adenoid cystic carcinoma of the right breast presented with painless lump in the upper outer quadrant managed with lumpectomy, axillary lymph node staging and adjuvant local external radiotherapy to the whole breast with simultaneous integrated boost to the site of primary disease using respiratory gated intensity modulated radiotherapy. The available literature is reviewed. KEYWORDS: Adenoid cystic cancer breast, mastectomy, adjuvant radiotherapy. PMID- 23339985 TI - Approaches to management of adenocarcinoma following colocystoplasty. AB - Primary adenocarcinoma of the urinary bladder is rare and more so is adenocarcinoma arising in an augmented colocystoplastic bladder. We present a case of adenocarcinoma developing in a urinary bladder after colocystoplasty which was managed by radical cystectomy with bilateral pelvic lymphadenectomy. The post-operative histopathology showed the lesion to be an Adenocarcinoma with spread to the pericolic lymphnodes and not the pelvic lymphnodes. There are no guidelines for bladder screening in these patients who appear to be at risk. Radical Cystectomy remains the treatment of choice. Though post op irradiation has been reported, its role is not clearly defined. Role of chemotherapy in the adjuvant setting is yet to be defined. Following this is the literature review and a discussion on Adenocarcinoma arising in a colocystoplastically augmented bladder. KEYWORDS: Adenocarcinoma, urinary bladder, cystoplastically augmented bladder, radical cystectomy. PMID- 23339986 TI - Primary Non-Hodgkin Lymphoma of frontal sinus diagnosed by fine needle aspiration cytology. AB - We present a rare case of primary non-Hodgkins Lymphoma of the frontal sinus diagnosed by Fine needle aspiration cytology (FNAC). FNAC is a safe, simple, rapid and effective technique that could be used to diagnose lesions even in unusual sites like paranasal sinuses with effective radiological guidance. Neoplasms of the frontal sinus could be easily misdiagnosed as an inflammatory process clinically. FNAC is a simple test to rule out a neoplasm. A review of a single case including radiographic, clinical, and pathologic findings was done, followed by a discussion on the pathological differential diagnosis highlighting relevant literature. Timely diagnosis is critical in the management of these cases. KEYWORDS: Fine needle aspiration cytology, non-Hodgkin lymphoma, diffuse large B cell lymphoma, frontal sinus. PMID- 23339987 TI - Photopatternable transparent conducting oxide nanoparticles for transparent electrodes. AB - We report a method to fabricate tailored transparent electrodes using photopatternable transparent conducting oxide nanoparticles (TCO NPs). We demonstrate solution-processed micropatterns by a conventional photolithography technique. We have synthesized indium tin oxide (ITO) NPs and functionalized them with a photolabile group, such as t-butoxycarbonyl (t-BOC), which can be deprotected by a chemical amplification reaction in the solid state film. The chemical amplification reaction leads to a shortening of the ligand that changes the solubility of the resulting ITO films. This ligand shortening process also contributes to a reduction of the sheet resistance in the resulting photopatterned ITO films. Furthermore, we have demonstrated the general viability and strength of this approach by also photopatterning zinc oxide (ZnO) NPs. PMID- 23339988 TI - Cyclic patterns of cerebral malaria admissions in Papua New Guinea for the years 1987-1996. AB - Data on the dynamics of malaria incidence, admissions and mortality and their best possible description are very important to better forecast and assess the implementation of programmes to register, monitor (e.g. by remote sensing) and control the disease, especially in endemic zones. Semi-annual and seasonal cycles in malaria rates have been observed in various countries and close similarity with cycles in the natural environment (temperature, heliogeophysical activity, etc.), host immunity and/or virulence of the parasite suggested. This study aimed at confirming previous results on malaria cyclicity by exploring whether trans year and/or multiannual cycles might exist. The exploration of underlying chronomes (time structures) was done with raw data (without smoothing) by linear and nonlinear parametric regression models, autocorrelation, spectral (Fourier) and periodogram regression analysis. The strongest cyclical patterns of detrended malaria admissions were (i) annual period of 1.0 year (12 months or seasonality); (ii) quasi-biennial cycle of about 2.25 years; and (iii) infrannual, circadecennial cycle of about 10.3 years. The seasonal maximum occurred in May with the minimum in September. Notably, these cycles corresponded to similar cyclic components of heliogeophysical activity such as sunspot seasonality and solar activity cyclicities and well-known climate/weather oscillations. Further analyses are thus warranted to investigate such similarities. In conclusion, multicomponent cyclical dynamics of cerebral malaria admissions in Papua New Guinea were observed thus allowing more specific analyses and modelling as well as correlations with environmental factors of similar cyclicity to be explored. Such further results might also contribute to and provide more precise estimates for the forecasting and prevention, as well as the better understanding, of the dynamics and aetiology of this vector-borne disease. PMID- 23339989 TI - Application of iChemExplorer in pharmaceutical pH stress testing. AB - pH stress testing is an integral part of pharmaceutical stress testing and is a regulatory requirement for validating a stability indicating analytical method and elucidating degradation products and degradation pathways. This paper reports the results of an evaluation of iChemExplorer (ICE) for drug substance and drug product pH stress testing in comparison with the conventional (manual) approach. ICE is a simple and inexpensive technology, and through real case studies it was demonstrated that ICE is an efficient and "fit-for-purpose" alternative in conducting pharmaceutical pH stress testing. In addition, when using a non isothermal ICE protocol, it is feasible to estimate the pH degradation kinetics (e.g., E(a)) using the ICE software. PMID- 23339990 TI - Development of LC-MS/MS method for the simultaneous analysis of the cardioprotective drug dexrazoxane and its metabolite ADR-925 in isolated cardiomyocytes and cell culture medium. AB - Dexrazoxane (DEX) is the only clinically used drug effective against anthracycline-induced cardiotoxicity and extravasation injury. However, the mechanism of its cardioprotective action still remains elusive. This paucity of comprehensive data is at least partially caused by the analytical difficulties associated with selective and sensitive simultaneous determination of the parent drug and its putative active metabolite ADR-925 in the relevant biological material. The aim of this study was to develop and validate the first LC-MS/MS method for simultaneous determination of DEX and ADR-925 in the isolated rat neonatal ventricular cardiomyocytes (NVCMs) and the cell culture medium. The analysis was performed on a Synergi Polar-RP column using the gradient profile of the mobile phase composed of 2mM ammonium formate and methanol. Electrospray ionization and ion trap mass analyzer were used as ionization and detection techniques, respectively. NVCMs were precipitated with methanol and the cell culture medium samples were diluted with the same solvent prior the LC-MS/MS analysis. The method was validated within the range of 4-80pmol/10(6) NVCMs and 7 70pmol/10(6) NVCMs for DEX and ADR-925, respectively, and at the concentrations of 8-100MUM for both compounds in the culture cell medium. The practical applicability of this method was confirmed by the pilot analysis of NVCMs and the corresponding cell medium samples from relevant in vitro experiment. Hence, the LC-MS/MS method developed in this study represents a modern analytical tool suitable for investigation of DEX bioactivation inside the cardiomyocytes. In addition, the basic utility of the method for the analysis of DEX and ADR-925 in plasma samples was proved in a pilot experiment. PMID- 23339991 TI - Dietary nutrients associated with short and long sleep duration. Data from a nationally representative sample. AB - Short sleep duration is associated with weight gain and obesity, diabetes, cardiovascular disease, psychiatric illness, and performance deficits. Likewise, long sleep duration is also associated with poor physical and mental health. The role of a healthy diet in habitual sleep duration represents a largely unexplored pathway linking sleep and health. This study evaluated associations between habitual sleep parameters and dietary/nutritional variables obtained via the National Health and Nutrition Examination Survey (NHANES), 2007-2008. We hypothesized that habitual very short (<5h) short (5-6h) and long (9+h) sleep durations are associated with intake of a number of dietary nutrient variables. Overall, energy intake varied across very short (2036kcal), short (2201kcal), and long (1926kcal) sleep duration, relative to normal (2151kcal) sleep duration (p=0.001). Normal sleep duration was associated with the greatest food variety (17.8), compared to very short (14.0), short (16.5) and long (16.3) sleep duration (p<0.001). Associations between sleep duration were found across nutrient categories, with significant associations between habitual sleep duration and proteins, carbohydrates, vitamins and minerals. In stepwise analyses, significant contributors of unique variance included theobromine (long sleep RR=0.910, p<0.05), vitamin C (short sleep RR=0.890, p<0.05), tap water (short sleep RR=0.952, p<0.001; very short (<5h) sleep RR=0.941, p<0.05), lutein+zeaxanthin (short sleep RR=1.123, p<0.05), dodecanoic acid (long sleep RR=0.812, p<0.05), choline (long sleep RR=0.450, p=0.001), lycopene (very short (<5h) sleep RR=0.950, p<0.05), total carbohydrate (very short (<5h) sleep RR=0.494, p<0.05; long sleep RR=0.509, p<0.05), selenium (short sleep RR=0.670, p<0.01) and alcohol (long sleep RR=1.172, p<0.01). Overall, many nutrient variables were associated with short and/or long sleep duration, which may be explained by differences in food variety. Future studies should assess whether these associations are due to appetite dysregulation, due to short/long sleep and/or whether these nutrients have physiologic effects on sleep regulation. In addition, these data may help us better understand the complex relationship between diet and sleep and the potential role of diet in the relationship between sleep and obesity and other cardiometabolic risks. PMID- 23339992 TI - Clinical and molecular study of a new form of hereditary myotonia in Murrah water buffalo. AB - Hereditary myotonia caused by mutations in CLCN1 has been previously described in humans, goats, dogs, mice and horses. The goal of this study was to characterize the clinical, morphological and genetic features of hereditary myotonia in Murrah buffalo. Clinical and laboratory evaluations were performed on affected and normal animals. CLCN1 cDNA and the relevant genomic region from normal and affected animals were sequenced. The affected animals exhibited muscle hypertrophy and stiffness. Myotonic discharges were observed during EMG, and dystrophic changes were not present in skeletal muscle biopsies; the last 43 nucleotides of exon-3 of the CLCN1 mRNA were deleted. Cloning of the genomic fragment revealed that the exclusion of this exonic sequence was caused by aberrant splicing, which was associated with the presence of a synonymous SNP in exon-3 (c.396C>T). The mutant allele triggered the efficient use of an ectopic 5' splice donor site located at nucleotides 90-91 of exon-3. The predicted impact of this aberrant splicing event is the alteration of the CLCN1 translational reading frame, which results in the incorporation of 24 unrelated amino acids followed by a premature stop codon. PMID- 23339994 TI - Papular mycosis fungoides on the legs: a case report. PMID- 23339995 TI - Effect of pulse repetition frequency and scan step size on the dimensions of the lesions formed in agar by HIFU histotripsy. AB - Histotripsy uses high-intensity focused ultrasound pulses at low duty cycle to generate energetic bubble clouds inside tissue to fractionate a region. As a potential tumor treatment modality, this cavitation-based non-invasive technique has the advantages of easy monitoring and sharp borders. Aiming at therapy efficiency, we experimentally investigated the effects of pulse repetition frequency (PRF) and lateral scan step size on the dimensions of lesions formed through HIFU histotripsy in agar mimicking tissue in terms of mechanical (not acoustical) properties. The single-element spherically focused source (1.1 MHz, 6.34 cm focal length, f/1) was excited to reach the peak compressional and rarefactional pressures of ~102 and 17 MPa, respectively. A targeted rectangular block of 4.5 mm wide (lateral) and 6mm deep (axial) was scanned in a raster pattern with a constant axial step size of 3mm. The lateral step size was varied between 375, 750, 1500, 2250 and 4500 MUm. Pulses at each treatment location consisted of 5000 20-cycle sine wave tone bursts with the PRF of 167, 333 or 1000 Hz. Results suggested that the bubble activity region could extend beyond the -3 dB region and that refining the lateral scan mesh and/or increasing PRF enlarged the lesion extent. The 1500 MUm-333 Hz and the 1500 MUm-1 kHz conditions were in a more favorable position to be viewed as optimal with regard to lesion volume generation rate, bubble activity region width, and the potential for thermal damage. PMID- 23339996 TI - A lateral field excited (yxl)88 degrees LiTaO3 bulk acoustic wave sensor with interdigital electrodes. AB - In this work, to improve the sensitivity of lateral field excited (LFE) sensors to changes of liquid conductivity, LFE bulk acoustic wave sensors with interdigital electrodes are investigated. LFE bulk acoustic wave on thickness shear mode is excited successfully by interdigital electrodes on (yxl)88 degrees LiTaO(3) and applied in liquid-phase sensor. The electric field direction of LFE (yxl)88 degrees LiTaO(3) plates is determined. Based on this, several LFE bulk acoustic wave sensors with interdigital electrodes are designed and fabricated to increase the sensitivity of LiTaO(3) LFE sensors. The results show that the (yxl)88 degrees LiTaO(3) LFE sensor with interdigital electrodes is 10.9 times and 2.1 times more sensitive to changes in liquid conductivity compared to traditional LFE devices with single gap circular electrodes and Archimedes spiral electrodes, respectively. The results are important for investigating high sensitivity LFE bulk acoustic wave sensors by using LiTaO(3) crystal. PMID- 23339997 TI - [A new case of the absence of N20 at early cerebral anoxia-ischemia evaluation by somatosensory evoked potentials]. PMID- 23339998 TI - [Acute respiratory distress syndrome criteria]. PMID- 23339999 TI - Testicular ischemia-reperfusion may alter micro-rheological parameters in laboratory rats. AB - Ischemia-reperfusion-caused hemorheological alterations have been widely studied but the effect of testicular ischemia-reperfusion has not so far. In this study 14 Sprague-Dawley rats were involved. In the ischemia-reperfusion group under general anaesthesia the left testis was explored by opening the scrotum then the deferent duct and vasculature were clamped for 30 minutes. Testicular microcirculation was monitored by laser Doppler flowmetry. The right testis was untouched. In the control group: only anaesthesia was induced. Blood sampling occurred before and after ischemia, at the 60th minute of reperfusion and on the 1st postoperative day for determining hematological parameters (microcell counter), erythrocyte deformability (slit-flow ektacytometer) and erythrocyte aggregation (light-transmission aggregometer). After the last blood sampling, testicles were removed for histological examination. Hematological parameter changes reflected inflammatory response. Erythrocyte deformability showed a worsening already at the 60th minute of reperfusion compared to base and control values. By the 1st postoperative day further decrease was observed. Erythrocyte aggregation significantly enhanced with great magnitude versus base and control values (p < 0.001). However, conventional histological examinations did not show marked testicular injury. The experienced changes can attract attention to the testicular ischemia-reperfusion causing significant effects on hemorheological parameters, which can lead to further harmful microcirculatory consequences. PMID- 23340000 TI - Hemorheological changes in ischemia-reperfusion: an overview on our experimental surgical data. AB - Blood vessel occlusions of various origin, depending on the duration and extension, result in tissue damage, causing ischemic or ischemia-reperfusion injuries. Necessary surgical clamping of vessels in vascular-, gastrointestinal or parenchymal organ surgery, flap preparation-transplantation in reconstructive surgery, as well as traumatological vascular occlusions, all present special aspects. Ischemia and reperfusion have effects on hemorheological state by numerous ways: besides the local metabolic and micro-environmental changes, by hemodynamic alterations, free-radical and inflammatory pathways, acute phase reactions and coagulation changes. These processes may be harmful for red blood cells, impairing their deformability and influencing their aggregation behavior. However, there are still many unsolved or non-completely answered questions on relation of hemorheology and ischemia-reperfusion. How do various organ (liver, kidney, small intestine) or limb ischemic-reperfusionic processes of different duration and temperature affect the hemorheological factors? What is the expected magnitude and dynamics of these alterations? Where is the border of irreversibility? How can hemorheological investigations be applied to experimental models using laboratory animals in respect of inter-species differences? This paper gives a summary on some of our research data on organ/tissue ischemia-reperfusion, hemorheology and microcirculation, related to surgical research and experimental microsurgery. PMID- 23340001 TI - Early micro-rheological consequences of single fraction total body low-dose photon irradiation in mice. AB - Despite of the studies on widespread biological effects of irradiation, surprisingly only little number of papers can be found dealing with its in vivo hemorheological impact. Furthermore, other studies suggested that low-dose irradiation might differ from high-dose in more than linear ways. On Balb/c Jackson female adult mice hematological and hemorheological impacts of total body irradiation were investigated 1 hour following 0.002, 0.005, 0.01, 0.02, 0.05 and 0.1 Gy dose irradiation. In case of 0.01 Gy further groups were analyzed 30 minutes, 2, 4, 6, 24 and 48 h after irradiation. According to the results, it seems that the dose-dependent changes of blood micro-rheological parameters are not linear. The irradiation dose of 0.01 Gy acted as a point of 'inflexion', because by this dose we found the most expressed changes in hematological parameters, as well as in red blood cell aggregation, deformability and osmoscan data. The time-dependent changes showed progressive decrease in pH, rise in lactate concentration, further decrease in erythrocyte aggregation index and deformability, with moderate shifting of the optimal osmolarity point and modulation in membrane stability. As conclusion, low-dose total body irradiation may cause micro-rheological changes, being non-linearly correlated with the irradiation dose. PMID- 23340003 TI - Molecular systematics and evolution of the Synallaxis ruficapilla complex (Aves: Furnariidae) in the Atlantic Forest. AB - The Neotropical Synallaxis ruficapilla complex is endemic to the Atlantic Forest and is comprised of three species: S. ruficapilla, S. whitneyi, and S. infuscata. This group is closely related to the Synallaxis moesta complex that occurs in the Andes, Tepuis, and Guianan shield. Here we used mitochondrial and nuclear gene sequences to infer the phylogeny and the time of diversification of the S. ruficapilla and S. moesta complexes. We also included samples of an undescribed population of Synallaxis that resembles other populations of the S. ruficapilla complex. Our results showed that different geographical lineages within the S. ruficapilla complex are reciprocally monophyletic, but the northern form (S. infuscata) grouped with an Andean taxon. This suggests that at least two lineages of this group independently colonized the Atlantic Forest. Specimens of the undescribed population formed a monophyletic clade with deep divergence. Estimated diversification dates were within the late Pliocene to Pleistocene (2.75-0.16 million of years ago). This suggests that at this time there was a higher connectivity between habitats in the rugged landscapes of the circum Amazonian bioregions. The observed Pleistocene diversification within the Atlantic Forest is congruent in space and time with studies of other co distributed organisms, and may be associated with climate changes and tectonic activity during this period. PMID- 23340004 TI - Vaccination of feedlot cattle with extracts and membrane fractions from two Mycoplasma bovis isolates results in strong humoral immune responses but does not protect against an experimental challenge. AB - Mycoplasma bovis is one of the most significant contributors to the bovine respiratory syndrome (BRD) that causes major losses in feedlot and dairy farms. Current experimental vaccines against M. bovis are ineffective and in some cases seem to enhance disease. Experimental infection with M. bovis induces a predominantly Th2 response and high levels of IgG1, which is an inferior opsonin and hence lacks protective capacity. In an attempt to induce a balanced (Th1/Th2) immune response, we have used CpG ODN 2007 as an adjuvant in a trial involving vaccination of cattle with M. bovis total extracts and/or membrane fractions and subsequent intranasal inoculation with an infective dose of M. bovis prepared from two different clinical isolates. Significant IgG1 serum responses were observed against both, extracts and fractions while IgG2 responses were significant against the extracts only. Proliferation of peripheral blood mononuclear cells (PBMC) after incubation with M. bovis cells was only observed in post-challenge samples of cattle vaccinated with both extracts and fractions but not in samples of cattle immunized with the membrane fractions alone. All groups showed transient weight losses and increased temperatures however, there were no significant differences in clinical parameters and survival rates between the groups. PMID- 23340006 TI - Breakfast and exercise contingently affect postprandial metabolism and energy balance in physically active males. AB - The present study examined the impact of breakfast and exercise on postprandial metabolism, appetite and macronutrient balance. A sample of twelve (blood variables n 11) physically active males completed four trials in a randomised, crossover design comprising a continued overnight fast followed by: (1) rest without breakfast (FR); (2) exercise without breakfast (FE); (3) breakfast consumption (1859 kJ) followed by rest (BR); (4) breakfast consumption followed by exercise (BE). Exercise was continuous, moderate-intensity running (expending approximately 2.9 MJ of energy). The equivalent time was spent sitting during resting trials. A test drink (1500 kJ) was ingested on all trials followed 90 min later by an ad libitum lunch. The difference between the BR and FR trials in blood glucose time-averaged AUC following test drink consumption approached significance (BR: 4.33 (SEM 0.14) v. FR: 4.75 (SEM 0.16) mmol/l; P=0.08); but it was not different between FR and FE (FE: 4.77 (SEM 0.14) mmol/l; P=0.65); and was greater in BE (BE: 4.97 (SEM 0.13) mmol/l) v. BR (P=0.012). Appetite following the test drink was reduced in BR v. FR (P=0.006) and in BE v. FE (P=0.029). Following lunch, the most positive energy balance was observed in BR and least positive in FE. Regardless of breakfast, acute exercise produced a less positive energy balance following ad libitum lunch consumption. Energy and fat balance is further reduced with breakfast omission. Breakfast improved the overall appetite responses to foods consumed later in the day, but abrogated the appetite suppressive effect of exercise. PMID- 23340005 TI - Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration resistant prostate cancer. AB - BACKGROUND: The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling and delays tumor growth in murine prostate cancer xenograft models. We conducted a noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole in men with metastatic prostate cancer. PATIENTS AND METHODS: We randomly assigned 46 men with chemotherapy-naive metastatic castration-resistant prostate cancer (CRPC) to receive low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole until disease progression or unacceptable toxicity. The primary endpoint was the prostate-specific antigen (PSA) progression-free survival (PPFS) rate at 24 weeks; a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints included the progression-free survival (PFS) rate and PSA response rate (Prostate Cancer Working Group criteria). Exploratory outcomes included circulating tumor cell (CTC) enumeration, serum androgen measurements, as well as pharmacokinetic and pharmacodynamic analyses. RESULTS: The high-dose arm enrolled to completion (n = 29), but the low-dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low-dose arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema. CONCLUSION: High-dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression. PMID- 23340007 TI - Genetics of biliary lithiasis from an ethnic perspective. AB - Gallstone disease represents one of the most common gastroenterological disorders worldwide. Gallstones affect over 15% of adults in Europe and 25-30% of Hispanic populations in Central and South America. The heritability of gallstones varies considerably according to ethnicity, with Native Americans and Hispanics with Amerindian admixture being the most susceptible populations. Genetic factors have been shown to account for 25-30% of total gallstone risk in Europe, however, in Hispanic populations, this risk percentage may increase to 45-65%. Recent genome wide association and candidate gene studies have identified common polymorphisms in enterohepatic transporters (ABCG5/8, SLC10A2) and the Gilbert syndrome UGT1A1 variant as genetic determinants of gallstone formation. Together, these polymorphisms cover a significant proportion of the previously predicted genetic background of gallstones in European populations. New lithogenic genes need to be discovered in future studies in high-risk populations. In this review, we address the latest developments in the genetic analysis of gallstones and discuss the ethnic background of this condition in European, Central and South American and Asian populations. PMID- 23340008 TI - The use of indirect calorimetry in the intensive care unit. AB - PURPOSE OF REVIEW: This review evaluates whether improvements have occurred in the value of predictive equations for use in designing nutritional therapeutic regimens in the ICU. The report also seeks to determine whether emerging strategies for nutrition therapy in the ICU change the need for an accurate measurement of energy requirements by indirect calorimetry. RECENT FINDINGS: Predictive equations remain problematic for use in the critically ill patient. Inaccuracy of predictive equations introduces error in the design of a nutritional therapy regimen. The epidemic of obesity renders the calculations of requirements by predictive equations increasingly inaccurate at extremes of BMI. Certain patient populations appear to be hypometabolic, contradicting the traditional notion that critical illness increases energy expenditure. More recent data indicates that determination of which patients benefit from nutritional therapy may be based both on assessment of nutrition risk and delivery of sufficient nutrition therapy. SUMMARY: The role of indirect calorimetry in the ICU should be expected to increase in the near future, as predictive equations may be too inaccurate to identify the appropriate goals of nutrition therapy. PMID- 23340009 TI - Lipids and liver dysfunction in patients receiving parenteral nutrition. AB - PURPOSE OF REVIEW: Abnormalities of liver function tests are common in patients with intestinal failure receiving parenteral nutrition. Lipid emulsions have been implicated in the development of hepatobiliary disease in patients receiving parenteral nutrition. RECENT FINDINGS: Lipid emulsions with reduced polyunsaturated fatty acids and specific omega6 : omega3 fatty acid ratios have been shown to have some beneficial effects on liver function, although the studies are small and generally of short duration in paediatric and adult patients. SUMMARY: There is good evidence to suggest that the parenteral lipid dose should be less than 1 g/kg body weight/day, but this may not apply to all patients. The evidence is presented for the different lipid emulsions and their effect on liver function. The benefit of these emulsions compared with simply giving a lower lipid dose has yet to be studied. PMID- 23340010 TI - Hormonal and nutritional drivers of intrauterine growth. AB - PURPOSE OF REVIEW: Size at birth is critical in determining life expectancy with both small and large neonates at risk of shortened life spans. This review examines the hormonal and nutritional drivers of intrauterine growth with emphasis on the role of foetal hormones as nutritional signals in utero. RECENT FINDINGS: Nutrients drive intrauterine growth by providing substrate for tissue accretion, whereas hormones regulate nutrient distribution between foetal oxidative metabolism and mass accumulation. The main hormonal drivers of intrauterine growth are insulin, insulin-like growth factors and thyroid hormones. Together with leptin and cortisol, these hormones control cellular nutrient uptake and the balance between accretion and differentiation in regulating tissue growth. They also act indirectly via the placenta to alter the materno-foetal supply of nutrients and oxygen. By responding to nutrient and oxygen availability, foetal hormones optimize the survival and growth of the foetus with respect to its genetic potential, particularly during adverse conditions. However, changes in the intrauterine growth of individual tissues may alter their function permanently. SUMMARY: In both normal and compromised pregnancies, intrauterine growth is determined by multiple hormonal and nutritional drivers which interact to produce a specific pattern of intrauterine development with potential lifelong consequences for health. PMID- 23340011 TI - Intensive care nurses' conceptions of a critical pathway in caring for aortic surgery patients: a phenomenographic study. AB - The aim of the present study was to identify and describe intensive care nurses' different conceptions of a critical pathway in caring for patients that have undergone aortic-surgery. Individual semi-structured interviews with eight specialist registered nurses at a Swedish intensive care unit were conducted and phenomenographically analysed. Three descriptive categories, with a total of five sub-categories, constituted the outcome-space of how the pathway was conceived of in caring: as a guide open to individual patients needs (clinical judgement governs caring and patient autonomy governs caring), as an instrument to promote patient safety (a source of knowledge, a planning tool and a reference standard) and as a source of support for professional confidence. In accordance with current literature, the nurses in the present study identified a number of advantages in applying the pathway in caring even if they were also conscious that the use of a pathway can give rise to unreflective standardisation. The nurses' conceptions indicate that the pathway prescribed for managing patients who have undergone aortic surgery is supportive and facilitates patient safety without jeopardising respect for the patient's individual care needs. This insight may be used to influence a thoughtful dialogue about the practice of pathways in intensive care. PMID- 23340012 TI - ICU-recovery in Scandinavia: a comparative study of intensive care follow-up in Denmark, Norway and Sweden. AB - OBJECTIVES: The aim of our study was to describe and compare models of intensive care follow-up in Denmark, Norway and Sweden to help inform clinicians regarding the establishment and continuation of ICU aftercare programmes. METHODS: Our study had a multi-centre comparative qualitative design with triangulation of sources, methods and investigators. We combined prospective data from semi structured key-informant telephone interviews and unreported data from a precursory investigation. RESULTS: Four basic models of follow-up were identified representing nurse-led or multidisciplinary programmes with or without the provision of patient diaries. A conceptual model was constructed including a catalogue of interventions related to the illness trajectory. We identified three temporal areas for follow-up directed towards the past, present or future. CONCLUSIONS: ICU follow-up programmes in the Scandinavian countries have evolved as bottom-up initiatives conducted on a semi-voluntary basis. We suggest reframing follow-up as an integral part of patient therapy. The Scandinavian programmes focus on the human experience of critical illness, with more attention to understanding the past than looking towards the future. We recommend harmonization of programmes with clear goals enabling programme assessment, while moving towards a paradigm of empowerment, enabling patient and family to take an active role in their recovery and wellbeing. PMID- 23340014 TI - Microbial kinetic model for the degradation of poorly soluble organic materials. AB - A novel mechanistic model is presented that describes the aerobic biodegradation kinetics of soybean biodiesel and petroleum diesel in batch experiments. The model was built on the assumptions that biodegradation takes place in the aqueous phase according to Monod kinetics, and that the substrate dissolution kinetics at the oil/water interface is intrinsically fast compared to biodegradation kinetics. Further, due to the very low aqueous solubility of these compounds, the change in the substrate aqueous-phase concentration over time was assumed to approaches zero, and that substrate aqueous concentration remains close to the saturation level while the non-aqueous phase liquid (NAPL) is still significant. No former knowledge of the saturation substrate concentration (S(sat)) and the Monod half-saturation constant (K(s)) was required, as the term S(sat)/(K(s) + S(sat)) in the Monod equation remained constant during this phase. The n-alkanes C10-C24 of petroleum diesel were all utilized at a relatively constant actual specific utilization rate of 0.01-0.02 mg-alkane/mg-biomass-hr, while the fatty acid methyl esters (FAMEs) of biodiesel were utilized at actual specific rates significantly higher with increasing carbon chain length and lower with increasing number of double bonds. The results were found to be in agreement with kinetic, genetic, and metabolic evidence reported in the literature pertaining to microbial decay rates, uptake mechanisms, and the metabolic pathway by which these compounds are assimilated into microorganisms. The presented model can be applied, without major modifications, to estimate meaningful kinetic parameters from batch experiments, as well as near source zone field application. We suggest the estimated actual microbial specific utilization rate (kC) of such materials to be a better measure of the degradation rate when compared to the maximum specific utilization rate (k), which might be orders of magnitude higher than kC and might never be observed in reality. PMID- 23340015 TI - Nitrogen removal and nitrifying and denitrifying bacteria quantification in a stormwater bioretention system. AB - In this study, we examine the biological processes involved in ammonia and nitrate removal in a bioretention system characterized by low infiltration rates and long drainage times. The system removed 33% of influent nitrate and 56% of influent total nitrogen. While influent ammonia concentrations were low (<0.3 mg/L), the bioretention cell also removed ammonia produced within the treatment system. Soil cores collected from the bioretention cell were analyzed for total 16S rDNA and both nitrification and denitrification genes (amoA, nirS, nirK, norB, and nosZ) using quantitative PCR. Total bacterial 16S rDNA levels in the surface layer were similar to those in very sandy soils. Gene counts for both nitrification and denitrification genes decreased as a function of depth in the media, and corresponded to similar changes in total 16S rDNA. The abundance of denitrification genes was also positively correlated with the average inundation time at each sampling location, as determined by modeling of stormwater data from a three-year period. These results suggest that both nitrification and denitrification can occur in bioretention media. Time of saturation, filter medium, and organic carbon content can all affect the extent of denitrification in bioretention systems. PMID- 23340016 TI - Estimation of chromophoric dissolved organic matter (CDOM) and photosynthetic activity of estuarine phytoplankton using a multiple-fixed-wavelength spectral fluorometer. AB - The utility of a multiple-fixed-wavelength spectral fluorometer, the Algae Online Analyser (AOA), as a means of quantifying chromophoric dissolved organic matter (CDOM) and phytoplankton photosynthetic activity was tested using algal cultures and natural communities from North Inlet estuary, South Carolina. Comparisons of AOA measurements of CDOM to those by spectrophotometry showed a significant linear relationship, but increasing amounts of background CDOM resulted in progressively higher over-estimates of chromophyte contributions to a simulated mixed algal community. Estimates of photosynthetic activity by the AOA at low irradiance (~ 80 MUmol quanta m(-2) s(-1)) agreed well with analogous values from the literature for the chlorophyte, Dunaliella tertiolecta, but were substantially lower than previous measurements of the maximum quantum efficiency of photosystem II (F(v)/F(m)) in Thalassiosira weissflogii (a diatom) and Rhodomonas salina (a cryptophyte). When cells were exposed to high irradiance (1500 MUmol quanta m(-2) s(-1)), declines in photosynthetic activity with time measured by the AOA mirrored estimates of cellular fluorescence capacity using the herbicide 3'-(3, 4-dichlorophenyl)-1',1'-dimethyl urea (DCMU). The AOA shows promise as a tool for the continuous monitoring of phytoplankton community composition, CDOM, and the group-specific photosynthetic activity of aquatic ecosystems. PMID- 23340017 TI - Epitaxial growth of visible to infra-red transparent conducting In2O3 nanodot dispersions and reversible charge storage as a Li-ion battery anode. AB - Unique bimodal distributions of single crystal epitaxially grown In2O3 nanodots on silicon are shown to have excellent IR transparency greater than 87% at IR wavelengths up to 4 MUm without sacrificing transparency in the visible region. These broadband antireflective nanodot dispersions are grown using a two-step metal deposition and oxidation by molecular beam epitaxy, and backscattered diffraction confirms a dominant (111) surface orientation. We detail the growth of a bimodal size distribution that facilitates good surface coverage (80%) while allowing a significant reduction in In2O3 refractive index. This unique dispersion offers excellent surface coverage and three-dimensional volumetric expansion compared to a thin film, and a step reduction in refractive index compared to bulk active materials or randomly porous composites, to more closely match the refractive index of an electrolyte, improving transparency. The (111) surface orientation of the nanodots, when fully ripened, allows minimum lattice mismatch strain between the In2O3 and the Si surface. This helps to circumvent potential interfacial weakening caused by volume contraction due to electrochemical reduction to lithium, or expansion during lithiation. Cycling under potentiodynamic conditions shows that the transparent anode of nanodots reversibly alloys lithium with good Coulombic efficiency, buffered by co insertion into the silicon substrate. These properties could potentially lead to further development of similarly controlled dispersions of a range of other active materials to give transparent battery electrodes or materials capable of non-destructive in situ spectroscopic characterization during charging and discharging. PMID- 23340018 TI - Precursor De13.1 from Conus delessertii defines the novel G gene superfamily. AB - Peptide de13a was previously purified from the venom of the worm-hunting cone snail Conus delessertii from the Yucatan Channel, Mexico. This peptide has eight cysteine (Cys) residues in the unique arrangement C-C-C-CC-C-C-C, which defines the cysteine framework XIII ("-" represents one or more non-Cys residues). Remarkably, delta-hydroxy-lysine residues have been found only in conotoxin de13a, which also contains an unusually high proportion of hydroxylated amino acid residues. Here, we report the cDNA cloning of the complete precursor De13.1 of a related peptide, de13b, which has the same Cys framework and inter-Cys spacings as peptide de13a, and shares high protein/nucleic acid sequence identity (87%/90%) with de13a, suggesting that both peptides belong to the same conotoxin gene superfamily. Analysis of the signal peptide of precursor De13.1 reveals that this precursor belongs to a novel conotoxin gene superfamily that we chose to name gene superfamily G. Thus far superfamily G only includes two peptides, each of which contains the same, distinctive Cys framework and a high proportion of amino acid residues with hydroxylated side chains. PMID- 23340019 TI - Antimicrobial activity of the synthetic peptide Lys-a1 against oral streptococci. AB - The peptide LYS-[TRP(6)]-Hy-A1 (Lys-a1) is a synthetic derivative of the peptide Hy-A1, initially isolated from the frog species Hypsiboas albopunctatus. According to previous research, it is a molecule with broad antimicrobial activity. The objective of this study was to evaluate the antimicrobial activity of the synthetic peptide Lys-a1 (KIFGAIWPLALGALKNLIK-NH2) on the planktonic and biofilm growth of oral bacteria. The methods used to evaluate antimicrobial activity include the following: determination of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) in microtiter plates for growth in suspension and quantification of biomass by crystal violet staining and counting of colony forming units for biofilm growth. The microorganisms Streptococcus oralis, Streptococcus sanguinis, Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus mutans and Streptococcus sobrinus were grown in Brain Heart Infusion broth at 37 degrees C under atmospheric pressure with 10% CO2. The peptide was solubilized in 0.1% acetic acid (v/v) at various concentrations (500-1.9 MUg mL(-1)). Chlorhexidine gluconate 0.12% was used as the positive control, and BHI culture medium was used as the negative control. The tested peptide demonstrated a remarkable antimicrobial effect, inhibiting the planktonic and biofilm growth of all strains tested, even at low concentrations. Thus, the peptide Lys-a1 is an important source for potential antimicrobial agents, especially for the control and prevention of microbial biofilms, which is one of the most important factors in cariogenic processes. PMID- 23340020 TI - Vasoactive intestinal peptide increases VEGF expression to promote proliferation of brain vascular endothelial cells via the cAMP/PKA pathway after ischemic insult in vitro. AB - Vasoactive intestinal peptide (VIP) enhances angiogenesis in rats with focal cerebral ischemia. In the present study, we investigated the molecular mechanism of the proangiogenic action of VIP using an in vitro ischemic model, in which rat brain microvascular endothelial cells (RBMECs) are subjected to oxygen and glucose deprivation (OGD). Western blotting and immunocytochemistry were carried out to examine the expression of VIP receptors and vascular endothelial growth factor (VEGF) in cultured RBMECs. The cell proliferation was assessed by the MTT assay. Cyclic adenosine monophosphate (cAMP) and VEGF levels were measured by using the enzyme-linked immunosorbent assay. The cultured RBMECs expressed VPAC1, VPAC2 and PAC1 receptors. Treatment with VIP significantly promoted the proliferation of RBMECs and increased OGD-induced expression of VEGF, and this effect was antagonized by the VPAC receptor antagonist VIP6-28 and VEGF antibody. VIP significantly increased contents of cAMP in RBMECs and VEGF in the culture medium. The VIP-induced VEGF production was blocked by H89, a protein kinase A (PKA) inhibitor. These data suggest that treatment with VIP promotes VEGF mediated endothelial cell proliferation after ischemic insult in vitro, and this effect appears to be initiated by the VPAC receptors leading to activation of the cAMP/PKA pathway. PMID- 23340021 TI - Bradykinin decreases nitric oxide release from microglia via inhibition of cyclic adenosine monophosphate signaling. AB - Bradykinin (BK) is a major potent inflammatory mediator outside the central nervous system. In Alzheimer's disease, BK release and BK receptor expression in brain tissues are upregulated relatively early during the course of the disease. Hence, BK was believed to promote neuroinflammation. However, BK was recently reported to possess anti-inflammatory and neuroprotective roles. Exposure of BV2 microglial cell line to BK lead to a decrease in NO release from unstimulated cells as well as a dose-dependent attenuation, mediated by both B1 and B2 receptors, in lipopolysaccharide (LPS)-induced NO production. In this study we examined whether cyclic adenosine monophosphate (cAMP) signaling is involved in BK-mediated effect in microglial nitric oxide (NO) production. A protein kinase A (PKA) inhibitor mimicked the effects of BK, while cAMP elevating agents antagonized BK-mediated NO decrease. Moreover, BK inhibited the activation of cAMP responsive element binding protein (CREB). In addition, BK protected microglial cells from death triggered by combinations of LPS and each of the cAMP elevating agents. Finally, the addition of Galphai protein inhibitor abrogated the effects of BK on NO release, and the expression of Galphai protein in the plasma membrane was induced by BK. These results suggest that BK-mediated reduction in microglial NO production depends on coupling to Gi protein and also involves inhibition of cAMP-PKA-CREB signaling. PMID- 23340022 TI - The epidemiology and molecular characterization of methicillin-resistant staphylococci sampled from a healthy Jordanian population. AB - The prevalence of natural carriage and molecular epidemiology of methicillin resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase negative staphylococci (MR-CoNS) isolates in a Jordanian community were investigated. The MRSA nasal carriage rate in 227 healthy volunteers was 7.5% and the majority (81%) of MRSA harboured the resistance element SCCmec type IVe and were of a novel spa type t9519 (76%); other significant spa gene types were t223 (14.7%) and t044 (5.9%). All MRSA isolates were susceptible to other classes of antibiotics, and tested positive for at least three virulence factor encoding genes, but only two harboured the pvl gene. MR-CoNS carriage was 54.2% and these isolates were characterized by single, double and untypable SCCmec elements, with Staphylococcus epidermidis SCCmec type IVa predominating. Of eight subjects with nasal co-colonization of MR-CoNS + MRSA, three shared SCCmec type IV in both groups of organisms. This is the first report of methicillin-resistant staphylococci carriage in a Jordanian community and its findings are important for epidemiological study and infection control measures of these organisms. PMID- 23340024 TI - Occurrence, distribution and potential affecting factors of antibiotics in sewage sludge of wastewater treatment plants in China. AB - The occurrence and distribution of eight quinolones, nine sulfonamides, and five macrolides were investigated in sewage sludge from 45 wastewater treatment plants in 23 cities in China. Among all the antibiotics considered, quinolones were the dominant antibiotics detected in all samples [total concentrations up to 8905 MUg/kg, dry weight (dw)], followed by macrolides (85.1 MUg/kg, dw), and sulfonamides (22.7 MUg/kg, dw). High concentrations of quinolones in sewage sludge indicated that antibiotics are widely used and extensive pollutants in China. Significant differences were observed for the total concentrations of antibiotics in sludge samples among the 45 WWTPs. To evaluate the potential factors affecting the antibiotic levels in sewage sludge, wastewater and sludge characteristics, as well as the operational conditions and treatment techniques in WWTPs were investigated. The results indicated that the antibiotic levels in sewage sludge depend to a great extent on wastewater characteristics. Significant correlation between total organic carbon (TOC) and total concentrations of antibiotics was also found in studied WWTPs, indicating that TOC could affect the sludge adsorption capability to the antibiotics to some extent. Moreover, the relation between treatment techniques and the total concentrations of antibiotics in sludge showed that antibiotic levels in sludge increased with longer solid retention time. PMID- 23340023 TI - Relationship between urinary triclosan and paraben concentrations and serum thyroid measures in NHANES 2007-2008. AB - Triclosan and parabens are broad spectrum antimicrobials used in a range of consumer products. In vitro and animal studies have suggested the potential for these compounds to disrupt thyroid function, though studies in humans have been limited. The objective of the study was to assess the relationship of urinary concentrations of triclosan and parabens with serum thyroid measures in a large, representative sample of the US population. We conducted an exploratory, cross sectional analysis of data on urinary biomarkers of triclosan and paraben exposure and serum thyroid measures obtained from 1831 subjects (ages>=12 years) as part of the 2007-2008 National Health and Nutrition Examination Survey (NHANES). We found evidence of some inverse associations between parabens and circulating thyroid hormone levels in adults, with the strongest and most consistent associations among females. We also observed a positive association between triclosan and total triiodothyonine (T3) concentrations in adolescents. These results, in accordance with the in vitro and animal literature, suggest that paraben, and potentially triclosan, exposures may be associated with altered thyroid hormone levels in humans. Further research is needed for confirmation and to determine the potential clinical and public health significance of these findings. PMID- 23340025 TI - Troubleshooting and deconvoluting label-free cell phenotypic assays in drug discovery. AB - INTRODUCTION: Central to drug discovery and development is to comprehend the target(s), potency, efficacy and safety of drug molecules using pharmacological assays. Owing to their ability to provide a holistic view of drug actions in native cells, label-free biosensor-enabled cell phenotypic assays have been emerging as new generation phenotypic assays for drug discovery. Despite the benefits associated with wide pathway coverage, high sensitivity, high information content, non-invasiveness and real-time kinetics, label-free cell phenotypic assays are often viewed to be a blackbox in the era of target-centric drug discovery. METHODS: This article first reviews the biochemical and biological complexity of drug-target interactions, and then discusses the key characteristics of label-free cell phenotypic assays and presents a five-step strategy to troubleshooting and deconvoluting the label-free cell phenotypic profiles of drugs. RESULTS: Drug-target interactions are intrinsically complicated. Label-free cell phenotypic signatures of drugs mirror the innate complexity of drug-target interactions, and can be effectively deconvoluted using the five-step strategy. DISCUSSION: The past decades have witnessed dramatic expansion of pharmacological assays ranging from molecular to phenotypic assays, which is coincident with the realization of the innate complexity of drug-target interactions. The clinical features of a drug are defined by how it operates at the system level and by its distinct polypharmacology, ontarget, phenotypic and network pharmacology. Approaches to examine the biochemical, cellular and molecular mechanisms of action of drugs are essential to increase the efficiency of drug discovery and development. Label-free cell phenotypic assays and the troubleshooting and deconvoluting approach presented here may hold great promise in drug discovery and development. PMID- 23340026 TI - The first influenza pseudopandemic of the 21st century? PMID- 23340027 TI - Injury-proneness of youth with attention-deficit hyperactivity disorder: a national clinical data analysis in Taiwan. AB - Limited literature documents injury-proneness of attention-deficit hyperactivity disorder in western population. However, only a few studies prospectively investigated the prediction of ADHD to injuries without considering other psychiatric and physical conditions and there is lack of such data in Asian population. To prospectively examine the prediction of ADHD to the risk of injury in a national sample of Taiwan, we conducted this study with samples including 1965 6-18-year-old youths with newly diagnosis of ADHD from 1999 to 2003, and 7860 sex-, age- and index day-matched non-ADHD controls from Taiwan's National Health Insurance Research Database (1997-2008). Relevant psychiatric and physical disorders, demographics, and medications were also included in the Cox proportional hazard models with injury as the outcome. Our results showed that ADHD cases had a roughly 2-fold and 5-fold higher risk of each injury, and overall injury than controls after considering all confounding factors, respectively. In addition to ADHD, use of anxiolytics, antidepressants, and antipsychotics, and comorbid physical illnesses also predicted the injury prospectively. Our findings strongly support that ADHD predicted injury risks and imply that physicians should take the risk of injury into consideration while prescribing medications other than stimulants to patients with ADHD, especially anxiolytics. PMID- 23340028 TI - Adult bone anchored hearing aid services in the United Kingdom: building a consensus for development. AB - AIMS AND OBJECTIVES: In October 2009, a multi-disciplinary group of UK clinicians met to review issues relating to bone-anchored hearing-aid (BAHA) development. The aim was to help define a model for BAHA services and service development via a process of widespread consultation with UK BAHA professionals. METHODS: A modified Delphi technique was used. Statements were proposed by the lead group and sent out for consultation. Those with >=90% agreement were approved without further discussion. Statements with 50-89% agreement were discussed by the lead group to determine whether they should be included in the final document. Any statement with <50% agreement was removed without discussion. A second consultation was then made, and the process repeated. This led to a final set of consensus statements. RESULTS: The final consensus comprises 33 statements validated by the modified Delphi process. All of these statements achieved >75% agreement, with only six statements having <90% agreement. When these statements were presented to the UK BAHA Professionals group at their annual conference there was 89% agreement from the group for the consensus statements to be accepted. DISCUSSION: The levels of agreement for the final questionnaire show that the mandate for the consensus statements was exceptionally high. Implementation of the consensus is discussed, as are each of the key areas of the consensus, such as funding and minimum assessment standards. PMID- 23340030 TI - Effect of CYP2C19*2 and *17 genetic variants on platelet response to clopidogrel and prasugrel maintenance dose and relation to bleeding complications. AB - The present study was performed to compare the influence of cytochrome P459 2C19 (CYP2C19) *2 and *17 genetic variants on the platelet response to clopidogrel and prasugrel maintenance therapy and to assess the relation between platelet reactivity and bleeding complications. A total of 730 patients were included (517 patients treated with clopidogrel 150 mg/day and 213 discharged with prasugrel 10 mg). Platelet reactivity was assessed at 1 month with the platelet reactivity index vasodilator-stimulated phosphoprotein (PRI VASP). High on-treatment platelet reactivity was defined as PRI VASP >50% and low on-treatment platelet reactivity (LTPR) as PRI VASP <20%. The patients were classified according to their genotypes as poor metabolizers (*2/non *17), intermediate metabolizers (*2/*17 or non *2/non *17) and ultrametabolizers (non *2/*17). At 1 month, the prasugrel response was significantly better than the clopidogrel response in all groups of patients, with a lower incidence of high on-treatment platelet reactivity but a greater incidence of LTPR, regardless of the genetic variants. The genetic distribution had a significant effect on the mean PRI VASP values, the incidence of high on-treatment platelet reactivity, and LTPR with both clopidogrel and prasugrel (p <0.05 for all). LTPR identified a group of patients at a greater risk of bleeding (odds ratio 4.8, 95% confidence interval 2.7 to 8.3; p <0.0001). In conclusion, the present study showed that both clopidogrel and prasugrel have genetic modulation by CYP2C19 *2 and *17 alleles and that prasugrel provides greater platelet inhibition, regardless of the genotypes. In addition, LTPR was associated with a greater risk of bleeding. PMID- 23340029 TI - Impact of fitness versus obesity on routinely measured cardiometabolic risk in young, healthy adults. AB - Obesity demonstrates a direct relation with cardiovascular risk and all-cause mortality, while cardiorespiratory fitness demonstrates an inverse relation. In clinical practice, several cardiometabolic (CM) risk factors are commonly measured to gauge cardiovascular risk, but the interaction between fitness and obesity with regard to CM risk has not been fully explored. In this study, 2,634 Brazilian adults referred for employer-sponsored heath exams were assessed. Obesity was defined as body mass index >30 kg/m(2) or waist circumference >102 cm in men or >88 cm in women when body mass index was 25 to 30 kg/m(2). Fitness was quantified by stage achieved on an Ellestad treadmill stress test, with those completing stage 4 considered fit. Hepatic steatosis was determined by ultrasound. CM risk factors were compared after stratifying patients into 4 groups: fit and normal weight, fit and obese, unfit and normal weight, and unfit and obese. Approximately 22% of patients were obese; 12% were unfit. Fitness and obesity were moderately correlated (rho = 0.38 to 0.50). The sample included 6.5% unfit and normal-weight subjects and 16% fit and obese subjects. In overweight and obese patients, fitness was negatively associated with CM risk (p <0.01 for all values). In fit patients, increasing body mass index was positively associated with CM risk (p <0.01 for all values). In instances of discordance between fitness and obesity, obesity was the stronger determinant of CM risk. In conclusion, fitness and obesity are independently associated with CM risk. The effects of fitness and obesity are additive, but obesity is more strongly associated with CM risk when fitness and obesity are discordant. These findings underscore the need for weight loss in obese patients and suggest an unmeasured benefit of fitness. PMID- 23340031 TI - Outcome of patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention during on- versus off-hours (a Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI] trial substudy). AB - Patients with ST-segment elevation myocardial infarction (STEMI) admitted during nonregular working hours (off-hours) have been reported to have greater mortality than those admitted during regular working hours (on-hours), perhaps because of the lower availability of catheterization laboratory services and longer door-to balloon times. This might not be the case, however, for hospital centers in which primary percutaneous coronary intervention (PCI) is invariably performed. We conducted a substudy using the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction study data to determine whether the STEMI arrival time was associated with differing clinical outcomes. We identified all patients with STEMI admitted to a PCI-capable hospital who underwent primary PCI. Patients presenting during on-hours were compared to those presenting during off hours. The primary outcome of death, major adverse cardiovascular events, and net adverse clinical events was examined. We identified 2,440 patients (1,205 [49%] on-hours and 1,235 [51%] off-hours). Similar baseline characteristics were observed. The off-hour patients had a significantly longer door-to-balloon time (92 vs 75 minutes; p <0.0001) and total ischemic time (209 vs 194 minutes; p <0.0001). Despite these differences, the risk-adjusted all-cause mortality, major adverse cardiovascular events, and net adverse clinical events rates were similar for both groups during the in-hospital, 1-year, and 3-year follow-up. In conclusion, patients with STEMI presenting to primary PCI hospitals during off hours might have slightly longer delays to revascularization; however, they experienced similar short- and long-term survival and clinical outcomes as those arriving during on-hours. PMID- 23340032 TI - Physical activity and other health behaviors in adults with hypertrophic cardiomyopathy. AB - The clinical expression of hypertrophic cardiomyopathy (HC) is undoubtedly influenced by modifying genetic and environmental factors. Lifestyle practices such as tobacco and alcohol use, poor nutritional intake, and physical inactivity are strongly associated with adverse cardiovascular outcomes and increased mortality in the general population. Before addressing the direct effect of such modifiable factors on the natural history of HC, it is critical to define their prevalence in this population. A voluntary survey, drawing questions in part from the 2007 to 2008 National Health and Nutrition Examination Survey (NHANES), was posted on the HC Association website and administered to patients with HC at the University of Michigan. Propensity score matching to NHANES participants was used. Dichotomous and continuous health behaviors were analyzed using logistic and linear regression, respectively, and adjusted for body mass index and propensity score quintile. Compared to the matched NHANES participants, the patients with HC reported significantly less alcohol and tobacco use but also less time engaged in physical activity at work and for leisure. Time spent participating in vigorous or moderate activity was a strong predictor of self reported exercise capacity. The body mass index was greater in the HC cohort than in the NHANES cohort. Exercise restrictions negatively affected emotional well being in most surveyed subjects. In conclusion, patients with HC are less active than the general United States population. The well-established relation of inactivity, obesity, and cardiovascular mortality might be exaggerated in patients with HC. More data are needed on exercise in those with HC to strike a balance between acute risks and the long-term health benefits of exercise. PMID- 23340033 TI - Effect of eplerenone on maintenance of sinus rhythm after catheter ablation in patients with long-standing persistent atrial fibrillation. AB - Several studies have demonstrated a relation between the rennin-angiotensin aldosterone system and atrial fibrillation (AF), but there are no reports on the effect of eplerenone, a selective aldosterone blocker, on the prevention of AF recurrence after radiofrequency catheter ablation (RFCA). The aim of this study was to evaluate the effects of eplerenone on clinical outcomes after RFCA in patients with long-standing persistent AF. A total of 161 consecutive patients with long-standing persistent AF (sustained AF duration 1 to 20 years, mean 3.4 +/- 3.8) who underwent RFCA were investigated. Eplerenone was used in 55 patients and not used in the remaining 106 patients. Other conventional pharmacologic agents, including angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor blockers, were used equally in the 2 groups. After 24 months of follow up, 47% of the patients were free from AF recurrence. The rate of freedom from AF recurrence was significantly greater in the eplerenone group (60%) than in the noneplerenone group (40%) (p = 0.011). By univariate analysis, the duration of sustained AF (p <0.001), left atrial diameter (p = 0.010), left atrial volume index (p = 0.017), and early AF recurrence (p <0.001) were significantly associated with AF recurrence, and the use of eplerenone was associated with maintenance of sinus rhythm after RFCA (p = 0.022). Multivariate Cox regression analysis showed that longer duration of sustained AF (>3 years) (p <0.001) and early AF recurrence (p <0.001) were significantly associated with AF recurrence, and only eplerenone therapy significantly improved maintenance of sinus rhythm (p = 0.017). In conclusion, eplerenone significantly improved maintenance of sinus rhythm after RFCA in patients with long-standing persistent AF. PMID- 23340034 TI - Intravascular ultrasound comparison of left main coronary artery disease between white and Asian patients. AB - We assessed the ethnic differences in coronary atherosclerosis lesion morphology between white and Asian patients. Our hypothesis was that left main coronary artery (LMCA) disease was more focal and less complex in Asian than in Western white patients. We studied 99 Asian patients (Japan and South Korea) and 99 matched control United States white patients with a stable clinical presentation and >30% LMCA angiographic diameter stenosis by visual estimation. The matching parameters included age, gender, and diabetes mellitus. The vessel and lumen areas and calcium arc were analyzed every 0.5 mm and normalized for analysis length. Overall, 75.1% of the patients were men and 34.1% had diabetes. The patient age was 68.0 +/- 10 years, with no differences between the Asian and white patients. The Asian patients had a lower prevalence of hyperlipidemia than the white patients (41.4% vs 81.8%; p <0.0001) and were smaller in size, and the white patients were more obese (body mass index 23.7 +/- 2.6 vs 27.6 +/- 4.1 kg/m(2), p <0.0001). The Asian patients had a smaller lumen area (5.2 +/- 1.8 vs 6.2 +/- 14 mm(2); p <0.0001), larger vessel area (20.0 +/- 4.9 vs 18.4 +/- 4.4 mm(2); p <0.0001), and larger plaque burden (72 +/- 10 vs 64 +/- 12%: p <0.0001) at the minimum lumen site and over the entire LMCA length. The white patients had more calcification, whether assessed by the maximum arc (82 degrees +/- 74 degrees vs 49 degrees +/- 45 degrees ; p <0.0001) or total length (3.6 +/- 3.2 vs 2.1 +/- 2.1 mm; p <0.0001). In conclusion, after matching well-known risk factors, there appeared to be ethnic differences in coronary atherosclerosis morphology between Asian and white patients, at least as it affected LMCA morphology. PMID- 23340035 TI - Coronary computed tomographic angiographic findings in asymptomatic patients with heterozygous familial hypercholesterolemia and null allele low-density lipoprotein receptor mutations. AB - Heterozygous familial hypercholesterolemia (HeFH) can be associated with early coronary artery disease (CAD) in asymptomatic patients. The objectives of the present study were to assess the prevalence and magnitude of subclinical CAD in patients with HeFH using coronary computed tomographic angiography (CCTA) and to determine the clinical and genetic profile of those at the greatest risk of CAD. The study included 50 consecutive patients with HeFH diagnosed according to the Dutch Lipid Clinic Network criteria and a control group of 70 healthy subjects. The findings from CCTA for the patients with HeFH were compared with those from the control group, who had been referred for CCTA as a part of a preventive medical examination. In 82% of the patients with HeFH, genetic DNA was screened for low-density lipoprotein receptor (LDLR) gene mutations using a microarray. CCTA revealed a significantly greater Agatston calcium score in the study group than in the control group (260 vs 46; p = 0.002). The prevalence of CAD in the patients with HeFH was 48%. It was significant in 26%, involving mainly the proximal segments of the coronary arteries. In the control group, the prevalence of CAD was 33% and was significant in 5% (p <0.05 for prevalence and severity of CAD compared to patients with HeFH). In those with HeFH, increased age, null allele LDLR mutations, and low high-density lipoprotein blood levels at diagnosis showed a statistically significant association with CAD (p <0.05). In conclusion, patients with HeFH present with a greater prevalence, extension, and severity of subclinical CAD than the general population. Increased age, low high-density lipoprotein levels, and LDLR null allele mutations are related to the occurrence of CAD. CCTA has emerged as a useful technique for the screening of subclinical CAD in patients with HeFH. PMID- 23340036 TI - Antihypertensive therapy in hypertrophic cardiomyopathy. AB - Patients with coexisting hypertrophic cardiomyopathy (HC) and hypertension present diagnostic and therapeutic dilemmas. A retrospective cohort study of patients with HC with coexisting hypertension referred to a specialized HC program was conducted. HC and hypertension were confirmed by strict criteria. Echocardiographic data were reviewed for peak instantaneous left ventricular outflow tract gradients, at rest and with provocation. Symptom control, left ventricular outflow tract gradients, and hypertension control were compared between the first and last visits. One hundred fifteen patients (94 obstructed and 21 nonobstructed) met the eligibility criteria for the study and were included in the analysis, with the mean follow-up duration of 36 months. Because of the treatment strategy, there was a significant decrease in the number of patients treated with direct vasodilators and an increase in the use of beta blockers and disopyramide. Twenty-one obstructed patients (22%) required septal reduction therapy. Overall, in obstructed patients, peak instantaneous left ventricular outflow tract gradient at rest decreased from 48 to 14 mm Hg (p <0.01), which was accompanied by significant improvement in functional class (2.4 vs 1.8, p <0.01). The prevalence of uncontrolled hypertension decreased from 56% at the initial visit to 37% at the last visit (p = 0.01). The cohort had a low rate of adverse cardiovascular outcomes such as death, acute coronary syndromes, and stroke. In conclusion, the present study demonstrates that stepwise, symptom oriented therapy is feasible and effective in patients with coexisting HC and hypertension. PMID- 23340037 TI - MR microscopy of human amyloid-beta deposits: characterization of parenchymal amyloid, diffuse plaques, and vascular amyloid. AB - Cerebral deposits of amyloid-beta peptides (Abeta) form the neuropathological hallmarks of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In the brain, Abeta can aggregate as insoluble fibrils present in amyloid plaques and vascular amyloid, or as diffuse plaques consisting of mainly non-fibrillar Abeta. Previously, magnetic resonance imaging (MRI) has been shown to be capable of detecting individual amyloid plaques, not only via the associated iron, but also Abeta itself has been suggested to be responsible for a decrease in the image intensity. In this current study we aim to investigate the MRI properties of the different cerebral Abeta deposits including diffuse plaques and vascular amyloid. Postmortem 60-MUm-thick brain sections of AD, CAA, and Down's syndrome patients, known to contain Abeta, were studied. High resolution T2*- and T2 weighted MRI scans and quantitative relaxation maps were acquired using a microcoil on a Bruker 9.4T MRI system. Specific MRI characteristics of each type of Abeta deposit were examined by co-registration of the MRI with Congo Red and Abeta-immunostainings of the same sections. Our results show that only fibrillar Abeta, present in both vascular and parenchymal amyloid, induced a significant change in T2* and T2 values. However, signal changes were not as consistent for all of the vessels affected by CAA, irrespective of possible dyshoric changes. In contrast, the non-fibrillar diffuse plaques did not create any detectable MRI signal changes. These findings are relevant for the interpretation and further development of (quantitative) MRI methods for the detection and follow-up of AD and CAA. PMID- 23340038 TI - Capsaicin ameliorates stress-induced Alzheimer's disease-like pathological and cognitive impairments in rats. AB - Hyperphosphorylated tau aggregated into neurofibrillary tangles is a hallmark lesion of Alzheimer's disease (AD) and is linked to synaptic and cognitive impairments. In animal models, cold water stress (CWS) can cause cognitive disorder and tau hyperphosphorylation. Capsaicin (CAP), a specific TRPV1 agonist, is neuroprotective against stress-induced impairment, but the detailed mechanisms are still elusive. Here, we investigated whether CAP mitigates CWS-induced cognitive and AD-like pathological alterations in rats. The animals were administered CAP (10 mg/kg in 0.2 ml, 0.1% ethanol) or a control (0.2 ml normal saline, 0.1% ethanol) by intragastric infusion 1 h before CWS treatment. Our results showed that CAP significantly attenuated CWS-induced spatial memory impairment and suppression of PP-DG long-term potentiation; CAP abolished CWS induced dendritic regression and enhanced several memory-associated proteins decreased by CWS, such as synapsin I and PSD93; CAP also prevented CWS-induced tau hyperphosphorylation by abolishing inhibition of protein phosphatase 2A. Taken together, this study demonstrated that activation of TRPV1 can mitigate CWS induced AD-like neuropathological alterations and cognitive impairment and may be a promising target for therapeutic intervention in AD. PMID- 23340039 TI - Cortical sources of resting state EEG rhythms are sensitive to the progression of early stage Alzheimer's disease. AB - Cortical sources of resting state electroencephalographic (EEG) rhythms are abnormal in subjects with Alzheimer's disease (AD). Here we tested the hypothesis that these sources are also sensitive to the progression of early stage AD over the course of one year. The resting state eyes-closed EEG data were recorded in 88 mild AD patients at baseline (Mini Mental State Evaluation, MMSE I = 21.7 +/- 0.2 standard error, SE) and at approximately one-year follow up (13.3 months +/- 0.5 SE; MMSE II = 20 +/- 0.4 SE). All patients received standard therapy with acetylcholinesterase inhibitors. EEG recordings were also performed in 35 normal elderly (Nold) subjects as controls. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz). Cortical EEG sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Compared to the Nold subjects, the mild AD patients were characterized by a power increase of widespread delta sources and by a power decrease of posterior alpha sources. In the mild AD patients, the follow-up EEG recordings showed increased power of widespread delta sources as well as decreased power of widespread alpha and posterior beta 1 sources. These results suggest that the resting state EEG sources were sensitive, at least at group level, to the cognitive decline occurring in the mild AD group over a one-year period, and might represent cost effective and non-invasive markers with which to enrich cohorts of AD patients that decline faster for clinical studies. PMID- 23340041 TI - First reported case of fatal tuberculosis in a wild African elephant with past human-wildlife contact. AB - Tuberculosis is emerging/re-emerging in captive elephant populations, where it causes morbidity and deaths, although no case of TB in wild African elephants has been reported. In this paper we report the first case of fatal TB in an African elephant in the wild. The infection with Mycobacterium tuberculosis was confirmed by post-mortem and histological examinations of a female sub-adult elephant aged >12 years that died in Tsavo East National Park, Kenya, while under treatment. This case is unique in that during its lifetime the elephant had contact with both humans and wild elephants. The source of the infection was unclear because the elephant could have acquired the infection in the orphanage or in the wild. However, our results show that wild elephants can maintain human TB in the wild and that the infection can be fatal. PMID- 23340040 TI - National Institutes of Health chronic graft-versus-host disease staging in severely affected patients: organ and global scoring correlate with established indicators of disease severity and prognosis. AB - Between 2004 and 2010, 189 adult patients were enrolled on the National Cancer Institute's cross-sectional chronic graft-versus-host disease (cGVHD) natural history study. Patients were evaluated by multiple disease scales and outcome measures, including the 2005 National Institutes of Health (NIH) Consensus Project cGVHD severity scores. The purpose of this study was to assess the validity of the NIH scoring variables as determinants of disease severity in severely affected patients in efforts to standardize clinician evaluation and staging of cGVHD. Out of 189 patients enrolled, 125 met the criteria for severe cGVHD on the NIH global score, 62 of whom had moderate disease, with a median of 4 (range, 1-8) involved organs. Clinician-assigned average NIH organ score and the corresponding organ scores assigned by subspecialists were highly correlated (r = 0.64). NIH global severity scores showed significant associations with nearly all functional and quality of life outcome measures, including the Lee Symptom Scale, Short Form-36 Physical Component Scale, 2-minute walk, grip strength, range of motion, and Human Activity Profile. Joint/fascia, skin, and lung involvement affected function and quality of life most significantly and showed the greatest correlation with outcome measures. The final Cox model with factors jointly predictive for survival included the time from cGVHD diagnosis (>49 versus <=49 months, hazard ratio [HR] = 0.23; P = .0011), absolute eosinophil count at the time of NIH evaluation (0-0.5 versus >0.5 cells/MUL, HR = 3.95; P = .0006), and NIH lung score (3 versus 0-2, HR = 11.02; P < .0001). These results demonstrate that NIH organs and global severity scores are reliable measures of cGVHD disease burden. The strong association with subspecialist evaluation suggests that NIH organ and global severity scores are appropriate for clinical and research assessments, and may serve as a surrogate for more complex subspecialist examinations. In this population of severely affected patients, NIH lung score is the strongest predictor of poor overall survival, both alone and after adjustment for other important factors. PMID- 23340042 TI - Early nasogastric tube feeding versus nil per os in mild to moderate acute pancreatitis: a randomized controlled trial. AB - BACKGROUND & AIMS: Nasojejunal tube feeding is a standard of care in patients with predicted severe acute pancreatitis (AP) and several recent trials suggested that nasogastric tube feeding (NGT) is as safe and efficient as nasojejunal tube feeding in these patients. The aim was to investigate whether NGT presents any benefit to patients with mild to moderate AP. METHODS: The study design was a randomized controlled trial. The patients in the intervention group received NGT within 24 h of hospital admission. The patients in the control group were on nil per os (NPO). The severity of acute pancreatitis was determined according to the new international multidisciplinary classification. RESULTS: There were 17 patients randomly allocated to the NGT group and 18 to the NPO group. The visual analogue pain score decreased to a significantly greater extent in the NGT group (from median 9 (range 7-9) at baseline to 1 (0-3) at 72 h after randomization) compared with the NPO group (from 7 (5-9) to 3 (1-4) (p = 0.036). The number of patients not requiring opiates at 48 h after randomization was significantly different (p = 0.024) between NGT (9/17) and NPO (3/18). Oral food intolerance was observed in 1/17 patient in the NGT group and 9/18 patients in the NPO group (p = 0.004). The overall hospital stay in the NGT group was 9 (5-12) days as compared with 8.5 (6-13) days in the NPO group (p = 0.91). CONCLUSIONS: NGT commenced within 24 h of hospital admission is well tolerated in patients with mild to moderate acute pancreatitis. Further, when compared with NPO, it significantly reduces the intensity and duration of abdominal pain, need for opiates, and risk of oral food intolerance, but not overall hospital stay. PMID- 23340043 TI - Utilizing multiple methods to classify malnutrition among elderly patients admitted to the medical and surgical intensive care units (ICU). AB - BACKGROUND & AIMS: The nutritional status of elderly patients requiring ICU admission is largely unknown. This study evaluated the prevalence of malnutrition in elderly patients (>65 years) admitted to the surgical and medical ICUs, agreement between assessment techniques and associations between malnutrition and adverse outcomes. METHODS: For this prospective cohort, nutritional status was classified concurrently using the Mini Nutrition Assessment (MNA), Subjective Global Assessment (SGA), Nutrition Risk Score 2002 (NRS 2002) and MNA-short form (MNA-SF). Demographic and relevant medical information were collected from the medical record prior to the nutrition interview and/or following hospital discharge. Descriptive statistics, inter-rater agreement and regression analyses were conducted. RESULTS: The average patient was 74.2 (+/-6.8) years of age with a mean APACHE II score of 11.9 (+/-3.6). Malnutrition was prevalent in 23-34% of patients (n = 260) with excellent agreement between raters. Compared to MNA, NRS 2002 had the highest sensitivity, while SGA and MNA-SF had higher specificity. Malnutrition at ICU admission was associated with longer hospital LOS, a lower propensity for being discharged home and a greater need for hospice care or death at discharge (all p values <0.05). These relationships were diminished when controlling for severity of illness. CONCLUSIONS: Future work in this elderly population needs to explore the role of disease acuity, inflammation and body composition in the nutrition assessment process and in the examination of outcomes. PMID- 23340044 TI - Evaluation of the association between osteoporosis and postural balance in postmenopausal women. AB - The incidence of osteoporosis has been increasing, as have fractures resulting from falls. Postural balance was evaluated in postmenopausal women with and without lumbar osteoporosis. One hundred and twenty-six postmenopausal women aged 55-65 years were evaluated and separated into two groups according to the bone mineral density values of their lumbar spine: the osteoporosis group and the control group, paired by age (P = 0.219) and physical activity (P = 0.611). There was no difference between the groups (P = 0.139) regarding falls reported in the previous 12 months. Functional mobility was evaluated through the Timed Up and Go Test. Postural balance was evaluated using a portable force platform in standard standing position, with eyes open and closed, for 60s. Muscle strength was evaluated through an isokinetic dynamometer. This study shows that there is no difference in knee muscle strength and functional mobility (P = 0.121), postural balance with eyes open [mediolateral displacement (P = 0.286) and mean velocity of the center of pressure (COP) (P = 0.173)] and with eyes closed [mediolateral displacement (P = 0.163), and the mean velocity of displacement of the COP (P = 0.09)] in both groups. Subjects reporting falls had greater mediolateral displacement (P = 0.028) in both groups. Postmenopausal women aged between 55 and 65 years do not present changes in postural balance irrespective of lumbar osteoporosis. Greater COP mediolateral displacement is related to the occurrence of falls in postmenopausal women in the previous year. PMID- 23340045 TI - Heart transplantation: 25 years' single-centre experience. AB - OBJECTIVES: Heart transplantation (HTx) is still one of the most effective therapies for end-stage heart disease for patients with no other medical or surgical therapy. We report the results of our 25-year orthotropic HTx single centre experience. METHODS: From November 1985, 905 orthotopic heart transplants have been performed at our centre. We exclude from the present analysis 13 patients who underwent re-transplantation and 14 pediatric cases (age at HTx <15 years). RESULTS: The present study collected the data of 878 primary adult orthotopic HTx performed at our centre. Mean age at HTx was of 49.6 +/- 11.6 years. Mean donor age was 36.9 +/- 14.8 years. Hospital mortality was 11.6% (102 patients), early graft failure was the principal cause of death (58 patients) followed by infections (18 cases) and acute rejection (7 patients). Overall actuarial survival was 78.1% at 5 years and 63.8% and 47.5%, respectively, at 10 and 15 years from HTx. Mean survival was 10.74 years; 257 late deaths were reported (33.1%); main causes were neoplasm in 83 patients, and cardiac causes included coronary allograft vasculopathy in 78 patients. Freedom from any infection at 5, 10 and 15 years was 52.2, 44.1 and 40.1%, respectively. Freedom from rejection at 5 years was 36.2%, with 493 patients experiencing at last one episode of rejection, the majority occurring during the first 2 months after transplantation. The long-term survival of HTx recipients is limited in large part by the development of coronary artery vasculopathy and malignancies. In our experience freedom from coronary allograft vasculopathy at 10 years was 66.9%, and 85 patients underwent percutaneous coronary revascularization. In our study population, 44 patients experienced posttransplant lymphoproliferative disorder and 91 patients experienced a solid neoplasm, mean survival free from neoplasm was 12.23 years. CONCLUSION: Over the past four decades the field of HTx has evolved considerably, with improvements in surgical techniques and postoperative patients' care. A careful patient selection and treatment of candidates for transplantation as well as accurate clinical follow-up combined with real multidisciplinary teamwork that involved different heart failure specialists, allowed us to obtain our excellent long-term results. PMID- 23340046 TI - Task-free electrocorticography frequency mapping of the motor cortex. AB - OBJECTIVE: Electrocortical stimulation mapping (ESM) is the current gold standard for functional mapping of the eloquent cortex prior to epilepsy surgery. The procedure is, however, time-consuming and quite demanding for patients. Electrocorticography frequency mapping (ECoG mapping) has been suggested as an adjunct method. Here, we investigated whether it is possible to perform mapping of motor regions using ECoG data of spontaneous movements. METHODS: Using the video registration of seven epilepsy patients who underwent electrocorticography and ESM, we selected periods of spontaneous hand and arm movements and periods of rest. Frequency analysis was performed, and electrodes showing a significant change in power (4-7, 8-14, 15-25, 26-45 or 65-95 Hz) were compared with those being identified as relevant for hand and/or arm movement by ESM. RESULTS: All frequency bands showed a high specificity (>0.80), and the 65-95 Hz frequency band additionally had a high sensitivity (0.82) for identifying ESM positive electrodes. CONCLUSIONS: Our data show a good match between ECoG mapping of spontaneous movements and ESM data. SIGNIFICANCE: The accurate match suggests that ECoG mapping of the motor cortex using spontaneous movements may be a valuable complement to ESM, especially when other options requiring patient cooperation fail. PMID- 23340047 TI - Current matching and efficiency optimization in a two-junction nanowire-on silicon solar cell. AB - Numerical simulation of the photocurrent density is performed for a two-junction nanowire (NW)-on-silicon solar cell under AM1.5G illumination. The photocurrent density is determined for NW diameters from 100-250 nm, period (spacing) from 250 1000 nm, and length of 5 MUm. The dependence of photocurrent density on NW bandgap is also determined. For each NW bandgap, the optimum diameter and period are determined to obtain current matching between the top NW cell and the bottom Si cell. PMID- 23340048 TI - GDNF promotes neurite outgrowth and upregulates galectin-1 through the RET/PI3K signaling in cultured adult rat dorsal root ganglion neurons. AB - Galectin-1 (GAL-1), a member of a family of beta-galactoside binding animal lectins, is predominantly expressed in isolectin B4 (IB4)-binding small non peptidergic (glial cell line-derived neurotrophic factor (GDNF)-responsive) sensory neurons in the sections of adult rat dorsal root ganglia (DRG), but its functional role and the regulatory mechanisms of its expression in the peripheral nervous system remain unclear. In the present study, both recombinant nerve growth factor (NGF) and GDNF (50 ng/ml) promoted neurite outgrowth from cultured adult rat DRG neurons, whereas GDNF, but not NGF, significantly increased the number of IB4-binding neurons and the relative protein expression of GAL-1 in the neuron-enriched culture of DRG. The GAL-1 expression in immortalized adult rat Schwann cells IFRS1 and DRG neuron-IFRS1 cocultures was unaltered by treatment with GDNF, which suggests that GDNF/GAL-1 signaling axis is more related to neurite outgrowth, rather than neuron-Schwann cell interactions. The GDNF-induced neurite outgrowth and GAL-1 upregulation were attenuated by anti-GDNF family receptor (RET) antibody and phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor LY294002, suggesting that the neurite-outgrowth promoting activity of GDNF may be attributable, at least partially, to the upregulation of GAL-1 through RET-PI3K pathway. On the contrary, no significant differences were observed between GAL-1 knockout and wild-type mice in DRG neurite outgrowth in the presence or absence of GDNF. Considerable immunohistochemical colocalization of GAL-3 with GAL-1 in DRG sections and GDNF-induced upregulation of GAL-3 in cultured DRG neurons imply the functional redundancy between these galectins. PMID- 23340049 TI - Obesity is associated with poor response to clopidogrel and an increased susceptibility to protease activated receptor-1 mediated platelet activation. AB - Obesity is associated with a prothrombotic state resulting from increased thrombin generation, platelet hyper-reactivity, and decreased fibrinolysis. Data on the influence of obesity on clopidogrel-mediated platelet inhibition are conflicting and limited to platelet function tests. Moreover, there are no data on thrombin-inducible platelet activation in obese patients. We therefore investigated response to clopidogrel therapy and protease activated receptor (PAR)-1 mediated platelet activation in obese and nonobese patients undergoing angioplasty and stenting for cardiovascular disease. The vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay, multiple electrode aggregometry (MEA) with adenosine diphosphate (ADP), and surface expressions of P-selectin and activated glycoprotein (GP) IIb/IIIa in response to ADP and thrombin receptor activating peptide (TRAP)-6 were assessed in 71 obese and 245 nonobese patients. Obesity was independently associated with higher residual platelet reactivity by the VASP assay and MEA ADP, and with platelet surface expressions of P-selectin and activated GPIIb/IIIa in response to ADP (all P <= 0.04). Further, high on treatment residual ADP-inducible platelet reactivity by the VASP assay and by MEA ADP were significantly more frequent in obese patients compared with nonobese patients (both P <= 0.04). Finally, PAR-1 mediated platelet activation as assessed by expression of P-selectin and activated GPIIb/IIIa in response to TRAP 6 was significantly more pronounced in obese patients than in patients without obesity (both P <= 0.02). In conclusion, obese patients undergoing angioplasty and stenting exhibit a diminished response to clopidogrel and an increased susceptibility to TRAP-6 inducible platelet activation. PMID- 23340050 TI - Prediction of scaled feed intake in weaner pigs using physico-chemical properties of fibrous feeds. AB - The objective of the present study was to predict scaled feed intake (SFI) using the physico-chemical measurements of feed bulk, such that gut capacity can be estimated in weaner pigs. A basal feed with 13.7 MJ digestible energy and 180 g crude protein per kg DM was diluted to six inclusion levels (0, 80, 160, 240, 320 and 400 g/kg DM) using lucerne hay, maize cob, maize stover, sawdust, sunflower husks or grass hay (veld grass). A total of 124 pigs weighing 18.1 (SD 1.37) kg body weight were used. Water-holding capacity (WHC; g water/g DM), bulk density (g DM/ml), neutral-detergent fibre (NDF) and acid-detergent fibre (ADF) influenced the SFI. The quadratic relationship between SFI and WHC was SFI = 19.1 (SEM 3.49)+10.04 (SEM 1.61) WHC-1.11 (SEM 0.17) WHC2 (P<0.01). SFI was also related (P<0.01) to NDF and ADF by quadratic functions SFI = 24.3 (SEM 3.55)+0.12 (SEM 0.229) NDF - 0.00 012 (SEM 0.000036) NDF2 and SFI = 30.2 (SEM 1.95)+0.112 (SEM 0.0232) ADF-0.000343 (SEM 0.0000612) ADF2, respectively. Using broken-stick analyses, the gut capacity was attained when WHC = 4.53 (SEM 1.25) g water/g DM, NDF = 367 (SEM 29) g/kg DM and ADF = 138 (SEM 77) g/kg DM. In conclusion, although threshold values for each were different, WHC, NDF and ADF contents of bulk feeds provide relationships with SFI that can be used to predict gut capacity in weaner pigs. PMID- 23340051 TI - Quantitation of integrated proviral DNA in viral reservoirs. AB - PURPOSE OF REVIEW: Integrated HIV DNA can give rise to infectious virus, and therefore may be a surrogate of reservoir size. How this form reflects the amount of replication competent virus in vivo remains to be established. This review highlights the technical hurdles involved in measuring integrated HIV DNA, progress toward overcoming these hurdles by repetitive sampling and recent important in-vivo findings monitoring this HIV DNA intermediate. RECENT FINDINGS: The dynamics of integration levels after antiretroviral therapy may provide clues to how reservoirs accumulate over time and why early intervention may be beneficial. Recent studies including a multilab collaboration showed that integrated HIV DNA correlate with several viral DNA intermediates including replication competent virus as measured by a quantitative coculture assay. Because this assay performs robustly over a large dynamic range and is reproducible, it may be useful for detecting small changes in reservoir size in trials that target reservoirs as suggested by a recent trial with interferon alpha. SUMMARY: Integrated HIV DNA provides an important surrogate for reservoir size and may be useful in trials that target HIV reservoirs. By performing large replicates (repetitive sampling), it is possible to provide more robust estimates and to detect small changes that other assays may overlook. This in turn is critical for evaluating eradication therapies that may have modest but important effects. PMID- 23340052 TI - Designing green plasticizers: influence of alkyl chain length on biodegradation and plasticization properties of succinate based plasticizers. AB - Phthalate diesters such as di (2-ethylhexyl) phthalate (DEHP) are considered ubiquitous contaminants and are poorly biodegraded in the environment. Moreover, both the parent compound and stable metabolites such as mono (2-ethylhexyl) phthalate (MEHP) are linked to several negative impacts on the environment and human health. Earlier work established that saturated diester compounds, such as succinates, showed better biodegradation characteristics and comparable plasticizer properties compared to DEHP. In this work we examine the effect of alkyl chain length of succinate molecules on plasticizer and biodegradation properties. This included both the side chains (n-ethyl to n-octyl) as well as substituents on the middle part of the succinate molecule. We showed that the common soil bacterium Rhodococcus rhodocrous could rapidly break down all unsubstituted succinates, without the appearance of stable metabolites. Furthermore, the organisms used the plasticizer metabolites as carbon source. The introduction of a large cyclohexyl substituent on the succinate resulted in a poorer degradation rate. Glass Transition Temperature (Tg) measurements were performed to evaluate plasticizer properties and showed that longer side chains reduced the Tg more efficiently, while large cyclohexyl substituents on the succinate decreased this effect. However, all compounds performed better or equal to DEHP at reducing the Tg. PMID- 23340053 TI - Magnetic zeolite NaA: synthesis, characterization based on metakaolin and its application for the removal of Cu2+, Pb2+. AB - The optimum parameters for synthesis of zeolite NaA based on metakaolin were investigated according to results of cation exchange capacity and static water adsorption of all synthesis products and selected X-ray diffraction (XRD). Magnetic zeolite NaA was synthesized by adding Fe3O4 in the precursor of zeolite. Zeolite NaA and magnetic zeolite NaA were characterized with scanning electron microscopy (SEM) and XRD. Magnetic zeolite NaA with different Fe3O4 loadings was prepared and used for removal of heavy metals (Cu(2+), Pb(2+)). The results show the optimum parameters for synthesis zeolite NaA are SiO2/Al2O3=2.3, Na2O/SiO2=1.4, H2O/Na2O=50, crystallization time 8h, crystallization temperature 95 degrees C. The addition of Fe3O4 makes the NaA zeolite with good magnetic susceptibility and good magnetic stability regardless of the Fe3O4 loading, confirming the considerable separation efficiency. Additionally, Fe3O4 loading had a little effect on removal of heavy metal by magnetic zeolite, however, the adsorption capacity still reaches 2.3 mmol g(-1) for Cu(2+), Pb(2+) with a removal efficiency of over 95% in spite of 4.7% Fe3O4 loading. This indicates magnetic zeolite can be used to remove metal heavy at least Cu(2+), Pb(2+) from water with metallic contaminants and can be separated easily after a magnetic process. PMID- 23340054 TI - A girl with Cardio-facio-cutaneous syndrome complicated with status epilepticus and acute encephalopathy. AB - We report a six-year-old girl with Cardio-facio-cutaneous (CFC) syndrome who developed acute encephalopathy after the recurrence of status epilepticus. While epileptic encephalopathy and severe epilepsy have been mentioned as frequent complications of the CFC syndrome, no previous reports have shown a case of the CFC syndrome complicated with acute encephalopathy. Here we discuss the possibility for the linkage between the development of acute encephalopathy and CFC syndrome which is generally susceptible to seizures or epilepsy. PMID- 23340055 TI - Suppression of annexin A2 by prostaglandin E2 impairs phagocytic ability of peritoneal macrophages in women with endometriosis. AB - STUDY QUESTION: Is annexin A2 involved in the reduced phagocytic ability of macrophages in endometriosis? SUMMARY ANSWER: Data from women with endometriosis and a murine model of the disease show that expression of annexin A2 in peritoneal macrophages is inhibited by prostaglandin E2 (PGE2) and this impairs the phagocytic ability of macrophages. WHAT IS ALREADY KNOWN: Endometriosis is a chronic inflammatory disease that recruits many immune cells, especially macrophages, to the peritoneal cavity. The phagocytic ability of peritoneal macrophages isolated from women with endometriosis is reduced. STUDY DESIGN, SIZE, DURATION: A laboratory study. Thirty-five patients (20 with and 15 without endometriosis) of reproductive age with normal menstrual cycles were recruited. PARTICIPANTS/MATERIALS, SETTING, METHODS: Peritoneal macrophages isolated from women with or without endometriosis were cultured and treated with vehicle, PGE2 and different EP receptor agonists, and the expression of annexin A2 was quantified by RT-PCR and western blotting. Annexin A2 was knocked down (by small interfering RNA) in normal macrophages or overexpressed (by treatment with recombinant protein) in endometriotic macrophages and their phagocytic ability was measured by flow cytometry. Peritoneal macrophages were isolated from a mouse model of endometriosis and treated with PGE2 or cyclo-oxygenase (COX) inhibitors, and annexin A2 mRNA was quantified. MAIN RESULTS AND THE ROLE OF CHANCE: Levels of annexin A2 were markedly reduced in peritoneal macrophages from women with endometriosis versus controls (mRNA: P < 0.01). The level of annexin A2 mRNA in the macrophages was reduced by PGE2 (P < 0.01/P < 0.05 in women without/with endometriosis versus control) via the EP2/EP4 receptor-dependent signaling pathway. Treatment with PGE2 or knockdown of annexin A2 inhibited the phagocytic ability of macrophages (P < 0.05 versus control), while treatment with annexin A2 recombinant protein enhanced phagocytosis. Autologous transplantation animal studies further confirmed that levels of annexin A2 in peritoneal macrophages were markedly reduced in mice treated with PGE2 (P < 0.01 versus control). In contrast, treatment with COX inhibitors to inhibit PGE2 production enhanced annexin A2 expression in peritoneal macrophages (P < 0.05 versus control). LIMITATIONS, REASONS FOR CAUTION: We have provided no direct demonstration that phagocytic activity is indeed decreased in peritoneal cells from patients with endometriosis or that their endometriotic fluid contains increased amounts of PGE2 when compared with control subjects. WIDER IMPLICATIONS OF THE FINDINGS: Inhibiting PGE2 signaling, in order to restore or enhance the phagocytic capability of macrophages, may represent a new direction of thinking in developing novel strategies against endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from National Science Council of Taiwan, Republic of China (NSC97-2314-B-006-020-MY3) to M.-H.W. and (NSC98-2320-B 006-026-MY3) to S.-J.T., and grants from the Chang Gung Memorial Hospital, Taiwan, Republic of China (CMRPG891432 and CMRPG8A0531) to P.-C.C. None of the authors have any conflicts of interest. PMID- 23340056 TI - The sperm protamine mRNA ratio as a clinical parameter to estimate the fertilizing potential of men taking part in an ART programme. AB - STUDY QUESTION: Could the protamine-1 to protamine-2 mRNA ratio serve as a biomarker to estimate the fertilizing capacity of sperm from men taking part in an IVF/ICSI programme? SUMMARY ANSWER: The protamine mRNA ratio clearly discriminates between fertile and subfertile men and sperm with a normal protamine mRNA ratio exhibit a higher fertilizing capacity in IVF/ICSI. WHAT IS KNOWN ALREADY: Aberrant sperm protamine ratios are associated with male factor infertility and mRNA ratio is comparable with protein ratio (due to transcriptional stop in elongating spermatids). STUDY DESIGN, SIZE, DURATION: The study population was drawn from subfertile men, whose female partners participated in IVF or ICSI programmes between September 2010 and February 2012. Normozoospermic healthy volunteers served as controls. Sperm cells were lysed, mRNA extracted, reverse transcribed and subjected to real-time quantitative PCR using specific primer pairs for protamine-1 and protamine-2. Relative protamine-1 and protamine-2 mRNA levels were analysed with the Mann-Whitney U-test (two tailed). PARTICIPANTS/MATERIALS, SETTING, METHODS: Quantitative RT-PCR for protamines 1 and 2 has been performed in ejaculates from 32 normozoospermic volunteers (control, University Clinic Giessen, Germany) and 306 patients, whose female partners took part in an IVF (n = 76; University Clinic Hamburg, Germany and Shanghai Jiaotong University, China) or an ICSI (n = 230; University Clinic Munich, Germany and Kinderwunschzentrum Wiesbaden, Germany) programme. MAIN RESULTS AND THE ROLE OF CHANCE: The sperm protamine mRNA ratio in normozoospermic men (0.98 +/- 0.3) differed significantly from that of ICSI patients (Munich 0.81 +/- 0.1; Wiesbaden 0.78 +/- 0.2; P < 0.001), while processed samples obtained from IVF patients revealed a normal protamine mRNA ratio (Hamburg 1.0 +/- 0.07; Shanghai 1.0 +/- 0.54). Normal protamine mRNA ratios were associated with a significantly higher total motile sperm count and a significantly higher percentage of progressively motile sperm. Sperm with a normal protamine mRNA ratio revealed a higher fertilization capacity (fc) in both IVF (53.6% of patients with fc > 80%; P = 0.017) and ICSI (65.1% of patients with fc > 70%; P = 0.028). LIMITATIONS, REASONS FOR CAUTION: The protamine mRNA ratio in an individual sperm cell used for ICSI may be different from the overall value obtained from a semen aliquot. WIDER IMPLICATIONS OF THE FINDINGS: Data are in line with current literature and suggest the protamine mRNA ratio as a diagnostic marker to estimate the fertilizing capacity of sperm. STUDY FUNDING: The German Research Foundation (DFG) to K.S., W.W. and A.P. (STE 892/9-2), as well as to A.S. and H.C.O. (SP721/1-3). COMPETING INTEREST(S): None. PMID- 23340057 TI - Day-specific probabilities of conception in fertile cycles resulting in spontaneous pregnancies. AB - STUDY QUESTION: When, within the female cycle, does conception occur in spontaneously fertile cycles? SUMMARY ANSWER: This study provides reference values of day-specific probabilities of date of conception in ongoing pregnancies. The maximum probability of being within a 5-day fertile window was reached on Day 12 following the last menstrual period (LMP). WHAT IS KNOWN ALREADY: The true date of conception is not observable and may only be estimated. Accuracy of these estimates impacts on obstetric management of ongoing pregnancies. Timing of ovulation and fertility has been extensively studied in prospective studies of non-pregnant fertile women using error-prone proxies, such as hormonal changes, body-basal temperature and ultrasound, yielding day-specific probabilities of conception and fertile windows. In pregnant women, date of conception may be retrospectively estimated from early pregnancy fetal measurement by ultrasound. STUDY DESIGN, SIZE, DURATION: Retrospective analysis of consecutive pregnancies in women referred for routine first-trimester screening, over a 3-year period (2009-2011) in a single ultrasound center (n = 6323). PARTICIPANTS/MATERIALS, SETTING, METHODS: Within the overall population, 5830 cases with a certain date of last menses were selected for analysis. The date of conception was estimated using a crown-rump length biometry and an equation derived from IVF/ICSI pregnancies. Day-specific probabilities of conception were estimated across several covariates, including age, cycle characteristics and ethnicity, using deconvolution methods to account for measurement error. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, the day-specific probability of conception sharply rises at 7 days after the LMP, reaching its maximum at 15 days and returning to zero by 25 days. Older women tend to conceive earlier within their cycle, as did women with regular cycles and white and black women compared with Asian ethnicity. The probability of being within the fertile window was 2% probability at Day 4, a maximum probability of 58% at Day 12 and a 5% probability by Day 21 of the cycle. LIMITATIONS, REASONS FOR CAUTION: Although conception is believed to occur within hours following ovulation, a discrepancy is theoretically possible. However, when comparing our results to those of prospective studies, no such difference was found. The equation used for estimating the date of pregnancy was estimated in IVF/ICSI pregnancies, which could lead to potential bias in spontaneous pregnancies. However, in our population, the observed bias was negligible. Non-fertile cycles and early pregnancy losses are necessarily overlooked because of the nature of our data. WIDER IMPLICATIONS OF THE FINDINGS: Because of the wider access to retrospective data and the potential bias in prospective studies of ovulation monitoring, this study should broaden the perspectives of future epidemiologic research in fertility and pregnancy monitoring. STUDY FUNDING/COMPETING INTERESTS: None. PMID- 23340058 TI - Multidetector-row computed tomography assessment of adding budesonide/formoterol to tiotropium in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), multidetector-row computed tomography (MDCT) showed that tiotropium dilated the inner diameters in airways from the third to the sixth generation of the bronchi. Here we aimed to evaluate the morphological effect by adding a budesonide/formoterol combination to tiotropium in COPD patients using three dimensional MDCT. METHODS: Pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ) and MDCT imaging studies were performed at the beginning and after budesonide/formoterol combination treatment for 12 weeks in 14 patients with COPD. RESULTS: The median age was 73.5 years and the mean forced expiratory volume in 1 s (FEV1) as a percentage of the predicted value was 57.2 +/- 18.3%. The luminal area in the fifth generation bronchi and the emphysema volume/CT derived total lung volume were significantly correlated with FEV1 at baseline (r = 0.682, p < 0.02 and r = -0.868, p < 0.001, respectively). The average luminal area and wall area percentage in the third, fourth and fifth generations were correlated with the SGRQ total score. Budesonide/formoterol induced insignificant pulmonary function changes and significant symptoms improvement. CT images showed an increased inner luminal area and decreased wall area after budesonide/formoterol treatment. Average luminal area was significantly increased from 24.3 +/- 9.7 to 26.0 +/- 9.9 mm(2) in the third generation, 13.0 +/- 6.5 to 14.7 +/- 7.3 mm(2) in the fourth generation, 8.0 +/- 4.8 to 9.4 +/- 4.9 mm(2) in the fifth generation and 5.6 +/- 2.7 to 6.7 +/- 3.6 mm(2) in the sixth generation (p < 0.01). The average increase of the third generation luminal area was correlated with the FEV1 increase (r = 0.632, p < 0.03). The wall area percentage significantly decreased from 51.5 +/- 9.2 to 49.1 +/- 9.7 in the third generation, 56.1 +/- 9.7 to 53.0 +/- 11.1 in the fourth generation, and 62.3 +/- 9.9 to 57.6 +/- 9.8 in the fifth generation (p < 0.05). Emphysema volume/CT derived total lung volume was unchanged with treatment. CONCLUSION: MDCT demonstrated budesonide/formoterol induced bronchodilation in the non-small airway. CT imaging can evaluate drug therapeutic effect and may provide additional insights into pharmacotherapy for COPD. PMID- 23340060 TI - Mucosal healing in inflammatory bowel disease. AB - It is becoming increasingly recognized that purely clinical endpoints may not be sufficient in the treatment of patients with inflammatory bowel disease. As such, mucosal disease assessment has become a prominent component of the majority of recent clinical trials in Crohn's disease and ulcerative colitis. There is mounting evidence that the attainment of mucosal healing leads to improved clinical outcomes in both Crohn's disease and ulcerative colitis. However, the use of mucosal healing as a therapeutic endpoint in inflammatory bowel disease is in its early stages, as a number of issues limit its application to routine clinical practice. PMID- 23340059 TI - Is magnetic resonance imaging a reliable diagnostic tool in the evaluation of active Crohn's disease in the small bowel? AB - GOALS: To evaluate the overall diagnostic accuracy of magnetic resonance imaging (MRI) in assessing the activity of Crohn's disease (CD) in the small bowel. BACKGROUND: Cross-sectional imaging techniques are playing an increasing role in the evaluation of suspected CD. Advantages of MRI include a lack of ionizing radiation, the ability to provide dynamic information regarding bowel distention and motility, improved soft-tissue contrast, and a relatively safe intravenous contrast agent profile. STUDY: Two reviewers searched MEDLINE, EMBASE, and other electronic databases to identify studies in which MRI imaging was evaluated for assessing the activity of CD in the small bowel from January 2001 to September 2011. Bivariate random-effects meta-analytic methods were used to estimate summary, sensitivity, specificity, and receiver operating characteristic curves. RESULTS: MRI had a pooled sensitivity of 0.87 [95% confidence interval (CI): 0.77, 0.93] and a pooled specificity of 0.91 (95% CI: 0.81, 0.96). Overall, likelihood ratio (LR)+ was 9.5 (95% CI: 4.4, 20.6) and LR- was 0.14 (95% CI: 0.08, 0.26). In patients with high pretest probabilities, MRI enabled confirmation of active CD; in patients with low pretest probabilities, MRI enabled exclusion of active CD. Worst-case-scenario (pretest probability, 50%) posttest probabilities were 90% and 13% for positive and negative MRI results, respectively. CONCLUSIONS: A limited number of small studies suggest that MRI has high sensitivity and specificity for diagnosis of active CD in the small bowel; MRI will likely also prove to be suitable as the primary modality for active CD imaging surveillance. PMID- 23340061 TI - Therapeutic strategies for laryngeal manifestations of gastroesophageal reflux disease. AB - Gastroesophageal reflux disease is increasingly associated with ear, nose, and throat symptoms, including laryngitis. Many patients are unaware of the gastroesophageal etiology of their symptoms. A variety of criteria are used to diagnose this condition, including laryngoscopy, esophagogastroduodenoscopy, and the use of ambulatory pH and impedance monitoring. However, no test serves as the gold standard for the diagnosis given their lack of sensitivity and specificity for reflux disease. Numerous trials have assessed the role of proton pump inhibitor therapy in patients with laryngopharyngeal reflux and most have revealed no benefit to acid suppression over placebo. Despite many uncertainties there has been some progress regarding the role of acid-suppressive therapy as well as other agents in this unique group of patients. In this review we explore therapeutic options and their rationale for patients with laryngeal signs and symptoms. PMID- 23340062 TI - Patients with obstructive jaundice and biliary stricture +/- mass lesion on imaging: prevalence of malignancy and potential role of EUS-FNA. AB - BACKGROUND: In patients with obstructive jaundice and biliary stricture, the role of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is debated for fear of missing a potentially resectable pancreatobiliary malignancy (PBM). We evaluated the prevalence of (1) PBM; (2) lesions that do not require a potentially curative cancer surgery; and (3) potentially resectable PBMs in patients with false-negative diagnosis by EUS-FNA. PATIENTS AND METHODS: This is a retrospective analysis of 342 patients who underwent EUS/EUS-FNA from 2002 to 2009 after presenting with obstructive jaundice and a biliary stricture. Of these, 170 patients had no definitive mass on computed tomography and 172 patients had definitive mass on computed tomography without evidence of unresectability. Final diagnosis was based on surgical pathology or definitive cytology and clinical follow-up of >= 12 months. RESULTS: The mean age of patients (176 male) was 68.0+/-12.5 years. A final diagnosis of malignancy was made in only 248 patients (72.5%; 95% confidence interval, 67.7, 77.2). The overall accuracy of EUS-FNA for diagnosing malignancy was 92.4% (89.0, 94.8), with 91.5% sensitivity (87.1, 94.5) and 80.9% negative predictive value (72.0, 87.5). Among 21 patients with false-negative diagnosis, 8 had cholangiocarcinoma (2 resectable), 13 had pancreatic cancer (5 resectable). EUS-FNA provided information to potentially modify surgical management in 116 patients (33.9%; 95% confidence interval, 29.1, 39.0): 89 patients diagnosed as true negatives, 24 with distant malignant lymphadenopathy, and 3 with malignant lymphoma. CONCLUSIONS: In above-defined patient subset, the risk of missing resectable tumors by EUS-FNA has been exaggerated because of artifactually low negative predictive value resulting from a high pretest probability of PBM. The actual miss rate for resectable PBM by EUS-FNA is rather small and was 2% in present cohort. Information from EUS-FNA can potentially modify surgical management in up to one third of patients. PMID- 23340063 TI - Interobserver agreement for confocal imaging of ampullary lesions: a multicenter single-blinded study. AB - BACKGROUND: Malignant ampullary lesions can be difficult to classify by endoscopy alone. Probe-based confocal laser endomicroscopy (pCLE) permits in vivo assessment of mucosal structures in the gastrointestinal tracts in the real time. AIM: The objective of this pilot multicenter study was to assess the interobserver agreement and variance in interpretation of pCLE of ampullary lesions. METHODS: Twelve pCLE video clips of ampullary lesions were distributed to 6 gastrointestinal specialists at 5 medical centers, blinded to final pathologic results. Six variables were assessed for interobserver agreement using kappa statistics. Variables included an epithelial outer border with irregular thickness, dark epithelium without discernable individual cells, heterogenously distributed elongated crypts, reduced number of goblet cells, neovascularization, and final diagnosis. RESULTS: The overall interobserver agreement for all observers was poor to slight for all variables (kappa=0.02, 0.05, -0.01, 0.04, 0.018) except for the first variable with fair degree of agreement (kappa=0.27). On the basis of experience, 3 observers were classified as less experienced, whereas 3 were classified as most experienced. Upon stratification, the less experienced observers had poor interobserver agreement for all variables, except 1. The most experienced observers had poor agreement for 2 variables, slight agreement for 3 variables, and fair agreement for the final diagnosis variable. CONCLUSIONS: The overall interpersonal agreement on pCLE for ampullary lesions was poor. The interobserver agreement was not substantially improved for experienced raters. Further standardization of pCLE image criteria is needed for ampullary lesions. Standardized training may improve interrater reliability to an acceptable level. PMID- 23340064 TI - Rifaximin in the treatment of irritable bowel syndrome: is there a high risk for development of antimicrobial resistance? AB - Irritable bowel syndrome (IBS), a chronic, nonfatal illness is commonly encountered in clinical practice; however, treatment options are limited and often ineffectual. Despite this, there is increasing evidence that bacterial overgrowth in the bowel (dysbiosis) may be an etiological factor in IBS. This has lead to studies in which the antibiotic agent rifaximin has been used to reduce the microbial burden in the bowel, to some extent alleviating the symptoms of IBS. Rifaximin is a member of the rifamycin class of antibiotics, which when administered orally has the distinctions of being gut specific coupled with poor systemic absorption, characteristics that are suggested to limit the development of bacterial resistance. The rifamycins are currently used to treat serious human diseases including tuberculosis, meningococcal disease, methicillin-resistant Staphylococcus aureus and Clostridium difficile infections. The use of rifamycins in the treatment of these diseases is associated with the development of antibiotic resistance over time. When considering the importance of the rifamycins in the treatment of serious human diseases, the large number of patients affected by IBS, and the lack of scientific evidence available on the development of antibiotic resistance to rifaximin over the long-term when used in the gut, it is advisable that the use of rifaximin as a therapy for IBS should be limited to single, acute, short-term treatment. PMID- 23340065 TI - Survival of hepatocellular carcinoma patients may be improved in surveillance interval not more than 6 months compared with more than 6 months: a 15-year prospective study. AB - GOALS: To compare hepatocellular carcinoma (HCC) stage, treatment modality, and survival between groups submitted to different surveillance interval. BACKGROUND: It is not clear if surveillance interval affects patient survival with HCC. STUDY: Clinical data from 10,307 patients at risk for HCC were prospectively collected from 1990 to 2005. The characteristics of cancer and 5-year survival in patients diagnosed as HCC during follow-up were compared between surveillance interval of <6 months and beyond 6 months. RESULTS: A total of 400 patients were diagnosed with HCC, with a mean tumor size of 3.5 cm and an annual detection rate of 2.4%. The tumor sizes detected in patients with surveillance interval <= 6 months were significantly smaller than those detected in patients with interval of >6 months (n=219; 3.0 +/- 1.7 cm vs. n=181; 4.0 +/- 2.6 cm, P<0.001). The survival benefit in patients with surveillance interval of <= 6 months was significant compared with those with interval of >6 months even after considering lead time with assumed tumor doubling time of 60 days. The 5-year survival of HCC patients surveyed between 2000 and 2004 was significantly higher compared with those surveyed between 1990 and 1994 or between 1995 and 1999 (41% vs. 17% and 19%, respectively, P<0.0001). Using a Cox regression model, Child-Pugh class, Japanese tumor-node-metastasis stage, and alpha-fetoprotein levels were independently associated with patient survival. CONCLUSIONS: Our data show that surveillance <= 6 months might be associated with early detection of HCC and improved survival in a hepatitis B endemic area. PMID- 23340066 TI - Off-protocol access to study therapies. AB - The ethics of allowing off-protocol access to a study therapy are explored, using the example of recombinant factor VIIa for intracerebral hemorrhage. rVIIa was later found to be ineffective. While the studies were being performed, researchers struggled with the question of whether a critically ill patient with intracerebral hemorrhage was actually indifferent between the treatment and placebo arms of the trial. PMID- 23340068 TI - Supporting autonomy for people with aphasia: use of the Life Interests and Values (LIV) Cards. AB - BACKGROUND: People with aphasia (PWA) are frequently disregarded as reliable respondents because their language problems may restrict their responses to oral and written questioning. Consequently, family members are often asked to speak on their behalf. The Life Interests and Values (LIV) Cards are a nonlinguistic, picture-based instrument designed for communicating directly with PWA about their current and desired life activities. PURPOSE: The goals of this study were to (1) explore utility of LIV Cards for interviewing PWA and (2) examine congruence between responses of PWA and proxies. METHOD: Study participants were 10 PWA with varying language and cognitive abilities and 10 family member proxies. Both groups participated in LIV Card interviews to identify current and preferred activities of the PWA. Core interview times for the PWA and percentage of selected activities for 4 activity categories were calculated, as was item-by item response congruency between PWA and proxies. RESULTS: All 10 PWA completed LIV Cards interviews in 45 minutes or less. There were individualized response patterns regarding activity participation and preferences. Mean point-to-point agreement between PWA and their proxies was 74% for current activities and 71% for activity preferences of the PWA. CONCLUSIONS: PWA were able to provide information about their current and preferred involvement in life activities through use of the LIV Cards. Family members did not predict activity choices and desires of PWA with full accuracy. The LIV Cards appear to be a viable tool for setting goals and discussing life priorities of PWA. PMID- 23340067 TI - Transcranial direct current stimulation and aphasia: the case of mr. C. AB - PURPOSE: To illustrate the ethical challenges that arose from investigating a novel treatment procedure, transcranial direct current stimulation (tDCS), in a research participant with aphasia. METHOD: We review the current evidence supporting the use of tDCS in aphasia research, highlighting methodological gaps in our knowledge of tDCS. Then, we examine the case of Mr. C, a person with chronic aphasia who participated in a research protocol investigating the impact of tDCS on aphasia treatment. We describe the procedures that he underwent and the resulting behavioral and neurophysiological outcomes. Finally, we share the steps that were taken to balance beneficence and nonmaleficence and to ensure Mr. C's autonomy. RESULTS: The objective data show that while Mr. C may not have benefitted from participating in the research, neither did he experience any harm. CONCLUSION: Researchers must consider not only the scientific integrity of their studies, but also potential ethical issues and consequences to the research participants. PMID- 23340069 TI - Personal narratives in aphasia: understanding narrative competence. AB - BACKGROUND: Personal narratives have been suggested as a way for persons post stroke to re-establish their identity. To relate tellable personal stories, narrative competence - along with its building blocks - is essential. OBJECTIVE: The objective of this study was to describe narrative competence in persons with mild to moderate aphasia. It addressed the areas of coherence, clarity, temporal causal structure, and reference in narratives. The study also examined the strategies used (evaluative language) as well as the topics and themes in personal narratives. METHODS: Sixteen individuals with mild to moderate aphasia were asked to relate the story of their stroke and stories of a memorable and a frightening experience. Stories were elicited using a "willing listener" procedure. Responses were analyzed quantitatively in terms of the number of propositions and the instances of temporal-causal sequences, reference, and evaluation. Qualitative analysis was performed to determine the overall coherence and clarity of the narratives. RESULTS: Narrative competence was present in the majority of participants. Although difficulties with reference were observed, high ratings of narrative coherence and clarity were attributed to sufficient amount of language, preserved temporal-causal sequencing, and the use of strategies (evaluative language). CONCLUSIONS: Narrative competence was exhibited in the personal narratives of individuals with mild to moderate aphasia. In addition to pinpointing essential elements of narrative competence, the use of personal narratives was deemed beneficial for both the clinician, by providing a better understanding of the individual with aphasia, and the individual with aphasia, by providing opportunities for self-disclosure. PMID- 23340070 TI - Does caregiver well-being predict stroke survivor depressive symptoms? A mediation analysis. AB - BACKGROUND AND PURPOSE: Studies suggest that family caregiver well-being (ie, depressive symptoms and life satisfaction) may affect stroke survivor depressive symptoms. We used mediation analysis to assess whether caregiver well-being might be a factor explaining stroke survivor depressive symptoms, after controlling for demographic factors and stroke survivor impairments and problems. METHODS: Caregiver/stroke participant dyads (N = 146) completed measures of stroke survivor impairments and problems and depressive symptoms and caregiver depressive symptoms and life satisfaction. Mediation analysis was used to examine whether caregiver well-being mediated the relationship between stroke survivor impairments and problems and stroke survivor depressive symptoms. RESULTS: As expected, more stroke survivor problems and impairments were associated with higher levels of stroke survivor depressive symptoms (P < .0001). After controlling for demographic factors, we found that this relationship was partially mediated by caregiver life satisfaction (29.29%) and caregiver depressive symptoms (32.95%). Although these measures combined to account for 40.50% of the relationship between survivor problems and impairments and depressive symptoms, the direct effect remained significant. CONCLUSIONS: Findings indicate that stroke survivor impairments and problems may affect family caregivers and stroke survivors and a high level of caregiver distress may result in poorer outcomes for stroke survivors. Results highlight the likely importance of intervening with both stroke survivors and family caregivers to optimize recovery after stroke. PMID- 23340071 TI - Participation in the chronic phase of stroke. AB - BACKGROUND: Participation is a multidimensional concept, consisting of an objective and a subjective dimension. Many studies have focused on determinants of only 1 dimension of participation post stroke. OBJECTIVE: To describe participation (both objective and subjective) and to determine how physical and cognitive independence and subjective complaints (pain, fatigue, and mood) influence participation in community-dwelling stroke survivors in the Netherlands. METHODS: The Utrecht Scale for Evaluation of Rehabilitation (USER) measures physical and cognitive independence and subjective complaints. USER Participation measures 3 dimensions of participation: frequency (objective perspective), restrictions (subjective perspective), and satisfaction (subjective perspective). Spearman correlations and backward linear regression analyses were used to analyze associations between the 3 USER-Participation scores with demographics, stroke characteristics, physical and cognitive independence, and subjective complaints. RESULTS: Of the 111 participants, 48.5% returned to work post stroke, but mostly for only 1 to 16 hours a week. Experienced participation restrictions were most prevalent in physical exercise, chores in/around the house, housekeeping, and outdoor activities. On average, participants were relatively satisfied with their participation, but dissatisfaction occurred in cognition, activities outdoors, and work/housekeeping. Regression analysis revealed that objective participation was determined by physical and cognitive independence, age, and education, whereas subjective participation was determined by physical and cognitive independence, fatigue, and mood. CONCLUSIONS: Most participants experienced participation problems, despite relatively good physical recovery. In addition to physical and cognitive factors, subjective complaints of persons with stroke should be addressed in the rehabilitation program. PMID- 23340072 TI - Does trunk, arm, or leg control correlate best with overall function in stroke subjects? AB - BACKGROUND: Attainment of functional independence is the ultimate goal of a sound stroke rehabilitation program. Good trunk stability is essential for balance and extremity use. Stroke patients may have upper extremity impairments that may affect functional activity and lower extremity impairments that may hinder mobility. Hence, quantifying the specific levels of impairment in the trunk, upper extremity, and lower extremity is helpful to determine the extent to which each might influence the ability to perform activities of daily living. OBJECTIVE: To assess the impairment of the trunk and the upper and lower extremity of stroke patients and correlate it with overall function. METHODS: A cross-sectional repeated correlation study. Twenty-three subjects with a first time stroke, between 50 and 75 years of age, of both genders, admitted in hospital within 5 weeks of stroke onset were included using purposive sampling technique. On the eighth day of the stroke, trunk impairment was assessed using the Trunk Impairment Scale, upper and lower limb impairment was assessed using the Simplified Stroke Rehabilitation Assessment of Movement (upper and lower limb subscale, respectively), and overall function was measured by FIM. RESULTS: Trunk activity showed highly significant correlation (r = 0.598, P = .003) with overall function compared with upper limb activity (r = 0.501, P = .015). Lower limb impairment showed no correlation with overall function (r = 0.208, P = .342). CONCLUSIONS: The overall functional independence in acute stroke patients is most closely correlated with the levels of impairments of trunk function, followed by upper limb impairments. PMID- 23340073 TI - Review of transcranial direct current stimulation in poststroke recovery. AB - Motor impairment, dysphagia, aphasia, and visual impairment are common disabling residual deficits experienced by stroke survivors. Recently, many novel rehabilitative modalities have been investigated for their potential to ameliorate such deficits and to improve functional outcomes. Noninvasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), have emerged as a promising tool to facilitate stroke recovery. tDCS can alter cortical excitability to induce brain plasticity by modulating the lesioned, contralesional, or bilateral hemispheres with various stimulation modalities. Along with peripheral therapies, tDCS can lead to subsequent sustained behavioral and clinical gains in patients with stroke. In this review, we summarize characteristics of tDCS (method of stimulation, safety profile, and mechanism) and its application in the treatment of various stroke-related deficits, and we highlight future directions for tDCS in this capacity. PMID- 23340074 TI - Altered taste and stroke: a case report and literature review. AB - Patients with altered taste perception following stroke are at risk for malnutrition and associated complications that may impede recovery and adversely affect quality of life. Such deficits often induce and exacerbate depressive symptomatology, which can further hamper recovery. It is important for clinicians and rehabilitation specialists to monitor stroke patients for altered taste perception so that this issue can be addressed. The authors present the case of a patient who experienced an isolated ischemic infarct affecting a primary cortical taste area. This case is unusual in that the isolated injury allowed the patient to remain relatively intact cognitively and functionally, and thus able to accurately describe her taste-related deficits. The case is further used to describe the relevant neurological taste pathways and review potential taste related therapies. PMID- 23340075 TI - United States version of the Stroke Driver Screening Assessment: a pilot study. AB - BACKGROUND: Most stroke survivors who resume driving in the United States do so within the first year. More than 87% of these individuals resume driving without a formal evaluation of their fitness to drive because of the absence of standard practices and generally accepted and valid screening tools. The Stroke Driver Screening Assessment (SDSA) is an established battery for predicting stroke survivors' driving performance but is not currently used in the United States. This pilot study investigated the predictive ability of the US version of the battery in a US-based cohort of stroke survivors. METHOD: Fifteen first-ever stroke survivors (age, 52+/-12 years) and 16 healthy adults (age, 40+/-16 years) were administered the US version of the SDSA in a standardized format. Performance on the SDSA was compared with driving performance in a high-fidelity driving simulator. RESULTS: Stroke and healthy participants' driving performance was predicted with 87% and 88% accuracy, respectively. CONCLUSION: The US version of the SDSA battery has the potential to be a good predictor of driving performance of mildly impaired stroke survivors. Larger studies are needed to further establish its predictive accuracy. PMID- 23340076 TI - A mathematical model for the inhibitory effects of lignin in enzymatic hydrolysis of lignocellulosics. AB - A new model for enzymatic hydrolysis of lignocellulosic biomass distinguishes causal influences from enzyme deactivation and restrictions on the accessibility of cellulose. It focuses on calculating the amount of unreacted cellulose at cessation of enzyme activity, unlike existing models that were constructed for calculating the time dependence of conversion. There are three adjustable parameters: (1) 'occluded cellulose' is defined as cellulose that cannot be hydrolysed regardless of enzyme loading or incubation time, (2) a 'characteristic enzyme loading' is sufficient to hydrolyse half of the non-occluded cellulose, (3) a 'mechanism index' measures deviations from first-order kinetics. This model was used to predict that the optimal incubation temperature is lower for lignocellulosics than for pure cellulose. For steam-exploded pine wood after 96h incubation, occluded cellulose was 24% and 26% at 30 degrees C and 50 degrees C, and the characteristic enzyme loadings were 10 and 18FPU/g substrate, respectively. PMID- 23340077 TI - Artificial activation of bovine and equine oocytes with cycloheximide, roscovitine, strontium, or 6-dimethylaminopurine in low or high calcium concentrations. AB - Knowledge on parthenogenetic activation of oocytes is important to improve the efficiency of nuclear transfer (NT) and intracytoplasmic sperm injection (ICSI) because artificial activation of oocyte (AOA) is an essential step to achieve embryo production. Although different procedures for AOA have been established, the efficiency of in vitro production of embryos remains low, especially in equines and Bos taurus bovines. In an attempt to improve the techniques of NT and ICSI in bovine and equine species, we tested different combinations of drugs that had different mechanisms of action for the parthenogenetic activation of oocytes in these animals. The oocytes were collected, in vitro matured for 24 to 30 h and activated artificially, in the presence of low or high concentrations of calcium, with combinations of calcium ionophore (ionomycin) with cycloheximide, roscovitine, strontium, or 6-dimethylaminopurine (6-DMAP). For assessment of activation rates, oocytes were stained with Hoechst 33342 and observed under an inverted microscope. We showed that all combinations of drugs were equally efficient in activating bovine oocytes, with the best results obtained when high concentrations of calcium were adopted. For equine oocytes, high concentrations of calcium were not beneficial for the parthenogenetic activation and the combination of ionomycin with either 6-DMAP or roscovitine was effective in inducing artificial activation of oocytes. We believe that our preliminary findings provide some clues for the development of a better AOA protocol to be used with these species. PMID- 23340080 TI - Childhood disintegrative disorder: distinction from autistic disorder and predictors of outcome. AB - Childhood disintegrative disorder, a rare, relentlessly progressive neurologic disorder, first described by Heller in 1908, remains a condition of great interest. It has long been debated whether it is a discrete disorder or simply a late-onset variant of childhood autism. We have studied 6 cases of childhood disintegrative disorder, collected over 8 years, and followed for 2.5 to 22 years (mean 8.6 years). Childhood disintegrative disorder begins later in life than autism, and following a period of entirely normal development; the regression is more global and more severe than in autism; seizures are more frequent than in autism, yet demonstrable organicity in childhood disintegrative disorder is decidedly rare. Lastly, the prognosis is usually much worse than in autism, but in those cases with neither seizures nor epileptiform activity on electroencephalography (EEG), the outcome may be more favorable. Childhood disintegrative disorder should be viewed as a condition distinct from childhood autism. PMID- 23340081 TI - The many faces of Glut1 deficiency syndrome. AB - Glucose transporter protein type 1 deficiency syndrome is a metabolic disorder manifesting as cognitive impairment, acquired microcephaly, epilepsy, and/or movement disorder caused by mutations in the SLC2A1 gene. We describe a cohort of isolated and familial cases of glucose transporter protein type 1 deficiency syndrome, emphasizing seizure semiology, electroencephalographic (EEG) features, treatment response and mutation pathogenicity. SLC2A1 mutations were detected in 3 sporadic and 4 familial cases. In addition, mutations were identified in 9 clinically unaffected family members in 2 families. The phenotypic spectrum of glucose transporter protein type 1 deficiency is wider than previously recognized, with considerable intra-familial variation. Diagnosis requires either hypoglycorrachia followed by SLC2A1 sequencing or direct gene sequencing. A ketogenic diet should be the first line of treatment, but more flexible diets, like the Atkins modified diet, can also be followed. Carbonic anhydrase inhibitors, such as acetazolamide or zonisamide, can be effective for seizure control. PMID- 23340082 TI - Vitamin D deficiency among children with epilepsy in South Queensland. AB - This study evaluated prevalence and risk factors for vitamin D deficiency among children with epilepsy on long-term antiepileptic drugs treated in South Queensland, Australia. Children with epilepsy seen in a tertiary neurology clinic were contacted requesting bone health blood tests during winter of 2011. Vitamin D deficiency was defined as 25-hydroxy vitamin D levels <20 ng/mL, and insufficiency between 21 and 29 ng/mL. One hundred thirty letters were sent, with 111 (85%) subsequently having blood tests performed. Vitamin D deficiency was identified in 24 (22%) of 111 and an additional 45 (41%) of 111 had vitamin D insufficiency. Multiple logistic regression analysis identified children on >2 antiepileptic drugs or with underlying genetic etiologies were more likely to have vitamin D deficiency. High proportion of children on long-term antiepileptic drugs in Queensland risk vitamin D deficiency and insufficiency despite living in the subtropics. Vitamin D monitoring and supplementation is important in the management of children on long-term antiepileptic drugs requiring tertiary care in Queensland. PMID- 23340083 TI - Familial distal monosomy 5p15.3-pter with trisomy 12q24.2-qter resulting in neurodevelopmental delay and dysmorphic features. AB - Developmental delay and brain anomalies leading to significant morbidity and mortality are frequently caused by chromosomal rearrangements. We report on a familial unbalanced translocation resulting in distal monosomy 5p15.3-pter with trisomy 12q24.2-qter in 2 half siblings with cerebral dysgenesis, severe intellectual disability, dysmorphic features, progressive weakness, and atrophy of muscles. PMID- 23340084 TI - Pulmonary puzzle: a precordial crunch. PMID- 23340085 TI - Sleep apnea in precapillary pulmonary hypertension. AB - OBJECTIVES: Pilot studies have described the occurrence of sleep apnea in patients with precapillary pulmonary hypertension (PH). However, there are no data on the prevalence of sleep-related breathing disorders in larger patient cohorts with PH. METHODS: 169 patients with a diagnosis of PH confirmed by right heart catheterisation and clinically stable in NYHA classes II or III were prospectively investigated by polygraphy (n = 105 females, mean age: 61.3 years, mean body mass index: 27.2 kg/m(2)). Recruitment was independent of sleep-related symptoms and the use of vasodilator drugs or nasal oxygen. RESULTS: 45 patients (i.e. 26.6%) had an apnea-hypopnea-index (AHI) >10/h. Of these, 27 patients (i.e. 16%) had obstructive sleep apnea (OSA) and 18 patients (i.e. 10.6%) had central sleep apnea (CSA). The mean AHI was 20/hour. As a polygraphy had been performed with nasal oxygen in half of the patients without evidence for sleep apnea, the frequency of CSA was probably underestimated. Patients with OSA were characterized by male gender and higher body mass index whereas, those with CSA were older and hypocapnic. CONCLUSIONS: At least every fourth patient with PH suffers from mild-to-moderate sleep apnea. Considering the anthropometric characteristics of the patients studied, the prevalence of both OSA and CSA seem to be higher in PH than in the general population. PMID- 23340086 TI - Maternal cognitions and depression in childhood behavioral insomnia and feeding disturbances. AB - OBJECTIVES: To investigate (1) maternal cognitions regarding infant's sleep and feeding and maternal depression among mothers of children with behavioral insomnia, feeding disturbances and healthy controls, and (2) the association between maternal cognitions about sleep and those about feeding. METHODS: Children 6-36 months of age with either behavioral insomnia or feeding disorders were recruited. Children 6-36 months of age who attended the well-baby clinics were recruited and served as controls. The participants' mothers completed three questionnaires on their cognitions/perceptions of their child's sleep and feeding habits and about their own feelings of depression. RESULTS: A total of 230 children (31 with behavioral insomnia, 29 with feeding disorders, 170 controls) were enrolled. Their mean age was 16.1 +/- 7.6 months. Maternal cognitions/perceptions about sleep (maternal cognition infant sleep questionnaire, MCISQ) did not differ significantly between the behavioral insomnia group and the feeding disorders group. The MCISQ score was significantly higher in the behavioral insomnia group compared with controls (P < .02). Mothers of children with feeding disorders reported being significantly more frustrated or anxious when they fed their child (P < .0005), less confident about their child getting enough food (P < .0005), and less confident in their ability to manage their child's behavior at mealtime (P < .02) compared to the controls. Significant positive correlations were found between the MCISQ scores and the Beck Depression Inventory scores (r = 0.29, P < .0002), and between the MCISQ scores and the maternal cognitions of their child's feeding scores (r = 0.26, P < .0002). The latter remained significant after controlling for maternal depression (r = 0.25, P < .002). CONCLUSIONS: Mothers of children with either behavioral insomnia or feeding disorders differ significantly from mothers of controls regarding their cognitions about sleep and feeding. Maternal cognitions about infant sleep behavior correlated with their cognitions about infant feeding. Maternal cognitions are a modifiable factor that may serve as a target for intervention in both sleep and feeding disorders in children. PMID- 23340088 TI - PI and other proposed measures to reduce night to night variability in RLS/PLMD patients. PMID- 23340087 TI - The association between atrial fibrillation and stroke in patients with obstructive sleep apnea: a population-based case-control study. AB - BACKGROUND: Obstructive sleep apnea (OSA) has been shown to be an independent risk factor for ischemic stroke and may increase the risk of atrial fibrillation (AF) by up to fourfold. Given these relationships, it is possible that OSA may provide a link between stroke and AF. A case-control study was conducted to examine the association between AF and stroke in patients with OSA. METHODS: Olmsted County, MN, USA, residents with a new diagnosis of OSA based on polysomnography (PSG) between 2005 and 2010 (N = 2980) who suffered a first-time ischemic stroke during the same period were identified as cases. Controls with no history of stroke were randomly chosen from the same database. Univariate and multiple logistic regression analyses were performed with age, gender, body mass index (BMI), smoking, hypertension, hyperlipidemia, diabetes mellitus, apnea hypopnea index (AHI) and coronary artery disease (CAD) as co-variates, with the diagnosis of AF as the variable of interest. RESULTS: A total of 108 subjects were studied. Mean age of cases (n = 34) was 73 +/- 12 years and 53% were men. Among controls (n = 74), mean age was 61 +/- 16 years and 55% were male. On univariate analyses, AF was significantly more common in the cases than among controls (50.0% vs 10.8%, p < 0.01). On multivariate regression analyses, the association between AF and stroke was significant after controlling for age, BMI, coronary artery disease, hypertension, diabetes mellitus, hyperlipidemia and smoking status (corrected odds ratio (OR): 5.34; 95% confidence interval (CI): 1.79-17.29). CONCLUSIONS: Patients with OSA who had a stroke had higher rates of AF even after accounting for potential confounders. PMID- 23340090 TI - MRI during cochlear implant assessment: Should we image the whole brain? AB - OBJECTIVES: Magnetic resonance imaging (MRI) is a standard part of a cochlear implant assessment in most centres. While there is ample literature on the temporal bone-specific imaging that is required, the role of whole brain imaging has not been as fully studied. We present the first report of the incidence of associated brain abnormalities in the whole cochlear implant population, including adults and consider their significance. METHODS: We retrospectively reviewed 51 (12 adults and 39 children) sequential cases since we added whole brain MRI sequences to our cochlear implant assessment protocol. We reviewed the scans for abnormalities of the cochlea and cochlear nerve and a neuroradiologist reviewed the images of the whole brain sequences for further abnormalities. RESULTS: We identified abnormalities on the whole brain sequences in 21 (41%) of these patients, 5 of 12 adults (42%) and 16 of 39 children (41%). Thirty-six (71%) patients subsequently had at least one implant inserted, 13 with abnormalities on whole brain MRI (36%) and 23 without. Of the 15 patients who did not undergo subsequent implantation, 8 had positive findings on their whole brain MRI sequence (53%). There was no statistical difference in the probability of finding an abnormality on the whole brain MRI between those who did and those who did not go on to have an implant (P = 0.35). There were abnormalities within the inner ear in five patients. DISCUSSION: The abnormalities detected on the whole brain images are heterogenous and of wide ranging clinical significance ranging from truly incidental findings to abnormalities that are so severe that they may predict a very poor prognosis such that an implant may contribute little. PMID- 23340091 TI - Performance of the HarmonyTM behind-the-ear processor with the first generation of Advanced BionicsTM implant systems. AB - OBJECTIVES: When new cochlear implant (CI) sound processors are being introduced by the manufacturers, usually the newest generation implants benefit first from the new technology in order to release the full potential of the new hardware. Subsequently, for the Advanced Bionics system the Harmony behind-the-ear processor was only compatible to the newer generation implants, i.e. the CII and HiRes90K, at the time of market release. After further development of a new Digital Signal Processing code the Harmony could also support the first implant generation, the 'C1' (Clarion 1.0 and 1.2). This study reports on a field trial with a new sound processor designed to be used with older generation CIs from Advanced Bionics, focussing on ergonomic and performance benefits. METHODS: Speech perception tests (Freiburger monosyllables, HSM sentence tests) were performed at a baseline appointment with the subject's clinical processor, followed by the fitting of the Harmony. After a 1 month take-home period the tests were repeated with the Harmony. Additionally, subjective evaluation through questionnaires and a structured interview were administered after upgrading to the sound processor 'C1 Harmony'. Adult users of Advanced Bionics C1 series CIs (n = 29) participated in this study. RESULTS: The new processor provided superior performance in many, though not all, of the speech recognition measurements. Subjective reports indicated certain practical benefits from the new processor, particularly for previous users of body-worn processors. Overall, 80% of the subjects preferred the new processor. CONCLUSION: The positive outcomes from this trial have resulted in the decision to make the new C1 Harmony processor available to all existing users of the early C1 devices. PMID- 23340092 TI - Gentle and fast atomic force microscopy with a piezoelectric scanning probe for nanorobotics applications. AB - A novel dual tip nanomanipulation atomic force microscope (AFM) platform operating in ambient conditions is presented. The system is equipped with a high frequency quartz piezoelectric self-sensing scanning probe for fast imaging and a passive cantilever for manipulation. The system is validated by imaging and selective pushing/pulling of gold colloid beads (diameters from 80 to 180 nm). This provides a more compact integration compared to an external optical lever and avoids several of its drawbacks such as optical interference and noise, and recalibration in the case of a moving cantilever and a fixed laser source and photodiode sensor. Moreover, as the quartz oscillator exhibits oscillation amplitudes in the sub-picometer range with a resonant frequency in the megahertz range, this dynamic force sensor is ideal for fast AFM imaging. Experiments show an increase by five times in imaging speed compared to a classical AFM system. PMID- 23340093 TI - Impact of cooking and handling conditions on furanic compounds in breaded fish products. AB - This study evaluates the influence of cooking and handling conditions on the quantity of furanic compounds (furan, 2-furfural, furfuryl alcohol, 2 pentylfuran, 5-hydroxymethylfurfural) in breaded fish products. Oven-baking and reheating in the microwave lead to low furanic compounds formation in comparison with deep-frying. The use of olive oil for deep-frying promoted higher levels of furanic compounds than sunflower oil. The amounts of these compounds diminished as the temperature and time of deep-frying decreased as well as after a delay after deep-frying. Thus, the generation of furanic compounds can be minimized by adjusting the cooking method and conditions, such as using an electric oven, deep frying in sunflower oil at 160 degrees C during 4min, or waiting 10min after cooking. However, these conditions that reduce furanic compounds levels also reduce the content of volatile compounds related to the aroma and flavour of fried foods. In this sense, new efforts should be done to reduce the formation of furanic compounds without being detrimental to the volatile profile. PMID- 23340094 TI - The influence of suture material on the strength of horizontal mattress suture configuration for meniscus repair. AB - PURPOSE: Comparison of the mechanical characteristics of meniscal repair fixation using horizontal sutures and six different sutures under submaximal cyclic and load to failure test conditions may aid physicians in selecting a suture type. METHODS: A 2-cm long anteroposterior vertical longitudinal incision was created in six groups of bovine medial menisci. Lesions were repaired using a No. 2 suture either composed of polyester or polyester and ultra high-molecular weight polyethylene (UHMWPE), or UHMWPE and polydioxanone or pure UHMWPE. Endpoints included ultimate failure load (N), pull-out stiffness (N/mm), pull-out displacement (mm), cyclic displacement (mm) after 100cycles, after 500cycles, and mode of failure. RESULTS: Polyester suture had lower ultimate load than all groups except the suture composed of polyester and UHMWPE (P<.05). Pure UHMWPE suture had higher ultimate failure load than sutures composed of either polyester or polyester plus UHMWPE (P<.05). Predominant failure mode was suture cutting through the meniscus for the groups except for polyester suture which failed by suture rupture. CONCLUSION: Under cyclic loading conditions in bovine meniscus, braided polyester suture fixation provided lower initial fixation strength than fixation with various high strength sutures composed of pure UHMWPE or a combination of absorbable monofilament polydioxanone and UHMWPE, except for combination of polyester and UHMWPE sutures. CLINICAL RELEVANCE: Present study does not support the usage of the braided polyester sutures instead of high strength sutures composed either partially or totally of ultra-high molecular weight polyethylene for the horizontal suture configuration of meniscus repair. PMID- 23340095 TI - Bilateral condyle fracture of tibial insert in mobile bearing total knee arthroplasty. AB - We report a case of polyethylene insert breakage in a 45-year-old man after 3.5 years of cruciate retaining type mobile bearing total knee arthroplasty (TKA). Interstingly, both condyles of the polyethylene insert have fractured. The visual assessment done by stereoscopic microscope in the investigation report suggested that the fracture propagation was a result of cyclic loading and that the fracture was from the articular surface as a result of tibio-femoral and anteroposterior shear loading. The initial flexion-extension gap mismatch and/or specific Asian habits like kneeling or deep knee bending could have been the possible factors for over-stress for the insert causing this complication. After replacement of the broken insert and modification for daily activity preventing deep knee flexion, the patient obtained complete relief of previous symptoms. It remains unclear whether insert breakage was secondary to polyethylene insufficient design or to the polyethylene material fracture propagation. PMID- 23340096 TI - Diffuse alveolar hemorrhage and Libman-Sacks endocarditis as a manifestation of possible primary antiphospholipid syndrome. AB - Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of circulating autoantibodies against phospholipid-binding plasma proteins, leading to an increased risk of thrombosis and pregnancy loss. The most common manifestation of lung disease in APS is pulmonary embolism, which may often be the presenting symptom. We present a 30-year-old man with probable primary APS (with no history of thromboses) presenting with diffuse alveolar hemorrhage, an uncommon presentation. He was also found to have severe mitral valve regurgitation and during valve replacement surgery had cardiac vegetations compatible with a presentation of Libman-Sacks endocarditis. There are only 21 other reported cases of diffuse alveolar hemorrhage occurring as a result of APS. This is the first case of Libman-Sacks endocarditis in the setting of probable APS and alveolar hemorrhage.Diffuse alveolar hemorrhage should be considered as a nonthrombotic manifestation of APS, even in the absence of known thromboses, and may be the presenting symptom. PMID- 23340097 TI - Chronic kidney disease--is it a true risk factor of reduced clopidogrel efficacy in elderly patients with stable coronary artery disease? AB - BACKGROUND: Chronic kidney disease (CKD) is an established predictor of recurrent ischemic events in patients with coronary artery disease (CAD). This association has been partially ascribed to high post-treatment platelet reactivity (HPPR) according to platelet function testing. However, the influencing factors of HPPR are assay-dependent, and the relevant data of elderly patients with stable CAD are absent. PATIENTS AND METHODS: 310 elderly patients (>80years of age) with stable CAD taking prolonged maintenance clopidogrel (75mg/day) were studied. Maximal platelet aggregation rate (MPA%) with light transmittance aggregometry and Platelet Reactive Units (PRU) with VerifyNow (VN) P2Y12 system were obtained. Markers of platelet activation, including PAC-1 and CD62P, were also determined. RESULTS: Patients on different stages of CKD presented similar MPA% and expression of PAC-1 and CD62P. Although severe CKD patients were more likely to present HPPR identified by VNP2Y12 (odds ratio: 1.85, p=0.038), multiple logistic regression diminished this effect (adjusted odds ratio: 1.19, p=0.642), and revealed anemia as a possible predictor of HPPR (adjusted odds ratio: 5.92, p=0.001). However, in a parallel way, hemoglobin correlated with baseline PRU values as well as with post-treatment values (r=-0.624 and r=-0.463, respectively, p<0.001). Association between hemoglobin and PRU inhibition rate was not found. Moreover, hemoglobin exerted no influence on MPA% at all. CONCLUSION: CKD is not necessarily associated with reduced antiplatelet effects of clopidogrel in elderly patients with stable CAD taking prolonged maintenance clopidogrel, and the seemingly influence of CKD on HPPR assessed by VNP2Y12 assay may be due to the artifactual effect of hemoglobin on VNP2Y12. PMID- 23340098 TI - Kinetics of psychrophilic anaerobic sequencing batch reactor treating flushed dairy manure. AB - In this study, a new strategy, improving biomass retention with fiber material present within the dairy manure as biofilm carriers, was evaluated for treating flushed dairy manure in a psychrophilic anaerobic sequencing batch reactor (ASBR). A kinetic study was carried out for process control and design by comparing four microbial growth kinetic models, i.e. first order, Grau, Monod and Chen and Hashimoto models. A volumetric methane production rate of 0.24L/L/d of and a specific methane productivity of 0.19L/gVSloaded were achieved at 6days HRT. It was proved that an ASBR using manure fiber as support media not only improved methane production but also reduced the necessary HRT and temperature to achieve a similar treating efficiency compared with current technologies. The kinetic model can be used for design and optimization of the process. PMID- 23340099 TI - Cloning, expression and medium optimization of validamycin glycosyltransferase from Streptomyces hygroscopicus var. jinggangensis for the biotransformation of validoxylamine A to produce validamycin A using free resting cells. AB - Validamycin A is widely used to control Basidiomycetes, which causes sheath blight disease in rice, potatoes, vegetables, and other crops as well as dumping off disease in vegetable seedlings, cotton, sugar beets, and other plants. In order to improve the content of validamycin A in the commercial products, valG from Streptomyces hygroscopicus was successfully cloned into Escherichia coli BL21(DE3) and was directly employed as the biocatalyst in the biotransformation from validoxylamine A to validamycin A with the existence of d-cellobiose using the free resting cells in the present study. The fermentation medium was optimized through single factor experiment and response surface method. With the optimized medium, which contained lactose 4.7g/L, yeast extract 49.5g/L, ammonium chloride 2.7g/L, potassium phosphate buffer solution 110mL/L, Ca(2+) 0.0352g/L, the biomass yield and enzyme activity reached 5.5g/L and 1.49U/mL, respectively, which were nearly twice higher than those with initial medium. PMID- 23340100 TI - In-depth investigation on the pyrolysis kinetics of raw biomass. Part I: kinetic analysis for the drying and devolatilization stages. AB - An in-depth investigation was conducted on the kinetic analysis of raw biomass using thermogravimetric analysis (TGA), from which the activation energy distribution of the whole pyrolysis process was obtained. Two different stages, namely, drying stage (Stage I) and devolatilization stage (Stage II), were shown in the pyrolysis process in which the activation energy values changed with conversion. The activation energy at low conversions (below 0.15) in the drying stage ranged from 10 to 30 kJ/mol. Such energy was calculated using the nonisothermal Page model, known as the best model to describe the drying kinetics. Kinetic analysis was performed using the distributed activation energy model in a wide range of conversions (0.15-0.95) in the devolatilization stage. The activation energy first ranged from 178.23 to 245.58 kJ/mol and from 159.66 to 210.76 kJ/mol for corn straw and wheat straw, respectively, then increasing remarkably with an irregular trend. PMID- 23340101 TI - Optimization of biodiesel production by supercritical methyl acetate. AB - This work has been done to find out the optimum condition of supercritical methyl acetate method in biodiesel production. The reaction temperature, pressure, time and molar ratio in methyl acetate to oil were the key parameters that must all be considered to produce an optimum condition. Evaluation of thermal decomposition on products, cis-trans isomerization and tocopherol content were required to further optimize the reaction condition. It was, therefore, concluded that for the supercritical methyl acetate method, reaction condition of 350 degrees C/20 MPa/45 min/42 M ratio gave the highest yields of FAME (96.7 wt.%) and triacetin (8.8 wt.%). Yet, at such a reaction condition, the optimum reaction condition was compromised due particularly to the unavoidable thermal decomposition of products, and tocopherols as natural anti-oxidants. PMID- 23340102 TI - Improving the stability of thermophilic anaerobic digesters treating SS-OFMSW through enrichment with compost and leachate seeds. AB - This paper examines the potential of improving the stability of thermophilic anaerobic digestion of source-sorted organic fraction of municipal solid waste (SS-OFMSW) by adding leachate and compost during inoculation. For this purpose, two stable thermophilic digesters, A (control) and B (with added leachate and compost), were subjected to a sustained substrate shock by doubling the organic loading rate for one week. Feeding was suspended then gradually resumed to reach the pre-shock loading rate (2 gVS/l/d). Digester A failed, exhibiting excessive increase in acetate and a corresponding decrease in pH and methane generation, and lower COD and solids removal efficiencies. In contrast, digester B was able to restore its functionality with 90% recovery of pre-shock methane generation rate at stable pH, lower hydrogen levels, and reduced VFAs and ammonia accumulation. PMID- 23340103 TI - High productivity cultivation of a heat-resistant microalga Chlorella sorokiniana for biofuel production. AB - To augment biomass and lipid productivities of heterotrophic cultured microalgae Chlorella sorokiniana, the influence of environmental temperature and medium factors, such as carbon source, nitrogen source, and their initial concentrations was investigated in this study. The microalga C. sorokiniana could tolerate up to 42 degrees C and showed the highest growth rate of 1.60d(-1) at 37 degrees C. The maximum dry cell weight (DCW) and corresponding lipid concentration was obtained with 80gL(-1) of initial glucose and 4gL(-1) of initial KNO3 at 37 degrees C. In 5-L batch fermentation, the DCW increased dramatically from 0.9gL(-1) to 37.6gL( 1) in the first 72h cultivation, with the DCW productivity of 12.2gL(-1)d(-1). The maximum lipid content of 31.5% was achieved in 96h and the lipid productivity was 2.9gL(-1)d(-1). The results showed C. sorokiniana could be a promising strain for biofuel production. PMID- 23340104 TI - Effects of brown sugar and calcium superphosphate on the secondary fermentation of green waste. AB - The generation of green waste is increasing rapidly with population growth in China, and green waste is commonly treated by composting. The objective of this work was to study the physical and chemical characteristics of composted green waste as affected by a two-stage composting process and by the addition of brown sugar (at 0.0%, 0.5%, and 1%) and calcium superphosphate (Ca(H2PO4)2.H2O) (at 0%, 3%, and 6%) during the second stage. With or without these additives, all the composts displayed two peaks in fermentation temperature and matured in only 30days. Compared to traditional industrial composting, the composting method described here increased the duration of high-temperature fermentation period, reduced the maturity time, and reduced costs. Addition of 0.5% brown sugar plus 6% calcium superphosphate produced the highest quality compost with respect to C/N ratio, pH, organic matter content, electrical conductivity, particle-size distribution, and other characteristics. PMID- 23340105 TI - Characteristics and applications of a recombinant alkaline serine protease from a novel bacterium Bacillus lehensis. AB - A highly alkaline protease (BLAP) from a novel psychrotolerant and alkaliphilic bacterium, Bacillus lehensis was cloned and expressed in Escherichia coli. BLAP belongs to subtilase S8 family of proteases, comprising 27 aa secretion signal, 83 aa prosequence and 269 aa mature BLAP. The amino acids Asp 141, His 171 and Ser 324 form catalytic triad, while Ile 214, Leu 233 and Asn 267 are other active site moieties. Recombinant alkaline protease (rBLAP) is a monomeric protein of 39.0+/-1.0kDa, and it is active over broad pH (8-12) and temperature (30-60 degrees C) ranges, with optima at pH 12.8 and 50 degrees C. rBLAP is stimulated by SDS, Co(2+), Ca(2+), beta-ME, and inhibited by Hg(2+) and PMSF. The rBLAP is compatible with commercial detergents, useful in silk degumming and silver recovery from the used photographic films and a potent biocontrol agent for arresting the development of eggs of the nematode Meloidogyne incognita. PMID- 23340106 TI - Thermogravimetry and Py-GC/MS techniques as fast qualitative methods for comparing the biochemical composition of Nannochloropsis oculata samples obtained under different culture conditions. AB - Microalgae have many applications, such as biodiesel production or food supplement. Depending on the application, the optimization of certain fractions of the biochemical composition (proteins, carbohydrates and lipids) is required. Therefore, samples obtained in different culture conditions must be analyzed in order to compare the content of such fractions. Nevertheless, traditional methods necessitate lengthy analytical procedures with prolonged sample turn-around times. Results of the biochemical composition of Nannochloropsis oculata samples with different protein, carbohydrate and lipid contents obtained by conventional analytical methods have been compared to those obtained by thermogravimetry (TGA) and a Pyroprobe device connected to a gas chromatograph with mass spectrometer detector (Py-GC/MS), showing a clear correlation. These results suggest a potential applicability of these techniques as fast and easy methods to qualitatively compare the biochemical composition of microalgal samples. PMID- 23340107 TI - Optimization of clean fractionation process applied to switchgrass to produce pulp for enzymatic hydrolysis. AB - The purpose of this study was to fractionate switchgrass (SG) to obtain hemicellulose-, lignin-rich fractions and highly digestible pulp, using a clean fractionation (CF) approach. The main objective was to produce highest glucose yield in the enzymatic hydrolysis of pulp. Effects of processing factors such as time (10-50 min), temperature (120-160 degrees C), catalyst concentration (0.21 0.93% w/w sulfuric acid) and organic solvent mixture composition (7-43% w/w methyl isobutyl ketone) were evaluated. Response surface methodology and central composite design were used for process optimization and statistical analyses. High lignin (75-93%) and xylan (83-100%) removal from biomass were obtained, leaving solid pulp rich in glucan (78-94%). High enzymatic hydrolysis glucose yields (more than 90%) were obtained for selected optimal conditions. Pulp can be used for ethanol production while separated xylan and lignin fractions can be used as a feedstock for value-added products which suggests the applicability of clean fractionation technology in a biorefinery concept. PMID- 23340108 TI - Algal bioproducts derived from suspended solids in intensive land-based aquaculture. AB - Land-based aquaculture produces suspended solids in culture pond and settlement pond waters that could be harvested as a bioresource. Suspended solids were quantified, characterised and harvested from these two sources to assess their suitability for conversion to bioproducts. The suspended solids of settlement ponds were less concentrated (87.6+/-24.7mgL(-1)) than those of culture ponds (131.8+/-8.8mgL(-1)), but had a higher concentration of microalgae (27.5+/-4.0%) and consequently higher particulate organic carbon (24.8+/-4.7%) and particulate nitrogen (4.0+/-0.8%). The microalgal community also differed between sources with a higher concentration of fatty acids in the biomass from settlement ponds. Consequently, biochar produced from biomass harvested from settlement ponds was higher in organic carbon and nitrogen, with a lower cation exchange capacity. In conclusion, we characterised a renewable and potentially valuable bioresource for algal bioproducts derived from suspended solids in intensive land-based aquaculture. PMID- 23340109 TI - Changes in the Archaea microbial community when the biogas fermenters are fed with protein-rich substrates. AB - Terminal restriction fragment length polymorphism (T-RFLP) was applied to study the changes in the composition of the methanogens of biogas-producing microbial communities on adaptation to protein-rich monosubstrates such as casein and blood. Specially developed laboratory scale (5-L) continuously stirred tank reactors have been developed and used in these experiments. Sequencing of the appropriate T-RF fragments selected from a methanogen-specific (mcrA gene-based) library revealed that the methanogens responded to the unconventional substrates by changing the community structure. T-RFLP of the 16S rDNA gene confirmed the findings. PMID- 23340110 TI - A process of applying polypyrrole-engineered pulp fibers prepared using hydrogen peroxide as oxidant to detoxification of Cr(VI)-contaminated water. AB - In this study, different from previous reports, an alternative process for detoxification of Cr(VI)-contaminated water with polypyrrole-engineered pulp fibers prepared using low cost hydrogen peroxide as oxidant was proposed. The process conditions in preparation of the engineered fibers as well as the water treatment conditions were optimized, and the behavior of Cr desorption from the engineered fibers was evaluated. The results showed that the proposed process was highly efficient in Cr(VI)-detoxification via the integration of adsorption with reduction. Compared with the previously reported polyaniline-engineered fibers prepared with hydrogen peroxide as oxidant, the engineered fibers studied in this work was much more effective. PMID- 23340111 TI - Waste oil derived biofuels in China bring brightness for global GHG mitigation. AB - This study proposed a novel way for global greenhouse gas reduction through reusing China's waste oil to produce biofuels. Life cycle greenhouse gas mitigation potential of aviation bio-kerosene and biodiesel derived from China's waste oil in 2010 was equivalent to approximately 28.8% and 14.7% of mitigation achievements on fossil-based CO2 emissions by Annex B countries of the Kyoto Protocol in the period of 1990-2008, respectively. China's potential of producing biodiesel from waste oil in 2010 was equivalent to approximately 7.4% of China's fossil-based diesel usage in terms of energy. Potential of aviation bio-kerosene derived from waste oil could provide about 43.5% of China's aviation fuel demand in terms of energy. Sectors key to waste oil generation are identified from both production and consumption perspectives. Measures such as technology innovation, government supervision for waste oil collection and financial subsidies should be introduced to solve bottlenecks. PMID- 23340112 TI - The holistic integration of virtual screening in drug discovery. AB - During the past decade, virtual screening (VS) has come of age. In this review, we document the evolution and maturation of VS from a rather exotic, stand-alone method toward a versatile hit and lead identification technology. VS campaigns have become fully integrated into drug discovery campaigns, evenly matched and complementary to high-throughput screening (HTS) methods. Here, we propose a novel classification of VS applications to help to monitor the advances in VS and to support future improvement of computational hit and lead identification methods. Several relevant VS studies from recent publications, in both academic and industrial settings, were selected to demonstrate the progress in this area. Furthermore, we identify challenges that lie ahead for the development of integrated VS campaigns. PMID- 23340114 TI - Physiological responses of medical team members to a simulated emergency in tropical field conditions. AB - INTRODUCTION: Responses to physical activity while wearing personal protective equipment in hot laboratory conditions are well documented. However less is known of medical professionals responding to an emergency in hot field conditions in standard attire. Therefore, the purpose of this study was to assess the physiological responses of medical responders to a simulated field emergency in tropical conditions. METHODS: Ten subjects, all of whom were chronically heat acclimatized health care workers, volunteered to participate in this investigation. Participants were the medical response team of a simulated field emergency conducted at the Northern Territory Emergency Services training grounds, Yarrawonga, NT, Australia. The exercise consisted of setting up a field hospital, transporting patients by stretcher to the hospital, triaging and treating the patients while dressed in standard medical response uniforms in field conditions (mean ambient temperature of 29.3 degrees C and relative humidity of 50.3%, apparent temperature of 27.9 degrees C) for a duration of 150 minutes. Gastrointestinal temperature was transmitted from an ingestible sensor and used as the index of core temperature. An integrated physiological monitoring device worn by each participant measured and logged heart rate, chest temperature and gastrointestinal temperature throughout the exercise. Hydration status was assessed by monitoring the change between pre- and post-exercise body mass and urine specific gravity (USG). RESULTS: Mean core body temperature rose from 37.5 degrees C at the commencement of the exercise to peak at 37.8 degrees C after 75 minutes. The individual peak core body temperature was 38.5 degrees C, with three subjects exceeding 38.0 degrees C. Subjects sweated 0.54 L per hour and consumed 0.36 L of fluid per hour, resulting in overall dehydration of 0.7% of body mass at the cessation of exercise. Physiological strain index was indicative of little to low strain. CONCLUSIONS: The combination of the unseasonably mild environmental conditions and moderate work rates resulted in minimal heat storage during the simulated exercise. As a result, low sweat rates manifested in minimal dehydration. When provided with access to fluids in mild environmental conditions, chronically heat-acclimatized medical responders can meet their hydration requirements through ad libitum fluid consumption. Whether such an observation is replicated under a harsher thermal load remains to be investigated. PMID- 23340113 TI - Shifting from the single to the multitarget paradigm in drug discovery. AB - Increasing evidence that several drug compounds exert their effects through interactions with multiple targets is boosting the development of research fields that challenge the data reductionism approach. In this article, we review and discuss the concepts of drug repurposing, polypharmacology, chemogenomics, phenotypic screening and high-throughput in vivo testing of mixture-based libraries in an integrated manner. These research fields offer alternatives to the current paradigm of drug discovery, from a one target-one drug model to a multiple-target approach. Furthermore, the goals of lead identification are being expanded accordingly to identify not only 'key' compounds that fit with a single target 'lock', but also 'master key' compounds that favorably interact with multiple targets (i.e. operate a set of desired locks to gain access to the expected clinical effects). PMID- 23340116 TI - N400 in schizophrenia patients. AB - PURPOSE OF REVIEW: The purpose of this article is to review major findings in event related potential (ERP) research in schizophrenia patients, specifically focusing on the N400 component. RECENT FINDINGS: Patients with chronic schizophrenia have difficulty using 'context' (understanding the meaning of the word relative to the sentence) in sentence processing studies and often show differences from control populations in language experiments using word priming. Both of these observations are associated with an abnormal N400 ERP component when compared with nonpsychotic individuals. Many studies of language function rely on priming paradigms that use pairs of words such that the first word in a pair is a 'prime' and a second word in a pair is a 'target', separated from the prime by a period of time known as the Stimulus Onset Asynchrony (SOA). If the SOA is short (i.e., below 400 ms) then it is believed that a priming study examines primarily processes of initial activation within semantic networks; if it is long (i.e., more than 400 ms) then it is believed that a priming study examines primarily processes of context use, generating predictions and matching these predictions against upcoming semantic information. Priming paradigms that use long SOAs are consistently associated with a more negative N400 (hence lack of priming) in schizophrenia, whereas priming paradigms using a short SOA produce either a normal N400 priming response or hyperpriming as shown by a reduced N400 and related to a hypothesized too rapid automatic spread of activation within the semantic memory pathway. Apparent differences among reported study results are likely due to paradigm differences that tap into different aspects of language processing. Although the presence of both hyperactivation within semantic networks and difficulties with the use of context is well known in schizophrenia, it is unclear whether these abnormalities are also present prior to illness onset in people who are at risk for development of schizophrenia or even present at the onset of illness. SUMMARY: In order to clarify the findings reviewed here, future studies will be needed that focus on examining the N400 response in young people at high risk for developing the illness using multiple paradigms that probe different aspects of language function. PMID- 23340115 TI - Drinking-water exposure to a mixture of nitrate and low-dose atrazine metabolites and small-for-gestational age (SGA) babies: a historic cohort study. AB - BACKGROUND: Groundwater, surface water and drinking water are contaminated by nitrates and atrazine, an herbicide. They are present as a mixture in drinking water and with their endocrine-disrupting activity, they may alter fetal growth. OBJECTIVES: To study an association between drinking-water atrazine metabolites/nitrate mixture exposure and small-for-gestational-age(SGA). METHODS: A historic cohort study based on birth records and drinking-water nitrate and pesticide measurements in Deux-Sevres (France) between 2005 and 2009 was carried out. Exposure to drinking-water atrazine metabolites/nitrate mixture was divided into 6 classes according to the presence or absence of atrazine metabolites and to terciles of nitrate concentrations in each trimester of pregnancy. Regression analysis of SGA by mixture exposure at second trimester was subsequently conducted. RESULTS: We included 11,446 woman-neonate couples of whom 37.0% were exposed to pesticides, while 99.9% of the women were exposed to nitrates. Average nitrate concentration was from 0 to 63.30 mg/L. In the second trimester of pregnancy, the risk of SGA was different with mixture exposure when drinking water atrazine metabolites, mainly 2 hydroxyatrazine and desethylatrazine, were present and nitrate dose exposure increased: compared to single first tercile of nitrate concentration exposure, single second tercile exposure OR was 1.74 CI 95% [1.10; 2.75] and atrazine metabolites presence in the third tercile of nitrate concentration exposure OR was 0.87 CI 95% [0.45;1.67]. CONCLUSIONS: It is possible that the association found at the second trimester of exposure with regard to birth weight may likewise be observed before birth, with regard to the estimated fetal weight, and that it might change in the event that the atrazine metabolites dose were higher or the nitrate dose lower. It would appear necessary to further explore the variability of effects. PMID- 23340118 TI - Double Meckel's diverticulum presenting as acute appendicitis: a case report and literature review. AB - BACKGROUND: Meckel's diverticulum is the most common developmental anomaly of the gastrointestinal tract, affecting 1-3% of the general population. This anomaly is caused by incomplete obliteration of the omphalomesenteric duct during the 7th week of gestation and is located in the last meter of the ileum in 90% of patients. Meckel's diverticulum is often an incidental finding during a laparotomy for other causes, such as acute appendicitis, and occasional complications are bleeding, obstruction, diverticulitis, and perforation. OBJECTIVE: Primary aim of this study was to present and share an extremely rare case of double Meckel's diverticulum. METHODS: A 20-year-old woman who was admitted due to symptoms of right lower quadrant pain, nausea, and vomiting. A laparotomy with a McBurney's incision was performed because of a presumed diagnosis of acute appendicitis. The surgical exploration revealed a double Meckel's diverticulum localized 50 cm proximal to the ileocecal valve, but no acute appendicitis. The operation was finished after a diverticulectomy and appendectomy. No complications occurred during the postoperative follow-up. CONCLUSIONS: We conducted a literature review of studies published in the English language on double Meckel's diverticulum, accessed via PubMed, Medline, and the Google Scholar databases. We found only five case reports of such a Meckel's diverticulum variant. PMID- 23340117 TI - Multiple sessions of low-frequency repetitive transcranial magnetic stimulation in focal hand dystonia: clinical and physiological effects. AB - PURPOSE: The ability of low-frequency repetitive transcranial magnetic stimulation (rTMS) to enhance intracortical inhibition has motivated its use as a potential therapeutic intervention in focal hand dystonia (FHD). In this preliminary investigation, we assessed the physiologic and behavioral effects of multiple sessions of rTMS in FHD. METHODS: 12 patients with FHD underwent five daily-sessions of 1 Hz rTMS to contralateral dorsal premotor cortex (dPMC). Patients held a pencil and made movements that did not elicit dystonic symptoms during rTMS. We hypothesized that an active but non-dystonic motor state would increase beneficial effects of rTMS. Five additional patients received sham-rTMS protocol. The area under curve (AUC) of the motor evoked potentials and the cortical silent period (CSP) were measured to assess changes in corticospinal excitability and intracortical inhibition, respectively. Behavioral measures included pen force and velocity during handwriting and subjective report. RESULTS: Multiple-session rTMS strengthened intracortical inhibition causing a prolongation of CSP after 3 days of intervention and pen force was reduced at day 1 and 5, leaving other measures unchanged. 68% of patients self-reported as 'responders' at day 5, and 58% at follow-up. Age predicted responders. CONCLUSIONS: A strong therapeutic potential of this rTMS paradigm in FHD was not supported but findings warrant further investigation. PMID- 23340119 TI - Compartment syndrome of the hand from prolonged immobilization secondary to drug overdose. PMID- 23340120 TI - Total and methyl-mercury in hair and milk of mothers living in the city of Porto Velho and in villages along the Rio Madeira, Amazon, Brazil. AB - High fish consumption and extended breastfeeding are hallmarks of traditional lifestyle in Western Amazonia. We studied sources of mercury exposure, fish methylmercury (meHg) and dental-amalgam filling, in 75 urban and 82 rural lactating mothers. Total mercury was determined in all samples while meHg concentrations were determined in subsamples of milk (45) and hair (27) of urban mothers living in Porto Velho (PV) and in hair (46) and milk (37) of mothers living in traditional communities (TC) of the Rio Madeira. The TC mothers showed significantly higher median hair-Hg concentrations (8.2MUgg(-1)) than PV mothers (1.3MUgg(-1)). Median total Hg in milk of PV mothers (0.36ngg(-1)) was significantly lower (p=0.0000) than that found in milk of TC mothers (2.30ngg( 1)). The median meHg concentrations in milk of TC mothers were also significantly higher (1.0ngg(-1)) than in milk of PV mothers (0.07ngg(-1)). For urban mothers with low fish consumption rates (and relatively higher dental amalgam fillings) the proportion of inorganic Hg in milk was higher (85%) than in TC (62%). In TC mothers 51% of breast milk Hg concentrations were above 2ngg(-1) (world median concentrations), contrasting with 8% in PV mothers. Despite this, there was no significant correlation between total Hg concentrations in milk and either amalgam filling or daily fish consumption. Socioeconomic changes occurring in Western Amazonia are causing changes in fish-eating habits of urban mothers. However, traditional lifestyle and attendant high fish consumption in riverine populations can still impact total Hg and methylmercury concentrations in mothers' milk and hair. PMID- 23340121 TI - Systems biology approaches to evaluate arsenic toxicity and carcinogenicity: an overview. AB - Long term exposure to arsenic, either through groundwater, food stuff or occupational sources, results in a plethora of dermatological and non dermatological health effects including multi-organ cancer and early mortality. Several epidemiological studies, across the globe have reported arsenic-induced health effects and cancerous outcomes; but the prevalence of such diseases varies depending on environmental factors (geographical location, exposure level), and genetic makeup (and variants thereof); which is further modulated by several other factors like ethnicity, age-sex, smoking status, diet, etc. It is also interesting to note that, chronic arsenic exposure to a similar extent, even among the same family members, result in wide inter-individual variations. To understand the adverse effect of this toxic metabolite on biological system (cellular targets), and to unravel the underlying molecular basis (at the level of transcript, proteome, or metabolite), a holistic, systems biology approach was taken. Due to the paradoxical nature and unavailability of any suitable animal model system; the literature review is primarily based on cell line and population based studies. Thus, here we present a comprehensive review on the systems biology approaches to explore the underlying mechanism of arsenic-induced carcinogenicity, along with our own observations and an overview of mitigation strategies and their effectiveness till date. PMID- 23340122 TI - Myocardial perfusion imaging with computed tomography: can it be used in clinical practice? PMID- 23340123 TI - Almanac 2012 adult cardiac surgery: the National Society Journals present selected research that has driven recent advances in clinical cardiology. AB - This review covers the important publications in adult cardiac surgery in the last few years, including the current evidence base for surgical revascularisation and the use of off-pump surgery, bilateral internal mammary arteries and endoscopic vein harvesting. The changes in conventional aortic valve surgery are described alongside the outcomes of clinical trials and registries for transcatheter aortic valve implantation, and the introduction of less invasive and novel approaches to conventional aortic valve replacement surgery. Surgery for mitral valve disease is also considered, with particular reference to surgery for asymptomatic degenerative mitral regurgitation. PMID- 23340124 TI - The contribution of Alexandrian physicians to cardiology. PMID- 23340125 TI - The Athens TAVR Registry of newer generation transfemoral aortic valves: 30-day outcomes. AB - INTRODUCTION: Transcatheter aortic valve replacement (TAVR) is a documented treatment for patients with symptomatic aortic stenosis who are at very high or prohibitive operative risk. We sought to investigate the outcomes of transfemoral procedures with the newer generation valves in four TAVR centres in Athens, Greece. METHODS: The ATHENS TAVR Registry included all patients who underwent transfemoral implantation of the newer generation valves in 4 Athens TAVR centres (self-expanding valve 67 patients, balloon-expandable valve 59 patients). We present the procedural and echocardiographic data and the 30-day clinical outcomes according to valve type. RESULTS: A total of 126 patients underwent 126 procedures (67 CoreValve, Medtronic; 59 SAPIEN XT, Edwards Lifesciences). The mean age and logistic EuroSCORE were 80 +/- 8 years and 25 +/- 13%. The procedural and device success rates were 100% and 98%, respectively. The 30-day mortality was 1% (n=1), the major vascular event rates 9% (similar for both valve types), and a new permanent pacemaker was implanted more often during the same hospitalisation after CoreValve (33% vs. 9%, p=0.001). The mean effective aortic valve area increased and the mean transvalvular pressure gradient declined post implantation (from 0.66 +/- 0.15 cm(2) to 1.61 +/- 0.43 cm(2), p<0.001; from 51 +/- 14 mm Hg to 10 +/- 3 mm Hg, p<0.001). The mean grade of aortic insufficiency increased after CoreValve (from 1.2 +/- 0.6 to 1.5 +/- 0.7, p=0.03) but remained stable after SAPIEN XT (1.0 +/- 0.8 and 1.0 +/- 0.6, p=0.88) implantation. CONCLUSIONS: TAVR outcomes with both the newer generation transfemoral valves in the ATHENS Registry were excellent. We observed a greater need for a new permanent pacemaker and a greater degree of aortic valve insufficiency after CoreValve implantation. PMID- 23340126 TI - Chest pain in patients with arterial hypertension, angiographically normal coronary arteries and stiff aorta: the aortic pain syndrome. AB - INTRODUCTION: Arterial hypertension is often associated with a stiff aorta as a result of collagen accumulation in the aortic wall and may produce chest pain. In the present study, possible interrelationships between aortic function, collagen turnover and exercise-induced chest pain in patients with arterial hypertension and angiographically normal coronary arteries were investigated. METHODS: Ninety seven patients with arterial hypertension, angiographically normal coronary arteries and no evidence of myocardial ischemia on nuclear cardiac imaging during exercise test were studied. Of these, 43 developed chest pain during exercise (chest pain group) while 54 did not (no chest pain group). Carotid femoral pulse wave velocity (PWVc-f) was used to assess the elastic properties of the aorta. Amino-terminal pro-peptides of pro-collagen type I, (PINP, reflecting collagen synthesis), serum telopeptides of collagen type I (CITP, reflecting collagen degradation), pro-metalloproteinase 1 (ProMMP-1), and tissue inhibitor of metalloproteinase 1 (TIMP-1, related to collagen turnover) were measured in plasma by immunoassay. RESULTS: The chest pain group had higher PWVc-f, higher and /CITP ratio, and lower proMMP-1/ TIMP-1 ratio compared to the no chest pain group. PWVc-f (t=2.53, p=0.02) and PINP (t=2.42, p=0.02) were independently associated with the presence of chest pain in multiple regression analysis. CONCLUSIONS: Patients with arterial hypertension, exercise-induced chest pain and angiographically normal coronary arteries, without evidence of exercise-induced myocardial ischemia, had a stiffer aorta compared to those without chest pain. Alterations in collagen type I turnover that favor collagen accumulation in the aortic wall may contribute to aortic stiffening and chest pain in these patients. PMID- 23340127 TI - Increased right atrial volume index predicts low Duke activity status index in patients with chronic heart failure. AB - INTRODUCTION: The aim of the present study was to examine the value of the right atrial volume index (RAVI) as predictor of functional capacity in patients with heart failure. METHODS: A total of 51 patients with stable chronic heart failure of ischaemic or non-ischaemic aetiology were prospectively enrolled. The systolic function of the right ventricle was quantified using the tricuspid annular plane systolic excursion (TAPSE). Right atrial volume was measured in the apical 4 chamber view and was indexed to body surface area. The functional capacity was assessed by the Duke Activity Status Index (DASI). RESULTS: Patients with a low functional capacity (DASI<10) had lower TAPSE (1.4 +/- 0.3 cm versus 2.0 +/- 0.4 cm, p<0.001), higher RAVI (42 +/- 15 ml/m(2) versus 22 +/- 9 ml/m(2), p<0.001), higher estimated right ventricular systolic pressure (61 +/- 13 mmHg versus 40 +/ 16 mmHg, p<0.001), larger right ventricular end-diastolic diameter (4.7 +/- 0.8 cm versus 3.6 +/- 0.7 cm, p<0.001) and lower left ventricular ejection fraction (26 +/- 6% versus 30 +/- 7%, p=0.022). Multivariate analysis revealed that TAPSE was the single independent predictor of DASI. In the subgroup of patients with reduced right ventricular systolic function (TAPSE<2 cm), RAVI was the single independent predictor of low DASI. In the overall population RAVI=30.6 ml/m(2) had 75% sensitivity and 83% specificity in predicting DASI<10. Within the subgroup of patients with TAPSE<2 cm, RAVI=30.6 ml/m(2) had better sensitivity and specificity (79% and 90% respectively) in predicting DASI<10. CONCLUSIONS: Increased right atrial volume index predicts low functional capacity quantified by the Duke Activity Status Index in patients with stable chronic heart failure. PMID- 23340128 TI - Programmed ventricular stimulation--indications and limitations: a comprehensive update and review. PMID- 23340129 TI - Echocardiography in the evaluation of a hypertensive patient: an invaluable tool or simply following the routine? PMID- 23340130 TI - Pulmonary endarterectomy for thromboembolic pulmonary hypertension. PMID- 23340131 TI - Large left atrial myxoma in an oligosymptomatic young woman. AB - We present the case of a young female with a large sporadic left atrial myxoma. Interestingly, despite the tumor's large size, this patient had only mild exertional dyspnea without any embolic events or constitutional symptoms. PMID- 23340132 TI - A case report of Gordon's syndrome in a 20-year-old male with free medical family history. AB - Gordon's syndrome is a rare autosomal dominant disease that manifests in childhood. It is characterized by hypertension, hyperkalemic hyperchloremic metabolic acidosis, low renin and usually normal aldosterone levels, and it is sensitive to thiazide diuretics. A 20-year-old male with a history of diagnosed Gordon's syndrome was referred to a nephrology clinic for evaluation. The patient, who was under treatment with hydrochlorothiazide, had been diagnosed with Gordon's syndrome at the age of 11, when he presented hypertension and episodes of hyperkalemic hyperchloremic metabolic acidosis. However, none of his relatives had been diagnosed with this syndrome. Therefore, we assume that our patient might be a case of de novo gene mutation. PMID- 23340133 TI - Giant right coronary artery aneurysm in an adult male patient with non-ST myocardial infarction. AB - The combination of a giant coronary aneurysm with multiple coronary aneurysms in adults is an extremely rare entity--especially in atherosclerotic patients, since it is most commonly associated with Kawasaki disease in children. We report an interesting case of a 59-year-old male patient with multiple atherosclerotic aneurysms of the left coronary system and a giant aneurysm of the right coronary artery. The patient was admitted to our hospital because of a non-ST myocardial infarction. Diagnosis was established by echocardiography, computed tomography angiogram, and coronary angiography. In view of the clinical symptoms and the extent of the giant right coronary aneurysm, with the associated risk of rupture, the patient was successfully treated with urgent surgical intervention. We also present a review of the current literature on this anomaly and a statistical analysis of all atherosclerotic giant coronary artery aneurysms previously reported. PMID- 23340134 TI - Stroke prevention in atrial fibrillation. PMID- 23340135 TI - Economic crisis: the role of cardiovascular medicine. PMID- 23340136 TI - Differential selectivity of JAK2 inhibitors in enzymatic and cellular settings. AB - Small molecule inhibitors of Janus kinase (JAK) family members (JAK1, JAK2, JAK3, and Tyk2) are currently being pursued as potential new modes of therapy for a variety of diseases, including the inhibition of JAK2 for the treatment of myeloproliferative disorders. Selective inhibition within the JAK family can be beneficial in avoiding undesirable side effects (e.g., immunosuppression) caused by parallel inhibition of other JAK members. In an effort to design an assay paradigm for the development of JAK2 selective inhibitors, we investigated whether compound selectivity differed between cellular and purified enzyme environments. A set of JAK2 inhibitors was tested in a high-throughput JAK family cell assay suite and in corresponding purified enzyme assays. The high-throughput JAK cell assay suite comprises Ba/F3 cells individually expressing translocated ETS leukemia (TEL) fusions of each JAK family member (TEL-JAK Ba/F3) and an AlphaScreen phosphorylated-STAT5 (pSTAT5) immunoassay. Compound potencies from the TEL-JAK Ba/F3 pSTAT5 assays were similar to those determined in downstream cell proliferation measurements and more physiologically relevant cytokine induced pSTAT5 PBMC assays. However, compound selectivity data between cell and purified enzyme assays were discrepant because of different potency shifts between cell and purified enzyme values for each JAK family member. For any JAK small molecule development program, our results suggest that relying solely on enzyme potency and selectivity data may be misleading. Adopting the high throughput TEL-JAK Ba/F3 pSTAT5 cell assay suite in lead development paradigms should provide a more meaningful understanding of selectivity and facilitate the development of more selective JAK inhibitors. PMID- 23340137 TI - Identification of non-cell-autonomous networks from engineered feeder cells that enhance murine hematopoietic stem cell activity. AB - In a previous gain-of-function screen, we identified 18 nuclear factors that enhance mouse hematopoietic stem cell (HSC) activity in vitro. Of these factors, the majority was believed to augment HSC function intrinsically. In the current study, we investigated the mechanisms of action of the previously identified agonists of HSC activity and tested whether human HSCs are also responsive to these factors. Our results unexpectedly revealed that the majority of the identified factors confer a competitive advantage to mouse HSCs in a non-cell autonomous manner. Five of these factors, namely FOS, SPI1, KLF10, TFEC, and PRDM16, show robust transcriptional cross-regulation and are often associated with osteoclastogenesis. These findings define at least one novel non-cell autonomous network in engineered niches. Surprisingly, and in contrast to their important effect on mouse HSCs, all engineered niches failed to significantly enhance the activity of human HSCs. This last finding further supports a lack of conservation in determinants that control HSC self-renewal in mouse versus human cells. PMID- 23340138 TI - Lymphoid malignancies: Another face to the Janus kinases. AB - Considerable attention has focused on the gain-of-function mutations in the Janus kinase-2 (JAK2) tyrosine kinase that are detectable in most patients with a myeloproliferative neoplasm. Activating mutations that target JAK2, as well as JAK1, or CRLF2 and IL7RA, two cytokine receptors with which the JAKs associate in lymphoid cells, have now been identified in a subset of pediatric patients diagnosed with acute lymphoblastic leukemia (ALL), many of whom have a poor prognosis. This review focuses on the biology of these acquired mutations, and discusses the therapeutic benefits for patients that are likely to arise as a consequence of their discovery. PMID- 23340139 TI - Evaluation of adamantane hydroxamates as botulinum neurotoxin inhibitors: synthesis, crystallography, modeling, kinetic and cellular based studies. AB - Botulinum neurotoxins (BoNTs) are the most lethal biotoxins known to mankind and are responsible for the neuroparalytic disease botulism. Current treatments for botulinum poisoning are all protein based and thus have a limited window of treatment opportunity. Inhibition of the BoNT light chain protease (LC) has emerged as a therapeutic strategy for the treatment of botulism as it may provide an effective post exposure remedy. Using a combination of crystallographic and modeling studies a series of hydroxamates derived from 1-adamantylacetohydroxamic acid (3a) were prepared. From this group of compounds, an improved potency of about 17-fold was observed for two derivatives. Detailed mechanistic studies on these structures revealed a competitive inhibition model, with a K(i)=27 nM, which makes these compounds some of the most potent small molecule, non-peptidic BoNT/A LC inhibitors reported to date. PMID- 23340140 TI - Uniformisation of units of measurement in clinical chemistry in Belgium starting December 2012. PMID- 23340141 TI - Is it time to apply genographics in medical diagnosis? PMID- 23340142 TI - Where does polymyalgia rheumatica end and giant cell arteritis begin? Lessons from positron emission tomography studies. PMID- 23340143 TI - A new era of anticoagulation. PMID- 23340144 TI - Immunotherapy in leukaemia. AB - Therapeutic cancer vaccination, e.g. by using tumour antigen-presenting dendritic cells (DCs) that 'educate' the immune system to recognise and attack tumour cells, represents a new concept of treatment in oncology. DCbased immunotherapy elicits both innate (NK) and adaptive (T cells) cellular responses correlated with clinical benefit. WT1 mRNA-transfected DCs emerge as a feasible and effective strategy to control residual disease in acute myeloid leukaemia (AML), in particular as a post-remission treatment to prevent full relapse. This innovative approach takes advantage of the intrinsic potential of the immune system to eradicate malignant disease. PMID- 23340145 TI - Blood pressure, cardiovascular outcomes and sodium intake, a critical review of the evidence. AB - Consideration of the role of NaCl (salt) in the pathogenesis and treatment of essential hypertension is one of the overriding research themes both in experimental and clinical medicine. The evidence relating blood pressure to salt intake in humans originates from population studies and randomized clinical trials of interventions on dietary salt intake. Estimates from meta-analyses of trials in normotensive subjects generally are similar to estimates derived from prospective population studies (+ 1.7-mmHg increase in systolic blood pressure per 100 mmol increment in 24-hour urinary sodium). This estimate, however, does not translate into an increased risk of incident hypertension in subjects consuming a high-salt diet. Prospective studies relating health outcomes to 24-h urinary sodium excretion produced inconsistent results. Taken together, available evidence does not support the current recommendations of a generalized and indiscriminate reduction of salt intake at the population level. The public should be properly educated about the pros and cons of a decrease in sodium intake, in particular if they are healthy. PMID- 23340146 TI - Predictive factors associated with primary failure to exenatide and non goal attainment in patients with type 2 diabetes. AB - OBJECTIVE: We prospectively analysed HbA1c changes after 12 months of exenatide therapy and determined which baseline clinical and/or biological factors predict response. RESEARCH DESIGN AND METHODS: Open-label cohort of 41 subjects with type 2 diabetes (56% male) poorly-controlled on maximally-tolerated oral dual therapy. Age (mean +/- 1SD) was 60 +/- 10 years, and known diabetes duration 11 +/- 8 years (mean +/- 1SD). Biometric changes in weight, body mass index (BMI), waist circumference (WC), HOMA modeling (Homeostasis Model Assessment) of beta-cell function (HOMA-B) and insulin sensitivity (HOMA-S) as well as in HbA1c were assessed at baseline, and after 6 or 12 months exenatide therapy. Patients were divided into three groups: goal-achievers (GA, n = 15), defined as achieving HbA1c <= 7.5% (58 mmol/mol) at 12 months; nongoal- achievers (NGA, n = 16; HbA1c > 7.5% (58 mmol/mol) at 12 months); and primary failure to exenatide therapy (early lack of efficacy; PF, n = 9). Non-responders represented the combined NGA plus PF patients. RESULTS: The addition of exenatide to maximally-tolerated oral dual therapy led to target HbA1c attainment (<= 7.5% (58 mmol/mol) at 1 year) in 37% of cases, associated with reduction in weight, BMI and waist circumference. GA were older than non-responders (64 +/- 9 vs. 57 +/- 10 years, p = 0.032). Diabetes duration was comparable. Baseline HbA1c was significantly lower in GA (8.3 +/- 0.9 vs. 9.5 +/- 0.9% in non-responders; p < 0.001). Baseline HOMA-B and HOMA-S were comparable, while HOMA product (BxS) was higher in GA (17 +/- 6 vs. 14 +/- 6% in non- responders, p = 0.04). At 12 months, HbA1c reached 7.0 +/- 0.6% in GA vs. 9.0 +/- 1.3% in non-responders. Weight, BMI and waist circumference decreased in both groups. In GA and non-responders, there was a marked relationship between baseline HbA1c and absolute decrement in HbA1c over the study period. Logistic regression demonstrated that baseline HbA1c was the strongest predictor for target attainment following exenatide therapy (p < 0.001), with age to a lesser degree (p = 0.089). CONCLUSION: Baseline HbA1c is a major predictor of response to exenatide treatment, defined as target HbA1c (<= 7.5%, 58 mmol/mol) attainment. The lower the baseline HbA1c, the greater the likelihood of reaching the target HbA1c at 12 months, even though patients with higher baseline HbA1c benefited from the largest absolute reduction in HbA1c levels. PMID- 23340147 TI - The cost-effectiveness of an extended course (12+12 weeks) of varenicline plus brief counselling compared with other reimbursed smoking cessation interventions in Belgium, from a public payer perspective. AB - OBJECTIVE: To evaluate the cost-effectiveness of an extended (12+12 weeks) course of varenicline plus brief counselling compared with the currently reimbursed smoking cessation interventions (in combination with brief counselling) in Belgium, from a public payer perspective. METHODS: The previously published version of the BENESCO model which included the extended course of varenicline was updated with recent publically available demographic and cost data from Belgium. RESULTS: The extended course of varenicline plus brief counselling has an incremental cost per quality adjusted life year gained of 1101? compared with a nonextended 12-week course of varenicline (plus brief counselling). The extended course of varenicline dominates all other comparators in this analysis. CONCLUSIONS: The extended course of varenicline (12 weeks followed by 12 weeks maintenance therapy in successful quitters) plus brief counselling is a highly cost-effective alternative to a non-extended (12 weeks only) course of varenicline plus brief counselling. This strategy dominates the other alternative smoking cessation interventions currently reimbursed in Belgium. PMID- 23340148 TI - A pharmacist-conducted medication review in nursing home residents: impact on the appropriateness of prescribing. AB - Medication use in nursing homes is often suboptimal. This study investigated the impact of a pharmacist-conducted medication review on the appropriateness of prescribing for Belgian nursing home residents. We conducted a 6-month controlled, non-randomized study in two nursing homes (one intervention and one control nursing home). Sixty-nine residents completed the study in the intervention group (92 residents were included). For the control group, that were 79 residents (100 residents were included). Primary outcome was the appropriateness of prescribing, assessed by a set of validated quality indicators. At baseline, this study detected three main problems associated with the appropriateness of medication use: (i) the Medication Appropriateness Index (MAI) could be improved (continuation of no longer indicated medication was the most common problem), (ii) potential overuse was present in about half of the group, and (iii) potential underuse was present in about 30% of the sample. Despite this, our pharmacist-conducted medication review only modestly improved the appropriateness of prescribing. This may be attributed to the low implementation rate of the pharmacist recommendations. PMID- 23340149 TI - Regional differences of HFE (C282Y, H63D) allele frequencies in the Netherlands A model case illustrating the significance of genographics and prehistorical population migration. AB - We investigated HFE C282Y and H63D allele frequencies in three Dutch towns in the Netherlands, as well as their association with cardiovascular disease (CVD) mortality. Study subjects were selected from participants of the Monitoring Project on Cardiovascular Disease Risk Factors in the Netherlands carried out in Amsterdam, Doetinchem and Maastricht among > 35000 subjects, 20-59 years of age. Mortality follow-up lasted 9 to 13 years. A random sample of the cohort (n = 1075) provided information on the total study population. The random sample and all CVD deaths (n = 301) were genotyped for the C282Y and H63D mutation. Adjusted hazard ratios (HR) for CVD mortality were calculated per genotype. C282Y allele frequencies differed significantly between the towns investigated (p = 0.017), whereas the allele frequencies of H63D were similar (p = 0.141) across towns. In Maastricht we found a C282Y allele frequency of 0.086 compared to 0.055 in Amsterdam and 0.054 in Doetinchem. C282Y and H63D heterozygosity did not predict fatal CVD in either men or women, whereas homozygosity for the H63D mutation increased fatal CVD in women (adjusted HR = 8.5; 95% CI = 2.3-31.1). The unexpected high C282Y allele frequency in Maastricht is in line with the recent evidence of a Celtic origin of citizens from the former southern Netherlands and with prehistorical population migrations revealed in the context of the international Genographic Project, a landmark study of prehistorical human migrations around the globe. We recommend that when designing national screening programmes and national registries for genetic disorders, potential regional prevalence differences should be taken into account. PMID- 23340150 TI - Taenia saginata a rare cause of acute cholangitis: a case report. AB - Parasitic infestations of the galdbladder and biliary tract are quite rare. Taenia saginata is an intestinal helmint and patients harbouring adult T.saginata tapeworms are mostly asymptomatic and discharge only fecal proglottids. In some cases there might be nonspecific symptoms like vomiting, nausea, epigastric pain, diarrhea and weight loss. Tenia saginata is a also rare cause of ileus, pancreatitis, cholecystitis and cholangitis. We report a case of acute cholangitis caused by T. saginata presenting with fever, nausea, vomiting, jaundice and right upper quadrant pain. Although parasites are not an uncommon cause of cholangitis especially in diseaseendemic areas like the Far East, this is not true for T. saginata causing acute cholangitis. PMID- 23340151 TI - Phototoxic reaction after parathyroid surgery: case report and review of the literature. AB - BACKGROUND: A woman of 41 years old underwent surgery for primary hyperparathyroidism. She developed a long-lasting sharply demarcated erythematous skin reaction, appearing one hour after parathyroid surgery. This erythematous reaction felt like sunburn and was limited to the light exposed skin of the operation field, leading to the diagnosis of a phototoxic reaction. Since this phototoxic reaction occurred just after changing the operation lamp from a halogen type to a Light-Emitting Diode (LED) type, we suspected that the type of operation lamp could be a part of the cause of this phototoxic reaction. This is because our department has never before diagnosed phototoxic reactions (with a halogen type of operation lamp) during methylene blue (MB) assisted parathyroid surgery. METHODS: To investigate the cause of this phototoxic reaction, we performed an analysis of the adverse effects of all administered peroperative drugs and an evaluation of altered operation conditions. RESULTS: MB, used as a peroperative surgical marker of the parathyroid glands, was the most likely causal agent of this phototoxic reaction. Emission spectrum analysis of the operation light shows that the new LED operation lamp gives a high intensity of blue light. This may have resulted in activation of MB leading to a phototoxic reaction. CONCLUSIONS: To our knowledge, this is the first described phototoxic reaction in adults due to MB used as peroperative marker. Although rare, this potential side effect should be considered when using high doses of MB in combination with high intensity of blue light. PMID- 23340152 TI - Calciphylaxis: an uncommon manifestation of primary hyperparathyroidism. A case report. AB - Calciphylaxis is a rare disorder which mainly affects patients with end-stage renal disease and secondary hyperparathyroidism. We report here a case of calciphylaxis in a 56-year-old woman with primary hyperparathyroidism, a much more uncommon association. Skin biopsy revealed the characteristic pictures of the disease. Soon after parathyroidectomy, the parameters of the phosphorus calcium metabolism normalised but the cutaneous lesions persisted for several months. PMID- 23340158 TI - Fabrication of a sub-10 nm silicon nanowire based ethanol sensor using block copolymer lithography. AB - This paper details the fabrication of ultrathin silicon nanowires (SiNWs) on a silicon-on-insulator (SOI) substrate as an electrode for the electro-oxidation and sensing of ethanol. The nanowire surfaces were prepared by a block copolymer (BCP) nanolithographic technique using low molecular weight symmetric poly(styrene)-block-poly(methyl methacrylate) (PS-b-PMMA) to create a nanopattern which was transferred to the substrate using plasma etching. The BCP orientation was controlled using a hydroxyl-terminated random polymer brush of poly(styrene) random-poly(methyl methacrylate) (HO-PS-r-PMMA). TEM cross-sections of the resultant SiNWs indicate an anisotropic etch process with nanowires of sub-10 nm feature size. The SiNWs obtained by etching show high crystallinity and there is no evidence of defect inclusion or amorphous region production as a result of the pattern transfer process. The high density of SiNWs at the substrate surface allowed the fabrication of a sensor for cyclic voltammetric detection of ethanol. The sensor shows better sensitivity to ethanol and a faster response time compared to widely used polymer nanocomposite based sensors. PMID- 23340159 TI - Constitutive androstane receptor upregulates Abcb1 and Abcg2 at the blood-brain barrier after CITCO activation. AB - ATP-driven efflux transporters are considered to be the major hurdle in the treatment of central nervous system (CNS) diseases. Abcb1 (P-glycoprotein) and Abcg2 (breast cancer resistance protein/brain multidrug resistance protein) belong to the best known ABC-transporters. These ABC-transporters limit the permeability of the blood-brain barrier and protect the brain against toxic compounds in the blood but on the other hand they also reduce the efficacy of CNS pharmacotherapy. Even after 40 years of extensive research, the regulatory mechanisms of these efflux transporters are still not completely understood. To unravel the efflux transporter regulation, we analyzed the effect of the nuclear receptor CAR (constitutive androstane receptor) on the expression of Abcb1 and Abcg2 in primary cultures of porcine brain capillary endothelial cells (PBCEC). CAR is a xenobiotic-activated transcription factor, which is, like the other important nuclear receptor pregnane X receptor (PXR), highly expressed in barrier tissue and known to be a positive regulator of ABC-transporters. We demonstrate that activation of porcine CAR by the human CAR (hCAR) ligand CITCO (6-(4 chlorophenyl)-imidazo[2,1-b]thiazole-5-carbaldehyde) leads to an up-regulation of both transporters, whereas the mouse-specific CAR ligand TCPOBOP (1,4-bis-[2-(3,5 dichloropyridyloxy)]benzene) had no effect on transporter expression. The stimulation of PBCEC with CITCO caused a significant up-regulation of both efflux transporters on RNA-level, protein level and transport level. Furthermore the additional application of a CAR inhibitor significantly decreased the transporter expression to control niveau. In conclusion our data prove CAR activation only by the human ligand CITCO leading to an increased ABC-transporter expression and transport activity. PMID- 23340160 TI - Window of opportunity: estrogen as a treatment for ischemic stroke. AB - The neuroprotection research in the last 2 decades has witnessed a growing interest in the functions of estrogens as neuroprotectants against neurodegenerative diseases including stroke. The neuroprotective action of estrogens has been well demonstrated in both in vitro and in vivo models of ischemic stroke. However, the major conducted clinical trials so far have raised concern for the protective effect of estrogen replacement therapy in postmenopausal women. The discrepancy could be partly due to the mistranslation between the experimental stroke research and clinical trials. While predominant experimental studies tested the protective action of estrogens on ischemic stroke using acute treatment paradigm, the clinical trials have mainly focused on the effect of estrogen replacement therapy on the primary and secondary stroke prevention which has not been adequately addressed in the experimental stroke study. Although the major conducted clinical trials have indicated that estrogen replacement therapy has an adverse effect and raise concern for long term estrogen replacement therapy for stroke prevention, these are not appropriate for assessing the potential effects of acute estrogen treatment on stroke protection. The well established action of estrogen in the neurovascular unit and its potential interaction with recombinant tissue Plasminogen Activator (rtPA) makes it a candidate for the combined therapy with rtPA for the acute treatment of ischemic stroke. On the other hand, the "critical period" and newly emerged "biomarkers window" hypotheses have indicated that many clinical relevant factors have been underestimated in the experimental ischemic stroke research. The development and application of ischemic stroke models that replicate the clinical condition is essential for further evaluation of acute estrogen treatment on ischemic stroke which might provide critical information for future clinical trials. This article is part of a Special Issue entitled Hormone Therapy. PMID- 23340162 TI - Histone-deacetylase inhibitors produce positive results in the GADD45a-GFP GreenScreen HC assay. AB - Histone-deacetylase inhibitors (HDACi) are able to induce cell-cycle arrest, apoptosis and differentiation in a variety of tumour cell lines. The mechanisms leading to these cellular outcomes are not fully understood, however, it is has been proposed that induction of cell-cycle arrest might be a result of genotoxic stress. Despite the potential for genotoxic activity of this class of compounds, there are very few data available to provide evidence for this, either in vitro or in vivo. In this study, four HDACi, viz. trichostatin A, sodium butyrate, APHA compound 8 and apicidin, were tested in the human lymphoblastoid TK6 cell line hosted GADD45a-GFP assay, which has high sensitivity and specificity in the detection of genotoxic carcinogens and in vivo genotoxicants. All four compounds produced positive genotoxicity results within the acceptable toxic dose range of the assay, with APHA compound 8 producing the weakest response. Taken alongside recent evidence demonstrating that GADD45a is not induced by non-genotoxic apoptogens, this study suggests that genotoxicity contributes to the anti-tumour activity of HDACi drugs. PMID- 23340161 TI - Progesterone-induced neuroprotection: factors that may predict therapeutic efficacy. AB - Both progesterone and estradiol have well-described neuroprotective effects against numerous insults in a variety of cell culture models, animal models and in humans. However, the efficacy of these hormones may depend on a variety of factors, including the type of hormone used (ex. progesterone versus medroxyprogesterone acetate), the duration of the postmenopausal period prior to initiating the hormone intervention, and potentially, the age of the subject. The latter two factors relate to the proposed existence of a "window of therapeutic opportunity" for steroid hormones in the brain. While such a window of opportunity has been described for estrogen, there is a paucity of information to address whether such a window of opportunity exists for progesterone and its related progestins. Here, we review known cellular mechanisms likely to underlie the protective effects of progesterone and furthermore, describe key differences in the neurobiology of progesterone and the synthetic progestin, medroxyprogesterone acetate (MPA). Based on the latter, we offer a model that defines some of the key cellular and molecular players that predict the neuroprotective efficacy of progesterone. Accordingly, we suggest how changes in the expression or function of these cellular and molecular targets of progesterone with age or prolonged duration of hormone withdrawal (such as following surgical or natural menopause) may impact the efficacy of progesterone. This article is part of a Special Issue entitled Hormone Therapy. PMID- 23340163 TI - [Reversible cerebral vasoconstriction and acute encephalopathy as a presentation form of Guillain-Barre syndrome]. PMID- 23340164 TI - High-normal diastolic blood pressure is a risk for development of microalbuminuria in the general population: the Watari study. AB - OBJECTIVE: Although hypertension is a well known risk factor for microalbuminuria, it is unclear whether blood pressure less than 140/90 mmHg could be a risk for microalbuminuria. We assessed the relationship between baseline blood pressure and the future onset of microalbuminuria in the general population. METHODS: We studied 2603 town inhabitants of Watari, located in the southeastern part of Miyagi prefecture, Japan. Demographic data, medical history, sitting blood pressure, fasting blood chemistry, and urinary albumin-creatinine ratio were measured at baseline and were followed annually during the next 3 years. RESULTS: Among 2338 individuals who were normoalbuminuric at baseline (albumin-creatinine ratio <30 mg/g Cr), 161 developed microalbuminuria (albumin creatinine ratio 30-299 mg/g Cr) during a mean follow-up period of 2.4 years. Incident microalbuminuria patients were older (63.7 +/- 8.6 vs. 61.4 +/- 10.5 years; P < 0.01), included fewer men (31.1 vs. 40.1%; P < 0.05), had a greater BMI (23.8 +/- 3.6 vs. 23.1 +/- 3.1 kg/m2; P < 0.01), higher blood pressures (133.5 +/- 18.1/75.8 +/- 11.9 vs. 127.6 +/- 18.1/73.4 +/- 11.0 mmHg; P < 0.01 for both systolic and diastolic), higher triglycerides (median 1.18 vs. 1.02 mmol/l; P < 0.01), higher fasting blood glucose (median 5.05 vs. 4.94 mmol/l; P < 0.01), higher urinary albumin excretion (median 13.0 vs. 5.9 mg/g Cr; P < 0.001), and lower serum creatinine concentrations (59.2 +/- 12.8 vs. 61.4 +/- 13.2 MUmol/l; P < 0.05) compared to persistent normoalbuminuric individuals. Multivariate Cox proportional hazards analysis including all covariates revealed that only baseline urinary albumin excretion was an independent predictor for future microalbuminuria, whereas high-normal DBP, triglyceride, and fasting blood glucose concentrations were all significant predictors in the model excluding urinary albumin excretion. CONCLUSIONS: High-normal DBP associated with metabolic disorders could initiate glomerular damage, leading to future microalbuminuria. PMID- 23340165 TI - Day surgery laparoscopic cholecystectomy: initial experience in 43 consecutive patients. AB - AIM: Analyze the results of an early experience in day-case LC (laparoscopic cholecystectomy) in a single laparoscopic unit, in terms of clinical outcome, unexpected admissions, readmissions, patients satisfaction. MATERIALS AND METHODS: During three years, 200 consecutive patients underwent LC. Emergency procedures (32pts) and patients scheduled for cholecystectomy plus other surgical procedures (21pts) were excluded. Thus, 147 patients underwent elective LC and 43 were scheduled for DSLC (day-surgery laparoscopic cholecystectomy). RESULTS: Six patients (13,9%) were considered not eligible for a same day discharge and admitted to the inpatients ward for overnight observation. The re-admission rate was 2,3% and 41 patients (95.3%) were completely satisfied. DISCUSSION: Patients satisfaction was complete in 95.3% of cases, related to a correct preoperative information and the reduction in hospital costs amounted approximately to 41%. Despite the evidence of feasibility and safety of the daycase procedure, the Italian cultural background is nowadays inadequate for a clean acceptance of the DSLC. The provision of adequate staff education and training prior to full DSLC introduction is mandatory to the success of this organizational model. CONCLUSIONS: LC can be performed safely in an outpatient setting if there's a careful education of patients and the surgical and anesthesiologist team is well trained. Besides, good results can be achieved considering inclusion criteria. For the admission to be kept to a minimum, postoperative pain and nausea management has to be carefully planned such as discharge criteria evaluated. For selected patients, day-case LC is feasible and safe and can provide a reduction in hospital costs. PMID- 23340166 TI - Peer relationships of children with traumatic brain injury. AB - This study examined peer relationships in children with traumatic brain injury (TBI) relative to children with orthopedic injuries (OI), and explored whether differences in peer relationships correlated with white matter volumes. Classroom procedures were used to elicit peer perceptions of social behavior, acceptance, and friendships for eighty-seven 8- to 13-year-old children, 15 with severe TBI, 40 with complicated mild/moderate TBI, and 32 with OI. Magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) were used to investigate volumetric correlates of peer relationship measures. Children with severe TBI were rated higher in rejection-victimization than children with OI, and were less likely than children with OI to have a mutual friendship in their classroom (47% vs. 88%). Children with TBI without a mutual friend were rated lower than those with a mutual friend on sociability-popularity and prosocial behavior and higher on rejection-victimization, and had lower peer acceptance ratings. Mutual friendship ratings were related to white matter volumes in several posterior brain regions, but not to overall brain atrophy. Severe TBI in children is associated with detrimental peer relationships that are related to focal volumetric reductions in white matter within regions of the brain involved in social information processing. PMID- 23340167 TI - Meta-analysis: serious adverse events in Crohn's disease patients treated with TNF-alpha inhibitors. AB - BACKGROUND/AIMS: It remains a question whether anti-TNF-a treatment is associated with an increase of serious adverse events (SAE) in Crohn's Disease (CD) patients. This study aims to assess the risk of SAE of anti-TNF-a treatment in CD patients. METHODOLOGY: Literature search of EMBASE, PubMed, ScienceDirect, Cochrane Library and ClinicalTrials.gov until June 2012 was conducted. Eligible studies were randomized controlled trials (RCTs) ofTNF-a inhibitors treated for at least 24 weeks in CD patients. RESULTS: Thirteen RCTs, involving 4,257 patients with CD were included in analysis. SAE were reported in 364 patients (14.26%) in treatment groups and 263 patients (15.43%) in control groups. The proportion of patients with SAE was lower with TNF-a inhibitors than with placebo (OR, 0.80; 95% CI, 0.67-0.96; p=0.01). Compared with controls, the risks of malignancy and serious infection treated with TNF-a inhibitors showed no significant difference (p>0.05). CONCLUSIONS: In CD patients, anti-TNF-a treatment, especially for adalimumab, could decrease the incidence of SAE, without an increased risk of malignancy or serious infection. TNF-a inhibitors are safe in treatment of CD patients. To assess the risk of SAE, larger samples of randomized control trials with long term follow-up are needed. PMID- 23340168 TI - The role of TRAIL signal pathway in acute pancreatitis. AB - BACKGROUND/AIMS: The incidence of acute pancreatitis has been increasing recently. This study aims to elucidatethe role of TRAIL signal pathway in the process of acute pancreatitis. METHODOLOGY: Pancreatitis models were constructed by cerulein or cerulein plus lipopolysaccharide. Amylase and lipidase were measured in different groups. The mRNA expression of TRAIL, DR5, DcR1 and DcR2 were studied by means of relative Quantitative-Real-Time PCR. In addition, the expression of TUNEL and Caspase 3 was studied by immunohistochemistry. RESULTS: The establishment of pancreatitis model was successful. There were significant differences of amylase and lipidase in the three groups (p<0.05), with highest in MAP group. The mRNA expression of TRAIL was upregulated in SAP group and downregulated in MAP group. The expressions of DcR1 were detected to be statistically upregulated in MAP group and SAP group. The expressions of DR5 and DcR2 were not significant different from each other among the three groups (p>0.05). There were no siginificant differences among the three groups for the expression of Caspase 3 which indicated the apoptosis of acinar cell. The correlation coefficient between the expression of TUNEL and Caspase 3 was 0.383 (p=0.037). CONCLUSIONS: TRAIL signal pathway might play a role in the process of acute pancreatitis which needs to be explored further. PMID- 23340169 TI - Low and declining enrollment of women in Canadian diagnostic radiology programs. PMID- 23340170 TI - Cucurbitacin B potently suppresses non-small-cell lung cancer growth: identification of intracellular thiols as critical targets. AB - Cucurbitacin B (CuB), has recently emerged as a potent anticancer agent; however, its efficacy in non-small-cell lung cancer (NSCLC) and the mechanism(s) initiating its biological effects remain largely unclear. In this study, CuB potently suppressed the growth of four NSCLC cells (H1299, A549, HCC-827 and H661) in vitro and the highly aggressive H1299 xenograft in vivo. CuB significantly altered the actin cytoskeletal assembly, induced G2/M cell-cycle arrest and mitochondrial apoptosis through the modulation of several key molecular targets mediating the aforementioned processes. Interestingly, all cellular effects of CuB were completely attenuated only by the thiol antioxidant N-acetylcysteine (NAC). Furthermore, pretreatment with glutathione synthesis inhibitor butithione-sulfoxime (BSO), significantly exacerbated CuB's cytotoxic effects. To this end, cells treated with CuB revealed a rapid and significant decrease in the levels of protein thiols and GSH/GSSG ratio, suggesting disruption of cellular redox balance as the primary event in CuB's cytotoxic arsenal. Using UV and FTICR mass spectrometry we also demonstrate for the first time a physical interaction of CuB with NAC and GSH in a cell-free system suggesting that CuB interacts with and modulates cellular thiols to mediate its anti-cancer effects. Collectively, our data sheds new light on the working mechanisms of CuB and demonstrate its therapeutic potential against NSCLC. PMID- 23340171 TI - Oct-4 is required for an antiapoptotic behavior of chemoresistant colorectal cancer cells enriched for cancer stem cells: effects associated with STAT3/Survivin. AB - Cancer stem cells (CSCs) have been implicated in multidrug resistance, a phenomenon responsible for the failure of cancer chemotherapy. However, the underlying mechanisms are still unclear. In our study, we established two oxaliplatin-resistant colorectal cancer cell lines displaying some CSCs characteristics. Oct4 overexpression was observed in these two lines. We performed Oct4 knock down by lentiviral vector-mediated specific shRNA. Knockdown increased apoptosis, decreased CSCs marker expression and weakened tumorigenicity in drug-resistant cell lines. In conclusion, we show that these events can be at least in part attributed to the STAT3/Survivin pathway. PMID- 23340172 TI - Phosphorylation of 4E-BP1 predicts sensitivity to everolimus in gastric cancer cells. AB - We studied the effect of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) on human gastric cancer cell lines. Cell proliferation in 3 of 8 cell lines was effectively inhibited by everolimus. Basal phosphorylation level of 4E-BP1 (T37/46, T70) was significantly higher in everolimus-sensitive cells than in everolimus-resistant cells. In subcutaneous xenograft model, immunohistochemistry analysis revealed that everolimus-sensitive cells expressed high levels of phospho-4E-BP1 (T37/46). In conclusion, phosphorylation of 4E-BP1 may be a predictive biomarker of everolimus sensitivity in gastric cancer. PMID- 23340173 TI - Functional analysis of the two reciprocal fusion genes MLL-NEBL and NEBL-MLL reveal their oncogenic potential. AB - MLL gene aberrations are frequently diagnosed in infant acute myeloid leukemia (AML). We previously described the MLL-NEBL and NEBL-MLL genomic fusions in an infant AML patient with a chromosomal translocation t(10;11)(p12;q23). NEBL was the second Nebulin family member (LASP1, NEBL) which was found to be involved in MLL rearrangements. Here, we report on our attempts to unravel the oncogenic properties of both fusion genes. First, RT-PCR analyses revealed the presence of the MLL-NEBL and NEBL-MLL mRNAs in the diagnostic sample of the patient. Next, expression cassettes for MLL-NEBL and NEBL-MLL were cloned into a sleeping beauty vector backbone. After stable transfection, the biological effects of MLL-NEBL, NEBL-MLL or the combination of both fusion proteins were investigated in a conditional cell culture model. NEBL-MLL but also co-transfected cells displayed significantly higher growth rates according to the data obtained by cell proliferation assay. The focus formation experiments revealed differences in the shape and number of colonies when comparing MLL-NEBL, NEBL-MLL- and co transfected cells. The results obtained in this study suggest that the reciprocal fusion genes of the Nebulin gene family might be of biological importance. PMID- 23340174 TI - Anti-apoptotic proteins on guard of melanoma cell survival. AB - Apoptosis plays a pivotal role in sustaining proper tissue development and homeostasis. Evading apoptosis by cancer cells is a part of their adaption to microenvironment and therapies. Cellular integrity is predominantly maintained by pro-survival members of Bcl-2 family and IAPs. Melanoma cells are characterized by a labile and stage-dependent phenotype. Pro-survival molecules can protect melanoma cells from apoptosis and mediate other processes, thus enhancing aggressive phenotype. The essential role of Bcl-2, Mcl-1, Bcl-X(L), livin, survivin and XIAP was implicated for melanoma, often in a tumor stage-dependent fashion. In this review, the current knowledge of pro-survival machinery in melanoma is discussed. PMID- 23340175 TI - Synergistic anticancer activity of HS-173, a novel PI3K inhibitor in combination with Sorafenib against pancreatic cancer cells. AB - The RAF/MEK/ERK and PI3K/AKT pathways are highly implicated in the development of pancreatic cancer. The principal objective of this study was to assess the synergic effect between Sorafenib (a RAF inhibitor) and HS-173 (a novel PI3K inhibitor) to gain insight into novel therapeutic strategies for treating pancreatic cancer. We first investigated the cytotoxic effect of co-treatment with Sorafenib and HS-173 using the Calcusyn program. Combined treatment of the two drugs synergistically inhibited the viability of Panc-1 cells (combination index<1). Concomitantly, the co-treatment induced G2/M arrest and increased apoptosis with the loss of mitochondrial membrane potential. Apoptosis resulting from the co-treatment was accompanied by increased levels of cleaved caspase-3 and PARP as well as greater numbers of TUNEL-positive apoptotic cells compared to treatment with either drug alone. Furthermore, combined treatment with these drugs decreased the expression of HIF-1alpha and VEGF which play an important role in angiogenesis. This anti-angiogenic effect was confirmed by the suppressed tube formation of VEGF-induced human umbilical vein endothelial cells and inhibition of blood vessel formation in a Matrigel plug assay in mice. Taken together, our study demonstrates that combined treatment with Sorafenib and HS 173 has a synergistic anti-cancer effect on pancreatic cancer cells, indicating that simultaneously targeting the RAF/MEK and PI3K/AKT pathways can induce a synergistic inhibitory effect on pancreatic cancers in which both pathways are activated. Based on the observations from our study, we suggest that the combined administration of these two drugs may be considered to be a new therapeutic regimen for treating pancreatic cancer. PMID- 23340176 TI - ABCB2 (TAP1) as the downstream target of SHH signaling enhances pancreatic ductal adenocarcinoma drug resistance. AB - Hedgehog signaling plays critical roles in drug resistance of PDAC. We demonstrate that SHH is highly expressed in PDAC patients and cell lines. SHH signaling protects PDAC cells against gemcitabine induced apoptosis, because either over-expression or knockdown of SHH in PDAC cells affects the sensitivity to gemcitabine. Mechanistic studies show that ABCB2 serves as the downstream target of SHH signaling, leading to the drug resistance of PDAC cells. Combinational treatments with gemcitabine and cyclopamine yield synergistic antitumor effects in vitro and in vivo. Our study suggests that inhibiting SHH signaling or targeting ABCB2 gene improves the efficacy of chemotherapy in patients with PDAC. PMID- 23340177 TI - KRC-327, a selective novel inhibitor of c-Met receptor tyrosine kinase with anticancer activity. AB - c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been reported to be involved in tumorigenesis and metastatic progression. We synthesized a novel triazolopyridazine derivative KRC-327 which selectively targets the c-Met. When we performed receptor tyrosine kinases (RTKs) array with 42 different phosphorylated-RTKs, KRC-327 strongly inhibited expression of activated c-Met in MKN-45 cancer cells. This was confirmed by immunofluorescence staining. Also, KRC-327 decreased the expression of Gab1, Akt, signal transducer and activator of transcription 3 (STAT3) and Erk, down-stream signals of c-Met. KRC-327 strongly suppressed the growth of c-Met over-expressed cancer cells (MKN 45, SNU-638, SNU-5), while not in c-Met absent cancer cell lines (MKN-1, SNU-1). Furthermore, KRC-327 effectively induced cell cycle arrest, especially G0/G1 arrest by increasing expression of p21, p27 and decreasing that of cyclin D1. In the ligand-induced functional studies, KRC-327 inhibited proliferation of HGF stimulated BxPC-3 cells, the migration of HGF-stimulated AGS cancer cells, and suppressed colony formation in HGF-stimulated U-87MG cells. In xenograft animal models, KRC-327 significantly not only delayed tumor growth but also suppressed phosphorylation of c-Met and its signaling cascades as well as proliferation. Taken together, these results demonstrate that KRC-327 selectively targets c-Met, resulting in inhibition of cell growth and proliferation. Therefore, we suggest that KRC-327 may be a novel drug candidate with the therapeutic potential of targeting c-Met in human cancer. PMID- 23340178 TI - Hsp90 inhibition by NVP-AUY922 and NVP-BEP800 decreases migration and invasion of irradiated normoxic and hypoxic tumor cell lines. AB - This study explores the impact of Hsp90 inhibitors NVP-AUY922 and NVP-BEP800 in combination with ionizing radiation (IR) on the migration and invasion of lung carcinoma A549 and glioblastoma SNB19 cells, under normoxia or hypoxia. Independent of oxygen concentration, both drugs decreased the migration and invasion rates of non-irradiated tumor cells. Combined drug-IR treatment under hypoxia inhibited cell invasion to a greater extent than did each treatment alone. Decreased migration of cells correlated with altered expression of several matrix-associated proteins (FAK/p-FAK, Erk2, RhoA) and impaired F-actin modulation. The anti-metastatic efficacy of the Hsp90 inhibitors could be useful in combinational therapies of cancer. PMID- 23340179 TI - Understanding high grade glioma: molecular mechanism, therapy and comprehensive management. AB - High-grade gliomas (HGGs) account for the vast majority of all gliomas, including glioblastoma (World Health Organization (WHO) grade IV) and anaplasticgliomas (WHO grade III). Despite tremendous efforts in developing multimodal treatments, the overall prognosis remains poor; however, survival time varies considerably between patients. The nature of diffuse permeation into surrounding brain parenchyma poses dilemma for neurosurgeons between extensive surgical resection to eliminate as much as tumor cells as possible and adverse effects associated with brain function. Heterogeneity in both cytology and gene expression makes it difficult to coordinate an effective therapy which works for every patient. This article reviews recent advancements in the molecular mechanism, multimodal treatment and clinical management, and the updated view on the biomarkers in patients with HGG, both in primary and recurrent setting, with an emphasis on targeted therapies tailored to the patient. PMID- 23340181 TI - Emerging avenues linking inflammation, angiogenesis and Sjogren's syndrome. AB - Sjogren's syndrome (SS) is an autoimmune disease characterized by an inflammatory mononuclear infiltration and the destruction of epithelial cells of the lachrymal and salivary glands. The aetiology is unknown. The expression "autoimmune epithelitis" has been proposed as an alternative to SS, in view of the emerging central role of the epithelial cells in the disease pathogenesis. At the biomolecular level, the epithelial cells play an important role in triggering the autoimmune condition via antigen presentation, apoptosis, and chemokine and cytokines release. Inflammation and angiogenesis are frequently coupled in the pathological conditions associated to autoimmune diseases, and an angiogenic imbalance contributes to the pathogenesis of a number of inflammatory disorders. This work reviews the current knowledge of the molecular and cellular mechanisms underlying the pathogenesis of the inflammatory reactions that characterize SS. The literature and our data on the role of angiogenesis in the pathophysiology of the disease are discussed. PMID- 23340180 TI - MicroRNA-135b acts as a tumor promoter by targeting the hypoxia-inducible factor pathway in genetically defined mouse model of head and neck squamous cell carcinoma. AB - Here in, we investigated the mechanism underlying overexpression of miR-135b in the human head and neck squamous cell carcinoma (HNSCC) cell lines and in the HNSCC mouse model. Exogenous expression of miR-135b in these cell lines increased cell proliferation, migration, and colony formation. Gene silencing analysis revealed that miR-135b affects a regulator that inhibits hypoxia-inducible factor (HIF). Increased miR-135b expression was positively correlated with HIF-1alpha expression and microvessel density in the HNSCC model. Thus, our data demonstrate that miR-135b acts as a tumor promoter by promoting cancer cell proliferation, colony formation, survival, and angiogenesis through activation of HIF-1alpha in HNSCC. PMID- 23340182 TI - Expanding roles of ABCG1 and sterol transport. AB - PURPOSE OF REVIEW: To offer a comprehensive review on the role of ABCG1 in cellular sterol homeostasis. RECENT FINDINGS: Early studies with Abcg1 mice indicated that ABCG1 was crucial for tissue lipid homeostasis, especially in the lung. More recent studies have demonstrated that loss of ABCG1 has wide-ranging consequences and impacts lymphocyte and stem cell proliferation, endothelial cell function, macrophage foam cell formation, as well as insulin secretion from pancreatic beta cells. Recent studies have also demonstrated that ABCG1 functions as an intracellular lipid transporter, localizes to intracellular vesicles/endosomes, and that the transmembrane domains are sufficient for localization and transport function. SUMMARY: ABCG1 plays a crucial role in maintaining intracellular sterol and lipid homeostasis. Loss of this transporter has significant, cell-type-specific consequences ranging from effects on cellular proliferation, to surfactant production and/or insulin secretion. Elucidation of the mechanisms by which ABCG1 affects intracellular sterol flux/movement should provide important information that may link ABCG1 to diseases of dysregulated tissue lipid homeostasis. PMID- 23340183 TI - Connecting communities to health research: development of the Project CONNECT minority research registry. AB - INTRODUCTION: Prevention and treatment standards are based on evidence obtained in behavioral and clinical research. However, racial and ethnic minorities remain relatively absent from the science that develops these standards. While investigators have successfully recruited participants for individual studies using tailored recruitment methods, these strategies require considerable time and resources. Research registries, typically developed around a disease or condition, serve as a promising model for a targeted recruitment method to increase minority participation in health research. This study assessed the tailored recruitment methods used to populate a health research registry targeting African-American community members. METHODS: We describe six recruitment methods applied between September 2004 and October 2008 to recruit members into a health research registry. Recruitment included direct (existing studies, public databases, community outreach) and indirect methods (radio, internet, and email) targeting the general population, local universities, and African American communities. We conducted retrospective analysis of the recruitment by method using descriptive statistics, frequencies, and chi-square statistics. RESULTS: During the recruitment period, 608 individuals enrolled in the research registry. The majority of enrollees were African American, female, and in good health. Direct and indirect methods were identified as successful strategies for subgroups. Findings suggest significant associations between recruitment methods and age, presence of existing health condition, prior research participation, and motivation to join the registry. CONCLUSIONS: A health research registry can be a successful tool to increase minority awareness of research opportunities. Multi-pronged recruitment approaches are needed to reach diverse subpopulations. PMID- 23340184 TI - Clinical use of cerebral oximetry in extremely preterm infants is feasible. AB - INTRODUCTION: The research programme Safeguarding the Brains of our smallest Children (SafeBoosC) aims to test the benefits and harms of cerebral near infrared spectroscopy (NIRS) oximetry in infants born before 28 weeks of gestation. In a phase II trial, infants will be randomised to visible cerebral NIRS oximetry with pre-specified treatment guidelines compared to standard care with blinded NIRS-monitoring. The primary outcome is duration multiplied with the extent outside the normal range of regional tissue oxygen saturation of haemoglobin (rStO2) of 55 to 85% in percentage hours (burden). This study was a pilot of the Visible -Oximetry Group. MATERIAL AND METHODS: This was an observational study including ten infants. RESULTS: The median gestational age was 26 weeks+three days, and the median start-up time was 133 minutes after delivery. The median recording time was 69.7 hours, mean rStO2 was 64.2+/-4.5%, median burden of hyper- and hypoxia was 30.3% hours (range 2.8-112.3). Clinical staff responded to an out of range value 29 times--only once to values above 85%. In comparison, there were 83 periods of more than ten minutes with an rStO2 below 55% and four episodes with an rStO2 above 85%. These periods accounted for 72% of the total hypoxia burden. A total of 18 of the 29 interventions were adjustments of FiO2 which in 13 of the 18 times resulted in an out-of-range SpO2. Two infants suffered second-degree burns from the sensor. Five infants died. In all cases, this was unrelated to NIRS monitoring and treatment. CONCLUSION: The intervention of early cerebral NIRS monitoring proved feasible, but prolonged periods of hypoxia went untreated. Thus, a revision of the treatment guideline and an alarm system is required. FUNDING: The Elsass Foundation funded the present study. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01530360. PMID- 23340185 TI - Chronic obstructive pulmonary disease involves substantial health-care service and social benefit costs. AB - INTRODUCTION: The present study compared health care-related costs and the use of social benefits and transfer payments in participants with and without chronic obstructive pulmonary disease (COPD), and related the costs to the severity of the COPD. MATERIAL AND METHODS: Spirometry data from a cohort study performed in Denmark during 2004-2006 were linked with national register data that identified the costs of social benefits and health-care services. The cohort comprised 546 participants with COPD (forced expiratory volume in the first sec. (FEV1)/forced vital capacity (FVC) ratio<0.7 following bronchodilator administration) and 3,995 without COPD (in addition, 9,435 invited participants were non-responders and 331 were excluded). The costs were adjusted for gender, age, co-morbidity and educational level. RESULTS: Health care-related costs were 4,779 (2,404-7,154) Danish kroner (DKK) higher for participants with COPD than for those without COPD, and 2,882 (556-5,208) DKK higher than for non-responders. The higher costs were mainly due to the cost of medicines and inpatient care. The health-care costs increased with disease severity Global Initiative for Chronic Obstructive Lung Disease (GOLD grade). In participants<65 years of age, the annual cost of social benefits and transfer payments was 15,901 (5,966-25,837) DKK higher and the total costs were 20,454 (7,559-33,350) DKK higher in those with COPD than in those without COPD; this was due mostly to the high cost of dis-ability pensions. CONCLUSION: Health care-related costs and costs for social benefits and transfer payments were higher for participants with COPD than for non-COPD participants and non-responders. FUNDING: This study was supported by The Obel Family Foundation, The Danish Lung Association and The Health Insurance Foundation. TRIAL REGISTRATION: Not relevant. PMID- 23340186 TI - Emergency department physicians spend only 25% of their working time on direct patient care. AB - INTRODUCTION: In modern hospital medicine, there is a growing awareness of the need for efficient and secure -patient care. Authorities seek to improve this by adding requirements for documentation, administrative tasks and standardized patient programmes. However, it is rarely investigated how much time physicians spend on these tasks and it is therefore difficult to assess how changes in the system might affect workflow and thus time efficacy. The aim of this study was to investigate how physicians in the emergency department (ED) of a public hospital in Denmark spend their time. Results were stratified for physicians working in the emergency room (ER) and the admission area of our ED. MATERIAL AND METHODS: We used a work sampling approach and observed nine physicians at three-minute intervals for a total of 137 hours during day shifts. Activities were documented in predefined categories. RESULTS: Results showed that physicians spent 25% of their time in direct patient contact, 5.8% with indirect patient care, 24% communicating with other staff, 31% documenting their work and 6% on transport. Personal time ac-counted for 5% and other activities for 3%. Interestingly, no differences in main categories were observed between -physicians admitting patients and physicians working in the fast track of the ER. CONCLUSION: Our results confirm earlier studies. Furthermore, they suggest that the specialty, the severity of disease and the nature of the contact (in-patient versus out patient) have only a minor influence on the time spent on various tasks. We speculate whether it is really administrative systems and IT-solutions that influence time distribution in physicians' work. FUNDING: Not relevant. TRIAL REGISTRATION: ClinicalTrials.gov NCT01722721. PMID- 23340187 TI - Limited evidence for intranasal fentanyl in the emergency department and the prehospital setting--a systematic review. AB - INTRODUCTION: The intranasal (IN) mode of application may be a valuable asset in non-invasive pain management. Fentanyl demonstrates pharmacokinetic and pharmacodynamic properties that are desirable in the management of acute pain, and IN fentanyl may be of value in the prehospital setting. The aim of this systematic review was to evaluate the current evidence for the use of IN fentanyl in the emergency department (ED) and prehospital setting. METHOD: Reports of trials of IN fentanyl in (ED) and prehospital treatment of pain were systematically sought using the PubMed database, Embase, Google scholar, the Cochrane database and the Cumulative Index to Nursing and Allied Health Literature. RESULTS: Twelve studies of IN fentanyl in the (ED) and prehospital setting were included in the final analysis. In the ED, analgesic non-inferiority and superiority were demonstrated when comparing IN fentanyl with intravenous (IV) and intramuscular morphine, respectively. Non-blinded, non-controlled studies demonstrated an analgesic effect of IN fentanyl in patients with moderate and severe pain. In the prehospital setting, both analgesic inferiority and non inferiority were demonstrated when IN fentanyl was compared with IV morphine. Finally, a significant analgesic effect of IN fentanyl was demonstrated when IN fentanyl was compared with methoxyflurane. CONCLUSION: Only limited quality evidence exists for the efficacy of IN fentanyl in the ED and in the prehospital setting, and more double-blinded, randomised, controlled trials are urgently needed to validate the use of IN fentanyl in this context. PMID- 23340188 TI - Acceptable outcome after laparoscopic appendectomy in children. AB - INTRODUCTION: An increasing proportion of childhood -appendicitis is being treated with laparoscopic appendectomy (LA). We wanted to elucidate the outcome of childhood appendicitis treated primarily by residents in a university hospital. MATERIAL AND METHODS: All children (age<16 years) with appendectomy treated surgically in our department between January 2006 and January 2011 were identified retrospectively. Readmission, reoperation or post-operative length of hospital stay (LOS) exceeding five days were considered non-satisfactory outcomes. RESULTS: A total of 390 children had an appendectomy performed. The mean age was 9.8 years, and mortality was 0.0%. The surgeon was a resident in 92% of the cases. A total of 246 (63.1%) had an LA. The rate of LA increased over the five-year period from 45% to 88% (p=0.01). The conversion rate decreased from 28% to 15% (p=0.02). The median post-operative LOS was one and three days for simple and complicated appendicitis, respectively. A total of 45 patients (11.5%) had a complication, 40 patients (10.3%) were readmitted, and 56 patients (14.4%) had a non-satisfactory outcome. Logistic regression found open surgery and complicated appendicitis to be associated with an increased risk of complications (p<0.01). CONCLUSION: Increased use of LA did not increase the number of patients with a non-satisfactory outcome. Residents manage this treatment at a highly professional level. Readmission due to pain and discomfort was frequent and more targeted and systematic post-operative analgesic care of our children is called for. FUNDING: Not relevant. TRIAL REGISTRATION: The study was submitted to ClinicalTrials.gov (NCT01657565). PMID- 23340189 TI - Paediatric intensive care is feasible in a neonatal department. AB - INTRODUCTION: Intensive care of infants below one year of age has been centralized in a paediatric intensive care unit (PICU) related to the neonatal intensive care unit (NICU) at Rigshospitalet, the University Hospital in Copenhagen in eastern Denmark (approximately 2.5 million inhabitants) since 2002. The aim of this paper was to evaluate the experiences from the PICU. MATERIAL AND METHODS: A descriptive study including data from the 01.01.2002-31.12.2010-period from all the admissions to the PICU for infants below one year of age fulfilling one of two criteria: 1) born preterm and admitted to the department after 40 weeks of gestational age or 2) born at term and admitted to the department at an age -older than 28 days. Data were registered prospectively including information on primary diagnoses at admission, the need for mechanical ventilation and the duration of mechanical ventilation. Mortality was evaluated in the three year period 2008-2010 by use of the Paediatric Index of Mortality 2 score (PIM2 score). RESULTS: The nine-year period saw 927 admissions to the PICU and 355 infants received mechanical ventilation (median three days). The PIM2 score was 6.7% and the mortality was 6.7% in the period during which PIM2 score was registered. The incidence of mechanical ventilation due to respiratory failure was 0.74/1,000 infants born in the -region. CONCLUSION: The experience from the NICU seems to -compensate for a low volume of infants in the PICU. The -incidence of mechanically ventilated infants due to respiratory disease in eastern Denmark is relatively low. FUNDING: Not relevant. TRIAL REGISTRATION: Not relevant. The study was not registered, as it is an observational study. PMID- 23340190 TI - Young Danes' experiences with unsafe sex. AB - INTRODUCTION: Surveying sexual behaviour of the general population serves to identify key points of preventive interventions, monitor the effect and interpret changes in patterns of disease. Validated questionnaires describing sexual behaviour can be adapted to some extent from other countries, but national adaption, refinement and validation are needed due to cultural differences. The aim of this study was to identify factors influencing sexual risk behaviour among Danish adolescents with a view to designing and -initiating a national sexual behaviour surveillance programme in Denmark. MATERIAL AND METHODS: We conducted four semi-structured focus group interviews with a total of 19 sexually experienced adolescents aged 18-23 years who attended a Danish Folk High School. Data were transcribed verbatim and analysed using qualitative description. RESULTS: Four main categories of sexual risk behaviour were identified: 1) alcohol consumption which was associated with lack of condom use, 2) one-night stands after a night out partying, at festivals or on vacations, 3) low self esteem which increased the risk of pushing one's personal boundaries, thus resulting in promiscuous sexual behaviour, 4) increased sexual experience which resulted in lack of condom use. CONCLUSION: This study identified four categories that may lead to unsafe sex. These results should be taken into consideration when planning future preventive programmes aiming to reduce sexually transmitted infections and unwanted pregnancies among adolescents and young adults. FUNDING: Not relevant. TRIAL REGISTRATION: Not relevant. PMID- 23340191 TI - Cervical ultrasound elastography may hold potential to predict risk of preterm birth. AB - INTRODUCTION: Freehand ultrasound real-time elastography (RTE) is a simple technique allowing direct visualization of the elastogramme superimposed on the B mode -image. The objective of RTE is to investigate stiffness and related parameters such as local tissue strain with a view to adding new information related to tissue morphology and architecture. MATERIAL AND METHODS: This was a pilot study in 12 healthy pregnant women who underwent transvaginal ultrasound. The RTE (Hitachi) information was colour-coded and superimposed on the B-mode scan. Elastography images were analyzed by means of a software tool to identify thresholds for the colours red (soft), green (medium hard) and blue (hard). The cervical strain rate was measured in three different parts. Additional information obtained included age of gestation, number of pregnancies and deliveries, previous preterm births and gestational age at delivery in current pregnancy. RESULTS: The softness of cervix increases towards portio. Within the colour spectrum, green was predominant. Strain ratio can be used as a comparative index among different subjects rather than as an absolute strain measurement. CONCLUSION: The elastographic image allowed for easy correlation between colour distribution and the anatomical structures as it is superimposed on the B-mode image. The elasticity of the cervix increases towards portio. FUNDING: Not relevant. TRIAL REGISTRATION: Not relevant. PMID- 23340192 TI - Municipal tobacco control in the Capital Region of Denmark can be improved. AB - INTRODUCTION: Smoking remains the single preventable factor with the highest impact on morbidity and mortality in Denmark. The aims of this study were to assess the quality of municipal tobacco control (TC) in the 29 municipalities of the Capital Region of Denmark, and to compare the quality of the TC and the priority given to TC with the prevalence of daily smoking across municipalities. MATERIAL AND METHODS: In March 2012 a questionnaire regarding municipal TC was sent to the 29 municipalities of the Region. The response rate was 100%. Data were merged with information from the Health Survey under-taken in the Capital Region in 2010 which included 49,806 respondents. We assessed the quality of TC using two measures: self-reported priority (scale 1-10) and calculated quality score (scale 0-70), and compared these measures with the prevalence of daily smoking two years before. RESULTS: There were large differences in TC between the municipalities of the region. A high smoking prevalence in 2010 was significantly associated with a high priority given to TC in 2012 (p=0.03). The mean priority of TC was 7.1 (range 3-10) and the mean quality score was 37.1 (range 17-55). Smoking cessation services and prevention of second-hand smoking exposure seem to be the main areas of focus, while several at-risk groups were given a low priority. CONCLUSION: In some municipalities, TC seems to be neglected, while others have achieved high standards. We call for major improvements in TC in the majority of municipalities. FUNDING: The trial was funded by the Capital Region of Denmark (Region Hovedstaden) and the Health Foundation (Helsefonden). TRIAL REGISTRATION: Not relevant. PMID- 23340193 TI - Facile synthesis, growth mechanism and reversible superhydrophobic and superhydrophilic properties of non-flaking CuO nanowires grown from porous copper substrates. AB - Reversible superhydrophobic and superhydrophilic surfaces based on porous substrates covered with CuO nanowires are developed in this study. A facile thermal oxidation method is used to synthesize non-flaking bicrystalline CuO nanowires on porous copper substrates in static air. The effects of thermal oxidation temperature and duration are systemically studied. The growth mechanism of the obtained non-flaking CuO nanowires is presented and the compression stress is believed to be the key driving force. The wettability of the CuO nanowires after chemical modification with trichloro(1H,1H,2H,2H-perfluorooctyl)silane is systemically investigated. The porous substrates covered with CuO nanowires exhibit excellent superhydrophobic performance with almost no water adhesion and no apparent drag resistance, and a maximum static water contact angle of 162 +/- 2 degrees is observed. Moreover, a rapid reversibly switchable wettability between superhydrophobic and superhydrophilic states is realized by the alternation of air-plasma treatment and surface fluorination. The porous substrates covered with CuO nanowires will find promising applications in surface and corrosion protection, liquid transportation, oil-water separation, and self cleaning surfaces. PMID- 23340194 TI - The effects of an RGD-PAMAM dendrimer conjugate in 3D spheroid culture on cell proliferation, expression and aggregation. AB - By presenting biomolecular ligands on the surface in high density, ligand decorated dendrimers are capable of binding to membrane receptors and cells with specificity and avidity. Despite the various uses, fundamental investigations on ligand-dendrimer conjugates have mainly focused on their binding behavior with cells, whereas their potential bioactivity and applications in multicellular systems, especially in three-dimensional (3D) culture systems, remains untapped. In this study, a typical adhesive peptide ligand - RGD - was modified to generation 4 polyamidoamine (PAMAM), and the bioactivity of suspended RGD-PAMAM conjugates was investigated on cells cultured as multicellular spheroids. Our results demonstrate that the RGD-PAMAM conjugates, after being incorporated into the 3D spheroids, were able to promote cellular proliferation and aggregation, and affect the mRNA expression of extracellular factors by NIH 3T3 cells. These bioactive functions were multivalency-dependent, as none of similar effects was observed for monovalent RGD ligand. Our study suggests that multivalent ligand dendrimer conjugates may act as a unique type of artificial factors to mediate the cellular microenvironment in 3D culture, a property attributable to the spatial organization of the ligands and possible "cell-gluing" function of multivalent conjugates. This new finding opens the door for further exploring multivalent ligand-dendrimer conjugates for applications in 3D cell culture and tissue engineering. PMID- 23340195 TI - Hemostatic properties and the role of cell receptor recognition in human hair keratin protein hydrogels. AB - Driven by new discoveries in stem-cell biology and regenerative medicine, there is broad interest in biomaterials that go beyond basic interactions with cells and tissues to actively direct and sustain cellular behavior. Keratin biomaterials have the potential to achieve these goals but have been inadequately described in terms of composition, structure, and cell-instructive characteristics. In this manuscript we describe and characterize a keratin-based biomaterial, demonstrate self-assembly of cross-linked hydrogels, investigate a cell-specific interaction that is dependent on the hydrogel structure and mediated by specific biomaterial-receptor interactions, and show one potential medical application that relies on receptor binding - the ability to achieve hemostasis in a lethal liver injury model. Keratin biomaterials represent a significant advance in biotechnology as they combine the compatibility of natural materials with the chemical flexibility of synthetic materials. These characteristics allow for a system that can be formulated into several varieties of cell-instructive biomaterials with potential uses in tissue engineering, regenerative medicine, drug and cell delivery, and trauma. PMID- 23340196 TI - In vivo biodistribution and toxicology of functionalized nano-graphene oxide in mice after oral and intraperitoneal administration. AB - Graphene oxide (GO) and its functionalized derivatives have attracted great attention in biomedicine in recent years. A number of groups including ours have studied the in vivo behaviors of functionalized nano-graphene after intravenous injection or inhalation, and uncovered the surface coating & size dependent biodistribution and toxicology profiles for this type of nanomaterials. However, the fate of GO derivatives in animals after oral feeding and intraperitoneal (i.p.) injection, which are two other major drug administration routes, remain unclear. Therefore, in this work, we sought to systematically investigate in vivo biodistribution and potential toxicity of as-made GO and a number of polyethylene glycol (PEG) functionalized GO derivatives with different sizes and surface coatings, after oral and intraperitoneal administration at high doses. It is found that (125)I labeled PEGylated GO derivatives show no obvious tissue uptake via oral administration, indicating the rather limited intestinal adsorption of those nanomaterials. In contrast, high accumulation of PEGyalted GO derivatives, but not as-made GO, in the reticuloendothelial (RES) system including liver and spleen is observed after i.p. injection. Further investigations based on histological examination of organ slices and hematological analysis discover that although GO and PEGylated GO derivatives would retain in the mouse body over a long period of time after i.p. injection, their toxicity to the treated animals is insignificant. Our work is an important fundamental study that offers a deeper understanding of in vivo behaviors and toxicology of functionalized nano-graphene in animals, depending on their different administration routes. PMID- 23340198 TI - Effects of exercise interventions on peripheral vascular endothelial vasoreactivity in patients with heart failure with reduced ejection fraction. AB - Changes in vascular function, such as endothelial dysfunction are linked to the progression of heart failure (HF) and poorer outcomes, such as increased hospitalisations. Exercise training may positively influence endothelial function in HF patients with reduced ejection fraction. The aim of this manuscript is to summarise HF studies evaluating the influence of exercise training on endothelial function as measured by flow mediated vasodilation as a primary outcome and to provide recommendations for future research studies designed to improve peripheral vascular function in HF. Databases were searched for studies published between 1995 and December 2011. Two reviewers determined eligibility and extracted information on study characteristics and quality, exercise interventions, and endothelial function. Eleven articles (N=318 HF participants with an ejection fraction <40%) were eligible for full review. Aerobic, resistance, or combined exercise training improved endothelium-dependent vasodilation as measured by ultrasound or plethysmography. There is less evidence supporting improvement in endothelium-independent function with exercise training. Sample sizes were small and predominantly male. Future research is needed to address the best mode and optimal dose of exercise for all patients with HF including women and subgroups with specific co-morbidities. PMID- 23340199 TI - Relationship of cellular topoisomerase IIalpha inhibition to cytotoxicity and published genotoxicity of fluoroquinolone antibiotics in V79 cells. AB - Fluoroquinolone (FQ) antibiotics are bacteriocidal through inhibition of the bacterial gyrase and at sufficient concentrations in vitro, they can inhibit the homologous eukaryotic topoisomerase (TOPO) II enzyme. FQ exert a variety of genotoxic effects in mammalian systems through mechanisms not yet established, but which are postulated to involve inhibition of TOPO II enzymes. To assess the relationship of inhibition of cell nuclear TOPO II to cytotoxicity and reported genotoxicity, two FQ, clinafloxacin (CLFX) and lomefloxacin (LOFX), having available genotoxicity data showing substantial differences with CLFX being more potent than LOFX, were selected for study. The relative inhibitory activities of these FQ on nuclear TOPO IIalpha in cultured Chinese hamster lung fibroblasts (V79 cells) over dose ranges and at equimolar concentrations were assessed by measuring nuclear stabilized cleavage complexes of TOPO IIalpha-DNA. Cytotoxicity was measured by relative cell counts. Both FQ inhibited V79 cell nuclear TOPO IIalpha. The lowest-observed-adverse-effect levels for TOPO IIalpha inhibition were 55 MUM for CLFX, and 516 MUM for LOFX. The no-observed-adverse-effect-levels were 41 MUM for CLFX, and 258 MUM for LOFX. At equimolar concentrations (175 MUM), CLFX was more potent than LOFX. Likewise, CLFX was more cytotoxic than LOFX. Thus, the two FQ, inhibited TOPO IIalpha in intact V79 cells, differed in their potencies and exhibited no-observed-adverse-effect levels. These findings are in concordance with published genotoxicity data and observed cytotoxicity. PMID- 23340200 TI - The LRRK2 G2019S mutation in a series of Argentinean patients with Parkinson's disease: clinical and demographic characteristics. AB - OBJECTIVES: To determine clinical characteristics and frequency of leucine-rich repeat kinase 2 gene (LRRK2) mutations in a cohort of patients with Parkinson's disease (PD) from Argentina. BACKGROUND: Variation in the LRRK2 gene represents the most common genetic determinant of PD, only few data are available from Latin America. DESIGN/METHODS: Informed consent was obtained and all studies were approved by the Institutional Review Boards. Fifty five consecutive PD patients were recruited. A structured interview and neurological examination were used to collect demographic and clinical information. Blood samples were obtained and DNA extracted from patient venous blood. All LRRK2 exons from 25 exon to 51 exon were screened in all patients. RESULTS: Clinical and molecular data of 55 patients with PD were analyzed. Mean age was 68.8+/-10.6 years. Jewish and Basque ancestries were found positive in 9 and 7 patients, respectively; family history of PD was identified in 16 patients. The G2019S mutation was present in 3 Ashkenazi Jewish subjects (5.45%); all of them reported family history of PD in first-degree relatives. Although Argentina possesses one of the most important Basque communities outside Spain, non R1414G mutation was identified in this cohort. Eleven single polymorphisms (SNP) were identified in this cohort. The mean age at onset was higher in G2019S mutation carriers than non-carriers (66.67 vs 58.78 years). Asymmetrical tremor as initial symptom and non-motor symptoms occurred at similar frequencies in both groups. The G2019S mutation carriers showed a non significant increase in dyskinesias, and 2/3 developed Dopamine Dysregulation Syndrome and visual hallucinations. Systemic disorder identified in G2019S mutation carriers included: celiac disease, hypothyroidism, Hashimoto's Thyroiditis and arterial hypertension. CONCLUSIONS: The prevalence of LRRK2 G2019S mutation in this Argentinean cohort was similar to other international series, with a higher prevalence in Ashkenazi Jewish. The phenotype was indistinguishable from patients with idiopathic PD. Interestingly, we identified immune mediated disorders in two PD patients carrying the G2019S mutation. Within this context, recent studies have identified full-length LRRK2 as a relatively common constituent of many cell types in the immune system including human peripheral blood mononuclear cells. Nevertheless, a casual association could not be excluded and the analysis of more extensive series is required. PMID- 23340201 TI - New nicotinic analogue ZY-1 enhances cognitive functions in a transgenic mice model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive loss of memory and cognitive function. One of the new approaches for treating AD is direct stimulation of nicotinic acetylcholine receptors (nAChRs) in the brain. alpha4beta2-nAChR agonists have shown promising potential in preclinical cognition models of AD. The present report describes the pharmacological properties of ZY-1, a new nicotinic analogue that activates alpha4beta2-nAChR. We describe in detail the binding profile and pharmacological effects of ZY-1 on transgenic AD mice. ZY-1 has high affinity to alpha4beta2-nAChR. In a Morris water maze test, ZY-1 significantly decreases the escape latency and increases both the times in the platform quadrant and the times of platform crossing of transgenic mice. ZY-1 enhances cognitive functions in transgenic mice models of AD. As a novel nicotinic analogue, ZY-1 deserves further study as a potential candidate against AD. PMID- 23340202 TI - VI nerve palsy after intravenous immunoglobulin in Kawasaki disease. PMID- 23340204 TI - Association of sociodemographic and nutritional factors with risk of neural tube defects in the North Indian population: a case-control study. AB - OBJECTIVE: To assess the role of sociodemographic and nutritional factors in the incidence of births affected by neural tube defects (NTD) in the North Indian population. DESIGN: Case-control study. SETTING: Government hospitals of Delhi, India. SUBJECTS: Subjects comprised 284 mothers of NTD children (cases) and 568 mothers of healthy children (controls). RESULTS: Significant differences were found between case and control mothers with respect to maternal age (P = 0.005), type of drinking water (P = 0.03) and consumption of milk (P = 0.01). Univariate and multivariate analysis suggested an association of unpasteurized milk use, low consumption of vegetables, low consumption of fruits and vegetarian dietary habits with NTD births. Further, variation in the risk factors for upper and lower NTD types was also observed, pointing towards phenotypic heterogeneity in the aetiology. CONCLUSIONS: The results of the present study suggest an increased risk of NTD infants in mothers with low consumption of vegetables, fruits and milk and having vegetarian dietary habits. So, in order to reduce these devastating birth defects in future offspring, better nutritional care should be provided to mothers by suggesting dietary modifications and augmenting additional micronutrient supplementation during the periconceptional period. PMID- 23340203 TI - Prospective study of alcohol consumption and the incidence of the metabolic syndrome in US men. AB - Few studies have evaluated the effects of alcohol consumption on the incidence of the metabolic syndrome (MetS). Therefore, the objective of the present study was to examine the association between alcohol consumption and incident MetS in a population of US men. This is a prospective study of 7483 Caucasian men, who were free of the MetS and CVD at baseline. Information was collected on alcohol consumption, health status and fitness level at an initial clinical examination. Additional health information and determination of incident cases of the MetS were obtained at follow-up clinical examinations between 1979 and 2005. Compared with non-drinkers, the multivariate hazard ratios of the MetS for light (1-3 drinks/week), moderate (4-7 drinks/week), moderate-heavy (8-13 drinks/week) and heavy ( >= 14 drinks/week) drinkers were 0.81 (95 % CI 0.68, 0.95), 0.68 (95 % CI 0.57, 0.80), 0.70 (95 % CI 0.59, 0.83) and 0.78 (95 % CI 0.66, 0.91), respectively. This association was seen across age groups, in men with one or more pre-existing MetS risk factors, and those with BMI >= 25 kg/m2, and in all alcohol beverage types at most levels of alcohol consumption. An inverse dose response association between alcohol consumption and low HDL concentrations was observed, while significant associations were observed between high fasting glucose concentrations and moderate, moderate-heavy and heavy levels of alcohol consumption. Alcohol consumption was not significantly associated with central obesity, hypertriacylglycerolaemia or hypertension. All levels of alcohol consumption provided significant inverse associations with incidence of the MetS. In particular, this effect was observed in overweight and/or obese individuals, in those who had pre-existing risk factors for the MetS, and extended across all types of alcoholic beverages consumed. PMID- 23340205 TI - The role of loop closure propensity in the refolding of Rop protein probed by molecular dynamics simulations. AB - Rop protein is a homo-dimer of helix-turn-helix and has relatively slow folding and unfolding rates compared to other dimeric proteins of similar size. Fluorescence studies cited in literature suggest that mutation of turn residues D30-A31 to G30-G31 (Gly2) increases its folding and unfolding rates considerably. A further increase in number of glycines in the turn region results in decrease of folding rates compared to Gly2 mutant. To understand the effect of glycine mutation on folding/unfolding rates of Rop and the conformational nature of turn region involved in formation of early folding species, we performed molecular dynamics simulations of turn peptides, 25KLNELDADEQ34 (DA peptide), 25KLNELGGDEQ34 (G2 peptide), 25KLNELGGGDEQ35 (G3 peptide) and 25KLNELGGGEQ34 (G3(') peptide) from Rop at 300 K. Further Wt-Rop and mutant G2-Rop monomers and dimers were also studied separately by molecular dynamics simulations. Our results show that glycine based peptides (G(n) peptides) have a higher loop closure propensity compared to DA. Comparison of monomeric and dimeric Rop simulations suggests that dimeric Rop necessarily requires alpha(L) conformation to be sampled at D30/G30 position in the turn region. Since glycine (at position 30) can readily adopt alpha(L) conformation, G(n) loop plays a dual role in both facilitating loop closure as well as facilitating reorganization/packing of helices required for structural adjustment during dimer formation in the folding of Rop. Based on our simulation results and available literature, we suggest a tentative kinetic model for Rop folding which allows us to estimate the contribution of loop closure propensity to the overall folding rates. PMID- 23340206 TI - Bilateral giant extracranial carotid artery aneurysms. AB - Extracranial carotid artery aneurysms (ECAAs) are rare and extremely challenging disease entities. Untreated ECAAs can lead to serious neurologic sequelae, primarily from thromboembolism. Because of the high incidence of major neurologic complications, surgical intervention is warranted in most cases. We report a 63 year-old woman with voice fatigue and difficulty swallowing. Upon work-up, we discovered bilateral giant ECAAs and treated them with a combination of aneurysmectomy, primary anastomosis, and an interposition polytetrafluoroethylene graft. Unique features of the aneurysms include their unprecedented size and bilaterality, which is exceedingly rare. PMID- 23340207 TI - TAF7: traffic controller in transcription initiation. AB - TAF7, a component of the TFIID complex, controls the first steps of transcription. It interacts with and regulates the enzymatic activities of transcription factors that regulate RNA polymerase II progression. Its diverse functions in transcription initiation are consistent with its essential role in cell proliferation. PMID- 23340208 TI - Double strand breaks: hurdles for RNA polymerase II transcription? AB - DNA lesions pose a physical obstacle to DNA-dependent cellular transactions such as replication and transcription. A great deal is known regarding RNA polymerase II (RNAP II) transcription stalling in the presence of lesions induced by UV, but recent studies have uncovered previously uncharacterized behavior of the RNAP II machinery in the presence of double strand breaks (DSBs). These new data, although contradictory, contribute to our understanding of a vital cellular mechanism that defends against the production of aberrant transcripts and protects cell viability. PMID- 23340210 TI - P2X7 receptor and cytokines contribute to extra-territorial facial pain. AB - The whisker pad area (WP) is innervated by the second branch of the trigeminal nerve and experiences allodynia and hyperalgesia following transection of the mental nerve (MN; the third branch of the trigeminal nerve). However, the mechanisms of this extra-territorial pain remain unclear. The ionotropic P2X(7) ATP receptor (P2X(7)) in microglia is known to potentiate, via cytokines, the perception of noxious stimuli, raising the possibility that P2X(7) and cytokines are involved in this extra-territorial pain. One day after MN transection (MNT), WP allodynia/hyperalgesia developed, which lasted for > 8 wks. Activation of microglia and up-regulation of P2X(7), membrane-bound tumor necrosis factor (TNF) alpha (mTNF-alpha), and soluble TNF-alpha (sTNF-alpha) in the trigeminal sensory nuclear complex (TNC) were evident for up to 6 wks after MNT. Allodynia/hyperalgesia after MNT was blocked by intracisternal administration of etanercept, a recombinant TNF-alpha receptor (p75)-Fc fusion protein. Intracisternal A438079, a P2X(7) antagonist, also attenuated allodynia/hyperalgesia and blocked up-regulation of mTNF-alpha and sTNF-alpha in the TNC. We conclude that sTNF-alpha released by microglia following P2X(7) activation may be important in both the initiation and maintenance of extra territorial pain after MNT. PMID- 23340209 TI - Mediator MED23 regulates basal transcription in vivo via an interaction with P TEFb. AB - The Mediator is a multi-subunit complex that transduces regulatory information from transcription regulators to the RNA polymerase II apparatus. Growing evidence suggests that Mediator plays roles in multiple stages of eukaryotic transcription, including elongation. However, the detailed mechanism by which Mediator regulates elongation remains elusive. In this study, we demonstrate that Mediator MED23 subunit controls a basal level of transcription by recruiting elongation factor P-TEFb, via an interaction with its CDK9 subunit. The mRNA level of Egr1, a MED23-controlled model gene, is reduced 4-5 fold in Med23 (-/-) ES cells under an unstimulated condition, but Med23-deficiency does not alter the occupancies of RNAP II, GTFs, Mediator complex, or activator ELK1 at the Egr1 promoter. Instead, Med23 depletion results in a significant decrease in P-TEFb and RNAP II (Ser2P) binding at the coding region, but no changes for several other elongation regulators, such as DSIF and NELF. ChIP-seq revealed that Med23 deficiency partially reduced the P-TEFb occupancy at a set of MED23-regulated gene promoters. Further, we demonstrate that MED23 interacts with CDK9 in vivo and in vitro. Collectively, these results provide the mechanistic insight into how Mediator promotes RNAP II into transcription elongation. PMID- 23340211 TI - Occlusal effects on longitudinal bone alterations of the temporomandibular joint. AB - The pathological changes of subchondral bone during osteoarthritis (OA) development in the temporomandibular joint (TMJ) are poorly understood. In the present study, we investigated the longitudinal alterations of subchondral bone using a rat TMJ-OA model developed in our laboratory. Changes in bone mass were examined by micro-CT, and changes in osteoblast and osteoclast activities were analyzed by real-time PCR, immunohistochemistry, and TRAP staining. Subchondral bone loss was detected from 8 weeks after dental occlusion alteration and reached the maximum at 12 weeks, followed by a repair phase until 32 weeks. Although bone mass increased at late stages, poor mechanical structure and lower bone mineral density (BMD) were found in these rats. The numbers of TRAP-positive cells were increased at 12 weeks, while the numbers of osteocalcin-expressing cells were increased at both 12 and 32 weeks. Levels of mRNA expression of TRAP and cathepsin K were increased at 12 weeks, while levels of ALP and osteocalcin were increased at both 12 and 32 weeks. These findings demonstrated that there is an active bone remodeling in subchondral bone in TMJs in response to alteration in occlusion, although new bone was formed with lower BMD and poor mechanical properties. PMID- 23340212 TI - Monomer-collagen interactions studied by saturation transfer difference NMR. AB - Functional monomers in dentin adhesives are involved in wetting dental substrates, demineralization, and the formation of calcium salts. However, the interaction of these monomers with collagen is not understood at a molecular/atomic level. We performed saturation transfer difference (STD) NMR spectroscopy to investigate the binding interaction of 2 functional monomers, 4 methacryloyloxyethyl trimellitate anhydride (4-META) and 10-methacryloyloxydecyl dihydrogenphosphate (MDP), with atelocollagen as a triple-helical peptide model. High STD intensities were detected on the protons in the aliphatic region in MDP, whereas they were not detected for 4-META. The STD results imply that MDP has a relatively stable interaction with the collagen, because of the hydrophobic interactions between the hydrophobic MDP moieties and the hydrophobic collagen surface. This finding indicates that MDP-collagen complexation accounts for stable dentin bonding. PMID- 23340213 TI - Outcome prediction in pregnancies of unknown location using endometrial thickness measurement: is this of real clinical value? AB - OBJECTIVE: To re-evaluate the role of measuring endometrial thickness (ET) in prediction of intrauterine pregnancy (IUP) among women with pregnancy of unknown location (PUL). STUDY DESIGN: 987 women with PUL were included in a prospective observational multicenter study. Transvaginal ultrasonography was performed to measure ET and a blood sample was taken to measure serum beta-hCG and progesterone levels. All patients were then managed expectantly till the final PUL outcome was diagnosed. RESULTS: 78 patients (8.9%) were finally diagnosed as having IUP. The best cutoff point of ET as a possible predictor for IUP was 10mm, with an area under receiver-operating characteristic (ROC) curve of 69.0%. At this cutoff point, ET was able to predict IUP with positive likelihood ratio (PLR) and negative likelihood ratio (NLR) of 1.43 and 0.19, respectively. Serum progesterone at a cutoff point of 50 nmol/L was able to predict IUP with PLR and NLR of 9.0 and 0.06, respectively. Variables showing statistically significant differences among those with IUP and those with the other PUL outcomes using univariate analysis (ET, gestational age, beta-hCG, parity, serum progesterone and maternal age) were entered into logistic regression analysis. Logistic regression models were constructed. The performance of these models was better than using ET alone to predict the outcome of PUL. CONCLUSION: Measurement of ET is not recommended as a single clinical test for intrauterine pregnancy prediction in women with pregnancy of unknown location. PMID- 23340214 TI - Retroperitonoscopic pyelopexy for pelviureteral junction obstruction with crossing vessel in adolescents: Hellstrom principle revisited. AB - OBJECTIVE: To present our new approach using a minimally invasive technique for the management of pelviureteral junction (PUJ) obstruction with a crossing vessel. MATERIALS AND METHODS: In December 2009 to December 2011, out of 23 cases of retroperitoneoscopic laparoscopic pyeloplasty, four adolescents presenting with PUJ obstruction due to an aberrant crossing vessel, with intermittent attacks of renal colic and mild dilatation of the renal pelvis and calyces, were operated by retroperitoneoscopic pyelopexy. A retroperitoneoscopic approach was used in all patients using three trocars. After dissection of the PUJ from the anterior crossing vessel, and ensuring good funneling of the PUJ that proved to show mild dilatation, an interrupted 3/0 polyglycolic suture was used to fix the renal pelvis to the psoas muscle away from the crossing vessel (pyelopexy). A retrograde DJ stent was placed at the end of the procedure. RESULTS: The four patients had a mean age of 18.25 years (16-20): 2 males and 2 females, two right sided and two left sided. Average operative time was 46 min (40-55). All patients were discharged on the same day. No intraoperative complications were encountered. The DJ stent was removed 6 weeks postoperatively. After a mean follow up of 2.125 years (6 months-3 years) no recurrences were observed. CONCLUSION: Retroperitoneoscopic pyelopexy is shown to be a reliable, effective, safe and minimally invasive technique for the management of PUJ obstruction with a crossing vessel in selected cases. Long-term follow up is needed to assess any recurrence or development of complications. PMID- 23340215 TI - Metabolic syndrome and chronic kidney disease. AB - PURPOSE OF REVIEW: The association of the metabolic syndrome (MetS) with cardiovascular risk, mortality, type 2 diabetes mellitus, stroke, nonfatty liver disease and gout is well known. However, the association of the MetS with chronic kidney disease (CKD) is now emerging. This review discusses the epidemiology, pathology and potential mechanisms for the relationship of MetS with CKD. RECENT FINDINGS: Studies show that patients with MetS have a 2.5-fold higher risk of developing CKD. The risk of microalbuminuria is also increased two-fold in the MetS. Renal dysfunction becomes apparent long before the appearance of hypertension or diabetes in MetS. Compared with healthy controls, patients with MetS have increased microvascular disease-tubular atrophy, interstitial fibrosis, arterial sclerosis and global and segmental sclerosis. Studies suggest that the renal fibrosis seen in MetS might be caused by a constellation of insulin resistance, hypertension, dyslipidemias and inflammation, and result in a heightened expression of adipocytokines, angiotensin and inflammatory cytokines such as interleukin-6 and tumour necrosis factor-alpha. SUMMARY: Despite the strong association of MetS with CKD, a causal relationship has not been proven. More studies are needed to precisely elucidate the mechanisms that might lead upstream factors such as insulin resistance, hypertension, dyslipidemia and inflammation to cause renal fibrosis. PMID- 23340216 TI - Recent insights into life expectancy with and without dialysis. AB - PURPOSE OF REVIEW: Elderly patients comprise the fastest growing population initiating dialysis and also experience the worst outcomes, including increased mortality, loss of functional status, and impaired quality of life. Nephrologists are often challenged with how best to engage in dialysis decision-making discussions within this population. Prognostication tools can assist nephrologists in engaging in these discussions, especially in patients for whom survival benefits may be outweighed by the burdens of treatment. RECENT FINDINGS: This review includes the latest research in the survival of elderly patients with and without dialysis; prognostic factors associated with renal progression and survival; and integrative prognostic models to predict both short-term and long term prognosis. The concept of kidney illness disease trajectory is defined with important outcomes including survival, health-related quality of life, and symptoms with and without dialysis. This prognostic information will then be integrated into an individualized approach to shared decision-making regarding treatment decision-making.(Figure is included in full-text article.) SUMMARY: Treatment decision-making for elderly patients with advanced kidney disease necessitates an active process between nephrologist and patient, incorporating medical information as well as patient preferences. Prognostic information and observational data can facilitate nephrologists' ability to foresee and foretell the illness trajectory both with and without dialysis, further guiding these conversations. PMID- 23340217 TI - Effects of Sn doping on the growth morphology and electrical properties of ZnO nanowires. AB - This study examines the effects of doping ZnO nanowires (NWs) with Sn on the growth morphology and electrical properties. ZnO NWs with various Sn contents (1 3 at.%) were synthesized using the vapor-liquid-solid method. Scanning electron and transmission electron microscopy analyses showed that all of the Sn-doped NWs grew in a bamboo-like morphology, in which stacking faults enriched with Sn were periodically inserted. We fabricated a hybrid film of InZnO sol-gel and Sn-doped ZnO NW networks to characterize the effects of Sn doping on the electrical properties of the NWs. With increasing doping density, the carrier concentration increases significantly while the mobility decreases greatly. The resistivity remains scattered, which suggests that Sn doping in ZnO is not an effective method for the enhancement of conductivity, since Sn does not readily incorporate into the ZnO structure. PMID- 23340218 TI - Glucocorticoids reduce intracellular calcium concentration and protects neurons against glutamate toxicity. AB - Glucocorticoids are steroid hormones which act through the glucocorticoid receptor. They regulate a wide variety of biological processes. Two glucocorticoids, the naturally occurring corticosterone and chemically produced dexamethasone, have been used to investigate the effect of glucocorticoids on Ca(2+)-signalling in cortical co-cultures of neurons and astrocytes. Dexamethasone and to a lesser degree corticosterone both induced a decrease in cytosolic Ca(2+) concentration in neurons and astrocytes. The effect of both compounds can be blocked by inhibition of the plasmamembrane ATPase, calmodulin and by application of a glucocorticoid receptor antagonist, while inhibition of NMDA receptors or the endoplasmic reticulum calcium pump had no effect. Glucocorticoid treatment further protects against detrimental calcium signalling and cell death by modulating the delayed calcium deregulation in response to glutamate toxicity. At the concentrations used dexamethasone and corticosterone did not show cell toxicity of their own. Thus, these results indicate that dexamethasone and corticosterone might be used for protection of the cells from calcium overload. PMID- 23340219 TI - Mechanisms of vasorelaxation induced by oleoylethanolamide in the rat small mesenteric artery. AB - The actions of the anandamide-like mono-unsaturated fatty acid oleoylethanolamide (OEA) were first linked to satiety and control of food intake and recently reported to relax resistance vessels. This study characterizes its vasorelaxant mechanisms. Vasorelaxation to OEA were assessed in third order branches of rat superior mesenteric artery using a wire myograph. The roles of the endothelium, KCa channels, perivascular sensory nerves, NO, cannabinoid receptors, and the phospholipase C (PLC)/inositol trisphosphate (InsP3) and RhoA/ROCK signalling pathways, were assessed. OEA caused concentration- and endothelium-dependent vasorelaxation (pEC50=6.7+/-0.1, Rmax=93.1+/-2.5%). L-NAME greatly reduced the response (residual relaxation of only 24.6+/-12.8%). Capsaicin and pertussis toxin significantly reduced the vasorelaxation. Precontraction with KCl abolished the response. TRAM-34 had no effect, but both iberiotoxin and apamin+charybdotoxin markedly shifted the OEA concentration-response curve to the right (~5-fold). O-1918 but not rimonabant attenuated the vasorelaxation. Both the CB1 receptor antagonist, AM251 and the CB2 receptor antagonist, AM630, given alone or in combination, reduced the response to OEA. Inhibition of PLC by U73122, ROCK by Y-27632 and antagonism of inositol trisphosphate (InsP3) receptors by 2-APB abolished OEA vasorelaxation. OEA vasorelaxation involves an endothelial site of action but not the known cannabinoid receptors. It involves Ca(2+) released from InsP3-sensitive endothelial stores by mechanisms involving RhoA kinase and phospholipase C. It is likely that the released Ca(2+) causes NO generation and opening of mainly large-conductance KCa channels. This study demonstrates a possible novel endothelial target that might be important in the control of regional blood flow induced by this lipid molecule. PMID- 23340220 TI - Modulation by 17beta-estradiol of anandamide vasorelaxation in normotensive and hypertensive rats: a role for TRPV1 but not fatty acid amide hydrolase. AB - Recent studies suggest that endocannabinoid signaling is modulated by 17beta estradiol (17Ebeta) however it is unclear if this applies to the cardiovascular actions of anandamide, a major endocannabinoid. This study examined the in vitro effects of 17Ebeta on vasorelaxation to anandamide in myograph-mounted small mesenteric arteries obtained from Wistar rats and Spontaneously Hypertensive Rats (SHRs) of both sexes. Treatment with 1MUM 17Ebeta but not its enantiomer 17Ealpha significantly enhanced relaxation to anandamide in male Wistar rats. This effect was independent of a functional endothelium but was blocked by the Transient Receptor Potential Vanilloid type 1 (TRPV1) receptor antagonist SB366791 (2MUM) or prolonged treatment with the TRPV1 agonist capsaicin (10MUM). A TRPV1 dependent potentiation by 17Ebeta was also observed in male SHRs, but not in female Wistar rats or female SHRs. Whilst inhibition of anandamide hydrolysis by 1MUM URB597 (an inhibitor of fatty acid amide hydrolase; FAAH) similarly augmented anandamide relaxation in male, but not female, Wistar rats and SHRs, URB597 did not affect the 17Ebeta-induced potentiation. Female SHRs displayed a larger maximal relaxation to anandamide; however sex difference was not found in Wistar rats. We conclude that pharmacological levels of 17Ebeta potentiate mesenteric relaxation to anandamide through mechanisms dependent on TRPV1 receptors but not FAAH-mediated hydrolysis in male Wistar rats and male SHRs. Sexual dimorphism was observed in the modulatory effects of 17Ebeta and URB597, which does not necessarily lead to a greater anandamide response in female rats. PMID- 23340221 TI - Correlations between behavioural and oxidative parameters in a rat quinolinic acid model of Huntington's disease: protective effect of melatonin. AB - The present study was designed to examine the correlations between behavioural and oxidative parameters in a quinolinic acid model of Huntington's disease in rats. The protective effect of melatonin against the excitotoxicity induced by quinolinic acid was investigated. Rats were pre-treated with melatonin (5 or 20mg/kg) before injection of quinolinic acid (240nmol/site; 1MUl) into their right corpora striata. The locomotor and exploratory activities as well as the circling behaviour were recorded. The elevated body swing test was also performed. After behavioural experiments, biochemical determinations were carried out. Melatonin partially protected against the increase of circling behaviour caused by quinolinic acid injection. No alteration was found in the number of crossings and rearings of animals treated with melatonin and/or quinolinic acid. Melatonin decreased the percentage of contralateral biased swings induced by quinolinic acid. Melatonin protected against the increase in reactive species and protein carbonyl levels as well as the inhibition of superoxide dismutase activity resulting from quinolinic acid injection. Melatonin was partially effective against the inhibition of striatal catalase activity and a decrease of non-protein thiol levels induced by quinolinic acid. Melatonin was not effective against the inhibition of Na(+), K(+) ATPase activity caused by quinolinic acid injection. There were significant correlations between circling behaviour and oxidative parameters. The antioxidant property of melatonin is involved, at least in part, in its neuroprotective effect. The results reinforce the idea that melatonin could be useful in overwhelming neurotoxicity caused by quinolinic acid, a rat model of Huntington's disease. PMID- 23340222 TI - Involvement of prostacyclin and potassium channels in the diabetes-induced hyporeactivity of the rabbit carotid artery to B-type natriuretic peptide. AB - The relation between diabetes and stroke is bidirectional: diabetes is an important risk factor for ischemic stroke, and acute stroke frequently induces hyperglycemia. On the other hand, plasma B-type natriuretic peptide (BNP) levels are raised in diabetes and stroke. The purpose was to study how alloxan-induced diabetes might modify the effects of BNP in rabbit carotid arteries and the mechanisms involved in such actions. To do this, isometric tension in isolated rabbit carotid artery was recorded and prostanoids release and plasma NT-proBNP were measured by enzyme immunoassay. BNP induced a relaxation of phenylephrine precontracted carotid arteries, and this relaxation was lower in diabetic than in control rabbits. Endothelium removal did not modify the relaxation to BNP in control rabbits but increased this relaxation in diabetic rabbits. In control rabbits, indomethacin inhibited the BNP-induced relaxation in the presence and in the absence of endothelium. In diabetic rabbits, indomethacin did not modify the BNP-induced relaxation in arteries with endothelium and inhibited it in arteries without endothelium. In the presence of BNP the carotid artery released thromboxane A2 and prostacyclin, and the release of endothelial prostacyclin was inhibited in diabetic rabbits. Glibenclamide and 4-aminopyridine inhibited the relaxation to BNP, and these inhibitions were lower in diabetic than in control rabbits. In conclusion, our results provide a new understanding concerning the mechanisms of the diabetes-induced hyporeactivity of the carotid artery to BNP, that at least include the loss of endothelial prostacyclin and a reduced participation of ATP-sensitive K(+) channels (KATP) and voltage-sensitive K(+) channels (KV). PMID- 23340223 TI - Nicotine-morphine interactions at alpha4beta2, alpha7 and alpha3(*) nicotinic acetylcholine receptors. AB - Nicotine and opioids share several behavioral and rewarding properties. Although both opioids and nicotine have their own specific mechanism of action, there is empirical and experimental evidence of interactions between these drugs. We studied receptor-level interactions of nicotine and morphine at alpha4beta2, alpha7 and alpha3(*) nicotinic acetylcholine receptors. [(3)H]epibatidine displacement was used to determine if morphine binds competitively to nicotinic acetylcholine receptors. Functional interactions of morphine and nicotine were studied with calcium fluorometry and (86)Rb(+) efflux assays. Morphine displaced [(3)H]epibatidine from nicotinic agonist binding sites in all cell lines studied. The Ki values for morphine were 13.2MUM in SH-EP1-halpha4beta2 cells, 0.16MUM and 126MUM in SH-SY5Y cells and 43.7MUM in SH-EP1-halpha7 cells. In SH-EP1 halpha4beta2 cells expressing alpha4beta2 nicotinic acetylcholine receptors, morphine acted as a partial agonist of (86)Rb(+) efflux comparable to cytisine (with EC50 values of 53.3MUM for morphine and 5.38MUM for cytisine). The effect of morphine was attenuated concentration-dependently by the nicotinic antagonist mecamylamine. In the SH-SY5Y cell line expressing several subtypes of nicotinic acetylcholine receptors morphine had an inhibitory effect on nicotine induced (86)Rb(+) ion efflux mediated by alpha3(*) nicotinic acetylcholine receptors. These results suggest that morphine acts as a partial agonist at alpha4beta2 nicotinic acetylcholine receptors and as a weak antagonist at alpha3(*) nicotinic acetylcholine receptors. PMID- 23340224 TI - Investigation of signalling cascades induced by neurotrophic synaptolepis factor K7 reveals a critical role for novel PKCepsilon. AB - This study elucidates signalling cascades involved in the neurotrophic effects induced by an active compound of Synaptolepis kirkii, a plant that is used against snakebites and for treatment of epilepsy. The active compound of this plant, synaptolepis factor K7 (K7), is suggested to exert anti-tumoral and neurotrophic actions via modulation of PKC. In SH-SY5Y cells synthesis of the neuronal marker growth-associated protein 43 was increased upon 48h treatment with K7. Immunofluorescent staining of neurites revealed an increased neurite formation by synaptolepis factor K7. Short-term signal transduction events were followed at the level of extracellular-regulated kinase phosphorylation. Extracellular-regulated kinase (ERK) phosphorylation was transiently increased upon stimulation with synaptolepis factor K7 (300nM) with a maximal effect at 30min. Use of the general PKC inhibitor bisindolylmaleimide I blocked the K7 induced ERK phosphorylation suggesting involvement of PKC. Conversely, inhibition of conventional PKCs, alpha, beta and gamma by treatment with Go6976 did not inhibit ERK phosphorylation up to 1MUM. Use of a specific-PKCepsilon translocation inhibitor peptide or RNAi-mediated knockdown of PKC-epsilon (epsilon) abolished the K7-induced ERK phosphorylation implicating PKCepsilon in K7 function. This was confirmed by the observed increase in PKCepsilon translocation and autophosphorylation induced by the compound. These data show that synaptolepis factor K7 induces neuronal differentiation of SH-SY5Y cells concomitant with a transient increase in ERK phosphorylation that is mediated by activation of PKCepsilon. PMID- 23340225 TI - Characterization of human rotaviruses circulating in Iraq in 2008: atypical G8 and high prevalence of P[6] strains. AB - Fecal samples from 976 children with gastroenteritis were collected and analyzed for group A rotavirus (RVA), in three different cities in Iraq between January 2008 and December 2008. RVA antigen was detected in 394 (40%) of the samples, and 98 samples were available for further genotype analyses using multiplex RT-PCR and sequence analyses for untypeable strains. The G/P-genotype combination was determined for 69 samples, and 19, 2 and 8 samples remained P-untypeable, G untypeable and G/P-untypeable (UT), respectively. The most prevalent genotype was G2 (40%, 39/98) most often associated with P[6]. G1 was the second most common genotype (16%, 16/98) mainly associated with P[8] and P[UT]. G3, G4 and G9 were detected at a lower prevalence (3%, 11%, 3%, respectively), mainly associated with P[6]. Surprisingly, five G8P[6], and seven G12 RVA strains in combination with P[6] and P[8] were also detected for the first time in Iraq. Overall, a striking high prevalence of 47% of the analyzed samples possessed the P[6] genotype (65% of the P-typed RVA strains). Atypical genotype combinations such as G1P[4], G1P[6], G2P[8] or strains with mixed G-types were detected sporadically. The detection of unusual G8P[6] RVA strains prompted us to further analyze the NSP2, NSP3, NSP4 and NSP5 gene segments of three selected G8P[6] strains, resulting in their designation to the N2, T2, E2 and H2 genotypes, respectively. The VP7, VP4, NSP2, NSP3 and NSP5 gene segments clustered closely with common human RVA strains, whereas the NSP4 gene sequences were found to cluster with animal derived RVA strains, suggesting a potential reassortment event. The high prevalence of RVA strains with the G8, G12 and P[6] genotypes in combination with a DS-1-like genotype constellation in Iraq, needs to be monitored closely as these RVA strains might challenge the effectiveness of current RVA vaccines. PMID- 23340226 TI - Methicillin-resistant Staphylococcus aureus ST30-SCCmec IVc clone as the major cause of community-acquired invasive infections in Argentina. AB - Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have become a major concern worldwide. We conducted a prospective multicenter study of invasive CA-MRSA to evaluate clinical features and genotype of strains causing invasive infections in Argentina. A total of 55 patients with invasive CA-MRSA infections were included. Most patients (60%) had bloodstream infections, 42% required admission to intensive care unit and 16% died. No CA MRSA isolates were multiresistant (resistant ?3 classes of antibiotics). All isolates carried Panton-Valentine leukocidin (PVL) genes and staphylococcal cassette chromosome (SCCmec) type IV. The majority CA-MRSA strains belonged to ST30 and had identical pulsed-field gel electrophoresis (PFGE) patterns, qualifying as a clonal dissemination of a highly transmissible strain. The main clone recovered from patients with CA-MRSA invasive infections was genotyped as pulsed-field gel electrophoresis type C-ST30, SCCmec type IVc-spa type 019, PVL positive. It has become predominant and replaced the previously described CA-MRSA clone (PFGE type A, ST5, SCCmec type IV, spa type 311). PMID- 23340227 TI - Infective larvae of Cercopithifilaria spp. (Nematoda: Onchocercidae) from hard ticks (Ixodidae) recovered from the Japanese serow (Bovidae). AB - Hard ticks taken from the Japanese serow, Capricornis crispus, in Yamagata Prefecture, Honshu, harboured infective larvae of onchocercid filariae after incubation from the 22nd to the 158th day. Haemaphysalis flava and H. japonica contained one to eight filarial larvae; females, males and a nymph of the ticks were infected. The 44 infective larvae recovered were 612-1,370 MUm long, and 11 of them, 930-1,340 MUm long, were studied in detail. The larvae possessed the morphologic characteristics of the larvae of the genus Cercopithifilaria, namely an oesophagus with a posterior glandular part, no buccal capsule and a long tail with three terminal lappets. Five types (A to E) of infective larvae were identified based on the morphologic characteristics. While to date five species of Cercopithifilaria have been described from the Japanese serow, a specific identification of the larvae found in this study was generally not possible. Only type E larvae could be tentatively assigned to Cercopithifilaria tumidicervicata, as they had a cervical swelling similar to that of the adults of this species. A key for the identification of the five larval types is presented. The study presents circumstantial evidences indicating that H. flava and H. japonica may transmit Cercopithifilaria spp. to Japanese serows. It also suggests the possibility that such filarial larvae will be found in hard ticks anywhere, because Cercopithifilaria is distributed worldwide, though this genus generally goes unnoticed, as its microfilariae occur in the skin, not in the blood, of host animals. PMID- 23340228 TI - Identification of an exported heat shock protein 70 in Plasmodium falciparum. AB - Host cell remodelling is a hallmark of malaria pathogenesis. It involves protein folding, unfolding and trafficking events and thus participation of chaperones such as Hsp70s and Hsp40s is well speculated. Until recently, only Hsp40s were thought to be the sole representative of the parasite chaperones in the exportome. However, based on the re-annotated Plasmodium falciparum genome sequence, a putative candidate for exported Hsp70 has been reported, which otherwise was known to be a pseudogene. We raised a specific antiserum against a C-terminal peptide uniquely present in PfHsp70-x. Immunoblotting and immunofluorescence-based approaches in combination with sub-cellular fractionation by saponin and streptolysin-O have been taken to determine the expression and localization of PfHsp70-x in infected erythrocyte. The re annotated sequence of PfHsp70-x reveals it to be a functional protein with an endoplasmic reticulum signal peptide. It gets maximally expressed at the schizont stage of intra-erythrocytic life cycle. Majority of the protein localizes to the parasitophorous vacuole and some of it gets exported to the erythrocyte compartment where it associates with Maurer's clefts. The identification of an exported parasite Hsp70 chaperone presents us with the fact that the parasite has evolved customized chaperones which might be playing crucial roles in aspects of trafficking and host cell remodelling. PMID- 23340229 TI - High infection rate of zoonotic Eucoleus aerophilus infection in foxes from Serbia. AB - The respiratory capillariid nematode Eucoleus aerophilus (Creplin, 1839) infects wild and domestic carnivores and, occasionally, humans. Thus far, a dozen of human infections have been published in the literature but it cannot be ruled out that lung capillariosis is underdiagnosed in human medicine. Also, the apparent spreading of E. aerophilus in different geographic areas spurs new studies on the epidemiology of this nematode. After the recognition of the first human case of E. aerophilus infection in Serbia, there is a significant merit in enhancing knowledge on the distribution of the nematode. In the present work the infection rate of pulmonary capillariosis was investigated in 70 red foxes (Vulpes vulpes) from the northern part of Serbia by autopsy. The estimated infection rate with Eucoleus aerophilus was 84%. In contrast, by copromicroscopic examination only 38% of foxes were positive. In addition, 10 foxes were investigated for the closely related species in nasal cavity, Eucoleus boehmi, and nine were positive. Our study demonstrates one of the highest infection rates of pulmonary capillariosis in foxes over the world. PMID- 23340231 TI - Clinical value of immunoscintigraphy in the rectal carcinomas: immunoscintigraphy of rectal carcinomas. AB - BACKGROUND/AIM: The aim of this study was to evaluate the clinical reliability of the immunoscintigraphy with radiolabeled monoclonal antibodies for the detection of metastases and recurrences of rectal carcinomas. METHODOLOGY: A total of 65 patients underwent immunoscintigraphy with radiolabeled monoclonal antibodies. Indication for that examination was suspicious rectal cancer or suspicious rectal cancer recurrence and/or metastases. RESULTS: The method proved to have 92.7% sensitivity, specificity 83.3%, positive predictive value 90.5%, negative predictive value 87.0% and accuracy 89.2%. There was a statistically significant relationship between immunoscintigraphy findings and rectoscopy findings (rs=0.415, p=0.013), as well as significant relationship between immunoscintigraphy findings and US findings (rs=0.332, p=0.001). Tumor marker levels were in positive correlation with findings of immunoscintigraphy (rs=0.845, p=0.001), especially raised CEA level (rs=0.816, p=0.004). Patients with higher CA19-9 level had higher Duke's stage (p=0.025). CONCLUSIONS: We can conclude that immunoscintigraphy can be helpful in the detection of metastases and recurrences of colon carcinomas. PMID- 23340232 TI - Histological complete response after neoadjuvant XELOX in advanced gastric carcinoma. AB - We report on a case of a 65-year-old Chinese male with locally advanced gastric adenocarcinoma achieving pathological complete response after neoadjuvant chemotherapy with capecitabine and oxaliplatin (XELOX) regimen. He underwent esophagogastroduodenoscopy, which revealed a 6x5cm gastric ulcer. Biopsy of gastric ulcer revealed adenocarcinoma. Further workups with abdominal enhancement computed tomography (CT) staged his cancer as T4N2M0. He received 2 cycles of neoadjuvant chemotherapy with XELOX without severe toxicity. Afterwards, he underwent curative surgery consisting of total gastrectomy with extended D2 lymph node dissections and a Roux-en-Y esophagojejunostomy. On microscopic examination, no tumor cells were detected in the ulcer scar of the resected stomach and in the regional lymph nodes. The benefit of XELOX regimen as neoadjuvant chemotherapy in gastric cancer is worth further investigation. PMID- 23340233 TI - Recent advances in trauma and reconstructive surgery of the hand and upper extremity. Guest editorial. PMID- 23340234 TI - Effects of chronic passive smoking on the regeneration of rat femoral defects filled with hydroxyapatite and stimulated by laser therapy. AB - Defects associated with bone mass loss are frequently treated by autogenous bone grafting. However, synthetic biomaterials such as calcium phosphate ceramics can substitute autologous grafts as long as they are biocompatible with bone tissue. In addition, low-level laser therapy (LLLT) is used to enhance bone regeneration by stimulating the local microcirculation and increasing the synthesis of collagen by bone cells. However, bone health is fundamental for osseointegration of the graft and bone repair. In this respect, excessive tobacco consumption can compromise expected outcomes because of its deleterious effects on bone metabolism that predispose to the development of osteoporosis. The objective of this study was to evaluate the regeneration of bone defects implanted with biomaterial and stimulated by LLLT in rats submitted to passive cigarette smoking. Porous hydroxyapatite granules were implanted into critical-size defects induced experimentally in the distal epiphysis of the right femur of 20 female Wistar rats submitted to passive smoking for 8 months in a smoking box. The defect site was irradiated with a gallium-arsenide laser at an intensity of 5.0 J/cm2. The animals were divided into four groups: control (non-smoking) rates submitted (G2) or not (G1) to laser irradiation, and smoking rats submitted (G4) or not (G3) to laser irradiation. The animals were sacrificed 8 weeks after biomaterial implantation. The right femurs were removed for photodocumentation, radiographed, and processed for routine histology. The results showed good radiopacity of the implant site and of the hydroxyapatite granules. Histologically, formation of new trabecular bone was observed adjacent to the hydroxyapatite granules in G1 and G2. In G3 and G4, the granules were surrounded mainly by connective tissue. In conclusion, passive smoking compromised bone neoformation in the defects and the LLLT protocol was not adequate to stimulate local osteogenesis. PMID- 23340235 TI - A new surgical treatment for mallet finger deformity: deepithelialised pedicled skin flap technique. AB - INTRODUCTION: Mallet finger, well-known also as drop finger or baseball finger, is a frequent deformity after extensor tendons injury in the fingers. Although numerous nonoperative or operative techniques have been used in managing this deformity, the treatment still remains a debated subject. PATIENTS AND METHODS: Starting from 1996, 121 fingers in 118 patients with neglected deformity or unsuccessful splinting older than 10 days underwent surgical treatment. In 101 patients a tendinous mallet finger was present, and in 20 patients a bony mallet finger. After immobilising the distal interphalangeal (DIP) joint at 0 degrees extension with a Kirschner wire, the extensor tendon was repaired by using a dorsal deepithelialised skin flap reinserted transosseous. The DIP joint was immobilised for 6 weeks in a thermoplastic splint, and after that it was gradually weaned from the immobilisation. An overnight splint was used for 4-6 weeks after starting the mobilisation. RESULTS: The mean follow-up period was 10 months (range: 3-120 months). An excellent result in 89 fingers and a good result in 32 fingers were obtained, according to Crawford's evaluation criteria. CONCLUSION: This method seems to be a new reliable alternative in the treatment of chronic mallet finger. PMID- 23340236 TI - Reconstruction of the thumb amputation at the carpometacarpal joint level by groin flap and second toe transfer. AB - INTRODUCTION: Traumatic loss of thumb at the carpometacarpal (CMC) joint level is very disabling to an individual. Pollicisation is the recommended technique of reconstruction for loss of thumb at this level. On occasions, injury to the rest of the hand or amputation of additional fingers may make pollicisation an impossible option. Microsurgical transfer of second toe is an option in such situations. Although many large series of toe transfers are available in the literature, no series deals exclusively with this subset of patients. MATERIALS AND METHODS: Eight patients who had amputation of the thumb at or proximal to the CMC joint level were reconstructed by second toe transfer by us in the period 2002-2011. All had preliminary groin flap cover in the area of the thumb during the acute stage of treatment. Second toe with the metatarsal was transferred for thumb reconstruction after a mean duration of 3 months after flap cover. Patients were assessed for their ability to pinch, hold large objects and opposition achieved by Kapandji score. Average follow up is 4 years and 6 months with a minimum of 1 year. RESULTS: All toe transfers survived. They reached their maximum functional potential by 1 year. All patients actively used the reconstructed thumb for day to day activities. Pinch was possible in all patients except two patients who did not have any fingers. Six of them registered grip strength of at least 50% of the opposite hand. When fingers were present, opposition was possible in all patients with Kapandji scores ranging from 5 to 8. Extent of usage was less in patients who did not have good function in other fingers. CONCLUSION: Second toe transfer is a viable option for reconstruction of thumb loss at or proximal to the CMC joint level. Proper planning of the preliminary flap cover determines the length of the thumb reconstruction. Strategic position of the transferred toe of adequate length and the functional status of the other fingers are important determinants of functional outcome. PMID- 23340237 TI - The reconstruction of large bone defects in the upper limb. AB - Large bone defects in the upper limb pose many challenges in reconstructive surgery. Conventional and innovative methods have been described, employing the use of microsurgical and non-microsurgical techniques to overcome both bony and soft tissue defects. This article reviews the success and pitfalls of different techniques of reconstruction of large bone defects in the upper limb, including microsurgical transfer of the free vascularised fibula graft as a diaphyseal bone replacement and as a hemivascularised joint transplant, and non-microsurgical options using conventional bone grafting, the induced membrane technique and the role of callotatic distraction-lengthening procedures. PMID- 23340238 TI - Integrated recovery management model for ex-offenders with co-occurring mental health and substance use disorders and high rates of HIV risk behaviors. AB - This paper provides outcomes from an evaluation of a federally funded program combining HIV prevention services with an integrated mental health and substance abuse treatment program to a population of primarily African American ex offenders living with, or at high risk for contracting HIV in Memphis, Tennessee. During the 5-year evaluation, data were collected from 426 individuals during baseline and 6-month follow-up interviews. A subset of participants (n = 341) completed both interviews. Results suggest that the program was successful in reducing substance use and mental health symptoms but had mixed effects on HIV risk behaviors. These findings are important for refining efforts to use an integrated services approach to decrease (a) the effects of substance use and mental health disorders, (b) the disproportionate impact of criminal justice system involvement, and (c) the HIV infection rate in African American ex offenders in treatment. PMID- 23340239 TI - Dualities of living with HIV/HCV co-infection: patients' perspectives from those who are ineligible for or nonresponsive to treatment. AB - In Europe, an estimated 33% of HIV-infected individuals are co-infected with the hepatitis C virus (HCV). The aim of this study was to develop an understanding of the experiences of patients ineligible for or not responding to treatment. Patients attending an HIV/HCV clinic were interviewed. A qualitative design using hermeneutic interpretive phenomenology was employed. Transcripts, field notes, and a reflexive journal were analyzed to extract themes and identify commonalities, differences, and hidden meanings. In line with the duality of co infection, duality was observed in responses. Participants described defining negative moments in their lives that resulted in developing positive health care strategies. Another dichotomy was one of loneliness and of social relationships. Finally, participants described a revival phenomenon, moving from feelings of death to looking forward to unexpected futures. Those working with co-infected patients need to be aware of how duality impacts people who are ineligible for or nonresponsive to treatment. PMID- 23340240 TI - An intervention to decrease intravaginal practices in hiv-infected women in Zambia: a pilot study. AB - Intravaginal practices (IVP) are those in which women introduce products inside the vagina for hygienic, health, or sexuality reasons. IVP are associated with bacterial vaginosis (BV) and potentially implicated in HIV transmission. This report presents the results of a pilot study of a behavioral intervention to decrease IVP in HIV-infected women in Zambia. At baseline, all of the enrolled women (n =40) engaged in IVP and rates of BV were high. Women receiving the intervention reported a decrease of the insertion of water and cloths inside the vagina. Communication with sexual partners regarding IVP was higher for women receiving the intervention. Results from this study suggest that a behavioral intervention could decrease IVP in HIV-infected women in Zambia and this may have an impact in decreasing HIV transmission from women to sexual partners and newborns. PMID- 23340241 TI - Prediagnostic circulating sex hormones are not associated with mortality for men with prostate cancer. AB - BACKGROUND: Sex hormones play an important role in the growth and development of the prostate, and low androgen levels have been suggested to carry an adverse prognosis for men with prostate cancer (PCa). OBJECTIVE: To examine the association between prediagnostic circulating sex hormones and lethal PCa in two prospective cohort studies, the Physicians' Health Study (PHS) and the Health Professionals Follow-up Study (HPFS). DESIGN, SETTING, AND PARTICIPANTS: We included 963 PCa cases (700 HPFS; 263 PHS) that provided prediagnostic blood samples, in 1982 for PHS and in 1993-1995 for HPFS, in which circulating sex hormone levels were assayed. OUTCOME MEASURES AND STATISTICAL ANALYSIS: The primary end point was lethal PCa (defined as cancer-specific mortality or development of metastases), and we also assessed total mortality through March 2011. We used Cox proportional hazards models to evaluate the association of prediagnostic sex hormone levels with time from diagnosis to development of lethal PCa or total mortality. RESULTS AND LIMITATIONS: PCa cases were followed for a mean of 12.0+/-4.9 yr after diagnosis. We confirmed 148 cases of lethal PCa and 421 deaths overall. Using Cox proportional hazard models, we found no significant association between quartile of total testosterone, sex hormone binding globulin (SHBG), SHBG-adjusted testosterone, free testosterone, dihydrotestosterone, androstanediol glucuronide, or estradiol and lethal PCa or total mortality. In subset analyses stratified by Gleason score, TNM stage, age, and interval between blood draw and diagnosis, there was also no consistent association between lethal PCa and sex hormone quartile. CONCLUSIONS: We found no overall association between prediagnostic circulating sex hormones and lethal PCa or total mortality. Our null results suggest that reverse causation may be responsible in prior studies that noted adverse outcomes for men with low circulating androgens. PMID- 23340242 TI - Development and evaluation of a brief questionnaire to assess dietary fat quality in low-income overweight women in the southern United States. AB - OBJECTIVE: To develop a brief questionnaire to assess dietary fat quality, the Dietary Fat Quality Assessment (DFQA), for use in dietary counseling to reduce heart disease risk. METHODS: A subsample of 120 underserved, midlife women enrolled in a randomized, controlled weight loss trial completed baseline and follow-up telephone surveys. Main outcome measures included dietary fat components (total fat, saturated fat, polyunsaturated fat, monounsaturated fat, omega-3 fatty acids, and cholesterol). RESULTS: Assessments of major dietary fat components using the DFQA and a food frequency questionnaire were significantly correlated, with correlation coefficients of 0.54-0.66 (P < .001). Intra-class correlation coefficients to assess reliability ranged from 0.48 to 0.59 for each of the fat components studied. CONCLUSIONS AND IMPLICATIONS: The DFQA provides a reasonable assessment of dietary fat quality associated with coronary heart disease risk and may prove useful as a brief assessment tool to guide dietary counseling given to reduce heart disease risk. PMID- 23340243 TI - Dynamic evolving spiking neural networks for on-line spatio- and spectro-temporal pattern recognition. AB - On-line learning and recognition of spatio- and spectro-temporal data (SSTD) is a very challenging task and an important one for the future development of autonomous machine learning systems with broad applications. Models based on spiking neural networks (SNN) have already proved their potential in capturing spatial and temporal data. One class of them, the evolving SNN (eSNN), uses a one pass rank-order learning mechanism and a strategy to evolve a new spiking neuron and new connections to learn new patterns from incoming data. So far these networks have been mainly used for fast image and speech frame-based recognition. Alternative spike-time learning methods, such as Spike-Timing Dependent Plasticity (STDP) and its variant Spike Driven Synaptic Plasticity (SDSP), can also be used to learn spatio-temporal representations, but they usually require many iterations in an unsupervised or semi-supervised mode of learning. This paper introduces a new class of eSNN, dynamic eSNN, that utilise both rank-order learning and dynamic synapses to learn SSTD in a fast, on-line mode. The paper also introduces a new model called deSNN, that utilises rank-order learning and SDSP spike-time learning in unsupervised, supervised, or semi-supervised modes. The SDSP learning is used to evolve dynamically the network changing connection weights that capture spatio-temporal spike data clusters both during training and during recall. The new deSNN model is first illustrated on simple examples and then applied on two case study applications: (1) moving object recognition using address-event representation (AER) with data collected using a silicon retina device; (2) EEG SSTD recognition for brain-computer interfaces. The deSNN models resulted in a superior performance in terms of accuracy and speed when compared with other SNN models that use either rank-order or STDP learning. The reason is that the deSNN makes use of both the information contained in the order of the first input spikes (which information is explicitly present in input data streams and would be crucial to consider in some tasks) and of the information contained in the timing of the following spikes that is learned by the dynamic synapses as a whole spatio-temporal pattern. PMID- 23340245 TI - The human insula: Architectonic organization and postmortem MRI registration. AB - The human insula has been the focus of great attention in the last decade due to substantial progress in neuroimaging methodology and applications. Anatomical support for functional localization and interpretations, however, is still fragmented. The aim of the present study was to re-examine the microanatomical organization of the insula and relate cytoarchitectonic maps to major sulcal/gyral patterns by registration to high-resolution MR images of the same brains. The insula was divided into seven architectonic subdivisions (G, Ig, Id1 3, Ia1-2) that were charted on unfolded maps of the insula following a method used previously in monkeys. The results reveal overall similar patterns of Nissl, and to some extent also, myelin and parvalbumin (PV), as in monkeys, with a postero-dorsal to antero-ventral gradient of hypergranular to granular, dysgranular and agranular fields. Reversals occur ventrally along the inferior peri-insular sulcus (IPS), at the margin with the temporal operculum, and anteriorly at the limit with orbitofrontal cortex (OFC). A large portion of agranular cortex is characterized by a dense accumulation of the spindle-shaped von Economo neurons (VENs) in layer V. The distribution of VENs is not restricted to agranular insula but also extends into the anterior part of dysgranular fields. The patterns of intracortical myelin and of PV neuropil in the middle layers follow decreasing gradients from postero-dorsal granular to antero-ventral agranular insula, with particularly strong staining in posterior and dorsal insula. A separate PV enhanced area in the middle-dorsal insula corresponds in location to the presumed human gustatory area. Projections of the cytoarchitectonic maps onto high-resolution stereotactic MRI reveal a near concentric organization around the limen insula, with each cytoarchitectonic subdivision encompassing several major insular gyri/sulci. The dysgranular domain is the largest, taking up about half of the insula. The present study of the human insula provides a new anatomical basis for MR imaging and clinical applications. PMID- 23340244 TI - Translational developmental studies of stress on brain and behavior: implications for adolescent mental health and illness? AB - Adolescence is the transition from childhood to adulthood, with onset marked by puberty and the offset by relative independence from parents. Across species, it is a time of incredible change that carries increased risks and rewards. The ability of the individual to respond adequately to the mental, physical and emotional stresses of life during this time is a function of both their early environment and their present state. In this article, we focus on the effects that acute threat and chronic stress have on the brain and behavior in humans and rodents. First, we highlight developmental changes in frontolimbic function as healthy individuals transition into and out of adolescence. Second, we examine genetic factors that may enhance susceptibility to stress in one individual over another using translation from genetic mouse models to human neuroimaging. Third, we examine how the timing and nature of stress varies in its impact on brain and behavior. These findings are discussed in the context of implications for adolescent mental health and illness. PMID- 23340246 TI - The continuing enigma of the fetal echogenic intracardiac focus in prenatal ultrasound. AB - PURPOSE OF REVIEW: The present article aims to review recent literature about intracardiac echogenic foci (ICEFs), with special emphasis in potential causes, relationships with aneuploidy and cardiac function. RECENT FINDINGS: The presence of an ICEF may be considered as a soft marker that may be of interest only in high-risk populations for chromosomal abnormalities. In cases of isolated ICEF in euploid fetuses there is not evidence of an altered cardiac function and a detailed echocardiogram is not recommended as long as the second trimester scan is normal. Cases of fetal myocardial diffuse or multiple calcifications may be related to inflammatory and hypoxic changes in fetal heart, but the relationships between these conditions and isolated ICEF remain unclear. SUMMARY: The origin of ICEF remains unclear. It is considered a normal developmental variant, but either inflammatory or hypoxic processes could be involved in its appearance. In low risk populations for aneuploidy, the presence of an ICEF is not an indication for invasive procedures. In high-risk populations this depends on the previous calculated risk. In euploid fetuses, cardiac function is not significantly altered but further studies in specific populations may be justified. Fetuses with diffuse myocardial calcification or multiple foci may need further investigations. PMID- 23340247 TI - Strategies to reduce maternal mortality in developed countries. AB - PURPOSE OF REVIEW: To review the recent literature regarding maternal mortality, especially in developed countries, and to provide suggestions for clinical action addressing the rising trend. RECENT FINDINGS: Worldwide maternal deaths declined over the past 20 years; however, it is unlikely that the United Nations' Millennium Development Goal 5 for a 75% reduction in maternal mortality by 2015 will be achieved. Ninety-nine percent of the annual preventable maternal deaths from complications of pregnancy and childbirth occur in developing countries, particularly sub-Saharan Africa. In developed countries, including the United States, numerous strategies have developed to recognize the factors leading to maternal death and to implement systems' changes allowing interventions. In many cases, maternal death is avoidable but oftentimes a patient is saddled with life long medical consequences. Near-misses are increasing which place a burden not only on the family but also on the healthcare system and overall community. SUMMARY: The United States has a rising trend in maternal deaths. To achieve a reduction within all developed countries there must be coordinated death review activities that investigate every case along with near-misses. Recommendations for changes within the medical system will continue to improve maternal health not only in developed countries but also worldwide. PMID- 23340248 TI - Polydextrose results in a dose-dependent reduction in ad libitum energy intake at a subsequent test meal. AB - Previous studies have reported that polydextrose can reduce food intake; however, the optimal dose required to achieve this effect is currently unknown. The present study investigated the effects of consuming a range of doses of polydextrose on appetite and energy intake (EI) using a randomised within subject, cross-over design. For this purpose, twenty-one participants (n 12 men, n 9 women) consumed an 837 kJ liquid preload containing 0 g (control), 6.3, 12.5 or 25 g polydextrose. Subjective appetite ratings were collected using visual analogue scales and an ad libitum test meal was served 90 min later. Participants recorded EI for the remainder of the day in a food diary. Test meal EI following the control preload (5756 (sem 423) kJ) was significantly higher than following the 6.3 g (5048 (sem 384) kJ), 12.5 g (4722 (sem 384) kJ) and 25 g (4362 (sem 316) kJ) preloads (P< 0.05), and EI following the 6.3 g preload was significantly higher than following the 25 g preload (P< 0.01). There were no differences in self-reported EI during the remainder of the day between the preloads containing the varying doses of polydextrose. Total EI (breakfast+preload+ad libitum test meal+remainder of the day) was significantly higher when the control preload was consumed (12,051 (sem 805) kJ) compared with either the 12.5 g (10,854 (sem 589) kJ) or 25 g (10,658 (sem 506) kJ) preload (P< 0.05). These differences in EI were not accompanied by corresponding differences in subjective appetite ratings. In summary, polydextrose effectively reduces subsequent EI in a dose-dependent manner. PMID- 23340249 TI - Tyrosyl phosphorylated PAK1 regulates breast cancer cell motility in response to prolactin through filamin A. AB - The p21-activated serine-threonine kinase (PAK1) is activated by small GTPase dependent and -independent mechanisms and regulates cell motility. Both PAK1 and the hormone prolactin (PRL) have been implicated in breast cancer by numerous studies. We have previously shown that the PRL-activated tyrosine kinase JAK2 (Janus tyrosine kinase 2) phosphorylates PAK1 in vivo and identified tyrosines (Tyr) 153, 201, and 285 in the PAK1 molecule as sites of JAK2 tyrosyl phosphorylation. Here, we have used human breast cancer T47D cells stably overexpressing PAK1 wild type or PAK1 Y3F mutant in which Tyr(s) 153, 201, and 285 were mutated to phenylalanines to demonstrate that phosphorylation of these three tyrosines are required for maximal PRL-dependent ruffling. In addition, phosphorylation of these three tyrosines is required for increased migration of T47D cells in response to PRL as assessed by two independent motility assays. Finally, we show that PAK1 phosphorylates serine (Ser) 2152 of the actin-binding protein filamin A to a greater extent when PAK1 is tyrosyl phosphorylated by JAK2. Down-regulation of PAK1 or filamin A abolishes the effect of PRL on cell migration. Thus, our data presented here bring some insight into the mechanism of PRL-stimulated motility of breast cancer cells. PMID- 23340250 TI - Impaired fertility and FSH synthesis in gonadotrope-specific Foxl2 knockout mice. AB - Impairments in pituitary FSH synthesis or action cause infertility. However, causes of FSH dysregulation are poorly described, in part because of our incomplete understanding of mechanisms controlling FSH synthesis. Previously, we discovered a critical role for forkhead protein L2 (FOXL2) in activin-stimulated FSH beta-subunit (Fshb) transcription in immortalized cells in vitro. Here, we tested the hypothesis that FOXL2 is required for FSH synthesis in vivo. Using a Cre/lox approach, we selectively ablated Foxl2 in murine anterior pituitary gonadotrope cells. Conditional knockout (cKO) mice developed overtly normally but were subfertile in adulthood. Testis size and spermatogenesis were significantly impaired in cKO males. cKO females exhibited reduced ovarian weight and ovulated fewer oocytes in natural estrous cycles compared with controls. In contrast, ovaries of juvenile cKO females showed normal responses to exogenous gonadotropin stimulation. Both male and female cKO mice were FSH deficient, secondary to diminished pituitary Fshb mRNA production. Basal and activin-stimulated Fshb expression was similarly impaired in Foxl2 depleted primary pituitary cultures. Collectively, these data definitively establish FOXL2 as the first identified gonadotrope-restricted transcription factor required for selective FSH synthesis in vivo. PMID- 23340251 TI - IGF-I signaling is essential for FSH stimulation of AKT and steroidogenic genes in granulosa cells. AB - FSH and IGF-I synergistically stimulate gonadal steroid production; conversely, silencing the FSH or the IGF-I genes leads to infertility and hypogonadism. To determine the molecular link between these hormones, we examined the signaling cross talk downstream of their receptors. In human and rodent granulosa cells (GCs), IGF-I potentiated the stimulatory effects of FSH and cAMP on the expression of steroidogenic genes. In contrast, inhibition of IGF-I receptor (IGF IR) activity or expression using pharmacological, genetic, or biochemical approaches prevented the FSH- and cAMP-induced expression of steroidogenic genes and estradiol production. In vivo experiments demonstrated that IGF-IR inactivation reduces the stimulation of steroidogenic genes and follicle growth by gonadotropins. FSH or IGF-I alone stimulated protein kinase B (PKB), which is also known as AKT and in combination synergistically increased AKT phosphorylation. Remarkably, blocking IGF-IR expression or activity decreased AKT basal activity and abolished AKT activation by FSH. In GCs lacking IGF-IR activity, FSH stimulation of Cyp19 expression was rescued by overexpression of constitutively active AKT. Our findings demonstrate, for the first time, that in human, mouse, and rat GCs, the well-known stimulatory effect of FSH on Cyp19 and AKT depends on IGF-I and on the expression and activation of the IGF-IR. PMID- 23340252 TI - The endocrine disrupting chemical tolylfluanid alters adipocyte metabolism via glucocorticoid receptor activation. AB - Glucocorticoid signaling plays a critical role in regulating energy metabolism. Emerging data implicate environmental endocrine-disrupting chemicals as contributors to the obesity and diabetes epidemics. Previous studies have shown that the phenylsulfamide fungicide tolylfluanid (TF) augments glucocorticoid receptor (GR)-dependent luciferase expression in 3T3-L1 preadipocytes while modulating insulin action in primary murine and human adipocytes. Studies were performed to interrogate glucocorticoid signaling in primary adipocytes exposed to TF. TF mimicked the gene transcription profile of the murine glucocorticoid corticosterone (Cort). Cellular fractionation assays demonstrated that TF treatment promoted the activating serine phosphorylation of GR, augmenting its cytoplasmic-to-nuclear translocation as well as its enrichment at glucocorticoid response elements on the glucocorticoid-induced leucine zipper gene promoter. After acute treatment, Cort or TF promoted insulin receptor substrate-1 (IRS-1) gene and protein expression. Either treatment also enriched GR binding at an identified glucocorticoid response element in the IRS-1 gene. TF or Cort each increased insulin-stimulated lipogenesis, an effect resulting from increased lipogenic gene expression and enhanced insulin-stimulated dephosphorylation of acetyl-coenzyme A carboxylase. The augmentation of insulin-stimulated lipogenesis was mediated through a specific enhancement of Akt phosphorylation at T308. These findings support modulation of IRS-1 levels as a mechanism for glucocorticoid mediated changes in insulin action in primary adipocytes. Albeit with less affinity than Cort, in silico analysis suggests that TF can interact with the ligand binding pocket of GR. Collectively, these studies identify TF as a structurally unique environmental glucocorticoid. Glucocorticoid signaling may thus represent a novel pathway by which environmental toxicants promote the development of metabolic diseases. PMID- 23340253 TI - Research resource: the Endometrium Database Resource (EDR). AB - In order to understand the biology of the endometrium and potentially develop new diagnostic tools and treatments for endometrial diseases, the highly orchestrated gene expression/regulation that occurs within the uterus must first be understood. Even though a wealth of information on endometrial gene expression/regulation is available, this information is scattered across several different resources in formats that can be difficult for the average bench scientist to query, integrate, and utilize. The Endometrium Database Resource (EDR) was created as a single evolving resource for protein- and micro-RNA encoding genes that have been shown by gene expression microarray, Northern blot, or other experiments in the literature to have their expression regulated in the uterus of humans, mice, rats, cows, domestic pigs, guinea pigs, and sheep. Genes are annotated in EDR with basic gene information (eg, gene symbol and chromosome), gene orthologs, and gene ontologies. Links are also provided to external resources for publication/s, nucleic and amino acid sequence, gene product function, and Gene Expression Omnibus (GEO) phase expression graph information. The resource also allows for direct comparison of relative gene expression in different microarray experiments for genes shown in the literature to be differentially expressed in the uterus. It is available via a user friendly, web-based interface and is available without charge or restriction to the entire scientific community. The EDR can be accessed at http://edr.research.bcm.edu. PMID- 23340255 TI - Time to eat? The relationship between food security and food-related time use. AB - OBJECTIVES: In the present analysis, we seek to establish a relationship between time spent on food-related activities and food security status as well as between time spent on these activities and Supplemental Nutrition Assistance Program (SNAP, formerly called the Food Stamp Program) participation and benefit level. DESIGN: After matching similar households using Coarsened Exact Matching, we estimate the relationship between food-related time, food insecurity and SNAP participation and benefit level using a comprehensive data set that combines two subsets of the Current Population Survey from years 2004-2010: the Food Security Supplement and the American Time Use Survey. SETTING: City, suburban and rural areas of the USA. SUBJECTS: Non-institutionalized US population over the age of 15 years. Total sample size is 10 247 households. RESULTS: In single households, food insecurity and SNAP participation are associated with 20% more time in meal preparation and 13% less time eating. Similarly, in married households, SNAP participation and benefit level are associated with 32% less time in meal preparation while food insecurity is associated with 17% less time eating and 14% less time in grocery shopping. CONCLUSIONS: A significant relationship exists between time spent on food-related activities and food insecurity and SNAP. This implies that federal and state government may need to consider the time constraints many low-income households face when reforming food assistance programmes. PMID- 23340254 TI - SIRT1 positively regulates breast cancer associated human aromatase (CYP19A1) expression. AB - Breast cancer remains one of the leading causes of death in women diagnosed with cancer. In breast cancer, aberrant expression of the CYP19A1 gene, which encodes the aromatase enzyme, contributes to increased intratumoral levels of estradiol. Regardless of whether this estrogen is produced by peripheral tissues or within specific subpopulations of cells within the breast tumor, it is clear that the aromatase enzymatic activity is critical for the growth of estrogen-dependent tumors. Currently, aromatase inhibitors have proven to be highly effective in blocking the growth of estrogen-dependent forms of breast cancer. CYP19A1 transcription is tightly controlled by 10 tissue-specific promoters. In breast cancer, however, aromatase transcription is driven by multiple promoters that somehow override the tissue-specific regulation of normal tissue. Here, we explore the role that the deacetylase, sirtuin-1 (SIRT1), plays in positively regulating aromatase in breast cancer. We demonstrate that the use of cambinol and the SIRT1/2 inhibitor VII, 2 small molecule inhibitors of SIRT1 and SIRT2, as well as small molecule inhibitors and small interfering RNA specific to SIRT1, all reduce the levels of aromatase mRNA. We further demonstrate that pharmacologic inhibition causes a marked reduction in aromatase protein levels. Additionally, by chromatin immunoprecipitation, we demonstrate that SIRT1 occupies the promoter regions PI.3/PII and PI.4, and its inhibition leads to increased acetylation of estrogen-related receptoralpha, a transcription factor that positively regulates CYP19A1 transcription in epithelial cells. Finally, we demonstrate by immunohistochemistry that SIRT1 is significantly up-regulated in invasive ductal carcinoma relative to normal tissue adjacent to tumor, further suggesting a role of SIRT1 in breast cancer. This work uncovers a new mechanism for the regulation of aromatase and provides rationale for further investigation of how the inhibition of specific sirtuins may provide a unique strategy for inhibiting aromatase that may complement or synergize with existing therapies. PMID- 23340256 TI - Chemical constituents of Caesalpinia decapetala (Roth) Alston. AB - The current study targets the chemical constituents of Caesalpinia decapetala (Roth) Alston and investigates the bioactivities of the isolated compounds. Fourteen known compounds were isolated using column chromatography, and structural identification was performed by physical and spectral analyses. The biological activities of the compounds were also evaluated by 3-(4,5 dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and 2,2-diphenlyl-1 picrylhydrazyl (DPPH) assays. Emodin (6), baicalein (9), and apigenin (12) displayed antitumor activities against the MGC-803 cell line, while quercetin (2), rutin (5), baicalein (9), and epicatechin (13) showed stronger DPPH scavenging activities compared with ascorbic acid. Andrographolide (1), quercetin (2), bergenin (4), rutin (5), emodin (6), betulin (7), baicalein (9), polydatin (10), salicin (11), and apigenin (12), were obtained from C. decapetala (Roth) Alston for the first time. PMID- 23340257 TI - Determination of the spring constants of the higher flexural modes of microcantilever sensors. AB - A method for the simultaneous calibration of the spring constants of all flexural modes of microcantilevers is presented. It is based on a flow of gas from a microchannel that interacts with the microcantilever. The gas flow causes a measurable shift in the resonance frequencies of thermal noise spectra of the flexural modes. From the magnitude of the frequency shifts of the individual modes the spring constants can be determined with high accuracy and precision. The method is non-invasive and does not risk damage to the cantilever. Experimental data are presented for several V-shaped and rectangular cantilevers with nominal fundamental spring constants in the range of 0.03-1.75 N m(-1). The spring constants of the fundamental modes compare favorably to those obtained using the Sader method. The higher modes of oscillation are readily calibrated with experimental uncertainties of 5-10%. PMID- 23340258 TI - Continuity and change in the history of Mexican public health. Introduction. PMID- 23340259 TI - A history of altruism focusing on Darwin, Allee and E.O. Wilson. AB - The problem of altruism refers to the apparent difficulty in reconciling the existence of altruists, individuals who reduce their own fitness to increase the fitness of others, with natural selection. A historical and philosophical overview of solutions to this apparent contradiction is presented through a close reading of the key texts of Charles Darwin, Warder C. Allee and Edward O. Wilson. Following an analysis of Darwin's explanation for altruism, I examine the ideas of group selection and kin selection advanced by Allee and Wilson, respectively, Attention is also given to the philosophical implications each associated with their respective solutions. PMID- 23340260 TI - In vivo and in vitro demonstration of herb-drug interference in human breast cancer cells treated with tamoxifen and trastuzumab. AB - OBJECTIVE: In recent trends, patients with breast cancer seek integrative medical treatment when receiving either hormonal (tamoxifen [Tam]) or target (trastuzumab) therapy. Our previous in vitro studies demonstrated that the Chinese medicine Si-Wu-Tang (SWT) stimulates MCF-7 cell growth via activation of estrogen receptor alpha and human epidermal growth factor receptor 2 (HER2) signaling. The present study demonstrates herb-drug interference with cell proliferation in tumor-bearing mice treated with SWT and Tam in vivo and with proliferation capacity in breast cancer cells treated with SWT and trastuzumab in vitro. METHODS: To assess in vivo SWT + Tam interference, we randomly separated female MCF-7-implanted athymic nude mice into five groups, namely, vehicle (n = 11), estradiol (n = 8), SWT (n = 8), Tam (n = 11), and SWT + Tam (n = 8). All mice were killed after 21 days of treatment. Body weight, uterine weight, tumor volume, and tumor weight were measured. To assess in vitro SWT-trastuzumab interference, we cotreated BT-474 and SK-BR-3 breast cancer cells with SWT and trastuzumab. This was followed by (4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays and cell cycle analysis to measure cell proliferation and by Western blot analysis to analyze protein expression in growth-related signal pathways. RESULTS: SWT reversed Tam-induced antiproliferative effects on tumor weight and tumor volume and increased estrogen receptor alpha and N cadherin expression in the SWT + Tam-treated group compared with the Tam-treated group. Furthermore, SWT reversed trastuzumab-induced antiproliferative activity in HER2 cell lines (SK-BR-3 and BT-474) through increased phosphorylation of the cell cycle regulatory protein p27(Kip1) and possibly of the antiapoptosis protein P38. CONCLUSIONS: Based on the in vivo and in vitro demonstration of herb-drug interference in breast cancer cells, we conclude that physicians should pay more attention to such interference when treating patients with receptor-positive (estrogen receptor-positive, progesterone receptor-positive, or HER2) breast cancers. PMID- 23340261 TI - In response to Cuce et al. PMID- 23340262 TI - To the editor: acute aromatase inhibition. PMID- 23340263 TI - Sexual outcomes of aromatase inhibitor therapy in women with breast cancer: time for intervention. PMID- 23340264 TI - Antidepressant use after discontinuation of hormone therapy: what can one infer about post-hormone therapy depression? PMID- 23340265 TI - A rose without thorns? Neutralizing the vice and magnifying the virtue of conjugated equine estrogens. PMID- 23340267 TI - NFAT2 mediates high glucose-induced glomerular podocyte apoptosis through increased Bax expression. AB - BACKGROUND: Hyperglycemia promotes podocyte apoptosis and plays a key role in the pathogenesis of diabetic nephropathy. However, the mechanisms that mediate hyperglycemia-induced podocyte apoptosis is still far from being fully understood. Recent studies reported that high glucose activate nuclear factor of activated T cells (NFAT) in vascular smooth muscle or pancreatic beta-cells. Here, we sought to determine if hyperglycemia activates NFAT2 in cultured podocyte and whether this leads to podocyte apoptosis. Meanwhile, we also further explore the mechanisms of NFAT2 activation and NFAT2 mediates high glucose induced podocyte apoptosis. METHODS: Immortalized mouse podocytes were cultured in media containing normal glucose (NG), or high glucose (HG) or HG plus cyclosporine A (a pharmacological inhibitor of calcinerin) or 11R-VIVIT (a special inhibitor of NFAT2). The activation of NFAT2 in podocytes was detected by western blotting and immunofluorescence assay. The role of NFAT2 in hyperglycemia induced podocyte apoptosis was further evaluated by observing the inhibition of NFAT2 activation by 11R-VIVIT using flow cytometer. Intracellular Ca(2+) was monitored in HG-treated podcocytes using Fluo-3/AM. The mRNA and protein expression of apoptosis gene Bax were measured by real time-qPCR and western blotting. RESULTS: HG stimulation activated NFAT2 in a time- and dose-dependent manner in cultured podocytes. Pretreatment with cyclosporine A (500nM) or 11R VIVIT (100nM) completely blocked NFAT2 nuclear accumulation. Meanwhile, the apoptosis effects induced by HG were also abrogated by concomitant treatment with 11R-VIVIT in cultured podocytes. We further found that HG also increased [Ca(2+)]i, leading to activation of calcineurin, and subsequent increased nuclear accumulation of NFAT2 and Bax expression in cultured podocytes. CONCLUSION: Our results identify a new finding that HG-induced podocyte apoptosis is mediated by calcineurin/NFAT2/Bax signaling pathway, which may present a promising target for therapeutic intervention. PMID- 23340269 TI - Lyme borreliosis: the need for more research. PMID- 23340270 TI - A comparison between manual and automated evaluations of tissue microarray patterns of protein expression. AB - Tissue microarray technology enables us to evaluate the pattern of protein expression in large numbers of samples. However, manual data acquisition and analysis still represent a challenge because they are subjective and time consuming. Automated analysis may thus increase the speed and reproducibility of evaluation. However, the reliability of automated analysis systems should be independently evaluated. Herein, the expression of phosphorylated AKT and mTOR was determined by ScanScope XT (Aperio; Vista, CA) and ACIS III (Dako; Glostrup, Denmark) and compared with the manual analysis by two observers. The percentage of labeled pixels or nuclei analysis had a good correlation between human observers and automated systems (kappa = 0.855 and 0.879 for ScanScope vs. observers and kappa = 0.765 and 0.793 for ACIS III vs. observers). The intensity of labeling determined by ScanScope was also correlated with that found by the human observers (correlation index of 0.946 and 0.851 for pAKT and 0.851 and 0.875 for pmTOR). However, the correlation between ACIS III and human observation varied for labeling intensity and was considered poor in some cases (correlation index of 0.718 and 0.680 for pAKT and 0.223 and 0.225 for pmTOR). Thus, the percentage of positive pixels or nuclei determination was satisfactorily performed by both systems; however, labeling intensity was better identified by ScanScope XT. PMID- 23340271 TI - Levonorgestrel-releasing intrauterine system versus conventional medical therapy for heavy menstrual bleeding in the Asia-Pacific region. AB - OBJECTIVE: To compare clinical outcomes, including cumulative continuation rate (CCR), in the treatment of idiopathic heavy menstrual bleeding (HMB) with the levonorgestrel-releasing intrauterine system (LNG-IUS) and with conventional medical therapies (CMTs), including combined oral contraceptives, oral progestins, and antifibrinolytics, either alone or in combination, in the Asia Pacific region. METHODS: In a prospective observational cohort study conducted between September 2008 and December 2010, 647 women (LNG-IUS, n=483; CMTs, n=164), aged 18-45 years and diagnosed with HMB, were recruited from 8 countries and followed for up to 1 year. The primary outcome was the CCR at 12 months. Secondary outcomes included bleeding pattern, an assessment of treatment efficacy by the treating physician, and safety. RESULTS: The CCR at 12 months was significantly higher for LNG-IUS than for CMTs (87.6% vs 56.3% P<0.05). Compared with CMTs, LNG-IUS offered a better reduction in both subjectively assessed menstrual blood loss and the number of bleeding days, and had better efficacy for HMB, as determined by the physician's final evaluation. CONCLUSION: The present study provides information on the real-life patterns of treatment of HMB in the Asia-Pacific region. The efficacy of CMTs was inferior compared with LNG-IUS in the clinical outcomes measured. ClinicalTrials.gov:NCT00864136. PMID- 23340272 TI - Time between skin incision and delivery during cesarean. AB - OBJECTIVE: To investigate factors influencing skin incision-to-delivery time (including sub-divisions thereof) and the effect of these surgical intervals on immediate neonatal outcome. METHODS: A prospective cohort analysis was conducted of all women undergoing cesarean delivery at Tygerberg Hospital, Cape Town, South Africa, from May 24 to November 2, 2010. Three surgical intervals were evaluated: skin incision to myometrium, myometrium to delivery, and skin incision to delivery. Neonatal outcome was assessed by the 5-minute Apgar score. RESULTS: Of 1120 cesarean deliveries recorded during the study period, 77.2% were emergency procedures, which were performed more quickly at all surgical planes (P<0.01). Adhesions in the surgical field were present in 7.4% of all primary procedures versus 67.7% of all third procedures (P<0.001). The skin incision-to-delivery time was significantly extended among repeat procedures (P<0.001) and increased progressively with degree of obesity (P<0.001). Although the 3 surgical intervals were calculated individually, none of the median values correlated with a 5 minute Apgar score below 7 for emergency deliveries. CONCLUSION: Repeat procedures, adhesions, and obesity prolonged the time taken for cesarean delivery. Nevertheless, the effect of these factors on the 5-minute Apgar score was minimal. PMID- 23340273 TI - Levetiracetam-induced sexual disorders. PMID- 23340274 TI - Subcortical structural abnormalities in juvenile myoclonic epilepsy (JME): MR volumetry and vertex based analysis. AB - PURPOSE: Imaging studies in juvenile myoclonic epilepsy (JME) have shown abnormalities of the thalamus and frontal cortex. The purpose of this study was to systematically investigate the morphological changes in the deep gray matter (GM) structures using techniques of voxel based morphometry (VBM), MR volumetry and shape analysis. METHODOLOGY: The study included 40 patients with JME (M:F=21:19; age 22.8+/-5.3 years) and 19 matched controls (M:F=13:6; age 24.5+/ 4.2 years). All subjects underwent MRI using standard protocol that included T1 3D TFE (Turbo Field Echo) images with 1mm thickness. VBM analysis and MR volumetry were performed. The volumes of deep subcortical GM structures were extracted and vertex-wise shape analysis was performed using FSL-FIRST (FSL Integrated Registration and Segmentation Toolbox) software. RESULTS: VBM analysis with a thalamic mask revealed focal thalamic alterations in the anteromedial aspect of the thalamus (p<0.05, false discovery rate (FDR) corrected) which remained significant after adjusting for age, gender and intracranial volume (ICV). Significant volume loss was noted in both the thalami. Vertex-wise shape analysis showed significant focal surface reductions in the thalami bilaterally in patients that were predominantly seen in the medial as well as lateral aspects of the thalamus (p<0.05, FDR corrected). The disease duration correlated with left hippocampus volume while age of onset correlated with right hippocampus volume. CONCLUSIONS: This study confirms the presence of thalamic alterations in patients with JME. Shape analysis technique provided complementary information and disclosed the presence of focal atrophic changes in patients' thalami. The striatum and hippocampus did not show any significant alterations. PMID- 23340275 TI - Cardiac dysfunction in rats prone to audiogenic epileptic seizures. AB - PURPOSE: Cardiac dysfunction is one of the possible causes of sudden unexpected death in epilepsy (SUDEP). Therefore, the objective of this study was to evaluate cardiac and electrocardiographic parameters in rats with audiogenic epileptic seizures (WAR--Wistar audiogenic rats). METHODS: In vivo arterial pressure, heart rate (HR), autonomic tone and electrocardiography (ECG) were measured in awake animals in order to examine cardiac function and rhythm. Ex vivo, the Langendorff technique was used to analyze the cardiac function and the severity of reperfusion arrhythmias. In vitro, confocal microscopy was used to evaluate calcium transient parameters of isolated ventricular cardiomyocytes. RESULTS: In vivo autonomic tone evaluation revealed enhanced sympathetic activity, changes in cardiac function with increased systolic arterial pressure and higher basal HR in WAR. In addition, ECG analysis demonstrated electrical alterations with prolongation of the QT interval and QRS complex in these animals. Ex vivo, we observed a decrease in systolic tone and HR and an increase in the duration of ischemia/reperfusion arrhythmias in WAR. Moreover, intracellular Ca2+ handling analysis revealed an increase in the peak of calcium and calcium transient decay in audiogenic rats. Treatment with atenolol (beta1-adrenergic antagonist) normalized the systolic tone, reduced cardiac hypertrophy and the associated increase in the susceptibility to reperfusion arrhythmias observed in WAR. CONCLUSION: We present evidence that chronic disturbances in sympathetic tone in WAR cause increases the risk to life-threatening arrhythmias. Our results support a relationship between seizures, cardiac dysfunction and cardiac arrhythmias, which may contribute to the occurrence of SUDEP. PMID- 23340276 TI - A combination therapy protocol of plasmapheresis, intravenous immunoglobulins and betamethasone to treat anti-Ro/La-related congenital atrioventricular block. A case series and review of the literature. AB - OBJECTIVES: The aim of this report was to evaluate the efficacy and safety of a combined treatment protocol used to treat 2nd and 3rd degree anti-Ro/La-related congenital atrioventricular block (CAVB). METHODS: Six consecutive women diagnosed with 2nd degree (three cases) or 3rd degree block (three cases) between 2009 and 2011 referred to our outpatient clinic underwent a combination therapy protocol composed of weekly plasmapheresis, fortnightly 1g/kg intravenous immunoglobulins (IVIG) and daily betamethasone (4mg/day) throughout pregnancy. IVIG (1g/kg) treatment in the neonates was begun at birth and administered every fifteen days until passive maternal antibodies became undetectable. RESULTS: The fetuses affected with 2nd degree block (cases 1, 2 and 3) reverted to a normal atrioventricular conduction after combined therapy, while those with a 3rd degree block remained stable (case 4), showed an increase in the ventricular rate (case 5) or an improvement in cardiac function (case 6). None of the fetuses with 3rd degree CAVB had other cardiac complications such as cardiomyopathy or fetal hydrops. The follow-up of the children affected with 2nd degree CAVB revealed a complete regression of the block in cases 1 and 3, and no signs of relevant worsening in case 2. The infants affected with 3rd degree block (cases 4, 5, and 6) remained stable and until now only one has required a pacemaker at the age of 10months. CONCLUSIONS: If these results are confirmed by large-scale studies, this protocol could lead to improved outcomes in the treatment of this devastating disease. PMID- 23340277 TI - Advances in CTLA-4-Ig-mediated modulation of inflammatory cell and immune response activation in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a multifactorial and polygenic immune-mediated disease, the pathogenesis of which involves different cell types. T and B lymphocytes, macrophages, endothelial cells, fibroblasts and osteoclasts have all been implicated in mediating the production of autoantibodies, proinflammatory cytokines and ultimately bone erosions. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4-Ig, abatacept) is a unique biologic agent targeting the co-stimulatory molecules CD80/CD86, and is indicated for the treatment of moderate-to-severe RA in patients who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs, including methotrexate or anti-tumor necrosis factor agents. There is a growing body of evidence that, through selective modulation of the CD80/CD86 co-stimulatory molecules expressed by a variety of activated cell types, CTLA-4-Ig may inhibit the pathogenic RA process at several levels, both directly and indirectly. Here, we provide an overview of recent mechanistic studies of the action of CTLA-4-Ig on different cell types involved in mediating inflammation and joint damage in RA. PMID- 23340278 TI - Can endoscopic sphincterotomy be performed safely in elderly patients aged 80 years or older with pancreatic and biliary diseases? AB - BACKGROUND/AIMS: The purpose of this study was to investigate whether endoscopic sphincterotomy (EST) can be usefully and safely performed in elderly patients aged 80 years or older. METHODOLOGY: The eligible patients with pancreatic and biliary diseases who required EST were divided into two groups depending on their age: under 80 (group A) and 80 or older (group B). Patient characteristics, EST success rate and incidence of the related complications were evaluated. RESULTS: Of the 720 patients who required EST, 522 patients were in group A and 198 in group B. Group B incidences of patient characteristics at baseline disease and anticoagulant/antiplatelet therapy were significantly higher than in group A (p<0.05). The EST success rates were 97.1% (507/522) in group A and 96.5% (191/198) in group B. The incidences of the related complications were 8.8% (46/522) in group A and 4% (8/198) in group B, respectively, again without significant difference. CONCLUSIONS: The EST success rate and the incidence of related complications were comparable between patients in groups A and B, indicating that EST can be safely performed even in the elderly aged 80 years or older. PMID- 23340279 TI - Evaluation of a focused sentinel lymph node protocol in node-negative gastric cancer patients. AB - BACKGROUND/AIMS: A specific preoperative work-up was used to access a limited number of high-risk lymph nodes with RT-qPCR for micrometastatic sentinel lymph node involvement. We validated our protocol with IHC screening for micrometastases and long-term survival analysis. METHODOLOGY: From the 32 patients included 22 were node-negative patients. With a specific preoperative protocol sentinel lymph nodes (1-2 per patient) were extracted for further RT qPCR analysis for CEA and CK20 expression. In 10 patients from the study group, the remaining lymph nodes around the extracted sentinel lymph node from the first compartment were additionally screened using IHC for missed micrometastases. RESULTS: Micrometastases were detected in seven of 22 (31.8%) node-negative patients. RT-qPCR identified micrometastases in four of 10 haematoxylin-eosin negative lymph nodes (40%), and in three of eight IHC negative lymph nodes (37.5%). The cumulative 3-year survival for the study group was 80.8%. The 3-year survival in the RT-qPCR-negative group was 90%, compared with 66.7% in the RT qPCR-positive group (p=0.289). CONCLUSIONS: Encouraged by these results, we will include more patients in our focused sentinel lymph node protocol. With a refinement of our method, we believe the focused sentinel lymph node protocol can be implemented for intraoperative tailoring of extent of lymphadenectomy. PMID- 23340280 TI - Evaluating the antioxidant capacity of natural products: a review on chemical and cellular-based assays. AB - Oxidative stress is associated with several pathologies like cardiovascular, neurodegenerative, cancer and even aging. It has been suggested that a diet rich in antioxidants would be beneficial to human health and a lot of interest is focused on the determination of antioxidant capacity of natural products. Different chemical methods have been developed including the popular ORAC that evaluates the potential of a sample as inhibitor of a target molecule oxidation. Chemical-based methods are useful for screening, they are low cost, high throughput and yield an index value (expressed as equivalents of Trolox) that allows comparing and ordering different products. More recently, nanoparticles based assays have been developed to sense the antioxidant power of natural products. However, the antioxidant capacity indexes obtained by chemical assays cannot extrapolate the performance of the sample in vivo. Considering that antioxidant action is not limited to scavenging free radicals but includes upregulation of antioxidant and detoxifying enzymes, modulation of redox cell signaling and gene expression, it is necessary to move to cellular assays in order to evaluate the potential antioxidant activity of a compound or extract. Animal models and human studies are more appropriate but also more expensive and time-consuming, making the cell culture assays very attractive as intermediate testing methods. Cellular antioxidant activity (CAA) assays, activation of redox transcription factors, inhibition of oxidases or activation of antioxidant enzymes are reviewed and compared with the classical in vitro chemical-based assays for evaluation of antioxidant capacity of natural products. PMID- 23340281 TI - Novel combination of non-aqueous capillary electrophoresis and multivariate curve resolution-alternating least squares to determine phenolic acids in virgin olive oil. AB - This paper presents the development of a non-aqueous capillary electrophoresis method coupled to UV detection combined with multivariate curve resolution alternating least-squares (MCR-ALS) to carry out the resolution and quantitation of a mixture of six phenolic acids in virgin olive oil samples. p-Coumaric, caffeic, ferulic, 3,4-dihydroxyphenylacetic, vanillic and 4-hydroxyphenilacetic acids have been the analytes under study. All of them present different absorption spectra and overlapped time profiles with the olive oil matrix interferences and between them. The modeling strategy involves the building of a single MCR-ALS model composed of matrices augmented in the temporal mode, namely spectra remain invariant while time profiles may change from sample to sample. So MCR-ALS was used to cope with the coeluting interferences, on accounting the second order advantage inherent to this algorithm which, in addition, is able to handle data sets deviating from trilinearity, like the data herein analyzed. The method was firstly applied to resolve standard mixtures of the analytes randomly prepared in 1-propanol and, secondly, in real virgin olive oil samples, getting recovery values near to 100% in all cases. The importance and novelty of this methodology relies on the combination of non-aqueous capillary electrophoresis second-order data and MCR-ALS algorithm which allows performing the resolution of these compounds simplifying the previous sample pretreatment stages. PMID- 23340282 TI - Paper-based solid-state electrochemiluminescence sensor using poly(sodium 4 styrenesulfonate) functionalized graphene/nafion composite film. AB - Herein, highly efficient solid-state ECL sensor was introduced for the first time onto the screen printed electrodes of the paper-based chips (PCs) based on the composite film of poly(sodium 4-styrenesulfonate) functionalized graphene (PSSG) and Nafion. Attributed to the cooperative characteristics of both PSS and graphene, PSSG ensured both effective Ru(bpy)(3)(2+) immobilization and fast electron transfer of Ru(bpy)(3)(2+) in the composite film. The ECL behaviors at the developed sensor were investigated using tripropylamine as a representative analyte and low detection limit (SN(-1)=3) of 5.0 nM was obtained. It also exhibited more excellent reproducibility (relative standard deviations of 0.63% for continuous 45 cycles) and long-term stability (~80% of its initial ECL intensity could be retained over 3 months). More importantly, assisted by the developed ECL sensor, discrimination of 1.0 nM single-nucleotide mismatch in human urine matrix could be realized on the PCs for the first attempt. Thus, the developed sensor was confirmed with the advantages of highly sensitivity, long term stability, simplicity, low cost, disposability, high efficiency and potential applicability. PMID- 23340283 TI - Numerical study of a novel induced-charge electrokinetic micro-mixer. AB - A novel micro-mixer based on the induced-charge electrokinetic motion of an electrically conducting particle is proposed and numerically demonstrated in this paper. For most microfluidic applications, it is desired to mix different streams of solutions rapidly in a continuous flow mode. Therefore, in this work, we consider a mixing chamber containing an electrically conducting particle and the mixing chamber is located in the middle of a microchannel. Vortices are generated around the electrically conducting particle in an aqueous solution due to the interaction of the applied electric field and the induced surface charge on the particle. These vortices will enhance significantly the mixing of different solutions around the particle. The effectiveness of mixing the two streams entering the mixing chamber is numerically studied as functions of the applied electric field. Excellent mixing can be achieved in this system under two perpendicularly applied electric fields. The proposed micro-mixer is simple and easy to be fabricated for lab-on-a-chip applications. PMID- 23340284 TI - Surface-enhanced Raman scattering from magneto-metal nanoparticle assemblies. AB - Binary nanoparticles composed of a superparamagnetic Fe(3)O(4) core and an Au nanoshell (Fe(3)O(4)@Au) were prepared via a simple co-precipitation method followed by seed-mediated growth process. The nanoparticles exhibited functions of both fast magnetic response and local surface plasmon resonance. The Fe(3)O(4)@Au nanoparticles were used as probes for surface-enhanced Raman scattering (SERS) using p-thiocresol (p-TC) as reporter molecule. With the ability of analyte capture and concentration magnetically, the Fe(3)O(4)@Au nanoparticles showed significant SERS properties with excellent reproducibility. Under non-optimized conditions, detection limit as low as 4.55 pM of analyte can be reached using Fe(3)O(4)@Au nanoparticle assemblies, which excel remarkably the cases with traditional Au nanoprobes. PMID- 23340285 TI - A high-throughput homogeneous immunoassay based on Forster resonance energy transfer between quantum dots and gold nanoparticles. AB - A novel homogeneous immunoassay based on Forster resonance energy transfer for sensitive detection of tumor, e.g., marker with carcinoembryonic antigen (CEA), was proposed. The assay was consisted of polyclonal goat anti-CEA antibody labeled luminescent CdTe quantum dots (QDs) as donor and monoclonal goat anti-CEA antibody labeled gold nanoparticles (AuNPs) as acceptor. In presence of CEA, the bio-affinity between antigen and antibody made the QDs and AuNPs close enough, thus the photoluminescence (PL) quenching of CdTe QDs occurred. The PL properties could be transformed into the fluorometric variation, corresponding to the target antigen concentration, and could be easily monitored and analyzed with the home made image analysis software. The fluorometric results indicated a linear detection range of 1-110 ng mL(-1) for CEA, with a detection limit of 0.3 ng mL( 1). The proposed assay configuration was attractive for carcinoma screening or single sample in point-of-care testing, and even field use. In spite of the limit of available model analyte, this approach could be easily extended to detection of a wide range of biomarkers. PMID- 23340286 TI - High resolution characterization of uranium in sediments by DGT and DET techniques ACA-S-12-2197. AB - Diffusive equilibrium (DET) and diffusive gradient in thin film (DGT) techniques with an inductively coupled plasma mass spectrometry detection of elements were applied to characterize uranium, manganese, iron and (238)U/(235)U isotopic ratio depth profiles in sediment pore water at high spatial resolution and to monitor uranium uptake/remobilization processes in uranium spiked sediment core samples under laboratory, well controlled conditions. Modified constrained sediment DGT probes, packed with Spheron-Oxin((r)) resin gel, were employed for selective uranium measurements. Spatially resolved DET and DGT responses were indicative of local redistribution of uranium in naturally uranium poor and rich sediments. PMID- 23340287 TI - Differentiation and characterization of isotopically modified silver nanoparticles in aqueous media using asymmetric-flow field flow fractionation coupled to optical detection and mass spectrometry. AB - The principal objective of this work was to develop and demonstrate a new methodology for silver nanoparticle (AgNP) detection and characterization based on asymmetric-flow field flow fractionation (A4F) coupled on-line to multiple detectors and using stable isotopes of Ag. This analytical approach opens the door to address many relevant scientific challenges concerning the transport and fate of nanomaterials in natural systems. We show that A4F must be optimized in order to effectively fractionate AgNPs and larger colloidal Ag particles. With the optimized method one can accurately determine the size, stability and optical properties of AgNPs and their agglomerates under variable conditions. In this investigation, we couple A4F to optical absorbance (UV-vis spectrometer) and scattering detectors (static and dynamic) and to an inductively coupled plasma mass spectrometer. With this combination of detection modes it is possible to determine the mass isotopic signature of AgNPs as a function of their size and optical properties, providing specificity necessary for tracing and differentiating labeled AgNPs from their naturally occurring or anthropogenic analogs. The methodology was then applied to standard estuarine sediment by doping the suspension with a known quantity of isotopically enriched (109)AgNPs stabilized by natural organic matter (standard humic and fulvic acids). The mass signature of the isotopically enriched AgNPs was recorded as a function of the measured particle size. We observed that AgNPs interact with different particulate components of the sediment, and also self-associate to form agglomerates in this model estuarine system. This work should have substantial ramifications for research concerning the environmental and biological fate of AgNPs. PMID- 23340288 TI - Simultaneous detection of single nucleotide polymorphisms and copy number variations in the CYP2D6 gene by multiplex polymerase chain reaction combined with capillary electrophoresis. AB - CYP2D6 (cytochrome P450 2D6) is one of the most important enzymes involved in drug metabolism, and CYP2D6 gene variants may cause toxic effects of therapeutic drugs or treatment failure. In this research, a rapid and simple method for genotyping the most common mutant alleles in the Asian population (CYP2D6*1/*1, CYP2D6*1/*10, CYP2D6*10/*10, CYP2D6*1/*5, CYP2D6*5/*10, and CYP2D6*5/*5) was developed by allele-specific polymerase chain reaction (AS-PCR) combined with capillary electrophoresis (CE). We designed a second mismatch nucleotide next to the single nucleotide polymorphism (SNP) site in allele-specific primers to increase the difference in PCR amplification. Besides, we established simulation equations to predict the CYP2D6 genotypes by analyzing the DNA patterns in the CE chromatograms. The multiplex PCR combined with CE method was applied to test 50 patients, and all of the test results were compared with the DNA sequencing method, long-PCR method and real-time PCR method. The correlation of the analytical results between the proposed method and other methods were higher than 90%, and the proposed method is superior to other methods for being able to simultaneous detection of SNPs and copy number variations (CNV). Furthermore, we compared the plasma concentration of aripiprazole (a CYP2D6 substrate) and its major metabolites with the genotype of 25 patients. The results demonstrate the proposed genotyping method is effective for estimating the activity of the CYP2D6 enzyme and shows potential for application in personalized medicine. Similar approach can be applied to simultaneous detection of SNPs and CNVs of other genes. PMID- 23340289 TI - Impaired DNA methylation and its mechanisms in CD4(+)T cells of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies against a series of nuclear antigens. Although the exact cause of SLE is still unknown, the influence of environment, which is largely reflected by the epigenetic mechanisms, with DNA methylation changes in particular, are generally considered as key players in the pathogenesis of SLE. As an important post-translational modification, DNA methylation mainly suppresses the expression of relevant genes. Accumulating evidence has indicated that abnormal DNA hypomethylation in T cells is an important epigenetic hallmark in SLE. Apart from those classic methylation sensitive autoimmunity-related genes in lupus, such as CD11a (ITGAL), Perforin (PRF1), CD70 (TNFSF7), CD40 ligand (TNFSF5) and PP2Acalpha, the genome-wide methylation pattern has also been explored recently, providing us a more and more full-scale picture of the abnormal status of DNA methylation in SLE. On the other hand, certain miRNAs, RFX1, defective ERK pathway signaling, Gadd45alpha and DNA hydroxymethylation have been proposed as potential mechanisms leading to DNA hypomethylation in lupus. In this review, we summarize current understanding of T cell DNA methylation changes and the consequently altered gene expressions in lupus, and how they contribute to the development of SLE. Possible mechanisms underlying these aberrancies are also discussed based on the reported literature and our own findings. PMID- 23340290 TI - E4BP4 overexpression: a protective mechanism in CD4+ T cells from SLE patients. AB - Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by various immunological abnormalities, including dysregulated activation of T and B lymphocytes, which trigger autoantibody production and immune-complex deposition. E4BP4, also known as NFIL3, has emerged as a major transcription factor that regulates the development and function of immune cells in a number of lineages. E4BP4 has been shown to regulate cytokines expression, and its synthesis is in turn controlled by various cytokines. To date, the roles of E4BP4 in immune dysregulation and autoimmune disorders are unclear. In this study, we demonstrated that E4BP4 expression is increased in CD4(+) T cells isolated from patients with active systemic lupus erythematosus (SLE), especially in patients treated with glucocorticoid (GC). Increased expression of E4BP4 inhibited the activation and self-reactivity of T cells stimulated by anti CD3/CD28 antibodies. In contrast, the self-reactivity was enhanced in CD4(+) T cells from SLE patients following E4BP4 gene silencing and the production of autoantibody was increased in autologous B cells. We further demonstrated that E4BP4 directly regulated CD40L expression by binding to the promoter region and altering histone acetylation and methylation of the CD40L loci. Taken together, our data provide evidence that E4BP4 can inhibit CD40L expression through epigenetic modifications in the promoter region of CD40L, thus negatively regulating self-reactivity of SLE CD4(+) T cells. Furthermore, our data demonstrate that overexpression of E4BP4 initiates a protective mechanism in SLE CD4(+) T cells, which may be a promising target in the therapy for SLE. PMID- 23340291 TI - Surgical strategy in endometriosis. AB - Endometriosis is a common disease affecting young women. Its clinical manifestations include pain and infertility, and it can dramatically affect quality of life. Treatments should be tailored to address the wishes of women according to the specific characteristics of the disease. Although many questions remain unanswered, strong evidence supports the use of laparoscopic surgery to improve pain and infertility. The systematisation of strategy is essential to make surgery more reproducible, safer and less time-consuming. Nevertheless, even in the most expert hands, complications may occur. Further investigations are needed to compare the different approaches. Outcomes must, however, include pain, fertility, organ dysfunction, and quality of life. PMID- 23340292 TI - Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells. AB - PURPOSE: The most common genetic lesions in pancreatic ductal adenocarcinoma (PDAC) have been identified. However, significant gaps still exist in our understanding of how such genetic alterations act in concert to induce PDAC development. In this study, we investigated the mechanism of tumorigenic transformation in the immortalized human pancreatic ductal epithelial (HPDE) cell line by sequentially introducing PDAC signature alterations into this cell line. EXPERIMENTAL DESIGN: The phenotype for stable expression of mutant K-ras, Her2, p16/p14shRNA, and Smad4shRNA in HPDE cells was examined by assays for cell proliferation, migration, invasion, soft agar, and orthotopic tumorigenesis. The mechanisms of tumorigenic transformation were further explored by gene expression profiling and pathway analyses. RESULTS: The transformed cells exhibited enhanced proliferation, migration, and invasion, displayed anchorage-independent growth in soft agar, and grew orthotopic tumors with some histopathologic features of PDAC. We found that Smad4 played key roles in the tumorigenic transformation of HPDE cells. We further found that MDM2 and Bmi-1 were overexpressed in the tumorigenic HPDE cells and that Bmi-1 overexpression was regulated by Smad4. Ingenuity Pathway Analysis software analysis of microarray data revealed that dysregulation of integrin-linked kinase signaling and the cell cycle were the most significant changes involved in tumorigenic transformation. Altogether, this cell culture model closely recapitulated human pancreatic carcinogenesis from gene lesions, activation of specific signaling pathways, and some histopathologic features. CONCLUSION: The combination of activated K-ras and Her2 with inactivated p16/p14 and Smad4 was sufficient and essential to transform HPDE cells, thus revealing the potential tumorigenic mechanism. PMID- 23340293 TI - Personalized chemotherapy profiling using cancer cell lines from selectable mice. AB - PURPOSE: High-throughput chemosensitivity testing of low-passage cancer cell lines can be used to prioritize agents for personalized chemotherapy. However, generating cell lines from primary cancers is difficult because contaminating stromal cells overgrow the malignant cells. EXPERIMENTAL DESIGN: We produced a series of hypoxanthine phosphoribosyl transferase (hprt)-null immunodeficient mice. During growth of human cancers in these mice, hprt-null murine stromal cells replace their human counterparts. RESULTS: Pancreatic and ovarian cancers explanted from these mice were grown in selection media to produce pure human cancer cell lines. We screened one cell line with a 3,131-drug panel and identified 77 U.S. Food and Drug Administration (FDA)-approved drugs with activity, and two novel drugs to which the cell line was uniquely sensitive. Xenografts of this carcinoma were selectively responsive to both drugs. CONCLUSION: Chemotherapy can be personalized using patient-specific cell lines derived in biochemically selectable mice. PMID- 23340295 TI - Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib glucuronide. AB - PURPOSE: Many tyrosine kinase inhibitors (TKI) undergo extensive hepatic metabolism, but mechanisms of their hepatocellular uptake remain poorly understood. We hypothesized that liver uptake of TKIs is mediated by the solute carriers OATP1B1 and OATP1B3. EXPERIMENTAL DESIGN: Transport of crizotinib, dasatinib, gefitinib, imatinib, nilotinib, pazopanib, sorafenib, sunitinib, vandetanib, and vemurafenib was studied in vitro using artificial membranes (PAMPA) and HEK293 cell lines stably transfected with OATP1B1, OATP1B3, or the ortholog mouse transporter, Oatp1b2. Pharmacokinetic studies were conducted with Oatp1b2-knockout mice and humanized OATP1B1- or OATP1B3-transgenic mice. RESULTS: All 10 TKIs were identified as substrates of OATP1B1, OATP1B3, or both. Transport of sorafenib was investigated further, as its diffusion was particularly low in the PAMPA assay (<4%) than other TKIs that were transported by both OATP1B1 and OATP1B3. Whereas Oatp1b2 deficiency in vivo had minimal influence on parent and active metabolite N-oxide drug exposure, plasma levels of the glucuronic acid metabolite of sorafenib (sorafenib-glucuronide) were increased more than 8-fold in Oatp1b2-knockout mice. This finding was unrelated to possible changes in intrinsic metabolic capacity for sorafenib-glucuronide formation in hepatic or intestinal microsomes ex vivo. Ensuing experiments revealed that sorafenib glucuronide was itself a transported substrate of Oatp1b2 (17.5-fold vs. control), OATP1B1 (10.6-fold), and OATP1B3 (6.4-fold), and introduction of the human transporters in Oatp1b2-knockout mice provided partial restoration of function. CONCLUSIONS: These findings signify a unique role for OATP1B1 and OATP1B3 in the elimination of sorafenib-glucuronide and suggest a role for these transporters in the in vivo handling of glucuronic acid conjugates of drugs. PMID- 23340294 TI - Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. AB - PURPOSE: Accumulating evidence supports the existence of breast cancer stem cells (BCSC), which are characterized by their capacity to self-renew and divide indefinitely and resistance to conventional therapies. The Notch pathway is important for stem cell renewal and is a potential target for BCSC-directed therapy. EXPERIMENTAL DESIGN: Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in patients with advanced breast cancer, designed to determine the maximum-tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies. RESULTS: Treatment with GSI reduced BCSCs in MC1 and BCM-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically, meaningful doses of both drugs were possible with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44(+)/CD24(-), ALDH(+), and mammosphere-forming efficiency were observed in tumors of patients undergoing serial biopsies. CONCLUSIONS: These preclinical data show that pharmacologic inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial shows feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer. PMID- 23340296 TI - MicroRNA-200a promotes anoikis resistance and metastasis by targeting YAP1 in human breast cancer. AB - PURPOSE: The process of metastases involves the dissociation of cells from the primary tumor, penetration into the basement membrane, invasion, and exiting from the vasculature to seed and colonize distant tissues. miR-200a is involved in this multistep metastatic cascade. This study aimed to test the hypothesis that miR-200a promotes metastasis through increased anoikis resistance in breast cancer. EXPERIMENTAL DESIGN: Breast cancer cells transfected with mimic or inhibitor for miR-200a were assayed for anoikis in vitro. miR-200a expression was assessed by quantitative real-time PCR (qRT-PCR). Luciferase assays, colony formation assays, and animal studies were conducted to identify the targets of miR-200a and the mechanism by which it promotes anoikis resistance. RESULTS: We found that overexpression of miR-200a promotes whereas inhibition of miR-200a suppresses anoikis resistance in breast cancer cells. We identified Yes associated protein 1 (YAP1) as a novel target of miR-200a. Our data showed that targeting of YAP1 by miR-200a resulted in decreased expression of proapoptotic proteins, which leads to anoikis resistance. Overexpression of miR-200a protected tumor cells from anoikis and promoted metastases in vivo. Furthermore, knockdown of YAP1 phenocopied the effects of miR-200a overexpression, whereas restoration of YAP1 in miR-200a overexpressed breast cancer cells reversed the effects of miR 200a on anoikis and metastasis. Remarkably, we found that YAP1 expression was inversely correlated with miR-200a expression in breast cancer clinical specimens, and miR-200a expression was associated with distant metastasis in patients with breast cancer. CONCLUSIONS: Our data suggest that miR-200a functions as anoikis suppressor and contributes to metastasis in breast cancer. PMID- 23340297 TI - PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction. AB - PURPOSE: Ovarian cancer often progresses by disseminating to the peritoneal cavity, but how the tumor cells evade host immunity during this process is poorly understood. Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be expressed in cancer cells. The purpose of this study is to elucidate the function of PD-L1 in peritoneal dissemination. EXPERIMENTAL DESIGN: Ovarian cancer cases were studied by microarray and immunohistochemistry. PD-L1 expression in mouse ovarian cancer cell line in various conditions was assessed by flow cytometry. PD-L1-overexpression cell line and PD-L1-depleted cell line were generated, and cytolysis by CTLs was analyzed, and alterations in CTLs were studied by means of timelapse and microarray. These cell lines were injected intraperitoneally to syngeneic immunocompetent mice. RESULTS: Microarray and immunohistochemistry in human ovarian cancer revealed significant correlation between PD-L1 expression and peritoneal positive cytology. PD-L1 expression in mouse ovarian cancer cells was induced upon encountering lymphocytes in the course of peritoneal spread in vivo and coculture with lymphocytes in vitro. Tumor cell lysis by CTLs was attenuated when PD-L1 was overexpressed and promoted when it was silenced. PD-L1 overexpression inhibited gathering and degranulation of CTLs. Gene expression profile of CTLs caused by PD-L1-overexpressing ovarian cancer was associated with CTLs exhaustion. In mouse models, PD-L1 depletion resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. CONCLUSION: PD-L1 expression in tumor cell promotes peritoneal dissemination by repressing CTL function. PD-L1-targeted therapy is a promising strategy for preventing and treating peritoneal dissemination. PMID- 23340298 TI - Can the "right" EGFR-specific mAb dramatically improve EGFR-targeted therapy? AB - EGF receptor (EGFR)-specific monoclonal antibodies (mAb) display limited therapeutic efficacy in EGFR-positive solid tumors. To overcome this limitation, the significant improvement of the antibody-dependent cell-mediated cytotoxicity mediated antitumor activity of a novel EGFR-specific mAb is described. Its potential impact on the efficacy of immunotherapy for EGFR-positive solid tumors is discussed. PMID- 23340299 TI - Biomarker analysis of neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or Paclitaxel in early-stage breast cancer. AB - PURPOSE: Predictive biomarkers offer the potential to improve the benefit:risk ratio of a therapeutic agent. Ixabepilone achieves comparable pathologic complete response (pCR) rates to other active drugs in the neoadjuvant setting. This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent. EXPERIMENTAL DESIGN: Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received neoadjuvant doxorubicin/cyclophosphamide, followed by 1:1 randomization to ixabepilone (n = 148) or paclitaxel (n = 147). Rates of pCR were compared between treatment arms based on predefined biomarker sets: TUBB3, TACC3, and CAPG gene expression, a 20- and 26-gene expression model, MDR1 protein expression, and other potential markers of sensitivity. betaIII-tubulin protein expression is reported separately but is referred to here for completeness. All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis before chemotherapy. Gene expression profiling data were used for molecular subtyping. RESULTS: There was no significant difference in the rate of pCR in both treatment arms in betaIII-tubulin-positive patients. Higher pCR rates were observed among betaIII tubulin-positive patients than in betaIII-tubulin-negative patients. Furthermore, no correlation was evident between TUBB3, TACC3, and CAPG gene expression, MDR1 protein expression, multi-gene expression models, and the efficacy of ixabepilone or paclitaxel, even within the estrogen receptor-negative subset. CONCLUSION: These results indicate that betaIII-tubulin protein and mRNA expression, MDR1 protein expression, TACC3 and CAPG gene expression, and multigene expression models (20- and 26-gene) are not predictive markers for differentiating treatment benefit between ixabepilone and paclitaxel in early-stage breast cancer. PMID- 23340300 TI - Rab25 regulates invasion and metastasis in head and neck cancer. AB - PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is one of the 10 most common cancers with a 50% five-year survival rate, which has remained unchanged for the past three decades. One of the major reasons for the aggressiveness of this cancer is that HNSCCs readily metastasize to cervical lymph nodes that are abundant in the head and neck region. Hence, discovering new molecules controlling the metastatic process as well as understanding their regulation at the molecular level are essential for effective therapeutic strategies. EXPERIMENTAL DESIGN: Rab25 expression level was analyzed in HNSCC tissue microarray. We used a combination of intravital microscopy in live animals and immunofluorescence in an in vitro invasion assay to study the role of Rab25 in tumor cell migration and invasion. RESULTS: In this study, we identified the small GTPase Rab25 as a key regulator of HNSCC metastasis. We observed that Rab25 is downregulated in HNSCC patients. Next, we determined that reexpression of Rab25 in a metastatic cell line is sufficient to block invasion in a three dimensional collagen matrix and metastasis to cervical lymph nodes in a mouse model for oral cancer. Specifically, Rab25 affects the organization of F-actin at the cell surface, rather than cell proliferation, apoptosis, or tumor angiogenesis. CONCLUSION: These findings suggest that Rab25 plays an important role in tumor migration and metastasis, and that understanding its function may lead to the development of new strategies to prevent metastasis in oral cancer patients. PMID- 23340301 TI - HIC1 modulates prostate cancer progression by epigenetic modification. AB - PURPOSE: Prostate cancer is the second leading cause of cancer deaths among men in Western counties, which has also occurred in Chinese male with markedly increasing incidence in recent years. Although the mechanism underlying its progression still remains unclear, epigenetic modifications are important ethological parameters. The purpose of this study is to determine the methylation status and function of hypermethylatioted in cancer 1 (HIC1) in prostate cancer progression. EXPERIMENTAL DESIGN: The methylation status of HIC1 promoter was assayed in cell lines, tissues, and plasma of patients with prostate cancer by using methylation-specific PCR and bisulfate sequencing PCR. The ability of HIC1 to regulate proliferation, migration, and invasion was assessed by MTT, scratch healing assay, and reconstituted extracellular matrices in porous culture chambers. Tumorigenesis, metastases, and bone destruction were analyzed in mice bearing prostate cancer cells restoring HIC1 by using Xenogen IVIS with radiographic system and small-animal positron emission tomography computed tomographic images. Microarrays were searched for genes that had correlated expression with HIC1 mRNA. Reporter gene assays were used to determine whether HIC1 affected the expression of CXCR7, and chromatin immunoprecipitation was used to determine whether HIC1 bound to CXCR7 promoters. All P values were determined using 2-sided tests. RESULTS: The methylation status of 11 CpG sites within HIC1 promoter was abundantly methylated in cell lines, tissues, and plasma of patients with prostate cancer compared with those of respective normal controls. Restoring HIC1 expression in prostate cancer cells markedly inhibited proliferation, migration, and invasion and induced the apoptosis in these cells. Moreover, mice bearing prostate cancer-restoring HIC1 cells had a marked effect on reducing tumor growth, multiple tissue metastases, and bone destruction. Notably, we also identified that the chemokine receptor CXCR7 is a direct downstream target gene of HIC1. Finally, we showed that CXCR7 promoter in prostate cancer cells is negatively regulated by HIC1, which may be responsible for prostate cancer progression. CONCLUSIONS: Our data show for the first time that hypermethylation of HIC1 promoter results in loss of its repressive function, responsible for prostate cancer progression and invasion. These findings suggest that therapies targeting epigenetic events regulating HIC1 expression may provide a more effective strategy for prostate cancer treatment. PMID- 23340302 TI - Establishment and validation of circulating tumor cell-based prognostic nomograms in first-line metastatic breast cancer patients. AB - PURPOSE: Circulating tumor cells (CTC) represent a new outcome-associated biomarker independent from known prognostic factors in metastatic breast cancer (MBC). The objective here was to develop and validate nomograms that combined baseline CTC counts and the other prognostic factors to assess the outcome of individual patients starting first-line treatment for MBC. EXPERIMENTAL DESIGN: We used a training set of 236 patients with MBCs starting a first-line treatment from the M.D. Anderson Cancer Center (Houston, TX) to establish nomograms that calculated the predicted probability of survival at different time points: 1, 2, and 5 years for overall survival (OS) and 6 months and 1 and 2 years for progression-free survival (PFS).The covariates computed in the model were age, disease subtype, visceral metastases, performance status, and CTC counts by CellSearch. Nomograms were independently validated with 210 patients with MBCs from the Institut Curie (Paris, France) who underwent first-line chemotherapy. The discriminatory ability and accuracy of the models were assessed using Harrell c-statistic and calibration plots at different time points in both training and validation datasets. RESULTS: Median follow-up was of 23 and 29 months in the MD Anderson and Institut Curie cohorts, respectively. Nomograms showed good c statistics: 0.74 for OS and 0.65 for PFS and discriminated OS prediction at 1, 2, and 5 years, and PFS prediction at 6 months and 1 and 2 years. CONCLUSIONS: Nomograms, which relied on CTC counts as a continuous covariate, easily facilitated the use of a web-based tool for estimating survival, supporting treatment decisions and clinical trial stratification in first-line MBCs. PMID- 23340303 TI - Prognostic and predictive value of tumor vascular endothelial growth factor gene amplification in metastatic breast cancer treated with paclitaxel with and without bevacizumab; results from ECOG 2100 trial. AB - PURPOSE: Clinically validated biomarkers for anti-angiogenesis agents are not available. We have previously reported associations between candidate VEGFA single-nucleotide polymorphisms (SNP) and overall survival (OS) in E2100. The associations between tumor VEGFA amplification and outcome are evaluated here. EXPERIMENTAL DESIGN: E2100 was a phase III trial comparing paclitaxel with or without bevacizumab for patients with metastatic breast cancer. FISH to assess gene amplification status for VEGFA was conducted on paraffin-embedded tumors from 363 patients in E2100. Evaluation for association between amplification status and outcomes was conducted. RESULTS: Estrogen receptor (ER)+ or progesterone receptor (PR)+ tumors were less likely to have VEGFA amplification than ER/PR- tumors (P = 0.020). VEGFA amplification was associated with worse OS (20.2 vs. 25.3 months; P = 0.013) in univariate analysis with a trend for worse OS in multivariate analysis (P = 0.08). There was a significant interaction between VEGFA amplification, hormone receptor status, and study arm. Patients with VEGFA amplification and triple-negative breast cancers (TNBC) or HER2 amplification had inferior OS (P = 0.047); amplification did not affect OS for those who were ER+ or PR+ and HER2-. Those who received bevacizumab with VEGFA amplification had inferior progression-free survival (PFS; P = 0.010) and OS (P = 0.042); no association was seen in the control arm. Test for interaction between study arm and VEGFA amplification with OS was not significant. CONCLUSION: VEGFA amplification in univariate analysis was associated with poor outcomes; this was particularly prominent in HER2+ or TNBCs. Additional studies are necessary to confirm the trend for poor OS seen on multivariate analysis for patients treated with bevacizumab. PMID- 23340304 TI - ZEB1 Promotes invasiveness of colorectal carcinoma cells through the opposing regulation of uPA and PAI-1. AB - PURPOSE: Carcinoma cells enhance their invasive capacity through dedifferentiation and dissolution of intercellular adhesions. A key activator of this process is the ZEB1 transcription factor, which is induced in invading cancer cells by canonical Wnt signaling (beta-catenin/TCF4). Tumor invasiveness also entails proteolytic remodeling of the peritumoral stroma. This study aimed to investigate the potential regulation by ZEB1 of the plasminogen proteolytic system constituted by the urokinase plasminogen activator (uPA), and its inhibitor, plasminogen activator inhibitor-1 (PAI-1). EXPERIMENTAL DESIGN: Through multiple experimental approaches, colorectal carcinoma (CRC) cell lines and samples from human primary CRC and ZEB1 (-/-) mice were used to examine ZEB1 mediated regulation of uPA and PAI-1 at the protein, mRNA, and transcriptional level. RESULTS: ZEB1 regulates uPA and PAI-1 in opposite directions: induces uPA and inhibits PAI-1. In vivo expression of uPA depends on ZEB1 as it is severely reduced in the developing intestine of ZEB1 null (-/-) mice. Optimal induction of uPA by Wnt signaling requires ZEB1 expression. ZEB1 binds to the uPA promoter and activates its transcription through a mechanism implicating the histone acetyltransferase p300. In contrast, inhibition of PAI-1 by ZEB1 does not involve transcriptional repression but rather downregulation of mRNA stability. ZEB1 mediated tumor cell migration and invasion depend on its induction of uPA. ZEB1 coexpresses with uPA in cancer cells at the invasive front of CRCs. CONCLUSIONS: ZEB1 promotes tumor invasiveness not only via induction in cancer cells of a motile dedifferentiated phenotype but also by differential regulation of genes involved in stroma remodeling. PMID- 23340305 TI - Perfluoroalkylated compounds induce cell death and formation of reactive oxygen species in cultured cerebellar granule cells. AB - The present communication investigates the effects of different perfluoroalkylated compounds (PFCs) on formation of reactive oxygen species (ROS) and cell death in cultured cerebellar granule cells. This allows direct comparison with similar effects found for other environmental contaminants like polychlorinated biphenyls and brominated flame-retardants. The increase in ROS formation and cell death was assayed using the fluorescent probe 2,7 dichlorofluorescin diacetate (DCFH-DA) and the trypan blue exclusion assay. The effects of the PFCs were structure dependent. Cell death was induced at relatively low concentrations by perfluorooctyl sulfonate (PFOS), perfluorooctane sulfonylamide (PFOSA) and the fluorotelomer alcohol 1H, 1H, 2H, 2H perfluorodecanol (FTOH 8:2) with EC(50)-values of 62 +/- 7.6, 13 +/- 1.8 and 15 +/- 4.2 MUM (mean +/- SD) respectively. PFOS, perfluorooctanoic acid (PFOA) and PFOSA induced a concentration dependent increase in ROS formation with EC(50) values of 27 +/- 9.0, 25 +/- 11 and 57 +/- 19MUM respectively. Reduced cell viability and ROS formation were observed at concentration level close to what is found in serum of occupationally exposed workers. The effect of PFCs on ROS formation and cell viability was compared with other halogenated compounds and future investigations should emphasize effects of mixtures and how physical chemical properties of the compounds influence their toxicity. PMID- 23340306 TI - MicroRNA aberrances in head and neck cancer: pathogenetic and clinical significance. AB - PURPOSE OF REVIEW: MicroRNAs (miRNAs) play crucial roles in modulating the neoplastic process of cancers including head and neck squamous cell carcinoma (HNSCC). miRNAs modulate pathogenesis by inhibiting target genes. Understanding how aberrant miRNAs are involved in HNSCC pathogenesis should help to validate potential clinical applications that target these entities. RECENT FINDINGS: miR 21, miR-31, miR-504 and miR-10b are important oncogenic miRNAs that are involved in HNSCC and target tumour suppressor genes. The tumour suppressor roles of the let-7 family, the miR-99 family, miR-107, miR-133a, miR-137, miR-138 and miR-375 with respect to their targeting of oncogenes are unequivocal and have been confirmed by many studies. In addition, miR-21, let-7, miR-107, miR-138 and miR 200c seem to play complicated roles in regulating stemness or the epithelial mesenchymal transition of tumour cells. The clinical implications of these tumour associated miRNAs are generally in agreement with their functional roles. SUMMARY: A number of pathways that become disregulated by aberrant miRNAs have been identified specifically for HNSCC. Analysis of these networks and their therapeutic interception might facilitate the prediction of disease status and help with the design of therapeutic trials. PMID- 23340307 TI - A HPLC method for simultaneous determination of 5-aminoimidazole-4-carboxamide riboside and its active metabolite 5-aminoimidazole-4-carboxamide ribotide in tumor-bearing nude mice plasma and its application to pharmacokinetics study. AB - A HPLC method with on-line solid phase extraction (SPE) and column switching was developed for simultaneous determination of 5-aminoimidazole-4-carboxamide riboside (AICA riboside) and its active metabolite 5-aminoimidazole-4-carboxamide ribotide (AICA ribotide) in nude mice plasma. Plasma sample was deproteinized by adding a half volume of 10% trichloroacetic acid (TCA), and the resulting supernatant was extracted with diethyl ether to remove TCA. 50 MUl aqueous fraction was injected onto a WAX-1 SPE column, and AICA ribotide was trapped on the SPE column, while AICA riboside was eluted from the SPE column. The chromatographic separation of AICA riboside was achieved on CG16 column, and separation of AICA ribotide was performed on HILIC-10 and WAX-1 column. The columns temperature was maintained at 40 degrees C, and the optimal detection wavelength was 268 nm for both AICA riboside and AICA ribotide. The total analytical run time was 40 min. The proposed method was linear over the range of 0.1-500 MUg/ml for AICA riboside and 0.03-50 MUg/ml for AICA ribotide. The lower limit of quantification (LLOQ) was 100 and 30 ng/ml for AICA riboside and AICA ribotide, respectively. The sensitivity, accuracy and precision of this method were within acceptable limits during validation period. The method was successfully applied to investigate the pharmacokinetics characteristics of AICA riboside and its active metabolite AICA ribotide in nude mice bearing MCF-7 cell xenografts. PMID- 23340308 TI - Coumarin: an alternative candidate for the treatment of non-alcoholic steatohepatitis? PMID- 23340309 TI - Sulfatide attenuates experimental Staphylococcus aureus sepsis through a CD1d dependent pathway. AB - Natural killer T (NKT) lymphocytes are implicated in the early response to microbial infection. Further, sulfatide, a myelin self-glycosphingolipid, activates a type II NKT cell subset and can modulate disease in murine models. We examined the role of NKT cells and the effect of sulfatide treatment in a murine model of Staphylococcus aureus sepsis. The lack of CD1d-restricted NKT cells did not alter survival after a lethal inoculum of S. aureus. In contrast, sulfatide treatment significantly improved the survival rate of mice with S. aureus sepsis, accompanied by decreased levels of tumor necrosis factor alpha and interleukin-6 in the blood. The protective effect of sulfatide treatment depended on CD1d but not on type I NKT cells, suggesting that activation of type II NKT cells by sulfatide has beneficial effects on the outcome of S. aureus sepsis in this model. PMID- 23340310 TI - Killer cell lectin-like receptor G1 deficiency significantly enhances survival after Mycobacterium tuberculosis infection. AB - The expression of T cell differentiation markers is known to increase during Mycobacterium tuberculosis infection, and yet the biological role of such markers remains unclear. We examined the requirement of the T cell differentiation marker killer cell lectin-like receptor G1 (KLRG1) during M. tuberculosis infection using mice deficient in KLRG1. KLRG1(-/-) mice had a significant survival extension after M. tuberculosis infection compared to wild-type controls, and maintained a significantly lower level of pulmonary M. tuberculosis throughout chronic infection. Improved control of M. tuberculosis infection was associated with an increased number of activated pulmonary CD4(+) T cells capable of secreting gamma interferon (IFN-gamma). Our report is the first to show an in vivo impact of KLRG1 on disease control. PMID- 23340311 TI - Myeloid dendritic cells (DCs) of mice susceptible to paracoccidioidomycosis suppress T cell responses whereas myeloid and plasmacytoid DCs from resistant mice induce effector and regulatory T cells. AB - The protective adaptive immune response in paracoccidioidomycosis, a mycosis endemic among humans, is mediated by T cell immunity, whereas impaired T cell responses are associated with severe, progressive disease. The early host response to Paracoccidioides brasiliensis infection is not known since the disease is diagnosed at later phases of infection. Our laboratory established a murine model of infection where susceptible mice reproduce the severe disease, while resistant mice develop a mild infection. This work aimed to characterize the influence of dendritic cells in the innate and adaptive immunity of susceptible and resistant mice. We verified that P. brasiliensis infection induced in bone marrow-derived dendritic cells (DCs) of susceptible mice a prevalent proinflammatory myeloid phenotype that secreted high levels of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-beta, whereas in resistant mice, a mixed population of myeloid and plasmacytoid DCs secreting proinflammatory cytokines and expressing elevated levels of secreted and membrane bound transforming growth factor beta was observed. In proliferation assays, the proinflammatory DCs from B10.A mice induced anergy of naive T cells, whereas the mixed DC subsets from resistant mice induced the concomitant proliferation of effector and regulatory T cells (Tregs). Equivalent results were observed during pulmonary infection. The susceptible mice displayed preferential expansion of proinflammatory myeloid DCs, resulting in impaired proliferation of effector T cells. Conversely, the resistant mice developed myeloid and plasmacytoid DCs that efficiently expanded gamma interferon-, IL-4-, and IL-17-positive effector T cells associated with increased development of Tregs. Our work highlights the deleterious effect of excessive innate proinflammatory reactions and provides new evidence for the importance of immunomodulation during pulmonary paracoccidioidomycosis. PMID- 23340312 TI - RegR virulence regulon of rabbit-specific enteropathogenic Escherichia coli strain E22. AB - AraC-like regulators play a key role in the expression of virulence factors in enteric pathogens, such as enteropathogenic Escherichia coli (EPEC), enterotoxigenic E. coli, enteroaggregative E. coli, and Citrobacter rodentium. Bioinformatic analysis of the genome of rabbit-specific EPEC (REPEC) strain E22 (O103:H2) revealed the presence of a gene encoding an AraC-like regulatory protein, RegR, which shares 71% identity to the global virulence regulator, RegA, of C. rodentium. Microarray analysis demonstrated that RegR exerts 25- to 400 fold activation on transcription of several genes encoding putative virulence associated factors, including a fimbrial operon (SEF14), a serine protease, and an autotransporter adhesin. These observations were confirmed by proteomic analysis of secreted and heat-extracted surface-associated proteins. The mechanism of RegR-mediated activation was investigated by using its most highly upregulated gene target, sefA. Transcriptional analyses and electrophoretic mobility shift assays showed that RegR activates the expression of sefA by binding to a region upstream of the sefA promoter, thereby relieving gene silencing by the global regulatory protein H-NS. Moreover, RegR was found to contribute significantly to virulence in a rabbit infection experiment. Taken together, our findings indicate that RegR controls the expression of a series of accessory adhesins that significantly enhance the virulence of REPEC strain E22. PMID- 23340313 TI - Altered immune response differentially enhances susceptibility to Cryptococcus neoformans and Cryptococcus gattii infection in mice expressing the HIV-1 transgene. AB - Cryptococcus neoformans var. grubii is the most frequent cause of AIDS-associated cryptococcosis worldwide, while Cryptococcus gattii usually infects immunocompetent people. To understand the mechanisms which cause differential susceptibility to these cryptococcal species in HIV infection, we established and characterized a model of cryptococcosis in CD4C/HIV(MutA) transgenic (Tg) mice expressing gene products of HIV-1 and developing an AIDS-like disease. Tg mice infected intranasally with C. neoformans var. grubii strain H99 or C23 consistently displayed reduced survival compared to non-Tg mice at three graded inocula, while shortened survival of Tg mice infected with C. gattii strain R265 or R272 was restricted to a single high inoculum. HIV-1 transgene expression selectively augmented systemic dissemination to the liver and spleen for strains H99 and C23 but not strains R265 and R272. Histopathologic examination of lungs of Tg mice revealed large numbers of widely scattered H99 cells, with a minimal inflammatory cell response, while in the non-Tg mice H99 was almost completely embedded within extensive mixed inflammatory cell infiltrates. In contrast to H99, R265 was dispersed throughout the lung parenchyma and failed to induce a strong inflammatory response in both Tg and non-Tg mice. HIV-1 transgene expression reduced pulmonary production of CCL2 and CCL5 after infection with H99 or R265, and production of these two chemokines was lower after infection with R265. These results indicate that an altered immune response in these Tg mice markedly enhances C. neoformans but not C. gattii infection. This model therefore provides a powerful new tool to further investigate the immunopathogenesis of cryptococcosis. PMID- 23340314 TI - Role of host xanthine oxidase in infection due to enteropathogenic and Shiga toxigenic Escherichia coli. AB - Xanthine oxidase (XO), also known as xanthine oxidoreductase, has long been considered an important host defense molecule in the intestine and in breastfed infants. Here, we present evidence that XO is released from and active in intestinal tissues and fluids in response to infection with enteropathogenic Escherichia coli (EPEC) and Shiga-toxigenic E. coli (STEC), also known as enterohemorrhagic E. coli (EHEC). XO is released into intestinal fluids in EPEC and STEC infection in a rabbit animal model. XO activity results in the generation of surprisingly high concentrations of uric acid in both cultured cell and animal models of infection. Hydrogen peroxide (H(2)O(2)) generated by XO activity triggered a chloride secretory response in intestinal cell monolayers within minutes but decreased transepithelial electrical resistance at 6 to 22 h. H(2)O(2) generated by XO activity was effective at killing laboratory strains of E. coli, commensal microbiotas, and anaerobes, but wild-type EPEC and STEC strains were 100 to 1,000 times more resistant to killing or growth inhibition by this pathway. Instead of killing pathogenic bacteria, physiologic concentrations of XO increased virulence by inducing the production of Shiga toxins from STEC strains. In vivo, exogenous XO plus the substrate hypoxanthine did not protect and instead worsened the outcome of STEC infection in the rabbit ligated intestinal loop model of infection. XO released during EPEC and STEC infection may serve as a virulence-inducing signal to the pathogen and not solely as a protective host defense. PMID- 23340315 TI - Characterization of BcaA, a putative classical autotransporter protein in Burkholderia pseudomallei. AB - Burkholderia pseudomallei is a tier 1 select agent, and the causative agent of melioidosis, a disease with effects ranging from chronic abscesses to fulminant pneumonia and septic shock, which can be rapidly fatal. Autotransporters (ATs) are outer membrane proteins belonging to the type V secretion system family, and many have been shown to play crucial roles in pathogenesis. The open reading frame Bp1026b_II1054 (bcaA) in B. pseudomallei strain 1026b is predicted to encode a classical autotransporter protein with an approximately 80-kDa passenger domain that contains a subtilisin-related domain. Immediately 3' to bcaA is Bp11026_II1055 (bcaB), which encodes a putative prolyl 4-hydroxylase. To investigate the role of these genes in pathogenesis, large in-frame deletion mutations of bcaA and bcaB were constructed in strain Bp340, an efflux pump mutant derivative of the melioidosis clinical isolate 1026b. Comparison of Bp340DeltabcaA and Bp340DeltabcaB mutants to wild-type B. pseudomallei in vitro demonstrated similar levels of adherence to A549 lung epithelial cells, but the mutant strains were defective in their ability to invade these cells and to form plaques. In a BALB/c mouse model of intranasal infection, similar bacterial burdens were observed after 48 h in the lungs and liver of mice infected with Bp340DeltabcaA, Bp340DeltabcaB, and wild-type bacteria. However, significantly fewer bacteria were recovered from the spleen of Bp340DeltabcaA-infected mice, supporting the idea of a role for this AT in dissemination or in survival in the passage from the site of infection to the spleen. PMID- 23340316 TI - Does milk cause constipation? A crossover dietary trial. AB - The aims of this study were to: (1) determine whether replacement of cow's milk protein with soy resolves Chronic Functional Constipation (CFC); and (2) investigate the effects of cow's milk beta casein A1 and cow's milk beta casein A2 on CFC. Children diagnosed with CFC were recruited to one of two crossover trials: Trial 1 compared the effects of cow's milk and soy milk; Trial 2 compared the effects of cow's milk beta casein A1 and cow's milk beta casein A2. Resolution of constipation was defined as greater than eight bowel motions during a two week intervention. Thirteen children (18 to 144 months) participated in Trial 1 (6 boys, 7 girls). Nine participants who completed the soy epoch all experienced resolution (p < 0.05). Thirty-nine children (21 to 144 months) participated in Trial 2 (25 boys, 14 girls). Resolution of constipation was highest during the washout epoch, 81%; followed by cow's milk beta casein A2, 79%; and cow's milk beta casein A1, 57%; however, the proportions did not differ statistically. The results of Trial 1 demonstrate an association between CFC and cow's milk consumption but Trial 2 failed to show an effect from type of casein. Some other component in cow's milk common to both A1 and A2 milk may be causing a problem in these susceptible children. PMID- 23340317 TI - A national observational study of the prevalence and use of enteral tube feeding, parenteral nutrition and intravenous glucose in cancer patients enrolled in specialized palliative care. AB - The use of artificial nutrition remains controversial for cancer patients in palliative care, and its prevalence is largely unknown. We therefore conducted a national study to investigate the prevalence, indications for, and perceived benefit of enteral/parenteral nutrition and intravenous glucose in this patient group. A cross-sectional study was performed within the palliative care research network in Sweden (PANIS), using a web-based survey with 24 questions on demographics, prescribed nutritional treatment, estimated survival and benefit from treatment. Data was received from 32 palliative care units throughout the country, representing 1083 patients with gastrointestinal and gynecological malignancies being the most common diagnoses. Thirteen percent of the patients received enteral/parenteral nutrition or intravenous glucose. Parenteral nutrition (PN) was significantly more common in home care units serving the urban Stockholm region (11%) than in other parts of the country (4%). Weight and appetite loss were the predominant indications for PN, with this treatment deemed beneficial for 75% of the palliative patients. Data show that there was great variation in PN use within the country. PN was predominately initiated when patients had weight and appetite loss but still had oral intake, indicating a use of PN that extends beyond the traditional use for patients with obstruction/semi obstruction. PMID- 23340318 TI - Food sources of energy and nutrients among children in the United States: National Health and Nutrition Examination Survey 2003-2006. AB - BACKGROUND: Recent detailed analyses of data on dietary sources of energy and nutrients in US children are lacking. The objective of this study was to identify food sources of energy and 28 nutrients for children in the United States. METHODS: Analyses of food sources were conducted using a single 24-h recall collected from children 2 to 18 years old (n = 7332) in the 2003-2006 National Health and Nutrition Examination Survey. Sources of nutrients contained in foods were determined using nutrient composition databases. Food grouping included ingredients from disaggregated mixtures. Mean energy and nutrient intakes from the total diet and from each food group were adjusted for the sample design using appropriate weights. Percentages of the total dietary intake that food sources contributed were tabulated by rank order. RESULTS: The two top ranked food/food group sources of energy and nutrients were: energy - milk (7% of energy) and cake/cookies/quick bread/pastry/pie (7%); protein - milk (13.2%) and poultry (12.8%); total carbohydrate - soft drinks/soda (10.5%) and yeast bread/rolls (9.1%); total sugars - soft drinks/soda (19.2%) and yeast breads and rolls (12.7%); added sugars - soft drinks/soda (29.7%) and candy/sugar/sugary foods (18.6%); dietary fiber - fruit (10.4%) and yeast bread/rolls (10.3%); total fat - cheese (9.3%) and crackers/popcorn/pretzels/chips (8.4%); saturated fatty acids - cheese (16.3%) and milk (13.3%); cholesterol - eggs (24.2%) and poultry (13.2%); vitamin D - milk (60.4%) and milk drinks (8.3%); calcium - milk (33.2%) and cheese (19.4%); potassium - milk (18.8%) and fruit juice (8.0%); and sodium - salt (18.5%) and yeast bread and rolls (8.4%). CONCLUSIONS: Results suggest that many foods/food groupings consumed by children were energy dense, nutrient poor. Awareness of dietary sources of energy and nutrients can help health professionals design effective strategies to reduce energy consumption and increase the nutrient density of children's diets. PMID- 23340320 TI - Prenatal ethanol exposure does not cause neurological alterations in adult CD1 mice. AB - Genetic factors are involved in variation in fetal alcohol spectrum disorders (FASD), which is also observed among various inbred mouse strains. The CD1 mouse strain is often used in toxicological and genetic experiments. However, there is little literature using this strain to study long-term neurologic abnormalities of FASD. In the present study, we addressed the effect of prenatal ethanol exposure on neurological alterations in adult CD1 mice. The female CD1 mice received exposure to ethanol solution (10 vol%) starting from 2 weeks before mating up to pups born (postnatal day 1). At 24 weeks after the birth, the prenatal ethanol-exposed mice and control mice showed no difference in spatial learning and memory performance in a Morris water maze. Consistently, pathological changes, such as increased neuronal apoptosis, decreased synaptic protein synaptophysin expression, synaptic loss and reactive astrogliosis, were not observed in the hippocampus of mice prenatally exposed to ethanol. These results suggest that CD1 mice are highly resistant to prenatal alcohol exposure and may serve as genetic modification models of FASD. PMID- 23340321 TI - Dynamic environmental transmission electron microscopy observation of platinum electrode catalyst deactivation in a proton-exchange-membrane fuel cell. AB - Spherical-aberration-corrected environmental transmission electron microscopy (AC ETEM) was applied to study the catalytic activity of platinum/amorphous carbon electrode catalysts in proton-exchange-membrane fuel cells (PEMFCs). These electrode catalysts were characterized in different atmospheres, such as hydrogen and air, and a conventional high vacuum of 10(-5) Pa. A high-speed charge coupled device camera was used to capture real-time movies to dynamically study the diffusion and reconstruction of nanoparticles with an information transfer down to 0.1 nm, a time resolution below 0.2 s and an acceleration voltage of 300 kV. With such high spatial and time resolution, AC-ETEM permits the visualization of surface-atom behaviour that dominates the coalescence and surface-reconstruction processes of the nanoparticles. To contribute to the development of robust PEMFC platinum/amorphous carbon electrode catalysts, the change in the specific surface area of platinum particles was evaluated in hydrogen and air atmospheres. The deactivation of such catalysts during cycle operation is a serious problem that must be resolved for the practical use of PEMFCs in real vehicles. In this paper, the mechanism for the deactivation of platinum/amorphous carbon electrode catalysts is discussed using the decay rate of the specific surface area of platinum particles, measured first in a vacuum and then in hydrogen and air atmospheres for comparison. PMID- 23340322 TI - Current state of palliative and end-of-life care in home versus inpatient facilities and urban versus rural settings in Africa. AB - OBJECTIVE: Because palliative care in sub-Saharan Africa may not fit the style of delivery of palliative care in the global north, exploring the evidence can serve to reduce existing barriers and help streamline national policies that determine the optimal setting to implement formal palliative and end-of-life services. METHOD: A search was conducted in Ovid MEDLINE(r), PubMed, and Google Scholar databases using the search terms nursing care, terminal care, end of life care, palliative care, dying, death, hospice, opioids, morphine, Africa, sub-Saharan Africa, caregivers, and place of death. Eighty-seven relevant articles were found using the search terms. Of these, 22 matched inclusion criteria and were reviewed. RESULTS: Opioid availability and distribution is best accessed at the inpatient level, and hence, pain and end-of-life symptoms are best managed at the inpatient level. Despite the great need, nurses' lack of prescription power in the home-based setting is a shortcoming. Home deaths have not been adequately studied, but research suggests that palliative care generally causes economic strain, psychosocial distress on family members, and increased risk of transmission of communicable disease. Hospice is understudied but shows favorable outcomes. SIGNIFICANCE OF RESULTS: Funding and research need to focus on development of inpatient palliative and hospice care units in urban areas. In rural areas, the priority should be a home-based care model that involves nurses who are privileged to prescribe opioids and adjunctive medication therapies. PMID- 23340319 TI - Calcium nutrition and extracellular calcium sensing: relevance for the pathogenesis of osteoporosis, cancer and cardiovascular diseases. AB - Through a systematic search in Pubmed for literature, on links between calcium malnutrition and risk of chronic diseases, we found the highest degree of evidence for osteoporosis, colorectal and breast cancer, as well as for hypertension, as the only major cardiovascular risk factor. Low calcium intake apparently has some impact also on cardiovascular events and disease outcome. Calcium malnutrition can causally be related to low activity of the extracellular calcium-sensing receptor (CaSR). This member of the family of 7-TM G-protein coupled receptors allows extracellular Ca2+ to function as a "first messenger" for various intracellular signaling cascades. Evidence demonstrates that Ca2+/CaSR signaling in functional linkage with vitamin D receptor (VDR)-activated pathways (i) promotes osteoblast differentiation and formation of mineralized bone; (ii) targets downstream effectors of the canonical and non-canonical Wnt pathway to inhibit proliferation and induce differentiation of colorectal cancer cells; (iii) evokes Ca2+ influx into breast cancer cells, thereby activating pro apoptotic intracellular signaling. Furthermore, Ca2+/CaSR signaling opens Ca2+ sensitive K+ conductance channels in vascular endothelial cells, and also participates in IP(3)-dependent regulation of cytoplasmic Ca2+, the key intermediate of cardiomyocyte functions. Consequently, impairment of Ca2+/CaSR signaling may contribute to inadequate bone formation, tumor progression, hypertension, vascular calcification and, probably, cardiovascular disease. PMID- 23340323 TI - Differential proteomic profiles from distinct Toxoplasma gondii strains revealed by 2D-difference gel electrophoresis. AB - Toxoplasma gondii is an obligate intracellular protozoan that infects mammals and birds. Human infection during pregnancy may cause severe damage to the fetus. Reactivation of latent infection in immunocompromised patients can cause life threatening encephalitis. T. gondii strains are highly diverse but only a few lineages (Type I, II and III) are widely spread. In mouse model, Type I strains are highly virulent, whereas Type II and III strains are intermediately or non virulent. It is not clear how much quantitative difference exists in proteomic profiles among these distinct T. gondii lineages. In the present study, the proteomic profiles of T. gondii tachyzoites from these lineages were investigated by two dimensional fluorescence difference gel electrophoresis (2D-DIGE) and mass spectrometry (MS) technologies. A total of 2321 protein spots were detected. Overall, the GT1 strain of Type I lineage and the strain PTG of Type II lineage have highly similar proteomic profiles and both are different from that of the CTG strain of Type III lineage. Eighty-four protein spots were differentially expressed by greater than 1.5-fold in relative abundance and 10 of them were identified to 7 T. gondii proteins in existing database. Investigation of the quantitative differences in proteomics among distinct T. gondii strains should facilitate our understanding of difference in biological processes and pathogenesis of distinct T. gondii genotypes, which will provide basic information to determine treatment regimen for different manifestation of toxoplasmosis. PMID- 23340324 TI - Inhibition of IL-1 Signaling by Antisense Oligonucleotide-mediated Exon Skipping of IL-1 Receptor Accessory Protein (IL-1RAcP). AB - The cytokine interleukin 1(IL-1) initiates a wide range of proinflammatory cascades and its inhibition has been shown to decrease inflammation in a variety of diseases. IL-1 receptor accessory protein (IL-1RAcP) is an indispensible part of the IL-1R complex that stabilizes IL-1/IL-1R interaction and plays an important role in the signal transduction of the receptor complex. The soluble form of IL-1RAcP (sIL-1RAcP) contains only the extracellular domain and serves as a natural inhibitor of IL-1 signaling. Therefore, increasing sIL-1RAcP levels might be an attractive therapeutic strategy to inhibit IL-1-driven inflammation. To achieve this we designed specific antisense oligonucleotides (AON), to redirect pre-mRNA IL-1RAcP splicing by skipping of the transmembrane domain encoding exon 9. This would give rise to a novel Delta9IL-1RAcP mRNA encoding a soluble, secreted form of IL-1RAcP, which might have similar activity as natural sIL-1RAcP. AON treatment resulted in exon 9 skipping both in vitro and in vivo. A single dose injection of 10 mg AON/kg body weight induced 90% skipping in mouse liver during at least 5 days. The truncated mRNA encoded for a secreted, soluble Delta9IL-1RAcP protein. IL-1RAcP skipping resulted in a substantial inhibition of IL-1 signaling in vitro. These results indicate that skipping of the transmembrane encoding exon 9 of IL-1RAcP using specific AONs might be a promising therapeutic strategy in a variety of chronic inflammatory diseases.Molecular Therapy - Nucleic Acids (2013) 2, e66; doi:10.1038/mtna.2012.58; published online 22 January 2013. PMID- 23340325 TI - Porous starch based self-assembled nano-delivery system improves the oral absorption of lipophilic drug. AB - The therapeutic efficacy of lipophilic drugs is commonly restricted by the low systemic exposure after oral administration. In this work, a new delivery system combining the advantages of porous starch and self-assembled nanocarrier was designed to improve the oral absorption of lipophilic drugs. The lipophilic probucol loaded porous starch based self-assembled nano-delivery (PSN) system was developed and characterized. The probucol loaded nanocarrier (PLN) could be formed by self-assembly when PSN was dispersed into the gastrointestinal (GI) fluids. PLN was nanometer-sized particles with narrow size distribution and exhibited good stability in GI fluids. The aqueous solubility of probucol was increased over 50,000-fold by PSN delivery system and the cumulative release of lipophilic probucol was increased over 80% in GI fluids. The distribution of probucol in duodenum, jejunum and ileum was respectively improved 7.17, 15.99 and 33.61-fold by PSN. In particular, the oral bioavailability of probucol from PSN was greatly improved about 9.96-fold than that from free drug suspension and 3.71 fold higher than that from the directed adsorbed probucol loaded porous starch system, which effectively confirmed the high potential of the strategy in enhancing the oral absorption of lipophilic drugs. PMID- 23340326 TI - Immunological effects of microneedle-mediated insulin delivery: preliminary rat studies. AB - The objective of the present study is to compare the immunogenicity of insulin by microneedle-mediated intradermal delivery or subcutaneous injection. Female and male rats were treated with insulin by either microneedle-mediated intradermal delivery or subcutaneous injection twice a week for 4 weeks. A control group without insulin administration was also studied. Human anti-insulin antibody (AIA) levels were measured by radioimmunoassay (RIA) before starting insulin treatment and after that within 20 weeks. The male rats did not induce positive AIA levels, and there was no significant difference between all male groups. In contrast, in female rats the AIA levels were significantly higher in microneedle group compared with injection group, and lasted from 6 to 20 weeks after starting insulin treatment. The increased immunogenicity of insulin delivery by microneedle might be due to the large number of immune cells in skin. PMID- 23340327 TI - Stability and physicochemical characterization of novel milk-based oral formulations. AB - PURPOSE: The purpose of this work was to assess the colloidal stability of novel milk-based formulations. METHODS: Milk-based formulations were prepared in situ by adding into milk alkaline- or ethanolic-drug solutions containing an array of drugs namely; ketoprofen, tolfenamic acid, meloxicam, tenoxicam and nimesulide, mefenamic acid, cyclosporine A, danazol and clopidogrel besylate. The produced formulations were characterized by means of dynamic lightscattering, zeta potential studies, atomic force microscopy, fluorescence spectroscopy, Raman spectroscopy complemented with ab initio calculations and stability studies. RESULTS: The presence of the drugs did not induce significant changes in most cases to the particle size and zeta-potential values of the emulsions pointing to the colloidal stability of these formulations. Raman spectroscopy studies revealed interactions of the drugs and the milk at the intermolecular level. Complementary analysis with ab initio calculations confirmed the experimental observations obtained by Raman spectroscopy. Finally the produced drug containing alkaline/ethanolic solutions exhibited stability over a period of up to 12 months. CONCLUSIONS: The current data demonstrate that milk is a promising drug carrier. PMID- 23340328 TI - Interventions on mealtime difficulties in older adults with dementia: a systematic review. AB - OBJECTIVES: To evaluate the effects of interventions on mealtime difficulties in older adults with dementia. DESIGN: A systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA Statement. DATA SOURCES: Pubmed, Medline (OVID), CINAHL (EBSCOHost), EBM Reviews (OVID) and PsychINFO (OVID) were searched between January 2004 and September 2012 by using keywords as dementia, Alzheimer, feed(ing), eat(ing), mealtime(s), oral intake, nutrition, intervention, experimental, quasi-experimental and any matched terms. Other sources included Google Scholar and relevant bibliographies. REVIEW METHODS: Eligibility criteria were established by defining the population, intervention, comparator, outcomes, timing and setting of interest. Studies were reviewed by title and abstract screening, and full-text assessing for eligibility. Data were abstracted from eligible studies using a self-made structured tool. Eligible studies were classified by intervention, accessed for quality using the Quality Assessment Tool for Quantitative Studies, and graded for evidence using the Grading of Recommendations, Assessment, Development and Evaluation Working Group criteria. RESULTS: Twenty-two intervention studies (9 RCTs), including a total of 2082 older adults with dementia and 95 professionals from more than 85 long-term care facilities, were selected, and classified into five types: nutritional supplements, training/education programs, environment/routine modification, feeding assistance and mixed interventions. Eight studies were strong, eleven moderate and three weak in quality. Limitations of body of research included lack of randomization and/or control group, small sample size without power analysis, lack of theory-based interventions and blinding, inadequate statistical analysis and plausible confounding bias. "Nutritional supplements" showed moderate evidence to increase food intake, body weight and BMI. "Training/education programs" demonstrated moderate evidence to increase eating time and decrease feeding difficulty. Both "training/education programs" and "feeding assistance" were insufficient to increase food intake. "Environment/routine modification" indicated low evidence to increase food intake, and insufficient to decrease agitation. Evidence was sparse on nutritional status, eating ability, behavior disturbance, behavioral and cognitive function, or level of dependence. CONCLUSIONS: This review provides updated evidence for clinical practice and points out priorities for nursing research. Current evidence is based on a body of research with moderate quality and existing limitations, and needs to be further explored with more rigorous studies. PMID- 23340330 TI - Management of noninfectious lung injury following hematopoietic cell transplantation. AB - PURPOSE OF REVIEW: Over the past 20 years, tremendous strides have been made to decrease treatment-related morbidity and mortality following allogeneic transplant, including management of acute and chronic lung injury. Within this context, three distinct entities are recognized, idiopathic pneumonia syndrome (IPS), bronchiolitis obliterans syndrome (BOS), and bronchiolitis obliterans organizing pneumonia (BOOP). Management options for each of these disorders are now reviewed. RECENT FINDINGS: A recent pilot study and subsequent phase II trial suggest that tumor necrosis factor (TNF) inhibitors hold promise in treating IPS. A randomized phase III trial ended prematurely, without a definitive conclusion regarding TNF inhibitors established. Few prospective trials for BOS have been performed, with current therapy based on observational studies and small case reports. Therapy for BOOP is based upon minimal clinical evidence. SUMMARY: Although corticosteroids remain the backbone of therapy for IPS, BOS, and BOOP, TNF inhibition may augment management of IPS and potentially BOS as well. Diagnostic criteria for IPS and BOS have been established, although optimal treatment strategies will ultimately require consensus monitoring and response criteria, coupled with an improved understanding of the pathophysiology underlying each disorder. For BOS and BOOP in particular, therapy has been based upon a paucity of data and anecdotal experiences. PMID- 23340329 TI - fMRI and DTI assessment of patients undergoing radical epilepsy surgery. AB - Hemispherectomy is effective for young patients suffered from unilateral cortical disease and severe drug-resistant epilepsy, but a major concern for hemispherectomy is the remaining brain functions and function recovery in patients after such surgery. In this study, seven patients were evaluated with clinical and imaging assessment pre- and post-surgery. Among them, four underwent anatomic hemispherectomy (AH) and three underwent subtotal hemispherectomy (functional hemispherectomy, FH). After the surgery, 71.4% (5/7) patients [(4/4) with AH and (1/3) with FH] became seizure free (Engel class I). Motor function of the paretic upper extremity unchanged in 4 patients and deteriorated in 3. Functional imaging results indicated that relocation of hand motor function (to the ipsilateral hemisphere) could take place before or after the surgery, or did not occur. Similar observations were made in the motor cortex activation on the paretic foot movement. In addition, both the affected and unaffected hemispheres underwent post-surgical changes in the corticospinal tracks (CST) in various degrees, but significant reinforcement of the CST in the remaining unaffected hemisphere was not evident. Further research is needed to reveal the true functional and structural changes of the remaining brain after surgery and to explore the mechanisms of such functional relocation and reorganization in patients underwent hemispherectomy. PMID- 23340331 TI - Implications of pH manipulation methods for metal toxicity: not all acidic environments are created equal. AB - The toxicity of many metals is impacted by environmental pH, through both competition and complexation by hydroxide and carbonate ions. To establish safe environmental regulation it is important to properly define the relationship between pH and metal toxicity, a process that involves manipulating the pH of test water in the lab. The current study compares the effects of the three most common pH manipulation methods (carbon dioxide, acid-base addition, and chemical buffers) on acute Pb toxicity of a model fish species, Pimephales promelas. Acidification of test water revealed that the Pb and Pb(2+) LC50 values were impacted by the pH manipulation method, with the following order of effects: HCl= 49 years) of the Blue Mountains Eye Study with fasting blood specimens and dietary intake data at baseline and 5-year follow-up. Multi level mixed regression analysis was used to relate dietary GI and sugar, starch and fibre intake to the liver enzymes alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT), as well as fasting TAG and HDL-cholesterol (HDL-C). After adjustment for potential confounding factors, a lower fibre intake was cross-sectionally related to higher GGT (P= 0.02) and fasting TAG (P= 0.002) levels, with fruit fibre being the most relevant fibre source (P= 0.095 for GGT; P= 0.003 for TAG). A higher dietary GI was associated with lower HDL-C (P= 0.046). Changes in carbohydrate quality during 5 years were not related to changes in ALT, GGT, TAG or HDL-C (P>= 0.08). In conclusion, the absence of longitudinal associations between carbohydrate quality and liver enzymes and serum lipids in this older population does not support a major role of carbohydrate nutrition in liver function among the elderly. PMID- 23340337 TI - Dynamic ICG fluorescence provides better intraoperative understanding of arteriovenous fistulae. AB - BACKGROUND: Sufficient perfusion is crucial during and after vascular neurosurgical procedures. Intraoperative indocyanine green (ICG) angiography has evolved into a useful tool in aneurysm and arteriovenous malformation surgery. Semiquantitative ICG fluorescence analysis Flow 800 may, in addition, lead to a better understanding of local perfusion. OBJECTIVE: We report the applicability and utility of semiquantitative ICG fluorescence in the surgical treatment of 5 patients with pial or dural arteriovenous fistulae. METHODS: Five patients with pial or dural arteriovenous fistulae were operated on using intraoperative semiquantitative ICG fluorescence Flow 800 (5 mg ICG bolus via central venous line). Before and after occlusion of fistulae, rise time of parenchyma and transit time from artery to parenchyma were measured. RESULTS: The analysis of flow parameters allowed detection of small fistulae and revealed a significant change in flow dynamics in the draining vein after surgical occlusion. ICG "flow" analysis showed rise time and transit time to be significantly shorter comparing pre-occlusion with post-occlusion (P = .025 and P = .039, respectively), leading to a significantly enhanced perfusion of neighboring brain parenchyma. CONCLUSION: In all 5 patients, dynamic analysis of fluorescence revealed a better understanding of intravascular rheology intraoperatively, allowing confident identification and treatment of pathology. Dynamic ICG fluorescence measurements provide additional perfusion information about flow characteristics in the draining vein and tissue perfusion, which facilitates surgical treatment of arteriovenous fistulae. PMID- 23340339 TI - Re-engineering protein interfaces yields copper-inducible ferritin cage assembly. AB - The ability to chemically control protein-protein interactions would allow the interrogation of dynamic cellular processes and lead to a better understanding and exploitation of self-assembling protein architectures. Here we introduce a new engineering strategy--reverse metal-templated interface redesign (rMeTIR)- that transforms a natural protein-protein interface into one that only engages in selective response to a metal ion. We have applied rMeTIR to render the self assembly of the cage-like protein ferritin controllable by divalent copper binding, which has allowed the study of the structure and stability of the isolated ferritin monomer, the demonstration of the primary role of conserved hydrogen-bonding interactions in providing geometric specificity for cage assembly and the uniform chemical modification of the cage interior under physiological conditions. Notably, copper acts as a structural template for ferritin assembly in a manner that is highly reminiscent of RNA sequences that template virus capsid formation. PMID- 23340340 TI - Pulmonary metastasectomy for colorectal cancer: long-term survival and prognostic factors. AB - BACKGROUND: Despite the development of novel chemotherapy and biological agents, surgery is still an important option for patients with pulmonary metastases. Predictors of survival usually include disease-free interval, histology of the primary tumor, number of metastases and complete resection. The aim of this study was to report the outcomes of patients with pulmonary metastases from colorectal carcinoma submitted to surgical resection, and to identify prognostic factors that significantly affect overall survival. METHODS: We retrospectively analyzed 120 patients with previously treated colorectal carcinoma that had developed pulmonary metastases, admitted between 1990 and 2006. Overall survival was estimated using Kaplan-Meier analysis. The log-rank and Breslow tests were used to compare survival differences for each variable. Multivariate analyses to determine the independent prognostic factors for overall survival were performed using the Cox proportional hazard model as identified by the univariate analyses. RESULTS: The median follow-up was 20.3 months (range: 3.27-134.2 months). The patients included in this study underwent a total of 165 thoracotomies (mean of 1.37 thoracotomies/patient). The median overall survival for all patients was 34.73 months, with an estimated 5-year survival rate of 24.39%. Multivariate analyses identified unilateral lesions, neoadjuvant chemotherapy at lung resection and complete resection as independent prognostic factors for overall survival. CONCLUSIONS: These results indicate that prognostic factors identified in studies on pulmonary metastasectomy for all primary tumors should be interpreted carefully for patients with possibility of pulmonary metastasectomy from colorectal carcinoma. PMID- 23340338 TI - PUMA binding induces partial unfolding within BCL-xL to disrupt p53 binding and promote apoptosis. AB - Following DNA damage, nuclear p53 induces the expression of PUMA, a BH3-only protein that binds and inhibits the antiapoptotic BCL-2 repertoire, including BCL xL. PUMA, unique among BH3-only proteins, disrupts the interaction between cytosolic p53 and BCL-xL, allowing p53 to promote apoptosis via direct activation of the BCL-2 effector molecules BAX and BAK. Structural investigations using NMR spectroscopy and X-ray crystallography revealed that PUMA binding induced partial unfolding of two alpha-helices within BCL-xL. Wild-type PUMA or a PUMA mutant incapable of causing binding-induced unfolding of BCL-xL equivalently inhibited the antiapoptotic BCL-2 repertoire to sensitize for death receptor-activated apoptosis, but only wild-type PUMA promoted p53-dependent, DNA damage-induced apoptosis. Our data suggest that PUMA-induced partial unfolding of BCL-xL disrupts interactions between cytosolic p53 and BCL-xL, releasing the bound p53 to initiate apoptosis. We propose that regulated unfolding of BCL-xL provides a mechanism to promote PUMA-dependent signaling within the apoptotic pathways. PMID- 23340341 TI - One size does not fit all: the oligomeric states of alphaB crystallin. AB - Small Heat Shock Proteins (sHSPs) are a diverse family of molecular chaperones that delay protein aggregation through interactions with non-native and aggregate prone protein states. This function has been shown to be important to cellular viability and sHSP function/dysfunction is implicated in many diseases, including Alzheimer's and Alexander disease. Though their gene products are small, many sHSPs assemble into a distribution of large oligomeric states that undergo dynamic subunit exchange. These inherent properties present significant experimental challenges for characterizing sHSP oligomers. Of the human sHSPs, alphaB crystallin is a paradigm example of sHSP oligomeric properties. Advances in our understanding of sHSP structure, oligomeric distribution, and dynamics have prompted the proposal of several models for the oligomeric states of alphaB. The aim of this review is to highlight characteristics of alphaB crystallin (alphaB) that are key to understanding its structure and function. The current state of knowledge, existing models, and outstanding questions that remain to be addressed are presented. PMID- 23340342 TI - Negative control of cell size in the cyanobacterium Synechococcus elongatus PCC 7942 by the essential response regulator RpaB. AB - The essential NblS-RpaB pathway for photosynthesis regulation and acclimatization to a variety of environmental conditions is the most conserved two-component system in cyanobacteria. To get insights into the RpaB implication in cell homeostasis we investigated the phenotypic impact of altering expression of the essential rpaB gene of Synechococcus elongatus PCC 7942 and determined the in vivo levels of the RpaB and RpaB~P polypeptides. Our results implicate non phosphorylated RpaB in controlling cell length and shape and suggest that intrinsic regulation may be important to prevent drastic variations in RpaB levels and activity. PMID- 23340343 TI - The effects of microenvironment in mesenchymal stem cell-based regeneration of intervertebral disc. AB - BACKGROUND CONTEXT: Recent studies have demonstrated new therapeutic strategy using transplantation of mesenchymal stem cells (MSCs), especially bone marrow derived MSCs (BM-MSCs), to preserve intervertebral disc (IVD) structure and functions. It is important to understand whether and how the MSCs survive and thrive in the hostile microenvironment of the degenerated IVD. Therefore, this review majorly examines how resident disc cells, hypoxia, low nutrition, acidic pH, mechanical loading, endogenous proteinases, and cytokines regulate the behavior of the exogenous MSCs. PURPOSE: To review and summarize the effect of the microenvironment in biological characteristics of BM-MSCs for IVD regeneration; the presence of endogenous stem cells and the state of the art in the use of BM-MSCs to regenerate the IVD in vivo were also discussed. STUDY DESIGN: Literature review. METHODS: MEDLINE electronic database was used to search for articles concerning stem/progenitor cell isolation from the IVD, regulation of the components of microenvironment for MSCs, and MSC-based therapy for IVD degeneration. The search was limited to English language. RESULTS: Stem cells are probably resident in the disc, but exogenous stem cells, especially BM MSCs, are currently the most popular graft cells for IVD regeneration. The endogenous disc cells and the biochemical and biophysical components in the degenerating disc present a complicated microenvironment to regulate the transplanted BM-MSCs. Although MSCs regenerate the mildly degenerative disc effectively in the experimental and clinical trials, many underlying questions are in need of further investigation. CONCLUSIONS: There has been a dramatic improvement in the understanding of potential MSC-based therapy for IVD regeneration. The use of MSCs for IVD degeneration is still at the stage of preclinical and Phase 1 studies. The effects of the disc microenvironment in MSCs survival and function should be closely studied for transferring MSC transplantation from bench to bedside successfully. PMID- 23340344 TI - Long-term culture of bovine nucleus pulposus explants in a native environment. AB - BACKGROUND CONTEXT: Chronic low back pain is a disease with tremendous financial and social implications, and it is often caused by intervertebral disc degeneration. Regenerative therapies for disc repair are promising treatments, but they need to be tested in physiological models. PURPOSE: To develop a physiological in vitro explant model that incorporates the native environment of the intervertebral disc, for example, hypoxia, low glucose, and high tissue osmolarity. STUDY DESIGN: Bovine nucleus pulposus (NP) explants were cultured for 42 days in conditions mimicking the native physiological environment. Two different approaches were used to balance the swelling pressure of the NP: raised medium osmolarity or an artificial annulus. METHODS: Bovine NP explants were either cultured in media with osmolarity balanced at isotonic and hypertonic levels compared with the native tissue or cultured inside a fiber jacket used as an artificial annulus. Oxygen and glucose levels were set at either standard (21% O2 and 4.5 g/L glucose) or physiological (5% O2 and 1 g/L glucose) levels. Samples were analyzed at Day 0, 3, and 42 for tissue composition (water, sulfated glycosaminoglycans, DNA, and hydroxyproline contents and fixed charge density), tissue histology, cell viability, and cellular behavior with messenger RNA (mRNA) expression. RESULTS: Both the hypertonic culture and the artificial annulus approach maintained the tissue matrix composition for 42 days. At Day 3, mRNA expressions of aggrecan, collagen Type I, and collagen Type II in both hypertonic and artificial annulus cultures were not different from Day 0; however, at Day 42, the artificial annulus preserved the mRNA expression closer to Day 0. Gene expressions of matrix metalloprotease 13, tissue inhibitor of matrix metalloprotease 1, and tissue inhibitor of matrix metalloprotease 2 were downregulated under physiological O2 and glucose levels, whereas the other parameters analyzed were not affected. CONCLUSIONS: Although the hypertonic culture and the artificial annulus approach are both promising models to test regenerative therapies, the artificial annulus was better able to maintain a cellular behavior closer to the native tissue in longer term cultures. PMID- 23340345 TI - Characterization of bidirectional molecular motor-assisted transport models. AB - Intracellular cargos that are transported by groups of molecular motors often display bidirectional movement. This can be seen experimentally by tracking the trajectories of individual cargos in vivo. Typically, the cargo trajectories display many turning events that result from the stochastic nature of the involved motor processes. In this paper, we simulate cargo trajectories for different binding mechanisms. We introduce a series of statistical tools to analyze and quantitatively characterize these trajectories. As we demonstrate for specified single-motor properties, the novel statistical methods allow us to quantitatively distinguish between different models for bidirectional transport. In this way, the tools provide a quantitative connection between the statistical properties of the cargo trajectories and the molecular properties of the motor proteins. Such methods are also applicable to experimentally measured cargo trajectories and should be helpful in elucidating the mechanisms that lead to bidirectional transport. PMID- 23340346 TI - Prevention of chronic postsurgical pain: the ongoing search for the holy grail of anesthesiology. PMID- 23340348 TI - Mashed potatoes and maize: are the starches safe? PMID- 23340349 TI - Starkey's compound oxygen as a hygienic for ailments chronic. PMID- 23340350 TI - G.B. Snow's inhaler or chloroform mixer. PMID- 23340351 TI - A double-blind randomized trial of wound and intercostal space infiltration with ropivacaine during breast cancer surgery: effects on chronic postoperative pain. AB - BACKGROUND: The efficacy of local anesthetic wound infiltration for the treatment of acute and chronic postoperative pain is controversial and there are no detailed studies. The primary objective of this study was to evaluate the influence of ropivacaine wound infiltration on chronic pain after breast surgery. METHODS: In this prospective, randomized, double-blind, parallel-group, placebo controlled study, 236 patients scheduled for breast cancer surgery were randomized (1:1) to receive ropivacaine or placebo infiltration of the wound, the second and third intercostal spaces and the humeral insertion of major pectoralis. Acute pain, analgesic consumption, nausea and vomiting were assessed every 30 min for 2 h in the postanesthesia care unit and every 6 h for 48 h. Chronic pain was evaluated 3 months, 6 months, and 1 yr after surgery by the brief pain inventory, hospital anxiety and depression, and neuropathic pain questionnaires. RESULTS: Ropivacaine wound infiltration significantly decreased immediate postoperative pain for the first 90 min, but did not decrease chronic pain at 3 months (primary endpoint), or at 6 and 12 months postoperatively. At 3 months, the incidence of chronic pain was 33% and 27% (P = 0.37) in the ropivacaine and placebo groups, respectively. During follow-up, brief pain inventory, neuropathic pain, and anxiety increased over time in both groups (P < 0.001) while depression remained stable. No complications occurred. CONCLUSION: This multicenter, prospective study shows that ropivacaine wound infiltration after breast cancer surgery decreased immediate postoperative pain but did not decrease chronic pain at 3, 6, and 12 months postoperatively. PMID- 23340352 TI - Effect of waxy maize-derived hydroxyethyl starch 130/0.4 on renal function in surgical patients. AB - BACKGROUND: The aim of this meta-analysis was to evaluate renal safety with the active substance of the latest generation of waxy maize-derived hydroxyethyl starch in surgical patients. The authors focused on prospective, randomized, controlled studies that documented clinically relevant variables with regard to renal effects of waxy maize-derived hydroxyethyl starch 130/0.40. MATERIALS AND METHODS: The authors carefully searched for all available prospective, randomized studies and evaluated the greatest delta from baseline values in renal safety variables (serum creatinine values, calculated creatinine clearance, incidence of renal replacement therapy, and acute renal failure). The authors included 17 studies that analyzed patients (n = 1,230) undergoing a variety of surgical procedures. RESULTS: For maximum serum creatinine values, the effect size estimate was 0.068 (95% CI = -0.227 to 0.362), P = 0.65. For calculated creatinine clearance values, pooled risk difference was 0.302 (95% CI = -0.098 to 0.703), P = 0.14. For incidence of acute renal failure, pooled risk difference was 0.0003 (95% CI = -0.018 to 0.019), P = 0.98. For incidence of renal replacement therapy, pooled risk difference was -0.003 (95% CI = -0.028 to 0.022), P = 0.85. CONCLUSIONS: The authors found no evidence for renal dysfunction caused by modern waxy maize-derived hydroxyethyl starch 130/0.40 in surgical patients. PMID- 23340353 TI - Nerve injury-related autoimmunity activation leads to chronic inflammation and chronic neuropathic pain. AB - BACKGROUND: Peripheral nerve injuries that provoke neuropathic pain are associated with chronic inflammation and nervous lesions. The authors hypothesized that chronic neuropathic pain might be caused by chronic inflammation resulting from a nervous autoimmune reaction triggered by nerve injury. METHODS: The authors observed chronic inflammation and neuropathic behaviors for up to 12 weeks after nerve injury in T lymphocyte-deficient nude mice and their heterozygous littermates. Lymphocyte proliferation and Schwann cell apoptosis were examined after coculture of each population with various neural tissues from normal rats and those with nerve injury. RESULT: Nude mice recovered faster and exhibited less thermal hyperalgesia after nerve injury compared to their heterozygous littermates. A large number of IL-17 cells indicative of lymphocyte activation were found in the injured sciatic nerve and spinal cord (L4-6) of heterozygous littermates, but far fewer of these populations were found in nude mice. In vitro lymphocyte proliferation was enhanced after coculture with nerve tissues from normal rats compared to nerve tissue-free phosphate-buffered saline controls. In particular, coculture with sciatic nerve tissue enhanced proliferation by 80%, dorsal root ganglion by 46%, and spinal cord by 14%. Moreover, neural tissues from rats with nerve injury markedly increased the lymphocyte proliferation compared to coculture with tissues from corresponding normal rats. Schwann cell apoptosis was triggered in vitro when cocultured with lymphocytes from neuropathic rats. CONCLUSION: Our study suggests that chronic neuropathic pain might be caused by chronic inflammation resulting from a nervous autoimmune reaction triggered by nerve injury. PMID- 23340354 TI - Role of capsaicin in a murine model of labor and delivery. AB - BACKGROUND: The objectives of this study were to develop a murine model of labor and delivery and to use this model to examine whether capsaicin diminishes labor pain and expedites delivery. METHODS: To develop a murine model of labor pain, the authors identified and compared the incidence of four proposed pain behaviors in 46 mice: (1) No analgesia in labor and the postpartum period, and (2) increasing doses of an analgesic, morphine. The model was then used to examine the impact of topical cervical capsaicin on: (1) labor pain behaviors and (2) labor progress by examining its impact on the time from treatment to delivery of the first pup and on the duration of delivery per pup. The treatment was randomly allocated and the behavioral observation was blinded. RESULTS: In the absence of analgesia, there was a statistically significant decrease in all four proposed pain behaviors in the postpartum period compared with labor (cumulative 55.0 +/- 16.1/h vs. 16.1 +/- 8.7/h; P < 0.0001). Additionally, morphine reduced their incidence during labor in a dose-dependent manner (cumulative 55.0 +/- 16.1.7/h control, 46.4 +/- 15.8 morphine 0.1 mg/kg/h, 34.6 +/- 5.6/h, morphine 0.5 mg/kg/h; P = 0.1988, 0.0014). In addition, the incidence of identified pain behaviors was reduced by pericervical capsaicin (cumulative 55.0 +/- 16.1.7/h control, 38.9 +/- 15.4 capsaicin, P = 0.02). CONCLUSIONS: In this pilot study, the authors developed a novel mouse model of labor and delivery. Pericervical capsaicin applied days before delivery reduces labor pain behaviors. PMID- 23340356 TI - Fiberoptic versus videolaryngoscopic management of the difficult airway: problems with postrandomization patient exclusion. PMID- 23340357 TI - Flexible bronchoscopy still the definitive standard for airway management. PMID- 23340358 TI - Is video laryngoscopy easier to learn than fiberoptic intubation? PMID- 23340359 TI - Awake intubation with video laryngoscope and fiberoptic bronchoscope in difficult airway patients. PMID- 23340360 TI - In reply. PMID- 23340361 TI - In reply. PMID- 23340362 TI - Controls should exist for hyperoxic and normoxic conditions in all experiments involving anesthetics. PMID- 23340363 TI - In reply. PMID- 23340364 TI - Other factors to consider when deciding whether or not to infuse volume because of arterial blood pressure waveform variation. PMID- 23340365 TI - In reply. PMID- 23340366 TI - Pharyngeal cooling, brain temperature reduction and a neglect of history. PMID- 23340367 TI - In reply. PMID- 23340368 TI - Regarding William T.G. Morton. PMID- 23340369 TI - In reply. PMID- 23340374 TI - Affective information processing in pregnancy and postpartum with and without major depression. AB - Adults with clinical depression exhibit systematic errors in their recognition and interpretation of affective stimuli. This study investigated the extent to which depression and phases of pregnancy and postpartum influence affective processing of positive and negative information, and the extent to which affective information processing in pregnancy predicts depressive symptoms in postpartum. Data were collected from 80 unmedicated women, diagnosed with major depressive disorder (MDD) or with no psychiatric disorder and between ages 18 and 44 years, during 32-36 weeks of pregnancy and during 6-8 weeks postpartum. All completed a Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) Axis I review, symptom reports, and a computer task measuring affective information processing. Significant group differences were found in which postpartum women with major depression were less responsive to negative stimuli, with lower ratings of intensity and reactions to negative pictorial stimuli, compared with postpartum healthy women. Also, lower ratings of the intensity and reactions to negative stimuli during pregnancy among depressed women predicted postpartum depression severity, even after controlling for depressive severity and affect ratings in pregnancy. Blunted affective reactivity to negative stimuli is a characteristic of depression that was observed among depressed women during pregnancy and postpartum in our study. PMID- 23340375 TI - Relationship between catalase haplotype and arterial aging. AB - BACKGROUND: Although many conventional factors have been associated with the development of arterial aging, cardiovascular diseases remain the first cause of death in old age. Therefore, identification of new risk factors may prove promising for monitoring this serious health problem. Oxidative stress and particularly catalase (CAT), an antioxidant enzyme, play an important role in endothelial cell pathophysiology, in shear stress response and ultimately in arterial aging. OBJECTIVE: Examine the relationships between CAT haplotypes and phenotypes of arterial aging (mean internal diameter, mean intima-media thickness of the common carotid arteries (CCA), presence of atheromatous plaques) in two French cohorts. METHODS AND RESULTS: 564 middle-aged French individuals (mean age 53 +/- 12 years) from two cohorts (ERA and STANISLAS cohorts) were included in the study. Blood pressure, CCA intima-media thickness, CCA internal diameter and number of atheromatous plaques were measured. Catalase rs769214 SNP genotyping was performed. We identified a CAT haplotype that influences arterial aging. Individuals carrying the CAT2 haplotype had a higher mean internal diameter of CCA with aging and/or with an SBP >=140 mmHg and were associated with a greater number of atheromatous plaques than CAT1 haplotypes carriers. This CAT2 haplotype appeared as an independent risk factor of arterial aging, similarly to previously identified factors such as age, systolic blood pressure, male, sex, tobacco use, hs-CRP, BMI and diabetes. CONCLUSION: The present study highlights the roles of CAT haplotypes in arterial aging and underlines the beneficial impact of the CAT1 haplotype on mean internal diameter of the CCA and atheromatous plaque number as well as on potential associated diseases. PMID- 23340376 TI - The role of NF-kB in SAA-induced peroxisome proliferator-activated receptor gamma activation. AB - Serum amyloid A (SAA) is an acute phase protein whose expression increases markedly during bacterial infection, tissue damage, and inflammation. The potential beneficial roles of SAA include its involvement in the reverse cholesterol transport and possibly extracellular lipid deposition at sites of inflammation and tissue repair. It is an attractive therapeutic target for the treatment of atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a major regulatory role in adipogenesis, and the expression of genes involved in lipid metabolism. Activation of PPARgamma leads to multiple changes in gene expression, some of which are believed to be atherogenic while others are antiatherogenic. In this study, we demonstrated that SAA upregulated COX-2 expression and induced PPARgamma activity through NF-kB pathway. The effect of SAA on NF-kB activity is mediated by FPRL-1 and TLR4. PMID- 23340377 TI - Sexual dimorphisms and prediction of conversion in the NAPLS psychosis prodrome. AB - Sex differences in age at onset, symptomatology, clinical course (see Walker et al., 2002) and functional impairment (Thorup et al., 2007) are well documented in psychosis. The general pattern of findings is that males manifest an earlier onset, more severe symptoms and poorer prognosis than females. Limited studies examining individuals at clinical high-risk (CHR) suggest a similar pattern of sexual dimorphism (Holtzman et al., in review; Corcoran et al., 2011). As part of the North American Prodrome Longitudinal Study (NAPLS), the current study prospectively examined sexual dimorphisms in relationships among CHR symptoms, childhood (premorbid) academic and social functioning, baseline social and role functioning, and conversion to psychosis. Subjects included 276 (113F/163M) CHR NAPLS participants (ages 12-36.8years). All measures/criteria were assessed at baseline except conversion status, assessed at 6-month intervals up to 30months. Results show sex differences in baseline social and role functioning (though not in early childhood adjustment) that predate psychosis onset, with sexually dimorphic patterns in relation to prodromal symptoms. Among male (but not female) CHRs, baseline social functioning and positive prodromal symptoms predicted conversion. These findings help elucidate early course of vulnerability for, and maximally sensitive and specific etiological and prediction models of, psychosis conversion. Findings highlight the importance of considering sexually differentiated predictors of longitudinal course and outcome, in the context of emerging risk profiles. This may optimize efforts at early identification and individually tailored preventive interventions targeting different neurobiological markers/systems and/or cognitive-behavioral approaches. We speculate a contemporary, multidimensional model of psychosis risk that posits a role of sexually dimorphic, genetically linked influences that converge with a modulating role of gonadal hormones (see Walder et al., 2012) across a temporally sensitive neurodevelopmental trajectory towards conferring risk. PMID- 23340378 TI - Response properties underlying selectivity for the rate of frequency modulated sweeps in the auditory cortex of the mouse. AB - This study focused on the response properties underlying selectivity for the rate of frequency modulated (FM) sweeps in the auditory cortex of anesthetized C57bl/6 (C57) mice. Linear downward FM sweeps with rates between 0.08 and 20 kHz/ms were tested. We show that at least two different response properties predict FM rate selectivity: sideband inhibition and duration tuning. Sideband inhibition was determined using the two-tone inhibition paradigm in which excitatory and inhibitory tones were presented with different delays. Sideband inhibition was present in the majority (88%, n = 53) of neurons. The spectrotemporal properties of sideband inhibition predicted rate selectivity and exclusion of the sideband from the sweep reduced/eliminated rate tuning. The second property predictive of sweep rate selectivity was duration tuning for tones. Theoretically, if a neuron is selective for the duration that a sweep spends in the excitatory frequency tuning curve, then rate selectivity will ensue. Duration tuning for excitatory tones was present and predicted rate selectivity in ~34% of neurons (n = 97). Both sideband inhibition and duration tuning predicted rate selectivity equally well, but sideband inhibition was present in a larger percentage of neurons suggesting that it is the dominant mechanism in the C57 mouse auditory cortex. Similar mechanisms shape sweep rate selectivity in the auditory system of bats and mice and movement-velocity selectivity in the visual system, suggesting similar solutions to analogous problems across sensory systems. This study provides baseline data on basic spectrotemporal processing in the C57 strain for elucidation of changes that occur in presbycusis. PMID- 23340379 TI - Progressive hereditary hearing impairment caused by a MYO6 mutation resembles presbyacusis. AB - Since deafness is the most common sensorineural disorder in humans, better understanding of the underlying causes is necessary to improve counseling and rehabilitation. A Dutch family with autosomal dominantly inherited sensorineural hearing loss was clinically and genetically assessed. The MYO6 gene was selected to be sequenced because of similarities with other, previously described DFNA22 phenotypes and a pathogenic c.3610C > T (p.R1204W) mutation was found to co segregate with the disease. This missense mutation results in a flat configured audiogram with a mild hearing loss, which becomes severe to profound and gently to steeply downsloping later in life. The age-related typical audiograms (ARTA) constructed for this family resemble presbyacusis. Speech audiometry and results of loudness scaling support the hypothesis that the phenotype of this specific MYO6 mutation mimics presbyacusis. PMID- 23340382 TI - Diplopia after laser in situ keratomileusis (LASIK) in a patient with a history of strabismus. AB - In patients with a history of strabismus, refractive surgery can result in decompensation of ocular alignment, with subsequent diplopia. Refractive surgery in the management of strabismus has been described, although it remains controversial. We present a young adult with past history of strabismus surgery and new-onset diplopia after refractive surgery. Binocular diplopia was treated surgically with laser in situ keratomileusis. PMID- 23340380 TI - Influenza A virus entry inhibitors targeting the hemagglutinin. AB - Influenza A virus (IAV) has caused seasonal influenza epidemics and influenza pandemics, which resulted in serious threat to public health and socioeconomic impacts. Until now, only 5 drugs belong to two categories are used for prophylaxis and treatment of IAV infection. Hemagglutinin (HA), the envelope glycoprotein of IAV, plays a critical role in viral binding, fusion and entry. Therefore, HA is an attractive target for developing anti-IAV drugs to block the entry step of IAV infection. Here we reviewed the recent progress in the study of conformational changes of HA during viral fusion process and the development of HA-based IAV entry inhibitors, which may provide a new choice for controlling future influenza pandemics. PMID- 23340384 TI - Cheese surface microbiota complexity: RT-PCR-DGGE, a tool for a detailed picture? AB - In this work, a culture-independent approach, based on PCR-DGGE and RT-PCR-DGGE, has been used to study the succession of bacterial communities that are encountered in Fontina PDO cheese. As already found for other smear ripened cheeses, it appeared that coryneform bacteria were actively present and could therefore be considered determinant in rind formation. DGGE profiles, especially at the RNA level, have shown the presence of Brevibacterium, Corynebacterium and Arthrobacter genera. RT-PCR-DGGE gels have lead to a richer band profile than the one obtained on the basis of DNA analysis, thus indicating that RNA analysis can highlight bacterial species that DNA analysis is not able to show. Thus, the biodiversity of the Fontina PDO surface has been described better by means of RT PCR-DGGE, and RNA molecules should be considered a more informative target than DNA. PMID- 23340383 TI - Formulation and characterization of an immobilized laccase biocatalyst and its application to eliminate organic micropollutants in wastewater. AB - Over the past decades, water pollution by trace organic compounds (ng L(-1)) has become one of the key environmental issues for developed countries. To date there is no effective and sustainable remediation strategy available. Laccases from white rot fungi were found particularly attractive for the removal of some micropollutants such as the plasticizer bisphenol A (BPA), the anti-inflammatory drug diclofenac (DF) and the steroidal hormone 17-alpha-ethinylestradiol (EE2). Laccase immobilization is a prerequisite for their use in continuous water treatment processes. In this study, laccase from Coriolopsis gallica was immobilized on mesoporous silica spheres in a two-step adsorption-crosslinking process. The initial laccase activity, crosslinker (glutaraldehyde) concentration and extra protein (albumin) concentration were varied following a central composite experimental design and optimized with respect to the immobilization yield, activity and thermal stability of the biocatalysts. After a multi objective optimization of the biocatalyst formulation, a maximum biocatalyst activity of 383 Ug(-1), determined with 2,2'-azino-bis(3-ethylbenzthiazoline-6 sulfonate) at pH 4.5, was obtained. Biocatalyst particles were physically characterized by means of scanning electron microscopy, Brunauer-Emmett-Teller surface area and Barrett-Joyner-Halenda pore size analyses revealing few modifications of the surface area and structure during/after the immobilization procedure. The biocatalyst showed a significantly higher thermostability than the free enzyme with a half-life of 31.5 hours and 3.9 hours compared to 6.1 hours and 0.6 hours at 55 degrees C and 75 degrees C respectively. The biocatalyst was able to eliminate in a continuously stirred membrane reactor more than 95% of BPA 10 MUM and EE2 10 MUM and 70% of DF 10 MUM when treated individually and more than 90% when treated as a mixture in aqueous buffered solution (pH 5) for more than 60 reactor volumes. In real wastewater conditions (pH 7.8) the biocatalyst could degrade more than 85% of BPA and EE2 along with 30% of DF when tested in mixture for more than 80 hours, which illustrates the potential of this biocatalyst for the treatment of aquatic micropollutants. PMID- 23340385 TI - Phenotypic analysis of mutant and overexpressing strains of lipid metabolism genes in Saccharomyces cerevisiae: implication in growth at low temperatures. AB - The growing demand for wines with a more pronounced aromatic profile calls for low temperature alcoholic fermentations (10-15 degrees C). However, there are certain drawbacks to low temperature fermentations such as reduced growth rate, long lag phase and sluggish or stuck fermentations. The lipid metabolism of Saccharomyces cerevisiae plays a central role in low temperature adaptation. The aim of this study was to detect lipid metabolism genes involved in cold adaptation. To do so, we analyzed the growth of knockouts in phospholipids, sterols and sphingolipids, from the EUROSCARF collection S. cerevisiae BY4742 strain at low and optimal temperatures. Growth rate of these knockouts, compared with the control, enabled us to identify the genes involved, which were also deleted or overexpressed in a derivative haploid of a commercial wine strain. We identified genes involved in the phospholipid (PSD1 and OPI3), sterol (ERG3 and IDI1) and sphingolipid (LCB3) pathways, whose deletion strongly impaired growth at low temperature and whose overexpression reduced generation or division time by almost half. Our study also reveals many phenotypic differences between the laboratory strain and the commercial wine yeast strain, showing the importance of constructing mutant and overexpressing strains in both genetic backgrounds. The phenotypic differences in the mutant and overexpressing strains were correlated with changes in their lipid composition. PMID- 23340381 TI - Cellular aspects of prion replication in vitro. AB - Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders in mammals that are caused by unconventional agents predominantly composed of aggregated misfolded prion protein (PrP). Prions self propagate by recruitment of host-encoded PrP into highly ordered b-sheet rich aggregates. Prion strains differ in their clinical, pathological and biochemical characteristics and are likely to be the consequence of distinct abnormal prion protein conformers that stably replicate their alternate states in the host cell. Understanding prion cell biology is fundamental for identifying potential drug targets for disease intervention. The development of permissive cell culture models has greatly enhanced our knowledge on entry, propagation and dissemination of TSE agents. However, despite extensive research, the precise mechanism of prion infection and potential strain effects remain enigmatic. This review summarizes our current knowledge of the cell biology and propagation of prions derived from cell culture experiments. We discuss recent findings on the trafficking of cellular and pathologic PrP, the potential sites of abnormal prion protein synthesis and potential co-factors involved in prion entry and propagation. PMID- 23340386 TI - Structure of an Aspergillus flavus population from maize kernels in northern Italy. AB - In order to gain insight into the causal agents of aflatoxin contamination of maize in Italy, populations of Aspergillus flavus on maize produced in the most affected area were characterized. Forty-six percent of A. flavus, isolated from maize kernels collected in 5 districts of northern Italy between 2003 and 2010, were unable to produce detectable levels of aflatoxins. The genetic diversity of the population was assessed by analysis of vegetative compatibility groups (VCGs) and presence or absence of several aflatoxin biosynthesis genes. Forty-eight VCGs were identified through complementation between nitrate non-utilizing mutants. Twenty-five VCGs contained only atoxigenic isolates, and the remaining 23 only aflatoxin producers. Members of the largest atoxigenic VCG (IT6) were found in 4 of the 5 districts sampled. Six deletion patterns of genes in the aflatoxin biosynthesis gene cluster were detected. No deletions in the cluster were detected for twelve atoxigenic isolates and 10 had the entire cluster deleted. One isolate had a deletion pattern only seen once before in Nigeria. The basis for initial selection of endemic atoxigenic strains of A. flavus for biological control of aflatoxin contamination of maize in Italy is provided. PMID- 23340387 TI - Biocide tolerance in bacteria. AB - Biocides have been employed for centuries, so today a wide range of compounds showing different levels of antimicrobial activity have become available. At the present time, understanding the mechanisms of action of biocides has also become an important issue with the emergence of bacterial tolerance to biocides and the suggestion that biocide and antibiotic resistance in bacteria might be linked. While most of the mechanisms providing antibiotic resistance are agent specific, providing resistance to a single antimicrobial or class of antimicrobial, there are currently numerous examples of efflux systems that accommodate and, thus, provide tolerance to a broad range of structurally unrelated antimicrobials, both antibiotics and biocides. If biocide tolerance becomes increasingly common and it is linked to antibiotic resistance, not only resistant (even multi-resistant) bacteria could be passed along the food chain, but also there are resistance determinants that can spread and lead to the emergence of new resistant microorganisms, which can only be detected and monitored when the building blocks of resistance traits are understood on the molecular level. This review summarizes the main advances reached in understanding the mechanism of action of biocides, the mechanisms of bacterial resistance to both biocides and antibiotics, and the incidence of biocide tolerance in bacteria of concern to human health and the food industry. PMID- 23340388 TI - Wheat bulb fly (Delia coarctata, Fallen, Diptera: Anthomyiidae) larval response to hydroxamic acid constituents of host-plant root exudates. AB - Wheat bulb fly (WBF, Delia coarctata, Fallen, Diptera: Anthomyiidae) is a pest of commercial importance in wheat, barley and rye, with attacked crops failing to produce full potential yields. Females do not oviposit in association with a host plant; therefore, prompt location of a suitable host is critical to the survival of the newly hatched larvae. The objective of this study was to conduct choice test bioassays to assess the attraction of WBF larvae to specific chemical constituents of WBF host-plant root exudates, the hydroxamic acids DIMBOA (2,4 dihydroxy-7-methoxy-1,4-benzoxazin-3-one) and MBOA (6-methoxy-benzoxazolin-2 one). The larval response to four concentrations of each test compound was assessed in arena bioassays. Analysis using a Rayleigh test of uniformity of the final resting positions of larvae in response to these chemicals indicated attraction. These results go some way to explaining the mechanisms by which WBF larvae locate host plants, giving the potential to develop semiochemical based control strategies. PMID- 23340389 TI - Bilateral pleural effusions in a 23-year-old man: a clinical puzzle. PMID- 23340390 TI - Intrathecal metastases causing conus medullaris syndrome. PMID- 23340392 TI - Methylisothiazolinone. AB - The preservative methylisothiazolinone (MI) is the American Contact Dermatitis Society Contact Allergen of the Year for 2013. Because the use of MI in cosmetics and toiletries in the United States rises, MI exposure also rises. Although it might seem likely that testing with methylchloroisothiazolinone (MCI)/MI would be adequate to pick up contact allergy to MI alone, the mix misses approximately 40% of allergy to MI, likely because of the low concentration of MI in the MCI/MI combination patch test. In Europe, several groups have documented frequency of allergy to this preservative of approximately 1.5%. The frequency of allergy to this preservative in the United States is unknown. If you are not testing for allergy to this preservative, you may be overlooking the importance of a very relevant preservative allergen that, to date, has managed to stay under the radar in the United States. This report reviews the background and reasons for adding MI to our routine screening patch testing series. PMID- 23340393 TI - American contact dermatitis society core allergen series. AB - Evidence for the effectiveness of patch testing and the need for an expanded series that provides experience and evidence-based suggestions for an extended patch testing series are examined in this review. Many of those testing with shorter allergen series are interested in expanding the spectrum of patch testing. The American Contact Dermatitis Society (ACDS) Core Allergen Series Group has arranged a group of suggested allergen groups that can be logically scaled up or down depending on the needs of the patch tester and the community being tested. This is not an "ACDS 80 Standard." We suggest a core group of allergens similar to the TRUE Test (SmartPractice, Phoenix, Ariz) with subsequent trays providing a greater breadth of coverage in a logical fashion, with more likely allergens being higher in the tray. For more extensive testing, specialty trays (ie, cosmetics, metals, plant, etc) are recommended. PMID- 23340394 TI - North American Contact Dermatitis Group patch test results for 2007-2008. AB - BACKGROUND: The North American Contact Dermatitis Group (NACDG) tests patients with suspected allergic contact dermatitis to a broad series of screening allergens and publishes periodic reports. OBJECTIVE: The aims of this study were to report the NACDG patch-testing results from January 1, 2007, to December 31, 2008, and to compare results to pooled test data from the previous 2 and 10 years to analyze trends in allergen sensitivity. METHODS AND MATERIALS: Standardized patch testing with 65 allergens was used at 13 centers in North America. chi analysis was used for comparisons. RESULTS: A total of 5085 patients were tested; 11.8% (598) had an occupationally related skin condition, and 65.3% (3319) had at least 1 allergic patch test reaction, which is identical to the NACDG data from 2005 to 2006. The top 15 most frequently positive allergens were nickel sulfate (19.5%), Myroxylon pereirae (11.0%), neomycin (10.1%), fragrance mix I (9.4%), quaternium-15 (8.6%), cobalt chloride (8.4%), bacitracin (7.9%), formaldehyde (7.7%), methyldibromoglutaronitrile/phenoxyethanol (5.5%), p-phenylenediamine (5.3%), propolis (4.9%), carba mix (4.5%), potassium dichromate (4.1%), fragrance mix II (3.6%), and methylchloroisothiazolinone/methylisothiazolinone (3.6%). There were significant increases in positivity rates to nickel, methylchloroisothiazolinone/methylisothiazolinone, and benzophenone-3. During the same period of study, there were significant decreases in positivity rates to neomycin, fragrance mix I, formaldehyde, thiuram mix, cinnamic aldehyde, propylene glycol, epoxy resin, diazolidinyl urea, amidoamine, ethylenediamine, benzocaine, p-tert-butylphenol formaldehyde resin, dimethylol dimethyl hydantoin, cocamidopropyl betaine, glutaraldehyde, mercaptobenzothiazole, tosylamide formaldehyde resin, budesonide, disperse blue 106, mercapto mix, and chloroxylenol. Twenty-four percent (1221) had a relevant positive reaction to a non-NACDG supplementary allergen; and 180 of these reactions were occupationally relevant. CONCLUSIONS: Periodic analysis, surveillance, and publication of multicenter study data sets document trends in allergen reactivity incidence assessed in the patch test clinic setting and provide information on new allergens of relevance. PMID- 23340396 TI - Allergic and photoallergic contact dermatitis: a 10-year experience. AB - BACKGROUND: Photoallergic contact dermatitis (PACD) is a hypersensitivity reaction that occurs when a previously photosensitized exogenous agent comes into contact with UV radiation. Currently, there are no studies profiling photoallergic reactions in Canada. Because the photoallergen profile changes over time, it is necessary to continually update our knowledge to ensure proper recognition of allergens and appropriate treatment of patients. OBJECTIVE: This study aimed to profile photoallergic reactions in Canada. METHODS: A retrospective chart review of all patients who underwent photopatch testing at Toronto Western Hospital between January 2001 and December 2010 was completed. Photoallergic, allergic, and irritant reactions were recorded for 26 common allergens. RESULTS: Ninety-nine patients (61.9%) had at least 1 positive reaction to the test allergens. Fifty-four patients (33.8%) had at least 1 photoallergic reaction. All 26 allergens produced at least 1 allergic or photoallergic reaction. The most common relevant photoallergens were benzophenone-3, octyl dimethyl para-aminobenzoic acid (PABA) in 5% alcohol, and butylmethoxy dibenzoylmethane. CONCLUSIONS: This study is the first to profile photoallergic contact reactions in Canada. It is clear that the culprit photoallergen in PACD can often be identified in a properly selected population. Future surveillance is necessary to continue to characterize PACD trends in Canada and to help better treat and screen this patient population. PMID- 23340395 TI - Occupationally related contact dermatitis in North American food service workers referred for patch testing, 1994 to 2010. AB - BACKGROUND: Contact dermatoses are common in food service workers (FSWs). OBJECTIVES: This study aims to (1) determine the prevalence of occupationally related contact dermatitis among FSWs patch tested by the North American Contact Dermatitis Group (NACDG) and (2) characterize responsible allergens and irritants as well as sources. METHODS: Cross-sectional analysis of patients patch tested by the NACDG, 1994 to 2010, was conducted. RESULTS: Of 35,872 patients patch tested, 1237 (3.4%) were FSWs. Occupationally related skin disease was significantly more common in FSWs when compared with employed non-FSWs. Food service workers were significantly more likely to have hand (P < 0.0001) and arm (P < 0.0006) involvement. The rates for irritant and allergic contact dermatitis in FSWs were 30.6% and 54.7%, respectively. Although the final diagnosis of irritant contact dermatitis was statistically higher in FSWs as compared with non-FSWs, allergic contact dermatitis was lower in FSWs as compared with non-FSWs. The most frequent currently relevant and occupationally related allergens were thiuram mix (32.5%) and carba mix (28.9%). Gloves were the most common source of responsible allergens. The NACDG standard tray missed at least 1 occupationally related allergen in 38 patients (4.3%). CONCLUSIONS: Among FSWs patch tested by the NACDG between 1994 and 2010, the most common allergens were thiuram mix and carba mix. Gloves were the most common source of responsible allergens. PMID- 23340397 TI - Whole exome sequencing. AB - Our goal is to highlight annually a methodology of significance to the journal's domains, either because it has been used clinically or researchwise for our fields of interest or because it holds promise as a tool in diagnosing, treating, or investigating corresponding diseases.We hope another strength of this new section is simplicity of language that can be readily grasped by our readers. PMID- 23340398 TI - Nickel-induced systemic contact dermatitis and intratubal implants: the baboon syndrome revisited. AB - Permanent sterilization using intratubal implants is becoming increasingly popular worldwide. We report the first case of a 40-year-old woman presenting a systemic contact dermatitis due to nickel-containing intratubal implants: the Essure system. The diagnosis was confirmed with positive patch test result for nickel and total clearance of dermatitis after removing the implants that contain a metallic spiral of nitinol (alloy of 55% nickel and 45% titanium). Systemic contact dermatitis to the intratubal implants could be explained by the corrosion of nitinol after implantation resulting in the release of nickel. In the literature, no similar case has been reported despite the introduction of intratubal implants since 2002. Dermatologists and gynecologists need to be aware of this type of complication. In practice, a thorough assessment for possible nickel contact dermatitis in a woman undergoing sterilization with Essure is recommended. Preoperative patch testing must be carried out if there is any doubt. PMID- 23340399 TI - EMPACT syndrome associated with phenobarbital. AB - Intracranial malignancies can be complicated by seizure activity, and anticonvulsants such as phenytoin are usually administered to prevent this neurological kind of complication. Cranial radiation therapy is instead the treatment of choice when the tumor is unresectable. Anyway, the combination of phenytoin and cranial radiation therapy can lead to a rare and severe mucocutaneous complication called EMPACT syndrome. It is composed of "erythema (E) multiforme (M) associated with phenytoin (P) and (A) cranial radiation (C) therapy (T)." Herein, we report 2 cases of EMPACT syndrome related to the use of phenobarbital instead of phenytoin as usually described in literature. PMID- 23340400 TI - Human seminal plasma hypersensitivity and successful conception. PMID- 23340401 TI - The UV filter tinosorb M, containing decyl glucoside, is a frequent cause of allergic contact dermatitis. PMID- 23340402 TI - Investigating longitudinal changes in the mechanical properties of MCF-7 cells exposed to paclitaxol using particle tracking microrheology. AB - Evidence suggests that compression and shear wave elastography are sensitive to the mechanical property changes occuring in dying cells following chemotherapy, and can hence be used to monitor cancer treatment response. A qualitative and quantitative understanding of the mechanical changes at the cellular level would allow to better infer how these changes affect macroscopic tissue mechanical properties and therefore allow the optimization of elastographic techniques (such as shear wave elastography) for the monitoring of cancer therapy. We used intracellular particle tracking microrheology (PTM) to investigate the mechanical property changes of cells exposed to paclitaxol, a mitotic inhibitor used in cancer chemotherapy. The average elastic and viscous moduli of the cytoplasm of treated MCF-7 breast cancer cells were calculated for frequency ranges between 0.2 and 100 rad s(-1) (corresponding to 0.03 and 15.92 Hz, respectively). A significant increase in the complex shear modulus of the cell cytoplasm was detected at 12 h post treatment. At 24 h after drug exposure, the elastic and viscous moduli increased by a total of 191.3 Pa (>8000*) and 9 Pa (~9*), respectively for low frequency shear modulus measurements (at 1 rad s(-1)). At higher frequencies (10 rad s(-1)), the elastic and viscous moduli increased by 188.5 Pa (~60*) and 1.7 Pa (~1.1*), respectively. Our work demonstrates that PTM can be used to measure changes in the mechanical properties of treated cells and that cell elasticity significantly increases by 24 h after chemotherapy exposure. PMID- 23340403 TI - Bioavailability as a tool in site management. AB - Bioavailability can form the basis for describing potential risks that contaminants pose to the environment and human health, and for determining remedial options to reduce risks of contaminant dispersal and toxicity. In assessments of polluted sites, methods to measure bioavailability can lead to a realistic appraisal of the potential risks from exposure to contaminants. For remediation purposes the application of the principles of bioavailability can result in practices that reduce bioavailability and consequently the risk of contaminants. Moreover the costs of remediation can be reduced. Examples from projects with organic contaminants (PAHs, pesticides and PFOS) and heavy metals in The Netherlands, Mali, Mauretania, Australia and Taiwan are presented. It is shown that using bioavailability principles in risk-based approaches is an attractive option in terms of both cost and in situ management of contaminated sites. Regulatory and public acceptance is, however, still the Achilles heel of these new remediation strategies. PMID- 23340404 TI - WITHDRAWN: Deposition and uptake of metals in urban canopy: Atmospheric arsenic sequestration. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23340405 TI - Visualizing the atomic-scale electronic structure of the Ca2CuO2Cl2 Mott insulator. AB - Although the mechanism of superconductivity in the cuprates remains elusive, it is generally agreed that at the heart of the problem is the physics of doped Mott insulators. A crucial step for solving the high temperature superconductivity puzzle is to elucidate the electronic structure of the parent compound and the behaviour of doped charge carriers. Here we use scanning tunnelling microscopy to investigate the atomic-scale electronic structure of the Ca(2)CuO(2)Cl(2) parent Mott insulator of the cuprates. The full electronic spectrum across the Mott Hubbard gap is uncovered for the first time, which reveals the particle-hole symmetric and spatially uniform Hubbard bands. Defect-induced charge carriers are found to create broad in-gap electronic states that are strongly localized in space. We show that the electronic structure of pristine Mott insulator is consistent with the Zhang-Rice singlet model, but the peculiar features of the doped electronic states require further investigations. PMID- 23340406 TI - A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells. AB - In eukaryotes, hydrogen sulphide acts as a signalling molecule and cytoprotectant. Hydrogen sulphide is known to be produced from L-cysteine by cystathionine beta-synthase, cystathionine gamma-lyase and 3-mercaptopyruvate sulfurtransferase coupled with cysteine aminotransferase. Here we report an additional biosynthetic pathway for the production of hydrogen sulphide from D cysteine involving 3-mercaptopyruvate sulfurtransferase and D-amino acid oxidase. Unlike the L-cysteine pathway, this D-cysteine-dependent pathway operates predominantly in the cerebellum and the kidney. Our study reveals that administration of D-cysteine protects primary cultures of cerebellar neurons from oxidative stress induced by hydrogen peroxide and attenuates ischaemia reperfusion injury in the kidney more than L-cysteine. This study presents a novel pathway of hydrogen sulphide production and provides a new therapeutic approach to deliver hydrogen sulphide to specific tissues. PMID- 23340408 TI - The random mass Dirac model and long-range correlations on an integrated optical platform. AB - Long-range correlation--the non-local interdependence of distant events--is a crucial feature in many natural and artificial environments. In the context of solid state physics, impurity spins in doped spin chains and ladders with antiferromagnetic interaction are a prominent manifestation of this phenomenon, which is the physical origin of the unusual magnetic and thermodynamic properties of these materials. It turns out that such systems are described by a one dimensional Dirac equation for a relativistic fermion with random mass. Here we present an optical configuration, which implements this one-dimensional random mass Dirac equation on a chip. On this platform, we provide a miniaturized optical test-bed for the physics of Dirac fermions with variable mass, as well as of antiferromagnetic spin systems. Moreover, our data suggest the occurence of long-range correlations in an integrated optical device, despite the exclusively short-ranged interactions between the constituting channels. PMID- 23340409 TI - The mechanism of ultrafast structural switching in superionic copper (I) sulphide nanocrystals. AB - Superionic materials are multi-component solids with simultaneous characteristics of both a solid and a liquid. Above a critical temperature associated with a structural phase transition, they exhibit liquid-like ionic conductivities and dynamic disorder within a rigid crystalline structure. Broad applications as electrochemical storage materials and resistive switching devices follow from this abrupt change in ionic mobility, but the microscopic pathways and speed limits associated with this switching process are largely unknown. Here we use ultrafast X-ray spectroscopy and scattering techniques to obtain an atomic-level, real-time view of the transition state in copper sulphide nanocrystals. We observe the transformation to occur on a twenty picosecond timescale and show that this is determined by the ionic hopping time. PMID- 23340407 TI - Monitoring and robust induction of nephrogenic intermediate mesoderm from human pluripotent stem cells. AB - A method for stimulating the differentiation of human pluripotent stem cells into kidney lineages remains to be developed. Most cells in kidney are derived from an embryonic germ layer known as intermediate mesoderm. Here we show the establishment of an efficient system of homologous recombination in human pluripotent stem cells by means of bacterial artificial chromosome-based vectors and single-nucleotide polymorphism array-based detection. This system allowed us to generate human-induced pluripotent stem cell lines containing green fluorescence protein knocked into OSR1, a specific intermediate mesoderm marker. We have also established a robust induction protocol for intermediate mesoderm, which produces up to 90% OSR1(+) cells. These human intermediate mesoderm cells can differentiate into multiple cell types of intermediate mesoderm-derived organs in vitro and in vivo, thereby supplying a useful system to elucidate the mechanisms of intermediate mesoderm development and potentially providing a cell source for regenerative therapies of the kidney. PMID- 23340410 TI - A pairwise maximum entropy model accurately describes resting-state human brain networks. AB - The resting-state human brain networks underlie fundamental cognitive functions and consist of complex interactions among brain regions. However, the level of complexity of the resting-state networks has not been quantified, which has prevented comprehensive descriptions of the brain activity as an integrative system. Here, we address this issue by demonstrating that a pairwise maximum entropy model, which takes into account region-specific activity rates and pairwise interactions, can be robustly and accurately fitted to resting-state human brain activities obtained by functional magnetic resonance imaging. Furthermore, to validate the approximation of the resting-state networks by the pairwise maximum entropy model, we show that the functional interactions estimated by the pairwise maximum entropy model reflect anatomical connexions more accurately than the conventional functional connectivity method. These findings indicate that a relatively simple statistical model not only captures the structure of the resting-state networks but also provides a possible method to derive physiological information about various large-scale brain networks. PMID- 23340411 TI - A high-mobility two-dimensional electron gas at the spinel/perovskite interface of gamma-Al2O3/SrTiO3. AB - The discovery of two-dimensional electron gases at the heterointerface between two insulating perovskite-type oxides, such as LaAlO(3) and SrTiO(3), provides opportunities for a new generation of all-oxide electronic devices. Key challenges remain for achieving interfacial electron mobilities much beyond the current value of approximately 1,000 cm(2) V(-1) s(-1) (at low temperatures). Here we create a new type of two-dimensional electron gas at the heterointerface between SrTiO(3) and a spinel gamma-Al(2)O(3) epitaxial film with compatible oxygen ions sublattices. Electron mobilities more than one order of magnitude higher than those of hitherto-investigated perovskite-type interfaces are obtained. The spinel/perovskite two-dimensional electron gas, where the two dimensional conduction character is revealed by quantum magnetoresistance oscillations, is found to result from interface-stabilized oxygen vacancies confined within a layer of 0.9 nm in proximity to the interface. Our findings pave the way for studies of mesoscopic physics with complex oxides and design of high-mobility all-oxide electronic devices. PMID- 23340412 TI - A genetically female brain is required for a regular reproductive cycle in chicken brain chimeras. AB - Sexual differentiation leads to structural and behavioural differences between males and females. Here we investigate the intrinsic sex identity of the brain by constructing chicken chimeras in which the brain primordium is switched between male and female identities before gonadal development. We find that the female chimeras with male brains display delayed sexual maturation and irregular oviposition cycles, although their behaviour, plasma concentrations of sex steroids and luteinizing hormone levels are normal. The male chimeras with female brains show phenotypes similar to typical cocks. In the perinatal period, oestrogen concentrations in the genetically male brain are higher than those in the genetically female brain. Our study demonstrates that male brain cells retain male sex identity and do not differentiate into female cells to drive the normal oestrous cycle, even when situated in the female hormonal milieu. This is clear evidence for a sex-specific feature that develops independent of gonadal steroids. PMID- 23340413 TI - Dimensionality of brain networks linked to life-long individual differences in self-control. AB - The ability to delay gratification in childhood has been linked to positive outcomes in adolescence and adulthood. Here we examine a subsample of participants from a seminal longitudinal study of self-control throughout a subject's life span. Self-control, first studied in children at age 4 years, is now re-examined 40 years later, on a task that required control over the contents of working memory. We examine whether patterns of brain activation on this task can reliably distinguish participants with consistently low and high self-control abilities (low versus high delayers). We find that low delayers recruit significantly higher-dimensional neural networks when performing the task compared with high delayers. High delayers are also more homogeneous as a group in their neural patterns compared with low delayers. From these brain patterns, we can predict with 71% accuracy, whether a participant is a high or low delayer. The present results suggest that dimensionality of neural networks is a biological predictor of self-control abilities. PMID- 23340414 TI - Controllable unzipping for intramolecular junctions of graphene nanoribbons and single-walled carbon nanotubes. AB - Graphene is often regarded as one of the most promising candidates for future nanoelectronics. As an indispensable component in graphene-based electronics, the formation of junctions with other materials not only provides utility functions and reliable connexions, but can also improve or alter the properties of pristine graphene, opening up possibilities for new applications. Here we demonstrate an intramolecular junction produced by the controllable unzipping of single-walled carbon nanotubes, which combines a graphene nanoribbon and single-walled carbon nanotube in a one-dimensional nanostructure. This junction shows a strong gate dependent rectifying behaviour. As applications, we demonstrate the use of the junction in prototype directionally dependent field-effect transistors, logic gates and high-performance photodetectors, indicating its potential in future graphene-based electronics and optoelectronics. PMID- 23340415 TI - Quantum-coupled radial-breathing oscillations in double-walled carbon nanotubes. AB - Van der Waals-coupled materials, ranging from multilayers of graphene and MoS(2) to superlattices of nanoparticles, exhibit rich emerging behaviour owing to quantum coupling between individual nanoscale constituents. Double-walled carbon nanotubes provide a model system for studying such quantum coupling mediated by van der Waals interactions, because each constituent single-walled nanotube can have distinctly different physical structures and electronic properties. Here we systematically investigate quantum-coupled radial-breathing mode oscillations in chirality-defined double-walled nanotubes by combining simultaneous structural, electronic and vibrational characterizations on the same individual nanotubes. We show that these radial-breathing oscillations are collective modes characterized by concerted inner- and outer-wall motions, and determine quantitatively the tube dependent van der Waals potential governing their vibration frequencies. We also observe strong quantum interference between Raman scattering from the inner- and outer-wall excitation pathways, the relative phase of which reveals chirality dependent excited-state potential energy surface displacement in different nanotubes. PMID- 23340417 TI - Removal of stacking-fault tetrahedra by twin boundaries in nanotwinned metals. AB - Stacking-fault tetrahedra are detrimental defects in neutron- or proton irradiated structural metals with face-centered cubic structures. Their removal is very challenging and typically requires annealing at very high temperatures, incorporation of interstitials or interaction with mobile dislocations. Here we present an alternative solution to remove stacking-fault tetrahedra discovered during room temperature, in situ Kr ion irradiation of epitaxial nanotwinned Ag with an average twin spacing of ~8 nm. A large number of stacking-fault tetrahedra were removed during their interactions with abundant coherent twin boundaries. Consequently the density of stacking-fault tetrahedra in irradiated nanotwinned Ag was much lower than that in its bulk counterpart. Two fundamental interaction mechanisms were identified, and compared with predictions by molecular dynamics simulations. In situ studies also revealed a new phenomenon: radiation-induced frequent migration of coherent and incoherent twin boundaries. Potential migration mechanisms are discussed. PMID- 23340416 TI - On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. AB - Temporal lobe epilepsy is the most common type of epilepsy in adults, is often medically refractory, and due to broad actions and long-time scales, current systemic treatments have major negative side-effects. However, temporal lobe seizures tend to arise from discrete regions before overt clinical behaviour, making temporally and spatially specific treatment theoretically possible. Here we report the arrest of spontaneous seizures using a real-time, closed-loop, response system and in vivo optogenetics in a mouse model of temporal lobe epilepsy. Either optogenetic inhibition of excitatory principal cells, or activation of a subpopulation of GABAergic cells representing <5% of hippocampal neurons, stops seizures rapidly upon light application. These results demonstrate that spontaneous temporal lobe seizures can be detected and terminated by modulating specific cell populations in a spatially restricted manner. A clinical approach built on these principles may overcome many of the side-effects of currently available treatment options. PMID- 23340418 TI - Strain-controlled magnetic domain wall propagation in hybrid piezoelectric/ferromagnetic structures. AB - The control of magnetic order in nanoscale devices underpins many proposals for integrating spintronics concepts into conventional electronics. A key challenge lies in finding an energy-efficient means of control, as power dissipation remains an important factor limiting future miniaturization of integrated circuits. One promising approach involves magnetoelectric coupling in magnetostrictive/piezoelectric systems, where induced strains can bear directly on the magnetic anisotropy. While such processes have been demonstrated in several multiferroic heterostructures, the incorporation of such complex materials into practical geometries has been lacking. Here we demonstrate the possibility of generating sizeable anisotropy changes, through induced strains driven by applied electric fields, in hybrid piezoelectric/spin-valve nanowires. By combining magneto-optical Kerr effect and magnetoresistance measurements, we show that domain wall propagation fields can be doubled under locally applied strains. These results highlight the prospect of constructing low-power domain wall gates for magnetic logic devices. PMID- 23340419 TI - Catalytic subsurface etching of nanoscale channels in graphite. AB - Catalytic hydrogenation of graphite has recently attracted renewed attention as a route for nanopatterning of graphene and to produce graphene nanoribbons. These reports show that metallic nanoparticles etch the surface layers of graphite or graphene anisotropically along the crystallographic zig-zag <11-20> or armchair <10-10> directions. The etching direction can be influenced by external magnetic fields or the supporting substrate. Here we report the subsurface etching of highly oriented pyrolytic graphite by Ni nanoparticles, to form a network of tunnels, as seen by scanning electron microscopy and scanning tunnelling microscopy. In this new nanoporous form of graphite, the top layers bend inward on top of the tunnels, whereas their local density of states remains fundamentally unchanged. Engineered nanoporous tunnel networks in graphite allow for further chemical modification and may find applications in various fields and in fundamental science research. PMID- 23340420 TI - Non-uniform membrane diffusion enables steady-state cell polarization via vesicular trafficking. AB - Actin-based vesicular trafficking of Cdc42, leading to a polarized concentration of the GTPase, has been implicated in cell polarization, but it was recently debated whether this mechanism allows stable maintenance of cell polarity. Here we show that endocytosis and exocytosis are spatially segregated in the polar plasma membrane, with sites of exocytosis correlating with microdomains of higher concentration and slower diffusion of Cdc42 compared with surrounding regions. Numerical simulations using experimentally obtained diffusion coefficients and trafficking geometry revealed that non-uniform membrane diffusion of Cdc42 in fact enables temporally sustained cell polarity. We show further that phosphatidylserine, a phospholipid recently found to be crucial for cell polarity, is enriched in Cdc42 microdomains. Weakening a potential interaction between phosphatidylserine and Cdc42 enhances Cdc42 diffusion in the microdomains but impedes the strength of polarization. These findings demonstrate a critical role for membrane microdomains in vesicular trafficking-mediated cell polarity. PMID- 23340421 TI - Gender identification of the Mesozoic bird Confuciusornis sanctus. AB - Hundreds of specimens of the beaked bird Confuciusornis sanctus have been recovered from Early Cretaceous lake deposits of northeastern China. These birds show remarkable variation in size and plumage, with some displaying two long, central ornamental rectrices (tail feathers) and others lacking them altogether. Although, traditionally specimens with ornamental rectrices were interpreted as males and those without them as females, this supposed sexual dimorphism has remained unconfirmed. Here we report on the discovery of medullary bone, a tissue unique to reproductively active female birds, in a specimen of C. sanctus (DNHM D1874) lacking these feathers. Our discovery constitutes the first case of gender identification in a Mesozoic bird, and it provides undisputed evidence that individuals of C. sanctus without ornamental rectrices are females. By permitting gender identification in C. sanctus, our results provide insight into the onset of sexual maturity and attainment of adult body size of this and other early birds. PMID- 23340422 TI - Analysis of protein-coding mutations in hiPSCs and their possible role during somatic cell reprogramming. AB - Recent studies indicate that human-induced pluripotent stem cells contain genomic structural variations and point mutations in coding regions. However, these studies have focused on fibroblast-derived human induced pluripotent stem cells, and it is currently unknown whether the use of alternative somatic cell sources with varying reprogramming efficiencies would result in different levels of genetic alterations. Here we characterize the genomic integrity of eight human induced pluripotent stem cell lines derived from five different non-fibroblast somatic cell types. We show that protein-coding mutations are a general feature of the human induced pluripotent stem cell state and are independent of somatic cell source. Furthermore, we analyse a total of 17 point mutations found in human induced pluripotent stem cells and demonstrate that they do not generally facilitate the acquisition of pluripotency and thus are not likely to provide a selective advantage for reprogramming. PMID- 23340423 TI - Environmental conditions and community evenness determine the outcome of biological invasion. AB - Biological invasion is widely studied, however, conclusions on the outcome of this process mainly originate from observations in systems that leave a large number of experimental variables uncontrolled. Here using a fully controlled system consisting of assembled bacterial communities, we evaluate the degree of invasion and the effect on the community functionality in relation to the initial community evenness under specific environmental stressors. We show that evenness influences the level of invasion and that the introduced species can promote functionality under stress. The evenness-invasibility relationship is negative in the absence and neutral in the presence of stress. Under these conditions, the introduced species is able to maintain the functionality of uneven communities. These results indicate that communities, initially having the same genetic background, in the presence of the same invader, react in a different way with respect to invasibility and functionality depending on specific environmental conditions and community evenness. PMID- 23340424 TI - Creation of helical Dirac fermions by interfacing two gapped systems of ordinary fermions. AB - Topological insulators are a unique class of materials characterized by a Dirac cone state of helical Dirac fermions in the middle of a bulk gap. When the thickness of a three-dimensional topological insulator is reduced, however, the interaction between opposing surface states opens a gap that removes the helical Dirac cone, converting the material back to a normal system of ordinary fermions. Here we demonstrate, using density function theory calculations and experiments, that it is possible to create helical Dirac fermion state by interfacing two gapped films-a single bilayer Bi grown on a single quintuple layer Bi(2)Se(3) or Bi(2)Te(3). These extrinsic helical Dirac fermions emerge in predominantly Bi bilayer states, which are created by a giant Rashba effect with a coupling constant of ~4 eV.A due to interfacial charge transfer. Our results suggest that this approach is a promising means to engineer topological insulator states on non-metallic surfaces. PMID- 23340425 TI - The oldest echinoderm faunas from Gondwana show that echinoderm body plan diversification was rapid. AB - The earliest fossil echinoderms have, until now, come almost exclusively from North America and are represented by few taxa, all of which have a radiate body plan. Here we report the discovery of two new echinoderm faunas from the early part of the Cambrian of Morocco (West Gondwana). The former represents the oldest echinoderm fauna from Gondwana, approximately equivalent in age to those from North America, and the latter the oldest diversified fauna from Gondwana. In both cases, the appearance of well-preserved echinoderms coincides with a change in palaeogeographic regime. The presence of four markedly different echinoderm body plans in these earliest faunas indicates that considerable diversification had already taken place by 510 Ma. Yet all share the same distinctive biomineralized skeleton that, based on the fossil record and ocean geochemistry, probably evolved just 10-15 my earlier. This suggests that a rapid rate of morphological divergence took place during the initial stages of echinoderm evolution. PMID- 23340426 TI - Spatial organization of frequency preference and selectivity in the human inferior colliculus. AB - To date, the functional organization of human auditory subcortical structures can only be inferred from animal models. Here we use high-resolution functional magnetic resonance imaging at ultra-high magnetic fields (7T) to map the organization of spectral responses in the human inferior colliculus, a subcortical structure fundamental for sound processing. We reveal a tonotopic map with a spatial gradient of preferred frequencies approximately oriented from dorsolateral (low frequencies) to ventromedial (high frequencies) locations. Furthermore, we observe a spatial organization of spectral selectivity (tuning) of functional magnetic resonance imaging responses in the human inferior colliculus. Along isofrequency contours, functional magnetic resonance imaging tuning is narrowest in central locations and broadest in the surrounding regions. Finally, by comparing subcortical and cortical auditory areas we show that functional magnetic resonance imaging tuning is narrower in human inferior colliculus than on the cortical surface. Our findings pave the way to noninvasive investigations of sound processing in human subcortical nuclei and for studying the interplay between subcortical and cortical neuronal populations. PMID- 23340428 TI - High heat flow and ocean acidification at a nascent rift in the northern Gulf of California. AB - The prevailing tectonic setting in the Gulf California suggests the presence of an undetermined number of short spreading centres with associated hydrothermal systems. However, to date, active seafloor spreading phenomena have been documented in only three of the eight tectonically active basins. Here we report heat flow values as high as 15,436 mW m(-2) in two of the northernmost basins of the Gulf of California, providing evidence of intense hydrothermal activity associated with the transition from continental rifting to seafloor spreading. The mean heat flow for the Wagner and Consag basins area is 1,875 mW m(-2), more than 15 times higher than the mean value for oceanic crust (105.4 mW m(-2)). Additional evidence for vigorous hydrothermal circulation and a shallow heat source includes intense gas discharge (CO(2) and CH(4)), widespread low pH (average 7.7), locally high (222)Rn concentrations in the bottom water and a high extent of organic matter maturation in the sediments. PMID- 23340427 TI - Evolution of the protein stoichiometry in the L12 stalk of bacterial and organellar ribosomes. AB - The emergence of ribosomes and translation factors is central for understanding the origin of life. Recruitment of translation factors to bacterial ribosomes is mediated by the L12 stalk composed of protein L10 and several copies of protein L12, the only multi-copy protein of the ribosome. Here we predict stoichiometries of L12 stalk for >1,200 bacteria, mitochondria and chloroplasts by a computational analysis, and validate the predictions by quantitative mass spectrometry. The majority of bacteria have L12 stalks allowing for binding of four or six copies of L12, largely independent of the taxonomic group or living conditions of the bacteria, whereas some cyanobacteria have eight copies. Mitochondrial and chloroplast ribosomes can accommodate six copies of L12. The last universal common ancestor probably had six molecules of L12 molecules bound to L10. Changes of the stalk composition provide a unique possibility to trace the evolution of protein components of the ribosome. PMID- 23340429 TI - Globally homochiral assembly of two-dimensional molecular networks triggered by co-absorbers. AB - Understanding the chirality induction and amplification processes, and the construction of globally homochiral surfaces, represent essential challenges in surface chirality studies. Here we report the induction of global homochirality in two-dimensional enantiomorphous networks of achiral molecules via co-assembly with chiral co-absorbers. The scanning tunnelling microscopy investigations and molecular mechanics simulations demonstrate that the point chirality of the co absorbers transfers to organizational chirality of the assembly units via enantioselective supramolecular interactions, and is then hierarchically amplified to the global homochirality of two-dimensional networks. The global homochirality of the network assembly shows nonlinear dependence on the enantiomeric excess of chiral co-absorber in the solution phase, demonstrating, for the first time, the validation of the 'majority rules' for the homochirality control of achiral molecules at the liquid/solid interface. Such an induction and nonlinear chirality amplification effect promises a new approach towards two dimensional homochirality control and may reveal important insights into asymmetric heterogeneous catalysis, chiral separation and chiral crystallization. PMID- 23340430 TI - Unraveling quantum pathways using optical 3D Fourier-transform spectroscopy. AB - Predicting and controlling quantum mechanical phenomena require knowledge of the system Hamiltonian. A detailed understanding of the quantum pathways used to construct the Hamiltonian is essential for deterministic control and improved performance of coherent control schemes. In complex systems, parameters characterizing the pathways, especially those associated with inter-particle interactions and coupling to the environment, can only be identified experimentally. Quantitative insight can be obtained provided the quantum pathways are isolated and independently analysed. Here we demonstrate this possibility in an atomic vapour using optical three-dimensional Fourier-transform spectroscopy. By unfolding the system's nonlinear response onto three frequency dimensions, three-dimensional spectra unambiguously reveal transition energies, relaxation rates and dipole moments of each pathway. The results demonstrate the unique capacity of this technique as a powerful tool for resolving the complex nature of quantum systems. This experiment is a critical step in the pursuit of complete experimental characterization of a system's Hamiltonian. PMID- 23340431 TI - The ghost of nestedness in ecological networks. AB - Ecologists are fascinated by the prevalence of nestedness in biogeographic and community data, where it is thought to promote biodiversity in mutualistic systems. Traditionally, nestedness has been treated in a binary sense: species and their interactions are either present or absent, neglecting information on abundances and interaction frequencies. Extending nestedness to quantitative data facilitates the study of species preferences, and we propose a new detection method that follows from a basic property of bipartite networks: large dominant eigenvalues are associated with highly nested configurations. We show that complex ecological networks are binary nested, but quantitative preferences are non-nested, indicating limited consumer overlap of favoured resources. The spectral graph approach provides a formal link to local dynamical stability analysis, where we demonstrate that nested mutualistic structures are minimally stable. We conclude that, within the binary constraint of interaction plausibility, species preferences are partitioned to avoid competition, thereby benefiting system-wide resource allocation. PMID- 23340432 TI - Observation of a large spin-dependent transport length in organic spin valves at room temperature. AB - The integration of organic semiconductors and magnetism has been a fascinating topic for fundamental scientific research and future applications in electronics, because organic semiconductors are expected to possess a large spin-dependent transport length based on weak spin-orbit coupling and weak hyperfine interaction. However, to date, this length has typically been limited to several nanometres at room temperature, and a large length has only been observed at low temperatures. Here we report on a novel organic spin valve device using C(60) as the spacer layer. A magnetoresistance ratio of over 5% was observed at room temperature, which is one of the highest magnetoresistance ratios ever reported. Most importantly, a large spin-dependent transport length of approximately 110 nm was experimentally observed for the C(60) layer at room temperature. These results provide insights for further understanding spin transport in organic semiconductors and may strongly advance the development of spin-based organic devices. PMID- 23340434 TI - Reduced plumage and flight ability of a new Jurassic paravian theropod from China. AB - Feathered theropods were diverse in the Early Cretaceous Jehol Group of western Liaoning Province, China. Recently, anatomically distinct feathered taxa have been discovered in the older Middle-Late Jurassic Tiaojishan Formation in the same region. Phylogenetic hypotheses including these specimens have challenged the pivotal position of Archaeopteryx in bird phylogeny. Here we report a basal troodontid from the Tiaojishan Formation that resembles Anchiornis, also from Jianchang County (regarded as sister-taxa). The feathers of Eosinopteryx are less extensive on the limbs and tail than Anchiornis and other deinonychosaurians. With reduced plumage and short uncurved pedal claws, Eosinopteryx would have been able to run unimpeded (with large foot remiges cursorial locomotion was likely problematic for Anchiornis). Eosinopteryx increases the known diversity of small bodied dinosaurs in the Jurassic, shows that taxa with similar body plans could occupy different niches in the same ecosystem and suggests a more complex picture for the origin of flight. PMID- 23340435 TI - Application of microwave irradiation to fast and efficient isolation of benzodiazepines from human hair. AB - The aim of this research was to develop, optimize and validate a modern and rapid method of preparation of human hair samples using microwave irradiation for the purpose of determination of six benzodiazepines: alprazolam, estazolam, lorazepam, clonazepam, diazepam and tetrazepam, with lormetazepam as an internal standard (IS). Extracts were analyzed ultrahigh performance liquid chromatography with mass spectrometry time of flight detection (UHPLC-MS-TOF). Optimal parameters of microwave-assisted extraction (type of extraction solvent, extraction temperature, extraction time and pH of borate buffer) for these drugs in spiked hair samples were defined. The limit of detection ((0.003-0.025 ng/mg), intra- (1.5-4.3%) and interday (2.3-8.3%) precision (CV) and accuracy of the assay (89.8-105.7%) at three concentration levels: 0.22, 2.22 and 5.56 ng/mg were calculated. The optimized and validated MAE/UHPLC-MS-TOF method was then applied for analysis of clinical hair sample. PMID- 23340433 TI - MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. AB - Chemotherapy resistance frequently drives tumour progression. However, the underlying molecular mechanisms are poorly characterized. Epithelial-to mesenchymal transition has been shown to correlate with therapy resistance, but the functional link and signalling pathways remain to be elucidated. Here we report that microRNA-30c, a human breast tumour prognostic marker, has a pivotal role in chemoresistance by a direct targeting of the actin-binding protein twinfilin 1, which promotes epithelial-to-mesenchymal transition. An interleukin 6 family member, interleukin-11 is identified as a secondary target of twinfilin 1 in the microRNA-30c signalling pathway. Expression of microRNA-30c inversely correlates with interleukin-11 expression in primary breast tumours and low interleukin-11 correlates with relapse-free survival in breast cancer patients. Our study demonstrates that microRNA-30c is transcriptionally regulated by GATA3 in breast tumours. Identification of a novel microRNA-mediated pathway that regulates chemoresistance in breast cancer will facilitate the development of novel therapeutic strategies. PMID- 23340436 TI - Capillary electrophoresis for the monitoring of phenolic compounds in bioprocesses. AB - Hydrolysates of lignocellulosic biomass, used as substrates for the sustainable production of fuels and chemicals often contain high amounts of phenolic compounds inhibiting the production microbiota. Quantification of these inhibitor compounds may help to understand possible difficulties in bioprocessing and further the development of more efficient, robust and tolerable processes. A separation method based on capillary electrophoresis with UV detection was developed for the simultaneous quantification of 10 phenolic compounds that may have inhibitor properties. Intraday relative standard deviations were less than 0.7% for migration times and between 2.6% and 6.4% for peak areas. Interday relative standard deviations were less than 3.0% for migration times and between 5.0% and 7.2% for peak areas. The method was applied to demonstrate that Saccharomyces cerevisiae was able to decrease the concentrations of vanillin, coniferyl aldehyde, syringaldehyde, acetoguaiacone and cinnamic acid during the cultivation, whereas the concentrations of phenols increased. PMID- 23340437 TI - Regulation of tumour intracellular pH: a mathematical model examining the interplay between H+ and lactate. AB - Non-invasive measurements of pH have shown that both tumour and normal cells have intracellular pH (pHi) that lies on the alkaline side of neutrality (7.1-7.2). However, extracellular pH (pHe) is reported to be more acidic in some tumours compared to normal tissues. Many cellular processes and therapeutic agents are known to be tightly pH dependent which makes the study of intracellular pH regulation of paramount importance. We develop a mathematical model that examines the role of various membrane-based ion transporters in tumour pH regulation, in particular, with a focus on the interplay between lactate and H(+) ions and whether the lactate/H(+) symporter activity is sufficient to give rise to the observed reversed pH gradient that is seen is some tumours. Using linear stability analysis and numerical methods, we are able to gain a clear understanding of the relationship between lactate and H(+) ions. We extend this analysis using perturbation techniques to specifically examine a rapid change in H(+)-ion concentrations relative to variations in lactate. We then perform a parameter sensitivity analysis to explore solution robustness to parameter variations. An important result from our study is that a reversed pH gradient is possible in our system but for unrealistic parameter estimates-pointing to the possible involvement of other mechanisms in cellular pH gradient reversal, for example acidic vesicles, lysosomes, golgi and endosomes. PMID- 23340438 TI - Pattern formation by two-layer Turing system with complementary synthesis. AB - Many multicellular organisms have a layered structure. The interaction between these layers plays an essential role in many developmental processes, and key molecules involved in these processes are often expressed in a layer-specific manner. On the other hand, pattern formation of organisms has been frequently discussed in connection with the Turing system. However, the Turing system has so far been studied mainly in single-layered space. In this paper, we thus investigate a two-layer Turing system with complementary synthesis, in which two interacting molecules are exclusively synthesized in different layers. From a linear stability analysis, we determine the Turing condition of the complementary system, and show that this condition requires stronger regulatory interactions of the molecules than that of the system with usual ubiquitous synthesis. We then confirm that this complementary system affects pattern types in fixed and expanding two-dimensional spaces in a similar way to the system with ubiquitous synthesis. In addition, the two-layer system includes two types of diffusion, lateral and transversal, and these have distinct effects on pattern formation with lateral diffusion mainly determining the periodicity of patterns generated and transversal diffusion affecting pattern type. These results suggest that the transversal diffusion functions as a time delay in the two-layer system. Finally, we apply this complementary system to explain pattern formation of the shoot apical meristem of plants. These findings provide an understanding of pattern formation caused by the interaction between cell layers in multicellular organisms. PMID- 23340439 TI - Identifying a species tree subject to random lateral gene transfer. AB - A major problem for inferring species trees from gene trees is that evolutionary processes can sometimes favor gene tree topologies that conflict with an underlying species tree. In the case of incomplete lineage sorting, this phenomenon has recently been well-studied, and some elegant solutions for species tree reconstruction have been proposed. One particularly simple and statistically consistent estimator of the species tree under incomplete lineage sorting is to combine three-taxon analyses, which are phylogenetically robust to incomplete lineage sorting. In this paper, we consider whether such an approach will also work under lateral gene transfer (LGT). By providing an exact analysis of some cases of this model, we show that there is a zone of inconsistency when majority rule three-taxon gene trees are used to reconstruct species trees under LGT. However, a triplet-based approach will consistently reconstruct a species tree under models of LGT, provided that the expected number of LGT transfers is not too high. Our analysis involves a novel connection between the LGT problem and random walks on cyclic graphs. We have implemented a procedure for reconstructing trees subject to LGT or lineage sorting in settings where taxon coverage may be patchy and illustrate its use on two sample data sets. PMID- 23340440 TI - Association between collagen production and mechanical stretching in dermal extracellular matrix: in vivo effect of cross-linked hyaluronic acid filler. A randomised, placebo-controlled study. AB - BACKGROUND: The effects of hyaluronic acid (HA) injection on tissue collagen anabolism are suggested to be related to the induction of mechanical stress, causing biochemical changes in skin physiology. OBJECTIVES: To ascertain the association between dermal mechanics modulated by a hyaluronic acid-based filler effect and metabolism. METHODS: Sixty females were randomised to receive a 0.5mL injection of HA gel or isotonic sodium chloride (control) in the arm. Skin biopsies were taken at baseline and after 1, 3 and 6 months. Protein and gene expression of procollagen, matrix metalloproteinases (MMP) and MMP tissue inhibitors (TIMP1) were measured blind by ELISA and qPCR, respectively. Injected volumes were measured by high-frequency ultrasound and radiofrequency analysis. Skin layer effects of injections were analysed by finite element digital modelling. RESULTS: One month after injection, the filler induced an increase in procollagen (p=0.0016) and TIMP-1 (p=0.0485) levels and relative gene expression of procollagen III and I isoforms compared with the controls. After 3 months, procollagen levels remained greater than in the controls (p=0.0005), whereas procollagen expression and TIMP-1 and MMP content were no longer different. Forty three percent of the injected filler volume was found at 1 month, 26% after 3 months and 20% after 6 months. LIMITATIONS: The ultrasound imaging technique limited the scope of the investigation and precluded an evaluation of the action of the filler at the hypodermic level. CONCLUSIONS: Integrating both mechanical and biological aspects, our results suggest that mechanical stress generated by cross-linked HA plays a role in dermal cell biochemical response. PMID- 23340441 TI - Total coumarins from Urtica dentata Hand prevent murine autoimmune diabetes via suppression of the TLR4-signaling pathways. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Urtica dentata Hand (UDH), the root of Laportea bulbifera (Sieb. et. Zucc.) Wedd, has been traditionally used in traditional Chinese medicine as an anti-inflammatory and immuno-regulatory agent for rheumatoid arthritis and some other autoimmune diseases treatment. And the coumarins are the major components of UDH. AIM OF THE STUDY: To investigate the effect of total coumarins (TC) isolated from UDH on the development of autoimmune diabetes. MATERIALS AND METHODS: Eight-week-old non-obese diabetic (NOD) mice were randomly divided into four groups: control group, low-dose (37.5 mg/kg), middle-dose (75 mg/kg), and high-dose (150 mg/kg) TC-treatment groups. NOD mice were then given with a suspension of TC or saline by intragastric (i.g.) administration every other day. After 4 weeks of treatment, 8 mice at 12-weeks of age per group were randomly selected to be sacrificed to perform intraperitoneal glucose tolerance test, examine histopathological insulitis, spleen T lymphocyte proliferation, the percentage of CD4+CD25+Foxp3+ T regulatory cell (Treg), dendritic cell (DC) surface molecules, toll-like receptor (TLR)4 expression and signal pathways involved. The remaining 10 mice per group were kept until 26 weeks of age to assess the incidence of diabetes. We also studied the direct effect of TC on DC and CD4+CD25+ Tregs in vitro. RESULTS: Treatment with TC for 4 weeks significantly inhibited insulitis, increased pancreatic islet number, delayed the onset and decreased the development of diabetes by 26 weeks of age in NOD mice, compared with the untreated control mice. TC suppressed spleen T lymphocyte proliferation, induced Th2-biased cytokine response, the generation of CD4+CD25+Foxp3+ Tregs and Foxp3 mRNA expression. And TC-treated DCs were characterized as low expression of MHC class II and CD86 molecules. TLR4 gene and protein expressions in the spleen, thymus and pancreas were down-regulated in TC treated groups. The key molecules in the downstream signaling cascades of TLR4, including myeloid differentiation factor (MyD)88, nuclear factor (NF)-kappaB, IL 1beta, Toll-IL-1 receptor domain-containing adaptor inducing interferon beta(TRIF), TRIF-related adaptor molecule (TRAM), interferon regulatory factor (IRF)-3 and IFN-beta, all decreased significantly in TC groups, suggesting that TC inhibits both MyD88-dependent and -independent pathways of TLR4. At the cellular level, however, TLR4 protein expression in DCs, but not in Tregs, was downregulated by TC. And TC strengthened the role of DC, not Treg, in negative immune regulation in vitro. In contrast, anti-TLR4 antibody could block the effect of TC on DCs immune function. CONCLUSION: These results suggest that TC extracted from UDH prevent the development of autoimmune diabetes in NOD mice via suppression of the TLR4-signaling pathways. TC maintain the DCs in an immature tolerogenic state, at least in part, mediated by down-regulating TLR4-signaling pathways in DCs, then enhance Treg differentiation, shift toward Th2 and suppress T lymphocyte proliferation. PMID- 23340442 TI - Collagen binding provides a sensitive screen for variant von Willebrand disease. AB - BACKGROUND: von Willebrand factor (VWF) is a multimeric protein that binds platelets and collagen, facilitating hemostasis at sites of vessel injury. Measurement of VWF multimer distribution is critical for diagnosis of variant von Willebrand disease (VWD), particularly types 2A and 2B, but the typical measurement by gel electrophoresis is technically difficult and time-consuming. A comparison of VWF collagen binding (VWF:CB) and VWF multimer distribution was performed to evaluate the utility of VWF:CB as a diagnostic test. METHODS: Participants were enrolled in the Zimmerman Program for the Molecular and Clinical Biology of VWD. VWF:CB was analyzed with type III collagen and multimer distribution by agarose gel electrophoresis. The study population included 146 healthy controls, 351 individuals with type 1 VWD, and 77 with type 2 VWD. Differences between individuals with multimer group results within (controls) and outside the reference intervals were assessed with Mann-Whitney tests. RESULTS: The mean VWF:CB/VWF antigen ratio was 1.10 for individuals with multimer distribution within the reference intervals and 0.51 for those with multimer distribution outside the reference intervals (P < 0.001). Sensitivity of VWF:CB for multimer abnormalities was 100% for healthy controls, 99% for patients with type 1, and 100% for patients with type 2A and type 2B VWD using a VWF:CB/VWF antigen cutoff ratio of 0.6, and decreased to 99% for all patients with a ratio of 0.7. With the exception of individuals with novel or unclassified mutations, the VWF:CB was able to correctly categorize participants with variant VWD. CONCLUSIONS: These findings suggest that VWF:CB may substitute for multimer distribution in initial VWD testing, although further studies are needed to validate the clinical utility of VWF:CB. PMID- 23340443 TI - More data, please! PMID- 23340444 TI - Transversus abdominis plane block associated with locoregional anesthesia with a laparotenser for gynecologic surgery in an awake state. AB - The laparotenser instrument is used to perform isobaric laparoscopy to avoid adverse effects in the pneumoperitoneum. To decrease hospitalization time and increase the rate of same-day discharge, we investigated the safety of isobaric laparoscopy using the Laparotenser, a new subcutaneous abdominal wall-lifting system, with transversus abdominis plane (TAP) block combined with locoregional anesthesia (subarachnoid, peridural, spino-peridural) for patients undergoing minor and major gynecologic surgeries. With this combination of anesthetics, TAP block enabled us to anesthetize the supraumbilical region while the pelvic region was covered by locoregional anesthesia. We describe our experience with TAP blockade associated with locoregional anesthesia during gasless laparoscopy. We performed ultrasound-guided TAP block with ropivacaine 0.25% 20 mL to cover the supraumbilical region in association with locoregional anesthesia (lumbar subarachnoid-peridural-spinoperidural) and bupivacaine 0.5% (10 mg/3 mL) to cover the lower pelvic region. Successful outcome was reported in 81.3% (13/16) of the patients. PMID- 23340445 TI - A shift to Th2 immune response caused by constitutive expression of IPSE/alpha-1 in transfected pig fibroblasts in mice. AB - The IPSE/alpha-1 gene (IL-4-inducing principle of Schistosoma mansoni eggs) is a major secreted glycoprotein of S. mansoni eggs that has a potent IL-4-inducing effect. To test the hypothesis that the immune evasion mechanism can be used to overcome the xenograft immune response, the IPSE/alpha-1 gene was transferred into pig fibroblasts, and the transgenic cells were transplanted into KM mice by subcutaneously injecting 10(5)cells per mouse. Cytokine levels were measured to examine the immune response polarization by real-time PCR and ELISA. Mice injected with pig fibroblasts containing a pIRES2-EGFP expression vector were used as a control group. In this group, both cellular and humoral immune responses were activated to reject the grafts alongside increases in all measured cytokine levels. In contrast, the experimental group injected with cells constitutively expressing the IPSE/alpha-1 gene demonstrated a significant decrease in Th1 response cytokines and a significant increase in Th2 response cytokines compared with the control group. These results imply that constitutive IPSE/alpha-1 expression can shift the Th1/Th2 balance of xenograft rejections toward the Th2 response while suppressing the Th1 response. In conclusion, IPSE/alpha-1 could influence the polarization of immune responses during xenograft rejection and suppress the Th1 response. Therefore, this parasitic immune evasion mechanism could be helpful in overcoming xenograft rejection. PMID- 23340446 TI - Immune responses and protective efficacy of a novel DNA vaccine encoding outer membrane protein of avian Pasteurella multocida. AB - Avian Pasteurella multocida is a causative agent of fowl cholera. Two proteins OmpH and OmpA are the major immunogenic antigens of avian P. multocida, which play an important role in inducing immune responses that confer resistance against infections. In the present study, we used pcDNA3.1(+) as a vector and constructed DNA vaccines with the genes encoding the two antigens mentioned above. These DNA vaccines include monovalent (pcDNA-OMPH, pOMPH and pcDNA-OMPA, pOMPA), divalent combination (pcDNA-OMPH+pcDNA-OMPA, pOMPH+pOMPA) and fusion of two gene vaccines (pcDNA-OMPH/OMPA, pOMPHA). The immune responses to these DNA vaccines were evaluated by serum antibody titers, lymphocyte proliferation assay and titers of a cytokines, IFN-gamma. The protective efficacy after challenging with a virulent avian P. multocida strain, CVCC474, was evaluated by survival rate. A significant increase in serum antibody levels was observed in chickens vaccinated with divalent combination and fusion DNA vaccines. Additionally, the lymphocyte proliferation (SI value) and the levels of IFN-gamma were both higher in chickens immunized with divalent combination and fusion DNA vaccines than in those vaccinated with monovalent DNA vaccines (P<0.05). Furthermore, the protection provided by divalent combination and fusion DNA vaccines was superior to that provided by monovalent DNA vaccines after challenging with the avian P. multocida strain CVCC474. And the protective efficacy in chickens immunized three times with the fusion DNA vaccine was equivalent to the protective efficacy in chickens vaccinated once with the attenuated live vaccine. This suggests that divalent combination and fusion DNA vaccines represent a promising approach for the prevention of fowl cholera. PMID- 23340447 TI - Expression of TLR4 in swine as assessed by a newly developed monoclonal antibody. AB - Toll-like receptors (TLRs) constitute an ancient family of pattern recognition receptors for conserved microbial structures that allow rapid detection of invading pathogens, triggering immune responses. TLR4 binds lipopolysaccharides (LPS) being involved in the recognition of Gram-negative bacteria. Herein we describe the generation and characterisation of a monoclonal antibody, named 3H3, against porcine TLR4. Its specificity was confirmed by reactivity with TLR4 expressing CHO cell transfectants. On peripheral blood leukocytes TLR4 was preferentially expressed on myelomonocytic cells, with monocytes expressing higher levels than granulocytes. Staining of lung tissue sections showed that TLR4 is also expressed on epithelial cells lining the bronchial tract, a distribution consistent with a surveillance function of bacterial invasion. PMID- 23340448 TI - Comment on 'cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells'. PMID- 23340450 TI - Reply: Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. PMID- 23340451 TI - Phosphorylated forms of GNMT in mouse liver. PMID- 23340452 TI - Analytical model for BTEX natural attenuation in the presence of fuel ethanol and its anaerobic metabolite acetate. AB - Flow-through column studies were conducted to mimic the natural attenuation of ethanol and BTEX mixtures, and to consider potential inhibitory effects of ethanol and its anaerobic metabolite acetate on BTEX biodegradation. Results were analyzed using a one-dimensional analytical model that was developed using consecutive reaction differential equations based on first-order kinetics. Decrease in pH due to acetogenesis was also modeled, using charge balance equations under CaCO(3) dissolution conditions. Delay in BTEX removal was observed and simulated in the presence of ethanol and acetate. Acetate was the major volatile fatty acid intermediate produced during anaerobic ethanol biodegradation (accounting for about 58% of the volatile fatty acid mass) as suggested by the model data fit. Acetate accumulation (up to 1.1 g/L) near the source zone contributed to a pH decrease by almost one unit. The anaerobic degradation of ethanol (2 g/L influent concentration) at the source zone produced methane at concentrations exceeding its solubility (~/=26mg/L). Overall, this simple analytical model adequately described ethanol degradation, acetate accumulation and methane production patterns, suggesting that it could be used as a screening tool to simulate lag times in BTEX biodegradation, changes in groundwater pH and methane generation following ethanol-blended fuel releases. PMID- 23340449 TI - Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas. AB - BACKGROUND: The polyamine-inhibitory regimen difluoromethylornithine (DFMO)+sulindac has marked efficacy in preventing metachronous colorectal adenomas. Polyamines are synthesised endogenously and obtained from dietary sources. Here we investigate dietary polyamine intake and outcomes in the DFMO+sulindac colorectal adenoma prevention trial. METHODS: Dietary polyamine data were available for 188 of 267 patients completing the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and categorised into two groups: highest (>75-100%) vs the lower three quartiles (0-25, 25-50 and 50-75%). Baseline tissue polyamine concentration and ODC1 genotype were determined. Logistic regression models were used for risk estimation. RESULTS: A significant interaction was detected between dietary polyamine group and treatment with regard to adenoma recurrence (P=0.012). Significant metachronous adenoma risk reduction was observed after DFMO+sulindac treatment in dietary polyamine quartiles 1-3 (risk ratio (RR) 0.19; 95% confidence interval (CI) 0.08-0.42; P<0.0001) but not in quartile 4 (RR 1.51; 95% CI 0.53-4.29; P=0.44). However, a lower number of events in the placebo group within dietary quartile 4 confound the aforementioned risk estimates. CONCLUSION: These preliminary findings reveal complex relationships between diet and therapeutic prevention, and they support further clinical trial-based investigations where the dietary intervention itself is controlled. PMID- 23340453 TI - Estimation of scattering phase function utilizing laser Doppler power density spectra. AB - A new method for the estimation of the light scattering phase function of particles is presented. The method allows us to measure the light scattering phase function of particles of any shape in the full angular range (0 degrees 180 degrees ) and is based on the analysis of laser Doppler (LD) power density spectra. The theoretical background of the method and results of its validation using data from Monte Carlo simulations will be presented. For the estimation of the scattering phase function, a phantom measurement setup is proposed containing a LD measurement system and a simple model in which a liquid sample flows through a glass tube fixed in an optically turbid material. The scattering phase function estimation error was thoroughly investigated in relation to the light scattering anisotropy factor g. The error of g estimation is lower than 10% for anisotropy factors larger than 0.5 and decreases with increase of the anisotropy factor (e.g. for g = 0.98, the error of estimation is 0.01%). The analysis of influence of the noise in the measured LD spectrum showed that the g estimation error is lower than 1% for signal to noise ratio higher than 50 dB. PMID- 23340454 TI - Remating behavior in Anastrepha fraterculus (Diptera: Tephritidae) females is affected by male juvenile hormone analog treatment but not by male sterilization. AB - The sterile insect technique (SIT) has been proposed as an area-wide method to control the South American fruit fly, Anastrepha fraterculus (Wiedemann). This technique requires sterilization, a procedure that affects, along with other factors, the ability of males to modulate female sexual receptivity after copulation. Numerous pre-release treatments have been proposed to counteract the detrimental effects of irradiation, rearing and handling and increase SIT effectiveness. These include treating newly emerged males with a juvenile hormone mimic (methoprene) or supplying protein to the male's diet to accelerate sexual maturation prior to release. Here, we examine how male irradiation, methoprene treatment and protein intake affect remating behavior and the amount of sperm stored in inseminated females. In field cage experiments, we found that irradiated laboratory males were equally able to modulate female remating behavior as fertile wild males. However, females mated with 6-day-old, methoprene treated males remated more and sooner than females mated with naturally matured males, either sterile or wild. Protein intake by males was not sufficient to overcome reduced ability of methoprene-treated males to induce refractory periods in females as lengthy as those induced by wild and naturally matured males. The amount of sperm stored by females was not affected by male irradiation, methoprene treatment or protein intake. This finding revealed that factors in addition to sperm volume intervene in regulating female receptivity after copulation. Implications for SIT are discussed. PMID- 23340455 TI - Using personal response systems to assess speech perception within the classroom: an approach to determine the efficacy of sound field amplification in primary school classrooms. AB - OBJECTIVES: The assessment of the combined effect of classroom acoustics and sound field amplification (SFA) on children's speech perception within the "live" classroom poses a challenge to researchers. The goals of this study were to determine: (1) Whether personal response system (PRS) hand-held voting cards, together with a closed-set speech perception test (Chear Auditory Perception Test [CAPT]), provide an appropriate method for evaluating speech perception in the classroom; (2) Whether SFA provides better access to the teacher's speech than without SFA for children, taking into account vocabulary age, middle ear dysfunction or ear-canal wax, and home language. DESIGN: Forty-four children from two school-year groups, year 2 (aged 6 years 11 months to 7 years 10 months) and year 3 (aged 7 years 11 months to 8 years 10 months) were tested in two classrooms, using a shortened version of the four-alternative consonant discrimination section of the CAPT. All children used a PRS to register their chosen response, which they selected from four options displayed on the interactive whiteboard. The classrooms were located in a 19th-century school in central London, United Kingdom. Each child sat at their usual position in the room while target speech stimuli were presented either in quiet or in noise. The target speech was presented from the front of the classroom at 65 dBA (calibrated at 1 m) and the presented noise level was 46 dBA measured at the center of the classroom. The older children had an additional noise condition with a noise level of 52 dBA. All conditions were presented twice, once with SFA and once without SFA and the order of testing was randomized. White noise from the teacher's right-hand side of the classroom and International Speech Test Signal from the teacher's left-hand side were used, and the noises were matched at the center point of the classroom (10sec averaging [A-weighted]). Each child's expressive vocabulary age and middle ear status were measured individually and each child's home language and any special educational needs were recorded. RESULTS: All children were able to use the PRS handsets, and the CAPT speech perception test was sufficiently sensitive to highlight differences in perception in the different listening conditions. Scores were higher in quiet than in any noise condition. Results showed that group performance was significantly better with SFA than without it. The main demographic predictor of performance was expressive vocabulary age. SFA gave more benefit to the poorer performers in the group. There were no significant effects on performance relating to middle ear status or home language; however, the size of the population was too small to be able to fully explore these aspects in greater detail. CONCLUSION: PRS together with the CAPT provides a sensitive measure for in situ speech perception testing within the classroom. Vocabulary age has a large effect on a child's ability to perceive the speech signal. SFA leads to improved speech perception, when the speech signal has been degraded because of poor acoustics or background noise and has a particularly large effect for children with lower vocabulary ages. PMID- 23340456 TI - Predicting the degree of hearing loss using click auditory brainstem response in babies referred from newborn hearing screening. AB - OBJECTIVES: The predictive ability of the auditory brainstem response (ABR) is an important factor governing the program sensitivity of neonatal hearing screens. The study examined the accuracy of the click-evoked auditory brainstem response (ck-ABR) when undertaken below the age of 6 months (from expected date of delivery) in predicting the pure-tone thresholds subsequently found to be present in children with a congenital permanent childhood hearing impairment. DESIGN: Children with permanent childhood hearing impairment were ascertained from neonatal screening programs that have been subject to longitudinal evaluation. Ninety-two children who had ck-ABR recorded when below 6 months of age and repeatable ear specific pure-tone audiometry were recruited. Those with recognized temporary middle ear effusions at either test were excluded. The relationship between ABR and pure-tone thresholds was tested using the Pearson correlation coefficient with a linear regression model used to estimate pure-tone threshold (dependent variable) from ABR (independent variable). Correlation coefficients were obtained for pure-tone frequencies at octave intervals between 0.25 kHz and 4 kHz and at various frequency combinations. The difference between ABR and pure-tone threshold was analyzed. Those with a difference of greater than 20 dB were further examined. The ABR and pure-tone differences were also compared in babies born at term and prematurely. RESULTS: Of the 92 children recruited to the study two children had a confirmed auditory neuropathy spectrum disorder (2%) and 10 (11%) had an audiometrically confirmed progressive hearing impairment. When these children were excluded, there was a high linear positive correlation (r = 0.90, SE = 14.3 dB) between the ABR and pure-tone thresholds averaged at 2 to 4 kHz. Although the correlation varied for different audiometric configurations, in all cases with a sloping hearing loss the correlation with their best frequency was weaker than the correlation at 2 to 4 kHz. For the total cohort the mean difference between ABR and pure-tone thresholds averaged at 2 to 4 kHz was 4.4 dB (SD = 19.29). The modal difference was 0 dB (58%) and 76 % had a difference of 20 dB or less. ABR underestimated the subsequently recorded pure tone thresholds by more than 20 dB in 11 children and 10 of these children showed progression of their hearing loss measured by serial pure-tone audiometry. ABR overestimated the pure-tone thresholds by more than 20 dB in 15 children. Nine of these children (60%) had suffered a perinatal illness and the mean difference between the pure-tone and ABR thresholds was significantly greater in those born at <35 weeks of gestation (p < 0.001). CONCLUSIONS: There is a high positive linear correlation between ck-ABR and pure-tone average thresholds at 2 to 4 kHz. However, the predictive value of ABR is reduced in certain neonatal groups. The cause for this is discussed as are the implications for undertaking a test battery at this age to improve the predictive accuracy. PMID- 23340457 TI - Tailoring the band gap of ZnO/MgZnO coaxial nanowires by the size and the component of Mg. AB - Based on first principles calculations, we investigate the changes of the band gaps of wurtzite ZnO/Mg(x)Zn(1-x)O coaxial nanowires by varying the size and Mg components. Our findings show that the band gaps of the concerned nanowires are tunable in different ways: the size of the shell (or the core) dominantly induces a band offset of the conduction band minimum, while the Mg concentration in the shell mainly causes a band offset of the valence band maximum. Statistic analysis reveals that such size- and Mg-component dependent band gaps are tightly correlated with enhanced hybridization between Zn and O induced by the Mg atoms in the shell. PMID- 23340458 TI - Anterolateral thigh flap thinning: techniques and complications. AB - BACKGROUND: A thinned anterolateral thigh flap is often necessary to achieve optimal skin resurfacing. In this article, we describe the techniques available for immediate flap thinning and the vascular complications that can follow trimming. MATERIALS AND METHODS: A systematic literature review was performed to identify the different thinning techniques and any possible complications. Data were identified by performing a systematic search on Medline, Ovid, Embase, the Cochrane Database of Systematic Reviews, Current Contents, PubMed, Google, and Google Scholar. We cross-referenced the identified articles and conference abstracts in the English and French languages. RESULTS: The study selection process was adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, and 34 were articles compiled by using the study inclusion criteria. These articles were then reviewed for the author name(s), the publication year, the flap dimensions, the flap thickness (both before and after thinning), the perforator type, the type of flap transfer, the complications that followed the thinning, the thinning technique used, the amount of deep fascia preserved around the perforator, the number of cases in the study, the area of application, and the technique used for donor-site closure. We analyzed the possible vascular complications that stemmed from the flap area site selected, the flap thickness, the thinning technique used, and whether the deep fascia was spared. CONCLUSIONS: The subfascial dissection of anterolateral thigh flaps revealed that the safest method for minimizing vascular complications accounted for a 3.1% probability for marginal necrosis, which can be managed conservatively. The overall breakdown of the vascular-related complications that followed flap thinning totals 13.4% and can be broken down as follows: partial flap loss of 4.1%, partial distal necrosis of 3.5%, marginal necrosis of 3.1%, and total flap loss of 2.5%. PMID- 23340459 TI - How to spot cocaine-induced pseudovasculitis. AB - The prevalence of cocaine-induced pseudovasculitis (CIP) causing cutaneous destruction is increasing, and plastic surgeons need to be aware of this condition because they are a part of the multidisciplinary treatment team. Differentiation of CIP from a true autoimmune vasculitis can be exceedingly challenging, and misdiagnosis with ensuing treatment may be fatal. This article is a succinct review of CIP, guided by a clinical case of 30% total body surface area skin necrosis, to familiarize the reader with this syndrome. Diagnostic aids include history of cocaine use, localized disease manifestation to skin or mucosa, discordance of antineutrophil cytoplasmic antibody and target antibody patterns typical for true vasculitis, and testing for antihuman neutrophil elastase and levamisole. Treatment is primarily supportive, and wound care, with regard to dressings and surgery, is a cross between to that of burns and meningococcemia patients. PMID- 23340460 TI - Correction of postburn equinus deformity. AB - BACKGROUND: Equinus deformity is characterized by an abnormal tiptoe gait and does not allow normal walking, hence needing correction. Congenital causes of equinus deformity include neurological diseases such as cerebral palsy and poliomyelitis. Acquired causes include injuries such as extensive trauma. We have corrected equinus deformity from extensive lower leg burns by a single operation through excisional release of the scar, Achilles lengthening, and radial forearm free flap. METHODS: Fifteen patients with postburn equinus deformity who were treated between January 2000 and March 2012 were retrospectively studied. We investigated their age, sex, cause and severity of burn injury, equinus degree, ankle range of motion and the changes in the activity, extent of Achilles lengthening, flap size, complication, and the recurrence in these patients. RESULTS: The average degree of equinus deformity before the operation was 45 degrees. With an average Achilles lengthening of 4.6 cm, all patients achieved neutral position. The patients who had poor activity due to tiptoe gait before the operation showed good to fair levels of walking ability postoperatively. During an average follow-up period of 3 years and 9 months, no patients had a recurrence. CONCLUSIONS: Equinus deformity causes significant restrictions to walking and the reconstruction is a challenging problem. Although prevention is more important during the initial stages of treatment, we have successfully corrected patients with existing equinus deformity by scar release, Z-tenoplasty of Achilles, and radial forearm free flap. PMID- 23340463 TI - Beware the impact factor. PMID- 23340461 TI - Submillisievert median radiation dose for coronary angiography with a second generation 320-detector row CT scanner in 107 consecutive patients. AB - PURPOSE: To (a) use a new second-generation wide-volume 320-detector row computed tomographic (CT) scanner to explore optimization of radiation exposure in coronary CT angiography in an unselected and consecutive cohort of patients referred for clinical purposes and (b) compare estimated radiation exposure and image quality with that from a cohort of similar patients who underwent imaging with a previous first-generation CT system. MATERIALS AND METHODS: The study was approved by the institutional review board, and all subjects provided written consent. Coronary CT angiography was performed in 107 consecutive patients with a new second-generation 320-detector row unit. Estimated radiation exposure and image quality were compared with those from 100 consecutive patients who underwent imaging with a previous first-generation scanner. Effective radiation dose was estimated by multiplying the dose-length product by an effective dose conversion factor of 0.014 mSv/mGy ? cm and reported with size-specific dose estimates (SSDEs). Image quality was evaluated by two independent readers. RESULTS: The mean age of the 107 patients was 55.4 years +/- 12.0 (standard deviation); 57 patients (53.3%) were men. The median body mass index was 27.3 kg/m(2) (range, 18.1-47.2 kg/m(2)); however, 71 patients (66.4%) were overweight, obese, or morbidly obese. A tube potential of 100 kV was used in 97 patients (90.6%), single-volume acquisition was used in 104 (97.2%), and prospective electrocardiographic gating was used in 106 (99.1%). The mean heart rate was 57.1 beats per minute +/- 11.2 (range, 34-96 beats per minute), which enabled single heartbeat scans in 100 patients (93.4%). The median radiation dose was 0.93 mSv (interquartile range [IQR], 0.58-1.74 mSv) with the second-generation unit and 2.67 mSv (IQR, 1.68-4.00 mSv) with the first-generation unit (P < .0001). The median SSDE was 6.0 mGy (IQR, 4.1-10.0 mGy) with the second-generation unit and 13.2 mGy (IQR, 10.2-18.6 mGy) with the first-generation unit (P < .0001). Overall, the radiation dose was less than 0.5 mSv for 23 of the 107 CT angiography examinations (21.5%), less than 1 mSv for 58 (54.2%), and less than 4 mSv for 103 (96.3%). All studies were of diagnostic quality, with most having excellent image quality. Three of four image quality indexes were significantly better with the second-generation unit compared with the first-generation unit. CONCLUSION: The combination of a gantry rotation time of 275 msec, wide volume coverage, iterative reconstruction, automated exposure control, and larger x-ray power generator of the second-generation CT scanner provides excellent image quality over a wide range of body sizes and heart rates at low radiation doses. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122621/-/DC1. PMID- 23340469 TI - Cell membranes: Glycans' imprints. PMID- 23340470 TI - Quantum information: Best of both worlds. PMID- 23340471 TI - Photonic crystals: Sustainable sensors from silk. PMID- 23340473 TI - Electrocatalysis: Interfacing electrochemistry. PMID- 23340472 TI - Material witness: Watching ice spin. PMID- 23340474 TI - Drug shortages: the cycle of quantity and quality. AB - Shortages of pharmaceutical drugs pose a serious and growing threat to public health. Although the number of drugs in shortage in the United States in any given year is very small, the number of prescription drug shortages in the country nearly tripled between 2005 and 2010. Drug shortages are becoming more severe as well as more frequent. The affected medicines include cancer treatments, anesthesia drugs, and other drugs that are critical to the treatment and prevention of serious diseases and life-threatening conditions. (The White House, Office of the Press Secretary, Executive Order 13588-Reducing Prescription Drug Shortages (http://www.whitehouse.gov/the-press-office/2011/10/31/executive order-reducing-prescription-drug-shortages)). PMID- 23340475 TI - Imaging of TKI-target interactions for personalized cancer therapy. PMID- 23340476 TI - Physiologically based pharmacokinetic models of tyrosine kinase inhibitors: a systems pharmacological approach to drug disposition. PMID- 23340477 TI - Playing Russian roulette with tyrosine kinase inhibitors. PMID- 23340478 TI - Response to "pretransplantation pharmacokinetic assessments to predict posttransplantation dosing requirements in renal transplant recipients: what is known?". PMID- 23340479 TI - Evolutionary conservation of the oocyte transcriptome among vertebrates and its implications for understanding human reproductive function. AB - Cross-phylum and cross-species comparative transcriptomic analyses provide an evolutionary perspective on how specific tissues use genomic information. A significant mRNA subset present in the oocytes of most vertebrates is stabilized or stored for post-LH surge use. Since transcription is arrested in the oocyte before ovulation, this RNA is important for completing maturation and sustaining embryo development until zygotic genome activation. We compared the human oocyte transcriptome with an oocyte-enriched subset of mouse, bovine and frog (Xenopus laevis) genes in order to evaluate similarities between species. Graded temperature stringency hybridization on a multi-species oocyte cDNA array was used to measure the similarity of preferentially expressed sequences to the human oocyte library. Identity analysis of 679 human orthologs compared with each identified official gene symbol found in the subtractive (somatic-oocyte) libraries comprising our array revealed that bovine/human similarity was greater than mouse/human or frog/human similarity. However, based on protein sequence, mouse/human similarity was greater than bovine/human similarity. Among the genes over-expressed in oocytes relative to somatic tissue in Xenopus, Mus and Bos, a high level of conservation was found relative to humans, especially for genes involved in early embryonic development. PMID- 23340480 TI - Thrombopoietin modulates the proliferation, migration and cytokine profile of decidual cell subsets during early gestation. AB - During early gestation, a considerable increase in different leukocyte subsets can be observed in the decidualized endometrium concomitantly to the invasion of cytotrophoblast cells (CTB). To date, it is still in question which factors induce this accumulation of immune cells and whether it is evoked by an in situ proliferation or by a migratory process. Studies on hepatoblastoma cells identified thrombopoietin (TPO) as a novel factor, which elicits dose-dependent chemotactic and chemokinetic effects. However, the impact and function of TPO on decidual cells has not been clarified yet. This study analyses the expression and function of TPO and its receptor c-Mpl in decidua during early gestation. Applying western blot analysis, we detected that TPO is expressed by decidual immune cells (uNK cells and CD14+ monocytes) as well as CTB and decidual stromal cells (DSCs). Expression of the different isoforms of c-Mpl was found in uNK cells, CD14+ monocytes and DSC. Studying the signalling pathway proteins in the uNK cells, an activation of STAT3/Tyr by TPO, was detected. The investigation of the proliferative effects of TPO on the decidual cell subsets revealed that TPO enhances the proliferation of uNK cells and CTB. No change of the proliferative activity after TPO incubation was found in DSC and even a decrease in CD14+ monocytes. In addition, TPO was observed to induce significantly the migratory activity of uNK cells, CD14+ monocytes and CTB. Investigating the effects of TPO on the cytokine profile of the isolated decidual cells, we observed a decrease in the secretion of IL-8, IL-10 and IL-1beta of isolated uNK cells, CD14+ monocytes and CTB, although these changes did not reach statistical significance. Thus, we here identified TPO as a novel factor modulating the proliferation, migration and possibly cytokine secretion of decidual cell subsets. PMID- 23340481 TI - Lost in vision: ERP correlates of exogenous tactile attention when engaging in a visual task. AB - Behavioural studies have shown that when engaging in a visual task response facilitation to tactile stimuli at exogenously cued locations is diminished. Here we investigated behavioural and also neural correlates of tactile exogenous attention when participants either watched a visual stream (single task) or also detected targets in the visual stream (dual task). During the visual stream, tactile cues were presented to the left or right hand followed by tactile targets at the same or opposite hand. Behavioural results demonstrated slowed responses to tactile targets at cued locations (i.e., IOR) in the single whilst no attention effect in the dual task. Concurrently recorded EEG revealed multiple stages of tactile processing to be attenuated when engaging in a visual task: First, the amplitude of the cueelicited somatosensory P100 component was suppressed suggesting relative early cross-modality effects in the dual task. Second, correlates of cue-induced attentional control processes showed a reduced late somatosensory negativity (LSN) in the dual compared to the single task suggesting smaller preparatory processes. Finally, early attentional selection correlates of post-target ERPs (N80) were absent in the dual task. This study demonstrated for the first time that engaging in a visual task abolished behavioural IOR in touch. ERP analyses showed that early somatosensory processing as well as specific correlates of tactile attentional orienting and target selection are diminished under visual engagement. Our findings are in line with a supramodal account of attention. PMID- 23340482 TI - Neural correlates of spontaneous deception: A functional near-infrared spectroscopy (fNIRS)study. AB - Deception is commonly seen in everyday social interactions. However, most of the knowledge about the underlying neural mechanism of deception comes from studies where participants were instructed when and how to lie. To study spontaneous deception, we designed a guessing game modeled after Greene and Paxton (2009) "Proceedings of the National Academy of Sciences, 106(30), 12506-12511", in which lying is the only way to achieve the performance level needed to end the game. We recorded neural responses during the game using near-infrared spectroscopy (NIRS). We found that when compared to truth-telling, spontaneous deception, like instructed deception, engenders greater involvement of such prefrontal regions as the left superior frontal gyrus. We also found that the correct-truth trials produced greater neural activities in the left middle frontal gyrus and right superior frontal gyrus than the incorrect-truth trials, suggesting the involvement of the reward system. Furthermore, the present study confirmed the feasibility of using NIRS to study spontaneous deception. PMID- 23340483 TI - Oligodendrogenesis from neural stem cells: perspectives for remyelinating strategies. AB - Mobilization of remyelinating cells spontaneously occurs in the adult brain. These cellular resources are specially active after demyelinating episodes in early phases of multiple sclerosis (MS). Indeed, oligodendrocyte precursor cells (OPCs) actively proliferate, migrate to and repopulate the lesioned areas. Ultimately, efficient remyelination is accomplished when new oligodendrocytes reinvest nude neuronal axons, restoring the normal properties of impulse conduction. As the disease progresses this fundamental process fails. Multiple causes seem to contribute to such transient decline, including the failure of OPCs to differentiate and enwrap the vulnerable neuronal axons. Regenerative medicine for MS has been mainly centered on the recruitment of endogenous self repair mechanisms, or on transplantation approaches. The latter commonly involves grafting of neural precursor cells (NPCs) or neural stem cells (NSCs), with myelinogenic potential, in the injured areas. Both strategies require further understanding of the biology of oligodendrocyte differentiation and remyelination. Indeed, the success of transplantation largely depends on the pre commitment of transplanted NPCs or NSCs into oligodendroglial cell type, while the endogenous differentiation of OPCs needs to be boosted in chronic stages of the disease. Thus, much effort has been focused on finding molecular targets that drive oligodendrocytes commitment and development. The present review explores several aspects of remyelination that must be considered in the design of a cell based therapy for MS, and explores more deeply the challenge of fostering oligodendrogenesis. In this regard, we discuss herein a tool developed in our research group useful to search novel oligodendrogenic factors and to study oligodendrocyte differentiation in a time- and cost-saving manner. PMID- 23340484 TI - Fast and sensitive UHPLC methods with fluorescence and tandem mass spectrometry detection for the determination of tetracycline antibiotics in surface waters. AB - In this paper two fast and highly sensitive ultra-high performance liquid chromatography (UHPLC) methods for the determination of tetracycline antibiotics (oxytetracycline, tetracycline, doxycycline, demeclocycline, chlortetracycline, minocycline and degradation product epitetracycline) in surface waters have been developed using fluorescence (FL) and mass spectrometry (MS) detection. ACQUITY UPLC BEH C8 and ACQUITY CSH C18 columns were employed for FL and MS detection, respectively, both packed with 1.7MUm particles. Mixed-mode separation mechanism of CSH (charged surface technology) sorbent was found particularly useful in analysis of TCs, which possess problematic amphoteric structures. The FL methodology was based on chelation of tetracyclines with calcium ions to perform on-column derivatisation. The developed methods were compared in the terms of validation parameters including linearity, sensitivity, precision and accuracy. The linearity range for FL detection was within 7ngmL(-1) to 50MUgmL(-1) with method limit of detection (MLOD) as low as 0.2ngmL(-1) for most of the analytes. MS detection showed even higher sensitivity reaching MLOD of 0.003ngmL(-1), which is the highest sensitivity reported so far in analysis of TCs. Matrix matched calibration curves in the range of 0.01-50ngmL(-1) were used for quantification to compensate for matrix effects with the correlation coefficients demonstrating good linearity (0.9940-0.9999). The extraction of the antibiotics from surface waters was performed using solid phase extraction with Oasis HLB cartridges. Accuracy was expressed as recovery with values ranging from 96.52% to 127.30% and from 91.66% to 123.70% for FL and MS detection, respectively. PMID- 23340485 TI - Time from adenosine di-phosphate receptor antagonist discontinuation to coronary bypass surgery in patients with acute coronary syndrome: meta-analysis and meta regression. AB - BACKGROUND: Adenosine di-phosphate receptor antagonists (ADPRAs) blunt hemostasis for several days after administration. This effect, aimed at preventing cardiac ischemic complications particularly in patients with acute coronary syndromes (ACS), may increase perioperative bleeding in the case of cardiac surgery. Practice Guidelines recommend withholding ADPRAs for at least 5days prior to surgery, though with a weak base of evidence. The purpose of this study was to systematically review observational and experimental studies of early or late preoperative discontinuation of ADPRAs prior to coronary artery bypass grafting (CABG) for patients with ACS. METHODS: MEDLINE, EMBASE, the Cochrane Library databases up to December 2011; and reference lists. Observational and experimental studies that compared early ADPRA discontinuation with late discontinuation, or no discontinuation, in patients with ACS undergoing CABG. RESULTS: There were 19 studies, including 14,046 participants, 395 deaths and 309 reoperations due to bleeding. ADPRA late discontinuation up to CABG was associated with an increased risk of postoperative mortality (OR 1.46, 95% confidence interval (CI) 1.10 to 1.93) and reoperations due to bleeding (OR 2.18; 95% CI 1.47 to 2.62). Between-study heterogeneity was low. Meta-analysis limited to high quality or prospective studies gave consistent results. In most instances, the 95% prediction intervals for summary risk estimates confirmed the risk across study groups. CONCLUSIONS: ADPRA late discontinuation prior to CABG is associated with an increased risk of death and reoperations due to bleeding in patients with ACS. The confidence in the estimates of risk for late discontinuation is moderate to high. PMID- 23340486 TI - Pulsatile haemodynamic parameters are predictors of survival in paediatric pulmonary arterial hypertension. AB - BACKGROUND: There is a need for reliable prognostic parameters in pulmonary arterial hypertension (PAH), especially in children. Pulsatile components of the right ventricular afterload, represented by pulmonary arterial compliance (PACi) and pulmonary stroke volume (PSVi), may provide important additional prognostic information to conventional static haemodynamic parameters. The aim of this study was to determine the prognostic value of PACi and PSVi in paediatric PAH. METHODS: Right heart catheterization data of 52 consecutive paediatric idiopathic/hereditary PAH and PAH associated with congenital heart disease patients with full haemodynamic evaluation seen at the Dutch national referral centre for paediatric pulmonary hypertension between 1993 and 2010 were reviewed. A control group was composed of patients with normal pulmonary vascular resistance. PSVi and PACi were calculated and tested for predictive value for transplant-free survival. RESULTS: PAH patients had significantly lower PSVi and PACi compared to control patients. PSVi and PACi were lower in patients with higher WHO-functional class compared to those with lower functional classes. Higher PSVi, PACi and mSAP and lower mPAP/mSAP and heart rate were associated with improved survival, independent from WHO-functional class and PAH-targeted therapy. In multivariate analyses PSVi, heart rate and mSAP emerged as the strongest haemodynamic predictors of survival. The effect of vasodilator challenge on the haemodynamic variables did not provide additional prognostic information. CONCLUSIONS: The parameters of both the pulsatile and static pulmonary circulations are strong independent predictors for transplant-free survival, and therefore can be of complementary value in assessing disease severity, predicting survival and guiding treatment in paediatric PAH. PMID- 23340487 TI - Acute myocardial infarction--historical notes. AB - For the time being, acute myocardial infarction represents a history of success concerning diagnose, management and treatment, whereas it was considered a fatal disease in the beginning of the 1900s. The present paper is aimed at reviewing the landmarks of acute myocardial infarction, as key historical concepts are an important tool for understanding disease management, the daily dilemmas and future perspectives. PMID- 23340488 TI - Structural diversity among copper(I) ethylene adducts of 3,6-bis(2-pyridyl) 1,2,4,5-tetrazine. AB - The reaction of Cu(ClO(4)).6H(2)O, Cu turnings, and 3,6-bis(2-pyridyl)-1,2,4,5 tetrazine (bptz) in Me(2)CO under C(2)H(4) afforded brownish-red needle crystals of {[Cu(2)(bptz(-))(C(2)H(4))(2)](ClO(4))}(2) (1) as a minor product and brown plate crystals of [Cu(2)(2,5-H(2)bptz)(C(2)H(4))(2)](ClO(4))(2).2Me(2)CO (2). The X-ray crystallographic study showed that complex 1 is composed of two independent [Cu(2)(bptz(-))(C(2)H(4))(2)](+) cation moieties and two ClO(4)(-) anions. In both of the cation moieties, each Cu(I) atom is coordinated by two chelate N atoms of bptz(-) and the C=C bond of C(2)H(4) in the trigonal-planar geometry to form a unique transoid dinuclear Cu(I)-bptz(-)/C(2)H(4) adduct bearing a metal stabilized tetrazine anion radical, bptz(-), which was produced by the one electron reduction of bptz. In contrast, complex 2 consists of one [Cu(2)(2,5 H(2)bptz)(C(2)H(4))(2)](2+) cation moiety, two ClO(4)(-) anions, and two solvated Me(2)CO molecules. Each Cu(I) atom is coordinated by two chelate N atoms of 2,5 H(2)bptz and the C=C bond of C(2)H(4) in the trigonal-planar geometry to afford a transoid dinuclear Cu(I)-C(2)H(4) adduct with 2,5-H(2)bptz, which was produced by the two-electron reduction of bptz. Additionally, the similar reaction of Cu(ClO(4)).6H(2)O, Cu turnings, and bptz in Me(2)CO or MeEtCO under C(2)H(4) in the presence of ferrocene afforded orange brick crystals of [Cu(2)(bpdpyz)(C(2)H(4))(2)](ClO(4))(2).Me(2)CO (3) and [Cu(2)(bpdpyz)(C(2)H(4))(2)](ClO(4))(2) (4), respectively, together with complex 1 in higher yield. This result shows that 3,6-bis(2-pyridyl)-4,5 dihydropyridazine (bpdpyz) was produced by the cycloaddition of bptz with C(2)H(4)via a Diels-Alder addition and retro-Diels-Alder elimination of dinitrogen. In complexes 3 and 4, each Cu(I) atom is coordinated by two chelate N atoms of bpdpyz and the C=C bond of C(2)H(4) to afford an unusual cisoid dinuclear Cu(I)-C(2)H(4) adduct. Further attempts to react excess [Cu(C(2)H(4))(n)]ClO(4) with bptz in Me(2)CO under C(2)H(4) afforded black brick crystals of [Cu(4)(4,5-H(2)bptz)(4)](ClO(4))(4).2Me(2)CO (5) together with complex 1. Complex is the first [4 * 4] grid-like tetranuclear Cu(I) complex constructed by the combination of Cu(I) ion and 4,5-H(2)bptz. The four Cu(I) atoms are spanned by four 4,5-H(2)bptz ligands, with two lying above the Cu(4) mean plane and two lying below. In contrast, the similar reaction of excess [Cu(C(2)H(4))(n)]ClO(4) with bptz in Me(2)CO under C(2)H(4) in the presence of ferrocene afforded reddish-brown brick crystals of {[Cu(2)(2,5 H(2)bptz)(C(2)H(4))(2)](ClO(4))(2)}(2).Me(2)CO (6) together with complexes 1 and 5. Complex 6 is composed of two independent [Cu(2)(2,5 H(2)bptz)(C(2)H(4))(2)](2+) cation moieties, four ClO(4)(-) anions, and a solvated Me(2)CO molecule. It is interesting that the structures of the two [Cu(2)(2,5-H(2)bptz)(C(2)H(4))(2)](2+) cation moieties are different: one has a nearly planar structure and the other possesses a boat conformation owing to the bent central dihydrotetrazine ring. PMID- 23340489 TI - Detection of high molecular weight proteins by MALDI imaging mass spectrometry. AB - MALDI imaging mass spectrometry (IMS) is a unique technology to explore the spatial distribution of biomolecules directly on tissues. It allows the in situ investigation of a large number of small proteins and peptides. Detection of high molecular weight proteins through MALDI IMS still represents an important challenge, as it would allow the direct investigation of the distribution of more proteins involved in biological processes, such as cytokines, enzymes, neuropeptide precursors and receptors. In this work we compare the traditional method performed with sinapinic acid with a comparable protocol using ferulic acid as the matrix. Data show a remarkable increase of signal acquisition in the mass range of 20k to 150k Th. Moreover, we report molecular images of biomolecules above 70k Th, demonstrating the possibility of expanding the application of this technology both in clinical investigations and basic science. PMID- 23340490 TI - Conformational equilibria in carboxylic acid bimolecules: a rotational study of acrylic acid-formic acid. AB - The bimolecule acrylic acid-formic acid has been investigated by pulsed jet Fourier transform microwave spectroscopy. The complex adopts two different conformational shapes, according to the cis or trans forms of the acrylic acid moiety. The measurements have been extended to four deuterated and to four (13)C (natural abundance) species, and their combinations, for each conformer. These data allowed us to determine the carbon skeleton structures and to size quantitatively the structural effect caused by the OH -> OD isotopic substitutions (the Ubbelohde effect). PMID- 23340491 TI - Propargyl vinyl ethers as heteroatom-tethered enyne surrogates: diversity oriented strategies for heterocycle synthesis. AB - This article presents recent progress in the conversion of propargyl vinyl ethers into heterocyclic scaffolds and how this goal can be reached in a diversity oriented approach. The article also includes examples of transformations of propargyl vinyl ethers where the propargyl vinyl ether moieties are formed in situ. Furthermore, related reactions transforming propargyl vinyl amines to heterocycles are discussed. PMID- 23340492 TI - Effect of dietary intervention to reduce the n-6/n-3 fatty acid ratio on maternal and fetal fatty acid profile and its relation to offspring growth and body composition at 1 year of age. AB - BACKGROUND/OBJECTIVE: Evidence is accumulating that the long-chain PUFA (LCPUFA) are associated with offspring growth and body composition. We investigated the relationship between LCPUFAs in red blood cells (RBCs) of pregnant women/breastfeeding mothers and umbilical cord RBCs of their neonates with infant growth and body composition <= 1 year of age. SUBJECTS/METHODS: In an open-label randomized, controlled trial, 208 healthy pregnant women received a dietary intervention (daily supplementation with 1200 mg n-3 LCPUFAs and dietary counseling to reduce arachidonic acid (AA) intake) from the 15th week of gestation until 4 months of lactation or followed their habitual diet. Fatty acids of plasma phospholipids (PLs) and RBCs from maternal and cord blood were determined and associated with infant body weight, body mass index (BMI), lean body mass and fat mass assessed by skinfold thickness measurements and ultrasonography. RESULTS: Dietary intervention significantly reduced the n-6/n-3 LCPUFA ratio in maternal and cord-blood plasma PLs and RBCs. Maternal RBCs docosahexaenoic acid (DHA), n-3 LCPUFAs and n-6 LCPUFAs at the 32nd week of gestation were positively related to birth weight. Maternal n-3 LCPUFAs, n-6 LCPUFAs and AA were positively associated with birth length. Maternal RBCs AA and n-6 LCPUFAs were significantly negatively related to BMI and Ponderal Index at 1 year postpartum, but not to fat mass. CONCLUSION: Maternal DHA, AA, total n-3 LCPUFAs and n-6 LCPUFAs might serve as prenatal growth factors, while n-6 LCPUFAs also seems to regulate postnatal growth. The maternal n-6/n-3 LCPUFA ratio does not appear to have a role in adipose tissue development during early postnatal life. PMID- 23340493 TI - Chloride sensing via suppression of excited state intramolecular proton transfer in squaramides. AB - A new design strategy is described for chloride ion sensors based on suppression of excited state intramolecular proton transfer in squaramides as a fluorescence "turn on" mechanism. PMID- 23340495 TI - Organometallic mediated radical polymerization of vinyl acetate using bis(imino)pyridine vanadium trichloride complexes. AB - The synthesis and characterization of one novel proligand and six novel vanadium(III) trichloride complexes is described. The controlled radical polymerization activity towards vinyl acetate of these, and eight other bis(imino)pyridine vanadium trichloride complexes previously reported, is investigated. Those complexes possessing variation at the N-aryl para-position with no steric protection offered by ortho-substituents (4 examples) result in poor control over poly(vinyl acetate) polymerization. Control is improved with increasing steric bulk at the ortho-position of the N-aryl substituent (4 examples) although attempts to increase steric bulk past isopropyl were unsuccessful. Synthesizing bis(imino)pyridine vanadium trichloride complexes with substituted imine backbones restores polymerization control when aliphatic substituents are used (4 examples) but ceases to make any drastic improvements on catalyst lifetime. Modification of the polymerization conditions is also investigated, in an attempt to improve the catalyst lifetime. Expansion of the monomer scope to include other vinyl esters, particularly those derived from renewable resources, shows promising results. PMID- 23340494 TI - Membrane tethered bursicon constructs as heterodimeric modulators of the Drosophila G protein-coupled receptor rickets. AB - The study of complex heterodimeric peptide ligands has been hampered by a paucity of pharmacological tools. To facilitate such investigations, we have explored the utility of membrane tethered ligands (MTLs). Feasibility of this recombinant approach was explored with a focus on Drosophila bursicon, a heterodimeric cystine-knot protein that activates the G protein-coupled receptor rickets (rk). Rk/bursicon signaling is an evolutionarily conserved pathway in insects required for wing expansion, cuticle hardening, and melanization during development. We initially engineered two distinct MTL constructs, each composed of a type II transmembrane domain, a peptide linker, and a C terminal extracellular ligand that corresponded to either the alpha or beta bursicon subunit. Coexpression of the two complementary bursicon MTLs triggered rk-mediated signaling in vitro. We were then able to generate functionally active bursicon MTLs in which the two subunits were fused into a single heterodimeric peptide, oriented as either alpha beta or beta-alpha. Carboxy-terminal deletion of 32 amino acids in the beta-alpha MTL construct resulted in loss of agonist activity. Coexpression of this construct with rk inhibited receptor-mediated signaling by soluble bursicon. We have thus generated membrane-anchored bursicon constructs that can activate or inhibit rk signaling. These probes can be used in future studies to explore the tissue and/or developmental stage-dependent effects of bursicon in the genetically tractable Drosophila model organism. In addition, our success in generating functionally diverse bursicon MTLs offers promise that such technology can be broadly applied to other complex ligands, including the family of mammalian cystine-knot proteins. PMID- 23340497 TI - [Operative versus non-operative therapy of unstable distal radius fractures in patients elderly 65 years old]. PMID- 23340498 TI - Redox-proteomic analysis of doxorubicin-induced altered thiol activity in cardiomyocytes. AB - Doxorubicin is an anticancer drug used in a wide range of cancer therapies, yet some side effects have been reported. One of these is cardiotoxicity, including cardiomyopathy and ultimately congestive heart failure. This damage to the heart has been shown to result from doxorubicin-induced reactive oxygen species. However, the cellular targets of doxorubicin-induced oxidative damage on cardiomyocytes are largely unknown. For this, a cysteine-labeling-based two dimensional difference gel electrophoresis (2D-DIGE) combined with MALDI-TOF/TOF mass spectrometry (MALDI-TOF/TOF MS) were employed to analyze the impact of doxorubicin treatment on the redox regulation in rat cardiomyocytes. This study demonstrated 25 unique protein features that had significantly changed in their thiol reactivity and revealed that doxorubicin-induced cardiotoxicity involves dysregulation of protein folding, translational regulation and cytoskeleton regulation. Our work shows that this combined proteomic strategy provides a rapid method to study the molecular mechanisms of doxorubicin-induced cytotoxicity in the heart. The identified targets may be useful for further evaluation as potential cardiotoxic biomarkers during damage to the heart induced by doxorubicin, as well as possible diagnostic or therapeutic applications. PMID- 23340499 TI - Factors affecting the selectivity of the photocatalytic conversion of nitroaromatic compounds over TiO2 to valuable nitrogen-containing organic compounds. AB - The photocatalytic conversion of various nitroaromatic compounds in alcohols employing four different types of TiO(2) (Sachtleben Hombikat UV100 as anatase, Crystal Global R34 as rutile, Evonik-Degussa Aeroxide P25 as an anatase-rutile mixture, and home-made mesoporous anatase) has been studied. The effect of platinization of these different types of TiO(2) on the reaction sequence has also been investigated. Upon irradiation of an ethanolic solution of m nitrotoluene, as a model reaction, in the presence of the bare photocatalyst, different products were obtained according to the applied photocatalyst. It was found that the surface properties of the photocatalyst play an important role in the reaction pathway and thus in the selectivity of the products. In all cases, a simultaneous reduction of the nitro compound and an oxidation of the alcohol are induced by the photogenerated electrons and holes, respectively. An imine is then produced upon condensation of the generated aldehyde and amino compounds. Rutile was found to be more selective towards the primary amino compound (m-toluedine) while anatase catalysts gave a mixture of m-toluidine and its imine (N-ethylidene 3-methylaniline). A cyclization reaction of the produced imine to generate methyl quinoline was observed when Aeroxide P25 was used as a photocatalyst. Employing platinized TiO(2), the hydrogenation of the produced imine yielding N-alkylated products was found to occur in all cases. However, the selectivity towards the mono N-alkylated product was the best using platinized Hombikat UV100. This selectivity was found to be also influenced by the loaded amount of Pt, the platinization method, and the illumination time but not by the light intensity. PMID- 23340500 TI - Novel microbial populations in deep granitic groundwater from Grimsel Test Site, Switzerland. AB - Freshwater aquifers in granitic rocks are widespread microbial habitats in the terrestrial subsurface. Microbial populations in deep granitic groundwater from two recently drilled (1 and 2 years) and two old boreholes (14 and 25 years) were compared. The 16S rRNA gene sequences related to "Candidatus Magnetobacterium bavaricum", Thermodesulfovibrio spp. of Nitrospirae (90.5-93.1 % similarity) and a novel candidate division with <90 % similarity to known cultivated species were dominant in all boreholes. Most of the environmental clones closely related to the novel lineages in Nitrospirae, which have been detected exclusively in deep groundwater samples. In contrast, betaproteobacterial sequences related to the family Rhodocyclaceae were obtained only from the recently drilled boreholes, which had higher total cell numbers. Catalyzed reporter deposition-fluorescence in situ hybridization (CARD-FISH) analysis supported the result from clone library analysis; betaproteobacterial cells were dominantly detected in recently drilled boreholes. These results suggest that while indigenous microbial populations represented by the novel phylotypes persisted in the boreholes for 25 years, betaproteobacterial species disappeared after 2 years owing to the change of substrate availability. PMID- 23340501 TI - Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment. AB - Early life adversity, including adverse gestational and postpartum maternal environment, is a contributing factor in the development of autism, attention deficit hyperactivity disorder (ADHD), anxiety and depression but little is known about the underlying molecular mechanism. In a model of gestational maternal adversity that leads to innate anxiety, increased stress reactivity and impaired vocal communication in the offspring, we asked if a specific DNA methylation signature is associated with the emergence of the behavioral phenotype. Genome wide DNA methylation analyses identified 2.3% of CpGs as differentially methylated (that is, differentially methylated sites, DMSs) by the adverse environment in ventral-hippocampal granule cells, neurons that can be linked to the anxiety phenotype. DMSs were typically clustered and these clusters were preferentially located at gene bodies. Although CpGs are typically either highly methylated or unmethylated, DMSs had an intermediate (20-80%) methylation level that may contribute to their sensitivity to environmental adversity. The adverse maternal environment resulted in either hyper or hypomethylation at DMSs. Clusters of DMSs were enriched in genes that encode cell adhesion molecules and neurotransmitter receptors; some of which were also downregulated, indicating multiple functional deficits at the synapse in adversity. Pharmacological and genetic evidence links many of these genes to anxiety. PMID- 23340502 TI - 1-42 beta-amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death. AB - 1-42 beta-Amyloid (Abeta(1-42)) peptide is a key molecule involved in the development of Alzheimer's disease. Some of its effects are manifested at the neuronal morphological level. These morphological changes involve loss of neurites due to cytoskeleton alterations. However, the mechanism of Abeta(1-42) peptide activation of the neurodegenerative program is still poorly understood. Here, Abeta(1-42) peptide-induced transduction of cellular death signals through the phosphatidylinositol 3-kinase (PI3K)/phosphoinositol-dependent kinase (PDK)/novel protein kinase C (nPKC)/Rac 1 axis is described. Furthermore, pharmacological inhibition of PDK1 and nPKC activities blocks Rac 1 activation and neuronal cell death. Our results provide insights into an unsuspected connection between PDK1, nPKCs and Rac 1 in the same signal-transduction pathway and points out nPKCs and Rac 1 as potential therapeutic targets to block the toxic effects of Abeta(1-42) peptide in neurons. PMID- 23340503 TI - Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. AB - Autism spectrum disorder (ASD) has been associated with mitochondrial disease (MD). Interestingly, most individuals with ASD and MD do not have a specific genetic mutation to explain the MD, raising the possibility of that MD may be acquired, at least in a subgroup of children with ASD. Acquired MD has been demonstrated in a rodent ASD model in which propionic acid (PPA), an enteric bacterial fermentation product of ASD-associated gut bacteria, is infused intracerebroventricularly. This animal model shows validity as it demonstrates many behavioral, metabolic, neuropathologic and neurophysiologic abnormalities associated with ASD. This animal model also demonstrates a unique pattern of elevations in short-chain and long-chain acyl-carnitines suggesting abnormalities in fatty-acid metabolism. To determine if the same pattern of biomarkers of abnormal fatty-acid metabolism are present in children with ASD, the laboratory results from a large cohort of children with ASD (n=213) who underwent screening for metabolic disorders, including mitochondrial and fatty-acid oxidation disorders, in a medically based autism clinic were reviewed. Acyl-carnitine panels were determined to be abnormal if three or more individual acyl-carnitine species were abnormal in the panel and these abnormalities were verified by repeated testing. Overall, 17% of individuals with ASD demonstrated consistently abnormal acyl-carnitine panels. Next, it was determined if specific acyl carnitine species were consistently elevated across the individuals with consistently abnormal acyl-carnitine panels. Significant elevations in short chain and long-chain, but not medium-chain, acyl-carnitines were found in the ASD individuals with consistently abnormal acyl-carnitine panels-a pattern consistent with the PPA rodent ASD model. Examination of electron transport chain function in muscle and fibroblast culture, histological and electron microscopy examination of muscle and other biomarkers of mitochondrial metabolism revealed a pattern consistent with the notion that PPA could be interfering with mitochondrial metabolism at the level of the tricarboxylic-acid cycle (TCAC). The function of the fatty-acid oxidation pathway in fibroblast cultures and biomarkers for abnormalities in non-mitochondrial fatty-acid metabolism were not consistently abnormal across the subgroup of ASD children, consistent with the notion that the abnormalities in fatty-acid metabolism found in this subgroup of children with ASD were secondary to TCAC abnormalities. Glutathione metabolism was abnormal in the subset of ASD individuals with consistent acyl-carnitine panel abnormalities in a pattern similar to glutathione abnormalities found in the PPA rodent model of ASD. These data suggest that there are similar pathological processes between a subset of ASD children and an animal model of ASD with acquired mitochondrial dysfunction. Future studies need to identify additional parallels between the PPA rodent model of ASD and this subset of ASD individuals with this unique pattern of acyl-carnitine abnormalities. A better understanding of this animal model and subset of children with ASD should lead to better insight in mechanisms behind environmentally induced ASD pathophysiology and should provide guidance for developing preventive and symptomatic treatments. PMID- 23340504 TI - Behavioral, neurochemical and morphological changes induced by the overexpression of munc18-1a in brain of mice: relevance to schizophrenia. AB - Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D(1) receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia. The animal could provide valuable insights into phenotypic aspects of this psychiatric disorder. PMID- 23340505 TI - Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene-gene-environment interaction. AB - Epistatic gene-gene interactions could contribute to the heritability of complex multigenic disorders, but few examples have been reported. Here, we focus on the role of aberrant dopaminergic signaling, involving the dopamine transporter DAT, a cocaine target, and the dopamine D2 receptor, which physically interacts with DAT. Splicing polymorphism rs2283265 of DRD2, encoding D2 receptors, were shown to confer risk of cocaine overdose/death (odds ratio ~3) in subjects and controls from the Miami Dade County Brain Bank.(1) Risk of cocaine-related death attributable to the minor allele of rs2283265 was significantly enhanced to OR=7.5 (P=0.0008) in homozygous carriers of the main 6-repeat allele of DAT rs3836790, a regulatory VNTR in intron8 lacking significant effect itself. In contrast, carriers of the minor 5-repeat DAT allele showed no significant risk (OR=1.1, P=0.84). DAT rs3836790 and DRD2 rs2283265 also interacted by modulating DAT protein activity in the ventral putamen of cocaine abusers. In high-linkage disequilibrium with the VNTR, DAT rs6347 in exon9 yielded similar results. Assessing the impact of DAT alone, a rare DAT haplotype formed by the minor alleles of rs3836790 and rs27072, a regulatory DAT variant in the 3'-UTR, occurred in nearly one-third of the cocaine abusers but was absent in African American controls, apparently conferring strong risk. These results demonstrate gene-gene-drug interaction affecting risk of fatal cocaine intoxication. PMID- 23340508 TI - Eccentric inorganic-polymeric nanoparticles formation by thermal induced cross linked esterification and conversion of eccentricity to raspberry-like Janus. AB - The thermally induced cross-linked esterification occurs for the formation of eccentric inorganic-polymeric nanoparticles. By taking advantage of eccentricity, Ag-PSMA eccentric structure is converted to raspberry-like Au-based Janus nanoparticles. PMID- 23340506 TI - Pharmacometabolomic mapping of early biochemical changes induced by sertraline and placebo. AB - In this study, we characterized early biochemical changes associated with sertraline and placebo administration and changes associated with a reduction in depressive symptoms in patients with major depressive disorder (MDD). MDD patients received sertraline or placebo in a double-blind 4-week trial; baseline, 1 week, and 4 weeks serum samples were profiled using a gas chromatography time of flight mass spectrometry metabolomics platform. Intermediates of TCA and urea cycles, fatty acids and intermediates of lipid biosynthesis, amino acids, sugars and gut-derived metabolites were changed after 1 and 4 weeks of treatment. Some of the changes were common to the sertraline- and placebo-treated groups. Changes after 4 weeks of treatment in both groups were more extensive. Pathway analysis in the sertraline group suggested an effect of drug on ABC and solute transporters, fatty acid receptors and transporters, G signaling molecules and regulation of lipid metabolism. Correlation between biochemical changes and treatment outcomes in the sertraline group suggested a strong association with changes in levels of branched chain amino acids (BCAAs), lower BCAAs levels correlated with better treatment outcomes; pathway analysis in this group revealed that methionine and tyrosine correlated with BCAAs. Lower levels of lactic acid, higher levels of TCA/urea cycle intermediates, and 3-hydroxybutanoic acid correlated with better treatment outcomes in placebo group. Results of this study indicate that biochemical changes induced by drug continue to evolve over 4 weeks of treatment and that might explain partially delayed response. Response to drug and response to placebo share common pathways but some pathways are more affected by drug treatment. BCAAs seem to be implicated in mechanisms of recovery from a depressed state following sertraline treatment. PMID- 23340509 TI - Phosphorylation at intrinsically disordered regions of PAM2 motif-containing proteins modulates their interactions with PABPC1 and influences mRNA fate. AB - Cytoplasmic poly(A)-binding protein (PABP) C1 recruits different interacting partners to regulate mRNA fate. The majority of PABP-interacting proteins contain a PAM2 motif to mediate their interactions with PABPC1. However, little is known about the regulation of these interactions or the corresponding functional consequences. Through in silico analysis, we found that PAM2 motifs are generally embedded within an extended intrinsic disorder region (IDR) and are located next to cluster(s) of potential serine (Ser) or threonine (Thr) phosphorylation sites within the IDR. We hypothesized that phosphorylation at these Ser/Thr sites regulates the interactions between PAM2-containing proteins and PABPC1. In the present study, we have tested this hypothesis using complementary approaches to increase or decrease phosphorylation. The results indicate that changing the extent of phosphorylation of three PAM2-containing proteins (Tob2, Pan3, and Tnrc6c) alters their ability to interact with PABPC1. Results from experiments using phospho-blocking or phosphomimetic mutants in PAM2-containing proteins further support our hypothesis. Moreover, the phosphomimetic mutations appreciably affected the functions of these proteins in mRNA turnover and gene silencing. Taken together, these results provide a new framework for understanding the roles of intrinsically disordered proteins in the dynamic and signal-dependent control of cytoplasmic mRNA functions. PMID- 23340510 TI - Positive selection of protective variants for type 2 diabetes from the Neolithic onward: a case study in Central Asia. AB - The high prevalence of type 2 diabetes and its uneven distribution among human populations is both a major public health concern and a puzzle in evolutionary biology. Why is this deleterious disease so common, while the associated genetic variants should be removed by natural selection? The 'thrifty genotype' hypothesis proposed that the causal genetic variants were advantageous and selected for during the majority of human evolution. It remains, however, unclear whether genetic data support this scenario. In this study, we characterized patterns of selection at 10 variants associated with type 2 diabetes, contrasting one herder and one farmer population from Central Asia. We aimed at identifying which alleles (risk or protective) are under selection, dating the timing of selective events, and investigating the effect of lifestyle on selective patterns. We did not find any evidence of selection on risk variants, as predicted by the thrifty genotype hypothesis. Instead, we identified clear signatures of selection on protective variants, in both populations, dating from the beginning of the Neolithic, which suggests that this major transition was accompanied by a selective advantage for non-thrifty variants. Combining our results with worldwide data further suggests that East Asia was particularly prone to such recent selection of protective haplotypes. As much effort has been devoted so far to searching for thrifty variants, we argue that more attention should be paid to the evolution of non-thrifty variants. PMID- 23340511 TI - Citizens' perspectives on personalized medicine: a qualitative public deliberation study. AB - Our objective was to explore citizens' informed and reasoned values and expectations of personalized medicine, a timely yet novel genomics policy issue. A qualitative, public deliberation study was undertaken using a citizens' reference panel on health technologies, established to provide input to the health technology assessment process in Ontario, Canada. The citizens' panel consisted of five women and nine men, aged 18-71 years, with one member selected from each health authority region. There were shared expectations among the citizens' panel members for the potential of personalized medicine technologies to improve care, provided they are deemed clinically valid and effective. These expectations were tempered by concerns about value for money and the possibility that access to treatment may be limited by personalized medicine tests used to stratify patients. Although they questioned the presumed technological imperative presented by personalized medicine technologies, they called for increased efforts to prepare the health-care system to effectively integrate these technologies. This study represents an early but important effort to explore public values toward personalized medicine. This study also provides evidence of the public's ability to form coherent judgments about a new policy issue. Concerned that personalized tests might be used to ration care, they suggested that treatment should be made available if patients wanted it, irrespective of tests that indicate little benefit. This issue raises clinical and policy challenges that may undermine the value of personalized medicine. Further efforts to deliberate with the public are warranted to inform effective, efficient and equitable translation of personalized medicine. PMID- 23340512 TI - A Delphi study to determine the European core curriculum for Master programmes in genetic counselling. AB - Genetic counsellors have been working in some European countries for at least 30 years. Although there are great disparities between the numbers, education, practice and acceptance of these professionals across Europe, it is evident that genetic counsellors and genetic nurses in Europe are working autonomously within teams to deliver patient care. The aim of this study was to use the Delphi research method to develop a core curriculum to guide the educational preparation of these professionals in Europe. The Delphi method enables the researcher to utilise the views and opinions of a group of recognised experts in the field of study; this study consisted of four phases. Phases 1 and 4 consisted of expert workshops, whereas data were collected in phases 2 and 3 (n=35) via online surveys. All participants in the study were considered experts in the field of genetic counselling. The topics considered essential for genetic counsellor training have been organised under the following headings: (1) counselling; (2) psychological issues; (3) medical genetics; (4) human genetics; (5) ethics, law and sociology; (6) professional practice; and (7) education and research. Each topic includes the knowledge, skills and attitudes required to enable genetic counsellors to develop competence. In addition, it was considered by the experts that clinical practice should comprise 50% of the educational programme. The core Master programme curriculum will enable current courses to be assessed and inform the design of future educational programmes for European genetic counsellors. PMID- 23340513 TI - Custom oligonucleotide array-based CGH: a reliable diagnostic tool for detection of exonic copy-number changes in multiple targeted genes. AB - The frequency of disease-related large rearrangements (referred to as copy-number mutations, CNMs) varies among genes, and search for these mutations has an important place in diagnostic strategies. In recent years, CGH method using custom-designed high-density oligonucleotide-based arrays allowed the development of a powerful tool for detection of alterations at the level of exons and made it possible to provide flexibility through the possibility of modeling chips. The aim of our study was to test custom-designed oligonucleotide CGH array in a diagnostic laboratory setting that analyses several genes involved in various genetic diseases, and to compare it with conventional strategies. To this end, we designed a 12-plex CGH array (135k; 135 000 probes/subarray) (Roche Nimblegen) with exonic and intronic oligonucleotide probes covering 26 genes routinely analyzed in the laboratory. We tested control samples with known CNMs and patients for whom genetic causes underlying their disorders were unknown. The contribution of this technique is undeniable. Indeed, it appeared reproducible, reliable and sensitive enough to detect heterozygous single-exon deletions or duplications, complex rearrangements and somatic mosaicism. In addition, it improves reliability of CNM detection and allows determination of boundaries precisely enough to direct targeted sequencing of breakpoints. All of these points, associated with the possibility of a simultaneous analysis of several genes and scalability 'homemade' make it a valuable tool as a new diagnostic approach of CNMs. PMID- 23340514 TI - Exploring resources for intrafamilial communication of cancer genetic risk: we still need to talk. AB - While the importance of intrafamilial communication of hereditary cancer risk has been acknowledged, the factors that promote and act as barriers to patients disclosing their information to their families are complex and emerging. This raises the question: How are patients guided in practice to contemplate intrafamilial communication? Focusing on breast cancer, we conducted an exploratory study examining current resources supporting patients and health-care professionals, and isolated the messages surrounding intrafamilial communication of cancer risk. We find the duty for health-care professionals to counsel patients regarding intrafamilial communication is acknowledged to varying degrees by multiple actors in the cancer care delivery landscape, including health-care professional associations, health service organizations, and patient groups. A range of medical, psychosocial, and other factors underlying intrafamilial communication are acknowledged in messages to patients. Patients, however, are often referred to a single group of health-care professionals to discuss their diverse and complex needs. At the same time, messages aimed at patients appear to place the emphasis on barriers that could exist for patients contemplating intrafamilial communication, while highlighting the benefits families derive from such communication. Taken together, this points to a lack of coherence within materials directed to patients and suggests the need to do coordinated research among stakeholders to address two related issues: (1) determining who are the actors best positioned to send messages surrounding intrafamilial communication to patients and (2) addressing the content of messages conveyed in patient materials. PMID- 23340515 TI - Functional and genetic characterization of two extremely rare cases of Williams Beuren syndrome associated with chronic granulomatous disease. AB - Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder with multi systemic manifestations, caused by a heterozygous segmental deletion of 1.55-1.83 Mb at chromosomal band 7q11.23. The deletion can include the NCF1 gene that encodes the p47(phox) protein, a component of the leukocyte NADPH oxidase enzyme, which is essential for the defense against microbial pathogens. It has been postulated that WBS patients with two functional NCF1 genes are more susceptible to occurrence of hypertension than WBS patients with only one functional NCF1 gene. We now describe two extremely rare WBS patients without any functional NCF1 gene, because of a mutation in NCF1 on the allele not carrying the NCF1-removing WBS deletion. These two patients suffer from chronic granulomatous disease with increased microbial infections in addition to WBS. Interestingly, one of these patients did suffer from hypertension, indicating that other factors than NADPH oxidase in vascular tissue may be involved in causing hypertension. PMID- 23340516 TI - Newborn bloodspot screening for Duchenne muscular dystrophy: 21 years experience in Wales (UK). AB - Duchenne muscular dystrophy (DMD), a progressive X-linked neuromuscular disorder, has an estimated worldwide incidence of 1:3500 male births. Currently, there are no curative treatments and the mean age of diagnosis is 5 years. In addition, subsequent pregnancies frequently occur before a diagnosis is made in an index case. An 'opt in' screening programme was introduced in Wales in 1990 with the aim to: reduce the diagnostic delay, permit reproductive choice and allow planning of the care of the affected boy. Newborn bloodspots were collected routinely as part of the Wales newborn screening programme. Specific consent was obtained for this test separately from the other tests. During the 21-year period, 369,780 bloodspot cards were received from male infants, of these 343,170 (92.8%) were screened using a bloodspot creatine kinase (CK) assay following parental consent. A total of 145 cases had a raised CK activity (>=250 U/l) and at follow-up, at 6-8 weeks of age, 79 cases had a normal serum CK (false-positive rate 0.023%) and 66 cases had an elevated serum CK. DMD was confirmed in 56 cases by genotyping/muscle biopsy studies, Becker muscular dystrophy in 5 cases and other rarer forms of muscular dystrophy in 5 cases. This long-term study has so far identified 13 false-negative cases. The incidence of DMD in Wales of 1:5136 during this period is lower than that of 1:4046 before commencement of screening in Wales. Screening has reduced the diagnostic delay enabling reproductive choice for parents of affected boys and earlier administration of current therapies. PMID- 23340517 TI - Humic acids-based one-step fabrication of SERS substrates for detection of polycyclic aromatic hydrocarbons. AB - A facile one-step approach to fabricate substrates for surface-enhanced Raman scattering (SERS) detection of polycyclic aromatic hydrocarbons (PAHs) was explored by reduction of silver nitrate with humic acids (HAs). This simple process readily delivers silver nanoparticles (Ag NPs) decorated with HAs (HAs-Ag NPs), and an average diameter of 50 nm. More importantly, it compares favorably to Ag NPs prepared by the usual sodium citrate method, HAs-Ag NPs show excellent SERS activity for PAHs and display a remarkable capacity to absorb aromatic molecules through presumed pi-pi stacking interactions. Furthermore, the HAs-Ag NPs displayed good SERS stability, possibly due to the fact that HAs form loose coils or networks around the nanoparticles thus preventing aggregation. The investigation of qualitative and quantitative detection of PAHs on HAs-Ag NPs indicate that different PAHs can be distinguished easily from their discriminant SERS peaks, and the SERS responses exhibited a linear dependence on PAH concentrations over two orders of magnitude, with tens of nM detection limits. In addition, the HAs-Ag NPs performed well in the multicomponent analysis of PAH mixtures by the SERS technique without pre-separation. PMID- 23340518 TI - GluN2B antagonism affects interneurons and leads to immediate and persistent changes in synaptic plasticity, oscillations, and behavior. AB - Although antagonists to GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) have been widely considered to be neuroprotective under certain pathological conditions, their immediate and lasting impacts on synaptic, circuit, and cognitive functions are poorly understood. In hippocampal slices, we found that the GluN2B-selective antagonist Ro25-6981 (Ro25) reduced synaptic NMDAR responses and consequently neuronal output in a subpopulation of GABAergic interneurons, but not pyramidal neurons. Consistent with these effects, Ro25 reduced GABAergic responses in pyramidal neurons and hence could affect circuit functions by altering the excitation/inhibition balance in the brain. In slices from Ts65Dn mice, a Down syndrome model with excess inhibition and cognitive impairment, acutely applied Ro25-rescued long-term potentiation (LTP) and gamma oscillation deficits, whereas prolonged dosing induced persistent rescue of LTP. In contrast, Ro25 did not impact LTP in wild-type (wt) mice but reduced gamma oscillations both acutely and following prolonged treatment. Although acute Ro25 treatment impaired memory performance in wt mice, memory deficits in Ts65Dn mice were unchanged. Thus, GluN2B-NMDARs contribute to the excitation/inhibition balance via impacts on interneurons, and blocking GluN2B-NMDARs can alter functions that depend on this balance, including synaptic plasticity, gamma oscillations, and memory. That prolonged GluN2B antagonism leads to persistent changes in synaptic and circuit functions, and that the influence of GluN2B antagonism differs between wt and disease model mice, provide critical insight into the therapeutic potential and possible liabilities of GluN2B antagonists. PMID- 23340519 TI - Methylphenidate normalizes resting-state brain dysfunction in boys with attention deficit hyperactivity disorder. AB - We used resting-state functional magnetic resonance imaging (RS-fMRI) to investigate the acute effects of methylphenidate hydrochloride (MPH) on spontaneous brain activity in children with attention deficit hyperactivity disorder (ADHD). In all, 23 boys with ADHD were scanned twice, under either 10 mg dose of MPH or placebo, in a randomized, cross-over, counterbalanced placebo controlled design. 32 Matched healthy controls were scanned once for comparison. Seven of the 23 ADHD boys participated in a follow-up 8-week MPH treatment. A regional homogeneity (ReHo) method was applied to characterize the local synchronization of spontaneous brain activity. ADHD boys under placebo compared with controls showed decreased ReHo in bilateral dorsolateral prefrontal cortices and increased ReHo in bilateral sensorimotor and parieto-visual cortices. Relative to placebo, MPH upregulated ReHo in bilateral ventral prefrontal cortices and cerebellar vermis, and downregulated ReHo in right parietal and visual areas that overlapped with the abnormally enhanced activities. When under MPH, ReHo differences between patients and controls were no longer observed. The preliminary prediction analysis revealed that the decreased ReHo in right parietal cortex after the acute MPH was positively correlated with the decreased symptom scores after the 8-week MPH treatment in the seven patients. We show that an acute dose of MPH normalized all fronto-parieto-cerebellar dysfunctions in boys with ADHD during the resting state. Preliminary findings furthermore suggest the potential of RS-fMRI as a prognostic imaging tool to identify response to MPH treatment. PMID- 23340521 TI - A bolaamphiphilic sexithiophene with liquid crystalline triangular honeycomb phase. AB - A new bolaamphiphile comprising a 5,5'''''-diphenyl-sexithiophene core with glycerol groups at each end and four lateral decyl chains was synthesized, which self-assembles into a liquid crystalline phase representing a nanoscale honeycomb composed of quasi-infinite triangular cylinders of pi-conjugated sexithiophenes. PMID- 23340520 TI - Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity. AB - Although it is well established that cannabinoid drugs can influence cognitive performance, the findings-describing both enhancing and impairing effects-have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2 (0.1, 0.3, or 1.0 mg/kg) on short- and long-term retention of object recognition memory under two conditions that differed in their training-associated arousal level. In male Sprague-Dawley rats that were not previously habituated to the experimental context, WIN55,212-2 administered immediately after a 3-min training trial, biphasically impaired retention performance at a 1-h interval. In contrast, WIN55,212-2 enhanced 1-h retention of rats that had received extensive prior habituation to the experimental context. Interestingly, immediate posttraining administration of WIN55,212-2 to non-habituated rats, in doses that impaired 1-h retention, enhanced object recognition performance at a 24-h interval. Posttraining WIN55,212-2 administration to habituated rats did not significantly affect 24-h retention. In light of intimate interactions between cannabinoids and the hypothalamic-pituitary-adrenal axis, we further investigated whether cannabinoid administration might differently influence training-induced glucocorticoid activity in rats in these two habituation conditions. WIN55,212-2 administered after object recognition training elevated plasma corticosterone levels in non-habituated rats whereas it decreased corticosterone levels in habituated rats. Most importantly, following pretreatment with the corticosterone synthesis inhibitor metyrapone, WIN55,212-2 effects on 1- and 24-h retention of non-habituated rats became similar to those seen in the low-aroused habituated animals, indicating that cannabinoid-induced regulation of adrenocortical activity contributes to the environmentally sensitive effects of systemically administered cannabinoids on short- and long-term retention of object recognition memory. PMID- 23340522 TI - Mental health promotion and the prevention of mental disorders in South Africa. AB - The need for greater attention to mental health promotion and the prevention of mental disorders in South Africa is highlighted by the cycle of poverty and mental ill-health, the potential for social gains, the question of affordability of treatment in the face of the increasing burden of mental disorders, and the limitations of existing treatment methods. This article, which provides a desk review of the current status of mental health promotion and prevention of mental disorders in South Africa, suggests that South Africa has a number of policies that bode well for promoting mental health from infancy through to old age. There is, however, a need for programmatic interventions to promote resilience in vulnerable populations. Of note, is the need for programmes to address maternal depression and strengthen attachment and psychosocial stimulation during infancy, strengthen families, promote health enhancing school environments, and address intimate partner violence and build health enhancing social capital. Given the multifaceted nature of risk and protective influences, the need for a multi sectoral plan of action is highlighted. PMID- 23340523 TI - Ocular traumatology: from military medicine to individual brilliance. PMID- 23340524 TI - Palladium nanoparticles supported on nitrogen-doped HOPG: a surface science and electrochemical study. AB - We have investigated by photoemission spectroscopy and scanning tunnelling microscopy what are the chemical and structural changes induced by nitrogen ion implantation (500 eV) on highly oriented pyrolytic graphite and how the defects induced by this process modify the growth and thermal stability of palladium nanoparticles, deposited in situ by physical vapour deposition. Since nitrogen derived defects are mostly buried below the surface, they are not accessible for a chemical interaction with metal nanoparticles; however, the amorphization induced by the ion beam in the outermost layers of the substrate beneficially affects the metal morphology, limiting the size of the nanoparticles and improving their thermal stability. The supported nanoparticles have been tested towards the oxygen reduction reaction indicating that the electrochemical activity does not depend significantly on the ion implantation, but mostly on the amount of palladium. PMID- 23340525 TI - Discovery and optimization of triazine derivatives as ROCK1 inhibitors: molecular docking, molecular dynamics simulations and free energy calculations. AB - Rho-associated protein kinases (ROCK1 and ROCK2) are promising targets for a number of diseases, including cardiovascular disorders, nervous system diseases, cancers, etc. Recently, we have successfully identified a ROCK1 inhibitor (1) with the triazine core. In order to gain a deeper insight into the microscopic binding of this inhibitor with ROCK1 and design derivatives with improved potency, the interactions between ROCK1 and a series of triazine/pyrimidine-based inhibitors were studied by using an integrated computational protocol that combines molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and binding energy decomposition analysis. First, three docking protocols, rigid receptor docking, induced fit docking, QM-polarized ligand docking, were used to determine the binding modes of the studied inhibitors in the active site of ROCK1. The results illustrate that rigid receptor docking achieves the best performance to rank the binding affinities of the studied inhibitors. Then, based on the predicted structures from molecular docking, MD simulations and MM/GBSA free energy calculations were employed to determine the dynamic binding process and compare the binding modes of the inhibitors with different activities. The binding free energies predicted by MM/GBSA are in good agreement with the experimental bioactivities, and the analysis of the individual energy terms suggests that the van der Waals interaction is the major driving force for ligand binding. In addition, the residue-inhibitor interaction spectra were obtained by the MM/GBSA free energy decomposition analysis, and the important residues for achieving strong binding were highlighted, which affords important guidance for the rational design of novel ROCK inhibitors. Finally, a variety of derivatives of inhibitor 1 were designed and four of them showed promising potency according to the predictions. We expect that our study can provide significant insight into the development of improved inhibitors of ROCK1. PMID- 23340526 TI - An unprecedented octahedral {Cd30} nanocage supported by twelve pendant-armed tetraacetate macrocyclic ligands. AB - An unprecedented octahedral {Cd(30)} nanocage supported by twelve pendant-armed tetraacetate macrocyclic ligands was synthesized through the reaction of macrocyclic tetraethyl ester and Cd(OAc)(2).2H(2)O in a 1 : 2 stoichiometry, where the surface photovoltage and photoluminescent properties have been studied for the nanocage. PMID- 23340527 TI - An ultrasensitive electrochemical aptasensor for thrombin based on the triplex amplification of hemin/G-quadruplex horseradish peroxidase-mimicking DNAzyme and horseradish peroxidase decorated FeTe nanorods. AB - In the present study, we fabricated an ultrasensitive sandwich-type electrochemical aptasensor for thrombin (TB) based on a triplex signal amplification strategy. The hemin/G-quadruplex horseradish peroxidase-mimicking DNAzyme (HRP-DNAzyme) as well as blocking reagent-horseradish peroxidase (HRP) and iron telluride nanorods (FeTe NRs) could simultaneously amplify the electrochemical signal of thionine (Thi) in the presence of H(2)O(2). Herein, FeTe NRs, as a newly discovered HRP-mimicking enzyme, were employed to construct an aptasensor for the first time. And, the FeTe NRs decorated by gold nanoparticles (abbreviated as AuNPs@FeTe NRs), were not only used as carriers of secondary thrombin aptamer (TBA 2), electron mediator thionine (Thi) and HRP, but also catalyzed the electrochemical reaction of Thi in the presence of H(2)O(2). As can be seen from experiment results, with the triplex signal amplification strategy, the reduction peak current of the fabricated aptasensor was logarithmically related to the concentration of thrombin (TB) over a wide range from 1 pM to 20 nM, and a detection limit of 0.5 pM was obtained. Hence, the proposed aptamer-based sandwich sensing approach for amplified detection of TB could provide a promising way for highly sensitive determination of other analytes. PMID- 23340529 TI - Cooled sacroiliac radiofrequency denervation for the treatment of pain secondary to tumor infiltration: a case-based focused literature review. AB - BACKGROUND: The sacroiliac (SI) joint is a common cause of low back pain, for which radiofrequency (RF) denervation has been shown to provide long-term relief. However, controversy exists surrounding the innervation, which treatment paradigm to utilize, and how best to select patients who might benefit. OBJECTIVE: To describe a patient with terminal breast cancer and tumor infiltration of the sacroiliac joint who was treated with cooled RF of the sacral lateral branches as an end-of-life palliative measure. The objectives of this review are to provide insight into the innervation of the SI joint; address controversial issues surrounding the targeted nerves in a patient with transitional anatomy; outline risk-mitigation strategies; and highlight the need for individually tailored treatment plans. METHODS: Case-based focused literature review in a patient treated with cooled RF ablation of the L4-S3 primary dorsal rami and lateral branches. RESULTS: Treatment was tailored to facilitate the rapid treatment of this terminal patient by performing the prognostic blocks and RF ablation at the same visit. Until her death 5 days post-procedure, the patient reported significant pain relief and began to ambulate and use the bathroom on her own, activities she could not do before treatment. In addition to functional improvement, she was also able to significantly reduce her opioid intake. CONCLUSION: This is the first report of cooled SI joint RF ablation to treat cancer pain. Our patient's positive response to the procedure suggests the possibility that the lateral branches innervate not only the posterior ligaments, but also the bony articulation. The decision to proceed with RF ablation on the same day as a prognostic lateral branch block was based on our patient's terminal condition, and the fact that cooled RF does not require sensory stimulation to ensure proximity to the target nerves. Because of her transitional anatomy, we elected to target L4. PMID- 23340528 TI - Disengaging the Smc3/kleisin interface releases cohesin from Drosophila chromosomes during interphase and mitosis. AB - Cohesin's Smc1, Smc3, and kleisin subunits create a tripartite ring within which sister DNAs are entrapped. Evidence suggests that DNA enters through a gate created by transient dissociation of the Smc1/3 interface. Release at the onset of anaphase is triggered by proteolytic cleavage of kleisin. Less well understood is the mechanism of release at other stages of the cell cycle, in particular during prophase when most cohesin dissociates from chromosome arms in a process dependent on the regulatory subunit Wapl. We show here that Wapl-dependent release from salivary gland polytene chromosomes during interphase and from neuroblast chromosome arms during prophase is blocked by translational fusion of Smc3's C-terminus to kleisin's N-terminus. Our findings imply that proteolysis independent release of cohesin from chromatin is mediated by Wapl-dependent escape of DNAs through a gate created by transient dissociation of the Smc3/kleisin interface. Thus, cohesin's DNA entry and exit gates are distinct. PMID- 23340530 TI - Efficacy of pulsed radiofrequency in the treatment of thoracic postherpetic neuralgia from the angulus costae: a randomized, double-blinded, controlled trial. AB - BACKGROUND: Postherpetic neuralgia (PHN) is often refractory to existing treatments. Pulsed radiofrequency (PRF) is known to be effective for treating neuropathic pain. In common, the targets of PRF treatment were the segmental dorsal root ganglion (DRG) neurons responsible for the pain. A potential complication that can occasionally occur with PRF treatment is damage to the adjacent tissue and organ. The effectiveness of the angulus costae as a puncture site for PRF has not been tested in thoracic PHN treatment. OBJECTIVE: The goal of this study was to investigate the therapeutic efficacy and safety of PRF for treating thoracic PHN through the puncture of the angulus costae. STUDY DESIGN: Prospective, randomized, double-blinded study. SETTING: Department of Anesthesiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine. METHODS: Ninety-six patients with thoracic (T2-11) PHN were equally randomized assigned into 2 groups. The electrode needle punctured through the angulus costae of each patient guided by x-ray; PRF at 42 degrees C for 120 seconds was applied after inducing paresthesia involving the affected dermatome area. PRF was applied in the PRF group (n = 48) twice. It was also applied in the sham group (n = 48) twice without radiofrequency energy output. The treatment was done once a week for 3 weeks. Tramadol was used for flare pain when the visual analog scale (VAS) >= 3. OUTCOMES ASSESSMENT: The therapeutic effect was evaluated by VAS, SF-36 health survey questionnaire, side effects (type, frequency, and onset time) before treatment, at days 3, 7, and 14, and at months one, 2, 3 and 6 after PRF. The average of tramadol (mg/d) administered within the first month after treatment was also recorded. RESULTS: The postprocedure VAS scores in the PRF group were significantly lower than those in the sham group and lasted for 6 months after treatment (P < 0.05). The SF-36 score, such as physical functioning, physical role, bodily pain, general health perceptions, social function, emotional role, and mental health index were significantly improved until 6 months after treatment in the PRF group compared to the sham group (P < 0.01 0.05). The average dosage of tramadol administrated (mg/d) within the first month after treatment was also significantly reduced in the PRF group compared to the sham group (P < 0.05). There were no obvious signs of pneumothorax, bleeding, infection, or other severe side effects in either group (P > 0.05). LIMITATIONS: Single center study, relatively small number of patients. CONCLUSIONS: The strategy that the angulus costae be used as the PRF puncture point of an electrode needle and the final localization of the needle tip as determined by sensory testing is an effective and safe therapeutic alternative for thoracic PHN treatment. Benefits include that the procedure is minimally invasive, provides short-term pain relief, and improves quality of life. CLINICAL TRIAL REGISTRATION: NO ISRCTN25588650. PMID- 23340531 TI - Efficacy of tapentadol ER for managing moderate to severe chronic pain. AB - BACKGROUND: Chronic non-cancer-related pain affects a large proportion of the adult population and is often difficult to manage effectively. Although opioid analgesics have been used to relieve chronic pain of different etiologies, opioids are associated with a range of side effects that may reduce patient quality of life and lead to reduced compliance with treatment.Tapentadol is a centrally acting analgesic with 2 mechanisms of action, MU-opioid receptor agonism and norepinephrine reuptake inhibition, that is available in an extended release formulation for the management of chronic pain. OBJECTIVE: To review the efficacy of tapentadol extended release (ER) for the management of moderate to severe chronic nociceptive and neuropathic pain. METHODS: Efficacy results are summarized for four 15-week phase 3 studies of tapentadol ER in patients with moderate to severe chronic osteoarthritis knee pain (2 studies; ClinicalTrials.gov Identifiers: NCT00421928 and NCT00486811), low back pain (NCT00449176), and pain related to diabetic peripheral neuropathy (DPN; NCT00455520); a one-year phase 3 study of tapentadol ER in patients with moderate to severe chronic osteoarthritis pain or low back pain (NCT00361504); and a pooled analysis of data from the 15-week studies in patients with osteoarthritis knee pain or low back pain. A summary of the comparative tolerability for tapentadol ER and the active comparator used in these studies, oxycodone controlled release (CR), is provided. RESULTS: Results of these studies showed that tapentadol ER (100 - 250 mg bid) was effective for the management of moderate to severe chronic osteoarthritis knee pain, low back pain, and pain related to DPN. Tapentadol ER (100 - 250 mg bid) has been shown to provide comparable pain relief to oxycodone HCl CR (20 - 50 mg bid) for chronic osteoarthritis knee pain and low back pain over up to one year of treatment. Tapentadol ER (100 - 250 mg bid) was associated with an improved tolerability profile, particularly gastrointestinal tolerability profile, and with lower rates of treatment discontinuations and adverse event-related discontinuations compared with oxycodone HCl CR (50 - 250 mg bid) over up to one year of treatment in patients with osteoarthritis knee pain and low back pain. LIMITATIONS: Differences in the design and duration of these phase 3 studies may limit comparisons of the efficacy results; nevertheless, this summary of efficacy results demonstrates the broad efficacy of tapentadol ER for different types of nociceptive and neuropathic pain. CONCLUSIONS: Tapentadol ER (100 - 250 mg bid) is effective for moderate to severe osteoarthritis pain, low back pain, and pain related to DPN and provides efficacy similar to that of oxycodone HCl CR (20 - 50 mg bid) for patients with osteoarthritis and low back pain. Tapentadol ER treatment has been associated with better gastrointestinal tolerability and compliance with therapy than oxycodone CR, which suggests that tapentadol ER may be a better option for the long-term management of chronic pain. PMID- 23340532 TI - Tramadol induced paradoxical hyperalgesia. AB - Opioids have been the mainstay analgesics for postoperative, cancerous, and chronic noncancerous pain. Common concerns regarding the use of opioids include the development of physical dependence and addiction. However, as a potential complication of opioid therapy, opioid-induced hyperalgesia (OIH) is often overlooked. That is, patients receiving opioids to control their pain may paradoxically become more sensitive to pain as a consequence of opioid therapy. OIH is a very important issue because it may complicate the clinical course of pain treatment and even worsen the suffering of patients receiving opioids because of the development of excruciating pain. Three OIH types were defined: 1) in the context of maintenance dosing and withdrawal, 2) at very high or escalating doses, and 3) at ultra-low doses. In the literature, most attention has been paid to the first 2 forms, and almost all cases of reported OIH have been ascribed to morphine administration. The third form of OIH has not been documented in humans, although it has been observed in animals. We present 2 cases of OIH resulting from administration of tramadol, which is a synthetic analogue of codeine and exhibits 10-fold less affinity for mu-opioid receptors, in patients suffering from chronic pain. The 2 cases presented herein imply the importance of recognizing OIH in patients medicated with tramadol if analgesic effects are lost in the context of dose titration, when generalized pain is reported without any evidence of disease exacerbation. While OIH associated with ultra-low dose opiates seems to be quite rare, if it is suspected, switching to other drugs and an appropriate treatment should be considered. PMID- 23340533 TI - Influence of CYP2D6 activity on pre-emptive analgesia by the N-methyl-D-aspartate antagonist dextromethorphan in a randomized controlled trial of acute pain. AB - BACKGROUND: There is some evidence that dextromethorphan (DM) is effective as a pre-emptive analgesic agent. DM is mainly metabolized to dextrorphan (DOR) by CYP2D6 whose activity can be inhibited by pharmacologic intervention. OBJECTIVES: To investigate the efficacy of DM as a pre-emptive analgesic agent and describe the population pharmacokinetics in the presence of normal and poor CYP2D6 metabolism in acute post-operative pain. STUDY DESIGN: Double blind, randomized, placebo-controlled trial SETTING: Post-surgical analgesic consumption after knee ligament surgery, a setting of acute pain. METHODS: Forty patients were randomized to a single oral dose of 50 mg quinidine or placebo, administered 12 hours before 50 mg DM. Patients were genotyped for the major CYP2D6 and ABCB1 variants and phenotyped for CYP2D6 using urine DM/DOR metabolic ratios and blood samples for population pharmacokinetic modeling. RESULTS: Quinidine was effective in inhibiting CYP2D6 activity, with 2-fold reduction of DM to DOR biotransformation clearance, prolonged DM half-life, and increased DM systemic availability. Patients in the quinidine group required significantly less often NSAIDs than patients in the placebo group (35.3% vs. 75.0%, P = 0.022). The odds ratio for NSAID consumption in the placebo vs. quinidine group was 5.5 (95% confidence interval (CI) 1.3 - 22.7) at 48 hours after surgery. LIMITATIONS: While this study shows an impact of DM on pre-emptive analgesia and is mechanistically interesting, the findings need to be confirmed in larger trials. CONCLUSION: CYP2D6 inhibition by quinidine influenced the pre-emptive analgesic effectiveness of DM confirming that CYP2D6 phenotypic switch increases the neuromodulatory effect of oral dextromethorphan. PMID- 23340534 TI - Proximal ischemia is a frequent cause of exercise-induced pain in patients with a normal ankle to brachial index at rest. AB - BACKGROUND: Excluding a vascular origin of exercise-related pain is often difficult in clinical practice. Recent papers have underlined the frequent association of concurrent lumbar spine degenerative disease and peripheral arterial disease. Furthermore, even when suspected, isolated exercise-induced proximal ischemia is difficult to diagnose. Measurement of transcutaneous oxygen pressure (tcpO2) is an interesting and accurate method to differentiate proximal (buttock) from distal (calf) regional blood flow impairment (RBFI) during exercise. OBJECTIVES: We searched for isolated proximal-without-distal RBFI as a possible cause of claudication, in patients with borderline (ABI-b: 0.91 - 0.99) or normal (ABI-n: 1.00 to 1.40) ankle to brachial index at rest. STUDY DESIGN: Retrospective cohort design study. We analyzed patients referred to our laboratory with symptom limiting claudication and an ankle brachial index within normal limits. SETTING: University-based exercise-investigation center. METHODS: Over a 12-year period, we identified 463 patients referred to our laboratory that had their lowest resting ABI between 0.90 and 1.40. The tcpO2 on chest, buttocks, and calves were recorded during treadmill walking tests (3.2 km/h, 10% slope) in 220 ABI-b and 243 ABI-n unique consecutive patients complaining of limiting claudication (each patient's ABI was the lowest of the 2 legs). Limiting claudication was defined as the reported inability to walk 1 kilometer without stopping. A DROP index (limb tcpO2-changes minus chest tcpO2-changes from rest) below -15 mmHg was used to indicate a positive result (i.e. exercise-induced RBFI). RESULTS: Treadmill exercise showed evidence for proximal or distal RBFI, of at least one side, in 128 out of 220 patients (58.2%) and in 86 out of 243 (35.4%) patients with ABI-b and ABI-n, respectively. Isolated proximal-without distal RBFI was found in 32 out of the 128 (25.0 %) positive tests in ABI-b and 32 out of the 86 (37.2%) positive tests in ABI-n patients. LIMITATIONS: Study limitations include the absence of systematic follow-up of diagnosed patients and absence of systematic search for cardio-respiratory co-morbid conditions. CONCLUSION: Isolated proximal-without distal RBFI is found in approximately one out of 7 patients complaining of symptom limiting claudication with a borderline or normal resting ABI. Exercise-tcpO2 may help to discriminate patients with arterial claudication that could benefit from invasive vascular investigations and procedures. PMID- 23340535 TI - A negative correlation between hyperalgesia and analgesia in patients with chronic radicular pain: is hydromorphone therapy a double-edged sword? AB - BACKGROUND: Opioids are the cornerstone therapy for the treatment of moderate to severe pain. Yet, unconfirmed evidence suggests that chronic exposure to opioids may cause hypersensitivity to pain, a phenomenon known as opioid-induced hyperalgesia (OIH). OBJECTIVES: The current preliminary prospective study was aimed to explore the relationship between experimental OIH and clinical opioid induced analgesia (OIA) in a model of experimental OIH in patients with chronic radicular pain using intermediate-term opioid therapy. STUDY DESIGN: Prospective evaluation SETTING: Interdisciplinary Pain Clinic at a referral Health Care Campus METHODS: Thirty patients with chronic neuropathic (radicular) pain were assessed prior to and following 4 weeks of an individually titrated dose of oral hydromorphone treatment (4-20 mg/d). The assessments included an evaluation of experimental OIH by testing for heat pain intensity and cold pain tolerance and an assessment of OIA by completing pain and disability questionnaires. RESULTS: Hydromorphone was found to induce hyperalgesia, as measured by an elevation of phasic heat pain intensity (P < 0.05). At the same time, hydromorphone caused significant clinical analgesic effects. There was a notable reduction in average daily pain scores (primary analgesic outcome) of 26 Visual Analog Scale (0-100) points. A significant negative correlation was found between OIH and all OIA measures (r = -0.389, P < 0.05 for the primary analgesic outcome). Hydromorphone dosage was positively correlated with OIH (P < 0.01, r = 0.467) and negatively correlated with OIA parameters (r = -0.592, P < 0.01 for the primary analgesia outcome). LIMITATIONS: The nonrandomized, open-label, prospective evaluation. CONCLUSION: A 4-week regimen of open-label hydromorphone therapy results in a dose-dependent OIH, which negatively correlates with its analgesic effect. Future randomized, controlled, and blinded studies are needed to verify these preliminary results. PMID- 23340536 TI - Opioids and risk of type 2 diabetes in adults with non-cancer pain. AB - BACKGROUND: While the use of opioids for chronic non-cancer pain (CNCP) has increased dramatically in the past 2 decades, concern exists about the safety of opioids, particularly with the extensive use among individuals with CNCP. OBJECTIVE: To assess the risk of type 2 diabetes (T2D) among adults exposed to opioids for non-cancer pain. STUDY DESIGN: Nested case-control study. SETTING: United Kingdom-based General Practice Research Database (GPRD). METHODS: Among 1.7 million opioid users with at least one prescription for an opioid to treat non-cancer pain in the GPRD (1990 - 2008), we identified all incident T2D cases with at least 2 years of medical history before their first diagnosis (index date). For each case we randomly selected up to 2 controls matched on age, gender, index date, and general practice. The same eligibility requirements were applied to controls as to cases. We defined "any exposure" as at least 2 prescriptions for an opioid within 2 years before the index date and defined "nonuse" as no use or only one prescription within 2 years (reference). For any exposure to opioids we further evaluated timing of use, cumulative use, and individual opioid type. Conditional logistic regression was used to estimate adjusted odds ratios (AORs) and 95% confidence intervals (CIs) controlling for confounders. RESULTS: We identified 50,468 T2D cases to which we matched 100,415 controls. Cases were more likely than controls to be former smokers, heavier, and to have more co-morbidities, co-medications, and visits to their general practitioners. After adjusting for important confounders there was no increased risk for T2D among those exposed to any opioid compared to nonusers (AOR = 1.03, 95% CI 1.00 - 1.06). The results did not change when we evaluated timing of use, cumulative use, or individual opioid type. LIMITATIONS: Misclassification of exposure may have occurred; limited data for some individual opioid types. CONCLUSION: This study found no association between use of opioids and risk of T2D among non-cancer adults. PMID- 23340537 TI - Doctor shopping reveals geographical variations in opioid abuse. AB - BACKGROUND: Prescription opioid abuse is not homogeneous due to varying patterns of use and different geographic preferences. Because doctor shopping is one of the main sources of diversion, it has previously been used to estimate drug abuse. OBJECTIVES: The aim of this study was to describe and compare opioid abuse in 2008 using doctor shopping to estimate abuse in 3 French regions. SETTING: Data for this study came from the General Health Insurance (GHI) reimbursement database, which covers 77% of the French population. All individuals living in Provence-Alpes-Cote d'Azur-Corse (PACA), Rhone-Alpes (RA), or Midi-Pyrenees (MP) that received at least one reimbursement for oral opioids from the GHI in 2008 were included. METHODS: Oral opioids under study were opioids for mild to moderate pain (dextropropoxyphene, codeine, tramadol, dihydrocodeine), opoids for moderately severe to severe pain (oral morphine, oxycodone, buprenorphine painkiller, hydromorphone), and opioid maintenance treatments (buprenorphine maintenance, methadone). For a given opioid, the Doctor Shopping Quantity (DSQ) is the quantity obtained by overlapping prescriptions from several prescribers. It is used to estimate the magnitude of abuse. The Doctor Shopping Indicator (DSI) is the DSQ divided by the total dispensed quantity. It is used to estimate the abuse corrected for use. RESULTS: The total DSQ for opioids in PACA (213.3 DDD/1,000 inhabitants) was twofold superior to that in RA (115.1 DDD/1,000) and in MP (106.2 DDD/1,000). The DSQ of opioids for mild to moderate pain was 75.5DDD/1000 (DSI=1.1%), 19.7DDD/1,000 (DSI=5.0%) for opioids for moderately severe to severe pain, and 55.3DDD/1,000 (DSI=6.2%) for opioid maintenance treatments. Emergent signals of abuse have been observed at a regional level for oxycodone in MP and dihydrocodeine in RA and MP. LIMITATIONS: The main limitation of this study is that the GHI reimbursement database provides information about dispensed and reimbursed prescription drugs, and not necessarily the actual quantity used. CONCLUSION: These results confirm important variations in the 3 French regions despite them being geographically close. Besides, they highlight different rates of opioid abuse between opioids for mild to moderate pain, opioids for moderately severe to severe pain, and opioid maintenance treatments, as well as differences within these groups. PMID- 23340538 TI - Prevalence and influence of diagnostic criteria in the assessment of hypogonadism in intrathecal opioid therapy patients. AB - BACKGROUND: Hypogonadism is frequently diagnosed based on total testosterone (TT) levels alone. However, 99% of testosterone is bound to the sex hormone-binding globulin (SHBG) with only 1% free testosterone. Alternative assessment methods consist of assay of free testosterone (FT) or bioavailable testosterone (BT) by equilibrium dialysis, calculation of FT and BT through the Vermeulen equations, and calculation of the free androgen index (FAI). OBJECTIVES: The aim of this study was to investigate the prevalence of hypogonadism in male chronic non cancer pain patients undertaking long-term intrathecal opioid therapy and the existence of diagnostic discrepancies according to the criteria used. STUDY DESIGN: Prospective observational study. SETTING: Department of Pain Management, Russells Hall Hospital, Dudley, United Kingdom. METHODS: Twenty consecutive male patients undertaking long-term intrathecal opioid therapy had the gonadal axis evaluated by assays of luteinising hormone (LH), follicle stimulating hormone (FSH), TT, SHBG and by calculating the FT, BT and FAI. RESULTS: Hypogonadism was present in 17 (85%) of the patients based on TT; 17 (85%) according to FT and BT calculations; and 14 (70%) when calculating FAI. Based on either TT or FT being low or borderline/low, 19 (95%) of the investigated patients were biochemically hypogonadal. Significant differences were observed between diagnosis based on FT and FAI (P < 0.05). No significant differences were observed between diagnosis based on TT and FT (P = 0.40) or TT and FAI (P = 0.20). CONCLUSION: Hypogonadism is common in patients undertaking intrathecal opioid therapy for the management of chronic non-malignant pain; however, diagnostic criteria can influence the diagnosis of this side effect. The assessment of the hypothalamic-pituitary gonadal axis should include evaluation of total serum testosterone, free testosterone, or bioavailable testosterone. PMID- 23340539 TI - A prospective evaluation of psychotherapeutic and illicit drug use in patients presenting with chronic pain at the time of initial evaluation. AB - BACKGROUND: Reports of chronic pain and associated opioid use, abuse, and fatalities continue to increase at an alarming rate, not only in the United States but also across the globe. In light of the many resultant fatalities, multiple authors and authorities have cautioned against the excessive use of opioids. Consequently, the Food and Drug Administration, Drug Enforcement Administration, and multiple state authorities have been proposing and implementing a plethora of regulations to curb opioid overuse and abuse. In the majority of cases, pain physicians have been portrayed as the perpetrators responsible for escalating use and abuse and resultant fatalities. OBJECTIVES: To assess the patterns of psychotherapeutic drug use and illicit drug use at the time of initial evaluation. STUDY DESIGN: A prospective evaluation. SETTING: A private, specialty referral interventional pain management clinic in the United States. METHODS: Participants were all new patients presenting to interventional pain management evaluated by one physician. Inclusion criteria was patients over 18 years of age with chronic spinal pain of at least one year duration. RESULTS: The results of this evaluation indicate that 94% of patients were on long-term opioids prior to presenting to interventional pain management. Illicit drug use is also common, although it has declined significantly. While a large proportion of individuals (45.7%) have used illicit drugs at some point in the past, current illicit drug use is present in only 7.9% of patients, both past and current use are similar to that of the general population. More importantly, a significant proportion of patients have been on opioids (high doses of more than 40 mg equivalents of morphine 48.8%) on a long-term basis, initiated and maintained by primary care physicians, prior to presenting to interventional pain management. Further, 35% were on benzodiazepines, and 9.2% on carisoprodol prior to presenting to interventional pain management. LIMITATIONS: The limitations of this evaluation include that it is a prospective, single center evaluation by one physician that is partially dependent on subjective recall of the patient. CONCLUSION: This study shows an overwhelming majority of patients were initiated and maintained with opioids in managing chronic noncancer pain. They were frequently on high doses over a long period of time with multiple drug combinations prescribed by primary care physicians. PMID- 23340540 TI - Repeated onabotulinumtoxin-a injections provide better results than single injection in treatment of painful bladder syndrome. AB - BACKGROUND: Onabotulinumtoxin-A (BoNT-A) is effective for the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS). However, long-term follow-up does not show successful outcome after a single injection. OBJECTIVES: To evaluate the efficacy and safety of repeated intravesical BoNT-A injections for treatment of IC/PBS and compare the success rates among patient groups receiving different injection numbers. STUDY DESIGN: Prospective interventional study. SETTING: Tertiary medical center. METHODS: Intravesical injection of 100 U of BoNT-A was performed in 81 patients every 6 months for up to 4 times or until patients' symptoms significantly improved. Patients who received a single injection served as active controls. Measured parameters included O'Leary-Sant symptom indexes (ICSI) and problem indexes (ICPI), visual analogue score (VAS) for pain, voiding diary variables, urodynamic parameters, maximal bladder capacity under anesthesia, glomerulation grade, and global response assessment. Multiple measurements and Kaplan-Meier analysis were used for comparison of consecutive data and success rates among groups. RESULTS: Among 81 patients, 20 received single injections, 19 received 2 injections, 12 received 3 injections, and 30 received 4 injections. The mean (+/- standard deviation) of ICSI, ICPI, total scores, VAS, functional bladder capacity, and daytime frequency all showed significant improvement after repeated BoNT-A treatment with different injections. Significantly better success rates were noted in patients who received 4 repeated injections (P = 0.0242) and 3 injections (P = 0.050), compared to those who received a single injection. However, there was no significant difference of long-term success rates among patients who received 2, 3, and 4 injections. LIMITATIONS: Lack of placebo control group is the main limitation. CONCLUSION: Repeated intravesical BoNT-A injections were safe and effective for pain relief and they increased bladder capacity and provided a better long-term success rate than a single injection did for treatment of IC/PBS. PMID- 23340541 TI - Cigarette smokers have reduced risk for post-dural puncture headache. AB - BACKGROUND: Although headache is the most common complication of dural puncture, knowledge gaps remain about patient-related risks. Data are lacking on the role, if any, of tobacco smoking, race, anxiety, depression, and Post Traumatic Stress Disorder (PTSD) in conferring risk for post-dural puncture headache (PDPH). OBJECTIVE: To determine the influence of tobacco smoking, race, anxiety,depressed mood, and PTSD on the risk for PDPH. STUDY DESIGN: Retrospective chart review, single site. METHODS: We determined the incidence of significant PDPH according to age, sex, race, smoking status, and psychiatric diagnosis in 153 consecutive research patients at the Cincinnati Veterans Affairs Medical Center who had continuous cerebrospinal fluid (CFS) sampling performed after using a large-bore (17 gauge) Tuohy needle to place a 20-gauge polyamide catheter in the lumbar spinal canal. RESULTS: Thirty-nine subjects (25.5%) had significant PDPH, defined as requiring an epidural blood patch for therapy (an average of 4 days post-procedure). Greater age was associated with a decreased risk of PDPH (P = 0.008); subjects over the age of 40 had the lowest incidence (15.7%). Women and men had a 31.4% and 23.7% incidence of PDPH, respectively; these were not significantly different (P = 0.38). Neither were rates of PDPH in Caucasians (28.0%) and African-Americans (15.6%) significantly different (P = 0.18) Healthy controls had a higher incidence of PDPH than patients with PTSD (P = 0.032). Smokers had a lower incidence of PDPH than non-smokers, 13.7% vs. 34.1% (P = 0.009). LIMITATIONS: This was not a prospective study, rather a retrospective chart review. CONCLUSION: Most notably, smokers had a considerably reduced rate of PDPH in comparison with non-smokers. This information could be a useful addition to the clinical assessment of relative risk for PDPH. Further research into the mechanisms by which tobacco smoking may inhibit PDPH, such as nicotine stimulation of dopamine neurotransmission or alterations in coagulation, appears warranted. PMID- 23340542 TI - Endoscopic transforaminal discectomy for an extruded lumbar disc herniation. AB - Microsurgery for lumbar herniated discs that require surgical intervention is a very successful and well-described technique, whether performed through more traditional "open" microsurgical retractors or through minimally-invasive "tube" retractors. Surgery for extruded lumbar disc fragments that migrate caudad or cephalad from the disc origin may typically require modifying the standard hemilaminotomy by removing additional laminar bone to retrieve the migrated fragment. Although midline and paramedian Wiltse approaches have been the standard methods for resecting herniated lumbar disc fragments, advances in neuroendoscopic techniques have expanded the potential targets for transforaminal endoscopic treatment to include extruded lumbar disc fragments. Sequestrations migrated cephalad or caudal to the disc can be removed using specialized flexible instruments. The instruments enable the surgeon to circumnavigate and reach into the epidural space and as far as the mid-vertebral body. The authors present a case of an endoscopically resected lumbar herniated disc fragment extruded caudad behind the inferior vertebral body through a transforaminal approach in an awake patient using local anesthetic. Radiographic and endoscopic visualization make it possible to access intracanal pathology. Although more traditional lumbar disc surgery is widely performed and is safe and effective, neuroendoscopic procedures may also allow a safe and effective approach for even extruded disc fragments for patients who cannot tolerate general anesthesia or are seeking the most minimally invasive option. Endoscopic discectomy is a minimally invasive alternative to open back surgery. Maintained spinal stability and absence or minimal formation of scar tissue allow for ease of subsequent surgeries, both open and minimally invasive (if needed). PMID- 23340543 TI - Effectiveness of percutaneous transforaminal adhesiolysis in patients with lumbar neuroforaminal spinal stenosis. AB - BACKGROUND: Lumbar foraminal spinal stenosis (LFSS) is a narrowing of the bony exit of a nerve root, which causes mechanical compression of spinal nerve roots. Low back pain and/or leg pain, and possibly neurogenic claudication, may result due to mechanical neural compression. Transforaminal epidural steroid injections (TFESIs) are commonly used for treating LFSS. Patients refractory to TFESIs may benefit from percutaneous epidural adhesiolysis. OBJECTIVE: Our intent was to assess transforaminal adhesiolysis (TFA) as treatment for LFSS, analyzing patient response by severity of stenosis and evaluating the short-term effectiveness of TFA. STUDY DESIGN: Prospective study. METHODS: Following IRB approval, 35 patients with LFSS were enrolled, all of whom underwent magnetic resonance imaging (MRI) of the lumbar spine. Sagittal MRI views were evaluated to grade the severity of LFSS. TFA was routinely conducted in the operating room. One hour after the procedure, each patient received 6 mL of 10% sodium chloride, infused over 30 minutes, with monitoring. Posttreatment outcomes were determined at 2 weeks and 3 months using a 5-point patient satisfaction scale. To test predictive value, patients were stratified by response (improvement versus no improvement). RESULTS: Improvement (defined as little pain, moderate pain, or no pain) was observed in 25 patients (71.4%) at 2 weeks and in 22 patients (62.8%) at 3 months following the procedure. Among patients showing improvement, those with Grade 3 spinal stenosis outnumbered those with Grade 2. At the 3-month follow-up, no statistically significant correlations between pain relief and the grade of LFSS was evident. LIMITATIONS: Secondary outcomes were not measured and the follow-up period was relatively brief. CONCLUSION: Short-term results indicate that percutaneous TFA is an effective treatment for LFSS, although therapeutic outcomes and the severity of LFSS showed no correlation. PMID- 23340544 TI - A systematic review of RCTs with nucleoplasty - an update. PMID- 23340545 TI - Possible mechanism of spinal T9 stimulation-induced acute renal failure: a virally mediatedtranssynaptic tracing study in transgenic mouse model. PMID- 23340546 TI - Percutaneous osteoplasty for the treatment of a painful osteochondral lesion of the talus: how to prevent hydroxyapatite bone cement leakage. PMID- 23340547 TI - Enhancement of CO2 selectivity in a pillared pcu MOM platform through pillar substitution. AB - Pillar substitution in a long-known metal-organic material with saturated metal centres, [Cu(bipy)(2)(SiF(6))](n), has afforded the first crystallographically characterized porous materials based upon TiF(6)(2-) and SnF(6)(2-) anions as pillars. Gas adsorption studies revealed similar surface areas and adsorption isotherms but enhanced selectivity towards CO(2)vs. CH(4) and N(2). PMID- 23340548 TI - High density DNA loading on the M13 bacteriophage provides access to colorimetric and fluorescent protein microarray biosensors. AB - We report the synthesis, characterization, and protein sensing capabilities of M13 bacteriophage-DNA bioconjugates. DNA oligonucleotides were conjugated to M13 through acyl hydrazone linkages. In one case, DNAzymes retained their catalytic ability when anchored to the virus coat, and in a separate study, the dynamic nature of the hydrazone allowed for liberation of DNA from the phage under mild conditions. PMID- 23340549 TI - Cu(II)-azide polynuclear complexes of Cu4 building clusters with Schiff-base co ligands: synthesis, structures, magnetic behavior and DFT studies. AB - Three new copper-azido complexes [Cu(4)(N(3))(8)(L(1))(2)](n) (1), [Cu(4)(N(3))(6)(L(2))(2)(H(2)O)(2)] (2), and [Cu(4)(N(3))(6)(L(3))(2)](n) (3) [L(1) is the imine resulting from the condensation of pyridine-2-carboxaldehyde with N-methylethylenediamine, HL(2) and HL(3) are the condensation products of 2 hydroxy-3-methoxybenzaldehyde with N,N-diethylethylenediamine and N ethylethylenediamine respectively] have been synthesized by using 0.5 molar equivalents of the Schiff base ligands with Cu(NO(3))(2).3H(2)O and an excess of NaN(3). Single crystal X-ray structures show that the basic unit of these complexes contains very similar Cu(II)(4) building blocks. While 1 and 3 have overall 1D structures, 2 forms discrete tetranuclear clusters due to blocking of two coordination sites on the tetranuclear cluster by water molecules. Magnetic susceptibility measurements over a wide range of temperatures exhibit the presence of both antiferromagnetic and ferromagnetic exchanges within the tetranuclear unit structures. Density functional theory calculations (using B3LYP functional and two different basis sets) have been performed on the complexes 1-3 to provide a qualitative theoretical interpretation of their overall magnetic behavior. PMID- 23340550 TI - Reducing the frequency of acute otitis media by individualized care. AB - OBJECTIVE: We sought to determine if use of more stringent diagnostic criteria for acute otitis media (AOM) than currently advocated by the American Academy of Pediatrics, tympanocentesis and pathogen-specific antibiotic treatment (individualized care) would result in reducing the incidence of recurrent AOM and consequent tympanostomy tube surgery. METHODS: A 5-year longitudinal, prospective study in Rochester, NY, was conducted from July 2006 to July 2011 involving 254 individualized care children. When this individualized care group developed symptoms of AOM, strict diagnostic criteria were applied and a tympanocentesis was performed. Pathogen resistance to empiric high-dose amoxicillin/clavulanate (80 mg/kg of amoxicillin component) caused a change in antibiotic to an optimized choice. Legacy controls (n = 208) were diagnosed with the same diagnostic criteria by the same physicians as the individualized care group and received the same empiric amoxicillin/clavulanate (80 mg/kg of amoxicillin component) but no tympanocentesis or change in antibiotic. Community control children (n = 1020) were diagnosed according to current American Academy of Pediatrics guidelines and treated with high-dose amoxicillin (80 mg/kg) without tympanocentesis as guideline recommended. RESULTS: 5.9% of children of the individualized care group compared with 14.4% of Legacy controls and 27.3% of community controls became otitis prone, defined as 3 episodes of AOM within a 6-month time span or 4 AOM episodes within a 12-month time span (P < 0.0001). 2.4% of the individualized care group compared with 6.3% of Legacy controls, and 14.8% of community controls received tympanostomy tubes (P < 0.0001). CONCLUSIONS: Individualized care of AOM significantly reduces the frequency of AOM and tympanostomy tube surgery. Use of strict diagnostic criteria for AOM and empiric antibiotic treatment using evidence-based knowledge of circulating otopathogens and their antimicrobial susceptibility profile also produces improved outcomes. PMID- 23340552 TI - Clinical and microbiologic characteristics of children treated at the Fort de France university hospital after the 2010 Haiti earthquake. AB - Few data related to the care of children injured in an earthquake are available. The objective of our study was to analyze the results of clinical and microbiologic characteristics of children treated in a Fort de France hospital after the Haiti earthquake. Bacteria were mainly Gram-negative bacteria. Some of these infections seemed to be environmental; a significant portion was related to acquisition during hospitalization. PMID- 23340553 TI - MRSA nasal colonization in children: prevalence meta-analysis, review of risk factors and molecular genetics. AB - BACKGROUND: We report a meta-analysis of methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization prevalence in children and a review of the risk factors as well as molecular genetic characterization. METHODS: All relevant studies reporting prevalence data on MRSA nasal colonization in children published between January 2000 and August 2010 were retrieved from the MEDLINE database and analyzed. RESULTS: After screening 544 studies, 50 studies were included. We obtained an estimate of MRSA prevalence of 2.7% (95% confidence interval [CI]: 2.2-3.1); of 5.2% (95% CI: 3.1-7.3) in children with underlying conditions and of 2.3% (95% CI: 1.8-2.7) in healthy children; 5.4% (95% CI: 3.1 7.7) in children recruited in hospitals and 3% (95% CI: 2.4-3.6) in children recruited in the community. Staphylococcal cassette chromosome mec type IV is the most diffused cassette globally. CONCLUSION: The hospital remains the environment where the microorganism circulates most. Children with underlying conditions could act as vectors of microorganisms between the hospital and the community. MRSA prevention strategies should be tailored to each specific institution, taking into account the nosocomial prevalence of MRSA nasal colonization and infections, and the prevalence of nasal colonization in the community that refers to the specific health care center. PMID- 23340551 TI - Candida parapsilosis is a significant neonatal pathogen: a systematic review and meta-analysis. AB - BACKGROUND: Candida is the third most common cause of late-onset neonatal sepsis in infants born at <1500 g. Candida parapsilosis infections are increasingly reported in preterm neonates in association with indwelling catheters. METHODS: We systematically reviewed neonatal literature and synthesized data pertaining to percentage of C. parapsilosis infections and mortality by meta-analyses. We also reviewed risk factors, virulence determinants, antimicrobial susceptibility patterns and outlined clinical management strategies. RESULTS: C. parapsilosis infections comprised 33.47% (95% confidence interval [CI]: 30.02, 37.31) of all neonatal Candida infections. C. parapsilosis rates were similar in studies performed before the year 2000, 33.53% (95% CI: 30.06, 37.40) (28 studies), to those after 2000, 27.00% (95% CI: 8.25, 88.37) (8 studies). The mortality due to neonatal C. parapsilosis infections was 10.02% (95% CI: 7.66, 13.12). Geographical variations in C. parapsilosis infections included a low incidence in Europe and higher incidence in North America and Australia. Biofilm formation was a significant virulence determinant and predominant risk factors for C. parapsilosis infections were prematurity, prior colonization and catheterization. Amphotericin B remains the antifungal drug of choice and combination therapy with caspofungin or other echinocandins may be considered in resistant cases. CONCLUSION: C. parapsilosis is a significant neonatal pathogen, comprises a third of all Candida infections and is associated with 10% mortality. Availability of tools for genetic manipulation of this organism will identify virulence determinants and organism characteristics that may explain predilection for preterm neonates. Strategies to prevent horizontal transmission in the neonatal unit are paramount in decreasing infection rates. PMID- 23340554 TI - Eighteen months of "matching Michigan" at a UK neonatal intensive care unit. AB - Our "Matching Michigan" program has 3 focuses for identifying and reducing nosocomial infection. First, practical training to optimize infection control; second, root cause analysis of blood-culture positives; and third, feedback and use of results to develop new guidelines. Our infection rates are comparable with adult units. Interventions have reduced coagulase-negative staphylococcal infections whereas other infection rates have reduced relative to increased activity. PMID- 23340555 TI - Acquisition of Streptococcus pneumoniae in pneumococcal conjugate vaccine-naive South African children and their mothers. AB - BACKGROUND: Pneumococcal nasopharyngeal colonization is a prerequisite to developing pneumococcal disease. We investigated the dynamics of pneumococcal colonization in perinatal HIV-unexposed and HIV-exposed children and their mothers and risk factors associated with new serotypes acquisition. METHODS: Two hundred forty-three mother-child pairs (120 HIV-infected, 123 HIV-uninfected mothers) were studied at 4.4, 7.2, 9.4, 12.3 and 16.0 months of the child's age. Demographic data, nasopharyngeal swabs, as well as oropharyngeal swabs, from mothers were collected for pneumococcal conventional culture and serotyping by the Quellung method. RESULTS: The rate of new serotype acquisition during the 16 months did not differ between HIV-exposed (49.1%) and HIV-unexposed (52.0%) children, or between HIV-infected (18.9%) and HIV-uninfected (19.5%) mothers. Serotypes included in the 7-valent pneumococcal conjugate vaccine (PCV7) were acquired more often by HIV-infected (10.0%) compared with HIV-uninfected mothers (6.4%; P = 0.03). On multivariate analysis, day-care attendance (adjusted odds ratio [AOR], = 1.80, P = 0.02) and maternal pneumococcal colonization (AOR = 1.54, P = 0.01) were positively associated with pneumococcal acquisition in the child, whereas breast-feeding had a protective effect on PCV7-serotype acquisition in HIV-uninfected children. New acquisition of PCV7 and PCV13 serotypes in the mother was positively associated with colonization in the child (AOR = 2.01, P = 0.006 and AOR = 2.04, P = 0.002, respectively). CONCLUSIONS: There is an association of acquisition of PCV7 and PCV13 serotypes between young children and their mothers. The higher prevalence of PCV7 serotype in HIV infected mothers suggests that they may be a reservoir for transmission of these serotypes, which could delay indirect effects of PCV in settings with a high HIV burden. PMID- 23340556 TI - Accuracy and interobserver variation of three clinical decision rules for the diagnosis of streptococcal pharyngitis. AB - We evaluated the accuracy and interobserver variation of 3 clinical decision rules for streptoccocal pharyngitis diagnosis. Oropharyngeal swab culture was the reference. The Abu Reesh rule had the highest sensitivity and the World Health Organization rule showed the highest specificity. The interobserver variation of those rules indicates the need for better training of clinicians. PMID- 23340557 TI - Commentary: antibiotic recommendations for acute otitis media and acute bacterial sinusitis in 2013--the conundrum. PMID- 23340558 TI - Efficacy and safety of whole body skin cleansing with chlorhexidine in neonates- a systemic review. AB - BACKGROUND: Cord cleansing with chlorhexidine has been shown to reduce the risk of neonatal mortality in low-resource settings. The effect of whole body skin cleansing with chlorhexidine in neonates is, however, not clear. METHODS: We searched MEDLINE and other databases and included all studies that evaluated the effect of chlorhexidine cleansing on neonatal mortality rate (NMR) and/or the incidence of neonatal sepsis. We estimated the pooled relative risks by fixed effect and random-effects models and also explored the sources of heterogeneity by subgroup meta-analysis. RESULTS: Seven randomized trials and 2 before-and after studies that evaluated single cleansing with chlorhexidine were included in the review. Pooled analysis showed no significant effect on NMR in either the fixed effect (5 studies; relative risk: 0.91; 95% confidence interval: 0.80 to 1.04) or random-effects model (0.83; 0.63 to 1.08). On subgroup analysis, the before-and-after study conducted in high-NMR setting showed significant reduction in mortality (0.68; 0.50 to 0.93) but the randomized controlled trials from low NMR settings did not show any benefit (0.97; 0.84 to 1.13). Pooled analysis of 5 studies that reported the rates of sepsis revealed substantial heterogeneity (I = 80.2%). Pooled result by random-effects model as well as the sensitivity analysis including only the randomized trials found no significant effect (0.65; 0.40 to 1.05 and 0.97; 0.80 to 1.18, respectively). CONCLUSIONS: There is no conclusive evidence for any beneficial effect after single skin cleansing with chlorhexidine. However, given the heterogeneity in the major outcomes it seems prudent to generate more evidence from randomized trials in high-NMR settings. Until such time, this intervention cannot be recommended in any settings. PMID- 23340559 TI - No benefit of glutamine supplementation on persistent diarrhea in Ugandan children. AB - We evaluated the efficacy of oral glutamine supplementation in children 2 to 60 months of age with persistent diarrhea by 1:1 randomization to standard treatment alone or together with twice daily glutamine. The failure rate was similar in both arms (relative risk: 1.8 [95% confidence interval: 0.8-3.7], P = 0.12). Glutamine supplementation showed no benefit on the outcome of persistent diarrhea. PMID- 23340560 TI - Epidemiology of bloodstream infections in children with sickle cell disease. AB - The incidence of invasive Streptococcus pneumoniae and Haemophilus influenzae type b infections in the sickle cell disease population has declined. In this report, we determine the predominant organisms responsible for bloodstream infections in a pediatric sickle cell disease population during the postheptavalent conjugate vaccine era. Central venous access device associated infections are a new burden to efforts aimed at preventing bloodstream infections in this population. PMID- 23340562 TI - Vitamin D deficiency associated with increased incidence of gastrointestinal and ear infections in school-age children. AB - BACKGROUND: Vitamin D deficiency (VDD) is highly prevalent among children worldwide. The effects of VDD include alterations of the immune response and increased risk of infection but little evidence exists in school-age children. We investigated the association of vitamin D status with morbidity in a prospective study of school-age children from Bogota, Colombia. METHODS: We measured plasma 25-hydroxyvitamin D (25(OH)D) concentrations in a random sample of 475 children (mean +/- standard deviation age: 8.9 +/- 1.6 years) and followed them for an academic year. Caregivers were asked to record daily information on the incidence of morbidity episodes using pictorial diaries. Baseline vitamin D status was classified according to 25(OH)D concentrations as deficient (<50 nmol/L), insufficient (>=50 and <75 nmol/L) or sufficient (>=75 nmol/L). We used Poisson regression to estimate incidence rate ratios and 95% confidence intervals for days with diarrhea, vomiting, diarrhea with vomiting, cough with fever and earache or discharge with fever, comparing vitamin D-deficient with vitamin D sufficient children. Estimates were adjusted for child's age, sex and household socioeconomic status. RESULTS: The prevalence of VDD was 10%; an additional 47% of children were vitamin D-insufficient. VDD was associated with increased rates of diarrhea with vomiting (adjusted incidence rate ratio: 2.05; 95% confidence interval: 1.19, 3.53) and earache/discharge with fever (adjusted incidence rate ratio: 2.36; 95% confidence interval: 1.26, 4.44). VDD was not significantly related to cough with fever. CONCLUSIONS: These results suggest that VDD is related to increased incidence of gastrointestinal and ear infections in school age children. The effect of correcting VDD on reducing risk of these infections needs to be tested in supplementation trials. PMID- 23340561 TI - Safety of perinatal exposure to antiretroviral medications: developmental outcomes in infants. AB - BACKGROUND: This study evaluated effects of perinatal exposure to antiretroviral (ARV) medications on neurodevelopment of HIV-exposed, uninfected infants. METHODS: HIV-exposed, uninfected infants (age 9-15 months) enrolled in Surveillance Monitoring for Antiretroviral Therapy Toxicities, a multisite prospective surveillance study, completed the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III), assessing cognition, language, motor skills, social-emotional development and adaptive behavior. Linear regression models were used to evaluate associations between Bayley-III outcomes in infants with and without perinatal and neonatal ARV exposure, by regimen (combination ARV [cARV] versus non-cARV), type of regimen (defined by drug class) and individual ARVs (for infants with cARV exposure), adjusting for maternal and infant health and demographic covariates. RESULTS: As of May 2010, 374 infants had valid Bayley III evaluations. Median age at testing was 12.7 months; 49% male, 79% black and 16% Hispanic. Seventy-nine percent were exposed to regimens containing protease inhibitors (9% of protease inhibitor-containing regimens also included non nucleoside reverse transcriptase inhibitors), 5% to regimens containing non nucleoside reverse transcriptase inhibitors (without protease inhibitor) and 14% to regimens containing only nucleoside reverse transcriptase inhibitors. Overall, 83% were exposed to cARV. No Bayley-III outcome was significantly associated with overall exposure to cARV, ARV regimen or neonatal prophylaxis. For individual ARVs, following sensitivity analyses, the adjusted group mean on the Language domain was within age expectations but significantly lower for infants with perinatal exposure to atazanavir (P = 0.01). CONCLUSIONS: These results support the safety of perinatal ARV use. Continued monitoring for adverse neurodevelopmental outcomes in older children is warranted, and the safety of atazanavir merits further study. PMID- 23340563 TI - Hospital-based surveillance for rotavirus gastroenteritis using molecular testing and immunoassay during the 2011 season in Botswana. AB - We describe rotavirus testing and clinical characteristics for children admitted with acute gastroenteritis during Botswana's 2011 rotavirus season. The rotavirus season extended from June to October with rotavirus-specific case fatality being 2.8%. Using molecular testing as reference, the immunochromatographic test had a sensitivity of 76.5% and specificity of 68.0%. Rotavirus vaccine may significantly reduce childhood morbidity and mortality in Botswana. PMID- 23340564 TI - Antibody persistence for up to 5 years after a fourth dose of Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine (HibMenCY-TT) given at 12-15 months of age. AB - BACKGROUND: A 4-dose series of recently licensed Haemophilus influenzae type b meningococcal serogroups C and Y-tetanus toxoid conjugate vaccine (HibMenCY-TT) was immunogenic with a clinically acceptable safety profile in infants, with antibodies persisting in most participants for 1 year following dose 4. This study assessed antibody persistence up to 5 years after vaccination. METHODS: Participants had received HibMenCY-TT or Hib-TT at 2, 4 and 6 months of age. At age 12-15 months, HibMenCY-TT vaccinees received a fourth HibMenCY-TT dose (HibMenCY x 4 group), whereas those who received Hib-TT received a fourth dose of either Hib-TT (Hib) or HibMenCY-TT (HibMenCY x 1). Blood samples were collected 1 month and 1, 3 and 5 years after the last dose for measurement of antipolyribosylribitol phosphate (the Hib capsular polysaccharide) antibodies and serum bactericidal activity (human complement source) against meningococcal serogroups C and Y. RESULTS: Five years after the fourth dose, the percentages of children with antipolyribosylribitol phosphate >=0.15 MUg/mL in HibMenCY x 4, HibMenCY x 1 and Hib groups were 98.8% (95% confidence interval: 93.5%-100%), 97.3% (85.8%-99.9%) and 92.3% (79.1%-98.4%), respectively. The percentages with human complement serum bactericidal activity >=1:8 for meningococcal serogroup C were 82.9% (72.5%-90.6%), 73.5% (55.6%-87.1%) and 21.1% (9.6%-37.3%), respectively. The percentages with human complement serum bactericidal activity >=1:8 for serogroup Y were 69.5% (58.4%-79.2%), 54.3% (36.6%-71.2%) and 18.4% (7.7%-34.3%), respectively. CONCLUSIONS: HibMenCY-TT given as a 4-dose series or as a single dose at 12-15 months of age induced immune responses for all 3 antigens that lasted for up to 5 years after vaccination in more than half of recipients. PMID- 23340565 TI - Improved vancomycin dosing in children using area under the curve exposure. AB - BACKGROUND: : Our objectives were to (1) determine the pharmacokinetic indices of vancomycin in pediatric patients; and (2) compare attainment of 2 target exposures: area under curve (AUC) / minimum inhibitory concentration (MIC) >=400 and trough concentration >=15 mcg/mL. METHODS: : The population-based pharmacokinetic modeling was performed using NONMEM 7.2 for children >=3 months old who received vancomycin for >=48 hours from 2003 to 2011. A 1-compartment model with first-order kinetics was used to estimate clearance, volume of distribution and AUC. Empiric Bayesian post hoc individual parameters and Monte Carlo simulations (N = 11,000) were performed. RESULTS: : Analysis included 702 patients with 1660 vancomycin serum concentrations. Median age was 6.6 (interquartile range 2.2-13.4) years, weight 22.7 (12.6-46) kg and baseline serum creatinine 0.40 (0.30-0.60) mg/dL. Final model pharmacokinetic indices were clearance (L/h) = 0.248 * Wt * (0.48/serum creatinine) * (ln(age)/7.8) and volume of distribution (L) = 0.636 * Wt. Using these parameters and the observed MIC distribution, Monte Carlo simulation indicated that the initial median dose of 44 (39-52) mg/kg/day was inadequate in most subjects. Regimens of 60 mg/kg/day for subjects >=12 years old and 70 mg/kg/day for those <12 years old achieved target AUC/MIC in ~75% and trough concentrations >=15 in ~45% of virtual subjects. An AUC/MIC ~400 corresponded to trough concentration ~8 to 9 mcg/mL. CONCLUSIONS: : Targeted exposure using vancomycin AUC/MIC, compared with trough concentrations, is a more realistic target in children. Depending on age, serum creatinine and MIC distribution, vancomycin in a dosage of 60 to 70 mg/kg/day was necessary to achieve AUC/MIC >= 400 in 75% of patients. PMID- 23340566 TI - Etiology of empyema thoracis and parapneumonic pleural effusion in Taiwanese children and adolescents younger than 18 years of age. AB - We analyzed blood and pleural fluid samples from 89 Taiwanese children with empyema thoracis and parapneumonic pleural effusion. Streptococcus pneumoniae was the major pathogen, identified in 12 children by bacterial culture and 53 children by molecular techniques, and serotype 19A was the dominant serotype. Also noteworthy was the detection of pneumococcal serotype 1, Haemophilus influenzae and Mycoplasma pneumoniae in these children. PMID- 23340567 TI - Surveillance of multidrug-resistant Gram-negative pathogens in high-risk neonates -does it make a difference? PMID- 23340568 TI - Stem cells: A metabolic switch. PMID- 23340575 TI - Beyond a pedagogical tool: 30 years of Molecular biology of the cell. AB - In 1983, a bulky and profusely illustrated textbook on molecular and cell biology began to inhabit the shelves of university libraries worldwide. The effect of capturing the eyes and souls of biologists was immediate as the book provided them with a new and invigorating outlook on what cells are and what they do. PMID- 23340576 TI - Nanoreactors: a novel biosensing platform for protein assay. AB - We have constructed a colorimetric protein assay platform based on a nanoreactor. The novel strategy presents high sensitivity and excellent performance for the detection of thrombin. The linear range is 5.58 * 10(-10) to 6.50 * 10(-9) M and the detection limit down to 0.19 nM is achieved. PMID- 23340577 TI - Influence of catalyst choices on transport behaviors of InAs NWs for high performance nanoscale transistors. AB - The influence of the catalyst materials on the electron transport behaviors of InAs nanowires (NWs) grown by a conventional vapor transport technique is investigated. Utilizing the NW field-effect transistor (FET) device structure, ~20% and ~80% of Au-catalyzed InAs NWs exhibit strong and weak gate dependence characteristics, respectively. In contrast, ~98% of Ni-catalyzed InAs NWs demonstrate a uniform n-type behavior with strong gate dependence, resulting in an average OFF current of ~10(-10) A and a high I(ON)/I(OFF) ratio of >10(4). The non-uniform device performance of Au-catalyzed NWs is mainly attributed to the non-stoichiometric composition of the NWs grown from a different segregation behavior as compared to the Ni case, which is further supported by the in situ TEM studies. These distinct electrical characteristics associated with different catalysts were further investigated by the first principles calculation. Moreover, top-gated and large-scale parallel-array FETs were fabricated with Ni catalyzed NWs by contact printing and channel metallization techniques, which yield excellent electrical performance. The results shed light on the direct correlation of the device performance with the catalyst choice. PMID- 23340578 TI - Metagenomic exploration reveals high levels of microbial arsenic metabolism genes in activated sludge and coastal sediments. AB - Arsenic contamination in a water system is an urgent environmental problem that has caused severe endemic arsenicosis in south and southeast Asian countries. It is well known that microbially mediated arsenic metabolism can enhance arsenic mobility, bioavailability, and toxicity. Here, for the first time, we applied the Illumina high-throughput metagenomic and metatranscriptomic approaches to study the distribution, diversity, abundance, and expression of microbial arsenic metabolism genes in activated sludge and five coastal sediments. An average depth of ~2.6 Gb clean data for each sample was finally obtained for BLAST analysis after quality filtration and normalization. The results revealed that: (1) highly diverse arsenic metabolism-like genes were found and the overall abundance varied from 0.18 % to 0.26 % in the six metagenomic data sets; (2) arsenic metabolism like genes were expressed with extremely low levels or no expression at all in activated sludge; and (3) the distribution, diversity, and abundance of aioA like, arrA-like, arsB-like, ACR3-like, and arsM-like genes varied significantly in the six surveyed environments. This study provided a novel perspective on understanding the ecology of arsenic metabolism in different water environments using high-throughput sequencing technique. PMID- 23340574 TI - Caveolae as plasma membrane sensors, protectors and organizers. AB - Caveolae are submicroscopic, plasma membrane pits that are abundant in many mammalian cell types. The past few years have seen a quantum leap in our understanding of the formation, dynamics and functions of these enigmatic structures. Caveolae have now emerged as vital plasma membrane sensors that can respond to plasma membrane stresses and remodel the extracellular environment. Caveolae at the plasma membrane can be removed by endocytosis to regulate their surface density or can be disassembled and their structural components degraded. Coat proteins, called cavins, work together with caveolins to regulate the formation of caveolae but also have the potential to dynamically transmit signals that originate in caveolae to various cellular destinations. The importance of caveolae as protective elements in the plasma membrane, and as membrane organizers and sensors, is highlighted by links between caveolae dysfunction and human diseases, including muscular dystrophies and cancer. PMID- 23340579 TI - Contact toxicities of anuran skin alkaloids against the fire ant (Solenopsis invicta). AB - Nearly 500 alkaloids, representing over 20 structural classes, have been identified from the skin of neotropical poison frogs (Dendrobatidae). These cutaneous compounds, which are derived from arthropod prey of the frogs, generally are believed to deter predators. We tested the red imported fire ant (Solenopsis invicta) for toxicosis following contact with 20 alkaloids (12 structural classes) identified from dendrobatids or other anurans. Individual ants forced to contact the dried residues of 13 compounds exhibited convulsions and/or reduced ambulation. We estimated the cutaneous concentrations of several compounds based on their reported recoveries from skin extracts of free-ranging frogs and our measurements of the skin surface areas of museum specimens. Pumiliotoxin 251D exhibited contact toxicity below its estimated cutaneous concentration in the Ecuadorian frog, Epipedobates anthonyi, an observation consistent with the hypothesized role of this compound in anuran chemical defense. Our results and those of a previous study of mosquitoes indicate that some anuran skin compounds function defensively as contact toxins against arthropods, permeating their exoskeleton. PMID- 23340580 TI - Variable virulence among isolates of Ascosphaera apis: testing the parasite pathogen hypothesis for the evolution of polyandry in social insects. AB - The queens of many eusocial insect species are polyandrous. The evolution of polyandry from ancestral monoandry is intriguing because polyandry undermines the kin-selected benefits of high intracolonial relatedness that are understood to have been central to the evolution of eusociality. An accumulating body of evidence suggests that polyandry evolved from monoandry in part because genetically diverse colonies better resist infection by pathogens. However, a core assumption of the "parasite-pathogen hypothesis", that there is variation in virulence among strains of pathogens, remains largely untested in vivo. Here, we demonstrate variation in virulence among isolates of Ascosphaera apis, the causative organism of chalkbrood disease in its honey bee (Apis mellifera) host. More importantly, we show a pathogen-host genotypic interaction for resistance and pathogenicity. Our findings therefore support the parasite-parasite hypothesis as a factor in the evolution of polyandry among eusocial insects. PMID- 23340581 TI - Functional conservation of Drosophila FTZ-F1 and its mammalian homologs suggests ligand-independent regulation of NR5A family transcriptional activity. AB - Drosophila Ftz-F1 is an orphan nuclear receptor required for segmentation and metamorphosis. Its mammalian orthologs, SF-1 and LRH-1, function in sexual development and homeostasis, and have been implicated in stem cell pluripotency maintenance and tumorigenesis. These NR5A family members bind DNA as monomers and strongly activate transcription. However, controversy exists as to whether their activity is regulated by ligand-binding. Structural evidence suggested that SF-1 and human LRH-1 bind regulatory ligands, but mouse LRH-1 and Drosophila FTZ-F1 are active in the absence of ligand. We found that Dm-Ftz-F1 and mLRH-1, thought not to bind ligand, or mSF-1 and hLRH-1, predicted to bind ligand, each efficiently rescued the defects of Drosophila ftz-f1 mutants. Further, each correctly activated expression of a Dm-Ftz-F1 target gene in Drosophila embryos. The functional equivalence of ftz-f1 orthologs in these sensitive in vivo assays argues against specific activating ligands for NR5A family members. PMID- 23340582 TI - Formation of a supramolecular assembly between a Na(+)-templated G-quartet and a Ni(II)-porphyrin complex. AB - Formation of a pi-pi stacked assembly between a Na(+)-templated G-quartet and octaethylporphyrinatonickel(II) was observed by spectroscopic methods in methanol/chloroform and the formation dynamics of the assembly was elucidated. PMID- 23340583 TI - Single-molecule DNA detection using a novel SP1 protein nanopore. AB - SP1 protein as a new type of biological nanopore is described and is utilized to distinguish single-stranded DNA at the single-molecule level. Using the SP1 nanopore to investigate single molecule detection broadens the existing research areas of pore-forming biomaterials from unsymmetrical biological nanopores to symmetrical biological nanopores. This novel nanopore could provide a good candidate for single-molecule detection and characterization of biomaterial applications. PMID- 23340584 TI - The integrated response of primary metabolites to gene deletions and the environment. AB - Intracellular metabolites arise from the molecular integration of genomic and environmental factors that jointly determine metabolic activity. However, it is not clear how the interplay of genotype, nutrients, growth, and fluxes affect metabolite concentrations globally. Here we used quantitative metabolomics to assess the combined effect of environment and genotype on the metabolite composition of a yeast cell. We analyzed a panel of 34 yeast single-enzyme knockout mutants grown on three archetypical carbon sources, generating a dataset of 400 unique metabolome samples. The different carbon sources globally affected the concentrations of intermediates, both directly, by changing the thermodynamic potentials (Delta(r)G) as a result of the substrate influx, and indirectly, by cellular regulation. In contrast, enzyme deletion elicited only local accumulation of the metabolic substrate immediately upstream of the lesion. Key biosynthetic precursors and cofactors were generally robust under all tested perturbations in spite of changes in fluxes and growth rate. PMID- 23340585 TI - Effects of robotic knee exoskeleton on human energy expenditure. AB - A number of studies discuss the design and control of various exoskeleton mechanisms, yet relatively few address the effect on the energy expenditure of the user. In this paper, we discuss the effect of a performance augmenting exoskeleton on the metabolic cost of an able-bodied user/pilot during periodic squatting. We investigated whether an exoskeleton device will significantly reduce the metabolic cost and what is the influence of the chosen device control strategy. By measuring oxygen consumption, minute ventilation, heart rate, blood oxygenation, and muscle EMG during 5-min squatting series, at one squat every 2 s, we show the effects of using a prototype robotic knee exoskeleton under three different noninvasive control approaches: gravity compensation approach, position based approach, and a novel oscillator-based approach. The latter proposes a novel control that ensures synchronization of the device and the user. Statistically significant decrease in physiological responses can be observed when using the robotic knee exoskeleton under gravity compensation and oscillator based control. On the other hand, the effects of position-based control were not significant in all parameters although all approaches significantly reduced the energy expenditure during squatting. PMID- 23340586 TI - High-accuracy patient-to-image registration for the facilitation of image-guided robotic microsurgery on the head. AB - Image-guided microsurgery requires accuracies an order of magnitude higher than today's navigation systems provide. A critical step toward the achievement of such low-error requirements is a highly accurate and verified patient-to-image registration. With the aim of reducing target registration error to a level that would facilitate the use of image-guided robotic microsurgery on the rigid anatomy of the head, we have developed a semiautomatic fiducial detection technique. Automatic force-controlled localization of fiducials on the patient is achieved through the implementation of a robotic-controlled tactile search within the head of a standard surgical screw. Precise detection of the corresponding fiducials in the image data is realized using an automated model-based matching algorithm on high-resolution, isometric cone beam CT images. Verification of the registration technique on phantoms demonstrated that through the elimination of user variability, clinically relevant target registration errors of approximately 0.1 mm could be achieved. PMID- 23340587 TI - PVP stabilized Pt nano particles catalyzed de-oxygenation of phenoxazine group by hydrazine in physiological buffer media: surfactant competes with reactants for the same surface sites. AB - PVP capped platinum nano particles (PNP) of 5 nm diameter were prepared and characterized as homogeneous and of spherical nature. At physiological pH range (6.0-8.0), these PNP catalyze the deoxygenation of phenoxazine group containing resazurin (1) by hydrazine. The observed rate constants (k(o)), increase linearly with [PNP] at constant [1] and [Hydrazine]; but first increase and then after reaching a maximum it decrease with increase in [1] as well as in [Hydrazine]. The k(o) values increase linearly with 1/[H(+)] indicating N(2)H(4) as the reducing species that generates from the PNP assisted deprotonation of N(2)H(5)(+). The kinetic observations suggest Langmuir-Hinshelwood type surface reaction mechanism where both 1 and hydrazine are adsorbed on nano particles surface and compete for the same sites. Interestingly, the surfactant molecules, polyvinylpyrrolidone (PVP), though do not take part into reduction reaction but having same type of functional groups as reactants, competes with them for the same surface sites. Adsorption on PNP with same type of functional group is further supported by the FTIR spectra of Pt-PVP and Pt-1. Thus on increasing [PVP], k(o) decreases linearly and only when [PVP] is held constant, the plot of k(o) vs. [PNP] passes through the origin indicating the insignificance of uncatalyzed reaction. The plot of ln k(o) vs. [1] or [Hydrazine] shows two different linear zones with different exponent values with respect to [1] and [Hydrazine]. This indicates that along with the complex heterogeneous surface adsorption processes, the mutual interactions between the reactants are also changing with the relative concentrations of reactants or, in general, with the molar ratio ([Hydrazine]/[1]). PMID- 23340589 TI - Electronic control in frustrated Lewis pair chemistry: adduct formation of intramolecular FLP systems with -P(C(6)F(5))(2) Lewis base components. AB - 2-Propenylbis(pentafluorophenyl)phosphane adds Piers' borane [HB(C(6)F(5))(2)] with anti-Markovnikov orientation to yield the intramolecular vicinal frustrated P/B Lewis pair 10. The FLP 10 adds pyridine, acetonitrile or alkyl isocyanides to form simple boron Lewis acid adducts 11-14, all of which were characterized by X ray diffraction. The FLP 10 reacts with trans-cinnamic aldehyde to give a boron carbonyl adduct 15 that was characterized by an X-ray crystal structure analysis. In contrast, the geminal FLP (C(6)F(5))(2)P-CHEt-B(C(6)F(5))(2) (3) undergoes 1,2 carbonyl addition reactions with benzaldehyde or trans-cinnamic aldehyde to yield the respective five-membered heterocyclic products (7, 8, both characterized by X ray diffraction). The FLP 10 undergoes 1,2-P/B addition to p-tolylacetylene and to 2-methylbutenyne, respectively, to yield the corresponding six-membered heterocyclic products 17 and 18, respectively (both were characterized by X-ray diffraction). PMID- 23340588 TI - Effect of pressure support vs unassisted breathing through a tracheostomy collar on weaning duration in patients requiring prolonged mechanical ventilation: a randomized trial. AB - IMPORTANCE: Patients requiring prolonged mechanical ventilation (>21 days) are commonly weaned at long-term acute care hospitals (LTACHs). The most effective method of weaning such patients has not been investigated. OBJECTIVE: To compare weaning duration with pressure support vs unassisted breathing through a tracheostomy collar in patients transferred to an LTACH for weaning from prolonged ventilation. DESIGN, SETTING, AND PARTICIPANTS: Between 2000 and 2010, a randomized study was conducted in tracheotomized patients transferred to a single LTACH for weaning from prolonged ventilation. Of 500 patients who underwent a 5-day screening procedure, 316 did not tolerate the procedure and were randomly assigned to receive weaning with pressure support (n = 155) or a tracheostomy collar (n = 161). Survival at 6- and 12-month time points was also determined. MAIN OUTCOME MEASURE: Primary outcome was weaning duration. Secondary outcome was survival at 6 and 12 months after enrollment. RESULTS: Of 316 patients, 4 were withdrawn and not included in analysis. Of 152 patients in the pressure-support group, 68 (44.7%) were weaned; 22 (14.5%) died. Of 160 patients in the tracheostomy collar group, 85 (53.1%) were weaned; 16 (10.0%) died. Median weaning time was shorter with tracheostomy collar use (15 days; interquartile range [IQR], 8-25) than with pressure support (19 days; IQR, 12-31), P = .004. The hazard ratio (HR) for successful weaning rate was higher with tracheostomy collar use than with pressure support (HR, 1.43; 95% CI, 1.03-1.98; P = .033) after adjusting for baseline clinical covariates. Use of the tracheostomy collar achieved faster weaning than did pressure support among patients who did not tolerate the screening procedure between 12 and 120 hours (HR, 3.33; 95% CI, 1.44 7.70; P = .005), whereas weaning time was equivalent with the 2 methods in patients who did not tolerate the screening procedure within 0 to 12 hours. Mortality was equivalent in the pressure-support and tracheostomy collar groups at 6 months (55.92% vs 51.25%; 4.67% difference, 95% CI, -6.4% to 15.7%) and at 12 months (66.45% vs 60.00%; 6.45% difference, 95% CI, -4.2% to 17.1%). CONCLUSION AND RELEVANCE: Among patients requiring prolonged mechanical ventilation and treated at a single long-term care facility, unassisted breathing through a tracheostomy, compared with pressure support, resulted in shorter median weaning time, although weaning mode had no effect on survival at 6 and 12 months. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01541462. PMID- 23340591 TI - Feature-based image patch approximation for lung tissue classification. AB - In this paper, we propose a new classification method for five categories of lung tissues in high-resolution computed tomography (HRCT) images, with feature-based image patch approximation. We design two new feature descriptors for higher feature descriptiveness, namely the rotation-invariant Gabor-local binary patterns (RGLBP) texture descriptor and multi-coordinate histogram of oriented gradients (MCHOG) gradient descriptor. Together with intensity features, each image patch is then labeled based on its feature approximation from reference image patches. And a new patch-adaptive sparse approximation (PASA) method is designed with the following main components: minimum discrepancy criteria for sparse-based classification, patch-specific adaptation for discriminative approximation, and feature-space weighting for distance computation. The patch wise labelings are then accumulated as probabilistic estimations for region-level classification. The proposed method is evaluated on a publicly available ILD database, showing encouraging performance improvements over the state-of-the arts. PMID- 23340590 TI - Quantitative analysis of cardiac tissue including fibroblasts using three dimensional confocal microscopy and image reconstruction: towards a basis for electrophysiological modeling. AB - Electrophysiological modeling of cardiac tissue is commonly based on functional and structural properties measured in experiments. Our knowledge of these properties is incomplete, in particular their remodeling in disease. Here, we introduce a methodology for quantitative tissue characterization based on fluorescent labeling, 3-D scanning confocal microscopy, image processing and reconstruction of tissue micro-structure at sub-micrometer resolution. We applied this methodology to normal rabbit ventricular tissue and tissue from hearts with myocardial infarction. Our analysis revealed that the volume fraction of fibroblasts increased from 4.83+/-0.42% (mean +/- standard deviation) in normal tissue up to 6.51+/-0.38% in myocardium from infarcted hearts. The myocyte volume fraction decreased from 76.20+/-9.89% in normal to 73.48+/-8.02% adjacent to the infarct. Numerical field calculations on 3-D reconstructions of the extracellular space yielded an extracellular longitudinal conductivity of 0.264+/-0.082 S/m with an anisotropy ratio of 2.095+/-1.11 in normal tissue. Adjacent to the infarct, the longitudinal conductivity increased up to 0.400+/-0.051 S/m, but the anisotropy ratio decreased to 1.295+/-0.09. Our study indicates an increased density of gap junctions proximal to both fibroblasts and myocytes in infarcted versus normal tissue, supporting previous hypotheses of electrical coupling of fibroblasts and myocytes in infarcted hearts. We suggest that the presented methodology provides an important contribution to modeling normal and diseased tissue. Applications of the methodology include the clinical characterization of disease-associated remodeling. PMID- 23340592 TI - A genome-wide pairwise-identity-based proposal for the classification of viruses in the genus Mastrevirus (family Geminiviridae). PMID- 23340593 TI - 124I PET/CT in the pretherapeutic staging of differentiated thyroid carcinoma: comparison with posttherapy 131I SPECT/CT. AB - PURPOSE: To compare pretherapy (124)I PET/CT and posttherapy (131)I SPECT/CT in the identification of pathological lesions and the staging of patients with differentiated thyroid carcinoma. METHODS: (124)I SPECT with low-dose CT in addition to a standard whole-body scan was performed 5 days following (131)I therapy with the administration of 1,110-7,728 MBq. Pretherapy (124)I PET/CT was done 24 h and 96 h after oral ingestion of 20-28 MBq, including a noncontrast high-dose CT scan. Scans were evaluated by two independent experienced nuclear physicians. In addition to the total number of lesions found, patient-based analyses and lesion-based analyses were performed to ascertain the discrepancies between the findings of the two scanning techniques, as well as to evaluate the clinical impact of the findings. RESULTS: A group of 20 consecutive patients were analysed. In the lesion-based analysis, a total of 62 foci were found with all modalities together. Of these, (124)I PET/CT found 57 (92 %), (131)I SPECT/CT 50 (81 %) and planar imaging 39 (63 %). In the patient-based analysis, in 50 % of patients complete concordance between the findings of (124)I PET and (131)I SPECT was seen, in 5 % complete discordance and in the remaining 45 % partial discordance, i.e. a focus or some foci seen with both modalities but another or others seen more or less with one or other modality. In 5 of the 20 patients (25 %), tumour stage was changed according to the findings of one of the modalities. In 60 % of these patients this was only with the findings of (124)I PET/CT. CONCLUSION: This study showed that (124)I PET/CT is preferred over (131)I imaging for staging differentiated thyroid carcinoma. PMID- 23340594 TI - Temporal analysis of intratumoral metabolic heterogeneity characterized by textural features in cervical cancer. AB - PURPOSE: The aim of this pilot study was to explore heterogeneity in the temporal behavior of intratumoral [(18)F]fluorodeoxyglucose (FDG) accumulation at a regional scale in patients with cervical cancer undergoing chemoradiotherapy. METHODS: Included in the study were 20 patients with FIGO stages IB1 to IVA cervical cancer treated with combined chemoradiotherapy. Patients underwent FDG PET/CT before treatment, during weeks 2 and 4 of treatment, and 12 weeks after completion of therapy. Patients were classified based on response to therapy as showing a complete metabolic response (CMR), a partial metabolic response (PMR), or residual disease and the development of new disease (NEW). Based on the presence of residual primary tumor following therapy, patients were divided into two groups, CMR and PMR/NEW. Temporal profiles of intratumoral FDG heterogeneity as characterized by textural features at a regional scale were assessed and compared with those of the standardized uptake value (SUV) indices (SUVmax and SUVmean) within the context of differentiating response groups. RESULTS: Textural features at a regional scale with emphasis on characterizing contiguous regions of high uptake in tumors decreased significantly with time (P < 0.001) in the CMR group, while features describing contiguous regions of low uptake along with those measuring the nonuniformity of contiguous isointense regions in tumors exhibited significant temporal changes in the PMR/NEW group (P < 0.03) but showed no persistent trends with time. Both SUV indices showed significant changes during the course of the disease in both patient groups (P < 0.001 for SUVmax and SUVmean in the CMR group; P = 0.0109 and 0.0136, respectively, for SUVmax and SUVmean in the PMR/NEW group), and also decreased at a constant rate in the CMR group and decreased up to the 4th week of treatment and then increased in the PMR/NEW group. CONCLUSION: The temporal changes in the heterogeneity of intratumoral FDG distribution characterized at a regional scale using image-based textural features may provide an adjunctive or alternative option for understanding tumor response to chemoradiotherapy and interpreting FDG accumulation dynamics in patients with malignant cervical tumors during the course of the disease. PMID- 23340596 TI - A mild method for generation of o-quinone methides under basic conditions. The facile synthesis of trans-2,3-dihydrobenzofurans. AB - A novel and efficient method for the generation of o-quinone methide intermediates was developed from the readily available 2-tosylalkylphenols under the mild basic conditions, and their reactions with sulfur ylides were investigated for the stereoselective synthesis of trans-2,3-dihydrobenzofurans. PMID- 23340595 TI - Clinical value of 11C-methionine PET/CT in patients with plasma cell malignancy: comparison with 18F-FDG PET/CT. AB - PURPOSE: PET/CT using FDG has been widely used for the imaging of various malignant tumours, including plasma cell malignancy (PCM), but (11)C-methionine (MET), as a radiolabelled amino acid tracer, may also be useful because PCM is able to activate protein synthesis. The purpose of this study was to evaluate the clinical value of PET/CT imaging using MET in PCM, including multiple myeloma, compared with that of FDG PET/CT. METHODS: The study group comprised 20 patients with histologically proven PCM who underwent FDG PET/CT and MET PET/CT scans before (n = 6) or after (n = 14) treatment. Semiquantitative analysis was performed on a lesion basis. We also visually evaluated the scans qualitatively using a five-point scale (0, negative; 1, probably negative; 2, equivocal; 3, probably positive; 4, positive) on a lesion and a patient basis. The results were compared between the two scans. RESULTS: Active PCM was confirmed in 15 patients, including two patients with extramedullary lesions. Uptake of MET tended to be higher (maximum standardized uptake value 10.3 +/- 5.6, mean +/- SD) than that of FDG (3.4 +/- 2.7, p < 0.001), and more lesions of grade 3 or 4 were depicted by MET (MET 156 lesions vs. FDG 58 lesions). On a patient basis, two patients were accurately diagnosed only by MET. In the remaining 18 patients, consistent results were obtained, but potential upgrade of staging or restaging was necessary in 6 of 11 positive patients because more abnormal lesions were demonstrated by MET. The patient-based sensitivity, specificity and accuracy of MET for restaging were 89 %, 100 % and 93 %, respectively, while those of FDG were 78 %, 100 % and 86 %, respectively. CONCLUSION: MET revealed an equal or greater number of lesions in PCM than FDG. MET may be especially useful when negative or inconclusive findings are obtained by FDG despite highly suspicious indications of recurrence. PMID- 23340597 TI - Hollow 0.3Li2MnO3.0.7LiNi(0.5)Mn(0.5)O2 microspheres as a high-performance cathode material for lithium-ion batteries. AB - Hollow 0.3Li(2)MnO(3).0.7LiNi(0.5)Mn(0.5)O(2) microspheres are synthesized on a large scale through a simple in situ template-sacrificial route. Starting from porous MnO(2) microspheres, the hollow microspheres assembled with 0.3Li(2)MnO(3).0.7LiNi(0.5)Mn(0.5)O(2) nanocrystals are formed by a nanoscale Kirkendall effect. The nanocrystal-assembled hollow 0.3Li(2)MnO(3).0.7LiNi(0.5)Mn(0.5)O(2) microspheres exhibit a highly reversible capacity as high as 295 mAh g(-1) over 100 cycles and excellent rate capability (125 mAh g(-1) at 1000 mA g(-1)). Benefitting from a unique hollow and nanocrystalline architecture, the as-formed hollow microspheres show much enhanced high-temperature (55 degrees C) electrochemical performances, compared with the products obtained by conventional sol-gel/solid-state reaction methods. This work demonstrates that a fabrication strategy based on the present in situ template-sacrificial approach offers a new method for the design of high performance cathode materials with hollow interiors for Li-ion battery applications. PMID- 23340598 TI - Platinum complexes of cationic ligands for the aerobic oxidation of "inert" perfluoro-substituted alcohols. AB - Trifluoroethanol was oxidized with O(2) to trifluoroethyl trifluoracetate (>98% selectivity) using Pt(II)(dppz)Cl(2) as a catalyst in the presence of H(2)SO(4); Pt(II)(phen)Cl(2) was inactive. Kinetic isotope effects suggest the C-H bond activation as the rate determining step and DFT calculations showed different frontier orbitals for Pt(II)(dppz) and Pt(II)(phen)-based catalysts. PMID- 23340599 TI - Building synthetic gene circuits from combinatorial libraries: screening and selection strategies. AB - The promise of wide-ranging biotechnology applications inspires synthetic biologists to design novel genetic circuits. However, building such circuits rationally is still not straightforward and often involves painstaking trial-and error. Mimicking the process of natural selection can help us to bridge the gap between our incomplete understanding of nature's design rules and our desire to build functional networks. By adopting the powerful method of directed evolution, which is usually applied to protein engineering, functional networks can be obtained through screening or selecting from randomised combinatorial libraries. This review first highlights the practical options to introduce combinatorial diversity into gene circuits and then examines strategies for identifying the potentially rare library members with desired functions, either by screening or selection. PMID- 23340600 TI - Sex-specific clines support incipient speciation in a common European mammal. AB - Hybrid zones provide excellent opportunities to study processes and mechanisms underlying reproductive isolation and speciation. Here we investigated sex specific clines of molecular markers in hybrid zones of morphologically cryptic yet genetically highly-diverged evolutionary lineages of the European common vole (Microtus arvalis). We analyzed the position and width of four secondary contact zones along three independent transects in the region of the Alps using maternally (mitochondrial DNA) and paternally (Y-chromosome) inherited genetic markers. Given male-biased dispersal in the common vole, a selectively neutral secondary contact would show broader paternal marker clines than maternal ones. In a selective case, for example, involving a form of Haldane's rule, Y chromosomal clines would not be expected to be broader than maternal markers because they are transmitted by the heterogametic sex and thus gene flow would be restricted. Consistent with the selective case, paternal clines were significantly narrower or at most equal in width to maternal clines in all contact zones. In addition, analyses using maximum likelihood cline-fitting detected a shift of paternal relative to maternal clines in three of four contact zones. These patterns suggest that processes at the contact zones in the common vole are not selectively neutral, and that partial reproductive isolation is already established between these evolutionary lineages. We conclude that hybrid zone movement, sexual selection and/or genetic incompatibilities are likely associated with an unusual unidirectional manifestation of Haldane's rule in this common European mammal. PMID- 23340601 TI - Asymmetric direct alpha-alkylation of 2-oxindoles with Michler's hydrol catalyzed by bis-cinchona alkaloid-Bronsted acid via an SN1-type pathway. AB - An enantioselective direct alpha-alkylation of 2-oxindoles with Michler's hydrol via an S(N)1-type pathway in the non-covalent activation mode using the bis cinchona alkaloid and Bronsted acid as a co-catalyst was developed and good to high yields and enantioselectivities were obtained. PMID- 23340602 TI - Understanding urban green space as a health resource: a qualitative comparison of visit motivation and derived effects among park users in Sheffield, UK. AB - With increasing interest in the use of urban green space to promote human health, there is a need to understand the extent to which park users conceptualize these places as a resource for health and well-being. This study sought to examine park users' own reasons for and benefits from green space usage and compare these with concepts and constructs in existing person-environment-health theories and models of health. Conducted in 13 public green spaces in Sheffield, UK, we undertook a qualitative content analysis of 312 park users' responses to open-ended interview questions and identified a breadth, depth and salience of visit motivators and derived effects. Findings highlight a discrepancy between reasons for visiting and derived effects from the use of urban green space. Motivations emphasized walking, green space qualities, and children. Derived effects highlighted relaxation, positive emotions within the self and towards the place, and spiritual well-being. We generate a taxonomy of motivations and derived effects that could facilitate operationalization within empirical research and articulate a conceptual framework linking motivators to outcomes for investigating green space as a resource for human health and well-being. PMID- 23340603 TI - Pain: microglia take control in chronic pain. PMID- 23340604 TI - Learning and memory: knockout blow for 'memory molecule'. PMID- 23340605 TI - Cationic arene ruthenium(II) complexes with chelating P-functionalized alkyl phenyl sulfide and sulfoxide ligands as potent anticancer agents. AB - The synthesis and characterization of cationic ruthenium(II) complexes of the type [Ru(eta(6)-p-cym)Cl{Ph(2)P(CH(2))(n)S(O)(x)Ph-kappaP,kappaS}][PF(6)] (n = 1 3; x = 0, 1; p-cym = p-cymene) are presented. Furthermore, their high biological potential even against cisplatin-resistant tumor cell lines and their structure activity relationships are discussed. PMID- 23340607 TI - Urea-functionalized crystalline capsules for recognition and separation of tetrahedral oxoanions. AB - The persistent ability of tripodal TREN-based tris-urea receptors (TREN = tris(2 aminoethyl)amine) to self-assemble with a variety of oxoanions into dimeric capsules upon crystallization is reviewed. The capsule crystallization allows for charge-, shape-, and size-selective encapsulation of tetrahedral XO(4)(n-) anions (n = 2,3), and provides an effective way to separate these anions from competitive aqueous environments. PMID- 23340606 TI - Attenuation of oxidative damage-associated cognitive decline by Withania somnifera in rat model of streptozotocin-induced cognitive impairment. AB - Oxidative stress is a critical contributing factor to age-related neurodegenerative disorders. Therefore, the inhibition of oxidative damage, responsible for chronic detrimental neurodegeneration, is an important strategy for neuroprotective therapy. Withania somnifera (WS) extract has been reported to have potent antioxidant and free radical quenching properties in various disease conditions. The present study evaluated the hypothesis that WS extract would reduce oxidative stress-associated neurodegeneration after intracerebroventricular injection of streptozotocin (ICV-STZ) in rats. To test this hypothesis, male Wistar rats were pretreated with WS extract at doses of 100, 200, and 300 mg/kg body weight once daily for 3 weeks. On day 22nd, the rats were infused bilaterally with ICV-STZ injection (3 mg/kg body weight) in normal saline while sham group received only saline. Two weeks after the lesioning, STZ infused rats showed cognitive impairment in the Morris water maze test. The rats were sacrificed after 3 weeks of the lesioning for the estimation of the contents of lipid peroxidation, reduced glutathione, and activities of glutathione reductase, glutathione peroxidase, and catalase. Pretreatment with WS extract attenuated behavioral, biochemical, and histological alterations significantly in dose-dependent manner in the hippocampus and cerebral cortex of ICV-STZ-infused rats. These results suggest that WS affords a beneficial effect on cognitive deficit by ameliorating oxidative damage induced by streptozotocin in a model of cognitive impairment. PMID- 23340608 TI - Imaging state of charge and its correlation to interaction variation in an LiMn(0.75)Fe(0.25)PO(4) nanorods-graphene hybrid. AB - Visualization of the state of charge (SOC) in an LiMn(0.75)Fe(0.25)PO(4) nanorods graphene hybrid nanostructure (LMFP-C) is realized by chemical mapping of the Fe valance state using scanning transmission X-ray microscopy (STXM). The LMFP graphene interaction strength variation studied by C K-edge STXM has been correlated to SOC variation, i.e. a stronger interaction was observed for sample regions with a higher SOC in LMFP. Such structure-performance correlation opens new perspectives for a rational design of a better performance olivine cathode for lithium ion batteries. PMID- 23340610 TI - Stable iron isotope tracing reveals significant brain iron uptake in adult rats. AB - Iron deposits in the brain are a common hallmark of Alzheimer's disease and Parkinson's disease. This has spurred the hypothesis that iron may play a functional role in the pathogenesis of neurodegenerative disorders through free radical damage. Previous short-term studies using radiotracers suggested that brain iron uptake is small as compared to other tissues in adult rodents. This has led to the assumption that brain iron uptake must also be marginal in humans after brain development is complete. In this study we applied a novel approach to determine directly the fraction of iron that was transferred over time from diet to brain and other organs in adult rats. A known amount of a stable iron isotope ((57)Fe) was fed with drinking water to adult rats over 4 months. Uptake of the tracer iron and final iron content in tissues were assessed by Negative Thermal Ionization Mass Spectrometry (NTI-MS). We found that only a very small amount of dietary iron entered the brain (0.000537 +/- 0.000076%). This amount, however, is considerable relative to the total brain iron content (9.19 +/- 0.71%), which was lower but comparable to percentage uptake in other tissues. Whereas it remains unclear whether excessive dietary iron intake is a risk factor in neurodegenerative diseases or whether high systemic iron correlates with iron deposits in the brain, our study suggests that uptake of dietary iron is much higher than previously thought. This finding challenges current beliefs and points to a possible role of iron nutrition in the pathogenesis of neurodegenerative disorders. PMID- 23340614 TI - Medical America seen with foreign eyes. PMID- 23340615 TI - Emergency department imaging concerns raised for academic medical centers. PMID- 23340616 TI - Researchers seek new ways to counter the harmful toll of stress on the brain. PMID- 23340623 TI - Blood culture collection for suspected bacteremia. PMID- 23340624 TI - Blood culture collection for suspected bacteremia--reply. PMID- 23340625 TI - Measures of adiposity and fat distribution and risk of diabetes. PMID- 23340626 TI - Measures of adiposity and fat distribution and risk of diabetes--reply. PMID- 23340627 TI - Attending physicians on ward rounds. PMID- 23340628 TI - Attending physicians on ward rounds--reply. PMID- 23340629 TI - Characteristics of hospitals receiving penalties under the Hospital Readmissions Reduction Program. PMID- 23340632 TI - Thirty-day readmissions: the clock is ticking. PMID- 23340633 TI - Time to get serious about pay for performance. PMID- 23340634 TI - Tension between quality measurement, public quality reporting, and pay for performance. PMID- 23340635 TI - Recasting readmissions by placing the hospital role in community context. PMID- 23340636 TI - A piece of my mind. Hating hope. PMID- 23340637 TI - Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. AB - IMPORTANCE: To better guide strategies intended to reduce high rates of 30-day readmission after hospitalization for heart failure (HF), acute myocardial infarction (MI), or pneumonia, further information is needed about readmission diagnoses, readmission timing, and the relationship of both to patient age, sex, and race. OBJECTIVE: To examine readmission diagnoses and timing among Medicare beneficiaries readmitted within 30 days after hospitalization for HF, acute MI, or pneumonia. DESIGN, SETTING, AND PATIENTS: We analyzed 2007-2009 Medicare fee for-service claims data to identify patterns of 30-day readmission by patient demographic characteristics and time after hospitalization for HF, acute MI, or pneumonia. Readmission diagnoses were categorized using an aggregated version of the Centers for Medicare & Medicaid Services' Condition Categories. Readmission timing was determined by day after discharge. MAIN OUTCOME MEASURES: We examined the percentage of 30-day readmissions occurring on each day (0-30) after discharge; the most common readmission diagnoses occurring during cumulative periods (days 0-3, 0-7, 0-15, and 0-30) and consecutive periods (days 0-3, 4-7, 8 15, and 16-30) after hospitalization; median time to readmission for common readmission diagnoses; and the relationship between patient demographic characteristics and readmission diagnoses and timing. RESULTS: From 2007 through 2009, we identified 329,308 30-day readmissions after 1,330,157 HF hospitalizations (24.8% readmitted), 108,992 30-day readmissions after 548,834 acute MI hospitalizations (19.9% readmitted), and 214,239 30-day readmissions after 1,168,624 pneumonia hospitalizations (18.3% readmitted). The proportion of patients readmitted for the same condition was 35.2% after the index HF hospitalization, 10.0% after the index acute MI hospitalization, and 22.4% after the index pneumonia hospitalization. Of all readmissions within 30 days of hospitalization, the majority occurred within 15 days of hospitalization: 61.0%, HF cohort; 67.6%, acute MI cohort; and 62.6%, pneumonia cohort. The diverse spectrum of readmission diagnoses was largely similar in both cumulative and consecutive periods after discharge. Median time to 30-day readmission was 12 days for patients initially hospitalized for HF, 10 days for patients initially hospitalized for acute MI, and 12 days for patients initially hospitalized for pneumonia and was comparable across common readmission diagnoses. Neither readmission diagnoses nor timing substantively varied by age, sex, or race. CONCLUSION AND RELEVANCE: Among Medicare fee-for-service beneficiaries hospitalized for HF, acute MI, or pneumonia, 30-day readmissions were frequent throughout the month after hospitalization and resulted from a similar spectrum of readmission diagnoses regardless of age, sex, race, or time after discharge. PMID- 23340638 TI - Use of hospital-based acute care among patients recently discharged from the hospital. AB - IMPORTANCE: Current efforts to improve health care focus on hospital readmission rates as a marker of quality and on the effectiveness of transitions in care during the period after acute care is received. Emergency department (ED) visits are also a marker of hospital-based acute care following discharge but little is known about ED use during this period. OBJECTIVES: To determine the degree to which ED visits and hospital readmissions contribute to overall use of acute care services within 30 days of discharge from acute care hospitals, to describe the reasons patients return for ED visits, and to describe these patterns among Medicare beneficiaries and those not covered by Medicare insurance. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of patients aged 18 years or older (mean age: 53.4 years) who were discharged between July 1, 2008, and September 31, 2009, from acute care hospitals in 3 large, geographically diverse states (California, Florida, and Nebraska) with data recorded in the Healthcare Cost and Utilization Project state inpatient and ED databases. MAIN OUTCOME MEASURES: The 3 primary outcomes during the 30-day period after hospital discharge were ED visits not resulting in admission (treat-and-release encounters), hospital readmissions from any source, and a combined measure of ED visits and hospital readmissions termed hospital-based acute care. RESULTS: The final cohort included 5,032,254 index hospitalizations among 4,028,555 unique patients. In the 30 days following discharge, 17.9% (95% CI, 17.9%-18.0%) of hospitalizations resulted in at least 1 acute care encounter. Of these 1,233,402 postdischarge acute care encounters, ED visits comprised 39.8% (95% CI, 39.7%-39.9%). For every 1000 discharges, there were 97.5 (95% CI, 97.2-97.8) ED treat-and-release visits and 147.6 (95% CI, 147.3-147.9) hospital readmissions in the 30 days following discharge. The number of ED treat-and-release visits ranged from a low of 22.4 (95% CI, 4.6-65.4) encounters per 1000 discharges for breast malignancy to a high of 282.5 (95% CI, 209.7-372.4) encounters per 1000 discharges for uncomplicated benign prostatic hypertrophy. Among the highest volume discharges, the most common reason patients returned to the ED was always related to their index hospitalization. CONCLUSIONS AND RELEVANCE: After discharge from acute care hospitals in 3 states, ED visits within 30 days were common among adults and accounted for 39.8% of postdischarge hospital-based acute care visits. Improving care transitions should focus not only on decreasing readmissions but also on ED visits. PMID- 23340639 TI - Pediatric readmission prevalence and variability across hospitals. AB - IMPORTANCE: Readmission rates are used as an indicator of the quality of care that patients receive during a hospital admission and after discharge. OBJECTIVE: To determine the prevalence of pediatric readmissions and the magnitude of variation in pediatric readmission rates across hospitals. DESIGN, SETTING, AND PATIENTS: We analyzed 568,845 admissions at 72 children's hospitals between July 1, 2009, and June 30, 2010, in the National Association of Children's Hospitals and Related Institutions Case Mix Comparative data set. We estimated hierarchical regression models for 30-day readmission rates by hospital, accounting for age and Chronic Condition Indicators. Hospitals with adjusted readmission rates that were 1 SD above and below the mean were defined as having "high" and "low" rates, respectively. MAIN OUTCOME MEASURES: Thirty-day unplanned readmissions following admission for any diagnosis and for the 10 admission diagnoses with the highest readmission prevalence. Planned readmissions were identified with procedure codes from the International Classification of Diseases, Ninth Revision, Clinical Modification. RESULTS: The 30-day unadjusted readmission rate for all hospitalized children was 6.5% (n = 36,734). Adjusted rates were 28.6% greater in hospitals with high vs low readmission rates (7.2% [95% CI, 7.1%-7.2%] vs 5.6% [95% CI, 5.6%-5.6%]). For the 10 admission diagnoses with the highest readmission prevalence, the adjusted rates were 17.0% to 66.0% greater in hospitals with high vs low readmission rates. For example, sickle cell rates were 20.1% (95% CI, 20.0%-20.3%) vs 12.7% (95% CI, 12.6%-12.8%) in high vs low hospitals, respectively. CONCLUSIONS AND RELEVANCE: Among patients admitted to acute care pediatric hospitals, the rate of unplanned readmissions at 30 days was 6.5%. There was significant variability in readmission rates across conditions and hospitals. These data may be useful for hospitals' quality improvement efforts. PMID- 23340641 TI - Hypopigmented patches on the skin. PMID- 23340642 TI - A requirement to reduce readmissions: take care of the patient, not just the disease. PMID- 23340643 TI - Pediatric readmissions as a hospital quality measure. PMID- 23340640 TI - Association between quality improvement for care transitions in communities and rehospitalizations among Medicare beneficiaries. AB - IMPORTANCE: Medicare beneficiaries experience errors during transitions among care settings, yielding harms that include unnecessary rehospitalizations. OBJECTIVE: To evaluate whether implementation of improved care transitions for patients with Medicare fee-for-service (FFS) insurance is associated with reduced rehospitalizations and hospitalizations in geographic communities. DESIGN, SETTING, AND PARTICIPANTS: Quality improvement initiative for care transitions by health care and social services personnel and Medicare Quality Improvement Organization staff in defined geographic areas, with monitoring by community specific and aggregate control charts and evaluation with pre-post comparison of performance differences for 14 intervention communities and 50 comparison communities from before (2006-2008) and during (2009-2010) implementation. Intervention communities had between 22,070 and 90,843 Medicare FFS beneficiaries. INTERVENTION: Quality Improvement Organizations facilitated community-wide quality improvement activities to implement evidence-based improvements in care transitions by community organizing, technical assistance, and monitoring of participation, implementation, effectiveness, and adverse effects. MAIN OUTCOME MEASURES: The primary outcome measure was all-cause 30-day rehospitalizations per 1000 Medicare FFS beneficiaries; secondary outcome measures were all-cause hospitalizations per 1000 Medicare FFS beneficiaries and all-cause 30-day rehospitalizations as a percentage of hospital discharges. RESULTS: The mean rate of 30-day all-cause rehospitalizations per 1000 beneficiaries per quarter was 15.21 in 2006-2008 and 14.34 in 2009-2010 in the 14 intervention communities and was 15.03 in 2006-2008 and 14.72 in 2009-2010 in the 50 comparison communities, with the pre-post between-group difference showing larger reductions in rehospitalizations in intervention communities (by 0.56/1000 per quarter; 95% CI, 0.05-1.07; P = .03). The mean rate of hospitalizations per 1000 beneficiaries per quarter was 82.27 in 2006-2008 and 77.54 in 2009-2010 in intervention communities and was 82.09 in 2006-2008 and 79.48 in 2009-2010 in comparison communities, with the pre-post between-group difference showing larger reductions in hospitalizations in intervention communities (by 2.12/1000 per quarter; 95% CI, 0.47-3.77; P = .01). Mean community-wide rates of rehospitalizations as a percentage of hospital discharges in the intervention communities were 18.97% in 2006-2008 and 18.91% in 2009-2010 and were 18.76% in 2006-2008 and 18.91% in 2009-2010 in the comparison communities, with no significant difference in the pre-post between-group differences (0.22%; 95% CI, 0.08% to 0.51%; P = .14). Process control charts signaled onset of improvement coincident with initiating intervention. CONCLUSIONS AND RELEVANCE: Among Medicare beneficiaries in intervention communities, compared with those in uninvolved communities, all-cause 30-day rehospitalization and all-cause hospitalization declined. However, there was no change in the rate of all-cause 30-day rehospitalizations as a percentage of hospital discharges. PMID- 23340644 TI - Revisiting hospital readmissions. PMID- 23340645 TI - JAMA patient page. Discharge planning. PMID- 23340646 TI - A rationally designed dual role anode material for lithium-ion and sodium-ion batteries: case study of eco-friendly Fe3O4. AB - Identifying dual role electrode materials capable of storing both lithium and sodium are thought to be highly relevant, as these materials could find potential applications simultaneously in lithium and sodium ion batteries. In this regard, the concept of dual alkali storage is demonstrated in Fe(3)O(4) anode material undergoing conversion reaction. To enable improved storage, a rational active material and electrode design is proposed. Accordingly, the following features were simultaneously incorporated into the design: (i) an optimal particle size, (ii) a conducting matrix, (iii) adequately large active material surface area and (iv) strong electrode material-current collector integrity. Electrodes incorporating this rational design exhibit excellent high rate performance and impressive cyclability during lithium storage. For instance, Fe(3)O(4) electrodes deliver a charge capacity of 950 mAh g(-1) at 1.2 C (~2.6 times higher than graphite and 5.4 times higher than Li(4)Ti(5)O(12)). Further, these electrodes show no signs of capacity fade even up to 1100 cycles. Impressively, the cells could also be charged-discharged to 65% of their theoretical capacity in just 5 min or 12 C (11.11 A g(-1)). The rate performance and cyclability of lithium storage achieved here are amongst the highest reported values in the literature for the conversion reaction in Fe(3)O(4). Besides lithium storage, the dual role of this anode is shown by demonstrating its sodium storage ability by conversion reaction for the first time. PMID- 23340647 TI - A paramagnetic microspheres based automation-friendly rapid chemiluminescent immunoassay method for sensitive detection of chicken interferon-gamma. AB - We describe an automation-friendly chemiluminescent immunoassay method for sensitive and rapid determination of chicken interferon-gamma at the sub-picogram per millilitre level based on the monoclonal antibody immobilized paramagnetic microspheres and flow-through system. PMID- 23340648 TI - Blood microRNAs in low or no risk ischemic stroke patients. AB - Ischemic stroke is a multi-factorial disease where some patients present themselves with little or no risk factors. Blood microRNA expression profiles are becoming useful in the diagnosis and prognosis of human diseases. We therefore investigated the blood microRNA profiles in young stroke patients who presented with minimal or absence of risk factors for stroke such as type 2 diabetes, dyslipidemia and hypertension. Blood microRNA profiles from these patients varied with stroke subtypes as well as different functional outcomes (based on modified Rankin Score). These microRNAs have been shown to target genes that are involved in stroke pathogenesis. The findings from our study suggest that molecular mechanisms in stroke pathogenesis involving low or no risk ischemic stroke patients could differ substantially from those with pre-existing risk factors. PMID- 23340649 TI - Pre-Treatment of platinum resistant ovarian cancer cells with an MMP-9/MMP-2 inhibitor prior to cisplatin enhances cytotoxicity as determined by high content screening. AB - Platinum resistance is a major cause of treatment failure in ovarian cancer. We previously identified matrix metalloproteinase 9 (MMP-9) as a potential therapeutic target of chemoresistant disease. A2780cis (cisplatin-resistant) and A2780 (cisplatin-sensitive) ovarian carcinoma cell lines were used. The cytotoxic effect of MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) alone or in combination with cisplatin was determined using high content screening. Protein expression was examined using immunohistochemistry and ELISA. Co-incubation of cisplatin and an MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) resulted in significantly greater cytotoxicity as compared to either treatment alone in a cisplatin resistant MMP-9 overexpressing cell line; A2780cis. In addition, pre-incubating with MMP-9i prior to cisplatin further enhances the cytotoxic effect. No significant difference was observed in MMP-9 protein in tissue but a trend towards increased MMP-9 was observed in recurrent serum. We propose that MMP-9/MMP-2i may be utilized in the treatment of recurrent/chemoresistant ovarian cancers that overexpress MMP-9 mRNA but its role in vivo remains to be evaluated. PMID- 23340650 TI - Metabolic profiles of brain metastases. AB - Metastasis to the brain is a feared complication of systemic cancer, associated with significant morbidity and poor prognosis. A better understanding of the tumor metabolism might help us meet the challenges in controlling brain metastases. The study aims to characterize the metabolic profile of brain metastases of different origin using high resolution magic angle spinning (HR MAS) magnetic resonance spectroscopy (MRS) to correlate the metabolic profiles to clinical and pathological information. Biopsy samples of human brain metastases (n = 49) were investigated. A significant correlation between lipid signals and necrosis in brain metastases was observed (p < 0.01), irrespective of their primary origin. The principal component analysis (PCA) showed that brain metastases from malignant melanomas cluster together, while lung carcinomas were metabolically heterogeneous and overlap with other subtypes. Metastatic melanomas have higher amounts of glycerophosphocholine than other brain metastases. A significant correlation between microscopically visible lipid droplets estimated by Nile Red staining and MR visible lipid signals was observed in metastatic lung carcinomas (p = 0.01), indicating that the proton MR visible lipid signals arise from cytoplasmic lipid droplets. MRS-based metabolomic profiling is a useful tool for exploring the metabolic profiles of metastatic brain tumors. PMID- 23340651 TI - Low oxygen tension maintains multipotency, whereas normoxia increases differentiation of mouse bone marrow stromal cells. AB - Optimization of mesenchymal stem cells (MSC) culture conditions is of great importance for their more successful application in regenerative medicine. O(2) regulates various aspects of cellular biology and, in vivo, MSC are exposed to different O(2) concentrations spanning from very low tension in the bone marrow niche, to higher amounts in wounds. In our present work, we isolated mouse bone marrow stromal cells (BMSC) and showed that they contained a population meeting requirements for MSC definition. In order to establish the effect of low O(2) on cellular properties, we examined BSMC cultured under hypoxic (3% O(2)) conditions. Our results demonstrate that 3% O(2) augmented proliferation of BMSC, as well as the formation of colonies in the colony-forming unit assay (CFU-A), the percentage of quiescent cells, and the expression of stemness markers Rex-1 and Oct-4, thereby suggesting an increase in the stemness of culture when exposed to hypoxia. In contrast, intrinsic differentiation processes were inhibited by 3% O(2). Overall yield of differentiation was dependent on the adjustment of O(2) tension to the specific stage of BMSC culture. Thus, we established a strategy for efficient BMSC in vitro differentiation using an initial phase of cell propagation at 3% O(2), followed by differentiation stage at 21% O(2). We also demonstrated that 3% O(2) affected BMSC differentiation in p53 and reactive oxygen species (ROS) independent pathways. Our findings can significantly contribute to the obtaining of high-quality MSC for effective cell therapy. PMID- 23340653 TI - Induction of heat shock protein 70 ameliorates ultraviolet-induced photokeratitis in mice. AB - Acute ultraviolet (UV) B exposure causes photokeratitis and induces apoptosis in corneal cells. Geranylgeranylacetone (GGA) is an acyclic polyisoprenoid that induces expression of heat shock protein (HSP)70, a soluble intracellular chaperone protein expressed in various tissues, protecting cells against stress conditions. We examined whether induction of HSP70 has therapeutic effects on UV photokeratitis in mice. C57 BL/6 mice were divided into four groups, GGA-treated (500 mg/kg/mouse) and UVB-exposed (400 mJ/cm2), GGA-untreated UVB-exposed (400 mJ/cm2), GGA-treated (500 mg/kg/mouse) but not exposed and naive controls. Eyeballs were collected 24 h after irradiation, and corneas were stained with hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). HSP70, reactive oxygen species (ROS) production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and protein kinase B (Akt) expression were also evaluated. Irradiated corneal epithelium was significantly thicker in the eyes of mice treated with GGA compared with those given the vehicle alone (p < 0.01). Significantly fewer TUNEL-positive cells were observed in the eyes of GGA-treated mice than controls after irradiation (p < 0.01). Corneal HSP70 levels were significantly elevated in corneas of mice treated with GGA (p < 0.05). ROS signal was not affected by GGA. NF-kappaB activation was reduced but phospho-(Ser/Ther) Akt substrate expression was increased in corneas after irradiation when treated with GGA. GGA-treatment induced HSP70 expression and ameliorated UV-induced corneal damage through the reduced NF-kappaB activation and possibly increased Akt phosphorilation. PMID- 23340652 TI - Innovative therapeutic strategies in the treatment of brain metastases. AB - Brain metastases (BM) are the most common intracranial tumors and their incidence is increasing. Untreated brain metastases are associated with a poor prognosis and a poor performance status. Metastasis development involves the migration of a cancer cell from the bulk tumor into the surrounding tissue, extravasation from the blood into tissue elsewhere in the body, and formation of a secondary tumor. In the recent past, important results have been obtained in the management of patients affected by BM, using surgery, radiation therapy, or both. Conventional chemotherapies have generally produced disappointing results, possibly due to their limited ability to penetrate the blood-brain barrier. The advent of new technologies has led to the discovery of novel molecules and pathways that have better depicted the metastatic process. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review, we will report current data on targeted therapies. A brief review about brain metastatic process will be also presented. PMID- 23340654 TI - Effect of repetitive lysine-tryptophan motifs on the eukaryotic membrane. AB - In a previous study, we synthesized a series of peptides containing simple sequence repeats, (KW)(n)-NH(2) (n = 2,3,4 and 5) and determined their antimicrobial and hemolytic activities, as well as their mechanism of antimicrobial action. However, (KW)(5) showed undesirable cytotoxicity against RBC cells. In order to identify the mechanisms behind the hemolytic and cytotoxic activities of (KW)(5), we measured the ability of these peptides to induce aggregation of liposomes. In addition, their binding and permeation activities were assessed by Trp fluorescence, calcein leakage and circular dichrorism using artificial phospholipids that mimic eukaryotic liposomes, including phosphatidylcholine (PC), PC/sphingomyelin (SM) (2:1, w/w) and PC/cholesterol (CH) (2:1, w/w). Experiments confirmed that only (KW)(5) induced aggregation of all liposomes; it formed much larger aggregates with PC:CH (2:1, w/w) than with PC or PC:SM (2:1, w/w). Longer peptide (KW)(5), but not (KW)(3) or (KW)(4), strongly bound and partially inserted into PC:CH compared to PC or PC:SM (2:1, w/w). Calcein release experiments showed that (KW)(5) induced calcein leakage from the eukaryotic membrane. Greater calcein leakage was induced by (KW)(5) from PC:CH than from PC:SM (2:1, w/w) or PC, whereas (KW)(4) did not induce calcein leakage from any of the liposomes. Circular dichroism measurements indicated that (KW)(5) showed higher conformational transition compared to (KW)(4) due to peptide-liposome interactions. Taken together, our results suggest that (KW)(5) reasonably mediates the aggregation and permeabilization of eukaryotic membranes, which could in turn explain why (KW)(5) displays efficient hemolytic activity. PMID- 23340655 TI - Adhesion-induced phase behavior of two-component membranes and vesicles. AB - The interplay of adhesion and phase separation is studied theoretically for two component membranes that can phase separate into two fluid phases such as liquid ordered and liquid-disordered phases. Many adhesion geometries provide two different environments for these membranes and then partition the membranes into two segments that differ in their composition. Examples are provided by adhering vesicles, by hole- or pore-spanning membranes, and by membranes supported by chemically patterned surfaces. Generalizing a lattice model for binary mixtures to these adhesion geometries, we show that the phase behavior of the adhering membranes depends, apart from composition and temperature, on two additional parameters, the area fraction of one membrane segment and the affinity contrast between the two segments. For the generic case of non-vanishing affinity contrast, the adhering membranes undergo two distinct phase transitions and the phase diagrams in the composition/temperature plane have a generic topology that consists of two two-phase coexistence regions separated by an intermediate one phase region. As a consequence, phase separation and domain formation is predicted to occur separately in each of the two membrane segments but not in both segments simultaneously. Furthermore, adhesion is also predicted to suppress the phase separation process for certain regions of the phase diagrams. These generic features of the adhesion-induced phase behavior are accessible to experiment. PMID- 23340656 TI - Heart rate-mediated blood pressure control in preterm fetal sheep under normal and hypoxic-ischemic conditions. AB - BACKGROUND: The understanding of hypoxemia-induced changes in baroreflex function is limited and may be studied in a fetal sheep experiment before, during, and after standardized hypoxic conditions. METHODS: Preterm fetal lambs were instrumented at 102 d gestation (term: 146 d). At 106 d, intrauterine hypoxia- ischemia was induced by 25 min of umbilical cord occlusion (UCO). Baroreflex related fluctuations were calculated at 30-min intervals during the first week after UCO by transfer function (cross-spectral) analysis between systolic blood pressure (SBP) and R-R interval fluctuations, estimated in the low-frequency (LF, 0.04-0.15 Hz) band. LF transfer gain (baroreflex sensitivity) and delay (s) reflect the baroreflex function. RESULTS: Baseline did not differ in LF transfer gain and delay between controls and the UCO group. In controls, LF gain showed postnatal increase. By contrast, LF gain gradually decreased in the UCO group, resulting in significantly lower values 4-7 d after UCO. In the UCO group, LF delay increased and differed significantly from controls. CONCLUSION: Our results show that intrauterine hypoxia-ischemia results in reduced baroreflex sensitivity over a period of 7 d, indicating limited efficacy to buffer BP changes by adapting heart rate. Cardiovascular dysregulation may augment already present cerebral damage after systemic hypoxia-ischemia in the reperfusion period. PMID- 23340657 TI - Lanthanide-corrole conjugates. AB - Ditopic corroles with lanthanide-binding motifs were prepared and shown to be dual-range emitters, in the visible and near-IR, in ambient conditions. PMID- 23340658 TI - Stereoselective access to heteroarylmethylene-substituted pyrrolidines: fully organocatalytic Mannich-hydroamination reactions. AB - A one-pot sequence of organocatalytic transformations delivers heteroarylmethylene-substituted pyrrolidines with high stereo- and enantioselectivity. A Mannich coupling of N-heteroarylalkyne aldehydes with aldimine and an original metal-free hydroamination of the resulting adducts are the key transformations of the process delivering highly functionalized molecules with high potential for synthetic applications. PMID- 23340659 TI - Quinacrine reactivity with prion proteins and prion-derived peptides. AB - Quinacrine is a drug that is known to heal neuronal cell culture infected with prions, which are the causative agents of neurodegenerative diseases called transmissible spongiform encephalopathies. However, the drug fails when it is applied in vivo. In this work, we analyzed the reason for this failure. The drug was suggested to "covalently" modify the prion protein via an acridinyl exchange reaction. To investigate this hypothesis more closely, the acridine moiety of quinacrine was covalently attached to the thiol groups of cysteines belonging to prion-derived peptides and to the full-length prion protein. The labeled compounds were conveniently monitored by fluorescence and absorption spectroscopy in the ultraviolet and visible spectral regions. The acridine moiety demonstrated characteristic UV-vis spectrum, depending on the substituent at the C-9 position of the acridine ring. These results confirm that quinacrine almost exclusively reacts with the thiol groups present in proteins and peptides. The chemical reaction alters the prion properties and increases the concentration of the acridine moiety in the prion protein. PMID- 23340660 TI - Isolation and synthesis of falcitidin, a novel myxobacterial-derived acyltetrapeptide with activity against the malaria target falcipain-2. AB - A 384-well microtitre plate fluorescence cleavage assay was developed to identify inhibitors of the cysteine protease falcipain-2, an important antimalarial drug target. Bioassay-guided isolation of a MeOH extract from a myxobacterium Chitinophaga sp. Y23 isolated from soil collected in Singapore, led to the identification of a new acyltetrapeptide, falcitidin (1), which displayed an IC50 value of 6 MUM against falcipain-2. The planar structure of 1 was secured by NMR and MS/MS analysis. Attempts to isolate further material for biological testing were hampered by inconsistent production and by a low yield (<100 MUg l(-1)). The absolute configuration of 1 was determined by Marfey's analysis and the structure was confirmed through total synthesis as isovaleric acid-D-His-L-Ile-L-Val-L-Pro NH2. Falcitidin (1) is the first member of a new class of falcipain-2 inhibitors and, unlike other peptide-based inhibitors, does not contain reactive groups that irreversibly bind to active cysteine sites. PMID- 23340661 TI - New structural scaffold 14-membered macrocyclic lactone ring for selective inhibitors of cell wall peptidoglycan biosynthesis in Staphylococcus aureus. PMID- 23340662 TI - Two new antitumor constituents from a soil fungus Curvularia inaequalis (strain HS-FG-257). PMID- 23340663 TI - PJS, a novel isocoumarin with hexahydropyrimidine ring from Bacillus subtilis PJS. PMID- 23340664 TI - Epothilone O, a new member of this family from Sorangium cellulosum strain So0157 2. PMID- 23340665 TI - Streptomyces hundungensis sp. nov., a novel actinomycete with antifungal activity and plant growth promoting traits. AB - A novel actinobacterium MBRL 251(T), isolated from a sample collected from a limestone quarry at Hundung, Manipur, India, was characterized using a polyphasic approach. The 16S ribosomal RNA gene sequence of strain MBRL 251(T) showed closest similarities with Streptomyces xanthochromogenes NRRL B-5410(T) (99.6%) and Streptomyces michiganensis NBRC 12797(T) (99.6%). The DNA relatedness between MBRL 251(T) and S. xanthochromogenes NBRC 12828(T), and S. michiganensis NBRC 12797(T) was 46.6% and 40.7%, respectively. Strain MBRL 251(T) contained LL diaminopimelic acid as the diagnostic diamino acid, with glucose and xylose as the main cell wall sugars, whereas small amounts of galactose, mannose, rhamnose and ribose were also detected in the whole-cell wall hydrolysates. The major fatty acids identified were anteiso-C15:0 (35.1%), iso-C16:0 (21.1%) and anteiso C17:1 (13.2%). The predominant menaquinones detected were MK-9(H6) and MK-9(H8), whereas the polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositolmannosides. The G+C content of the genomic DNA was 72.3%. The phenotypic and genotypic data showed that strain MBRL 251(T) merits the recognition as a representative of a novel species of the genus Streptomyces. It is proposed that the isolate should be classified in the genus Streptomyces as a novel species, Streptomyces hundungensis sp. nov. The type strain is MBRL 251(T) (=JCM 17577(T)=KCTC 29124(T)). PMID- 23340666 TI - Magnetic-field-induced deposition to fabricate multifunctional nanostructured Co, Ni, and CoNi alloy films as catalysts, ferromagnetic and superhydrophobic materials. AB - A novel and facile magnetic-field-induced deposition process was put forward to fabricate nanostructured Co, Ni and CoNi alloy films supported on Cu foil, which are multifunctional nanomaterials with wide applications in different areas due to their ferromagnetic and superhydrophobic properties, as well as their excellent catalytic performance. PMID- 23340667 TI - Testosterone modulation of dendritic spines of somatosensory cortical pyramidal neurons. AB - Brain structures and functions are increasingly recognized to be directly affected by gonadal hormones, which classically determine reproductive functions and sexual phenotypes. In this regard, we found recently that ovariectomy trimmed the dendritic spines of female rat primary somatosensory cortical neurons and estradiol supplement reversed it. Here, we investigated whether in the male androgen also has a cortical modulatory effect. The dendritic arbors and spines of rat somatosensory cortical pyramidal neurons were studied following intracellular dye injection and three-dimensional reconstruction. Dendritic spines, but not length, of the layers III and V pyramidal neurons were found reduced at 2 weeks and rebounded slightly at 4 weeks and further at 8 and 24 weeks following castration, which, however, remained significantly fewer than those of the intact animals. Two weeks of osmotic pump-delivered testosterone treatment to animals castrated for 4 weeks replenished serum testosterone and reversed the densities of dendritic spines on these neurons to control animal levels. Androgen receptor appears to mediate this effect as its antagonist flutamide reduced the dendritic spines of normal adult rats while causing a mild feedback surge of serum testosterone. On the other hand, blocking the conversion of testosterone to estrogen with the aromatase inhibitor anastrozole failed to alter the dendritic spine densities in male adult rats. In conclusion, these results support our hypothesis that testosterone acts directly on the androgen receptor in males to modulate the dendritic spines of somatosensory cortical output neurons. PMID- 23340668 TI - Fundamental optical processes in armchair carbon nanotubes. AB - Single-wall carbon nanotubes provide ideal model one-dimensional (1-D) condensed matter systems in which to address fundamental questions in many-body physics, while, at the same time, they are leading candidates for building blocks in nanoscale optoelectronic circuits. Much attention has been recently paid to their optical properties, arising from 1-D excitons and phonons, which have been revealed via photoluminescence, Raman scattering, and ultrafast optical spectroscopy of semiconducting carbon nanotubes. On the other hand, dynamical properties of metallic nanotubes have been poorly explored, although they are expected to provide a novel setting for the study of electron-hole pairs in the presence of degenerate 1-D electrons. In particular, (n,n)-chirality, or armchair, metallic nanotubes are truly gapless with massless carriers, ideally suited for dynamical studies of Tomonaga-Luttinger liquids. Unfortunately, progress towards such studies has been slowed by the inherent problem of nanotube synthesis whereby both semiconducting and metallic nanotubes are produced. Here, we use post-synthesis separation methods based on density gradient ultracentrifugation and DNA-based ion-exchange chromatography to produce aqueous suspensions strongly enriched in armchair nanotubes. Through resonant Raman spectroscopy of the radial breathing mode phonons, we provide macroscopic and unambiguous evidence that density gradient ultracentrifugation can enrich ensemble samples in armchair nanotubes. Furthermore, using conventional, optical absorption spectroscopy in the near-infrared and visible range, we show that interband absorption in armchair nanotubes is strongly excitonic. Lastly, by examining the G-band mode in Raman spectra, we determine that observation of the broad, lower frequency (G(-)) feature is a result of resonance with non-armchair "metallic" nanotubes. These findings regarding the fundamental optical absorption and scattering processes in metallic carbon nanotubes lay the foundation for further spectroscopic studies to probe many-body physical phenomena in one dimension. PMID- 23340669 TI - Imaging the static dielectric constant in vitro and in living cells by a bioconjugable GFP chromophore analog. AB - A fluorescent probe structurally similar to the GFP chromophore is demonstrated to report the local static dielectric constant. This probe can be chemically functionalized for selective targeting at the intracellular level. PMID- 23340670 TI - NMR crystallography of alpha-poly(L-lactide). AB - A complementary approach that combines NMR measurements, analysis of X-ray and neutron powder diffraction data and advanced quantum mechanical calculations was employed to study the alpha-polymorph of L-polylactide. Such a strategy, which is known as NMR crystallography, to the best of our knowledge, is used here for the first time for the fine refinement of the crystal structure of a synthetic polymer. The GIPAW method was used to compute the NMR shielding parameters for the different models, which included the alpha-PLLA structure obtained by 2 dimensional wide-angle X-ray diffraction (WAXD) at -150 degrees C (model M1) and at 25 degrees C (model M2), neutron diffraction (WAND) measurements (model M3) and the fully optimized geometry of the PLLA chains in the unit cell with defined size (model M4). The influence of changes in the chain conformation on the (13)C sigma(ii) NMR shielding parameters is shown. The correlation between the sigma(ii) and delta(ii) values for the M1-M4 models revealed that the M4 model provided the best fit. Moreover, a comparison of the experimental (13)C NMR spectra with the spectra calculated using the M1-M4 models strongly supports the data for the M4 model. The GIPAW method, via verification using NMR measurements, was shown to be capable of the fine refinement of the crystal structures of polymers when coarse X-ray diffraction data for powdered samples are available. PMID- 23340672 TI - Effect of radiation on the Notch signaling pathway in osteoblasts. AB - Notch signaling has been shown to be important in osteoblast differentiation. Therapeutic radiation has been shown to alter the skeletal system, yet little information is available on the changes in Notch signaling in irradiated osteoblasts. The purpose of this study was to analyze the effect of radiation therapy with 2 and 4 Gy on Notch signaling in osteoblasts. In order to assess the radiation damage on osteoblast differentiation, total RNA and protein were collected three days after exposure to radiation. The effects of radiation on Notch signaling at the early and terminal stages of osteoblastic MC3T3-E1 cell differentiation was analyzed by qRT-PCR and western blot analysis. Our study applied a previously established method to induce MC3T3-E1 cell differentiation into osteoblasts and osteoblast precursors. Our results showed that the expression of Notch receptors (Notch1-4), ligands (Jagged1, Jagged2 and Delta1), target of Notch signaling (Hes1) and markers (ALP, M-CSF, RANKL and OPG) were altered following 2 and 4 Gy of irradiation. The present research did not indicate a strong relationship between Notch1 regulation and suppression of osteoblast differentiation. We found Hes1 may play a role in the radiation effect on osteoblast differentiation. Our results indicate that radiated osteoblast precursors and osteoblasts promoted osteoclast differentiation and proliferation. PMID- 23340673 TI - Vascularised greater trochanter bone graft, combined free iliac flap and impaction bone grafting for osteonecrosis of the femoral head. AB - PURPOSE: To investigate the curative efficacy of osteonecrosis of the femoral head (ONFH) in a hip-preserving operative approach, by grafting a vascularized greater trochanter flap combined with a free iliac flap, in an attempt to seek an innovative approach for patients who suffered middle to late stage ONFH without total hip arthroplasty (THA) surgery. METHOD: Our research included a total of 60 patients (66 hips) who accepted hip-preserving surgery by grafting a vascularized greater trochanter flap combined with a free iliac flap which was tightly filled by hammering because of ONFH (most were Association Research Circulation Osseous (ARCO) stage III patients) from January, 2006 to December, 2010. A Harris Hip Score was obtained during follow-ups, evaluating the clinical efficacy, X-rays were taken regularly for image assessing, and the SF-36 scale was used for estimating quality of life. Terminal observation time was considered when patients had symptom-dependant indications for performing another hip-preserving surgery or THA surgery. RESULTS: Fifty-eight patients (64 hips) were eventually contacted by telephone for an out-patient clinic return visit, with a mean follow up time of 35.8 months (varied from 12 months to 60 months), but two patients lost contact for various reasons. The demographic data were as follows: there were 16 ARCO IIIA cases, 22 ARCO IIIB cases, and 26 ARCO IIIC cases, respectively. Postoperative X-rays revealed a well-repaired necrotic area of the femoral head and improvement of femoral-acetabulum coverage. The last follow-up mean Harris Hip Score was 86.56 +/- 7.38 (excellent results reached 87.50%), which were greatly improved compared to 50.95 +/- 6.86 pre-operatively. Also the postoperative mean scores of all dimensions of the SF-36 scale were improved to some extent. Additionally the physical component summary (PSC) scores were enhanced from 42 +/- 13 pre-operatively to 78 +/- 11, while the postoperative mental component summary (MCS) scores (76 +/- 11) largely increased in contrast to pre-operative scores (51 +/- 10), with both target indices having statistical significance (p = 0.005, p = 0.01), signifying hugely improvement of the quality of life of the patients. A correlation was found between Harris Hip Score and all dimensions of SF-36 scale (r = 0.32-0.72), especially closely correlated with physical functioning (PF), role-physical (RP) and bodily pain (BP) in PCS aspect (r = 0.72, p < 0.01; r = 0.58, p < 0.01; r = 0.65, p < 0.01, respectively). CONCLUSION: There is definite curative efficacy for the treatment of ONFH with an hip-preserving operative approach by grafting a vascularized greater trochanter flap combined with a free iliac flap which was tightly filled by hammering. This kind of operative approach reconstructs the biological stability of femoral head, which promotes repair of necrotic areas and indirectly preserves the femoral head of patients and a majority of hip function. It possesses vast clinical as well as practical significance, because the long-term efficacy can satisfy fundamental life requirements, especially for those young and middle-aged patients who suffer ONFH to avoid or put off the time of total hip arthroplasty (THA) surgery. PMID- 23340674 TI - The natural history of asymptomatic osteonecrosis of the femoral head. AB - PURPOSE: To observe the natural history of asymptomatic osteonecrosis of the femoral head, and to analyse the associations between the subsequent development of symptoms, epidemiological risk factors and the character of the lesions. METHODS: Sixty-eight patients were diagnosed with asymptomatic osteonecrosis of the femoral head. The patients were classified based on the development of symptoms. Relations were sought between symptom development and epidemiological risk factors, and the size and location of the necrotic lesions. RESULTS: Thirty eight patients developed symptoms (55.9%) at a mean 2.27 years after diagnosis. Symptoms developed in 18 of 28 patients with alcohol-related necrosis (64.3%), in eight of 14 patients with steroid-related necrosis (57.1%), and in 12 of 26 patients with idiopathic necrosis (46.2%). None of the following: gender, age, body mass index (BMI), smoking status, or cholesterol level, was found to be significantly associated with the development of symtoms in asymptomatic osteonecrosis of femoral head (ONFH). Duration and amount of exposure to steroid were not significantly associated with symptom development. In the groups of heavy alcohol drinkers, large necrotic lesions and laterally located lesions showed a higher prevalence of symptom development. CONCLUSION: Symptoms developed in 55.9% of asymptomatic osteonecrosis of the femoral head. Prevalence of symptom development was significantly higher in heavy alcohol drinkers and large-sized lateral lesions. PMID- 23340675 TI - Comment on Xu et al.: A retrospective study of posterior malleolus fractures. PMID- 23340676 TI - Comparative proteomic analysis reveals proteins putatively involved in toxin biosynthesis in the marine dinoflagellate Alexandrium catenella. AB - Alexandrium is a neurotoxin-producing dinoflagellate genus resulting in paralytic shellfish poisonings around the world. However, little is known about the toxin biosynthesis mechanism in Alexandrium. This study compared protein profiles of A. catenella collected at different toxin biosynthesis stages (non-toxin synthesis, initial toxin synthesis and toxin synthesizing) coupled with the cell cycle, and identified differentially expressed proteins using 2-DE and MALDI-TOF TOF mass spectrometry. The results showed that toxin biosynthesis of A. catenella occurred within a defined time frame in the G1 phase of the cell cycle. Proteomic analysis indicated that 102 protein spots altered significantly in abundance (P < 0.05), and 53 proteins were identified using database searching. These proteins were involved in a variety of biological processes, i.e., protein modification and biosynthesis, metabolism, cell division, oxidative stress, transport, signal transduction, and translation. Among them, nine proteins with known functions in paralytic shellfish toxin-producing cyanobacteria, i.e., methionine S adenosyltransferase, chloroplast ferredoxin-NADP+ reductase, S adenosylhomocysteinase, adenosylhomocysteinase, ornithine carbamoyltransferase, inorganic pyrophosphatase, sulfotransferase (similar to), alcohol dehydrogenase and arginine deiminase, varied significantly at different toxin biosynthesis stages and formed an interaction network, indicating that they might be involved in toxin biosynthesis in A. catenella. This study is the first step in the dissection of the behavior of the A. catenella proteome during different toxin biosynthesis stages and provides new insights into toxin biosynthesis in dinoflagellates. PMID- 23340678 TI - Cyclodextrin-based multivalent glycodisplays: covalent and supramolecular conjugates to assess carbohydrate-protein interactions. AB - Covalent attachment of biorecognizable sugar ligands in several copies at precise positions of cyclomaltooligosaccharide (cyclodextrin, CD) macrocycles has proven to be an extremely flexible strategy to build multivalent conjugates. The commercial availability of the native CDs in three different sizes, their axial symmetry and the possibility of position- and face-selective functionalization allow a strict control of the valency and spatial orientation of the recognition motifs (glycotopes) in low, medium, high and hyperbranched glycoclusters, including glycodendrimer-CD hybrids. "Click-type" ligation chemistries, including copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC), thiol-ene coupling or thiourea-forming reactions, have been implemented to warrant full homogeneity of the adducts. The incorporation of different glycotopes to investigate multivalent interactions in heterogeneous environments has also been accomplished. Not surprisingly, multivalent CD conjugates have been, and continue to be, major actors in studies directed at deciphering the structural features ruling carbohydrate recognition events. Nanometric glycoassemblies endowed with the capability of adapting the inter-saccharide distances and orientations in the presence of a receptor partner or capable of mimicking the fluidity of biological membranes have been conceived by multitopic inclusion complex formation, rotaxanation or self-assembling. Applications in the fields of sensors, site specific drug and gene delivery or protein stabilization attest for the maturity of the field. PMID- 23340677 TI - Glutamate metabolism is impaired in transgenic mice with tau hyperphosphorylation. AB - In neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia, the protein tau is hyperphosphorylated and eventually aggregates to develop neurofibrillary tangles. Here, the consequences of tau hyperphosphorylation on both neuronal and astrocytic metabolism and amino-acid neurotransmitter homeostasis were assessed in transgenic mice expressing the pathogenic mutation P301L in the human tau gene (pR5 mice) compared with nontransgenic littermate controls. Mice were injected with the neuronal and astrocytic substrate [1-(13)C]glucose and the astrocytic substrate [1,2 (13)C]acetate. Hippocampus and cerebral cortex extracts were analyzed using (1)H and (13)C nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry and high-performance liquid chromatography. The glutamate level was reduced in the hippocampus of pR5 mice, accompanied by reduced incorporation of (13)C label derived from [1-(13)C]glucose in glutamate. In the cerebral cortex, glucose utilization as well as turnover of glutamate, glutamine, and GABA, were increased. This was accompanied by a relative increase in production of glutamate via the pyruvate carboxylation pathway in cortex. Overall, we revealed that astrocytes as well as glutamatergic and GABAergic neurons in the cortex of pR5 mice were in a hypermetabolic state, whereas in the hippocampus, where expression levels of mutant human tau are the highest, glutamate homeostasis was impaired. PMID- 23340680 TI - Inflammatory bowel disease in Chinese children: a multicenter analysis over a decade from Shanghai. AB - BACKGROUND: The purpose was to estimate the incidence and characteristics of childhood inflammatory bowel disease (IBD) during 2000-2010 in Shanghai, China. METHODS: IBD patients between the ages of 0 and 18 years old were identified by survey of computerized medical information. Relevant data were extracted from their corresponding medical records. RESULTS: A total of 153 IBD cases were included in the study. Among them, 107 were males and 46 were females (male/female ratio, 2.3:1.0). Eighty-two had Crohn's disease (CD) and 71 had ulcerative colitis (UC). The peak prevalence of IBD was observed in the 10-14 year-old age group. The annual incidence of IBD in the 0 to 14 years age group of Shanghai residents steadily increased from 2000 to 2010. The most common symptoms of IBD were diarrhea (68.6%), bloody stool (68.6%), and abdominal pain (61.4%). More CD than UC patients had anemia and raised erythrocyte sedimentation rate and C-reactive protein levels. Ileocolonic type disease was more common in CD patients, and left-side colon involvement was more common in UC. Of all CD patients, 33 had mild active disease and 49 had moderate/severe disease. In UC patients, 34 were mild and 37 were moderate/severe disease. CONCLUSIONS: This retrospective, multicenter hospital-based study over a decade shows a steadily increasing trend of childhood IBD in China. This suggests a need for population based epidemiological studies to explore the risk factors. PMID- 23340679 TI - Adenomas in patients with inflammatory bowel disease are associated with an increased risk of advanced neoplasia. AB - BACKGROUND: It is still unclear whether inflammatory bowel disease (IBD) patients with adenomas have a higher risk of developing high-grade dysplasia (HGD) or colorectal cancer (CRC) than non-IBD patients with sporadic adenomas. We compared the risk of advanced neoplasia (AN, defined as HGD or CRC) in IBD patients with adenomas to IBD patients without adenomas and patients without IBD with adenomas. METHODS: IBD patients with a histological adenoma diagnosis (IBD + adenoma), age matched IBD patients without adenoma (IBD-nonadenoma), and adenoma patients without IBD (nonIBD + adenoma) were enrolled in this study. Medical charts were reviewed for adenoma characteristics and development of AN. The endoscopic appearance of the adenomas was characterized as typical (solitary sessile or pedunculated) or atypical (all other descriptions). RESULTS: A total of 110 IBD + adenoma patients, 123 IBD-nonadenoma patients, and 179 nonIBD + adenoma patients were included. Mean duration of follow-up was 88 months (SD +/-41). The 5-year cumulative risks of AN were 11%, 3%, and 5% in IBD + adenoma, IBD-nonadenoma, and nonIBD + adenoma patients, respectively (P < 0.01). In IBD patients atypical adenomas were associated with a higher 5-year cumulative risk of AN compared to IBD patients with typical adenomas (18% vs. 7%, P = 0.03). CONCLUSIONS: IBD patients with a histological diagnosis of adenoma have a higher risk of developing AN than adenoma patients without IBD and IBD patients without adenomas. The presence of atypical adenomas in particular was associated with this increased risk, although patients with typical adenomas were found to carry an additional risk as well. PMID- 23340681 TI - Professional conferences enrich and energise. PMID- 23340682 TI - Synthesis of mono-amidinate-ligated rare-earth-metal bis(silylamide) complexes and their reactivity with [Ph3C][B(C6F5)4], AlMe3 and isoprene. AB - Amine elimination of rare-earth-metal tris(silylamide) complexes Ln[N(SiHMe(2))(2)](3)(THF)(x) (Ln = Sc, x = 1; Ln = Y, x = 2) with 1 equiv. of the amidines [PhC(N-2,6-R(2)C(6)H(3))(2)]H afforded a series of neutral mono(amidinate) rare-earth-metal bis(silylamide) complexes [PhC(N-2,6 R(2)C(6)H(3))(2)]Ln[N(SiHMe(2))(2)](2)(THF)(y) (R = Me, Ln = Sc, y = 0 (1); R = Me, Ln = Y, y = 1 (2); R = (i)Pr, Ln = Y, y = 1 (3)). Treatment of 1-3 with 1 equiv. of [Ph(3)C][B(C(6)F(5))(4)] in THF generated the corresponding cationic amidinate rare-earth-metal mono(silylamide) complexes [{PhC(N-2,6 R(2)C(6)H(3))(2)}Ln{N(SiHMe(2))(2)}(THF)(3)][B(C(6)F(5))(4)] (R = Me, Ln = Sc (4), Y (5); R = (i)Pr, Ln = Y (6)). When 1-3 were first activated with 1 equiv. of [Ph(3)C][B(C(6)F(5))(4)] in toluene, then treatment with THF gave the unexpected cationic amidinate rare-earth-metal amide complexes [{PhC(N-2,6 R(2)C(6)H(3))(2)}LnN{SiHMe(2)}{SiMe(2)N(SiHMe(2))(2)}(THF)(n)][B(C(6)F(5))(4)] (R = Me, Ln = Sc, n = 2 (7); R = Me, Ln = Y, n = 4 (8); R = (i)Pr, Ln = Y, n = 2 (9)). The reaction of 1-3 with excess AlMe(3) produced the heterometallic Ln/Al methyl complexes [PhC(N-2,6-R(2)C(6)H(3))(2)]Ln[(MU-Me)(2)AlMe(2)](2) (R = Me, Ln = Sc (10), Y (11); R = (i)Pr, Ln = Y (12)). All these complexes were well characterized by elemental analysis, NMR spectroscopy and FT-IR spectroscopy. 2, 6 and 11 were further structurally authenticated by X-ray crystallography. The binary catalyst system of 1/[Ph(3)C][B(C(6)F(5))(4)] in toluene showed activity toward 3,4-selective polymerization of isoprene, whilst the tertiary catalyst systems of 1-3/[Ph(3)C][B(C(6)F(5))(4)]/AlMe(3) were highly active for cis-1,4 selective polymerization of isoprene. PMID- 23340683 TI - [Indications and technique of fetal magnetic resonance imaging]. AB - CLINICAL/METHODICAL ISSUE: Evaluation and confirmation of fetal pathologies previously suspected or diagnosed with ultrasound. STANDARD RADIOLOGICAL METHODS: Ultrasound and magnetic resonance imaging (MRI). METHODICAL INNOVATIONS: Technique for prenatal fetal examination. PERFORMANCE: Fetal MRI is an established supplementary technique to prenatal ultrasound. ACHIEVEMENTS: Fetal MRI should only be used as an additional method in prenatal diagnostics and not for routine screening. PRACTICAL RECOMMENDATIONS: Fetal MRI should only be performed in perinatal medicine centers after a previous level III ultrasound examination. PMID- 23340684 TI - [Contrast agents in radiology: current agents approved, recommendations, and safety aspects]. AB - The manuscript summarizes current approved contrast media and their indications. Contrast agents that are discussed include iodinated contrast agents, magnetic resonance (MR) contrast agents, and ultrasound contrast agents. Allergic and non allergic renal adverse events are described. The clinical issue of metformin and the administration of contrast agents are updated. Nephrogenic systemic fibrosis (NSF) is discussed and safety issues of available MR contrast agents are analyzed. The most recent changes in European Society of Urogenital Radiology (ESUR) guidelines are also presented. PMID- 23340685 TI - [Complex space-occupying lesion of the lesser pelvis]. PMID- 23340686 TI - [Integrating the healthcare enterprise (IHE) for radiology: status 2013]. AB - The term integrating the healthcare enterprise (IHE) has been known for more than 10 years and provides an innovative approach to ensure interoperability based on a synthesis of different standards for defined scenarios. Acceptance and deployment are, however limited in Germany compared with other countries. In this article the basic principles and the potential of IHE are described. PMID- 23340687 TI - [Lumbosacral junction disorders - and it hurts!]. PMID- 23340688 TI - Hydrothermal synthesis of thiol-capped CdTe nanoparticles and their optical properties. AB - Water soluble nanoparticles (NPs) with a high emission property were synthesized via hydrothermal routes. In this report, we chose thiol ligand N-acetyl-L cysteine as the ideal stabilizer and have successfully employed it to synthesize readily size-controllable CdTe NPs in a reaction of only one step. Hydrothermal synthesis of CdTe NPs has been carried out in neutral or basic conditions so far. We found out that the pH value of precursor solutions plays an important role in the uniformity of the particle size. Actually, high quality CdTe NPs were synthesized under mild acidic conditions of pH 5. The resultant NPs indicated good visible light-emitting properties and stability. Further, the experimental results showed that the reaction temperature influenced significantly the growth rate and the maximum size of the NPs. The CdTe NPs with a high photoluminescence quantum yield (the highest value: 57%) and narrower half width at half maximum (the narrowest value: 33 nm) were attained in very short time, within 40 minutes, reaching diameters of 2.3 to 4.3 nm. The PL intensity was increased with an increase in the reaction time, reflecting the suppression of nonradiative recombination processes. Furthermore, the formation of CdTe/CdS core-shell structures was discussed from the viewpoint of PL dynamics and X-ray diffraction studies. PMID- 23340689 TI - Photoelectron imaging of small aluminum clusters: quantifying s-p hybridization. AB - Photoelectron imaging experiments and detailed calculations are conducted on Al(n)(-) clusters (n = 3-6) and a calibration method is developed for connecting experimental observations of photoelectron angular distributions to theoretical predictions. It is shown that this method can be used to quantify the degree to which the molecular orbitals are built from s- or p-like atomic orbitals. The highest occupied molecular orbitals of these small aluminum clusters are found to contain varying degrees of s-p mixing, with Al(3)(-) containing the "most hybridized" orbital and Al(4)(-) containing the "least hybridized" orbital. It is shown experimentally that s-p hybridization is already present for the trimer species and, similar to other properties of small metal clusters, oscillates with cluster size. PMID- 23340691 TI - Iodine-catalyzed tandem synthesis of terminal acetals and glycol mono esters from olefins. AB - A new metal-free protocol is described for the synthesis of terminal acetals by tandem oxidative rearrangement of olefins using oxone as an oxidant in the presence of iodine. Moreover, a one-pot procedure for the preparation of glycol mono esters from olefins is also presented for the first time using the same reagent system. PMID- 23340690 TI - Interactions of disulfide-constrained cyclic tetrapeptides with Cu(2+). AB - The purpose of this work is to characterize the interactions of two disulfide constrained cyclic tetrapeptides [c(Ac-Cys-Pro-Phe-Cys-NH(2)), SS1; c(Ac-Cys-Pro Gly-Cys-NH(2)), SS2] with Cu(2+) ions in order to facilitate the design of cyclic peptides as sensors for metal ions. The Cu(2+)-peptide complex cations at m/z 569.1315 for Cu(2+)-SS1 and m/z 479.0815 for Cu(2+)-SS2 were detected by mass spectrometry. The gas-phase fragmentation of the Cu(2+)-peptide complexes was studied by collision-induced dissociation and suggests the atoms involved in the coordination. Cu(2+) ion binds to a single SS1 or SS2 with K (d(app)) of 0.57 +/- 0.02 and 0.55 +/- 0.01 MUM, respectively. Isothermal titration calorimetry data indicate both enthalpic and entropic contributions for the binding of Cu(2+) ion to SS1 and SS2. The characteristic wavenumber of 947 cm(-1) and the changes at 1,664 and 1,530 cm(-1) in the infrared spectrum suggest that the sulfydryl of cysteine, the carbonyl group, and amide II are involved in the coordination of Cu(2+). The X-ray absorption near-edge structure signal from the Cu(2+)-peptide complex corresponds to the four-coordination structure. The extended X-ray absorption fine structure and electron paramagnetic resonance results demonstrate the Cu(2+) ion is in an S/N/2O coordination environment, and is a distinct type II copper center. Theoretical calculations further demonstrate that Cu(2+) ion binds to SS1 or SS2 in a slightly distorted tetragonal geometry with an S/N/2O environment and the minimum potential energy. PMID- 23340692 TI - Interactions between fluorescence of atomically layered graphene oxide and metallic nanoparticles. AB - Graphene oxide (GO) demonstrates interesting photoluminescence (PL) because of its unique heterogeneous atomic structure, which consists of variable sp(2)- and sp(3)-bonded carbons. In this study, we report the interaction between the luminescence of GO ranging from a single atomic layer to few-layered thin films and localized surface plasmon resonance (LSPR) from silver nanoparticles (Ag NPs). The photoluminescence of GO in the vicinity of the Ag NPs is enhanced significantly due to the near-field plasmonic effect by coupling electron-hole pairs of GO with oscillating electrons in Ag NPs, leading to an increased PL intensity and a decreased PL decay lifetime. The maxima 30-fold enhancement in PL intensity is obtained with an optimized film thickness of GO, and the luminescence image from a single atomic layer GO sheet is successfully observed with the assistance of the LSPR effect. The results provide an ideal platform for exploring the interactions between the fluorescence of two-dimensional layered materials and the LSPR effect. PMID- 23340693 TI - Hydrogen-rich saline attenuates vascular smooth muscle cell proliferation and neointimal hyperplasia by inhibiting reactive oxygen species production and inactivating the Ras-ERK1/2-MEK1/2 and Akt pathways. AB - Hydrogen-rich saline has been reported to prevent neointimal hyperplasia induced by carotid balloon injury. The purpose of the present study was to further investigate the molecular mechanisms underlying this phenomenon. Daily injection of a hydrogen-rich saline solution (HRSS) in rats was employed to study the effect of hydrogen on balloon injury-induced neointimal hyperplasia and the neointima/media ratio was assessed. HRSS significantly decreased the neointima area and neointima/media ratio in a dose-dependent manner. In vitro effects of hydrogen on fetal bovine serum (FBS)-induced vascular smooth muscle cell (VSMC) proliferation were also investigated. Hydrogen-rich medium (HRM) inhibited rat VSMC proliferation and migration induced by 10% FBS. FBS-induced reactive oxygen species (ROS) production and activation of intracellular Ras, MEK1/2, ERK1/2, proliferative cell nuclear antigen (PCNA), Akt were significantly inhibited by HRM. In addition, HRM blocked FBS-induced progression from the G0/G1 to the S phase and increased the apoptosis rate of VSMCs. These results showed that hydrogen-rich saline was able to attenuate FBS-induced VSMC proliferation and neointimal hyperplasia by inhibiting ROS production and inactivating the Ras ERK1/2-MEK1/2 and Akt pathways. Thus, HRSS may have potential therapeutic relevance for the prevention of human restenosis. PMID- 23340695 TI - Long-term survival after gastrectomy for cancer in randomized, controlled oncological trials: comparison between West and East. AB - BACKGROUND: The presence of mixed evidence about the value of lymphadenectomy in gastric cancer surgery coupled with the difference in patients' demographics and tumor stage between the West and East have doubted the needs to standardize surgical techniques in Western clinical practice. The purpose of this study was to compare survival rates between the West and East following gastrectomy in randomized, controlled, oncological trials with appropriate adjustment for confounding variables. METHODS: Systematic search revealed 25 trials that have randomization into surgery and chemotherapy versus surgery alone between 1995 and 2012 (n = 7 (East) and n = 18 (West)). End points were 5-year survival and cancer recurrence. RESULTS: There was association between gastrectomy performed in the East and improved 5-year survival (pooled odds ratio (OR) 4.83; 95 % confidence interval (CI) 3.27-7.12) and reduced cancer recurrence (pooled OR 0.33; 95 % CI 0.2-0.54). Association of improved 5-year survival with surgery in the East remained when meta-regression adjusted for the effect of age, sex, chemotherapy, tumor depth and nodal status, and gastrectomy type. Association of reduced cancer recurrence also persisted with meta-regression adjusting for age, chemotherapy, nodal status, and gastrectomy type. However, when adjustment for the percentage of patients with tumor depth T1 or 2 was made statistical significance was lost. CONCLUSIONS: This analysis shows association between gastrectomy performed in Eastern countries and improved survival. The known difference in surgical techniques between the East and the West is one potential unexamined variable that may be responsible in part for such discrepancy in outcomes. PMID- 23340696 TI - [Combination therapy of benign prostate syndrome/lower urinary tract symptoms]. AB - The pathophysiology of lower urinary tract symptoms (LUTS) is multifactorial. The fact that none of the available drugs impacts on more than one of these pathomechanisms, provides the rationale for combined medical treatment strategies. The combination of alpha-blocker and a 5-reductase inhibitor is recommended by all major benign prostate hyperplasia (BPH/LUTS) guidelines as a first line approach for men with moderate to severe LUTS and a higher risk for disease progression. The efficacy of this approach has been proven in prospective randomized trials for up to 4 years. The combination of alpha-blocker and antimuscarinics has been tested in several randomized trials as a primary approach or as add on therapy but the maximum study duration was only 3 months. The add on approach is suitable in particular for men with persisting storage symptoms under alpha-blockade. The risk for acute retention in appropriately selected men is low. The scientific basis for all other combinations is not solid enough to recommend the use outside clinical trials. PMID- 23340697 TI - Preliminary experience on treatment of infantile hemangioma with low-dose propranolol in China. AB - We aimed to assess the efficacy and safety of low-dose propranolol for treatment of infantile hemangiomas (IHs) in China. Our prospective study included data from 89 patients with IH, aged 1-12 months. Plasma renin activity, angiotensin II, and aldosterone were measured before initiation of propranolol therapy. Patients were administered propranolol (0.75-1 mg/kg/day) under close observation. The volume, texture, and color of lesions were used to evaluate efficacy. Safety endpoints included heart rate, systolic and diastolic blood pressures, alanine transaminase, aspartate transaminase, thyroid function tests, and fasting blood glucose. Adverse effects were recorded. Mean plasma angiotensin II concentration in patients with IH was higher than that in age-matched healthy children, whereas mean plasma renin activity was lower. Mean aldosterone level was higher at 1-3 months but lower at 4-12 months, than values reported previously. After propranolol therapy for 6 months, IH regression was classed as grade IV in 44 patients (49.4 %), grade III in 21 patients (23.6 %), and grade II in 24 patients (27.0 %); none were grade I. Mild adverse effects, including diarrhea, restless sleep, nausea, cold extremities, and hypoglycemia, occurred in 12 patients (13.5 %). Slight decreases in heart rate and blood pressure occurred in all patients (p < 0.05). The IHs of four patients (4.5 %) relapsed after treatment cessation at 4 5 months. CONCLUSION: Low-dose propranolol is effective and safe for Chinese children with IH, and larger-scale studies are merited. Mechanisms underlying IH pathogenesis, and possible involvement of the renin-angiotensin-aldosterone system, deserve study. PMID- 23340699 TI - Lack of CD4+CD25+FOXP3+ regulatory T cells is associated with resistance to intravenous immunoglobulin therapy in patients with Kawasaki disease. AB - The aim of this study was to investigate changes in CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) throughout the clinical course of Kawasaki disease (KD) and correlations with response to intravenous immunoglobulin (IVIg) therapy. Participants comprised 18 patients who fulfilled the diagnostic criteria for KD and 20 healthy subjects. Expressions of CD25 and FOXP3 among all CD4(+) T cells in peripheral blood mononuclear cells were analyzed by flow cytometry before and 7 and 30 days after IVIg therapy. Before treatment, percentages of CD4(+)CD25(+)FOXP3(+) Tregs among total CD4(+) Tregs were significantly lower among KD patients (4.19 %; range, 0.16-8.11 %) than among healthy subjects (7.32 %; 4.18-13.42 %; P = 0.0001). Both percentages and absolute numbers of CD4(+)CD25(+)FOXP3(+) Tregs on day 7 after IVIg therapy were significantly increased compared with values before treatment (8.02 % (range, 0.51-12.6 %) vs. 4.19 % (range, 0.16-8.11 %), P = 0.0005; 93.25/ MUL (range, 6.67-258.05) vs. 41.85/ MUL (range, 0.44-160.62), P < 0.0001, respectively). Moreover, percentages and absolute numbers of CD4(+)CD25(+)FOXP3(+) Tregs before treatment were significantly lower in the IVIg-resistant group than in the IVIg-sensitive group (0.18 % (range, 0.16-3.34 %) vs. 4.52 % (range, 2.8-8.11 %), P = 0.0022; 0.68/MUL (range, 0.44-53.81) vs. 51.66/MUL (range, 2.88-160.62), P = 0.0098, respectively). The frequency of CD4(+)CD25(+)FOXP3(+) Tregs in four of the five IVIg-resistant patients at diagnosis was more than 3 standard deviations below that in healthy subjects. Two of these four patients displayed coronary abnormalities, and one of these two patients developed coronary aneurysm. CONCLUSION: Lack of CD4(+)CD25(+)FOXP3(+) Tregs before treatment may predict resistance to IVIg therapy in patients with KD. PMID- 23340698 TI - Cardiovascular disease in childhood: the role of obesity. AB - In recent years, childhood obesity is becoming an epidemic health problem. It is now evident from many studies that childhood obesity is correlated with adult excess weight status and the development of risk factors for cardiovascular diseases in adulthood, including hypertension, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome. The exposure to obesity and to the above risk factors during childhood subsequently lead to atherosclerotic development, such as altered vascular structure and function, although the mechanisms are still unclear. Several non-invasive, and thus easy-to-obtain measures of arterial structure and function, have been shown to be clinically useful in providing information about vasculature early in the course of atherosclerosis, including measurement of endothelial function, carotid intima media thickness, and arterial stiffness. The early detection of cardiovascular abnormalities is essential because the control of the atherogenic process is more effective during its early stages. The present review focuses on the cardiovascular consequences of obesity, on the mechanisms and the methods of measurement of endothelial dysfunction in obese children and adolescents, and on the ways of intervention for the improvement of vascular health. PMID- 23340700 TI - Foot morphology in normal-weight, overweight, and obese schoolchildren. AB - This study compared the foot morphology of Spanish schoolchildren based on their body mass index and age and analyzed whether body mass index affects the child's foot development at primary school. Cross-sectional study of 1,032 schoolchildren (497 boys and 535 girls), 6-12 years old. Height and weight were measured to calculate body mass index. Children were classified as obese, overweight, and normal-weight. Measurements of foot morphology were obtained with a three dimensional feet digitizer in static standing. Significant differences were found between the feet of children with normal-weight and overweight (2.6 to 9.0 %) and among children with normal-weight and obese for all variables (3.9 to 17.3 %). Differences in width, ball height, and arch height (5.3 to 7.6 %) were only found among overweight and obese children. There were no changes in the foot morphology of children between 6 and 7 years and between 10 and 12 years. Obese children showed more gradual changes in the foot measurements. The average percentage increase by year in children with normal-weight and obese were similar (3.6 and 3.4 %, respectively); however, morphological measurements of the foot of overweight children increased at a faster rate (4.0 %). CONCLUSION: Excess weight affects the foot structure of children. The differences between age groups seem to indicate that the feet of children with overweight and obesity follow a different growth pattern than that of normal-weight children. With these results, the shoe manufacturers can design shoes for children depending on their age and weight. PMID- 23340702 TI - Exploring prenatal outdoor air pollution, birth outcomes and neonatal health care utilization in a nationally representative sample. AB - The impact of air pollution on fetal growth remains controversial, in part, because studies have been limited to sub-regions of the United States with limited variability. No study has examined air pollution impacts on neonatal health care utilization. We performed descriptive, univariate and multivariable analyses on administrative hospital record data from 222,359 births in the 2000, 2003 and 2006 Kids Inpatient Database linked to air pollution data drawn from the US Environmental Protection Agency's Aerometric Information Retrieval System. In this study, air pollution exposure during the birth month was estimated based on birth hospital address. Although air pollutants were not individually associated with mean birth weight, a three-pollutant model controlling for hospital characteristics, demographics, and birth month identified 9.3% and 7.2% increases in odds of low birth weight and very low birth weight for each MUg/m(3) increase in PM(2.5) (both P<0.0001). PM(2.5) and NO(2) were associated with -3.0% odds/p.p.m. and +2.5% odds/p.p.b. of preterm birth, respectively (both P<0.0001). A four-pollutant multivariable model indicated a 0.05 days/p.p.m. NO(2) decrease in length of the birth hospitalization (P=0.0061) and a 0.13 days increase/p.p.m. CO (P=0.0416). A $1166 increase in per child costs was estimated for the birth hospitalization per p.p.m. CO (P=0.0002) and $964 per unit increase in O(3) (P=0.0448). A reduction from the 75th to the 25th percentile in the highest CO quartile for births predicts annual savings of $134.7 million in direct health care costs. In a national, predominantly urban, sample, air pollutant exposures during the month of birth are associated with increased low birth weight and neonatal health care utilization. Further study of this database, with enhanced control for confounding, improved exposure assessment, examination of exposures across multiple time windows in pregnancy, and in the entire national sample, is supported by these initial investigations. PMID- 23340703 TI - Does apartment's distance to an in-built transformer room predict magnetic field exposure levels? AB - It has been shown that magnetic field exposure in apartments located directly on top or adjacent to transformer rooms is higher compared with exposure in apartments located further away from the transformer rooms. It is unclear whether this also translates into exposure contrast among individuals living in these apartments. We performed spot measurements of magnetic fields in 35 apartments in 14 apartment buildings with an in-built transformer and additionally performed 24 h personal measurements in a subsample of 24 individuals. Apartments placed directly on top of or adjacent to a transformer room had on average exposures of 0.42 MUT, apartments on the second floor on top of a transformer room, or sharing a corner or edge with the transformer room had 0.11 MUT, and apartments located further away from the transformer room had levels of 0.06 MUT. Personal exposure levels were approximately a factor 2 lower compared with apartment averages, but still showed exposure contrasts, but only for those individuals who live in the apartments directly on top or adjacent to a transformer room compared with those living further away, with 0.23 versus 0.06 MUT for personal exposure when indoors, respectively. A classification of individuals into 'high' and 'low' exposed based on the location of their apartment within a building with an in built transformer is possible and could be applied in future epidemiological studies. PMID- 23340704 TI - High-resolution modeling of residential outdoor particulate levels in Sweden. AB - Large-scale exposure assessments that include both between- and within-city differences in air pollution levels are lacking. The objective of this study was to model long-term particle exposure for the whole of Sweden, separating long range transport from local sources, which were further separated into combustion and road dust. Annual regional, urban and local traffic PM exposure contributions were modeled for 26,000 addresses from a national survey, using a European scale model, an urban model and a local traffic model. Total PM(10) was overall dominated by the regional contribution, ranging from 3.5 MUg/m(3) (northernmost) to 13.5 MUg/m(3) (southernmost). Local traffic and urban sources contributed nationally on average to 16% of total PM(10), but for urban populations this contribution was larger (for Stockholm around 30%). Generalized to the Swedish adult population, the average residential exposure contributions from regional, urban and local traffic PM(10) were 10.2, 1.3 and 0.2 MUg/m(3), respectively. Corresponding exposure to PM(1) was 5.1, 0.5 and 0.03 MUg/m(3), respectively. Long-range transport dominates average Swedish residential PM(1) and PM(10) levels, but for urban populations the contributions from urban and local traffic sources are important and may even dominate for residences close to heavily trafficked roads. The study shows the importance of considering both national and city-scale gradients. The approach to exposure modeling at home addresses of a Swedish cohort includes both the regional scale and the urban and local traffic contributions to total PM exposure. With this we can resolve both between- and within-city gradients in national exposure assessments. The within-city exposure is further divided into a submicron (combustion) and a supermicron (road dust generated by studded tires) part. This gives new possibilities to study health impacts of different particles generated in Scandinavian cities. PMID- 23340705 TI - Prebiotic chemistry in icy grain mantles in space. An experimental and observational approach. AB - A compendium of different solid carbonaceous materials detected in space is presented, focussing on the search for organic matter of prebiotic interest. This journey takes us from the carbon grains likely formed in the atmospheres of evolved stars to organic grain mantles made from ice processing thought to be present in dense interstellar clouds and circumstellar regions, making a stop in solar system objects that could have delivered organic species to the early Earth. The most abundant carbon materials detected to date in space appear to be of little biological relevance. On the other hand, organic refractory residues, made in the laboratory from UV-photoprocessing followed by warm-up of interstellar ice analogs, are a hydrocarbon material rich in O and N containing chemical compounds that could act as initiators of prebiotic chemistry. A similar material might be present in dust grains inside dense clouds or circumstellar regions, some comets, and as a minor component in carbonaceous chondrites. We use infrared spectroscopy as a tool to spot organic refractory matter in various space environments. The delivery of organic materials via comets, (micro-) meteorites, and interplanetary dust particles to the primitive Earth might have contributed as a starting material for prebiotic chemistry. To test this hypothesis, it is first essential to characterize the composition of exogenous organic matter. PMID- 23340706 TI - Complex hepatectomy under total vascular exclusion of the liver: impact of ischemic preconditioning on clinical outcomes. AB - BACKGROUND: Hepatic inflow clamping during hepatectomy introduces ischemia reperfusion (I/R) injury, and many authors regard the addition of caval occlusion as adding increased risk. Ischemic preconditioning (IPC) is one of the protective strategies employed to reduce I/R injury in animal experiments and limited clinical series. The aim of the present study was to determine the impact of systematic adoption of IPC in patients undergoing complex hepatectomy under total hepatic vascular exclusion (TVE) based on outcomes review. METHODS: The records of 93 patients who underwent major hepatectomy involving TVE at our center from February 1998 to December 2008 were reviewed. These patients were divided into two groups: group 1 (n = 55, TVE alone) and group 2 (n = 38, TVE with IPC). IPC was performed by portal triad clamping for 10 min followed by 3-5 min of reperfusion prior to TVE and resection. RESULTS: The two groups were comparable regarding demographics, underlying liver diseases, indications for hepatectomy, duration of TVE, and preoperative liver and kidney function tests. Overall postoperative laboratory results of liver function tests were not significantly different between the two groups. Creatinine levels and prothrombin times were not significantly different between the groups. The use of IPC had no impact on the duration of the operation, blood loss, or hospital stay. The morbidity rates were 37.5 and 34.2 %, respectively. CONCLUSIONS: Our adoption of IPC as a protective strategy against I/R injury under TVE did not affect operative or laboratory parameters and clinical outcomes when compared to continuous clamping for comparable ischemic periods. PMID- 23340707 TI - Mosquito net mesh for abdominal wall hernioplasty: a comparison of material characteristics with commercial prosthetics. AB - BACKGROUND: The use of sterilized mosquito net as a cheaper alternative to commercial mesh used in hernia repair has previously been published. However, as no standards with regard to the material have been documented, we aimed to define the characteristics of a commonly available and low-cost mosquito net, which has already been shown to be clinically efficacious in groin hernia repair. We compared its characteristics to other commercially available meshes, in keeping with the well-established FDA and MHRA regulatory processes. METHODS: The macromolecular structure of the mosquito net was determined by vibrational spectroscopy. The ultrastructure of the meshes was examined with scanning electron microscopy, and uniaxial and burst tensile strength testing was performed. The following parameters were assessed: polymer type, filament characteristics, pore size, weight, linear density, elasticity, and tensile strength. RESULTS: The mosquito net was a polyethylene homopolymer, knitted from monofilament fibers with a mean filament diameter of 109.7 MUm and a mean mesh thickness of 480 MUm. The mean pore maximum diameter was 1.9 mm, with 91.2 % porosity, 53.7 g/m(2) mean mesh weight, and a linear mass density of 152 denier. This was comparable to the "large pore" (class I) commercial meshes. The bursting force for polyethylene mosquito net was greater than for UltraPro and Vypro (43.0 vs. 35.5 and 27.2 N/cm, respectively), and the mosquito net exhibited less anisotropy compared to the commercial meshes. CONCLUSIONS: The material and mechanical properties of the polyethylene mosquito net are substantially equivalent to those of commonly used lightweight commercial meshes. PMID- 23340708 TI - Clinicopathological features of recurrence in patients after 10-year disease-free survival following curative hepatic resection of hepatocellular carcinoma. AB - BACKGROUND: The present study aimed to clarify the clinicopathologic features of long-term disease-fee survival after resection of hepatocellular carcinoma (HCC). METHODS: This retrospective study identified 940 patients who underwent curative resection of HCC between 1991 and 2000 at five university hospitals. Seventy-four patients with 10 years of recurrence-free survival were identified and followed up. They were divided into two groups, 60 recurrence-free and 14 with recurrence after a 10-year recurrence-free period. RESULTS: Overall survival rates of recurrence and non-recurrence groups were 68 and 91 % at 16 years, and 34 and 91 % at 20 years (p = 0.02), respectively. There were five (36 %), and two deaths (3 %), respectively, after 10 recurrence-free years. A second resection for recurrence was performed in four patients (29 %), and mean survival was 15.3 years after the first hepatectomy. Although three patients in the non-recurrence group (5 %) developed esophageal and/or gastric varices, seven patients in the recurrence group (50 %) developed varices during 10 years (p < 0.0001). In multivariate analysis, preoperative and 10-year platelet count was identified as a favorable independent factor for maintained recurrence-free survival after a 10 year recurrence-free period following curative hepatic resection of HCC. CONCLUSIONS: Recurrence of HCC may occur even after a 10-year recurrence-free period. Long-term follow-up after resection of HCC is important, and should be life-long. Patients with higher preoperative and 10-year platelet counts are more likely to have long-term survival after resection. A low platelet count, related to the degree of liver fibrosis, is a risk factor for recurrence and survival of HCC after curative resection. PMID- 23340709 TI - Identifying and addressing preventable process errors in trauma care. AB - BACKGROUND: Management of the acute trauma patient is complex, with potential for error and adverse events. Avoidable injuries and deaths are not well understood. Analysis of error incidence, type, and severity can aid in greater understanding of the root causes and guide future development of error reduction strategies. METHODS: Weekly case review meetings for a UK trauma center were retrospectively reviewed over 1 year. Errors were identified and corroborated with case-note review by a reviewer blinded to any identified events. All events were classified according to the Joint Commission on Accreditation of Healthcare Organisations taxonomy and were typified as structural or process errors and omission or commission errors. RESULTS: A total of 1,752 major trauma patients were admitted over the study period, and 169 preventable errors were identified through analysis of case review meetings and case-note review. Clear patient harm was identified in 3.6 % of cases, with risk of harm in 30 %. Most errors occurred during the initial phase of care in the emergency department (51 %) and resulted most commonly in delays (56 %). The majority of errors were identified as process related (88 %), with 62 % of them considered errors of omission. CONCLUSIONS: This study reports error incidence in trauma and typifies them according to type and root cause. It identifies process errors and errors of omission in particular as the most common recurring events. Error theory suggests that protocols or checklists may most effectively address these errors. Further study should be prospective and may aid in the development of such interventions. PMID- 23340710 TI - Epidemiology, clinical data, and treatment of viral hepatitis in a large cohort of intravenous drug users. AB - OBJECTIVES: The aim of this study was to evaluate retrospectively the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, epidemiological parameters, and the clinical data from the antiviral treatment of hepatitis C in a large cohort of intravenous drug users (IDUs) followed-up from 1994 until 2008. PATIENTS AND METHODS: A total of 1179 former IDUs followed up either in the liver unit or in the context of a substitution program organization were included in this study. A retrospective chart review was prepared to retrieve data on the patients' demographic characteristics, the prevalence of viral hepatitis, and information on HCV treatment. RESULTS: The prevalence of HBsAg positive was 5%. A substantial number of patients were anti-HCV positive (847/1170, 73%), 189 were lost to follow-up, 526 (80%) were HCV RNA positive and 132 (20%) had a self limited disease. The most prevalent genotype was 3 (59.7%). Twenty-five percent of the study population received antiviral treatment against HCV infection. Patients seen in the Liver Unit were more likely to receive antiviral treatment. The sustained virological response (SVR) was 80% with patients treated with pegylated interferon and ribavirin having a significantly higher SVR rate. CONCLUSIONS: Our results show that (a) the majority of IDUs in Greece have chronic hepatitis C and the prevalent genotype is 3 (b) patients who complete therapy have SVR rates similar to those without drug-dependence, and (c) since IDUs constitute the core of the hepatitis C epidemic and the main route of HCV transmission, efforts to treat these patients should be made. PMID- 23340712 TI - Organosulphur and related ligands in Suzuki-Miyaura C-C coupling. AB - Suzuki-Miyaura C-C cross coupling (SMC), an important synthetic strategy for many organic molecules, has several advantages such as mild reaction conditions, high tolerance toward various functional groups and ease in isolation of the product. Palladium(II) ligated with phosphines (particularly bulky and electron-rich) and N-heterocyclic carbenes (NHCs) has been found to be efficient in the catalysis of SMC. The drawback with many of these catalysts is their air/moisture sensitivity. Since 2000, palladium(II) complexes of organosulphur and related ligands have emerged as viable alternatives to palladium-phosphine/carbene complexes as they have sufficient thermal stability, air and moisture insensitivity. Moreover synthesis of complexes of such ligands is easy. In this perspective Suzuki Miyaura C-C coupling reactions catalyzed with palladium(II)-complexes of organosulphur ligands have been reviewed. Catalysis of SMC with palladium(II) complexes of organoselenium and tellurium ligands, studied much less in comparison to those of organosulphur ligands, is also included. PMID- 23340713 TI - Theoretical investigations into the nucleation of silica growth in basic solution part I--ab initio studies of the formation of trimers and tetramers. AB - We have performed the first ab initio study that considers all possible oligomerization reactions available to silicic acid in basic solution (ignoring high-energy multiply charged species), up to and including tetramers. Energies have been computed at the MP2/6-31+G(d)//HF/6-31+G(d) level of theory, with a hybrid solvation model which includes explicit waters and CPCM continuum corrections to account for solvent effects. The explicit waters have been found to be extremely important in providing additional stabilization of intermediates and transition states which are not accounted for properly by more conventional implicit solvent approaches, suggesting some of the known pathways are more facile than previously predicted. Additionally, a number of previously neglected bimolecular growth pathways such as dimer/dimer and monomer/cyclic trimer additions, and unimolecular cyclization steps such as branched 3-ring formation from branching tetramers and the formation of highly condensed bicyclic and tetrahedral clusters have been studied in detail. Many are found to be very energetically feasible and consequently could have considerable impacts on the initial stages of silica nucleation. PMID- 23340711 TI - Demographic and clinical characteristics of middle-aged versus younger adults enrolled in a clinical trial of a web-delivered psychosocial treatment for substance use disorders. AB - OBJECTIVE: Evidence suggests that substance abuse is becoming more prevalent in middle-aged adults. The objective of this secondary analysis was to add to the growing empirical literature on the unique features of middle-aged substance abuse populations. METHODS: We descriptively compared baseline demographic and clinical characteristics of middle-aged (age 45-62 years, n = 111) and younger (age 18-44 years, n = 395) substance abusers entering a Web-based psychosocial treatment study as part of the National Institute on Drug Abuse Clinical Trials Network. RESULTS: A significantly greater percentage of middle-aged adults were nonwhite and had a marital status other than single/never married. There was a significant association between frequency of Internet use and the age group. Forty-six percent of middle-aged adults versus 21% of younger adults reported no Internet use in the prior 90 days. A significantly greater percentage of middle aged adults used cocaine, and a significantly greater percentage of younger adults used marijuana and opioids. Clinically significant cognitive impairment (z < -1.0) was found for the average participant in both groups on logical association of familiar concepts. CONCLUSIONS: This secondary analysis of a National Institute on Drug Abuse Clinical Trials Network study provides additional information on the unique features of middle-aged substance abusers. Increasing knowledge of similarities and differences between younger and middle aged substance abusers can help with potential age-specific substance abuse treatment planning. PMID- 23340714 TI - The strain effect on colossal oxygen ionic conductivity in nanoscale zirconia electrolytes: a first-principles-based study. AB - Density functional theory calculations and first-principles molecular dynamics (MD) simulations have been performed to examine the strain effect on the colossal oxygen ionic conductivity in selected sandwich structures of zirconia electrolytes. For the KTaO(3)/YSZ/KTaO(3) sandwich structure with 9.7% lattice mismatch, transition state calculations indicate that the strain effect changes the oxygen migration pathways from straight line into zigzag form and reduces the energy barrier by 0.2 eV. On the basis of our computational results, a possible oxygen ion diffusion highway is suggested. By finite-temperature MD simulations, an activation barrier of 0.33 eV is obtained, corresponding to an oxygen ionic conductivity which is 6.4 * 10(7) times higher than that of the unstrained bulk zirconia at 500 K. A nearly linear relationship is identified between the energy barrier and the lattice mismatch in the sandwich structures. PMID- 23340715 TI - Manipulation of viscous all-aqueous jets by electrical charging. AB - We demonstrate the manipulation of viscous all-aqueous jets by electrical charging. At sufficiently high voltages, the folding of an uncharged viscous jet is suppressed, and the jet diameter can be adjusted by varying the applied voltage or the fluid flow rates. This inspires new ways to fabricate biocompatible fibers. PMID- 23340716 TI - Bortezomib-enhanced radiosensitization through the suppression of radiation induced nuclear factor-kappaB activity in human oral cancer cells. AB - Oral cancer cells have a significantly augmented nuclear factor-kappaB (NF kappaB) activity and the inhibition of this activity suppresses tumor growth. Bortezomib is a proteasome inhibitor and a drug used for molecular-targeted therapy (targets NF-kappaB). In this study, we investigated whether bortezomib would be effective as an inhibitor of proliferation and a radiosensitizer for the treatment of oral cancer. We demonstrate that bortezomib inhibits NF-kappaB activity and cell proliferation. The combined treatment with bortezomib and radiation (RT) suppressed NF-kappaB activity and cell growth in vitro and in vivo compared with RT treatment alone. To investigate the mechanisms by which bortezomib suppresses tumor growth, the expression of signaling molecules downstream of NF-kappaB were examined by ELISA. The combined treatment significantly inhibited the radiation-induced production of angiogenic factors and decreased the number of blood vessels in the tumor tissues. Although the expression of anti-apoptotic proteins was upregulated by RT, bortezomib downregulated the RT-induced expression of these proteins. Moreover, the expression of cleaved poly(ADP-ribose) polymerase in vitro and in vivo was enhanced by bortezomib, indicating that bortezomib inhibits tumor growth by inducing apoptosis. This study clearly demonstrates that bortezomib significantly inhibits tumor growth and that the combined treatment with bortezomib and RT results in a significant inhibition of tumor growth. The mechanisms underlying the inhibition of tumor growth by bortezomib include the suppression of angiogenesis and the induction of apoptosis. A novel molecular targeting therapy including bortezomib may be effective in the treatment of oral cancer by suppressing NF-kappaB activity. PMID- 23340717 TI - Saliva fluoride before and during 3 years of supervised use of fluoride toothpaste. AB - OBJECTIVES: The purpose of the study was to examine pre-brushing saliva fluoride concentrations before and during a large, 3-year, prospective toothpaste study on the effect of post-brushing rinsing on dental caries. The aims were to study saliva fluoride over time and the effect of rinsing on saliva fluoride and to relate saliva fluoride to caries increments and accumulation of plaque. MATERIALS AND METHODS: Saliva samples (baseline and 1, 2, and 3 years) were collected from 11-year-old children attending two schools (A and B) in Kaunas, Lithuania, who refrained from brushing the evening and morning before saliva collection. Numbers of saliva samples collected varied from 264 at baseline to 188 at the 3-year follow-up. Children in school A rinsed with water after daily brushing, while children in school B did not rinse. Total caries and visible plaque were registered at baseline and after 3 years. RESULTS: Mean saliva fluoride concentrations at baseline and after 1, 2, and 3 years from school A (rinsing) were 0.014, 0.026, 0.029, and 0.034 ppm and from school B (no rinsing) were 0.013, 0.028, 0.031, and 0.031 ppm, respectively. Increases in saliva fluoride from baseline were significant (Wilcoxon's test, p < 0.001), but the increase from baseline to year 1 was not statistically significantly different between schools. Saliva fluoride did not increase beyond year 1 and did at no time point differ between schools. Reductions in numbers of tooth surfaces with dental plaque were significantly positively related to the number of caries reversals over the 3 years. CONCLUSIONS: Background saliva fluoride concentration is increased by brushing at least once daily on schooldays, does not increase further over 3 years, and is not affected by rinsing after brushing. CLINICAL RELEVANCE: Continuous use of fluoride toothpaste produces ambient saliva fluoride levels similar to saliva fluoride in areas with fluoridated water. PMID- 23340719 TI - Community structure of helminth parasites of the "Cururu" toad, Rhinella icterica (Anura: Bufonidae) from southern Brazil. AB - Sixty specimens of the "cururu" toad, Rhinella icterica (Spix 1824) (Bufonidae), were collected in Campo Belo do Sul, State of Santa Catarina, Brazil, between May 2009 and January 2011, and were examined for the presence of helminth parasites. Nine species of adult helminths were found: Catadiscus cohni, Rudolphitrema rudolphii, Cylindrotaenia sp., Rhabdias fuelleborni, Strongyloides sp., Cosmocerca rara, Cosmocerca brasiliensis, Aplectana elenae, and Oxyascaris sp., in addition to an unidentified adult nematode species. Females of cosmocercid nematodes, proteocephalan plerocercoid, and acanthocephalan cystacanth were found but not identified for lack absolute of taxonomic characters. The sex of the anurans had no influence on prevalence, abundance, and richness of helminth species. Length and body mass of hosts did not influence the prevalence and richness of helminths, while the abundance of R. fuelleborni was significantly correlated with both parameters. PMID- 23340718 TI - Lcc1 and Lcc5 are the main laccases secreted in liquid cultures of Coprinopsis cinerea strains. AB - The litter-degrading dung fungus Coprinopsis cinerea has the high number of seventeen different laccase genes. In this work, ten different monokaryons were compared in their ability to produce laccases in two different complete media at different temperatures. Few strains showed laccase activity at the optimal growth temperature of 37 degrees C. Nine of the strains gave laccase activities between 0.2 and 5.9 U mL(-1) at the suboptimal temperature of 25 degrees C in mKjalke medium. Laccase activities in YMG/T medium were detected for only three strains (0.5-4.5 U mL(-1)). Zymograms of supernatants from mKjalke medium resulted in total in 10 different laccase bands but strains differed in distribution. LC MS/MS analysis with Mascot searches of the annotated C. cinerea genome identified isoenzymes from five different genes (Lcc1, Lcc2, Lcc5, Lcc9 and Lcc10) and of Lcc1 three and of Lcc5 two distinct electrophoretical forms. Lcc1 and Lcc5 were expressed in all laccase positive strains, but not all forms were found in all of the strains. Lcc2, Lcc9 and Lcc10 occurred only in three strains as minor laccases, indicating that Lcc1 and Lcc5 are the main laccases of C. cinerea secreted in liquid mKjalke medium. PMID- 23340722 TI - Photovoltaic properties of high efficiency plastic dye-sensitized solar cells employing interparticle binding agent "nanoglue". AB - An interparticle binding agent, or nanoglue, was synthesized by a sol-gel process, which facilitated the preparation of well-interconnected TiO2 electrodes at low-temperatures for plastic dye-sensitized solar cells. The viscosity of the nanoglue-based pastes was seven times higher than that obtained in pastes without any nanoglue. The increased viscosity was sufficiently high enough for coating thick films to fabricate TiO2 electrodes. The structural and photovoltaic properties of the films were extensively investigated by varying the amounts of nanoglue. A reduced pore size and greatly enhanced surface area were observed in the nanoglue-based films. Improved interparticle connectivity, resulting in faster electron transport, was confirmed by photocurrent transient spectroscopy and electrochemical impedance measurements of the nanoglue-based films. The electron diffusion length and charge collection efficiency were also enhanced in these nanoglue-based films. A maximum conversion efficiency of 5.43% was achieved in films containing 20 wt% nanoglue fabricated on a plastic substrate under one sun illumination, even without any additional treatment. PMID- 23340720 TI - Antimalarial activities of medicinal plants and herbal formulations used in Thai traditional medicine. AB - Malaria is one of the world's leading killer infectious diseases with high incidence and morbidity. The problem of multidrug-resistant Plasmodium falciparum has been aggravating particularly in Southeast Asia. Therefore, development of new potential antimalarial drugs is urgently required. The present study aimed to investigate antimalarial activities of a total of 27 medicinal plants and 5 herbal formulations used in Thai traditional medicine against chloroquine resistant (K1) and chloroquine-sensitive (3D7) P. falciparum clones. Antimalarial activity of the ethanolic extracts of all plants/herbal formulations against K1 and 3D7 P. falciparum clones was assessed using SYBR Green I-based assay. All plants were initially screened at the concentration of 50 MUg/ml to select the candidate plants that inhibited malaria growth by >=50%. Each candidate plant was further assessed for the IC50 value (concentration that inhibits malaria growth by 50%) to select the potential plants. Selectivity index (SI) of each extract was determined from the IC50 ratio obtained from human renal epithelial cell and K1 or 3D7 P. falciparum clone. The ethanolic extracts from 19 medicinal plants/herbal formulation exhibited promising activity against both K1 and 3D7 clones of P. falciparum with survival of less than 50% at the concentration of 50 MUg/ml. Among these, the extracts from the eight medicinal plants (Plumbago indica Linn., Garcinia mangostana Linn., Dracaena loureiri Gagnep., Dioscorea membranacea Pierre., Artemisia annua Linn., Piper chaba Hunt., Myristica fragrans Houtt., Kaempferia galanga Linn.) and two herbal formulations (Benjakul Formulation 1 and Pra-Sa-Prao-Yhai Formulation) showed potent antimalarial activity with median range IC50 values of less than 10 MUg/ml against K1 or 3D7 P. falciparum clone or both. All except G. mangostana Linn. and A. annua Linn. showed high selective antimalarial activity against both clones with SI>10. Further studies on antimalarial activities in an animal model including molecular mechanisms of action of the isolated active moieties are required. PMID- 23340723 TI - [Urinary bladder function disorders in childhood]. AB - Bladder dysfunction in children is a very common and heterogeneous problem. There can be disturbances either in bladder storage or during voiding phases. First of all it is important to distinguish between non-neurogenic and neuropathic bladder dysfuction. In this article the most common causes, the basic diagnostic evaluation and therapeutic interventions are summarized. PMID- 23340724 TI - [Diagnostics and therapy of urinary tract infections]. AB - In infants and young children, urinary tract infections (UTI) often present with unspecific symptoms. Appropriate techniques of urine sampling play an important role for accurate microbiological diagnosis. In infants urine sampling by bladder puncture or transurethral catheter is recommended. In young infants with suspected pyelonephritis, calculated antibiotic treatment should be initiated parenterally with a combination of a third generation cephalosporin or an aminoglycoside with ampicillin. After the age of 3-6 months group 3 oral cephalosporins can be used in uncomplicated pyelonephritis. With the first febrile UTI early sonography is recommended to provide information about renal parenchymal involvement and to exclude malformations of the kidneys and urinary tract. Strategies for the recognition of vesicoureteral reflux and renal damage are under discussion. Recently published guidelines by the American Academy of Pediatrics for the diagnosis and management of UTI in febrile children and infants aged 2-24 months will most likely influence the still pending German guidelines. PMID- 23340725 TI - [Primary megaureter]. AB - A primary megaureter is an anomaly with a prevesical or overall dilated ureter of more than 6 mm in diameter. It is important to distinguish between cases of primary non-refluxing and primary obstructive-refluxing megaureters, as the treatment of both is completely different. The basic diagnostic work-up includes ultrasonography and voiding cystourethrography. Diuretic renography is used to detect split renal function and the degree of upper urinary tract obstruction. In most cases of primary non-refluxing megaureter surgical treatment is unnecessary due to the high remission rate, whereas obstructive refluxing megaureters commonly only need to be corrected. Antibiotic prophylaxis may be indicated in infants with a primary obstructive megaureter during the first 6 months of life due to a higher risk of complications due to pyelonephritis especially in this age group. PMID- 23340726 TI - [Varicocele in adolescents]. AB - Testicular varicocele is present in 15 % of adolescent boys. The very impact of this pathology and who will be at risk of developing into infertility remains unclear. Research on the pathophysiology, results of surgical or radiological interventions and potential predictors for long-term impairment of spermatogenesis and thus fertility is still ongoing. Indications for treatment are mainly based on differences in testicular volumes as semen parameters are most often not available; however, whether testicular volume is a valuable prognostic parameter for later fertility remains questionable. Approximately 50 % of adolescent patients with varicocele experience spontaneous increase of testicular volume without any intervention. PMID- 23340728 TI - [Releases of the DGU. Published by the Board of the German Society of Urology]. PMID- 23340729 TI - [URO -- telegram]. PMID- 23340732 TI - An R(1rho) expression for a spin in chemical exchange between two sites with unequal transverse relaxation rates. AB - An analytical expression is derived for the rotating frame relaxation rate, R(1rho), of a spin exchanging between two sites with different transverse relaxation times. A number of limiting cases are examined, with the equation reducing to formulae derived previously under the assumption of equivalent relaxation rates at each site. The measurement of a pair off-resonance R(1rho) values, with the carrier displaced equally on either side of the observed correlation, forms the basis of one of the approaches for obtaining signs of chemical shift differences, Deltaomega, of exchanging nuclei. The results presented here establish that this method is relatively insensitive to differential transverse relaxation rates between the exchaning states, greatly simplifying the calculation of optimal parameters in R(1rho) based experiments that are used for measurement of signs of Deltaomega. PMID- 23340733 TI - Comment on 'does a history of eczema predict a future Basal cell carcinoma?'. PMID- 23340734 TI - Mutations in ERBB4 may have a minor role in melanoma pathogenesis. PMID- 23340735 TI - TAK1 is required for dermal wound healing and homeostasis. AB - Dermal connective tissue is a supportive structure required for skin's barrier function; dysregulated dermal homeostasis results in chronic wounds and fibrotic diseases. The multifunctional cytokine transforming growth factor (TGF) beta promotes connective tissue deposition, repair, and fibrosis. TGF-beta acts through well-defined canonical pathways; however, the non-canonical pathways through which TGF-beta selectively promotes connective tissue deposition are unclear. In dermal fibroblasts, we show that inhibition of the non-canonical TGF beta-activated kinase 1 (TAK1) selectively reduced the ability of TGF-beta to induce expression of a cohort of wound healing genes, such as collagens, CCN2, TGF-beta1, and IL-6. Fibroblast-specific TAK1-knockout mice showed impaired cutaneous tissue repair and decreased collagen deposition, alpha-smooth muscle actin and CCN2 expression, proliferating cell nuclear antigen staining, and c-Jun N-terminal kinase and p38, but not Smad3, phosphorylation. TAK1-deficient fibroblasts showed reduced cell proliferation, migration, cell attachment/spreading, and contraction of a floating collagen gel matrix. TAK1 deficient mice also showed progressively reduced skin thickness and collagen deposition. Thus, TAK1 is essential for connective tissue deposition in the dermis. PMID- 23340736 TI - Autophagy is induced by UVA and promotes removal of oxidized phospholipids and protein aggregates in epidermal keratinocytes. AB - The skin is exposed to environmental insults such as UV light that cause oxidative damage to macromolecules. A centerpiece in the defense against oxidative stress is the Nrf2 (nuclear factor (erythroid-derived-2)-like 2) mediated transcriptional upregulation of antioxidant and detoxifying enzymes and the removal of oxidatively damaged material. Autophagy has an important role in the intracellular degradation of damaged proteins and entire organelles, but its role in the epidermis has remained elusive. Here, we show that both UVA and UVA oxidized phospholipids induced autophagy in epidermal keratinocytes. Oxidative stressors induced massive accumulation of high-molecular-weight protein aggregates containing the autophagy adaptor protein p62/SQSTM1 in autophagy deficient (autophagy-related 7 (ATG7) negative) keratinocytes. Strikingly, even in the absence of exogenous stress, the expression of Nrf2-dependent genes was elevated in autophagy-deficient keratinocytes. Furthermore, we show that autophagy-deficient cells contained significantly elevated levels of reactive oxidized phospholipids. Thus, our data demonstrate that autophagy is crucial for both the degradation of proteins and lipids modified by environmental UV stress and for limiting Nrf2 activity in keratinocytes. Lipids that promote inflammation and tissue damage because of their reactivity and signaling functions are commonly observed in aged and diseased skin, and thus targeting autophagy may be a promising strategy to counteract the damage promoted by excessive lipid oxidation. PMID- 23340737 TI - Probing the picosecond kinetics of the photosystem II core complex in vivo. AB - Photosystems I (PSI) and II (PSII) are two major pigment-protein complexes of photosynthetic organisms that function in series to convert sunlight energy into chemical energy. We have studied the picosecond fluorescence behaviour of the core of both photosystems in vivo by using two Synechocystis PCC 6803 mutants: BE cells contain PSI but are lacking both PSII and the light-harvesting complexes called phycobilisomes (PBs) whereas PAL cells contain both PSI and PSII but lack the PBs. Measurements were performed at room temperature and at 77 K. The fluorescence kinetics of PSI and PSII can nicely be separated, en passant providing the PSI/PSII ratio. At room temperature, the PSI kinetics are identical to those of isolated PSI whereas the PSII kinetics can equally well be described by the in vitro trap-limited model of Y. Miloslavina, M. Szczepaniak, M. G. Muller, J. Sander, M. Nowaczyk, M. Rogner and A. R. Holzwarth, Biophys J., 2009, 96(2), 621-631, and by the transfer-to-the-trap-limited model of C. D. van der Weij-de Wit, J. P. Dekker, R. van Grondelle and I. H. M. van Stokkum, J. Phys. Chem. A, 2011, 115(16), 3947-3956, albeit that the in vivo kinetics turn out to be somewhat slower. At 77 K several low-energy pigments are observed in both photosystems which complicate the overall dynamics but the PSII kinetics can still be described by both a trap-limited and a transfer-to-the-trap-limited model. PMID- 23340738 TI - Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia. AB - Bendamustine demonstrated clinical activity in pre-treated hematological malignancies due to its unique mechanism of action distinct from standard alkylating agents. This study assessed its efficacy in patients with chronic lymphocytic leukemia pre-treated with an alkylator, in comparison to fludarabine. Patients with relapsed chronic lymphocytic leukemia requiring treatment after one previous systemic regimen (usually chlorambucil-based) were randomized to either receive bendamustine 100 mg/m(2) on days 1 and 2 of a 4-week cycle or standard fludarabine treatment consisting of 25 mg/m(2) on days 1 to 5 every 4 weeks. The primary objective was to achieve non-inferior progression-free survival (PFS) with bendamustine. Out of a total of 96 patients randomized, 92 were eligible, 49 allocated to bendamustine and 43 to fludarabine. About half of the patients received six or more cycles. Overall response rates were 76 % on bendamustine and 62 % on fludarabine, with clinical complete response rates of 27 and 9 %, respectively. Median PFS was 20.1 and 14.8 months (hazard ratio, 0.87; 90 % confidence interval, 0.60-1.27), median overall survival 43.8 and 41.0 months (hazard ratio, 0.82). Thrombocytopenia and gastrointestinal toxicities were marginally more frequent on bendamustine, albeit CTC grade 3/4 event incidence was similar. These data suggest at least comparable efficacy of bendamustine vs. fludarabine, pointing to an alternative treatment option in relapsing CLL patients after chlorambucil containing initial chemotherapy. PMID- 23340739 TI - Auto-tandem catalysis: synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones via copper catalyzed aza-Michael addition-aerobic dehydrogenation-intramolecular amidation. AB - A copper-catalyzed domino synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones has been developed from 1,4-enediones and 2-aminoheterocycles with air as the oxidant. PMID- 23340740 TI - Luminescent gold-silver complexes derived from neutral bis(perfluoroaryl)diphosphine gold(I) precursors. AB - Complex [Au{4-C(6)F(4)(4-C(6)BrF(4))}(tht)] reacts with diphosphines (L-L) such as bis(diphenylphosphino)methane (dppm) or 1,2-bis(diphenylphosphino)benzene (dppb) in a 2 : 1 molar ratio in dichloromethane, leading to neutral products of stoichiometry [(Au{4-C(6)F(4)(4-C(6)BrF(4))})(2)(MU-L-L)] (L-L = dppm (1), dppb (2)). In the crystal structure of complex 2 short Au...Au interactions of 2.9367(5) and 2.9521(5) A appear. This complex displays an orange emission, which is assigned to arise from a charge transfer transition from a metal centered Au Au orbital to an orbital located at the diphosphine ligand. Addition of silver trifluoroacetate to these complexes in a 1 : 1 or a 2 : 1 molar ratio generates polymeric heterometallic gold-silver compounds of stoichiometry [Ag(2)Au(2){4 C(6)F(4)(4-C(6)BrF(4))}(2)(CF(3)CO(2))(2)(MU-L-L)](n) (L-L = dppm (3), dppb (4)), which confirms the capability of the neutral [(Au{4-C(6)F(4)(4 C(6)BrF(4))})(2)(MU-diphosphine)] units to act as electron density donors when treated with a Lewis acid substrate. These heterometallic derivatives show blue emissions indicating large HOMO-LUMO band gaps, due to the stabilization that the gold-based HOMO orbitals suffer when the electron withdrawing silver trifluoroacetate fragments interact with them. PMID- 23340741 TI - CD133 glycosylation is enhanced by hypoxia in cultured glioma stem cells. AB - The cancer stem cell (CSC) marker CD133 is widely expressed in gliomas and employed mostly by use of the CD133/1 antibody which binds the extracellular glycosylated AC133 epitope. CD133 recognition may, however, be affected by its glycosylation pattern and oxygen tension. The present study investigates the effect of oxygen deprivation on CD133 expression and glycosylation status employing a high AC133-expressing glioblastoma multiforme (GBM) cell line, IN699. IN699 cells were cultured under normoxic (21% O2) and hypoxic (3% O2) conditions. CD133 expression was analysed by western blotting (WB), qRT-PCR, immunocytochemistry (ICC) and flow cytometry using the glycosylation-specific antibody CD133/1 and ab19898 which binds the unglycosylated intra-cellular residues of CD133. By flow cytometry, ab19898 detected 94.1% and 96.2% CD133+ cells under normoxia and hypoxia, respectively. Hypoxia significantly increased the percentage of CD133+ cells from 69% to 92% using CD133/1 (p<0.005). Moreover, a significantly higher geomean fluorescence intensity (GMI) was demonstrated by ab19898 (p<0.005) in CD133+ cells. WB and qRT-PCR results were consistent with flow cytometry data. Furthermore, over a period of 72-h incubation under normoxic and hypoxic conditions after autoMACS sorting, an average of 31.8% and 42.2%, respectively, of CD133-negative IN699 cells became positive using CD133/1. Our data show that a) previously reported CD133- cells may have been misidentified using the glycosylation-specific CD133/1 as constitutive expression of CD133 was detected by the intracellular antibody ab19898; b) hypoxia promotes glycosylation status of CD133, indicating possible involvement of glycosylated CD133 in the process of anti-hypoxia-mediated apoptosis. PMID- 23340742 TI - Xylan O-acetylation impacts xylem development and enzymatic recalcitrance as indicated by the Arabidopsis mutant tbl29. PMID- 23340743 TI - Recent progress in understanding PAMP- and effector-triggered immunity against the rice blast fungus Magnaporthe oryzae. AB - Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is one of the most destructive diseases of rice worldwide. The rice-M. oryzae pathosystem has become a model in the study of plant-fungal interactions because of its scientific advancement and economic importance. Recent studies have identified a number of new pathogen-associated molecular patterns (PAMPs) and effectors from the blast fungus that trigger rice immune responses upon perception. Interaction analyses between avirulence effectors and their cognate resistance proteins have provided new insights into the molecular basis of plant-fungal interactions. In this review, we summarize the recent research on the characterization of those genes in both M. oryzae and rice that are important for the PAMP- and effector triggered immunity recognition and signaling processes. We also discuss future directions for research that will further our understanding of this pathosystem. PMID- 23340744 TI - NAC transcription factor ORE1 and senescence-induced BIFUNCTIONAL NUCLEASE1 (BFN1) constitute a regulatory cascade in Arabidopsis. AB - Senescence is a highly regulated process that involves the action of a large number of transcription factors. The NAC transcription factor ORE1 (ANAC092) has recently been shown to play a critical role in positively controlling senescence in Arabidopsis thaliana; however, no direct target gene through which it exerts its molecular function has been identified previously. Here, we report that BIFUNCTIONAL NUCLEASE1 (BFN1), a well-known senescence-enhanced gene, is directly regulated by ORE1. We detected elevated expression of BFN1 already 2 h after induction of ORE1 in estradiol-inducible ORE1 overexpression lines and 6 h after transfection of Arabidopsis mesophyll cell protoplasts with a 35S:ORE1 construct. ORE1 and BFN1 expression patterns largely overlap, as shown by promoter-reporter gene (GUS) fusions, while BFN1 expression in senescent leaves and the abscission zones of maturing flower organs was virtually absent in ore1 mutant background. In vitro binding site assays revealed a bipartite ORE1 binding site, similar to that of ORS1, a paralog of ORE1. A bipartite ORE1 binding site was identified in the BFN1 promoter; mutating the cis-element within the context of the full-length BFN1 promoter drastically reduced ORE1-mediated transactivation capacity in transiently transfected Arabidopsis mesophyll cell protoplasts. Furthermore, chromatin immunoprecipitation (ChIP) demonstrates in vivo binding of ORE1 to the BFN1 promoter. We also demonstrate binding of ORE1 in vivo to the promoters of two other senescence-associated genes, namely SAG29/SWEET15 and SINA1, supporting the central role of ORE1 during senescence. PMID- 23340745 TI - Optical anisotropy in packed isotropic spherical particles: indication of nanometer scale anisotropy in packing structure. AB - We investigated the origin of birefringence in colloidal films of spherical silica particles. Although each particle is optically isotropic in shape, colloidal films formed by drop drying demonstrated birefringence. While periodic particle structures were observed in silica colloidal films, no regular pattern was found in blended films of silica and latex particles. However, since both films showed birefringence, regular film structure patterns were not required to exhibit birefringence. Instead, we propose that nanometer-scale film structure anisotropy causes birefringence. Due to capillary flow from the center to the edge of a cast suspension, particles are more tightly packed in the radial direction. Directional packing results in nanometer-scale anisotropy. The difference in the interparticle distance between radial and circumferential axes was estimated to be 10 nm at most. Nanometer-scale anisotropy in colloidal films and the subsequent optical properties are discussed. PMID- 23340746 TI - Armchair research and the astigmatism of the retrospectoscope: caveat lector. PMID- 23340747 TI - Intraoperative 3-dimensional echocardiography for mitral valve surgery: just pretty pictures or ready for prime time? PMID- 23340748 TI - Perioperative management of cardiovascular implantable electronic devices: what every anesthesiologist needs to know. PMID- 23340749 TI - Ethical contributions to research articles by medical writers. PMID- 23340750 TI - Unusual complication and potential safety hazard from simply drawing up a medication in the operating room. PMID- 23340751 TI - About predictors of acute kidney injury after lung resection. PMID- 23340752 TI - Hypertension and ventricular tachycardia with perioperative use of Vick's Vapor InhalerR. PMID- 23340753 TI - Pregabalin effective for the prevention of chronic postsurgical pain: really? PMID- 23340754 TI - Another sensitive and safe method to observe lung separation during single-lung ventilation. PMID- 23340755 TI - Complex regional pain syndrome: a review. AB - Complex regional pain syndrome, formally known as reflex sympathetic dystrophy, is a poorly understood condition that describes a collection of clinical symptoms and signs occurring in the peripheries most commonly after trauma. Pain is the main problem. It is generally out of proportion to the degree of injury and can be unresponsive to narcotics. In addition joint stiffness, temperature and colour changes, and swelling occur. The diagnosis and treatment are challenging for any clinician and a multidisciplinary approach is often necessary with physiotherapy, occupational therapy, and the pain team. The hand surgeon is involved for two reasons, firstly as the upper limb is the most frequently involved, and secondly because the condition may be a complication of the patient's surgery and result in a much prolonged recovery. This review elucidates the recent advances in the knowledge of the aetiology, classification and treatment of this fascinating condition. PMID- 23340756 TI - Thumb reconstruction without formal pollicization in mirror hand deformity: a series of four cases. AB - Thumb reconstruction in mirror hands is usually done by pollicization. However, objective pinch strength and power grip data in mirror hands following pollicization are lacking. Alternative thumb reconstruction techniques include doing nothing, rotation osteotomy or syndactylization of the radial digits. In this article, we report a series of four cases of mirror hand deformity where the thumb was not reconstructed by formal pollicization. Two cases had non-classic mirror hand deformity (the forearm contained a radius and an ulna) and the other two had classic ulnar dimelia. In all cases, thumb reconstruction was done by keeping one of the radial fingers in place (without pollicization) as the new thumb; and then (if required) performing a secondary osteotomy procedure to rotate the new thumb into pronation. The four cases were recalled back to the clinic for functional assessment at ages 20 years, 5 years, 4 years and 2 years, respectively. The overall hand function was considered 'fair' in the case with concurrent unique features, and was considered 'excellent' in the other three cases. It was concluded that the technique of thumb reconstruction used in the current series is an acceptable option. However, objective measurements, especially with regards to pinch strength and power grip, need to be compared with the pollicization technique. PMID- 23340757 TI - Assessment of scapholunate instability and review of evidence for management in the absence of arthritis. AB - Scapholunate ligament tear is a common wrist injury and may lead to degenerative arthritis of the wrist in the long term. We review the assessment and classification of scapholunate instability and discuss the findings from our search for evidence for the management of scapholunate instability in the absence of arthritis. Strong evidence (level 1 or 2) for management is lacking and published recommendations are largely experience-based. The choice of procedure in the absence of arthritis depends on the extent of the tear, quality of the ligament remnants, and reducibility of the joint. Prospective, randomized studies with validated outcome measures are needed to establish the efficacy of intervention on symptoms and function and its effect on the risk of future arthritis. PMID- 23340758 TI - Paediatric hand fractures. AB - This retrospective study reviews the demographics, morphology and management of paediatric hand fractures. Notes of all children with hand injuries attending a plastic surgery paediatric trauma clinic over a one-year period were reviewed. Non-bony injuries were excluded. A total of 303 fractures in 283 patients were included. Fracture incidence rose after the age of seven, peaking at 14 years of age; 76% of fractures occurred in males. Sporting injuries accounted for 47% of fractures. Physeal fractures were present in 39% of cases. Open fractures accounted for only 4% of all fractures. Management was primarily conservative. Only 5% of cases required surgical fixation; 6% of patients experienced complications. PMID- 23340759 TI - Value of anatomic landmarks in carpal tunnel surgery. AB - This study investigated which anatomic landmarks were most useful for correct and safe incision placement in carpal tunnel surgery. Kirschner wires were attached to the hands to mark previously defined landmarks. The bony attachments of the transverse carpal ligament, which were identified previously, were drawn on an anteroposterior digital x-ray of the hand, with the thumb in full abduction. The relationship between anatomic landmarks and these bony attachments were examined. In all hands, either the line along the third web space or the crease between the thenar and the hypothenar regions, or both, were on the ulnar half of the transverse carpal ligament. During incision placement, we recommend selecting the most ulnar choice between the line drawn along the third web space and the crease between the thenar and hypothenar regions in order to be at safe distance from the recurrent motor branch of the median nerve. PMID- 23340760 TI - Mycobacterium bovis: a rare cause of hand tenosynovitis. PMID- 23340761 TI - Carpal tunnel release: a randomized comparison of three surgical methods. AB - A single-blind, randomized, controlled trial was done to compare the results of carpal tunnel release using classic incision, short incision, or endoscopic technique. In total, 90 consecutive cases were included. Follow-up was 24 weeks. We found a significantly shorter sick leave in the endoscopic group. No significant differences in pain, paraesthesiae, range of motion, pillar pain, and grip strength could be found at 24 weeks of follow-up, although intermediate significant differences were seen, especially in grip strength, in favour of endoscopic technique. No major advantage to using a short incision could be found. There were no serious complications in either group. The results indicate that the endoscopic procedure is safe and has the benefit of faster rehabilitation and return to work. PMID- 23340762 TI - The wrist hyperflexion and abduction of the thumb (WHAT) test: a more specific and sensitive test to diagnose de Quervain tenosynovitis than the Eichhoff's Test. AB - De Quervain's disease has different clinical features. Different tests have been described in the past, the most popular test being the Eichhoff's test, often wrongly named as the Finkelstein's test. Over the years, a misinterpretation has occurred between these two tests, the latter being confused with the first. To compare the Eichhoff's test with a new test, the wrist hyperflexion and abduction of the thumb test, we set up a prospective study over a period of three years for a cohort of 100 patients (88 women, 12 men) presenting spontaneous pain over the radial side of the styloid of the radius (de Quervain tendinopathy). The purpose of the study was to compare the accuracy of the Eichhoff's test and wrist hyperflexion and abduction of the thumb test to diagnose correctly de Quervain's disease by comparing clinical findings using those tests with the results on ultrasound. The wrist hyperflexion and abduction of the thumb test revealed greater sensitivity (0.99) and an improved specificity (0.29) together with a slightly better positive predictive value (0.95) and an improved negative predictive value (0.67). Moreover, the study showed us that the wrist hyperflexion and abduction of the thumb test is very valuable in diagnosing dynamic instability after successful decompression of the first extensor compartment. Our results support that the wrist hyperflexion and abduction of the thumb test is a more precise tool for the diagnosis of de Quervain's disease than the Eichhoff's test and thus could be adopted to guide clinical diagnosis in the early stages of de Quervain's tendinopathy. PMID- 23340763 TI - A simple procedure to determine the infectivity and host range of viruses infecting anaerobic and hyperthermophilic microorganisms. AB - Plaque assay is the method traditionally used to isolate and purify lytic viruses, to determine the viral titer and host range. Whereas most bacterioviruses are either temperate or lytic, the majority of known archeoviruses are not lytic (i.e. they are temperate or chronic). In view of the widespread occurrence of such viruses in extreme environments, we designed an original method, called the inverted spot test, to determine the host range and infectivity of viruses isolated from anaerobic hyperthermophilic and sulfur reducing microorganisms. Here, we used this approach to prove for the first time the infectivity of Pyrococcus abyssi virus 1 (PAV1) and to confirm the host range of Thermococcus prieurii virus 1 (TPV1), the only two viruses isolated so far from any of the described marine hyperthermophilic archaea (Euryarchaeota phylum, Thermococcales order). PMID- 23340764 TI - Anammox bacterial populations in deep marine hypersaline gradient systems. AB - To extend the knowledge of anaerobic ammonium oxidation (anammox) habitats, bacterial communities were examined in two hypersaline sulphidic basins in Eastern Mediterranean Sea. The 2 m thick seawater-brine haloclines of the deep anoxic hypersaline basins Bannock and L'Atalante were sampled in intervals of 10 cm with increasing salinity. (15)N isotope pairing incubation experiments showed the production of (29)N2 and (30)N2 gases in the chemoclines, ranging from 6.0 to 9.2 % salinity of the L'Atalante basin. Potential anammox rates ranged from 2.52 to 49.65 nmol N2 L(-1) day(-1) while denitrification was a major N2 production pathway, accounting for more than 85.5 % of total N2 production. Anammox-related 16S rRNA genes were detected along the L'Atalante and Bannock haloclines up to 24 % salinity, and the amplification of the hydrazine synthase genes (hzsA) further confirmed the presence of anammox bacteria in Bannock. Fluorescence in situ hybridisation and sequence analysis of 16S rRNA genes identified representatives of the marine anammox genus 'Candidatus Scalindua' and putatively new operational taxonomic units closely affiliated to sequences retrieved in marine environments that have documented anammox activity. 'Scalindua brodae' like sequences constituted up to 84.4 % of the sequences retrieved from Bannock. The anammox community in L'Atalante was different than in Bannock and was stratified according to salinity increase. This study putatively extends anammox bacterial habitats to extremely saline sulphidic ecosystems. PMID- 23340765 TI - An alpine treeline in a carbon dioxide-rich world: synthesis of a nine-year free air carbon dioxide enrichment study. AB - We evaluated the impacts of elevated CO2 in a treeline ecosystem in the Swiss Alps in a 9-year free-air CO2 enrichment (FACE) study. We present new data and synthesize plant and soil results from the entire experimental period. Light saturated photosynthesis (A max) of ca. 35-year-old Larix decidua and Pinus uncinata was stimulated by elevated CO2 throughout the experiment. Slight down regulation of photosynthesis in Pinus was consistent with starch accumulation in needle tissue. Above-ground growth responses differed between tree species, with a 33 % mean annual stimulation in Larix but no response in Pinus. Species specific CO2 responses also occurred for abundant dwarf shrub species in the understorey, where Vaccinium myrtillus showed a sustained shoot growth enhancement (+11 %) that was not apparent for Vaccinium gaultherioides or Empetrum hermaphroditum. Below ground, CO2 enrichment did not stimulate fine root or mycorrhizal mycelium growth, but increased CO2 effluxes from the soil (+24 %) indicated that enhanced C assimilation was partially offset by greater respiratory losses. The dissolved organic C (DOC) concentration in soil solutions was consistently higher under elevated CO2 (+14 %), suggesting accelerated soil organic matter turnover. CO2 enrichment hardly affected the C-N balance in plants and soil, with unaltered soil total or mineral N concentrations and little impact on plant leaf N concentration or the stable N isotope ratio. Sustained differences in plant species growth responses suggest future shifts in species composition with atmospheric change. Consistently increased C fixation, soil respiration and DOC production over 9 years of CO2 enrichment provide clear evidence for accelerated C cycling with no apparent consequences on the N cycle in this treeline ecosystem. PMID- 23340766 TI - LEI0258 microsatellite variability in Khorasan, Marandi, and Arian chickens. AB - Microsatellite LEI0258 is a genetic marker for chicken MHC haplotypes and can be used as an indicator of the influence of population genetics on immune responses. LEI0258 microsatellite variability in three Iranian indigenous chicken populations (Khorasan, Marandi, and Arian) was investigated. In total, 142 Khorasan, 42 Marandi, and 58 Arian chickens were examined. Collectively, 25 different alleles and 79 genotypes could be found. The observed levels of heterozygosity were 81% in Khorasan and Marandi and 34% in Arian chickens. Our results indicate that LEI0258 diversity in Marandi chickens is higher than in the other populations. Allelic diversity in Iranian chickens is relatively higher than in the local chicken breeds reported for Brazil and Vietnam. PMID- 23340767 TI - The c.42_52del11 mutation in TPRN and progressive hearing loss in a family from Pakistan. AB - The DFNB79 locus harbors TPRN mutations in which have been reported in a few families with deafness. Four frameshift mutations in TPRN have been described to cause severe or severe-to-profound hearing loss in Moroccan and Pakistani families, and a single frameshift mutation was associated with progressive hearing loss in deaf individuals in a Dutch family. We identified a Pakistani family in which the affected individuals were homozygous for a pathogenic mutation, c.42_52del11, in TPRN (p.G15Afs150X). In contrast to the previously reported individuals affected by the same mutation, hearing loss is likely to be progressive in this family. Thus the same mutation of TPRN can be associated with different thresholds of hearing as well as differences in the stability of the phenotype. PMID- 23340768 TI - Enhancement of the spectral selectivity of complex samples by measuring them in a frozen state at low temperatures in order to improve accuracy for quantitative analysis. Part I. Raman spectroscopic compositional analysis of synthetic hydrocarbon mixtures. AB - A simple strategy for enhancing the Raman spectral selectivity of complex mixture samples by measuring them in a frozen state at low temperatures has been demonstrated and proven to improve the accuracy for compositional analysis. For evaluation, the Raman spectra of synthetic hydrocarbon mixtures that were composed of eleven hydrocarbons (n-hexane, n-heptane, n-octane, n-nonane, isooctane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, and indan) were continuously collected during the elevation of their temperature from cryogenic to near room temperature. The accuracy of determination of n-paraffin concentrations improved significantly when the samples were measured at the temperature range between approximately -175 and -155 degrees C in comparison to the measurements at room temperature. However, the improvement of accuracy was relatively marginal for the concentration determination of naphthenic and aromatic components. Since n-paraffins are easily compressible and deformable in frozen conditions, the subsequent spectral variations could be diverse depending on their molecular structures. Due to this fact, the spectral discrimination among the paraffin components, as well as in comparison to other components, was enhanced and the improved spectral selectivity eventually led to more accurate determination of concentrations. Overall, the proposed strategy is simple and effective, so it is applicable for analysis of real complex mixture samples. PMID- 23340769 TI - Enabling screening in 3D microenvironments: probing matrix and stromal effects on the morphology and proliferation of T47D breast carcinoma cells. AB - During breast carcinoma progression, the three-dimensional (3D) microenvironment is continuously remodeled, and changes in the composition of the extracellular matrix (ECM) occur. High throughput screening platforms have been used to decipher the complexity of the microenvironment and to identify ECM components responsible for cancer progression. However, traditional screening platforms are typically limited to two-dimensional (2D) cultures, and often exclude the influence of ECM and stromal components. In this work, a system that integrates 3 dimensional cell culture techniques with an automated microfluidic platform was used to create a new ECM screening platform that cultures cells in more physiologically relevant 3D in vitro microenvironments containing stromal cells and different ECM molecules. This new ECM screening platform was used to culture T47D breast carcinoma cells in mono- and co-culture with human mammary fibroblasts (HMF) with seven combinations of three different ECM proteins (collagen, fibronectin, laminin). Differences in the morphology of T47D clusters, and the proliferation of T47D cells were found in ECM compositions rich in fibronectin or laminin. In addition, an MMP enzyme activity inhibition screening showed the capabilities of the platform for small molecule screening. The platform presented in this work enables screening for the effects of matrix and stromal compositions and show promises for providing new insights in the identification of key ECM components involved in breast cancer. PMID- 23340770 TI - Annual incidence rate of schizophrenia and schizophrenia spectrum disorders in a longitudinal population-based cohort study. AB - BACKGROUND: Longitudinal incidence studies of schizophrenia spectrum disorders (SSD) performed in mental health service organizations are prone to confounding factors not found in research performed in the general population. OBJECTIVES: To estimate the incidence rates (IRs) over a 10-year period of SSD (broadly defined) and schizophrenia (narrowly defined) in the general population and to analyze associated risk factors. METHODS: A cohort study (1996-2006) in a large general practitioners research database was conducted with longitudinal medical records of 350,524 patients throughout the Netherlands. Cases of SSD were identified and classified by systematic review of medical records. Age- and gender-specific IRs were calculated per calendar year, date of birth, degree of urbanicity and deprivation. RESULTS: Overall IR of SSD in this population was 22/100,000 person years (PY) (95% CI 19-24). IR of schizophrenia was 12/100,000 PY (95% CI 10-14). Period prevalence was 3.5 per 1,000 PY. IRs were higher in men compared to women, had a peak at age 15-25 years, decreasing rapidly after 25 years by 40% per 10 years. IRs of SSD were significantly higher in urban areas, irrespective of deprivation. No association was found between IRs of SSD and living in deprived areas or month of birth. There was no significant time trend of the IR during the period under study. CONCLUSIONS: IRs of SSD are higher in urban areas, independent of social deprivation. Age- and gender-specific differences in IR were found. The magnitude of these differences was larger in narrowly defined schizophrenia than in SSD. PMID- 23340771 TI - Prevalence and factors related to depressive symptoms among family caregivers of nursing home residents in Taiwan. AB - PURPOSE: The purpose of this cross-sectional study was to understand the prevalence and risk factors for depressive symptoms among nursing home residents' family caregivers in Taiwan. METHODS: Family caregivers (n = 191) of nursing home residents were recruited by stratified random sampling from 16 nursing homes throughout Taiwan. Data were collected from caregivers in face-to-face interviews on depressive status (using the Center for Epidemiologic Studies Depression Scale; CES-D), on meaning ascribed to visiting nursing home residents (using the Family Meaning of Nursing-Home Visits scale), and on demographic data. Factors related to depressive symptoms were analyzed by multiple logistic regression. RESULTS: The prevalence of depressive status among family caregivers was 29.8 % as determined by the CES-D cutoff score of >=10. The non-depressed group (CES-D <10) tended to visit residents for emotional maintenance (odds = 0.54), while the depressed group (CES-D >=10) tended to visit due to sense of responsibility for monitoring care quality (odds = 3.25). These results demonstrate that risk factors for depressive symptoms in family caregivers were their age, self perceived health status, education level, and being the resident's main caregiver before admission. CONCLUSION: These results fill a gap in knowledge by providing detailed, evidence-based data on family caregivers' priorities for visiting nursing home residents and it is related to depression. These results also provide useful information for designing intervention protocols to reduce depressive symptoms in family caregivers of nursing home residents, not only in Asian countries, but also in western countries with many Chinese/Asian immigrants. PMID- 23340772 TI - Rapid one-pot propargylamine synthesis by plasmon mediated catalysis with gold nanoparticles on ZnO under ambient conditions. AB - Surface plasmon excitation of gold nanoparticles on ZnO in the presence of an aldehyde, an amine and phenylacetylene led to rapid and selective formation of propargylamines with good yields (50-95%) at room temperature. Plasmon mediated catalysis is the best available route for this ternary coupling. PMID- 23340775 TI - The heart beats anew. PMID- 23340773 TI - CCR4 agonists CCL22 and CCL17 are elevated in pediatric OMS sera: rapid and selective down-regulation of CCL22 by ACTH or corticosteroids. AB - PURPOSE: To study the role of Th2-attracting chemokines in opsoclonus-myoclonus syndrome (OMS), a serious neurological paraneoplastic disorder in need of better immunological understanding and therapy. METHODS: The CCR4 agonists CCL22 and CCL17 were measured in serum by ELISA in children with OMS (238 and 260, respectively), pediatric controls (115 and 143), and other inflammatory neurological disorders (33 and 24). RESULTS: Both CCL22 (+55 %) and CCL17 (+121 %) were significantly elevated in untreated OMS compared to controls and inter correlated (p < 0.0001). Their concentrations in untreated OMS also were higher than in OIND (21 %, 41 %). The concentration of CCL22 in ACTH and steroids groups (not IVIg) was 51 % lower than in controls, but only a smaller effect of ACTH on CCL17 was found. Prospective longitudinal studies revealed a precipitous 81 % drop in CCL22 even by the first week of high-dose ACTH therapy, staying below control mean for at least 12 weeks, and a 34 % reduction after 8 months of combined treatment. Response to ACTH was dose-related (r = -0.50, p < 0.0001). Luminex detection confirmed the ELISA results for CCL22, which were about 200 % higher. CONCLUSIONS: These data reveal an elevated serum concentration of Th2 attracting chemokines CCL22 and CCL17 in OMS. Marked and rapid reduction in CCL22, not CCL17, with either ACTH or steroid therapy suggests differential regulation and cellular sources of CCR4 ligands, and CCL22 as a potential candidate biomarker for ACTH or corticosteroid effect. PMID- 23340776 TI - Immune recovery after hibernation and HIV infection. PMID- 23340778 TI - Predicting cardiac event risk in silico. PMID- 23340779 TI - 'Pet scans': training dogs to sniff out disease. PMID- 23340781 TI - 63rd AALAS national meeting. PMID- 23340782 TI - The internal compass of the pigeon. PMID- 23340783 TI - Response to Protocol Review Scenario: pilot study. PMID- 23340784 TI - Delay between adaptation and experimentation. PMID- 23340785 TI - Response to Protocol Review Scenario: IACUC observation team. PMID- 23340786 TI - Response to Protocol Review Scenario: is the change significant? PMID- 23340788 TI - The effects of music on animal physiology, behavior and welfare. AB - Physiological and psychological effects of listening to music have been documented in humans. The changes in physiology, cognition and brain chemistry and morphology induced by music have been studied in animal models, providing evidence that music may affect animals similarly to humans. Information about the potential benefits of music to animals suggests that providing music may be used as a means of improving the welfare of laboratory animals, such as through environmental enrichment, stress relief and behavioral modification. The authors review the current research on music's effect on animals' physiology and behavior and discuss its potential for improving animal welfare. They conclude that the benefits of providing music to laboratory animals depend on the species and the type of music. PMID- 23340790 TI - Training for a disaster. PMID- 23340789 TI - A co-housing strategy to improve fecundity of mice in timed matings. AB - Timed matings of mice are often carried out to obtain offspring of a precise age when required for a study. Timed matings involve housing male and female mice together for a limited time period, typically overnight. A limitation of this practice is that many mouse pairs fail to mate during the brief co-housing period. The authors co-housed each breeding pair in the same cage but separated by a transparent partition for 3 d before carrying out timed matings. This co housing strategy resulted in increased copulation during the timed mating period and also significantly increased the average number of pups produced per breeding pair. The authors suggest that co-housing likely permits male urine-borne pheromones to induce female estrus and also enables the expression of male and female mating behaviors. PMID- 23340791 TI - The common denominator. PMID- 23340792 TI - Caring for animals like they are her own. PMID- 23340793 TI - Developments in understanding and controlling self assembly of DNA-functionalized colloids. AB - In this article we review the latest achievements in understanding and controlling DNA-mediated interactions between colloidal particles. We report the results of experiments, theoretical studies and computer simulations designed to investigate interactions and aggregation/melting behaviour of DNA-functionalized colloids. The unprecedented insight into the physical effects influencing the interactions and their relation with the tunable parameters of the grafted DNA has resulted in innovative DNA coatings, which are expected to solve the decennial issues encountered in the self assembly of DNA-coated colloids. PMID- 23340794 TI - Effect of dietary sodium restriction on body water, blood pressure, and inflammation in hemodialysis patients: a prospective randomized controlled study. AB - PURPOSE: Accumulating evidence suggests an association between body volume overload and inflammation in chronic kidney diseases. The purpose of this study was to evaluate the effect of dietary sodium reduction in body fluid volume, blood pressure (BP), and inflammatory state in hemodialysis (HD) patients. METHODS: In this prospective controlled study, adult patients on HD for at least 90 days and those with C-reactive protein (CRP) levels >= 0.7 mg/dl were randomly allocated into two groups: group A, which included 21 patients treated with 2 g of sodium restriction on their habitual diet; and group B, which included 18 controls. Clinical, inflammatory, biochemical, hematological, and nutritional markers were assessed at baseline and after 8 and 16 weeks. RESULTS: Baseline characteristics were not significantly different between the groups. Group A showed a significant reduction in serum concentrations of CRP, tumor necrosis factor-alpha, and interleukin-6 during the study period, while BP and extracellular water (ECW) did not change. In group B, there were no changes in serum concentrations of inflammatory markers, BP, and ECW. CONCLUSIONS: Dietary sodium restriction is associated with the attenuation of the inflammatory state, without changes in BP and ECW, suggesting inhibition of a salt-induced inflammatory response. PMID- 23340796 TI - Synthesis, characterization and electrochemiluminescent properties of cyclometalated platinum(II) complexes with substituted 2-phenylpyridine ligands. AB - Two neutral cyclometalated platinum(II) complexes, Pt(DPP)(acac) and Pt(BPP)(acac) (DPP = 2,4-diphenylpyridine, BPP = 2-(4-tert-butylphenyl)-4 phenylpyridine, acac = acetylacetone), have been synthesized and characterized by (1)H NMR spectroscopy, mass spectrometry, elemental analyses and by X-ray crystallography for Pt(DPP)(acac). Electrogenerated chemiluminescence (ECL) of the two complexes in the absence or presence of coreactant tri-n-propylamine (TPrA) in different solvents (CH(3)CN, CH(2)Cl(2), DMF, CH(3)CN/H(2)O (V, 50 : 50)) has been studied. The ECL spectra are identical to their own PL spectra, indicating that ECL processes lead to the same metal-to-ligand charge-transfer ((3)MLCT) excited state that is generated by light excitation. The ECL potentials of Pt(DPP)(acac) and Pt(BPP)(acac)/TPrA in CH(3)CN and CH(3)CN/H(2)O solution were at ~0.75 V vs. SCE, and significantly negatively shifted by about 0.6 V compared to that of the Ru(bpy)(3)(2+)/TPrA system. The ECL quantum efficiencies of the complexes are comparable to that of the Ru(bpy)(3)(2+)/TPrA system. The significant increase of the ECL signal in the coreactant system is due to the formation of the strongly reducing intermediate TPrA. It is noteworthy that the ECL efficiencies of the synthesized compounds are much higher than that of the tridentate polypyridyl ligands. PMID- 23340795 TI - Nek2-targeted ASO or siRNA pretreatment enhances anticancer drug sensitivity in triple-negative breast cancer cells. AB - Although the anticancer drugs paclitaxel and doxorubicin are commonly used to treat many solid tumors, their effectiveness is highly variable due to tumor cell resistance. Therefore, it is important to find mechanisms that can be targeted to increase the sensitivity of cancer cells to current chemotherapeutic agents. NIMA related kinase 2 (Nek2), a serine/threonine kinase is emerging as an important oncogene because of its regulatory role in mitosis. Thus, regulation of the Nek2 expression levels may prove important as a target for cancer treatment. The purpose of our study was to determine whether drug sensitivity was increased in the triple negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 by using small interfering RNA (siRNA) and antisense oligonucleotides (ASOs) against Nek2. To this end, MDA-MB-231 and MDA-MB-468 breast cancer cells transfected with Nek2 siRNA or ASO were exposed to various concentrations of paclitaxel and doxorubicin. Cell viability, cell cycle distribution and apoptosis were evaluated. We observed that drug susceptibility in these transfected cells was dramatically increased compared with either agent alone. FACS results showed that apoptosis was induced in siRNA- and ASO-transfected cells as expected due to the regulatory function of Nek2 in centrosome duplication. Interestingly, the cell cyle was not arrested in transfected cells. We found that siRNA and ASO against Nek2 worked synergistically with paclitaxel and doxorubicin by promoting cell apoptosis. Our results suggest that these drugs in combination with Nek2 siRNA or ASO treatment may improve the sensitivity of cancer cells during chemotherapy treatments. PMID- 23340797 TI - The first dehydration and the competing reaction pathways of glucose homogeneously and heterogeneously catalyzed by acids. AB - The dehydration mechanisms for glucose in beta-pyranose (BP) and in open-chain (OC) forms, catalyzed by acids homogeneously and heterogeneously, were investigated using density functional and two-layer ONIOM calculations. The first dehydration reaction and competing reaction pathways are the main focus of the present study. The energetics of five dehydration and two isomerization pathways were examined for the protonated form of BP in acidic aqueous solutions and the most favorable pathway of these was found to be the dehydration at the anomeric site. No dehydration pathway of OC glucose is favored over its isomerization to BP or to fructose. The relative ease of dehydration over isomerization depends on the selection of the reaction media for the protonated form of BP. These two reaction pathways catalyzed by a surface Bronsted acid site were then examined and the isomerization pathway was found to be more favorable than dehydration at the anomeric site on a surface acid site. These mechanistic insights provide an important guide for the catalyst design/selection of the reaction media for glucose dehydration. PMID- 23340799 TI - Enhancing polyhydroxybutyrate production from high cell density fed-batch fermentation of Bacillus megaterium BA-019. AB - This study demonstrated the improved polyhydroxybutyrate (PHB) production via high cell density cultivation of Bacillus megaterium BA-019 with balanced initial total sugar concentration and carbon to nitrogen (C/N) weight ratio. In the 10 L stirred fermentor operated at 30 degrees C, pH 7.0, 600 rpm, and 1.0 vvm air, with the initial total sugar concentration of 60 g/L and urea at the C/N weight ratio of 10:1, 32.48 g/L cell biomass with the corresponding PHB weight content of 26.94 % and volumetric productivity of 0.73 g/L h were obtained from batch cultivation. Continuing cultivation by intermittent feeding of the sugarcane molasses along with urea at the C/N weight ratio of 12.5:1 gave much improved biomass and PHB production (90.71 g/L biomass with 45.84 % PHB content and 1.73 g/L h PHB productivity). Similar biomass and PHB yields were obtained in the 90 L stirred fermentor when using the impeller tip speed as the scale-up criterion. PMID- 23340800 TI - Energy drink use and its relationship to masculinity, jock identity, and fraternity membership among men. AB - The present study examined whether previous findings linking masculinity constructs and health behaviors applied to a relatively recent health risk behavior for men, the consumption of energy drinks. In addition, it also examined whether self-identifying as a jock and being a member of a fraternity would moderate the relationships between masculinity constructs and energy drink consumption. A total of 589 men completed measures of three masculinity constructs (endorsement of traditional masculinity ideology, conformity to masculine norms, and gender role conflict), energy drink consumption, jock identity, and fraternity membership, in addition to a demographic questionnaire. Age, endorsement of traditional masculinity ideology, and conforming to the masculine norms of risk taking and primacy of work were identified to be significant predictors of energy drink consumption. Furthermore, jock identity moderated the relationship between the endorsement of traditional masculinity ideology and energy drink consumption whereas fraternity membership moderated the relationship between conforming to the masculine norm of violence and energy drink consumption. Limitations, implications, and potential future directions are discussed. PMID- 23340801 TI - E. coli as an all-rounder: the thin line between commensalism and pathogenicity. AB - Escherichia coli is a paradigm for a versatile bacterial species which comprises harmless commensal as well as different pathogenic variants with the ability to either cause intestinal or extraintestinal diseases in humans and many animal hosts. Because of this broad spectrum of lifestyles and phenotypes, E. coli is a well-suited model organism to study bacterial evolution and adaptation to different growth conditions and niches. The geno- and phenotypic diversity, however, also hampers risk assessment and strain typing. A marked genome plasticity is the key to the great variability seen in this species. Acquisition of genetic information by horizontal gene transfer, gene loss as well as other genomic modifications, like DNA rearrangements and point mutations, can constantly alter the genome content and thus the fitness and competitiveness of individual variants in certain niches. Specific gene subsets and traits have been correlated with an increased potential of E. coli strains to cause intestinal or extraintestinal disease. Intestinal pathogenic E. coli strains can be reliably discriminated from non-pathogenic, commensal, or from extraintestinal E. coli pathogens based on genome content and phenotypic traits. An unambiguous distinction of extraintestinal pathogenic E. coli and commensals is, nevertheless, not so easy, as strains with the ability to cause extraintestinal infection are facultative pathogens and belong to the normal flora of many healthy individuals. Here, we compare insights into phylogeny, geno-, and phenotypic traits of commensal and pathogenic E. coli. We demonstrate that the borderline between extraintestinal virulence and intestinal fitness can be blurred as improved adaptability and competitiveness may promote intestinal colonization as well as extraintestinal infection by E. coli. PMID- 23340803 TI - Silencing of integrin-linked kinase suppresses in vivo tumorigenesis of human ovarian carcinoma cells. AB - Integrin-linked kinase (ILK) plays a role in the regulation of multiple cellular functions (e.g., promoting cell migration and proliferation, but inhibiting cell adhesion). This study investigated the inhibitory effects of ILK gene knockdown on the regulation of in vivo tumorigenesis of human ovarian carcinoma cells in nude mouse xenografts. HO-8910 cells were transfected with an ILK antisense oligonucleotide (ILK-ASO) to silence the ILK gene. Expression of ILK mRNA and protein was evaluated by RT-PCR and western blotting, respectively. The cell cycle was assessed by flow cytometric analysis. Cells with or without ILK-ASO transfection were subcutaneously injected into nude mice. The mouse body weight, tumor formation, tumor size and tumor weight were determined up to 30 days after inoculation. Tumor cells transfected with ILK-ASO had significantly decreased ILK mRNA and protein expression (P<0.01) when compared to the control cells. ILK gene silencing significantly increased the number of cells in the G0/G1 phase (67.61 vs. 43.29%, chi2=1197.15, P<0.01). After tumor cell inoculation, tumor cells transfected with ILK-ASO showed significantly delayed tumor formation when compared to control (9.10+/-0.74 vs. 5.30+/-0.67 days, respectively; P<0.01). In addition, tumor growth was suppressed in the 30 days following inoculation (P<0.01 compared with the controls). The average tumor weight in the ILK-ASO group was statistically lower than that of the control group (1.29+/-0.11 vs. 1.57+/-0.13 g, respectively; P<0.01). This study demonstrated that ILK-ASO transfection efficiently downregulated ILK expression in human ovarian carcinoma HO-8910 cells and that ILK gene silencing suppressed tumor growth in nude mice xenografts. PMID- 23340804 TI - Cyclic (amino)(imino)carbene complexes by borylene transfer to isocyanides. AB - Here we report the facile formation of boron-containing cyclic (amino)(imino)carbene complexes by reaction of a chromium borylene complex [(OC)(5)Cr=B=N(SiMe(3))(2)] with isocyanides. PMID- 23340802 TI - C/EBPalpha and MYB regulate FLT3 expression in AML. AB - The interaction between the receptor FLT3 (FMS-like tyrosine kinase-3) and its ligand FL leads to crucial signalling during the early stages of the commitment of haematopoietic stem cells. Mutation or over-expression of the FLT3 gene, leading to constitutive signalling, enhances the survival and expansion of a variety of leukaemias and is associated with an unfavourable clinical outcome for acute myeloid leukaemia (AML) patients. In this study, we used a murine cellular model for AML and primary leukaemic cells from AML patients to investigate the molecular mechanisms underlying the regulation of FLT3 gene expression and identify its key cis- and trans-regulators. By assessing DNA accessibility and epigenetic markings, we defined regulatory domains in the FLT3 promoter and first intron. These elements permit in vivo binding of several AML-related transcription factors, including the proto-oncogene MYB and the CCAAT/enhancer binding protein C/EBPalpha, which are recruited to the FLT3 promoter and intronic module, respectively. Substantiating their relevance to the human disease, our analysis of gene expression profiling arrays from AML patients uncovered significant correlations between FLT3 expression level and that of MYB and CEBPA. The latter relationship permits discrimination between patients with CEBPA mono- and bi-allelic mutations, and thus connects two major prognostic factors for AML. PMID- 23340805 TI - "Judging a body by its cover": young Lebanese-Canadian women's discursive constructions of the "healthy" body and "health" practices. AB - Our interest stems from the dramatic increase in the number of obesity studies, which expose Canadian women to a huge amount of information that links health to weight. Using feminist poststructuralist and postcolonial lenses, this paper investigates young Lebanese-Canadian women's constructions of the body and "health" practices within the context of the dominant obesity discourse. Participant-centered conversations were held with 20 young Christian Lebanese Canadian women. A thematic analysis was first conducted and was followed by a poststructuralist discourse analysis to further our understanding of how the participants construct themselves as subjects within various discourses surrounding health, obesity, and the body. Our findings reveal that most participants conflate the "healthy" body and the "ideal" body, both of which they ultimately portray as thin. The young women construct the "healthy"/"ideal" body as a solely individual responsibility, thus reinforcing the idea of "docile bodies." The majority of participants report their frequent involvement in disciplinary practices such as rigorous physical activity and dietary restrictions, and a few young women mention the use of other extreme forms of bodily monitoring such as detoxes, dieting pills, and compulsive exercise. We discuss the language employed by participants to construct their multiple and shifting subjectivities. For instance, many of these Lebanese-Canadian women use the term "us" to dissociate themselves from Lebanese women ("them"), whom they portray as overly focused on thinness and beauty and engaged in physical activity and other bodily practices for "superficial" purposes. The participants also use the "us/them" trope to distance themselves from "Canadian" women (read: white Euro-Canadian women), whom they portray as very physically active for purposes beyond the improvement of the physical appearance of the body. We discuss the impacts of the young Christian Lebanese-Canadian women's hybrid cultural identities and diasporic spaces on their discursive constructions of the body and "health" practices. Finally, we examine the participants' fluid subject positions: On one hand, they construct themselves as neoliberal subjects re citing elements of dominant neoliberal discourses (self-responsibility for health, traditional femininity, and obesity) but, on the other hand, they at times construct themselves as "timid" poststructuralist subjects expressing awareness of, and "micro-resistance" to such discourses. PMID- 23340806 TI - Tuberculosis among homeless population from Medellin, Colombia: associated mental disorders and socio-demographic characteristics. AB - Homeless people are highly susceptible to tuberculosis. It has been suggested that this population have high rates of mental disorders associated with tuberculosis. We assessed tuberculosis incidence, its transmission patterns and association with socio-demographic factors and mental disorders in Colombian homeless people. Prospective study which socio-demographic characteristics and mental disorders were assessed through interviews. Sputa from patients with respiratory symptoms were processed and clinical isolates analyzed by IS6110 RFLP. Multivariate analysis performed by logistic regression model. From 426 homeless studied, tuberculosis incidence found was 7.9 %. 44 % of isolates were clustering. It was found high risk of having tuberculosis associated with income from drugs trade (OR: 3.40 [95 % CI: 1.28-9.05]), dysthymia (OR: 2.54 [95 % CI: 1.10-5.86]) and receiving food from other homeless (OR: 2.47 [95 % CI: 1.16 5.25]). Tuberculosis incidence and degree of transmission are high in homeless studied. Implementing programs to better control tuberculosis among homeless population must consider socio-demographic factors and mental disorders associated with the disease. PMID- 23340807 TI - Polarisabilities of alkylimidazolium ionic liquids. AB - The molar polarisability and molar volume for 71 ionic liquids were extracted from 157 measurements of their refractive index and density, which were then further deconstructed into atomic contributions by means of a Designed Regression analysis. Using this approach, the density and refractive index for any chosen ionic liquid with alkyl-substituted imidazolium cations can be predicted in good agreement with experimental data. PMID- 23340808 TI - Marked enhancement in the artemisinin content and biomass productivity in Artemisia annua L. shoots co-cultivated with Piriformospora indica. AB - A significant enhancement in artemisinin content, an important anti-malarial compound, has been achieved in Artemisia annua L. shoots by co-cultivating with Piriformospora indica, a mycorrhiza-like fungus. The in vitro shoots derived from nodal cultures of A. annua were implanted on four different culture media namely, (i) Murashige & Skoog (MS) basal, (ii) MS + 5 MUM indole-3-butyric acid (IBA), (iii) MS + P. indica and, (iv) MS + 5 MUM IBA + P. indica. After 2 months, it was observed that the cultures reared on MS + 5 MUM IBA + P. indica showed optimum growth in terms of shoot and root proliferation over those cultured without P. indica. The average shoot number on MS + 5 MUM IBA + P. indica was 17.83 +/- 1.01 and on MS + P. indica alone was 12.75 +/- 1.10. A drastic decline in shoot number was observed without P. indica which was 2.0 +/- 0.12 on basal and 4.9 +/- 1.52 on 5 MUM IBA. Similarly, a maximum average of 16.83 +/- 0.82 roots were achieved on MS + 5 MUM IBA + P. indica which declined to 10.75 +/- 1.02 on MS + P. indica. A further decrease in root number occurred in shoots without P. indica, their average being 2.5 +/- 0.12 on basal and 8.91 +/- 1.57 on 5 MUM IBA. HPLC analysis of the aforesaid cultures revealed that the quantity of artemisinin was significantly higher (1.30 +/- 0.03 %) in shoots cultured on 5 MUM IBA + P. indica compared to those of control (0.80 +/- 0.01 %). PMID- 23340809 TI - Self-sustained carbon monoxide oxidation oscillations on size-selected platinum nanoparticles at atmospheric pressure. AB - High-quality mass spectrometry data of the oscillatory behavior of CO oxidation on SiO(2) supported Pt-nanoparticles at atmospheric pressure have been acquired as a function of pressure, coverage, gas composition and nanoparticle size. The oscillations are self-sustained for several days at constant temperature, pressure and CO/O(2) ratio. The frequency of the oscillations is very well defined and increases over time. The oscillation frequency is furthermore strongly temperature dependent with increasing temperature resulting in increasing frequency. A plausible mechanism for the oscillations is proposed based on an oxidation-reduction cycle of the nanoparticles which change the rate of CO oxidation on the particles. PMID- 23340810 TI - Genome damage in peripheral blood lymphocytes of diabetic and non-diabetic individuals after intervention with vegetables and plant oil. AB - Recent studies suggest increased cancer risk in patients with type 2 diabetes mellitus (T2DM) compared with healthy individuals. The present study aims to assess whether T2DM is associated with increased genome instability and whether a healthy diet with natural foods can improve genome stability in peripheral blood lymphocytes (PBLs). Seventy-six diabetic and 21 non-diabetic individuals were randomly assigned to either an 'intervention' or an 'information only' group. All participants received information about the beneficial effects of a healthy diet, while subjects of the intervention group received additionally 300g of vegetables and 25ml of plant oil rich in polyunsaturated fatty acids per day for 8 weeks. Chromosomal damage was assessed using the cytokinesis-block micronucleus (MN) cytome assay. Levels of chromosomal damage did not differ between diabetic and non-diabetic individuals. However, diabetic individuals with MN frequency above the high 50th percentile had significantly higher levels of fasting plasma glucose, glycosylated haemoglobin and were at higher risk for cardiovascular disease (CVD), assessed by the Framingham general cardiovascular risk score. Non diabetic individuals with MN frequency above the 50th percentile had significantly lower vitamin B12 levels. The intervention with vegetables and plant oil led to significant increases in folate, gamma-tocopherol, alpha- and beta-carotene while vitamin B12 was significantly reduced. Levels of chromosomal damage were not altered, only apoptosis was slightly increased. The results suggest interactions between glycaemic control, CVD risk and genome stability in individuals with T2DM. However, a healthy diet does not improve genome damage in PBLs. PMID- 23340811 TI - Micronucleus induction in the bone marrow of rats by pharmacological mechanisms. I: glucocorticoid receptor agonism. AB - A novel selective glucocorticoid receptor (GR) agonist, AZD2906, was found to increase the incidence of micronucleated immature erythrocytes (MIE) in the bone marrow of rats given two oral doses at the maximum tolerated level. Because GR agonists as a class are considered not to be genotoxic and AZD2906 showed no activity in the standard in vitro tests or in vivo in a rat liver comet assay, investigative studies were performed to compare AZD2906 with a reference traditional GR agonist, prednisolone. Emphasis was placed on blood and bone marrow parameters in these studies because GR activation has been reported to induce erythropoiesis which, in turn, is known to increase MIE in the bone marrow. Both compounds induced almost identical, small increases in micronucleus frequency at all doses tested. Directly comparable changes in haematological and bone marrow parameters were also seen with significant decreases in lymphoid cells in both compartments and significant increases in numbers of circulating neutrophils. Although no evidence of increased erythropoiesis was seen as increased immature erythrocyte numbers either in the blood or in the bone marrow, histopathological examination showed focal areas in the bone marrow where the erythroid population was enriched in association with an atrophic myeloid lineage. This could have been due to direct stimulation of the erythroid lineage or a secondary effect of myelosuppression inducing a rebound increase in erythropoiesis into the vacant haematopoietic cell compartment. It was concluded that the increased MIE frequencies induced by both AZD2906 and prednisolone are a consequence of their pharmacological effects on the bone marrow, either by directly inducing erythropoiesis or by some other unknown effect on cellular function, and do not indicate potential genotoxicity. This conclusion is supported by the lack of carcinogenic risk in man demonstrated by decades of clinical use of prednisolone and other GR agonists. PMID- 23340812 TI - Mathematical modelling of miRNA mediated BCR.ABL protein regulation in chronic myeloid leukaemia vis-a-vis therapeutic strategies. AB - Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disease resulting from an aberrant BCR.ABL gene and protein. To predict BCR.ABL protein abundance and phosphorylation in individual cells in a population of CML cells, we modelled BCR.ABL protein regulation through associated miRNAs using a systems approach. The model rationalizes the level of BCR.ABL protein heterogeneity in CML cells in correlation with the heterogeneous BCR.ABL mRNA levels. We also measured BCR.ABL mRNA and BCR.ABLp phosphorylation in individual cells. The experimental data were consistent with the modelling results, thereby partly validating the model. Provided it is tested further, the model may be used to support effective therapeutic strategies including the combined application of a tyrosine kinase inhibitor and miRNAs targeting BCR.ABL. It appears able to predict different effects of the two types of drug on cells with different expression levels and consequently different effects on the generation of resistance. PMID- 23340813 TI - Performance of the OTSC System in the endoscopic closure of iatrogenic gastrointestinal perforations: a systematic review. AB - BACKGROUND: Reliable closure is a prerequisite for conventional and innovative endoscopic procedures, such as NOTES. The purpose of this study is the systematic evaluation of the procedural and clinical success rates in closure of iatrogenic gastrointestinal perforations and acute anastomotic leaks by means of the over the-scope-clip system (OTSC((r))). DESIGN: PubMed and other sources were searched systematically for clinical and preclinical research on the evaluation of the OTSC System for closure of gastrointestinal perforations and leaks. Appraisal of studies for inclusion and data extraction was performed independently by two reviewers using an a priori determined data extraction grid. Major endpoints to be extracted were data on procedural success (successful clip application) and clinical access (durable closure of defect without secondary adjunct therapy). RESULTS: A total of 17 clinical research articles/abstracts and 22 preclinical research articles/abstracts were identified. The examined clinical studies comprised case series and clinical single-arm studies. The reviewed studies revealed a consistently high mean rate of procedural success of 80-100 % and durable clinical success of 57-100 %. An identified major drawback preventing successful clip application was occurrence of fibrotic or inflamed lesion edges. Usage of the OTSC System was accompanied by neither major clip-related nor application-related complication. In experimental settings, closure of larger perforations and gastric access sites of NOTES or endoscopic full-thickness resection were achieved with high rates of success. CONCLUSIONS: Because randomized, clinical trials are not available in this field of indication, the evaluation is based on small case series. Nevertheless, by pooling all experience gained, we conclude that endoscopic closure of iatrogenic gastrointestinal perforations and acute anastomotic leaks by means of the OTSC System is a safe and effective method. PMID- 23340815 TI - Tissue Doppler imaging, volume responsiveness and impaired relaxation. PMID- 23340814 TI - Surgical techniques to minimize shoulder pain after laparoscopic cholecystectomy. A systematic review. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is the treatment of choice for symptomatic cholecystolithiasis. Despite the many advantages over open surgery, many patients complain about referred pain to the shoulder during the postoperative course. The purpose of this review was to evaluate different intraoperative surgical methods to minimize shoulder pain (SP). METHODS: A search of the literature was conducted using PubMed, Excerpta Medica Database (EMBASE), and Cochrane database of systematic reviews. Eligibility criteria were: randomized clinical trials or meta-analysis evaluating intraoperative surgical methods applied to minimize incidence or severity of SP after LC. Only papers published in English were included. Data extracted were year of publication, number of participants and allocation, nonsignificant or significant effect on incidence or severity of SP. RESULTS: A total of 31 papers where included in the review. Seven, 8, and 12 papers investigated the effect of drains, abdominal wall lift (AWL), and low-pressure pneumoperitoneum respectively. Four papers investigated drain suction, active gas aspiration, low insufflation flow or N2O insufflation respectively. The interventions that overall showed a significant reduction on either the incidence or severity of SP were low-pressure pneumoperitoneum, low insufflation rate, and active gas aspiration. CONCLUSIONS: Drainage and AWL are not recommended to reduce SP after LC. Low-pressure pneumoperitoneum with carbon dioxide is the best documented intraoperative surgical method to minimize both the incidence and severity of SP after LC. PMID- 23340816 TI - Tissue Doppler imaging, volume responsiveness and impaired relaxation: reply to comment by Wiersema. PMID- 23340817 TI - Alkyl groups as synthetic vehicles in gold-mediated oxidative coupling reactions. AB - The use of surface-bound alkyl and phenyl groups as synthetic vehicles in coupling reactions on oxygen-activated Au(111) is demonstrated by the formation of ethers via alkyl and phenyl iodides. Ethers are formed by successive additions of surface-bound alkyl groups to adsorbed atomic oxygen to form first the alkoxy and then the ether. The addition of the ethyl group to adsorbed oxygen on Au(111) is the rate-limiting step leading to diethyl ether formation. Alkyl groups also add to adsorbed alkoxy groups formed from alcohols. An unusual feature of the alkyl iodide reactions on Au is that oxygen is not required for the activation step; hence, opening new potential reactive pathways on metallic Au. PMID- 23340818 TI - Development of a novel drive mode to prevent aortic insufficiency during continuous-flow LVAD support by synchronizing rotational speed with heartbeat. AB - Aortic insufficiency (AI) is a serious complication for patients on long-term support with left ventricular assist devices (LVAD). Postoperative aortic valve opening is an important predictor of AI. A system is presently available that can promote native aortic flow by reducing rotational speed (RS) for defined intervals. However, this system can cause a reduction in pump flow and lead to insufficient support. We therefore developed a novel "delayed copulse mode" to prevent AI by providing both minimal support for early systole and maximal support shortly after aortic valve opening by changing the RS in synchronization with heartbeat. To evaluate whether our drive mode could open the aortic valve while maintaining a high total flow (sum of pump flow and native aortic flow), we installed a centrifugal LVAD (EVAHEART((r)); Sun Medical) in seven goats each with normal hearts and acute LV dysfunction created by micro-embolization of the coronary artery. We intermittently switched the drive mode from continuous (constant RS) with 100 % bypass to delayed copulse mode with 90 % bypass. Total flow did not significantly change between the two modes. The aortic valve opened when the delayed copulse mode was activated. The delayed copulse mode allowed the aortic valve to open while maintaining a high total flow. This novel drive mode may considerably benefit patients with severe heart failure on long-term LVAD support by preventing AI. PMID- 23340819 TI - Achyranthes bidentata polysaccharides induce chondrocyte proliferation via the promotion of the G1/S cell cycle transition. AB - Achyranthes bidentata polysaccharides (ABPS) are the major bioactive constituents of Radix Achyranthes bidentata (AB), which has been widely used in traditional Chinese medicine for the treatment of osteoarthritis. However, the molecular mechanisms behind the therapeutic effect of ABPS remain unclear. In the present study, chondrocytes were isolated from Sprague-Dawley rats. The effects of ABPS on the G1/S cell cycle transition in primary chondrocytes were investigated. The chondrocytes treated with and without ABPS were analyzed and it was observed that ABPS treatment was able to enhance chondrocyte proliferation in a dose- and time dependent manner and promote the progression of chondrocyte cell cycle proliferation via the promotion of the G1 to S phase transition. Furthermore, using RT-PCR and western blot analysis, ABPS were observed as significantly upregulating the expression of cyclin D1 and the cyclin-dependent kinases (CDKs) CDK4 and CDK6. These results suggest that ABPS are able to promote chondrocyte proliferation via the promotion of the G1/S cell cycle transition. PMID- 23340820 TI - Plasmacytoid dendritic cells are scarcely represented in the human gut mucosa and are not recruited to the celiac lesion. AB - Celiac disease (CD) is a chronic small intestinal inflammation precipitated by gluten ingestion. According to case reports, interferon (IFN)-alpha administration may induce development of overt CD. Plasmacytoid dendritic cells (PDCs) were thought to be the source of IFN-alpha and promote a T helper type 1 response leading to lesion formation. Surprisingly and contradicting to earlier findings, PDCs were described as the main antigen-presenting cells (APCs) in human duodenal mucosa and particularly in CD. Here we show that when assessed by flow cytometry and in situ staining, PDCs represent < 1% of APCs in both normal duodenal mucosa and the celiac lesion. Low levels of IFN-alpha were detected in the celiac lesion assessed by western blot, reverse transcriptase (RT)-PCR, and immunohistochemistry. In four cell populations sorted from the celiac lesion (based on their expression of HLA-DR and CD45), we found that equally low levels of mRNA for IFN-alpha were distributed among these cell populations. Together, these results suggest that relatively small amount of IFN-alpha, produced by a variety of cell types, is present in the celiac mucosa. IFN-lambda, a type III IFN important in intestinal antiviral defense, was produced mainly by APCs, but its expression was not increased in the celiac lesion. PMID- 23340822 TI - Negative regulation of human mononuclear phagocyte function. AB - At mucosal surfaces, phagocytes such as macrophages coexist with microbial communities; highly controlled regulation of these interactions is essential for immune homeostasis. Pattern-recognition receptors (PRRs) are critical in recognizing and responding to microbial products, and they are subject to negative regulation through various mechanisms, including downregulation of PRR activating components or induction of inhibitors. Insights into these regulatory mechanisms have been gained through human genetic disease-association studies, in vivo mouse studies utilizing disease models or targeted gene perturbations, and in vitro and ex vivo human cellular studies examining phagocytic cell functions. Although mouse models provide an important approach to study macrophage regulation, human and mouse macrophages exhibit differences, which must be considered when extrapolating mouse findings to human physiology. This review discusses inhibitory regulation of PRR-induced macrophage functions and the consequences of dysregulation of these functions and highlights mechanisms that have a role in intestinal macrophages and in human macrophage studies. PMID- 23340821 TI - Genome-wide transcriptional analysis of differentially expressed genes in flagellin-pretreated mouse corneal epithelial cells in response to Pseudomonas aeruginosa: involvement of S100A8/A9. AB - We previously showed that pre-exposure of the cornea to Toll-like receptor 5 ligand flagellin induces profound mucosal innate protection against infections by modifying gene expression. Taking advantage of easily procurable epithelial cell population, this study is the first report to use genome-wide cDNA microarray approach to document genes associated with flagellin-induced protection against Pseudomonas aeruginosa in corneal epithelial cells (CECs). Infection altered the expression of 675 genes (497 up and 178 down), while flagellin pretreatment followed by infection resulted in a great increase in 890 gene upregulated and 37 genes downregulated. Comparing these two groups showed 209 differentially expressed genes (157 up, 52 down). Notably, among 114 genes categorized as defense related, S100A8/A9 are the two most highly induced genes by flagellin, and their expression in the corneal was confirmed by realtime PCR and immunohistochemistry. Neutralization of S100A8 and, to a less extent, A9, resulted in significantly increased bacterial burden and severe keratitis. Collectively, our study identifies many differentially expressed genes by flagellin in CECs in response to Pseudomonas. These novel gene expression signatures provide new insights and clues into the nature of protective mechanisms established by flagellin and new therapeutic targets for reducing inflammation and for controlling microbial infection. PMID- 23340823 TI - Natural killer cells protect mice from DSS-induced colitis by regulating neutrophil function via the NKG2A receptor. AB - Natural killer (NK) cells are traditionally considered in the context of tumor surveillance and infection defense but their role in chronic inflammatory disorders such as inflammatory bowel disease is less clear. Here, we investigated the role of NK cells in dextran sodium sulfate (DSS)-induced colitis in mice. Depletion of NK cells impairs the survival of mice with colitis and is linked with dramatic increases in colonic damage, leukocyte infiltration, and pro inflammatory profiles. Mice depleted of NK cells had increased numbers of neutrophils in colons and mesenteric lymph nodes, compared with control mice, in addition to acquiring a hyper-activation status. In vitro and in vivo studies demonstrate that NK cells downregulate pro-inflammatory functions of activated neutrophils, including reactive oxygen species and cytokine production, by direct cell-to-cell contact involving the NK cell-inhibitory receptor NKG2A. Our results indicate an immunoregulatory mechanism of action of NK cells attenuating DSS induced colitis neutrophil-mediated inflammation and tissue injury via NKG2A dependent mechanisms. PMID- 23340824 TI - An awareness approach to analyze ECG streaming data. AB - Real-time remote health monitoring systems are experiencing tremendous advancement resulting from improvements in low power, reliable sensors; yet they are still constrained to low-level interpretation. Automatic data analysis continues to be a tedious task due to a lack of efficient, reliable platforms for data analysis. In this paper, we present a system for monitoring patients remotely by emphasizing the strength of Complex Event Processing (CEP) and Situation Awareness. In this approach, the system makes decisions in a declarative way, which helps medical experts to understand the situation in a more realistic manner. The primary objective of this paper is to explicate the different components inside the system. To verify the technical feasibility of each component, the proposed system is implemented and tested using ECG data. PMID- 23340825 TI - Closing the feedback loop: an interactive voice response system to provide follow up and feedback in primary care settings. AB - In primary care settings, follow-up regarding the outcome of acute outpatient visits is largely absent. We sought to develop an automated interactive voice response system (IVRS) for patient follow-up with feedback to providers capable of interfacing with multiple pre-existing electronic medical records (EMRs). A system was designed to extract data from EMRs, integrate with the IVRS, call patients for follow-up, and provide a feedback report to providers. Challenges during the development process were analyzed and summarized. The components of the technological solution and details of its implementation are reported. Lessons learned include: (1) Modular utilization of system components is often needed to adapt to specific clinic workflow and patient population needs (2) Understanding the local telephony environment greatly impacts development and is critical to success, and (3) Ample time for development of the IVRS questionnaire (mapping all branching paths) and speech recognition tuning (sensitivity, use of barge-in tuning, use of "known voice") is needed. With proper attention to design and development, modular follow-up and feedback systems can be integrated into existing EMR systems providing the benefits of IVRS follow-up to patients and providers across diverse practice settings. PMID- 23340826 TI - Health information technology adoption in U.S. acute care hospitals. AB - Previous studies show that the healthcare industry lags behind many other economic sectors in the adoption of information technology. The purpose of this study is to understand differences in structural characteristics between providers that do and that do not adopt Health Information Technology (HIT) applications. Publicly available secondary data were used from three sources: American Hospital Association (AHA) annual survey, Healthcare Information and Management Systems Society (HIMSS) analytics annual survey, and Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS) databases. Fifty two information technologies were grouped into three clusters: clinical, administrative, and strategic decision making ITs. Negative binomial regression was applied with adoption of technology as the dependent variables and eight organizational and contextual factors as the independent variables. Hospitals adopt a relatively larger proportion of administrative information technology as compared to clinical and strategic IT. Large size, urban location and HMO penetration were found to be the most influential hospital characteristics that positively affect information technology adoption. There are still considerable variations in the adoption of information technology across hospitals and in the type of technology adopted. Organizational factors appear to be more influential than market factors when it comes to information technology adoption. The future research may examine whether the Electronic Health Record (EHR) Incentive Program in 2011 would increase the information technology uses in hospitals as it provides financial incentives for HER adoptions and uses among providers. PMID- 23340827 TI - Efficient conversion of arylene precursors into photoluminescent phosphonates for surface modification of metal oxides. AB - Three highly fluorescent phosphonates have been prepared in good yields from different arylene bridged 5-iodothiophenes by following an optimized four-step procedure. The compounds have been immobilised on mesoporous zirconia, alumina and titania particles in order to probe their luminescence properties on the surfaces. The organic compounds as well as the obtained hybrid materials have been characterised using liquid phase or MAS NMR spectroscopy, N2 physisorption measurements, ATR-IR spectroscopy and elemental analysis. The luminescence intensity of the organic molecules was found to be in general much more dependent on the surface used for grafting rather than on the dye loading obtained for different metal oxides powders. The luminescence extinction, which has been detected for all coated TiO2 samples, is most likely due to the different electronic properties of this semiconducting support compared to the other surfaces. The method described shows how fluorescent tracers can be easily synthesised and applied in surface analytics after exploring the interaction of the corresponding organophosphonates with several ceramic interfaces. PMID- 23340828 TI - An integrative network inference approach to predict mechanisms of cancer chemoresistance. AB - We present an integrative general network inference methodology to infer genetic and metabolic pathways associated with oncological drug chemoresistance. This methodology is general because it can infer different kinds of networks from different kinds of data. It is integrative because it integrates model simulation in its framework and it assembles into a larger integrated network all the inferred networks. The inference model is a variational approximation of Bayesian inference for stochastic processes. We used the Bayesian framework due to its ability to incorporate prior knowledge and constraints in the inference procedure and to treat both partial data and a large amount of data whose dynamics laws are mostly unknown. We show the performance of this approach using a case study of the gemcitabine chemoresistance in pancreatic cancer cells. Our method, inferred from time series data of gene expressions and metabolites, concentrates first the network of interactions of genes responsible for the sensitivity and resistance to gemcitabine, then the metabolic network, and finally it merges the two networks into a larger network predicting the correlations between genes and metabolizing enzymes. PMID- 23340829 TI - A self-assembled molecular nanostructure for trapping the native adatoms on Cu(110). AB - The native copper adatoms get trapped in a self-assembled molecular nanostructure which is mainly formed by the intermolecular van der Waals interactions, and two dominating specific binding modes between the adatoms and the molecules are revealed at the atomic scale by high-resolution STM imaging. PMID- 23340830 TI - Management of peripherally inserted central catheter associated deep vein thrombosis in children. AB - INTRODUCTION: No protocol exists for prophylaxis or therapeutic management of peripherally inserted central catheter (PICC) related deep venous thrombosis (DVT) in children. Currently, very few patients are provided prophylaxis for DVT. In this study, we analyzed our current practice of PICC placement to identify the frequency of DVT, analyze risk factors and determine current treatment patterns in order to determine the need for protocols. METHODS: The dataset was retrospectively collected from January 1, 2000 to December 31, 2011. Patients with an upper extremity PICC were assessed for subsequent DVT formation. Variables included: demographics, co-morbidities, method of DVT diagnosis, treatment course, and recurrence. RESULTS: There were 1,289 PICC placements, with 24 (1.9 %) per line events of DVT in 23 patients, of which 3 had recent surgery, 2 had sepsis, 1 had a family history of clots, and 2 had a malignancy. All but one was symptomatic. Diagnosis was made in 92 % by ultrasound, the remaining with CT. No patients had prophylaxis. Of the seven patients who underwent hypercoagulable work-up, three were positive. 15 patients were treated with enoxaparin, 5 patients were treated with heparin, 2 treated with tissue plasminogen activator and 2 were observed. 84 % were treated with long-term enoxaparin for a mean of 3.3 months with 54 % proven clot resolution and 1 patient had recurrence of UE DVT. CONCLUSIONS: The risk of DVT with PICC placement is small in children and prophylaxis can probably be reserved for those with previous DVT or known hypercoagulable state. PMID- 23340831 TI - Repair of congenital diaphragmatic hernias through umbilical skin incisions. AB - The use of thoracoscopy and laparoscopy in the treatment of congenital diaphragmatic hernias (CDHs) has been recently reported; however, the use of these procedures still remains controversial due to CO2 insufflation and limited working space. In addition, because of difficult techniques, it has not been widely accepted. Among CDH patients, mild cases whose lung is not hypoplastic, and not associated with persistent pulmonary hypertension of the neonate (PPHN) often develop small defects in the diaphragm that can be repaired using "direct closure." Because direct closure does not require as wide an operative field as that needed for patch closure, we repaired CDH through umbilical skin windows in two neonates with mild CDH to minimize the wounds. With the creation of additional radical small incisions, the surgeries were successfully performed without any intra- or postoperative complications, and the wounds were cosmetically pleasing. The repair of CDHs through umbilical skin windows is a feasible and useful approach in neonates with mild CDH. PMID- 23340832 TI - Graphene oxide based surface-enhanced Raman scattering probes for cancer cell imaging. AB - The intrinsic Raman signals provide the potential of graphene oxide (GO) for cellular imaging. Herein, novel surface-enhanced Raman scattering (SERS) labels based on GO-Ag nanoparticle (NP) composites are developed for fast cellular probing and imaging. The optimum SERS signals of the hybrids can be well controlled by adjusting the weight ratio between AgNO(3) and GO. Utilizing GO AgNPs as the highly sensitive optical probes, fast SERS imaging of cancer cells is realized with a very short integration time of about 0.06 s per pixel. Furthermore, folic acid (FA) is covalently conjugated to GO for targeting specific cancer cells with folate receptors (FRs). Targeted SERS images can be acquired after 2 h incubation with FA-GO-AgNPs, which are specifically located on the surface of FR-positive cancer cells. In conclusion, the GO-based Raman probes mentioned here open up exciting opportunities for biomedical imaging. PMID- 23340833 TI - The association between hepatitis B virus infection and disease activity, synovitis, or joint destruction in rheumatoid arthritis. AB - The prevalence of chronic hepatitis B virus (HBV) infection in China is high. Four percent of patients with HBV infection can present with polyarthritis and positive rheumatic factor similar to rheumatoid arthritis (RA). Here, we investigated the association between HBV infection and serological, radiological, or histological disease status in RA. According to HBV infection status, 223 consecutive hospitalized Chinese patients with RA were divided into the groups of chronic HBV infection, past HBV infection, and no HBV infection. Clinical data and hand radiographs were collected. Synovium was obtained by closed-needle biopsy, and serial tissue sections were stained immunohistochemically for HBV surface antigen (HBsAg) and cluster of differentiation (CD) markers. (1) The prevalence of HBsAg positivity and chronic hepatitis B in RA was consistent with the age-matched general Chinese population (11.2 vs. 8.7 %, 1.7 vs. 1.0 %, respectively, P > 0.05). (2) Clinical parameters, disease activity score in 28 joints, or Sharp scores showed no significant difference among the three groups in 206 RA or 140 treatment-naive patients, both with active disease (all P > 0.05). (3) Synovial immunohistochemical staining showed negative HBsAg in ten RA patients with HBV carrier status and ten RA patients with past HBV infection. Except for higher subintimal CD3+ cell density in the past HBV infection group, Krenn's synovitis score, mean densities of subintima positive-staining cells (CD20, CD38, CD79a, and CD68), and CD34+ microvessel counts showed no significant difference among RA patients with HBV carrier status, past HBV infection, or no HBV infection (all P > 0.05). Chronic HBV infection may have no significant effect on disease activity, synovitis, or joint destruction in RA. PMID- 23340834 TI - The effect of vitamin D levels on the assessment of disease activity in rheumatoid arthritis. AB - Disease activity in rheumatoid arthritis (RA) is assessed by a combination of objective and subjective tests, combined to produce a disease activity score in 28 joints (DAS28). There is some evidence that RA disease activity, as assessed by DAS28, can be influenced by vitamin D levels. It is difficult to know whether this is due to a true immunomodulatory effect of vitamin D or a more subjective effect of low vitamin D on pain perception. We addressed this issue by comparing vitamin D levels with disease activity, analysing each component of the DAS28 score separately. We measured 25-hydroxy vitamin D levels in 176 outpatients with RA at two different centres and recorded a DAS28 score using an ESR checked at the same time. We calculated DAS28 both with and without the patient's rating of their symptoms on the visual analogue score (VAS) to assess the effect of VAS on DAS28. The vitamin D results were expressed as nanomole per litre with 50 nmol/l taken as the lower limit of normal. We calculated mean levels of vitamin D and undertook a multivariate regression analysis to assess correlations between vitamin D levels and DAS28 (and its individual components), corrected for centre, age and gender. The overall mean DAS28 score was 3.66 (SE +/- 0.11) using all four criteria and 3.43 (SE +/- 0.10) using just three criteria (omitting VAS). The mean vitamin D level was 39.42 nmol/l (SE +/- 1.55). There was no significant correlation between vitamin D and DAS28 scores with or without the inclusion of VAS. However, there was a significant inverse relationship between vitamin D and VAS itself (coefficient = 0.249, p = 0.013). The mean DAS28 score was greater in vitamin D-deficient patients and this was explained by their higher VAS scores. Our data confirms that vitamin D deficiency is common in RA. This paper provides evidence that the VAS component, assessing patient perception of symptoms, is inversely related to vitamin D, with lower levels producing higher VAS values. Although there was no overall correlation between vitamin D levels and DAS28, patients may perceive themselves or be perceived by assessors as having responded less well to disease modification in the presence of vitamin D deficiency. This could have major implications for subsequent management, and clinicians need to be aware of the potential confounding effect of vitamin D deficiency in assessing RA disease activity using the full DAS28 tool. PMID- 23340836 TI - Improved accuracy in computer-assisted unicondylar knee arthroplasty: a meta analysis. AB - PURPOSE: Inaccurate implantation rates of up to 30 % have been reported in cases using the conventional technique for implantation of a unicompartmental knee arthroplasty. Navigation should permit a more precise implantation, and several studies have investigated its role, albeit with a limited number of patients and inconsistent results. The aim of this meta-analysis was to compare risks of unsatisfactory outcomes in patients with navigated and conventional technique. METHODS: An electronic search was performed, and ten studies were eligible and included in the meta-analysis, with a total of 258 prostheses implanted with the navigated technique and 295 with the conventional one. The following items were analysed: radiological positioning of the femoral and the tibial component in the AP and lateral view, radiological analysis of the tibiofemoral mechanical axis and the difference in operating time between the two groups. Relative risks (RR) were calculated from the reported percentages of implants outside the optimal ranges defined by the manufacturers or the study groups. Natural logarithms of the relative risks were pooled by means of random effects models. RESULTS: For all the analysed radiological parameters, the RR of measurements outside the optimal ranges were less than 1 in the navigation group suggesting a reduction in the risk of outliers with navigation. The average operating time in the navigated group was 15.4 min (95 % CI: 10.2-20.6) longer than in the conventional group. CONCLUSION: The meta-analysis shows that the use of navigation systems in UKA leads to a more precise component position. Whether the more accurate position in UKA results in a better clinical outcome or long-term survival is yet unknown. Nevertheless, as a precise implant position appears to be beneficial, the use of navigation should be recommended for UKA. The limits defined by the manufacturers for an optimal positioning are not consistent. PMID- 23340837 TI - Quantitative evaluation of the pivot shift by image analysis using the iPad. AB - PURPOSE: To enable comparison of test results, a widely available measurement system for the pivot shift test is needed. Simple image analysis of lateral knee joint translation is one such system that can be installed on a prevalent computer tablet (e.g. iPad). The purpose of this study was to test a novel iPad application to detect the pivot shift. It was hypothesized that the abnormal lateral translation in ACL deficient knees would be detected by the iPad application. METHODS: Thirty-four consecutive ACL deficient patients were tested. Three skin markers were attached on the following bony landmarks: (1) Gerdy's tubercle, (2) fibular head and (3) lateral epicondyle. A standardized pivot shift test was performed under anaesthesia, while the lateral side of the knee joint was monitored. The recorded movie was processed by the iPad application to measure the lateral translation of the knee joint. Lateral translation was compared between knees with different pivot shift grades. RESULTS: Valid data sets were obtained in 20 (59 %) ACL deficient knees. The remaining 14 data sets were invalid because of failure to detect translation or detection of excessive translation. ACL deficient knees had larger lateral translation than the contra lateral knees (p < 0.01). In the 20 valid data sets, which were graded as either grade 1 (n = 10) or grade 2 (n = 10), lateral translation was significantly larger in the grade 2 pivot shift (3.6 +/- 1.2 mm) than the grade 1 pivot shift (2.7 +/- 0.6 mm, p < 0.05). CONCLUSION: Although some technical corrections, such as testing manoeuvre and recording procedure, are needed to improve the image data sampling using the iPad application, the potential of the iPad application to classify the pivot shift was demonstrated. PMID- 23340838 TI - Effect of open wedge high tibial osteotomy on the lateral tibiofemoral compartment in sheep. Part II: standard and overcorrection do not cause articular cartilage degeneration. AB - PURPOSE: To evaluate whether medial open wedge high tibial osteotomy (HTO) results in structural changes in the articular cartilage in the lateral tibiofemoral compartment of adult sheep. METHODS: Three experimental groups received biplanar osteotomies of the right proximal tibiae: (a) closing wedge HTO (4.5 degrees of tibial varus), (b) opening wedge HTO (4.5 degrees tibial valgus; standard correction), and (c) opening wedge HTO (9.5 degrees of valgus; overcorrection), each of which was compared to the contralateral knees that only received an arthrotomy. After 6 months, the macroscopic and microscopic characteristics of the articular cartilage of the lateral tibiofemoral compartment were assessed. RESULTS: The articular cartilage in the central region of the lateral tibial plateau in sheep had a higher safranin O staining intensity and was 4.6-fold thicker than in the periphery (covered by the lateral meniscus). No topographical variation in the type-II collagen immunoreactivity was seen. All lateral tibial plateaus showed osteoarthritic changes in regions not covered by the lateral meniscus. No osteoarthritis was seen in the peripheral submeniscal regions of the lateral tibial plateau and the lateral femoral condyle. Opening wedge HTO resulting in both standard and overcorrection was not associated with significant macroscopic and microscopic structural changes between groups in the articular cartilage of the lateral tibial plateau and femoral condyle after 6 months in vivo. CONCLUSION: Opening wedge HTO resulting in both standard and overcorrection is a safe procedure for the articular cartilage in an intact lateral tibiofemoral compartment of adult sheep at 6 months postoperatively. PMID- 23340839 TI - Widespread splicing changes in human brain development and aging. AB - While splicing differences between tissues, sexes and species are well documented, little is known about the extent and the nature of splicing changes that take place during human or mammalian development and aging. Here, using high throughput transcriptome sequencing, we have characterized splicing changes that take place during whole human lifespan in two brain regions: prefrontal cortex and cerebellum. Identified changes were confirmed using independent human and rhesus macaque RNA-seq data sets, exon arrays and PCR, and were detected at the protein level using mass spectrometry. Splicing changes across lifespan were abundant in both of the brain regions studied, affecting more than a third of the genes expressed in the human brain. Approximately 15% of these changes differed between the two brain regions. Across lifespan, splicing changes followed discrete patterns that could be linked to neural functions, and associated with the expression profiles of the corresponding splicing factors. More than 60% of all splicing changes represented a single splicing pattern reflecting preferential inclusion of gene segments potentially targeting transcripts for nonsense-mediated decay in infants and elderly. PMID- 23340840 TI - Shared control of gene expression in bacteria by transcription factors and global physiology of the cell. AB - Gene expression is controlled by the joint effect of (i) the global physiological state of the cell, in particular the activity of the gene expression machinery, and (ii) DNA-binding transcription factors and other specific regulators. We present a model-based approach to distinguish between these two effects using time-resolved measurements of promoter activities. We demonstrate the strength of the approach by analyzing a circuit involved in the regulation of carbon metabolism in E. coli. Our results show that the transcriptional response of the network is controlled by the physiological state of the cell and the signaling metabolite cyclic AMP (cAMP). The absence of a strong regulatory effect of transcription factors suggests that they are not the main coordinators of gene expression changes during growth transitions, but rather that they complement the effect of global physiological control mechanisms. This change of perspective has important consequences for the interpretation of transcriptome data and the design of biological networks in biotechnology and synthetic biology. PMID- 23340841 TI - An in vivo control map for the eukaryotic mRNA translation machinery. AB - Rate control analysis defines the in vivo control map governing yeast protein synthesis and generates an extensively parameterized digital model of the translation pathway. Among other non-intuitive outcomes, translation demonstrates a high degree of functional modularity and comprises a non-stoichiometric combination of proteins manifesting functional convergence on a shared maximal translation rate. In exponentially growing cells, polypeptide elongation (eEF1A, eEF2, and eEF3) exerts the strongest control. The two other strong control points are recruitment of mRNA and tRNA(i) to the 40S ribosomal subunit (eIF4F and eIF2) and termination (eRF1; Dbp5). In contrast, factors that are found to promote mRNA scanning efficiency on a longer than-average 5'untranslated region (eIF1, eIF1A, Ded1, eIF2B, eIF3, and eIF5) exceed the levels required for maximal control. This is expected to allow the cell to minimize scanning transition times, particularly for longer 5'UTRs. The analysis reveals these and other collective adaptations of control shared across the factors, as well as features that reflect functional modularity and system robustness. Remarkably, gene duplication is implicated in the fine control of cellular protein synthesis. PMID- 23340842 TI - Autonomous bacterial localization and gene expression based on nearby cell receptor density. AB - Escherichia coli were genetically modified to enable programmed motility, sensing, and actuation based on the density of features on nearby surfaces. Then, based on calculated feature density, these cells expressed marker proteins to indicate phenotypic response. Specifically, site-specific synthesis of bacterial quorum sensing autoinducer-2 (AI-2) is used to initiate and recruit motile cells. In our model system, we rewired E. coli's AI-2 signaling pathway to direct bacteria to a squamous cancer cell line of head and neck (SCCHN), where they initiate synthesis of a reporter (drug surrogate) based on a threshold density of epidermal growth factor receptor (EGFR). This represents a new type of controller for targeted drug delivery as actuation (synthesis and delivery) depends on a receptor density marking the diseased cell. The ability to survey local surfaces and initiate gene expression based on feature density represents a new area-based switch in synthetic biology that will find use beyond the proposed cancer model here. PMID- 23340843 TI - Systematic analysis of somatic mutations in phosphorylation signaling predicts novel cancer drivers. AB - Large-scale cancer genome sequencing has uncovered thousands of gene mutations, but distinguishing tumor driver genes from functionally neutral passenger mutations is a major challenge. We analyzed 800 cancer genomes of eight types to find single-nucleotide variants (SNVs) that precisely target phosphorylation machinery, important in cancer development and drug targeting. Assuming that cancer-related biological systems involve unexpectedly frequent mutations, we used novel algorithms to identify genes with significant phosphorylation associated SNVs (pSNVs), phospho-mutated pathways, kinase networks, drug targets, and clinically correlated signaling modules. We highlight increased survival of patients with TP53 pSNVs, hierarchically organized cancer kinase modules, a novel pSNV in EGFR, and an immune-related network of pSNVs that correlates with prolonged survival in ovarian cancer. Our findings include multiple actionable cancer gene candidates (FLNB, GRM1, POU2F1), protein complexes (HCF1, ASF1), and kinases (PRKCZ). This study demonstrates new ways of interpreting cancer genomes and presents new leads for cancer research. PMID- 23340844 TI - Genome-wide analysis of FOXO3 mediated transcription regulation through RNA polymerase II profiling. AB - Forkhead box O (FOXO) transcription factors are key players in diverse cellular processes affecting tumorigenesis, stem cell maintenance and lifespan. To gain insight into the mechanisms of FOXO-regulated target gene expression, we studied genome-wide effects of FOXO3 activation. Profiling RNA polymerase II changes shows that FOXO3 regulates gene expression through transcription initiation. Correlative analysis of FOXO3 and RNA polymerase II ChIP-seq profiles demonstrates FOXO3 to act as a transcriptional activator. Furthermore, this analysis reveals a significant part of FOXO3 gene regulation proceeds through enhancer regions. FOXO3 binds to pre-existing enhancers and further activates these enhancers as shown by changes in histone acetylation and RNA polymerase II recruitment. In addition, FOXO3-mediated enhancer activation correlates with regulation of adjacent genes and pre-existence of chromatin loops between FOXO3 bound enhancers and target genes. Combined, our data elucidate how FOXOs regulate gene transcription and provide insight into mechanisms by which FOXOs can induce different gene expression programs depending on chromatin architecture. PMID- 23340845 TI - Accurate measurements of dynamics and reproducibility in small genetic networks. AB - Quantification of gene expression has become a central tool for understanding genetic networks. In many systems, the only viable way to measure protein levels is by immunofluorescence, which is notorious for its limited accuracy. Using the early Drosophila embryo as an example, we show that careful identification and control of experimental error allows for highly accurate gene expression measurements. We generated antibodies in different host species, allowing for simultaneous staining of four Drosophila gap genes in individual embryos. Careful error analysis of hundreds of expression profiles reveals that less than ~20% of the observed embryo-to-embryo fluctuations stem from experimental error. These measurements make it possible to extract not only very accurate mean gene expression profiles but also their naturally occurring fluctuations of biological origin and corresponding cross-correlations. We use this analysis to extract gap gene profile dynamics with ~1 min accuracy. The combination of these new measurements and analysis techniques reveals a twofold increase in profile reproducibility owing to a collective network dynamics that relays positional accuracy from the maternal gradients to the pair-rule genes. PMID- 23340848 TI - Reading and writing omes. PMID- 23340846 TI - High-throughput sequencing for biology and medicine. AB - Advances in genome sequencing have progressed at a rapid pace, with increased throughput accompanied by plunging costs. But these advances go far beyond faster and cheaper. High-throughput sequencing technologies are now routinely being applied to a wide range of important topics in biology and medicine, often allowing researchers to address important biological questions that were not possible before. In this review, we discuss these innovative new approaches including ever finer analyses of transcriptome dynamics, genome structure and genomic variation-and provide an overview of the new insights into complex biological systems catalyzed by these technologies. We also assess the impact of genotyping, genome sequencing and personal omics profiling on medical applications, including diagnosis and disease monitoring. Finally, we review recent developments in single-cell sequencing, and conclude with a discussion of possible future advances and obstacles for sequencing in biology and health. PMID- 23340849 TI - Rational design of [Co(acacen)L2]+ inhibitors of protein function. AB - Cobalt(III) Schiff base complexes, such as [Co(acacen)L(2)](+), inhibit the function of Zn(II)-dependent proteins through dissociative exchange of the axial ligands with key histidine residues of the target protein. Consequently the efficacy of these compounds depends strongly on the lability of the axial ligands. A series of [Co(acacen)L(2)](+) complexes with various axial ligands was investigated using DFT to determine the kinetics and thermodynamics of ligand exchange and hydrolysis. Results showed excellent agreement with experimental data, indicating that axial ligand lability is determined by several factors: pK(a) of the axial ligand, the kinetic barrier to ligand dissociation, and the relative thermodynamic stability of the complexes before and after exchange. Hammett plots were constructed to determine if the kinetics and thermodynamics of exchange can be modulated by the addition of an electron-withdrawing group (EWG) to either the axial ligand itself or to the equatorial acacen ligand. Results predict that addition of an EWG to the axial ligand will shift the kinetics and thermodynamics so as to promote axial ligand exchange, while addition of an EWG to acacen will decrease axial ligand lability. These investigations will aid in the design of the next generation of [Co(acacen)L(2)](2+), allowing researchers to develop new, more effective inhibitors. PMID- 23340850 TI - Photoelectric probing of the interfacial trap density-of-states in ZnO nanowire field-effect transistors. AB - We have fabricated transparent top-gate ZnO nanowire (NW) field effect transistors (FETs) on glass and measured their trap density-of-states (DOS) at the dielectric/ZnO NW interface with monochromatic photon beams during their operation. Our photon-probe method showed clear signatures of charge trap DOS at the interface, located near 2.3, 2.7, and 2.9 eV below the conduction band edge. The DOS information was utilized for the photo-detecting application of our transparent NW-FETs, which demonstrated fast and sensitive photo-detection of visible lights. PMID- 23340847 TI - Genome-scale engineering for systems and synthetic biology. AB - Genome-modification technologies enable the rational engineering and perturbation of biological systems. Historically, these methods have been limited to gene insertions or mutations at random or at a few pre-defined locations across the genome. The handful of methods capable of targeted gene editing suffered from low efficiencies, significant labor costs, or both. Recent advances have dramatically expanded our ability to engineer cells in a directed and combinatorial manner. Here, we review current technologies and methodologies for genome-scale engineering, discuss the prospects for extending efficient genome modification to new hosts, and explore the implications of continued advances toward the development of flexibly programmable chasses, novel biochemistries, and safer organismal and ecological engineering. PMID- 23340851 TI - Psychosomatic symptom profiles in patients with restless legs syndrome. AB - PURPOSE: It has been reported that restless legs syndrome (RLS) might be associated with multiple psychosomatic symptoms. We aimed to identify which psychosomatic symptom is the most related in RLS patients compared to healthy controls. We also attempted to determine the relation between psychosomatic comorbidity and RLS severity regardless of sleep-related symptoms. METHODS: One hundred two newly diagnosed patients with RLS and 37 healthy control subjects participated in the present study. The RLS patients were categorized as mild and severe based on the International RLS Study Group rating scale. Data on demographics were collected. All participants completed the Pittsburgh Sleep Quality Index, Athens Insomnia Scale, and Epworth Sleepiness Scale as sleep related questionnaires. All participants completed the Symptom Checklist-90 Revision (SCL-90-R). RESULTS: RLS patients were found to have pervasive comorbid psychosomatic symptoms. Somatization was found to be the most significant contributing factor (OR 1.145, 95 % CI 1.061-1.234, p < 0.001) for psychosomatic comorbidity in RLS. Severe RLS patients were found to have poorer sleep quality than mild RLS patients. Furthermore, severe RLS patients had higher scores for most psychosomatic symptom domains in SCL-90-R. Anxiety was found to be the most independent contributing factor for psychosomatic comorbidity according to RLS severity (OR 1.145, 95 % CI 1.043-1.257, p = 0.005). CONCLUSIONS: Our study demonstrates that comorbid psychosomatic distress is considerable in patients with RLS. Furthermore, most psychosomatic comorbidity is increased with the RLS severity in association with poorer sleep quality. PMID- 23340852 TI - Serum EPO and VEGF levels in patients with sleep-disordered breathing and acute myocardial infarction. AB - BACKGROUND: A high level of endogenous erythropoietin (EPO) may be associated with a smaller infarct size determined by the release of necrosis markers. Sleep disordered breathing (SDB) is a well-known risk factor for cardiovascular diseases. In contrast, protective effects of SDB have also been described. The potential role of increased levels of EPO and vascular endothelial growth factor (VEGF) is suggested in this process. The study aimed to explore the EPO and VEGF serum levels in SDB and non-SDB patients during the acute phase of myocardial infarction. METHODS: Thirty-seven patients undergoing successful primary percutaneous coronary intervention in the acute myocardial infarction have been examined for the levels of EPO, VEGF, and troponin I (Tn). In the following, patients had an overnight polysomnography to determine breathing disturbances during sleep. RESULTS: Both on admission day (day 1) and day 3 of hospitalization, EPO levels showed statistically significant differences in both SDB-positive and SDB-negative patient groups (p = 0.003 and p = 0.018, respectively). There was no statistically significant difference in VEGF levels. No correlation was found between the EPO and Tn levels. CONCLUSIONS: SDB patients tend to have higher levels of EPO during acute myocardial infarction. No statistically significant differences in VEGF levels were observed. PMID- 23340853 TI - Clinical and polysomnographic differences between OSAH patients with/without excessive daytime sleepiness. AB - PURPOSE: The purpose of this study is to describe the clinical and polysomnographic differences found in patients diagnosed with obstructive sleep apnea-hypopnea (OSAH), with or without excessive daytime sleepiness (EDS) measured by the Epworth Sleepiness Scale (ESS). METHODS: A physical examination, ESS, and polysomnography were applied to all the participants, considering an ESS score of >10 to indicate EDS and an ESS score of >= 16 to indicate severe EDS. Univariate (chi-squared or Student's t test) and multivariate (multiple logistic regression) analysis approaches were used. A value of p < .05 was considered statistically significant. RESULTS: The study covered 151 OSAH patients, including 129 (85 %) male patients, 66 (44 %) with EDS and 23 (21 %) with severe EDS. In the univariate analysis of demographic and polysomnographic variables, a comparison between patients without and with EDS showed that the latter had a larger neck circumference, maximum O2 desaturation, and increased sleep time at <90 % O2 saturation, with significant statistical differences. In the multivariate analysis, this statistical significance disappears. A comparison between patients without EDS and with severe EDS did not reveal differences in demographic or polysomnographic variables. CONCLUSIONS: Patients with OSAH and ESD showed more hypoxemia, but we did not find significant differences between OSAH patients with or without EDS. PMID- 23340854 TI - Impact of preoperative serum interleukin-2 receptor alpha levels on survival and its correlation with clinicopathological parameters in colorectal cancer. PMID- 23340855 TI - Should mean arterial pressure be included in the definition of ambulatory hypertension in children? AB - BACKGROUND: The diagnosis of hypertension (HTN)/normotension (NT) on ambulatory blood pressure monitoring (ABPM) is usually based on systolic (SBP) or diastolic blood pressure (DBP). The goal of this study was to analyze whether inclusion of mean arterial pressure (MAP) improves the detection of HTN on ABPM. METHODS: We retrospectively studied ABPM records in 229 children (116 boys, median age = 15.3 years) who were referred for evaluation of HTN. A diagnosis of HTN was made if: (A) MAP or SBP or DBP was >= 1.65 SDS (95th percentile); (B) SBP or DBP was >= 1.65 SDS (95th percentile), during 24-h or daytime or night-time in both definitions. RESULTS: Using definition A, 46/229 patients had HTN compared to definition B by which only 37/229 patients had HTN (p = 0.001). The level of agreement between the two definitions was very good (kappa = 0.86 +/- 0.04), however nine patients (19.5 %) were missed by not using MAP in the definition of HTN. These nine patients had only mild HTN with a median Z score of 1.69. CONCLUSIONS: The inclusion of MAP in the definition of ambulatory HTN significantly increased the number of hypertensive patients. MAP may be very helpful in detecting mild HTN in patients with normal/borderline SBP and DBP. PMID- 23340858 TI - Bandgap broadly tunable GaZnSeAs alloy nanowires. AB - Composition-tunable semiconductor alloy nanowires are emerging as an important class of materials for the realization of high-performance laterally-arranged multiple bandgap (LAMB) solar cells. Here we report the first growth of GaZnSeAs quaternary alloy nanowires with composed elements between two different groups using a temperature/space-selective CVD route. Under laser excitation, these special quaternary alloy nanowires exhibit composition-related characteristic emissions, with peak wavelengths gradually tunable from 470 nm (2.64 eV) to 832 nm (1.49 eV), covering almost the entire visible spectrum. Surface photovoltage measurements further reveal that these alloy nanowires have tunable bandgaps along the length of the substrate, making them promising candidates for developing high-efficiency LAMB solar cells. These quaternary alloy nanowires represent a new advancement in material synthesis and would have potential applications in a variety of function-tunable and broadband-response optoelectronic devices. PMID- 23340856 TI - From bone abnormalities to mineral metabolism dysregulation in autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of kidney failure. It is a systemic disorder, not only affecting the kidneys, but also associated with cyst formation in other organs such as the liver, spleen, pancreas, and seminal vesicles. Other extra-renal symptoms may consist of intracranial arterial aneurysms, cardiac valvular defects, abdominal and inguinal hernias and colonic diverticulosis. Very little is known regarding bone involvement in ADPKD; however, recent evidence has revealed the potential role of fibroblast growth factor 23 (FGF23). FGF23 is an endocrine fibroblast growth factor acting in the kidney as a phosphaturic hormone and a suppressor of active vitamin D with key effects on the bone/kidney/parathyroid axis, and has been shown to increase in patients with ADPKD, even with normal renal function. The aim of this review is to provide an overview of bone and mineral abnormalities found in experimental models and in patients with ADPKD, and to discuss the possible role of FGF23 in this disease. PMID- 23340857 TI - Long-term outcome of children treated with rituximab for idiopathic nephrotic syndrome. AB - BACKGROUND: Rituximab (RTX) has recently showed promising results in the treatment of steroid-dependent idiopathic nephrotic syndrome (SDNS). METHODS: This was a retrospective multicenter study of 18 children treated with RTX for SDNS, with a mean follow-up of 3.2 years. RTX was introduced because of side effects or relapses during therapy with immunosuppressive agents. The children received one to four infusions of RTX during the first course of treatment, and subsequent infusions were given due to CD19-cell recovery (CD19 >1 %; 54 % of children) or relapse (41 %), as well as systematically (5 %). RESULTS: Treatment with RTX maintained sustained remission without relapse in 22 % of patients and increased the duration of remission in all other patients. The time between two successive relapses was 9 months in the absence of re-treatment and 24.5 months when infusions were performed at the time of CD19-cell recovery. At the last follow-up, 44.5 % of patients were free of oral drug therapy. Of those still receiving oral drugs, all doses had been decreased. No serious adverse events occurred. CONCLUSION: The results of this retrospective study confirm the efficacy and very good safety of RTX in the treatment of SDNS. The optimal therapeutic protocol seems to be a repeated single infusion at the time of CD19 cell recovery. PMID- 23340859 TI - A dual role of boronate affinity in high-sensitivity detection of vicinal diol brassinosteroids from sub-gram plant tissues via UPLC-MS/MS. AB - Based on the dual role of specific boronate affinity, making use of both novel self-synthesized boronate affinity-functionalized magnetic nanoparticles and a high-efficiency organic boronic acid-type derivatization reagent, we report a simple, convenient and highly-sensitive method for detection of endogenous brassinosteroids from real plant materials. PMID- 23340860 TI - Thiol-ubiquinone assisted fragmentation of gold nanoparticles. AB - We report the spontaneous fragmentation of gold nanoparticles (AuNPs) induced, in aqueous solution at room temperature, by thiol derivative of ubiquinone, which involves the energetic electron injection from thiol-ubiquinone to the gold nanoparticles. PMID- 23340861 TI - Repeat sentinel node biopsy in patients with locally recurrent breast cancer: a systematic review and meta-analysis of the literature. AB - Axillary staging in patients with locally recurrent breast cancer is important for obtaining locoregional control and predicting prognosis. The aim of the present study is to determine technical feasibility, validity, aberrant drainage patterns and clinical consequences of performing repeat sentinel node biopsy (SNB) in these patients. We performed a systematic review and meta-analysis of the literature and included all studies on repeat SNB in locally recurrent breast cancer. A total of 692 patients were described, 301 after a previous SNB, 361 after a previous axillary lymph node dissection (ALND), and 30 with no previous axillary surgery. Sentinel node identification was successful in 452 of the 692 patients (65.3 %), which was significantly higher in patients who had undergone previous SNB compared to previous ALND (81.0 vs. 52.2 %) (P < 0.0001). In 175 of 405 patients with successful lymphatic mapping aberrant drainage pathways were visualized (43.2 %), which were seen more frequently after previous ALND than after previous SNB (69.2 vs. 17.4 %) (P < 0.0001). In 19.2 % of the patients the sentinel node was tumor positive and 27.5 % of these metastases were found in aberrant lymph drainage basins. Overall, 213 patients could be spared an ALND and in 17.9 % of the patients the information derived from the repeat SNB led to a change in adjuvant radiotherapy or systemic treatment plans. The procedure had a false-negative rate of 0.2 %. Repeat SNB is technically feasible and accurate. Next to sparing patients an unnecessary ALND, the information can lead to a change in adjuvant treatment strategy. PMID- 23340862 TI - Vaccination for the prevention and treatment of breast cancer with special focus on Her-2/neu peptide vaccines. AB - Immunologic interventions in a subset of breast cancer patients represent a well established therapeutic approach reflecting individualized treatment modalities. Thus, the therapeutic administration of monoclonal antibodies targeting tumor associated antigens (TAA), such as Her-2/neu, represents a milestone in cancer treatment. However, passive antibody administration suffers from several drawbacks, including frequency and long duration of treatment. These undesirables may be avoidable in an approach based on generating active immune responses against these same targets. Only recently has the significance of tumors in relation to their microenvironments been understood as essential for creating an effective cancer vaccine. In particular, the immune system plays an important role in suppressing or promoting tumor formation and growth. Therefore, activation of appropriate triggers (such as induction of Th1 cells, CD8+ T cells, and suppression of regulatory cells in combination with generation of antibodies with anti-tumor activity) is a desirable goal. Current vaccination approaches have concentrated on therapeutic vaccines using certain TAA. Many cancer antigens, including breast cancer antigens, have been described and also given priority ranking for use as vaccine antigens by the US National Cancer Institute. One of the TAA antigens which has been thoroughly examined in numerous trials is Her-2/neu. This review will discuss delivery systems for this antigen with special focus on T and B cell peptide vaccines. Attention will be given to their advantages and limitations, as well as the use of certain adjuvants to improve anti-cancer responses. PMID- 23340863 TI - Effect of clinical spectrum, inoculum size and physician characteristics on sensitivity of a rapid antigen detection test for group A streptococcal pharyngitis. AB - We aimed to assess the independent effect of clinical spectrum, bacterial inoculum size and physician characteristics on the sensitivity of a rapid antigen detection test (RADT) for group A streptococcus (GAS) in children. Double throat swabs were collected from 1,482 children with pharyngitis and 294 asymptomatic children in a French prospective, office-based, multicenter (n = 17) study, from October 2009 to May 2011. Patient- and physician-level factors potentially affecting RADT sensitivity were studied by univariate and multivariate multilevel analysis, with laboratory throat culture as the reference test. In children with pharyngitis and asymptomatic children, the prevalence of GAS was 38 % (95 % confidence interval 36-41 %) and 11 % (7-14 %), respectively. Overall, RADT sensitivity was 87 % (84-90 %). On stratified and multivariate multilevel analysis, RADT sensitivity was higher for children with pharyngitis than asymptomatic children (89 % vs. 41 %), children <9 than >= 9 years old (88 % vs. 79 %) and those with heavy than light inoculum (94 % vs. 53 %). RADT sensitivity was influenced by the physician performing the test (range 56-96 %, p = 0.01) and was higher for physicians with hospital-based clinical activity in addition to office-based practice (adjusted odds ratio 3.4 [95 % confidence interval 1.9 6.3], p < 0.001); inter-physician variations in RADT sensitivity were largely explained by this variable (proportional change in variance >99 %). The sensitivity of the RADT is independently affected by patient- and physician-level factors. Physicians who base their diagnosis of GAS pharyngitis on the results of a RADT alone should consider diagnostic accuracy monitoring and adequate training when needed. PMID- 23340864 TI - Combinations of cefoxitin plus other beta-lactams are synergistic in vitro against community associated methicillin-resistant Staphylococcus aureus. AB - In vitro studies demonstrate that oxacillin minimal inhibitory concentrations (MICs) of methicillin-resistant S. aureus (MRSA) strains USA300 and 400 decrease in the presence of cefoxitin. The aim of this study was to characterize the activity of cefoxitin plus beta-lactams against a collection of MRSA isolates. We assessed the in vitro antimicrobial activity of a selection of beta-lactams alone and together with subinhibitory concentrations of cefoxitin against a collection of MRSA, methicillin-susceptible S. aureus (MSSA), and vancomycin-intermediate S. aureus (VISA) isolates using MICs and time kill assays. For community-associated (CA) MRSA strains USA300 and USA400, MICs of nafcillin, cefazolin, cephalexin, cefuroxime, ceftriaxone and cefotaxime decreased by 8- to 64-times in the presence of 10 MUg/ml cefoxitin. In contrast, for hospital-associated (HA) strains COLn, N315, and Mu50, there was no change in any beta-lactam MIC in the presence of cefoxitin. When combined with cefoxitin, the cephalexin MIC decreased for eight CA-MRSA and five MSSA sequence types but did not change for seven HA MRSA sequence types. beta-lactam/cefoxitin combinations were synergistic against CA- but not HA-MRSA strains in time kill assays. Cefoxitin combined with a variety of beta-lactams enhances their activity against CA-MRSA strains in vitro. Further studies of combination beta-lactam therapy may provide insight into beta lactam biology, penicillin binding protein cooperativity, and novel therapeutic strategies against MRSA. PMID- 23340866 TI - Preparation, characterization, and bacteriostasis of AgNP-coated beta-CD grafting cellulose beads. AB - A novel functional material of beta-cyclodextrin (beta-CD) grafting cellulose beads containing immobilized silver nanoparticles (AgNPs) is presented in this paper. The morphology was characterized by scanning electron microscopy, energy dispersive X-ray, and X-ray photoelectron spectroscopy. Phenolphthalein probe molecule technique was used to detect the activity of the grafting beta-CD, and the results demonstrated that the deposition of AgNPs had no influence on its encapsulation ability. Acid resistance of the AgNPs on the bead material was studied by atomic absorption spectrometry. The stability of the AgNPs was enhanced due to the grafting of beta-CD. Tube dilution method was applied to study the bacteriostatic effect, and the minimal inhibitory doses of the novel material against Escherichia coli and Staphylococcus aureus were 12.5 and 25 mg, respectively. The minimal bactericidal doses for the two bacteria were 25 and 25 mg, respectively. PMID- 23340865 TI - Lipopolysaccharide-induced failure of the gut barrier is site-specific and inhibitable by growth hormone. AB - BACKGROUND: Gut barrier failure caused by endotoxemia is a life-threatening problem. The present study aimed to determine whether any specific intestinal site is highly correlated with gut barrier failure, and whether recombinant human growth hormone (rhGH) can ameliorate gut barrier failure in a rat model of endotoxemia. METHODS: Enterostomy tubes were surgically placed in adult male Sprague-Dawley rats three days before induction of endotoxemia by lipopolysaccharide (LPS) injection. Controls received no LPS. Rats were then randomly assigned to receive subcutaneous injections of rhGH (experimental, n = 30) or 0.9 % saline (control, n = 15) at 24, 48, or 72 h after LPS injection. Escherichia coli labeled with green fluorescent protein (GFP) were injected into the intestinal segment of all rats through the enterostomy tubes. The number of GFP-labeled E. coli detected in mesenteric lymph nodes was examined after 96 h. Apoptosis and proliferation rates of intestinal epithelial cells, and intestinal permeability were measured. RESULTS: Endotoxemia led to high mortality, compared with the control group, and rhGH treatment did not improve survival. Intestinal permeability, reflected by translocation rates of GFP-labeled E. coli, and apoptosis rates in the LPS-induced endotoxemia group were higher than those in the non-endotoxemia control group, and the endotoxemia ileum group had the highest rates of both bacterial translocation and apoptosis. The LPS+GH group had less bacterial translocation and apoptosis than the LPS-induced endotoxemia group. In contrast, the proliferation rates were lower in the LPS group compared to the LPS+GH group. CONCLUSIONS: Endotoxemia can induce gut barrier failure in rats, and the ileum is the site of greatest risk. The GH can reduce the incidence of endotoxemia-induced gut barrier failure, but not the associated mortality. PMID- 23340867 TI - Structural insights on Mycobacterium tuberculosis thiazole synthase--a molecular dynamics/docking approach. AB - Tuberculosis (TB), an epidemic disease, affects the world with death rate of two million people every year. The bacterium Mycobacterium tuberculosis was found to be a more potent and disease-prolonged bacterium among the world due to multi drug resistance. Emergence of new drug targets is needed to overcome the bacterial resistance that leads to control epidemic tuberculosis. The pathway thiamine biosynthesis was targeting M. tuberculosis due to its role in intracellular growth of the bacterium. The screening of enzymes involved in thiamin biosynthesis showed novel target thiazole synthase (ThiG) involved in catalysis of rearrangement of 1-deoxy-D-xylulose 5-phosphate (DXP) to produce the thiazole phosphate moiety of thiamine. We carried out homology modeling for ThiG to understand the structure-function relationship, and the model was refined with MD simulations. The results showed that the model predicted with (alpha + beta)8 fold of synthase family proteins. Molecular docking of ThiG model with substrate DXP showed binding mode and key residues ARG46, ASN69, THR41, and LYS96 involved in the catalysis. First-line anti-tuberculosis drugs were docked with ThiG to identify the inhibition. The report showed the anti-tuberculosis drugs interact well with ThiG which may lead to block thiamin biosynthesis pathway. PMID- 23340868 TI - Characterization of novel EGs reconstructed from Bacillus subtilis endoglucanase. AB - Bacterial cellulases have taken on satisfactory application performance and economic value in detergent industry. Neutral endoglucanase (EG1) gene was cloned from Bacillus subtilis and expressed Pichia pastoris in our previous study. Redesigned endoglucanases enhanced cellulase domain, added and deleted carbohydrate-binding module (CBM), named EG2, EG3, and EG4, respectively, were constructed in this study. The redesigned EG genes were expressed in P. pastoris, and their characters were also discussed. The optimal temperature and pH value of the all EGs was 65 degrees C and 6.0, respectively, where their enzymatic activities in P. pastoris cultivation supernatant reached 867, 651, 966, and 881 U/mL. EG2 showed 24.9 % enzymatic activity loss compared to natural endoglucanase. EG4 showed specific activity 30 % loss and thermostability decrease compared to EG1, which suggested CBM played an important role in improving the catalytic power and heat stability of cellulase family which attached. The specific activity of EG2 and EG3 showed similar to EG1, which suggested neither enhancement of CD nor CBM to endoglucanase can improve its catalytic power, which might rest with its intact topologic structure. PMID- 23340869 TI - Plant regeneration through callus organogenesis and true-to-type conformity of plants by RAPD analysis in Desmodium gangeticum (Linn.) DC. AB - An efficient plant regeneration protocol was established for an endangered ethnomedicinal plant Desmodium gangeticum (Linn.) DC. Morphogenic calli were produced from 96 % of the cultures comprising the immature leaf explants on Murashige and Skoog (MS) medium supplemented with 2,4-dichlorophenoxyacetic acid (4.0 mg l(-1)) in combination with 6-benzylaminopurine (BA; 0.8 mg l(-1)). For callus regeneration, various concentrations of BA (1.0-5.0 mg l(-1)) or thidiazuron (TDZ; 1.0-5.0 mg l(-1)) alone or in combination with indole-3-acetic acid (IAA; 0.2-1.0 mg l(-1)) were used. Highest response of shoot regeneration was observed on MS medium fortified with TDZ (4.0 mg l(-1)) and IAA (0.5 mg l( 1)) combination. Here, 100 % cultures responded with an average number of 22.3 shoots per gram calli. Inclusion of indole-3-butyric acid in half MS medium favored rooting of recovered shoots. Out of 45 rooted plants transferred to soil, 40 survived. Total DNA was extracted from the leaves of the acclimatized plants of D. gangeticum. Analysis of random amplified polymorphic DNA using 13 arbitrary decanucleotide primers showed the genetic homogeneity in all the ten plants regenerated from callus with parental plant, suggesting that shoot regeneration from callus could be used for the true-to-type multiplication of this plant. PMID- 23340870 TI - RNA interference--a silent but an efficient therapeutic tool. AB - RNA interference (RNAi) is an evolutionary conserved gene regulation pathway that has emerged as an important discovery in the field of molecular biology. One of the important advantages of RNAi in therapy is that it brings about efficient downregulation of gene expression by targeting complementary transcripts in comparison with other antisense-based techniques. RNAi can be can be achieved by introducing chemically synthesized small interfering RNAs (siRNAs) into a cell system. A more stable knockdown effect can be brought about by the use of plasmid or viral vectors encoding the siRNA. RNAi has been used in reverse genetics to understand the function of specific genes and also as a therapeutic tool in treating human diseases. This review provides a brief insight into the therapeutic applications of RNAi against debilitating diseases. PMID- 23340871 TI - The solvent effect on the luminescence of silver nanoclusters. AB - The solvent effect on the luminescence properties of highly stable water-soluble silver nanoclusters is discussed in this study. The polymer nanosphere templates swollen by organic solvents lead to the changes in the surrounding environments of silver nanoclusters, thus resulting in a significant influence on their luminescence. PMID- 23340872 TI - Quality of life in nursing homes following the group-living principle: a pilot study measuring the quality of life from the subjective perspective of dependent living elderly. AB - BACKGROUND: The purpose of this study was to analyze the subjective quality of life in elderly people in nursing homes following the group-living principle. METHODS: The Nottingham Health Profile (NHP) was employed. A comparison with the German representative subsample of elderly living independently age-group over 75 was conducted. Psychometric properties and appropriateness were analyzed. RESULTS: The mean NHP scale scores suggest an acceptable perception of residents' quality of life (n = 145). Our findings indicate that with exception of the NHP scale physical mobility, the perceived quality of life of group-living nursing home residents and independently living elderly over 75 years (German reference values) are nearly on the same level. With the exception of the subscale social isolation, the results of the current study show that the NHP is suitable for assessing the subjective quality of life in nursing home environments. CONCLUSION: The results of the first pilot study in the research field of subjective quality of life in group-living nursing homes are presented. The study focused on very old people with age-specific reduced physical and mental abilities. The NHP should also be considered as a reliable, valid and useful alternative to resident satisfaction surveys. PMID- 23340873 TI - Evaluation of the shear force of single cancer cells by vertically aligned carbon nanotubes suitable for metastasis diagnosis. AB - Vertically aligned carbon nanotube (VACNT) arrays have been demonstrated as probes for rapid quantifying of cancer cell deformability with high resolution. Through entrapment of various cancer cells on CNT arrays, the deflections of the nanotubes during cell deformation were used to derive the lateral cell shear force using a large deflection mode method. It is observed that VACNT beams act as sensitive and flexible agents, which transfer the shear force of cells trapped on them by an observable deflection. The metastatic cancer cells have significant deformable structures leading to a further cell traction force (CTF) than primary cancerous one on CNT arrays. The elasticity of different cells could be compared by their CTF measurement on CNT arrays. This study presents a nanotube-based methodology for quantifying the single cell mechanical behavior, which could be useful for understanding the metastatic behavior of cells. PMID- 23340874 TI - Fluorogenic label to quantify the cytosolic delivery of macromolecules. AB - The delivery of a macromolecule to the cytosol of human cells is assessed by using a pendant di-O-glycosylated derivative of fluorescein. Its fluorescence is unmasked by Escherichia colibeta-galactosidase installed in the cytosol. Background is diminished by using RNAi to suppress the expression of GLB1, which encodes a lysosomal beta-galactosidase. This strategy was used to quantify the cytosolic entry of a highly cationic protein, ribonuclease A. PMID- 23340879 TI - Activity restrictions after gynecologic surgery: is there evidence? AB - Many surgeons recommend rest and restricting activities to their patients after surgery. The aim of this review is to summarize the literature regarding types of activities gynecologic surgeons restrict and intra-abdominal pressure during specific activities and to provide an overview of negative effects of sedentary behavior (rest). We searched PubMed and Scopus for years 1970 until present and excluded studies that described recovery of activities of daily living after surgery as well as those that assessed intra-abdominal pressure for other reasons such as abdominal compartment syndrome and hypertension. For our review of intra abdominal pressure, we excluded studies that did not include a generally healthy population, or did not report maximal intra-abdominal pressures. We identified no randomized trial or prospective cohort study that studied the association between postoperative activity and surgical success after pelvic floor repair. The ranges of intra-abdominal pressures during specific activities are large and such pressures during activities commonly restricted and not restricted after surgery overlap considerably. There is little concordance in mean peak intra-abdominal pressures across studies. Intra-abdominal pressure depends on many factors, but not least the manner in which it is measured and reported. Given trends towards shorter hospital stays and off work intervals, which both predispose women to higher levels of physical activity, we urge research efforts towards understanding the role of physical activity on recurrence of pelvic organ prolapse and urinary incontinence after surgery. PMID- 23340880 TI - Controlled synthesis and Li-electroactivity of rutile TiO2 nanostructure with walnut-like morphology. AB - Herein, we report on the synthesis of phase-pure rutile walnut-like TiO(2) (W TiO(2)) spheres composed of single-crystalline nanorod-building blocks using a surfactant-free non-aqueous acidic modified "benzyl alcohol route". Based on the various HCl concentration- and reaction time-dependent experiments, an effect of hydrochloric acid on the phase formation mechanism in a non-aqueous system is suggested. As anodes for Li-ion batteries, the W-TiO(2) sphere electrodes exhibited superior cycling performance at a rate of 0.2 C without any conducting layers coated onto the anodes; this result is attributed to their high crystallinity and large surface area. PMID- 23340881 TI - [Chronic non-cancer-related pain. Long-term treatment with rapid-release and short-acting opioids in the context of misuse and dependency]. AB - Annually published data show a continual increase in the volume of opioid prescriptions in Germany, thus indicating an intensification of opioid therapy. The majority of opioids are prescribed to treat chronic non-cancer-related pain. On the basis of current guidelines, as well as in terms of the lack of data regarding long-term use of opioids and their effectiveness beyond a period of 3 months, this development must be viewed critically. With reference to four case reports, we discuss and evaluate opioid therapy in relation to medication misuse and the development of drug dependency. Particular emphasis is placed on the administration of rapid-release and short-acting opioid preparations, which we consider to be particularly problematic. PMID- 23340882 TI - Impact of critical limb ischemia on long-term cardiac mortality in diabetic patients undergoing percutaneous coronary revascularization. AB - OBJECTIVE: Development of critical limb ischemia (CLI) has been reported as an independent predictor of cardiac mortality in diabetic patients. We aimed to determine whether CLI, managed in a structured setting of close collaboration between different vascular specialists and treated with early endovascular intervention, has any impact on long-term cardiac mortality of diabetic patients initially presenting with symptomatic coronary artery disease (CAD). RESEARCH DESIGN AND METHODS: We designed a prospective observational study of 764 consecutive diabetic patients undergoing percutaneous coronary intervention (PCI) in whom development of CLI was assessed by a dedicated diabetic foot clinic. Cardiac mortality at 4-year follow-up was the primary end point of the study. RESULTS: Among the 764 patients, 111 (14%) developed CLI (PCI-CLI group) and underwent revascularization of 145 limbs, with procedural success in 140 (96%). PCI-CLI patients at baseline had lower left ventricular ejection fraction (51 +/- 11% vs. 53 +/- 10%, P = 0.008), higher prevalence of dialysis (7% vs. 0.3%, P < 0.0001), and longer diabetes duration (13 +/- 8 vs. 11 +/- 7 years, P = 0.02) compared with PCI-only patients. At 4-year follow-up, cardiac mortality occurred in 10 (9%) PCI-CLI patients vs. 42 (6%) PCI-only patients (P = 0.2). Time dependent Cox regression model for cardiac death revealed that CLI was not associated with an increased risk of cardiac mortality (hazard ratio 1.08 [95% CI 0.89-3.85]; P = 0.1). CONCLUSIONS: The development of promptly assessed and aggressively treated CLI was not significantly associated with increased risk of long-term cardiac mortality in diabetic patients initially presenting with symptomatic CAD. PMID- 23340883 TI - History of medically treated diabetes and risk of Alzheimer disease in a nationwide case-control study. AB - OBJECTIVE: Type 2 diabetes in midlife or late life increases the risk of Alzheimer disease (AD), and type 1 diabetes has been associated with a higher risk of detrimental cognitive outcomes, although studies from older adults are lacking. We investigated whether individuals with AD were more likely to have a history of diabetes than matched controls from the general aged population. RESEARCH DESIGN AND METHODS: Information on reimbursed diabetes medication (including both type 1 and 2 diabetes) of all Finnish individuals with reimbursed AD medication in 2005 (n = 28,093) and their AD-free control subjects during 1972 2005 was obtained from a special reimbursement register maintained by the Social Insurance Institute of Finland. RESULTS: The prevalence of diabetes was 11.4% in the whole study population, 10.7% (n = 3,012) among control subjects, and 12.0% (n = 3,372) among AD case subjects. People with AD were more likely to have diabetes than matched control subjects (unadjusted OR 1.14 [95% CI 1.08-1.20]), even after adjusting for cardiovascular diseases (OR 1.31 [1.22-1.41]). The associations were stronger with diabetes diagnosed at midlife (adjusted OR 1.60 [1.34-1.84] and 1.25 [1.16-1.36] for midlife and late-life diabetes, respectively). CONCLUSIONS: Individuals with clinically verified AD are more likely to have a history of clinically verified and medically treated diabetes than the general aged population, although the difference is small. PMID- 23340885 TI - myo-Inositol supplementation and onset of gestational diabetes mellitus in pregnant women with a family history of type 2 diabetes: a prospective, randomized, placebo-controlled study. AB - OBJECTIVE: To check the hypothesis that myo-inositol supplementation may reduce gestational diabetes mellitus (GDM) onset in pregnant women with a family history of type 2 diabetes. RESEARCH DESIGN AND METHODS: A 2-year, prospective, randomized, open-label, placebo-controlled study was carried out in pregnant outpatients with a parent with type 2 diabetes who were treated from the end of the first trimester with 2 g myo-inositol plus 200 ug folic acid twice a day (n = 110) and in the placebo group (n = 110), who were only treated with 200 ug folic acid twice a day. The main outcome measure was the incidence of GDM in both groups. Secondary outcome measures were as follows: the incidence of fetal macrosomia (>4,000 g), gestational hypertension, preterm delivery, caesarean section, shoulder dystocia, neonatal hypoglycemia, and neonatal distress respiratory syndrome. GDM diagnosis was performed according to the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) recommendations. RESULTS: Incidence of GDM was significantly reduced in the myo-inositol group compared with the placebo group: 6 vs. 15.3%, respectively (P = 0.04). In the myo inositol group, a reduction of GDM risk occurrence was highlighted (odds ratio 0.35). A statistically significant reduction of fetal macrosomia in the myo inositol group was also highlighted together with a significant reduction in mean fetal weight at delivery. In the other secondary outcome measures, there were no differences between groups. CONCLUSIONS: myo-Inositol supplementation in pregnant women with a family history of type 2 diabetes may reduce GDM incidence and the delivery of macrosomia fetuses. PMID- 23340884 TI - Identification of minimal clinically important difference scores of the PedsQL in children, adolescents, and young adults with type 1 and type 2 diabetes. AB - OBJECTIVE: To establish minimal clinically important difference (MCID) scores representing the smallest detectable change in quality of life (QOL), using the Pediatric Quality of Life Inventory (PedsQL) Generic Core and Diabetes Module among youth with diabetes and their parents, and to identify demographic and clinical correlates of QOL change over 1 year. RESEARCH DESIGN AND METHODS: Participants in the SEARCH for Diabetes in Youth Study aged >5 years and parents of youth aged <18 years completed PedsQL surveys at their initial and 12-month study visits. MCIDs for each PedsQL module were calculated using one standard error of measurement. Demographic and clinical characteristics associated with QOL change were identified through multiple linear and logistic regression analyses. RESULTS: The sample comprised 5,004 youth (mean age, 12.5 +/- 4.7 years; mean diabetes duration, 3.4 +/- 3.7 years). Of 100 possible points, PedsQL total score MCIDs for youth with type 1 and type 2 diabetes, respectively, were Generic Core, 4.88, 6.27 (parent) and 4.72, 5.41 (youth); Diabetes Module, 4.54, 6.06 (parent) and 5.27, 5.96 (youth). Among 1,402 youth with a follow-up visit, lower baseline QOL, male sex, private insurance, having type 1 diabetes, longer diabetes duration, and better glycemic control predicted improvements in youth- and parent-reported PedsQL total scores over 1 year. Clinically meaningful (>=1 MCID) improvements in total score for at least one PedsQL module were predicted by private insurance, lower BMI, and lower A1C at baseline. CONCLUSIONS: These diabetes-specific reference points to interpret clinically meaningful change in PedsQL scores can be used in clinical care and research for youth with type 1 and type 2 diabetes. PMID- 23340886 TI - Prevalence of morphometric vertebral fractures in patients with type 1 diabetes. AB - OBJECTIVE: Several studies showed low bone mineral density (BMD) and elevated risk of symptomatic fractures in patients with type 1 diabetes (T1D). To our knowledge, there has been no investigation on the prevalence of asymptomatic vertebral fractures (VFx) in T1D. In the current study, we assessed BMD and the prevalence of VFx in T1D. RESEARCH DESIGN AND METHODS: We evaluated 82 T1D patients (26 males and 56 females, aged 31.1 +/- 8.6 years, BMI 23.5 +/- 3.3 kg/m(2), disease duration 12.8 +/- 8.3 years) and 82 controls (22 females and 60 males, aged 32.9 +/- 5.8 years, BMI 23.9 +/- 4.8 kg/m(2)). Spinal and femoral BMD (as Z-score, Z-LS and Z-FN, respectively) and the prevalence of VFx were evaluated by dual X-ray absorptiometry. RESULTS: T1D patients had lower Z-LS and Z-FN than controls (-0.55 +/- 1.3 vs. 0.35 +/- 1.0, P < 0.0001, and -0.64 +/- 1.1 vs. 0.29 +/- 0.9, P < 0.0001, respectively) and a higher prevalence of VFx (24.4 vs. 6.1%, P = 0.002). Age, diabetes duration, age at diabetes manifestation, glycosylated hemoglobin, Z-LS, Z-FN, and the prevalence of chronic complications were similar for patients with and without VFx. In the logistic regression analysis, the presence of VFx was associated with the presence of T1D but not with lumbar spine BMD. Whereas moderate or severe VFx was associated with low lumbar spine BMD in the whole combined group of T1D patients and controls, there was no association between moderate or severe VFx and lumbar spine BMD in the T1D group. CONCLUSIONS: T1D patients have low BMD and elevated prevalence of asymptomatic VFx, which is associated with the presence of T1D independently of BMD. PMID- 23340887 TI - Early-adulthood cardiovascular disease risk factor profiles among individuals with and without diabetes in the Framingham Heart Study. AB - OBJECTIVE: Many studies of diabetes have examined risk factors at the time of diabetes diagnosis instead of considering the lifetime burden of adverse risk factor levels. We examined the 30-year cardiovascular disease (CVD) risk factor burden that participants have up to the time of diabetes diagnosis. RESEARCH DESIGN AND METHODS: Among participants free of CVD, incident diabetes cases (fasting plasma glucose >= 126 mg/dL or treatment) occurring at examinations 2 through 8 (1979-2008) of the Framingham Heart Study Offspring cohort were age- and sex-matched 1:2 to controls. CVD risk factors (hypertension, high LDL cholesterol, low HDL cholesterol, high triglycerides, obesity) were measured at the time of diabetes diagnosis and at time points 10, 20, and 30 years prior. Conditional logistic regression was used to compare risk factor levels at each time point between diabetes cases and controls. RESULTS: We identified 525 participants with new-onset diabetes who were matched to 1,049 controls (mean age, 60 years; 40% women). Compared with those without diabetes, individuals who eventually developed diabetes had higher levels of hypertension (odds ratio [OR], 2.2; P = 0.003), high LDL (OR, 1.5; P = 0.04), low HDL (OR, 2.1; P = 0.0001), high triglycerides (OR, 1.7; P = 0.04), and obesity (OR, 3.3; P < 0.0001) at time points 30 years before diabetes diagnosis. After further adjustment for BMI, the ORs for hypertension (OR, 1.9; P = 0.02) and low HDL (OR, 1.7; P = 0.01) remained statistically significant. CONCLUSIONS: CVD risk factors are increased up to 30 years before diagnosis of diabetes. These findings highlight the importance of a life course approach to CVD risk factor identification among individuals at risk for diabetes. PMID- 23340888 TI - Increasing incidence of type 1 diabetes in youth: twenty years of the Philadelphia Pediatric Diabetes Registry. AB - OBJECTIVE: The purpose of this study was to describe the incidence of type 1 diabetes in children in Philadelphia from 2000-2004, compare the epidemiology to the previous three cohorts in the Philadelphia Pediatric Diabetes Registry, and, for the first time, describe the incidence of type 2 diabetes. RESEARCH DESIGN AND METHODS: Diabetes cases were obtained through a retrospective population based registry. Hospital inpatient and outpatient records were reviewed for cases of type 1 and type 2 diabetes diagnosed from 1 January 2000 to 31 December 2004. The secondary source of validation was the School District of Philadelphia. Time series analysis was used to evaluate the changing pattern of incidence over the 20-year period. RESULTS: The overall age-adjusted incidence rate in 2000-2004 of 17.0 per 100,000 per year was significantly higher than that of previous cohorts, with an average yearly increase of 1.5% and an average 5-year cohort increase of 7.8% (P = 0.025). The incidence in white children (19.2 per 100,000 per year) was 48% higher than in the previous cohort. Children aged 0-4 years had a 70% higher incidence (12.2 per 100,000 per year) than the original cohort; this increase was most marked in young black children. The overall age-adjusted incidence of type 2 diabetes was 5.8 per 100,000 per year and was significantly higher in black children. CONCLUSIONS: The incidence of type 1 diabetes is rising among children in Philadelphia. The incidence rate has increased by 29% since the 1985-1989 cohort. The most marked increases were among white children ages 10-14 years and black children ages 0-4 years. The incidence of type 1 diabetes is 18 times higher than that of type 2 in white children but only 1.6 times higher in black children. PMID- 23340889 TI - Circulating prolactin associates with diabetes and impaired glucose regulation: a population-based study. AB - OBJECTIVE: Prolactin is a major stimulus for the beta-cell adaptation during gestation and guards postpartum women against gestational diabetes. Most studies of the role of prolactin on glucose metabolism have been conducted in humans and animals during pregnancy. However, little is known concerning the association between circulating prolactin and glucose metabolism outside pregnancy in epidemiological studies. We aimed to determine whether the variation of circulating prolactin concentration associates with diabetes and impaired glucose regulation (IGR) in a cross-sectional study. RESEARCH DESIGN AND METHODS: We recruited 2,377 participants (1,034 men and 1,343 postmenopausal women) without hyperprolactinemia, aged 40 years and older, in Shanghai, China. Diabetes and IGR were determined by an oral glucose tolerance test. Multinomial logit analyses were performed to evaluate the relationship of prolactin with diabetes and IGR. RESULTS: Prolactin levels decreased from normal glucose regulation to IGR to diabetes. Multinomial logit analyses, adjusted for potential confounding factors, showed that high circulating prolactin was associated with lower prevalence of diabetes and IGR. The adjusted odds ratios (95% CI) for IGR and diabetes for the highest compared with the lowest quartile of prolactin were 0.54 (95% CI 0.33 0.89) and 0.38 (0.24-0.59) in men and 0.54 (0.36-0.81) and 0.47 (0.32-0.70) in women. CONCLUSIONS: High circulating prolactin associates with lower prevalence of diabetes and IGR in the current study. Further studies are warranted to confirm this association. PMID- 23340890 TI - Endothelial progenitor cells are related to glycemic control in children with type 1 diabetes over time. AB - OBJECTIVE: The risk of cardiovascular death before the age of 40 is 20-fold higher in patients with type 1 diabetes mellitus (T1DM). Endothelial progenitor cells (EPCs) predict cardiovascular morbidity and mortality in patients without diabetes. We hypothesized that EPCs are modified in children with T1DM and are related to characteristics of T1DM such as glycemic control. RESEARCH DESIGN AND METHODS: Children (n = 190; 156 T1DM subjects and 34 control subjects) were included in an observational cohort study and matched for age and sex. EPCs were enumerated by flow cytometry at the beginning (cross-sectional) and 1 year later (longitudinal). To analyze changes of variables during the observation, Delta values were calculated. RESULTS: EPCs were significantly reduced in T1DM children versus control subjects (609 +/- 359 vs. 1,165 +/- 484, P < 0.001). Multivariate regression modeling revealed that glycated hemoglobin A1c (HbA1c) was the strongest independent predictor of EPCs (beta = -0.355, P < 0.001). Overall glycemic control at the beginning and end of study did not differ (7.8 +/- 1.2 vs. 7.8 +/- 1.2 relative %, P = NS), but we observed individual HbA1c changes of 4.30/+3.10 relative %. The strongest EPC increase was observed in the patients with the most favorable HbA1c lowering during the 1-year follow-up. Accordingly, the strongest EPC decrease was demonstrated in the patients with the strongest HbA1c worsening during the time period. CONCLUSIONS: This is the first prospective study demonstrating diminished EPCs in children with T1DM. The association of better glycemic control with an increase in EPC numbers within 1 year suggests that a reduction of the high cardiovascular disease burden might be mediated likewise. PMID- 23340891 TI - Prospective association between inflammatory markers and progression of coronary artery calcification in adults with and without type 1 diabetes. AB - OBJECTIVE: The role of inflammation in the increased risk of cardiovascular disease in type 1 diabetes is unclear. We examined the association of inflammation and progression of coronary artery calcification (CAC)-a marker of subclinical atherosclerosis-in adults with and without type 1 diabetes. RESEARCH DESIGN AND METHODS: A nested case-control study was performed within the prospective cohort of the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. Participants underwent two CAC measurements ~2.5 years apart. Case subjects (n = 204) were those with significant progression of CAC. Control subjects (n = 258) were frequency-matched to case subjects on diabetes status, sex, age, and baseline CAC status. Inflammatory marker assessments were performed on stored blood samples from baseline. A principal components analysis (PCA) was performed and a composite score derived from that analysis. The composite score was constructed by assigning a value of 1 for each PCA component where at least one of the markers exceeded the 75th percentile (range 0-4). Conditional logistic regression was used for the matching strategy. RESULTS: The first two components of the PCA were modestly (odds ratio 1.38 [95% CI 1.08-1.77] and 1.27 [1.02 1.59], respectively) associated with CAC progression after adjustment for other risk factors. The composite score was more strongly associated with CAC progression for those with elevated markers in three or four of the principal components compared with those with none. CONCLUSIONS: Measures of inflammation were associated with progression of CAC in a population of adults with and without type 1 diabetes. PMID- 23340892 TI - Visit-to-visit blood pressure variability is a novel risk factor for the development and progression of diabetic nephropathy in patients with type 2 diabetes. AB - OBJECTIVE: Recent study has suggested that not only the presence of hypertension but also the variability in systolic blood pressure (SBP) are risk factors for vascular disease and organ damage. The aim of this study was to investigate the relationship between visit-to-visit variability in SBP and change in urinary albumin excretion (UAE) or development of albuminuria in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We measured SBP in 354 consecutive patients at every visit during 1 year and calculated the coefficient of variation (CV) of SBP. We performed a follow-up study to assess change in UAE or development of albuminuria, the mean interval of which was 3.76 +/- 0.71 years. Then, we evaluated relationships of variability of SBP to diabetic nephropathy using multiple regression analysis and multiple Cox regression model. RESULTS: Multiple regression analysis demonstrated that CV of SBP was independently associated with change in UAE (beta = 0.1758; P = 0.0108). Adjusted Cox regression analyses demonstrated that CV of SBP was associated with an increased hazard of development of albuminuria; hazard ratio was 1.143 (95% CI 1.008 1.302). CONCLUSIONS: Visit-to-visit variability in SBP could be a novel risk factor for the development and progression of diabetic nephropathy in patients with type 2 diabetes. PMID- 23340894 TI - The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. AB - OBJECTIVE: The requirement to inject current basal insulin analogs at a fixed time each day may complicate adherence and compromise glycemic control. This trial evaluated the efficacy and safety of varying the daily injection time of insulin degludec (IDeg), an ultra-long-acting basal insulin. RESEARCH DESIGN AND METHODS: This 26-week, open-label, treat-to-target trial enrolled adults (>=18 years) with type 2 diabetes who were either insulin naive and receiving oral antidiabetic drugs (OADs) (HbA(1c) = 7-11%) or previously on basal insulin +/- OAD(s) (HbA(1c) = 7-10%). Participants were randomized to 1) once-daily (OD) IDeg in a prespecified dosing schedule, creating 8-40-h intervals between injections (IDeg OD Flex; n = 229); 2) once-daily IDeg at the main evening meal (IDeg OD; n = 228); or 3) once-daily insulin glargine at the same time each day (IGlar OD; n = 230). The primary outcome was noninferiority of IDeg OD Flex to IGlar OD in HbA(1c) reduction after 26 weeks. RESULTS: After 26 weeks, IDeg OD Flex, IDeg OD, and IGlar OD improved HbA(1c) by 1.28, 1.07, and 1.26% points, respectively (estimated treatment difference [IDeg OD Flex - IGlar OD]: 0.04% points [-0.12 to 0.20], confirming noninferiority). No statistically significant differences in overall or nocturnal hypoglycemia were found between IDeg OD Flex and IGlar OD. Comparable glycemic control and rates of hypoglycemia were seen with IDeg OD Flex and IDeg OD. Adverse event profiles were similar across groups. CONCLUSIONS: The use of extreme dosing intervals of 8-40 h demonstrates that the daily injection time of IDeg can be varied without compromising glycemic control or safety. PMID- 23340895 TI - Randomized crossover study to examine the necessity of an injection-to-meal interval in patients with type 2 diabetes and human insulin. AB - OBJECTIVE: Patients with diabetes and insulin therapy with human insulin were usually instructed to use an interval of 20-30 min between the injection and meal. We examined the necessity of the injection-to-meal interval (IMI) in patients with type 2 diabetes mellitus (T2DM) and flexible insulin therapy with human insulin. RESEARCH DESIGN AND METHODS: In this randomized, open crossover trial, 100 patients with T2DM (47% men, mean age = 66.7 years) were randomized to the IMI first group (phase 1, IMI 20 min; phase 2, no IMI) or IMI last group (phase 1, no IMI; phase 2, IMI 20 min). The main outcome measures were HbA1c, blood glucose profile, incidence of hypoglycemia, quality of life, treatment satisfaction, and patient preference. RESULTS: Forty-nine patients were randomized to the IMI first group and 51 patients to the IMI last group. Omitting the IMI only slightly increases HbA1c (average intraindividual difference = 0.08% [95% CI 0.01-0.15]). Since the difference is not clinically relevant, a therapy without IMI is noninferior to its application (P < 0.001). In the secondary outcomes, the incidence of mild hypoglycemia also did not differ between no IMI and IMI significantly (mean of differences = -0.10, P = 0.493). No difference in the blood glucose profile of both groups was found. Treatment satisfaction increased markedly, by 8.08, if IMI was omitted (P < 0.001). The total score of the quality of life measure did not show differences between applying an IMI or not. Insulin therapy without IMI was preferred by 86.5% of patients (P < 0.001). CONCLUSIONS: An IMI for patients with T2DM and preprandial insulin therapy is not necessary. PMID- 23340896 TI - Television viewing and low leisure-time physical activity in adolescence independently predict the metabolic syndrome in mid-adulthood. AB - OBJECTIVE: We investigated whether television (TV) viewing and low leisure-time physical activity in adolescence predict the metabolic syndrome in mid-adulthood. RESEARCH DESIGN AND METHODS: TV viewing habits and participation in leisure-time physical activity at age 16 years were assessed by self-administered questionnaires in a population-based cohort in Northern Sweden. The presence of the metabolic syndrome at age 43 years was ascertained in 888 participants (82% of the baseline sample) using the International Diabetes Federation criteria. Odds ratios (ORs) and CIs were calculated using logistic regression. RESULTS: The overall prevalence of the metabolic syndrome at age 43 years was 26.9%. Adjusted OR for the metabolic syndrome at age 43 years was 2.14 (95% CI 1.24-3.71) for those who reported "watching several shows a day" versus "one show/week" or less and 2.31 (1.13-4.69) for leisure-time physical activity "several times/month" or less compared with "daily" leisure-time physical activity at age 16 years. TV viewing at age 16 years was associated with central obesity, low HDL cholesterol, and hypertension at age 43 years, whereas low leisure-time physical activity at age 16 years was associated with central obesity and triglycerides at age 43 years. CONCLUSIONS: Both TV viewing and low leisure-time physical activity in adolescence independently predicted the metabolic syndrome and several of the metabolic syndrome components in mid-adulthood. These findings suggest that reduced TV viewing in adolescence, in addition to regular physical activity, may contribute to cardiometabolic health later in life. PMID- 23340897 TI - 25-Hydroxyvitamin D in obese youth across the spectrum of glucose tolerance from normal to prediabetes to type 2 diabetes. AB - OBJECTIVE: To 1) determine if plasma 25-hydroxyvitamin D (25[OH]D) concentrations differ among obese youth with normal glucose tolerance (NGT) versus prediabetes versus type 2 diabetes and 2) assess the relationships between 25(OH)D and in vivo insulin sensitivity and beta-cell function in this cohort. RESEARCH DESIGN AND METHODS: Plasma 25(OH)D concentrations were examined in banked specimens in 9 to 20-year-old obese youth (n = 175; male 42.3%, black 46.3%) (NGT, n = 105; impaired glucose tolerance [IGT], n = 43; type 2 diabetes, n = 27) who had in vivo insulin sensitivity and secretion measured by hyperinsulinemic-euglycemic and hyperglycemic clamp techniques and had an assessment of total body composition and abdominal adiposity. RESULTS: The mean age and BMI of the subjects were 14.3 +/- 2.1 years and 35.7 +/- 5.6 kg/m(2), respectively. BMI, plasma 25(OH)D, and the proportion of vitamin D-deficient and -insufficient children did not differ across the three groups. Furthermore, there was no association between 25(OH)D and in vivo insulin sensitivity or beta-cell function relative to insulin sensitivity (disposition index) in all groups combined or in each group separately. CONCLUSIONS: Our data in obese youth show 1) no differences in plasma 25(OH)D concentrations across the glucose tolerance groups and 2) no relationship between 25(OH)D and in vivo insulin sensitivity and beta cell function relative to insulin sensitivity in any of the groups. It remains uncertain if enhancement of the vitamin D status could improve pathophysiological mechanisms of prediabetes and type 2 diabetes in obese youth. PMID- 23340898 TI - Approximation and spatial regionalization of rainfall erosivity based on sparse data in a mountainous catchment of the Yangtze River in Central China. AB - In densely populated countries like China, clean water is one of the most challenging issues of prospective politics and environmental planning. Water pollution and eutrophication by excessive input of nitrogen and phosphorous from nonpoint sources is mostly linked to soil erosion from agricultural land. In order to prevent such water pollution by diffuse matter fluxes, knowledge about the extent of soil loss and the spatial distribution of hot spots of soil erosion is essential. In remote areas such as the mountainous regions of the upper and middle reaches of the Yangtze River, rainfall data are scarce. Since rainfall erosivity is one of the key factors in soil erosion modeling, e.g., expressed as R factor in the Revised Universal Soil Loss Equation model, a methodology is needed to spatially determine rainfall erosivity. Our study aims at the approximation and spatial regionalization of rainfall erosivity from sparse data in the large (3,200 km(2)) and strongly mountainous catchment of the Xiangxi River, a first order tributary to the Yangtze River close to the Three Gorges Dam. As data on rainfall were only obtainable in daily records for one climate station in the central part of the catchment and five stations in its surrounding area, we approximated rainfall erosivity as R factors using regression analysis combined with elevation bands derived from a digital elevation model. The mean annual R factor (R a) amounts for approximately 5,222 MJ mm ha(-1) h(-1) a(-1). With increasing altitudes, R a rises up to maximum 7,547 MJ mm ha(-1) h(-1) a(-1) at an altitude of 3,078 m a.s.l. At the outlet of the Xiangxi catchment erosivity is at minimum with approximate R a=1,986 MJ mm ha(-1) h(-1) a(-1). The comparison of our results with R factors from high-resolution measurements at comparable study sites close to the Xiangxi catchment shows good consistance and allows us to calculate grid-based R a as input for a spatially high-resolution and area specific assessment of soil erosion risk. PMID- 23340893 TI - Most youth with type 1 diabetes in the T1D Exchange Clinic Registry do not meet American Diabetes Association or International Society for Pediatric and Adolescent Diabetes clinical guidelines. AB - OBJECTIVE: To assess the proportion of youth with type 1 diabetes under the care of pediatric endocrinologists in the United States meeting targets for HbA1c, blood pressure (BP), BMI, and lipids. RESEARCH DESIGN AND METHODS: Data were evaluated for 13,316 participants in the T1D Exchange clinic registry younger than 20 years old with type 1 diabetes for >=1 year. RESULTS: American Diabetes Association HbA1c targets of <8.5% for those younger than 6 years, <8.0% for those 6 to younger than 13 years old, and <7.5% for those 13 to younger than 20 years old were met by 64, 43, and 21% of participants, respectively. The majority met targets for BP and lipids, and two-thirds met the BMI goal of <85th percentile. CONCLUSIONS: Most children with type 1 diabetes have HbA1c values above target levels. Achieving American Diabetes Association goals remains a significant challenge for the majority of youth in the T1D Exchange registry. PMID- 23340899 TI - Effect of in vivo chronic exposure to clotrimazole on zebrafish testis function. AB - Clotrimazole is an azole fungicide used as a human pharmaceutical that is known to inhibit cytochrome P450 (CYP) enzymatic activities, including several steroidogenic CYP. In a previous report, we showed that a 7-day exposure to clotrimazole induced the expression of genes related to steroidogenesis in the testes as a compensatory response, involving the activation of the Fsh/Fshr pathway. In this context, the aim of the present study was to assess the effect of an in vivo 21-day chronic exposure to clotrimazole (30-197 MUg/L) on zebrafish testis function, i.e., spermatogenesis and androgen release. The experimental design combined (1) gene transcript levels measurements along the brain-pituitary gonad axis, (2) 11-ketotestosterone (11-KT) quantification in the blood, and (3) histology of the testes, including morphometric analysis. The chronic exposure led to an induction of steroidogenesis-related genes and fshr in the testes as well as fshbeta in the pituitary. Moreover, increases of the gonadosomatic index and of the volume proportion of interstitial Leydig cells were observed in clotrimazole-exposed fish. In accordance with these histological observations, the circulating concentration of 11-KT had increased. Morphometric analysis of the testes did not show an effect of clotrimazole on meiotic (spermatocytes) or postmeiotic (spermatids and spermatozoa) stages, but we observed an increase in the number of type A spermatogonia, in agreement with an increase in mRNA levels of piwil1, a specific molecular marker of type A spermatogonia. Our study demonstrated that clotrimazole is able to affect testicular physiology and raised further concern about the impact of clotrimazole on reproduction. PMID- 23340900 TI - The troponin I: inhibitory peptide uncouples force generation and the cooperativity of contractile activation in mammalian skeletal muscle. AB - Hodges and his colleagues identified a 12 amino acid fragment of troponin I (TnI ip) that inhibits Ca(2+)-activated force and reduces the effectiveness Ca(2+) as an activator. To understand the role of troponin C (TnC) in the extended cooperative interactions of thin filament activation, we compared the effect of TnI-ip with that of partial troponin TnC extraction. Both methods reduce maximal Ca(2+)-activated force and increase [Ca(2+)] required for activation. In contrast to TnC extraction, TnI-ip does not reduce the extended cooperative interactions between adjacent thin filament regulatory units as assessed by the slope of the pCa/force relationship. Additional evidence that TnI-ip does not interfere with extended cooperativity comes from studies that activate muscle by rigor crossbridges (RXBs). TnI-ip increases both the cooperativity of activation and the concentration of RXBs needed for maximal force. This shows that TnI-ip binding to TnC increases the stability of the relaxed state of the thin filament. TnI-ip, therefore, uncouples force generation from extended cooperativity in both Ca(2+) and RXB activated muscle contraction. Because maximum force can be reduced with no change-or even an increase-in cooperativity, force-generating crossbridges do not appear to be the primary activators of cooperativity between thin filament regulatory units of skeletal muscle. PMID- 23340901 TI - Experimental determination of chemical diffusion within secondary organic aerosol particles. AB - Formation, properties, transformations, and temporal evolution of secondary organic aerosol (SOA) particles depend strongly on SOA phase. Recent experimental evidence from both our group and several others indicates that, in contrast to common models' assumptions, SOA constituents do not form a low-viscosity, well mixed solution, yielding instead a semisolid phase with high, but undetermined, viscosity. We find that when SOA particles are made in the presence of vapors of semi-volatile hydrophobic compounds, such molecules become trapped in the particles' interiors and their subsequent evaporation rates and thus their rates of diffusion through the SOA can be directly obtained. Using pyrene as the tracer molecule and SOA derived from alpha-pinene ozonolysis, we find that it takes ~24 hours for half the pyrene to evaporate. Based on the observed pyrene evaporation kinetics we estimate a diffusivity of 2.5 * 10(-21) m(2) s(-1) for pyrene in SOA. Similar measurements on SOA doped with fluoranthene and phenanthrene yield diffusivities comparable to that of pyrene. Assuming a Stokes-Einstein relation, an approximate viscosity of 10(8) Pa s can be calculated for this SOA. Such a high viscosity is characteristic of tars and is consistent with published measurements of SOA particle bounce, evaporation kinetics, and the stability of two reverse-layered morphologies. We show that a viscosity of 10(8) Pa s implies coalescence times of minutes, consistent with the findings that SOA particles formed by coagulation are spherical on the relevant experimental timescales. Measurements on aged SOA particles doped with pyrene yield an estimated diffusivity ~3 times smaller, indicating that hardening occurs with time, which is consistent with the increase in SOA oligomer content, decrease in water uptake, and decrease in evaporation rates previously observed with aging. PMID- 23340902 TI - Immunohistochemical expression of RAGE and its ligand (S100A9) in cervical lesions. AB - Altered expressions of receptor for advanced glycation end-products (RAGE) and its ligand (S100A9) are observed in many cancers and play a key role in inflammation-associated cancer. In our previous study, by two-dimensional gel electrophoresis followed by mass spectrometry, the expression of S100A9 protein was found to increase in squamous cervical cancer compared with adjacent normal cervical tissues. Therefore, in the present study we observed the expressions of S100A9 and RAGE in 30 chronic cervicitis, 50 cervical intraepithelial neoplasia (CIN), and 40 squamous cervical cancer (SCC) using immunohistochemical analysis and analyzed the differential expression and possible role of S100A9 and RAGE in cancer development. Immunohistochemical findings were as follows: the expressions of S100A9 and RAGE were demonstrated in chronic cervicitis, CIN, and SCC. Moreover, their expressions were gradually increasing as the tumor progressed. In SCC, the staining scores of S100A9 and RAGE were significantly higher in well differentiated tumors compared to moderately and poorly differentiated tumors. The expression of S100A9 in epithelial cells exhibited a positive correlation to RAGE expression in chronic cervicitis, CIN, and SCC. There were no significant difference of S100A9 immunoreactivity in stromal cells among chronic cervicitis, CIN, and SCC. Moreover, there was no correlation between S100A9 immunoreactivity in stromal cells of SCC and clinicopathological parameters. Finally, double immunohistochemistry illustrated that RAGE and S100A9 co-express in SCC. In conclusion, RAGE binds its ligand (S100A9), which plays an important role in the development of SCC. In addition, the expressions of S100A9 and RAGE in SCC tumor cells were closely associated with histological differentiation. PMID- 23340903 TI - Core Curriculum Illustration: marked head rotation following blunt trauma. PMID- 23340904 TI - Shape selective plate-form Ga(2)O(3) with strong metal-support interaction to overlying Pd for hydrogenation of CO(2) to CH(3)OH. AB - A stronger metal-support interaction between Pd and plate-form Ga(2)O(3) nanocrystals covered with the predominant 002 surface than other Ga(2)O(3) surfaces is found, which gives higher methanol yield in catalytic CO(2) hydrogenation. PMID- 23340906 TI - Enhanced separation of colloidal particles in an AsPFF device with a tilted sidewall and vertical focusing channels (t-AsPFF-v). AB - Here, we report an enhanced separation of colloidal particles using a novel type AsPFF (asymmetric pinched flow fractionation) device with two additional features (t-AsPFF-v). Particularly, by adding a tilted sidewall and vertical focusing channels to the conventional AsPFF device, a significant enhancement in the separation resolution (R(m,n)) has been achieved, which was estimated to be 10.4 for 6 and 10 MUm PS particles and found to be 11.6 times better than that of a conventional AsPFF. PMID- 23340905 TI - Prediagnostic plasma vitamin B6 (pyridoxal 5'-phosphate) and survival in patients with colorectal cancer. AB - PURPOSE: Higher plasma pyridoxal 5'-phosphate (PLP) levels are associated with a decreased incidence of colorectal cancer, but the influence of plasma PLP on survival of patients with colorectal cancer is unknown. We prospectively examined whether prediagnostic plasma PLP levels are associated with mortality among colorectal cancer patients. METHODS: We included 472 incident cases of colorectal cancer identified in the Nurses' Health Study, the Health Professionals Follow-up Study, and the Physicians' Health Study from 1984 to 2002. The patients provided blood samples two or more years before cancer diagnosis. Stratified Cox proportional hazards models were used to calculate hazard ratios (HR) with 95 % confidence intervals (CI) adjusted for other risk factors for cancer survival. RESULTS: Higher plasma PLP levels were not associated with a significant reduction in colorectal cancer-specific (169 deaths) or overall mortality (259 deaths). Compared with patients who had less than 45 pmol/ml of plasma PLP (median: 33.6 pmol/ml), those who had 110 pmol/ml or higher levels (median: 158.8 pmol/ml) had multivariable HRs of 0.85 (95 % CI 0.50-1.45, p trend = 0.37) and 0.87 (95 % CI 0.56-1.35, p trend = 0.24) for colorectal cancer-specific and overall mortality. Higher plasma PLP levels, however, seemed to be associated with better survival among patients who had lower circulating 25-hydroxyvitamin D3 levels (<26.5 ng/ml) (p interaction <=.005). CONCLUSIONS: Higher prediagnostic plasma PLP levels were not associated with an improvement on colorectal cancer survival overall. Further research is needed to clarify the influence of vitamin B6 on colorectal cancer progression and survival. PMID- 23340907 TI - New insights into prebiotic chemistry from Stanley Miller's spark discharge experiments. AB - 1953 was a banner year for biological chemistry: The double helix structure of DNA was published by Watson and Crick, Sanger's group announced the first amino acid sequence of a protein (insulin) and the synthesis of key biomolecules using simulated primordial Earth conditions has demonstrated by Miller. Miller's studies in particular transformed the study of the origin of life into a respectable field of inquiry and established the basis of prebiotic chemistry, a field of research that investigates how the components of life as we know it can be formed in a variety of cosmogeochemical environments. In this review, I cover the continued advances in prebiotic syntheses that Miller's pioneering work has inspired. The main focus is on recent state-of-the-art analyses carried out on archived samples of Miller's original experiments, some of which had never before been analyzed, discovered in his laboratory material just before his death in May 2007. One experiment utilized a reducing gas mixture and an apparatus configuration (referred to here as the "volcanic" apparatus) that could represent a water-rich volcanic eruption accompanied by lightning. Another included H(2)S as a component of the reducing gas mixture. Compared to the limited number of amino acids Miller identified, these new analyses have found that over 40 different amino acids and amines were synthesized, demonstrating the potential robust formation of important biologic compounds under possible cosmogeochemical conditions. These experiments are suggested to simulate long-lived volcanic island arc systems, an environment that could have provided a stable environment for some of the processes thought to be involved in chemical evolution and the origin of life. Some of the alternatives to the Miller-based prebiotic synthesis and the "primordial soup" paradigm are evaluated in the context of their relevance under plausible planetary conditions. PMID- 23340909 TI - [Tubulointerstitial nephritis with uveitis (TINU) syndrome. A relatively rare rheumatological differential diagnosis with unexplained uveitis]. AB - The tubulo-interstitial nephritis and uveitis (TINU) syndrome, first described in 1975, is a rare disease most probably of autoimmune origin that is characterized by unilateral or bilateral uveitis and tubulointerstitial nephritis. Most patients are adolescents and it is sometimes associated with other autoimmune diseases, such as spondyloarthritis, rheumatoid arthritis and hyperthyroidosis. This article reports the case of a 43-year-old female patient who presented with refractory recurrent bilateral uveitis despite therapy with high doses of corticosteroids in combination with cyclosporin. When the patient was referred to this hospital for rheumatological examination after almost 1 year of therapy, mild renal insufficiency and proteinuria were found. The kidney biopsy revealed interstitial nephritis, partly crescent-shaped and partly chronic. A diagnosis of TINU syndrome was made and treatment with adalimumab in combination with methotrexate was started. The favorable clinical outcome indicated that tumor necrosis factor (TNF) alpha may play an important role in the pathogenesis of TINU syndrome. PMID- 23340908 TI - The NuRD architecture. AB - The nucleosome remodeling and deacetylase (NuRD) complex regulates chromatin organization, gene transcription, genomic stability and developmental signaling. NuRD has a unique dual enzymatic activity, containing an ATPase and a histone deacetylase among its six core subunits. Recent studies indicate that NuRD composition and the interplay between subunits may dictate the diverse functions of the complex. In this review, we examine the structures and biological roles of the NuRD subunits and discuss new avenues of research to advance our understanding of the NuRD-mediated signaling network. PMID- 23340910 TI - The relationship between long-term sunlight radiation and cognitive decline in the REGARDS cohort study. AB - Sunlight may be related to cognitive function through vitamin D metabolism or circadian rhythm regulation. The analysis presented here sought to test whether ground and satellite measures of solar radiation are associated with cognitive decline. The study used a 15-year residential history merged with satellite and ground monitor data to determine sunlight (solar radiation) and air temperature exposure for a cohort of 19,896 cognitively intact black and white participants aged 45+ from the 48 contiguous United States. Exposures of 15, 10, 5, 2, and 1 year were used to predict cognitive status at the most recent assessment in logistic regression models; 1-year insolation and maximum temperatures were chosen as exposure measures. Solar radiation interacted with temperature, age, and gender in its relationships with incident cognitive impairment. After adjustment for covariates, the odds ratio (OR) of cognitive decline for solar radiation exposure below the median vs above the median in the 3rd tertile of maximum temperatures was 1.88 (95 % CI: 1.24, 2.85), that in the 2nd tertile was 1.33 (95 % CI: 1.09, 1.62), and that in the 1st tertile was 1.22 (95 % CI: 0.92, 1.60). We also found that participants under 60 years old had an OR = 1.63 (95 % CI: 1.20, 2.22), those 60-80 years old had an OR = 1.18 (95 % CI: 1.02, 1.36), and those over 80 years old had an OR = 1.05 (0.80, 1.37). Lastly, we found that males had an OR = 1.43 (95 % CI: 1.22, 1.69), and females had an OR = 1.02 (0.87, 1.20). We found that lower levels of solar radiation were associated with increased odds of incident cognitive impairment. PMID- 23340912 TI - Impact of pharmacy technician-centered medication reconciliation on optimization of antiretroviral therapy and opportunistic infection prophylaxis in hospitalized patients with HIV/AIDS. AB - PURPOSE: This study aimed to examine the role of a pharmacy technician-centered medication reconciliation (PTMR) program in optimization of medication therapy in hospitalized patients with HIV/AIDS. METHODS: A chart review was conducted for all inpatients that had a medication reconciliation performed by the PTMR program. Adult patients with HIV and antiretroviral therapy (ART) and/or the opportunistic infection (OI) prophylaxis listed on the medication reconciliation form were included. The primary objective is to describe the (1) number and types of medication errors and (2) the percentage of patients who received appropriate ART. The secondary objective is a comparison of the number of medication errors between standard mediation reconciliation and a pharmacy-led program. RESULTS: In the PTMR period, 55 admissions were evaluated. In all, 50% of the patients received appropriate ART. In 27of the 55 admissions, there were 49 combined ART and OI-related errors. The most common ART-related errors were drug-drug interactions. The incidence of ART-related medication errors that included drug drug interactions and renal dosing adjustments were similar between the pre-PTMR and PTMR groups (P = .0868). Of the 49 errors in the PTMR group, 18 were intervened by a medication reconciliation pharmacist. CONCLUSION: A PTMR program has a positive impact on optimizing ART and OI prophylaxis in patients with HIV/AIDS. PMID- 23340911 TI - Iron-responsive bacterial small RNAs: variations on a theme. AB - For most living organisms, iron is both essential and potentially toxic, making the precise maintenance of iron homeostasis necessary for survival. To manage this paradox, bacteria regulate the acquisition, utilization, and storage of iron in response to its availability. The iron-dependent ferric uptake repressor (Fur) often mediates this iron-responsive regulation by both direct and indirect mechanisms. In 2002, Masse and Gottesman identified a novel target of Fur mediated regulation in Escherichia coli: a gene encoding a small regulatory RNA (sRNA) termed RyhB. Under conditions of iron-limitation, RyhB is produced and functions to regulate the expression of several target genes encoding iron utilizing enzymes, iron acquisition systems, and iron storage factors. This pivotal finding provided the missing link between environmental iron-limitation and previously observed decreases in certain iron-dependent metabolic pathways, a phenomenon now referred to as an "iron-sparing" response. The discovery of RyhB opened the door to the rapidly expanding field of bacterial iron-regulated sRNAs, which continue to be identified and described in numerous bacterial species. Most striking are findings that the impact of iron-responsive sRNA regulation often extends beyond iron homeostasis, particularly with regard to production of virulence-associated factors by pathogenic bacteria. This review discusses trends in the collective body of work on iron-regulated sRNAs, highlighting both the regulatory mechanisms they utilize to control target gene expression and the impact of this regulation on basic processes controlling bacterial physiology and virulence. PMID- 23340913 TI - Persistent hypoglycemia of unknown etiology in a patient without diabetes: a case report and review. AB - PURPOSE: This case report reviews the presentation, evaluation, and treatment of persistent hypoglycemia in a patient without a history of diabetes. The use of laboratory tests to differentiate between drug-induced and disease-induced hypoglycemia is reviewed. SUMMARY: A 51-year-old female with multiple medical conditions including bipolar disorder and no history of diabetes was admitted for evaluation and treatment of hypoglycemia. Pharmacotherapy included intravenous dextrose infusions and bolus doses. A battery of tests was ordered to evaluate intrinsic and extrinsic causes. Endocrine Society guidelines for hypoglycemia exist and have recommendations for testing and strategies to rule out drug related causes. Her insulin level was 57 IU/mL (normal range < 17). Her proinsulin level was 356.8 pmol/L (normal range <8.8). CONCLUSION: The guidelines recommend a battery of laboratory tests; however, the results are not rapidly available necessitating a structured follow-up process. In our patient, exposure to hypoglycemic agents and exogenous insulin can be ruled out. Autoimmune hypoglycemia or a hypoglycemic reaction to one of her home medications is very unlikely, but cannot be ruled out. An insulinoma is the most likely etiology of her hypoglycemia, but that cannot be confirmed. PMID- 23340914 TI - Structured pharmaceutical representative interactions and counterdetailing sessions as components of medical resident education. AB - INTRODUCTION: Educational activities should be developed to teach residents how to constructively interact with pharmaceutical representatives and how to critically assess the provided information. METHODS: An educational study was implemented during the 2010-2011 academic year in an internal medicine residency program. The study included an initial educational session on physician-industry relations and then 4 interactive sessions with the pharmaceutical representatives, each followed by a counterdetailing session provided by a clinical pharmacist. Study surveys were conducted to evaluate resident attitudes concerning pharmaceutical representative presented information before and after the counterdetailing sessions. RESULTS: A total of 27 residents (n = 27) participated in the study. The study results revealed that residents learned new relevant product information from the representatives (P = .002) and strongly agreed that counterdetailing was beneficial (P = .009). Residents further agreed that they would recommend counterdetailing presentations to peers, suggested minimal changes to session formatting, and recommended its continued inclusion in their curriculum. CONCLUSIONS: This study demonstrated benefits of a comprehensive program to teach residents how to constructively interact with the pharmaceutical representatives and critically assess the information provided by the representatives. Best practices for incorporating interaction and counterdetailing sessions into medical resident curriculum should be further studied. PMID- 23340915 TI - Assessing student pharmacist impact on patient over-the-counter medication selection. AB - OBJECTIVE: To evaluate the financial and clinical outcomes of an over-the-counter (OTC) medication consultation performed by doctorate of pharmacy student pharmacists in a community pharmacy. DESIGN: Cross-sectional survey. SETTING: Independent and chain community pharmacy locations in Pittsburgh, Pennsylvania. PARTICIPANTS: Fourth professional year (PY4) advanced experiential student pharmacists on community rotations at the designated settings who performed OTC consultations and the participants of these encounters. MAIN OUTCOME MEASURED: Financial and clinical impact of an OTC consultation performed by student pharmacists on rotation. RESULTS: A total of 559 OTC consultations were offered in 5 participating community pharmacy settings over a period of 1 year. Student pharmacists initiated 62.4% of all documented interactions and 60.5% of all participants accepted the consultation offer. The student pharmacists' OTC recommendations resulted in significant cost savings to the participant. Those participants accepting consultation reported being more likely to consult with a pharmacist in the future. PY4 students were also able to demonstrate capability in impacting clinical outcomes on several occasions by implementing OTC medication changes due to patient safety concerns. CONCLUSION: Student pharmacist OTC consultations have the potential to positively impact both financial and clinical outcomes associated with the use of OTC medications. PMID- 23340916 TI - Voluntary exercise can strengthen the circadian system in aged mice. AB - Consistent daily rhythms are important to healthy aging according to studies linking disrupted circadian rhythms with negative health impacts. We studied the effects of age and exercise on baseline circadian rhythms and on the circadian system's ability to respond to the perturbation induced by an 8 h advance of the light:dark (LD) cycle as a test of the system's robustness. Mice (male, mPer2(luc)/C57BL/6) were studied at one of two ages: 3.5 months (n = 39) and >18 months (n = 72). We examined activity records of these mice under entrained and shifted conditions as well as mPER2::LUC measures ex vivo to assess circadian function in the suprachiasmatic nuclei (SCN) and important target organs. Age was associated with reduced running wheel use, fragmentation of activity, and slowed resetting in both behavioral and molecular measures. Furthermore, we observed that for aged mice, the presence of a running wheel altered the amplitude of the spontaneous firing rate rhythm in the SCN in vitro. Following a shift of the LD cycle, both young and aged mice showed a change in rhythmicity properties of the mPER2::LUC oscillation of the SCN in vitro, and aged mice exhibited longer lasting internal desynchrony. Access to a running wheel alleviated some age related changes in the circadian system. In an additional experiment, we replicated the effect of the running wheel, comparing behavioral and in vitro results from aged mice housed with or without a running wheel (>21 months, n = 8 per group, all examined 4 days after the shift). The impact of voluntary exercise on circadian rhythm properties in an aged animal is a novel finding and has implications for the health of older people living with environmentally induced circadian disruption. PMID- 23340917 TI - Neck dissection after chemoradiotherapy for oropharyngeal and hypopharyngeal cancer: the correlation between cervical lymph node metastasis and prognosis. AB - BACKGROUND: Recently, the role of chemoradiotherapy (CRT) for preserving organs in the treatment of head and neck cancer has been increasing. However, the indication for post-CRT neck dissection (ND) and its surgical extent is still controversial. The purpose of this study was to discuss the indications for post CRT ND and the proper extent of the surgical procedure. METHODS: We performed a retrospective analysis on N2-3 oropharyngeal and hypopharyngeal squamous cell carcinoma (OHSCC) patients treated with CRT in our institute from 1995 to 2008, and determined the prognostic impact of post-CRT ND and the distribution of cervical lymph node (CLN) metastasis based on the pathological results of ND. RESULTS: The patients without pathological CLN metastases had good prognoses, whereas patients with pathological CLN metastases exhibited a significantly high recurrence rate (P = 0.033). Based on the pathological results of ND, performing selective ND at levels II-IV can contain 88 and 85 % of CLN metastasis of the oropharynx and hypopharynx, respectively. In all cases, when pathological CLN metastases were found at level V in ND following CRT, distant metastases developed. CONCLUSIONS: The presence of pathological CLN metastasis affects prognosis, but also a diffuse distribution of CLN metastasis worsens prognosis; that is, the presence of CLN metastasis at level V after CRT appears to be an indicator of distant metastasis. Post-CRT ND may not make sense as a salvage intervention for improving the prognosis in such situations. We concluded that the proper extent of post-CRT ND of OHSCC is selective ND including levels II-IV. PMID- 23340918 TI - Serum 25-hydroxyvitamin D, parathyroid hormone, and their association with metabolic syndrome in Chinese. AB - Increasing evidence suggests that 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) levels are associated with metabolic syndrome (MetS). In 2010, we explored the association of serum 25(OH)D and PTH levels with MetS in 1,390 Chinese participants, aged 20-83 years. Anthropometric phenotypes, blood pressure, and the incidence of MetS were evaluated. In addition, serum lipids, 25(OH)D, and PTH were measured. The median concentration of 25(OH)D and PTH were 55.3 nmol/l and 2.8 pmol/l, respectively. The prevalence of vitamin D deficiency (<50 nmol/l) was 39.9 %, with 34.5 % in men and 47.8 % in women. After accounting for confounding factors and serum PTH, a 10 nmol/l higher serum 25(OH)D level was associated with a 10 % lower risk of MetS (OR = 0.90, 95 % CI 0.84-0.96, P = 0.0007). Furthermore, participants with vitamin D sufficiency had a 35 % lower risk of MetS than those with vitamin D deficiency (OR = 0.65, 95 % CI 0.51-0.84, P = 0.0009). PTH was not associated with the risk of MetS after adjustment for confounding factors. These results were confirmed in both men and women. Thus in this cohort of Chinese individuals, vitamin D deficiency is common and optimal vitamin D level is inversely associated with MetS, independent of several confounders and PTH level. The clinical significance of these findings warrants further study. PMID- 23340919 TI - Activation of Si-Si and Si-H bonds at Pt: a catalytic hydrogenolysis of silicon silicon bonds. AB - The activation of Ph(2)HSiSiHPh(2) and Me(3)SiSiMe(3) at [Pt(PEt(3))(3)] (1) yielded the products of oxidative addition. The formation of [Pt(SiHPh(2))(2)(PEt(3))(2)] (2) as a mixture of the cis and trans isomers appears to proceed quantitatively, whereas a conversion to give cis [Pt(SiMe(3))(2)(PEt(3))(2)] (3) was not complete. Treatment of 1 with one equivalent of H(2)SiPh(2) led to cis-and trans-[Pt(H)(SiHPh(2))(PEt(3))(2)] (cis 4, trans-4) together with the dinuclear complex [(Et(3)P)(2)(H)Pt(MU-SiPh(2))(MU eta(2)-HSiPh(2))Pt(PEt(3))] (5). In contrast, HSiMe(3) reacts with [Pt(PEt(3))(3)] to yield cis-[Pt(H)(SiMe(3))(PEt(3))(2)] (7) exclusively. Catalytic reactions of dihydrogen with the disilanes Ph(2)HSiSiHPh(2) or Me(3)SiSiMe(3) in the presence of catalytic amounts of [Pt(PEt(3))(3)] (1) led to the products of hydrogenolysis, H(2)SiPh(2) and HSiMe(3). The conversion of Me(3)SiSiMe(3) is much slower and needs higher temperature to proceed. PMID- 23340920 TI - Characterization of drug permeability in Caco-2 monolayers by mass spectrometry on a membrane-based microfluidic device. AB - In this study, an integrated microfluidic device was developed for drug permeability assays with real-time online detection by a directly coupled mass spectrometer. The integrated microfluidic device contained two independent channels sandwiched by a semipermeable polycarbonate membrane for cell culture, and micro solid-phase extraction (SPE) columns for sample clean-up and concentration prior to mass spectrometry detection. Curcumin, a model drug, was delivered to an upper or bottom channel by a pressure-driven flow to mimic dynamic in vivo conditions, and it was forced to permeate into the other side channel. The concentration of curcumin permeated with time was directly detected by an electrospray ionization quadrupole time-of-flight mass spectrometer (ESI-Q TOF MS) with high sensitivity after micro-SPE pretreatment. The total analysis time only needed about 30 min, and only 6 MUL of the drug solution was required for each permeation experiment. The measured permeability of curcumin was consistent with the literature reported value. In addition, this technique offers the potential for parallelization and increasing throughput compared to conventional methods. Thus, the established platform provides a useful tool for drug permeability studies, which is crucial for drug discovery and development. PMID- 23340921 TI - Comparison of dexketoprofen trometamol and dipyrone in the treatment of renal colic. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used for pain relief in patients with renal colic. Dexketoprofen trometamol is an NSAID that has demonstrated good analgesic efficacy and a good safety profile after oral administration in different models of acute and chronic pain. OBJECTIVE: To assess the analgesic efficacy and safety of single intramuscular doses of dexketoprofen trometamol (25 and 50mg) compared with dipyrone (2g) in moderate to severe pain due to renal colic. STUDY DESIGN: Multicentre, randomised, double-blind, parallel-group study. PATIENTS: PATIENTS of both sexes aged 18-70 years with a diagnosis of renal colic were eligible for randomisation if they presented with at least moderate pain as assessed by visual analogue scale (VAS) scoring >=40mm on a scale of 100mm immediately before study drug administration. METHODS: Assessment of analgesic efficacy was done using standard pain intensity and pain relief scales. Total scores from baseline to 6 hours after study drug administration were calculated for the sum of pain intensity differences relative to baseline (SPID), sum of analogue pain intensity differences relative to baseline (SAPID) and total pain relief scores (TOTPAR) as primary efficacy endpoints. Secondary efficacy and safety variables were also analysed. RESULTS: A total of 333 patients (dexketoprofen 25mg, n = 112; dexketoprofen 50mg, n = 113; dipyrone 2g, n = 108) were included in the study. No significant differences were found between the treatment groups with regard to SPID (p = 0.797), SAPID (p = 0.852) and TOTPAR (p = 0.716). The time-effect course for pain intensity differences and pain relief showed significantly (p < 0.05) higher values for both doses of dexketoprofen trometamol compared with dipyrone during the first hour after treatment administration. More than 90% of the patients in all three groups achieved pain relief of at least 50% as compared with baseline. Similarly, over 70% of the patients in all three groups considered the received treatment as excellent or good in the overall assessment of efficacy at the end of the study. No dose-effect relationship was observed in this pain model between both doses of dexketoprofen trometamol. All three treatments were well tolerated, showing mostly mild to moderate adverse events. CONCLUSION: Dexketoprofen trometamol is a good analgesic for the treatment of moderate to severe pain due to renal colic, with a good safety profile and an efficacy comparable to that of dipyrone. The significantly greater effect of dexketoprofen trometamol early after administration suggests a faster onset of action, which can be of paramount importance in this condition. PMID- 23340922 TI - Atorvastatin versus Bezafibrate in Mixed Hyperlipidaemia : Randomised Clinical Trial of Efficacy and Safety (the ATOMIX Study). AB - OBJECTIVE: Combined hyperlipidaemia is a common and highly atherogenic lipid phenotype with multiple lipoprotein abnormalities that are difficult to normalise with single-drug therapy. The ATOMIX multicentre, controlled clinical trial compared the efficacy and safety of atorvastatin and bezafibrate in patients with diet-resistant combined hyperlipidaemia. PATIENTS AND STUDY DESIGN: Following a 6 week placebo run-in period, 138 patients received atorvastatin 10mg or bezafibrate 400mg once daily in a randomised, double-blind, placebo-controlled trial. To meet predefined low-density lipoprotein-cholesterol (LDL-C) target levels, atorvastatin dosages were increased to 20mg or 40mg once daily after 8 and 16 weeks, respectively. RESULTS: After 52 weeks, atorvastatin achieved greater reductions in LDL-C than bezafibrate (percentage decrease 35 vs 5; p < 0.0001), while bezafibrate achieved greater reductions in triglyceride than atorvastatin (percentage decrease 33 vs 21; p < 0.05) and greater increases in high-density lipoprotein-cholesterol (HDL-C) [percentage increase 28 vs 17; p < 0.01 ]. Target LDL-C levels (according to global risk) were attained in 62% of atorvastatin recipients and 6% of bezafibrate recipients, and triglyceride levels <200 mg/dL were achieved in 52% and 60% of patients, respectively. In patients with normal baseline HDL-C, bezafibrate was superior to atorvastatin for raising HDL-C, while in those with baseline HDL-C <35 mg/dL, the two drugs raised HDL-C to a similar extent after adjustment for baseline values. Both drugs were well tolerated. CONCLUSION: The results show that atorvastatin has an overall better efficacy than bezafibrate in concomitantly reaching LDL-C and triglyceride target levels in combined hyperlipidaemia, thus supporting its use as monotherapy in patients with this lipid phenotype. PMID- 23340923 TI - Pharmacokinetic-pharmacodynamic modelling of recombinant human erythropoietin in athletes : a population approach. AB - OBJECTIVE: To develop a pharmacokinetic model able to take into account the negative feedback loop of endogenous erythropoietin production observed after repeated administration of recombinant human erythropoietin (rHuEPO), and to propose a pharmacokinetic-pharmacodynamic model capable of assessing and quantifying the relationship between changes in: (i) serum soluble transferrin receptor (sTfR) levels, (ii) reticulocyte haematocrit (RetHct), and (iii) percentage macrocytes (%Macro) secondary to repeated administration of rHuEPO. SUBJECTS AND METHODS: Eighteen trained athletes (three females and 15 males) participated in this study. They received subcutaneous injections of rHuEPO-alpha 50 U/kg bodyweight for 26 days (days 1, 3, 5, 9, 10, 12, 15, 17, 19, 22, 24 and 26) with iron supplementation. Venous blood samples were collected before, during and after rHuEPO treatment for determination of serum erythropoietin concentrations, haematological parameters (RetHct, %Macro) and sTfR levels. Population pharmacokinetic-pharmacodynamic calculations were performed using NONMEM(r) software. RESULTS: The serum erythropoietin concentration-time profile was compatible with a one-compartment open model and first-order input rate. The mean half-lives calculated from the first and the terminal log-linear parts of the curves were 5.2 and 35.8 hours, respectively. After subcutaneous administration of rHuEPO, the terminal part of the curve should correspond to the absorption rather than the elimination phase ('flip-flop' phenomenon). The total clearance divided by bio-availability was 4.33 L/h. The pharmacodynamic relationship based on a sigmoid E(max) model can be reasonably used to relate changes observed in haematological and biochemical markers after rHuEPO administration to changes in serum erythropoietin concentrations. rHuEPO induces a delayed increase in sTfR levels, RetHct and %Macro. The half-life (t1/2) k(0) (equilibration delay) values were 10.2 days for sTfR, 2 days for RetHct and 10.2 days for %Macro. The pharmaco-kinetic-pharmacodynamic approach developed in this study allowed below-base-line decreases in RetHct levels (i.e. from days 10-26 after the end of rHuEPO treatment) to be taken into account. A negative-feedback loop of red blood cell production further to high haemoglobin and haematocrit values could explain this decrease. CONCLUSIONS: The approach described here may provide an additional tool in the war against drug abuse by athletes; indeed, the model could be useful for simulating pharmacokinetic-pharmacodynamic relationships according to different rHuEPO dosage schedules. PMID- 23340924 TI - One-Year Evaluation of the Safety and Efficacy of Ipratropium Bromide HFA and CFC Inhalation Aerosols in Patients with Chronic Obstructive Pulmonary Disease. AB - INTRODUCTION: Ipratropium bromide (IB) is an established and effective first-line maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). A new IB metered-dose inhaler (MDI) using hydrofluoroalkane 134a propellant (IB HFA) has been developed as an alternative to the MDI containing chlorofluorocarbon (IB CFC). OBJECTIVE: To compare the long-term safety and efficacy of IB HFA and IB CFC in patients with COPD. STUDY DESIGN: This was a randomised, open-label, parallel-group, 1-year, multi-centre trial. Primary endpoints included adverse events (AEs) and vital signs. Secondary endpoints included therapeutic response (>15% increase in forced expiratory volume in 1 second [FEV(1)] peak change from baseline), FEV(1) area under the response-time curve (AUC). PATIENTS AND INTERVENTIONS: Patients (n = 456) with moderate-to severe COPD, who received either IB HFA (n = 305) or IB CFC (n = 151 ), both 42ug four times daily. RESULTS: There were no significant differences in the incidences of individual AEs between groups over the short and long term; respiratory disorders were the most common. The incidence of anticholinergic AEs possibly related to treatment was low (1.3% IB HFA, 0.7% IB CFC). Serious AEs occurred in 19.0% and 20.5%, and discontinuations due to AEs in 7.2% and 7.3%, of patients receiving IB HFA and IB CFC, respectively. Therapeutic bronchodilatory responses were achieved in 76-81% and 72-84% of patients, and AUC ranged from 0.117-0.148L and 0.117-0.174L, in patients receiving IB HFA and IB CFC, respectively. CONCLUSIONS: IB HFA had similar efficacy and tolerability to IB CFC over 1 year, supporting a seamless transition from the CFC MDI to the HFA MDI in both short- and long-term treatment. PMID- 23340925 TI - Effects of d-003, a new hypocholesterolaemic and antiplatelet compound, on lipid profile and lipid peroxidation in healthy volunteers. AB - BACKGROUND: D-003 is a mixture of long-chain aliphatic primary acids purified from sugarcane wax with hypocholesterolaemic effects proven in rabbits and healthy volunteers; it lowers serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) and increases high-density lipoprotein cholesterol (HDL-C). D-003 also prevents lipoprotein lipid peroxidation in experimental models. OBJECTIVE: To investigate the effects of D-003 on lipid profile and lipid peroxidation in healthy human volunteers. PARTICIPANTS: Forty six healthy volunteers (24 women, 22 men). METHODS: This double-blind, randomised, placebo-controlled study investigated the effects of D-003 at 5 and 10 mg/day on the susceptibility of LDL to lipid peroxidation induced by copper ions in healthy volunteers. Forty-six individuals were randomised (1 : 2) to placebo or D-003 at 5 or 10 mg/day, the tablets being taken once a day with the evening meal for 8 weeks. Laboratory determinations and physical examination were performed at baseline and after 4 and 8 weeks of therapy, and compliance and adverse experience assessments were performed at weeks 4 and 8. RESULTS: All groups were well matched at baseline. At study completion, D-003 at 5 and 10 mg/day significantly (p < 0.001) lowered LDL-C, the primary response variable, by 20.8% and 28.8%, respectively. In addition, D-003 at 5 and 10 mg/day reduced (p < 0.001) TC (12.7% and 17.5%, respectively), LDL-C/ HDL-C (25.9% and 36.3%, respectively) and TC/HDL-C (18.6% and 26.3%, respectively), while significantly (p < 0.01) increasing HDL-C (7.7% and 12.4%, respectively). Triglycerides were significantly (p < 0.05) reduced (8.8% and 13.1%, respectively) with respect to baseline, but not versus placebo. Responses assessed at 4 weeks showed significant reductions of LDL-C, TC and atherogenic ratios with both doses of D 003, whereas HDL-C was significantly increased. Triglycerides, however, remained unchanged. No significant changes in any lipid profile variable occurred in the placebo group. D-003 at 5 and 10 mg/day significantly (p < 0.05) increased lag time (18.3% and 32.0%, respectively) and decreased maximum rate of diene propagation (V(max)) [12.7% and 19.1%, respectively] of copper-induced LDL peroxidation. D-003 5 and 10 mg/day attenuated the reduction of the reactivity against 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) by 19.9% and 32.0%, respectively. The treatment was well tolerated. Three subjects (one from each group) discontinued the study. Only one, treated with D-003 5 mg/day, discontinued because of an adverse event (gastritis). CONCLUSIONS: D-003 at 5 and 10 mg/day demonstrated dose-dependent cholesterol-lowering effects in healthy volunteers characterised by reductions in LDL-C, TC and atherogenic ratios, and increases in HDL-C. Effects on triglycerides were modest and uncertain. As expected from experimental studies, D-003 inhibited the susceptibility of LDL to lipid peroxidation assessed by three indicators lag time V(max) and reactivity versus TNBS. Further studies investigating the effect of larger doses and treatment duration must be conducted to confirm the reproducibility of the present results in different study populations. PMID- 23340926 TI - Management options for gynaecomastia and breast pain associated with nonsteroidal antiandrogen therapy : case report series. AB - OBJECTIVE: To present management options for gynaecomastia and mastodynia associated with nonsteroidal antiandrogen therapy, supported by relevant data and case studies. BACKGROUND: Gynaecomastia (male breast enlargement) and breast pain/ sensitivity (mastodynia or mastalgia) are pharmacologically expected adverse effects of nonsteroidal antiandrogen therapy for prostate cancer. They are caused by proliferation of glandular tissue in response to an increase in the ratio of estrogen to androgen. Gynaecomastia and mastodynia are benign conditions, and many patients choose to tolerate them as acceptable, usually mild or moderate, adverse effects of therapy. Recent data show that nonsteroidal antiandrogen monotherapy significantly reduces disease progression in localised and locally advanced prostate cancer, a finding that may result in wider and more long-term use of this treatment. Therefore, both clinicians and patients may benefit from increased awareness of the options available for the management of gynaecomastia and mastodynia. Management options, data and case studies: Management options for gynaecomastia and mastodynia are illustrated in a schematic flow diagram. Options identified are: (1) risk reduction using pretreatment breast irradiation; (2) stopping antiandrogen therapy; (3) acceptance of gynaecomastia and/or mastodynia in the context of the significant clinical benefit of antiandrogen treatment; (4) prompt treatment (liposuction/breast tissue excision, hormonal manipulation or pain control with irradiation or analgesics); and (5) later treatment (liposuction/breast tissue excision, hormonal manipulation or pain control with irradiation or analgesics). Where available, relevant data are discussed and the options are illustrated by case studies. CONCLUSIONS: The risk of developing gynaecomastia is lessened by prophylactic breast irradiation. Following the development of gynaecomastia, treatment options include readjustment of the estrogen-to-androgen ratio using antiestrogens, surgery in the form of liposuction or, for more advanced cases, breast tissue excision. Mastodynia may be controlled by post-treatment irradiation or analgesics. PMID- 23340927 TI - Increased warfarin sensitivity complicated by retroperitoneal haemorrhage in a patient with merkel cell carcinoma. PMID- 23340928 TI - Photoluminescent organosilane-functionalized carbon dots as temperature probes. AB - Organosilane-functionalized carbon dots (SiC-dots) were prepared by a simple one pot hydrothermal approach. The photoluminescence (PL) properties of the SiC-dots revealed a reversible response toward the temperature (293-343 K). Through Si-O Si bonding, temperature-sensitive PL SiC-dot films could be easily fabricated on glass substrates. PMID- 23340929 TI - Micro-organisms isolated from cadaveric samples of allograft musculoskeletal tissue. AB - Allograft musculoskeletal tissue is commonly used in orthopaedic surgical procedures. Cadaveric donors of musculoskeletal tissue supply multiple allografts such as tendons, ligaments and bone. The microbiology laboratory of the South Eastern Area Laboratory Services (SEALS, Australia) has cultured cadaveric allograft musculoskeletal tissue samples for bacterial and fungal isolates since 2006. This study will retrospectively review the micro-organisms isolated over a 6-year period, 2006-2011. Swab and tissue samples were received for bioburden testing and were inoculated onto agar and/or broth culture media. Growth was obtained from 25.1 % of cadaveric allograft musculoskeletal tissue samples received. The predominant organisms isolated were coagulase-negative staphylococci and coliforms, with the heaviest bioburden recovered from the hemipelvis. The rate of bacterial and fungal isolates from cadaveric allograft musculoskeletal tissue samples is higher than that from living donors. The type of organism isolated may influence the suitability of the allograft for transplant. PMID- 23340931 TI - [Major importance of independent clinical research for the evaluation of new treatment modalities]. PMID- 23340932 TI - [Risk stratification prior to peripheral vascular interventions]. PMID- 23340930 TI - Soluble FAS ligand as a biomarker of disease recurrence in differentiated thyroid cancer. AB - BACKGROUND: Reliable predictive biomarkers are required to address the challenge of disease recurrence after thyroid cancer surgery. For this study, the authors assessed the association of cellular-based and serum-based immunologic mediators with thyroid cancer recurrence. METHODS: Leukocyte subset counts and immune regulatory cytokine levels were determined in peripheral blood samples using multiparameter flow cytometry and 51-panel, multiplex enzyme-linked immunosorbent assays, respectively. The functional activity of circulating B-lymphocytes, T lymphocytes, and natural killer lymphocytes was assessed ex vivo. Differences in mean biomarker levels between defined patient groups and correlations between biomarkers and cancer recurrence were assessed using t tests or Wilcoxon tests and by univariate and multivariate analyses with Cox models. Optimal cutoff values of significantly correlated biomarkers that best predicted disease recurrence after surgery were established by receiver operating characteristics and were validated by using an optimal cutpoint determination algorithm. RESULTS: In total, 35 patients were enrolled (median age, 49.4 year), including 24 women and 15 patients with recurrent disease; and there were 21 individuals in the control group. Patients without recurrence had higher levels of soluble FAS (tumor necrosis receptor superfamily, member 6) ligand (sFASL), transforming growth factor-beta, regulatory T cells, and programmed death 1/ programmed death ligand 1-expressing leukocytes. sFASL (hazard ratio, 0.60; 95% confidence interval, 0.38-0.95; P = .031) and interferon-alpha (hazard ratio, 1.55; 95% confidence interval, 1.03-2.34; P = .038) were associated significantly with disease recurrence. There was a significant difference in progression-free survival between patient groups stratified by an sFASL optimal cutpoint of 15 pg/mL (log-rank P = .0009). CONCLUSIONS: sFASL and IFN-alpha levels were correlated significantly with thyroid cancer recurrence and may be useful for risk-adapted surveillance strategies in patients with thyroid cancer. PMID- 23340933 TI - [Obesity and inflammation]. PMID- 23340934 TI - [Intensive care in the elderly]. PMID- 23340935 TI - [Breast cancer: tumor biology-based concepts for surgical and drug treatment]. PMID- 23340936 TI - [Pneumococcal vaccination in adults: background of the current discussion]. PMID- 23340937 TI - [Extracorporeal membrane oxygenation]. PMID- 23340938 TI - [Cardiovascular magnetic resonance imaging: new developments]. PMID- 23340939 TI - [Diagnosis, course and treatment of autosomal dominant polycystic kidney disease]. PMID- 23340940 TI - [Recent advances in pleural diseases]. PMID- 23340941 TI - [Rheumatoid arthritis: cardiovascular risk is high, but manageable]. PMID- 23340942 TI - [Treatment of inflammatory bowel disease]. PMID- 23340943 TI - [28-year-old man with fever and abnormalities in chest radiograph]. PMID- 23340944 TI - [Acute coronary syndrom as a cardiac manifestation of granulomatosis with polyangiitis]. AB - HISTORY AND ADMISSION FINDINGS: A 49-year-old patient was admitted to our ward because of a troponin elevation (non ST-elevation myocardial infarction) following a rhinoscopy in an external hospital. The patient complained of typical angina, chronic rhinitis and epistaxis. Analysis of the nasal biopsy had shown the histological finding of granulomatosis with polyangiitis (Wegener's granulomatosis). INVESTIGATION: The consecutively performed catheterization showed a coronary one-vessel disease without significant stenosis. Echocardiography showed diastolic dysfunction as well as hemodynamically not significant pericardial effusion. The MRI scan of the heart revealed multiple myocardial scars located ventricular apical and septal. Extended bilateral pulmonary opacities in the thoracic CT scan, microhematuria, leukocyturia and proteinuria indicated multi-organ involvement of the small vessel disease. TREATMENT AND COURSE: The patient's condition improved quickly in response to steroids and cyclophosphamide, followed by attenuation of clinical symptoms and normalizing blood and renal parameters. CONCLUSION: The prognosis of granulomatosis with polyangiitis is mainly limited by renal and pulmonal involvement. Cardiac involvement is commonly rare and associated with clinical courses refractory to immunosuppressive therapy. Generally, all cardiac structures can be affected, thereby impending serious cardiac events. Normally, granulomatosis with polyangiitis responds quickly to immunosuppressive therapy, associated with a rather good prognosis without higher mortality. PMID- 23340945 TI - [Transcatheter aortic valve implantation (TAVI) for the treatment of aortic stenosis: aspects of health care research]. PMID- 23340946 TI - Fabrication of a PANI/CPs composite material: a feasible method to enhance the photocatalytic activity of coordination polymers. AB - To improve the photocatalytic activity of a coordination polymer in the visible light region, polyaniline (PANI) was loaded onto its surface through a facile in situ chemical oxidation polymerization process. The resulting PANI loaded coordination polymer composite materials with excellent stability exhibit significantly higher photocatalytic activities than the pure coordination polymer photocatalyst on the degradation of methyl orange (MO) under visible light irradiation. This enhancement can be ascribed to the introduction of PANI on the surface of the coordination polymer, which leads to efficient separation of photogenerated electron-hole pairs as well as a significant expansion of the photoresponse region. Finally, we discussed the influence of acidity on the morphology and photocatalytic activity of the composite material. An optimal condition to obtain the PANI loaded coordination polymer composite material with excellent photocatalytic activity has been obtained. PMID- 23340948 TI - Do patients with osteoporosis have an increased prevalence of periodontal disease? A cross-sectional study. AB - The study examined if women with osteoporosis were at increased risk of periodontal disease. Three hundred eighty females aged 45-65 years with recent dual-energy X-ray absorptiometry (DXA) scans of the spine and proximal femur agreed to a dental examination. No association was established between the presence of severe periodontal disease and osteoporosis. INTRODUCTION: The purpose of this study is to determine whether patients with osteoporosis have an increased severity and extent of periodontal disease, taking full account of confounding factors. METHODS: Volunteer dentate women (45-65 years), who had undergone recent DXA of the femur and lumbar spine, received a clinical examination of their periodontal tissues by a single trained operator who was blind to the subject's osteoporosis status. Clinical examinations were performed within 6 months of the DXA. Basic Periodontal Examination score, gingival bleeding score, periodontal pocket depth, recession and calculus were the periodontal outcome measures. Potential confounding factors were recorded. Logistic regression was performed for the dichotomous outcome measure of severe periodontal disease (present or absent) with osteoporotic status, adjusting for confounding factors. RESULTS: There were 380 dentate participants for whom DXA data were available. Of these, 98 had osteoporosis. When compared with osteoporotic subjects, those with normal bone mineral density were significantly younger (p = 0.01), had a higher body mass index (p = 0.03) and had more teeth (p = 0.01). The prevalence of severe periodontal disease in the sample was 39 %. The unadjusted odds ratio for the association between osteoporosis and severe periodontal disease was 1.21 (0.76 to 1.93). The adjusted odds ratio analysis including other covariates (age, smoking, hormone replacement therapy, alcohol) was 0.99 (0.61 to 1.61). CONCLUSION: No association was established between the presence of severe periodontal disease and osteoporosis. PMID- 23340947 TI - Direct healthcare costs for 5 years post-fracture in Canada: a long-term population-based assessment. AB - High direct incremental healthcare costs post-fracture are seen in the first year, but total costs from a third-party healthcare payer perspective eventually fall below pre-fracture levels. We attribute this to higher mortality among fracture cases who are already the heaviest users of healthcare ("healthy survivor bias"). Economic analyses that do not account for the possibility of a long-term reduction in direct healthcare costs in the post-fracture population may systematically overestimate the total economic burden of fracture. INTRODUCTION: High healthcare costs in the first 1-2 years after an osteoporotic fracture are well recognized, but long-term costs are uncertain. We evaluated incremental costs of non-traumatic fractures up to 5 years from a third-party healthcare payer perspective. METHODS: A total of 16,198 incident fracture cases and 48,594 matched non-fracture controls were identified in the province of Manitoba, Canada (1997-2002). We calculated the difference in median direct healthcare costs for the year pre-fracture and 5 years post-fracture expressed in 2009 Canadian dollars with adjustment for expected age-related healthcare cost increases. RESULTS: Incremental median costs for a hip fracture were highest in the first year ($25,306 in women, $21,396 in men), remaining above pre-fracture baseline to 5 years in women but falling below pre-fracture costs by 5 years in men. In those who survived 5 years following a hip fracture, incremental costs remained above pre-fracture costs at 5 years ($12,670 in women, $7,933 in men). Incremental costs were consistently increased for 5 years after spine fracture in women. Total incremental healthcare costs for all incident fractures combined showed a large increase over pre-fracture costs in the first year ($137 million in women, $57 million in men), but fell below pre-fracture costs within 3-4 years. Elevated total healthcare costs were seen at year 5 in women after wrist, humerus and spine fractures, but these were somewhat offset by decreases in total healthcare costs for other fractures. CONCLUSIONS: High direct healthcare costs post-fracture are seen in the first year, but total costs eventually fall below pre-fracture levels. Among those who survive 5 years following a fracture, healthcare costs remain above pre-fracture levels. PMID- 23340949 TI - Hospital burden of vertebral fractures in France: influence of vertebroplasty. AB - We described the whole population of patients hospitalized for vertebral fractures in France in 2009. Only 6.4 % of them were operated by vertebroplasty; these patients were younger and healthier than non-operated patients. INTRODUCTION: This study aims to describe the burden of vertebral fractures from the 2009 French Hospital National Database in acute care in people aged 60 years and over, with or without vertebroplasty. METHODS: All stays due to nonmalignant and nontraumatic vertebral fractures as primary cause were selected. Patients' characteristics were described and compared between patients with or without vertebroplasty. The in-patient mortality was compared to the one related to hip and upper humerus fracture in patients hospitalized during the same year. RESULTS: In 2009, 13,624 patients were hospitalized for vertebral fracture. Men accounted for 29.3 % of cases. Length of stay was 9.6 +/- 8.2 days, higher in patients with at least one comorbidity than in patients without (11.2 +/- 8.6 and 7.8 +/- 7.2 days, respectively). The in-patient mortality was 0.9 %; it was 3.8 and 1.1 % for hip and upper humerus fractures, respectively. Vertebroplasty was performed in 6.4 % of them. Patients with vertebroplasty were younger (mean age of 75 +/- 8 versus 79 +/- 9 years), had a less duration of stay (7 +/- 7.5 versus 9.8 +/- 8.2 days), less comorbidities (at least one comorbidity, 45 versus 54 %), and less in-patient mortality (0.1 versus 0.9 %). Rehospitalization for vertebral fracture occurred in 9 and 6 % of the patient with and without vertebroplasty. CONCLUSION: This is the first French study assessing the national burden of vertebral fractures based on hospital data. In-hospital death rate is lower in patients with vertebroplasty, who are younger and have less comorbidities than the general population with vertebral fractures. PMID- 23340951 TI - [Secondary sclerosing cholangitis after multiple trauma and long-term intensive care treatment: case report of a characteristic course]. AB - This article reports on a patient who needed intensive care treatment because of multiple trauma. The patient had no preexisting liver disease but developed secondary sclerosing cholangitis and finally died. The etiology, diagnosis and therapeutic options of this clinical picture are discussed and a review of the literature is presented. PMID- 23340952 TI - Somatic symptoms among US adolescent females: associations with sexual and physical violence exposure. AB - The objective of this study is to examine the association between physical and sexual violence exposure and somatic symptoms among female adolescents. We studied a nationally representative sample of 8,531 females, aged 11-21 years, who participated in the 1994-1995 Wave I of the National Longitudinal Study of Adolescent Health (Add Health). Female adolescents were asked how often they had experienced 16 specific somatic symptoms during the past 12 months. Two summary categorical measures were constructed based on tertiles of the distributions for the entire female sample: (a) total number of different types of symptoms experienced, and (b) number of frequent (once a week or more often) different symptoms experienced. Groups were mutually exclusive. We examined associations between adolescents' violence exposure and somatic symptoms using multinomial logistic regression analyses. About 5 % of adolescent females reported both sexual and non-sexual violence, 3 % reported sexual violence only, 36 % reported non-sexual violence only, and 57 % reported no violence. Adolescents who experienced both sexual and non-sexual violence were the most likely to report many different symptoms and to experience very frequent or chronic symptoms. Likelihood of high symptomatology was next highest among adolescents who experienced sexual violence only, followed by females who experienced non-sexual violence only. Findings support an exposure-response association between violence exposure and somatic symptoms, suggesting that symptoms can be markers of victimization. Treating symptoms alone, without addressing the potential violence experienced, may not adequately improve adolescents' somatic complaints and well being. PMID- 23340953 TI - TG13 diagnostic criteria and severity grading of acute cholecystitis (with videos). AB - Since its publication in 2007, the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) have been widely adopted. The validation of TG07 conducted in terms of clinical practice has shown that the diagnostic criteria for acute cholecystitis are highly reliable but that the definition of definite diagnosis is ambiguous. Discussion by the Tokyo Guidelines Revision Committee concluded that acute cholecystitis should be suspected when Murphy's sign, local inflammatory findings in the gallbladder such as right upper quadrant abdominal pain and tenderness, and fever and systemic inflammatory reaction findings detected by blood tests are present but that definite diagnosis of acute cholecystitis can be made only on the basis of the imaging of ultrasonography, computed tomography or scintigraphy (HIDA scan). These proposed diagnostic criteria provided better specificity and accuracy rates than the TG07 diagnostic criteria. As for the severity assessment criteria in TG07, there is evidence that TG07 resulted in clarification of the concept of severe acute cholecystitis. Furthermore, there is evidence that severity assessment in TG07 has led to a reduction in the mean duration of hospital stay. As for the factors used to establish a moderate grade of acute cholecystitis, such as leukocytosis, ALP, old age, diabetes, being male, and delay in admission, no new strong evidence has been detected indicating that a change in the criteria used in TG07 is needed. Therefore, it was judged that the severity assessment criteria of TG07 could be applied in the updated Tokyo Guidelines (TG13) with minor changes. TG13 presents new standards for the diagnosis, severity grading and management of acute cholecystitis. Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html. PMID- 23340954 TI - TG13 antimicrobial therapy for acute cholangitis and cholecystitis. AB - Therapy with appropriate antimicrobial agents is an important component in the management of patients with acute cholangitis and/or acute cholecystitis. In the updated Tokyo Guidelines (TG13), we recommend antimicrobial agents that are suitable from a global perspective for management of these infections. These recommendations focus primarily on empirical therapy (presumptive therapy), provided before the infecting isolates are identified. Such therapy depends upon knowledge of both local microbial epidemiology and patient-specific factors that affect selection of appropriate agents. These patient-specific factors include prior contact with the health care system, and we separate community-acquired versus healthcare-associated infections because of the higher risk of resistance in the latter. Selection of agents for community-acquired infections is also recommended on the basis of severity (grades I-III). Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html. PMID- 23340955 TI - Unravelling molecular mechanisms in the fluorescence spectra of doxorubicin in aqueous solution by femtosecond fluorescence spectroscopy. AB - Doxorubicin (DOX) is a potent anti-tumoral agent widely used for cancer therapy. Despite numerous studies, the fluorescence properties of DOX, usually exploited for the characterization of the interaction with biological media, have until now led to controversial interpretations, mainly due to self-association of the drug in aqueous solution. We present here the first femtosecond study of DOX based on measurements with the fluorescence up-conversion technique in combination with time-correlated single photon counting using the same laser source. We provide evidence that fluorescence signals of DOX stem from monomers and dimers. DOX dimerization induces a dramatic decrease in the fluorescence quantum yield from 3.9 * 10(-2) to 10(-5) associated with the red shift of the fluorescence spectrum by ~25 nm. While the fluorescence lifetime of the monomer is 1 ns, the dimer fluorescence is found to decay with a lifetime of about 2 ps. In contrast to monomers, the fluorescence anisotropy of dimers is found to be negative. These experimental observations are consistent with an ultrafast internal conversion (<200 fs) between two exciton states, possibly followed by a charge separation process. PMID- 23340956 TI - High precision isotope measurements reveal poor control of copper metabolism in parkinsonism. AB - Disordered copper metabolism may be important in the aetiology of Parkinsonism, as caeruloplasmin is a key enzyme in handling oxidative stress and is involved in the synthesis pathway of dopamine. The human Cu metabolism of ten Parkinsonism patients was compared to ten healthy controls with the aid of a stable (65)Cu isotope tracer. The analyses of blood serum (65)Cu/(63)Cu ratios yielded individual isotopic profiles, which indicate that the Cu metabolism is less controlled in patients with Parkinsonism. Modelling based on both isotope tracer and total Cu concentrations suggests that 30% of the subjects affected by Parkinsonism have abnormally large Cu stores in tissues. To detect the small differences in Cu metabolism between Parkinsonism and controls, the analysis of stable isotope composition must be performed using multiple-collector inductively coupled plasma mass spectrometry and the associated sample preparation techniques. This pilot investigation supports full-scale medical studies into the Cu metabolism of those with Parkinsonism. PMID- 23340957 TI - Identification of the active components in Shenmai injection that differentially affect Cyp3a4-mediated 1'-hydroxylation and 4-hydroxylation of midazolam. AB - Shenmai injection (SMI) is a popular herbal preparation that is widely used for the treatment of atherosclerotic coronary heart disease and viral myocarditis. In our previous study, SMI was shown to differentially affect CYP3A4-mediated 1' hydroxylation and 4-hydroxylation of midazolam (MDZ). The present study was conducted to identify the active components in SMI responsible for the differential effects on MDZ metabolism, using in vitro incubation systems (rat and human liver microsomes and a recombinant CYP3A4 system) to measure 1' hydroxylation and 4-hydroxylation of MDZ. First, different fractions of SMI were obtained by gradient elution on an solid phase extraction system and individually tested for their effects on MDZ metabolism. The results demonstrated that lipid soluble constituents were likely to be the predominant active components of SMI. Second, the possible active components were gradually separated on an high performance liquid chromatography system under different conditions and individually tested in vitro for their effects on MDZ metabolism. Third, the active component obtained in the above experiment was collected and subjected to structural analysis, and identified as panaxytriol (PXT). Finally, it was validated that PXT had significant differential effects on 1'-hydroxylation and 4 hydroxylation of MDZ in various in vitro systems that were similar to those of SMI. We conclude that PXT is the constituent of SMI responsible for the differential effects on CYP3A4-mediated 1'-hydroxylation and 4-hydroxylation of MDZ. PMID- 23340958 TI - Retrospective analysis of P-glycoprotein-mediated drug-drug interactions at the blood-brain barrier in humans. AB - To date, the in vitro-in vivo correlation (IVIVC) of P-glycoprotein (P-gp) mediated drug-drug interaction (DDI) at the blood-brain barrier (BBB) in rats indicated that the cutoff value to significantly affect the brain penetration of digoxin was [I,unbound/Ki] of 1, where I,unbound is the unbound plasma concentration of P-gp inhibitors. On the basis of the IVIVC in rats, we speculated that clinically used P-gp inhibitors do not cause DDI at the human BBB, because none of the compounds studied was [I,unbound/Ki]>1 at therapeutic doses. Recently, positron emission tomography studies with P-gp substrates, such as [(11)C]verapamil, [(11)C]N-desmethyl loperamide, and [(11)C]loperamide, together with potent P-gp inhibitors, have indicated that increases in the influx rate constant for brain entry were observed in humans. Therefore, we aimed to retrospectively analyze the results of P-gp-mediated DDIs with in vitro P-gp inhibition assays and to confirm the appropriate cutoff value. In vitro P-gp inhibition assays using verapamil, N-desmethyl loperamide, and loperamide as P-gp probe substrates were performed in human multidrug resistance protein 1 expressing LLC-PK1 cells. The efflux ratios decreased in the presence of P-gp inhibitors, and the Ki of tariquidar was 10 nmol/L, regardless of probe substrates. Taking the in vitro Ki and unbound plasma concentrations in clinical DDI studies together, the criterion [I,unbound/Ki] of 1 was an appropriate cutoff limit to observe significant P-gp-mediated DDI at the BBB in humans. On the other hand, no significant DDI was observed in cases in which [I,unbound/Ki] was less than 0.1. This criterion was comparable to the previous IVIVC result in rats. PMID- 23340959 TI - Single-port access surgery resection of a presacral schwannoma. PMID- 23340960 TI - Amine templated open-framework vanadium(III) phosphites with catalytic properties. AB - Four novel amine templated open-framework vanadium(III) phosphites with the formula (C(5)N(2)H(14))(0.5)[V(H(2)O)(HPO(3))(2)], 1 (C(5)N(2)H(14) = 2 methylpiperazinium), and (L)(4-x)(H(3)O)(x)[V(9)(H(2)O)(6)(HPO(3))(14 y)(HPO(4))(y)(H(2)PO(3))(3-z)(H(2)PO(4))z].nH(2)O (2, L = cyclopentylammonium, x = 0, y = 3.5, z = 3, n = 0; , L = cyclohexylammonium, x = 1, y = 0, z = 0.6, n = 2.33; , L = cycloheptylammonium, x = 1, y = 0, z = 0, n = 2.33) were synthesized employing solvothermal reactions and characterized by single-crystal X-ray diffraction, ICP-AES and elemental analyses, thermogravimetric and thermodiffractometric analyses, and IR and UV/vis spectroscopy. Single-crystal data indicate that 1 crystallizes in the triclinic system, space group P1, whereas 2, 3 and 4 crystallize in the hexagonal space group P6(3)/m. Compound 1 has a two-dimensional motif with anionic sheets of [V(H(2)O)(HPO(3))(2)](-) formula, whose charge is compensated by the 2-methylpiperazinium cations embedded between the layers. In contrast, 2, 3 and 4 present a pillar-layer network giving rise to a three-dimensional framework containing intersecting 16-ring channels with the primary amine templates and the crystallization water molecules enclosed in them. 1, 2, 3 and 4 behave as heterogeneous catalysts for the selective oxidation of alkyl aryl sulfides, with tert-butylhydroperoxide (TBHP) as the oxidizing agent, being active, selective and recyclable for several successive cycles of reaction. PMID- 23340961 TI - Sickle cell disease with double stroke in a Moroccan family. AB - The sickle-cell disease is a group of chronic hemolytic diseases which associates three types of injuries: severe anemia, severe infections, and ischemic vaso occlusive crisis that are secondary to conflicts between small vessels and red blood cells too deformable. Thus, organic various complications may arise. Its prevalence in Europe is estimated to be about 1/150 and reaches 15 % in the Mediterranean areas. Clinical manifestations vary widely from one person to another and from one moment to another. In addition to anemia and bacterial infections, vaso-occlusive crisis may manifest by focal ischemia. In the long term, the VOC may compromise the function of a particular tissue or organ. The transmission is autosomal recessive. The sickle-cell diseases are determined by combinations of two abnormal alleles of beta globin gene including at least one which carries the mutation beta 6 glu-val (Hb S). We report the case of a girl aged 11 years, who presented two strokes in the interval of 8 months, which manifested by a complete right hemiplegia and aphasia confirmed by head CT scan; the electrophoresis of the hemoglobin and the molecular test had confirmed the diagnosis of sickle-cell disease, and we were allowed to spread better reflection on the prevention of stroke, which remains a frequent and serious complication of sickle-cell disease. PMID- 23340962 TI - Patient specific fluid-structure ventricular modelling for integrated cardiac care. AB - Cardiac diseases represent one of the primary causes of mortality and result in a substantial decrease in quality of life. Optimal surgical planning and long-term treatment are crucial for a successful and cost-effective patient care. Recently developed state-of-the-art imaging techniques supply a wealth of detailed data to support diagnosis. This provides the foundations for a novel approach to clinical planning based on personalisation, which can lead to more tailored treatment plans when compared to strategies based on standard population metrics. The goal of this study is to develop and apply a methodology for creating personalised ventricular models of blood and tissue mechanics to assess patient-specific metrics. Fluid-structure interaction simulations are performed to analyse the diastolic function in hypoplastic left heart patients, who underwent the first stage of a three-step surgical palliation and whose condition must be accurately evaluated to plan further intervention. The kinetic energy changes generated by the blood propagation in early diastole are found to reflect the intraventricular pressure gradient, giving indications on the filling efficiency. This suggests good agreement between the 3D model and the Euler equation, which provides a simplified relationship between pressure and kinetic energy and could, therefore, be applied in the clinical context. PMID- 23340964 TI - Dioxole functionalized metal-organic frameworks. AB - The synthesis and physical properties of dioxole functionalized metal-organic frameworks (MOFs) are reported. Combination of benzo[d][1,3]dioxole-4,7 dicarboxylic acid (dioxole-BDC) and Zn(II) under solvothermal conditions yields either an isoreticular metal-organic framework analog (IRMOF-1-dioxole) or a new MOF material (MOF-1-dioxole). With the addition of a co-ligand, namely 4,4' bipyridine, a mixed-linker Zn(II)-paddlewheel MOF (BMOF-2-dioxole) is obtained. The structure of all three MOFs has been determined by single-crystal X-ray diffraction studies. MOF-1-dioxole reveals that the dioxole group binds to the Zn(II) ions, while there is no such binding in IRMOF-1-dioxole or BMOF-2-dioxole, hence preserving the parent topology of these frameworks. Thermal gravimetric analysis and gas sorption studies reveal quite different physical properties for each of these functionalized MOFs. PMID- 23340963 TI - Yeast (1,3)-(1,6)-beta-glucan helps to maintain the body's defence against pathogens: a double-blind, randomized, placebo-controlled, multicentric study in healthy subjects. AB - PURPOSE: The effect of brewers' yeast (1,3)-(1,6)-beta-D-glucan consumption on the number of common cold episodes in healthy subject was investigated. METHODS: In a placebo-controlled, double-blind, randomized, multicentric clinical trial, 162 healthy participants with recurring infections received 900 mg of either placebo (n = 81) or an insoluble yeast (1,3)-(1,6)-beta-D-glucan preparation (n = 81) per day over a course of 16 weeks. Subjects were instructed to document each occurring common cold episode in a diary and to rate ten predefined infection symptoms during an infections period, resulting in a symptom score. The subjects were examined by the investigator during the episode visit on the 5th day of each cold episode. RESULTS: In the per protocol population, supplementation with insoluble yeast (1,3)-(1,6)-beta-glucan reduced the number of symptomatic common cold infections by 25% as compared to placebo (p = 0.041). The mean symptom score was 15% lower in the beta-glucan as opposed to the placebo group (p = 0.125). Beta-glucan significantly reduced sleep difficulties caused by cold episode as compared to placebo (p = 0.028). Efficacy of yeast beta-glucan was rated better than the placebo both by physicians (p = 0.004) participants (p = 0.012). CONCLUSION: The present study demonstrated that yeast beta-glucan preparation increased the body's potential to defend against invading pathogens. PMID- 23340965 TI - A label-free DC impedance-based microcytometer for circulating rare cancer cell counting. AB - Quantification of circulating tumor cells (CTCs) in blood samples is believed to provide valuable evidence of cancer progression, cancer activity status, response to therapy in patients with metastatic cancer, and possible cancer diagnosis. Recently, a number of researchers reported that CTCs tend to lose their epithelial cell adhesion molecule (EpCAM) by an epithelial-mesenchymal transition (EMT). As such, label-free CTC detection methods are attracting worldwide attention. Here, we describe a label-free DC impedance-based microcytometer for CTCs by exploiting the difference in size between CTCs and blood cells. This system detects changes in DC impedance between two polyelectrolytic gel electrodes (PGEs) under low DC voltages. Using spiked ovarian cancer cell lines (OVCAR-3) in blood as a model system, we were able to count the cells using a microcytometer with 88% efficiency with a flow rate of 13 MUl min(-1) without a dilution process. Furthermore, we examined blood samples from breast cancer patients using the cytometer, and detected CTCs in 24 out of 24 patient samples. Thus, the proposed DC impedance-based microcytometer presents a facile and fast way of CTC evaluation regardless of their biomarkers. PMID- 23340967 TI - The anti-neoplastic effects of coumarin: an emerging concept. AB - The recent article by Liu et al. provided for highly interesting reading. Interestingly, recent data suggests that coumarin may exert significant anti neoplastic effects in a number of systemic malignancies. Coumarin is also of clinical benefit in mammary malignancies. For instance, it attenuates the extent of extremity lymphedema following breast cancer surgery and radiation therapy. In one recent study, an almost 12.5 % decline in the volume of upper extremity lymphedema was noticed. As a result, quality of life is significantly improved. Similar attenuation of tumor growth has been seen in pulmonary malignancies. It mediates these anti-neoplastic effects by attenuating Bcl-2 expression within the tumor cells. On the other hand, Bax expression within the tumor cells is markedly accentuated. These changes have recently been confirmed in A549 cells. PMID- 23340966 TI - Kinetic studies of recombinant rabies virus glycoprotein (RVGP) cDNA transcription and mRNA translation in Drosophila melanogaster S2 cell populations. AB - Recombinant rabies virus glycoprotein (RVGP) was expressed in cell membranes of stably transfected Drosophila S2 cells using constitutive and inducible promoters. Although with quantitative differences of RVGP expression in both systems, the cDNA transcription, as evaluated by relative RVGP mRNA levels measured by qRT-PCR, sustained the amount of RVGP producing cells and the RVGP volumetric (PiRVGP) productivity. At the transition to the stationary cell growth phase, once the cell culture slowed down its rate of multiplication, an accumulation of RVGP mRNA and RVGP was clearly observed in both cell populations. Nevertheless, cell cultures performed under sub-optimal temperatures indicated that an envisaged increase in the RVGP production is not only dependent on cell growth rate, but essentially on optimal cell metabolic state. PMID- 23340969 TI - [Dysfunctional emotion regulation as a basic factor of anxiety and depressive disorders in adolescents]. AB - OBJECTIVE: Depression and anxiety disorders are among the most common mental disorders in adolescents and show high comorbidity. The aim of the current study was to investigate emotion regulation as a conjoint as well as restricting factor. METHODS: Matched samples of depressive and anxious adolescents and a control group (12-16 years; n = 60) were compared for their emotion regulation. Analyses of variance and t-tests were used to analyse group differences in emotion regulation. Individual differences in regulation strategies between the two types of disorders were analysed exploratorily. RESULTS: Results indicate more dysfunctional emotion regulation in anxious and depressive adolescents compared to a control group. Neither dysfunctional emotion regulation in sum, nor single strategies differentiated between the two disorder groups. CONCLUSION: Identification and modification of dysfunctional emotion regulation in anxious and depressive adolescents can support future prevention and intervention. PMID- 23340970 TI - [X-linked recessive ichthyosis (XRI), cerebellar ataxia and neuropsychiatric symptoms]. AB - X-Linked ichthyosis (XRI) is a keratinisation disorder caused by a mutation of the steroid sulfatase gene. An association with mental retardation and epilepsy has been reported earlier. Here, we report on a patient suffering from cerebellar symptoms such as yes/yes head tremor, scanning dysarthria, pronounced dysmetria and intention tremor, without any abnormalities of the cerebellum in MRI, in addition to XRI proven by molecular genetics. Furthermore, the patient suffered from anxiety disorder, depression, and a male pattern baldness. One of the patient' s brothers and a nephew showed a similar clinical presentation. Because of the fact that several members of the patient's family suffered from similar symptoms, we consider a syndromic link between XRI and cerebellar disorder to be possible. PMID- 23340971 TI - [Secondary prevention of ischemic stroke--part 2]. PMID- 23340972 TI - Multiplexed colorimetric detection of Kaposi's sarcoma associated herpesvirus and Bartonella DNA using gold and silver nanoparticles. AB - Kaposi's sarcoma (KS) is an infectious cancer occurring most commonly in human immunodeficiency virus (HIV) positive patients and in endemic regions, such as Sub-Saharan Africa, where KS is among the top four most prevalent cancers. The cause of KS is the Kaposi's sarcoma-associated herpesvirus (KSHV, also called HHV 8), an oncogenic herpesvirus that while routinely diagnosed in developed nations, provides challenges to developing world medical providers and point-of-care detection. A major challenge in the diagnosis of KS is the existence of a number of other diseases with similar clinical presentation and histopathological features, requiring the detection of KSHV in a biopsy sample. In this work we develop an answer to this challenge by creating a multiplexed one-pot detection system for KSHV DNA and DNA from a frequently confounding disease, bacillary angiomatosis. Gold and silver nanoparticle aggregation reactions are tuned for each target and a multi-color change system is developed capable of detecting both targets down to levels between 1 nM and 2 nM. The system developed here could later be integrated with microfluidic sample processing to create a final device capable of solving the two major challenges in point-of-care KS detection. PMID- 23340973 TI - [Improve your skills!: evaluation of a 2.5-day basic course in vascular surgery for surgical trainees]. AB - BACKGROUND: The traditional surgical training in the operating room (OR) is often complemented by participation in workshops and on simulators. The foundation Vascular International offers basic courses for vascular surgery techniques with training on pulsatile circulation, lifelike anatomical models. The aim of this study was to assess the efficacy of a 2.5-day intensive course on basic skills in vascular surgery. MATERIAL AND METHODS: A total of 24 participants (67% male with an average age of 35 years) performed a vein patch-plasty before and after the basic vascular surgery instruction course. Endpoints of the study were the time needed for suturing and the technical quality, which were evaluated by two course trainers on a scale of 0-10. Furthermore, the participants were asked to evaluate their own technical competence. The statistical analysis was carried out using MS Excel (t-test and analysis of correlation). RESULTS: A significantly shortened time for the suturing (19.5 min versus 14.1 min, p < 0.001) and improved quality of the vein patch were found after the workshop (p < 0.05) with a high correlation between the two observers (r = 0.885). The participants also evaluated their own surgical competence better at the end of the training but there was no correlation between the self-assessment and the quality of the patch (r = 0.146 before and r = 0.109 after the workshop). CONCLUSIONS: A significant improvement in the time needed for suturing and the quality of the vein patch plasty was shown in this study. Further studies are necessary to demonstrate the long-term success and possible shortening of the learning curve in hospitals with professional training. With regard to the current curriculum of surgical trainees in Germany basic vascular surgery courses should be considered as a potential valuable part of the surgical common trunk. PMID- 23340974 TI - [Diagnostic error and the patient's rights act]. AB - The question which party bears the burden of proof has significant influence on the result of a medical liability process. The party that bears the burden of proof and cannot provide the proof loses the lawsuit. Particularly important in this context is an omitted medical examination. In the case of such an omitted medical examination the courts may grant reversal of the burden of proof to patients in subsequent medical processes. The civil courts differentiate between a simple mistake or a grave error in treatment and furthermore, the medical examination has to be distinguished from the duty of diagnosis.In the new patients' rights act the burden of proof is established by law. Thereafter in principle the patient must still prove that the doctor made a mistake and that this was the cause of the damage. PMID- 23340975 TI - [No advantage for single-port or mini-laparoscopic over conventional laparoscopic cholecystectomy]. PMID- 23340976 TI - Cytotoxicity of lymphocytes activated by superantigen toxic-shock-syndrome toxin 1 against colorectal cancer LoVo cells. AB - Toxic-shock-syndrome toxin-1 (TSST-1), a superantigen, can stimulate T cell activation and be used for immunotherapy. In this study, we employed the carcinoembryonic antigen (CEA)-positive LoVo cells to test whether retrovirus mediated TSST-1 expression could activate human T cells and promote cytotoxicity against tumor cells. We first generated plasmids of pLEGFP-N1-5HRE-CEAp-TSST-1 linker-CD80TM containing a fusion gene of the CEA promoter, 5 copies of the hypoxia-response elements (HRE) as an enhancer, the fragments for TSST-1, and the transmembrane domain of CD80 (CD80TM) and control pLEGFP-N1-5HRE-CEAp (without TSST-1) and generated retroviruses of 5HCTC and 5HC, respectively. After infection with 5HC and 5HCTC retroviruses to establish cell lines, the high levels of TSST-1 expression were observed on the membrane and cytoplasm of the 5HCTC-infected LoVo cells, particularly culture under a hypoxic condition, but not on CEA(-) HeLa cells. Furthermore, the TSST-1-expressing LoVo cell lysates, but not the control cell lysates, stimulated human T cell proliferation, and the co-culture of the TSST-1-expressing LoVo, but not control cells, with human peripheral blood mononuclear cells (PBMC) induced a high frequency of TNF-alpha- and IL-2-secreting T cells in vitro, particularly under hypoxic conditions. More importantly, co-culture of the TSST-1-expressing LoVo cells, particularly under hypoxic conditions, but not control cells, with different numbers of PBMC promoted potent cytotoxicity against LoVo cells in a dose-dependent manner in vitro. These data provide proof of the principle that selective induction of TSST1 expression in CEA(+) colorectal cancer (CRC) cells activates T cells that destroy tumor cells, particularly under a hypoxic condition. Therefore, our findings may aid in the design of new immunotherapy for the intervention of CRC at clinic. PMID- 23340977 TI - Two-dimensional supramolecular electron spin arrays. AB - A bottom-up approach is introduced to fabricate two-dimensional self-assembled layers of molecular spin-systems containing Mn and Fe ions arranged in a chessboard lattice. We demonstrate that the Mn and Fe spin states can be reversibly operated by their selective response to coordination/decoordination of volatile ligands like ammonia (NH3). PMID- 23340978 TI - A universal strategy for the hierarchical assembly of functional 0/2D nanohybrids. AB - We report a universal strategy for the hierarchical assembly of nanoparticles on various 2D materials, resulting in functional 0/2D nanohybrids holding great promise in catalysis, energy storage, and chemical and biological sensing. PMID- 23340979 TI - Syntheses, structure diversity and properties of complexes with 4-acyl pyrazolone salicylidene hydrazide derivatives. AB - Five new complexes [Zn(HL(1))(OAc)(CH(3)CH(2)OH)] (1), [Cd(2)(HL(1))(2)(OAc)(2)(CH(3)CH(2)OH)(2)] (2), [Cu(6)(L(1))(6)] (3) (H(2)L(1) = N-(1-phenyl-3-phenmethyl-4-phenylethylene-pyrazolone-5)-salicylidene hydrazide, OAc = acetate anion), {[Zn(L(2))(CH(3)OH)].(CH(3)OH)}(n) (4) (H(2)L(2) = N-(1 phenyl-3-phenmethyl-4-ethylene-pyrazolone-5)-salicylidene hydrazine), [Cu(L(3))](n) (5) (H(2)L(3) = N-(1-phenyl-3-phenmethyl-4-benzylidene-pyrazolone 5)-salicylidene hydrazide) have been synthesized and characterized by chemical and spectroscopic techniques. Complexes 1-3 feature mononuclear, dinuclear and rare hexanuclear structures, respectively. The different molecular structures and different coordination modes of H(2)L(1) in complexes 1-3 indicate that the coordination geometry of the metal atoms have a remarkable impact on the structure of these complexes. Complexes 4 and 5 have 1D chain structures. Comparing complexes 4 and 1 or 5 and 3, it can be concluded that the substituents at the 4-position of the ligands have a significant effect on the structure of the resulting complexes. It is worth noting that N(2) atoms of the pyrazolyl ring play an important role in building the two-dimensional networks for 1 and 2 by hydrogen bonds, a novel hexanuclear unit for 3, and the 1D polymer chain for 4 and 5 by bridging bonds. Complexes 1, 2 and 4 show strong fluorescent behavior in the solid state. The magnetic property of complex 3 shows the presence of intramolecular antiferromagnetic exchange (J = -8.63 cm(-1)). PMID- 23340980 TI - Mercury exposure and neurochemical biomarkers in multiple brain regions of Wisconsin river otters (Lontra canadensis). AB - River otters are fish-eating wildlife that bioaccumulate high levels of mercury (Hg). Mercury is a proven neurotoxicant to mammalian wildlife, but little is known about the underlying, sub-clinical effects. Here, the overall goal was to increase understanding of Hg's neurological risk to otters. First, Hg values across several brain regions and tissues were characterized. Second, in three brain regions with known sensitivity to Hg (brainstem, cerebellum, and occipital cortex), potential associations among Hg levels and neurochemical biomarkers [N methyl-D-aspartic acid (NMDA) and gamma-aminobutyric acid (GABAA) receptor] were explored. There were no significant differences in Hg levels across eight brain regions (rank order, highest to lowest: frontal cortex, cerebellum, temporal cortex, occipital cortex, parietal cortex, basal ganglia, brainstem, and thalamus), with mean values ranging from 0.7 to 1.3 ug/g dry weight. These brain levels were significantly lower than mean values in the muscle (2.1 +/- 1.4 ug/g), liver (4.7 +/- 4.3 ug/g), and fur (8.8 +/- 4.8 ug/g). While a significant association was found between Hg and NMDA receptor levels in the brain stem (P = 0.028, rp = -0.293), no relationships were found in the cerebellum and occipital cortex. For the GABA receptor, no relationships were found. The lack of consistent Hg-associated neurochemical changes is likely due to low brain Hg levels in these river otters, which are amongst the lowest reported. PMID- 23340981 TI - Effects of acute and sub-chronic nicotine on impulsive choice in rats in a probabilistic delay-discounting task. AB - RATIONALE: Cigarette smokers typically display impulsivity by preferring immediate rewards over larger, delayed rewards at shorter delays than do non smokers. Suggesting causality, nicotine injections in rats increase the choice for an immediate reward over a larger, delayed reward. OBJECTIVES: To examine the generality of this latter effect, the present study employed a delay-discounting task to determine if acute and sub-chronic nicotine will also increase impulsive choice when subjective reward value is manipulated by changes in the probability, rather than magnitude, of reward. MATERIALS AND METHODS: Rats were presented with two levers, one of which delivered an immediate water reward on half of the trials, while the other lever delivered the same reward on every trial, but only after one of five increasing delays. RESULTS: Acute injections of 1.2 mg/kg, but not 0.8 mg/kg, of nicotine increased the preference for the immediate (but less certain) reward lever at intermediate delays. Moreover, twice-daily injections of 0.8 mg/kg of nicotine for 6 days progressively increased the preference for the immediate reward. Latency to make the first response on each trial was not affected by nicotine. CONCLUSIONS: The similar increases in impulsive choice produced by both acute and sub-chronic nicotine in delay-discounting paradigms whether subjective reward value is manipulated by changes in reward magnitude or probability suggests that nicotine may be increasing what is common to these paradigms, namely delay discounting. Whatever the mechanism, these data indicate that both acute and sub-chronic nicotine may help develop and maintain an addiction by increasing impulsivity. PMID- 23340982 TI - A worrying decline in anesthesia journal publications from Japan. PMID- 23340983 TI - The effects of anesthetic technique and ambient temperature on thermoregulation in lower extremity surgery. AB - PURPOSE: The purpose of our study was to determine the effects of anesthetic technique and ambient temperature on thermoregulation for patients undergoing lower extremity surgery. METHODS: Our study included 90 male patients aged 18-60 years in American Society of Anesthesiologists Physical Status groups I or II who were scheduled for lower extremity surgery. Patients were randomly divided into three groups according to anesthetic technique: general anesthesia (GA), epidural anesthesia (EA), and femoral-sciatic block (FS). These groups were divided into subgroups according to room temperature: the temperature for group I was 20-22 degrees C and that for group II was 23-25 degrees C. Therefore, we labeled the groups as follows: GA I, GA II, EA I, EA II, FS I, and FS II. Probes for measuring tympanic membrane and peripheral temperature were placed in and on the patients, and mean skin temperature (MST) and mean body temperature (MBT) were assessed. Postoperative shivering scores were recorded. RESULTS: During anesthesia, tympanic temperature and MBT decreased whereas MST increased for all patients. There was no significant difference between tympanic temperatures in either the room temperature or anesthetic method groups. MST was lower in group GA I than in group GA II after 5, 10, 15, 20, 60 and 90 min whereas MBT was significantly lower at the basal level (p < 0.05). MST after 5 min was significantly lower in group GA I than in group FS I (p < 0.05). Shivering score was significantly higher in group GA I (p < 0.05). CONCLUSIONS: There were no significant differences in thermoregulation among anesthetic techniques. Room temperature affected thermoregulation in Group GA. PMID- 23340984 TI - Outcome of neuroblastoma in India. AB - OBJECTIVES: To assess the outcome of childhood neuroblastoma in India over the last 2 decades, identify management lacunae and suggest remedial measures. METHODS: A comprehensive search to identify literature addressing outcome of childhood neuroblastoma from India was performed. International Society of Paediatric Oncology and American Society of Clinical Oncology Annual-Meeting abstracts were hand searched to identify unpublished data. Clinico-demographic and outcome data was extracted. RESULTS: Outcome of approximately 700 patients has been published over the last 2 decades with predominantly small to moderate single center series from 6 cities. Primarily non-myeloablative multiagent chemotherapy protocols alongwith surgery, have been used for treatment. A large majority of patients had stage III/IV neuroblastoma. Limited diagnostic facilities were available at most centers. Survival outcome of 8.7 to 80 % has been reported with high death and relapse rates alongwith high incomplete control/disease progression and treatment abandonment. Few series have identified prognostic parameters. Few patients with high-risk disease have been adequately treated and cured. CONCLUSIONS: There is a clear need for replicating neuroblastoma outcomes at centers of excellence in other cancer centers, improving diagnostic and laboratory facilities, administering adequate and appropriate contemporary therapy, assessing disease response and improving supportive care. National data management infrastructure along with better financial and social support initiatives are key factors. PMID- 23340985 TI - Management of a child with vomiting. AB - Vomiting is a protective reflex that results in forceful ejection of stomach contents up to and out of the mouth. It is a common complaint and may be the presenting symptom of several life-threatening conditions. It can be caused by a variety of organic and nonorganic disorders; gastrointestinal (GI) or outside of GI. Acute gastritis and gastroenteritis (AGE) are the leading cause of acute vomiting in children. Important life threatening causes in infancy include congenital intestinal obstruction, atresia, malrotation with volvulus, necrotizing enterocolitis, pyloric stenosis, intussusception, shaken baby syndrome, hydrocephalus, inborn errors of metabolism, congenital adrenal hypoplasia, obstructive uropathy, sepsis, meningitis and encephalitis, and severe gastroenteritis, and in older children appendicitis, intracranial mass lesion, diabetic ketoacidosis, Reye's syndrome, toxic ingestions, uremia, and meningitis. Initial evaluation is directed at assessment of airway, breathing and circulation, assessment of hydration status and red flag signs (bilious or bloody vomiting, altered sensorium, toxic/septic/apprehensive look, inconsolable cry or excessive irritability, severe dehydration, concern for symptomatic hypoglycemia, severe wasting, Bent-over posture). The history and physical examination guides the approach in an individual patient. The diverse nature of causes of vomiting makes a "routine" laboratory or radiologic screen impossible. Investigations (Serum electrolytes and blood gases,renal and liver functions and radiological studies) are required in any child with dehydration or red flag signs, to diagnose surgical causes. Management priorities include treatment of dehydration, stoppage of oral fluids/feeds and decompression of the stomach with nasogastric tube in patients with bilious vomiting. Antiemetic ondansetron(0.2 mg/kg oral; parenteral 0.15 mg/kg; maximum 4 mg) is indicated in children unable to take orally due to persistent vomiting, post-operative vomiting, chemotherapy induced vomiting, cyclic vomiting syndrome and acute mountain sickness. PMID- 23340986 TI - Febrile myoclonus: a missed clinical diagnosis. AB - Myoclonic jerks presenting with fever have only rarely been reported and have often been misdiagnosed as febrile seizures. The presentation may be dramatic enough to provoke unnecessary investigation and treatment. Considering the benign nature of this condition, it is important that the condition is recognized by the physician so that hospitalisation and diagnostic procedures such as lumbar puncture and electroencephalogram are prevented. The authors report three cases of febrile myoclonus and review the subject. PMID- 23340987 TI - (1)H NMR-based metabolomics exploring biomarkers in rat cerebrospinal fluid after cerebral ischemia/reperfusion. AB - In our study, metabolomics was used to investigate biochemical changes in the early stages of rats focal cerebral ischemia/reperfusion (I/R) injury. Cerebrospinal fluid (CSF) samples at 0, 0.5, 1, 3, and 6 h of reperfusion (n = 10), based on (1)H NMR spectroscopy and multivariate data analyses, were tested to analyze the changing of metabolites during the early disease process. Partial least squares-discriminant analysis scores plots of the (1)H NMR data revealed clear differences among the experiment groups. Combining the results of the loading plot and t-test, we found that twenty-seven metabolites were changed significantly (p < 0.05) in the CSF samples among the different groups. Among that, the potential biomarkers in CSF of ischemic rats were: acetic acid, 3 hydroxyisovaleric acid, 3-hydroxybutyric acid, choline, l-alanine, creatine, creatinine, glycine, pyruvic acid, glycerol, glutamic acid, d-fructose, l-lactic acid and acetone. These findings help us understand the biochemical metabolite changes in CSF of I/R rats in early stages. What's more, metabolomics may, therefore, have the potential to be developed into a clinically useful diagnostic tool of ischemic brain injury. PMID- 23340988 TI - In human glioblastomas transcript elongation by alternative polyadenylation and miRNA targeting is a potent mechanism of MGMT silencing. AB - Favorable outcome after chemotherapy of glioblastomas cannot unequivocally be linked to promoter hypermethylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene encoding a DNA repair enzyme associated with resistance to alkylating agents. This indicates that molecular mechanisms determining MGMT expression have not yet been fully elucidated. We here show that glioblastomas are capable to downregulate MGMT expression independently of promoter methylation by elongation of the 3'-UTR of the mRNA, rendering the alternatively polyadenylated transcript susceptible to miRNA-mediated suppression. While the elongated transcript is poorly expressed in normal brain, its abundance in human glioblastoma specimens is inversely correlated with MGMT mRNA expression. Using a bioinformatically guided experimental approach, we identified miR-181d, miR-767-3p, and miR-648 as significant post-transcriptional regulators of MGMT in glioblastomas; the first two miRNAs induce MGMT mRNA degradation, the latter affects MGMT protein translation. A regression model including the two miRNAs influencing MGMT mRNA expression and the MGMT methylation status reliably predicts The Cancer Genome Atlas MGMT expression data. Responsivity of MGMT expressing T98G glioma cells to temozolomide was significantly enhanced after transfection of miR-181d, miR-767 3p, and miR-648. Taken together, our results uncovered alternative polyadenylation of the MGMT 3'-UTR and miRNA targeting as new mechanisms of MGMT silencing. PMID- 23340990 TI - Interplay of flagellar motility and mucin degradation stimulates the association of Pseudomonas aeruginosa with human epithelial colorectal adenocarcinoma (Caco 2) cells. AB - Pseudomonas aeruginosa can penetrate the extracellular mucin barrier formed by the intestinal epithelial cell layer and establish gut-derived sepsis in immunocompromised patients. We found that two efficient mechanisms, flagellar motility and mucin degradation, are needed for penetration of P. aeruginosa through the mucin barrier. Deletion of the flagellar motility-related gene, the filament protein gene fliC, the cap protein gene fliD, and the motor complex protein genes motABCD from P. aeruginosa PAO1 decreased association of P. aeruginosa with the apical surface of human epithelial colorectal adenocarcinoma (Caco-2) cells. A penetration experiment using an artificial mucin layer suggested that the decreased penetration is caused by attenuation of mucin penetration ability. Additionally, the presence of P. aeruginosa decreased the total mucin, including the secreted mucin protein MUC2, on the surface of the Caco-2 cell monolayer, regardless of flagellar motility. Construction of the PAO1 mutant series knocked out 12 putative serine protease genes and identified the mucD gene, which participated in degradation of total mucin, including MUC2. Furthermore, decreased association with the surface of the Caco-2 cell monolayer was observed in the mucD mutant, and the decrease was synergistically amplified by double knockout with fliC. We conclude that P. aeruginosa can penetrate the mucin layer using flagellar motility and mucin degradation, which is dependent on the MucD protease or the mucD gene-related protease. PMID- 23340989 TI - Histone methyltransferase Suv39h1 deficiency prevents Myc-induced chromosomal instability in murine myeloid leukemias. AB - Suv39h1 mediates heterochromatin formation in pericentric and telomeric regions by trimethylation of lysine 9 of histone 3 (H3K9me3). Yet, its role in the induction of chromosomal instability is poorly understood. We established a leukemia model by retrovirally expressing Myc in wild-type and histone methyltransferase Suv39h1-deficient hematopoietic cells and characterized the resulting leukemias for chromosomal instability. All mice that received cells overexpressing Myc developed myeloid leukemia with a median survival of 44 days posttransplantation. Myc-overexpressing wild-type leukemias demonstrated clones with numerical chromosomal aberrations (5/16). In secondary transplantations of these leukemic cells, structural changes, mostly end-to-end fusions of chromosomes, appeared (10/12). In contrast, leukemic cells overexpressing Myc with reduced or no Suv39h1 expression had a normal karyotype in primary, secondary, and tertiary transplantations (16/16). Myc-transduced Suv39h1 deficient cells showed less critically short telomeres (P < 0.05) compared with Myc-transduced wild-type bone marrow cells. Gene expression analysis showed upregulation of genes involved in the alternative lengthening of telomeres (ALT) mechanism. Thus, we hypothesize that loss of Suv39h1 implies activation of the ALT mechanism, in turn ensuring telomere length and stability. Our data show for the first time that Suv39h1 deficiency may prevent chromosomal instability by more efficient telomere stabilization in hematopoietic bone marrow cells overexpressing Myc. PMID- 23340991 TI - Cystic neoplasms of the pancreas. AB - Pancreatic cysts are being identified with increasing frequency due to a combination of increased awareness and more frequent use of cross sectional imaging. Cystic neoplasms of the pancreas range from completely benign to frankly malignant. Identifying pre-malignant cysts offers the opportunity to prevent the development of pancreatic cancer. This article reviews the presentation, workup, and non-operative and operative management of premalignant and malignant pancreatic cysts. PMID- 23340994 TI - [Angiogenesis and vascularisation in adipose tissue engineering]. AB - The current standard for the reconstruction of large soft tissue defects with exposed bone, nerves or blood vessels, for example after extensive tumor resections, complex injuries, severe burns or infections, is the local or free microsurgical tissue transfer. Despite the development of new surgical techniques and many synthetic materials, there are still a large number of limitations and complications at the donor and recipient site. Thus, in a subset of patients either complete treatment is not possible or poses problems. Therefore, there is a great need for the development of new methods and materials allowing for a permanent replacement with body own soft tissue. A promising therapeutic approach is the soft tissue replacement with autologous adipose tissue. Innovative research on the reconstruction of soft tissue by adipose tissue, and clinical and experimental studies on the long-term survival and transplantation of autologous adipose tissue showed that the free fat tissue graft without direct vascular connection come along with disappointing results. Often a loss of volume or a complete resorption of the graft because of insufficient tissue quality by lack of cell differentiation was observed. This fact points to the special role of the maintenance and development of the graft's blood supply (angiogenesis and vascularization) crucial for maintaining a constant volume of the tissue. The rapidly growing interdisciplinary field of tissue engineering offers alternative solutions to the existing treatment options with the aim to produce autologous adipose tissue, stable in volume in vitro as well as in vivo, which can be transplanted as a permanent tissue replacement to corresponding parts of the body. Numerous studies have demonstrated the important and most critical factor of vascularisation for quality, volume and long-term survival of transplanted newly generated adipose tissue constructs. Although our understanding of the regulatory mechanisms of adipogenesis is still limited, there are clear indications that the complex sequences of cell interactions in the differentiation and proliferation of adipocytes is directly related to angiogenesis. PMID- 23340992 TI - Time trends and disparities in lymphadenectomy for gastrointestinal cancer in the United States: a population-based analysis of 326,243 patients. AB - BACKGROUND: The value of lymphadenectomy in most localized gastrointestinal (GI) malignancies is well established. Our objectives were to evaluate the time trends of lymphadenectomy in GI cancer and identify factors associated with inadequate lymphadenectomy in a large population-based sample. METHODS: Using the National Cancer Institute's Surveillance Epidemiology and End Results Database (1998 2009), a total of 326,243 patients with surgically treated GI malignancy (esophagus, 13,165; stomach, 18,858; small bowel, 7,666; colon, 232,345; rectum, 42,338; pancreas, 12,141) were identified. Adequate lymphadenectomy was defined based on the National Cancer Center Network's recommendations as more than 15 esophagus, 15 stomach, 12 small bowel, 12 colon, 12 rectum, and 15 pancreas. The median number of lymph nodes removed and the prevalence of adequate and/or no lymphadenectomy for each cancer type were assessed and trended over the ten study years. Multivariate logistic regression was employed to identify factors predicting adequate lymphadenectomy. RESULTS: The median number of excised nodes improved over the decade of study in all types of cancer: esophagus, from 7 to 13; stomach, 8-12; small bowel, 2-7; colon, 9-16; rectum, 8-13; and pancreas, 7 13. Furthermore, the percentage of patients with an adequate lymphadenectomy (49 % for all types) steadily increased, and those with zero nodes removed (6 % for all types) steadily decreased in all types of cancer, although both remained far from ideal. By 2009, the percentages of patients with adequate lymphadenectomy were 43 % for esophagus, 42 % for stomach, 35 % for small intestine, 77 % for colon, 61 % for rectum, and 42 % for pancreas. Men, patients >65 years old, or those undergoing surgical therapy earlier in the study period and living in areas with high poverty rates were significantly less likely to receive adequate lymphadenectomy (all p < 0.0001). CONCLUSIONS: Lymph node retrieval during surgery for GI cancer remains inadequate in a large proportion of patients in the USA, although the median number of resected nodes increased over the last 10 years. Gender and socioeconomic disparities in receiving adequate lymphadenectomy were observed. PMID- 23340995 TI - Cross-cultural validation of a disease-specific patient-reported outcome measure for lupus in Philippines. AB - OBJECTIVE: LupusPRO is a disease-targeted patient-reported outcome measure that was developed and validated among US patients with systemic lupus erythematosus (SLE). We report the cross-cultural validation results of the LupusPRO English language version among Filipino SLE patients. METHOD: The 43-item LupusPRO was pretested in 15 SLE individuals, then administered to 106 SLE patients, along with short-form SF36 and the EQ5D visual analogue scale. A mail/drop-back LupusPRO and change in health status item survey were returned within two to three days. Demographics, clinical and serological characteristics, disease activity and damage measured by PGA, SELENA-SLEDAI, LFA Flare, and SLICC-ACR SLE damage index (SDI) were collected. Internal consistency reliability (ICR), test retest reliability (TRT), convergent validity (corresponding SF36 domains) and criterion validity (against general health and disease activity measures) were tested. Reported p values are two tailed. RESULTS: A total of 121 Filipino SLE subjects (95% women, median age 31.0 +/- 16 years) with at least a high school level of English instruction participated. Median (IQR) PGA, SLEDAI and SDI were 0.0 (1.0), 2.0 (10) and 0 (1), respectively. ICR exceeded 0.7 for all domains except the lupus symptoms domain. TRT was greater than 0.85 for all LupusPRO domains. Convergent and criterion validity were observed against corresponding SF36 domains and disease activity measures. The tool was well received by patients. Confirmatory factor analysis showed good fit. CONCLUSION: English LupusPRO has fair psychometric properties among SLE patients in the Philippines, and is now available for inclusion in clinical trials and longitudinal studies to test responsiveness to change. PMID- 23340996 TI - Resource utilization and direct medical costs in adult systemic lupus erythematosus patients from a commercially insured population. AB - OBJECTIVE: Our aim was to estimate annual health care resource use and medical costs associated with systemic lupus erythematosus (SLE) in a large US managed care health plan. METHODS: Subjects at least 18 years of age and with claims based evidence of SLE (ICD-9-CM 710.0x) were identified from a health plan database. Subjects were matched on the basis of demographic and clinical characteristics to unaffected controls. Resource use and costs were determined during a fixed 12-month period. A generalized linear model (GLM) was used to adjust costs for demographic and clinical characteristics. RESULTS: In total, 1278 newly diagnosed SLE subjects were matched to 3834 controls, and 10,152 subjects with existing SLE were matched to 30,456 controls. Health care resource use was significantly higher among SLE subjects than matched controls, including average annual numbers of ambulatory visits, specialist visits, and inpatient hospital stays (all p < 0.001). SLE subjects had significantly higher overall mean annual medical costs than matched controls (newly diagnosed: $19,178 vs. $4909; existing: $15,487 vs. $5156; both p < 0.001). Evidence of specific organ involvement including renal failure and central nervous system complications, were each associated with increased costs (both p < 0.001). CONCLUSIONS: Subjects with SLE have high resource use and medical costs relative to controls. PMID- 23340997 TI - Microwave-assisted technology for the clearing and staining of arbuscular mycorrhizal fungi in roots. AB - The use of microwave irradiation as a source of energy to clear and stain intra radical arbuscular mycorrhizal fungi propagules has been tested on a variety of indigenous and cultivated herbaceous plants. The aim of the study was to evaluate the efficiency of microwave irradiation on root softening, fungi tissue staining, and preservation of DNA integrity for subsequent molecular analyses. The proposed methodology has been adapted from the standard procedures used to detect and quantify mycorrhizal root colonization levels. Using a domestic microwave oven, tissue clearing and staining required together between 30 s and 1.5 min of microwave treatment to be completed, depending the diameter size of the roots. The well-performing chemical stains tested were acid fuchsin, trypan blue, and aniline blue. The acid fuchsin clearing and staining processes, as performed, were also demonstrated to preserve DNA integrity for further molecular analyses. Irradiation by microwaves has been used with success in our laboratory within the frame of several studies. It offers considerable time saving over traditional method, reducing processing times from several hours to a few minutes while decreasing considerably the amount of chemicals and energy required to perform analyses. PMID- 23341000 TI - Competition in structural analysis--old wine in new skins. PMID- 23340998 TI - Adenosine signaling during acute and chronic disease states. AB - Adenosine is a signaling nucleoside that is produced following tissue injury, particularly injury involving ischemia and hypoxia. The production of extracellular adenosine and its subsequent signaling through adenosine receptors plays an important role in orchestrating injury responses in multiple organs. There are four adenosine receptors that are widely distributed on immune, epithelial, endothelial, neuronal,and stromal cells throughout the body. Interestingly, these receptors are subject to altered regulation following injury. Studies in mouse models and human cells and tissues have identified that the production of adenosine and its subsequent signaling through its receptors plays largely beneficial roles in acute disease states, with the exception of brain injury. In contrast, if elevated adenosine levels are sustained beyond the acute injury phase, adenosine responses can become detrimental by activating pathways that promote tissue injury and fibrosis. Understanding when during the course of disease adenosine signaling is beneficial as opposed to detrimental and defining the mechanisms involved will be critical for the advancement of adenosine-based therapies for acute and chronic diseases. The purpose of this review is to discuss key observations that define the beneficial and detrimental aspects of adenosine signaling during acute and chronic disease states with an emphasis on cellular processes, such as inflammatory cell regulation, vascular barrier function, and tissue fibrosis. PMID- 23341002 TI - Conducting polymer-based hybrid assemblies for electrochemical sensing: a materials science perspective. AB - In this topical review, progress achieved in amperometric sensing of different analytes over conducting polymer-based hybrid electrocatalysts is summarized. We report a variety of synthetic methods and the resulting hybrid assemblies, with the effectiveness of such strategies, for designing conjugated polymer-based hybrids as robust sensors for amperometric detection. Beyond incorporation of metal nanoparticles, metal-oxide and non-oxide semiconductors, carbon-based nanomaterials (nanotubes, graphene, and graphene oxide), and special dopant ions are also discussed. Moreover, some particularly interesting miscellaneous approaches, for example photo-amperometric sensing or use of overoxidized polymers, are also emphasized. Determination of dissolved gases (for example O2, NO, and NO2), ions (sulfite, nitrite, nitrate, chlorate, bromate, and iodate) and smaller and larger molecules (for example H2O2, ascorbic acid (AA), dopamine (DA), urea (UA), amino acids, hydrazine, NADH, serotonin, and epinephrine) is discussed. These achievements are reviewed from the materials perspective, addressing both synthetic and electrocatalytic aspects of the polymer-based modified electrodes. Beyond simple or more sophisticated mixing, a wide range of methods of preparation is presented, including chemical (one-pot polymerization, impregnation), electrochemical (co-deposition, doping type inclusion, etc.) and combined strategies. Classification of such synthetic routes is also included. However, it is important to note that we omit studies in which conducting polymers alone were used for determination of different species. Furthermore, because excellent reviews--cited in this work also--are available on immobilization of biomolecules (for example enzymes) for biosensing purposes, this topic, also, is excluded. PMID- 23340999 TI - Microchip-based electrochemical detection for monitoring cellular systems. AB - The use of microchip devices to study cellular systems is a rapidly growing research area. There are numerous advantages of using on-chip integrated electrodes to monitor various cellular processes. The purpose of this review is to give examples of advancements in microchip-based cellular analysis, specifically where electrochemistry is used for the detection scheme. These examples include on-chip detection of single-cell quantal exocytosis, electrochemical analysis of intracellular contents, the ability to integrate cell culture/immobilization with electrochemistry, and the use of integrated electrodes to ensure cell confluency in longer-term cell culture experiments. A perspective on future trends in this area is also given. PMID- 23341001 TI - Sweeteners from plants--with emphasis on Stevia rebaudiana (Bertoni) and Siraitia grosvenorii (Swingle). AB - In addition to their widely recognized use as dietary supplement ingredients, plant-derived compounds are increasingly used as natural sweeteners. The search for nonnutritive sweeteners has been stimulated over the last 20-30 years by concern over demonstrated or suspected relationships between consumption of sucrose and high-fructose corn syrups and a variety of health-related conditions. In the USA, there is increased use of plant extracts known to contain highly sweet terpenoids. Purified extracts of Stevia rebaudiana (Bertoni) containing the diterpene glycosides stevioside and rebaudioside A are popular as sweeteners and are also used as dietary supplements, and soft drinks and nutritional and energy shakes incorporating extracts of Siraitia grosvenorii (Swingle) fruits containing sweet triterpene glycosides such as mogroside V are also on the market. Here, we review recent studies on these two important sources of noncaloric natural sweeteners, including analytical methods used to identify and quantify specific constituents and structural features relating to their sweetness. We also review the generally recognized as safe status of specific components and their status with respect to review by the Joint FAO/WHO Expert Committee on Food Additives. PMID- 23341003 TI - In-situ identification of copper-based green pigments on paintings and manuscripts by reflection FTIR. AB - In this work non-invasive reflection infrared spectroscopy was used to discriminate between different Cu-based green pigments (namely, malachite, verdigris, chrysocolla, emerald green and phthalo green). The pigments, chosen because of their historical widespread use in artworks, were investigated as pure powders and in situ on painted models by reflection FTIR spectroscopy. The distortion arising as a result of the specular and diffuse component of reflected radiation was evaluated as function of the optical and surface properties of the investigated mock-ups. Use of the Kramers-Kronig (KK) algorithm to correct for the distortion arising from the surface reflection gave k index maxima shifted by more than 20 cm(-1) relative to those obtained in conventional transmission mode. These findings stress the need to carefully manage use of the KK algorithm on reflection spectra to avoid erroneous assignment. On the other hand, combination and overtone bands (which are enhanced by the diffuse reflection) were proved to enable reliable and sensitive identification of most of the pigments studied. Knowledge acquired by study of pure compounds and painted models was subsequently applied to interpret the spectra acquired from paintings and manuscripts. PMID- 23341004 TI - Electrochemical genosensor for detection of human mammaglobin in polymerase chain reaction amplification products of breast cancer patients. AB - Human mammaglobin (MG) has been found to be the most specific molecular marker for the hematogenous spread of breast cancer cells. In our study, an electrochemical impedance spectroscopic DNA biosensor was established for the detection of MG in breast cancer patients. The working conditions for the biosensor, such as immobilization time, rinse process, and hybridization process, were optimized. Under the optimal conditions, the charge transfer resistance of the proposed DNA biosensor shows excellent correlation with the amount of the complementary oligonucleotides in the range from 1.0 * 10(-9) to 2.0 * 10(-8) M. The detection limit is 5.0 * 10(-10) M. The proposed biosensor was used to detect the polymerase chain reaction amplification products of actual clinical breast cancer samples. The results were compared with that obtained by conventional gel electrophoresis. The results indicate that the electrochemical impedance spectroscopic assay is significantly sensitive and time-saving. The simple strategy described here is expected to be used in clinical application for early diagnosis of breast cancer. PMID- 23341005 TI - Influence of heteroatom pre-selection on the molecular formula assignment of soil organic matter components determined by ultrahigh resolution mass spectrometry. AB - Soil organic matter (SOM) is involved in many important ecosystem processes. Ultrahigh resolution mass spectrometry has become a powerful technique in the chemical characterization of SOM, allowing assignment of elemental formulae for thousands of peaks resolved in a typical mass spectrum. We investigated how the addition of N, S, and P heteroatoms in the formula calculation stage of the mass spectra processing workflow affected the formula assignments of mass spectra peaks. Dissolved organic matter extracted from plant biomass and soil as well as the soil humic acid fraction was studied. We show that the addition of S and P into the molecular formula calculation increased peak assignments on average by 17.3 % and 10.7 %, respectively, over the assignments based on the CHON elements frequently reported by SOM researchers using ultrahigh resolution mass spectrometry. The organic matter chemical characteristics as represented by van Krevelen diagrams were appreciably affected by differences in the heteroatom pre selection for the three organic matter samples investigated, especially so for the wheat-derived dissolved organic matter. These results show that inclusion of both S and P heteroatoms into the formula calculation step, which is not routinely done, is important to obtain a more chemically complete interpretation of the ultrahigh resolution mass spectra of SOM. PMID- 23341006 TI - Exploration of structural and physicochemical requirements and search of virtual hits for aminopeptidase N inhibitors. AB - Aminopeptidase N (APN) inhibitors have been reported to be effective in treating of life threatening diseases including cancer. Validated ligand- and structure based pharmacophore mapping approaches were combined with Bayesian modeling and recursive partitioning to identify structural and physicochemical requirements for highly active APN inhibitors. Based on the assumption that ligand- and structure-based pharmacophore models are complementary, the efficacy of 'multiple pharmacophore screening' for filtering true positive virtual hits was investigated. These multiple pharmacophore screening methods were utilized to search novel virtual hits for APN inhibition. The number of hits was refined and reduced by recursive partitioning, drug-likeliness, pharmacokinetic property prediction, and comparative molecular-docking studies. Four compounds were proposed as the potential virtual hits for APN enzyme inhibition. PMID- 23341007 TI - An efficient and facile synthesis of 3-amino-5-chromenyl-butenolides from 3 formyl chromone, dialkyl acetylenedicarboxylate, and primary amines. AB - A three-component reaction of 3-formyl chromones, dialkyl acetylenedicarboxylate, and isocyanides in the presence of POCl(3) was used as a highly efficient and practical approach for the synthesis of 3-amino-5-chromenyl-butenolides. High yields and high bond forming efficiency, and simple operations are the advantages of this method. Graphical abstract. PMID- 23341008 TI - Disruption and destabilization of meibomian lipid films caused by increasing amounts of ceramides and cholesterol. AB - PURPOSE: We evaluated quantitatively direct effects of ceramide (Cer) and free cholesterol (FC) on meibomian lipid films (MLF) using a Langmuir trough (LT) and a Brewster angle microscope (BAM). METHODS: Meibum was obtained from healthy volunteers. A series of mixtures of meibum with Cer or FC (mixed MLF) taken in different ratios were tested. Standard rheologic parameters, such as elasticity and hysteresis of MLF, were computed. BAM was used to study the morphology of MLF. RESULTS: Pure MLF were capable of withstanding multiple compression/expansion cycles with little hysteresis observed (1.9 J/G meibum). The films made of either pure CER or pure FC were clearly collapsible, and had much higher rigidity and hysteresis than pure meibum. Adding progressively higher amounts of CER or FC to meibum had a strong impact on the rigidity, stability, and morphology of the mixed MLF: their hysteresis increased many fold compared to pure meibum. A concomitant increase in the rigidity and collapsibility of the mixed MLF was observed. CONCLUSIONS: Cer and FC changed the surface properties of mixed MLF in a way that implied their destabilization and/or disruption. One of the mechanisms that might lead to these effects is strong aggregation of meibum lipids with FC or Cer that leads to the formation of smaller particles of meibum surrounded by a thinner layer of FC or Cer. As Cer and FC can be elevated in meibum and the tear film because of certain pathologic processes, or can be of exogenous nature, our results can explain (partially) a less stable tear film in those subjects. PMID- 23341009 TI - Impact of glaucoma severity and laterality on vision-specific functioning: the Singapore Malay eye study. AB - PURPOSE: We determined the impact of glaucoma severity and laterality on vision specific functioning (VF) in an Asian population. METHODS: The Singapore Malay Eye Study (SiMES) was a population-based cross-sectional study of 3280 Malays aged 40 to 80 years. VF was assessed using the VF-11 questionnaire. Associations between VF-11 score and glaucoma clinical indices (glaucoma severity in better and worse eyes, and laterality) were determined by multivariate regression modeling. Glaucoma severity was defined as mild, moderate, advanced, and severe based on the Hodapp-Anderson-Parish system. Rasch analysis was used to validate the VF-11 and determine its psychometric properties. RESULTS: Of 926 persons analyzed, 123 had glaucoma (13.3% glaucoma prevalence in analyzed sample). The mean +/- SD VF score was 3.64 +/- 1.05 log of odds units (Logits). In multivariate models adjusting for sociodemographic, ocular, and systemic variables, poorer VF was associated with increasingly worse eye visual field loss (beta = 0.016, 95% confidence interval [CI] 0.004-0.029, P < 0.001), but not that of the better eye (P > 0.05). Compared to controls, VF was reduced in individuals with worse eye advanced and severe glaucoma (beta = -0.65, 95% CI -1.03 to -0.28, P < 0.05), but not mild or moderate glaucoma (P > 0.05). Compared to controls, VF was reduced in unilateral (beta = -0.29, 95% CI -0.54 to -0.04, P < 0.05), but not bilateral glaucoma (P > 0.05). These associations remained significant after adjusting for presenting and best-corrected visual acuity. CONCLUSIONS: Among Singaporean Malays, unilateral, and advanced and severe glaucoma in the worse eye significantly impacts on VF. Identifying early-stage glaucoma, preventing progression, and visual rehabilitation in advanced glaucoma are important aspects of glaucoma management. PMID- 23341010 TI - Broad-spectrum virucidal activity of (NVC-422) N,N-dichloro-2,2-dimethyltaurine against viral ocular pathogens in vitro. AB - PURPOSE: Viral conjunctivitis is a highly contagious infection often causing major epidemics. A safe broad-spectrum antiviral agent is needed to treat this unmet medical need. The purpose of this study is to demonstrate that in vitro NVC 422 is a safe, broad-spectrum topical virucidal agent with activity against ophthalmic viral pathogens. METHODS: The virucidal activity of NVC-422 against several serotypes of human adenovirus (HAdV), coxsackievirus A24, enterovirus 70, and herpes simplex-virus-1 (HSV-1) was tested in standard in vitro titer reduction assays with or without tears. An in vitro irritancy score for NVC-422 was determined using the MatTek EpiOcular tissue system. RESULTS: NVC-422 reduced the viral titer of HAdV-5, HAdV-8, HAdV-19, HAdV-37, and HSV-1 by at least 4 logs after 1 hour incubation at 250 MUM. Incubation of coxsackievirus A24 and enterovirus 70 with 2.5 mM NVC-422 for 1 hour reduced the viral titer by 4 logs and 4.5 logs, respectively. The virucidal activity of NVC-422 is maintained in the presence of 10% synthetic tears. In the EpiOcular corneal tissue model, NVC 422 was nonirritating at concentrations up to 41 mM. CONCLUSIONS: NVC-422 has potent, rapid in vitro virucidal activity against major causes of conjunctivitis. Its broad-spectrum virucidal activity combined with favorable safety profile validates NVC-422 as a potential new therapeutic agent against viral conjunctivitis. PMID- 23341011 TI - Evaluation of a vision-related utility instrument: the German vision and quality of life index. AB - PURPOSE: Multi-attribute utility instruments (MAUIs), which contain a descriptive system, including several health dimensions with associated levels of increasing severity, are used commonly to measure utilities. However, the validity of the descriptive systems rarely is examined using modern psychometric theory. Therefore, we evaluated the psychometric properties of the German version of the Vision and Quality of Life Index (VisQol), a six-item vision-related MAUI. METHODS: The German VisQol was self-administered to 340 patients and 280 controls. All subjects underwent a full ophthalmologic examination, including best-corrected visual acuity (VA) testing. The psychometric properties of the VisQoL were assessed using Rasch analysis. RESULTS: The VisQoL's descriptive system did not function in controls. In patients, after collapsing response categories to resolve disordered thresholds and omitting misfitting persons, the measurement properties (i.e., precision, unidimensionality, and targeting) of the German VisQoL were satisfactory. Most person misfit related to unexpected responses to item 4 ("organizing assistance"). Rasch-generated person estimates were not different between age categories, sex, or underlying ocular condition, but decreased significantly with presence of visual impairment in the better eye (LogMAR >= 0.5, 1.20 +/- 4.62 compared to 3.46 +/- 3.52, P < 0.001). CONCLUSIONS: The German VisQoL's descriptive system displayed adequate fit to the Rasch model after removal of a large proportion of patients with poor fit statistics. However, the wording of item four should be revised to reduce respondent confusion and measurement "noise." The scale's descriptive system does not function in a sample of visually unimpaired persons, most likely due to a lack of variance in the measured trait. PMID- 23341012 TI - The repeatability of mean defect with size III and size V standard automated perimetry. AB - PURPOSE: The mean defect (MD) of the visual field is a global statistical index used to monitor overall visual field change over time. Our goal was to investigate the relationship of MD and its variability for two clinically used strategies (Swedish Interactive Threshold Algorithm [SITA] standard size III and full threshold size V) in glaucoma patients and controls. METHODS: We tested one eye, at random, for 46 glaucoma patients and 28 ocularly healthy subjects with Humphrey program 24-2 SITA standard for size III and full threshold for size V each five times over a 5-week period. The standard deviation of MD was regressed against the MD for the five repeated tests, and quantile regression was used to show the relationship of variability and MD. A Wilcoxon test was used to compare the standard deviations of the two testing methods following quantile regression. RESULTS: Both types of regression analysis showed increasing variability with increasing visual field damage. Quantile regression showed modestly smaller MD confidence limits. There was a 15% decrease in SD with size V in glaucoma patients (P = 0.10) and a 12% decrease in ocularly healthy subjects (P = 0.08). CONCLUSIONS: The repeatability of size V MD appears to be slightly better than size III SITA testing. When using MD to determine visual field progression, a change of 1.5 to 4 decibels (dB) is needed to be outside the normal 95% confidence limits, depending on the size of the stimulus and the amount of visual field damage. PMID- 23341014 TI - Inhibition of PVR with a tyrosine kinase inhibitor, dasatinib, in the swine. AB - PURPOSE: We tested the efficacy of dasatinib, a Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor, to prevent proliferative vitreoretinopathy (PVR). METHODS: The effect of dasatinib on RPE sheet growth was determined by measuring enlargement of cultured RPE sheets in the presence or absence of dasatinib. Epithelial-mesenchymal transition (EMT) of RPE cells was assessed by expression of S100A4. A scratch wound assay, cell number count, and type I collagen contraction assay were used to examine the effect of dasatinib on migration, proliferation, and extracellular matrix (ECM) contraction, respectively. Our swine model of experimental PVR with green fluorescent protein positive (GFP+) RPE cells was used to assess the efficacy of dasatinib in preventing traction retinal detachment (TRD) caused by PVR. Full-field electroretinography and histologic examination were used to determine the retinal toxicity of dasatinib. RESULTS: Dasatinib prevented RPE sheet growth, cell migration, proliferation, EMT, and ECM contraction in a concentration-dependent manner. 0.1 MUM dasatinib inhibited nearly 80% of vitreous fluid-stimulated collagen gel contraction. Dasatinib also prevented TRD caused by PVR in vivo. Only 1/11 eyes had a TRD in the presence of dasatinib, while all 11 controls eyes had a TRD. Dasatinib did not cause any detectable toxicity of the retina. CONCLUSIONS: Dasatinib significantly inhibited PVR-related RPE changes in vitro and prevented TRD in an experimental PVR model in the swine without any detectable toxicity. Our data suggested that dasatinib may be effective in the prevention of PVR. PMID- 23341013 TI - A cationic peptide, TAT-Cd degrees , inhibits herpes simplex virus type 1 ocular infection in vivo. AB - PURPOSE: To test the in vivo activity of a peptide derived from the protein transducing domain of the human immunodeficiency virus (HIV) Tat protein, TAT-Cd degrees , in a murine herpes simplex type 1 (HSV-1) keratitis model. METHODS: the efficacy of TAT-CD degrees was assessed in a postinfection treatment model with different concentrations (1 mg/mL, 0.1 mg/mL, 0.01 mg/mL) of the peptide in one of four delivery vehicles: artificial tears, PBS, methylcellulose, and aquaphor cream. Treatment began within 4 or 24 hours postinfection. Viral titers in the tear film were determined by plaque assay. RESULTS: TAT-Cd degrees reduced the severity of keratitis in all of the delivery vehicles tested when treatment started, 4 hours postinfection. Peptide in the tears or PBS delivery vehicle had the most significant reduction in disease severity and delayed the onset of vascularization and stromal keratitis. The percentage of mice presenting with disease was also significantly reduced and viral titers were reduced by 1 log at 24 hours postinfection in mice treated with 1 mg/mL TAT-Cd degrees , suggesting that inhibiting replication early is sufficient to achieve clinical effects. Lower concentrations were not effective and delaying treatment by 24 hours was also not effective. CONCLUSIONS: This study shows that TAT-Cd degrees is an effective antiviral against HSV-1 strain KOS when applied shortly postinfection and that aqueous-based formulations are more suitable. PMID- 23341015 TI - Oral proton pump inhibitors disrupt horizontal cell-cone feedback and enhance visual hallucinations in macular degeneration patients. AB - PURPOSE: Visual hallucinations (VHs) occur in macular degeneration patients with poor vision but normal cognitive function. The underlying mechanisms are poorly understood. We report the identification of pharmaceutical agents that enhance VH and use these agents to examine the contribution of retinal neurons to this syndrome. METHODS: We detail clinical observations on VH in five macular degeneration patients treated with proton pump inhibitors having the core structure, 2-pyridyl-methylsulfinyl-benzimidazole. We tested possible retinal mechanisms using paired whole cell recordings to examine effects of these compounds on feedback interactions between horizontal cells and cones in amphibian retina. RESULTS: Five patients with advanced wet macular degeneration described patterned VHs that were induced or enhanced by oral proton pump inhibitors. The abnormal images increased with light, disappeared in the dark, and originated in the retina, based on ophthalmodynamometry. Simultaneous paired whole cell recordings from amphibian cones and horizontal cells showed that 2 pyridyl-methylsulfinyl-benzimidazoles blocked the negative shift in voltage dependence and increase in amplitude of the calcium current (ICa) in cones that is induced by changes in horizontal cell membrane potential. These effects disrupt the negative feedback from horizontal cells to cones that is important for the formation of center-surround receptive fields in bipolar and ganglion cells, and thus for normal spatial and chromatic perception. CONCLUSIONS: Our study suggests that changes in the output of retinal neurons caused by disturbances in outer retinal feedback mechanisms can enhance patterned visual hallucinations. PMID- 23341016 TI - Intervisit variability of visual parameters in Leber congenital amaurosis caused by RPE65 mutations. AB - PURPOSE: To determine the intervisit variability of kinetic visual fields and visual acuity in patients with Leber congenital amaurosis (LCA) caused by mutations in the RPE65 (Retinal Pigment Epithelium-specific protein 65kDa) gene. METHODS: RPE65-LCA patients (n = 20; ages 11-40 years) were studied on at least two visits separated by fewer than 120 days using Goldmann visual field (GVF) and ETDRS visual acuity (VA) in a retrospective review. GVFs were quantified by computing the spherical coordinates of their vertices and calculating the solid angle subtended, and reported in normalized solid-angle units (nsu) as a percentage of average normal field extent. Repeatability coefficients were calculated using 95% confidence intervals on log(10)-converted variables. RESULTS: Visual field extents in RPE65-LCA spanned a wide range from 4 to 95 nsu. The repeatability coefficient was 0.248 (log(10)nsu), suggesting cutoffs for significant change (in nsu) of +77% for improvement and -44% for worsening. VA in RPE65-LCA ranged from logMAR = 0.14 to 1.96 (20/40 to 20/1250). The repeatability coefficient was 0.170 (logMAR) (+/-8.5 ETDRS letters). Comparisons with published studies of ungenotyped retinitis pigmentosa showed that the RPE65-LCA patients had higher variability in kinetic field extent. VA variability in RPE65-LCA fell within reported results for retinitis pigmentosa. CONCLUSIONS: Variability data for GVF and VA are provided to permit interpretation of the significance of increases and decreases of these functional outcomes in ongoing and planned clinical trials of therapy for LCA caused by RPE65 mutations. PMID- 23341018 TI - SU9518 inhibits proliferative vitreoretinopathy in fibroblast and genetically modified Muller cell-induced rabbit models. AB - PURPOSE: Proliferative vitreoretinopathy (PVR) is a complication of retinal detachment that can lead to surgical failure and vision loss. Previous studies suggest that a variety of retinal cells, including RPE and Muller glia, may be responsible. Platelet-derived growth factor receptor alpha (PDGFRalpha) has been strongly implicated in the pathogenesis, and found to be intrinsic to the development of PVR in rabbit models. We examine whether SU9518, a tyrosine kinase inhibitor with PDGFRalpha specificity, can inhibit the development of PVR in fibroblast and Muller cell rabbit models of PVR. METHODS: SU9518 was injected in rabbit eyes along with fibroblasts, Muller cells (MIO-M1), or Muller cells transfected to increase their expression of PDGFRalpha (MIO-M1alpha). Indirect ophthalmoscopy and histopathology were used to assess efficacy and toxicity. RESULTS: SU9518 was an effective inhibitor of PVR in both fibroblast and Muller cell models of PVR. No toxic effects were identified by indirect ophthalmoscopy or histopathology. CONCLUSIONS: SU9518 is an effective and safe inhibitor of PVR in rabbit models, and could potentially be used in humans for the treatment of this and other proliferative diseases of the retina involving fibrosis and gliosis. Further animal studies need to be performed to examine retinal toxicity and sustained delivery mechanisms. PMID- 23341019 TI - Stem cells from trabecular meshwork home to TM tissue in vivo. AB - PURPOSE: To investigate the potential of human trabecular meshwork stem cells (TMSCs) for homing to mouse TM tissue and survival in vivo. METHODS: Human TMSCs and fibroblasts were labeled with fluorescent membrane dye DiO and injected into normal mouse anterior chamber. Stem cell and TM cell markers were identified by immunofluorescent staining of cryosections or tissue whole mounts. Apoptosis was determined by TUNEL assay. Replicating and inflammatory cells were detected by bromodeoxyuridine (BrdU) incorporation and anti-CD45 staining, respectively. Quantitative RT-PCR detected gene expression of injected cells after isolation by fluorescence activated cell sorting. Intraocular pressure was measured using a TonoLab rebound tonometer. RESULTS: Expanded cultures of DiO-labeled TMSCs expressed stem cell markers preferentially in DiO positive cells, demonstrating a slow-cycling, label-retaining stem cell phenotype. DiO-labeled TMSCs injected into the anterior chamber of normal mice localized primarily in TM, remaining in the tissue at least 4 months. Within 1 week, TM-associated TMSCs began expressing TM marker protein CHI3L1. Fibroblasts injected in mouse anterior chamber showed distributed localization in corneal endothelium, lens epithelium, and TM and did not express CHI3L1. Little apoptosis was detected in injected TM tissue and intraocular pressure was not elevated during the experiment. Dividing cells or CD45-staining cells were not detected after TMSC-injection. CONCLUSIONS: Stem cells isolated from human TM and expanded in vitro exhibit the ability to home to the TM and differentiate into TM cells in vivo. Such cells present a potential for development of a novel cell-based therapy for glaucoma. PMID- 23341020 TI - Dilation of porcine retinal arterioles to cilostazol: roles of eNOS phosphorylation via cAMP/protein kinase A and AMP-activated protein kinase and potassium channels. AB - PURPOSE: Cilostazol, a selective inhibitor of phosphodiesterase 3, has antiplatelet aggregation and peripheral vasodilation effects. We examined the effects of cilostazol on the retinal microvascular diameter to determine its dependence on the endothelium and/or smooth muscle to reveal the signaling mechanisms involved in this vasomotor activity. METHODS: Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded the diametric responses to cilostazol. RESULTS: The retinal arterioles dilated in response to cilostazol in a dose dependent (100 pM-10 MUM) manner; the dilation decreased by 60% after endothelial removal. The nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited cilostazol-induced vasodilation comparable to denudation. Inhibition of soluble guanylyl cyclase and blockade of protein kinase A (PKA) were comparable to L-NAME. Compound C, an AMP-activated protein kinase (AMPK) inhibitor, partially inhibited cilostazol-induced vasodilation, which exhibited a weaker inhibitory effect on cilostazol-induced vasodilation than blockade of PKA. The large-conductance Ca2+-activated K channel (BK(Ca) channel) blocker, iberiotoxin, also inhibited cilostazol-induced vasodilation. The residual vasodilation decreased further with co-administration of L-NAME and iberiotoxin. CONCLUSIONS: Cilostazol elicits endothelium-dependent and independent dilation of the retinal arterioles mediated by NO release and BK(Ca) channel activation, respectively. Endothelial nitric oxide synthase (eNOS) phosphorylation via the cAMP/PKA and AMPK pathways and consequent activation of the soluble guanylyl cyclase/cyclic guanosine monophosphate pathway might play an important role in cilostazol-induced vasodilation of the retinal arterioles. PMID- 23341017 TI - Protein phosphatase 2A dephosphorylates CaBP4 and regulates CaBP4 function. AB - PURPOSE: CaBP4 is a neuronal Ca(2+)-binding protein that is expressed in the retina and in the cochlea, and is essential for normal photoreceptor synaptic function. CaBP4 is phosphorylated by protein kinase C zeta (PKCzeta) in the retina at serine 37, which affects its interaction with and modulation of voltage gated Ca(v)1 Ca(2+) channels. In this study, we investigated the potential role and functional significance of protein phosphatase 2A (PP2A) in CaBP4 dephosphorylation. METHODS: The effect of protein phosphatase inhibitors, light, and overexpression of PP2A subunits on CaBP4 dephosphorylation was measured in in vitro assays. Pull-down experiments using retinal or transfected HEK293 cell lysates were used to investigate the association between CaBP4 and PP2A subunits. Electrophysiologic recordings of cotransfected HEK293 cells were performed to analyze the effect of CaBP4 dephosphorylation in modulating Ca(v)1.3 currents. RESULTS: PP2A inhibitors, okadaic acid (OA), and fostriecin, but not PP1 selective inhibitors, NIPP-1, and inhibitor 2, block CaBP4 dephosphorylation in retinal lysates. Increased phosphatase activity in light-dependent conditions reverses phosphorylation of CaBP4 by PKCzeta. In HEK293 cells, overexpression of PP2A enhances the rate of dephosphorylation of CaBP4. In addition, inhibition of protein phosphatase activity by OA increases CaBP4 phosphorylation and potentiates the modulatory effect of CaBP4 on Ca(v)1.3 Ca(2+) channels in HEK293T cells. CONCLUSIONS: This study provides evidence that CaBP4 is dephosphorylated by PP2A in the retina. Our findings reveal a novel role for protein phosphatases in regulating CaBP4 function in the retina, which may fine tune presynaptic Ca(2+) signals at the photoreceptor synapse. PMID- 23341021 TI - Spatial modeling of visual field data for assessing glaucoma progression. AB - PURPOSE: In order to reduce noise and account for spatial correlation, we applied disease mapping techniques to visual field (VF) data. We compared our calculated rates of progression to other established techniques. METHODS: Conditional autoregressive (CAR) priors, weighted to account for physiologic correlations, were employed to describe spatial and spatiotemporal correlation over the VF. Our model is extended to account for several physiologic features, such as the nerve fibers serving adjacent loci on the VF not mapping to the adjacent optic disc regions, the presence of the blind spot, and large measurement fluctuation. The models were applied to VFs from 194 eyes and fitted within a Bayesian framework using Metropolis-Hastings algorithms. RESULTS: Our method (SPROG for Spatial PROGgression) showed progression in 42% of eyes. Using a clinical reference, our method had the best receiver operating characteristics compared with the point wise linear regression methods. Because our model intrinsically accounts for the large variation of VF data, by adjusting for spatial correlation, the effects of outliers are minimized, and spurious trends are avoided. CONCLUSIONS: by using CAR priors, we have modeled the spatial correlation in the eye. combining this with physiologic information, we are able to provide a novel method for VF analysis. model diagnostics, sensitivity, and specificity show our model to be apparently superior to CURRENT POINT-wise linear regression methods. (http://www.anzctr.org.au number, ACTRN12608000274370.). PMID- 23341022 TI - The essential elements of a therapeutic presence. PMID- 23341023 TI - All five forms of cytosine revealed in the gas phase. PMID- 23341026 TI - Methods for controlling structure and photophysical properties in polyfluorene solutions and gels. AB - Knowledge of the phase behavior of polyfluorene solutions and gels has expanded tremendously in recent years. The relationship between the structure formation and photophysics is known at the quantitative level. The factors which we understand control these relationships include virtually all important materials parameters such as solvent quality, side chain branching, side chain length, molecular weight, thermal history and myriad functionalizations. This review describes advances in controlling structure and photophysical properties in polyfluorene solutions and gels. It discusses the demarcation lines between solutions, gels, and macrophase separation in conjugated polymers and reviews essential solid state properties needed for understanding of solutions. It gives an insight into polyfluorene and polyfluorene beta phase in solutions and gels and describes all the structural levels in solvent matrices, ranging from intramolecular structures to the diverse aggregate classes and network structures and agglomerates of these units. It goes on to describe the kinetics and thermodynamics of these structures. It details the manifold molecular parameters used in their control and continues with the molecular confinement and touches on permanently cross-linked networks. Particular focus is placed on the experimental results of archetypical polyfluorenes and solvent matrices and connection between structure and photonics. A connection is also made to the mean field type theories of hairy-rod like polymers. This altogether allows generalizations and provides a guideline for materials scientists, synthetic chemists and device engineers as well, for this important class of semiconductor, luminescent polymers. PMID- 23341027 TI - Obstructive pulmonary disease in old age among individuals born preterm. AB - There are only few studies of the association between preterm birth and risk of chronic lung disease in old age. The aim of this study was to assess the association between poor fetal growth, preterm birth, sex and risk of asthma and Chronic Obstructive Pulmonary Disease (COPD) in adulthood. We have followed up a cohort of all infants born preterm (<35 weeks) or with low birth weight (<2,000 and <2,100 g for girls and boys, respectively) and an equal number of controls in a source population of 250,000 individuals born from 1925 through 1949 in Sweden (6,425 subjects in total). Cases of asthma and COPD were identified through the Swedish Patient Register and we considered cohort subjects as cases if they had a main or additional discharge diagnosis of asthma or COPD. For any obstructive airways disease, there was a statistically significant increase in risk with decreasing birth weight and gestational duration among women but not among men. Compared to women born at term, women born before 32 weeks of gestation had a hazard ratio for any obstructive airways disease and asthma of 2.77 (95% CI 1.39 5.54) and 5.67 (1.73-18.6), respectively. Low birth weight and preterm birth are risk factors for obstructive airways disease also among the old, but the importance of these risk factors differs between the sexes. PMID- 23341028 TI - Transepidermal water loss in young and aged healthy humans: a systematic review and meta-analysis. AB - Transepidermal water loss (TEWL) is regarded as one of the most important parameters for characterizing skin barrier function but an agreed upon definition of what a "normal" TEWL is does not exist. In order to determine generalizable TEWL values for healthy adults, a systematic review and meta-analysis was conducted. The databases MEDLINE and EMBASE and publication lists were screened. After full-text appraisal of 398 studies, 231 studies were excluded due to unclear or insufficient reporting. 167 studies providing data about 50 skin areas were included in the final data synthesis. Pooled sample sizes ranged from n = 5 for the left cheek and the left lower back to a maximum of n = 2,838 for the right midvolar forearm area. The lowest TEWL of 2.3 (95 % CI 1.9-2.7) g/m(2)/h was calculated for the breast skin, the highest TEWL of 44.0 (39.8-48.2) g/m(2)/h for the axilla. TEWL in individuals being 65 years and above was consistently lower compared to the group of 18- to 64-year-old individuals. The quality of reporting TEWL in humans should be increased in future studies. PMID- 23341029 TI - The POU domain transcription factors Oct-6 and Oct-11 negatively regulate loricrin gene expression in keratinocytes: association with AP-1 and Sp1/Sp3. AB - Loricrin is a major component of the epidermal cornified cell envelope, and is expressed only in terminally differentiated keratinocytes. This cell differentiation-specific expression pattern suggests specific regulatory mechanisms for activation and suppression of loricrin gene transcription in differentiated keratinocytes. Here, we identified a regulatory element in the proximal promoter region of the loricrin gene involved in suppression of its expression in keratinocytes. A database search indicated that this sequence contained a POU transcription factor binding motif. Electrophoretic mobility shift assay revealed that Oct-1, Oct-6, and Oct-11 actually bind to the motif. Constructs with point mutations in the POU-binding motif showed increased reporter activity, indicating that the POU factors negatively regulate loricrin gene transcription. Cotransfection experiments suggested that Oct-6 and Oct-11 suppress loricrin gene transcription in a cooperative manner with AP-1 and Sp1. Furthermore, in vitro experiments indicated that the Oct-6 and Oct-11 can physically associate with both AP-1 factors and Sp1/Sp3. These findings indicate that Oct-6 and Oct-11 contribute to the regulation of loricrin gene transcription via interaction with AP-1 factors and Sp1/Sp3. PMID- 23341030 TI - What is the nature of the mitochondrial permeability transition pore and what is it not? AB - Since about 60 years a phenomenon now called permeability transition is known in mitochondria. It involves a large pore in the inner mitochondrial membrane, the permeability transition pore (PTP) whose molecular structure is still unknown. Year after year, new hypotheses have been developed how this pore could look like and which proteins cold be structural elements. Enormous progress was made in understanding function, rich pharmacology, and possible biochemical modulation of the PTP. However, many of the structural hypotheses that seemed to be well established by experiments had to be rejected later after their falsification by further experiments. The aim of this review is to give a brief insight into confirmed and less known details of the nature of the pore and of its function. Thereafter, this review will critically report about some of the unknown elements and hypotheses that had to be rejected. PMID- 23341031 TI - Helium ion microscopy: a new tool for imaging novel mesoporous silica and organosilica materials. AB - Helium ion microscopy (HIM) has been used to image mesoporous silica and organosilica for the first time. Images of chiral nematic silica, ethylenesilica, and new benzenesilica reveal the structural organization, pore dimensions and connectivity of these materials on the nanometer length scale. PMID- 23341032 TI - Usefulness of x-ray in the detection of complications and side effects after laparoscopic sleeve gastrectomy. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is a surgical procedure which reduces the gastric volume causing a feeling of early fullness while decreasing hunger due to a reduced secretion of ghrelin. This leads to a considerable loss of body weight. The purpose of this study was to assess the usefulness of early x ray examination and subsequent x-ray follow-up in the detection of postoperative complications and long-term functional recovery. METHODS: From March 2010 to April 2011, 101 consecutive patients underwent LSG for morbid obesity and were subsequently included in this retrospective study. All patients were submitted to early x-ray examination 1-3 days after surgery and x-ray follow-up 3-6 months after surgery to detect the presence and persistence of surgical and functional complications. RESULTS: Early postoperative x-ray examination detected one case of suture leakage 1 day after surgery as well as one abscess and one gastric fistula in two patients who had become symptomatic 9 and 10 days after surgery. CONCLUSIONS: Early x-ray examination showed that complications were mainly functional and rarely surgical. Subsequent follow-up showed that functional disturbances were significantly reduced over time. X-ray is an easy and reliable method for detecting complications and side effects of LSG. However, in view of the extremely low incidence of surgical complications revealed at the early x-ray examination, this procedure may not be required as a routine examination in all operated patients and should be performed only in patients who become symptomatic and those considered at risk of developing more serious complications. PMID- 23341033 TI - Gastric bypass is a cost-saving procedure: results from a comprehensive Markov model. AB - BACKGROUND: Obesity is a growing public health problem in industrialized countries and is directly and indirectly responsible for almost 10% of all health expenditures. Bariatric surgery is the best available treatment, however, associated with important economical expenditures. So, cost-effectiveness analysis of the available surgical options is paramount. METHODS: We developed a Markov model for three different strategies: best medical management, gastric band, and gastric bypass. The Markov model was constructed to allow for the evaluation of the impact of several obesity-related comorbidities. The results were derived for a representative population of morbidly obese patients, and subgroup analyses were performed for patients without comorbidities, patients with diabetes mellitus, different age, and body mass index (BMI) groups. Cost effectiveness analysis was performed accounting for lifetime costs and from a societal perspective. RESULTS: Gastric bypass is a dominant strategy, rendering a significant decrease in lifetime costs and increase in quality-adjusted life years (QALYs). Comparing with the best medical management, in the global population of patients with a BMI of > 35 kg/m2, gastric bypass renders 1.9 extra QALYs and saves on average 13,244? per patient. Younger patients, patients with a BMI between 40 and 50 kg/m2, and patients without obesity-related diseases are the ones with a bigger benefit in terms of cost effectiveness. CONCLUSIONS: Gastric bypass surgery increases quality-adjusted survival and saves resources to health systems. As such, it can be an important process to control the ever increasing health expenditure. PMID- 23341034 TI - Scapula fractures. AB - Over the past decade, there has been an increased interest in understanding the operative indications and techniques in treating scapular fractures and tracking their outcomes. Multiple studies have documented poor functional outcomes following nonoperative management of displaced scapular fractures. There is a groundswell of recognition that severe deformity from scapular malunion is associated with functional consequences for patients. This has led to a growing recognition that scapular fractures should be held to the same standards as other bodily fractures with regard to fracture fixation principles, including anatomic articular reduction, proper alignment, and stable internal fixation. Through research, there has been an improved understanding of scapular fracture patterns and the relevant surgical approaches and exposures used for fracture fixation. As with many bones, however, there still remains the absence of a compelling study that defines thresholds for surgical indication based on degrees of deformity and amounts of displacement. PMID- 23341036 TI - Intronic deletion and duplication proximal of the EXT1 gene: a novel causative mechanism for multiple osteochondromas. AB - Multiple osteochondromas (MO) is a syndrome in which benign cartilage-capped neoplasms develop at the surface of the long bones. Most cases are caused by exonic changes in EXT1 or EXT2, but 15% are negative for these changes. Here we report for the first time a family of MO patients with germline genomic alterations at the EXT1 locus without detectable mutations or copy number alterations of EXT exonic sequences. Array-CGH showed an 80.7 kb deletion of Intron 1 of EXT1 and a 68.9 kb duplication proximal of EXT1. We identified a breakpoint between the distal end of the duplicated region and a sequence distal of the deleted region in the first intron. This breakpoint was absent in non affected family members. The configuration of the breakpoint indicates a direct insertion of the duplicated region into the deletion. However, no other breakpoint was found, which suggests a more complex genomic rearrangement has occurred within the duplicated region. Our results reveal intronic deletion and duplication as a new causative mechanism for MO not detected by conventional diagnostic methods. PMID- 23341037 TI - Dual function of MIPS1 as a metabolic enzyme and transcriptional regulator. AB - Because regulation of its activity is instrumental either to support cell proliferation and growth or to promote cell death, the universal myo-inositol phosphate synthase (MIPS), responsible for myo-inositol biosynthesis, is a critical enzyme of primary metabolism. Surprisingly, we found this enzyme to be imported in the nucleus and to interact with the histone methyltransferases ATXR5 and ATXR6, raising the question of whether MIPS1 has a function in transcriptional regulation. Here, we demonstrate that MIPS1 binds directly to its promoter to stimulate its own expression by locally inhibiting the spreading of ATXR5/6-dependent heterochromatin marks coming from a transposable element. Furthermore, on activation of pathogen response, MIPS1 expression is reduced epigenetically, providing evidence for a complex regulatory mechanism acting at the transcriptional level. Thus, in plants, MIPS1 appears to have evolved as a protein that connects cellular metabolism, pathogen response and chromatin remodeling. PMID- 23341038 TI - Turning gold into 'junk': transposable elements utilize central proteins of cellular networks. AB - The numerous discovered cases of domesticated transposable element (TE) proteins led to the recognition that TEs are a significant source of evolutionary innovation. However, much less is known about the reverse process, whether and to what degree the evolution of TEs is influenced by the genome of their hosts. We addressed this issue by searching for cases of incorporation of host genes into the sequence of TEs and examined the systems-level properties of these genes using the Saccharomyces cerevisiae and Drosophila melanogaster genomes. We identified 51 cases where the evolutionary scenario was the incorporation of a host gene fragment into a TE consensus sequence, and we show that both the yeast and fly homologues of the incorporated protein sequences have central positions in the cellular networks. An analysis of selective pressure (Ka/Ks ratio) detected significant selection in 37% of the cases. Recent research on retrovirus host interactions shows that virus proteins preferentially target hubs of the host interaction networks enabling them to take over the host cell using only a few proteins. We propose that TEs face a similar evolutionary pressure to evolve proteins with high interacting capacities and take some of the necessary protein domains directly from their hosts. PMID- 23341040 TI - Editorial comment: Re: The neoaortic root in children with transposition of the great arteries after an arterial switch operation. PMID- 23341041 TI - The neoaortic root in children with transposition of the great arteries after an arterial switch operation. AB - OBJECTIVES: Neoaortic root changes in children with transposition of the great arteries (TGA) are reportedly risk factors for the development of neoaortic regurgitation (NeoAR). The aims of this study were to assess the neoaortic root diameter and relative proportion in children with TGA after surgical correction and to identify possible correlations with the development of neoaortic insufficiency. METHODS: Of the 611 children who had the arterial switch operation performed in the Cardiology Department of the Polish Mother's Memorial Hospital, 172 consecutive patients were qualified for this study. The inclusion criteria were: anatomical correction performed during the neonatal period, more than 10 years of postoperative observation and at least two full echocardiographic examinations. RESULTS: NeoAR increased during postoperative follow-up and at the end of the observation period, 76% of the patients had NeoAR (27%-trace, 42% mild, 7%-moderate and 0.6%-severe). Among the analysed risk factors for NeoAR development, the significant ones were arterial valve discrepancy (OR = 2.05; 95% CI: 1.04-4.02; P = 0.031) and the non-facing commissures (OR = 4.05; 95% CI: 1.34 11.9; P = 0.01). The neoaortic root diameter was not statistically significantly correlated with the presence of NeoAR or with the heart defects associated with transposition. The neoaortic root was initially, on average, 37% (z-score = 1.58) bigger than the aortic root in healthy children. This disproportion increased during the follow-up evaluations to 57% (z-score = 2.09). CONCLUSIONS: The neoaortic root in children after the arterial switch procedure develops differently from that in healthy children, but this is not evidently related to NeoAR development or associated heart defects. PMID- 23341039 TI - CREB regulates the expression of neuronal glucose transporter 3: a possible mechanism related to impaired brain glucose uptake in Alzheimer's disease. AB - Impaired brain glucose uptake and metabolism precede the appearance of clinical symptoms in Alzheimer disease (AD). Neuronal glucose transporter 3 (GLUT3) is decreased in AD brain and correlates with tau pathology. However, what leads to the decreased GLUT3 is yet unknown. In this study, we found that the promoter of human GLUT3 contains three potential cAMP response element (CRE)-like elements, CRE1, CRE2 and CRE3. Overexpression of CRE-binding protein (CREB) or activation of cAMP-dependent protein kinase significantly increased GLUT3 expression. CREB bound to the CREs and promoted luciferase expression driven by human GLUT3 promoter. Among the CREs, CRE2 and CRE3 were required for the promotion of GLUT3 expression. Full-length CREB was decreased and truncation of CREB was increased in AD brain. This truncation was correlated with calpain I activation in human brain. Further study demonstrated that calpain I proteolysed CREB at Gln28-Ala29 and generated a 41-kDa truncated CREB, which had less activity to promote GLUT3 expression. Importantly, human brain GLUT3 was correlated with full-length CREB positively and with activation of calpain I negatively. These findings suggest that overactivation of calpain I caused by calcium overload proteolyses CREB, resulting in a reduction of GLUT3 expression and consequently impairing glucose uptake and metabolism in AD brain. PMID- 23341042 TI - Reply to Bertolaccini et al. PMID- 23341043 TI - Matrix effects in the determination of beta-receptor agonists in animal-derived foodstuffs by ultra-performance liquid chromatography tandem mass spectrometry with immunoaffinity solid-phase extraction. AB - Matrix effects in determination of three beta-receptor agonists including salbutamol (SAL), clenbuterol, and terbutaline in animal-derived foodstuffs were studied by ultra-performance LC-MS/MS with cleanup of immunoaffinity SPE column (IAC). Some animal tissue samples including pig liver, swine muscle, and fish muscle were hydrolyzed by the mixed enzyme solution or HCl solution, and the cleanup efficiencies with SAL IAC, MCX SPE column, and C(18) -SCX tandem columns were examined and compared by using spiked experiments. The results showed that the matrix effects in the determination of SAL and terbutaline can be eliminated with SAL IAC cleanup, and the average recoveries of SAL were 77.4~81.5%, 79.0~80.3%, and 85.0~87.2% in pig liver, swine muscle, and fish muscle, respectively. The decision limit (ccalpha) and detection capability (ccbeta) for SAL in pig liver were 0.02 and 0.05 MUg/kg, respectively. PMID- 23341045 TI - Understanding the need for spinal registries: Lee Breakwell reviews the importance of registries in spinal research and explains why the British Association of Spinal Surgeons (BASS) has decided to set up its own registry. PMID- 23341044 TI - Comparison of scoliosis measurements based on three-dimensional vertebra vectors and conventional two-dimensional measurements: advantages in evaluation of prognosis and surgical results. AB - PURPOSE: A new concept of vertebra vectors based on spinal three-dimensional (3D) reconstructions of images from the EOS system, a new low-dose X-ray imaging device, was recently proposed to facilitate interpretation of EOS 3D data, especially with regard to horizontal plane images. This retrospective study was aimed at the evaluation of the spinal layout visualized by EOS 3D and vertebra vectors before and after surgical correction, the comparison of scoliotic spine measurement values based on 3D vertebra vectors with measurements using conventional two-dimensional (2D) methods, and an evaluation of horizontal plane vector parameters for their relationship with the magnitude of scoliotic deformity. METHODS: 95 patients with adolescent idiopathic scoliosis operated according to the Cotrel-Dubousset principle were subjected to EOS X-ray examinations pre- and postoperatively, followed by 3D reconstructions and generation of vertebra vectors in a calibrated coordinate system to calculate vector coordinates and parameters, as published earlier. Differences in values of conventional 2D Cobb methods and methods based on vertebra vectors were evaluated by means comparison T test and relationship of corresponding parameters was analysed by bivariate correlation. Relationship of horizontal plane vector parameters with the magnitude of scoliotic deformities and results of surgical correction were analysed by Pearson correlation and linear regression. RESULTS: In comparison to manual 2D methods, a very close relationship was detectable in vertebra vector-based curvature data for coronal curves (preop r 0.950, postop r 0.935) and thoracic kyphosis (preop r 0.893, postop r 0.896), while the found small difference in L1-L5 lordosis values (preop r 0.763, postop r 0.809) was shown to be strongly related to the magnitude of corresponding L5 wedge. The correlation analysis results revealed strong correlation between the magnitude of scoliosis and the lateral translation of apical vertebra in horizontal plane. The horizontal plane coordinates of the terminal and initial points of apical vertebra vectors represent this (r 0.701; r 0.667). Less strong correlation was detected in the axial rotation of apical vertebras and the magnitudes of the frontal curves (r 0.459). CONCLUSIONS: Vertebra vectors provide a key opportunity to visualize spinal deformities in all three planes simultaneously. Measurement methods based on vertebral vectors proved to be just as accurate and reliable as conventional measurement methods for coronal and sagittal plane parameters. In addition, the horizontal plane display of the curves can be studied using the same vertebra vectors. Based on the vertebra vectors data, during the surgical treatment of spinal deformities, the diminution of the lateral translation of the vertebras seems to be more important in the results of the surgical correction than the correction of the axial rotation. PMID- 23341046 TI - Evoked thalamic neuronal activity following DRG application of two nucleus pulposus derived cell populations: an experimental study in rats. AB - PURPOSE: To investigate the effects on evoked thalamic neuronal activity of application of notochordal cells and chondrocyte-like cells derived from nucleus pulposus (NP) onto a dorsal root ganglion (DRG) and to compare these effects with a previously reported increased thalamic activity induced by NP. METHODS: Nucleus pulposus was harvested from tail discs of adult rats and the disc cells were separated into two cell populations, notochordal cells and chondrocyte-like cells. The two cell populations were applied separately, or in combination, to the L4 DRG of anaesthetised female Sprague-Dawley rats during acute electrophysiological experiments. In control experiments, cell suspension medium was applied on the DRG. Recordings from the contralateral thalamus were sampled for 40 min while electrically stimulating the ipsilateral sciatic nerve at above Adelta-fibre thresholds. RESULTS: Application of notochordal cells resulted in a decrease in evoked thalamic activity within 10 min while chondrocyte-like cells did not induce any changes during the 40 min of recording. The difference in evoked thalamic activity 40 min after notochordal and chondrocyte-like cell application, respectively, was statistically significant. Neither an increased concentration of chondrocyte-like cells alone nor a combination of the two cell populations induced any changes in thalamic activity. CONCLUSIONS: Separate exposure of the DRG to the two NP-derived cell populations induced different effects on evoked thalamic activity, but none of the tested cell samples induced an increase in neuronal activity similar to that previously observed with NP. This indicates a high complexity of the interaction between NP and nervous tissue. PMID- 23341047 TI - Antifungal activity of geldanamycin alone or in combination with fluconazole against Candida species. AB - A standardized broth microdilution method was used to test the antifungal activity of geldanamycin (GA), an inhibitor of heat shock protein 90 (Hsp90), alone or in combination with the antifungal agent fluconazole (FLC) against 32 clinical isolates of Candida spp. In addition, a disk diffusion test was also used to evaluate the antifungal effect of these two drugs against Candida spp. by measuring the inhibition zone diameters. We found that the range of minimal inhibitory concentrations (MICs) for GA alone against Candida spp. was 3.2-12.8 mg/L and the geometric mean of MICs was 6.54 mg/L. In addition, the combination of GA with FLC showed synergistic effects in vitro against 2 FLC-susceptible and 6 FLC-resistant isolates of C. albicans. As for the other isolates, indifference but no antagonism was observed. In the disk diffusion assay, the diameter of inhibition zones for FLC combined with GA against FLC-resistant C. albicans isolates was 30 mm, while no inhibition was observed with FLC alone. These results demonstrate that GA possesses antifungal activity against Candida spp., and the combination of GA with FLC shows in vitro synergistic activity against some C. albicans isolates, especially those resistant to FLC. PMID- 23341048 TI - Naturally rolled-up C/Si/C trilayer nanomembranes as stable anodes for lithium ion batteries with remarkable cycling performance. PMID- 23341049 TI - Survival analysis for economic evaluations alongside clinical trials- extrapolation with patient-level data: inconsistencies, limitations, and a practical guide. AB - BACKGROUND: In health technology assessments (HTAs) of interventions that affect survival, it is essential to accurately estimate the survival benefit associated with the new treatment. Generally, trial data must be extrapolated, and many models are available for this purpose. The choice of extrapolation model is critical because different models can lead to very different cost-effectiveness results. A failure to systematically justify the chosen model creates the possibility of bias and inconsistency between HTAs. OBJECTIVE: To demonstrate the limitations and inconsistencies associated with the survival analysis component of HTAs and to propose a process guide that will help exclude these from future analyses. METHODS: We reviewed the survival analysis component of 45 HTAs undertaken for the National Institute for Health and Clinical Excellence (NICE) in the cancer disease area. We drew upon our findings to identify common limitations and to develop a process guide. RESULTS: The chosen survival models were not systematically justified in any of the HTAs reviewed. The range of models considered was usually insufficient, and the rationale for the chosen model was universally limited: In particular, the plausibility of the extrapolated portion of fitted survival curves was very rarely explicitly considered. Limitations. We do not seek to describe and review all methods available for performing survival analysis-several approaches exist that are not mentioned in this article. Instead we seek to analyze methods commonly used in HTAs and limitations associated with their application. CONCLUSIONS: Survival analysis has not been conducted systematically in HTAs. A systematic approach such as the one proposed here is required to reduce the possibility of bias in cost-effectiveness results and inconsistency between technology assessments. PMID- 23341050 TI - First case of intracardiac foregut cyst occurring in the left-ventricular outflow tract. AB - An 11 day-old female infant underwent resection of a mass in the subaortic region secondary to critical aortic stenosis. At 3 months of age, recurrent severe left ventricular outflow obstruction (LVOT) in the setting of heart failure prompted redo surgery, and the resected mass revealed an intracardiac foregut cyst, which is a rare finding. To our knowledge, this is the first case describing obstruction of the LVOT. PMID- 23341051 TI - Spontaneous thrombotic obstruction of aneurysmal coronary arteriovenous fistula. PMID- 23341052 TI - Giant cell myocarditis and endomyocardial calcification in a 2.5-month-old infant triggered by excessive maternal alcohol abuse: case study of an unusual association. AB - This report describes an unusual case of a 2.5-month-old infant's sudden death secondary to giant cell myocarditis and endomyocardial calcification, both unusual entities in pediatric patients. The mother had a history of excessive alcohol consumption during pregnancy and the postnatal period. No infectious etiologies, hypersensivity, or autoimmune disorders were identified. Therefore, the authors assume that alcohol exposure might be responsible for the inflammatory giant cell process complicated with endomyocardial calcification in susceptible infants. This report is the first to describe the rare form of noninfectious myocarditis complicated with endomyocardial calcification possibly triggered by a toxic agent. The authors discuss the possible interaction between these processes that led to the infant's sudden death. PMID- 23341054 TI - Supra-amphiphiles formed by complexation of azulene-based amphiphiles and pyrene in aqueous solution: from cylindrical micelles to disklike nanosheets. AB - We have fabricated supra-amphiphiles by charge-transfer complexation of azulene based amphiphiles and pyrene in water, and the self-assembled nanostructures can reversibly change between cylindrical micelles and disklike nanosheets in response to interaction with guest molecules. PMID- 23341055 TI - Hepatic endometriosis diagnosed by liquid-based cytology: a case report. AB - A 44-year-old woman presented to Emergency Department with sudden onset of severe upper abdominal pain. T2-weighted MRI image showed a large cystic mass with a thickened wall measuring 9.5 * 9.1 * 11.2 cm in the right hepatic lobe. It was radiologically interpreted as a cystic mass with differential diagnosis including echinococcal cyst, biliary cystadenoma, and malignant neoplasm. The cystic mass was intraoperatively aspirated and a liquid-based cytology preparation (ThinPrep) and a cell block were made. The ThinPrep slides showed three dimensional clusters of epithelioid cells with scant delicate cytoplasm and tissue fragments composed of small stromal cells with round to oval shaped nuclei and a small amount of dense cytoplasm lined by the cuboidal epithelial cells. Occasional ciliated cells and abundant hemosiderin laden macrophages were also present. The cell block showed many tissue fragments containing glands and stroma with associated hemorrhage and hemosiderin laden macrophages, typical of endometrial tissue. Although it is uncommon, hepatic endometriosis should be considered in the differential diagnosis of cystic liver mass in women, especially those with a history of endometriosis or obstetric/gynecologic surgery. PMID- 23341056 TI - Monitoring of pesticide residues in South Indian tea. AB - Tea is the most commonly consumed beverage in the world. Tea infusion is prepared by pouring boiling hot water over cured leaves of the Camellia sinensis plant. Such a beverage should be free from toxic chemicals. Studies on the monitoring of pesticide residues in tea of South India had been carried. Tea samples collected from different districts of South India were analysed for the residues of certain pesticide such as dicofol, ethion, quinalphos, hexaconazole, fenpropathrin, fenvalerate and propargite. These pesticides are commonly used for the control of pests and diseases in tea. The results of study indicated that among 468 samples examined, only one sample contained hexaconazole residue that exceeded the maximum residue limit (MRL). Though the residues of ethion, quinalphos, hexaconazole, dicofol, propargite and fenpropathrin were most commonly found, only one sample exceeded the MRL. PMID- 23341057 TI - Comprehensive analysis of an ecological risk assessment of the Daliao River estuary, China. AB - At present, most estuarine ecological risk studies are based on terrestrial ecosystem models, which ignore spatial heterogeneity. The Daliao River estuary has representative characteristics of many estuaries in China, and we used this estuary as the study area to formulate an estuarine ecological risk evaluation model. Targeting the estuary's special hydrodynamic condition, this model incorporated variables that were under the influence of human activities and used them as the major factors for partitioning sections of the river according to risk values. It also explored the spatial and temporal distribution laws of estuarine ecological risk. The results showed that, on the whole, the ecological risk of the Daliao River estuary area was relatively high. At a temporal level, runoff was the main factor resulting in differences in ecological risk, while at the spatial level, the ecological risk index was affected by pollutants carried by runoff from upstream, as well as downstream pollution emissions and dilution by seawater at the mouth of the sea. The characteristics of this model make it possible to simulate the spatial and temporal risk distribution in different regions and under different rainfall regimes. This model can thus be applied in other estuarine areas and provides some technical support for analysis and control of ecological destruction in estuary areas. PMID- 23341058 TI - Altered growth and enzyme expression profile of ZnO nanoparticles exposed non target environmentally beneficial bacteria. AB - The extensive production and usage of nanoparticles with ultimate disposal in the environment leads to unintentional exposure of non-target environmentally beneficial bacteria thereby posing a serious threat to the native soil inhabitants. Soil microflora is an important link in the biogeochemical cycling of nutrients, affecting ecosystem functioning and productivity. This study evaluates the effect of one of the widely used nanoparticles, zinc oxide on two predominant soil bacteria, Gram-positive Bacillus subtilis and Gram-negative Pseudomonas aeruginosa with respect to their biocatalytic activities. Growth profiles of these bacteria in the presence of zinc oxide nanoparticles (ZnONPs) at a concentration of 20 ppm exhibited a prolonged lag phase in B. subtilis, whereas no significant effect was observed in the case of P. aeruginosa even at 200 ppm. Interestingly, the enzymatic profile of both the organisms was affected at non-lethal ZnONPs concentrations. The most pronounced effect was on the enzymes associated with amylolytic activity, denitrification and urea degradation wherein total inhibition of activity was noted in B. subtilis. The enzyme activities were lowered in the case of P. aeruginosa. The results presented here reiterate a critical need for exposure assessment and risk characterization of nanomaterial disposal on soil microflora while formalizing waste management strategies. PMID- 23341059 TI - Engineering the assemblies of biomaterial nanocarriers for delivery of multiple theranostic agents with enhanced antitumor efficacy. AB - The rapid development of nanotechnology holds great promise for revolutionizing the current landscape of tumor drug delivery. However, one of the biggest challenges is developing a simple nanocarrier platform to co-deliver various therapeutic agents. Here, a strategy for fabricating nanocarriers with many desirable features is demonstrated. The resulting nanoparticles achieve both high antitumor efficacy and effective inhibition of tumor metastasis with minimal side effects. PMID- 23341060 TI - Relationship between maternal thyroid hormones and the biochemical markers of the first trimester aneuploidy screening. AB - PURPOSE: The role of thyroid function in biochemical markers of first trimester screening has not been assessed. The aim of the present study was to investigate if there were any relation between maternal thyroid hormones and free-beta subunit of human chorionic gonadotropin (fbeta-hCG) and pregnancy-associated plasma protein A (PAPP-A) levels as the biochemical markers of the combined first trimester aneuploidy screening. METHODS: 375 pregnant women between 11 and 14 weeks of gestation who were offered routine first trimester prenatal aneuploidy screening and whose thyroid hormone levels (Thyroid stimulating hormone (TSH), free and total thyroxine, free and total triiodothyronine, anti thyroid peroxidase antibody) were measured were assessed. Correlation of free-beta-hCG and PAPP-A with maternal thyroid hormones was analyzed. RESULTS: There was no statistically significant correlation between maternal TSH, free and total thyroxine, free and total triiodothyronine, anti-thyroid peroxidase antibodies and free-beta-hCG and PAPP-A as biochemical markers of first trimester aneuploidy screening. CONCLUSION: Maternal thyroid function does not seem to affect secretion of fbeta-hCG and PAPP-A. PMID- 23341061 TI - Diaphragmatic surgery during cytoreduction for primary or recurrent epithelial ovarian cancer: a review of the literature. AB - PURPOSE: Surgical cytoreduction remains a cornerstone in the management of patients with advanced and recurrent epithelial ovarian cancer (EOC). Diaphragm involvement is a common site of metastases and represents a major limit in the achievement of an optimal cytoreduction. The purpose of this manuscript is to discuss the rationale of diaphragmatic surgery and the morbidity related to this procedure in advanced and recurrent EOC. METHODS: A search of the National Library of Medicine's MEDLINE/PubMed database until August 2012 was performed using the keywords: 'diaphragmatic surgery' and 'ovarian cancer'. RESULTS: Surgical treatment of diaphragmatic disease in advanced stage and recurrent EOC patients leads to high rates of optimal cytoreduction. It also correlates with an improved survival in advanced-stage EOC. The most common post-operative complication is a pleural effusion with rates ranging from 10 to 60 %. Pleural effusions are more common after diaphragmatic resections as compared to diaphragmatic stripping or coagulation. The need for post-operative thoracentesis or chest tube placement is low. The routine use of intraoperative trans diaphragmatic decompression of pneumothorax reduces these rates. Diaphragmatic lesions at the time of interval debulking are less frequent and smaller in size. The morbidity of diaphragmatic surgery in this setting is lower as compared to a primary debulking; this is probably related to the fewer multivisceral radical procedures performed. CONCLUSIONS: Diaphragmatic surgery at the time of cytoreduction increases rates of optimal cytoreduction and improves survival in advanced-stage and recurrent EOC patients. Gynecologic oncologists should be confident with its indication, technique and morbidity. PMID- 23341064 TI - Challenges in modern biomarker discovery--17th HUPO BPP workshop: May 24-25, 2012, Sao Paulo, Brazil. AB - The HUPO Brain Proteome Project (HUPO BPP) held its 17(th) workshop in Sao Paulo, Brazil, on May 24 and 25, 2012. The focus was on the progress on the Human Brain Proteome Atlas as well as ideas, strategies and methodological aspects in clinical neuroproteomics. PMID- 23341065 TI - Progresses in neuroproteomics of neurodegenerative diseases--18th HUPO BPP workshop: September 12, 2012, Boston, USA. AB - The HUPO Brain Proteome Project (HUPO BPP) held its 18(th) workshop in Boston, USA, September 12(th) 2012 during the HUPO 11th Annual Word Congress. The focus was on the progress on the Human Brain Proteome Atlas as well as ideas, strategies and methodological aspects. PMID- 23341066 TI - Focus on bioinformatics in proteomics. PMID- 23341071 TI - A novel mosaic NSD1 intragenic deletion in a patient with an atypical phenotype. AB - Sotos syndrome, which is characterized by overgrowth, macrocephaly, distinctive facial features, and developmental delay, arises from mutations and deletions of the NSD1 gene at 5q35.3. Sixteen NSD1 intragenic deletions (including one in a mosaic condition) and one partial duplication have been reported in patients with Sotos syndrome. Here, we describe a boy aged 4 years and 10 months that showed facial dysmorphism (including frontal bossing, widely spaced eyes, deeply set eyes, a wide nasal bridge, anteverted nares, and a wide mouth), normal growth, and a psychomotor delay. High-resolution array comparative genomic hybridization (CGH) analysis identified a mosaic heterozygous intragenic NSD1 deletion of 38 kb, which included part of intron 2 and the entire exon 3, and led to NSD1 haploinsufficiency. The deletion somatic mosaicism was subsequently confirmed by fluorescence in situ hybridization (FISH) analysis using fosmid clones. This patient presents the most atypical phenotype thus far associated with NSD1 haploinsufficiency. It is possible that this atypical phenotype may have resulted from the somatic mosaicism of the NSD1 defect. Our study confirms the usefulness of array CGH for increasing the detection rate of NSD1 abnormalities and for diagnosing syndromic patients that do not present an easily recognized phenotype. PMID- 23341072 TI - Low malignancy risk of thyroid follicular lesion of undetermined significance in patients from post-endemic areas. AB - OBJECTIVE: New classification of the thyroid fine-needle aspiration biopsy (FNAB) results tries to stratify the risk of malignancy of thyroid follicular lesions using 'follicular lesion of undetermined significance' (FLUS) subcategory. Clinical significance of this category in the endemic (or post-endemic) areas has not been clearly established. DESIGN: The aim of the study was to determine the risk of malignancy for FLUS as well as to evaluate ultrasound (US) malignancy risk features (MRF) in such nodules in comparison with 'suspicious for neoplasm' (SFN) and 'benign lesions' (BL). METHODS: The US images and cytological diagnoses of 589 thyroid follicular lesions were analysed from January 2010 to July 2012. Cytological follow-up was assessed in 110 cases and surgical one in 100 cases. RESULTS: FLUS was diagnosed in 340 cases (3.8% of all cytological diagnoses and 57% of thyroid follicular lesions). Altogether, clinical and/or surgical follow up revealed thyroid cancer in 3.2% patients with FLUS nodules. Repeat FNAB led to more specific diagnosis in 74.4% of FLUS (3.5%, papillary cancers or their suspicion; 2.3%, SFN; 68.6%, BL). The histopathological examination showed thyroid cancer in 6.4% cases of FLUS and 7.0% of SFN and follicular adenoma in 8.5% of FLUS and 11.6% of SFN (NS, FLUS vs SFN). FLUS showed MRF of intermediate values between BL and SFN; SFN more often than FLUS showed at least two MRF (53 vs 30%, P<0.0001). CONCLUSIONS: The risk of cancer in FLUS in areas with recently corrected iodine supply is low. In such areas, repeated biopsy leads to more precise cytological diagnosis in about 3/4 cases. PMID- 23341073 TI - Integrated analysis of genome-wide copy number alterations and gene expression in microsatellite stable, CpG island methylator phenotype-negative colon cancer. AB - Microsatellite stable (MSS), CpG island methylator phenotype (CIMP)-negative colorectal tumors, the most prevalent molecular subtype of colorectal cancer, are associated with extensive copy number alteration (CNA) events and aneuploidy. We report on the identification of characteristic recurrent CNA (with frequency >25%) events and associated gene expression profiles for a total of 40 paired tumor and adjacent normal colon tissues using genome-wide microarrays. We observed recurrent CNAs, namely gains at 1q, 7p, 7q, 8p12-11, 8q, 12p13, 13q, 20p, 20q, Xp, and Xq and losses at 1p36, 1p31, 1p21, 4p15-12, 4q12-35, 5q21-22, 6q26, 8p, 14q, 15q11-12, 17p, 18p, 18q, 21q21-22, and 22q. Within these genomic regions we identified 356 genes with significant differential expression (P < 0.0001 and +/-1.5-fold change) in the tumor compared to adjacent normal tissue. Gene ontology and pathway analyses indicated that many of these genes were involved in functional mechanisms that regulate cell cycle, cell death, and metabolism. An amplicon present in >70% of the tumor samples at 20q11-20q13 contained several cancer-related genes (AHCY, POFUT1, RPN2, TH1L, and PRPF6) that were upregulated and demonstrated a significant linear correlation (P < 0.05) for gene dosage and gene expression. Copy number loss at 8p, a CNA associated with adenocarcinoma and poor prognosis, was observed in >50% of the tumor samples and demonstrated a significant linear correlation for gene dosage and gene expression for two potential tumor suppressor genes, MTUS1 (8p22) and PPP2CB (8p12). The results from our integration analysis illustrate the complex relationship between genomic alterations and gene expression in colon cancer. PMID- 23341074 TI - Interactive effects of a high-quality protein diet and high stocking density on the stress response and some innate immune parameters of Senegalese sole Solea senegalensis. AB - Amino acids (AA) regulate key metabolic pathways, including some immune responses. Therefore, this study aimed to assess whether an increased availability of dietary AA can mitigate the expected increase in plasma cortisol and metabolites levels due to high stocking density and its subsequent immunosuppression. Senegalese sole (Solea senegalensis) were maintained at low stocking density (LSD; 3.5 kg m(-2)) or high stocking density (HSD; 12 kg m(-2)) for 18 days. Additionally, both treatments were fed a control or a high protein (HP) diet (LSD, LSD HP, HSD and HSD HP). The HP diet slightly increased the levels of digestible indispensable AA, together with tyrosine and cysteine. HSD was effective in inducing a chronic stress response after 18 days of treatment since fish held at HSD presented higher plasma cortisol, glucose and lactate levels. Moreover, this increase in stress indicators translated in a decrease in plasma lysozyme, alternative complement pathway (ACP) and peroxidase activities, suggesting some degree of immunosuppression. Interestingly, while plasma glucose and lactate levels in HSD HP specimens decreased to similar values than LSD fish, plasma lysozyme, ACP and peroxidase activities increased, with even higher values than LSD groups for ACP activity. It is suggested that the HP diet may be used as functional feed since it may represent a metabolic advantage during stressful events and may counteract immunosuppression in sole. PMID- 23341076 TI - Use of first derivative of displacement vs. force profiles to determine deformation behavior of compressed powders. AB - Displacement (D) vs. force (F) profiles obtained during compaction of powders have been reported by several researchers. These profiles are usually used to obtain mechanical energies associated with the compaction of powders. In this work, we obtained displacement-force data associated with the compression of six powders; Avicel PH101, Avicel PH301, pregelatinized corn starch, anhydrous lactose, dicalcium phosphate, and mannitol. The first three powders are known to deform predominantly by plastic behavior while the later ones are known to deform predominantly by brittle fracture. Displacement-force data was utilized to perform in-die Heckel analysis and to calculate the first derivative (dD/dF) of displacement-force plots. First derivative results were then plotted against mean force (F') at each point and against 1/F' at compression forces between 1 and 20 kN. Results of the in-die Heckle analysis are in very good agreement with the known deformation behavior of the compressed materials. First derivative plots show that materials that deform predominantly by plastic behavior have first derivative values (0.0006-0.0016 mm/ N) larger than those of brittle materials (0.0004 mm/N). Moreover, when dD/dF is plotted against 1/F' for each powder, a linear correlation can be obtained (R2=>0.98). The slopes of the dD/dF vs. 1/F' plots for plastically deforming materials are relatively larger than those for materials that deform by brittle behavior. It is concluded that first derivative plots of displacement-force profiles can be used to determine deformation behavior of powders. PMID- 23341075 TI - A family-based association analysis and meta-analysis of the reading disabilities candidate gene DYX1C1. AB - Reading disabilities (RD) have a significant genetic basis and have shown linkage to multiple regions including chromosome 15q. Dyslexia susceptibility 1 candidate gene 1 (DYX1C1) on chromosome 15q21 was originally proposed as a candidate gene with two potentially functional polymorphisms at the -3G/A and 1249G/T positions showing association with RD. However, subsequent studies have yielded mixed results. We performed a literature review and meta-analysis of the -3G/A and 1249G/T polymorphisms, including new unpublished data from two family-based samples. Ten markers in DYX1C1 were genotyped in the two independently ascertained samples. Single marker and -3G/A:1249G/T haplotype analyses were performed for RD in both samples, and quantitative trait analyses using standardized reading-related measures was performed in one of the samples. For the meta-analysis, we used a random-effects model to summarize studies that tested for association between -3G/A or 1249G/T and RD. No significant association was found between the DYX1C1 SNPs and RD or any of the reading related measures tested after correction for the number of tests performed. The previously reported risk haplotype (-3A:1249T) was not biased in transmission. A total of 9 and 10 study samples were included in the meta-analysis of the -3G/A and 1249G/T polymorphisms, respectively. Neither polymorphism reached statistical significance, but the heterogeneity for the 1249G/T polymorphism was high. The results of this study do not provide evidence for association between the putatively functional SNPs -3G/A and 1249G/T and RD. PMID- 23341077 TI - Liquid AP-UV-MALDI enables stable ion yields of multiply charged peptide and protein ions for sensitive analysis by mass spectrometry. PMID- 23341078 TI - Am(m)ines make the difference: organoruthenium am(m)ine complexes and their chemistry in anticancer drug development. AB - With the aim of systematically studying fundamental structure-activity relationships as a basis for the development of Ru(II) arene complexes (arene = p cymene or biphenyl) bearing mono-, bi-, or tridentate am(m)ine ligands as anticancer agents, a series of ammine, ethylenediamine, and diethylenetriamine complexes were prepared by different synthetic routes. Especially the synthesis of mono-, di-, and triammine complexes was found to be highly dependent on the reaction conditions, such as stoichiometry, temperature, and time. Hydrolysis and protein-binding studies were performed to determine the reactivity of the compounds, and only those containing chlorido ligands undergo aquation or form protein adducts. These properties correlate well with in vitro tumor-inhibiting potency of the compounds. The complexes were found to be active in anticancer assays when meeting the following criteria: stability in aqueous solution and low rates of hydrolysis and binding to proteins. Therefore, the complexes least reactive to proteins were found to be the most cytotoxic in cancer cells. In general, complexes with biphenyl as arene ligand inhibited the growth of tumor cells more effectively than the cymene analogues, consistent with the increase in lipophilicity. This study highlights the importance of finding a proper balance between reactivity and stability in the development of organometallic anticancer agents. PMID- 23341079 TI - Comments on 'Social contagion theory: examining dynamic social networks and human behavior' by Nicholas Christakis and James Fowler. PMID- 23341080 TI - The social contagion hypothesis: comment on 'Social contagion theory: examining dynamic social networks and human behavior'. AB - I reflect on the statistical methods of the Christakis-Fowler studies on network based contagion of traits by checking the sensitivity of these kinds of results to various alternate specifications and generative mechanisms. Despite the honest efforts of all involved, I remain pessimistic about establishing whether binary health outcomes or product adoptions are contagious if the evidence comes from simultaneously observed data. PMID- 23341081 TI - Inference for influence over multiple degrees of separation on a social network. AB - States and behaviors of different individuals are expected to be correlated across a social network. Christakis and Fowler have proposed a 'three degrees of influence rule' to characterize the extent of such dependence. In this paper, we discuss three distinct interpretations of such a rule, one involving only associations (which is the interpretation for which Christakis and Fowler give evidence), one involving actual causation, generally referred to as contagion or social influence, and one involving direct effects. We discuss analytic procedures appropriate for assessing evidence for each possible interpretation and the increasingly difficult methodological challenges present in each interpretation. PMID- 23341083 TI - Comments on 'A distribution-free test of constant mean in linear mixed effects models'. PMID- 23341084 TI - Response to letter to the editor by Dr. Vossoughi. PMID- 23341085 TI - Remarks on 'A simple decision analytic solution to the comparison of two binary diagnostic tests' by Vickers et al. PMID- 23341088 TI - Imaging of primary bone tumors: determination of tumor extent by non-contrast sequences. AB - Magnetic resonance imaging (MRI) is the modality of choice for determining the extent of a primary bone tumor. This article will discuss the MRI techniques needed to accurately define the intramedullary extent of a bone sarcoma, emphasizing the need for non-contrast T1-weighted sequences and highlighting the role of chemical shift imaging. PMID- 23341089 TI - Role of plain radiography and CT angiography in the evaluation of obstructed total anomalous pulmonary venous connection. AB - BACKGROUND: Obstructed total anomalous pulmonary venous connection (TAPVC) is frequently misdiagnosed as pulmonary disease and without operative correction early death is common. It is important to make a correct diagnosis before surgery. OBJECTIVE: The purpose of this study was to describe the chest radiographic features of obstructed TAPVC and compare CT angiography with transthoracic echocardiography in the evaluation of obstructed TAPVC. MATERIALS AND METHODS: Eighteen children with obstructed TAPVC were assessed. Their clinical and imaging data were retrospectively reviewed. The characteristic radiographic findings were analyzed and compared with surgical results, and the diagnostic accuracy of CT angiography and transthoracic echocardiography was evaluated in terms of pulmonary venous drainage and obstruction detection. RESULTS: The common radiographic features included pulmonary venous congestion or edema or both (16 of 18 cases, 89%), and absence of cardiomegaly (12 of 18 cases, 67%). CT angiography correctly diagnosed TAPVC and clearly revealed the draining sites in all children (five with supracardiac TAPVC, three with cardiac TAPVC, eight with infracardiac TAPVC and two with mixed TAPVC). The diagnostic agreement between CT angiography and surgery was 100%. Transthoracic echocardiography only correctly revealed the draining sites in 11 children (5 with supracardiac TAPVC, 2 with cardiac TAPVC and 4 with infracardiac TAPVC). The diagnostic agreement between transthoracic echocardiography and surgery was 61%. The diagnostic accuracy of CT angiography was higher than that of transthoracic echocardiography (P = 0.0156). Thirty-four sites of obstruction were correctly detected by CT angiography (11 in the mediastinum, 1 at the diaphragmatic level, 9 below the diaphragm and 13 stenotic individual pulmonary veins in the lung). The diagnostic agreement between CT angiography and surgery was 92%. Transthoracic echocardiography only correctly detected 15 sites of obstruction (11 in the mediastinum, 1 at the diaphragmatic level and 3 below the diaphragm). The diagnostic agreement between transthoracic echocardiography and surgery was 41%. The rate of detection for sites of obstruction with transthoracic echocardiography was much lower than that of CT angiography (P = 0.0002). CONCLUSION: In children with obstructed TAPVC, plain radiographs usually show a characteristic pattern of pulmonary venous congestion or edema, or both, and a normal cardiac silhouette. CT angiography is superior to transthoracic echocardiography in the evaluation of pulmonary venous drainage and obstruction, especially in children with infracardiac and mixed TAPVC. PMID- 23341090 TI - Effect of vertical positioning on organ dose, image noise and contrast in pediatric chest CT--phantom study. AB - BACKGROUND: CT optimization has a special importance in children. Smaller body size accentuates the importance of patient positioning affecting both radiation dose and image quality. OBJECTIVE: To determine the effect of vertical positioning on organ dose, image noise and contrast in pediatric chest CT examination. MATERIALS AND METHODS: Chest scans of a pediatric 5-year anthropomorphic phantom were performed in different vertical positions (-6 cm to +5.4 cm) with a 64-slice CT scanner. Organ doses were measured with metal-oxide semiconductor field-effect transistor (MOSFET) dosimeters. Image noise and contrast were determined from the CT number histograms corresponding to different tissues. RESULTS: Significant changes in organ doses resulting from vertical positioning were observed, especially in radiosensitive anterior organs. The breast dose increased up to 16% and the thyroid dose up to 24% in lower positions. The noise was increased up to 45% relative to the centre position in the highest and lowest vertical positions, with a particular increase observed on the anterior and posterior sides, respectively. Off-centering also affected measured image contrast. CONCLUSION: Vertical off-centering markedly affects organ doses and measured image-quality parameters in pediatric chest CT examination. Special attention should be given to correct patient centering when preparing patients for CT scans, especially when imaging children. PMID- 23341091 TI - High-resolution loss of heterozygosity screening implicates PTPRJ as a potential tumor suppressor gene that affects susceptibility to Non-Hodgkin's lymphoma. AB - We employed a Hidden-Markov-Model (HMM) algorithm in loss of heterozygosity (LOH) analysis of high-density single nucleotide polymorphism (SNP) array data from Non Hodgkin's lymphoma (NHL) entities, follicular lymphoma (FL), and diffuse large B cell lymphoma (DLBCL). This revealed a high frequency of LOH over the chromosomal region 11p11.2, containing the gene encoding the protein tyrosine phosphatase receptor type J (PTPRJ). Although PTPRJ regulates components of key survival pathways in B-cells (i.e., BCR, MAPK, and PI3K signaling), its role in B-cell development is poorly understood. LOH of PTPRJ has been described in several types of cancer but not in any hematological malignancy. Interestingly, FL cases with LOH exhibited down-regulation of PTPRJ, in contrast no significant variation of expression was shown in DLBCLs. In addition, sequence screening in Exons 5 and 13 of PTPRJ identified the G973A (rs2270993), T1054C (rs2270992), A1182C (rs1566734), and G2971C (rs4752904) coding SNPs (cSNPs). The A1182 allele was significantly more frequent in FLs and in NHLs with LOH. Significant over representation of the C1054 (rs2270992) and the C2971 (rs4752904) alleles were also observed in LOH cases. A haplotype analysis also revealed a significant lower frequency of haplotype GTCG in NHL cases, but it was only detected in cases with retention. Conversely, haplotype GCAC was over-representated in cases with LOH. Altogether, these results indicate that the inactivation of PTPRJ may be a common lymphomagenic mechanism in these NHL subtypes and that haplotypes in PTPRJ gene may play a role in susceptibility to NHL, by affecting activation of PTPRJ in these B-cell lymphomas. PMID- 23341092 TI - Health care provider communication: an empirical model of therapeutic effectiveness. AB - BACKGROUND: Patients who are facing life-threatening and life-limiting cancer almost invariably experience psychological distress. Responding effectively requires therapeutic sensitivity and skill. In this study, we examined therapeutic effectiveness within the setting of cancer-related distress with the objective of understanding its constituent parts. METHODS: Seventy-eight experienced psychosocial oncology clinicians from 24 health care centers across Canada were invited to participate in 3 focus groups each. In total, 29 focus groups were held over 2 years, during which clinicians articulated the therapeutic factors deemed most helpful in mitigating patient psychosocial distress. The content of each focus group was summarized into major themes and was reviewed with participants to confirm their accuracy. Upon completion of the focus groups, workshops were held in various centers, eliciting participant feedback on an empirical model of therapeutic effectiveness based on the qualitative analysis of focus group data. RESULTS: Three primary, interrelated therapeutic domains emerged from the data, forming a model of optimal therapeutic effectiveness: 1) personal growth and self-care (domain A), 2) therapeutic approaches (domain B), and 3) creation of a safe space (domain C). Areas of domain overlap were identified and labeled accordingly: domain AB, therapeutic humility; domain BC, therapeutic pacing; and domain AC, therapeutic presence. CONCLUSIONS: This empirical model provides detailed insights regarding the elements and pedagogy of effective communication and psychosocial care for patients who are experiencing cancer-related distress. PMID- 23341093 TI - Increased levels of mean platelet volume: a possible relationship with idiopathic sudden hearing loss. AB - Mean platelet volume (MPV) is one of the platelet function indices which reflects the platelet production rate and functions. While vascular occlusion, acute or chronic syndromes and vasculitis are increasing the MPV levels, infections, autoimmune diseases, and inflammatory situations reduce it. The indicator for idiopathic sudden sensorineural hearing loss (ISHL) etiology remains a matter of debate because it is associated with many different disorders. We evaluated MPV levels in ISHL patients. Forty patients with ISHL and 40 healthy, age and sex matched subjects were enrolled to the study. Audiometer and laboratory results were recorded. Comparative multivariate analyses between indicator factors and hearing outcomes were conducted. MPV and platelet distribution width is significantly higher in ISHL. Platelet count is lower in the ISHL than control group (p < 0.001), (p < 0.001), (p = 0.003), respectively. Our findings indicate that, ISHL appears to be characterized by ischaemic or thrombotic events. Considering the increased MPV levels; MPV may be used to evaluate ISHL as an hepler indicator. PMID- 23341094 TI - Comparison of narrow-band imaging and conventional nasopharyngoscopy for the screening of unaffected members of families with nasopharyngeal carcinoma. AB - Familial aggregation of nasopharyngeal carcinoma (NPC) has been widely reported. The excess risk is about 4-8-fold among first-degree relatives of NPC patients compared with those without a family history of the disease. We used nasopharyngoscopy and a narrow-band image system (NBI) to screen NPC high-risk patients and identify a good tool for the early detection of NPC in these high risk groups. We recruited all available, affected blood relations of the patients. When NPC patients were more distant relatives, such as cousins, we recruited their shared second-degree relatives, such as unaffected aunts and uncles, to genetically connect the NPC cases. We performed transnasal endoscopy, first in white-light mode, then under the NBI system. There were two NBI patterns in NPC: microvascular proliferation and engorged blood vessels. The NBI pattern in normal nasopharyngeal mucosa was a regular cobblestone pattern. A prospective study included 211 asymptomatic members from 154 NPC families. We found four cases of NPC, all with a tumor stage of T1. In one patient (1/4), MRI revealed a 2-cm-diameter neck lymphadenopathy (N1). The correlation between conventional nasopharyngoscopy and NBI was very high (kappa = 0.798, P = 0.000). In conclusions, NBI is not superior to conventional nasopharyngoscopy for the early detection of NPC in unaffected members of families with NPC history. The long term follow-up is necessary in high-risk NPC patients. Further studies will be needed to determine which screening tool-conventional nasopharyngoscopy, NBI, or EB virus titer-is most effective. PMID- 23341095 TI - Utility of immunocytochemistry in diagnosing leptomeningeal metastases from an intrahepatic cholangiocarcinoma. AB - Isolated spinal leptomeningeal metastases (LMM) without brain metastases are infrequent, accounting for about 1% of all solid tumors. In LMM, cerebrospinal fluid (CSF) analyses are mostly abnormal. Demonstrations of intrathecal tumor markers are highly suggestive, but only a positive cytology is diagnostic. The initial CSF cytology can give a false negative result in up to 40-50% of patients with pathologically proven LMM on autopsy. We report a case of intrahepatic cholangiocarcinoma with spinal LMM confirmed using cytokeratin7 and pancytokeratin (AE1/AE3) immunocytochemical studies on paucicellular cerebrospinal fluid cytospin preparation. Given the paucicellularity of the smears and difficult morphologic categorization, immunocytochemistry is vital for confirmatory diagnosis and can help reduce false negative results. To the best of our knowledge this is the first case report of cytologically confirmed LMM from an intrahepatic cholangiocarcinoma while the patient was undergoing treatment. PMID- 23341096 TI - Diagnostic tools of early brain disturbances in an asymptomatic neonate with maple syrup urine disease. AB - Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder resulting from the defective activity of branched-chain 2-ketoacid dehydrogenase complex. Routine screening of newborn with tandem mass spectroscopy on the third day of life may detect elevated branched-chain amino acids in blood before the appearance of encephalopathic symptoms in MSUD cases. If undiagnosed by such a routine screening test, patients often present with encephalopathy and seizures. Clinical neurologic examination is supplemented by electroencephalography and imaging. Here, we report abnormal amplitude-integrated electroencephalography, electroencephalography, magnetic resonance imaging, and magnetic resonance imaging spectroscopy findings in a neurologically asymptomatic male newborn who was diagnosed with MSUD at the third week of life. These neurologic disturbances disappeared at the fourth month of life with appropriate special diet. Therefore, even in already asymptomatic cases, early neurologic deterioration of brain metabolism and structure can be detected with these early laboratory findings, indicating the importance of early diagnosis and management. Patients may also benefit from these investigations during the follow-up period. PMID- 23341098 TI - Organosiloxane supramolecular liquids--surface-energy-driven phase transitions. AB - Autocondensation of organoalkoxysilanes and subsequent anion exchange produces organosiloxane supramolecular liquids which are core-free and solvent-free nanoparticle nanofluids. This hybrid supramolecular liquid, [C(81)H(156)NO(3)S(SiO([2>x>3/2]))](y), exhibits (see TEM image; 200 nm width) interparticle menisci and softness (from imputed deformations) of interparticle potential. PMID- 23341099 TI - Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family. AB - Growing evidence for genetic overlap between schizophrenia (SCZ) and bipolar disorder (BPD) suggests that causal variants of large effect on disease risk may cross traditional diagnostic boundaries. Extended multigenerational families with both SCZ and BPD cases can be a valuable resource for discovery of shared biological pathways because they can reveal the natural evolution of the underlying genetic disruptions and their phenotypic expression. We investigated a deletion at the SLC1A1 glutamate transporter gene originally identified as a copy number variant exclusively carried by members of a 5-generation Palauan family. Using an expanded sample of 21 family members, quantitative PCR confirmed the deletion in all seven individuals with psychosis, three "obligate-carrier" parents and one unaffected sibling, while four marry-in parents were non carriers. Linkage analysis under an autosomal dominant model generated a LOD score of 3.64, confirming co-segregation of the deletion with psychosis. For more precise localization, we determined the approximate deletion end points using alignment of next-generation sequencing data for one affected deletion-carrier and then designed PCR amplicons to span the entire deletion locus. These probes established that the deletion spans 84,298 bp, thus eliminating the entire promoter, the transcription start site, and the first 59 amino acids of the protein, including the first transmembrane Na(2+)/dicarboxylate symporter domain, one of the domains that perform the glutamate transport action. Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders. PMID- 23341101 TI - Artificial multi-enzyme networks for the asymmetric amination of sec-alcohols. AB - Various artificial network designs that involve biocatalysts were tested for the asymmetric amination of sec-alcohols to the corresponding alpha-chiral primary amines. The artificial systems tested involved three to five redox enzymes and were exemplary of a range of different sec-alcohol substrates. Alcohols were oxidised to the corresponding ketone by an alcohol dehydrogenase. The ketones were subsequently aminated by employing a omega-transaminase. Of special interest were redox-neutral designs in which the hydride abstracted in the oxidation step was reused in the amination step of the cascade. Under optimised conditions up to 91 % conversion of an alcohol to the amine was achieved. PMID- 23341100 TI - Gliomatosis cerebri: clinical characteristics, management, and outcomes. AB - Gliomatosis cerebri is a rare diffusely infiltrating primary neoplastic glial process of the brain. Our objective is to review clinical presentation, management, and outcome in a large single institution series of gliomatosis cerebri patients. 54 consecutive gliomatosis cerebri cases presenting to Mayo Clinic Rochester between 1991 and 2008 were retrospectively reviewed. Inclusion criteria included involvement of at least three cerebral lobes, lack of a single discrete mass and pathological confirmation of diffuse glioma. Median overall survival (OS) was 18.5 months. Age, gender, presenting symptoms, and contrast enhancement did not correlate significantly with survival, though there was a trend toward decreased overall survival in patients above the median age of 46 years. Karnofsky performance score <70 was associated with poor OS (median 9.5 vs. 20.5 months, p = 0.02). Higher histologic grade was associated with poor progression-free survival (PFS; median for WHO grades II, III, and IV: 21.5, 6.5, and 4 months; p = 0.03) and OS (median 34, 15.5, and 8.5 months; p < 0.05). Radiation therapy was strongly associated with better prognosis (PFS 16.5 vs. 4.5 months, p < 0.01; OS 27.5 vs. 6.5, p < 0.01), but chemotherapy was not. Gliomatosis cerebri patients have a poor prognosis. Lower KPS upon presentation and higher histologic grade predict decreased survival. Surgery's role is limited beyond biopsy for diagnostic purposes. Radiotherapy appears beneficial, although selection bias could be present in this retrospective study. Chemotherapy's value is not as clear but this must be interpreted with caution given variable treatment regimens in this series. PMID- 23341102 TI - Case report of severe bradycardia due to transdermal fentanyl. AB - BACKGROUND: This case report describes a patient who developed severe bradycardia due to transdermal fentanyl. There have been no prior case reports of this occurring in palliative care, but the frequency of association of fentanyl with bradycardia in the anesthesia setting suggests it may be more common than realized. Palliative care settings often have a policy of not routinely checking vital signs, and symptoms of bradycardia could be misinterpreted as the dying process. CASE PRESENTATION: A patient with recurrent ovarian cancer was admitted with nausea and abdominal pain due to bowel obstruction and fever from a urinary tract infection. A switch from injectable hydromorphone to transdermal fentanyl resulted in symptomatic severe bradycardia within 36 h, without any other signs of opioid toxicity and with good analgesic effect. CASE MANAGEMENT: The fentanyl patch was removed. Atropine was not required. CASE OUTCOME: The patient made an uneventful recovery. Transdermal buprenorphine was subsequently used satisfactorily for long-term background pain control, with additional hydromorphone when needed. CONCLUSIONS: The delayed absorption of fentanyl via the transdermal route makes early identification of fentanyl-induced bradycardia key to prompt reversal. Patients with resting or relative bradycardia may be at higher than average risk. PMID- 23341104 TI - Bioinformatics analysis reveals potential candidate drugs for HCC. AB - In our study, we used the GSE17967 series to identify differentially expressed genes between cirrhosis and hepatocellular carcinoma, aiming to analyse the mechanism of the progression of cirrhosis to hepatocellular carcinoma and identify the sub-pathways closely related to this progression, and find the small molecule drugs to interfere this progression. From the result of our study, we find that many small molecule drugs closely related with carcinoma have been linked by our method. We also find some new small molecule drugs related to this progression. It is demonstrated that bioinformatics analysis is useful in identification of the candidate drugs in hepatocellular carcinoma. PMID- 23341105 TI - Heterozygous mutations in the PALB2 hereditary breast cancer predisposition gene impact on the three-dimensional nuclear organization of patient-derived cell lines. AB - PALB2/FANCN is a BRCA1- and BRCA2-interacting Fanconi Anemia (FA) protein crucial for key BRCA2 genome caretaker functions. Heterozygous germline mutations in PALB2 predispose to breast cancer and biallelic mutations cause FA. FA proteins play a critical role in the telomere maintenance pathway, with telomeric shortening observed in FA cells. Less is known about telomere maintenance in the heterozygous state. Here, we investigate the roles of PALB2 heterozygous mutations in genomic instability, an important carcinogenesis precursor. Patient derived lymphoblastoid (LCL) and fibroblast (FCL) cell lines with monoallelic truncating PALB2 mutations were investigated using a combination of molecular imaging techniques including centromeric FISH, telomeric Q-FISH and spectral karyotyping (SKY). Mitomycin C and Cisplatin sensitivity was assayed via cellular metabolism of WST-1. The PALB2 c.229delT FCL showed increases in telomere counts associated with increased mean intensity compared with two wild-type FCLs generated from first-degree relatives (P =1.04E-10 and P =9.68E-15) and it showed evidence of chromosomal rearrangements. Significant differences in centromere distribution were observed in one of three PALB2 heterozygous FCLs analyzed when compared with PALB2 wild-type, BRCA1 and BRCA2 heterozygous FCLs. No significant consistently increased sensitivity to Mitomycin C or Cisplatin was observed in LCLs. Our results are suggestive of an altered centromere distribution profile and a telomere instability phenotype. Together, these may indicate critical nuclear organization defects associated with the predisposition to transformation and early stage development of PALB2-related cancers. PMID- 23341107 TI - Medullary breast carcinoma in an 18-year-old female: report on one case diagnosed on fine-needle cytology sample. AB - Medullary breast carcinoma (MBC) is a rare epithelial malignancy of the breast accounting for about 1-7% of all breast carcinomas. It is characterized by well defined borders, a syncytial/solid pattern of growth of high grade atypical cells showing no glandular differentiation and a massive diffuse lympho-plasmacytic peritumoral infiltrate. Despite the high-grade atypias characterizing this neoplasm, MBC has been reported to have a better prognosis when compared with the common infiltrating duct carcinoma. MBCs typically lack estrogen and progesterone receptor (ER and PgR) expression and have a low incidence of ERBB2 overexpression. Genetically, they are often associated with BRCA-1 oncogene mutations and TP53 alterations. While MBC generally occurs in middle-aged women, ranging from 45 to 52 years of age, we report the case of a 18-year-old female patient which was diagnosed by means of fine-needle cytology sample. PMID- 23341108 TI - [Psychosocial interventions in somatic diseases]. AB - The literature dealing with the topic of this paper seems almost unmanageable. Accordingly, a schema to sort research results is proposed discriminating goal population, service model, indication as well as the treatment model and setting of psychosocial interventions. The state of the art is exemplarily described by testing the integration of psychosocial research results into current guidelines for the treatment of somatic diseases. Results related to psychosocial factors actually have been integrated into guidelines. Nevertheless, questions related to the implementation of guidelines into the reality of the health service system as well as numerous methodological problems connected with an adequate evaluation of psychosocial interventions still need to be solved. PMID- 23341109 TI - [Internet- and media-assisted therapy]. AB - With the Internet-hype around the turn of the millenium some pioneers started initiatives of what is called E-Mental Health today. Evidence is growing since then, that E-Mental Health can contribute to a better mental health care. Some approaches have proved in studies as beneficial, that transfer into clinical routine can be tried out. Others showed promising results, and again others indicate clearly that not all hopes will become true. In this paper we will present our experience in exploring the potential of E-Mental Health in various projects over the last 10 years and what we believe to have learnt from projects in nextdoor garden. We hope that our conclusions will initiate a discussion about the future role of E-Mental Health for mental health care and research. PMID- 23341106 TI - Alterations in cardiac DNA methylation in human dilated cardiomyopathy. AB - Dilated cardiomyopathies (DCM) show remarkable variability in their age of onset, phenotypic presentation, and clinical course. Hence, disease mechanisms must exist that modify the occurrence and progression of DCM, either by genetic or epigenetic factors that may interact with environmental stimuli. In the present study, we examined genome-wide cardiac DNA methylation in patients with idiopathic DCM and controls. We detected methylation differences in pathways related to heart disease, but also in genes with yet unknown function in DCM or heart failure, namely Lymphocyte antigen 75 (LY75), Tyrosine kinase-type cell surface receptor HER3 (ERBB3), Homeobox B13 (HOXB13) and Adenosine receptor A2A (ADORA2A). Mass-spectrometric analysis and bisulphite-sequencing enabled confirmation of the observed DNA methylation changes in independent cohorts. Aberrant DNA methylation in DCM patients was associated with significant changes in LY75 and ADORA2A mRNA expression, but not in ERBB3 and HOXB13. In vivo studies of orthologous ly75 and adora2a in zebrafish demonstrate a functional role of these genes in adaptive or maladaptive pathways in heart failure. PMID- 23341110 TI - [Embodied inequalities: challenges for psychosomatic medicine]. AB - Even though highly criticized, the reductionist biomedical paradigm dominates medicine until today. This downplays that we as humans are not only biological organisms but simultaneously also social beings which live in socially organized societies. Disease and premature mortality are thus embodied expressions of the conditions under which we live and work. The paper outlines that a large part of prevailing diseases are strongly influenced by social, economic and political determinants and analyses how social inequalities get under the skin and cause adverse health. Considering social as well as biological processes can generate new evidence, how we biologically incorporate our lived experience and thus create social patterns of health and illness not only in societies but also between societies. PMID- 23341111 TI - [New guidelines on functional and somatoform disorders]. AB - The S3 guideline "Dealing with patients with non-specific, functional and somatoform bodily symptoms" emphasizes the similarities in the management of the manifold manifestations of so called "medically unexplained symptoms" and gives recommendations for a stepped and collaborative diagnostic and therapeutic approach in all subspecialties and all levels of health care. It has a special focus on recommendations regarding attitude, physician-patient-relationship, communication, the parallelization of somatic and psychosocial diagnostics and a stepped therapeutic approach. The "Evidence-based guideline psychotherapy in somatoform disorders and associated syndromes" provides a differentiated analysis of the current evidence regarding the effectiveness of various psychotherapeutic interventions for the most relevant manifestations of functional and somatoform disorders. In combination, both guidelines pose important advances for treatment quality in Germany, but also illustrate remarkable structural and research deficits. PMID- 23341112 TI - ['Richtlinien'-psychotherapy - quo vadis?]. AB - Within the frame of the 'Richtlinien'- psychotherapy the dichotome education and treatment situation for medical and psychological psychotherapists (cognitive behavioural therapy (CBT) or psychodynamic and psychoanalytic therapy (PD/PT), respectively) does not correspond to the demands of a transnosologic and disorder oriented understanding of mental disorders which has been successfully practiced both in out- and inpatient psychotherapy. Instead of the frequently accidentally choice of a psychotherapist and his psychotherapeutic procedure there is a need for an adaptive indication taking into account the patients' characteristics, his or her mental disorder and the treatment goals. The basis for this adaptive indication could be the integration of CBT and PD/PA, respectively, from which both transnosologic specific competence and disorder specific interventions can be developed. PMID- 23341113 TI - [Real-time monitoring of psychotherapeutic change processes]. AB - Since several years, internet-based technologies for the monitoring of psychotherapy processes were partially established in in-patient and day treatment centres. We discuss the usefulness and some methodological requirements of process monitoring devices, with a more detailed description of the Synergetic Navigation System (SNS). Continuous self-ratings and the use of feedback-tools like the SNS will have therapeutic implications on patients as well as therapists and their professional cooperation with the patient. Studies on the effects of feedback-systems on patients and therapists should be realized, and the quality of feedback-sessions as well as the competencies in the management of nonlinear processes and feedback-systems should be enhanced. Real-time monitoring is ready to get an integrated part of clinical practice and of clinical training programs. PMID- 23341114 TI - [Computer adaptive tests in medicine]. AB - Measurement of Patient-reported Outcomes (PRO) still lacks behind clinical standards. Most established tools are also either too burdensome or too imprecise to be used in clinical practice. Item Response Theory (IRT) methods and Computer Adaptive Tests (CAT) promise to overcome these shortcomings. Simulation studies have shown that individually tailored CATs can provide more precise and less burdensome measurements over a larger measurement range than static tools. Several studies with real CAT application have supported the psychometric superiority of CATs, but results from longitudinal studies are still scarce. IRT item banks also allow scoring different established tools measuring the same construct on one common metric, which could greatly facilitate the harmonization of PRO-assessments. PMID- 23341115 TI - [Psychodynamic short-term group treatment for social phobia: description of the treatment concept and a case study]. AB - Based upon the concept of supportive-expressive therapy (SET), we developed a psychodynamic group treatment manual for social phobia, with a special focus on the patients' individual core conflictual relationship themes, their universality, as well as interventions promoting group processes and therapeutic factors of group therapy. We introduce the new concept and report results of a pilot case study (N=8). Analyses revealed a pre-post-treatment effect size of g=0.64 (95% CI [0.29; 1.00]) on the primary outcome measure, the Liebowitz Social Anxiety Scale (LSAS). Furthermore we obtained positive evidence with regard to acceptance, safety and feasibility of the psychodynamic group therapy concept for social phobia. Subsequent proof-of-concept studies are required to foster treatment development and to proof the replicability of results. PMID- 23341117 TI - Fashioning the immunological self: the biological individuality of F. Macfarlane Burnet. AB - During the 1940s and 1950s, the Australian microbiologist F. Macfarlane Burnet sought a biologically plausible explanation of antibody production. In this essay, we seek to recover the conceptual pathways that Burnet followed in his immunological theorizing. In so doing, we emphasize the influence of speculations on individuality, especially those of philosopher Alfred North Whitehead; the impact of cybernetics and information theory; and the contributions of clinical research into autoimmune disease that took place in Melbourne. We point to the influence of local experimental and intellectual currents on Burnet's work. Accordingly, this essay describes an arc distinct from most other tracings of Burnet's conceptual development, which focus on his early bacteriophage research, his fascination with the work of Julian Huxley and other biologists in the 1920s, and his interest in North Atlantic experimental investigations in the life sciences. No doubt these too were potent influences, but they seem insufficient to explain, for example, Burnet's sudden enthusiasm in the 1940s for immunological definitions of self and not-self. We want to demonstrate here how Burnet's deep involvement in philosophical biology - along with attention to local clinical research - provided him with additional theoretic tools and conceptual equipment, with which to explain immune function. PMID- 23341118 TI - Brain-derived neurotrophic factor Val66Met polymorphism and early life adversity affect hippocampal volume. AB - The interaction between adverse life events during childhood and genetic factors is associated with a higher risk to develop major depressive disorder (MDD). One of the polymorphisms found to be associated with MDD is the Val66MET polymorphism of brain-derived neurotrophic factor (BDNF). The aim of our two-center study was to determine how the BDNF Val66Met polymorphism and childhood adversity affect the volumetric measures of the hippocampus in healthy individuals and people with MDD. In this two-center study, 62 adult patients with MDD and 71 healthy matched controls underwent high-resolution magnetic resonance imaging. We used manual tracing of the bilateral hippocampal structure with help of the software BRAINS2, assessed childhood adversity using the Childhood Trauma Questionnaire and genotyped Val66Met BDNF SNP (rs6265). MDD patients had smaller hippocampal volumes, both in the left and right hemispheres (F = 5.4, P = 0.022). We also found a significant interaction between BDNF allele and history of childhood adversity (F = 6.1, P = 0.015): Met allele carriers in our samples showed significantly smaller hippocampal volumes when they did have a history of childhood adversity, both in patients and controls. Our results highlight how relevant stress-gene interactions are for hippocampal volume reductions. Subjects exposed to early life adversity developed smaller hippocampal volumes when they carry the Met-allele of the BDNF polymorphism. PMID- 23341116 TI - Sjogren's syndrome in older patients: aetiology, diagnosis and management. AB - Sjogren's syndrome (SS) is a systemic autoimmune disease, characterized by chronic inflammation of exocrine glands that results in development of xerostomia and keratoconjunctivitis sicca. The disease activity of SS is not restricted to exocrine glands, and many other organs and organ systems can be involved. Diagnosis of SS in the elderly population can be challenging because xerostomia, dry eyes, symptoms of fatigue, weight loss and muscle pain are also common features of old age. Delay between clinical onset and diagnosis of SS in the elderly may be due to the shared features of SS and old age. The 2002 revised American-European Consensus Group (AECG) classification criteria for SS are the preferred tool used to confirm diagnosis of SS, but recently alternative criteria have been put forward by the American College of Rheumatology (ACR). The AECG criteria set combines subjective symptoms of dry eyes and dry mouth with objective signs of keratoconjunctivitis sicca, salivary gland dysfunction and histopathological (salivary gland biopsy) and serological (autoantibodies against SSA/Ro and SSB/La antigens) features. Treatment of SS in the elderly does not differ from that in younger patients. The aims of the treatment of SS are to control glandular and extraglandular manifestations, to prevent damage to organ systems and loss of function, and to decrease morbidity and mortality. Treatment of the elderly can be complicated by co-morbidities, an increased rate of adverse events related to therapeutic agents, and polypharmacy. Therefore, careful follow up of the treatment is required. PMID- 23341119 TI - Silver-catalyzed hydrotrifluoromethylation of unactivated alkenes with CF3SiMe3. PMID- 23341120 TI - The antiretroviral protease inhibitor ritonavir accelerates glutathione export from cultured primary astrocytes. AB - Antiretroviral protease inhibitors are a class of important drugs that are used for the treatment of human immunodeficiency virus infections. Among those compounds, ritonavir is applied frequently in combination with other antiretroviral protease inhibitors, as it has been reported to boost their therapeutic efficiency. To test whether ritonavir affects the viability and the glutathione (GSH) metabolism of brain cells, we have exposed primary astrocyte cultures to this protease inhibitor. Application of ritonavir in low micromolar concentrations did not compromise cell viability, but caused a time- and concentration-dependent loss of GSH from the cells which was accompanied by a matching increase in the extracellular GSH content. Half-maximal effects were observed for ritonavir in a concentration of 3 MUM. The ritonavir-induced stimulated GSH export from astrocytes was completely prevented by MK571, an inhibitor of the multidrug resistance protein 1. In addition, continuous presence of ritonavir was essential to maintain the stimulated GSH export, since removal of ritonavir terminated the stimulated GSH export. Ritonavir was more potent to stimulate GSH export from astrocytes than the antiretroviral protease inhibitors indinavir and nelfinavir, but combinations of ritonavir with indinavir or nelfinavir did not further stimulate astrocytic GSH export compared to a treatment with ritonavir alone. The strong effects of ritonavir and other antiretroviral protease inhibitors on the GSH metabolism of astrocytes suggest that a chronic treatment of patients with such compounds may affect their brain GSH metabolism. PMID- 23341121 TI - Synthesis and morphogenesis of organic and inorganic polymers by means of biominerals and biomimetic materials. AB - We have studied the simultaneous synthesis and morphogenesis of polymer materials with hierarchical structures from nanoscopic to macroscopic scales. The morphologies of the original materials can be replicated to the polymer materials. In general, it is not easy to achieve the simultaneous synthesis and morphogenesis of polymer material even using host materials. In the present work, four biominerals and three biomimetic mesocrystal structures are used as the host materials or templates and polypyrrole, poly(3-hexylthiopehene), and silica were used as the precursors for the simultaneous syntheses and morphogenesis of polymer materials. The host materials with the hierarchical structure possess the nanospace for the incorporation of the monomers. After the incorporation of the monomers, the polymerization reaction proceeds in the nanospace with addition of the initiator agents. Then, the dissolution of the host materials leads to the formation and morphogenesis of the polymer materials. The scheme of the replication can be classified into the three types based on the structures of the host materials (types I-III). The type I template facilitates the hierarchical replication of the whole host material, type II mediates the hierarchical surface replication, and type III induces the formation of the two-dimensional nanosheets. Based on these results, the approach for the coupled synthesis and morphogenesis can be applied to a variety of combinations of the templates and polymer materials. PMID- 23341124 TI - Nuclear remodeling of telomeres in chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is a hematologic cancer characterized by the proliferation of myeloid cells and the translocation between chromosomes 9 and 22, [t(9;22)(q34.1;q11.2)]. At the chronic phase (CP), CML cells present longer telomeres than at the other clinical phases, display arm-specific maintenance of individual telomere lengths, and are chromosomally stable. We asked whether an alteration of nuclear organization of telomeres, which is associated with genomic instability, occurs in CML cells at the CP. We used fluorescent in situ hybridization of telomeres combined with three-dimensional (3D) quantification to study the nuclear telomeric architecture of CML cells at the CP. We found that cells can exhibit high telomere numbers, different telomere distributions, and alterations in peripheral or central nuclear location of telomeres. Also, we show that CML cells can be categorized in two groups according to the number of their telomere aggregates (TAs). We propose that the presence of high TAs in some samples is associated with the increased genomic instability and could be an indication of the clinical transitional phase. Also, alterations of nuclear organization of telomeres at the CP confirm that nuclear remodeling of telomeres can occur at an early clinical stage of a cancer. PMID- 23341125 TI - Is evaluation of the presence of prepectoral edema on T2-weighted with fat suppression 3 T breast MRI a simple and readily available noninvasive technique for estimation of prognosis in patients with breast cancer? AB - BACKGROUND: The specificity of breast MRI is only moderate. The unsatisfactory specificity of breast MRI has prompted evaluation of high signal intensity (SI) on T2-weighted imaging (T2WI). The purpose of the study was to investigate the prevalence of prepectoral edema determined using high SI on T2WI with fat suppression 3 T MRI and to correlate its presence with prognostic factors of breast cancer. METHODS: The retrospective study comprised 589 consecutive histopathologically confirmed lesions, 460 malignant and 129 benign, identified by 3 T MRI. Presence of prepectoral edema was evaluated on T2WI with fat suppression, and its diagnostic value for malignancies and correlation with clinicopathological findings in histopathologically confirmed breast cancer were assessed. RESULTS: Prepectoral edema was present in 54 of the 460 breast cancers (9 % of the total 589) and none of the 129 benign lesions. Its sensitivity and specificity were 12 and 100 %, respectively. The positive predictive value was 100 %. Young age (p = 0.01), large tumor size (p < 0.0001), high histological grade (p < 0.0001), invasive ductal carcinoma (p < 0.0001), high lymphovascular invasion degree (p < 0.0001), high axillary lymph node positivity (p < 0.0001), high inflammatory breast cancer rate (p < 0.0001), high neoadjuvant chemotherapy rate (p < 0.0001), and chemoresistant breast cancers (p < 0.0001) were significantly associated with prepectoral edema. There was no association of the morphological lesion type on MRI and dynamic enhancement imaging pattern with the presence of prepectoral edema. CONCLUSION: Prepectoral edema has low prevalence but is specific for breast cancer and correlated with prognostic factors. PMID- 23341126 TI - Are artemisinin-based combination therapies effective against Plasmodium malariae? PMID- 23341127 TI - Ceftaroline in the treatment of concomitant methicillin-resistant and daptomycin non-susceptible Staphylococcus aureus infective endocarditis and osteomyelitis: case report. PMID- 23341128 TI - A validated ultra-performance liquid chromatography-tandem mass spectrometry method for the quantification of polymyxin B in mouse serum and epithelial lining fluid: application to pharmacokinetic studies. AB - OBJECTIVES: A rapid, sensitive and robust ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed for the quantification of four major polymyxin B components (polymyxin B1, polymyxin B2, polymyxin B3 and isoleucine-polymyxin B1) in serum and epithelial lining fluid (ELF) samples. METHODS: A Waters Acquity UPLC HSS C18 column was used with 0.1% formic acid in water/acetonitrile as mobile phases. Analysis was performed in a positive ionization mode with multiple-reactions monitoring scan type. Five percent trichloroacetic acid was used to precipitate proteins in biological samples and to increase the sensitivity of detection. RESULTS: Our results showed a linear concentration range of 0.0065-3.2 mg/L for all the major polymyxin B components in both serum and ELF, respectively; the interday variation was <10% and the accuracy was 88%-115%. The validated method was used to characterize the pharmacokinetics (serum and ELF) of polymyxin B in mice. CONCLUSIONS: This is the first report, to date, examining the individual pharmacokinetics of various polymyxin B components in mice. Our results revealed no considerable differences in clearances among the components. The limited exposure of polymyxin B in ELF observed was consistent with the less favourable efficacy of polymyxin B reported for the treatment of pulmonary infections. This method can be used to further examine the pharmacokinetics of polymyxin B in a variety of clinical and experimental settings. PMID- 23341129 TI - Detection of a phylogenetically distinct IMP-type metallo-beta-lactamase, IMP-35, in a CC235 Pseudomonas aeruginosa from the Dutch-German border region (Euregio). AB - OBJECTIVES: To characterize a highly divergent IMP-type metallo-beta-lactamase (MBL) variant detected in a multidrug-resistant Pseudomonas aeruginosa clinical isolate. METHODS: P. aeruginosa isolate 1876 was recovered from an anal swab of an inpatient at a German hospital in the Dutch-German border region (Euregio), where cross-border patient healthcare occurs. MICs were determined by agar dilution and phenotypic screening for MBL production by Etest MBL. Typing was performed by multilocus sequence typing (MLST). PCR assays and nucleotide sequencing were employed for identification of bla gene types. The class 1 integron carrying the blaIMP-type gene was characterized by PCR mapping and sequencing using a set of specific primers. A phylogenetic tree was constructed for the new blaIMP variant. RESULTS: Isolate 1876 was phenotypically positive for MBL production, exhibited resistance to carbapenems and harboured a new blaIMP type gene, blaIMP-35. MLST showed that the allelic profile corresponded to ST622, which belongs to the prevalent international clonal complex CC235. The blaIMP-35 gene was located in a class 1 integron as the first gene cassette, followed by blaOXA-35, aacA6, qacEDelta1 and sul1, suggesting its recent integration. IMP-35 was highly divergent, possessing 33/246 (13.4%) different amino acid residues from its closest IMP variants (IMP-8 and IMP-12) and was phylogenetically distinct, representing a separate group in the phylogenetic tree of IMP proteins. CONCLUSIONS: The identification of this phylogenetically distinct IMP-type variant in a CC235 P. aeruginosa suggests the ongoing spread of new IMP-type carbapenemases as well as the potential of the blaIMP-35 gene to evolve in the hospital environment. PMID- 23341131 TI - [Aneurysm of the superior mesenteric artery following chronic traction injury due to giant abdominal hernia]. PMID- 23341130 TI - A novel small molecule RAD51 inactivator overcomes imatinib-resistance in chronic myeloid leukaemia. AB - RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug-resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic myeloid leukaemia (CML). Directly targeting RAD51 and attenuating the deregulated RAD51 activity has therefore been proposed as an alternative and supplementary strategy for cancer treatment. Here we show that a newly identified small molecule, IBR2, disrupts RAD51 multimerization, accelerates proteasome-mediated RAD51 protein degradation, reduces ionizing radiation-induced RAD51 foci formation, impairs HR, inhibits cancer cell growth and induces apoptosis. In a murine imatinib-resistant CML model bearing the T315I Bcr-abl mutation, IBR2, but not imatinib, significantly prolonged animal survival. Moreover, IBR2 effectively inhibits the proliferation of CD34(+) progenitor cells from CML patients resistant to known BCR-ABL inhibitors. Therefore, small molecule inhibitors of RAD51 may suggest a novel class of broad-spectrum therapeutics for difficult-to-treat cancers. PMID- 23341132 TI - Development of implantable autologous small-calibre vascular grafts from peripheral blood samples. AB - INTRODUCTION: At present the generation of a small-calibre (<=5 mm) vascular replacement for artificial bypasses remains a challenge for tissue engineering. The biocompatibility of bioartificial vessel replacements is of decisive significance for function and depends on the materials used. A completely autologous vessel substitute must exhibit high biocompatibility and functionality. For this purpose we developed and optimised a technique for the engineering of an autologous bypass material from a fibrin scaffold and vascular cells isolated from the same sample of peripheral blood in a porcine model. MATERIALS AND METHODS: Fibrinogen, late outgrowth endothelial and smooth muscle cells were isolated from peripheral blood samples (n=14, 100 mL each). Fibroblasts were isolated from porcine aortic adventitial tissue (n=4). Tubular seeded fibrin segments were obtained using an injection moulding technique with the simultaneous incorporation of the in vitro expanded cells into the fibrin matrix. The segments were cultivated under dynamic conditions with pulsatile perfusion in a bioreactor. Morphological and functional characterization was done. RESULTS: Artificial vascular segments with a length of 150 mm were reproducibly obtained with a hierarchical arrangement of incorporated cells similar to the structure of the vascular wall. By additional seeding of fibroblasts, suturable segments with biomechanical properties suitable for implantation into the arterial system were obtained. CONCLUSIONS: Implantable bioartificial vascular grafts can be generated from blood. After cultivation under dynamic conditions the vascular segments possess a structure similar to that of the vascular wall and exhibit biomechanical properties sufficient for implantation as arterial substitutes. PMID- 23341133 TI - [Early results after peripheral vascular replacement with biosynthetic collagen prosthesis in cases of graft infection]. AB - INTRODUCTION: Vascular graft infection in peripheral bypass surgery represents a highly significant risk with regard to limb loss and morbidity. In the absence of autologous superficial veins, finding a suitable replacement material can be difficult. Silver-coated polyester grafts, homografts, or use of deep veins can pose additional risks. Use of a biosynthetic collagen prosthesis on a Dacron matrix ("Omniflow-II(r)") was investigated as an alternative method, and the cost effectiveness was evaluated. MATERIALS AND METHODS: From December 2010 to December 2011, eight patients with clinical symptoms of vascular graft infection, confirmed by imaging, were treated. Graft function or acute graft failure due to the infection was necessary for enrollment in the study. Infected material was removed, microbiological specimens taken and, in the absence of superficial veins, an "Omniflow-II(r)" prosthesis was implanted in an orthotopic position. Patients were followed up to evaluate their outcome, and the cost-effectiveness of the procedure was also analysed. RESULTS: The technical feasibility of the procedure was assessed in all cases. Pathogens were detected in five of eight cases. After a mean follow-up of 8 months, seven of eight patients showed that they were clinically cured of infection. Primary patency was 63%, secondary patency was 75%, and prevalence of limb salvage was 88%. One patient had to undergo limb amputation to avoid sepsis, and another unsuccessfully underwent thrombectomy after 12 months. Four PET-CT follow-up studies showed a reduction of uptake in the affected area. To generate adequate revenue by using this technique, specialised knowledge of the diagnosis-related group system is necessary. DISCUSSION: Treatment of vascular graft infections in peripheral bypass surgery in the absence of endogenous material necessitates the use of infection-resistant materials. The present study showed promising results using a collagen-biosynthetic prosthesis. Due to a lack of long-term results, the graft should be used only after detailed informed consent is obtained from the patient. The expenses incurred by using the biosynthetic graft should be covered adequately by revenues from these patients. PMID- 23341134 TI - [V. A. C. INSTILL(r) therapy - new option in septic thoracic surgery]. AB - BACKGROUND: The V. A. C. INSTILL(r) therapy is an innovative process for treating chronic wounds that are not optimally accessible to a systemic antibiotic therapy or infected with multi-resistant pathogens. We report on our first experience and applications of V. A. C. INSTILL(r) therapy in the field of septic thoracic surgery. MATERIALS AND METHODS: V. A. C. INSTILL therapy was used in 11 cases between 11/2009 and 01/2012. Three patients had sternum osteomyelitis (2 MRSA, 1 Finegoldia magna). In 3 patients chronic pleural empyema after lobectomy (1 Streptococcus viridans, 1 mixed infection with MRSA among others) and after pneumectomy (1 MRSA) were detected. In 2 cases there was an acute pleural empyema with extensive phlegmona in the region of the thoracic soft tissues (2 streptococci). In 1 patient a chronic pleural empyema with MRSA infection was treated. Septic arthritis of the sternoclavicular joint with joint destruction and extensive phlegmona in the region of the cervical soft tissues (1 Streptococcus pneumoniae, 1 Staphylococcus aureus) was treated in 2 patients. In all cases instillation of the wound was performed with Lavasept 0.2 %. Swabs of the wound were taken before starting and after ending V. A. C. INSTILL(r) therapy as well as before wound closure. RESULTS: Mean patient age was 48.8 +/- 18.9 years. V. A. C. INSTILL(r) therapy was performed for 6.5 +/- 1.7 days. Instillation time amounted to 21.7 +/- 5.7 s. The duration of action was standardised at 18 min in all cases. In 2 cases (1 MESA, 1 finegoldia) the V. A. C. INSTILL(r) therapy was repeated. In 10 patients a sterile wound status was achieved before secondary wound closure. All wounds underwent secondary closure without recurrence. CONCLUSIONS: Chronic osteomyelitis with MRSA infections as well as chronically infected residual cavities after empyema surgery and extensive phlegmona are possible indications for V. A. C. INSTILL(r) therapy in order to help eradicating the infection as quickly and as completely as possible. PMID- 23341135 TI - Epithelioid schwannoma of the facial nerve masquerading as pleomorphic adenoma: a case report. AB - Schwannomas arising in the parotid gland or peri-parotid region is frequently misdiagnosed as pleomorphic adenoma on cytologic preparations. The epithelioid variant of schwannoma is particularly susceptible to misdiagnosis because this neoplasm typically has epithelioid and spindled cells, which are associated with fibrillar stroma and mimic the epithelial, myoepithelial, and stromal components of a pleomorphic adenoma. Preoperative diagnosis of schwannoma is critical in order to plan appropriate management and to avoid inadvertent injury to the associated nerve during surgical resection. Thus, awareness of the distinct clinical, radiological, and cytomorphological features of schwannoma is important in order to guide clinical management. If the cytomorphological features are equivocal, immunohistochemical staining may provide a valuable alternative for distinguishing between pleomorphic adenoma and schwannoma. PMID- 23341136 TI - Effects of retrograde autologous priming on blood transfusion and clinical outcomes in adults: a meta-analysis. AB - OBJECTIVE: Reducing the priming volume is an effective means of decreasing hemodilution and blood transfusion during cardiopulmonary bypass (CPB). The patient's own blood was used to replace the crystalloid in the CPB circuit by retrograde autologous priming (RAP) in order to decrease the priming volume. Therefore, we performed a meta-analysis to investigate whether RAP could reduce blood transfusion and improve clinical outcomes. MATERIALS AND METHODS: A comprehensive search was conducted for randomized, controlled trials (RCTs) exploring RAP in PubMed, Embase, The Cochrane Library, Google Scholar and Chinese literature databases (WanFang, WeiPu and CNKI). Clinical parameters and outcomes were focused on the lowest hematocrit (Hct) during CPB, the number of patients transfused blood intraoperatively, the number of patients transfused blood perioperatively, the number of blood units transfused, 24-hour chest tube drainage, hours to extubation, length of ICU stay, and length of hospital stay. RESULTS: Ten trials, with a total of 1123 patients, were included. The number of patients transfused blood intraoperatively (RR = 0.39, 95% CI = [0.29, 0.53], p<0.00001, I(2) = 40%) and perioperatively (RR = 0.53, 95% CI = [0.43, 0.66], p<0.00001, I(2) = 0%) and the number of blood units transfused (SMD = -0.53, 95% CI = [-0.73, -0.33], p<0.00001, I(2) = 14%) were all significantly reduced in the RAP group. No differences in the hours to extubation (SMD = -0.11, 95% CI = [ 0.33, 0.12], p=0.37, I(2) = 0%) and the length of ICU stay (SMD = -0.17, 95% CI = [-0.41, 0.08], p=0.18, I(2) = 0%) were observed between the two groups. CONCLUSION: Compared to conventional priming, RAP could reduce transfusion in adults significantly, but had no effect on clinical outcomes, comparing to conventional priming. Further studies involving RAP are expected to investigate if this technique is beneficial to the patient. PMID- 23341137 TI - Stille coupling involving bulky groups feasible with gold cocatalyst. PMID- 23341142 TI - Coupling between GABA-A receptor and chloride transporter underlies ionic plasticity in cerebellar Purkinje neurons. AB - Ionic plasticity, a form of synaptic plasticity unique to inhibitory neurotransmission, can be induced in cerebellar Purkinje neurons by brain-derived neurotrophic factor (BDNF). It is expressed as a decrease in synaptic strength of GABA-A transmission onto Purkinje neurons due to reduced transmembrane chloride gradient. By making whole-cell recordings, we found that the effect of BDNF is mediated by neuronal potassium and chloride transporter KCC2 because it is blocked by inhibitors of KCC2 or by raising the intracellular chloride concentration. Under these conditions in which KCC2 activity is reduced, BDNF augments evoked GABA-A currents suggesting a direct facilitatory effect of BDNF on GABA-A receptor. We also found that the effect of BDNF is highly localized at the GABA-A synapse and is secured by physical coupling between GABA-A receptor and KCC2, as revealed by coimmunoprecipitation studies. Based on these results, we hypothesize that the interaction between KCC2 and specific subunit of GABA-A receptor represents a fundamental mechanism rendering the rapid induction of ionic plasticity in individual or input-specific GABA synapses possible. Such a mechanism may be important for the function of Purkinje neurons that are known to express GABA-A receptors with different subunit compositions. PMID- 23341143 TI - Regional inhibition of cholinesterase in free-ranging western pond turtles (Emys marmorata) occupying California mountain streams. AB - The present study investigated the potential effects of cholinesterase (ChE) inhibiting pesticides on western pond turtles (Emys marmorata) occupying streams in two regions of California, USA. The southern region was suspected of having increased exposure to atmospheric deposition of contaminants originating from Central Valley agriculture. The northern region represented reference ChE activities because this area was located outside of the prominent wind patterns that deposit pesticides into the southern region. Total ChE activity was measured in plasma from a total of 81 turtles from both regions. Cholinesterase activity of turtles was significantly depressed by 31% (p = 0.005) in the southern region after accounting for additional sources of variation in ChE activity. Male turtles had significantly increased ChE activity compared with females (p = 0.054). Cloaca temperature, length, mass, handling time, body condition, and lymph presence were not significant predictors of turtle ChE activity. In the southern region, 6.3% of the turtles were below the diagnostic threshold of two standard deviations less than the reference site mean ChE activity. Another diagnostic threshold determined that 75% of the turtles from the southern region had ChE activities depressed by 20% of the reference mean. The decrease in ChE activity in the southern region suggests sublethal effects of pesticide exposure, potentially altering neurotransmission, which can result in various deleterious behaviors. PMID- 23341145 TI - An echocardiographic finding leading to the diagnosis of giant cell arteritis. PMID- 23341146 TI - Three-dimensional dynamic assessment of tricuspid and mitral annuli using cardiovascular magnetic resonance. AB - AIMS: To explore the potentiality of cardiovascular magnetic resonance (CMR) in the quantitative evaluation of mitral valve annulus (MVA) and tricuspid valve annulus (TVA) morphology and dynamics. METHODS AND RESULTS: CMR was performed in 13 normal subjects and 9 patients with mitral (n = 7) or tricuspid regurgitation (n = 2), acquiring cine-images in 18 radial long-axis planes passing through the middle of MVA or TVA. A novel algorithm was used to obtain dynamic three dimensional (3D) reconstruction of MVA and TVA. Analysis was feasible in all cases, allowing accurate 3D annular reconstruction and tracking. The 3D area increased from systole [MVA, median = 10.0 cm(2) (first quartile = 8.6, third quartile = 11.4); TVA, 11.2 cm(2) (8.8-13.2)] to diastole [MVA, 10.6 cm(2) (9.4, 11.7); TVA, 11.9 cm(2) (9.2-13.5)], with TVA larger than MVA. While the longest diameter showed similar systolic and diastolic values, the shortest diameter elongated from systole [MVA, 30 mm (29-33); TVA, 33 mm (31-36)] to diastole [MVA, 31 mm (29-32); TVA, 36 mm (33-39)]. Also, TVA became more circular than MVA. TVA showed lower peak systolic excursion in the septal [15.9 mm (13.0-18.5)] and anterior regions [17.9 mm (12.2-20.7)] compared with the posterior [21.9 mm (18.6 24.0)] segment. Values in MVA were smaller than in TVA, slightly higher in anterior [11.2 mm (9.5-13.0)] than in posterior [12.4 mm (10.2-14.6)] segments. Valvular regurgitation was associated with enlarged, flattened, and more circular annuli. CONCLUSION: The applied method was feasible and accurate in normal and regurgitant valves, and may potentially have an impact on diagnosis, improvement of surgical techniques and design of annular prostheses. PMID- 23341144 TI - Selected rapporteur summaries from the XX World Congress of Psychiatric Genetics, Hamburg, Germany, October 14-18, 2012. AB - The XXth World Congress of Psychiatric Genetics (WCPG), sponsored by The International Society of Psychiatric Genetics (ISPG) took place in Hamburg, Germany on October 14-18, 2012. Approximately 600 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned sessions as rapporteurs. This manuscript represents topics covered in most, but not all, oral presentations during the conference, and some of the major notable new findings reported at this 2012 WCPG. PMID- 23341147 TI - Differences in tissue characterization of restenotic neointima between sirolimus eluting stent and bare-metal stent: integrated backscatter intravascular ultrasound analysis for in-stent restenosis. AB - AIMS: The pathogenesis of in-stent restenosis (ISR) after drug-eluting stent (DES) implantation remains unclear. The purpose of this study is to analyse tissue characterizations of neointima in restenosis lesions after sirolimus eluting stent (SES), comparing with those after bare metal stent (BMS) using integrated backscatter intravascular ultrasound (IB-IVUS). METHODS AND RESULTS: A total of 54 consecutive patients who had ISR lesions after SES (n = 20) or BMS (n = 34) implantation were enrolled. For tissue characterization of neointima, IB IVUS was performed by cross-sectional (at the minimum lumen area) and volumetric (within the stented segment) analyses. In addition, angiographic patterns of restenosis were evaluated with division into focal and diffuse. The focal angiographic pattern of restenosis was predominantly observed in the SES group (SES vs. BMS; 80.0 vs. 26.5%; P = 0.0001), whereas the diffuse pattern was more common in the BMS group (SES vs. BMS; 20.0 vs. 73.5%; P = 0.0001). On both cross sectional and volumetric IB-IVUS analyses, the neointimal tissue in restenosis lesions after SES implantation had a significantly larger percentage of lipid tissue (cross-sectional: 23.3 +/- 12.7 vs. 15.7 +/- 11.9%; P = 0.033; volumetric: 22.8 +/- 10.4 vs. 16.3 +/- 7.0%; P = 0.008) and a significantly smaller percentage of fibrous tissue compared with that after BMS implantation (cross sectional: 73.6 +/- 11.6 vs. 82.0 +/- 11.2%; P = 0.011, volumetric: 73.8 +/- 9.5 vs. 80.5 +/- 6.7%; P = 0.004). CONCLUSION: This IB-IVUS study indicates that larger amounts of lipid tissue are present in neointima of SES when compared with BMS, suggesting that neoatherosclerosis may in part be responsible for ISR after SES implantation. PMID- 23341148 TI - Giant unruptured left ventricular pseudoaneurysm as a rare cause of heart failure after an unnoticed coronary ischaemic event. PMID- 23341149 TI - Co-conformational isomerism in a neutral ion-paired supramolecular system. AB - Two different counter-ion-free host-guest complexes have been prepared and isolated. These compounds were formed from two equally and opposite doubly charged species, the viologen guests 1 a(2+) and 1 b(2+) and the anti disulfodibenzo[24]crown-8 [DSDB24C8](2-) host, which gave rise to the 1:1 neutral complexes [1 a?DSDB24C8] and [1 b?DSDB24C8]. These species are held together by hydrogen bonding and pi stacking, as well as strong electrostatic interactions. The investigation of these neutral ion-paired supramolecular systems in solution and in the solid state allowed us to establish their co-conformational preferences. Compound [1 a?DSDB24C8], with small methyl groups as substituents on the viologen unit, may adopt three different geometries, 1) an exo nonthreaded, 2) a partially threaded, and 3) a threaded arrangement, depending on the relative spatial orientation between the host and guest: The partially-threaded structure is preferred in solution and in the solid state. The presence of bulky tert butylbenzyl groups in the viologen moiety in compound [1 b?DSDB24C8] restricts the possible geometrical arrangements to one: The exo nonthreaded arrangement. This structure was confirmed in the solid state by X-ray crystallography. The stability of the neutral complexes in solution was determined by UV/Vis spectrophotometry. The stoichiometry of the complexes was established by continuous variation experiments, and overall equilibrium constants and DeltaG degrees values were determined on the basis of dilution experiments. The results observed are a consequence of only the intrinsic stability of the complexes as there are no additional contributions from counter ions. PMID- 23341150 TI - The Louis-Jeantet Prize 2013: Michael Stratton, Peter Hegemann and Georg Nagel. PMID- 23341151 TI - Individual differences in fear potentiated startle in behaviorally inhibited children. AB - Behavioral inhibition (BI) is a temperament characterized during early childhood by increased fearfulness to novelty, social reticence to unfamiliar peers, and heightened risk for the development of anxiety. Heightened startle responses to safety cues have been found among behaviorally inhibited adolescents who have an anxiety disorder suggesting that this measure may serve as a biomarker for the development of anxiety amongst this risk population. However, it is unknown if these aberrant startle patterns emerge prior to the manifestation of anxiety in this temperament group. The current study examined potentiated startle in 7-year old children characterized with BI early in life. High behaviorally inhibited children displayed increased startle magnitude to safety cues, particularly during the first half of the task, and faster startle responses compared to low behaviorally inhibited children. These findings suggest that aberrant startle responses are apparent in behaviorally inhibited children during early childhood prior to the onset of a disorder and may serve as a possible endophenotype for the development of anxiety. PMID- 23341153 TI - Preface. Radiation Protection Publication 91 (RP 91). PMID- 23341154 TI - Addressing patient safety through the use of 'criteria of acceptability' for medical radiation equipment. AB - Patient safety should be considered in the use of ionising radiation equipment in medicine. The International Atomic Energy Agency (IAEA) establishes standards of safety and provides for the application of these standards, also in the area of medical use of radiation. Equipment acceptability, as it relates to radiation in medicine, is the need to satisfy the requirements or standards prior to the use of the device in patient imaging or treatment. Through IAEA activities in establishing and developing Safety Standards, Safety Reports and recommendations to regulatory authorities and end-users, it encourages the adoption of acceptability criteria that are relevant to the medical equipment and its use. PMID- 23341152 TI - MIR846 and MIR842 comprise a cistronic MIRNA pair that is regulated by abscisic acid by alternative splicing in roots of Arabidopsis. AB - MicroRNAs (miRNAs) are ~21-nucleotide long endogenous small RNAs that regulate gene expression through post-transcriptional or transcriptional gene silencing and/or translational inhibition. miRNAs can arise from the "exon" of a MIRNA gene, from an intron (e.g. mirtrons in animals), or from the antisense strand of a protein coding gene (natural antisense microRNAs, nat-miRNAs). Here we demonstrate that two functionally related miRNAs, miR842 and miR846, arise from the same transcription unit but from alternate splicing isoforms. miR846 is expressed only from Isoform1 while in Isoforms2 and -3, a part of pre-miR846 containing the miRNA* sequence is included in the intron. The splicing of the intron truncates the pre-MIRNA and disrupts the expression of the mature miR846. We name this novel phenomenon splicing-regulated miRNA. Abscisic acid (ABA) is shown to mediate the alternative splicing event by reducing the functional Isoform1 and increasing the non-functional Isoform3, thus repressing the expression of miR846 concomitant with accumulation of an ABA-inducible target jacalin At5g28520 mRNA, whose cleavage was shown by modified 5'-RACE. This regulation shows the functional importance of splicing-regulated miRNA and suggests possible mechanisms for altered ABA response phenotypes of miRNA biogenesis mutants. Arabidopsis lyrata-MIR842 and Aly-MIR846 have conserved genomic arrangements with A. thaliana and candidate target jacalins, similar primary transcript structures and intron processing, and better miRNA-miRNA* pairings, suggesting that the interactions between ABA, MIR842, MIR846 and jacalins are similar in A. lyrata. Together, splicing-regulated miRNAs, nat miRNAs/inc-miRNAs and mirtrons illustrate the complexity of MIRNA genes, the importance of introns in the biogenesis and regulation of miRNAs, and raise questions about the processes and molecular mechanisms that drive MIRNA evolution. PMID- 23341155 TI - Parotid gland tumors: correlation between routine cytology and cytomorphometry by digital image analysis using conventional and newly introduced cytomorphometric parameters. AB - The objective of this study was to compare qualitative cytomorphology and morphometric characteristics of parotid gland tumor cells, with the aid of a computer-assisted system of image analysis. Routine qualitative cytologic and quantitative morphometric results from 64 parotid gland tumors were compared. Ultrasound (US)-guided fine-needle aspiration (FNA) specimens were taken from 54 patients. Eleven conventionally used morphometric parameters were studied: area, perimeter, convex area, convexity, maximal and minimal radius, length, breadth, form factor (FF), elongation factor, and nuclear- cytoplasmatic (N/C) ratio. Two newly introduced nuclear form factors were also measured: area symmetry factor and perimeter symmetry factor. The following nuclear morphometric parameters were significantly different between malignant and benign tumors: area, perimeter, convex area, convexity, maximal and minimal radius, length, breadth, FF, elongation factor, area symmetry factor, and perimeter symmetry factor. Comparing the cutoff values and receiver operating characteristic (ROC) curves the following nuclear morphometric parameters were found most useful in separating benign from malignant tumors: area, perimeter, convex area, maximal radius, length, and FF. The following whole cell morphometric parameters were significantly different between malignant and benign tumors: minimal and maximal radius, convexity, breadth, FF, and elongation factor. N/C ratio was significantly higher in malignant tumors. The quantitative morphometric analysis is a useful tool in the cytological differentiation between benign and malignant parotid gland tumors. Computerized image analysis may add to morphological evaluation by turning qualitative data into quantitative values. PMID- 23341156 TI - Clinical outcomes assessment for articular cartilage restoration. AB - The purpose of this article is to provide an overview and perspective of the available options for clinical outcomes evaluation of articular cartilage repair in the knee. A nonsystematic literature review of reported clinical measures for functional, qualitative, and quantitative structural outcomes evaluation after knee articular cartilage repair was performed. Several outcome scores have been validated for articular cartilage repair in the knee with the International Knee Documentation Committee score, Lysholm score, and Knee injury Osteoarthritis Outcome Score being reported most frequently. Activity measures including Tegner and Marx activity scales and the rate of return to sports have direct practical relevance for athletically active patients. Macroscopic and histological assessment provides important structural information about repair cartilage quality and quantity. In addition, magnetic resonance imaging (MRI) outcome scoring and functional MRI are gaining increasing popularity and promise less invasive systematic assessment. In summary, clinical outcome evaluation after cartilage repair can be performed by various established and validated functional outcome instruments as well as several evolving outcome parameters that provide clinically relevant outcome information for researchers, clinicians, and patients. PMID- 23341157 TI - Copper-catalyzed direct secondary and tertiary C-H alkylation of azoles through a heteroarene-amine-aldehyde/ketone coupling reaction. AB - Coupling the strangers: A copper-catalyzed three-component heteroarene-amine aldehyde/ketone coupling affords a novel approach to the hitherto difficult direct secondary/tertiary C-H alkylation of azoles. This simple method allows the facile installation of diversely substituted, branched and nitrogen-containing alkyl or alkaloid side chains on the azole moiety by using readily available starting materials. PMID- 23341158 TI - Pharmacotherapy considerations in patients with HIV and psychiatric disorders: focus on antidepressants and antipsychotics. AB - OBJECTIVE: To review the evidence for the efficacy and safety of pharmacologic agents for the treatment of depressive and psychotic disorders in patients with HIV infection and to provide clinical considerations for the treatment of depression and psychosis in these patients. DATA SOURCES: PubMed was searched for articles published between 1966 and August 1, 2012, using the search terms antiretrovirals, HIV, AIDS, depression, psychosis, schizophrenia, antidepressant, antipsychotic, and individual drug names (fluoxetine, sertraline, paroxetine, citalopram, escitalopram, venlafaxine, duloxetine, mirtazapine, bupropion, haloperidol, perphenazine, fluphenazine, aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone). STUDY SELECTION AND DATA EXTRACTION: For the purposes of evaluating efficacy data, we limited our selection to randomized placebo-controlled or active comparator-controlled trials for agents that have been used for depression and psychosis in HIV-infected patients. DATA SYNTHESIS: We found 11 studies for depression treatment and 1 study for psychosis treatment that met our inclusion and exclusion criteria. Selective serotonin reuptake inhibitors (SSRIs; especially fluoxetine) and tricyclic antidepressants appear to be effective in treating depressive symptoms in patients with HIV infection without affecting immune status. Testosterone, stimulants, and dehydroepiandrosterone may also be effective in subsyndromal depression; however, studies on these agents in general were limited by small sample size. There are limited data for antipsychotics, with the only controlled study found for haloperidol and chlorpromazine used for AIDS delirium. Drug-drug interactions and potentiation of metabolic syndrome are concerns for the combined use of antidepressants and antipsychotics with antiretrovirals. CONCLUSIONS: Larger controlled studies are needed to validate the current findings as well as expand knowledge for non-SSRI antidepressants and second-generation antipsychotics for use in HIV-infected patients. PMID- 23341159 TI - Nitrofurantoin contraindication in patients with a creatinine clearance below 60 mL/min: looking for the evidence. AB - OBJECTIVE: To investigate the evidence leading to nitrofurantoin contraindication in patients with a creatinine clearance (CrCl) below 60 mL/min. DATA SOURCES: Literature was searched in PubMed (1965-June 2012) by using the key words and MeSH terms urinary tract infections-drug therapy, chronic kidney insufficiency, kidney diseases, pharmacokinetics, safety, and efficacy, combined with nitrofurantoin. Articles were limited to the English language. References from the identified studies, Food and Drug Administration-approved product information packets, drug information resources, and pharmacology books were also reviewed. DATA SYNTHESIS: The contraindication of nitrofurantoin in patients with a CrCl below 60 mL/min was included in the product information packets sometime between 1988 and 2003. The 1988 Macrodantin product information indicated a CrCl cutoff level of 40 mL/min, but the current contraindication of less than 60 mL/min is found in the 2003 Macrobid product information. It is unclear when and why this change occurred, but it may have followed the work of Sachs and colleagues in 1968, who reported very little drug recovery in the urine of patients with a CrCl below 60 mL/min. This and previous studies have several and severe limitations, such as the inclusion of a small number of patients, an undefined or poorly defined method to determine CrCl and renal impairment, measurement of amounts of nitrofurantoin excreted in the urine instead of urinary concentrations, and most importantly, a lack of clinical efficacy end points. More recently, a chart review on clinical cure of urinary tract infections treated with nitrofurantoin provided grounds for further investigations on the utility of this drug for patients with a CrCl of 60 mL/min or lower. Concerns of increased risks of serious adverse reactions in patients with reduced renal function have further limited the use of nitrofurantoin. However, although not completely clear, these complications seem to be linked most often to prolonged treatment, genetic variability, and predisposition to hypersensitivity. CONCLUSIONS: Data supporting the contraindication of nitrofurantoin for patients with a CrCl less than 60 mL/min are nonexistent. Well-designed clinical trials with urinary concentration information and clinical end points on patients with various degrees of renal impairment are much needed. Until such a study becomes available, the limited data available would support considering using this drug in patients with a CrCl of 40 mL/min or higher. PMID- 23341160 TI - Prolonged infusion antibiotics for suspected gram-negative infections in the ICU: a before-after study. AB - BACKGROUND: beta-Lactam antibiotics demonstrate time-dependent killing. Prolonged infusion of these agents is commonly performed to optimize the time the unbound concentration of an antibiotic remains greater than the minimum inhibitory concentration and decrease costs, despite limited evidence suggesting improved clinical results. OBJECTIVE: To determine whether prolonged infusion of beta lactam antibiotics improves outcomes in critically ill patients with suspected gram-negative infection. METHODS: We conducted a single-center, before-after, comparative effectiveness trial between January 2010 and January 2011 in the intensive care units at Barnes-Jewish Hospital, an urban teaching hospital affiliated with the Washington University School of Medicine in St. Louis, MO. Outcomes were compared between patients who received standardized dosing of meropenem, piperacillin-tazobactam, or cefepime as an intermittent infusion over 30 minutes (January 1, 2010, to June 30, 2010) and patients who received prolonged infusion over 3 hours (August 1, 2010, to January 31, 2011). RESULTS: A total of 503 patients (intermittent infusion, n = 242; prolonged infusion, n = 261) treated for gram-negative infection were included in the clinically evaluable population. Approximately 50% of patients in each group received cefepime and 20% received piperacillin-tazobactam. More patients in the intermittent infusion group received meropenem (35.5% vs 24.5%; p = 0.007). Baseline characteristics were similar between groups, with the exception of a greater occurrence of chronic obstructive pulmonary disease (COPD) in the intermittent infusion group. Treatment success rates in the clinically evaluable group were 56.6% for intermittent infusion and 51.0% for prolonged infusion (p = 0.204), and in the microbiologically evaluable population, 55.2% for intermittent infusion and 49.5% for prolonged infusion (p = 0.486). Fourteen-day, 30-day, and inhospital mortality rates in the clinically evaluable population for the intermittent and prolonged infusion groups were 13.2% versus 18.0% (p = 0.141), 23.6% versus 25.7% (p = 0.582), and 19.4% versus 23.0% (p = 0.329). CONCLUSIONS: Routine use of prolonged infusion of time-dependent antibiotics for the empiric treatment of gram-negative bacterial infections offers no advantage over intermittent infusion antibiotic therapy with regard to treatment success, mortality, or hospital length of stay. These results were confirmed after controlling for potential confounders in a multivariate analysis. PMID- 23341161 TI - Evaluation of the treatment of vancomycin-resistant enterococcal urinary tract infections in a large academic medical center. AB - BACKGROUND: Vancomycin-resistant enterococci (VRE) are a common cause of nosocomial urinary tract infections (UTIs) among hospitalized patients. Clinicians need to differentiate between VRE-associated urinary colonization, asymptomatic bacteriuria, and UTIs to determine the need for treatment and length of therapy. OBJECTIVE: To characterize the diagnosis and management of VRE from urinary sources, including compliance with institutional treatment guidelines, and identify risk factors associated with clinical failure. METHODS: We performed a retrospective, single-center, cohort study among patients with VRE-positive cultures from urinary sources over a 3-year study period (July 2008-September 2011). Descriptive statistics were used to evaluate demographics, diagnostics, guideline compliance, pharmacotherapy, and outcomes. Risk factors associated with clinical failure were identified by multivariate logistic regression analysis. RESULTS: Two hundred sixty-nine distinct episodes of VRE met inclusion criteria among 252 patients. Forty-seven percent and 77% of episodes occurred in patients admitted to an intensive care unit and hospitalized for 7 or more days, respectively. Fifty-eight percent of the episodes were classified as asymptomatic bacteriuria or colonization. Compliance with institutional treatment guidelines for the appropriate drug, dose, and duration occurred in approximately 70% of the cases. Among noncompliant cases (n = 83), 48 (58%) were overtreated, and 35 (42%) were undertreated. Clinical failure among all cases was common, including mortality (17.1%). Factors independently associated with clinical failure determined on multivariate analysis included weight 100 kg or more (OR 5.30; 95% CI 1.42-12.21; p = 0.014), renal disease (OR 2.57; 95% CI 1.02-6.47; p = 0.048), indwelling catheter (OR 4.62; 95% CI 1.05-18.24; p = 0.046), and VRE bloodstream infection (OR 15.71; 95% CI 2.9-128.7; p < 0 .001). CONCLUSIONS: Improved education is needed to minimize cases of overtreatment and undertreatment of VRE associated UTIs and decrease inappropriate drug-related costs and clinical failure rates. Risk factors for clinical failure can be used to risk stratify VRE associated UTIs and further guide treatment decisions. PMID- 23341162 TI - Objects don't object: evidence that self-objectification disrupts women's social activism. AB - Integrating system-justification and objectification theories, the research reported here broadens the scope of prior work on women's self-objectification to examine its system-justifying function. I investigated the relation of trait and state self-objectification to support for the gender status quo and engagement in gender-based social activism among U.S. college women. Study 1 established that greater trait self-objectification was related to more gender-specific system justification and less engagement in gender-based social activism. The data supported a mediational model in which gender-specific system justification mediated the link between trait self-objectification and social activism. Results from Study 2, in which self-objectification was situationally activated, confirmed the same mediational model. These findings suggest that trait and state self-objectification may be part of a wider pattern of system-justifying behavior that maintains gender inequality and thwarts women's pursuit of social justice. PMID- 23341163 TI - Epigenetic regulation of inflammation: progressing from broad acting histone deacetylase (HDAC) inhibitors to targeting specific HDACs. AB - Inhibition of histone deacetylases (HDAC) is emerging as a novel approach to treat a variety of diseases. Recently, broad acting inhibitors of HDAC have been shown to have anti-inflammatory effects both in vitro and in vivo. It is significant that these anti-inflammatory effects are observed at 10-100 fold lower concentrations than their anti-cancer effects. The broad action of these compounds makes it difficult to determine which HDAC enzymes are important in inflammation. Although showing promise it is unlikely that these drugs will progress to the clinic for treating inflammatory diseases due to number of HDACs they affect and the widespread activity of the enzymes throughout the body. Accordingly, research is now progressing to targeting specific HDAC enzymes to improve efficacy of treatment as well as reduce the risk of any unwanted side effects. Understanding the role specific HDACs play in inflammatory disease will help us to identify novel anti-inflammatory treatments. This manuscript is designed to review our limited knowledge in this field. PMID- 23341164 TI - 25-Hydroxy vitamin D3 modulates dendritic cell phenotype and function in Crohn's disease. AB - BACKGROUND: In Crohn's disease (CrD), vitamin D may help to balance an exaggerated immune response and thereby improve the disease course. The immunomodulating effects depend on the activation of 25-hydroxy vitamin D3 (25 D3), into 1,25-dihydroxy vitamin D3 (1,25-D3). This activation has previously been shown to take place in dendritic cells (DC) from healthy individuals. We hypothesised that DC from CrD patients are able to regulate and control inflammatory responses through 25-D3 activation. METHODS: During differentiation, monocyte-derived DC from 20 CrD patients were cultured with either 25-D3 or 1,25 D3 and matured with lipopolysaccharide (LPS). We examined DC surface marker expression, cytokine production, and the ability to induce cell proliferation in an allogeneic mixed leukocyte reaction. RESULTS: Following stimulation with LPS, DC exposed to either 25-D3 or 1,25-D3 exhibited lower expression levels of CD80, CD83, CD86, and HLA-DR and diminished TNF-alpha production compared with DC cultured with LPS alone. In contrast, CD14 expression and IL-6 production were higher following 25-D3 or 1,25-D3 treatment. Compared with LPS alone, both forms of vitamin D3 reduced the ability of DC to activate lymphocytes. CONCLUSIONS: Following stimulation with 25-D3, DC from CrD patients displayed a reduced response to LPS with a diminished capability to activate T cells compared with DC stimulated with LPS alone. These data indicate that intrinsic activation of 25-D3 occurs in DC from CrD patients and show that 25-D3 can modulate DC function in CrD. Our data suggest that vitamin D deficiency may contribute to the uncontrolled inflammatory process seen in CrD. PMID- 23341165 TI - The epidural electric stimulation test does not predict local anesthetic spread or consumption in labour epidural analgesia. AB - PURPOSE: The epidural electrical stimulation test (EEST) is a highly specific and sensitive test for confirming placement of the epidural catheter in the epidural space. The purpose of this study was to investigate if the EEST could predict the spread and consumption of local anesthetic solutions during labour epidural analgesia. METHODS: This observational study was conducted in labouring parturients requesting epidural analgesia. The EEST was performed after the epidural catheter placement (T0) and repeated five minutes after a test dose with 2% lidocaine 3 mL (T1). The minimum current required to elicit the motor response at each time point was recorded. A loading dose of 0.125% bupivacaine 10 mL and fentanyl 50 MUg was administered and followed by patient-controlled epidural analgesia with 0.0625% bupivacaine and fentanyl 2 MUg.mL(-1) (baseline infusion 10 mL.hr(-1), bolus dose 5 mL, lockout interval ten minutes, maximum dose 20 mL.hr(-1)). The primary outcome was the correlation between the current required to elicit motor responses at T0 and T1 and the consumption of bupivacaine in the first two hours of epidural administration. The secondary outcomes included the muscle contraction patterns determined by the EEST and the incidence of failed, inadequate, or asymmetric blocks. RESULTS: The study was conducted in 102 parturients. The mean electric current required to elicit muscle response was 4.43 mA (range 1-10 mA) at T0, 5.97 mA (range 1-14 mA) at T1, and the mean Delta (T1-T0) current was 1.54 mA (range 0-8 mA). There was no correlation between either the mean baseline current required or the Delta (T1-T0) current and the total bupivacaine consumption at two hours. The incidence of inadequate blocks at two hours was 18%; however, none of the catheters required replacement. Unilateral left (34%) or right (31%) leg contraction was the most frequent pattern elicited by the EEST. CONCLUSIONS: The EEST shows a wide range of electrical current requirements and elicits a variety of muscle twitch patterns on the lower limbs. Although it confirms the epidural placement of the catheter, the EEST cannot be used to predict the spread or consumption of the local anesthetic solution during labour epidural analgesia. PMID- 23341170 TI - Developmental trajectories of respiratory sinus arrhythmia: associations with social responsiveness. AB - The present longitudinal study examined relations between respiratory sinus arrhythmia (RSA) development and social responsiveness characteristics associated with autism spectrum disorders. Group-based developmental trajectory modeling was used to characterize RSA development patterns in 106 typically developing children across 5, 10, 24, 36, and 48 months of age. A two-group model fit of RSA development was found: a "typically" and "atypically" developing group. The typical group gradually increased in RSA across 5-48 months of age. The atypical group, however, increased in RSA from 5 to 24 months and demonstrated a plateau or "delay" in RSA development from 24 to 48 months. The atypical RSA development group also demonstrated more difficulties in parent-reported social responsiveness at 48 months. The results support current literature that identifies RSA as a marker of social functioning level. PMID- 23341171 TI - Identifying leukocyte populations in fresh and cryopreserved sputum using flow cytometry. AB - BACKGROUND: Airway inflammation is commonly assessed by sputum induction followed by a differential cell count (DCC) using light microscopy. This method is prone to intercounter variability and poor reproducibility. We aimed to develop a more objective method using flow cytometry (FCM). METHODS: Fifty-six sputum inductions were conducted in 41 adults (23 asthmatics). Sputum was processed, a cytospin prepared for DCC, and the remainder immunolabeled for FCM using CD45, CD14, and CD16-specific antibodies to distinguish major leukocyte populations. Aliquots of 15 samples were frozen at -80 degrees C to assess the effects of cryostorage. DCC and FCM were compared, and viability of individual cell populations was determined by FCM. RESULTS: FCM and DCC, and fresh and frozen samples, were significantly correlated, R = 0.54-0.87; all P < 0.0001, and R = 0.57 to 1; P < 0.005, respectively. There was a significant neutrophil loss after cryostorage (from median 30.5-17.4% of total leukocytes; P < 0.0001). Cell viability was higher for lymphocytes compared to granulocytes or macrophages (P < 0.001). With the exception of the expected higher levels of eosinophils (P < 0.005), no significant difference in cell differentials or viability was observed between asthmatics and nonasthmatics using either DCC or FCM. CONCLUSIONS: FCM is a suitable means of assessing leukocyte populations in induced sputum. Sample storage at -80 degrees C prior to FCM is feasible, but may be detrimental to neutrophils, although good correlations were still observed between fresh and frozen samples. Large differences in viability were found between individual cell populations suggesting that viability dye use may be necessary. PMID- 23341167 TI - Novel type II fatty acid biosynthesis (FAS II) inhibitors as multistage antimalarial agents. AB - Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood- and pre erythrocytic liver stages of the parasite. P. falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial type II fatty acid biosynthesis (FAS II). It has been shown to be essential for liver-stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood-stage parasite growth with IC(50) values of 1.7 and 3.0 MUM and lead to a more prominent developmental attenuation of liver-stage parasites than the gold-standard drug, primaquine. PMID- 23341172 TI - Stereoselective multiple bond-forming transformations (MBFTs): the power of 1,2- and 1,3-dicarbonyl compounds. AB - Although long known, 1,2- and 1,3-dicarbonyl compounds have recently come more and more to prevalence as ideal substrates for the invention of new stereoselective multiple bond-forming transformations (MBFTs). Herein, a critical appraisal is presented of some of the most spectacular of these MBFTs, which allow the formation from three up to six bonds in highly step- and atom economical processes. PMID- 23341173 TI - Quality of life of people who inject drugs: characteristics and comparisons with other population samples. AB - PURPOSE: To assess the quality of life (QOL) of persons who inject drugs. METHODS: Some 483 current injecting drug users visiting a large NSP over a 2-week period in October 2009 were interviewed using a structured questionnaire. QOL was measured using the WHOQOL-BREF. Data were collected on age, gender, injecting patterns, current drug treatment status and hepatitis C status. Participant QOL profiles were compared to published domain scores for a range of other population groups. RESULTS: People who inject drugs (PWID) experience a very poor QOL irrespective of socio-demographic characteristics, injecting patterns, hepatitis C sero-status and drug treatment status. Sample participants (PWID) experience a QOL below that experienced by many population groups in the community affected by disabling chronic illnesses. CONCLUSIONS: Injecting drug use is associated with a poor QOL. Some PWID may be self-medicating for chronic non-malignant pain, and it is likely that these people had a low QOL prior to the decision to inject. Despite this caveat, it remains likely that injecting drug use does little to enhance the QOL of the user. PMID- 23341174 TI - Evaluation of the Social Participation Questionnaire in adult patients with depressive symptoms using Rasch analysis. AB - PURPOSE: The aim of this study was to explore the psychometric properties of the 22-item Social Participation Questionnaire (SPQ). METHODS: The SPQ was administered to 789 adult primary care patients with depressive symptoms. As the items were intended to be summed together to provide total score, Rasch analysis (partial credit model) was applied to assess the overall fit of the model, individual item fit, differential item functioning (DIF), targeting of persons, response dependency, unidimensionality and person separation. RESULTS: To improve the scale's fit, it was necessary to re-score the response format. Two items demonstrated some DIF for gender and eight items showed DIF for age. To support the assumption of unidimensionality post hoc principal component analysis was performed. The analysis showed two subtests of the residuals with positive and negative loadings, but the person estimates derived from these two subtests were not statistically different to that derived from all items taken together. The response dependence between two items was identified; however, the magnitude of difficulty was very small. Although the questionnaire appeared to have insufficient items to assess the full spectrum of informal social contact, the SPQ was reasonably well targeted. CONCLUSION: The SPQ is a promising questionnaire for the measurement of social participation although it could benefit from the inclusion of further items to measure informal social contact. This study found support for the internal validity, internal consistency reliability, and unidimensionality. A future study will investigate whether targeting can be improved when additional items are included. PMID- 23341175 TI - A refined aquatic ecological risk assessment for a pyrethroid insecticide used for adult mosquito management. AB - The use of pyrethroid insecticides has increased substantially throughout the world over the past few decades as the use of organophorous, carbamate, and organochlorine insecticides is being phased out. Pyrethroids are the most common class of insecticides for ultralow-volume (ULV) aerosol applications used to manage high densities of adult mosquitoes. Pyrethroids are highly toxic to nontarget organisms such as certain aquatic organisms, and there have been concerns about the effect of applications of ULV insecticides on these organisms. To address the uncertainties associated with the risks of ULV applications and the contradictory findings of other ecological risk assessments, the authors performed a probabilistic aquatic ecological risk assessment for permethrin using actual environmental deposition on surfaces to estimate permethrin concentrations in water. The present study is the first ecological risk assessment for pyrethroids to quantitatively integrate the reduction in bioavailability resulting from the presence of dissolved organic matter. As part of the risk assessment, the authors incorporated a species sensitivity distribution to take into account the differences in toxicity for different species. The 95th percentile estimated concentration would result in less than 0.0001% of the potentially affected fraction of species reaching the lethal concentration that kills 50% of a population. The results of the present study are supported by the weight of evidence that pyrethroids applied by ground-based ULV equipment will not result in deleterious effects on aquatic organisms. PMID- 23341176 TI - Diastereoselective intramolecular allyl transfer from allyl carbamate accompanied by 5-endo-trig ring closure. AB - To All(oc) involved: A palladium-catalyzed formal 5-endo-trig heteroannulation of enones generated in situ from amino acid derived beta-keto nitriles has been realized (see scheme; Alloc=allyl carbamate). The reaction proceeds with allyl group transfer from the carbamate protecting group to generate two new contiguous stereocenters, including one quaternary center, with high selectivity. PMID- 23341177 TI - Epigenetic alterations in colorectal cancer: the CpG island methylator phenotype. AB - DNA methylation is one of the key mechanisms of epigenetic modification, and genome-wide hypomethylation and CpG island hypermethylation are characteristics of cancer cells. The CpG island methylator phenotype (CIMP) is a distinctive subtype of colorectal cancers (CRCs) that show concordant hypermethylation of numerous promoter CpG island loci. CIMP-positive CRCs are associated with a proximal location in the colon, microsatellite instability, BRAF mutation and a relatively poor clinical outcome. CIMP-positive CRCs have their own precursor lesions, serrated adenomas, distinct from conventional adenomas which progress and transform into CIMP-negative CRCs. Although the existence of CIMP-positive CRCs is generally accepted, there has been controversy over technical issues with gene markers, the methodology used to define CIMP, and the prognostic or predictive role of CIMP. This review addresses recent advances in the field of CIMP-related research. PMID- 23341178 TI - A comparison of computer-aided detection (CAD) effectiveness in pulmonary nodule identification using different methods of bone suppression in chest radiographs. AB - This study aimed to compare the diagnostic effectiveness of computer-aided detection (CAD) software (OnGuardTM 5.2) in combination with hardware-based bone suppression (dual-energy subtraction radiography (DESR)), software-based bone suppression (SoftViewTM, version 2.4), and standard posteroanterior images with no bone suppression. A retrospective pilot study compared the diagnostic performance of two commercially available methods of bone suppression when used with commercially available CAD software. Chest images from 27 patients with computed tomography (CT) and pathology-proven malignant pulmonary nodules (8-34 mm) and 25 CT-negative patient controls were used for analysis. The Friedman, McNemar, and chi-square tests were used to compare diagnostic performance and the kappa statistic was used to evaluate method agreement. The average number of regions of interest and false-positives per image identified by CAD were not found to be significantly different regardless of the bone suppression methods evaluated. Similarly, the sensitivity, specificity, and test efficiency were not found to be significantly different. Agreement between the methods was between poor and excellent. The accuracy of CAD (OnGuardTM, version 5.2) is not statistically different with either DESR or SoftViewTM (version 2.4) bone suppression technology in digital chest images for pulmonary nodule identification. Low values for sensitivity (<80 %) and specificity (<50 %) may limit their utility for clinical radiology. PMID- 23341179 TI - Bleeding risk assessment using whole blood impedance aggregometry and rotational thromboelastometry in patients following cardiac surgery. AB - Excessive bleeding after cardiopulmonary bypass (CPB) is risk factor for adverse outcomes after elective cardiac surgery (ECS). Differentiating between patients who bleed due to surgical issues and those whose excessive chest tube output (CTO) is due to coagulopathy, remains challenging. Bedside suitable tests to identify hemostatic disturbances and predict excessive bleeding are desirable. The study sought to evaluate prediction of excessive bleeding after ECS using two bedside suitable devices for platelet function and viscoelastic blood clot properties assessment. We enrolled 148 patients (105 male and 43 female) undergoing ECS in a prospective observational study. Patients were characterized as bleeders if their 24 h CTO exceeded the 75th percentile of distribution. Multiple electrode aggregometry (MEA, with ASPI, ADP and the TRAP test) and rotational thromboelastometry (TEM, with ExTEM, HepTEM and FibTEM test), were performed at three time points: preoperatively (T1), during CPB (T2), and after protamine administration (T3). The primary endpoint was CTO and the secondary endpoint was administration of blood products, 30-day and 1 year mortality. The best predictors of increased bleeding tendency were the tests performed after protamine administration (T3). At T3, patients characterized as bleeders had significantly lower MEA ASPI (median, 14 vs. 27 AUC, p = 0.004) and ADP test values (median, 22 vs. 41 AUC, p = 0.002) as well as TEM values expressed in maximum clot firmness after 30 min (MCF 30) for ExTEM (53 vs. 56 mm, p = 0.005), HepTEM (48 vs. 52 mm, p = 0.003) and FibTEM (8 vs. 11 mm, p < 0.001) test. 24 h CTO inversely correlated with both the MEA (ASPI test: r = -0.236, p = 0.004; ADP test: r = -0.299, p < 0.001), and TEM MCF 30 (ExTEM: r = -0.295, p < 0.001; HepTEM: -0.329, p < 0.001; FibTEM: -0.377, p < 0.001) test values. Our study showed that MEA and TEM are useful methods for prediction of excessive bleeding after ECS. In order to prevent excessive postoperative CTO, hemostatic interventions with timely and targeted blood component therapy according to MEA and TEM results should be considered. PMID- 23341180 TI - Oral anticoagulants in older adults with atrial fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia in adults and contributes directly to adverse clinical events, ranging from ischemic stroke to heart failure and cardiovascular death. Because the incidence of AF and its attendant complications increase with age, there is a strong and growing need to develop safe, effective and widely available therapies. The following review summarizes the use of oral anticoagulants in older adults with AF, focusing on practical topics such as drug metabolism, drug-drug interactions, co-morbidities and cost considerations in a complex payer environment. PMID- 23341181 TI - Prognostic significance of p53 expression in malignant bone tumors: a meta analysis. AB - Osteosarcoma and Ewing's sarcoma are the two most common primary malignant bone tumors, and findings of prognostic factors are important for clinicians to decide treatment options. High p53 expression has been implicated in tumor development and progression, but studies investigating the prognostic role of p53 overexpression in malignant bone tumors report conflicting findings. We performed a meta-analysis to assess the relationship between p53 overexpression and the survival of malignant bone tumors. A meta-analysis of 13 studies with a total of 703 patients was carried out to evaluate the association between p53 overexpression and overall survival (OS) and disease-free survival (DFS) in patients with malignant bone tumors. The pooled hazard ratio (HR) with its 95 % confidence interval (CI) was used as the effect size estimate. There was no between-study heterogeneity in both OS studies (I (2) = 0.0 %) and DFS studies (I(2) = 0.0 %). Overall, high p53 expression predicted both poor OS (HR 2.13, 95 % CI 1.81-2.52, P < 0.001) and poor DFS (HR 2.06, 95 % CI 1.58-2.69, P < 0.001) in patients with malignant bone tumors. Subgroup analyses by tumor types suggested that p53 expression predicted poor OS in both osteosarcoma patients (HR 2.15, 95 % CI 1.78-2.60, I (2) = 15.2 %, P < 0.001) and Ewing's sarcoma patients (HR 2.09, 95 % CI 1.47-2.97, I(2) = 0.0 %, P < 0.001). Besides, p53 expression also predicted poor DFS in both osteosarcoma patients (HR 2.38, 95 % CI 1.60 3.52, I(2) = 0.0 %, P < 0.001) and Ewing's sarcoma patients (HR 1.83, 95 % CI 1.28-2.63, I(2) = 0.0 %, P = 0.001). Egger's test also did not suggest evidence for publication bias in both OS studies (P = 0.615) and DFS studies (P = 0.258). High p53 expression indicates a poorer prognosis for patients with osteosarcoma and Ewing's sarcoma. PMID- 23341182 TI - Bcl-2 family proteins and cytoskeleton changes involved in DM-1 cytotoxic effect on melanoma cells. AB - Melanoma is one of the most aggressive types of skin cancer and its incidence rate is still increasing. All existing treatments are minimally effective. Consequently, new therapeutic agents for melanoma treatment should be developed. The DM-1 compound is a curcumin analog that possesses several curcumin characteristics, such as antiproliferative, antitumor, and anti-metastatic properties. The aim of this study was to evaluate the different signaling pathways involved in the cytotoxic effect of DM-1 on melanoma cells. The apoptotic process and cytoskeletal changes were evaluated by immunoblotting and immunofluorescence, respectively, in melanoma cells. After DM-1 treatment, SK-MEL 5 melanoma cells showed actin filament disorganization with spicule formation throughout the cytoskeleton and significant reduction of focal adhesion as well as they were present only at cell extremities, conferring a poor connection between the cell and the substrate. Besides this, there was significant filopodium retraction and loss of typical cytoskeleton scaffold. These modifications contributed to cell detachment followed by cell death. Furthermore, DM-1-induced apoptosis was triggered by multiple Bcl-2 proteins involved in both the extrinsic and the intrinsic apoptotic pathways. SK-MEL-5 cells showed a death mechanism mainly by Bcl-2/Bax ratio decrease, whereas A375 cells presented apoptosis induction by Mcl-1 and Bcl-xL downregulation. In SK-MEL-5 and A375 melanoma cells, there was a significant increase in the active form of caspase 9, and the inactive form of the effector caspase 3 was decreased in both cell lines. Expression of cleaved poly ADP ribose polymerase was increased after DM-1 treatment in these melanoma cell lines, demonstrating that the apoptotic process occurred. Altogether, these data elucidate the cellular and molecular mechanisms involved in the cytotoxicity induced by the antitumor agent DM-1 in melanoma cells. PMID- 23341183 TI - A "clickable" MTX reagent as a practical tool for profiling small-molecule intracellular target interactions via MASPIT. AB - We present a scalable synthesis of a versatile MTX reagent with an azide ligation handle that allows rapid gamma-selective conjugation to yield MTX fusion compounds (MFCs) appropriate for MASPIT, a three-hybrid system that enables the identification of mammalian cytosolic proteins that interact with a small molecule of interest. We selected three structurally diverse pharmacologically active compounds (tamoxifen, reversine, and FK506) as model baits. After acetylene functionalization of these baits, MFCs were synthesized via a CuAAC reaction, demonstrating the general applicability of the MTX reagent. In analytical mode, MASPIT was able to give concentration-dependent reporter signals for the established target proteins. Furthermore, we demonstrate that the sensitivity obtained with the new MTX reagent was significantly stronger than that of a previously used non-regiomeric conjugate mixture. Finally, the FK506 MFC was explored in a cellular array screen for targets of FK506. Out of a pilot collection of nearly 2000 full-length human ORF preys, FKBP12, the established target of FK506, emerged as the prey protein that gave the highest increase in luciferase activity. This indicates that our newly developed synthetic strategy for the straightforward generation of MFCs is a promising asset to uncover new intracellular targets using MASPIT cellular array screening. PMID- 23341184 TI - Comparing the Tonojet disposable tonometer with the traditional Goldmann tonometer in glaucomatous and non-glaucomatous eyes. AB - Applanation tonometry is widely performed as the most accurate method of measuring intraocular pressure in the clinical setting. Disposable tonometer heads reduce the risk of transmitting infection during applanation and eliminate tonometer head cleaning, which is time-consuming. We performed a study to investigate whether the Tonojet disposable tonometer (Luneau, France) gave comparable intraocular pressure measurements to the standard Goldmann tonometer produced by Haag Streit (Switzerland). The study was performed in a busy general secondary referral ophthalmology clinic in Beaumont Hospital over a 15-day period. We measured intraocular pressure with the Goldmann and Tonojet tonometers in 293 eyes. Patients were randomised as to which tonometer was used first. A diagnosis of glaucoma or ocular hypertension was noted. Central corneal thickness (CCT) was measured. The measurements taken with the Tonojet were on average 2.2 mmHg lower than corresponding measurements taken with the Goldmann applanation tonometer head. The bias was present over the entire range of pressures. The 95 % limits of agreement between the two tonometers ranged from -5.9 to +1.4 mmHg. In the cohort of eyes with ocular hypertension/glaucoma the difference was significantly higher (2.8 vs. 2.1 mmHg). The bias was independent of CCT. We found that the Tonojet disposable tonometer tends to underestimate intraocular pressure compared with the Goldmann. The bias is non-systematic, present over the entire range of pressures and independent of corneal thickness. We conclude that the Tonojet is not sufficiently accurate to constitute a suitable alternative to the Goldmann. PMID- 23341185 TI - Atypical findings in delayed presentation of unilateral acute idiopathic maculopathy. AB - Unilateral acute idiopathic maculopathy is a rare disease affecting young healthy patients resulting in moderate to severe unilateral visual loss preceded by prodromal flu-like illness. We present a case of delayed presentation of unilateral acute idiopathic maculopathy associated with hand, foot and mouth disease. PMID- 23341187 TI - Calixarenes and cations. AB - The synthesis in 1985 by the group led by Tony McKervey of numerous calix[4]arene derivatives capable of acting as neutral, multidentate ligands proved to be a seminal step in the development of various applications of calixarenes as metal ion binding agents. PMID- 23341186 TI - Evolutionary conservation of the polyproline II conformation surrounding intrinsically disordered phosphorylation sites. AB - Intrinsically disordered (ID) proteins function in the absence of a unique stable structure and appear to challenge the classic structure-function paradigm. The extent to which ID proteins take advantage of subtle conformational biases to perform functions, and whether signals for such mechanism can be identified in proteome-wide studies is not well understood. Of particular interest is the polyproline II (PII) conformation, suggested to be highly populated in unfolded proteins. We experimentally determine a complete calorimetric propensity scale for the PII conformation. Projection of the scale into representative eukaryotic proteomes reveals significant PII bias in regions coding for ID proteins. Importantly, enrichment of PII in ID proteins, or protein segments, is also captured by other PII scales, indicating that this enrichment is robustly encoded and universally detectable regardless of the method of PII propensity determination. Gene ontology (GO) terms obtained using our PII scale and other scales demonstrate a consensus for molecular functions performed by high PII proteins across the proteome. Perhaps the most striking result of the GO analysis is conserved enrichment (P < 10(-8) ) of phosphorylation sites in high PII regions found by all PII scales. Subsequent conformational analysis reveals a phosphorylation-dependent modulation of PII, suggestive of a conserved "tunability" within these regions. In summary, the application of an experimentally determined polyproline II (PII) propensity scale to proteome-wide sequence analysis and gene ontology reveals an enrichment of PII bias near disordered phosphorylation sites that is conserved throughout eukaryotes. PMID- 23341188 TI - Linolelaidic acid induces a stronger proliferative effect on human umbilical vein smooth muscle cells compared to elaidic acid. AB - Trans fatty acids (TFA) have been considered as an independent risk factor of coronary heart disease, sudden death and insulin-resistance, and different TFA isomers may have different effects on the progression of cardiovascular diseases such as atherosclerosis. The aim of the study was to investigate the effects of two major TFA, elaidic acid and linolelaidic acid which have the same number of carbons but a different number and configuration of trans bonds, on the proliferation of human umbilical vein smooth muscle cells (HUVSMC). Methyl thiazolyl tetrazolium and flow cytometry assays showed that the cell proliferation rose to 115.37 +/- 0.39 and 117.5 +/- 0.57 % and the cell number in the S phase of the cell cycle reached 27.7 +/- 0.7 and 25.8 +/- 2.8 % when treated with 50 MUM elaidic acid and 20 MUM linolelaidic acid, respectively. Quantitative real-time reverse transcriptase-polymerase chain reaction and Western blotting analyses showed that the two TFA increased the mRNA and protein expression levels of PCNA, CDK2 and Cyclin E in HUVSMC. Moreover, gas chromatography analysis showed that the total PUFA level of HUVSMC was lower after treatment with the two TFA, especially n-3 PUFA. These results suggested that linolelaidic acid exhibited a stronger proliferative effect on HUVSMC than elaidic acid, and regulation of CDK2 and Cyclin E may be important for the effect of the TFA on atherosclerosis. PMID- 23341189 TI - Flow cytometry is of limited utility in the early identification of "double-hit" B-cell lymphomas. AB - BACKGROUND: B-cell lymphomas with concurrent translocations of MYC and BCL2 or BCL6, also known as "double-hit" lymphomas (DHL), are rare malignancies characterized by aggressive clinical behavior and poor prognosis. Previous reports suggest that decreased CD20 and/or CD19 expression by flow cytometry is relatively common in DHL and may help to identify cases requiring additional cytogenetic analysis. METHODS: We conducted a retrospective analysis of 26 cases of DHL, and compared their flow cytometric characteristics to cases of Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). Cases were analyzed by four-color flow cytometry, and bivariate dot-plots were reviewed for light scatter characteristics, CD19, CD20, CD45, and surface light chain. RESULTS: Relatively few DHL cases showed dim expression of CD19 or CD20, and statistically significant differences were found only in the frequency of dim CD19 expression between DHL and BL or DLBCL. Although concomitant dim CD19 and CD20 expression was exclusive to DHL, it was present in only a minority of cases. CONCLUSIONS: We conclude that although a subset of DHL expresses aberrant levels of CD19 and/or CD20 by flow cytometry, these findings are of limited utility in identifying cases requiring cytogenetic analysis due to their low frequency. Until more sensitive pathologic parameters can be identified and validated, the decision to perform cytogenetic analysis should rest on a combination of clinical, morphologic, and immunophenotypic features suggestive of high-grade, aggressive disease. PMID- 23341190 TI - Vagus nerve neuromonitoring during carotid endarterectomy. AB - To determine the causes and site(s) of nerve injury and to identify potential predictors of vocal fold paralysis (VFP) after carotid endarterectomy (CEA) by application of intraoperative neuromonitoring (IONM). A total of 68 CEA patients were enrolled in this study. A 3-step IONM procedure was designed to obtain vocal fold EMG data at V1 (just after identification of the vagus nerve [VN]), V2 (just before arteriotomy), and V3 (just before wound closure). We also performed IONM before/after hemostasis near the VN using bipolar forceps and before/after dissection of the VN. All patients underwent laryngoscopy to assess postoperative VFP. One patient showed loss of EMG signals between V2 and V3 and developed VFP that persisted for 11 months. The other 62 patients had no loss of EMG signals, but 2 patients had confirmed VFP for 1 month after CEA. There were no changes of EMG signal before and after VN dissection or hemostasis with bipolar forceps near the VN. PMID- 23341191 TI - The role of silver and vanadium release in the toxicity of silver vanadate nanowires toward Daphnia similis. AB - Nanomaterials are used in a wide spectrum of applications, including nanowires that are objects with at least one of its dimensions in the range of 1 to 100 nm. Recently, a new type of silver vanadate nanowire decorated with silver nanoparticles (SVSN-LQES1) with promising antimicrobial activity against different pathogenic bacteria was described. The objective of the present study was to evaluate the role of silver and vanadium release in the acute toxicity of this material using Daphnia similis. To verify the effect of the presence of the nanowires in the test solution, tests were performed before and after filtration. Total silver release to the testing media was determined using the method of inductively coupled plasma atomic emission spectroscopy (ICP-AES). Silver vanadate nanowires decorated with silver nanoparticles (SVSN-LQES1) are acutely toxic to D. similis. The release of silver from the nanomaterial trapped in the gut along with the silver released to the test media seems to be responsible for the observed toxicity. Although toxic to Daphnia, vanadium does not contribute to the toxicity of SVSN-LQES1. The observed increase in lipid droplets appears to be related to the exposure of the organisms to the nanomaterials, but the significance of this response needs further investigation. PMID- 23341193 TI - Two-step boron and nitrogen doping in graphene for enhanced synergistic catalysis. PMID- 23341194 TI - Retigabine for the adjunctive treatment of adults with partial-onset seizures in epilepsy with and without secondary generalization : a NICE single technology appraisal. AB - The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of retigabine (GlaxoSmithKline) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of adults with partial onset seizures in epilepsy, with and without secondary generalization, as part of the Institute's single technology appraisal (STA) process. The Centre for Reviews and Dissemination was commissioned to act as the Evidence Review Group (ERG). The ERG undertakes a critical review of the clinical and cost-effectiveness evidence of the technology based upon the manufacturer's submission to NICE. The ERG also independently searches for relevant evidence and evaluates modifications to the manufacturer's decision-analytic model. This paper provides a description of the company submission, the ERG review and NICE's subsequent decisions. The clinical effectiveness data were derived from three placebo-controlled randomized controlled trials (RCTs). A meta-analysis pooling across all doses of retigabine found beneficial effects of retigabine in terms of responder rate (odds ratio [OR] 2.79; 95 % CI 2.08, 3.76) and rate of seizure freedom (OR 2.54; 95 % CI 0.92, 6.98) [both double-blind phase analyses]. When compared in a network meta analysis with the selected comparator antiepileptic drugs (AEDs) [eslicarbazepine acetate, lacosamide, pregabalin, tiagabine and zonisamide], retigabine offered broadly similar efficacy in terms of responder rate and freedom from seizure. The de novo decision-analytic model presented within the submission evaluated the cost effectiveness of retigabine compared with these AEDs and no treatment (i.e. maintenance therapy). After numerous additional analyses, the ERG considered the use of retigabine to be not cost effective for NICE at thresholds below L43,000 if no treatment was considered a relevant comparator. The NICE Appraisal Committee decided that an appropriate comparator was an active treatment. The Committee recommended that retigabine is offered as an option for the adjunctive treatment of partial-onset seizures with or without secondary generalization in adults aged 18 years and older with epilepsy, only when previous treatment with carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate and topiramate has not provided an adequate response, or has not been tolerated. PMID- 23341195 TI - Live weight, carcass ultrasound images, and visual scores in Angus cattle under feeding regimes in Brazil. AB - This study aimed to evaluate visual precocity, muscling, conformation, skeletal, and breed scores; live weights at birth, at 205, and at 550 days of age; and, besides, rib eye area and fat thickness between the 12th and 13th ribs obtained by ultrasound. Those traits were evaluated in 1,645 Angus cattle kept in five feeding conditions as follows: supplemented or non-supplemented, grazing native pasture or grazing cultivated pasture, and feedlot. Descriptive statistics, Pearson's correlations, and principal component analysis were carried out. Gender and feeding conditions were fixed effects, while animal's age and mother's weight at weaning were the covariates analyzed. Gender and feeding conditions were very significant for the studied traits, but visual scores were not influenced by gender. Animal's age and mother's weight at weaning influenced many traits and must be appropriately adjusted in the statistical models. An important correlation between visual scores, live weights, and carcass traits obtained by ultrasound was found, which can be analyzed by univariate procedure. However, the multivariate approach revealed some information that cannot be neglected in order to ensure a more detailed assessment. PMID- 23341196 TI - Central ghrelin signaling mediates the metabolic response of C57BL/6 male mice to chronic social defeat stress. AB - Chronic stressors promote metabolic disturbances, including obesity and metabolic syndrome. Ghrelin, a peptide that promotes appetite and the accumulation of adipose tissue, is also secreted in response to stressors to protect the brain and peripheral tissues from the effects of these stressors. Here we demonstrate that elevated ghrelin levels produced by chronic exposure to social stress are associated with increased caloric intake and body weight gain in male C57BL mice. In contrast, stressed mice lacking ghrelin receptors (GHSR KO mice) or C57BL mice receiving chronic intracerebroventricular delivery of the ghrelin receptor antagonist [d-Lys(3)]-GHRP-6 show attenuated weight gain and feeding responses under the same social stress paradigm. Interestingly, stressed GHSR KO mice showed depleted sc and intrascapular brown fat depots, whereas stressed young wild-type mice did not. In old wild-type mice, chronic social defeat increased visceral and intrascapular brown fat depots in association with increases in obesity markers like hyperleptinemia and hyperinsulinemia along with increased hypothalamic expression of neuropeptide Y and Agouti related peptide. Importantly, the elevated expression of these peptides persisted least for 2 weeks after cessation of the stressor regimen. In contrast, old GHSR KO mice did not show these alterations after chronic social defeat. These results suggest that ghrelin plays an important role in the metabolic adaptations necessary to meet the energetic demands posed by stressors, but chronic exposure to stress induced ghrelin elevations ultimately could lead to long lasting metabolic dysfunctions. PMID- 23341197 TI - Where polarity meets fusion: role of Par6 in trophoblast differentiation during placental development and preeclampsia. AB - Trophoblast cell fusion is a prerequisite for proper human placental development. Herein we examined the contribution of Par6 (Partitioning defective protein 6), a key regulator of cell polarity, to trophoblast cell fusion in human placental development. During early placentation, Par6 localized to nuclei of cytotrophoblast cells but with advancing gestation Par6 shifted its localization to the cytoplasm and apical brush border of the syncytium. Exposure of primary isolated trophoblasts to 3% O(2) resulted in elevated Par6 expression, maintenance of tight junction marker ZO-1 at cell boundaries, and decreased fusogenic syncytin 1 expression compared with cells cultured at 20% O(2). Treatment of choriocarcinoma BeWo cells with forskolin, a known inducer of fusion, increased syncytin 1 expression but decreased that of Par6 and ZO-1. Par6 overexpression in the presence of forskolin maintained ZO-1 at cell boundaries while decreasing syncytin 1 levels. In contrast, silencing of Par6 disrupted ZO-1 localization at cell boundaries and altered the expression and distribution of acetylated alpha-tubulin. Par6 expression was elevated in preeclamptic placentas relative to normotensive preterm controls and Par6 located to trophoblast cells expressing ZO-1. Together, our data indicate that Par6 negatively regulates trophoblast fusion via its roles on tight junctions and cytoskeleton dynamics and provide novel insight into the contribution of this polarity marker in altered trophoblast cell fusion typical of preeclampsia. PMID- 23341198 TI - [Laparoscopic repair of enterovesical fistula in patient affected by left megaureter]. AB - INTRODUCTION: Enterovesical fistula (EVF) is an abnormal communication between the intestine and the bladder. We present the case of EVF secondary to diverticular disease in a male with congenital megaureter. A laparoscopic repair of the colon vesical fistula was performed with colon resection. MATERIALS AND METHODS: With the patient in the Trendelenburg position -30 degrees degrees on the right side, 5 trocars are positioned trans-peritoneally. The exploration of the abdominal cavity shows the sigmoid diverticular disease adhering tenaciously to the posterior wall of the bladder. The intestinal loops are medialized. The inferior mesenteric vein is isolated, clipped and divided. The mesosigma is isolated and the inferior mesenteric artery is closed 2 cm from its emergence from the aorta with EndoGIATM 45 stapler. The left colon is isolated from its splenic flexure to the mesorectum. The peritoneum between the bladder and sigmoid colon at the site of the tenacious adhesions is incised. The left megaureter is isolated from the diverticular disease and the bladder is opened on the site of the fistula, to permit a wide resection of the fistula. The posterior wall of the bladder is then closed with double running sutures. Section of the rectum with EndoGIATM 45 stapler. Extraction of 20 cm of sigma comprising diverticular disease by a 5 cm suprapubic laparotomy. The sigma is cut and the proximal head of the circular stapler is inserted and closed with a running suture. The left colon is put back in place into the peritoneal cavity. The laparotomy is closed and the surgery is reconverted into laparoscopy. A colorectal end-to-end anastomosis according to Knight Griffen is performed with ILS 29 circular stapler. The anastomosis is tested for leakage with hydropneumatic test: no evidence of spillage. A laminar drainage is placed close to the anastomosis and the incisions are closed. RESULTS: The operative time was 240 minutes. There were no intra- or post-operative complications. The bladder catheter was removed on day 7 after cystography. The patient was discharged asymptomatic on the 8th post operative day. CONCLUSIONS: Laparoscopic treatment of enterovesical fistulas for benign disease is a safe and standardized procedure. It remains a difficult procedure with a conversion rate higher than laparoscopy for uncomplicated diverticulitis or malignancy. The procedure in a single session with intracorporeal bowel anastomosis is the standard. PMID- 23341199 TI - [Renal and ureteral stones in V.A.C.T.E.R.L. association: endourological management]. AB - BACKGROUND: The endourological technique is a safe and effective approach in the treatment of large stones in the pediatric population with congenital malformations. INTRODUCTION: The VACTERL association is a group of congenital malformations that include vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula with atresia, renal defects, and radial upper limb dysplasia. Renal anomalies are found in approximately 90% of patients. MATERIALS AND METHODS: We present a case of a 7-year-old girl with VACTERL association and cloacal malformations, undergoing multiple surgeries with subsequent Mitrofanoff continent appendico-vesicostomy. She presented at our attention for centimetric left ureteral and inferior pyelo-calyceal stones. She underwent flexible ureteroscopy with laser lithotripsy of both stones. A ureteral catheter and a nephrostomy tube have been left at the end of the procedure. RESULTS: The ureteral catheter was removed in the 2nd post-operative day, the tubes were removed after a nephrostogram in the 8th post-operative day. The patient is stone free. No complications were observed in the post-operative time. CONCLUSIONS: Endoscopy is the method of choice for the management of pediatric urolithiasis with complex renal calculi, due to its low incidence of major complications and a high stone-free rate. PMID- 23341200 TI - [Laparoscopic removal of polycystic kidney through retroperitoneal approach: technical notes]. AB - INTRODUCTION: We present our technique of laparoscopic nephrectomy with intact specimen extraction for patient with autosomal dominant polycystic kidney disease (ADPKD). MATERIALS AND METHODS: A 5-port retroperitoneal laparoscopic approach was used to dissect the involved kidney, which was then removed intact through a Gibson modified incision. RESULTS: The operative time was 110 minutes. Blood loss accounted for 50 mL. There were no intra or post-operative complications. The hospital stay was 4 days. CONCLUSIONS: Laparoscopic nephrectomy for ADKD is technically feasible and clinically safe. The advantages of these technique compared to transperitoneal laparoscopy are the quick access to the hilar vessels and the strict extraperitoneal route, which prevent the risk of sepsis. PMID- 23341201 TI - [Management of iatrogenic gynecologic injuries with urologic relevance. Causes and prevention of complications: the gynecologist's opinion]. AB - OBJECTIVE: To detect and prevent urinary tract injuries in gynecological surgery. METHODS: A brief review of the literature about recognition and prevention of ureteral and bladder injuries. RESULTS: It is well known that factors as intra operative bleeding, pelvic adhesions and infections, pelvic masses, endometriosis and obesity can make surgery difficult. For these reasons the study of the urinary tract and the use of ureteral catheters may be helpful when alterations of the urinary tract anatomy is suspected. However the surgeon should always operate under direct vision of the ureters with a judicious use of diathermy and taking care when separating bladder from the uterus where the blunt dissection is blind and dangerous. When there are some doubts about the integrity of ureters, the control with i.v. infusion of indigo-carmine or with ureteral catheters should be performed. The same applies for the bladder: the cystoscopy should be in the armamentarium of gynecological surgeons to control the ureteral efflux and the bladder integrity. To fill the bladder with methylene blue at the end of the surgery is also helpful in revealing, under the pressure, even very small lesions as well as partial thickness of the bladder that can cause a delayed fistula. CONCLUSIONS: Surgeons' training is the most important factor in avoiding and detecting urinary tract injuries. This is important not only for the technique but also in the selection of patients, and then in planning the more appropriate pre-operative study and in recognizing the presence of injuries during surgery. PMID- 23341202 TI - Health and environmental implications of rural female entrepreneurship practices in osun state Nigeria. AB - In rural Nigeria, food processing is mostly engaged in by women and children. Most of these processes are done using outdated technologies that make use of traditional woodstoves. This article presents the health and environmental implications of the rural female entrepreneurs involved in food processing and proffer means of bettering the lot of these women to handle these hazards. A partially structured questionnaire and focus group discussion was used to capture data from respondents. The study revealed that about 73 % of women involved in direct production of garri and palm oil processing could be at risk of early death or disability-adjusted life years from the mentioned diseases. The article concludes that the rural female entrepreneur needs to be better positioned to handle these hazards, for her health, that of her children, as well as for the environment. PMID- 23341203 TI - Biotransformation and improved enzymatic extraction of chlorogenic acid from coffee pulp by filamentous fungi. AB - The highest enzymatic extraction of covalent linked chlorogenic (36.1%) and caffeic (CA) (33%) acids from coffee pulp (CP) was achieved by solid-state fermentation with a mixture of three enzymatic extracts produced by Aspergillus tamarii, Rhizomucor pusillus, and Trametes sp. Enzyme extracts were produced in a practical inexpensive way. Synergistic effects on the extraction yield were observed when more than one enzyme extract was used. In addition, biotransformation of chlorogenic acid (ChA) by Aspergillus niger C23308 was studied. Equimolar transformation of ChA into CA and quinic acids (QA) was observed during the first 36 h in submerged culture. Subsequently, after 36 h, equimolar transformation of CA into protocatechuic acid was observed; this pathway is being reported for the first time for A. niger. QA was used as a carbon source by A. niger C23308. This study presents the potential of using CP to produce enzymes and compounds such as ChA with biological activities. PMID- 23341204 TI - Reassessing the type I dehydroquinate dehydratase catalytic triad: kinetic and structural studies of Glu86 mutants. AB - Dehydroquinate dehydratase (DHQD) catalyzes the third reaction in the biosynthetic shikimate pathway. Type I DHQDs are members of the greater aldolase superfamily, a group of enzymes that contain an active site lysine that forms a Schiff base intermediate. Three residues (Glu86, His143, and Lys170 in the Salmonella enterica DHQD) have previously been proposed to form a triad vital for catalysis. While the roles of Lys170 and His143 are well defined-Lys170 forms the Schiff base with the substrate and His143 shuttles protons in multiple steps in the reaction-the role of Glu86 remains poorly characterized. To probe Glu86's role, Glu86 mutants were generated and subjected to biochemical and structural study. The studies presented here demonstrate that mutant enzymes retain catalytic proficiency, calling into question the previously attributed role of Glu86 in catalysis and suggesting that His143 and Lys170 function as a catalytic dyad. Structures of the Glu86Ala (E86A) mutant in complex with covalently bound reaction intermediate reveal a conformational change of the His143 side chain. This indicates a predominant steric role for Glu86, to maintain the His143 side chain in position consistent with catalysis. The structures also explain why the E86A mutant is optimally active at more acidic conditions than the wild-type enzyme. In addition, a complex with the reaction product reveals a novel, likely nonproductive, binding mode that suggests a mechanism of competitive product inhibition and a potential strategy for the design of therapeutics. PMID- 23341205 TI - Turn-on fluorescence detection of apoptotic cells using a zinc(II)-dipicolylamine functionalized poly(diacetylene) liposome. AB - A liposome-based fluorescence sensing system for apoptotic cells has been developed from stimuli-responsive poly(diacetylene)-liposomes for the first time. The combination of the liposome components, a phosphatidylserine-binding Zn(II) dipicolylamine component and an alcohol-terminated component in the ratio of 2:1, has led to an efficient detection system for apoptotic cells, as demonstrated by confocal fluorescence microscopy and FACS analysis. The liposome shows a color change from blue to reddish purple and emits fluorescence in the turn-on mode upon interaction with phosphatidylserine. The present system thus avoids the washing steps required for "always-on"-type sensing systems. PMID- 23341206 TI - Permeation through phospholipid bilayers, skin-cell penetration, plasma stability, and CD spectra of alpha- and beta-oligoproline derivatives. AB - After a survey of the special role, which the amino acid proline plays in the chemistry of life, the cell-penetrating properties of polycationic proline containing peptides are discussed, and the widely unknown discovery by the Giralt group (J. Am. Chem. Soc. 2002, 124, 8876) is acknowledged, according to which fluorescein-labeled tetradecaproline is slowly taken up by rat kidney cells (NRK 49F). Here, we describe details of our previously mentioned (Chem. Biodiversity 2004, 1, 1111) observation that a hexa-beta(3)-Pro derivative penetrates fibroblast cells, and we present the results of an extensive investigation of oligo-L- and oligo-D-alpha-prolines, as well as of oligo-beta(2)h- and oligo beta(3)h-prolines without and with fluorescence labels (1-8; Fig. 1). Permeation through protein-free phospholipid bilayers is detected with the nanoFAST biochip technology (Figs. 2-4). This methodology is applied for the first time for quantitative determination of translocation rates of cell-penetrating peptides (CPPs) across lipid bilayers. Cell penetration is observed with mouse (3T3) and human foreskin fibroblasts (HFF; Figs. 5 and 6-8, resp.). The stabilities of oligoprolines in heparin-stabilized human plasma increase with decreasing chain lengths (Figs. 9-11). Time- and solvent-dependent CD spectra of most of the oligoprolines (Figs. 13 and 14) show changes that may be interpreted as arising from aggregation, and broadening of the NMR signals with time confirms this assumption. PMID- 23341207 TI - Nucleoterpenes of thymidine and 2'-deoxyinosine: synthons for a biomimetic lipophilization of oligonucleotides. AB - 2'-Deoxyinosine (1) and thymidine (7) were N-alkylated with geranyl and farnesyl moieties. These hydrophobic derivatives, 3a and 3b, and 9a and 9b, respectively, represent the first synthetic biomimetic nucleoterpenes and were subsequently 5' protected and converted into the corresponding 3'-O-phosphoramidites, 5a and 5b and 11a and 11b, respectively. The latter were used to prepare a series of lipophilized oligonucleotide dodecamers, a part of which were additionally labelled with indocarbocyanine fluorescent dyes (Cy3 or Cy5), 18-23. The insertion of the lipooligonucleotides into, as well as duplex formation at artificial lipid bilayers was studied by single-molecule fluorescence spectroscopy and fluorescence microscopy. PMID- 23341208 TI - Simulations in evolution. III. Randomness as a generator of opportunities. AB - In Neo-Darwinism, variation and natural selection are the two evolutionary mechanisms which propel biological evolution. Our previous reports presented a histogram model to simulate the evolution of populations of individuals classified into bins according to an unspecified, quantifiable phenotypic character, and whose number in each bin changed generation after generation under the influence of fitness, while the total population was maintained constant. The histogram model also allowed Shannon entropy (SE) to be monitored continuously as the information content of the total population decreased or increased. Here, a simple Perl (Practical Extraction and Reporting Language) application was developed to carry out these computations, with the critical feature of an added random factor in the percent of individuals whose offspring moved to a vicinal bin. The results of the simulations demonstrate that the random factor mimicking variation increased considerably the range of values covered by Shannon entropy, especially when the percentage of changed offspring was high. This increase in information content is interpreted as facilitated adaptability of the population. PMID- 23341209 TI - Synthesis and evaluation of gambogic acid derivatives as antitumor agents. Part III. AB - Gambogic acid (GA) has been reported as a potent apoptosis inducer. Previously, we have reported chemical modification at C(34) and C(39) of GA, leading to some agents with improved activity. To investigate the further structure-activity relationship (SAR) and preliminary mechanism of GA activity, a series of derivatives with modified prenyl side chains of GA were synthesized and evaluated. Most of the derivatives showed potent inhibitory activities against the proliferation of HepG2 and A549 cell lines. Compound 4 was selected for further mechanistic studies due to its outstanding activity. It was established that 4 induces the apoptosis of HepG2 cells by using Annexin-V/PI double staining and Western blot assay, thus, compound 4 can serve as a promising lead compound for the development of novel apoptosis in anticancer treatment. PMID- 23341210 TI - On the pathways for CO egress from carboxy human cytoglobin. A molecular-dynamics investigation. AB - This work discloses two bona fide gates through which the CO ligand can leave the distal cavity of carboxy human cytoglobin, reaching the solvent. The investigation was based on molecular dynamics, aided by a minimal randomly oriented force applied to the ligand. The shortest pathway progresses toward the main gate, H81-R84, in the open state, with the H81 imidazole moiety turned toward the solvent. A longer pathway develops toward the diametrically opposed W31-W151 gate. In between, CO may be entrapped into binding cavities, either along the path toward the gates, or in a cul-de-sac, from which CO may even be incapable to escape. This behavior contrasts with carboxy myoglobin, where the corresponding H64 gate, when opened, is the sole used by CO to get to the solvent. These observations, which could hold also for other small ligands of biological interest, such as O(2), NO, and NO(3)(-), provide an answer to a neglected aspect of the mysterious six-coordinated globins. PMID- 23341211 TI - Chemical constituents and biological activities of plants from the genus Ligustrum. PMID- 23341212 TI - Chemical variability of Algerian Myrtus communis L. AB - The composition of 55 samples of essential oil isolated from the aerial parts of wild growing Myrtus communis L. harvested in 16 locations from East to West Algeria were investigated by GC (determination of retention indices) and (13) C NMR analyses. The essential oils consisted mainly of monoterpenes, alpha-pinene (27.4-59.2%) and 1,8-cineole (6.1-34.3%) being the major components. They were also characterized by the absence of myrtenyl acetate. The compositions of the 55 oils were submitted to k-means partitioning and principal component analysis, which allowed the distinction of two groups within the oil samples, which could be subdivided into two subgroups each. Groups I (78% of the samples) and II were differentiated on the basis of the contents of alpha-pinene, linalool, and linalyl acetate. Subgroups IA and IB could be distinguished by their contents of alpha-pinene and 1,8-cineole. Subgroups IIA and IIB differed substantially in their contents of 1,8-cineole and limonene. All the samples contained 3,3,5,5,8,8 hexamethyl-7-oxabicyclo[4.3.0]non-1(6)-ene-2,4-dione (up to 4.9%). PMID- 23341213 TI - Effect of initial temperature on water aggregation at a cold surface. AB - Cellular automata models of water at two initial temperatures were created. Each model was exposed to a freezing surface. The formation of fully bonded water cells, f(4), was observed over time, beginning with a model of initially warm water and with initially cool water. The warm water formed more f(4) cells earlier than the initially cool water. A high percentage of f(4) cells is interpreted as the formation of ice. This is a model of the Mpemba effect. A description of the initial states for these two temperatures is offered in explanation of this effect. PMID- 23341214 TI - Variability of the needle essential oils of Juniperus deltoides R.P.ADAMS from different populations in Serbia and Croatia. AB - The essential-oil compositions of one Croatian and three Serbian populations of Juniperus deltoides R.P.ADAMS have been determined by GC/MS analysis. In total, 147 compounds were identified, representing 97.3-98.3% of the oil composition. The oils were dominated by monoterpenes, which are characteristic components for the species of the section Juniperus. Two monoterpenes, alpha-pinene and limonene, were the dominant constituents, with a summed-up average content of 49.45%. Statistical methods were used to determine the diversity of the terpene classes and the common terpenes between the newly described J. deltoides populations from Serbia and Croatia. Only reports on several specimens from this species have been reported so far, and there are no studies that treat population diversity. Cluster analysis of the oil contents of 21 terpenes showed high correlation with the geographical distribution of the populations, separating the Croatian from the Serbian populations. The comparison of the essential-oil compositions obtained in the present study with literature data, showed the separation of J. deltoides and J. oxycedrus ssp. oxycedrus from the western Mediterranean region. PMID- 23341215 TI - Variation in the fatty-acid content in seeds of various black, red, and white currant varieties. AB - Currant seeds, a by-product of juice production, are recognized as a valuable source of oil rich in polyunsaturated fatty acids. We have evaluated 28 currant varieties for their oil content and fatty-acid composition. The oil content in the seeds ranged from 18.2-27.7%, and no statistical difference between varieties of different fruit color were recorded. Furthermore, the estimated oil yields in the field production ranged from 26.4-212.4 kg/ha. The GC and GC/MS chemical profiles of the seed oils extracted from all examined varieties were common for currants. Linoleic acid (LA) was the major component, with contents ranging from 32.7-46.9% of total fatty acids, followed by alpha-linolenic acid (ALA; 2.9-32.0 %), oleic acid (OA; 9.8-19.9%), gamma-linolenic acid (GLA; 3.3-18.5%), palmitic acid (PA; 4.4-8.1%), stearidonic acid (SDA; 2.2-4.7%), and stearic acid (SA; 1.2 2.4%). Quantitative differences in the fatty-acid profiles between varieties of different fruit color were observed. Blackcurrant varieties showed significantly higher contents of LA, GLA, and PA than red and white currant varieties, whereas significantly higher amounts of ALA and OL were detected in the red and white varieties. Cluster analysis based on the chemical oil profiles joined the blackcurrants in one group, while most of the red and white cultivars joined in a second group at the same linkage distance. PMID- 23341217 TI - Moo1 obesity quantitative trait locus in BTBR T+ Itpr3tf/J mice increases food intake. AB - The rising prevalence of obesity is one of the greatest health challenges facing the world today. Discovery of genetic factors affecting obesity risk will provide important insight to its etiology that could suggest new therapeutic approaches. We have previously identified the Modifier of obese 1 (Moo1) quantitative trait locus (QTL) in a cross between leptin-deficient BTBR T(+) Itpr3(tf)/J (BTBR) and C57BL/6J (B6) mice. Understanding the mechanism by which this locus acts will aid in the identification of candidate genes. Here we refined the location of this QTL and sought to determine the mechanism by which Moo1 affects body weight. We found that the effects of Moo1 also alter high fat diet-induced obesity in mice having functional leptin. In detailed metabolic analyses we determined that this locus acts by increasing food intake in BTBR mice, without affecting energy expenditure. The expression levels of the main molecular mediators of food intake in the hypothalamus were not altered, suggesting this locus affects an independent pathway, consistent with its identification in mice lacking functional leptin. Finally, we show that the increased adiposity resulting from Moo1 is sufficient to affect glucose tolerance. These studies show that the Moo1 obesity QTL affects food intake, likely through a novel mechanism, and indicate that modulation of the underlying pathway may not only ameliorate obesity but also its clinical consequences. PMID- 23341218 TI - SLC22A2 is associated with tubular creatinine secretion and bias of estimated GFR in renal transplantation. AB - Genome-wide association studies reported SLC22A2 variants to be associated with serum creatinine. As SLC22A2 encodes the organic cation transporter 2 (OCT2), the association might be due to an effect on tubular creatinine handling. To test this hypothesis we studied the association of SLC22A2 polymorphisms with phenotypes of net tubular creatinine secretion: fractional creatinine excretion (FEcreat) and bias of estimated glomerular filtration rate (eGFR). We also studied the association with end-stage renal disease (ESRD) and graft failure (GF) in renal transplant recipients. SLC22A2 single nucleotide polymorphisms (SNPs), rs3127573 and rs316009, were genotyped in 1,142 ESRD patients receiving renal transplantation and 1,186 kidney donors as controls. GFR was measured with (125)I-iothalamate clearance. Creatinine clearance was also assessed. FEcreat was calculated from the simultaneous clearances of creatinine and (125)I-iothalamate. Donor rs316009 was associated with FEcreat (beta -0.053, P = 0.024) and with estimated [modification of diet in renal disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] but not measured GFR. In line with this, donor rs316009 was associated with bias of the MDRD and CKD-EPI but not the Cockroft-Gault equation. Both SNPs were associated with ESRD: odds ratios [95% CI] 1.39 [1.16-1.67], P = 0.00065, and 1.23 [1.02-1.48], P = 0.042, for rs3127573 and rs316009, respectively. Neither SNP was associated with GF. Thus, SLC22A2 is associated with phenotypes of net tubular creatinine secretion and ESRD. PMID- 23341219 TI - Clonal isolation of an intermediate pluripotent stem cell state. AB - Pluripotent stem cells of different embryonic origin respond to distinct signaling pathways. Embryonic stem cells (ESCs), which are derived from the inner cell mass of preimplantation embryos, are dependent on LIF-Stat3 signaling, while epiblast stem cells (EpiSCs), which are established from postimplantation embryos, require activin-Smad2/3 signaling. Recent studies have revealed heterogeneity of ESCs and the presence of intermediate pluripotent stem cell populations, whose responsiveness to growth factors, gene expression patterns, and associated chromatic signatures are compatible to a state in between ESCs and EpiSCs. However, it remains unknown whether such cell populations represent a stable entity at single-cell level. Here, we describe the identification of clonal stem cells from mouse ESCs with global gene expression profiles representing such a state. These pluripotent stem cells display dual responsiveness to LIF-Stat3 and activin-Smad2/3 at single-cell level and thus named as intermediate epiblast stem cells (IESCs). Furthermore, these cells show accelerated temporal gene expression kinetics during embryoid body differentiation in vitro consistent with a more advanced differentiation stage than that of ESCs. The successful isolation of IESCs supports the notion that traverse from naive ground state toward lineage commitment occurs gradually in which transition milestones can be captured as clonogenic entity. Our finding provides a new model to better understand the multiple pluripotent states. PMID- 23341220 TI - Toxicity of four sulfonamide antibiotics to the freshwater amphipod Hyalella azteca. AB - Sulfonamides are a widely used class of antibiotics; however, there are few toxicological data available with which to conduct environmental risk assessments for these compounds. Therefore, the toxicity of four sulfonamides (sulfaguanidine, sulfathiazole, sulfamerazine, and sulfasalazine) to Hyalella azteca was assessed in chronic (four-week), water-only exposures. Survival was evaluated weekly, and growth was measured at the end of the test. Four-week lethal concentrations associated with 50% mortality (LC50s) for sulfaguanidine, sulfathiazole, and sulfamerazine were 0.90, 1.6, and 3.9 uM, respectively. Sulfaguanidine caused effects on survival more quickly and at lower concentrations than sulfathiazole or sulfamerazine. These differences were more pronounced at week 1 than week 4, when sulfaguanidine LC50s were 8 to 20 times lower and 2 to 4 times lower, respectively. Growth was affected by sulfathiazole but was a less sensitive end point than survival, with an effective concentration associated with 50% reduction in growth (EC50) of 13 uM, whereas sulfaguanidine and sulfamerazine caused negligible effects on growth. Sulfasalazine had no effect on survival or growth at any concentration tested, up to 13 uM. The effects observed in the present study occurred at concentrations exceeding those typically found in environmental waters. However, given that LC50s decreased with exposure duration (except for sulfasalazine), the present study demonstrates the importance of conducting longer-term tests to adequately assess the environmental toxicity of sulfonamides. PMID- 23341221 TI - [Systemic hantavirus-infection in a comatose HIV patient]. AB - SYMPTOMS: A 40 year old, disoriented, HIV- and Hepatitis B positive male patient was admitted with 40.3 degrees C. Clinically he presented a sinustachycardia (160/min) and hypotension (70/60 mmHg). INVESTIGATIONS/DIAGNOSIS: Laboratory analyses showed elevated infection parameters, azotemia, proteinuria and thrombopenia. CD(4+)T-helper cells: 320/ul (32 %), HIV RNA: <40 copies/ml, Hepatitis B DNA: 20800 copies/ml. Hantavirus serology (immunofluorescence antibody assay): 1:2048; serotype Puumala. TREATMENT/COURSE: An early-goal directed therapy and antibiotic treatment with Piperacillin and Tazobactam was initiated. The patient developed a bipulmonal infiltrate and an acute respiratory distress syndrome (ARDS ) requiring tracheal intubation, as well as a triad of fever, renal failure and profound hemorrhagic symptoms. This led to the diagnosis of the Puumala infection. Due to the parallel HIV- and Hepatits B infection an antiretroviral therapy was initiated. CONCLUSION: In summary the Puumala infection bears the potential for a severe multi-organ failure, which is not typical for this usually benign infection. PMID- 23341223 TI - Interaction of cationic manganese porphyrin with G-quadruplex nucleic acids probed by differential labeling of the two faces of the porphyrin. PMID- 23341224 TI - Age-dependent molecular alterations in the autophagy pathway in HIVE patients and in a gp120 tg mouse model: reversal with beclin-1 gene transfer. AB - Aged (>50 years old) human immunodeficiency virus (HIV) patients are the fastest growing segment of the HIV-infected population in the USA and despite antiretroviral therapy, HIV-associated neurocognitive disorder (HAND) prevalence has increased or remained the same among this group. Autophagy is an intracellular clearance pathway for aggregated proteins and aged organelles; dysregulation of autophagy is implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, and HAND. Here, we hypothesized that dysregulated autophagy may contribute to aging-related neuropathology in HIV-infected individuals. To explore this possibility, we surveyed autophagy marker levels in postmortem brain samples from a cohort of well-characterized <50 years old (young) and >50 years old (aged) HIV+ and HIV encephalitis (HIVE) patients. Detailed clinical and neuropathological data showed the young and aged HIVE patients had higher viral load, increased neuroinflammation and elevated neurodegeneration; however, aged HIVE postmortem brain tissues showed the most severe neurodegenerative pathology. Interestingly, young HIVE patients displayed an increase in beclin-1, cathepsin-D and light chain (LC)3, but these autophagy markers were reduced in aged HIVE cases compared to age-matched HIV+ donors. Similar alterations in autophagy markers were observed in aged gp120 transgenic (tg) mice; beclin-1 and LC3 were decreased in aged gp120 tg mice while mTor levels were increased. Lentivirus-mediated beclin-1 gene transfer, that is known to activate autophagy pathways, increased beclin-1, LC3, and microtubule associated protein 2 expression while reducing glial fibrillary acidic protein and Iba1 expression in aged gp120 tg mice. These data indicate differential alterations in the autophagy pathway in young versus aged HIVE patients and that autophagy reactivation may ameliorate the neurodegenerative phenotype in these patients. PMID- 23341225 TI - Chronic inflammatory muscle diseases and risk of coronary artery disease. AB - Despite recent advancements in the treatment of coronary artery disease (CAD), it remains the commonest cause of death in the world. Although traditional risk factors partially account for the development of CAD, other novel risk factors have recently been implicated. Specifically, chronic inflammation has been postulated to play a role in the development and propagation of this disease. The purpose of this review is to examine the available evidence to determine if patients with chronic inflammatory muscle diseases have higher rates of cardiovascular disease. PMID- 23341226 TI - Duty-cycled bipolar/unipolar radiofrequency ablation for symptomatic atrial fibrillation induces significant pulmonary vein narrowing at long-term follow-up. AB - AIMS: A novel duty-cycled bipolar/unipolar ablation catheter pulmonary vein ablation catheter (PVAC) has been developed to achieve pulmonary vein (PV) isolation in patients with atrial fibrillation (AF). Ablation with PVAC was recently found to induce PV narrowing at 3 months follow-up. The long-term effects of this catheter on PV dimensions are however unknown and were evaluated with this study. METHODS AND RESULTS: Patients (n = 62, 71% male, age 60 +/- 7 years) with drug-refractory AF scheduled for a first ablation procedure were evaluated. A multi-slice computed tomography (MSCT) scan was performed before and 1 year after the initial procedure. Pulmonary vein dimensions and left atrial (LA) volume were measured on MSCT. To correct for reverse remodelling of the LA, the ostial area/LA volume ratio before and after PVAC was calculated. As reverse remodelling may depend on procedural outcome, patients were divided in two groups depending on sinus rhythm (SR) maintenance or AF recurrence 1 year after ablation. Baseline characteristics were comparable between the SR group (n = 41) and the AF recurrence group (n = 21). At one year follow-up, ostial area of the PVs (n = 219) was significantly reduced from 236 +/- 7.0 to 173 +/- 7.4 mm(2) (27% narrowing, P < 0.01), independent of ablation outcome. Pulmonary vein narrowing was mild in 37% of PVs (25-50%), 9% was moderate (50-70%), and 3% severe (>70%). Left atrial volumes were found to be significantly reduced after ablation (14 and 5% for the SR group and AF recurrence group, respectively, P < 0.01). After adjustment for LA volume reduction, narrowing of PV ostial area remained significant in these patients (P < 0.01). CONCLUSION: Ablation with PVAC results in a significant decrease in PV dimensions after long-term follow-up. In line with previous literature, PV narrowing was mild and patients did not develop any clinical symptoms. PMID- 23341230 TI - Continued growth in clinical proteomics. PMID- 23341232 TI - Proteomics clinical applications reviews 2013. PMID- 23341233 TI - Affinity-based microarrays for proteomic analysis of cancer tissues. AB - Based on about a decade of technical developments in analysing the human proteome with antibody microarrays and experience in performing such analyses, now there are the means at hand for detailed and simultaneously global investigations of this kind. Many technical aspects have been dealt with of both the microarray format itself - such as overcoming kinetic and mass transport limitations and thus achieving accurate measurements - and ancillary processes - such as extraction procedures that provide good protein solubilisation, produce reproducible yields and preserve the native protein conformation as much as possible. The overall analysis process is robust and reproducible, highly sensitive down to the level of single-molecule detection and permits an analysis of several parameters on many molecules at a time. While the study of body liquids is widely applied, analyses of tissue proteomes are still scarce. However, conditions do exist to perform the latter at a quality level that meets the standards for clinical applications. This review highlights methodological aspects relevant for a biomedically useful analysis of cellular samples and discusses the potential of such studies, in particular, in view of personalised medicine approaches. PMID- 23341234 TI - Breast cancer biomarker measurements and standards. AB - Cancer is a heterogeneous disease characterized by changes in the levels and activities of important cellular proteins, including oncogenes and tumor suppressors. Genetic mutations cause changes in protein activity and protein expression levels that result in the altered metabolism, proliferation, and metastasis seen in cancer cells. The identification of the critical biochemical changes in cancer has led to advances in its detection and treatment. An important example of this is the measurement of human epidermal growth factor receptor 2 (HER2), where increased expression occurs in approximately 20-30% of breast cancer tumors. HER2 is a member of the epidermal growth factor receptor family and is an important biomarker expressed on the cell surface. Measurement of the HER2 levels in tumor cells provides diagnostic, prognostic, and treatment information, because a targeted therapeutic is available. The most common methods to measure HER2 levels are immunohistochemistry and in situ hybridization assays. The accurate and reliable measurements of the specific changes in protein biomarkers for detection and treatment of cancer are important challenges. This review is focused on efforts to improve the quantitation and reliability of cancer biomarkers by using standards and reference materials. PMID- 23341240 TI - Reactive template synthesis of polypyrrole nanotubes for fabricating metal/conducting polymer nanocomposites. AB - Unique nanocomposites of polypyrrole/Au and polypyrrole/Pt hybrid nanotubes are synthesized employing polypyrrole (PPy) nanotubes as an advanced support by solution reduction. The conducting polymer PPy nanotubes are fabricated by using pre-prepared MnO2 nanowires as the reactive templates. MnO2 nanowires induce the 1D polymerization of pyrrole monomers and the simultaneous dissolution of the templates affords the hollow tube-like structure. The loading content of metal nanoparticles in the nanocomposites could be adjusted by simply changing the amount of metal precursors. This work provides an efficient approach to fabricate an important kind of metal/conducting polymer hybrid nanotubes that are potentially useful for electrocatalyst and sensor materials. PMID- 23341241 TI - Accumulation of dietary methylmercury and effects on growth and survival in two estuarine forage fish: Cyprinodon variegatus and Menidia beryllina. AB - Dietary methylmercury (MeHg) uptake by fish in relation to life stage, species, and level of exposure is poorly understood in lower trophic levels, particularly in estuarine species. The authors compared accumulation of dietary MeHg as well as sensitivity (survival and growth) to dietary MeHg exposure in two species of estuarine forage fish, Cyprinodon variegatus and Menidia beryllina. Fish were fed one of five dietary MeHg concentrations (ranging from 0.04 to 14 ug/g dry wt) over a period of 70 d. Growth rate and the level of dietary exposure influenced MeHg tissue concentrations in both species. Mercury in the diet exhibited a strong linear relationship with fish Hg tissue concentrations. Additionally, the authors found that M. beryllina was more sensitive to dietary MeHg exposure than C. variegatus. Both species showed some decreases in growth related to MeHg exposure, although these patterns were not consistent among treatments. Overall, C. variegatus and M. beryllina were found to have a high tolerance for dietary MeHg exposure. If fish occupying low trophic levels are capable of surviving with high Hg body burdens, this tolerance has important implications for Hg exposure of organisms occupying higher trophic levels. PMID- 23341242 TI - The four and a half LIM-domain 2 controls early cardiac cell commitment and expansion via regulating beta-catenin-dependent transcription. AB - The multiphasic regulation of the Wnt/beta-catenin canonical pathway is essential for cardiogenesis in vivo and in vitro. To achieve tight regulation of the Wnt/beta-catenin signaling, tissue- and cell-specific coactivators and repressors need to be recruited. The identification of such factors may help to elucidate mechanisms leading to enhanced cardiac differentiation efficiency in vitro as well as promote regeneration in vivo. Using a yeast-two-hybrid screen, we identified four-and-a-half-LIM-domain 2 (FHL2) as a cardiac-specific beta-catenin interaction partner and activator of Wnt/beta-catenin-dependent transcription. We analyzed the role of this interaction for early cardiogenesis in an in vitro model by making use of embryoid body cultures from mouse embryonic stem cells (ESCs). In this model, stable FHL2 gain-of-function promoted mesodermal cell formation and cell proliferation while arresting cardiac differentiation in an early cardiogenic mesodermal progenitor state. Mechanistically, FHL2 overexpression enhanced nuclear accumulation of beta-catenin and activated Wnt/beta-catenin-dependent transcription leading to sustained upregulation of the early cardiogenic gene Igfbp5. In an alternative P19 cell model, transient FHL2 overexpression led to early activation of Wnt/beta-catenin-dependent transcription, but not sustained high-level of Igfbp5 expression. This resulted in enhanced cardiogenesis. We propose that early Wnt/beta-catenin-dependent transcriptional activation mediated by FHL2 is important for the transition to and expansion of early cardiogenic mesodermal cells. Collectively, our findings offer mechanistic insight into the early cardiogenic code and may be further exploited to enhance cardiac progenitor cell activity in vitro and in vivo. PMID- 23341243 TI - Use of a metallopeptide-based mimic provides evidence for a proton-coupled electron-transfer mechanism for superoxide reduction by nickel-containing superoxide dismutase. AB - Sneaky little SOD! A metallopeptide-based mimic of nickel-containing superoxide dismutase was used to probe the mechanism of superoxide reduction by the metalloenzyme. Kinetic studies suggest a proton-coupled electron-transfer mechanism; large H/D kinetic isotope effects (KIE) are observed. XAS studies suggest the transferred H-atom is in the form of a Ni(II) -S(H)-Cys moiety. PMID- 23341244 TI - Prevention and treatment of urinary catheter-associated infections. AB - Catheter-associated urinary tract infections (CA-UTIs) are the most common nosocomial infection worldwide. Prolonged catheterization is the most important risk factor for CA-UTIs. As is the case with all device-related infections, the biofilm plays a central role in the pathogenesis of CA-UTIs. The diagnosis is often difficult, given the lack of good diagnostic tests. The most effective way to prevent infection is to limit catheter use and discontinue the catheter when no longer needed. Catheter removal or exchange is also useful in management. This review summarizes and analyzes the results of published studies of CA-UTIs and assesses the role of prevention approaches and management strategies. PMID- 23341245 TI - Familiarity influences odor memory stability. AB - It has been suggested that olfactory perception relies on a memory-based pattern matching system. In this experiment, we tested a prediction derived from this approach, namely that representations of unfamiliar odors are less stable than those of familiar odors. Participants provided qualitative descriptions of odors either immediately after smelling them or after a 1- or 3-min delay. Later, participants were given a surprise test in which they were asked to match their earlier descriptions to those same odors. Delay exerted no effect on familiar odors. However, for unfamiliar odors, while their matching performance was equivalent to that for familiar odors when descriptions were made immediately, delay significantly impaired performance. The better capacity to name familiar odors only assisted matching performance at the longest (3-min) delay. These findings suggest that unfamiliar odors have less stable representations than do familiar odors. Pattern-matching theory suggests that this occurs because unfamiliar odors weakly activate many nodes in memory, resulting in less-stable percepts. PMID- 23341246 TI - Femoral neck structure and function in early hominins. AB - All early (Pliocene-Early Pleistocene) hominins exhibit some differences in proximal femoral morphology from modern humans, including a long femoral neck and a low neck-shaft angle. In addition, australopiths (Au. afarensis, Au. africanus, Au. boisei, Paranthropus boisei), but not early Homo, have an "anteroposteriorly compressed" femoral neck and a small femoral head relative to femoral shaft breadth. Superoinferior asymmetry of cortical bone in the femoral neck has been claimed to be human-like in australopiths. In this study, we measured superior and inferior cortical thicknesses at the middle and base of the femoral neck using computed tomography in six Au. africanus and two P. robustus specimens. Cortical asymmetry in the fossils is closer overall to that of modern humans than to apes, although many values are intermediate between humans and apes, or even more ape-like in the midneck. Comparisons of external femoral neck and head dimensions were carried out for a more comprehensive sample of South and East African australopiths (n = 17) and two early Homo specimens. These show that compared with modern humans, femoral neck superoinferior, but not anteroposterior breadth, is larger relative to femoral head breadth in australopiths, but not in early Homo. Both internal and external characteristics of the australopith femoral neck indicate adaptation to relatively increased superoinferior bending loads, compared with both modern humans and early Homo. These observations, and a relatively small femoral head, are consistent with a slightly altered gait pattern in australopiths, involving more lateral deviation of the body center of mass over the stance limb. PMID- 23341247 TI - Biosafety and bioapplication of nanomaterials by designing protein-nanoparticle interactions. AB - The protein-nanoparticle (NP) interface is a current frontier of multiple disciplines, full of challenges and opportunities. The unique behaviors of nanomaterials (NMs) bring many exciting applications, and also raise safety concerns. Beyond bioapplications, various NMs could also enter human bodies from the environment. When entering human bodies, NPs interact with various biomolecules, especially proteins, forming a protein corona. This protein-NP complex is what the biosystems 'see' and 'respond to'. Therefore, understanding how NPs interact with proteins is crucial for both bioapplications and the biosafety of NMs. In this review, the current understanding of protein-NP interactions is summarized, including the theoretical background, experimental results, and computational progresses. Guidelines for improving bioapplication performance and reducing the potential biosafety hazard of NMs by designing the protein-NP interactions are discussed, along with future directions and challenges in this exciting field. PMID- 23341248 TI - Silver nanoparticle toxicity effect on growth and cellular viability of the aquatic plant Lemna gibba. AB - The toxicity effect of silver nanoparticles (AgNPs) on growth and cellular viability was investigated on the aquatic plant Lemna gibba exposed over 7 d to 0, 0.01, 0.1, 1, and 10 mg/L of AgNPs. Growth inhibition was demonstrated by a significant decrease of frond numbers dependent on AgNP concentration. Under these conditions, reduction in plant cellular viability was detected for 0.1, 1, and 10 mg/L of AgNPs within 7 d of AgNPs treatment. This effect was highly correlated with the production of intracellular reactive oxygen species (ROS). A significant increase of intracellular ROS formation was triggered by 1 and 10 mg/L of AgNP exposure. The induced oxidative stress was related to Ag accumulation within L. gibba plant cells and with the increasing concentration of AgNP exposure in the medium. The authors' results clearly suggested that AgNP suspension represented a potential source of toxicity for L. gibba plant cells. Due to the low release capacity of free soluble Ag from AgNP dissolution in the medium, it is most likely that the intracellular uptake of Ag was directly from AgNPs, triggering cellular oxidative stress that may be due to the release of free Ag inside plant cells. Therefore, the present study demonstrated that AgNP accumulation in an aquatic environment may represent a potential source of toxicity and a risk for the viability of duckweeds. PMID- 23341249 TI - Efficient generation of astrocytes from human pluripotent stem cells in defined conditions. AB - Astrocytes can be generated from various tissue sources including human pluripotent stem cells (PSC). In this manuscript, we describe a chemically defined xeno-free medium culture system for rapidly generating astrocytes from neural stem cells derived from PSC. We show that astrocyte development in vitro, mimics normal development in vivo, and also passes through a CD44(+) astrocyte precursor stage. Astrocytes generated by our method display similar gene expression patterns, morphological characteristics and functional properties to primary astrocytes, and they survive and integrate after xenotransplantation. Whole genome expression profiling of astrocyte differentiation was performed at several time points of differentiation, and the results indicate the importance of known regulators and identify potential novel regulators and stage-specific lineage markers. PMID- 23341250 TI - Neonatal screening for critical cardiovascular anomalies using pulse oximetry. AB - INTRODUCTION: Babies with cardiac anomalies are often asymptomatic at birth, and many remain undetected despite routine newborn examination. We retrospectively assessed the effect of routine pulse oximetry in detection of such anomalies from a hospital birth population of 31 946 babies born between 1 April 1999 and 31 March 2009. METHOD: 29 925 babies who were not admitted to the neonatal unit at birth underwent postductal oxygen saturation measurement before discharge. If saturation was below 95% an examination was performed. If this was abnormal or saturation remained low, an echocardiogram was performed. All babies with cardiac anomaly diagnosed before 1-year were identified from the region's fetal abnormality database. RESULTS: Critical anomalies affected 27 infants (1 in 1180); 10 identified prenatally, 2 after echocardiogram was performed because of other anomalies, 2 in preterm infants, 2 when symptomatic before screening, 5 by oximetry screening, 1 when symptomatic in hospital after a normal screen and 5 after discharge home. Serious anomalies affected 50 infants (1 in 640); 8 identified antenatally, 7 because of other anomalies, 3 in the neonatal unit, 5 by pulse oximetry screening, 11 by routine newborn examination, and 16 after discharge home. CONCLUSIONS: Routine pulse oximetry aided detection of 5/27 of critical and 5/50 of serious anomalies in this sample, but did not prevent five babies with critical and 15 with serious anomalies being discharged undiagnosed. Results from screening over 250 000 babies have now been published, but this total includes only 49 babies with transposition, and even smaller numbers of rarer anomalies. PMID- 23341251 TI - Detection of metabolic syndrome in schizophrenia and implications for antipsychotic therapy : is there a role for folate? AB - In general, the presence of metabolic syndrome is associated with significant cardiovascular mortality and represents a growing public health concern in the USA. Patients with schizophrenia have a three times greater risk of death than the general population, with cardiovascular disease being the most common cause of this mortality. Use of atypical antipsychotics (AAPs) to treat schizophrenia contributes significantly to this cardiovascular risk. While several different clinical guidelines currently exist to monitor the metabolic consequences of AAP use, implementation is lacking. Because of under-monitoring of side effects and the lack of alternative treatment choices in schizophrenia, research has focused on identification of various biomarkers and pharmacogenomic targets to focus on the patients at greatest risk of metabolic syndrome, thus aiming to increase the efficacy and minimize the side effects of AAPs. This has led to several different lines of research. This review focuses on summarizing the differing metabolic syndrome criteria, monitoring guidelines for use of AAPs, and the role of folic acid as it relates to metabolic syndrome within the schizophrenia population. It concentrates not only on the pharmacogenomics of folic acid metabolism but also on its epigenetic interaction with the environment. From this work, genetic variation within both the methylenetetrahydrofolate reductase (MTHFR) gene and the catechol-O-methyltransferase (COMT) gene has been associated with an increased risk of metabolic syndrome in schizophrenia patients treated with AAPs. Furthermore, work on the combination of folate pharmacogenetics and epigenetics has uncovered relationships between methylation, schizophrenia disease, treatment type, and metabolic syndrome. Despite several areas of biomarker research into schizophrenia-related metabolic syndrome, translation into the clinical setting is still lacking, and further studies are needed to bridge this gap. In the future, folate supplementation may prove to be an easy and effective clinical tool for prevention and/or treatment of metabolic syndrome associated with AAP treatment, but clearly more research needs to be done in this area. PMID- 23341253 TI - Transferable graphene oxide by stamping nanotechnology: electron-transport layer for efficient bulk-heterojunction solar cells. PMID- 23341252 TI - Latest American and European updates on infantile spasms. AB - Infantile spasms remain a challenging condition to study and treat, and although they form the commonest epilepsy syndrome with onset in infancy, the challenge is broadened by the wide range of potential underlying causes. The field of study remains dynamic, with debates relating to case definitions and organising structures for classification of seizures and epilepsies in general, and a newly proposed genetic and biologic classification specifically for infantile spasms. There have been recent consensus statements, a Delphi process eliciting prioritised quality-of-care indicators, systematic reviews of treatment, and a survey of clinical practice in the USA. There is increasing evidence that longer duration of spasms is associated with poorer neurodevelopmental outcomes. It has taken many years to develop an animal model that reasonably represents infantile spasms, but there are now several animal models, and they are leading to innovative and valuable studies that suggest novel treatments. PMID- 23341254 TI - Neuropeptides trigger oocyte maturation and subsequent spawning in the hydrozoan jellyfish Cytaeis uchidae. AB - Oocyte maturation and subsequent spawning in hydrozoan jellyfish are generally triggered by light-dark cycles. To examine if the initiation of the maturation process after light stimulus is mediated by neurotransmitters, neuropeptides isolated originally from Hydra magnipapillata were applied to sexually mature female medusae of the hydrozoan jellyfish Cytaeis uchidae. Among the Hydra neuropeptides tested, Hym-53 (NPYPGLW-NH2 ), as well as a nonphysiological peptide, CGLWamide (CGLW-NH2 ), were most effective in inducing oocyte maturation and spawning. Hym-355 (FPQSFLPRG-NH2 ) also triggered these events, but the stimulatory effect was weaker. Since Hym-53-OH (NPYPGLW) and Hym-355-OH (FPQSFLPRG) had no effect, amidation at the C-terminus may be critical for the stimulatory activities of the peptides. Exposure to Hym-53 for 2 min was sufficient to trigger of oocyte maturation, and the spawned eggs were able to be fertilized and to develop normally. Transmission electron microscopy confirmed that bundles of axon-like structures that contain dense-core synaptic vesicles and microtubules are present in the ovarian ectodermal epithelium overlying the oocytes. In addition, immunohistological analyses revealed that some of the neurons in the ectodermal epithelium are GLWamide- and PRGamide-positive. These results suggest that a neuropeptide signal transduction pathway is involved in mediating the induction of oocyte maturation and spawning in this jellyfish. PMID- 23341255 TI - Enhancement of extracellular molecule uptake in plasmonic laser perforation. AB - The use of laser induced surface plasmons on metal nanoparticles has proven to be an excellent tool for the delivery of molecules like siRNA and DNA into cells. However, a detailed understanding of the basic mechanisms of molecular uptake and the influence of parameters like biological environment is missing. In this study we analyzed the uptake of fluorescent dextrans with sizes from 10 to 2000 kDa, which resembles a wide range of biologically relevant molecules in size using a 532 nm picosecond laser system and 200 nm gold nanoparticles. Our results show a strong uptake-dependence on cell medium or buffer, but no dominant dependence on osmotic conditions. The relation between pulse energy and number of pulses for a given perforation efficiency revealed that multiphoton ionization of water might contribute to perforation. Moreover, a seven-fold uptake-enhancement could be reached with optimized parameters, providing a very promising basis for further studies and applications. PMID- 23341256 TI - Demographic expansions in South America: enlightening a complex scenario with genetic and linguistic data. AB - Native Americans are characterized by specific and unique patterns of genetic and cultural/linguistic diversities, and this information has been used to understand patterns of geographic dispersion, and the relationship between these peoples. Particularly interesting are the Tupi and Je speaker dispersions. At present, a large number of individuals speak languages of these two stocks; for instance, Tupi-Guarani is one of the official languages in Paraguay, Bolivia, and the Mercosul economic block. Although the Tupi expansion can be compared in importance to the Bantu migration in Africa, little is known about this event relative to others. Equal and even deeper gaps exist concerning the Je-speakers' expansion. This study aims to elucidate some aspects of these successful expansions. To meet this purpose, we analyzed Native American mtDNA complete control region from nine different populations and included HVS-I sequences available in the literature, resulting in a total of 1,176 samples investigated. Evolutionary relationships were explored through median-joining networks and genetic/geographic/linguistic correlations with Mantel tests and spatial autocorrelation analyses. Both Tupi and Je showed general traces of ancient or more recent fission-fusion processes, but a very different pattern of demographic expansion. Tupi populations displayed a classical isolation-by-distance pattern, while Je groups presented an intricate and nonlinear mode of dispersion. We suggest that the collective memory and other cultural processes could be important factors influencing the fission-fusion events, which likely contributed to the genetic structure, evolution, and dispersion of Native American populations. PMID- 23341257 TI - Photosensitizer-incorporated quadruplex DNA-gated nanovechicles for light triggered, targeted dual drug delivery to cancer cells. AB - A novel light-operated vehicle for targeted intracellular drug delivery is constructed using photosensitizer-incorporated G-quadruplex DNA-capped mesoporous silica nanoparticles. Upon light irradiation, the photosensitizer generates ROS, causing the DNA capping to be cleaved and allowing cargo to be released. Importantly, this platform makes it possible to develop a drug-carrier system for the synergistic combination of chemotherapy and PDT for cancer treatment with spatial/temporal control. Furthermore, the introducing of targeting ligands further improves tumor targeting efficiency. The excellent biocompatibility, cell specific intracellular drug delivery, and cellular uptake properties set up the basis for future biomedical application that require in vivo controlled, targeted drug delivery. PMID- 23341258 TI - Toxic effects of environment-friendly antifoulant nonivamide on Phaeodactylum tricornutum. AB - Nonivamide, a synthetic derivate of natural capsaicin, has an effective antifouling activity. However, the poor understanding of the toxicity mechanism limits the application of nonivamide in antifouling paints. The present study investigated the inhibitory effects and toxicity mechanism of nonivamide on Phaeodactylum tricornutum. Under a 1.5 * 10(5) cells/ml of initial algal density (IAD), the effective concentration causing 50% inhibition at 4- d (4 d-EC50) value of nonivamide was 5.1 mg/L. Reactive oxygen species (ROS) level was significantly increased in nonivamide-treated algae. Algal antioxidants, including catalases (CAT), peroxidases (POD), superoxide dismutases (SOD), and glutathione (GSH), were all stimulated by the ROS burst. The excessive ROS substances led to the loss of algal photosynthetic pigments and also damage to the integrity of the lipid membrane. Furthermore, ROS-related genes, including psbA, psbD, psaB, rbcL, nad1, and cob, were found to be suppressed in the chloroplasts and mitochondria of nonivamide-treated algae, and the concentration of cytoplasmic Ca(2+) , an important regulator of chloroplast and mitochondrion, was elevated. The present study demonstrates that nonivamide could cause peroxidative damages to P. tricornutum by inducing ROS overproduction, which may be initiated by the suppression of ROS-related genes in algal chloroplasts and mitochondria. PMID- 23341259 TI - Exploring the relationship between dental wear and status in late medieval subadults from England. AB - Dental wear patterns were recorded on 458 deciduous molar teeth, of 142 subadults from late medieval (AD 1086-1539) England, to explore the relationship between dental wear and burial status of children. A new ordinal method for scoring dental wear stages on the deciduous molar teeth was devised. It was postulated that if a discernible relationship between dental wear stage and burial location could be seen then this could reflect a difference in diet between those receiving higher or lower status burial. The dental wear stages recorded were statistically similar for the dentitions of subadults from different cemeteries, as well as from different burial locations, indicating a comparable diet for the children studied. PMID- 23341260 TI - Sharpening the thermal release of DNA from nanoparticles: towards a sequential release strategy. AB - Unlike the sharp melting behavior of DNA-linked nanoparticle aggregates, the melting of DNA strands from individual gold nanoparticles is broad despite the high surface density of bound DNA. Here, it is demonstrated how sharpened melting can be achieved in colloidal nanoparticle systems using branched DNA-doubler structures hybridized with complementary DNA-doublers bound to the gold nanoparticle. Moreover, sharpened transitions are observed when DNA-doublers are hybridized with linear DNA-modified gold nanoparticles. This result suggests that the DNA density on nanoparticles is intrinsically great enough to form cooperative structures with the DNA-doublers. Finally, by introducing abasic destabilizing groups, the melting temperature of these DNA-doublers decreases without decreasing the sharpness. Consequently, by varying the temperature, two DNA-doublers with different stabilities dissociate sequentially from the gold nanoparticle surface, without overlapping and within a narrow temperature window. Owing to the excellent thermal selectivities exhibited by this system, the implementation of DNA-doublers in sequential photothermal therapies and with other nanomedicine delivery agents that rely on DNA dissociation as the mechanism of selective release is anticipated. PMID- 23341261 TI - The relation between botulinum toxin-A and fracture healing. comment on Hao et al.: short-term muscle atrophy caused by botulinum toxin-A local injection impairs fracture healing in the rat femur. PMID- 23341263 TI - Differentiation-related response to DNA breaks in human mesenchymal stem cells. AB - We have recently shown that the in vitro differentiation of human mesenchymal stem cells (hMSCs) was accompanied by an increased sensitivity toward apoptosis; however, the mechanism responsible for this shift is not known. Here, we show that the repair of DNA double-strand breaks (DSBs) was more rapid in undifferentiated hMSCs than in differentiated osteoblasts by quantification of the disappearance of gamma-H2AX foci in the nuclei after gamma-irradiation induced DNA damage. In addition, there was a marked and prolonged increase in the level of nuclear Ku70 and an increased phosphorylation of DNA-PKcs. This was accompanied by an augmentation in the phosphorylation of ATM in hMSCs post irradiation suggesting the nonhomologous end joining repair mechanism. However, when hMSCs were induced to differentiate along the osteogenic or adipogenic pathways; irradiation of these cells caused an expeditious and robust cell death, which was primarily apoptotic. This was in sharp contrast to undifferentiated hMSCs, which were highly resistant to irradiation and/or temozolomide-induced DSBs. In addition, we observed a 95% recovery from DSB in these cells. Our results suggest that apoptosis and DNA repair are major safeguard mechanisms in the control of hMSCs differentiation after DNA damage. PMID- 23341264 TI - PipelineTM embolization device for the treatment of complex intracranial aneurysms: a NICE Medical Technology Guidance. AB - As part of its Medical Technologies Evaluation Programme, the National Institute of Health and Clinical Excellence (NICE) invited the manufacturer, Covidien, to provide clinical and economic evidence for the evaluation of the PipelineTM embolization device (PED) for the treatment of complex intracranial aneurysms. Cedar; a consortium between Cardiff and Vale University Health Board and Cardiff University, was commissioned to act as an External Assessment Centre (EAC) for NICE to independently critique the manufacturers' submissions. This article gives an overview of the evidence provided, the findings of the EAC and the final guidance published by NICE. The scope issued by NICE considered PED as the intervention in a patient population with complex unruptured intracranial aneurysms (IAs), specifically large/giant, wide-necked and fusiform aneurysms. The comparator treatments identified were stent-assisted coiling, parent vessel occlusion, neurosurgical techniques and conservative management. The manufacturer claimed that PED fulfils a currently unmet clinical need in the treatment of large or giant, wide-necked or fusiform IAs. Thirteen studies were identified by the manufacturer as being relevant to the decision problem, with two of these included for data extraction. The EAC identified 16 studies as relevant, three of which had been published after the manufacturer's search. Data extraction was carried out on these studies as, although many were low level research comprising of case reports and case series, they provided useful, pertinent safety and outcome data. No relevant economic studies of the device were identified; therefore, a new economic model was designed by the manufacturer. The base-case scenario provided recognized the costs of PED to be higher than the costs for endovascular parent vessel occlusion, neurosurgical parent vessel occlusion, neurosurgical clipping and conservative management. However, PED was found to be cost saving compared with stent-assisted coiling, with a saving of L13,110 per patient. Analysis of the clinical data suggested that treatment with PED has high rates of clinical success with high rates of aneurysm occlusion and acceptable adverse events for the patient population. Economic evidence suggested that the costs in the base-case for PED may have been underestimated, meaning that PED would only become cost saving in patients who would otherwise require treatment with 32 coils or more. NICE Medical Technologies Guidance MTG10, issued in May 2012, recommends the adoption of PED in selected patients within the UK National Health Service (NHS). PMID- 23341265 TI - Beetles do it differently: two stereodivergent cyclisation modes in iridoid producing leaf-beetle larvae. AB - Larvae of the Chrysomelina species Phaedon cochleariae, Hydrothassa marginella, Phratora vulgatissima, Gastrophysa viridula, Gastrophysa atrocyanea, Gastrophysa cyanea and Gastrophysa polygoni produce the iridoid chrysomelidial (1) to defend themselves against predators. Feeding experiments with a deuterated precursor ([(2)H(5)]8-hydroxygeraniol 9) and in vitro isotope exchange experiments with defensive secretion in (2)H(2)O revealed differences in the cyclisation of the ultimate precursor 8-oxogeranial (8) to 1, between members of the genus Gastrophysa and all other species. In P. cochleariae, H. marginella and P. vulgatissima 1 is most likely produced by a Rauhut-Currier-type cyclisation via a "transoid dienamine", with loss of a single deuterium atom from C(4) of the precursor. In contrast, members of the genus Gastrophysa cyclise 8 via a "cisoid dienamine" intermediate, with exchange of all three deuterium atoms from the methyl group at C(3). To study whether the different cyclisation modes influence the stereochemistry of 1, the absolute configuration of 1 of the larvae was determined by GC-MS on a chiral column. In accordance with literature (J. Meinwald, T. H. Jones, J. Am. Chem. Soc. 1978, 100, 1883 and N. Shimizu, R. Yakumaru, T. Sakata, S. Shimano, Y. Kuwahara, J. Chem. Ecol. 2012, 38, 29), we found (5S,8S)-chrysomelidial (1) in H. marginella and P. vulgatissima, but P. cochleariae and all investigated members of the genus Gastrophysa synthesise (5R,8R)-chrysomelidial (1). PMID- 23341266 TI - Prospective study on loss of signal on the first side during neuromonitoring of the recurrent laryngeal nerve in total thyroidectomy. AB - BACKGROUND: Staged thyroidectomy has been recommended when loss of the signal from intraoperative nerve monitoring is observed after first-side dissection of the recurrent laryngeal nerve. There is no high-quality evidence supporting this recommendation. In addition, it is not clear whether signal loss predicts postoperative vocal cord paralysis. METHODS: This was a prospective observational study of consecutive adult patients undergoing neuromonitored total thyroidectomy for either malignancy or multinodular goitre. The prevalence of first-side loss of signal was recorded. Surgery was completed, and vagus and laryngeal nerves on the first side were rechecked at the end of the procedure. RESULTS: Two-hundred and ninety patients were included. Loss of signal on the first side was noted in 16 procedures (5.5 per cent). Thyroidectomy was completed and, at retesting, 15 of 16 initially silent nerves recovered an electromyographic signal with a mean(s.d.) amplitude of 132(26) mcV. Mean time to recovery was 20.2 (range 10-35) min. In no patient was the signal lost on the opposite side. Only three of 15 nerves with a recovered signal were associated with transient vocal cord dysfunction. CONCLUSION: After loss of signal of the recurrent laryngeal nerve dissected initially, there was a 90 per cent chance of intraoperative signal recovery. In this setting, judicious bilateral thyroidectomy can be performed without risk of bilateral recurrent nerve paresis. PMID- 23341267 TI - Intra-operative ex vivo photoacoustic nodal staging in a rat model using a clinical superparamagnetic iron oxide nanoparticle dispersion. AB - The ability to accurately detect tumor metastases in lymph nodes is essential for intra-operative staging of various malignancies. Histopathological assessment of nodes has the drawback of a time delay before results are available to the surgeon and a likelihood of missing metastases. Photoacoustic (PA) imaging has been shown to possess the potential to detect melanoma metastases in resected in toto lymph nodes based on intrinsic contrast. To extend application of the method to other malignancies, extrinsic contrast for lymphatic mapping is important. We investigate in a metastatic animal model whether clinically approved superparamagnetic iron oxide (SPIO) nanoparticles, applied for MRI, can help PA imaging for staging in an intra-operative ex vivo setting. Imaging results are compared with 14 Tesla MR images and histology. We observe that irregularities in SPIO distribution in PA images of the nodes and a decrease in contrast correlate with metastatic involvement as seen in MR images and histology. The results show that a PA based imaging technique may be valuable for nodal staging in the field of surgical oncology. PMID- 23341268 TI - Development and application of a new 25,27-bis(L-phenylalaninemethylester-N carbonylmethoxy)-26,28-dihydroxy-para-tert-butylcalix[4]arene stationary phase. AB - A 25,27-bis(L-phenylalaninemethylester-N-carbonylmethoxy)-26,28-dihydroxy- para tert-butylcalix[4]arene-bonded silica gel stationary phase was synthesized, structurally characterized and used for LC. Its separation mechanism was studied and compared with octadecyl-bonded stationary phase, as well as our previously prepared para-tert-butylcalix[4]arene-1,2-crown-4 stationary phase. Meanwhile, the chromatographic behaviors were investigated by using polycyclic aromatic hydrocarbons, monosubstituted benzenes, anilines, phenols, Tanaka tests solutes, fluoroquinolones, and flavonoids as probes. Mechanisms involved in the chromatographic separation included hydrophobic, pi-pi and pi-electron transfer, hydrogen bonding, and inclusion interactions. Moreover, the column was successfully employed for the analysis of the illegal additive of melamine in milk product. PMID- 23341269 TI - Application of molecularly imprinted polymers to determine B1, B2, and B3 fumonisins in cereal products. AB - The aim of this study was to develop an analytical method for qualitative and quantitative determination of the B(1), B(2,) and B(3) fumonisins in cereal products. A LC coupled to an IT-MS was used as the analytical instrument. The AFFINIMIP FumoZON Molecularly Imprinted Polymer SPE cartridges (Polyintell) were used to isolate fumonisins from the analyzed samples and the clean-up step. Statistical parameters evaluated in some validation experiments were as follows: mean recovery 95-106%, precision <17% (expressed as recovery RSD). The developed method was used to determine fumonisins in 49 cereals (42 maize-based and seven wheat-based products). In most cases, concentrations of the studied compounds found in the analyzed samples were low. The highest total concentration of the B(1), B(2), and B(3) fumonisins was found in maize flour samples (range, 26-1102 MUg/kg, mean 498 MUg/kg). PMID- 23341270 TI - Coupling of ultrasound-assisted extraction and expanded bed adsorption for simplified medicinal plant processing and its theoretical model: extraction and enrichment of ginsenosides from Radix Ginseng as a case study. AB - A high-efficient and environmental-friendly method for the preparation of ginsenosides from Radix Ginseng using the method of coupling of ultrasound assisted extraction with expanded bed adsorption is described. Based on the optimal extraction conditions screened by surface response methodology, ginsenosides were extracted and adsorbed, then eluted by the two-step elution protocol. The comparison results between the coupling of ultrasound-assisted extraction with expanded bed adsorption method and conventional method showed that the former was better than the latter in both process efficiency and greenness. The process efficiency and energy efficiency of the coupling of ultrasound-assisted extraction with expanded bed adsorption method rapidly increased by 1.4-fold and 18.5-fold of the conventional method, while the environmental cost and CO(2) emission of the conventional method were 12.9-fold and 17.0-fold of the new method. Furthermore, the theoretical model for the extraction of targets was derived. The results revealed that the theoretical model suitably described the process of preparing ginsenosides by the coupling of ultrasound-assisted extraction with expanded bed adsorption system. PMID- 23341273 TI - Multisensory impairment reported by veterans with and without mild traumatic brain injury history. AB - With the use of Veterans Health Administration and Department of Defense databases of veterans who completed a Department of Veterans Affairs comprehensive traumatic brain injury (TBI) evaluation, the objectives of this study were to (1) identify the co-occurrence of self-reported auditory, visual, and vestibular impairment, referred to as multisensory impairment (MSI), and (2) examine demographic, deployment-related, and mental health characteristics that were potentially predictive of MSI. Our sample included 13,746 veterans with either a history of deployment-related mild TBI (mTBI) (n = 9,998) or no history of TBI (n = 3,748). The percentage of MSI across the sample was 13.9%, but was 17.4% in a subsample with mTBI history that experienced both nonblast and blast injuries. The factors that were significantly predictive of reporting MSI were older age, being female, lower rank, and etiology of injury. Deployment-related mTBI history, posttraumatic stress disorder, and depression were also significantly predictive of reporting MSI, with mTBI history the most robust after adjusting for these conditions. A better comprehension of impairments incurred by deployed servicemembers is needed to fully understand the spectrum of blast and nonblast dysfunction and may allow for more targeted interventions to be developed to address these issues. PMID- 23341274 TI - Sensorintegrative dysfunction underlying vestibular disorders after traumatic brain injury: a review. AB - Vestibular symptoms are persistent and problematic sequelae of blast exposure. Several lines of evidence suggest that these symptoms often stem from injury to the central nervous system. Current methods of assessing the vestibular system have described vestibular deficits that follow traumatic brain injury and differentiate blunt and blast trauma but have not examined the full range of vestibular functions that depend on the cerebral structures above the midbrain. Damage to the central vestibular circuits can lead to deficits in vital processes of spatial perception and navigation, in addition to dizziness and disequilibrium, and may also affect emotional functioning, particularly noradrenergically modulated states of anxiety. Perceptual functions can be assessed to determine the extent of central nervous system involvement in vestibular symptoms and to provide greater confidence when vestibular dysfunction is to be excluded. The ability to detect central vestibular dysfunction will significantly enhance our response to the dizziness and balance symptoms that are a common source of distress for Veterans. PMID- 23341275 TI - Audiological issues and hearing loss among Veterans with mild traumatic brain injury. AB - We examined the prevalence, severity, etiology, and treatment of audiology problems among Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) Veterans with mild traumatic brain injury (TBI). A retrospective chart review was performed of 250 Veterans with mild TBI. Results of a comprehensive second-level mild TBI evaluation and subsequent visits to audiology were evaluated. We found the vast majority (87%) of Veterans reported some level of hearing disturbance and those involved in blast injuries reported a higher incidence of hearing disturbance than those with other injury etiologies. Audiology referrals were given to 75 Veterans and 37 attended. At this visit, Veterans reported tinnitus (75.7%) and hearing loss (59.8%). Nearly half (48.6%) of Veterans were diagnosed with conductive hearing loss, sensorineural hearing loss, or central auditory dysfunction. An additional 24.3% of Veterans had subclinical levels of auditory dysfunction. Our study has highlighted the increased prevalence of hearing loss among OIF/OEF Veterans and, thus, the need for appropriate referrals and treatment. Strategies to address perceived stigma associated with hearing loss may increase attendance at follow-up visits. Additionally, while only a third of audiograms were found to be abnormal, advanced testing resulted in a significant percentage of our population being diagnosed with auditory dysfunction. PMID- 23341276 TI - Performance on tests of central auditory processing by individuals exposed to high-intensity blasts. AB - Thirty-six blast-exposed patients and twenty-nine non-blast-exposed control subjects were tested on a battery of behavioral and electrophysiological tests that have been shown to be sensitive to central auditory processing deficits. Abnormal performance among the blast-exposed patients was assessed with reference to normative values established as the mean performance on each test by the control subjects plus or minus two standard deviations. Blast-exposed patients performed abnormally at rates significantly above that which would occur by chance on three of the behavioral tests of central auditory processing: the Gaps In-Noise, Masking Level Difference, and Staggered Spondaic Words tests. The proportion of blast-exposed patients performing abnormally on a speech-in-noise test (Quick Speech-In-Noise) was also significantly above that expected by chance. These results suggest that, for some patients, blast exposure may lead to difficulties with hearing in complex auditory environments, even when peripheral hearing sensitivity is near normal limits. PMID- 23341277 TI - Pilot study to develop telehealth tinnitus management for persons with and without traumatic brain injury. AB - Tinnitus, or "ringing in the ears," affects 10%-15% of adults; cases can be problematic and require lifelong management. Many people who have experienced traumatic brain injury (TBI) also experience tinnitus. We developed Progressive Tinnitus Management (PTM), which uses education and counseling to help patients learn how to self-manage their reactions to tinnitus. We adapted PTM by delivering the intervention via telephone and by adding cognitive-behavioral therapy. A pilot study was conducted to evaluate the feasibility and potential efficacy of this approach for individuals with and without TBI. Participants with clinically significant tinnitus were recruited into three groups: probable symptomatic mild TBI (n = 15), moderate to severe TBI (n = 9), and no symptomatic TBI (n = 12). Participants received telephone counseling (six sessions over 6 months) by an audiologist and a psychologist. Questionnaires were completed at baseline, 12 weeks, and 24 weeks. All groups showed trends reflecting improvement in self-perceived functional limitations due to tinnitus. A follow-up randomized clinical study is underway. PMID- 23341278 TI - Blast exposure and dual sensory impairment: an evidence review and integrated rehabilitation approach. AB - Combat exposures to blast can result in both peripheral damage to the ears and eyes and central damage to the auditory and visual processing areas in the brain. The functional effects of the latter include visual, auditory, and cognitive processing difficulties that manifest as deficits in attention, memory, and problem solving--symptoms similar to those seen in individuals with visual and auditory processing disorders. Coexisting damage to the auditory and visual system is referred to as dual sensory impairment (DSI). The number of Operation Iraqi Freedom/Operation Enduring Freedom Veterans with DSI is vast; yet currently no established models or guidelines exist for assessment, rehabilitation, or service-delivery practice. In this article, we review the current state of knowledge regarding blast exposure and DSI and outline the many unknowns in this area. Further, we propose a model for clinical assessment and rehabilitation of blast-related DSI that includes development of a coordinated team-based approach to target activity limitations and participation restrictions in order to enhance reintegration, recovery, and quality of life. PMID- 23341279 TI - Implications of blast exposure for central auditory function: a review. AB - Auditory system functions, from peripheral sensitivity to central processing capacities, are all at risk from a blast event. Accurate encoding of auditory patterns in time, frequency, and space are required for a clear understanding of speech and accurate localization of sound sources in environments with background noise, multiple sound sources, and/or reverberation. Further work is needed to refine the battery of clinical tests sensitive to the sorts of central auditory dysfunction observed in individuals with blast exposure. Treatment options include low-gain hearing aids, remote-microphone technology, and auditory training regimens, but clinical evidence does not yet exist for recommending one or more of these options. As this population ages, the natural aging process and other potential brain injuries (such as stroke and blunt trauma) may combine with blast-related brain changes to produce a population for which the current clinical diagnostic and treatment tools may prove inadequate. It is important to maintain an updated understanding of the scope of the issues present in this population and to continue to identify those solutions that can provide measurable improvements in the lives of Veterans who have been exposed to high intensity blasts during the course of their military service. PMID- 23341280 TI - Visual symptomatology and referral patterns for Operation Iraqi Freedom and Operation Enduring Freedom veterans with traumatic brain injury. AB - Advances in protective armor technology and changes in the "patterns of war" have created a population of Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) veterans with traumatic brain injury (TBI) that provide a unique challenge to Department of Veterans Affairs (VA) healthcare practitioners. The purpose of the study was to determine the frequency of symptomatic ocular and visual sequelae of TBI in OIF/OEF veterans at the Portland VA Medical Center, a Polytrauma Support Clinic Team site. A retrospective analysis of 100 OIF/OEF veterans with TBI was conducted to determine the prevalence of ocular and visual complaints. Referral patterns were also investigated. Visual symptoms were reported in approximately 50% of veterans with TBI. Loss of consciousness, but not number of deployments or number of blast exposures, was found to have a statistically significant association with severity of reported visual symptoms. The most commonly reported symptoms included blurred vision (67%), photosensitivity (50%), and accommodative problems (40%). Visual symptoms of OIF/OEF veterans at the Portland VA Medical Center are reported at slightly lower rates than similar studies conducted at the Palo Alto and Edward Hines Jr VA facilities. PMID- 23341281 TI - Vergence in mild traumatic brain injury: a pilot study. AB - Vergence dysfunction in individuals with mild traumatic brain injury (mTBI) may have a negative effect on quality of life, functional abilities, and rehabilitative progress. In this study, we used a range of dynamic and static objective and subjective measures of vergence to assess 21 adult patients with mTBI and nearwork symptoms. The results were compared with 10 control adult subjects. With respect to dynamic parameters, responses in those with mTBI were slowed, variable, and delayed. With respect to static parameters, reduced near point of convergence and restricted near vergence ranges were found in those with mTBI. The present results provide evidence for the substantial adverse effect of mTBI on vergence function. PMID- 23341282 TI - Mild traumatic brain injury and posttraumatic stress disorder: investigation of visual attention in Operation Iraqi Freedom/Operation Enduring Freedom veterans. AB - Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are prevalent dual impairments in veterans returning from the wars in Iraq and Afghanistan. Attention problems are a common self-reported complaint of veterans with mTBI, but relatively few studies have investigated the types and levels of behavioral attentional deficits present in veterans with mTBI and PTSD. The purpose of this study was to compare visual attentional performance between samples of veterans with both mTBI and PTSD (mTBI+PTSD), PTSD only, and a control group. Overall, the attentional responses of the mTBI+PTSD group were slower than those of the PTSD and control groups. The response times were also more variable, suggesting difficulty with attentional vigilance. Additionally, we found evidence of hemispheric asymmetries in attentional performance. Participants with mTBI+PTSD were less efficient in orienting visual attention to stimuli flashed to the left visual field (LVF), suggesting a right hemisphere deficit. Overall, we found that veterans who had sustained an mTBI and had a coexisting PTSD diagnosis displayed longer response times and were less accurate than the PTSD and control groups, especially when cues were presented to the LVF. PMID- 23341283 TI - Relationship of screen-based symptoms for mild traumatic brain injury and mental health problems in Iraq and Afghanistan veterans: Distinct or overlapping symptoms? AB - This study used factor analytic techniques to differentiate distinct from overlapping screen-based symptoms of traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), and depression in Iraq and Afghanistan veterans. These symptoms were derived from screen results of 1,549 veterans undergoing Department of Veterans Affairs postdeployment screening between April 2007 and January 2010. Veterans with positive TBI screens were approximately twice as likely to also screen positive for depression and PTSD (adjusted relative risks = 1.9 and 2.1, respectively). Irritability was a shared symptom between TBI and PTSD, and emotional numbing was a shared symptom between PTSD and depression. Symptoms unique to TBI included dizziness, headaches, memory problems, and light sensitivity. Four separate constructs emerged: TBI, PTSD, depression, and a fourth construct consisting of hypervigilance and sleep problems. These findings illuminate areas of overlap between TBI and common postdeployment mental health problems. Discriminating symptoms of TBI from mental health problems may facilitate diagnosis, triage to specialty care, and targeted symptom management. The emergence of a fourth factor consisting of sleep problems and hypervigilance highlights the need to attend to specific symptoms in the postdeployment screening process. PMID- 23341284 TI - Mild traumatic brain injury and pain in Operation Iraqi Freedom/Operation Enduring Freedom veterans. AB - The purpose of this study was to describe the pain experience in Operation Iraqi Freedom/Operation Enduring Freedom veterans with and without a history of mild traumatic brain injury (mTBI) who present to polytrauma clinics for evaluation and management. We sought to evaluate the relationship between a veteran's history of mTBI and posttraumatic stress (PTS) on axial pain, head/headache pain, and pain interference. We performed retrospective chart reviews of 529 Iraq/Afghanistan veterans referred for evaluation at two Department of Veterans Affairs medical centers. Problems with head/headache, low back, and neck pain were frequently endorsed. Subjective pain interference was reported in 21% of patients without a history of mTBI, 31.9% of patients with a history of mTBI with disorientation only, and 36.1% of patients with a history of mTBI with loss of consciousness. Statistically significant differences existed between the mTBI groups on PTS symptom endorsement, and PTS was predictive of pain experience and interference. A history of mTBI with loss of consciousness predicted head/headache pain, but otherwise did not predict pain or pain interference. PTS was strongly related to the pain experience. Pain is common in polytrauma patients. PTS severity is strongly associated with both pain report and pain interference, with head/headache pain showing a unique association with a history of mTBI. Implications for evaluation and management of pain in this complex population are discussed. PMID- 23341285 TI - Preliminary framework for Familiar Auditory Sensory Training (FAST) provided during coma recovery. AB - Since there remains a need to examine the nature of the neural effect and therapeutic efficacy/effectiveness of sensory stimulation provided to persons in states of seriously impaired consciousness, a passive sensory stimulation intervention, referred to as the Familiar Auditory Sensory Training (FAST) protocol, was developed for examination in an ongoing, double-blind, randomized clinical trial (RCT). The FAST protocol is described in this article according to the preliminary framework, which is a synthesis of knowledge regarding principles of plasticity and capabilities of the human brain to automatically and covertly process sensory input. Feasibility issues considered during the development of the intervention are also described. To enable replication of this intervention, we describe procedures to create the intervention and lessons learned regarding the creation process. The potential effect of the intervention is illustrated using functional brain imaging of nondisabled subjects. This illustration also demonstrates the relevance of the rationale for designing the FAST protocol. To put the intervention within the context of the scientific development process, the article culminates with a description of the study design for the ongoing RCT examining the efficacy of the FAST protocol. PMID- 23341287 TI - Guest editorial: Sensory and communication disorders in traumatic brain injury. PMID- 23341286 TI - Preliminary studies on differential expression of auditory functional genes in the brain after repeated blast exposures. AB - The mechanisms of central auditory processing involved in auditory/vestibular injuries and subsequent tinnitus and hearing loss in Active Duty servicemembers exposed to blast are not currently known. We analyzed the expression of hearing related genes in different regions of the brain 6 h after repeated blast exposures in mice. Preliminary data showed that the expression of the deafness related genes otoferlin and otoancorin was significantly changed in the hippocampus after blast exposures. Differential expression of cadherin and protocadherin genes, which are involved in hearing impairment, was observed in the hippocampus, cerebellum, frontal cortex, and midbrain after repeated blasts. A series of calcium-signaling genes that are known to be involved in auditory signal processing were also found to be significantly altered after repeated blast exposures. The hippocampus and midbrain showed significant increase in the gene expression of hearing loss-related antioxidant enzymes. Histopathology of the auditory cortex showed more significant injury in the inner layer compared to the outer layer. In summary, mice exposed to repeated blasts showed injury to the auditory cortex and significant alterations in multiple genes in the brain known to be involved in age- or noise-induced hearing impairment. PMID- 23341288 TI - Guest editorial: Cognitive-communication rehabilitation for combat-related mild traumatic brain injury. PMID- 23341291 TI - Changing times and people and publishers. PMID- 23341290 TI - Iobitridol: a review of its use as a contrast medium in diagnostic imaging. AB - Iobitridol is a water-soluble, non-ionic, monomeric, low-osmolar, iodine-based contrast medium in which the potential for interaction with membrane proteins in the body has been minimized by stable masking of the molecule's lipophilic tri iodinated benzene ring. It is approved in various countries worldwide for use as an intravascular contrast medium in adults and children. This article reviews the diagnostic efficacy and tolerability of iobitridol use as an intravascular contrast agent in diagnostic imaging, and briefly overviews its pharmacological properties. In randomized controlled trials, the global image quality and diagnostic quality with iobitridol did not differ from those with other low osmolar contrast media (iohexol, iopromide, iopamidol, iomeprol and ioxaglate) or the iso-osmolar contrast medium iodixanol in adults or children undergoing radiographic imaging. Large post-marketing surveillance studies have confirmed that iobitridol produces good or excellent opacification and is an effective contrast agent in the vast majority of patients. Iobitridol was generally well tolerated and had a tolerability profile similar to that of other low-osmolar and iso-osmolar contrast media. Thus, iobitridol is an effective intravascular agent for contrast enhancement in diagnostic imaging. PMID- 23341292 TI - Poisoning: fact or fiction? AB - Analytical toxicology is a complex discipline. Simply detecting a poison in a biological sample does not necessarily mean that the individual from whom the sample was obtained had been poisoned. An analysis can prove exposure and perhaps give an indication of the magnitude of exposure, but the results have to be placed in proper context. Even if sampling was ante-mortem an analysis does not necessarily prove the effects that the drug or poison had on the victim immediately before or at the time of sampling. Tolerance is one big issue, the mechanism of exposure (how the drug got into the body) is another, and of course with post-mortem work there are always additional considerations such as site of sample collection and the possibility of post-mortem change in analyte concentration. There are also questions of quality and reliability, and whether a particular analysis and the interpretation placed upon the result are appropriate in a particular case. PMID- 23341293 TI - An editorial response to the Mangalore air disaster. PMID- 23341289 TI - Estrogen and progesterone together expand murine endometrial epithelial progenitor cells. AB - Synchronous with massive shifts in reproductive hormones, the uterus and its lining the endometrium expand to accommodate a growing fetus during pregnancy. In the absence of an embryo the endometrium, composed of epithelium and stroma, undergoes numerous hormonally regulated cycles of breakdown and regeneration. The hormonally mediated regenerative capacity of the endometrium suggests that signals that govern the growth of endometrial progenitors must be regulated by estrogen and progesterone. Here, we report an antigenic profile for isolation of mouse endometrial epithelial progenitors. These cells are EpCAM(+) CD44(+) ITGA6(hi) Thy1(-) PECAM1(-) PTPRC(-) Ter119(-), comprise a minor subpopulation of total endometrial epithelia and possess a gene expression profile that is unique and different from other cells of the endometrium. The epithelial progenitors of the endometrium could regenerate in vivo, undergo multilineage differentiation and proliferate. We show that the number of endometrial epithelial progenitors is regulated by reproductive hormones. Coadministration of estrogen and progesterone dramatically expanded the endometrial epithelial progenitor cell pool. This effect was not observed when estrogen or progesterone was administered alone. Despite the remarkable sensitivity to hormonal signals, endometrial epithelial progenitors do not express estrogen or progesterone receptors. Therefore, their hormonal regulation must be mediated through paracrine signals resulting from binding of steroid hormones to the progenitor cell niche. Discovery of signaling defects in endometrial epithelial progenitors or their niche can lead to development of better therapies in diseases of the endometrium. PMID- 23341294 TI - The Mangalore aircrash of 22 May 2010: practical problems related to identification of the dead in a populous developing country. AB - It was a sad and emotional moment for the citizens of Mangalore, India when the "Dubai to Mangalore" Air India Express Boeing 737-800 flight IX-812 crashed at the Mangalore International Airport on 22 May 2010, killing 158 people on board. Identification of the victims was difficult as most of the bodies were charred beyond easy recognition. The practical problems faced by the legal authorities in identifying the charred victims in a populous and developing country like India are discussed in this paper. PMID- 23341295 TI - Hotel Holloway/staycation: Holloway prison visit. PMID- 23341296 TI - Negligence claims in UK total hip arthroplasty: a series of 167 consecutive cases. AB - A review of negligence reports, detailing 227 complaints from the practices of two orthopedic surgeons, was undertaken. There were demonstrable differences in the number of complaints over leg-length discrepancy; femoral fracture and cup malposition when cemented versus uncemented implants were compared. Surgeons must appreciate the less forgiving nature of uncemented hip implants and the importance of preoperative planning particularly in the presence of abnormal anatomy. PMID- 23341297 TI - Characteristics of French users of child pornography: description of a cohort subjected to forensic evaluation. AB - Child pornography is a form of sexual exploitation of children. The virtual aspect of this offence appears to be encouraged by the internet. It is important to know the profiles of the people downloading these images. The aim of our study was to identify the characteristics of people who are drawn to child pornography. Our study was based on psychiatric assessments carried out at the request of the law courts. The feeling of loneliness and poor social integration are evoked by a lot of users of child pornography. Generally, they have no criminal record. PMID- 23341298 TI - "The deadly weed" in peace and war. PMID- 23341299 TI - Consensus conferencing in forensic toxicology for the coronial system. PMID- 23341301 TI - Operation mechanism of F(o) F(1)-adenosine triphosphate synthase revealed by its structure and dynamics. AB - F(o) F(1) -Adenosine triphosphate (ATP) synthase, a complex of two rotary motor proteins, reversibly converts the electrochemical potential of protons across the cell membrane into phosphate transfer potential of ATP to provide the energy currency of the cell. The water-soluble motor is F(1) -ATPase, which possesses ATP synthesis/hydrolysis catalytic sites. Isolated F(1) hydrolyses ATP to rotate the rotary shaft against the stator ring. The membrane-embedded motor is F(o) , which is driven by proton flow down the proton electrochemical potential. In the F(o) F(1) complex, the direction of mechanical rotation, the chemical reaction, and the proton transport are determined by the relative amplitudes between the Gibbs free energy of the ATP hydrolysis reaction and the electrochemical potential of protons across the membrane. Therefore, F(o) F(1) -ATP synthase is a highly efficient molecular device in which the chemical, mechanical, and potential energies are tightly and reversibly converted. In this critical review, we summarize our latest knowledge about the operation mechanism of this sophisticated nanomachine, revealed by its structure and dynamics. PMID- 23341303 TI - Application of dispersive liquid-liquid microextraction based on solidification of floating organic drop for simultaneous determination of alachlor and atrazine in aqueous samples. AB - Dispersive liquid-liquid microextraction based on solidification of floating organic drop coupled with HPLC-UV detection as a fast and inexpensive technique was applied to the simultaneous extraction and determination of traces of two common herbicides, alachlor and atrazine, in aqueous samples. The critical experimental parameters, including type of the extraction and disperser solvents as well as their volumes, sample pH, salt addition, and extraction time were investigated and optimized. Under the optimum conditions, the calibration graphs found to be linear in the range of 0.1-200 MUg/L with LOD in the range of 0.02 0.05 MUg/L. The RSDs were in the range of 4.2-5.3% (n = 5). The relative recoveries of well, tap, and river water samples which have been spiked with different levels of herbicides were 94.0-106.0, 99.0-105.0, and 88.5-97.0%, respectively. PMID- 23341302 TI - Anion-conductive membranes with ultralow vanadium permeability and excellent performance in vanadium flow batteries. AB - Anion exchange membranes prepared from quaternized poly(tetramethyl diphenyl ether sulfone) (QAPES) were first investigated in the context of vanadium flow battery (VFB) applications. The membranes showed an impressive suppression effect on vanadium ions. The recorded vanadium permeability was 0.02*10(-7)-0.09*10(-7) cm(2) min(-1), which was two orders of magnitude lower than that of Nafion 115. The self-discharge duration of a VFB single cell with a QAPES membrane is four times longer than that of Nafion 115. The morphological difference in hydrophilic domains between QAPES and Nafion was confirmed by TEM. After soaking the membranes in VO(2)(+) solution, adsorbed vanadium ions can barely be found in QAPES, whereas the hydrophilic domains of Nafion were stained. In the ex situ chemical stability test, QAPES showed a high tolerance to VO(2)(+) and remained intact after immersion in VO(2)(+) solution for over 250 h. The performance of a VFB single cell assembled with QAPES membranes is equal to or even better than that of Nafion 115 and remains stable in a long-term cycle test. These results indicate that QAPES membranes can be an ideal option in the fabrication of high performance VFBs with low electric capacity loss. PMID- 23341304 TI - Trial and error. PMID- 23341305 TI - Aspirin extends life of some patients with colorectal cancer. PMID- 23341306 TI - Cancer care costs expected to double in some states by 2020. PMID- 23341307 TI - Patients with least aggressive breast cancer still face risk of death years later. PMID- 23341309 TI - Case report of modified Box and Blocks test with motion capture to measure prosthetic function. AB - This case study report demonstrates the use of motion analysis with a modification of the Box and Blocks test. The goal was to quantify observed improvements in compensatory movements and simultaneous control in a subject using different prostheses before and after targeted muscle reinnervation (TMR) surgery. This is a single case study with data collection using a body-powered prosthesis pre-TMR surgery and 6 mo postfitting with a TMR myoelectric prosthesis. The Box and Blocks test was modified for cyclical motion within a motion capture laboratory. With the TMR myoelectric prosthesis, the subject was able to simultaneously activate the hand and elbow. Task performance was slower, but there was improved elbow flexion and less trunk compensatory motion than with the body-powered prosthesis. There are several limitations to the case study because there is no direct comparison of myoelectric performance before and after TMR surgery; however, the current report presents a potential method to quantify quality of motion and compensatory movements of prosthetic users. With further study, this test procedure has the potential to be a useful outcome measure for future standardized assessments of upper-limb prosthetic function. PMID- 23341310 TI - Pilot study of Internet-based early intervention for combat-related mental distress. AB - This article evaluates an Internet-based early intervention combining online cognitive-behavioral therapy (CBT) with electronic peer-to-peer support intended to promote mental health and well-being among combat veterans. We conducted a phase 1 clinical trial of 50 Iraq and Afghanistan veterans using a pre and post single-arm design. We evaluated feasibility and changes in mental health symptoms (depression and posttraumatic stress disorder [PTSD]), functional status, and attitudes toward treatment seeking at baseline and weeks 4, 8, and 12. A diverse group of veterans was enrolled (26% ethnic minority, 90% male, 66% with income <$30,000/year, 88% with no prior treatment for depression). Participants completed a mean of 4 of 6 lessons (standard deviation = 2.54). From baseline to week 12, there were significant declines in the Center for Epidemiologic Studies Depression scale score (effect size [ES] = 0.41) and PTSD Checklist-Military version score (ES = 0.53). There were significant improvements in willingness to accept diagnosis (ES = 1.08) and perceived social norms and stigma regarding friends (ES = 1.51). Although lack of a control group is a limitation, the Internet-based program combining CBT-based coping skills training and peer-to peer support demonstrated potential feasibility and evidenced benefit in symptom remediation for depression and PTSD. PMID- 23341308 TI - Provider factors associated with disparities in human papillomavirus vaccination among low-income 9- to 17-year-old girls. AB - BACKGROUND: Many women who develop cervical cancer are eligible for or are participants of Medicaid. Providing human papillomavirus (HPV) vaccination to girls enrolled in Medicaid may reduce cervical cancer disparities in low-income and minority women. This study evaluated provider characteristics associated with HPV vaccination among 9- to 17-year-old female Medicaid enrollees. METHODS: A random sample of 800 providers from the Florida Medicaid Master Provider File was mailed a survey in October 2009 that evaluated demographic and practice characteristics, HPV information and knowledge, barriers to HPV vaccination, vaccine practices, and vaccine recommendation practices. To measure HPV vaccination, Medicaid claims data were used to calculate the proportion of eligible patients who received at least 1 dose of the vaccine from participating providers within the study period. Provider factors associated with vaccination at the bivariate level were evaluated in a multiple linear regression model. RESULTS: The response rate was 68.3% (N = 485). After excluding ineligible respondents, the current analysis included 433 providers. HPV vaccination prevalence ranged from 0% to 61.9% (M = 20.4, standard deviation = 14.5). HPV vaccination rates were higher among providers who were pediatricians, had a private practice, practiced in a single specialty setting, were providers under the Vaccines for Children program, saw primarily non-Hispanic white patients, used 2 or more strategies for vaccine series completion, and did not refer out for HPV vaccination. CONCLUSIONS: Despite financial coverage for Medicaid eligible girls, HPV vaccination rates are low. Study findings can be used to target health services interventions to providers least likely to administer HPV vaccine to female Medicaid enrollees. PMID- 23341311 TI - Rehabilitation of injured U.S. servicemember with traumatic brain injury, stroke, spinal cord injury, and bilateral amputations: a case report. AB - The complexity of injuries that can arise from combat situations, specifically as a result of the Operation Iraqi Freedom/Operation Enduring Freedom conflicts, is challenging. As injured troops leave the war zone early for medical care, they are treated by an interwoven system of care that includes both the Department of Defense and Veterans Health Administration. Physicians across these settings are increasingly faced with patients who have multiple rehabilitation diagnoses as a result of the severity of blast injuries; therefore, the importance of active communication across the system must be highlighted. This case describes the seamless transition of an injured soldier across the continuum of care. PMID- 23341313 TI - Absence of verbal recall or memory for symptom acquisition in fear and trauma exposure: a conceptual case for fear conditioning and learned nonuse in assessment and treatment. AB - Absence of memory or verbal recall for symptom acquisition in fear and trauma exposure, as well as absence of successful coping behavior for life events, is associated with a number of diagnoses, including traumatic brain injury, posttraumatic stress disorder, pain, and anxiety. The difficulty with diagnosis and treatment planning based on the absence of recall, memory, and successful coping behavior is threefold: (1) these assessments do not distinguish between disruption of behavior and lack of capacity, (2) the absence of verbal recall and memory complicates cognitive-based treatment, and (3) a confounding issue is the same absent behavior can be observed at different times and contexts. While memory of the specific details of the initial traumatic event(s) may not be available to verbal report, the existence of time- and context-dependent relationships for the initial as well as subsequent experiences is arguable. The absence of memory or lack of verbal recall does not rule out measurable physiological bodily responses for the initial trauma(s), nor does it help to establish the effects of subsequent experiences for symptom expression. Also, the absence of memory must include the prospect of fear-based learning that does not require or involve the cortex. It is posited that the literatures of fear conditioning and learned nonuse provide complementary illustrations of how the time and context of the initial trauma(s) and subsequent experiences affect behavior, which is not dependent on the effected individual being able to provide a memory-based verbal report. The replicated clinical application demonstrates that, without scientific demonstration, neither neuroanatomy nor verbal report can be assumed sufficient to predict overt behavior or physiologic responses. For example, while commonly assumed to be predictively so, autonomic nervous system innervation is insufficient to define the unique stimulus- and context-dependent physiological responses of an individual. By recording simultaneous physiological responses to the controlled presentation of a context-dependent stimulus, the unique relationships of physiology and overt behaviors for the individual can be demonstrated. Using this process also allows more complex virtual reality or other in vivo stimulus assessments to be incorporated for the development of individually tailored assessments and therapeutic plans. Thus, with or without memory or verbal recall, the use of multiple time- and context-specific simultaneous physiological measures and overt behavior can guide clinical effort as well as serve to objectively assess the ongoing treatment and its outcome. PMID- 23341312 TI - Postdeployment symptom changes and traumatic brain injury and/or posttraumatic stress disorder in men. AB - In Operation Iraqi Freedom and Operation Enduring Freedom, blast-related injuries associated with combat are frequent and can result in traumatic brain injury (TBI) symptoms that may be difficult to distinguish from psychological problems. Using data from the Post-Deployment Health Assessment and Reassessment, we identified 12,046 male U.S. Navy sailors and Marines with reported combat exposure from 2008 to 2009. Symptoms potentially associated with blast-related TBI and posttraumatic stress disorder (PTSD) that were reported immediately after deployment were compared with symptoms present several months later. Our study supports others that have found that subjects with blast-related injuries may experience the development or worsening of symptoms during the months following deployment. Additionally, our study found that those who screened positive for PTSD and TBI formed a unique group, with the presence of TBI exacerbating development of PTSD symptoms at reassessment. Providers should recognize the late development of symptoms, consider the possibility of comorbidity, and be prepared to treat multiple symptoms rather than a specific diagnostic category. PMID- 23341314 TI - Advancement of physical process by mental activation: a prospective controlled study. AB - According to the literature, patients who are significantly impaired by physical mobility limitations can be rehabilitated if the patient's working memory is used to capacity. The conclusion that periodic mental activity improves physical rehabilitation should be evaluated. This is a prospective, controlled, and randomized open study of patients who underwent a total hip arthroplasty (THA). Sixteen patients who played the video game Dr. Kawashima's Brain Training: How Old Is Your Brain? were compared in terms of rehabilitation progress to 16 individuals who did not play. Harris Hip and Merle d'Aubigne scores were evaluated 1 d preoperation and again 12 +/- 1 d postoperation. Preoperation, no significant differences in hip scores between the gaming and control groups were found (median Harris Hip score: 39 vs 33, respectively, p = 0.304; median Merle D'Aubigne score: 12 vs 9, respectively, p = 0.254). Postoperation, there were significant differences between the gaming and control groups (median Harris Hip score: 76.0 vs 56.5, respectively, p = 0.001; median Merle D'Aubigne score: 16.0 vs 13.5, respectively, p = 0.014). Within both groups, the posttest scores significantly improved; however, the increase for the gaming group was greater for both measures. Because the influence of age, sex, and level of education can be excluded, it can be assumed that mental activities can improve physical rehabilitation after THA. PMID- 23341315 TI - Device to monitor sock use in people using prosthetic limbs: technical report. AB - A device using radio frequency identification (RFID) technology was developed to continuously monitor sock use in people who use prosthetic limbs. RFID tags were placed on prosthetic socks worn by subjects with transtibial limb loss, and a high-frequency RFID reader and antenna were placed in a portable unit mounted to the outside of the prosthetic socket. Bench testing showed the device to have a maximum read range between 5.6 cm and 12.7 cm, depending on the RFID tag used. Testing in a laboratory setting on three participants with transtibial amputation showed that the device correctly monitored sock presence during sitting, standing, and walking activity when one or two socks were worn but was less reliable when more socks were used. Accurate detection was sensitive to orientation of the tag relative to the reader, presence of carbon fiber in the prosthetic socket, pistoning of the limb in the socket, and overlap among the tags. Use of ultra-high-frequency RFID may overcome these limitations. With improvements, the technology may prove useful to practitioners prescribing volume accommodation strategies for patients by providing information about sock use between clinical visits, including timing and consistency of daily sock-ply changes. PMID- 23341316 TI - Can vibratory feedback be used to improve postural stability in persons with transtibial limb loss? AB - The use of vibration as a feedback modality to convey motion of the body has been shown to improve measures of postural stability in some groups of patients. Because individuals using transtibial prostheses lack sensation distal to the amputation, vibratory feedback could possibly be used to improve their postural stability. The current investigation provided transtibial prosthesis users (n = 24, mean age 48 yr) with vibratory feedback proportional to the signal received from force transducers located under the prosthetic foot. Postural stability was evaluated by measuring center of pressure (CoP) movement, limits of stability, and rhythmic weight shift while participants stood on a force platform capable of rotations in the pitch plane (toes up/toes down). The results showed that the vibratory feedback increased the mediolateral displacement amplitude of CoP in standing balance and reduced the response time to rapid voluntary movements of the center of gravity. The results suggest that the use of vibratory feedback in an experimental setting leads to improvements in fast open-loop mechanisms of postural control in transtibial prosthesis users. PMID- 23341317 TI - Energy consumption during prosthetic walking and physical fitness in older hip disarticulation amputees. AB - The objective of this study is to investigate energy consumption during prosthetic walking and physical fitness in older hip disarticulation (HD) subjects and to examine the ambulatory outcome in a community setting. The subjects were seven unilateral HD amputees with an average age of 67.7 +/- 3.9 yr. Energy consumption was measured during prosthetic walking at each individual's comfortable walking speed (CWS) by means of a portable telemetric system. An incremental exercise test was performed to evaluate fitness. The average CWS for the subjects was 30.5 +/- 9.6 m/min. The average oxygen consumption rate at each CWS was 18.3 +/- 2.4 mL/kg/min, and the average oxygen cost was 0.639 +/- 0.165 mL/kg/m. The maximum oxygen uptake during exercise as a proportion of predicted maximum oxygen uptake (%VO2max) for the subjects was 57.2 +/- 11.1. Five subjects continued prosthetic walking on return to their communities. Two subjects abandoned prosthetic walking. The %VO2max for the five who continued prosthetic walking after discharge ranged from 55.8 to 72.0. The subjects who abandoned prosthetic walking had lower %VO2max of 43.3 and 44.2. Energy consumption during prosthetic walking at CWS seemed not to be excessive. Older HD amputees in good physical condition were able to successfully walk with a prosthesis in a community setting. A lower level of fitness appears to make community walking prohibitive. PMID- 23341318 TI - Activity monitor accuracy in persons using canes. AB - The StepWatch activity monitor has not been validated on multiple indoor and outdoor surfaces in a population using ambulation aids. The aims of this technical report are to report on strategies to configure the StepWatch activity monitor on subjects using a cane and to report the accuracy of both leg-mounted and cane-mounted StepWatch devices on people ambulating over different surfaces while using a cane. Sixteen subjects aged 67 to 85 yr (mean 75.6) who regularly use a cane for ambulation participated. StepWatch calibration was performed by adjusting sensitivity and cadence. Following calibration optimization, accuracy was tested on both the leg-mounted and cane-mounted devices on different surfaces, including linoleum, sidewalk, grass, ramp, and stairs. The leg-mounted device had an accuracy of 93.4% across all surfaces, while the cane-mounted device had an aggregate accuracy of 84.7% across all surfaces. Accuracy of the StepWatch on the stairs was significantly less accurate (p < 0.001) when comparing surfaces using repeated measures analysis of variance. When monitoring community mobility, placement of a StepWatch on a person and his/her ambulation aid can accurately document both activity and device use. PMID- 23341319 TI - The Unified Parkinson's Disease Rating Scale as a predictor of peak aerobic capacity and ambulatory function. AB - The Unified Parkinson's Disease Rating Scale (UPDRS) is a widely applied index of disease severity. Our objective was to assess the utility of UPDRS for predicting peak aerobic capacity (VO2 peak) and ambulatory function. Participants (n = 70) underwent evaluation for UPDRS (Total and Motor ratings), VO2 peak, 6-minute walk distance (6MW), and 30-foot self-selected walking speed (SSWS). Using regression, we determined the extent to which the Total and Motor UPDRS scores predicted each functional capacity measure after adjusting for age and sex. We also tested whether adding the Hoehn and Yahr scale (H-Y) to the model changed predictive power of the UPDRS. Adjusted for age and sex, both the Total UPDRS and Motor UPDRS subscale failed to predict VO2 peak. The Total UPDRS did weakly predict 6MW and SSWS (both p < 0.05), but the Motor UPDRS subscale did not predict these ambulatory function tests. After adding H-Y to the model, Total UPDRS was no longer an independent predictor of 6MW but remained a predictor of SSWS. We conclude that Total and Motor UPDRS rating scales do not predict VO2 peak, but that a weak relationship exists between Total UPDRS and measures of ambulatory function. PMID- 23341320 TI - Age-related changes in consonant and sentence processing. AB - Speech understanding in noise declines with age, even in older subjects with normal hearing (ONH). These age-related declines could reflect reductions in phonological processing ability or impairments in semantic and lexical processing required for sentence understanding. In experiment 1, we used the California Syllable Test (CaST) to examine age-related changes in the ability of subjects to identify consonants in consonant-vowel-consonant syllables in noise. ONH subjects showed impaired performance in comparison with younger subjects with normal hearing, particularly for hard-to-identify consonants, but otherwise showed similar influences of consonant position, lexicality, and vowel nuclei. Regression analyses showed that CaST performance was independently affected by both age and audiometric thresholds. In experiment 2, we examined sentence reception thresholds (SeRTs) using the Quick Speech in Noise Test and Hearing in Noise Test. No significant age-related changes in SeRTs were observed for either test. SeRT preservation in ONH subjects appeared to reflect the age-resistant ability to identify easy consonants in noise as well as intact top-down contextual and lexical processing. These results establish benchmark values that can be used to evaluate the success of audiological rehabilitation in older subjects with hearing impairment. PMID- 23341321 TI - The perils of copy and paste: plagiarism in scientific publishing. PMID- 23341322 TI - Servicemembers and veterans with disabilities: addressing unique needs through professional rehabilitation counseling. AB - The rehabilitation counseling field has a long history of working with veterans with disabilities. This unique discipline pays special attention to person centered client factors and encourages a long-term team effort. Another important characteristic of the field is that each client is uniquely assessed to identify strengths and not deficits. In doing so, rehabilitation counselors work with clients to set goals based on their strengths, with the ultimate goal of a high quality of life. Advocacy is an essential part of the rehabilitation counselor's job. Counselors are strongly committed to the concepts of holistic counseling, full inclusion in society and in the counseling process, and empowerment. Rehabilitation counselors place an emphasis on the rights of individuals with disabilities to live independent, integrated lives and on collaboration between counselor and client. For persons with disabilities, the journey to full community participation has been a long one that can be described as a work in progress. The movement away from the perspective of care and protection to expectation and involvement of persons with disabilities in planning for their future is reflected in the growing use of person-centered planning strategies PMID- 23341323 TI - Gait Coordination Protocol for recovery of coordinated gait, function, and quality of life following stroke. PMID- 23341324 TI - Triazine-based carbon nitrides for visible-light-driven hydrogen evolution. AB - A new dimension: The doping of amorphous poly(triazine imide) (PTI) through ionothermal copolymerization of dicyandiamide with 4-amino-2,6 dihydroxypyrimidine (4AP) results in triazine-based carbon nitrides with increased photoactivity for water splitting compared to crystalline poly(triazine imide) (PTI/Li(+)Cl(-), see picture) and melon-type carbon nitrides. This family of carbon nitride semiconductors has potential as low-cost, environmentally clean photocatalysts for solar fuel production. PMID- 23341325 TI - Hereditary uveal melanoma: a report of a germline mutation in BAP1. AB - Melanoma of the eye is a rare and distinct subtype of melanoma, which only rarely are familial. However, cases of uveal melanoma (UM) have been found in families with mixed cancer syndromes. Here, we describe a comprehensive search for inherited genetic variation in a family with multiple cases of UM but no aggregation of other cancer diagnoses. The proband is a woman diagnosed with UM at 16 years who within 6 months developed liver metastases. We also identified two older paternal relatives of the proband who had died from UM. We performed exome sequencing of germline DNA from members of the affected family. Exome-wide analysis identified a novel loss-of-function mutation in the BAP1 gene, previously suggested as a tumor suppressor. The mutation segregated with the UM phenotype in this family, and we detected a loss of the wild-type allele in the UM tumor of the proband, strongly supporting a causative association with UM. Screening of BAP1 germline mutations in families predisposed for UM may be used to identify individuals at increased risk of disease. Such individuals may then be enrolled in preventive programs and regular screenings to facilitate early detection and thereby improve prognosis. PMID- 23341326 TI - Mitochondrial protein homeostasis. AB - Mitochondria use 800-1,500 proteins to perform their biological functions in the eukaryotic cells. Distinct transport and sorting mechanisms are responsible for the delivery of proteins to the correct location within mitochondria. Mitochondrial proteins undergo processing events and form functional assemblies. Finally, non-functional proteins are cleared to maintain healthy mitochondria. We provide an overview of the processes collectively contributing to the maintenance of mitochondrial protein homeostasis, which is critical for cell physiology and survival. PMID- 23341327 TI - Simultaneous determination of bisphenol A, tetrabromobisphenol A, and perfluorooctanoic acid in small household electronics appliances of "Prohibition on Certain Hazardous Substances in Consumer Products" instruction using ultra performance liquid chromatography-tandem mass spectrometry with accelerated solvent extraction. AB - Simultaneous determination of bisphenol A, tetrabromobisphenol A, and perfluorooctanoic acid in small household electronics appliances by accelerated solvent extraction-ultra-performance liquid chromatography-tandem mass spectrometry was established. Samples, heated for 5 min, were extracted by toluene/methanol (10:1, v/v) under the pressure 1500 psi at 100 degrees C, and were extracted 3 static cycles with 20 min per cycle. And then 15 mL extractant solvent was used to wash the samples, and at last the sample was purged by nitrogen for 100 s. The partial extractant (10 mL) was concentrated by nitrogen and re-dissolved with 1 mL methanol/water (1:1, v/v). The three compounds were separated by BEH C18 column effectively in 3 min and detected by electrospray ionization mode mass spectrometry. The linear ranges for bisphenol A, perfluorooctanoic acid, and tetrabromobisphenol A were 1-100, 10-1000 ng/mL, and 0.1-10 MUg/mL, respectively. The correlation coefficient was greater than 0.996. The LOD and limit of quantitation for three compounds were 0.1, 10, 1 ng/mL, and 0.5, 50, 5 ng/mL, respectively. And the recoveries were 84-92, 76-82, and 72-74%, respectively, with RSD < 5%. The method was successfully used in determining the real samples. The method and the result were confirmed by liquid chromatography ion trap-time of flight mass spectrometry. PMID- 23341328 TI - Rac1 recruitment to the archipelago structure of the focal adhesion through the fluid membrane as revealed by single-molecule analysis. AB - The focal adhesion (FA) is an integrin-based structure built in/on the plasma membrane (PM), linking the extracellular matrix to the actin stress-fibers, working as cell migration scaffolds. Previously, we proposed the archipelago architecture of the FA, in which FA largely consists of fluid membrane, dotted with small islands accumulating FA proteins: membrane molecules enter the inter island channels in the FA zone rather freely, and the integrins in the FA-protein islands rapidly exchanges with those in the bulk membrane. Here, we examined how Rac1, a small G-protein regulating FA formation, and its activators alphaPIX and betaPIX, are recruited to the FA zones. PIX molecules are recruited from the cytoplasm to the FA zones directly. In contrast, majorities of Rac1 molecules first arrive from the cytoplasm on the general inner PM surface, and then enter the FA zones via lateral diffusion on the PM, which is possible due to rapid Rac1 diffusion even within the FA zones, slowed only by a factor of two to four compared with that outside. The constitutively-active Rac1 mutant exhibited temporary and all-time immobilizations in the FA zone, suggesting that upon PIX induced Rac1 activation at the FA-protein islands, Rac1 tends to be immobilized at the FA-protein islands. PMID- 23341329 TI - Using primary site as a predictor of survival in mantle cell lymphoma. AB - BACKGROUND: Mantle cell lymphoma (MCL) is a rare B cell lymphoma that varies in clinical behavior with some patients experiencing aggressive disease with short survival, whereas others have indolent behavior. We examined the association between primary disease site and survival in MCL patients to identify subgroups with distinct characteristics. METHODS: We analyzed the United States Surveillance, Epidemiology and End Results Program database for MCL cases reported from 2000 through 2009. Kaplan-Meier curves and Cox proportional hazard models were used to estimate the effect of primary site on survival. RESULTS: Among 4477 cases included in our study, 19.6% of patients presented with an extranodal primary site. The most common extranodal primary sites were of the gastrointestinal (GI) tract (7.8%), the head and neck (6.2%), and the hematologic/reticuloendothelial systems (3.6%). Asians/Pacific Islanders were more likely than whites or blacks to have GI tract or head and neck disease (P < .0001 and P = .002, respectively). Advanced disease and B symptoms were less common in those with primary disease of the GI tract or head and neck than in those with primary disease of the lymph nodes (both P < .0001). In a multivariate Cox regression model, patients with primary disease of the GI tract and head and neck had superior survival compared to those with primary disease of the lymph nodes; hazard ratios 0.75 (95% CI = 0.62-0.90) and 0.68 (95% CI = 0.55-0.85), respectively. CONCLUSIONS: Primary site of disease may be an important prognostic factor for patients with MCL. Further studies elucidating a biological basis for these differences are needed. PMID- 23341330 TI - Effectiveness of 17-alpha-hydroxyprogesterone caproate on preterm birth prevention in women with history-indicated cerclage. AB - OBJECTIVE: To determine whether 17-alpha-hydroxyprogesterone caproate (17P) reduces the incidence of preterm birth in women with a history-indicated cerclage. STUDY DESIGN: Retrospective cohort study of women who received a cerclage for a prior preterm birth, analyzed based on exposure to 17P. The primary outcome variable was delivery < 35 weeks. Secondary outcomes were preterm birth < 37, 32, 28, and 24 weeks; interval between cerclage placement and delivery; gestational age at delivery; and infant birth weight. RESULTS: Fourteen women received 17P and 80 did not. Baseline characteristics did not differ between these two groups. Preterm delivery at < 35 weeks did not differ between those who received 17P and those who did not (29% versus 15%, p = 0.46). There were no significant differences between the groups for any other outcome. CONCLUSION: 17P does not appear to have an effect on preterm birth < 35 weeks in women with a history-indicated cerclage. PMID- 23341331 TI - Anisotropic topological surface states on high-index Bi2Se3 films. AB - A high-index topological insulator thin film, Bi2 Se3 (221), is grown on a faceted InP(001) substrate by molecular-beam epitaxy (see model in figure (a)). Angle-resolved photoemission spectroscopy measurement reveals the Dirac cone structure of the surface states on such a surface (figure (b)). The Fermi surface is elliptical (figure (c)), suggesting an anisotropy along different crystallographic directions. Transport studies also reveal a strong anisotropy in Hall conductance. PMID- 23341332 TI - Nonreciprocal chromosomal translocations in renal cancer involve multiple DSBs and NHEJ associated with breakpoint inversion but not necessarily with transcription. AB - Chromosomal translocations and other abnormalities are central to the initiation of cancer in all cell types. Understanding the mechanism is therefore important to evaluate the evolution of cancer from the cancer initiating events to overt disease. Recent work has concentrated on model systems to develop an understanding of the molecular mechanisms of translocations but naturally occurring events are more ideal case studies since biological selection is absent from model systems. In solid tumours, nonreciprocal translocations are most commonly found, and accordingly we have investigated the recurrent nonreciprocal t(3;5) chromosomal translocations in renal carcinoma to better understand the mechanism of these naturally occurring translocations in cancer. Unexpectedly, the junctions of these translocations can be associated with site-specific, intrachromosomal inversion involving at least two double strand breaks (DSB) in cis and rejoining by nonhomologous end joining or micro-homology end joining. However, these translocations are not necessarily associated with transcribed regions questioning accessibility per se in controlling these events. In addition, intrachromosomal deletions also occur. We conclude these naturally occurring, nonreciprocal t(3;5) chromosomal translocations occur after complex and multiple unresolved intrachromosomal DSBs leading to aberrant joining with concurrent interstitial inversion and that clonal selection of cells is the critical element in cancer development emerging from a plethora of DSBs that may not always be pathogenic. PMID- 23341333 TI - Rapid characterization of hydrogen exchange in proteins. AB - Kinetics and thermodynamics of amide hydrogen exchange in proteins can be investigated with two-dimensional (13)CO-(15)N NMR correlation experiments. The spectra are acquired with high resolution and sensitivity. A single type of experiment on one sample serves to characterize hydrogen-deuterium fractionation factors and hydrogen-exchange rates that span three orders of magnitude. PMID- 23341334 TI - Cytochrome c assembly. AB - Cytochromes c are central proteins in energy transduction processes by virtue of their functions in electron transfer in respiration and photosynthesis. They have heme covalently attached to a characteristic CXXCH motif via protein-catalyzed post-translational modification reactions. Several systems with diverse constituent proteins have been identified in different organisms and are required to perform the heme attachment and associated functions. The necessary steps are translocation of the apocytochrome polypeptide to the site of heme attachment, transport and provision of heme to the appropriate compartment, reduction and chaperoning of the apocytochrome, and finally, formation of the thioether bonds between heme and two cysteines in the cytochrome. Here we summarize the established classical models for these processes and present recent progress in our understanding of the individual steps within the different cytochrome c biogenesis systems. PMID- 23341336 TI - Organ evolution in angiosperms driven by correlated divergences of gene sequences and expression patterns. AB - The evolution of a species involves changes in its genome and its transcriptome. Divergence in expression patterns may be more important than divergence in sequences for determining phenotypic changes, particularly among closely related species. We examined the relationships between organ evolution, sequence evolution, and expression evolution in Arabidopsis thaliana, rice (Oryza sativa), and maize (Zea mays). We found correlated divergence of gene sequences and expression patterns, with distinct divergence rates that depend on the organ types in which a gene is expressed. For instance, genes specifically expressed in reproductive organs (i.e., stamen) evolve more quickly than those specifically expressed in vegetative organs (e.g., root). The different rates in organ evolution may be due to different degrees of functional constraint associated with the different physiological functions of plant organs. Additionally, the evolutionary rate of a gene sequence is correlated with the breadth of its expression in terms of the number of tissues, the number of coregulation modules, and the number of species in which the gene is expressed, as well as the number of genes with which it may interact. This linkage supports the hypothesis that constitutively expressed genes may experience higher levels of functional constraint accumulated from multiple tissues than do tissue-specific genes. PMID- 23341335 TI - Orchestration of thiamin biosynthesis and central metabolism by combined action of the thiamin pyrophosphate riboswitch and the circadian clock in Arabidopsis. AB - Riboswitches are natural RNA elements that posttranscriptionally regulate gene expression by binding small molecules and thereby autonomously control intracellular levels of these metabolites. Although riboswitch-based mechanisms have been examined extensively, the integration of their activity with global physiology and metabolism has been largely overlooked. Here, we explored the regulation of thiamin biosynthesis and the consequences of thiamin pyrophosphate riboswitch deficiency on metabolism in Arabidopsis thaliana. Our results show that thiamin biosynthesis is largely regulated by the circadian clock via the activity of the THIAMIN C SYNTHASE (THIC) promoter, while the riboswitch located at the 3' untranslated region of this gene controls overall thiamin biosynthesis. Surprisingly, the results also indicate that the rate of thiamin biosynthesis directs the activity of thiamin-requiring enzymes and consecutively determines the rate of carbohydrate oxidation via the tricarboxylic acid cycle and pentose phosphate pathway. Our model suggests that in Arabidopsis, the THIC promoter and the thiamin-pyrophosphate riboswitch act simultaneously to tightly regulate thiamin biosynthesis in a circadian manner and consequently sense and control vital points of core cellular metabolism. PMID- 23341338 TI - Can filament treadmilling alone account for the F-actin turnover in lamellipodia? AB - Actin forms a polarized filament that grows at the barbed end and shrinks at the pointed end. This phenomenon known as "treadmilling" is believed to govern actin filament turnover. However, in the cell, whether actin turnover proceeds by treadmilling or by other reactions, including filament severing, is a debatable issue. Our previous fluorescence single-molecule speckle (SiMS) analysis has yielded data about the lifetime distribution of F-actin, the uncapping kinetics of both the barbed and pointed ends of the filaments and the elongation rate of the barbed end in lamellipodia. Given these parameters, we estimated the rate of disassembly of the pointed end required to achieve the observed fast actin turnover under the assumption of exclusive filament treadmilling. We derived a method for calculating the lifetime of an individual F-actin subunit at a given position in the Arp2/3 complex-nucleated filament. Extension of this derivation revealed that in the absence of disassembly in the other portions of the filaments, at least 100-fold acceleration of the in vitro pointed end disassembly rate is required to achieve observed F-actin lifetime distribution in lamellipodia. It is, therefore, unlikely that treadmilling solely accounts for the actin filament turnover in vivo. Accumulating evidence obtained by SiMS analysis implies a non-treadmilling actin turnover mechanism in which a substantial amount of F-actin might disassemble near the barbed end of the filament. PMID- 23341339 TI - Simultaneous determination of two-component isotherm parameters and lumped mass transfer coefficients in RPLC with the 0-1 model-inverse method. AB - The 0-1 model-inverse method of nonequilibrium nonlinear chromatography was developed to simultaneously determine the isotherm parameters and the lumped mass transfer coefficients of the two-component systems in RPLC. By comparing the simulated elution curves with experimental curves with regard to profiles and areas, the suitable isotherm parameters and the lumped mass transfer coefficients were obtained with the 0-1 model-inverse method. With a solute cell unit width of 1*10(-3) cm, the average errors of the peak areas were 0.178% for one component and -0.40% for two components, and the numerical diffusions of the 0-1 model for the contribution to band broadening may be negligible. In addition, the results showed that the lumped mass transfer coefficients decrease as the solute concentration increases. The 0-1 model-inverse method has not only the advantages of high calculation speed (less than 10 min for one-component systems or approximately 3 h for two-component systems using an ordinary computer) and high accuracy in simultaneously obtaining thermodynamic parameters and kinetic parameters of two-component systems, but this method also possesses the potential to optimally design and control the time-variant preparative chromatographic system due to the thermodynamic state recursion and the Lagrangian-Eulerian presentation of the 0-1 model. PMID- 23341337 TI - Endodermal ABA signaling promotes lateral root quiescence during salt stress in Arabidopsis seedlings. AB - The endodermal tissue layer is found in the roots of vascular plants and functions as a semipermeable barrier, regulating the transport of solutes from the soil into the vascular stream. As a gateway for solutes, the endodermis may also serve as an important site for sensing and responding to useful or toxic substances in the environment. Here, we show that high salinity, an environmental stress widely impacting agricultural land, regulates growth of the seedling root system through a signaling network operating primarily in the endodermis. We report that salt stress induces an extended quiescent phase in postemergence lateral roots (LRs) whereby the rate of growth is suppressed for several days before recovery begins. Quiescence is correlated with sustained abscisic acid (ABA) response in LRs and is dependent upon genes necessary for ABA biosynthesis, signaling, and transcriptional regulation. We use a tissue-specific strategy to identify the key cell layers where ABA signaling acts to regulate growth. In the endodermis, misexpression of the ABA insensitive1-1 mutant protein, which dominantly inhibits ABA signaling, leads to a substantial recovery in LR growth under salt stress conditions. Gibberellic acid signaling, which antagonizes the ABA pathway, also acts primarily in the endodermis, and we define the crosstalk between these two hormones. Our results identify the endodermis as a gateway with an ABA-dependent guard, which prevents root growth into saline environments. PMID- 23341340 TI - Binge ethanol intoxication heightens subsequent ethanol intake in adolescent, but not adult, rats. AB - A question still to be answered is whether ethanol initiation has a greater effect on ethanol consumption if it occurs during adolescence than in adulthood. This study assessed the effect of ethanol initiation during adolescence or adulthood on voluntary ethanol consumption when animals were still within the same age range. Adolescent or adult rats were given 5, 2, or 0 ethanol exposures. The animals were tested for ethanol consumption through two-bottle choice tests, before undergoing a 1-week deprivation. A two-bottle assessment was conducted after the deprivation. Adolescents, but not adults, given two ethanol administrations during initiation exhibited significantly higher ethanol intake during the pre-deprivation period. These adolescents also exhibited a threefold increase in ethanol intake after 7 days of drug withdrawal, when compared with controls. These findings suggest that very brief experience with binge ethanol intoxication in adolescence, but not in adulthood, impacts later predisposition to drink. PMID- 23341341 TI - Male breast cancer according to tumor subtype and race: a population-based study. AB - BACKGROUND: Breast cancer occurs rarely in men. To the authors' knowledge, no population-based estimates of the incidence of human epidermal growth factor receptor 2 (HER2)-positive breast cancer or of the distribution of breast cancer subtypes among male breast cancer patients have been published to date. Therefore, the objective of the current study was to explore breast tumor subtype distribution by race/ethnicity among men in the large, ethnically diverse population of California. METHODS: This study included men who were diagnosed with invasive breast cancer between 2005 and 2009 with known estrogen receptor (ER) and progesterone receptor (PR) (together, hormone receptor [HR]) status and HER2 status reported to the California Cancer Registry. Among the men with HR positive tumors, survival probabilities between groups were compared using log rank tests. RESULTS: Six hundred six patients were included. The median age at diagnosis was 68 years. Four hundred ninety-four men (81.5%) had HR-positive tumors (defined as ER-positive and/or PR-positive and HER2-negative). Ninety men (14.9%) had HER2-positive tumors, and 22 (3.6%) had triple receptor-negative (TN) tumors. Among the patients with HR-positive tumors, non-Hispanic black men and Hispanic men were more likely to have PR-negative tumors than non-Hispanic white men. No statistically significant differences in survival were observed according to tumor subtype (P = .08). Differences in survival according to race/ethnicity were observed among all patients (P = .087) and among those with HR-positive tumors (P = .0170), and non-Hispanic black men had poorer outcomes. CONCLUSIONS: In this large, representative cohort of men with breast cancer, the distribution of tumor subtypes was different from that reported for women and varied by patient race/ethnicity. Non-Hispanic black men were more likely to have TN tumors and ER-positive/PR-negative tumors than white men. PMID- 23341342 TI - A robust route to enzymatically functional, hierarchically self-assembled peptide frameworks. AB - The addition of enzyme biofunctionality to self-assembling peptide nanofibers is challenging since such additions can inhibit functionality or self-assembly. We introduce a method for peptide nanofiber enzyme functionalization, demonstrated by the attachment of a polymerization synthase to peptide nanofibers. The enzyme generates a biocompatible, biodegradable biopolyester coat on the fibers with applicablity in medical engineering. This approach provides a template for generation of functional bionanomaterials. PMID- 23341343 TI - [Differential diagnosis of abnormal liver function tests]. PMID- 23341344 TI - The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL. AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and heterogeneous disease. The diagnosis is predominantly based on immunophenotyping. In addition to known cytogenetic abnormalities molecular mutations were recently identified. Here, 90 adult T-ALL cases were investigated for mutations in NOTCH1, FBXW7, PHF6, CDKN2A, DNMT3A, FLT3, PTEN, and RUNX1 using 454 next-generation amplicon sequencing and melting curve analyses. These data were further complemented by FISH, chromosome banding, array CGH, and CDKN2B promoter methylation analyses. NOTCH1 was the most frequently mutated gene with a 71.1% frequency followed by FBXW7 (18.9%), PHF6 (39.5%), DNMT3A (17.8%), RUNX1 (15.5%), PTEN (10.0%), CDKN2A (4.4%), FLT3-ITD (2.2%), and FLT3-TKD (1.1%). In total, 84/90 (93.3%) cases harbored at least one mutation. Combining these data with CDKN2A/B deletions and CDKN2B methylation status, we detected minimum one aberration in 89/90 (98.9%) patients. Survival analyses revealed the subtype as defined by the immunophenotype as the strongest independent prognostic factor. When restricting the survival analysis to the early T-ALL subtype, a strong association of RUNX1 (P = 0.027) and DNMT3A (P = 0.005) mutations with shorter overall survival was observed. In conclusion, RUNX1 and DNMT3A are frequently mutated in T-ALL and are associated with poor prognosis in early T-ALL. PMID- 23341345 TI - Self-ordering electron donor-acceptor nanohybrids based on single-walled carbon nanotubes across different scales. PMID- 23341346 TI - Mitochondrial involvement in neurodegenerative diseases. AB - The classical bioenergetical view of the involvement of mitochondria in neurogeneration is based on the fact that mitochondria are the central players of ATP synthesis in neurons and their failure leads to neuronal dysfunction and eventually to cell death. Mutations in at least 39 genes in inherited neurodegenerative disorders seem to alter directly or indirectly mitochondrial function. Most of these mutations do not directly affect oxidative phosphorylation, but act through disturbed mitochondrial dynamics and quality control. This, however, does not invalidate the bioenergetic hypothesis. Neurodegeneration is not necessarily associated with a gross failure of ATP production, but might rather be a consequence of local insufficiencies of ATP supply in critical compartments of neurons, like the presynaptic terminal. We hypothesize that slow disease progression, at least in a subgroup of neurodegenerative diseases, can be explained by the parallel action of subcellular ATP insufficiency and clonal expansion of somatic mitochondrial DNA mutations, and particularly deletions. PMID- 23341347 TI - Fast microwave-assisted extraction of rotenone for its quantification in seeds of yam bean (Pachyrhizus sp.). AB - The aim of this study was to find if fast microwave-assisted extraction could be an alternative to the conventional Soxhlet extraction for the quantification of rotenone in yam bean seeds by SPE and HPLC-UV. For this purpose, an experimental design was used to determine the optimal conditions of the microwave extraction. Then the values of the quantification on three accessions from two different species of yam bean seeds were compared using the two different kinds of extraction. A microwave extraction of 11 min at 55 degrees C using methanol/dichloromethane (50:50) allowed rotenone extraction either equivalently or more efficiently than the 8-h-Soxhlet extraction method and was less sensitive to moisture content. The selectivity, precision, trueness, accuracy, and limit of quantification of the method with microwave extraction were also demonstrated. PMID- 23341349 TI - Performance of ProEx C and PreTect HPV-Proofer E6/E7 mRNA tests in comparison with the hybrid capture 2 HPV DNA test for triaging ASCUS and LSIL cytology. AB - The clinical usefulness of the ProEx C (Becton Dickinson) and PreTect HPV-Proofer E6/E7 mRNA tests (Proofer; Norchip) for the triage of ASCUS and LSIL cytology was determined in comparison with the Hybrid Capture 2 HPV DNA test (HC2; Qiagen). The study population consisted of women with a history of abnormal cytology referred to colposcopy. Histology-confirmed CIN 2+ served as the disease endpoint. The study was based on 1,360 women (mean age 30.7 years), of whom 380 had CIN 2+. Among 315 with ASCUS (CIN 2+, n = 67), the sensitivities of ProEx C, Proofer, and HC2 to detect CIN 2+ were, 71.6, 71.6, and 95.5%, respectively, with a corresponding specificity of 74.6, 74.2, and 35.1%. Among 363 with LSIL (CIN 2+, n = 108), the sensitivities of ProEx C, Proofer, and HC2 were, 67.6, 74.1, and 96.3%, respectively, with a corresponding specificity of 60, 68.2, and 18.4%. Among 225 HC2-positive ASCUS (CIN 2+, n = 64), 105 tested positive by ProEx C, reducing colposcopy referral by 53.3% and detecting 71.9% of CIN 2+; Proofer was positive in 112/225, reducing colposcopy referral by 50.2% and detecting 75.0% of CIN 2+. Among 312 HC2-positive LSIL (CIN 2+, n = 104), 160 tested positive by ProEx C, reducing coloposcopy referral by 48.7% and detecting 66.3% of CIN 2+; Proofer was positive in 159/312, reducing colposcopy referral by 49.0% and detecting 75.0% of CIN 2+. In conclusion, both ProEx C and Proofer have a similar performance profile with a significantly higher specificity but lower sensitivity than HC2 for the detection of CIN 2+. Consequently, although they can reduce colposcopy referral, they will miss a proportion of CIN 2+ cases. This is a major limitation and should be taken into account if these tests are considered for ASCUS or LSIL triage. PMID- 23341350 TI - Tactile-feedback stabilized molecular junctions for the measurement of molecular conductance. AB - Handling the (AFM) tip: The duration of stable molecular junctions was prolonged using a tactile feedback method in which the operator can sense the force of the AFM tip on the sample surface. The movement of the tip is adjusted accordingly, maintaining a more consistent current (i) and voltage (V), instead of having the tip move at a constant preset speed, as in the conventional setup. PMID- 23341351 TI - Targeting of the signal transducer Smo links microRNA-326 to the oncogenic Hedgehog pathway in CD34+ CML stem/progenitor cells. AB - Aberrant expression and function of microRNAs (miRNAs) in leukemia have added a new layer of complexity to the understanding of development and progression of the disease state. However, their targeting of specific signaling pathways responsible for the maintenance and survival properties of leukemic stem cell (LSC) still remains to be further clarified. Hedgehog (Hh) signaling, a highly conserved developmental pathway, has been proven as a functional pathway for LSCs, and loss of this pathway impairs the development of BCR-ABL-induced chronic myeloid leukemia (CML) and depletes CML stem cells. Here, we revealed that upregulation of the Hh smoothened (Smo) signal transducer was associated with reduced expression of miR-326 in the CD34(+) cells from a group of patients with CML at diagnosis. Additionally, overexpression of miR-326 led to downregulation of Smo, resulted in decreased cell proliferation and elevated rate of apoptosis in CML CD34(+) cells. Interestingly, restoration of Smo expression levels reversed the effect of miR-326 and rescued K562 cells from the antiproliferative effects of this miRNA. Thus, Smo appears to be an essential target of miR-326 during the pathogenesis of CML. These findings lead us to suggest that downregulation of miR-326 may be a possible mechanism for unrestricted activation of Smo signal transducer of the oncogenic Hh pathway in CML; therefore, the restoration of miR-326 expression could be of benefit in eradicating CD34(+) CML stem/progenitor cells that represent a potential source of relapse in patients suffering CML. PMID- 23341353 TI - Individual decision making in relation to participation in cardiovascular screening: a study of revealed and stated preferences. AB - AIMS: The (cost-)effectiveness of a screening programme may be strongly influenced by the participation rate. The objective of this study was to compare participants' and non-participants' motives for the attendance decision as well as their overall preferences for participation in cardiovascular disease screening. METHODS: This study sampled 1053 participants and 1006 non participants from a screening trial and randomly allocated the participants to receive different levels of additional information about the screening programme. An ad hoc survey questionnaire about doubt and arguments in relation to the participation decision was given to participants and non-participants along with a contingent valuation task. RESULTS: Among participants, 5% had doubt about participation and the most frequent argument was that they did not want the test result. Among non-participants, 40% would reconsider their non-participation decision after having received additional information while the remainder 60% stood by their decision and provided explicit arguments for it. After having received additional information the participants still valued the programme significantly higher than non-participants, but the difference was relatively small. CONCLUSIONS: Participants and non-participants in cardiovascular screening programmes seem to have different strengths of preferences, which signals that their behavioural choice is founded in rational thinking. Furthermore, it appears that additional information and a second reflection about the participation decision may affect a substantial proportion of non-participants to reverse their decision, a finding that should receive policy interest. PMID- 23341348 TI - Insulin-like growth factor pathway genes and blood concentrations, dietary protein and risk of prostate cancer in the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). AB - It has been hypothesized that a high intake of dairy protein may increase prostate cancer risk by increasing the production of insulin-like growth factor 1 (IGF-1). Several single nucleotide polymorphisms (SNPs) have been weakly associated with circulating concentrations of IGF-1 and IGF binding protein 3 (IGFBP-3), but none of these SNPs was associated with risk of prostate cancer. We examined whether an association between 16 SNPs associated with circulating IGF-1 or IGFBP-3 concentrations and prostate cancer exists within subgroups defined by dietary protein intake in 5,253 cases and 4,963 controls of European ancestry within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). The BPC3 includes nested case-control studies within large North-American and European cohorts. Per-allele odds ratios for prostate cancer for the SNPs were compared across tertiles of protein intake, which was expressed as the percentage of energy derived from total, animal, dairy or plant protein sources, using conditional logistic regression models. Total, animal, dairy and plant protein intakes were significantly positively associated with blood IGF-1 (p < 0.01), but not with IGFBP-3 concentrations (p > 0.10) or with risk of prostate cancer (p > 0.20). After adjusting for multiple testing, the SNP-prostate cancer associations did not differ by intakes of protein, although two interactions by intake of plant protein were of marginal statistical significance [SSTR5 (somatostatin receptor 5)-rs197056 (uncorrected p for interaction, 0.001); SSTR5-rs197057 (uncorrected p for interaction, 0.002)]. We found no strong evidence that the associations between 16 IGF pathway SNPs and prostate cancer differed by intakes of dietary protein. PMID- 23341354 TI - Social differences in self-reported health among men and women in 31 countries in Europe. AB - AIMS: The aim of this study was to examine educational differences in self reported health (SRH) among men and women in Europe. METHODS: The study was based on a sample of 15,362 men and 20,272 women from the nationally representative European Quality of Life Survey conducted in 31 European countries in 2007. SRH was measured using a single item and dichotomised into good (very good, good) and poor (fair, bad, very bad) health. Education was classified into seven categories according to the International Standard Classification of Education. Relative index of inequality, multilevel logistic regression analyses, and interaction tests were conducted. RESULTS: Educational differences in SRH were found in almost all countries. After adjustment for covariates, no differences were found in Austria, Denmark, or the Netherlands. The highest differences were observed for both genders in Ireland and Macedonia. Women had significant larger educational differences in SRH than men in Portugal but significant lower differences in Czech Republic and Lithuania. CONCLUSIONS: The study underlined that the magnitude of educational differences in SRH varied according to gender and country. PMID- 23341355 TI - The sixth survey of the Tromso Study (Tromso 6) in 2007-08: collaborative research in the interface between clinical medicine and epidemiology: study objectives, design, data collection procedures, and attendance in a multipurpose population-based health survey. AB - AIMS: To provide a synopsis of the sixth survey of the Tromso Study, Tromso 6, objectives and new target areas, study design, follow-up studies, data collection, attendance, and participant characteristics. METHODS: The Tromso Study, initiated in 1974, is an epidemiological, prospective study of health conditions and chronic diseases, and a resource for the surveillance of disease risk factors. The purpose of Tromso 6 (2007-08) was to collect novel and repeated measurements of exposure data and to assess levels of disease risk factors. Tromso 6 included a main study that comprised two screening visits and several follow-up studies. Main study data collection: First visit (n=12,984): questionnaires, interviews, measurements of height, weight, hip and waist circumference, heart rate, blood pressure, forearm bone density, grip strength, pain sensitivity measurements, and blood and hair samples and nose and throat swab cultures. Second visit (n=7307): sampling of biological specimens (blood, urine, nose and throat swab cultures) and clinical examinations (12-lead electrocardiography, cognitive tests, visual acuity test, retinal photography, carotid ultrasound, spirometry, dual-energy X-ray absorptiometry, and echocardiography. RESULTS: A total of 12,984 participants aged 30-87 years were examined. The attendance rate was 66%, lower than in previous Tromso Study surveys. The attendance was lowest in the youngest and oldest, those invited for the first time, and lower in men than women. CONCLUSIONS: The completion of the survey with this comprehensive data collection went satisfactorily. The decreasing attendance rate calls for new recruitment strategies and optimisation of the study organisation to facilitate attendance. PMID- 23341356 TI - School performance as a precursor of adult health: exploring associations to disease-specific hospital care and their possible explanations. AB - AIMS: While past research has shown that school performance is associated with some specific health outcomes in adulthood, few studies have taken a general approach to the link between school performance and adult disease. The aim of the present study was therefore to investigate sixth grade school performance in relation to disease-specific hospital care in adulthood and, moreover, to examine whether other conditions in childhood could account for any such associations. METHODS: The data used was the Stockholm Birth Cohort, consisting of 14,294 individuals born in 1953. Associations between school performance and disease specific hospital care were analysed by means of Cox regression. RESULTS: Poor school performance was shown to be linked to a variety of diseases in adulthood, e.g. drug dependence, stomach ulcer, cerebrovascular diseases, and accidents. Some differences according to gender were found. Most associations, but not all, were explained by the simultaneous inclusion of various family-related and individual factors (e.g. social class, cognitive ability, and behavioural problems). CONCLUSIONS: In sum, the results of this study suggest that poor school performance may be an essential part of risk clustering in childhood with important implications for the individual's health career. PMID- 23341359 TI - Low pH, aluminum, and phosphorus coordinately regulate malate exudation through GmALMT1 to improve soybean adaptation to acid soils. AB - Low pH, aluminum (Al) toxicity, and low phosphorus (P) often coexist and are heterogeneously distributed in acid soils. To date, the underlying mechanisms of crop adaptation to these multiple factors on acid soils remain poorly understood. In this study, we found that P addition to acid soils could stimulate Al tolerance, especially for the P-efficient genotype HN89. Subsequent hydroponic studies demonstrated that solution pH, Al, and P levels coordinately altered soybean (Glycine max) root growth and malate exudation. Interestingly, HN89 released more malate under conditions mimicking acid soils (low pH, +P, and +Al), suggesting that root malate exudation might be critical for soybean adaptation to both Al toxicity and P deficiency on acid soils. GmALMT1, a soybean malate transporter gene, was cloned from the Al-treated root tips of HN89. Like root malate exudation, GmALMT1 expression was also pH dependent, being suppressed by low pH but enhanced by Al plus P addition in roots of HN89. Quantitative real time PCR, transient expression of a GmALMT1-yellow fluorescent protein chimera in Arabidopsis protoplasts, and electrophysiological analysis of Xenopus laevis oocytes expressing GmALMT1 demonstrated that GmALMT1 encodes a root cell plasma membrane transporter that mediates malate efflux in an extracellular pH-dependent and Al-independent manner. Overexpression of GmALMT1 in transgenic Arabidopsis, as well as overexpression and knockdown of GmALMT1 in transgenic soybean hairy roots, indicated that GmALMT1-mediated root malate efflux does underlie soybean Al tolerance. Taken together, our results suggest that malate exudation is an important component of soybean adaptation to acid soils and is coordinately regulated by three factors, pH, Al, and P, through the regulation of GmALMT1 expression and GmALMT1 function. PMID- 23341360 TI - Role and interrelationship of Galpha protein, hydrogen peroxide, and nitric oxide in ultraviolet B-induced stomatal closure in Arabidopsis leaves. AB - Heterotrimeric G proteins have been shown to transmit ultraviolet B (UV-B) signals in mammalian cells, but whether they also transmit UV-B signals in plant cells is not clear. In this paper, we report that 0.5 W m(-2) UV-B induces stomatal closure in Arabidopsis (Arabidopsis thaliana) by eliciting a cascade of intracellular signaling events including Galpha protein, hydrogen peroxide (H2O2), and nitric oxide (NO). UV-B triggered a significant increase in H2O2 or NO levels associated with stomatal closure in the wild type, but these effects were abolished in the single and double mutants of AtrbohD and AtrbohF or in the Nia1 mutants, respectively. Furthermore, we found that UV-B-mediated H2O2 and NO generation are regulated by GPA1, the Galpha-subunit of heterotrimeric G proteins. UV-B-dependent H2O2 and NO accumulation were nullified in gpa1 knockout mutants but enhanced by overexpression of a constitutively active form of GPA1 (cGalpha). In addition, exogenously applied H2O2 or NO rescued the defect in UV-B mediated stomatal closure in gpa1 mutants, whereas cGalpha AtrbohD/AtrbohF and cGalpha nia1 constructs exhibited a similar response to AtrbohD/AtrbohF and Nia1, respectively. Finally, we demonstrated that Galpha activation of NO production depends on H2O2. The mutants of AtrbohD and AtrbohF had impaired NO generation in response to UV-B, but UV-B-induced H2O2 accumulation was not impaired in Nia1. Moreover, exogenously applied NO rescued the defect in UV-B-mediated stomatal closure in the mutants of AtrbohD and AtrbohF. These findings establish a signaling pathway leading to UV-B-induced stomatal closure that involves GPA1 dependent activation of H2O2 production and subsequent Nia1-dependent NO accumulation. PMID- 23341361 TI - SlARF4, an auxin response factor involved in the control of sugar metabolism during tomato fruit development. AB - Successful completion of fruit developmental programs depends on the interplay between multiple phytohormones. However, besides ethylene, the impact of other hormones on fruit quality traits remains elusive. A previous study has shown that down-regulation of SlARF4, a member of the tomato (Solanum lycopersicum) auxin response factor (ARF) gene family, results in a dark-green fruit phenotype with increased chloroplasts (Jones et al., 2002). This study further examines the role of this auxin transcriptional regulator during tomato fruit development at the level of transcripts, enzyme activities, and metabolites. It is noteworthy that the dark-green phenotype of antisense SlARF4-suppressed lines is restricted to fruit, suggesting that SlARF4 controls chlorophyll accumulation specifically in this organ. The SlARF4 underexpressing lines accumulate more starch at early stages of fruit development and display enhanced chlorophyll content and photochemical efficiency, which is consistent with the idea that fruit photosynthetic activity accounts for the elevated starch levels. SlARF4 expression is high in pericarp tissues of immature fruit and then undergoes a dramatic decline at the onset of ripening concomitant with the increase in sugar content. The higher starch content in developing fruits of SlARF4 down-regulated lines correlates with the up-regulation of genes and enzyme activities involved in starch biosynthesis, suggesting their negative regulation by SlARF4. Altogether, the data uncover the involvement of ARFs in the control of sugar content, an essential feature of fruit quality, and provide insight into the link between auxin signaling, chloroplastic activity, and sugar metabolism in developing fruit. PMID- 23341363 TI - The telomere/telomerase binding factor PinX1 is a new target to improve the radiotherapy effect of oesophageal squamous cell carcinomas. AB - Chemoradiotherapy (CRT) is a standard treatment for oesophageal squamous cell carcinoma (ESCC) in its advanced stages. The telomerase/telomere interacting protein PinX1 contributes to telomere maintenance, tumourigenicity, and influences the DNA damage agent-induced apoptotic response in telomerase-positive cancer cells. However, the clinical and biological significance of PinX1 in human ESCCs remains unclear. We examined the expression dynamics of PinX1 by immunohistochemistry in a learning cohort (n = 98) and a validation cohort (n = 59) of ESCC patients treated with definite chemoradiotherapy (CRT). A series of in vivo and in vitro assays were performed to elucidate the effect of PinX1 on ESCC cells' CRT response and underlying mechanisms. Knockdown of PinX1 did not affect ESCC cells' chemosensitivities to 5-fluorouracil and cisplatin, but substantially increased ESCC cells' therapeutic efficacy of radiation both in vitro and in vivo. Ectopic overexpression of PinX1 dramatically enhanced ESCC cells' resistance to radiotherapy. Furthermore, we demonstrated that PinX1 resistance to radiotherapy (RT) was attributed to PinX1 maintaining telomere stability, reducing ESCC cell death by RT-induced mitosis catastrophe (MC). High expression of Pinx1 correlated positively with ESCC's resistance to CRT, and was a strong and independent predictor for short disease-specific survival (DSS) of ESCC patients. Our data suggest that PinX1 could serve as a novel predictor for a CRT response to ESCC patients, and the pathway of PinX1-mediated telomere stability might represent a new target to improve the RT effect of ESCC. PMID- 23341364 TI - Decitabine represses translocated MYC oncogene in Burkitt lymphoma. AB - Burkitt lymphoma (BL) is caused by translocation of the MYC gene to an immunoglobulin locus resulting in its constitutive expression depending on the activity of the immunoglobulin (Ig) enhancer elements. Treatment of BL cell lines with epigenetic modifiers is known to repress B-cell-specific genes and to up regulate B-cell-inappropriate genes including the transcription repressor ID2 expression. We found that the DNA methyltransferase inhibitor decitabine/5-aza-2 deoxycytidine (5-aza-dC) represses the MYC oncogene on RNA and protein levels by inducing ID2. Down-regulation of MYC was associated with repression of transcriptional activity of the Ig locus and with inhibition of proliferation. The induction of ID2 can be in part explained by activation of the transcription factor NF-kappaB. We conclude that up-regulation of ID2 contributes to anti tumour activity of 5-aza-dC via repression of Ig locus activity and consequently MYC expression. PMID- 23341365 TI - The Swedish national public health policy report 2010. AB - BACKGROUND: In 2003, the Swedish Parliament adopted a cross-sectorial national public health policy based on the social determinants of health, with an overarching aim--to create societal conditions that will ensure good health, on equal terms, for the entire population--and eleven objective domains. At that time the policy was globally unique, and serves as guidance for public health practice at the national, regional and local levels. The development of the public health policy and the determinants of health are presented regularly in various reports by the Swedish National Institute of Public Health. This supplement is a condensed version of the 174-page Public Health Policy Report 2010, the second produced since the national policy was adopted in 2003. METHODS: In order to provide a holistic approach to analysing implemented measures and providing new recommendations within the eleven objective domains of the Swedish national public health policy, we have divided these in three strategic areas. These are: Good Living Conditions, Health-Promoting Living Environments and Living Habits, and Alcohol, Illicit Drugs, Doping, Tobacco and Gambling, each described in the respective introductions for Chapters 3-5. The production of the report was supported by a common analytical model that clarified the societal prerequisites for health in the eleven objective domains. These are factors that can be influenced by political actions in order to create a change. Economic analyses have also been developed to provide a priority basis for political decisions. Analyses of the development of public health determinants were based on data from the National Public Health Survey and data delivered from about 15 various national agencies. Measures that have been implemented between 2004 and 2009 are analysed in details, as the basis for new recommendations for future measures. RESULTS: The introduction describes Swedish public health policy in the new millennium and how it has developed, the role of the Swedish National Institute of Public Health and other important stakeholders. Approaches, models and methods used in carrying out the commission to produce the public health policy report are also described. In the following chapters, the trends of important determinants of public health, in relation to the overarching aim and the 11 objective domains as grouped in the three strategic areas, are analysed. The final chapter presents the proposed prioritisation for the large number of recommendations that were made, and a presentation of the annual costs of ill health in Sweden. These are compared with the costs of implementing recommended measures. The final chapter also describes how the Public Health Policy Report 2010 was received and lists the recommendations that the Swedish Government has taken action on as of September 2012. CONCLUSIONS: Public health trends have generally been stable or positive, although health inequalities persist. Economic analyses demonstrate that ill-health in Sweden costs 12 billion SEK every year, yet a large amount of this ill-health can be prevented. Sixty-eight recommendations were presented in the report. The government's response to recommendations has been very positive; approximately 60% of the recommendations in the three strategic areas have been adopted less than two years after the Public Health Policy Report 2010 was published. PMID- 23341362 TI - Overexpression of the trehalase gene AtTRE1 leads to increased drought stress tolerance in Arabidopsis and is involved in abscisic acid-induced stomatal closure. AB - Introduction of microbial trehalose biosynthesis enzymes has been reported to enhance abiotic stress resistance in plants but also resulted in undesirable traits. Here, we present an approach for engineering drought stress tolerance by modifying the endogenous trehalase activity in Arabidopsis (Arabidopsis thaliana). AtTRE1 encodes the Arabidopsis trehalase, the only enzyme known in this species to specifically hydrolyze trehalose into glucose. AtTRE1 overexpressing and Attre1 mutant lines were constructed and tested for their performance in drought stress assays. AtTRE1-overexpressing plants had decreased trehalose levels and recovered better after drought stress, whereas Attre1 mutants had elevated trehalose contents and exhibited a drought-susceptible phenotype. Leaf detachment assays showed that Attre1 mutants lose water faster than wild-type plants, whereas AtTRE1-overexpressing plants have a better water retaining capacity. In vitro studies revealed that abscisic acid-mediated closure of stomata is impaired in Attre1 lines, whereas the AtTRE1 overexpressors are more sensitive toward abscisic acid-dependent stomatal closure. This observation is further supported by the altered leaf temperatures seen in trehalase-modified plantlets during in vivo drought stress studies. Our results show that overexpression of plant trehalase improves drought stress tolerance in Arabidopsis and that trehalase plays a role in the regulation of stomatal closure in the plant drought stress response. PMID- 23341367 TI - The role of the FOLFIRINOX regimen for advanced pancreatic cancer. AB - In 2010, the FOLFIRINOX regimen (bolus and infusional 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) emerged as a new option in patients with metastatic pancreatic cancer and a good performance status. However, at that time, some doubts were raised regarding safety issues. Similarly, no data on FOLFIRINOX were published in patients with unresectable/locally advanced or borderline resectable pancreatic cancer. This article presents the available experience with FOLFIRINOX outside clinical trials in metastatic and locally advanced pancreatic cancer patients. The safety of the regimen in patients with biliary stents and in previously treated patients is also described. FOLFIRINOX usage in clinical practice, including modification of the regimen (omission of bolus 5 fluorouracil; FOLFOXIRI regimen), is also presented. These data suggest that a phase III randomized study is warranted to further explore the role of FOLFIRINOX in locally advanced pancreatic cancer. PMID- 23341368 TI - Enzalutamide, a second generation androgen receptor antagonist: development and clinical applications in prostate cancer. AB - Enzalutamide, formerly known as MDV3100, is an oral second generation androgen receptor (AR) inhibitor that was chosen from a screen of agents and shown in preclinical studies to have greater affinity for the AR than its predecessors without any agonistic effects. The pre-clinical work that led to the interest in studying this agent and the history of the clinical development of enzalutamide from first in man phase 1 through phase 3 and regulatory approval are reviewed. Information about the toxicity profile and prescribing enzalutamide are discussed in detail. The availability of enzalutamide is put into context with the five other agents that modify survival outcomes in metastatic castration resistant prostate cancer. Some of the new challenges confronting the field regarding sequencing and combinations of these agents and the potential for a change in the natural history of the disease, are also discussed. PMID- 23341370 TI - Prevalence and risk factors of hepatitis C and B virus infections in hemodialysis patients and their spouses: a multicenter study in Beijing, China. AB - Hemodialysis patients are at risk for hepatitis C and B virus infections. This study investigated the prevalences and risk factors of HCV and HBV infection and the distribution of HCV genotypes among hemodialysis patients and their spouses. From August to November 2011, a cross-sectional study was conducted on 20 hemodialysis units in Beijing to investigate prevalences and risk factors for markers of HCV and HBV among 2,120 patients and 409 spouses. In hemodialysis patients, prevalences of anti-HCV, HCV RNA, and hepatitis B surface antigen (HBsAg) were 6.1%, 4.6%, and 7.0%, respectively. The prevalence of HCV antibodies among spouses was 0.5%, of HCV RNA was 0.2%, and of HBsAg was 4.2%. Risk factors for HCV infection were dialysis duration, blood transfusion, and attending more than one dialysis unit. HBV infection was independently associated with age, family member with hepatitis infection, gender, and surgery. The predominant HCV genotypes were 1b (89.0%) and 2a (7.7%), and genotypes 3a, 3b, and 6a were each 1.1%. A significant decrease in HCV and HBV prevalences in Chinese dialysis units showed that infection control measures were effective. However, because nosocomial transmissions persist, strict adherence to infection control measures should be emphasized to reduce the risk of transmission. PMID- 23341369 TI - Subtype CRF01_AE dominate the sexually transmitted human immunodeficiency virus type 1 epidemic in Guangxi, China. AB - Human immunodeficiency virus type 1 (HIV-1) infection by sexual transmission in Guangxi, China had increased dramatically. However, limited information is available on the genetic characterization of the HIV-1 epidemic. In this study, HIV-1 seropositive drug-naive patients infected by heterosexual transmission were enrolled. The full length gag and pol genes were sequenced followed by phylogenetic analysis, recombinant analysis and drug resistant analysis. Multiple subtypes were identified, including CRF01_AE (80.1%), CRF07_BC (6.4%), CRF08_BC (10.2%), subtype B (1.7%), and URFs (1.7%). In the phylogenetic tree, two large CRF01_AE clusters were identified. One cluster is originating from Vietnam strains as being reported previously in intravenous drug users. One novel cluster was identified and showed close relationship to strains from Fujian province. Inter-subtype recombination among CRF01_AE, subtype B and C was identified. Low level drug-resistance in drug-naive heterosexually transmitted infections was found. The results suggested that multiple originating CRF01_AE strains dominated the HIV-1 epidemic in heterosexual transmission in Guangxi province. PMID- 23341372 TI - Environmental surveillance of enterovirus in Northern India using an integrated shell vial culture with a semi-nested RT PCR and partial sequencing of the VP1 gene. AB - Enteroviruses have been reported in epidemic form during last 10 years in northern India. Environmental surveillance of sewage is the method of choice in limited resources countries for detection of enterovirus serotypes circulating in the community. Twenty-four sewage samples collected between January, 2009 and December, 2010 were tested for enterovirus by using a new modified integrated shell vial culture (ISVC) with a semi-nested RT-PCR of a partial VP1 gene and virus isolation integrated with semi-nested RT-PCR of a partial VP1 gene. Twenty one (87.5%) out of 24 samples were positive for enterovirus by the conventional method and all samples (100%) by the ISVC-RT-PCR. The additional positive samples detected by ISVC-RT-PCR was typed as six different enterovirus serotypes (Sabin poliovirus 3, Coxsackievirus B3, Coxsackievirus A13, Coxsackievirus A17, Echovirus 33, and Enterovirus 75). Phylogenetic analysis of a partial VP1 gene of Echovirus 19 showed that one genetic lineage clustered with isolates from Georgia suggesting their importation into northern India. Detection of wild poliovirus in the absence of clinical cases with 16 different co-circulating enterovirus serotypes supports the need of increased molecular surveillance of sewage. Rapid identification and characterization of enterovirus serotypes is necessary to study their transmission and evolution in different geographical regions to prevent future outbreak. PMID- 23341371 TI - Allium sativum-derived allitridin inhibits Treg amplification in cytomegalovirus infection. AB - This study investigated the effects of allitridin compound on murine cytomegalovirus (MCMV)-induced regulatory T cell (Treg; CD4(+) CD25(+) Foxp3(+) ) amplification in vivo and in vitro. One hundred twenty MCMV-infected mice were allocated at random into two groups for treatment with allitridin or placebo. Another 120 mock-infected mice were randomly allocated as controls for the allitridin treatment and placebo treatment groups. The mice were euthanized at various time points after infection (out to 120 days) to evaluate the effects of treatment on Treg presence and function, as well as MCMV infective load. Co culture with mouse embryo fibroblasts (MEF) and MCMV was performed to evaluate allitridin-mediated Treg and anti-CMV effects. The maximum tolerance concentration (MTC) of allitridin was used to treat cells for 3 days. Changes in Foxp3 mRNA and protein levels, percentages of T cell subsets, and Treg-related cytokines (IL-10 and TGF-beta) were measured. Allitridin treatment did not influence Foxp3 expression and Treg proportion in uninfected mice, but did down regulate each in infected mice during the chronic infection period. Additionally, allitridin treatment reduced the MCMV load in salivary glands. MTC allitridin treatment of co-cultures partially blocked MCMV induction of Foxp3 mRNA and protein expression. In vitro treatment with allitridin also increased significantly the percentages of Tc1, Tc2, and Th1, reduced the secreted levels of IL-10 and TGF-beta1, and significantly suppressed viral loads. In conclusion, allitridin can promote MCMV-induced Treg expansion and Treg-mediated anti-MCMV immunosuppression. Therefore, allitridin may be useful as a therapeutic agent to enhance the specific cellular immune responses against CMV. PMID- 23341373 TI - Trimodality therapy for bladder conservation in treatment of invasive bladder cancer. AB - During the past 25 years, prospective clinical trials have established that bladder preservation therapy for select patients with muscle-invasive bladder cancer is a safe and effective alternative to an immediate cystectomy. Cisplatin based chemoradiation is the most well-studied and accepted component of trimodality therapy; however, other systemic agents have recently been shown effective in combination with radiation therapy, increasing the range of options to allow for better personalization of care. In this review, the most recent advances in the field of bladder-preserving trimodality therapy are presented, and future directions for improving the outcomes are outlined. PMID- 23341374 TI - Update on use of enhanced imaging to optimize lymphadenectomy in patients undergoing minimally invasive surgery for urothelial cancer of the bladder. AB - The most commonly used imaging modalities for diagnostic investigation of bladder carcinoma are contrast-enhanced computed tomography, magnetic resonance imaging, and positron emission tomography. More recently, radioisotope and fluorescence staining are being used before, or even during, open or laparoscopic surgery. We report recent results obtained with these imaging modalities and their limitations. PMID- 23341375 TI - Value of fluorescence cystoscopy in high risk non-muscle invasive bladder cancer. AB - Photodynamic Diagnosis (PDD), an adjunct to white light cystoscopy, has been shown to improve detection and thoroughness of resection of bladder cancer by enhancing visualisation of malign lesions during transurethral resection of bladder tumours (TURBT) compared to the sole use of standard white light cystoscopy. The PDD also has been shown to improve recurrence of free survival in non-muscle invasive bladder cancer. Little data on its impact on outcome in non muscle invasive bladder cancer of high risk of progression is available however. The few trials and studies available demonstrate improved accuracy of diagnosis especially of flat malign lesions. In addition, improved recurrence rates have been suggested without an impact on progression rates in early invasive bladder cancer indicating little influence of thoroughness of resection on the tumour biology in those tumour stages. While no specific and larger data on impact of PDD on cancer specific survival exist to date and the few long-term data suggest little impact, improved accuracy of diagnosis is suggested to be beneficial for clinical decision making and thus a value of PDD is postulated in the management of high-risk non-muscle invasive bladder cancer. PMID- 23341376 TI - Spleen stiffness and splenoportal venous flow: assessment before and after transjugular intrahepatic portosystemic shunt placement. AB - OBJECTIVES: To prospectively assess changes in spleen stiffness and splenoportal venous flow before and after transjugular intrahepatic portosystemic shunt (TIPS) placement. METHODS: We prospectively evaluated spleen stiffness measured by the mean shear wave velocity with acoustic radiation force impulse imaging and the splenoportal venous velocity with color Doppler sonography in 12 patients (mean age +/- SD, 42.6 +/- 11.0 years; range, 29-65 years) who underwent TIPS placement for portal hypertension and gastroesophageal bleeding. The mean shear wave velocity and angle-corrected splenoportal venous velocity at the main portal and splenic veins were measured 1 day before and 3 to 9 days after TIPS placement (mean interval, 6.0 +/- 1.95 days; range, 4-10 days) and were compared with portal vein pressure measured during the procedure. RESULTS: There was a significant difference in portal vein pressure before and after TIPS (25.34 +/- 6.21 versus 15.66 +/- 6.07 mm Hg; P = .0005). After TIPS, the mean shear wave velocity decreased significantly in all 12 cases (3.50 +/- 0.46 versus 3.15 +/- 0.39 m/s before and after TIPS; P = .00015). The flow velocity at the main portal vein increased significantly after TIPS (22.21 +/- 4.13 versus 47.25 +/- 12.37 cm/s; P = .0000051). The splenic vein velocity and spleen index measured 25.57 +/ 6.98 cm/s and 55.99 +/- 21.27 cm(2), respectively, before TIPS and 35.72 +/- 11.10 cm/s and 50.11 +/- 21.12 cm(2) after TIPS (P = .0004 and .003). CONCLUSIONS: A significant decrease in the mean shear wave velocity and increase in the splenoportal venous velocity occurred with reduced portal vein pressure after TIPS placement. Hence, both parameters can be used as noninvasive quantitative markers for monitoring TIPS function after placement. PMID- 23341377 TI - Value of the ultrasound attenuation index for noninvasive quantitative estimation of hepatic steatosis. AB - OBJECTIVES: To assess the value of the ultrasound (US) attenuation index for noninvasive estimation of hepatic steatosis and determine its optimal cutoff value for severe steatosis in potential living liver donors. METHODS: Two hundred forty potential donors underwent US-guided biopsy. The target site was scanned at 4 and 8 MHz. On the sonogram, the observer drew 3 * 3-mm square regions of interest in superficial (3-cm) and deep (5-cm) areas. The attenuation index was defined as the difference between superficial and deep echogenicity/superficial echogenicity * 100. On biopsy specimens, replacement of hepatic parenchyma was evaluated on a percentage scale. Severe steatosis was defined as macrovesicular fatty change of 30% or greater. Spearman rank correlation (rho) was used to determine correlation coefficients between the attenuation index and steatosis degree; receiver operating characteristic analysis was performed to determine the optimal attenuation index cutoff value for severe steatosis. RESULTS: The median steatosis degree was 3% (interquartile range [IQR], 0%-10%). Severe steatosis was found in 10 donors. The attenuation index ranged from -27.4 to 36.6 (median, 4.0; IQR, -1.6-10.4) at 4 MHz and -18.0 to 78.1 (median, 14.5; IQR, 7.2-21.9) at 8 MHz. There was a minimal positive correlation between steatosis and the attenuation index at 4 MHz (total steatosis: rho = 0.339; P < .001; macrovesicular steatosis: rho = 0.360; P < .001). However, there was a significant moderate correlation between steatosis and the attenuation index at 8 MHz (total steatosis: rho = 0.669; P < .001; macrovesicular steatosis: rho = 0.645; P < .001). The optimal attenuation index cutoff value for severe steatosis at 8 MHz was 31.0. CONCLUSIONS: The US attenuation index at 8 MHz is a useful indicator for noninvasive quantitative estimation of hepatic steatosis and diagnosis of severe steatosis in potential living liver donors. PMID- 23341378 TI - Positioning of a suburethral sling at the bladder neck is associated with a higher recurrence rate of stress urinary incontinence. AB - OBJECTIVES: The purpose of this study was to investigate the relationship between the suburethral sling position and the outcome of anti-incontinence surgery. METHODS: From 1998 to 2010, the medical records of 153 consecutive women with stress urinary incontinence undergoing the pubovaginal sling procedure were retrospectively reviewed. All patients received preoperative and postoperative transrectal sonography of the bladder and urethra, and the suburethral sling position was used to compare the postoperative continence status and lower urinary tract symptoms. RESULTS: The mean patient age +/- SD was 60.7 +/- 10.6 years (range, 34-85 years), and the mean follow-up was 66.3 +/- 42.1 months (range, 6-149 months). The slings were located at the bladder neck in 18 patients (11.8%), proximal urethra in 81 (52.9%), middle urethra in 45 (29.4%), and distal urethra in 9 (5.9%). The overall rate of recurrent stress urinary incontinence was 24.2% (37 patients). Among the 153 patients, there was a significantly higher stress urinary incontinence recurrence rate in the bladder neck group (bladder neck, 50.0%; proximal urethra, 18.5%; middle urethra, 22.2%; and distal urethra, 33.3%; P = .037). De novo urge and voiding symptoms occurred in 19.0% and 20.3% of overall patients, respectively. There was no significant difference in either de novo urge or voiding symptoms among groups. CONCLUSIONS: Positioning of the suburethral sling at the bladder neck appears to be associated with a higher stress urinary incontinence recurrence rate. Patients with slings located at the proximal and middle urethra had the best postsurgical continence rates. The suburethral sling position had no direct association with de novo urge or voiding symptoms. PMID- 23341379 TI - Value of 3-dimensional and power Doppler sonography for diagnosis of endometrial polyps. AB - OBJECTIVES: To investigate whether the endometrial thickness, endometrial volume, and endometrial and subendometrial vascularization index, flow index, and vascularization-flow index were useful for diagnosing endometrial polyps in infertility. METHODS: Transvaginal and 3-dimesional power Doppler sonography was performed to calculate the endometrial echogenicity, endometrial thickness, endometrial volume, and endometrial and subendometrial vascularization index, flow index, and vascularization-flow index, followed by hysteroscopy in the follicular phase of the menstrual cycle (postmenstrual days 3-7). A total of 555 patients were selected, and 4 groups were defined according to the comparison of sonographic and hysteroscopic diagnoses: group A (sonographically positive but hysteroscopically negative), group B (sonographically and hysteroscopically negative), group C (sonographically negative but hysteroscopically positive), and group D (sonographically and hysteroscopically positive). RESULTS: A total of 426 patients were enrolled in the final analysis. Significantly higher endometrial thickness and volume were found in groups C and D compared with groups A and B (P < .05). There were no significant differences among the 4 groups in terms of the endometrial and subendometrial vascularization index, flow index, and vascularization-flow index (P > .05). The sensitivity, specificity, and positive and negative predictive values of endometrial thickness and volume in predicting endometrial polyps were 62.7%, 69.8%, 26.9%, and 91.9% and 39.3%, 88.2%, 35.8%, and 89.7%, respectively. Combined sonographic evaluation (sonographic echogenicity, endometrial thickness, and endometrial volume) showed higher sensitivity, specificity, and positive and negative predictive values (65.6%, 89.0%, 50.0%, and 93.9%) compared with a single indicator. CONCLUSIONS: A combination of endometrial echogenicity, thickness, and volume on sonography may be better than a single indicator for predicting endometrial polyps in infertility. However, the endometrial or subendometrial vascularization index, flow index, and vascularization-flow index are not useful for prediction. PMID- 23341381 TI - Application of real-time ultrasound elastography for discrimination of low- and high-grade serous ovarian carcinoma. AB - OBJECTIVES: The purpose of this study was to evaluate real-time qualitative ultrasound elastography as an adjunct to conventional sonography for discrimination of low- and high-grade serous ovarian carcinoma. METHODS: Eighty six patients suspected of having serous ovarian cancer on the basis of clinical and biochemical evaluations underwent transvaginal and transabdominal sonography and then elastography and later underwent surgery. RESULTS: Histopathologic analysis revealed 64 serous ovarian carcinomas (74.4%): 39 (60.9%) high grade and 25 (39.1%) low grade. The mean elasticity score +/- SD was statistically significantly higher for low-grade lesions (3.40 +/- 0.76) than high-grade lesions (2.08 +/- 0.58; P < .001). There was a trend for high-grade lesions to be less stiff than low-grade lesions due to rapidly developing necrosis; conversely, low-grade lesions developed relatively slowly so that their solid areas were stiffer and less elastic. The median elasticity score for low-grade lesions (based on a 4-point scale used to grade cervical lymph nodes) was 4 (stiffest), and the score for high-grade lesions was 2. When the score of 4 was used for diagnosis of low-grade carcinoma, elastography had 56.0% sensitivity, 100% specificity, a 100% positive predictive value, a 78.0% negative predictive value, and 82.8% accuracy. When the score of 2 was used for the diagnosis of high-grade carcinoma, elastography had 66.7% sensitivity, 84.0% specificity, an 86.7% positive predictive value, a 61.8% negative predictive value, and 73.4% accuracy. CONCLUSIONS: Our results suggest that ultrasound elastography could be helpful for discrimination of low- and high-grade serous ovarian carcinoma. Low-grade lesions are stiffer and not as elastic as high-grade lesions. PMID- 23341382 TI - Fetal umbilical vein deviation in congenital diaphragmatic hernia. AB - OBJECTIVES: Deviation of the intra-abdominal umbilical vein has been described as a marker of congenital diaphragmatic hernia (CDH) and has been shown to help identify liver herniation into the fetal chest. The purpose of this study was to quantify the degree of deviation in affected fetuses and to determine the accuracy of measurements for diagnosing liver herniation. METHODS: In patients undergoing prenatal sonography for CDH, the midhepatic portion of the umbilical vein was identified, and the distance between the lateral edge of the vein and the inner rib margin was measured. The same was done on the right, and the ratio of the left to right measurement was termed the "umbilical vein ratio." The accuracy of the umbilical vein ratio for predicting the presence and side of the hernia and for diagnosing liver herniation was determined. RESULTS: All but 1 of the cases with right-sided hernias had an umbilical vein ratio above the normal range, and all had liver herniation. Of those with a left-sided hernia, only 2 had a ratio within the normal range. Of those with a left-sided hernia, an umbilical vein ratio less than 0.4 was shown by receiver operating characteristic curve analysis to be the best predictor of liver herniation. This cutoff had sensitivity of 89% for predicting herniation, with a false-positive rate of 14%. CONCLUSIONS: Ninety-three percent of right-sided CDH lesions and 98% of left sided lesions have an umbilical vein ratio outside the normal range. This finding shows that deviation may a useful indicator of CDH in screening ultrasound examinations. An umbilical vein ratio less than 0.4 is predictive of liver herniation. PMID- 23341383 TI - Reference ranges for fetal brain fissure development on 3-dimensional sonography in the multiplanar mode. AB - OBJECTIVES: To determine reference ranges for measurements of fetal cerebral fissures by 3-dimensional (3D) sonography in the multiplanar mode and to evaluate the reliability and concordance of these measurements. METHODS: A cross-sectional study was conducted on 393 women with normal pregnancies at 22 weeks to 33 weeks 6 days. The distances between the internal bone plate of the fetal calvaria and the sylvian, parieto-occipital, hippocampal, and calcarine fissures were assessed. To obtain the distances for the first 3 fissures, a 3D sweep was made in the axial plane, at the level of the lateral ventricles. To obtain the distance for the calcarine fissure, a coronal sweep was used, at the level of the occipital lobes. To evaluate the correlation between the fissures and gestational age, polynomial regression was performed with adjustments using the coefficient of determination (R(2)). Reliability was determined with intraclass correlation coefficients and concordance with concordance limits. RESULTS: The mean distances +/- SD to the sylvian, parieto-occipital, hippocampal, and calcarine fissures were 10.42 +/- 2.28, 22.38 +/- 3.23, 24.88 +/- 4.67, and 21.19 +/- 2.73 mm, respectively. These distances correlated with gestational age such that the best fit with the linear equation produced R(2) values of 0.582, 0.627, 0.860, and 0.458 for the sylvian, parieto-occipital, hippocampal, and calcarine fissures. Reliability analyses showed intraobserver and interobserver intraclass correlation coefficients of 0.90 to 0.95 and 0.85 to 0.97. The concordance limits were-1.33 to 1.30 and -2.38 to 2.28 mm for the intraobserver evaluation and -1.60 to 2.57 and -3.51 to 2.73 mm for the interobserver evaluation. CONCLUSIONS: Cerebral fissures can be measured by 3D sonography at 22 to 33 weeks of pregnancy with acceptable reliability and concordance. Reference ranges for this gestational period have thus been described. PMID- 23341384 TI - Developmental programming of cardiovascular risk in intrauterine growth restricted twin fetuses according to aortic intima thickness. AB - OBJECTIVES: We aimed to test the hypothesis that aortic intima thickness is greater in intrauterine growth-restricted (IUGR) twin fetuses compared to normally developing twins, thus defining an increased cardiovascular risk that reflects genetic factors in fetuses sharing the same womb. METHODS: We conducted a prospective study performed on twins from January 2009 to July 2011. Twins were classified into 3 groups: IUGR fetuses with an estimated fetal weight below the 10th percentile and an umbilical artery pulsatility index of greater than 2 SDs (group A), fetuses with an estimated fetal weight below the 10th percentile and normal Doppler findings (group B), and fetuses with an estimated fetal weight appropriate for gestational age (group C). Aortic intima thickness was measured at a median gestational age of 32 weeks. Values were compared among groups and between each twin and cotwin, also considering sex and chorionicity. RESULTS: Twenty-five fetuses were classified as group A, 36 as group B, and 95 as group C. The median aortic intima thickness values were 0.9 mm in group A, 0.7 mm in group B, and 0.6 mm in group C (P < .0001). There was a statistically significant difference between the aortic intima thickness of the twins and cotwins in groups A and B (P < .0001). Sex and chorionicity did not correlate with aortic intima thickness. CONCLUSIONS: In this study, IUGR fetuses with Doppler abnormalities had greater aortic intima thickness, and IUGR twins with normal Doppler findings had intermediate thickness, supporting a genetic predisposition to cardiovascular risk independent of sex and chorionicity. PMID- 23341385 TI - Role of acoustic shear wave velocity measurement in characterization of breast lesions. AB - OBJECTIVES: To analyze the value of acoustic radiation force impulse imaging quantification in characterization of breast lesions and to analyze the stiffness of glandular and subcutaneous fatty tissue in benign and malignant lesions. METHODS: A total of 175 breast lesions (67 malignant and 108 benign) in 173 women were studied. With acoustic radiation force impulse imaging, shear wave velocity (SWV), which can reflect the stiffness of tissue, was measured within the lesion (internal SWV [SWVi]), in the boundary zone (boundary SWV [SWVb]), in normal appearing glandular tissue (glandular SWV [SWVg]), and in subcutaneous fatty tissue (fatty SWV [SWVf]). All lesions underwent core needle biopsy or surgical excision. Differences among the SWV types in malignant and benign lesions were evaluated. We also assessed how different lesion types affected the SWV types. Receiver operating characteristic analysis was performed to assess the sensitivity and specificity of the SWV types in differentiating malignant from benign lesions. RESULTS: Internal SWV was significantly higher than SWVb, SWVg, and SWVf; SWVb was significantly higher than SWVg and SWVf; and SWVg was significantly higher than SWVf in both malignant and benign groups (P < .05). All 4 SWV types were significantly higher in the malignant group than the benign group (P < .05). In the malignant group, grade 3 invasive ductal carcinoma had the highest SWVi. The sensitivity and specificity for differentiating malignant lesions were 55.2% and 95.8% for SWVi, 85.1% and 53.3% for SWVb, 68.2% and 69.6% for SWVg, and 67.2% and 66.0% for SWVf. CONCLUSIONS: Acoustic radiation force impulse imaging has potential to characterize breast lesions, both internally and within the boundary zone, and to reflect changes in stiffness within surrounding glandular and subcutaneous fatty tissues caused by malignant tumors. PMID- 23341386 TI - Clinical experience with elasticity imaging in a community-based breast center. AB - OBJECTIVES: The aim of this study was to evaluate compression elasticity imaging in combination with standard B-mode imaging for assessment of benign versus malignant breast lesions and correlation with needle biopsy. METHODS: Institutional Review Board approval was obtained, and patients were prospectively enrolled from 2007 to 2011. A total of 221 patients yielding 230 elastograms recommended for biopsy were the basis of this analysis. Information collected included patient demographics, lesion laterality and location, and needle biopsy method and results. The longest dimension of the lesion between B-mode and elasticity imaging was measured, and an elasticity imaging/B mode ratio of 1.0 or greater was considered to represent malignancy; a ratio of less than 1.0 was benign. Statistical analysis included calculation of descriptive statistics and generation of figures. RESULTS: Of the 230 biopsies performed, cancer was revealed in 100 cases (43.5%). One hundred thirty (56.5%) benign findings were observed. Of the 100 malignant lesions, 99 had an elasticity imaging/B-mode ratio greater than or equal to 1.0 (99.0%). Of the 130 benign lesions, 119 had an elasticity imaging/B-mode ratio of less than 1.0 (91.5%). These results indicate 99.0% (99 of 100) sensitivity and 91.5% (119 of 130) specificity. Furthermore, we found a positive predictive value of 90.0% (99 of 110) and a negative predictive value of 99.2% (119 of 120). CONCLUSIONS: In this study, elasticity imaging had high sensitivity for malignant and benign lesions. Elasticity imaging in the clinical setting may prove to be an additional tool that is helpful to the breast clinician for characterization of lesions as benign or malignant. At this time, we are continuing our data collection because additional research is still necessary. PMID- 23341387 TI - Comparison of sonographically guided core needle biopsy and excision in breast papillomas: clinical and sonographic features predictive of malignancy. AB - OBJECTIVES: The aim of this study was to evaluate the clinical factors and sonographic features of benign papillomas of the breast proven by sonographically guided 14-gauge core needle biopsy and their upgrade or malignancy rate after sonographically guided vacuum-assisted excision or surgical excision. METHODS: We reviewed the medical records of patients who underwent core needle biopsy from July 2005 to December 2011. We evaluated 39 benign papillomas without atypia in 34 patients. The papillomas were diagnosed by core needle biopsy and underwent surgical or vacuum-assisted excision. After core needle biopsy, imaging histologic correlation was performed to determine concordance. The upgrade and malignancy rates were assessed after surgical or vacuum-assisted excision, and associated clinical and radiologic factors, including patient age, lesion size, distance from the nipple, sonographic features, and American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) category were evaluated. RESULTS: Three lesions (7.7 %) among 39 papillomas were upgraded to papilloma with atypia after surgical excision. There was no malignancy after excision. The upgrade rates for BI-RADS categories 3, 4a, 4b, and 4c were 0%, 6.9%, 0%, and 20%, respectively. There were no significant differences in the upgrade to papilloma with atypia in terms of the presence of symptoms, lesion size, distance from the nipple, BI-RADS category, or imaging-histologic correlation. CONCLUSIONS: Prediction of papilloma with atypia, not malignancy, was challenging because there were no associated clinical or radiologic factors to predict papilloma with atypia before excision. However, there was no malignancy after excision. Therefore, intensive surveillance is preferable to immediate surgical excision for benign papillomas diagnosed on core needle biopsy. PMID- 23341388 TI - Differences in lateral ankle ligaments between affected and unaffected legs in children with spastic hemiplegic cerebral palsy. AB - OBJECTIVES: To investigate the architectural alterations of the lateral ankle ligaments in spastic hemiplegic cerebral palsy. METHODS: Eight children (5 male and 3 female; mean age +/- SD, 5.2 +/- 2.7 years) with spastic hemiplegic cerebral palsy were recruited. A modified Ashworth scale and passive ankle dorsiflexion angle were evaluated. Sonograms of the anterior talofibular ligament and calcaneofibular ligament were obtained to measure ligament thickness, and the anterior talofibular/calcaneofibular ligament thickness ratio was calculated. Two sonographic measurements were taken to check for intra-rater reliability. RESULTS: The interclass correlation coefficients of the repeated anterior talofibular ligament and calcaneofibular ligament thickness measurements in the unaffected/affected legs were 0.960/0.945 and 0.922/0.933, respectively. The anterior talofibular ligament thickness in the affected legs was significantly greater than that in the unaffected legs (2.50 +/- 0.35 versus 1.40 +/- 0.28 mm; P = .011), but the calcaneofibular ligament thickness in the affected legs was significantly less than that in the unaffected legs (0.80 +/- 0.18 versus 1.28 +/ 0.31 mm; P = .021). The anterior talofibular/calcaneofibular ligament thickness ratio in the affected legs was significantly greater than that in unaffected legs (2.10 +/- 0.81 versus 1.03 +/- 0.13; P = .012). The ratio was positively correlated with the modified Ashworth scale and age but negatively correlated with the passive ankle dorsiflexion angle in the affected legs. CONCLUSIONS: This study revealed an increased anterior talofibular ligament thickness and a decreased calcaneofibular ligament thickness in the affected legs compared with the unaffected legs. These architectural features of the lateral ankle ligaments may contribute to the equinovarus deformity of the ankle together with spastic leg muscles in children with spastic hemiplegic cerebral palsy. PMID- 23341389 TI - Sonographically assisted percutaneous removal of screws in dynamization of the interlocking intramedullary nail. AB - OBJECTIVES: Dynamization is a method of removing the interlocking screw(s) farthest from the fracture site for improving healing in femoral and tibial fractures that show delayed healing after static interlocking nailing. We describe a simple sonographically assisted technique for percutaneous dynamization of deep-seated impalpable screws. METHODS: Between March 2001 and March 2005, 20 dynamization procedures were completed using the developed technique under the diagnosis of delayed healing or a nonunion at a mean of 4.8 months after index surgery. After adequately positioning the involved leg, the transducer was placed on the area of the inlet of the screw. Longitudinal and transverse sonographically scanned sections, used to show the head of the screw, were then marked on the skin where the two sections intersected. After this precise marking, a small incision on the mark allowed insertion of the screwdriver and easy percutaneous removal of the screw using only local anesthesia for pain control. RESULTS: We removed 31 screws: 9 proximal femoral screws, 20 distal femoral screws, and 2 proximal tibial screws. The mean depth of the screws was 3.4 cm. The mean operation times were 1.6 minutes for the sonographic examination and 3.5 minutes for removal of one screw. No infections or morbidities were caused by the procedure. CONCLUSIONS: Sonography is an effective tool for localizing a locked screw and facilitates percutaneous removal of screws under only local anesthesia for dynamization. This method needs no special instruments and reduces the time needed for dissecting the tissue and locating the screw. PMID- 23341390 TI - Increased enthesopathy in patients with familial Mediterranean fever: evaluation with a new sonographic enthesitis index. AB - OBJECTIVES: The aim of this study was to determine the frequency of enthesopathy in familial Mediterranean fever by using a newly developed sonographic method, the Madrid Sonographic Enthesitis Index (MASEI). METHODS: The study included 50 consecutive patients with familial Mediterranean fever and 57 healthy sex- and age-matched control participants. Six entheseal sites (olecranon tuberosity, superior and inferior poles of the patella, tibial tuberosity, and superior and inferior poles of the calcaneus) on both lower limbs were evaluated. All sonographic findings were identified according to MASEI. Validity was analyzed by receiver operating characteristic curves. P < .05 was considered significant. RESULTS: Mean total enthesitis scores +/- SD were 7.54 +/- 4.99 for patients and 3.63 +/- 3.03 for controls (P < .001). No statistically significant correlation was found between the MASEI score and familial Mediterranean fever duration or colchicine treatment duration. There was no difference between the MASEI score and the presence or absence of arthritic involvement among the patients. The area under the receiver operating characteristic curve was 0.74 (95% confidence interval, 0.649-0.839). When analyzed by sex, men with familial Mediterranean fever had significantly higher MASEI scores than women (P < .05). CONCLUSIONS: This study showed significant enthesopathy in patients with familial Mediterranean fever. The findings support the hypothesis that familial Mediterranean fever and spondyloarthropathy may have common inflammatory mechanisms and suggest that the MASEI scoring system can be incorporated into clinical protocols for studying patients with familial Mediterranean fever in daily practice. PMID- 23341391 TI - Focused transthoracic echocardiography by sports medicine physicians: measurements relevant to hypertrophic cardiomyopathy. AB - OBJECTIVES: The purpose of this study was to investigate whether sports medicine physicians can use portable echocardiography to obtain measurements pertinent to hypertrophic cardiomyopathy. METHODS: Thirty male collegiate athletes, aged 18 to 21 years, were prospectively enrolled. Focused portable echocardiography was performed by a board-certified sports medicine physician and a resident physician, followed by comprehensive echocardiography within 2 weeks by a registered diagnostic cardiac sonographer. A left parasternal long-axis view was acquired to measure 3 dimensions: (1) end-diastolic interventricular septal thickness (IVSd), (2) end-diastolic left ventricular internal diameter (LVIDd), and (3) end-diastolic left ventricular posterior wall thickness (LVPWd). RESULTS: Intraclass correlation coefficients between the sports medicine physician and the sonographer were strong: 0.77 for IVSd, 0.73 for LVIDd, and 0.64 for LVPWd. Intraclass correlation coefficients between measurements by the resident physician and sonographer were strong to moderate: 0.61 for IVSd, 0.62 for LVIDd, and 0.63 for LVPWd. Across all 3 readers, intraclass correlation coefficient calculations were 0.77 for IVSd, 0.81 LVIDd, and 0.75 for LVPWd, which indicated strong inter-rater reliability. CONCLUSIONS: Sports medicine physicians are able to obtain measurements relevant to the diagnosis of hypertrophic cardiomyopathy with focused portable echocardiography that are consistent with comprehensive echocardiography by a registered sonographer. PMID- 23341392 TI - Meta-analysis of sonography in the diagnosis of inguinal hernias. AB - Groin hernias are common conditions, and there is a need for accurate imaging when the clinical diagnosis is not clear. A meta-analysis was undertaken to investigate the diagnostic accuracy of sonography in the diagnosis of inguinal hernias. After review of literature searches, 9 original articles were included. Data were pooled and statistically analyzed. In the studies included, sensitivity ranged from 92.7% to 100%; specificity ranged from 22.2% to 100%; the positive predictive value ranged from 83.3 to 100%; and the negative predictive value ranged from 40 to 100%. Sonography has overall sensitivity of 96.6 %, specificity of 84.8%, and a positive predictive value of 92.6%. In cases of diagnostic uncertainty, sonography offers value as an initial imaging modality. It has advantages over other radiologic methods, as it is inexpensive and has minimal complications. When the clinical diagnosis of an inguinal hernia is uncertain, sonographic findings should be interpreted in conjunction with clinical judgment, as its diagnostic accuracy is reduced in the absence of any clinically palpable hernia. PMID- 23341393 TI - Diffuse sclerosing variant of papillary thyroid carcinoma: sonography and specimen radiography. AB - The purpose of this pictorial essay is to show the limitations of sonography and complementary usefulness of specimen radiography in detecting microcalcifications of the diffuse sclerosing variant of papillary thyroid carcinoma, which mostly manifests as diffusely scattered microcalcifications in the thyroid gland. PMID- 23341394 TI - Small liver nodule detection with a high-frequency transducer in patients with chronic liver disease: report of 3 cases. AB - We report 3 cases in which small liver lesions were revealed on sonography with the supplemental use of a high-frequency transducer. In all 3 cases, the patients had cirrhosis or chronic liver disease. The lesions were not seen on computed tomography or magnetic resonance imaging. Sonography plays a pivotal role in surveillance for hepatocellular carcinoma and, with modern transducer technology, may be the first imaging modality to show an early small tumor. A more thorough search for focal liver lesions with adjunctive use of high-frequency transducers may prolong the examination time but can improve surveillance for hepatocellular carcinoma. PMID- 23341395 TI - Abdominal sonography for diagnosis of vaginal grains in Chinese children. AB - Grains embedded as vaginal foreign bodies sometime occur in Chinese children. We summarized the sonographic characteristics of vaginal grains in 4 Chinese children and retrospectively analyzed the clinical data. Abdominal sonography can be the first choice for diagnosis of vaginal grains because of its noninvasive nature, high specificity, and low cost. PMID- 23341397 TI - Superficial papillary adenomatosis of the nipple: a rare disease diagnosed by sonography and histopathologically confirmed by nipple-preserving total excision. PMID- 23341396 TI - Segmental testicular infarction: sonographic findings and pathologic correlation. AB - Segmental testicular infarction can mimic testicular carcinoma on sonography and can lead to unnecessary orchiectomy. This case series describes and correlates sonographic and histologic findings of 7 pathologically proven segmental testicular infarction cases. Segmental testicular infarction should be suspected on sonography when a geographic lesion with low or mixed echogenicity has absent or near-absent flow in a patient with scrotal pain. A hyperechoic rim and peripheral hyperemia correspond to interstitial hemorrhage and inflammatory changes. As an infarct evolves, it becomes more discrete and hypoechoic as ghost outlines replace seminiferous tubules. Follow-up or contrast-enhanced magnetic resonance imaging or sonography can increase diagnostic confidence in suspected cases and prevent unnecessary orchiectomy. PMID- 23341398 TI - Spontaneous heterotopic cervical pregnancy and successful pregnancy outcome. PMID- 23341399 TI - [Defence and progress for health sciences in Iceland]. PMID- 23341400 TI - [Pulmonary embolism: victories and future hopes]. PMID- 23341401 TI - [Pulmonary embolism at Landspitali, the National University Hospital of Iceland 2005-2007 - incidence, clinical manifestations, risk factors and outcome]. AB - INTRODUCTION: Pulmonary embolism is a serious disease and common among hospitalized patients. The incidence of pulmonary embolism in Iceland is largely unknown. The purpose of this study was to evaluate the incidence, clinical presentation, risk factors and outcome among patients diagnosed with pulmonary embolism at Landspitali, The National University Hospital of Iceland. MATERIAL AND METHODS: A retrospective analysis of medical records of patients diagnosed with the ICD-10 diagnosis I26 (Pulmonary embolism) between 2005-2007 was carried out. Data were retrieved on age, clinical manifestations, treatment, risk factors, diagnostic procedures and outcome. RESULTS: The total number of patients was 312 and the in-hospital incidence was 5 per 1.000. Thirty day mortality was 9.9% (95% CI 6.6-13.3). Dyspnea was the most common symptom (81%) and diagnosis was most often established by computed tomography of the pulmonary vasculature (88,8%). Anticoagulation was by far the most common management (96%) but thrombolysis, thrombectomy or use of inferior vena cava filters were very rare. The frequency of atrial fibrillation was significantly higher in patients with pulmonary hypertension by echocardiography than without, 32.4% and 9.7%, respectively (p= 0.026). Thirty day mortality was significantly higher in women than in men (13.2% versus 6.5%, p=0.049), and in patients with no classic symptoms of pulmonary embolism at diagnosis (36.4% versus 8.1%, p=0.012). DISCUSSION: The hospital incidence of pulmonary embolism, 5/1000 patients, at Landspitali The National University Hospital of Iceland is higher than found in similar studies in many other countries. Mortality, while similar, has fallen markedly during the past 40 years. PMID- 23341402 TI - [Diet of six-year-old Icelandic children - National dietary survey 2011-2012]. AB - AIM: Knowledge of dietary habits makes the basis for public nutrition policy. The aim of this study was to assess dietary intake of Icelandic six-year-olds. MATERIAL AND METHODS: Subjects were randomly selected six-year-old children (n=162). Dietary intake was assessed by three-day-weighed food records. Food and nutrient intake was compared with the Icelandic food based dietary guidelines (FBDG) and recommended intake of vitamins and minerals. RESULTS: Fruit and vegetable intake was on average 275+/-164 g/d, and less than 20% of the subjects consumed >=400 g/day. Fish and cod liver oil intake was in line with the FBDG among approximately 25% of subjects. Most subjects (87%) consumed at least two portions of dairy products daily. Food with relatively low nutrient density (cakes, cookies, sugar sweetened drinks, sweets and ice-cream) provided up to 25% of total energy intake. The contribution of saturated fatty acids to total energy intake was 14.1%. Less than 20% of the children consumed dietary fibers in line with recommendations, and for saturated fat and salt only 5% consumed less than the recommended upper limits. Average intake of most vitamins and minerals, apart from vitamin-D, was higher than the recommended intake. CONCLUSION: Although the vitamin and mineral density of the diet seems adequate, with the exception of vitamin-D, the contribution of low energy density food to total energy intake is high. Intake of vegetables, fruits, fish and cod liver oil is not in line with public recommendations. Strategies aiming at improving diet of young children are needed. PMID- 23341403 TI - [Brain abscess - overview]. AB - Brain abscess is a life threatening illness, demanding rapid diagnosis and treatment. Its development requires seeding of an organism into the brain parenchyma, often in an area of damaged brain tissue or in a region with poor microcirculation. The lesion evolves from a cerebritis stage to capsule formation. Brain abscesses can be caused by contiguous or haematogenous spread of an infection, or by head trauma/ neurosurgical procedure. The most common presentation is that of headache and vomiting due to raised intracranial pressure. Seizures have been reported in up to 50% of cases. Focal neurological deficits may be present, depending on the location of the lesion. Treatment of a brain abscess involves aspiration or excision, along with parenteral antibiotic therapy. The outcome has improved dramatically in the last decades due to improvement in diagnostic techniques, neurosurgery, and broad-spectrum antibiotics. The authors provide an overview of the pathogenesis, diagnosis and management of brain abscesses. PMID- 23341404 TI - The cultural meaning of children sleeping outdoors in Finnish winter: a qualitative study from the viewpoint of mothers. AB - PURPOSE: Little is known about children sleeping outdoors in a northern winter climate, although it is a common practice in northern countries. The article describes the cultural meaning of this child care practice from the viewpoint of mothers. DESIGN: Explorative descriptive study design was adopted and unstructured interviews were processed by qualitative content analysis. PARTICIPANTS: Twenty-one mothers of families in northern Finland participated. RESULTS: Family, cultural outdoor sleeping practice and northern winter environment constituted compatibility, which consisted of four generic categories: strengthening family well-being through outdoor sleeping, taking notice of security perspectives, adaptation to the northern winter environment, and cultural knowledge-building processes. CONCLUSIONS: Family well-being was strengthened through outdoor sleeping of children when all security perspectives were first taken into account. Families were adapted to the northern winter environment and cultural knowledge was built. A fit was found between families, cultural child care practice, and northern winter environment constituting a coherent whole. PMID- 23341405 TI - Correlates of depressive symptoms in married immigrant women in Korea. AB - PURPOSE: The purpose of this study was to identify the correlates of depressive symptoms among women who have immigrated to Korea for marriage. DESIGN: Cross sectional data reflecting Korean language fluency, acculturation, acculturative stress, general stress, and marital satisfaction were collected from 223 married immigrant women. FINDINGS: There was a significant negative correlation between depressive symptoms and Korean language fluency as well as between depressive symptoms and Korean acculturation. Multiple linear regression revealed that depressive symptoms among married immigrant women were predicted by levels of acculturative stress, general stress, marital satisfaction, and type of household. The model including each of these variables accounted for 41.9% of the variance in depressive symptoms in these women. CONCLUSIONS: Prevention programs for the management of depression in immigrant women should include an evaluation of acculturative conflict and stress and should consider marital and family conditions. PMID- 23341406 TI - Health beliefs and practice of breast self-examination among young Cypriot women. AB - PURPOSE: Breast cancer is the leading form of cancer affecting Cypriot women. This study is aimed at examining the factors influencing the choice of Cypriot women to perform breast self-examination (BSE). DESIGN: A cross-sectional, descriptive, and correlational study, with a sample of 94 young Cypriot women, was conducted. METHOD: The Greek version of Champion's Health Belief Model was used. Various statistical tests were implemented. FINDINGS: Almost all women (91.5%) had heard about BSE, and 71.3% had performed it sometime in the past. The susceptibility factor was significant in influencing women's behavior, while barriers and self-confidence were associated with practicing BSE. Knowledge on BSE and a high level of education were positively related with the frequency of practicing BSE. CONCLUSIONS: Proper education on BSE is important in shaping young women's attitudes. Any related health strategy should consider the concepts of Health Belief Model, especially the factors that make a female susceptible to breast cancer. PMID- 23341407 TI - Awareness of palliative care and end-of-life options among African Canadians in Nova Scotia. AB - PURPOSE: To assess, using qualitative methods, the knowledge African Canadians living in Nova Scotia have regarding their options for palliative and end-of-life (EOL) care. DESIGN: This project engaged caregivers in a Black community in Nova Scotia, Canada, in an exploration of palliative and EOL care. A group of six caregivers who cared for someone who had died were recruited through purposive sampling. The caregivers met three times to (1) discuss their experiences, (2) receive a presentation from the palliative care service, and (3) discuss whether those services would be beneficial. This was followed by a community meeting to discuss the findings. FINDINGS: Knowledge of options for palliative care services is limited. Family centered care may be a reason why "system" is generally not aware of the EOL experiences of African Nova Scotians. DISCUSSION: Information about palliative care services is not filtering down to the community in a way that is meaningful to families. Families tend to self-select services that assist them in providing care in the home setting. There is a need to engage Black communities and palliative care services in developing culturally appropriate services. PMID- 23341408 TI - Malaria prevention in Zambia: a practical application of the diffusion of innovations model. AB - Transcultural nursing educators can be change agents for health issues in other cultures. Yet unfamiliar disease processes and the foreign environment provide challenges that must be overcome to achieve a lasting, effective, and positive change. Rogers's Diffusion of Innovations Model can be used to plan and implement community-focused interventions into the cultures of developing nations, specifically malaria prevention in Zambia. Transcultural nurse educators could use concepts from the model to effect change in other cultures or communities. PMID- 23341409 TI - Factors affecting decision making in Hispanics experiencing myocardial infarction. AB - It was estimated that 785,000 new myocardial infarctions (MIs), 470,000 recurrent MIs, and 195,000 silent MIs will occur during 2010 in the United States. Cardiovascular disease, including heart disease and stroke, is the cause of death for 27% of Hispanic males and 31.5% of Hispanic females. There has been an increasing discrepancy between Hispanic knowledge in recognition of MI symptoms compared with non-Hispanic Whites. Only 5.6 % to 27.4 % of Hispanics know all MI symptoms and the need to immediately activate emergency medical services, compared with 11.9% to 45.8% of non-Hispanic Whites. The health belief model is used to explore the factors affecting decision making in Hispanics experiencing MI. Modifying factors explored include acculturation, language spoken, education, socioeconomic status, and access to health care. The results include recommendations for future research and clinical practice to assist in planning targeted interventions in Hispanic populations nationwide. PMID- 23341410 TI - Targeting tumor stroma: exploiting apoptotic priming. PMID- 23341411 TI - Neurotoxicity: better living through chemistry. PMID- 23341412 TI - Alpha brain-wave neurofeedback training reduces psychopathology in a cohort of male and female Canadian aboriginals. AB - OBJECTIVE: The study was conducted to determine if alpha brain-wave neurofeedback training can have positive psychological results by reducing anxiety and other psychopathology. METHOD: The cohort participated in alpha brain-wave neurofeedback training for 76 minutes (day 1) to 120 or more minutes (days 5-7) daily for 7 days. Electroencephalogram (EEG) electrodes were attached to the head with conductive gel according to the 10-20 International Electrode Placement System. During training, participants were seated in a comfortable armchair within a soundproof and lightproof room. Brain-wave signals were amplified for processing by analog-to-digital converters and polygraphs, then filtered to the pure delta, theta, alpha, beta, and gamma bands as well as subbands of these bands of the EEG. For 2-minute epochs, trainees sat with their eyes closed in the dark listening to their feedback tones as the filtered alpha brain-wave EEG signals controlled the loudness of the tones. Then a "ding" sounded and the tones stopped. For 8 seconds, a monitor lit up with dimly illuminated, static numbers, indicating the strength of their alpha brain waves, after which the feedback tones resumed and the process was repeated. PARTICIPANTS: 40 adult volunteers were recruited from the aboriginal population (First Nations, Metis, and Inuit) of Canada. The cohort ranged in age from 25 to 60 years and included males and females. SETTING: The study was conducted at Biocybernaut Institute of Canada in Victoria, British Columbia. PRIMARY OUTCOME MEASURES: Data was obtained to determine the effectiveness of this training by giving four psychological tests (Minnesota Multi-Phasic Personality Inventory, and the trait forms of the Multiple Affect Adjective Check List, Clyde Mood Scale, and Profile of Mood States) on the first day prior to commencing training and on the seventh day upon completion of the training. EEG data was also compiled throughout the training and analyzed as a factor of the training process. RESULTS: Postintervention data showed positive results with reduction of psychopathology when compared to the data from testing prior to the training. Analysis of this data showed improvement in several areas of psychopathology. CONCLUSION: Alpha brain-wave neurofeedback training daily for 7 days does have positive psychological results in adult male and female Canadian aboriginals as measured by data from four psychological tests on the participants. PMID- 23341413 TI - An orthomolecular approach to the prevention and treatment of psychiatric disorders. AB - Orthomolecular medicine is based on the use of endogenous and naturally occurring substances to supplement deficiencies in vitamins, minerals, and other essential substances in the human body. Although the medical community has long regarded it as a nonscientific approach to healing, scientific and clinical evidence is emerging for the supplemental use of orthomolecular medicine in the treatment of schizophrenia, depression, bipolar disorder, generalized anxiety disorder, and attention deficit hyperactivity disorder. Psychiatrists currently treat these common psychiatric disorders using a wide range of pharmacological approaches that often have significant side effects, resulting in patients' noncompliance. With newly gained knowledge about the neurophysiology and neuropathophysiology of psychiatric disorders, researchers now can link potential mechanisms for both pharmacological and orthomolecular treatments to physiological processes. In many cases, the use of orthomolecular supplements may provide a feasible addition to conventional drug therapy. PMID- 23341414 TI - Babies Need Healthy Moms: an innovative postpartum screening and education class for women who had gestational diabetes mellitus. AB - PURPOSE: Healthy Babies Need Healthy Moms (HBNHM) is an innovative education program that combines the recommended 2-hour postpartum oral glucose tolerance test (OGTT) with diabetes prevention education for women who had gestational diabetes mellitus. During the class, the 2-hour OGTT is performed, and in the time between venipunctures, the women participate in group education focused on evidence-based diabetes prevention strategies that promote healthy family nutrition and lifestyle behavior, importance of preconception care for subsequent pregnancies, and the need for follow-up care for women who screen positive for abnormal glucose levels. The purpose of this article is to describe this model to encourage replication in other diabetes programs. CONCLUSION: The HBNHM program is a low-budget education program that provides postpartum OGTT screening for women who had gestational diabetes mellitus during their pregnancies while simultaneously offering education designed to improve future outcomes. For those women whose screening is positive for overt diabetes or prediabetes, the educational strategies are directed at encouraging follow-up care. For those patients who have normal screening results, the program is designed to help the patient prevent the future development of type 2 diabetes. Preconception counseling is included in an effort to improve outcomes in future pregnancies and provide patients with the tools needed to help enhance the health of their families. PMID- 23341415 TI - Novel sexual-cycle-specific gene silencing in Aspergillus nidulans. AB - We report a novel sexual-cycle-specific gene-silencing system in the genetic model Aspergillus nidulans. Duplication of the mating type matA(HMG) gene in this haploid organism triggers Mat-induced silencing (MatIS) of both endogenous and transgenic matA genes, eliminates function of the encoded SRY structural ortholog, and results in formation of barren fruiting bodies. MatIS is spatiotemporally restricted to the prezygotic stage of the sexual cycle and does not interfere with vegetative growth, asexual reproduction, differentiation of early sexual tissues, or fruiting body development. MatIS is reversible upon deletion of the matA transgene. In contrast to other sex-specific silencing phenomena, MatIS silencing has nearly 100% efficiency and appears to be independent of homologous duplicated DNA segments. Remarkably, transgene-derived matA RNA might be sufficient to induce MatIS. A unique feature of MatIS is that RNA-mediated silencing is RNA interference/Argonaute-independent and is restricted to the nucleus having the duplicated gene. The silencing phenomenon is recessive and does not spread between nuclei within the common cytoplasm of a multinucleate heterokaryon. Gene silencing induced by matA gene duplication emerges as a specific feature associated with matA(HMG) regulation during sexual development. PMID- 23341416 TI - A comparison of models to infer the distribution of fitness effects of new mutations. AB - Knowing the distribution of fitness effects (DFE) of new mutations is important for several topics in evolutionary genetics. Existing computational methods with which to infer the DFE based on DNA polymorphism data have frequently assumed that the DFE can be approximated by a unimodal distribution, such as a lognormal or a gamma distribution. However, if the true DFE departs substantially from the assumed distribution (e.g., if the DFE is multimodal), this could lead to misleading inferences about its properties. We conducted simulations to test the performance of parametric and nonparametric discretized distribution models to infer the properties of the DFE for cases in which the true DFE is unimodal, bimodal, or multimodal. We found that lognormal and gamma distribution models can perform poorly in recovering the properties of the distribution if the true DFE is bimodal or multimodal, whereas discretized distribution models perform better. If there is a sufficient amount of data, the discretized models can detect a multimodal DFE and can accurately infer the mean effect and the average fixation probability of a new deleterious mutation. We fitted several models for the DFE of amino acid-changing mutations using whole-genome polymorphism data from Drosophila melanogaster and the house mouse subspecies Mus musculus castaneus. A lognormal DFE best explains the data for D. melanogaster, whereas we find evidence for a bimodal DFE in M. m. castaneus. PMID- 23341417 TI - Relationships between level of spiritual transformation and medical outcome. AB - CONTEXT: Culturally defined healers operate in most of the world, and to various degrees, blend traditional healing practices with those of the dominant religion in the region. They practice more or less openly and more or less in conjunction with science-based health professionals. Nonindigenous peoples are seeking out these healers more often, especially for conditions that carry dire prognoses, such as cancer, and usually after science-based medicine has failed. Little is known about the medical outcomes of people who seek Native North American healing, which is thought by its practitioners to work largely through spiritual means. OBJECTIVE: This study explored the narratives produced through interviews and writings of people working with traditional Aboriginal healers in Canada to assess the degree of spiritual transformation and to determine whether a relationship might exist between that transformation and subsequent changes in medical outcome. DESIGN: Before and after participation in traditional healing practices, participants were interviewed within a narrative inquiry framework and also wrote stories about their lives, their experiences of working with traditional healers, and the changes that the interactions produced. The current study used a variety of traditional healers who lived in Alberta, Saskatchewan, and Manitoba. SETTING: Urban and Rural Reserves of the Canadian Prairie Provinces. PARTICIPANTS: One hundred fifty non-Native individuals requested help from Dr Mehl-Madrona in finding traditional Aboriginal healing and spiritual practitioners and agreed to participate in this study of the effects of their work with the healers. INTERVENTION: The healers used methods derived from their specific cultural traditions, though all commonly used storytelling, These methods included traditional Aboriginal ceremonies and sweat lodge ceremonies, as well as other diagnosing ceremonies, such as the shaking tent among the Ojibway or the yuwipi ceremony of the Dakota, Nakota, and Lakota, and sacred-pipe-related practices. OUTCOME MEASURES: The research team used a combination of grounded theory modified from a critical constructivist point of view and narrative analysis to rate the degree of spiritual transformation experienced. Medical outcome was measured by a 5-point Likert scale and was confirmed with medical practitioners and other family members. RESULTS: A 5-year follow-up revealed that 44 of the reports were assessed as showing profound levels of persistent spiritual transformation, defined as a sudden and powerful improvement in the spiritual dimension of their lives. The level of spiritual transformation achieved through interaction with healers was associated in a doseresponse relationship with subsequent improvement in medical illness in 134 of 155 people (P < .0001). CONCLUSIONS: The degree and intensity of spiritual transformation appeared related to the degree of physical and psychological change among people interacting with traditional North American Indigenous healers. Further research is warranted. PMID- 23341418 TI - Massage for perioperative pain and anxiety in placement of vascular access devices. AB - CONTEXT: Despite major advances in cancer treatment, many patients undergo painful procedures during treatment and suffer debilitating side effects as well as report a decrease in quality of life (QOL). This problem is exacerbated for low-income, racial, and ethnic minorities with cancer. Minority cancer patients often enter care with larger tumors and with a more aggressive disease, increasing the risk of debilitating symptoms, such as pain and anxiety. Researchers have never assessed the feasibility and effectiveness of offering massage therapy for low-income, underserved cancer patients who are undergoing port insertion. OBJECTIVE: This study examined the feasibility of conducting a randomized, controlled trial (RCT) that would assess the use of massage therapy to reduce pain and anxiety in urban patients with cancer who undergo surgical placement of a vascular access device (port). The study also assessed the effectiveness of the intervention in reducing perioperative pain and anxiety. DESIGN: The research team conducted a 9-month RC T of 60 cancer patients undergoing port placement. The research team randomly assigned patients in a 2:1 ratio to usual care with massage therapy (intervention group) versus usual care with structured attention (control group). SETTING: The study took place at Boston Medical Center (BMC), which is an urban, tertiary-referral, safety-net hospital. PARTICIPANTS: Participants were cancer patients undergoing port placement. Sixty-seven percent were racial or ethnic minorities, and the majority were female and unemployed, with annual household incomes <$30 000 and publicly funded health insurance coverage. INTERVENTION: For the intervention, an expert panel developed a reproducible, standardized massage therapy intended for individuals undergoing surgical port insertion. Both groups received 20-minute interventions immediately pre- and postsurgery. The research team collected data on pain and anxiety before and after the preoperative and postoperative interventions as well as 1 day after the surgery. OUTCOME MEASURES: With respect to feasibility, the study examined (1) data about recruitment--time to complete enrollment and proportion of racial and ethnic minorities enrolled; (2) participants' retention; and (3) adherence to treatment allocation. The efficacy outcomes included measuring (1) participants' average pain level using an 11 point numerical rating scale (0 = no pain to 10 = worst possible pain) and (2) participants' situational anxiety using the State-Trait Anxiety Inventory (STAI). RESULTS: The research team assigned the 60 patients to the groups over 53 weeks. Sixty-seven percent of the participants were racial or ethnic minorities. A majority were female and unemployed, with annual household incomes <$30 000 and publicly funded health insurance coverage. Of the 40 patients allocated to massage therapy, the majority (n = 33) received both the pre- and postoperative interventions. Massage therapy participants had a statistically significant, greater reduction in anxiety after the first intervention compared with individuals receiving structured attention (-10.27 vs -5.21, P = .0037). CONCLUSIONS: Recruitment of low-income, minority patients into an RCT of massage therapy for perioperative pain and anxiety is feasible. Both massage therapy and structured attention proved beneficial for alleviating preoperative anxiety in cancer patients undergoing port placement. PMID- 23341419 TI - David Perlmutter, MD, FACN, ABIHM: Combating inflammation in the brain--what is good for the body is good for the brain. Interview by Karen Burnett. PMID- 23341420 TI - One hundred two tumors in 100 goats (1987-2011). AB - Of 1146 caprine necropsy or biopsy specimens submitted from 1987 through 2011 to the Veterinary Diagnostic Laboratory at Oregon State University, 100 goats (8.7%) had 102 tumors. Detailed records were available for 89 cases. Fifty-five goats were female, 17 were castrated males, and 12 were intact males. Breeds included 21 Nubian, 16 Pygmy, 10 Pygora, 8 Alpine, 4 Angora, 4 Saanen, 2 Toggenburg, and 9 crossbred goats. Dwarf, Nubian, and Saanen goats were overrepresented and Alpine and Boer goats underrepresented among cases with neoplastic disease in comparison to submissions overall. Age ranged from 7 months to 19 years (median, 7 years). Histopathology was performed on 97 tumors. Lymphoma (n = 17) was the most common tumor, followed by cutaneous squamous cell carcinoma (n = 10) and thymoma (n = 9). Most lymphomas were multicentric. All 7 mammary neoplasms were adenocarcinomas. Five of 7 vascular proliferations were hemangiosarcomas. All 4 melanocytic tumors were classified as (malignant) melanoma. Rarely reported caprine tumors included a choroid plexus carcinoma, 2 rhabdomyosarcomas, and 3 pheochromocytomas. Cutaneous round cell tumors were provisionally diagnosed as 2 histiocytomas and 5 mast cell tumors. Single cases of previously unreported caprine tumors included amyloid-producing odontogenic tumor, myxosarcoma, sebaceous carcinoma, apocrine sweat gland adenoma, and thyroid carcinoma. Nonneoplastic entities included 2 cases of mammary fibroadenomatous hyperplasia and single cases of vascular hamartoma, cervical adenomatous hyperplasia, and cervical leiomyofibromatosis. The results of this 25-year retrospective study indicate that lymphoma in particular and tumors in general are common in goats. PMID- 23341422 TI - Pesticides: our children in jeopardy. PMID- 23341423 TI - For the assessment of intestinal permeability, size matters. AB - The purpose of this review is to demonstrate that an intestine leaky to small molecules can be impermeable to large antigenic molecules. The author proposes that the permeability of the epithelium to very small sugar molecules such as lactulose/mannitol-used for the past 50 years to gauge intestinal permeability does not necessarily correlate with epithelial permeability to macromolecules. This article begins with the history and science behind the use of small sugars to measure permeability, a method developed in 1899. The lactulose/mannitol test may give useful information regarding the overall condition of the digestive tract; however, the author suggests that the test is not indicative of the transport of macromolecules such as bacterial toxins and food antigens, which have the capacity to damage the structure of the intestinal barrier and/or challenge the immune system. This article describes the various mechanisms and physiological transport pathways through which increased antigen uptake may result in immunological reactions to food antigens and bacterial lipopolysaccharides, resulting in the pathogenesis of disease. Finally, the article presents evidence indicating that increased intestinal, antigenic permeability plays a key role in the development of various inflammatory and autoimmune disorders. Therefore, more knowledge about the epithelium's permeability to large molecules undoubtedly contributes not only to early detection but also to secondary prevention of many inflammatory autoimmune, neuroimmune, and neurodegenerative disorders. PMID- 23341424 TI - Anti-inflammatory activity of the hexane extract of Byrsonima crassifolia seeds in experimental animal models. AB - CONTEXT: Byrsonima crassifolia is a tropical tree, commonly known as nance and distributed widely in Mexico and Central and South America. Since pre- Hispanic times, the seeds of the fruits have been used in folklore medicine as an anti inflammatory; however, currently no researchers have examined its potential pharmacological properties in scientific studies. OBJECTIVE: This study investigated the anti-inflammatory activity of extracts obtained with the solvents n-hexane, chloroform, and methanol from seeds of B crassifolia. DESIGN: The research team induced edemas in Wistar rats with 12-O-tetradecanoylphorbol (TPA), formaldehyde, carrageenan, and histamine to study the anti-inflammatory activity of the three organic extracts of seeds from B crassifolia. The team also used the cotton-pellet granuloma method to induce edemas in Wistar rats and study the inhibitory effect of the three extracts from B crassifolia. Finally, the team examined the participation of the nitric oxide (NO) system in the anti inflammatory activity of the hexane extract of nance seeds (NS), diclorofenac, and L-NAME as well as the effects of L-arginine and D-arginine on the antiinflammatory actions of the compounds. SETTING: This research was conducted in the Laboratory of Research of Natural Products, School of Chemical Engineering, National Polytechnic Institute (IPNESIQIE) and Department of Biotechnology and Bioengineering, Cinvestav-IPN, Av. IPN 2508, Col. San Pedro Zacatenco, Mexico D.F., CP 07360, Mexico. OUTCOME MEASURES: The research team measured the edema that the solvents caused, either in the ears of rats for tetradecanoylphorbol or in the paws for formaldehyde, carrageenan, and histamine. To study the antiproliferative effects of the extracts after implantation of the cotton-pellet granuloma, the team determined the wet and dry weights of the pellets, after drying at 70 degrees C for 1 hour in the second case. To study the participation of the NO system in the anti-inflammatory activity of the hexane extract of NS, diclofenac, and L-NAME, the research team measured paw edema. RESULTS: Among the extracts tested, NS showed the most significant anti inflammatory activity. That extract decreased the paw edema that carrageenan, formaldehyde, histamine, and cotton pellet-induced, either by oral or topical administration at doses of 200 mg/kg, with 31%, 66%, 83%, and 58.2% inhibition respectively. In addition, NS inhibited the ear edema that TPA induced by 62%. Methanol and chloroform extracts produced a small effect, so the team does not present the results in this article. L-arginine, a precursor of NO, significantly inhibited the anti-inflammatory effects of NS and L-NAME, an anti-inflammatory drug, on mouse paw edema, but D-arginine did not. In contrast, neither D-arginine nor L-arginine inhibited the anti-inflammatory effects that diclofenac produced. These results indicate that the anti-inflammatory effect of NS on mouse paw edema occurs via the inhibition of NO production, as does the anti-inflammatory effect of L-NAME but not the anti-inflammatory effect of diclofenac. The anti inflammatory activity of NS was comparable to standard anti-inflammatory drugs such as indomethacin, dexamethasone, and sodium diclofenac. CONCLUSIONS: The hexane extract from seeds of B crassifolia exhibited significant anti inflammatory activity in both acute and chronic inflammatory models with a partial contribution of inhibitory actions on some cellular inflammatory responses. The anti-inflammatory mechanism of NS may be related to the other isoform (iNOS). PMID- 23341425 TI - Arterial blood pressure and cardiovascular responses to yoga practice. AB - CONTEXT: Yoga is qualitatively different from any other mode of physical activity in that it consists of a unique combination of isometric muscular contractions, stretching exercises, relaxation techniques, and breathing exercises. In particular, yoga postures consist of systemic isometric contractions that are known to elicit marked increases in mean blood pressure that are not observed during dynamic exercise. Stretching can also induce increases in blood pressure and sympathetic nerve activity in the muscles. Currently, not much is known about changes in blood pressure and other cardiovascular responses to yoga practice. OBJECTIVE: The study intended to determine the acute effects of one session of hatha yoga practice on blood pressure and other cardiovascular responses. To gain insight into the long-term effects of yoga practice, both novice (n = 19) and advanced (n = 18) yoga practitioners were studied. DESIGN: The two groups were matched for age, gender, BMI, and blood pressure. SETTING: The setting was a research laboratory at a university. PARTICIPANTS: Thirty-six apparently healthy, nonobese, sedentary, or recreationally active individuals from the community participated in the study. Intervention The intervention comprised one session of yoga practice, in which participants followed a custom made instructional video providing a yoga routine that consisted of a series of 23 hatha-based yoga postures. OUTCOME MEASURES: Prior to arriving at the laboratory, each participant completed a research health questionnaire, a training-status questionnaire, and a yoga-experience questionnaire. Prior to the yoga practice, each participant's height, body fat percentage, trunk or lumbar flexibility, and arterial stiffness as assessed by carotid femoral pulse wave velocity (cfPWV) were measured. For each posture during the yoga practice, the study continuously measured systolic, mean, and diastolic blood pressures, heart rate, stroke volume, and cardiac output. RESULTS: Systolic, mean, and diastolic blood pressures increased significantly during the yoga practice. The magnitude of these increases in blood pressure was greatest with standing postures. Heart rate and cardiac output increased significantly during yoga practice, especially with standing postures. Overall, no differences existed in cardiovascular responses between the novice and advanced practitioners throughout the yoga testing session; cfPWV velocity was significantly and inversely associated with lumbar flexion but not with sit and-reach test scores. CONCLUSIONS: The research team concluded that a variety of hatha yoga postures, especially standing postures, evoked significant increases in blood pressure. The elevation in blood pressure due to yoga practice was associated with increases in cardiac output and heart rate, which are responses similar to those observed in isometric exercise. The lack of obvious differences in blood pressure and other cardiovascular responses between novice and advanced yoga practitioners suggests that long-term yoga practice does not attenuate acute yoga responses. PMID- 23341426 TI - Acute electroencephalographic effects from repeated olfactory administration of homeopathic remedies in individuals with self-reported chemical sensitivity. AB - BACKGROUND: Homeopaths report that individuals with heightened self-reported environmental chemical intolerance (CI) exhibit increased reactivity to homeopathic remedies. Persons high in CI sensitize their electroencephalographic (EEG) alpha responses to repeated intermittent chemical exposures. PRIMARY STUDY OBJECTIVE: The present feasibility study explored interactions between CI and one of two specific homeopathic remedies over time (Sulphur or Pulsatilla nigricans [Pulsatilla]). DESIGN: This study used a two-arm, double-blind, placebo controlled repeated measures design. Intervention Participants underwent a series of three once-weekly sessions during which they repeatedly sniffed one remedy (6c, 12c, 30c; one potency per week) matched to their Homeopathic Constitutional Type Questionnaire (CTQ) type and two solvent controls (distilled water and a waterethanol [95%] solution). Within sessions, remedies and control solvents were administered via 2-second sniffs (eight sniffs of each of four different succussion levels per potency, in randomized order). PARTICIPANTS: Participants were college student volunteers (N = 96, ages 18-30, both sexes), screened for good health and relatively elevated Sulphur or Pulsatilla symptom pattern scores on the Homeopathic Constitutional Type Questionnaire (CTQ). Participants also completed a validated trait CI scale. PRIMARY OUTCOME MEASURES: Average 19-lead relative EEG alpha power (alpha 1 8-10 Hz; alpha 2 10-12 Hz). RESULTS: Trait CI interacted significantly with time factors for each remedy (both over visit weeks and over sniff cycles during sessions). The patterns were nonlinear and differed between the two remedies. Individuals high in CI showed greater variability over time in remedy EEG alpha effects than did those low in CI. CONCLUSION: The data suggest that CI, with an underlying susceptibility to time-dependent sensitization and oscillatory responses, could contribute to nonlinear dose response patterns and inconsistent reproducibility of homeopathic clinical care and research. PMID- 23341427 TI - Chinese medicine for mental disorder and its applications in psychosomatic diseases. AB - With the development of modern medicine, an increasing awareness has developed regarding the limitations of a specialized and compartmentalized approach to clinical practice that largely ignores the interconnectedness of the mind, body, and spirit. Although contemporary medicine now accepts this interconnectedness, practitioners tend to think that the emotions play a secondary or excitatory role in producing disease rather than being a primary causative factor. Traditional Chinese medicine (TCM), which stems from Confucianism, Buddhism, and Daoism, views the body and the spirit as inseparable. This construct provides the foundation for the whole system of TCM, and therefore constitutes the backbone of TCM. This article presents the ways in which emotion can act as an internal etiological factor that produces a pathogenic mechanism and that underlies various psychosomatic diseases. Therefore, this article intends to integrate the ancient classic treatise established in the Yellow Emperor's Canon of Internal Medicine with current data. Likewise, the authors discuss their empirical experience to illustrate the following concepts: (1) the factors contributing to emotional impairment; (2) the holistic approach to diagnosing psychosomatic disease; (3) the integrative therapy necessary to restore the balance of body and mind; and (4) the role of emotional theory in nursing care and the prevention of psychosomatic disease. PMID- 23341428 TI - Aristo Vojdani, PhD: environmental factors and autoimmune disease. PMID- 23341429 TI - Contradictory results with high-dosage rifamycin in mice and humans. PMID- 23341430 TI - Reply to "Contradictory results with high-dosage rifamycin in mice and humans". PMID- 23341432 TI - Late diagnosis, delayed presentation and late presentation in HIV: proposed definitions, methodological considerations and health implications. AB - Contemporary literature emphasizes HIV treatment across multiple stages of the care continuum, beginning with HIV testing, followed by linkage and retention in medical care. As a sizeable global population remains undiagnosed or not engaged in medical care, researchers must evaluate the earliest phases of the HIV treatment cascade in order to optimize individual health outcomes and treatment as-prevention initiatives. Because ambiguity persists for classification of these early stages of HIV care, the aim of this review is to propose a congruous approach to defining the constructs of late diagnosis, delayed presentation and late presentation for HIV medical care, as well as focus attention on methodological considerations and associated clinical and public health implications for these entities. PMID- 23341433 TI - Scattering by linear defects in graphene: a tight-binding approach. AB - We develop an analytical scattering formalism for computing the transmittance through periodic defect lines within the tight-binding model of graphene. We first illustrate the method with a relatively simple case, the pentagon-only defect line. Afterwards, more complex defect lines are treated, namely the zz(558) and the zz(5757) ones. The formalism developed uses only simple tight binding concepts, reducing the problem to matrix manipulations which can be easily worked out by any computational algebraic calculator. PMID- 23341434 TI - Semantic fluency and phonemic fluency: regression-based norms for the Portuguese population. AB - The main goal of this study was to produce adjusted normative data for the Portuguese population on two verbal fluency measures: the semantic fluency test (animals category) and the phonemic fluency test (letters M, R, and P). The study included 950 community-dwelling individuals (624 women and 326 men) aged between 18 and 98 (mean = 57.8, SD = 19.0), who had educational backgrounds ranging from 0 to 20 years (mean = 8.8, SD = 5.2). The results showed that age and education were significantly associated with semantic fluency and phonemic fluency performance. These demographic characteristics accounted for 42% of the semantic fluency and between 23% and 31% of the phonemic fluency performance variance. No significant sex effects were found. The normative data are presented as regression-based algorithms to adjust test scores for age and education, with subsequent correspondence between adjusted scores and percentile distribution. PMID- 23341435 TI - Developmental aspects of working and associative memory. AB - Developmental differences between working and long-term associative memory were evaluated through a cross-sectional age difference study based on data from a memory battery's standardization sample. The scores of 856 children and adolescents ranging from 5 to 17 years of age were compared on memory subtests that assess verbal working and long-term memory. Data were examined using curve fitting and ANOVA procedures that evaluated age group and years of age differences. The major finding was that the developmental trajectories across age differed substantially between the two memory domains. The working memory trajectory was linear until age 11, whereas the long-term memory trajectory was curvilinear with an inflection point at age 8. Both trajectories plateaued after age 11. ANOVAs produced significant interactions between tests of working and associative memory with age, supporting the view that the age trajectories had differing courses. The results are discussed in terms of neurobiological implications for the two memory systems studied. PMID- 23341436 TI - Study of B1 (NaCl-type) to B2 (CsCl-type) pressure-induced structural phase transition in BaS, BaSe and BaTe using ab initio computations. AB - We have studied the pressure-induced phase transitions from NaCl-type (B1) to CsCl-type (B2) structure in BaS, BaSe and BaTe by using ab initio density functional theory computations in the local density approximation. The Buerger and WTM mechanisms were explored by mapping the enthalpy contours in two- and four-dimensional configuration space for the two mechanisms, respectively. Transition pressures for BaS, BaSe and BaTe were determined to be 5.5 GPa, 4.9 GPa and 3.4 GPa, respectively. From these configuration space landscapes, a low enthalpy barrier path was constructed for the transitions to proceed at three different pressures. We obtained barriers of 0.18, 0.16 and 0.15 eV/pair (17.4, 15.4 and 14.5 kJ mol(-1)) for the Buerger mechanism and 0.13, 0.13 and 0.12 eV/pair (12.5, 12.5 and 11.6 kJ mol(-1)) for the WTM mechanism at the transition pressures for BaS, BaSe and BaTe, respectively, indicating that the WTM mechanism is slightly more favorable in these compounds. We describe the difference between the two mechanisms by differences in their symmetry and atomic coordination. PMID- 23341437 TI - Combinations of stressors in midlife: examining role and domain stressors using regression trees and random forests. AB - OBJECTIVES: Global perceptions of stress (GPS) have major implications for mental and physical health, and stress in midlife may influence adaptation in later life. Thus, it is important to determine the unique and interactive effects of diverse influences of role stress (at work or in personal relationships), loneliness, life events, time pressure, caregiving, finances, discrimination, and neighborhood circumstances on these GPS. METHOD: Exploratory regression trees and random forests were used to examine complex interactions among myriad events and chronic stressors in middle-aged participants' (N = 410; mean age = 52.12) GPS. RESULTS: Different role and domain stressors were influential at high and low levels of loneliness. Varied combinations of these stressors resulting in similar levels of perceived stress are also outlined as examples of equifinality. Loneliness emerged as an important predictor across trees. DISCUSSION: Exploring multiple stressors simultaneously provides insights into the diversity of stressor combinations across individuals--even those with similar levels of global perceived stress--and answers theoretical mandates to better understand the influence of stress by sampling from many domain and role stressors. Further, the unique influences of each predictor relative to the others inform theory and applied work. Finally, examples of equifinality and multifinality call for targeted interventions. PMID- 23341438 TI - Derivation of multiple cranial tissues and isolation of lens epithelium-like cells from human embryonic stem cells. AB - Human embryonic stem cells (hESCs) provide a powerful tool to investigate early events occurring during human embryonic development. In the present study, we induced differentiation of hESCs in conditions that allowed formation of neural and non-neural ectoderm and to a lesser extent mesoderm. These tissues are required for correct specification of the neural plate border, an early embryonic transient structure from which neural crest cells (NCs) and cranial placodes (CPs) originate. Although isolation of CP derivatives from hESCs has not been previously reported, isolation of hESC-derived NC-like cells has been already described. We performed a more detailed analysis of fluorescence-activated cell sorting (FACS)-purified cell populations using the surface antigens previously used to select hESC-derived NC-like cells, p75 and HNK-1, and uncovered their heterogeneous nature. In addition to the NC component, we identified a neural component within these populations using known surface markers, such as CD15 and FORSE1. We have further exploited this information to facilitate the isolation and purification by FACS of a CP derivative, the lens, from differentiating hESCs. Two surface markers expressed on lens cells, c-Met/HGFR and CD44, were used for positive selection of multiple populations with a simultaneous subtraction of the neural/NC component mediated by p75, HNK-1, and CD15. In particular, the c-Met/HGFR allowed early isolation of proliferative lens epithelium-like cells capable of forming lentoid bodies. Isolation of hESC derived lens cells represents an important step toward the understanding of human lens development and regeneration and the devising of future therapeutic applications. PMID- 23341439 TI - Reprogramming of fibroblasts from older women with pelvic floor disorders alters cellular behavior associated with donor age. AB - We aimed to derive induced pluripotent stem cell (iPSC) lines from vaginal fibroblasts from older women with pelvic organ prolapse. We examined the effect of donor age on iPSCs and on the cells redifferentiated from these iPSCs. Vaginal fibroblasts were isolated from younger and older subjects for reprogramming. iPSCs were generated simultaneously using an excisable polycistronic lentiviral vector expressing Oct4, Klf4, Sox2, and cMyc. The pluripotent markers of iPSCs were confirmed by immunocytochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Spectral karyotyping was performed. The ability of the iPSCs to differentiate into three germ layers was confirmed by embryoid body and teratoma formation. Senescence marker (p21, p53, and Bax) expressions were determined by qRT-PCR and Western blot. The iPSCs were redifferentiated to fibroblasts and were evaluated with senescence-associated beta-galactosidase (SA) activity and mitotic index using time-lapse dark-field microscopy. iPSCs derived from both the younger and older subjects expressed pluripotency markers and showed normal karyotype and positive teratoma assays. There was no significant difference in expression of senescence and apoptosis markers (p21, p53, and Bax) in iPSCs derived from the younger subject compared with the older subject. Furthermore, fibroblasts redifferentiated from these iPSCs did not differ in SA activity or mitotic index. We report successful derivation of iPSCs from women with pelvic organ prolapse. Older age did not interfere with successful reprogramming. Donor age differences were not observed in these iPSCs using standard senescence markers, and donor age did not appear to affect cell mitotic activity in fibroblasts redifferentiated from iPSCs. PMID- 23341440 TI - Comparative analysis of targeted differentiation of human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells reveals variability associated with incomplete transgene silencing in retrovirally derived hiPSC lines. AB - Functional hepatocytes, cardiomyocytes, neurons, and retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) could provide a defined and renewable source of human cells relevant for cell replacement therapies, drug discovery, toxicology testing, and disease modeling. In this study, we investigated the differences between the differentiation potentials of three hESC lines, four retrovirally derived hiPSC lines, and one hiPSC line derived with the nonintegrating Sendai virus technology. Four independent protocols were used for hepatocyte, cardiomyocyte, neuronal, and RPE cell differentiation. Overall, cells differentiated from hESCs and hiPSCs showed functional similarities and similar expression of genes characteristic of specific cell types, and differences between individual cell lines were also detected. Reactivation of transgenic OCT4 was detected specifically during RPE differentiation in the retrovirally derived lines, which may have affected the outcome of differentiation with these hiPSCs. One of the hiPSC lines was inferior in all directions, and it failed to produce hepatocytes. Exogenous KLF4 was incompletely silenced in this cell line. No transgene expression was detected in the Sendai virus-derived hiPSC line. These findings highlight the problems related to transgene expression in retrovirally derived hiPSC lines. PMID- 23341441 TI - Differentiation of CD133+ stem cells from amyotrophic lateral sclerosis patients into preneuron cells. AB - Improvements in quality of life and life expectancy have been observed in amyotrophic lateral sclerosis (ALS) patients transplanted with CD133(+) stem cells into their frontal motor cortices. However, questions have emerged about the capacity of cells from these patients to engraft and differentiate into neurons. The objective of this work was to evaluate the in vitro capacity of CD133(+) stem cells from 13 ALS patients to differentiate into neuron lineage. Stem cells were obtained through leukapheresis and cultured in a control medium or a neuroinduction medium for 2-48 hours. Expression of neuronal genes was analyzed by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical techniques. Fluorescence microscopy demonstrated that CD133(+) stem cells from ALS patients incubated for 48 hours in a neuroinduction medium increased the detection of neuronal proteins such as nestin, beta-tubulin III, neuronal-specific enolase, and glial fibrillary acidic protein. RT-PCR assays demonstrated an increase in the expression of beta-tubulin III, nestin, Olig2, Islet-1, Hb9, and Nkx6.1. No correlation was found between age, sex, or ALS functional scale and the CD133(+) stem cell response to the neuroinduction medium. We conclude that CD133(+) stem cells from ALS patients, like the stem cells of healthy subjects, are capable of differentiating into preneuron cells. PMID- 23341443 TI - A Markovian kinetic equation approach to electron transport through a quantum dot coupled to superconducting leads. AB - We present a derivation of the Markovian master equation for an out-of equilibrium quantum dot connected to two superconducting reservoirs, which are described by the Bogoliubov-de Gennes Hamiltonians and have the chemical potentials, the temperatures, and the complex order parameters as the relevant quantities. We consider a specific example in which the quantum dot is represented by the Anderson impurity model and study the transport properties, proximity effect and Andreev bound states in equilibrium as well as far-from equilibrium setups. PMID- 23341442 TI - Elevated nuclear factor erythroid-2 levels promote epo-independent erythroid maturation and recapitulate the hematopoietic stem cell and common myeloid progenitor expansion observed in polycythemia vera patients. AB - The molecular etiology of polycythemia vera (PV) remains incompletely understood. Patients harbor increased numbers of hematopoietic stem cells and display Epo independent erythroid maturation. However, the molecular mechanism underlying Epo hypersensitivity and stem cell expansion is unclear. We have previously shown that the transcription factor nuclear factor erythroid-2 (NF-E2) is overexpressed in the majority of PV patients. Here we demonstrated that elevation of NF-E2 expression in healthy CD34(+) cells to levels observed in PV caused Epo independent erythroid maturation and expansion of hematopoietic stem cell (HSC) and common myeloid progenitor (CMP) cell numbers. Silencing NF-E2 in PV patients reverted both aberrancies, demonstrating for the first time that NF-E2 overexpression is both required and sufficient for Epo independence and HSC/CMP expansion in PV. PMID- 23341444 TI - 2012 -- That was the year that was. AB - Geriatric medicine has an encyclopaedic sweep, reflecting the complexity of both the ageing process and of our patient group. Keeping up with, and making sense of, the relevant scientific literature is challenging, especially as ageing has increased in prominence as a focus of research across many branches of the sciences and the humanities. This review of research published in 2012 in generalist, geriatric medicine and gerontology journals has been compiled with a view to extracting those aspects of research into ageing which could be considered relevant not only to the practice of geriatric medicine, but also to our understanding of the ageing process and the relationship of geriatric medicine to other medical specialties and public health. The research discussed includes new insights into global ageing and the compression of morbidity; nosological, clinical and therapeutic aspects of dementia; an innovative study on the microbiome and ageing; epidemiological perspectives into multi-morbidity; an overview of the impact of the first waves of Baby Boomers; fresh thinking on geriatric syndromes such as orthostatic hypotension, kyphosis, urinary incontinence after stroke, frailty and elder abuse; an update of the Beers criteria and the first stirrings of recognition of the longevity dividend in the biomedical literature. PMID- 23341445 TI - The experiences of suffering of palliative care informal caregivers in Malaysia: a thematic analysis. AB - A qualitative study was conducted with semi-structured interviews to explore the experiences of suffering in 15 palliative care informal caregivers in University Malaya Medical Centre. The data were thematically analyzed. Seven basic themes were generated (1) empathic suffering, (2) anticipatory grief, (3) obsessive compulsive suffering, (4) helpless-powerless suffering, (5) obligatory suffering, (6) impedimental suffering, and (7) repercussion suffering. A model of compassion suffering was conceptualized from the analysis. This model may serve as a guide in the assessment and management of suffering in palliative care informal caregivers. PMID- 23341447 TI - beta-Arrestin recruitment and G protein signaling by the atypical human chemokine decoy receptor CCX-CKR. AB - Chemokine receptors form a large subfamily of G protein-coupled receptors that predominantly activate heterotrimeric Gi proteins and are involved in immune cell migration. CCX-CKR is an atypical chemokine receptor with high affinity for CCL19, CCL21, and CCL25 chemokines, but is not known to activate intracellular signaling pathways. However, CCX-CKR acts as decoy receptor and efficiently internalizes these chemokines, thereby preventing their interaction with other chemokine receptors, like CCR7 and CCR9. Internalization of fluorescently labeled CCL19 correlated with beta-arrestin2-GFP translocation. Moreover, recruitment of beta-arrestins to CCX-CKR in response to CCL19, CCL21, and CCL25 was demonstrated using enzyme-fragment complementation and bioluminescence resonance energy transfer methods. To unravel why CCX-CKR is unable to activate Gi signaling, CCX CKR chimeras were constructed by substituting its intracellular loops with the corresponding CCR7 or CCR9 domains. The signaling properties of chimeric CCX-CKR receptors were characterized using a cAMP-responsive element (CRE)-driven reporter gene assay. Unexpectedly, wild type CCX-CKR and a subset of the chimeras induced an increase in CRE activity in response to CCL19, CCL21, and CCL25 in the presence of the Gi inhibitor pertussis toxin. CCX-CKR signaling to CRE required an intact DRY motif. These data suggest that inactive Gi proteins impair CCX-CKR signaling most likely by hindering the interaction of this receptor with pertussis toxin-insensitive G proteins that transduce signaling to CRE. On the other hand, recruitment of the putative signaling scaffold beta-arrestin to CCX CKR in response to chemokines might allow activation of yet to be identified signal transduction pathways. PMID- 23341446 TI - Identification of biologically relevant enhancers in human erythroid cells. AB - Identification of cell type-specific enhancers is important for understanding the regulation of programs controlling cellular development and differentiation. Enhancers are typically marked by the co-transcriptional activator protein p300 or by groups of cell-expressed transcription factors. We hypothesized that a unique set of enhancers regulates gene expression in human erythroid cells, a highly specialized cell type evolved to provide adequate amounts of oxygen throughout the body. Using chromatin immunoprecipitation followed by massively parallel sequencing, genome-wide maps of candidate enhancers were constructed for p300 and four transcription factors, GATA1, NF-E2, KLF1, and SCL, using primary human erythroid cells. These data were combined with gene expression analyses, and candidate enhancers were identified. Consistent with their predicted function as candidate enhancers, there was statistically significant enrichment of p300 and combinations of co-localizing erythroid transcription factors within 1-50 kb of the transcriptional start site (TSS) of genes highly expressed in erythroid cells. Candidate enhancers were also enriched near genes with known erythroid cell function or phenotype. Candidate enhancers exhibited moderate conservation with mouse and minimal conservation with nonplacental vertebrates. Candidate enhancers were mapped to a set of erythroid-associated, biologically relevant, SNPs from the genome-wide association studies (GWAS) catalogue of NHGRI, National Institutes of Health. Fourteen candidate enhancers, representing 10 genetic loci, mapped to sites associated with biologically relevant erythroid traits. Fragments from these loci directed statistically significant expression in reporter gene assays. Identification of enhancers in human erythroid cells will allow a better understanding of erythroid cell development, differentiation, structure, and function and provide insights into inherited and acquired hematologic disease. PMID- 23341448 TI - A structural view on the functional importance of the sugar moiety and steroid hydroxyls of cardiotonic steroids in binding to Na,K-ATPase. AB - The Na,K-ATPase is specifically inhibited by cardiotonic steroids (CTSs) like digoxin and is of significant therapeutic value in the treatment of congestive heart failure and arrhythmia. Recently, new interest has arisen in developing Na,K-ATPase inhibitors as anticancer agents. In the present study, we compare the potency and rate of inhibition as well as the reactivation of enzyme activity following inhibition by various cardiac glycosides and their aglycones at different pH values using shark Na,K-ATPase stabilized in the E2MgPi or in the E2BeFx conformations. The effects of the number and nature of various sugar residues as well as changes in the positions of hydroxyl groups on the beta-side of the steroid core of cardiotonic steroids were investigated by comparing various cardiac glycoside compounds like ouabain, digoxin, digitoxin, and gitoxin with their aglycones. The results confirm our previous hypothesis that CTS binds primarily to the E2-P ground state through an extracellular access channel and that binding of extracellular Na(+) ions to K(+) binding sites relieved the CTS inhibition. This reactivation depended on the presence or absence of the sugar moiety on the CTS, and a single sugar is enough to impede reactivation. Finally, increasing the number of hydroxyl groups of the steroid was sterically unfavorable and was found to decrease the inhibitory potency and to confer high pH sensitivity, depending on their position on the steroid beta-face. The results are discussed with reference to the recent crystal structures of Na,K-ATPase in the unbound and ouabain-bound states. PMID- 23341449 TI - The polysialyltransferases interact with sequences in two domains of the neural cell adhesion molecule to allow its polysialylation. AB - The neural cell adhesion molecule (NCAM) is the major substrate for the polysialyltransferases (polySTs), ST8SiaII/STX and ST8SiaIV/PST. The polysialylation of NCAM N-glycans decreases cell adhesion and alters signaling. Previous work demonstrated that the first fibronectin type III repeat (FN1) of NCAM is required for polyST recognition and the polysialylation of the N-glycans on the adjacent Ig5 domain. In this work, we highlight the importance of an FN1 acidic patch in polyST recognition and also reveal that the polySTs are required to interact with sequences in the Ig5 domain for polysialylation to occur. We find that features of the Ig5 domain of the olfactory cell adhesion molecule (OCAM) are responsible for its lack of polysialylation. Specifically, two basic OCAM Ig5 residues (Lys and Arg) found near asparagines equivalent to those carrying the polysialylated N-glycans in NCAM substantially decrease or eliminate polysialylation when used to replace the smaller and more neutral residues (Ser and Asn) in analogous positions in NCAM Ig5. This decrease in polysialylation does not reflect altered glycosylation but instead is correlated with a decrease in polyST-NCAM binding. In addition, inserting non-conserved OCAM sequences into NCAM Ig5, including an "extra" N-glycosylation site, decreases or completely blocks NCAM polysialylation. Taken together, these results indicate that the polySTs not only recognize an acidic patch in the FN1 domain of NCAM but also must contact sequences in the Ig5 domain for polysialylation of Ig5 N-glycans to occur. PMID- 23341450 TI - Ubiquitinated proteins activate the proteasomal ATPases by binding to Usp14 or Uch37 homologs. AB - Degradation of ubiquitinated proteins by 26 S proteasomes requires ATP hydrolysis, but it is unclear how the proteasomal ATPases are regulated and how proteolysis, substrate deubiquitination, degradation, and ATP hydrolysis are coordinated. Polyubiquitinated proteins were shown to stimulate ATP hydrolysis by purified proteasomes, but only if the proteins contain a loosely folded domain. If they were not ubiquitinated, such proteins did not increase ATPase activity. However, they did so upon addition of ubiquitin aldehyde, which mimics the ubiquitin chain and binds to 26 S-associated deubiquitinating enzymes (DUBs): in yeast to Ubp6, which is essential for the ATPase activation, and in mammalian 26 S to the Ubp6 homolog, Usp14, and Uch37. Occupancy of either DUB by a ubiquitin conjugate leads to ATPase stimulation, thereby coupling deubiquitination and ATP hydrolysis. Thus, ubiquitinated loosely folded proteins, after becoming bound to the 26 S, interact with Ubp6/Usp14 or Uch37 to activate ATP hydrolysis and enhance their own destruction. PMID- 23341451 TI - Fucoidan is a novel platelet agonist for the C-type lectin-like receptor 2 (CLEC 2). AB - Fucoidan, a sulfated polysaccharide from Fucus vesiculosus, decreases bleeding time and clotting time in hemophilia, possibly through inhibition of tissue factor pathway inhibitor. However, its effect on platelets and the receptor by which fucoidan induces cellular processes has not been elucidated. In this study, we demonstrate that fucoidan induces platelet activation in a concentration dependent manner. Fucoidan-induced platelet activation was completely abolished by the pan-Src family kinase (SFK) inhibitor, PP2, or when Syk is inhibited. PP2 abolished phosphorylations of Syk and Phospholipase C-gamma2. Fucoidan-induced platelet activation had a lag phase, which is reminiscent of platelet activation by collagen and CLEC-2 receptor agonists. Platelet activation by fucoidan was only slightly inhibited in FcRgamma-chain null mice, indicating that fucoidan was not acting primarily through GPVI receptor. On the other hand, fucoidan-induced platelet activation was inhibited in platelet-specific CLEC-2 knock-out murine platelets revealing CLEC-2 as a physiological target of fucoidan. Thus, our data show fucoidan as a novel CLEC-2 receptor agonist that activates platelets through a SFK-dependent signaling pathway. Furthermore, the efficacy of fucoidan in hemophilia raises the possibility that decreased bleeding times could be achieved through activation of platelets. PMID- 23341452 TI - Solid-state NMR study reveals collagen I structural modifications of amino acid side chains upon fibrillogenesis. AB - In vivo, collagen I, the major structural protein in human body, is found assembled into fibrils. In the present work, we study a high concentrated collagen sample in its soluble, fibrillar, and denatured states using one and two dimensional {(1)H}-(13)C solid-state NMR spectroscopy. We interpret (13)C chemical shift variations in terms of dihedral angle conformation changes. Our data show that fibrillogenesis increases the side chain and backbone structural complexity. Nevertheless, only three to five rotameric equilibria are found for each amino acid residue, indicating a relatively low structural heterogeneity of collagen upon fibrillogenesis. Using side chain statistical data, we calculate equilibrium constants for a great number of amino acid residues. Moreover, based on a (13)C quantitative spectrum, we estimate the percentage of residues implicated in each equilibrium. Our data indicate that fibril formation greatly affects hydroxyproline and proline prolyl pucker ring conformation. Finally, we discuss the implication of these structural data and propose a model in which the attractive force of fibrillogenesis comes from a structural reorganization of 10 to 15% of the amino acids. These results allow us to further understand the self assembling process and fibrillar structure of collagen. PMID- 23341453 TI - The molecular mechanism of Hsp100 chaperone inhibition by the prion curing agent guanidinium chloride. AB - The Hsp100 chaperones ClpB and Hsp104 utilize the energy from ATP hydrolysis to reactivate aggregated proteins in concert with the DnaK/Hsp70 chaperone system, thereby playing an important role in protein quality control. They belong to the family of AAA+ proteins (ATPases associated with various cellular activities), possess two nucleotide binding domains per monomer (NBD1 and NBD2), and oligomerize into hexameric ring complexes. Furthermore, Hsp104 is involved in yeast prion propagation and inheritance. It is well established that low concentrations of guanidinium chloride (GdmCl) inhibit the ATPase activity of Hsp104, leading to so called "prion curing," the loss of prion-related phenotypes. Here, we present mechanistic details about the Hsp100 chaperone inhibition by GdmCl using the Hsp104 homolog ClpB from Thermus thermophilus. Initially, we demonstrate that NBD1 of ClpB, which was previously considered inactive as a separately expressed construct, is a fully active ATPase on its own. Next, we show that only NBD1, but not NBD2, is affected by GdmCl. We present a crystal structure of ClpB NBD1 in complex with GdmCl and ADP, showing that the Gdm(+) ion binds specifically to the active site of NBD1. A conserved essential glutamate residue is involved in this interaction. Additionally, Gdm(+) interacts directly with the nucleotide, thereby increasing the nucleotide binding affinity of NBD1. We propose that both the interference with the essential glutamate and the modulation of nucleotide binding properties in NBD1 is responsible for the GdmCl-specific inhibition of Hsp100 chaperones. PMID- 23341454 TI - Small angle X-ray scattering analysis of Clostridium thermocellum cellulosome N terminal complexes reveals a highly dynamic structure. AB - Clostridium thermocellum produces the prototypical cellulosome, a large multienzyme complex that efficiently hydrolyzes plant cell wall polysaccharides into fermentable sugars. This ability has garnered great interest in its potential application in biofuel production. The core non-catalytic scaffoldin subunit, CipA, bears nine type I cohesin modules that interact with the type I dockerin modules of secreted hydrolytic enzymes and promotes catalytic synergy. Because the large size and flexibility of the cellulosome preclude structural determination by traditional means, the structural basis of this synergy remains unclear. Small angle x-ray scattering has been successfully applied to the study of flexible proteins. Here, we used small angle x-ray scattering to determine the solution structure and to analyze the conformational flexibility of two overlapping N-terminal cellulosomal scaffoldin fragments comprising two type I cohesin modules and the cellulose-specific carbohydrate-binding module from CipA in complex with Cel8A cellulases. The pair distribution functions, ab initio envelopes, and rigid body models generated for these two complexes reveal extended structures. These two N-terminal cellulosomal fragments are highly dynamic and display no preference for extended or compact conformations. Overall, our work reveals structural and dynamic features of the N terminus of the CipA scaffoldin that may aid in cellulosome substrate recognition and binding. PMID- 23341455 TI - Catalysis by N-acetyl-D-glucosaminylphosphatidylinositol de-N-acetylase (PIG-L) from Entamoeba histolytica: new roles for conserved residues. AB - We showed previously that Entamoeba histolytica PIG-L exhibits a novel metal independent albeit metal-stimulated activity. Using mutational and biochemical analysis, here we identify Asp-46 and His-140 of the enzyme as being important for catalysis. We show that these mutations neither affect the global conformational of the enzyme nor alter its metal binding affinity. The defect in catalysis, due to the mutations, is specifically due to an effect on V(max) and not due to altered substrate affinity (or K(m)). We propose a general acid-base pair mechanism to explain our results. PMID- 23341456 TI - The stress protein BAG3 stabilizes Mcl-1 protein and promotes survival of cancer cells and resistance to antagonist ABT-737. AB - Members of the Bcl-2 family of proteins are important inhibitors of apoptosis in human cancer and are targets for novel anticancer agents such as the Bcl-2 antagonists, ABT-263 (Navitoclax), and its analog ABT-737. Unlike Bcl-2, Mcl-1 is not antagonized by ABT-263 or ABT-737 and is considered to be a major factor in resistance. Also, Mcl-1 exhibits differential regulation when compared with other Bcl-2 family members and is a target for anticancer drug discovery. Here, we demonstrate that BAG3, an Hsp70 co-chaperone, protects Mcl-1 from proteasomal degradation, thereby promoting its antiapoptotic activity. Using neuroblastoma cell lines, with a defined Bcl-2 family dependence, we found that BAG3 expression correlated with Mcl-1 dependence and ABT-737 resistance. RNA silencing of BAG3 led to a marked reduction in Mcl-1 protein levels and overcame ABT-737 resistance in Mcl-1-dependent cells. In ABT-737-resistant cells, Mcl-1 co-immunoprecipitated with BAG3, and loss of Mcl-1 after BAG3 silencing was prevented by proteasome inhibition. BAG3 and Mcl-1 were co-expressed in a panel of diverse cancer cell lines resistant to ABT-737. Silencing BAG3 reduced Mcl-1 protein levels and overcame ABT-737 resistance in several of the cell lines, including triple negative breast cancer (MDA-MB231) and androgen receptor-negative prostate cancer (PC3) cells. These studies identify BAG3-mediated Mcl-1 stabilization as a potential target for cancer drug discovery. PMID- 23341457 TI - PRIP (phospholipase C-related but catalytically inactive protein) inhibits exocytosis by direct interactions with syntaxin 1 and SNAP-25 through its C2 domain. AB - Membrane fusion for exocytosis is mediated by SNAREs, forming trans-ternary complexes to bridge vesicle and target membranes. There is an array of accessory proteins that directly interact with and regulate SNARE proteins. PRIP (phospholipase C-related but catalytically inactive protein) is likely one of these proteins; PRIP, consisting of multiple functional modules including pleckstrin homology and C2 domains, inhibited exocytosis, probably via the binding to membrane phosphoinositides through the pleckstrin homology domain. However, the roles of the C2 domain have not yet been investigated. In this study, we found that the C2 domain of PRIP directly interacts with syntaxin 1 and SNAP-25 but not with VAMP2. The C2 domain promoted PRIP to co-localize with syntaxin 1 and SNAP-25 in PC12 cells. The binding profile of the C2 domain to SNAP-25 was comparable with that of synaptotagmin I, and PRIP inhibited synaptotagmin I in binding to SNAP-25 and syntaxin 1. It was also shown that the C2 domain was required for PRIP to suppress SDS-resistant ternary SNARE complex formation and inhibit high K(+)-induced noradrenalin release from PC12 cells. These results suggest that PRIP inhibits regulated exocytosis through the interaction of its C2 domain with syntaxin 1 and SNAP-25, potentially competing with other SNARE-binding, C2 domain-containing accessory proteins such as synaptotagmin I and by directly inhibiting trans-SNARE complex formation. PMID- 23341458 TI - The factor VII-activating protease (FSAP) enhances the activity of bone morphogenetic protein-2 (BMP-2). AB - Factor VII-activating protease (FSAP) is a circulating protease involved in the pathogenesis of atherosclerosis, calcification, and fibrotic processes. To understand how FSAP controls the balance of local growth factors, we have investigated its effect on the regulation of bone morphogenetic proteins (BMPs). BMP-2 is produced as a large pro-form and secreted as a mature heparin-binding growth factor after intracellular processing by pro-protein convertases (PCs). In this study, we discovered that FSAP enhances the biological activity of mature BMP-2 as well as its pro-form, as shown by osteogenic differentiation of C2C12 myoblasts. These findings were complemented by knockdown of FSAP in hepatocytes, which revealed BMP-2 processing by endogenous FSAP. N-terminal sequencing indicated that pro-BMP-2 was cleaved by FSAP at the canonical PC cleavage site, giving rise to mature BMP-2 (Arg(282)?Gln(283)), as well as in the N-terminal heparin binding region of mature BMP-2, generating a truncated mature BMP-2 peptide (Arg(289)?Lys(290)). Similarly, mature BMP-2 was also cleaved to a truncated peptide within its N-terminal region (Arg(289)?Lys(290)). Plasmin exhibited a similar activity, but it was weaker compared with FSAP. Thrombin, Factor VIIa, Factor Xa, and activated protein C were not effective. These results were further supported by the observation that the mutation of the heparin binding region of BMP-2 inhibited the processing by FSAP but not by PC. Thus, the proteolysis and activation of pro-BMP-2 and mature BMP-2 by FSAP can regulate cell differentiation and calcification in vasculature and may explain why polymorphisms in the gene encoding for FSAP are related to vascular diseases. PMID- 23341459 TI - Essential role for endocytosis in the growth factor-stimulated activation of ERK1/2 in endothelial cells. AB - Vascular endothelial growth factor (VEGF) stimulates angiogenesis by binding to VEGF receptor 2 (VEGFR2) on endothelial cells (ECs). Downstream activation of the extracellular related kinases 1/2 (ERK1/2) is important for angiogenesis to proceed. Receptor internalization has been implicated in VEGFR2 signaling, but its role in the activation of ERK1/2 is unclear. To explore this question we utilized pitstop and dynasore, two small molecule inhibitors of endocytosis. First, we confirmed that both inhibitors block the internalization of VEGFR2 in ECs. We then stimulated ECs with VEGF in the presence and absence of the inhibitors and examined VEGFR2 signaling to ERK1/2. Activation of VEGFR2 and C Raf still occurred in the presence of the inhibitors, whereas the activation of MEK1/2 and ERK1/2 was abrogated. Therefore, although internalization is not required for activation of either VEGFR2 or C-Raf in ECs stimulated with VEGF, internalization is necessary to activate the more distal kinases in the cascade. Importantly, inhibition of internalization also prevented activation of ERK1/2 when ECs were stimulated with other pro-angiogenic growth factors, namely fibroblast growth factor 2 and hepatocyte growth factor. In contrast, the same inhibitors did not block ERK1/2 activation in fibroblasts or cancer cells stimulated with growth factors. Finally, we show that these small molecule inhibitors of endocytosis block angiogenesis in vitro and in vivo. Therefore, receptor internalization may be a generic requirement for pro-angiogenic growth factors to activate ERK1/2 signaling in human ECs, and targeting receptor trafficking may present a therapeutic opportunity to block tumor angiogenesis. PMID- 23341460 TI - p53 and translation attenuation regulate distinct cell cycle checkpoints during endoplasmic reticulum (ER) stress. AB - Cell cycle checkpoints ensure that proliferation occurs only under permissive conditions, but their role in linking nutrient availability to cell division is incompletely understood. Protein folding within the endoplasmic reticulum (ER) is exquisitely sensitive to energy supply and amino acid sources because deficiencies impair luminal protein folding and consequently trigger ER stress signaling. Following ER stress, many cell types arrest within the G(1) phase, although recent studies have identified a novel ER stress G(2) checkpoint. Here, we report that ER stress affects cell cycle progression via two classes of signal: an early inhibition of protein synthesis leading to G(2) delay involving CHK1 and a later induction of G(1) arrest associated both with the induction of p53 target genes and loss of cyclin D(1). We show that substitution of p53/47 for p53 impairs the ER stress G(1) checkpoint, attenuates the recovery of protein translation, and impairs induction of NOXA, a mediator of cell death. We propose that cell cycle regulation in response to ER stress comprises redundant pathways invoked sequentially first to impair G(2) progression prior to ultimate G(1) arrest. PMID- 23341461 TI - The HsiB1C1 (TssB-TssC) complex of the Pseudomonas aeruginosa type VI secretion system forms a bacteriophage tail sheathlike structure. AB - Protein secretion systems in Gram-negative bacteria evolved into a variety of molecular nanomachines. They are related to cell envelope complexes, which are involved in assembly of surface appendages or transport of solutes. They are classified as types, the most recent addition being the type VI secretion system (T6SS). The T6SS displays similarities to bacteriophage tail, which drives DNA injection into bacteria. The Hcp protein is related to the T4 bacteriophage tail tube protein gp19, whereas VgrG proteins structurally resemble the gp27/gp5 puncturing device of the phage. The tube and spike of the phage are pushed through the bacterial envelope upon contraction of a tail sheath composed of gp18. In Vibrio cholerae it was proposed that VipA and VipB assemble into a tail sheathlike structure. Here we confirm these previous data by showing that HsiB1 and HsiC1 of the Pseudomonas aeruginosa H1-T6SS assemble into tubules resulting from stacking of cogwheel-like structures showing predominantly 12-fold symmetry. The internal diameter of the cogwheels is ~100 A, which is large enough to accommodate an Hcp tube whose external diameter has been reported to be 85 A. The N-terminal 212 residues of HsiC1 are sufficient to form a stable complex with HsiB1, but the C terminus of HsiC1 is essential for the formation of the tubelike structure. Bioinformatics analysis suggests that HsiC1 displays similarities to gp18-like proteins in its C-terminal region. In conclusion, we provide further structural and mechanistic insights into the T6SS and show that a phage sheathlike structure is likely to be a conserved element across all T6SSs. PMID- 23341462 TI - Forskolin-inducible cAMP pathway negatively regulates T-cell proliferation by uncoupling the interleukin-2 receptor complex. AB - Cytokine-mediated regulation of T-cell activity involves a complex interplay between key signal transduction pathways. Determining how these signaling pathways cross-talk is essential to understanding T-cell function and dysfunction. In this work, we provide evidence that cross-talk exists between at least two signaling pathways: the Jak3/Stat5 and cAMP-mediated cascades. The adenylate cyclase activator forskolin (Fsk) significantly increased intracellular cAMP levels and reduced proliferation of the human T-cells via inhibition of cell cycle regulatory genes but did not induce apoptosis. To determine this inhibitory mechanism, effects of Fsk on IL-2 signaling was investigated. Fsk treatment of MT 2 and Kit 225 T-cells inhibited IL-2-induced Stat5a/b tyrosine and serine phosphorylation, nuclear translocation, and DNA binding activity. Fsk treatment also uncoupled IL-2 induced association of the IL-2Rbeta and gammac chain, consequently blocking Jak3 activation. Interestingly, phosphoamino acid analysis revealed that Fsk-treated cells resulted in elevated serine phosphorylation of Jak3 but not Stat5, suggesting that Fsk can negatively regulate Jak3 activity possibly mediated through PKA. Indeed, in vitro kinase assays and small molecule inhibition studies indicated that PKA can directly serine phosphorylate and functionally inactivate Jak3. Taken together, these findings suggest that Fsk activation of adenylate cyclase and PKA can negatively regulate IL-2 signaling at multiple levels that include IL-2R complex formation and Jak3/Stat5 activation. PMID- 23341463 TI - Identification and analysis of a novel dimerization domain shared by various members of c-Jun N-terminal kinase (JNK) scaffold proteins. AB - Mitogen-activated protein kinases (MAPKs) form a kinase tier module in which MAPK, MAP2K, and MAP3K are held by scaffold proteins. The scaffold proteins serve as a protein platform for selective and spatial kinase activation. The precise mechanism by which the scaffold proteins function has not yet been fully explained. WDR62 is a novel scaffold protein of the c-Jun N-terminal kinase (JNK) pathway. Recessive mutations within WDR62 result in severe cerebral cortical malformations. One of the WDR62 mutant proteins found in a patient with microcephaly encodes a C-terminal truncated protein that fails to associate efficiently with JNK and MKK7beta1. The present article shows that the WDR62 C terminal region harbors a novel dimerization domain composed of a putative loop helix domain that is necessary and sufficient for WDR62 dimerization and is critical for its scaffolding function. The loop-helix domain is highly conserved between orthologues and is also shared by the JNK scaffold protein, JNKBP1/MAPKBP1. Based on the high sequence conservation of the loop-helix domain, our article shows that MAPKBP1 homodimerizes and heterodimerizes with WDR62. Endogenous WDR62 and MAPKBP1 co-localize to stress granules following arsenite treatment, but not during mitosis. This study proposes another layer of complexity, in which coordinated activation of signaling pathways is mediated by the association between the different JNK scaffold proteins depending on their biological function. PMID- 23341464 TI - Streptococcus pneumoniae endopeptidase O (PepO) is a multifunctional plasminogen- and fibronectin-binding protein, facilitating evasion of innate immunity and invasion of host cells. AB - Streptococcus pneumoniae infections remain a major cause of morbidity and mortality worldwide. Therefore a detailed understanding and characterization of the mechanism of host cell colonization and dissemination is critical to gain control over this versatile pathogen. Here we identified a novel 72-kDa pneumococcal protein endopeptidase O (PepO), as a plasminogen- and fibronectin binding protein. Using a collection of clinical isolates, representing different serotypes, we found PepO to be ubiquitously present both at the gene and protein level. In addition, PepO protein was secreted in a growth phase-dependent manner to the culture supernatants of the pneumococcal isolates. Recombinant PepO bound human plasminogen and fibronectin in a dose-dependent manner and plasminogen did not compete with fibronectin for binding PepO. PepO bound plasminogen via lysine residues and the interaction was influenced by ionic strength. Moreover, upon activation of PepO-bound plasminogen by urokinase-type plasminogen activator, generated plasmin cleaved complement protein C3b thus assisting in complement control. Furthermore, direct binding assays demonstrated the interaction of PepO with epithelial and endothelial cells that in turn blocked pneumococcal adherence. Moreover, a pepO-mutant strain showed impaired adherence to and invasion of host cells compared with their isogenic wild-type strains. Taken together, the results demonstrated that PepO is a ubiquitously expressed plasminogen- and fibronectin-binding protein, which plays role in pneumococcal invasion of host cells and aids in immune evasion. PMID- 23341465 TI - Lytic activity of the Vibrio cholerae type VI secretion toxin VgrG-3 is inhibited by the antitoxin TsaB. AB - The type VI secretion system (T6SS) of Gram-negative bacteria has been implicated in microbial competition; however, which components serve purely structural roles, and which serve as toxic effectors remains unresolved. Here, we present evidence that VgrG-3 of the Vibrio cholerae T6SS has both structural and toxin activity. Specifically, we demonstrate that the C-terminal extension of VgrG-3 acts to degrade peptidoglycan and hypothesize that this assists in the delivery of accessory T6SS toxins of V. cholerae. To avoid self-intoxication, V. cholerae expresses an anti-toxin encoded immediately downstream of vgrG-3 that inhibits VgrG-3-mediated lysis through direct interaction. PMID- 23341466 TI - Sarcolipin protein interaction with sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) is distinct from phospholamban protein, and only sarcolipin can promote uncoupling of the SERCA pump. AB - Sarco(endo)plasmic reticulum Ca(2+)ATPase (SERCA) pump activity is modulated by phospholamban (PLB) and sarcolipin (SLN) in cardiac and skeletal muscle. Recent data suggest that SLN could play a role in muscle thermogenesis by promoting uncoupling of the SERCA pump (Lee, A.G. (2002) Curr. Opin. Struct. Biol. 12, 547 554 and Bal, N. C., Maurya, S. K., Sopariwala, D. H., Sahoo, S. K., Gupta, S. C., Shaikh, S. A., Pant, M., Rowland, L. A., Bombardier, E., Goonasekera, S. A., Tupling, A. R., Molkentin, J. D., and Periasamy, M. (2012) Nat. Med. 18, 1575 1579), but the mechanistic details are unknown. To better define how binding of SLN to SERCA promotes uncoupling of SERCA, we compared SLN and SERCA1 interaction with that of PLB in detail. The homo-bifunctional cross-linker (1,6 bismaleimidohexane) was employed to detect dynamic protein interaction during the SERCA cycle. Our studies reveal that SLN differs significantly from PLB: 1) SLN primarily affects the Vmax of SERCA-mediated Ca(2+) uptake but not the pump affinity for Ca(2+); 2) SLN can bind to SERCA in the presence of high Ca(2+), but PLB can only interact to the ATP-bound Ca(2+)-free E2 state; and 3) unlike PLB, SLN interacts with SERCA throughout the kinetic cycle and promotes uncoupling of the SERCA pump. Using SERCA transmembrane mutants, we additionally show that PLB and SLN can bind to the same groove but interact with a different set of residues on SERCA. These data collectively suggest that SLN is functionally distinct from PLB; its ability to interact with SERCA in the presence of Ca(2+) causes uncoupling of the SERCA pump and increased heat production. PMID- 23341469 TI - Lead monoxide alpha-PbO: electronic properties and point defect formation. AB - The electronic properties of polycrystalline lead oxide consisting of a network of single-crystalline alpha-PbO platelets and the formation of native point defects in the alpha-PbO crystal lattice are studied using first-principles calculations. The results suggest that the polycrystalline nature of alpha-PbO causes the formation of lattice defects (i.e., oxygen and lead vacancies) in such a high concentration that defect related conductivity becomes the dominant mechanism of charge transport. The neutral O vacancy forms a defect state at 1.03 eV above the valence band which can act as a deep trap for electrons, while the Pb vacancy forms a shallow trap for holes located just 0.1 eV above the valence band. The ionization of O vacancies can account for the experimentally found dark current decay in ITO/PbO/Au structures. PMID- 23341467 TI - Autophagy protects the retina from light-induced degeneration. AB - Autophagy is a conserved feature of lysosome-mediated intracellular degradation. Dysregulated autophagy is implicated as a contributor in neurodegenerative diseases; however, the role of autophagy in retinal degeneration remains largely unknown. Here, we report that the photo-activated visual chromophore, all-trans retinal, modulated autophagosome formation in ARPE19 retinal cells. Increased formation of autophagosomes in these cells was observed when incubated with 2.5 MUM all-trans-retinal, a condition that did not cause cell death after 24 h in culture. However, autophagosome formation was decreased at concentrations, which caused cell death. Increased expression of activating transcription factor 4 (Atf4), which indicates the activation of oxidative stress, was recorded in response to light illumination in retinas of Abca4(-/-)Rdh8(-/-) mice, which showed delayed clearance of all-trans-retinal after light exposure. Expression of autophagosome marker LC3B-II and mitochondria-specific autophagy, mitophagy, regulator Park2, were significantly increased in the retinas of Abca4(-/-)Rdh8(-/ ) mice after light exposure, suggesting involvement of autophagy and mitophagy in the pathogenesis of light-induced retinal degeneration. Deletion of essential genes required for autophagy, including Beclin1 systemically or Atg7 in only rod photoreceptors resulted in increased susceptibility to light-induced retinal damage. Increased photoreceptor cell death was observed when retinas lacking the rod photoreceptor-specific Atg7 gene were coincubated with 20 MUM all-trans retinal. Park2(-/-) mice also displayed light-induced retinal degeneration. Ultra structural analyses showed mitochondrial and endoplasmic reticulum impairment in retinas of these model animals after light exposure. Taken together, these observations provide novel evidence implicating an important role of autophagy and mitophagy in protecting the retina from all-trans-retinal- and light-induced degeneration. PMID- 23341468 TI - Brassinosteroid-regulated GSK3/Shaggy-like kinases phosphorylate mitogen activated protein (MAP) kinase kinases, which control stomata development in Arabidopsis thaliana. AB - Brassinosteroids (BRs) are steroid hormones that coordinate fundamental developmental programs in plants. In this study we show that in addition to the well established roles of BRs in regulating cell elongation and cell division events, BRs also govern cell fate decisions during stomata development in Arabidopsis thaliana. In wild-type A. thaliana, stomatal distribution follows the one-cell spacing rule; that is, adjacent stomata are spaced by at least one intervening pavement cell. This rule is interrupted in BR-deficient and BR signaling-deficient A. thaliana mutants, resulting in clustered stomata. We demonstrate that BIN2 and its homologues, GSK3/Shaggy-like kinases involved in BR signaling, can phosphorylate the MAPK kinases MKK4 and MKK5, which are members of the MAPK module YODA-MKK4/5-MPK3/6 that controls stomata development and patterning. BIN2 phosphorylates a GSK3/Shaggy-like kinase recognition motif in MKK4, which reduces MKK4 activity against its substrate MPK6 in vitro. In vivo we show that MKK4 and MKK5 act downstream of BR signaling because their overexpression rescued stomata patterning defects in BR-deficient plants. A model is proposed in which GSK3-mediated phosphorylation of MKK4 and MKK5 enables for a dynamic integration of endogenous or environmental cues signaled by BRs into cell fate decisions governed by the YODA-MKK4/5-MPK3/6 module. PMID- 23341470 TI - Disaster preparedness: what training do our interns receive during medical school? AB - Disaster preparedness training is a critical component of medical student education. Despite recent natural and man-made disasters, there is no national consensus on a disaster preparedness curriculum. The authors designed a survey to assess prior disaster preparedness training among incoming interns at an academic teaching hospital. In 2010, the authors surveyed incoming interns (n = 130) regarding the number of hours of training in disaster preparedness received during medical school, including formal didactic sessions and simulation, and their level of self-perceived proficiency in disaster management. Survey respondents represented 42 medical schools located in 20 states. Results demonstrated that 47% of interns received formal training in disaster preparedness in medical school; 64% of these training programs included some type of simulation. There is a need to improve the level of disaster preparedness training in medical school. A national curriculum should be developed with aspects that promote knowledge retention. PMID- 23341472 TI - Follistatin induction by nitric oxide through cyclic GMP: a tightly regulated signaling pathway that controls myoblast fusion. PMID- 23341471 TI - Generation of a human bone marrow-derived mesenchymal stem cell line expressing and secreting high levels of bioactive alpha-melanocyte-stimulating hormone. AB - alpha-Melanocyte-stimulating hormone (alpha-MSH) functions as a mediator of inflammation and immunity; however, the short half-life and high dose needed limit the comprehensive clinical application of alpha-MSH. The aim of this study was to generate human bone marrow-derived mesenchymal stem cells (MSCs) that express and secrete high levels of bioactive alpha-MSH. MSCs were obtained from a normal donor and assessed for proliferation, surface markers, and adipogenic and osteogenic differentiation. A lentivirus-encoding alpha-MSH was constructed. MSCs were infected with this lentivirus-encoding alpha-MSH and assessed for stability and the expression and secretion of bioactive alpha-MSH. The cumulative MSC expansion rates pre- and post-lentivirus infection were not significantly different (P > 0.05). The MSCs remained stable after infection with the lentivirus-encoding alpha-MSH. The concentration of alpha-MSH in the supernatants of MSCs infected with the lentivirus-encoding alpha-MSH was 17.55 ng/ml (P < 0.001), and a melanin assay indicated that bioactive alpha-MSH was secreted from MSCs infected with the lentivirus-encoding alpha-MSH, with an optical absorbance at OD(405) of 0.886 (P < 0.001). These results suggested that MSCs were promising cell carriers for the expression and secretion of high levels of bioactive alpha MSH. PMID- 23341473 TI - Do former substance users with psychosis differ in their symptoms or function from non-substance users? A systematic meta-analysis. AB - OBJECTIVE: To compare the symptoms and function of patients with psychosis who have ceased using substances to those who have psychosis but do not have a history of substance use. METHOD: The databases EMBASE, MEDLINE and PsycINFO were searched for peer-reviewed publications in English reporting the characteristics of patients with psychotic illness who had stopped using substances and those who had never used substances. The searches yielded 20 articles that met the inclusion criteria. Four key outcome variables - positive symptoms, negative symptoms, depression and global function - and four other outcome measures reported in five or more studies were examined using meta-analysis. RESULTS: Former substance-using patients were significantly younger than non-substance using patients and were more likely to be male, but did not differ in age at onset of psychosis or in their level of education. There were no significant differences between former substance users and non-substance users in ratings of positive symptoms, negative symptoms, depression or global function. Among first episode patients there was a trend towards former substance users having less severe depressive symptoms than non-substance users. In contrast, among non-first episode patients, former substance users had significantly more depressive symptoms than non-substance users. In studies rated as being of higher quality, former substance users had significantly less severe positive symptoms than non substance users. CONCLUSION: The absence of significant differences between the two groups suggests that a history of substance use is not a poor prognostic indicator for patients who are able to stop using substances. PMID- 23341474 TI - Further evidence for slow binocular rivalry rate as a trait marker for bipolar disorder. AB - OBJECTIVE: Binocular rivalry refers to a situation where contradictory information is presented simultaneously to the same location of each eye. This leads to the alternation of images every few seconds. The rate of alternation between images has been shown to be slower in euthymic participants with bipolar disorder than in healthy controls. The alternation rate is not uniformly slowed in bipolar disorder patients and may be influenced by clinical variables. The present study examined whether bipolar disorder patients have slower alternation rates, examined the influence of depression and explored the role of clinical variables and cognitive functions on alternation rate. METHOD: Ninety-six patients with bipolar disorder and 24 control participants took part in the study. Current mood status and binocular rivalry performance were analysed with nonparametric tests. A slow and a normal alternation group were created by median split. We subsequently explored the distribution of several clinical variables across these groups. Further, we investigated associations between alternation rate and various cognitive functions, such as visual processing, memory, attention and general motor speed. RESULTS: The median alternation rate was significantly slower for participants with bipolar disorder type I (0.39 Hz) and for participants with bipolar spectrum disorder (0.43 Hz) than for control participants (0.47 Hz). Depression had no effect on alternation rate. There were no differences between participants with bipolar disorder type I and type II and in regard to medication regime and predominance of one rivalry image. There were also no differences in regard to the clinical variables and no significant associations between alternation rate and the cognitive functions explored. CONCLUSION: We replicated a slowing in alternation rate in some bipolar disorder participants. The alternation rate was not affected by depressed mood or any of the other factors explored, which supports views of binocular rivalry rates as a trait marker in bipolar disorder. PMID- 23341475 TI - The developmental and social history of repetitively aggressive mental health patients. AB - OBJECTIVE: A small subgroup of patients is primarily responsible for the large number of aggressive and violent incidents in psychiatric inpatient units. This study aims to identify the developmental, social and interpersonal histories of repeatedly aggressive patients in order to better understand their treatment needs. METHODS: A total of 1269 consecutive inpatients were studied over 18 months, identifying 64 who were repeatedly aggressive; 128 non-aggressive patients were randomly matched to the aggressive patients by age, sex and diagnosis. Developmental, social, interpersonal and familial histories were obtained from a chart review. RESULTS: Repeatedly aggressive patients were significantly more likely to have had a history of aggression, physical and sexual abuse, and experienced interpersonal problems and parental divorce. CONCLUSIONS: Aggressive patients do not just need short-term skills training, but interventions that target interpersonal and personality disorder deficits associated with their developmental histories. PMID- 23341476 TI - Metabolite profiles in the anterior cingulate cortex of depressed patients differentiate those taking N-acetyl-cysteine versus placebo. AB - BACKGROUND: Increased oxidative stress is thought to contribute to the pathophysiology of major depressive disorder (MDD), which is in part due to diminished levels of glutathione, the primary anti-oxidant of the brain. Oral administration of N-acetyl-cysteine (NAC) replenishes glutathione and has therefore been shown to reduce depressive symptoms. Proton magnetic spectroscopy ((1)H-MRS) that allows quantification of brain metabolites pertinent to both MDD and oxidative biology may provide some novel insights into the neurobiological effects of NAC, and in particular metabolite concentrations within the anterior cingulate cortex (ACC) are likely to be important given the key role of this region in the regulation of affect. OBJECTIVE: The aim of this study was to determine whether the metabolite profile of the ACC in MDD patients predicts treatment with adjunctive NAC versus placebo. METHODS: This study was nested within a multicentre, randomized, double-blind, placebo-controlled study of MDD participants treated with adjunctive NAC. Participants (n = 76) from one site completed the spectroscopy component at the end of treatment (12 weeks). Spectra from a single-voxel in the ACC were acquired and absolute concentrations of glutamate (Glu), glutamate-glutamine (Glx), N-acetyl-aspartate (NAA) and myo inositol (mI) were obtained. Binary logistic regression analysis was performed to determine whether metabolite profiles could predict NAC versus placebo group membership. RESULTS: When predicting group outcome (NAC or placebo), Glx, NAA and mI were a significant model, and had 75% accuracy, while controlling for depression severity and sex. However, the Glu, NAA and mI profile was only predictive at a trend level, with 68.3% accuracy. For both models, the log of the odds of a participant being in the NAC group was positively related to NAA, Glx and Glu levels and negatively related to mI levels. CONCLUSION: The finding of higher Glx and NAA levels being predictive of the NAC group provides preliminary support for the putative anti-oxidative role of NAC in MDD. PMID- 23341477 TI - Emotions delay care-seeking in patients with an acute myocardial infarction. AB - BACKGROUND: In acute myocardial infarction the risk of death and loss of myocardial tissue is at its highest during the first few hours. However, the process from symptom onset to the decision to seek medical care can take time. To comprehend patients' pre-hospital delay, attention must be focused on the circumstances preceding the decision to seek medical care. AIM: To add a deeper understanding of patients' thoughts, feelings and actions that preceded the decision to seek medical care when afflicted by an acute myocardial infarction. METHODS: Fourteen men and women with a first or second acute myocardial infarction were interviewed individually in semi-structured interviews. Data were analysed by qualitative content analysis. RESULTS: Four themes were conceptualized: 'being incapacitated by fear, anguish and powerlessness', 'being ashamed of oneself', 'fear of losing a healthy identity' and 'striving to avoid fear by not interacting with others'. Patients were torn between feelings such as anguish, fear, shame and powerlessness. They made an effort to uphold their self image as being a healthy person thus affected by an unrecognized discomfort. This combined with a struggle to protect others from involvement, strengthened the barriers to seeking care. CONCLUSIONS: The present study indicates that emotional reactions are important and influence patients' pre-hospital behaviour. Being ashamed of oneself stood out as a novel finding. Emotions might be an important explanation of undesired and persisting patient delays. However, our findings have to and should be evaluated quantitatively. Such a study is in progress. PMID- 23341478 TI - Perspectives on obesity and its treatment: health care providers and the general public in rural West Virginia and urban Baltimore. AB - OBJECTIVE: To determine and compare the perspectives of the general public and health care providers (HCPs) on obesity and its treatment in rural West Virginia (WV) and Baltimore, MD. METHOD: Surveys were completed in both locations by the general public (WV: n = 200; Baltimore: n = 171) and HCPs (WV: n = 25; Baltimore: n = 15). RESULTS: BMI (body mass index) >= 30 (WV: n = 94; Baltimore: n = 58) was associated with a stronger belief in the heritability of obesity and with the ability to control obesity by controlling food cost, compared with those with normal BMI (WV: n = 42; Baltimore: n = 57). Those with a high school education (WV: n = 112; Baltimore: n = 113) were less likely to agree that obesity is a problem in the community and that proper diet and exercise are realistic expectations, compared with those with at least some higher education. Perspectives of HCPs differed significantly from the general public in both locations. CONCLUSION: Many differences in perspective on obesity exist between WV and Baltimore, within both populations, and between HCPs and the general public in both settings. A better understanding of patient views is important for effective obesity management. HCPs must consider each patient's level of understanding when discussing management and consequences of obesity. More time spent with patients who have less insight into their obesity may improve patient adherence with treatment and overall patient outcomes. PMID- 23341479 TI - Speeding dating for docetaxel and recent debutantes in castration-resistant prostate cancer: 'plus or minus' may be a minus. PMID- 23341480 TI - Reply to 'Different outcome variables yield different results', by O. Brouckaert et al. PMID- 23341481 TI - Staging for distant metastases in operable breast cancer: a suggested expansion of the ESMO guideline recommendation for staging imaging of node-negative, hormonal receptor-negative disease. PMID- 23341482 TI - Reply to 'Staging for distant metastases in operable breast cancer: a suggested expansion of the ESMO guideline recommendation for staging imaging of node negative, hormonal receptor-negative disease' by U. Gueth et al. PMID- 23341483 TI - The low opioid consumption in Italy depends on late palliative care. PMID- 23341484 TI - Induction of cell death in renal cell carcinoma with combination of D-fraction and vitamin C. AB - HYPOTHESIS: Although several conventional therapeutic options for advanced renal cell carcinoma (RCC) are currently available, the unsatisfactory outcomes demand establishing more effective interventions. D-fraction (PDF), a bioactive proteoglucan of Maitake mushroom, demonstrates anticancer and immunomodulatory activities, which are also shown to be potentiated by vitamin C (VC). We thus hypothesized that a combination of PDF and VC (PDF + VC) could be an alternative approach to more effectively inhibit the growth of RCC. STUDY DESIGN: We examined the dose-dependent effects of PDF + VC on RCC cell viability and also performed biochemical assays to explore the growth regulatory mechanism. METHODS: Human RCC, ACHN cell line, was employed and exposed to varying concentrations of PDF or VC and their combinations. Cell viability at specified times was determined by MTT assay. Lipid peroxidation assay, cell cycle analysis, and Western blot analysis were also performed. RESULTS: PDF or VC alone led to the significant reduction in cell viability at 72 hours with PDF >500 ug/mL and VC >=300 uM. When various combinations of PDF and VC were tested, the combination of the ineffective concentrations of PDF (300 ug/mL) and VC (200 uM) resulted in ~90% cell death in 24 hours. Lipid peroxidation assay then indicated significantly (~2.5 fold) elevated oxidative stress with this PDF + VC. Cell cycle analysis also indicated a G1 cell cycle arrest following a 6-hour PDF + VC treatment. Western blots further revealed a downregulation of Bcl2, an upregulation of Bax, and proteolytic activation of PARP (poly[ADP-ribose] polymerase) in PDF + VC treated cells, indicating induction of apoptosis. CONCLUSION: The present study demonstrates that the combination of PDF and VC can become highly cytotoxic, inducing severe cell death in ACHN cells. This cytotoxic mechanism appears to be primarily attributed to oxidative stress, accompanied by a G1 cell cycle arrest. Such cell death induced by PDF + VC could be more likely linked to apoptosis, as indicated by the modulation of apoptosis regulators (Bcl2, Bax, and PARP). Therefore, as PDF and VC may work synergistically to induce apoptotic cell death, they may have clinical implications in an alternative, improved therapeutic modality for advanced RCC. PMID- 23341485 TI - Is paediatric epilepsy getting less common? PMID- 23341487 TI - Twenty-four hour energy expenditure and skeletal muscle gene expression changes after bariatric surgery. AB - CONTEXT: Obesity is characterized by decreased insulin-stimulated glucose uptake in muscle and shift from glucose to lipid oxidation, the so-called metabolic inflexibility. Biliopancreatic diversion (BPD), a mainly malabsorptive bariatric operation, determines a prompt improvement of insulin resistance, but the mechanisms are still unclear. OBJECTIVE: We aimed to estimate the response of glucose transporter 4 (GLUT4) and hexokinase-II (HKII) gene expression to hyperinsulinemia before and after surgical treatment with a BPD or dietary induced weight loss. The association with 24-hour energy expenditure and its different components-diet-induced thermogenesis (DIT), resting energy expenditure, physical activity (PA) of daily living, and physical exercise-was also determined. DESIGN, SETTING, AND MAIN OUTCOME MEASURES: Case-control study: 20 subjects, BPD vs diet-induced weight loss. Four subjects withdrew in the surgical arm and 1 subject withdrew in the dietary arm. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp. Energy expenditure was assessed by indirect calorimetry over 24 hours. Muscle biopsies were obtained during the clamp to measure gene expression: GLUT4 and HKII. RESULTS: Insulin sensitivity increased significantly (P < .01) only after BPD (0.101 +/- 0.012 to 0.204 +/- 0.033 MUmol/kg/min/pM). Enhanced GLUT4 and HKII mRNA levels were observed after surgery (P < .0001 and P = .021, respectively), whereas they were not affected by diet-induced weight loss. Carbohydrate oxidation (P = .0027), DIT (P = .033), PA (P = .036), and energy expenditure during the exercise (P = .017) increased only in the BPD group. CONCLUSIONS: BPD improved impaired glucose metabolism and insulin resistance through increased glucose uptake, glycogen synthesis, and glucose oxidation. Furthermore, the concomitant increase in DIT, PA, and exercise in BPD patients may partly explain their ability to sustained long-term weight loss and may contribute to the improved insulin sensitivity. PMID- 23341486 TI - Efficacy and safety of strontium ranelate in the treatment of osteoporosis in men. AB - CONTEXT: Strontium ranelate reduces vertebral and nonvertebral fracture risk in postmenopausal osteoporosis. OBJECTIVE: The objective of this study was to determine the efficacy and safety of strontium ranelate in osteoporosis in men over 2 years (main analysis after 1 year). DESIGN: This was an international, unbalanced (2:1), double-blind, randomized placebo-controlled trial (MALEO [MALE Osteoporosis]). SETTING: This international study included 54 centers in 14 countries. PARTICIPANTS: PARTICIPANTS were 261 white men with primary osteoporosis. INTERVENTION: Strontium ranelate at 2 g/d (n = 174) or placebo (n = 87) was administered. MAIN OUTCOME MEASURES: Lumbar spine (L2-L4), femoral neck, and total hip bone mineral density (BMD), biochemical bone markers, and safety were measured. RESULTS: Baseline characteristics were similar in both groups in the whole population (age, 72.9 +/- 6.0 years; lumbar spine BMD T-score, -2.7 +/- 1.0; femoral neck BMD T-score, -2.3 +/- 0.7). Men who received strontium ranelate over 2 years had greater increases in lumbar spine BMD than those who received placebo (relative change from baseline to end, 9.7% +/- 7.5% vs 2.0% +/- 5.5%; between-group difference estimate (SE), 7.7% (0.9%); 95% confidence interval, 5.9%-9.5%; P < .001). There were also significant between-group differences in relative changes in femoral neck BMD (P < .001) and total hip BMD (P < .001). At the end of treatment, mean levels of serum cross-linked telopeptides of type I collagen, a marker of bone resorption, were increased in both the strontium ranelate group (10.7% +/- 58.0%; P = .022) and the placebo group (34.9% +/- 65.8%; P < .001). The corresponding mean changes of bone alkaline phosphatase, a marker of bone formation, were 6.4% +/- 28.5% (P = .005) and 1.9% +/- 25.4% (P = .505), respectively. After 2 years, the blood strontium level (129 +/- 66 MUmol/L) was similar to that in trials of postmenopausal osteoporosis. Strontium ranelate was generally well tolerated. CONCLUSIONS: The effects of strontium ranelate on BMD in osteoporotic men were similar to those in postmenopausal osteoporotic women, supporting its use in the treatment of osteoporosis in men. PMID- 23341488 TI - Wrist circumference as a novel predictor of diabetes and prediabetes: results of cross-sectional and 8.8-year follow-up studies. AB - OBJECTIVE: Our objective was to examine whether wrist circumference is associated with incident type 2 diabetes mellitus, independently of general (body mass index [BMI]) or central (waist circumference [WC]) adiposity measures in a cohort of an Iranian adult population. RESEARCH DESIGN AND METHODS: A total of 9330 subjects >= 20 years of age were included in the cross-sectional study. For prospective analysis, subjects with prevalent diabetes were excluded, leaving 6393 subjects (2716 males and 3677 females). The standard 2-hour postchallenge plasma glucose test was performed at baseline and during follow-up. Cox regression analysis was used to estimate the hazard ratio of diabetes for wrist circumference. RESULTS: During a mean follow-up of 8.8 years, 649 new cases of diabetes occurred. At baseline, using linear regression models, we showed significant linear associations between wrist circumference and diabetes risk factors in both genders, and this association remained significant after controlling for BMI or WC among females. In prospective evaluation, wrist circumference was significantly associated with incident diabetes (multivariable-adjusted hazard ratio = 1.17 [1.03-1.32] and 1.31 [1.18-1.45] for males and females, respectively). After controlling for the subjects' BMI or WC, wrist circumference was an independent predictor of diabetes only among females. Wrist circumference was an independent predictor of metabolic syndrome only among women even after adjustment for BMI, WC, or both. CONCLUSIONS: Wrist circumference is a significant predictor of diabetes in both genders of adult population. However, its predictability is independent of BMI or WC only among females. Because of its simple and easy-to-detect nature, wrist circumference could be considered as a new anthropometric assessment for prediction of type 2 diabetes and metabolic syndrome. PMID- 23341489 TI - TBS (trabecular bone score) and diabetes-related fracture risk. AB - CONTEXT: Type 2 diabetes is associated with increased fracture risk but paradoxically greater bone mineral density (BMD). Trabecular bone score (TBS) is derived from the texture of the spine dual x-ray absorptiometry (DXA) image and is related to bone microarchitecture and fracture risk, providing information independent of BMD. OBJECTIVE: This study evaluated the ability of lumbar spine TBS to account for increased fracture risk in diabetes. DESIGN AND SETTING: We performed a retrospective cohort study using BMD results from a large clinical registry for the province of Manitoba, Canada. PATIENTS: We included 29,407 women 50 years old and older with baseline DXA examinations, among whom 2356 had diagnosed diabetes. MAIN OUTCOME MEASURES: Lumbar spine TBS was derived for each spine DXA examination blinded to clinical parameters and outcomes. Health service records were assessed for incident nontraumatic major osteoporotic fractures (mean follow-up 4.7 years). RESULTS: Diabetes was associated with higher BMD at all sites but lower lumbar spine TBS in unadjusted and adjusted models (all P < .001). The adjusted odds ratio (aOR) for a measurement in the lowest vs the highest tertile was less than 1 for BMD (all P < .001) but was increased for lumbar spine TBS [aOR 2.61, 95% confidence interval (CI) 2.30-2.97]. Major osteoporotic fractures were identified in 175 women (7.4%) with and 1493 (5.5%) without diabetes (P < .001). Lumbar spine TBS was a BMD-independent predictor of fracture and predicted fractures in those with diabetes (adjusted hazard ratio 1.27, 95% CI 1.10-1.46) and without diabetes (hazard ratio 1.31, 95% CI 1.24 1.38). The effect of diabetes on fracture was reduced when lumbar spine TBS was added to a prediction model but was paradoxically increased from adding BMD measurements. CONCLUSIONS: Lumbar spine TBS predicts osteoporotic fractures in those with diabetes, and captures a larger portion of the diabetes-associated fracture risk than BMD. PMID- 23341490 TI - Circulating growth arrest-specific 6 protein is associated with adiposity, systemic inflammation, and insulin resistance among overweight and obese adolescents. AB - CONTEXT: Growth arrest-specific 6 (Gas6) is a vitamin K-dependent protein secreted by immune cells, endothelial cells, vascular smooth muscle cells, and adipocytes. Preclinical studies indicate that Gas6 and its receptors of the TAM (Tyro-3, Axl, Mer) family may be involved in the pathogenesis of obesity and its complications, including systemic inflammation and insulin resistance. Until now, little has been known about the clinical significance of the Gas6/TAM system in childhood obesity. OBJECTIVES: This study aimed to determine whether circulating Gas6 and soluble Axl (sAxl) levels are associated with adiposity, inflammation, and insulin resistance status among Taiwanese adolescents. METHODS: Cross sectional analyses using the data from the Taipei Children Heart Study-III were performed. A total of 832 adolescents (average age, 13.3 years) were included; they were divided into 3 groups: lean, overweight, and obese. Circulating Gas6 and sAxl levels, adiposity, inflammatory markers, and insulin resistance status were examined. RESULTS: Levels of circulating Gas6 and sAxl were significantly higher in overweight and obese adolescents than in the lean group (both P < .05). Circulating Gas6 levels were significantly positively correlated with body mass index Z-score (P = .045), waist circumference (P < .001), waist to hip circumference ratio (P < .001), body fat mass (P = .02), serum high-sensitivity C reactive protein (P = .005), and tumor necrosis factor-alpha levels (P = .039) among overweight and obese adolescents. The correlations remained significant after adjusting for age, gender, Tanner stage, smoking status, and drinking status. In addition, every 1 ng/mL increase in circulating Gas6 concentration corresponded to a 15% to 19% increase in the risk of developing insulin resistance among overweight and obese adolescents. CONCLUSIONS: Circulating Gas6 levels are strongly associated with adiposity, inflammation, and insulin resistance status among overweight and obese adolescents. The potential role of the Gas6/TAM system in the initiation of childhood obesity and obesity-associated complications deserves further attention. PMID- 23341492 TI - Recommended IGF-I dosage causes greater fat accumulation and osseous maturation than lower dosage and may compromise long-term growth effects. AB - CONTEXT: The maximum dose of IGF-I recommended for treatment of GH insensitivity is commonly used. OBJECTIVE: The aim was to test the hypothesis that a lower dose is as effective as a high dose of IGF-I in growth promotion and has fewer deleterious effects. DESIGN AND SETTING: Subjects were treated for 3 years with regular examinations including bone age and dual energy x-ray absorptiometry and for 1 year with abdominal ultrasound studies at a clinical research institute in Quito, Ecuador. SUBJECTS: The study included 21 subjects ages 3.2-15.9 years with GH insensitivity due to the same splice site mutation on the GH receptor gene. INTERVENTIONS: Subjects were allocated to receive 120 (n = 14) or 80 (n = 7) MUg/kg IGF-I twice daily. MAIN OUTCOME MEASURES: Height velocity, osseous maturation, height SD scores (SDS), body composition, abdominal organ growth, and side effects were assessed. RESULTS: There were no differences in growth velocity or height SDS increment by dosage, and the SDS increase was greater than in other reported series. Osseous maturation over 3 years with the high dose was nearly twice as rapid as with the lower dose (P < .001) and correlated with an increase in percentage body fat (r = .64; P < .001) and with adrenal size increase over 1 year (r = .32; P = .03). The ratio of bone age to height age was lower in the high-dose group after 3 years of treatment (P = .007). CONCLUSIONS: The commonly used IGF-I dosage of 120 MUg/kg twice a day is excessive in comparison to a dose of 80 MUg/kg twice a day, disproportionately accelerating osseous maturation, probably from the combined effects of obesity and inappropriate adrenal growth, thus likely compromising adult height potential. Moreover, the lower dose decreases direct treatment cost by one-third. PMID- 23341491 TI - Responsiveness to a physiological regimen of GnRH therapy and relation to genotype in women with isolated hypogonadotropic hypogonadism. AB - CONTEXT: Isolated hypogonadotropic hypogonadism (IHH) is caused by defective GnRH secretion or action resulting in absent or incomplete pubertal development and infertility. Most women with IHH ovulate with physiological GnRH replacement, implicating GnRH deficiency as the etiology. However, a subset does not respond normally, suggesting the presence of defects at the pituitary or ovary. OBJECTIVES: The objective of the study was to unmask pituitary or ovarian defects in IHH women using a physiological regimen of GnRH replacement, relating these responses to genes known to cause IHH. DESIGN, SETTING, AND SUBJECTS: This study is a retrospective analysis of 37 IHH women treated with iv pulsatile GnRH (75 ng/kg per bolus). MAIN OUTCOME MEASURES: Serum gonadotropin and sex steroid levels were measured, and 14 genes implicated in IHH were sequenced. RESULTS: During their first cycle of GnRH replacement, normal cycles were recreated in 60% (22 of 37) of IHH women. Thirty percent of women (12 of 37) demonstrated an attenuated gonadotropin response, indicating pituitary resistance, and 10% (3 of 37) exhibited an exaggerated FSH response, consistent with ovarian resistance. Mutations in CHD7, FGFR1, KAL1, TAC3, and TACR3 were documented in IHH women with normal cycles, whereas mutations were identified in GNRHR, PROKR2, and FGFR1 in those with pituitary resistance. Women with ovarian resistance were mutation negative. CONCLUSIONS: Although physiological replacement with GnRH recreates normal menstrual cycle dynamics in most IHH women, hypogonadotropic responses in the first week of treatment identify a subset of women with pituitary dysfunction, only some of whom have mutations in GNRHR. IHH women with hypergonadotropic responses to GnRH replacement, consistent with an additional ovarian defect, did not have mutations in genes known to cause IHH, similar to our findings in a subset of IHH men with evidence of an additional testicular defect. PMID- 23341495 TI - Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose. AB - Glucagon-like peptide-1 (GLP-1) suppresses food intake via activation of a central (i.e., brain) GLP-1 receptor (GLP-1R). Central AMP-activated protein kinase (AMPK) is a nutrient-sensitive regulator of food intake that is inhibited by anorectic signals. The anorectic effect elicited by hindbrain GLP-1R activation is attenuated by the AMPK stimulator AICAR. This suggests that central GLP-1R activation suppresses food intake via inhibition of central AMPK. The present studies examined the mechanism(s) by which central GLP-1R activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (icv) administration of the GLP-1R agonist exendin-4 (Ex-4). We demonstrate that Ex-4 stimulates glycolysis and suppresses AMPK phosphorylation in a glucose-dependent manner in hypothalamic GT1 7 cells. This suggests that inhibition of AMPK and food intake by Ex-4 requires central glucose metabolism. Supporting this, the glycolytic inhibitor 2 deoxyglucose (2-DG) attenuated the anorectic effect of Ex-4. However, icv glucose did not enhance the suppression of food intake by Ex-4. AICAR had no effect on Ex 4-mediated reduction in locomotor activity. We also tested whether other carbohydrates affect the anorectic response to Ex-4. Intracerebroventricular pretreatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex-4. This potentially explains the increased food intake observed in sucrose-fed mice. In summary, we propose a model whereby activation of the central GLP-1R reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central GLP-1R action. This has significant implications given the correlation between sugar consumption and obesity. PMID- 23341493 TI - Genomic insights into cancer-associated aberrant CpG island hypermethylation. AB - Carcinogenesis is thought to occur through a combination of mutational and epimutational events that disrupt key pathways regulating cellular growth and division. The DNA methylomes of cancer cells can exhibit two striking differences from normal cells; a global reduction of DNA methylation levels and the aberrant hypermethylation of some sequences, particularly CpG islands (CGIs). This aberrant hypermethylation is often invoked as a mechanism causing the transcriptional inactivation of tumour suppressor genes that directly drives the carcinogenic process. Here, we review our current understanding of this phenomenon, focusing on how global analysis of cancer methylomes indicates that most affected CGI genes are already silenced prior to aberrant hypermethylation during cancer development. We also discuss how genome-scale analyses of both normal and cancer cells have refined our understanding of the elusive mechanism(s) that may underpin aberrant CGI hypermethylation. PMID- 23341494 TI - A survey of tools for variant analysis of next-generation genome sequencing data. AB - Recent advances in genome sequencing technologies provide unprecedented opportunities to characterize individual genomic landscapes and identify mutations relevant for diagnosis and therapy. Specifically, whole-exome sequencing using next-generation sequencing (NGS) technologies is gaining popularity in the human genetics community due to the moderate costs, manageable data amounts and straightforward interpretation of analysis results. While whole exome and, in the near future, whole-genome sequencing are becoming commodities, data analysis still poses significant challenges and led to the development of a plethora of tools supporting specific parts of the analysis workflow or providing a complete solution. Here, we surveyed 205 tools for whole-genome/whole-exome sequencing data analysis supporting five distinct analytical steps: quality assessment, alignment, variant identification, variant annotation and visualization. We report an overview of the functionality, features and specific requirements of the individual tools. We then selected 32 programs for variant identification, variant annotation and visualization, which were subjected to hands-on evaluation using four data sets: one set of exome data from two patients with a rare disease for testing identification of germline mutations, two cancer data sets for testing variant callers for somatic mutations, copy number variations and structural variations, and one semi-synthetic data set for testing identification of copy number variations. Our comprehensive survey and evaluation of NGS tools provides a valuable guideline for human geneticists working on Mendelian disorders, complex diseases and cancers. PMID- 23341496 TI - Multiple mechanisms of GW-9508, a selective G protein-coupled receptor 40 agonist, in the regulation of glucose homeostasis and insulin sensitivity. AB - Activation of G protein-coupled receptor 40 (GPR40) by agonists increases insulin release in isolated islets, whereas it is inconclusive whether GPR40 antagonists decrease blood glucose and increase insulin sensitivity. Although some clinical trials indicated that administration of a GPR40 agonist shows benefits in the regulation of blood glucose homeostasis, the pharmacological mechanisms of this receptor in the improvement of glycemic control remain unclear. Therefore, we used a selective GPR40 agonist, GW-9508, to clarify the role of GPR40 in the regulation of blood glucose. Bolus intraperitoneal injection of GW-9508 in mice showed a slight decrease in blood glucose, with an increase in plasma insulin levels under glucose stimuli. However, long-term treatment with low doses of GW 9508 in high-fat diet-induced (HFD) diabetic mice decreased blood glucose with decreased plasma insulin significantly and improved glucose intolerance and insulin resistance. Using small interfering ribonucleic acid to delete GPR40 in HepG2 cells, we demonstrated that GW-9508 reversed palmitate-induced insulin signaling impairment through a GPR40-dependent pathway. We also found that GW 9508 activates the Akt/GSK-3beta pathway to increase glycogen levels in HepG2 cells. Furthermore, administration of GW-9508 decreased the hepatic expression of fetuin-A in HFD mice significantly and regulated high-glucose- or palmitate induced fetuin-A expression to increase insulin sensitivity through a GPR40/PLC/PKC pathway in HepG2 cells. Taken together, GW-9508 exerts a partial agonist effect to regulate blood glucose through multiple mechanisms. Investigation of chemicals that act on GPR40 might be a new strategy for the treatment of diabetes. PMID- 23341497 TI - Human prostasomes express glycolytic enzymes with capacity for ATP production. AB - Prostasomes are prostate-derived, exosome-like microvesicles that transmit signaling complexes between the acinar epithelial cells of the prostate and sperm cells. The vast majority of prostasomes have a diameter of 30-200 nm, and they are generally surrounded by a classical membrane bilayer. Using a selected proteomic approach, it became increasingly clear that prostasomes harbor distinct subsets of proteins that may be linked to adenosine triphosphate (ATP) metabolic turnover that in turn might be of importance in the role of prostasomes as auxiliary instruments in the fertilization process. Among the 21 proteins identified, most of the enzymes of anaerobic glycolysis were represented, and three of the glycolytic enzymes present are among the top 10 proteins found in most exosomes, once again linking prostasomes to the exosome family. Other prostasomal enzymes involved in ATP turnover were adenylate kinase, ATPase, 5' nucleotidase, and hexose transporters. The identified enzymes in their prostasomal context were operational for ATP formation when supplied with substrates. The net ATP production was low due to a high prostasomal ATPase activity that could be partially inhibited by vanadate that was utilized to profile the ATP-forming ability of prostasomes. Glucose and fructose were equivalent as glycolytic substrates for prostasomal ATP formation, and the enzymes involved were apparently surface located on prostasomes, since an alternative substrate not being membrane permeable (glyceraldehyde 3-phosphate) was operative, too. There is no clear-cut function linked to this subset of prostasomal proteins, but some possible roles are discussed. PMID- 23341499 TI - Towards more effective behavioral interventions in the prison setting. PMID- 23341498 TI - Gustducin couples fatty acid receptors to GLP-1 release in colon. AB - Sweet taste receptor subunits and alpha-gustducin found in enteroendocrine cells of the small intestine have been implicated in release of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in response to glucose and noncaloric sweeteners. alpha-Gustducin has also been found in colon, although its function there is unclear. We examined expression of alpha-gustducin, GLP-1, and GIP throughout the intestine. The number of alpha-gustducin-expressing cells and those coexpressing alpha-gustducin together with GLP-1 and/or GIP increased from small intestine to colon. alpha Gustducin also was coexpressed with fatty acid G protein-coupled receptor (GPR) 40, GPR41, GPR43, GPR119, GPR120, and bile acid G protein-coupled receptor TGR5 in enteroendocrine cells of the colon. In colon, GPR43 was coexpressed with GPR119 and GPR120, but not with TGR5. Treatment of colonic mucosa isolated from wild-type mice with acetate, butyrate, oleic acid, oleoylethanolamide, or lithocholic acid stimulated GLP-1 secretion. However, GLP-1 release in response to these fatty acids was impaired in colonic tissue from alpha-gustducin knockout mice. PMID- 23341500 TI - TACTICS, an interactive platform for customized high-content bioimaging analysis. AB - We describe a modular MATLAB(r) Toolbox named TACTICS for time-lapse image analysis that meets several requirements not generally offered by currently available software packages: (i) the ability to assess quality of extracted imaging information by directly linking data end points to the original position, (ii) massively parallel analysis of each parameter, for flow cytometry-like assessment of possible relationships between parameters within sub-populations of the images, (iii) options for user control of the tracking such as an interface to restrict the analysis region, (iv) manual correction of automated processes and (v) user interfaces for post-tracking analysis that is linked to the original images, including options to view cell pedigrees and normalized polarization ratios based on fluorescence ratiometric measurements. PMID- 23341501 TI - Composition and abstraction of logical regulatory modules: application to multicellular systems. AB - MOTIVATION: Logical (Boolean or multi-valued) modelling is widely used to study regulatory or signalling networks. Even though these discrete models constitute a coarse, yet useful, abstraction of reality, the analysis of large networks faces a classical combinatorial problem. Here, we propose to take advantage of the intrinsic modularity of inter-cellular networks to set up a compositional procedure that enables a significant reduction of the dynamics, yet preserving the reachability of stable states. To that end, we rely on process algebras, a well-established computational technique for the specification and verification of interacting systems. RESULTS: We develop a novel compositional approach to support the logical modelling of interconnected cellular networks. First, we formalize the concept of logical regulatory modules and their composition. Then, we make this framework operational by transposing the composition of logical modules into a process algebra framework. Importantly, the combination of incremental composition, abstraction and minimization using an appropriate equivalence relation (here the safety equivalence) yields huge reductions of the dynamics. We illustrate the potential of this approach with two case-studies: the Segment-Polarity and the Delta-Notch modules. PMID- 23341503 TI - Computational phosphorylation site prediction in plants using random forests and organism-specific instance weights. AB - MOTIVATION: Phosphorylation is the most important post-translational modification in eukaryotes. Although many computational phosphorylation site prediction tools exist for mammals, and a few were created specifically for Arabidopsis thaliana, none are currently available for other plants. RESULTS: In this article, we propose a novel random forest-based method called PHOSFER (PHOsphorylation Site FindER) for applying phosphorylation data from other organisms to enhance the accuracy of predictions in a target organism. As a test case, PHOSFER is applied to phosphorylation sites in soybean, and we show that it more accurately predicts soybean sites than both the existing Arabidopsis-specific predictors, and a simpler machine-learning scheme that uses only known phosphorylation sites and non-phosphorylation sites from soybean. In addition to soybean, PHOSFER will be extended to other organisms in the near future. PMID- 23341502 TI - Genome Fusion Detection: a novel method to detect fusion genes from SNP-array data. AB - MOTIVATION: Fusion genes result from genomic rearrangements, such as deletions, amplifications and translocations. Such rearrangements can also frequently be observed in cancer and have been postulated as driving event in cancer development. to detect them, one needs to analyze the transition region of two segments with different copy number, the location where fusions are known to occur. Finding fusion genes is essential to understanding cancer development and may lead to new therapeutic approaches. RESULTS: Here we present a novel method, the Genomic Fusion Detection algorithm, to predict fusion genes on a genomic level based on SNP-array data. This algorithm detects genes at the transition region of segments with copy number variation. With the application of defined constraints, certain properties of the detected genes are evaluated to predict whether they may be fused. We evaluated our prediction by calculating the observed frequency of known fusions in both primary cancers and cell lines. We tested a set of cell lines positive for the BCR-ABL1 fusion and prostate cancers positive for the TMPRSS2-ERG fusion. We could detect the fusions in all positive cell lines, but not in the negative controls. PMID- 23341508 TI - Overall and cancer-specific survival of patients with breast, colon, kidney, and lung cancers with and without chronic lymphocytic leukemia: a SEER population based study. AB - PURPOSE: Chronic lymphocytic leukemia (CLL) is associated with an increased risk of developing second cancers. However, it is unknown whether CLL alters the disease course of these cancers once they occur. PATIENTS AND METHODS: All patients with cancers of the breast (n = 579,164), colorectum (n = 412,366), prostate (n = 631,616), lung (n = 489,053), kidney (n = 95,795), pancreas (n = 82,116), and ovary (n = 61,937) reported to the SEER program from 1990 to 2007 were identified. Overall survival (OS; death resulting from any cause) and cancer specific survival were examined, comparing patients with and without pre-existing CLL. Cancer-specific survival was evaluated for each tumor type in a site specific manner (eg, death resulting from breast cancer in a patient with breast cancer). RESULTS: Patients with cancers of the breast (hazard ratio [HR], 1.70; P < .001), colorectum (HR, 1.65; P < .001), kidney (HR, 1.54; P < .001), prostate (HR, 1.92; P < .001), or lung (HR, 1.19; P < .001) had inferior OS if they had a pre-existing diagnosis of CLL after adjusting for age, sex, race, and disease stage. These results for OS remained significant for patients with cancers of the breast, colorectum, and prostate after excluding or censoring CLL-related deaths. Cancer-specific survival was also inferior for patients with cancers of the breast (HR, 1.41; P = .005) and colorectum (HR, 1.46; P < .001) who had pre existing CLL after adjusting for age, sex, race, and disease stage. CONCLUSION: Inferior OS and cancer-specific survival was observed for several common cancers in patients with pre-existing CLL. Additional studies are needed to determine the optimal management of these malignancies in patients with CLL and whether more aggressive screening or alternative approaches to adjuvant therapy are needed. PMID- 23341509 TI - Inclusion of patients with advanced cancer in phase I trials: is this a tool for improving optimism and emotional well-being? PMID- 23341510 TI - Associations of recreational physical activity and leisure time spent sitting with colorectal cancer survival. AB - PURPOSE: Little is known about the association of recreational physical activity or leisure time spent sitting with survival after colorectal cancer diagnosis. This study examined the associations of prediagnosis and postdiagnosis recreational physical activity and leisure time spent sitting with mortality among patients with colorectal cancer. PATIENTS AND METHODS: From a cohort of adults without colorectal cancer at baseline in 1992-1993, we identified 2,293 participants who were diagnosed with invasive, nonmetastatic colorectal cancer up to mid-2007. At baseline, before their cancer diagnosis, and again after their cancer diagnosis, participants completed detailed questionnaires that included information concerning recreational physical activity and leisure time spent sitting. RESULTS: During a maximum follow-up of 16.1 years after colorectal cancer diagnosis, 846 patients with colorectal cancer died, 379 of them from colorectal cancer. Engaging in 8.75 or more metabolic equivalent (MET) hours per week of recreational physical activity (equivalent to approximately 150 minutes per week of walking) compared with fewer than 3.5 MET hours per week was associated with lower all-cause mortality (prediagnosis physical activity: relative risk [RR], 0.72; 95% CI, 0.58 to 0.89; postdiagnosis physical activity: RR, 0.58; 95% CI, 0.47 to 0.71). Spending 6 or more hours per day of leisure time sitting compared with fewer than 3 hours per day was associated with higher all cause mortality (prediagnosis sitting time: RR, 1.36; 95% CI, 1.10 to 1.68; postdiagnosis sitting time: RR, 1.27; 95% CI, 0.99 to 1.64). CONCLUSION: More recreational physical activity before and after colorectal cancer diagnosis was associated with lower mortality, whereas longer leisure time spent sitting was associated with higher risk of death. PMID- 23341511 TI - Collaborating to conquer cancer: lessons from our children. PMID- 23341512 TI - Refractory hypoglycemia controlled by sorafenib in solitary fibrous tumor. PMID- 23341513 TI - Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer. AB - PURPOSE: Although gemcitabine and carboplatin (GCa) is a standard option for patients with advanced urothelial cancer (UC) who are ineligible for cisplatin, outcomes remain poor. This trial evaluated the efficacy and safety of bevacizumab with GCa in advanced UC. PATIENTS AND METHODS: Patients with Karnofsky performance status of 60% to 70%, creatinine clearance less than 60 mL/min, visceral metastasis, or solitary kidney were eligible and received a lead-in dose of bevacizumab 10 mg/kg followed 2 weeks later by gemcitabine 1,000 mg/m(2) on days 1 and 8 and carboplatin at area under the [concentration-time] curve (AUC) 5.0 or 4.5 and bevacizumab 15 mg/kg on day 1 every 21 days for six cycles. Patients achieving at least stable disease (SD) continued bevacizumab 15 mg/kg every 21 days for 18 additional cycles. The study was powered to detect a 50% improvement in median progression-free survival (PFS) over a historical control. RESULTS: Fifty-one patients, median age 67 years (range, 42 to 83 years), were enrolled onto the study and were evaluable for toxicity. Twenty (39%) experienced grade 3 to 4 toxicity, and 10 (20%) had thromboembolic events (deep venous thrombosis or pulmonary embolism). Four received one or fewer cycles leaving 47 evaluable for outcomes. Twenty-three (49%) achieved response (three complete; 20 partial), and 11 had SD. Median PFS was 6.5 months (95% CI, 4.7 to 7.8 months); PFS was greater in the carboplatin AUC 5.0 group (P = .04). Median overall survival (OS) was 13.9 months. CONCLUSION: The 95% one-sided lower confidence bound of 4.77 months for median PFS did not meet the predesignated PFS of more than 4.8 months considered sufficient for further study. Median OS was greater than expected. An ongoing phase III trial in patients who are eligible for therapy with cisplatin will define the role of bevacizumab in UC. PMID- 23341515 TI - Adaptive randomization versus interim monitoring. PMID- 23341514 TI - Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the Cologne interscore comparison study. AB - PURPOSE: Radioiodinated metaiodobenzylguanidine ((123)I-mIBG) scintigraphy is an established imaging method in neuroblastoma. Semiquantitative scoring systems have been developed to assess the extent of disease and response to chemotherapy. We present the results of the comparison between the SIOPEN [International Society of Pediatric Oncology Europe Neuroblastoma Group] score and the modified Curie score. PATIENTS AND METHODS: We retrospectively analyzed 147 mIBG scans of 58 patients older than 1 year of age with stage 4 neuroblastoma from German Neuroblastoma Trial NB97 that were assessed according to the SIOPEN and the Curie scoring method. mIBG examinations were performed at diagnosis and after four and six cycles of chemotherapy. RESULTS: Scoring results were highly correlated between both methods, and interobserver reliability was excellent. A Curie score <= 2 and a SIOPEN score <= 4 (best cutoff) at diagnosis were correlated to significantly better event-free and overall survival compared with higher scores. After four cycles of chemotherapy, overall survival was significantly better for mIBG-negative patients compared with those with any residual mIBG-positive metastases. After six cycles of chemotherapy, there was no difference in survival between mIBG-negative patients and patients with residual mIBG-positive metastases. Patients without mIBG-positive metastases after four and six cycles of chemotherapy had a better overall survival, but late clearance of mIBG positive metastases did not improve outcome. CONCLUSION: Higher mIBG scores at diagnosis and occurrence of any residual mIBG-positive metastases after four cycles of chemotherapy predicted unfavorable outcome for patients with stage 4 neuroblastoma. Later clearance of metastases did not improve prognosis. The Curie and the SIOPEN score were equally reliable and predictive. PMID- 23341516 TI - Larynx preservation for patients with locally advanced laryngeal cancer. AB - A 53-year-old man presented with a 6-month history of mild hoarseness, with no associated pain, dysphagia, or stridor. At nasoendoscopy, a lesion was detected involving the whole length of the left vocal cord, with abnormal mucosa also seen in the right ventricle (Fig 1). The left vocal cord movement was impaired. There were no palpable neck nodes. Biopsy under anesthesia revealed moderately differentiated squamous cell carcinoma. He was a current smoker of 30 cigarettes per day (45 pack-year smoking history), and he consumed four standard drinks of alcohol per day. His Eastern Cooperative Oncology Group performance status was 1, and he had no significant comorbidities. Radiologic review of his outside computed tomography scan noted that it was of poor quality, and a magnetic resonance imaging scan was recommended, which showed low-volume T4a disease based on focal thyroid cartilage penetration (Fig 2). A positron emission tomography (PET) scan revealed no evidence of nodal or distant metastasis. PMID- 23341517 TI - Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. AB - PURPOSE: To compare the efficacy and safety of induction chemotherapy (ICT) followed by chemoradiotherapy (CRT) or bioradiotherapy (BRT) for larynx preservation (LP). PATIENTS AND METHODS: Previously untreated patients with stage III to IV larynx/hypopharynx squamous cell carcinoma received three cycles of ICT docetaxel and cisplatin 75 mg/m(2) each on day 1 and fluorouracil 750 mg/m(2) per day on days 1 through 5. Poor responders (< 50% response) underwent salvage surgery. Responders (>= 50% response) were randomly assigned to conventional radiotherapy (RT; 70 Gy) with concurrent cisplatin 100 mg/m(2) per day on days 1, 22, and 43 of RT (arm A) or concurrent cetuximab 400 mg/m(2) loading dose and 250 mg/m(2) per week during RT (arm B). Primary end point was LP at 3 months. Secondary end points were larynx function preservation (LFP) and overall survival (OS) at 18 months. RESULTS: Of the 153 enrolled patients, 116 were randomly assigned after ICT (60, arm A; 56, arm B). Overall toxicity of both CRT and BRT was substantial following ICT. However, treatment compliance was higher in the BRT arm. In an intent-to-treat analysis, there was no significant difference in LP at 3 months between arms A and B (95% and 93%, respectively), LFP (87% and 82%, respectively), and OS at 18 months (92% and 89%, respectively). There were fewer local treatment failures in arm A than in arm B; salvage surgery was feasible in arm B only. CONCLUSION: There is no evidence that one treatment was superior to the other or could improve the outcome reported with ICT followed by RT alone (French Groupe Oncologie Radiotherapie Tete et Cou [GORTEC] 2000-01 trial [Induction CT by Cisplatin, 5FU With or Without Docetaxel in Patients With T3 and T4 Larynx and Hypopharynx Carcinoma]). The protocol that can best compare with RT alone after ICT is still to be determined. PMID- 23341518 TI - Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. AB - PURPOSE: Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case, anthracycline-only CT-in selected BC subtypes. PATIENTS AND METHODS: We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years. RESULTS: There was no significant prognostic association in the global nor estrogen receptor (ER) -positive/human epidermal growth factor receptor 2 (HER2) -negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018). CONCLUSION: In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes. PMID- 23341519 TI - Fertile future? Potential social implications of oncofertility. PMID- 23341520 TI - Lives in the balance: women with cancer and the right to fertility care. PMID- 23341521 TI - Molecular profiling of gastric cancer: toward personalized cancer medicine. PMID- 23341522 TI - Competing roads to larynx preservation. PMID- 23341523 TI - Diagnostic and therapeutic implications of tumor-infiltrating lymphocytes in breast cancer. PMID- 23341524 TI - Antiangiogenic agents, chemotherapy, and the treatment of metastatic transitional cell carcinoma. AB - A 69-year-old man with a 100 pack-year history of smoking developed gross hematuria. His medical history included hypertension, a silent myocardial infarction, and a cerebrovascular accident complicated by seizures. Cystoscopy and biopsy showed a 4-cm mass at the right ureteral orifice positive for a high grade papillary transitional cell carcinoma (TCC) with muscularis propria invasion (Fig 1). The computed tomography (CT)/positron emission tomography (PET) scan of the chest, abdomen, and pelvis showed hydronephrosis and hydroureter with marked cortical thinning and multiple bilateral PET-avid pulmonary nodules, with the largest in the left upper lung measuring 3.0 * 2.5 cm (Figs 2A, 3A), biopsy of which showed invasive high-grade urothelial carcinoma. The patient consented to join a clinical trial for metastatic TCC (USON [US Oncology Network study] 06040) involving treatment with gemcitabine, cisplatin, and sunitinib (GCS) 37.5 mg per day. Four days later, he experienced a 10-day hospitalization for acute pancreatitis and neutropenia. Sunitinib was discontinued, and he completed four additional cycles of GC. CT/PET showed that the right ureteral mass and all lung nodules had regressed or disappeared (Figs 2B, 3B). The largest remaining lung nodule at 1.4 cm showed no metabolic activity. He underwent a radical cystoprostatectomy and right nephroureterectomy, disclosing residual high-grade urothelial carcinoma infiltrating the full thickness of the ureteral wall. There was carcinoma in situ of the bladder, and 42 nodes were negative for cancer. The surgery was followed by a small, uncomplicated myocardial infarction. A scheduled left thoracotomy to remove the remaining nodule was cancelled. No additional chemotherapy was administered, and the patient remains free of recurrence 2 years from initiation of chemotherapy. The 1.4-cm nodule has calcified and remains stable and metabolically inactive. He has no sequelae of chemotherapy or surgery, with a creatinine level of 1.35 mg/dL. PMID- 23341525 TI - Nonfunctional parathyroid carcinoma after breast carcinoma. PMID- 23341527 TI - Identification of a patient with atypical MUTYH-associated polyposis through detection of the KRAS c.34G>T mutation in liver metastasis. PMID- 23341526 TI - Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. AB - PURPOSE: Brain metastasis (BM) is a leading cause of death from non-small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety. PATIENTS AND METHODS: Eligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility. RESULTS: Forty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade >= 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations. CONCLUSION: Erlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination. PMID- 23341528 TI - Primary jejunal adenocarcinoma incidentally diagnosed on positron emission tomography/computed tomography in a patient with metastatic colorectal cancer: suspicion of Lynch syndrome and effect on therapeutic management. PMID- 23341530 TI - Does sex affect survival of patients with squamous cell esophageal cancer? PMID- 23341529 TI - Systematic review of acupuncture in cancer care: a synthesis of the evidence. AB - PURPOSE: Many cancer centers offer acupuncture services. To date, a comprehensive systematic review of acupuncture in cancer care has not been conducted. The purpose of this review was to evaluate the efficacy of acupuncture for symptom management in patients with cancer. METHODS: Medline, Embase, CINAHL, Cochrane (all databases), Scopus, and PubMed were searched from inception through December 2011 for prospective randomized clinical trials (RCT) evaluating acupuncture for symptom management in cancer care. Only studies involving needle insertion into acupuncture points were included. No language limitations were applied. Studies were assessed for risk of bias (ROB) according to Cochrane criteria. Outcomes by symptom were designated as positive, negative, or unclear. RESULTS: A total of 2,151 publications were screened. Of those, 41 RCTs involving eight symptoms (pain, nausea, hot flashes, fatigue, radiation-induced xerostomia, prolonged postoperative ileus, anxiety/mood disorders, and sleep disturbance) met all inclusion criteria. One positive trial of acupuncture for chemotherapy-induced nausea and vomiting had low ROB. Of the remaining studies, eight had unclear ROB (four positive, three negative, and one with unclear outcomes). Thirty-three studies had high ROB (19 positive, 11 negative, and three with both positive and negative outcomes depending on the symptom). CONCLUSION: Acupuncture is an appropriate adjunctive treatment for chemotherapy-induced nausea/vomiting, but additional studies are needed. For other symptoms, efficacy remains undetermined owing to high ROB among studies. Future research should focus on standardizing comparison groups and treatment methods, be at least single-blinded, assess biologic mechanisms, have adequate statistical power, and involve multiple acupuncturists. PMID- 23341532 TI - Let's get SEERious: more accurate staging with consequent high management impact is not just stage migration. PMID- 23341531 TI - Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. AB - PURPOSE: TNFerade biologic is a novel means of delivering tumor necrosis factor alpha to tumor cells by gene transfer. We herein report final results of the largest randomized phase III trial performed to date among patients with locally advanced pancreatic cancer (LAPC) and the first to test gene transfer against this malignancy. PATIENTS AND METHODS: In all, 304 patients were randomly assigned 2:1 to standard of care plus TNFerade (SOC + TNFerade) versus standard of care alone (SOC). SOC consisted of 50.4 Gy in 28 fractions with concurrent fluorouracil (200 mg/m(2) per day continuous infusion). TNFerade was injected intratumorally before the first fraction of radiotherapy each week at a dose of 4 * 10(11) particle units by using either a percutaneous transabdominal or an endoscopic ultrasound approach. Four weeks after chemoradiotherapy, patients began gemcitabine (1,000 mg/m(2) intravenously) with or without erlotinib (100 to 150 mg per day orally) until progression or toxicity. RESULTS: The analysis included 187 patients randomly assigned to SOC + TNFerade and 90 to SOC by using a modified intention-to-treat approach. Median follow-up was 9.1 months (range, 0.1 to 50.5 months). Median survival was 10.0 months for patients in both the SOC + TNFerade and SOC arms (hazard ratio [HR], 0.90; 95% CI, 0.66 to 1.22; P = .26). Median progression-free survival (PFS) was 6.8 months for SOC + TNFerade versus 7.0 months for SOC (HR, 0.96; 95% CI, 0.69 to 1.32; P = .51). Among patients treated on the SOC + TNFerade arm, multivariate analysis showed that TNFerade injection by an endoscopic ultrasound-guided transgastric/transduodenal approach rather than a percutaneous transabdominal approach was a risk factor for inferior PFS (HR, 2.08; 95% CI, 1.06 to 4.06; P = .032). The patients in the SOC + TNFerade arm experienced more grade 1 to 2 fever and chills than those in the SOC arm (P < .001) but both arms had similar rates of grade 3 to 4 toxicities (all P > .05). CONCLUSION: SOC + TNFerade is safe but not effective for prolonging survival in patients with LAPC. PMID- 23341533 TI - Somatic mutations and deletions of the E-cadherin gene predict poor survival of patients with gastric cancer. AB - PURPOSE: The prognosis of gastric cancer (GC) is poor, and the molecular pathogenesis players are vastly unknown. Surgery remains the primary option in GC treatment. The aim of this study was to investigate the impact of somatic CDH1 alterations in prognosis and survival of patients with GC. PATIENTS AND METHODS: A series of patients with sporadic and familial GC (diffuse and intestinal; n = 246) were analyzed for somatic CDH1 mutations, promoter hypermethylation, and loss of heterozygosity (LOH) by polymerase chain reaction sequencing. E-cadherin protein expression was determined by immunohistochemistry. Associations between molecular, clinicopathologic, and survival data were analyzed. RESULTS: CDH1 somatic alterations were found in approximately 30% of all patients with GC. Both histologic types of sporadic GC displayed LOH in 7.5%, mutations in 1.7%, and hypermethylation in 18.4% of patients. Primary tumors from hereditary diffuse GC, lacking germline CDH1 alterations, showed exclusively CDH1 promoter hypermethylation in 50% of patients. Familial intestinal GC (FIGC) tumors showed LOH in 9.4% and hypermethylation in 17.0%. CDH1 alterations did not associate with a particular pattern of E-cadherin expression. Importantly, the worst patient survival rate among all GCs analyzed was seen in patients with tumors carrying CDH1 structural alterations, preferentially those belonging to FIGC families. CONCLUSION: CDH1 somatic alterations exist in all clinical settings and histotypes of GC and associate with different survival rates. Their screening at GC diagnosis may predict patient prognosis and is likely to improve management of patients with this disease. PMID- 23341534 TI - Contrasting historical and recent gene flow among African buffalo herds in the Caprivi Strip of Namibia. AB - Population genetic structure is often used to infer population connectivity, but genetic structure may largely reflect historical rather than recent processes. We contrasted genetic structure with recent gene-flow estimates among 6 herds of African buffalo (Syncerus caffer) in the Caprivi Strip, Namibia, using 134 individuals genotyped at 10 microsatellite loci. We tested whether historical and recent gene flows were influenced by distance, potential barriers (rivers), or landscape resistance (distance from water). We also tested at what scales individuals were more related than expected by chance. Genetic structure across the Caprivi Strip was weak, indicating that historically, gene flow was strong and was not affected by distance, barriers, or landscape resistance. Our analysis of simulated data suggested that genetic structure would be unlikely to reflect human disturbances in the last 10-20 generations (75-150 years) because of slow predicted rates of genetic drift, but recent gene-flow estimates would be affected. Recent gene-flow estimates were not consistently affected by rivers or distance to water but showed that isolation by distance appears to be developing. Average relatedness estimates among individuals exceeded random expectations only within herds. We conclude that historically, African buffalo moved freely throughout the Caprivi Strip, whereas recent gene flow has been more restricted. Our findings support efforts to maintain the connectivity of buffalo herds across this region and demonstrate the utility of contrasting genetic inferences from different time scales. PMID- 23341535 TI - Biogeography and historical demography of the Juan Fernandez Rock Lobster, Jasus frontalis (Milne Edwards, 1837). AB - The genetic structure of present-day populations has been highly affected by glacial periods and physical oceanographic forcing, particularly with respect to species distributions and population gene-flow patterns. We assessed the current genetic composition of the Jasus frontalis population in the southeastern Pacific Islands off the coast of Chile to evaluate their connectivity modulated by contemporary and historic oceanographic processes. Population structure and demographical history for this species were assessed based on classic and Bayesian approaches using 84 sequences of cytochrome oxidase subunit I. In addition, we estimated the time of origin of J. frontalis in the different geographic zones. The analyses show a panmictic population with high gene flow between subcomponents and a lack of genetic structure (F (ST) < 0.008). This high gene flow is mainly modulated by mesoscale oceanographic factors such as eddies and meanders. In a historical spatial context, the most probable common ancestor of J. frontalis could have colonized the region around 0.258 million years before present (MYBP), first becoming established in the Juan Fernandez Archipelago and then expanding toward the Desventuradas Islands. The demographic history shows a consistent increase in the effective population size (N ( e )) starting approximately 0.130 MYBP, which is highly correlated with sea-level changes during the last glacial maximum. PMID- 23341536 TI - Effectiveness of monovalent 2009 pandemic influenza A virus subtype H1N1 and 2010 2011 trivalent inactivated influenza vaccines in Wisconsin during the 2010-2011 influenza season. AB - BACKGROUND: The 2009 influenza A virus subtype H1N1 (A[H1N1]pdm09) did not exhibit antigenic drift during the 2010-2011 influenza season, providing an opportunity to investigate the duration of protection after vaccination. We estimated the independent effects of 2010-2011 seasonal trivalent inactivated influenza vaccine (TIV) and A(H1N1)pdm09 vaccine for preventing medically attended influenza A virus infection during the 2010-2011 season. METHODS: Individuals were tested for influenza A virus by real-time reverse transcription polymerase chain reaction (rRT-PCR) after a clinical encounter for acute respiratory illness. Case-control analyses compared participants with rRT-PCR confirmed influenza A virus infection and test-negative controls. Vaccine effectiveness was estimated separately for monovalent pandemic vaccine and TIV and was calculated as 100 * [1 - adjusted odds ratio], where the odds ratio was adjusted for potential confounders. RESULTS: The effectiveness of TIV against influenza A virus infection was 63% (95% confidence interval [CI], 37%-78%). The effectiveness of TIV against A(H1N1)pdm09 infection was 77% (95% CI, 44%-90%). Monovalent vaccine administered between October 2009 and April 2010 was not protective during the 2010-2011 season, with an effectiveness of -1% (95% CI, 146% to 59%) against A(H1N1)pdm09 infection. CONCLUSIONS: Monovalent vaccine provided no sustained protection against A(H1N1)pdm09 infection during the 2010 2011 season. This waning effectiveness supports the need for annual revaccination, even in the absence of antigenic drift in A(H1N1)pdm09. PMID- 23341537 TI - Leptin up-regulates TLR2 in human monocytes. AB - The adipokine leptin elicits changes in the expression of the activation markers CD40 and CD69 in PBMCs and DCs, yet its effect on PRRs remains to be elucidated. Serum leptin concentrations are elevated in obesity and T2DM, which are both diseases associated with a proinflammatory state. We therefore investigated a possible role for leptin in monocyte TLR and CD14 expression. Leptin increased TLR2 cell-surface and mRNA expression in THP-1 and primary human monocytes. In contrast, leptin had no effect on monocyte TLR4 expression in THP-1 or primary monocytes. CD14 cell-surface and mRNA expression were increased after leptin stimulation in THP-1 monocytes. However, no change in cell-surface CD14 expression was observed after leptin treatment in primary human monocytes. Leptin also up-regulated the expression of PU.1 and EGR2, transcription factors involved in myeloid cell differentiation. Additionally, leptin potentiated Escherichia coli and Porphyromonas gingivalis LPS-induced TNF-alpha secretion in THP-1 monocytes. In conclusion, we show that leptin and LPS differentially influence monocyte phenotype and demonstrate, for the first time, a regulatory effect of leptin on the monocyte expression of TLR2. Leptin-stimulated TLR2 expression may potentiate innate immunity and inflammation in conditions of hyperleptinemia, such as obesity and T2DM. PMID- 23341538 TI - Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness. AB - Human blood DCs encompass pDCs and two subsets of mDCs: CD1c(+) mDCs and CD141(+) mDCs. The rare CD141(+) DC population is thought to be the equivalent of mouse CD8alpha(+) cDCs that play a significant role in antigen cross-presentation. Here, we analyzed by Q-PCR TLR1-10 expression in blood DC subsets. Whereas CD1c(+) DCs express all TLR except TLR9, CD141(+) DCs present a more restricted pattern with high expression of TLR3 and -10, expression of TLR1,-2, -6, and -8, and lack of TLR4, -5, -7, and -9. The in vitro analysis of isolated mDC subset reponsiveness to an extensive panel of TLR ligands confirmed these results, with CD141(+) DCs responding only to TLR1/2, -3, and -7/8. The cytokine/chemokine production profile of isolated CD141(+) DCs was also more restricted, as they produced mainly proinflammatory cytokines but no IL-12 and to a lower level, in comparison with CD1c(+) DCs, except for CXCL10, CCL5, and IFN-beta. In contrast, with the use of a whole blood assay, we found that CD141(+) DCs produce IL-12 in response to TLR1/2, -3, and more surprisingly, -9. Finally, both mDC subsets are potent inducers of Th1 response, particularly after TLR3 triggering. Taken together, these data confirmed functional differences between blood mDC subsets. The major response of CD141(+) mDCs to TLR3 ligand and their cytokine production pattern suggest a role for these cells in antiviral immunity. PMID- 23341539 TI - Blood CD33(+)HLA-DR(-) myeloid-derived suppressor cells are increased with age and a history of cancer. AB - As we age, the composition of our peripheral leukocytes changes dramatically. Many of these alterations contribute to the general immune dysfunction that burdens the elderly, which in turn, contributes to increased susceptibility to disease. MDSCs represent a heterogeneous population of immunosuppressive leukocytes that are elevated in the peripheral blood of cancer patients. Given the relation between cancer incidence and age, this study examined the frequency of peripheral blood CD33(+)HLA-DR(-) MDSCs across three cohorts: healthy adults (19-59 years old), community-dwelling seniors (61-76 years old), and frail elderly (67-99 years old). This analysis is the first to demonstrate that MDSCs and specifically the CD11b(+)CD15(+) MDSC subset are increased with age. Proinflammatory cytokines that are required for the differentiation of MDSCs (e.g., TNF-alpha, IL-6, and IL-1beta) were similarly found to be increased in the serum of the frail elderly. Furthermore, the proportion of MDSCs and the CD11b(+)CD15(+) subset were found to be elevated significantly in elderly donors with a history of cancer. This age-related elevation in the frequency of MDSCs may contribute to the increased cancer incidence that occurs with age. Further investigation into the functional consequences of elevated MDSCs will provide valuable insight into the progression of age-related pathologies. PMID- 23341540 TI - Bcl-2 overexpression ameliorates immune complex-mediated arthritis by altering FcgammaRIIb expression and monocyte homeostasis. AB - RA is a chronic autoimmune disease characterized by accumulation of inflammatory cells within synovial joints. RA is associated with a failure of apoptosis of infiltrating leukocytes, thought to be a result of overexpression of prosurvival Bcl-2 proteins. Overexpression of Bcl-2 in hematopoietic cells can result in spontaneous autoimmunity. We therefore hypothesized that increased Bcl-2 in the hematopoietic compartment would reduce apoptosis and thereby, exacerbate inflammatory arthritis. Paradoxically, we found that overexpression of Bcl-2 in mice (vav-bcl-2) markedly reduced pathology in antibody-dependent models of RA (CIA and K/BxN serum transfer arthritis). No such protection was observed in a model of CD4(+) T cell-dependent, B cell-independent arthritis (mBSA/IL-1-induced arthritis). In CIA, vav-bcl-2 Tg mice had lower antibody production to CII, which might explain reduced disease. However, Bcl-2 overexpression also reduced passive K/BxN serum transfer arthritis. Overexpression of Bcl-2 caused a monocytosis, with preferential expansion of Ly6C(lo) monocytes and increased expression of the inhibitory receptor for IgG, FcgammaRIIb, on leukocytes. Skewing of the myeloid cell population, increases in FcgammaRIIb, and reduced arthritis were independent of the hypergammaglobulinemia found in vav-bcl-2 Tg mice. These data reveal selective effects of the Bcl-2-regulated apoptotic pathway on monocyte differentiation and the expression of FcRs critical for regulation of antibody/immune complex-mediated disease. PMID- 23341541 TI - P110alpha-mediated constitutive PI3K signaling limits the efficacy of p110delta selective inhibition in mantle cell lymphoma, particularly with multiple relapse. AB - Phosphoinositide-3 kinase (PI3K) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis, but early-phase studies of the PI3K p110delta inhibitor GS-1101 have reported inferior responses in MCL compared with other non Hodgkin lymphomas. Because the relative importance of the class IA PI3K isoforms p110alpha, p110beta, and p110delta in MCL is not clear, we studied expression of these isoforms and assessed their contribution to PI3K signaling in this disease. We found that although p110delta was highly expressed in MCL, p110alpha showed wide variation and expression increased significantly with relapse. Loss of phosphatase and tensin homolog expression was found in 16% (22/138) of cases, whereas PIK3CA and PIK3R1 mutations were absent. Although p110delta inhibition was sufficient to block B-cell receptor-mediated PI3K activation, combined p110alpha and p110delta inhibition was necessary to abolish constitutive PI3K activation. In addition, GDC-0941, a predominantly p110alpha/delta inhibitor, was significantly more active compared with GS-1101 against MCL cell lines and primary samples. We found that a high PIK3CA/PIK3CD ratio identified a subset of primary MCLs resistant to GS-1101 and this ratio increased significantly with relapse. These findings support the use of dual p110alpha/p110delta inhibitors in MCL and suggest a role for p110alpha in disease progression. PMID- 23341542 TI - ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia. AB - BH3-only proteins trigger the stress apoptosis pathway and chemical mimetics have great potential for cancer therapy. BH3-only proteins inhibit antiapoptotic members of the Bcl-2 family. Promising BH3 mimetic ABT-737 and the related orally available compound ABT-263 (navitoclax) bind avidly to antiapoptotic Bcl-2, Bcl xL, and Bcl-w. However, their interaction with Bcl-xL provokes thrombocytopenia, which has proven to be the dose-limiting toxicity. We have tested the efficacy of ABT-199, a new Bcl-2-specific BH3 mimetic, against aggressive progenitor cell lymphomas derived from bitransgenic myc/bcl-2 mice. As a single agent, ABT-199 was as effective as ABT-737 in prolonging survival of immunocompetent tumor bearing mice without causing thrombocytopenia. Both drugs acted rapidly but, contrary to prevailing models, their apoptotic activity did not rely upon the BH3 only protein Bim. When ABT-737 was combined with the proteosome inhibitor bortezomib or CDK inhibitor purvalanol, many treated animals achieved long-term remission. PMID- 23341545 TI - Bed bug infestation. PMID- 23341544 TI - 3'-Deoxy-3'-18F-fluorothymidine PET predicts response to (V600E)BRAF-targeted therapy in preclinical models of colorectal cancer. AB - Selective inhibition of oncogenic targets and associated signaling pathways forms the basis of personalized cancer medicine. The clinical success of (V600E)BRAF inhibition in melanoma, coupled with the emergence of acquired resistance, underscores the importance of rigorously validating quantitative biomarkers of treatment response in this and similar settings. Because constitutive activation of BRAF leads to proliferation in tumors, we explored 3'-deoxy-3'-(18)F fluorothymidine ((18)F-FLT) PET to noninvasively quantify changes in tumor proliferation that are associated with pharmacologic inhibition of (V600E)BRAF downstream effectors and that precede changes in tumor volume. METHODS: Human colorectal cancer (CRC) cell lines expressing (V600E)BRAF were used to explore relationships between upregulation of p27 and phosphorylation of BRAF downstream effectors on small-molecule (V600E)BRAF inhibitor exposure. Athymic nude mice bearing (V600E)BRAF-expressing human CRC cell line xenografts were treated with a small-molecule (V600E)BRAF inhibitor (or vehicle) daily for 10 d. Predictive (18)F-FLT PET was conducted before changes in tumor volume occurred. Correlations were evaluated among PET, inhibition of phosphorylated MEK (p-MEK) and phosphorylated-ERK (p-ERK) by Western blot, tumor proliferation by histology, and small-molecule exposure by matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS). RESULTS: Treatment of CRC cell lines with PLX4720 reduced proliferation associated with target inhibition and upregulation of p27. In vivo, PLX4720 treatment reduced (18)F-FLT uptake, but not (18)F-FDG uptake, in Lim2405 xenografts before quantifiable differences in xenograft volume. Reduced (18)F-FLT PET reflected a modest, yet significant, reduction of Ki67 immunoreactivity, inhibition of p-MEK and p-ERK, and elevated tumor cell p27 protein levels. Both (18)F-FLT PET and (18)F-FDG PET accurately reflected a lack of response in HT-29 xenografts, which MALDI imaging mass spectrometry suggested may have stemmed from limited PLX4720 exposure. CONCLUSION: We used preclinical models of CRC to demonstrate (18)F-FLT PET as a sensitive predictor of response to (V600E)BRAF inhibitors. Because (18)F-FLT PET predicted reduced proliferation associated with attenuation of BRAF downstream effectors, yet (18)F-FDG PET did not, these data suggest that (18)F-FLT PET may represent an alternative to (18)F FDG PET for quantifying clinical responses to BRAF inhibitors. PMID- 23341546 TI - Off-label marketing: free speech or illegal promotion? PMID- 23341543 TI - Glucose metabolism impacts the spatiotemporal onset and magnitude of HSC induction in vivo. AB - Many pathways regulating blood formation have been elucidated, yet how each coordinates with embryonic biophysiology to modulate the spatiotemporal production of hematopoietic stem cells (HSCs) is currently unresolved. Here, we report that glucose metabolism impacts the onset and magnitude of HSC induction in vivo. In zebrafish, transient elevations in physiological glucose levels elicited dose-dependent effects on HSC development, including enhanced runx1 expression and hematopoietic cluster formation in the aorta-gonad-mesonephros region; embryonic-to-adult transplantation studies confirmed glucose increased functional HSCs. Glucose uptake was required to mediate the enhancement in HSC development; likewise, metabolic inhibitors diminished nascent HSC production and reversed glucose-mediated effects on HSCs. Increased glucose metabolism preferentially impacted hematopoietic and vascular targets, as determined by gene expression analysis, through mitochondrial-derived reactive oxygen species (ROS) mediated stimulation of hypoxia-inducible factor 1alpha (hif1alpha). Epistasis assays demonstrated that hif1alpha regulates HSC formation in vivo and mediates the dose-dependent effects of glucose metabolism on the timing and magnitude of HSC production. We propose that this fundamental metabolic-sensing mechanism enables the embryo to respond to changes in environmental energy input and adjust hematopoietic output to maintain embryonic growth and ensure viability. PMID- 23341547 TI - A pilot trial of a stress management intervention for primary caregivers of children newly diagnosed with cancer: preliminary evidence that perceived social support moderates the psychosocial benefit of intervention. AB - OBJECTIVES: (1) To examine the acceptability and feasibility of a stress management intervention for caregivers of children recently diagnosed with cancer. (2) To explore whether caregivers with lower baseline perceived social support derive greater benefit from the intervention than those with higher perceived support. METHODS: 45 primary caregivers were randomly assigned to intervention or standard care. Of these, 37 completed measures of social support, depression, anxiety, and perceived stress at both pre-intervention (T1; mean = 24 days post-diagnosis) and post-intervention time points (T2; mean = 165 days post diagnosis). RESULTS: Enrollment, retention, and satisfaction data support feasibility and acceptability of the intervention. There was no overall significant impact of participation in the intervention on levels of distress at T2. However, T1 social support moderated intervention response, with caregivers who perceived lower T1 support showing greater psychological benefit from the intervention. CONCLUSIONS: Primary caregivers with lower levels of perceived social support may benefit from preemptive stress management intervention. PMID- 23341548 TI - Cognitive emotion regulation strategies moderate the effect of parenting self efficacy beliefs on parents' anxiety following their child's surgery. AB - OBJECTIVE: To explore the role of cognitive emotion regulation (CER) in the association between parenting self-efficacy (PSE) and state anxiety in parents of children undergoing surgery. METHOD: In a prospective design, parents of 114 children admitted to hospital for planned surgical interventions completed self report questionnaires assessing PSE, CER, and state anxiety. Mediational and moderational analyses were conducted to test competing theoretical models regarding the role of CER in the relationship between PSE and parents' anxiety. RESULTS: The mediational model was rejected, whereas the findings supported a moderational model. The use of nonadaptive CER moderated the effect of PSE on parents' anxiety. Higher PSE only predicted lower postsurgery anxiety when low use of nonadaptive CER was present. CONCLUSIONS: Interacting cognitive factors contribute to parents' anxiety after a child's surgery. Both PSE and CER should be targeted in parent interventions promoting successful adjustments to surgery on children. PMID- 23341549 TI - Comparative genomics of recent Shiga toxin-producing Escherichia coli O104:H4: short-term evolution of an emerging pathogen. AB - The large outbreak of diarrhea and hemolytic uremic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli O104:H4 in Europe from May to July 2011 highlighted the potential of a rarely identified E. coli serogroup to cause severe disease. Prior to the outbreak, there were very few reports of disease caused by this pathogen and thus little known of its diversity and evolution. The identification of cases of HUS caused by E. coli O104:H4 in France and Turkey after the outbreak and with no clear epidemiological links raises questions about whether these sporadic cases are derived from the outbreak. Here, we report genome sequences of five independent isolates from these cases and results of a comparative analysis with historical and 2011 outbreak isolates. These analyses revealed that the five isolates are not derived from the outbreak strain; however, they are more closely related to the outbreak strain and each other than to isolates identified prior to the 2011 outbreak. Over the short time scale represented by these closely related organisms, the majority of genome variation is found within their mobile genetic elements: none of the nine O104:H4 isolates compared here contain the same set of plasmids, and their prophages and genomic islands also differ. Moreover, the presence of closely related HUS-associated E. coli O104:H4 isolates supports the contention that fully virulent O104:H4 isolates are widespread and emphasizes the possibility of future food-borne E. coli O104:H4 outbreaks. IMPORTANCE: In the summer of 2011, a large outbreak of bloody diarrhea with a high rate of severe complications took place in Europe, caused by a previously rarely seen Escherichia coli strain of serogroup O104:H4. Identification of subsequent infections caused by E. coli O104:H4 raised questions about whether these new cases represented ongoing transmission of the outbreak strain. In this study, we sequenced the genomes of isolates from five recent cases and compared them with historical isolates. The analyses reveal that, in the very short term, evolution of the bacterial genome takes place in parts of the genome that are exchanged among bacteria, and these regions contain genes involved in adaptation to local environments. We show that these recent isolates are not derived from the outbreak strain but are very closely related and share many of the same disease-causing genes, emphasizing the concern that these bacteria may cause future severe outbreaks. PMID- 23341550 TI - Modulation of Epstein-Barr virus glycoprotein B (gB) fusion activity by the gB cytoplasmic tail domain. AB - Epstein-Barr virus (EBV), along with other members of the herpesvirus family, requires a set of viral glycoproteins to mediate host cell attachment and entry. Viral glycoprotein B (gB), a highly conserved glycoprotein within the herpesvirus family, is thought to be the viral fusogen based on structural comparison of EBV gB and herpes simplex virus (HSV) gB with the postfusion crystal structure of vesicular stomatitis virus fusion protein glycoprotein G (VSV-G). In addition, mutational studies indicate that gB plays an important role in fusion function. In the current study, we constructed a comprehensive library of mutants with truncations of the C-terminal cytoplasmic tail domain (CTD) of EBV gB. Our studies indicate that the gB CTD is important in the cellular localization, expression, and fusion function of EBV gB. However, in line with observations from other studies, we conclude that the degree of cell surface expression of gB is not directly proportional to observed fusion phenotypes. Rather, we conclude that other biochemical or biophysical properties of EBV gB must be altered to explain the different fusion phenotypes observed. IMPORTANCE: Epstein-Barr virus (EBV), like all enveloped viruses, fuses the virion envelope to a cellular membrane to allow release of the capsid, resulting in virus infection. To further characterize the function of EBV glycoprotein B (gB) in fusion, a comprehensive library of mutants with truncations in the gB C-terminal cytoplasmic tail domain (CTD) were made. These studies indicate that the CTD of gB is important for the cellular expression and localization of gB, as well as for the function of gB in fusion. These studies will lead to a better understanding of the mechanism of EBV induced membrane fusion and herpesvirus-induced membrane fusion in general, which will ultimately lead to focused therapies guided at preventing viral entry into host cells. PMID- 23341552 TI - Five new genes are important for common polysaccharide antigen biosynthesis in Pseudomonas aeruginosa. AB - Common polysaccharide antigen (CPA) is a conserved cell surface polysaccharide produced by Pseudomonas aeruginosa. It contains a rhamnan homopolymer and is one of the two forms of O polysaccharide attached to P. aeruginosa lipopolysaccharide (LPS). Our laboratory has previously characterized an eight-gene cluster (pa5447 pa5454 in P. aeruginosa PAO1) required for biosynthesis of CPA. Here we demonstrate that an adjacent five-gene cluster pa5455-pa5459 is also involved. Using reverse transcriptase PCR (RT-PCR), we showed that the original eight-gene cluster and the new five-gene cluster are both organized as operons. We have analyzed the LPS phenotypes of in-frame deletion mutants made in each of the five genes, and the results verified that these five genes are indeed required for CPA biosynthesis, extending the CPA biosynthesis locus to contain 13 contiguous genes. By performing overexpression experiments of different sets of these biosynthesis genes, we were able to obtain information about their possible functions in CPA biosynthesis. IMPORTANCE: Lipopolysaccharide (LPS) is an important cell surface structure of Gram-negative bacteria. The human opportunistic pathogen Pseudomonas aeruginosa simultaneously produces an O antigen-specific (OSA) form and a common polysaccharide antigen (CPA) form of LPS. CPA, the focus of this study, is composed of alpha-1-2, alpha1-3-linked d rhamnose sugars and has been shown to be important for attachment of the bacteria to human airway epithelial cells. Genome sequencing of this species revealed a new five-gene cluster that we predicted to be involved in CPA biosynthesis and modification. In this study, we have generated chromosomal knockouts by performing in-frame deletions and allelic replacements. Characterizing the function of each of the five genes is important for us to better understand CPA biosynthesis and the mechanisms of chain length termination and regulation of this unique D-rhamnan polysaccharide. PMID- 23341553 TI - Males are overrepresented among life science researchers committing scientific misconduct. AB - A review of the United States Office of Research Integrity annual reports identified 228 individuals who have committed misconduct, of which 94% involved fraud. Analysis of the data by career stage and gender revealed that misconduct occurred across the entire career spectrum from trainee to senior scientist and that two-thirds of the individuals found to have committed misconduct were male. This exceeds the overall proportion of males among life science trainees and faculty. These observations underscore the need for additional efforts to understand scientific misconduct and to ensure the responsible conduct of research. IMPORTANCE: As many of humanity's greatest problems require scientific solutions, it is critical for the scientific enterprise to function optimally. Misconduct threatens the scientific enterprise by undermining trust in the validity of scientific findings. We have examined specific demographic characteristics of individuals found to have committed research misconduct in the life sciences. Our finding that misconduct occurs across all stages of career development suggests that attention to ethical aspects of the conduct of science should not be limited to those in training. The observation that males are overrepresented among those who commit misconduct implies a gender difference that needs to be better understood in any effort to promote research integrity. PMID- 23341551 TI - Genomic insights into the atopic eczema-associated skin commensal yeast Malassezia sympodialis. AB - Malassezia commensal yeasts are associated with a number of skin disorders, such as atopic eczema/dermatitis and dandruff, and they also can cause systemic infections. Here we describe the 7.67-Mbp genome of Malassezia sympodialis, a species associated with atopic eczema, and contrast its genome repertoire with that of Malassezia globosa, associated with dandruff, as well as those of other closely related fungi. Ninety percent of the predicted M. sympodialis protein coding genes were experimentally verified by mass spectrometry at the protein level. We identified a relatively limited number of genes related to lipid biosynthesis, and both species lack the fatty acid synthase gene, in line with the known requirement of these yeasts to assimilate lipids from the host. Malassezia species do not appear to have many cell wall-localized glycosylphosphatidylinositol (GPI) proteins and lack other cell wall proteins previously identified in other fungi. This is surprising given that in other fungi these proteins have been shown to mediate interactions (e.g., adhesion and biofilm formation) with the host. The genome revealed a complex evolutionary history for an allergen of unknown function, Mala s 7, shown to be encoded by a member of an amplified gene family of secreted proteins. Based on genetic and biochemical studies with the basidiomycete human fungal pathogen Cryptococcus neoformans, we characterized the allergen Mala s 6 as the cytoplasmic cyclophilin A. We further present evidence that M. sympodialis may have the capacity to undergo sexual reproduction and present a model for a pseudobipolar mating system that allows limited recombination between two linked MAT loci. IMPORTANCE: Malassezia commensal yeasts are associated with a number of skin disorders. The previously published genome of M. globosa provided some of the first insights into Malassezia biology and its involvement in dandruff. Here, we present the genome of M. sympodialis, frequently isolated from patients with atopic eczema and healthy individuals. We combined comparative genomics with sequencing and functional characterization of specific genes in a population of clinical isolates and in closely related model systems. Our analyses provide insights into the evolution of allergens related to atopic eczema and the evolutionary trajectory of the machinery for sexual reproduction and meiosis. We hypothesize that M. sympodialis may undergo sexual reproduction, which has important implications for the understanding of the life cycle and virulence potential of this medically important yeast. Our findings provide a foundation for the development of genetic and genomic tools to elucidate host-microbe interactions that occur on the skin and to identify potential therapeutic targets. PMID- 23341554 TI - Profile of Michael I. Jordan. PMID- 23341556 TI - Learning from Jacintha Saldanha's death. PMID- 23341557 TI - NICE guidance on ectopic pregnancy and miscarriage restricts access and choice and may be clinically unsafe. PMID- 23341558 TI - Authors' reply to Bourne and colleagues. PMID- 23341559 TI - Another loophole exploited by the drug industry. PMID- 23341560 TI - Flynn Pharma's reply to Brunet. PMID- 23341561 TI - Developing a new drug costs less than $100m, not $900m. PMID- 23341562 TI - Increased funding needed for mental health research. PMID- 23341563 TI - Alternatives to hospital for older people must be found, says NHS chief. PMID- 23341564 TI - Cardiopulmonary resuscitation should be extended to more than 35 minutes for children, study shows. PMID- 23341565 TI - Hepatitis C database will provide information and tissue samples for researchers. PMID- 23341566 TI - Labour proposes scheme to merge health and social care. PMID- 23341567 TI - Are antidepressants overprescribed? No. PMID- 23341568 TI - Are antidepressants overprescribed? Yes. PMID- 23341569 TI - How long can we expect to live? PMID- 23341570 TI - Determination of molecular markers for BRCA1 and BRCA2 heterozygosity using gene expression profiling. AB - Approximately 5% of all breast cancers can be attributed to an inherited mutation in one of two cancer susceptibility genes, BRCA1 and BRCA2. We searched for genes that have the potential to distinguish healthy BRCA1 and BRCA2 mutation carriers from noncarriers based on differences in expression profiling. Using expression microarrays, we compared gene expression of irradiated lymphocytes from BRCA1 and BRCA2 mutation carriers versus control noncarriers. We identified 137 probe sets in BRCA1 carriers and 1,345 in BRCA2 carriers with differential gene expression. Gene Ontology analysis revealed that most of these genes relate to regulation pathways of DNA repair processes, cell-cycle regulation, and apoptosis. Real-time PCR was conducted on the 36 genes, which were most prominently differentially expressed in the microarray assay; 21 genes were shown to be significantly differentially expressed in BRCA1 and/or BRCA2 mutation carriers as compared with controls (P < 0.05). On the basis of a validation study with 40 mutation carriers and 17 noncarriers, a multiplex model that included six or more coincidental genes of 18 selected genes was constructed to predict the risk of carrying a mutation. The results using this model showed sensitivity 95% and specificity 88%. In summary, our study provides insight into the biologic effect of heterozygous mutations in BRCA1 and BRCA2 genes in response to ionizing irradiation-induced DNA damage. We also suggest a set of 18 genes that can serve as a prediction and screening tool for BRCA1 or BRCA2 mutational carriers by using easily obtained lymphocytes. PMID- 23341571 TI - Personalized immune-interception of cancer and the battle of two adaptive systems -when is the time right? AB - A growing body of evidence points to a coevolutionary model of cancer, wherein the cross-talk between tumor cells (or their subclones) and the host determine the malignant potential of individual tumors. Most of this natural history is clinically invisible and includes preneoplastic states. The capacity of the immune system to recognize these incipient lesions provides the basis for targeting them immunologically to arrest the development of preneoplasia toward clinical cancer. Kimura and colleagues provide evidence of immunogenicity of a potential cancer vaccine in patients with a history of advanced colon adenomas. These studies provide proof-of-principle or feasibility of such an approach in the clinic. Here, we discuss emerging opportunities and challenges in harnessing the immune system to "intercept" the precursor or preneoplastic lesions. Both cancer cells as well as the immune system represent independent and complex systems with plasticity and adaptive potential. It is therefore likely that specific aspects of the cross-talk between tumor cells and host may differ between individual tumors and determine the evolution of both tumors and the host response. We try to make the case to consider individualized approaches based on the genetic make-up of tumor cells and properties of the host response. Such strategies may be needed to optimally position the immune system to prevent cancers. PMID- 23341572 TI - Gene expression changes in adipose tissue with diet- and/or exercise-induced weight loss. AB - Adipose tissue plays a role in obesity-related cancers via increased production of inflammatory factors, steroid hormones, and altered adipokines. The impact of weight loss on adipose tissue gene expression may provide insights into pathways linking obesity with cancer risk. We conducted an ancillary study within a randomized trial of diet, exercise, or combined diet + exercise versus control among overweight/obese postmenopausal women. In 45 women, subcutaneous adipose tissue biopsies were conducted at baseline and after 6 months, and changes in adipose tissue gene expression were determined by microarray with an emphasis on prespecified candidate pathways as well as by unsupervised clustering of more than 37,000 transcripts (Illumina). Analyses were conducted first by randomization group and then by degree of weight change at 6-months in all women combined. At 6 months, diet, exercise, and diet + exercise participants lost a mean of 8.8, 2.5, and 7.9 kg (all P < 0.05 vs. no change in controls). There was no significant change in candidate gene expression by intervention group. In analysis by weight change category, greater weight loss was associated a decrease in 17beta-hydroxysteroid dehydrogenase-1 (HSD17B1, Ptrend < 0.01) and leptin (LEP, Ptrend < 0.01) expression, and marginally significant increased expression of estrogen receptor-1 (ESR1, Ptrend = 0.08) and insulin-like growth factor binding protein-3 (IGFBP3, Ptrend = 0.08). Unsupervised clustering revealed 83 transcripts with statistically significant changes. Multiple gene expression changes correlated with changes in associated serum biomarkers. Weight loss was associated with changes in adipose tissue gene expression after 6 months, particularly in two pathways postulated to link obesity and cancer, that is, steroid hormone metabolism and IGF signaling. Cancer Prev Res; 6(3); 217-31. (c)2013 AACR. PMID- 23341573 TI - Cooperative activation of tissue-specific genes by pRB and E2F1. AB - The retinoblastoma tumor suppressor protein pRB is conventionally regarded as an inhibitor of the E2F family of transcription factors. Conversely, pRB is also recognized as an activator of tissue-specific gene expression along various lineages including osteoblastogenesis. During osteoblast differentiation, pRB directly targets Alpl and Bglap, which encode the major markers of osteogenesis alkaline phosphatase and osteocalcin. Surprisingly, p130 and repressor E2Fs were recently found to cooccupy and repress Alpl and Bglap in proliferating osteoblast precursors before differentiation. This raises the further question of whether these genes convert to E2F activation targets when differentiation begins, which would constitute a remarkable situation wherein pRB and E2F would be cotargeting genes for activation. Chromatin immunoprecipitation analysis in an osteoblast differentiation model shows that Alpl and Bglap are indeed targeted by an activator E2F, i.e., is E2F1. Promoter occupation of Alpl and Bglap by E2F1 occurs specifically during activation, and depletion of E2F1 severely impairs their induction. Mechanistically, promoter occupation by E2F1 and pRB is mutually dependent, and without this cooperative effect, activation steps previously shown to be dependent on pRB, including recruitment of RNA polymerase II, are impaired. Myocyte- and adipocyte-specific genes are also cotargeted by E2F1 and pRB during differentiation along their respective lineages. The finding that pRB and E2F1 cooperate to activate expression of tissue-specific genes is a paradigm distinct from the classical concept of pRB as an inhibitor of E2F1, but is consistent with the observed roles of these proteins in physiological models. PMID- 23341574 TI - Suicidal erythrocyte death, eryptosis, as a novel mechanism in heart failure associated anaemia. AB - AIMS: Suicidal death of erythrocytes (eryptosis) is characterized by cell shrinkage and exposure of phosphatidylserine (PS) residues at the cell surface. Excessive eryptosis may lead to anaemia. We aimed to study the role of eryptosis in heart failure (HF)-associated anaemia. METHODS AND RESULTS: We measured eryptosis in rodent models of HF. Typical measures of eryptosis including PS exposure, increased intracellular Ca(2+) levels, and decreased cell volume were determined by flow cytometry. Transgenic REN2 rats displayed mild anaemia which was associated with a two-fold increase in erythrocyte PS-exposure when compared with Sprague Dawley (SD) control rats (P < 0.01). Upon stimulation with eryptotic triggers such as oxidative stress, hyperosmotic shock and energy depletion, eryptosis was more prominent in REN2 as shown by increased PS-exposure, cytosolic Ca(2+) influx, and cell shrinkage (P < 0.05 vs. SD). Increasing cytosolic Ca(2+) levels resulted in a stronger increase in PS-exposure in REN2 erythrocytes (P < 0.01 vs. SD). Accordingly, inhibition of Ca(2+) entry blunted the increased PS exposure upon oxidative stress. The REN2 rats had significantly higher reticulocytes (REN2: 10.6 +/- 2.3%; SD: 5.4 +/- 0.1%; P < 0.05) and erythrocyte turnover was increased, indicated by increased clearance of eryptotic erythrocytes. Eryptosis was also increased in a rat model of hypertensive cardiac remodelling (uninephrectomized rats implanted with deoxycorticosterone acetate pellets), in mice after transverse aortic constriction, as well as in a small proof-of-concept study in human HF patients. CONCLUSION: Eryptosis is increased during HF development and could contribute to HF-associated anaemia. Eryptosis may therefore become a novel target for therapy in HF-associated anaemia. PMID- 23341575 TI - FGF-2 protects cardiomyocytes from doxorubicin damage via protein kinase C dependent effects on efflux transporters. AB - AIMS: The anti-cancer anthracycline doxorubicin (DOX) increases the risk of cardiac damage, indicating a need to protect the heart and still allow the benefits of drug treatment. Fibroblast growth factor-2 (FGF-2) is cardioprotective against ischaemia-reperfusion injury. Our aim is to investigate: (i) the ability of FGF-2 to protect against DOX-induced cardiomyocyte damage and (ii) the contribution of efflux drug transport to any increase in injury resistance. METHODS AND RESULTS: Neonatal rat cardiomyocyte damage was assessed by measuring cell death markers and lactate dehydrogenase (LDH) activity in the culture medium. LDH activity was increased significantly after incubation with 0.5 MUM DOX for 24 h in the absence but not presence of 10 nM FGF-2; this beneficial effect of FGF-2 was blocked by tyrosine kinase (FGF) receptor inhibition. An increase in efflux drug transporter RNA levels was also detected after FGF-2 treatment in the presence of DOX. The beneficial effect of FGF-2 against cell damage and increased transporter RNA levels were blunted with protein kinase C (PKC) inhibition. Finally, FGF-2 stimulated efflux transport of calcein and DOX, and treatment with efflux transporter inhibitors significantly attenuated the protective effect of FGF-2 from DOX-induced injury. CONCLUSION: Administered FGF-2 increases resistance to DOX-induced cardiomyocyte damage, by a mechanism dependent on PKC as well as regulation of efflux transporter production and/or function. PMID- 23341576 TI - The new antiarrhythmic drug vernakalant: ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation. AB - AIMS: Vernakalant is a newly developed antiarrhythmic drug against atrial fibrillation (AF). However, its electrophysiological actions on human myocardium are unknown. METHODS AND RESULTS: Action potentials (APs) and ion currents were recorded in right atrial trabeculae and cardiomyocytes from patients in sinus rhythm (SR) and chronic AF. Vernakalant prolonged early repolarization in SR and AF, but late only in AF. AP amplitude (APA) and dV/dtmax were reduced in a concentration- and frequency-dependent manner with IC50 < 10 uM at >3 Hz. Effective refractory period was increased more than action potential duration (APD) in SR and AF. INa was blocked with IC50s of 95 and 84 uM for SR and AF, respectively (0.5 Hz). Vernakalant did not reduce outward potassium currents compared with time-matched controls. However, area under the current-time curve was reduced due to acceleration of current decline with IC50s of 19 and 12 uM for SR and AF, respectively. Vernakalant had less effect on APD than the IKr blocker E-4031, blocked IK,ACh, and had a small inhibitory effect on IK1 at 30 uM. L-Type Ca(2+) currents (SR) were reduced with IC50 of 84 uM. CONCLUSION: Rate-dependent block of Na(+) channels represents the main antiarrhythmic mechanism of vernakalant in the fibrillating atrium. Open channel block of early transient outward currents and IK,ACh could also contribute. PMID- 23341577 TI - Atrial selectivity in Na+channel blockade by acute amiodarone. AB - AIMS: Na(+) channel blockers are often used to treat atrial fibrillation (AF), but may sometimes cause ventricular contractile dysfunction. However, amiodarone, a multi-channel blocker with Na(+) channel block, causes less contractile dysfunction. In this study, we tested the hypothesis that Na(+) channel block by amiodarone is selective in atrial myocytes (AM) compared with ventricular myocytes (VM). METHODS AND RESULTS: Na(+) currents (INa) were measured using whole-cell patch-clamp technique in isolated rabbit AM and VM. Amiodarone inhibited INa in AM (IC50: 1.8 +/- 1.1 MUM; n = 8) much more than in VM (40.4 +/- 11.9 MUM; n = 7, P < 0.01). Amiodarone at 10 MUM shifted the steady-state inactivation relationship in AM (-16.2 +/- 1.7 mV shift, n = 12) compared with VM (-5.9 +/- 0.7 mV shift; n = 13; P < 0.01). For mexiletine, the inhibition of INa and inactivation curve shifts were comparable for AM and VM. The effects of amiodarone and mexiletine on conduction velocity (CV) in Langendorff-perfused rabbit hearts were evaluated using an optical mapping system. The decrease of CV by 3 MUM amiodarone was significantly larger in the atrium (-18.9 +/- 3.8% change; n = 5) compared with the ventricle (-3.7 +/- 3.7%; n = 5; P < 0.01). In contrast, mexiletine reduced CV equally in the atrium and the ventricle. CONCLUSION: Amiodarone preferentially inhibits INa of AM compared with VM. Atrial selective Na(+) channel block by amiodarone may contribute to treating AF with less effect on ventricular contractility than other Na(+) channel blockers. PMID- 23341578 TI - Redox-dependent increases in glutathione reductase and exercise preconditioning: role of NADPH oxidase and mitochondria. AB - AIMS: We have previously shown that exercise leads to sustainable cardioprotection through a mechanism involving improved glutathione replenishment. This study was conducted to determine if redox-dependent modifications in glutathione reductase (GR) were involved in exercise cardioprotection. Furthermore, we sought to determine if reactive oxygen species generated by NADPH oxidase and/or mitochondria during exercise were triggering events for GR modulations. METHODS AND RESULTS: Rats were exercised for 10 consecutive days, after which isolated hearts were exposed to ischaemia/reperfusion (25 min/120 min). Exercise protected against infarction and arrhythmia, and preserved coronary flow. The GR inhibitor BCNU abolished the beneficial effects. GR activity was increased following exercise in a redox dependent manner, with no change in GR protein levels. Because fluorescent labelling of GR protein thiols showed lower amounts of reduced thiols after exercise, we sought to determine the source of intracellular reactive oxygen species that may be activating GR. Subsets of animals were exercised immediately after treatment with either NADPH-oxidase inhibitors apocynin or Vas2870, or with mitoTEMPO or Bendavia, which reduce mitochondrial reactive oxygen species levels. The cardioprotective effects of exercise were abolished if animals exercised in the presence of NADPH oxidase inhibitors, in clear contrast to the mitochondrial reagents. These changes correlated with thiol-dependent modifications of GR. CONCLUSION: Adaptive cardioprotective signalling is triggered by reactive oxygen species from NADPH oxidase, and leads to improved glutathione replenishment through redox-dependent modifications in GR. PMID- 23341579 TI - The absence of macrophage Nrf2 promotes early atherogenesis. AB - AIMS: The loss of nuclear factor E2-related factor 2 (Nrf2) has been shown to protect against atherogenesis in apoE-deficient mice. The mechanism by which Nrf2 deficiency affords atheroprotection in this model is currently unknown, but combined systemic and local vascular effects on lesion macrophages have been proposed. We investigated the effect of bone marrow-specific loss of Nrf2 on early atherogenesis in low-density lipoprotein (LDL) receptor-deficient (LDLR(-/ )) mice, and assessed the effect of Nrf2 on cellular accumulation of modified LDLs and the expression of inflammatory markers in macrophages. METHODS AND RESULTS: The effect of bone marrow-specific loss of Nrf2 on atherogenesis was studied using bone marrow transplantation of wild-type (WT) or Nrf2(-/-) bone marrow to LDLR(-/-) mice. Mice transplanted with Nrf2(-/-) bone marrow and fed a high-fat diet for 6 weeks exhibited significantly larger atherosclerotic lesions than WT bone marrow transplanted mice. Moreover, in thioglycollate-elicited Nrf2( /-) macrophages, the uptake of acetylated and malondialdehyde-modified LDLs was increased in comparison with WT controls, with the concomitant increase in the expression of scavenger receptor A and toll-like receptor 4. In addition, the expression of pro-inflammatory monocyte chemoattractant protein-1 and interleukin 6 were increased in Nrf2(-/-) vs. WT macrophages. CONCLUSION: Nrf2 deficiency specific to bone marrow-derived cells aggravates atherosclerosis in LDLR(-/-) mice. Furthermore, the loss of Nrf2 in macrophages enhances foam cell formation and promotes the pro-inflammatory phenotype. PMID- 23341580 TI - High glucose condition increases NADPH oxidase activity in endothelial microparticles that promote vascular inflammation. AB - AIMS: Diabetes is a major risk factor for cardiovascular diseases. Circulating endothelial microparticles (EMP) are increased in diabetic patients, but their potential contribution in atherogenesis is unclear. We sought to determine the role of EMP derived under high glucose conditions in the development of atherosclerosis. METHODS AND RESULTS: EMP were generated from human coronary endothelial cells (HCAEC) exposed to high glucose concentrations in order to mimic diabetic conditions. These EMP were defined as 'injured' EMP (iEMP) and their effects were compared with EMP generated from 'healthy' untreated HCAEC. iEMP injection significantly impaired endothelial function in ApoE(-/-) mice compared with EMP and vehicle treatment. Immunofluorescent experiments showed increased macrophage infiltration and adhesion protein expression in atherosclerotic lesions of iEMP-treated ApoE(-/-) mice compared with controls. To further investigate the underlying mechanism of iEMP-induced vascular inflammation, additional in vitro experiments were performed. iEMP, but not EMP, induced activation of HCAEC in a time- and dose-dependent manner and increased monocyte adhesion. Further experiments demonstrated that iEMP induced activation of HCAEC by phosphorylation of p38 into its biologically active form phospho-p38. Inhibition of p38 activation abrogated iEMP-dependent induction of adhesion proteins and monocyte adhesion on HCAEC. Moreover, we could demonstrate that iEMP show increased NADPH oxidase activity and contain significantly higher level of reactive oxygen species (ROS) than EMP. iEMP triggered ROS production in HCAEC and thereby activate p38 in an ROS-dependent manner. CONCLUSION: High glucose condition increases NADPH oxidase activity in endothelial microparticles that amplify endothelial inflammation and impair endothelial function by promoting activation of the endothelium. These findings provide new insights into the pathogenesis of diabetes-associated atherosclerosis. PMID- 23341581 TI - Acute inflammatory neuropathy with monoclonal anti-GM2 IgM antibodies, IgM-kappa paraprotein and additional autoimmune processes in association with a diffuse large B-cell non-Hodgkin's lymphoma. AB - Lymphoproliferative disorders are often associated with autoimmune processes preceding or following the occurrence of a lymphoma. Here, we describe a patient with a history of recurrent diffuse large B-cell non-Hodgkin's lymphoma who suffered from an acute inflammatory neuropathy with specific monoclonal anti-GM2 IgM antibodies and associated IgM-kappa paraprotein. It was possible in this case to prove that both, anti-GM2 IgM antibodies and IgM-kappa paraprotein, share the same binding characteristic. In addition, the patient possibly suffered from an immune thrombocytopenia and an early-stage bullous pemphigoid with anti-BP-230 IgG antibodies. Intravenous immunoglobulin and plasmapheresis alleviated the acute neuropathy and thrombocytopenia, while the bullous pemphigoid has been aggravated. In summary, the simultaneous occurrence of multiple autoimmune processes was a sign of a dysfunctional immune system preceding the relapse of a B-cell non-Hodgkin's lymphoma. PMID- 23341582 TI - Rituximab seems to be a safer alternative in patients with active rheumatoid arthritis with tuberculosis. AB - Demonstrating the efficiency and safety of rituximab (Rtx) in the treatment of active rheumatoid arthritis (RA) and tuberculosis (TB). Two cases of RA with active TB were followed up to 3 years following the initiation of Rtx. The former case presented with a history of concomitant diagnosis of both RA and TB and the latest one, also diagnosed with RA and reactivation of TB developed during the anti-tumour necrosis factor treatment. After a sufficient time of follow-up, we have observed that Rtx seems to be safer and efficient in the treatment of active RA and TB. PMID- 23341583 TI - Multiple pulmonary artery aneurysms in tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is a rare genetic disorder characterised by multiple hamartomas, caused by inactivating mutations of the TSC1/TSC2 tumour suppressor genes. Classical pulmonary involvement in tuberous sclerosis complex (TSC) consists of lymphangioleiomyomatosis and/or multiple micronodular pneumocyte hyperplasia (MMPH). Association of TSC with pulmonary artery aneurysm (PAA) has been only exceptionally described. We report here the first case of TSC with multiple PAA in combination with MMPH, cardiac rhabdomyomas and bone, skin and brain involvement. PMID- 23341584 TI - Confusion and altered behaviour? Cause. AB - We describe the case of a 65-year-old man who presented with confusion and change in behaviour, and describe the investigative steps that were taken before a diagnosis was made. This patient was eventually diagnosed with leptomeningeal carcinomatosis secondary to a previously undiagnosed oesophageal carcinoma. PMID- 23341585 TI - Intra-abdominal haematoma. PMID- 23341586 TI - UFO in the heart: revealed during balloon mitral valvuloplasty for severe mitral stenosis. PMID- 23341587 TI - Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1. AB - Circadian rhythms govern a wide variety of physiological and metabolic functions in many organisms, from prokaryotes to humans. We previously reported that silent information regulator 1 (SIRT1), a NAD(+)-dependent deacetylase, contributes to circadian control. In addition, SIRT1 activity is regulated in a cyclic manner in virtue of the circadian oscillation of the coenzyme NAD(+). Here we used specific SIRT1 activator compounds both in vitro and in vivo. We tested a variety of compounds to show that the activation of SIRT1 alters CLOCK:BMAL1-driven transcription in different systems. Activation of SIRT1 induces repression of circadian gene expression and decreases H3 K9/K14 acetylation at corresponding promoters in a time-specific manner. Specific activation of SIRT1 was demonstrated in vivo using liver-specific SIRT1-deficient mice, where the effect of SIRT1 activator compounds was shown to be dependent on SIRT1. Our findings demonstrate that SIRT1 can fine-tune circadian rhythm and pave the way to the development of pharmacological strategies to address a broad range of therapeutic indications. PMID- 23341588 TI - Experiments and simulations show how long-range contacts can form in expanded unfolded proteins with negligible secondary structure. AB - The sizes of unfolded proteins under highly denaturing conditions scale as N(0.59) with chain length. This suggests that denaturing conditions mimic good solvents, whereby the preference for favorable chain-solvent interactions causes intrachain interactions to be repulsive, on average. Beyond this generic inference, the broader implications of N(0.59) scaling for quantitative descriptions of denatured state ensembles (DSEs) remain unresolved. Of particular interest is the degree to which N(0.59) scaling can simultaneously accommodate intrachain attractions and detectable long-range contacts. Here we present data showing that the DSE of the N-terminal domain of the L9 (NTL9) ribosomal protein in 8.3 M urea lacks detectable secondary structure and forms expanded conformations in accord with the expected N(0.59) scaling behavior. Paramagnetic relaxation enhancements, however, indicate the presence of detectable long-range contacts in the denatured-state ensemble of NTL9. To explain these observations we used atomistic thermal unfolding simulations to identify ensembles whose properties are consistent with all of the experimental observations, thus serving as useful proxies for the DSE of NTL9 in 8.3 M urea. Analysis of these ensembles shows that residual attractions are present under mimics of good solvent conditions, and for NTL9 they result from low-likelihood, medium/long-range contacts between hydrophobic residues. Our analysis provides a quantitative framework for the simultaneous observation of N(0.59) scaling and low-likelihood long-range contacts for the DSE of NTL9. We propose that such low-likelihood intramolecular hydrophobic clusters might be a generic feature of DSEs that play a gatekeeping role to protect against aggregation during protein folding. PMID- 23341589 TI - RNA editing of hepatitis B virus transcripts by activation-induced cytidine deaminase. AB - Activation-induced cytidine deaminase (AID) is essential for the somatic hypermutation (SHM) and class-switch recombination (CSR) of Ig genes. The mechanism by which AID triggers SHM and CSR has been explained by two distinct models. In the DNA deamination model, AID converts cytidine bases in DNA into uridine. The uridine is recognized by the DNA repair system, which produces DNA strand breakages and point mutations. In the alternative model, RNA edited by AID is responsible for triggering CSR and SHM. However, RNA deamination by AID has not been demonstrated. Here we found that C-to-T and G-to-A mutations accumulated in hepatitis B virus (HBV) nucleocapsid DNA when AID was expressed in HBV replicating hepatic cell lines. AID expression caused C-to-T mutations in the nucleocapsid DNA of RNase H-defective HBV, which does not produce plus-strand viral DNA. Furthermore, the RT-PCR products of nucleocapsid viral RNA from AID expressing cells exhibited significant C-to-T mutations, whereas viral RNAs outside the nucleocapsid did not accumulate C-to-U mutations. Moreover, AID was packaged within the nucleocapsid by forming a ribonucleoprotein complex with HBV RNA and the HBV polymerase protein. The encapsidation of the AID protein with viral RNA and DNA provides an efficient environment for evaluating AID's RNA and DNA deamination activities. A bona fide RNA-editing enzyme, apolipoprotein B mRNA editing catalytic polypeptide 1, induced a similar level of C-to-U mutations in nucleocapsid RNA as AID. Taken together, the results indicate that AID can deaminate the nucleocapsid RNA of HBV. PMID- 23341590 TI - Lessons learned and concepts formed from study of the pathogenesis of the two negative-strand viruses lymphocytic choriomeningitis and influenza. AB - Viruses have unique lifestyles. To describe the pathogenesis and significance of viral infection in terms of host responses, resultant injury, and therapy, we focused on two RNA viruses: lymphocytic choriomeningitis (LCMV) and influenza (Flu). Many of the currently established concepts and consequences about viruses and immunologic tolerance, virus-induced immunosuppression, virus-induced autoimmunity, immune complex disease, and virus-lymphocyte and virus-dendritic cell interactions evolved through studies of LCMV in its natural murine host. Similarly, the mechanisms, aftermath, and treatment of persistent RNA viruses emerged, in large part, from research on LCMV. Analysis of acute influenza virus infections uncovered the prominent direct role that cytokine storm plays in the pathogenesis, morbidity, and mortality from this disease. Cytokine storm of influenza virus infection is initiated via a pulmonary endothelial cell amplification loop involving IFN-producing cells and virus-infected pulmonary epithelial cells. Importantly, the cytokine storm is chemically treatable with specific agonist therapy directed to the sphingosphine 1 phosphate receptor 1, which is located on pulmonary endothelial cells, pointing to the endothelial cells as the gatekeepers of this hyperaggressive host immune response. PMID- 23341591 TI - Endoplasmic reticulum-associated mitochondria-cortex tether functions in the distribution and inheritance of mitochondria. AB - To elucidate the functional roles of mitochondrial dynamics in vivo, we identified genes that become essential in cells lacking the dynamin-related proteins Fzo1 and Dnm1, which are required for mitochondrial fusion and division, respectively. The screen identified Num1, a cortical protein implicated in mitochondrial division and distribution that also functions in nuclear migration. Our data indicate that Num1, together with Mdm36, forms a physical tether that robustly anchors mitochondria to the cell cortex but plays no direct role in mitochondrial division. Our analysis indicates that Num1-dependent anchoring is essential for distribution of the static mitochondrial network in fzo1 dnm1 cells. Consistently, expression of a synthetic mitochondria-cortex tether rescues the viability of fzo1 dnm1 num1 cells. We find that the cortical endoplasmic reticulum (ER) also is a constituent of the Num1 mitochondria-cortex tether, suggesting an active role for the ER in mitochondrial positioning in cells. Thus, taken together, our findings identify Num1 as a key component of a mitochondria ER-cortex anchor, which we termed "MECA," that functions in parallel with mitochondrial dynamics to distribute and position the essential mitochondrial network. PMID- 23341592 TI - Bile salt-induced intermolecular disulfide bond formation activates Vibrio cholerae virulence. AB - To be successful pathogens, bacteria must often restrict the expression of virulence genes to host environments. This requires a physical or chemical marker of the host environment as well as a cognate bacterial system for sensing the presence of a host to appropriately time the activation of virulence. However, there have been remarkably few such signal-sensor pairs identified, and the molecular mechanisms for host-sensing are virtually unknown. By directly applying a reporter strain of Vibrio cholerae, the causative agent of cholera, to a thin layer chromatography (TLC) plate containing mouse intestinal extracts, we found two host signals that activate virulence gene transcription. One of these was revealed to be the bile salt taurocholate. We then show that a set of bile salts cause dimerization of the transmembrane transcription factor TcpP by inducing intermolecular disulfide bonds between cysteine (C)-207 residues in its periplasmic domain. Various genetic and biochemical analyses led us to propose a model in which the other cysteine in the periplasmic domain, C218, forms an inhibitory intramolecular disulfide bond with C207 that must be isomerized to form the active C207-C207 intermolecular bond. We then found bile salt-dependent effects of these cysteine mutations on survival in vivo, correlating to our in vitro model. Our results are a demonstration of a mechanism for direct activation of the V. cholerae virulence cascade by a host signal molecule. They further provide a paradigm for recognition of the host environment in pathogenic bacteria through periplasmic cysteine oxidation. PMID- 23341593 TI - Evolution of fairness in the one-shot anonymous Ultimatum Game. AB - Classical economic models assume that people are fully rational and selfish, while experiments often point to different conclusions. A canonical example is the Ultimatum Game: one player proposes a division of a sum of money between herself and a second player, who either accepts or rejects. Based on rational self-interest, responders should accept any nonzero offer and proposers should offer the smallest possible amount. Traditional, deterministic models of evolutionary game theory agree: in the one-shot anonymous Ultimatum Game, natural selection favors low offers and demands. Experiments instead show a preference for fairness: often responders reject low offers and proposers make higher offers than needed to avoid rejection. Here we show that using stochastic evolutionary game theory, where agents make mistakes when judging the payoffs and strategies of others, natural selection favors fairness. Across a range of parameters, the average strategy matches the observed behavior: proposers offer between 30% and 50%, and responders demand between 25% and 40%. Rejecting low offers increases relative payoff in pairwise competition between two strategies and is favored when selection is sufficiently weak. Offering more than you demand increases payoff when many strategies are present simultaneously and is favored when mutation is sufficiently high. We also perform a behavioral experiment and find empirical support for these theoretical findings: uncertainty about the success of others is associated with higher demands and offers; and inconsistency in the behavior of others is associated with higher offers but not predictive of demands. In an uncertain world, fairness finishes first. PMID- 23341595 TI - Trifoliate encodes an MYB transcription factor that modulates leaf and shoot architecture in tomato. AB - Leaf morphology and the pattern of shoot branching determine to a large extent the growth habit of seed plants. Until recently, the developmental processes that led to the establishment of these morphological structures seemed unrelated. Here, we show that the tomato Trifoliate (Tf) gene plays a crucial role in both processes, affecting the formation of leaflets in the compound tomato leaf and the initiation of axillary meristems in the leaf axil. Tf encodes a myeloblastosis oncoprotein (MYB)-like transcription factor related to the Arabidopsis thaliana LATERAL ORGAN FUSION1 (LOF1) and LOF2 proteins. Tf is expressed in the leaf margin, where leaflets are formed, and in the leaf axil, where axillary meristems initiate. During tomato ontogeny, expression of Tf in young leaf primordia increases, correlating with a rise in leaf dissection (heteroblasty). Formation of leaflets and initiation of axillary meristems can be traced back to groups of pluripotent cells. Tf function is required to inhibit differentiation of these cells and thereby to maintain their morphogenetic competence, a fundamental process in plant development. KNOTTED1-LIKE proteins, which are known regulators in tomato leaf dissection, require Tf activity to exert their function in the basal part of the leaf. Similarly, the plant hormone auxin needs Tf activity to initiate the formation of lateral leaflets. Thus, leaf dissection and shoot branching rely on a conserved mechanism that regulates the morphogenetic competence of cells at the leaf margin and in the leaf axil. PMID- 23341596 TI - Linking animal-borne video to accelerometers reveals prey capture variability. AB - Understanding foraging is important in ecology, as it determines the energy gains and, ultimately, the fitness of animals. However, monitoring prey captures of individual animals is difficult. Direct observations using animal-borne videos have short recording periods, and indirect signals (e.g., stomach temperature) are never validated in the field. We took an integrated approach to monitor prey captures by a predator by deploying a video camera (lasting for 85 min) and two accelerometers (on the head and back, lasting for 50 h) on free-swimming Adelie penguins. The movies showed that penguins moved the heads rapidly to capture krill in midwater and fish (Pagothenia borchgrevinki) underneath the sea ice. Captures were remarkably fast (two krill per second in swarms) and efficient (244 krill or 33 P. borchgrevinki in 78-89 min). Prey captures were detected by the signal of head acceleration relative to body acceleration with high sensitivity and specificity (0.83-0.90), as shown by receiver-operating characteristic analysis. Extension of signal analysis to the entire behavioral records showed that krill captures were spatially and temporally more variable than P. borchgrevinki captures. Notably, the frequency distribution of krill capture rate closely followed a power-law model, indicating that the foraging success of penguins depends on a small number of very successful dives. The three steps illustrated here (i.e., video observations, linking video to behavioral signals, and extension of signal analysis) are unique approaches to understanding the spatial and temporal variability of ecologically important events such as foraging. PMID- 23341594 TI - Distinct features of neurotransmitter systems in the human brain with focus on the galanin system in locus coeruleus and dorsal raphe. AB - Using riboprobe in situ hybridization, we studied the localization of the transcripts for the neuropeptide galanin and its receptors (GalR1-R3), tryptophan hydroxylase 2, tyrosine hydroxylase, and nitric oxide synthase as well as the three vesicular glutamate transporters (VGLUT 1-3) in the locus coeruleus (LC) and the dorsal raphe nucleus (DRN) regions of postmortem human brains. Quantitative real-time PCR (qPCR) was used also. Galanin and GalR3 mRNA were found in many noradrenergic LC neurons, and GalR3 overlapped with serotonin neurons in the DRN. The qPCR analysis at the LC level ranked the transcripts in the following order in the LC: galanin >> GalR3 >> GalR1 > GalR2; in the DRN the ranking was galanin >> GalR3 >> GalR1 = GalR2. In forebrain regions the ranking was GalR1 > galanin > GalR2. VGLUT1 and -2 were strongly expressed in the pontine nuclei but could not be detected in LC or serotonin neurons. VGLUT2 transcripts were found in very small, nonpigmented cells in the LC and in the lateral and dorsal aspects of the periaqueductal central gray. Nitric oxide synthase was not detected in serotonin neurons. These findings show distinct differences between the human brain and rodents, especially rat, in the distribution of the galanin system and some other transmitter systems. For example, GalR3 seems to be the important galanin receptor in both the human LC and DRN versus GalR1 and -2 in the rodent brain. Such knowledge may be important when considering therapeutic principles and drug development. PMID- 23341597 TI - Spatial mismatch between the Na+ flux and spike initiation in axon initial segment. AB - It is widely believed that, in cortical pyramidal cells, action potentials (APs) initiate in the distal portion of axon initial segment (AIS) because that is where Na(+) channel density is highest. To investigate the relationship between the density of Na(+) channels and the spatiotemporal pattern of AP initiation, we simultaneously recorded Na(+) flux and action currents along the proximal axonal length. We found that functional Na(+) channel density is approximately four times lower in the AP trigger zone than in the middle of the AIS, where it is highest. Computational analysis of AP initiation revealed a paradoxical mismatch between the AP threshold and Na(+) channel density, which could be explained by the lopsided capacitive load imposed on the proximal end of the AIS by the somatodendritic compartment. Favorable conditions for AP initiation are therefore achieved in the distal AIS portion, close to the edge of myelin, where the current source-load ratio is highest. Our findings suggest that cable properties play a central role in determining where the AP starts, such that small plastic changes in the local AIS Na(+) channel density could have a large influence on neuronal excitability as a whole. PMID- 23341598 TI - Neurocomputational account of how the human brain decides when to have a break. AB - No pain, no gain: cost-benefit trade-off has been formalized in classical decision theory to account for how we choose whether to engage effort. However, how the brain decides when to have breaks in the course of effort production remains poorly understood. We propose that decisions to cease and resume work are triggered by a cost evidence accumulation signal reaching upper and lower bounds, respectively. We developed a task in which participants are free to exert a physical effort knowing that their payoff would be proportional to their effort duration. Functional MRI and magnetoencephalography recordings conjointly revealed that the theoretical cost evidence accumulation signal was expressed in proprioceptive regions (bilateral posterior insula). Furthermore, the slopes and bounds of the accumulation process were adapted to the difficulty of the task and the money at stake. Cost evidence accumulation might therefore provide a dynamical mechanistic account of how the human brain maximizes benefits while preventing exhaustion. PMID- 23341599 TI - Circadian acetylome reveals regulation of mitochondrial metabolic pathways. AB - The circadian clock is constituted by a complex molecular network that integrates a number of regulatory cues needed to maintain organismal homeostasis. To this effect, posttranslational modifications of clock proteins modulate circadian rhythms and are thought to convert physiological signals into changes in protein regulatory function. To explore reversible lysine acetylation that is dependent on the clock, we have characterized the circadian acetylome in WT and Clock deficient (Clock(-/-)) mouse liver by quantitative mass spectrometry. Our analysis revealed that a number of mitochondrial proteins involved in metabolic pathways are heavily influenced by clock-driven acetylation. Pathways such as glycolysis/gluconeogenesis, citric acid cycle, amino acid metabolism, and fatty acid metabolism were found to be highly enriched hits. The significant number of metabolic pathways whose protein acetylation profile is altered in Clock(-/-) mice prompted us to link the acetylome to the circadian metabolome previously characterized in our laboratory. Changes in enzyme acetylation over the circadian cycle and the link to metabolite levels are discussed, revealing biological implications connecting the circadian clock to cellular metabolic state. PMID- 23341600 TI - Variation and constraint in Hox gene evolution. AB - Despite enormous body plan variation, genes regulating embryonic development are highly conserved. Here, we probe the mechanisms that predispose ancient regulatory genes to reutilization and diversification rather than evolutionary loss. The Hox gene fushi tarazu (ftz) arose as a homeotic gene but functions as a pair-rule segmentation gene in Drosophila. ftz shows extensive variation in expression and protein coding regions but has managed to elude loss from arthropod genomes. We asked what properties prevent this loss by testing the importance of different protein motifs and partners in the developing CNS, where ftz expression is conserved. Drosophila Ftz proteins with mutated protein motifs were expressed under the control of a neurogenic-specific ftz cis-regulatory element (CRE) in a ftz mutant background rescued for segmentation defects. Ftz CNS function did not require the variable motifs that mediate differential cofactor interactions involved in homeosis or segmentation, which vary in arthropods. Rather, CNS function did require the shared DNA-binding homeodomain, which plays less of a role in Ftz segmentation activity. The Antennapedia homeodomain substituted for Ftz homeodomain function in the Drosophila CNS, but full-length Antennapedia did not rescue CNS defects. These results suggest that a core CNS function retains ftz in arthropod genomes. Acquisition of a neurogenic CRE led to ftz expression in unique CNS cells, differentiating its role from neighboring Hox genes, rendering it nonredundant. The inherent flexibility of modular CREs and protein domains allows for stepwise acquisition of new functions, explaining broad retention of regulatory genes during animal evolution. PMID- 23341601 TI - Antimicrobial drug resistance affects broad changes in metabolomic phenotype in addition to secondary metabolism. AB - Bacteria develop resistance to many classes of antibiotics vertically, by engendering mutations in genes encoding transcriptional and translational apparatus. These severe adaptations affect global transcription, translation, and the correspondingly affected metabolism. Here, we characterize metabolome scale changes in transcriptional and translational mutants in a genomically characterized Nocardiopsis, a soil-derived actinomycete, in stationary phase. Analysis of ultra-performance liquid chromatography-ion mobility-mass spectrometry metabolomic features from a cohort of streptomycin- and rifampicin resistant mutants grown in the absence of antibiotics exhibits clear metabolomic speciation, and loadings analysis catalogs a marked change in metabolic phenotype. Consistent with derepression, up to 311 features are observed in antibiotic-resistant mutants that are not detected in their progenitors. Mutants demonstrate changes in primary metabolism, such as modulation of fatty acid composition and the increased production of the osmoprotectant ectoine, in addition to the presence of abundant emergent potential secondary metabolites. Isolation of three of these metabolites followed by structure elucidation demonstrates them to be an unusual polyketide family with a previously uncharacterized xanthene framework resulting from sequential oxidative carbon skeletal rearrangements. Designated as "mutaxanthenes," this family can be correlated to a type II polyketide gene cluster in the producing organism. Taken together, these data suggest that biosynthetic pathway derepression is a general consequence of some antibiotic resistance mutations. PMID- 23341602 TI - Specular reflections and the estimation of shape from binocular disparity. AB - Binocular stereopsis is a powerful visual depth cue. To exploit it, the brain matches features from the two eyes' views and measures their interocular disparity. This works well for matte surfaces because disparities indicate true surface locations. However, specular (glossy) surfaces are problematic because highlights and reflections are displaced from the true surface in depth, leading to information that conflicts with other cues to 3D shape. Here, we address the question of how the visual system identifies the disparity information created by specular reflections. One possibility is that the brain uses monocular cues to identify that a surface is specular and modifies its interpretation of the disparities accordingly. However, by characterizing the behavior of specular disparities we show that the disparity signals themselves provide key information ("intrinsic markers") that enable potentially misleading disparities to be identified and rejected. We presented participants with binocular views of specular objects and asked them to report perceived depths by adjusting probe dots. For simple surfaces--which do not exhibit intrinsic indicators that the disparities are "wrong"--participants incorrectly treat disparities at face value, leading to erroneous judgments. When surfaces are more complex we find the visual system also errs where the signals are reliable, but rejects and interpolates across areas with large vertical disparities and horizontal disparity gradients. This suggests a general mechanism in which the visual system assesses the origin and utility of sensory signals based on intrinsic markers of their reliability. PMID- 23341603 TI - Historical collections reveal patterns of diffusion of sweet potato in Oceania obscured by modern plant movements and recombination. AB - The history of sweet potato in the Pacific has long been an enigma. Archaeological, linguistic, and ethnobotanical data suggest that prehistoric human-mediated dispersal events contributed to the distribution in Oceania of this American domesticate. According to the "tripartite hypothesis," sweet potato was introduced into Oceania from South America in pre-Columbian times and was then later newly introduced, and diffused widely across the Pacific, by Europeans via two historically documented routes from Mexico and the Caribbean. Although sweet potato is the most convincing example of putative pre-Columbian connections between human occupants of Polynesia and South America, the search for genetic evidence of pre-Columbian dispersal of sweet potato into Oceania has been inconclusive. Our study attempts to fill this gap. Using complementary sets of markers (chloroplast and nuclear microsatellites) and both modern and herbarium samples, we test the tripartite hypothesis. Our results provide strong support for prehistoric transfer(s) of sweet potato from South America (Peru-Ecuador region) into Polynesia. Our results also document a temporal shift in the pattern of distribution of genetic variation in sweet potato in Oceania. Later reintroductions, accompanied by recombination between distinct sweet potato gene pools, have reshuffled the crop's initial genetic base, obscuring primary patterns of diffusion and, at the same time, giving rise to an impressive number of local variants. Moreover, our study shows that phenotypes, names, and neutral genes do not necessarily share completely parallel evolutionary histories. Multidisciplinary approaches, thus, appear necessary for accurate reconstruction of the intertwined histories of plants and humans. PMID- 23341604 TI - Inward-facing conformation of the zinc transporter YiiP revealed by cryoelectron microscopy. AB - YiiP is a dimeric Zn(2+)/H(+) antiporter from Escherichia coli belonging to the cation diffusion facilitator family. We used cryoelectron microscopy to determine a 13-A resolution structure of a YiiP homolog from Shewanella oneidensis within a lipid bilayer in the absence of Zn(2+). Starting from the X-ray structure in the presence of Zn(2+), we used molecular dynamics flexible fitting to build a model consistent with our map. Comparison of the structures suggests a conformational change that involves pivoting of a transmembrane, four-helix bundle (M1, M2, M4, and M5) relative to the M3-M6 helix pair. Although accessibility of transport sites in the X-ray model indicates that it represents an outward-facing state, our model is consistent with an inward-facing state, suggesting that the conformational change is relevant to the alternating access mechanism for transport. Molecular dynamics simulation of YiiP in a lipid environment was used to address the feasibility of this conformational change. Association of the C terminal domains is the same in both states, and we speculate that this association is responsible for stabilizing the dimer that, in turn, may coordinate the rearrangement of the transmembrane helices. PMID- 23341605 TI - MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and IL-23 signaling. AB - Myeloid differentiation primary response protein 88 (MyD88) is classically known as an adaptor, linking TLR and IL-1R to downstream signaling pathways in the innate immune system. In addition to its role in innate immune cells, MyD88 has been shown to play an important role in T cells. How MyD88 regulates helper T cell differentiation remains largely unknown, however. Here we demonstrate that MyD88 is an important regulator of IL-17-producing CD4(+) T helper cells (Th17) cell proliferation. MyD88-deficient CD4(+) T cells showed a defect in Th17 cell differentiation, but not in Th1 cell or Th2 cell differentiation. The impaired IL 17 production from MyD88-deficient CD4(+) T cells is not a result of defective RAR-related orphan receptor gammat (RORgammat) expression. Instead, MyD88 is essential for sustaining the mammalian target of rapamycin (mTOR) activation necessary to promote Th17 cell proliferation by linking IL-1 and IL-23 signaling. MyD88-deficient CD4(+) T cells showed impaired mTOR activation and, consequently, reduced Th17 cell proliferation. Importantly, the absence of MyD88 in T cells ameliorated disease in the experimental autoimmune encephalomyelitis model. Taken together, our results demonstrate that MyD88 has a dual function in Th17 cells by delivering IL-1 signaling during the early differentiation stage and integrating IL-23 signaling to the mTOR complex to expand committed Th17 cells. PMID- 23341606 TI - JNK inhibition reduces apoptosis and neovascularization in a murine model of age related macular degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of registered blindness among the elderly and affects over 30 million people worldwide. It is well established that oxidative stress, inflammation, and apoptosis play critical roles in pathogenesis of AMD. In advanced wet AMD, although, most of the severe vision loss is due to bleeding and exudation of choroidal neovascularization (CNV), and it is well known that vascular endothelial growth factor (VEGF) plays a pivotal role in the growth of the abnormal blood vessels. VEGF suppression therapy improves visual acuity in AMD patients. However, there are unresolved issues, including safety and cost. Here we show that mice lacking c-Jun N terminal kinase 1 (JNK1) exhibit decreased inflammation, reduced CNV, lower levels of choroidal VEGF, and impaired choroidal macrophage recruitment in a murine model of wet AMD (laser-induced CNV). Interestingly, we also detected a substantial reduction in choroidal apoptosis of JNK1-deficient mice. Intravitreal injection of a pan-caspase inhibitor reduced neovascularization in the laser induced CNV model, suggesting that apoptosis plays a role in laser-induced pathological angiogenesis. Intravitreal injection of a specific JNK inhibitor decreased choroidal VEGF expression and reduced pathological CNV. These results suggest that JNK1 plays a key role in linking oxidative stress, inflammation, macrophage recruitment apoptosis, and VEGF production in wet AMD and pharmacological JNK inhibition offers a unique and alternative avenue for prevention and treatment of AMD. PMID- 23341607 TI - Oxygen tolerance of an in silico-designed bioinspired hydrogen-evolving catalyst in water. AB - Certain bacterial enzymes, the diiron hydrogenases, have turnover numbers for hydrogen production from water as large as 10(4)/s. Their much smaller common active site, composed of earth-abundant materials, has a structure that is an attractive starting point for the design of a practical catalyst for electrocatalytic or solar photocatalytic hydrogen production from water. In earlier work, our group has reported the computational design of [FeFe](P)/FeS(2), a hydrogenase-inspired catalyst/electrode complex, which is efficient and stable throughout the production cycle. However, the diiron hydrogenases are highly sensitive to ambient oxygen by a mechanism not yet understood in detail. An issue critical for practical use of [FeFe](P)/FeS(2) is whether this catalyst/electrode complex is tolerant to the ambient oxygen. We report demonstration by ab initio simulations that the complex is indeed tolerant to dissolved oxygen over timescales long enough for practical application, reducing it efficiently. This promising hydrogen-producing catalyst, composed of earth-abundant materials and with a diffusion-limited rate in acidified water, is efficient as well as oxygen tolerant. PMID- 23341608 TI - Simplified protein design biased for prebiotic amino acids yields a foldable, halophilic protein. AB - A compendium of different types of abiotic chemical syntheses identifies a consensus set of 10 "prebiotic" alpha-amino acids. Before the emergence of biosynthetic pathways, this set is the most plausible resource for protein formation (i.e., proteogenesis) within the overall process of abiogenesis. An essential unsolved question regarding this prebiotic set is whether it defines a "foldable set"--that is, does it contain sufficient chemical information to permit cooperatively folding polypeptides? If so, what (if any) characteristic properties might such polypeptides exhibit? To investigate these questions, two "primitive" versions of an extant protein fold (the beta-trefoil) were produced by top-down symmetric deconstruction, resulting in a reduced alphabet size of 12 or 13 amino acids and a percentage of prebiotic amino acids approaching 80%. These proteins show a substantial acidification of pI and require high salt concentrations for cooperative folding. The results suggest that the prebiotic amino acids do comprise a foldable set within the halophile environment. PMID- 23341609 TI - Structures of a Na+-coupled, substrate-bound MATE multidrug transporter. AB - Multidrug transporters belonging to the multidrug and toxic compound extrusion (MATE) family expel dissimilar lipophilic and cationic drugs across cell membranes by dissipating a preexisting Na(+) or H(+) gradient. Despite its clinical relevance, the transport mechanism of MATE proteins remains poorly understood, largely owing to a lack of structural information on the substrate bound transporter. Here we report crystal structures of a Na(+)-coupled MATE transporter NorM from Neisseria gonorrheae in complexes with three distinct translocation substrates (ethidium, rhodamine 6G, and tetraphenylphosphonium), as well as Cs(+) (a Na(+) congener), all captured in extracellular-facing and drug bound states. The structures revealed a multidrug-binding cavity festooned with four negatively charged amino acids and surprisingly limited hydrophobic moieties, in stark contrast to the general belief that aromatic amino acids play a prominent role in multidrug recognition. Furthermore, we discovered an uncommon cation-pi interaction in the Na(+)-binding site located outside the drug-binding cavity and validated the biological relevance of both the substrate- and cation binding sites by conducting drug resistance and transport assays. Additionally, we uncovered potential rearrangement of at least two transmembrane helices upon Na(+)-induced drug export. Based on our structural and functional analyses, we suggest that Na(+) triggers multidrug extrusion by inducing protein conformational changes rather than by directly competing for the substrate binding amino acids. This scenario is distinct from the canonical antiport mechanism, in which both substrate and counterion compete for a shared binding site in the transporter. Collectively, our findings provide an important step toward a detailed and mechanistic understanding of multidrug transport. PMID- 23341610 TI - Dependence receptor TrkC is a putative colon cancer tumor suppressor. AB - The TrkC neurotrophin receptor belongs to the functional dependence receptor family, members of which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer tumor-suppressor activity. Indeed, cells that express these receptors are thought to be dependent on ligand availability for their survival, a mechanism that inhibits uncontrolled tumor cell proliferation and migration. TrkC is a classic tyrosine kinase receptor and therefore generally considered to be a proto-oncogene. We show here that TrkC expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, we show that TrkC silencing by promoter methylation is a selective advantage for colorectal cell lines to limit tumor cell death. Furthermore, reestablished TrkC expression in colorectal cancer cell lines is associated with tumor cell death and inhibition of in vitro characteristics of cell transformation, as well as in vivo tumor growth. Finally, we provide evidence that a mutation of TrkC detected in a sporadic cancer is a loss-of-proapoptotic function mutation. Together, these data support the conclusion that TrkC is a colorectal cancer tumor suppressor. PMID- 23341611 TI - Antimony-resistant but not antimony-sensitive Leishmania donovani up-regulates host IL-10 to overexpress multidrug-resistant protein 1. AB - The molecular mechanism of antimony-resistant Leishmania donovani (Sb(R)LD) driven up-regulation of IL-10 and multidrug-resistant protein 1 (MDR1) in infected macrophages (Ms) has been investigated. This study showed that both promastigote and amastigote forms of Sb(R)LD, but not the antimony-sensitive form of LD, express a unique glycan with N-acetylgalactosamine as a terminal sugar. Removal of it either by enzyme treatment or by knocking down the relevant enzyme, galactosyltransferase in Sb(R)LD (KD Sb(R)LD), compromises the ability to induce the above effects. Infection of Ms with KD Sb(R)LD enhanced the sensitivity toward antimonials compared with infection with Sb(R)LD, and infection of BALB/c mice with KD Sb(R)LD caused significantly less organ parasite burden compared with infection induced by Sb(R)LD. The innate immune receptor, Toll-like receptor 2/6 heterodimer, is exploited by Sb(R)LD to activate ERK and nuclear translocation of NF-kappaB involving p50/c-Rel leading to IL-10 induction, whereas MDR1 up-regulation is mediated by PI3K/Akt and the JNK pathway. Interestingly both recombinant IL-10 and Sb(R)LD up-regulate MDR1 in M with different time kinetics, where phosphorylation of PI3K was noted at 12 h and 48 h, respectively, but Ms derived from IL-10(-/-) mice are unable to show MDR1 up regulation on infection with Sb(R)LD. Thus, it is very likely that an IL-10 surge is a prerequisite for MDR1 up-regulation. The transcription factor important for IL-10-driven MDR1 up-regulation is c-Fos/c-Jun and not NF-kappaB, as evident from studies with pharmacological inhibitors and promoter mapping with deletion constructs. PMID- 23341612 TI - Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons. AB - Developmental transcription factors important in early neuron specification and differentiation often remain expressed in the adult brain. However, how these transcription factors function to mantain appropriate neuronal identities in adult neurons and how transcription factor dysregulation may contribute to disease remain largely unknown. The transcription factor Nurr1 has been associated with Parkinson's disease and is essential for the development of ventral midbrain dopamine (DA) neurons. We used conditional Nurr1 gene-targeted mice in which Nurr1 is ablated selectively in mature DA neurons by treatment with tamoxifen. We show that Nurr1 ablation results in a progressive pathology associated with reduced striatal DA, impaired motor behaviors, and dystrophic axons and dendrites. We used laser-microdissected DA neurons for RNA extraction and next-generation mRNA sequencing to identify Nurr1-regulated genes. This analysis revealed that Nurr1 functions mainly in transcriptional activation to regulate a battery of genes expressed in DA neurons. Importantly, nuclear-encoded mitochondrial genes were identified as the major functional category of Nurr1 regulated target genes. These studies indicate that Nurr1 has a key function in sustaining high respiratory function in these cells, and that Nurr1 ablation in mice recapitulates early features of Parkinson's disease. PMID- 23341613 TI - Centennial-scale analysis of the creation and fate of reactive nitrogen in China (1910-2010). AB - Human mobilization and use of reactive nitrogen (Nr) has been one of the major aspects of global change over the past century. Nowhere has that change been more dramatic than in China, where annual net Nr creation increased from 9.2 to 56 Tg from 1910 to 2010. Since 1956, anthropogenic Nr creation exceeded natural Nr creation, contributing over 80% of total Nr until 2010. There is great interest and uncertainty in the fate and effects of this Nr in China. Here, a comprehensive inventory of Nr in China shows that Nr (including recycled Nr) has continuously and increasingly accumulated on land (from 17 to 45 Tg), accompanied by increasing transfers to the atmosphere (before deposition; from 7.6 to 20 Tg), inland waters (from 2.7 to 9.6 Tg), and coastal waters (from 4.5 to 7.7 Tg) over the past 30 y. If current trends continue, Nr creation from human activities will increase to 63 Tg by 2050, raising concerns about deleterious environmental consequences for land, air, and water at regional and global scales. Tremendous amounts of Nr have accumulated in plants, soils, and waters in China over the past 30 y, but the retention capacity of the terrestrial landscape seems to be declining. There is a possibility that the negative environmental effects of excessive Nr may accelerate in coming decades, increasing the urgency to alter the trajectory of increasing Nr imbalance. Here, a conceptual framework of the relationships between human drivers and Nr cycling in China is oriented and well targeted to Chinese abatement strategies for Nr environmental impact. PMID- 23341614 TI - Generous economic investments after basolateral amygdala damage. AB - Contemporary economic models hold that instrumental and impulsive behaviors underlie human social decision making. The amygdala is assumed to be involved in social-economic behavior, but its role in human behavior is poorly understood. Rodent research suggests that the basolateral amygdala (BLA) subserves instrumental behaviors and regulates the central-medial amygdala, which subserves impulsive behaviors. The human amygdala, however, typically is investigated as a single unit. If these rodent data could be translated to humans, selective dysfunction of the human BLA might constrain instrumental social-economic decisions and result in more impulsive social-economic choice behavior. Here we show that humans with selective BLA damage and a functional central-medial amygdala invest nearly 100% more money in unfamiliar others in a trust game than do healthy controls. We furthermore show that this generosity is not caused by risk-taking deviations in nonsocial contexts. Moreover, these BLA-damaged subjects do not expect higher returns or perceive people as more trustworthy, implying that their generous investments are not instrumental in nature. These findings suggest that the human BLA is essential for instrumental behaviors in social-economic interactions. PMID- 23341615 TI - Structure of ADP-aluminium fluoride-stabilized protochlorophyllide oxidoreductase complex. AB - Photosynthesis uses chlorophylls for the conversion of light into chemical energy, the driving force of life on Earth. During chlorophyll biosynthesis in photosynthetic bacteria, cyanobacteria, green algae and gymnosperms, dark operative protochlorophyllide oxidoreductase (DPOR), a nitrogenase-like metalloenzyme, catalyzes the chemically challenging two-electron reduction of the fully conjugated ring system of protochlorophyllide a. The reduction of the C 17=C-18 double bond results in the characteristic ring architecture of all chlorophylls, thereby altering the absorption properties of the molecule and providing the basis for light-capturing and energy-transduction processes of photosynthesis. We report the X-ray crystallographic structure of the substrate bound, ADP-aluminium fluoride-stabilized (ADP.AlF(3)-stabilized) transition state complex between the DPOR components L(2) and (NB)(2) from the marine cyanobacterium Prochlorococcus marinus. Our analysis permits a thorough investigation of the dynamic interplay between L(2) and (NB)(2). Upon complex formation, substantial ATP-dependent conformational rearrangements of L(2) trigger the protein-protein interactions with (NB)(2) as well as the electron transduction via redox-active [4Fe-4S] clusters. We also present the identification of artificial "small-molecule substrates" of DPOR in correlation with those of nitrogenase. The catalytic differences and similarities between DPOR and nitrogenase have broad implications for the energy transduction mechanism of related multiprotein complexes that are involved in the reduction of chemically stable double and/or triple bonds. PMID- 23341617 TI - Midlatitude atmospheric OH response to the most recent 11-y solar cycle. AB - The hydroxyl radical (OH) plays an important role in middle atmospheric photochemistry, particularly in ozone (O(3)) chemistry. Because it is mainly produced through photolysis and has a short chemical lifetime, OH is expected to show rapid responses to solar forcing [e.g., the 11-y solar cycle (SC)], resulting in variabilities in related middle atmospheric O(3) chemistry. Here, we present an effort to investigate such OH variability using long-term observations (from space and the surface) and model simulations. Ground-based measurements and data from the Microwave Limb Sounder on the National Aeronautics and Space Administration's Aura satellite suggest an ~7-10% decrease in OH column abundance from solar maximum to solar minimum that is highly correlated with changes in total solar irradiance, solar Mg-II index, and Lyman-alpha index during SC 23. However, model simulations using a commonly accepted solar UV variability parameterization give much smaller OH variability (~3%). Although this discrepancy could result partially from the limitations in our current understanding of middle atmospheric chemistry, recently published solar spectral irradiance data from the Solar Radiation and Climate Experiment suggest a solar UV variability that is much larger than previously believed. With a solar forcing derived from the Solar Radiation and Climate Experiment data, modeled OH variability (~6-7%) agrees much better with observations. Model simulations reveal the detailed chemical mechanisms, suggesting that such OH variability and the corresponding catalytic chemistry may dominate the O(3) SC signal in the upper stratosphere. Continuing measurements through SC 24 are required to understand this OH variability and its impacts on O(3) further. PMID- 23341616 TI - Uracil DNA glycosylase initiates degradation of HIV-1 cDNA containing misincorporated dUTP and prevents viral integration. AB - HIV-1 reverse transcriptase discriminates poorly between dUTP and dTTP, and accordingly, viral DNA products become heavily uracilated when viruses infect host cells that contain high ratios of dUTP:dTTP. Uracilation of invading retroviral DNA is thought to be an innate immunity barrier to retroviral infection, but the mechanistic features of this immune pathway and the cellular fate of uracilated retroviral DNA products is not known. Here we developed a model system in which the cellular dUTP:dTTP ratio can be pharmacologically increased to favor dUTP incorporation, allowing dissection of this innate immunity pathway. When the virus-infected cells contained elevated dUTP levels, reverse transcription was found to proceed unperturbed, but integration and viral protein expression were largely blocked. Furthermore, successfully integrated proviruses lacked detectable uracil, suggesting that only nonuracilated viral DNA products were integration competent. Integration of the uracilated proviruses was restored using an isogenic cell line that had no detectable human uracil DNA glycosylase (hUNG2) activity, establishing that hUNG2 is a host restriction factor in cells that contain high dUTP. Biochemical studies in primary cells established that this immune pathway is not operative in CD4+ T cells, because these cells have high dUTPase activity (low dUTP), and only modest levels of hUNG activity. Although monocyte-derived macrophages have high dUTP levels, these cells have low hUNG activity, which may diminish the effectiveness of this restriction pathway. These findings establish the essential elements of this pathway and reconcile diverse observations in the literature. PMID- 23341619 TI - Ice nucleation and dehydration in the Tropical Tropopause Layer. AB - Optically thin cirrus near the tropical tropopause regulate the humidity of air entering the stratosphere, which in turn has a strong influence on the Earth's radiation budget and climate. Recent high-altitude, unmanned aircraft measurements provide evidence for two distinct classes of cirrus formed in the tropical tropopause region: (i) vertically extensive cirrus with low ice number concentrations, low extinctions, and large supersaturations (up to ~70%) with respect to ice; and (ii) vertically thin cirrus layers with much higher ice concentrations that effectively deplete the vapor in excess of saturation. The persistent supersaturation in the former class of cirrus is consistent with the long time-scales (several hours or longer) for quenching of vapor in excess of saturation given the low ice concentrations and cold tropical tropopause temperatures. The low-concentration clouds are likely formed on a background population of insoluble particles with concentrations less than 100 L(-1) (often less than 20 L(-1)), whereas the high ice concentration layers (with concentrations up to 10,000 L(-1)) can only be produced by homogeneous freezing of an abundant population of aqueous aerosols. These measurements, along with past high-altitude aircraft measurements, indicate that the low-concentration cirrus occur frequently in the tropical tropopause region, whereas the high concentration cirrus occur infrequently. The predominance of the low concentration clouds means cirrus near the tropical tropopause may typically allow entry of air into the stratosphere with as much as ~1.7 times the ice saturation mixing ratio. PMID- 23341618 TI - Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. AB - Huntington disease (HD) is a devastating, late-onset, inherited neurodegenerative disorder that manifests with personality changes, movement disorders, and cognitive decline. It is caused by a CAG repeat expansion in exon 1 of the HTT gene that translates to a polyglutamine tract in the huntingtin protein (HTT). The formation of HTT fragments has been implicated as an essential step in the molecular pathogenesis of HD and several proteases that cleave HTT have been identified. However, the importance of smaller N-terminal fragments has been highlighted by their presence in HD postmortem brains and by the fact that nuclear inclusions are only detected by antibodies to the N terminus of HTT. Despite an intense research effort, the precise length of these fragments and the mechanism by which they are generated remains unknown. Here we show that CAG repeat length-dependent aberrant splicing of exon 1 HTT results in a short polyadenylated mRNA that is translated into an exon 1 HTT protein. Given that mutant exon 1 HTT proteins have consistently been shown to be highly pathogenic in HD mouse models, the aberrant splicing of HTT mRNA provides a mechanistic basis for the molecular pathogenesis of HD. RNA-targeted therapeutic strategies designed to lower the levels of HTT are under development. Many of these approaches would not prevent the production of exon 1 HTT and should be reviewed in light of our findings. PMID- 23341621 TI - Income diversification and risk for fishermen. AB - Catches and prices from many fisheries exhibit high interannual variability, leading to variability in the income derived by fishery participants. The economic risk posed by this may be mitigated in some cases if individuals participate in several different fisheries, particularly if revenues from those fisheries are uncorrelated or vary asynchronously. We construct indices of gross income diversification from fisheries at the level of individual vessels and find that the income of the current fleet of vessels on the US West Coast and in Alaska is less diverse than at any point in the past 30 y. We also find a dome shaped relationship between the variability of individuals' income and income diversification, which implies that a small amount of diversification does not reduce income risk but that higher levels of diversification can substantially reduce the variability of income from fishing. Moving from a single fishery strategy to a 50-25-25 split in revenues reduces the expected coefficient of variation of gross revenues between 24% and 65% for the vessels included in this study. The increasing access restrictions in many marine fisheries through license reductions and moratoriums have the potential to limit fishermen's ability to diversify their income risk across multiple fisheries. Catch share programs often result in consolidation initially and may reduce diversification. However, catch share programs also make it feasible for fishermen to build a portfolio of harvest privileges and potentially reduce their income risk. Therefore, catch share programs create both threats and opportunities for fishermen wishing to maintain diversified fishing strategies. PMID- 23341620 TI - SLC4A2-mediated Cl-/HCO3- exchange activity is essential for calpain-dependent regulation of the actin cytoskeleton in osteoclasts. AB - Bone remodeling requires osteoclasts to generate and maintain an acidified resorption compartment between the apical membrane and the bone surface to solubilize hydroxyapatite crystals within the bone matrix. This acidification process requires (i) apical proton secretion by a vacuolar H(+)-ATPase, (ii) actin cytoskeleton reorganization into a podosome belt that forms a gasket to restrict lacunar acid leakage, and (iii) basolateral chloride uptake and bicarbonate extrusion by an anion exchanger to provide Cl(-) permissive for apical acid secretion while preventing cytoplasmic alkalinization. Here we show that osteoclast-targeted deletion in mice of solute carrier family 4 anion exchanger member 2 (Slc4a2) results in osteopetrosis. We further demonstrate a previously unrecognized consequence of SLC4A2 loss of function in the osteoclast: dysregulation of calpain-dependent podosome disassembly, leading to abnormal actin belt formation, cell spreading, and migration. Rescue of SLC4A2-deficient osteoclasts with functionally defined mutants of SLC4A2 indicates regulation of actin cytoskeletal reorganization by anion-exchange activity and intracellular pH, independent of SLC4A2's long N-terminal cytoplasmic domain. These data suggest that maintenance of intracellular pH in osteoclasts through anion exchange regulates the actin superstructures required for bone resorption. PMID- 23341622 TI - Earthquake-like dynamics in Myxococcus xanthus social motility. AB - Myxococcus xanthus is a bacterium capable of complex social organization. Its characteristic social ("S")-motility mechanism is mediated by type IV pili (TFP), linear actuator appendages that propel the bacterium along a surface. TFP are known to bind to secreted exopolysaccharides (EPS), but it is unclear how M. xanthus manages to use the TFP-EPS technology common to many bacteria to achieve its unique coordinated multicellular movements. We examine M. xanthus S-motility, using high-resolution particle-tracking algorithms, and observe aperiodic stick slip movements. We show that they are not due to chemotaxis, but are instead consistent with a constant TFP-generated force interacting with EPS, which functions both as a glue and as a lubricant. These movements are quantitatively homologous to the dynamics of earthquakes and other crackling noise systems. These systems exhibit critical behavior, which is characterized by a statistical hierarchy of discrete "avalanche" motions described by a power law distribution. The measured critical exponents from M. xanthus are consistent with mean field theoretical models and with other crackling noise systems, and the measured Lyapunov exponent suggests the existence of highly branched EPS. Such molecular architectures, which are common for efficient lubricants but rare in bacterial EPS, may be necessary for S-motility: We show that the TFP of leading "locomotive" cells initiate the collective motion of follower cells, indicating that lubricating EPS may alleviate the force generation requirements on the lead cell and thus make S-motility possible. PMID- 23341623 TI - Elasticity and wrinkled morphology of Bacillus subtilis pellicles. AB - Wrinkled morphology is a distinctive phenotype observed in mature biofilms produced by a great number of bacteria. Here we study the formation of macroscopic structures (wrinkles and folds) observed during the maturation of Bacillus subtilis pellicles in relation to their mechanical response. We show how the mechanical buckling instability can explain their formation. By performing simple tests, we highlight the role of confining geometry and growth in determining the symmetry of wrinkles. We also experimentally demonstrate that the pellicles are soft elastic materials for small deformations induced by a tensile device. The wrinkled structures are then described by using the equations of elastic plates, which include the growth process as a simple parameter representing biomass production. This growth controls buckling instability, which triggers the formation of wrinkles. We also describe how the structure of ripples is modified when capillary effects are dominant. Finally, the experiments performed on a mutant strain indicate that the presence of an extracellular matrix is required to maintain a connective and elastic pellicle. PMID- 23341624 TI - Subtropical high predictability establishes a promising way for monsoon and tropical storm predictions. AB - Monsoon rainfall and tropical storms (TSs) impose great impacts on society, yet their seasonal predictions are far from successful. The western Pacific Subtropical High (WPSH) is a prime circulation system affecting East Asian summer monsoon (EASM) and western North Pacific TS activities, but the sources of its variability and predictability have not been established. Here we show that the WPSH variation faithfully represents fluctuations of EASM strength (r = -0.92), the total TS days over the subtropical western North Pacific (r = -0.81), and the total number of TSs impacting East Asian coasts (r = -0.76) during 1979-2009. Our numerical experiment results establish that the WPSH variation is primarily controlled by central Pacific cooling/warming and a positive atmosphere-ocean feedback between the WPSH and the Indo-Pacific warm pool oceans. With a physically based empirical model and the state-of-the-art dynamical models, we demonstrate that the WPSH is highly predictable; this predictability creates a promising way for prediction of monsoon and TS. The predictions using the WPSH predictability not only yields substantially improved skills in prediction of the EASM rainfall, but also enables skillful prediction of the TS activities that the current dynamical models fail. Our findings reveal that positive WPSH-ocean interaction can provide a source of climate predictability and highlight the importance of subtropical dynamics in understanding monsoon and TS predictability. PMID- 23341625 TI - Diagnostic testing and treatment under ambiguity: using decision analysis to inform clinical practice. AB - Partial knowledge of patient health status and treatment response is a pervasive concern in medical decision making. Clinical practice guidelines (CPGs) make recommendations intended to optimize patient care, but optimization typically is infeasible with partial knowledge. Decision analysis shows that a clinician's objective, knowledge, and decision criterion should jointly determine the care he prescribes. To demonstrate, this paper studies a common scenario regarding diagnostic testing and treatment. A patient presents to a clinician, who obtains initial evidence on health status. The clinician can prescribe a treatment immediately or he can order a test yielding further evidence that may be useful in predicting treatment response. In the latter case, he prescribes a treatment after observation of the test result. I analyze this scenario in three steps. The first poses a welfare function and characterizes optimal care. The second describes partial knowledge of response to testing and treatment that might realistically be available. The third considers decision criteria. I conclude with reconsideration of clinical practice guidelines. PMID- 23341626 TI - Lesions of cortical area LIP affect reach onset only when the reach is accompanied by a saccade, revealing an active eye-hand coordination circuit. AB - The circuits that drive visually guided eye and arm movements transform generic visual inputs into effector-specific motor commands. As part of the effort to elucidate these circuits, the primate lateral intraparietal area (LIP) has been interpreted as a priority map for saccades (oculomotor-specific) or a salience map of space (not effector-specific). It has also been proposed as a locus for eye-hand coordination. We reversibly inactivated LIP while monkeys performed memory-guided saccades and reaches. Coordinated saccade and reach reaction times were similarly impaired, consistent with a nonspecific role. However, reaches made without an accompanying saccade remained intact, and the relative temporal coupling of saccades and reaches was unchanged. These results suggest that LIP contributes to saccade planning but not to reach planning. Coordinated reaches are delayed as a result of an eye-hand coordination mechanism, located outside of LIP, that actively delays reaches until shortly after the onset of an associated saccade. We conclude with a discussion of how to reconcile specificity for saccades with a possible role in directing attention. PMID- 23341627 TI - Small open reading frames associated with morphogenesis are hidden in plant genomes. AB - It is likely that many small ORFs (sORFs; 30-100 amino acids) are missed when genomes are annotated. To overcome this limitation, we identified ~8,000 sORFs with high coding potential in intergenic regions of the Arabidopsis thaliana genome. However, the question remains as to whether these coding sORFs play functional roles. Using a designed array, we generated an expression atlas for 16 organs and 17 environmental conditions among 7,901 identified coding sORFs. A total of 2,099 coding sORFs were highly expressed under at least one experimental condition, and 571 were significantly conserved in other land plants. A total of 473 coding sORFs were overexpressed; ~10% (49/473) induced visible phenotypic effects, a proportion that is approximately seven times higher than that of randomly chosen known genes. These results indicate that many coding sORFs hidden in plant genomes are associated with morphogenesis. We believe that the expression atlas will contribute to further study of the roles of sORFs in plants. PMID- 23341628 TI - A double-integration hypothesis to explain ocean ecosystem response to climate forcing. AB - Long-term time series of marine ecological indicators often are characterized by large-amplitude state transitions that can persist for decades. Understanding the significance of these variations depends critically on the underlying hypotheses characterizing expected natural variability. Using a linear autoregressive model in combination with long-term zooplankton observations off the California coast, we show that cumulative integrations of white-noise atmospheric forcing can generate marine population responses that are characterized by strong transitions and prolonged apparent state changes. This model provides a baseline hypothesis for explaining ecosystem variability and for interpreting the significance of abrupt responses and climate change signatures in marine ecosystems. PMID- 23341630 TI - Nitrogen trifluoride global emissions estimated from updated atmospheric measurements. AB - Nitrogen trifluoride (NF(3)) has potential to make a growing contribution to the Earth's radiative budget; however, our understanding of its atmospheric burden and emission rates has been limited. Based on a revision of our previous calibration and using an expanded set of atmospheric measurements together with an atmospheric model and inverse method, we estimate that the global emissions of NF(3) in 2011 were 1.18 +/- 0.21 Gg?y(-1), or ~20 Tg CO(2)-eq?y(-1) (carbon dioxide equivalent emissions based on a 100-y global warming potential of 16,600 for NF(3)). The 2011 global mean tropospheric dry air mole fraction was 0.86 +/- 0.04 parts per trillion, resulting from an average emissions growth rate of 0.09 Gg?y(-2) over the prior decade. In terms of CO(2) equivalents, current NF(3) emissions represent between 17% and 36% of the emissions of other long-lived fluorinated compounds from electronics manufacture. We also estimate that the emissions benefit of using NF(3) over hexafluoroethane (C(2)F(6)) in electronics manufacture is significant-emissions of between 53 and 220 Tg CO(2)-eq?y(-1) were avoided during 2011. Despite these savings, total NF(3) emissions, currently ~10% of production, are still significantly larger than expected assuming global implementation of ideal industrial practices. As such, there is a continuing need for improvements in NF(3) emissions reduction strategies to keep pace with its increasing use and to slow its rising contribution to anthropogenic climate forcing. PMID- 23341629 TI - Inactivation of the microRNA-183/96/182 cluster results in syndromic retinal degeneration. AB - The microRNA-183/96/182 cluster is highly expressed in the retina and other sensory organs. To uncover its in vivo functions in the retina, we generated a knockout mouse model, designated "miR-183C(GT/GT)," using a gene-trap embryonic stem cell clone. We provide evidence that inactivation of the cluster results in early-onset and progressive synaptic defects of the photoreceptors, leading to abnormalities of scotopic and photopic electroretinograms with decreased b-wave amplitude as the primary defect and progressive retinal degeneration. In addition, inactivation of the miR-183/96/182 cluster resulted in global changes in retinal gene expression, with enrichment of genes important for synaptogenesis, synaptic transmission, photoreceptor morphogenesis, and phototransduction, suggesting that the miR-183/96/182 cluster plays important roles in postnatal functional differentiation and synaptic connectivity of photoreceptors. PMID- 23341631 TI - A vector-free microfluidic platform for intracellular delivery. AB - Intracellular delivery of macromolecules is a challenge in research and therapeutic applications. Existing vector-based and physical methods have limitations, including their reliance on exogenous materials or electrical fields, which can lead to toxicity or off-target effects. We describe a microfluidic approach to delivery in which cells are mechanically deformed as they pass through a constriction 30-80% smaller than the cell diameter. The resulting controlled application of compression and shear forces results in the formation of transient holes that enable the diffusion of material from the surrounding buffer into the cytosol. The method has demonstrated the ability to deliver a range of material, such as carbon nanotubes, proteins, and siRNA, to 11 cell types, including embryonic stem cells and immune cells. When used for the delivery of transcription factors, the microfluidic devices produced a 10-fold improvement in colony formation relative to electroporation and cell-penetrating peptides. Indeed, its ability to deliver structurally diverse materials and its applicability to difficult-to-transfect primary cells indicate that this method could potentially enable many research and clinical applications. PMID- 23341632 TI - Domain-swapped chain connectivity and gated membrane access in a Fab-mediated crystal of the human TRAAK K+ channel. AB - TRAAK (TWIK-related arachidonic acid-stimulated K(+) channel, K2P4.1) K(+) ion channels are expressed predominantly in the nervous system to control cellular resting membrane potential and are regulated by mechanical and chemical properties of the lipid membrane. TRAAK channels are twofold symmetric, which precludes a direct extension of gating mechanisms that close canonical fourfold symmetric K(+) channels. We present the crystal structure of human TRAAK in complex with antibody antigen-binding fragments (Fabs) at 2.75-A resolution. In contrast to a previous structure, this structure reveals a domain-swapped chain connectivity enabled by the helical cap that exchanges two opposing outer helices 180 degrees around the channel. An unrelated conformational change of an inner helix seals a side opening to the membrane bilayer and is associated with structural changes around the K(+)-selectivity filter that may have implications for mechanosensitivity and gating of TRAAK channels. PMID- 23341633 TI - Control of cell-fate plasticity and maintenance of multipotency by DAF-16/FoxO in quiescent Caenorhabditis elegans. AB - The Caenorhabditis elegans vulval precursor cells (VPCs) offer a paradigm for investigating how multipotency of progenitor cells is maintained during periods of quiescence. The VPCs are born in the first larval stage. When hermaphrodites are grown under favorable conditions, the EGF-mediated "inductive" signal and the LIN-12/Notch-mediated "lateral" signal confer a precise spatial pattern of distinct vulval cell fates in the third larval stage, a day after hatching. Under adverse conditions, hermaphrodites undergo a prolonged quiescent period as dauer larvae, which can endure for several months with progenitor cells such as VPCs in developmental arrest. If favorable conditions ensue, larvae recover and resume development as postdauer third stage larvae, with the same VPC spatial-patterning events as in continuously developing third stage larvae. Here, we identify several consequences of dauer life history for VPC specification. In wild-type dauers, VPCs undergo a phenomenon reminiscent of natural direct reprogramming to maintain or reestablish multipotency; they acquire an active block to signal transduction by EGF receptor and LIN-12/Notch and have a different mechanism for regulating transcription of the lateral signal. Furthermore, DAF-16/FoxO, a target of insulin/insulin-like growth factor signaling, is required to promote VPC fate plasticity during dauer and for normal vulval patterning after passage through dauer, suggesting that DAF-16/FoxO coordinates environment and life history with plasticity of cell fate. PMID- 23341634 TI - Fas expression by tumor stroma is required for cancer eradication. AB - The contribution of molecules such as perforin, IFN-gamma (IFNgamma), and particularly Fas ligand (FasL) by transferred CD8(+) effector T (T(E)) cells to rejection of large, established tumors is incompletely understood. Efficient attack against large tumors carrying a surrogate tumor antigen (mimicking a "passenger" mutation) by T(E) cells requires action of IFNgamma on tumor stroma cells to avoid selection of antigen-loss variants. Because "cancer-driving" antigens (CDAs) are rarely counterselected, IFNgamma may be expected to be dispensable in elimination of cancers by targeting a CDA. Here, initial regression of large, established tumors required neither IFNgamma, FasL, nor perforin by transferred CD8(+) T(E) cells targeting Simian Virus (SV) 40 large T as CDA. However, cytotoxic T(E) cells lacking IFNgamma or FasL could not prevent relapse despite retention of the rejection antigen by the cancer cells. Complete tumor rejection required IFNgamma-regulated Fas by the tumor stroma. Therefore, T(E) cells lacking IFNgamma or FasL cannot prevent progression of antigenic cancer because the tumor stroma escapes destruction if its Fas expression is down regulated. PMID- 23341635 TI - Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. AB - Leber congenital amaurosis (LCA) associated with retinal pigment epithelium specific protein 65 kDa (RPE65) mutations is a severe hereditary blindness resulting from both dysfunction and degeneration of photoreceptors. Clinical trials with gene augmentation therapy have shown partial reversal of the dysfunction, but the effects on the degeneration are not known. We evaluated the consequences of gene therapy on retinal degeneration in patients with RPE65-LCA and its canine model. In untreated RPE65-LCA patients, there was dysfunction and degeneration of photoreceptors, even at the earliest ages. Examined serially over years, the outer photoreceptor nuclear layer showed progressive thinning. Treated RPE65-LCA showed substantial visual improvement in the short term and no detectable decline from this new level over the long term. However, retinal degeneration continued to progress unabated. In RPE65-mutant dogs, the first one quarter of their lifespan showed only dysfunction, and there was normal outer photoreceptor nuclear layer thickness retina-wide. Dogs treated during the earlier dysfunction-only stage showed improved visual function and dramatic protection of treated photoreceptors from degeneration when measured 5-11 y later. Dogs treated later during the combined dysfunction and degeneration stage also showed visual function improvement, but photoreceptor loss continued unabated, the same as in human RPE65-LCA. The results suggest that, in RPE65 disease treatment, protection from visual function deterioration cannot be assumed to imply protection from degeneration. The effects of gene augmentation therapy are complex and suggest a need for a combinatorial strategy in RPE65-LCA to not only improve function in the short term but also slow retinal degeneration in the long term. PMID- 23341636 TI - HSV carrying WT REST establishes latency but reactivates only if the synthesis of REST is suppressed. AB - HSVs transit from vigorous replication at the portal of entry into the body to a latent state in sensory neurons in which only noncoding (e.g., latency-associated transcript) and micro-RNAs are expressed. In productive infection, viral genes must be sequentially derepressed at two checkpoints. A leading role in the repression of viral genes is carried out by histone deacetylase (HDAC)/corepressor element-1 silencing transcription factor (CoREST)/lysinespecific demethylase1(LSD1)/RE1-silencing transcription factor (REST) repressor complex (HCLR). Previously, we reported that to define the role of the components of the HCLR complex in the establishment of latency, we constructed recombinant virus (R112) carrying a dominant-negative REST that bound response elements in DNA but could not recruit repressive proteins. This recombinant virus was unable to establish latency. In the current studies, we constructed a virus (R111) carrying WT REST with a WT genome. We report the following findings: (a) R111 readily established latent infection in trigeminal ganglia; however, although the amounts of viral DNAs in latently infected neurons were similar to those of WT virus, the levels of latency-associated transcript and micro-RNAs were 50- to 100-fold lower; (b) R111 did not spontaneously reactivate in ganglionic organ cultures; however, viral genes were expressed if the synthesis of REST was blocked by cycloheximide; and (c) histone deacetylase inhibitors reactivated the WT parent but not the R111 recombinant virus. The results suggest that REST plays a transient role in the establishment of latency but not in reactivation and suggest the existence of at least two phases at both establishment and reactivation. PMID- 23341637 TI - DNA analysis of an early modern human from Tianyuan Cave, China. AB - Hominins with morphology similar to present-day humans appear in the fossil record across Eurasia between 40,000 and 50,000 y ago. The genetic relationships between these early modern humans and present-day human populations have not been established. We have extracted DNA from a 40,000-y-old anatomically modern human from Tianyuan Cave outside Beijing, China. Using a highly scalable hybridization enrichment strategy, we determined the DNA sequences of the mitochondrial genome, the entire nonrepetitive portion of chromosome 21 (~30 Mbp), and over 3,000 polymorphic sites across the nuclear genome of this individual. The nuclear DNA sequences determined from this early modern human reveal that the Tianyuan individual derived from a population that was ancestral to many present-day Asians and Native Americans but postdated the divergence of Asians from Europeans. They also show that this individual carried proportions of DNA variants derived from archaic humans similar to present-day people in mainland Asia. PMID- 23341639 TI - Republished: perception of lung function, adherence to inhaled corticosteroids, and the role of peak expiratory flow feedback in paediatric asthma. PMID- 23341638 TI - Extensive changes in DNA methylation are associated with expression of mutant huntingtin. AB - The earliest stages of Huntington disease are marked by changes in gene expression that are caused in an indirect and poorly understood manner by polyglutamine expansions in the huntingtin (HTT) protein. To explore the hypothesis that DNA methylation may be altered in cells expressing mutated HTT, we use reduced representation bisulfite sequencing (RRBS) to map sites of DNA methylation in cells carrying either wild-type or mutant HTT. We find that a large fraction of the genes that change in expression in the presence of mutant huntingtin demonstrate significant changes in DNA methylation. Regions with low CpG content, which have previously been shown to undergo methylation changes in response to neuronal activity, are disproportionately affected. On the basis of the sequence of regions that change in methylation, we identify AP-1 and SOX2 as transcriptional regulators associated with DNA methylation changes, and we confirm these hypotheses using genome-wide chromatin immunoprecipitation sequencing (ChIP-Seq). Our findings suggest new mechanisms for the effects of polyglutamine-expanded HTT. These results also raise important questions about the potential effects of changes in DNA methylation on neurogenesis and cognitive decline in patients with Huntington disease. PMID- 23341640 TI - Republished: developing capable quality improvement leaders. AB - BACKGROUND/OBJECTIVE: Cincinnati Children's Hospital Medical Center created the Intermediate Improvement Science Series (I(2)S(2)) training course to develop organisational leaders to do improvement, lead improvement and get results on specific projects. DESIGN METHODS: Each multidisciplinary class consists of 25-30 participants and 12 in-class training days over 6 months. Instructional methods include lectures, case studies, interactive application exercises and dialogue, participant reports and assigned readings. Participants demonstrate competence in improvement science by completing a project with improvement in outcome and/or process measures. They present on their projects and receive feedback during each session and one-on-one coaching between sessions. RESULTS: Since 2006, 279 participants in 11 classes have completed the I(2)S(2) course. Participant evaluations have consistently rated satisfaction, learning, application, impact and value very high. Large and statistically significant changes were observed in pre-course to post-course self-assessment of knowledge of five quality improvement topics. Approximately 85% of the projects demonstrated measurable improvement. At follow-up, 72% of improvement projects were completed and made a part of everyday operations in the participant's unit or were the focus of continuing improvement work. Many changes were spread to other units or programmes. Most (88%) responding graduates continued to participate in formal quality improvement efforts and many led other improvement projects. Nearly half of the respondents presented their results at one or more professional conference. CONCLUSIONS: Through the I(2)S(2) course, the authors are developing improvement leaders, accelerating the shift in the culture from a traditional academic medical centre to an improvement-focused culture, and building cross silo relationships by developing leaders who understand the organisation as a large system of interdependent subsystems focused on improving health. PMID- 23341641 TI - Republished: failure of reflux inhibitors in clinical trials: bad drugs or wrong patients? AB - Treatment modalities for gastro-oesophageal reflux disease (GORD) mirror the pathophysiology of the disease. Since acid plays a key role in GORD-associated mucosal lesions, proton pump inhibitors (PPIs) are the dominant GORD treatment, being the most potent inhibitors of acid secretion available. However, the clinical effectiveness of PPIs varies with the specific symptoms being treated; they are more effective for heartburn than for regurgitation than for extra oesophageal symptoms. An alternative therapeutic approach to GORD is to prevent the most fundamental cause of reflux symptoms, reflux itself, which most commonly occurs by transient lower oesophageal sphincter relaxation (TLOSR). Among potential pharmaceutical agents developed to target TLOSRs, the most advanced are GABA(B) (gamma-aminobutyric acid) agonists, which experimentally reduce the occurrence of TLOSRs by about 40% in both animal and human studies. However, the effectiveness of GABA(B) agonists in clinical trials of patients with GORD with an incomplete response to PPI treatment has been modest. In part, this is probably attributable to the difficult problem of patient selection in these trials. Identifying patients by partial response to PPI treatment results in a heterogeneous population, including those with persistent weakly acidic reflux, patients with visceral hypersensitivity and those with functional heartburn, dyspepsia, or chest pain. From the clinical data available, the best treatment results and, hence, the patients most likely to benefit from reflux inhibitors, are those with persistent reflux, most commonly manifest as persistent regurgitation despite PPI treatment. PMID- 23341642 TI - On redundancy. PMID- 23341644 TI - Editorial: with just a memory. PMID- 23341643 TI - A structural bioinformatics approach for identifying proteins predisposed to bind linear epitopes on pre-selected target proteins. AB - We have developed a protocol for identifying proteins that are predisposed to bind linear epitopes on target proteins of interest. The protocol searches through the protein database for proteins (scaffolds) that are bound to peptides with sequences similar to accessible, linear epitopes on the target protein. The sequence match is considered more significant if residues calculated to be important in the scaffold-peptide interaction are present in the target epitope. The crystal structure of the scaffold-peptide complex is then used as a template for creating a model of the scaffold bound to the target epitope. This model can then be used in conjunction with sequence optimization algorithms or directed evolution methods to search for scaffold mutations that further increase affinity for the target protein. To test the applicability of this approach we targeted three disease-causing proteins: a tuberculosis virulence factor (TVF), the apical membrane antigen (AMA) from malaria, and hemagglutinin from influenza. In each case the best scoring scaffold was tested, and binders with Kds equal to 37 MUM and 50 nM for TVF and AMA, respectively, were identified. A web server (http://rosettadesign.med.unc.edu/scaffold/) has been created for performing the scaffold search process with user-defined target sequences. PMID- 23341646 TI - Achieving care goals for people with chronic health conditions. PMID- 23341648 TI - Hypertension in elderly patients: recommended systolic targets are not evidence based. PMID- 23341650 TI - Drivers of overtesting. PMID- 23341651 TI - Accounting for the costs of tests. PMID- 23341652 TI - Ethics of physician-assisted death. PMID- 23341653 TI - Clinical review: modified 5 As: minimal intervention for obesity counseling in primary care. AB - OBJECTIVE: To adapt the 5 As model in order to provide primary care practitioners with a framework for obesity counseling. SOURCES OF INFORMATION: A systematic literature search of MEDLINE using the search terms 5 A's (49 articles retrieved, all relevant) and 5 A's and primary care (8 articles retrieved, all redundant) was conducted. The National Institute of Health and the World Health Organization websites were also searched. MAIN MESSAGE: The 5 As (ask, assess, advise, agree, and assist), developed for smoking cessation, can be adapted for obesity counseling. Ask permission to discuss weight; be nonjudgmental and explore the patient's readiness for change. Assess body mass index, waist circumference, and obesity stage; explore drivers and complications of excess weight. Advise the patient about the health risks of obesity, the benefits of modest weight loss, the need for a long-term strategy, and treatment options. Agree on realistic weight-loss expectations, targets, behavioural changes, and specific details of the treatment plan. Assist in identifying and addressing barriers; provide resources, assist in finding and consulting with appropriate providers, and arrange regular follow-up. CONCLUSION: The 5 As comprise a manageable evidence based behavioural intervention strategy that has the potential to improve the success of weight management within primary care. PMID- 23341654 TI - Mothersisk update: reproductive outcomes after assisted conception. AB - QUESTION: Increasingly my patients are undergoing assisted conception. These patients are excitedly anticipating pregnancy, but are there risks to the fetus when using assisted reproductive technology (ART)? ANSWER: The current medical literature suggests only a mild increase in preterm deliveries, low birth weight, birth defects, and genetic imprinting defects. These results might, in part, be related to the indication for ART, rather than the ART itself. PMID- 23341655 TI - Child health update: estrogen cream for labial adhesion in girls. AB - QUESTION: Should I prescribe estrogen cream to treat labial adhesion in my prepubertal female patients? ANSWER: Many physicians offer young girls estrogen cream to be applied on the labia for several weeks to treat labial adhesion. While no randomized controlled trial data are available, the success rate of such creams is reported in the literature to be close to 90%. Side effects of estrogen cream are mild and transient. Although the ideal frequency and length of treatment with estrogen cream has yet to be determined, most treatment recommendations suggest application of the cream 1 to 2 times a day; treatment should be applied for a few weeks before considering surgical alternatives. PMID- 23341656 TI - Emergency files: acute pericarditis, myocarditis, and worse! PMID- 23341657 TI - Tools for practice: screening and diagnosis of type 2 diabetes with HbA1c. PMID- 23341658 TI - Case report: furosemide and pancreatitis: Importance of dose and latency period before reaction. PMID- 23341659 TI - Physical activity series: cardiovascular risks of physical activity in apparently healthy individuals: risk evaluation for exercise clearance and prescription. PMID- 23341660 TI - Top 10 forgotten diagnostic procedures: suprapubic bladder aspiration. PMID- 23341661 TI - Dermacase. Can you identify this condition? Mycobacterium marinum infection. PMID- 23341662 TI - Family practice patients' use of acetylsalicylic acid for cardiovascular disease prevention. AB - OBJECTIVE: To determine the prevalence of acetylsalicylic acid (ASA) use among family practice patients and the proportions of patients using ASA for primary and secondary cardiovascular prevention. DESIGN: Cross-sectional, self-reported, waiting room questionnaire. SETTING: Two family medicine clinics in Alberta. PARTICIPANTS: Patients 50 years of age and older. MAIN OUTCOME MEASURES: Overall prevalence of ASA use, proportion of ASA use for primary or secondary cardiovascular prevention, ASA use by patient age and sex, the proportion of patients who initiated ASA therapy on the advice of a physician, adverse events, and patient beliefs about ASA therapy. RESULTS: A total of 807 patients completed the questionnaire; the response rate was 89.1%. Overall, 39.8% of patients reported taking ASA regularly. Of those who took ASA, 87.0% did so for cardiovascular prevention (53.1% for primary prevention and 46.9% for secondary prevention). Of patients taking ASA for primary prevention, 62.8% did so upon the advice of their family physicians. Patients who took ASA believed that the benefits of taking ASA outweighed the risks; those who did not take ASA were unsure of the benefit-to-risk profile. CONCLUSION: Many family practice patients take ASA, and more than half of those taking ASA take it for primary cardiovascular prevention. Family physicians appear to have an influence on patients' decisions to take ASA. Educating family physicians and patients about the potential benefits and risks of ASA therapy would help promote the use of ASA in those who might receive the greatest overall benefit. PMID- 23341663 TI - Stories in family medicine commentary: the power of stories. PMID- 23341664 TI - Best English story by a family physician: premature. PMID- 23341665 TI - Best story by a resident: 43 minutes. PMID- 23341667 TI - [The faces of family medicine]. PMID- 23341668 TI - Teaching moment: reflection in medicine: models and application. PMID- 23341669 TI - Sentinel eye: improving usability of smoking data in EMR systems. PMID- 23341673 TI - Cumulative profile: a new era. PMID- 23341670 TI - President's message: toward a patient-centred health care system. PMID- 23341674 TI - Association of primary care physician sex with cervical cancer and mammography screening. AB - OBJECTIVE: To assess whether the sex of primary care physicians is associated with differing rates of cervical cancer and mammography screening in a contemporary multicultural context. DESIGN: Structured medical record review of a retrospectively defined cohort. SETTING: Academic urban primary care clinic in Montreal, Que. PARTICIPANTS: Seven male physicians and 9 female physicians, and all female patients aged 14 to 69 years registered to one of the physicians (N = 1948). MAIN OUTCOME MEASURES: Screening compliance rates as measured by the elapsed time between the last visit and cervical cancer screening for all women in the study. In addition, in women aged 50 to 69 years, elapsed time between the last visit and mammography screening. RESULTS: Crude rates of Papanicolaou tests for patients of female primary care physicians were higher than for patients of male primary care physicians in all patient age groups. The lowest rates of Pap testing were among the youngest and oldest patients. After adjustment for patient age, first language, and region of birth, as well as physician age, the odds ratio of having a Pap test was 2.24 (95% CI 1.18 to 4.28) for the patients of female physicians, relative to those of male physicians. The adjusted odds ratio for mammography screening was 1.25 (95% CI 0.97 to 1.61) for patients of female physicians. CONCLUSION: Male primary care physician sex is associated with lower rates of cervical cancer screening in an urban multicultural context. The study did not detect a physician sex effect in the mammography cohort. PMID- 23341675 TI - Assessment of the Siksika chronic disease nephropathy-prevention clinic. AB - OBJECTIVE: To determine if a community-based multifactorial intervention clinic led by a nurse practitioner would improve management of First Nations people at risk of developing chronic kidney disease. DESIGN: Qualitative descriptive study. SETTING: A nephropathy-prevention clinic in Siksika Nation, Alta. PARTICIPANTS: First Nations people with diabetes, hypertension, or dyslipidemia who were referred to the clinic. MAIN OUTCOME MEASURES: Changes in blood pressure (BP), hemoglobin A(1c), and low-density lipoprotein levels, as well as in use of antiplatelet therapy, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker medications, and statin therapy. RESULTS: Members of the Siksika Nation were treated according to clinical practice guidelines. A total of 78 patients had at least 2 visits to the clinic and were included in this analysis (61.5% were women; mean age 56 years). Among those initially above target, a significant reduction was achieved in mean hemoglobin A(1c) (0.96%; P < .01), systolic BP (15.84 mm Hg; P < .05), diastolic BP (7.16 mm Hg; P < .001), and low density lipoprotein (0.62 mmol/L; P < .01) levels. There was a significant increase in the proportion of patients with clinical indications who were treated with acetylsalicylic acid (42.4%; P < .01), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker medications (35.9%; P < .01), or statin therapy (35.9%; P < .01). CONCLUSION: A community-based, nurse practitioner-led clinic can improve many clinically relevant factors in patients at risk of developing chronic kidney disease. Studies have shown that achieving treatment targets is associated with a reduced risk of early death and cardiovascular events; the effect in the First Nations population on these hard clinical end points remains to be determined. PMID- 23341676 TI - Exercise behaviour and attitudes among fourth-year medical students at the University of British Columbia. AB - OBJECTIVE: To describe the physical activity (PA) levels and counseling attitudes of Canadian undergraduate medical students. DESIGN: Online or paper survey. SETTING: The University of British Columbia (UBC). PARTICIPANTS: Fourth-year medical students at UBC from 2007 to 2010. MAIN OUTCOME MEASURES: Physical activity levels, relationship between exercise behaviour and attitudes toward counseling, and student perception of training in the area of exercise prescription. RESULTS: A total of 546 out of 883 students participated in the survey (62% response rate). Sixty-four percent of students met the Canadian Society for Exercise Physiology 2011 recommendations for PA. Attitudes toward healthy living were related to PA levels, but the rate of counseling patients about exercise was not; however, students who engaged in more strenuous PA were more likely to perceive exercise counseling as being highly relevant to future clinical practice (P = .018). Overall, 69% of students perceived exercise counseling to be highly relevant to clinical practice, but 86% thought that their training in this area was less than extensive. CONCLUSION: Fourth-year UBC medical students engage in more strenuous PA than average age-matched Canadians, which affects their attitudes toward perceived future counseling practices. Encouraging more student participation in strenuous PA and encouraging academic training in the area of exercise counseling might be important next steps in preparing future physicians to effectively prescribe exercise to their patients. PMID- 23341677 TI - What do Victoria family physicians think about housecalls? AB - OBJECTIVE: To determine the proportion of family physicians doing housecalls, the types of patients they think are appropriate to visit at home, whether physicians are satisfied with the number of housecalls they make, reasons family physicians list for not doing housecalls, and what they consider acceptable remuneration and travel time for housecalls. DESIGN: A 12-question paper survey was formulated specifically for this study and piloted by 6 family physicians in British Columbia. It was then mailed with a cover letter to 250 physicians' offices and faxed back anonymously. SETTING: Family physicians' private offices in Victoria, BC, between December 1 and 19, 2010. PARTICIPANTS: A total of 250 randomly selected family physicians from a list of 552 physicians practising in Victoria on the College of Physicians and Surgeons of British Columbia website. MAIN OUTCOME MEASURES: Proportion of physicians doing housecalls, reasons stated for not doing housecalls, and mean acceptable remuneration and travel time for a housecall. RESULTS: A total of 73 surveys (29.2%) were returned, 5 of which were not fully completed but were included for the questions that were answered. Sixty four physicians (87.7%) did at least 1 housecall in the past year, 23 (31.5%) did housecalls at least once a month, and 12 (16.4%) did them at least once a week. Of 71 respondents, 64 physicians (90.1%) listed lack of time as a barrier to performing housecalls, 37 (52.1%) listed unsatisfactory remuneration, and 35 (49.3%) listed lengthy travel times. Most physicians indicated that appropriate remuneration for a housecall was either $142.21 (n = 30, 42.9%) or $108.41 (n = 26, 37.1%). Thirty-seven physicians (52.9%) noted that 20 minutes was an acceptable maximum 1-way travel time for a housecall, while 29 (41.4%) listed 10 minutes. CONCLUSION: Several systemic factors, including lack of time, unsatisfactory remuneration, and large geographic catchment areas, make it difficult for urban family physicians to do housecalls. PMID- 23341682 TI - Best French story by a family physician: wisteria. PMID- 23341678 TI - Maternal age-based prenatal screening for chromosomal disorders: attitudes of women and health care providers toward changes. AB - OBJECTIVE: To explore views of women and health care providers (HCPs) about the changing recommendations regarding maternal age-based prenatal screening. DESIGN: Mixed-methods design. SETTING: Ontario. PARTICIPANTS: A sample of women who had given birth within the previous 2 years and who had attended a family medicine centre, midwifery practice, or baby and mother wellness program (n = 42); and a random sample of family physicians (n = 1600), and all Ontario obstetricians (n = 694) and midwives (n = 334) who provided prenatal care. METHODS: We used focus groups (FGs) to explore women's views. Content analysis was used to uncover themes and delineate meaning. To explore HCPs' views, we conducted a cross sectional self-completion survey. MAIN FINDINGS: All FG participants (42 women in 6 FGs) expressed the importance of individual choice of prenatal screening modality, regardless of age. They described their perception that society considers women older than 35 to be at high obstetric risk and raised concerns that change in the maternal age-related screening policy would require education. The HCP survey response rate was 40%. Results showed 24% of HCPs agreed that women of any age should be eligible for invasive diagnostic testing regardless of prenatal screening results; 15% agreed that the age for diagnostic testing should be increased to 40 years, 14% agreed that diagnostic testing should be reserved for women with positive prenatal screening results, and 45% agreed that prenatal screening should remain unchanged. CONCLUSION: Maternity care organizations have recommended that maternal age-based prenatal screening is no longer appropriate. Informed choice is of paramount importance to women and should be part of any change. Health care providers need to be engaged in and educated about any change to screening guidelines to offer women informed choices. PMID- 23341687 TI - Effects of surface functional groups on the formation of nanoparticle-protein corona. AB - Herein, we examined the dependence of protein adsorption on the nanoparticle surface in the presence of functional groups. Our UV-visible spectrophotometry, transmission electron microscopy, infrared spectroscopy, and dynamic light scattering measurements evidently suggested that the functional groups play an important role in the formation of nanoparticle-protein corona. We found that uncoated and surfactant-free silver nanoparticles derived from a laser ablation process promoted a maximum protein (bovine serum albumin) coating due to increased changes in entropy. On the other hand, bovine serum albumin displayed a relatively lower affinity for electrostatically stabilized nanoparticles due to the constrained entropy changes. PMID- 23341688 TI - Experimental techniques for imaging and measuring transient vapor nanobubbles. AB - Imaging and measuring transient vapor bubbles at nanoscale pose certain experimental challenges due to their reduced dimensions and lifetimes, especially in a single event experiment. Here, we analyze three techniques that employ optical scattering and acoustic detection in identifying and quantifying individual photothermally induced vapor nanobubbles (NBs) at a wide range of excitation energies. In optically transparent media, the best quantitative detection can be achieved by measuring the duration of the optical scattering time-response, while in an opaque media, the amplitude of the acoustic time response well describes NBs in the absence of stress waves. PMID- 23341689 TI - Elastic, dielectric and piezoelectric characterization of single domain PIN-PMN PT: Mn crystals. AB - Mn modified 0.26Pb(In(1/2)Nb(1/2))O(3)-0.42Pb(Mg(1/3)Nb(2/3))O(3)-0.32PbTiO(3) (PIN-PMN-PT:Mn) single crystals with orthorhombic perovskite crystal structure were polarized along [011] direction, resulting in the single domain state "1O." The complete set of material constants was determined using the combined resonance and ultrasonic methods. The thickness shear piezoelectric coefficient d(15) and electromechanical coupling factor k(15) were found to be on the order of 3100 pC/N and 94%, respectively, much higher than longitudinal d(33) ~ 270 pC/N and k(33) ~ 70%. Using the single domain data, the rotated value of d(33)* along [001] direction was found to be 1230 pC/N, in agreement with the experimentally determined d(33) value of 1370 pC/N, conferring extrinsic contributions being about 10%, which was also confirmed using the Rayleigh analysis. In addition, the mechanical quality factors Q(m) were evaluated for different "1O" vibration modes, where the longitudinal Q(m) was found to be ~1200, much higher than the value for "4O" crystals, ~300. PMID- 23341690 TI - Assessment of oxidative stress and antioxidant property using electron spin resonance (ESR) spectroscopy. AB - The pathophysiology of hypertension or stroke is associated with an excess of ROS generation in the vascular system, and results in induction of various pathological cascades of cerebrovascular damage. We have demonstrated that electron spin resonance methods using a spin trap or spin probe will be useful for understanding redox status under conditions of oxidative stress in the spontaneously hypertensive rat or stroke-prone spontaneously hypertensive rat brain. We have used electron spin resonance imaging and noninvasive L-band electron spin resonance to characterize the higher degree of brain oxidative stress in the stroke-prone spontaneously hypertensive rat and spontaneously hypertensive rat than in the Wistar-Kyoto rat brain, and the lower extent of oxidative stress in the spontaneously hypertensive rat than in the stroke-prone spontaneously hypertensive rat brain. Indeed, we may be able to confirm propofol medium-chain triglyceride/long-chain triglyceride (MCT/LCT) as neuroprotective anesthesia and crocetin as antioxidant food factor against human stroke after screening for antioxidant properties in stroke models such as stroke-prone spontaneously hypertensive rat. Thus, our electron spin resonance biomedical application suggests that it could be used to assess antioxidant effects on oxidative stress in the brain using spontaneously hypertensive rat and stroke prone spontaneously hypertensive rat. We hope that further advances in the instrumentation used for electron spin resonance imaging and the development of optimized nontoxic spin probes will make this technology even more promising for novel clinical prediction or noninvasive diagnosis of human stroke. After screening drugs or foods for antioxidant property using in vitro or in vivo electron spin resonance assessment, it will be possible to find and develop novel drugs or food factors with such properties for the prevention of stroke in the near future. PMID- 23341691 TI - Lipid peroxidation biomarkers for evaluating oxidative stress and assessing antioxidant capacity in vivo. AB - Recently, the biological roles of lipid peroxidation products have received a great deal of attention not only for elucidating pathological mechanisms but also for practical clinical applications as biomarkers. In the last 50 years, lipid peroxidation has been the subject of extensive studies from the viewpoints of mechanisms, dynamics, product analysis, involvement in diseases, inhibition, and biological signaling. Lipid hydroperoxides are formed as major primary products, but they are substrates for various enzymes and they also undergo various secondary reactions. During this decade, hydroxyoctadecadienoic acid from linoleates, F(2)-isoprostanes from arachidonates, and neuroprostanes from docosahexanoates have been proposed as biomarkers for evaluating oxidative stress in vivo and its related diseases. The implications of lipid peroxidation products in vivo will be briefly reviewed and their practical applications will be discussed. PMID- 23341692 TI - Inducible nitric oxide synthase plays important roles in allergic reactions of pollinosis in mice sensitized with pollen allergy. AB - To elucidate the possible involvement of nitric oxide (NO) derived from inducible NO-synthase (iNOS) in the pathogenesis of patients with allergic rhinitis, we analyzed changes in the frequency of sneezing, plasma levels of NO metabolites, alpha-melanocyte-stimulating hormone (MSH) and immunoglobulin E and tracheal expression of IgA and mast cell tryptase in control and iNOS(-/-) mice. Eight week-old control and iNOS(-/-) male C57BL/6j mice were sensitized with Cry j I antigen. After the last intranasal challenge of antigen, changes in the frequency of sneezing and plasma levels of IgE, alpha-MSH and NO metabolites and tracheal expression of iNOS, IgA and mast cell tryptase were analyzed by ELISA and immunohistochemistry using specific antibodies. The sensitization of mice with Cry j I antigen increased plasma levels of NO metabolites, alpha-MSH and IgE and tracheal expression of iNOS, IgA and mast cell tryptase in control not but in iNOS(-/-) mice. Administration of N(G)-nitro-L-arginine methyl ester strongly inhibited all these changes occurred in control mice. These results indicate that the symptom of pollinosis including sneezing is enhanced by iNOS derived NO through activation of alpha-MSH-receptor containing mast cells enriched with tryptase. PMID- 23341693 TI - Dietary advanced glycation end products restriction diminishes inflammation markers and oxidative stress in patients with type 2 diabetes mellitus. AB - The augmented consumption of dietary advanced glycation end products (dAGEs) has been associated with increased oxidative stress and inflammation, however, there is insufficient information over the effect on insulin resistance. The objective of the present study is to investigate the effect of dAGEs restriction on tumor necrosis factor-alpha (TNF-alpha), malondialdehyde, C-reactive protein (CRP), and insulin resistance in DM2 patients. We carried out a randomized 6 weeks prospective study in two groups of patients: subjects with a standard diet (n = 13), vs low dAGEs (n = 13). At the beginning and the end of study, we collected anthropometric measurements, and values of circulating glucose, HbA1c, lipids, insulin, serum AGEs, CRP, TNF-alpha and malondialdehyde. Anthropometric measurements, glucose, and lipids were similar in both groups at base line and at the end of the study. Estimation of basal dAGEs was similar in both groups; after 6 weeks it was unchanged in the standard group but in the low dAGEs group decreased by 44% (p<0.0002). Changes in TNF-alpha levels were different under standard diet (12.5 +/- 14.7) as compared with low dAGEs (-18.36 +/- 17.1, p<0.00001); changes in malondialdehyde were different in the respective groups (2.0 +/- 2.61 and -0.83 +/- 2.0, p<0.005) no changes were found for insulin levels or HOMA-IR. In conclusion, The dAGEs restriction decreased significantly TNF-alpha and malondialdehyde levels. PMID- 23341694 TI - Thioredoxin-1 and oxidative stress status in pregnant women at early third trimester of pregnancy: relation to maternal and neonatal characteristics. AB - This study examined the clinical and biological importance of thioredoxin-1, a redox-active defensive protein that controls multiple biological functions, in pregnant women. We measured serum concentrations of thioredoxin-1, total hydroperoxides, and redox potential in 60 pregnant women at the early third trimester: gestational age of 27-29 weeks. The thioredoxin-1 concentration (mean +/- SD) was 90 +/- 42 ng/ml. Total hydroperoxides was 471 +/- 105 U.CARR (1 U.CARR = 0.08 mg/dl H(2)O(2)). Redox potential was 2142 +/- 273 umol/l. The total hydroperoxides: redox potential ratio (oxidative stress index) was 0.23 +/- 0.08. Thioredoxin-1, total hydroperoxides, and oxidative stress index were higher and redox potential was lower than in blood of healthy adults. Total hydroperoxides and redox potential were mutually correlated significantly and negatively. Thioredoxin-1 correlated significantly and negatively and redox potential correlated significantly and positively with body weight and body mass index. Thioredoxin-1 and redox potential correlated significantly and positively with uric acid and albumin, respectively. Thioredoxin-1 and oxidative stress index correlated significantly and negatively and redox potential significantly and positively with neonatal birth weight. These results suggest that high concentrations of thioredoxin-1 are linked to high oxidative stress status in pregnant women and that neonatal birth weight is affected by the maternal oxidative condition during later pregnancy. PMID- 23341695 TI - Gamma-tocotrienol reduces the triacylglycerol level in rat primary hepatocytes through regulation of fatty acid metabolism. AB - The present study was carried out to investigate the effect of vitamin E analogs, especially gamma-tocotrienol (gamma-T3), on hepatic TG accumulation and enzymes related to fatty acid metabolism in three types of rat primary hepatocytes: (1) normal hepatocytes, (2) hepatocytes incubated in the presence of palmitic acid (PA), and (3) hepatocytes with fat accumulation. Our results showed that gamma-T3 significantly reduced the TG content of normal hepatocytes. gamma-T3 also increased the expression of carnitine palmitoyltransferase 1 (CPT1A) mRNA, and tended to reduce that of sterol regulatory element binding protein 1c (SREBP-1c) mRNA. In addition, gamma-T3 markedly suppressed the gene expression of both C/EBP homologous protein (CHOP) and SREBP-1c induced by PA. As these two genes are located downstream of endoplasmic reticulum (ER) stress, their suppression by gamma-T3 might result from a decrease of ER stress. Moreover, gamma-T3 suppressed the expression of interleukin 1beta (IL-1beta), which lies downstream of CHOP signaling. Taken together, our data suggest that gamma-T3 might prevent hepatic steatosis and ameliorate ER stress and subsequent inflammation in the liver. PMID- 23341696 TI - Serum uric acid and appropriate cutoff value for prediction of metabolic syndrome among Chinese adults. AB - The relation between serum uric acid and metabolic syndrome is observed not only with frank hyperuricemia but also with serum uric acid levels within the normal range. The current "normal" range set for hyperuricemia often fails to identify patients with potential metabolic disorders. We investigate the association between serum uric acid within the normal range and incident metabolic syndrome risk, and further to determine the optimal cut-off value of serum uric acid for the diagnosis or prediction of metabolic syndrome. A total of 7399 Chinese adults (2957 men and 4442 women; >=20 years) free of metabolic syndrome were followed for 3 years. During the 3-year follow-up, 1190 normouricemic individuals developed metabolic syndrome (16.1%). After adjusting the associated variables, the top quartile of serum uric acid levels was associated with higher metabolic syndrome development compared with the bottom quartile in men (hazard ratio (HR), 1.29; p<0.05) and women (HR, 1.62; p<0.05). ROC curve analysis indicated that the optimal cut-off values for serum uric acid to identify metabolic syndrome were 6.3 mg/dl in men and 4.9 mg/dl in women. Our results suggested that high baseline serum uric acid levels within the normal range predict future development of metabolic syndrome after 3 y of follow-up. PMID- 23341697 TI - Maternal protein restriction induces alterations in insulin signaling and ATP sensitive potassium channel protein in hypothalami of intrauterine growth restriction fetal rats. AB - It is well recognized that intrauterine growth restriction leads to the development of insulin resistance and type 2 diabetes mellitus in adulthood. To investigate the mechanisms behind this "metabolic imprinting" phenomenon, we examined the impact of maternal undernutrition on insulin signaling pathway and the ATP sensitive potassium channel expression in the hypothalamus of intrauterine growth restriction fetus. Intrauterine growth restriction rat model was developed through maternal low protein diet. The expression and activated levels of insulin signaling molecules and K(ATP) protein in the hypothalami which were dissected at 20 days of gestation, were analyzed by western blot and real time PCR. The tyrosine phosphorylation levels of the insulin receptor substrate 2 and phosphatidylinositol 3'-kinase p85alpha in the hypothalami of intrauterine growth restriction fetus were markedly reduced. There was also a downregulation of the hypothalamic ATP sensitive potassium channel subunit, sulfonylurea receptor 1, which conveys the insulin signaling. Moreover, the abundances of gluconeogenesis enzymes were increased in the intrauterine growth restriction livers, though no correlation was observed between sulfonylurea receptor 1 and gluconeogenesis enzymes. Our data suggested that aberrant intrauterine milieu impaired insulin signaling in the hypothalamus, and these alterations early in life might contribute to the predisposition of the intrauterine growth restriction fetus toward the adult metabolic disorders. PMID- 23341698 TI - Standardized chungkookjang, short-term fermented soybeans with Bacillus lichemiformis, improves glucose homeostasis as much as traditionally made chungkookjang in diabetic rats. AB - As the traditional homemade chungkookjang is replaced by standardized chungkookjang fermented by inoculating Bacillus spp., it is desirable to maintain the anti-diabetic efficacy of the most potent traditional varieties. Preliminary in vitro research suggested that anti-diabetic efficacy can be achieved by using B. lichemiformis as a starter and fermenting for 48 h. Experimental type 2 diabetic male rats induced by partial pancreatectomy and high fat diets were administered either control diet, 10% cooked soybeans, 10% traditional chungkookjang with potent anti-diabetic efficacy, or standardized chungkookjang fermented with B. lichemiformis for 48 h. Rats were fed their respective diets for 8 weeks after surgery. Cooked soybeans as well as both chungkookjangs partially restored fasting serum glucose concentrations, but only the chungkoojangs increased fasting insulin levels. That trend was also seen in the glucose-stimulated insulin secretion during hyperglycemic clamp and was explained by the greater beta-cell mass and BrdU incorporation indicating increased proliferation of beta-cells. The euglycemic hyperinsulinemic clamp indicated that all soy products improved insulin sensitivity. Phosphorylation of Akt and AMPK in the liver increased in an ascending order of the control, cooked soybeans, traditional chungkookjang and standardized chungkookjang while PEPCK expression was lowered in a descending order of the control, cooked soybeans, traditional chungkookjang and standardized chungkookjang. These results indicate that standardized chungkookjang is most effective for improving hepatic insulin signaling. In conclusion, chungkookjang fermented with B. lichemiformis retains the anti-diabetic properties of the most efficacious traditional chungkookjang and it may be even more effective for improving insulin function than traditionally prepared chungkookjang. PMID- 23341699 TI - Mild exercise suppresses exacerbation of dermatitis by increasing cleavage of the beta-endorphin from proopiomelanocortin in NC/Nga mice. AB - This study investigated the mechanism by which the strength and weakness of exercise stress affects the skin symptoms of atopic dermatitis (AD). Specific pathogen-free (SPF) and conventional NC/Nga mice were used. Conventional mice, but not the SPF, spontaneously develop dermal symptoms similar to that of patients with AD. There were two types of stress, mild (20 m/min for 60 min) or strong exercise (25 m/min for 90 min), using a treadmill four times per day. The symptom of the conventional group were strongly exacerbated by strong exercise but ameliorated by mild exercise. The plasma concentrations of alpha-melanocyte stimulating hormone (alpha-MSH) and the expression of melanocortin receptor-1 in skin elevated after strong exercise but decreased after mild exercise. The plasma levels of beta-endorphin and the expression of u-opioid receptor in skin were increased by mild exercise. In addition, the expression of prohormone convertase (PC) 1/3, PC2 and carboxypeptidase E (CPE) in pituitary gland were higher in the conventional group than in the SPF group. The level of PC2 was suppressed by mild exercise in the conventional groups, and elevated further by strong exercise. The level of PC1/3 becomes higher with the increase of the exercise load. On the other hand, the expression of the CPE was further increase by mild exercise but suppressed by strong exercise. These observations suggested that exercise-induced stress significantly affect the symptoms of AD in a pivotal manner depending on the levels of alpha-MSH and beta-endorphin, and the expression of pituitary PC2 and CPE. PMID- 23341700 TI - Effects of anticancer agents on cell viability, proliferative activity and cytokine production of peripheral blood mononuclear cells. AB - We investigated the effects of anticancer agents on peripheral blood mononuclear cells for the purpose of providing data to support new translational chemoimmunotherapy regimens. Peripheral-blood mononuclear cells were treated with one of four anticancer agents (5-fluorouracil, irinotecan, cisplatin, and gemcitabine) for 2 h, after which cell viability was determined. For assessment of effects of each drug on proliferation and cytokine production, cells were stimulated with phytohemagglutinin for 48 h. As a result, the anticancer agents did not affect cell viability. Cell proliferation was unaffected by 5 fluorouracil and irinotecan but inhibited by cisplatin and gemcitabine. Treatment with gemcitabine enhanced the production of IFN-gamma and decreased the number of regulatory T cells. gemcitabine treatment increased IFN-gamma production among CD4 T cells but not among CD8 T cells. The results indicated that GEM had immunoregulatory properties that might support immune response against cancer. This finding has implications for designing chemoimmunotherapy strategies. PMID- 23341701 TI - Neutralization of complement component C5 ameliorates the development of dextran sulfate sodium (DSS)-colitis in mice. AB - The complement system is a potent effector of innate immunity. To elucidate the pathophysiological role of the complement system in inflammatory bowel disease, we evaluated the effects of anti-C5 antibodies on the development of dextran sulfate sodium-induced colitis in mice. Dextran sulfate sodium-colitis was induced in BALB/c mice with intraperitoneal administrations of anti-C5 antibodies (1 mg/body [DOSAGE ERROR CORRECTED]) every 48 h. Tissue samples were evaluated by standard histological procedures. The mucosal mRNA expression of the inflammatory cytokines was analyzed by real-time PCR. Body weight loss in the mice was completely blocked by the administration of anti-C5 antibody. The disease activity index was significantly lower in the anti-C5 antibody-treated mice than the dextran sulfate sodium mice. The colonic weight/length ratio, histological colitis score and mucosal myeloperoxidase activity were significantly lower in the anti-C5 antibody-treated mice than the dextran sodium sulfate mice. The administration of the anti-C5 antibody significantly reduced the mucosal expression of mRNAs for tumor necrosis factor-alpha, interleukin-1beta and interleukin-6. In conclusion, the complement system plays a role in the development of dextran sodium sulfate-induced experimental colitis. PMID- 23341702 TI - The daily response for proton pump inhibitor treatment in Japanese reflux esophagitis and non-erosive reflux disease. AB - We investigated comparison according to reflux esophagitis and non-erosive reflux disease about "daily" symptom improvement for proton pump inhibitor treatment. We enrolled 57 reflux esophagitis and 90 non-erosive reflux disease patients. They took rabeprazole 10 mg/day for 28 days and completed "daily" in the Frequency Scale for the Symptoms of GERD from baseline until day 14, and after 28 days of treatment. The efficacy endpoint was the improvement rates in Frequency Scale for the Symptoms of GERD, based on baseline. Frequency Scale for the Symptoms of GERD was decreased in reflux esophagitis and non-erosive reflux disease (p<0.001) and was significantly lower in reflux esophagitis than in non-erosive reflux disease from the first day of treatment (p<0.05). Symptomatic improvement rates were also significantly higher in reflux esophagitis (50.3 +/- 44.9%) than in non-erosive reflux disease (31.7 +/- 43.2%) from the first day of treatment (p<0.0001). The symptomatic improvement rates in reflux esophagitis were significant increased from the second day of treatment until after 28 days of treatment (p = 0.0006), however, these in non-erosive reflux disease were significant increased from third days until after 28 days of treatment (p = 0.0002). In non-erosive reflux disease, the improvement of dysmotility symptom was particularly gradual as well as of reflux symptom, too. As for results of prediction of proton pump inhibitor response (completed symptom resolution) form early symptom improvement within 1 week, it was able to predict proton pump inhibitor response from the symptom improvement rate on 3 days in reflux esophagitis and on day 7 in non-erosive reflux disease. In conclusion, the prediction of the proton pump inhibitor response in non-erosive reflux disease was slow in comparison with reflux esophagitis. The cause was gradual improvement of dysmotility symptom. PMID- 23341703 TI - Comparison of the relationships of alcoholic and nonalcoholic fatty liver with hypertension, diabetes mellitus, and dyslipidemia. AB - We compared the relationships of alcoholic fatty liver and nonalcoholic fatty liver with hypertension, diabetes mellitus, and dyslipidemia. Using a nationwide Japanese survey, we collected data on subjects with biopsy-proven alcoholic fatty liver or nonalcoholic fatty liver. Multiple logistic regression analysis was performed to determine whether alcoholic fatty liver and nonalcoholic fatty liver are associated factors for these diseases. Data on 191 subjects (65, alcoholic fatty liver; 126, nonalcoholic fatty liver) were analyzed. Alcoholic fatty liver (odds ratio, 2.54; 95% confidence interval, 1.06-6.32; p = 0.040), age >=55 years, and body mass index >=25 kg/m(2) were correlated with hypertension, whereas nonalcoholic fatty liver (odds ratio, 2.32; 95% confidence interval, 1.08 5.20; p = 0.035) and serum gamma-glutamyl transpeptidase levels >=75 IU/l were correlated with dyslipidemia. Furthermore, we found that there were biological interactions between alcoholic fatty liver and body mass index >=25 kg/m(2) in >=55-year-old subjects (attributable proportion due to interaction, 0.68; 95% confidence interval, 0.19-1.17), as well as between alcoholic fatty liver and age >=55 years in subjects with body mass index >=25 kg/m(2) (attributable proportion due to interaction, 0.71; 95% confidence interval, 0.24-1.18). Alcoholic fatty liver was more strongly associated with hypertension than nonalcoholic fatty liver and nonalcoholic fatty liver was more strongly associated with dyslipidemia than alcoholic fatty liver. Moreover, alcoholic fatty liver, obesity, and older age may interact to influence hypertension status. PMID- 23341704 TI - Arm span-height difference is correlated with gastroesophageal reflux symptoms in aged Japanese subjects. AB - Previous studies have indicated an association between the symptoms of gastroesophageal reflux disease (GERD) and aging plus height. In this study we investigated whether the arm span-height difference was related to GERD symptoms with a focus on aged subjects in the general population, since the arm span reflects the height in young adulthood before decreasing due to vertebral deformities from aging. A total of 285 elderly individuals (105 females) who visited nursing homes for the elderly in Japan were enrolled in this study. The GERD symptoms were evaluated by the Frequency Scale for the Symptoms of GERD (FSSG). The body weight, height and arm span were measured, and information regarding medications and complications were reviewed in each nursing record. 50.5% of women had more than 3 cm of arm span-height difference. In contrast, only 37.3% of men had more than 3 cm of arm span-height difference. The FSSG scores indicated more than 70% of subjects complained of any GERD symptoms. There was a significant correlation between the FSSG score and the arm span-height difference in the subjects with more than 3 cm of arm span-height difference (r = 0.236; p = 0.012). The correlation between the arm span-height difference and the FSSG score was significant only in women in females in the present study. In conclusion, our findings indicate that vertebral deformity evaluated by the arm span-height difference might have some positive relationship to the pathogenesis of GERD symptoms in elderly Japanese individuals. PMID- 23341705 TI - Life-sustaining medical treatment for terminal patients in Korea. PMID- 23341706 TI - Clinical implications of pneumococcal serotypes: invasive disease potential, clinical presentations, and antibiotic resistance. AB - Streptococcus pneumoniae can asymptomatically colonize the nasopharynx and cause a diverse range of illnesses. This clinical spectrum from colonization to invasive pneumococcal disease (IPD) appears to depend on the pneumococcal capsular serotype rather than the genetic background. According to a literature review, serotypes 1, 4, 5, 7F, 8, 12F, 14, 18C, and 19A are more likely to cause IPD. Although serotypes 1 and 19A are the predominant causes of invasive pneumococcal pneumonia, serotype 14 remains one of the most common etiologic agents of non-bacteremic pneumonia in adults, even after 7-valent pneumococcal conjugate vaccine (PCV7) introduction. Serotypes 1, 3, and 19A pneumococci are likely to cause empyema and hemolytic uremic syndrome. Serotype 1 pneumococcal meningitis is prevalent in the African meningitis belt, with a high fatality rate. In contrast to the capsule type, genotype is more closely associated with antibiotic resistance. CC320/271 strains expressing serotype 19A are multidrug resistant (MDR) and prevalent worldwide in the era of PCV7. Several clones of MDR serotype 6C pneumococci emerged, and a MDR 6D clone (ST282) has been identified in Korea. Since the pneumococcal epidemiology of capsule types varies geographically and temporally, a nationwide serosurveillance system is vital to establishing appropriate vaccination strategies for each country. PMID- 23341708 TI - Social inequality in birth outcomes in Korea, 1995-2008. AB - Social inequality in adverse birth outcomes has been demonstrated in several countries. The present study examined the separate and joint effects of parental education and work in order to investigate the causal pathways of social class effects on adverse birth outcomes in Korea. The occurrence of low birth weight, preterm births, and intrauterine growth retardation was examined among 7,766,065 births in Korea from 1995 to 2008. The effect of social inequality, as represented by parental education and work, was examined against adverse birth outcomes using multivariate logistic regression after controlling for other covariates. Parental education had the most significant and greatest effect on all three adverse outcomes, followed by parental work and employment, which had lesser effects. For adverse birth outcomes, the gap between educational levels increased steadily in Korea from 1995 to 2008. Throughout the analysis, the effect of maternal manual work on adverse birth outcomes was apparent in the study results. Given this evidence of social inequality in education and employment, social interventions should aim at more in-depth and distal determinants of health. PMID- 23341707 TI - Trends in the incidence of hospitalized acute myocardial infarction and stroke in Korea, 2006-2010. AB - This study attempted to calculate and investigate the incidence of hospitalized acute myocardial infarction (AMI) and stroke in Korea. Using the National Health Insurance claim data, we investigated patients whose main diagnostic codes included AMI or stroke during 2006 to 2010. As a result, we found out that the number of AMI hospitalized patients had decreased since 2006 and amounted to 15,893 in 2010; and that the number of those with stroke had decreased since 2006 and amounted to 73,501 in 2010. The age-standardized incidence rate of hospitalized AMI, after adjustment for readmission, was 41.6 cases per 100,000 population in 2006, and had decreased to 29.4 cases in 2010 (for trend P < 0.001). In the case of stroke was estimated at 172.8 cases per 100,000-population in 2006, and had decreased to 135.1 cases in 2010 (for trend P < 0.001). In conclusion, the age-standardized incidence rates of both hospitalized AMI and stroke in Korea had decreased continuously during 2006 to 2010. We consider this decreasing trend due to the active use of pharmaceuticals, early vascular intervention, and the national cardio-cerebrovascular disease care project as the primary and secondary prevention efforts. PMID- 23341709 TI - Respiratory viral infections after hematopoietic stem cell transplantation in children. AB - This study was performed to characterize respiratory viral infections in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Study samples included 402 respiratory specimens obtained from 358 clinical episodes that occurred in the 116 children of the 175 consecutive HSCT cohort at Seoul National University Children's Hospital, Korea from 2007 to 2010. Multiplex reverse-transcription polymerase chain reactions were performed for rhinovirus, respiratory syncytial virus (RSV), parainfluenza viruses (PIVs), adenovirus, human coronavirus (hCoV), influenza viruses and human metapneumovirus. Viruses were identified in 89 clinical episodes that occurred in 58 patients. Among the 89 clinical episodes, frequently detected viruses were rhinovirus in 25 (28.1%), RSV in 23 (25.8%), PIV-3 in 16 (18.0%), adenovirus in 12 (13.5%), and hCoV in 10 (11.2%). Lower respiratory tract infections were diagnosed in 34 (38.2%). Neutropenia was present in 24 (27.0%) episodes and lymphopenia was in 31 (34.8%) episodes. Sixty-three percent of the clinical episodes were hospital-acquired. Three patients died of respiratory failure caused by respiratory viral infections. Respiratory viral infections in pediatric patients who have undergone HSCT are common and are frequently acquired during hospitalization. Continuous monitoring is required to determine the role of respiratory viruses in immunocompromised children and the importance of preventive strategies. PMID- 23341710 TI - Pediatric liver transplantation outcomes in Korea. AB - Pediatric liver transplantation is the standard of care for treatment of liver failure in children. The aim of this study was to identify the characteristics of pediatric liver transplantation in centers located in Korea and determine factors that influence outcomes. This retrospective study was performed using data from between 1988 and 2010 and included all recipients 18 yr old and younger who underwent pediatric liver transplantation in Korea during that period. Our data sources were hospital medical records and the outcome measure was overall patient survival. Univariate and multivariate statistical analyses were undertaken using the Cox proportional hazards model. Five hundred and thirty-four pediatric liver transplantations were performed in 502 children. Median age and average pediatric end-stage liver disease (PELD) score were 20 months and 18 point, respectively. Biliary atresia (57.7%, 308/534) was the most common cause of liver disease. Eighty-two (15.3%) were deceased donor liver transplantations and 454 (84.7%) were living donor liver transplantations. Retransplantation was performed in 32 cases (6%). Overall, 1-, 5-, and 10-yr patient survival rates were 87.8%, 82.2%, and 78.1%, respectively. In multivariate analysis, independent significant predictors of poor patient survival were chronic rejection and retransplantation. This study presents the epidemiologic data for nearly all pediatric liver transplantation in Korea and shows that the independent prognostic factors in patient survival are chronic rejection and retransplantation. PMID- 23341711 TI - Serum cystatin C is a major predictor of vancomycin clearance in a population pharmacokinetic analysis of patients with normal serum creatinine concentrations. AB - We developed a population pharmacokinetic model of vancomycin by integrating the effects of cystatin C and other demographic factors in a large population of Korean patients with normal serum creatinine concentrations to elucidate the precise role of serum cystatin C concentrations in the prediction of vancomycin clearance. A population pharmacokinetic model of vancomycin was developed using NONMEM software from a total of 1,373 vancomycin concentration measurements in 678 patients whose serum creatinine concentrations were lower than 1.2 mg/dL. Covariate selection revealed that cystatin C was the most influential factor and had negative influence ((-0.78)) in the relationship. Total body weight, sex, age, and serum creatinine were also significantly correlated with the clearance. The estimated intersubject variabilities of clearance and volume of distribution were 24.7% and 25.1%, respectively. A 14-fold difference in predicted trough concentrations was observed according to only cystatin C concentrations in a population of simulated individuals with median demographic characteristics. The use of serum cystatin C as marker of vancomycin clearance for more accurate predictions of serum vancomycin concentrations could be useful, particularly among patients with normal serum creatinine concentrations. PMID- 23341712 TI - Changes in anti-group a rotavirus antibody seroprevalence and levels in the Western Gyeongnam province of Korea over 16 years. AB - To observe how anti-group A rotavirus antibody seropositivity rates and levels have changed in the western region of Gyeongnam Province, 2,030 serum samples collected at four collection periods (1989-1990, 1994-1995, 1999-2000, and 2004 2005) were tested by Enzyme-Linked Immunosorbent Assay for IgG, and IgA antibodies reacting to recombinant VP6 protein. The seroprevalences exhibit no regular patterns over a 16-yr period. For all four collection periods, the anti rVP6 IgG levels rose steadily during the first 5 months of life, after which they remained high. However, the 2-9 yr and 10-39 yr groups had significantly higher IgG levels in 1999-2000 and 2004-2005, respectively, than in the other collection periods. The 1-5 mo, 40- >= 60 yr, and 4-29 yr groups had significantly higher IgA levels in 1989-1990, 1999-2000, and 2004-2005, respectively. The 4 yr (25.0%), 5-9 yr (18.8%), 10-14 yr (41.1%), 20-29 yr (35.0%), and 30-39 yr (20.0%) groups in 2004-2005 had significant higher IgA seropositivity rate compared to the other three collection periods. These observations suggest that in the western region of Gyeongnam Province since the late 1990s, rotavirus reinfection has occurred more frequently than previously, with all ages being at risk. PMID- 23341713 TI - Antimicrobial susceptibility of stenotrophomonas maltophilia isolates from Korea, and the activity of antimicrobial combinations against the isolates. AB - The aim of this study was to determine antimicrobial susceptibility of recent clinical Stenotrophomonas maltophilia isolates from Korea, and to compare the activity levels of several combinations of antimicrobials. A total of 206 non duplicate clinical isolates of S. maltophilia was collected in 2010 from 11 university hospitals. Antimicrobial susceptibility testing was performed using the Clinical Laboratory Standards Institute agar dilution method. In vitro activity of antimicrobial combinations was tested using the checkerboard method. The susceptibility rates to trimethoprim-sulfamethoxazole and minocycline were 96% and 99%, respectively. The susceptibility rate to levofloxacin was 64%. All of four antimicrobial combinations showed synergy against many S. maltophilia isolates. A combination of trimethoprim-sulfamethoxazole plus ticarcillin clavulanate was most synergistic among the combinations. None of the combinations showed antagonistic activity. Therefore, some of the combinations may be more useful than individual drugs in the treatment of S. maltophilia infection. Further clinical studies are warranted to validate our in vitro test results. PMID- 23341714 TI - Trends of mortality and cause of death among HIV-infected patients in Korea, 1990 2011. AB - Although a decrease in acquired immunodeficiency syndrome (AIDS)-related mortality has been documented in highly active antiretroviral therapy (HAART) era, there are no published data comparing specific causes of death between pre HAART and HAART era in Korea. Mortality and cause of death were analyzed in three treatment periods; pre-HAART (1990-1997), early-HAART (1998-2001), and late-HAART period (2002-2011). The patients were retrospectively classified according to the treatment period in which they were recruited. Although mortality rate per 100 person-year declined from 8.7 in pre-HAART to 4.9 in late-HAART period, the proportion of deaths within 3 months of initial visit to study hospital significantly increased from 15.9% in pre-HAART to 55.1% in late-HAART period (P < 0.001). Overall, 59% of deaths were attributable to AIDS-related conditions, and Pneumocystis pneumonia (PCP) was the most common cause of death (20.3%). The proportion of PCP as cause of death significantly increased from 8.7% in pre HAART to 31.8% in late-HAART period (P < 0.001). Despite of significant improvement of survival, there was still a high risk of early death in patients presenting in HAART era, mainly due to late human immunodeficiency virus (HIV) diagnosis and late presentation to care. PMID- 23341715 TI - The indoor level of house dust mite allergen is associated with severity of atopic dermatitis in children. AB - We attempted to investigate the correlation between the severity of atopic dermatitis (AD) in children and the indoor level of house dust mite (HDM) allergens. Ninety-five patients (31.1 +/- 19.5 months of age) with AD were enrolled in this study, and serum specific IgE against Dermatophagoides pteronyssinus and D. farinae was measured. The severity of AD was assessed using the visual analogue scale on the same day of house dust collection. Living rooms and mattresses where the child usually slept were vacuumed for 2 minutes and concentrations of Der f 1 were measured by enzyme-linked immunosorbent assay. The skin symptoms were more severe in patients with Der f 1 concentrations in living room > 2 ug/g dust than <= 2 ug/g dust (P = 0.018). This difference was noted in AD patients without sensitization to HDM (P = 0.004), but not in patients with sensitization. There was no difference in symptom severity according to Der f 1 concentrations in mattresses (P = 0.062). The severity of skin symptoms is associated with indoor concentrations of HDM in children with AD, and it is likely to act as nonspecific irritants as well as allergens in AD skin lesions. PMID- 23341716 TI - Early response to bortezomib combined chemotherapy can help predict survival in patients with multiple myeloma who are ineligible for stem cell transplantation. AB - Novel agents to treat multiple myeloma (MM) have increased complete respone (CR) rates compared with conventional chemotherapy, and the quality of the response to treatment has been correlated with survival. The purpose of our study was to show how of early response to bortezomib combined chemotherapy influences survival in patients with newly diagnosed MM who are ineligible for stem cell transplantation. We assessed patient responses to at least four cycles of bortezomib using the International Myeloma Working Group response criteria. The endpoints were comparisons of progression free survival (PFS) and overall survival (OS) between early good response group (A group) and poor response group (B group). We retrospectively analyzed data from 129 patients registered by the Korean Multiple Myeloma Working Party, a nationwide registration of MM patients. The 3 yr PFS for the A and B groups was 55.6% and 18.4%, respectively (P < 0.001). The 3 yr OS for the A and B groups was 65.3% and 52.9%, respectively (P = 0.078). The early response to at least four cycle of bortezomib before next chemotherapy may help predict PFS in patients with MM who are ineligible stem cell transplantation. PMID- 23341717 TI - Peripheral artery disease in korean patients undergoing percutaneous coronary intervention: prevalence and association with coronary artery disease severity. AB - Peripheral artery disease (PAD) is an important marker for the risk stratification of patients with coronary artery disease (CAD). We investigated the prevalence of PAD in patients undergoing percutaneous coronary intervention (PCI) with CAD and the relationship between ankle-brachial pressure index (ABPI) and CAD severity. A total of 711 patients undergoing PCI for CAD from August 2009 to August 2011 were enrolled. PAD diagnosis was made using the ABPI. The prevalence of PAD was 12.8%. In PAD patients, mean values of right and left ABPI were 0.71 +/- 0.15 and 0.73 +/- 0.15. Patients with PAD had a higher prevalence of left main coronary disease (14.3% vs 5.8%, P = 0.003), more frequently had multivessel lesions (74.9% vs 52.1%, P < 0.001) and had higher SYNTAX score (18.2 +/- 12.3 vs 13.1 +/- 8.26, P = 0.002). Using multivariate analysis, we determined that left main CAD (OR, 2.954; 95% CI, 1.418-6.152, P = 0.004) and multivessel CAD (OR, 2.321; 95% CI, 1.363-3.953, P = 0.002) were both independently associated with PAD. We recommend that ABPI-based PAD screening should be implemented in all patients undergoing PCI with CAD, especially in severe cases. PMID- 23341718 TI - Computational quantification of the cardiac energy consumption during intra aortic balloon pumping using a cardiac electromechanics model. AB - To quantify the reduction in workload during intra-aortic balloon pump (IABP) therapy, indirect parameters are used, such as the mean arterial pressure during diastole, product of heart rate and peak systolic pressure, and pressure-volume area. Therefore, we investigated the cardiac energy consumption during IABP therapy using a cardiac electromechanics model. We incorporated an IABP function into a previously developed electromechanical model of the ventricle with a lumped model of the circulatory system and investigated the cardiac energy consumption at different IABP inflation volumes. When the IABP was used at inflation level 5, the cardiac output and stroke volume increased 11%, the ejection fraction increased 21%, the stroke work decreased 1%, the mean arterial pressure increased 10%, and the ATP consumption decreased 12%. These results show that although the ATP consumption is decreased significantly, stroke work is decreased only slightly, which indicates that the IABP helps the failed ventricle to pump blood efficiently. PMID- 23341719 TI - The role of urinary liver-type fatty acid-binding protein in critically ill patients. AB - Although several urinary biomarkers have been validated as early diagnostic markers of acute kidney injury (AKI), their usefulness as outcome predictors is not well established. This study aimed to determine the diagnostic and prognostic abilities of urinary liver-type fatty acid-binding protein (L-FABP) in heterogeneous critically ill patients. We prospectively collected data on patients admitted to medical and surgical intensive care units (ICUs) from July 2010 to June 2011. Urine neutrophil gelatinase-associated lipocalin (NGAL) and L FABP at the time of ICU admission were quantitated. Of the 145 patients, 54 (37.2%) had AKI defined by the Acute Kidney Injury Network (AKIN) criteria. AKI patients showed significantly higher level of urinary NGAL and L-FABP and also higher mortality than non-AKI patients. The diagnostic performances, assessed by the area under the ROC curve, were 0.773 for NGAL and 0.780 for L-FABP, demonstrating their usefulness in diagnosing AKI. In multivariate Cox analysis, urinary L-FABP was an independent predictor for 90-day mortality. Urinary L-FABP seems to be promising both for the diagnosis of AKI and for the prediction of prognosis in heterogeneous ICU patients. It needs to be further validated for clinical utility. PMID- 23341720 TI - Growth after hematopoietic stem cell transplantation in children with acute myeloid leukemia. AB - Previous studies have shown that hematopoietic stem cell transplantation (HSCT) may result in growth impairment. The purpose of this study was to evaluate the growth during 5 yr after HSCT and to determine factors that influence final adult height (FAH). We retrospectively reviewed the medical records of acute myeloid leukemia (AML) patients who received HSCT. Among a total of 37 eligible patients, we selected 24 patients who began puberty at 5 yr after HSCT (Group 1) and 19 patients who reached FAH without relapse (Group 2). In Group 1, with younger age at HSCT, sex, steroid treatment, hypogonadism and hypothyroidism were not significantly associated with growth impairment 5 yr after HSCT. History of radiotherapy (RT) significantly impaired the 5 yr growth after HSCT. Chronic graft-versus-host disease (cGVHD) only temporarily impaired growth after HSCT. In Group 2, with younger age at HSCT, steroid treatment and hypogonadism did not significantly reduce FAH. History of RT significantly reduced FAH. Growth impairment after HSCT may occur in AML patients, but in patients without a history of RT, growth impairment seemed to be temporary and was mitigated by catch-up growth. PMID- 23341721 TI - Prognostic usefulness of eosinopenia in the pediatric intensive care unit. AB - Eosinopenia, a biomarker for infection, has recently been shown to be a predictor of adult mortality in the intensive care unit (ICU). Our study assessed the usefulness of eosinopenia as a mortality and an infection biomarker in the pediatric ICU (PICU). We compared the PICU mortality scores, eosinophil count and percentage at ICU admission between children who survived and those who did not survive and between children with infection and those without infection. A total of 150 patients were evaluated. The initial eosinophil count and percentage were significantly lower in the group that did not survive when compared to those that did survive (P < 0.001; P < 0.001). However, there was no significant difference in the eosinophil count and percentage seen in patients with and without infection. Eosinopenia, defined as an eosinophil count < 15 cells/uL and an eosinophil percentage < 0.25%, (hazard ratio [HR]: 2.96; P = 0.008) along with a Pediatric Index of Mortality (PIM) 2 (HR: 1.03; P = 0.004) were both determined to be independent predictors of mortality in the PICU. The presence of eosinopenia at the ICU admission can be a useful biomarker for mortality in children, but is not useful as a biomarker for infection. PMID- 23341722 TI - Risk factors for neurologic complications of hand, foot and mouth disease in the Republic of Korea, 2009. AB - In 2009, the first outbreak of hand, foot and mouth disease (HFMD) or herpangina (HP) caused by enterovirus 71 occurred in the Republic of Korea. This study inquired into risk factors associated with complications of HFMD or HP. A retrospective medical records review was conducted on HFMD or HP patients for whom etiologic viruses had been verified in 2009. One hundred sixty-eight patients were examined for this investigation. Eighty patients were without complications while 88 were accompanied by complications, and 2 had expired. Enterovirus 71 subgenotype C4a was the most prevalent in number with 67 cases (54.9%). In the univariate analysis, the disease patterns of HFMD rather than HP, fever longer than 4 days, peak body temperature over 39C, vomiting, headache, neurologic signs, serum glucose over 100 mg/dL, and having an enterovirus 71 as a causative virus were significant risk factors of the complications. After multiple logistic analysis, headache (Odds ratio [OR], 10.75; P < 0.001) and neurologic signs (OR, 42.76; P < 0.001) were found to be the most significant factors. Early detection and proper management of patients with aforementioned risk factors would be necessary in order to attain a better clinical outcome. PMID- 23341723 TI - Prevalence and correlates of depressive symptoms in korean adults: results of a 2009 korean community health survey. AB - The aim of this study was to investigate the prevalence and correlates of depressive symptoms in the largest number of Korean individuals examined to date. We analyzed cross-sectional data collected from 229,595 Korean adults aged 19 yr and above who participated in a Korean Community Health Survey conducted in 2009. The Center for Epidemiologic Studies Depression Scale (CES-D) was used as the measurement tool for depressive symptoms (CES-D score over 16) and definite depression (CES-D score over 25). Multivariate logistic regression analysis was performed to identify associations between sociodemographic factors and depressive symptoms. The percentages of depressive symptoms and definite depression in the total study population were 11% (7.8% for men, 14.0% for women) and 3.7%, (2.4% for men, 5.0% for women), respectively. Female gender, older age, disrupted marital status, low education and income level, multigenerational household composition and metropolitan residence were associated with greater risk of depressive symptoms. The present study provides a valid prevalence and correlates of depressive symptoms, using the largest representative sample of the Korean general population to date. Various sociodemographic factors contribute to the prevalence and effects of depressive symptoms in Korea. PMID- 23341725 TI - Tinea incognito in Korea and its risk factors: nine-year multicenter survey. AB - Tinea incognito (TI) is a dermatophytic infection which has lost its typical clinical appearance because of improper use of steroids or calcineurin inhibitors. The incidence of TI is increasing nowadays. We conducted retrospective review on 283 patients with TI from 25 dermatology training hospitals in Korea from 2002-2010 to investigate the demographical, clinical, and mycological characteristics of TI, and to determine the associated risk factors. More than half (59.3%) patients were previously treated by non-dermatologists or self-treated. The mean duration of TI was 15.0 +/- 25.3 months. The most common clinical manifestations were eczema-like lesion, psoriasis-like, and lupus erythematosus-like lesion. The trunk and face were frequently involved, and 91 patients (32.2%) also had coexisting fungal infections. Among 67 isolated strains, Trichophyton rubrum was the most frequently detected (73.1%). This is the largest study of TI reported to date and the first investigational report concerning TI in Korea. We suggest that doctors should consider TI when a patient has intractable eczema-like lesions accompanied by tinea pedis/unguium. Furthermore, there should be a policy change, which would make over-the-counter high-potency topical steroids less accessible in some countries, including Korea. PMID- 23341724 TI - Baseline characteristics and risk factors of retinal vein occlusion: a study by the Korean RVO Study Group. AB - We investigated the demographic characteristics and risk factors of Korean patients with naIve central or branch retinal vein occlusion (CRVO or BRVO). This study enrolled 41 clinical sites throughout Korea and included 557 consecutive patients with retinal vein occlusion (RVO) from May through November 2010. A total of 557 patients with new-onset RVO participated in this study. Two hundred and three (36.4%) patients were diagnosed with CRVO and 354 (63.6%) patients were diagnosed with BRVO. Comparisons between the two groups showed that the prevalence of diabetes mellitus was significantly higher in CRVO patients and hypertension was significantly higher in BRVO patients (P = 0.001 and 0.002, respectively). Poor baseline visual acuity was significantly associated with female and old age in BRVO patients (P = 0.002 and 0.013, respectively), whereas the wide intraretinal hemorrhage (CRVO, P = 0.029; BRVO, P < 0.001) and the macular ischemia (CRVO, P < 0.001; BRVO, P < 0.001) were associated with both groups. The study results show the clinical features of RVO in Korean patients. Hypertension is strongly associated with BRVO and diabetes mellitus is more strongly associated with CRVO in Korean patients with RVO. As the first nationwide study performed by the Korean Retinal Society, the results of this study can be applied to future studies on RVO. PMID- 23341726 TI - An adult case of Fisher syndrome subsequent to Mycoplasma pneumoniae infection. AB - Reported herein is an adult case of Fisher syndrome (FS) that occurred as a complication during the course of community-acquired pneumonia caused by Mycoplasma pneumoniae. A 38-yr-old man who had been treated with antibiotics for serologically proven M. pneumoniae pneumonia presented with a sudden onset of diplopia, ataxic gait, and areflexia. A thorough evaluation including brain imaging, cerebrospinal fluid examination, a nerve conduction study, and detection of serum anti-ganglioside GQ1b antibody titers led to the diagnosis of FS. Antibiotic treatment of the underlying M. pneumoniae pneumonia was maintained without additional immunomodulatory agents. A complete and spontaneous resolution of neurologic abnormalities was observed within 1 month, accompanied by resolution of lung lesions. PMID- 23341727 TI - A Case of medullary thyroid carcinoma with de novo V804M RET germline mutation. AB - Many cases of RET proto-oncogene mutations of hereditary medullary thyroid carcinoma (MTC) have been reported in Korea. However, MTC with V804M RET proto oncogene germline mutations have not been reported in Korea. A 33-yr-old man was diagnosed with a 0.7-cm sized thyroid nodule. Laboratory testing revealed serum calcitonin was elevated. The patient underwent total thyroidectomy with central compartment neck dissection for the thyroid tumor. RET gene analysis was performed in both the index patient and his family. There were no V804M RET mutation and abnormal laboratory findings within his family except the index patient. Therefore, this patient was a de novo V804M RET germline mutation. PMID- 23341728 TI - A case of congenital infantile fibrosarcoma of sigmoid colon manifesting as pneumoperitoneum in a newborn. AB - Congenital infantile fibrosarcoma (CIF) is a rare soft-tissue tumor in the pediatric age group and seldom involves the gastrointestinal tract. A 2-day-old boy was transferred to our hospital with a pneumpoperitoneum. After emergency operation, we could find a solid mass wrapping around a sigmoid colon and performed a segmental resection of sigmoid colon including a mass. Histopathologic examination showed an infantile fibrosarcoma origining from the muscular layer of colon. The baby was discharged on the 17th hospital day and followed for 1 yr without recurrence. PMID- 23341729 TI - A case of hypersensitivity to mosquito bites without peripheral natural killer cell lymphocytosis in a 6-year-old Korean boy. AB - Hypersensitivity to mosquito bites (HMB) is a rare disease characterized by intense skin reactions such as bulla and necrotic ulcerations at bite sites, accompanied by general symptoms such as high-grade fever and malaise occurred after mosquito bites. It has been suggested that HMB is associated with chronic Epstein-Barr virus (EBV) infection and natural killer (NK) cell leukemia/lymphoma. We describe here a Korean child who presented with 3-yr history of HMB without natural killer cell lymphocytosis. He has been ill for 6 yr with HMB. Close observation and examination for the development of lymphoproliferative status or hematologic malignant disorders is needed. PMID- 23341730 TI - Subacute course of common iliac arterial laceration in lumbar disc surgery. AB - Vascular injuries in lumbar disc surgery are serious complications which may be overlooked due to a broad range of clinical manifestations. It is important to be aware of the perioperative implications of this rare occurrence to lower mortality risk. A 20-yr-old man with a right L4-5 lumbar disc protrusion was operated on routinely under a surgical microscope. A bloody surgical field was noted temporarily during a discectomy along with a decreased blood pressure. After fluid resuscitation with an ephedrine injection, the bleeding soon stopped spontaneously and his vital signs were stabilized. Fifty hours after the operation, the patient showed signs of hypovolemic hypotension with abdominal distension. The right femoral artery pulsation was absent on palpation. An enhanced CT angiography revealed a retroperitoneal hematoma and obstruction of the left common iliac artery. An urgent laparotomy was done to repair the injured vessel by excision and interposition of a graft. The patient had an uneventful recovery.The subacute course of deterioration might have been due to intermittent blood leakage from the lacerated common iliac artery, which was sealed spontaneously. It is very important to pay close attention to post-surgical clinical manifestations to avoid a potentially fatal outcome in lumbar disc surgery. PMID- 23341731 TI - Primary probing for congenital nasolacrimal duct obstruction with manually curved Bowman probes. AB - PURPOSE: To evaluate the effect of the shape of Bowman probes on the success of primary probing for congenital nasolacrimal duct obstruction. MATERIALS AND METHODS: Records of 42 nasolacrimal duct obstructions in 37 children who underwent probing with straight Bowman probes (group A) and 128 nasolacrimal duct obstructions in 110 children who underwent probing with Bowman probes manually bent to mimic the natural curve of the bony nasolacrimal pathway (group B) were evaluated and compared. All children were under 2 years of age. The main outcome was successful probing. Successful probing was defined as a complete resolution of signs and symptoms. RESULTS: The mean age of the patients was 16.4 +/- 4.1 months (range 8-24 months) in group A and 16.8 +/- 4.2 months (range 7-24 months) in group B. No canalicular or nasolacrimal sac pathologies were diagnosed during probing. The success rate was 76.2% (32/42) in group A and 91.4% (117/128) in group B. The difference was statistically significant (P < 0.01). CONCLUSION: Manually curved probes can be used efficiently during probing and increase the success rates. PMID- 23341732 TI - New treatments for myasthenia: a focus on antisense oligonucleotides. AB - Autoimmune myasthenia gravis (MG) is a neuromuscular disorder caused by autoantibodies directed against the acetylcholine receptor (AChR). Current symptomatic therapy is based on acetylcholinesterase (AChE) drugs. The available long-term current therapy includes steroids and other immunomodulatory agents. MG is associated with the production of a soluble, rare isoform of AChE, also referred as the "read-through" transcript (AChE-R). Monarsen (EN101) is a synthetic antisense compound directed against the AChE gene. Monarsen was administered in 16 patients with MG and 14 patients achieved a clinically significant response. The drug is now in a Phase II study. Further investigations are required to confirm its long-term effects. PMID- 23341733 TI - Impact of ghrelin on vitreous cytokine levels in an experimental uveitis model. AB - BACKGROUND: The purpose of this study was to investigate the effect of intraperitoneal ghrelin on vitreous levels of interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-alpha) and to compare its effects with those of intraperitoneal infliximab in an experimental uveitis model. METHODS: Twenty-four male rats were assigned to four groups of six rats in each. All the rats, except for those in group 1 (controls), were injected intravitreally with concanavalin A to induce experimental uveitis. Rats in group 2 (sham) were not given any treatment after uveitis was induced. Rats in group 3 were given intraperitoneal infliximab 0.5 mg/100 mL on days 0, 1, 3, 5, and 7 following induction of uveitis on day 14 of the study. Rats in group 4 were given intraperitoneal ghrelin 10 ng/kg/day for 7 days following induction of uveitis. On day 21 of the study, enucleated globes were subjected to histopathologic examination. Vitreous levels of IL-1, IL-6, and TNF-alpha were measured by enzyme-linked immunosorbent assay. RESULTS: Vitreous levels of IL-1, IL-6, and TNF-alpha were significantly increased in the sham group relative to the control group (P < 0.05), but showed a significant decrease in the group treated with infliximab (P < 0.05). Cytokine levels also decreased in the ghrelin-treated group, but the decrease was not statistically significant (P > 0.05). CONCLUSION: Ghrelin failed to decrease the IL-1, IL-6, and TNF-alpha levels that play a critical role in the pathogenesis of uveitis. PMID- 23341734 TI - Failure to refill essential prescription medications for asthma among pediatric Medicaid beneficiaries with persistent asthma. AB - The problem of patients not taking medications as prescribed, also known as "lack of medication adherence," is widely discussed as an issue related to suboptimal outcomes and excess health care expenditure. Although medication adherence is defined as patients not taking medications as prescribed, there are two elements to it: first, those who fail to follow the medication regimen by skipping a dose or not following the instructions, resulting in poor adherence with prescribed medicines; and, second, the patient who does not take the medication at all or stops after the initial fill. The existing literature contains a lot of studies on the first element, but very little is known about those who stop taking their medication after the initial fill or do not take it at all. In this study, our focus is on identifying patients who fail to refill a prescription for essential medicines, such as asthma-controlling drugs. Using Medicaid claims datasets, this study analyzed a pediatric population diagnosed with persistent asthma that discontinued an essential controlling medication after the initial fill. We found that more than half of this population did not continue their medication after the first fill. While there might be many reasons behind the failure to refill such medications, our data indicate that race/ethnicity, comorbid illness, and type of Medicaid plan are potentially associated with such behavior. Future research is warranted to understand this issue further and identify specific factors causing such behavior, such that strategies may be formulated by which poor adherence can be minimized. PMID- 23341735 TI - Buccal midazolam for pediatric convulsive seizures: efficacy, safety, and patient acceptability. AB - Prolonged seizures and status epilepticus are a common acute neurological presentation in pediatric practice. As a result, there is a need for effective and safe medications that can be delivered to convulsing children to effect rapid seizure termination both in hospital and community settings. The challenges of achieving intravenous access, particularly in young children, mandate alternative routes of administration for these drugs. Over the last ten years, midazolam delivered via the buccal mucosa has been demonstrated to be efficacious, safe, and acceptable to children and their caregivers, and a formulation has recently been licensed for use in Europe. The aim of this article is to review the clinical pharmacology with respect to these issues. PMID- 23341736 TI - Exenatide extended-release; clinical trials, patient preference, and economic considerations. AB - Type 2 diabetes remains an escalating problem worldwide, despite a range of treatments being available. The revelation that insulin secretion is under the control of a gut hormone, glucagon-like peptide 1, has led to a new paradigm in the management of type 2 diabetes, ie, use of medicines that directly stimulate or prolong the actions of endogenous glucagon-like peptide 1 at its receptors. Exenatide is an agonist at the glucagon-like peptide 1 receptor, and was initially developed as a subcutaneous medication twice daily (ExBID). Clinical trials with ExBID established a role for exenatide in the treatment of type 2 diabetes. Subsequently, exenatide once weekly (ExQW) was shown to have advantages over ExBID, and there is now more emphasis on the development of ExQW. ExQW alone reduces glycosylated hemoglobin (HbA(1c)) and body weight, and is well tolerated. ExQW has been compared with sitagliptin, pioglitazone, and metformin, and been shown to have a greater ability to reduce HbA(1c) than these other medicines. The only preparation of insulin with which ExQW has been compared is insulin glargine, and ExQW had some favorable properties in this comparison, notably causing weight loss compared with the weight gain on insulin glargine. ExQW has been compared with another glucagon-like peptide 1 receptor agonist, liraglutide, and was noninferior to liraglutide in reducing HbA(1c). The small amount of evidence available shows that subjects with type 2 diabetes prefer ExQW to ExBID, and that adherence is high in the clinical trial setting. Health care and economic modeling suggests that ExQW will reduce diabetic complications and be cost-effective, compared with other medications, in long-term use. Little is known about whether subjects with type 2 diabetes prefer ExQW to other medicines, and whether adherence is good with ExQW in practice. These important topics require further study. PMID- 23341737 TI - Characteristics of patients with Alzheimer's disease who switch to rivastigmine transdermal patches in routine clinical practice. AB - BACKGROUND: The aim of this study was to assess the sociodemographic and clinical characteristics of patients with Alzheimer's disease who switched from any oral cholinesterase inhibitor to rivastigmine patches. METHODS: An observational, retrospective, multicenter study was conducted in patients with a diagnosis of Alzheimer's disease who had switched to rivastigmine patches within the previous year in the routine clinical practice of 150 neurologists. Sociodemographic, clinical, and therapeutic data were collected in one office visit. Stepwise logistic regression models were used to find associations. RESULTS: Data were obtained from a total of 1022 patients and their caregivers, and showed a mean age of 78.4 +/- 6.62 years, 62.61% being women, and mostly having a family caregiver. The switch to rivastigmine patches was mainly instigated on the initiative of the physician (82.39%) or on request of the caregiver (21.23%) or patient (10.37%). Reasons for the switch included improving ease of administration (56.65%), tolerability (36.79%), efficacy (31.60%), and adherence (18.59%). Prior treatment with oral rivastigmine versus donepezil or galantamine increased the probability of switching in order to improve ease of administration (odds ratio, oral rivastigmine versus donepezil 4.20, P < 0.0001; odds ratio, oral rivastigmine versus galantamine 3.55, P < 0.0001). Conversely, previous treatment with donepezil or galantamine produced an approximate four-fold increase in the odds of switching due to lack of efficacy. A higher level of education as well as more concomitant diseases increased the probability of switching because of intolerance. CONCLUSION: Improved ease of administration was the main reason for switching to transdermal rivastigmine. Other reasons involved in the decision to switch to rivastigmine patches included sociodemographic and clinical characteristics, including the educational level of patients and caregivers, number of concomitant diseases, and previous treatment for Alzheimer's disease. PMID- 23341738 TI - Enhancing cognitive functioning in the elderly: multicomponent vs resistance training. AB - PURPOSE: The primary purpose of this study was to compare the effects of two different exercise training programs on executive cognitive functions and functional mobility in older adults. A secondary purpose was to explore the potential mediators of training effects on executive function and functional mobility with particular reference to physical fitness gains. METHODS: A sample of 42 healthy community dwelling adults aged 65 to 75 years participated twice weekly for 3 months in either: (1) multicomponent training, prioritizing neuromuscular coordination, balance, agility, and cognitive executive control; or (2) progressive resistance training for strength conditioning. Participants were tested at baseline (T(1)), following a 4-week control period (T(2)), and finally at postintervention (T(3)) for executive function (inhibition and cognitive flexibility) and functional mobility (maximal walking speed with and without additional task requirements). Cardiorespiratory and muscular fitness were also assessed as potential mediators. RESULTS: Indices of inhibition, the functions involved in the deliberate withholding of prepotent or automatic responses, and measures of functional mobility improved after the intervention, independent of training type. Mediation analysis suggested that different mechanisms underlie the effects of multicomponent and progressive resistance training. While multicomponent training seemed to directly affect inhibitory capacity, resistance training seemed to affect it indirectly through gains in muscular strength. Physical fitness and executive function variables did not mediate functional mobility changes. CONCLUSION: These results confirm that physical training benefits executive function and suggest that different training types might lead to such benefits through different pathways. Both types of training also promoted functional mobility in older adulthood; however, neither inhibitory capacity, nor muscular strength gains seemed to explain functional mobility outcomes. PMID- 23341739 TI - Green biosynthesis of silver nanoparticles using Curcuma longa tuber powder. AB - Green synthesis of noble metal nanoparticles is a vastly developing area of research. Metallic nanoparticles have received great attention from chemists, physicists, biologists, and engineers who wish to use them for the development of a new-generation of nanodevices. In this study, silver nanoparticles were biosynthesized from aqueous silver nitrate through a simple and eco-friendly route using Curcuma longa tuber-powder extracts, which acted as a reductant and stabilizer simultaneously. Characterizations of nanoparticles were done using different methods, which included ultraviolet-visible spectroscopy, powder X-ray diffraction, transmission electron microscopy, scanning electron microscopy, energy-dispersive X-ray fluorescence spectrometry, and Fourier-transform infrared spectroscopy. The ultraviolet-visible spectrum of the aqueous medium containing silver nanoparticles showed an absorption peak at around 415 nm. Transmission electron microscopy showed that mean diameter and standard deviation for the formation of silver nanoparticles was 6.30 +/- 2.64 nm. Powder X-ray diffraction showed that the particles are crystalline in nature, with a face-centered cubic structure. The most needed outcome of this work will be the development of value added products from C. longa for biomedical and nanotechnology-based industries. PMID- 23341740 TI - Expression of novel tumor markers of pancreatic adenocarcinomas in intrahepatic cholangiocarcinomas. AB - Intrahepatic cholangiocarcinomas (IHCCs) are morphologically and biologically similar to pancreatic ductal adenocarcinomas (PDACs), so newly identified PDAC associated genes or proteins could provide clues for screening novel biomarkers for IHCC. In this study, the expression of three novel PDAC tumor markers (T-box transcription factor-4 [TBX4], heat shock protein-60 [HSP60], and Parkinson protein-7 [DJ-1]) identified in previous proteomic studies in IHCC tumors were immunohistochemically detected. The current study confirmed that three novel pancreatic cancer biomarkers TBX4, HSP60, and DJ-1 were also overexpressed in IHCC tumors, but with a relatively lower expression level than PDAC. No significant association was found between tumor marker expression and the clinicopathological characteristics of IHCC patients except that TBX4 expression correlated with tumor grades. Moreover, DJ-1 was demonstrated to be an independent prognostic factor for these patients. The current findings suggest that DJ-1 might play an important role in the malignant progression of IHCC, and its exact mechanism during IHCC progression deserves further investigation. PMID- 23341741 TI - Persistent hypertriglyceridemia in statin-treated patients with type 2 diabetes mellitus. AB - PURPOSE: This paper reports the results of an audit that assessed the prevalence of residual hypertriglyceridemia and the potential need for intensified management among patients with statin-treated type 2 diabetes mellitus (T2DM) in primary care in the UK. PATIENTS AND METHODS: A cross-sectional, observational, systematic audit of patients with diagnosed diabetes from 40 primary care practices was undertaken. The audit collected basic demographic information and data on prescriptions issued during the preceding 4 months. T2DM patients were stratified according to the proportion that attained European Society of Cardiology treatment targets. RESULTS: The audit collected data from 14,652 patients with diagnosed diabetes: 89.5% (n = 13,108) of the total cohort had T2DM. Of the people with T2DM, 22.2% (2916) were not currently receiving lipid lowering therapy. Up to approximately 80% of these people showed evidence of dyslipidemia. Among the group that received lipid-lowering therapy, 94.7% (9647) were on statin monotherapy, which was usually simvastatin (69.5% of patients receiving statin monotherapy; 6707). The currently available statins were prescribed, with the most common dose being 40 mg simvastatin (44.2%; 4267). Irrespective of the statin used, around half of the patients receiving statin monotherapy did not attain the European Society of Cardiology treatment targets for triglycerides, low-density lipoprotein, high-density lipoprotein, and total cholesterol. CONCLUSION: T2DM patients managed in UK primary care commonly show persistent lipid abnormalities. Clinicians need to optimize compliance with lipid lowering and other medications. Clinicians also need to consider intensifying statin regimens, prescribing additional lipid- modifying therapies, and specific treatments aimed at triglyceride lowering to improve dyslipidemia control in statin-treated patients with T2DM. PMID- 23341742 TI - Variation in floral scent compounds recognized by honeybees in Brassicaceae crop species. AB - Floral scent attracts pollinators. We investigated the floral scent compounds recognized by pollinators in six Brassica crop species, including allogamous species with different genomes and autogamous species with two parental genomes and radish (Raphanus sativus). Biologically active compounds recognized by honeybees were screened from all floral compounds by combined gas chromatography electroantennogram analysis and their profiles were determined by gas chromatography-mass spectrometry. Fourteen of the 52 compounds were active. All accessions had more than two active compounds, but the compounds greatly differed between the two genera. On the basis of similarities in whether active compounds were presence or absence, their amount and their composition ratio, we divided the Brassica accessions into three to five groups by cluster analyses. Most groups were composed of a mixture of allogamous and autogamous species sharing same genome, indicating that the variation depended on genome, not species. These results suggest that all species require pollinator visits for reproduction, despite their different reproductive systems. However, the inter-genus and intra specific variations shown by the multiple groups within a species might cause different visitation frequencies by pollinators between genera and among accessions within a species, resulting in insufficient seed production in some accessions or species. PMID- 23341743 TI - Genetic analyses of agronomic traits in Tartary buckwheat (Fagopyrum tataricum (L.) Gaertn.). AB - The consumption of products made from Tartary buckwheat (Fagopyrum tataricum (L.) Gaertn.) has increased in recent years in Japan. Increased consumer demand has led to recognition of the need for early varieties of this crop with high and stable yields. In order to accomplish this, more information is needed on the genetic mechanisms affecting earliness and yield. We conducted genetic analysis of 3 agronomic traits (days to flowering, plant height and total seed weight per plant) to segregate F(2) and F(3) populations derived from a cross between Tartary buckwheat cultivars 'Hokuriku No. 4' and 'Ishisoba'. Broad-sense heritability estimates for days to flowering, plant height and total seed weight were 0.70, 0.62 and 0.75, respectively, in F(3) population. Narrow-sense heritability for total seed weight (0.51) was highest, followed by heritability for days to flowering (0.37), with heritability for plant height (0.26) lowest. Later flowering was associated with increased plant height and higher yields. From the F(4) generation, we identified twelve candidate plants with earlier maturity and reduced plant height compared to 'Hokuriku No. 4', but almost the same total seed weight. These results suggest that hybridization breeding using the single seed descent (SSD) method is an effective approach for improving agronomic characteristics of Tartary buckwheat. PMID- 23341744 TI - Genetic analysis and fine mapping of LH1 and LH2, a set of complementary genes controlling late heading in rice (Oryza sativa L.). AB - Heading date in rice (Oryza sativa L.) is a critical agronomic trait with a complex inheritance. To investigate the genetic basis and mechanism of gene interaction in heading date, we conducted genetic analysis on segregation populations derived from crosses among the indica cultivars Bo B, Yuefeng B and Baoxuan 2. A set of dominant complementary genes controlling late heading, designated LH1 and LH2, were detected by molecular marker mapping. Genetic analysis revealed that Baoxuan 2 contains both dominant genes, while Bo B and Yuefeng B each possess either LH1 or LH2. Using larger populations with segregant ratios of 3 : 1, we fine-mapped LH1 to a 63-kb region near the centromere of chromosome 7 flanked by markers RM5436 and RM8034, and LH2 to a 177-kb region on the short arm of chromosome 8 between flanking markers Indel22468-3 and RM25. Some candidate genes were identified through sequencing of Bo B and Yuefeng B in these target regions. Our work provides a solid foundation for further study on gene interaction in heading date and has application in marker-assisted breeding of photosensitive hybrid rice in China. PMID- 23341745 TI - Association of molecular markers with cold tolerance and green period in zoysiagrass (Zoysia Willd.). AB - Cold tolerance and the green period are key traits in the breeding of zoysiagrass (Zoysia Willd.). Identification of molecular markers associated with cold tolerance and the green period of zoysiagrass will contribute to efficient selection of elite cultivars. These two traits were measured in 96 zoysiagrass accessions in 2004 and 2005-2006, respectively. The mapping population was screened with 29 pairs of simple sequence repeat (SSR) primers and 54 pairs of sequence-related amplified polymorphism (SRAP) primers. A multi-loci in silico mapping approach implemented with an empirical Bayes method was applied for association mapping of cold tolerance and green period. We detected 254 SSR polymorphic loci and 338 SRAP polymorphic loci, among which three SSR loci (Xgwm131-3B-187, Xgwm469-6D-194 and Xgwm234-5B-244) and one SRAP locus (Me11Em7 406) were significantly associated with cold tolerance with effect values of 57.83%, 38.05%, 36.92% and 37%, respectively. Three SSR loci (Xgwm132-6B-225, Xgwm111-7D-34 and Xgwm102-2D-97) and two SRAP loci (Me19Em5-359 and Me16Em8-483) were significantly associated with the green period with effect values of 79.54%, 62.59%, 99.04%, 49.01% and 82.57%. These markers will be useful for genetic improvement of the cold tolerance and green period of zoysiagrass by marker assisted breeding. PMID- 23341746 TI - Persistent C genome chromosome regions identified by SSR analysis in backcross progenies between Brassica juncea and B. napus. AB - Given that feral transgenic canola (Brassica napus) from spilled seeds has been found outside of farmer's fields and that B. juncea is distributed worldwide, it is possible that introgression to B. juncea from B. napus has occurred. To investigate such introgression, we characterized the persistence of B. napus C genome chromosome (C-chromosome) regions in backcross progenies by B. napus C chromosome specific simple sequence repeat (SSR) markers. We produced backcross progenies from B. juncea and F(1) hybrid of B. juncea * B. napus to evaluate persistence of C-chromosome region, and screened 83 markers from a set of reported C-chromosome specific SSR markers. Eighty-five percent of the SSR markers were deleted in the BC(1) obtained from B. juncea * F(1) hybrid, and this BC(1) exhibited a plant type like that of B. juncea. Most markers were deleted in BC(2) and BC(3) plants, with only two markers persisting in the BC(3). These results indicate a small possibility of persistence of C-chromosome regions in our backcross progenies. Knowledge about the persistence of B. napus C-chromosome regions in backcross progenies may contribute to shed light on gene introgression. PMID- 23341747 TI - Close linkage of a blast resistance gene, Pias(t), with a bacterial leaf blight resistance gene, Xa1-as(t), in a rice cultivar 'Asominori'. AB - It has long been known that a bacterial leaf blight-resistant line in rice obtained from a crossing using 'Asominori' as a resistant parent also has resistance to blast, but a blast resistance gene in 'Asominori' has not been investigated in detail. In the present study, a blast resistance gene in 'Asominori', tentatively named Pias(t), was revealed to be located within 162-kb region between DNA markers YX4-3 and NX4-1 on chromosome 4 and to be linked with an 'Asominori' allele of the bacterial leaf blight resistance gene Xa1, tentatively named Xa1-as(t). An 'Asominori' allele of Pias(t) was found to be dominant and difference of disease severity between lines having the 'Asominori' allele of Pias(t) and those without it was 1.2 in disease index from 0 to 10. Pias(t) was also closely linked with the Ph gene controlling phenol reaction, suggesting the possibility of successful selection of blast resistance using the phenol reaction. Since blast-resistant commercial cultivars have been developed using 'Asominori' as a parent, Pias(t) is considered to be a useful gene in rice breeding for blast resistance. PMID- 23341748 TI - Evaluation of fresh pasta-making properties of extra-strong common wheat (Triticum aestivum L.). AB - The relationship between characterictics of flour of common wheat varieties and fresh pasta-making qualitites was examined, and the fresh pasta-making properties of extra-strong varieties that have extra-strong dough were evaluated. There was a positive correlation between mixing time (PT) and hardness of boiled pasta, indicating that the hardness of boiled pasta was affected by dough properties. Boiled pasta made from extra-strong varieties, Yumechikara, Hokkai 262 and Hokkai 259, was harder than that from other varieties and commercial flour. There was a negative correlation between flour protein content and brightness of boiled pasta. The colors of boiled pasta made from Yumechikara and Hokkai 262 grown under the condition of standard manuring culture were superior to those of boiled pasta made from other varieties. Discoloration of boiled pasta made from Yumechikara grown under the condition of heavy manuring culture was caused by increase of flour protein content. On the other hand, discoloration of boiled pasta made from Hokkai 262 grown under the condition of heavy manuring culture was less than that of boiled pasta made from Yumechikara. These results indicate that pasta made from extra-strong wheat varieties has good hardness and that Hokkai 262 has extraordinary fresh pasta-making properties. PMID- 23341749 TI - Polyacrylamide gel electrophoresis of S-RNase fragments for identification of S genotypes of Japanese pear (Pyrus pyrifolia). AB - Japanese pear (Pyrus pyrifolia) exhibits gametophytic self-incompatibility (GSI) controlled by a complex and multiallelic S locus. The pistil-part product of the S locus is the polymorphic ribonuclease, S-RNase. Information on S-genotypes is important for the production and breeding of Japanese pears. Molecular analyses of S-genotypes of Japanese pear have been conducted with the CAPS (cleaved amplified polymorphic sequence) system; PCR amplification of S-RNase fragments by a common primer pair followed by digestion with restriction enzymes each of which cleaves a specific S haplotype. Here, we show that the separation of S-RNase fragments by polyacrylamide gel electrophoresis (PAGE) distinguishes four out of nine S haplotypes of Japanese pear without restriction digestion. S(3)-, S(5)-, S(6)- and S(8)-RNases were identified as distinct bands by PAGE. S(3)- and S(5) RNases were separated by PAGE despite their identical fragment sizes. Using this system, three Japanese pear lines with unknown S-genotypes were analyzed. The newly determined S-genotypes of the lines were confirmed by CAPS analysis. PMID- 23341750 TI - DNA profiling of pineapple cultivars in Japan discriminated by SSR markers. AB - We developed 18 polymorphic simple sequence repeat (SSR) markers in pineapple (Ananas comosus) by using genomic libraries enriched for GA and CA motifs. The markers were used to genotype 31 pineapple accessions, including seven cultivars and 11 breeding lines from Okinawa Prefecture, 12 foreign accessions and one from a related species. These SSR loci were highly polymorphic: the 31 accessions contained three to seven alleles per locus, with an average of 4.1. The values of expected heterozygosity ranged from 0.09 to 0.76, with an average of 0.52. All 31 accessions could be successfully differentiated by the 18 SSR markers, with the exception of 'N67-10' and 'Hawaiian Smooth Cayenne'. A single combination of three markers TsuAC004, TsuAC010 and TsuAC041, was enough to distinguish all accessions with one exception. A phenogram based on the SSR genotypes did not show any distinct groups, but it suggested that pineapples bred in Japan are genetically diversed. We reconfirmed the parentage of 14 pineapple accessions by comparing the SSR alleles at 17 SSR loci in each accession and its reported parents. The obtained information will contribute substantially to protecting plant breeders' rights. PMID- 23341751 TI - Traits of shattering resistant buckwheat 'W/SK86GF'. AB - Seed shattering is a significant problem with buckwheat, especially at harvesting time. Several reports have shown that a green-flower mutant of buckwheat, such as W/SK86GF, has a strong pedicel. Although a strong pedicel may provide some resistance to shattering in the field, no study has thoroughly examined this issue. In this paper, we demonstrate that a W/SK86GF has shattering resistance by comparing the degrees of shattering of W/SK86GF and Kitawasesoba (leading variety of Hokkaido with non-green-flower traits) through a test for four years, including a typhoon hit year in the field. In a non-typhoon year, the shattering seed ratio (shattering seed weight/(yield + shattering seed weight) * 100) of W/SK86GF at maturing time +15 days (+15D) was lower than that of Kitawasesoba. In a typhoon hit year, the shattering seed ratios of Kitawasesoba at maturing time and +15D were surprisingly high, 14.4 and 21.1%, respectively. On the other hand, those of W/SK86GF were only 3.08% and 2.57%, respectively; indicating W/SK86GF is promising as a shattering resistant line even in a typhoon hit year. From these results, shattering resistance of W/SK86GF can be evaluated after maturing time such as +15D and pedicel strength would confer W/SK86GF a shattering resistant trait. PMID- 23341752 TI - Characterization of HMW-GS and evaluation of their diversity in morphologically elite synthetic hexaploid wheats. AB - High molecular weight glutenin subunit composition and variation in 95 Elite-1 synthetic hexaploid (SH) wheats (Triticum turgidum/Aegilops tauschii; 2n = 6* = 42; AABBDD) were determined by sodium dodecyl sulphate polyacrylamide gel electrophoresis method (SDS-PAGE). Twenty two different alleles at Glu-1 loci in SHs were observed. Forty four different patterns of HMW-GS in synthetics were found. This higher HMW glutenin composition was due to higher proportion of D genome encoded subunits in these SHs. 8% urea/SDS-PAGE better discriminated subunit 2* than 12% gels. However 12% urea/SDS-PAGE allowed differentiated mobility of Glu-D(t)1 subunits. Genetic variability at Glu-D(t)1 locus was greater than Glu-A1 and Glu-B1 loci. The relative high frequency of superior alleles, Glu-B1b and Glu-D(t)1d indicated the superior bread making quality attributes embedded in these synthetic hexaploid wheats. Of the 95 Elite-1 SHs 27.1% possessed superior alleles at Glu-A1 and 51% had superior alleles at Glu-B1 locus. At Glu-D(t)1 frequency of inferior allele 1Dx2 + 1Dy12 was very low (5.26%) and nine different rare alleles along with the higher frequency (22.1%) of D-genome encoded subunit, 1Dx5 + 1Dy10, were observed. These superior alleles shall form the priority selective sieve for their usage in wheat improvement efforts. PMID- 23341753 TI - Toward an understanding of disengagement from HIV treatment and care in sub Saharan Africa: a qualitative study. AB - BACKGROUND: The rollout of antiretroviral therapy in sub-Saharan Africa has brought lifesaving treatment to millions of HIV-infected individuals. Treatment is lifelong, however, and to continue to benefit, patients must remain in care. Despite this, systematic investigations of retention have repeatedly documented high rates of loss to follow-up from HIV treatment programs. This paper introduces an explanation for missed clinic visits and subsequent disengagement among patients enrolled in HIV treatment and care programs in Africa. METHODS AND FINDINGS: Eight-hundred-ninety patients enrolled in HIV treatment programs in Jos, Nigeria; Dar es Salaam, Tanzania; and Mbarara, Uganda who had extended absences from care were tracked for qualitative research interviews. Two-hundred eighty-seven were located, and 91 took part in the study. Interview data were inductively analyzed to identify reasons for missed visits and to assemble them into a broader explanation of how missed visits may develop into disengagement. Findings reveal unintentional and intentional reasons for missing, along with reluctance to return to care following an absence. Disengagement is interpreted as a process through which missed visits and ensuing reluctance to return over time erode patients' subjective sense of connectedness to care. CONCLUSIONS: Missed visits are inevitable over a lifelong course of HIV care. Efforts to prevent missed clinic visits combined with moves to minimize barriers to re-entry into care are more likely than either approach alone to keep missed visits from turning into long-term disengagement. PMID- 23341754 TI - Equipartition Principle for Internal Coordinate Molecular Dynamics. AB - The principle of equipartition of (kinetic) energy for all-atom Cartesian molecular dynamics states that each momentum phase space coordinate on the average has 1/2kT of kinetic energy in a canonical ensemble. This principle is used in molecular dynamics simulations to initialize velocities, and to calculate statistical properties such as entropy. Internal coordinate molecular dynamics (ICMD) models differ from Cartesian models in that the overall kinetic energy depends on the generalized coordinates and includes cross-terms. Due to this coupled structure, no such equipartition principle holds for ICMD models. In this paper we introduce non-canonical modal coordinates to recover some of the structural simplicity of Cartesian models and develop a new equipartition principle for ICMD models. We derive low-order recursive computational algorithms for transforming between the modal and physical coordinates. The equipartition principle in modal coordinates provides a rigorous method for initializing velocities in ICMD simulations thus replacing the ad hoc methods used until now. It also sets the basis for calculating conformational entropy using internal coordinates. PMID- 23341755 TI - Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone phi, psi and side-chain chi(1) and chi(2) dihedral angles. AB - While the quality of the current CHARMM22/CMAP additive force field for proteins has been demonstrated in a large number of applications, limitations in the model with respect to the equilibrium between the sampling of helical and extended conformations in folding simulations have been noted. To overcome this, as well as make other improvements in the model, we present a combination of refinements that should result in enhanced accuracy in simulations of proteins. The common (non Gly, Pro) backbone CMAP potential has been refined against experimental solution NMR data for weakly structured peptides, resulting in a rebalancing of the energies of the alpha-helix and extended regions of the Ramachandran map, correcting the alpha-helical bias of CHARMM22/CMAP. The Gly and Pro CMAPs have been refitted to more accurate quantum-mechanical energy surfaces. Side-chain torsion parameters have been optimized by fitting to backbone-dependent quantum mechanical energy surfaces, followed by additional empirical optimization targeting NMR scalar couplings for unfolded proteins. A comprehensive validation of the revised force field was then performed against data not used to guide parametrization: (i) comparison of simulations of eight proteins in their crystal environments with crystal structures; (ii) comparison with backbone scalar couplings for weakly structured peptides; (iii) comparison with NMR residual dipolar couplings and scalar couplings for both backbone and side-chains in folded proteins; (iv) equilibrium folding of mini-proteins. The results indicate that the revised CHARMM 36 parameters represent an improved model for the modeling and simulation studies of proteins, including studies of protein folding, assembly and functionally relevant conformational changes. PMID- 23341756 TI - The effects of city streets on an urban disease vector. AB - With increasing urbanization vector-borne diseases are quickly developing in cities, and urban control strategies are needed. If streets are shown to be barriers to disease vectors, city blocks could be used as a convenient and relevant spatial unit of study and control. Unfortunately, existing spatial analysis tools do not allow for assessment of the impact of an urban grid on the presence of disease agents. Here, we first propose a method to test for the significance of the impact of streets on vector infestation based on a decomposition of Moran's spatial autocorrelation index; and second, develop a Gaussian Field Latent Class model to finely describe the effect of streets while controlling for cofactors and imperfect detection of vectors. We apply these methods to cross-sectional data of infestation by the Chagas disease vector Triatoma infestans in the city of Arequipa, Peru. Our Moran's decomposition test reveals that the distribution of T. infestans in this urban environment is significantly constrained by streets (p<0.05). With the Gaussian Field Latent Class model we confirm that streets provide a barrier against infestation and further show that greater than 90% of the spatial component of the probability of vector presence is explained by the correlation among houses within city blocks. The city block is thus likely to be an appropriate spatial unit to describe and control T. infestans in an urban context. Characteristics of the urban grid can influence the spatial dynamics of vector borne disease and should be considered when designing public health policies. PMID- 23341757 TI - Approximate Bayesian computation. AB - Approximate Bayesian computation (ABC) constitutes a class of computational methods rooted in Bayesian statistics. In all model-based statistical inference, the likelihood function is of central importance, since it expresses the probability of the observed data under a particular statistical model, and thus quantifies the support data lend to particular values of parameters and to choices among different models. For simple models, an analytical formula for the likelihood function can typically be derived. However, for more complex models, an analytical formula might be elusive or the likelihood function might be computationally very costly to evaluate. ABC methods bypass the evaluation of the likelihood function. In this way, ABC methods widen the realm of models for which statistical inference can be considered. ABC methods are mathematically well founded, but they inevitably make assumptions and approximations whose impact needs to be carefully assessed. Furthermore, the wider application domain of ABC exacerbates the challenges of parameter estimation and model selection. ABC has rapidly gained popularity over the last years and in particular for the analysis of complex problems arising in biological sciences (e.g., in population genetics, ecology, epidemiology, and systems biology). PMID- 23341758 TI - How evolving heterogeneity distributions of resource allocation strategies shape mortality patterns. AB - It is well established that individuals age differently. Yet the nature of these inter-individual differences is still largely unknown. For humans, two main hypotheses have been recently formulated: individuals may experience differences in aging rate or aging timing. This issue is central because it directly influences predictions for human lifespan and provides strong insights into the biological determinants of aging. In this article, we propose a model which lets population heterogeneity emerge from an evolutionary algorithm. We find that whether individuals differ in (i) aging rate or (ii) timing leads to different emerging population heterogeneity. Yet, in both cases, the same mortality patterns are observed at the population level. These patterns qualitatively reproduce those of yeasts, flies, worms and humans. Such findings, supported by an extensive parameter exploration, suggest that mortality patterns across species and their potential shapes belong to a limited and robust set of possible curves. In addition, we use our model to shed light on the notion of subpopulations, link population heterogeneity with the experimental results of stress induction experiments and provide predictions about the expected mortality patterns. As biology is moving towards the study of the distribution of individual-based measures, the model and framework we propose here paves the way for evolutionary interpretations of empirical and experimental data linking the individual level to the population level. PMID- 23341759 TI - Visual data mining of biological networks: one size does not fit all. AB - High-throughput technologies produce massive amounts of data. However, individual methods yield data specific to the technique used and biological setup. The integration of such diverse data is necessary for the qualitative analysis of information relevant to hypotheses or discoveries. It is often useful to integrate these datasets using pathways and protein interaction networks to get a broader view of the experiment. The resulting network needs to be able to focus on either the large-scale picture or on the more detailed small-scale subsets, depending on the research question and goals. In this tutorial, we illustrate a workflow useful to integrate, analyze, and visualize data from different sources, and highlight important features of tools to support such analyses. PMID- 23341760 TI - Identifying transmission cycles at the human-animal interface: the role of animal reservoirs in maintaining gambiense human african trypanosomiasis. AB - Many infections can be transmitted between animals and humans. The epidemiological roles of different species can vary from important reservoirs to dead-end hosts. Here, we present a method to identify transmission cycles in different combinations of species from field data. We used this method to synthesise epidemiological and ecological data from Bipindi, Cameroon, a historical focus of gambiense Human African Trypanosomiasis (HAT, sleeping sickness), a disease that has often been considered to be maintained mainly by humans. We estimated the basic reproduction number [Formula: see text] of gambiense HAT in Bipindi and evaluated the potential for transmission in the absence of human cases. We found that under the assumption of random mixing between vectors and hosts, gambiense HAT could not be maintained in this focus without the contribution of animals. This result remains robust under extensive sensitivity analysis. When using the distributions of species among habitats to estimate the amount of mixing between those species, we found indications for an independent transmission cycle in wild animals. Stochastic simulation of the system confirmed that unless vectors moved between species very rarely, reintroduction would usually occur shortly after elimination of the infection from human populations. This suggests that elimination strategies may have to be reconsidered as targeting human cases alone would be insufficient for control, and reintroduction from animal reservoirs would remain a threat. Our approach is broadly applicable and could reveal animal reservoirs critical to the control of other infectious diseases. PMID- 23341761 TI - ADEMA: an algorithm to determine expected metabolite level alterations using mutual information. AB - Metabolomics is a relatively new "omics" platform, which analyzes a discrete set of metabolites detected in bio-fluids or tissue samples of organisms. It has been used in a diverse array of studies to detect biomarkers and to determine activity rates for pathways based on changes due to disease or drugs. Recent improvements in analytical methodology and large sample throughput allow for creation of large datasets of metabolites that reflect changes in metabolic dynamics due to disease or a perturbation in the metabolic network. However, current methods of comprehensive analyses of large metabolic datasets (metabolomics) are limited, unlike other "omics" approaches where complex techniques for analyzing coexpression/coregulation of multiple variables are applied. This paper discusses the shortcomings of current metabolomics data analysis techniques, and proposes a new multivariate technique (ADEMA) based on mutual information to identify expected metabolite level changes with respect to a specific condition. We show that ADEMA better predicts De Novo Lipogenesis pathway metabolite level changes in samples with Cystic Fibrosis (CF) than prediction based on the significance of individual metabolite level changes. We also applied ADEMA's classification scheme on three different cohorts of CF and wildtype mice. ADEMA was able to predict whether an unknown mouse has a CF or a wildtype genotype with 1.0, 0.84, and 0.9 accuracy for each respective dataset. ADEMA results had up to 31% higher accuracy as compared to other classification algorithms. In conclusion, ADEMA advances the state-of-the-art in metabolomics analysis, by providing accurate and interpretable classification results. PMID- 23341762 TI - Evolutionary optimization of protein folding. AB - Nature has shaped the make up of proteins since their appearance, [Formula: see text]3.8 billion years ago. However, the fundamental drivers of structural change responsible for the extraordinary diversity of proteins have yet to be elucidated. Here we explore if protein evolution affects folding speed. We estimated folding times for the present-day catalog of protein domains directly from their size-modified contact order. These values were mapped onto an evolutionary timeline of domain appearance derived from a phylogenomic analysis of protein domains in 989 fully-sequenced genomes. Our results show a clear overall increase of folding speed during evolution, with known ultra-fast downhill folders appearing rather late in the timeline. Remarkably, folding optimization depends on secondary structure. While alpha-folds showed a tendency to fold faster throughout evolution, beta-folds exhibited a trend of folding time increase during the last [Formula: see text]1.5 billion years that began during the "big bang" of domain combinations. As a consequence, these domain structures are on average slow folders today. Our results suggest that fast and efficient folding of domains shaped the universe of protein structure. This finding supports the hypothesis that optimization of the kinetic and thermodynamic accessibility of the native fold reduces protein aggregation propensities that hamper cellular functions. PMID- 23341763 TI - Effects of ligand binding on the mechanical properties of ankyrin repeat protein gankyrin. AB - Ankyrin repeat proteins are elastic materials that unfold and refold sequentially, repeat by repeat, under force. Herein we use atomistic molecular dynamics to compare the mechanical properties of the 7-ankyrin-repeat oncoprotein Gankyrin in isolation and in complex with its binding partner S6-C. We show that the bound S6-C greatly increases the resistance of Gankyrin to mechanical stress. The effect is specific to those repeats of Gankyrin directly in contact with S6 C, and the mechanical 'hot spots' of the interaction map to the same repeats as the thermodynamic hot spots. A consequence of stepwise nature of unfolding and the localized nature of ligand binding is that it impacts on all aspects of the protein's mechanical behavior, including the order of repeat unfolding, the diversity of unfolding pathways accessed, the nature of partially unfolded intermediates, the forces required and the work transferred to the system to unfold the whole protein and its parts. Stepwise unfolding thus provides the means to buffer repeat proteins and their binding partners from mechanical stress in the cell. Our results illustrate how ligand binding can control the mechanical response of proteins. The data also point to a cellular mechano-switching mechanism whereby binding between two partner macromolecules is regulated by mechanical stress. PMID- 23341764 TI - Reward from punishment does not emerge at all costs. AB - The conundrum of cooperation has received increasing attention during the last decade. In this quest, the role of altruistic punishment has been identified as a mechanism promoting cooperation. Here we investigate the role of altruistic punishment on the emergence and maintenance of cooperation in structured populations exhibiting connectivity patterns recently identified as key elements of social networks. We do so in the framework of Evolutionary Game Theory, employing the Prisoner's Dilemma and the Stag-Hunt metaphors to model the conflict between individual and collective interests regarding cooperation. We find that the impact of altruistic punishment strongly depends on the ratio q/p between the cost of punishing a defecting partner (q) and the actual punishment incurred by the partner (p). We show that whenever q/p<1, altruistic punishment turns out to be detrimental for cooperation for a wide range of payoff parameters, when compared to the scenario without punishment. The results imply that while locally, the introduction of peer punishment may seem to reduce the chances of free-riding, realistic population structure may drive the population towards the opposite scenario. Hence, structured populations effectively reduce the expected beneficial contribution of punishment to the emergence of cooperation which, if not carefully dosed, may in fact hinder the chances of widespread cooperation. PMID- 23341765 TI - Durable resistance to crop pathogens: an epidemiological framework to predict risk under uncertainty. AB - Increasing the durability of crop resistance to plant pathogens is one of the key goals of virulence management. Despite the recognition of the importance of demographic and environmental stochasticity on the dynamics of an epidemic, their effects on the evolution of the pathogen and durability of resistance has not received attention. We formulated a stochastic epidemiological model, based on the Kramer-Moyal expansion of the Master Equation, to investigate how random fluctuations affect the dynamics of an epidemic and how these effects feed through to the evolution of the pathogen and durability of resistance. We focused on two hypotheses: firstly, a previous deterministic model has suggested that the effect of cropping ratio (the proportion of land area occupied by the resistant crop) on the durability of crop resistance is negligible. Increasing the cropping ratio increases the area of uninfected host, but the resistance is more rapidly broken; these two effects counteract each other. We tested the hypothesis that similar counteracting effects would occur when we take account of demographic stochasticity, but found that the durability does depend on the cropping ratio. Secondly, we tested whether a superimposed external source of stochasticity (for example due to environmental variation or to intermittent fungicide application) interacts with the intrinsic demographic fluctuations and how such interaction affects the durability of resistance. We show that in the pathosystem considered here, in general large stochastic fluctuations in epidemics enhance extinction of the pathogen. This is more likely to occur at large cropping ratios and for particular frequencies of the periodic external perturbation (stochastic resonance). The results suggest possible disease control practises by exploiting the natural sources of stochasticity. PMID- 23341766 TI - Saccadic momentum and facilitation of return saccades contribute to an optimal foraging strategy. AB - The interest in saccadic IOR is funneled by the hypothesis that it serves a clear functional purpose in the selection of fixation points: the facilitation of foraging. In this study, we arrive at a different interpretation of saccadic IOR. First, we find that return saccades are performed much more often than expected from the statistical properties of saccades and saccade pairs. Second, we find that fixation durations before a saccade are modulated by the relative angle of the saccade, but return saccades show no sign of an additional temporal inhibition. Thus, we do not find temporal saccadic inhibition of return. Interestingly, we find that return locations are more salient, according to empirically measured saliency (locations that are fixated by many observers) as well as stimulus dependent saliency (defined by image features), than regular fixation locations. These results and the finding that return saccades increase the match of individual trajectories with a grand total priority map evidences the return saccades being part of a fixation selection strategy that trades off exploration and exploitation. PMID- 23341767 TI - An integrative model of ion regulation in yeast. AB - Yeast cells are able to tolerate and adapt to a variety of environmental stresses. An essential aspect of stress adaptation is the regulation of monovalent ion concentrations. Ion regulation determines many fundamental physiological parameters, such as cell volume, membrane potential, and intracellular pH. It is achieved through the concerted activities of multiple cellular components, including ion transporters and signaling molecules, on both short and long time scales. Although each component has been studied in detail previously, it remains unclear how the physiological parameters are maintained and regulated by the concerted action of all components under a diverse range of stress conditions. In this study, we have constructed an integrated mathematical model of ion regulation in Saccharomyces cerevisiae to understand this coordinated adaptation process. Using this model, we first predict that the interaction between phosphorylated Hog1p and Tok1p at the plasma membrane inhibits Tok1p activity and consequently reduces Na(+) influx under NaCl stress. We further characterize the impacts of NaCl, sorbitol, KCl and alkaline pH stresses on the cellular physiology and the differences between the cellular responses to these stresses. We predict that the calcineurin pathway is essential for maintaining a non-toxic level of intracellular Na(+) in the long-term adaptation to NaCl stress, but that its activation is not required for maintaining a low level of Na(+) under other stresses investigated. We provide evidence that, in addition to extrusion of toxic ions, Ena1p plays an important role, in some cases alongside Nha1p, in re-establishing membrane potential after stress perturbation. To conclude, this model serves as a powerful tool for both understanding the complex system-level properties of the highly coordinated adaptation process and generating further hypotheses for experimental investigation. PMID- 23341768 TI - Binding of nucleoid-associated protein fis to DNA is regulated by DNA breathing dynamics. AB - Physicochemical properties of DNA, such as shape, affect protein-DNA recognition. However, the properties of DNA that are most relevant for predicting the binding sites of particular transcription factors (TFs) or classes of TFs have yet to be fully understood. Here, using a model that accurately captures the melting behavior and breathing dynamics (spontaneous local openings of the double helix) of double-stranded DNA, we simulated the dynamics of known binding sites of the TF and nucleoid-associated protein Fis in Escherichia coli. Our study involves simulations of breathing dynamics, analysis of large published in vitro and genomic datasets, and targeted experimental tests of our predictions. Our simulation results and available in vitro binding data indicate a strong correlation between DNA breathing dynamics and Fis binding. Indeed, we can define an average DNA breathing profile that is characteristic of Fis binding sites. This profile is significantly enriched among the identified in vivo E. coli Fis binding sites. To test our understanding of how Fis binding is influenced by DNA breathing dynamics, we designed base-pair substitutions, mismatch, and methylation modifications of DNA regions that are known to interact (or not interact) with Fis. The goal in each case was to make the local DNA breathing dynamics either closer to or farther from the breathing profile characteristic of a strong Fis binding site. For the modified DNA segments, we found that Fis-DNA binding, as assessed by gel-shift assay, changed in accordance with our expectations. We conclude that Fis binding is associated with DNA breathing dynamics, which in turn may be regulated by various nucleotide modifications. PMID- 23341769 TI - Redirector: designing cell factories by reconstructing the metabolic objective. AB - Advances in computational metabolic optimization are required to realize the full potential of new in vivo metabolic engineering technologies by bridging the gap between computational design and strain development. We present Redirector, a new Flux Balance Analysis-based framework for identifying engineering targets to optimize metabolite production in complex pathways. Previous optimization frameworks have modeled metabolic alterations as directly controlling fluxes by setting particular flux bounds. Redirector develops a more biologically relevant approach, modeling metabolic alterations as changes in the balance of metabolic objectives in the system. This framework iteratively selects enzyme targets, adds the associated reaction fluxes to the metabolic objective, thereby incentivizing flux towards the production of a metabolite of interest. These adjustments to the objective act in competition with cellular growth and represent up-regulation and down-regulation of enzyme mediated reactions. Using the iAF1260 E. coli metabolic network model for optimization of fatty acid production as a test case, Redirector generates designs with as many as 39 simultaneous and 111 unique engineering targets. These designs discover proven in vivo targets, novel supporting pathways and relevant interdependencies, many of which cannot be predicted by other methods. Redirector is available as open and free software, scalable to computational resources, and powerful enough to find all known enzyme targets for fatty acid production. PMID- 23341770 TI - Atomic model of rabbit hemorrhagic disease virus by cryo-electron microscopy and crystallography. AB - Rabbit hemorrhagic disease, first described in China in 1984, causes hemorrhagic necrosis of the liver. Its etiological agent, rabbit hemorrhagic disease virus (RHDV), belongs to the Lagovirus genus in the family Caliciviridae. The detailed molecular structure of any lagovirus capsid has yet to be determined. Here, we report a cryo-electron microscopic (cryoEM) reconstruction of wild-type RHDV at 6.5 A resolution and the crystal structures of the shell (S) and protruding (P) domains of its major capsid protein, VP60, each at 2.0 A resolution. From these data we built a complete atomic model of the RHDV capsid. VP60 has a conserved S domain and a specific P2 sub-domain that differs from those found in other caliciviruses. As seen in the shell portion of the RHDV cryoEM map, which was resolved to ~5.5 A, the N-terminal arm domain of VP60 folds back onto its cognate S domain. Sequence alignments of VP60 from six groups of RHDV isolates revealed seven regions of high variation that could be mapped onto the surface of the P2 sub-domain and suggested three putative pockets might be responsible for binding to histo-blood group antigens. A flexible loop in one of these regions was shown to interact with rabbit tissue cells and contains an important epitope for anti RHDV antibody production. Our study provides a reliable, pseudo-atomic model of a Lagovirus and suggests a new candidate for an efficient vaccine that can be used to protect rabbits from RHDV infection. PMID- 23341771 TI - Predicting mendelian disease-causing non-synonymous single nucleotide variants in exome sequencing studies. AB - Exome sequencing is becoming a standard tool for mapping Mendelian disease causing (or pathogenic) non-synonymous single nucleotide variants (nsSNVs). Minor allele frequency (MAF) filtering approach and functional prediction methods are commonly used to identify candidate pathogenic mutations in these studies. Combining multiple functional prediction methods may increase accuracy in prediction. Here, we propose to use a logit model to combine multiple prediction methods and compute an unbiased probability of a rare variant being pathogenic. Also, for the first time we assess the predictive power of seven prediction methods (including SIFT, PolyPhen2, CONDEL, and logit) in predicting pathogenic nsSNVs from other rare variants, which reflects the situation after MAF filtering is done in exome-sequencing studies. We found that a logit model combining all or some original prediction methods outperforms other methods examined, but is unable to discriminate between autosomal dominant and autosomal recessive disease mutations. Finally, based on the predictions of the logit model, we estimate that an individual has around 5% of rare nsSNVs that are pathogenic and carries ~22 pathogenic derived alleles at least, which if made homozygous by consanguineous marriages may lead to recessive diseases. PMID- 23341772 TI - E. coli Fis protein insulates the cbpA gene from uncontrolled transcription. AB - The Escherichia coli curved DNA binding protein A (CbpA) is a poorly characterised nucleoid associated factor and co-chaperone. It is expressed at high levels as cells enter stationary phase. Using genetics, biochemistry, and genomics, we have examined regulation of, and DNA binding by, CbpA. We show that Fis, the dominant growth-phase nucleoid protein, prevents CbpA expression in growing cells. Regulation by Fis involves an unusual "insulation" mechanism. Thus, Fis protects cbpA from the effects of a distal promoter, located in an adjacent gene. In stationary phase, when Fis levels are low, CbpA binds the E. coli chromosome with a preference for the intrinsically curved Ter macrodomain. Disruption of the cbpA gene prompts dramatic changes in DNA topology. Thus, our work identifies a novel role for Fis and incorporates CbpA into the growing network of factors that mediate bacterial chromosome structure. PMID- 23341773 TI - Integrative genomics in combination with RNA interference identifies prognostic and functionally relevant gene targets for oral squamous cell carcinoma. AB - In oral squamous cell carcinoma (OSCC), metastasis to lymph nodes is associated with a 50% reduction in 5-year survival. To identify a metastatic gene set based on DNA copy number abnormalities (CNAs) of differentially expressed genes, we compared DNA and RNA of OSCC cells laser-microdissected from non-metastatic primary tumors (n = 17) with those from lymph node metastases (n = 20), using Affymetrix 250K Nsp single-nucleotide polymorphism (SNP) arrays and U133 Plus 2.0 arrays, respectively. With a false discovery rate (FDR)<5%, 1988 transcripts were found to be differentially expressed between primary and metastatic OSCC. Of these, 114 were found to have a significant correlation between DNA copy number and gene expression (FDR<0.01). Among these 114 correlated transcripts, the corresponding genomic regions of each of 95 transcripts had CNAs differences between primary and metastatic OSCC (FDR<0.01). Using an independent dataset of 133 patients, multivariable analysis showed that the OSCC-specific and overall mortality hazards ratio (HR) for patients carrying the 95-transcript signature were 4.75 (95% CI: 2.03-11.11) and 3.45 (95% CI: 1.84-6.50), respectively. To determine the degree by which these genes impact cell survival, we compared the growth of five OSCC cell lines before and after knockdown of over-amplified transcripts via a high-throughput siRNA-mediated screen. The expression-knockdown of 18 of the 26 genes tested showed a growth suppression >= 30% in at least one cell line (P<0.01). In particular, cell lines derived from late-stage OSCC were more sensitive to the knockdown of G3BP1 than cell lines derived from early-stage OSCC, and the growth suppression was likely caused by increase in apoptosis. Further investigation is warranted to examine the biological role of these genes in OSCC progression and their therapeutic potentials. PMID- 23341774 TI - A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. AB - Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 * 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations. PMID- 23341775 TI - Genetic disruption of the copulatory plug in mice leads to severely reduced fertility. AB - Seminal fluid proteins affect fertility at multiple stages in reproduction. In many species, a male's ejaculate coagulates to form a copulatory plug. Although taxonomically widespread, the molecular details of plug formation remain poorly understood, limiting our ability to manipulate the structure and understand its role in reproduction. Here I show that male mice knockouts for transglutaminase IV (Tgm4) fail to form a copulatory plug, demonstrating that this gene is necessary for plug formation and lending a powerful new genetic tool to begin characterizing plug function. Tgm4 knockout males show normal sperm count, sperm motility, and reproductive morphology. However, very little of their ejaculate migrates into the female's reproductive tract, suggesting the plug prevents ejaculate leakage. Poor ejaculate migration leads to a reduction in the proportion of oocytes fertilized. However, Tgm4 knockout males fertilized between 3-11 oocytes, which should be adequate for a normal litter. Nevertheless, females mated to Tgm4 knockout males for approximately 14 days were significantly less likely to give birth to a litter compared to females mated to wild-type males. Therefore, it appears that the plug also affects post-fertilization events such as implantation and/or gestation. This study shows that a gene influencing the viscosity of seminal fluid has a major influence on male fertility. PMID- 23341776 TI - Tbx2 controls lung growth by direct repression of the cell cycle inhibitor genes Cdkn1a and Cdkn1b. AB - Vertebrate organ development relies on the precise spatiotemporal orchestration of proliferation rates and differentiation patterns in adjacent tissue compartments. The underlying integration of patterning and cell cycle control during organogenesis is insufficiently understood. Here, we have investigated the function of the patterning T-box transcription factor gene Tbx2 in lung development. We show that lungs of Tbx2-deficient mice are markedly hypoplastic and exhibit reduced branching morphogenesis. Mesenchymal proliferation was severely decreased, while mesenchymal differentiation into fibrocytes was prematurely induced. In the epithelial compartment, proliferation was reduced and differentiation of alveolar epithelial cells type 1 was compromised. Prior to the observed cellular changes, canonical Wnt signaling was downregulated, and Cdkn1a (p21) and Cdkn1b (p27) (two members of the Cip/Kip family of cell cycle inhibitors) were strongly induced in the Tbx2-deficient lung mesenchyme. Deletion of both Cdkn1a and Cdkn1b rescued, to a large degree, the growth deficits of Tbx2 deficient lungs. Prolongation of Tbx2 expression into adulthood led to hyperproliferation and maintenance of mesenchymal progenitor cells, with branching morphogenesis remaining unaffected. Expression of Cdkn1a and Cdkn1b was ablated from the lung mesenchyme in this gain-of-function setting. We further show by ChIP experiments that Tbx2 directly binds to Cdkn1a and Cdkn1b loci in vivo, defining these two genes as direct targets of Tbx2 repressive activity in the lung mesenchyme. We conclude that Tbx2-mediated regulation of Cdkn1a and Cdkn1b represents a crucial node in the network integrating patterning information and cell cycle regulation that underlies growth, differentiation, and branching morphogenesis of this organ. PMID- 23341777 TI - Genome-wide association study identifies a novel susceptibility locus at 12q23.1 for lung squamous cell carcinoma in han chinese. AB - Adenocarcinoma (AC) and squamous cell carcinoma (SqCC) are two major histological subtypes of lung cancer. Genome-wide association studies (GWAS) have made considerable advances in the understanding of lung cancer susceptibility. Obvious heterogeneity has been observed between different histological subtypes of lung cancer, but genetic determinants in specific to lung SqCC have not been systematically investigated. Here, we performed the GWAS analysis specifically for lung SqCC in 833 SqCC cases and 3,094 controls followed by a two-stage replication in additional 2,223 lung SqCC cases and 6,409 controls from Chinese populations. We found that rs12296850 in SLC17A8-NR1H4 gene region at12q23.1 was significantly associated with risk of lung SqCC at genome-wide significance level [additive model: odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.72 0.84, P = 1.19*10(-10)]. Subjects carrying AG or GG genotype had a 26% (OR = 0.74, 95% CI = 0.67-0.81) or 32% (OR = 0.68, 95% CI = 0.56-0.83) decreased risk of lung SqCC, respectively, as compared with AA genotype. However, we did not observe significant association between rs12296850 and risk of lung AC in a total of 4,368 cases with lung AC and 9,486 controls (OR = 0.96, 95% CI = 0.90-1.02, P = 0.173). These results indicate that genetic variations on chromosome 12q23.1 may specifically contribute to lung SqCC susceptibility in Chinese population. PMID- 23341778 TI - Secondary metabolism and development is mediated by LlmF control of VeA subcellular localization in Aspergillus nidulans. AB - Secondary metabolism and development are linked in Aspergillus through the conserved regulatory velvet complex composed of VeA, VelB, and LaeA. The founding member of the velvet complex, VeA, shuttles between the cytoplasm and nucleus in response to alterations in light. Here we describe a new interaction partner of VeA identified through a reverse genetics screen looking for LaeA-like methyltransferases in Aspergillus nidulans. One of the putative LaeA-like methyltransferases identified, LlmF, is a negative regulator of sterigmatocystin production and sexual development. LlmF interacts directly with VeA and the repressive function of LlmF is mediated by influencing the localization of VeA, as over-expression of llmF decreases the nuclear to cytoplasmic ratio of VeA while deletion of llmF results in an increased nuclear accumulation of VeA. We show that the methyltransferase domain of LlmF is required for function; however, LlmF does not directly methylate VeA in vitro. This study identifies a new interaction partner for VeA and highlights the importance of cellular compartmentalization of VeA for regulation of development and secondary metabolism. PMID- 23341779 TI - NBR1-mediated selective autophagy targets insoluble ubiquitinated protein aggregates in plant stress responses. AB - Plant autophagy plays an important role in delaying senescence, nutrient recycling, and stress responses. Functional analysis of plant autophagy has almost exclusively focused on the proteins required for the core process of autophagosome assembly, but little is known about the proteins involved in other important processes of autophagy, including autophagy cargo recognition and sequestration. In this study, we report functional genetic analysis of Arabidopsis NBR1, a homolog of mammalian autophagy cargo adaptors P62 and NBR1. We isolated two nbr1 knockout mutants and discovered that they displayed some but not all of the phenotypes of autophagy-deficient atg5 and atg7 mutants. Like ATG5 and ATG7, NBR1 is important for plant tolerance to heat, oxidative, salt, and drought stresses. The role of NBR1 in plant tolerance to these abiotic stresses is dependent on its interaction with ATG8. Unlike ATG5 and ATG7, however, NBR1 is dispensable in age- and darkness-induced senescence and in resistance to a necrotrophic pathogen. A selective role of NBR1 in plant responses to specific abiotic stresses suggest that plant autophagy in diverse biological processes operates through multiple cargo recognition and delivery systems. The compromised heat tolerance of atg5, atg7, and nbr1 mutants was associated with increased accumulation of insoluble, detergent-resistant proteins that were highly ubiquitinated under heat stress. NBR1, which contains an ubiquitin-binding domain, also accumulated to high levels with an increasing enrichment in the insoluble protein fraction in the autophagy-deficient mutants under heat stress. These results suggest that NBR1-mediated autophagy targets ubiquitinated protein aggregates most likely derived from denatured or otherwise damaged nonnative proteins generated under stress conditions. PMID- 23341781 TI - Human disease-associated genetic variation impacts large intergenic non-coding RNA expression. AB - Recently it has become clear that only a small percentage (7%) of disease associated single nucleotide polymorphisms (SNPs) are located in protein-coding regions, while the remaining 93% are located in gene regulatory regions or in intergenic regions. Thus, the understanding of how genetic variations control the expression of non-coding RNAs (in a tissue-dependent manner) has far-reaching implications. We tested the association of SNPs with expression levels (eQTLs) of large intergenic non-coding RNAs (lincRNAs), using genome-wide gene expression and genotype data from five different tissues. We identified 112 cis-regulated lincRNAs, of which 45% could be replicated in an independent dataset. We observed that 75% of the SNPs affecting lincRNA expression (lincRNA cis-eQTLs) were specific to lincRNA alone and did not affect the expression of neighboring protein-coding genes. We show that this specific genotype-lincRNA expression correlation is tissue-dependent and that many of these lincRNA cis-eQTL SNPs are also associated with complex traits and diseases. PMID- 23341780 TI - Multiple opposing constraints govern chromosome interactions during meiosis. AB - Homolog pairing and crossing over during meiosis I prophase is required for accurate chromosome segregation to form euploid gametes. The repair of Spo11 induced double-strand breaks (DSB) using a homologous chromosome template is a major driver of pairing in many species, including fungi, plants, and mammals. Inappropriate pairing and crossing over at ectopic loci can lead to chromosome rearrangements and aneuploidy. How (or if) inappropriate ectopic interactions are disrupted in favor of allelic interactions is not clear. Here we used an in vivo "collision" assay in budding yeast to test the contributions of cohesion and the organization and motion of chromosomes in the nucleus on promoting or antagonizing interactions between allelic and ectopic loci at interstitial chromosome sites. We found that deletion of the cohesin subunit Rec8, but not other chromosome axis proteins (e.g. Red1, Hop1, or Mek1), caused an increase in homolog-nonspecific chromosome interaction, even in the absence of Spo11. This effect was partially suppressed by expression of the mitotic cohesin paralog Scc1/Mdc1, implicating Rec8's role in cohesion rather than axis integrity in preventing nonspecific chromosome interactions. Disruption of telomere-led motion by treating cells with the actin polymerization inhibitor Latrunculin B (Lat B) elevated nonspecific collisions in rec8Delta spo11Delta. Next, using a visual homolog-pairing assay, we found that the delay in homolog pairing in mutants defective for telomere-led chromosome motion (ndj1Delta or csm4Delta) is enhanced in Lat B-treated cells, implicating actin in more than one process promoting homolog juxtaposition. We suggest that multiple, independent contributions of actin, cohesin, and telomere function are integrated to promote stable homolog specific interactions and to destabilize weak nonspecific interactions by modulating the elastic spring-like properties of chromosomes. PMID- 23341782 TI - Mendelian and non-Mendelian regulation of gene expression in maize. AB - Transcriptome variation plays an important role in affecting the phenotype of an organism. However, an understanding of the underlying mechanisms regulating transcriptome variation in segregating populations is still largely unknown. We sought to assess and map variation in transcript abundance in maize shoot apices in the intermated B73 * Mo17 recombinant inbred line population. RNA-based sequencing (RNA-seq) allowed for the detection and quantification of the transcript abundance derived from 28,603 genes. For a majority of these genes, the population mean, coefficient of variation, and segregation patterns could be predicted by the parental expression levels. Expression quantitative trait loci (eQTL) mapping identified 30,774 eQTL including 96 trans-eQTL "hotspots," each of which regulates the expression of a large number of genes. Interestingly, genes regulated by a trans-eQTL hotspot tend to be enriched for a specific function or act in the same genetic pathway. Also, genomic structural variation appeared to contribute to cis-regulation of gene expression. Besides genes showing Mendelian inheritance in the RIL population, we also found genes whose expression level and variation in the progeny could not be predicted based on parental difference, indicating that non-Mendelian factors also contribute to expression variation. Specifically, we found 145 genes that show patterns of expression reminiscent of paramutation such that all the progeny had expression levels similar to one of the two parents. Furthermore, we identified another 210 genes that exhibited unexpected patterns of transcript presence/absence. Many of these genes are likely to be gene fragments resulting from transposition, and the presence/absence of their transcripts could influence expression levels of their ancestral syntenic genes. Overall, our results contribute to the identification of novel expression patterns and broaden the understanding of transcriptional variation in plants. PMID- 23341783 TI - Positional cloning reveals strain-dependent expression of Trim16 to alter susceptibility to bleomycin-induced pulmonary fibrosis in mice. AB - Pulmonary fibrosis is a disease of significant morbidity, with no effective therapeutics and an as yet incompletely defined genetic basis. The chemotherapeutic agent bleomycin induces pulmonary fibrosis in susceptible C57BL/6J mice but not in mice of the C3H/HeJ strain, and this differential strain response has been used in prior studies to map bleomycin-induced pulmonary fibrosis susceptibility loci named Blmpf1 and Blmpf2. In this study we isolated the quantitative trait gene underlying Blmpf2 initially by histologically phenotyping the bleomycin-induced lung disease of sublines of congenic mice to reduce the linkage region to 13 genes. Of these genes, Trim16 was identified to have strain-dependent expression in the lung, which we determined was due to sequence variation in the promoter. Over-expression of Trim16 by plasmid injection increased pulmonary fibrosis, and bronchoalveolar lavage levels of both interleukin 12/23-p40 and neutrophils, in bleomycin treated B6.C3H-Blmpf2 subcongenic mice compared to subcongenic mice treated with bleomycin only, which follows the C57BL/6J versus C3H/HeJ strain difference in these traits. In summary we demonstrate that genetic variation in Trim16 leads to its strain-dependent expression, which alters susceptibility to bleomycin-induced pulmonary fibrosis in mice. PMID- 23341785 TI - Increasing trend of colorectal cancer incidence in Korea, 1999-2009. AB - PURPOSE: This study was conducted in order to demonstrate changing trends in colorectal cancer incidence according to sex, age group, and anatomical location in the Korean population. MATERIALS AND METHODS: Data from the Korea Central Cancer Registry between 1999 and 2009 were analyzed. Annual percent changes (APCs) of sex- and age-specific incidence rates for cancer of the proximal colon (International Statistical Classification of Diseases and Related Health Problems, 10th revision [ICD-10] code C18.0-18.5), distal colon (C18.6-18.7), and rectum (C19-20), and male-to-female incidence rate ratios (IRR) were calculated. RESULTS: The age-standardized incidence rate (ASR) of colorectal cancer was 27 (per 100,000) in 1999 and increased to 50.2 in 2009 among men (APC, 6.6%). The ASR for women was 17.2 in 1999 and 26.9 in 2009 (APC, 5.1%). The rectum was the most common site of cancer among both men and women during 1999 and 2009. However, the distal colon had the highest APC (10.8% among men and 8.4% among women), followed by the proximal colon (7.9% among men and 6.6% among women), and rectum (5.2% among men and 2.4% among women). The proportion of rectal cancer decreased from 51.5% in 1999 to 47.1% in 2009 among men, and from 50.5% to 42.8% among women. An increase in the male-to-female IRR was observed for distal colon cancer and rectal cancer, whereas the IRR for proximal colon cancer was stable. CONCLUSION: The rapid increase in colorectal cancer incidence is mainly attributed to the increase in colon cancer, especially distal colon cancer, and may be explained by a transition of risk factors for subsites or by the effect of colorectal cancer screening. PMID- 23341784 TI - Magel2 is required for leptin-mediated depolarization of POMC neurons in the hypothalamic arcuate nucleus in mice. AB - Prader-Willi Syndrome is the most common syndromic form of human obesity and is caused by the loss of function of several genes, including MAGEL2. Mice lacking Magel2 display increased weight gain with excess adiposity and other defects suggestive of hypothalamic deficiency. We demonstrate Magel2-null mice are insensitive to the anorexic effect of peripherally administered leptin. Although their excessive adiposity and hyperleptinemia likely contribute to this physiological leptin resistance, we hypothesized that Magel2 may also have an essential role in intracellular leptin responses in hypothalamic neurons. We therefore measured neuronal activation by immunohistochemistry on brain sections from leptin-injected mice and found a reduced number of arcuate nucleus neurons activated after leptin injection in the Magel2-null animals, suggesting that most but not all leptin receptor-expressing neurons retain leptin sensitivity despite hyperleptinemia. Electrophysiological measurements of arcuate nucleus neurons expressing the leptin receptor demonstrated that although neurons exhibiting hyperpolarizing responses to leptin are present in normal numbers, there were no neurons exhibiting depolarizing responses to leptin in the mutant mice. Additional studies demonstrate that arcuate nucleus pro-opiomelanocortin (POMC) expressing neurons are unresponsive to leptin. Interestingly, Magel2-null mice are hypersensitive to the anorexigenic effects of the melanocortin receptor agonist MT-II. In Prader-Willi Syndrome, loss of MAGEL2 may likewise abolish leptin responses in POMC hypothalamic neurons. This neural defect, together with increased fat mass, blunted circadian rhythm, and growth hormone response pathway defects that are also linked to loss of MAGEL2, could contribute to the hyperphagia and obesity that are hallmarks of this disorder. PMID- 23341786 TI - Definitive Radiotherapy versus Postoperative Radiotherapy for Tonsil Cancer. AB - PURPOSE: The purpose of this study is to analyze treatment outcome of radiotherapy (RT) in patients with stage III-IV tonsil cancer managed by surgery followed by postoperative RT (SRT) and definitive chemoradiotherapy (CRT), and to thereby evaluate the most feasible treatment modality. MATERIALS AND METHODS: Of 124 patients, 67 underwent CRT, and 57 underwent SRT. We compared survival and complication rates in both groups. RESULTS: The median follow-up time was 57 months (range, 19 to 255 months) for surviving patients. At five years, locoregional progression-free survival (LRPFS) and overall survival (OS) were 88% and 80%, respectively. No significant difference in LRPFS (p=0.491) and OS (p=0.177) was observed between CRT and SRT. In multivariate analysis, old age and higher T stage showed a significant association with poor LRPFS, PFS, and OS; higher N stage showed an association with poor PFS and a trend of poor LRPFS, while no association with OS was observed; treatment modality (CRT and SRT) showed no association with LRFPS, PFS, and OS. Grade 3 or higher mucositis was observed in 12 patients (21%) in the SRT group, and 25 patients (37%) in the CRT group. CONCLUSION: Definitive CRT and SRT have similar treatment outcomes for patients with stage III-IV tonsil cancer. Although acute complication rate appears to be higher in the CRT group, it should be noted that not all data on complications were included in this retrospective study. To determine the most feasible treatment modality, not only mucositis and xerostomia, but also emotional aspect and quality of life, should be considered. PMID- 23341787 TI - Outcomes of third-line docetaxel-based chemotherapy in advanced gastric cancer who failed previous oxaliplatin-based and irinotecan-based chemotherapies. AB - PURPOSE: Little is known about outcomes in the use of third-line chemotherapy in cases of advanced gastric cancer (AGC). The primary aim of this retrospective study was to evaluate outcomes of docetaxel-based chemotherapy in patients with AGC that progressed after both oxaliplatin-based and irinotecan-based regimens. MATERIALS AND METHODS: Eligible patients were those with AGC who had previous chemotherapy including fluoropyrimidine and oxaliplatin as well as fluoropyrimidine and irinotecan and who received subsequent docetaxel-based chemotherapy. Thirty-five patients were retrospectively recruited from 5 medical centers in Korea. Patients received either weekly or 3 weekly with docetaxel +/- cisplatin. RESULTS: Thirty-one out of 35 patients were evaluated for treatment response. A total of 94 cycles of chemotherapy (median, 2; range, 1 to 7) were administered. The overall response rate was 14.3%, and the disease control rate was 45.7%. The median progression-free survival (PFS) was 1.9 months (95% confidence interval [CI], 1.1 to 2.7 months). The median overall survival (OS) was 3.6 months (95% CI, 2.8 to 4.4 months). PFS and OS were significantly prolonged in patients of the Eastern Cooperative Oncology Group, with performance status of 0 or 1 in multivariate analysis (PFS: hazard ratio[HR], 0.411; 95% CI, 0.195 to 0.868; p=0.020 and OS: HR, 0.390; 95% CI, 0.184 to 0.826; p=0.014, respectively). Four of the 35 patients enrolled in the study died due to infection associated with neutropenia. CONCLUSION: Our findings suggest that salvage docetaxel-based chemotherapy is a feasible treatment option for AGC patients with good performance status (PS), whereas chemotherapy for patients with poor PS (PS<=2) should be undertaken with caution for those who previously failed oxaliplatin- and irinotecan-based regimens. PMID- 23341788 TI - Influence of Comorbidities on the Efficacy of Radiotherapy with or without Chemotherapy in Elderly Stage III Non-small Cell Lung Cancer Patients. AB - PURPOSE: The current study was conducted in order to evaluate the clinical outcome of radical radiotherapy (RT) with or without chemotherapy for elderly patients with stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Between 1990 and 2010, 125 patients, aged 70 years or more, received radical RT with or without chemotherapy for treatment of stage III NSCLC. We reviewed the patients' prognostic factors, including comorbidities. Comorbidity status was evaluated using a simplified comorbidity score (SCS). Of the patients reviewed, 82 received radical RT alone, whereas the other 43 patients underwent chemoradiotherapy (CRT). A platinum-based chemotherapy regimen was most commonly used (42/43). RESULTS: The two-year overall-survival (OS) and progression-free survival (PFS) rates were 32.2% and 21.8%, respectively. SCS was the independent prognostic factor for OS. In the frail elderly subgroup with a SCS of >=10, CRT demonstrated a significant difference in PFS, but not in OS. In contrast, OS and PFS following CRT were significantly superior to RT in the fit elderly subgroup with a SCS of <10. The incidence of severe pulmonary toxicities in the frail elderly subgroup was significantly higher than that in the fit elderly subgroup. CONCLUSION: Multiple comorbidities evaluated according to the SCS are related to poor OS in elderly patients with stage III NSCLC. CRT improved clinical outcome when compared to RT in the fit elderly subgroup, however, the gain from this treatment was negated in the frail elderly subgroup with multiple comorbidities. Therefore, evaluation of comorbidity is necessary in order to determine whether chemotherapy should be combined with RT in elderly patients with stage III NSCLC. PMID- 23341789 TI - The Blocking of c-Met Signaling Induces Apoptosis through the Increase of p53 Protein in Lung Cancer. AB - PURPOSE: c-Met is an attractive potential target for novel therapeutic inhibition of human cancer, and c-Met tyrosine kinase inhibitors (TKIs) are effective growth inhibitors of various malignancies. However, their mechanisms in anticancer effects are not clear. In the present study, we investigated the possibility that blocking c-Met signaling induces p53-mediated growth inhibition in lung cancer. MATERIALS AND METHODS: The growth inhibitory effects of c-Met TKI (SU11274) on lung cancer cells and a xenograft model were assessed using the MTT assay, flow cytometry, and terminal deoxyribonucleotide transferase-mediated nick-end labeling staining. The role of p53 protein in the sensitivity of c-Met TKI (SU11274) was examined by Western blot analysis and immunohistochemistry. RESULTS: SU11274 significantly induced apoptosis in A549 cells with wild-type p53, compared with that in Calu-1 cells with null-type p53. SU11274 increased p53 protein by enhancing the stability of p53 protein. Increased p53 protein by SU11274 induced up-regulation of Bax and PUMA expression and down-regulation of Bcl-2 expression, subsequently activating caspase 3. In p53 knock-out and knock in systems, we confirmed that SU11274 caused apoptosis through the p53-mediated apoptotic pathway. Likewise, in the A549 xenograft model, SU11274 effectively shrank tumor volume and induced apoptosis via increased p53 protein expression. Blocking c-Met signaling increased the level of p53 protein. CONCLUSION: Our finding suggested that p53 plays an important role in SU11274-induced apoptosis, and p53 status seems to be related to the sensitivity to SU11274 in lung cancer. PMID- 23341790 TI - CD10 Is Again Expressed at a Certain Stage during the Neoplastic Process of Bladder Transitional Cell Carcinomas. AB - PURPOSE: CD10, a membrane-bound zinc-dependent metallopeptidase, is normally expressed in many tissues. Accordingly, the derangement of CD10 expression may be related to development or progression in a variety of tumors. The aim of this study is to examine any association between CD10 expression and clinicopathological parameters in bladder transitional cell carcinomas (TCCs) and the relationship between expression of E-cadherin and CD10. MATERIALS AND METHODS: Immunohistochemical staining was performed for CD10 and E-cadherin in tissues of 94 TCCs and 10 non-neoplastic bladder mucosa. RESULTS: Positive immunoreactivity for CD10 was observed in non-neoplastic urothelium at a proportion of 80% and TCCs were observed at a rate of 23%. A positive rate of CD10 expression was observed in 10% of total cases of a low grade tumor and in 35% of those of a high grade tumor. It was also observed in 15% of pTa tumors, 13% of pT1 tumors, and 48% of pT2 tumors. In addition, CD10 expression showed reciprocal correlation with expression of membranous E-cadherin in tumors. CONCLUSION: CD10 is again expressed at a certain stage during the neoplastic process of TCCs and could play some roles intheir carcinogenesis. PMID- 23341791 TI - A case of locally advanced breast cancer complicated by pulmonary tumor thrombotic microangiopathy. AB - Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare, malignancy-related complication that causes marked pulmonary hypertension, right heart failure, and death. We report on a patient with locally advanced breast cancer whose course was complicated by fatal PTTM based on clinical and laboratory findings. PMID- 23341792 TI - Poorly differentiated neuroendocrine carcinoma in a perigastric lymph node from an unknown primary site. AB - Neuroendocrine carcinomas from an unknown primary site are uncommon. The authors report on a case of neuroendocrine carcinoma in a perigastric lymph node (LN) with no primary site. A 52-year-old male patient with early gastric adenocarcinoma underwent treatment by endoscopic submucosal dissection, and, six months later, findings on a computed tomographic scan of the abdomen revealed a LN enlargement measuring 2.0 cm in the perigastric region. The patient underwent subtotal gastrectomy and regional LN dissection under a suggestive preoperative diagnosis of gastric adenocarcinoma with LN metastasis. However, microscopically, no residual tumor was found in the stomach, and the perigastric LN showed poorly differentiated neuroendocrine carcinoma (PDNEC). After an extensive workup, no primary site was identified. The patient also received four cycles of etoposide and cisplatin. Despite its extremely rare incidence, this case suggests that PDNEC of an unknown primary site is limited to a single site, and that resection should be considered in combination with chemotherapy. PMID- 23341793 TI - Mucoepidermoid carcinoma in the external auditory canal: a case report. AB - Mucoepidermoid carcinoma in the external auditory canal is extremely rare. Strategies used for treatment of mucoepidermoid carcinoma remain controversial. We present a case of mucoepidermoid carcinoma of the external auditory canal. The patient underwent lateral temporal bone resection and the surgical defect was obliterated with temporal muscle. He is currently disease-free, four years after surgery. Proper diagnostic measures and strategy for treatment of mucoepidermoid carcinoma are discussed. PMID- 23341794 TI - Commentary on "a case of erdheim-chester disease with asymptomatic renal involvement". PMID- 23341795 TI - Reply to commentary on "a case of erdheim-chester disease with asymptomatic renal involvement". PMID- 23341796 TI - Resected pleomorphic carcinoma of the gallbladder. AB - Pleomorphic carcinoma is a rare lesion and the literature contains few reports of pleomorphic carcinoma of the gallbladder. The present study reports a rare case of primary pleomorphic carcinoma of the gallbladder for which we were able to perform curative surgery. A 77-year-old woman with dementia developed nausea and anorexia, and computed tomography demonstrated irregular thickening of the gallbladder wall. Drip infusion cholangiography and endoscopic retrograde cholangiopancreatography revealed no stenosis of the common and intrahepatic bile ducts. We suspected carcinoma of the gallbladder without lymph node metastasis and invasion to the common bile duct. We guessed it to be resectable and performed open laparotomy. At operation, the fundus of the gallbladder was adherent to the transverse colon, but no lymph node and distant metastases were detected. Therefore, we performed curative cholecystectomy with partial colectomy. Histopathology and immunostaining showed coexistence of an adenocarcinoma, squamous cell carcinoma and sarcomatous tumor of spindle-shaped cell, as well as transition zones between these tumors. We diagnosed stage I pleomorphic carcinoma of the gallbladder. No recurrence has been observed for one and a half years. The biological behavior of pleomorphic carcinoma of the gallbladder remains unknown. It will be necessary to accumulate more case reports of this tumor in order to define diagnostic criteria. PMID- 23341797 TI - Intestinal Obstruction due to Complete Transmural Migration of a Retained Surgical Sponge into the Intestine. AB - A 56-year-old woman with a history of gynecological surgery for cervical cancer 18 years previously was referred to our hospital for colicky abdominal pain, nausea and vomiting. Intestinal obstruction was diagnosed by contrast-enhanced computed tomography (CT) which showed dilation of the small intestine and suggested obstruction in the terminal ileum. In addition, CT showed a thick walled cavitary lesion communicating with the proximal jejunum. (18)F fluorodeoxyglucose positron emission tomography showed abnormal uptake at the same location as the cavitary lesion revealed by CT. The patient underwent laparotomy for the ileus and resection of the cavitary lesion. At laparotomy, we found a retained surgical sponge in the ileum 60 cm from the ileocecal valve. The cavitary tumor had two fistulae communicating with the proximal jejunum. The tumor was resected en bloc together with the transverse colon, part of the jejunum and the duodenum. Microscopic examination revealed fibrous encapsulation and foreign body giant cell reaction. Since a retained surgical sponge without radiopaque markers is extremely difficult to diagnose, retained surgical sponge should be considered in the differential diagnosis of intestinal obstruction in patients who have undergone previous abdominal surgery. PMID- 23341798 TI - Esophageal perforation: a rare complication of transesophageal echocardiography in a patient with asymptomatic esophagitis. AB - Transesophageal echocardiography (TEE) is a commonly used procedure in patients with suspected endocarditis. A rare but dreadful complication of this procedure is perforation of the esophagus. We report the case of an elderly female with multiple comorbidities, who presented with polyarticular septic arthritis. TEE was performed to rule out endocarditis. Though the standard procedure protocol was followed, she developed esophageal perforation. It was managed with esophageal stenting but she developed multiorgan failure and did not survive. This case highlights the potential of severe morbidity and mortality associated with TEE. Appropriate screening must be done and high-risk individuals must be identified before such procedures are attempted. PMID- 23341799 TI - Combination Therapy with Intensive Granulocyte and Monocyte Adsorptive Apheresis plus Adalimumab: Therapeutic Outcomes in 5 Cases with Refractory Crohn's Disease. AB - Adalimumab (ADA) is applied to induce remission in patients with Crohn's disease (CD) naive to chimeric anti-tumor necrosis factor-alpha (anti-TNF-alpha), infliximab or patients with loss of response to scheduled maintenance infliximab. Adsorptive granulocyte and monocyte apheresis (GMA) depletes elevated/activated myeloid lineage leucocytes as sources of inflammatory cytokines and has been used to treat patients with CD. This study was to investigate the efficacy of intensive GMA in combination with ADA as remission induction therapy in cases of CD refractory to medications including anti-TNF-alpha therapies. Between December 2010 and February 2012, 5 consecutive cases with refractory CD were treated with intensive GMA (2 sessions per week) plus ADA to induce remission. CD activity index (CDAI), C-reactive protein (CRP), and endoscopic findings based on the simple endoscopic score for CD (SES-CD) at baseline and 10 weeks post 5 ADA injections were applied to determine treatment efficacy outcomes. At week 10 post ADA treatment, clinical remission together with normal CRP levels were achieved in all 5 cases, while SES-CD scores reflected marked improvement in 3 cases and partial improvement in 2 cases who had extensive deep longitudinal CD lesions. The CDAI and CRP values at baseline were 324 +/- 118 and 4.9 +/- 3.3 mg/dl, respectively. The corresponding values after treatment were 100 +/- 28 (p = 0.024) and 0.2 +/- 0.2 mg/dl (p = 0.038). In these 5 cases with medication refractory CD, combination therapy with intensive GMA followed by 5 ADA shots appeared to be an effective and safe intervention for inducing clinical remission. PMID- 23341800 TI - Angiosarcoma involving solid organs and the gastrointestinal tract with life threatening bleeding. AB - We report a rare case of angiosarcoma involving the gastrointestinal tract, liver, spleen, pancreas, kidney, lung and vertebrae, as well as bulky dissemination in the pleuroperitoneal membranes. A 72-year-old man with no history of illness became aware of melena. Laboratory findings revealed anemia, and upper gastrointestinal endoscopy revealed multiple reddish nodules in the stomach and duodenum. However, biopsy specimens showed no evidence of histological features. Computed tomography and fluorodeoxyglucose positron emission tomography showed space-occupying lesions in the spleen, liver and vertebrae. Angiosarcoma was diagnosed by endoscopic ultrasound and fine needle aspiration biopsy of the spleen and repeated endoscopic biopsy of the stomach. We performed laparoscopic splenectomy to avoid rupture of the involved spleen. Due to continuous gastrointestinal bleeding, double balloon endoscopy was performed and multiple bleeding lesions were detected throughout the small intestine. Surgical hemostasis was performed by partial enterectomy, but anemia continued to worsen. Therefore, we conducted transcatheter arterial embolization. Despite attempting several modalities and frequent daily blood transfusion, the anemia did not improve, and the patient expired due to hemorrhagic shock. Subsequent autopsy revealed the cause of death as rupture and bleeding due to disseminated involvement of the small intestine. PMID- 23341801 TI - All the wrong places: an unusual case of foreign body ingestion and inhalation. AB - Intentional ingestion of foreign bodies is common in psychiatric patients and prison inmates. Timing of endoscopy for ingested foreign bodies varies and depends on the type and location of the foreign body in the gastrointestinal tract. We present the case of a 26-year-old man who was brought from a correctional facility after confessing to have swallowed a few shower curtain hooks. Abdominal X-ray done in the emergency room revealed multiple foreign bodies in the stomach. An upper endoscopy was done in the emergency room with the use of an overtube. The first metal piece was caught by a snare and removed with the endoscope. All other foreign bodies which were present on the abdominal X-ray could not be visualized initially as there was retained food in the stomach. After multiple attempts, four other foreign bodies were found and each one was caught by the forceps and then the scope was removed with the forceps holding the foreign body. There was an additional foreign body in the right mainstem bronchus. The patient had coughed up the foreign body and swallowed it into the gastrointestinal tract. A computed tomography scan of chest and abdomen was done for evaluation, which showed the foreign body in the cecum. To our knowledge, this is the first case report of a patient intentionally transferring a foreign body from one organ system to another. Colonoscopy was done and the foreign body was removed rectally with a snare without any complications. PMID- 23341802 TI - IGF-II Producing Hepatocellular Carcinoma Treated with Sorafenib: Metabolic Complications and a Foresight to Molecular Targeting Therapy to the IGF Signal. AB - Hypoglycemia is a rare paraneoplastic manifestation of patients with neoplasms. Hypoglycemia can be induced by several causes, including an aberrant increase of hypoglycemic agents and adrenal insufficiency. Sorafenib is the first agent to demonstrate a survival benefit in the treatment of advanced hepatocellular carcinoma (HCC). This small molecule inhibits serine/threonine kinase RAF in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature and decreases tumor growth and angiogenesis. In this paper, we report a case of HCC who was treated with sorafenib and showed severe hypoglycemia. This hypoglycemia might be induced by two causes, both adrenal insufficiency as an adverse effect of sorafenib and activation of the insulin-like growth factor (IGF) signal by excessive secretion of incompletely processed precursors of IGF-II. Although the IGF signal is suggested to be involved in aberrant growth of HCC in some cases, there is no other report showing the influence of sorafenib on HCC with active IGF signal. Unfortunately, the effect of sorafenib was limited in the present case. However, emerging drugs that directly inhibit the IGF signal can be expected to be highly effective in the treatment of HCC with hypoglycemia. PMID- 23341803 TI - First diagnosis of inflammatory bowel disease in a 91-year-old man. AB - Inflammatory bowel diseases (IBDs) are diseases that occur primarily in adolescence and early adult life. A second peak of IBD incidence occurs at the age of 50-80 years, while reports of first diagnosis after the age of 80 years are extremely rare. It is difficult to establish the true incidence of IBD in older patients due to problems of case definition, population, and particularly because it may be confused with other clinical conditions. A 91-year-old man was admitted to the Emergency Department with progressively worsening abdominal pain and 2-4 episodes of bloody diarrhea daily for the last month. Similar symptoms were not reported by the patient or his family during the past. Complete blood count and biochemical tests were normal, while stool examination showed erythrocytes and white blood cells. Pelvic CT showed inflammatory changes and loss of homogeneity in the perirectal fat together with considerable bowel wall thickening of both the rectum and sigmoid. Colonoscopy revealed edema, hyperemia and spontaneous friability, as well as microulcerations of the rectosigmoid mucosa. Tissue biopsies revealed histopathological lesions compatible with IBD. Finally the patient was treated with metronidazole, ciprofloxacin and mesalazine, with clear clinical improvement during the 5th day of treatment, and was finally discharged with almost normal stools. In conclusion, we report the case of first diagnosis of IBD in a 91-year-old man. The prevalence of IBD in patients aged >80 years is difficult to determine. Diagnostic tools are the same as for other age groups, but diagnosis may be difficult because there are a number of clinical conditions that may mimic IBD at this age. The treatment options are those used in younger patients, but special precautions should be taken. PMID- 23341804 TI - Synchronous Double Malignant Tumors Consisting of Stomach and Hodgkin's Lymphoma with Collision between Gastric Adenocarcinoma and Hodgkin's Lymphoma in the Stomach. AB - We report the rare case of a 72-year-old man with double cancers (gastric adenocarcinoma and Hodgkin's lymphoma) with collision between gastric adenocarcinoma and Hodgkin's lymphoma. Abdominal computed tomography showed increased wall thickness in the fundus region of the stomach and multiple lymph node swellings in the lesser curvature, periceliac and left cardial regions. Upper gastrointestinal endoscopy showed an ulcer approximately 5 cm in diameter with a malignant appearance in the fundus region of the stomach. On histopathologic examination, two completely different tumors were recognized in the stomach. One tumor was a poorly differentiated adenocarcinoma characterized by poorly developed tubular structures associated with prominent lymphoid infiltration of the stroma. The other tumor was found to have proliferated in the wall of the stomach, with diffuse granulomatous lesions and bordering the adenocarcinoma. Large atypical lymphoid cells with prominent nucleoli and enlarged mononuclei or multinuclei were seen in the latter tumor. Hodgkin's lymphoma was also found in the swollen lesser curvature lymph nodes. As a result, gastric adenocarcinoma and metastasis of Hodgkin's lymphoma were collided in the stomach. In conclusion, this case might be helpful in exploring the occurrence mechanism of tumor collision between lymphoma and carcinoma. PMID- 23341805 TI - Massive ascites as the initial manifestation of mantle cell lymphoma: a challenge for the gastroenterologist. AB - Involvement of the serosa may be the presenting feature in a wide and complex variety of lymphoproliferative diseases, with differing clinical outcomes covering a spectrum of benign and malignant conditions. Effusions involving peritoneal and pericardial cavities are uncommon during the course of hematological malignancies. Obstructive and/or infiltrative tumor mass or vascular leakage due to stimulation by vascular endothelial growth factor contribute to the pathogenesis. In addition to clinical findings, cytomorphology and flow cytometric immunophenotyping of the serosal fluid yield valuable information in the differential diagnosis of lymphocytic infiltrates. Herein, we describe the case of primary mantle cell lymphoma in a 75-year-old man presenting with abdominal fullness and weight loss, suggesting a gastrointestinal pathology. PMID- 23341806 TI - Optical coherence tomography and its role in mohs micrographic surgery: a case report. AB - Optical coherence tomography (OCT) is an imaging technology with the potential to provide high-resolution images of the skin non-invasively. With this device, it is possible to identify a host of skin structures including tumors. In this case report, we demonstrate the use of an OCT device in delineating a lateral tumor margin of an ill-defined basal cell carcinoma prior to Mohs micrographic surgery. Following surgery, the OCT images are compared to histologic sections to confirm their accuracy. OCT technology has the potential to be a vital tool for dermatologists and particularly Mohs surgeons in identifying tumor margins and potentially reducing the number of invasive procedures needed. PMID- 23341807 TI - Treatment of severe cold contact urticaria with omalizumab: case reports. AB - We report 2 patients with cold urticaria with different response to treatment with omalizumab (Xolair((r))). Cold contact urticaria (CCU) is a common subtype of physical urticaria. It is characterized by the development of wheal and/or angioedema within minutes after cold contact. Clinical manifestation of CCU can range from mild, localized whealing to life-threatening anaphylactic shock reactions. Omalizumab has been described to be useful in cases of chronic urticaria and may be an interesting option for treatment of CCU. We describe one patient with significant and long-lasting improvement of symptoms and one without any improvement after anti-immunoglobulin E therapy. In our case reports, we want to highlight that there is still a small group of patients without benefit from omalizumab treatment. It is necessary to identify this minor subgroup of patients where omalizumab does not represent an effective treatment possibility. PMID- 23341808 TI - Long-term disease control of a non-operable neuroendocrine tumor of the lung with lanreotide: a case study. AB - Bronchopulmonary neuroendocrine tumors (NETs) are malignant tumors that represent approximately 20% of all lung cancers. The therapeutic option for advanced or metastatic bronchopulmonary NETs is mainly palliation of symptoms; options need to be individualized and, therefore, rely on the knowledge of multidisciplinary teams. Somatostatin analogs have been widely used in NETs for control of hormonal syndromes and are currently under evaluation for their antiproliferative activity. Here, we present a case of NET of the lung, for which we achieved long term disease control with a treatment comprising the somatostatin analog lanreotide Autogel((r)) in a patient with limited therapeutic options due to considerable comorbidity, while preserving his quality of life. PMID- 23341809 TI - Benign cystic mesothelioma of the peritoneum: a rare case and review of the literature. AB - A 19-year-old male presented with right lower quadrant pain. Imaging studies revealed a cystic peritoneal mass. At surgery, a large peritoneal mass was excised. The pathology report revealed a benign cystic mesothelioma, and a right hemicolectomy with cytoreductive surgery was completed. PMID- 23341810 TI - Primary yolk sac tumor of the omentum: a case report and literature review. AB - Yolk sac tumor (YST) is a rare malignant tumor originating from germ cells. YST normally originates from the gonads, rarely occurring in extragonadal sites. We report a 35-year-old man with YST arising in the omentum, which is the first reported case of a primary YST of the omentum in an adult male. The patient presented to the community hospital with abdominal distension. A CT scan showed thickening of the omentum with ascites. The patient underwent open biopsy of the omental mass. The Pathology Department of the hospital could not make a definitive diagnosis at that time, and the tumor was considered a cancer of unknown primary (CUP) origin with features of primary colorectal cancer based on the immunohistochemistry (IHC) findings of the biopsy specimen (CK7-/CK20+ and CDX-2+). He was then referred to our hospital. We found that serum alpha fetoprotein was abnormally elevated to 7,144 ng/ml (normal <10.0), and reevaluation of the biopsy specimen revealed microcystic or reticular patterns of tumor cells with Schiller-Duval bodies typical of YST. The present case suggests that IHC is a very useful diagnostic tool for subtyping CUP but should be interpreted in the context of clinical and morphological findings. PMID- 23341811 TI - Durable complete remission of a brainstem glioma treated with a combination of bevacizumab and cetuximab. AB - Treatment of a relapsed glioma is a clinical challenge nowadays. New active treatments are required to treat these difficult diseases. Here we present a durable complete remission of a relapsed glioblastoma that has achieved a complete radiologic response with the combination of cetuximab and bevacizumab, in a third-line setting, that has offered a progression-free survival of 20 months. We consider here both potential mechanisms for the explanation of this result. First, the potential target of the cancer stem cells (CSCs) with these two antibodies, and second, the potential recruitment of the immune system to directly pursue the CSCs. PMID- 23341812 TI - A case of successful placement of a fully covered metallic stent for hemobilia secondary to hepatocellular carcinoma with bile duct invasion. AB - Hemobilia represents gastrointestinal bleeding that develops as a result of communication between blood vessels and the biliary tract, which causes the blood to reach the duodenal papilla. It is characterized by biliary colic as the initial symptom, and the complications of cholangitis, obstructive jaundice and/or anemia. In general, definitive diagnosis is made by esophagogastroduodenoscopy which confirms bleeding from the duodenal papilla. Abdominal US and abdominal enhanced CT are performed to identify the source of the bleeding, as well as ERCP for biliary drainage to control the comorbid cholangitis. If active hemorrhage accompanied by worsening of the anemia is suspected, abdominal angiography is performed to selectively image the hepatic artery. Then, embolization of the culprit vessel is recommended. In our patients with difficult hemostasis, because of the direct compression hemostasis to the tumor site achieved with the fully covered metallic stent and secondary compression hemostasis due to blood clots, the bleeding could be controlled. PMID- 23341813 TI - Long-Term Complete Remission with nab-Paclitaxel, Bevacizumab, and Gemcitabine Combination Therapy in a Patient with Triple-Negative Metastatic Breast Cancer. AB - This is a case study of a 52-year-old female patient diagnosed in June 2007 with primary metastatic invasive ductal carcinoma of the left breast and synchronous metastases in the bone, lymph nodes, and lung. Biopsy results of the tumor tissue were negative for the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). In November 2007, she participated in a phase II study of metastatic HER2-negative breast cancer. Treatment consisted of systemic chemotherapy with gemcitabine 1,500 mg/m(2), nab-paclitaxel 150 mg/m(2), and bevacizumab 10 mg/kg once every other week. The patient experienced pain relief in her sternum after 5 weeks of chemotherapy, and her analgesic therapy was discontinued. After 7 months, the patient achieved a complete radiographic response, which was maintained for nearly 2 additional years. She continued receiving treatment throughout this period, requiring 1 dose reduction due to fatigue. The patient experienced no other adverse events, including neuropathy, and continued working uninterrupted throughout her treatment. The patient was discontinued from the study in May 2010 after disease progression, almost a full 3 years after diagnosis. The patient showed minimal response to subsequent therapies but had disease stabilization and died from her disease in April 2012. Median overall survival for patients with metastatic triple-negative breast cancer is between 12 and 13.3 months. This patient survived nearly 5 years following diagnosis. This case exemplifies how therapy with nab-paclitaxel, bevacizumab, and gemcitabine may prolong survival, with minimal toxicity, in select patients with triple-negative metastatic breast cancer. PMID- 23341814 TI - 'Possessed': acute confusional migraine in an adolescent, prevented by topiramate. AB - Acute confusional migraine (ACM) is recognized as a rare, but highly disabling migraine equivalent, mostly reported in children and adolescents. Herein we describe the case of a 12-year-old girl admitted to hospital for an acute confusional state and severe psychomotor agitation, associated with a pulsating headache and nausea, which turned out to be a manifestation of ACM. The girl was discharged on topiramate prophylaxis, titrated up to 75 mg/die; no recurrence of confusional and/or headache episodes has been reported over the last 14 months to date. Due to the rarity of this clinical entity, only anecdotal reports about acute and prophylactic treatment of ACM are available in the literature. The case reported herein suggests that topiramate seems to be effective in ACM prophylaxis, although a longer observation period in our patient and more cases are needed to confirm any long-term clinical benefit. PMID- 23341815 TI - Stereotypic Movements in Case of Sporadic Creutzfeldt-Jakob Disease: Possible Role of Anti-NMDA Receptor Antibodies. AB - Sporadic Creutzfeldt-Jakob disease (sCJD) and anti-NMDA receptor antibody encephalitis (NMDAE) can both produce a rapidly progressive dementia with resulting state of catatonia or akinetic mutism. Both are associated with movement disorders. In published case series, myoclonus appears to be the most frequent movement disorder in sCJD, while stereotypic, synchronized, one-cycle per-second movements such as arm or leg elevation, jaw opening, grimacing, head turning, and eye deviation are seen in NMDAE. We report a case of a 59-year-old woman with rapidly worsening cognitive disturbance leading to a nearly catatonic state interrupted by stereotypic movements. sCJD was diagnosed via periodic sharp wave complexes on EEG as well as cerebrospinal fluid (CSF) 14-3-3 and tau protein elevation. Characteristic movement disorder of NMDAE was present in absence of ovarian mass or CSF pleiocytosis. Given prior case reports of presence of anti NMDA receptor antibodies in sCJD, we propose that the movement disorder in this case was caused by anti-NMDA receptor antibodies whose formation was secondary to neuronal damage from prion disease. It is important to consider sCJD even in cases that have some clinical features suggestive of NMDAE. PMID- 23341816 TI - Poor Outcome in a Mitochondrial Neurogastrointestinal Encephalomyopathy Patient with a Novel TYMP Mutation: The Need for Early Diagnosis. AB - Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a devastating autosomal recessive disorder due to mutations in TYMP, which cause loss of function of thymidine phosphorylase (TP), nucleoside accumulation in plasma and tissues and mitochondrial dysfunction. The clinical picture includes progressive gastrointestinal dysmotility, cachexia, ptosis and ophthalmoparesis, peripheral neuropathy and diffuse leukoencephalopathy, which usually lead to death in early adulthood. Therapeutic options are currently available in clinical practice (allogeneic hematopoietic stem cell transplantation and carrier erythrocyte entrapped TP therapy) and newer, promising therapies are expected in the near future. However, successful treatment is strictly related to early diagnosis. We report on an incomplete MNGIE phenotype in a young man harboring the novel heterozygote c.199 C>T (Q67X) mutation in exon 2, and the previously reported c.866 A>C (E289A) mutation in exon 7 in TYMP. The correct diagnosis was achieved many years after the onset of symptoms and unfortunately, the patient died soon after diagnosis because of multiorgan failure due to severe malnutrition and cachexia before any therapeutic option could be tried. To date, early diagnosis is essential to ensure that patients have the opportunity to be treated. MNGIE should be suspected in all patients who present with both gastrointestinal and nervous system involvement, even if the classical complete phenotype is lacking. PMID- 23341817 TI - Subretinal Fibrosis in Stargardt's Disease with Fundus Flavimaculatus and ABCA4 Gene Mutation. AB - PURPOSE: To report on 4 patients affected by Stargardt's disease (STGD) with fundus flavimaculatus (FFM) and ABCA4 gene mutation associated with subretinal fibrosis. METHODS: Four patients with a diagnosis of STGD were clinically examined. All 4 cases underwent a full ophthalmologic evaluation, including best corrected visual acuity measured by the Snellen visual chart, biomicroscopic examination, fundus examination, fundus photography, electroretinogram, microperimetry, optical coherence tomography and fundus autofluorescence. All patients were subsequently screened for ABCA4 gene mutations, identified by microarray genotyping and confirmed by conventional DNA sequencing of the relevant exons. RESULTS: In all 4 patients, ophthalmologic exam showed areas of subretinal fibrosis in different retinal sectors. In only 1 case, these lesions were correlated to an ocular trauma as confirmed by biomicroscopic examination of the anterior segment that showed a nuclear cataract dislocated to the superior site and vitreous opacities along the lens capsule. The other patients reported a lifestyle characterized by competitive sport activities. The performed instrumental diagnostic investigations confirmed the diagnosis of STGD with FFM in all patients. Moreover, in all 4 affected individuals, mutations in the ABCA4 gene were found. CONCLUSIONS: Patients with the diagnosis of STGD associated with FFM can show atypical fundus findings. We report on 4 patients affected by STGD with ABCA4 gene mutation associated with subretinal fibrosis. Our findings suggest that this phenomenon can be accelerated by ocular trauma and also by ocular microtrauma caused by sport activities, highlighting that lifestyle can play a role in the onset of these lesions. PMID- 23341818 TI - Combined lateral orbitotomy and endoscopic transnasal orbital decompression in a case of orbital aspergillosis with impending intracranial invasion. AB - A 64-year-old man with a known history of diabetes and hypertension presented to the Accident and Emergency Department with a 2-day history of sudden decreased vision in the right eye. Temporal arteritis was suspected with an elevated erythrocyte sedimentation rate (71 mm/h), and oral prednisolone was started immediately. Four days later, the patient's right eye vision deteriorated from 0.6 to 0.05, with a grade-4 relative afferent pupillary defect and ophthalmoplegia. Computed tomography showed a contrast-enhancing orbital apex mass in the right orbit abutting the medial and lateral portions of the optic nerve with extension to the posterior ethmoid and sphenoid sinuses. A transethmoidal biopsy was performed which yielded septate hyphae suggestive of Aspergillus infection. Ten days later, the patient's right eye vision further deteriorated to hand movement with total ophthalmoplegia. MRI of the orbit showed suspicion of cavernous sinus thrombosis. A combined lateral orbitotomy and transethmoidal orbital apex drainage and decompression were performed to eradicate the orbital apex abscess. Drained pus cultured Aspergillus. The patient was prescribed systemic voriconazole for a total of 22 weeks. The latest MRI scan, performed 8 months after surgery, showed residual inflammatory changes with no signs of recurrence of the disease. To our knowledge, this is the first case report which describes the use of a combined open and endoscopic approach for orbital decompression and drainage in a case of orbital aspergillosis. We believe the combined approach gives good exposure to the orbital apex, and allows the abscess in this region to be adequately drained. PMID- 23341819 TI - Recurrence of macular hole retinal detachment after intravitreal ranibizumab injection for the treatment of choroidal neovascularization from the remaining macular hole edge. AB - PURPOSE: To report a case who had recurrence of macular hole retinal detachment (MHRD) after intravitreal ranibizumab injection (IVR) for the treatment of choroidal neovascularization (CNV) that arose from the damaged retinal pigment epithelium of the remaining macular hole (MH) edge, which had been successfully treated by pars plana vitrectomy (PPV) 15 years previously. CASE REPORT: A 67 year-old man with previous PPV for MHRD secondary to high myopia in the right eye had been under observation for 15 years after surgery. The retina had been successfully attached, but the MH remained open. He had CNV which arose from the remaining MH edge. IVR was performed for the treatment of CNV. One month after the injection, CNV was contracted but recurrence of MHRD occurred. PPV with an additional internal limiting membrane peeling, removal of the CNV membrane and 20% SF6 gas tamponade was performed. One year after the last surgery, his right retina was attached and the MH was closed successfully. CONCLUSION: We propose that patients who undergo IVR should be carefully maintained and followed up for possible complications including the recurrence of MHRD. PMID- 23341820 TI - Artisan aphakic lens for cataract surgery in anterior megalophthalmos. AB - A 44-year-old man with anterior megalophthalmos arrived at the clinic presenting a cataract in the right eye. The corneal diameter was 13 mm. Iridodonesis and phacodonesis were evident during slit lamp examination. Anterior chamber depth was 5.89 mm, and the diameter of the capsular bag was approximately 14.45 mm. Due to the large capsular bag, a standard posterior chamber intraocular lens was considered inadequate because of potential instability. Phacoemulsification and an implantation of an iris-claw lens (Artisan for aphakia((r)), Ophtec) in the posterior chamber were performed with good results. In the fourth postoperative month, uncorrected distance visual acuity was 20/30, and 20/20 was achieved with +0.75 -1.25 * 10 degrees . We consider retropupillary aphakic iris-claw intraocular lenses to be a worthwhile option in these cases of megalophthalmos and cataract, since instability is avoided and the procedure is less challenging than suturing the lens. PMID- 23341821 TI - Intravitreal injection of bevacizumab in a case of occlusive retinal vasculitis accompanied by syphilitic intraocular inflammation. AB - BACKGROUND: We report a rare case of syphilitic intraocular inflammation with occlusive retinal vasculitis treated with intravitreal injection of bevacizumab (IVB) in addition to conventional therapy for syphilis. CASE: A 24-year-old woman who complained floaters in both her eyes showed occlusive retinal vasculitis OU. According to the high titer of the Treponema antigen and characteristic cutaneous eruption, she was diagnosed as secondary syphilis. OBSERVATION: She was treated with oral amoxicillin and retinal photocoagulation OU. Then, administration of prednisolone was required to the intraocular inflammations considered as Jarisch Herxheimer reactions. IVB was also performed toward exacerbated retinal neovascularization and showed transient effects. CONCLUSION: We experienced a rare case of occlusive retinal vasculitis accompanied by syphilis intraocular inflammation. IVB was considered to be effective as an adjunctive therapy for inflammatory neovascularizations. PMID- 23341822 TI - Two cases of accidental dislocation of the silicone sleeve of an extrusion cannula into the vitreous cavity. AB - BACKGROUND: Fluid-air exchange during vitreoretinal surgery is often used as a tool for subretinal fluid endodrainage. Soft-tipped flexible extrusion cannulas are commonly used to aspirate the posterior subretinal fluid. METHODS: This is an observational two-case series describing two patients who underwent 20-G pars plana vitrectomy complicated by the accidental fall of the silicone sleeve of a soft-tipped extrusion cannula into the vitreous cavity. In the first case, the cannula had inadvertently been subjected to sterilization process. RESULTS: While withdrawing the soft-tipped extrusion cannula from the eye, following internal drainage of transvitreal and subretinal fluid, the loose silicone sleeve probably got entangled at the inner lip of the sclerotomy and finally fell on the retinal surface. In both cases, the silicone sleeve was held and removed with an intraocular forceps. CONCLUSIONS: This rare complication has been reported in the literature only once previously. Sterilization of disposable subretinal fluid cannulas is not advisable because of the risk of dislocation of the silicone sleeve into the eye. Besides this, it is important to check the integrity of the silicone sleeve before and after surgery. PMID- 23341823 TI - A clear cell renal cell carcinoma inhibiting the response to intravitreal antivascular endothelial growth factor therapy in wet age-related macular disease. AB - PURPOSE: Wet age-related macular degeneration (AMD) is an ocular disorder that can be successfully treated with intravitreal antivascular endothelial growth factor (VEGF) therapy. We report a case of incomplete response to intravitreal therapy associated with a clear cell renal cell carcinoma (ccRCC). METHODS: A 72 year-old male with wet AMD responded poorly to intravitreal bevacizumab and ranibizumab injections. The removal of a ccRCC led to the spontaneous stabilization of the choroidal neovascular lesion. The renal carcinoma was examined for Von Hippel-Lindau (VHL) gene alterations. Immunohistochemical profiling of the hypoxia-inducible factor (HIF) pathway addressing the marker HIF 1alpha and its downstream targets VEGF, glucose transporter 1 and carbonic anhydrase IX was performed. RESULTS: Genotyping of the ccRCC revealed the presence of a truncating VHL mutation (p.E134fs*25). Immunohistochemistry displayed HIF pathway target activation and VEGF expression in the ccRCC tumour cells. Following tumour removal, the neovascular lesion remained stable for 6 months without any further anti-VEGF therapy. CONCLUSION: The somatic VHL mutation correlates with persistent high levels of HIF-1alpha pathway targets and VEGF expression in the ccRCC. We postulate that this increased VEGF in the tumour and subsequently in the plasma levels could have caused the incomplete response to intravitreal anti-VEGF therapy. Stabilization of the wet AMD following tumour removal indicates that the angiogenic secreting tumour (ccRCC) abrogates the response to VEGF inhibitor therapy. Thus, in cases of poor response to intravitreal anti-VEGF therapy, systemic evaluation including plasma levels of VEGF and/or systemic screening for VEGF-producing tumours should be considered. PMID- 23341824 TI - Validation of the scandinavian stroke scale in a multicultural population in Brazil. AB - BACKGROUND: The objective of this study was to evaluate the consistency, coherence, and interobserver reliability of the Portuguese version of the Scandinavian Stroke Scale (SSS) in a multicultural population of stroke. METHODS: The SSS was translated, culturally adapted, and applied by two independent investigators. This was a randomized transverse study involving two groups: group 1 included 20 patients in the acute phase and group 2 included 20 patients in the subacute phase after stroke was confirmed by computed tomography with a pre stroke modified Rankin Scale score of 0. Each patient also underwent National Institutes of Health Stroke Scale (NIHSS) evaluation at hospital entry and at the time of the SSS evaluation for correlation with our current standard hospital practice. Consistency and coherence were analyzed by Cronbach's alpha and interobserver reliability by kappa. RESULTS: Forty patients were evaluated with 0.88 consistency and coherence in both stroke phases. Mean interobserver kappa was 0.76, with reliability considered excellent and good for most scale items, and moderate for only the facial palsy item. CONCLUSION: The SSS is adequate and validated to study post-stroke patients in a multicultural Brazilian population and in the Portuguese language. PMID- 23341826 TI - Added Diagnostic Value of (11)C-PiB-PET in Memory Clinic Patients with Uncertain Diagnosis. AB - INTRODUCTION: The added diagnostic value of (11)C-PiB-PET for the assessment of the accumulation of cortical beta-amyloid in memory clinic patients with uncertain diagnosis remains undetermined. METHODS: All patients who underwent PiB PET at the Copenhagen Memory Clinic between March 2008 and November 2011 were included in this uncontrolled, retrospective study. The standard diagnostic evaluation program included physical and neurological examination, cognitive and functional assessment, a cranial CT or MRI, functional imaging and cerebrospinal fluid sampling. Based on anonymized case reports, three experienced clinicians reached a consensus diagnosis and rated their confidence in the diagnosis before and after disclosure of PiB-PET ratings. PiB-PET scans were rated as either positive or negative. RESULTS: A total of 57 patients (17 females, 30 males; age 65.7 years, range 44.2-82.6) were included in the study. Twenty-seven had a positive PiB-PET scan. At the first diagnostic evaluation, 16 patients were given a clinical Alheimer's disease diagnosis (14 PiB positive). Of the 57 patients, 13 (23%) were diagnostically reclassified after PiB-PET ratings were disclosed. The clinicians' overall confidence in their diagnosis increased in 28 (49%) patients. CONCLUSION: PiB-PET adds to the specialist clinical evaluation and other supplemental diagnostic investigations in the diagnostic classification of patients with uncertain diagnosis in a specialized memory clinic. PMID- 23341827 TI - A longitudinal study of physical function in patients with early-onset dementia. AB - BACKGROUND: The aim of this study was to explore changes in mobility in terms of ambulation and transfer over 1 year in patients with early-onset Alzheimer's disease (EOAD), and to compare mobility in EOAD with patients with other types of early-onset dementia (EOOD). METHOD: Forty-two patients with EOAD and 30 patients with EOOD were included. All patients were home-dwelling and had mild or moderate degree of dementia. Mobility was assessed using the Timed Up and Go Test (TUG), a modified version of the Clinical Outcome Variables Scale, timed stair walking, and timed rise from the floor. RESULTS: The EOAD group performed significantly better than the EOOD group on all mobility tests. After 1 year, 25 persons with EOAD were tested again. The performance on TUG (p = 0.028) and stair walking (p = 0.02) had deteriorated at the 1-year follow-up in the EOAD group. CONCLUSION: Patients with EOAD performed better on mobility tasks than patients with EOOD, but their performance deteriorated at 1-year follow-up. PMID- 23341825 TI - Recommended measures for the assessment of cognitive and physical performance in older patients with dementia: a systematic review. AB - AIM/GOAL: To recommend a set of neuropsychological and physical exercise tests for researchers to assess cognition and physical fitness in clinical trials with older patients with dementia; to create consensus, decrease heterogeneity, and improve research quality. METHODS: A literature search (2005-2011) yielded 89 randomized controlled trials. To provide information on test recommendations the frequency of test use, effect size of the test outcome, study quality, and psychometric properties of tests were analyzed. RESULTS: Fifty-nine neuropsychological tests (cognitive domains: global cognition, executive functioning, memory, and attention) and 10 exercise tests (physical domains: endurance capacity, muscle strength, balance, and mobility) were found. CONCLUSION: The Severe Impairment Battery, Mini Mental State Examination, and Alzheimer Disease Assessment Scale - cognitive subscale were recommended to measure global cognition. The Verbal Fluency Test Category/Letters, Clock Drawing Test, and Trail Making Test-B were recommended to measure executive functioning. No specific memory test could be recommended. The Digit Span Forward, Digit Span Backward, and Trail Making Test-A were recommended to measure attention. As physical exercise tests, the Timed Up and Go and Six Meter Walk for mobility, the Six Minute Walk Distance for endurance capacity, and the Tinetti Balance Scale were recommended. PMID- 23341828 TI - Association of BACE1 Gene Polymorphism with Cerebellar Volume but Not Cognitive Function in Normal Individuals. AB - AIMS: beta-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a biological and positional candidate gene for Alzheimer's disease (AD). Previous studies found that BACE1-null mice had impaired performance on cognition and neurodegeneration during the aging process. Additionally, a synonymous polymorphism of BACE1 (rs638405) in exon 5 has been reported to be associated with risk for AD. We hypothesized that this BACE1 gene variant might influence regional brain volumes and cognitive tests in normal individuals. METHODS: Participants were 330 normal volunteers between 21 and 92 years of age (mean age 56.3 +/- 22.0 years; 191 males, 139 females). Cognitive tests (the Mini-Mental State Examination and Digit Spans), magnetic resonance imaging, and genotyping of BACE1 rs638405 were examined for each subject. The differences in regional gray matter (GM) volumes between G homozygotes and C-allele carriers were tested using optimized voxel-based morphometry. RESULTS: Compared to C-allele carriers, G homozygotes exhibited significantly larger GM volumes in the left cerebellar culmen and right cerebellar lingual area, but no significant differences on cognitive function tests. CONCLUSION: The findings suggest that the BACE1 rs638405 polymorphism may affect cerebellar morphology, but not cognitive function in healthy humans. PMID- 23341830 TI - How much is a picture worth? Putting amyloid imaging to the test. PMID- 23341829 TI - Caregiver burden and psychoeducational interventions in Alzheimer's disease: a review. AB - BACKGROUND: Caring for a patient with Alzheimer's disease (AD) is associated with poor quality of life and deteriorating health for the caregiver. METHODS: This comprehensive review was performed to investigate the current literature on caregiver burden, factors affecting caregiver burden and the effectiveness of different types of intervention. RESULTS: Successful psychoeducational interventions for caregivers have included provision of information about AD, care planning, advice about patient management and the importance of self-care, skills training to aid patient management, stress management training, and problem-solving and decision-making guidance. CONCLUSION: Interventions that are individually tailored to the caregiver are particularly effective at reducing caregiver burden and should be further investigated. The use of effective pharmacological treatment for the improvement and/or stabilisation of AD symptoms in the patient is also likely to improve caregiver burden. PMID- 23341831 TI - Conformation-dependent oligomers in cerebrospinal fluid of presymptomatic familial Alzheimer's disease mutation carriers. AB - BACKGROUND/AIMS: Oligomerization of amyloid beta (Abeta) is a hypothesized step in the formation of plaques in Alzheimer's disease (AD) but has been difficult to demonstrate in vivo in humans. As persons destined to develop familial AD (FAD) due to fully penetrant autosomal dominant mutations are essentially certain to develop the disease, they provide the opportunity to identify oligomers during the presymptomatic stage of the disease. METHODS: We measured levels of Abeta(42) using a conventional immunoassay and prefibrillar, fibrillar, and annular protofibrillar oligomers using polyclonal conformation-dependent antibodies in the cerebrospinal fluid (CSF) of 7 persons at risk for inheriting FAD mutations. Levels of oligomers were compared between FAD mutation carriers and noncarriers. RESULTS: Compared to 2 noncarriers, annular protofibrillar oligomers were elevated, prefibrillar and fibrillar oligomers trended towards elevation and Abeta(42) monomer trended towards being decreased in 5 FAD mutation carriers. CONCLUSION: Our data provide evidence for an identifiable elevation of CSF oligomers during the presymptomatic phase of FAD. PMID- 23341832 TI - Effects of carperitide on contrast-induced acute kidney injury with a minimum volume of contrast in chronic kidney disease patients. AB - BACKGROUND/AIMS: Although contrast-induced acute kidney injury (CIAKI) is a major complication associated with angiography, the prophylaxis is not well established. Use of a low dose of carperitide for preventing CIAKI remains controversial. We examined the protective effect of carperitide on CIAKI after coronary angiography with a small contrast volume in chronic kidney disease (CKD) patients with coronary artery disease. METHODS: We randomly assigned 112 consecutive patients to a carperitide or a control group. The contrast volume was kept under 150 ml. The primary endpoint was the incidence of CIAKI defined by a serum creatinine of >=25% or a serum creatinine of >=0.5 mg/dl from baseline within 48 h. The secondary endpoint was a change in renal function at 1 week after the procedure. RESULTS: The baseline characteristics and contrast volumes (carperitide group: 67.4 +/- 38.2 ml vs. control group: 64.8 +/- 20.5 ml, p = 0.661) were comparable in the two groups. The incidence of CIAKI was similar in the two groups (carperitide group: 8.5% vs. control group: 5.7%, p = 0.564). A multivariate analysis revealed that a hypotension >=20 mm Hg was a significant predictor of developing CIAKI in the carperitide group (p = 0.015). The incidence of CIAKI in the carperitide group without hypotension was rare, but not significantly different (carperitide group: 2.4% vs. control group: 5.7%, p = 0.432). CONCLUSIONS: This study indicated that the use of a small contrast volume suppressed the incidence of CIAKI and that carperitide had no prophylactic effect against CIAKI. Our results also revealed the impact of hypotension on the development of CIAKI in the carperitide group. PMID- 23341833 TI - Relative Change in NT-proBNP Level: An Important Risk Predictor of Cardiovascular Congestion in Haemodialysis Patients. AB - BACKGROUND: Cross-sectional studies have shown that B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) are predictive of cardiovascular death in haemodialysis (HD) patients. In the present study, we tested the hypothesis that monitoring NT-proBNP measurements adds further prognostic information, i.e. predicts congestive heart failure (CHF) events. METHODS: In a prospective cohort of 236 HD patients, NT-proBNP levels were measured monthly during 18 months. Patients were divided according to the occurrence of CHF events. In a nested case-control study, we assessed the evolution of NT-proBNP levels. RESULTS: On average, the 236 HD patients were followed up for 12.5 months, a period during which 44 patients developed a CHF event (half requiring hospitalisation). At baseline, patients who developed a CHF event had significantly more dilated cardiomyopathy and/or altered left ventricular ejection fraction and higher NT-proBNP levels compared with patients who did not develop a CHF event. During follow-up, we observed a significant increase in NT proBNP levels preceding the CHF event. At a 20% relative increase of NT-proBNP, the sensitivity of NT-proBNP as a predictor of CHF events was 0.57 and the specificity 0.77. CONCLUSION: The relative change in NT-proBNP levels is a significant risk predictor of a CHF event. PMID- 23341834 TI - Typical Features of Amelogenesis Imperfecta in Two Patients with Bartter's Syndrome. AB - BACKGROUND/AIMS: Amelogenesis imperfecta (AI) is due to many inherited defects of enamel formation that affect the quantity and quality of enamel, leading to delay in tooth eruption and cosmetic consequences. AI has been described in association with nephrocalcinosis, which is called the enamel-renal syndrome. The aim of this case report is to describe typical features of AI in 2 patients with Bartter's syndrome (BS) for the first time. METHODS: -Eight patients with confirmed BS were systematically screened for dental abnormalities as part of protocol. Those with suggestive clinical features of AI were submitted to panoramic X-ray and decayed teeth were analyzed by scanning electron microscopy. RESULTS: Typical features of AI were detected in 2 girls with BS. These 2 patients showed nephrocalcinosis, and diagnosis and adequate clinical control were delayed. Genetic analysis detected the mutation responsible for BS in 1 of these patients. In this case, BS was due to a homozygous mutation of exon 5 of the KCNJ1 gene resulting in a substitution of valine for alanine at the codon 214 (A214V). CONCLUSIONS: The finding of typical features of AI in BS might constitute preliminary evidence that abnormalities of the biomineralization process found in patients with renal tubular disorders might also affect calcium deposition in dental tissues. PMID- 23341835 TI - Preventive treatment of alveolar pulmonary edema of cardiogenic origin. AB - OBJECTIVE: To evaluate the efficacy of preventive treatment (PT) on alveolar pulmonary edema (APE) of cardiogenic origin using a monitor based on principles of internal thoracic impedance (ITI) measurements. METHODS: We conducted blinded clinical trials on patients with ST-elevation myocardial infarction (STEMI) and monitored whether the condition would progress to APE. ITI was measured non invasively by the Edema Guard Monitor (EGM, model RS-207) every 30 min. The measurement threshold for the diagnosis of APE was fixed at > 12% decrease in ITI from baseline as described in our methodology. The patients were divided into one group that received standard treatment after the appearance of clinical signs of APE without considering the prediction of APE by EGM devise (Group 1), and another group of asymptomatic patients in whom development of APE was predicted by using only EGM measurements (Group 2). The latter participants' PT consisted of furosemide, intravenous nitroglycerine and supplemental oxygen. RESULTS: One hundred and fifty patients with acute STEMI were enrolled into this study. Group 1 included 100 patients (53% males, age 64.1 +/- 12.6 years). Treatment was started after the clinical appearance of overt signs of APE. Group 2 included 50 patients (54% males, age 65.2 +/- 11.9 years) who received PT based on EGM measurements. Group 2 had significantly fewer cases of APE (n = 4, 8%) than Group 1 (n = 100, 100%) (P > 0.001). While APE was lethal in six (6%) Group 1 patients, PT resulted in prompt resolution of APE in all four (8%) Group 2 patients. CONCLUSION: ITI is a useful modality for early diagnosis and PT of pulmonary edema of cardiogenic origin. PMID- 23341836 TI - Long term survival of patients with raised pulmonary arterial systolic pressure utilizing echocardiography-a five-year prospective study. AB - BACKGROUND: Pulmonary arterial systolic pressure (PASP) can be estimated with transthoracic echocardiography. However, the significance of raised PASP on routine echocardiography is uncertain. In this study, we evaluated the mortality and hospitalization rates of subjects with raised PASP in a cohort of patients referred directly by their general practitioners for routine outpatient (open access) echocardiography for further analysis of suspected heart failure. RESULTS: A total of 485 subjects were referred for open access echocardiography at our hospital in 2002. A cohort of 209/485 (43%) consecutive subjects with measurable tricuspid regurgitation were followed for a minimum of five years investigating hospitalization rates and survival. Some 62 of 209 (30%) subjects had pulmonary hypertension (PH). Subjects with PH were significantly more likely to have four or more hospital admissions (22% vs. 8%; P < 0.01) and > 30 days of cumulative hospital stay over five years (29% vs. 13%; P < 0.01). PH was significantly associated with mortality (P = 0.003), while moderate to severe PH was an independent predictor of mortality (hazard ratio: 4.31; 95% confidence interval (95% CI): 1.51-12.30). Records from the Office of National Statistics revealed that subjects with PH were more likely to have chronic lung diseases recorded as immediate or contributory causes of death (50% vs. 14%; P < 0.05). CONCLUSIONS: PASP >= 36 mmHg on routine echocardiography is associated with recurrent hospital admissions, prolonged hospitalizations and increased cause of mortality. Therefore, the diagnosis of PH on echocardiography deserves further clinical evaluation, with future studies designed at defining a suitable diagnostic strategy. PMID- 23341837 TI - Incomplete revascularization in the drug eluting stent era permits meaningful long-term (12-78 months) outcomes in patients >= 75 years with acute coronary syndrome. AB - OBJECTIVE: To compare long-term prognosis between complete revascularization (CR) and incomplete revascularization (IR) in elderly patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). METHODS: We prospectively enrolled patients >= 75 years with ACS and multi-lesion disease between January 2005 and December 2010 at our center (Institute of Geriatric Cardiology, Chinese PLA General Hospital). Baseline clinical characteristics, PCI parameters and long-term (12 to 78 months) outcomes including main adverse cardiac and cerebral events (MACCE) were compared between CR and IR groups. We used the Kaplan-Meier curve to describe the survival rates, and variables reported to be associated with prognosis were included in Cox regression. RESULTS: Of the 502 patients, 230 patients obtained CR, and the other 272 patients underwent IR. Higher SYNTAX score was an independent predictor of IR [Odds ratio (OR): 1.141, 95% confidence interval (95% CI): 1.066-1.221, P = 0.000]. A total of 429 patients (85.5%) were followed with a duration ranging from 12 months to 78 months. There were no significant differences in cumulative survival rates and event free survival rates between the two groups, even for patients with multi-vessel disease. Older age (OR: 1.079, 95% CI: 1.007-1.157, P = 0.032), prior myocardial infarction (OR: 1.440, 95% CI: 1.268-2.723, P = 0.001) and hypertension (OR: 1. 653, 95% CI: 1.010-2.734, P = 0.050) were significant independent predictors of long-term MACCE. CONCLUSIONS: Given that both clinical and coronary lesion characteristics are much more complex in patients >=75 years with ACS and multi-lesion disease, IR may be an option allowing low risk hospital results and meaningful long-term (12 to 78 months) outcomes. PMID- 23341838 TI - Association of inflammation with atrial fibrillation in hyperthyroidism. AB - OBJECTIVES: The aim of this study was to evaluate the relationship between inflammation and development of atrial fibrillation (AF) in patients with hyperthyroidism. METHODS: A total of 65 patients with newly diagnosed hyperthyroidism, 35 of whom were in sinus rhythm and 30 of whom in AF. Thirty five age- and gender-matched patients in a control group were included in the study. Factors associated with the development of AF were evaluated by multivariate regression analysis. RESULTS: FACTORS ASSOCIATED WITH AF IN MULTIVARIATE ANALYSIS INCLUDED HIGH SENSITIVITY C REACTIVE PROTEIN (HSCRP) [ODDS RATIO (OR): 11.19; 95% confidence interval (95% CI): 1.80-69.53; P = 0.003], free T4 (OR: 8.76; 95% CI: 2.09-36.7; P = 0.003), and left atrial diameter (OR: 1.25; 95% CI: 1.06-1.47; P = 0.008). CONCLUSIONS: The results of the present study suggest that HsCRP, an indicator of inflammation, free T4 and left atrial diameter are associated with the development AF in patients with hyperthyroidism. PMID- 23341839 TI - A head-to-head comparison of the coronary calcium score by computed tomography with myocardial perfusion imaging in predicting coronary artery disease. AB - OBJECTIVES: The coronary artery calcium (CAC) score has been shown to predict future cardiac events. However the extent to which the added value of a CAC score to the diagnostic performance of myocardial perfusion imaging (MPI) by single photon emission computed tomography (SPECT) is unclear. The purpose of this study is to investigate the correlation between CAC score and SPECT in patients with suspected coronary artery disease. METHODS: A retrospective review of the CAC scores by use of the Agatston calcium scoring method and cardiac SPECT diagnostic reports was conducted in 48 patients, who underwent both coronary computed tomography (CT) and SPECT examinations due to suspected coronary artery disease. A Pearson correlation test was used to determine the relation between CAC scores and MPI-SPECT assessments with regard to the evaluation of the extent of disease. RESULTS: Forty-seven percent of the patients had CAC scores more than 100, while 42% of these patients demonstrated abnormal, or probably abnormal, MPI-SPECT. Of the 23% of patients with a zero CAC score, only 7% had normal MPI-SPECT findings. No significant correlation was found between the CAC scores and MPI-SPECT assessments (r value ranged from 0.012 to 0.080), regardless of the degree of coronary calcification. CONCLUSIONS: There is a lack of correlation between the CAC scores and the MPI-SPECT findings in the assessment of the extent of coronary artery disease. CAC scores and MPI-SPECT should be considered complementary approaches in the evaluation of patients with suspected coronary artery disease. PMID- 23341840 TI - Chronic kidney disease: an independent risk factor of all-cause mortality for elderly Chinese patients with chronic heart failure. AB - OBJECTIVE: To evaluate the prognostic value of chronic kidney disease (CKD) in elderly Chinese patients with chronic heart failure (CHF). METHODS: The study consisted of 327 elderly patients with CHF. All-cause mortality was chosen as an endpoint over the median follow-up period of 345 days. Cox regression analysis was used to identify the risk factors of mortality. RESULTS: The median age of the entire cohort was 85 years (60-100 years). The mortality for 168 elderly patients with CHF and CKD (51.4% of entire cohort) was 39.9% (67 deaths), which was higher than the mortality for CHF patients without CKD [25.2% (40/159 deaths)] and the mortality for entire cohort with CHF [32.7% (107/327 deaths)]. The Cox regression analysis showed that old age [hazard ratio (HR): 1.033; 95% confidence interval (95% CI): 1.004-1.064], CKD (HR: 1.705; 95% CI: 1.132-2.567), CHF New York Heart Association (NYHA) class IV (HR: 1.913; 95% CI: 1.284-2.851), acute myocardial infarction (AMI) (HR: 1.696; 95% CI: 1.036-2.777), elevated resting heart rate (HR: 1.021; 95% CI: 1.009-1.033), and decreased plasma albumin (HR: 0.883; 95% CI: 0.843-0.925) were independent risk factors of mortality for elderly patients with CHF. CONCLUSIONS: CKD was an independent risk factor of mortality for elderly Chinese patients with CHF. PMID- 23341841 TI - Secular trends in the etiology and comorbidity of hospitalized patients with congestive heart failure: A single-center retrospective study. AB - OBJECTIVE: To assess the secular trends in the etiology and comorbidity of patients hospitalized with congestive heart failure (CHF). METHODS: Data of 7,319 patients (mean age 59.6 years, 62.1% male) with a primary discharge diagnosis of CHF, hospitalized from January 1, 1993 to December 31, 2007 at the Chinese People's Liberation Army (PLA) General Hospital were extracted and analyzed. These patients were divided into three groups according to hospitalization period: 1993-1997 (n = 1623), 1998-2002 (n = 2444), and 2003-2007 (n = 3252). The etiological characteristics and comorbidities were assessed. RESULTS: Over the study period, the proportion of patients with ischemic heart disease (IHD) increased from 37.2% during the period 1993-1997 to 46.8% during the period 2003 2007, while that with valvular heart disease (VHD) decreased from 35.2% during the period 1993-1997 to 16.6% during the period 2003-2007 (both P < 0.05). Atrial fibrillation (AF) was the most common comorbidity of heart failure (23.2%, 23.0% and 20.6%, respectively, in the three periods). Compared to that of the period of 1993-1997 with that of, the proportion of patients with myocardial infarction, pneumonia, renal function impairment and hepatic cirrhosis of the period of 2003 2007 increased significantly (P < 0.05) and the proportion of patients with chronic obstructive pulmonary disease and atrial fibrillation decreased significantly (P < 0.05). CONCLUSIONS: This study implies that IHD has became a more common etiology of CHF, while VHD has deceased as an etiology of CHF in Chinese patients during the last two decades. PMID- 23341842 TI - Rationale and design of the ETN-STEP (Early administration of Tirofiban in mid to high risk patients with non-ST elevation acute coronary syndrome referred for percutaneous coronary intervention) project: A multi-center, randomized, controlled clinic trial in Chinese patients. AB - As a member of Glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors, Tirofiban had been shown to improve myocardial reperfusion and clinical outcomes in patients undergoing percutaneous coronary intervention (PCI), but the optimal timing of administration of Tirofiban remains unclear. In order to compare the effects of upstream versus downstream administration of Tirofiban in Chinese patients with mid to high risk, non-ST elevation acute coronary syndrome (ACS) referred for PCI, a multi-center, randomized, controlled, prospective study will be conducted. A total of 500 mid to high risk, non-ST-segment elevation myocardial infarction (NSTEMI) ACS patients will be recruited for this study. Patients will be randomized to Tirofiban upstream administration group (initiated 12 h before PCI) and Tirofiban downstream administration group (initiated at cath-lab after angiography). Thrombolysis in myocardial infarction (TIMI) flow grades, TIMI myocardial perfusion grades (TMPG), and Corrected TIMI frame counting (CTFC) before and after PCI, as well as clinical outcomes during the hospital stay, and within 30 days after PCI will be compared between the two groups. This study will provide evidence on the optimal timing for initiating administration of Tirofiban in mid to high NSTEMI ACS subjects undergoing PCI. PMID- 23341843 TI - Atrial fibrillation in the elderly: the potential contribution of reactive oxygen species. AB - Atrial fibrillation (AF) is the most commonly encountered cardiac arrhythmia, and is a significant source of healthcare expenditures throughout the world. It is an arrhythmia with a very clearly defined predisposition for individuals of advanced age, and this fact has led to intense study of the mechanistic links between aging and AF. By promoting oxidative damage to multiple subcellular and cellular structures, reactive oxygen species (ROS) have been shown to induce the intra- and extra-cellular changes necessary to promote the pathogenesis of AF. In addition, the generation and accumulation of ROS have been intimately linked to the cellular processes which underlie aging. This review begins with an overview of AF pathophysiology, and introduces the critical structures which, when damaged, predispose an otherwise healthy atrium to AF. The available evidence that ROS can lead to damage of these critical structures is then reviewed. Finally, the evidence linking the process of aging to the pathogenesis of AF is discussed. PMID- 23341844 TI - Past and present of cardiocirculatory assist devices: a comprehensive critical review. AB - During the last 20 years, the management of heart failure has significantly improved by means of new pharmacotherapies, more timely invasive treatments and device assisted therapies. Indeed, advances in mechanical support, namely with the development of more efficient left ventricular assist devices (LVADs), and the total artificial heart have reduced mortality and morbidity in patients awaiting transplantation, so much so, that LVADs are now approved of as a strategy for destination therapy. In this review, the authors describe in detail the current basic indications, functioning modalities, main limitations of surgical LAVDs, total artificial heart development, and percutaneous assist devices, trying to clarify this complex, but fascinating topic. PMID- 23341846 TI - Is hydrotherapy an appropriate form of exercise for elderly patients with biventricular systolic heart failure? AB - Hydrotherapy (exercise in warm water) is considered to be a safe and beneficial method to use in the rehabilitation of stable heart failure patients, but there is little information on the effect of the increased venous return and enhanced preload in elderly patients with biventricular heart failure. We present a case of an elderly man who was recruited to participate in a hydrotherapy study. We compared echocardiographic data during warm water immersion with land measurements, and observed increases in stroke volume from 32 mL (land) to 42 mL (water), left ventricular ejection fraction from 22% to 24%, left ventricular systolic velocity from 4.8 cm/s to 5.0 cm/s and left atrioventricular plane displacement from 2.1 mm to 2.2 mm. By contrast, right ventricular systolic velocity decreased from 11.2 cm/s to 8.4 cm/s and right atrioventricular plane displacement from 8.1 mm to 4.7 mm. The tricuspid pressure gradient rose from 18 mmHg on land to 50 mmHg during warm water immersion. Thus, although left ventricular systolic function was relatively unaffected during warm water immersion, we observed a decrease in right ventricular function with an augmented right ventricular pressure. We recommend further investigations to observe the cardiac effect of warm water immersion on patients with biventricular systolic heart failure and at risk of elevated right ventricular pressure. PMID- 23341845 TI - High density lipoproteins and atherosclerosis: emerging aspects. AB - High density lipoproteins (HDL) promote the efflux of excess cholesterol from peripheral tissues to the liver for excretion. This ability is responsible for the most relevant anti-atherogenic effect of HDL. The ability of HDL to promote cholesterol efflux results also in the modulation of a series of responses in the immune cells involved in atherosclerosis, including monocyte-macrophages, B and T lymphocytes. Furthermore, during inflammation, the composition of this class of lipoproteins varies to a large extent, thus promoting the formation of dysfunctional HDL. The aim of this review is to discuss the emerging role of HDL in modulating the activity of immune cells and immune-inflammatory mediators during atherogenesis. PMID- 23341847 TI - Imatinib-induced decompensated heart failure in an elderly patient with chronic myeloid leukemia: case report and literature review. AB - Because it is safe and well tolerated, imatinib is a standard first-line therapy for chronic myeloid leukemia (CML). Although there have been sporadic reports of imatinib-induced cardiotoxicity, including left ventricle (LV) dysfunction and heart failure, the evidence for it is contradictory. Here, we reported a case of an 88-year-old male patient with CML developed decompensated heart failure following imatinib therapy. Four days after the initiation of imatinib, the patient developed orthopnea, edema and a pleural effusion accompanied by abdominal distension, nausea and vomiting. The chest X-ray film showed an enlarged cardiac profile. The echocardiogram demonstrated a decreased LV ejection fraction and enlarged left-side cardiac chambers. B-type natriuretic peptide concentrations were markedly increased. The patient recovered soon after the withdrawal of imatinib and introduction of comprehensive therapy for heart failure. Imatinib-induced cardiotoxicity in elderly patients is a potentially serious complication that merits further evaluation. PMID- 23341849 TI - Metagenomic analysis of subgingival microbiota following non-surgical periodontal therapy: a pilot study. AB - This study tested the feasibility of a high throughput metagenomic approach to analyze the pre- and posttreatment of subgingival plaque in two subjects with aggressive periodontitis. DNA was extracted from subgingival samples and subjected to PCR amplification of the c2-c4 regions of the 16S rDNA using primers with bar codes to identify individual samples. The PCR products were pooled and sequenced for the v4 region of the 16S rDNA using the 454 FLX standard platform. The results were analyzed for species/phylotypes in the Human Oral Microbiome Database (HOMD) and Ribosomal Database Project (RDP) database. The sequencing of the amplicons resulted in 24,673 reads and identified 208 species/phylotypes. Of those, 129 species/phylotypes were identified in both patients but their proportions varied. While >120 species/phylotypes were identified in all samples, 28-42 species/phylotypes cumulatively represent 90% of all subgingival bacteria in each sample. The remaining species/phylotypes each constituted <=0.2% of the total subgingival bacteria. In conclusion, the subgingival microbiota are characterized by high species richness dominated by a few species/ phylotypes. The microbiota changed after periodontal therapy. High throughput metagenomic analysis is applicable to assess the complexity and changes of the subgingival microbiota. PMID- 23341848 TI - Current status of low intensity pulsed ultrasound for dental purposes. AB - Over the past few years, tissue engineering applied to the dental field has achieved relevant results. Tissue engineering can be described by actions taken to improve biological functions. Several methods have been described to enhance cellular performance and low intensity pulsed ultrasound (LIPUS) has shown to play an important role in cell metabolism. The present article provides an overview about the current status of LIPUS as a tissue engineering tool to be used to enhance tooth and periodontal regeneration. PMID- 23341850 TI - No positive effect of Acid etching or plasma cleaning on osseointegration of titanium implants in a canine femoral condyle press-fit model. AB - PURPOSE: Implant surface treatments that improve early osseointegration may prove useful in long-term survival of uncemented implants. We investigated Acid Etching and Plasma Cleaning on titanium implants. METHODS: In a randomized, paired animal study, four porous coated Ti implants were inserted into the femurs of each of ten dogs. PC (Porous Coating; control)PC+PSHA (Plasma Sprayed Hydroxyapatite; positive control)PC+ET (Acid Etch)PC+ET+PLCN (Plasma Cleaning) After four weeks mechanical fixation was evaluated by push-out test and osseointegration by histomorphometry. RESULTS: The PSHA-coated implants were better osseointegrated than the three other groups on outer surface implant porosity (p<0.05) while there was no statistical difference in deep surface implant porosity when compared with nontreated implant. Within the deep surface implant porosity, there was more newly formed bone in the control group compared to the ET and ET+PCLN groups (p<0.05). In all compared groups, there was no statistical difference in any biomechanical parameter. CONCLUSIONS: In terms of osseointegration on outer surface implant porosity PC+PSHA was superior to the other three groups. Neither the acid etching nor the plasma cleaning offered any advantage in terms of implant osseointegration. There was no statistical difference in any of the biomechanical parameters among all groups in the press-fit model at 4 weeks of evaluation time. PMID- 23341851 TI - Effects of indigo carmine on human chondrocytes in vitro. AB - Joint infections following or accompanying superficious soft tissue infections are severe complication in orthopedic surgery. The use of intra-articular blue staining is a helpful method to visualize a fistula and to differentiate between superficial and intra-articular infections. Regarding this clinical implication data about the effects of indigo carmine, a frequently used blue staining substance, on cartilage is missing. The hypothesis of this study was that indigo carmine damages human chondrocytes in a time and concentration dependent manner. Human chondrocytes were isolated from donors with osteoarthritis who were treated with TKA. Cells were cultivated and treated with different concentrations of indigo carmine for 5 and 10 minutes. Morphologic damage was examined by light microscopy. Toxicity was quantified by counting vital cell number and lactate dehydrogenase (LDH) expression. Analysis by light microscopy showed defected cell structure and loss of cell number after treatment with 100% indigo carmine for 10 minutes. Treatment with 10% and 1% indigo carmine showed no significant cell defects and loss of cells. Counting vital cell number showed loss of vital cells after treatment with 100% and 10% indigo carmine for 10 minutes. LDH expression was significantly increased after treatment with 100% indigo carmine.Toxic effects were shown after treatment with indigo carmine. Therefore, it should be used in 1:100 dilution. This is both, sufficient for visualizing a fistula in a possible clinical application and could be protective for chondrocytes. PMID- 23341852 TI - Loss of HPV16 E2 Protein Expression Without Disruption of the E2 ORF Correlates with Carcinogenic Progression. AB - Integration of the viral DNA in the cellular genome has been suggested to be critical in carcinogenic progression of HPV-associated cervical neoplasia. This event can be accompanied by disruption of the open reading frame (ORF) encoding the E2 repressor, thus leading to transcriptional up-regulation of the E6 and E7 viral oncogenes. At this stage, it is unclear whether disruption of the E2 ORF is mandatory for carcinogenic progression. We measured E2 RNA and protein expression in clinical samples of various grades of HPV16-associated cervical neoplasia and compared it with the status of the viral genome. RNA extracted from paraffin embedded tissues was hybridized to specific probes and quantified by the NanoString technology. Protein expression was appreciated by immunohistochemistry and the status of viral DNA was determined by in situ hybridization, all performed on serial sections of the same samples. E2 protein was found highly expressed in CIN1, CIN2 lesions where the HPV DNA was highly replicative, while it was decreased in more advanced grade lesions where replication is decreased or lost (CIN3 and SCC). In contrast, E2 transcripts could be elevated even in conditions of no or low expression of the protein, as found in the Caski cell line. Our data demonstrate that integration of the viral DNA in the cellular genome does not always lead to disruption of the E2 ORF and drastic reduction of E2 transcripts, while in contrast, expression of the E2 protein is always drastically reduced. PMID- 23341853 TI - The HPV E2-Host Protein-Protein Interactions: A Complex Hijacking of the Cellular Network. AB - Over 100 genotypes of human papillomaviruses (HPVs) have been identified as being responsible for unapparent infections or for lesions ranging from benign skin or genital warts to cancer. The pathogenesis of HPV results from complex relationships between viral and host factors, driven in particular by the interplay between the host proteome and the early viral proteins. The E2 protein regulates the transcription, the replication as well as the mitotic segregation of the viral genome through the recruitment of host cell factors to the HPV regulatory region. It is thereby a pivotal factor for the productive viral life cycle and for viral persistence, a major risk factor for cancer development. In addition, the E2 proteins have been shown to engage numerous interactions through which they play important roles in modulating the host cell. Such E2 activities are probably contributing to create cell conditions appropriate for the successive stages of the viral life cycle, and some of these activities have been demonstrated only for the oncogenic high-risk HPV. The recent mapping of E2-host protein-protein interactions with 12 genotypes representative of HPV diversity has shed some light on the large complexity of the host cell hijacking and on its diversity according to viral genotypes. This article reviews the functions of E2 as they emerge from the E2/host proteome interplay, taking into account the large scale comparative interactomic study. PMID- 23341854 TI - The biology of papillomavirus latency. AB - The presence of viral DNA in the absence of disease has suggested that papillomaviruses, like many other viruses, can exist as latent infections in the skin or other epithelial sites. In animal models, where detailed investigation has been carried out, papillomavirus DNA can be found at sites of previous infection following immune regression, with the site of latent infection being the epithelial basal layer. Such studies suggest that immune surveillance can restrict viral gene expression in the basal and parabasal layers without efficiently suppressing viral genome replication, most probably through the action of memory T-cells in the skin or dermis. Although gradual papillomavirus genome loss appears to occur over time at latent sites, immunosuppression can arrest this, and can lead to an elevation in viral genome copy number in experimental systems. In addition to immune-mediated latency, it appears that a similar situation can be achieved following infection at low virus titres and/or infection at epithelial sites where the virus life cycle is not properly supported. Such silent of asymptomatic infections do not necessarily involve the host immune system and may be controlled by different mechanisms. It appears that virus reactivation can be triggered by mechanical irritation, wounding or by UV irradiation which changes the local environment. Although the duration of papillomavirus latency in humans is not yet known, it is likely that some of the basic principles will resemble those elucidated in these model systems, and that persistence in the absence of disease may be the default outcome for at least some period of time following regression. PMID- 23341855 TI - Evidence and impact of human papillomavirus latency. AB - At present, there is no consensus in the scientific community regarding the ability for human papillomavirus (HPV) infections to establish latency. Based on animal studies, a model of papillomavirus latency has been proposed in which papillomaviruses can be retained in the basal epithelial stem cell pool as latent infections and periodically induced to reactivate when the stem cell divides and one daughter cell is committed to terminal differentiation and induction of the viral life cycle. Tissue resident memory T-cells are hypothesized to control these periodic reactivation episodes and thus limit their duration. In this paper, evidence from human studies consistent with this model of papillomavirus latency is reviewed. Given the strong circumstantial evidence supporting a natural history of HPV infection which includes a immunologically controlled latent state, the longer term implications of HPV latency on a highly infected and aging population may warrant a more serious evaluation. PMID- 23341856 TI - RNA interference for the treatment of papillomavirus disease. AB - Human Papillomavirus (HPV)-induced diseases are a significant burden on our healthcare system and current therapies are not curative. Vaccination provides significant prophylactic protection but effective therapeutic treatments will still be required. RNA interference (RNAi) has great promise in providing highly specific therapies for all HPV diseases yet this promise has not been realised. Here we review the research into RNAi therapy for HPV in vitro and in vivo and examine the various targets and outcomes. We discuss the idea of using RNAi with current treatments and address delivery of RNAi, the major issue holding back clinical adoption. Finally, we present our view of a potential path to the clinic. PMID- 23341857 TI - A Decade of Global mRNA and miRNA Profiling of HPV-Positive Cell Lines and Clinical Specimens. AB - For more than a decade, global gene expression profiling has been extensively used to elucidate the biology of human papillomaviruses (HPV) and their role in cervical- and head-and-neck cancers. Since 2008, the expression profiling of miRNAs has been reported in multiple HPV studies. Two major strategies have been employed in the gene and miRNA profiling studies: In the first approach, HPV positive tumors were compared to normal tissues or to HPV negative tumors. The second strategy relied on analysis of cell cultures transfected with single HPV oncogenes or with HPV genomes compared to untransfected cells considered as models for the development of premalignant and malignant transformations.In this review, we summarize what we have learned from a decade of global expression profiling studies. We performed comprehensive analysis of the overlap of the lists of differentially expressed genes and microRNAs, in both tissue samples and cell culture based studies. The review focuses mainly on HPV16, however reports from other HPV species are used as references. We discuss the low degree of consensus among different studies and the limitation of differential expression analysis as well as the fragmented miRNA-mRNA target correlation evidence. Furthermore, we propose an approach for future research to include more comprehensive miRNA-mRNA target correlation analysis and to apply systems biology/gene networks methodology. PMID- 23341858 TI - Human papillomavirus infections and cancer stem cells of tumors from the uterine cervix. AB - Different rate of development of productive infections (as low grade cervical intraepithelial neoplasias), or high grade lesions and cervical malignant tumors associated with infections of the Transformation zone (TZ) by High-Risk Human Papillomavirus (HR-HPV), could suggest that different epithelial host target cells could exist. If there is more than one target cell, their differential infection by HR-HPV may play a central role in the development of cervical cancer. Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support in several solid tumors, including cervical cancer (CC). According to the cancer stem cell (CSC) hypothesis, CC can now be considered a disease in which stem cells of the TZ are converted to cervical cancer stem cells by the interplay between HR-HPV viral oncogenes and cellular alterations that are thought to be finally responsible for tumor initiation and maintenance. Current studies of CSC could provide novel insights regarding tumor initiation and progression, their relation with viral proteins and interplay with the tumor micro-environment. This review will focus on the biology of cervical cancer stem cells, which might contribute to our understanding of the mechanisms responsible for cervical tumor development. PMID- 23341859 TI - The immune response to papillomavirus during infection persistence and regression. AB - Human papillomavirus (HPV) infections cause a significant global health burden, predominantly due to HPV-associated cancers. HPV infects only the epidermal cells of cutaneous and mucosal skin, without penetration into the dermal tissues. Infections may persist for months or years, contributed by an array of viral immune evasion mechanisms. However in the majority of cases immunity-based regression of HPV lesions does eventually occur. The role of the innate immune response to HPV in persistence and regression of HPV infection is not well understood. Although an initial inflammatory infiltrate may contribute to disease regression, sustained inflammation at the HPV-induced lesions, characterized by macrophage and neutrophil infiltration, has been observed in persistence. Pathogen-associated molecular patterns (PAMPs) are important in innate recognition. The double stranded DNA and an L1 and L2 capsid components of the HPV virion are potential PAMPs that can trigger signaling through cellular pattern recognition receptors, including toll-like receptors (TLR). TLR expression is increased in regressing HPV disease but is reduced in persistent lesions, suggesting a role for TLR in HPV regression. With regard to the adaptive immune response, a key indicator of regression in humans is infiltration of the lesion with both CD4 and CD8 T cells. In individuals with persistent lesions, CD8 T cell and immune suppressive regulatory T cells (Tregs) infiltrate the infection site. There is no association between persistence or regression and the presence of serum antibodies to the viral capsid antigens of HPV. There is still much to be learned about the immunological events that trigger regression of HPV disease. Understanding the viral and host factors that influence persistence and regression is important for the development of better immunotherapeutic treatments for HPV-associated disease. PMID- 23341860 TI - The invisible enemy - how human papillomaviruses avoid recognition and clearance by the host immune system. AB - Human papillomavirus (HPV) needs to persist in squamous epithelia for a certain amount of time to complete its reproductive cycle. Therefore, the virus has evolved multiple immune evasion strategies. The interplay of these immune evasion mechanisms with the host immune system decides whether a HPV infection is cleared or becomes persistent. Clearance of HPV-induced lesions is mediated by a cellular immune response, consisting of both cytotoxic T lymphocyte and T helper cell responses. Persistent HPV infection, on the other hand, is the single most important risk factor for the development of HPV-associated premalignant lesions and HPV-driven cancers. This article reviews the immune evasion mechanisms employed by high-risk HPVs to escape host immune recognition and attack. PMID- 23341861 TI - Immunotherapy of human papilloma virus induced disease. AB - Immunotherapy is the generic name for treatment modalities aiming to reinforce the immune system against diseases in which the immune system plays a role. The design of an optimal immunotherapeutic treatment against chronic viruses and associated diseases requires a detailed understanding of the interactions between the target virus and its host, in order to define the specific strategies that may have the best chance to deliver success at each stage of disease. Recently, a first series of successes was reported for the immunotherapy of Human Papilloma Virus (HPV)-induced premalignant diseases but there is definitely room for improvement. Here I discuss a number of topics that in my opinion require more study as the answers to these questions allows us to better understand the underlying mechanisms of disease and as such to tailor treatment. PMID- 23341862 TI - Therapeutic Human Papillomavirus (HPV) Vaccines: A Novel Approach. AB - Cervical cancer is the second largest cause of cancer-related death in women worldwide, and it occurs following persistent infection, sometimes for decades, with a specific subset of human papillomavirus (HPV) types; the approximately 13 oncogenic subtypes. Prophylactic vaccines against HPV infections hold promise for cost-effective reductions in the incidence of cervical cancer, but this may not be enough. Two prophylactic HPV vaccines are presently available and both contain L1 virus-like particles (VLPs) derived from the HPV subtypes most frequently associated with cervical cancer, HPV-16 and -18. Since the L1-VLP vaccines can only effectively prevent infection by the specific HPV subtype against which the vaccine was developed, cervical cancers caused by high-risk HPV subtypes other than HPV-16 and -18 may still occur in recipients of the current HPV vaccines. Furthermore, HPV vaccination coverage for adolescents is insufficient in most countries and therefore even HPV-16 and -18 infections are unlikely to be fully eradicated using the existing strategies. The development of HPV therapeutic vaccines remains essential. Many therapeutic vaccines aimed at clearing HPV related cervical lesions have been developed and tested in patients with HPV16 positive cervical intraepithelial lesions (CIN) or cervical cancers. To date, definitive clinical efficacy and appropriate immunological responses have never been demonstrated for cervical neoplasia although promising results have been reported in patients with vulvar intraepithelial neoplasia. Here we discuss shortcomings of previous HPV therapeutic vaccine candidates and propose a novel vaccination strategy that leverages newly gained knowledge about mucosal immunity and the induction of mucosal immune responses. PMID- 23341863 TI - Virus-Like Particles Harboring CCL19, IL-2 and HPV16 E7 Elicit Protective T Cell Responses in HLA-A2 Transgenic Mice. AB - Infection by high-risk genotypes of human papillomaviruses (HR-HPVs) is the cause of cancer of the uterine cervix. Although prophylactic vaccines directed against the two most prevalent HR-HPV types (HPV16 and 18) have been commercialized recently, there is a need for effective therapeutic vaccines against HR-HPVs. We have tested in mice a chimeric protein composed of the hepatitis B small surface antigen (HBsAg(S)) flanked at its N-terminus by chemokine CC ligand 19/macrophage inflammatory protein-3beta (CCL19/MIP-3beta), and at the C-terminus by interleukin 2 (IL-2) and an artificial HPV16 E7 polytope. This protein is assembled into nanoparticles and both CCL19 and IL-2 conserve their functionality. HLA-A2 (AAD) transgenic mice immunized with a plasmid encoding this protein mounted specific T cell responses against E7 without the need of an adjuvant. Furthermore, vaccination prevented the development of tumors after implantation of the E6/E7-expressing TC-1/A2 tumor cell line. Our results suggest that vaccines based on HBsAg(S) nanoparticles carrying short E7 epitopes and immune-stimulatory domains might be of therapeutic value in the treatment of patients suffering from cervical pre-cancer or cancer lesions caused by HR-HPVs. PMID- 23341864 TI - Genotype distribution of human papillomaviruses in Japanese women with abnormal cervical cytology. AB - We report the prevalence and genotype distribution of human papillomaviruses (HPVs) among Japanese women with abnormal cervical cytology using the PGMY-CHUV assay, one of PGMY-PCR-based lineblot assays that was validated and shown to be suitable for the detection of multiple HPV types in a specimen with minimum bias. Total DNA was extracted from cervical exfoliated cells collected from 326 outpatients with abnormal Pap smears. Overall, 307 specimens (94%) were HPV positive, 30% of which contained multiple genotypes. The prevalence of HPV DNA was 83% (49/59 samples) in atypical squamous cells of undetermined significance (ASC-US); 91% (20/22 samples) in atypical squamous cells, cannot exclude high grade squamous intraepithelial lesion (ASC-H); 97% (130/134 samples) in low-grade squamous intraepithelial lesion (LSIL); and 99% (85/86 samples) in high-grade squamous intraepithelial lesion (HSIL). Three most frequent HPV types detected in HSIL were HPV16 (36%), HPV52 (24%), and HPV58 (14%). Our results suggest that multiple HPV infections are more prevalent in Japanese women than previously reported, and confirm that HPV52 and 58 are more dominant in their cervical precancerous lesions when compared to those reported in Western countries. PMID- 23341865 TI - Evaluating the hazard of foetal death following H1N1 influenza vaccination; a population based cohort study in the UK GPRD. AB - BACKGROUND: To evaluate the risk of foetal loss associated with pandemic influenza vaccination in pregnancy. Retrospective cohort study. UK General Practice Research Database Pregnancies ending in delivery or spontaneous foetal death after 21 October 2009 and starting before 01 January 2010. METHODOLOGY/PRINCIPAL FINDINGS: Hazard ratios of foetal death for vaccinated compared to unvaccinated pregnancies were estimated for gestational weeks 9 to 12, 13 to 24 and 25 to 43 using discrete-time survival analysis. Separate models were specified to evaluate whether the potential effect of vaccination on foetal loss might be transient (for ~4 weeks post vaccination only) or more permanent (for the duration of the pregnancy). 39,863 pregnancies meeting our inclusion criteria contributed a total of 969,322 gestational weeks during the study period. 9,445 of the women were vaccinated before or during pregnancy. When the potential effect of vaccination was assumed to be transient, the hazard of foetal death during gestational weeks 9 through 12 (HR(unadj) 0.56; CI(95) 0.43 to 0.73) and 13 through 24 (HR(unadj) 0.45; CI(95) 0.28 to 0.73) was lower in the 4 weeks after vaccination than in other weeks. Where the more permanent exposure definition was specified, vaccinated pregnancies also had a lower hazard of foetal loss than unvaccinated pregnancies in gestational weeks 9 through 12 (HR(unadj) 0.74; CI(95) 0.62 to 0.88) and 13 through 24 (HR(unadj) 0.59; CI(95) 0.45 to 0.77). There was no difference in the hazard of foetal loss during weeks 25 to 43 in either model. Sensitivity analyses suggest the strong protective associations observed may be due in part to unmeasured confounding. CONCLUSIONS/SIGNIFICANCE: Influenza vaccination during pregnancy does not appear to increase the risk of foetal death. This study therefore supports the continued recommendation of influenza vaccination of pregnant women. PMID- 23341866 TI - Expansion of microsatellites on evolutionary young Y chromosome. AB - Sex chromosomes are an ideal system to study processes connected with suppressed recombination. We found evidence of microsatellite expansion, on the relatively young Y chromosome of the dioecious plant sorrel (Rumex acetosa, XY1Y2 system), but no such expansion on the more ancient Y chromosomes of liverwort (Marchantia polymorpha) and human. The most expanding motifs were AC and AAC, which also showed periodicity of array length, indicating the importance of beginnings and ends of arrays. Our data indicate that abundance of microsatellites in genomes depends on the inherent expansion potential of specific motifs, which could be related to their stability and ability to adopt unusual DNA conformations. We also found that the abundance of microsatellites is higher in the neighborhood of transposable elements (TEs) suggesting that microsatellites are probably targets for TE insertions. This evidence suggests that microsatellite expansion is an early event shaping the Y chromosome where this process is not opposed by recombination, while accumulation of TEs and chromosome shrinkage predominate later. PMID- 23341868 TI - Rare variant analysis for family-based design. AB - Genome-wide association studies have been able to identify disease associations with many common variants; however most of the estimated genetic contribution explained by these variants appears to be very modest. Rare variants are thought to have larger effect sizes compared to common SNPs but effects of rare variants cannot be tested in the GWAS setting. Here we propose a novel method to test for association of rare variants obtained by sequencing in family-based samples by collapsing the standard family-based association test (FBAT) statistic over a region of interest. We also propose a suitable weighting scheme so that low frequency SNPs that may be enriched in functional variants can be upweighted compared to common variants. Using simulations we show that the family-based methods perform at par with the population-based methods under no population stratification. By construction, family-based tests are completely robust to population stratification; we show that our proposed methods remain valid even when population stratification is present. PMID- 23341867 TI - Angiotensin AT(2) receptor contributes towards gender bias in weight gain. AB - Obesity is a major disease condition, in turn leading to pathological changes collectively recognized as metabolic syndrome. Recently angiotensin receptor AT(2)R has been associated negatively with body weight (BW) gain in male mice. However, the gender differences in AT(2)R and BW changes have not been studied. To understand the gender based role of AT(2)R involving BW changes, we fed male and female wild type (WT) and AT(2)R knock out (AT(2)KO) mice with C57BL6 background with high fat diet (HFD) for 16 weeks. The male AT(2)KO had higher HFD calorie intake (WT: 1280+/-80; AT(2)KO:1680+/-80 kcal) but gained less BW compared with the WT (WT: 13; AT(2)KO: 6 g). Contrary to the male animals, the female AT(2)KO mice with equivalent caloric intake (WT: 1424+/-48; AT(2)KO:1456+/ 80 kcal) gained significantly more BW than the WT mice (WT: 9 g; AT(2)KO: 15 g). The male AT(2)KO on HFD displayed lower plasma insulin level, less impaired glucose tolerance (GT), and higher plasma T3 compared with WT males on HFD; whereas the female AT(2)KO mice on HFD showed elevated levels of plasma insulin, more impaired GT, lower plasma T3 and higher free fatty acid and hepatic triglycerides compared with WT females on HFD. Interestingly, compared with WT, AT(2)KO female mice had significantly lower estrogen, which was further reduced by HFD. These results suggest that AT(2)R in female mice via potentially regulating estrogen may have protective role against BW gain and impaired glucose tolerance and lipid metabolism. PMID- 23341869 TI - Linkage to care and treatment for TB and HIV among people newly diagnosed with TB or HIV-associated TB at a large, inner city South African hospital. AB - OBJECTIVE: To assess the outcomes of linkage to TB and HIV care and identify risk factors for poor referral outcomes. DESIGN: Cohort study of TB patients diagnosed at an urban hospital. METHODS: Linkage to care was determined by review of clinic files, national death register, and telephone contact, and classified as linked to care, delayed linkage to care (>7 days for TB treatment, >30 days for HIV care), or failed linkage to care. We performed log-binomial regression to identify patient and referral characteristics associated with poor referral outcomes. RESULTS: Among 593 TB patients, 23% failed linkage to TB treatment and 30.3% of the 77.0% who linked to care arrived late. Among 486 (86.9%) HIV infected TB patients, 38.3% failed linkage to HIV care, and 32% of the 61.7% who linked to care presented late. One in six HIV-infected patients failed linkage to both TB and HIV care. Only 20.2% of HIV-infected patients were referred to a single clinic for integrated care. A referral letter was present in 90.3%, but only 23.7% included HIV status and 18.8% CD4 cell count. Lack of education (RR 1.85) and low CD4 count (CD4<=50 vs. >250cells/mm(3); RR 1.66) were associated with failed linkage to TB care. Risk factors for failed linkage to HIV care were antiretroviral-naive status (RR 1.29), and absence of referral letter with HIV or CD4 cell count (RR1.23). CONCLUSIONS: Linkage to TB/HIV care should be strengthened by communication of HIV and CD4 results, ART initiation during hospitalization and TB/HIV integration at primary care. PMID- 23341870 TI - High osmolality vitrification: a new method for the simple and temperature permissive cryopreservation of mouse embryos. AB - Procedures for cryopreserving embryos vary considerably, each having its specific advantages and disadvantages in terms of technical feasibility, embryo survival yield, temperature permissibility and species- or strain-dependent applicability. Here we report a high osmolality vitrification (HOV) method that is advantageous in these respects. Cryopreservation by vitrification is generally very simple, but, unlike slow freezing, embryos should be kept at a supercooling temperature (below -130 degrees C) to avoid cryodamage. We overcame this problem by using an HOV solution containing 42.5% (v/v) ethylene glycol, 17.3% (w/v) Ficoll and 1.0 M sucrose. This solution is more viscous than other cryopreservation solutions, but easy handling of embryos was assured by employing a less viscous equilibration solution before vitrification. Most (>80%) embryos cryopreserved in this solution survived at -80 degrees C for at least 30 days. Normal mice were recovered even after intercontinental transportation in a conventional dry-ice package for 2-3 days, indicating that special containers such as dry shippers with liquid nitrogen vapor are unnecessary. The HOV solution could also be employed for long term storage in liquid nitrogen, as with other conventional cryoprotectants. Finally, we confirmed that this new vitrification method could be applied successfully to embryos of all six strains of mice we have tested so far. Thus, our HOV method provides an efficient and reliable strategy for the routine cryopreservation of mouse embryos in animal facilities and biomedical laboratories, and for easy and cheap transportation. PMID- 23341871 TI - Living with lions: the economics of coexistence in the Gir forests, India. AB - Rarely human communities coexist in harmony with large predators. Most often communities suffer due to predation on their stock while large carnivores suffer losses and at times extirpation due to retaliation. We examine the mechanisms permitting the coexistence of Asiatic lions (Panthera leo persica) and pastoral communities (Maldharis) in the Gir forests, India. We monitored six Maldhari settlements between 2005 and 2007 to quantify seasonal livestock holding, density and losses due to predation and other causes. Lion density, estimated by mark recapture, was 15+/-0.1 SE/100 km(2). Livestock density, estimated by total counts, ranged between 25/km(2)-31/km(2) with buffaloes being most abundant. Average livestock holding of Maldhari families was 33+/-3 SE. Lions predated mostly on unproductive cattle (30%). Scat analysis (n = 165), predation events (n = 180) and seven continuous monitoring sessions of 1,798 hours on four radio collared lions estimated livestock to contribute between 25 to 42% of lions' biomass consumptions, of which only 16% was predated; rest scavenged. With free grazing rights within Gir forests, Maldharis offset 58+/-0.2 SE% of annual livestock rearing cost in comparison to non-forest dwelling pastoralists. With government compensation scheme for livestock predation, this profit margin augmented to 76+/-0.05 SE%. Lion density was higher in areas with Maldhari livestock in comparison to areas without livestock. Thus, the current lifestyles and livestock holdings of Maldharis seem to be beneficial to both lions and local pastoralists. We conclude that a combination of strict protection regime for lions, Maldharis' traditional reverence towards lions and the livelihood economics permit the delicate balance of lion-Maldhari coexistence. Indefinite increase in human and livestock population within Gir might upset this equilibrium undermining the conservation objectives. We see no end to compensation programs worldwide as they constitute a crucial element needed for human-carnivore coexistence. PMID- 23341872 TI - Pain facilitation brain regions activated by nalbuphine are revealed by pharmacological fMRI. AB - Nalbuphine, an agonist-antagonist kappa-opioid, produces brief analgesia followed by enhanced pain/hyperalgesia in male postsurgical patients. However, it produces profound analgesia without pain enhancement when co-administration with low dose naloxone. To examine the effect of nalbuphine or nalbuphine plus naloxone on activity in brain regions that may explain these differences, we employed pharmacological magnetic resonance imaging (phMRI) in a double blind cross-over study with 13 healthy male volunteers. In separate imaging sessions subjects were administered nalbuphine (5 mg/70 kg) preceded by either saline (Sal-Nalb) or naloxone 0.4 mg (Nalox-Nalb). Blood oxygen level-dependent (BOLD) activation maps followed by contrast and connectivity analyses revealed marked differences. Sal Nalb produced significantly increased activity in 60 brain regions and decreased activity in 9; in contrast, Nalox-Nalb activated only 14 regions and deactivated only 3. Nalbuphine, like morphine in a previous study, attenuated activity in the inferior orbital cortex, and, like noxious stimulation, increased activity in temporal cortex, insula, pulvinar, caudate, and pons. Co administration/pretreatment of naloxone selectively blocked activity in pulvinar, pons and posterior insula. Nalbuphine induced functional connectivity between caudate and regions in the frontal, occipital, temporal, insular, middle cingulate cortices, and putamen; naloxone co-admistration reduced all connectivity to non-significant levels, and, like phMRI measures of morphine, increased activation in other areas (e.g., putamen). Naloxone pretreatment to nalbuphine produced changes in brain activity possess characteristics of both analgesia and algesia; naloxone selectively blocks activity in areas associated with algesia. Given these findings, we suggest that nalbuphine interacts with a pain salience system, which can modulate perceived pain intensity. PMID- 23341873 TI - Influence of serotonin transporter gene polymorphism (5-HTTLPR polymorphism) on the relation between brain 5-HT transporter binding and heart rate corrected cardiac repolarization interval. AB - OBJECTIVE: Serotonin transporter gene polymorphism (5-HTTLPR polymorphism) predicts the degree of structural and functional connectivity in the brain, and less consistently the degree of vulnerability for anxiety and depressive disorders. It is less known how 5-HTTLPR polymorphism influences on the coupling between brain and neuronal cardiovascular control. The present study demonstrates the impact of 5-HTTLPR polymorphism on the relations between heart rate (HR) corrected cardiac repolarization interval (QTc interval) and the brain 5-HTT binding. MATERIAL AND METHODS: Thirty healthy young adults (fifteen monozygotic twin pairs) (mean age 26+/-1.3 years, 16 females) were imagined with single photon emission computed tomography (SPECT) using iodine-123 labeled 2beta carbomethoxy-3beta-(4-iodophenyl) nortropane (nor-beta-CIT). Continuous ECG recording was obtained from each participant at supine rest. Signal averaged QTc interval on continuous ECG was calculated and compared with the brain imaging results. RESULTS: In the two groups [l homozygotes (n = 16, 10 females), s carriers (n = 14, 8 female)] HR and the length of QTc interval were not influenced by 5-HTTLPR polymorphism. There were no significant relations between HR and 5-HTT binding in the brain. There were significant associations between QTc interval and nor-beta-CIT binding in the brain in l homozygotes, but not in s carriers (correlations for QTc interval and nor-beta-CIT binding of striatum, thalamus and right temporal region were -0.8--0.9, (p<0.0005), respectively). CONCLUSION: The finding of longer QTc interval with less 5-HTT binding availability in major serotonergic binding sites in l homozygotes, but not in s carriers, implicate to differentiated control of QTc interval by 5-HTTLPR polymorphism. PMID- 23341875 TI - Highly informative ancient DNA 'snippets' for New Zealand moa. AB - BACKGROUND: Analysis of ancient DNA has provided invaluable information on past ecologies, ancient populations, and extinct species. We used a short snippet of highly variable mitochondrial control region sequence from New Zealand's moa to characterise a large number of bones previously intractable to DNA analysis as well as bone fragments from swamps to gain information about the haplotype diversity and phylogeography that existed in five moa species. METHODOLOGY/PRINCIPAL FINDINGS: By targeting such 'snippets', we show that moa populations differed substantially in geographic structure that is likely to be related to population mobility and history. We show that populations of Pachyornis geranoides, Dinornis novaezealandiae, and Dinornis robustus were highly structured and some appear to have occupied the same geographic location for hundreds of thousands of years. In contrast, populations of the moa Anomalopteryx didiformis and Euryapteryx curtus were widespread, with specific populations of the latter occupying both the North and South Islands of New Zealand. We further show that for a specific area, in this case a North Island swamp, complete haplotype diversity and even sex can be recovered from collections of small, often discarded, bone fragments. CONCLUSIONS/SIGNIFICANCE: Short highly variable mitochondrial 'snippets' allow successful typing of environmentally damaged and fragmented skeletal material, and can provide useful information about ancient population diversity and structure without the need to sample valuable, whole bones often held by museums. PMID- 23341874 TI - Mutations in the fusion protein cleavage site of avian paramyxovirus serotype 4 confer increased replication and syncytium formation in vitro but not increased replication and pathogenicity in chickens and ducks. AB - To evaluate the role of the F protein cleavage site in the replication and pathogenicity of avian paramyxoviruses (APMVs), we constructed a reverse genetics system for recovery of infectious recombinant APMV-4 from cloned cDNA. The recovered recombinant APMV-4 resembled the biological virus in growth characteristics in vitro and in pathogenicity in vivo. The F cleavage site sequence of APMV-4 (DIQPR?F) contains a single basic amino acid, at the -1 position. Six mutant APMV-4 viruses were recovered in which the F protein cleavage site was mutated to contain increased numbers of basic amino acids or to mimic the naturally occurring cleavage sites of several paramyxoviruses, including neurovirulent and avirulent strains of NDV. The presence of a glutamine residue at the -3 position was found to be important for mutant virus recovery. In addition, cleavage sites containing the furin protease motif conferred increased replication and syncytium formation in vitro. However, analysis of viral pathogenicity in 9-day-old embryonated chicken eggs, 1-day-old and 2-week old chickens, and 3-week-old ducks showed that none the F protein cleavage site mutations altered the replication, tropism, and pathogenicity of APMV-4, and no significant differences were observed among the parental and mutant APMV-4 viruses in vivo. Although parental and mutant viruses replicated somewhat better in ducks than in chickens, they all were highly restricted and avirulent in both species. These results suggested that the cleavage site sequence of the F protein is not a limiting determinant of APMV-4 pathogenicity in chickens and ducks. PMID- 23341876 TI - Suppressing the encoding of new information in memory: a behavioral study derived from principles of hippocampal function. AB - Cognitive processes do not occur in isolation. Interactions between cognitive processes can be observed as a cost in performance following a switch between tasks, a cost that is greatest when the cognitive requirements of the sequential tasks compete. Interestingly, the long-term mnemonic goals associated with specific cognitive tasks can also directly compete. For example, encoding the sequential order in which stimuli are presented in the commonly-utilised 2-Back working memory (WM) tasks is counter-productive to task performance, as this task requires the continual updating of the contents of one's current mental set. Performance of this task consistently results in reduced activity within the medial temporal lobe (MTL), and this response is believed to reflect the inhibitory mnemonic component of the task. Conversely, there are numerous cognitive paradigms in which participants are explicitly instructed to encode incoming information and performance of these tasks reliably increases MTL activity. Here, we explore the behavioural cost of sequentially performing two tasks with conflicting long-term mnemonic goals and contrasting neural profiles within the MTL. We hypothesised that performing the 2-Back WM prior to a hippocampal-dependent memory task would impair performance on the latter task. We found that participants who performed the 2-Back WM task, prior to the encoding of novel verbal/face-name stimuli, recollected significantly fewer of these stimuli, compared to those who had performed a 0-Back control task. Memory processes believed to be independent of the MTL were unaffected. Our results suggest that the inhibition of MTL-dependent mnemonic function persists beyond the cessation of the 2-Back WM task and can alter performance on entirely separate and subsequently performed memory tasks. Furthermore, they indicate that performance of such tasks may induce a temporarily-sustained, virtual lesion of the hippocampus, which could be used as a probe to explore cognitive processes in the absence of hippocampal involvement. PMID- 23341877 TI - Implementation of non-pharmaceutical interventions by New York City public schools to prevent 2009 influenza A. AB - INTRODUCTION: Children are important transmitters of influenza in the community and a number of non-pharmaceutical interventions (NPIs), including hand washing and use of hand sanitizer, have been recommended to mitigate the transmission of influenza, but limited information is available regarding schools' ability to implement these NPIs during an influenza outbreak. We evaluated implementation of NPIs during fall 2009 in response to H1N1 pandemic influenza (pH1N1) by New York City (NYC) public schools. METHODS: From January 25 through February 9, 2010, an online survey was sent to all the 1,632 NYC public schools and principals were asked to participate in the survey or to designate a school nurse or other school official with knowledge of school policies and characteristics to do so. RESULTS: Of 1,633 schools, 376(23%) accessed and completed the survey. Nearly all respondents (99%) implemented at least two NPIs. Schools that had a Flu Response Team (FRT) as a part of school emergency preparedness plan were more likely to implement the NPI guidelines recommended by NYC public health officials than schools that did not have a FRT. Designation of a room for isolating ill students, for example, was more common in schools with a FRT (72%) than those without (53%) (p<0.001). CONCLUSIONS: Implementing an NPI program in a large school system to mitigate the effects of an influenza outbreak is feasible, but there is potential need for additional resources in some schools to increase capacity and adherence to all recommendations. Public health influenza preparedness plans should include school preparedness planning and FRTs. PMID- 23341878 TI - Probabilistic MRI brain anatomical atlases based on 1,000 Chinese subjects. AB - Brain atlases are designed to provide a standard reference coordinate system of the brain for neuroscience research. Existing human brain atlases are widely used to provide anatomical references and information regarding structural characteristics of the brain. The majority of them, however, are derived from one paticipant or small samples of the Western population. This poses a limitation for scientific studies on Eastern subjects. In this study, 10 new Chinese brain atlases for different ages and genders were constructed using MR anatomical images based on HAMMER (Hierarchical Attribute Matching Mechanism for Elastic Registration). A total of 1,000 Chinese volunteers ranging from 18 to 70 years old participated in this study. These population-specific brain atlases represent the basic structural characteristics of the Chinese population. They may be utilized for basic neuroscience studies and clinical diagnosis, including evaluation of neurological and neuropsychiatric disorders, in Chinese patients and those from other Eastern countries. PMID- 23341879 TI - Investigating the antiproliferative activity of high affinity DNA aptamer on cancer cells. AB - Vascular endothelial growth factor (VEGF) is an angiogenic mitogen involved in promoting tumor angiogenesis inside the body. VEGF is a key protein required for progression of tumor from benign to malignant phenotype. In this study, we investigated the binding affinity of a previously selected 26-mer DNA aptamer sequence (SL(2)-B) against heparin binding domain (HBD) of VEGF(165) protein. The SL(2)-B was first chemically modified by introduction of phosphorothioate linkages (PS-linkages). Subsequently, surface plasmon resonance (SPR) spectroscopy and circular dichroism (CD) were used to determine the binding affinity, specificity and to deduce the conformation of PS-modified SL(2)-B sequence. Finally, antiproliferative activity of the modified SL(2)-B sequence on Hep G2 cancer cells was investigated. Our results demonstrate a marked enhancement in the biostability of the SL(2)-B sequence after PS modification. The modified SL(2)-B sequence also exhibits enhanced antiproliferative activity against Hep G2 cancer cells in hypoxia conditions. In addition, modified SL(2)-B sequence inhibits the expression of Jagged-1 protein, which is one of the ligands to VEGF linked delta/jagged-notch signaling pathway. PMID- 23341880 TI - Routine HIV testing among providers of HIV care in the United States, 2009. AB - In 2006, CDC recommended HIV screening as part of routine medical care for all persons aged 13-64 years. We examined adherence to the recommendations among a sample of HIV care providers in the US to determine if known providers of HIV care are offering routine HIV testing in outpatient settings. Data were from the CDC's Medical Monitoring Project Provider Survey, administered to physicians, nurse practitioners and physician assistants from June-September 2009. We assessed bivariate associations between testing behaviors and provider and practice characteristics and used multivariate regression to determine factors associated with offering HIV screening to all patients aged 13-64 years. Sixty percent of providers reported offering HIV screening to all patients 13 to 64 years of age. Being a nurse practitioner (aOR = 5.6, 95% CI = 2.6-11.9) compared to physician, age<39 (aOR = 1.9, 95% CI = 1.0-3.5) or 39-49 (aOR = 2.1, 95% CI = 1.4-3.3) compared with >=50 years, and black race (aOR = 2.6, 95% CI = 1.2-6.0) compared with white race was associated with offering testing to all patients. Providers with low (aOR = 0.2, 95% CI = 0.1-0.3) or medium (aOR = 0.4, 95% CI = 0.2-0.6) HIV-infected patient loads were less likely to offer HIV testing to all patients compared with providers with high patient loads. Many providers of HIV care are still conducting risk-based rather than routine testing. We found that provider profession, age, race, and HIV-infected patient load were associated with offering HIV testing. Health care providers should use patient encounters as an opportunity to offer routine HIV testing to patients as outlined in CDC's revised recommendations for HIV testing in health care settings. PMID- 23341881 TI - Long-term unemployment and suicide: a systematic review and meta-analysis. AB - PURPOSE: There have been a number of reviews on the association+ between unemployment and suicide, but none have investigated how this relationship is influenced by duration of unemployment. METHOD: A systematic review and meta analysis was conducted of those studies that assessed duration of unemployment as a risk factor for suicide. Studies considered as eligible for inclusion were population-based cohort or case-control designs; population-based ecological designs, or hospital based clinical cohort or case-control designs published in the year 1980 or later. RESULTS: The review identified 16 eligible studies, out of a possible 10,358 articles resulting from a search of four databases: PubMed, Web of Knowledge, Scopus and Proquest. While all 16 studies measured unemployment duration in different ways, a common finding was that longer duration of unemployment was related to greater risk of suicide and suicide attempt. A random effects meta-analysis on a subsample of six cohort studies indicated that the pooled relative risk of suicide in relation to average follow-up time after unemployment was 1.70 (95% CI 1.22 to 2.18). However, results also suggested a possible habituation effect to unemployment over time, with the greatest risk of suicide occurring within five years of unemployment compared to the employed population (RR = 2.50, 95% CI 1.83 to 3.17). Relative risk appeared to decline in studies of those unemployed between 12 and 16 years compared to those currently employed (RR = 1.21, 95% CI 1.10 to 1.33). CONCLUSION: Findings suggest that long term unemployment is associated with greater incidence of suicide. Results of the meta-analysis suggest that risk is greatest in the first five years, and persists at a lower but elevated level up to 16 years after unemployment. These findings are limited by the paucity of data on this topic. PMID- 23341882 TI - ADAM17 mediates MMP9 expression in lung epithelial cells. AB - The purposes were to study the role of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha/nuclear factor-kappaB (NF-kappaB) signaling in matrix metalloproteinase 9 (MMP9) expression in A549 cells and to investigate the effects of lentivirus-mediated RNAi targeting of the disintegrin and metalloproteinase 17 (ADAM17) gene on LPS-induced MMP9 expression. MMP9 expression induced by LPS in A549 cells was significantly increased in a dose- and time-dependent manner (p<0.05). Pyrrolidine dithiocarbamate (PDTC) and a TNFR1 blocking peptide (TNFR1BP) significantly inhibited LPS-induced MMP9 expression in A549 cells (p<0.05). TNFR1BP significantly inhibited LPS-induced TNF-alpha production (p<0.05). Both PDTC and TNFR1BP significantly inhibited the phosphorylation of IkappaBalpha and expression of phosphorylation p65 protein in response to LPS (p<0.05), and the level of IkappaBalpha in the cytoplasm was significantly increased (p<0.05). Lentivirus mediated RNA interference (RNAi) significantly inhibited ADAM17 expression in A549 cells. Lentivirus-mediated RNAi targeting of ADAM17 significantly inhibited TNF-alpha production in the supernatants (p<0.05), whereas the level of TNF-alpha in the cells was increased (p<0.05). Lentiviral ADAM17 RNAi inhibited MMP9 expression, IkappaBalpha phosphorylation and the expression of phosphorylation p65 protein in response to LPS (p<0.05). PDTC significantly inhibited the expression of MMP9 and the phosphorylation of IkappaBalpha, as well as the expression of phosphorylation p65 protein in response to TNF-alpha (p<0.05). Lentiviral RNAi targeting of ADAM17 down-regulates LPS-induced MMP9 expression in lung epithelial cells via inhibition of TNF-alpha/NF-kappaB signaling. PMID- 23341883 TI - TanshinoneIIA and cryptotanshinone protect against hypoxia-induced mitochondrial apoptosis in H9c2 cells. AB - Mitochondrial apoptosis pathway is an important target of cardioprotective signalling. Tanshinones, a group of major bioactive compounds isolated from Salvia miltiorrhiza, have been reported with actions against inflammation, oxidative stress, and myocardial ischemia reperfusion injury. However, the actions of these compounds on the chronic hypoxia-related mitochondrial apoptosis pathway have not been investigated. In this study, we examined the effects and molecular mechanisms of two major tanshonones, tanshinone IIA (TIIA) and cryptotanshinone (CT) on hypoxia induced apoptosis in H9c2 cells. Cultured H9c2 cells were treated with TIIA and CT (0.3 and 3 MUMU) 2 hr before and during an 8 hr hypoxic period. Chronic hypoxia caused a significant increase in hypoxia inducible factor 1alpha expression and the cell late apoptosis rate, which was accompanied with an increase in caspase 3 activity, cytochrome c release, mitochondria membrane potential and expression of pro-apoptosis proteins (Bax and Bak). TIIA and CT (0.3 and 3 MUMU), in concentrations without affecting the cell viability, significantly inhibited the late apoptosis and the changes of caspase 3 activity, cytochrome c release, and mitochondria membrane potential induced by chronic hypoxia. These compounds also suppressed the overexpression of Bax and reduced the ratio of Bax/Bcl-2. The results indicate that TIIA and CT protect against chronic hypoxia induced cell apoptosis by regulating the mitochondrial apoptosis signaling pathway, involving inhibitions of mitochondria hyperpolarization, cytochrome c release and caspase 3 activity, and balancing anti- and pro-apoptotic proteins in Bcl-2 family proteins. PMID- 23341884 TI - Climate change or urbanization? Impacts on a traditional coffee production system in East Africa over the last 80 years. AB - Global environmental changes (GEC) such as climate change (CC) and climate variability have serious impacts in the tropics, particularly in Africa. These are compounded by changes in land use/land cover, which in turn are driven mainly by economic and population growth, and urbanization. These factors create a feedback loop, which affects ecosystems and particularly ecosystem services, for example plant-insect interactions, and by consequence agricultural productivity. We studied effects of GEC at a local level, using a traditional coffee production area in greater Nairobi, Kenya. We chose coffee, the most valuable agricultural commodity worldwide, as it generates income for 100 million people, mainly in the developing world. Using the coffee berry borer, the most serious biotic threat to global coffee production, we show how environmental changes and different production systems (shaded and sun-grown coffee) can affect the crop. We combined detailed entomological assessments with historic climate records (from 1929 2011), and spatial and demographic data, to assess GEC's impact on coffee at a local scale. Additionally, we tested the utility of an adaptation strategy that is simple and easy to implement. Our results show that while interactions between CC and migration/urbanization, with its resultant landscape modifications, create a feedback loop whereby agroecosystems such as coffee are adversely affected, bio diverse shaded coffee proved far more resilient and productive than coffee grown in monoculture, and was significantly less harmed by its insect pest. Thus, a relatively simple strategy such as shading coffee can tremendously improve resilience of agro-ecosystems, providing small-scale farmers in Africa with an easily implemented tool to safeguard their livelihoods in a changing climate. PMID- 23341885 TI - Triphenylmethane derivatives have high in vitro and in vivo activity against the main causative agents of cutaneous leishmaniasis. AB - The current standard of care for cutaneous leishmaniasis (CL) is organic antimonial compounds, but the administration of these compounds is complicated by a low therapeutic - toxic index, as well as parenteral administration. Thus, there is an urgent need for the development of new and inexpensive therapies for the treatment of CL. In this study, we evaluate the activity of the triphenylmethane (TPM) class of compounds against three species of Leishmania which are pathogenic in humans. The TPM have a history of safe use in humans, dating back to the use of the original member of this class, gentian violet (GV), from the early 20(th) century. Initially, the in vitro efficacy against Leishmania (Viannia) braziliensis, L. (Leishmania) amazonensis and L. (L.) major of 9 newly synthesized TPM, in addition to GV, was tested. Inhibitory concentrations (IC) IC(50) of 0.025 to 0.84 uM had been found in promastigotes in vitro assays. The four most effective compounds were then tested in amastigote intracellular assays, resulting in IC(50) of 0.10 to 1.59 uM. A high degree of selectivity of antiparasitic activity over toxicity to mammalian cells was observed. Afterwards, GV and TPM 6 were tested in a topical formulation in mice infected with L. (L.) amazonensis leading to elimination of parasite burdens at the site of lesion/infection. These results demonstrated that TPM present significant anti-leishmanial activities and provide a rationale for human clinical trials of GV and other TPM. TPM are inexpensive and safe, thus using them for treatment of CL may have a major impact on public health. PMID- 23341886 TI - Safety of and cellular response to segmental bronchoprovocation in allergic asthma. AB - RATIONALE: Despite its incorporation into research studies, the safety aspects of segmental allergen bronchoprovocation and differences in cellular response among different allergens have received limited consideration. METHODS: We performed 87 segmental challenges in 77 allergic asthma subjects. Allergen dose was based on each subject's response to whole lung allergen challenge. Bronchoalveolar lavage was performed at 0 and 48 hours. Safety indicators included spirometry, oxygen saturation, heart rate, and symptoms. RESULTS: Among subjects challenged with ragweed, cat dander, or house dust mite, there were no differences in safety indicators. Subjects demonstrated a modest oxygen desaturation and tachycardia during the procedure that returned to normal prior to discharge. We observed a modest reduction in forced vital capacity and forced expiratory volume in one second following bronchoscopy. The most common symptoms following the procedure were cough, sore throat and fatigue. Total bronchoalveolar lavage fluid cell numbers increased from 13+/-4 to 106+/-108*10(4) per milliliter and eosinophils increased from 1+/-2 to 44+/-20 percent, with no significant differences among the three allergens. CONCLUSIONS: In mild allergic asthma, segmental allergen bronchoprovocation, using individualized doses of aeroallergens, was safe and yielded similar cellular responses. PMID- 23341887 TI - Cost-effectiveness analysis of a national neonatal hearing screening program in China: conditions for the scale-up. AB - BACKGROUND: In 2009, the Chinese Ministry of Health recommended scale-up of routine neonatal hearing screening - previously performed primarily only in select urban hospitals - throughout the entire country. METHODS: A decision analytical model for a simulated population of all live births in china was developed to compare the costs and health effects of five mutually exclusive interventions: 1) universal screening using Otoacoustic Emission (OAE) and Automated Auditory Brainstem Response (AABR); 2) universal OAE; 3) targeted OAE and AABR; 4) targeted OAE; and 5) no screening. Disability-Adjusted Life Years (DALYs) were calculated for health effects. RESULTS AND DISCUSSION: Based on the cost-effectiveness and potential health outcomes, the optimal path for scale-up would be to start with targeted OAE and then expand to universal OAE and universal OAE plus AABR. Accessibility of screening, diagnosis, and intervention services significantly affect decision of the options. CONCLUSION: In conclusion, to achieve cost-effectiveness and best health outcomes of the NHS program, the accessibility of screening, diagnosis, and intervention services should be expanded to reach a larger population. The results are thus expected to be of particular benefit in terms of the 'rolling out' of the national plan. PMID- 23341888 TI - Comorbidities and mortality in hypercapnic obese under domiciliary noninvasive ventilation. AB - BACKGROUND: The higher mortality rate in untreated patients with obesity associated hypoventilation is a strong rationale for long-term noninvasive ventilation (NIV). The impacts of comorbidities, medications and NIV compliance on survival of these patients remain largely unexplored. METHODS: Observational cohort of hypercapnic obese patients initiated on NIV between March 2003 and July 2008. Survival curves were estimated by the Kaplan-Meier method. Anthropometric measurements, pulmonary function, blood gases, nocturnal SpO(2) indices, comorbidities, medications, conditions of NIV initiation and NIV compliance were used as covariates. Univariate and multivariate Cox models allowed to assess predictive factors of mortality. RESULTS: One hundred and seven patients (56% women), in whom NIV was initiated in acute (36%) or chronic conditions, were followed during 43+/-14 months. The 1, 2, 3 years survival rates were 99%, 94%, and 89%, respectively. In univariate analysis, death was associated with older age (>61 years), low FEV1 (<66% predicted value), male gender, BMI*time, concomitant COPD, NIV initiation in acute condition, use of inhaled corticosteroids, beta-blockers, nonthiazide diuretics, angiotensin-converting enzyme inhibitors and combination of cardiovascular drugs (one diuretic and at least one other cardiovascular agent). In multivariate analysis, combination of cardiovascular agents was the only factor independently associated with higher risk of death (HR = 5.3; 95% CI 1.18; 23.9). Female gender was associated with lower risk of death. CONCLUSION: Cardiovascular comorbidities represent the main factor predicting mortality in patient with obesity-associated hypoventilation treated by NIV. In this population, NIV should be associated with a combination of treatment modalities to reduce cardiovascular risk. PMID- 23341889 TI - Impact of genetic polymorphisms of SLC2A2, SLC2A5, and KHK on metabolic phenotypes in hypertensive individuals. AB - OBJECTIVE: In the past few decades, consumption of added sugars has increased dramatically. Studies have linked high sugar intake with increased risk for a number of diseases. Importantly, fructose, a component of sugar, has been linked with the development of features of metabolic syndrome. This study determined if single nucleotide polymorphisms in genes involved in fructose transport (solute carrier family 2 facilitated glucose transporter, member 2 (SLC2A2) and solute carrier family 2 facilitated glucose/fructose transporter, member 5 (SLC2A5)) and metabolism (ketohexokinase (KHK)) affect inter-individual variability in metabolic phenotypes, such as increased serum uric acid levels. MATERIALS/METHODS: The influence of SLC2A2, SLC2A5, and KHK SNPs on metabolic phenotypes was tested in 237 European Americans and 167 African Americans from the Pharmacogenomic Evaluation and Antihypertensive Responses (PEAR) study. Using baseline untreated fasting data, associations were considered significant if p<=0.005. These SNPs were then evaluated for potential replication (p<=0.05) using data from the Genetic Epidemiology of Responses to Antihypertensives (GERA) studies. RESULTS: SLC2A5 rs5438 was associated with an increase in serum uric acid in European American males. However, we were unable to replicate the association in GERA. The minor allele of SLC2A2 rs8192675 showed an association with lower high-density lipoproteins in European Americans (A/A: 51.0 mg/dL, A/G: 47.0 mg/dL, G/G: 41.5 mg/dL, p = 0.0034) in PEAR. The association between rs8192675 and lower high-density lipoproteins was replicated in the combined European American GERA study samples (A/A: 47.6 mg/dL, A/G: 48.6 mg/dL, G/G: 41.9 mg/dL, p = 0.0315). CONCLUSIONS: The association between SLC2A2 rs8192675 and high-density lipoproteins suggests the polymorphism may play a role in influencing high-density lipoproteins and thus metabolic risk of cardiovascular disease. PMID- 23341890 TI - Clinical significance of EML4-ALK fusion gene and association with EGFR and KRAS gene mutations in 208 Chinese patients with non-small cell lung cancer. AB - The EML4-ALK fusion gene has been recently identified in a small subset of non small cell lung cancer (NSCLC) patients who respond positively to ALK inhibitors. The characteristics of the EML4-ALK fusion gene in Chinese patients with NSCLC are poorly understood. Here, we report on the prevalence of EML4-ALK, EGFR status and KRAS mutations in 208 Chinese patients with NSCLC. EGFR mutations were found in 24.5% (51/208) of patients. In concordance with previous reports, these mutations were identified at high frequencies in females (47.5% vs 15.0% in males; P<0.05); never-smokers (42.3% vs 13.9% in smokers; P<0.05), and adenocarcinoma patients (44.2% vs 8.0% in non-adenocarcinoma patients; P<0.05). There were only 2.88% (6/208) patients with KRAS mutations in our study group. We identified 7 patients who harbored the EML4-ALK fusion gene (3.37%, 7/208), including 4 cases with variant 3 (57.1%), 2 with variant 1, and 1 with variant 2. All positive cases corresponded to female patients (11.5%, 7/61). Six of the positive cases were non-smokers (7.69%, 6/78). The incidence of EML4-ALK translocation in female, non-smoking adenocarcinoma patients was as high as 15.2% (5/33). No EGFR/KRAS mutations were detected among the EML4-ALK positive patients. Pathological analysis showed no difference between solid signet-ring cell pattern (4/7) and mucinous cribriform pattern (3/7) in ALK-positive patients. Immunostaining showed intratumor heterogeneity of ALK rearrangement in primary carcinomas and 50% (3/6) of metastatic tumors with ALK-negative staining. Meta-analysis demonstrated that EML4-ALK translocation occurred in 4.84% (125/2580) of unselected patients with NSCLC, and was also predominant in non smoking patients with adenocarcinoma. Taken together, EML4-ALK translocations were infrequent in the entire NSCLC patient population, but were frequent in the NSCLC subgroup of female, non-smoker, adenocarcinoma patients. There was intratumor heterogeneity of ALK rearrangement in primary carcinomas and at metastatic sites. PMID- 23341891 TI - The Type II Hsp40 Sis1 cooperates with Hsp70 and the E3 ligase Ubr1 to promote degradation of terminally misfolded cytosolic protein. AB - Mechanisms for cooperation between the cytosolic Hsp70 system and the ubiquitin proteasome system during protein triage are not clear. Herein, we identify new mechanisms for selection of misfolded cytosolic proteins for degradation via defining functional interactions between specific cytosolic Hsp70/Hsp40 pairs and quality control ubiquitin ligases. These studies revolved around the use of S. cerevisiae to elucidate the degradation pathway of a terminally misfolded reporter protein, short-lived GFP (slGFP). The Type I Hsp40 Ydj1 acts with Hsp70 to suppress slGFP aggregation. In contrast, the Type II Hsp40 Sis1 is required for proteasomal degradation of slGFP. Sis1 and Hsp70 operate sequentially with the quality control E3 ubiquitin ligase Ubr1 to target slGFP for degradation. Compromise of Sis1 or Ubr1 function leads slGFP to accumulate in a Triton X-100 soluble state with slGFP degradation intermediates being concentrated into perinuclear and peripheral puncta. Interestingly, when Sis1 activity is low the slGFP that is concentrated into puncta can be liberated from puncta and subsequently degraded. Conversely, in the absence of Ubr1, slGFP and the puncta that contain slGFP are relatively stable. Ubr1 mediates proteasomal degradation of slGFP that is released from cytosolic protein handling centers. Pathways for proteasomal degradation of misfolded cytosolic proteins involve functional interplay between Type II Hsp40/Hsp70 chaperone pairs, PQC E3 ligases, and storage depots for misfolded proteins. PMID- 23341892 TI - Imaging and quantification of subbasal nerve plexus in healthy volunteers and diabetic patients with or without retinopathy. AB - BACKGROUND: The alterations of subbasal nerve plexus (SBP) innervation and corneal sensation were estimated non-invasively and compared with the values in healthy volunteers. Additionally, this study addressed the relation of SBP changes to the retinal status, glycemic control and diabetes duration. METHODOLOGY/PRINCIPAL FINDINGS: Eighteen eyes of diabetic patients with peripheral diabetic neuropathy aged 68.8+/-8.8 years and twenty eyes of healthy volunteers aged 66.3+/-13.3 yrs. were investigated with in vivo confocal laser scanning microscopy (CLSM). An adapted algorithm for image analysis was used to quantify the morphological and topological properties of SBP. These properties were correlated to incidence of diabetic retinopathy (DR) and corneal sensation (Cochet-Bonnet esthesiometer). The developed algorithm allows a fully automated analysis of pre-segmented SBP structures. Altogether, 10 parameters were analysed, and all of them revealed significant differences between diabetic patients and healthy volunteers. The nerve fibre density, total fibre length and nerve branches were found to be significantly lower in patients with diabetes than those of control subjects (nerve fibre density 0.006+/-0.002 vs. 0.020+/ 0.007 mm/mm(2); total fibre length 6223+/-2419 vs. 19961+/-6553 um; nerve branches 25.3+/-28.6 vs. 141.9+/-85.7 in healthy volunteers). Also the corneal sensation was significantly lower in diabetic group when compared to controls (43+/-11 vs. 59+/-18 mm). There was found no difference in SBP morphology or corneal sensation in the subgroups with (DR) or without (NDR) diabetic retinopathy. CONCLUSIONS/SIGNIFICANCE: SBP parameters were significantly reduced in diabetic patients, compared to control group. Interestingly, the SBP impairment could be shown even in the diabetic patients without DR. Although automatic adapted image analysis simplifies the evaluation of in vivo CLSM data, image acquisition and quantitative analysis should be optimised for the everyday clinical practice. PMID- 23341893 TI - SDR9C7 promotes lymph node metastases in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: The major reason for the poor prognosis of esophageal squamous cell carcinoma (ESCC) patients is lymph node (LN) metastases. METHODOLOGY/PRINCIPAL: In the present study, gene expression profiling assay (GEP) was performed to identify the differences in gene expression profiles between primary ESCC tumors that were with LN metastases (N(+)) and those without LN metastases (N(-)). CONCLUSIONS/SIGNIFICANCE: A total of 23 genes were identified as being significantly elevated, and 30 genes were sharply decreased in ESCC tumors that were N(+) compared with N- tumors. Among these genes, two transcripts of the short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) were observed 7 times more frequently in N(+) compared with N(-) tumors. Immunohistochemical staining showed that SDR9C7 expression closely correlated with metastasis, and would be a prognostic marker for ESCC patients. To investigate the role of SDR9C7 in the ESCC metastasis, repeated transwell assays were adopted to establish highly and non-invasive ESCC sublines, and western blot showed that SDR9C7 expression was markedly higher in highly invasive cells compared with non invasive ones. Down-regulation of SDR9C7 dramatically inhibited the metastatic abilities in vitro and in vivo, and repressed the expression of MMP11 in highly invasive cells, indicating that SDR9C7 promotes ESCC metastasis partly through regulation of MMP11, and might be a potential prognostic and therapeutic marker for ESCC patients. PMID- 23341894 TI - Cell-cell interactions influence vascular reprogramming by Prox1 during embryonic development. AB - Lymphangiogenesis is a highly regulated process that involves the reprogramming of venous endothelial cells into early lymphatic endothelial cells. This reprogramming not only displays a polarized expression pattern from the cardinal vein, but also demonstrates vascular specificity; early lymphatics only develop from the cardinal vein and not the related dorsal aorta. In our transgenic model of lymphangiogenesis, we demonstrate that Prox1 overexpression has the ability to reprogram venous endothelium but not early arterial endothelial cells in vivo, in spite of the fact that Prox1 expression is forced onto both vascular beds. Our observations suggest that this specificity during embryogenesis may be due to cell-cell interactions between the developing arterial endothelial cells and smooth muscle cells. These conclusions have far reaching implications on how we understand the vascular specificity of lymphangiogenesis. PMID- 23341895 TI - Impact of tobacco-related health warning labels across socioeconomic, race and ethnic groups: results from a randomized web-based experiment. AB - BACKGROUND: The U.S. Family Smoking Prevention and Tobacco Control Act of 2009 requires updating of the existing text-only health warning labels on tobacco packaging with nine new warning statements accompanied by pictorial images. Survey and experimental research in the U.S. and other countries supports the effectiveness of pictorial health warning labels compared with text-only warnings for informing smokers about the risks of smoking and encouraging cessation. Yet very little research has examined differences in reactions to warning labels by race/ethnicity, education or income despite evidence that population subgroups may differ in their ability to process health information. The purpose of the present study was to evaluate the potential impact of pictorial warning labels compared with text-only labels among U.S. adult smokers from diverse racial/ethnic and socioeconomic subgroups. METHODS/FINDINGS: Participants were adult smokers recruited from two online research panels (n = 3,371) into a web based experimental study to view either the new pictorial warnings or text-only warnings. Participants viewed the labels and reported their reactions. Adjusted regression models demonstrated significantly stronger reactions for the pictorial condition for each outcome salience (b = 0.62, p<.001); perceived impact (b = 0.44, p<.001); credibility (OR = 1.41, 95% CI = 1.22-1.62), and intention to quit (OR = 1.30, 95% CI = 1.10-1.53). No significant results were found for interactions between condition and race/ethnicity, education, or income. The only exception concerned the intention to quit outcome, where the condition-by education interaction was nearly significant (p = 0.057). CONCLUSIONS: Findings suggest that the greater impact of the pictorial warning label compared to the text-only warning is consistent across diverse racial/ethnic and socioeconomic populations. Given their great reach, pictorial health warning labels may be one of the few tobacco control policies that have the potential to reduce communication inequalities across groups. Policies that establish strong pictorial warning labels on tobacco packaging may be instrumental in reducing the toll of the tobacco epidemic, particularly within vulnerable communities. PMID- 23341896 TI - Identification of rare recurrent copy number variants in high-risk autism families and their prevalence in a large ASD population. AB - Structural variation is thought to play a major etiological role in the development of autism spectrum disorders (ASDs), and numerous studies documenting the relevance of copy number variants (CNVs) in ASD have been published since 2006. To determine if large ASD families harbor high-impact CNVs that may have broader impact in the general ASD population, we used the Affymetrix genome-wide human SNP array 6.0 to identify 153 putative autism-specific CNVs present in 55 individuals with ASD from 9 multiplex ASD pedigrees. To evaluate the actual prevalence of these CNVs as well as 185 CNVs reportedly associated with ASD from published studies many of which are insufficiently powered, we designed a custom Illumina array and used it to interrogate these CNVs in 3,000 ASD cases and 6,000 controls. Additional single nucleotide variants (SNVs) on the array identified 25 CNVs that we did not detect in our family studies at the standard SNP array resolution. After molecular validation, our results demonstrated that 15 CNVs identified in high-risk ASD families also were found in two or more ASD cases with odds ratios greater than 2.0, strengthening their support as ASD risk variants. In addition, of the 25 CNVs identified using SNV probes on our custom array, 9 also had odds ratios greater than 2.0, suggesting that these CNVs also are ASD risk variants. Eighteen of the validated CNVs have not been reported previously in individuals with ASD and three have only been observed once. Finally, we confirmed the association of 31 of 185 published ASD-associated CNVs in our dataset with odds ratios greater than 2.0, suggesting they may be of clinical relevance in the evaluation of children with ASDs. Taken together, these data provide strong support for the existence and application of high-impact CNVs in the clinical genetic evaluation of children with ASD. PMID- 23341897 TI - Pearl microstructure and expression of shell matrix protein genes MSI31 and MSI60 in the pearl sac epithelium of Pinctada fucata by in situ hybridization. AB - Expression patterns of the shell matrix protein genes MSI31 and MSI60 in the pearl sac epithelium were examined by in situ hybridization 38 days after implantation, and related to pearl quality. A pearl sac that produced a nacreous pearl showed very weak expression of MSI31 and strong expression of MSI60. A pearl sac, which yielded a prismatic pearl, strongly expressed MSI31 and very weakly expressed MSI60. In a complex pearl, whose surface consisted of a mosaic of both nacreous and prismatic layers, the expression pattern of MSI31 and MSI60 similarly corresponded to the underlying surface structures of the pearl. A nacreous pearl whose pearl sac showed strong MSI31 expression had an entirely nacreous surface composed of a laminar structure with unusual tablet growth at the corresponding site. MSI31 and MSI60 are the major components of the shell matrix proteins of the nacreous and prismatic layers. Clearly, high expression of MSI31 does not always result in prismatic secretion. These observations cannot be explained solely on the basis of the expression patterns of MSI31 and MSI60. We propose that, in addition to the MSI genes that form the prismatic and nacreous layers, upstream from these genes there are regulatory master genes that determine whether a nacreous layer (aragonite) or a prismatic layer (calcite) is formed. PMID- 23341898 TI - Mucosal and cutaneous human papillomaviruses detected in raw sewages. AB - Epitheliotropic viruses can find their way into sewage. The aim of the present study was to investigate the occurrence, distribution, and genetic diversity of Human Papillomaviruses (HPVs) in urban wastewaters. Sewage samples were collected from treatment plants distributed throughout Italy. The DNA extracted from these samples was analyzed by PCR using five PV-specific sets of primers targeting the L1 (GP5/GP6, MY09/MY11, FAP59/64, SKF/SKR) and E1 regions (PM-A/PM-B), according to the protocols previously validated for the detection of mucosal and cutaneous HPV genotypes. PCR products underwent sequencing analysis and the sequences were aligned to reference genomes from the Papillomavirus Episteme database. Phylogenetic analysis was then performed to assess the genetic relationships among the different sequences and between the sequences of the samples and those of the prototype strains. A broad spectrum of sequences related to mucosal and cutaneous HPV types was detected in 81% of the sewage samples analyzed. Surprisingly, sequences related to the anogenital HPV6 and 11 were detected in 19% of the samples, and sequences related to the "high risk" oncogenic HPV16 were identified in two samples. Sequences related to HPV9, HPV20, HPV25, HPV76, HPV80, HPV104, HPV110, HPV111, HPV120 and HPV145 beta Papillomaviruses were detected in 76% of the samples. In addition, similarity searches and phylogenetic analysis of some sequences suggest that they could belong to putative new genotypes of the beta genus. In this study, for the first time, the presence of HPV viruses strongly related to human cancer is reported in sewage samples. Our data increases the knowledge of HPV genomic diversity and suggests that virological analysis of urban sewage can provide key information useful in supporting epidemiological studies. PMID- 23341899 TI - Alterations with movement duration in the kinematics of a whole body pointing movement. AB - Our aim was to investigate how the organization of a whole body movement is altered when movement duration (MD) is varied. Subjects performed the same whole body pointing movement over long, normal and short MDs. The kinematic trajectories were then analyzed on a normalized time base. A principal components analysis (PCA) revealed that the degree of coordination between the elevation angles of the body did not change with MD. This lack of significant differences in the coordination was interesting given that small spatial and temporal differences were observed in the individual kinematic trajectories. They were revealed by studying the trajectories of the elevation angles, joint markers and center of mass. The elevation angle excursions displayed modifications primarily in their spatial characteristics. These alterations were more marked for the short rather than long duration movements. The temporal characteristics of the elevation angles as measured by the time to peak of angular velocity were not modified in the same fashion hence displaying a dissociation in the tuning of the spatial and temporal aspects of the elevation angles. Modifications in the temporal characteristics of the movement were also studied by examining the velocity profiles of the joint markers. Interestingly, unlike the disordered nature of this variable for the elevation angles, the time to peak velocity was neatly ordered as a function of MD for the joint markers - It arrived first for the short duration movements, followed by those of the normal and finally long duration movements. Despite the modifications observed in the kinematic trajectories, a PCA with the elevation angle excursions at different MDs revealed that two principal components were sufficient to account for nearly all the variance in the data. Our results suggest that although similar, the kinematic trajectories at different MDs are not achieved by a simple time scaling. PMID- 23341900 TI - Modeling extracellular matrix reorganization in 3D environments. AB - Extracellular matrix (ECM) remodeling is a key physiological process that occurs in a number of contexts, including cell migration, and is especially important for cellular form and function in three-dimensional (3D) matrices. However, there have been few attempts to computationally model how cells modify their environment in a manner that accounts for both cellular properties and the architecture of the surrounding ECM. To this end, we have developed and validated a novel model to simulate matrix remodeling that explicitly defines cells in a 3D collagenous matrix. In our simulation, cells can degrade, deposit, or pull on local fibers, depending on the fiber density around each cell. The cells can also move within the 3D matrix. Different cell phenotypes can be modeled by varying key cellular parameters. Using the model we have studied how two model cancer cell lines, of differing invasiveness, modify matrices with varying fiber density in their vicinity by tracking the metric of fraction of matrix occupied by fibers. Our results quantitatively demonstrate that in low density environments, cells deposit more collagen to uniformly increase fibril fraction. On the other hand, in higher density environments, the less invasive model cell line reduced the fibril fraction as compared to the highly invasive phenotype. These results show good qualitative and quantitative agreement with existing experimental literature. Our simulation is therefore able to function as a novel platform to provide new insights into the clinically relevant and physiologically critical process of matrix remodeling by helping identify critical parameters that dictate cellular behavior in complex native-like environments. PMID- 23341901 TI - Utility of NT-proBNP for identifying LV failure in patients with acute exacerbation of chronic bronchitis. AB - BACKGROUND: NT-proBNP has been widely regarded as a useful tool for diagnosis or exclusion of heart failure (HF) in many settings. However, in patients with acute exacerbation of chronic bronchitis (AECB), its roles have not been well described. The objective of this study was to evaluate the diagnostic performance of NT-proBNP for identifying left ventricular (LV) failure in such patients. METHODS AND RESULTS: 311 AECB patients and 102 stable chronic bronchitis patients with no history of HF were enrolled. Plasma NT-proBNP concentrations were measured using Roche Elecsys. The European Society of Cardiology (ESC) diagnostic principles were adopted to identify HF and the diagnostic performance of NT proBNP was evaluated by ROC. Our results showed, the median NT-proBNP level in patients with LV failure [4828.4 (2044.4-9203.6) ng/L] was significantly higher than that in those without LV failure [519.2 (179.1-1409.8) ng/L, p<0.001] and stable controls [207.5 (186.5-318.2) ng/L, p<0.001]. LV failure, renal function, atrial fibrillation and systolic pulmonary artery pressure were independent predictors of NT-proBNP levels (all p<0.05). The area under ROC curve (AUC) of NT proBNP for identifying LV failure was 0.884, significantly superior to clinical judgment alone (AUC 0.835, p = 0.0294). At the optimal cutoff value of 935.0 ng/L, NT-proBNP yielded sensitivity 94.4%, specificity 68.2%, accuracy 74.3% and negative predictive value 97.6%. Adding the results of NT-proBNP to those of clinical judgment improved the diagnostic accuracy for LV failure. CONCLUSION: As a tool for diagnosis or exclusion of HF, NT-proBNP can help physicians identify LV failure in patients with AECB. PMID- 23341902 TI - Clinical use of HIV integrase inhibitors: a systematic review and meta-analysis. AB - BACKGROUND: Optimal regimen choice of antiretroviral therapy is essential to achieve long-term clinical success. Integrase inhibitors have swiftly been adopted as part of current antiretroviral regimens. The purpose of this study was to review the evidence for integrase inhibitor use in clinical settings. METHODS: MEDLINE and Web-of-Science were screened from April 2006 until November 2012, as were hand-searched scientific meeting proceedings. Multiple reviewers independently screened 1323 citations in duplicate to identify randomized controlled trials, nonrandomized controlled trials and cohort studies on integrase inhibitor use in clinical practice. Independent, duplicate data extraction and quality assessment were conducted. RESULTS: 48 unique studies were included on the use of integrase inhibitors in antiretroviral therapy-naive patients and treatment-experienced patients with either virological failure or switching to integrase inhibitors while virologically suppressed. On the selected studies with comparable outcome measures and indication (n = 16), a meta-analysis was performed based on modified intention-to-treat (mITT), on-treatment (OT) and as-treated (AT) virological outcome data. In therapy-naive patients, favorable odds ratios (OR) for integrase inhibitor-based regimens were observed, (mITT OR 0.71, 95% CI 0.59-0.86). However, integrase inhibitors combined with protease inhibitors only did not result in a significant better virological outcome. Evidence further supported integrase inhibitor use following virological failure (mITT OR 0.27; 95% CI 0.11-0.66), but switching to integrase inhibitors from a high genetic barrier drug during successful treatment was not supported (mITT OR 1.43; 95% CI 0.89-2.31). Integrase inhibitor-based regimens result in similar immunological responses compared to other regimens. A low genetic barrier to drug resistance development was observed for raltegravir and elvitegravir, but not for dolutegravir. CONCLUSION: In first-line therapy, integrase inhibitors are superior to other regimens. Integrase inhibitor use after virological failure is supported as well by the meta-analysis. Careful use is however warranted when replacing a high genetic barrier drug in treatment-experienced patients switching successful treatment. PMID- 23341904 TI - Rapid northward spread of a zooxanthellate coral enhanced by artificial structures and sea warming in the western Mediterranean. AB - The hermatypic coral Oculina patagonica can drive a compositional shift in shallow water benthic marine communities in the northwestern Mediterranean. Here, we analyze a long-term, large-scale observational dataset to characterize the dynamics of the species' recent northward range shift along the coast of Catalonia and examine the main factors that could have influenced this spread. The variation in the distributional range of Oculina patagonica was examined by monitoring 223 locations including natural and artificial habitats along >400 km of coastline over the last 19 years (1992-2010). Abundance of the species increased from being present in one location in 1992 to occur on 19% of the locations in 2010, and exhibited an acceleration of its spreading over time driven by the join action of neighborhood and long-distance dispersal. However, the pattern of spread diverged between artificial and natural habitats. A short lag phase and a high slope on the exponential phase characterized the temporal pattern of spread on artificial habitats in contrast to that observed on natural ones. Northward expansion has occurred at the fastest rate (22 km year(-1)) reported for a coral species thus far, which is sufficiently fast to cope with certain climate warming predictions. The pattern of spread suggests that this process is mediated by the interplay of (i) the availability of open space provided by artificial habitats, (ii) the seawater temperature increase with the subsequent extension of the growth period, and (iii) the particular biological features of O. patagonica (current high growth rates, early reproduction, and survival to low temperature and in polluted areas). These results are indicative of an ongoing fundamental modification of temperate shallow water assemblages, which is consistent with the predictions indicating that the Mediterranean Sea is one of the most sensitive regions to global change. PMID- 23341903 TI - Zolmitriptan: a novel portal hypotensive agent which synergizes with propranolol in lowering portal pressure. AB - OBJECTIVE: Only a limited proportion of patients needing pharmacological control of portal hypertension are hemodynamic responders to propranolol. Here we analyzed the effects of zolmitriptan on portal pressure and its potential interaction with propranolol. METHODS: ZOLMITRIPTAN, PROPRANOLOL OR BOTH WERE TESTED IN TWO RAT MODELS OF PORTAL HYPERTENSION: common bile duct ligation (CBDL) and CCl4-induced cirrhosis. In these animals we measured different hemodynamic parameters including portal venous pressure, arterial renal flow, portal blood flow and cardiac output. We also studied the changes in superior mesenteric artery perfusion pressure and in arterial wall cAMP levels induced by zolmitriptan, propranolol or both. Moreover, we determined the effect of splanchnic sympathectomy on the response of PVP to zolmitriptan. RESULTS: In both models of portal hypertension zolmitriptan induced a dose-dependent transient descent of portal pressure accompanied by reduction of portal flow with only slight decrease in renal flow. In cirrhotic rats, splanchnic sympathectomy intensified and prolonged zolmitriptan-induced portal pressure descent. Also, propranolol caused more intense and durable portal pressure fall when combined with zolmitriptan. Mesenteric artery perfusion pressure peaked for about 1 min upon zolmitriptan administration but showed no change with propranolol. However propranolol enhanced and prolonged the elevation in mesenteric artery perfusion pressure induced by zolmitriptan. In vitro studies showed that propranolol prevented the inhibitory effects of beta2-agonists on zolmitriptan-induced vasoconstriction and the combination of propranolol and zolmitriptan significantly reduced the elevation of cAMP caused by beta2-agonists. CONCLUSION: Zolmitriptan reduces portal hypertension and non-selective beta-blockers can improve this effect. Combination therapy deserves consideration for patients with portal hypertension failing to respond to non-selective beta-blockers. PMID- 23341905 TI - Protective effect of gadolinium chloride on early warm ischemia/reperfusion injury in rat bile duct during liver transplantation. AB - BACKGROUND: Activation of Kupffer cell (KC) is acknowledged as a key event in the initiation and perpetuation of bile duct warm ischemia/reperfusion injury. The inhibitory effect of gadolinium chloride (GdCl(3)) on KC activation shows potential as a protective intervention in liver injury, but there is less research with regard to bile duct injury. METHODS: Sixty-five male Sprague-Dawley rats (200-250 g) were randomly divided into three experimental groups: a sham group (n = 15), a control group (n = 25), and a GdCl(3) group (n = 25). Specimen was collected at 0.5, 2, 6, 12 and 24 h after operation. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TBIL) of serum were measured. Tumor necrosis factor-alpha (TNF-alpha), Capase-3 activity and soluble Fas (sFas) were detected. The pathologic changes of bile duct were observed. Immunochemistry for bile duct Fas was performed. Apoptosis of bile duct cells was evaluated by the terminal UDP nick end labeling assay. RESULTS: GdCl(3) significantly decreased the levels of ALT, ALP and TBIL at 2, 6, 12, and 24 h, and increased serum sFas at 2, 6 and 12 h (P<0.05). TNF-alpha was lower in the GdCl(3) group than in the control group at 2, 6, 12 and 24 h (P<0.05). Preadministration of GdCl(3) significantly reduced the Caspase-3 activity and bile duct cell apoptosis at 2, 6, 12 and 24 h. After operation for 2, 6 and 12 h, the expression of Fas protein was lower in the GdCl(3) group than in the control group (P<0.05). CONCLUSIONS: GdCl(3) plays an important role in suppressing bile duct cell apoptosis, including decreasing ALT, ALP, TBIL and TNF-alpha; suppressing Fas-FasL-Caspase signal transduction during transplantation. PMID- 23341906 TI - Identification of upregulated genes under cold stress in cold-tolerant chickpea using the cDNA-AFLP approach. AB - Low temperature injury is one of the most significant causes of crop damage worldwide. Cold acclimatization processes improve the freezing tolerance of plants. To identify genes of potential importance for acclimatzation to the cold and to elucidate the pathways that regulate this process, global transcriptome expression of the chickpea (Cicer arietinum L), a species of legume, was analyzed using the cDNA-AFLP technique. In total, we generated 4800 transcript-derived fragments (TDFs) using cDNA-AFLP in conjunction with 256 primer combinations. We only considered those cDNA fragments that seemed to be up-regulated during cold acclimatization. Of these, 102 TDFs with differential expression patterns were excised from gels and re-amplified by PCR. Fifty-four fragments were then cloned and sequenced. BLAST search of the GenBank non-redundant (nr) sequence database demonstrated that 77 percent of the TDFs belonged to known sequences with putative functions related to metabolism (31), transport (10), signal transduction pathways (15) and transcription factors (21). The last group of expressed transcripts showed homology to genes of unknown function (22). To further analyze and validate our cDNA-AFLP experiments, the expression of 9 TDFs during cold acclimatzatiion was confirmed using real time RT-PCR. The results of this research show that cDNA-AFLP is a powerful technique for investigating the expression pattern of chickpea genes under low-temperature stress. Moreover, our findings will help both to elucidate the molecular basis of low-temperature effects on the chickpea genome and to identify those genes that could increase the cold tolerance of the chickpea plant. PMID- 23341907 TI - Declining abundance of beaked whales (family Ziphiidae) in the California Current large marine ecosystem. AB - Beaked whales are among the most diverse yet least understood groups of marine mammals. A diverse set of mostly anthropogenic threats necessitates improvement in our ability to assess population status for this cryptic group. The Southwest Fisheries Science Center (NOAA) conducted six ship line-transect cetacean abundance surveys in the California Current off the contiguous western United States between 1991 and 2008. We used a Bayesian hidden-process modeling approach to estimate abundance and population trends of beaked whales using sightings data from these surveys. We also compiled records of beaked whale stranding events (3 genera, at least 8 species) on adjacent beaches from 1900 to 2012, to help assess population status of beaked whales in the northern part of the California Current. Bayesian posterior summaries for trend parameters provide strong evidence of declining beaked whale abundance in the study area. The probability of negative trend for Cuvier's beaked whale (Ziphius cavirostris) during 1991 2008 was 0.84, with 1991 and 2008 estimates of 10771 (CV = 0.51) and ~7550 (CV = 0.55), respectively. The probability of decline for Mesoplodon spp. (pooled across species) was 0.96, with 1991 and 2008 estimates of 2206 (CV = 0.46) and 811 (CV = 0.65). The mean posterior estimates for average rate of decline were 2.9% and 7.0% per year. There was no evidence of abundance trend for Baird's beaked whale (Berardius bairdii), for which annual abundance estimates in the survey area ranged from ~900 to 1300 (CV~1.3). Stranding data were consistent with the survey results. Causes of apparent declines are unknown. Direct impacts of fisheries (bycatch) can be ruled out, but impacts of anthropogenic sound (e.g., naval active sonar) and ecosystem change are plausible hypotheses that merit investigation. PMID- 23341908 TI - Image classification of human carcinoma cells using complex wavelet-based covariance descriptors. AB - Cancer cell lines are widely used for research purposes in laboratories all over the world. Computer-assisted classification of cancer cells can alleviate the burden of manual labeling and help cancer research. In this paper, we present a novel computerized method for cancer cell line image classification. The aim is to automatically classify 14 different classes of cell lines including 7 classes of breast and 7 classes of liver cancer cells. Microscopic images containing irregular carcinoma cell patterns are represented by subwindows which correspond to foreground pixels. For each subwindow, a covariance descriptor utilizing the dual-tree complex wavelet transform (DT-[Formula: see text]WT) coefficients and several morphological attributes are computed. Directionally selective DT [Formula: see text]WT feature parameters are preferred primarily because of their ability to characterize edges at multiple orientations which is the characteristic feature of carcinoma cell line images. A Support Vector Machine (SVM) classifier with radial basis function (RBF) kernel is employed for final classification. Over a dataset of 840 images, we achieve an accuracy above 98%, which outperforms the classical covariance-based methods. The proposed system can be used as a reliable decision maker for laboratory studies. Our tool provides an automated, time- and cost-efficient analysis of cancer cell morphology to classify different cancer cell lines using image-processing techniques, which can be used as an alternative to the costly short tandem repeat (STR) analysis. The data set used in this manuscript is available as supplementary material through http://signal.ee.bilkent.edu.tr/cancerCellLineClassificationSampleImages.html. PMID- 23341909 TI - Mechanisms underlying ectopic persistent tooth-pulp pain following pulpal inflammation. AB - In order to clarify the peripheral mechanisms of ectopic persistent pain in a tooth pulp following pulpal inflammation of an adjacent tooth, masseter muscle activity, phosphorylated extracellular signal-regulated protein kinase (pERK) and TRPV1 immunohistochemistries and satellite cell activation using glial fibrillary acidic protein (GFAP) immunohistochemistry in the trigeminal ganglion (TG) were studied in the rats with molar tooth-pulp inflammation. And, Fluorogold (FG) and DiI were also used in a neuronal tracing study to analyze if some TG neurons innervate more than one tooth pulp. Complete Freund's adjuvant (CFA) or saline was applied into the upper first molar tooth pulp (M1) in pentobarbital anesthetized rats, and capsaicin was applied into the upper second molar tooth pulp (M2) on day 3 after the CFA or saline application. Mean EMG activity elicited in the masseter muscle by capsaicin application to M2 was significantly larger in M1 CFA-applied rats compared with M1 vehicle-applied rats. The mean number of pERK-immunoreactive (IR) TG cells was significantly larger in M1 CFA applied rats compared with M1 vehicle-applied rats. Application of the satellite cell inhibitor fluorocitrate (FC) into TG caused a significant depression of capsaicin-induced masseter muscle activity and a significant reduction of satellite cell activation. The number of TRPV1-IR TG cells innervating M2 was significantly larger in M1 CFA-applied rats compared with M1 vehicle-applied rats, and that was decreased following FC injection into TG. Furthermore, 6% of TG neurons innervating M1 and/or M2 innervated both M1 and M2. These findings suggest that satellite cell activation following tooth pulp inflammation and innervation of multiple tooth pulps by single TG neurons may be involved in the enhancement of the activity of TG neurons innervating adjacent non-inflamed teeth that also show enhancement of TRPV1 expression in TG neurons, resulting in the ectopic persistent tooth-pulp pain following pulpal inflammation of adjacent teeth. PMID- 23341910 TI - Feasibility and effectiveness of indicator condition-guided testing for HIV: results from HIDES I (HIV indicator diseases across Europe study). AB - Improved methods for targeting HIV testing among patients most likely to be infected are required; HIDES I aimed to define the methodology of a European wide study of HIV prevalence in individuals presenting with one of eight indicator conditions/diseases (ID); sexually transmitted infection, lymphoma, cervical or anal cancer/dysplasia, herpes zoster, hepatitis B/C, mononucleosis-like illness, unexplained leukocytopenia/thrombocytopenia and seborrheic dermatitis/exanthema, and to identify those with an HIV prevalence of >0.1%, a level determined to be cost effective. A staff questionnaire was performed. From October 2009- February 2011, individuals, not known to be HIV positive, presenting with one of the ID were offered an HIV test; additional information was collected on previous HIV testing behaviour and recent medical history. A total of 3588 individuals from 16 centres were included. Sixty-six tested positive for HIV, giving an HIV prevalence of 1.8% [95% CI: 1.42-2.34]; all eight ID exceeded 0.1% prevalence. Of those testing HIV positive, 83% were male, 58% identified as MSM and 9% were injecting drug users. Twenty percent reported previously having potentially HIV related symptoms and 52% had previously tested HIV negative (median time since last test: 1.58 years); which together with the median CD4 count at diagnosis (400 cell/uL) adds weight to this strategy being effective in diagnosing HIV at an earlier stage. A positive test was more likely for non-white individuals, MSM, injecting drug users and those testing in non-Northern regions. HIDES I describes an effective strategy to detect undiagnosed HIV infection. All eight ID fulfilled the >0.1% criterion for cost effectiveness. All individuals presenting to any health care setting with one of these ID should be strongly recommended an HIV test. A strategy is being developed in collaboration with ECDC and WHO Europe to guide the implementation of this novel public health initiative across Europe. PMID- 23341911 TI - The effects of target skeletal muscle cells on dorsal root ganglion neuronal outgrowth and migration in vitro. AB - Targets of neuronal innervations play a vital role in regulating the survival and differentiation of innervating neurotrophin-responsive neurons. During development, neurons extend axons to their targets, and then their survival become dependent on the trophic substances secreted by their target cells. Sensory endings were present on myoblasts, myotubes, and myofibers in all intrafusal bundles regardless of age. The interdependence of sensory neurons and skeletal muscle (SKM) cells during both embryonic development and the maintenance of the mature functional state has not been fully understood. In the present study, neuromuscular cocultures of organotypic dorsal root ganglion (DRG) explants and dissociate SKM cells were established. Using this culture system, the morphological relationship between DRG neurons and SKM cells, neurites growth and neuronal migration were investigated. The migrating neurons were determined by fluorescent labeling of microtubule-associated protein-2 (MAP-2) and neurofilament 200 (NF-200) or growth-associated protein 43 (GAP-43). The expression of NF-200 and GAP-43 and their mRNAs was evaluated by Western blot assay and real time-PCR analysis. The results reveal that DRG explants showed more dense neurites outgrowth in neuromuscular cocultures as compared with that in the culture of DRG explants alone. The number of total migrating neurons (the MAP-2-expressing neurons) and the percentage NF-200-immunoreactive (IR) and GAP 43-IR neurons increased significantly in the presence of SKM cells. The levels of NF-200 and GAP-43 and their mRNAs increased significantly in neuromuscular cocultures as compared with that in the culture of DRG explants alone. These results suggested that target SKM cells play an important role in regulating neuronal protein synthesis, promoting neuritis outgrowth and neuronal migration of DRG explants in vitro. These results not only provide new clues for a better understanding of the association of SKM cells with DRG sensory neurons during development, they may also have implications for axonal regeneration after nerve injury. PMID- 23341912 TI - Detection of genomic idiosyncrasies using fuzzy phylogenetic profiles. AB - Phylogenetic profiles express the presence or absence of genes and their homologs across a number of reference genomes. They have emerged as an elegant representation framework for comparative genomics and have been used for the genome-wide inference and discovery of functionally linked genes or metabolic pathways. As the number of reference genomes grows, there is an acute need for faster and more accurate methods for phylogenetic profile analysis with increased performance in speed and quality. We propose a novel, efficient method for the detection of genomic idiosyncrasies, i.e. sets of genes found in a specific genome with peculiar phylogenetic properties, such as intra-genome correlations or inter-genome relationships. Our algorithm is a four-step process where genome profiles are first defined as fuzzy vectors, then discretized to binary vectors, followed by a de-noising step, and finally a comparison step to generate intra- and inter-genome distances for each gene profile. The method is validated with a carefully selected benchmark set of five reference genomes, using a range of approaches regarding similarity metrics and pre-processing stages for noise reduction. We demonstrate that the fuzzy profile method consistently identifies the actual phylogenetic relationship and origin of the genes under consideration for the majority of the cases, while the detected outliers are found to be particular genes with peculiar phylogenetic patterns. The proposed method provides a time-efficient and highly scalable approach for phylogenetic stratification, with the detected groups of genes being either similar to their own genome profile or different from it, thus revealing atypical evolutionary histories. PMID- 23341913 TI - Knowledge, attitude and practices of diabetic patients in the United Arab Emirates. AB - INTRODUCTION: Diabetes self-management education is a cornerstone of diabetes care. However, many diabetics in the United Arab Emirates (UAE) lack sufficient knowledge about their disease due to illiteracy. Thus, before considering any possible intervention it was imperative to assess present knowledge, attitudes, and practices of patients towards the management of diabetes. METHODS: A random sample of 575 DM patients was selected from diabetes outpatient's clinics of Tawam and Al-Ain hospitals in Al-Ain city (UAE) during 2006-2007, and their knowledge attitude and practice assessed using a questionnaire modified from the Michigan Diabetes Research Training Center instrument. RESULTS: Thirty-one percent of patients had poor knowledge of diabetes. Seventy-two had negative attitudes towards having the disease and 57% had HbA(1c) levels reflecting poor glycemic control. Only seventeen percent reported having adequate blood sugar control, while 10% admitted non-compliance with their medications. Knowledge, practice and attitude scores were all statistically significantly positively, but rather weakly, associated, but none of these scores was significantly correlated with HbA(1c). CONCLUSIONS: The study showed low levels of diabetes awareness but positive attitudes towards the importance of DM care and satisfactory diabetes practices in the UAE. Programs to increase patients' awareness about DM are essential for all diabetics in the UAE in order to improve their understanding, compliance and management and, thereby, their ability to cope with the disease. PMID- 23341914 TI - Transcriptional profiling of human dendritic cell populations and models--unique profiles of in vitro dendritic cells and implications on functionality and applicability. AB - BACKGROUND: Dendritic cells (DCs) comprise heterogeneous populations of cells, which act as central orchestrators of the immune response. Applicability of primary DCs is restricted due to their scarcity and therefore DC models are commonly employed in DC-based immunotherapy strategies and in vitro tests assessing DC function. However, the interrelationship between the individual in vitro DC models and their relative resemblance to specific primary DC populations remain elusive. OBJECTIVE: To describe and assess functionality and applicability of the available in vitro DC models by using a genome-wide transcriptional approach. METHODS: Transcriptional profiling was performed with four commonly used in vitro DC models (MUTZ-3-DCs, monocyte-derived DCs, CD34-derived DCs and Langerhans cells (LCs)) and nine primary DC populations (dermal DCs, LCs, blood and tonsillar CD123(+), CD1c(+) and CD141(+) DCs, and blood CD16(+) DCs). RESULTS: Principal Component Analysis showed that transcriptional profiles of each in vitro DC model most closely resembled CD1c(+) and CD141(+) tonsillar myeloid DCs (mDCs) among primary DC populations. Thus, additional differentiation factors may be required to generate model DCs that more closely resemble other primary DC populations. Also, no model DC stood out in terms of primary DC resemblance. Nevertheless, hierarchical clustering showed clusters of differentially expressed genes among individual DC models as well as primary DC populations. Furthermore, model DCs were shown to differentially express immunologically relevant transcripts and transcriptional signatures identified for each model DC included several immune-associated transcripts. CONCLUSION: The unique transcriptional profiles of in vitro DC models suggest distinct functionality in immune applications. The presented results will aid in the selection of an appropriate DC model for in vitro assays and assist development of DC-based immunotherapy. PMID- 23341915 TI - Distortions in development of intestinal microbiota associated with late onset sepsis in preterm infants. AB - Late onset sepsis (LOS) is a major contributor to neonatal morbidity and mortality, especially in premature infants. Distortions in the establishment of normal gut microbiota, commensal microbes that colonize the digestive tract, might increase the risk of LOS via disruption of the mucosal barrier with resultant translocation of luminal contents. Correlation of distortions of the intestinal microbiota with LOS is a necessary first step to design novel microbiota-based screening approaches that might lead to early interventions to prevent LOS in high risk infants. Using a case/control design nested in a cohort study of preterm infants, we analyzed stool samples that had been prospectively collected from ten preterm infants with LOS and from 18 matched controls. A 16S rRNA based approach was utilized to compare microbiota diversity and identify specific bacterial signatures that differed in their prevalence between cases and controls. Overall alpha-diversity (Chao1) was lower in cases two weeks before (p<0.05) but not one week before or at the time of diagnosis of LOS. Overall microbiota structure (Unifrac) appeared distinct in cases 2 weeks and 1 week before but not at diagnosis (p<0.05). Although we detected few operational taxonomic units (OTUs) unique or enriched in cases, we found many OTUs common in controls that were lacking in cases (p<0.01). Bifidobacteria counts were lower in cases at all time points. Our results support the hypothesis that a distortion in normal microbiota composition, and not an enrichment of potential pathogens, is associated with LOS in preterm infants. PMID- 23341916 TI - The functional role of the triceps surae muscle during human locomotion. AB - AIM: Despite numerous studies addressing the issue, it remains unclear whether the triceps surae muscle group generates forward propulsive force during gait, commonly identified as 'push-off'. In order to challenge the push-off postulate, one must probe the effect of varying the propulsive force while annulling the effect of the progression velocity. This can be obtained by adding a load to the subject while maintaining the same progression velocity. METHODS: Ten healthy subjects initiated gait in both unloaded and loaded conditions (about 30% of body weight attached at abdominal level), for two walking velocities, spontaneous and fast. Ground reaction force and EMG activity of soleus and gastrocnemius medialis and lateralis muscles of the stance leg were recorded. Centre of mass velocity and position, centre of pressure position, and disequilibrium torque were calculated. RESULTS: At spontaneous velocity, adding the load increased disequilibrium torque and propulsive force. However, load had no effect on the vertical braking force or amplitude of triceps activity. At fast progression velocity, disequilibrium torque, vertical braking force and triceps EMG increased with respect to spontaneous velocity. Still, adding the load did not further increase braking force or EMG. CONCLUSIONS: Triceps surae is not responsible for the generation of propulsive force but is merely supporting the body during walking and restraining it from falling. By controlling the disequilibrium torque, however, triceps can affect the propulsive force through the exchange of potential into kinetic energy. PMID- 23341917 TI - Population and landscape genetics of an introduced species (M. fascicularis) on the island of Mauritius. AB - The cynomolgus macaque, Macaca fascicularis, was introduced onto the island of Mauritius in the early 17(th) century. The species experienced explosive population growth, and currently exists at high population densities. Anecdotes collected from nonhuman primate trappers on the island of Mauritius allege that animals from the northern portion of the island are larger in body size than and superior in condition to their conspecifics in the south. Although previous genetic studies have reported Mauritian cynomolgus macaques to be panmictic, the individuals included in these studies were either from the southern/central or an unknown portion of the island. In this study, we sampled individuals broadly throughout the entire island of Mauritius and used spatial principle component analysis to measure the fine-scale correlation between geographic and genetic distance in this population. A stronger correlation between geographic and genetic distance was found among animals in the north than in those in the southern and central portions of the island. We found no difference in body weight between the two groups, despite anecdotal evidence to the contrary. We hypothesize that the increased genetic structure among populations in the north is related to a reduction in dispersal distance brought about by human habitation and tourist infrastructure, but too recent to have produced true genetic differentiation. PMID- 23341918 TI - Effects of trampling on morphological and mechanical traits of dryland shrub species do not depend on water availability. AB - In semiarid drylands water shortage and trampling by large herbivores are two factors limiting plant growth and distribution. Trampling can strongly affect plant performance, but little is known about responses of morphological and mechanical traits of woody plants to trampling and their possible interaction with water availability. Seedlings of four shrubs (Caragana intermedia, Cynanchum komarovi, Hedysarum laeve and Hippophae rhamnoides) common in the semiarid Mu Us Sandland were grown at 4% and 10% soil water content and exposed to either simulated trampling or not. Growth, morphological and mechanical traits were measured. Trampling decreased vertical height and increased basal diameter and stem resistance to bending and rupture (as indicated by the increased minimum bend and break force) in all species. Increasing water availability increased biomass, stem length, basal diameter, leaf thickness and rigidity of stems in all species except C. komarovii. However, there were no interactive effects of trampling and water content on any of these traits among species except for minimum bend force and the ratio between stem resistance to rupture and bending. Overall shrub species have a high degree of trampling resistance by morphological and mechanical modifications, and the effects of trampling do not depend on water availability. However, the increasing water availability can also affect trade off between stem strength and flexibility caused by trampling, which differs among species. Water plays an important role not only in growth but also in trampling adaptation in drylands. PMID- 23341919 TI - Functional relevance for associations between genetic variants and systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a serious prototype autoimmune disease characterized by chronic inflammation, auto-antibody production and multi-organ damage. Recent association studies have identified a long list of loci that were associated with SLE with relatively high statistical power. However, most of them only established the statistical associations of genetic markers and SLE at the DNA level without supporting evidence of functional relevance. Here, using publically available datasets, we performed integrative analyses (gene relationship across implicated loci analysis, differential gene expression analysis and functional annotation clustering analysis) and combined with expression quantitative trait loci (eQTLs) results to dissect functional mechanisms underlying the associations for SLE. We found that 14 SNPs, which were significantly associated with SLE in previous studies, have cis-regulation effects on four eQTL genes (HLA-DQA1, HLA-DQB1, HLA-DQB2, and IRF5) that were also differentially expressed in SLE-related cell groups. The functional evidence, taken together, suggested the functional mechanisms underlying the associations of 14 SNPs and SLE. The study may serve as an example of mining publically available datasets and results in validation of significant disease association results. Utilization of public data resources for integrative analyses may provide novel insights into the molecular genetic mechanisms underlying human diseases. PMID- 23341920 TI - Application of stable isotope analysis to study temporal changes in foraging ecology in a highly endangered amphibian. AB - BACKGROUND: Understanding dietary trends for endangered species may be essential to assessing the effects of ecological disturbances such as habitat modification, species introductions or global climate change. Documenting temporal variation in prey selection may also be crucial for understanding population dynamics. However, the rarity, secretive behaviours and obscure microhabitats of some endangered species can make direct foraging observations difficult or impossible. Furthermore, the lethality or invasiveness of some traditional methods of dietary analysis (e.g. gut contents analysis, gastric lavage) makes them inappropriate for such species. Stable isotope analysis facilitates non-lethal, indirect analysis of animal diet that has unrealized potential in the conservation of endangered organisms, particularly amphibians. METHODOLOGY/FINDINGS: I determined proportional contributions of aquatic macroinvertebrate prey to the diet of an endangered aquatic salamander Eurycea sosorum over a two-year period using stable isotope analysis of (13/12)C and (15/14)N and the Bayesian stable isotope mixing model SIAR. I calculated Strauss' dietary electivity indices by comparing these proportions with changing relative abundance of potential prey species through time. Stable isotope analyses revealed that a previously unknown prey item (soft bodied planarian flatworms in the genus Dugesia) made up the majority of E. sosorum diet. Results also demonstrate that E. sosorum is an opportunistic forager capable of diet switching to include a greater proportion of alternative prey when Dugesia populations decline. There is also evidence of intra-population dietary variation. CONCLUSIONS/SIGNIFICANCE: Effective application of stable isotope analysis can help circumvent two key limitations commonly experienced by researchers of endangered species: the inability to directly observe these species in nature and the invasiveness or lethality of traditional methods of dietary analysis. This study illustrates the feasibility of stable isotope analysis in identifying preferred prey species that can be used to guide conservation management of both wild and captive food sources for endangered species. PMID- 23341921 TI - Amphitremida (poche, 1913) is a new major, ubiquitous labyrinthulomycete clade. AB - Micro-eukaryotic diversity is poorly documented at all taxonomic levels and the phylogenetic affiliation of many taxa - including many well-known and common organisms - remains unknown. Among these incertae sedis taxa are Archerella flavum (Loeblich and Tappan, 1961) and Amphitrema wrightianum (Archer, 1869) (Amphitremidae), two filose testate amoebae commonly found in Sphagnum peatlands. To clarify their phylogenetic position, we amplified and sequenced the SSU rRNA gene obtained from four independent DNA extractions of A. flavum and three independent DNA extractions of A. wrightianum. Our molecular data demonstrate that genera Archerella and Amphitrema form a fully supported deep-branching clade within the Labyrinthulomycetes (Stramenopiles), together with Diplophrys sp. (ATCC50360) and several environmental clones obtained from a wide range of environments. This newly described clade we named Amphitremida is diverse genetically, ecologically and physiologically. Our phylogenetic analysis suggests that osmotrophic species evolved most likely from phagotrophic ancestors and that the bothrosome, an organelle that produces cytoplasmic networks used for attachment to the substratum and to absorb nutrients from the environments, appeared lately in labyrithulomycete evolution. PMID- 23341922 TI - The influence of vibratory courtship on female mating behaviour in orb-web spiders (Argiope keyserlingi, Karsch 1878). AB - Web-building spiders are important models for sexual selection. While our understanding of post-copulatory mechanisms including sperm competition and cryptic female choice is considerable, our knowledge of courtship and how it influences male and female mating decisions is still extremely poor. Here, we provide the first comprehensive description of male courtship behaviour and vibrations generated in the web by the orb-web spider, Argiope keyserlingi - a recognised model species. We identified three main elements of male courtship: shudders, abdominal wags and mating thread dances (including both plucks and bounces). The vibrations generated by these behaviours are described in detail. Male shuddering behaviour appears to have a strong influence on female latency to mate acceptance, with males that shudder at high rates without compromising shudder duration being preferred. Shuddering behaviour may also mediate female aggressive behaviour, with males that generate long shudders less likely to be cannibalised after copulation. Male abdominal wagging behaviour, however, appears to have only limited influence on female mating decisions. This study provides avenues for future work that synthesises pre- and post-copulatory mechanisms in web-building spiders to generate an all-encompassing model of how sexual selection operates. PMID- 23341923 TI - Time-varying wing-twist improves aerodynamic efficiency of forward flight in butterflies. AB - Insect wings can undergo significant chordwise (camber) as well as spanwise (twist) deformation during flapping flight but the effect of these deformations is not well understood. The shape and size of butterfly wings leads to particularly large wing deformations, making them an ideal test case for investigation of these effects. Here we use computational models derived from experiments on free-flying butterflies to understand the effect of time-varying twist and camber on the aerodynamic performance of these insects. High-speed videogrammetry is used to capture the wing kinematics, including deformation, of a Painted Lady butterfly (Vanessa cardui) in untethered, forward flight. These experimental results are then analyzed computationally using a high-fidelity, three-dimensional, unsteady Navier-Stokes flow solver. For comparison to this case, a set of non-deforming, flat-plate wing (FPW) models of wing motion are synthesized and subjected to the same analysis along with a wing model that matches the time-varying wing-twist observed for the butterfly, but has no deformation in camber. The simulations show that the observed butterfly wing (OBW) outperforms all the flat-plate wings in terms of usable force production as well as the ratio of lift to power by at least 29% and 46%, respectively. This increase in efficiency of lift production is at least three-fold greater than reported for other insects. Interestingly, we also find that the twist-only-wing (TOW) model recovers much of the performance of the OBW, demonstrating that wing twist, and not camber is key to forward flight in these insects. The implications of this on the design of flapping wing micro-aerial vehicles are discussed. PMID- 23341924 TI - Explaining global increases in water use efficiency: why have we overestimated responses to rising atmospheric CO(2) in natural forest ecosystems? AB - BACKGROUND: The analysis of tree-ring carbon isotope composition (delta(13)C) has been widely used to estimate spatio-temporal variations in intrinsic water use efficiency (iWUE) of tree species. Numerous studies have reported widespread increases in iWUE coinciding with rising atmospheric CO(2) over the past century. While this could represent a coherent global response, the fact that increases of similar magnitude were observed across biomes with no apparent effect on tree growth raises the question of whether iWUE calculations reflect actual physiological responses to elevated CO(2) levels. METHODOLOGY/RESULTS: Here we use Monte Carlo simulations to test if an artifact of calculation could explain observed increases in iWUE. We show that highly significant positive relationships between iWUE and CO(2) occur even when simulated data (randomized delta(13)C values spanning the observed range) are used in place of actual tree ring delta(13)C measurements. From simulated data sets we calculated non physiological changes in iWUE from 1900 to present and across a 4000 m altitudinal range. This generated results strikingly similar to those reported in recent studies encompassing 22 species from tropical, subtropical, temperate, boreal and mediterranean ecosystems. Only 6 of 49 surveyed case studies showed increases in iWUE significantly higher than predicted from random values. CONCLUSIONS/SIGNIFICANCE: Our results reveal that increases in iWUE estimated from tree-ring delta(13)C occur independently of changes in (13)C discrimination that characterize physiological responses to elevated CO(2). Due to a correlation with CO(2) concentration, which is used as an independent factor in the iWUE calculation, any tree-ring delta(13)C data set would inevitably generate increasing iWUE over time. Therefore, although consistent, previously reported trends in iWUE do not necessarily reflect a coherent global response to rising atmospheric CO(2). We discuss the significance of these findings and suggest ways to distinguish real from artificial responses in future studies. PMID- 23341926 TI - Olfactory cues are subordinate to visual stimuli in a neotropical generalist weevil. AB - The tropical root weevil Diaprepes abbreviatus is a major pest of multiple crops in the Caribbean Islands and has become a serious constraint to citrus production in the United States. Recent work has identified host and conspecific volatiles that mediate host- and mate-finding by D. abbreviatus. The interaction of light, color, and odors has not been studied in this species. The responses of male and female D. abbreviatus to narrow bandwidths of visible light emitted by LEDs offered alone and in combination with olfactory stimuli were studied in a specially-designed multiple choice arena combined with a locomotion compensator. Weevils were more attracted to wavelengths close to green and yellow compared with blue or ultraviolet, but preferred red and darkness over green. Additionally, dim green light was preferred over brighter green. Adult weevils were also attracted to the odor of its citrus host + conspecifics. However, the attractiveness of citrus + conspecific odors disappeared in the presence of a green light. Photic stimulation induced males but not females to increase their speed. In the presence of light emitted by LEDs, turning speed decreased and path straightness increased, indicating that weevils tended to walk less tortuously. Diaprepes abbreviatus showed a hierarchy between chemo- and photo-taxis in the series of experiments presented herein, where the presence of the green light abolished upwind anemotaxis elicited by the pheromone + host plant odor. Insight into the strong responses to visual stimuli of chemically stimulated insects may be provided when the amount of information supplied by vision and olfaction is compared, as the information transmission capacity of compound eyes is estimated to be several orders of magnitude higher compared with the olfactory system. Subordination of olfactory responses by photic stimuli should be considered in the design of strategies aimed at management of such insects. PMID- 23341925 TI - Identification and characterization of proteins involved in nuclear organization using Drosophila GFP protein trap lines. AB - BACKGROUND: Strains from a collection of Drosophila GFP protein trap lines express GFP in the normal tissues where the endogenous protein is present. This collection can be used to screen for proteins distributed in the nucleus in a non uniform pattern. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed four lines that show peripheral or punctate nuclear staining. One of these lines affects an uncharacterized gene named CG11138. The CG11138 protein shows a punctate distribution in the nuclear periphery similar to that of Drosophila insulator proteins but does not co-localize with known insulators. Interestingly, mutations in Lamin proteins result in alterations in CG11138 localization, suggesting that this protein may be a novel component of the nuclear lamina. A second line affects the Decondensation factor 31 (Df31) gene, which encodes a protein with a unique nuclear distribution that appears to segment the nucleus into four different compartments. The X-chromosome of males is confined to one of these compartments. We also find that Drosophila Nucleoplasmin (dNlp) is present in regions of active transcription. Heat shock leads to loss of dNlp from previously transcribed regions of polytene chromosome without redistribution to the heat shock genes. Analysis of Stonewall (Stwl), a protein previously found to be necessary for the maintenance of germline stem cells, shows that Stwl is present in a punctate pattern in the nucleus that partially overlaps with that of known insulator proteins. Finally we show that Stwl, dNlp, and Df31 form part of a highly interactive network. The properties of other components of this network may help understand the role of these proteins in nuclear biology. CONCLUSIONS/SIGNIFICANCE: These results establish screening of GFP protein trap alleles as a strategy to identify factors with novel cellular functions. Information gained from the analysis of CG11138 Stwl, dNlp, and Df31 sets the stage for future studies of these proteins. PMID- 23341927 TI - Molecular species delimitation in the Racomitrium canescens complex (Grimmiaceae) and implications for DNA barcoding of species complexes in mosses. AB - In bryophytes a morphological species concept is still most commonly employed, but delimitation of closely related species based on morphological characters is often difficult. Here we test morphological species circumscriptions in a species complex of the moss genus Racomitrium, the R. canescens complex, based on variable DNA sequence markers from the plastid (rps4-trnT-trnL region) and nuclear (nrITS) genomes. The extensive morphological variability within the complex has led to different opinions about the number of species and intraspecific taxa to be distinguished. Molecular phylogenetic reconstructions allowed to clearly distinguish all eight currently recognised species of the complex plus a ninth species that was inferred to belong to the complex in earlier molecular analyses. The taxonomic significance of intraspecific sequence variation is discussed. The present molecular data do not support the division of the R. canescens complex into two groups of species (subsections or sections). Most morphological characters, albeit being in part difficult to apply, are reliable for species identification in the R. canescens complex. However, misidentification of collections that were morphologically intermediate between species questioned the suitability of leaf shape as diagnostic character. Four partitions of the molecular markers (rps4-trnT, trnT-trnL, ITS1, ITS2) that could potentially be used for molecular species identification (DNA barcoding) performed almost equally well concerning amplification and sequencing success. Of these, ITS1 provided the highest species discrimination capacity and should be considered as a DNA barcoding marker for mosses, especially in complexes of closely related species. Molecular species identification should be complemented by redefining morphological characters, to develop a set of easy-to-use molecular and non-molecular identification tools for improving biodiversity assessments and ecological research including mosses. PMID- 23341928 TI - The 50 most important questions relating to the maintenance and restoration of an ecological continuum in the European Alps. AB - The European Alps harbour a unique and species-rich biodiversity, which is increasingly impacted by habitat fragmentation through land-use changes, urbanization and expanding transport infrastructure. In this study, we identified the 50 most important questions relating to the maintenance and restoration of an ecological continuum - the connectedness of ecological processes across many scales including trophic relationship and disturbance processes and hydro ecological flows in the European Alps. We initiated and implemented a trans national priority setting exercise, inviting 48 institutions including researchers, conservation practitioners, NGOs, policymakers and administrators from the Alpine region. The exercise was composed of an initial call for pertinent questions, a first online evaluation of the received questions and a final discussion and selection process during a joint workshop. The participating institutions generated 484 initial questions, which were condensed to the 50 most important questions by 16 workshop participants. We suggest new approaches in tackling the issue of an ecological continuum in the Alps by analysing and classifying the characteristics of the resulting questions in a non-prioritized form as well as in a visual conceptualisation of the inter-dependencies among these questions. This priority setting exercise will support research and funding institutions in channelling their capacities and resources towards questions that need to be urgently addressed in order to facilitate significant progress in biodiversity conservation in the European Alps. PMID- 23341929 TI - Immunologic targeting of FOXP3 in inflammatory breast cancer cells. AB - The forkhead transcription factor FOXP3 is necessary for induction of regulatory T lymphocytes (Tregs) and their immunosuppressive function. We have previously demonstrated that targeting Tregs by vaccination of mice with murine FOXP3 mRNA transfected dendritic cells (DCs) elicits FOXP3-specific T cell responses and enhances tumor immunity. It is clear that FOXP3 expression is not restricted to T cell lineage and herein, using RT-PCR, flow cytometry, and western immunoblot we demonstrate for the first time that FOXP3 is expressed in inflammatory breast cancer (IBC) cells, SUM149 (triple negative, ErbB1-activated) and SUM190 (ErbB2 overexpressing). Importantly, FOXP3-specific T cells generated in vitro using human FOXP3 RNA-transfected DCs as stimulators efficiently lyse SUM149 cells. Interestingly, an isogenic model (rSUM149) derived from SUM149 with an enhanced anti-apoptotic phenotype was resistant to FOXP3-specific T cell mediated lysis. The MHC class I cellular processing mechanism was intact in both cell lines at the protein and transcription levels suggesting that the resistance to cytolysis by rSUM149 cells was not related to MHC class I expression or to the MHC class I antigen processing machinery in these cells. Our data suggest that FOXP3 may be an effective tumor target in IBC cells however increased anti-apoptotic signaling can lead to immune evasion. PMID- 23341930 TI - The sesquiterpene lactone dehydroleucodine triggers senescence and apoptosis in association with accumulation of DNA damage markers. AB - Sesquiterpene lactones (SLs) are plant-derived compounds that display anti-cancer effects. Some SLs derivatives have a marked killing effect on cancer cells and have therefore reached clinical trials. Little is known regarding the mechanism of action of SLs. We studied the responses of human cancer cells exposed to various concentrations of dehydroleucodine (DhL), a SL of the guaianolide group isolated and purified from Artemisia douglasiana (Besser), a medicinal herb that is commonly used in Argentina. We demonstrate for the first time that treatment of cancer cells with DhL, promotes the accumulation of DNA damage markers such as phosphorylation of ATM and focal organization of gammaH2AX and 53BP1. This accumulation triggers cell senescence or apoptosis depending on the concentration of the DhL delivered to cells. Transient DhL treatment also induces marked accumulation of senescent cells. Our findings help elucidate the mechanism whereby DhL triggers cell cycle arrest and cell death and provide a basis for further exploration of the effects of DhL in in vivo cancer treatment models. PMID- 23341931 TI - Understanding the threats posed by non-native species: public vs. conservation managers. AB - Public perception is a key factor influencing current conservation policy. Therefore, it is important to determine the influence of the public, end-users and scientists on the prioritisation of conservation issues and the direct implications for policy makers. Here, we assessed public attitudes and the perception of conservation managers to five non-native species in the UK, with these supplemented by those of an ecosystem user, freshwater anglers. We found that threat perception was not influenced by the volume of scientific research or by the actual threats posed by the specific non-native species. Media interest also reflected public perception and vice versa. Anglers were most concerned with perceived threats to their recreational activities but their concerns did not correspond to the greatest demonstrated ecological threat. The perception of conservation managers was an amalgamation of public and angler opinions but was mismatched to quantified ecological risks of the species. As this suggests that invasive species management in the UK is vulnerable to a knowledge gap, researchers must consider the intrinsic characteristics of their study species to determine whether raising public perception will be effective. The case study of the topmouth gudgeon Pseudorasbora parva reveals that media pressure and political debate has greater capacity to ignite policy changes and impact studies on non-native species than scientific evidence alone. PMID- 23341932 TI - Perfusion network shift during seizures in medial temporal lobe epilepsy. AB - BACKGROUND: Medial temporal lobe epilepsy (MTLE) is associated with limbic atrophy involving the hippocampus, peri-hippocampal and extra-temporal structures. While MTLE is related to static structural limbic compromise, it is unknown whether the limbic system undergoes dynamic regional perfusion network alterations during seizures. In this study, we aimed to investigate state specific (i.e. ictal versus interictal) perfusional limbic networks in patients with MTLE. METHODS: We studied clinical information and single photon emission computed tomography (SPECT) images obtained with intravenous infusion of the radioactive tracer Technetium- Tc 99 m Hexamethylpropyleneamine Oxime (Tc-99 m HMPAO) during ictal and interictal state confirmed by video electroencephalography (VEEG) in 20 patients with unilateral MTLE (12 left and 8 right MTLE). Pair-wise voxel-based analyses were used to define global changes in tracer between states. Regional tracer uptake was calculated and state specific adjacency matrices were constructed based on regional correlation of uptake across subjects. Graph theoretical measures were applied to investigate global and regional state specific network reconfigurations. RESULTS: A significant increase in tracer uptake was observed during the ictal state in the medial temporal region, cerebellum, thalamus, insula and putamen. From network analyses, we observed a relative decreased correlation between the epileptogenic temporal region and remaining cortex during the interictal state, followed by a surge of cross-correlated perfusion in epileptogenic temporal-limbic structures during a seizure, corresponding to local network integration. CONCLUSIONS: These results suggest that MTLE is associated with a state specific perfusion and possibly functional organization consisting of a surge of limbic cross-correlated tracer uptake during a seizure, with a relative disconnection of the epileptogenic temporal lobe in the interictal period. This pattern of state specific shift in metabolic networks in MTLE may improve the understanding of epileptogenesis and neuropsychological impairments associated with MTLE. PMID- 23341933 TI - Overexpression of ANXA1 in penile carcinomas positive for high-risk HPVs. AB - The incidence of penile cancer varies between populations but is rare in developed nations. Penile cancer is associated with a number of established risk factors and associated diseases including phimosis with chronic inflammation, human papillomavirus (HPV) infection, poor hygiene and smoking. The objective of this study was to identify genes related to this type of cancer. The detection of HPV was analyzed in 47 penile squamous cell carcinoma samples. HPV DNA was detected in 48.9% of penile squamous cell carcinoma cases. High-risk HPV were present in 42.5% of cases and low-risk HPV were detected in 10.6% of penile squamous cell carcinomas. The RaSH approach identified differential expression of Annexin A1 (ANXA1), p16, RPL6, PBEF1 and KIAA1033 in high-risk HPV positive penile carcinoma; ANXA1 and p16 were overexpressed in penile squamous cells positive for high-risk HPVs compared to normal penile samples by qPCR. ANXA1 and p16 proteins were significantly more expressed in the cells from high-risk HPV positive penile carcinoma as compared to HPV-negative tumors (p<0.0001) independently of the subtype of the carcinoma. Overexpression of ANXA1 might be mediated by HPV E6 in penile squamous cell carcinoma of patients with high-risk HPVs, suggesting that this gene plays an important role in penile cancer. PMID- 23341934 TI - Solid phase synthesis of mitochondrial triphenylphosphonium-vitamin E metabolite using a lysine linker for reversal of oxidative stress. AB - Mitochondrial targeting of antioxidants has been an area of interest due to the mitochondria's role in producing and metabolizing reactive oxygen species. Antioxidants, especially vitamin E (alpha-tocopherol), have been conjugated to lipophilic cations to increase their mitochondrial targeting. Synthetic vitamin E analogues have also been produced as an alternative to alpha-tocopherol. In this paper, we investigated the mitochondrial targeting of a vitamin E metabolite, 2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC), which is similar in structure to vitamin E analogues. We report a fast and efficient method to conjugate the water-soluble metabolite, alpha-CEHC, to triphenylphosphonium cation via a lysine linker using solid phase synthesis. The efficacy of the final product (MitoCEHC) to lower oxidative stress was tested in bovine aortic endothelial cells. In addition the ability of MitoCEHC to target the mitochondria was examined in type 2 diabetes db/db mice. The results showed mitochondrial accumulation in vivo and oxidative stress decrease in vitro. PMID- 23341936 TI - Prevalence and risk factors of fluid overload in Southern Chinese continuous ambulatory peritoneal dialysis patients. AB - BACKGROUND: Fluid overload is frequently present in CAPD patients and one of important predictors of mortality. The aim of this study is to investigate the prevalence and associated risk factors in a cohort study of Southern Chinese CAPD patients. METHODS: The patients (receiving CAPD 3 months and more) in our center were investigated from January 1, 2008 to December 31, 2009. Multi-frequency bioelectrical impedance analysis was used to assess the patient's body composition and fluid status. RESULTS: A total of 307 CAPD patients (43% male, mean age 47.8+/-15.3 years) were enrolled, with a median duration of PD 14.6 (5.9 30.9) months. Fluid overload (defined by Extracellular water/Total body water (ECW/TBW)>=0.40) was present in 205 (66.8%) patients. Univariate analysis indicated that ECW/TBW were inversely associated with body mass index (r = -0.11, P = 0.047), subjective global assessment score (r = -0.11, P = 0.004), body fat mass (r = -0.15, P = 0.05), serum albumin (r = -0.32, P<0.001), creatinine (r = 0.14, P = 0.02), potassium (r = -0.15, P = 0.02), and residual urine output (r = 0.14, P = 0.01), positively associated with age (r = 0.27, P<0.001), Chalrlson Comorbidity Index score (r = 0.29, P<0.001), and systolic blood pressure (r = 0.22, P<0.001). Multivariate linear regression showed that lower serum albumin (beta = -0.223, P<0.001), lower body fat mass (beta = -0.166, P = 0.033), old age (beta = 0.268, P<0.001), higher systolic blood pressure (beta = 0.16, P = 0.006), less residual urine output (beta = -0.116, P = 0.042), and lower serum potassium (beta = -0.126, P = 0.03) were independently associated with higher ECW/TBW. After 1 year of follow-up, the cardiac event rate was significantly higher in the patients with fluid overload (17.1% vs 6.9%, P = 0.023) than that of the normal hydrated patients. CONCLUSIONS: The prevalence of fluid overload was high in CAPD patients. Fluid overload in CAPD patients were independently associated with protein-energy wasting, old age, and decreased residual urine output. Furthermore, CAPD patients with fluid overload had higher cardiac event rate than that of normal hydrated patents. PMID- 23341935 TI - Down-regulation of vitamin D receptor in mammospheres: implications for vitamin D resistance in breast cancer and potential for combination therapy. AB - Vitamin D signaling in mammary cancer stem cells (MCSCs), which are implicated in the initiation and progression of breast cancer, is poorly understood. In this study, we examined vitamin D signaling in mammospheres which are enriched in MCSCs from established breast cancer cell lines. Breast cancer cells positive for aldehyde dehydrogenase (ALDH(+)) had increased ability to form mammospheres compared to ALDH(-) cells. These mammospheres expressed MCSC-specific markers and generated transplantable xenografts in nude mice. Vitamin D receptor (VDR) was significantly down-regulated in mammospheres, as well as in ALDH(+) breast cancer cells. TN aggressive human breast tumors as well as transplantable xenografts obtained from SKBR3 expressed significantly lower levels of VDR but higher levels of CD44 expression. Snail was up-regulated in mammospheres isolated from breast cancer cells. Inhibition of VDR expression by siRNA led to a significant change in key EMT-specific transcription factors and increased the ability of these cells to form mammospheres. On the other hand, over-expression of VDR led to a down-regulation of Snail but increased expression of E-cad and significantly compromised the ability of cells to form mammospheres. Mammospheres were relatively insensitive to treatment with 1,25-dihydroxyvitamin D (1,25D), the active form of vitamin D, compared to more differentiated cancer cells grown in presence of serum. Treatment of H-Ras transformed HMLE(HRas) cells with DETA NONOate, a nitric oxide (NO)-donor led to induction of MAP-kinase phosphatase -1 (MKP-1) and dephosphorylation of ERK1/2 in the mammospheres. Combined treatment of these cells with 1,25D and a low-concentration of DETA NONOate led to a significant decrease in the overall size of mammospheres and reduced tumor volume in nude mice. Our findings therefore, suggest that combination therapy using 1,25D with drugs specifically targeting key survival pathways in MCSCs warrant testing in prospective clinical trial for treatment of aggressive breast cancer. PMID- 23341937 TI - Characterization of the calcium binding protein family in zebrafish. AB - Calcium Binding Proteins (CaBPs), part of the vast family of EF-Hand-domain containing proteins, modulate intracellular calcium levels. They thereby contribute to a broad spectrum of biological processes - amongst others cell migration, gene expression and neural activity. In this study we identified twelve members of this protein family in zebrafish including one gene (cabp4b) currently not present in the zebrafish genome assembly. To gain insight into their biological functions, we carried out a detailed analysis of the expression patterns of these genes during zebrafish late embryonic and early larval development. We detected specific transcription for most of them in different neuronal cell populations including the neuroretina, the inner ear and the notochord. Our data supports potential roles for CaBPs during neuronal development and function and provides a starting point for genetic studies to examine CaBPs' function in these tissues and organs. PMID- 23341938 TI - Relationship between insulin resistance and coronary artery calcium in young men and women. AB - BACKGROUND: The gender disparity in cardiovascular disease (CVD) risk is greatest between young men and women. However, the causes of that are not fully understood. The objective of this study was to evaluate the relationship between insulin resistance and the presence of coronary artery calcium (CAC) to identify risk factors that may predispose young men and women to CVD. METHODOLOGY/PRINCIPAL FINDINGS: Insulin resistance and CVD risk factors were examined in 8682 Korean men and 1829 women aged 30-45 years old. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR), and CAC was measured using computed tomography. Women were less likely to be insulin resistant (upper quartile of HOMA-IR, 18% vs. 27%, p<0.001) and had a lower prevalence of CAC (1.6% vs. 6.4%, p<0.001). Even when equally insulin resistant men and women were compared, women continued to have lower prevalence of CAC (3.1% vs. 7.2%, p = 0.004) and a more favorable CVD risk profile. Finally, after adjustment for traditional CVD risk factors, insulin resistance remained an independent predictor of CAC only in men (p = 0.03). CONCLUSIONS/SIGNIFICANCE: Young women have a lower risk for CVD and a lower CAC prevalence compared with men. This favorable CVD risk profile in women appears to occur regardless of insulin sensitivity. Unlike men, insulin resistance was not a predictor of CAC in women in this cohort. Therefore, insulin resistance has less impact on CVD risk and CAC in young women compared with men, and insulin resistance alone does not explain the gender disparity in CVD risk that is observed at an early age. PMID- 23341939 TI - Measuring unsafe abortion-related mortality: a systematic review of the existing methods. AB - BACKGROUND: The WHO estimates that 13% of maternal mortality is due to unsafe abortion, but challenges with measurement and data quality persist. To our knowledge, no systematic assessment of the validity of studies reporting estimates of abortion-related mortality exists. STUDY DESIGN: To be included in this study, articles had to meet the following criteria: (1) published between September 1(st), 2000-December 1(st), 2011; (2) utilized data from a country where abortion is "considered unsafe"; (3) specified and enumerated causes of maternal death including "abortion"; (4) enumerated >=100 maternal deaths; (5) a quantitative research study; (6) published in a peer-reviewed journal. RESULTS: 7,438 articles were initially identified. Thirty-six studies were ultimately included. Overall, studies rated "Very Good" found the highest estimates of abortion related mortality (median 16%, range 1-27.4%). Studies rated "Very Poor" found the lowest overall proportion of abortion related deaths (median: 2%, range 1.3-9.4%). CONCLUSIONS: Improvements in the quality of data collection would facilitate better understanding global abortion-related mortality. Until improved data exist, better reporting of study procedures and standardization of the definition of abortion and abortion-related mortality should be encouraged. PMID- 23341940 TI - A virtual retina for studying population coding. AB - At every level of the visual system - from retina to cortex - information is encoded in the activity of large populations of cells. The populations are not uniform, but contain many different types of cells, each with its own sensitivities to visual stimuli. Understanding the roles of the cell types and how they work together to form collective representations has been a long standing goal. This goal, though, has been difficult to advance, and, to a large extent, the reason is data limitation. Large numbers of stimulus/response relationships need to be explored, and obtaining enough data to examine even a fraction of them requires a great deal of experiments and animals. Here we describe a tool for addressing this, specifically, at the level of the retina. The tool is a data-driven model of retinal input/output relationships that is effective on a broad range of stimuli - essentially, a virtual retina. The results show that it is highly reliable: (1) the model cells carry the same amount of information as their real cell counterparts, (2) the quality of the information is the same - that is, the posterior stimulus distributions produced by the model cells closely match those of their real cell counterparts, and (3) the model cells are able to make very reliable predictions about the functions of the different retinal output cell types, as measured using Bayesian decoding (electrophysiology) and optomotor performance (behavior). In sum, we present a new tool for studying population coding and test it experimentally. It provides a way to rapidly probe the actions of different cell classes and develop testable predictions. The overall aim is to build constrained theories about population coding and keep the number of experiments and animals to a minimum. PMID- 23341941 TI - Maternal and paternal genomes differentially affect myofibre characteristics and muscle weights of bovine fetuses at midgestation. AB - Postnatal myofibre characteristics and muscle mass are largely determined during fetal development and may be significantly affected by epigenetic parent-of origin effects. However, data on such effects in prenatal muscle development that could help understand unexplained variation in postnatal muscle traits are lacking. In a bovine model we studied effects of distinct maternal and paternal genomes, fetal sex, and non-genetic maternal effects on fetal myofibre characteristics and muscle mass. Data from 73 fetuses (Day153, 54% term) of four genetic groups with purebred and reciprocal cross Angus and Brahman genetics were analyzed using general linear models. Parental genomes explained the greatest proportion of variation in myofibre size of Musculus semitendinosus (80-96%) and in absolute and relative weights of M. supraspinatus, M. longissimus dorsi, M. quadriceps femoris and M. semimembranosus (82-89% and 56-93%, respectively). Paternal genome in interaction with maternal genome (P<0.05) explained most genetic variation in cross sectional area (CSA) of fast myotubes (68%), while maternal genome alone explained most genetic variation in CSA of fast myofibres (93%, P<0.01). Furthermore, maternal genome independently (M. semimembranosus, 88%, P<0.0001) or in combination (M. supraspinatus, 82%; M. longissimus dorsi, 93%; M. quadriceps femoris, 86%) with nested maternal weight effect (5-6%, P<0.05), was the predominant source of variation for absolute muscle weights. Effects of paternal genome on muscle mass decreased from thoracic to pelvic limb and accounted for all (M. supraspinatus, 97%, P<0.0001) or most (M. longissimus dorsi, 69%, P<0.0001; M. quadriceps femoris, 54%, P<0.001) genetic variation in relative weights. An interaction between maternal and paternal genomes (P<0.01) and effects of maternal weight (P<0.05) on expression of H19, a master regulator of an imprinted gene network, and negative correlations between H19 expression and fetal muscle mass (P<0.001), suggested imprinted genes and miRNA interference as mechanisms for differential effects of maternal and paternal genomes on fetal muscle. PMID- 23341942 TI - From QTL to QTN: candidate gene set approach and a case study in porcine IGF1 FoxO pathway. AB - Unraveling the genetic background of economic traits is a major goal in modern animal genetics and breeding. Both candidate gene analysis and QTL mapping have previously been used for identifying genes and chromosome regions related to studied traits. However, most of these studies may be limited in their ability to fully consider how multiple genetic factors may influence a particular phenotype of interest. If possible, taking advantage of the combined effect of multiple genetic factors is expected to be more powerful than analyzing single sites, as the joint action of multiple loci within a gene or across multiple genes acting in the same gene set will likely have a greater influence on phenotypic variation. Thus, we proposed a pipeline of gene set analysis that utilized information from multiple loci to improve statistical power. We assessed the performance of this approach by both simulated and a real IGF1-FoxO pathway data set. The results showed that our new method can identify the association between genetic variation and phenotypic variation with higher statistical power and unravel the mechanisms of complex traits in a point of gene set. Additionally, the proposed pipeline is flexible to be extended to model complex genetic structures that include the interactions between different gene sets and between gene sets and environments. PMID- 23341943 TI - Access to alcohol outlets, alcohol consumption and mental health. AB - The objective of this study was to investigate residential exposure to alcohol outlets in relation to alcohol consumption and mental health morbidity (anxiety, stress, and depression). This was a cross-sectional study of 6,837 adults obtained from a population representative sample for the period 2006-2009 in Perth, Western Australia. The number of alcohol outlets was ascertained for a 1600 m service area surrounding the residential address. Zero-inflated negative binomial and logistic regression were used to assess associations with total alcohol consumption, harmful alcohol consumption (7-10 drinks containing 10 g of alcohol for men, 5-6 drinks for women) and medically diagnosed and hospital contacts (for anxiety, stress, and depression), respectively. The rate ratio for the number of days of harmful consumption of alcohol per month and the number of standard drinks of alcohol consumed per drinking day was 1.06 (95% CI: 1.02, 1.11) and 1.01 (95% CI: 1.00, 1.03) for each additional liquor store within a 1600 m service area, respectively. The odds ratio of hospital contact for anxiety, stress, or depression was 1.56 (95% CI: 0.98, 2.49) for those with a liquor store within the service area compared to those without. We observed strong evidence for a small association between residential exposure to liquor stores and harmful consumption of alcohol, and some support for a moderate-sized effect on hospital contacts for anxiety, stress, and depression. PMID- 23341944 TI - Histological analysis and 3D reconstruction of winter cereal crowns recovering from freezing: a unique response in oat (Avena sativa L.). AB - The crown is the below ground portion of the stem of a grass which contains meristematic cells that give rise to new shoots and roots following winter. To better understand mechanisms of survival from freezing, a histological analysis was performed on rye, wheat, barley and oat plants that had been frozen, thawed and allowed to resume growth under controlled conditions. Extensive tissue disruption and abnormal cell structure was noticed in the center of the crown of all 4 species with relatively normal cells on the outside edge of the crown. A unique visual response was found in oat in the shape of a ring of cells that stained red with Safranin. A tetrazolium analysis indicated that tissues immediately inside this ring were dead and those outside were alive. Fluorescence microscopy revealed that the barrier fluoresced with excitation between 405 and 445 nm. Three dimensional reconstruction of a cross sectional series of images indicated that the red staining cells took on a somewhat spherical shape with regions of no staining where roots entered the crown. Characterizing changes in plants recovering from freezing will help determine the genetic basis for mechanisms involved in this important aspect of winter hardiness. PMID- 23341945 TI - A genome-wide association study identifies genomic regions for virulence in the non-model organism Heterobasidion annosum s.s. AB - The dense single nucleotide polymorphisms (SNP) panels needed for genome wide association (GWA) studies have hitherto been expensive to establish and use on non-model organisms. To overcome this, we used a next generation sequencing approach to both establish SNPs and to determine genotypes. We conducted a GWA study on a fungal species, analysing the virulence of Heterobasidion annosum s.s., a necrotrophic pathogen, on its hosts Picea abies and Pinus sylvestris. From a set of 33,018 single nucleotide polymorphisms (SNP) in 23 haploid isolates, twelve SNP markers distributed on seven contigs were associated with virulence (P<0.0001). Four of the contigs harbour known virulence genes from other fungal pathogens and the remaining three harbour novel candidate genes. Two contigs link closely to virulence regions recognized previously by QTL mapping in the congeneric hybrid H. irregulare * H. occidentale. Our study demonstrates the efficiency of GWA studies for dissecting important complex traits of small populations of non-model haploid organisms with small genomes. PMID- 23341946 TI - Understanding the role of keratins 8 and 18 in neoplastic potential of breast cancer derived cell lines. AB - BACKGROUND: Breast cancer is a complex disease which cannot be defined merely by clinical parameters like lymph node involvement and histological grade, or by routinely used biomarkers like estrogen receptor (ER), progesterone receptor (PGR) and epidermal growth factor receptor 2 (HER2) in diagnosis and prognosis. Breast cancer originates from the epithelial cells. Keratins (K) are cytoplasmic intermediate filament proteins of epithelial cells and changes in the expression pattern of keratins have been seen during malignant transformation in the breast. Expression of the K8/18 pair is seen in the luminal cells of the breast epithelium, and its role in prognostication of breast cancer is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have modulated K8 expression to understand the role of the K8/18 pair in three different breast epithelium derived cell lines: non-transformed MCF10A, transformed but poorly invasive MDA MB 468 and highly invasive MDA MB 435. The up-regulation of K8 in the invasive MDA MB 435 cell line resulted in a significant decrease in proliferation, motility, in-vitro invasion, tumor volume and lung metastasis. The down-regulation of K8 in MDA MB 468 resulted in a significant increase in transformation potential, motility and invasion in-vitro, while MCF10A did not show any changes in cell transformation assays. CONCLUSIONS/SIGNIFICANCE: These results indicate the role of K8/18 in modulating invasion in breast cancer -its presence correlating with less invasive phenotype and absence correlating with highly invasive, dedifferentiated phenotype. These data may have important implications for prognostication of breast cancer. PMID- 23341947 TI - Two weeks of metformin treatment enhances mitochondrial respiration in skeletal muscle of AMPK kinase dead but not wild type mice. AB - Metformin is used as an anti-diabetic drug. Metformin ameliorates insulin resistance by improving insulin sensitivity in liver and skeletal muscle. Reduced mitochondrial content has been reported in type 2 diabetic muscles and it may contribute to decreased insulin sensitivity characteristic for diabetic muscles. The molecular mechanism behind the effect of metformin is not fully clarified but inhibition of complex I in the mitochondria and also activation of the 5'AMP activated protein kinase (AMPK) has been reported in muscle. Furthermore, both AMPK activation and metformin treatment have been associated with stimulation of mitochondrial function and biogenesis. However, a causal relationship in skeletal muscle has not been investigated. We hypothesized that potential effects of in vivo metformin treatment on mitochondrial function and protein expressions in skeletal muscle are dependent upon AMPK signaling. We investigated this by two weeks of oral metformin treatment of muscle specific kinase dead alpha(2) (KD) AMPK mice and wild type (WT) littermates. We measured mitochondrial respiration and protein activity and expressions of key enzymes involved in mitochondrial carbohydrate and fat metabolism and oxidative phosphorylation. Mitochondrial respiration, HAD and CS activity, PDH and complex I-V and cytochrome c protein expression were all reduced in AMPK KD compared to WT tibialis anterior muscles. Surprisingly, metformin treatment only enhanced respiration in AMPK KD mice and thereby rescued the respiration defect compared to the WT mice. Metformin did not influence protein activities or expressions in either WT or AMPK KD mice.We conclude that two weeks of in vivo metformin treatment enhances mitochondrial respiration in the mitochondrial deficient AMPK KD but not WT mice. The improvement seems to be unrelated to AMPK, and does not involve changes in key mitochondrial proteins. PMID- 23341948 TI - Rabbit neonates and human adults perceive a blending 6-component odor mixture in a comparable manner. AB - Young and adult mammals are constantly exposed to chemically complex stimuli. The olfactory system allows for a dual processing of relevant information from the environment either as single odorants in mixtures (elemental perception) or as mixtures of odorants as a whole (configural perception). However, it seems that human adults have certain limits in elemental perception of odor mixtures, as suggested by their inability to identify each odorant in mixtures of more than 4 components. Here, we explored some of these limits by evaluating the perception of three 6-odorant mixtures in human adults and newborn rabbits. Using free sorting tasks in humans, we investigated the configural or elemental perception of these mixtures, or of 5-component sub-mixtures, or of the 6-odorant mixtures with modified odorants' proportion. In rabbit pups, the perception of the same mixtures was evaluated by measuring the orocephalic sucking response to the mixtures or their components after conditioning to one of these stimuli. The results revealed that one mixture, previously shown to carry the specific odor of red cordial in humans, was indeed configurally processed in humans and in rabbits while the two other 6-component mixtures were not. Moreover, in both species, such configural perception was specific not only to the 6 odorants included in the mixture but also to their respective proportion. Interestingly, rabbit neonates also responded to each odorant after conditioning to the red cordial mixture, which demonstrates their ability to perceive elements in addition to configuration in this complex mixture. Taken together, the results provide new insights related to the processing of relatively complex odor mixtures in mammals and the inter-species conservation of certain perceptual mechanisms; the results also revealed some differences in the expression of these capacities between species putatively linked to developmental and ecological constraints. PMID- 23341949 TI - An evaluation of epidemiological and reporting characteristics of complementary and alternative medicine (CAM) systematic reviews (SRs). AB - BACKGROUND: Systematic reviews (SRs) are abundant. The optimal reporting of SRs is critical to enable clinicians to use their findings to make informed treatment decisions. Complementary and alternative medicine (CAM) therapies are widely used therefore it is critical that conduct and reporting of systematic research in this field be of high quality. Here, methodological and reporting characteristics of a sample of CAM-related SRs and a sample of control SRs are evaluated and compared. METHODS: MEDLINE((r)) was searched to identify non-Cochrane SRs indexed from January 2010 to May 2011. Control SRs were retrieved and a search filter was used to identify CAM SRs. Citations were screened and publications that met a pre specified definition of a SR were included. Pre-designed, standardized data extraction forms were developed to capture reporting and methodological characteristics of the included reviews. Where appropriate, samples were compared descriptively. RESULTS: A total of 349 SRs were identified, of which 174 were CAM related SRs and 175 were conventional SRs. We compared 131 CAM-related non Cochrane SRs to the 175 conventional non-Cochrane reviews. Fifty-seven percent (75/131) of CAM SRs specified a primary outcome compared to 21% (37/175) of conventional sample reviews. Reporting of publication bias occurred in less than 5% (6/131) of the CAM sample versus 46% (80/175) of the conventional sample of SRs. Source of funding was frequently and consistently under-reported. Less than 5% (11/306) of all SRs reported public availability of a review protocol. CONCLUSION: The two samples of reviews exhibited different strengths and weaknesses. In some cases there were consistencies across items which indicate the need for continued improvements in reporting for all SR reports. We advise authors to utilise the PRISMA Statement or other SR guidance when reporting SRs. PMID- 23341950 TI - Synchrotron-generated microbeam sensorimotor cortex transections induce seizure control without disruption of neurological functions. AB - Synchrotron-generated X-ray microplanar beams (microbeams) are characterized by the ability to deliver extremely high doses of radiation to spatially restricted volumes of tissue. Minimal dose spreading outside the beam path provides an exceptional degree of protection from radio-induced damage to the neurons and glia adjacent to the microscopic slices of tissue irradiated. The preservation of cortical architecture following high-dose microbeam irradiation and the ability to induce non-invasively the equivalent of a surgical cut over the cortex is of great interest for the development of novel experimental models in neurobiology and new treatment avenues for a variety of brain disorders. Microbeams (size 100 um/600 um, center-to-center distance of 400 um/1200 um, peak entrance doses of 360-240 Gy/150-100 Gy) delivered to the sensorimotor cortex of six 2-month-old naive rats generated histologically evident cortical transections, without modifying motor behavior and weight gain up to 7 months. Microbeam transections of the sensorimotor cortex dramatically reduced convulsive seizure duration in a further group of 12 rats receiving local infusion of kainic acid. No subsequent neurological deficit was associated with the treatment. These data provide a novel tool to study the functions of the cortex and pave the way for the development of new therapeutic strategies for epilepsy and other neurological diseases. PMID- 23341951 TI - Multi-exposure and clustering of adverse childhood experiences, socioeconomic differences and psychotropic medication in young adults. AB - PURPOSE: Stressful childhood experiences have negative long-term health consequences. The present study examines the association between adverse childhood experiences, socioeconomic position, and risk of psychotropic medication in young adulthood. METHODS: This register-based cohort study comprises the birth cohorts between 1985 and 1988 in Sweden. We followed 362 663 individuals for use of psychotropic medication from January 2006 until December 2008. Adverse childhood experiences were severe criminality among parents, parental alcohol or drug abuse, social assistance recipiency, parental separation or single household, child welfare intervention before the age of 12, mentally ill or suicidal parents, familial death, and number of changes in place of residency. Estimates of risk of psychotropic medication were calculated as odds ratio (OR) with 95% confidence intervals (CIs) using logistic regression analysis. RESULTS: Adverse childhood experiences were associated with increased risks of psychotropic medication. The OR for more than three adverse childhood experiences and risk of psychotropic medication was for women 2.4 (95% CI 2.3 2.5) and for men 3.1 (95% CI 2.9-3.2). The risk of psychotropic medication increased with a higher rate of adverse childhood experiences, a relationship similar in all socioeconomic groups. CONCLUSIONS: Accumulation of adverse childhood experiences increases the risk of psychotropic medication in young adults. Parental educational level is of less importance when adjusting for adverse childhood experiences. The higher risk for future mental health problems among children from lower socioeconomic groups, compared to peers from more advantaged backgrounds, seems to be linked to a higher rate of exposure to adverse childhood experiences. PMID- 23341952 TI - Dialysis purification of integrase-DNA complexes provides high-resolution atomic force microscopy images: dimeric recombinant HIV-1 integrase binding and specific looping on DNA. AB - It remains difficult to obtain high-resolution atomic force microscopy images of HIV-1 integrase bound to DNA in a dimeric or tetrameric fashion. We therefore constructed specific target DNAs to assess HIV-1 integrase binding and purified the complex by dialysis prior to analysis. Our resulting atomic force microscopy analyses indicated precise size of binding human immunodeficiency virus type 1 (HIV-1) recombinant integrase in a tetrameric manner, inducing formation of a loop-like or figure-eight-like secondary structure in the target DNA. Our findings regarding the target DNA secondary structure provide new insights into the intermediate states of retroviral integration. PMID- 23341953 TI - Pituitary stalk interruption syndrome in Chinese people: clinical characteristic analysis of 55 cases. AB - OBJECTIVE: Pituitary stalk interruption syndrome (PSIS) is characterized by the absence of pituitary stalk, pituitary hypoplasia, and ectopic posterior pituitary. Due to the rarity of PSIS, clinical data are limited, especially in Chinese people. Herein, we analyzed the clinical characteristics of patients diagnosed with PSIS from our center over 10 years. PATIENTS AND METHODS: We retrospectively analyzed the clinical manifestations and laboratory and MRI findings in 55 patients with PSIS. RESULTS: Of the 55 patients with PSIS, 48 (87.3%) were male. The average age was 19.7+/-6.7 years and there was no familial case. A history of breech delivery was documented in 40 of 45 patients (88.9%) and 19 of 55 patients (34.5%) had a history of dystocia. Short stature was found in 47 of 55 patients (85.5%) and bone age delayed 7.26+/-5.37 years. Secondary sex characteristics were poor or undeveloped in most patients. The prevalence of deficiencies in growth hormone, gonadotropins, corticotropin, and thyrotropin were 100%, 95.8%, 81.8%, 76.3%, respectively. Hyperprolactinemia was found in 36.4% of patients. Three or more pituitary hormone deficiencies were found in 92.7% of the patients. All patients had normal posterior pituitary function and absent pituitary stalk on imaging. The average height of anterior pituitary was 28 mm, documented anterior pituitary hypoplasia. Midline abnormalities were presented in 9.1% of patients. CONCLUSIONS: The clinical features of our Chinese PSIS patients seem to be different from other reported patients in regarding to the higher degree of hypopituitarism and lower prevalence of midline defects. In addition, our patients were older at the time of case detection and the bone age was markedly delayed. We also had no cases of familial PSIS. PMID- 23341954 TI - Feeling voices. AB - Two experiments investigated deaf individuals' ability to discriminate between same-sex talkers based on vibrotactile stimulation alone. Nineteen participants made same/different judgments on pairs of utterances presented to the lower back through voice coils embedded in a conforming chair. Discrimination of stimuli matched for F0, duration, and perceived magnitude was successful for pairs of spoken sentences in Experiment 1 (median percent correct = 83%) and pairs of vowel utterances in Experiment 2 (median percent correct = 75%). Greater difference in spectral tilt between "different" pairs strongly predicted their discriminability in both experiments. The current findings support the hypothesis that discrimination of complex vibrotactile stimuli involves the cortical integration of spectral information filtered through frequency-tuned skin receptors. PMID- 23341955 TI - The genotypic false positive rate determined by V3 population sequencing can predict the burden of HIV-1 CXCR4-using species detected by pyrosequencing. AB - OBJECTIVE: The false-positive rate (FPR) is a percentage-score provided by Geno2Pheno-algorithm indicating the likelihood that a V3-sequence is falsely predicted as CXCR4-using. We evaluated the correlation between FPR obtained by V3 population-sequencing and the burden of CXCR4-using variants detected by V3 ultra deep sequencing (UDPS) and Enhanced-Sensitivity Trofile assay (ESTA). METHODS: 54 HIV-1 B-subtype infected-patients (all maraviroc-naive), with viremia >10,000copies/ml, were analyzed. HIV-tropism was assessed by V3 population sequencing, UDPS (considering variants with >0.5% prevalence), and ESTA. RESULTS: By UDPS, CCR5-using variants were detected in 53/54 patients, irrespective of FPR values, and their intra-patient prevalence progressively increased by increasing the FPR obtained by V3 population-sequencing (rho = 0.75, p = 5.0e-8). Conversely, the intra-patient prevalence of CXCR4-using variants in the 54 patients analyzed progressively decreased by increasing the FPR (rho = -0.61; p = 9.3e-6). Indeed, no CXCR4-using variants were detected in 13/13 patients with FPR>60. They were present in 7/18 (38.8%) patients with FPR 20-60 (intra-patient prevalence range: 2.1%-18.4%), in 5/7 (71.4%) with FPR 10-20, in 4/6 (66.7%) with FPR 5-10, and in 10/10(100%) with FPR<5 (intra-patient prevalence range: 12.1% 98.1%). CONCLUSIONS: FPR by V3 population-sequencing can predict the burden of CXCR4-using variants. This information can be used to optimize the management of tropism determination in clinical practice. Due to its low cost and short turnaround time, V3 population-sequencing may represent the most feasible test for HIV-1 tropism determination. More sensitive methodologies (as UDPS) might be useful when V3 population-sequencing provides a FPR >20 (particularly in the range 20-60), allowing a more careful identification of patients harboring CXCR4 using variants. PMID- 23341956 TI - Comparative analysis of the transcriptome in tissues secreting purple and white nacre in the pearl mussel Hyriopsis cumingii. AB - The triangle sail mussel Hyriopsis cumingii (Lea) is the most important mussel species used for commercial freshwater pearl production in China. Mussel color is an important indicator of pearl quality. To identify genes involved in the nacre coloring, we conducted RNA-seq and obtained 541,268 sequences (298 bp average size) and 440,034 sequences (293 bp average size) in secreting purple and white nacre libraries (P- and W-libraries), respectively. The 981,302 Expressed Sequence Tags (ESTs) were assembled into 47,812 contigs and 289,386 singletons. In BLASTP searches of the deduced protein, 22,495 were proteins with functional annotations. Thirty-three genes involved in pearl or shell formation were identified. Digital expression analysis identified a total of 358 differentially expressed genes, and 137 genes in the P-library and 221 genes in the W-library showed significantly higher expression. Furthermore, a set of SSR motifs and SNPs between the two samples was identified from the ESTs, which provided the markers for genetic linkage, QTL analysis and future breeding. These EST sequences provided valuable information to further understand the molecular mechanisms involved in the formation, color determination and evolution of the pearl or shell. PMID- 23341957 TI - Monoclonal antibodies against Hepatitis C genotype 3a virus like particle inhibit virus entry in cell culture system. AB - The envelope protein (E1-E2) of Hepatitis C virus (HCV) is a major component of the viral structure. The glycosylated envelope protein is considered to be important for initiation of infection by binding to cellular receptor(s) and also known as one of the major antigenic targets to host immune response. The present study was aimed at identifying mouse monoclonal antibodies which inhibit binding of virus like particles of HCV to target cells. The first step in this direction was to generate recombinant HCV-like particles (HCV-LPs) specific for genotypes 3a of HCV (prevalent in India) using the genes encoding core, E1 and E2 envelop proteins in a baculovirus expression system. The purified HCV-LPs were characterized by ELISA and electron microscopy and were used to generate monoclonal antibodies (mAbs) in mice. Two monoclonal antibodies (E8G9 and H1H10) specific for the E2 region of envelope protein of HCV genotype 3a, were found to reduce the virus binding to Huh7 cells. However, the mAbs generated against HCV genotype 1b (D2H3, G2C7, E1B11) were not so effective. More importantly, mAb E8G9 showed significant inhibition of the virus entry in HCV JFH1 cell culture system. Finally, the epitopic regions on E2 protein which bind to the mAbs have also been identified. Results suggest a new therapeutic strategy and provide the proof of concept that mAb against HCV-LP could be effective in preventing virus entry into liver cells to block HCV replication. PMID- 23341959 TI - Initial antihypertensive prescription and switching: a 5 year cohort study from 250,851 patients. AB - PURPOSE: Adverse effects of antihypertensive therapy incur substantial cost. We evaluated whether any major classes of antihypertensive drugs were significantly associated with switching as a proxy measure of medication side effects in a large Chinese population in Hong Kong. METHODS: From a clinical database, all adult patients newly prescribed an antihypertensive mono-therapy in Hong Kong between the years 2001-2003 and 2005 were included. Those who paid only one visit, died or stayed in the cohort for <180 days after the prescription, or prescribed more than one antihypertensive agent were excluded. The factors associated with switching at 180 days were evaluated by multivariate regression analyses. Age, gender, payment status, service type, district of residence, drug class, systolic and diastolic blood pressure levels were predictor variables. RESULTS: From 250,851 subjects, 159,813 patients were eligible. A total of 6,163 (3.9%) switched their medications within 180 days. Patients prescribed thiazide diuretics had the highest switching rate (5.6%), followed by ACEIs (4.5%), CCBs (4.4%) and beta-blockers (3.2%). When compared with ACEIs, patients on thiazide diuretics were significantly more likely to be switchers (adjusted odds ratio [AOR] 1.49, 95% C.I. 1.31-1.69, p<0.001), whilst patients prescribed CCBs and beta-blockers were similarly likely to have switching. Following these patients up for 5 years showed that thiazide had the most marked increase in switching rate. CONCLUSIONS: The higher rates of switching among thiazide diuretics in this study might raise a probably greater incidence of their adverse effects in this Chinese population, yet other factors might also influence switching rates. Patients prescribed thiazide diuretics for longer term should be observed for their intolerability. PMID- 23341958 TI - Alteration in endoglin-related angiogenesis in refractory cytopenia with multilineage dysplasia. AB - The functional mechanisms involved in angiogenesis and the potential role of endoglin (ENG), recently described as a new marker for this process, have not been explored in Myelodysplastic Syndromes (MDS). In order to gain insight in MDS angiogenesis a combined analysis in bone marrow (BM) of gene expression levels, angiogenesis-related soluble factors and functional angiogenesis-related studies was carried out. Ninety-seven MDS patients and forty-two normal BM samples were studied. The morphology of the capillary-like structures originated by two endothelial cells lines in the BM environment of patients with refractory cytopenia with multilineage dysplasia (RCMD) was different from those of the remaining MDS. In addition, the BM mononuclear cells from RCMD patients displayed over-expression of VEGF, HIF and FN1 while they showed reduced expression of ENG in contrast to the normal ENG expression of the remaining low-risk MDS and the high expression of ENG in high-risk MDS subtype. Moreover, higher soluble ENG and soluble FLT-1 levels in BM microenvironment were observed in RCMD cases, which distinguished them from other individuals. Therefore, the present study suggests that the patterns of angiogenesis are different between the MDS subtypes. The differences in angiogenesis observed in RCMD patients could be related to ENG abnormalities. PMID- 23341960 TI - Interleukin-1beta regulates fat-liver crosstalk in obesity by auto-paracrine modulation of adipose tissue inflammation and expandability. AB - The inflammasome has been recently implicated in obesity-associated dys metabolism. However, of its products, the specific role of IL-1beta was clinically demonstrated to mediate only the pancreatic beta-cell demise, and in mice mainly the intra-hepatic manifestations of obesity. Yet, it remains largely unknown if IL-1beta, a cytokine believed to mainly function locally, could regulate dysfunctional inter-organ crosstalk in obesity. Here we show that High fat-fed (HFF) mice exhibited a preferential increase of IL-1beta in portal compared to systemic blood. Moreover, portally-drained mesenteric fat transplantation from IL-1betaKO donors resulted in lower pyruvate-glucose flux compared to mice receiving wild-type (WT) transplant. These results raised a putative endocrine function for visceral fat-derived IL-1beta in regulating hepatic gluconeogenic flux. IL-1betaKO mice on HFF exhibited only a minor or no increase in adipose expression of pro-inflammatory genes (including macrophage M1 markers), Mac2-positive crown-like structures and CD11b-F4/80-double-positive macrophages, all of which were markedly increased in WT-HFF mice. Further consistent with autocrine/paracrine functions of IL-1beta within adipose tissue, adipose tissue macrophage lipid content was increased in WT-HFF mice, but significantly less in IL-1betaKO mice. Ex-vivo, adipose explants co-cultured with primary hepatocytes from WT or IL-1-receptor (IL-1RI)-KO mice suggested only a minor direct effect of adipose-derived IL-1beta on hepatocyte insulin resistance. Importantly, although IL-1betaKOs gained weight similarly to WT-HFF, they had larger fat depots with similar degree of adipocyte hypertrophy. Furthermore, adipogenesis genes and markers (pparg, cepba, fabp4, glut4) that were decreased by HFF in WT, were paradoxically elevated in IL-1betaKO-HFF mice. These local alterations in adipose tissue inflammation and expansion correlated with a lower liver size, less hepatic steatosis, and preserved insulin sensitivity. Collectively, we demonstrate that by promoting adipose inflammation and limiting fat tissue expandability, IL-1beta supports ectopic fat accumulation in hepatocytes and adipose-tissue macrophages, contributing to impaired fat-liver crosstalk in nutritional obesity. PMID- 23341961 TI - N-acetylglucosamine kinase, HXK1 is involved in morphogenetic transition and metabolic gene expression in Candida albicans. AB - Candida albicans, a common fungal pathogen which diverged from the baker's yeast Saccharomyces cerevisiae has the unique ability to utilise N-acetylglucosamine, an amino sugar and exhibits phenotypic differences. It has acquired intricate regulatory mechanisms at different levels in accordance with its life style. N acetylglucosamine kinase, a component of the N-acetylglucosamine catabolic cascade is an understudied gene since Saccharomyces cerevisiae lacks it. We report HXK1 to act as both positive and negative regulator of transcription of genes involved in maintaining cellular homeostasis. It is involved in repression of hyphal specific genes in addition to metabolic genes. Its regulation of filamentation and GlcNAc metabolism is independent of the known classical regulators like EFG1, CPH1, RAS1, TPK2 or TUP1. Moreover, Hxk1-GFP is localised to cytoplasm, nucleus and mitochondria in a condition specific manner. By employing two-step affinity purification, we report the interaction of HXK1 with SIR2 under filamentation inducing conditions. Our work highlights a novel regulatory mechanism involved in filamentation repression and attempts to decipher the GlcNAc catabolic regulatory cascade in eukaryotes. PMID- 23341962 TI - Cholecystokinin A receptor (CCKAR) gene variation is associated with language lateralization. AB - Schizophrenia is a psychiatric disorder associated with atypical handedness and language lateralization. However, the molecular mechanisms underlying these functional changes are still poorly understood. Therefore, the present study was aimed at investigating whether variation in schizophrenia-related genes modulates individual lateralization patterns. To this end, we genotyped 16 single nucleotide polymorphisms that have previously been linked to schizophrenia on a meta-analysis level in a sample of 444 genetically unrelated healthy participants and examined the association of these polymorphisms with handedness, footedness and language lateralization. We found a significant association of the cholecystokinin-A receptor (CCKAR) gene variation rs1800857 and language lateralization assessed using the dichotic listening task. Individuals carrying the schizophrenia risk allele C of this polymorphism showed a marked reduction of the typical left-hemispheric dominance for language processing. Since the cholecystokinin A receptor is involved in dopamine release in the central nervous system, these findings suggest that genetic variation in this receptor may modulate language lateralization due to its impact on dopaminergic pathways. PMID- 23341963 TI - Biased diversity metrics revealed by bacterial 16S pyrotags derived from different primer sets. AB - In recent years, PCR-based pyrosequencing of 16S rRNA genes has continuously increased our understanding of complex microbial communities in various environments of the Earth. However, there is always concern on the potential biases of diversity determination using different 16S rRNA gene primer sets and covered regions. Here, we first report how bacterial 16S rRNA gene pyrotags derived from a series of different primer sets resulted in the biased diversity metrics. In total, 14 types of pyrotags were obtained from two-end pyrosequencing of 7 amplicon pools generated by 7 primer sets paired by 1 of 4 forward primers (V1F, V3F, V5F, and V7F) and 1 of 4 reverse primers (V2R, V4R, V6R, and V9R), respectively. The results revealed that: i) the activated sludge exhibited a large bacterial diversity that represented a broad range of bacterial populations and served as a good sample in this methodology research; ii) diversity metrics highly depended on the selected primer sets and covered regions; iii) paired pyrotags obtained from two-end pyrosequencing of each short amplicon displayed different diversity metrics; iv) relative abundance analysis indicated the sequencing depth affected the determination of rare bacteria but not abundant bacteria; v) the primer set of V1F and V2R significantly underestimated the diversity of activated sludge; and vi) the primer set of V3F and V4R was highly recommended for future studies due to its advantages over other primer sets. All of these findings highlight the significance of this methodology research and offer a valuable reference for peer researchers working on microbial diversity determination. PMID- 23341964 TI - The earliest fleshy cone of Ephedra from the early cretaceous Yixian Formation of northeast China. AB - Bracts of female cones of extant gymnosperm Ephedra (Joint fir) are either colorful and fleshy (section Ephedra), or dry-winged and membranous (section Alatae), or dry and coriaceous (section Asarca), which have played a crucial role in long-distance seed dispersal that is responsible for a wide distribution of the genus in semiarid and arid areas of Eurasia, North Africa, North America, and South America. Recent molecular systematic studies on Ephedra have suggested that the fleshy bracts in character evolution may be plesiomorphic relative to the dry, membranous and coriaceous bracts. However, little is known about when the fleshy bracts of Ephedra have made their debut in the geological past. Herein, we describe a novel, fleshy bract-bearing female cone macrofossil from the Early Cretaceous (ca. 120-125 Ma) Yixian Formation in Liaoning, northeastern China. This cone bears three ellipsoid seeds subtended by only one whorl of fleshy bracts. Each seed has a thin outer envelope and an inner integument that extends upward and passes through the opening of the outer envelope, forming a thin and straight micropylar tube. Such a syndrome shows the closest similarity to an extant triovulate species Ephedra intermedia in the section Ephedra, but the latter bears a whorl of terminal fertile bracts and more than one whorl of inferior sterile bracts, and a thick outer envelope. Hence, we establish a new fossil species Ephedra carnosa. Our discovery provides the first direct macrofossil evidence for the previous molecular systematics of Ephedra, implying that the origin of fleshy bracts in Ephedra should not have been later than that of the membranous and coriaceous bracts by at least the Early Cretaceous. PMID- 23341965 TI - Methyl fluoride affects methanogenesis rather than community composition of methanogenic archaea in a rice field soil. AB - The metabolic pathways of methane formation vary with environmental conditions, but whether this can also be linked to changes in the active archaeal community structure remains uncertain. Here, we show that the suppression of aceticlastic methanogenesis by methyl fluoride (CH(3)F) caused surprisingly little differences in community composition of active methanogenic archaea from a rice field soil. By measuring the natural abundances of carbon isotopes we found that the effective dose for a 90% inhibition of aceticlastic methanogenesis in anoxic paddy soil incubations was <0.75% CH(3)F (v/v). The construction of clone libraries as well as t-RFLP analysis revealed that the active community, as indicated by mcrA transcripts (encoding the alpha subunit of methyl-coenzyme M reductase, a key enzyme for methanogenesis), remained stable over a wide range of CH(3)F concentrations and represented only a subset of the methanogenic community. More precisely, Methanocellaceae were of minor importance, but Methanosarcinaceae dominated the active population, even when CH(3)F inhibition only allowed for aceticlastic methanogenesis. In addition, we detected mcrA gene fragments of a so far unrecognised phylogenetic cluster. Transcription of this phylotype at methyl fluoride concentrations suppressing aceticlastic methanogenesis suggests that the respective organisms perform hydrogenotrophic methanogenesis. Hence, the application of CH(3)F combined with transcript analysis is not only a useful tool to measure and assign in situ acetate usage, but also to explore substrate usage by as yet uncultivated methanogens. PMID- 23341966 TI - Endothelial progenitor cells in the pathogenesis of idiopathic pulmonary fibrosis: an evolving concept. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has been associated with abnormal vascular remodeling. Bone marrow derived endothelial progenitor cells (EPCs) are considered to possess lung tissue repair and vascular remodeling properties. OBJECTIVES: The study aimed to assess early EPCs levels and EPCs endogenous vascular endothelial growth factor (VEGF) expression in IPF. In order to examine alterations in the mobilization of EPCs from the bone marrow we measured plasma VEGF. MAIN RESULTS: Twenty-three patients with IPF and fifteen healthy subjects were included. The number of early EPCs colonies was markedly reduced in IPF patients vs controls (6.00+/-6.49 vs 49.68+/-16.73, respectively, p<0.001). EPCs were further decreased in patients presenting systolic pulmonary arterial pressure (sPAP)>=35 mmHg. The number of colonies per well correlated negatively with P((A-a))O(2) (r = -0.750, p<0.001). Additionally, VEGF mRNA levels were significantly increased in IPF patients. There were no differences observed in VEGF plasma levels in IPF patients when compared to controls. CONCLUSIONS: The current data suggest that inadequate levels of early EPCs may potentially contribute to suppressed repair and recovery of the damaged pulmonary endothelium and thereby may drive the sequence of events in profibrogenic direction. Increased VEGFmRNA levels in the clinical context of IPF may represent a compensatory mechanism to overcome reduced EPCs levels. PMID- 23341967 TI - Pentraxin 3 (PTX3) is associated with severe sepsis and fatal disease in emergency room patients with suspected infection: a prospective cohort study. AB - BACKGROUND: Early diagnostic and prognostic stratification of patients with suspected infection is a difficult clinical challenge. We studied plasma pentraxin 3 (PTX3) upon admission to the emergency department in patients with suspected infection. METHODS: The study comprised 537 emergency room patients with suspected infection: 59 with no systemic inflammatory response syndrome (SIRS) and without bacterial infection (group 1), 67 with bacterial infection without SIRS (group 2), 54 with SIRS without bacterial infection (group 3), 308 with sepsis (SIRS and bacterial infection) without organ failure (group 4) and 49 with severe sepsis (group 5). Plasma PTX3 was measured on admission using a commercial solid-phase enzyme-linked immunosorbent assay (ELISA). RESULTS: The median PTX3 levels in groups 1-5 were 2.6 ng/ml, 4.4 ng/ml, 5.0 ng/ml, 6.1 ng/ml and 16.7 ng/ml, respectively (p<0.001). The median PTX3 concentration was higher in severe sepsis patients compared to others (16.7 vs. 4.9 ng/ml, p<0.001) and in non-survivors (day 28 case fatality) compared to survivors (14.1 vs. 5.1 ng/ml, p<0.001). A high PTX3 level predicted the need for ICU stay (p<0.001) and hypotension (p<0.001). AUC(ROC) in the prediction of severe sepsis was 0.73 (95% CI 0.66-0.81, p<0.001) and 0.69 in case fatality (95% CI 0.58-0.79, p<0.001). PTX3 at a cut-off level for 14.1 ng/ml (optimal cut-off value for severe sepsis) showed 63% sensitivity and 80% specificity. At a cut-off level 7.7 ng/ml (optimal cut-off value for case fatality) showed 70% sensitivity and 63% specificity in predicting case fatality on day 28.In multivariate models, high PTX3 remained an independent predictor of severe sepsis and case fatality after adjusting for potential confounders. CONCLUSIONS: A high PTX3 level on hospital admission predicts severe sepsis and case fatality in patients with suspected infection. PMID- 23341968 TI - The protective effect of glycyrrhetinic acid on carbon tetrachloride-induced chronic liver fibrosis in mice via upregulation of Nrf2. AB - This study was designed to investigate the potentially protective effects of glycyrrhetinic acid (GA) and the role of transcription factor nuclear factor erythroid 2(NF-E2)-related factor 2 (Nrf2) signaling in the regulation of Carbon Tetrachloride (CCl(4))-induced chronic liver fibrosis in mice. The potentially protective effects of GA on CCl(4)-induced chronic liver fibrosis in mice were depicted histologically and biochemically. Firstly, histopathological changes including regenerative nodules, inflammatory cell infiltration and fibrosis were induced by CCl(4).Then, CCl(4) administration caused a marked increase in the levels of serum aminotransferases (GOT, GPT), serum monoamine oxidase (MAO) and lipid peroxidation (MDA) as well as MAO in the mice liver homogenates. Also, decreased nuclear Nrf2 expression, mRNA levels of its target genes such as superoxide dismutase 3 (SOD3), catalase (CAT), glutathione peroxidase 2 (GPX2), and activity of cellular antioxidant enzymes were found after CCl(4) exposure. All of these phenotypes were markedly reversed by the treatment of the mice with GA. In addition, GA exhibited the antioxidant effects in vitro by on FeCl(2) ascorbate induced lipid peroxidation in mouse liver homogenates, and on DPPH scavenging activity. Taken together, these results suggested that GA can protect the liver from oxidative stress in mice, presumably through activating the nuclear translocation of Nrf2, enhancing the expression of its target genes and increasing the activity of the antioxidant enzymes. Therefore, GA may be an effective hepatoprotective agent and viable candidate for treating liver fibrosis and other oxidative stress-related diseases. PMID- 23341969 TI - Risk for eating disorders modulates startle-responses to body words. AB - Body image disturbances are core symptoms of eating disorders (EDs). Recent evidence suggests that changes in body image may occur prior to ED onset and are not restricted to in-vivo exposure (e.g. mirror image), but also evident during presentation of abstract cues such as body shape and weight-related words. In the present study startle modulation, heart rate and subjective evaluations were examined during reading of body words and neutral words in 41 student female volunteers screened for risk of EDs. The aim was to determine if responses to body words are attributable to a general negativity bias regardless of ED risk or if activated, ED relevant negative body schemas facilitate priming of defensive responses. Heart rate and word ratings differed between body words and neutral words in the whole female sample, supporting a general processing bias for body weight and shape-related concepts in young women regardless of ED risk. Startle modulation was specifically related to eating disorder symptoms, as was indicated by significant positive correlations with self-reported body dissatisfaction. These results emphasize the relevance of examining body schema representations as a function of ED risk across different levels of responding. Peripheral physiological measures such as the startle reflex could possibly be used as predictors of females' risk for developing EDs in the future. PMID- 23341970 TI - Wnt5a does not support hematopoiesis in stroma-free, serum-free cultures. AB - Previously we reported that Wnt5a is highly expressed in the murine urogenital ridge-derived UG26-1B6 cells but not embryonic liver-derived EL08-1D2 cells. Mouse long-term repopulating hematopoietic stem cells (LTR-HSC) were maintained in non-contact UG26-1B6 cultures but not EL08-1D2 non-contact cultures, unless Wnt5a was also added to the cultures, suggesting a role for Wnt5a in the in vitro maintenance of LTR-HSC. Here, we investigated if the effect of Wnt5a on adult LTR HSC activity is HSC-autonomous. To test the effect of Wnt5a on maintenance of LTR HSC, we performed limiting dilution competitive transplantation assays of murine Lin-Sca1(+) c-kit(+) (LSK) cells cultured for 5 days with TPO and SCF with and without Wnt5a. The effect of Wnt5a on the generation of colony forming units (CFU) and the homing ability of LSK progeny was also tested. No effects were found of Wnt5a on total cell expansion, the number of CFU, or homing ability of day 5 LSK progeny. Furthermore, addition of Wnt5a did not improve, but may have impeded maintenance of LTR-HSC. In conclusion, our data indicate that Wnt5a does not enhance the maintenance and expansion of adult murine LTR-HSCs or committed progenitors cultured in vitro in serum- and stroma-free conditions. PMID- 23341971 TI - Serum vitamin D in patients with chronic obstructive lung disease does not correlate with mortality--results from a 10-year prospective cohort study. AB - BACKGROUND: Recent studies have found vitamin D (25-OHD) deficiency and insufficiency to be common among patients with COPD. Serum level of 25-OHD seems to correlate to pulmonary function, COPD disease staging, and increased susceptibility to respiratory infections. We wanted to investigate whether vitamin D deficiency or insufficiency was associated with mortality rate in patients suffering from advanced COPD. METHODS: 25-OHD serum levels were measured in 462 patients suffering from moderate to very severe COPD. Patients were stratified into three groups according to serum levels of 25-OHD. Outcome measure was mortality in a 10 year follow-up period. Kaplan-Meier curves (KM) were plotted and mortality hazard ratios (HR) were calculated using Cox Proportional Hazard regression (Cox PH). RESULTS: Serum 25-OHD deficiency and insufficiency were prevalent. We were unable to demonstrate any association between baseline serum levels of 25-OHD and mortality rate. We found an association between mortality and age [HR 1.05 (CI 95%: 1.03-1.06)], Charlson score [HR 1.49 (CI 95%: 1.06-2.09)], increasing neutrophil count [HR 1.05 (CI 95%: 1.02-1.09)], severe [HR 1.41 (CI 95%: 1.06-1.86)]/very severe COPD [HR 2.19 (CI 95%: 1.58-3.02)] and a smoking history of more than 40 pack years [HR 1.27 (CI 95%: 1.02-1.70)]. CONCLUSIONS: Serum level of 25-OHD does not seem to be associated with mortality rate, suggesting no or only a minor role of 25-OHD in disease progression in patients with moderate to very severe COPD. PMID- 23341973 TI - Innovative techniques for estimating illegal activities in a human-wildlife management conflict. AB - Effective management of biological resources is contingent upon stakeholder compliance with rules. With respect to disease management, partial compliance can undermine attempts to control diseases within human and wildlife populations. Estimating non-compliance is notoriously problematic as rule-breakers may be disinclined to admit to transgressions. However, reliable estimates of rule breaking are critical to policy design. The European badger (Meles meles) is considered an important vector in the transmission and maintenance of bovine tuberculosis (bTB) in cattle herds. Land managers in high bTB prevalence areas of the UK can cull badgers under license. However, badgers are also known to be killed illegally. The extent of illegal badger killing is currently unknown. Herein we report on the application of three innovative techniques (Randomized Response Technique (RRT); projective questioning (PQ); brief implicit association test (BIAT)) for investigating illegal badger killing by livestock farmers across Wales. RRT estimated that 10.4% of farmers killed badgers in the 12 months preceding the study. Projective questioning responses and implicit associations relate to farmers' badger killing behavior reported via RRT. Studies evaluating the efficacy of mammal vector culling and vaccination programs should incorporate estimates of non-compliance. Mitigating the conflict concerning badgers as a vector of bTB requires cross-disciplinary scientific research, departure from deep-rooted positions, and the political will to implement evidence-based management. PMID- 23341972 TI - Involvement of EphB1 receptors signalling in models of inflammatory and neuropathic pain. AB - EphB receptors tyrosine kinases and ephrinB ligands were first identified as guidance molecules involved in the establishment of topographical mapping and connectivity in the nervous system during development. Later in development and into adulthood their primary role would switch from guidance to activity dependent modulation of synaptic efficacy. In sensory systems, they play a role in both the onset of inflammatory and neuropathic pain, and in the establishment of central sensitisation, an NMDA-mediated form of synaptic plasticity thought to underlie most forms of chronic pain. We studied wild type and EphB1 knockout mice in a range of inflammatory and neuropathic pain models to determine 1), whether EphB1 expression is necessary for the onset and/or maintenance of persistent pain, regardless of origin; 2), whether in these models cellular and molecular changes, e.g. phosphorylation of the NR2B subunit of the NMDA receptor, increased c-fos expression or microglial activation, associated with the onset of pain, are affected by the lack of functional EphB1 receptors. Differences in phenotype were examined behaviourally, anatomically, biochemically and electrophysiologically. Our results establish firstly, that functional EphB1 receptors are not essential for the development of normal nociception, thermal or mechanical sensitivity. Secondly, they demonstrate a widespread involvement of EphB1 receptors in chronic pain. NR2B phosphorylation, c-fos expression and microglial activation are all reduced in EphB1 knockout mice. This last finding is intriguing, since microglial activation is supposedly triggered directly by primary afferents, therefore it was not expected to be affected. Interestingly, in some models of long-term pain (days), mechanical and thermal hyperalgesia develop both in wild type and EphB1 knockout mice, but recovery is faster in the latter, indicating that in particular models these receptors are required for the maintenance, rather than the onset of, thermal and mechanical hypersensitivity. This potentially makes them an attractive target for analgesic strategies. PMID- 23341974 TI - Incomplete lineage sorting is common in extant gibbon genera. AB - We sequenced reduced representation libraries by means of Illumina technology to generate over 1.5 Mb of orthologous sequence from a representative of each of the four extant gibbon genera (Nomascus, Hylobates, Symphalangus, and Hoolock). We used these data to assess the evolutionary relationships between the genera by evaluating the likelihoods of all possible bifurcating trees involving the four taxa. Our analyses provide weak support for a tree with Nomascus and Hylobates as sister taxa and with Hoolock and Symphalangus as sister taxa, though bootstrap resampling suggests that other phylogenetic scenarios are also possible. This uncertainty is due to short internal branch lengths and extensive incomplete lineage sorting across taxa. The true phylogenetic relationships among gibbon genera will likely require a more extensive whole-genome sequence analysis. PMID- 23341975 TI - Out-of-hospital cardiac arrests and outdoor air pollution exposure in Copenhagen, Denmark. AB - Cardiovascular disease is the number one cause of death globally and air pollution can be a contributing cause. Acute myocardial infarction and cardiac arrest are frequent manifestations of coronary heart disease. The objectives of the study were to investigate the association between 4 657 out-of-hospital cardiac arrests (OHCA) and hourly and daily outdoor levels of PM(10), PM(2.5), coarse fraction of PM (PM(10-2.5)), ultrafine particle proxies, NO(x), NO(2), O(3) and CO in Copenhagen, Denmark, for the period 2000-2010. Susceptible groups by age and sex was also investigated. A case-crossover design was applied. None of the hourly lags of any of the pollutants were significantly associated with OHCA events. The strongest association with OHCA events was observed for the daily lag4 of PM(2.5), lag3 of PM(10), lag3 of PM(10-2.5), lag3 of NO(x) and lag4 of CO. An IQR increase of PM(2.5) and PM(10) was associated with a significant increase of 4% (95% CI: 0%; 9%) and 5% (95% CI: 1%; 9%) in OHCA events with 3 days lag, respectively. None of the other daily lags or other pollutants was significantly associated with OHCA events. Adjustment for O(3) slightly increased the association between OHCA and PM(2.5) and PM(10). No susceptible groups were identified. PMID- 23341976 TI - Polymorphism in the ELOVL6 gene is associated with a major QTL effect on fatty acid composition in pigs. AB - BACKGROUND: The ELOVL fatty acid elongase 6 (ELOVL6), the only elongase related to de novo lipogenesis, catalyzes the rate-limiting step in the elongation cycle by controlling the fatty acid balance in mammals. It is located on pig chromosome 8 (SSC8) in a region where a QTL affecting palmitic, and palmitoleic acid composition was previously detected, using an Iberian x Landrace intercross. The main goal of this work was to fine-map the QTL and to evaluate the ELOVL6 gene as a positional candidate gene affecting the percentages of palmitic and palmitoleic fatty acids in pigs. METHODOLOGY AND PRINCIPAL FINDINGS: The combination of a haplotype-based approach and single-marker analysis allowed us to identify the main, associated interval for the QTL, in which the ELOVL6 gene was identified and selected as a positional candidate gene. A polymorphism in the promoter region of ELOVL6, ELOVL6:c.-533C>T, was highly associated with the percentage of palmitic and palmitoleic acids in muscle and backfat. Significant differences in ELOVL6 gene expression were observed in backfat when animals were classified by the ELOVL6:c.-533C>T genotype. Accordingly, animals carrying the allele associated with a decrease in ELOVL6 gene expression presented an increase in C16:0 and C16:1(n-7) fatty acid content and a decrease of elongation activity ratios in muscle and backfat. Furthermore, a SNP genome-wide association study with ELOVL6 relative expression levels in backfat showed the strongest effect on the SSC8 region in which the ELOVL6 gene is located. Finally, different potential genomic regions associated with ELOVL6 gene expression were also identified by GWAS in liver and muscle, suggesting a differential tissue regulation of the ELOVL6 gene. CONCLUSIONS AND SIGNIFICANCE: Our results suggest ELOVL6 as a potential causal gene for the QTL analyzed and, subsequently, for controlling the overall balance of fatty acid composition in pigs. PMID- 23341977 TI - Hsmar1 transposition is sensitive to the topology of the transposon donor and the target. AB - Hsmar1 is a member of the Tc1-mariner superfamily of DNA transposons. These elements mobilize within the genome of their host by a cut-and-paste mechanism. We have exploited the in vitro reaction provided by Hsmar1 to investigate the effect of DNA supercoiling on transposon integration. We found that the topology of both the transposon and the target affect integration. Relaxed transposons have an integration defect that can be partially restored in the presence of elevated levels of negatively supercoiled target DNA. Negatively supercoiled DNA is a better target than nicked or positively supercoiled DNA, suggesting that underwinding of the DNA helix promotes target interactions. Like other Tc1 mariner elements, Hsmar1 integrates into 5'-TA dinucleotides. The direct vicinity of the target TA provides little sequence specificity for target interactions. However, transposition within a plasmid substrate was not random and some TA dinucleotides were targeted preferentially. The distribution of intramolecular target sites was not affected by DNA topology. PMID- 23341978 TI - Gene expression deregulation in postnatal skeletal muscle of TK2 deficient mice reveals a lower pool of proliferating myogenic progenitor cells. AB - Loss of thymidine kinase 2 (TK2) causes a heterogeneous myopathic form of mitochondrial DNA (mtDNA) depletion syndrome (MDS) in humans that predominantly affects skeletal muscle tissue. In mice, TK2 deficiency also affects several tissues in addition to skeletal muscle, including brain, heart, adipose tissue, kidneys and causes death about 3 weeks after birth. We analysed skeletal muscle and heart muscle tissues of Tk2 knockout mice at postnatal development phase and observed that TK2 deficient pups grew slower and their skeletal muscles appeared significantly underdeveloped, whereas heart was close to normal in size. Both tissues showed mtDNA depletion and mitochondria with altered ultrastructure, as revealed by transmission electron microscopy. Gene expression microarray analysis showed a strong down-regulation of genes involved in cell cycle and cell proliferation in both tissues, suggesting a lower pool of undifferentiated proliferating cells. Analysis of isolated primary myoblasts from Tk2 knockout mice showed slow proliferation, less ability to differentiate and signs of premature senescence, even in absence of mtDNA depletion. Our data demonstrate that TK2 deficiency disturbs myogenic progenitor cells function in postnatal skeletal muscle and we propose this as one of the causes of underdeveloped phenotype and myopathic characteristic of the TK2 deficient mice, in addition to the progressive mtDNA depletion, mitochondrial damage and respiratory chain deficiency in post-mitotic differentiated tissue. PMID- 23341979 TI - The species dilemma of Northeast Indian Mahseer (Actinopterygii: Cyprinidae): DNA barcoding in clarifying the riddle. AB - BACKGROUND: The taxonomic validity of Northeast Indian endemic Mahseer species, Tor progeneius and Neolissochilus hexastichus, has been argued repeatedly. This is mainly due to disagreements in recognizing the species based on morphological characters. Consequently, both the species have been concealed for many decades. DNA barcoding has become a promising and an independent technique for accurate species level identification. Therefore, utilization of such technique in association with the traditional morphotaxonomic description can resolve the species dilemma of this important group of sport fishes. METHODOLOGY/PRINCIPAL FINDINGS: Altogether, 28 mahseer specimens including paratypes were studied from different locations in Northeast India, and 24 morphometric characters were measured invariably. The Principal Component Analysis with morphometric data revealed five distinct groups of sample that were taxonomically categorized into 4 species, viz., Tor putitora, T. progeneius, Neolissochilus hexagonolepis and N. hexastichus. Analysis with a dataset of 76 DNA barcode sequences of different mahseer species exhibited that the queries of T. putitora and N. hexagonolepis clustered cohesively with the respective conspecific database sequences maintaining 0.8% maximum K2P divergence. The closest congeneric divergence was 3 times higher than the mean conspecific divergence and was considered as barcode gap. The maximum divergence among the samples of T. progeneius and T. putitora was 0.8% that was much below the barcode gap, indicating them being synonymous. The query sequences of N. hexastichus invariably formed a discrete and a congeneric clade with the database sequences and maintained the interspecific divergence that supported its distinct species status. Notably, N. hexastichus was encountered in a single site and seemed to be under threat. CONCLUSION: This study substantiated the identification of N. hexastichus to be a true species, and tentatively regarded T. progeneius to be a synonym of T. putitora. It would guide the conservationists to initiate priority conservation of N. hexastichus and T. putitora. PMID- 23341980 TI - Laser capture microdissected mucosa versus whole tissue specimens for assessment of radiation-induced dynamic molecular and pathway changes in the small intestine. AB - BACKGROUND: The intestinal mucosa is the compartment that sustains the most severe injury in response to radiation and is therefore of primary interest. The use of whole gut extracts for analysis of gene expression may confound important changes in the mucosa. On the other hand, laser capture microdissection (LCM) is hampered by the unstable nature of RNA and by a more complicated collection process. This study assessed, in parallel samples from a validated radiation model, the indications for use of LCM for intestinal gene expression analysis. METHODOLOGY/PRINCIPAL FINDINGS: RNA was extracted from mouse whole intestine and from mucosa by LCM at baseline and 4 h, 24 h, and 3.5 d after total body irradiation and subjected to microarray analysis. Among mucosal genes that were altered > = 2-fold, less than 7% were present in the whole gut at 4 and 24 h, and 25% at 3.5 d. As expected, pathway analysis of mucosal LCM samples showed that radiation activated the coagulation system, lymphocyte apoptosis, and tight junction signaling, and caused extensive up-regulation of cell cycle and DNA damage repair pathways. Using similar stringent criteria, regulation of these pathways, with exception of the p53 pathway, was undetectable in the whole gut. Radiation induced a dramatic increase of caspase14 and ectodysplasin A2 receptor (Eda2r), a TNFalpha receptor, in both types of samples. CONCLUSIONS/SIGNIFICANCE: LCM-isolated mucosal specimens should be used to study cellular injury, cell cycle control, and DNA damage repair pathways. The remarkable increase of caspase14 and Eda2r suggests a novel role for these genes in regulating intestinal radiation injury. Comparative gene expression data from complex tissues should be interpreted with caution. PMID- 23341981 TI - Autologous bone marrow mononuclear cell transplantation in patients with decompensated alcoholic liver disease: a randomized controlled trial. AB - OBJECTIVE: Impaired liver regeneration is associated with a poor outcome in patients with decompensated alcoholic liver disease (ALD). We assessed whether autologous bone marrow mononuclear cell transplantation (BMMCT) improved liver function in decompensated ALD. DESIGN: 58 patients (mean age 54 yrs; mean MELD score 19, all with cirrhosis, 81% with alcoholic steatohepatitis at baseline liver biopsy) were randomized early after hospital admission to standard medical therapy (SMT) alone (n = 30), including steroids in patients with a Maddrey's score >=32, or combined with G-CSF injections and autologous BMMCT into the hepatic artery (n = 28). Bone marrow cells were harvested, isolated and reinfused the same day. The primary endpoint was a >=3 points decrease in the MELD score at 3 months, corresponding to a clinically relevant improvement in liver function. Liver biopsy was repeated at week 4 to assess changes in Ki67+/CK7+ hepatic progenitor cells (HPC) compartment. RESULTS: Both study groups were comparable at baseline. After 3 months, 2 and 4 patients died in the BMMCT and SMT groups, respectively. Adverse events were equally distributed between groups. Moderate alcohol relapse occurred in 31% of patients. The MELD score improved in parallel in both groups during follow-up with 18 patients (64%) from the BMMCT group and 18 patients (53%) from the SMT group reaching the primary endpoint (p = 0.43 (OR 1.6, CI 0.49-5.4) in an intention to treat analysis. Comparing liver biopsy at 4 weeks to baseline, steatosis improved (p<0.001), and proliferating HPC tended to decrease in both groups (-35 and -33%, respectively). CONCLUSION: Autologous BMMCT, compared to SMT is a safe procedure but did not result in an expanded HPC compartment or improved liver function. These data suggest either insufficient regenerative stimulation after BMMCT or resistance to liver regenerative drive in patients with decompensated alcoholic cirrhosis. TRIAL REGISTRATION: Controlled Trials.com ISRCTN83972743. PMID- 23341982 TI - No major differences found between the effects of microwave-based and conventional heat treatment methods on two different liquid foods. AB - Extension of shelf life and preservation of products are both very important for the food industry. However, just as with other processes, speed and higher manufacturing performance are also beneficial. Although microwave heating is utilized in a number of industrial processes, there are many unanswered questions about its effects on foods. Here we analyze whether the effects of microwave heating with continuous flow are equivalent to those of traditional heat transfer methods. In our study, the effects of heating of liquid foods by conventional and continuous flow microwave heating were studied. Among other properties, we compared the stability of the liquid foods between the two heat treatments. Our goal was to determine whether the continuous flow microwave heating and the conventional heating methods have the same effects on the liquid foods, and, therefore, whether microwave heat treatment can effectively replace conventional heat treatments. We have compared the colour, separation phenomena of the samples treated by different methods. For milk, we also monitored the total viable cell count, for orange juice, vitamin C contents in addition to the taste of the product by sensory analysis. The majority of the results indicate that the circulating coil microwave method used here is equivalent to the conventional heating method based on thermal conduction and convection. However, some results in the analysis of the milk samples show clear differences between heat transfer methods. According to our results, the colour parameters (lightness, red-green and blue-yellow values) of the microwave treated samples differed not only from the untreated control, but also from the traditional heat treated samples. The differences are visually undetectable, however, they become evident through analytical measurement with spectrophotometer. This finding suggests that besides thermal effects, microwave-based food treatment can alter product properties in other ways as well. PMID- 23341983 TI - Does learning or instinct shape habitat selection? AB - Habitat selection is an important behavioural process widely studied for its population-level effects. Models of habitat selection are, however, often fit without a mechanistic consideration. Here, we investigated whether patterns in habitat selection result from instinct or learning for a population of grizzly bears (Ursus arctos) in Alberta, Canada. We found that habitat selection and relatedness were positively correlated in female bears during the fall season, with a trend in the spring, but not during any season for males. This suggests that habitat selection is a learned behaviour because males do not participate in parental care: a genetically predetermined behaviour (instinct) would have resulted in habitat selection and relatedness correlations for both sexes. Geographic distance and home range overlap among animals did not alter correlations indicating that dispersal and spatial autocorrelation had little effect on the observed trends. These results suggest that habitat selection in grizzly bears are partly learned from their mothers, which could have implications for the translocation of wildlife to novel environments. PMID- 23341984 TI - Comparative demography of an at-risk African elephant population. AB - Knowledge of population processes across various ecological and management settings offers important insights for species conservation and life history. In regard to its ecological role, charisma and threats from human impacts, African elephants are of high conservation concern and, as a result, are the focus of numerous studies across various contexts. Here, demographic data from an individually based study of 934 African elephants in Samburu, Kenya were summarized, providing detailed inspection of the population processes experienced by the population over a fourteen year period (including the repercussions of recent increases in illegal killing). These data were compared with those from populations inhabiting a spectrum of xeric to mesic ecosystems with variable human impacts. In relation to variability in climate and human impacts (causing up to 50% of recorded deaths among adults), annual mortality in Samburu fluctuated between 1 and 14% and, unrelatedly, natality between 2 and 14% driving annual population increases and decreases. Survivorship in Samburu was significantly lower than other populations with age-specific data even during periods of low illegal killing by humans, resulting in relatively low life expectancy of males (18.9 years) and females (21.8 years). Fecundity (primiparous age and inter-calf interval) were similar to those reported in other human impacted or recovering populations, and significantly greater than that of comparable stable populations. This suggests reproductive effort of African savanna elephants increases in relation to increased mortality (and resulting ecological ramifications) as predicted by life history theory. Further comparison across populations indicated that elongated inter-calf intervals and older ages of reproductive onset were related to age structure and density, and likely influenced by ecological conditions. This study provides detailed empirical data on elephant population dynamics strongly influenced by human impacts (laying the foundation for modeling approaches), supporting predictions of evolutionary theory regarding demographic responses to ecological processes. PMID- 23341985 TI - Paleo-Balkan and Slavic contributions to the genetic pool of Moldavians: insights from the Y chromosome. AB - Moldova has a rich historical and cultural heritage, which may be reflected in the current genetic makeup of its population. To date, no comprehensive studies exist about the population genetic structure of modern Moldavians. To bridge this gap with respect to paternal lineages, we analyzed 37 binary and 17 multiallelic (STRs) polymorphisms on the non-recombining portion of the Y chromosome in 125 Moldavian males. In addition, 53 Ukrainians from eastern Moldova and 54 Romanians from the neighboring eastern Romania were typed using the same set of markers. In Moldavians, 19 Y chromosome haplogroups were identified, the most common being I M423 (20.8%), R-M17* (17.6%), R-M458 (12.8%), E-v13 (8.8%), R-M269* and R-M412* (both 7.2%). In Romanians, 14 haplogroups were found including I-M423 (40.7%), R M17* (16.7%), R-M405 (7.4%), E-v13 and R-M412* (both 5.6%). In Ukrainians, 13 haplogroups were identified including R-M17 (34.0%), I-M423 (20.8%), R-M269* (9.4%), N-M178, R-M458 and R-M73 (each 5.7%). Our results show that a significant majority of the Moldavian paternal gene pool belongs to eastern/central European and Balkan/eastern Mediterranean Y lineages. Phylogenetic and AMOVA analyses based on Y-STR loci also revealed that Moldavians are close to both eastern/central European and Balkan-Carpathian populations. The data correlate well with historical accounts and geographical location of the region and thus allow to hypothesize that extant Moldavian paternal genetic lineages arose from extensive recent admixture between genetically autochthonous populations of the Balkan-Carpathian zone and neighboring Slavic groups. PMID- 23341986 TI - Efficient arsenic metabolism--the AS3MT haplotype is associated with DNA methylation and expression of multiple genes around AS3MT. AB - Arsenic is a very potent toxicant. One major susceptibility factor for arsenic related toxicity is the efficiency of arsenic metabolism. The efficiency, in turn, is associated with non-coding single nucleotide polymorphisms (SNPs) in the arsenic methyltransferase AS3MT on chromosome 10q24. However, the mechanism of action for these SNPs is not yet clarified. Here, we assessed the influence of genetic variation in AS3MT on DNA methylation and gene expression within 10q24, in people exposed to arsenic in drinking water. DNA was extracted from peripheral blood from women in the Argentinean Andes (N = 103) and from cord blood from new borns in Bangladesh (N = 127). AS3MT SNPs were analyzed with Sequenom or Taqman assays. Whole genome epigenetic analysis with Infinium HumanMethylation450 BeadChip was performed on bisulphite-treated DNA. Whole genome gene expression analysis was performed with Illumina DirectHyb HumanHT-12 v4.0 on RNA from peripheral blood. Arsenic exposure was assessed by HPLC-ICPMS. In the Argentinean women, the major AS3MT haplotype, associated with more efficient arsenic metabolism, showed increased methylation of AS3MT (p = 10(-6)) and also differential methylation of several other genes within about 800 kilobasepairs: CNNM2 (p<10(-16)), NT5C2 (p<10(-16)), C10orf26 (p = 10(-8)), USMG5 (p = 10(-5)), TRIM8 (p = 10(-4)), and CALHM2 (p = 0.038) (adjusted for multiple comparisons). Similar, but weaker, associations between AS3MT haplotype and DNA methylation in 10q24 were observed in cord blood (Bangladesh). The haplotype-associated altered CpG methylation was correlated with reduced expression of AS3MT and CNNM2 (r(s) = -0.22 to -0.54), and with increased expression of NT5C2 and USMG5 (r(s) = 0.25 to 0.58). Taking other possibly influential variables into account in multivariable linear models did only to a minor extent alter the strength of the associations. In conclusion, the AS3MT haplotype status strongly predicted DNA methylation and gene expression of AS3MT as well as several genes in 10q24. This raises the possibility that several genes in this region are important for arsenic metabolism. PMID- 23341987 TI - Detection of alveolar fibrocytes in idiopathic pulmonary fibrosis and systemic sclerosis. AB - BACKGROUND: Fibrocytes are circulating precursors for fibroblasts. Blood fibrocytes are increased in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to determine whether alveolar fibrocytes are detected in broncho-alveolar lavage (BAL), to identify their prognostic value, and their potential association with culture of fibroblasts from BAL. METHODS: We quantified fibrocytes in BAL from 26 patients with IPF, 9 patients with Systemic Sclerosis(SSc)-interstitial lung disease (ILD), and 11 controls. BAL cells were cultured to isolate alveolar fibroblasts. RESULTS: Fibrocytes were detected in BAL in 14/26 IPF (54%) and 5/9 SSc patients (55%), and never in controls. Fibrocytes were in median 2.5% [0.4-19.7] and 3.0% [2.7-3.7] of BAL cells in IPF and SSc-ILD patients respectively. In IPF patients, the number of alveolar fibrocytes was correlated with the number of alveolar macrophages and was associated with a less severe disease but not with a better outcome. Fibroblasts were cultured from BAL in 12/26 IPF (46%), 5/9 SSc-ILD (65%) and never in controls. The detection of BAL fibrocytes did not predict a positive culture of fibroblasts. CONCLUSION: Fibrocytes were detected in BAL fluid in about half of the patients with IPF and SSc-ILD. Their number was associated with less severe disease in IPF patients and did not associate with the capacity to grow fibroblasts from BAL fluid. PMID- 23341988 TI - Genetic instability and intratumoral heterogeneity in neuroblastoma with MYCN amplification plus 11q deletion. AB - BACKGROUND/AIM: Genetic analysis in neuroblastoma has identified the profound influence of MYCN amplification and 11q deletion in patients' prognosis. These two features of high-risk neuroblastoma usually occur as mutually exclusive genetic markers, although in rare cases both are present in the same tumor. The purpose of this study was to characterize the genetic profile of these uncommon neuroblastomas harboring both these high-risk features. METHODS: We selected 18 neuroblastomas with MNA plus 11q loss detected by FISH. Chromosomal aberrations were analyzed using Multiplex Ligation-dependent Probe Amplification and Single Nucleotide Polymorphism array techniques. RESULTS AND CONCLUSION: This group of tumors has approximately the same high frequency of aberrations as found earlier for 11q deleted tumors. In some cases, DNA instability generates genetic heterogeneity, and must be taken into account in routine genetic diagnosis. PMID- 23341989 TI - Prognostic value of malondialdehyde serum levels in severe sepsis: a multicenter study. AB - OBJECTIVE: The oxidant/antioxidant state in septic patients has only been studied in small series. We wished to determine whether malondialdehyde (MDA) serum levels were associated with severity and 30-day mortality in a large series of patients with sepsis. METHODS: We performed an observational, prospective, multicenter study in six Spanish Intensive Care Units. Serum levels of MDA were measured in a total of 228 patients (145 survivors and 83 non-survivors) with severe sepsis and 100 healthy controls. RESULTS: Serum levels of MDA were higher in severe septic patients than in healthy controls. Non-surviving septic patients had higher MDA values than survivors. MDA serum levels were associated with severity markers (lactic acid, SOFA, APACHE-II) and coagulation indices. Regression analysis showed that MDA serum levels were associated with 30-day survival (Hazard ratio = 1.05; 95% confidence interval = 1.009-1.091; p = 0.016). Receiver operating characteristic analysis showed that the area under curve of MDA serum levels to predict 30-day survival was 0.62 (95% CI = 0.56-0.69; P = 0.002). The risk of death in septic patients with MDA serum levels above 4.11 nmol/mL was higher than in patients with lower values (Hazard Ratio = 2.43; 95% CI = 1.49-3.94; p<0.001). CONCLUSIONS: The novel findings of our study on severe septic patients, to our knowledge the largest series providing data on the oxidative state, are that elevated MDA serum levels probably represent an unbalanced oxidant state and are related with poor prognosis in patients with severe sepsis. PMID- 23341991 TI - Compliance of health care workers with hand hygiene practices: independent advantages of overt and covert observers. AB - BACKGROUND: Evaluation and feedback of hand hygiene (HH) compliance are important elements of the WHO multimodal strategy for hospital infection control. Overt observation is recommended, but it may be confounded by Hawthorne effect. Covert observation offers the opportunity to decrease observer bias. In this study we conducted a one year hospital-wide HH promotion program that included medical students (MS) as covert observers. METHODS: HH compliance for the five WHO indications was determined by trained and validated observers. The overt observers consisted of eleven infection control nurses (ICNs) and two unit HH ambassadors (UAs) in each of 83 wards. The covert observers consisted of nine MS during their rotating clinical clerkships. Feedback was provided to department heads and staff each quarter. RESULTS: Of the 23,333 HH observations 76.0% were by MS, 5.3% by ICNs and 18.7% by UAs. The annual compliance rates were MS 44.1%, ICNs 74.4% and UAs 94.1%; P<0.001. The MS found significantly lower annual compliance rates for 4/5 HH indications compared to ICNs and UAs; P<0.05. The ICNs reported significantly improvement from the first to the fourth quarter; P<0.001. This was associated with feedback from the MS of very poor compliance by nurses during the first quarter. CONCLUSIONS: Based on these findings we recommend a two-pronged approach to HH programs. The role of ICNs and UAs is to educate, serve as role models, establish, sustain good HH practices and provide direct feedback. The role of the covert observers is to measure compliance and provide independent feedback. PMID- 23341990 TI - The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. AB - BACKGROUND: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. METHODS AND FINDINGS: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patients delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. CONCLUSION: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects. PMID- 23341992 TI - Hypoxia/reoxygenation cardiac injury and regeneration in zebrafish adult heart. AB - AIMS: the adult zebrafish heart regenerates spontaneously after injury and has been used to study the mechanisms of cardiac repair. However, no zebrafish model is available that mimics ischemic injury in mammalian heart. We developed and characterized zebrafish cardiac injury induced by hypoxia/reoxygenation (H/R) and the regeneration that followed it. METHODS AND RESULTS: adult zebrafish were kept either in hypoxic (H) or normoxic control (C) water for 15 min; thereafter fishes were returned to C water. Within 2-6 hours (h) after reoxygenation there was evidence of cardiac oxidative stress by dihydroethidium fluorescence and protein nitrosylation, as well as of inflammation. We used Tg(cmlc2:nucDsRed) transgenic zebrafish to identify myocardial cell nuclei. Cardiomyocyte apoptosis and necrosis were evidenced by TUNEL and Acridine Orange (AO) staining, respectively; 18 h after H/R, 9.9+/-2.6% of myocardial cell nuclei were TUNEL(+) and 15.0+/ 2.5% were AO(+). At the 30-day (d) time point myocardial cell death was back to baseline (n = 3 at each time point). We evaluated cardiomyocyte proliferation by Phospho Histone H3 (pHH3) or Proliferating Cell Nuclear Antigen (PCNA) expression. Cardiomyocyte proliferation was apparent 18-24 h after H/R, it achieved its peak 3-7d later, and was back to baseline at 30d. 7d after H/R 17.4+/-2.3% of all cardiomyocytes were pHH3(+) and 7.4+/-0.6% were PCNA(+) (n = 3 at each time point). Cardiac function was assessed by 2D-echocardiography and Ventricular Diastolic and Systolic Areas were used to compute Fractional Area Change (FAC). FAC decreased from 29.3+/-2.0% in normoxia to 16.4+/-1.8% at 18 h after H/R; one month later ventricular function was back to baseline (n = 12 at each time point). CONCLUSIONS: zebrafish exposed to H/R exhibit evidence of cardiac oxidative stress and inflammation, myocardial cell death and proliferation. The initial decrease in ventricular function is followed by full recovery. This model more closely mimics reperfusion injury in mammals than other cardiac injury models. PMID- 23341993 TI - Impact of obesity on pregnancy outcome in different ethnic groups: calculating population attributable fractions. AB - OBJECTIVES: To quantify the proportion of adverse pregnancy outcome attributable to maternal obesity. DESIGN: Cross sectional analysis of routine obstetric dataset. SETTING: Guy's and St Thomas's NHS Foundation Trust (GSTFT). POPULATION: 23,668 women who had singleton deliveries at GSTFT between 2004 and 2008. METHODS: Logistic regression was used to estimate the association between BMI and outcome in different ethnic groups. Adjusted odds ratios, and the proportions of obese women, were used to calculate population attributable risk fractions (PAFs). MAIN OUTCOME MEASURES: (I) MATERNAL OUTCOMES: diabetes, type of delivery, post-partum haemorrhage, and preterm delivery. (ii) Perinatal outcomes: macrosomia, low birth weight, admission to neonatal intensive care/special care baby unit, and perinatal death. RESULTS: The prevalence of maternal obesity was 14%. Increasing BMI was independently associated with increasing risk of adverse obstetric and neonatal outcome. At the individual level, the effect of obesity on diabetes was highest in Asian women compared to white women (p for interaction = 0.03). Calculation of population attributable risk fractions demonstrated that one third of diabetes cases and one in six Caesarean sections could be avoided in this population if all obese women were of normal BMI. At the population level, the contribution of obesity to diabetes was highest for Black women (42%), and lowest for oriental women (8%). Seven percent of neonatal macrosomia in all the population, and 13% in Black mothers, were attributable to obesity. CONCLUSIONS: Preventing obesity prior to pregnancy will substantially reduce the burden of obstetric and neonatal morbidity in this population. This reduction will be higher in Black women. PMID- 23341994 TI - An examination of the generalizability of motor costs. AB - Most approaches to understanding human motor control assume that people maximize their rewards while minimizing their motor efforts. This tradeoff between potential rewards and a sense of effort is quantified with a cost function. While the rewards can change across tasks, our sense of effort is assumed to remain constant and characterize how the nervous system organizes motor control. As such, when a proposed cost function compares well with data it is argued to be the underlying cause of a motor behavior, and not simply a fit to the data. Implicit in this proposition is the assumption that this cost function can then predict new motor behaviors. Here we examined this idea and asked whether an inferred cost function in one setting could explain subject's behavior in settings that differed dynamically but had identical rewards. We found that the pattern of behavior observed across settings was similar to our predictions of optimal behavior. However, we could not conclude that this behavior was consistent with a conserved sense of effort. These results suggest that the standard forms for quantifying cost may not be sufficient to accurately examine whether or not human motor behavior abides by optimality principles. PMID- 23341995 TI - Warming rather than increased precipitation increases soil recalcitrant organic carbon in a semiarid grassland after 6 years of treatments. AB - Improved understanding of changes in soil recalcitrant organic carbon (C) in response to global warming is critical for predicting changes in soil organic C (SOC) storage. Here, we took advantage of a long-term field experiment with increased temperature and precipitation to investigate the effects of warming, increased precipitation and their interactions on SOC fraction in a semiarid Inner Mongolian grassland of northern China since April 2005. We quantified labile SOC, recalcitrant SOC and stable SOC at 0-10 and 10-20 cm depths. Results showed that neither warming nor increased precipitation affected total SOC and stable SOC at either depth. Increased precipitation significantly increased labile SOC at the 0-10 cm depth. Warming decreased labile SOC (P = 0.038) and marginally but significantly increased recalcitrant SOC at the 10-20 cm depth (P = 0.082). In addition, there were significant interactive effects of warming and increased precipitation on labile SOC and recalcitrant SOC at the 0-10 cm depth (both P<0.05), indicating that that results from single factor experiments should be treated with caution because of multi-factor interactions. Given that the absolute increase of SOC in the recalcitrant SOC pool was much greater than the decrease in labile SOC, and that the mean residence time of recalcitrant SOC is much greater, our results suggest that soil C storage at 10-20 cm depth may increase with increasing temperature in this semiarid grassland. PMID- 23341996 TI - Carbon and nitrogen isotopic survey of northern peruvian plants: baselines for paleodietary and paleoecological studies. AB - The development of isotopic baselines for comparison with paleodietary data is crucial, but often overlooked. We review the factors affecting the carbon (delta(13)C) and nitrogen (delta(15)N) isotopic compositions of plants, with a special focus on the carbon and nitrogen isotopic compositions of twelve different species of cultivated plants (n = 91) and 139 wild plant species collected in northern Peru. The cultivated plants were collected from nineteen local markets. The mean delta(13)C value for maize (grain) was -11.8+/-0.4 0/00 (n = 27). Leguminous cultigens (beans, Andean lupin) were characterized by significantly lower delta(15)N values and significantly higher %N than non leguminous cultigens. Wild plants from thirteen sites were collected in the Moche River Valley area between sea level and ~4,000 meters above sea level (masl). These sites were associated with mean annual precipitation ranging from 0 to 710 mm. Plants growing at low altitude sites receiving low amounts of precipitation were characterized by higher delta(15)N values than plants growing at higher altitudes and receiving higher amounts of precipitation, although this trend dissipated when altitude was >2,000 masl and MAP was >400 mm. For C(3) plants, foliar delta(13)C was positively correlated with altitude and precipitation. This suggests that the influence of altitude may overshadow the influence of water availability on foliar delta(13)C values at this scale. PMID- 23341997 TI - Polymorphisms in the gene regions of the adaptor complex LAMTOR2/LAMTOR3 and their association with breast cancer risk. AB - BACKGROUND: The late endosomal LAMTOR complex serves as a convergence point for both the RAF/MEK/ERK and the PI3K/AKT/mTOR pathways. Interestingly, both of these signalling cascades play a significant role in the aetiology of breast cancer. Our aim was to address the possible role of genetic polymorphisms in LAMTOR2 and LAMTOR3 as genetic risk factors for breast cancer. METHODOLOGY/RESULTS: We sequenced the exons and exon-intron boundaries of LAMTOR2 (p14) and LAMTOR3 (MP1) in 50 prospectively collected pairs of cancerous tissue and blood samples from breast cancer patients and compared their genetic variability. We found one single nucleotide polymorphism (SNP) in LAMTOR2 (rs7541) and two SNPs in LAMTOR3 (rs2298735 and rs148972953) in both tumour and blood samples, but no somatic mutations in cancerous tissues. In addition, we genotyped all three SNPs in 296 samples from the Risk Prediction of Breast Cancer Metastasis Study and found evidence of a genetic association between rs148972953 and oestrogen (ER) and progesterone receptor negative status (PR) (ER: OR = 3.60 (1.15-11.28); PR: OR = 4.27 (1.43-12.72)). However, when we additionally genotyped rs148972953 in the MARIE study including 2,715 breast cancer cases and 5,216 controls, we observed neither a difference in genotype frequencies between patients and controls nor was the SNP associated with ER or PR. Finally, all three SNPs were equally frequent in breast cancer samples and female participants (n = 640) of the population-based SAPHIR Study. CONCLUSIONS: The identified polymorphisms in LAMTOR2 and LAMTOR3 do not seem to play a relevant role in breast cancer. Our work does not exclude a role of other not yet identified SNPs or that the here annotated polymorphism may in fact play a relevant role in other diseases. Our results underscore the importance of replication in association studies. PMID- 23341999 TI - Mining of novel thermo-stable cellulolytic genes from a thermophilic cellulose degrading consortium by metagenomics. AB - In this study, metagenomics was applied to characterize the microbial community and to discover carbohydrate-active genes of an enriched thermophilic cellulose degrading sludge. The 16S analysis showed that the sludge microbiome was dominated by genus of cellulolytic Clostridium and methanogenesis Methanothermobacter. In order to retrieve genes from the metagenome, de novo assembly of the 11,930,760 Illumina 100 bp paired-end reads (totally 1.2 Gb) was carried out. 75% of all reads was utilized in the de novo assembly. 31,499 ORFs (Open Reading Frame) with an average length of 852 bp were predicted from the assembly; and 64% of these ORFs were predicted to present full-length genes. Based on the Hidden Markol Model, 253 of the predicted thermo-stable genes were identified as putatively carbohydrate-active. Among them the relative dominance of GH9 (Glycoside Hydrolase) and corresponding CBM3 (Carbohydrate Binding Module) revealed a cellulosome-based attached metabolism of polysaccharide in the thermophilic sludge. The putative carbohydrate-active genes ranged from 20% to 100% amino acid sequence identity to known proteins in NCBI nr database, with half of them showed less than 50% similarity. In addition, the coverage of the genes (in terms of ORFs) identified in the sludge were developed into three clear trends (112*, 29* and 8*) in which 85% of the high coverage trend (112*) mainly consisted of phylum of Firmicutes while 49.3% of the 29* trend was affiliated to the phylum of Chloroflexi. PMID- 23341998 TI - Regulation of mitochondrial morphogenesis by annexin A6. AB - Mitochondrial homeostasis is critical in meeting cellular energy demands, shaping calcium signals and determining susceptibility to apoptosis. Here we report a role for anxA6 in the regulation of mitochondrial morphogenesis, and show that in cells lacking anxA6 mitochondria are fragmented, respiration is impaired and mitochondrial membrane potential is reduced. In fibroblasts from AnxA6(-/-) mice, mitochondrial Ca(2+) uptake is reduced and cytosolic Ca(2+) transients are elevated. These observations led us to investigate possible interactions between anxA6 and proteins with roles in mitochondrial fusion and fission. We found that anxA6 associates with Drp1 and that mitochondrial fragmentation in AnxA6(-/-) fibroblasts was prevented by the Drp1 inhibitor mdivi-1. In normal cells elevation of intracellular Ca(2+) disrupted the interaction between anxA6 and Drp1, displacing anxA6 to the plasma membrane and promoting mitochondrial fission. Our results suggest that anxA6 inhibits Drp1 activity, and that Ca(2+) binding to anxA6 relieves this inhibition to permit Drp1-mediated mitochondrial fission. PMID- 23342000 TI - Inferring hierarchical orthologous groups from orthologous gene pairs. AB - Hierarchical orthologous groups are defined as sets of genes that have descended from a single common ancestor within a taxonomic range of interest. Identifying such groups is useful in a wide range of contexts, including inference of gene function, study of gene evolution dynamics and comparative genomics. Hierarchical orthologous groups can be derived from reconciled gene/species trees but, this being a computationally costly procedure, many phylogenomic databases work on the basis of pairwise gene comparisons instead ("graph-based" approach). To our knowledge, there is only one published algorithm for graph-based hierarchical group inference, but both its theoretical justification and performance in practice are as of yet largely uncharacterised. We establish a formal correspondence between the orthology graph and hierarchical orthologous groups. Based on that, we devise GETHOGs ("Graph-based Efficient Technique for Hierarchical Orthologous Groups"), a novel algorithm to infer hierarchical groups directly from the orthology graph, thus without needing gene tree inference nor gene/species tree reconciliation. GETHOGs is shown to correctly reconstruct hierarchical orthologous groups when applied to perfect input, and several extensions with stringency parameters are provided to deal with imperfect input data. We demonstrate its competitiveness using both simulated and empirical data. GETHOGs is implemented as a part of the freely-available OMA standalone package (http://omabrowser.org/standalone). Furthermore, hierarchical groups inferred by GETHOGs ("OMA HOGs") on >1,000 genomes can be interactively queried via the OMA browser (http://omabrowser.org). PMID- 23342001 TI - Record-breaking early flowering in the eastern United States. AB - Flowering times are well-documented indicators of the ecological effects of climate change and are linked to numerous ecosystem processes and trophic interactions. Dozens of studies have shown that flowering times for many spring flowering plants have become earlier as a result of recent climate change, but it is uncertain if flowering times will continue to advance as temperatures rise. Here, we used long-term flowering records initiated by Henry David Thoreau in 1852 and Aldo Leopold in 1935 to investigate this question. Our analyses demonstrate that record-breaking spring temperatures in 2010 and 2012 in Massachusetts, USA, and 2012 in Wisconsin, USA, resulted in the earliest flowering times in recorded history for dozens of spring-flowering plants of the eastern United States. These dramatic advances in spring flowering were successfully predicted by historical relationships between flowering and spring temperature spanning up to 161 years of ecological change. These results demonstrate that numerous temperate plant species have yet to show obvious signs of physiological constraints on phenological advancement in the face of climate change. PMID- 23342002 TI - MAIT cell recognition of MR1 on bacterially infected and uninfected cells. AB - Mucosal-associated invariant T cells are a unique population of T cells that express a semi-invariant alphabeta TCR and are restricted by the MHC class I related molecule MR1. MAIT cells recognize uncharacterized ligand(s) presented by MR1 through the cognate interaction between their TCR and MR1. To understand how the MAIT TCR recognizes MR1 at the surface of APCs cultured both with and without bacteria, we undertook extensive mutational analysis of both the MAIT TCR and MR1 molecule. We found differential contribution of particular amino acids to the MAIT TCR-MR1 interaction based upon the presence of bacteria, supporting the hypothesis that the structure of the MR1 molecules with the microbial-derived ligand(s) differs from the one with the endogenous ligand(s). Furthermore, we demonstrate that microbial-derived ligand(s) is resistant to proteinase K digestion and does not extract with common lipids, suggesting an unexpected class of antigen(s) might be recognized by this unique lymphocyte population. PMID- 23342003 TI - PIP5KIbeta selectively modulates apical endocytosis in polarized renal epithelial cells. AB - Localized synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)] at clathrin coated pits (CCPs) is crucial for the recruitment of adaptors and other components of the internalization machinery, as well as for regulating actin dynamics during endocytosis. PtdIns(4,5)P(2) is synthesized from phosphatidylinositol 4-phosphate by any of three phosphatidylinositol 5-kinase type I (PIP5KI) isoforms (alpha, beta or gamma). PIP5KIbeta localizes almost exclusively to the apical surface in polarized mouse cortical collecting duct cells, whereas the other isoforms have a less polarized membrane distribution. We therefore investigated the role of PIP5KI isoforms in endocytosis at the apical and basolateral domains. Endocytosis at the apical surface is known to occur more slowly than at the basolateral surface. Apical endocytosis was selectively stimulated by overexpression of PIP5KIbeta whereas the other isoforms had no effect on either apical or basolateral internalization. We found no difference in the affinity for PtdIns(4,5)P(2)-containing liposomes of the PtdIns(4,5)P(2) binding domains of epsin and Dab2, consistent with a generic effect of elevated PtdIns(4,5)P(2) on apical endocytosis. Additionally, using apical total internal reflection fluorescence imaging and electron microscopy we found that cells overexpressing PIP5KIbeta have fewer apical CCPs but more internalized coated structures than control cells, consistent with enhanced maturation of apical CCPs. Together, our results suggest that synthesis of PtdIns(4,5)P(2) mediated by PIP5KIbeta is rate limiting for apical but not basolateral endocytosis in polarized kidney cells. PtdIns(4,5)P(2) may be required to overcome specific structural constraints that limit the efficiency of apical endocytosis. PMID- 23342004 TI - Kar3Vik1 uses a minus-end directed powerstroke for movement along microtubules. AB - We have used cryo-electron microscopy (cryo-EM) and helical averaging to examine the 3-D structure of the heterodimeric kinesin-14 Kar3Vik1 complexed to microtubules at a resolution of 2.5 nm. 3-D maps were obtained at key points in Kar3Vik1's nucleotide hydrolysis cycle to gain insight into the mechanism that this motor uses for retrograde motility. In all states where Kar3Vik1 maintained a strong interaction with the microtubule, we found, as observed by cryo-EM, that the motor bound with one head domain while the second head extended outwards. 3-D reconstructions of Kar3Vik1-microtubule complexes revealed that in the nucleotide free state, the motor's coiled-coil stalk points toward the plus-end of the microtubule. In the ATP-state, the outer head is shown to undergo a large rotation that reorients the stalk ~75 degrees to point toward the microtubule minus-end. To determine which of the two heads binds to tubulin in each nucleotide state, we employed specific Nanogold(r)-labeling of Vik1. The resulting maps confirmed that in the nucleotide-free, ATP and ADP+Pi states, Kar3 maintains contact with the microtubule surface, while Vik1 extends away from the microtubule and tracks with the coiled-coil as it rotates towards the microtubule minus-end. While many previous investigations have focused on the mechanisms of homodimeric kinesins, this work presents the first comprehensive study of the powerstroke of a heterodimeric kinesin. The stalk rotation shown here for Kar3Vik1 is highly reminiscent of that reported for the homodimeric kinesin-14 Ncd, emphasizing the conservation of a mechanism for minus-end directed motility. PMID- 23342005 TI - In vivo targeting of ADAM9 gene expression using lentivirus-delivered shRNA suppresses prostate cancer growth by regulating REG4 dependent cell cycle progression. AB - Cancer cells respond to stress by activating a variety of survival signaling pathways. A disintegrin and metalloproteinase (ADAM) 9 is upregulated during cancer progression and hormone therapy, functioning in part through an increase in reactive oxygen species. Here, we present in vitro and in vivo evidence that therapeutic targeting of ADAM9 gene expression by lentivirus-delivered small hairpin RNA (shRNA) significantly inhibited proliferation of human prostate cancer cell lines and blocked tumor growth in a murine model of prostate cancer bone metastasis. Cell cycle studies confirmed an increase in the G1-phase and decrease in the S-phase population of cancer cells under starvation stress conditions, which correlated with elevated intracellular superoxide levels. Microarray data showed significantly decreased levels of regenerating islet derived family member 4 (REG4) expression in prostate cancer cells with knockdown of ADAM9 gene expression. This REG4 downregulation also resulted in induction of expression of p21(Cip1/WAF1), which negatively regulates cyclin D1 and blocks the G1/S transition. Our data reveal a novel molecular mechanism of ADAM9 in the regulation of prostate cancer cell proliferation, and suggests a combined modality of ADAM9 shRNA gene therapy and cytotoxic agents for hormone refractory and bone metastatic prostate cancer. PMID- 23342007 TI - Characterisation of the maternal response to chronic phase shifts during gestation in the rat: implications for fetal metabolic programming. AB - Disrupting maternal circadian rhythms through exposure to chronic phase shifts of the photoperiod has lifelong consequences for the metabolic homeostasis of the fetus, such that offspring develop increased adiposity, hyperinsulinaemia and poor glucose and insulin tolerance. In an attempt to determine the mechanisms by which these poor metabolic outcomes arise, we investigated the impact of chronic phase shifts (CPS) on maternal and fetal hormonal, metabolic and circadian rhythms. We assessed weight gain and food consumption of dams exposed to either CPS or control lighting conditions throughout gestation. At day 20, dams were assessed for plasma hormone and metabolite concentrations and glucose and insulin tolerance. Additionally, the expression of a range of circadian and metabolic genes was assessed in maternal, placental and fetal tissue. Control and CPS dams consumed the same amount of food, yet CPS dams gained 70% less weight during the first week of gestation. At day 20, CPS dams had reduced retroperitoneal fat pad weight (-15%), and time-of-day dependent decreases in liver weight, whereas fetal and placental weight was not affected. Melatonin secretion was not altered, yet the timing of corticosterone, leptin, glucose, insulin, free fatty acids, triglycerides and cholesterol concentrations were profoundly disrupted. The expression of gluconeogenic and circadian clock genes in maternal and fetal liver became either arrhythmic or were in antiphase to the controls. These results demonstrate that disruptions of the photoperiod can severely disrupt normal circadian profiles of plasma hormones and metabolites, as well as gene expression in maternal and fetal tissues. Disruptions in the timing of food consumption and the downstream metabolic processes required to utilise that food, may lead to reduced efficiency of growth such that maternal weight gain is reduced during early embryonic development. It is these perturbations that may contribute to the programming of poor metabolic homeostasis in the offspring. PMID- 23342006 TI - Green tea polyphenols reduced fat deposits in high fat-fed rats via erk1/2 PPARgamma-adiponectin pathway. AB - OBJECTIVE: Hypoadiponectinemia contributes to the development of obesity and related disorders such as diabetes, hyperlipidemia, and cardiovascular diseases. In this study we investigated the effects of green tea polyphenols (GTPs) on adiponectin levels and fat deposits in high fat (HF) fed rats, the mechanism of signaling pathway was explored as well. METHODS AND RESULTS: Male Wistar rats were fed with high-fat diet. GTPs (0.8, 1.6, 3.2 g/L) were administered via drinking water. Serum adiponectin and insulin were measured by ELISA, mRNA levels of adiponectin and PPARgamma in visceral adipose tissue (VAT) were determined by Real-time PCR, protein levels of PPARgamma, phospho (p) - PPARgamma, extracellular signal regulated kinase (erk) 1/2 and p-erk1/2 in VAT were determined by western blot. GTPs treatment attenuated the VAT accumulation, hypoadiponectinemia and the decreased mRNA level of adiponectin in VAT induced by HF. Decreased expression and increased phosphorylation of PPARgamma (the master regulator of adiponectin), and increased activation of erk1/2 were observed in HF group, and these effects could be alleviated by GTPs treatment. To explore the underlying mechanism, VAT was cultured in DMEM with high glucose to mimic the hyperglycemia condition in vitro. Similar to the results of in vivo study, decreased adiponectin levels, decreased expression and increased phosphorylation of PPARgamma, and elevated erk1/2 phosphorylation in cultured VAT were observed. These effects could be ameliorated by co-treatment with GTPs or PD98059 (a selective inhibitor of erk1/2). CONCLUSION: GTPs reduced fat deposit, ameliorated hypoadiponectinemia in HF-fed rats, and relieved high glucose-induced adiponectin decrease in VAT in vitro. The signaling pathway analysis indicated that PPARgamma regulation mediated via erk1/2 pathway was involved. PMID- 23342008 TI - Breast feeding increases vasoconstriction induced by electrical field stimulation in rat mesenteric artery. Role of neuronal nitric oxide and ATP. AB - OBJECTIVES: The aim of this study was to investigate in rat mesenteric artery whether breast feeding (BF) affects the vasomotor response induced by electrical field stimulation (EFS), participation by different innervations in the EFS induced response and the mechanism/s underlying these possible modifications. METHODS: Experiments were performed in female Sprague-Dawley rats (3 months old), divided into three groups: Control (in oestrous phase), mothers after 21 days of BF, and mothers that had recovered their oestral cycle (After BF, in oestrous phase). Vasomotor response to EFS, noradrenaline (NA) and nitric oxide (NO) donor DEA-NO were studied. Neuronal NO synthase (nNOS) and phosphorylated nNOS (P-nNOS) protein expression were analysed and NO, superoxide anion (O(2)(.-)), NA and ATP releases were also determined. RESULTS: EFS-induced contraction was higher in the BF group, and was recovered after BF. 1 umol/L phentolamine decreased the response to EFS similarly in control and BF rats. NA vasoconstriction and release were similar in both experimental groups. ATP release was higher in segments from BF rats. 0.1 mmol/L L-NAME increased the response to EFS in both control and BF rats, but more so in control animals. BF decreased NO release and did not modify O(2)(.-) production. Vasodilator response to DEA-NO was similar in both groups, while nNOS and P-nNOS expressions were decreased in segments from BF animals. CONCLUSION: Breast feeding increases EFS-induced contraction in mesenteric arteries, mainly through the decrease of neuronal NO release mediated by decreased nNOS and P-nNOS expression. Sympathetic function is increased through the increased ATP release in BF rats. PMID- 23342009 TI - Localizing non-retinotopically moving objects. AB - How does the brain determine the position of moving objects? It turns out to be rather complex to answer this question when we realize that the brain has to solve the motion correspondence problem in two kinds of reference frames: Retinotopic and non-retinotopic ones. We show that visual objects are mislocalized along a non-retinotopic motion direction. Observers viewed two successive movie frames each consisting of an outlined square and two target elements inside the square. In the non-retinotopic condition the elements as well as the square moved vertically while two bars also centripetally or centrifugally moved. In the retinotopic condition the vertical movement of them was removed from the stimuli. The task of the observers was to judge a relative position of the elements. Consequently, the elements were mislocalized in the direction of both retinotopic and non-retinotopic motion, although the mislocalization was significantly larger in the retinotopic than in the non-retinotopic conditions. The results suggest that non-retinotopic as well as retinotopic motion processing contributes to the determination of perceived positions of moving objects. PMID- 23342010 TI - Glytube: a conical tube and parafilm M-based method as a simplified device to artificially blood-feed the dengue vector mosquito, Aedes aegypti. AB - Aedes aegypti, the main vector of dengue virus, requires a blood meal to produce eggs. Although live animals are still the main blood source for laboratory colonies, many artificial feeders are available. These feeders are also the best method for experimental oral infection of Ae. aegypti with Dengue viruses. However, most of them are expensive or laborious to construct. Based on principle of Rutledge-type feeder, a conventional conical tube, glycerol and Parafilm-M were used to develop a simple in-house feeder device. The blood feeding efficiency of this apparatus was compared to a live blood source, mice, and no significant differences (p = 0.1189) were observed between artificial-fed (51.3% of engorgement) and mice-fed groups (40.6%). Thus, an easy to assemble and cost effective artificial feeder, designated "Glytube" was developed in this report. This simple and efficient feeding device can be built with common laboratory materials for research on Ae. aegypti. PMID- 23342012 TI - Detecting cheaters without thinking: testing the automaticity of the cheater detection module. AB - Evolutionary psychologists have suggested that our brain is composed of evolved mechanisms. One extensively studied mechanism is the cheater detection module. This module would make people very good at detecting cheaters in a social exchange. A vast amount of research has illustrated performance facilitation on social contract selection tasks. This facilitation is attributed to the alleged automatic and isolated operation of the module (i.e., independent of general cognitive capacity). This study, using the selection task, tested the critical automaticity assumption in three experiments. Experiments 1 and 2 established that performance on social contract versions did not depend on cognitive capacity or age. Experiment 3 showed that experimentally burdening cognitive resources with a secondary task had no impact on performance on the social contract version. However, in all experiments, performance on a non-social contract version did depend on available cognitive capacity. Overall, findings validate the automatic and effortless nature of social exchange reasoning. PMID- 23342011 TI - The pan-genome of the animal pathogen Corynebacterium pseudotuberculosis reveals differences in genome plasticity between the biovar ovis and equi strains. AB - Corynebacterium pseudotuberculosis is a facultative intracellular pathogen and the causative agent of several infectious and contagious chronic diseases, including caseous lymphadenitis, ulcerative lymphangitis, mastitis, and edematous skin disease, in a broad spectrum of hosts. In addition, Corynebacterium pseudotuberculosis infections pose a rising worldwide economic problem in ruminants. The complete genome sequences of 15 C. pseudotuberculosis strains isolated from different hosts and countries were comparatively analyzed using a pan-genomic strategy. Phylogenomic, pan-genomic, core genomic, and singleton analyses revealed close relationships among pathogenic corynebacteria, the clonal like behavior of C. pseudotuberculosis and slow increases in the sizes of pan genomes. According to extrapolations based on the pan-genomes, core genomes and singletons, the C. pseudotuberculosis biovar ovis shows a more clonal-like behavior than the C. pseudotuberculosis biovar equi. Most of the variable genes of the biovar ovis strains were acquired in a block through horizontal gene transfer and are highly conserved, whereas the biovar equi strains contain great variability, both intra- and inter-biovar, in the 16 detected pathogenicity islands (PAIs). With respect to the gene content of the PAIs, the most interesting finding is the high similarity of the pilus genes in the biovar ovis strains compared with the great variability of these genes in the biovar equi strains. Concluding, the polymerization of complete pilus structures in biovar ovis could be responsible for a remarkable ability of these strains to spread throughout host tissues and penetrate cells to live intracellularly, in contrast with the biovar equi, which rarely attacks visceral organs. Intracellularly, the biovar ovis strains are expected to have less contact with other organisms than the biovar equi strains, thereby explaining the significant clonal-like behavior of the biovar ovis strains. PMID- 23342013 TI - Multi-functional roles of chitosan as a potential protective agent against obesity. AB - Chitosan, a natural polysaccharide comprising copolymers of glucosamine and N acetylglucosamine, has been shown to have anti-obesity properties. Two experiments (Exp. 1 and Exp. 2) were performed to determine the role of chitosan on dietary intake, body weight gain, and fat deposition in a pig model, as well as identifying potential mechanisms underlying the anti-obesity effect of chitosan. In Exp. 1, the nutrient digestibility experiment, 16 pigs (n = 4/treatment) were randomly allocated to one of four dietary treatments as follows: 1) basal diet; 2) basal diet plus 300 ppm chitosan; 3) basal diet plus 600 ppm chitosan; 4) basal diet plus 1200 ppm chitosan. The main observation was that crude fat digestibility was lower in the 1200 ppm chitosan group when compared with the control group (P<0.05). In Exp. 2, a total of 80 pigs (n = 20/treatment) were offered identical dietary treatments to that offered to animals in Exp. 1. Blood samples were collected on day 0, day 35 and at the end of the experiment (day 57). Animals offered diets containing 1200 ppm chitosan had a lower daily dietary intake (P<0.001) and body weight gain (P<0.001) from day 35 to 57 when compared with all the other treatment groups. Animals offered diets containing 1200 ppm chitosan had a significantly lower final body weight (P<0.01) when compared with all the other treatment groups. The decreased dietary intake observed in the 1200 ppm chitosan group was associated with increased serum leptin concentrations (P<0.001) and a decrease in serum C-reactive protein (CRP) concentrations (P<0.05). In conclusion, the results of this study highlight novel endocrine mechanisms involving the modulation of serum leptin and CRP concentrations by which chitosan exhibits anti-obesity properties in vivo. PMID- 23342014 TI - PhoB regulates the survival of Bacteroides fragilis in peritoneal abscesses. AB - In response to phosphate limitation, bacteria employ the Pho regulon, a specific regulatory network for phosphate acquisition. The two-component signal transduction system of PhoRB plays a crucial role in the induction of Pho regulon genes, leading to the adaptation to phosphate starvation. Herein, we identified the PhoRB system in Bacteroides fragilis, a commensal gut bacterium, and evaluated its role in gut colonization and survival in peritoneal abscesses. BF1575 and BF1576 encoded PhoR (sensor histidine kinase) and PhoB (response regulator) in the sequenced B. fragilis strain YCH46, respectively. Transcriptome analysis revealed that deletion of phoB affected the expression of 585 genes (more than 4-fold change) in B. fragilis, which included genes for stress response (chaperons and heat shock proteins), virulence (capsular polysaccharide biosynthesis) and phosphate metabolism. Deletion of phoB reduced the ability of the bacterium to persist in peritoneal abscesses induced by an intra-abdominal challenge of B. fragilis. Furthermore, PhoB was necessary for survival of this anaerobe in peritoneal abscesses but not for in vitro growth in rich media or in intestinal colonization. These results indicate that PhoB plays an important role in the survival of B. fragilis under stressful extraintestinal conditions. PMID- 23342016 TI - Chaetognatha of the Namibian upwelling region: taxonomy, distribution and trophic position. AB - In October 2010, the vertical distribution, biodiversity and maturity stages of Chaetognatha species were investigated at four stations located off Walvis Bay, Namibia. Seventeen species were detected and classified as pelagic, shallow mesopelagic, deep-mesopelagic and bathypelagic species based upon the weighted mean depth derived from their average vertical distribution. High abundances of Chaetognatha were found in the upper 100 m at all stations of the Walvis Bay transect with a maximum value of 20837 ind. 1000 m(-3) at the outer shelf station near the surface. The community was dominated by species of the Serratodentata group. Furthermore, the distribution of Chaetognatha did not seem to be influenced by low oxygen concentrations. Stable isotope ratios of carbon and nitrogen in Chaetognatha were determined for seven different areas located off northern Namibia. The values of delta(15)N ranged from 6.05 0/00 to 11.39 0/00, while the delta(13)C values varied between -23.89 0/00 and -17.03 0/00. The highest values for delta(15)N were observed at the Walvis Bay shelf break station. The lowest delta(13)C values were found at the Rocky Point offshore station, which was statistically different from all other areas. Stable isotopes of carbon and nitrogen were determined for four taxa (Sagitta minima, Planctonis group, Sagitta enflata, Sagitta decipiens). In this case, the delta(15)N values ranged from 6.17 0/00 to 10.38 0/00, whereas the delta(13)C values varied from 22.70 0/00 to -21.56 0/00. The lowest delta(15)N values were found for S. minima. The C- and N-content revealed maximum C-values for S. decipiens and maximum N values for the Planctonis group. The C:N ratio of Chaetognatha ranged between 5.25 and 6.20. Overall, Chaetognatha are a diverse group in the pelagic food web of the Benguela Upwelling System and act as competitors of fish larvae and jelly fish by preying on copepods. PMID- 23342015 TI - Female Nur77-deficient mice show increased susceptibility to diet-induced obesity. AB - Adipose tissue is essential in the regulation of body weight. The key process in fat catabolism and the provision of energy substrate during times of nutrient deprivation or enhanced energy demand is the hydrolysis of triglycerides and the release of fatty acids and glycerol. Nur77 is a member of the NR4A subfamily of nuclear receptors that plays an important metabolic role, modulating hepatic glucose metabolism and lipolysis in muscle. However, its endogenous role on white adipose tissue, as well as the gender dependency of these mechanisms, remains largely unknown. Male and female wild type and Nur77 deficient mice were fed with a high fat diet (45% calories from fat) for 4 months. Mice were analyzed in vivo with the indirect calorimetry system, and tissues were analyzed by real-time PCR and Western blot analysis. Female, but not male Nur77 deficient mice, gained more weight and fat mass when compared to wild type mice fed with high fat diet, which can be explained by decreased energy expenditure. The lack of Nur77 also led to a decreased pHSL/HSL ratio in white adipose tissue and increased expression of CIDEA in brown adipose tissue of female Nur77 deficient mice. Overall, these findings suggest that Nur77 is an important physiological modulator of lipid metabolism in adipose tissue and that there are gender differences in the sensitivity to deletion of the Nur77 signaling. The decreased energy expenditure and the actions of Nur77 on liver, muscle, brown and white adipose tissue contribute to the increased susceptibility to diet-induced obesity in females lacking Nur77. PMID- 23342017 TI - Interspecific interactions between Phragmites australis and Spartina alterniflora along a tidal gradient in the Dongtan wetland, Eastern China. AB - The invasive species Spartina alterniora Loisel was introduced to the eastern coast of China in the 1970s and 1980s for the purposes of land reclamation and the prevention of soil erosion. The resulting interspecific competition had an important influence on the distribution of native vegetation, which makes studying the patterns and mechanisms of the interactions between Spartina alterniora Loisel and the native species Phragmites australis (Cav.) Trin ex Steud in this region very important. There have been some researches on the interspecific interactions between P. australis and S. alterniora in the Dongtan wetland of Chongming, east China, most of which has focused on the comparison of their physiological characteristics. In this paper, we conducted a neighbor removal experiment along a tidal gradient to evaluate the relative competitive abilities of the two species by calculating their relative neighbor effect (RNE) index. We also looked at the influence of environmental stress and disturbance on the competitive abilities of the two species by comparing interaction strength (I) among different tidal zones both for P. australis and S. alterniora. Finally, we measured physiological characteristics of the two species to assess the physiological mechanisms behind their different competitive abilities. Both negative and positive interactions were found between P. australis and S. alterniora along the environmental gradient. When the direction of the competitive intensity index for P. australis and S. alterniora was consistent, the competitive or facilitative effect of S. alterniora on P. australis was stronger than that of P. australis on S. alterniora. The interspecific interactions of P. australis and S. alterniora varied with environmental conditions, as well as with the method used, to measure interspecific interactions. PMID- 23342018 TI - Germline DNA copy number aberrations identified as potential prognostic factors for breast cancer recurrence. AB - Breast cancer recurrence (BCR) is a common treatment outcome despite curative intent primary treatment of non-metastatic breast cancer. Currently used prognostic and predictive factors utilize tumor-based markers, and are not optimal determinants of risk of BCR. Germline-based copy number aberrations (CNAs) have not been evaluated as determinants of predisposition to experience BCR. In this study, we accessed germline DNA from 369 female breast cancer subjects who received curative-intent primary treatment following diagnosis. Of these, 155 experienced BCR and 214 did not, after a median duration of follow up after breast cancer diagnosis of 6.35 years (range = 0.60-21.78) and 8.60 years (range = 3.08-13.57), respectively. Whole genome CNA genotyping was performed on the Affymetrix SNP array 6.0 platform. CNAs were identified using the SNP-Fast Adaptive States Segmentation Technique 2 algorithm implemented in Nexus Copy Number 6.0. Six samples were removed due to poor quality scores, leaving 363 samples for further analysis. We identified 18,561 CNAs with >=1 kb as a predefined cut-off for observed aberrations. Univariate survival analyses (log rank tests) identified seven CNAs (two copy number gains and five copy neutral loss of heterozygosities, CN-LOHs) showing significant differences (P<2.01*10( 5)) in recurrence-free survival (RFS) probabilities with and without CNAs.We also observed three additional but distinct CN-LOHs showing significant differences in RFS probabilities (P<2.86*10(-5)) when analyses were restricted to stratified cases (luminal A, n = 208) only. After adjusting for tumor stage and grade in multivariate analyses (Cox proportional hazards models), all the CNAs remained strongly associated with the phenotype of BCR. Of these, we confirmed three CNAs at 17q11.2, 11q13.1 and 6q24.1 in representative samples using independent genotyping platforms. Our results suggest further investigations on the potential use of germline DNA variations as prognostic markers in cancer-associated phenotypes. PMID- 23342019 TI - Comparing cognitive and somatic symptoms of depression in myocardial infarction patients and depressed patients in primary and mental health care. AB - Depression in myocardial infarction patients is often a first episode with a late age of onset. Two studies that compared depressed myocardial infarction patients to psychiatric patients found similar levels of somatic symptoms, and one study reported lower levels of cognitive/affective symptoms in myocardial infarction patients. We hypothesized that myocardial infarction patients with first depression onset at a late age would experience fewer cognitive/affective symptoms than depressed patients without cardiovascular disease. Combined data from two large multicenter depression studies resulted in a sample of 734 depressed individuals (194 myocardial infarction, 214 primary care, and 326 mental health care patients). A structured clinical interview provided information about depression diagnosis. Summed cognitive/affective and somatic symptom levels were compared between groups using analysis of covariance, with and without adjusting for the effects of recurrence and age of onset. Depressed myocardial infarction and primary care patients reported significantly lower cognitive/affective symptom levels than mental health care patients (F (2,682) = 6.043, p = 0.003). Additional analyses showed that the difference between myocardial infarction and mental health care patients disappeared after adjusting for age of onset but not recurrence of depression. These group differences were also supported by data-driven latent class analyses. There were no significant group differences in somatic symptom levels. Depression after myocardial infarction appears to have a different phenomenology than depression observed in mental health care. Future studies should investigate the etiological factors predictive of symptom dimensions in myocardial infarction and late-onset depression patients. PMID- 23342020 TI - Hand movement effects on word learning and retrieval in adults. AB - The present study investigated the effect of performing an intentional non meaningful hand movement on subsequent lexical acquisition and retrieval in healthy adults. Twenty-five right-handed healthy individuals were required to learn the names (2-syllable legal nonwords) for a series of unfamiliar objects. Participants also completed a familiar picture naming task to investigate the effects of the intentional non-meaningful movement on lexical retrieval. Results revealed that performing this hand movement immediately before linguistic tasks interfered with both new word learning and familiar picture naming when compared with no movement. These results extend previous findings of dual task interference effects in healthy individuals, suggesting that complex, non meaningful, hand movements can also interfere with subsequent lexical acquisition and retrieval. PMID- 23342021 TI - Public information influences sperm transfer to females in sailfin molly males. AB - In animals, including humans, the social environment can serve as a public information network in which individuals can gather public information about the quality of potential mates by observing conspecifics during sexual interactions. The observing individual itself is also a part of this information network. When recognized by the observed conspecifics as an audience, his/her presence could influence the sexual interaction between those individuals, because the observer might be considered as a potential mate or competitor. One of the most challenging questions in sexual selection to date is how the use of public information in the context of mate choice is linked to the fitness of individuals. Here, we could show that public information influences mate-choice behaviour in sailfin molly males, Poecilia latipinna, and influences the amount of sperm males transfer to a female partner. In the presence of an audience male, males spent less time with the previously preferred, larger of two females and significantly more time with the previously non-preferred, smaller female. When males could physically interact with a female and were faced with an audience male, three audience females or no audience, males transferred significantly more sperm to a female partner in the presence of an audience male than with female audience or no audience and spent less time courting his female partner. This is the first study showing that public information use turns into fitness investment, which is the crucial factor to understand the role of public information in the dynamic processes in sexual selection. PMID- 23342022 TI - Urbanization, trace metal pollution, and malaria prevalence in the house sparrow. AB - Anthropogenic pollution poses a threat for the environment and wildlife. Trace metals (TMs) are known to have negative effects on haematological status, oxidative balance, and reproductive success in birds. These pollutants particularly increase in concentration in industrialized, urbanized and intensive agricultural areas. Pollutants can also interfere with the normal functioning of the immune system and, as such, alter the dynamics of host-parasite interactions. Nevertheless, the impact of pollution on infectious diseases has been largely neglected in natural populations of vertebrates. Here, we used a large spatial scale monitoring of 16 house sparrow (Passer domesticus) populations to identify environmental variables likely to explain variation in TMs (lead, cadmium, zinc) concentrations in the feathers. In five of these populations, we also studied the potential link between TMs, prevalence of infection with one species of avian malaria, Plasmodium relictum, and body condition. Our results show that lead concentration is associated with heavily urbanized habitats and that areas with large woodland coverage have higher cadmium and zinc feather concentrations. Our results suggest that lead concentration in the feathers positively correlates with P. relictum prevalence, and that a complex relationship links TM concentrations, infection status, and body condition. This is one of the first studies showing that environmental pollutants are associated with prevalence of an infectious disease in wildlife. The mechanisms underlying this effect are still unknown even though it is tempting to suggest that lead could interfere with the normal functioning of the immune system, as shown in other species. We suggest that more effort should be devoted to elucidate the link between pollution and the dynamics of infectious diseases. PMID- 23342023 TI - Probiotic bacteria induce a 'glow of health'. AB - Radiant skin and hair are universally recognized as indications of good health. However, this 'glow of health' display remains poorly understood. We found that feeding of probiotic bacteria to aged mice induced integumentary changes mimicking peak health and reproductive fitness characteristic of much younger animals. Eating probiotic yogurt triggered epithelial follicular anagen-phase shift with sebocytogenesis resulting in thick lustrous fur due to a bacteria triggered interleukin-10-dependent mechanism. Aged male animals eating probiotics exhibited increased subcuticular folliculogenesis, when compared with matched controls, yielding luxuriant fur only in probiotic-fed subjects. Female animals displayed probiotic-induced hyperacidity coinciding with shinier hair, a feature that also aligns with fertility in human females. Together these data provide insights into mammalian evolution and novel strategies for integumentary health. PMID- 23342024 TI - Cigarette experimentation and the population attributable fraction for associated genetic and non-genetic risk factors. AB - BACKGROUND: We, and others, have shown that experimenting with cigarettes is a function of both non-genetic and genetic factors. In this analysis we ask: how much of the total risk of experimenting with cigarettes, among those who had not experimented with cigarettes when they enrolled in a prospective cohort, is attributable to genetic factors and to non-genetic factors? METHODS: Participants (N = 1,118 Mexican origin youth), recruited from a large population-based cohort study in Houston, Texas, provided prospective data on cigarette experimentation over three years. Non-genetic data were elicited twice - baseline and follow-up. Participants were genotyped for 672 functional and tagging variants in the dopamine, serotonin and opioid pathways. RESULTS: In the overall model, the adjusted combined non-genetic PAF was 71.2% and the adjusted combined genetic PAF was 58.5%. Among committed never smokers the adjusted combined non-genetic PAF was 67.0% and the adjusted combined genetic PAF was 53.5%. However, among cognitively susceptible youth, the adjusted combined non-genetic PAF was 52.0% and the adjusted combined genetic PAF was 68.4%. CONCLUSIONS: Our results suggest there may be differences in genotypes between youth who think they will try cigarettes in the future compared to their peers who think they will not and underscore the possibility that the relative influence of genetic vs. non-genetic factors on the uptake of smoking may vary between these two groups of youth. IMPACT: A clearer understanding of the relative role of genetic vs. non-genetic factors in the uptake of smoking may have implications for the design of prevention programs. PMID- 23342025 TI - Distinct transmission networks of Chlamydia trachomatis in men who have sex with men and heterosexual adults in Amsterdam, The Netherlands. AB - BACKGROUND: Genovar distributions of Chlamydia trachomatis based on ompA typing differ between men who have sex with men (MSM) and heterosexuals. We investigated clonal relationships using a high resolution typing method to characterize C. trachomatis types in these two risk groups. METHODS: C. trachomatis positive samples were collected at the STI outpatient clinic in Amsterdam between 2008 and 2010 and genotyped by multilocus sequence typing. Clusters were assigned using minimum spanning trees and these were combined with epidemiological data of the hosts. RESULTS: We typed 526 C. trachomatis positive samples: 270 from MSM and 256 from heterosexuals. Eight clusters, containing 10-128 samples were identified of which 4 consisted of samples from MSM (90%-100%), with genovars D, G, J, and L2b. The other 4 clusters consisted mainly of samples from heterosexuals (87% 100%) with genovars D, E, F, I, and J. Genetic diversity was much lower in the MSM clusters than in heterosexual clusters. Significant differences in number of sexual partners and HIV-serostatus were observed for MSM-associated clusters. CONCLUSIONS: C. trachomatis transmission patterns among MSM and heterosexuals were largely distinct. We hypothesize that these differences are due to sexual host behavior, but bacterial factors may play a role as well. PMID- 23342026 TI - A study of the impact of thirteen celebrity suicides on subsequent suicide rates in South Korea from 2005 to 2009. AB - A number of ecological studies have found a pattern of increasing suicide rates after suicides of several Asian entertainment celebrities. However, the finding may be subject to positive outcome bias where cases with no perceived impact may be routinely excluded. In this study, we deploy interrupted time-series analysis using ARIMA transfer function models to investigate systematically the impact of thirteen celebrity suicides on subsequent suicide rates in South Korea. We find that three out of eleven cases were found to be followed by a significant increase in suicide rate, while controlling for seasonality, secular trends, and unemployment rates. Such significant increases could last for nine weeks. Non significance cases may be attributable to the small amount of media coverage, the "displacement" effect of preceding case, and the negative connotation of celebrity deaths. We therefore conclude that whether or not the impacts were detected may be largely conditioned by various contextual factors. Current evidence based on ecological studies is insufficient to draw a firm conclusion. Further studies using multiple approaches should be developed. PMID- 23342027 TI - Why the long face? The mechanics of mandibular symphysis proportions in crocodiles. AB - BACKGROUND: Crocodilians exhibit a spectrum of rostral shape from long snouted (longirostrine), through to short snouted (brevirostrine) morphologies. The proportional length of the mandibular symphysis correlates consistently with rostral shape, forming as much as 50% of the mandible's length in longirostrine forms, but 10% in brevirostrine crocodilians. Here we analyse the structural consequences of an elongate mandibular symphysis in relation to feeding behaviours. METHODS/PRINCIPAL FINDINGS: Simple beam and high resolution Finite Element (FE) models of seven species of crocodile were analysed under loads simulating biting, shaking and twisting. Using beam theory, we statistically compared multiple hypotheses of which morphological variables should control the biomechanical response. Brevi- and mesorostrine morphologies were found to consistently outperform longirostrine types when subject to equivalent biting, shaking and twisting loads. The best predictors of performance for biting and twisting loads in FE models were overall length and symphyseal length respectively; for shaking loads symphyseal length and a multivariate measurement of shape (PC1- which is strongly but not exclusively correlated with symphyseal length) were equally good predictors. Linear measurements were better predictors than multivariate measurements of shape in biting and twisting loads. For both biting and shaking loads but not for twisting, simple beam models agree with best performance predictors in FE models. CONCLUSIONS/SIGNIFICANCE: Combining beam and FE modelling allows a priori hypotheses about the importance of morphological traits on biomechanics to be statistically tested. Short mandibular symphyses perform well under loads used for feeding upon large prey, but elongate symphyses incur high strains under equivalent loads, underlining the structural constraints to prey size in the longirostrine morphotype. The biomechanics of the crocodilian mandible are largely consistent with beam theory and can be predicted from simple morphological measurements, suggesting that crocodilians are a useful model for investigating the palaeobiomechanics of other aquatic tetrapods. PMID- 23342028 TI - A nature-inspired betalainic probe for live-cell imaging of Plasmodium-infected erythrocytes. AB - A model betalainic dye was semisynthesized from betanin, the magenta pigment of the red beet, and was effective for live-cell imaging of Plasmodium-infected red blood cells. This water-soluble fluorescent probe is photostable, excitable in the visible region and cell membrane-permeable, and its photophysical properties are not notably pH-sensitive. Fluorescence imaging microscopy of erythrocytes infected with Plasmodium falciparum, a causative agent of malaria in humans, showed that only the parasite was stained. Z-stacking analysis suggested that the probe accumulates proximal to the nucleus of the parasite. Indicaxanthin, one of the natural fluorescent betalains found in the petals of certain flowers, did not stain the parasite or the red blood cell. PMID- 23342029 TI - Inter-annual variations of methane emission from an open fen on the Qinghai Tibetan Plateau: a three-year study. AB - The study aimed to understand the inter-annual variations of methane (CH(4)) emissions from an open fen on the Qinghai-Tibetan Plateau (QTP) from 2005 to 2007. The weighted mean CH(4) emission rate was 8.37+/-11.32 mg CH(4) m(-2 )h(-1) during the summers from 2005 to 2007, falling in the range of CH(4) fluxes reported by other studies, with significant inter-annual and spatial variations. The CH(4) emissions of the year of 2006 (2.11+/-3.48 mg CH(4) m(-2 )h(-1)) were 82% lower than the mean value of the years 2005 and 2007 (13.91+/-17.80 mg CH(4) m(-2 )h(-1) and 9.44+/-14.32 mg CH(4) m(-2 )h(-1), respectively), responding to the inter-annual changes of standing water depths during the growing season of the three years. Significant drawdown of standing water depth is believed to cause such significant reduction in CH(4) emissions from wetlands in the year 2006, probably through changing the methanogen composition and decreasing its community size as well as activating methanotrophs to enhance CH(4) oxidation. Our results are helpful to understand the inter-annual variations of CH(4) emission and provide a more reasonable regional budget of CH(4) emission from wetlands on the QTP and even for world-wide natural wetlands under climate change. PMID- 23342030 TI - Associations and impact factors between living arrangements and functional disability among older Chinese adults. AB - OBJECTIVES: To examine the association of living arrangements with functional disability among older persons and explore the mediation of impact factors on the relationship. DESIGN: Cross-sectional analysis using data from Healthy Aging study in Zhejiang Province. PARTICIPANTS: Analyzed sample was drawn from a representative rural population of older persons in Wuyi County, Zhejiang Province, including 1542 participants aged 60 and over in the second wave of the study. MEASUREMENTS: Living arrangements, background, functional disability, self rated health, number of diseases, along with contemporaneous circumstances including income, social support (physical assistance and emotional support). Instrument was Activities of Daily Living (ADL) scale, including Basic Activities Daily Living (BADL) and Instrumental Activities of Daily Living (IADL). RESULTS: Living arrangements were significantly associated with BADL, IADL and ADL disability. Married persons living with or without children were more advantaged on all three dimensions of functional disability. Unmarried older adults living with children only had the worst functional status, even after controlling for background, social support, income and health status variables (compared with the unmarried living alone, beta for BADL: -1.262, beta for IADL: -2.112, beta for ADL: -3.388; compared with the married living with children only, beta for BADL: 1.166, beta for IADL: -2.723, beta for ADL: -3.902). In addition, older adults without difficulty in receiving emotional support, in excellent health and with advanced age had significantly better BADL, IADL and ADL function. However, a statistically significant association between physical assistance and functional disability was not found. CONCLUSION: Functional disabilities vary by living arrangements with different patterns and other factors. Our results highlight the association of unmarried elders living with children only and functioning decline comparing with other types. Our study implies policy makers should pay closer attention to unmarried elders living with children in community. Community service especially emotional support such as psychological counseling is important social support and should be improved. PMID- 23342031 TI - The V protein of Tioman virus is incapable of blocking type I interferon signaling in human cells. AB - The capacity of a virus to cross species barriers is determined by the development of bona fide interactions with cellular components of new hosts, and in particular its ability to block IFN-alpha/beta antiviral signaling. Tioman virus (TioV), a close relative of mumps virus (MuV), has been isolated in giant fruit bats in Southeast Asia. Nipah and Hendra viruses, which are present in the same bat colonies, are highly pathogenic in human. Despite serological evidences of close contacts between TioV and human populations, whether TioV is associated to some human pathology remains undetermined. Here we show that in contrast to the V protein of MuV, the V protein of TioV (TioV-V) hardly interacts with human STAT2, does not degrade STAT1, and cannot block IFN-alpha/beta signaling in human cells. In contrast, TioV-V properly binds to human STAT3 and MDA5, and thus interferes with IL-6 signaling and IFN-beta promoter induction in human cells. Because STAT2 binding was previously identified as a host restriction factor for some Paramyxoviridae, we established STAT2 sequence from giant fruit bats, and binding to TioV-V was tested. Surprisingly, TioV-V interaction with STAT2 from giant fruit bats is also extremely weak and barely detectable. Altogether, our observations question the capacity of TioV to appropriately control IFN alpha/beta signaling in both human and giant fruit bats that are considered as its natural host. PMID- 23342032 TI - Demonstration of a melanoma-specific CD44 alternative splicing pattern that remains qualitatively stable, but shows quantitative changes during tumour progression. AB - The role of CD44 in the progression of human melanoma has mostly been characterised by qualitative changes in expression of its individual variable exons. These exons however, may be expressed to form a number of molecules, the alternative splice variants of CD44, which may be structurally and functionally different. Using real-time PCR measurements with variable exon specific primers we have determined that all are expressed in human melanoma. To permit comparison between different tumours we identified a stable CD44 variable exon (CD44v) expression pattern, or CD44 'fingerprint'. This was found to remain unchanged in melanoma cell lines cultured in different matrix environments. To evaluate evolution of this fingerprint during tumour progression we established a scid mouse model, in which the pure expression pattern of metastatic primary tumours, circulating cells and metastases, non-metastatic primary tumours and lung colonies could be studied. Our analyses demonstrated, that although the melanoma CD44 fingerprint is qualitatively stable, quantitative changes are observed suggesting a possible role in tumour progression. PMID- 23342034 TI - A secretory protein of necrotrophic fungus Sclerotinia sclerotiorum that suppresses host resistance. AB - SSITL (SS1G_14133) of Sclerotinia sclerotiorum encodes a protein with 302 amino acid residues including a signal peptide, its secretion property was confirmed with immunolocalization and immunofluorescence techniques. SSITL was classified in the integrin alpha N-terminal domain superfamily, and its 3D structure is similar to those of human integrin alpha4-subunit and a fungal integrin-like protein. When S. sclerotiorum was inoculated to its host, high expression of SSITL was detected during the initial stages of infection (1.5-3.0 hpi). Targeted silencing of SSITL resulted in a significant reduction in virulence; on the other hand, inoculation of SSITL silenced transformant A10 initiated strong and rapid defense response in Arabidopsis, the highest expressions of defense genes PDF1.2 and PR-1 appeared at 3 hpi which was 9 hr earlier than that time when plants were inoculated with the wild-type strain of S. sclerotiorum. Systemic resistance induced by A10 was detected by analysis of the expression of PDF1.2 and PR-1, and confirmed following inoculation with Botrytis cinerea. A10 induced much larger lesions on Arabidopsis mutant ein2 and jar1, and slightly larger lesions on mutant pad4 and NahG in comparison with the wild-type plants. Furthermore, both transient and constitutive expression of SSITL in Arabidopsis suppressed the expression of PDF1.2 and led to be more susceptible to A10 and the wild-type strain of S. sclerotiorum and B. cinerea. Our results suggested that SSITL is an effector possibly and plays significant role in the suppression of jasmonic/ethylene (JA/ET) signal pathway mediated resistance at the early stage of infection. PMID- 23342033 TI - Standardized environmental enrichment supports enhanced brain plasticity in healthy rats and prevents cognitive impairment in epileptic rats. AB - Environmental enrichment of laboratory animals influences brain plasticity, stimulates neurogenesis, increases neurotrophic factor expression, and protects against the effects of brain insult. However, these positive effects are not constantly observed, probably because standardized procedures of environmental enrichment are lacking. Therefore, we engineered an enriched cage (the MarlauTM cage), which offers: (1) minimally stressful social interactions; (2) increased voluntary exercise; (3) multiple entertaining activities; (4) cognitive stimulation (maze exploration), and (5) novelty (maze configuration changed three times a week). The maze, which separates food pellet and water bottle compartments, guarantees cognitive stimulation for all animals. Compared to rats raised in groups in conventional cages, rats housed in MarlauTM cages exhibited increased cortical thickness, hippocampal neurogenesis and hippocampal levels of transcripts encoding various genes involved in tissue plasticity and remodeling. In addition, rats housed in MarlauTM cages exhibited better performances in learning and memory, decreased anxiety-associated behaviors, and better recovery of basal plasma corticosterone level after acute restraint stress. MarlauTM cages also insure inter-experiment reproducibility in spatial learning and brain gene expression assays. Finally, housing rats in MarlauTM cages after severe status epilepticus at weaning prevents the cognitive impairment observed in rats subjected to the same insult and then housed in conventional cages. By providing a standardized enriched environment for rodents during housing, the MarlauTM cage should facilitate the uniformity of environmental enrichment across laboratories. PMID- 23342035 TI - Associations between aromatase CYP19 rs10046 polymorphism and breast cancer risk: from a case-control to a meta-analysis of 20,098 subjects. AB - Lifetime exposure to estrogen is a factor that plays an important role in the pathogenesis and progression of breast cancer. Genetic variants in genes of the biosynthesis and metabolism of estrogen have been associated with breast cancer risk. Among them, the CYP19 gene encodes for aromatase, the enzyme that catalyzes the conversion of androgens to estrogens. The rs10046 polymorphism on the CYP19 gene has been related to levels of circulating estradiol and to the estradiol/testosterone ratio. To date, epidemiological studies of rs10046 have been performed in different populations with contradictory results. In the present study, we have conducted a case-control analysis (522 cases and 1221 controls) in a Spanish population. Furthermore, we have performed a meta-analysis including 20,098 subjects (7,998 cases and 12,100 controls) to summarize the data available for rs10046 and breast cancer risk. An odds ratio (OR) with a 95% confidence interval (CI) was applied to assess the association. The results of our case-control study show an association between the carriers of at least one C allele (dominant model) and breast cancer risk (OR = 1.29, 95% CI 1.01-1.66, p value = 0.038). The meta-analysis shows no significant association with breast cancer risk in any of the genetic models tested. The analysis by ethnic subgroups also failed to produce associations. The evaluation of heterogeneity, influence analysis, and publication bias confirms the reliability of the analysis. We can conclude that the rs10046 polymorphism on CYP19 by itself does not constitute breast cancer risk. We cannot, however, reject the possibility that it could contribute (interact), together with other genetic variants, to modify the circulating levels of estradiol. PMID- 23342036 TI - Evolution and expression plasticity of opsin genes in a fig pollinator, Ceratosolen solmsi. AB - Figs and fig pollinators have co-evolved species-specific systems of mutualism. So far, it was unknown how visual opsin genes of pollinators have evolved in the light conditions inside their host figs. We cloned intact full-length mRNA sequences of four opsin genes from a species of fig pollinator, Ceratosolen solmsi, and tested for selective pressure and expressional plasticity of these genes. Molecular evolutionary analysis indicated that the four opsin genes evolved under different selective constraints. Subsets of codons in the two long wavelength sensitive opsin (LW1, LW2) genes were positively selected in ancestral fig pollinators. The ultraviolet sensitive opsin (UV) gene was under strong purifying selection, whereas a relaxation of selective constrains occurred on several amino acids in the blue opsin. RT-qPCR analysis suggested that female and male fig pollinators had different expression patterns possibly due to their distinct lifestyles and different responses to light within the syconia. Co evolutionary history with figs might have influenced the evolution and expression plasticity of opsin genes in fig pollinators. PMID- 23342038 TI - Temperature sensitivity of soil organic carbon mineralization along an elevation gradient in the Wuyi Mountains, China. AB - Soil organic carbon (SOC) actively participates in the global carbon (C) cycle. Despite much research, however, our understanding of the temperature sensitivity of soil organic carbon (SOC) mineralization is still very limited. To investigate the responses of SOC mineralization to temperature, we sampled surface soils (0 10 cm) from evergreen broad-leaf forest (EBF), coniferous forest (CF), sub-alpine dwarf forest (SDF), and alpine meadow (AM) along an elevational gradient in the Wuyi Mountains, China. The soil samples were incubated at 5, 15, 25, and 35 degrees C with constant soil moisture for 360 days. The temperature sensitivity of SOC mineralization (Q(10)) was calculated by comparing the time needed to mineralize the same amount of C at any two adjacent incubation temperatures. Results showed that the rates of SOC mineralization and the cumulative SOC mineralized during the entire incubation significantly increased with increasing incubation temperatures across the four sites. With the increasing extent of SOC being mineralized (increasing incubation time), the Q(10) values increased. Moreover, we found that both the elevational gradient and incubation temperature intervals significantly impacted Q(10) values. Q(10) values of the labile and recalcitrant organic C linearly increased with elevation. For the 5-15, 15-25, and 25-35 degrees C intervals, surprisingly, the overall Q(10) values for the labile C did not decrease as the recalcitrant C did. Generally, our results suggest that subtropical forest soils may release more carbon than expected in a warmer climate. PMID- 23342037 TI - Expansion on stromal cells preserves the undifferentiated state of human hematopoietic stem cells despite compromised reconstitution ability. AB - Lack of HLA-matched hematopoietic stem cells (HSC) limits the number of patients with life-threatening blood disorders that can be treated by HSC transplantation. So far, insufficient understanding of the regulatory mechanisms governing human HSC has precluded the development of effective protocols for culturing HSC for therapeutic use and molecular studies. We defined a culture system using OP9M2 mesenchymal stem cell (MSC) stroma that protects human hematopoietic stem/progenitor cells (HSPC) from differentiation and apoptosis. In addition, it facilitates a dramatic expansion of multipotent progenitors that retain the immunophenotype (CD34+CD38-CD90+) characteristic of human HSPC and proliferative potential over several weeks in culture. In contrast, transplantable HSC could be maintained, but not significantly expanded, during 2-week culture. Temporal analysis of the transcriptome of the ex vivo expanded CD34+CD38-CD90+ cells documented remarkable stability of most transcriptional regulators known to govern the undifferentiated HSC state. Nevertheless, it revealed dynamic fluctuations in transcriptional programs that associate with HSC behavior and may compromise HSC function, such as dysregulation of PBX1 regulated genetic networks. This culture system serves now as a platform for modeling human multilineage hematopoietic stem/progenitor cell hierarchy and studying the complex regulation of HSC identity and function required for successful ex vivo expansion of transplantable HSC. PMID- 23342039 TI - Comparative transcriptome analysis of the accessory sex gland and testis from the Chinese mitten crab (Eriocheir sinensis). AB - The accessory sex gland (ASG) is an important component of the male reproductive system, which functions to enhance the fertility of spermatozoa during male reproduction. Certain proteins secreted by the ASG are known to bind to the spermatozoa membrane and affect its function. The ASG gene expression profile in Chinese mitten crab (Eriocheir sinensis) has not been extensively studied, and limited genetic research has been conducted on this species. The advent of high throughput sequencing technologies enables the generation of genomic resources within a short period of time and at minimal cost. In the present study, we performed de novo transcriptome sequencing to produce a comprehensive transcript dataset for the ASG of E. sinensis using Illumina sequencing technology. This analysis yielded a total of 33,221,284 sequencing reads, including 2.6 Gb of total nucleotides. Reads were assembled into 85,913 contigs (average 218 bp), or 58,567 scaffold sequences (average 292 bp), that identified 37,955 unigenes (average 385 bp). We assembled all unigenes and compared them with the published testis transcriptome from E. sinensis. In order to identify which genes may be involved in ASG function, as it pertains to modification of spermatozoa, we compared the ASG and testis transcriptome of E. sinensis. Our analysis identified specific genes with both higher and lower tissue expression levels in the two tissues, and the functions of these genes were analyzed to elucidate their potential roles during maturation of spermatozoa. Availability of detailed transcriptome data from ASG and testis in E. sinensis can assist our understanding of the molecular mechanisms involved with spermatozoa conservation, transport, maturation and capacitation and potentially acrosome activation. PMID- 23342040 TI - Simultaneous beat-by-beat investigation of the effects of the Valsalva maneuver on left and right ventricular filling and the possible mechanism. AB - Although the influence of the Valsalva maneuver on the heart and circulatory system has been investigated, the mechanism of intrathoracic pressure influencing cardiovascular function is unclear. To test our hypothesis that the interaction between the anatomy-determined partially-intrathoracic system and the fully intrathoracic system might explain those issues and help to disclose the mechanism, we used the Hitachi dual pulse wave Doppler echocardiographic apparatus to investigate simultaneously the beat-by-beat influence of 40-mmHg Valsalva maneuver on left and right cardiac ventricular filling in 30 male adult volunteers. The mitral and tricuspid blood inflow velocity spectra during the Valsalva maneuver were recorded simultaneously. The peak velocity (PV), velocity time integral (VTI) and inflow volume (IV) of each cycle were measured or calculated. The PV, VTI and IV of the left heart remained unchanged at the first beat after the Valsalva maneuver onset (compared with those at rest, p>0.1) and then decreased gradually to the lowest at the 11+/-1.2th beat (range, 9th to 12th beat). Simultaneously, the PV, VTI and IV of the right heart decreased significantly (p<0.05) at the first cycle, decreased rapidly to the lowest at the 6+/-0.8th beat (range, 4th to 7th beat) and then increased gradually to the 9+/ 1.3th beat (range, 8th to 10th beat). These results suggest that the left heart and right heart have different physiological responses to the Valsalva maneuver. These could be explained by our hypothesis, the interaction between the partially intrathoracic system and the fully-intrathoracic system, which might help to disclose the mechanism of how intrathoracic pressure influences the heart and circulatory system. PMID- 23342041 TI - Population biology of Streptococcus pneumoniae in West Africa: multilocus sequence typing of serotypes that exhibit different predisposition to invasive disease and carriage. AB - BACKGROUND: Little is known about the population biology of Streptococcus pneumoniae in developing countries, although the majority of pneumococcal infections occur in this setting. The aim of the study was to apply MLST to investigate the population biology of S. pneumoniae in West Africa. METHODS: Seventy three invasive and carriage S. pneumoniae isolates from three West African countries including The Gambia, Nigeria and Ghana were investigated. The isolates covered seven serotypes (1, 3, 5, 6A, 11, 14, 23F) and were subjected to multilocus sequence typing and antibiotic susceptibility testing. RESULTS: Overall, 50 different sequence types (STs) were identified, of which 38% (29) were novel. The most common ST was a novel clone-ST 4012 (6.5%), and some clones including STs 913, 925, 1737, 2160 and 3310 appeared to be specific to the study region. Two STs including ST 63 and ST 4012 were associated with multiple serotypes indicating a history of serotype switching. ST 63 was associated with serotypes 3 and 23F, while ST 4012 was associated with serotypes 6A and 23. eBURST analyses using the stringent 6/7 identical loci definition grouped the 50 STs into 5 clonal complexes and 65 singletons, expressing a high level of genetic diversity among the isolates. Compared to the other serotypes, serotypes 1 and 5 isolates appeared to be more clonal. Internationally recognized antibiotic resistant clones of S. pneumoniae were generally absent in the population investigated and the only multidrug resistant isolate identified (1/66) belong to the Pneumocococcal Epidemiology Network clone ST 63. CONCLUSIONS: The pneumococcal population in West Africa is quite divergent, and serotypes that are common in invasive disease (such as serotypes 1 and 5) are more likely to be clonal than serotypes that are common in carriage. PMID- 23342042 TI - Enhancement of auranofin-induced apoptosis in MCF-7 human breast cells by selenocystine, a synergistic inhibitor of thioredoxin reductase. AB - Thioredoxin system plays an important role in regulation of intracellular redox balance and various signaling pathways. Thioredoxin reductase (TrxR) is overexpressed in many cancer cells and has been identified as a potential target of anticancer drugs. Auranofin (AF) is potent TrxR inhibitor with novel in vitro and in vivo anticancer activities. Selenocystine (SeC) is a nutritionally available selenoamino acid with selective anticancer effects through induction of apoptosis. In the present study, we demonstrated the synergistic effects and the underlying molecular mechanisms of SeC in combination with AF on MCF-7 human breast cancer cells. The results showed that SeC and AF synergistically inhibited the cancer cell growth through induction of ROS-dependent apoptosis with the involvement of mitochondrial dysfunction. DNA damage-mediated p53 phosphorylation and down-regulation of phosphorylated AKT and ERK also contributed to cell apoptosis. Moreover, we demonstrated the important role of TrxR activity in the synergistic action of SeC and AF. Taken together, our results suggest the strategy to use SeC and AF in combination could be a highly efficient way to achieve anticancer synergism by targeting TrxR. PMID- 23342043 TI - Improving the efficacy of ERP-based BCIs using different modalities of covert visuospatial attention and a genetic algorithm-based classifier. AB - We investigated whether the covert orienting of visuospatial attention can be effectively used in a brain-computer interface guided by event-related potentials. Three visual interfaces were tested: one interface that activated voluntary orienting of visuospatial attention and two interfaces that elicited automatic orienting of visuospatial attention. We used two epoch classification procedures. The online epoch classification was performed via Independent Component Analysis, and then it was followed by fixed features extraction and support vector machines classification. The offline epoch classification was performed by means of a genetic algorithm that permitted us to retrieve the relevant features of the signal, and then to categorise the features with a logistic classifier. The offline classification, but not the online one, allowed us to differentiate between the performances of the interface that required voluntary orienting of visuospatial attention and those that required automatic orienting of visuospatial attention. The offline classification revealed an advantage of the participants in using the "voluntary" interface. This advantage was further supported, for the first time, by neurophysiological data. Moreover, epoch analysis was performed better with the "genetic algorithm classifier" than with the "independent component analysis classifier". We suggest that the combined use of voluntary orienting of visuospatial attention and of a classifier that permits feature extraction ad personam (i.e., genetic algorithm classifier) can lead to a more efficient control of visual BCIs. PMID- 23342044 TI - An S-locus independent pollen factor confers self-compatibility in 'Katy' apricot. AB - Loss of pollen-S function in Prunus self-compatible cultivars has been mostly associated with deletions or insertions in the S-haplotype-specific F-box (SFB) genes. However, self-compatible pollen-part mutants defective for non-S-locus factors have also been found, for instance, in the apricot (Prunus armeniaca) cv. 'Canino'. In the present study, we report the genetic and molecular analysis of another self-compatible apricot cv. termed 'Katy'. S-genotype of 'Katy' was determined as S(1)S(2) and S-RNase PCR-typing of selfing and outcrossing populations from 'Katy' showed that pollen gametes bearing either the S(1)- or the S(2)-haplotype were able to overcome self-incompatibility (SI) barriers. Sequence analyses showed no SNP or indel affecting the SFB(1) and SFB(2) alleles from 'Katy' and, moreover, no evidence of pollen-S duplication was found. As a whole, the obtained results are compatible with the hypothesis that the loss-of function of a S-locus unlinked factor gametophytically expressed in pollen (M' locus) leads to SI breakdown in 'Katy'. A mapping strategy based on segregation distortion loci mapped the M'-locus within an interval of 9.4 cM at the distal end of chr.3 corresponding to ~1.29 Mb in the peach (Prunus persica) genome. Interestingly, pollen-part mutations (PPMs) causing self-compatibility (SC) in the apricot cvs. 'Canino' and 'Katy' are located within an overlapping region of ~273 Kb in chr.3. No evidence is yet available to discern if they affect the same gene or not, but molecular markers seem to indicate that both cultivars are genetically unrelated suggesting that every PPM may have arisen independently. Further research will be necessary to reveal the precise nature of 'Katy' PPM, but fine-mapping already enables SC marker-assisted selection and paves the way for future positional cloning of the underlying gene. PMID- 23342045 TI - The interactive effects of cytoskeleton disruption and mitochondria dysfunction lead to reproductive toxicity induced by microcystin-LR. AB - The worldwide occurrence of cyanobacterial blooms evokes profound concerns. The presence of microcystins (MCs) in waters and aquatic food increases the risk to human health. Some recent studies have suggested that the gonad is the second most important target organ of MCs, however, the potential toxicity mechanisms are still unclear. For a better understanding of reproductive toxicity of MCs on animals, we conducted the present experimental investigation. Male rats were intraperitoneally injected with MC-LR for 50 d with the doses of 1 and 10 ug/kg body weight per day. After prolonged exposure to MC-LR, the testes index significantly decreased in 10 ug/kg group. Light microscope observation indicated that the space between the seminiferous tubules was increased. Ultrastructural observation showed some histopathological characteristics, including cytoplasmic shrinkage, cell membrane blebbing, swollen mitochondria and deformed nucleus. Using Q-PCR methods, the transcriptional levels of some cytoskeletal and mitochondrial genes were determined. MC-LR exposure affected the homeostasis of the expression of cytoskeletal genes, causing possible dysfunction of cytoskeleton assembly. In MC-LR treatments, all the 8 mitochondrial genes related with oxidative phosphorylation (OXPHOS) significantly increased. The reactive oxygen species (ROS) level significantly increased in 10 ug/kg group. The mitochondria swelling and DNA damage were also determined in 10 ug/kg group. Hormone levels of testis significantly changed. The present study verified that both cytoskeleton disruption possibly due to cytoskeletal reorganization or depolymerization and mitochondria dysfunction interact with each other through inducing of reactive oxygen species and oxidative phosphorylation, and jointly result in testis impairment after exposure to MC-LR. PMID- 23342046 TI - The genome sequences of Cellulomonas fimi and "Cellvibrio gilvus" reveal the cellulolytic strategies of two facultative anaerobes, transfer of "Cellvibrio gilvus" to the genus Cellulomonas, and proposal of Cellulomonas gilvus sp. nov. AB - Actinobacteria in the genus Cellulomonas are the only known and reported cellulolytic facultative anaerobes. To better understand the cellulolytic strategy employed by these bacteria, we sequenced the genome of the Cellulomonas fimi ATCC 484(T). For comparative purposes, we also sequenced the genome of the aerobic cellulolytic "Cellvibrio gilvus" ATCC 13127(T). An initial analysis of these genomes using phylogenetic and whole-genome comparison revealed that "Cellvibrio gilvus" belongs to the genus Cellulomonas. We thus propose to assign "Cellvibrio gilvus" to the genus Cellulomonas. A comparative genomics analysis between these two Cellulomonas genome sequences and the recently completed genome for Cellulomonas flavigena ATCC 482(T) showed that these cellulomonads do not encode cellulosomes but appear to degrade cellulose by secreting multi-domain glycoside hydrolases. Despite the minimal number of carbohydrate-active enzymes encoded by these genomes, as compared to other known cellulolytic organisms, these bacteria were found to be proficient at degrading and utilizing a diverse set of carbohydrates, including crystalline cellulose. Moreover, they also encode for proteins required for the fermentation of hexose and xylose sugars into products such as ethanol. Finally, we found relatively few significant differences between the predicted carbohydrate-active enzymes encoded by these Cellulomonas genomes, in contrast to previous studies reporting differences in physiological approaches for carbohydrate degradation. Our sequencing and analysis of these genomes sheds light onto the mechanism through which these facultative anaerobes degrade cellulose, suggesting that the sequenced cellulomonads use secreted, multidomain enzymes to degrade cellulose in a way that is distinct from known anaerobic cellulolytic strategies. PMID- 23342048 TI - Native birds and alien insects: spatial density dependence in songbird predation of invading oak gallwasps. AB - Revealing the interactions between alien species and native communities is central to understanding the ecological consequences of range expansion. Much has been learned through study of the communities developing around invading herbivorous insects. Much less, however, is known about the significance of such aliens for native vertebrate predators for which invaders may represent a novel food source. We quantified spatial patterns in native bird predation of invading gall-inducing Andricus wasps associated with introduced Turkey oak (Quercus cerris) at eight sites across the UK. These gallwasps are available at high density before the emergence of caterpillars that are the principle spring food of native insectivorous birds. Native birds showed positive spatial density dependence in gall attack rates at two sites in southern England, foraging most extensively on trees with highest gall densities. In a subsequent study at one of these sites, positive spatial density dependence persisted through four of five sequential week-long periods of data collection. Both patterns imply that invading galls are a significant resource for at least some native bird populations. Density dependence was strongest in southern UK bird populations that have had longest exposure to the invading gallwasps. We hypothesise that this pattern results from the time taken for native bird populations to learn how to exploit this novel resource. PMID- 23342047 TI - Collagen metabolism of human osteoarthritic articular cartilage as modulated by bovine collagen hydrolysates. AB - Destruction of articular cartilage is a characteristic feature of osteoarthritis (OA). Collagen hydrolysates are mixtures of collagen peptides and have gained huge public attention as nutriceuticals used for prophylaxis of OA. Here, we evaluated for the first time whether different bovine collagen hydrolysate preparations indeed modulate the metabolism of collagen and proteoglycans from human OA cartilage explants and determined the chemical composition of oligopeptides representing collagen fragments. Using biophysical techniques, like MALDI-TOF-MS, AFM, and NMR, the molecular weight distribution and aggregation behavior of collagen hydrolysates from bovine origin (CH-Alpha(r), PeptanTM B 5000, PeptanTM B 2000) were determined. To investigate the metabolism of human femoral OA cartilage, explants were obtained during knee replacement surgery. Collagen synthesis of explants as modulated by 0-10 mg/ml collagen hydrolysates was determined using a novel dual radiolabeling procedure. Proteoglycans, NO, PGE(2), MMP-1, -3, -13, TIMP-1, collagen type II, and cell viability were determined in explant cultures. Groups of data were analyzed using ANOVA and the Friedman test (n = 5-12). The significance was set to p<=0.05. We found that collagen hydrolysates obtained from different sources varied with respect to the width of molecular weight distribution, average molecular weight, and aggregation behavior. None of the collagen hydrolysates tested stimulated the biosynthesis of collagen. PeptanTM B 5000 elevated NO and PGE(2) levels significantly but had no effect on collagen or proteoglycan loss. All collagen hydrolysates tested proved not to be cytotoxic. Together, our data demonstrate for the first time that various collagen hydrolysates differ with respect to their chemical composition of collagen fragments as well as by their pharmacological efficacy on human chondrocytes. Our study underscores the importance that each collagen hydrolysate preparation should first demonstrate its pharmacological potential both in vitro and in vivo before being used for both regenerative medicine and prophylaxis of OA. PMID- 23342049 TI - Acute inactivation of PSD-95 destabilizes AMPA receptors at hippocampal synapses. AB - Postsynatptic density protein (PSD-95) is a 95 kDa scaffolding protein that assembles signaling complexes at synapses. Over-expression of PSD-95 in primary hippocampal neurons selectively increases synaptic localization of AMPA receptors; however, mice lacking PSD-95 display grossly normal glutamatergic transmission in hippocampus. To further study the scaffolding role of PSD-95 at excitatory synapses, we generated a recombinant PSD-95-4c containing a tetracysteine motif, which specifically binds a fluorescein derivative and allows for acute and permanent inactivation of PSD-95. Interestingly, acute inactivation of PSD-95 in rat hippocampal cultures rapidly reduced surface AMPA receptor immunostaining, but did not affected NMDA or transferrin receptor localization. Acute photoinactivation of PSD-95 in dissociated neurons causes ~80% decrease in GluR2 surface staining observed by live-cell microscopy within 15 minutes of PSD 95-4c ablation. These results confirm that PSD-95 stabilizes AMPA receptors at postsynaptic sites and provides insight into the dynamic interplay between PSD-95 and AMPA receptors in live neurons. PMID- 23342050 TI - How large should whales be? AB - The evolution and distribution of species body sizes for terrestrial mammals is well-explained by a macroevolutionary tradeoff between short-term selective advantages and long-term extinction risks from increased species body size, unfolding above the 2 g minimum size induced by thermoregulation in air. Here, we consider whether this same tradeoff, formalized as a constrained convection reaction-diffusion system, can also explain the sizes of fully aquatic mammals, which have not previously been considered. By replacing the terrestrial minimum with a pelagic one, at roughly 7000 g, the terrestrial mammal tradeoff model accurately predicts, with no tunable parameters, the observed body masses of all extant cetacean species, including the 175,000,000 g Blue Whale. This strong agreement between theory and data suggests that a universal macroevolutionary tradeoff governs body size evolution for all mammals, regardless of their habitat. The dramatic sizes of cetaceans can thus be attributed mainly to the increased convective heat loss is water, which shifts the species size distribution upward and pushes its right tail into ranges inaccessible to terrestrial mammals. Under this macroevolutionary tradeoff, the largest expected species occurs where the rate at which smaller-bodied species move up into large bodied niches approximately equals the rate at which extinction removes them. PMID- 23342051 TI - The chick embryo as an experimental system for melanoma cell invasion. AB - BACKGROUND: A primary cutaneous melanoma will not kill the patient, but its metastases. Since in vitro studies on melanoma cells in 2-D cultures do often not reflect reality, 3-D models might come closer to the physiological situation in the patient during cancer initiation and progression. METHODOLOGY/PRINCIPAL FINDINGS: Here, we describe the chick embryo model for in vivo studies of melanoma cell migration and invasion. After transplantation of neural crest derived melanoma cells into the neural tube, the melanoma cells resume neural crest cell migration along the medial and lateral pathways and finally undergo apoptosis in the target areas. Upon transplantation into ectopic areas such as the hindbrain or the optic cup malignant invasion and local tissue destruction occurs. In contrast, melanocytes are not able to spontaneously resume neural crest cell migration. However, malignant invasion can be induced in melanocytes by pre-treatment with the TGF-beta family members bone morphegenetic protein-2 or nodal. Transplantation of MCF7 breast cancer cells yields a different growth pattern in the rhombencephalon than melanoma cells. CONCLUSIONS/SIGNIFICANCE: The chick embryo model is a feasible, cost-effective in vivo system to study invasion by cancer cells in an embryonic environment. It may be useful to study invasive behavior induced by embryonic oncogenes and for targeted manipulation of melanoma or breast cancer cells aiming at ablation of invasive properties. PMID- 23342052 TI - Salt content impacts food preferences and intake among children. AB - Decreasing dietary sodium intake, which can be achieved by reducing salt content in food, is recommended. Salt contributes to the taste of foods and makes them more enjoyable. Whether a food is liked or disliked is an important determinant of food intake, especially among children. However, the role of salt in children's food acceptance has received little attention. The impact of salt content on children's hedonic rating and intake of two foods was investigated in children. Using a within-subject crossover design, we recruited 75 children (8-11 years) to participate in five lunches in their school cafeteria. The target foods were green beans and pasta. The added salt content was 0, 0.6 or 1.2 g/100 g. The children's intake (g) of all lunch items was measured. The children provided their hedonic rating of the food, a preference ranking and a saltiness ranking in the laboratory. Children could rank the foods according to salt content, and they preferred the two saltier options. A food-specific effect of salt content on intake was observed. Compared to the intermediate level (0.6 g salt/100 g), not adding salt decreased green bean intake (-21%; p = 0.002), and increasing the salt content increased pasta intake (+24%; p<0.0001). Structural Equation Modeling was used to model the relative weights of the determinants of intake. It showed that the primary driver of food intake was the child's hunger; the second most important factor was the child's hedonic rating of the food, regardless of its salt content, and the last factor was the child's preference for the particular salt content of the food. In conclusion, salt content has a positive and food-specific effect on intake; it impacted food preferences and intake differently in children. Taking into account children's preferences for salt instead of their intake may lead to excessive added salt. PMID- 23342053 TI - Increased carotid intima-media thickness and reduced distensibility in human class III obesity: independent and differential influences of adiposity and blood pressure on the vasculature. AB - Carotid intima-media-thickness (cIMT) and carotid distensibility (distensibility), structural and functional properties of carotid arteries respectively, are early markers, as well as strong predictors of cardiovascular disease (CVD). The characteristic of these two parameters in individuals with BMI>40.0 kg/m(2) (Class III obesity), however, are largely unknown. The present study was designed to document cIMT and distensibility in this population and to relate these to other factors with established association with CVD in obesity. The study included 96 subjects (65 with BMI>40.0 kg/m(2) and 31, age- and gender matched, with BMI of 18.5 to 30.0 kg/m(2)). cIMT and distensibility were measured by non-invasive high resolution ultrasonography, circulatory CD133(+)/KDR(+) angiogenic cells and endothelial microparticles (EMP) by flow cytometry, and plasma levels of adipokines, growth factors and cytokines by Luminex immunoassay kits. The study results demonstrated increased cIMT (0.62+/-0.11 mm vs. 0.54+/ 0.08 mm, P = 0.0002) and reduced distensibility (22.52+/-10.79 10(-3)kpa(-1)vs. 29.91+/-12.37 10(-3)kpa(-1), P<0.05) in individuals with BMI>40.0 kg/m(2). Both cIMT and distensibility were significantly associated with traditional CVD risk factors, adiposity/adipokines and inflammatory markers but had no association with circulating angiogenic cells. We also demonstrated, for the first time, elevated plasma EMP levels in individuals with BMI>40.0 kg/m(2). In conclusion, cIMT is increased and distensibility reduced in Class III obesity with the changes predominantly related to conventional CVD risk factors present in this condition, demonstrating that both cIMT and distensibility remain as CVD markers in Class III obesity. PMID- 23342054 TI - A functional alternative splicing mutation in AIRE gene causes autoimmune polyendocrine syndrome type 1. AB - Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare autosomal recessive disease defined by the presence of two of the three conditions: mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Loss-of-function mutations of the autoimmune regulator (AIRE) gene have been linked to APS-1. Here we report mutational analysis and functional characterization of an AIRE mutation in a consanguineous Chinese family with APS-1. All exons of the AIRE gene and adjacent exon-intron sequences were amplified by PCR and subsequently sequenced. We identified a homozygous missense AIRE mutation c.463G>A (p.Gly155Ser) in two siblings with different clinical features of APS-1. In silico splice-site prediction and minigene analysis were carried out to study the potential pathological consequence. Minigene splicing analysis and subsequent cDNA sequencing revealed that the AIRE mutation potentially compromised the recognition of the splice donor of intron 3, causing alternative pre-mRNA splicing by intron 3 retention. Furthermore, the aberrant AIRE transcript was identified in a heterozygous carrier of the c.463G>A mutation. The aberrant intron 3-retaining transcript generated a truncated protein (p.G155fsX203) containing the first 154 AIRE amino acids and followed by 48 aberrant amino acids. Therefore, our study represents the first functional characterization of the alternatively spliced AIRE mutation that may explain the pathogenetic role in APS-1. PMID- 23342055 TI - Novel oxytocin gene expression in the hindbrain is induced by alcohol exposure: transgenic zebrafish enable visualization of sensitive neurons. AB - BACKGROUND: Fetal Alcohol Spectrum Disorders (FASD) are a collection of disorders resulting from fetal ethanol exposure, which causes a wide range of physical, neurological and behavioral deficits including heightened susceptibility for alcoholism and addictive disorders. While a number of mechanisms have been proposed for how ethanol exposure disrupts brain development, with selective groups of neurons undergoing reduced proliferation, dysfunction and death, the induction of a new neurotransmitter phenotype by ethanol exposure has not yet been reported. PRINCIPAL FINDINGS: The effects of embryonic and larval ethanol exposure on brain development were visually monitored using transgenic zebrafish expressing cell-specific green fluorescent protein (GFP) marker genes. Specific subsets of GFP-expressing neurons were highly sensitive to ethanol exposure, but only during defined developmental windows. In the med12 mutant, which affects the Mediator co-activator complex component Med12, exposure to lower concentrations of ethanol was sufficient to reduce GFP expression in transgenic embryos. In transgenic embryos and larva containing GFP driven by an oxytocin-like (oxtl) promoter, ethanol exposure dramatically up-regulated GFP expression in a small group of hindbrain neurons, while having no effect on expression in the neuroendocrine preoptic area. CONCLUSIONS: Alcohol exposure during limited embryonic periods impedes the development of specific, identifiable groups of neurons, and the med12 mutation sensitizes these neurons to the deleterious effects of ethanol. In contrast, ethanol exposure induces oxtl expression in the hindbrain, a finding with profound implications for understanding alcoholism and other addictive disorders. PMID- 23342056 TI - Antiretroviral treatment knowledge and stigma--implications for programs and HIV treatment interventions in rural Tanzanian populations. AB - OBJECTIVE: To analyse antiretroviral treatment (ART) knowledge and HIV- and ART related stigma among the adult population in a rural Tanzanian community. DESIGN: Population-based cross-sectional survey of 694 adults (15-49 years of age). METHODS: Latent class analysis (LCA) categorized respondents' levels of ART knowledge and of ART-related stigma. Multinomial logistic regression assessed the association between the levels of ART knowledge and HIV- and ART-related stigma, while controlling for the effects of age, gender, education, marital status and occupation. RESULTS: More than one-third of men and women in the study reported that they had never heard of ART. Among those who had heard of ART, 24% were east informed about ART, 8% moderately informed, and 68% highly informed. Regarding ART-related stigma, 28% were least stigmatizing, 41% moderately stigmatizing, and 31% highly stigmatizing toward persons taking ART. Respondents that had at least primary education were more likely to have high levels of knowledge about ART (OR 3.09, 95% CI 1.61-5.94). Participants highly informed about ART held less HIV- and ART-related stigma towards ART patients (OR 0.26, 95% CI 0.09-0.74). CONCLUSION: The lack of ART knowledge is broad, and there is a strong association between ART knowledge and individual education level. These are relevant findings for both HIV prevention and HIV treatment program interventions that address ART related stigma across the entire spectrum of the community. PMID- 23342057 TI - Ack1: activation and regulation by allostery. AB - The non-receptor tyrosine kinase Ack1 belongs to a unique multi-domain protein kinase family, Ack. Ack is the only family of SH3 domain containing kinases to have an SH3 domain following the kinase domain; others have their SH3 domains preceding the kinase domain. Previous reports have suggested that Ack1 does not require phosphorylation for activation and the enzyme activity of the isolated kinase domain is low relative to other kinases. It has been shown to dimerize in the cellular environment, which augments its enzyme activity. The molecular mechanism of activation, however, remains unknown. Here we present structural and biochemical data on Ack1 kinase domain, and kinase domain+SH3 domain that suggest that Ack1 in its monomeric state is autoinhibited, like EGFR and CDK. The activation of the kinase domain may require N-lobe mediated symmetric dimerization, which may be facilitated by the N-terminal SAM domain. Results presented here show that SH3 domain, unlike in Src family tyrosine kinases, does not directly control the activation state of the enzyme. Instead we speculate that the SH3 domain may play a regulatory role by facilitating binding of the MIG6 homologous region to the kinase domain. We postulate that features of Ack1 activation and regulation parallel those of receptor tyrosine kinase EGFR with some interesting differences. PMID- 23342058 TI - The evaporative function of cockroach hygroreceptors. AB - Insect hygroreceptors associate as antagonistic pairs of a moist cell and a dry cell together with a cold cell in small cuticular sensilla on the antennae. The mechanisms by which the atmospheric humidity stimulates the hygroreceptive cells remain elusive. Three models for humidity transduction have been proposed in which hygroreceptors operate either as mechanical hygrometers, evaporation detectors or psychrometers. Mechanical hygrometers are assumed to respond to the relative humidity, evaporation detectors to the saturation deficit and psychrometers to the temperature depression (the difference between wet-bulb and dry-bulb temperatures). The models refer to different ways of expressing humidity. This also means, however, that at different temperatures these different types of hygroreceptors indicate very different humidity conditions. The present study tested the adequacy of the three models on the cockroach's moist and dry cells by determining whether the specific predictions about the temperature-dependence of the humidity responses are indeed observed. While in previous studies stimulation consisted of rapid step-like humidity changes, here we changed humidity slowly and continuously up and down in a sinusoidal fashion. The low rates of change made it possible to measure instantaneous humidity values based on UV-absorption and to assign these values to the hygroreceptive sensillum. The moist cell fitted neither the mechanical hygrometer nor the evaporation detector model: the temperature dependence of its humidity responses could not be attributed to relative humidity or to saturation deficit, respectively. The psychrometer model, however, was verified by the close relationships of the moist cell's response with the wet-bulb temperature and the dry cell's response with the dry-bulb temperature. Thus, the hygroreceptors respond to evaporation and the resulting cooling due to the wetness or dryness of the air. The drier the ambient air (absolutely) and the higher the temperature, the greater the evaporative temperature depression and the power to desiccate. PMID- 23342060 TI - Additive effects of threat-of-shock and picture valence on startle reflex modulation. AB - The present study examined the effects of sustained anticipatory anxiety on the affective modulation of the eyeblink startle reflex. Towards this end, pleasant, neutral and unpleasant pictures were presented as a continuous stream during alternating threat-of-shock and safety periods, which were cued by colored picture frames. Orbicularis-EMG to auditory startle probes and electrodermal activity were recorded. Previous findings regarding affective picture valence and threat-of-shock modulation were replicated. Of main interest, anticipating aversive events and viewing affective pictures additively modulated defensive activation. Specifically, despite overall potentiated startle blink magnitude in threat-of-shock conditions, the startle reflex remained sensitive to hedonic picture valence. Finally, skin conductance level revealed sustained sympathetic activation throughout the entire experiment during threat- compared to safety periods. Overall, defensive activation by physical threat appears to operate independently from reflex modulation by picture media. The present data confirms the importance of simultaneously manipulating phasic-fear and sustained-anxiety in studying both normal and abnormal anxiety. PMID- 23342059 TI - Blocking the class I histone deacetylase ameliorates renal fibrosis and inhibits renal fibroblast activation via modulating TGF-beta and EGFR signaling. AB - BACKGROUND: Histone deacetylase (HDAC) inhibitors are promising anti-fibrosis drugs; however, nonselective inhibition of class I and class II HDACs does not allow a detailed elucidation of the individual HDAC functions in renal fibrosis. In this study, we investigated the effect of MS-275, a selective class I HDAC inhibitor, on the development of renal fibrosis in a murine model of unilateral ureteral obstruction (UUO) and activation of cultured renal interstitial fibroblasts. METHODS/FINDINGS: The UUO model was established by ligation of the left ureter and the contralateral kidney was used as a control. At seven days after UUO injury, kidney developed fibrosis as indicated by deposition of collagen fibrils and increased expression of collagen I, fibronectin and alpha smooth muscle actin (alpha-SMA). Administration of MS-275 inhibited all these fibrotic responses and suppressed UUO-induced production of transforming growth factor-beta1 (TGF-beta), increased expression of TGF-beta receptor I, and phosphorylation of Smad-3. MS-275 was also effective in suppressing phosphorylation and expression of epidermal growth factor receptor (EGFR) and its downstream signaling molecule, signal transducer and activator of transcription 3. Moreover, class I HDAC inhibition reduced the number of renal tubular cells arrested in the G2/M phase of the cell cycle, a cellular event associated with TGF-beta1overproduction. In cultured renal interstitial fibroblasts, MS-275 treatment inhibited TGF-beta induced phosphorylation of Smad-3, differentiation of renal fibroblasts to myofibroblasts and proliferation of myofibroblasts. CONCLUSIONS AND SIGNIFICANCE: These results demonstrate that class I HDACs are critically involved in renal fibrogenesis and renal fibroblast activation through modulating TGF-beta and EGFR signaling and suggest that blockade of class I HDAC may be a useful treatment for renal fibrosis. PMID- 23342061 TI - Activation of p53 by chemotherapeutic agents enhances reovirus oncolysis. AB - Mammalian reovirus is a benign virus that possesses the natural ability to preferentially infect and kill cancer cells (reovirus oncolysis). Reovirus exploits aberrant Ras signalling in many human cancers to promote its own replication and spread. In vitro and in vivo studies using reovirus either singly or in combination with anti-cancer drugs have shown very encouraging results. Presently, a number of reovirus combination therapies are undergoing clinical trials for a variety of cancers. Previously we showed that accumulation of the tumor suppressor protein p53 by Nutlin-3a (a specific p53 stabilizer) enhanced reovirus-induced apoptosis, and resulted in significantly higher levels of reovirus dissemination. In this study, we examined the role of p53 in combination therapies involving reovirus and chemotherapeutic drugs. We showed that sub lethal concentrations of traditional chemotherapy drugs actinomycin D or etoposide, but not doxorubicin, enhanced reovirus-induced apoptosis in a p53 dependent manner. Furthermore, NF-kappaB activation and expression of p53-target genes (p21 and bax) were important for the p53-dependent enhancement of cell death. Our results show that p53 status affects the efficacy of combination therapy involving reovirus. Choosing the right combination partner for reovirus and a low dosage of the drug may help to both enhance reovirus-induced cancer elimination and reduce drug toxicity. PMID- 23342062 TI - A reduction in age-enhanced gluconeogenesis extends lifespan. AB - The regulation of energy metabolism, such as calorie restriction (CR), is a major determinant of cellular longevity. Although augmented gluconeogenesis is known to occur in aged yeast cells, the role of enhanced gluconeogenesis in aged cells remains undefined. Here, we show that age-enhanced gluconeogenesis is suppressed by the deletion of the tdh2 gene, which encodes glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a protein that is involved in both glycolysis and gluconeogenesis in yeast cells. The deletion of TDH2 restores the chronological lifespan of cells with deletions of both the HST3 and HST4 genes, which encode yeast sirtuins, and represses the activation of gluconeogenesis. Furthermore, the tdh2 gene deletion can extend the replicative lifespan in a CR pathway-dependent manner. These findings demonstrate that the repression of enhanced gluconeogenesis effectively extends the cellular lifespan. PMID- 23342063 TI - Seroepidemiological survey for Coxiella burnetii antibodies and associated risk factors in Dutch livestock veterinarians. AB - Since 2007, Q fever has become a major public health problem in the Netherlands and goats were the most likely source of the human outbreaks in 2007, 2008 and 2009. Little was known about the consequences of these outbreaks for those professional care providers directly involved. The aim of this survey was to estimate the seroprevalence of antibodies against C. burnetii among Dutch livestock veterinarians and to determine possible risk factors. Single blood samples from 189 veterinarians, including veterinary students in their final year, were collected at a veterinary conference and a questionnaire was filled in by each participant. The blood samples were screened for IgG antibodies against phase I and phase II antigen of C. burnetii using an indirect immunofluorescent assay, and for IgM antibodies using an ELISA. Antibodies against C. burnetii were detected in 123 (65.1%) out of 189 veterinarians. Independent risk factors associated with seropositivity were number of hours with animal contact per week, number of years graduated as veterinarian, rural or sub urban living area, being a practicing veterinarian, and occupational contact with swine. Livestock veterinarians should be aware of this risk to acquire an infection with C. burnetii. Physicians should consider potential infection with C. burnetii when treating occupational risk groups, bearing in mind that the burden of disease among veterinarians remains uncertain. Vaccination of occupational risk groups should be debated. PMID- 23342064 TI - Measures of the constitutive immune system are linked to diet and roosting habits of neotropical bats. AB - Ecological and social factors are central in the emergence and transmission of infectious diseases, thus bearing the potential for shaping a species' immune functions. Although previous studies demonstrated a link between social factors and the cellular immune system for captive mammals, it is yet poorly understood how ecological factors are connected with the different branches of the immune system in wild populations. Here, we tested how variation in aspects of the constitutive cellular and humoral immune system of free ranging bats is associated with two ecological factors that likely influence the putative risk of species to become infected by parasites and pathogens: diet and shelter. We found that white blood cell counts of 24 syntopic Neotropical bat species varied with the species' diet and body mass. Bats that included at least partially vertebrates in their diet exhibited the highest white blood cell counts, followed by phytophagous and insectivorous species, which is in agreement with the assumption that the immune system varies with the pathogen transmission risk of a trophic level. The soluble part of the constitutive immune response, assessed by an in vitro bacterial killing assay, decreased with increasing roost permanence. Our results suggest that the ecology is an important factor in the evolution of the immune system in bats and probably also other mammals. PMID- 23342065 TI - New production regulates export stoichiometry in the ocean. AB - The proportion in which carbon and growth-limiting nutrients are exported from the oceans' productive surface layer to the deep sea is a crucial parameter in models of the biological carbon pump. Based on >400 vertical flux observations of particulate organic carbon (POC) and nitrogen (PON) from the European Arctic Ocean we show the common assumption of constant C:N stoichiometry not to be met. Exported POC:PON ratios exceeded the classical Redfield atomic ratio of 6.625 in the entire region, with the largest deviation in the deep Central Arctic Ocean. In this part the mean exported POC:PON ratio of 9.7 (a:a) implies c. 40% higher carbon export compared to Redfield-based estimates. When spatially integrated, the potential POC export in the European Arctic was 10-30% higher than suggested by calculations based on constant POC:PON ratios. We further demonstrate that the exported POC:PON ratio varies regionally in relation to nitrate-based new production over geographical scales that range from the Arctic to the subtropics, being highest in the least productive oligotrophic Central Arctic Ocean and subtropical gyres. Accounting for variations in export stoichiometry among systems of different productivity will improve the ability of models to resolve regional patterns in carbon export and, hence, the oceans' contribution to the global carbon cycle will be predicted more accurately. PMID- 23342066 TI - Soil TPH concentration estimation using vegetation indices in an oil polluted area of eastern China. AB - Assessing oil pollution using traditional field-based methods over large areas is difficult and expensive. Remote sensing technologies with good spatial and temporal coverage might provide an alternative for monitoring oil pollution by recording the spectral signals of plants growing in polluted soils. Total petroleum hydrocarbon concentrations of soils and the hyperspectral canopy reflectance were measured in wetlands dominated by reeds (Phragmites australis) around oil wells that have been producing oil for approximately 10 years in the Yellow River Delta, eastern China to evaluate the potential of vegetation indices and red edge parameters to estimate soil oil pollution. The detrimental effect of oil pollution on reed communities was confirmed by the evidence that the aboveground biomass decreased from 1076.5 g m(-2) to 5.3 g m(-2) with increasing total petroleum hydrocarbon concentrations ranging from 9.45 mg kg(-1) to 652 mg kg(-1). The modified chlorophyll absorption ratio index (MCARI) best estimated soil TPH concentration among 20 vegetation indices. The linear model involving MCARI had the highest coefficient of determination (R(2) = 0.73) and accuracy of prediction (RMSE = 104.2 mg kg(-1)). For other vegetation indices and red edge parameters, the R(2) and RMSE values ranged from 0.64 to 0.71 and from 120.2 mg kg(-1) to 106.8 mg kg(-1) respectively. The traditional broadband normalized difference vegetation index (NDVI), one of the broadband multispectral vegetation indices (BMVIs), produced a prediction (R(2) = 0.70 and RMSE = 110.1 mg kg(-1)) similar to that of MCARI. These results corroborated the potential of remote sensing for assessing soil oil pollution in large areas. Traditional BMVIs are still of great value in monitoring soil oil pollution when hyperspectral data are unavailable. PMID- 23342067 TI - Association of glutathione S transferases polymorphisms with glaucoma: a meta analysis. AB - BACKGROUND: Glutathione S transferase (GST) polymorphisms have been considered risk factors for the development of glaucoma, including primary open angle glaucoma (POAG) and other types of glaucoma. However, the results remain controversial. In this study, we have conducted a meta-analysis to assess the association between polymorphisms of GSTM1, GSTT1 and GSTP1 and glaucoma risk. METHODS: Published literature from PubMed and other databases were retrieved. All studies evaluating the association between GSTM1, GSTT1 and GSTP1 polymorphisms and glaucoma risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model. RESULTS: Twelve studies on GSTM1 (1109 cases and 844 controls), ten studies on GSTT1 (709 cases and 664 controls) and four studies on GSTP1 (543 cases and 511 controls) were included. By pooling all the studies, either GSTM1 or GSTT1 null polymorphism was not associated with a POAG risk, and this negative association maintained in Caucasian. The GSTP1 Ile 105 Val polymorphism was significantly correlated with increased POAG risk among Caucasian in a recessive model (Val/Val vs. Ile/Ile+Ile/Val: OR, 1.62, 95%CI: 1.00-2.61). Interestingly, increased glaucoma risk was associated with the combined GSTM1 and GSTT1 null genotypes (OR, 2.20; 95% CI, 1.47-3.31), and with the combined GSTM1 null and GSTP1 Val genotypes (OR, 1.86; 95% CI, 1.15-3.01). CONCLUSIONS: This meta-analysis suggests that combinations of GST polymorphisms are associated with glaucoma risk. Given the limited sample size, the associations between single GST polymorphism and glaucoma risk await further investigation. PMID- 23342068 TI - Contributions of PHOX2B in the pathogenesis of Hirschsprung disease. AB - Hirschsprung disease (HSCR) is a congenital malformation of the hindgut resulting from a disruption of neural crest cell migration during embryonic development. It has a complex genetic aetiology with several genes involved in its pathogenesis. PHOX2B plays a key function in the development of neural crest derivatives, and heterozygous mutations cause a complex dysautonomia associating HSCR, Congenital Central Hypoventilation Syndrome (CCHS) and neuroblastoma (NB) in various combinations. In order to determine the role of PHOX2B in isolated HSCR, we performed a mutational screening in a cohort of 207 Spanish HSCR patients. Our most relevant finding has been the identification of a de novo and novel deletion (c.393_410del18) in a patient with HSCR. Results of in silico and functional assays support its pathogenic effect related to HSCR. Therefore our results support that PHOX2B loss-of-function is a rare cause of HSCR phenotype. PMID- 23342069 TI - The frequency of granulocytes with spontaneous somatic mutations: a wide distribution in a normal human population. AB - Germ-line mutation rate has been regarded classically as a fundamental biological parameter, as it affects the prevalence of genetic disorders and the rate of evolution. Somatic mutation rate is also an important biological parameter, as it may influence the development and/or the course of acquired diseases, particularly of cancer. Estimates of this parameter have been previously obtained in few instances from dermal fibroblasts and lymphoblastoid cells. However, the methodology required has been laborious and did not lend itself to the analysis of large numbers of samples. We have previously shown that the X-linked gene PIG A, since its product is required for glycosyl-phosphatidylinositol-anchored proteins to become surface bound, is a good sentinel gene for studying somatic mutations. We now show that by this approach we can accurately measure the proportion of PIG-A mutant peripheral blood granulocytes, which we call mutant frequency, f. We found that the results are reproducible, with a variation coefficient (CV) of 45%. Repeat samples from 32 subjects also had a CV of 44%, indicating that f is a relatively stable individual characteristic. From a study of 142 normal subjects we found that log f is a normally distributed variable; f variability spans a 80-fold range, from less than 1*10-6 to 37.5*10-6, with a median of 4.9*10-6. Unlike other techniques commonly employed in population studies, such as comet assay, this method can detect any kind of mutation, including point mutation, as long as it causes functional inactivation of PIG-A gene. Since the test is rapid and requires only a small sample of peripheral blood, this methodology will lend itself to investigating genetic factors that underlie the variation in the somatic mutation rate, as well as environmental factors that may affect it. It will be also possible to test whether f is a determinant of the risk of cancer. PMID- 23342070 TI - Computer assisted assembly of connectomes from electron micrographs: application to Caenorhabditis elegans. AB - A rate-limiting step in determining a connectome, the set of all synaptic connections in a nervous system, is extraction of the relevant information from serial electron micrographs. Here we introduce a software application, Elegance, that speeds acquisition of the minimal dataset necessary, allowing the discovery of new connectomes. We have used Elegance to obtain new connectivity data in the nematode worm Caenorhabditis elegans. We analyze the accuracy that can be obtained, which is limited by unresolvable ambiguities at some locations in electron microscopic images. Elegance is useful for reconstructing connectivity in any region of neuropil of sufficiently small size. PMID- 23342071 TI - PGC1alpha plays a critical role in TWEAK-induced cardiac dysfunction. AB - BACKGROUND: Inflammatory cytokines play an important role in the pathogenesis of heart failure. We have recently found the cytokine TWEAK (tumor necrosis factor (TNF)-like weak inducer of apoptosis), a member of the TNF superfamily, to be increased in patients with cardiomyopathy and result in the development of heart failure when overexpressed in mice. The molecular mechanisms underlying TWEAK induced cardiac pathology, however, remain unknown. METHODOLOGY AND CRITICAL FINDING: Using mouse models of elevated circulating TWEAK levels, established through intravenous injection of adenovirus expressing TWEAK or recombinant TWEAK protein, we find that TWEAK induces a progressive dilated cardiomyopathy with impaired contractile function in mice. Moreover, TWEAK treatment is associated with decreased expression of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC1alpha) and genes required for mitochondrial oxidative phosphorylation, which precede the onset of cardiac dysfunction. TWEAK-induced downregulation of PGC1alpha requires expression of its cell surface receptor, fibroblast growth factor-inducible 14 (Fn14). We further find that TWEAK downregulates PGC1alpha gene expression via the TNF receptor-associated factor 2 (TRAF2) and NFkappaB signaling pathways. Maintaining PGC1alpha levels through adenoviral-mediated gene expression is sufficient to protect against TWEAK induced cardiomyocyte dysfunction. CONCLUSION: Collectively, our data suggest that TWEAK induces cardiac dysfunction via downregulation of PGC1alpha, through FN14-TRAF2-NFkappaB-dependent signaling. Selective targeting of the FN14-TRAF2 NFkappaB-dependent signaling pathway or augmenting PGC1alpha levels may serve as novel therapeutic strategies for cardiomyopathy and heart failure. PMID- 23342072 TI - Quantitative immunohistochemical analysis reveals association between sodium iodide symporter and estrogen receptor expression in breast cancer. AB - BACKGROUND: Human sodium iodide symporter (hNIS) gene over-expression is under active consideration worldwide as an alternative target molecule for breast cancer (BC) diagnosis and targeted radio-iodine treatment. However, the field demands better stratified analysis of endogenous hNIS expression across major BC subtypes. Therefore, we have analyzed subtype-specific variation of hNIS overexpression in breast tumor tissue samples by immunohistochemistry (IHC) and also report the development of a homogeneous, quantitative analysis method of digital IHC images. METHODS: hNIS expression was analyzed from 108 BC tissue samples by IHC. Sub-cellular localization of hNIS protein was analyzed by dual immunofluorescence (IF) staining method using hNIS and HER2 antibodies. An ImageJ based two-step digital analysis method was developed and applied for the bias free analysis of the images. RESULTS: Staining of the tumor samples show 70% cases are hNIS positive indicating high incidence of hNIS positive cases in BC. More importantly, a subtype specific analysis done for the first time shows that hNIS expression is overly dominated in estrogen receptor (ER) positive cases than the receptor negative cases. Further, 56% of the ER+ve, PgR+ve, HER2-ve and 36% of ER+ve, PgR+ve, HER2+ve cases show highest intensity staining equivalent to the thyroid tissue. A significant positive correlation is also observed between hNIS and estrogen receptor expression (p = 0.0033, CI = 95%) suggesting hNIS mediated targeted radio-iodine therapy procedures may benefit both ER+ve, PgR+ve, HER2-ve as well as HER2+ve cases. Further, in a few cases, hNIS and HER2 protein localization is demonstrated by overlapping membrane co-expression. ImageJ based image analysis method shows over 70% match with manual pathological scoring method. CONCLUSION: The study indicates a positive link between hNIS and ER expression in BC. The quantitative IHC image analysis method reported here will further help in patient stratification and potentially benefit global clinical assessment where hNIS mediated targeted 131I radio-ablative therapy is aimed. PMID- 23342073 TI - Genetic and epigenetic variations induced by wheat-rye 2R and 5R monosomic addition lines. AB - BACKGROUND: Monosomic alien addition lines (MAALs) can easily induce structural variation of chromosomes and have been used in crop breeding; however, it is unclear whether MAALs will induce drastic genetic and epigenetic alterations. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, wheat-rye 2R and 5R MAALs together with their selfed progeny and parental common wheat were investigated through amplified fragment length polymorphism (AFLP) and methylation-sensitive amplification polymorphism (MSAP) analyses. The MAALs in different generations displayed different genetic variations. Some progeny that only contained 42 wheat chromosomes showed great genetic/epigenetic alterations. Cryptic rye chromatin has introgressed into the wheat genome. However, one of the progeny that contained cryptic rye chromatin did not display outstanding genetic/epigenetic variation. 78 and 49 sequences were cloned from changed AFLP and MSAP bands, respectively. Blastn search indicated that almost half of them showed no significant similarity to known sequences. Retrotransposons were mainly involved in genetic and epigenetic variations. Genetic variations basically affected Gypsy like retrotransposons, whereas epigenetic alterations affected Copia-like and Gypsy-like retrotransposons equally. Genetic and epigenetic variations seldom affected low-copy coding DNA sequences. CONCLUSIONS/SIGNIFICANCE: The results in the present study provided direct evidence to illustrate that monosomic wheat-rye addition lines could induce different and drastic genetic/epigenetic variations and these variations might not be caused by introgression of rye chromatins into wheat. Therefore, MAALs may be directly used as an effective means to broaden the genetic diversity of common wheat. PMID- 23342074 TI - Mitochondrial DNA damage and dysfunction, and oxidative stress are associated with endoplasmic reticulum stress, protein degradation and apoptosis in high fat diet-induced insulin resistance mice. AB - BACKGROUND: Recent studies showed a link between a high fat diet (HFD)-induced obesity and lipid accumulation in non-adipose tissues, such as skeletal muscle and liver, and insulin resistance (IR). Although the mechanisms responsible for IR in those tissues are different, oxidative stress and mitochondrial dysfunction have been implicated in the disease process. We tested the hypothesis that HFD induced mitochondrial DNA (mtDNA) damage and that this damage is associated with mitochondrial dysfunction, oxidative stress, and induction of markers of endoplasmic reticulum (ER) stress, protein degradation and apoptosis in skeletal muscle and liver in a mouse model of obesity-induced IR. METHODOLOGY/PRINCIPAL FINDINGS: C57BL/6J male mice were fed either a HFD (60% fat) or normal chow (NC) (10% fat) for 16 weeks. We found that HFD-induced IR correlated with increased mtDNA damage, mitochondrial dysfunction and markers of oxidative stress in skeletal muscle and liver. Also, a HFD causes a change in the expression level of DNA repair enzymes in both nuclei and mitochondria in skeletal muscle and liver. Furthermore, a HFD leads to activation of ER stress, protein degradation and apoptosis in skeletal muscle and liver, and significantly reduced the content of two major proteins involved in insulin signaling, Akt and IRS-1 in skeletal muscle, and Akt in liver. Basal p-Akt level was not significantly influenced by HFD feeding in skeletal muscle and liver. CONCLUSIONS/SIGNIFICANCE: This study provides new evidence that HFD-induced mtDNA damage correlates with mitochondrial dysfunction and increased oxidative stress in skeletal muscle and liver, which is associated with the induction of markers of ER stress, protein degradation and apoptosis. PMID- 23342075 TI - Deciphering structural intermediates and genotoxic fibrillar aggregates of albumins: a molecular mechanism underlying for degenerative diseases. AB - The misfolding and aggregation of proteins is involved in some of the most prevalent neurodegenerative disorders. The importance of human serum albumin (HSA) stems from the fact that it is involved in bio-regulatory and transport phenomena. Here the effect of acetonitrile (ACN) on the conformational stability of HSA and by comparison, ovalbumin (OVA) has been evaluated in the presence and absence of NaCl. The results show the presence of significant amount of secondary structure in HSA at 70% ACN and in OVA at 50% ACN, as evident from far-UV Circular Dichroism (CD) and Attenuated Total Reflection Fourier transformed infra red spectroscopy (ATR-FTIR). Tryptophan and 8-Anilino-1-Naphthalene-Sulphonic acid (ANS) fluorescence indicate altered tryptophan environment and high ANS binding suggesting a compact "molten globule"-like conformation with enhanced exposure of hydrophobic surface area. However, in presence of NaCl no intermediate state was observed. Detection of aggregates in HSA and OVA was possible at 90% ACN. Aggregates possess extensive beta-sheet structure as revealed by far-UV CD and ATR-FTIR. These aggregates exhibit increase Thioflavin T (Th T) fluorescence with a red shift of Congo red (CR) absorption spectrum. X ray diffraction (XRD) and Scanning Electron Microscopy (SEM) analysis confirmed the presence of fibrillar aggregates. Single cell gel electrophoresis (SCGE) assay of these fibrillar aggregates showed the DNA damage resulting in cell necrosis confirming their genotoxic nature. Some proteins not related to any human disease form fibrils in vitro. In the present study ACN gives access to a model system to study the process of aggregation. PMID- 23342076 TI - The influence of a single nucleotide polymorphism within CNDP1 on susceptibility to diabetic nephropathy in Japanese women with type 2 diabetes. AB - BACKGROUND: Several linkage analyses have mapped a susceptibility locus for diabetic nephropathy to chromosome 18q22-23, and polymorphisms within the carnosine dipeptidase 1 gene (CNDP1), located on 18q22.3, have been shown to be associated with diabetic nephropathy in European subjects with type 2 diabetes. However, the association of this locus with diabetic nephropathy has not been evaluated in the Japanese population. In this study, we examined the association of polymorphisms within the CNDP1/CNDP 2 locus with diabetic nephropathy in Japanese subjects with type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped a leucine repeat polymorphism (D18S880) that is within CNDP1 along with 29 single nucleotide polymorphisms (SNPs) in the CNDP1/CNDP2 locus for 2,740 Japanese subjects with type 2 diabetes (1,205 nephropathy cases with overt nephropathy or with end-stage renal disease [ESRD], and 1,535 controls with normoalbuminuria). The association of each polymorphism with diabetic nephropathy was analysed by performing logistic regression analysis. We did not observe any association between D18S880 and diabetic nephropathy in Japanese subjects with type 2 diabetes. None of the 29 SNPs within the CNDP1/CNDP2 locus were associated with diabetic nephropathy, but a subsequent sex-stratified analysis revealed that 1 SNP in CNDP1 was nominally associated with diabetic nephropathy in women (rs12604675-A; p = 0.005, odds ratio [OR] = 1.76, 95% confidence interval [CI], 1.19-2.61). Rs12604675 was associated with overt proteinuria (p = 0.002, OR = 2.18, 95% CI, 1.32-3.60), but not with ESRD in Japanese women with type 2 diabetes. CONCLUSIONS/SIGNIFICANCE: Rs12604675-A in CNDP1 may confer susceptibility to overt proteinuria in Japanese women with type 2 diabetes. PMID- 23342077 TI - Low-power laser irradiation suppresses inflammatory response of human adipose derived stem cells by modulating intracellular cyclic AMP level and NF-kappaB activity. AB - Mesenchymal stem cell (MSC)-based tissue regeneration is a promising therapeutic strategy for treating damaged tissues. However, the inflammatory microenvironment that exists at a local injury site might restrict reconstruction. Low-power laser irradiation (LPLI) has been widely applied to retard the inflammatory reaction. The purpose of this study was to investigate the anti-inflammatory effect of LPLI on human adipose-derived stem cells (hADSCs) in an inflammatory environment. We showed that the hADSCs expressed Toll-like Receptors (TLR) 1, TLR2, TLR3, TLR4, and TLR6 and that lipopolysaccharide (LPS) significantly induced the production of pro-inflammatory cytokines (Cyclooxygenase-2 (Cox-2), Interleukin-1beta (IL 1beta), Interleukin-6 (IL-6), and Interleukin-8 (IL-8)). LPLI markedly inhibited LPS-induced, pro-inflammatory cytokine expression at an optimal dose of 8 J/cm2. The inhibitory effect triggered by LPLI might occur through an increase in the intracellular level of cyclic AMP (cAMP), which acts to down-regulate nuclear factor kappa B (NF-kappaB) transcriptional activity. These data collectively provide insight for further investigations of the potential application of anti inflammatory treatment followed by stem cell therapy. PMID- 23342078 TI - Community change within a Caribbean coral reef Marine Protected Area following two decades of local management. AB - Structural change in both the habitat and reef-associated fish assemblages within spatially managed coral reefs can provide key insights into the benefits and limitations of Marine Protected Areas (MPAs). While MPA zoning effects on particular target species are well reported, we are yet to fully resolve the various affects of spatial management on the structure of coral reef communities over decadal time scales. Here, we document mixed affects of MPA zoning on fish density, biomass and species richness over the 21 years since establishment of the Saba Marine Park (SMP). Although we found significantly greater biomass and species richness of reef-associated fishes within shallow habitats (5 meters depth) closed to fishing, this did not hold for deeper (15 m) habitats, and there was a widespread decline (38% decrease) in live hard coral cover and a 68% loss of carnivorous reef fishes across all zones of the SMP from the 1990s to 2008. Given the importance of live coral for the maintenance and replenishment of reef fishes, and the likely role of chronic disturbance in driving coral decline across the region, we explore how local spatial management can help protect coral reef ecosystems within the context of large-scale environmental pressures and disturbances outside the purview of local MPA management. PMID- 23342079 TI - The stigma of migraine. AB - BACKGROUND: People who have a disease often experience stigma, a socially and culturally embedded process through which individuals experience stereotyping, devaluation, and discrimination. Stigma has great impact on quality of life, behavior, and life chances. We do not know whether or not migraine is stigmatizing. METHODS: We studied 123 episodic migraine patients, 123 chronic migraine patients, and 62 epilepsy patients in a clinical setting to investigate the extent to which stigma attaches to migraine, using epilepsy as a comparison. We used the stigma scale for chronic illness, a 24-item questionnaire suitable for studying chronic neurologic diseases, and various disease impact measures. RESULTS: Patients with chronic migraine had higher scores (54.0+/-20.2) on the stigma scale for chronic illness than either episodic migraine (41.7+/-14.8) or epilepsy patients (44.6+/-16.3) (p<0.001). Subjects with migraine reported greater inability to work than epilepsy subjects. Stigma correlated most strongly with the mental component score of the short form of the medical outcomes health survey (SF-12), then with ability to work and migraine disability score for chronic and episodic migraine and the Liverpool impact on epilepsy scale for epilepsy. Analysis of covariance showed adjusted scores for the stigma scale for chronic illness were similar for chronic migraine (49.3; 95% confidence interval, 46.2 to 52.4) and epilepsy (46.5; 95% confidence interval, 41.6 to 51.6), and lower for episodic migraine (43.7; 95% confidence interval, 40.9 to 46.6). Ability to work was the strongest predictor of stigma as measured by the stigma scale for chronic illness. CONCLUSION: In our model, adjusted stigma was similar for chronic migraine and epilepsy, which were greater than for episodic migraine. Stigma correlated most strongly with inability to work, and was greater for chronic migraine than epilepsy or episodic migraine because chronic migraine patients had less ability to work. PMID- 23342080 TI - Gene expression signatures that predict outcome of tamoxifen-treated estrogen receptor-positive, high-risk, primary breast cancer patients: a DBCG study. AB - BACKGROUND: Tamoxifen significantly improves outcome for estrogen receptor positive (ER+) breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono therapy. METHODOLOGY/PRINCIPAL FINDINGS: Post-menopausal breast cancer patients diagnosed no later than 2002, being ER+ as defined by >1% IHC staining and having a frozen tumor sample with >50% tumor content were included. Tumor samples from 108 patients treated with adjuvant Tamoxifen were analyzed for the expression of 59 genes using quantitative-PCR. End-point was clinically verified recurrence to distant organs or ipsilateral breast. Gene profiles were identified using a model building procedure based on conditional logistic regression and leave-one-out cross-validation, followed by a non-parametric bootstrap (1000x re-sampling). The optimal profiles were further examined in 5 previously-reported datasets containing similar patient populations that were either treated with Tamoxifen or left untreated (n = 623). Three gene signatures were identified, the strongest being a 2-gene combination of BCL2-CDKN1A, exhibiting an accuracy of 75% for prediction of outcome. Independent examination using 4 previously-reported microarray datasets of Tamoxifen-treated patient samples (n = 503) confirmed the potential of BCL2-CDKN1A. The predictive value was further determined by comparing the ability of the genes to predict recurrence in an additional, previously-published, cohort consisting of Tamoxifen-treated (n = 58, p = 0.015) and untreated patients (n = 62, p = 0.25). CONCLUSIONS/SIGNIFICANCE: A novel gene expression signature predictive of outcome of Tamoxifen-treated patients was identified. The validation suggests that BCL2-CDKN1A exhibit promising predictive potential. PMID- 23342081 TI - Efficacy of single and multiple injections of human umbilical tissue-derived cells following experimental stroke in rats. AB - INTRODUCTION: Human umbilical tissue-derived cells (hUTC) are a promising source of cells for regenerative treatment of stroke. In this study, we tested the efficacy of hUTC in experimental stroke and whether multiple injections of hUTC provide additional therapeutic benefits as compared to a single injection. METHODS: Adult male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo), and randomly selected animals were injected (i.v) with 3*106 hUTC or with vehicle control (at day: 1, 1&3 or 1&7 after MCAo, n = 8 9/group). A battery of functional outcome tests was performed at days 1, 7, 14, 21, 28, 35, 42, 49, 56 and 63 after MCAo. Rats were sacrificed at 63 days after MCAo and lesion volumes were measured. To investigate the underlying mechanism of hUTC treatment of stroke, Von Willebrand Factor (vWF), and Synaptophysin immunostaining were performed. RESULTS: All hUTC treated groups, single or multiple injections, had better functional recovery compared to control (p<0.01). There was no statistically significant difference between a single and multiple injections of hUTC (p = 0.23) or between different multiple injections groups (p>0.07) in functional outcome. All hUTC treatment groups showed significant increases in Synaptophysin, vascular density and perimeter compared to the control group (p<0.05). There was no statistically significant difference between a single and multiple injections of hUTC or between the two groups of multiple injections in all immunohistochemical measurements (p>0.1). CONCLUSION: hUTC treatment significantly improves long term functional outcome after stroke and promotes vascular density and synaptic plasticity. At the proscribed doses, multiple injections of hUTC were not superior to single injection therapy in both functional outcome and histological assessments. PMID- 23342082 TI - Middle ear cavity morphology is consistent with an aquatic origin for testudines. AB - The position of testudines in vertebrate phylogeny is being re-evaluated. At present, testudine morphological and molecular data conflict when reconstructing phylogenetic relationships. Complicating matters, the ecological niche of stem testudines is ambiguous. To understand how turtles have evolved to hear in different environments, we examined middle ear morphology and scaling in most extant families, as well as some extinct species, using 3-dimensional reconstructions from micro magnetic resonance (MR) and submillimeter computed tomography (CT) scans. All families of testudines exhibited a similar shape of the bony structure of the middle ear cavity, with the tympanic disk located on the rostrolateral edge of the cavity. Sea Turtles have additional soft tissue that fills the middle ear cavity to varying degrees. When the middle ear cavity is modeled as an air-filled sphere of the same volume resonating in an underwater sound field, the calculated resonances for the volumes of the middle ear cavities largely fell within testudine hearing ranges. Although there were some differences in morphology, there were no statistically significant differences in the scaling of the volume of the bony middle ear cavity with head size among groups when categorized by phylogeny and ecology. Because the cavity is predicted to resonate underwater within the testudine hearing range, the data support the hypothesis of an aquatic origin for testudines, and function of the middle ear cavity in underwater sound detection. PMID- 23342083 TI - Invasive fishes generate biogeochemical hotspots in a nutrient-limited system. AB - Fishes can play important functional roles in the nutrient dynamics of freshwater systems. Aggregating fishes have the potential to generate areas of increased biogeochemical activity, or hotspots, in streams and rivers. Many of the studies documenting the functional role of fishes in nutrient dynamics have focused on native fish species; however, introduced fishes may restructure nutrient storage and cycling freshwater systems as they can attain high population densities in novel environments. The purpose of this study was to examine the impact of a non native catfish (Loricariidae: Pterygoplichthys) on nitrogen and phosphorus remineralization and estimate whether large aggregations of these fish generate measurable biogeochemical hotspots within nutrient-limited ecosystems. Loricariids formed large aggregations during daylight hours and dispersed throughout the stream during evening hours to graze benthic habitats. Excretion rates of phosphorus were twice as great during nighttime hours when fishes were actively feeding; however, there was no diel pattern in nitrogen excretion rates. Our results indicate that spatially heterogeneous aggregations of loricariids can significantly elevate dissolved nutrient concentrations via excretion relative to ambient nitrogen and phosphorus concentrations during daylight hours, creating biogeochemical hotspots and potentially altering nutrient dynamics in invaded systems. PMID- 23342085 TI - Examining the cross-cultural sensitivity of the Revised Two-Factor Study Process Questionnaire (R-SPQ-2F) and validation of a Dutch version. AB - The Revised Two-Factor Study Process Questionnaire (R-SPQ-2F) is used to examine students' study approaches in higher education. The questionnaire assumes to measure two factors: a deep and a surface study approach. Analyses into the validity and reliability of the original English R-SPQ-2F yielded positive results. In this study, we examined the degree to which these positive results can also be found for the Dutch version that we developed. By comparing our results with the results of earlier studies in different cultures, we conclude cross-cultural sensitivity is an important point to be borne in mind when using the R-SPQ-2F. Our research supports the validity and reliability of our Dutch version of the R-SPQ-2F. PMID- 23342084 TI - Early growth response 3 (Egr3) is highly over-expressed in non-relapsing prostate cancer but not in relapsing prostate cancer. AB - Members of the early growth response (EGR) family of transcription factors play diverse functions in response to many cellular stimuli, including growth, stress, and inflammation. Egr3 has gone relatively unstudied, but here through use of the SPECS (Strategic Partners for the Evaluation of Predictive Signatures of Prostate Cancer) Affymetrix whole genome gene expression database we report that Egr3 mRNA is significantly over-expressed in prostate cancer compared to normal prostate tissue (5-fold). The Human Protein Atlas (http://www.proteinatlas.org), a database of tissue microarrays labeled with antibodies against over 11,000 human proteins, was utilized to quantify Egr3 protein expression in normal prostate and prostate cancer patients. In agreement with the SPECS data, we found that Egr3 protein is significantly increased in prostate cancer. The SPECS database has the benefit of extensive clinical follow up for the prostate cancer patients. Analysis of Egr3 mRNA expression in relation to the relapse status reveals that Egr3 mRNA expression is increased in tumor cells of non-relapsed samples (n = 63) compared to normal prostate cells, but is significantly lower in relapsed samples (n = 38) compared to non-relapse. The observations were confirmed using an independent data set. A list of genes correlating with this unique expression pattern was determined. These Egr3-correlated genes were enriched with Egr binding sites in their promoters. The gene list contains inflammatory genes such as IL-6, IL-8, IL1beta and COX-2, which have extensive connections to prostate cancer. PMID- 23342086 TI - The adipocytokine Nampt and its product NMN have no effect on beta-cell survival but potentiate glucose stimulated insulin secretion. AB - AIMS/HYPOTHESIS: Obesity is associated with a dysregulation of beta-cell and adipocyte function. The molecular interactions between adipose tissue and beta cells are not yet fully elucidated. We investigated, whether or not the adipocytokine Nicotinamide phosphoribosyltransferase (Nampt) and its enzymatic product Nicotinamide mononucleotide (NMN), which has been associated with obesity and type 2 diabetes mellitus (T2DM) directly influence beta-cell survival and function. METHODS: The effect of Nampt and NMN on viability of INS-1E cells was assessed by WST-1 assay. Apoptosis was measured by Annexin V/PI and TUNEL assay. Activation of apoptosis signaling pathways was evaluated. Adenylate kinase release was determined to assess cytotoxicity. Chronic and acute effects of the adipocytokine Nampt and its enzymatic product NMN on insulin secretion were assessed by glucose stimulated insulin secretion in human islets. RESULTS: While stimulation of beta-cells with the cytokines IL-1beta, TNFalpha and IFN-gamma or palmitate significantly decreased viability, Nampt and NMN showed no direct effect on viability in INS-1E cells or in human islets, neither alone nor in the presence of pro-diabetic conditions (elevated glucose concentrations and palmitate or cytokines). At chronic conditions over 3 days of culture, Nampt and its product NMN had no effects on insulin secretion. In contrast, both Nampt and NMN potentiated glucose stimulated insulin secretion acutely during 1 h incubation of human islets. CONCLUSION/INTERPRETATION: Nampt and NMN neither influenced beta-cell viability nor apoptosis but acutely potentiated glucose stimulated insulin secretion. PMID- 23342087 TI - The intestine plays a substantial role in human vitamin B6 metabolism: a Caco-2 cell model. AB - BACKGROUND: Vitamin B6 is present in various forms (vitamers) in the diet that need to be metabolized to pyridoxal phosphate (PLP), the active cofactor form of vitamin B6. In literature, the liver has been reported to be the major site for this conversion, whereas the exact role of the intestine remains to be elucidated. OBJECTIVE: To gain insight into the role of the intestine in human vitamin B6 metabolism. MATERIALS AND METHODS: Expression of the enzymes pyridoxal kinase (PK), pyridox(am)ine phosphate oxidase (PNPO) and PLP-phosphatase was determined in Caco-2 cells and in lysates of human intestine. Vitamin B6 uptake, conversion and excretion were studied in polarized Caco-2 cell monolayers. B6 vitamer concentrations (pyridoxine (PN), pyridoxal (PL), PLP, pyridoxamine (PM), pyridoxamine phosphate (PMP)) and pyridoxic acid (PA) were quantified by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) using stable isotope-labeled internal standards. RESULTS: The enzymatic system involved in vitamin B6 metabolism (PK, PNPO and PLP-phosphatase) is fully expressed in Caco-2 cells as well as in human intestine. We show uptake of PN, PM and PL by Caco-2 cells, conversion of PN and PM into PL and excretion of all three unphosphorylated B6 vitamers. CONCLUSION: We demonstrate, in a Caco-2 cell model, that the intestine plays a substantial role in human vitamin B6 metabolism. PMID- 23342088 TI - Transcriptome of Dickeya dadantii infecting Acyrthosiphon pisum reveals a strong defense against antimicrobial peptides. AB - The plant pathogenic bacterium Dickeya dadantii has recently been shown to be able to kill the aphid Acyrthosiphon pisum. While the factors required to cause plant disease are now well characterized, those required for insect pathogeny remain mostly unknown. To identify these factors, we analyzed the transcriptome of the bacteria isolated from infected aphids. More than 150 genes were upregulated and 300 downregulated more than 5-fold at 3 days post infection. No homologue to known toxin genes could be identified in the upregulated genes. The upregulated genes reflect the response of the bacteria to the conditions encountered inside aphids. While only a few genes involved in the response to oxidative stress were induced, a strong defense against antimicrobial peptides (AMP) was induced. Expression of a great number of efflux proteins and transporters was increased. Besides the genes involved in LPS modification by addition of 4-aminoarabinose (the arnBCADTEF operon) and phosphoethanolamine (pmrC, eptB) usually induced in Gram negative bacteria in response to AMPs, dltBAC and pbpG genes, which confer Gram positive bacteria resistance to AMPs by adding alanine to teichoic acids, were also induced. Both types of modification confer D. dadantii resistance to the AMP polymyxin. A. pisum harbors symbiotic bacteria and it is thought that it has a very limited immune system to maintain these populations and do not synthesize AMPs. The arnB mutant was less pathogenic to A. pisum, which suggests that, in contrast to what has been supposed, aphids do synthesize AMP. PMID- 23342090 TI - Early cenozoic differentiation of polar marine faunas. AB - The widespread assumption that the origin of polar marine faunas is linked to the onset of major global cooling in the Late Eocene-Early Oligocene is being increasingly challenged. The Antarctic fossil record in particular is suggesting that some modern Southern Ocean taxa may have Early Eocene or even Paleocene origins, i.e. well within the Early Cenozoic greenhouse world. A global analysis of one of the largest marine clades at the present day, the Neogastropoda, indicates that not only is there a decrease in the number of species from the tropics to the poles but also a decrease in the evenness of their distribution. A small number of neogastropod families with predominantly generalist trophic strategies at both poles points to the key role of seasonality in structuring the highest latitude marine assemblages. A distinct latitudinal gradient in seasonality is temperature-invariant and would have operated through periods of global warmth such as the Early Cenozoic. To test this concept a second global analysis was undertaken of earliest Cenozoic (Paleocene) neogastropods and this does indeed show a certain degree of faunal differentiation at both poles. The Buccinidae, s.l. is especially well developed at this time, and this is a major generalist taxon at the present day. There is an element of asymmetry associated with this development of Paleocene polar faunas in that those in the south are more strongly differentiated than their northern counterparts; this can in turn be linked to the already substantial isolation of the southern high latitudes. The key role of seasonality in the formation of polar marine faunas has implications for contemporary ecosystem structure and stability. PMID- 23342089 TI - Life history trade-offs and behavioral sensitivity to testosterone: an experimental test when female aggression and maternal care co-occur. AB - Research on male animals suggests that the hormone testosterone plays a central role in mediating the trade-off between mating effort and parental effort. However, the direct links between testosterone, intrasexual aggression and parental care are remarkably mixed across species. Previous attempts to reconcile these patterns suggest that selection favors behavioral insensitivity to testosterone when paternal care is essential to reproductive success and when breeding seasons are especially short. Females also secrete testosterone, though the degree to which similar testosterone-mediated trade-offs occur in females is much less clear. Here, I ask whether testosterone mediates trade-offs between aggression and incubation in females, and whether patterns of female sensitivity to testosterone relate to female life history, as is often the case in males. I experimentally elevated testosterone in free-living, incubating female tree swallows (Tachycineta bicolor), a songbird with a short breeding season during which female incubation and intrasexual aggression are both essential to female reproductive success. Testosterone-treated females showed significantly elevated aggression, reduced incubation temperatures, and reduced hatching success, relative to controls. Thus, prolonged testosterone elevation during incubation was detrimental to reproductive success, but females nonetheless showed behavioral sensitivity to testosterone. These findings suggest that the relative importance of both mating effort and parental effort may be central to understanding patterns of behavioral sensitivity in both sexes. PMID- 23342091 TI - Role of vaspin in human eating behaviour. AB - OBJECTIVE: The adipokine vaspin (visceral adipose tissue derived serine protease inhibitor, serpinA12) follows a meal-related diurnal variation in humans and intracerebroventricular vaspin administration leads to acutely reduced food intake in db/db mice. We therefore hypothesized that vaspin may play a role in human eating behaviour. MATERIALS AND METHODS: We measured serum vaspin concentrations in 548 subjects from a self-contained population of Sorbs (Germany) who underwent detailed metabolic testing including eating behaviour assessments using the three-factor eating questionnaire. In addition, genetic variation within vaspin was assessed by genotyping 28 single nucleotide polymorphisms (SNPs) in all study subjects. RESULTS: Serum vaspin concentrations correlated positively with restraint, disinhibition and hunger (all P<0.05), although the correlations did not withstand further adjustments for age, gender and BMI (all P>0.05). Independent of observed correlations, genetic variants in vaspin were associated with serum vaspin levels but showed no significant association with any of the eating behaviour phenotypes after accounting for multiple testing (P>=0.05 after adjusting for age, gender and BMI). CONCLUSION: Our data suggest that serum vaspin concentrations might modulate human eating behaviour, which does not seem to be affected by common genetic variation in vaspin. PMID- 23342092 TI - Violence as a barrier for HIV prevention among female sex workers in Argentina. AB - BACKGROUND: Violence against female sex workers (FSWs) has been increasingly reported as an important determinant of HIV infection risk. This study explores the frequency of different violent experiences (sexual abuse, rejection, beating and imprisonment) among FSWs in Argentina and its association with condom use and HIV and T. pallidum prevalence. METHODS: A convenience sample of 1255 FSWs was included in a cross-sectional study conducted between October 2006 and November 2009. RESULTS: Sexual abuse was reported by 24.1% (219/907) of women. A total of 34.7% (42/1234) reported rejection experiences, 21.9% (267/1215) reported having been beaten and 45.4% (561/1236) stated having been arrested because of their sex work activity. There was a higher frequency of inconsistent condom use with clients among FSWs who had experienced sexual abuse, rejection, and police detention. A higher frequency of HIV and T. pallidum infection was detected among FSWs who reported having been arrested by the police. CONCLUSION: The study shows for the first time the frequency of different violent situations among FSWs in Argentina. The association between violence against sex workers, condom use and STI prevalence demonstrated here calls for measures to reduce stigma and violence against FSWs. Such violent experiences may increase vulnerability to STI through coerced unprotected sex. PMID- 23342093 TI - Diversifying selection on flavanone 3-hydroxylase and isoflavone synthase genes in cultivated soybean and its wild progenitors. AB - Soybean isoflavone synthase (IFS) and flavanone 3-hydroxylase (F3H) are two key enzymes catalyzing the biosynthesis of isoflavonoids and flavonoids, both of which play diverse roles in stress responses. However, little is known about the evolutionary pattern of these genes in cultivated soybean and its wild progenitors. Herein, we investigated the nucleotide polymorphisms in Isoflavone synthase (IFS1, IFS2) and Flavanone 3-hydroxylase (F3H2) genes from 33 soybean accessions, including 17 cultivars (Glycine max) and 16 their wild progenitors (Glycine soja). Our data showed that the target genes shared the levels of nucleotide polymorphism with three reference genes involved in plant-microbe interactions, but possessed a much higher nucleotide polymorphism than other reference genes. Moreover, no significant genetic differentiation was found between cultivated soybean and its wild relatives in three target genes, despite of considering bottleneck and founder effect during domestication. These results indicate that IFS and F3H genes could have experienced gene introgressions or diversifying selection events during domestication process. Especially, F3H2 gene appears to evolve under positive selection and enjoy a faster evolutionary rate than IFS1 and IFS2 genes. PMID- 23342094 TI - MudPIT profiling reveals a link between anaerobic metabolism and the alkaline adaptive response of Listeria monocytogenes EGD-e. AB - Listeria monocytogenes is a foodborne human pathogen capable of causing life threatening disease in susceptible populations. Previous proteomic analysis we performed demonstrated that different strains of L. monocytogenes initiate a stringent response when subjected to alkaline growth conditions. Here, using multidimensional protein identification technology (MudPIT), we show that in L. monocytogenes EGD-e this response involves an energy shift to anaerobic pathways in response to the extracellular pH environment. Importantly we show that this supports a reduction in relative lag time following an abrupt transition to low oxygen tension culture conditions. This has important implications for the packaging of fresh and ready-to-eat foods under reduced oxygen conditions in environments where potential exists for alkaline adaptation. PMID- 23342095 TI - Analysis of substrate specificity and kinetics of cyclic nucleotide phosphodiesterases with N'-methylanthraniloyl-substituted purine and pyrimidine 3',5'-cyclic nucleotides by fluorescence spectrometry. AB - As second messengers, the cyclic purine nucleotides adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) play an essential role in intracellular signaling. Recent data suggest that the cyclic pyrimidine nucleotides cytidine 3',5'-cyclic monophosphate (cCMP) and uridine 3',5'-cyclic monophosphate (cUMP) also act as second messengers. Hydrolysis by phosphodiesterases (PDEs) is the most important degradation mechanism for cAMP and cGMP. Elimination of cUMP and cCMP is not completely understood, though. We have shown that human PDEs hydrolyze not only cAMP and cGMP but also cyclic pyrimidine nucleotides, indicating that these enzymes may be important for termination of cCMP- and cUMP effects as well. However, these findings were acquired using a rather expensive HPLC/mass spectrometry assay, the technical requirements of which are available only to few laboratories. N' Methylanthraniloyl-(MANT-)labeled nucleotides are endogenously fluorescent and suitable tools to study diverse protein/nucleotide interactions. In the present study, we report the synthesis of new MANT-substituted cyclic purine- and pyrimidine nucleotides that are appropriate to analyze substrate specificity and kinetics of PDEs with more moderate technical requirements. MANT-labeled nucleoside 3',5'-cyclic monophosphates (MANT-cNMPs) are shown to be substrates of various human PDEs and to undergo a significant change in fluorescence upon cleavage, thus allowing direct, quantitative and continuous determination of hydrolysis via fluorescence detection. As substrates of several PDEs, MANT-cNMPs show similar kinetics to native nucleotides, with some exceptions. Finally, they are shown to be also appropriate tools for PDE inhibitor studies. PMID- 23342096 TI - Brief exposure to novel or enriched environments reduces sucrose cue-reactivity and consumption in rats after 1 or 30 days of forced abstinence from self administration. AB - Environmental enrichment (EE) reduces drug and sucrose cue-reactivity in rats. In a previous study we reported that 1 month of EE (large cage, toys, and social cohorts) significantly reduced sucrose cue-reactivity. In the present study, we examined whether overnight (22 h) EE would be as effective. We also examined whether social enrichment (SE), enrichment alone (SoloEE), or exposure to an alternative environment (AEnv) might account for the EE effect. Rats self administered 10% sucrose (.2 mL/delivery) in 10 daily 2-h sessions. Sucrose delivery was accompanied by a tone+light cue. Rats were then exposed to enrichment or alternative environment conditions overnight (acute) or for 29 days (chronic). Sucrose cue-reactivity was measured after this period of forced abstinence in a session identical to training, but no sucrose was delivered with the cue. All acute conditions markedly reduced sucrose cue-reactivity after 1 day of forced abstinence compared to single-housed rats in standard vivarium housing (CON). Sucrose consumption was also significantly reduced in all groups but SoloEE in a next-day test. All acute conditions but SE significantly reduced sucrose cue-reactivity when administered just prior to Day 30 of forced abstinence; all reduced sucrose consumption in a next-day test. All chronic conditions except for SE and AEnv significantly reduced sucrose cue-reactivity on the Day 30 test and sucrose consumption in a next day test. For both acute and chronic comparisons, EE manipulations were the most effective at reducing sucrose cue-reactivity and consumption. SoloEE and EE were equally effective at reducing sucrose cue-reactivity and similarly effective at reducing sucrose consumption. This indicates that social interaction is not a necessary condition for reducing sucrose-motivated behaviors. These results may be useful in the development of anti-relapse strategies for drug and food addictions. PMID- 23342097 TI - Validation of the zebrafish pentylenetetrazol seizure model: locomotor versus electrographic responses to antiepileptic drugs. AB - Zebrafish have recently emerged as an attractive in vivo model for epilepsy. Seven-day-old zebrafish larvae exposed to the GABA(A) antagonist pentylenetetrazol (PTZ) exhibit increased locomotor activity, seizure-like behavior, and epileptiform electrographic activity. A previous study showed that 12 out of 13 antiepileptic drugs (AEDs) suppressed PTZ-mediated increases in larval movement, indicating the potential utility of zebrafish as a high throughput in vivo model for AED discovery. However, a question remained as to whether an AED-induced decrease in locomotion is truly indicative of anticonvulsant activity, as some drugs may impair larval movement through other mechanisms such as general toxicity or sedation. We therefore carried out a study in PTZ-treated zebrafish larvae, to directly compare the ability of AEDs to inhibit seizure-like behavioral manifestations with their capacity to suppress epileptiform electrographic activity. We re-tested the 13 AEDs of which 12 were previously reported to inhibit convulsions in the larval movement tracking assay, administering concentrations that did not, on their own, impair locomotion. In parallel, we carried out open-field recordings on larval brains after treatment with each AED. For the majority of AEDs we obtained the same response in both the behavioral and electrographic assays. Overall our data correlate well with those reported in the literature for acute rodent PTZ tests, indicating that the larval zebrafish brain is more discriminatory than previously thought in its response to AEDs with different modes of action. Our results underscore the validity of using the zebrafish larval locomotor assay as a rapid first-pass screening tool in assessing the anticonvulsant and/or proconvulsant activity of compounds, but also highlight the importance of performing adequate validation when using in vivo models. PMID- 23342098 TI - Application of scan statistics to detect suicide clusters in Australia. AB - BACKGROUND: Suicide clustering occurs when multiple suicide incidents take place in a small area or/and within a short period of time. In spite of the multi national research attention and particular efforts in preparing guidelines for tackling suicide clusters, the broader picture of epidemiology of suicide clustering remains unclear. This study aimed to develop techniques in using scan statistics to detect clusters, with the detection of suicide clusters in Australia as example. METHODS AND FINDINGS: Scan statistics was applied to detect clusters among suicides occurring between 2004 and 2008. Manipulation of parameter settings and change of area for scan statistics were performed to remedy shortcomings in existing methods. In total, 243 suicides out of 10,176 (2.4%) were identified as belonging to 15 suicide clusters. These clusters were mainly located in the Northern Territory, the northern part of Western Australia, and the northern part of Queensland. Among the 15 clusters, 4 (26.7%) were detected by both national and state cluster detections, 8 (53.3%) were only detected by the state cluster detection, and 3 (20%) were only detected by the national cluster detection. CONCLUSIONS: These findings illustrate that the majority of spatial-temporal clusters of suicide were located in the inland northern areas, with socio-economic deprivation and higher proportions of indigenous people. Discrepancies between national and state/territory cluster detection by scan statistics were due to the contrast of the underlying suicide rates across states/territories. Performing both small-area and large-area analyses, and applying multiple parameter settings may yield the maximum benefits for exploring clusters. PMID- 23342100 TI - Association between plasma neutrophil gelatinase associated lipocalin level and obstructive sleep apnea or nocturnal intermittent hypoxia. AB - BACKGROUND: Both obstructive sleep apnea (OSA) and a novel lipocalin, neutrophil gelatinase associated lipocalin (Ngal), have been reported to be closely linked with cardiovascular disease and loss of kidney function through chronic inflammation. However, the relationship between OSA and Ngal has never been investigated. OBJECTIVES: To evaluate the relationship between Ngal and OSA in clinical practice. METHODS: In 102 patients, polysomnography was performed to diagnose OSA and plasma Ngal levels were measured. The correlations between Ngal levels and OSA severity and other clinical variables were evaluated. Of the 46 patients who began treatment with continuous positive airway pressure (CPAP), Ngal levels were reevaluated after three months of treatment in 25 patients. RESULTS: The Ngal level correlated significantly with OSA severity as determined by the apnea hypopnea index (r = 0.24, p = 0.01) and 4% oxygen desaturation index (ODI) (r = 0.26, p = 0.01). Multiple regression analysis showed that the Ngal level was associated with 4%ODI independently of other clinical variables. Compliance was good in 13 of the 25 patients who used CPAP. Although the OSA (4%ODI: 33.1+/-16.7 to 1.1+/-1.9/h, p<0.01) had significantly improved in those with good compliance, the Ngal levels were not significantly changed (60.5+/-18.1 before CPAP vs 64.2+/-13.9 ng/ml after CPAP, p = 0.27). CONCLUSIONS: Plasma Ngal levels were positively associated with the severity of OSA. However, the contribution rate of OSA to systemic Ngal secretion was small and changes in Ngal levels appeared to be influenced largely by other confounding factors. Therefore, it does not seem reasonable to use the Ngal level as a specific biomarker of OSA in clinical practice. PMID- 23342099 TI - Identification and characterization of microRNAs in channel catfish (Ictalurus punctatus) by using Solexa sequencing technology. AB - Channel catfish (Ictalurus spp.) is an economically important species in freshwater aquaculture around the world and occupies a prominent position in the aquaculture industry of the United States. MicroRNAs (miRNAs) play important roles in the regulation of almost every biological process in eukaryotes; however, there is little information available concerning miRNAs in channel catfish. In this study, a small-RNA cDNA library was constructed from 10 tissues of channel catfish, and Solexa sequencing technology was used to perform high throughput sequencing of the library. A total of 14,919,026 raw reads, representing 161,288 unique sequences, were obtained from the small-cDNA library. After comparing the small RNA sequences with the RFam database, 4,542,396 reads that represent 25,538 unique sequences were mapped to the genome sequence of zebrafish to perform distribution analysis and to screen for candidate miRNA genes. Subsequent bioinformatic analysis identified 237 conserved miRNAs and 45 novel miRNAs in the channel catfish. Stem-loop RT-PCR was applied to validate and profile the expression of the novel miRNAs in 10 tissues. Some novel miRNAs, such as ipu-miR-129b, ipu-miR-7562 and ipu-miR-7553, were expressed in all tissues examined. However, some novel miRNAs appear to be tissue specific. Ipu-miR-7575 is predominantly expressed in stomach. Ipu-miR-7147 and ipu-miR-203c are highly expressed in heart, but are relatively weakly expressed in other tissues. Based on sequence complementarity between miRNAs and mRNA targets, potential target sequences for the 45 novel miRNAs were identified by searching for antisense hits in the reference RNA sequences of the channel catfish. These potential target sequences are involved in immune regulation, transcriptional regulation, metabolism and many other biological functions. The discovery of miRNAs in the channel catfish genome by this study contributes to a better understanding of the role miRNAs play in regulating diverse biological processes in fish and vertebrates. PMID- 23342101 TI - Over-expression of VvWRKY1 in grapevines induces expression of jasmonic acid pathway-related genes and confers higher tolerance to the downy mildew. AB - Most WRKY transcription factors activate expression of defence genes in a salicylic acid- and/or jasmonic acid-dependent signalling pathway. We previously identified a WRKY gene, VvWRKY1, which is able to enhance tolerance to fungal pathogens when it is overexpressed in tobacco. The present work analyzes the effects of VvWRKY1 overexpression in grapevine. Microarray analysis showed that genes encoding defence-related proteins were up-regulated in the leaves of transgenic 35S::VvWRKY1 grapevines. Quantitative RT-PCR analysis confirmed that three genes putatively involved in jasmonic acid signalling pathway were overexpressed in the transgenic grapes. The ability of VvWRKY1 to trans-activate the promoters of these genes was demonstrated by transient expression in grape protoplasts. The resistance to the causal agent of downy mildew, Plasmopara viticola, was enhanced in the transgenic plants. These results show that VvWRKY1 can increase resistance of grapevine against the downy mildew through transcriptional reprogramming leading to activation of the jasmonic acid signalling pathway. PMID- 23342102 TI - Are human mating preferences with respect to height reflected in actual pairings? AB - Pair formation, acquiring a mate to form a reproductive unit, is a complex process. Mating preferences are a step in this process. However, due to constraining factors such as availability of mates, rival competition, and mutual mate choice, preferred characteristics may not be realised in the actual partner. People value height in their partner and we investigated to what extent preferences for height are realised in actual couples. We used data from the Millennium Cohort Study (UK) and compared the distribution of height difference in actual couples to simulations of random mating to test how established mate preferences map on to actual mating patterns. In line with mate preferences, we found evidence for: (i) assortative mating (r = .18), (ii) the male-taller norm, and, for the first time, (iii) for the male-not-too-tall norm. Couples where the male partner was shorter, or over 25 cm taller than the female partner, occurred at lower frequency in actual couples than expected by chance, but the magnitude of these effects was modest. We also investigated another preference rule, namely that short women (and tall men) prefer large height differences with their partner, whereas tall women (and short men) prefer small height differences. These patterns were also observed in our population, although the strengths of these associations were weaker than previously reported strength of preferences. We conclude that while preferences for partner height generally translate into actual pairing, they do so only modestly. PMID- 23342103 TI - Comparative RNA-seq analysis of early-infected peach leaves by the invasive phytopathogen Xanthomonas arboricola pv. pruni. AB - Xanthomonas arboricola pv. pruni is a quarantine bacterial pathogen that threatens peach production by causing necrotic spots on leaves and fruits, thus with the potential of severely reducing yields. The current understanding of the host plant defense responses to the pathogen is very limited. Using whole transcriptome sequencing, differential gene expression was analyzed at two time points, 2 h and 12 h post inoculation (hpi), by comparing the inoculated samples to their respective controls. On the total of 19,781 known peach genes that were expressed in all time points and conditions, 34 and 263 were differentially expressed at 2 and 12 hpi, respectively. Of those, 82% and 40% were up-regulated, respectively; and 18% and 60% were down-regulated, respectively. The functional annotation based on gene ontology (GO) analysis highlighted that genes involved in metabolic process and response to stress were particularly represented at 2 hpi whereas at 12 hpi cellular and metabolic processes were the categories with the highest number of genes differentially expressed. Of particular interest among the differentially expressed genes identified were several pathogen associated molecular pattern (PAMP) receptors, disease resistance genes including several RPM1-like and pathogenesis related thaumatin encoding genes. Other genes involved in photosynthesis, in cell wall reorganization, in hormone signaling pathways or encoding cytochrome were also differentially expressed. In addition, novel transcripts were identified, providing another basis for further characterization of plant defense-related genes. Overall, this study gives a first insight of the peach defense mechanisms during the very early stages of infection with a bacterial disease in the case of a compatible interaction. PMID- 23342104 TI - Pyocyanin-enhanced neutrophil extracellular trap formation requires the NADPH oxidase. AB - Beyond intracellular killing, a novel neutrophil-based antimicrobial mechanism has been recently discovered: entrapment and killing by neutrophil extracellular traps (NETs). NETs consist of extruded nuclear DNA webs decorated with granule proteins. Although NET formation is an important innate immune mechanism, uncontrolled NET release damages host tissues and has been linked to several diseases including cystic fibrosis (CF). The major CF airway pathogen Pseudomonas aeruginosa establishes chronic infection. Pseudomonas imbedded within biofilms is protected against the immune system, but maintains chronic inflammation that worsens disease symptoms. Aberrant NET release from recruited neutrophils was found in CF, but the underlying mechanisms remain unclear. One of the most important Pseudomonas virulence factors is pyocyanin, a redox-active pigment that has been associated with diminished lung function in CF. Here we show that pyocyanin promotes NET formation in a time- and dose-dependent manner. Most CF Pseudomonas clinical isolates tested produce pyocyanin in vitro. Pyocyanin derived reactive oxygen species are required for its NET release. Inhibitor experiments demonstrated involvement of Jun N-terminal Kinase (JNK) and phosphatidylinositol 3-Kinase (PI3K) in pyocyanin-induced NET formation. Pyocyanin-induced NETs also require the NADPH oxidase because NET release in chronic granulomatous disease neutrophils was greatly reduced. Comparison of neutrophils from gp91phox- and p47phox-deficient patients revealed that pyocyanin triggered NET formation is proportional to their residual superoxide production. Our studies identify pyocyanin as the first secreted bacterial toxin that enhances NET formation. The involvement of NADPH oxidase in pyocyanin-induced NET formation represents a novel mechanism of pyocyanin toxicity. PMID- 23342105 TI - Tracking the evolution of dengue virus strains D2S10 and D2S20 by 454 pyrosequencing. AB - Dengue virus is the most prevalent mosquito-borne virus worldwide. In this study, we used pyrosequencing to analyze the whole viral genome of two mouse-adapted strains, D2S10 and D2S20, that induce a dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS)-like lethal disease in mice lacking the type I and/or type II interferon receptors. Previous experiments with D2S10 indicated that N124D and K128E mutations in the envelope protein were responsible for the severe disease induced in mice compared to its parental strain PL046. Here we demonstrate that D2S20 is more virulent than D2S10 and captured the presence of five key amino acid mutations--T70I, N83D, and K122I in envelope (E), and A62T in nonstructural protein 2A (NS2A) and G605V in nonstructural protein 5 (NS5)--that may account for this. These findings set the foundation for further dissection of the viral determinants responsible for dengue disease manifestations in mouse models. PMID- 23342106 TI - Mechanistic target of rapamycin (Mtor) is essential for murine embryonic heart development and growth. AB - Mechanistic target of rapamycin (Mtor) is required for embryonic inner cell mass proliferation during early development. However, Mtor expression levels are very low in the mouse heart during embryogenesis. To determine if Mtor plays a role during mouse cardiac development, cardiomyocyte specific Mtor deletion was achieved using alpha myosin heavy chain (alpha-MHC) driven Cre recombinase. Initial mosaic expression of Cre between embryonic day (E) 10.5 and E11.5 eliminated a subset of cardiomyocytes with high Cre activity by apoptosis and reduced overall cardiac proliferative capacity. The remaining cardiomyocytes proliferated and expanded normally. However loss of 50% of cardiomyocytes defined a threshold that impairs the ability of the embryonic heart to sustain the embryo's circulatory requirements. As a result 92% of embryos with cardiomyocyte Mtor deficiency died by the end of gestation. Thus Mtor is required for survival and proliferation of cardiomyocytes in the developing heart. PMID- 23342107 TI - Association of common mental disorders and quality of life with the frequency of attendance in Slovenian family medicine practices: longitudinal study. AB - BACKGROUND: Most research on frequent attendance has been cross-sectional and restricted to one year attendance rates. A few longitudinal studies suggest that frequent attendance is self-limiting. Frequent attenders are more likely to have social and psychiatric problems, medically unexplained physical symptoms, chronic somatic diseases (especially diabetes) and are prescribed more psychotropic medication and analgesics. RESEARCH QUESTION: To describe the attendance rates in a longitudinal study and to test if depression, panic syndrome, other anxiety syndrome, alcohol misuse and general quality of life are associated with frequent attendance in next two consecutive years. METHODS: 1118 consecutive family practice attendees, aged 18 to 75 years from randomly selected family medicine practices were recruited at baseline and followed up at 12 and 24 months. We identified frequent attenders in the top 10 centile within one year. Using a multivariate model, we ascertained if presence of common mental disorders and quality of life assessed at baseline in 2003 predict frequent attendance in 2004 and 2005. RESULTS: 40% of frequent attenders continue to be frequent attenders in the following year and 20% of the frequent attenders were so for the 24 month period. Lower physical scores on the SF-12 questionnaire were strongly associated with future frequent attendance at 12 and 24 months. There was a trend for people with greater than elementary school education to be less likely to become frequent attenders at both 12 and 24 months. For other variables these effects were less consistent. Presence of major depression, panic syndrome, other anxiety syndrome and alcohol misuse were not predictive of frequent attendance in the following two years. CONCLUSION: Low physical quality of life is strongly predictive of higher frequent attendance and similar finding was observed for people with lower educational level but further confirmatory research is required to establish this association. PMID- 23342108 TI - Transforming growth factor-beta1 and -beta2 in gastric precancer and cancer and roles in tumor-cell interactions with peripheral blood mononuclear cells in vitro. AB - Transforming growth factor-beta1 (TGF-beta1) and -beta2 are correlated with poorer prognosis in gastric cancer (GC), which act in both tumor and immune cells. However, their expressions in precancer and tumor-cell interactions with peripheral blood mononuclear cells (PBMCs) remain unclear. Protein levels of TGF beta1 and -beta2 were analyzed by immunohistochemistry and corresponding mRNA levels were determined by quantitative real-time polymerase chain reaction in 93 surgical and biopsy specimens. Serum TGF-beta concentration was detected by enzyme-linked immunosorbent assays. AGS and MKN45 cell lines were directly or indirectly cocultured with PBMCs in vitro. TGF-beta and Smad molecules were detected after cocultures and the growths of GC cells and PBMCs were assessed by cell proliferation assay. The results showed positive staining for TGF-beta1 was detected in 20% of control samples, 52.3% of precancer, 59.1% of early GC and 66.7% of advanced GC samples, correlated with lesion progression (chi2 = 9.487, P = 0.002). All tissues were positive for TGF-beta2. TGF-beta1 mRNA levels were increased in advanced cancers, while TGF-beta2 increased earlier. TGF-beta1 mRNA levels were higher in tumor than in peritumor, which positively correlated with Smad2 and Smad7. Serum TGF-beta levels were significantly higher in patients with early and advanced cancers compared to controls (TGF-beta1?50.08+/-4.38 and 45.76+/-5.00 vs. 27.78+/-6.11 ng/mL; TGF-beta2?133.61+/-21.90 and 111.34+/-15.76 vs. 59.41+/-15.42 ng/mL, both P<0.05). The levels of TGF-beta1 mRNA and cytokine secretion were higher in GC cells after direct coculture compared to indirect culture. TGF-beta1 was decreased and TGF-beta2 was increased in PBMCs after cocultures. Moreover, TGF-beta1 inhibited the viability of PBMCs but not cancer cells. Collectively, neoplastic transformation may be an early event involving the increase of TGF-beta1 in the general and local environment. TGF-beta1 production is promoted by the direct interaction between GC cells and PBMCs, which might facilitate cancer development. PMID- 23342109 TI - The role of hypoxia-inducible factor 1alpha in determining the properties of castrate-resistant prostate cancers. AB - BACKGROUND: Castrate-resistant prostate cancer (CRPC) is a lethal condition in patients receiving androgen deprivation therapy for prostate cancer (PC). Despite numerous studies showing the expression of HIF1alpha protein under normoxia in PC cell lines, the role of this normoxic HIF1alpha expression in chemo-resistance and migration has not been investigated previously. As no method is currently available to determine which tumors will progress to CRPC, the role of HIF1alpha in PC and its potential for predicting the development of CRPC was also investigated. METHODS: The effect of HIF1alpha protein knockdown on chemo resistance and migration of PC3 cells was assessed by cell counting and Transwell assays, respectively. Translation efficiency of HIF1alpha mRNA was determined in PC cells using a HIF1alpha 5'UTR-luciferase construct. Clinical outcomes were correlated following the staining of 100 prostate tumors for HIF1alpha expression. RESULTS: The CRPC-like cell lines (PC3 and DU145) expressed more HIF1alpha protein than an androgen sensitive cell line (LNCaP). Migration rate and chemo-resistance were higher in the PC3 cells and both were decreased when HIF1alpha expression was reduced. Increased translation of HIF1alpha mRNA may be responsible for HIF1alpha overexpression in PC3 cells. Patients whose tumors expressed HIF1alpha had significantly decreased metastasis-free survival and the patients who were on androgen-deprivation therapy had decreased CRPC-free survival on Kaplan-Meier analysis. On multivariate analysis HIF1alpha was an independent risk factor for progression to metastatic PC (Hazard ratio (HR) 9.8, p = 0.017) and development of CRPC (HR 10.0, p = 0.021) in patients on androgen deprivation therapy. Notably the tumors which did not express HIF1alpha did not metastasize or develop CRPC. CONCLUSIONS: HIF1alpha is likely to contribute to metastasis and chemo-resistance of CRPC and targeted reduction of HIF1alpha may increase the responsiveness of CRPCs to chemotherapy. Expression of HIF1alpha may be a useful screening tool for development of CRPC. PMID- 23342110 TI - Prediction of contact residue pairs based on co-substitution between sites in protein structures. AB - Residue-residue interactions that fold a protein into a unique three-dimensional structure and make it play a specific function impose structural and functional constraints in varying degrees on each residue site. Selective constraints on residue sites are recorded in amino acid orders in homologous sequences and also in the evolutionary trace of amino acid substitutions. A challenge is to extract direct dependences between residue sites by removing phylogenetic correlations and indirect dependences through other residues within a protein or even through other molecules. Rapid growth of protein families with unknown folds requires an accurate de novo prediction method for protein structure. Recent attempts of disentangling direct from indirect dependences of amino acid types between residue positions in multiple sequence alignments have revealed that inferred residue-residue proximities can be sufficient information to predict a protein fold without the use of known three-dimensional structures. Here, we propose an alternative method of inferring coevolving site pairs from concurrent and compensatory substitutions between sites in each branch of a phylogenetic tree. Substitution probability and physico-chemical changes (volume, charge, hydrogen bonding capability, and others) accompanied by substitutions at each site in each branch of a phylogenetic tree are estimated with the likelihood of each substitution, and their direct correlations between sites are used to detect concurrent and compensatory substitutions. In order to extract direct dependences between sites, partial correlation coefficients of the characteristic changes along branches between sites, in which linear multiple dependences on feature vectors at other sites are removed, are calculated and used to rank coevolving site pairs. Accuracy of contact prediction based on the present coevolution score is comparable to that achieved by a maximum entropy model of protein sequences for 15 protein families taken from the Pfam release 26.0. Besides, this excellent accuracy indicates that compensatory substitutions are significant in protein evolution. PMID- 23342111 TI - Serotypes and patterns of antibiotic resistance in strains causing invasive pneumococcal disease in children less than 5 years of age. AB - OBJECTIVE: The serotypes and patterns of antibiotic resistance of Streptococcus pneumoniae (S. pneumoniae) strains that cause invasive pneumococcal disease (IPD) in infants were analyzed to provide guidance for clinical disease prevention and treatment. METHODS: The clinical features of confirmed IPD were evaluated in 61 patients, less than 5 years of age, who were admitted to our hospital between January 2009 and December 2011. The serotypes and antibiotic resistance of strains of S.pneumoniae were determined using the capsular swelling method and the E-test. RESULTS: A total of 61 invasive strains were isolated. The serotype distribution of those isolates were 19A (41.0%), 14 (19.7%), 19F (11.5%), 23F (9.8%), 8 (4.9%), 9V (4.9%), 1 (3.3%), and 4, 6B, and 20 (each 1.6%). The percentage of S. pneumoniae strains resistant to erythromycin, clindamycin, and cotrimoxazole were 100%, 86.9%, and 100%, respectively. The percentage of S. pneumoniae strains resistant to penicillin, amoxicillin/clavulanic acid, cefuroxime, ceftriaxone, cefotaxime, cefepime, and meropenem were 42.6%, 18.0%, 82.0%, 18.0%, 13.1%, 13.1%, and 36.1%, respectively. The percentage of multidrug resistant strains was 95.6%. Strains of all serotypes isolated in this study were highly resistant to erythromycin, cotrimoxazole, and clindamycin. Strains with serotype 19A had the highest rates of resistance. CONCLUSIONS: Serotype 19A strains were most frequently isolated from children with IPD treated in our hospital. The strains causing IPD are highly resistant to antibiotics. PMID- 23342112 TI - Quercetin enhances the antitumor activity of trichostatin A through upregulation of p53 protein expression in vitro and in vivo. AB - This study investigated the effects of quercetin on the anti-tumor effect of trichostatin A (TSA), a novel anticancer drug, in vitro and in vivo and the possible mechanisms of these effects in human lung cancer cells. We first showed that quercetin (5 uM) significantly increased the growth arrest and apoptosis in A549 cells (expressing wild-type p53) induced by 25 ng/mL of (82.5 nM) TSA at 48 h by about 25% and 101%, respectively. However, such enhancing effects of quercetin (5 uM) were not significant in TSA-exposed H1299 cells (a p53 null mutant) or were much lower than in A549 cells. In addition, quercetin significantly increased TSA-induced p53 expression in A549 cells. Transfection of p53 siRNA into A549 cells significantly but not completely diminished the enhancing effects of quercetin on TSA-induced apoptosis. Furthermore, we demonstrated that quercetin enhanced TSA-induced apoptosis through the mitochondrial pathway. Transfection of p53 siRNA abolished such enhancing effects of quercetin. However, quercetin increased the acetylation of histones H3 and H4 induced by TSA in A549 cells, even with p53 siRNA transfection as well as in H1299 cells. In a xenograft mouse model of lung cancer, quercetin enhanced the antitumor effect of TSA. Tumors from mice treated with TSA in combination with quercetin had higher p53 and apoptosis levels than did those from control and TSA treated mice. These data indicate that regulation of the expression of p53 by quercetin plays an important role in enhancing TSA-induced apoptosis in A549 cells. However, p53-independent mechanisms may also contribute to the enhancing effect of quercetin. PMID- 23342113 TI - Akt1 mediates neuronal differentiation in zebrafish via a reciprocal interaction with notch signaling. AB - Akt1 is well known for its role in regulating cell proliferation, differentiation, and apoptosis and is implicated in tumors and several neurological disorders. However, the role of Akt1 in neural development has not been well defined. We have isolated zebrafish akt1 and shown that this gene is primarily transcribed in the developing nervous system, and its spatiotemporal expression pattern suggests a role in neural differentiation. Injection of akt1 morpholinos resulted in loss of neuronal precursors with a concomitant increase in post-mitotic neurons, indicating that knockdown of Akt1 is sufficient to cause premature differentiation of neurons. A similar phenotype was observed in embryos deficient for Notch signaling. Both the ligand (deltaA) and the downstream target of Notch (her8a) were downregulated in akt1 morphants, indicating that Akt1 is required for Delta-Notch signaling. Furthermore, akt1 expression was downregulated in Delta-Notch signaling-deficient embryos and could be induced by constitutive activation of Notch signaling. In addition, knockdown of Akt1 was able to nullify the inhibition of neuronal differentiation caused by constitutive activation of Notch signaling. Taken together, these results provide in vivo evidence that Akt1 interacts with Notch signaling reciprocally and provide an explanation of why Akt1 is essential for the inhibition of neuronal differentiation. PMID- 23342114 TI - Irradiated riboflavin diminishes the aggressiveness of melanoma in vitro and in vivo. AB - Melanoma is one of the most aggressive skin cancers due to its high capacity to metastasize. Treatment of metastatic melanomas is challenging for clinicians, as most therapeutic agents have failed to demonstrate improved survival. Thus, new candidates with antimetastatic activity are much needed. Riboavin (RF) is a component of the vitamin B complex and a potent photosensitizer. Previously, our group showed that the RF photoproducts (iRF) have potential as an antitumoral agent. Hence, we investigated the capacity of iRF on modulating melanoma B16F10 cells aggressiveness in vitro and in vivo. iRF decreases B16F10 cells survival by inhibiting mTOR as well as Src kinase. Moreover, melanoma cell migration was disrupted after treatment with iRF, mainly by inhibition of metalloproteinase (MMP) activity and expression, and by increasing TIMP expression. Interestingly, we observed that the Hedgehog (HH) pathway was inhibited by iRF. Two mediators of HH signaling, GLI1 and PTCH, were downregulated, while SUFU expression (an inhibitor of this cascade) was enhanced. Furthermore, inhibition of HH pathway signaling by cyclopamine and Gant 61 potentiated the antiproliferative action of RF. Accordingly, when a HH ligand was applied, the effect of iRF was almost completely abrogated. Our findings indicate that Hedgehog pathway is involved on the modulation of melanoma cell aggressiveness by iRF. Moreover, iRF treatment decreased pulmonary tumor formation in a murine experimental metastasis model. Research to clarify the molecular action of flavins, in vivo, is currently in progress. Taken together, the present data provides evidence that riboflavin photoproducts may provide potential candidates for improving the efficiency of melanoma treatment. PMID- 23342115 TI - SPIN90 phosphorylation modulates spine structure and synaptic function. AB - The correct rearrangement of postsynaptic components in dendritic spines is important for driving changes of spine structure and synaptic function. SPIN90 plays an essential role in many cellular processes including actin polymerization, endocytosis, growth cone formation and dendritic spine morphogenesis. Here, we demonstrate that SPIN90, which is a binding partner of PSD95 and Shank in spines, is targeted to synapses and leads to enhanced synaptic activity in neurons. We show, using in vitro and in vivo kinase assays, that SPIN90 is tyrosine phosphorylated by Src kinase. SPIN90 that was tyrosine phosphorylated by Src was targeted to dendritic spines in cultured hippocampal neurons. Moreover, a SPIN90 phospho-deficient mutant was unable to accumulate at dendritic spines whereas SPIN90 WT and a phospho-mimicking mutant were localized at spines and bound PSD95 and Shank with increased efficiency. Consistent with these findings, hippocampal neurons that overexpressed SPIN90 WT or a phospho mimicking mutant had enlarged spine heads, leading to enhanced postsynaptic function in terms of both amplitude and frequency. Together, our findings show that SPIN90 modulates synaptic activity in neurons as a result of its phosphorylation. PMID- 23342116 TI - Leptin in whales: validation and measurement of mRNA expression by absolute quantitative real-time PCR. AB - Leptin is the primary hormone in mammals that regulates adipose stores. Arctic adapted cetaceans maintain enormous adipose depots, suggesting possible modifications of leptin or receptor function. Determining expression of these genes is the first step to understanding the extreme physiology of these animals, and the uniqueness of these animals presents special challenges in estimating and comparing expression levels of mRNA transcripts. Here, we compare expression of two model genes, leptin and leptin-receptor gene-related product (OB-RGRP), using two quantitative real-time PCR (qPCR) methods: "relative" and "absolute". To assess the expression of leptin and OB-RGRP in cetacean tissues, we first examined how relative expression of those genes might differ when normalized to four common endogenous control genes. We performed relative expression qPCR assays measuring the amplification of these two model target genes relative to amplification of 18S ribosomal RNA (18S), ubiquitously expressed transcript (Uxt), ribosomal protein 9 (Rs9) and ribosomal protein 15 (Rs15) endogenous controls. Results demonstrated significant differences in the expression of both genes when different control genes were employed; emphasizing a limitation of relative qPCR assays, especially in studies where differences in physiology and/or a lack of knowledge regarding levels and patterns of expression of common control genes may possibly affect data interpretation. To validate the absolute quantitative qPCR methods, we evaluated the effects of plasmid structure, the purity of the plasmid standard preparation and the influence of type of qPCR "background" material on qPCR amplification efficiencies and copy number determination of both model genes, in multiple tissues from one male bowhead whale. Results indicate that linear plasmids are more reliable than circular plasmid standards, no significant differences in copy number estimation based upon background material used, and that the use of ethanol precipitated, linearized plasmid preparation produce the most reliable results. PMID- 23342117 TI - Population genetics of Ceratitis capitata in South Africa: implications for dispersal and pest management. AB - The invasive Mediterranean fruit fly (medfly), Ceratitis capitata, is one of the major agricultural and economical pests globally. Understanding invasion risk and mitigation of medfly in agricultural landscapes requires knowledge of its population structure and dispersal patterns. Here, estimates of dispersal ability are provided in medfly from South Africa at three spatial scales using molecular approaches. Individuals were genotyped at 11 polymorphic microsatellite loci and a subset of individuals were also sequenced for the mitochondrial cytochrome oxidase subunit I gene. Our results show that South African medfly populations are generally characterized by high levels of genetic diversity and limited population differentiation at all spatial scales. This suggests high levels of gene flow among sampling locations. However, natural dispersal in C. capitata has been shown to rarely exceed 10 km. Therefore, documented levels of high gene flow in the present study, even between distant populations (>1600 km), are likely the result of human-mediated dispersal or at least some form of long-distance jump dispersal. These findings may have broad applicability to other global fruit production areas and have significant implications for ongoing pest management practices, such as the sterile insect technique. PMID- 23342118 TI - Drosophila clueless is highly expressed in larval neuroblasts, affects mitochondrial localization and suppresses mitochondrial oxidative damage. AB - Mitochondria are critical for neuronal function due to the high demand of ATP in these cell types. During Drosophila development, neuroblasts in the larval brain divide asymmetrically to populate the adult central nervous system. While many of the proteins responsible for maintaining neuroblast cell fate and asymmetric cell divisions are known, little is know about the role of metabolism and mitochondria in neuroblast division and maintenance. The gene clueless (clu) has been previously shown to be important for mitochondrial function. clu mutant adults have severely shortened lifespans and are highly uncoordinated. Part of their lack of coordination is due to defects in muscle, however, in this study we have identified high levels of Clu expression in larval neuroblasts and other regions of the dividing larval brain. We show while mitochondria in clu mutant neuroblasts are mislocalized during the cell cycle, surprisingly, overall brain morphology appears to be normal. This is explained by our observation that clu mutant larvae have normal levels of ATP and do not suffer oxidative damage, in sharp contrast to clu mutant adults. Mutations in two other genes encoding mitochondrial proteins, technical knockout and stress sensitive B, do not cause neuroblast mitochondrial mislocalization, even though technical knockout mutant larvae suffer oxidative damage. These results suggest Clu functions upstream of electron transport and oxidative phosphorylation, has a role in suppressing oxidative damage in the cell, and that lack of Clu's specific function causes mitochondria to mislocalize. These results also support the previous observation that larval development relies on aerobic glycolysis, rather than oxidative phosphorylation. Thus Clu's role in mitochondrial function is not critical during larval development, but is important for pupae and adults. PMID- 23342119 TI - From darwin to the census of marine life: marine biology as big science. AB - With the development of the Human Genome Project, a heated debate emerged on biology becoming 'big science'. However, biology already has a long tradition of collaboration, as natural historians were part of the first collective scientific efforts: exploring the variety of life on earth. Such mappings of life still continue today, and if field biology is gradually becoming an important subject of studies into big science, research into life in the world's oceans is not taken into account yet. This paper therefore explores marine biology as big science, presenting the historical development of marine research towards the international 'Census of Marine Life' (CoML) making an inventory of life in the world's oceans. Discussing various aspects of collaboration--including size, internationalisation, research practice, technological developments, application, and public communication--I will ask if CoML still resembles traditional collaborations to collect life. While showing both continuity and change, I will argue that marine biology is a form of natural history: a specific way of working together in biology that has transformed substantially in interaction with recent developments in the life sciences and society. As a result, the paper does not only give an overview of transformations towards large scale research in marine biology, but also shines a new light on big biology, suggesting new ways to deepen the understanding of collaboration in the life sciences by distinguishing between different 'collective ways of knowing'. PMID- 23342120 TI - Dyrk1A is dynamically expressed on subsets of motor neurons and in the neuromuscular junction: possible role in Down syndrome. AB - Individuals with Down syndrome (DS) present important motor deficits that derive from altered motor development of infants and young children. DYRK1A, a candidate gene for DS abnormalities has been implicated in motor function due to its expression in motor nuclei in the adult brain, and its overexpression in DS mouse models leads to hyperactivity and altered motor learning. However, its precise role in the adult motor system, or its possible involvement in postnatal locomotor development has not yet been clarified. During the postnatal period we observed time-specific expression of Dyrk1A in discrete subsets of brainstem nuclei and spinal cord motor neurons. Interestingly, we describe for the first time the presence of Dyrk1A in the presynaptic terminal of the neuromuscular junctions and its axonal transport from the facial nucleus, suggesting a function for Dyrk1A in these structures. Relevant to DS, Dyrk1A overexpression in transgenic mice (TgDyrk1A) produces motor developmental alterations possibly contributing to DS motor phenotypes and modifies the numbers of motor cholinergic neurons, suggesting that the kinase may have a role in the development of the brainstem and spinal cord motor system. PMID- 23342121 TI - Are Thai MSM willing to take PrEP for HIV prevention? An analysis of attitudes, preferences and acceptance. AB - OBJECTIVE: We aimed to understand the attitudes, preferences and acceptance of oral and parenteral PrEP among men who have sex with men (MSM) in Thailand. BACKGROUND: Pre-exposure prophylaxis (PrEP), the use of antiretrovirals to prevent HIV acquisition, has shown promising results in recent trials. To assess the potential impact of this new HIV prevention method, in addition to efficacy data, we need to understand which psychosocial factors are likely to determine its uptake among members of potential user groups. METHODS AND FINDINGS: Surveys of willingness to use PrEP products were administered to MSM. Spearman's rank tests were used to uncover associations between questionnaire items. Mann-Whitney tests were performed to ascertain differences between groups. Conjoint analysis was used to examine the attitudes and preferences of MSM towards PrEP attributes. Most participants were willing to consider taking PrEP (39.2% "yes, definitely" and 49.2% "yes, probably") and perceived PrEP as giving them new possibilities in their lives (38.5% "a lot of hope" and 55.8% "some hope"), even after being instructed of potential side effects and costs. HIV testing was considered the most important attribute and a daily pill and longer lasting injection in the arm were the preferred routes of administration. CONCLUSIONS: Despite its multiple challenges, MSM in Thailand would be willing to take PrEP, even if they had to experience inconvenience and expense. If PrEP were to be implemented in Thailand, our findings show that its uptake could be considerable. PMID- 23342122 TI - A single valine residue plays an essential role in peripherin/rds targeting to photoreceptor outer segments. AB - Peripherin/retinal degeneration slow (rds) is an integral membrane protein specifically localized to the light-sensing organelle of the photoreceptor cell, the outer segment. Within the outer segment, peripherin is found at the edges of photoreceptor discs, where it plays a critical role in disc morphogenesis and maintenance. Peripherin loss or mutations are often associated with severe forms of visual impairments. Like all other resident outer segment proteins, peripherin is synthesized in the photoreceptor cell body and subsequently transported to the outer segment. In an effort to further examine peripherin's delivery to outer segments, we undertook a careful examination of its targeting sequence. Using a fluorescently labeled reporter expressed in the rods of transgenic tadpoles, we narrowed peripherin's targeting sequence to ten amino acids within its C-terminal tail. This small stretch of amino acid residues is both necessary and sufficient for outer segment targeting. We also conducted alanine scanning of all residues within this sequence and found that only a single residue, valine at position 332, is essential for outer segment targeting. This valine is conserved in all species and its mutation is sufficient to completely abrogate the targeting of full-length peripherin in mouse rods. PMID- 23342123 TI - CcpA-independent glucose regulation of lactate dehydrogenase 1 in Staphylococcus aureus. AB - Lactate Dehydrogenase 1 (Ldh1) is a key enzyme involved in Staphylococcus aureus NO.-resistance. Full ldh1-induction requires the presence of glucose, and mutants lacking the Carbon-Catabolite Protein (CcpA) exhibit decreased ldh1 transcription and diminished Ldh1 activity. The redox-regulator Rex represses ldh1 directly by binding to Rex-sites within the ldh1 promoter (P(ldh1)). In the absence of Rex, neither glucose nor CcpA affect ldh1 expression implying that glucose/CcpA mediated activation requires Rex activity. Rex-mediated repression of ldh1 depends on cellular redox status and is maximal when NADH levels are low. However, compared to WT cells, the DeltaccpA mutant exhibited impaired redox balance with relatively high NADH levels, yet ldh1 was still poorly expressed. Furthermore, CcpA did not drastically alter Rex transcript levels, nor did glucose or CcpA affect the expression of other Rex-regulated genes indicating that the glucose/CcpA effect is specific for P(ldh1). A putative catabolite response element (CRE) is located ~30 bp upstream of the promoter-distal Rex binding site in P(ldh1). However, CcpA had no affinity for P(ldh1) in vitro and a genomic mutation of CRE upstream of P(ldh1) in S. aureus had no affect on Ldh1 expression in vivo. In contrast to WT, DeltaccpA S. aureus preferentially consumes non-glycolytic carbon sources. However when grown in defined medium with glucose as the primary carbon source, DeltaccpA mutants express high levels of Ldh1 compared to growth in media devoid of glucose. Thus, the actual consumption of glucose stimulates Ldh1 expression rather than direct CcpA interaction at P(ldh1). PMID- 23342124 TI - Hypoxia promotes dopaminergic differentiation of mesenchymal stem cells and shows benefits for transplantation in a rat model of Parkinson's disease. AB - Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into dopaminergic (DAergic) neurons, which is one of the major cell types damaged in Parkinson's disease (PD). For this reason, MSCs are considered a potential cell source for PD therapy. It has been proved that hypoxia is involved in the proliferation and differentiation of stem cells. In this study, we investigated the effect of hypoxia on MSC proliferation and DAergic neuronal differentiation. Our results demonstrate that 3% O2 treatment can enhance rat MSC proliferation by upregulation of phosphorylated p38 MAPK and subsequent nuclear translocation of hypoxia inducible factor (HIF)-1alpha. During neural differentiation, 3% O2 treatment increases the expression of HIF-1alpha, phosphorylated ERK and p38 MAPK. These changes are followed by promotion of neurosphere formation and further DAergic neuronal differentiation. Furthermore, we explored the physiological function of hypoxia-induced DAergic neurons from human fetal MSCs by transplanting them into parkinsonian rats. Grafts induced with hypoxia display more survival of DAergic neurons and greater amelioration of behavioral impairments. Altogether, these results suggest that hypoxia can promote MSC proliferation and DAergic neuronal differentiation, and benefit for intrastriatal transplantation. Therefore, this study may provide new perspectives in application of MSCs to clinical PD therapy. PMID- 23342125 TI - B cell activating factor of the tumor necrosis factor family (BAFF) behaves as an acute phase reactant in acute pancreatitis. AB - OBJECTIVE: To determine if B cell activating factor of the tumor necrosis factor family (BAFF) acts as an acute phase reactant and predicts severity of acute pancreatitis. METHODS: 40 patients with acute pancreatitis were included in this single center cohort pilot study. Whole blood and serum was analyzed on day of admission and nine consecutive days for BAFF, c-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), and leucocyte numbers. Different severity Scores (Ranson, APACHE II, SAPS II, SAPS III) and the clinical course of the patient (treatment, duration of stay, duration ICU) were recorded. RESULTS: Serum BAFF correlates with CRP, an established marker of severity in acute pancreatitis at day of admission with a timecourse profil similar to IL-6 over the first nine days. Serum BAFF increases with Ranson score (Kruskal-Wallis: Chi2 = 10.8; p = 0.03) similar to CRP (Kruskal-Wallis: Chi2 = 9.4; p = 0.05 ). Serum BAFF, IL-6, and CRP levels are elevated in patients that need intensive care for more than seven days and in patients with complicated necrotizing pancreatitis. Discriminant analysis and receiver operator characteristics show that CRP (wilks lambda = 0.549; ROC: AUC 0.948) and BAFF (wilks-lambda = 0.907; ROC: AUC 0.843) serum levels at day of admission best predict severe necrotizing pancreatitis or death, outperforming IL-6, PCT, and number of leucocytes. CONCLUSION: This study establishes for the first time BAFF as an acute phase reactant with predictive value for the course of acute pancreatitis. BAFF outperforms established markers in acute pancreatitis, like IL-6 and PCT underscoring the important role of BAFF in the acute inflammatory response. PMID- 23342126 TI - A novel protective MHC-I haplotype not associated with dominant Gag-specific CD8+ T-cell responses in SIVmac239 infection of Burmese rhesus macaques. AB - Several major histocompatibility complex class I (MHC-I) alleles are associated with lower viral loads and slower disease progression in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. Immune-correlates analyses in these MHC-I-related HIV/SIV controllers would lead to elucidation of the mechanism for viral control. Viral control associated with some protective MHC-I alleles is attributed to CD8+ T-cell responses targeting Gag epitopes. We have been trying to know the mechanism of SIV control in multiple groups of Burmese rhesus macaques sharing MHC-I genotypes at the haplotype level. Here, we found a protective MHC-I haplotype, 90-010-Id (D), which is not associated with dominant Gag-specific CD8+ T-cell responses. Viral loads in five D+ animals became significantly lower than those in our previous cohorts after 6 months. Most D+ animals showed predominant Nef-specific but not Gag-specific CD8+ T-cell responses after SIV challenge. Further analyses suggested two Nef-epitope specific CD8+ T-cell responses exerting strong suppressive pressure on SIV replication. Another set of five D+ animals that received a prophylactic vaccine using a Gag-expressing Sendai virus vector showed significantly reduced viral loads compared to unvaccinated D+ animals at 3 months, suggesting rapid SIV control by Gag-specific CD8+ T-cell responses in addition to Nef-specific ones. These results present a pattern of SIV control with involvement of non-Gag antigen-specific CD8+ T-cell responses. PMID- 23342127 TI - The association between self-reported sleep quality and metabolic syndrome. AB - OBJECTIVES: Short and long sleep duration are associated with metabolic syndrome. However, there is limited research on the association between sleep quality and metabolic syndrome, and thus the aim of this study is to investigate this relationship. MATERIALS AND METHODS: The cross-sectional baseline data were collected from the decoded database of the Prevention Health Center of National Cheng Kung University Hospital from 2002 to 2006. The diagnosis of metabolic syndrome was according to the statement of the American Heart Association/National Heart, Lung, and Blood Institute. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). A higher global PSQI score indicates poorer sleep quality, and a global PSQI score greater than five differentiates poor from good sleepers. RESULTS: Of the 3,435 subjects recruited, 899 (26.2%) had metabolic syndrome. Subjects with metabolic syndrome had higher PSQI and prevalence of poor sleepers than those without metabolic syndrome. The multivariate lineal regression analysis showed that female gender, metabolic syndrome, sleep duration, snoring, alcohol drinking, and habitual exercise were independent predictors of PSQI. When substituting metabolic syndrome with the five components, hyperglycemia and low high-density lipoprotein cholesterol (HDL C) were positively associated with PSQI. The multivariate logistic regression analyses showed that female gender, metabolic syndrome, sleep duration, and snoring were independently associated with being poor sleepers. Of the five components, only low HDL-C was an independent predictor of being poor sleepers. CONCLUSIONS: Subjects with metabolic syndrome have higher global PSQI scores and a higher risk of being poor sleepers. Of the five components of metabolic syndrome, hyperglycemia and low HDL-C are independently associated with the global PSQI scores, while low HDL-C is an independent predictor of being poor sleepers. PMID- 23342128 TI - Cranial remain from Tunisia provides new clues for the origin and evolution of Sirenia (Mammalia, Afrotheria) in Africa. AB - Sea cows (manatees, dugongs) are the only living marine mammals to feed solely on aquatic plants. Unlike whales or dolphins (Cetacea), the earliest evolutionary history of sirenians is poorly documented, and limited to a few fossils including skulls and skeletons of two genera composing the stem family of Prorastomidae (Prorastomus and Pezosiren). Surprisingly, these fossils come from the Eocene of Jamaica, while stem Hyracoidea and Proboscidea--the putative sister-groups to Sirenia--are recorded in Africa as early as the Late Paleocene. So far, the historical biogeography of early Sirenia has remained obscure given this paradox between phylogeny and fossil record. Here we use X-ray microtomography to investigate a newly discovered sirenian petrosal from the Eocene of Tunisia. This fossil represents the oldest occurrence of sirenians in Africa. The morphology of this petrosal is more primitive than the Jamaican prorastomids' one, which emphasizes the basal position of this new African taxon within the Sirenia clade. This discovery testifies to the great antiquity of Sirenia in Africa, and therefore supports their African origin. While isotopic analyses previously suggested sirenians had adapted directly to the marine environment, new paleoenvironmental evidence suggests that basal-most sea cows were likely restricted to fresh waters. PMID- 23342129 TI - A reevaluation of the morphology, paleoecology, and phylogenetic relationships of the enigmatic walrus Pelagiarctos. AB - BACKGROUND: A number of aberrant walruses (Odobenidae) have been described from the Neogene of the North Pacific, including specialized suction-feeding and generalist fish-eating taxa. At least one of these fossil walruses has been hypothesized to have been a specialized predator of other marine mammals, the middle Miocene walrus Pelagiarctos thomasi from the Sharktooth Hill Bonebed of California (16.1-14.5 Ma). METHODOLOGY/PRINCIPAL FINDINGS: A new specimen of Pelagiarctos from the middle Miocene "Topanga" Formation of southern California (17.5-15 Ma) allows a reassessment of the morphology and feeding ecology of this extinct walrus. The mandibles of this new specimen are robust with large canines, bulbous premolars with prominent paraconid, metaconid, hypoconid cusps, crenulated lingual cingula with small talonid basins, M2 present, double-rooted P3-M1, single-rooted P1 and M2, and a P2 with a bilobate root. Because this specimen lacks a fused mandibular symphysis like Pelagiarctos thomasi, it is instead referred to Pelagiarctos sp. This specimen is more informative than the fragmentary holotype of Pelagiarctos thomasi, permitting Pelagiarctos to be included within a phylogenetic analysis for the first time. Analysis of a matrix composed of 90 cranial, dental, mandibular and postcranial characters indicates that Pelagiarctos is an early diverging walrus and sister to the late Miocene walrus Imagotaria downsi. We reevaluate the evidence for a macropredatory lifestyle for Pelagiarctos, and we find no evidence of specialization towards a macrophagous diet, suggesting that Pelagiarctos was a generalist feeder with the ability to feed on large prey. CONCLUSIONS/SIGNIFICANCE: This new specimen of Pelagiarctos adds to the knowledge of this problematic taxon. The phylogenetic analysis conclusively demonstrates that Pelagiarctos is an early diverging walrus. Pelagiarctos does not show morphological specializations associated with macrophagy, and was likely a generalist predator, feeding on fish, invertebrates, and the occasional warm-blooded prey item. PMID- 23342131 TI - Mosquitofish (Gambusia affinis) preference and behavioral response to animated images of conspecifics altered in their color, aspect ratio, and swimming depth. AB - Mosquitofish (Gambusia affinis) is an example of a freshwater fish species whose remarkable diffusion outside its native range has led to it being placed on the list of the world's hundred worst invasive alien species (International Union for Conservation of Nature). Here, we investigate mosquitofish shoaling tendency using a dichotomous choice test in which computer-animated images of their conspecifics are altered in color, aspect ratio, and swimming level in the water column. Pairs of virtual stimuli are systematically presented to focal subjects to evaluate their attractiveness and the effect on fish behavior. Mosquitofish respond differentially to some of these stimuli showing preference for conspecifics with enhanced yellow pigmentation while exhibiting highly varying locomotory patterns. Our results suggest that computer-animated images can be used to understand the factors that regulate the social dynamics of shoals of Gambusia affinis. Such knowledge may inform the design of control plans and open new avenues in conservation and protection of endangered animal species. PMID- 23342130 TI - It's all in the eyes: subcortical and cortical activation during grotesqueness perception in autism. AB - Atypical face processing plays a key role in social interaction difficulties encountered by individuals with autism. In the current fMRI study, the Thatcher illusion was used to investigate several aspects of face processing in 20 young adults with high-functioning autism spectrum disorder (ASD) and 20 matched neurotypical controls. "Thatcherized" stimuli were modified at either the eyes or the mouth and participants discriminated between pairs of faces while cued to attend to either of these features in upright and inverted orientation. Behavioral data confirmed sensitivity to the illusion and intact configural processing in ASD. Directing attention towards the eyes vs. the mouth in upright faces in ASD led to (1) improved discrimination accuracy; (2) increased activation in areas involved in social and emotional processing; (3) increased activation in subcortical face-processing areas. Our findings show that when explicitly cued to attend to the eyes, activation of cortical areas involved in face processing, including its social and emotional aspects, can be enhanced in autism. This suggests that impairments in face processing in autism may be caused by a deficit in social attention, and that giving specific cues to attend to the eye-region when performing behavioral therapies aimed at improving social skills may result in a better outcome. PMID- 23342132 TI - Two-component system response regulators involved in virulence of Streptococcus pneumoniae TIGR4 in infective endocarditis. AB - Streptococci resident in the oral cavity have been linked to infective endocarditis (IE). While other viridans streptococci are commonly studied in relation to IE, less research has been focused on Streptococcus pneumoniae. We established for the first time an animal model of S. pneumoniae IE, and examined the virulence of the TIGR4 strain in this model. We hypothesized that two component systems (TCS) may mediate S. pneumoniae TIGR4 strain virulence in IE and examined TCS response regulator (RR) mutants of TIGR4 in vivo with the IE model. Thirteen of the 14 RR protein genes were mutagenized, excluding only the essential gene SP_1227. The requirement of the 13 RRs for S. pneumoniae competitiveness in the IE model was assessed in vivo through use of quantitative real-time PCR (qPCR) and competitive index assays. Using real-time PCR, several RR mutants were detected at significantly lower levels in infected heart valves compared with a control strain suggesting the respective RRs are candidate virulence factors for IE. The virulence reduction of the DeltaciaR mutant was further confirmed by competitive index assay. Our data suggest that CiaR is a virulence factor of S. pneumoniae strain TIGR4 for IE. PMID- 23342133 TI - Vav1 fine tunes p53 control of apoptosis versus proliferation in breast cancer. AB - Vav1 functions as a signal transducer protein in the hematopoietic system, where it is exclusively expressed. Vav1 was recently implicated in several human cancers, including lung, pancreatic and neuroblasoma. In this study, we analyzed the expression and function of Vav1 in human breast tumors and breast cancer cell lines. Immunohistochemical analysis of primary human breast carcinomas indicated that Vav1 is expressed in 62% of 65 tumors tested and is correlated positively with estrogen receptor expression. Based on published gene profiling of 50 breast cancer cell lines, several Vav1-expressing cell lines were identified. RT-PCR confirmed Vav1 mRNA expression in several of these cell lines, yet no detectable levels of Vav1 protein were observed due to cbl-c proteasomal degradation. We used two of these lines, MCF-7 (Vav1 mRNA negative) and AU565 (Vav1 mRNA positive), to explore the effect of Vav1 expression on breast cell phenotype and function. Vav1 expression had opposite effects on function in these two lines: it reduced proliferation and enhanced cell death in MCF-7 cells but enhanced proliferation in AU565 cells. Consistent with these findings, transcriptome analysis revealed an increase in expression of proliferation-related genes in Vav1-expressing AU565 cells compared to controls, and an increase in apoptosis related genes in Vav1-expressing MCF-7 cells compared with controls. TUNEL and gamma-H2AX foci assays confirmed that expression of Vav1 increased apoptosis in MCF-7 cells but not AU565 cells and shRNA experiments revealed that p53 is required for this pro-apoptotic effect of Vav1 in these cells. These results highlight for the first time the potential role of Vav1 as an oncogenic stress activator in cancer and the p53 dependence of its pro-apoptotic effect in breast cells. PMID- 23342134 TI - Relationship between water soluble carbohydrate content, aphid endosymbionts and clonal performance of Sitobion avenae on cocksfoot cultivars. AB - Aphids feed on plant phloem sap, rich in sugars but poor in essential amino acids. However, sugars cause osmotic regulation problems for aphids, which they overcome by hydrolysing the sugars in their gut and polymerising the hydrolysis products into oligosaccharides, excreted with honeydew. Aphids harbour primary bacterial endosymbionts, which supply them with essential amino acids necessary for survival. They also harbour secondary (facultative) endosymbionts (sfS), some of which have a positive impact on life history traits, although it is not yet known whether they also play a role in providing effective tolerance to differing levels of water soluble carbohydrates (WSCs). We investigated the relationship between WSC content of cocksfoot cultivars and performance of clones of the English grain aphid Sitobion avenae F. We evaluated how clone genotype and their sfS modulate performance on these different cultivars. We therefore examined the performance of genetically defined clones of S. avenae, collected from different host plants, harbouring different sfS. The performance was tested on 10 Dactylis glomerata L. cultivars with varying WSC content. D. glomerata is known as a wild host plant for S. avenae and is also commercially planted. We found that high WSCs levels are responsible for the resistance of D. glomerata cultivars to specific S. avenae clones. The minimum level of WSCs conferring resistance to D. glomerata cultivars was 1.7% dw. Cultivars with a WSC content of 2.2% or higher were resistant to S. avenae and did not allow reproduction. Our results further indicate that sfS modulate to some extend host plant cultivar adaptation in S. avenae. This is the first study revealing the importance of WSCs for aphid performance. Cocksfoot cultivars with a high content of WSCs might be therefore considered for aphid control or used for resistance breeding in this and other grass species, including cereals. PMID- 23342135 TI - Coverage, diversity, and functionality of a high-latitude coral community (Tatsukushi, Shikoku Island, Japan). AB - BACKGROUND: Seawater temperature is the main factor restricting shallow-water zooxanthellate coral reefs to low latitudes. As temperatures increase, coral species and perhaps reefs may move into higher-latitude waters, increasing the chances of coral reef ecosystems surviving despite global warming. However, there is a growing need to understand the structure of these high-latitude coral communities in order to analyze their future dynamics and to detect any potential changes. METHODOLOGY/PRINCIPAL FINDINGS: The high-latitude (32.75 degrees N) community surveyed was located at Tatsukushi, Shikoku Island, Japan. Coral cover was 60+/-2% and was composed of 73 scleractinian species partitioned into 7 functional groups. Although only 6% of species belonged to the 'plate-like' functional group, it was the major contributor to species coverage. This was explained by the dominance of plate-like species such as Acropora hyacinthus and A. solitaryensis. Comparison with historical data suggests a relatively recent colonization/development of A. hyacinthus in this region and a potential increase in coral diversity over the last century. Low coverage of macroalgae (2% of the benthic cover) contrasted with the low abundance of herbivorous fishes, but may be reasonably explained by the high density of sea urchins (12.9+/-3.3 individuals m-2). CONCLUSIONS/SIGNIFICANCE: The structure and composition of this benthic community are relatively remarkable for a site where winter temperature can durably fall below the accepted limit for coral reef development. Despite limited functionalities and functional redundancy, the current benthic structure might provide a base upon which a reef could eventually develop, as characterized by opportunistic and pioneer frame-building species. In addition to increasing seawater temperatures, on-going management actions and sea urchin density might also explain the observed state of this community. A focus on such 'marginal' communities should be a priority, as they can provide important insights into how tropical corals might cope with environmental changes. PMID- 23342136 TI - Function of mouse embryonic stem cell-derived supporting cells in neural progenitor cell maturation and long term expansion. AB - BACKGROUND: In the differentiation of mouse embryonic stem (ES) cells into neurons using the 5-stage method, cells in stage 4 are in general used as neural progenitors (NPs) because of their ability to give rise to neurons. The choice of stage 4 raises several questions about neural progenitors such as the type of cell types that are specifically considered to be neural progenitors, the exact time when these progenitors become capable of neurogenesis and whether neurogenesis is an independent and autonomous process or the result of an interaction between NP cells and the surrounding cells. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we found that the confluent monolayer cells and neural sphere like cell clusters both appeared in the culture of the first 14 days and the subsequent 6 weeks. However, only the sphere cells are neural progenitors that give rise to neurons and astrocytes. The NP cells require 14 days to mature into neural lineages fully capable of differentiation. We also found that although the confluent monolayer cells do not undergo neurogenesis, they play a crucial role in the growth, differentiation, and apoptosis of the sphere cells, during the first 14 days and long term culture, by secreted factors and direct cell to cell contact. CONCLUSIONS/SIGNIFICANCE: The sphere cells in stage 4 are more committed to developing into neural progenitors than monolayer cells. Interaction between the monolayer cells and sphere cells is important in the development of stage 4 cell characteristics. PMID- 23342137 TI - Neutralization by metal ions of the toxicity of sodium selenide. AB - Inert metal-selenide colloids are found in animals. They are believed to afford cross-protection against the toxicities of both metals and selenocompounds. Here, the toxicities of metal salt and sodium selenide mixtures were systematically studied using the death rate of Saccharomyces cerevisiae cells as an indicator. In parallel, the abilities of these mixtures to produce colloids were assessed. Studied metal cations could be classified in three groups: (i) metal ions that protect cells against selenium toxicity and form insoluble colloids with selenide (Ag+, Cd2+, Cu2+, Hg2+, Pb2+ and Zn2+), (ii) metal ions which protect cells by producing insoluble metal-selenide complexes and by catalyzing hydrogen selenide oxidation in the presence of dioxygen (Co2+ and Ni2+) and, finally, (iii) metal ions which do not afford protection and do not interact (Ca2+, Mg2+, Mn2+) or weakly interact (Fe2+) with selenide under the assayed conditions. When occurring, the insoluble complexes formed from divalent metal ions and selenide contained equimolar amounts of metal and selenium atoms. With the monovalent silver ion, the complex contained two silver atoms per selenium atom. Next, because selenides are compounds prone to oxidation, the stabilities of the above colloids were evaluated under oxidizing conditions. 5,5'-dithiobis-(2 nitrobenzoic acid) (DTNB), the reduction of which can be optically followed, was used to promote selenide oxidation. Complexes with cadmium, copper, lead, mercury or silver resisted dissolution by DTNB treatment over several hours. With nickel and cobalt, partial oxidation by DTNB occurred. On the other hand, when starting from ZnSe or FeSe complexes, full decompositions were obtained within a few tens of minutes. The above properties possibly explain why ZnSe and FeSe nanoparticles were not detected in animals exposed to selenocompounds. PMID- 23342138 TI - The history of Slavs inferred from complete mitochondrial genome sequences. AB - To shed more light on the processes leading to crystallization of a Slavic identity, we investigated variability of complete mitochondrial genomes belonging to haplogroups H5 and H6 (63 mtDNA genomes) from the populations of Eastern and Western Slavs, including new samples of Poles, Ukrainians and Czechs presented here. Molecular dating implies formation of H5 approximately 11.5-16 thousand years ago (kya) in the areas of southern Europe. Within ancient haplogroup H6, dated at around 15-28 kya, there is a subhaplogroup H6c, which probably survived the last glaciation in Europe and has undergone expansion only 3-4 kya, together with the ancestors of some European groups, including the Slavs, because H6c has been detected in Czechs, Poles and Slovaks. Detailed analysis of complete mtDNAs allowed us to identify a number of lineages that seem specific for Central and Eastern Europe (H5a1f, H5a2, H5a1r, H5a1s, H5b4, H5e1a, H5u1, some subbranches of H5a1a and H6a1a9). Some of them could possibly be traced back to at least ~4 kya, which indicates that some of the ancestors of today's Slavs (Poles, Czechs, Slovaks, Ukrainians and Russians) inhabited areas of Central and Eastern Europe much earlier than it was estimated on the basis of archaeological and historical data. We also sequenced entire mitochondrial genomes of several non-European lineages (A, C, D, G, L) found in contemporary populations of Poland and Ukraine. The analysis of these haplogroups confirms the presence of Siberian (C5c1, A8a1) and Ashkenazi-specific (L2a1l2a) mtDNA lineages in Slavic populations. Moreover, we were able to pinpoint some lineages which could possibly reflect the relatively recent contacts of Slavs with nomadic Altaic peoples (C4a1a, G2a, D5a2a1a1). PMID- 23342139 TI - Nationwide prevalence of groin hernia repair. AB - INTRODUCTION: Groin hernia repair is a commonly performed surgical procedure in the western world but large-scaled epidemiologic data are sparse. Large-scale data on the occurrence of groin hernia repair may provide further understanding to the pathophysiology of groin hernia development. This study was undertaken to investigate the age and gender dependent prevalence of groin hernia repair. METHODS: In a nationwide register-based study, using data from the Civil Registration System covering all Danish citizens, we established a population based cohort of all people living in Denmark on December 31(st), 2010. Within this population all groin hernia repairs during the past 5 years were identified using data from the ICD 10(th) edition in the Danish National Hospital Register. RESULTS: The study population covered n = 5,639,885 persons. During the five years study period 46,717 groin hernia repairs were performed (88.6% males, 11.4% females). Inguinal hernias comprised 97% of groin hernia repairs (90.2% males, 9.8% females) and femoral hernias 3% of groin hernia repairs (29.8% males, 70.2% females). Patients between 0-5 years and 75-80 years constituted the two dominant groups for inguinal hernia repair. In contrast, the age-specific prevalence of femoral hernia repair increased steadily throughout life peaking at age 80-90 years in both men and women. CONCLUSION: The age distribution of inguinal hernia repair is bimodal peaking at early childhood and old age, whereas the prevalence of femoral hernia repair increased steadily throughout life. This information can be used to formulate new hypotheses regarding disease etiology with regard to age and gender specifications. PMID- 23342140 TI - Application of Gurson-Tvergaard-Needleman constitutive model to the tensile behavior of reinforcing bars with corrosion pits. AB - Based on meso-damage mechanics and finite element analysis, the aim of this paper is to describe the feasibility of the Gurson-Tvergaard-Needleman (GTN) constitutive model in describing the tensile behavior of corroded reinforcing bars. The orthogonal test results showed that different fracture pattern and the related damage evolution process can be simulated by choosing different material parameters of GTN constitutive model. Compared with failure parameters, the two constitutive parameters are significant factors affecting the tensile strength. Both the nominal yield and ultimate tensile strength decrease markedly with the increase of constitutive parameters. Combining with the latest data and trial-and error method, the suitable material parameters of GTN constitutive model were adopted to simulate the tensile behavior of corroded reinforcing bars in concrete under carbonation environment attack. The numerical predictions can not only agree very well with experimental measurements, but also simplify the finite element modeling process. PMID- 23342142 TI - Association of FTO polymorphisms with obesity and obesity-related outcomes in Portuguese children. AB - BACKGROUND: Several studies have reported an association between single nucleotide polymorphisms in the first intron of the FTO gene and body mass index (BMI) or obesity. However, this association has not yet been studied among the Portuguese population. This study aims to assess the association of three FTO polymorphisms (rs1861868, rs1421085 and rs9939609) with obesity-related outcomes in a sample of Portuguese children. METHODS: We examined a total of 730 children, 256 normal-weight (55.9% girls), 320 overweight (45.3% girls) and 154 obese (53.2% girls), aging from 6 to 12-years-old, recruited randomly from public schools in the central region of Portugal. DNA samples were genotyped for the three polymorphisms by allelic discrimination TaqMan assay. Association of the FTO polymorphisms with several anthropometric traits was investigated. Additionally, we tested association with the risk of obesity using overweight and obese vs. normal-weight children. RESULTS: We found significant associations of rs9939609 and rs1421085 polymorphisms with weight, BMI, BMI Z-score, waist circumference and hip circumference, even after age and gender adjustment (p<0.05 in all traits). For rs1861868 polymorphism, marginally significant associations were obtained with weight (p = 0.081) and BMI (p = 0.096) after adjustment for age and gender. In case-control studies, both rs9939609 and rs1421085 polymorphisms were significantly associated with obesity (OR 1.97; 95% CI, 1.08 3.59; p = 0.026; OR 2.11; 95% CI, 1.17-3.81; p = 0.013, respectively) but not with overweight (p>0.05). Haplotype analyses identified two combinations (ACA and GCA) associated with a higher risk of obesity (OR 1.53; 95% CI, 1.06-2.22; p = 0.023; OR 1.73; 95% CI, 1.06-2.87; p = 0.030, respectively). CONCLUSIONS: This study provides the first evidence for the association of FTO polymorphisms with anthropometric traits and risk of obesity in Portuguese children. PMID- 23342141 TI - Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein. AB - Breast cancer is one of the most lethal diseases in women; however, the precise etiological factors are still not clear. Genistein (GE), a natural isoflavone found in soybean products, is believed to be a potent chemopreventive agent for breast cancer. One of the most important mechanisms for GE inhibition of breast cancer may involve its potential in impacting epigenetic processes allowing reversal of aberrant epigenetic events during breast tumorigenesis. To investigate epigenetic regulation for GE impedance of breast tumorigenesis, we monitored epigenetic alterations of several key tumor-related genes in an established breast cancer transformation system. Our results show that GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21(WAF1) (p21) and p16(INK4a) (p16), although it decreased expression of two tumor promoting genes, BMI1 and c MYC. GE treatment led to alterations of histone modifications in the promoters of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes. In addition, an orally-fed GE diet prevented breast tumorigenesis and inhibited breast cancer development in breast cancer mice xenografts. Our results suggest that genistein may repress early breast tumorigenesis by epigenetic regulation of p21 and p16 by impacting histone modifications as well as the BMI1-c-MYC complex recruitment to the regulatory region in the promoters of these genes. These studies will facilitate more effective use of soybean product in breast cancer prevention and also help elucidate the mechanisms during the process of early breast tumorigenesis. PMID- 23342143 TI - Understanding the impact of subsidizing artemisinin-based combination therapies (ACTs) in the retail sector--results from focus group discussions in rural Kenya. AB - BACKGROUND: There is considerable interest in the potential of private sector subsidies to increase availability and affordability of artemisinin-based combination therapies (ACTs) for malaria treatment. A cluster randomized trial of such subsidies was conducted in 3 districts in Kenya, comprising provision of subsidized packs of paediatric ACT to retail outlets, training of retail staff, and community awareness activities. The results demonstrated a substantial increase in ACT availability and coverage, though patient counselling and adherence were suboptimal. We conducted a qualitative study in order to understand why these successes and limitations occurred. METHODOLOGY/PRINCIPAL FINDINGS: Eighteen focus group discussions were conducted, 9 with retailers and 9 with caregivers, to document experiences with the intervention. Respondents were positive about intervention components, praising the focused retailer training, affordable pricing, strong promotional activities, dispensing job aids, and consumer friendly packaging, which are likely to have contributed to the positive access and coverage outcomes observed. However, many retailers still did not stock ACT, due to insufficient supplies, lack of capital and staff turnover. Advice to caregivers was poor due to insufficient time, and poor recall of instructions. Adherence by caregivers to dosing guidelines was sub-optimal, because of a wish to save tablets for other episodes, doses being required at night, stopping treatment when the child felt better, and the number and bitter taste of the tablets. Caregivers used a number of strategies to obtain paediatric ACT for older age groups. CONCLUSIONS/SIGNIFICANCE: This study has highlighted that important components of a successful ACT subsidy intervention are regular retailer training, affordable pricing, a reliable supply chain and community mobilization emphasizing patient adherence and when to seek further care. PMID- 23342144 TI - Bicarbonate-dependent secretion and proteolytic processing of recombinant myocilin. AB - Myocilin is an extracellular glycoprotein of poorly understood function. Mutations of this protein are involved in glaucoma, an optic neuropathy characterized by a progressive and irreversible visual loss and frequently associated with elevated intraocular pressure. We previously showed that recombinant myocilin undergoes an intracellular proteolytic processing by calpain II which cleaves the central region of the protein, releasing one N- and one C terminal fragment. Myocilin cleavage is reduced by glaucoma mutations and it has been proposed to participate in intraocular pressure modulation. To identify possible factors regulating the proteolytic processing of recombinant myocilin, we used a cellular model in which we analyzed how different culture medium parameters (i.e., culture time, cell density, pH, bicarbonate concentration, etc.) affect the presence of the extracellular C-terminal fragment. Extracellular bicarbonate depletion associated with culture medium acidification produced a reversible intracellular accumulation of full-length recombinant myocilin and incremented its intracellular proteolytic processing, raising the extracellular C terminal fragment percentage. It was also determined that myocilin intracellular accumulation depends on its N-terminal region. These data suggest that aqueous humor bicarbonate variations could also modulate the secretion and cleavage of myocilin present in ocular tissues. PMID- 23342145 TI - Lizard and frog prestin: evolutionary insight into functional changes. AB - The plasma membrane of mammalian cochlear outer hair cells contains prestin, a unique motor protein. Prestin is the fifth member of the solute carrier protein 26A family. Orthologs of prestin are also found in the ear of non-mammalian vertebrates such as zebrafish and chicken. However, these orthologs are electrogenic anion exchangers/transporters with no motor function. Amphibian and reptilian lineages represent phylogenic branches in the evolution of tetrapods and subsequent amniotes. Comparison of the peptide sequences and functional properties of these prestin orthologs offer new insights into prestin evolution. With the recent availability of the lizard and frog genome sequences, we examined amino acid sequence and function of lizard and frog prestins to determine how they are functionally and structurally different from prestins of mammals and other non-mammals. Somatic motility, voltage-dependent nonlinear capacitance (NLC), the two hallmarks of prestin function, and transport capability were measured in transfected human embryonic kidney cells using voltage-clamp and radioisotope techniques. We demonstrated that while the transport capability of lizard and frog prestin was compatible to that of chicken prestin, the NLC of lizard prestin was more robust than that of chicken's and was close to that of platypus. However, unlike platypus prestin which has acquired motor capability, lizard or frog prestin did not demonstrate motor capability. Lizard and frog prestins do not possess the same 11-amino-acid motif that is likely the structural adaptation for motor function in mammals. Thus, lizard and frog prestins appear to be functionally more advanced than that of chicken prestin, although motor capability is not yet acquired. PMID- 23342146 TI - An ERP study of good production vis-a-vis poor perception of tones in Cantonese: implications for top-down speech processing. AB - This study investigated a theoretically challenging dissociation between good production and poor perception of tones among neurologically unimpaired native speakers of Cantonese. The dissociation is referred to as the near-merger phenomenon in sociolinguistic studies of sound change. In a passive oddball paradigm, lexical and nonlexical syllables of the T1/T6 and T4/T6 contrasts were presented to elicit the mismatch negativity (MMN) and P3a from two groups of participants, those who could produce and distinguish all tones in the language (Control) and those who could produce all tones but specifically failed to distinguish between T4 and T6 in perception (Dissociation). The presence of MMN to T1/T6 and null response to T4/T6 of lexical syllables in the dissociation group confirmed the near-merger phenomenon. The observation that the control participants exhibited a statistically reliable MMN to lexical syllables of T1/T6, weaker responses to nonlexical syllables of T1/T6 and lexical syllables of T4/T6, and finally null response to nonlexical syllables of T4/T6, suggests the involvement of top-down processing in speech perception. Furthermore, the stronger P3a response of the control group, compared with the dissociation group in the same experimental conditions, may be taken to indicate higher cognitive capability in attention switching, auditory attention or memory in the control participants. This cognitive difference, together with our speculation that constant top-down predictions without complete bottom-up analysis of acoustic signals in speech recognition may reduce one's sensitivity to small acoustic contrasts, account for the occurrence of dissociation in some individuals but not others. PMID- 23342147 TI - miRNA gene promoters are frequent targets of aberrant DNA methylation in human breast cancer. AB - miRNAs are important regulators of gene expression that are frequently deregulated in cancer, with aberrant DNA methylation being an epigenetic mechanism involved in this process. We previously identified miRNA promoter regions active in normal mammary cell types and here we analyzed which of these promoters are targets of aberrant DNA methylation in human breast cancer cell lines and breast tumor specimens. Using 5-methylcytosine immunoprecipitation coupled to miRNA tiling microarray hybridization, we performed comprehensive evaluation of DNA methylation of miRNA gene promoters in breast cancer. We found almost one third (55/167) of miRNA promoters were targets for aberrant methylation in breast cancer cell lines. Breast tumor specimens displayed DNA methylation of majority of these miRNA promoters, indicating that these changes in DNA methylation might be clinically relevant. Aberrantly methylated miRNA promoters were, similar to protein coding genes, enriched for promoters targeted by polycomb in normal cells. Detailed analysis of selected miRNA promoters revealed decreased expression of miRNA linked to increased promoter methylation for mir-31, mir-130a, let-7a-3/let-7b, mir-155, mir-137 and mir-34b/mir-34c genes. The proportion of miRNA promoters we found aberrantly methylated in breast cancer is several fold larger than that observed for protein coding genes, indicating an important role of DNA methylation in miRNA deregulation in cancer. PMID- 23342148 TI - A shared neural substrate for mentalizing and the affective component of sentence comprehension. AB - Using event-related fMRI in a sample of 42 healthy participants, we compared the cerebral activity maps obtained when classifying spoken sentences based on the mental content of the main character (belief, deception or empathy) or on the emotional tonality of the sentence (happiness, anger or sadness). To control for the effects of different syntactic constructions (such as embedded clauses in belief sentences), we subtracted from each map the BOLD activations obtained during plausibility judgments on structurally matching sentences, devoid of emotions or ToM. The obtained theory of mind (ToM) and emotional speech comprehension networks overlapped in the bilateral temporo-parietal junction, posterior cingulate cortex, right anterior temporal lobe, dorsomedial prefrontal cortex and in the left inferior frontal sulcus. These regions form a ToM network, which contributes to the emotional component of spoken sentence comprehension. Compared with the ToM task, in which the sentences were enounced on a neutral tone, the emotional sentence classification task, in which the sentences were play-acted, was associated with a greater activity in the bilateral superior temporal sulcus, in line with the presence of emotional prosody. Besides, the ventromedial prefrontal cortex was more active during emotional than ToM sentence processing. This region may link mental state representations with verbal and prosodic emotional cues. Compared with emotional sentence classification, ToM was associated with greater activity in the caudate nucleus, paracingulate cortex, and superior frontal and parietal regions, in line with behavioral data showing that ToM sentence comprehension was a more demanding task. PMID- 23342149 TI - Solution structures of two homologous venom peptides from Sicarius dolichocephalus. AB - We present solution-state NMR structures for two putative venom peptides from Sicarius dolichocephalus. These peptides were identified from cDNA libraries created from venom gland mRNA and then recombinantly expressed. They are the first structures from any species of Sicarius spiders, and the first peptide structures for any haplogyne spiders. These peptides are homologous to one another, and while they have at most only 20% sequence identity with known venom peptides their structures follow the inhibitor cystine knot motif that has been found in a broad range of venom peptides. PMID- 23342150 TI - Characteristic face: a key indicator for direct diagnosis of 22q11.2 deletions in Chinese velocardiofacial syndrome patients. AB - Velocardiofacial syndrome (VCFS) is a disease in human with an expansive phenotypic spectrum and diverse genetic mechanisms mainly associated with copy number variations (CNVs) on 22q11.2 or other chromosomes. However, the correlations between CNVs and phenotypes remain ambiguous. This study aims to analyze the types and sizes of CNVs in VCFS patients, to define whether correlations exist between CNVs and clinical manifestations in Chinese VCFS patients. In total, 55 clinically suspected Chinese VCFS patients and 100 normal controls were detected by multiplex ligation-dependent probe amplification (MLPA). The data from MLPA and all the detailed clinical features of the objects were documented and analyzed. A total of 44 patients (80.0%) were diagnosed with CNVs on 22q11.2. Among them, 43 (78.2%) presented with 22q11.2 heterozygous deletions, of whom 40 (93.0%) had typical 3-Mb deletion, and 3 (7.0%) exhibited proximal 1.5-Mb deletion; no patient was found with atypical deletion on 22q11.2. One patient (1.8%) presented with a 3-Mb duplication mapping to the typical 3-Mb region on 22q11.2, while none of the chromosomal abnormalities in the MLPA kit were found in the other 11 patients and 100 normal controls. All the 43 patients with 22q11.2 deletions displayed characteristic face and palatal anomalies; 37 of them (86.0%) had cognitive or behavioral disorders, and 23 (53.5%) suffered from immune deficiencies; 10 patients (23.3%) manifested congenital heart diseases. Interestingly, all patients with the characteristic face had 22q11.2 heterozygous deletions, but no difference in phenotypic spectrum was observed between 3-Mb and 1.5-Mb deletions. Our data suggest that the characteristic face can be used as a key indicator for direct diagnosis of 22q11.2 deletions in Chinese VCFS patients. PMID- 23342151 TI - Using gross energy improves metabolizable energy predictive equations for pet foods whereas undigested protein and fiber content predict stool quality. AB - Because animal studies are labor intensive, predictive equations are used extensively for calculating metabolizable energy (ME) concentrations of dog and cat pet foods. The objective of this retrospective review of digestibility studies, which were conducted over a 7-year period and based upon Association of American Feed Control Officials (AAFCO) feeding protocols, was to compare the accuracy and precision of equations developed from these animal feeding studies to commonly used predictive equations. Feeding studies in dogs and cats (331 and 227 studies, respectively) showed that equations using modified Atwater factors accurately predict ME concentrations in dog and cat pet foods (r2= 0.97 and 0.98, respectively). The National Research Council (NRC) equations also accurately predicted ME concentrations in pet foods (r2 = 0.97 for dog and cat foods). For dogs, these equations resulted in an average estimate of ME within 0.16% and 2.24% of the actual ME measured (equations using modified Atwater factors and NRC equations, respectively); for cats these equations resulted in an average estimate of ME within 1.57% and 1.80% of the actual ME measured. However, better predictions of dietary ME in dog and cat pet foods were achieved using equations based on analysis of gross energy (GE) and new factors for moisture, protein, fat and fiber. When this was done there was less than 0.01% difference between the measured ME and the average predicted ME (r2 = 0.99 and 1.00 in dogs and cats, respectively) whereas the absolute value of the difference between measured and predicted was reduced by approximately 50% in dogs and 60% in cats. Stool quality, which was measured by stool score, was influenced positively when dietary protein digestibility was high and fiber digestibility was low. In conclusion, using GE improves predictive equations for ME content of dog and cat pet foods. Nondigestible protein and fiber content of diets predicts stool quality. PMID- 23342152 TI - Determinants of burnout in acute and critical care military nursing personnel: a cross-sectional study from Peru. AB - BACKGROUND: Evidence on the prevalence and determinants of burnout among military acute and critical care nursing personnel from developing countries is minimal, precluding the development of effective preventive measures for this high-risk occupational group. In this context, we aimed to examine the association between the dimensions of burnout and selected socio-demographic and occupational factors in military acute/critical care nursing personnel from Lima, Peru. METHODS AND FINDINGS: We conducted a cross-sectional study in 93 nurses/nurse assistants from the acute and critical care departments of a large, national reference, military hospital in Lima, Peru, using a socio-demographic/occupational questionnaire and a validated Spanish translation of the Maslach Burnout Inventory. Total scores for each of the burnout dimensions were calculated for each participant. Higher emotional exhaustion and depersonalisation scores, and lower personal achievement scores, implied a higher degree of burnout. We used linear regression to evaluate the association between each of the burnout dimensions and selected socio demographic and occupational characteristics, after adjusting for potential confounders. The associations of the burnout dimensions were heterogeneous for the different socio-demographic and occupational factors. Higher emotional exhaustion scores were independently associated with having children (p<0.05) and inversely associated with the time working in the current department (p<0.05). Higher depersonalization scores were independently associated with being single compared with being divorced, separated or widowed (p<0.01), working in the emergency room/intensive care unit compared with the recovery room (p<0.01), and inversely associated with age (p<0.05). Finally, higher personal achievement scores were independently associated with having children (p<0.05). CONCLUSION: Among Peruvian military acute and critical care nursing personnel, potential screening and preventive interventions should focus on younger/less experienced nurses/nurse assistants, who are single, have children, or work in the most acute critical care areas (e.g. the emergency room/intensive care unit). PMID- 23342153 TI - Transcriptomic immune response of Tenebrio molitor pupae to parasitization by Scleroderma guani. AB - BACKGROUND: Host and parasitoid interaction is one of the most fascinating relationships of insects, which is currently receiving an increasing interest. Understanding the mechanisms evolved by the parasitoids to evade or suppress the host immune system is important for dissecting this interaction, while it was still poorly known. In order to gain insight into the immune response of Tenebrio molitor to parasitization by Scleroderma guani, the transcriptome of T. molitor pupae was sequenced with focus on immune-related gene, and the non-parasitized and parasitized T. molitor pupae were analyzed by digital gene expression (DGE) analysis with special emphasis on parasitoid-induced immune-related genes using Illumina sequencing. METHODOLOGY/PRINCIPAL FINDINGS: In a single run, 264,698 raw reads were obtained. De novo assembly generated 71,514 unigenes with mean length of 424 bp. Of those unigenes, 37,373 (52.26%) showed similarity to the known proteins in the NCBI nr database. Via analysis of the transcriptome data in depth, 430 unigenes related to immunity were identified. DGE analysis revealed that parasitization by S. guani had considerable impacts on the transcriptome profile of T. molitor pupae, as indicated by the significant up- or down regulation of 3,431 parasitism-responsive transcripts. The expression of a total of 74 unigenes involved in immune response of T. molitor was significantly altered after parasitization. CONCLUSIONS/SIGNIFICANCE: obtained T. molitor transcriptome, in addition to establishing a fundamental resource for further research on functional genomics, has allowed the discovery of a large group of immune genes that might provide a meaningful framework to better understand the immune response in this species and other beetles. The DGE profiling data provides comprehensive T. molitor immune gene expression information at the transcriptional level following parasitization, and sheds valuable light on the molecular understanding of the host-parasitoid interaction. PMID- 23342154 TI - Systemic overexpression of TNFalpha-converting enzyme does not lead to enhanced shedding activity in vivo. AB - TNFalpha-converting enzyme (TACE/ADAM17) is a membrane-bound proteolytic enzyme with a diverse set of target molecules. Most importantly, TACE is indispensable for the release and activation of pro-TNFalpha and the ligands for epidermal growth factor receptor in vivo. Previous studies suggested that the overproduction of TACE is causally related to the pathogenesis of inflammatory diseases and cancers. To test this hypothesis, we generated a transgenic line in which the transcription of exogenous Tace is driven by a CAG promoter. The Tace transgenic mice were viable and exhibited no overt defects, and the quantitative RT-PCR and Western blot analyses confirmed that the transgenically introduced Tace gene was highly expressed in all of the tissues examined. The Tace transgenic mice were further crossed with Tace-/+ mice to abrogate the endogenous TACE expression, and the Tace-transgenic mice lacking endogenous Tace gene were also viable without any apparent defects. Furthermore, there was no difference in the serum TNFalpha levels after lipopolysaccharide injection between the transgenic mice and control littermates. These observations indicate that TACE activity is not necessarily dependent on transcriptional regulation and that excess TACE does not necessarily result in aberrant proteolytic activity in vivo. PMID- 23342155 TI - Identification of discrete sites in Yip1A necessary for regulation of endoplasmic reticulum structure. AB - The endoplasmic reticulum (ER) of specialized cells can undergo dramatic changes in structural organization, including formation of concentric whorls. We previously reported that depletion of Yip1A, an integral membrane protein conserved between yeast and mammals, caused ER whorl formation reminiscent of that seen in specialized cells. Yip1A and its yeast homologue Yip1p cycle between the ER and early Golgi, have been implicated in a number of distinct trafficking steps, and interact with a conserved set of binding partners including Yif1p/Yif1A and the Ypt1/Ypt31 Rab GTPases. Here, we carried out a mutational analysis of Yip1A to obtain insight into how it regulates ER whorl formation. Most of the Yip1A cytoplasmic domain was dispensable, whereas the transmembrane (TM) domain, especially residues within predicted TM helices 3 and 4, were sensitive to mutagenesis. Comprehensive analysis revealed two discrete functionally required determinants. One was E95 and flanking residues L92 and L96 within the cytoplasmic domain; the other was K146 and nearby residue V152 within the TM domain. Notably, the identified determinants correspond closely to two sites previously found to be essential for yeast viability (E76 and K130 in Yip1p corresponding to E95 and K146 in Yip1A, respectively). In contrast, a third site (E89) also essential for yeast viability (E70 in Yip1p) was dispensable for regulation of whorl formation. Earlier work showed that E76 (E95) was dispensable for binding Yif1p or Ypt1p/Ypt31p, whereas E70 (E89) was required. Collectively, these findings suggest that the ability of Yip1A to bind its established binding partners may be uncoupled from its ability to control ER whorl formation. In support, Yif1A knockdown did not cause ER whorl formation. Thus Yip1A may use the sites identified herein to interact with a novel binding partner to regulate ER membrane organization. PMID- 23342156 TI - Establishment of HRAS(G12V) transgenic medaka as a stable tumor model for in vivo screening of anticancer drugs. AB - Most targeted anticancer drugs have been identified by screening at the molecular or cellular level in vitro. However, many compounds selected by such costly and time-consuming screening do not prove effective against tumors in vivo. The development of anticancer drugs would thus be facilitated by the availability of an in vivo screening system based on a multicellular organism. We have now established a transgenic line of the freshwater fish medaka in which melanophores (melanocytes) proliferate in a manner dependent on heat shock-induced signaling by a human RAS oncoprotein. The human HRAS(G12V) oncogene was expressed under the control of a melanophore-specific gene promoter in order to allow visualization of tumor growth in live fish maintained in a water tank. The expression of HRAS(G12V) was induced as a result of Cre-mediated recombination by exposure of the fish to a temperature of 37 degrees C for 30 min, given that the Cre gene was placed under the control of a medaka heat shock promoter. One of the stable transgenic lines developed abnormal pigment cell proliferation in the eyes and epidermis with 100% penetrance by 6 months postfertilization. Sorafenib, an inhibitor of RAS signaling, was administered to the transgenic fish and was found both to reduce the extent of melanophore proliferation and to improve survival. The transgenic medaka established here thus represents a promising in vivo system with which to screen potential anticancer drugs that target RAS signaling, and this system can readily be adapted for the screening of agents that target other oncogenes. PMID- 23342157 TI - Social investigation and long-term recognition memory performance in 129S1/SvImJ and C57BL/6JOlaHsd mice and their hybrids. AB - When tested for their behavioural performance, the mixed genetic background of transgenic mice is a critical, but often ignored, issue. Such issues can arise because of the significant differences in defined behavioural parameters between embryonic stem cell donor and recipient strains. In this context, the commonly used stem cell donor strain '129' shows 'deficits' in different paradigms for learning and long-term memory. We investigated the long-term social recognition memory performance and the investigative behaviour in commercially available 129S1/SvImJ and C57BL/6JOlaHsd mice and two F1-hybrids (129S1/SvImJ*C57BL/6JOlaHsd) by using the social discrimination procedure and its modification, the volatile fraction cage (VFC). Our data revealed an unimpaired olfactory long-term recognition memory not only in female and male 129S1/SvImJ and C57BL/6JOlaHsd mice but also in the two hybrid lines (129S1/SvImJxC57BL/6JOlaHsd) when the full 'olfactory signature' of the 'to-be recognized' conspecific was presented. Under these conditions we also failed to detect differences in the long-term recognition memory between male and female mice of the tested strains and revealed that the oestrus cycle did not affect the performance in this memory task. The performance in the VFC, based only on the volatile components of the 'olfactory signature' of the 'to-be-recognized' conspecific, was similar to that observed under direct exposure except that females of one F1 hybrid group failed to show an intact long-term memory. Thus, the social discrimination procedure allowing direct access between the experimental subject and the stimulus animal(s) is highly suitable to investigate the impact of genetic manipulations on long-term memory in male and female mice of the strain 129S1/SvImJ, C57BL/6JOlaHsd and 129S1/SvImJxC57BL/6JOlaHsd hybrids. PMID- 23342158 TI - Understanding the social meaning of infertility and childbearing: a qualitative study of the perception of childbearing and childlessness in Northern Ghana. AB - BACKGROUND: Infertility is a major medical condition that affects many married couples in sub-Saharan African and as such associated with several social meanings. This study therefore explored community's perception of childbearing and childlessness in Northern Ghana using the Upper West Region as a case study. METHODS: The study was exploratory and qualitative using in-depth and key informant interviews and focus group discussions. Fifteen marriage unions with infertility (childless), forty-five couples with children, and eight key informants were purposively sampled and interviewed using a semi-structured interview guides. Three focus group discussions were also carried out, one for childless women, one for women with children and one with men with children. The data collected were transcribed, coded, arranged, and analyzed for categories and themes and finally triangulated. RESULTS: The study revealed that infertility was caused by both social and biological factors. Socially couples could become infertile through supernatural causes such as bewitchment, and disobediences of social norms. Abortion, masturbation and use of contraceptives were also identified as causes of infertility. Most childless couples seek treatment from spiritualist, traditional healers and hospital. These sources of treatment are used simultaneously. CONCLUSION: Childbearing is highly valued in the community and Childlessness is highly engendered, and stigmatised in this community with manifold social consequences. In such a community therefore, the concept of reproductive choice must encompass policies that make it possible for couples to aspire to have the number of children they wish. PMID- 23342159 TI - Lentiviral and Moloney retroviral expression of green fluorescent protein in somatotrophs in vivo. AB - Previous studies have shown that the locus control region (LCR) and the promoter of the growth hormone (GH) gene can control the expression of GH. Therefore, lenti- and retro-viral vectors with these elements might be useful to monitor the activation of the GH gene and the development of newborn somatotrophs. To test this, we first constructed a lentiviral vector, which expresses green fluorescent protein (GFP) under the control of these elements, and injected them into rat pituitaries in situ and in vivo. The lentiviral vector expressed GFP specifically in the anterior lobe, and nearly all GFP-positive cells were anti-GH immunoreactive. The GFP expression was upregulated by the administration of growth hormone releasing hormone and an IGF-1 receptor blocker. Furthermore, the social isolation stress, which was shown to decrease the GH secretion, decreased the GFP expression. Second, we injected the retroviral vector into neonatal rat pituitaries in vivo. At 30 days postinjection (DPI), almost all GFP-positive cells were anti-GH positive and anti-prolactin negative as the lentiviral expression. However, GFP was transiently expressed by developing lactotrophs at 8 and 16 DPI, suggesting that our vector lacks an element(s) which suppresses the expression. Meanwhile, the retrovirally labeled cells tended to cluster with the cells of same type. An analysis of cell numbers in each cluster revealed some features of cell proliferation. These viral vectors are shown to be useful tools to monitor the activation of the GH gene and the development of somatotrophs. PMID- 23342160 TI - Association between GRN rs5848 polymorphism and Parkinson's disease in Taiwanese population. AB - A single nucleotide polymorphism GRN rs5848 (3'UTR+78 C>T) was reported to alter the risk for frontotemporal lobar degeneration. Herein, we investigated the effect of GRN rs5848 on the risk of Parkinson's disease (PD) by genotyping 573 Taiwanese patients with PD and 490 age-matched control subjects. Compared to subjects with CC genotype, those with TT genotype had a 1.58-fold increased risk of PD (95% CI: 1.77~2.34, P = 0.021). PD patients demonstrate a higher frequency of T allele (37.2%) than controls (32.2%; odds ratio [OR] = 1.24, 95% CI: 1.04~1.49, P = 0.017). This susceptibility was particularly observed in female subjects, in which TT genotype had a 2.16-fold increased risk of PD as compared with controls(95% CI: 1.24~3.78, P = 0.006). The frequency of T allele (39.3%) in female PD patients was higher than in female control subjects (31.1%; OR = 1.43, CI: 1.11~1.87, P = 0.007). No association was observed between GRN rs5848 and susceptibility in male subjects. These findings show that the GRN rs5848 TT genotype and T allele are risk factors for female Taiwanese patients with PD. PMID- 23342161 TI - Comparision of piceid and resveratrol in antioxidation and antiproliferation activities in vitro. AB - BACKGROUND: The clinic therapeutic effect of resveratrol is limited due to its low oral bioavailability. Piceid, a precursor of resveratrol, is the most abundant form of resveratrol in nature. A number of studies have hypothesized that piceid may have the same bioactivities like those of resveratrol. The aim of this work is to compare piceid with resveratrol in antioxidation and antiproliferation activities in vitro. METHODS: The antioxidative effects of resveratrol and piceid were evaluated by phenanthroline-Fe2+ method and H2O2 induced oxidative injury cell model. The antiproliferation effects were determined by MTT method in human liver tumor HepG2 cells, human breast cancer MDA-MB-231 cells and MCF-7 cells. The effects of resveratrol and piceid on the cell cycle and the apoptosis were evaluated by flow cytometry. Additionally, the uptake profiles of resveratrol and piceid in cancer cells were observed using fluorescence microscopy and clarified by LC-MS/MS. CONCLUSION: Piceid exhibited higher scavenging activity against hydroxyl radicals than resveratrol in vitro. Resveratrol showed a significant protective effect against H2O2-induced cell damage. What is more, resveratrol had biphasic effects on tumor cells. Resveratrol and piceid only showed significant cytotoxicity on tumor cells at high concentration (>=50 umol/L), while low concentration of resveratrol (<30 umol/L) increased the cell viability. The principal effect of resveratrol and piceid on the viability of tumor cells was caused by the cell cycle arrest, while the effect on apoptosis was relatively minor. The reason that piceid showed lower biological activity than resveratrol at the same concentration was probably because piceid was more difficult in being uptaken by cells. PMID- 23342163 TI - High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway. AB - In diabetes, some of the cellular changes are similar to aging. We hypothesized that hyperglycemia accelerates aging-like changes in the endothelial cells (ECs) and tissues leading to structural and functional damage. We investigated glucose induced aging in 3 types of ECs using senescence associated beta-gal (SA beta gal) staining and cell morphology. Alterations of sirtuins (SIRTs) and their downstream mediator FOXO and oxidative stress were investigated. Relationship of such alteration with histone acetylase (HAT) p300 was examined. Similar examinations were performed in tissues of diabetic animals. ECs in high glucose (HG) showed evidence of early senescence as demonstrated by increased SA beta-gal positivity and reduced replicative capacities. These alterations were pronounced in microvascular ECs. They developed an irregular and hypertrophic phenotype. Such changes were associated with decreased SIRT (1-7) mRNA expressions. We also found that p300 and SIRT1 regulate each other in such process, as silencing one led to increase of the others' expression. Furthermore, HG caused reduction in FOXO1's DNA binding ability and antioxidant target gene expressions. Chemically induced increased SIRT1 activity and p300 knockdown corrected these abnormalities slowing aging-like changes. Diabetic animals showed increased cellular senescence in renal glomerulus and retinal blood vessels along with reduced SIRT1 mRNA expressions in these tissues. Data from this study demonstrated that hyperglycemia accelerates aging-like process in the vascular ECs and such process is mediated via downregulation of SIRT1, causing reduction of mitochondrial antioxidant enzyme in a p300 and FOXO1 mediated pathway. PMID- 23342162 TI - Pax6 interactions with chromatin and identification of its novel direct target genes in lens and forebrain. AB - Pax6 encodes a specific DNA-binding transcription factor that regulates the development of multiple organs, including the eye, brain and pancreas. Previous studies have shown that Pax6 regulates the entire process of ocular lens development. In the developing forebrain, Pax6 is expressed in ventricular zone precursor cells and in specific populations of neurons; absence of Pax6 results in disrupted cell proliferation and cell fate specification in telencephalon. In the pancreas, Pax6 is essential for the differentiation of alpha-, beta- and delta-islet cells. To elucidate molecular roles of Pax6, chromatin immunoprecipitation experiments combined with high-density oligonucleotide array hybridizations (ChIP-chip) were performed using three distinct sources of chromatin (lens, forebrain and beta-cells). ChIP-chip studies, performed as biological triplicates, identified a total of 5,260 promoters occupied by Pax6. 1,001 (133) of these promoter regions were shared between at least two (three) distinct chromatin sources, respectively. In lens chromatin, 2,335 promoters were bound by Pax6. RNA expression profiling from Pax6+/- lenses combined with in vivo Pax6-binding data yielded 76 putative Pax6-direct targets, including the Gaa, Isl1, Kif1b, Mtmr2, Pcsk1n, and Snca genes. RNA and ChIP data were validated for all these genes. In lens cells, reporter assays established Kib1b and Snca as Pax6 activated and repressed genes, respectively. In situ hybridization revealed reduced expression of these genes in E14 cerebral cortex. Moreover, we examined differentially expressed transcripts between E9.5 wild type and Pax6-/- lens placodes that suggested Efnb2, Fat4, Has2, Nav1, and Trpm3 as novel Pax6-direct targets. Collectively, the present studies, through the identification of Pax6 direct target genes, provide novel insights into the molecular mechanisms of Pax6 gene control during mouse embryonic development. In addition, the present data demonstrate that Pax6 interacts preferentially with promoter regions in a tissue specific fashion. Nevertheless, nearly 20% of the regions identified are accessible to Pax6 in multiple tissues. PMID- 23342164 TI - Human embryonic stem cell derived mesenchymal progenitors express cardiac markers but do not form contractile cardiomyocytes. AB - Mesenchymal progenitors or stromal cells have shown promise as a therapeutic strategy for a range of diseases including heart failure. In this context, we explored the growth and differentiation potential of mesenchymal progenitors (MPs) derived in vitro from human embryonic stem cells (hESCs). Similar to MPs isolated from bone marrow, hESC derived MPs (hESC-MPs) efficiently differentiated into archetypical mesenchymal derivatives such as chondrocytes and adipocytes. Upon treatment with 5-Azacytidine or TGF-beta1, hESC-MPs modified their morphology and up-regulated expression of key cardiac transcription factors such as NKX2-5, MEF2C, HAND2 and MYOCD. Nevertheless, NKX2-5+ hESC-MP derivatives did not form contractile cardiomyocytes, raising questions concerning the suitability of these cells as a platform for cardiomyocyte replacement therapy. Gene profiling experiments revealed that, although hESC-MP derived cells expressed a suite of cardiac related genes, they lacked the complete repertoire of genes associated with bona fide cardiomyocytes. Our results suggest that whilst agents such as TGF-beta1 and 5-Azacytidine can induce expression of cardiac related genes, but treated cells retain a mesenchymal like phenotype. PMID- 23342165 TI - Inhibition of ceramide metabolism sensitizes human leukemia cells to inhibition of BCL2-like proteins. AB - The identification of novel combinations of effective cancer drugs is required for the successful treatment of cancer patients for a number of reasons. First, many "cancer specific" therapeutics display detrimental patient side-effects and second, there are almost no examples of single agent therapeutics that lead to cures. One strategy to decrease both the effective dose of individual drugs and the potential for therapeutic resistance is to combine drugs that regulate independent pathways that converge on cell death. BCL2-like family members are key proteins that regulate apoptosis. We conducted a screen to identify drugs that could be combined with an inhibitor of anti-apoptotic BCL2-like proteins, ABT-263, to kill human leukemia cells lines. We found that the combination of D,L threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) hydrochloride, an inhibitor of glucosylceramide synthase, potently synergized with ABT-263 in the killing of multiple human leukemia cell lines. Treatment of cells with PDMP and ABT-263 led to dramatic elevation of two pro-apoptotic sphingolipids, namely ceramide and sphingosine. Furthermore, treatment of cells with the sphingosine kinase inhibitor, SKi-II, also dramatically synergized with ABT-263 to kill leukemia cells and similarly increased ceramides and sphingosine. Data suggest that synergism with ABT-263 requires accumulation of ceramides and sphingosine, as AMP-deoxynojirimycin, (an inhibitor of the glycosphingolipid pathway) did not elevate ceramides or sphingosine and importantly did not sensitize cells to ABT 263 treatment. Taken together, our data suggest that combining inhibitors of anti apoptotic BCL2-like proteins with drugs that alter the balance of bioactive sphingolipids will be a powerful combination for the treatment of human cancers. PMID- 23342166 TI - EHD1 functions in endosomal recycling and confers salt tolerance. AB - Endocytosis is a crucial process in all eukaryotic organisms including plants. We have previously shown that two Arabidopsis proteins, AtEHD1 and AtEHD2, are involved in endocytosis in plant systems. Knock-down of EHD1 was shown to have a delayed recycling phenotype in mammalians. There are many works in mammalian systems detailing the importance of the various domains in EHDs but, to date, the domains of plant EHD1 that are required for its activity have not been characterized. In this work we demonstrate that knock-down of EHD1 causes a delayed recycling phenotype and reduces Brefeldin A sensitivity in Arabidopsis seedlings. The EH domain of EHD1 was found to be crucial for the localization of EHD1 to endosomal structures. Mutant EHD1 lacking the EH domain did not localize to endosomal structures and showed a phenotype similar to that of EHD1 knock-down seedlings. Mutants lacking the coiled-coil domain, however, showed a phenotype similar to wild-type or EHD1 overexpression seedlings. Salinity stress is a major problem in current agriculture. Microarray data demonstrated that salinity stress enhances the expression of EHD1, and this was confirmed by semi quantitative RT PCR. We demonstrate herein that transgenic plants over expressing EHD1 possess enhanced tolerance to salt stress, a property which also requires an intact EH domain. PMID- 23342167 TI - Human life history evolution explains dissociation between the timing of tooth eruption and peak rates of root growth. AB - We explored the relationship between growth in tooth root length and the modern human extended period of childhood. Tooth roots provide support to counter chewing forces and so it is advantageous to grow roots quickly to allow teeth to erupt into function as early as possible. Growth in tooth root length occurs with a characteristic spurt or peak in rate sometime between tooth crown completion and root apex closure. Here we show that in Pan troglodytes the peak in root growth rate coincides with the period of time teeth are erupting into function. However, the timing of peak root velocity in modern humans occurs earlier than expected and coincides better with estimates for tooth eruption times in Homo erectus. With more time to grow longer roots prior to eruption and smaller teeth that now require less support at the time they come into function, the root growth spurt no longer confers any advantage in modern humans. We suggest that a prolonged life history schedule eventually neutralised this adaptation some time after the appearance of Homo erectus. The root spurt persists in modern humans as an intrinsic marker event that shows selection operated, not primarily on tooth tissue growth, but on the process of tooth eruption. This demonstrates the overarching influence of life history evolution on several aspects of dental development. These new insights into tooth root growth now provide an additional line of enquiry that may contribute to future studies of more recent life history and dietary adaptations within the genus Homo. PMID- 23342168 TI - Absolute consistency: individual versus population variation in annual-cycle schedules of a long-distance migrant bird. AB - Flexibility in scheduling varies throughout an organism's annual cycle, reflecting relative temporal constraints and fitness consequences among life history stages. Time-selection can act at different scales, either by limiting the range of alternative strategies in the population, or by increasing the precision of individual performance. We tracked individual bar-tailed godwits Limosa lapponica baueri for two full years (including direct observation during non-breeding seasons in New Zealand and geolocator tracking of round-trip migrations to Alaska) to present a full annual-cycle view of molt, breeding, and migration schedules. At both population and individual scales, temporal variation was greater in post-breeding than pre-breeding stages, and greater in molts than in movements, but schedules did not tighten across successive stages of migration toward the breeding grounds. In general, individual godwits were quite consistent in timing of events throughout the year, and repeatability of pre-breeding movements was particularly high (r = 0.82-0.92). However, we demonstrate that r values misrepresent absolute consistency by confounding inter- and intra individual variation; the biological significance of r values can only be understood when these are considered separately. By doing so, we show that some stages have considerable tolerance for alternative strategies within the population, whereas scheduling of northbound migratory movements was similar for all individuals. How time-selection simultaneously shapes both individual and population variation is central to understanding and predicting adaptive phenological responses to environmental change. PMID- 23342169 TI - Comparative functional analysis of ZFP36 genes during Xenopus development. AB - ZFP36 constitutes a small family of RNA binding proteins (formerly known as the TIS11 family) that target mRNA and promote their degradation. In mammals, ZFP36 proteins are encoded by four genes and, although they show similar activities in a cellular RNA destabilization assay, there is still a limited knowledge of their mRNA targets and it is not known whether or not they have redundant functions. In the present work, we have used the Xenopus embryo, a model system allowing gain- and loss-of-function studies, to investigate, whether individual ZFP36 proteins had distinct or redundant functions. We show that overexpression of individual amphibian zfp36 proteins leads to embryos having the same defects, with alteration in somites segmentation and pronephros formation. In these embryos, members of the Notch signalling pathway such as hairy2a or esr5 mRNA are down regulated, suggesting common targets for the different proteins. We also show that mouse Zfp36 protein overexpression gives the same phenotype, indicating an evolutionary conserved property among ZFP36 vertebrate proteins. Morpholino oligonucleotide-induced loss-of-function leads to defects in pronephros formation, reduction in tubule size and duct coiling alterations for both zfp36 and zfp36l1, indicating no functional redundancy between these two genes. Given the conservation in gene structure and function between the amphibian and mammalian proteins and the conserved mechanisms for pronephros development, our study highlights a potential and hitherto unreported role of ZFP36 gene in kidney morphogenesis. PMID- 23342170 TI - Glycogen synthase kinase 3beta promotes osteogenic differentiation of murine adipose-derived stromal cells. AB - Although the role of glycogen synthase kinase 3beta (GSK3beta) in osteogenic differentiation of bone marrow-derived mesenchymal stromal cells (BMSCs) is well characterized as a negative regulator of beta-catenin, its effect on osteogenesis of adipose-derived stromal cells (ADSCs) is poorly understood. Here, we show that GSK3beta positively regulates osteogenic differentiation of murine ADSCs. Gain-of function studies showed that GSK3beta promotes in vitro osteogenesis of ADSCs. Regulation of GSK3beta activity in ADSCs, either by small interfering RNA (siRNA) mediated GSK3beta silencing or by pharmacological inhibitors, blunted osteogenesis and the expression of osteogenic markers. Importantly, we demonstrated that transgenic mice, engineered to overexpress the constitutively active GSK3beta (GSK3beta-S9A) mutant, exhibited a marked increase in osteogenesis, whereas expression of the catalytically inactive GSK3beta (GSK3beta K85A) in mice inhibits osteogenic differentiation. Molecular analyses showed that the enhanced osteoblast differentiation induced by GSK3beta was mediated by downregulation of beta-catenin. Remarkably, beta-catenin silencing enhances osteogenesis and osteoblast marker gene expression such as alkaline phosphatase (ALP) and osterix. Taken together, these findings demonstrate a novel role for GSK3beta in the regulation of osteogenic differentiation in ADSCs. PMID- 23342171 TI - MasABK proteins interact with proteins of the type IV pilin system to affect social motility of Myxococcus xanthus. AB - Gliding motility is critical for normal development of spore-filled fruiting bodies in the soil bacterium Myxococcus xanthus. Mutations in mgl block motility and development but one mgl allele can be suppressed by a mutation in masK, the last gene in an operon adjacent to the mgl operon. Deletion of the entire 5.5 kb masABK operon crippled gliding and fruiting body development and decreased sporulation. Expression of pilAGHI, which encodes type IV pili (TFP) components essential for social (S) gliding, several cryptic pil genes, and a LuxR family protein were reduced significantly in the Deltamas mutant while expression of the myxalamide operon was increased significantly. Localization and two-hybrid analysis suggest that the three Mas proteins form a membrane complex. MasA-PhoA fusions confirmed that MasA is an integral cytoplasmic membrane protein with a ~100 amino acid periplasmic domain. Results from yeast two-hybrid assays showed that MasA interacts with the lipoprotein MasB and MasK, a protein kinase and that MasB and MasK interact with one another. Additionally, yeast two-hybrid analysis revealed a physical interaction between two gene products of the mas operon, MasA and MasB, and PilA. Deletion of mas may be accompanied by compensatory mutations since complementation of the Deltamas social gliding and developmental defects required addition of both pilA and masABK. PMID- 23342172 TI - Nischarin is differentially expressed in rat brain and regulates neuronal migration. AB - Nischarin is a protein known to inhibit breast cancer cell motility by regulating the signaling of the Rho GTPase family. However, little is known about its location and function in the nervous system. The aim of the present study was to investigate the regional and cellular expression and functions of Nischarin in the adult rodent brain. As assessed by real-time PCR, Western blot analysis and immunostaining, we found that Nischarin was widely distributed throughout the brain, with a higher expression in the cerebral cortex and hippocampus. Double labeling showed that Nischarin was expressed in neurons and was mainly located in the perinuclear region and F-actin-rich protrusions. The expression pattern of Nischarin in the brain was thought to be closely associated with its function. This was verified by our findings from cell migration assays that Nischarin regulated neuronal migration. These results provide a preliminary survey of the distribution of Nischarin in different regions and cell types in the rat brain. This might help to elucidate its physiological roles, and to evaluate its potential clinical implications. PMID- 23342173 TI - An intradermal inoculation model of scrub typhus in Swiss CD-1 mice demonstrates more rapid dissemination of virulent strains of Orientia tsutsugamushi. AB - Scrub typhus is an important endemic disease of the Asia-Pacific region caused by Orientia tsutsugamushi. To develop an effective vaccine to prevent scrub typhus infection, a better understanding of the initial host-pathogen interaction is needed. The objective of this study was to investigate early bacterial dissemination in a CD-1 Swiss outbred mouse model after intradermal injection of O. tsutsugamushi. Three human pathogenic strains of O. tsutsugamushi (Karp, Gilliam, and Woods) were chosen to investigate the early infection characteristics associated with bacterial virulence. Tissue biopsies of the intradermal injection site and draining lymph nodes were examined using histology and immunohistochemistry to characterize bacterial dissemination, and correlated with quantitative real-time PCR for O. tsutsugamushi in blood and tissue from major organs. Soluble adhesion molecules were measured to examine cellular activation in response to infection. No eschar formation was seen at the inoculation site and no clinical disease developed within the 7 day period of observation. However, O. tsutsugamushi was localized at the injection site and in the draining lymph nodes by day 7 post inoculation. Evidence of leukocyte and endothelial activation was present by day 7 with significantly raised levels of sL-selectin, sICAM-1 and sVCAM-1. Infection with the Karp strain was associated with earlier and higher bacterial loads and more extensive dissemination in various tissues than the less pathogenic Gilliam and Woods strains. The bacterial loads of O. tsutsugamushi were highest in the lungs and spleens of mice inoculated with Karp and Gilliam, but not Woods strains. Strains of higher virulence resulted in more rapid systemic infection and dissemination in this model. The CD-1 mouse intradermal inoculation model demonstrates features relevant to early scrub typhus infection in humans, including the development of regional lymphadenopathy, leukocyte activation and distant organ dissemination after low-dose intradermal injection with O. tsutsugamushi. PMID- 23342174 TI - Two panels of plasma microRNAs as non-invasive biomarkers for prediction of recurrence in resectable NSCLC. AB - The diagnosis of non-small cell lung carcinoma (NSCLC) at an early stage, as well as better prediction of outcome remains clinically challenging due to the lack of specific and robust non-invasive markers. The discovery of microRNAs (miRNAs), particularly those found in the bloodstream, has opened up new perspectives for tumor diagnosis and prognosis. The aim of our study was to determine whether expression profiles of specific miRNAs in plasma could accurately discriminate between NSCLC patients and controls, and whether they are able to predict the prognosis of resectable NSCLC patients. We therefore evaluated a series of seventeen NSCLC-related miRNAs by quantitative real-time (qRT)-PCR in plasma from 52 patients with I-IIIA stages NSCLC, 10 patients with chronic obstructive pulmonary disease (COPD) and 20-age, sex and smoking status-matched healthy individuals. We identified an eleven-plasma miRNA panel that could distinguish NSCLC patients from healthy subjects (AUC = 0.879). A six-plasma miRNA panel was able to discriminate between NSCLC patients and COPD patients (AUC = 0.944). Furthermore, we identified a three-miRNA plasma signature (high miR-155-5p, high miR-223-3p, and low miR-126-3p) that significantly associated with a higher risk for progression in adenocarcinoma patients. In addition, a three-miRNA plasma panel (high miR-20a-5p, low miR-152-3p, and low miR-199a-5p) significantly predicted survival of squamous cell carcinoma patients. In conclusion, we identified two plasma miRNA expression profiles that may be useful for predicting the outcome of patients with resectable NSCLC. PMID- 23342175 TI - Signaling through the TGF beta-activin receptors ALK4/5/7 regulates testis formation and male germ cell development. AB - The developing testis provides an environment that nurtures germ cell development, ultimately ensuring spermatogenesis and fertility. Impacts on this environment are considered to underlie aberrant germ cell development and formation of germ cell tumour precursors. The signaling events involved in testis formation and male fetal germ cell development remain largely unknown. Analysis of knockout mice lacking single Tgfbeta family members has indicated that Tgfbeta's are not required for sex determination. However, due to functional redundancy, it is possible that additional functions for these ligands in gonad development remain to be discovered. Using FACS purified gonadal cells, in this study we show that the genes encoding Activin's, TGFbeta's, Nodal and their respective receptors, are expressed in sex and cell type specific patterns suggesting particular roles in testis and germ cell development. Inhibition of signaling through the receptors ALK4, ALK5 and ALK7, and ALK5 alone, demonstrated that TGFbeta signaling is required for testis cord formation during the critical testis-determining period. We also show that signaling through the Activin/NODAL receptors, ALK4 and ALK7 is required for promoting differentiation of male germ cells and their entry into mitotic arrest. Finally, our data demonstrate that Nodal is specifically expressed in male germ cells and expression of the key pluripotency gene, Nanog was significantly reduced when signaling through ALK4/5/7 was blocked. Our strategy of inhibiting multiple Activin/NODAL/TGFbeta receptors reduces the functional redundancy between these signaling pathways, thereby revealing new and essential roles for TGFbeta and Activin signaling during testis formation and male germ cell development. PMID- 23342176 TI - Neural bases for individual differences in the subjective experience of short durations (less than 2 seconds). AB - The current research was designed to establish whether individual differences in timing performance predict neural activation in the areas that subserve the perception of short durations ranging between 400 and 1600 milliseconds. Seventeen participants completed both a temporal bisection task and a control task, in a mixed fMRI design. In keeping with previous research, there was increased activation in a network of regions typically active during time perception including the right supplementary motor area (SMA) and right pre-SMA and basal ganglia (including the putamen and right pallidum). Furthermore, correlations between neural activity in the right inferior frontal gyrus and SMA and timing performance corroborate the results of a recent meta-analysis and are further evidence that the SMA forms part of a neural clock that is responsible for the accumulation of temporal information. Specifically, subjective lengthening of the perceived duration were associated with increased activation in both the right SMA (and right pre-SMA) and right inferior frontal gyrus. PMID- 23342178 TI - Happy new year! PMID- 23342177 TI - Comparison of the pathogenicity of Nipah virus isolates from Bangladesh and Malaysia in the Syrian hamster. AB - Nipah virus is a zoonotic pathogen that causes severe disease in humans. The mechanisms of pathogenesis are not well described. The first Nipah virus outbreak occurred in Malaysia, where human disease had a strong neurological component. Subsequent outbreaks have occurred in Bangladesh and India and transmission and disease processes in these outbreaks appear to be different from those of the Malaysian outbreak. Until this point, virtually all Nipah virus studies in vitro and in vivo, including vaccine and pathogenesis studies, have utilized a virus isolate from the original Malaysian outbreak (NiV-M). To investigate potential differences between NiV-M and a Nipah virus isolate from Bangladesh (NiV-B), we compared NiV-M and NiV-B infection in vitro and in vivo. In hamster kidney cells, NiV-M-infection resulted in extensive syncytia formation and cytopathic effects, whereas NiV-B-infection resulted in little to no morphological changes. In vivo, NiV-M-infected Syrian hamsters had accelerated virus replication, pathology and death when compared to NiV-B-infected animals. NiV-M infection also resulted in the activation of host immune response genes at an earlier time point. Pathogenicity was not only a result of direct effects of virus replication, but likely also had an immunopathogenic component. The differences observed between NiV-M and NiV-B pathogeneis in hamsters may relate to differences observed in human cases. Characterization of the hamster model for NiV-B infection allows for further research of the strain of Nipah virus responsible for the more recent outbreaks in humans. This model can be used to study NiV-B pathogenesis, transmission, and countermeasures that could be used to control outbreaks. PMID- 23342180 TI - Critical limb ischemia: introduction. PMID- 23342181 TI - Critical limb ischemia: advanced medical therapy. AB - Systemic atherosclerosis and its risk factors are present in the majority of patients with critical limb ischemia. Aggressive medical therapy is an immediate and necessary part of the work-up and management of these patients and will involve a multidisciplinary approach. Risk stratification based on a patient's current clinical cardiovascular condition is important in determining the most appropriate and safe intervention and will allow both the patient and physician to make an informed decision regarding risk- and cost-benefits of treatment. PMID- 23342182 TI - Criticial limb ischemia: epidemiology. AB - Critical limb ischemia is found in 12% of the U.S. adult population. Its clinical presentation varies from no symptoms to intermittent claudication, atypical leg pain, rest pain, ischemic ulcers, or gangrene. Those with critical limb ischemia have a high incidence of cardiovascular comorbidities that reflect a significant systemic atherosclerotic burden; they have increased functional impairment and increased rates of functional decline compared with persons without critical limb ischemia. Interventions for critical limb ischemia and the impact of major amputation have a significant social and economic impact. At 1 year, 25% of patients will be dead, 30% will have undergone amputation, and only 45% will remain alive with both limbs. At 5 years, more than 60% of patients with critical limb ischemia will be dead. PMID- 23342183 TI - Critical limb ischemia: reporting outcomes and quality. AB - The impetus to pursue quality in limb salvage is high in the current economic environment. This has been spurred on by the diffusion of multiple technologies, the lack of well-defined cost-effectiveness benchmarks, and the paucity of process and structure benchmarks. Furthermore, no national database exists to capture current activity and trends, and lead structure and process changes that could analyze outcomes and improve standards in peripheral interventions for limb salvage. This manuscript examines the challenges in measuring outcomes and quality in limb salvage and explores the components necessary for ensuring quality in limb salvage interventions. PMID- 23342184 TI - Critical limb ischemia: cell and molecular therapies for limb salvage. AB - There is a growing interest in developing new limb salvage therapies for patients with severe peripheral artery disease who have no alternative to amputation. Cell and gene therapy studies are showing promise in controlling pain and minor ulceration in patients with significant critical limb ischemia. Among cardiovascular cell and molecular therapy programs, The Methodist Hospital is one of the leading centers in both gene and cell therapy for critical limb ischemia. Randomized controlled trials continue to be performed, and these experimental therapies will move from research to pharmacy within the decade. In conjunction with aggressive medical and surgical management, these emergent therapies may help patients with critical limb ischemia avoid a major amputation and are one of the foundations of any advanced limb salvage program. PMID- 23342185 TI - Advanced imaging in limb salvage. AB - The evaluation of patients at risk for limb loss secondary to peripheral arterial disease begins with a complete history and physical exam, and noninvasive studies in the vascular lab, including duplex ultrasonography. However, successful revascularization depends on high-quality, accurate imaging of the lower extremity vasculature. The traditional gold standard for vascular imaging, digital subtraction angiography, has been improved upon as technologic advances have enabled high-quality alternatives for preoperative (i.e., computed tomography [CT] angiography and magnetic resonance angiography [MRA]) and intraoperative imaging (i.e., intravascular ultrasound [IVUS], cone beam CT, and CO(2) angiography). Here we describe these advanced invasive and noninvasive imaging alternatives and their utility in limb salvage procedures. PMID- 23342186 TI - In situ fenestration for branch vessel preservation during EVAR. PMID- 23342187 TI - Bypass surgery for lower extremity limb salvage: vein bypass. AB - Bypass surgery for limb salvage in cases of chronic limb ischemia is a well established treatment modality. Use of an autogenous vein provides the best conduit for infrainguinal arterial bypass procedures, particularly for bypass to the infrapopliteal arteries. In this article, we discuss infrainguinal vein bypass surgery including indications, perioperative care, and long-term follow up. We also discuss the outcomes of the procedure with regard to patient survival and limb salvage. The autogenous vein continues to be the best available conduit with the highest patency rate and the best treatment option. Compared to all other revascularization options for infrainguinal disease, the vein bypass has the best limb salvage and long-term survival in patients appropriately selected for the procedure. PMID- 23342188 TI - Bypass surgery in limb salvage: polytetrafluoroethylene prosthetic bypass. AB - Polytetrafluoroethylene (PTFE) grafts have proven to be an adequate alternative conduit for peripheral bypass operations. Whether or not one uses PTFE depends on several factors: surgeon preference, individual patient circumstances, or when autologous greater saphenous vein is not available or adequate. These conventional grafts have evolved and undergone modification. The intraluminal surface has been coated with carbon or bonded with heparin. The structure of grafts has been modified with the creation of a hood or cuff, with the incorporation of a stent-graft segment for a sutureless anastomosis, or the fusion of PTFE with an outer polyester layer to minimize suture hole bleeding. This evolution intends to limit graft thrombogenicity, ameliorate the formation of intimal hyperplasia, decrease complications, and improve overall graft patency. PMID- 23342189 TI - Recapturing the Art of Medicine: From the Selma and Lois DeBakey Lectureship in Biomedical Communications, given in the winter of 2011. PMID- 23342190 TI - Giant aneurysm of the ascending aorta. PMID- 23342191 TI - How I prepare a manuscript for publication in a medical journal. PMID- 23342192 TI - Museum of TMH Multimodality Imaging Center: Secundum atrial septal defect. PMID- 23342193 TI - What the primary care provider needs to know for limb salvage. AB - Primary care providers are often the first providers to evaluate a patient for peripheral arterial disease (PAD). Understanding the various presentations of PAD symptoms can prevent the disease from progressing to critical limb ischemia and eventual limb loss. This article provided the primary care provider with information needed to prevent limb loss and promote limb salvage, including risk factor management, clinical presentation, physical exam findings, and treatment options. PMID- 23342195 TI - But it was too late. PMID- 23342197 TI - Rules for the road. PMID- 23342198 TI - Structure-activity relationships and molecular modeling of 1,2,4-triazoles as adenosine receptor antagonists. AB - The structure-activity relationship (SAR) for a novel class of 1,2,4-triazole antagonists of the human A(2A) adenosine receptor (hA(2A)AR) was explored. Thirty three analogs of a ligand that was discovered in a structure-based virtual screen against the hA(2A)AR were tested in hA(1), A(2A), and A(3) radioligand binding assays and in functional assays for the A(2B)AR subtype. As a series of closely related analogs of the initial lead, 1, did not display improved binding affinity or selectivity, molecular docking was used to guide the selection of more distantly related molecules. This resulted in the discovery of 32, a hA(2A)AR antagonist (K(i) 200 nM) with high ligand efficiency. In the light of the SAR for the 1,2,4-triazole scaffold, we also investigated the binding mode of these compounds based on docking to several A(2A)AR crystal structures. PMID- 23342199 TI - Partial agonism of 5-HT3 receptors: a novel approach to the symptomatic treatment of IBS-D. AB - Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain, discomfort, and altered bowel habits, which have a significant impact on quality of life for approximately 10-20% of the population. IBS can be divided into three main types IBS-D (diarrhea predominant), IBS-C (constipation predominant), and mixed or alternating IBS. 5-HT(3) receptor antagonism has proved to be an efficacious treatment option for IBS-D. For example, alosetron displays efficacy in the treatment of multiple symptoms, including abdominal pain, discomfort, urgency, stool frequency and consistency. However, significant constipation occurred in approximately 25% of patients, leading to withdrawal of up to 10% of patients in clinical trials. Targeting compounds with partial agonist activity at the 5-HT(3) receptor represents a mechanistic departure from the classic 5-HT(3) receptor antagonist approach and should result in agents that are applicable to a broader array of IBS patient populations. Attenuation of the activity of the ion channel without completely abolishing its function may control or normalize bowel function without leading to a total block associated with severe constipation. We have identified a new class of selective, orally active 5-HT(3) receptor ligands with high 5-HT(3) receptor affinity and low partial agonist activity currently in preclinical development that should offer a significant advantage over existing therapies. PMID- 23342200 TI - Ultrasound sonography at the pain clinic in Korea: past, present and future. PMID- 23342201 TI - Opioid pharmacotherapy for chronic noncancer pain: the american experience. AB - Chronic noncancer pain is a significant and growing public health challenge in the United States. Lacking effective alternative interventions for effective chronic noncancer pain management, many physicians have turned to opioid pharmacotherapy. Increased opioid prescribing brings not only gains in therapeutic benefit but also a higher incidence of adverse drug events including increased medication misuse and opioid related mortality. Currently the United States must confront the dual problems of widespread undertreated chronic noncancer pain and a prescription opioid abuse crisis. Withholding pain relieving drugs from patients in need is unjustifiable, yet drug diversion, abuse and adverse drug events have become major social as well as medical problems. At the heart of this crisis is the lack of definitive evidence about the risk to benefit ratio of opioid pharmacotherapy for chronic noncancer pain both on an individual case and on a population basis. This article describes the extent and severity of the American chronic noncancer pain problem and the history of opioid pharmacotherapy for chronic noncancer pain in the United States. It then discusses the concept of evidence based practice and reviews current evidence supporting opioid pharmacotherapy for chronic noncancer pain as well as adverse drug events related to opioid pharmacotherapy including misuse and abuse. Finally, it considers the conflict of providing pain relief versus protecting society and reviews steps that governmental agencies, industry and others are taking to contain and ultimately resolve the problems of excessive prescribing and conflicting priorities. PMID- 23342202 TI - Antinociceptive effect of intrathecal nefopam and interaction with morphine in formalin-induced pain of rats. AB - BACKGROUND: Nefopam, a non-opiate analgesic, has been regarded as a substance that reduces the requirement for morphine, but conflicting results have also been reported. The inhibition of monoamine reuptake is a mechanism of action for the analgesia of nefopam. The spinal cord is an important site for the action of monoamines however, the antinociceptive effect of intrathecal nefopam was not clear. This study was performed to examine the antinociceptive effect of intrathecal (i.t.) nefopam and the pattern of pharmacologic interaction with i.t. morphine in the formalin test. METHODS: Male Sprague-Dawley rats were implanted with an i.t. catheter, and were randomly treated with a vehicle, nefopam, or morphine. Formalin was injected into the hind-paw 10 min. after an i.t. injection of the above experiment drugs. After obtaining antinociceptive ED(50) of nefopam and morphine, the mixture of nefopam and morphine was tested for the antinociceptive effect in the formalin test at a dose of 1/8, 1/4, 1/2 of ED(50), or ED(50) of each drug followed by an isobolographic analysis. RESULTS: Intrathecal nefopam significantly reduced the flinching responses in both phases of the formalin test in a dose-dependent manner. Its effect, however, peaked at a dose of 30 ug in phase 1 (39.8% of control) and 10 ug during phase 2 (37.6% of control). The isobolograhic analysis indicated an additive interaction of nefopam and morphine during phase 2, and a synergy effect in antinociception during phase 1. CONCLUSIONS: This study demonstrated that i.t. nefopam produces an antinociceptive effect in formalin induced pain behavior during both phases of the formalin test, while interacting differently with i.t. morphine, synergistically during phase 1, and additively during phase 2. PMID- 23342203 TI - Survey on the treatment of postherpetic neuralgia in Korea; multicenter study of 1,414 patients. AB - BACKGROUND: Postherpetic neuralgia (PHN) is a serious complication resulting from herpes zoster infections, and it can impair the quality of life. In order to relieve pain from PHN, various treatments, including pharmacological and interventional methods have been used. However, little information on the recommendations for the interventional treatment of PHN, along with a lack of nation-wide surveys on the current status of PHN treatment exists. This multicenter study is the first survey on the treatment status of PHN in Korea. METHODS: Retrospective chart reviews were conducted on the entire patients who visited the pain clinics of 11 teaching hospitals from January to December of 2011. Co-morbid disease, affected site of PHN, routes to pain clinic visits, parenteral/topical medications for treatment, drugs used for nerve block, types and frequency of nerve blocks were investigated. RESULTS: A total of 1,414 patients' medical records were reviewed. The most commonly affected site was the thoracic area. The anticonvulsants and interlaminar epidural blocks were the most frequently used pharmacological and interventional methods for PHN treatment. For the interval of epidural block, intervals of 5 or more-weeks were the most popular. The proportion of PHN patients who get information from the mass media or the internet was only 0.8%.The incidence of suspected zoster sine herpete was only 0.1%. CONCLUSIONS: The treatment methods for PHN vary among hospitals. The establishment of treatment recommendation for PHN treatment is necessary. In addition, public relations activities are required in order to inform the patients of PHN treatments by pain clinicians. PMID- 23342204 TI - The survey of the patient received the epiduroscopic laser neural decompression. AB - BACKGROUND: Neuroplasty using a Racz catheter or epiduroscope and percutaneous endoscopic laser discectomy are performed as treatment for chronic refractory low back and/or lower extremity pain, but they are limited in that they cannot completely remove the causing pathology. Lately, epiduroscopic laser neural decompression (ELND) has been receiving attention as an alternative treatment, but there are insufficient reports of results. Hence we aimed to investigate and report the data in our hospital. METHODS: Seventy-seven patients were selected who had received ELND via the anterior and posterior epidural approach through the pain clinic in our hospital from March 2011 to July 2012. Their medical records including age, diagnosis, epiduroscopic findings and degree of symptom relief were investigated. The degree of symptom relief following the procedure was categorized into 5 stages of very good (5), good (4), no change (3), bad (2), and very bad (1) at 2 weeks and 1 month after the procedure. RESULTS: The subjects were 30 males and 47 females. Mean age was 54.6 for males and 59.6 for females, so the overall mean age was 58.1 years old, with the youngest being 23 and the oldest 88 years old. In epiduroscopic images of all patients, more than one situation of herniated disc, fibrous tissue and adhesion, or inflammation was observed. Sixty-seven patients (87.0%) showed symptom relief 2 weeks after the procedure and 63 patients (81.8%) showed relief after 1 month. CONCLUSIONS: ELND is considered to be an effective treatment alternative for chronic refractory low back and/or lower extremity pain, including lumbar disc herniation, lumbar spinal stenosis, and failed back surgery syndrome which cannot be alleviated with existing non-invasive conservative treatment. PMID- 23342205 TI - Continuous intrathecal morphine administration for cancer pain management using an intrathecal catheter connected to a subcutaneous injection port: a retrospective analysis of 22 terminal cancer patients in korean population. AB - BACKGROUND: Intrathecal opioid administration has been used widely in patients suffering from severe cancer pain that is not managed with conventional modalities. However, the potential serious neurological complications from the procedure and the side effects of intrathecal opioids have made many clinicians reluctant to employ continuous intrathecal analgesia as a first-line therapeutic option despite its dramatic effect on intractable pain. We retrospectively investigated the efficacy, side effects, and complications of intrathecal morphine administration through intrathecal catheters connected to a subcutaneous injection port (ICSP) in 22 Korean terminal cancer patients with successful intrathecal morphine trials. METHODS: Patient demographic data, the duration of intrathecal opioid administration, preoperative numerical pain rating scales (NRS) and doses of systemic opioids, side effects and complications related to intrathecal opioids and the procedure, and the numerical pain rating scales and doses of intrathecal and systemic opioids on the 1(st), 3(rd), 7(th) and 30(th) postoperative days were determined from medical records. RESULTS: Intrathecal morphine administration for 46.0 +/- 61.3 days significantly reduced NRS from baseline on all the postoperative days. A significant increase in intrathecal opioids with a nonsignificant decrease in systemic opioids was observed on the 7(th) and 30(th) postoperative days compared to the 1(st) postoperative day. The most common side effects of intrathecal opioids were nausea/vomiting (31.8%) and urinary retention (38.9%), which were managed with conservative therapies. CONCLUSIONS: Intrathecal morphine administration using ICSP provided immediate and beneficial effects on pain scores with tolerable side effects in terminal cancer patients. PMID- 23342206 TI - Patient-controlled Epidural Analgesia with Ropivacaine and Fentanyl: Experience with 2,276 Surgical Patients. AB - BACKGROUND: Good postoperative pain control is an important part of adequate postoperative care. Patient-controlled epidural analgesia (PCEA) provided better postoperative analgesia compared to other conventional analgesic methods, but several risks have been observed as well. We therefore surveyed the efficacy and safety of PCEA in this retrospective observational study. METHODS: We analyzed collected data on 2,276 elective surgical patients who received PCEA with ropivacaine and fentanyl. Patients were assessed by a PCA service team in the post-anesthesia care unit (PACU), at 1-6 h, 6-24 h, and 24-48 h postoperatively for adequate pain control. The presence of PCEA-related adverse events was also assessed. RESULTS: Numerical pain score (median [interquartile range]) were 3 [1 4], 5 [4-7], 4 [3-5], and 3 [3-5] in the PACU, at 1-6 h, 6-24 h, and 24-48 h postoperatively. Median pain scores in patients underwent major abdominal or thoracic surgery were higher than other surgical procedure in the PACU, at 1-6 h after surgery. Nausea and vomiting (20%) and numbness and motor weakness (15%) were revealed as major PCEA-related adverse events during the postoperative 48 h period. There were 329 patients (14%) for whom PCEA was ceased within 48 h following surgery. CONCLUSIONS: Our data suggest that the use of PCEA provides proper analgesia in the postoperative 48 h period after a wide variety of surgical procedures and that is associated with few serious complications. However, more careful pain management and sustainable PCEA monitoring considering the type of surgical procedure undergone is needed in patients with PCEA. PMID- 23342207 TI - The effect of acupuncture on relieving pain after inguinal surgeries. AB - BACKGROUND: Postoperative pain is one of the most prevalent and bothersome issues found in the surgical department. Nowadays, there are various methods of acupuncture used for relieving pain without the complications found in some routine postoperative analgesics. These methods could be especially useful for high risk patients prone to complications from analgesics, such as transplantation recipients. The aim of this study was to evaluate the efficacy of electro-acupuncture on postoperative pain control after inguinal surgeries. METHODS: Ninety male patients, who were referred to our department with indications of inguinal surgery, were included in the study and randomly divided into two groups, such as acupuncture and control. We used electro-acupuncture for the acupuncture group and no actual acupuncture (but placed needle electrodes similar to the acupuncture group) for the control group. Postoperative pain was quantified by a blind observer in both groups using a visual analogue scale (VAS) standard score before being compared. RESULTS: Pain intensity and analgesic use were significantly higher in the control group (P < 0.05). In the acupuncture group, the VAS pain scores were significantly lower than the control group at 0.5, 1 and 2 hours post operation. When the opioid related side effects were compared for each group, the results showed that the number of subjects who experienced dizziness in the acupuncture group was significantly lower than the control group (P < 0.05). CONCLUSIONS: Acupuncture in patients, after inguinal surgery, can reduce the need of analgesics, which also directly reduces the complications that may occur when analgesics are used in relieving pain postoperatively. PMID- 23342208 TI - Radiation Exposure of the Hand and Chest during C-arm Fluoroscopy-Guided Procedures. AB - BACKGROUND: The C-arm fluoroscope is an essential tool for the intervention of pain. The aim of this study was to investigate the radiation exposure experienced by the hand and chest of pain physicians during C-arm fluoroscopy-guided procedures. METHODS: This is a prospective study about radiation exposure to physicians during transforaminal epidural steroid injection (TFESI) and medial branch block (MBB). Four pain physicians were involved in this study. Data about effective dose (ED) at each physician's right hand and left side of the chest, exposure time, radiation absorbed dose (RAD), and the distance from the center of the X-ray field to the physician during X-ray scanning were collected. RESULTS: Three hundred and fifteen cases were included for this study. Demographic data showed no significant differences among the physicians in the TFESIs and MBBs. In the TFESI group, there was a significant difference between the ED at the hand and chest in all the physicians. In physician A, B and C, the ED at the chest was more than the ED at the hand. The distance from the center of the X-ray field to physician A was more than that of the other physicians, and for the exposure time, the ED and RAD in physician A was less than that of the other physicians. In the MBB group, there was no difference in the ED at the hand and chest, except for physician D. The distance from the center of the X-ray field to physician A was more than that of the other physicians and the exposure time in physician A was less than that of the other physicians. CONCLUSIONS: In conclusion, the distance from the radiation source, position of the hand, experience and technique can correlate with the radiation dose. PMID- 23342209 TI - Long-term Results of Stellate Ganglion Block in Patients with Olfactory Dysfunction. AB - BACKGROUND: Olfactory dysfunction, including anosmia and hyposmia is difficult to treat. Although the mechanism is not well known, stellate ganglion block (SGB) is used to treat olfactory dysfunction. There are no prior studies on the long-term effects of SGB on olfactory dysfunction. The purpose of this study was to evaluate the continuity of therapeutic effects and patient satisfaction with SGB treatment. METHODS: This was a follow-up study carried out via a telephonic survey. The olfactory function of the patient was evaluated using a visual analog scale (VAS). We checked VAS three times: VAS-I (pre-treatment VAS), VAS-A (post treatment VAS), and VAS-C (VAS at follow up telephone survey). We divided the subjects into 2 groups according to their responsiveness to SGB: the responsive (R group) and the unresponsive groups (UR group). Patient satisfaction was evaluated using a Likert scale. RESULTS: Out of the 40 subjects, 37 responded to the telephone survey. In the UR group, there was difference in the olfactory function. However, in the R group, there were significant VAS differences; VAS-I was 9.6 +/- 0.7, VAS-A was 5.1 +/- 4.2, and VAS-C was 2.7 +/- 2.7 (P < 0.05). On the Likert scale, patient satisfaction was as follows: grade 1, 17 patients (45.9%); grade 2, 6 patients (16.2%); grade 3, 6 patients (16.2%); and grade 4, 8 patients (21.6%). CONCLUSIONS: SGB is a safe, long-lasting, and effective therapeutic modality for olfactory dysfunction treatment. PMID- 23342210 TI - Intractable hemifacial spasm treated by pulsed radiofrequency treatment. AB - Hemifacial spasm is defined as unilateral, involuntary, irregular twitching of all or parts of the muscles innervated by facial nerves. Here, we present a case of recurrent hemifacial spasm after microvascular decompression (MVD) treated with pulsed radiofrequency (PRF) treatment with good results. A 35-year-old woman suffered from recurrent hemifacial spasm after MVD that was refractory to medical treatment and botulinum toxin injections. We attempted a left facial nerve block twice. Then, we applied PRF at a maximum temperature of 42C for 120 sec. Some response was observed, so we applied PRF two additional times. The frequency of twitch decreased from 3-4 Hz to < 0.5 Hz, and subjective severity on a visual analogue scale also decreased from 10/10 to 2-3/10. PRF treatment might be an effective medical treatment for refractory hemifacial spasm and has fewer complications and is less invasive compared with those of surgery. PMID- 23342211 TI - Scrambler therapy for patients with cancer pain - case series -. AB - More than 80% of cancer patients experience cancer pain. Among them, more than 50% experience moderate to severe pain. To control cancer pain, a variety of methods have been used, including medications and nerve blocks. In some patients, however, it is impossible to perform nerve blocks due to caner metastasis into the epidural space, while in other patients, opioid dose escalation is impossible due to opioid side effects; thus, cancer pain management is difficult. Scrambler therapy is a novel approach for pain control that uses EKG-like pads, which are applied above and below the site of pain. Scrambler therapy synthesizes 16 different types of nerve action potentials that provide "non-pain" information via cutaneous nerves. The advantages of this treatment are that it is non invasive and safe and has no significant side effects. In this case series, we report the treatment results of using scrambler therapy in three cancer patients with intractable pain. PMID- 23342212 TI - Spinal arteriovenous malformation masquerating zoster sine herpete. AB - Zoster sine herpete (ZSH) is difficult to diagnosis during an acute period due to the absence of the characteristic zosteriform dermatomal rash; therefore, progression to postherpetic neuralgia is more common than typical zoster. In addition, misdiagnosis of other neuropathic pain as ZSH is common in clinical situations. Here, we report a case of spinal arteriovenous malformation that mimics ZSH. This is a rare condition; therefore, high clinical suspicion for a correct diagnosis and proper examination are not easy. However, early diagnosis and definitive treatment are essential to prevent neurologic deficit and mortality. PMID- 23342213 TI - Newly developed urinary retention and motor weakness of lower extremities in a postherpetic neuralgia patient. AB - During the early stage of postherpetic neuralgia, an epidural block on the affected segment is helpful in controlling pain and preventing progression to a chronic state. The main neurologic complication following an epidural block is cord compression symptom due to an epidural hematoma. When neurologic complications arise from an epidural block for the treatment of postherpetic neuralgia, it is important to determine whether the complications are due to the procedure or due to the herpes zoster itself. We report a case of a patient who was diagnosed with herpes zoster myelitis during treatment for postherpetic neuralgia. The patient complained of motor weakness in the lower extremities after receiving a thoracic epidural block six times. Although initially, we believed that the complications were due to the epidural block, it was ultimately determined to be from the herpes zoster myelitis. PMID- 23342214 TI - Stevens-johnson syndrome induced by carbamazepine treatment in a patient who previously had carbamazepine induced pruritus - a case report -. AB - Stevens-Johnson syndrome (SJS) is a rare but life-threatening skin reaction disease and carbamazepine is one of its most common causes. We report a case of SJS secondary to carbamazepine in a patient with previous pruritus due to carbamazepine which was given for treatment of trigeminal neuralgia. We would like to caution all providers that carbamazepine readministration should be avoided in the patient with a previous history of SJS or adverse skin reaction. In addition, we strongly recommend gradual titration when initiating treatment with carbamazepine. PMID- 23342215 TI - Ultrasound-guided infraorbital nerve pulsed radiofrequency treatment for intractable postherpetic neuralgia - a case report -. AB - A 60-year-old man presented with pain on the left cheek and lateral nose. The patient had been diagnosed with facial herpes zoster in the left V2 area 6 months previously. Medical treatment was prescribed for 6 months but it had little effect. We blocked the left infraorbital nerve under ultrasound guidance, but pain relief was short term. Therefore, we performed pulsed radiofrequency treatment on the left infraorbital nerve under ultrasound guidance. Six months after the procedure, the reduction of pain was still maintained, and there was no need for further management. PMID- 23342216 TI - Effectiveness of oral glycopyrrolate use in compensatory hyperhidrosis patients. AB - Compensatory hyperhidrosis or reflex hyperhidrosis is the increase in sweating in the postoperative stage of thoracic sympathectomy or lumbar sympathectomy. It shares several features with anxiety disorders and has a negative impact on a patient's quality of life. Oralglycopyrrolate is one of the treatment options available. This study reviewed case notes in a series of 19 patients with compensatory hyperhidrosis. We made a comparison between the Milanez de Campos score of a pre-glycopyrrolate medication group and the Milanez de Campos score of a post-glycopyrrolate medication group. The Beck Depression Inventory (BDI) score, Beck Anxiety Inventory (BAI) score, and autonomic nervous system (ANS) scale score were also compared between the pre-medication and post-medication groups. In the post-glycopyrrolate medication group, there was decrease in the Milanez de Campos score, BAI score, and BDI score (P < 0.05). But no meaningful change was seen in the ANS score in the post-glycopyrrolate medication group (P > 0.05). Glycopyrrolate is an effective medication in the treatment of compensatory hyperhidrosis that, can alleviate anxiety and improve patients' quality of life. PMID- 23342218 TI - Clinical experiences on the effect of scrambler therapy for patients with postherpetic neuralgia. AB - Postherpetic neuralgia (PHN) is a debilitating complication of herpes zoster, especially in elderly and comorbid patients. Unfortunately, the currently available treatments have shown limited efficacy and some adverse events that are poorly tolerated in elderly patients. Scrambler Therapy, proposed as an alternative treatment for chronic neuropathic pain recently, is a noninvasive approach to relieve pain by changing pain perception at the brain level. Here, we report our clinical experiences on the effect of Scrambler Therapy for three patients with PHN refractory to conventional treatment. PMID- 23342217 TI - Repeat vertebroplasty for the subsequent refracture of procedured vertebra. AB - Vertebroplasty (VP) can effectively treat pain and immobility caused by vertebral compression fracture. Because of complications such as extravasation of bone cement (polymethylmethacrylate, PMMA) and adjacent vertebral fractures, some practitioners prefer to inject a small volume of PMMA. In that case, however, insufficient augmentation or a subsequent refracture of the treated vertebrae can occur. A 65-year-old woman visited our clinic complaining of unrelieved severe low back and bilateral flank pain even after she had undergone VP on the 1(st) and 4(th) (L1 and L4) lumbar vertebrae a month earlier. Radiologic findings showed the refracture of L1. We successfully performed the repeat VP by filling the vertebra with a sufficient volume of PMMA, and no complications occurred. The patient's pain and immobility resolved completely three days after the procedure and she remained symptom-free a month later. In conclusion, VP with small volume cement impaction may fail to relieve fracture-induced symptoms, and the refracture of an augmented vertebral body may occur. In this case, repeat VP can effectively resolve both the persistent symptoms and problems of new onset resulting from refracture of the augmented vertebral body due to insufficient volume of bone cement. PMID- 23342219 TI - Is Fluoroscopy-guided Suprascapular Nerve Block Better Than Other Techniques? PMID- 23342220 TI - Changes in bone turnover markers and bone mass with reducing levels of jumping exercise regimens in female rats. AB - PURPOSE: To date, little is known about the effects of a reduced level of jumping exercise regimens on bone turnover markers and mass. This study investigates the effects of different jumping exercise regimens with varying exercise loads on serum bone turnover markers and bone mass in female rats. METHODS: A total of 144 female rats aged 12 weeks, were divided into 12 groups as follows: no exercise for 8 (8S) or 32 weeks (32S), or 8 weeks of standard training program (8STP) consisting of 200 jumps per week (200J/w), given at 40 jumps per day (40J/d) for 5 days per week (5d/w) (8STP24E), followed by 24 weeks of exercise at loads of either 10J/d or 20J/d or 40J/d, for either 5d/w, or 3d/w, or 1d/w. Serum osteocalcin, alkaline phosphatase, C-terminal telopeptide of type 1 collagen (1CTP) concentrations, and tibial fat free dry weight were measured. RESULTS: Tibial mass was significantly higher in 8STP than 8S. No changes were evident in serum markers of bone turnover parameters after 8STP. Significant increases in tibial mass were observed in rats that continued to exercise at workloads of 30J/w and above after 8STP. Serum alkaline phosphatase concentrations increase whereas serum 1CTP concentrations decrease in rats given workloads of 40J/w and above. CONCLUSIONS: It appears, an exercise load of 30J/w, i.e. 10J/d for 3d/w, was the minimum level of continuous exercise load that was required to maintain the 8STP-induced bone gains. In addition, significant increases in bone mass in young rats following 8STP might not always be reflected by changes in serum levels of osteocalcin, alkaline phosphatase and 1CTP. PMID- 23342221 TI - The Effects of Music on High-intensity Short-term Exercise in Well Trained Athletes. AB - PURPOSE: The purpose of this investigation was to assess the effects of listening to music during warm-up on short-term supramaximal performances during the 30-s Wingate test in highly trained athletes. METHODS: Twelve young male athletes (20.6+/-1.8 yrs, 177+/-4.4 cm and 72.3+/-5.3 kg) underwent two Wingate tests in separate sessions with a recovery period of 48 h in-between, either after a 10 min of warm-up with (MWU) or without (NMWU) music. High tempo music (>120 to 140bpm) was selected for the study. Heart rate (HR) and rate of perceived exertion (RPE) were recorded after the warm-up (for HR = average of warm-up) and immediately after the Wingate test. RESULTS: HR, RPE and the fatigue index during the Wingate test are not affected by the incorporation of music during warm-up. However, power output (P(peak) and P(mean)) was significantly higher after MWU than NMWU (P<0.05). The relative increases were 4.1 +/- 3.6 and 4.0 +/- 3.7 W.kg( 1) for P(peak) and P(mean) respectively. These findings demonstrated the beneficial effect of music during warm-up on short-term supramaximal performances. CONCLUSIONS: As it's a legal method and an additional aid, music may be used during warm-up before performing activities requiring powerful lower limbs' muscles contractions during short-term supramaximal exercises. PMID- 23342222 TI - Effect of short-term maximal exercise on biochemical markers of muscle damage, total antioxidant status, and homocysteine levels in football players. AB - PURPOSE: Prolonged physical exercise results in transient elevations of biochemical markers of muscular damage. This study examined the effect of short term maximal exercise on these markers, homocysteine levels (Hcy), and total antioxidant status (TAS) in trained subjects. METHODS: Eighteen male football players participated in this study. Blood samples were collected 5-min before and 3-min after a 30-s Wingate test. RESULTS: The results indicated that plasma biochemical markers of muscle injury increased significantly after the Wingate test (P<0.05). Moreover, significant increase of white blood Cells and their main subpopulations (i.e. monocytes, neutrophiles, and lymphocytes) (P<0.001) has been observed. Likewise, uric acid, total bilirubin, and TAS increased significantly after exercise (P<0.05). However, Hcy levels were unaffected by the Wingate test (for 3-min post-exercise measurement). CONCLUSIONS: Short-term maximal exercise (e.g. 30-s Wingate test) is of sufficient intensity and duration to increase markers of muscle damage, and TAS; but not Hcy levels. Increases in the selected enzymes probably come primarily from muscle damage, rather than liver damage. Moreover, increase of TAS confirms the Wingate test induced oxidative stress. PMID- 23342223 TI - Does Muscle Mass Affect Running Times in Male Long-distance Master Runners? AB - PURPOSE: The aim of the present study was to investigate associations between skeletal muscle mass, body fat and training characteristics with running times in master athletes (age > 35 years) in half-marathon, marathon and ultra-marathon. METHODS: We compared skeletal muscle mass, body fat and training characteristics in master half-marathoners (n=103), master marathoners (n=91) and master ultra marathoners (n=155) and investigated associations between body composition and training characteristics with race times using bi- and multi-variate analyses. RESULTS: After multi-variate analysis, body fat was related to half-marathon (beta=0.9, P=0.0003), marathon (beta=2.2, P<0.0001), and ultra-marathon (beta=10.5, P<0.0001) race times. In master half-marathoners (beta=-4.3, P<0.0001) and master marathoners (beta=-11.9, P<0.0001), speed during training was related to race times. In master ultra-marathoners, however, weekly running kilometers (beta=-1.6, P<0.0001) were related to running times. CONCLUSIONS: To summarize, body fat and training characteristics, not skeletal muscle mass, were associated with running times in master half-marathoners, master marathoners, and master ultra-marathoners. Master half-marathoners and master marathoners rather rely on a high running speed during training whereas master ultra-marathoners rely on a high running volume during training. The common opinion that skeletal muscle mass affects running performance in master runners needs to be questioned. PMID- 23342225 TI - Reliability of 1-repetition maximum estimation for upper and lower body muscular strength measurement in untrained middle aged type 2 diabetic patients. AB - PURPOSE: The 1-repetition maximum (1-RM) test is the gold standard test for evaluating maximal dynamic strength of groups of muscles. However, safety of actual 1-RM testing is questionable in clinical situations such as type 2 diabetes (T2D), where an estimated 1-RM test is preferred. It is unclear if acceptable test retest reliability exists for the estimated 1-RM test in middle aged T2D patients. This study examined the reliability of the estimated 1-RM strength test in untrained middle aged T2D subjects. METHODS: Twenty five untrained diabetic males (n=19) and females (n=6) aged 40.7+0.4 years participated in the study. Participants undertook the first estimated 1-RM test for five exercises namely supine bench press, leg press, lateral pull, leg extension and seated biceps curls. A familiarisation session was provided three to five days before the first test. 1-RM was estimated for all participants by Brzycki 1-RM prediction equation. Another identical 1-RM estimation procedure occurred one week after first test. Intraclass correlation coefficients (ICC), paired t-test, standard error of measurement (SEM), Bland-Altman plots, and estimation of 95% CI were used to assess reliability. RESULTS: Test-retest reliability was excellent (ICC(2,1)=0.98-0.99) for all measurements with the highest for leg extension (ICC(2,1)=0.99). The SEM was lowest for lateral pull and leg extension exercises. Paired t-tests showed non-significant differences between the means of 2 sessions across three of five exercises. CONCLUSIONS: The study findings suggest that estimation of 1-RM is reliable for upper and lower body muscular strength measurement in untrained middle aged T2D patients. PMID- 23342224 TI - Body Composition and Dietary Intake of Elite Cross-country Skiers Members of the Greek National Team. AB - PURPOSE: To assess the anthropometric characteristics and dietary intake of the Greek national cross-country skiing team. METHODS: Thirty-three athletes (10 females aged 20 +/- 5 years; 23 males aged 20 +/- 6 years old) participated in the study. All athletes were members of the Greek national ski team, and they had been selected to take part in the Winter Olympics, World Ski Championships, European Ski Championships or other international events, according to their performance. Body composition was estimated by bioelectrical impedance (BIA) and skinfold thickness. The athletes recorded their physical activity and dietary intake for 3 training days, and on a competition day. RESULTS: The female skiers had 14.2+/-1.9% body fat, the men 11.0+/-1.5% body fat. Female athletes consumed a diet of 1988+/-319 Kcal during training days and 2011+/-330 Kcal during competition days. Male athletes consumed 2255+/-790 Kcal and 2125+/-639 Kcal respectively. These values are below those recommended for highly active people. During the training period, carbohydrate, fat and protein contributed to 44.5+/ 7.1%, 39.2+/-5.3% and 16.1+/-3.7% of the total energy intake (EI) respectively for the males, and to 52.8+/-5.6%, 33.0+/-3.7% and 14.3+/-2.5% of the EI of the women. Between training and competition days, men demonstrated an increased carbohydrate and reduced fat consumption when competing (P<0.001 for both). Women, on the other hand, consumed more carbohydrate and less protein during competition days (P<0.05 for both). Protein intake was within the recommended range for both males and females, but fat exceeded the recommended values and was consumed at the expense of carbohydrate. Vitamins B(12), D, E and K, biotin, folate, Ca, Mg, K, I were inadequately consumed (below the RDA) by both women and men, while the women also exhibited inadequate intakes of iron and the men of manganese. CONCLUSIONS: The inadequate energy and nutrient intake in the Greek national cross-country ski team could put the athletes at risk of nutritional deficiencies, and possibly compromise their athletic performance. PMID- 23342226 TI - Effects of prefabricated ankle orthoses on postural stability in basketball players with chronic ankle instability. AB - PURPOSE: Ankle sprain is one of the most common injuries among athletes and instability and injury to this joint is responsible for long time loss of physical and recreational activity. Also, it can impose high costs to sport teams. Prevention of this injury is an important concern of practice and rehabilitation. One way of reducing the possibility of ankle joint injury is using an ankle orthosis. The present study aimed at inspecting the effects of two ankle orthoses on dynamic and semi-dynamic postural stability in athletes with chronic ankle instability (CAI). METHODS: Twenty basketball players with CAI and fifteen non-injured athletes volunteered to participate in this study. Biodex Balance System was used to assess the participants' postural stability in bilateral position at level 8 and level 2. Repeated measures analysis of variance (ANOVA) was performed in order to examine the effects of ankle orthoses. Statistical significance level was determined at P< 0.05. RESULTS: Statistical analyses revealed the significant effect of ankle supports on dynamic and semi dynamic postural stability in the two groups and results indicated there wasn't significant difference between groups. CONCLUSIONS: According to our results the orthoses improved both dynamic and semi-dynamic postural stability. Therefore, orthoses can prevent injury and its reoccurrence. PMID- 23342227 TI - Resistance training and vibration improve muscle strength and functional capacity in female patients with multiple sclerosis. AB - PURPOSE: The purpose of this study was to evaluate the effect of an eight-week progressive resistance training and vibration program on strength and ambulatory function in multiple sclerosis (MS) patients. METHODS: Twenty-Four female MS patients with the following demographics: age 27-45 years, and expanded disability status scale (EDSS) 2-4, participated in this study. The subjects were randomly allocated to one of two groups. The exercise group (n = 12) trained according to a progressive program, mainly consisting of resistance training and vibration, three times a week for eight weeks and compared with subjects in the control group (n = 12) that received no intervention. Subjects completed one set of 5-12 reps at%50-70 maximal voluntary contraction (MVC). After 5-10 minutes rest, six postures on plate vibration were done. Isotonic MVC of knee extensors, abduction of the scapula and downward rotation of the scapular girdle muscle groups were predicted by using the Brzycki formula. Right leg balance (RLB), left leg balance (LLB), and walking speed (10-Meter Walk Test) were assessed before and after the training program. Descriptive statistics and Co-variance were used for analyzing data. RESULTS: After eight weeks of training the exercise group showed significant increase in MVC of Knee extensors (32.3%), Abduction of the scapula (24.7%) and Downward Rotation Scapular (39.1%) muscle groups, RLB (33.5%), LLB (9.5%), and decrease in 10-Meter Walk Test (10MWT) (9.3%), (P<0.05). CONCLUSIONS: The results of this study indicated this type of training can cause improvements in muscle strength and functional capacity in patients with multiple sclerosis. PMID- 23342228 TI - Fatalities Among Iranian High-altitude Outdoor Enthusiasts: Causes and Mechanisms. AB - PURPOSE: This study was performed to determine the possible causes and mechanisms of fatalities among Iranian mountaineers during climbing. METHODS: By contacting several sources, deceased mountaineers were identified. Data about the causes and mechanism of death was retrospectively obtained using a standard questionnaire for each case. RESULTS: A total of 29 deaths were identified from March 2006 to June 2010. Deceased subjects had a mean age of 39 years (SD: 12.8, Range: 20-67). Falling was the most common accident leading to death of outdoor enthusiasts (n = 14, 48%). Asphyxia (n = 6, 24%) was the most common cause of death among the subjects, followed by heart attack, internal bleeding, cerebral hemorrhage and hypothermia (17%, 17%, 17% and 10%, respectively). CONCLUSIONS: Our findings suggest that education of medical service providers of the climbing groups on facing victims in high altitude areas, where they have limited resources, can be particularly helpful. In addition, a national program to educate mountaineers might help to reduce fatalities. PMID- 23342229 TI - Pelvic incidence and lumbar spine instability correlations in patients with chronic low back pain. AB - PURPOSE: Many factors such as lumbar instability and spinopelvic alignment are associated with low back pain. Our purpose was to analyze the pelvic incidence - one of spinopelvic alignment parameters- and spine instability correlations in patients with chronic low back pain. METHODS: Fifty-two patients suffering from chronic low back pain entered this case control study. Lateral spine radiography was taken from patients. pelvic incidence and L3, L4 and L5's vertebral body width were measured for all patients, and lumbar instability was evaluated in 3 different levels: L5-S1, L4-L5 and L3-L4. RESULTS: Thirty-two patients having lumbar instability formed group A and 20 patients without lumbar spine instability allocated to group B. Average age, mean weight, height, body mass index and mean vertebral width of both groups did not differ meaningfully. Pelvic incidence's mean amounts set to 53.9 in group B and 57.7 in group A without any significant difference; but pelvic incidence was significantly lower in patients with lumbar instability of L5-S1 origin (P=0.01). CONCLUSIONS: Overall, pelvic incidence did not differ between two groups. However, separate evaluation of each level revealed lumbar instability of L5-S1 segment to be associated with lower pelvic incidence. PMID- 23342230 TI - Behavior and Knowledge of Iranian Professional Athletes towards Smoking. AB - PURPOSE: This study aimed to assess the rate of tobacco consumption among professional athletes in Iran and assessing their knowledge and attitude in this regard. METHODS: A total of 738 athletes from 10 different types of sports were evaluated. Athletes were all members of the priority leagues. After obtaining consent from the Physical Education Organization and coordination with the related federations, athletes were asked to fill out the standard questionnaire. RESULTS: All understudy subjects were males. The mean age was 28.4+/-2.7 yrs. The mean age of initiation of sport in these subjects was reported to be 12.3+/-4.01 yrs. A total of 178 (24.6%) subjects had experienced cigarette smoking and 308 (42.3%) had experienced hookah smoking. Sixty four subjects (9%) were current smokers. The mean score of knowledge about hazards of smoking was 5.6+/-0.9 among those who had experienced smoking. This score was 7.9+/-0.5 among those with no smoking experience (P=0.04). CONCLUSIONS: Rate of smoking among professional athletes is lower than general population average. So participation in organized sports may be a protective factor against tobacco use in people. PMID- 23342231 TI - Aflibercept in wet age-related macular degeneration: a perspective review. AB - In the treatment of neovascular age-related macular degeneration (AMD), vascular endothelial growth factor (VEGF) has emerged as a key target of therapy. Currently, patients with neovascular AMD are treated with monthly intravitreal injections of anti-VEGF medications. Aflibercept is a novel recombinant fusion protein engineered to bind all isoforms of VEGF-A, VEGF-B, and placental growth factor. It is the latest medication to receive US Federal Drug Administration (FDA) approval for the treatment of neovascular AMD. Theoretical models suggest this molecule may have a longer duration of action compared with current treatments. The results of the VEGF Trap-Eye: Investigation of Efficacy and Safety in wet Age-related Macular Degeneration studies (VIEW 1 and VIEW 2) support this by demonstrating that aflibercept, dosed every 2 months after a monthly loading dose for 3 months, was noninferior in the proportion of patients who maintained or improved vision at 52 weeks compared with monthly injections of ranibizumab. These results were maintained over the 2 years of the studies. Aflibercept (Eylea; Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA and Bayer, Basel, Switzerland) was approved by the FDA for the treatment of neovascular AMD on 18 November 2011. PMID- 23342232 TI - Blood pressure lowering in acute phase of stroke: latest evidence and clinical implications. AB - Persistent controversy exists as to whether there are worthwhile beneficial effects of early, rapid lowering of elevated blood pressure (BP) in acute stroke. Elevated BP or 'hypertension' (i.e. systolic >140 mmHg) is common in stroke, especially in patients with pre-existing hypertension and large strokes, due to variable 'autonomic stress' and raised intracranial pressure. While positive associations between BP levels and poor outcomes are evident across a range of studies, very low BP levels and large reductions in BP have also been shown to predict death and dependence, more so for ischaemic stroke (IS) than intracerebral haemorrhage (ICH). Accumulating evidence indicates that early BP lowering can reduce haematoma expansion in ICH, but there is uncertainty over whether this translates into improved clinical outcomes, particularly since such an effect was not evident from haemostatic therapy in clinical trials. Guidelines generally recommend control of high systolic BP (>180 mmHg), but recent evidence indicates that even more modest elevation (>140 mmHg) increases risks of cerebral oedema and haemorrhagic transformation following thrombolysis in IS. Thus, any potential benefits of rapid BP lowering in acute stroke, particularly in IS, must be balanced against the potential risks of worsening cerebral ischaemia from altered autoregulation/perfusion. This paper explores current knowledge regarding the management of hypertension in acute stroke and introduces ongoing clinical trials aimed at resolving such a critical issue in the care of patients with acute stroke. PMID- 23342233 TI - Oral renin inhibitors in clinical practice: a perspective review. AB - Hypertension is an important risk factor for cardiovascular morbidity and mortality. The importance of the renin-angiotensin-aldosterone system (RAAS) in cardiovascular and renal diseases has long been recognized: for this reason the conventional therapies, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), beta-blockers, and aldosterone antagonists represent the backbone of current antihypertensive therapy. Aliskiren is the first direct renin inhibitor (DRI) suitable for oral administration. By achieving more complete renin-angiotensin system inhibition, direct renin inhibitors may afford greater protection from hypertensive complications. Present evidence indicates that aliskiren reduces baseline systolic and diastolic blood pressure greater than placebo and that it is as effective as other first-line antihypertensive agents. Extra advantages can be reached when it is used in combination therapy. Clinical trials and in vitro studies also suggest that aliskiren has several cardioprotective and renoprotective effects. Therapy with aliskiren is well tolerated, but recently some concerns have arisen because of the early termination of the ALTITUDE study due to an increased incidence of adverse effects. PMID- 23342234 TI - Management of patients with Alzheimer's disease: pharmacological treatment and quality of life. AB - A methodological approach to quality of life (QoL) assessment in Alzheimer's disease (AD) is challenging and few clinical trials have included it among outcomes, with conflicting results. In this review an indirect appraisal of evidence has been performed, searching the literature for the effect of drug treatments on determinants of QoL in AD. Among clinical factors associated with QoL, possible targets of drugs include cognition, which seems to be associated with QoL in early disease and can be positively affected by cholinesterase inhibitors (CIs) in this stage; functional decline, the risk of which can be decreased by CIs and memantine (MEM); behavioral and psychological symptoms, which can be reduced by MEM and atypical antipsychotics. Long-term observational studies have associated CIs and MEM treatment with a reduced institutionalization risk. According to the evidence, drug treatment of depression associated with AD should not be first choice from a QoL perspective, while treatment of pain can have beneficial effects on wellbeing indicators also in the late stages of the disease. Possible drug-related adverse events can affect QoL and should always be weighed against expected benefits from the patient's perspective. For this reason antipsychotic treatment is often problematic in AD and should be limited to severe psychosis and aggression, using the lowest effective doses for the shortest possible period. Conversely titration of CIs is necessary to reach the most effective dosages, although dose-related risk of adverse events has to be taken into account. Finally, CIs and MEM have been shown to reduce caregiver burden in randomized trials, possibly affecting caregivers' QoL. PMID- 23342235 TI - The case for more intensive use of statins. PMID- 23342236 TI - Once-daily gastroretentive gabapentin for the management of postherpetic neuralgia: an update for clinicians. AB - Gabapentin was originally developed as an add-on anticonvulsant drug, but has been widely used in the USA for the management of postherpetic neuralgia since its approval for this indication in 2002. Gabapentin has a short elimination half life and limited absorption due to a saturable L-amino acid transport system, which is expressed predominantly in the proximal small intestine. Hence, the original immediate-release gabapentin formulation (gabapentin TID) must usually be taken three times a day for optimal efficacy. Gabapentin TID is also associated with a high incidence of dizziness and somnolence and some patients are unable to tolerate the doses required for maximum pain relief. A once-daily, gastroretentive formulation of gabapentin was recently approved by the US Food and Drug Administration (FDA) for the management of postherpetic neuralgia. This formulation provides gradual release of gabapentin to the optimal site of absorption in the proximal small intestine and reduces the chance of saturating intestinal uptake, thus enabling once-daily dosing of gabapentin. This gradual release and absorption have been demonstrated in pharmacokinetic studies in healthy subjects. The efficacy of once-daily gastroretentive gabapentin for the management of postherpetic neuralgia has been demonstrated in placebo-controlled clinical studies. In addition, data from these studies suggest that the incidence of dizziness and somnolence may be reduced compared with similar studies using gabapentin TID. This article provides an overview of the pharmacokinetics, efficacy, and safety of once-daily gastroretentive gabapentin for the management of postherpetic neuralgia. PMID- 23342237 TI - Prospects for treating osteoarthritis: enzyme-protein interactions regulating matrix metalloproteinase activity. AB - Primary osteoarthritis (OA) is a musculoskeletal disorder of unknown etiology. OA is characterized by an imbalance between anabolism and catabolism in, and altered homeostasis of articular cartilage. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motif are upregulated in OA joints. Extracellular matrix (ECM) proteins are critical for resistance to compressive forces and for maintaining the tensile properties of the tissue. Tissue inhibitor of metalloproteinases (TIMPs) is the endogenous inhibitor of MMPs, but in OA, TIMPs do not effectively neutralize MMP activity. Upregulation of MMP gene expression occurs in OA in a milieu of proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor alpha. Presently, the medical therapy of OA includes mainly nonsteroidal anti-inflammatory drugs and corticosteroids which dampen pain and inflammation but appear to have little effect on restoring joint function. Experimental interventions to restore the imbalance between anabolism and catabolism include small molecule inhibitors of MMP subtypes or inhibitors of the interaction between IL-1 and its receptor. Although these agents have some positive effects on reducing MMP subtype activity they have little efficacy at the clinical level. MMP-9 is one MMP subtype implicated in the degradation of articular cartilage ECM proteins. MMP-9 was found in OA synovial fluid as a complex with neutrophil gelatinase-associated lipocalin (NGAL) which protected MMP-9 from autodegradation. Suppressing NGAL synthesis or promoting NGAL degradation may result in reducing the activity of MMP-9. We also propose initiating a search for enzyme-protein interactions to dampen other MMP subtype activity which could suppress ECM protein breakdown. PMID- 23342238 TI - The older patient with hypertension: care and cure. AB - Hypertension is one of the most important clinical conditions affecting older people. Its prevalence in this group of subjects is above 60% and continues to grow. Isolated systolic hypertension accounts for the majority of cases as systolic blood pressure increases with advancing age, while diastolic blood pressure remains unchanged or even decreases. Nowadays hypertension is a well established risk factor for stroke and cardiovascular disease among older people and its treatment is considered mandatory. The general recommended blood pressure goal in uncomplicated hypertension is less than 140/90 mmHg, even if this target in older people is based mainly on expert opinion. All patients should receive nonpharmacological treatment, in particular reduction in excess body weight when body mass index is greater than 26 kg/m(2) and dietary salt restriction. Older patients with hypertension may also benefit from smoking cessation, physical activity and alcohol restriction. In relation to drug therapy, a low-dose thiazide diuretic could be a good first step. Other first-line drugs are long acting calcium channel blockers, generally dihydropyridines, and angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. The HYVET study showed a specific protective effect of indapamide with or without perindopril in people older than 80 years. Since monotherapy normalizes blood pressure in only 40-50% of cases, a combination of two or more drugs is often required. Moreover the addiction of a second drug may reduce the dose-related adverse effects of the first one. Finally, compliance with treatment should always be achieved by giving complete information to patients and simplifying the drug regimen as much as possible. PMID- 23342239 TI - Long-acting basal insulin analogs: latest developments and clinical usefulness. AB - All patients with type 1 diabetes mellitus need insulin treatment permanently, and many patients with type 2 diabetes will require insulin therapy. Basal insulin analogs are increasingly used in the treatment of diabetes, with the aim of offering a better replication of the pattern of basal endogenous secretion of insulin. Their flatter pharmacodynamic profile, with a much lower peak of action, their slow and continuous absorption into the systemic circulation, and prolonged duration, more closely duplicate the endogenous insulin secretion leading to physiological basal glycemic control and affording more flexible treatment with fewer hypoglycemia episodes. The basal analogs represent the most significant advances in 'basal insulin' supplementation, and can be used in different insulin regimens achieving the same clinical effectiveness over conventional insulins, with benefits in terms of hypoglycemia and less weight gain, and may be an option for patients with problematic hypoglycemia despite optimization of conventional insulin therapy. At present, there are no data on micro- or macrovascular endpoints, and indeed it is unlikely that these will become available, at least in the foreseeable future. The evidence for basal insulin analogs affecting the risk of cancer is limited, and overriding diabetes indications rather than putative cancer concerns should remain the principal consideration when selecting therapy in patients with diabetes. PMID- 23342240 TI - Steps in the management of psoriatic arthritis: a guide for clinicians. AB - Psoriatic arthritis is a common systemic inflammatory disorder, which in addition to skin and nail involvement may be associated with peripheral and axial joint involvement, enthesitis, dactylitis, and important comorbidities - especially cardiovascular morbidity. Better insights into the involved pathogenic mechanisms have resulted in an improved therapeutic armamentarium, which targets key pathways in its pathogenesis. This has resulted in significant clinical responses to newer therapeutic agents, especially those directed at inhibition of tumor necrosis factor alpha. Biological therapy leads to significant levels of remission, improved quality of life, and retards or improves structural radiological damage. PMID- 23342241 TI - Latest evidence on gout management: what the clinician needs to know. AB - Until recently, the last drug approved for the treatment of gout by the United States Food and Drug Administration was allopurinol in 1966. Since 2008, two new drugs for the treatment of gout, febuxostat and pegloticase, have been approved in the US. Febuxostat has been approved in the EU and pegloticase approval is anticipated. A new single-ingredient colchicine preparation is available in the US, and the treatment recommendations for the use of colchicine in acute gout have evolved, now favoring a low-dose regimen. Several other exciting drugs are in development. Herein, we review some of basic principles in the diagnosis and staging of gout. We then examine current treatment principles, with particular attention to febuxostat and pegloticase, offering suggestions as to where they might fit into a modern therapeutic algorithm for gout treatment. We then present available data on several exciting new agents in development, including interleukin-1 inhibitors, and relate them to advances in our understanding of gout pathogenesis. We conclude with some important nonpharmacologic principles for optimal management of this ancient and eminently treatable disease. Dedicated gout research, going on quietly in the background of other breathtaking advances in rheumatology, is now paying off. This comes at a time when the number of patients affected by gout continues to rise, mainly due to an epidemic of obesity. An effort to improve lifestyle choices as a society and better management of the disease by clinicians should have a positive impact on gout incidence and outcome in our lifetimes. PMID- 23342242 TI - Drug treatment developments in schizophrenia and bipolar mania: latest evidence and clinical usefulness. AB - Schizophrenia and bipolar disorder are often highly debilitating with chronic courses, and psychotropic drugs represent cornerstones in the treatment. The primary aim of the review was to summarize the latest evidence with regards to the efficacy and effectiveness of drug treatment of schizophrenia and the manic phases of bipolar disorder. Schizophrenia systematic reviews conclude that antipsychotic drugs are effective in treating overall symptoms of psychosis and in preventing relapse. Some of the newer agents, the second-generation antipsychotics (SGAs), have demonstrated superiority compared with the older first-generation drugs and other SGAs but side-effect differences among the drugs are of a greater magnitude than effect differences. The pragmatic randomized trials of effectiveness have shown a longer time until treatment discontinuation for olanzapine compared with other antipsychotics. Cohort studies have found superiority for the long-acting injection formulations compared with the oral formulations of the drugs, and lower total mortality risk in users of antipsychotics compared with non-users. In bipolar mania SGAs have shown superior antimanic efficacy compared with other mood-stabilizing drugs. In conclusion antipsychotics, in particular some of the SGAs, seem to be drugs of first choice for both schizophrenia and bipolar mania. This perspective review focused on mean effects but the group means may not always be particularly useful as schizophrenia and bipolar mania are biologically heterogeneous disorders with large inter-individual variations in drug response and tolerance. In patients with a prior drug history the different pharmacological and clinical profiles may be exploited in subsequent choices of drugs. PMID- 23342243 TI - Asenapine in bipolar I disorder: evidence and place in patient management. AB - Asenapine is a new second-generation antipsychotic approved in September 2010 by the European Medicines Agency for the treatment of bipolar disorder. It demonstrated significant efficacy compared with placebo in acute mania or mixed episodes as monotherapy or adjunctive therapy to mood stabilizers (lithium or valproate). Early improvement was noted at day 2 and was strongly associated with response and remission at week 3. Asenapine also appeared effective in treating acute mania in older patients with bipolar disorder. Post hoc analyses of asenapine showed efficacy in treating depressive symptoms during manic or mixed episodes compared with placebo. The efficacy of asenapine in patients with acute mania appeared to remain constant during maintenance treatment. Asenapine was reasonably well tolerated, especially with regard to metabolic effects. There were minimal signs of glucose elevation or lipid changes and the risk of weight gain appeared limited. The prolactin elevation was smaller than other antipsychotic comparators. Only oral hypoesthesia occurred as a new adverse event compared with other second-generation antipsychotics. Asenapine presents several advantages over other second-generation antipsychotics, such as sublingual formulation, early efficacy and good metabolic tolerability. This tolerability profile confirms the heterogeneity of the second-generation antipsychotic class and supports the view of some authors for the need to re-evaluate the boundaries of this group. PMID- 23342244 TI - Tocilizumab in rheumatoid arthritis: efficacy, safety and its place in therapy. AB - Tocilizumab is a humanized antihuman interleukin-6 (IL-6) receptor monoclonal antibody. It was developed in Japan as the first biological disease-modifying antirheumatic drug targeting IL-6 receptors. Many large-scale global studies have demonstrated its efficacy and safety, and in April 2008 it was approved in Japan for use in the treatment of rheumatoid arthritis, sooner than in other countries. In this paper, I review the efficacy and safety of tocilizumab in the light of front-line clinical data and data from large-scale studies, and I consider the place of tocilizumab treatment in real clinical practice. PMID- 23342246 TI - Recent advances in treating multiple sclerosis: efficacy, risks and place in therapy. AB - The development of new pharmacologic agents for the treatment of multiple sclerosis (MS) and advances in testing for exposure to the JC virus have led to changes in the treatment of MS. In addition several new agents are in late stage development for MS and their entry onto the market will provide additional treatment options. In 2012 and in early 2013, it is likely that both terifunomide and BG-12 will be approved by the United States Food and Drug Administration (FDA) for the treatment of relapsing forms of MS. The therapeutic environment has already changed and is likely to change rapidly over the next several years. Fingolimod was the first oral agent approved for the treatment of MS and this agent is now widely used in patients intolerant of injections and the side effects associated with the older platform therapies. In many settings it is also used a first-line agent. Owing to the risk of progressive multifocal leukoencephalopathy, natalizumab had previously been reserved for patients with active disease who were intolerant of first-line agents or patients who were worsening despite standard therapy. With the availability of JC virus antibody testing, natalizumab is now being used as a first-line agent in patients negative for JC virus antibodies. Teriflunomide and BG-12 will become available in the next year. Both agents have suitable efficacy and a favorable safety and tolerability profile. There are advantages and disadvantages associated with all of the oral agents. In this article we summarize the clinical trial results regarding the efficacy and safety of the oral agents and discuss the changes that are already taking place in the therapeutic landscape for MS. PMID- 23342247 TI - Personalized medicine at a prime time for cancer medicine - introducing Cancer Medicine. PMID- 23342245 TI - New findings in osteoarthritis pathogenesis: therapeutic implications. AB - This review focuses on the new perspectives which can provide insight into the crucial pathways that drive cartilage-bone physiopathology. In particular, we discuss the critical signaling and effector molecules that can activate cellular and molecular processes in both cartilage and bone cells and which may be relevant in cross talk among joint compartments: growth factors (bone morphogenetic proteins and transforming growth factor), hypoxia-related factors, cell-matrix interactions [discoidin domain receptor 2 (DDR2) and syndecan 4], signaling molecules [WNT, Hedgehog (Hh)]. With the continuous progression of our knowledge on the molecular pathways involved in cartilage and bone changes in osteoarthritis (OA), an increasing number of potentially effective candidates for OA therapy are already under scrutiny in clinical trials to ascertain their possible safe use in an attempt to identify molecules active in slowing or halting OA progression and reducing joint pain. We then review the principal molecules currently under clinical investigation. PMID- 23342249 TI - Overexpression of snail induces epithelial-mesenchymal transition and a cancer stem cell-like phenotype in human colorectal cancer cells. AB - Epithelial-mesenchymal transition (EMT) is a critical process providing tumor cells with the ability to migrate and escape from the primary tumor and metastasize to distant sites. Recently, EMT was shown to be associated with the cancer stem cell (CSC) phenotype in breast cancer. Snail is a transcription factor that mediates EMT in a number of tumor types, including colorectal cancer (CRC). Our study was done to determine the role of Snail in mediating EMT and CSC function in CRC. Human CRC specimens were stained for Snail expression, and human CRC cell lines were transduced with a retroviral Snail construct or vector control. Cell proliferation and chemosensitivity to oxaliplatin of the infected cells were determined by the MTT (colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assay. Migration and invasion were determined in vitro using modified Boyden chamber assays. EMT and putative CSC markers were analyzed using Western blotting. Intravenous injection of tumor cells was done to evaluate their metastatic potential in mice. Snail was overexpressed in human CRC surgical specimens. This overexpression induced EMT and a CSC-like phenotype in human CRC cells and enhanced cell migration and invasion (P < 0.002 vs. control). Snail overexpression also led to an increase in metastasis formation in vivo (P < 0.002 vs. control). Furthermore, the Snail-overexpressing CRC cells were more chemoresistant to oxaliplatin than control cells. Increased Snail expression induces EMT and the CSC-like phenotype in CRC cells, which enhance cancer cell invasion and chemoresistance. Thus, Snail is a potential therapeutic target in metastatic CRC. PMID- 23342250 TI - Interleukin-1beta mediates metalloproteinase-dependent renal cell carcinoma tumor cell invasion through the activation of CCAAT enhancer binding protein beta. AB - Effective treatment of metastatic renal cell carcinoma (RCC) remains a major medical concern, as these tumors are refractory to standard therapies and prognosis is poor. Although molecularly targeted therapies have shown some promise in the treatment of this disease, advanced RCC tumors often develop resistance to these drugs. Dissecting the molecular mechanisms underlying the progression to advanced disease is necessary to design alternative and improved treatment strategies. Tumor-associated macrophages (TAMs) found in aggressive RCC tumors produce a variety of inflammatory cytokines, including interleukin-1beta (IL-1beta). Moreover, the presence of TAMs and high serum levels of IL-1beta in RCC patients correlate with advanced disease. We hypothesized that IL-1beta in the tumor microenvironment promotes the development of aggressive RCC tumors by directing affecting tumor epithelial cells. To address this, we investigated the role of IL-1beta in mediating RCC tumor cell invasion as a measure of tumor progression. We report that IL-1beta induced tumor cell invasion of RCC cells through a process that was dependent on the activity of matrix metalloproteinases (MMPs) and was independent of migration rate. Specifically, IL-1beta induced the expression of MMP-1, MMP-3, MMP-10, and MT1-MMP in a mechanism dependent on IL 1beta activation of the transcription factor CCAAT enhancer binding protein beta (CEBPbeta). Consistent with its role in MMP gene expression, CEBPbeta knockdown significantly reduced invasion, but not migration, of RCC tumor cells. These results identify the IL-1beta /CEBPbeta/MMP pathway as a putative target in the design of anti-metastatic therapies for the treatment of advanced RCC. PMID- 23342251 TI - ERBB3 (HER3) is a key sensor in the regulation of ERBB-mediated signaling in both low and high ERBB2 (HER2) expressing cancer cells. AB - Aberrant expression and activation of EGFR and ERBB2 (HER2) have been successfully targeted for cancer therapeutics. Recent evidence from both basic and clinical studies suggests that ERBB3 (HER3) serves as a key activator of downstream signaling through dimerization with other ERBB proteins and plays a critical role in the widespread clinical resistance to EGFR and HER2 targeting cancer therapies. As a result, HER3 is actively pursued as an antibody therapeutic target for cancer. Ligand binding is thought to be a prerequisite for dimerization of HER3 with other ERBB proteins, which results in phosphorylation of its c-terminal tyrosine residues and activation of downstream AKT and MAPK signaling pathways. In this study, we report that an anti-HER2 monoclonal antibody (HER2Mab), which blocks HER2 dimerization with HER3, induces HER3 dimerization with EGFR in both low and high HER2 expressing cancer cells. Treatment of the low HER2 expressing MCF7 cancer cells with HER2Mab promoted cell proliferation and migration in the absence of HER3 ligand stimulation. Follow-up studies revealed that HER2Mab-induced HER3 signaling via EGFR/HER3 dimerization and activation of downstream AKT signaling pathways. These results suggest that equilibrium of dimerization among the ERBB proteins can be perturbed by HER2Mab and HER3 plays a key role in sensing the perturbation. PMID- 23342252 TI - Establishment and characterization of a novel lymphangiosarcoma cell line (MO LAS) compared with the hemangiosarcoma cell line (ISO-HAS). AB - The concept of "lymphangiosarcoma" remains obscure. Therefore, we reported a patient with lymphangiosarcoma, resistant to immunotherapy. The patient presented with impressive and discriminative features: clinically an ill-defined edematous lesion with lymphorrhea and pathologically atypical vascular channel formation without extravasation of blood, clearly distinguished from common angiosarcoma with hemorrhage. From this case, a lymphangiosarcoma cell line, MO-LAS, was established and its characteristics were compared with the hemangiosarcoma cell line, ISO-HAS. Flow cytometric analysis revealed that MO-LAS was negative for factor VIII-related antigen, but positive for CD31, D2-40, NZ-1, and vascular endothelial growth factor receptor-3 (VEGFR-3), similar to ISO-HAS. However, MO LAS expressed a much higher level of homeobox gene PROX1, indicating a lymphatic phenotype, compared with ISO-HAS. Furthermore, MO-LAS showed a much lesser expression of oncogenes and much lower sensitivity against lymphokine-activated killer (LAK) cells. Lymphangiosarcoma may be difficult to recognize by the immune system. Conclusively, the establishment of MO-LAS, a novel angiosarcoma cell line bearing lymphatic characters, strongly suggests the entity of lymphangiosarcoma. PMID- 23342253 TI - Exposure to welding fumes increases lung cancer risk among light smokers but not among heavy smokers: evidence from two case-control studies in Montreal. AB - We investigated relationships between occupational exposure to gas and arc welding fumes and the risk of lung cancer among workers exposed to these agents throughout the spectrum of industries. Two population-based case-control studies were conducted in Montreal. Study I (1979-1986) included 857 cases and 1066 controls, and Study II (1996-2001) comprised 736 cases and 894 controls. Detailed job histories were obtained by interview and evaluated by an expert team of chemist-hygienists to estimate degree of exposure to approximately 300 substances for each job. Gas and arc welding fumes were among the agents evaluated. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of lung cancer using logistic regression, adjusting for smoking history and other covariates. The two studies provided similar results, so a pooled analysis was conducted. Among all subjects, no significant association was found between lung cancer and gas welding fumes (OR = 1.1; 95% CI = 0.9-1.4) or arc welding fumes (OR = 1.0; 95% CI = 0.8-1.2). However, when restricting attention to light smokers, there was an increased risk of lung cancer in relation to gas welding fumes (OR = 2.9; 95% CI = 1.7-4.8) and arc welding fumes (OR = 2.3; 95% CI = 1.3-3.8), with even higher OR estimates among workers with the highest cumulative exposures. In conclusion, there was no detectable excess risk of lung cancer due to welding fumes among moderate to heavy smokers; but among light smokers we found an excess risk related to both types of welding fumes. PMID- 23342254 TI - Prevent cervical cancer by screening with reliable human papillomavirus detection and genotyping. AB - The incidence of cervical cancer is expected to rise sharply in China. A reliable routine human papillomavirus (HPV) detection and genotyping test to be supplemented by the limited Papanicolaou cytology facilities is urgently needed to help identify the patients with cervical precancer for preventive interventions. To this end, we evaluated a nested polymerase chain reaction (PCR) protocol for detection of HPV L1 gene DNA in cervicovaginal cells. The PCR amplicons were genotyped by direct DNA sequencing. In parallel, split samples were subjected to a Digene HC2 HPV test which has been widely used for "cervical cancer risk" screen. Of the 1826 specimens, 1655 contained sufficient materials for analysis and 657 were truly negative. PCR/DNA sequencing showed 674 infected by a single high-risk HPV, 188 by a single low-risk HPV, and 136 by multiple HPV genotypes with up to five HPV genotypes in one specimen. In comparison, the HC2 test classified 713 specimens as infected by high-risk HPV, and 942 as negative for HPV infections. The high-risk HC2 test correctly detected 388 (57.6%) of the 674 high-risk HPV isolates in clinical specimens, mislabeled 88 (46.8%) of the 188 low-risk HPV isolates as high-risk genotypes, and classified 180 (27.4%) of the 657 "true-negative" samples as being infected by high-risk HPV. It was found to cross-react with 20 low-risk HPV genotypes. We conclude that nested PCR detection of HPV followed by short target DNA sequencing can be used for screening and genotyping to formulate a paradigm in clinical management of HPV related disorders in a rapidly developing economy. PMID- 23342255 TI - RET expression and detection of KIF5B/RET gene rearrangements in Japanese lung cancer. AB - RET encodes the tyrosine kinase receptor of growth factors belonging to the glial derived neurotrophic factor family. Recently, RET gene rearrangements with N terminal of KIF5B gene were identified in lung adenocarcinomas from large-scale sequencing. We investigated RET mRNA expression by real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay using LightCycler, and KIF5B/RET gene rearrangements using newly established fluorescence in situ hybridization (FISH) analysis in surgically treated nonsmall cell lung cancer (NSCLC) cases. RET protein expression was also investigated by immunohistochemistry (IHC). This study included 157 surgically removed NSCLC cases for mRNA level analyses. The RET/beta actin mRNA levels were not significantly different between lung cancer (6.359 +/- 15.268) and adjacent normal lung tissues (8.205 +/- 28.931, P = 0.6332). Tumor/normal (T/N) ratio of RET/beta actin mRNA levels was not different within gender, stage, smoking status, and pathological subtypes. T/N ratio of RET/beta actin mRNA levels was significantly higher in KIF5B/RET rearrangement samples (161.763 +/- 123.488) than in wild-type samples (5.9013 +/- 17.148, P = 0.044). Although RET IHC positivity was not perfectly correlated with KIF5B/RET arrangement, we have detected the KIF5B/RET rearrangements using FISH analysis. Thus, we have successfully introduced FISH for diagnosing KIF5B/RET positive lung adenocarcinoma. This method facilitates the molecular evaluation for RET fusions and could be applicable in clinical practice to detect lung cancer that may be responsive to RET inhibitors. PMID- 23342256 TI - CIP2A protein expression in high-grade, high-stage bladder cancer. AB - Bladder cancer is one of the most common cancers in the United States. Numerous markers have been evaluated for suitability of bladder cancer detection and surveillance. However, few of them are acceptable as a routine tool. Therefore, there exists a continuing need for an assay that detects the presence of bladder cancer in humans. It would be advantageous to develop an assay with a protein that is associated with the development of bladder cancer. We have identified the cancerous inhibitor of PP2A (CIP2A) protein as a novel bladder cancer biomarker. In this study, Western blot analysis was used to assess the expression level of CIP2A protein in bladder cancer cell lines and bladder cancer patient tissues (n = 43). Our studies indicated CIP2A protein was abundantly expressed in bladder cancer cell lines but not in nontumor epithelial cell lines. Furthermore, CIP2A was specifically expressed in transitional cell carcinoma (TCC) of the bladder tumor tissues but not in adjacent nontumor bladder tissue. Our data showed that CIP2A protein detection in high-grade TCC tissues had a sensitivity of 65%, which is 3.4-fold higher than that seen in low-grade TCC tissues (19%). The level of CIP2A protein expression increased with the stage of disease (12%, 27%, 67%, and 100% for pTa, pT1, pT2, and pT3 tumor, respectively). In conclusion, our studies suggest that CIP2A protein is specifically expressed in human bladder tumors. CIP2A is preferentially expressed in high-grade and high-stage TCC tumors, which are high-risk and invasive tumors. Our studies reported here support the role of CIP2A in bladder cancer progression and its usefulness for the surveillance of recurrence or progression of human bladder cancer. PMID- 23342257 TI - Prevalence of human papillomavirus and survival in oropharyngeal cancer other than tonsil or base of tongue cancer. AB - Today, most oropharyngeal squamous cell carcinoma (OSCC) is human papillomavirus (HPV) positive and HPV alone or in combination with p16 is reported to be a favorable prognostic factor for OSCC. Patients with tumors at other OSCC sites (OOSCC) are often included in the same treatment and study protocols as patients with tonsillar- and base of tongue SCC, even though the prevalence and clinical significance of HPV infection in OOSCC is unknown. Since tonsillar and base of tongue SSC cover roughly 90% of all OSCC, there is an obvious risk that there may be a misinterpretation of the results for OOSCC. Herein, we therefore study the prevalence of HPV and p16 and their impact on survival in OOSCC. A total of 69 patients were included in the study, and 61 were included in the survival analysis. HPV and p16 were present in only 17% (12/69) and 25% (17/69) of the OOSCC cases, respectively, while the majority 69% (48/69) was both HPV and p16 negative. Neither HPV nor p16 had predictive value for clinical outcome in OOSCC in this study. In conclusion, the prevalence of HPV and/or p16 is much lower in OOSCC compared to earlier reports including all OSCC, or tonsillar- and base of tongue cancer alone and HPV and p16 had no impact on clinical outcome in OSCC in this study. Our data highlight the diversity of head neck cancer sub-sites and the importance of taking OSCC sub-sites in consideration in future clinical trials and treatment. PMID- 23342258 TI - Triple-negative breast cancer: multipronged approach, single-arm pilot phase II study. AB - Anthracyclines (A) and taxanes (T) are standard first-line chemotherapy agents for patients with advanced breast cancer. Platinum analogues have also shown activity in the triple-negative breast cancer (TNBC) histology, but clinical data are limited. Here we report the long-term follow-up of a phase II study on TNBC treated with a combined modality therapy, including induction with AT, cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with concurrent radiation therapy, and a dose-dense consolidation chemotherapy (HDCT) with carboplatin (CBDCA), ifosfamide (IFX), etoposide (VP-16). Patients' median age was 44 years, with 73% premenopausal. Epirubicin 75 mg/m(2) and docetaxel 75 mg/m(2) were administered to 70 patients with TNBC: as neoadjuvant and adjuvant therapy to 12 and 58 patients, respectively. Postoperative radiation therapy, 5000 cGy, was delivered, synchronous with triweekly CMF. After radiation therapy, two courses of HDCT with CBDCA, IFX, VP-16, were given, with hematological growth factors. After a median follow-up of 81 months, all patients were evaluable for toxicity and response. Most important toxicity were grade 3 skin reaction and grade 4 hematological in 3% and 31% of patients, respectively. Pathological complete response was observed in 25% of patients receiving preoperative chemotherapy. Treatment failures were as follows: eight visceral, four contralateral breast cancer, four locoregional, and one leukemia. Five-year progression-free survival and overall survival rate were 78% and 91%, respectively. Induction chemotherapy, followed by chemoradiation therapy and HDCT, provides a prolonged disease-free period and a significant increase in overall survival in TNBC, with an acceptable toxicity profile. PMID- 23342259 TI - Emphasizing the role of Wnt5a protein expression to predict favorable outcome after radical prostatectomy in patients with low-grade prostate cancer. AB - Wnt5a, a member of non-canonical wingless-related MMTV integration site family is a secreted glycoprotein that plays important roles in development and disease. Recent studies have shown that Wnt5a protein levels are up-regulated in prostate cancer, but contrasting reports exist on the role of Wnt5a to predict outcome after radical prostatectomy in patients with localized prostate cancer. Our group has recently shown that preserved high protein expression of Wnt5a in prostate cancer is associated with longer relapse-free time after radical prostatectomy. The present tissue microarray study emphasizes the role of Wnt5a protein expression in a different, well-defined, and independent cohort consisting of 312 prostate cancer patients. Kaplan-Meier curves plotted between Wnt5a expression and time to biochemical recurrence revealed that in low-grade prostate cancer, patients with preserved high-Wnt5a protein levels in their tumor cells have a lower risk of recurrence after radical prostatectomy compared to patients with low-Wnt5a protein expression. When Wnt5a protein expression was added to a Cox regression multivariate analysis, both Wnt5a protein expression and surgical margin status independently predict biochemical free survival. Herein we confirm Wnt5a positivity as a prognostic factor and show that preserved overexpression of Wnt5a protein is associated with increased time to biochemical recurrence in localized low-grade prostate cancer patients after radical prostatectomy. Our results emphasize that Wnt5a can be used as a predictive biomarker, and favoring the view of Wnt5a as a future therapeutic target in prostate cancer patients with tumor cells displaying low expression of Wnt5a. PMID- 23342261 TI - Heterogeneity of breast cancer stem cells as evidenced with Notch-dependent and Notch-independent populations. AB - Studies have suggested the potential importance of Notch signaling to the cancer stem cell population in some tumors, but it is not known whether all cells in the cancer stem cell fraction require Notch activity. To address this issue, we blocked Notch activity in MCF-7 cells by expressing a dominant-negative MAML-GFP (dnMAML) construct, which inhibits signaling through all Notch receptors, and quantified the effect on tumor-initiating activity. Inhibition of Notch signaling reduced primary tumor sphere formation and side population. Functional quantification of tumor-initiating cell numbers in vivo showed a significant decrease, but not a complete abrogation, of these cells in dnMAML-expressing cells. Interestingly, when assessed in secondary assays in vitro or in vivo, there was no difference in tumor-initiating activity between the dnMAML expressing cells and control cells. The fact that a subpopulation of dnMAML expressing cells was capable of forming primary and secondary tumors indicates that there are Notch-independent tumor-initiating cells in the breast cancer cell line MCF-7. Our findings thus provide direct evidence for a heterogeneous cancer stem cell pool, which will require combination therapies against multiple oncogenic pathways to eliminate the tumor-initiating cell population. PMID- 23342262 TI - EGFR targeting monoclonal antibody combines with an mTOR inhibitor and potentiates tumor inhibition by acting on complementary signaling hubs. AB - Nimotuzumab, an anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, has been used extensively in many solid tumors and confers significant survival advantage. The antibody has limited skin toxicity and is generally well tolerated. Similar to other anti-EGFR therapies, patients may relapse a few months after treatment. In this study we show for the first time, the use of Nimotuzumab along with Sirolimus has synergistic effect on tumor inhibition as compared with the drugs used individually, in Nimotuzumab responsive and nonresponsive cell lines. In vitro studies prove that while Sirolimus (25 nmol/L) affects the signal downstream to mammalian target of rapamycin (mTOR), Nimotuzumab (83 nmol/L) downregulates pTYR, pMAPK and pSTAT3 by 40%, 20% and 30%, respectively. The combination, targeting these two different signaling hubs, may be associated with the synergistic inhibition observed. In vivo, the use of half human therapeutic equivalent doses for both the drugs substantially reduces tumors established in nude as well as severe combined immunodeficiency (SCID) mice by EGFR overexpressing A-431 cells. The drug combination reduces cell proliferation and the expression of signal transduction molecules. Treated tumors are better differentiated as compared with those established in the control mice. Tumor microarray demonstrates that Nimotuzumab and the combination groups segregate independently to the Sirolimus and the control treatment. The combination uniquely downregulated 55% of the altered tumor genes, extending beyond the typical pathways associated with Nimotuzumab and Sirolimus downstream pathways inhibition. These results would suggest that this nontoxic drug combination improves therapeutic benefit even in patients with low-EGFR expression and severely immunocompromised because of their current medication. PMID- 23342263 TI - Molecular crosstalk between cancer cells and tumor microenvironment components suggests potential targets for new therapeutic approaches in mobile tongue cancer. AB - We characterized tumor microenvironment (TME) components of mobile tongue (MT) cancer patients in terms of overall inflammatory infiltrate, focusing on the protumorigenic/anti-inflammatory phenotypes and on cancer-associated fibroblasts (CAFs) in order to determine their interrelations and associations with clinical outcomes. In addition, by culturing tongue carcinoma cells (HSC-3) on a three dimensional myoma organotypic model that mimics TME, we attempted to investigate the possible existence of a molecular crosstalk between cancer cells and TME components. Analysis of 64 cases of MT cancer patients revealed that the overall density of the inflammatory infiltrate was inversely correlated to the density of CAFs (P = 0.01), but that the cumulative density of the protumorigenic/anti inflammatory phenotypes, including regulatory T cells (Tregs, Foxp3+), tumor associated macrophages (TAM2, CD163+), and potentially Tregs-inducing immune cells (CD80+), was directly correlated with the density of CAFs (P = 0.01). The hazard ratio (HR) for recurrence in a TME rich in CD163+ Foxp3+ CD80+ was 2.9 (95% CI 1.03-8.6, P = 0.043 compared with low in CD163+ Foxp3+ CD80+). The HR for recurrence in a TME rich in CAFs was 4.1 (95% confidence interval [CI] 1.3-12.8, P = 0.012 compared with low in CAFs). In vitro studies showed cancer-derived exosomes, epithelial-mesenchymal transition process, fibroblast-to-CAF-like cell transdifferentiation, and reciprocal interrelations between different cytokines suggesting the presence of molecular crosstalk between cancer cells and TME components. Collectively, these results highlighted the emerging need of new therapies targeting this crosstalk between the cancer cells and TME components in MT cancer. PMID- 23342264 TI - MicroRNA-142 is mutated in about 20% of diffuse large B-cell lymphoma. AB - MicroRNAs (miRNAs) are short 18-23 nucleotide long noncoding RNAs that posttranscriptionally regulate gene expression by binding to mRNA. Our previous miRNA profiling of diffuse large B-cell lymphoma (DLBCL) revealed a mutation in the seed sequence of miR-142-3p. Further analysis now showed that miR-142 was mutated in 11 (19.64%) of the 56 DLBCL cases. Of these, one case had a mutation in both alleles, with the remainder being heterozygous. Four mutations were found in the mature miR-142-5p, four in the mature miR-142-3p, and three mutations affected the miR-142 precursor. Two mutations in the seed sequence redirected miR 142-3p to the mRNA of the transcriptional repressor ZEB2 and one of them also targeted the ZEB1 mRNA. However, the other mutations in the mature miR-142-3p did not influence either the ZEB1 or ZEB2 3' untranslated region (3' UTR). On the other hand, the mutations affecting the seed sequence of miR-142-3p resulted in a loss of responsiveness in the 3' UTR of the known miR-142-3p targets RAC1 and ADCY9. In contrast to the mouse p300 gene, the human p300 gene was not found to be a target for miR-142-5p. In one case with a mutation of the precursor, we observed aberrant processing of the miR-142-5p. Our data suggest that the mutations in miR-142 probably lead to a loss rather than a gain of function. This is the first report describing mutations of a miRNA gene in a large percentage of a distinct lymphoma subtype. PMID- 23342265 TI - Significance of lymphovascular space invasion in epithelial ovarian cancer. AB - While the prognostic significance of lymphovascular space invasion (LVSI) is well established in endometrial and cervical cancer, its role in ovarian cancer is not fully understood. First, a training cohort was conducted to explore whether the presence and quantity of LVSI within the ovarian tumor correlated with nodal metastasis and survival (n = 127). Next, the results of the training cohort were applied to a different study population (validation cohort, n = 93). In both cohorts, histopathology slides of epithelial ovarian cancer cases that underwent primary cytoreductive surgery including pelvic and/or aortic lymphadenectomy were examined. In a post hoc analysis, the significance of LVSI was evaluated in apparent stage I cases (n = 53). In the training cohort, the majority of patients had advanced-stage disease (82.7%). LVSI was observed in 79.5% of cases, and nodal metastasis was the strongest variable associated with the presence of LVSI (odds ratio [OR]: 7.99, 95% confidence interval [CI]: 1.98-32.1, P = 0.003) in multivariate analysis. The presence of LVSI correlated with a worsened progression-free survival on multivariate analysis (hazard ratio [HR]: 2.06, 95% CI: 1.01-4.24, P = 0.048). The significance of the presence of LVSI was reproduced in the validation cohort (majority, early stage 61.3%). In apparent stage I cases, the presence of LVSI was associated with a high negative predictive value for nodal metastasis (100%, likelihood ratio, P = 0.034) and with worsened progression-free survival (HR: 5.16, 95% CI: 1.00-26.6, P = 0.028). The presence of LVSI is an independent predictive indicator of nodal metastasis and is associated with worse clinical outcome of patients with epithelial ovarian cancer. PMID- 23342266 TI - Coordinate regulation between expression levels of telomere-binding proteins and telomere length in breast carcinomas. AB - Telomere dysregulation occurs in both the in situ and invasive stages of many carcinomas, including breast. Knockout experiments have identified several telomere-associated proteins required for proper telomere function and maintenance, including telomere repeat-binding factor 1 and 2 (TRF1 and TRF2), protection of telomeres (POT1), and TRF1-interacting nuclear factor 2 (TIN2). Using telomere content assays and quantitative reverse transcription-polymerase chain reaction (RT-PCR), we examined the relationship between telomere length and the mRNA levels of telomere-associated proteins in breast tumors. The levels of TRF2, TRF1, TIN2, and POT1 mRNA, but not telomerase reverse transcriptase (TERT) RNA, are inversely correlated with telomere content in breast tumors. Significant associations were identified between the mRNA levels of TRF1, TIN2, and POT1; however, there were no significant associations with the mRNA levels of TRF2 or TERT. These associations suggest that a complex transcriptional program coordinately regulates the expression of these mRNAs. We examined the promoter regions of the telomere-associated proteins to identify transcription factors consistent with the observed patterns of presumed coordinate expression. We demonstrated in human breast cancer cell lines that expressions of TRF1, TIN2, and POT1 are upregulated by dexamethasone, suggesting activation of the glucocorticoid receptor, whereas TERT, TRF2, TRF1, TIN2, and POT1 are upregulated by tumor necrosis factor-alpha (TNF-alpha), suggesting activation of the nuclear factor kappa B transcription factor. These findings link telomere content in breast tumors to the coordinate expression of several telomere-associated proteins previously shown to be negative regulators of telomere length in cell lines. The results further suggest a possible link between the expressions of the telomere-associated proteins and mediators of stress and inflammation.Telomere content assays and quantitative RT-PCR demonstrate that the levels of TRF2, TRF1, TIN2, and POT1 mRNA, but not telomerase reverse transcriptase (TERT) RNA, are inversely correlated with telomere content in breast tumors. Within human breast cancer cell lines, expressions of TRF1, TIN2, and POT1 are upregulated by dexamethasone, suggesting activation of the glucocorticoid receptor, whereas TERT, TRF2, TRF1, TIN2, and POT1 are upregulated by TNF-alpha, suggesting activation of the NFkappaB transcription factor. These findings link telomere content in breast tumors to the expression of several telomere-associated proteins previously shown to be negative regulators of telomere length in cell lines and suggest a link between the expressions of the telomere-associated proteins and mediators of stress and inflammation. PMID- 23342267 TI - Epigenetic inactivation of inhibitor of differentiation 4 (Id4) correlates with prostate cancer. AB - The inhibitor of DNA-binding (Id) proteins, Id1-4 are negative regulators of basic helix-loop-helix (bHLH) transcription factors. As key regulators of cell cycle and differentiation, expression of Id proteins are increasingly observed in many cancers and associated with aggressiveness of the disease. Of all the four Id proteins, the expression of Id1, Id2, and to a lesser extent, Id3 in prostate cancer and the underlying molecular mechanism is relatively well known. On the contrary, our previous results demonstrated that Id4 acts as a potential tumor suppressor in prostate cancer. In the present study, we extend these observations and demonstrate that Id4 is down-regulated in prostate cancer due to promoter hypermethylation. We used prostate cancer tissue microarrays to investigate Id4 expression. Methylation specific PCR on bisulfite treated DNA was used to determine methylation status of Id4 promoter in laser capture micro-dissected normal, stroma and prostate cancer regions. High Id4 expression was observed in the normal prostate epithelial cells. In prostate cancer, a stage-dependent decrease in Id4 expression was observed with majority of high grade cancers showing no Id4 expression. Furthermore, Id4 expression progressively decreased in prostate cancer cell line LNCaP and with no expression in androgen-insensitive LNCaP-C81 cell line. Conversely, Id4 promoter hypermethylation increased in LNCaP C81 cells suggesting epigenetic silencing. In prostate cancer samples, loss of Id4 expression was also associated with promoter hypermethylation. Our results demonstrate loss of Id4 expression in prostate cancer due to promoter hypermethylation. The data strongly support the role of Id4 as a tumor suppressor. PMID- 23342268 TI - Id1 and Id3 expression is associated with increasing grade of prostate cancer: Id3 preferentially regulates CDKN1B. AB - As transcriptional regulators of basic helix-oop-helix (bHLH) transcription and non-bHLH factors, the inhibitor of differentiation (Id1, Id2, Id3, and Id4) proteins play a critical role in coordinated regulation of cell growth, differentiation, tumorigenesis, and angiogenesis. Id1 regulates prostate cancer (PCa) cell proliferation, apoptosis, and androgen independence, but its clinical significance in PCa remains controversial. Moreover, there is lack of evidence on the expression of Id2 and Id3 in PCa progression. In this study we investigated the expression of Id2 and Id3 and reevaluated the expression of Id1 in PCa. We show that increased Id1 and Id3 protein expression is strongly associated with increasing grade of PCa. At the molecular level, we report that silencing either Id1 or Id3 attenuates cell cycle. Although structurally and mechanistically similar, our results show that both these proteins are noncompensatory at least in PCa progression. Moreover, through gene silencing approaches we show that Id1 and Id3 primarily attenuates CDKN1A (p21) and CDKN1B (p27), respectively. We also demonstrate that silencing Id3 alone significantly attenuates proliferation of PCa cells as compared with Id1. We propose that increased Id1 and Id3 expression attenuates all three cyclin-dependent kinase inhibitors (CDKN2B, -1A, and -1B) resulting in a more aggressive PCa phenotype. PMID- 23342269 TI - Analysis of neurosensory adverse events induced by FOLFOX4 treatment in colorectal cancer patients: a comparison between two Asian studies and four Western studies. AB - The grades of neurosensory adverse events (NSAEs) induced by FOLFOX4 treatment were compared between Asian and Western colorectal cancer patients and correlated with cumulative oxaliplatin doses. A total of 3359 patients treated with FOLFOX4 were analyzed: 1515 from two Asian studies (Japanese Post Marketing Surveillance [J-PMS] and MASCOT) and 1844 from four Western studies (EFC2962, N9741, EFC4584, and MOSAIC). The onset of NSAEs was analyzed in terms of treatment duration and cumulative dose of oxaliplatin. The incidence of grade >=3 NSAEs ranged from 2.0% to 4.4% in Asian studies and 9.3% to 19% in Western studies. The cumulative doses of oxaliplatin that induced grade >=3 NSAEs in 10% of patients were higher in Asian studies (1526 mg/m(2) or not reached) than in Western studies (805-832 mg/m(2)). No significant correlations were noted between occurrence of grade >=3 NSAEs and demographic/baseline characteristics. The frequency of escalation from grade 0 to 1 in J-PMS was statistically significantly lower than that in EFC4584, and that from grade 0 to 1 and from grade 1 to 2 in MASCOT lower than that in MOSAIC. The cumulative oxaliplatin doses administered during grade escalation in J-PMS were similar to those in EFC2962 or EFC4584. All grade-3 NSAEs in MASCOT and 96% of those in MOSAIC improved to grade 2 or less within 12 months of follow up. The Asian populations accrued to these studies appear to be less susceptible to the neurotoxicity of oxaliplatin than the mainly Caucasian populations in the Western studies. PMID- 23342271 TI - Expression of RET finger protein predicts chemoresistance in epithelial ovarian cancer. AB - Resistance to platinum- and taxane-based chemotherapy is a major cause of treatment failure in ovarian cancer. Thus, it is necessary to develop a predictive marker and molecular target for overcoming drug resistance in ovarian cancer treatment. In a previous report, using an in vitro model, we found that the RET finger protein (RFP) (also known as tripartite motif-containing protein 27, TRIM27) confers cancer cell resistance to anticancer drugs. However, the significance of RFP expression in cancer patients remains elusive. In this study, we showed that RFP was expressed in 62% of ovarian cancer patients and its positivity significantly correlated with drug resistance. Consistent with clinical data, depletion of RFP by RNA interference (RNAi) in ovarian cancer cell lines, SKOV3 and HEY, significantly increased carboplatin- or paclitaxel-induced apoptosis and resulted in reduced anticancer drug resistance. In a nude mouse tumor xenograft model, inoculated RFP-knockdown ovarian cancer cells exhibited lower carboplatin resistance than control cells. These findings suggest that RFP could be a predictive marker for chemoresistance in ovarian cancer patients and also a candidate for a molecular-targeted agent. PMID- 23342270 TI - Biomarker-driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer. AB - Src tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP-sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6-month survival. A Simon MinMax two-stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28-day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6-month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker-driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin-like growth factor-binding protein 2 [IGFBP2] "top scoring pairs" polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker-positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3' untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6-month survival endpoint. As the frequency of biomarker-positive patients was very low (<3%), the study was closed. Although we were unable to conclude whether enriching for a subset of second/third line pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6-month survival, we demonstrate that testing pancreatic tumor samples for a biomarker-driven, multicenter study in metastatic pancreas cancer is feasible. PMID- 23342272 TI - 18-FDG PET/CT assessment of basal cell carcinoma with vismodegib. AB - The use of 18-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET/CT) in subjects with advanced basal cell carcinoma (BCC) has not been fully explored due to the rarity of disease presentation. This study evaluated PET/CTs from subjects with advanced BCC participating in a phase I dose escalation clinical trial of vismodegib. Fourteen subjects with BCC were imaged with 18-FDG PET/CT for lesion identification and response categorizing (European Organisation for Research and Treatment for Cancer [EORTC] and PET response criteria in solid tumors [PERCIST] 1.0). Several parameters including metabolic activity of target lesions, site of disease presentation and spread, treatment response, and prognostic significance of metabolic activity following therapy were evaluated. All subjects exhibited at least one hypermetabolic lesion. Most subjects had only four organ systems involved at study enrollment: skin-muscle (93%), lung (57%), lymph nodes (29%), and bone (21%). SUVmax measured across all lesions decreased (median 33%, SD +/- 45%) following therapy with metabolic activity normalizing or disappearing in 42% of lesions. No significant difference was observed between EORTC and PERCIST 1.0. Subjects that demonstrated at least a 33% reduction in SUVmax from baseline had a significantly longer progression-free survival (PFS) (median 17 months, 95% confidence interval [CI] +/-4 months vs. 9 months, 95% CI +/-5 months, P = 0.038) and overall survival (OS) (median 24 months, 95% CI +/-4 months vs. 17 months, 95% CI +/-13 months, P = 0.019). BCC lesions are hypermetabolic on 18-FDG PET/CT. A decrease in SUVmax was associated with improved PFS and OS. These results further support the incorporation of 18 FDG PET/CT scans in advanced BCC management. PMID- 23342274 TI - Soluble endothelial protein C receptor (sEPCR) is likely a biomarker of cancer associated hypercoagulability in human hematologic malignancies. AB - Elevated plasma level of soluble endothelial protein C receptor (sEPCR) may be an indicator of thrombotic risk. The present study aims to correlate leukemia associated hypercoagulability to high level plasma sEPCR and proposes its measurement in routine clinical practice. EPCR expressions in leukemic cell lines were determined by flow cytometry, immunocytochemistry, and reverse transcription polymerase chain reaction (RT-PCR). EPCR gene sequence of a candidate cell line HL-60 was also determined. Plasma samples (n = 76) and bone marrow aspirates (n = 72) from 148 patients with hematologic malignancies and 101 healthy volunteers were analyzed by enzyme-linked immunosorbent assay (ELISA) via a retrospective study for sEPCR and D-dimer. All leukemic cell lines were found to express EPCR. Also, HL-60 EPCR gene sequence showed extensive similarities with the endothelial reference gene. All single nucleotide polymorphisms (SNPs) originally described and some new SNPs were revealed in the promoter and intronic regions. Among these patients 67% had plasma sEPCR level higher than the controls (100 +/- 28 ng/mL), wherein 16.3% patients had experienced a previous thrombotic event. These patients were divided into: group-1 (n = 45) with amount of plasmatic sEPCR below 100 ng/mL, group-2 (n = 45) where the concentration of sEPCR was between 100 and 200, and group-3 (n = 20) higher than 200 ng/mL. The numbers of thrombotic incidence recorded in each group were four, six, and eight, respectively. These results reveal that EPCR is expressed not only by a wide range of human malignant hematological cells but also the detection of plasma sEPCR levels provides a powerful insight into thrombotic risk assessment in cancer patients, especially when it surpasses 200 ng/mL. PMID- 23342273 TI - Strategies for discovery and validation of methylated and hydroxymethylated DNA biomarkers. AB - DNA methylation, consisting of the addition of a methyl group at the fifth position of cytosine in a CpG dinucleotide, is one of the most well-studied epigenetic mechanisms in mammals with important functions in normal and disease biology. Disease-specific aberrant DNA methylation is a well-recognized hallmark of many complex diseases. Accordingly, various studies have focused on characterizing unique DNA methylation marks associated with distinct stages of disease development as they may serve as useful biomarkers for diagnosis, prognosis, prediction of response to therapy, or disease monitoring. Recently, novel CpG dinucleotide modifications with potential regulatory roles such as 5 hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine have been described. These potential epigenetic marks cannot be distinguished from 5 methylcytosine by many current strategies and may potentially compromise assessment and interpretation of methylation data. A large number of strategies have been described for the discovery and validation of DNA methylation-based biomarkers, each with its own advantages and limitations. These strategies can be classified into three main categories: restriction enzyme digestion, affinity based analysis, and bisulfite modification. In general, candidate biomarkers are discovered using large-scale, genome-wide, methylation sequencing, and/or microarray-based profiling strategies. Following discovery, biomarker performance is validated in large independent cohorts using highly targeted locus-specific assays. There are still many challenges to the effective implementation of DNA methylation-based biomarkers. Emerging innovative methylation and hydroxymethylation detection strategies are focused on addressing these gaps in the field of epigenetics. The development of DNA methylation- and hydroxymethylation-based biomarkers is an exciting and rapidly evolving area of research that holds promise for potential applications in diverse clinical settings. PMID- 23342275 TI - Differential expression of miRNAs in the serum of patients with high-risk oral lesions. AB - Oral cancer is one of the most commonly diagnosed cancers worldwide. Disease is often diagnosed at later stages, which is associated with a poor 5-year survival rate and a high rate of local recurrence. MicroRNAs (miRNAs), a group of small, noncoding RNAs, can be isolated from blood serum samples and have demonstrated utility as biomarkers in multiple cancer types. The aim of this study was to examine the expression profiles of circulating miRNAs in the serum of patients with high-risk oral lesions (HRLs; oral cancer or carcinoma in situ) and to explore their utility as potential oral cancer biomarkers. Global serum miRNA profiles were generated using quantitative PCR method from 1) patients diagnosed with HRLs and undergoing intent-to-cure surgical treatment (N = 30) and 2) a demographically matched, noncancer control group (N = 26). We next honed our list of serum miRNAs associated with disease by reducing the effects of interpatient variability; we compared serum miRNA profiles from samples taken both before and after tumor resections (N = 10). Based on these analyses, fifteen miRNAs were significantly upregulated and five were significantly downregulated based on presence of disease (minimum fold-change >2 in at least 50% of samples, P < 0.05, permutation). Five of these miRNAs (miR-16, let-7b, miR-338-3p, miR-223, and miR 29a) yielded an area under the ROC curve (AUC) >0.8, suggesting utility as noninvasive biomarkers for detection of oral cancer or high-grade lesions. Combining these serum miRNA profiles with other screening techniques could greatly improve the sensitivity in oral cancer detection. PMID- 23342276 TI - Dose-dependent effects of calorie restriction on gene expression, metabolism, and tumor progression are partially mediated by insulin-like growth factor-1. AB - The prevalence of obesity, an established risk and progression factor for breast and many other cancer types, remains very high in the United States and throughout the world. Calorie restriction (CR), a reduced-calorie dietary regimen typically involving a 20-40% reduction in calorie consumption, prevents or reverses obesity, and inhibits mammary and other types of cancer in multiple tumor model systems. Unfortunately, the mechanisms underlying the tumor inhibitory effects of CR are poorly understood, and a better understanding of these mechanisms may lead to new intervention targets and strategies for preventing or controlling cancer. We have previously shown that the anticancer effects of CR are associated with decreased systemic levels of insulin-like growth factor-1 (IGF-1), the primary source of which is liver. We have also reported that CR strongly suppresses tumor development and growth in multiple mammary cancer models. To identify CR-responsive genes and pathways, and to further characterize the role of IGF-1 as a mediator of the anticancer effects of CR, we assessed hepatic and mammary gland gene expression, hormone levels and growth of orthotopically transplanted mammary tumors in control and CR mice with and without exogenous IGF-1. C57BL/6 mice were fed either control AIN-76A diet ad libitum (AL), subjected to 20%, 30%, or 40% CR plus placebo timed-release pellets, or subjected to 30% or 40% CR plus timed-release pellets delivering murine IGF-1 (mIGF-1, 20 MUg/day). Compared with AL-fed controls, body weights were decreased 14.3% in the 20% CR group, 18.5% in the 30% CR group, and 38% in the 40% CR group; IGF-1 infusion had no effect on body weight. Hepatic transcriptome analyses indicated that compared with 20% CR, 30% CR significantly modulated more than twice the number of genes and 40% CR more than seven times the number of genes. Many of the genes specific to the 40% CR regimen were hepatic stress-related and/or DNA damage-related genes. Exogenous IGF-1 rescued the hepatic expression of several metabolic genes and pathways affected by CR. Exogenous IGF-1 also rescued the expression of several metabolism- and cancer related genes affected by CR in the mammary gland. Furthermore, exogenous IGF-1 partially reversed the mammary tumor inhibitory effects of 30% CR. We conclude that several genes and pathways, particularly those associated with macronutrient and steroid hormone metabolism, are associated with the anticancer effects of CR, and that reduced IGF-1 levels can account, at least in part, for many of the effects of CR on gene expression and mammary tumor burden. PMID- 23342278 TI - Identification of multiple subclones in peripheral T-cell lymphoma, not otherwise specified with genomic aberrations. AB - Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) with genomic aberrations has been shown to resemble lymphoma-type adult T-cell leukemia/lymphoma (ATLL) in terms of its genomic aberration patterns, histopathology, and prognosis. We have shown recently that a majority of patients with acute-type ATLL have multiple subclones that were likely produced in lymph nodes. In this study, we analyzed whether PTCL, NOS with genomic aberrations also has multiple subclones as found in ATLL by means of high-resolution oligo-array comparative genomic hybridization (CGH). Thirteen cases of PTCL, NOS were available for 44K high-resolution array CGH analysis. The results showed that 11 (84.6%) of the 13 cases had a log2 ratio imbalance, suggesting that multiple subclones exist in PTCL, NOS with genomic aberrations. In order to analyze the association between multiple subclones and prognosis, we used previous bacterial artificial chromosome (BAC) array analyses for 29 cases and found that the existence of multiple subclones was associated with a poor prognosis (P = 0.0279). PMID- 23342279 TI - Nisin, an apoptogenic bacteriocin and food preservative, attenuates HNSCC tumorigenesis via CHAC1. AB - Nisin, a bacteriocin and commonly used food preservative, may serve as a novel potential therapeutic for treating head and neck squamous cell carcinoma (HNSCC), as it induces preferential apoptosis, cell cycle arrest, and reduces cell proliferation in HNSCC cells, compared with primary keratinocytes. Nisin also reduces HNSCC tumorigenesis in vivo. Mechanistically, nisin exerts these effects on HNSCC, in part, through CHAC1, a proapoptotic cation transport regulator, and through a concomitant CHAC1-independent influx of extracellular calcium. In addition, although CHAC1 is known as an apoptotic mediator, its effects on cancer cell apoptosis have not been examined. Our studies are the first to report CHAC1's new role in promoting cancer cell apoptosis under nisin treatment. These data support the concept that nisin decreases HNSCC tumorigenesis in vitro and in vivo by inducing increased cell apoptosis and decreased cell proliferation; effects that are mediated by activation of CHAC1, increased calcium influxes, and induction of cell cycle arrest. These findings support the use of nisin as a potentially novel therapeutic for HNSCC, and as nisin is safe for human consumption and currently used in food preservation, its translation into a clinical setting may be facilitated. PMID- 23342280 TI - Modulation of CXCL-8 expression in human melanoma cells regulates tumor growth, angiogenesis, invasion, and metastasis. AB - CXCL-8, a chemokine secreted by melanoma and stromal cells, serves as a growth and angiogenic factor for melanoma progression. This study evaluated how modulation of CXCL-8 levels in melanoma cell lines with different tumorigenic and metastatic potentials affected multiple tumor phenotypes. A375P cells (CXCL-8 low expressor) were stably transfected with a CXCL-8 mammalian expression vector to overexpress CXCL-8, whereas A375SM cells (CXCL-8 high expressor) were transfected with a CXCL-8 antisense expression vector to suppress CXCL-8 expression. Subsequent cell proliferation, migration, invasion, and soft-agar colony formation were analyzed, and in vivo tumor growth and metastasis were evaluated using mouse xenograft models. Our data demonstrate that overexpression of CXCL-8 significantly enhanced primary tumor growth and lung metastasis, accompanied by increased microvessel density in vivo, as compared with vector control transfected cells. We also observed increased clonogenic ability, growth, and invasive potential of CXCL-8 overexpressing cells in vitro. Knockdown of CXCL-8 using an antisense vector resulted in increased cell death and reduced tumor growth relative to control. Taken together, these data confirm that CXCL-8 expression plays a critical role in regulating multiple cellular phenotypes associated with melanoma growth and metastasis. PMID- 23342281 TI - Effectiveness of aromatase inhibitors and tamoxifen in reducing subsequent breast cancer. AB - Tamoxifen (TAM) has been prescribed for decades and aromatase inhibitors (AIs) have been used since the early 2000s in preventing subsequent breast cancer. However, outside of clinical trials, the effectiveness of AIs is not established. We examined the long-term risk of subsequent breast cancer among survivors treated with TAM and AIs in a large health plan. The study included 22,850 survivors, diagnosed with initial breast cancer (stages 0-IV) from 1996 to 2006, and followed 13 years maximum. We compared the risk of subsequent breast cancer in those who used TAM and/or AIs versus nonusers (the reference group). Hazard ratios (HR) adjusted for patient, tumor, treatment, and health-care characteristics were estimated using Cox models with time-dependent drug use status. Women who used TAM/AIs had a large reduction in risk of subsequent breast cancer compared with nonusers. While confidence intervals (CI) for all hormone treatment groups overlapped, women with high adherence (medication possession ratio >=80%) who used AIs exclusively and had positive ER or PR receptor status had the greatest risk reduction (HR = 0.34, 95% CI: 0.28-0.41), followed by those who switched from TAM to AIs (HR = 0.39, 95% CI: 0.30-0.49), and those who used TAM exclusively (HR = 0.42, 95% CI: 0.36-0.47). Women with high adherence had the greatest risk reduction in subsequent breast cancer, but the results were not substantially different from women who took the drugs less regularly. Compared with nonusers, the reduction in subsequent breast cancer risk ranged from 58% to 66% across the hormone treatment groups and degree of adherence. PMID- 23342282 TI - Individual transcriptional activity of estrogen receptors in primary breast cancer and its clinical significance. AB - To predict the efficacy of hormonal therapy at the individual-level, immunohistochemical methods are used to analyze expression of classical molecular biomarkers such as estrogen receptor (ER), progesterone receptor (PgR), and HER2. However, the current diagnostic standard is not perfect for the individualization of diverse cases. Therefore, establishment of more accurate diagnostics is required. Previously, we established a novel method that enables analysis of ER transcriptional activation potential in clinical specimens using an adenovirus estrogen response element-green fluorescence protein (ERE-GFP) assay system. Using this assay, we assessed the ERE transcriptional activity of 62 primary breast cancer samples. In 40% of samples, we observed that ER protein expression was not consistent with ERE activity. Comparison of ERE activity with clinicopathological information revealed that ERE activity was significantly correlated with the ER target gene, PgR, rather than ER in terms of both protein and mRNA expression. Moreover, subgrouping of Luminal A-type breast cancer samples according to ERE activity revealed that ERalpha mRNA expression correlated with ER target gene mRNA expression in the high-, but not the low-, ERE-activity group. On the other hand, the low-ERE-activity group showed significantly higher mRNA expression of the malignancy biomarker Ki67 in association with disease recurrence in 5% of patients. Thus, these data suggest that ER expression does not always correlate with ER transcriptional activity. Therefore, in addition to ER protein expression, determination of ERE activity as an ER functional marker will be helpful for analysis of a variety of diverse breast cancer cases and the subsequent course of treatment. PMID- 23342283 TI - Considerations in setting up and conducting epidemiologic studies of cancer in middle- and low-income countries: the experience of a case-control study of inflammatory breast cancer in North Africa in the past 10 years. AB - This article illustrates some issues we faced during our experience in conducting an epidemiologic case-control study of inflammatory breast cancer in North Africa. We expect that some of the questions we had to ask in order to address these issues might be helpful to others in setting up epidemiologic studies in developing regions. We describe our experience from different angles including the use of multiple sites to achieve adequate sample size, standardizing diagnosis of disease, identifying cancer cases at the time of diagnosis, control selection procedures, logistics of study implementation, questionnaire development and interviewing, biologic specimens, and procedures for protection of human subjects. We have developed a brief checklist to summarize important issues for conducting future epidemiologic studies in these or similar low- or middle-income countries. PMID- 23342284 TI - Urban-rural disparities in colorectal cancer screening: cross-sectional analysis of 1998-2005 data from the Centers for Disease Control's Behavioral Risk Factor Surveillance Study. AB - Despite the existence of effective screening, colorectal cancer remains the second leading cause of cancer death in the United States. Identification of disparities in colorectal cancer screening will allow for targeted interventions to achieve national goals for screening. The objective of this study was to contrast colorectal cancer screening rates in urban and rural populations in the United States. The study design comprised a cross-sectional study in the United States 1998-2005. Behavioral Risk Factor Surveillance System data from 1998 to 2005 were the method and data source. The primary outcome was self-report up-to date colorectal cancer screening (fecal occult blood test in last 12 months, flexible sigmoidoscopy in last 5 years, or colonoscopy in last 10 years). Geographic location (urban vs. rural) was used as independent variable. Multivariate analysis controlled for demographic and health characteristics of respondents. After adjustment for demographic and health characteristics, rural residents had lower colorectal cancer screening rates (48%; 95% CI 48, 49%) as compared with urban residents (54%, 95% CI 53, 55%). Remote rural residents had the lowest screening rates overall (45%, 95% CI 43, 46%). From 1998 to 2005, rates of screening by colonoscopy or flexible sigmoidoscopy increased in both urban and rural populations. During the same time, rates of screening by fecal occult blood test decreased in urban populations and increased in rural populations. Persistent disparities in colorectal cancer screening affect rural populations. The types of screening tests used for colorectal cancer screening are different in rural and urban areas. Future research to reduce this disparity should focus on screening methods that are acceptable and feasible in rural areas. PMID- 23342285 TI - Association of diabetes and perineural invasion in pancreatic cancer. AB - Diabetes and perineural invasion are frequently observed in pancreatic cancer. In this study, we tested possible relations between diabetes and perineural invasion in patients with resected pancreatic cancer. We conducted a retrospective study in 544 cases of resected pancreatic adenocarcinoma seen at the University of Texas MD Anderson Cancer Center during 1996-2011. Information on tumor characteristics, diabetes history, and survival time was collected by personal interview and medical record review. Patients with diabetes before or at the time of the pancreatic cancer diagnosis were considered diabetes only. Pearson chi(2) test was used to compare categorical variables in diabetic and nondiabetic groups. Kaplan-Meier plot, log-rank test, and Cox proportional regression models were applied in survival analysis. The prevalence of diabetes and perineural invasion was 26.5% and 86.9%, respectively, in this study population. Patients with diabetes had a significantly higher prevalence of perineural invasion (92.4%) than those without diabetes (85%) (P = 0.025, chi(2) test). Diabetes was not associated with other pathological characteristics of the tumor, such as tumor size, lymphovascular invasion, tumor grade, lymph node metastasis, and resection margin status. Diabetic patients had a significantly lower frequency of abdominal pain (P = 0.01), but a slightly higher frequency of weight loss (P = 0.078) as early symptoms of their cancer. Both diabetes and perineural invasion were related to worse survival and increased risk of death after adjusting for tumor grade and margin and node status (P = 0.036 and 0.019, respectively). The observed associations of diabetes and perineural invasion as well as reduced frequency of pain as early symptom of pancreatic cancer support the hypothesis that diabetes may contribute to pancreatic progression via the mechanism of nerve damage. PMID- 23342286 TI - Measuring colorectal cancer care quality for the publicly insured in New York State. AB - The extent to which concordance with colorectal cancer treatment quality metrics varies by patient characteristics in the publicly insured is not well understood. Our objective was to evaluate the quality of colorectal cancer care for publicly insured residents of New York State (NYS). NYS cancer registry data were linked to Medicaid and Medicare claims and hospital discharge data. We identified colorectal cancer cases diagnosed from 2004 through 2006 and evaluated three treatment quality measures: adjuvant chemotherapy within 4 months of diagnosis for American Joint Cancer Committee (AJCC) stage III colon cancer, adjuvant radiation within 6 months of diagnosis for AJCC stage IIB or III rectal cancer, and adjuvant chemotherapy within 9 months of diagnosis for AJCC stage II-III rectal cancer. Concordance with guidelines was evaluated separately for Medicaid enrollees under age 65 years and Medicare-enrollees aged 65-79 years. For adjuvant chemotherapy for colon cancer, 79.4% (274/345) of the Medicaid cohort and 71.8% (585/815) of the Medicare cohort were guideline concordant. For adjuvant radiation for rectal cancer, 72.3% (125/173) of the Medicaid cohort and 66.9% (206/308) of the Medicare cohort were concordant. For adjuvant chemotherapy for rectal cancer, 89.5% (238/266) of the Medicaid cohort and 76.0% (392/516) of the Medicare cohort were concordant. Younger age was associated with higher adjusted odds of concordance for all three measures in the Medicare cohort. Racial differences were not evident in either cohort. There is room for improvement in concordance with accepted metrics of cancer care quality. Feedback about performance may assist in targeting efforts to improve care. PMID- 23342289 TI - Relationships between IL-17A and macrophages or MUC5AC in eosinophilic chronic rhinosinusitis and proposed pathological significance. AB - Recently, some researchers have reported that macrophages and neutrophils were related to severe asthma. Mucus hypersecretion and persistent airway inflammation result from increased expression of mucin gene (MUC5AC). Eosinophilic chronic rhinosinusitis (ECRS) is considered as intractable rhinosinusitis. From the viewpoint of "one way one disease," we examined whether ECRS is associated with infiltrating macrophages, neutrophils, their promotive factors, and MUC5AC. We examined 21 nasal polyps with CRS. Each specimen was fixed in 10% phosphate buffered formalin, embedded in paraffin, processed routinely, and then prepared as semithin sections (3.5 MUm). We immunohistochemically observed the macrophages by using CD68, neutrophils by using neutrophil elastase and the promotive factors, monocyte chemotactic protein (MCP) 1, IL-17A, and IL-8, in both ECRS and non-ECRS. The number of macrophages (CD68(+) cells), IL-17A, and MUC5AC(+) cells in ECRS were significantly greater than in non-ECRS. The mean number of MCP-1(+) cells in ECRS was greater than that in non-ECRS, but not significantly. There was a significant correlation in all cases between IL-17A and macrophages or MUC5AC(+) cells. Neither the numbers of neutrophils (positive cells for neutrophil elastase) nor the IL-8(+) cells showed any significant differences between ECRS and non-ECRS. Our study suggested that infiltrating macrophages, IL 17A and MUC5AC, as well as eosinophils could have roles in the development of ECRS. PMID- 23342288 TI - Idiopathic sclerosing inflammation presenting as sinusitis. AB - Idiopathic sclerosing orbital inflammation is a rare finding that is poorly delineated, immune mediated, and causes severe symptoms and disability. It has been described affecting the orbit in addition to other sites within the head and neck, but has rarely been described presenting as sinusitis. A case report and literature review were performed. A 14-year-old girl with right-sided face and eye pain and pressure for >1 month presented 3 days after endoscopic sinus surgery for presumed acute sinusitis. She subsequently developed ipsilateral vision loss and hypesthesia of the infraorbital nerve. MRI revealed a mildly enhancing soft tissue intensity lesion extending from the right maxillary sinus into the pterygopalatine fossa and orbital apex through the inferior orbital fissure. Biopsy specimens of the lesion were consistent with a sclerosing inflammatory lesion. High-dose steroids led to rapid improvement in vision and pain; however, the patient was unable to tolerate steroid weaning because of recurrence of eye pain and headache. Repeat imaging showed progression of the lesion. Rheumatology was consulted and the patient's steroid therapy was altered and her medications were expanded to include azathioprine. The patient's symptoms improved and subsequent imaging showed a reduction in the size and extent of the lesion. Idiopathic sclerosing inflammation is characterized by primary, chronic, and immunologically mediated fibrosis. Patients typically have a poor response to corticosteroid treatment or radiotherapy. Immunosuppressive therapy in addition to corticosteroids is the recommended treatment. PMID- 23342290 TI - The rate of epinephrine administration associated with allergy skin testing in a suburban allergy practice from 1997 to 2010. AB - Allergy skin testing is considered a safe method for testing for IgE-mediated allergic responses although anaphylactic events can occur. Reported rates of anaphylaxis per patient are not consistent and range from 0.008 to 4%. The aim of this study was to determine the rate of epinephrine use associated with allergy skin-prick testing (SPT) and intradermal testing (IDT) in a suburban practice over 13 years. This retrospective chart review used billing and procedure coding records during the time period from January 1997 to June 2010 to identify encounters where epinephrine was administered after SPT or IDT. Patient encounters with procedure codes for skin testing plus either parenteral epinephrine, corticosteroid, antihistamine, or i.v. fluid administration were identified. These patient charts were reviewed to determine if epinephrine was administered, whether systemic reactions developed, and rates of epinephrine administration were calculated. There were 28,907 patient encounters for SPT and 18,212 for IDT. Epinephrine was administered in six patient encounters (0.02%) where SPT was performed; no IDT encounters led to epinephrine administration. There were no fatalities. Allergy skin testing to a variety of allergens, when administered by well-trained personnel, is a safe procedure. This study, involving the largest population to date, showed a rate of systemic reactions requiring epinephrine of 20 per 100,000 SPT visits. No epinephrine was given after IDT. PMID- 23342291 TI - Measurement of osteotomy force during endoscopic sinus surgery. AB - Greater understanding of the surgeon's task and skills are required to improve surgical technique and the effectiveness of training. Currently, neither the objective measurement of osteotomy forces during endoscopic sinus surgery (ESS) nor the validity of the properties of cadaver materials, are well documented. Measurement was performed of peak axial osteotomy force during ESS. A comparison was made of results with previously published cadaver data to validate the force properties of cadaver models. A prospective, consecutive cohort of 25 patients was compared with data from 15 cadaver heads. A modified Storz sinus curette measured osteotomy force from uncinate, bulla ethmoidalis, and ground lamella. Independent variables were osteotomy site, age, gender, indication for surgery, and side. Corresponding cadaver data were analyzed for the independent variables of osteotomy site, side, and gender and then compared with the live patient data. Mean osteotomy force in live patients was 9.6 N (95% CI, 8.9-10.4 N). Mean osteotomy force in the cadaver heads was 6.4 N (95% CI, 5.7-7.0 N). Ethmoid osteotomy of live patients required 3.2 N (95% CI, 2.1-4.3 N) more force than the cadaver heads (p = 0.0001). This relationship was statistically significant at the bulla ethmoidalis (p = 0.002) and the ground lamella (p = 0.0001) but not at the uncinate (p = 0.068). Osteotomy in female live subjects required 1.6 N (95% CI, 0.1-3.1 N) more force than male live subjects (p = 0.03). Cadaver tissue may underestimate the mean osteotomy force required in osteotomy of living ethmoid sinus lamellae by a factor of 1.5 times. Caution may be required in extrapolating force estimates from cadaver tissue to those required in living patients. PMID- 23342292 TI - Diffusion lung capacity of carbon monoxide: A novel marker of airways remodeling in asthmatic children? AB - Asthma is universally considered a chronic inflammatory disorder of the airways. Several noninvasive markers, such as exhaled nitric oxide (FeNO) and exhaled breath temperature (PletM), have been proposed to evaluate the degree of airway inflammation and remodeling in asthmatic children. The aim of this study was to evaluate the relationship between diffusion lung capacity of carbon monoxide (DLCO) and these inflammatory markers in asthmatic children. We compared data of FeNO, PletM, and DLCO collected in 35 asthmatic children at admission (T0) and discharge (T1) after a period spent in a dust-mite-free environment (Misurina, Italian Dolomites, 1756 m). PletM showed a reduction from 29.48 degrees C at T0 to 29.13 degrees C at T1 (p = 0.17); DLCO passed from 93 to 102 (p = 0.085). FeNO mean value was 29.7 ppb at admission and 18.9 ppb at discharge (p = 0.014). Eosinophil mean count in induced sputum was 4 at T0 and 2 at T1 (p = 0.004). Spearman standardization coefficient beta was 0.414 between eosinophils and FeNO and -0.278 between eosinophils and DLCO. Pearson's correlation index between DLCO and PletM was -0.456 (p = 0.019). A negative correlation between DLCO and PletM was found. However, DLCO did not show a significant correlation with FeNO and eosinophils in the airways. Additional studies are needed to clarify the role of DLCO as a potential tool in monitoring childhood asthma. PMID- 23342294 TI - Cadaveric analysis of nasal valve suspension. AB - This study was designed to measure the efficacy of a nasal valve suspension technique and determine the adequate traction length without creation of nasofacial fullness in a cadaveric model. Seven fresh frozen cadaveric heads were evaluated. Minimal cross-sectional (MCA) areas were measured with a transient signal acoustic rhinometer (Ecco Vision; Hood Instruments, Pembroke, MA) before and after suspension. The adequate traction length, which did not cause obvious changes, was determined. Five millimeters of lateral nasal valve traction was determined to be the maximal traction achievable without creating facial fullness. After lateral nasal suspension, average MCA increased by 13.7%. Average distance to the MCA from the nostril changed from 1.57 to 1.76 cm. Postsuspension values were significantly higher than the presuspension values (p < 0.05). Nasal valve suspension with 5 mm of lateral traction has a significant impact on nasal valve area without obvious nasofacial changes. PMID- 23342293 TI - Group 10 allergens (tropomyosins) from house-dust mites may cause covariation of sensitization to allergens from other invertebrates. AB - Group 10 allergens (tropomyosins) have been assumed to be a major cause of cross reactivity between house-dust mites (HDMs) and other invertebrates. Despite all of the published data regarding the epidemiology, percent IgE binding and level of sensitization in the population, the role of tropomyosin as a cross-reactive allergen in patients with multiple allergy syndrome still remains to be elucidated. Homology between amino acid sequences reported in allergen databases of selected invertebrate tropomyosins was determined with Der f 10 as the reference allergen. The 66.9 and 54.4% identities were found with selected crustacean and insect species, respectively, whereas only 20.4% identity was seen with mollusks. A similar analysis was performed using reported B-cell IgE-binding epitopes from Met e1 (shrimp allergen) and Bla g7 (cockroach allergen) with other invertebrate tropomyosins. The percent identity in linear sequences was higher than 35% in mites, crustaceans, and cockroaches. The polar and hydrophobic regions in these groups were highly conserved. These findings suggest that tropomyosin may be a major cause of covariation of sensitization between HDMs, crustaceans, and some species of insects and mollusks. PMID- 23342295 TI - Signal transducer and activator of transcription 3 mutation with invasive eosinophilic disease. AB - Hyper-IgE syndrome (HIES), or Jobs disease, is a rare immunologic disorder characterized by the triad of staphylococcal abscesses, pneumonia with pneumatocele formation, and elevated IgE. It has been shown to have multiple modes of inheritance, autosomal dominant being more common than autosomal recessive, with sporadic cases as well. A mutation in signal transducer and activator of transcription 3 (STAT3) gene has been linked to the development of the sporadic and dominant forms of HIES. Peripheral eosinophilia, typically greater than two standard deviations from the normal population, is often seen in association with HIES. Despite these elevated levels of blood eosinophils, there have been no reported cases of invasive eosinophilic disease, such as eosonophilic esophagitic. Here we report the first description, to our knowledge, of a patient with HIES with a STAT3 mutation involving exon 12, Thr389Ile, and invasive eosinophilic disease of the esophagus. STAT3 modulates the expression of several genes that control central cell processes such as growth and death in response to external soluble stimuli. A mutation in the STAT3 molecule may affect the eosinophil's response to IL-5 and thus reduce the chemotaxic ability of those cells to migrate into tissues. This may then explain the paucity of eosinophilic infiltrative disease in patients with STAT3 mutations. The level of eosinophilic involvement may be related to the site or type of mutation within the STAT3 molecule. As more data are collected, we may be able to assess whether certain mutations dictate different clinical outcomes, which could prove helpful in directing therapy. PMID- 23342296 TI - Displaced nasal dilator caused severe pain: Case report and literature review. AB - Internal nasal dilators are widely used but have not been reported to cause severe symptoms. We describe a case in which a male adult had accidentally, during sleep, inhaled a nasal dilator into his right nasal cavity, and we review the relevant literature. A PubMed search was performed of nasal dilators, especially of the internal types, including "Nasaline Snooze'" (ENTPro, Stockholm, Sweden). A foreign body in adults may be an inhaled nasal dilator. It may be overlooked on computed tomography scans, and thorough inspection of the nose is diagnostic. PMID- 23342297 TI - Optical imaging of tumor microenvironment. AB - Tumor microenvironment plays important roles in tumor development and metastasis. Features of the tumor microenvironment that are significantly different from normal tissues include acidity, hypoxia, overexpressed proteases and so on. Therefore, these features can serve as not only biomarkers for tumor diagnosis but also theraputic targets for tumor treatment. Imaging modalities such as optical, positron emission tomography (PET) and magnetic resonance imaging (MRI) have been intensively applied to investigate tumor microenvironment. Various imaging probes targeting pH, hypoxia and proteases in tumor microenvironment were thus well developed. In this review, we will focus on recent examples on fluorescent probes for optical imaging of tumor microenvironment. Construction of these fluorescent probes were based on characteristic feature of pH, hypoxia and proteases in tumor microenvironment. Strategies for development of these fluorescent probes and applications of these probes in optical imaging of tumor cells or tissues will be discussed in this review paper. PMID- 23342298 TI - Utility of 3'-[(18)F]fluoro-3'-deoxythymidine as a PET tracer to monitor response to gene therapy in a xenograft model of head and neck carcinoma. AB - Noninvasive imaging methodologies are needed to assess treatment responses to novel molecular targeting approaches for the treatment of squamous cell carcinoma of the head and neck (SCCHN). Computer tomography and magnetic resonance imaging do not effectively distinguish tumors from fibrotic tissue commonly associated with SCCHN tumors. Positron emission tomography (PET) offers functional non invasive imaging of tumors. We determined the uptake of the PET tracers 2-deoxy-2 [(18)F]fluoro-D-glucose ([(18)F]FDG) and 3'-[(18)F]Fluoro-3'-deoxythymidine ([(18)F]FLT) in several SCCHN xenograft models. In addition, we evaluated the utility of [(18)F]FLT microPET imaging in monitoring treatment response to an EGFR antisense approach targeted therapy that has shown safety and efficacy in a phase I trial. Two of the 3 SCCHN xenograft models tested demonstrated no appreciable uptake or retention of [(18)F]FDG, but consistent accumulation of [(18)F]FLT. The third tumor xenograft SCCHN model (Cal33) demonstrated variable uptake of both tracers. SCCHN xenografts (1483) treated with EGFR antisense gene therapy decreased tumor volumes in 4/6 mice. Reduced uptake of [(18)F]FLT was observed in tumors that responded to epidermal growth factor antisense (EGFRAS) gene therapy compared to non-responding tumors or tumors treated with control sense plasmid DNA. These findings indicate that [(18)F]FLT PET imaging may be useful in monitoring SCCHN response to molecular targeted therapies, while [(18)F]FDG uptake in SCCHN xenografts may not be reflective of the level of metabolic activity characteristic of human SCCHN tumors. PMID- 23342299 TI - A comparison of image contrast with (64)Cu-labeled long circulating liposomes and (18)F-FDG in a murine model of mammary carcinoma. AB - Conjugation of the (64)Cu PET radioisotope (t(1/2) = 12.7 hours) to long circulating liposomes enables long term liposome tracking. To evaluate the potential clinical utility of this radiotracer in diagnosis and therapeutic guidance, we compare image contrast, tumor volume, and biodistribution of (64)Cu liposomes to metrics obtained with the dominant clinical tracer, (18)F-FDG. Twenty four female FVB mice with MET1 mammary carcinoma tumor grafts were examined. First, serial PET images were obtained with the (18)F-FDG radiotracer at 0.5 hours after injection and with the (64)Cu-liposome radiotracer at 6, 18, 24, and 48 hours after injection (n = 8). Next, paired imaging and histology were obtained at four time points: 0.5 hours after (18)F-FDG injection and 6, 24, and 48 hours after (64)Cu-liposome injection (n = 16). Tissue biodistribution was assessed with gamma counting following necropsy and tumors were paraffin embedded, sectioned, and stained with hematoxylin and eosin. The contrast ratio of images obtained using (18)F-FDG was 0.88 +/- 0.01 (0.5 hours after injection), whereas with the (64)Cu-liposome radiotracer the contrast ratio was 0.78 +/- 0.01, 0.89 +/- 0.01, 0.88 +/- 0.01, and 0.94 +/- 0.01 at 6, 18, 24, and 48 hours, respectively. Estimates of tumor diameter were comparable between (64)Cu liposomes and (18)F-FDG, (64)Cu-liposomes and necropsy, and (64)Cu-liposomes and ultrasound with Pearson's r-squared values of 0.79, 0.79, and 0.80, respectively. Heterogeneity of tumor tracer uptake was observed with both tracers, correlating with regions of necrosis on histology. The average tumor volume of 0.41 +/- 0.05 cc measured with (64)Cu-liposomes was larger than that estimated with (18)F-FDG (0.28 +/- 0.04 cc), with this difference apparently resulting primarily from accumulation of the radiolabeled particles in the pro-angiogenic tumor rim. The imaging of radiolabeled nanoparticles can facilitate tumor detection, identification of tumor margins, therapeutic evaluation and interventional guidance. PMID- 23342300 TI - One-step and one-pot-two-step radiosynthesis of cyclo-RGD-(18)F aryltrifluoroborate conjugates for functional imaging. AB - Arylboronates capture aqueous (18)F-fluoride in one step to afford a highly polar (18)F-labeled aryltrifluoroborate anion ((18)F-ArBF(3) (-)) that clears rapidly in vivo. To date however, there is little data to show that a ligand labeled with a prosthetic (18)F-ArBF(3) (-) will provide functional images. RGD, a high affinity ligand for integrins that are present on the cell surface of numerous tumors, has been labeled in many formats with many different radionuclides, and as such represents a well-established ligand that can be used to evaluate new labeling methods. Herein we have labeled RGD with a prosthetic (18)F-ArBF(3) (-) via two approaches for the first time: 1) a RGD-boronate bioconjugate is directly labeled in one step and 2) an alkyne-modified arylborimidine is first converted to the corresponding (18)F-ArBF(3) (-) which is then conjugated to an RGD-azide via Cu(+)-mediated [2+3] dipolar cycloaddition in one pot over two steps. RGD (18)F-ArBF(3) (-) bionconjugates were produced in reasonable radiochemical yields using low amounts of (18)F-fluoride anion (10-50 mCi). Despite relatively low specific activities, good tumor images are revealed in each case. PMID- 23342301 TI - (18)F-click labeling of a bombesin antagonist with an alkyne-(18)F-ArBF(3) (-): in vivo PET imaging of tumors expressing the GRP-receptor. AB - A clickable alkyne-modified arylborimidine is rapidly converted in 15 minutes to a highly polar (18)F-aryltrifluoroborate anion ((18)F-ArBF(3) (-)) at high specific activity. Following labeling, the alkyne-(18)F-ArBF(3) (-) was conjugated to the peptide bombesin (BBN) within 25 minutes in a second step without need for prior work-up making this one-pot-two-step method easy, user friendly, and generally applicable. Bombesin was chosen to provide functional PET images of prostate cancer xenografts in mice of which there are few. Whereas BBN is labeled to provide some of the first in vivo tumor images based on this technique, click-labeling is recognized for its generality and broad substrate scope. Hence these results are likely to be useful for click labeling most peptides and other biomolecules. PMID- 23342302 TI - Synthesis and preclinical evaluation of a new C-6 alkylated pyrimidine derivative as a PET imaging agent for HSV1-tk gene expression. AB - [(18)F]FHOMP (6-((1-[(18)F]-fluoro-3-hydroxypropan-2-yloxy)methyl)-5 methylpyrimidine-2,4(1H,3H)-dione), a C-6 substituted pyrimidine derivative, has been synthesized and evaluated as a potential PET agent for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression. [(18)F]FHOMP was prepared by the reaction of the tosylated precursor with tetrabutylammonium [(18)F]-fluoride followed by acidic cleavage of the protecting groups. In vitro cell accumulation of [(18)F]FHOMP and [(18)F]FHBG (reference) was studied with HSV1-tk transfected HEK293 (HEK293TK+) cells. Small animal PET and biodistribution studies were performed with HEK293TK+ xenograft-bearing nude mice. The role of equilibrative nucleoside transporter 1 (ENT1) in the transport and uptake of [(18)F] FHOMP was also examined in nude mice after treatment with ENT1 inhibitor nitrobenzylmercaptopurine ribonucleoside phosphate (NBMPR-P). [(18)F]FHOMP was obtained in a radiochemical yield of ~25% (decay corrected) and the radiochemical purity was greater than 95%. The uptake of [(18)F]FHOMP in HSV1 TK containing HEK293TK+ cells was 52 times (at 30 min) and 244 times (at 180 min) higher than in control HEK293 cells. The uptake ratios between HEK293TK+ and HEK293 control cells for [(18)F]FHBG were significantly lower i.e. 5 (at 30 min) and 81 (240 min). In vivo, [(18)F]FHOMP accumulated to a similar extend in HEK293TK+ xenografts as [(18)F]FHBG but with a higher general background. Blocking of ENT1 reduced [(18)F]FHOMP uptake into brain from a standardized uptake value (SUV) of 0.10+/-0.01 to 0.06+/-0.02, but did not reduce the general background signal in PET. Although [(18)F]FHOMP does not outperform [(18)F]FHBG in its in vivo performance, this novel C-6 pyrimidine derivative may be a useful probe for monitoring HSV1-tk gene expression in vivo. PMID- 23342303 TI - Characterization of primary prostate carcinoma by anti-1-amino-2-[(18)F] fluorocyclobutane-1-carboxylic acid (anti-3-[(18)F] FACBC) uptake. AB - Anti-1-amino-3-[(18)F] fluorocyclobutane-1-carboxylic acid (anti-3-[(18)F] FACBC) is a synthetic amino acid positron emission tomography (PET) radiotracer with utility in the detection of recurrent prostate carcinoma. The aim of this study is to correlate uptake of anti-3-[(18)F] FACBC with histology of prostatectomy specimens in patients undergoing radical prostatectomy and to determine if uptake correlates to markers of tumor aggressiveness such as Gleason score. Ten patients with prostate carcinoma pre-radical prostatectomy underwent 45 minute dynamic PET CT of the pelvis after IV injection of 347.8 +/- 81.4 MBq anti-3-[(18)F] FACBC. Each prostate was co-registered to a separately acquired MR, divided into 12 sextants, and analyzed visually for abnormal focal uptake at 4, 16, 28, and 40 min post-injection by a single reader blinded to histology. SUVmax per sextant and total sextant activity (TSA) was also calculated. Histology and Gleason scores were similarly recorded by a urologic pathologist blinded to imaging. Imaging and histologic analysis were then compared. In addition, 3 representative sextants from each prostate were chosen based on highest, lowest and median SUVmax for immunohistochemical (IHC) analysis of Ki67, synaptophysin, P504s, chromogranin A, P53, androgen receptor, and prostein. 79 sextants had malignancy and 41 were benign. Highest combined sensitivity and specificity was at 28 min by visual analysis; 81.3% and 50.0% respectively. SUVmax was significantly higher (p<0.05) for malignant sextants (5.1+/-2.6 at 4 min; 4.5+/-1.6 at 16 min; 4.0+/ 1.3 at 28 min; 3.8+/-1.0 at 40 min) compared to non-malignant sextants (4.0+/-1.9 at 4 min; 3.5+/-0.8 at 16 min; 3.4+/-0.9 at 28 min; 3.3+/-0.9 at 40 min), though there was overlap of activity between malignant and non-malignant sextants. SUVmax also significantly correlated (p<0.05) with Gleason score at all time points (r=0.28 at 4 min; r=0.42 at 16 min; r=0.46 at 28 min; r=0.48 at 40 min). There was no significant correlation of anti-3-[(18)F] FACBC SUVmax with Ki-67 or other IHC markers. Since there was no distinct separation between malignant and non-malignant sextants or between Gleason score levels, we believe that anti-3 [(18)F] FACBC PET should not be used alone for radiation therapy planning but may be useful to guide biopsy to the most aggressive lesion. PMID- 23342304 TI - "Kit like" (18)F labeling method for synthesis of RGD peptide-based PET probes. AB - Positron Emission Tomography (PET) has become a popular imaging technique widely used for diagnostic purposes. To date, much attention has been devoted to (18)F fluoride because of the characteristics of its nuclear decay, as well as its relative ease of preparation from (18)O-water. However, with a half-life of 110 minutes, swift and efficient incorporation of (18)F-fluorine into biomolecules is necessary to minimize loss of activity. Therefore, the discovery of rapid and reliable incorporation of (18)F-fluorine atoms into biomolecules would be highly beneficial, especially if these protocols can be carried out directly in irradiated 18O-water. In the study published in the American Journal of Nuclear Medicine and Molecular Imaging, cyclo-RGD-(18)F-aryltrifluoroborate conjugates were prepared based on one-step and one-pot-two-step methods. This paper represents recent efforts on the design and development of novel PET tracers based on the "Kit like" (18)F labeling method. PMID- 23342305 TI - Usefulness of (18)f-fluorodeoxyglucose positron emission tomography/computed tomography in management of cervical dystonia. AB - OBJECTIVE: To evaluate the usefulness of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in the management of cervical dystonia (CD) with botulinum toxin type A (BoNT-A) injection. METHOD: Thirty two subjects with CD were included. A BoNT-A injection was provided either by clinically targeting method (group 1) or by (18)F-FDG PET/CT-assisted, clinically targeting method (group 2). In group 2, selection of target muscles and dosage of BoNT-A were determined according to the increased (18)F-FDG uptake, in addition to physical examination and functional anatomy. The outcomes of BoNT A injection was compared between the two groups, in terms of the number of subjects who had reinjection before and after 6 months, the number of reinjections, the interval of reinjections, the duration to the minimal Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), the number of adverse events, the reduction rate of TWSTRS at 1-3 months and 3-6 months after injection, and the probability of reinjection-free living. RESULTS: The number of subjects who had reinjection within 6 months was significantly lower in group 2 than in group 1 (10 in group 1 vs. 3 in group 2). The reduction rate of TWSTRS after 3-6 months (37.8+/-15.7% of group 1 vs. 63.3+/-28.0% of group 2) and the probability of reinjection-free living were significantly higher in group 2 than in group 1. CONCLUSION: These findings suggest that (18)F-FDG PET/CT study could be useful in management of CD in terms of the identification of dystonic muscles if there is an increase in the (18)F-FDG uptake in the cervical muscle of the images. PMID- 23342306 TI - Hippotherapy in adult patients with chronic brain disorders: a pilot study. AB - OBJECTIVE: To investigate the effects of hippotherapy for adult patients with brain disorders. METHOD: Eight chronic brain disorder patients (7 males, mean age 42.4+/-16.6 years) were recruited. The mean duration from injury was 7.9+/-7.7 years. The diagnoses were stroke (n=5), traumatic brain disorder (n=2), and cerebral palsy (n=1). Hippotherapy sessions were conducted twice a week for eight consecutive weeks in an indoor riding arena. Each hippotherapy session lasted 30 minutes. All participants were evaluated by the Berg balance scale, Tinetti Performance-Oriented Mobility Assessment, 10 Meter Walking Test, Functional Ambulatory Category, Korean Beck Depression Inventory, and Hamilton Depression Rating Scale. We performed baseline assessments twice just before starting hippotherapy. We also assessed the participants immediately after hippotherapy and at eight weeks after hippotherapy. RESULTS: All participants showed no difference in balance, gait function, and emotion between the two baseline assessments before hippotherapy. During the eight-week hippotherapy program, all participants showed neither adverse effects nor any accidents; all had good compliance. After hippotherapy, there were significant improvements in balance and gait speed in comparison with the baseline assessment (p<0.05), and these effects were sustained for two months after hippotherapy. However, there was no significant difference in emotion after hippotherapy. CONCLUSION: We could observe hippotherapy to be a safe and effective alternative therapy for adult patients with brain disorders in improving balance and gait function. Further future studies are warranted to delineate the benefits of hippotherapy on chronic stroke patients. PMID- 23342307 TI - Therapeutic effects of mechanical horseback riding on gait and balance ability in stroke patients. AB - OBJECTIVE: To investigate the therapeutic effects of mechanical horseback riding for gait and balance parameters in post-stroke patients. METHOD: This study was a non randomized prospective positive-controlled trial over a 12 week period. From May 2011 to October 2011, 37 stroke patients were recruited from our outpatient clinic and divided into two groups. The control group received the conventional physiotherapy while the intervention group received the conventional physiotherapy along with mechanical horseback riding therapy for 12 weeks. Outcome measurements of gait included the Functional Ambulation Category (FAC) and gait part of the Performance Oriented Mobility Assessment (G-POMA) while those of balance included the Berg Balance Scale (BBS) and the balance part of the Performance Oriented Mobility Assessment (B-POMA). These measurements were taken before and after treatment. RESULTS: There were no significant differences in the baseline characteristics and initial values between the two groups. When comparing baseline and 12 weeks post treatment in each group, the intervention group showed significant improvement on BBS (39.9+/-5.7 -> 45.7+/-4.8, p=0.001) and B-POMA (10.4+/-2.6 -> 12.6+/-2.1, p=0.001), but significant improvement on gait parameters. When comparing the groups, the dynamic balance category of BBS in post treatment showed significant difference (p=0.02). CONCLUSION: This study suggests that mechanical horseback riding therapy may be an effective treatment tool for enhancing balance in adults with stroke. PMID- 23342308 TI - Factors affecting bone mineral density in adults with cerebral palsy. AB - OBJECTIVE: To clarify factors affecting bone mineral density (BMD) in adults with cerebral palsy (CP). METHOD: Thirty-five patients with CP participated in this study. Demographic data including gender, age, body mass index (BMI), subtype according to neuromotor type and topographical distribution, ambulatory function, and functional independence measure (FIM) were investigated. The BMD of the lumbar spine and femur were measured using Dual-energy X-ray absorptiometry, and the factors affecting BMD were analyzed. RESULTS: The BMD had no significant association with factors such as gender, age, and subtype in adults with CP. However, BMI was significantly correlated with the BMD of lumbar spine and femur (p<0.05). The FIM score was also positively correlated with the BMD of femur (p<0.05). Moreover, CP patients with higher ambulatory function had significantly higher BMD of femur (p<0.05). CONCLUSION: These findings suggest that BMI and functional levels such as FIM and ambulatory function can affect BMD in adults with CP. The results might be used as basic data, suggesting the importance of treatment including weight bearing exercise and gait training in adults with CP. PMID- 23342309 TI - The effect of rheological properties of foods on bolus characteristics after mastication. AB - OBJECTIVE: To evaluate the effects of physical properties of foods on the changes of viscosity and mass as well as the particle size distribution after mastication. METHOD: Twenty subjects with no masticatory disorders were recruited. Six grams of four solid foods of different textures (banana, tofu, cooked-rice, cookie) were provided, and the viscosity and mass after 10, 20, and 30 cycles of mastication and just before swallowing were measured. The physical properties of foods, such as hardness, cohesiveness, and adhesiveness, were measured with a texture analyzer. Wet sieving and laser diffraction were used to determine the distribution of food particle size. RESULTS: When we measured the physical characteristics of foods, the cookie was the hardest food, and the banana exhibited marked adhesiveness. Tofu and cooked-rice exhibited a highly cohesive nature. As the number of mastication cycles increased, the masses of all foods were significantly increased (p<0.05), and the viscosity was significantly decreased in the case of banana, tofu, and cooked-rice (p<0.05). The mass and viscosity of all foods were significantly different between the foods after mastication (p<0.05). Analyzing the distribution of the particle size, that of the bolus was different between foods. However, the curves representing the particle size distribution for each food were superimposable for most subjects. CONCLUSION: The viscosity and particle size distribution of the bolus were different between solid foods that have different physical properties. Based on this result, the mastication process and food bolus formation were affected by the physical properties of the food. PMID- 23342310 TI - Use of videofluoroscopic swallowing study in patients with aspiration pneumonia. AB - OBJECTIVE: To investigate the clinical characteristics of dysphagic elderly Korean patients diagnosed with aspiration pneumonia as well as to examine the necessity of performing a videofluoroscopic swallowing study (VFSS) in order to confirm the presence of dysphagia in such patients. METHOD: The medical records of dysphagic elderly Korean subjects diagnosed with aspiration pneumonia were retrospectively reviewed for demographic and clinical characteristics as well as for VFSS findings. RESULTS: In total, medical records of 105 elderly patients (81 men and 24 women) were reviewed in this study. Of the 105 patients, 82.9% (n=87) were admitted via the emergency department, and 41.0% (n=43) were confined to a bed. Eighty percent (n=84) of the 105 patients were diagnosed with brain disorders, and 68.6% (n=72) involved more than one systemic disease, such as diabetes mellitus, cancers, chronic cardiopulmonary disorders, chronic renal disorders, and chronic liver disorders. Only 66.7% (n=70) of the 105 patients underwent VFSS, all of which showed abnormal findings during the oral or pharyngeal phase, or both. CONCLUSION: In this study, among 105 dysphagic elderly patients with aspiration pneumonia, only 66.7% (n=70) underwent VFSS in order to confirm the presence of dysphagia. As observed in this study, the evaluation of dysphagia is essential in order to consider elderly patients with aspiration pneumonia, particularly in patients with poor functional status, brain disorders, or more than one systemic disease. A greater awareness of dysphagia in the elderly, as well as the diagnostic procedures thereof, particularly VFSS, is needed among medical professionals in Korea. PMID- 23342311 TI - Inter-rater Reliability of Videofluoroscopic Dysphagia Scale. AB - OBJECTIVE: To investigate the inter-rater agreement using the Videofluoroscopic Dysphagia Scale (VDS). METHOD: The present study was designed as a multicenter, single-blind trial. A Videofluoroscopic Swallowing Study (VFSS) was performed using the protocol described by J.A Logemann. Thick-fluid, pureed food, mechanically altered food, regularly textured food, and thin-fluid boluses were sequentially swallowed. Each participant received a 3 ml bolus followed by a 5 ml bolus of each food material, in the order mentioned above. All study procedures were video recorded. Discs containing these video recordings in random order were distributed to interpreters who were blinded to the participant information. The video recordings were evaluated using a standardized VDS sheet and the inter rater reliability was calculated. RESULTS: In total, 100 patients participated in this study and 10 interpreters analyzed the findings. Inter-rater reliability was fair in terms of lip closure (kappa: 0.325), oral transit time (0.253), delayed triggering of pharyngeal swallowing (0.300), vallecular residue (0.275), laryngeal elevation (0.345), pyriform sinus residue (0.310), coating of the pharyngeal wall (0.310), and aspiration (0.393). However, other parameters of the oral phase were lower than those of the pharyngeal phase (0.06-0.153). Moreover, the summation of VDS reliability (intraclass correlation coefficient: 0.556) showed moderate agreement. CONCLUSION: VDS shows a moderate rate of agreement for evaluating the swallowing function. However, many of the parameters demonstrated a lower rate of agreement, particularly the oral phase parameters. PMID- 23342312 TI - Fear of falling in subacute hemiplegic stroke patients: associating factors and correlations with quality of life. AB - OBJECTIVE: To determine the associating factors of fear of falling (FOF) and the correlations between FOF and quality of life (QOL) on subacute stroke patients in Korea. METHOD: Fifty hemiplegic subacute stroke patients in our clinic were recruited. We directly asked patients with their fear of falling and interviewed them with the Korean version of falls efficacy scale-international (KFES-I). We divided the participants into two groups; with FOF and without FOF. We compared these groups with the strength of hemiplegic hip abductor, knee extensor, ankle plantar flexor, functional ambulation category (FAC) scale, stroke specific quality of life (SSQOL), and hospital anxiety depression scale (HADS). RESULTS: Thirty-four participants were enrolled, and more than half of the patients with subacute stroke had FOF. We compared the patients with and without FOF. According to the results, FOF was associated with the strength of hemiplegic hip abductor, knee extensor and ankle plantar flexor, FAC, total SSQOL, and domains (energy, mobility, self care, upper extremity function) of SSQOL (p<0.05). FOF was also associated with the anxiety score of HADS (p<0.05). KFES-I had a significant negative correlation with the strength of hemiplegic hip abductor, knee extensor and ankle plantar flexor, FAC, total SSQOL, and domains (energy, mobility, self care, upper extremity function) of SSQOL (p<0.01). CONCLUSION: The FOF was associated with not only QOL but also with the physical and psychological factors, and in particular, anxiety. Therefore, further concerns about FOF in subacute stroke patients might be required. PMID- 23342313 TI - ICF Based Comprehensive Evaluation for Post-Acute Spinal Cord Injury. AB - OBJECTIVE: To evaluate the feasibility of the ICF for initial comprehensive evaluation of early post-acute spinal cord injury. METHOD: A comprehensive evaluation of 62 early post-acute spinal cord injury (SCI) patients was conducted by rehabilitation team members, such as physicians, physical therapists, occupational therapists, nutritionists, medical social-workers, and nurses. They recorded each of their evaluation according to the ICF first level classification. The contents of the comprehensive evaluation were linked to the ICF second level categories, retrospectively. The linked codes were analyzed descriptively and were also compared with the brief ICF core set for early post acute SCI. RESULTS: In the evaluation of early post-acute SCI patients based on the ICF first level categories, 19 items from the body functions domain, such as muscle power functions (b730) and urination functions (b620), 15 items from the body structures domain, including spinal cord and related structures (s120), 11 items from the activities and participation domain, such as transferring oneself (d420) and walking (d450), and 9 items from the environmental factors domain, e.g., health professionals (e355), were linked to the ICF second level categories. In total, 82.4% of all contents were linked to the brief ICF core set. Prognosis insight, a personal factor not linkable to an ICF code, was mentioned in 29.0% of all patients. CONCLUSION: First level ICF categories can provide a structural base for a comprehensive evaluation in early post-acute spinal cord injury. However, frequently linked items, including the brief core set, as well as personal factors should be considered via a checklist in order to prevent the omission of significant contents. PMID- 23342314 TI - Resilience as a possible predictor for psychological distress in chronic spinal cord injured patients living in the community. AB - OBJECTIVE: To investigate whether higher resilience level predicts low levels of psychological distress in chronic SCI patients living in the community. METHOD: Thirty seven patients (mean age 41.5+/-10.9, male : female=28 : 9) with chronic spinal cord injury (duration 8.35+/-7.0 years) living in the community are included, who were hospitalized for annual checkups from November, 2010 to May, 2011. First, their spinal cord injury level, completeness and complications were evaluated. The patients completed questionnaires about their educational status, religion, employment status, marital status, medical and psychological history and also the following questionnaires: Hospital Anxiety and Depression Scale (HADS), Connor-Davidson Resilience Scale (CD-RISC), Alcohol Use Disorders Identification Test-alcohol consumption questions (AUDIT-C) and Health-related quality of life (EQ-5D). The patients were divided into two subgroups: patients with HADS >=13 are classified as high psychological distress group and others as low psychological distress group. We compared the two groups to find statistically significant differences among the variables. RESULTS: CD-RISC, EQ 5D and employment status are significantly different between two groups (p<0.05). In a forward stepwise regression, we found that EQ-5D had a greater contribution than CD-RISC to the psychological distress level. CONCLUSION: In addition to health-related quality of life, resilience can be suggested as a possible predictor of psychological distress in chronic SCI patients. PMID- 23342315 TI - Asymmetry of the isokinetic trunk rotation strength of korean male professional golf players. AB - OBJECTIVE: To determine whether there is side to side difference of the trunk rotation muscle in Korean male professional golf players. Healthy controls who did not play golf were also evaluated and compared with professional golf players. METHOD: Fifty-one professional golf players and 50 healthy controls participated in this study. Bilateral isokinetic trunk rotation strength that represented the aiming side and non-aiming side trunk rotator function in a golf swing and other parameters were evaluated using the Biodex System III Isokinetic Dynamometer at angular velocities of 30, 60, and 120 degree per second. RESULTS: The professional golf players' peak torque and total work on their aiming sides were significantly higher than on their non-aiming side at all angular velocities. Additionally, the golf players' peak torque on their aiming side was significantly higher than those of the healthy controls only at the 60 degree per second angular velocity, but there was a slight and consistent trend in the others. Finally, the difference between the aiming side and the non-aiming side of the professional golf players and the healthy controls was also significant. CONCLUSION: The aiming side rotation strength of the male professional golf players was higher than that of non-aiming side. The controls showed no side-to side differences. This finding is attributed to the repetitive training and practice of professional golf players. A further study is needed to investigate if the strengthening of the trunk rotation muscle, especially on the aiming side, could improve golf performance. PMID- 23342316 TI - Sonography of affected and unaffected shoulders in hemiplegic patients: analysis of the relationship between sonographic imaging data and clinical variables. AB - OBJECTIVE: To explore the relationship between a number of clinically relevant variables and sonographic imaging data in respect to the level of impairment experienced in the affected and unaffected shoulders of hemiplegic stroke patients. METHOD: Fifty-one hemiplegic stroke patients (32 males, 19 females; 29 right-sided hemiplegics, 22 left-sided hemiplegics) participated in this study. A musculoskeletal radiologist conducted a sonographic exam on both the affected and unaffected shoulders of all patients and two physicians classified the severity of the injury on a six-point rating scale. Clinical variables including age, sex, duration of injury, spasticity and muscle power of the hemiplegic side, and level of functional activity of the shoulder were assessed. RESULTS: The sonographic rating scores of hemiplegic shoulders were positively correlated with age (p<0.01) and negatively correlated with level of muscle spasticity (p<0.05). The sonographic rating scores of unaffected shoulders were positively correlated with duration of injury (p<0.01). Affected shoulders received sonographic rating scores that reflected significantly more impairment than those of unaffected shoulders (p<0.001), and pre-morbid handedness did not affect the relationship between impairment rating and shoulder injury status. CONCLUSION: Hemiplegic stroke influences not only affected shoulders, but also unaffected sides. Proper management of spasticity, enhancement of motor recovery, and avoidance of unaffected shoulder overuse should be considered to prevent shoulder problems following strokes which result in hemiplegia. PMID- 23342317 TI - The Prevalence and Characteristics of Depression in Work-related Musculoskeletal Disease. AB - OBJECTIVE: To reveal the relationship between depression and WMSD. METHOD: Five physiatrists participated in the workplace musculoskeletal survey and diagnosed 724 office workers with WMSD by performing detailed history taking and physical examination. All subjects were asked to answer the Korean version of the Beck depressive inventory (K-BDI), and to express their pain according to the visual analogue scale (VAS) score. We categorized the subjects into 4 groups, myofascial pain syndrome (MPS), herniated intervertebral disk (HIVD), tenosynovitis, and others, and investigated the prevalence of depression in desk workers and relationship between WMSD and depression, and we compared pain intensity between the depression and non-depression groups. Correlation analysis was carried out between K-BDI and VAS scores in each group. RESULTS: The mean K-BDI score were 8.7+/-6.68. The prevalence of depression was higher in females than in male, and there was no relationship between age and depression. There was a significant connection between HIVD and depression (p<0.05). However, the other groups did not have significant connection to depression. The VAS score (5.02) of the depression group was significantly higher than that (4.10) of the non-depression group. In addition, there was a significant difference of VAS scores between the depression group and non-depression group in each disease group. CONCLUSION: The mean VAS score of the depression group in WMSD was significantly higher than in the non-depression group. The correlation between BDI and VAS scores in the subjects was present, and the highest was in the HIVD group. PMID- 23342318 TI - Comparing the Effect of Botulinum Toxin Type B Injection at Different Dosages for Patient with Drooling due to Brain Lesion. AB - OBJECTIVE: To investigate Botulinum toxin type B (BNT-B) injection's effect and duration depending on dose for patients with brain lesion. METHOD: Twenty one patients with brain lesion and severe drooling were included and divided into three groups. All patients received conventional dysphagia therapy. Group A patients (n=7) received an injection of 1,500 units and group B patients (n=7) received an injection of 2,500 units of BNT-B in submandibular gland under ultrasound guidance. Group C patients (n=7) received conventional dysphagia therapy. Saliva secretion was assessed quantitatively at baseline and at weeks 1, 2, 4, 8, and 12. The severity and frequency of drooling was assessed using the Drooling Quotient (DQ) by patients and/or caregivers. RESULTS: Group A and B reported a distinct improvement of the symptoms within 2 weeks after BNT-B injection. Compared to the baseline, the mean amount of saliva decreased significantly throughout the study. However, there was no meaningful difference between the two groups. The greatest reductions were achieved at 2 weeks and lasted up to 8 weeks after BNT-B injection. Group C did not show any differences. CONCLUSION: Local injection of 1,500 units of BNT-B into salivary glands under ultrasonic guidance proved to be a safe and effective dose for drooling in patient with brain lesion, as did 2,500 units. PMID- 23342319 TI - The effects of neuromuscular electrical stimulation on cardiopulmonary function in healthy adults. AB - OBJECTIVE: To evaluate the effect of neuromuscular electrical stimulation (NMES) on cardiopulmonary function in healthy adults. METHOD: Thirty-six healthy adults without a cardiac problem were enrolled. All patients were randomly assigned to either a control (17 subjects, mean age 29.41) or an electrical stimulation group (19 subjects, mean age 29.26). The electrical stimulation group received NMES on both sides of quadriceps muscle using a Walking Man II(r) in a sitting position for 30 minutes over 2 weeks. Maximum oxygen consumption (VO(2max)), metabolic equivalent (MET), resting, maximal heart rate (RHR, MHR), resting, maximal blood pressure (RBP, MBP), and maximal rate pressure product (MRPP), exercise tolerance test (ETT) duration were determined using an exercise tolerance test and a 6 minute walk test (6MWT) before and after treatment. RESULTS: The electrical stimulation group showed a significant increase in VO(2max) (p=0.03), 6MWT (p<0.01), MHR (p<0.04), MsBP (p<0.03), ETT duration (p<0.01) and a significant decrease in RsBP (p<0.02) as compared with the control group after two weeks. NMES induced changes improved only in RsBP (p<0.049) and ETT duration (p<0.01). The effects of NMES training were stronger in females. CONCLUSION: We suggest that NMES is an additional therapeutic option for cardiopulmonary exercise in disabled patients with severe refractory heart failure or acute AMI. PMID- 23342320 TI - CYP2C9 Mutation Affecting the Individual Variability of Warfarin Dose Requirement. AB - Warfarin is a frequently prescribed anticoagulant in rehabilitation patients. Adverse drug reactions of warfarin were reported as bleeding and cutaneous microvascular thrombosis. Major bleeding, such as intracranial hemorrhage and psoas hematoma, in patients receiving anticoagulation therapy is a rare condition, but sometimes very serious complication that can even be fatal. Patient-specific factors (eg, age, body size, race, concurrent diseases, and medications) explain some of the individual variability in warfarin dose, but genetic factors, which influence warfarin response, explain a significantly higher proportion of the variability in the dose. There are two identified genes that are responsible for the main proportion of the genetic effect: CYP2C9, which codes for the enzyme cytochrome P450 2C9 that metabolizes S-warfarin, and VKORC1, which codes for warfarin's target, vitamin K epoxide reductase. We report a case of intolerance to warfarin dosing, due to impaired drug metabolism in a patient with CYP2C9(*)1/(*)3 and VKORC 1173TT. Fortunately, there are no severe complications. PMID- 23342322 TI - A case of generalized auditory agnosia with unilateral subcortical brain lesion. AB - The mechanisms and functional anatomy underlying the early stages of speech perception are still not well understood. Auditory agnosia is a deficit of auditory object processing defined as a disability to recognize spoken languages and/or nonverbal environmental sounds and music despite adequate hearing while spontaneous speech, reading and writing are preserved. Usually, either the bilateral or unilateral temporal lobe, especially the transverse gyral lesions, are responsible for auditory agnosia. Subcortical lesions without cortical damage rarely causes auditory agnosia. We present a 73-year-old right-handed male with generalized auditory agnosia caused by a unilateral subcortical lesion. He was not able to repeat or dictate but to perform fluent and comprehensible speech. He could understand and read written words and phrases. His auditory brainstem evoked potential and audiometry were intact. This case suggested that the subcortical lesion involving unilateral acoustic radiation could cause generalized auditory agnosia. PMID- 23342321 TI - Dysphagia due to Retropharyngeal Abscess that Incidentally Detected in Subarachnoid Hemorrhage Patient. AB - Cerebral hemorrhage is one of the most common causes of dysphagia. In many cases, dysphagia gets better once the acute phase has passed. Structural lesions such as thyromegaly, cervical hyperostosis, congenital web, Zenker's diverticulum, neoplasm, radiation fibrosis, and retropharyngeal abscess must be considered as other causes of dysphagia as well. Retropharyngeal abscess seldom occur in adults and if it does so, a search for a prior dental procedure, trauma, head and neck infection is needed. The symptoms may include neck pain, dysphagia, sore throat, and in rare cases, dyspnea accompanied by stridor. We present a case and discuss a patient who had dysphagia and neck pain after a cerebral hemorrhage. Testing revealed a retropharyngeal abscess. The symptoms were successfully treated after the administration of antibiotics. PMID- 23342323 TI - Delayed Onset of Thoracic SCIWORA in Adults. AB - Spinal cord injury (SCI) without radiographic abnormality (SCIWORA) is estimated to account for 1-9% of the occurrence of SCI. Of these, cervical SCIWORA in children is common, but thoracic SCIWORA delayed onset in adult is much less common. We experienced a case of 38-years old male patient with lower extremity weakness; he had fallen down a week earlier before the investigation. At the time of admission, motor grade was 4 with voiding incontinence and ambulated with cane. He presented progressive weakness from G4 to G3 and hypoesthesia was below T8 dermatome and ambulated with wheelchair. Whole spine and lumbar MRI findings showed no abnormality and electrodiagnostic findings showed normal NCS, however, abnormal SEP on both the tibial nerves. After steroid therapy and proper rehabilitation program for 2 weeks, lower extremity strength was improved from G4 to G3, voiding was continent, and ambulation reached cane gait. PMID- 23342324 TI - Tracheo-innominate artery fistula after stroke. AB - Tracheo-innominate artery fistula (TIAF) is rare, yet the most fatal complication after tracheostomy. In the absence of immediate diagnosis and surgical management, the mortality rate is very high, because the complication can lead to sudden massive tracheal hemorrhage. Tracheal obstruction and hypovolemic shock are the major life threatening conditions. The 46-year-old woman received tracheostomy tube insertion after stroke. Three months later, there was occurrence of active bleeding at the site of tracheostomy in the patient, who participated in comprehensive rehabilitation program. Immediately, the patient received an endotracheal tube insertion into the tracheostomy site and thus massive bleeding was controlled. The patient was transferred to the intensive care unit, where her breathing was maintained by mechanical ventilation. Based on computed tomography and laryngoscopy, no remarkable findings about TIAF were detected. Nevertheless, transfemoral angiography findings revealed that innominate artery made small luminal outpouching to trachea at the carotid artery and at the subclavian artery bifurcation level, based on which a diagnosis of TIAF was made. She had an operation for TIAF, tracheoplasty with bypass graft. Subsequently, she was discharged after 15 weeks. In the present report, we describe a case of TIAF, which can occur in the patients with tracheostomy tube during rehabilitation. PMID- 23342325 TI - A case of delayed onset nephrogenic systemic fibrosis after gadolinium based contrast injection. AB - Nephrogenic systemic fibrosis (NSF) is a rare fibrosing disorder of the skin and joints that occurs in patients with advanced renal insufficiency. This condition is progressive and can be seriously disabling. Gadolinium based contrast agent (GBCA) has been identified as a potential cause of this condition. A 56-years-old man in hemodialysis developed stiffness and contracture of the whole limbs eight years after frequent GBCA exposure for cervical magnetic resonance imaging. For the first time in Korea, we report late-onset nephrogenic systemic fibrosis after GBCA exposure and performed an electrophysiologic study of this condition. PMID- 23342326 TI - Corticospinal tract and pontocerebellar fiber of central pontine myelinolysis. AB - Central pontine myelinolysis is a rare neurologic disorder that is defined by demyelination of longitudinally descending tracts and transversly crossing fibers in the basis pontis. Frequently observed clinical manifestations of this disorder include sudden weakness, dysphagia, loss of consciouness and locked-in syndrome. However, there have been a few studies that reported a benign course of this disease, which include cerebellar signs, such as ataxia, intention tremor, and dysarthria. Here we report on a 53-year-old male with a history of liver cirrhosis who showed the cerebellar type of central pontine myelinolysis. The patient was diagnosed with central pontine myelinolysis based on clinical presentations and magnetic resonance imaging findings after a liver transplantation. Conventional magenetic resonance imaging (MRI) revealed the preservation of the corticospinal tract and abnormal pontocerebellar fibers. However, these findings were not sufficient to define the pathophysiology of our patient. Electrophysiologic analysis and diffusion tensor imaging (DTI) were performed to investigate cerebellar signs in this case. Delayed central motor conduction time (CMCT) to the tibialis anterior muscle with transcranial magnetic stimulation (TMS) was observed, which indicated demyelination of the corticospinal tract. Also, diffusion tensor imaging showed abnormal pontocerebellar fibers, which might have been caused by cerebellar dysfunction in our patient. A combination of TMS and DTI was also used to determine the pathophysiology of this disease. PMID- 23342327 TI - Extensive intramuscular venous malformation in the lower extremity. AB - Typical venous malformations are easily diagnosed by skin color changes, focal edema or pain. Venous malformation in the skeletal muscles, however, has the potential to be missed because their involved sites are invisible and the disease is rare. In addition, the symptoms of intramuscular venous malformation overlaps with myofascial pain syndrome or muscle strain. Most venous malformation cases have reported a focal lesion involved in one or adjacent muscles. In contrast, we have experienced a case of intramuscular venous malformation that involved a large number of muscles in a lower extremity extensively. PMID- 23342328 TI - Mere idle curiosity, or do we need a new narrative? PMID- 23342329 TI - Prospective clinical split-mouth study of pressed and CAD/CAM all-ceramic partial coverage restorations: 7-year results. AB - The aim of this prospective clinical split-mouth study was to investigate the longterm performance of pressed and computer-aided design/computer-assisted manufacture (CAD/CAM) all-ceramic partial-coverage restorations (PCRs). Twentyfive patients were restored with 40 lithium disilicate pressed PCRs (IPS e.max-Press, Ivoclar Vivadent) and 40 leucite-reinforced glass-ceramic CAD/CAM PCRs (ProCAD, Ivoclar Vivadent). All restorations were placed in vital first or second molars. The 7-year Kaplan-Meier survival rate was 100% for pressed PCRs and 97% for CAD/ CAM PCRs. Both systems showed significant deterioration over time in all modified United States Public Health Service criteria. Increased surface roughness and impaired color match were significantly more prevalent with pressed PCRs. Based on the 7-year data, both all-ceramic systems can be considered reliable treatment options for posterior PCRs. PMID- 23342330 TI - Occlusal schemes for complete dentures: a systematic review. AB - PURPOSE: The aim of this study was to qualitatively review the literature regarding occlusal schemes for complete dentures. MATERIALS AND METHODS: An electronic search was executed using PubMed (MEDLINE) with the aid of Boolean operators to combine the following terms: "complete denture," "occlusion," "balanced," "lingualized," "anatomic," "flat," "monoplane," and "canine." The search was limited to English peer-reviewed articles published up to January 2012. The literature search was supplemented by manual searching of relevant journals and the reference lists of selected articles. RESULTS: A total of 565 articles were retrieved; however, only 12 articles met the inclusion criteria. The included studies evaluated the effects of posterior tooth morphology/arrangement and lateral occlusal guidance. In relation to morphology, the posterior teeth were either anatomical or flat. The posterior tooth arrangements showed conventional bilaterally balanced occlusion (CBBO), lingualized bilaterally balanced occlusion (LBBO), or monoplane occlusion (MO). The lateral occlusal guidance involved either balanced occlusion or anterior tooth-guided occlusion (ATGO). CONCLUSIONS: Within the limitations of this review, it can be concluded that anatomical teeth arranged in CBBO or LBBO are preferable to flat teeth arranged in MO. This is primarily related to patient acceptance. ATGO can also be considered for complete dentures. PMID- 23342331 TI - Tooth replacement related to number of natural teeth in a dentate adult population in Bulgaria: a cross-sectional study. AB - PURPOSE: This study aimed to explore the relationships among tooth replacement, number of present natural teeth, and sociodemographic and behavioral factors in an adult population in Bulgaria. MATERIALS AND METHODS: Quota sampling was used to recruit 2,531 dentate subjects aged 20 years and over from the capital city and four main urban centers, four towns, and seven small towns and villages of Bulgaria. Potential candidates for tooth replacement were classified as having functional dentitions (26 to 27 or 20 to 25 natural teeth present) or subfunctional dentitions (16 to 19 or 2 to 15 natural teeth present), not including third molars. Multiple logistic regression analyses were performed to determine the associations between tooth replacement and the factors of interest. RESULTS: Of the included subjects, 37% presented with tooth replacement, while 19% presented with fewer than 20 natural teeth. Molars were replaced significantly less often (P <= .017) than premolars and anterior teeth. The presence of tooth replacement was more likely in subjects with 2 to 15 teeth (odds ratio: 1.62) and less likely in subjects with 26 to 27 teeth (odds ratio: 0.29), but no significant difference was detected between subjects with 16 to 19 and 20 to 25 teeth. Tooth replacement was associated with age, occupational status, frequency of dental visits, and toothbrushing habits. CONCLUSIONS: In this Bulgarian population, the variables number of present teeth, age, dental visits, and toothbrushing were relevant factors with respect to tooth replacement. The cutoff value of 20 teeth did not discriminate high-risk from low risk subjects. PMID- 23342332 TI - The effect of glycine-powder airflow and hand instrumentation on peri-implant soft tissues: a split-mouth pilot study. AB - Fifteen edentulous patients with overdentures supported by two implants in the mandibular canine regions received periodontal therapy using both hand instrumentation with Teflon curettes and a glycine-based airflow system. Periodontal probing depth (PPD), bleeding on probing (BOP), and bacterial content (BC) within the gingival sulcus were analyzed. A significant effect modification of the glycine airflow with respect to time was found for PPD (P = .01), BOP (P < .001), and BC (P = .004), which were treated as ordered categorical variables. Glycine airflow may be more effective than Teflon curettes for the maintenance of periimplant soft tissues. PMID- 23342333 TI - Clinical and microbiologic effects of lingual cervical coverage by removable partial dentures. AB - PURPOSE: The effect of gingival coverage by removable partial dentures (RPDs) on bacterial accumulation has not been sufficiently established. The aim of this study was to evaluate the periodontal and microbiologic reactions to mandibular major connectors. It was hypothesized that the use of a lingual plate increases the risk of periodontal disease. MATERIALS AND METHODS: Fourteen subjects (mean age: 69.0 years) received oral hygiene instructions and ultrasonic debridement prior to examination. Each subject received an experimental RPD incorporating either a lingual bar or lingual plate for the first 8 weeks and was then switched to the other option for the next 8 weeks. Clinical parameters (Plaque Index, Gingival Index, probing depth, and tooth mobility) were recorded. Subgingival plaque samples were collected from the periodontal pocket in the test site to measure the colonization of periodontal pathogens after the use of each denture. RESULTS: The mean probing depth was significantly greater after use of the lingual plate compared to the lingual bar (P < .05), whereas the type of connector did not affect the levels of any of the microbial species. All subjects that exhibited at least one bacterial species showed smaller numbers of microorganisms at the second examination than at the first. CONCLUSIONS: The lingual cervical coverage did not precipitate the accumulation of anaerobic microorganisms, although it could potentially induce gingival inflammation. The results suggest that a lingual plate can be used as safely as a lingual bar if oral and denture hygiene are carefully monitored. PMID- 23342334 TI - The reproduction of implants and prepared teeth in one final master cast: a case report. AB - This case report describes a method to produce one final master cast for the simultaneous prosthetic treatment of implants and natural teeth in a single arch. After tooth preparation, a first impression was used to fabricate electroformed crown frameworks. In the next appointment, the crown frameworks were seated and collected with the implant transfer copings in a single-phase fixation impression, which was used to fabricate a final master cast. This procedure divides the treatment process into distinct steps, leading to a faster and less challenging workflow. PMID- 23342335 TI - Effects of abutment and screw access channel modification on dislodgement of cement-retained implant-supported restorations. AB - This study investigated the influence of implant abutment and screw access channel modification on the retention of copings. Titanium abutment access openings were either left open or modified by placing two vent holes 3 mm from the occlusal edge and 180 degrees apart. Access openings sealed with a resin material were used as controls. Metal copings were cemented and subjected to tensile testing until failure. Access openings with two vent holes resulted in significantly higher mean retention values compared to the opened or sealed screw access groups (P < .05). Cement flow was affected by the internal vent, which increased the area of cementabutment contact. PMID- 23342336 TI - Current state of craniofacial prosthetic rehabilitation. AB - PURPOSE: This study aimed to review the current state of the techniques and materials used to rehabilitate maxillofacial defects. MATERIALS AND METHODS: The MEDLINE and EMBASE databases were searched for articles pertinent to maxillofacial prostheses published from January 1990 to July 2011. The main clinical stages were the subject of analysis. RESULTS: A multidisciplinary approach is preferred when rehabilitating maxillofacial defects. Surgical reconstruction can be used for smaller defects, but larger defects require a prosthesis to achieve an esthetic rehabilitation. Implant retained prostheses are preferred over adhesive prostheses. Silicone elastomer is currently the best material available for maxillofacial prostheses; however, longevity and discoloration, which are greatly influenced by ultraviolet radiation, microorganisms, and environmental factors, remain significant problems. In the near future, the widespread availability and cost effectiveness of digital systems may improve the workflow and outcomes of facial prostheses. Patients report high satisfaction with their prostheses despite some areas that still need improvement. CONCLUSIONS: Maxillofacial prostheses are a reliable treatment option to restore maxillofacial defects and improve quality of life. Significant progress has been made in the application of implants for retention and digital technology for designing surgical guides, suprastructures, and craniofacial prostheses. Further improvements are necessary to enhance longevity of prostheses. PMID- 23342337 TI - The influence of relining or implant retaining existing mandibular dentures on health-related quality of life: a 2-year randomized study of dissatisfied edentulous patients. AB - PURPOSE: The purpose was to assess and compare self-reported oral health and oral and general health related quality of life (OHRQoL and HRQoL) in two groups of edentulous adults who reported dissatisfaction with their mandibular dentures, and who were treated with a conventional relining of this denture or by having it converted into an implant-retained one. MATERIALS AND METHODS: Sixty subjects were randomly allocated into two equal groups, a relined conventional denture (RCD) group and an implant-retained overdenture (IOD) group. Data on demographics, oral health, OHRQoL, and HRQoL were recorded by means of a self administered questionnaire at baseline, 3 months, and 2 years. RESULTS: Fifty four subjects completed the protocol, 28 in the IOD-group and 26 in the RCD group. The IOD group reported significant improvement in oral health and Oral Health Impact Profile (OHIP-20) sum score and all its domains after 3 months. The improvements remained stable at the 2-year control. The RCD group reported almost no significant improvements. Neither group reported improved HRQoL. CONCLUSION: The results of this study support the findings from other RCT studies that to implant-retain the mandibular denture significantly improves self-reported oral health and OHRQoL. This treatment modality should be a minimum standard of care in complete denture wearers dissatisfied with their mandibular denture. PMID- 23342338 TI - Polishing of denture base acrylic resin with chairside polishing kits: an SEM and surface roughness study. AB - Heat-cured acrylic resin specimens were polished using either conventional laboratory polishing, sandpaper, or three commercial chairside kits. The surface roughness of the polished specimens was measured with a contact profilometer. Scanning electron microscopy was used to obtain microphotographs of the polished surfaces. Laboratory polishing produced the smoothest surfaces in all cases, while sandpaper application produced the roughest. Use of the chairside polishing kits resulted in significantly rougher surfaces compared to those produced by laboratory polishing. Nonetheless, polishing of trimmed denture bases using chairside polishing kits is an effective alternative procedure for cases in which the laboratory procedure is not applicable. PMID- 23342339 TI - Retentiveness of various luting agents used with implant-supported prostheses: a preliminary in vitro study. AB - The aim of this preliminary in vitro study was to compare the retentiveness of a luting agent designed for use with dental implants to luting agents designed for use with tooth-retained restorations. The following luting agents were tested: (1) implant cement, (2) resin-bonded zinc oxide-eugenol cement, (3) zinc phosphate cement, (4) zinc polycarboxylate cement, and (5) glass-ionomer cement. After cementation, each sample was subjected to a pull-out test using a universal testing machine, and the loads required to remove the crowns were recorded. The mean values and standard deviations of cement failure loads were analyzed using analysis of variance and the Bonferroni test. The mean cement failure loads (N) were 333.86 +/- 18.91 for implant cement, 394.62 +/- 9.76 for resin-bonded zinc oxide-eugenol cement, 629.30 +/- 20.65 for zinc phosphate cement, 810.08 +/- 11.52 for zinc polycarboxylate cement, and 750.17 +/- 13.78 for glass-ionomer cement. The retention provided by polycarboxylate cement was significantly greater than that of all other luting agents; the implant cement showed the lowest retention values. These preliminary in vitro observations need to be confirmed under conditions that more closely approximate the clinical environment. PMID- 23342340 TI - Effect of the spray pattern, water flow rate, and cutting position on the cutting efficiency of high-speed dental handpieces. AB - The aim of this study was to evaluate the effect of the spray pattern, water flow rate, and cutting position on the cutting efficiency of high-speed dental handpieces. One- and three-port high-speed handpieces were selected. Cutting efficiency (mm/s) in different cutting positions was evaluated in vitro on machinable ceramic underwater flow rates of 15, 25, and 35 mL/min. Statistical analysis revealed significant differences in cutting efficiency for the various cutting positions and flow rates. The authors recommend multiport handpieces with a flow rate greater than 30 mL/min for use in clinical practice, especially during groove cutting. PMID- 23342341 TI - On crestal/marginal bone loss around dental implants. PMID- 23342342 TI - New bone formation at the site of autotransplanted developing mandibular canines: a case report. AB - Until recently, adequate bone at the recipient site has been a determinant for tooth autotransplantation. This article presents the transplantation of developing mandibular canines to a suboptimal position because of inadequate bone at the recipient sites. Five years later, after eruption and orthodontic alignment, all criteria for successful healing were fulfilled. In addition, new bone that was not present at the time of surgery was identified at the roots of the transplanted teeth, implying that transplanted developing teeth can stimulate bone to grow along their roots. PMID- 23342343 TI - Treatment of peri-implantitis around TiUnite-surface implants using Er:YAG laser microexplosions. AB - Implant therapy can lead to peri-implantitis, and none of the methods used to treat this inflammatory response have been predictably effective. It is nearly impossible to treat infected surfaces such as TiUnite (a titanium oxide layer) that promote osteoinduction, but finding an effective way to do so is essential. Experiments were conducted to determine the optimum irradiation power for stripping away the contaminated titanium oxide layer with Er:YAG laser irradiation, the degree of implant heating as a result of Er:YAG laser irradiation, and whether osseointegration was possible after Er:YAG laser microexplosions were used to strip a layer from the surface of implants placed in beagle dogs. The Er:YAG laser was effective at removing an even layer of titanium oxide, and the use of water spray limited heating of the irradiated implant, thus protecting the surrounding bone tissue from heat damage. PMID- 23342344 TI - Histologic evaluation of a retrieved endosseous implant: a case report. AB - An implant that had penetrated the nasal cavity of a 53-year-old woman was removed after 10 months. The implant had a resorbable blast media surface and an external connection. Histomorphometric evaluation showed that the mean bone implant contact ratio was 88.08%, and excellent osseointegration was observed. The mean bone fill between threads was 78.46%. PMID- 23342345 TI - Influence of enamel preservation on failure rates of porcelain laminate veneers. AB - The purpose of this study was to evaluate the failure rates of porcelain laminate veneers (PLVs) and the influence of clinical parameters on these rates in a retrospective survey of up to 12 years. Five hundred eighty laminate veneers were bonded in 66 patients. The following parameters were analyzed: type of preparation (depth and margin), crown lengthening, presence of restoration, diastema, crowding, discoloration, abrasion, and attrition. Survival was analyzed using the Kaplan-Meier method. Cox regression modeling was used to determine which factors would predict PLV failure. Forty-two veneers (7.2%) failed in 23 patients, and an overall cumulative survival rate of 86% was observed. A statistically significant association was noted between failure and the limits of the prepared tooth surface (margin and depth). The most frequent failure type was fracture (n = 20). The results revealed no significant influence of crown lengthening apically, presence of restoration, diastema, discoloration, abrasion, or attrition on failure rates. Multivariable analysis (Cox regression model) also showed that PLVs bonded to dentin and teeth with preparation margins in dentin were approximately 10 times more likely to fail than PLVs bonded to enamel. Moreover, coronal crown lengthening increased the risk of PLV failure by 2.3 times. A survival rate of 99% was observed for veneers with preparations confined to enamel and 94% for veneers with enamel only at the margins. Laminate veneers have high survival rates when bonded to enamel and provide a safe and predictable treatment option that preserves tooth structure. PMID- 23342346 TI - Subepithelial connective tissue graft with growth factor for the treatment of maxillary gingival recession defects. AB - Gingival recession is a challenging defect for clinicians to treat effectively. A number of recent systematic reviews have identified the connective tissue graft (CTG) in combination with coronally advanced flaps (CAFs) as the most consistently effective treatment for Miller Class I and II defects across all outcome measures. Recent advances in recombinant growth factor technology may provide opportunities for improved outcomes in conjunction with CAF + CTG procedures. In this prospective consecutive case series, recombinant human platelet-derived growth factor BB (rhPDGF-BB) was combined with CTGs for the treatment of Miller Class I or II gingival recession defects. Improved outcomes were seen for keratinized tissue gains and percent root coverage at 6 months postsurgery when compared to historic norms. All other outcome parameters appeared equivalent between the two treatment approaches. The addition of rhPDGF BB appeared to improve early wound healing as well. PMID- 23342347 TI - Virtual abutment design: a concept for delivery of CAD/CAM customized abutments-- report of a retrospective cohort. AB - This report presents early clinical experiences with the treatment of a consecutive cohort of 89 patients who received 125 prostheses supported by 205 milled abutments. Abutments were fabricated using unique computer-aided design software to deliver both titanium and zirconia abutments based on idealized values for tooth dimensions and emergence profiles as well as on a scan of the proposed definitive prosthesis. PMID- 23342348 TI - Radiographic appearance of commonly used cements in implant dentistry. AB - Cement-retained restorations allow for a conventional fixed partial denture approach to restoring dental implants. However, inadequate removal of excess cement at the time of cementation may introduce a severe complication: cement induced peri-implantitis. Radiopaque cements are more easily detected on radiographs and should improve the recognition of extravasated cement at the time of insertion. The purpose of this study was to evaluate the radiopacity of commercially available cements in vitro. Eighteen different cements commonly used for luting restorations to implants were tested at both 0.5- and 1.0-mm thicknesses. The cements examined were zinc oxide eugenol, zinc oxide, zinc polycarboxylate, zinc phosphate, resin-reinforced glass ionomer, urethane resin, resin, and composite resin. Two samples of each cement thickness underwent standardized radiography next to an aluminum step wedge as a reference. The mean grayscale value of each of the nine 1-mm steps in the step wedge were used as reference values and compared to each of the cement samples. Temp Bond Clear (resin), IMProv (urethane resin), Premier Implant Cement (resin), and Temrex NE (resin) were not radiographically detectable at either sample thickness. Cements containing zinc were the most detectable upon radiographic analysis. There are significant differences in the radiopacity of many commonly used cements. Since cementinduced peri-implantitis can lead to late implant failure, cements that can be visualized radiographically may reduce the incidence of this problem. PMID- 23342349 TI - Ridge preservation with and without primary wound closure: a case series. AB - The purpose of this study was to determine the clinical and histologic efficacy of the combination of alloplastic biphasic calcium phosphate composed of 30% hydroxyapatite and 70% Beta-tricalcium phosphate (Osteon II) and a cross-linked collagen membrane used to reconstruct an extraction socket with new bone formation. Twelve patients, from two private dental practices, requiring extraction of maxillary and mandibular nonmolar teeth (n = 30) received both Osteon II (0.5- to 1.0-mm particle size) and the collagen membrane. The primary healing intention group (group A, n = 12) received primary flap closure over the membrane, while in the secondary healing intention group (group B, n = 18), the membrane was left exposed. Early wound healing seemed to be slower in group B when compared to group A, but the difference was not noticeable after 4 weeks. Clinical reentry revealed that the dimensions of the ridge appeared to be maintained in both groups, and internal socket bone fill was evident. The grafted area appeared to be well vascularized, but clinically visible graft particles were noted in some cases. Light microscopic analysis revealed the formation of new bone directly apposing the surfaces of graft particles and bridging the space between them, indicating that the graft material behaved as an osteoconductive scaffold. The mean amount of vital bone in group A was 40.3% +/- 7.8%, while the remaining graft was 6.0% +/- 4.0%. The mean amount of vital bone in group B was 47.3% +/- 11.3%, while the remaining graft was 18.0% +/- 20.0%. The absence of primary flap closure did not affect the percentage of vital bone formation or residual graft. PMID- 23342350 TI - Surgical management of peri-implant soft tissue color mismatch caused by shine through effects of restorative materials: one-year follow-up. AB - Thin facial soft tissue may lead to visible soft tissue discoloration around implants and therefore to esthetic deficiencies. The aim of this article is to present a surgical approach to peri-implant soft tissue discoloration caused by the shinethrough effects of restorative materials in the anterior maxilla. A clinical case is used to illustrate the approach. A minimally invasive tunneling approach and connective tissue graft are used. The optical outcome is documented in an objective and standardized manner using a spectrophotometer after a follow up of 12 months. The presented technique clearly improved the clinical condition and esthetic outcome. Spectrophotometric follow-up revealed a soft tissue color difference between the implant and adjacent tooth (control) that was clearly less than initially presented. In the area 3 mm apical to the soft tissue margin, this difference was beneath the clinically perceptible threshold of 3.7. PMID- 23342351 TI - Pre-extractive interradicular implant bed preparation: case presentations of a novel approach to immediate implant placement at multirooted molar sites. AB - Immediate implant placement at multirooted molar sites involves a series of site specific anatomical challenges, including implant bed preparation in the presence of interradicular bone septa. The aim of this article is to present and discuss a novel approach that gives improved guidance during implant bed preparation for immediate implants at multirooted extraction sites in both the mandible and maxilla. Following decoronation of the concerned teeth, osteotomies were performed directly through the teeth's initially retained root complexes. After completion of the drilling protocol, the remaining root aspects were extracted, and treatment was continued in the usual manner. With the osteotomy drills stabilized and guided by the retained root aspects, this approach allows for precise positioning and angulation of the implant bed preparation, thus enabling ideal implant positioning during immediate implant placement at multirooted extraction sites. PMID- 23342352 TI - Recombinant human bone morphogenetic protein 2 in lateral ridge augmentation. AB - This case report describes the augmentation of severe lateral ridge defects in the maxilla and mandible using recombinant human bone morphogenetic protein 2 (rhBMP-2) on an absorbable collagen sponge (ACS). The surgical technique used tenting screws and a membrane to maintain space for the ACS. After 7 months of healing, the ridge width increased from 1 to 2 mm to 6 to 9 mm, thus allowing successful placement of dental implants. De novo bone formation through use of the surgical technique for space maintenance of rhBMP-2/ACS was demonstrated without the need for additional particulate bone grafting. PMID- 23342353 TI - In vitro color changes of soft tissues caused by dyed fluorescent zirconia and nondyed, nonfluorescent zirconia in thin mucosa. AB - Abutment material selection may have an effect on the color of the peri-implant soft tissue, especially in thin mucosa. The objective of this in vitro study was to investigate the effect of titanium, zirconia, and dyed fluorescent zirconia on the color of 1.5-mm-thick mucosa. Ten pig maxillae were used to simulate thin mucosa according to a previously published setup. Three different abutment materials were placed under the mucosa, and the color of the soft tissue was evaluated using a spectrophotometer. The test area without underlying material was used as a control. Whereas titanium induced visible color change values of DeltaE7.3, significantly above the threshold level of DeltaE3.7 (P < .05, Student t test), the changes after insertion of zirconia ( DeltaE3.7) and dyed fluorescent zirconia (3.5) were not statistically different from the visible threshold of DeltaE3.7 (P < .05, Student t test). The difference between the two zirconia specimens was not statistically significant, although the dyed zirconia material was darker; the color difference was DeltaE10.35 between the two. In contrast to titanium, neither nondyed zirconia nor dyed fluorescent zirconia changed the gingival coloration. Moreover, shading of white zirconia with a fluorescent dye leads to an all-ceramic abutment material that mimics the optical properties of natural teeth. PMID- 23342354 TI - Impact of interleukin 1 gene polymorphism and smoking on long-term stability following gingival recession treatment. AB - Risk factors such as smoking, genetic factors, and tissue biotype play an important role in the etiology, predictability, and long-term stability of gingival recession treatment. This study was designed to evaluate the influence of interleukin 1 (IL-1) polymorphism and smoking on the stability of gingival recession treatment after 1 and 3 years. All patients (n = 55) were treated for type I and II recession defects using a connective tissue graft. Clinical evaluations were performed, which included assessment of vertical recession depth, gingival inflammation, and clinical attachment level. A fingerstick blood sample was collected using specially provided DNA filter paper and mailed for processing in a laboratory using polymerase chain reaction-based methodology. The results indicated that 19 subjects were genotype positive (34.5%). Treatment of the localized recessions was effective and provided a similar amount of coverage in genotype-positive and genotype-negative subjects within smoking and nonsmoking groups after 1 year. In a 3-year period, nonsmoking patients with positive IL-1 genotype lost approximately 20% of the root coverage gained at 1 year and were almost four times more inferior compared with genotype-negative patients. Patients who smoked and had a positive IL-1 genotype lost approximately 35% of the gained root coverage. IL-1 polymorphism and smoking habit did not affect gingival recession treatment at 1 year but had a great impact on long-term stability. PMID- 23342355 TI - Proximal socket shield for interimplant papilla preservation in the esthetic zone. AB - Managing the interimplant papilla is one of the most challenging tasks in anterior implant esthetics, especially when replacing a failing tooth adjacent to an existing implant restoration. This article describes the maintenance of the interimplant papilla when replacing a failing tooth adjacent to an implant restoration using the proximal socket shield procedure in conjunction with immediate implant placement and provisionalization. PMID- 23342356 TI - Effect of various putty-wash impression techniques on marginal fit of cast crowns. AB - Marginal fit is an important clinical factor that affects restoration longevity. The accuracy of three polyvinyl siloxane putty-wash impression techniques was compared by marginal fit assessment using the nondestructive method. A stainless steel master cast containing three abutments with three metal crowns matching the three preparations was used to make 45 impressions: group A = single-step technique (putty and wash impression materials used simultaneously), group B = two-step technique with a 2-mm relief (putty as a preliminary impression to create a 2-mm wash space followed by the wash stage), and group C = two-step technique with a polyethylene spacer (plastic spacer used with the putty impression followed by the wash stage). Accuracy was assessed using a toolmaker microscope to measure and compare the marginal gaps between each crown and finish line on the duplicated stone casts. Each abutment was further measured at the mesial, buccal, and distal aspects. One-way analysis of variance was used for statistical analysis. P values and Scheffe post hoc contrasts were calculated. Significance was determined at .05. One-way analysis of variance showed significant differences among the three impression techniques in all three abutments and at all three locations (P < .001). Group B yielded dies with minimal gaps compared to groups A and C. The two-step impression technique with 2 mm relief was the most accurate regarding the crucial clinical factor of marginal fit. PMID- 23342357 TI - Analysis of soft tissue display during enjoyment smiling: part 1--Caucasians. AB - Esthetic considerations have become increasingly important in dental therapy. Evaluation of the soft tissue display during enjoyment smiling can provide useful information for esthetic oral rehabilitation. To date, no study has quantified the amount and frequency of soft tissue display in the area of the papilla. Photographic examination of 66 fully dentate patients with a mean age of 28.5 years was performed during enjoyment smiling. Digital processing and measurement of the tooth, gingival, and papillary display revealed that over 90% of subjects displayed papillae in the anterior teeth and first premolars during enjoyment smiling regardless of sex. The frequency of display in descending order consisted of maxillary lateral incisors (96%), central incisors (94%), canines (94%), first premolars (91%), second premolars (85%), and first molars (39%). The mean papillary display was 3.4 mm (range, 0.0 to 10.0 mm). There was no significant difference in the amount of papillary display between the sexes for anterior teeth, premolars, or first molars (P = .97, P = .79, and P = .48, respectively). PMID- 23342358 TI - Enhancement of the spectral selectivity of complex samples by measuring them in a frozen state at low temperatures in order to improve accuracy for quantitative analysis. Part II. Determination of viscosity for lube base oils using Raman spectroscopy. AB - The use of selectivity-enhanced Raman spectra of lube base oil (LBO) samples achieved by the spectral collection under frozen conditions at low temperatures was effective for improving accuracy for the determination of the kinematic viscosity at 40 degrees C (KV@40). A collection of Raman spectra from samples cooled around -160 degrees C provided the most accurate measurement of KV@40. Components of the LBO samples were mainly long-chain hydrocarbons with molecular structures that were deformable when these were frozen, and the different structural deformabilities of the components enhanced spectral selectivity among the samples. To study the structural variation of components according to the change of sample temperature from cryogenic to ambient condition, n-heptadecane and pristane (2,6,10,14-tetramethylpentadecane) were selected as representative components of LBO samples, and their temperature-induced spectral features as well as the corresponding spectral loadings were investigated. A two-dimensional (2D) correlation analysis was also employed to explain the origin for the improved accuracy. The asynchronous 2D correlation pattern was simplest at the optimal temperature, indicating the occurrence of distinct and selective spectral variations, which enabled the variation of KV@40 of LBO samples to be more accurately assessed. PMID- 23342359 TI - Respiratory syncytial virus persistence in macrophages alters the profile of cellular gene expression. AB - Viruses can persistently infect differentiated cells through regulation of expression of both their own genes and those of the host cell, thereby evading detection by the host's immune system and achieving residence in a non-lytic state. Models in vitro with cell lines are useful tools in understanding the mechanisms associated with the establishment of viral persistence. In particular, a model to study respiratory syncytial virus (RSV) persistence in a murine macrophage-like cell line has been established. Compared to non-infected macrophages, macrophages persistently infected with RSV show altered expression both of genes coding for cytokines and trans-membrane proteins associated with antigen uptake and of genes related to cell survival. The biological changes associated with altered gene expression in macrophages as a consequence of persistent RSV infection are summarized. PMID- 23342360 TI - Host genetic variants in the pathogenesis of hepatitis C. AB - Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA) were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR) and ABCB11 (bile salt export pump). Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment. PMID- 23342361 TI - The Staphylococci phages family: an overview. AB - Due to their crucial role in pathogenesis and virulence, phages of Staphylococcus aureus have been extensively studied. Most of them encode and disseminate potent staphylococcal virulence factors. In addition, their movements contribute to the extraordinary versatility and adaptability of this prominent pathogen by improving genome plasticity. In addition to S. aureus, phages from coagulase negative Staphylococci (CoNS) are gaining increasing interest. Some of these species, such as S. epidermidis, cause nosocomial infections and are therefore problematic for public health. This review provides an overview of the staphylococcal phages family extended to CoNS phages. At the morphological level, all these phages characterized so far belong to the Caudovirales order and are mainly temperate Siphoviridae. At the molecular level, comparative genomics revealed an extensive mosaicism, with genes organized into functional modules that are frequently exchanged between phages. Evolutionary relationships within this family, as well as with other families, have been highlighted. All these aspects are of crucial importance for our understanding of evolution and emergence of pathogens among bacterial species such as Staphylococci. PMID- 23342364 TI - Infertility: management in Australian general practice. AB - From April 2007 to March 2012 in the BEACH (Bettering the Evaluation and Care of Health) program, infertility/subfertility was managed at 652 encounters with 534 general practitioners (1.3 per 1000 encounters). PMID- 23342362 TI - Host cell factors in filovirus entry: novel players, new insights. AB - Filoviruses cause severe hemorrhagic fever in humans with high case-fatality rates. The cellular factors exploited by filoviruses for their spread constitute potential targets for intervention, but are incompletely defined. The viral glycoprotein (GP) mediates filovirus entry into host cells. Recent studies revealed important insights into the host cell molecules engaged by GP for cellular entry. The binding of GP to cellular lectins was found to concentrate virions onto susceptible cells and might contribute to the early and sustained infection of macrophages and dendritic cells, important viral targets. Tyrosine kinase receptors were shown to promote macropinocytic uptake of filoviruses into a subset of susceptible cells without binding to GP, while interactions between GP and human T cell Ig mucin 1 (TIM-1) might contribute to filovirus infection of mucosal epithelial cells. Moreover, GP engagement of the cholesterol transporter Niemann-Pick C1 was demonstrated to be essential for GP-mediated fusion of the viral envelope with a host cell membrane. Finally, mutagenic and structural analyses defined GP domains which interact with these host cell factors. Here, we will review the recent progress in elucidating the molecular interactions underlying filovirus entry and discuss their implications for our understanding of the viral cell tropism. PMID- 23342363 TI - Innate immunity to H5N1 influenza viruses in humans. AB - Avian influenza virus infections in the human population are rare due to their inefficient direct human-to-human transmission. However, when humans are infected, a strong inflammatory response is usually induced, characterized by elevated levels of cytokines and chemokines in serum, believed to be important in the severe pathogenesis that develops in a high proportion of these patients. Extensive research has been performed to understand the molecular viral mechanisms involved in the H5N1 pathogenesis in humans, providing interesting insights about the virus-host interaction and the regulation of the innate immune response by these highly pathogenic viruses. In this review we summarize and discuss the most important findings in this field, focusing mainly on H5N1 virulence factors and their impact on the modulation of the innate immunity in humans. PMID- 23342365 TI - Prion disease and the innate immune system. AB - Prion diseases or transmissible spongiform encephalopathies are a unique category of infectious protein-misfolding neurodegenerative disorders. Hypothesized to be caused by misfolding of the cellular prion protein these disorders possess an infectious quality that thrives in immune-competent hosts. While much has been discovered about the routing and critical components involved in the peripheral pathogenesis of these agents there are still many aspects to be discovered. Research into this area has been extensive as it represents a major target for therapeutic intervention within this group of diseases. The main focus of pathological damage in these diseases occurs within the central nervous system. Cells of the innate immune system have been proven to be critical players in the initial pathogenesis of prion disease, and may have a role in the pathological progression of disease. Understanding how prions interact with the host innate immune system may provide us with natural pathways and mechanisms to combat these diseases prior to their neuroinvasive stage. We present here a review of the current knowledge regarding the role of the innate immune system in prion pathogenesis. PMID- 23342368 TI - The doctor-patient. PMID- 23342367 TI - The Pneumonia Virus of Mice (PVM) model of acute respiratory infection. AB - Pneumonia Virus of Mice (PVM) is related to the human and bovine respiratory syncytial virus (RSV) pathogens, and has been used to study respiratory virus replication and the ensuing inflammatory response as a component of a natural host-pathogen relationship. As such, PVM infection in mice reproduces many of the clinical and pathologic features of the more severe forms of RSV infection in human infants. Here we review some of the most recent findings on the basic biology of PVM infection and its use as a model of disease, most notably for explorations of virus infection and allergic airways disease, for vaccine evaluation, and for the development of immunomodulatory strategies for acute respiratory virus infection. PMID- 23342369 TI - Oral glucose tolerance testing. PMID- 23342366 TI - Epstein-Barr Virus (EBV)-associated gastric carcinoma. AB - The ubiquitous Epstein-Barr virus (EBV) is associated with several human tumors, which include lymphoid and epithelial malignancies. It is known that EBV persistently infects the memory B cell pool of healthy individuals by activating growth and survival signaling pathways that can contribute to B cell lymphomagenesis. Although the monoclonal proliferation of EBV-infected cells can be observed in epithelial tumors, such as nasopharyngeal carcinoma and EBV associated gastric carcinoma, the precise role of EBV in the carcinogenic progress is not fully understood. This review features characteristics and current understanding of EBV-associated gastric carcinoma. EBV-associated gastric carcinoma comprises almost 10% of all gastric carcinoma cases and expresses restricted EBV latent genes (Latency I). Firstly, definition, epidemiology, and clinical features are discussed. Then, the route of infection and carcinogenic role of viral genes are presented. Of particular interest, the association with frequent genomic CpG methylation and role of miRNA for carcinogenesis are topically discussed. Finally, the possibility of therapies targeting EBV associated gastric carcinoma is proposed. PMID- 23342370 TI - Health professionals prescribing pathway project. PMID- 23342372 TI - Gatekeeper, shopkeeper, scientist, coach? PMID- 23342371 TI - A systems biology starter kit for arenaviruses. AB - Systems biology approaches in virology aim to integrate viral and host biological networks, and thus model the infection process. The growing availability of high throughput "-omics" techniques and datasets, as well as the ever-increasing sophistication of in silico modeling tools, has resulted in a corresponding rise in the complexity of the analyses that can be performed. The present study seeks to review and organize published evidence regarding virus-host interactions for the arenaviruses, from alterations in the host proteome during infection, to reported protein-protein interactions. In this way, we hope to provide an overview of the interplay between arenaviruses and the host cell, and lay the foundations for complementing current arenavirus research with a systems-level approach. PMID- 23342373 TI - Endocytic pathways involved in filovirus entry: advances, implications and future directions. AB - Detailed knowledge of the host-virus interactions that accompany filovirus entry into cells is expected to identify determinants of viral virulence and host range, and to yield targets for the development of antiviral therapeutics. While it is generally agreed that filovirus entry into the host cytoplasm requires viral internalization into acidic endosomal compartments and proteolytic cleavage of the envelope glycoprotein by endo/lysosomal cysteine proteases, our understanding of the specific endocytic pathways co-opted by filoviruses remains limited. This review addresses the current knowledge on cellular endocytic pathways implicated in filovirus entry, highlights the consensus as well as controversies, and discusses important remaining questions. PMID- 23342376 TI - Proceedings of the 2nd International Congress on Environmental Health (ICEH2012), May/June 2012, Lisbon, Portugal. PMID- 23342375 TI - Neonatal calf infection with respiratory syncytial virus: drawing parallels to the disease in human infants. AB - Respiratory syncytial virus (RSV) is the most common viral cause of childhood acute lower respiratory tract infections. It is estimated that RSV infections result in more than 100,000 deaths annually worldwide. Bovine RSV is a cause of enzootic pneumonia in young dairy calves and summer pneumonia in nursing beef calves. Furthermore, bovine RSV plays a significant role in bovine respiratory disease complex, the most prevalent cause of morbidity and mortality among feedlot cattle. Infection of calves with bovine RSV shares features in common with RSV infection in children, such as an age-dependent susceptibility. In addition, comparable microscopic lesions consisting of bronchiolar neutrophilic infiltrates, epithelial cell necrosis, and syncytial cell formation are observed. Further, our studies have shown an upregulation of pro-inflammatory mediators in RSV-infected calves, including IL-12p40 and CXCL8 (IL-8). This finding is consistent with increased levels of IL-8 observed in children with RSV bronchiolitis. Since rodents lack IL-8, neonatal calves can be useful for studies of IL-8 regulation in response to RSV infection. We have recently found that vitamin D in milk replacer diets can be manipulated to produce calves differing in circulating 25-hydroxyvitamin D3. The results to date indicate that although the vitamin D intracrine pathway is activated during RSV infection, pro inflammatory mediators frequently inhibited by the vitamin D intacrine pathway in vitro are, in fact, upregulated or unaffected in lungs of infected calves. This review will summarize available data that provide parallels between bovine RSV infection in neonatal calves and human RSV in infants. PMID- 23342374 TI - Epstein-Barr virus in systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis-association and causation. AB - Epidemiological data suggest that the Epstein-Barr virus (EBV) is associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. However, it is not clear whether EBV plays a role in the pathogenesis of these diseases, and if so, by which mechanisms the virus may contribute. In this review, we discuss possible viral and immunological mechanisms that might explain associations between EBV and autoimmune diseases and whether these associations represent causes or effects of inflammation and autoimmunity. PMID- 23342379 TI - Isolation, structure elucidation and total synthesis of lajollamide A from the marine fungus Asteromyces cruciatus. AB - The marine-derived filamentous fungus Asteromyces cruciatus 763, obtained off the coast of La Jolla, San Diego, USA, yielded the new pentapeptide lajollamide A (1), along with the known compounds regiolone (2), hyalodendrin (3), gliovictin (4), 1N-norgliovicitin (5), and bis-N-norgliovictin (6). The planar structure of lajollamide A (1) was determined by Nuclear Magnetic Resonance (NMR) spectroscopy in combination with mass spectrometry. The absolute configuration of lajollamide A (1) was unambiguously solved by total synthesis which provided three additional diastereomers of 1 and also revealed that an unexpected acid-mediated partial racemization (2:1) of the L-leucine and L-N-Me-leucine residues occurred during the chemical degradation process. The biological activities of the isolated metabolites, in particular their antimicrobial properties, were investigated in a series of assay systems. PMID- 23342378 TI - Hepatitis C virus in American Indian/Alaskan Native and Aboriginal peoples of North America. AB - Liver diseases, such as hepatitis C virus (HCV) infection, are "broken spirit" diseases. The prevalence of HCV infection for American Indian/Alaskan Native (AI/AN) in the United States and Canadian Aboriginals varies; nonetheless, incidence rates of newly diagnosed HCV infection are typically higher relative to non-indigenous people. For AI/AN and Aboriginal peoples risk factors for the diagnosis of HCV infection can reflect that of the general population: predominately male, a history of injection drug use, in midlife years, with a connection with urban centers. However, the face of the indigenous HCV infected individual is becoming increasingly female and younger compared to non-indigenous counterparts. Epidemiology studies indicate that more effective clearance of acute HCV infection can occur for select Aboriginal populations, a phenomenon which may be linked to unique immune characteristics. For individuals progressing to chronic HCV infection treatment outcomes are comparable to other racial cohorts. Disease progression, however, is propelled by elevated rates of co morbidities including type 2 diabetes and alcohol use, along with human immunodeficiency virus (HIV) co-infection relative to non-indigenous patients. Historical and personal trauma has a major role in the participation of high risk behaviors and associated diseases. Although emerging treatments provide hope, combating HCV-related morbidity and mortality will require interventions that address the etiology of broken spirit diseases. PMID- 23342380 TI - The impact of regulations, safety considerations and physical limitations on research progress at maximum biocontainment. AB - We describe herein, limitations on research at biosafety level 4 (BSL-4) containment laboratories, with regard to biosecurity regulations, safety considerations, research space limitations, and physical constraints in executing experimental procedures. These limitations can severely impact the number of collaborations and size of research projects investigating microbial pathogens of biodefense concern. Acquisition, use, storage, and transfer of biological select agents and toxins (BSAT) are highly regulated due to their potential to pose a severe threat to public health and safety. All federal, state, city, and local regulations must be followed to obtain and maintain registration for the institution to conduct research involving BSAT. These include initial screening and continuous monitoring of personnel, controlled access to containment laboratories, accurate and current BSAT inventory records. Safety considerations are paramount in BSL-4 containment laboratories while considering the types of research tools, workflow and time required for conducting both in vivo and in vitro experiments in limited space. Required use of a positive-pressure encapsulating suit imposes tremendous physical limitations on the researcher. Successful mitigation of these constraints requires additional time, effort, good communication, and creative solutions. Test and evaluation of novel vaccines and therapeutics conducted under good laboratory practice (GLP) conditions for FDA approval are prioritized and frequently share the same physical space with important ongoing basic research studies. The possibilities and limitations of biomedical research involving microbial pathogens of biodefense concern in BSL-4 containment laboratories are explored in this review. PMID- 23342381 TI - Subtype specific differences in NS5A domain II reveals involvement of proline at position 310 in cyclosporine susceptibility of hepatitis C virus. AB - Hepatitis C virus (HCV) is susceptible to cyclosporine (CsA) and other cyclophilin (CypA) inhibitors, but the genetic basis of susceptibility is controversial. Whether genetic variation in NS5A alters cell culture susceptibility of HCV to CypA inhibition is unclear. We constructed replicons containing NS5A chimeras from genotypes 1a, 2a and 4a to test how variation in carboxy terminal regions of NS5A altered the genotype 1b CsA susceptibility. All chimeric replicons including genotype 1b Con1LN-wt replicon exhibited some cell culture sensitivity to CsA with genotype 4a being most sensitive and 1a the least. The CypA binding pattern of truncated NS5A genotypes correlated with the susceptibility of these replicons to CsA. The Con1LN-wt replicon showed increased susceptibility towards CsA when proline at position 310P was mutated to either threonine or alanine. Furthermore, a 15 amino acid long peptide fused N terminally to GFP coding sequences confirmed involvement of proline at 310 in CypA binding. Our findings are consistent with CypA acting on multiple prolines outside of the previously identified CypA binding sites. These results suggest multiple specific genetic variants between genotype 1a and 1b in the C-terminus of NS5A alter the CsA susceptibility of replicons, and some variants may oppose the effects of others. PMID- 23342382 TI - Reflections on wisdom and self. AB - The end of the year is often a time of reflection. For most of us, 2012 will have brought events that were planned, perhaps for years, as well as others that were full of serendipity or unexpected misfortune. We are invariably older than we were in January. We approach December with our own rituals: summer holidays, Hanukkah, Christmas or New Year's Eve. We may reflect on our joys and disappointments, or our actions and lessons learnt. PMID- 23342383 TI - Add-on assessments of cervical vertebrae after trauma. PMID- 23342384 TI - A sulfated-polysaccharide fraction from seaweed Gracilaria birdiae prevents naproxen-induced gastrointestinal damage in rats. AB - Red seaweeds synthesize a great variety of sulfated galactans. Sulfated polysaccharides (PLSs) from seaweed are comprised of substances with pharmaceutical and biomedical potential. The aim of the present study was to evaluate the protective effect of the PLS fraction extracted from the seaweed Gracilaria birdiae in rats with naproxen-induced gastrointestinal damage. Male Wistar rats were pretreated with 0.5% carboxymethylcellulose (control group vehicle) or PLS (10, 30, and 90 mg/kg, p.o.) twice daily (at 09:00 and 21:00) for 2 days. After 1 h, naproxen (80 mg/kg, p.o.) was administered. The rats were killed on day two, 4 h after naproxen treatment. The stomachs were promptly excised, opened along the greater curvature, and measured using digital calipers. Furthermore, the guts of the animals were removed, and a 5-cm portion of the small intestine (jejunum and ileum) was used for the evaluation of macroscopic scores. Samples of the stomach and the small intestine were used for histological evaluation, morphometric analysis and in assays for glutathione (GSH) levels, malonyldialdehyde (MDA) concentration, and myeloperoxidase (MPO) activity. PLS treatment reduced the macroscopic and microscopic naproxen-induced gastrointestinal damage in a dose-dependent manner. Our results suggest that the PLS fraction has a protective effect against gastrointestinal damage through mechanisms that involve the inhibition of inflammatory cell infiltration and lipid peroxidation. PMID- 23342385 TI - Syphilis screening and treatment. PMID- 23342377 TI - Escape from human immunodeficiency virus type 1 (HIV-1) entry inhibitors. AB - The human immunodeficiency virus (HIV) enters cells through a series of molecular interactions between the HIV envelope protein and cellular receptors, thus providing many opportunities to block infection. Entry inhibitors are currently being used in the clinic, and many more are under development. Unfortunately, as is the case for other classes of antiretroviral drugs that target later steps in the viral life cycle, HIV can become resistant to entry inhibitors. In contrast to inhibitors that block viral enzymes in intracellular compartments, entry inhibitors interfere with the function of the highly variable envelope glycoprotein as it continuously adapts to changing immune pressure and available target cells in the extracellular environment. Consequently, pathways and mechanisms of resistance for entry inhibitors are varied and often involve mutations across the envelope gene. This review provides a broad overview of entry inhibitor resistance mechanisms that inform our understanding of HIV entry and the design of new inhibitors and vaccines. PMID- 23342386 TI - Chemical composition and antioxidant/antimicrobial activities in supercritical carbon dioxide fluid extract of Gloiopeltis tenax. AB - Gloiopeltis tenax (G. tenax) is widely distributed along the Chinese coastal areas and is commonly used in the treatment of diarrhea and colitis. This study aimed at investigating the bioactivities of the volatile constituents in G. tenax. We extracted the essential constituents of G. tenax by supercritical carbon dioxide extraction (CO2-SFE), then identified and analyzed the constituents by gas chromatography-mass spectrometry (GC-MS). In total, 30 components were identified in the G. tenax extract. The components showed remarkable antioxidant activity (radical scavenging activity of 2,2-diphenyl-1 picrylhydrazyl (DPPH)), lipid peroxidation inhibition capacity (in a beta carotene/linoleic acid-coupled oxidation reaction), and hydroxyl radical scavenging activity (by deoxyribose degradation by iron-dependent hydroxyl radical), compared to butylated hydroxytoluene. In microdilution assays, G. tenax extracts showed a moderate inhibitory effects on Staphyloccocus aureus (minimum inhibitory concentration (MIC) = 3.9 mg/mL), Enterococcus faecalis (7.8 mg/mL), Pseudomonas aeruginosa (15.6 mg/mL), and Escherichia coli (3.9 mg/mL). Antioxidant and antimicrobial activities of G. tenax were related to the active chemical composition. These results suggest that the CO2-SFE extract from G. tenax has potential to be used as a natural antioxidant and antimicrobial agent in food processing. PMID- 23342387 TI - Adjuvant activity of Sargassum pallidum polysaccharides against combined Newcastle disease, infectious bronchitis and avian influenza inactivated vaccines. AB - This study evaluates the effects of Sargassum pallidum polysaccharides (SPP) on the immune responses in a chicken model. The adjuvanticity of Sargassum pallidum polysaccharides in Newcastle disease (ND), infectious bronchitis (IB) and avian influenza (AI) was investigated by examining the antibody titers and lymphocyte proliferation following immunization in chickens. The chickens were administrated combined ND, IB and AI inactivated vaccines containing SPP at 10, 30 and 50 mg/mL, using an oil adjuvant vaccine as a control. The ND, IB and AI antibody titers and the lymphocyte proliferation were enhanced at 30 mg/mL SPP. In conclusion, an appropriate dose of SPP may be a safe and efficacious immune stimulator candidate that is suitable for vaccines to produce early and persistent prophylaxis. PMID- 23342388 TI - [Potential applications of mesenchymal stem cells in ocular diseases]. AB - Except for the characteristics of stem cells, mesenchymal stem cells (MSC) have other distinct functions such as prompting wound healing, anti-inflammatory and immunoregulatory ability, which has made them one of the most promising candidates for cell therapy. By taking advantage of their different characteristics and functions, MSC have been exploited in the treatment of many ocular diseases, such as corneal diseases, uveitis and retinal diseases. This paper will review the progress of the applications of MSC in ocular diseases in recent years. PMID- 23342389 TI - Inhibition of bladder tumor growth by chitooligosaccharides in an experimental carcinogenesis model. AB - Urinary bladder cancer is one of the most common cancers worldwide, with the highest incidence in industrialized countries. Patients with cancer commonly use unconventional and complementary therapy including nutraceuticals. In this study we evaluated the efficacy of chitooligosaccharides (in orange juice) in rat bladder cancer chemoprevention and as therapeutic agent, on a rat model of urinary bladder carcinogenesis induced with N-butyl-N-(4-hydroxybutyl) nitrosamine. Results indicate that chitooligosaccharides may have a preventive effect on bladder cancer development and a curative effect upon established bladder tumors, dependent on the concentration ingested 500 mg/kg b.w., every three days, showed capacity to inhibit and prevent the proliferation of bladder cancer; however, this was associated with secondary effects such as hypercholesterolemia and hypertriglyceridemia. The use of lower doses (50 and 250 mg/kg b.w.) showed only therapeutic effects. It is further suggested that this antitumor effect might be due to its expected anti-inflammatory action, as well as by mechanisms not directly dependent of COX-2 inhibition, such as cellular proliferation control and improvement in antioxidant profile. PMID- 23342390 TI - Characterization and cytotoxicity studies of the rare 21:4 n-7 acid and other polyunsaturated fatty acids from the marine opisthobranch Scaphander lignarius, isolated using bioassay guided fractionation. AB - The marine opisthobranch Scaphander lignarius has been analyzed in the systematic search for novel bioactive compounds in Arctic marine organisms using bioassay guided fractionation. A number of highly cytotoxic fractions were shown to contain mainly polyunsaturated fatty acids (PUFAs). Selected PUFAs were isolated and identified using both liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). It was shown that the opisthobranch contained unusual PUFAs such as several omega3 fatty acids and the omega7 heneicosa 5,8,11,14-tetraenoic acid (21:4 n-7) not isolated before. The organism was shown to be a very rich source of PUFAs and the activity of the isolated compounds against a range of human cancer cell lines (melanoma, colon carcinoma and breast carcinoma) is further reported. The omega7 PUFA was significantly more cytotoxic in comparison with reference omega6 arachidonic and omega3 eicosapentaenoic acid. A noteworthy non-selective cytotoxicity against normal lung fibroblasts was also established. The paper contains isolation protocols in addition to cytotoxicity data of the isolated compounds. The potential of marine mollusks as a source for rare PUFAs is also discussed. PMID- 23342391 TI - A new dibenz[b,e]oxepine derivative, 1-hydroxy-10-methoxy-dibenz[b,e]oxepin-6,11 dione, from a marine-derived fungus, Beauveria bassiana TPU942. AB - 1-Hydroxy-10-methoxy-dibenz[b,e]oxepin-6,11-dione (1) was obtained from the culture broth of a marine-derived fungus, Beauveria bassiana TPU942, isolated from a marine sponge collected at Iriomote Island in Okinawa, together with two known compounds, chrysazin (2) and globosuxanthone A (3). The structure of 1 was elucidated on the basis of its spectroscopic data (HREIMS, 1D and 2D NMR experiments including 1H--1H COSY, HMQC and HMBC spectra). Dibenz[b,e]oxepines are rare in nature, and only six natural products have been reported. Therefore, compound 1 is the seventh natural product in this class. Compounds 2 and 3 showed an antifungal activity against Candida albicans, and 3 inhibited the cell growth against two human cancer cell lines, HCT-15 (colon) and Jurkat (T-cell lymphoma). Compound 1 did not show an apparent activity in the same bioassays. PMID- 23342392 TI - Lipids of prokaryotic origin at the base of marine food webs. AB - In particular niches of the marine environment, such as abyssal trenches, icy waters and hot vents, the base of the food web is composed of bacteria and archaea that have developed strategies to survive and thrive under the most extreme conditions. Some of these organisms are considered "extremophiles" and modulate the fatty acid composition of their phospholipids to maintain the adequate fluidity of the cellular membrane under cold/hot temperatures, elevated pressure, high/low salinity and pH. Bacterial cells are even able to produce polyunsaturated fatty acids, contrarily to what was considered until the 1990s, helping the regulation of the membrane fluidity triggered by temperature and pressure and providing protection from oxidative stress. In marine ecosystems, bacteria may either act as a sink of carbon, contribute to nutrient recycling to photo-autotrophs or bacterial organic matter may be transferred to other trophic links in aquatic food webs. The present work aims to provide a comprehensive review on lipid production in bacteria and archaea and to discuss how their lipids, of both heterotrophic and chemoautotrophic origin, contribute to marine food webs. PMID- 23342394 TI - Surgical correction of female urinary incontinence: comparison of colporrhaphy, sling and suspension procedures. AB - OBJECTIVE: To analyse clinical outcomes of three types of pelvic surgery for the correction of female mixed or stress urinary incontinence. METHODS: Women who underwent surgery for urinary incontinence between January 2000 and June 2010 were included in the study (n = 268). Patients were nonrandomly assigned to undergo colporrhaphy, suspension procedure or sling procedure according to their clinical situation. Perioperative parameters were recorded. Short- (< 5 years) and long-term (5-10 years) success rates were determined for each group. RESULTS: The short- and long-term complete cure rates were significantly lower, and the duration of catheterization significantly longer, in patients who underwent colporrhaphy compared with both other groups, but there were no significant differences between suspension or sling procedures. CONCLUSION: Sling and suspension procedures were equally effective in this study, and both were preferable to colporrhaphy. PMID- 23342393 TI - Antitumor effect of a polypeptide fraction from Arca subcrenata in vitro and in vivo. AB - Arca subcrenata Lischke is a marine traditional Chinese medicine. The study investigated the antitumor effects of P2, a polypeptide fraction from A. subcrenata, and its toxicity in vitro and in vivo. The results showed that P2 could inhibit the proliferation of seven tumor cell lines, especially in HeLa and HT-29 cell lines. The IC50 values were 11.43 MUg/mL for HeLa and 13.00 MUg/mL for HT-29 treated by P2 for 48 h. P2 had little cytotoxicity on normal liver cells (L 02). The maximum tolerated dose (MTD) of P2 on KM mice was 1000 mg/kg by i.p. or i.v. The tumor growth inhibitory ratios of P2 were 26.4%, 41.4% and 46.4% for H 22, and 34.0%, 45.8% and 60.1% for S-180 tumor-bearing mice. The results demonstrated that P2 might be a potential antitumor agent with high efficiency in dose-dependent and time-dependent manners and low toxicity. PMID- 23342395 TI - Alcohol and scuba diving. PMID- 23342396 TI - Critical appraisal. Resin bonding to zirconia. AB - Research has focused on adhesion and bond strengths to zirconia, but the question is "what is the gold standard--what is the bond strength we are trying to achieve?" Clinical data are needed to further understand adhesion issues--and studies are just now being published. Preliminary clinical research indicates that some failures are due to loss of adhesion but more are due to chipping of veneer porcelain. Commercial adhesion products are continuously being developed and optimized for clinical use. It is anticipated that the use of zirconia in dentistry will increase in the future, so reliable clinical adhesion solutions are needed. Based on the literature and the commercial products available to clinicians today, using novel primers (e.g., Z-PrimePlus) coupled with low pressure air-abrasion would be more than sufficient for adequate bonding of resin cement. PMID- 23342397 TI - Retraction of manuscript, "Effects of enflurane and propofol on seizure and recovery profiles in electroconvulsive therapy.". PMID- 23342398 TI - A pressing question: is there a place for psychotherapy in PMHNP practice? PMID- 23342399 TI - A difficult dilemma. PMID- 23342400 TI - NEWSDIG: The National Early Warning Score Development and Implementation Group. PMID- 23342401 TI - Prevalence of use of complementary and alternative medicine (CAM) by physicians in the UK: a systematic review of surveys. AB - This systematic review aims to estimate the prevalence of use of complementary and alternative medicine (CAM) by physicians in the UK. Five databases were searched for surveys monitoring the prevalence of use of CAM, which were published between 1 January 1995 and 7 December 2011. In total, 14 papers that reported 13 separate surveys met our inclusion criteria. Most were of poor methodological quality. The average prevalence of use of CAM across all surveys was 20.6% (range 12.1-32%). The average referral rate to CAM was 39% (range 24.6 86%), and CAM was recommended by 46% of physicians (range 38-55%). The average percentage of physicians who had received training in CAM was 10.3% (range 4.8 21%). The three most commonly used methods of CAM were acupuncture, homeopathy and relaxation therapy. A sizable proportion of physicians in the UK seem to employ some type of CAM, yet many have not received any training in CAM. This raises issues related to medical ethics, professional competence and education of physicians. PMID- 23342402 TI - Misguided presumptions: British Medical Association (BMA) and National Institute for Health and Clinical Excellence (NICE) guidance on organ retrieval and 'opt out' or 'presumed consent'. AB - Three documents have been produced in an attempt to increase the number of organs available for transplant: a National Institute for Health and Clinical Excellence (NICE) clinical guideline, a British Medical Association (BMA) report and a Welsh Government white paper. All three are ethically flawed: NICE and the BMA recommend that whenever there is intention to withdraw life-sustaining treatment and death is expected, patients should instead be stabilised to assess for donation. This is contrary to patients' best interests, the principles of mental capacity legislation and current criteria for accessing intensive care units. Regarding consent, the BMA and Welsh Government recommend an 'opt-out' policy, but consent in law requires information and cannot be 'presumed' or 'deemed' on the basis of failure to express or register 'opting out'. The language of all three proposals is manipulative, and patient trust may be undermined because the doctor's attention must move from the interests of the patient to those of the unknown organ recipients. PMID- 23342403 TI - BMA and NICE guidance on organ retrieval: neither misguided nor presumptuous. AB - Organ donation from deceased donors should occur whenever appropriate: that is, when there is evidence, belief or understanding that donation was the stated wish of the potential donor or would be in accordance with their wishes, is lawful and in line with current guidelines and will not add further distress to the family. This is the underlying assumption of the British Medical Association (BMA) report, National Institute for Health and Clinical Excellence (NICE) Guideline and Welsh Government Assembly Report. For potential donors after circulatory death, it might be necessary to support the potential donor until the wishes of the person and their family are ascertained. Provided that such interventions are reasonable, explained and do not cause distress to the patient and their family, such measures are surely suitable and will also enable donation to occur when appropriate. Publication and adherence to guidelines that have clinical, legal and ethical validity will reassure the public. Organ donation not only improves the length and quality of life of recipients, but also saves resources for the NHS and provides benefit to the donor family. PMID- 23342404 TI - Learning to make a difference: introducing quality improvement methods to core medical trainees. AB - The 'Learning To Make a Difference' (LTMD) initiative was a Royal College of Physicians/Joint Royal Colleges of Physicians Training Board collaboration supported by The Health Foundation. It aimed to support the learning and development of new and relevant skills in quality improvement (QI) methodology by trainees to enable them to deliver effective QI projects at the frontline. Core medical trainees in five deaneries were offered the opportunity to undertake a QI project in place of a mandatory clinical audit during 2010-2011. In total, 61 trainees completed 46 QI projects. Evaluation of the project outcomes demonstrated the acceptability, feasibility and strengths of trainee-led small scale change and how this can deliver improvement in the quality of multidisciplinary working, clinical practice and patient care. The LTMD project supports the further development and spread of this approach, encouraging all physician trainees, and their supervisors, to understand, develop and embed appropriate skills in QI methodology as part of their professional role. In addition, the project has identified the necessary infrastructure to enable this to happen. PMID- 23342405 TI - An MBPhD programme in the UK: the UCL experience. AB - Traditionally, clinician scientists in the UK have been trained by a sequence of medical school, junior hospital posts, MRCP and research leading to a PhD. Thereafter they undertake a mixture of more senior middle-grade jobs leading to senior or lecturer consultant posts and beyond. Experience in the USA has shown how it is possible for young doctors to complete a PhD successfully while still at medical school, giving the graduate a combined MBBS and PhD qualification earlier in their career. UCL instituted such an 'MBPhD' scheme 18 years ago. The first graduates are now attaining chairs. Here, we review the experience of such a course in the UK context. PMID- 23342406 TI - The Cambridge Bachelor of Medicine (MB)/Doctor of Philosophy (PhD): graduate outcomes of the first MB/PhD programme in the UK. AB - We reviewed outcomes of the Cambridge Bachelor of Medicine (MB)/Doctor of Philosophy (PhD) programme for the period 1989-2010. Of the 90 alumni contacted, 80 (89%; 24 women) completed an anonymous questionnaire. Thirty were academic staff and 35 were in general professional (core) or higher medical training. Of the latter, 11 were specialty registrars, six were academic clinical fellows and three held academic foundation year posts. Eight alumni were overseas, including five in North America. Most (95%) respondents considered that their academic career goals were facilitated by the programme. Sixty-eight of the 80 alumni had conducted further research, 63 (79%) were active in research, and 90% had explicit plans for further full-time research. Twelve graduates had further substantive research support (six clinician scientist awards and three senior fellowships) and two were Wellcome Trust postdoctoral MB/PhD fellows. Alumni included two full university professors, one reader, six senior lecturers, two assistant professors and nine university clinical lecturers. MB/PhD programmes offer an alternative training pathway for clinician-scientists in UK medical schools: the Cambridge programme promotes scientific discovery and sustained academic development within the context of contemporary medicine and clinical practice. PMID- 23342407 TI - A rare cause of acute pulmonary oedema. PMID- 23342408 TI - Community-acquired pneumonia. AB - Community-acquired pneumonia (CAP) is one of the most common acute infections requiring admission to hospital. The main causative pathogens of CAP are Streptococcus pneumoniae, influenza A, Mycoplasma pneumoniae and Chlamydophila pneumoniae, and the dominant risk factors are age, smoking and comorbidities. The incidence of CAP and its common complications, such as the requirement for intensive care and complicated parapneumonic effusions, are increasing, making it essential for all physicians to have a good understanding of the management of CAP. Although the diagnosis and treatment of CAP is straightforward in most cases, it can be more complex, and recent data indicate that the mortality of CAP in the UK is surprisingly high. In the future, routine use of biomarkers to improve risk stratification and tailor management to individual patients could improve outcomes, and there is some evidence that modulation of CAP-associated inflammation could also be beneficial. Both research into host-microbial interactions in the lung and clinical trials of different management and preventative treatments are urgently needed to combat the increasing morbidity and mortality associated with CAP. PMID- 23342409 TI - Advances in the management of atrial fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia worldwide, increasing in incidence with the aging population. Substantial morbidity and mortality accompany its diagnosis. Management should focus on rate and rhythm management, on reducing thromboembolic risk, and also potentially on targeting the mechanisms responsible for its perpetuation. Current antiarrhythmic therapy has only modest efficacy and substantial side effects, and anticoagulation regimes are cumbersome and require regular monitoring. Novel anticoagulants and antiarrhythmics hold the promise of improved efficacy and safety. This review covers current therapy for AF, major advances in pharmacological management and future directions for therapy. PMID- 23342410 TI - Cardiac disease in pregnancy. AB - Cardiac disease is the leading cause of maternal mortality in the UK. The major causes of cardiac deaths in pregnancy include cardiomyopathy, myocardial infarction, ischaemic heart disease and dissection of the thoracic aorta. With increasing numbers of migrant women in the UK, rheumatic heart disease in pregnancy has also re-emerged. Women with uncorrected congenital heart disease and those who have undergone corrective or palliative surgery may have complicated pregnancies. Women with metal prosthetic valves face difficult decisions regarding anticoagulation in pregnancy and have an increased risk of haemorrhage. Not all women with significant heart disease are able to meet the increased physiological demands of pregnancy. The care of pregnant women with heart disease thus requires a multidisciplinary approach, involving obstetricians, cardiologists and anaesthetists. This allows appropriate surveillance of maternal and fetal wellbeing, as well as planning and documentation of the management of elective and emergency delivery. This review discusses common cardiac conditions encountered in pregnancy and their antenatal and intrapartum management. PMID- 23342411 TI - 'Everybody's business': transition and the role of adult physicians. AB - The outcome of transition from paediatric to adult care is often judged by what happens after transfer. Young people at the point of transfer are reported to have low levels of knowledge and independence. These observations could be interpreted in one of two ways: either that the transition process before transfer is inadequate or that the transition process needs to continue into young adulthood and therefore adult care. The second interpretation is further supported by brain development continuing into the third decade. There is also growing evidence for the effectiveness of young adult clinics in the process of transition. To optimise transition, adult physicians need not only to work with paediatricians to achieve continuity during transfer, but also to look critically at their service as to how it can be changed to meet the needs of young people. In addition, they need to develop knowledge, skills and attitudes to communicate effectively and address a young person's developmental and health needs. PMID- 23342412 TI - Glycated albumin is a potential diagnostic tool for diabetes mellitus. AB - Using a community-based population cross-sectional study, we investigated the validity of an enzymatic method for glycated albumin (GA) measurements and evaluated its utility as a diagnostic tool for diabetes mellitus (DM). In total, 1,211 participants from the city of Harbin, People's Republic of China, were enrolled in the study. A receiver operating characteristic (ROC) analysis for GA, fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) measurements in diagnosed and undiagnosed DM were compared, based on a definition of DM using 1999 WHO criteria. We also estimated the correlation among GA, HbA1c and other clinical characteristics. Significant and positive correlations of fasting serum GA with FPG (r = 0.8097) and HbA1c (r = 0.8976) were found in participants enrolled in the study. ROC analysis for GA predicting undiagnosed DM with a cut off point of 15.7% was similar to that of FPG and HbA1c. Therefore, our data indicate that GA is a potential tool for DM diagnosis. PMID- 23342413 TI - Nutrition: tips for the general physician. PMID- 23342414 TI - Gastrointestinal oncology--what you need to know. PMID- 23342415 TI - Colonic polyps and an update on the bowel cancer screening programme. PMID- 23342416 TI - Inpatient diarrhoea and Clostridium difficile infection. PMID- 23342417 TI - Managing acute upper gastrointestinal bleeding in the acute assessment unit. AB - AAUs should develop and review protocols and local guidelines for the multidisciplinary team management of upper GI bleeding, for example with respect to: Early and appropriate resuscitation. Use of the tools for assessing severity. Timing of endoscopy, including recognising low-risk patients who could be discharged for outpatient investigation. Postendoscopy drug treatment, including appropriate and limited use of iv PPIs and Helicobacter pylori eradication therapy. Follow up, including referral for repeat endoscopy and/or urea breath testing. Regular review and audit of local guidance of the management of UGIB should become an integral part of an acute trust's clinical governance programme. PMID- 23342418 TI - Diagnostic dilemma and sudden death outcome: a case of amyloid cardiomyopathy. PMID- 23342419 TI - The ataxic cirrhotic. PMID- 23342420 TI - Acute oxalate nephropathy. PMID- 23342421 TI - The death of Ivan Ilyich and the concept of 'total pain'. PMID- 23342422 TI - Compliance with NICE guidance on the use of anti-TNF agents in ankylosing spondylitis. PMID- 23342423 TI - Austerity: a failed experiment on the people of Europe. PMID- 23342424 TI - Simultaneous myocardial infarction and ischaemic stroke secondary to paradoxical emboli through a patent foramen ovale. PMID- 23342425 TI - Inpatient care: should the general physician now take charge? PMID- 23342426 TI - US-style hospitalists are unlikely to improve delivery of patient care in the NHS. PMID- 23342427 TI - In order to encourage general internal medicine (GIM) as a specialty we must learn from our peers outside the UK. PMID- 23342428 TI - Economic crisis and primary healthcare in Greece: 'disaster' or 'blessing'? PMID- 23342429 TI - Risk of developing acute kidney injury (AKI) following the administration of iodinated contrast medium. PMID- 23342430 TI - Respiratory specialty specific examinations in the south west. PMID- 23342431 TI - The virtual bronchoscopy simulator--a young physician's view. PMID- 23342432 TI - A to-do list for Washington. PMID- 23342433 TI - Creation, evolution and indisputable facts. PMID- 23342434 TI - Diamond planets. PMID- 23342435 TI - Safe from scorpions. PMID- 23342437 TI - The missing epoch. PMID- 23342436 TI - How to survive the next big storm. PMID- 23342438 TI - Crunch time. PMID- 23342439 TI - The escape hatch. PMID- 23342440 TI - Healthier ice cream? PMID- 23342441 TI - A feathered innovator. PMID- 23342443 TI - The trouble with touch screens. PMID- 23342442 TI - Is fasting good for you? PMID- 23342445 TI - The nuclear question. PMID- 23342444 TI - A drone in every driveway. PMID- 23342446 TI - A cure for what ails you. PMID- 23342447 TI - A tsunami of extinction. PMID- 23342449 TI - A bold and foolish effort to predict the future of computing. PMID- 23342448 TI - The fate of an engineered planet. PMID- 23342450 TI - Starship humanity. PMID- 23342451 TI - Strange and stringy. PMID- 23342452 TI - Bionic connections. PMID- 23342453 TI - Small wonders. PMID- 23342454 TI - The coming megafloods. PMID- 23342455 TI - A confederacy of senses. PMID- 23342456 TI - Logic-tight compartments. PMID- 23342457 TI - The true cost of risky behavior. PMID- 23342458 TI - The value proposition. Will you make health care more affordable? PMID- 23342459 TI - Managing change. Reengineered care delivery and payment models will have a huge impact on hospitals Interview by Bob Kehoe. PMID- 23342460 TI - Building for tomorrow. Decentralized care provides model for hospital planning, design and construction. PMID- 23342461 TI - Stressing science. Evidence-based cleaning practices and technology advances will drive safety improvements. PMID- 23342462 TI - Sustainable benefits. The incentives continue to grow for hospitals to reduce their impact on the environment. PMID- 23342463 TI - Coming together to build excellence. PMID- 23342464 TI - Environmental services and the 'wow' factor. PMID- 23342465 TI - Turn the page. Preparing for the new hazard communication standard. PMID- 23342466 TI - Cleaner than clean. How hospital laundry operations can guard against HAIs. PMID- 23342467 TI - Patches, pride & patients: consistent cooperation should be the goal. PMID- 23342468 TI - Closed door policy: keeping lines of communication open can help you & your staff. PMID- 23342470 TI - Naked & unconscious: crew's misdiagnosis could have cost patient her life. PMID- 23342471 TI - JEMS 2012 Salary & Workplace Survey: the future looks bright--but how bright? PMID- 23342472 TI - Health care reform: changes present an unparalleled opportunity for EMS. PMID- 23342473 TI - Mobile warming: lessons learned in hypothermia prevention under difficult field conditions. PMID- 23342474 TI - A study on safety: highlights from workshop on ambulance patient compartments. PMID- 23342475 TI - Innovative design: pumper/ambulance model takes service to a new level. PMID- 23342476 TI - Vital pathways: detect & treat symptoms related to hemorrhagic shock. PMID- 23342477 TI - Clenched teeth verbiage: why labels should be left out of politics. PMID- 23342478 TI - [Sleep disorders among adolescents--a major problem in mental health care]. AB - Sleep disturbances are common in adolescents. The etiologies include biological, environmental, and sociocultural factors. The structure of sleep changes during adolescence, and it is easy for adolescents to stay awake. Sleep deprivation causes psychiatric symptoms. On the other hand, many psychiatric disorders cause secondary insomnia. The primary care is sleep hygiene counselling and behavioural therapy. If the sleep disorder is secondary, treatment of the primary disorder is the most important help. The scientific data of pharmacological management of insomnia of adolescent is thin. Melatonin might be worth a try, since there is scientific data of its effectiveness and safety. PMID- 23342479 TI - [New insights in the pathogenesis and treatment of rosacea]. AB - The production of cathelicidin, an antimicrobial peptide is strongly increased in rosacea. Cathelicidin activates innate immunity, inflammation and angiogenesis. Cutaneous proteases produce inflammatory fragments of cathelicidin. UV-B irradiation and microbial components increase vitamin D3 and TLR2 expression in keratinocytes leading to an increase of cathelicidin production. Retinoids and doxycycline inhibit inflammation, proteases, angiogenesis and TLR2 expression. A multicenter study 2010 proved that isotretinoin with a dose of 0,3 mg/kg/d for 12 weeks and doxycycline with the dose of 100 mg/d for 14 days followed with 50 mg/d were equally effective. Doxycycline 40 mg/d is also effective in milder cases. PMID- 23342481 TI - [Multiple endocrine neoplasia type 1]. AB - Multiple endocrine neoplasia type 1 (MEN1) is a complex multisystem disease characterized by the combined occurrence of endocrine tumours of the parathyroid glands, anterior pituitary gland and adrenal glands and the neuroendocrine tumours (NET) of duodenum, pancreas, thymus and bronchus. Malignancy occurs commonly (up to 30 %) and malignant NETs are important causes of the MEN1-related morbidity and mortality. Regular clinical, biochemical and radiologic screening for the syndrome-related tumours are the basis of the life-long surveillance. Early detection and adequate management of these tumours reduce risk of death and morbidity. PMID- 23342480 TI - [Restrictions during psychiatric hospitalization]. AB - The Finnish Constitution affirms that everyone has the right to remain private and undisturbed. During the course of involuntary psychiatric treatment, only the exemptions stipulated in the Mental Health Act are allowed. The Act on the Status and Rights of Patients states that cooperation with the patient must also be attempted during involuntary treatment. The orders for restraints are different in psychiatric hospitals. For decades, restrictions were derived from early 19th century regulations, when all mentally ill individuals were considered to be incompetent. Nowadays, a patient's mental competence is based on functional disabilities, which should also apply to psychiatric treatment. PMID- 23342482 TI - [Thirst and extensive bone lesions in a previously basically healthy woman]. AB - A previously quite healthy 65-year-old woman sought emergency hospital care due to fatigue, weight loss and sensation of thirst appearing over a couple of months. Further analysis revealed a process affecting the neurohypophysis and extensive lytic sclerotic bone lesions. Eventually a rare generalized underlying disease was unraveled: the diagnosis included both Langerhans cell histiocytosis and Erdheim-Chester disease. PMID- 23342483 TI - [Peculiar "appendicitis" turning out to be an internal hernia]. AB - After abdominal muscle exercises a young man suffered from upper abdominal pains and vomiting. The pain moved to the lower abdomen and the abdominal wall hardened. Clinical picture and laboratory findings were in agreement with acute appendicitis, and the patient was operated. Unexpectedly the small intestine and the ascending colon appeared almost entirely gangrenous upon gridiron incision, and the surgical incision was widened. An extensive internal herniation was revealed, with the small intestine having protruded through the sigmoid mesentery, causing a disturbance of the blood circulation and necrosis of the bowel. Swift and sufficient resection of the bowel saved the patient's life. PMID- 23342484 TI - [Update on current care guidelines. A current care guideline: recurrent upper gastrointestinal symptoms]. AB - Dyspepsia, both organic and functional, and gastroesophageal reflux disease (GERD) are common among children and adults. Helicobacter pylori infection, when diagnosed, should be treated to diminish the risk of gastric ulcer and cancer, but the treatment does not always alleviate dyspeptic symptoms. Proton pump inhibitors are the first-line medication and H2-receptor antagonists the second line medication for dyspepsia and GERD. Alternative treatment modalities for dyspepsia, GERD and Helicobacter pylori-infection are described. PMID- 23342485 TI - [Precursors and propeptides of neurotrophic factors as the modulators of biological activity of its mature forms]. AB - Here, we review the problems of neurotrophic factors' folding, the role of its precursors (proneurotrophins) and the contribution of elements deleted during its maturation (propeptides) in biological functioning of these growth factors. PMID- 23342486 TI - [Recombinant human alpha-fetoprotein as a regulator of adipose tissue stromal cell activity]. AB - Recombinant human alpha-fetoprotein (rhAFP) expressed in yeast system as a glycoprotein, was isolated and purified to 98% by multistep method. The testing of the rhAFP in the culture of adipose tissue stromal cells (hASC) has revealed its ability to enhance hASC proliferation and migration as well as vascular endothelial growth factor production, with no significant influence on cell invasion and matrix metalloproteinase-2 and -9 secretion. It has been also estimated that rhAFP is internalized in hASC via clathrin-dependent mechanism. A study in the murine experimental model of hindlimb ischemia has shown the capability of rhAFP to enhance blood flow recovery. These data suggest that rhAFP is a promising agent for enhancement of the hASC regenerative ability. PMID- 23342487 TI - A novel 4-(tetrahydro-2-furanmethoxy)-N-octadecyl-1,8-naphthalimide based blue emitiing probe: solvent effect on the photophysical properties and protein detection. AB - A novel 4-(tetrahydro-2-furanmethoxy)-N-octadecyl-1,8-naphthalimide (4-TN1) blue emitting fluorophore was synthesized for solvent polarity probing and protein detection. The effect of various solvents on absorption and fluorescence spectra of 4-TNI was investigated. By comparison with other derivatives with heterocyclic electron-donating groups, 4-TNI had the advantage of higher fluorescence quantum yield. The bathochromic shift observed in absorption and fluorescence spectra of 4-TNI with increasing solvent polarity indicates that the transitions involved are pi --> pi*. The normalized transition energy value E(T)N showed some scattering when plotted versus deltav. According to the quantum mechanics second order perturbation method, the ground and excited state dipole moments of 4-TNI were calculated as 3.91 and 7.12 D, respectively. Density functional calculations were also used to obtain the ground and excited state dipole moments. The result was consistent with the experimental values. Binding of TNI with human serum albumin (HSA) was studied. Fluorescence data revealed that quenching of HSA fluorescence by 4-TNI was due to the formation of a 4-TNI-HSA complex. Hydrogen bonds and hydrophobic interactions are the driving force of complex formation. 4 TNI fluorescence was found to be very sensitive to quenching by HSA. Therefore, a new spectrofluorimetric method for detection of HSA in Tris-HCl buffer solution (pH 7.4) was developed. The linear range of the calibration curve was 0.1-14.2 x 10(-6) M for HSA, with a detection limit (3sigma) of 1.37 x 10(-10) M. The method was applied to determination of total protein in clinical samples of human serum and the results were in good agreement with the data obtained by using Coomassie Brilliant Blue G-250 colorimetry. PMID- 23342488 TI - [Recombinant granulocyte-colony stimulating factor (filgrastim): optimization of conjugation with polyethylene glycol]. AB - In order to create an active pharmaceutical substance of the drug with prolonged action the modification of recombinant human granulocyte colony-stimulating factor GCSF (filgrastim) with polyethylene glycol (PEG, M 21.5 kDa) was conducted. A method for preparation of PEG-filgrastim designed for the development and scaling-up of the technological process of production was described. Modification of proteins with PEG was performed by selective covalent attachment of the molecule alpha-methyl-PEG-propionaldehyde to the alpha-amino group of the N-terminal methionine amino acid residue of the recombinant GCSF. The conditions of the reaction, which provide the desired product yield at least 85% of the total protein, also high protein concentration in the reaction mixture (more than 9 mg/mL) and reduce consumption of PEG in terms of terminal alpha amino group of the protein was chosen. The data of RP HPLC and MALDI-mass spectrometry showed that the produced drug modified by the N-terminal residue and contains no more than 10% of products with a high degree of modification. PMID- 23342489 TI - [2'-Modified oligoribonucleotides, containing 1,2-diol and aldehyde groups. Synthesis and properties]. AB - 1,2-Diol-oligoribonucleotides were prepared using fully protected 2'-O-[2-(2,3 dihydroxypropyl)amino-2-oxoethyl]uridine 3'-phosphoramidite. Incorporation of the 2'-modified uridine residue into oligonucleotide chains does not significantly affect the thermal stability of RNA and RNA-DNA duplexes. Periodate oxidation of the 1,2-diol results in reactive 2'-aldehyde oligoribonucleotides. Further application of these oligonucleotides for cross-linking with bacterial ribonuclease P was investigated. PMID- 23342490 TI - [Unique steroid 21-hydroxylase gene CYP21A2 polymorphism in patients with hyperandrogenism signs]. AB - Hyperandrogenism is a medical condition characterized by excessive production of male sex hormones (androgens) in woman organism. One of the major causes of hyperandrogenism is the autosomal-recessive disorder--congenital adrenal hyperplasia (CAH). The mutational defects in the steroid 21-hydroxylase CYP21A2 gene causing steroid 21-hydroxylase deficiency account for over 90% of CAH cases. Our paper describes the sequencing results of entire CYP21A2 gene from 15 patients with hyperandrogenism signs, which had not nine most prevalent mutations associated with nonclassic CAH as it was previously established. 26 polymorphisms were found by sequencing among which 25 were known previously and 23 of them are referred to "normal" gene variants which do not associated with CAH. At the same time the gene of every patient had unique its own distinctive combination of polymorphisms. New SNP represents synonymous substitution C --> T in 3' part of exon 8. All detected SNPs are not regularly distributed but are clustered along the gene. Notably, they were found in the neighborhood of initiation and termination codons and near the intron-exon boundaries of introns 2, 6 and 8. We hypothesize that "normal" clinically insignificant per se SNPs in unique combinations may influence spatial structure of CYP21A2 mRNA or its pre-mRNA splicing efficiency and decrease gene expression level. This assumption may explain the mechanism of pathological phenotype development in our patients. PMID- 23342491 TI - [The estimation method of compounds opiate activity based on universal three dimensional model of the nonselective opiate pharmacophore]. AB - Created by means alternative strategy of structural similarity search universal three-dimensional model of the nonselective opiate pharmacophore and the estimation method of agonistic and antagonistic properties of opiate receptors ligands based on its were described. The examples of the present method use are given for opiate activity estimation of compounds essentially distinguished on the structure from opiates and traditional opioids. PMID- 23342492 TI - [Steroidal compounds from the Pacific starfish Mithrodia clavigera and their toxic properties against human melanoma cells]. AB - The new sulfated polyhydroxysteroid has been isolated from the Pacific starfish Mithrodia clavigera, collected from Maldives Islands and named as mitrotriol (I, Na-salt of (20S)-3beta,6alpha,20-trihydroxy-5alpha-cholest-9(11)-ene 3-O sulfate). In addition six previously known compounds, including glycosides: echinasteroside B, granulatoside A, linckoside K, forbeside L and thornasterol sulfate A and cholesterol sulfate were isolated and identified. The structure of mitrotriol was elucidated by spectroscopic methods (mainly 2D NMR: 1H, 13C, DEPT, COSY-45, NOESY, HSQC and HMBC) and mass-spectrometry. For selected compounds, concentrations that showed cytotoxic activity against melanoma cells SK-MEL-28, SK-MEL-5 and RPMI-7951 were determined. PMID- 23342493 TI - Synthesis and reactions of some new pyrrolylthieno[2,3-D]quinoxaline and pyrrolopyrazinothienoquinoxalines. AB - The synthesis of 3-pyrrolyl-2-substituted thieno[2,3-b]quinoxalines from the precursor 3-amino derivatives are described. Synthesized compounds were subjected to reactions with other reagents to synthesize poly-fused heterocyclic incorporated thienoquinoxaline moiety. Some of the synthesized compounds were screened for their antibacterial and antifungal activities. PMID- 23342494 TI - Green-synthesis, characterization, photostability and polarity studies of novel Schiff base dyes using spectroscopic methods. AB - Preparation, characterization, photostability and polarity studies of novel Schiff base dyes using spectroscopic methods were achieved. The Schiff base dyes were prepared by the reaction of salicylaldehyde/2-Hydroxy-1-naphthaldehyde with aminophenazone under microwave irradiation. The spectroscopic (FT-IR, 1H NMR, 13C NMR, Mass) studies and elemental analyses were in good agreement with chemical structure of synthesized compounds. In addition, UV-Vis and fluorescence spectroscopic experiments showed that these dyes are good absorbent and fluorescent. Based on the photostability study of these dyes, minimal to no loss in fluorescence intensities of 4-[(2-Hydroxy-benzylidene)-amino] 1,5-dimethyl-2 phenyl-1,2-dihydro-pyrazol-3-one (D1) (6.14%) and 4-[(2-Hydroxy-naphthalen-1 ylmethylene)-amino]-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (D2) (2.95%) was observed with an increase in the exposure time using time-based fluorescence steady-state experiments. These studies also inferred that these Schiffbase dyes have a high photostability against photobleaching. In addition, Dye 2 is found to be more sensitive than Dye 1 to the polarity of the microenvironment provided by different solvents based on the results of fluorescence polarity studies. PMID- 23342495 TI - Synthesis of eperezolid-like molecules and evaluation of their antimicrobial activities. AB - 3-Fluoro-4-(4-phenylpiperazin-1-yl)aniline (II) prepared from 3,4-difluoro nitrobenzene was converted to the corresponding Schiff bases (III) and (IV) by treatment with 4-methoxybenzaldehyde and indol-3-carbaldehyde, respectively. Treatment of amine (II) with 4-fluorophenyl isothiocyanate affordedthe corresponding thiourea derivative (V). Compound (V) was converted to thiazolidinone and thiazoline derivatives (VI) and (VII) by cyclocondensation with ethylbromoacetate or 4-chlorophenacylbromide, respectively. The synthesis of carbothioamide derivative (X) was performed starting from compound (II) by three steps. Treatment of compound (X) with sodium hydroxide, sulfuric acid, or chlorophenacyl bromide generated the corresponding 1,2,4-triazole (XI), 1,3,4 thiadiazole (XII), and 1,3-thiazolidinone (XIII) derivatives, respectively. The structural assignments of new compounds were based on their elemental analysis and spectral (IR, 1H-NMR, 13C-NMR, and LC-MS) data. In the antimicrobial activity study all the compounds revealed high anti-Mycobacterium smegmatis activity. PMID- 23342496 TI - [The neuroprotective action of enantiomers and racemate of 2-(3,7-dioxo-2,4,6,8 tetraazabicyclo[3.3.0]oct-2-yl)-4-methylthiobutanoic acid]. AB - Neurotropic, neuroprotective and antioxidant actions of the enantiomers and the racemate of 2-(3,7-dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)-4 methylthiobutanoic acid were investigated. Only (+)-(S)-2-(3,7-dioxo-2,4,6,8 tetraazabicyclo[3.3.0]oct-2-yl)-4-methylthiobutanoic acid was found to have neuroprotective properties. A distereoselective synthesis of enantiomers and racemate was performed by condensations of (S), (R) and (R,S)-N carbamoylmethionines with 4,5-dihydroxyimidazolidin-2-one (DHI), respectively. By the X-ray method, the major racemate was proved to crystallize from water as a conglomerate. No antioxidant activity was revealed. PMID- 23342497 TI - [Synthesis of novel terpenophenol-chlorin conjugates and evaluation of their membranotropic and membrane protective properties]. AB - A series of terpenophenol-chlorin conjugates where terpenophenolic fragment has amide bond with macrocycle of methylpheophorbide a, formed by amidation of 13(2) ester group were obtained by interaction of methylpheophorbide a and ortho aminomethyl derivatives of 2-isobornyl-4-methylphenol. The substances investigated ability to interact with the cell membrane was shown in blood erythrocytes surface structure with scanning electron microscope. The conjugates studied were established to have antioxidant and membrane protective properties resulted from inhibiting H2O2-induced erythrocytes hemolysis and decrease of lipid peroxidation secondary product accumulation. PMID- 23342498 TI - Bibliometry of Costa Rica biodiversity studies published in the Revista de Biologia Tropical/International Journal of Tropical Biology and Conservation (2000-2010): the content and importance of a leading tropical biology journal in its 60th anniversary. AB - Central America is recognized as a mega diverse "hot-spot" and one of its smaller countries, Costa Rica, as one of the world's leaders in the study and conservation of tropical biodiversity. For this study, inspired by the 60th anniversary of the journal Revista de Biologia Tropical, we tabulated all the scientific production on Costa Rican biodiversity published in Revista de Biologia Tropical between 2000 and 2010. Most articles are zoological (62%) and 67% of authors had only one publication in the jounal within that period. A 54% of articles were published in English and 46% in Spanish. A 41% of articles were written in collaboration among Costa Rican institutions and 36% in collaboration with foreign institutions. The Collaboration Index was 2.53 signatures per article. Visibility in American sources was 56% in Google Scholar and 42.66% in the Web of Science, but the real visibility and impact are unknown because these sources exclude the majority of tropical journals. Revista de Biologia Tropical is the main output channel for Costa Rican biology and despite its small size, Costa Rica occupies the 10th. place in productivity among Latin American countries, with productivity and impact levels that compare favorably with larger countries such as Brazil, Mexico, Argentina and Chile. PMID- 23342499 TI - Phenology of tropical understory trees: patterns and correlates. AB - Reproductive phenologies of plants are constrained by climate in highly seasonal regions. In contrast, plants growing in wet tropical forests are freed from many abiotic constraints, which in canopy tree communities lead to a rich diversity of phenological patterns within and among individuals, species and communities. However, basic descriptions of tropical phenological patterns and the processes that shape them are rare. Here, we document the individual-, population-, and landscape-level phenological patterns of two dominant families of understory woody plants important to avian frugivores, the Melastomataceae and Rubiaceae, along an elevational transect in Costa Rica. The 226 individual plants belonging to 35 species in this study, varied in the number of reproductive bouts/year, and the timing, duration, and synchrony of reproductive stages. This variation was not related to factors related to their interactions with mutualists and antagonists, nor did it appear to be constrained by phylogeny. Diverse phenological patterns among species led to relatively aseasonal patterns at the community and landscape level. Overall, evidence for biotic processes shaping temporal patterns of fruiting phenology was weak or absent. These findings reveal a number of unexplained patterns, and suggest that factors shaping phenology in relatively aseasonal forests operate in idiosyncratic ways at the species level. PMID- 23342500 TI - [Recovery of three tropical forest covers from mid-elevation sites in Costa Rica: oligochaetes, litter and soil analysis]. AB - In Costa Rica, the region of Rio Macho is a highly fragmented landscape with imminent risk of landslides. This area, which provides important environmental services, has been partially recovered to its original forest through intentional reforestation with exotic species or natural regeneration after abandonment. The aim of this study was to evaluate the bioindicator potential of oligochaete presence as well as some litter and soil characteristics. The ecosystem recovery of the two common restoration modes was measured within three different forest covers. For this, some substrate characteristics were analyzed and compared in a 50 years old secondary forest, a 13 years tacotal, and a 35 years cypress (Cupressus lusitanica) plantation. The three sites studied differed in density, biomass and average mass of oligochaetes, and in some litter (depth, nitrogen, phosphorus and C/N ratio of litter), and soil variables (soil water content (CA), pH, phosphorus, cation exchange capacity, and magnesium). The forest registered the lowest density of earthworms and soil pH, and the highest soil CA and phosphorus. CA was inversely related to the oligochaete density across sites. Besides, there were positive correlations between C/N and C/P ratios from the litter and soil pH, and inverse correlations of litter depth, litter N and P concentrations with soil P. Discriminant Analysis (AD) performed with all soil and litter variables, produced a sharp classification of the three forest cover types. AD suggests that site differences were mostly determined by soil CA and litter nitrogen concentration. Considering all the evaluated parameters, our results suggest in the first place, that oligochaetes are sensitive to changes in some soil and litter characteristics. Secondly, aside from the striking oligochaete differences between the old secondary forest and the other two sites, some soil and litter traits resulted good indicators of the present recovery of the three forest covers. In addition, comparing soil nutrients content (organic carbon, nitrogen, calcium, potassium and sulfur) among the three sites, our findings indicate that the cypress plantation had reached soil nutrient conditions similar to the old secondary forest, presumably by the accumulation of nutrients, as a result of low nutrient recirculation. In conclusion, ecosystem level studies throughout simple evaluation criteria (soils, oligochaetes and ground litter) can be used as rapid indicators of the state of some of the many and complex forest ecosystem compartments. PMID- 23342501 TI - [Frugivory and seed dispersal Oenocarpus bataua palm (Arecaceae) in a forest from the Colombian Andes]. AB - Seed dispersal is a key process that determines the spatial structure and dynamics of populations of plants, establishes the potential area of recruitment and in this way, the basis for subsequent processes such as predation, germination, competition and growth. The purpose of this research was to identify the guild of frugivores of the Oenocapus bataua palm in fragments of Andean forest, determine the effective dispersers and relate the spatial distribution of palm populations with the dispersion of seeds. To this end, between August 2005 June 2006, observations of the removal of fruits from eight clusters were done, and counting of consumption of fruits beneath 78 palms with mature fruits was undertaken; focal observations of 13 individuals during 90 hours; registration of frugivory with photographic traps during 165 days/nights for a total of 195 photographs and 144 consumption events; experiments with dispersion using 751 perforated fruits/seeds attached to strings and finally, plots to determine spatial distribution all were carried out. In the study area at least five species of mammals ate, dispersed, buried (Sciurus granatensis, Microsciurus mimulus, Dasyprocta punctata y Proechimys sp.), cover (Marmosa robinsoni) and carried the fruits of O. bataua off to caves (Marmosa robinsoni y Proechimys sp.) without damaging the seed. A 21.7% of the fruits were dispersed, 13.2 gnawed or peeled, 5.6% covered, buried and carried to caves. The average distance of removal of seeds and fruits was 3.1m although in a lesser proportion, dispersion events of >50m were recorded. The abundant production of fruits, their size and weight, their intense removal by frugivores, the short dispersion distances, the absence of large size frugivores (reduced by hunting and fragmentation), that might perform long-distance dispersion, and the increase of rodents, especially squirrels, that strongly pressure the fruit resource, generate a spatially restricted seed rain of seeds responsible for the aggregate patterns of distribution of seeds, seedlings and subsequently of juveniles and sub-adults. However the short time and high percentage of seed germination and the robustness of seeds and seedlings give O. bataua the capacity to survive in dense aggregations. Therefore, despite the limitations on dispersion, this is a dominant species in the study area. Populations of O. bataua have been reduced by intense exploitation and by the transformation and reduction of their natural habitat. The over-exploitation of the fruits or the juvenile phases of this palm can affect the age structure and population dynamics. Therefore, the management and exploitation of this palm in the future will depend to large degree on the conservation of forest habitats. PMID- 23342502 TI - Comparison of microsatellites and isozymes in genetic diversity studies of Oryza glumaepatula (Poaceae) populations. AB - The study of the genetic structure of wild plant populations is essential for their management and conservation. Several DNA markers have been used in such studies, as well as isozyme markers. In order to provide a better comprehension of the results obtained and a comparison between markers which will help choose tools for future studies in natural populations of Oryza glumaepatula, a predominantly autogamous species, this study used both isozymes and microsatellites to assess the genetic diversity and genetic structure of 13 populations, pointing to similarities and divergences of each marker, and evaluating the relative importance of the results for studies of population genetics and conservation. A bulk sample for each population was obtained, by sampling two to three seeds of each plant, up to a set of 50 seeds. Amplified products of eight SSR loci were electrophoresed on non-denaturing polyacrylamide gels, and the fragments were visualized using silver staining procedure. Isozyme analyses were conducted in polyacrylamide gels, under a discontinuous system, using six enzymatic loci. SSR loci showed higher mean levels of genetic diversity (A=2.83, p=0.71, A(p)=3.17, H(o)=0.081, H(e)=0.351) than isozyme loci (A=1.20, p=0.20, A(p)=1.38, H(o)=0.006, H(e)=0.056). Interpopulation genetic differentiation detected by SSR loci (R(ST)=0.631, equivalent to F(ST)=0.533) was lower than that obtained with isozymes (F(ST)=0.772). However, both markers showed high deviation from Hardy-Weinberg expectations (F(IS)=0.744 and 0.899, respectively for SSR and isozymes). The mean apparent outcrossing rate for SSR (t(a)=0.14) was higher than that obtained using isozymes (t(a)=0.043), although both markers detected lower levels of outcrossing in Amazonia compared to the Pantanal. The migrant number estimation was also higher for SSR (Nm=0.219) than isozymes (Nm=0.074), although a small number for both markers was expected due to the mode of reproduction of this species, defined as mixed with predominance of self fertilization. No correlation was obtained between genetic and geographic distances with SSR, but a positive correlation was found between genetic and geographic distances with isozymes. We conclude that these markers are divergent in detecting genetic diversity parameters in O. glumaepatula and that microsatellites are powerful for detecting information at the intra-population level, while isozymes are more powerful for inter-population diversity, since clustering of populations agreed with the expectations based on the geographic distribution of the populations using this marker. PMID- 23342503 TI - Germination and initial growth of tree seedlings on deforested and natural forest soil at Dulhazara, Bangladesh. AB - The destruction of natural forest is increasing due to urbanization, industrialization, settlement and for the agricultural expansion over last few decades, and studies for their recovery need to be undertaken. With this aim, this comparative study was designed to see the effects of deforested soil on germination and growth performance of five different tree species. In the experiment, five species namely Gmelina arborea, Swietenia mahagoni, Dipterocarpus turbinatus, Acacia auriculiformis and Syzygium grande were germinated for six weeks on seedbeds and raised in pots (25cm diameter, 30cm height), that were filled with two soil and type of land use: deforested and adjacent natural forest of Dulhazara Safari Park. Growth performance of seedling was observed up to 15 months based on height, collar diameter and biomass production at the end. Our results showed that the germination rate was almost similar in both type of land uses. Height growth of D. turbinatus, G. arborea and S. mahagoni seedlings was almost similar and A. auriculi formis and S. grande lower in deforested soil compared to natural forest soil, while collar diameter ofA. auriculi formis, G. arborea, S. grande and S. mahagoni lower and D. turbinatus similar in deforested soil compared to natural forest soil. After uprooting at 19 months, S. mahagoni seedlings were showed significantly (p< or =0.05) higher oven dry biomass, D. turbinatus and A. auriculiformis higher, while G. arborea showed significantly (p< or =0.05) lower and S. grande almost similar oven dry biomass in deforested soil compared to natural forest soil. Oven dry biomass of D. turbinatus seedlings at 19 month age in deforested soil was 21.96g (n=5) and in natural forest soil 18.86g (n=5). However, differences in germination rate and growth performance for different tree species indicated that soil are not too much deteriorated through deforestation at Dulhazara and without any failure such deforested lands would be possible to bring under forest through plantation. PMID- 23342504 TI - Floral sources to Tetragonisca angustula (Hymenoptera: Apidae) and their pollen morphology in a Southeastern Brazilian Atlantic Forest. AB - The stingless bees are important flowers visitors of several plant species, due to their feeding habits and foraging behavior, constituting an important group to maintain biodiversity and the dynamics of tropical communities. Among stingless bees, Tetragonisca angustula is widely distributed in tropical habitats, and has been considered an important pollinator of different plant families. To support a rational economic use of this group, there is a need to characterize the plant species that represent important sources as part of their diet, as preferred, alternative or casual food sources. The aim of this survey was to distinguish the plant species that T. angustula visited most often. The study was undertaken in four regions of the Atlantic Rainforest in Rio de Janeiro state (Brazil) over a year from March 2008 to February 2009. For this, we collected bees, flowering plants and bee pollen loads from the four sites, and evaluated pollen morphology in the laboratory. Field observations showed the presence of plants belonging to ten different families and pollen loads showed the presence of pollen types belonging to 26 plant families. There were strong differences between pollen types, especially regarding pollen grain shape. The present survey suggests a high value of these plant species as trophic resources for the T. angustula in the understory of Atlantic Rainforest. Changes in these fragments of this forest may compromise the availability of resources for Tetragonisca angustula species and other stingless bees. PMID- 23342505 TI - Leaf damage and density-dependent effects on six Inga species in a neotropical forest. AB - Many models have been proposed to explain the possible role of pests in the coexistence of a high diversity of plant species in tropical forests. Prominent among them is the Janzen-Connell model. This model suggests that specialized herbivores and pathogens limit tree recruitment as a function of their density or proximity to conspecifics. A large number of studies have tested the predictions of this model with respect to patterns of recruitment and mortality at different life stages, yet only a few have directly linked those density- or distance dependent effects to pest attack. If pest-attack is an important factor in density- or distance-dependent mortality, there should be spatial heterogeneity in pest pressure. I studied the spatial distribution of leaf damage in saplings of six common Inga species (Fabaceae: Mimosoideae) in the 50ha forest dynamic plot of Barro Colorado Island, Panama. The percent leaf damage of Inga saplings was not heterogeneous in space, and the density of conspecific, congener or confamilial neighbors was uncorrelated with the observed damage levels in focal plants. One of the focal species did suffer density-dependent mortality, suggesting that spatial variation in plant performance in these species is not directly driven by leaf damaging agents. While multiple studies suggest that density-dependent effects on performance are common in tropical plant communities, our understanding of the mechanisms that drive those effects is still incomplete and the underlying assumption that these patterns result from differential herbivore attack deserves more scrutiny. PMID- 23342506 TI - [Germinating requirements of common vines from Chaco Serrano of Cordoba, Argentina]. AB - Vines are conspicuous elements of floras in different ecosystems. Patterns of distribution and ecology of this group has been studied at regional scales, mainly in tropical areas, but less is known about factors affecting their distribution at smaller scales. In this study, the germinating requirements of common vines from two plant communities (open shrubland and woodland) in xerophytic mountain forests (Chaco serrano) were studied. A total of 21 species were selected and classified as typical of woodland, shrubland, or indifferent. Experimental treatments were three temperature regimes (15-5 degrees C, 25-15 degrees C and 35-20 degrees C), in light (12-12h daily photoperiod) and in continuous darkness. Total germination percentage, the relative light germination (RLG) and germination rate (T50) were recorded. Among results we found that the temperature was the main factor triggering the germination process. No differences in the mean RLG and T50 between woodland and shrubland patches were found. The patterns observed in this work support the idea that, independently of patch type, germination is associated with temperature of the time of the year when most of the rainfall occurs. Germination of the studied species would be responding to macroclimate's factors (seasonality of climate and rainfall), rather than to a microclimate. This indicates that differences in species composition between patches would not be due to the factors studied, rather than to characteristics of the later stages of the cycle life. 1523. Epub 2012 December 01. PMID- 23342507 TI - Reproductive biology characteristic of Jatropha curcas (Euphorbiaceae). AB - Jatropha curcas belongs to family of Euphorbiaceae, and is an important biological tree species for diesel production. The current descriptions of the phenotypic traits for male and female flowers are not comprehensive and there have been no reports about the process of J. curcas from pollen germination on stigma to pollen tubes conducting fertilization after entering the ovary and ovule. To assess this, experiments were undertaken to study the reproductive biology characteristic of J. curcas in Guiyang Guizhou Province, China. Floral structure and pollen germination process were described in detail and the breeding system was determined. The results showed that flower of J. curcas was both unisexual and monoecious, with a flowering phase between April-November. Both female and male flowers have five petals in contorted arrangement and five calyxes in imbricated arrangement. Female flower originated from bisexual flower finally formed unisexual flowers as the stamen ceased growth in different period. The pistil had 3-5 styles, connected at base and separated into 3-5 stigmas on the top. Each stigma had 2-4 lobes. The styles were hollow. The pollen germinated on the surface of the stigma, is then transported via the vascular tissues, which was arranged in bundles, and finally channeled through the micropyle to enter the blastula. The pollen tube was shaped in a long uneven cylinder. The top end of it became swollen and formed a small round hole for the purpose of releasing sperm nuclei while the pollen tube itself was growing and extending. Estimation of out crossing index and artificial pollination experiments indicated that J. curcas was capable of both self-pollination and cross-pollination. The germination speed of the pollen on the stigma did not differ so much between the one by self pollination and the one by cross-pollination, and the pollen from the two different sources could both reach the ovary within one day. Both artificial pollination test and out-crossing index have indicated that: J. curcas has both self-pollination and cross-pollination systems. PMID- 23342508 TI - Antibacterial and antifungal activities of crude plant extracts from Colombian biodiversity. AB - On a global scale, people have used plants to treat diseases and infections, and this has raised interest on the plant biodiversity potencial in the search of antimicrobial principles. In this work, 75 crude n-hexanes, dichloromethane and methanol extracts from the aerial parts of 25 plants belonging to four botanical families (Asteraceae, Euphorbiaceae, Rubiaceae and Solanaceae), collected at the Natural Regional Park Ucumari (Risaralda, Colombia), were evaluated for their antibacterial and antifungal activities by the agar well diffusion method. The antibacterial activities were assayed against two Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis, and three Gram-negative ones named, Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa. In addition, the same plant extracts were tested against the yeast Candida albicans and the fungi Aspergillus fumigatus and Fusarium solani. Overall, the plant extracts examined displayed better bactericide rather than fungicide activities. In general, the best antibacterial activity was showed by the plant extracts from the Rubiaceae family, followed in order by the extracts from the Euphorbiaceae and Solanaceae ones. It is important to emphasize the great activity displayed by the methanol extract of Alchornea coelophylla (Euphorbiaceae) that inhibited four out of five bacteria tested (B. Subtilis, P. aeruginosa, S. aureus and E. coli). Furthermore, the best Minimal Inhibitory Concentration for the extracts with antifungal activities were displayed by the dichloromethane extracts from Acalypha diversifolia and Euphorbia sp (Euphorbiaceae). The most susceptible fungus evaluated was F. Solani since 60% and 20% of the dichloromethane and methanol extracts evaluated inhibited the growth of this phytopathogenic fungus. The antimicrobial activity of the different plant extracts examined in this work could be related to the secondary metabolites contents and their interaction and susceptibility of pathogenic microorganism evaluated. PMID- 23342509 TI - [Pontoscolex corethrurus (Annelidae: Oligochaeta) soil quality indicator in Eucalyptus grandis (Myrtacea) sites with slash and burn management]. AB - Soil burning has been used in agricultural and forestry systems as a fundamental technique to clean the land and add some nutrients to the soil. In addition, earthworms are known to promote various soil functions since they contribute to aeration and organic matter and nutrients availability to other soil organisms. This study evaluated the effects of tropical forest crops management with presence-absence of Eucalyptus grandis on earthworm population in Huimanquillo, Tabasco, Mexico. Three sites (average area of 1-1.5ha each) with different management conditions were considered for soil and earthworm sampling (two depths and six replicates): without vegetation (SV) and recent slash-burned (38 days), forest crops of five years of production of E. grandis (Euc), and secondary vegetation of 15 years (Acah). Soil physico-chemical properties (apparent density, humidity, texture, pH, Ntot, OM, P, K, cationic capacity) were also evaluated, and earthworms were collected at the end of the rainy season (august october 2007). We found that the sites soil is an acrisol acid, with pH 3.0-4.5 in the first 30cm depth. Organic matter content (OM) and total nitrogen (Ntot) in the recently burned sites were significantly lower (6-8% y 0.19-0.22%, respectively) than in sites with vegetation (OM=9-11%; el Ntot=0.27-0.33%). Only one species (P. corethrurus) was found in all the sampled areas, where most of the individuals were at juvenile stage (80%). The highest densities and biomass were found in Euc. treatment (166.4ind/m2 y 36.8g/m2) followed by Acah (138.7ind/m2 y 19.1g/m2 respectively), while the SV treatment showed of about an 80% reduced earthworm populations when compared to other treatments. Even though 15 years have passed over the secondary vegetation (Acah) still some perturbations were observed as the low abundance of the oligochaeta group. We concluded that the management used to culture E. grandis produces negative effects over the abundance and diversity of earthworms and soil nutrient availability. PMID- 23342510 TI - The importance of plant diversity in maintaining the pollinator bee, Eulaema nigrita (Hymenoptera: Apidae) in sweet passion fruit fields. AB - The euglossine bee Eulaema nigrita plays an important role for the pollination of native and economically important plants, such as the sweet passion-fruit Passiflora alata. E. nigrita uniquely collects the nectar from the flowers of P. alata, nevertheless, it needs to visit other plants to collect pollen, nectar and other resources for its survival. There are two methods to identify the species of plants used by bees in their diet: by direct observation of the bees in the flowers, and through identification of pollen grains present in brood cells, feces, or in the bees' body. In order to identify the other plants that E. nigrita visits, we analyzed samples of pollen grains removed from the bee's body in the course of the flowering period of P. alata. Among our results, the flora visited by E. nigrita comprised 40 species from 32 genera and 19 families, some of them used as a pollen source or just nectar. In spite of being a polyletic species, E. nigrita exhibited preference for some plant species with poricidal anthers. P. alata which has high sugar concentration nectar was the main source of nectar for this bee in the studied area. Nonetheless, the pollinic analysis indicated that others nectariferous plant species are necessary to keep the populations of E. nigrita. Studies such as this one are important since they indicate supplementary pollen-nectar sources which must be used for the conservation of the populations of E. nigrita in crops neighbouring areas. In the absence of pollinators, growers are forced to pay for hand pollination, which increases production costs; keeping pollinators in cultivated areas is still more feasible to ensure sweet passion fruit production. PMID- 23342511 TI - Screening antimicrobial activity of various extracts of Urtica dioica. AB - Urtica dioica or stinging nettle is traditionally used as an herbal medicine in Western Asia. The current study represents the investigation of antimicrobial activity of U. dioica from nine crude extracts that were prepared using different organic solvents, obtained from two extraction methods: the Soxhlet extractor (Method I), which included the use of four solvents with ethyl acetate and hexane, or the sequential partitions (Method II) with a five solvent system (butanol). The antibacterial and antifungal activities of crude extracts were tested against 28 bacteria, three yeast strains and seven fungal isolates by the disc diffusion and broth dilution methods. Amoxicillin was used as positive control for bacteria strains, vancomycin for Streptococcus sp., miconazole nitrate (30 microg/mL) as positive control for fungi and yeast, and pure methanol (v/v) as negative control. The disc diffusion assay was used to determine the sensitivity of the samples, whilst the broth dilution method was used for the determination of the minimal inhibition concentration (MIC). The ethyl acetate and hexane extract from extraction method I (EA I and HE I) exhibited highest inhibition against some pathogenic bacteria such as Bacillus cereus, MRSA and Vibrio parahaemolyticus. A selection of extracts that showed some activity was further tested for the MIC and minimal bactericidal concentrations (MBC). MIC values of Bacillus subtilis and Methicillin-resistant Staphylococcus aureus (MRSA) using butanol extract of extraction method II (BE II) were 8.33 and 16.33mg/mL, respectively; while the MIC value using ethyl acetate extract of extraction method II (EAE II) for Vibrio parahaemolyticus was 0.13mg/mL. Our study showed that 47.06% of extracts inhibited Gram-negative (8 out of 17), and 63.63% of extracts also inhibited Gram-positive bacteria (7 out of 11); besides, statistically the frequency of antimicrobial activity was 13.45% (35 out of 342) which in this among 21.71% belongs to antimicrobial activity extracts from extraction method I (33 out of 152 of crude extracts) and 6.82% from extraction method II (13 out of 190 of crude extracts). However, crude extracts from method I exhibited better antimicrobial activity against the Gram-positive bacteria than the Gram-negative bacteria. The positive results on medicinal plants screening for antibacterial activity constitutes primary information for further phytochemical and pharmacological studies. Therefore, the extracts could be suitable as antimicrobial agents in pharmaceutical and food industry. PMID- 23342512 TI - [Population fluctuation of Xyleborus ferrugineus and X. affinis (Coleoptera: Curculionidae) in ecosystems of Tabasco, Mexico]. AB - The Scolytinae insects are commonly known as bark or ambrosial beetles because of their feeding habits. Among them, some species restrict their reproductive activity to a host plant or a small number of them, whereas others are highly polyphagous. In order to evaluate the population dynamics of Scolytinae species, populations of Xyleborusferrugineus and X. affinis in ecosystems from Tabasco, Mexico were studied. The study was carried out from November 2010-July 2011, February 2010-January 2011 and 2007. The trapping methods used were alcohol traps, light traps and direct capture on their host plants. A total of 688 specimens ofX ferrugineus and 3 911 specimens of X. affinis were collected. The population dynamics of X. ferrugineus showed low size population in the studied ecosystems, without any marked seasonality. The highest population sizes were recorded both in dry season (March-May) and rainy season (September-December). Unlike the populations of X. ferrugineus, those of X. affinis were more abundant and showed the highest peaks during the rainy seasons (except in May at the Botanical Garden "Jose Narciso Rovisora"). Alcohol and light traps can be complementary methods for monitoring the populations of these types of insects. They occur most of the year and theirs population dynamics depends on food resources availability as well as environmental factors such as temperature and humidity. Judging by the observed abundance it is suggested that X. affinis has been adapted and exploited resources in a better way than X. ferrugineus in those ecosystems. Correlations between abundance and climatic factors had both positive and negative values. The results reflect the behavior of populations. However, a detail assessment of the biological and abiotic factors that influence the fluctuations of these insects is required. PMID- 23342513 TI - [Intra- and inter-specific morphometric variation between Odontophrynus populations (Anura: Cycloramphidae) of central Argentina]. AB - Intra- and inter-specific morphometric variation between Odontophrynus populations (Anura: Cycloramphidae) of central Argentina. Morphometric analyses are particularly important, and for many years they have supported evolutionary and ecological phenomena, and have been useful for the classification of new species, mainly to the lowest taxonomic levels. In order to assess the degree of sexual dimorphism, the intra-specific morphometric variation and the inter specific morphological differences, we performed morphometric analyses of two morphologically cryptic species, Odontophrynus cordobae (diploid) and O. americanus (tetraploid). For this, we measured 15 morphometric variables on 211 individuals from 18 localities of Cordoba province. We found sexual dimorphism in six and three parameters in O. cordobae and O. americanus, respectively. Diploid and tetraploid males significantly differed in six morphometric variables. Discriminant Function Analysis (DFA) including all populations correctly classified a 76.37% of individuals within their respective species. DFA based on four groups (1- allopatric O. cordobae, 2-syntopic O. cordobae; 3- allopatric O. americanus; 4- syntopic O. americanus) accurately classified a 73.45% of individuals within their respective groups. Allopatric individuals of each species and, allopatric and syntopic individuals within each species were clearly segregated. Syntopic individuals of O. cordobae and O. americanus showed the lowest percentages of correct classification. Morphometric differences between sympatric diploids and tetraploids were not greater than those observed in allopatry. These findings deviate from the expected results under the hypothesis of character displacement, and they suggest that external morphological characters would not have a major influence on the recognition and choice of conspecific males by females. PMID- 23342514 TI - Chemosensory age discrimination in the snake Boa constrictor (Serpentes: Boidae). AB - Many snakes are able to use their chemosensory system to detect scent of conspecifics, which is important in many social contexts. Age discrimination based on chemical cues may be especially important to ensure access to sexually mature potential partners. In this study, we used 24 individual Boa constrictor snakes (12 adults mature and 12 non-mature individuals) that had been captured in different areas of Ecuador, and were maintained in captivity at the Vivarium of Quito. We used tongue-flick experiments to examine whether these snakes were able to discriminate between scents from mature and non-mature individuals. Results showed that B. constrictor snakes used chemical cues to recognize conspecifics and that the scent of individuals of different ages elicited chemosensory responses of different magnitudes. The scents from adult conspecifics elicited the quickest and highest chemosensory responses (i.e., short latency times and high tongue-flick rates), although we did not find differential responses to scent of males and females. The magnitude of the responses was lower to scent of sub adult individuals, and then even lower to scent of juvenile snakes, but in all cases the scent of snakes was discriminated from a blank control. We discuss the potential chemical mechanisms that may allow age recognition and its implications for social and sexual behavior of this snake species. PMID- 23342515 TI - Basic ecology of the Oaxacan Spiny-tailed Iguana Ctenosaura oaxacana (Squamata: Iguanidae), in Oaxaca, Mexico. AB - The Oaxacan Spiny-tailed Iguana Ctenosaura oaxacana is a restricted species to the Isthmus of Tehuantepec in Southern Oaxaca, Mexico. This reptile is one of the less known iguanid species. We census-tracked a population in the South ofNiltepec, Oaxaca, Mexico from May 2010 to April 2011. Throughout one year, a total of 10 line transects were situated and recorded in the study area to determine relative abundance and density, and habitat type use (dry forest, Nanchal, grassland, riparian vegetation, and mangrove) by the species. This study reports a new C. oaxacana population on the Southeastern limit of species range. Although this species has a very restricted distribution and is in danger of extinction, C. oaxacana has a high population density when compared to other Ctenosaura species. A total of 108 individuals were recorded throughout the study. Dry forest (33.75ind/ha) and Nanchal (18.75ind/ha) were the habitats with higher densities. Comparisons between habitat types showed no significant differences between dry forest and Nanchal (W=15, p=0.0808). Results between seasons were similar. The Oaxacan Spiny tailed Iguana preferred first the dry forest, and then Nanchal, while avoided grassland, riparian vegetation, and mangroves. There was no difference in habitat use between males and females. Mean perch heights were 1.23 +/- 0.32 (n=30) in Nanchal, 2.11 +/- 0.30 (n=9) in grassland, 1.90 +/- 0.56 (n=54) in dry forest, 1.91 +/- 0.28 (n=9) in mangrove and 2.30 +/- 0.37 (n=6) in riparian vegetation. Species observed as refuge and perch were B. crassifolia (Nanchal); C. alata (grassland); Tabebuia sp., Genipa americana, G. sepium, Acacia sp., Ficus sp. and Haematoxylon sp. (dry forest); G. sepium, Acacia sp. and Guazuma ulmifolia (riparian vegetation); and C. erecta (mangrove). Live trees hollows and branches were used by species. Main threats to the species are excessive hunting and habitat loss. Furthermore, grassland fires are still common in the study area during the dry season, which can result in habitat loss and territorial displacement of individuals. PMID- 23342517 TI - Monitoring the endangered population of the antelope Kobus leche smithemani (Artiodactyla: Bovidae), in the Bangweulu Ecosystem, Zambia. AB - Black lechwe (Kobus leche smithemani) is a semi-aquatic medium sized antelope currently enlisted on the IUCN red list of endangered species and is only endemic to the Bangweulu basin of Zambia. Its population has significantly decreased due to floods that took place during the period 1930-1940 from over 250 000-15000 leading the Zambian government to gazette all habitats of Black lechwe into state protected areas, and to establish urgent management strategies needed to save the remaining population from extinction. Using retrospective data, our findings show that the population has increased from 15000 animals in 1954 to 55 632 in 2009. The current population is estimated at 34.77% (55 632/160 000) of the carrying capacity of the Bangweulu basin. Although the Black lechwe is one of the 42 species offered for consumptive utilization by the Zambia Wildlife Authority (ZAWA), only 0.12% and 0.08% of the current stock was offered for safari and resident hunting annually for the period 2005-2009, respectively. Annual quota utilization were estimated at 67% (n=37) and 81% (n=37) for safari and resident hunting, respectively. Hence, overall income obtained from utilization of Black lechwe is very low accounting for only 2.1% of the total revenue earned from wildlife utilization. Although the current population trend is showing a unit increase of 639 animals per year, it is still far below levels ideal for the lucrative utilization. In this study, we demonstrate that adverse ecological changes on wildlife species, can lead to their vulnerability and danger of extinction, and that their recovery to full carrying capacity may demand a considerable amount of time. PMID- 23342516 TI - [Hummingbird abundance and flowers use in a template forest from Southeast Mexico]. AB - Hummingbird abundance varies with plant bloom phenology used for feeding. However, the information on hummingbird-flower interaction is limited for tropical mountain environments. We evaluated hummingbird abundance using mist nest and estimated monthly flowering phenology visited by hummingbirds in three different habitats (oak forest, cloud forest and bush) from January to August 2010 in Huitepec Ecological Reserve. We recorded four hummingbird species (Hylocharis leucotis, Lampornis amethystinus, Lamprolaima rhami and Eugenes fulgens), and their abundance varied among habitats (H3.8=14.8, p=0.001). Seven plant species were visited for hummingbirds and showed the highest number of flower species during dry season. Bush had the highest blossom. Fuchsia paniculata had the highest blossom period but only was visited by H. leucotis. Passiflora membranacea was the only species visited for all hummingbird species. The only positive association was E. fulgens abundance with P.a membranacea bloom (r(S)=0.93, p=0.02). Hummingbird abundance fluctuations in this study are determined for interactions with floral resources and their habitat distribution. PMID- 23342518 TI - [USJ Herbarium of Costa Rica: history and contributions]. AB - In 2011 the Herbarium USJ of the University of Costa Rica became 80 years old and came up with 100 000 specimens of all the taxa that traditional botany studies. Data and figures on the history, the founders, and contributions of USJ to the knowledge of Costa Rican flora are summarized. PMID- 23342519 TI - Costa Rica publications in the Science Citation Index Expanded: a bibliometric analysis for 1981-2010. AB - Despite of its small size, the Central American country of Costa Rica is internationally recognized as one of the world leaders in conservation and as the Central American leader in science. There have been no recent studies on the country's scientific production. The objective of this study was to analyze the Costa Rican scientific output as represented in the Science Citation Index Expanded. All documents with "Costa Rica" in the address field from 1981 to 2010 were included (total 6 801 publications). Articles (79%) were more frequent than other types of publication and were mostly in English (83%). Revista de Biologia Tropical published the most articles (17%), followed by Toxicon and Turrialba (2.5%). The New England Journal of Medicine had the highest impact factor (53.484) with nine articles. Of 5 343 articles with known institutional address, 63%were internationally collaborative articles (most with the USA) with h index 91 and citation per publication 18. A total of 81% of all articles were inter institutionally collaborative articles, led by the Universidad de Costa Rica. This reflects research and education agreements among these countries. Universidad de Costa Rica ranked top one in inter-institutionally collaborative articles, the rank of the total inter-institutionally collaborative articles, and the rank of first author articles and corresponding author articles. Studied subjects and journals in our sample are in agreement with dominant science fields and journals in Costa Rica. Articles with the highest citation were published in New England Journal of Medicine. The largest citation of medical articles reflects the general interest and wider readership of this subject. All corresponding and first authors of the high impact articles were not from Costa Rica. In conclusion, the scientific output of Costa Rican authors is strong in the areas related to conservation but the impact is higher for biomedical articles, and Costa Rican authors need to improve their position within research teams. PMID- 23342521 TI - [Validation of two indices of biological integrity (IBI) for the Angulo River subbasin in Central Mexico]. AB - Efforts to halt freshwater ecosystem degradation in central Mexico can benefit from using bio-monitoring tools that reflect the condition of their biotic integrity. We analyzed the applicability of two fish-based indices of biotic integrity using data from lotic and lentic systems in the Angulo River subbasin (Lerma-Chapala basin). Both independent data from our own collections during two consecutive years, and existing information detailing the ecological attributes of each species, were used to calculate indices of biological integrity for 16 sites in lotic and lentic habitats. We assessed environmental quality by combining independent evaluations water and habitat quality for each site. We found sites with poor, regular and good biotic integrity. Our study did not find sites with good environmental quality. Fish-based IBI scores were strongly and significantly correlated with scores from independent environmental assessment techniques. IBI scores were adequate at representing environmental conditions in most study sites. These results expand the area where a lotic system fish-based IBI can be used, and constitute an initial validation of a lentic system fish based IBI. Our results suggest that these bio-monitoring tools can be used in future conservation efforts in freshwater ecosystems in the Middle Lerma Basin. PMID- 23342520 TI - [Descriptive epidemiology and molecular genetics of hereditary breast cancer in Costa Rica]. AB - Breast cancer is first in incidence and mortality among Costa Rican women. In 2011 there is a projected 1 071 new cases. We selected 116 patients diagnosed with breast cancer and family history of breast cancer. A detailed family history and epidemiology data was obtained from each patient and a blood sample was processed for DNA extraction. We analyzed the prevalence of risk factors and BRCA1 and BRCA2 mutations. These mutations were detected by different techniques and were confirmed by direct sequencing. Six patients (5.2%) had a mutation, five of which were in the BRCA2 gene and only one in BRCA1. We found that the average age of women who carry a mutation is lower than in non-carrier women. All other risk factors analyzed were not different among carrier and non-carrier women. In addition, these results and the increased incidence of breast cancer in recent years in Costa Rica, should promote an increase in prevention policies and the establishment of efficient detection methods that allow early disease diagnosis. PMID- 23342522 TI - Effects of short-term sediment nutrient enrichment and grazer (Neritina Reclivata) removal on sediment microalgae in a shallow eutrophic estuary (Alabama, USA). AB - The olive snail (Neritina reclivata) is ubiquitous in tropical and sub-tropical systems of the Gulf of Mexico, however its impacts on sediment microalgae have been little studied. Many coastal systems around the world are being eutrophied due to human activities, and seemingly they will continue to be eutrophied to a further extent in the future. Exploring the single and combined impacts of further nutrient enrichment and grazing by the olive snail on sediment microalgae in such eutrophic systems is an important question for our understanding and management of these systems. Here we examine the effects of short-term nutrient enrichment and grazing by the olive snail N. reclivata on sediment microalgal biomass and composition in a shallow eutrophic estuary (Weeks Bay, Alabama, USA) of the Northern Gulf of Mexico. For this, we performed a series of factorial experiments adding or not nutrients and removing or not the snail, for a total of four treatments in each experiment: ambient grazing, ambient nutrients; ambient grazing, increased nutrients; no grazing, ambient nutrients; and no grazing, increased nutrients. We did not find any significant impact of nutrient addition in any of the eight short-term (i.e. four days) experiments carried out. Impacts by the snail were minor; we only found a decrease in biomass due to snail grazing in one of the eight experiments, and no impacts on microalgal (i.e. diatom) composition. High ambient nutrient concentrations in the sediment porewater and low snail abundances on the sediment could explain these findings. Our results suggest that ephemeral, short-term nutrient pulses into eutrophic coastal systems of the Northern Gulf of Mexico, such as Weeks Bay (Alabama, USA), should not greatly affect the abundance of sediment microalgae, even though those pulses occur in well-lit areas. The results further suggest the snail N. reclivata is not a major control of sediment microalgal populations in the subtidal sedimentary areas studied. Our findings contrast with the results of past work in sediments with well-lit and nutrient poor conditions, or sediments with high densities of other snail grazers. In conjunction this and other investigations indicate that the response of sediment microalgae to nutrient enrichment and modified grazer abundance depends to a large extent on the initial levels of nutrient availability and grazing before the system is altered. PMID- 23342523 TI - [Effects mangrove conversion to pasture on density and shell size of two gastropods in the Turbo River Delta (Uraba Gulf, Caribbean coast of Colombia)]. AB - Mangrove deforestation is widespread in the Greater Caribbean but its impact on macrobenthos has not been evaluated to date. In order to assess the impact of mangrove conversion to pasture, densities and shell sizes of two dominant gastropods (Neritina virginea and Melampus coffeus) were compared among four mangrove types: 1) Rhizophora mangle-dominated fringing mangroves, 2) Avicennia germinans-dominated basin mangroves, 3) Mixed-species basin mangroves, and 4) A. germinans- basin mangroves converted to pastures, in the Turbo River Delta (Uraba Gulf, Colombia). Mangrove types were polygon-delimited with satellite images and color aerial photographs were taken in 2009. Various (n<5) polygons per mangrove type were sampled in January, July and December 2009, and a total (n<20) 0.025m2 quadrats were randomly placed along each polygon. Forest structure variables, pore-water physicochemical variables and sediment-grain metrics were measured in the four mangrove types. Mean density and size of both gastropod species were measured. The results showed that the mean density and size of both species were significantly greater in R. mangle-fringing mangroves. N. virginea density decreased gradually towards the A. germinans-basin mangroves seemly related to the diadromous life-history. This species nearly disappeared in the neighboring pastures because individuals were constrained to a few remaining flooded areas. In the pastures, M. coffeus individuals were clumped in the remaining A. germinans trees due to its climbing behavior as a pulmonate. We hypothesize that the decline of these two gastropods was related to physical microhabitat (e.g. trees, prop roots, and seedlings) degradation, and alteration of soil properties (e.g. temperature, pH, organic matter content). Finally, we also hypothesize that the local extinction of N. virginea due to clear-cutting may exert strong negative effects on the ecosystem function because it is a dominant omnivore. PMID- 23342524 TI - [Stomolophus meleagris fecundity (Rhizostomeae: Stomolophidae) in the Gulf of California]. AB - The cannonball jellyfish Stomolophus meleagris is regarded as a fishery resource with high commercial value, but with scarce biological information. With the aim to generate preliminary information on reproductive aspects, the present study analyzes its fecundity, based on the estimated number of vitellogenic oocytes in the gonad; in addition, we evaluated its relationship with the jellyfish body length, diameter and wet weight; and we established the relationship of the gonadosomatic index (IGS) with the jellyfish diameter and length. For this, a total of 30 specimens were collected, measured and weighed in a monthly basis, in Las Guasimas lagoon from January to May 2006. In order to estimate the gonad volume, 60 mature females were analyzed and their gonads were extracted and stained with hematoxylin-eosin. Gonad images from histological preparations were analyzed and the number of vitellogenic and previtellogenic oocytes obtained. We used catch data from The Guasimas for population recruitment analysis, that was estimated with FISAT II. Among results, we found that fecundity increased with jellyfish length, diameter and total wet weight. The lower fecundity rates occured on February and the highest during May (11 873 071 and 37 528 197 millions of vitellogenic oocytes per gonad, respectively). The IGS increased with length and diameter of the specimens, at its maximum value of 3.7% was observed in May. A continuous production of previtellogenic oocytes were observed during the full collection period. The maximum recruitment was observed in July and November (37.50% and 28.01% respectively). The high fecundity observed in S meleagris, suggests a high population reproductive potential that may support the possibility of an important fishery consolidation on this jellyfish. PMID- 23342525 TI - [Medusae (Cnidaria: Hydrozoa) from a coastal upwelling zone, Culebra Bay, Pacific, Costa Rica]. AB - The hydromedusae have an important role in marine trophic webs due to their predatory feeding habits. This is the first study of this group of gelatinous marine zooplankton in a coastal upwelling area of Central America. The composition and abundance variability of hydromedusae were studied during six months in 1999 at four stations in Culebra Bay, Gulf of Papagayo, Pacific coast of Costa Rica (10 degrees 37' N-85 degrees 40' W). A total of 53 species were identified, of which 26 are new records for Costa Rica, 21 are new records for Central America, and eight are new records for the Eastern Tropical Pacific. The more abundant species (more than 30% of the total abundance) were Liriope tetraphylla, Solmundella bitentaculata and Aglaura hemistoma. Six species occurred throughout the sampling period, 10 were present only during the dry season (December-April), and 17 were so during the rainy season (May-November). Significant differences of medusan abundances were found between seasons (dry vs. rainy). Maximum abundance (2.1 +/- 4.3ind./m3) was recorded when upwelled deeper water influenced the Bay, as indicated by local higher oxygen concentrations and lower water temperatures. The relatively high species richness of medusae found in Culebra Bay is probably related to factors like the pristine condition of the Bay, the arrival of oceanic species transported by the Equatorial Counter Current (ECC), the eastward shoaling of the Costa Rica Dome, and local currents. Illustrations of the 15 more important species are included to facilitate their identification and foster future work in the region. PMID- 23342526 TI - [Growth and survival of the green mussel P. viridis (Bivalvia: Mytilidae) in bottom culture conditions in Turpialito, Golfo de Cariaco, Venezuela]. AB - Mussels represent one of the most important mollusk species for culture activities around the world, and their growth may depend on the culture system used and locality. In this study, we evaluated the growth of Perna viridis in bottom culture to test its performance when using natural food, and to decide its use as a culture species in the Gulf of Cariaco. For this, mussel seeds (35.81 +/ 1.41 mm in length) were obtained in the locality of Guaca (North coast of Sucre state) and transferred to the Hydrobiological Station of Turpialito, Gulf of Cariaco, Sucre state, Venezuela, where they were planted in "Spanish baskets" to evaluate their growth between July 2007 and February 2008. Monthly survival was determined and the maximum shell length, dry mass of muscle and remains tissues of the gonad. The environmental parameters (water temperature, salinity, dissolved oxygen, chlorophyll a, total seston and organic fraction), in the cultivation area were determined every 15 days. Monthly measurements were made of proteins, lipids and carbohydrates to seston. During the entire study the mussels showed continued growth, ultimately reaching a maximum length of 78.7 +/- 4.43 mm. However, the growth rate of the dry mass of somatic (muscle, other tissue) and reproductive tissues showed variability throughout the study, and observed a significant increase by the end of the experiment. The observed variations in the growth rate of the reproductive tissue mass depended on the reserves accumulated and food offered by the environment. The organic seston throughout the experience showed an independence of temperature and chlorophyll a values; this one maintained values above 1 mg/L, thus forming the main food resource for mussels. The high content of proteins, lipids and carbohydrates observed in the seston at the end of the study, might be mainly associated with coastal upwelling, which provides a great food contribution of phytoplankton and organic type. The high survival rate (>80%), increase in the length of the shell and the high gonad production, suggests an excellent physiological condition of P. viridis, related to the availability and quality of food particularly the organic type present in the medium. We concluded that the bottom culture can provide an alternative aquaculture production in the Gulf of Cariaco. PMID- 23342527 TI - Crustaceans from a tropical estuarine sand-mud flat, Pacific, Costa Rica, (1984 1988) revisited. AB - The availability of data sets for time periods of more than a year is scarce for tropical environments. Advances in hardware and software speed-up the re-analysis of old data sets and facilitates the description of population oscillations. Using recent taxonomic literature and software we have updated and re-analized the information on crustacean diversity and population fluctuations from a set of cores collected at a mud-sand flat in the mid upper Gulf of Nicoya estuary, Pacific coast of Costa Rica (1984-1988). A total of 112 morphological species of macroinvertebrates was found, of which 29 were crustaceans. Taxonomic problems, maily with the peracarids, prevented the identification of a group of species. The abundance patterns of the crab Pinnixa valerii, the ostracod Cyprideis pacifica, and the cumacean Coricuma nicoyensis were analized with the Generalized Additive Models of the free software R. The models evidenced a variety of population oscillations during the sampling period. These oscillations probably included perturbations induced by external factors, like the strong red tide events of 1985. In additon, early on 1984 the populations might have been at an altered state due to the inpact of El Nino 1982-83. Thus, the oscillations observed during the study period departed from the expected seasonality (dry vs rainy) pattern and are thus considered atypical for this tropical estuarine tidal flat. Crustacean diversity and population peaks were within the range of examples found in worldwide literature. However, abundances of the cumacean C. nicoyensis, an endemic species, are the highest reported for a tropical estuary. Comparative data from tropical tidal flat crustaceans continues to be scarce. Crustaceans (total vs groups) had population changes in response to the deployment of predator exclusion cages during the dry and rainy seasons of 1985. Temporal and spatial patchiness characterized the abundances of P. valeri, C. pacifica and C. nicoyenis. PMID- 23342528 TI - [Reproductive pattern and mean size of sexual maturity of female lobsters Panulirus gracilis (Decapoda: Palinuridae) in Playa Lagarto, Guanacaste, Costa Rica]. AB - The lobster P. gracilis is important as a fishery resource and also contributes to food security of fishers in coastal communities in the North Pacific of Costa Rica. Due to the importance of updating knowledge related to the reproductive pattern of this species, we analyzed 357 specimens of female lobsters caught by the fishing methods of "hookah" and lung diving, from November 2007 to October 2008 in Playa Lagarto. Furthermore, we examined the size composition by depth; monthly pattern of reproductive activity (RAI) associated with the relative increase in sea surface temperature, and also the mean size at maturity using Generalized Linear Models. Four physiological states of sexual maturity showed that females with no signs of mating or sexual maturity have a minimum mean size of 62.3mm of cephalothorax length (CL). There are characteristics of functional maturity from very small sizes ranging from 30 to 50mm CL, being the smallest berried female reported for this specie of 35.8mm CL and the highest percentage of mature females between 70 and 80mm CL. Percentages of RAI remained above 50% during the year except October and January. In addition, it observed an increase in the RAI that started from April and continued until August associated with a relative increase in temperature on March, although the correlation was not significant (r2=0.49, p>0.05). It is possible that the low mean size at maturity (70.2mm LC) for P. gracilis in this region is related to the fishing activity. It recommends the establishment of a ban in the region of at least five months (April-August) in order to protect the reproductive seasonality of the species and to promote a recruitment increase in the fishing areas. PMID- 23342529 TI - Darkedge midshipman Porichthys analis (Batrachoidiformes: Batrachoididae), a common shrimp-bycatch fish from the Gulf of California. AB - Shrimp fishery bycatch of the Gulf of California constitutes a wide variety of highly unknown fish, crustacean, and mollusk species with very low or null economic value, in contrast to those of commercial interest. However, there are no studies yet on the role of these low economic valued species have in the community structure and function, together with their possible effect on commercial populations. With the aim of contributing to the knowledge of Darkedge Midshipman fish Porichthys analis, the most common waste species in this fishery, we estimated some population characteristics. For this purpose, we obtained shrimp-bycatch fish during the 2004-2005 fishing season and performed some research surveys. A total of 1 725 Darkedge Midshipman were captured from 350 bycatch samples. Individual size ranged from 43-352mm SL. The weight to standard length relationship was determined as W=0.000092SL(3.0509). Von Bertalanffy's growth coefficient indicated a moderate growth rate (K=0.5) with an estimated asymptotic length of L(infinity) = 352mm standard length, and a longevity of 6yr. Natural mortality was estimated as 0.97 and total mortality as 4.67. The recruitment pattern, as estimated by ELEFAN II, was extended over the year, peaking during spring and summer seasons. Sexual proportion of male:female was 1.65:1. Mature organisms appeared from August to March, and length at maturity was 157mm SL, which is larger than the mean size at capture 135mm SL. We concluded that the species is indirectly protected by its own bathymetric distribution and the off-shrimping season. This is the first study that considers population characteristics from this common but still unknown species. PMID- 23342530 TI - The reproductive biology of Lutraria philippinarum (Veneroida: Mactridae) and its fishery in the Philippines. AB - The Snout Otter Clam, Lutraria philippinarum is a regularly harvested bivalve species for food and also as a source of income in the Philippines. For sustainable supply of this resource in the wild, efficient and effective management strategies are needed, and the evaluation of its reproductive biology and fishery are required. In this study, the reproductive biology and fishery of L. philippinarum in the Philippines were examined monthly from January to December 2010 in North Bais Bay, Manjuyod, Negros Oriental and Philippines. For reproductive biology, otter clams were sampled, and sex ratio (by microscopic observation), size at sexual maturity, shell length (with a vernier caliper), gonad development (by histological examination as resting, developing, mature, spawning and spent) and spawning season were determined. Other information such as water temperature, salinity, pH and dissolved oxygen were also measured. To obtain information on the L. philippinarum fishery, interviews were conducted in Negros Oriental, Bohol, Cebu and Sarangani. A total of 677 snout otter clams were sampled. The study showed that L. philippinarum sex ratio was 1:1.15 and showed no significant difference from 1:1 ratio. Males attained its first sexual maturity at 43mm shell length while the females at 46mm. Histological examination on gonad development indicated that gametogenesis, maturation and spawning season of L. philippinarum occurred throughout the year with two spawning peaks, January and June. Changes in water temperature in North Bais Bay may have influenced the spawning peaks of L. philippinarum. Data on the fishery of L. philippinarum revealed that the Catch Per Unit Effort of L. philippinarum in the Philippines ranged from 0.2kg/hr-man to 1.25kg/hr-man suggesting low shell catch. We recommend that some mature individuals have to be left in the population to allow in situ breeding. PMID- 23342531 TI - Intra and inter-annual structure of zooplankton communities in floodplain lakes: a long-term ecological research study. AB - Water flow management has significantly changed the natural dynamic of floods, which are responsible for the structure and dynamic of aquatic communities in river-floodplain systems. With the aim to elaborate a conceptual framework that describes the main ecological factors associated with zooplankton community structure in the Upper Parana River, we investigated the mechanisms that regulate the communities structure and their response to inter-annual and hydro sedimentological variations in the floodplain and the biological factors associated with species abundance in those communities. For this we conducted samplings every six months (potamophase in March and limnophase in September) to characterize intra and inter-annual variations in community structure between 2000 and 2008. The intra-annual differences on the species richness, abundance, Shannon diversity index, and evenness, were conducted using Bayesian procedures to show probabilistic predictions of the data fit to main variation sources. Non metric multi-dimensional scaling (NMDS), multi-response permutation procedure (MRPP), and indicator species analysis (IndVal) were run to assess and characterize the seasonality of the community structure. During high water (potamophase), hydrologic connectivity favoured exchange and dispersal of species in some lakes, increasing local diversity; during low water (limnophase), higher local productivity favoured opportunistic taxa, increasing species dominance and decreasing local diversity. Food resources and density of small-size fish were biological factors associated with the seasonal dynamic of the zooplankton community; these factors were dependent on hydrosedimentological phase (potamophase or limnophase). Water levels and limnological modifications related to water flow management have promoted replacement and impoverishment of aquatic biota in affected lakes and have indicated the ecological importance of a natural dynamic flood, which displays regular flood pulses. The conceptual model presented encompassed interactions between diverse environmental variables to more understandable mechanisms of the main sources of community variation. PMID- 23342532 TI - Movement patterns of stream-dwelling fishes from Mata Atlantica, Southeast Brazil. AB - The identification of mechanisms of spatial-temporal variation, obtained from the quantification of natural populations, is a central topic of ecological research. Despite its importance to life-history theory, as well as to conservation and management of natural populations, no studies concerning movement patterns and home range of small stream-dwelling fishes from Brazilian rain forests are known. In the present study we aimed to describe the longitudinal pattern of long distance movement as well as local patterns of short movement (daily home-range) of fishes from a Mata Atlantica stream from Southeast Brazil. We gathered information about movement dynamic in order to discuss the relationship between swimming ability, fish morphology and home range. Long distance movement data were obtained in a mark-recapture experiment held in the field between June and September - 2008, on five sites along the Ubatiba stream. For this study, we had one day to mark fishes, on June-19, and 14 events for recapture. Considering the ten species that inhabit the study area, our study showed that four species: Astyanax janeiroensis, Astyanax hastatus, Parotocinclus maculicauda and Pimelodella lateristriga, moved at least 6 000m in 60 days. The other six species did not present long distance movements, as they were recaptured in the same site 90 days after being marked. For short distance study, movement data were obtained in one mark-recapture experiment held in a 100m long site subdivided into five 20m stretches where fishes were marked with different elastomer colours. We marked 583 specimens that after recapture showed two groups of different movement patterns. The first group was called "Long Movement Group" and the second one was called "Short Movement Group". The Long Movement Group showed, on average, 89.8% of moving fishes and 10.2% of non moving fishes, against 21.3% and 78.7%, respectively, for the Short Movement Group. It was concluded that fish movement could explain the previously mentioned community stability, and that it is correlated to specific morphological attributes. PMID- 23342533 TI - Length-weight relationships for 36 freshwater fish species from two tropical reservoirs: Ayame I and Buyo, Cote d'Ivoire. AB - Nowadays, the successful management of small scale fisheries requires the use of biometric data collected in the field, in order to transform them into suitable indicators. The present study describes the length-weight relationships for 36 freshwater fish species from two tropical reservoirs Ayame I and Buyo, in Cote d'Ivoire. The main objective of the study was to provide a length weight key for a wide range of freshwater fish species from these tropical reservoirs exploited by the inland fisheries. The samplings were carried out at Buyo from July 1997 to August 1998, and from August 2004 to July 2005 in Ayame I. Fish specimens were collected from catches of artisanal fisheries using gill-nets, cast-nets, beach seines and bamboo traps. After landings, samples were identified, total weight for each specimen was recorded to the nearest gram and standard length was measured to the nearest millimetre. A total of 12 724 individuals belonging to 15 families and 24 genera were obtained in this study. The results indicated that the family with the highest number of species was Cichlidae with eight species. Six families were recorded with only one species per family. The value of the exponent b in the length weight relationships (W=aL(b)) ranged from 2.173 for Marcusenius furcidens to 3.472 for Polypterus endlicheri and the median of b was 2.756. The modal value of the exponent b equal to 2.70 indicates that most of the fish species in Ayame I and Buyo Reservoirs have negative allometric growth. The length weight parameters of the three species, Lates niloticus, Synodontis koensis and S. punctifer are described for the first time in these regions. The present length-weight key for 36 freshwater fish species could be used as a valuable tool for fishery managers, in order to improve the inland fisheries statistics largely based on hydropower reservoirs in Cote d'Ivoire. PMID- 23342534 TI - [Histology of reproductive cycle of tropical gar Atractosteus tropicus females (Lepisosteiformes: Lepisosteidae) in Tabasco, Mexico]. AB - In Southeast Mexico, A. tropicus is a species with great ecological, economic, cultural and aquaculture value, however wild populations have diminished due to diverse anthropological causes. The objective of this study was to characterize the reproductive cycle of A. tropicus, with a description of complete gonad structure and the changes in germinal and somatic elements during oogenesis, for better management and use of this species. Six sexually mature females (N=72) were captured monthly with drag nets during one year cycle (October 2003-October 2004) in wild populations of Pomposu lagoon, municipality of Jalpa de Mendez, Tabasco, Mexico. Females were sacrificed by decapitation and the ovaries were processed by standard histological methods; the diameter of 10-20 oocytes taken at random was determined in different stages of development. Gonadosmatic index (GSI), gonadal volume (gV) and follicule diameter (fD) were determined monthly. Among results we could determine eight oogenesis developmental stages: I: chromatin nucleolus stage, II: early perinucleolus stage, III: mid perinucleolus stage, IV: advanced perinucleolus stage, V: early vitellogenesis stage, VI: mid vitellogenesis stage, VII) advanced vitellogenesis stage and VIII: final maturation stage. The reproductive cycle could be divided in four phases: 1: proliferative phase, II: initial maturation phase, III: late maturation phase, IV: regressing phase. Analysis of the data obtained from the IGS, gV and fD values, oogenesis stages and reproductive phases, indicate that in December previtellogenesis phase restarts, from March through July yolk deposition (vitellogenesis) occurs, and from August to November the maximum reproductive activity takes place. Contrasting this pattern with local environmental factors such as temperature and precipitation, we suggested that these may serve as an environmental activator in the development of oogenesis and spawning of this species. PMID- 23342535 TI - [Food and reproductive biology of Farlowella vittata (Siluriformes: Loricariidae) in Guejar River Basin, Orinoco, Colombia]. AB - Neotropical fish live in streams with considerable spatial and temporal variability of their food items. Food availability depends on different factors such as discharge, channel morphology, physicochemical conditions and interactions with other species, as well as their food habits. On the other side, good food availability results in reproductive success. Because the study of those changes contributes to a better understanding of trophic interactions in fish populations, the present work describes and evaluates aspects of diet and reproduction of Farlowella vittata in Pringamosal Creek, Guejar River drainage, Orinoco River basin, Colombia. Five collecting expeditions were done during both high and low rain seasons of 2008 and 2009. Physical and chemical water parameters were measured, and fish were captured from several points along the total length of the 7km stream, to characterize their biometry and stomach contents. Our results showed that Pringamosal creek is a first order stream, about 3.5m wide and with an average depth of 1m in our study area. Dissolved oxygen values were 6.2mg/L during low water and 2.7mg/L during high water phase. The creek is classified as oligotrophic but with a tendency to eutrophication. A total of 130 fish samples were analyzed. Fishes were assigned to seven size range categories between 86.0 and 175.5mm standard length (SL). Stomach contents revealed that the diet of this species consisted mainly of algae (Bacillariophyceae) (84.6% Abundance Relative), but we observed a variation in the diet according to season; during low rainfall it feeds on phytoplankton (86.47% A.R.) and during high rainfall on zooplankton as well as plant material and organic material (0.685% A.R. and 18.83% A.R., respectively). A Kruskal Wallis ANOVA showed statistically significant differences in food items between sexes. The condition factor (K) indicated that the species was well fed. Size at sexual maturity was 154mm SL for males and 124mm SL for females. The gonadosomatic index (RGS) showed that this fish reproduced during high water (April-May) season, and females showed a fecundity of 1 819 ovocites, with an average diameter of 1.4mm. Although parental care was not observed during this study, it is well known that males protect their eggs and juveniles, making them easy to capture during the breeding periods identified in this study, and at the same time, vulnerable to overexploitation. We recommend an urgent management plan for the conservation of this species, since at this time, no fishing controls are enforced even though it is harvested as an ornamental species. PMID- 23342536 TI - Population assessment of the American crocodile, Crocodylus acutus (Crocodilia: Crocodylidae) on the Pacific coast of Costa Rica. AB - The American crocodile, Crocodylus acutus, is widely distributed in the American neotropics. It is endangered throughout most of its range and is listed as vulnerable by the International Union for the Conservation of Natural Fauna and Flora (IUCN) and on Appendix I of the Convention for the International Trade in Endangered Species of Wild Flora and Fauna (CITES). Despite this listing, there are few published reports on population status throughout most of its range. We investigated the status of the C. acutus, at several locations along the Pacific coast of Costa Rica. We carried out spotlight and nesting surveys from 2007-2009 along the Costa Rican Pacific coast in four distinct areas, coastal areas of Las Baulas (N=40) and Santa Rosa (N=9) National Parks and the Osa Conservation Area (N=13), and upriver in Palo Verde National Park (N=11). We recorded crocodile locations and standard environmental data at each observation. Encounter rates, population structure, distribution within each area and data on successful nesting (presence of hatchlings, nests, etc) were determined. We attempted to capture all crocodiles to record standard morphometrics. A total of 586 crocodiles were observed along 185.8km of survey route. The majority of animals encountered (54.9%) were either hatchlings (<0.5m) or juveniles (0.5-1.25m). The average non-hatchling encounter rate per survey for the Pacific coast was 3.1 crocodiles/km, with individual encounter rates ranging from 1.2 crocodiles/km to 4.3 crocodiles/ km in Las Baulas National Park and the Osa Conservation Area respectively. Distribution of size classes within the individual locations did not differ with the exception of Santa Rosa and Las Baulas National Parks, where hatchlings were found in water with lower salinities. These were the first systematic surveys in several of the areas studied and additional work is needed to further characterize the American crocodile population in Costa Rica. PMID- 23342537 TI - Is XDR-TB a sub-group of MDR-TB? need to reorganize alphabets again! PMID- 23342538 TI - Totally drug resistant tuberculosis--a fact or myth? PMID- 23342539 TI - Drug discovery in tuberculosis: a molecular approach. AB - Despite unquestionable success of the combination drug therapy, tuberculosis (TB) very recently has drawn major attention because of the global upsurge of MDR-TB, XDR -TB and HIV-TB co-infection cases. In the last four decades, only one compound is added to the treatment regimen leaving ample opportunities to find out a new generation of TB drugs. The modern concept of drug discovery utilizes the integrated knowledge of genomics, proteomics, molecular biology and systems biology to identify more specific targets. The purpose of this review is to revisit the field of tuberculosis drug discovery based on those new concepts to identify novel targets. PMID- 23342540 TI - A study of the socio-demographic profile and treatment outcome of paediatric tuberculosis patients in Bangalore Mahanagar Palike area. AB - BACKGROUND: Tuberculosis (TB) continues to be one of the most devastating and widespread infections in the world. Of the nine million annual tuberculosis cases, about one million (11%) occur in children (under 15 years of age). Childhood tuberculosis is a neglected aspect of the tuberculosis epidemic. OBJECTIVES: To know the socio-demographic profile, type of tuberculosis and treatment outcome in paediatric tuberculosis patients METHODOLOGY: The study was conducted in nine Tuberculosis units of Bangalore city from January 2009 to December 2009. Five Tuberculosis units from the nine tuberculosis units were selected by simple random sampling, paediatric patients diagnosed as having TB and registered under RNTCP were included in the study till the sample size of 209 was reached. Data regarding socio-demographic profile and type of TB was collected and the patients were followed up to assess treatment outcome. RESULTS: Most of the patients coming to the RNTCP centres belong to the under-privileged group. Most of the patients were in the age group of 1 to < 6 years, (37.7 %), male to female ratio was observed to be 0.6:1. Majority of the patients lived in nuclear families (73.2%), belonged to low socio-economic status (95.5%) and dwelled in overcrowded houses (89.5%). 23% reported history of contact with tuberculosis patients. More than half of the patients (57.4%) were undernurished. In the study, 56.5% had pulmonary TB and 43.5 % had extra-pulmonary TB. 94.7% of the patients completed treatment. CONCLUSION: Paediatric tuberculosis still continues to be a major problem in one-five years of age who are undernourished and belonging to low socio-economic status. PMID- 23342541 TI - Agreement between skin testing and QuantiFERON-TB Gold In-Tube assay (QFT-TB) in detecting latent tuberculosis infection among household contacts in India. AB - AIMS: The present study was designed to find the agreement between Tuberculin Skin Test and interferon gamma assay test in detecting latent tuberculosis infection in household contacts of sputum culture positive tuberculosis cases. SETTING: Department of Community Medicine, Christian Medical College, Vellore. METHODS: One hundred and fifty household contacts of sputum culture positive tuberculosis cases were tested with both the methods simultaneously and actual as well as kappa agreement was determined. RESULTS: The overall actual agreement between both the tests was found to be 82% with a kappa agreement of 0.57. CONCLUSION: The agreement was very high (both percentage agreement and Kappa) in pediatric contacts but it was poor in adult contacts. PMID- 23342542 TI - Equivalence of acid alone or acid-alcohol as decolourizing agent in Ziehl-Neelsen method. AB - BACKGROUND: Microscopists opine that acid-alcohol decolourized slides may enhance acid-fast bacilli (AFB) smear positivity, and published documents on equivalence of acid and acid-alcohol in ZN staining method are not easily accessible. SETTING: National Institute for Research in Tuberculosis, Chennai, India. OBJECTIVE: To document the equivalence of 25% sulphuric acid (ZN-acid method) and 3% hydrochloric acid-alcohol (ZN-alcohol method) as decolourizing agents in ZN method for detection of acid-fast bacilli. METHODS: Two smears from each of 253 sputum samples from pulmonary tuberculosis patients, prepared and allocated, one to ZN-acid method and another to ZN-alcohol method were read blind. All the specimens were cultured for Mycobacterium tuberculosis by modified Petroff's method. Culture of M. tuberculosis was gold standard. RESULTS: The concordance between the methods was 85% (kappa 0.68), and the sensitivity (79%) and specificity (89%) were same for both the methods. CONCLUSION: In conclusion, the common belief that acid-alcohol decolourized slides give enhanced smear positivity stands void. PMID- 23342543 TI - Perspective of tuberculosis patients on family support and care in rural Maharashtra. AB - BACKGROUND: Role of patients' family in TB-control programme has received least attention in research and negligible attention is paid to support and care experiences of patients in rural societies. AIM: Present study aims at collecting qualitative data on how tuberculosis patients define support and care during illness, and document their experiences and perspectives about care and support. METHODS: This is a qualitative study with grounded theory approach. Data were collected by conducting series of 15 focus group discussions (FGD) covering 113 patients from rural Pune district of Maharashtra. Thematic analysis was undertaken after preparing detailed transcripts of each FGD. RESULTS: Good support and care was considered as receiving necessary attention and help in daily routine, monitary help, emotional and moral support and motivation for early recovery. Family provided support by accompanying to the health centre, reminding about medicines, giving meals. Female patients reported less sympathetic attitude and unfair treatment at husband's home while males received emotional and physical support from spouse. Stigma led to discrimination and hindered the support and care mechanism. CONCLUSION: Family awareness and preparedness for providing support need to be strengthened. Counselling and motivation during each visit are the keys to successful completion of treatment. There is need to make counsellors/psychologists available in the existing system. PMID- 23342544 TI - Tuberculosis of larynx: a case report. AB - A case of tuberculosis of larynx in a 45-year-old male patient has been described here. Usually, the signs and symptoms of laryngeal tuberculosis resemble with malignant diseases of larynx. The diagnosis was made here by the microscopic examination of sputum smear for Acid Fast Bacilli, chest x-ray, direct laryngoscopy and biopsy from the laryngeal lesion. PMID- 23342545 TI - Multiple tuberculous abscesses and mediastinal lymphadenitis with no pulmonary involvement in an immunocompetent patient. AB - Tubercular cold abscesses secondary to neighbouring bone involvement are a well known clinical manifestation of extra-pulmonary tuberculosis. However, primary soft tissue tuberculous abscesses with no pulmonary involvement in immuno competent patients are very uncommon. A rare case of multiple primary intrathoracic and extraperitoneal soft tissue tuberculous abscesses and mediastinal lymph node tuberculosis with no pulmonary involvement is reported. This case demonstrates the need for a high index of suspicion for such rare presentations of extra-pulmonary tuberculosis in patients from endemic areas. PMID- 23342546 TI - Oro-facial granulomatosis--a case report. AB - Oro-facial granulomatosis includes a group of disorders which present as a chronic, non-ceasating granulomatous lesion involving the perioral tissues of face and oral mucosa. This condition was first referred by Mart in 1859, Hubschmann in 1894 and Luscher in 1949; later, Wiesenfeld in 1985 introduced the term "Oro-facial Granulomatosis" (OFG) which is characterized by persistent or recurrent soft tissue enlargement and oral ulceration. Hence, it is important to establish the diagnosis accurately because this condition sometimes is a manifestation of Crohn's disease or Sarcoidosis. A case of Orofacial granulomatosis in a 15-year-old male is reported. PMID- 23342547 TI - Knowledge and attitude towards tuberculosis amongst the tribal population of Jhabua, Madhya Pradesh. AB - A community-based cross-sectional survey was carried out amongst the tribal population of Jhabuain Madhya Pradesh. A total of 1385 individuals from randomly selected villages were interviewed using structured questionnaire. Eighty five per cent respondents had knowledge of the symptoms of tuberculosis. About a quarter of the respondents were not aware of any method for preventing TB. Though majority of the respondents (68.2%) stated that TB is a curable disease, most of them (67.2%) were not aware of the DOTS programme. The study emphasizes the need for extensive health education programme to create awareness about tuberculosis in tribal population of the region. PMID- 23342548 TI - Association of hearing loss with decreased employment and income among adults in the United States. AB - OBJECTIVES: We evaluated the association of hearing loss with employment and income in adults. METHODS: Patients with a coded diagnosis of hearing loss were identified from the 2006 and 2008 Medical Expenditure Panel Survey linked household and medical conditions files and compared to patients without hearing loss. Differences in employment, wage income, and Supplemental Security Income were evaluated with multivariate regression models after adjustment for several demographic and Charlson comorbidity variables. RESULTS: An estimated 933,921 +/- 88,474 adults were identified with hearing loss (54.7% of whom were male; mean age for all, 51.0 years). Patients with hearing loss were more likely to be unemployed or partly unemployed than those without hearing loss (adjusted odds ratio, 2.2; p < 0.001). Similarly, adults with hearing loss were less likely to have any wage income than those without hearing loss (adjusted odds ratio, 2.5; p < 0.001). The population with hearing loss earned a mean wage of $23,481 +/- $3,366, versus $31,272 +/- $517 for the population without hearing loss (difference in wages, $7,791; p < 0.001). The association between hearing loss and receiving Supplemental Security Income was not significant (p = 0.109). CONCLUSIONS: Adults with hearing loss are more likely to be unemployed and on average earn significantly less wage income than adults without hearing loss. Further work is needed to determine the potential impact of treatment on these differences. PMID- 23342549 TI - Significant post-tonsillectomy pain is associated with increased risk of hemorrhage. AB - OBJECTIVES: In this study, we set out to assess the association of postoperative pain types with the risk of hemorrhage after tonsillectomy. METHODS: The questionnaire-based study was conducted on 335 patients who had undergone tonsillectomy. Hemorrhage risk and postoperative pain were evaluated retrospectively with use of a visual analog scale for 5 time periods (day 1, days 2 to 3, days 4 to 7, days 7 to 14, and later). RESULTS: Five pain types were identified by a cluster analysis. The most frequent pain types, I (24.8%; 83 patients) and II (50.8%; 170 patients), show decreasing pain, with pain type II starting on a higher level than pain type I. Pain types III (10.7%; 36 patients) and IV (1.2%; 4 patients) start at a low level with increasing pain for the first few days. In type III, pain decreases after 1 week, whereas type IV consists of a high level of pain for more than 2 weeks. Pain type V (12.5%; 42 patients) involves a very high level of pain from the beginning, which decreases only gradually. Pain type I is associated with a low hemorrhage rate. Patients with increasing pain (types III and IV) and pain type V show a significantly higher hemorrhage risk. CONCLUSIONS: Patients who have severe or increasing pain in the first few days after tonsillectomy have a significantly higher risk of hemorrhage. PMID- 23342550 TI - Accuracy of cochlear implant recipients in speech reception in the presence of background music. AB - OBJECTIVES: This study examined speech recognition abilities of cochlear implant (CI) recipients in the spectrally complex listening condition of 3 contrasting types of background music, and compared performance based upon listener groups: CI recipients using conventional long-electrode devices, Hybrid CI recipients (acoustic plus electric stimulation), and normal-hearing adults. METHODS: We tested 154 long-electrode CI recipients using varied devices and strategies, 21 Hybrid CI recipients, and 49 normal-hearing adults on closed-set recognition of spondees presented in 3 contrasting forms of background music (piano solo, large symphony orchestra, vocal solo with small combo accompaniment) in an adaptive test. OUTCOMES: Signal-to-noise ratio thresholds for speech in music were examined in relation to measures of speech recognition in background noise and multitalker babble, pitch perception, and music experience. RESULTS: The signal to-noise ratio thresholds for speech in music varied as a function of category of background music, group membership (long-electrode, Hybrid, normal-hearing), and age. The thresholds for speech in background music were significantly correlated with measures of pitch perception and thresholds for speech in background noise; auditory status was an important predictor. CONCLUSIONS: Evidence suggests that speech reception thresholds in background music change as a function of listener age (with more advanced age being detrimental), structural characteristics of different types of music, and hearing status (residual hearing). These findings have implications for everyday listening conditions such as communicating in social or commercial situations in which there is background music. PMID- 23342551 TI - Is preoperative computed tomographic density measurement of soft tissues helpful in the diagnosis of cholesteatoma? AB - OBJECTIVES: We undertook to verify the usefulness of computed tomography Hounsfield units (HU) in differentiating cholesteatoma from inflammatory tissue. METHODS: In 91 enrolled cases, the lesions were classified according to the gross pathology, and the specific locations of each lesion were documented by 1 surgeon within 1 day after the operation. The densities in HU of cholesteatoma and non cholesteatoma lesions were retrospectively measured 3 times by the same examiner, and the difference between the two groups was analyzed. The interobserver reliability among the 3 examiners was assessed to verify the confidence level of the HU measurements in preoperative detection of cholesteatoma. RESULTS: The mean HU values of cholesteatoma were 35.7 to 66.6 HU, and those of non-cholesteatoma lesions were 32.9 to 51.3 HU. A general linear model-repeated-measures analysis of variance did not show any significant difference between the cholesteatoma and non-cholesteatoma lesions (p = 0.305). The general linear model-repeated-measures analysis of variance showed a significant difference of the measured HU levels among the 3 examiners (p = 0.021). CONCLUSIONS: This study showed that the HU values on preoperative computed tomography did not suffice for the detection of cholesteatoma lesions. A clinician's physical examination together with an interpretation of computed tomography is still the "gold standard" method. PMID- 23342552 TI - Vocal fold stem cells and their niche in the human vocal fold. AB - OBJECTIVES: Vocal fold stellate cells (VFSCs) in the maculae flavae have many morphological differences from conventional fibroblasts in the human vocal fold mucosa. It is uncertain whether the VFSCs are derived from the same embryonic source as conventional fibroblasts. The purpose of this study was to investigate the stemness of the VFSCs and whether the pericellular matrices in the maculae flavae are a hyaluronan-rich matrix, which is required for a stem cell niche. METHODS: Paraffin-embedded specimens were stained with Alcian blue (pH 2.5) for a hyaluronidase digestion study. Immunoreactivity to antibodies directed to CD44, CD133, Oct-4, Ki67, and telomerase was investigated in 5 human adult vocal fold mucosae. RESULTS: The VFSCs were resting cells (G0-phase) and expressed a mesenchymal stem cell marker. The VFSCs did not express hematopoietic or embryonic stem cell markers. Telomerase resided in the VFSCs. The hyaluronan concentration in the maculae flavae was high and the VFSCs expressed hyaluronan receptors, indicating that maculae flavae are characterized by a certain criterion of hyaluronan-rich matrix. CONCLUSIONS: There is growing evidence that the VFSCs in the human maculae flavae are somatic (mesenchymal) stem cells of the vocal fold, and that the maculae flavae may be a candidate for a stem cell niche that is a microenvironment nurturing a pool of VFSCs. PMID- 23342553 TI - Expression of reactive oxygen species during wound healing of vocal folds in a rat model. AB - OBJECTIVES: Previous studies have indicated that although normal wound healing requires low levels of reactive oxygen species (ROS), excessive amounts of ROS impair wound healing. In injured vocal folds, this excess may result in dysphonia due to scarring that is difficult to treat. However, the expression of ROS during vocal fold wound healing has yet to be investigated. In this study, we assessed the expression and localization of ROS in injured vocal folds by immunohistochemical analysis. METHODS: Vocal folds of Sprague-Dawley rats were unilaterally injured by stripping the mucosa under transoral endoscopy. The larynges were harvested at specific time points after injury and were immunohistochemically examined for 4-hydroxy-2-nonenal (4-HNE), an ROS marker, and for the presence of inflammatory cells. RESULTS: We found that 4-HNE immunopositive cells were significantly increased in the lamina propria of the injured vocal folds as compared to the normal vocal folds on postinjury days 1 and 3. More than half of the 4-HNE-immunopositive cells were also immunopositive for a macrophage- and granulocyte-specific antibody. CONCLUSIONS: This study suggests that a large amount of ROS is produced during early-phase wound healing, until postinjury day 3, and that this period may be crucial for regulating ROS levels. The results also suggest that inflammatory cells may contribute to ROS generation. PMID- 23342554 TI - Single-incision robot-assisted transaxillary surgery for early-stage papillary thyroid cancer. AB - OBJECTIVES: We describe the surgical details, results, and learning curve of a proposed technique for single-incision transaxillary robot-assisted thyroid surgery for early-stage thyroid cancer. METHODS: We performed single-incision transaxillary robot-assisted total thyroidectomy with the da Vinci surgical system in 29 patients (5 male, 24 female; median age, 45 years; age range, 19 to 69 years) with papillary thyroid cancer (cT1 NO) using our proposed technique with selected instrumentation. Preoperative ultrasound examination, fine-needle aspiration cytology, and contrast computed tomographic scanning were performed in all subjects. Ultrasound examination was carried out 1 month after surgery to assess the amount of residual thyroid tissue. RESULTS: No procedure was converted to conventional open surgery. The mean total operation time was 178.51 +/- 24.18 minutes, and the mean console time was 126.10 +/- 14.47 minutes. A progressive reduction of console time was noted (160 minutes for the first procedure versus 102 minutes for the last one). No cases of permanent hypocalcemia, recurrent laryngeal nerve palsy, or postoperative bleeding occurred. The mean amount of postoperative residual thyroid tissue on ultrasound examination was 8.93 +/- 2.15 mm. CONCLUSIONS: The single-incision transaxillary robot-assisted total thyroidectomy we propose is a feasible and relatively safe procedure in selected patients with early-stage thyroid cancer. PMID- 23342555 TI - Dysregulation of histone deacetylase and histone acetyltransferase in development of Wegener's granulomatosis. AB - OBJECTIVES: We investigated the function of the decreases in histone deacetylase (HDAC) and histone acetyltransferase (HAT) in Wegener's granulomatosis (WG) patients compared with healthy subjects. METHODS: Seven patients with WG, diagnosed according to the American College of Rheumatology criteria, were examined. Fresh peripheral blood mononuclear cells were isolated from the WG patients and healthy subjects, and then whole-cell proteins were prepared. We measured the total HDAC and HAT activity in peripheral blood mononuclear cells from WG patients. The HDAC2 expression was analyzed by Western blot. RESULTS: We found that total HDAC activity was significantly decreased in WG patients compared to that in healthy subjects (p < 0.05). Furthermore, we found a negative correlation between total HDAC activity and C-reactive protein titer. Total HAT activity was significantly increased in WG patients. CONCLUSIONS: These results demonstrated reduced HDAC activity and an increase in HAT activity in WG. These were associated with concomitant induction of WG-related inflammation. Thus, dysregulation of HDAC and HAT may contribute to the disease pathogenesis of WG. PMID- 23342556 TI - The very first cry: a multidisciplinary approach toward a model. AB - OBJECTIVES: In previous work, we showed that a rigid larynx-like geometry can generate a sound by itself. However, very little is known about the exact mechanisms and control of the larynx during the first cry of life. The goal of this work was to understand how the very first cry is generated. METHODS: Simultaneous high-speed imaging and sound recording on 2 excised 38-week term human fetus larynges were performed. The behaviors of the vocal folds and the false vocal folds were studied separately. The behavior of the vocal folds after resection of the supraglottic structures was also analyzed. A comparative acoustic analysis of the first cry and of the sound generated by the excised organs was performed. RESULTS: Our data showed that the vocal folds in a larynx with the pressure conditions of the first cry do not generate sound themselves, but induce aerodynamic conditions leading to vibrations of other parts of the larynx. CONCLUSIONS: The similarities between the sound generated by an excised larynx and the first cry suggest a lack of neurologic control of the larynx during production of the first cry. A model-algorithm is proposed. PMID- 23342557 TI - Temporary hypocalcemia is one of the most common complications of total thyroidectomy. PMID- 23342558 TI - Allotransplantation of tooth: a case report. AB - Tooth transplantation has attracted great interests since ancient times. A successful case of tooth allotransplantation is presented. A mandibular first premolar from the donor was implanted into the socket of maxillary central incisor Follow up after 12 months indicated good periapical healing with no resorption. Clinically, the transplantation site was free of symptoms and there was no evidence of periodontal disease or tooth mobility. This article suggests tooth transplantation as an alternative to other restorative options. PMID- 23342559 TI - Esthetic smile rehabilitation through autogenous bonding of dental fragment: a case report. AB - Autogenous tooth fragment bonding offers advantages over restorations with composite resins and porcelain, including better esthetics, greater durability, reestablishment of the natural function of the dental element and short execution time. A case is presented of a 14-year-old male patient who suffered an oblique crown fracture of the permanent right maxillary central incisor (11) due to a traumatic fall. The clinical examination revealed pulp exposure with no invasion of the biological space. Due to the extension of the fracture, endodontic treatment and the placement of an intra-root esthetic pin was needed. The tooth was restored using the autogenous fragment bonding method. Excellent esthetic and functional results were observed after two years of follow up. PMID- 23342560 TI - Evaluating the effect of probiotic containing milk on salivary mutans streptococci levels. AB - PURPOSE: To evaluate the changes in mutans streptococci counts in saliva after short term probiotic intervention and its delayed effects on salivary mutans streptococci count. METHODS: 40 children in the age group of 12-15 years with medium to high caries activity were randomly divided into Group I Control (plain milk group) and Group II Experimental (probiotic supplemented milk group). Duration of the study was 9 weeks; which was evenly divided into three phases: baseline, intervention and post-treatment period; each phase consisting of three weeks. After baseline period of 3 weeks, children in group I were given plain milk and in group II milk containing probiotic Lactobacillus rhamnosus hct 70 for 3 weeks; followed by a 3 weeks follow up period. After every phase saliva samples were collected to estimate salivary mutans streptococci counts. RESULTS: The difference in the post follow up mutans streptococci count of group I and group II, was highly significant with p value < 0.001. In the control group, the difference in the mean salivary baseline, post treatment and post follow up mutans streptococci counts was not statistically significant (p > 0.001). In the experimental probiotic group, the difference in mean salivary baseline, post treatment and post follow up mutans streptococci counts was statistically highly significant (p = 0.000, p < 0.001). CONCLUSIONS: Statistically significant reduction in salivary mutans streptococci counts immediately after consumption of probiotic Lactobacillus rhamnosus hct 70 containing milk suggest a beneficial effect of probiotic Lactobacillus rhamnosus hct 70 in the prevention of dental caries. PMID- 23342561 TI - Effectiveness of two flavored topical anesthetic agents in reducing injection pain in children: a comparative study. AB - Topical anesthesia is widely advocated in pediatric dentistry practice to reduce pain and anxiety produced by administration of local anesthesia. There are different combinations of topical anesthetic agents that are marketed worldwide. However, sparse literature reports exist regarding clinical efficacy of these agents. AIM: To compare the clinical effectiveness of two strawberry flavored topical anesthetics viz. Precaine (8% Lidocaine + 0.8% Dibucaine) and Precaine B (20% Benzocaine) in children before intra oral local anesthetic injections and for extraction of mobile primary teeth. STUDY DESIGN: This triple blind clinical study included sixty children divided equally under three techniques--palatal injections, inferior alveolar nerve block and extraction of mobile primary teeth. Both the products were used alternately using split mouth design in two visits and the child's pain response was assessed using VAS and SEM pain scale. The scores obtained were subjected to statistical analysis. RESULTS: Precaine has shown lower mean scores in all the techniques under both the pain scales, but were statistically insignificant. Gender wise comparison has also shown lower mean scores for Precaine for both males and females, however these were statistically insignificant. On visit wise comparison, Precaine B reported significant lower scores (p < 0.05) in visit 2 compared to visit 1 for inferior alveolar nerve block and extraction of mobile primary teeth under SEM pain scale. CONCLUSION: Precaine (8% Lidocaine + 0.8% Dibucaine) can be used as effectively as Precaine B (20% Benzocaine). PMID- 23342562 TI - Esthetic splint--a novel concept for the management of bilateral condylar fracture. AB - Mandibular condyle is one of the most common sites of injury in the facial skeleton. But many condylar injuries remain undiagnosed. In rare situations, these injuries may result in serious adverse sequel in the patient's growth and development that are more difficult to treat at a later stage. In growing individuals, conservative management results in better functional outcome and good remodelling of the condyle. The aim of this article is to present a case report of a bilateral sub-condylar injury in a young child with a novel concept- an esthetic splint. PMID- 23342563 TI - Salivary ferritin as a predictive marker of iron deficiency anemia in children. AB - OBJECTIVES: The objective of the study was to determine the salivary Ferritin levels in children with iron deficiency anemia and its reliability as a predictive marker of the disease and whether these levels could give a new hypothetical insight on the oral epithelial changes seen in patients with iron deficiency anemia. STUDY DESIGN: The study comprised of 60 children of which the study group comprised of 30 individuals; aged 8-14 years with iron deficiency anemia. Venous blood was collected and hematological examination was performed to determine the hemoglobin and serum ferritin levels to confirm the diagnosis. Saliva was then collected from 30 children with iron deficiency anemia and an equal number of controls. The ferritin levels in saliva were then analyzed using solid phase ELISA. RESULT: The mean value of salivary ferritin in iron deficient cases was 153.24 +/- 46.58 microg/dl and the mean ferritin levels in control subject were 93.87 +/- 30.15 microg/dl. Thus the salivary ferritin was found to be significantly higher in iron deficient subjects compared to the controls. CONCLUSION: The result of our research affirms the fact that the expression of ferritin in saliva of iron deficiency anemia may be due to the enzymatic functions in the saliva and the endocytosis of ferritin which can possibly elevate the salivary ferritin. The diminished level of cytochrome oxidase, together with its relatively high Ferritin content, depicts the association of oral epithelial changes and ferritin occurring in iron deficiency anemia. PMID- 23342564 TI - Effectiveness of oxidative potential water as an irrigant in pulpectomized primary teeth. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of oxidative potential water (OPW) as an irrigating solution in reducing bacterial loading in necrotic pulpectomized primary teeth. STUDY DESIGN: Forty necrotic teeth were included, 20 irrigated with OPW (experimental group) and 20 with 1% NaOCl (control group); in both groups, 2 microbiological samples from within the canals were taken with a sterile paper point, the first before irrigation (immediately before opening the crown), and the second after instrumentation and final irrigation (before filling). All samples were evaluated by McFarland's scale. RESULTS: After the samples were analyzed before and after irrigation in the control group, there was a significant decrease in bacterial load, as in the experimental group (P < 0.0001). When both groups were compared post irrigation, no significant difference was observed (P = 0.1519). CONCLUSION: The OPW was as effective as the NaOCl and is suggested as an alternative for irrigating after pulpectomy of necrotic primary teeth. PMID- 23342565 TI - Effect of various concentrations of sodium hypochlorite on primary dentin: an in vitro scanning electron microscopic study. AB - BACKGROUND: Sodium hypochlorite solutions have been evaluated for their effects in bonding procedures as they are found to deplete or remove the organic portion of the dentin, particularly the collagen fibrils. The aim of this in vitro study was to assess and compare the efficacies of 1%, 2.5%, 5% and 10% NaOCl at 30, 60 and 120s on etched primary dentin. METHODS: 84 primary anterior teeth were ground to expose a flat dentin area on the buccal surface. The specimens were divided into fourteen groups of six each based on the dentin surface treatment (35% phosphoric acid etching for 7 seconds-AE and/or NaOCl application), NaOCl solution concentrations (1%, 2.5%, 5% and 10%) and time of application (0, 30, 60 and 120s). Specimens were prepared for SEM and photomicrographs were taken of the surface and were scored against a five point scale, based on the smear layer and amount of collagen removed. The scores were submitted to Kruskal-Wallis and Mann Whitney tests. RESULTS: This study showed the presence of smear layer in the control group. The group treated with Acid Etchant showed a demineralized pattern of dentin with exposure of dentin tubules and collagen fibrils network on the intertubular and peritubular dentin which was not significantly different from the groups treated with 1% and 2.5% NaOCl. Groups treated with 5% NaOCI were not statistically different from each other the surface was corroded but collagen fibrils were not completely depleted. Groups treated with 10% NaOCl were not statistically different from each other and showed complete removal of collagen fibrils with wider tubular apertures and several secondary tubules on peritubular and intertubular dentin. CONCLUSION: Higher concentrations of NaOCl solutions (5% and 10%) produced significant changes in the etched primary dentin. The higher the concentration of the NaOCI solution, the lower can be the time for the application of the solution for the complete removal of collagen fibrils. PMID- 23342566 TI - Microhardness and surface roughness of glass ionomer cements after APF and TiF4 applications. AB - OBJECTIVE: To evaluate whether TiF4 solution and APF gel had any adverse effects on the surface morphology of newly developed glass ionomers. STUDY DESIGN: Fifteen disc-shaped specimens of Fuji IX Extra, Fuji II LC and Ketac N100 were prepared and stored in 2 ml of artificial saliva at 37 degrees C for 8 weeks. Specimens of each material were divided randomly into three subgroups as 1 and 4 minutes application of 1.23% APF gel and 1 minute application of 1% TiF4 solution. Specimens were reaged for another 8 weeks. Microhardness, surface roughness values and surface morphology were evaluated by using Vicker's hardness test, surface profilometry and scanning electron microscopy (SEM) for all time interventions, respectively. One-way Anova test was performed and differences were compared by Tukey's HSD and Dunnet T3 test RESULTS: APF and TiF4 applications decreased microhardness significantly in Fuji II LC. In Fuji IX Extra microhardness decreased significantly after 1- and 4-min APF applications. Ketac N100 showed no difference in microhardness after APF and TiF4 applications. Surface roughness was not affected at any time interval for three restorative materials. CONCLUSION: Within the limitations of this vitro study it was revealed that, potential adverse effects of APF and TiF4 applications might be material dependant. Hence, restorative materials should be selected in accordance with kind, frequency and application time of fluoridation to avoid deteriorations of the restorations. PMID- 23342567 TI - Hybrid layer width after conventional diamond, carbide and ultra-sound CVD burs. AB - OBJECTIVES: The aim of the present study was to evaluate hybrid layer thickness of primary molars sectioned with diamond, carbide and ultrasonic CVD burs. STUDY DESIGN: The occlusal enamel surfaces often molars were removed and superficial dentin was exposed. Three standardized cavities were prepared at mesial, central and distal exposed dentin with diamond, carbide and ultrasonic CVD burs, respectively. A self-etching adhesive system (Adhese, Ivoclar/Vivadent) was applied to prepared cavities and composite resin Z100 (3M/ESPE) was inserted according to manufacturers'instructions to hybridized dentin. Samples were light cured and the crown was sectioned mesio-distally dividing the restored cavities in two halves which were observed under scanning electron microscopy (SEM), in order to quantitatively evaluate hybrid layer thickness (microm). Three repeated measures were performed at mesial, central and distal sites and mean values obtained were submitted to one-way analysis of variance (ANOVA). RESULTS: Data (mean +/- sd) obtained were (microm): 2.69 (0.44), 3.38 (1.23) and 2.72 (1.18)for diamond, carbide and CVD burs, respectively. No differences were observed among groups (p > 0.05). The adhesive systems promoted mechanical retention, uniform and continuous hybrid layer and resin tags formation at all dentin sites for all instruments tested. CONCLUSION: The results suggest that the minimally invasive cavities prepared with diamond, carbide and CVD for ultrasound, promoted hybrid layer formation with a similar thickness regardless the bur used. PMID- 23342568 TI - An in vitro evaluation of antimicrobial efficacy of primary root canal filling materials. AB - OBJECTIVE: The present study aimed to evaluate and compare six different materials commonly used for filling the root canals of primary teeth for antimicrobial efficacy against some of the microorganisms commonly found in infected root canals. STUDY DESIGN: In this experimental in vitro study six root canal filling materials were tested for antimicrobial efficacy against eight microbial strains using the agar diffusion method. RESULTS: Zinc oxide eugenol paste exhibited the strongest antimicrobial potential followed by Endoflas, zinc oxide-calcium hydroxide-sodium fluoride mixture, zinc oxide-calcium hydroxide mixture and calcium hydroxide paste (Apexcal). The addition of sodium fluoride to the zinc oxide-calcium hydroxide mixture enhanced the antimicrobial efficacy. Metapex demonstrated minimal inhibition and Vaseline was non-inhibitory. CONCLUSIONS: All the test filling materials demonstrated varying antimicrobial activity against the microorganisms tested. Zinc oxide eugenol paste and materials containing zinc oxide were found to be more effective against the microorganisms compared to materials without zinc oxide. PMID- 23342569 TI - Idiopathic ulcers as an oral manifestation in pediatric patients with AIDS: multidisciplinary management. AB - HIV infection is a major global health problem affecting developing and developed countries alike. HIV infection is associated with multiple oral lesions, some of which are of value in diagnosing the disease. The aim of this report is to describe the clinical manifestations and their multidisciplinary management, in a 6-year-old girl with AIDS. The findings of this case report indicate that, it is essential to be familiar with the early oral manifestations of AIDS in order to understand the patient's dental health needs, apply preventive methods, control caries, and understand the value of oral lesions as diagnostic markers of disease progression in children with HIV infection. A multidisciplinary management is fundamental. PMID- 23342570 TI - Congenital Rubella Syndrome: dental manifestations and management in a 5 year old child. AB - Congenital Rubella Syndrome is a rare disorder comprised of a constellation of physical abnormalities that develop in infants as a result of maternal infection and subsequent fetal infection with rubella virus. The congenital lesions involve vital organs such as heart, eye, ear, brain and endocrine system and less frequently, teeth. The severity of systemic involvement depends on the stage of gestation at which maternal rubella infection occurs. With the implementation of immunization programs worldwide, its incidence has been dramatically reduced during the past half century. This article provides an insight into the prolonged effect of the virus on ameloblasts by highlighting the presence of hypoplastic enamel in primary teeth and erupting permanent teeth in a female child diagnosed with congenital rubella syndrome. PMID- 23342571 TI - Effect of continuous versus interrupted administration of nitrous oxide-oxygen inhalation on behavior of anxious pediatric dental patients: a pilot study. AB - OBJECTIVE: The purpose of this study was to determine the effect of interrupted administration of nitrous oxide (N2O) inhalation, after obtaining profound local anesthesia, on the behavior of mild to moderately anxious pediatric patients during routine restorative dentistry. STUDY DESIGN: Healthy children, 5 to 8 years old, requiring nitrous oxide/oxygen inhalation sedation and bilateral mandibular restorative treatment performed in two sequential appointments under local anesthesia were recruited for this study. After profoundness of the local anesthesia was confirmed, the subject was randomly assigned to either Protocol A (50% N2O/50% O2) or Protocol B (100% O2) and restorative dental care was completed. On the second appointment, the subject was assigned to the alternate protocol. RESULTS: Hemoglobin oxygen saturation remained constant with no episodes of oxygen desaturation recorded. There were no statistically significant differences (P > .05) in pulse rate or behavior change noted between the two protocols. CONCLUSION: The implication of this pilot study was significant in consideration of the desire to minimize chronic exposure to ambient nitrous oxide and its potential health hazards to the dental team. These findings challenge the traditional practice of N2O maintenance throughout the dental appointment. PMID- 23342572 TI - Salivary cortisol, alpha-amylase and heart rate variation in response to dental treatment in children. AB - OBJECTIVE: Anxiety and stress are usually related to the dental treatment situation. The objective was to investigate salivary cortisol and alpha-amylase levels (salivary biomarkers) and heart rate in children undergoing a minor dental procedure (dental prophylaxis). STUDY DESIGN: In total, 31 children (range 84-95 months) of both genders without caries or history of dental treatment/pain/trauma were selected. Three saliva samples were gathered: one prior to dental prophylaxis, one immediately after and one ten minutes later. Weight and height were assessed, and heart rate was evaluated prior to and during the procedure. Data were analyzed by correlation tests and t-test/Wilcoxon (alpha = 0.05). RESULTS: Higher cortisol and amylase levels were observed before prophylaxis compared to afterward. Cortisol and amylase levels did not show a significant correlation, nor did salivary biomarkers and body mass index. However, heart rate and amylase levels showed a significant positive correlation. CONCLUSIONS: In the studied sample, certain anticipation of the dental treatment was observed because higher cortisol and amylase levels were observed before, rather than after the event; moreover a significant correlation between amylase levels and heart rate was observed Thus, salivary biomarkers may be a valuable tool for evaluating anxiety-producing events, such as dental treatment, in children. PMID- 23342573 TI - Oral health status in children with renal disorders. AB - Advances in pediatric nephrology have resulted in increased survival rates of children with renal disorders. Renal disease is characterized by multiple organ involvement, including soft and hard tissues of the oral cavity. Data regarding the oral health status of Indian children with renal disorders is scarce. Thus, the aim of this study was to assess the oral health status of children with renal disorders in Jaipur city, India. Thirty six children in the age-group of 4-14 years, diagnosed with renal disorders were selected Data pertaining to demographics, medication history, body mass index and blood investigations were obtained from the hospital records. The World Health Organization (WHO) criteria were used to diagnose dental caries. Enamel defects were recorded according to Developmental Defects of Enamel index. Oral hygiene status, salivary pH and buffering capacity were also assessed. The mean blood hemoglobin value was 9.75 gm/dl, blood urea nitrogen 43.06 gm/dl and serum creatinine 1.5 mg/dl. Enamel defects were seen in 58.3% of children. Their mean deft and DMFT scores were 1.5 and 0.5, respectively. The mean Oral Hygiene Index-Simplified (OHI-S) score was 1.56. Gingival overgrowth was not present. Mean salivary pH was 6.92 and buffering capacity of stimulated saliva was 9.86. It is necessary for pediatric dentists to follow preventive oral health regimens that are tailored to these patients. PMID- 23342574 TI - Evaluation of facial anthropometric parameters in 11-17 year old boys. AB - BACKGROUND AND OBJECTIVE: Anthropometry is the study of qualitative specifications based on linear and angular measurements of human body. The aim of the present study was to determine anthropometric parameters of 11-17 year old boys of northeast Iran. METHOD: This cross-sectional analytical study was conducted on 583 boys of Fars ethnicity living in Mashhad with Class I skeletal and dental relationships. Digital photographs in natural head position were transferred to a computer and the desired anthropometric landmarks were traced on each image. Anthropometric parameters including the width of the forehead, the width of the face, the width of the cranial base, intergonial width, intercanthal width, binocular width, nasal width, mouth width, facial and nasal height and depth of superior, middle and inferior one-third of the face were measured by "Smile Analyzer" software. ANOVA, Tukey test, and linear regression were used for statistical analysis. RESULTS: Most of the parameters studied increased gradually with age. A growth spurt was evident at the ages of 15-16 years old for binocular width, nasal width, nasal height and depths of middle and inferior one-third of the face. Facial height was among some parameters which were found to increase slightly after 16. Unlike the other parameters, intercanthal width showed an irregular pattern of changes and statistical analysis did not show any significant differences among different age groups (P-value = 0.362). CONCLUSION: Aging of the face occurs in spurts and at different periods of life. During the studied time span, significant growth in most anthropometric parameters except intercanthal width was obvious. PMID- 23342575 TI - Malocclusion: social, functional and emotional influence on children. AB - OBJECTIVES: To determine the association between types of malocclusion and quality of life in children between 8-10 years of age and establish correlations between the severity of the malocclusion and particular bio-psychosocial variables. STUDY DESIGN: The sample was made up of 102 schoolchildren aged 8-10 years. Clinical exams were performed using the criteria of the Dental Aesthetic Index (DAI) to determine the presence and severity of malocclusions. The impact on quality of life was assessed using the Child Perceptions Questionnaire (CPQ8 10). Statistical analysis involved the chi-square test, Fisher's exact test and Spearman's correlation analysis. RESULTS: Malocclusions affected 61% of the children examined. There was a positive correlation between total CPQ8-10 and DAI scores (P = 0.034). The following types of malocclusion had a significant effect on the quality of life of the children: upper anterior irregularity > or = 2 mm, anterior open bite > or = 2 mm and diastema > or = 2 mm. Children with malocclusion experienced a greater negative impact on quality of life in comparison to those without malocclusion. CONCLUSIONS: Malocclusions had a negative influence over the quality of life of children between 8-10 years of age. More severe malocclusions had a greater impact with regard to social, emotional and functional aspects. PMID- 23342576 TI - Modified thermoplastic plate: a new proposal for correction of exaggerated overbite in mixed dentition. AB - Exaggerated overbite can be corrected by several treatment modalities. As the primary objective is to correct the problem by addressing its root cause, treatment options are closely related to etiology. Therefore, the main treatment strategies are: the extrusion of posterior teeth, intrusion of teeth (maxillary/mandibular) or the combination of these. The purpose of this paper is to describe the fabrication of a modified thermoplastic plate (MTP) for correction of exaggerated overbite in mixed dentition and describe a clinical case treated with this device. MTP favored the extrusion of posterior teeth, in addition to being shown to be a device that was easy to manufacture and effective in the treatment of excessive overbite, enabling patients to return to normal condition during the development of occlusion. PMID- 23342577 TI - Dentistry and childhood poverty in the United States. AB - The proportion and numbers of children living in low income families and without health insurance continues to increase. The magnitude of these problems is considered at localized levels in terms of the impact on the use of dental services. PMID- 23342578 TI - [Infectious diseases: progress in diagnosis and treatment. Editorial: Advance of clinical infectious diseases]. PMID- 23342579 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: I. Infectious diseases in unusual circumstances; 1. Infectious diseases post Great East Japan earthquake]. PMID- 23342580 TI - [Infectious diseases: progress in diagnosis and treatment topics: I. Infectious diseases in unusual circumstances. 2. The issue raised by 2011 NHCAP guideline in Japan]. PMID- 23342581 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: I. Infectious diseases in unusual circumstances: 3. The possibility of bioterrorism and its countermeasures]. PMID- 23342582 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: II. Measures to prevent the outbreaks; 1. Changes in medical care for influenza: before and after the H1N1 pandemic]. PMID- 23342583 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: II. Measures to prevent the outbreaks: 2. Epidemic of Mycoplasma pneumoniae infection and its management]. PMID- 23342584 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: II. Measures to prevent the outbreaks: 3. Adult pertussis, its diagnosis and treatment]. PMID- 23342585 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: II. Measures to prevent the outbreaks. 4. Emergence and control of a new multidrug resistant bacteria]. PMID- 23342586 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: III. Emerging and re-emerging infectious diseases; 1. Recent topics on HIV medicine]. PMID- 23342587 TI - [Infectious diseases:progress in diagnosis and treatment. Topics: III. Emerging and re-emerging infectious diseases; 2. Control and medical care of tuberculosis in "QFT" era]. PMID- 23342588 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: III. Emerging and re-emerging infectious diseases; 3. Gastrointestinal infection associated with consumption of raw meats]. PMID- 23342589 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: III. Emerging and re-emerging infectious diseases; 4. Emerging parasitic diseases]. PMID- 23342590 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: IV. Towards containing infectious diseases; 1. Most recent findings about vaccines for physician]. PMID- 23342591 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: IV. Towards containing infectious diseases; 2. Development of new antibiotics]. PMID- 23342592 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: IV. Towards containing infectious diseases: 3. Development of new antifungal drugs]. PMID- 23342593 TI - [Infectious diseases: progress in diagnosis and treatment. Topics: IV. Towards containing infectious diseases; 4. Impact of amending medical service fees about countermeasures against hospital infection]. PMID- 23342594 TI - [Discussion meeting on the effect of social event over the practice of infectious diseases]. PMID- 23342595 TI - [Case report; A case of Malassezia furfur fungemia induced by repeated administration of liposomal flurbiprofen axetil]. PMID- 23342596 TI - [Case report; Fibrinoid necrotizing angiitis of the gall bladder in a patient with systemic lupus erythematosus]. PMID- 23342597 TI - [Case report; A case of hepatic endometriosis with periodic right upper quadrant pain]. PMID- 23342598 TI - [Case report; A case of multiple myeloma which cells gained multiple gene and chromosome aberrations and changed their morphology to plasmablastoid and lymphoblastoid during less than two years course]. PMID- 23342599 TI - [The cutting-edge of medicine; application of medical informatics in internal medicine]. PMID- 23342600 TI - [The cutting-edge of medicine; development of diagnostic biomarkers for neurodegenerative diseases]. PMID- 23342601 TI - [Series: Knowledge of emergency required for internist; disseminated intravascular coagulation ]. PMID- 23342602 TI - [Report from the 13th Hokuriku Chapter Open Conference for the fellow of the Japanese Society of Internal Medicine: a case of 70-year-old woman who complained of fever and lumbago]. PMID- 23342603 TI - [Series: Diagnosis at a glance]. PMID- 23342604 TI - [Series: Let's think-clinical quiz (question); A patient presenting with multiple nodule irregular in size to progress rapidly]. PMID- 23342606 TI - [Series: For attending physicians; professionalism; moral intuitions as foundations for (medical) professionalism]. PMID- 23342605 TI - [Series: Clinical study from Japan and its reflections: CASCARD (Carotid artery stenting by Japanese CARDiologists)]. PMID- 23342607 TI - [Series: Physicians and disaster medical care: home care patients in disaster]. PMID- 23342608 TI - [Current state, challenges and prospects for the development of the Russian urological service]. AB - The present study was dedicated to the analysis of the incidence, prevalence and mortality from diseases of the urogenital system. The data on the effectiveness of the hospital bed usage, the patient profile at hospital, the treatment timing and outcomes, surgical activities in urological hospitals, the state of staff assistance in urological service, the efficacy of usage of working time of urologist and human resource of Russian urological service were analyzed. Data analysis revealed a number of issues of administrative and legal nature, which cause modest efficiency of activity of urological service. The ways for solutions of these problems are presented. PMID- 23342609 TI - [Application of alpha1-adrenoblockers in treatment of ureteral calculi]. AB - The results of evaluation of the efficacy of alpha1-adrenoblockers in treatment of ureteral calculi are presented. Comparative, prospective, placebo-uncontrolled nonrandomized single-center study was performed, which included 118 patients with solitary diagnosed calculi in various parts of ureter. After the pain relief, all the patients underwent conservative therapy aimed at spontaneous discharge of concretions. The maximum duration of conservative treatment was 28 days. Ultrasound monitoring was performed every week in all patients. The control group of patients received only Drotaverinum 40 mg three times a day, and analgesics. The main group received alpha1-adrenoblocker tamsulosin at a standard dose of 0.4 mg once a day along with Drotaverinum and analgesics. The overall probability of a discharge of concrements localized in the distal ureter was significantly (P = 0.02) higher in the patients treated with alpha1-adrenoblockers. Treatment regimen in main group of patients allowed better control of pain during all periods of observation, even if the discharge of concretions was not registered. The overall probability of migration of concrements from the proximal to the distal ureter in main group of patients was 52% versus 32% in controls (P = 0.17). The frequency of adverse effects was comparable in both groups. Vertigo, postural hypotension, and weakness were significantly more frequent in the main group of patients. Univariate and multivariate analyses of the proportional hazards model have demonstrated that the administration of alpha1-adrenoblocker increased the likelihood of a discharge of concrement from the distal ureter. It is shown that the nature of the applied therapy has directly influence on the risk of an earlier discharge of concretions. Inclusion of alpha1-adrenoblockers in the treatment scheme increased the probability of discharge of concrements at 4.11 times. PMID- 23342610 TI - [Treatment and metaphylaxis of gout complicated by nephropathy and urolithiasis]. AB - The evaluation of clinical efficacy of combined treatment and metaphylaxis in 58 patients with gout complicated by nephropathy and urolithiasis was performed. The study included 41 (71%) men and 27 (29%) women aged 44 to 88 years (mean age - 58 +/- 7 years). All patients received parenteral therapy with trometamol H, 5 -10 infusion for the course, an average of 7 infusions. For the metaphylaxis, all patients received biologically active supplement urisan 2 tablets 2 times a day during next three months against the background of drug therapy. Findings indicate a high clinical efficacy of the trometamol H in the combined treatment of patients with gout, complicated by nephropathy and urolithiasis, considering that improvement of renal function, microcirculation in the renal parenchyma, increased glomerular filtration rate, normalization of nitrogenous wastes levels, partial or complete dissolution of concretions of the kidneys, a significant decrease in the tophs size, an increase in motor activity were observed, which ultimately improves the quality of life for these patients. Metaphylaxis using urisan for 3 months on a background of traditional therapy contributed to a stable normalization of blood uric acid levels, which prevented the exacerbation of underlying disease and recurrent stone formation. These data allow to recommend reducing the dose of traditional anti-gout drugs and conducting repeated course of metaphylaxis with the urisan after 5-6 months during 3 months. PMID- 23342611 TI - [Ureterohydronephrosis at pelvic prolapse in women]. AB - The study was aimed to examination of prevalence of obstructive complications of the upper urinary tract in patients with pelvic prolapse and evaluation of the effectiveness of their correction using modern reconstructive surgery. Bilateral ureterohydronephrosis was detected in 14 (12%) of 117 patients. In patients with stage IV pelvic prolapse, proportion of patients with hydronephrosis was much higher--22.6%. Transvaginal reconstructive surgery with the installation of synthetic mesh prosthesis according to the Tension free Vaginal Mesh method ensured the restoration of normal anatomy of the pelvic floor and allowed to eliminate obstructive disorders of the upper urinary tract and their complications. PMID- 23342612 TI - [Solifenacin in the treatment of overactive bladder: results of a randomized double-blind, placebo-controlled study]. AB - The article presents the results of the evaluation of clinical efficacy and safety of the M-cholinoblocker solifenacin in the treatment of symptoms of overactive bladder (OAB). The study included 24 women aged from 47 to 69 years with symptoms of OAB lasting more than 3 months. It is shown that solifenacin at a dose of 5 mg reduces the quality of urinary urgency, improves the condition according to assessment of degree of discomfort due to symptoms of the OAB, treatment satisfaction and condition of the bladder. PMID- 23342613 TI - [Effectiveness of cycloferon in complex treatment of brucellosis patients with lesions of the scrotum]. AB - The article presents the results of urological examination (spermograms and data of ultrasound examination) of 22 patients with chronic brucellosis and diseases of the scrotum (6 patients with orchitis, 16 with orchiepididymitis) before and after conventional therapy (10 patients) and combined treatment with the inclusion of cycloferon (2 courses of 5 intramuscular injection [0.25 g] with an interval of 10 days)--12 patients. It is shown that the administration of cycloferon leads to more effective relief of intoxication symptoms and inflammation in the testes and appendages (reduction of scrotal wall thickness, size of testes and/or adjuncts, and the incidence and severity of hydrocele), and has a positive effect on spermatogenesis (reduction of semen viscosity, the number of white blood cells in semen, sperm agglutination associated with the formation of sperm antibodies in most patients after treatment), as well as reduces the number of exacerbations of chronic orchitis/orchiepididymitis by 2.4 times. PMID- 23342614 TI - [Correction of urodynamic disorders in women with obstructive urination]. AB - From a position of urodynamic evaluation, obstructive urination represents a violation of the phase of urinary bladder emptying. The study was aimed to evaluation of urodynamic parameters in women with obstructive urination on a background of conservative treatment. The study included 40 women with obstructive urination aged 26 to 72 years. All patients received alpha adrenoblocker Omnic Okas (tamsulosin) at a dose 0.4 mg once a day in the morning for 3 months. Initially, a visual assessment of uroflougramm revealed curves tipical for the obstructive type of urination. Quantitative parameters showed a decrease in the maximum urine flow rate and lengthening the time of urination. Treatment with alpha-adrenoblocker contributed to shortening the time of urination, and increased maximum urine flow rate. Before treatment, ultrasound examination revealed the presence of residual urine volume of 60-210 mL (mean 129 ml) after urination in 32 (80%) patients. After treatment, presence of residual urine volume of 50-90 ml (mean 65 ml) was noted only in 9 (22.5%) patients. It is concluded that the selective alpha-adrenoblocker Omnic-Okas neutralizes the effect mediated by alpha-adrenoceptors in the area of the bladder neck and proximal urethra, and contribute to the normal detrusor contraction, and therefore, eliminates the functional obstruction, while significantly improving the quality of life of patients. PMID- 23342615 TI - [Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe]. AB - BACKGROUND: Silodosin is a new selective therapy with a high pharmacologic selectivity for the a (1A)-adrenoreceptor. OBJECTIVE: Our aim was to test silodosin's superiority to placebo and noninferiority to tamsulosin and discuss the findings in the context of a comprehensive literature review of the new compound silodosin. DESIGN, SETTING, AND PARTICIPANTS: We conducted a multicenter double-blind, placebo-and active-controlled parallel group study. A total of 1228 men > or = 50 yr of age with an International Prostate Symptom Score (IPSS) < or = 13 and a urine maximum flow rate (Q(max))> 4 and < or = 15 ml/s were selected at 72 sites in 11 European countries. The patients were entered into a 2-wk wash out and a 4-wk placebo run-in period. A total of 955 patients were randomized (2:2:1) to silodosin 8 mg (n = 381), tamsulosin 0.4 mg (n = 384), or placebo (n = 190) once daily for 12 wk. MEASUREMENTS: We calculated the change from baseline in IPSS total score (primary), storage and voiding subscores, quality of life (QoL) due to urinary symptoms, and Q(max). Responders were defined on the basis of IPSS and Q(max) by a decrease of > or = 25% and an increase of > or = 30% from baseline, respectively. RESULTS AND LIMITATIONS: The change from baseline in the IPSS total score with silodosin and tamsulosin was significantly superior to that with placebo (p < 0.001): difference active placebo of -2.3 (95% confidence interval [CI], -3.2, -1.4) with silodosin and -2.0 (95% CI, -2.9, -1.1) with tamsulosin. Responder rates according to total IPSS were significantly higher (p < 0.001) with silodosin (66.8%) and tamsulosin (65.4%) than with placebo (50.8%). Active treatments were also superior to placebo in the IPSS storage and voiding subscore analyses, as well as in QoL due to urinary symptoms. Of note, only silodosin significantly reduced nocturia versus placebo (the change from baseline was -0.9, -0.8, and -0.7 for silodosin, tamsulosin, and placebo, respectively; p = 0.013 for silodosin vs placebo). An increase in Q(max) was observed in all groups. The adjusted mean change from baseline to end point was 3.77 ml/s for silodosin, 3.53 ml/s for tamsulosin, and 2.93 ml/s for placebo, but the change for silodosin and tamsulosin was not statistically significant versus placebo because of a particularly high placebo response (silodosin vs placebo: p = 0.089; tamsulosin vs placebo: p = 0.221). At end point, the percentage of responders by Q(max) was 46.6%, 46.5%, and 40.5% in the silodosin, tamsulosin, and placebo treatment groups, respectively. This difference was not statistically significant (p = 0.155 silodosin vs placebo and p = 0.141 tamsulosin vs placebo). Active treatments were well tolerated, and discontinuation rates due to adverse events were low in all groups (2.1%, 1.0%, and 1.6% with silodosin, tamsulosin, and placebo, respectively). The most frequent adverse event with silodosin was a reduced or absent ejaculation during orgasm (14%), a reversible effect as a consequence of the potent and selective a(1A)-adrenoreceptor antagonism of the drug. The incidence was higher than that observed with tamsulosin (2%); however, only 1.3% of silodosin-treated patients discontinued treatment due to this adverse event. CONCLUSIONS: Silodosin is an effective and well-tolerated treatment for the relief of both voiding and storage symptoms in patients with lower urinary tract symptoms suggestive of bladder outlet obstruction thought to be associated with benign prostatic hyperplasia. Its overall efficacy is not inferior to tamsulosin. Only silodosin showed a significant effect on nocturia over placebo. PMID- 23342616 TI - [Whether dyslipidemia plays the pathogenetic role in the development of noninflammatory chronic prostatitis/chronic pelvic pain syndrome?]. AB - The study examined symptomatology in 74 patients with chronic abacterial prostatitis. The features of blood lipid metabolism in inflammatory and noninflammatory forms of disease are redefined. Dynamic characteristics of arterial blood flow in the prostate gland of patients with chronic abacterial prostatitis are determined. Comparative analysis between groups revealed significant differences in some indices of blood lipid profile, and arterial flow velocity parameters of the prostate in patients studied; correlations between the intensity of pain, the type of dyslipoproteinemia and arterial ischemia of the prostate are shown. The feasibility of analysis of the blood lipoprotein spectrum in the differential diagnosis of inflammatory and noninflammatory forms of chronic abacterial prostatitis is demonstrated. PMID- 23342617 TI - [Combined therapy using phytopreparation prostagutt forte in patients with acute prostatitis]. AB - The results of study on evaluation of efficacy of combined treatment of patients with acute prostatitis are presented. The study included 34 patients with acute prostatitis aged 19 to 51 years. 13 patients in Group 1 received only basic therapy: fluoroquinolones (ciprofloxacin, 500 mg 2 times daily for 14 days), non steroidal anti-inflammatory drugs (suppositories voltaren 50 mg at bedtime for 7 days). Along with basic treatments, 21 patients in the Group 2 received phytopreparation prostagutt forte (at a dose 280 mg 2 times a day), which has antiestrogenic, antiproliferative, antiinflammatory, immunomodulatory properties. It was shown that patients receiving prostagutt forte experienced pronounced and significant decrease of white blood count in the prostatic secretion, the decrease of prostate volume according to the data of transrectal ultrasound examination, more rapid relief of the inflammatory process, which was manifested by reduction of hyperthermia and reduction of severity of bladder outlet obstruction associated with swelling of the prostate. PMID- 23342618 TI - [Treatment of erectile dysfunction in patients with chronic prostatitis using vibromagnetic lazer]. AB - The study was aimed to evaluation of the effectiveness of vibromagnitic lazer therapy (VMLT) of erectile dysfunction (ED) in patients with chronic prostatitis (CP). The study included 40 patients with CP, aged 22 to 45 years. CP duration ranged from 6 months to 9 years, ED--from 6 months to 7 years. All the patients underwent a survey on "Chart of sexological examination of man" with the calculation of sex constitution index, an transrectal ultrasonography of prostate gland (PG), uroflowmetry, clinical and functional assessment of components of the copulatory interval, and assessment of blood plasma concentrations of peptide and steroid hormones. All patients underwent a psychotherapeutic correction of sexual disadaptation, sex therapy using Masters-Johnson, Kaplan, and Lo Piccolo methods, and VMLT using "Matrix-Urologist" device. The control group included 20 healthy men aged 22 to 45 years. All studies were performed Before and 30 days after the end of the last VMLT session. As a result of the treatment, integral IIEF indicators were normalized in 60% of patients, the volume of the prostate--in 70%, hemodynamics in the phase of relaxation and erection--in 70%, venous blood flow in the PG--in 70%, dorsal artery hemodynamics in the phase of relaxation and erection--in 60%, and penile hemodynamics--in 60% of patients. Voiding bladder function was optimized in 75% of patients. The functional activity of the pituitary-adrenal-testicular system returned to normal level in 60% of patients. 1 year after treatment, sexual function was maintained at attained levels in 47.5% of patients. As a matter of findings, it was concluded that VMLT is high effective method of combined non-pharmacological correction of erectile dysfunction in CP patients with strong and medium sex constitution. PMID- 23342619 TI - [Cytoflavin in the treatment of patients with chronic abacterial prostatitis and erectile dysfunction]. AB - The problem of chronic prostatitis (CP) and erectile dysfunction (ED) involves not only their high prevalence, but also the insufficient effectiveness of their treatments. In this regard, there is need for administration the pathogenetic drugs with antihypoxic, antioxidant and neuroprotective effects and improving blood flow to the genitals. The study included 60 men with CP associated with ED, aged 22 to 60 years. Patients were randomized into 2 groups of 30 people. Patients of comparison group received baseline therapy (alpha1-adrenoblockers, non-specific anti-inflammatory drugs, digital prostate massage and vacuum phallostimulation). Antibiotics were applied on the basis of their potential effectiveness in chronic abacterial prostatitis. In addition to the above treatment, patients of main group received step-down therapy with cytoflavin (in infusion, then oral administration). Positive dynamics was noted in both groups of patients; however, according to the indicators of the severity of pain and dysuria, as well as quality of life, positive dynamics in the main group of patients was more significant. Similarly, the dynamics of objective criteria for inflammation in the prostate gland was more pronounced when using cytoflavin. After treatment, the rigid phase of erection during vacuum fallotest occurred within 2-3 min from the beginning of the procedure in 16 (53.3%) patients of main group and only in 9 (30%) patients of comparison group. During follow-up examination at 6 months after treatment, stable remission was found in 75% of patients of main group. Thus, the inclusion of cytoflavin in the scheme of complex treatment of patients with abacterial CP associated with ED is pathogenetically justified, makes it more efficient and provides good DFS. PMID- 23342620 TI - [Early diagnosis of prostate cancer using histoscanning device]. AB - For the purpose of improving diagnosis of prostate cancer (PC), the authors used an innovative HistoScanning device. According to the standard procedure accepted at the clinic, 326 patients admitted with suspected prostate cancer were evaluated. Patients with elevated prostate-specific antigen (PSA) were divided into three groups depending on the degree of its increase, which ranged from 1.09 to 209 ng/ml; Group 4 (conventional control) consisted of patients with BPH, and Group 5 (control) consisted of healthy men aged 21 to 28 years. At the next step, histoscanning was performed with construction of maps of the prostate, which was used when performing a biopsy. The results of histoscanning were compared with data of morphological examination of biopsy material, and with the data of visual and morphological studies of surgical specimens in patients undergoing radical prostatectomy. High diagnostic value of histoscanning was demonstrated, as even in patients of Group 1 sensitivity was 89%, specificity--96%, in patients of Group 2 and 3--96 and 94%, 99 and 97%, respectively. False positive results occurred in 11% of cases, false negative--only in 0.6%. PMID- 23342621 TI - [Serum A1-antitrypsin levels in prostate pathology]. AB - The serum alpha1-antitrypsin (AAT) levels were determined using enzyme-linked immunosorbent assay (ELISA) and turbidimetry in patients with prostate cancer, patients with benign prostatic hyperplasia and healthy volunteers. Both methods revealed a significant increase of serum AAT levels in patients with prostate cancer compared with patients with BPH and healthy men. ELISA, as used in study, was more sensitive to changes in the concentration of AAT, but the sensitivity of the turbidimetry allows to use this method in the early diagnosis of prostate cancer. PMID- 23342622 TI - [Place of transurethral contact nephrolithotripsy in the treatment of patients with kidney stones]. AB - Currently, the question of choosing the optimal treatment for patients with large (> 20 mm) concretions is still open. Extracorporeal shock wave lithotripsy (ESWL) and percutaneous nephrolitholapaxy (PNL) are the main methods for removing of such concretions, with efficiency of 45-63, and 86-100%, respectively. Development of semirigid and flexible endoscopes, the creation of new types of contact lithotriptors have expanded the possibilities for use of transurethral treatment of urolithiasis. Results of treatment of 63 patients who underwent transurethral nephrolithotripsy (TUNL) for the large concretions in pelvicalyceal system (PCS) were analyzed. Selection of energy type for contact lithotripsy depended on the location, size, density of stone and type of uretherorenoscope. According to ultrasound and urography data after 30 days, stones and their fragments in the urinary tract were not found in 36 (57.1%) patients, clusters of small residual fragments were identified in 21 (33.3%) patients. In these cases, the stent was removed. During re-examination at 3 months, the full discharge of the fragments was observed in 19 (90.5%) of 21 patients. A separate group consisted of 6 (9.52%) patients, in whom residual concrements in PCS of operated kidneys were found after 30 days. In this group, two patients underwent one session of ESWL; repeated endoscopic interventions were performed in other patients, culminating in the complete removal of stone from PCS. According to the ultrasound and x-ray examinations, 55 (87.3%) patients achieved full exemption from concretions in PCS and urinary tract after 60 days. Thus, TUNL in the treatment of large and multiple kidney stones is comparable with ESWL and PNL on clinical efficacy, and in some clinical situations can be considered as a method of choice for surgical treatment of nephrolithiasis. PMID- 23342623 TI - [Congenital disorders of gonadal differentiation: clinico-morphological variants and surgical treatment]. AB - The article presents the results of examination and surgical treatment of 25 patients with congenital disorders of gonadal differentiation. Survey plan included an assessment of the external genitalia, karyotyping and molecular analysis of Y-chromosome, determination of serum gonadotropins and testosterone levels, visualization of the gonads using ultrasound and laparoscopy methods, and intraoperative morphological examination of the material. Based on the results of a comprehensive survey, mixed testicular dysgenesis was identified in 25% of patients, complete testicular dysgenesis--in 16%, partial gonadal dysgenesis--in 44%, ovotesticular violation of sexualization--in 16% of patients. Clinical, macroscopic and morphological characteristics of each of these options are defined. The choice of sexual identity and tactics of surgical treatment are explained. PMID- 23342624 TI - [High-technology extraurethral adenomectomy]. AB - The article presents a method of organ-sparing radical transvesical extraurethral adenomectomy in which adenomatous prostate tissue are removed as individual fragments from semi-oval or wedge-shaped incision of the bladder neck and initial part of the prostatic urethra. Preservation ofprostatic urethra and its vascular plexus provides minimal intraoperative blood loss and less traumatic treatment. Correction of vesico-urethral segment is carried out with full preservation ofthe closing apparatus of the bladder. More than 2,000 patients were followed-up for postoperative immediate and long-term results. Mortality after this type of intervention was 0.89%. Urinary incontinence and urethral stricture were not reported in any patients. PMID- 23342625 TI - [Retropubic urethro- and vessel-preserving extraurethral adenomectomy]. AB - The article presents the results of an advanced method for retropubic removal of adenomatous prostate tissue. Retropubic extraurethral adenomectomy (REUA) was performed in 29 patients with benign prostatic hyperplasia. Distinctive features of REUA from Lidsky-Millin surgery consist in the fact that the new method of prostatectomy preserve dorsal and urethral vascular plexus and the integrity of the prostatic urethra. Adenomatous tissues fragments are removed through a parallel longitudinally incisions made on the front surface of the fibrous capsule to adenoma. Surgical intervention is accompanied by minimal blood loss and minimal postoperative complications. Hemodynamics of the prostate and external genitalia is not disturbed. PMID- 23342626 TI - [Fragmented migration of intrauterine device in the bladder]. PMID- 23342627 TI - [The first experience of percutaneous nephrolithotripsy without nephrostome]. PMID- 23342628 TI - [Stem cells and their use in modern clinical practice]. PMID- 23342629 TI - [Efficacy and safety of tamsulosin in women with bladder outlet obstruction]. PMID- 23342630 TI - [Practical aspects of use of hormone replacement therapy with testosterone for age-related androgen deficiency in men]. PMID- 23342631 TI - [Application of calixarenes for DNA transfection in cells]. AB - First results of non-ionic and poly-cationic calixarenes utilization for gene transfection are presented and analyzed in this survey. State of the art in the field of scientific searching for new non-viral vectors are shown in the general form. The prospects of supramolecular concept in design agents for transfection are demonstrated. Some relationships between calixarene architecture and calixarene ability to promote gene transfection are revealed, namely: formation of supramolecular self-assembled aggregates at water media facilitates hierarchical formation of complexes with DNA molecules. Latter particles will effectively transfect genes if they are nano-sized and positively-charged. PMID- 23342632 TI - [Biological aspects of non-enzymatic glycosylation]. AB - Non-enzymatic reactions commonly play an ambiguous role in living organism. It is well known that non-enzymatic glycosylation may lead to disruption of the structure and function of biomolecules, thus initiating the development and accompanying different diseases. On the other hand, under certain conditions the products of non-enzymatic glycosylation act as signaling molecules and play an important role in the immune response. Data concerning the influence of non enzymatic glycosylation and carbonyl stress on living organisms are summarized in the work. The role of reactive carbonyl compounds and reducing carbohydrates in glycation of biomolecules, involvement of non-enzymatic glycosylation in carbonyl stress development and interplay between glycation and free radical processes in living organisms are summarized. The basic ways to prevent glycation and formation of reactive carbonyl compounds that induce carbonyl stress are highlighted. Special attention is paid to the role of the yeast Saccharomyces cerevisiae as a model system to study the glycation processes in vivo. PMID- 23342633 TI - [Novel hybrid inhibitors of the phage T7 RNA polymerase: synthesis, docking and screening in vitro]. AB - A number of new hybrid heteroaromatic compounds, consisting of tricyclic fragments (acridone, thioxanthone and phenazine) and bicyclic fragments (benzimidazole, benzothiazole and benzoxazole) were synthesized using the method, developed by the authors. As a result of screening against the transcription model system of the phage T7 DNA-dependent RNA polymerase three effective inhibitors of the RNA syntheses with the IC50 value of 8.9, 5.7 and 19.8 microM were detected. To cast light on the mode of interaction between the synthesized compounds and the target, the molecular docking was applied to the model pocket of the phage T7 RNA polymerase transcription complex. It was established that these ligands form networks of H-bonds with residues of the pocket conservative amino acids and pi-interaction with the Mg2+ ion. A planar geometry of the hybrid molecules, realized due to the intramolecular H-bonds, proved to be an important structural feature, which correlates with an efficacious inhibitory activity. PMID- 23342634 TI - [Kinetics of dissociation and reactivation of rat liver holotransketolase]. AB - The work deals with isolation of transketolase from the rat liver by means of ion exchange chromatography and substrate elution of enzyme. Experimental data on the regulation of transketolase activity with thiamin pyrophosphate (TPP) and its anticoenzyme analogues are presented. The kinetics of dissociation of holo-TK at pH 4.0 and 5.0 and reactivation of apo-TK at a wide variation of the concentration of TPP and its derivatives with anticoenzyme properties has been studied. The dissociation of holo-TK into apoenzymes and coenzymes at the specified values of pH is characterised by most evident diphasic nature, both fast and slow process being observed. The most part of enzymic activity slowdown falls on the fast phase, while the remaining 20-30% take place within the slow phase. The kinetics research findings illustrate the nonidentity of enzyme active sites with respect to TPP binding with transketolase. The K(m) values for TPP both per the first and second active sites equalled 0.3-4.5 microM and 1.3-19.7 microM, accordingly. PMID- 23342635 TI - [Participation of proteinkinase CK2 in regulation of human erythrocytes plasma membrane redox system activity: relative contribution of ca(2+)-dependent and ca(2+)-independent mechanisms of its activation]. AB - Involvement of protein kinase CK2 (2.7.11.1) in modulation of live cells trans plasma membrane electron transport was first discovered. Using human erythrocytes a decrease of plasma membrane redox system (PMRS) activity is shown under the action of specific protein kinase CK2 inhibitors. Using inhibitory analysis the activity regulation of human erythrocytes PMRS by Ca(2+)-dependent and Ca(2+) independent mechanisms were investigated. It was shown that functional Ca(2+) antagonists (nitrendipine and calmidazolium) significantly increased, and functional Ca(2+)-agonists to some extent reduced or did not affect the trans plasma membrane electron transport in these cells. PMID- 23342636 TI - [Effect of electromagnetic field of extremely low frequency on ATPase activity of actomyosin]. AB - The Mg2+/Ca2+ and K(+)-ATPase actomyosin activity of rabbit skeletal muscle was evaluated by the Fiske-Subbarow method during a five-hour exposition of protein solutions in electromagnetic field of extremely low frequency of 8 Hz and 25 microT induction. The results of the study of the ATPase activity of actomyosin upon electromagnetic exposure have shown statistically significant changes that are characterized by a rather complex time dynamics. After 1, 2 and 4 hours of exposure of protein solutions the effect of ELF EMF exposure inhibits the ATPase activity compared to control samples, which are not exposed to the magnetic field. By the third and fifth hours of exposure to the electromagnetic field, there is a significant increase in the ATPase activity of actomyosin. It should be noted that a similar pattern of change in enzyme activity was universal, both for the environment by Mg2+ and Ca2+, and in the absence of these ions in the buffer. This can evidence for Ca(2+)-independent ways of the infuence of electromagnetic field (EMP) on biologic objects. In our opinion, the above effects are explained by EMP influence on the dynamic properties of actomyosin solutions, which are based on the processes of spontaneous dynamic formation of structure. PMID- 23342637 TI - [The influence of the penetrating cryoprotectors on protein synthesis in the cell free system of the rat liver]. AB - The influence of the penetrating cryoprotector and Mg2+ ions on the protein synthesizing activity of postmitochondrial supernantant of the rat liver as well as on aminoacylation processes has been investigated. The addition of the penetrating cryoprotectors--ethylene glycol and DMSO--resulted in the concentration-dependant reversible inhibition of the protein biosynthesis and aminoacylation reaction in the cell-free system. These cryoprotectors at low concentrations intensified the stimulating effect of Mg2+ on the cumulative protein synthesis in the cell-free system. PMID- 23342638 TI - [Endoplasmic-mitochondrial Ca(2+)-functional unit: dependence of respiration of secretory cells on activity of ryanodine- and IP3 - sensitive Ca(2+)-channels]. AB - Using Clark oxygen electrode, dependence of mitochondrial functions on Ca(2+) release channels activity of Chironomus plumosus L. larvae salivary glands suspension was investigated. Cells were ATP-permeabilized in order to enable penetration of exogenous oxidative substrates. Activation of plasmalemmal P2X receptors (as well as P2Y-receptors) per se does not modify the endogenous respiration of salivary gland suspension. That is, Ca(2+)-influx from extracellular medium does not influence functional activity of mitochondria, although they are located along the basal part of the plasma membrane. Activation of RyRs intensifies endogenous respiration and pyruvate-malate-stimulated respiration, but not succinate-stimulated respiration. Neither activation of IP3Rs (via P2Y-receptors activation), nor their inhibition alters endogenous respiration. Nevertheless, IP3Rs inhibition by 2-APB intensifies succinate stimulated respiration. All abovementioned facts testify that Ca2+, released from stores via channels, alters functional activity of mitochondria, and undoubtedly confirm the existence of endoplasmic-mitochondrial Ca(2+)-functional unit in Ch. plumosus larvae salivary glands secretory cells. In steady state of endoplasmic mitochondrial Ca(2+)-functional unit the spontaneous activity of IP3Rs is observed; released through IP3Rs, Ca2+ is accumulated in mitochondria via uniporter and modulates oxidative processes. Activation of RyRs induces the transition of endoplasmic-mitochondrial Ca(2+)-functional unit to the active state, which is required to intensify cell respiration and oxidative phosphorylation. As expected, the transition of endoplasmic-mitochondrial Ca(2+) functional unit to inactivated state (i. e. inhibition of Ca(2+)-release channels at excessive [Ca2+]i) limits the duration of signal transduction, has protective nature and prevents apoptosis. PMID- 23342639 TI - [Antioxidant and cerebroprotective action of N-,S-chinazolone derivative under rat brain ischemia]. AB - Under modelling of brain ischemia in rats the antioxidant and cerebroprotective action of new N-,S-chinazolone derivative--compound NC-224 has been established. The compensation of pathobiochemical abnormalities in the system "LPO-antioxidant protection" is observed, indicators of carbohydrate metabolism and energy-supply, and morpho-functional status of brain cells are improved under administration of the compound NC-224. Administration of the compound NC-224 to rats promoted a decrease of the lethality index and signs of neurological deficiency. PMID- 23342640 TI - [Mild oxidative stress in fruit fly Drosophila melanogaster caused by products of sucrose hydrolysis]. AB - The influence of 6% sucrose and equimolar mixture of glucose and fructose in larva diet on the level of oxidized proteins and lipids as well as the activity of antioxidant and associated enzymes in adult fruit fly Drosophila melanogaster was investigated. Larva growing on the diet with sucrose led to the mild oxidative stress development in adult insects, which was differently expressed in both sexes. In males mainly molecules of proteins were subjected to oxidative damages, whereas in females--lipid molecules. This is evidenced by 77% increased content of protein carbonyl groups and decreased (by 40%) level of protein SH groups in males fed on sucrose. In females fed on sucrose the content of lipid peroxides was by 44% higher, than in individuals, hold on the diet with equimolar mixture of glucose and fructose. The oxidative stress in females was accompanied with increased activity of catalase, superoxide dismutase and thiredoxin reductase by 30, 15 and 34%, respectively. The obtained results suggest that uptake mode of glucose and fructose affects free radical processes in fruit flies. PMID- 23342641 TI - [Fatty acid composition of structural lipids of normal and abnormal wool fibres]. AB - The purpose of this study was to determine the fatty acid composition of structural lipids, isolated from normal and abnormal wool fibers. The results of these studies show that regardless of the type of wool fibers defect there are quantitative changes in their fatty acid composition. It was shown that the main fatty acid of the covalently bound lipids, isolated from the wool fibers, is 18 methyleicosanoic acid (18-MEA), comprising 40% of the total fatty acid, while its amount in free lipids in norm is less than 4%. The decrease of 18-MEA content in the covalently bound lipid both in pathological thin and entangled wool fibers was established, which is associated with damage of the cuticle layer surface. Increasing of 18-MEA content in the free lipids in the entangled wool fibers may indicate a rupture of tioester links between lipids and proteins of cuticle layer lamellar structures. PMID- 23342642 TI - [Modification of spectrophotometric method for determination of protein carbonyl groups]. AB - Based on detailed study of optical absorption spectra of protein-hydrazones a modification of the spectrophotometric method determination of the protein carbonyl groups has been proposed. For the hydrazone adduct determination we proposed to measure the optical absorption at three wavelengths (320, 370 and 420 nm) instead of only one (at 370 nm). Two additional wavelengths are used for the linear approximation of the background optical spectrum. This modification improves the specificity and reduces the error when determining the content of CO groups in proteins. PMID- 23342643 TI - Effects of tyrosine kinase and phosphatase inhibitors on mitosis progression in synchronized tobacco BY-2 cells. AB - To test whether reversible tubulin phosphorylation plays any role in the process of plant mitosis the effects of inhibitors of tyrosine kinases, herbimycin A, genistein and tyrphostin AG 18, and of an inhibitor of tyrosine phosphatases, sodium orthovanadate, on microtubule organization and mitosis progression in a synchronized BY-2 culture has been investigated. It was found that treatment with inhibitors of tyrosine kinases of BY-2 cells at the G2/M transition did not lead to visible disturbances of mitotic microtubule structures, while it did reduce the frequency of their appearance. We assume that a decreased tyrosine phosphorylation level could alter the microtubule dynamic instability parameters during interphase/prophase transition. All types of tyrosine kinase inhibitors used caused a prophase delay: herbimycin A and genistein for 2 h, and tyrphostin AG18 for 1 h. Thereafter the peak of mitosis was displaced for 1 h by herbimycin A or genistein exposure, but after tyrphostin AG18 treatment the timing of the mitosis-peak was comparable to that in control cells. Enhancement of tyrosine phosphorylation induced by the tyrosine phosphatase inhibitor resulted in the opposite effect on BY-2 mitosis transition. Culture treatment with sodium orthovanadate during 1 h resulted in an accelerated start of the prophase and did not lead to the alteration in time of the mitotic index peak formation, as compared to control cells. We suppose that the reversible tyrosine phosphorylation can be involved in the regulation of interphase to M phase transition possibly through regulation of microtubule dynamics in plant cells. PMID- 23342644 TI - [Structural and functional aspects of heterophylly in Nuphar lutea (L.) Smith: ultrastructure and photosynthesis]. AB - Ultrastructure and functional characteristics of photosynthetic apparatus of the floating and submersed leaves of heterophyllous aquatic plant Nuphar lutea (L.) Sibth. et Sm. were examined. Differences in the mesophyll cell chloroplast ultrastructure, pigment content and chlorophyll fluorescence parameters of floating and submersed leaves as well as of submersed leaves at the different water depth were detected. The efficiency of PS II was established to reduce significantly under the chlorophyll fluorescence induction with light intensity higher than 60 micromol m(-2)s(-1). The obtained results may be considered as plant adaptation to reduced light intensity and changed light spectrum in the water. PMID- 23342645 TI - [Cytogenetic abnormalities in seedlings of Norway spruce (Picea abies (L.) Karst.) from the natural populations and introduction plantation]. AB - Comparative studies of the frequency and spectrum of pathological mitosis (PM), as well as of nucleoli number in the interphase cells of seedling roots have been performed in two natural populations of Norway spruce (Picea abies (L.) Karst.) of Ukrainian Polesie and introduction plantation in the Donbass. Low levels of PM in the seed progeny populations (0.32-0.38%) and slightly higher in the progeny plantation (0.40%) have been installed. Number of nucleoli was slightly higher in the plants of natural populations (5.35-5.85) than that of the plantation (4.95). The frequency of PM in the offspring of low-heterozygous plants was higher (0.43%) than in highly heterozygous individuals (0.28%). PMID- 23342646 TI - [Antiviral activity of extracts of transgenic cichory and lettuce plants with the human interferon alpha-2b gene]. AB - Biological activity of protein extracts from transgenic plants of chicory Cichorium intybus L. and lettuce Lactuca sativa L. with human interferon alpha2b gene was investigated against vesicular stomatitis virus. It was shown that the extracts from the hairy roots of chicory and lettuce transformed by A. rhizogenes possess the antiviral activity 1620...5400 IU/g weight, and the extracts from leaves of the plants transformed by A. tumefaciens--till 9375 IU/g weight. Dependence of plant extract biological activity on the transformation vector was shown. PMID- 23342647 TI - Mutagenic and antimutagenic properties of some lichen species grown in the Eastern Anatolia Region of Turkey. AB - All the methanol extracts did not show mutagenic activity in Ames/Salmonella and Z. mays MI test systems. Furthermore, some extracts showed significant antimutagenic activity against 9-AA in Ames test system. Inhibition rates for 9 AA mutagenicity ranged from 25.51% (P. furfuracea - 0.05 microg/plate) to 66.14% (C. islandica - 0.05 microg/plate). In addition, all of the extracts showed significant antimutagenic activity against sodium azide (NaN3) mutagenicity on MI values of Z. mays. PMID- 23342648 TI - [Genetic effects of root extracts of Glycyrrhiza glabra L. on different test systems]. AB - The antimutagenic and geroprotective activities of root extracts of Glycyrrhiza glabra have been demonstrated both on plant test systems--Allium fistulosum L., Allium cepa L., Vicia faba L. and on animals--Vistar rats. The possibilities of the mobilization of Glycyrrhiza glabra root extracts as antimutagenic agents are discussed. PMID- 23342649 TI - [Physiological and molecular principles of plant salinity stress]. AB - Due to the rising problem of salinity in modern agriculture, climate changes and global food crisis, the study of salinity stress is gaining the primary importance. The mechanism of plant response to salinity includes various processes that have to be coordinated. The high salinity leads to large accumulation of toxic ions (Na+, Cl-) in plant tissues, ion disequilibrium and hyperosmolarity. Salinity stress has a negative impact on plant nutrition and mineral homeostasis, particularly for Ca2+ and K+. The recent progress in trascriptomics, genomics and molecular biology has facilitated discoveries of new salt stress-related gene families. In this review the major fundamental principles of plant salt tolerance are described. Detailed analysis of main ion transport systems and their potential role in salinity stress is presented. The future perspective gene determinants, biotechnological and genetic strategies for enhancing salt tolerance in plants are discussed. PMID- 23342650 TI - [The genetic determination and function of RR-proteins--the regulators of photoperiodic reaction and circadian rhythms in plants]. AB - The present review devoted to the analysis of recent literature on genetic determination and the domain organization of the newly discovered two-component signaling systems in pro- and eukaryotes. These structures are involved in the regulation of numerous morphological and physiological processes in plants. RR proteins, it the key elements of signaling systems, they launch a cascade of phosphotransferase reactions and directly or indirectly regulate the transcription and activity other proteins, including enzymes, in response to hormones or environmental factors. Modern views on the molecular and genetic mechanisms of photoperiodic response, circadian rhythms and anti-stress responses in plants are set out in these positions. The relationship between gene expression and photoreceptor sensitivity of plants to photoperiod traced. We present our own data obtained on the isogenic lines of wheat, where been showed dependence expression of structural genes of enzymes on the allelic composition of individual PRR-loci and the duration action of low temperature. PMID- 23342651 TI - [10 years of testing of the HER2 status in breast cancer in Russia]. AB - The paper analyzes 10 years' experience in HER2 status testing in breast cancer in Russia. The ASCO/CAP HER2 testing guidelines adaptable to the work of pathologists in Russia are considered. PMID- 23342652 TI - [Adhesion of T cells and macrophages to the coronary artery endothelium in patients with coronary heart disease]. AB - The study has found a close relationship between the early signs of atherosclerosis, i.e. between the fine-dropwise (dust-like) lipid deposition in the intima and the adhesion of monocyte clusters to the endothelium in these places. In the intimal areas without lipid depositions, adherent monocytes were absent or detectable as single cells in the field of vision. The coronary arteries displayed large clusters of T cells (CD4, CD8) adhered to the endothelium and migrated into the intima. The clusters of these cells were encountered not only in the vascular atherosclerotic lesion areas, but also in the invisibly altered ones. Some patients (with atheromas and fibroatheromas in the coronary artery segments) were found to have en face specimens with endothelial layer damages, with one or 3-5 cells being absent in the endothelial layer. The bottom of such microerosions was lined by T-cell and macrophage infiltrations and it was part of the cap of an atherosclerotic plaque. These surface erosions may be considered as an early developmental stage of an unstable plaque. PMID- 23342653 TI - [Pathoanatomic criteria for dissecting aortic aneurysm]. AB - The authors present the basic pathoanatomic criteria for the diagnosis of dissecting aortic aneurysm on the basis of an analysis of 144 cases of this abnormality. Its mandatory signs are the inlet (of blind rupture of the wall of the aorta) and channel of its dissection. The inner surface of the dissection channel varies with the time of (rough to smooth) dissection with connective tissue bands. The optional criteria are the outlet that connects the false aortic lumen with the true one, as well as the propagation of dissection to the visceral aortic branches. When the visceral branches are involved in the process of dissection in more than half of all cases, there are no changes in the respective organs. At the same time there are ischemic changes in the organs, the vessels of which are not involved in this process. This is suggestive of complex circulatory disorders in this disease. The main mechanisms of tanatogenesis are due to the rupture of the outer sheet of a false passage, the propagation of dissection to the visceral branches or a combination of these two factors. The optimal autopsy procedure options are shown with regard to the pathoanatomic features of dissecting aortic aneurysm. PMID- 23342654 TI - [In vitro accumulation of the photosensitizer Photosens in the atherosclerotic plaque of the human carotid artery]. AB - The investigation was undertaken to study the accumulation of the photosensitizer Photosens in arterial atherosclerotic plaques and to immunohistochemically identify cellular elements in them. Specimens were obtained during carotid endarterectomy. The preferential accumulation of Photosens occurred in the plaque areas containing the largest number of cells, such as macrophages and lymphocytes. The photosensitizer accumulated to a greater extent in the unstable plaques than in the stable ones, which seems to be associated with the more marked infiltration of unstable plaques by the cells involved in the inflammatory reaction. PMID- 23342655 TI - [Immunohistochemical characteristics of human brain vascular plexuses]. AB - The paper gives the data of studying the cells belonging to neuroblast progeny in embryonic origin. Differentiation in these cells was studied by immunohistochemical assay using a number of neuronal markers. Expression of S 100, NCAM, and neuron-specific enolase was revealed in the epithelial layer of vascular plexuses. No neural proteins (neuron-specific beta-3 tubulin, neuron specific enolase, major myelin protein, neurofilaments, S-100, NCAM, synapsin I, and nerve growth factor receptors) were found in the stroma and the walls of the vascular plexuses in the lateral ventricles of the human brain. Nerve fibers were detected in the asinine choroid artery branches, by using neuron-specific beta-3 tubulin antibodies. PMID- 23342656 TI - [Light optical and ultrastructural characteristics of human focal cortical dysplasias]. AB - Focal cortical dysplasias (FCD) are one of the most common causes of drug resistant epilepsy. Morphological changes in the focal cortical dysplasia tissues obtained from epileptic patients during surgical interventions were analyzed. Eleven specimens of the cerebral cortex with FCD areas were explored. There were a variety of light optical and ultrastructural abnormalities affecting different portions of the cortical arrangement, as well as a considerable heterogeneity in these changes. Special emphasis was placed on morphological correlations between excitation and inhibition processes when possible mechanisms responsible for the epileptogenicity of dysplasia cells were assessed. The findings suggest that there is a preponderance of FCD tissue excitation processes along with depressed inhibition processes. PMID- 23342657 TI - [Duodenal atresia in the newborn]. AB - The specific features of intrauterine development and pheno- and genotypic characteristics were studied in newborn infants with duodenal atresia. Main anthropometric parameters at birth (weight, height, and head and chest circumferences), concomitant developmental malformations, gene frequencies and phenotypic combinations of ABO and Rhesus factor blood groups were analyzed. The babies with duodenal atresia were found to have considerably impaired intrauterine development, multiple concomitant hypoplastic developmental abnormalities, significantly higher frequencies of the ORh+ phenotype, and lower frequencies of the ARh+ phenotype. PMID- 23342658 TI - [Bcl-2 as a prognostic factor in different molecular genetic subtypes of breast cancer]. AB - It is well known that breast cancers (BC) are divided into 4 molecular genetic subgroups (luminal A, luminal B, HER2/neu-positive, and triple-negative (TNBC). The purpose of the investigation was to comparatively estimate the pattern of expression of Bcl-2, known as a good prognostic marker of BC, in different molecular genetic subgroups and to study the correlation of this protein with proliferative activity index and genetic aberrations on chromosome 17. The investigation covered 290 samples of invasive ductal BC. Bcl-2 expression was identified in 14% of HER2/neu-positive and TNBC cases while 77% of luminal B tumors and 100% of luminal A ones expressed Bcl-2. Loss of Bcl-2 expression correlated with clinically more aggressive BCs having a high proliferative activity and amplification of HER2/neu and chromosome 17 centromere. This may suggest the poor prognosis of luminal B, HER2/neu-positive and TNBC with no Bcl-2 expression and calls for further investigations on larger samples. PMID- 23342659 TI - [Results of karyometry of acinar adenocarcinoma of the prostate]. AB - The paper presents the results of karyometry of acinar adenocarcinoma of the prostate in the biopsy specimens with total Gleason scores of 6, 7, and 8-10. There are statistically significant differences in the morphometric characteristics of tumor cell nuclei (the long and short diameters of nuclei and nucleoli, their area and perimeter) in the biopsy specimens as compared with those with total Gleason scores of 6 and 7, as well as in those of the nucleoli as compared to those with total Gleason scores of 6 and 7 and 7 and 8-10. The findings suggest that there are karyometric differences in the cells of prostatic acinar adenocarcinoma in the groups with total Gleason scores of 6, 7, and 8-10. PMID- 23342660 TI - [Clonal origin of multiple foci of urinary bladder cancer]. AB - To analyze the pattern of molecular damages in urinary bladder cancer (UBC), the authors studied allelic imbalance of chromosome loci 9p21 and 17p13 in 22 patients diagnosed as having multiple primary UBC (2 to 5 foci in each patient). The state of markers has no informative value in 3 (13.6%) cases; in 9 (47.4%) of 19 informative cases, deletion of the same allele was determined in at least one of the loci in question in all tumor nodules, which may point to the monoclonal origin of multiple tumors in these patients. Five (26.3%) of the 19 patients exhibited deletion of the same allele in different tumor nodules, which is suggestive of the active process of clonal evolution and the feasibility of tumor subcloning, which does not preclude the possibility of monoclonal origin. Five (26.3%) of the 19 patients had an imbalance of different alleles in varying nodules, which may show the oligoclonal origin of the tumor nodules concerned. The concordant and discordant patterns of molecular damages are encountered virtually with the same frequency in the tumors of multiple primary UBC, which supports the view that its synchronous tumors can develop both monoclonally through intraluminal dissemination of tumor cells and when there are cancerization fields that determine the occurrence of oligoclonal tumors. PMID- 23342661 TI - [The effect of runihol and exogenous S-adenosyl-L-methionine on the morphological pattern of the liver upon hepatotoxic exposure to reserve-series antituberculous drugs]. AB - Experiments on 160 male albino outbred rats investigated the hepatoprotective activity of S-adenosyl-L-methionine (SAM) and runihol in liver damage caused by subtoxic doses of reserve-series antituberculous drugs (ATD) (PASA, cycloserine, prothionamide) and their combination. It was established that a combination of ATDs had the maximum hepatotoxic activity, cycloserine had the least. There was evidence that SAM versus runihol had a more pronounced ability to correct ATD induced evolving cytolysis syndrome. Histological study indicated that SAM and runihol also showed a marked hepatoprotective effect. When added to PASA, prothionamide, or a combination of ATDs, both drugs promoted recovery of the hepatic architectonics and a reduction in the prevalence of albuminous dystrophy. The use of SAM additionally led to activation of alterative processes in the hepatic parenchyma. PMID- 23342662 TI - [Nonspecific granulomatous inflammation in Crohn's disease]. AB - A comparative morphological study of intestinal wall tissues in such chronic colonic diseases, such as Crohn's disease, ulcerative colitis, and catarrhal rectal fistulas, allows the formation of giant cells of foreign bodies and their granulomas and sarcoid-type ones to be nonspecific. Their spread through and outside the colon is due to the migration of foreign bodies along the lymphatic vessels. Foreign inclusions of different shapes and structures in the cytoplasm of giant cells suggest that the colon contains the multiple particles of varying antigenic nature, which induce a unified morphological response medicated by innate and adaptive immunity cells. Consequently, the universally accepted substantiation of the diagnosis of Crohn's disease by the presence of granulomas is unconvincing. PMID- 23342663 TI - ["He has brought us the light of teaching..." (on the occasion of the 125th anniversary of Academician of the USSR Academy of Medical Sciences V.G. Garshin's birth)]. PMID- 23342664 TI - [BRAF mutation testing for the choice of melanoma treatment]. AB - Individual life-time risk of melanoma in white residents of highly developed countries may be as high as 2%. Continuing rise of melanoma incidence is directly related to the improving life standards, especially to growing opportunities of attending sea resorts and getting tanned. Melanoma is usually highly aggressive and resistant to standard cytotoxic therapy, therefore 5-years survival of patients with the metastatic disease does not exceed 10-15%. Approximately 50% of melanomas contain point mutation in codon 600 of the BRAF kinase. Specific inhibitors of activated BRAF have demonstrated unprecedented therapeutic efficacy, thus BRAF testing has become a mandatory component of treatment planning for inoperable melanoma. This review discusses key issues, which are related to various clinical, morphological, and molecular genetic aspects of determination of BRAF status in metastatic melanoma. PMID- 23342665 TI - Avoiding a pain in the neck. This common affliction can limit your daily activities if you don't take steps to prevent it. PMID- 23342666 TI - Ask the doctor. What can you tell me about cluster calcifications in the breast? PMID- 23342667 TI - No need for routine ovarian cancer screening. PMID- 23342668 TI - Predicting your odds of having a heart attack. The best screening tool for people at intermediate risk. PMID- 23342669 TI - For women: long-term weight-loss strategies. PMID- 23342670 TI - A screening update for smokers and ex-smokers. PMID- 23342671 TI - The link between sound sleep and independent living. PMID- 23342672 TI - The health benefits of spirituality. PMID- 23342673 TI - I always hear about the benefits of moderate exercise, but what does "moderate" mean, exactly? PMID- 23342674 TI - My wife, who has Alzheimer's, sometimes wanders away from our home. Can you suggest precautions I can take to keep her safe? PMID- 23342675 TI - A burning concern. PMID- 23342676 TI - Good news for teetotalers. PMID- 23342678 TI - Infection prediction for RA patients. PMID- 23342677 TI - Breast cancer drug warning. PMID- 23342679 TI - Cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A: results from the botulinum toxin for the upper limb after stroke (BoTULS) trial. AB - Stroke imposes significant burdens on health services and society, and as such there is a growing need to assess the cost-effectiveness of stroke treatment to ensure maximum benefit is derived from limited resources. This study compared the cost-effectiveness of treating post-stroke upper limb spasticity with botulinum toxin type A plus an upper limb therapy programme against the therapy programme alone. Data on resource use and health outcomes were prospectively collected for 333 patients with post-stroke upper limb spasticity taking part in a randomized trial and combined to estimate the incremental cost per quality adjusted life year (QALY) gained of botulinum toxin type A plus therapy relative to therapy alone. The base case incremental cost-effectiveness ratio (ICER) of botulinum toxin type A plus therapy was L93,500 per QALY gained. The probability of botulinum toxin type A plus therapy being cost-effective at the England and Wales cost-effectiveness threshold value of L20,000 per QALY was 0.36. The point estimates of the ICER remained above L20,000 per QALY for a range of sensitivity analyses, and the probability of botulinum toxin type A plus therapy being cost effective at the threshold value did not exceed 0.39, regardless of the assumptions made. PMID- 23342680 TI - MHC class II and non-MHC class II genes differentially influence humoral immunity to Bacillus anthracis lethal factor and protective antigen. AB - Anthrax Lethal Toxin consists of Protective Antigen (PA) and Lethal Factor (LF), and current vaccination strategies focus on eliciting antibodies to PA. In human vaccination, the response to PA can vary greatly, and the response is often directed toward non-neutralizing epitopes. Variable vaccine responses have been shown to be due in part to genetic differences in individuals, with both MHC class II and other genes playing roles. Here, we investigated the relative contribution of MHC class II versus non-MHC class II genes in the humoral response to PA and LF immunization using three immunized strains of inbred mice: A/J (H-2k at the MHC class II locus), B6 (H-2b), and B6.H2k (H-2k). IgG antibody titers to LF were controlled primarily by the MHC class II locus, whereas IgG titers to PA were strongly influenced by the non-MHC class II genetic background. Conversely, the humoral fine specificity of reactivity to LF appeared to be controlled primarily through non-MHC class II genes, while the specificity of reactivity to PA was more dependent on MHC class II. Common epitopes, reactive in all strains, occurred in both LF and PA responses. These results demonstrate that MHC class II differentially influences humoral immune responses to LF and PA. PMID- 23342681 TI - Sheep monoclonal antibodies prevent systemic effects of botulinum neurotoxin A1. AB - Botulinum neurotoxin (BoNT) is responsible for causing botulism, a potentially fatal disease characterized by paralysis of skeletal muscle. Existing specific treatments include polyclonal antisera derived from immunized humans or horses. Both preparations have similar drawbacks, including limited supply, risk of adverse effects and batch to batch variation. Here, we describe a panel of six highly protective sheep monoclonal antibodies (SMAbs) derived from sheep immunized with BoNT/A1 toxoid (SMAbs 2G11, 4F7) or BoNT/A1 heavy chain C-terminus (HcC) (SMAbs 1G4, 5E2, 5F7, 16F9) with or without subsequent challenge immunization with BoNT/A1 toxin. Although each SMAb bound BoNT/A1 toxin, differences in specificity for native and recombinant constituents of BoNT/A1 were observed. Structural differences were suggested by pI (5E2 = 8.2; 2G11 = 7.1; 4F7 = 8.8; 1G4 = 7.4; 5F7 = 8.0; 16F9 = 5.1). SMAb protective efficacy vs. 10,000 LD50 BoNT/A1 was evaluated using the mouse lethality assay. Although not protective alone, divalent and trivalent combinations of SMabs, IG4, 5F7 and/or 16F9 were highly protective. Divalent combinations containing 0.5-4 MUg/SMAb (1-8 MUg total SMAb) were 100% protective against death with only mild signs of botulism observed; relative efficacy of each combination was 1G4 + 5F7 > 1G4 + 16F9 >> 5F7 + 16F9. The trivalent combination of 1G4 + 5F7 + 16F9 at 0.25 MUg/SMAb (0.75 MUg total SMAb) was 100% protective against clinical signs and death. These results reflect levels of protective potency not reported previously. PMID- 23342683 TI - Nuggets of knowledge: aspirin-yes?-no?-maybe? PMID- 23342682 TI - Association with AflR in endosomes reveals new functions for AflJ in aflatoxin biosynthesis. AB - Aflatoxins are the most potent naturally occurring carcinogens of fungal origin. Biosynthesis of aflatoxin involves the coordinated expression of more than 25 genes. The function of one gene in the aflatoxin gene cluster, aflJ, is not entirely understood but, because previous studies demonstrated a physical interaction between the Zn2Cys6 transcription factor AflR and AflJ, AflJ was proposed to act as a transcriptional co-activator. Image analysis revealed that, in the absence of aflJ in A. parasiticus, endosomes cluster within cells and near septa. AflJ fused to yellow fluorescent protein complemented the mutation in A. parasiticus DeltaaflJ and localized mainly in endosomes. We found that AflJ co localizes with AflR both in endosomes and in nuclei. Chromatin immunoprecipitation did not detect AflJ binding at known AflR DNA recognition sites suggesting that AflJ either does not bind to these sites or binds to them transiently. Based on these data, we hypothesize that AflJ assists in AflR transport to or from the nucleus, thus controlling the availability of AflR for transcriptional activation of aflatoxin biosynthesis cluster genes. AflJ may also assist in directing endosomes to the cytoplasmic membrane for aflatoxin export. PMID- 23342684 TI - It's all about the pump: Maintaining the basics is key to effective cardiac resuscitation. PMID- 23342685 TI - 'New' methods? PMID- 23342686 TI - 'New' methods? PMID- 23342687 TI - 'New' methods? PMID- 23342688 TI - Introduction: Advances in cardiac & resuscitation call for new EMS field practices. PMID- 23342690 TI - Trends & changes in cardiac care: The state-of-the science in cardiac care & resuscitation. PMID- 23342689 TI - The sweet spot: Chest compressions between 100-120/minute optimize successful resuscitation from cardiac rest. PMID- 23342691 TI - Q&A with Joan Mellor: Program Manager, Medtronic Foundation's HeartRescue Project. Interview by Jenifer Goodwin. PMID- 23342692 TI - The merits of mechanical CPR: Do mechanical devices improve compression consistency and resuscitation outcomes? PMID- 23342693 TI - Depth perception: application provides feedback on compression depth. PMID- 23342694 TI - First day: now what? PMID- 23342695 TI - Stealth mode: is all this noise really necessary? PMID- 23342696 TI - Life & limb: tourniquet saves man severely injured in vehicle crash. PMID- 23342697 TI - Attacking cardiac arrest part II: feedback-driven team performance impacts survival. PMID- 23342698 TI - Expert & safe use of adenosine depends on patient's cardiac status. PMID- 23342699 TI - Going out on a limb: EMS provider becomes patient. PMID- 23342700 TI - From the school to the rig: Enhance EMS preparation using the field training & evaluation program model. PMID- 23342701 TI - MCI magnifiers: many factors can complicate an incident of any size. PMID- 23342702 TI - Survive & thrive: current goals & obstacles in cardiac arrest. PMID- 23342703 TI - Deadly dozen: dealing with the 12 types of thoracic injuries. AB - Although most thoracic trauma may be treated non-operatively, major thoracic trauma accounts for 25% of trauma deaths. Except for provision of a definitive airway and/or relief of a tension pneumothorax with a needle decompression, the vast majority of thoracic trauma is best served with "load and go," high-flow oxygen, placement of an IV line and administration of crystalloid solutions as the clinical scenario would indicate. Understanding the mechanism of injury is helpful in establishing both prehospital and in-hospital management priorities. Patients who sustain a single penetrating wound to the chest have the best survivability after a resuscitative thoracotomy. Practicing chest assessment skills is vital to being a good prehospital provider. Ultrasound, NIRS tissue oxygenation and telemedicine will likely become more commonly employed as prehospital monitoring options. PEEP, or "over bagging," may exacerbate a simple or open pneumothorax, converting it to a tension pneumothorax. PMID- 23342704 TI - Will MASH make our children safer? Part 1. PMID- 23342705 TI - Diabetes in children. Adjusting to normal life as a diabetic. AB - Diabetes is a chronic childhood condition, presenting with raised blood sugar. The classic signs and symptoms may not be evident early on, especially in younger children, so it is important that health professionals maintain a high level of suspicion about diabetes when presented with non-specific symptoms eg. abdominal pain, lethargy, delayed wound healing, etc. When a child is first diagnosed, not only does the young person and their family have to cope with the emotional impact of diagnosis, but they also need to understand the huge amounts of information given to them. Health care practitioners provide essential support in helping them come to terms with, as well as manage, this condition. In this article we explain how diabetes is diagnosed and some of the common issues that arise in the ongoing care of the young person, with a particular emphasis on managing daily challenges. Community practitioners play a vital role in detecting symptoms early and making a referral, as well as supporting children with diabetes post-diagnosis in the community. PMID- 23342706 TI - A topic in 10 questions: behavioural aspects of weaning. PMID- 23342708 TI - "6Cs: the new buzzword for 21st century nursing. PMID- 23342707 TI - Skin changes during pregnancy. Part 1. PMID- 23342709 TI - Putting the needs of families first. PMID- 23342710 TI - "Why I believe the new school age growth charts are not 'fit for purpose'.". PMID- 23342711 TI - Community case: clavicle fracture in the newborn. PMID- 23342712 TI - The long road ahead. PMID- 23342713 TI - Reaching your resolution goals. PMID- 23342714 TI - The state of South Dakota's child: 2012. AB - In 2011, South Dakota experienced a slight increase over the previous year in the number of live births with one in four births representing minorities. Paralleling national data, the rate of births per 1,000 15 to 17-year-olds has decreased to 1.65. The spike in low birth weight observed in 2010 was reversed in 2011 with 6.3 percent of all newborns weighing less than 2,500 grams compared to 8.1 percent nationally. The state's infant mortality rate (6.3 per 1,000 live births) also declined in 2011 but remained higher than the national rate of 6.1 per 1,000 live births. Though progress is noted in decreasing the ratio of minority to white infant deaths, a trend persists with South Dakota's minority post neonatal mortality rate remaining consistently higher than that noted for the nation. PMID- 23342715 TI - Hereditary hemochromatosis: implications for South Dakota physicians. AB - Hereditary Hemochromatosis (HH) still causes debate among health professionals regarding appropriateness of diagnostic and screening tools. The Hemochromatosis gene (HFE) was discovered in 1996 and is now recognized to cause the majority of HH cases. A C282Y missense mutation in the HFE gene causes up to 90 percent of HH cases. In northern European populations, prevalence of heterozygosity is estimated to be as high as 10 percent, with symptomatic iron overload developing in as many as one in 200 to 300. Many guidelines regarding population screening have been proposed. It is especially important to strike a balance between allocation of healthcare resources and patient well-being in areas such as South Dakota with a large northern European and high proportion of Medicare and Medicaid patient population. This article outlines a reasonable approach to diagnosis and management for primary care physicians in South Dakota centered on a prototypical case review. PMID- 23342716 TI - Is Apixaban (Eliquis) the "ideal" anticoagulant to replace warfarin for stroke prevention in atrial fibrillation? PMID- 23342717 TI - SDSMA launches Center for Physician Resources. PMID- 23342718 TI - Can you learn a new thing? PMID- 23342719 TI - The good patient. PMID- 23342720 TI - A new year--new challenges and opportunities. PMID- 23342721 TI - Identifying options as you manage change in healthcare. PMID- 23342722 TI - Practice visits provide lawmakers with context, perspective. PMID- 23342723 TI - Use CPT codes to analyze practice operations. PMID- 23342724 TI - Perspective is everything: look beyond reported losses. PMID- 23342725 TI - What's on your plate? Time-saving tips for nutritional advice. PMID- 23342726 TI - Optimizing staffing levels: a science and art. PMID- 23342727 TI - Are you a quiz wiz? PMID- 23342728 TI - A pressing matter: what drives ACO success? Here's what the final regulations don't tell you. PMID- 23342729 TI - Word of mouth: referral letters that improve patient care. PMID- 23342730 TI - Understanding your options: combinations, mergers & acquisitions. PMID- 23342731 TI - Dazed and confused? You're not alone. Making decisions about alignment options can be dizzying. PMID- 23342733 TI - The future is now: MGMA-ACMPE award winners adapt quickly and thrive in the shifting environment. PMID- 23342732 TI - Drill, baby! Drill! Get the data you need. PMID- 23342734 TI - Effectiveness of multimedia aids to enhance comprehension of research consent information: a systematic review. PMID- 23342735 TI - Forgive me. PMID- 23342736 TI - What you need to know regarding the general supervision statute. PMID- 23342737 TI - Hyperdontia in children--case reports. AB - Dental anomalies are craniofacial abnormalities of form, function or position of the teeth, bones and tissues of the jaw and mouth. Dental anomalies can range from missing or stained teeth to cleft palates. The National Institute of Dental and Craniofacial Research (NIDCR) estimates that in the United States a baby is born every hour with a craniofacial defect. Dental anomalies are caused by hereditary, systemic, traumatic or local factors. The abnormalities of the teeth can be divided into those that are influenced by environmental forces and those that are idiopathic or appear hereditary in nature. In many cases the cause and effect are obvious. In others the primary nature of the problem is less distinct. PMID- 23342738 TI - Oral pathology quiz #77. Case number 1. Lichenoid mucositis. PMID- 23342739 TI - Oral pathology quiz #77. Case number 2. Giant cell fibroma. PMID- 23342740 TI - Oral pathology quiz #77. Case number 3. Odontogenic myxoma. PMID- 23342741 TI - Oral pathology quiz #77. Case number 4. Odontogenic keratocyst. PMID- 23342742 TI - Recurrent oral herpes: diagnosis & management. PMID- 23342743 TI - UMDNJ-New Jersey Dental School garners $2.5 million grant for faculty development. PMID- 23342744 TI - Be sure you're as special as you think you are: advertising or attempting to treat beyond your skill set can get you into a whole lot of trouble. PMID- 23342745 TI - Role of mini-invasive surgery in the treatment of enteric duplications in paediatric age: a survey of 15 years. AB - BACKGROUND: Gastrointestinal tract duplications (ATD) are rare malformations that occur with an incidence of 1 in 4000-5000 live births, with heterogeneous clinical pictures in relation to the different location and size. The purpose of this study was to analyze the role of minimally invasive surgery in the management of ATDs, through a critical analysys of 15 years of experience of the Department of Paediatric Surgery, University of Bologna. METHODS: The medical records of 22 children diagnosed with ATDs were retrospectively reviewed (January 1995-August 2010). The study analyses: clinical presentation, preoperative diagnosis, site, anatomic type, treatment, and outcome. RESULTS: Children were 16 males and 6 females, with age ranged from 1 day to 10 years. 20 ATDs (91%) were cystic type, while 2 cases (9%) were tubular one. During the first period of our experience, 10 (45.5%) cases were approached with an open surgery. Then subsequent 8 (36.4%) cases were treated with a diagnostic laparoscopy. This approach permitted also to perform a minilaparotomy, close to the site of the malformation, with a short length of the scar. In 2 cases (9%), we realized an ileal resection with end-to-end anastomosis with a trans-umbilical video-assisted procedure. In 2 cases (9%), we performed a complete removal of the lesions, after complete ligation of the vascular pedicle through a laparoscopic approach. 10 cases (45.5%) were located in the ileum, 6 cases (27.3%) were esophageal duplication, 3 cases (13.6%) were gastric duplications, 2 cases (9%) were located in the colon-rectum. The postoperative course was uneventful in all the cases. DISCUSSIONS AND CONCLUSIONS: this study shows how, in the management of intestinal duplications, a mininvasive approach, is increasingly taking the field, along with increasing the "learning curve" with laparoscopy. In experienced hands, the laparoscopic approach allows an accurate definition of the exact site of duplication and a miniinvasive treatment with similar principles of open techniques. PMID- 23342746 TI - [Laparoscopic treatment of UPJ obstruction in ectopic pelvic kidneys in children]. AB - AIMS: To assess the feasibility and safety of a laparoscopic approach to UPJ obstruction (UPJO) in ectopic pelvic kidneys. MATERIAL AND METHODS: In a retrospective analysis we selected 14 children, aged 6 months to 17 years, 12 males, 2 females, who had been treated in our Department between January 2004 and June 2011. 9 patients presented ureteropelvic junction obstruction (in 3 cases pelvic stones coexisted) with normal/moderately reduced (> or = 25%) relative function at radionuclide scan (MAG3), 3 nonfunctioning kidneys associated or not to hypertension, 2 congenital hypo-dysplastic kidneys. The evaluation of each patient involved the medical history, ultrasound examination, VCUG, MAG3 diuresis renogram and MRI in some cases. Of the patients presenting UPJO, 5 underwent dismembered pyeloplasty with pyelolithotomy, if required, and 4 pelvic derotation with straightening of the uretero-pelvic junction. A previous cystoscopic placement of a Double J stent was utilized. This facilitated the identification and dissection around the pelvis. With the patient in Trendelenburg position we utilized an umbilical trocar and two trocar in the right and left iliac fossae; an additional trocar, when required, was inserted more cephalad on the midclavear line contralaterally to the lesion. The derotation of ureteropelvic junction was obtained by freeing the kidney's lower pole and by placing intraperitoneally the junction protected with a Double J stent. This was obtained by suturing the peritoneum behind the ureteropelvic junction resulting in a forward rotation of the major axis of the kidney and a straightening of the junction. The 5 patients presenting nonfunctioning ectopic kidneys underwent laparoscopic nephrectomy. While the removal of congenital hypoplasic kidneys resulted easy, the removal of nonfunctioning kidneys was more difficult due to their complex vascular situation and for the embryonic disposition. RESULTS: The operating time varied between 40 to 200 minutes. No patient required conversion to open surgery. The hypertension resolved after nephrectomy in all cases. 2 cases of dismembered pyeloplasty required a placement of Double J stent due the recurrence of symptoms and ! patient is waiting for redo operation. The pelvic derotation showed an improvement of diuretic MAG3 renogram and the function remained stable and patiens are symptoms-free. CONCLUSION: The UPJO in ectopic pelvic kidneys presents a large spectrum of presentation. The laparoscopic approach provides good surgical exposure, and operative times are acceptable compared to those of laparoscopic procedure in anatomically normal kidneys. It has also proved a very useful tool in the non-functioning kidney nephrectomy thank to the help of magnification in the identification of numerous aberrant vessels that are quite often found in the pelvic kidneys. The derotation of the pelvis seems a useful procedure in moderate obstruction even if a longer followup is needed. PMID- 23342747 TI - [Acute liver failure due to human herpesvirus 6 in an infant]. AB - We report a case of a 4-months infant with fever in the absence of other specific symptoms that has rapidly and unexpectedly developed acute liver failure (ALF) with coagulopathy and complicated with bone marrow failure without encephalopathy. The main viral infection agents (hepatitis virus A, B, C, Citomegalovirus, Ebstain Barr virus, Parvovirus B19, Adenovirus), drug-induced hepatotoxicity and metabolic disorders associated to ALF were excluded. Quantitative determination of Human Herpesvirus 6 (HHV6) genome was positive with a significant number of copies for mL. A favorable evolution of the clinical symptoms and a progressive hematochemical resolution were obtained. Plasma and Vitamin K were administrated as a support therapy for treating coagulopathy. The present case report and the cases' review from the literature, evidence the importance of always including screening for HHV6 infection in the diagnostic approach to acute onset of liver failure. HHV6 is a common virus in the pediatric population with a greater number of cases of fulminant viral non-A, non-B, non-C hepatitis in immunocompetent patients due to this virus: these forms have often a high mortality rate and maybe necessitate liver transplantation; for this reason correct etiological agent identification is mandatory for the prognosis and it has to be based on the quantitative search of the virus's genome. Pathogenesis of liver-induced damage associated to HHV6 remains unclear; however in vitro studies demonstrate the potential hepatotoxicity effects of this virus. PMID- 23342748 TI - [Nephrotic syndrome after treatment with d-penicillamine in a pediatric patient with Wilson's disease]. AB - We describe a case of nephrotic syndrome (NS) after a 7 months treatment with D penicillamine in a 14 years old girl with Wilson's disease, with a prompt regression at the discontinuation of the drug. Kidney function, proteinuria in particular, must be always monitored during the chelating therapy, and the drug must be discontinued as soon as signs of renal injury are detected. PMID- 23342749 TI - [Gastric atresia, diaphragmatic hernia, and gastroesophageal reflux: a rare malformation requiring a multiple approach]. AB - The first cases of atresia or web in the pyloric and prepyloric regions were described in the literature since 1937. To date, only one case of atresia at the junction between the fundus and the body of the stomach has been reported. We want to describe a complex case with incomplete atresia between fundus and gastric body, with left lateral diaphragmatic hernia, treated in several stages by endoscopic, open surgery and minimally invasive surgery PMID- 23342750 TI - Chronic massive fetomaternal hemorrhage in a newborn from immigrants. Clinical and organizational implications. AB - Fetomaternal hemorrhage (FMH) refers to the entry of fetal blood into the maternal bloodstream before or during delivery. FMH of more than 30 mL occurs with the frequency of about 1/300. Fetal outcomes may be compromised by still births, hydrops fetalis, cardiac complications, and increased rates of postpartum infant death. In most cases, the cause is not identified. Clinical manifestations of FMH depend on the volume of blood lost and the rate that it occurred. We report a case of chronic massive FMH in a newborn of an immigrant mother with a favorable outcome. Medical visits and tests during pregnancy, including ultrasound scans, were not performed. The baby was hemodynamically stable after birth, manifesting only pallor. The complete blood count revealed severe hypochromic anemia (hemoglobin 3,8 g/dl, hematocrit 14,4%) and reticulocytosis (reticulocyte 25,2%). There was no ABO blood type incompatibility and the result of direct Coomb's test was negative. The Kleihauer-Betke test revealed 5% of fetal erythrocytes in the maternal bloodstream equivalent to 180 mL. The fact that FMH can occur without prior risk factors, and the diagnosis is often postnatal, underscores the importance of heightened of medical suspicion particularly in infants born to immigrants where there is often the lack of prenatal visits. PMID- 23342752 TI - Leadership and management through financial crisis and uncertainty. PMID- 23342751 TI - [Drug effectiveness or drug toxicity?]. PMID- 23342753 TI - Managing the myths of health care. AB - Myths impede the effective management of health care, for example that the system is failing (indeed, that is a system), and can be fixed by detached social engineering and heroic leadership, or treating it more like a business. This field needs to reframe its management, as distributed beyond the "top"; its strategy as venturing, not planning; its organizing as collaboration beyond control, and especially itself, as a system beyond its parts. PMID- 23342754 TI - Health leadership and management competencies: a systemic approach. AB - The achievement of national and international health goals requires better performing health systems. Strengthening leadership and management of health systems thus becomes essential for achieving greater efficiency and responsiveness, ultimately improving health outcomes. Building a global framework of core competencies for leadership and management needs to be approached with systems thinking and methodologies akin to complexity science that takes into account all components and levels of the health system and the possible interactions between them that influence outcomes. The results will have important policy implications for national health authorities seeking to strengthen management capacity and building transformational leadership in health systems. PMID- 23342755 TI - Leadership and globalization: research in health management education. AB - The impact of globalization on graduate health care management education is evident, yet challenging to quantify. The Commission on Healthcare Management Education (CAHME) recently authorized two research studies to gather specific information and answer important questions about accredited graduate programs in the USA and Canada. Two surveys provided the most comprehensive data impacting international health management education efforts by 70 programs. An inventory was made of 22 countries; information was compiled on 21 accrediting or quality improvement organizations. Observations on leadership and the demand for qualified health care professionals is discussed in terms of accreditation, certification, competency models, outcome assessment, improving quality, and the impact of globalization on higher education. PMID- 23342756 TI - Leadership and management quality: key factors in effective health systems. AB - The effectiveness of health care systems in the developing world is related to the quality of their leadership and management, yet that factor has been neglected by academics and funders. Based on replicable existing models, the article proposes an approach to strengthening local management training institutions. PMID- 23342757 TI - Health and hospital reform in Australia--a local health district's perspective. AB - Health and hospital reform is not new on the international stage. Increasing demand for health care services due to aging populations and the increased burden of chronic disease, continued advances in medical technology (including the rapid expansion of information systems) and ever growing community expectations mean that the health care expenditure of most health systems is growing at a rate greater than GDP (OECD 2008). Most countries appear to be grappling with how they can create a sustainable health system for the future. This article provides an overview of reform occurring within the Australian and New South Wales (NSW) Public Healthcare Systems, which includes devolution to Local Health Districts, a smaller and more focused Ministry of Health, increased transparency and funding reform. The article examines the challenges this reform presents for Local Health Districts and how these challenges are being addressed locally. This reform has also highlights the competencies that are required of chief executives and other senior executives in health in managing and leading these complex health organizations. PMID- 23342758 TI - Current situation of health care in India and corporation in emerging economies- what is the way forward? AB - In this study, we examine the management and operational problems faced by different categories of health care delivery platforms such as corporate hospitals, medium level private hospitals and public hospitals in Mumbai. Some suggestions are made and we believe many of the short falls or limitations that exist in the current set up can be removed and a way forward can be made in alleviating the suffering of vast majority of humankind living in our mega cities. Three major issues emerged as far as a public health system is concerned- that is shifting of trained health manpower from the public system to private or corporate hospitals, severe strain on the public health system's infrastructure and support services compounded by lack of accountability as far as management and governance are concerned. PMID- 23342759 TI - Credentialing for health care leaders: an overview of ACHE's FACHE credential and its contributions to the health care management field. AB - The American College of Healthcare Executives' (ACHE's) credentialing program for health care executives has evolved to match the changing role of the health care leader, the health care environment and other external factors. The FACHE credential signifies board certification in health care management. Those who obtain the credential are referred to as ACHE Fellows. There are rigorous requirements for achieving the credential--including passing an exam based on the competencies necessary to perform the role of hospital administrator--as well as recertification requirements. ACHE's voluntary credentialing program contributes to the professionalism of the health care management field and supports lifelong learning and leaders' commitment to excellence in health care management. PMID- 23342760 TI - Is leadership compatible with hospitals? Lessons from 10 years of teaching leadership to hospital managers. AB - Leadership methods can be understood and applied by hospital managers in the same way teachers and the seminar's participants respect certain conventions. Each method should be discussed and adapted, recognizing its limitations for use within hospitals. This article first presents what is taught in a traditional leadership course and then, discusses ways the course can be adapted for use by hospital managers. PMID- 23342761 TI - Recent focus of hyperbaric oxygen therapy study: an editorial perspective. PMID- 23342762 TI - Effects of hyperbaric oxygenation on vascular reactivity to angiotensin II and angiotensin-(1-7) in rats. AB - OBJECTIVE: To assess and elucidate the mechanisms of hyperbaric oxygenation (HBO2) effects on vascular reactivity to angiotensin-(1-7) [ANG-(1-7)] and angiotensin II (ANG II). METHODS: Rat aortic rings (HBO2 vs. control group) were used to test responses to ANG II, ANG II+ ANG-(1-7) or ANG-(1-7) after noradrenaline precontraction in the presence/absence of MS-PPOH, a specific CYP 450-epoxygenase inhibitor, and glibenclamide, a KATP channels inhibitor. mRNA expression studies of specific CYP isozymes have been conducted as well. RESULTS: The mean contraction (expressed as percent of maximal contraction) for ANG II was similar between groups. Contraction for ANG II + ANG-(1-7) was 15% +/- 10 (HBO2) and 20% +/- 9 (control). There was a significant decrease between the contraction response to ANG II (HBO2) and the response to ANG II + ANG-(1-7) in the HBO2 group, without such a difference within the control group. Mean percentage of noradrenaline precontraction decrease after ANG-(1-7) addition was significantly different [10% +/- 9 (control) and 19% +/- 11 (HBO2)]. The epoxygenase inhibitor MS-PPOH in HBO2 animals reversed these changes. Glibenclamide had no effect on relaxation in response to ANG-(1-7). Expression of CYP4A2, CYP4A3 and CYP2J3 mRNA was not significantly altered with HBO, whereas CYP4A1 was significantly upregulated. CONCLUSIONS: Our results suggest a role for epoxyeicosatrienoic acids in modulating relaxation response to ANG-(1-7) with HBO2 that is conducted via potassium channels other than KATP channels. HBO2 increased the responses to ANG-(1-7) after precontraction with noradrenaline. The difference between the response to ANG II in the HBO2 group and ANG II + ANG-(1-7) in the HBO2 group (the contraction force of the peptide combination being lower), without such difference in the control group, suggests an influence ofHBO2 on vascular reactivity. PMID- 23342763 TI - Psychomotor function during mild narcosis induced by subanesthetic level of nitrous oxide: individual susceptibility beyond gender effect. AB - OBJECTIVE: We investigated the effect of narcosis induced by subanesthetic concentrations of nitrous oxide (N2O), a behavioral analogue for hyperbaric nitrogen, on psychomotor performance. In particular, we assessed individual susceptibility to narcosis. METHODS: The participants were 12 female and 12 male undergraduate students. Psychomotor assessment was conducted with a computerized Visual Simple Reaction Time (VSRT) test, and Trail Making Tests Part A (TMTA) and Part B (TMT-B). The tests were conducted on two separate occasions in the following order: VSRT, TMT-A, TMT-B. On the first occasion participants conducted the tests breathing room air (air trial), and during the second test they conducted the tests while breathing a normoxic mixture containing 30% N2O (N2O trial). RESULTS: Males had significantly (p = 0.036) shorter VSRT in the air trials. There was no effect of gender on psychomotor performance in the N2O trials. Overall, mean performance in the N2O trials degraded significantly (p = 0.004) only in VSRT. Performance of individual participants exhibited different and inconsistent direction of change in the N2O trials. CONCLUSION: N2O-induced alterations in psychomotor function are primarily dependent on individual susceptibility to narcosis (i.e., concentration threshold). PMID- 23342764 TI - Hyperbaric side effects in a traumatic brain injury randomized clinical trial. AB - OBJECTIVE: To catalog the side effects of 2.4 atmospheres absolute (atm abs) hyperbaric oxygen (HBO2) vs. sham on post-concussion symptoms in military service members with combat-related, mild traumatic brain injury (TBI). METHODS: Fifty subjects diagnosed with TBI were randomized to either a sham (1.3 atm abs breathing air) or treatment (2.4 atm abs breathing 100% oxygen) hyperbaric profile. Forty-eight subjects completed 30 exposures. Medical events during hyperbaric exposures were separately annotated by medical staff and chamber operators. After the blind was broken, events were segregated into the exposure groups. RESULTS: These side effects were observed as rate (sham/treatment): ear block (ear barotrauma) 5.51% (1.09%/5.91%), sinus squeeze 0.14% (0.0%/0.27%), and confinement anxiety 0.27% (0.27%/0.27%). Other conditions that occurred included: headache 0.61% (0.68%/0.54%); nausea 0.2% (0.14%/0.27%); numbness 0.07% (0%/0.13%); heartburn 0.07% (0.14%/0%); musculoskeletal chest pain 0.07% (0%/0.13%); latex allergy 0.07% (0.14%/0%); and hypertension 0.07% (0.14%/0%). CONCLUSION: This study demonstrated no major adverse events, such as pulmonary barotraumas, pulmonary edema or seizure. Given the infrequent, mild side effect profile, the authors feel the study demonstrated that hyperbaric oxygen therapy (HBO2T) was safe at a relatively high treatment pressure in TBI subjects, and these data can be used to evaluate the risk/ benefit calculation when deciding to utilize HBO2T for treatment of various diseases in the TBI population. PMID- 23342765 TI - Effect of hyperbaric oxygen therapy on patients with herpes zoster. AB - BACKGROUND: The purpose of this study was to observe the effect of hyperbaric oxygen (HBO2) therapy on patients with herpes zoster. METHODS: A total of 68 cases with herpes zoster were randomly divided into HBO2 and control groups. The patients in the control group were treated with drugs, while the patients in the HBO2 group were treated with both drugs and HBO2. Parameters of therapeutic efficacy including period of blister resolution, scar formation time and percentage of patients developing post-herpetic neuralgia (PHN) were determined for the patients in both groups. Numeric Pain Rating Scale (NPRS) and Hamilton Depression Rating Scale (HAMD) were also scored for the patients before and after treatment. RESULTS: The therapeutic efficacy in the control group was 81.25%, which was significantly lower than that (97.22%) in the HBO2 group (p < 0.05). The percentage of patients developing PHN, scar formation time and NPRS score in the HBO2 groups were significantly lower than those in the control group (p < 0.05). HAMD score in the HBO2 group was significantly lower than that in the control group (p < 0.05). CONCLUSION: HBO2 can significantly enhance therapeutic efficacy, relieve pain, accelerate herpes blister healing and lesion resolution, reduce the percentage of patients developing PHN and improve depression in patients with herpes zoster. PMID- 23342766 TI - Top-cited articles on hyperbaric oxygen therapy published from 2000 to 2010. AB - OBJECTIVE: Hyperbaric oxygen therapy (HBO2T) is a specialty with wide clinical applications and study fields. An evaluation of the major research direction of HBO2T studies would be helpful for researchers in this field. In this study, we identified the most frequently cited HBO2T articles to analyze the study focus of HBO2T research in the past 10 years. METHODS: "Hyperbaric oxygen" was used as the keyword to search articles in PubMed between January 2000 and November 2010. The cited times of an article were tracked in Google Scholar. The top 100 most-cited articles were identified and their publication year, author nationalities, journal, study field and style were recorded and analyzed. RESULTS: In total, 2,362 HBO2T-related articles were retrieved. The number of HBO2T articles published per year has been increasing during the past 10 years. More than half of the top-cited articles (52/100) were from studies in the United States. Studies focusing on stroke (20), radiation injury (11), carbon monoxide (10), and wounds (9) accounted for 50% of the top-cited articles. CONCLUSION: HBO2T has been a field of increasing scientific publications in the past 10 years. The focus of research fields were stroke, radiation injury, carbon monoxide and wounds. The United States maintains an important influence on HBO2T studies. PMID- 23342767 TI - Recommendations for rescue of a submerged unresponsive compressed-gas diver. AB - The Diving Committee of the Undersea and Hyperbaric Medical Society has reviewed available evidence in relation to the medical aspects of rescuing a submerged unresponsive compressed-gas diver. The rescue process has been subdivided into three phases, and relevant questions have been addressed as follows. Phase 1, preparation for ascent: If the regulator is out of the mouth, should it be replaced? If the diver is in the tonic or clonic phase of a seizure, should the ascent be delayed until the clonic phase has subsided? Are there any special considerations for rescuing rebreather divers? Phase 2, retrieval to the surface: What is a "safe" ascent rate? If the rescuer has a decompression obligation, should they take the victim to the surface? If the regulator is in the mouth and the victim is breathing, does this change the ascent procedures? If the regulator is in the mouth, the victim is breathing, and the victim has a decompression obligation, does this change the ascent procedures? Is it necessary to hold the victim's head in a particular position? Is it necessary to press on the victim's chest to ensure exhalation? Are there any special considerations for rescuing rebreather divers? Phase 3, procedure at the surface: Is it possible to make an assessment of breathing in the water? Can effective rescue breaths be delivered in the water? What is the likelihood of persistent circulation after respiratory arrest? Does the recent advocacy for "compression-only resuscitation" suggest that rescue breaths should not be administered to a non-breathing diver? What rules should guide the relative priority of in-water rescue breaths over accessing surface support where definitive CPR can be started? A "best practice" decision tree for submerged diver rescue has been proposed. PMID- 23342768 TI - Therapeutic effect of hyperbaric oxygen on inclusion body myositis. AB - An inflammatory myopathy, inclusion body myositis (IBM) presents with progressive muscle weakness against a background of elevated creatine kinase and diffuse endomysial damage. Typically occurring in patients greater than 50 years of age, it is commonly misdiagnosed as polymyositis or other rheumatological disease and is often ineffectively treated with steroids [1]. The approach to IBM is frequently a clinical challenge due to its unique and often aberrant response to common treatment modalities. Here we report an apparent improvement in the clinical course of and associated laboratory findings in a patient with co existing IBM following the use of hyperbaric oxygen therapy as an adjunct for managing ischemic colitis. PMID- 23342769 TI - Anal canal mucinous adenocarcinoma with invasion of gluteus and perineum treated with surgery and hyperbaric oxygen therapy. AB - The case of a 66-year-old female patient with late diagnosis of giant anal canal mucinous adenocarcinoma invading the gluteal and vulvar regions is reported. Because of the patient's severe clinical status and disease morbidity, surgical resection of the lesion was accomplished, with no adjuvant chemo- or radiotherapy. In the postoperative period, the patient received hyperbaric oxygen therapy, which facilitated and even accelerated local healing. Total closure of the raw flesh area was achieved, with no recurrence signals of cancer being detected after one-year follow-up. We are convinced that, in this difficult case, hyperbaric oxygen therapy played a crucial role in patient recovery and wound healing, allowing for early closure with good progression. PMID- 23342770 TI - Hyperbaric oxygen therapy and delayed radiation injuries (soft tissue and bony necrosis): 2012 update. AB - Informal surveys at CME meetings have shown that approximately one-third of patients in the United States receive hyperbaric oxygen (HBO2) for delayed radiation injury. More than 600,000 patients receive radiation for malignancy in our country annually, and about one-half will be long-term survivors. Serious radiation complications occur in 5-10% of survivors. A large population of patients is therefore at risk for radiation injury. HBO2 has been applied to treat patients with radiation injury since the mid-1970s. Published results are consistently positive, but the level of evidence for individual publications is usually not high level, consisting mostly of case series and case reports. Only a rare randomized controlled trial has been accomplished. Radiation injury is one of the UHMS "approved" indications, and third-party payors will usually reimburse for this application. This updated review summarizes the publications available reporting results in treating radiation-injured patients. Mechanisms of HBO2 in radiation injury are discussed briefly. Outcome is reported on a mostly anatomic basis though due to the nature of the injury a positive outcome at one anatomic site is supportive of HBO2 at other sites. The potential benefit of prophylactic HBO2 before frank damage is also discussed in high-risk patients. The concerns of HBO2 enhancing growth of or precipitating recurrence of malignancy is discussed and largely refuted. PMID- 23342771 TI - [Effect of electroacupuncture on expression of spinal neuronal nitric oxide synthase protein and mRNA in rats with neuropathic pain]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on expression of neuronal nitric oxide synthase (nNOS) protein and mRNA in the spinal cord in rats with chronic constrictive injury (CCI) of the sciatic nerve so as to explore its mechanisms underlying pain relief. METHODS: Thirty-six male SD rats were randomly divided into sham operation (control) group (n = 12), CCI model group (n = 12) and EA group (n = 12). EA was applied to bilateral "Weizhong" (BL 40) and "Huan tiao" (GB 30) on the injured side for 30 min, once a day for 7 days (from the 11th day on after CCI). The mechanical and thermal pain thresholds were measured before and after CCI. Spinal nNOS protein and mRNA expression levels were detected by Western blot and reverse transcription-polymerase chain reaction (RT PCR), respectively. RESULTS: In comparison with the control group, both mechanical and thermal pain thresholds were significantly lower in the model group (P < 0.01). Compared with the model group, the two types of pain threshold were increased considerably on the 16th day in the EA group (P < 0.01). In comparison with the control group, the spinal nNOS protein and mRNA expression levels were increased significantly in the model group (P < 0.05, P < 0.01). In comparison with the model group, both nNOS protein and mRNA expression levels in the spinal cord were down-regulated obviously in the EA group (P < 0.05). CONCLUSION: Electroacupuncture can alleviate neuropathic pain in CCI rats, which is closely related to its effect in down-regulating the expression of nNOS protein and mRNA in the spinal cord. PMID- 23342772 TI - [Effect of electroacupuncture at different acupoints on expression of cervico spinal GDNF and BDNF and their receptor genes in neck-incision pain rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Futu" (LI 18), etc. on the expression of genes of glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and their receptors in the cervico-spinal cord in neck-incision pain rats, so as to study its mechanism underlying incision-pain relief. METHODS: A total of 50 Sprague Dawley male rats were randomly divided into normal, model (incision pain), EA-Futu (LI 18), EA- Hegu (LI 4) - Neiguan (PC 6, LI 4-PC 6) and EA-Zusanli (ST 36)-Yanglingquan (GB 34, ST 36-GB 34) groups (n = 10/group). A 1.5 cm long longitudinal incision was made along the midline of the neck under anesthesia to duplicate neck-incision pain model. Thermal pain threshold (PT) was measured before and after modeling and after the treatment, respectively. EA (1-2 mA, 2 Hz/100 Hz) was applied to bilateral LI 18, PC 6-LI 4 and ST 36-GB 34 for 30 min. The expression of genes of GDNF and its receptor GFRalpha-1, and BDNF and its receptors TrkA, TrkB in the spinal cord (C1 - C4) tissue was detected by quantitative real-time-PCR. RESULTS: In comparison with pre-modeling in the same one group, the thermal PT levels were decreased obviously in the model, LI 18, LI 4-PC 6 and ST 36-GB 34 groups after neck incision (P < 0.05). Compared with the model group, the PT levels were increased markedly in LI 18, LI 4-PC 6 and ST 36-GB 34 groups after the EA treatment (P < 0.05). Correspondingly, the expression levels of spinal GDNF mRNA and GFRalpha-1 mRNA were obviously lower, as well as BDNF mRNA was markedly higher in the model group than in the control group (P < 0.05), and those of TrkA mRNA and TrkB mRNA were increased slightly in the model group than in the control group (P > 0.05). In comparison with the model group, the expression levels of spinal GDNF mRNA and GFRalpha-1 mRNA were up-regulated considerably (P < 0.001), whereas those of BDNF mRNA, TrkA mRNA and TrkB mRNA were decreased slightly (P > 0.05) in the LI 18, LI 4-PC 6 and ST 36-GB 34 groups after EA treatment. CONCLUSION: EA stimulation can significantly suppress pain reaction of neck incision, which is closely associated with its effects in up-regulating the expression of GDNF and its receptor GFRalpha-1 genes in the cervical spinal cord (C1 - C4). PMID- 23342773 TI - [Effects of acupoint injection of autoblood on expression of pulmonary transcription factor GATA 3 and T-bet proteins and genes in asthma rats]. AB - OBJECTIVE: To observe the effect of autoblood acupoint-injection (ABAI) on expression levels of pulmonary transacting T-cell-specific transcription factor GATA 3 (involving Th 2 cytokine expression), Th 1-specific T-box transcription factor T-box expressed in T-cells (T-bet) proteins and genes in asthmatic rats so as to explore its mechanisms underlying asthma relief. METHODS: Forty-eight male SD rats were randomized into normal control (n = 8), model (n = 10), saline acupoint-injection (SAI, n = 10), ABAI (n = 10), and Dexamethasone (DXM, n = 10) groups. Asthma model was established during 28 days by 10% Ovalbumin + 10% aluminium hydroxide solution injection (i. p.) and vapourized 2% Ovalbumin inhaling for 14 days. For rats of the ABAI group, 0.4 mL autoblood was injected into the bilateral "Feishu" (BL 13) or "Shenshu" (BL 23) alternately, once every other day for six times. For rats of the DXM group, 50% DXM solution (0.5 mg/kg, i. p.) was given from the 17th day on after starting the modeling, once every other day for 11 days. Pulmonary GATA 3 and T-bet protein expression was detected by immunohistochemistry, and GATA 3 mRNA and T-bet mRNA expression detected by real time-PCR. RESULTS: In comparison with the normal group, pulmonary GATA 3 protein and mRNA expression levels in the model group were up-regulated significantly (P < 0.01), while T-bet mRNA expression in the model group was down regulated obviously (P < 0.01). Compared to the model group, GATA 3 protein and mRNA expression levels were down-regulated significantly in both ABAI and DXM groups (P < 0.01), while T-bet protein expression in ABAI group and T-bet mRNA expression in both ABAI and DXM groups were up-regulated significantly (P < 0.01, P < 0.05). No significant differences were found between model and SAI groups, and between ABAI and DXM groups in GATA 3 protein expression levels; and between ABAI and DXM groups in GATA 3 mRNA expression levels; between normal and model groups, and between SAI and ABAI groups in T-bet protein expression levels; between model and SAI groups and between ABAI and DXM groups in T-bet mRNA expression levels (P > 0.05). The ratio of GATA 3 mRNA/T-bet mRNA expression was significantly higher in the model group than in the normal group (P < 0.01), while obviously lower in the SAI, ABAI and DXM groups than in the model group (P < 0.05, P < 0.01). Additionally, the ratios of GATA 3 mRNA/T-bet mRNA in ABAI and DXM groups were comparable (P > 0.05). CONCLUSION: Autoblood acupoint injection is comparable to DXM intraperitoneal injection in down-regulating asthma-induced increase of pulmonary GATA 3 protein and mRNA expression as well as ratio of GATA 3 mRNA/T-bet mRNA, and in up-regulating asthma-induced decrease of T-bet mRNA expression in asthma rats, which may contribute to their effects in relieving asthma. PMID- 23342774 TI - [Effect of acupuncture at "Zusanli" (ST 36 and "Taichong" (LR 3) on gastrointestinal hormone levels in rats with diarrhea type irritable bowel syndrome]. AB - OBJECTIVE: To observe the effect of acupuncture of "Zusanli" (ST 36) and "Taichong" (LR 3) on gastrointestinal hormone levels in diarrhea type irritable bowel syndrome (IBS-D) rats so as to provide experimental evidence for acupuncture treatment of IBS-D. METHODS: Forty-eight Wistar rats were randomly divided into control, model, acupuncture and medication groups, with 12 rats in each group. IBS-D model was established by chronic mild restraining stress combined with isolated raising and intragastric administration of Folium Sennae (10 mL/kg). For rats of the acupuncture group, bilateral "Zusanli" (ST 36) and "Taichong" (LR 3) were punctured and stimulated for 30 min, once daily for 14 days. The rats of the medication group were treated by gavage of Pinaverin bromide, once daily for 14 days, and those of the control and model groups were given with equal volume of saline. Somatostatin (SS), substance P (SP) and vasoactive intestinal peptide (VIP) in the rats' plasma and ileum tissues were detected by sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the control group, the body weight and food intake quantity were reduced significantly, while the diarrhea index was increased significantly in the model group (P < 0.05, P < 0.01). In comparison with the model group, the body weight and food intake volume in both acupuncture and medication groups were increased remarkably after the treatment (P < 0.05, P < 0.01) whereas the diarrhea index in the latter two groups was reduced obviously (P < 0.01). Compared with the control group, plasma VIP level was increased significantly in the model group (P < 0.01), while those in both acupuncture and medication groups were decreased remarkably compared with the model group (P < 0.05). No significant changes of plasma SP and SS levels were found after modeling and after both acupuncture and medication treatments. In comparison with the control group, ileum SP, VIP and SS levels in the model group were up-regulated significantly (P < 0.01), while those in both acupuncture and medication groups were down-regulated considerably compared with the model group (P < 0.01). No significant differences were found between acupuncture and medication groups in the levels of ileum SP, VIP and SS (P > 0.05). CONCLUSION: Acupuncture of ST 36 and LR 3 can effectively down regulate ileum SP, VIP and SS levels in IBS-D rats, which may contribute to its effect in relieving IBS-D. PMID- 23342775 TI - [Effect of electroacupuncture of "Chize" (LU 5) and "Shangjuxu" (ST 37) on mesenteric microcirculation and vasoactive intestinal peptide levels in the lung, colon and hypothalamus in rats with chronic obstructive pulmonary diseases]. AB - OBJECTIVE: To observe the influence of electroacupuncture (EA) of "Chize" (LU 5, He-sea acupoint) and "Shangjuxu" (ST 37, lower He-sea acupoint) on mesenteric microcirculation, vasoactive intestinal peptide (VIP) levels in the lung, colon and hypothalamus tissues in rats with chronic obstructive pulmonary disease (COPD), so as to investigate its mechanism underlying improvement of lung derived intestinal disorders in clinical practice. METHODS: Thirty-two male Wistar rats were randomly divided into normal control, model, EA-Chize (LU 5, EA-LU 5) and EA Shangjuxu (ST 37, EA-ST 37) groups, with 8 rats being in each group. COPD model was established by intratracheal infusion of Lipopolysaccharide (LPS, 1 mg/mL, 0.2 mL/rat) and forced inhaling smoke, once daily for 28 days. EA was applied to bilateral LU 5 and ST 37 for 20 min, once every other day for 12 sessions. The state of mesenteric microcirculation was observed under microscope and divided into grade 0 (stagnation of blood flow), I (slow flowing and silt-like state), II (faster flowing with slight or obvious grainy feeling) and III (fast flowing without grainy feeling). The contents of VIP in the lung, colon and hypothalamus were detected using radioimmunoassay (RIA). RESULTS: Following modeling, the microvascular calibers were increased slightly in the model, EA-LU 5 and EA-ST 37 groups. Compared with the normal group, the blood flow velocity was increased significantly in model group (P < 0.05). In comparison with the model group, the blood flow velocity was reduced significantly in EA-LU 5 and EA-ST 37 groups (P < 0.01). There were no significant differences between EA-LU 5 and EA-ST 37 groups in blood flow velocity, among the four groups in VIP contents of the lung tissue (P > 0.05). The content of VIP in the colon was markedly higher in the model group than in the normal group, and that in the hypothalamus was obviously lower in the EA-LU 5 group than in the model group (all P < 0.05). CONCLUSION: EA stimulation of "Chize" (LU 5) can notably reduce hypothalamic VIP content and slow down blood flow velocity of the mesenteric microvessels in COPD rats. PMID- 23342776 TI - [Effect of scalp acupuncture on learning ability and hippocampal VEGF expression in chronic cerebral ischemia rats]. AB - OBJECTIVE: To observe the effect of scalp cluster-needle intervention on cognitive ability and hippocampal vascular endothelial growth factor (VEGF) expression in cerebral ischemia (CI) rats. METHODS: Forty Wistar rats were randomized into sham operation (sham), model, scalp-acupuncture and medication groups. Chronic CI model was established by occlusion of the bilateral common carotid arteries. Acupuncture needles were inserted into "Baihui" (GV 20) and its left and right points (2 mm beside GV 20) and manipulated leftward and rightward for 3 min at a frequency of about 200 times/min, retained for 30 min. The treatment was conducted once daily, for 4 weeks. For rats of the medication group, Nimodipine (1 mg/kg) was given to the animal by gavage, once a day, for 4 weeks. The rats' learning ability was measured by Morris water maze. Changes of hip-pocampal cellular morphology were observed by HE staining and light microscope, and hippocampal VEGF expression was detected by immunohistochemistry. RESULTS: In comparison with the sham group, the escape latency of rats in the model group was prolonged significantly (P < 0.05), suggesting a decrease of learning ability after CI. Compared with the model group, the escape latency of both acupuncture and medication groups were reduced markedly after the treatment (P < 0.05). In comparison with the sham group, the number of VEGF immunoreaction (IR) positive cells in the model group was up-regulated significantly (P < 0.05), while compared with the model group, the numbers of both acupuncture and medication groups were increased further (P < 0.05). No significant differences were found between the acupuncture and medication groups in escape latency and VEGF expression levels (P > 0.05). HE staining showed that in the model group the hippocampal pyramidal cells were reduced in number, became vaguer in layers and nucleole, and got deformed in structure with karyopycnosis and disappearance of endochylema, and cavitation. These situations were relatively lighter in both acupuncture and medication groups. CONCLUSION: Scalp acupuncture intervention can significantly improve CI rats' congnitive ability and pathological changes, which may be related to its function in increasing the expression of VEGF in the hippocampus. PMID- 23342777 TI - [Involvement of cerebral neuroglobin in electroacupuncture preconditioning induced protection effect in cerebral ischemia-reperfusion rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) preconditioning on cerebral ischemia and the role of cerebral neuroglobin (NgB) in EA-induced brain protection in focal cerebral ischemia and reperfusion injury (CI/RI) rats. METHODS: Male SD rats were randomly assigned to sham control, CI/RI 6 h, CI/RI 24 h and CI/RI 72 h groups (n = 6) for observing changes of NgB at different time points. Additional SD rats were randomly assigned to sham, model, and EA preconditioning (EA-PC) groups (n = 16) for observing changes of cerebral NgB positive cell counts in the ischemic penumbra region 24 h after reperfusion. EA pre-conditioning was applied to "Baihui" (GV 20) for 30 min, once daily for 5 days before CI/RI. CI/RI model was established by occlusion of the right middle cerebral artery and reperfusion for 6 h, 24 h and 72 h respectively. The neurological behavior scores (NBS) of all the rats were evaluated according to Garcia's methods. The cerebral infarct volume was determined by 2,3,5 triphenyltetrazolium chloride (TTC) staining. The number of cerebral NgB positive cells was detected by immunofluorescent staining. RESULTS: No infarct loci were found in the sham group. The cerebral infarction volume percentage was significantly higher in the model group than in the EA-PC group (P < 0.01), while the NBS was significantly lower in the model group than in the EA-PC group (P < 0.01). The number of cerebral NgB positive cells in the ischemic penumbra was up regulated 6 h after CI/RI injury, peaked at 24 h and continued at 72 h. Compared with the sham group, the number of cerebral NgB positive cells of the model group was increased significantly, whereas that of the EA-PC group up-regulated further obviously in comparison with the model group (P < 0.01). CONCLUSION: EA pretreatment has a significant neuroprotective effect on cerebral ischemia reperfusion, which is closely related to its effect in up-regulating NgB protein expression. PMID- 23342778 TI - [Effects of electroacupuncture stimulation of scalp-point on cardiac sympathetic discharges, myocardial beta1-adrenoceptor protein expression and plasma norepinephrine concentration in myocardial ischemia-reperfusion injury rats]. AB - OBJECTIVE: To explore the mechanism of electroacupuncture (EA) of scalp-point in the management of myocardial ischemia-reperfusion injury (MI/RI) by examining its effects on left cardiac sympathetic nerve activity, myocardial beta1-adrenaline receptor (AR) protein expression and plasma norepinephrine (NE) concentration in MI/RI rats. METHODS: Eighteen Wistar rats were randomly divided into sham, model and EA groups (n = 6). MI/RI model was induced by ligation of the left anterior descending coronary artery for 30 min, followed by release of the ligation for 15 min. EA was applied to bilateral Epangxian I (MS 2) for 15 min. The left cardiac sympathetic nerve activity was recorded with BL-420 E+ biological signal acquisition system. Myocardial beta1-AR protein expression was examined by western blot and plasma NE level detected by enzyme-labeled immunosorbent assay. RESULTS: Compared with the sham group, the left cardiac sympathetic discharges and plasma NE levels and myocardial beta1-AR protein expression were markedly increased in the model group (P < 0.01), whereas in comparison with the model group, the sympathetic discharges, plasma NE level and myocardial beta1-AR protein expression in the EA group were down-regulated significantly (P < 0.05). CONCLUSION: Scalp-point EA intervention can suppress MI/RI induced increase of sympathetic nerve activity and plasma NE level, and beta1-AR protein expression, which may contribute to its effect in relieving myocardial ischemia. PMID- 23342779 TI - [Effect of cupping on hemodynamic levels in the regional sucked tissues in patients with lumbago]. AB - OBJECTIVE: To observe hemodynamic changes in the local sucked tissue of lower back undergoing negative pressure after cupping in patients with lumbago. METHODS: Twenty-two lumbago outpatients were recruited in the present study and 32 sucked tissues accepted measurements. The cupping was applied to the tenderpoint of the patients' lower back for 10 min by using a glass-mug (5 cm in diameter). Hemodynamic indexes [peak systolic velocity (PSV), end-diastolic velocity (EDV) and resistance index (RI)] of the sucked skin and subcutaneous tissues at the lower back were detected before and after cupping by using a color Doppler flow imaging. RESULTS: After cupping intervention at the lower back, the PSV [(14.2 +/- 1.8) cm/s] and EDV [(5.5 +/- 0.7) cm/s] levels were increased significantly in comparison with those [(5.9 +/- 0.9) and (1.9 +/- 0.3) cm/s] before cupping (P < 0.01), while RI was reduced evidently after cupping (0.61 +/- 0.05 vs 0.68 +/- 0.06, P < 0.01), suggesting an increase of the regional blood flow. CONCLUSION: Cupping therapy can increase the peak systolic velocity and end diastolic velocity and lower vascular resistance of the subcutaneous arterioles in the regional tissue, which may contribute to its effect in relieving lumbago. PMID- 23342780 TI - [Observation on therapeutic effect of scalp-acupoint catgut embedding for 33 cases of insomnia patients]. AB - OBJECTIVE: To observe the therapeutic effect of scalp-acupoint catgut embedding in the treatment of insomnia. METHODS: Sixty-four insomniacs were randomly divided into catgut embedding group (n = 33) and routine acupuncture group (n = 31). Baihui (GV 20), Shenting (GV 24) and bilateral Fengchi (GB 20) were selected for subcutaneous embedding of catgut, once a week for 4 weeks. GV 20, GV 24, bilateral GB 20, bilateral Shenmen (HT 7), bilateral Neiguan (PC 6) and bilateral Sanyinjiao (SP 6) were punctured with filiform needles for patients of the acupuncture group. The treatment was performed once every other day, 3 times a week for 4 weeks. The therapeutic effect was evaluated by using International Unified Sleep Efficiency Value and Pittsburgh Sleep Quality Index (PSQI). RESULTS: After the treatment, the falling asleep latency and PSQI scores of both catgut embedding and routine acupuncture groups were decreased significantly (P < 0.01) while the sleep duration and sleep efficiency increased considerably (P < 0.01) in comparison with pre-treatment. The effect of catgut embedding was obviously better than that of routine acupuncture in prolonging sleep duration and improving sleep efficiency (P < 0.05). No significant differences were found between the two groups in the falling asleep latency and the PSQI scores (P > 0.05). CONCLUSION: Both routine acupuncture and scalp-acupoint catgut embedding interventions can effectively reduce falling asleep latency and prolong sleep duration. The therapeutic effect of scalp-acupoint catgut embedding is relatively better in improving sleep duration and sleep efficiency. PMID- 23342781 TI - [Effects of acupuncture of Jianjing (GB 21) on gallbladder volume and symptoms of cholecystitis patients]. AB - OBJECTIVE: To observe the effect of acupuncture of Jianjing (GB 21) and non acupoint on gallbladder volume and clinical symptoms of chronic cholecystitis patients. METHODS: Sixty cases of chronic cholecystitis patients were equally randomized into Jianjing (GB 21) group and non-acupoint group. A filiform needle was inserted into Jianjing (GB 21) or non-acupoint (2 cun lateral to the mid point between the spinous processes of the 6th and 7th cervical vertebrae) on the right side, manipulated for a while till "Deqi", and retained for 30 min. A color Doppler ultrasound scanner was used to detect the volume of the gallbladder before and 15 min after acupuncture stimulation and 30 min after withdrawal of the acupuncture needle. Changes of the patients symptoms of shoulder-back pain, stomachache, distension and nausea were evaluated according to the patients' complaints. RESULTS: After acupuncture intervention, the remission rates of shoulder-back pain and stomachache in non-acupoint and GB 21 groups were 56.67% and 90.00% respectively, while the effective rates of the patients' gastric distention and nausea in non-acupoint and GB 21 groups were 16.67% and 23.33%, respectively. The therapeutic effect of Jianjing (GB 21) was apparently superior to that of non-acupoint in pain relief (P < 0.05). Fifteen min following acupuncture stimulation and 30 min after withdrawal of the acupuncture needle, the gallbladder volume in cholecystitis patients with deflated gallbladder was increased apparently in GB 21 group (P < 0.01), and that in patients with expanded gallbladder was decreased significantly (P < 0.01). No significant differences were found among pre-, during and post-treatment in the non-acupoint group in the effects of acupuncture on regulation of the deflated and expanded gallbladder volume (P > 0.05). CONCLUSION: Acupuncture stimulation of Jianjing (GB 21) can effectively relieve shoulder-back pain and stomachache, and regulate the volume of the deflated and expanded gallbladder in cholecystitis patients. The effect of acupuncture of non-acupoint is relatively poorer in relieving the cholecystitis patients' symptoms and regulating the gallbladder volume. PMID- 23342782 TI - [Comparison of therapeutic effects of different types of acupuncture interventions on herpes zoster in acute stage]. AB - OBJECTIVE: To compare the therapeutic effects of different types of acupuncture therapy on herpes zoster (acute stage). METHODS: A total of 189 cases of acute herpes zoster outpatients and inpatients were recruited in the present multicenters (3 hospitals) randomized controlled clinical trials. They were divided into (computer-aided random allocation): basic acupuncture (n = 36), cotton moxibustion (n = 35), fire needle (n = 43), tapping-cupping (n = 39) and medication (n = 36) groups. Ashi-points (around the locus), Jiaji (EX-B 2), Zhigou (SJ 6) and Houxi (SI 3) were used in this study. For patients of the acupuncture group, the abovementioned acupoints were punctured with filiform needles (encircled needling around the affected loci) and also stimulated with electroacupuncture (EA). For patients of the cotton moxibustion group, thin defated dry cotton pieces put over the Ashi-point were ignited, 3 times altogether, followed by EA and encircled needling stimulation which were the same to those in the basic acupuncture group. Patients of the fire needle group were treated by pricking the herpes (3-5 in number) with a hot-red needle, followed by EA and encircled needling treatment. Patients of the tapping-cupping group were treated by tapping Ashi-points repeatedly with a percussopunctator and cupping over the pricked region, followed by EA and encircled needling treatment. Patients of the medication group were treated by oral administration of Valaciclovir Hydrochlordide (300 mg/time, twice a day) and vitamin B1 (10 mg/time, t. i.d.) for 10 days. The acupuncture-moxibustion treatment was given once daily for 10 days. The time of blister-occurrence cease, scab formation and decrustation was recorded, and pain degree was evaluated using visual analog scale (VAS). The therapeutic effect was assessed according to the related standards. RESULTS: There were no significant differences among the 5 groups in the time of blister-occurrence cease, scab formation and decrustation, and in the therapeutic effect (P > 0.05). The VAS scores of the 5 groups were decreased gradually and apparently along with the treatment (P < 0.05), suggesting a pain relief after the treatment. In comparison with the medication group, the VAS scores of the basic acupuncture group, cotton moxibustion group, fire needle group and tapping-cupping group were significantly lower from the 7th day on following the treatment (P < 0.05). CONCLUSION: Acupuncture plus encircled needling and acupuncture plus encircled needling combined with cotton moxibustion, or with fire needle stimulation, or with tapping and cupping are effective in the treatment of herpes zoster at the acute stage, being comparable to the medication in the clinical curative effect and improvement of blisters, and better than medication in pain relief. PMID- 23342783 TI - [Effect of umbilicus moxibustion therapy on physical conditions of yang deficiency volunteers]. AB - OBJECTIVE: To observe the therapeutic effect of umbilicus moxibustion for sub health people with yang-deficiency constitution. METHODS: Sixty sub-health volunteers with yang-deficiency constitution were equally and randomly divided into treatment and control groups. The subjects of the two groups were treated conventionally with Jingui Shenqi Pill (Goldern Chamber Pill for strengthening the Kidney-qi), 8 pills each time, 3 times a day. Additionally, those subjects of the treatment group were also treated by moxibustion over the umbilicus, twice a week, 3 months altogether. The integrative score was assessed before and after the treatment in accordance with the criteria of "Quantization Diagnosis of Chinese Medicine". RESULTS: After umbilicus moxibustion intervention for 3 months, the integrative scores of symptoms of mental fatigue, cold limbs and warmth preference, lassitude in loin and limbs, and loose stool were decreased significantly in the treatment group (P < 0.05), suggesting an improvement of these symptoms and being superior to those of the control group in the curative effect (P < 0.05). Simple Jingui Shenqi Pill treatment was also effective in reducing scores of cold limbs and warmth preference, and lassitude in loin and legs after the treatment (P < 0.05). Of the two 30 cases in the treatment and control groups, 18 (60.0%) and 7 (23.3%) experienced marked improvement in their symptoms, 10 (33.3%) and 12 (40.0%) had an improvement, 2 (6.7%) and 11 (36.7%) were failed, with the effective rates being 93.3% and 63.3%, respectively. CONCLUSION: Umbilicus moxibustion therapy can effectively improve clinical symptoms of sub-health subjects with yang-deficiency constitution. PMID- 23342784 TI - [Differences of bi-directional regulative effects between acu-moxibustion and Chinese materia medica interventions]. AB - Bi-directional regulation is referred to a balancing effect of both acu moxibustion and Chinese materia medica interventions when the human body is experiencing a hyperactivity or hypoactivity due to abnormal intrinsic or external factors. In the present paper, the authors analyze their identical and different characteristics from: 1) definition; 2) characters of regulative effects of acu-moxibustion therapy: A) differentiation of meridian and zangfu organs being the basis of treatment, B) four factors (acupoint-location, body's functional state, acupoint-formula and needle-manipulation techniques) dependant, C) entirety regulation, and D) centrotaxis modulation; 3) characters of Chinese materia medica intervention: including a) correspondence between the drug property and the syndrome being the basis of the regulative effect, b) multi factors [components (antagonist and agonist), combination, dosages and processing quality of Chinese materia medica, and functional state of the human body] dependant, c) entirety regulation, and d) both centrotaxis and deviation adjustment. In one word, the bi-directional regulation effect is one of the basic characteristics of both acu-moxibustion and Chinese materia medica in clinical practice, but their basis and modes for inducing effects are different. PMID- 23342785 TI - [Basic rules and characteristics of acupoint application therapy based upon data mining]. AB - OBJECTIVE: To analyze the basic characteristics of effects of acupoint application therapy in order to guide clinical decision better. METHODS: A database on acupoint application therapy was established first by collection, sorting, screening, recording, collation, data extraction, and statistical analyses of the related literature published in recent 60 years, and using modern computer system. Then, its predominant indications and application rules in clinical practice were analyzed using data mining techniques. RESULTS: Outcomes of data mining showed that the acupoint application therapy was extensively utilized in the treatment of a variety of diseases or clinical conditions (142 in total) in different clinical departments, particularly in the internal medicine which contains 51 types of clinical conditions or diseases (accounting for 35.92%). Among them, the top 3 are asthma, cough, and abdominal pain, with the appearance frequency being 161, 79 and 45 times (= articles) in the domestic journals, respectively. The second one is the paediatric department, containing 30 kinds of diseases or clinical conditions (accounting for 21.13%). Among them, cough (106 articles), asthma (104 articles) and diarrhoea (82 articles) are frequently seen. The surgery department takes the third place, involving 27 disorders (accounting for 19.01%), with lumbago-leg pain being the most (31 articles). In the departments of ophthalmology and otorhinolaryngology, 14 types of disorders (accounting for 9.86%) have been reported, with nasosinusitis being the most (56 papers). This therapy has also been used to treat 10 types of gynecopathy (7.04%) and 10 kinds of dermopathy (7.04%), with dysmenorrhea (37 articles) and shingles (6 articles) being the most. For acupoint application, complex prescriptions of Chinese herbal medicines in the forms of paste and cataplasm are frequently adopted, but with fewer application of enhancer of cutaneous penetration. Regarding the utilized acupoint, local points are often chosen. In the light of the collected papers, the highest effective rate is for dermopathy, followed by surgical problems, gynecopathy, paediatric conditions, and disorders of the internal medicine, ophthalmology and otorhinolaryngology. CONCLUSION: Acupoint application therapy has been used for 142 kinds of disorders of different clinical departments, with the dominant indications being asthma, cough, abdominal pain, facial paralysis and constipation in the internal medicine, cough, asthma and diarrhoea in the paediatrics, lumbago-leg pain in the surgery, nasosinusitis in the otorhinolaryngology, and dysmenorrhea of gynecopathy. PMID- 23342786 TI - [Progress of researches on mechanisms of acupuncture intervention of Alzheimer's disease]. AB - Alzheimer's disease (AD) is one of the major diseases threatening the aged people's health. In the present paper, the authors reviewed development of studies on acupuncture treatment of AD from: 1) regulating release of neurotransmitters (cholinergic, amino-acids and monoamine neurotransmitters), 2) protecting cerebral neurons from apoptosis (anti-oxidative stress, improving synaptic plasticity, and suppressing apoptosis), 3) improving levels of neurotrophic factors, 4) regulating hippocampal intracellular signaling, 5) inhibiting inflammatory reactions of the brain tissue, 6) adjusting the level of abnormal proteins (microtubule-associated protein, beta-amyloid), and 7) up regulating the level of autophagy activity. However, current experimental studies can not completely answer clinical questions due to limited model designs and complicated pathological mechanisms of AD. Many findings of biological indexes need being verified further. Reasonable therapeutic regimens of acupuncture formulated according to syndrome differentiation will help improving clinical curative effect and the corresponding research on new therapeutic targets may be helpful to our understanding about the mechanism of acupuncture. PMID- 23342787 TI - [Bibliometrics study on indications of acupuncture therapy based on foreign acupuncture clinical trials]. AB - In the present paper, the authors make a bibliometrics study on clinical indications of acupuncture therapy based on the published foreign articles about acupuncture clinical trials collected from PubMed database and Excerpta Medica database (EMbase). In 1996, 64 acupuncture indications were declared by WHO in Milan conference. But in recent 15 years, clinical trials have been conducted extensively in the foreign countries. Till now, 77 new indications for acupuncture therapy have been found in the foreign journals. The authors recommended that 29 indications (knee osteoarthritis, critique age problems, muscular fasciae ache, anxiety, etc.) should be added to the first class, 4 indications (irritable bowel syndrome, malposition, backache, simple obesity) should be upgraded from the second class to the first class, and the other 3 indications (childbirth pain, male and female barren) should be upgraded from the third class to the first class due to their application frequency in clinical trials. Increase of clinical indications reflects extensive application of acupuncture therapy and may help providing a better service for people's health. PMID- 23342788 TI - [Current situation and thinking on therapy of hip fractures]. PMID- 23342789 TI - [Comparison of proximal femoral locking plate and Gamma nail in the treatment of the femoral intertrochanteric fractures in the elder]. AB - OBJECTIVE: To evaluate and compare the clinical effects of proximal femoral locking plate with Gamma nail in the treatment of the femoral intertrochanteric fractures in the elder. METHODS: From June 2008 to June 2010, 83 patients with femoral intertrochanteric fracture were randomly divided into two groups(group A and group B). In group A,there were 42 cases including 23 males and 19 females, the range of their age was from 64 to 92 years old;according to Jensen classification, there were 19 cases of type II fracture,17 of type III fracture, 4 of type IV fracture, 2 of type V fracture. In group B,there were 41 cases including 24 males and 17 females, the range of their age was from 65 to 90 years old; 20 cases were type II, 16 cases were type III, 3 cases were type IV, 2 cases were type V. The patients of group A were treated with locking plate, the patients of group B with Gamma nail. The observing and comparing items of the two groups included (1) After the operation, the operational duration was assessed; (2) After the operation, intraoperative bleeding volume was assessed; (3) Hemoglobin reduction was assessed in second day after the operation; (4) At the last follow-up, fracture healing time was assessed. (5) Functional recovery was evaluated according to Parker and Palmer mobility score. RESULTS: All patients were followed-up for 10.6 months in average (ranging from 8 to 12). In group A, the average operation time was (62.46 +/- 21.61) min, the range of intraoperative bleeding volume was from 50 to 260 ml, the average hemoglobin reduction after the operation was (18.20 +/- 6.25) g/L, the rang of fracture healing time was from 12 to 24 weeks and the average Parker-Palmer mobility score was (7.68 +/- 1.09) points. In group B, the average operation time was (67.42 +/- 19.46) min, the range of intraoperative bleeding volume was from 40 to 280 ml, the average hemoglobin reduction after the operation was (40.14 +/- 8.62) g/L, the rang of fracture healing time was from 14 to 22 weeks and the average Parker-Palmer mobility score was (7.59 +/- 1.12) points. There were no statistically significant differences (P > 0.05) between two groups for the average operation time,the volume of intraoperative bleeding and Park and Palmer mobility score. Hemoglobin reduction after the operation in group A was less than in group B, there were statistically significant differences (P < 0.05) between two groups. CONCLUSION: The method of proximal femoral locking plate had advantages of less bleeding after operation and relative strong fixing in the femoral intertrochanteric fractures, was more suitable for the femoral intertrochanteric fracture in the elder. PMID- 23342790 TI - [Risk early warning and multimodal prevention of postoperative venous thromboembolism for hip fractures]. AB - OBJECTIVE: To study the efficacy and safety of multimodal prevention of postoperative venous thromboembolism for hip fractures. METHODS: From March 2009 to July 2011, preoperatively, patients were assigned to two groups on the basis of an assessment of their risk factors. One hundred and twelve patients were considered to be low risk, involving 47 males and 65 females,with an average age of (72.40 +/- 13.29) years ranging from 42 to 88,and were managed with aspirin (100 mg once daily for 14 days) as well as intermittent gasing compression devices. Twenty-six patients were considered to be high risk, involving 12 males and 14 females with an average age of (78.50 +/- 12.76) years ranging from 65 to 84,and were managed with low-molecular-weight heparin (0.4 ml,subcutaneous injection once daily for 14 days) and intermittent gasing compression. All patients were underwent Doppler ultrasonography within 24 hours before hospital discharge. All patients were followed-up for 3 months postoperatively. The incidence of deep venous thrombosis of lower limb, pulmonary embolism, gastrointestinal hemorrhage were recorded. RESULTS: Overall, there were no fatal pulmonary embolism, 1 case of symptomatic pulmonary emboli in low risk group, and none were detected in the high-risk group. Deep venous thrombosis was detected in association with 6 (6.25%) of the 112 procedures in the low-risk group and 2 (7.69%) of the 26 operations in the high-risk group. Paitents were selected in opened reduction and internal fixation, the quantity of bleeding, decrease of hemoglobin, hematoma rate, and gastrointestinal hemorrhage rate of low risk group were (538.10 +/- 390.20) ml, (30 +/- 19) g/L, 0, and 1 (1.03%) respectively; those of the high-risk group were (585.95 +/- 403.96) mL, (32 +/- 20) g/L,1 (4.76%), (4.76%), there were no significant different between the two groups, all P > 0.05. CONCLUSION: There were no statistic significances between the aspirin as well as intermittent gasing compression devices and the low-molecular-weight heparin and intermittent gasing compression in preventing venous thromboembolism (VTE) in postoperative postoperative venous thromboembolism for hip fractures. However, there are potential advantages to reduce complications of bleeding and cardiovascular disease. Multimodal prevention of postoperative venous thromboembolism can protect postoperative patients with hip fractures. PMID- 23342791 TI - [Treatment of intertrochanteric fractures in the advanced age patients by external fixators]. AB - OBJECTIVE: To explore the effect of external fixators on the intertrochanteric fracture in the advanced age patients. METHODS: From June 2008 to September 2010,32 cases who failed to be operated by the regular open-sugery were divided into two groups randomly, 16 of those were put in traction and conservative treatment;and the other 16 patients were treated by external fixation under anesthetization. In the traction group, there were 9 males and 7 females with an average age of (79.19 +/- 1.83) years ranging from 78 to 85. In the external fixation group, there were 10 males and 6 females with an average age of (79.69 +/- 2.41) years ranging from 78 to 88 years. Acoording to the Evans-Jensen classification,in the traction group, there were 6 cases of type I ,6 cases of type II, 7 cases of type III and lieing in bed 45 days in average; in the external fixation group, there were 6 cases of type I ,5 cases of type II, 2 cases of type III, 2 cases of type IV, and non-weight loading walking after surgery in a week in average. RESULTS: In the traction group, 3 of them had decubitus, 3 of them had cardiopulmonary insufficiency, 2 of them had infection from traction needles, and 1 of them had pneumonia; in the external fixatioin group, only 2 of them had coxa vara. Based on the Harris scoring for the assessment of the function of hip join,in the traction group, the results were excellent in 4 cases,good in 3,fair in 3,poor in 6; in the external fixation group,the results were excellent in 10 cases, good in 3, fair in 2, poor in 1. CONCLUSION: Thus, the use of external fixation on the intertrochanteric fracture is a strong safe and effective method in treating intertrochanteric fracture of the advanced age patients. PMID- 23342792 TI - [Clinical application of the percutaneous retrograde acetabular anterior horn screw fixation]. AB - OBJECTIVE: To investigate the clinical usage of percutanious retrograde acetabular anterior horn screw fixation. METHODS: From June 2006 to November 2011,27 patients with anterior horn accetabular fractures were treated with percutaneous retrograde screw. There were 20 males and 7 females with an average age of 35 years (ranged,20 to 61). According to Tile classification,type A was in 5 cases,type B was in 18 cases and type C was in 4 cases. The intra-operative blood loss volume, fractured reduction and screw location were observed. RESULTS: Postoperative X-ray and CT scan showed good reduction. According to the standard of Matta, 10 cases got excellent results, 15 good and 2 poor. All fractures healed and no complications such as neurovascular injuries and femoral head necrosis were found. CONCLUSION: Percutanious retrograde acetabular anterior horn screw technique have advantages of little trauma, less blood loss volume, reliable fixation, which can be effectively used in clinic. PMID- 23342793 TI - [Modified Stoppa approach in treatment of pelvic and acetabular fractures]. AB - OBJECTIVE: To evaluate the modified Stoppa approach in treatment of pelvic and acetabular fractures. METHODS: From March 2010 to May 2012,16 patients with pelvic fractures and 7 patients with acetabutar fractures were treated by open reduction and internal fixation through the modified Stoppa approach,involving 18 males and 5 females with an average age of 39 years ranging from 17 to 65. By Tile classification, 16 cases of pelvic fractures included 1 case of B1, 2 of B2, 3 of B3, 4 of C1-1, 2 of C1-2, 2 of C1-3, and 1 of C2. By Letournel classification, 7 cases of acetabular fractures included 1 case of anterior column fractures, 1 of transverse fractures, 2 of type T, 1 of anterior column plus posterior transverse fractures, and 2 cases of both columns fractures. For 16 pelvic fractures, the modified Stoppa approach was used exclusively in 9 cases,in combination with the iliac fossa approach in 6 cases, and in combination with the posterior approach in 1 case. For 7 acetabular fractures, the modified Stoppa approach was used exclusively in 4 cases, in combination with the Kocher Langenbeck approach in 2 cases, and in combination with the Kocher-Langenbeck and iliac fossa approaches in 1 case of both columns fractures. RESULTS: The average operation time was 130 min (50 to 350 min) and the blood loss averaged 320 ml (100 to 1200 ml). There were no operative complications. The reductions of the pelvic and acetabular fractures were all excellent and good. Twenty-one patients were followed-up from 4 to 24 months (averaged 8 months). The fractures were all healed,the fracture healing time was 2.5 to 5 months (means 3.2 months). Among them, 1 case occurrenced screw loosening, 1 case had mild limited of hip flexion, no case had plate breakage and lateral ventral syndrome. CONCLUSION: The modified Stoppa approach can be used to treat pelvic and acetabular fractures effectively, and it has advantages of easy manipulation and a low complication rate. PMID- 23342794 TI - [Efficacy and safety of using denervation to treat the low back pain due to lumbar joint origin]. AB - OBJECTIVE: To explore efficacy and safety of using denervation of dorsal medial branch to treat the low back pain due to lumbar joint origin. METHODS: From March 2009 to October 2010,10 patients with the low back pain due to lumbar joint origin were enrolled in this study including 6 males and 4 females with an average age of 56.4 years old (41 to 68). The average disease duration was 1.2 years (0.5 to 3). All patients were operated by blocking the dorsal medial branch. Single branch (dorsal medial branch of the involved level), dual branches (dorsal medial branches of the involved and the upper or lower level, 5 with the upper level, 5 with the lower level), three branches (dorsal medial branches of the involved and the upper and lower levels), four branches (dorsal medial branches of the involved and the upper two and lower levels) were blocked by 0.5% lidocaine 15 ml compounded with betamethasone injection 1 ml (10 mg/ml) and a cobalt ammonium injection 500 microg at the junction of the superior articular process and the transverse process. Low back pain VAS, average EMG of multifidus of the involved level and low back muscle strength were assessed and statistically compared. Low back muscle strength was measured by the back power meter. RESULTS: The mean low back pain VAS of the 10 patients in the preoperation was 6.85 +/- 1.55, in single branch blocked group was 5.80 +/- 1.05, in dual branches blocked group was 3.65 +/- 1.20, in three branches blocked group was 2.80 +/- 1.10 and in four branches blocked group was 2.75 +/- 1.15. Average EMG of multifidus was 69.25 +/- 2.13 in the preoperation,in single branch blocked group was 62.15 +/- 1.85, in dual branches blocked group was 51.25 +/- 1.28, in three branches blocked group was 47.30 +/- 1.85 and in four branches blocked group was 45.96 +/- 1.98. The mean low back muscle strength was 60 kg in the preoperation, in single branch blocked group was 55 kg,in dual branches blocked group was 48 kg, in three branches blocked group was 44 kg and in four branches blocked group was 43 kg. Among the dual branches blocked group,low back pain VAS and low back muscle strength in the dorsal medial branches of the involved and the upper level blocked showed great decline compared with those in the dorsal medial branches of the involved and the lower level blocked. CONCLUSION: It is effective by denervation of dorsal medial branch to treat the low back pain due to lumbar joint origin. There are significant difference in low back pain VAS between every two among the preoperation,single branch blocked group,dual branches blocked group and three branches blocked group. There is no significant difference between four branches blocked group and three branches blocked group. In low back muscle strength and average EMG of multifidus, compared with the preoperation group,there is no significant decline in single branch blocked and dual branches blocked group,and there is significant decline in three branches blocked and four branches blocked group. Therefore, single or dual dorsal medial branch blocked is safety. Among the dual branches blocked group, dorsal medial branches of the involved and the upper level blocked should be given priority to. There is a certain risk in three or four dorsal medial branches blocked which should be used with caution. PMID- 23342795 TI - [Characteristics and treatment of traumatic cervical disc herniation]. AB - OBJECTIVE: To explore clinical presentations and the operational opportunity of traumatic cervical disc herniation. METHODS: From June 2002 to June 2009,40 patients with traumatic cervical disc herniation were treated. There were 24 males and 16 females, with an average age of 43.2 years old ranging from 30 to 56 years. There were 36 patients with single intervertebral disc herniation and 4 patients with double. The injury level of those patients were at C3,4 in 16 cases, C4,5 in 10 cases, C5,6 in 12 cases and C6,7 in 6 cases. Among them, 18 patients showed spinal cord signal changes by MRI, 5 patients suffered from nothing but neck and shoulder pain, 8 patients with nerve root stimulation; 10 patients with spinal cord compression, and 17 patients had both nerve root stimulation and spinal cord compression symptoms. Conservative treatment were applied to 13 patients with neck and shoulder pain and nerve root stimulation, 5 cases of which were transferred to operation in case of poor effects, and Odom criteria were used to assess operational effects. Twenty-seven patients with spinal cord compression accepted operation from 1 to 27days after their trauma, 16 of which were operated in 5 days (early operational group with an JOA score of 11.3 +/- 2.8), other 11 cases were operated from 5 to 27 days (delayed operational group with an JOA score of 11.4 +/- 2.9 ), then functional assessment of spinal cord were assessed according to JOA criteria. RESULTS: Three patients who were transferred from conservative treatment recovered excellently according to Odom criteria and the other 2 were good at final followed-up. JOA score of early operational group increased from (11.3 +/- 2.8) to (15.3 +/- 1.8) one week after operation (P < 0.01), and (15.9 +/- 1.4) at final followed-up (P < 0.01). JOA score of delayed operational group increased from (11.4 +/- 2.9) to (14.0 +/- 2.6) one week after operation (P < 0.01), and (15.3 +/- 1.5) at final followed-up (P < 0.01). The recovery ratio of JOA score of early operational group were (74.6 +/- 16.8)% 1 week after operation,and increased to (85.6 +/- 13.6)% at final followed-up; while that of delayed operational group were (50.9 +/- 17.5)% and (68.2 +/- 21.5)%, and there were significant difference between early operational group and delayed operational group both at 1 week postoperation and final followup (P < 0.05). CONCLUSION: There are some difference in pathological segment and imaging manifestation between traumatic cervical disc herniation and cervical spondylosis. Early operation is favorable to the recovery of neurological function in patients with spinal cord compression. PMID- 23342796 TI - [Clinical result of forefoot correction by the first ray stabilization combined with resection of the lesser metatarsal head procedure for patient with rheumatoid arthritis]. AB - OBJECTIVE: To introduce the procedure of the 1st ray stabilization combined with resection of the lesser metatarsal heads for patient with severe forefoot deformity caused by rheumatoid arthritis (RA) and evaluate the short to mid-term clinical results. METHODS: From Oct. 2006 to Aug. 2010,97 patients (129 feet) aged from 36 to 67 years (average 54), with forefoot deformity caused by rheumatoid arthritis were reviwed. There were 88 males and 9 females,65 single lateral involved and 32 bilateral involved, the average duration of disease was 17 years (6 to 32 years). The 1st ray instability and lesser metatarsophalangeal (MTP) joint stiff dislocation were found in all cases. The first ray stabilization combined with resection of the lesser metatarsal head procedure were performed for all cases. The radiographic Hallux valgus angle (HVA) and intermetatarsal angle (IMA) were measurde and the JSSF (Japanese Society for Surgery of the Foot) score were evaluated before operation and every follow up. RESULTS: The average followed-up was 37 months (6 to 52 months) for all patients except 5 (7 feet) and 1 died for acute cardiac infarction 1 year after operation. The average JSSF score improved from (33.2 +/- 8.2) points preoperative to (67.3 +/- 3.1) points at final followed-up (P < 0.01); the average HVA was corrected from (50.0 +/- 11.8) degrees preoperative to (21.2 +/- 3.2) degrees at final follow up (P < 0.01); the average IMA was corrected from (15.5 +/- 3.6) degrees preoperative to (9.7 +/- 6.6) degrees at final follow up (P < 0.01). MTP joint nonunion was found in 4 feet. A radiographic high density mass was found in the 1st cuneiform bone during 8 to 11 months followed-up in 3 feet; delayed wound healing was happened in 9 feet; MTP joint infection was happened in 2 feet; tarsometatarsal joint infection was happened in 1 foot; lesser MTP joints deformity recurrence were found in 16 feet. CONCLUSION: The characters of forefoot with RA in later stage are the 1st ray deformity and instability compound with the lesser toes deformity. The 1st ray stability procedure which include the 1st MTP arthrodesis and the Lapidus procedure can correct the 1st ray deformities and rebuilt its stability. The lesser toes metatarsal head resection is effective in correct their deformity. This combined procedure is reliable. It is suitable for patients with severe Hallux valgus, increased IMA, tarsometatarsal joint instability and the lesser MTP joint stiff dislocation. PMID- 23342797 TI - [Clinical efficiency of computer-assisted pedicle screw placement versus conventional method: a meta-analysis]. AB - OBJECTIVE: To compare the clinical efficacy of computer-assisted pedicle screw placement and conventional placement in the treatment of spinal disease. METHODS: A systematic search of studies published between Jan. 1990 and Feb. 2012 was conducted using Medline, Embase, OVID, ScienceDirect and Cochrane Review databases. Randomized controlled trials (RCTs) and prospective controlled trials of comparing computer-assisted pedicle screw placement to conventional method performed at one center or multi-centers providing data on accuracy of placement and clinical effects were identified. Two study authors independently reviewed the 93 articles originally identified and selected 10 for analysis. Study title,demographic characteristics,number of pedicle screw,anatomical area and outcomes were extracted manually from all selected studies. RevMan 5.1 software was used for meta-analysis. RESULTS: Ten studies encompassing 2813 pedicle screws met the inclusion criteria. Overall,the result of meta-analysis indicated that there were significant differences between two groups in accuracy in placement of pedicle screw [OR = 2.58, 95% CI (1.18, 5.63)], insertion time [WMD = -2.15, 95% CI (-2.36, -1.94)]. However, there was only one study reported preparation time of pedicle screw of navigation group was longer than conventional group. No neurological complication in navigation group was reported. CONCLUSION: As a safety supplementary measure, computer navigation provide better accuracy in placement of pedicle screw and insertion time. The preparation time of pedicle screw may prolong due to the complexity of navigation system. Further reseach should include randomized controlled trials with well-planned methodology to limit bias. PMID- 23342798 TI - [Discerning the femoral neck anteversion (FNA) from the torsion angle on 3D CT]. AB - OBJECTIVE: To discern the differences between femoral neck anteversion (FNA) and torsion angle through 3D CT reconstruction. METHODS: From March 2010 to October 2010,30 healthy adult volunteers' femur were reconstructed by 3D CT, included 15 males and 15 females with an average age of (43.66 +/- 7.57) years old ranging from 25 to 65 years. Display the FNA and the torsion angle by image post processing, measuring torsion angle by "Center way" and direct measurement of FNA. RESULTS: FNA was the angle between the axle wire of femoral neck and the shape face of femoral,the angle were (13.326 +/- 6.085) degrees. Torsion angle was the angle between the macropinacoid of cross section of femoral neck and the shape face of femoral, the angle were(31.335 +/- 2.079) degrees. There was no significant difference in left and right femur. CONCLUSION: FNA is different from torsion angle. FNA is the angle between the line and the surface with the sharp angle towards the lower outside. The torsion angle is the angle between the two surfaces with the sharp angle towards the lower back. PMID- 23342799 TI - [Surgical treatment of thoracolumbar fractures using reduction and short-segment pedicle screw at the fracture level with the approach through para-vertebral muscles]. AB - OBJECTIVE: To evaluate the efficacy and clinical outcome of reduction and pedicle screws fixation at the fracture level with the approach through para-vertebral muscles in treating thoraeolumbar fractures. METHODS: From January 2007 to March 2010,27 patients with thoracolumbar fractures were treated with posterior open reduction and internal fixation with the approach through para-vertebral muscles. There were 19 males and 8 females with the mean age of 36.3 years old (ranged,21 to 57). According to Magerl type, type A2 was in 5 cases, A3 in 14, B1 in 3, B2 in 5. According to Frankel classification of spinal cord injury: grade D was in 6 cases and grade E in 21 cases. X-rays and CT scans were performed after operation. Cobb angle of the injured vertebral segment,the percentage of vertebral compression,and sagittal diameter stenosis rate of the injured spinal canal were observed by radiographic data. Neurological function was evaluated by the Frankel grade. RESULTS: All patients were followed up from 12 to 28 months with an average of 19.6 months. The percentage of vertebral compression, Cobb angle of the injured vertebral segment, spinal canal sagittal diameter stenosis rate were respectively corrected from (46.6 +/- 10.5)%, (18.3 +/- 7.2) degrees, (30.2 +/- 7.2)% to postoperative (5.2 +/- 3.7)%, (5.3 +/- 5.1) degrees, (6.3 +/- 4.2)% and (6.7 +/- 4.6)%, (7.1 +/- 3.1), (7.2 +/- 4.5)% at last follow-up. There were significant difference in above items between preoperation and postoperation (P < 0.05); and there was no significant difference in above items between postoperation and last follow-up (P > 0.05). In aspect of nerve function, 3 cases with Frankel grade D recovered to grade E. CONCLUSION: Using reduction and short segment pedicle screws fixation at the fracture level through para-vertebral muscles approach is an effective method in treating thoracolumbar fractures. The method has advantages of simple operation,easy establishing screw, short operative time, less blood loss, which can obtain good reduction and stable, reliable fixation after operation. PMID- 23342800 TI - [Surgical treatment of thoracolumbar single compression fracture by using in situ rod rotation reduction]. AB - OBJECTIVE: To evaluate the efficacy and clinical outcome of the treatment of thoracolumbar single compression fracture by using in situ rod rotation reduction and short segment pedicle screw at the fracture level. METHODS: From December 2008 to May 2010,12 cases of traumatic thoracolumbar single compression fracture (T11-L2) were treated, including 9 males and 3 females, with an average age of 35.8 years old (ranging from 24 to 52). There were 2 case with T11 fracture, 2 cases with T12, 6 cases with L1 and 2 cases with L2, without osteoporosis,pathological fractures or neurologic deficits. Radiographic data were collected preoperatively, 5 days postoperatively and at last follow-up (at least 12 months). Cobb's angle, vetebral compression ratio, internal fixation state were observed. RESULTS: All patients were followed up from 12 to 30 months postoperatively,with an average of 19 months. There was no pseudoarticulation and solid bone fusion was achieved in all cases. There were no complications such as loosening or rupturing of internal fixation and so on. Sagittal kyphotic Cobb angle was corrected from preoperative (25.8 +/- 9.4) degrees to postoperative (6.7 +/- 2.3) degrees and (6.9 +/- 2.6) degrees at last follow-up. The percentage of vertebral compression was corrected from preoperative (42.5 +/- 10.4)% to postoperative (7.5 +/- 3.9)% and (8.4 +/- 4.5)% at last follow-up.There was significant difference between the postoperative data and preoperative data (P < 0.05), while the difference was not significant between the postoperative data and the last follow-up (P > 0.05). CONCLUSION: The thoracolumbar single compression fracture can obtain and maintain a good restoration by using the technic of in situ rod rotation reduction and short segment pedicle screw at the fracture level. The technique should be highly recommended. PMID- 23342801 TI - [Construction of epithelia membrane protein 1 gene-deficient in human fetal nucleus pulposus cell model by lentivirus -mediated RNA interference]. AB - OBJECTIVE: To construct Epithelia Membrane Protein 1 gene-deficient in human fetal nucleus pulposus model by lentivirus-mediated RNA interference for building a platform for illustrating the biomechanisms role of EMP-1 during human intervertebral disc degeneration. METHODS: The lentivirus vector with shRNA targeting EMP-1 mRNA was transected into 293FT cells by liposome. Then the lentivirus supernatant was obtained and used for infecting human fetal nucleus pulposus. The expression of GFP was observed under fluorescence microscope after 48 h. The viral particles were collected at 72 h after transfection. The efficacy of gene interference was tested by Western blot and Real-time RT-PCR. Analysis the results of the fluorescent microscope scenes and get the average values of EMP-1/GAPDH by detected the interference efficiency of various interference DNA sequences with western blot and semi quantitative RT-PCR methods. RESULTS: The lentivirns with high titer were obtained and the EMP-1 gene deficient cell strains were obtained. Semi quantitative RT-PCR and Western blot proved the average values of EMP-1/GAPDH decreased from 0.46 to 0.32 and 0.5 to 0.25 (P < 0.01). CONCLUSION: Lentivirus packaging technology can be mastered skillfully. EMP-1 gene-deficient cell models are successfully established. PMID- 23342802 TI - [Effect of HSP70 on apoptotic of cartilage cells in knee osteoarthritis]. AB - OBJECTIVE: To investigate the expression and relationship between HSP70 and caspase-3 in knee osteoarthritis. METHODS: Forty adult SD rats were divided into experimental group and control group. Thirty rats in experimental group, anterior cruciate ligament transaction (ACLT) was cut off and partial meniscectomy of 1/3 inside incision were performed to reproduce knee osteoarthritis (KOA) model according to Hulth methos, and the other 10 rats was treated with nothing as control group. The rats were sent to the cage and free to move. At 1, 2 and 4 weeks later, the arthritis cartilage of femoral and tibial end were observed through immunohistochemistry staining and light microscope. Meanwhile, Mankin scale system was adopted for histomorphology evaluation. RESULTS: Changes of KOA such as hyperplastic synovium,erosion on the surface of cartilage and so on were found in experiment group, the expression of HSP70 was augmentation all the time, but the expression of caspase-3 was reduction 1 week later; no similar changes were found in control group. Mankin scale system showed that there were significant differences in the first week as compared with the second week and 4th week (both P < 0.01). CONCLUSION: Heat shock protein inhibit the apoptosis of cartilage cells and protect the cartilage cells in knee osteoarthritis, the conservative treatment for clinical provide objective scientific basis. PMID- 23342803 TI - [Experimental study on fresh meniscal allografts combined with osteochondral allografts transplantation]. AB - OBJECTIVE: To investigate the effect of fresh meniscal allografts combined with osteochondral allografts transplantation for treatment of osteoarthritis. METHODS: Thirty-six rabbits were used in the experiment and were randomly divided into 3 groups: in group A, the fresh medial meniscal allografts combined with osteochondral allografts from medial tibial plateau were implanted into medial articular meniscal and medial tibial plateau osteochondral defects; in group B,the fresh medial meniscal allografts were implanted into medial meniscal allografts defects; in group C, the freezing medial meniscal allografts were implanted into medial meniscal allografts defects. General observation, histology examination and glycosaminoglycan (GAG) examination in cartilage of medial tibial plateau were performed at the 4th, 8th and 12th week after operation. RESULTS: There were no significant differences in cellular counting and amount of GAG between group A and group B, but the cellular amount of group A was significantly more than that of group C at the 12th week. CONCLUSION: Fresh meniscal allografts combined with osteochondral allografts transplantation can repair meniscal and osteochondral defects. PMID- 23342804 TI - [Comparison of two approaches for the treatment of distal radius fractures]. AB - OBJECTIVE: To discuss the effective operative approach for the treatment of distal radius fractures. METHODS: From March 2003 to April 2010,107 patients with distal radius fractures suffered internal fixation with locking compression plate (LCP). There were 48 males and 59 females with an average age of 51.27 years (ranged, 23 to 79). Of them, with directed volar approach was in 55 cases and Henry approach was in 52 cases. Surgical feature, fractured exposure time, operative time, median nerve complication, repair rate of the musculus pronator quadratus were compared between the two groups. Gartland-Werley wrist score (GW score), range of motion of wrist joint, grasp force and imageology score were observed in two groups at the first year after operation. RESULTS: The average fractured exposure time in directed volar approach group and Henry approach group was (21.18 +/- 1.69) min and (12.56 +/- 1.35) min,operative time was (89.90 +/- 4.86) min and (61.58 +/- 4.37) min, postoperative median nerve irritation rate was 34.55% and 5.77%, and repair rate of the musculus pronator quadratus was 52.73% and 100%,respectively;there was statistical difference between two groups (P < 0.01). At the one-year after operation, GW score was 3.25 +/- 2.29,and with rate of excellent and good of 90.91% in directed volar approach group;in Henry approach group that was 2.92 +/- 2.13 and 92.31%, respectively; there was no statistical difference between two groups (P > 0.05). There was no statistical difference in range of motion of wrist joint, grasp force and imageology score between two groups (P > 0.05). CONCLUSION: Henry approach can obtain the same operative result compared with directed volar approach in treating distal radius fractures. Henry approach has advantage of simple anatomy,easy operation,better repair rate of the the musculus pronator quadratus and lower postoperative median nerve complication,which should be used preferentially to treat distal radius fractures. PMID- 23342805 TI - [Treatment of refractory sinus in the lower leg with modified VSD technique]. AB - OBJECTIVE: To investigate the effects of modified vacuum sealing drainage (VSD) technique in treating refractory sinus in the lower leg. METHODS: From January 2010 to December 2011, 11 patients with refractory sinus in the lower leg, including 7 males and 4 females, with an average age of 34.5 years (ranged,23 to 56). These patients were treated with modified VSD technique after thorough cleaning sinus and continuous washing. After 14 to 21 days of treatment, removed VSD and re-debrided the sinus and sutured wound. RESULTS: Infections got control after operation, sinus in the lower leg healed. All patients were followed up from 6 to 14 months with an average of 10 months, no recidivations were found. CONCLUSION: Modified VSD technique is an effective method in the treatment of stubborn sinus in the lower leg. PMID- 23342806 TI - [A report of 4 cases about gluteal heterotopic ossification caused by injection]. AB - OBJECTIVE: To study the pathogenesis and treatment of gluteal heterotopic ossification caused by injection. METHODS: From April 2006 to May 2011, 4 old female patients with gluteal heterotopic ossification caused by injection were treated by resection. The average age was 71 years old ranging from 67 to 76. The illness were bilateral,the clinical character was pain and hard nodules in the both hip. The X-ray, CT and pathology matched the diagnosis of heterotopic ossification. Two of them were treated by totally removing the ossified tissues, and loosing the spastic and adhesive soft tissues. The other two were treated with local resection and soft-tissue lysis. RESULTS: The wound of all patients healed well, and there were no complication. All patients were followed-up from 2 to 64 months(averaged 26 months). There were no lump and pain in the location of surgical resection. CONCLUSION: Gluteal heterotopic ossification caused by injection is the drug reaction produced by injecting benzyl alcohol or other drugs,and happens in adults. The key for the treatment is to remove part or all of the painful lump,and loose the local fascia and other soft tissues of the gluteal muscles. PMID- 23342807 TI - [Analysis of curative effect of the intervertebral space lavaging for the treatment of incisions deep infections at early stage after posterior lumber internal fixation]. AB - OBJECTIVE: To explore the reason,diagnose outline,therapeutic tool of the incisions deep infections at early stage after lumber internal fixation. METHODS: From January 2001 to December 2011, 10 patients with incisions deep infections at the early stage after the posterior lumber internal fixation were treated with intervertebral space lavaging. There were 1 male and 9 females with an average age of 63 years, and an average infection started at the 6th day after operation. The main clinical features including backleg pain aggravating, fervescence, fresh seepage from the wound, and blood inflammatory index increased, etc. According to whether the wound could heal at the first treatment stage as a evaluation standard of curative effect. RESULTS: Ten cases were followed up with an average period of 17 months. The wounds of 9 cases healed at the first stage and no recurrence and complications were found. One case underwent debridgement of many times with the therapic period of 7 months,at last,after taking out the vertebral pedicle bolt,the wound healed,and no recurrence after follow-up of 18 months. CONCLUSION: The deep wound infections after the lumber internal fixation should receive intervertebral space lavaging as soon as possible. The method can finally remain internal fixations and obtain satisfactory effects, but avoiding too much tissue cutting and tube setting in the deep intervertebral space are the keys to the successful fixation. PMID- 23342808 TI - [Bone cement injection into tibial condyle for the prevention of degenerative osteoarthritis]. AB - OBJECTIVE: To observe therapeutic effects of preventing degenerative osteoarthritis by injecting bone cement into tibial condyle. METHODS: From January 2006 to Junary 2009, 24 patients with degenerative osteoarthritis were treated by injecting bone cement into tibial condyle, including 10 males and 14 females, ranging in age from 46 to 65 years, with an average of 50 years. The mean course of duation was 1 year. HSS scoring system was used to evaluate therapeutic effects preoperatively and one year after follow-up. RESULTS: All patients were followed up over 2 years. HSS score after two years follow-up was 66.65 +/- 6.30, which was higher than that of preoperative 35.70 +/- 4.80. There was no significant difference between preoperation and one year after follow-up in anatomy angle of tibia. CONCLUSION: Bone cement injection into tibial condyle can prevent degenerative osteoarthritis and varus knee. PMID- 23342809 TI - [Manipulative reduction and lateral percutaneous K-wire fixation for treatment of supracondylar humerus fractures in 128 children]. AB - OBJECTIVE: To explore the clinical effect of manipulative reduction and lateral percutaneous K-wire fixation on supracondylar humerus fractures. METHODS: From Feb. 2004 to Jun. 2010,128 cases of supracondylar humeros fractures in children (96 boys and 32 girls) were treated by manipulative reduction and lateral percutaneous K-wire fixation. The average age of the children was 8 years old ranging from 2 to 15 years. Among them, 112 cases were extension fractures, 16 were flexion type; 102 cases belonged to ulnar deviation, and 26 cases belonged to radial deviation. After treatment, the elbow flexion range and carrying angle of the children were measured under the Flynn evaluation standard while considering the postoperative complications status to analyze the clinical effect on manipulative reduction and lateral percutaneous K-wire fixation. RESULTS: All these children were followed up from 2 to 36 months (16 months on average). According to Flynn evaluation standard,the result were excellent in 116 children (90.6% of the total patients), good in 11 (8.6%), fair in 1 (0.8%). No infection, no ischemic muscular atrophy and no nerve damage had been found during the treatment. CONCLUSION: The manipulative reduction and lateral percutaneous K-wire fixation of supracondylar humerus fractures in children has small wound, is stable and reliable, easy to be operated, safe and effective and low cost. What's more, it can also avoid the complication caused by conservative treatment and operation. It is a good treatment of supracondylar humerus fractures in children. PMID- 23342810 TI - [Convolution-based restoration approach to the double fractures of the radius and ulna]. PMID- 23342811 TI - [Investigation of articular cavity medicating for treatment of knee osteoarthritis]. AB - Osteoarthritis (OA) is a common chronic progressing disease in the elderly. In current there are many methods of drug treatment for knee osteoarthritis, the intra-articular injection belongs to local application, can direct effect on arthritis, is the most used and most effective methods in osteoarthritis treatment. A single medication may exist that anti-inflammatory effects produce a marked effect but articular cartilage injury is induced, or articular cartilage repairing are promoted but anti-inflammatory effects is not ideal. Therefore,the best method of treatment should be a comprehensive analysis of articular structure, function and possible pathogenic factor to understand the expectations of level of recovery and use in patients to design an individualized treatment plan. PMID- 23342812 TI - [Safty action of heat shock protein 27 in reperfusion after spinal marrow ischemia]. AB - Heat shock protein 27 belongs to the heat shock protein family in the small molecular weight family. This review collected a number of literature to analyze the expression meaning and mechanism of HSP27,expounded HSP27 with inhibition of NO production, maintenance of cell protein stability and accelerated cell damage repair function. At the same time, HSP27 also has a resistance to apoptosis, protecting mitochondria, inhibiting activation of nuclear factor and other related functions. The heat shock protein 27 has protection in spinal cord ischemia-reperfusion. PMID- 23342813 TI - A preclinical medical student curriculum to introduce health disparities and cultivate culturally responsive care. AB - PURPOSE: To evaluate the efficacy of a newly reformed curriculum for teaching culturally responsive care and to build awareness of health and health care disparities in first-year medical students. Secondary outcomes were to determine if a progressive approach to teaching this content would improve not only knowledge of vulnerable groups but also awareness of inherent personal biases and cultural assumptions, which contribute to inequitable care. PROCEDURES: Students enrolled in Social and Cultural Issues in Health Care from October 2009 through December 2009, who agreed to participate, completed pretests and posttests that assessed their awareness and knowledge of culturally responsive care and health disparities. FINDINGS: In 3 of the questions assessing cultural awareness, the participants improved significantly after the course compared to before the course. Participants also significantly improved in 6 of the 7 knowledge-based questions. CONCLUSIONS: Our findings demonstrate that this innovative curriculum was successful in improving students' knowledge of vulnerable populations and health disparities. Our progressive curricular approach also successfully increased participant awareness of health disparities by requiring students to assess the socioeconomic and environmental factors of inequitable care. Additionally, it emphasized a process of continuous self-appraisal in delivering culturally responsive care. PMID- 23342814 TI - Engaging minority high school students as health disparities interns: findings and policy implications of a summer youth pipeline program. AB - PURPOSE: The purpose of this paper was to describe the development and implementation of a health disparities summer internship program for minority high school students that was created to increase their knowledge of health disparities, provide hands-on training in community-engaged research, support their efforts to advocate for policy change, and further encourage youth to pursue careers in the health professions. PROCEDURES: Fifty-one high school students who were enrolled in a well-established, science-enrichment after-school program in Brooklyn, New York, participated in a 4-week summer internship program. Students conducted a literature review, focus groups/interviews, geographic mapping or survey development that focused on reducing health disparities at 1 of 15 partnering CBOs. FINDINGS: Overall, student interns gained an increase in knowledge of racial/ethnic health disparities. There was a 36.2% increase in students expressing an interest in pursuing careers in minority health post program. The majority of the participating CBOs were able to utilize the results of the student-led research projects for their programs. In addition, research conclusions and policy recommendations based on the students' projects were given to local elected officials. CONCLUSIONS: As demonstrated by our program, community-academic partnerships can provide educational opportunities to strengthen the academic pipeline for students of color interested in health careers and health disparities research. PMID- 23342816 TI - Racial/Ethnic composition of study participants in FDA-approved oncology new molecular entities, 2006-2008. AB - The US Food and Drug Administration (FDA) has an ongoing interest in identifying the race/ethnicity of clinical trial participants to ensure they are representative of the people who will use the products once they are approved, and differences in response to medical products have already been observed in racial/ethnic subgroups of the US population. As a result, we reviewed the racial/ethnic composition of study participants in clinical trials of FDA approved oncology products. Oncology products were chosen because of the disparate incidence and impact of cancer in racial/ethnic communities. New Drug and Biologics Licensing Application databases were searched for new molecular entity (NME) approvals for oncologic treatment from January 1, 2006, through December 31, 2008. We then reviewed NME applications for the pivotal Phase II and III trials used for approval decisions. We then compared the racial/ethnic composition results from the recent trials with those conducted earlier. We also assessed FDA-approved labeling to determine the extent to which race-based findings were included. US participants averaged 20.3% (range, 11%-97%) of the total participants in the studies reviewed. A comparison of the racial/ ethnic composition showed the participation of whites and blacks or African Americans have decreased, while that of Latinos, Asians, and Native Hawaiians/Pacific Islanders has increased. The results suggest better attention to compliance with collection and reporting, as the percentage of US study participants whose race and/or ethnicity could not be determined decreased from 31% to < 1%. With respect to product labeling, the current study found 6 (60%) included race-based findings. PMID- 23342815 TI - Crohn's disease in Caucasians and African Americans, as defined by clinical predictors and single nucleotide polymorphisms. AB - OBJECTIVES: To compare three aspects of Crohn's disease (CD) between African Americans and Caucasians: (1) demographic data and environmental factors affecting CD susceptibility, (2) disease presentation and clinical course, and (3) genetic susceptibility via the use of single nucleotide polymorphism (SNP) data for inflammatory bowel disease (IBD) susceptibility loci. METHODS: Clinical data and peripheral blood were obtained from 1032 patients (554 CD patients and 478 controls) derived from a clinically well-defined university-based medical and surgical digestive disease practice and included those who were diagnosed with IBD. Genomic DNA was extracted and polymerase chain reaction (PCR) amplification and genotyping were performed for 11 SNPs, including the NOD2, IL-23r, OCTN 1, and the IGR gene variants. RESULTS: A total of 554 patients with CD were included in this study: 53 African Americans (10%), 485 Caucasians (87%), and 15 of other races (3%). The strongest demographic predictor of CD in African American patients was a family history of IBD. Ileocolic disease (L3) was the most common site involved in both African Americans and Caucasians, while the penetrating phenotype (B3) was the most common CD disease behavior in both races. Genotype association analysis showed a significant association between 2 IL23r gene SNPs and CD susceptibility in African Americans (p = .016 and .028, respectively). CONCLUSION: We believe this study is the first to report on genotype-phenotype associations in African American CD patients and compare findings to Caucasian CD patients within the same geographic area. We found no association between NOD2 gene SNPs and CD susceptibility in African Americans patients (p > .05). PMID- 23342817 TI - Heritability of arthritis in African American twins: findings from the Carolina African American Twins Study of Aging. AB - PURPOSE: To determine the genetic and environmental influences exerted on arthritis by measuring the distribution of self-reported arthritis diagnoses among monozygotic (MZ) and dizygotic (DZ) African American twins. METHODS: A cross-sectional study was conducted on 97 MZ and 113 DZ twin pairs recruited into the Carolina African American Twin Study of Aging (CAATSA). The sample had a mean age of 47 +/- 13.9 years. A twin design was used to determine correlations in arthritis diagnosis for MZ and DZ twins and to estimate the contribution of genes and environment to the variation in an arthritis diagnosis. RESULTS: The concordance rate for being diagnosed with arthritis was 42% for MZ twins, and 20% for DZ twins, resulting in a 2.1:1 ratio of MZ to DZ concordance. These results indicate a significant proportion of individual variability was due to genetic factors (43%) on an arthritis diagnosis as well as 57% of variance due to nonshared environmental influences. CONCLUSION: This research suggests that while there are genetic influences on arthritis diagnosis, environmental factors, such as infections, dietary factors, urbanization, and pollutants, also play a role in accounting for variability in the diagnosis and treatment of arthritis among diverse populations. PMID- 23342818 TI - Beliefs and perception of risks of HIV among women that have never been tested for HIV in the United States. AB - PURPOSE: To assess women's attitudes, beliefs, characteristics, the perception of risks, and their relationships with not utilizing human immunodeficiency virus (HIV) testing services. METHODS: This study is a retrospective study and secondary data analysis of the 2006 National Health Interview Survey. Parametric testing using univariate, bivariate, and multivariate analyses was performed to examine perception of HIV acquisition and the relationship with not utilizing HIV testing services among women in the United States. RESULTS: More than half of the women in this study had never been tested for HIV (52.26%). In the multivariate analysis, using SAS callable SUDAAN, women who had not been tested for HIV that believed they had no risk of getting HIV were more likely to have never been married (odds ratio [OR], 0.37; 95% CI, 0.31-28.73; p = .0013). In addition, women who had never been tested for HIV that believed they had no risk of getting HIV were more likely to have less than a high school diploma (OR, 0.35; 95% CI, 0.15-0.78; p = .0022). CONCLUSION: Findings from this study can lend themselves to the development of more efficient and sustainable interventions to prevent HIV infection and decrease high-risk behaviors among more susceptible populations and for the development of HIV testing policy. PMID- 23342819 TI - Sickle cell disease patients' perceptions of emergency department pain management. AB - Patients with sickle cell disease (SCD) experience painful crises that often require admission to the emergency department (ED) for pain management. Factors such as ED overcrowding and negative perception and stigmatization of SCD may impact patients' perceptions of the quality of pain management in the ED. Data from a multisite prospective cohort study was assessed to determine whether demographic (age and sex), clinical (time to administration of initial analgesia, number of analgesic doses, discharge disposition, and clinical site), or interpersonal factors (separately measured perceptions of being treated with trust and respect by ED triage nurses, nurses, and physicians) were associated with patient ratings of their pain management in the ED. Patients were adults with SCD seen at 3 EDs (2 urban and 1 rural). Demographic and clinical information was derived from medical record review; interpersonal and ED pain management ratings were derived from interviews conducted 1 week post ED visit. A total of 209 interviews by 98 patients were analyzed. Results indicated significant differences among the ED sites on the demographic, clinical, and interpersonal factors. Overall, patients reported being treated with trust and respect by ED clinicians. Adjusted logistic regression analyses indicated that ED clinical site 1 (odds ratio [OR], 10.42; 95% confidence interval [Cl], 1.44-7.36) and being treated with trust and respect by the ED physician (OR, 25.53; 95% CI, 2.07-314.96) predicted good ED pain management ratings. Interpersonal health care experiences may be an important indicator of patient satisfaction and quality of care received by patients with SCD in the ED. PMID- 23342820 TI - Circumcision in the United States: where are we? AB - Circumcision is one of the most common surgical procedures performed on males in the United States. Ethical considerations of the procedure have been considered for many years and, recently, research on the topic has shed more light on the debate. The purpose of this study was to review the history and emergence, current demographics, and practices of male circumcision, specifically, nonreligious, nonmedically indicated routine neonatal circumcision. A review of the current literature was conducted using PubMed and current practices from guidelines of major professional societies. Physicians should consider the various ethical concerns and provide the patient's guardians with unbiased counsel. There is a lack of evidence both in favor of and against recommending routine neonatal circumcisions in the United States. The question remains whether we should continue unwarranted male circumcisions, especially when the major tenet of medical ethics is "do no harm." PMID- 23342821 TI - Kikuchi-Fugimoto's disease in sickle cell disease: report of 2 cases. AB - Kikuchi-Fugimoto's Disease (KFD), also known as histiocytic necrotizing lymphadenitis, is most frequently seen in young women and has been associated with autoimmune disorders such as polymyositis and systemic lupus erythematosus. It is generally a self-limiting disease with recovery time ranging from weeks to months. A typical presentation of KFD includes painful cervical lymphadenopathy, usually consisting of unilateral involvement of the posterior cervical chain. To date, this condition has not been described in patients with sickle cell disease. We present 2 cases of KFD, 1 in a patient with sickle beta(o)-thalassemia (Sbeta(o)thal) and 1 in a patient with sickle cell anemia with hereditary persistence of fetal hemoglobin (HbS-HPFH). Both patients were young-adult African American females who presented with fever and unilateral tender cervical lymphadenopathy. Extensive infectious disease testing, including cultures and viral serologies, were all negative. Imaging was negative for abscesses. The first patient had a preceding history of benign carcinoid tumor and idiopathic thrombocytopenic purpura. The second patient had no history of autoimmune syndromes but was on hydroxyurea therapy at the time of her presentation; the first had never taken hydroxyurea. Treatment strategies included prednisone therapy in the first case and watchful monitoring in the second. Recovery time was approximately 2 months for each patient. Both developed thyroid disease subsequent to their episode of KFD. Currently, both patients are asymptomatic with no recurrence of KFD or active autoimmune disease. PMID- 23342822 TI - Is sickle cell disease a hematologic disorder? PMID- 23342823 TI - Major depressive disorder in the African American population. PMID- 23342824 TI - The neurocognitive effects of aripiprazole compared with risperidone in the treatment of schizophrenia. AB - Aripiprazole is a D2 and D3 receptor partial agonist that is unlike other second generation antipsychotics. The effectiveness of aripiprazole with regard to neurocognitive function and its adverse effects is unclear. The present study evaluates the comparative efficacy, effects on neurocognitive function, and adverse effects of aripiprazole and risperidone in the treatment of hospitalized patients with schizophrenia. This double-blind, cross-over study included 23 patients with schizophrenia who were randomly assigned to be treated first with either aripiprazole or risperidone. After eight weeks on one medication, the patients were switched to the other medication for eight weeks. The patient assessment included the Positive and Negative Syndrome Scale (PANSS), neurocognitive assessments, and adverse events including extrapyramidal symptoms, vital signs, electrocardiogram, and clinical laboratory tests. The study findings indicated that psychopathology assessed with the PANSS, extrapyramidal symptoms and other adverse effects did not differ between aripiprazole and risperidone for the subjects remaining in treatment. In the neurocognitive assessments, the score for disinhibition with aripiprazole was significantly lower than with risperidone (p < 0.05). In addition, serum prolactin levels were significantly lower with aripiprazole (p < 0.001). The treatment drop-out rate was higher for patients receiving aripiprazole than risperidone. In comparing aripiprazole and risperidone, risperidone is better from the viewpoint of treatment continuation. On the other hand, some adverse effects, such as hyperprolactinemia and disinhibition, are less severe with aripiprazole. Thus, for certain applications, aripiprazole may be a beneficial new treatment option for schizophrenia. PMID- 23342825 TI - Changes in cardiovascular risk factors over a 24-year follow-up period: a Japanese pediatric cohort study. AB - This study examined changes in body mass index (BMI), fasting blood sugar (FBS), total cholesterol (TC) and HDL-cholesterol (HDL-C) levels over a 24-year follow up period in a pediatric cohort. An appropriate starting age for intervention to prevent cardiovascular diseases is still unclear. The subjects were 655 children, aged 10-12. A follow-up survey was conducted when the subjects reached ages 13 15, 16-18, and 35-45, respectively, and height, weight, and blood tests including FBS, TC and HDL-C were examined. Forty (6%) of these subjects participated. BMI at ages 35-45 were significantly higher than those at ages 10-12 (p < 0.0001), 13 15 (p < 0.001), and 16-18 (p < 0.001). TC levels at ages 35-45 were significantly higher than at ages 10-12 (p < 0.0001), 13-15 (p < 0.0001), and 16-18 (p < 0.0001). BMI at the end of the follow-up (ages 35-45) had a significant correlation with BMI at ages 13-15 (R = 0.38, p = 0.041) and 16-18 (R = 0.41, p = 0.049). TC and HDL-C values at the end of the follow-up had a significant correlation with those at ages 10-12 (R = 0.55, p = 0.0004; R = 0.55, p = 0.016), 13-15 (R = 0.35, p = 0.045; R = 0.42, p = 0.015), and 16-18 (R = 0.47, p = 0.019; R = 0.44, p = 0.028). These results may suggest that intervention for children in Japan with cardiovascular risk factors should be initiated in the early years of life. PMID- 23342826 TI - Gender differences in D-aspartic acid content in skull bone. AB - In forensic medicine, the personal identification of cadavers is one of the most important tasks. One method of estimating age at death relies on the high correlation between racemization rates in teeth and actual age, and this method has been applied successfully in forensic odontology for several years. In this study, we attempt to facilitate the analysis of racemized amino acids and examine the determination of age at death on the basis of the extent of aspartic acid (Asp) racemization in skull bones. The specimens were obtained from 61 human skull bones (19 females and 42 males) that underwent judicial autopsy from October 2010 to May 2012. The amount of D-Asp and L-Asp, total protein, osteocalcin, and collagen I in the skull bones was measured. Logistic regression analysis was performed for age, sex, and each measured protein. The amount of D Asp in the female skull bones was significantly different from that in the male skull bones (p = 0.021), whereas the amount of L-Asp was similar. Thus, our study indicates that the amount of D-Asp in skull bones is different between the sexes. PMID- 23342827 TI - An ischemic stroke patient with free floating thrombus in carotid artery, successfully treated by open carotid thrombectomy: a first case report in Nepal. AB - Free floating thrombus in the carotid artery is a well-known phenomenon, though relatively rare. We present a case in which we performed open surgery and achieved successful retrieval of the thrombus. A 40 year-old male patient presented with ischemic stroke and mild left hemiparesis. Computerized tomography and magnetic resonance imaging showed infarction in the right parieto-occipital area. Carotid Doppler study showed carotid stenosis on the right side. Further investigation with CT angiography of the neck vessels confirmed significant carotid artery occlusion with a free-floating thrombus in the internal carotid artery. Carotid endarterectomy was planned under EEG monitoring. The right carotid artery was exposed with a vertical incision along the medial margin of the sternocleido-mastoid muscle. The carotid artery was opened and, as expected, showed a soft, mobile thrombus. Thus thrombectomy was planned. A 2 Fr fogarty catheter was introduced distal to the thrombus, the balloon was inflated and pulled back gently, which removed the thrombus completely. There was no postoperative complication and the patient is fine at 1 year follow-up. PMID- 23342828 TI - Arterial spin-labeling imaging at 3-T in dural arteriovenous fistulas of cavernous sinus before and after endovascular treatment. AB - A 72-year-old man presented with chemosis and ophthalmoplegia due to dural arteriovenous fistulas (DAVF) of the cavernous sinus (CS). Preoperative arterial spin-labeling (ASL) image showed visible vein in the bilateral superior ophthalmic vein (SOV). Endovascular transvenous embolization of the shunting points of the CS-DAVF was performed, and the postoperative angiogram showed complete obliteration of the CS-DAVF. Postoperative ASL showed no visible vein in the bilateral SOV. ASL in CS-DAVF was proved to have shown retrograde venous drainage from the CS-DAVF by comparing ASL before and after treatment. PMID- 23342829 TI - "Longitudinal study on physical fitness parameters influencing bone mineral density reduction in middle-aged and elderly women: bone mineral density in the lumbar spine, femoral neck, and femur". PMID- 23342830 TI - "Reaching out to new mums is a clever move". PMID- 23342831 TI - Nurses not only ones at "fault". PMID- 23342832 TI - "New institute will boost research and quality in health visiting". PMID- 23342833 TI - "Caring is a fundamental part of the job, not an optional extra". PMID- 23342834 TI - Caring around the Clock: rounding in practice. AB - A large acute trust in the East Midlands looked to the US to inform its implementation of hourly rounding, otherwise known as intentional rounding. A combination of transformational leadership and meaningful interactions form the basis of a new approach to rounding--Caring around the Clock. The trust piloted the concept on 10 wards with results showing a 32% reduction in call lights. The successful change in practice required an investment in staff education to equip staff with the necessary skills. The trust is currently rolling out Caring around Hourly rounding can reducethe Clock to 79 inpatient wards. PMID- 23342835 TI - Safe usage of fat-based emulsion supplements. PMID- 23342836 TI - Maintaining skin health in older people. AB - The article examines general skin care for older people, skin barrier function and the skin changes associated with the ageing process. Skin assessment and the use of washing products and emollients are discussed. Methods by which older people and nursing staff can help to promote and improve skin health are identified. PMID- 23342837 TI - Nursing management Sweet's syndrome. AB - Sweet's syndrome (SS) is an uncommon inflammatory condition. The main signs and symptoms are fever, malaise and skin lesions. Misdiagnosis is common and biopsy is needed to detect characteristic physiological changes in the upper dermis. Standard treatment is oral corticosteroids but SS can be difficult to manage, with symptoms recurring in at least 30% of cases. Nurses can offer advice and support for patients and their families, and show them where to find accurate information. PMID- 23342838 TI - Environments and autistic spectrum conditions. AB - Sensory differences for people with autistic spectrum conditions (ASC) have considerable impacts on their experiences and ability to function. In hospitals and other care settings, it may be difficult for this group to feel safe and comfortable. This article highlights the sensory differences and needs of people with ASC, and the impact that failure to understand these differences can have on them and those around them. It outlines nurses' roles in assessment, planning, intervention and management of the environment. PMID- 23342839 TI - More than just care in the air. PMID- 23342840 TI - Making a difference in infection control. PMID- 23342841 TI - Negative image of mental illness. PMID- 23342842 TI - Wake me up when it's over. PMID- 23342843 TI - Marriage bill not a union issue. PMID- 23342844 TI - NZNO not a moral mouthpiece. PMID- 23342845 TI - Choices for terminally ill patients. PMID- 23342846 TI - Organising 50-year class reunion. PMID- 23342847 TI - NKVD? No NZNO! Stalin lives, NIC ecstatic! PMID- 23342848 TI - White paper overlooks vital nursing role. PMID- 23342849 TI - Caregivers appreciate study days' clinical content. PMID- 23342850 TI - HPCA Act review pointing to deregulation. PMID- 23342851 TI - Not enough jobs for new graduates. PMID- 23342852 TI - Nurses urged to register for disaster team. PMID- 23342853 TI - Profiling the presidental candidates. PMID- 23342854 TI - 'Let's move beyond the hand-washing image'. PMID- 23342855 TI - Antibiotics and the rise of superbugs. PMID- 23342856 TI - Sharps injuries are a significant occupational health risk. PMID- 23342857 TI - Solving an infection control mystery. PMID- 23342858 TI - Unregulated staff administering medications. PMID- 23342859 TI - Improving safety in health care. PMID- 23342860 TI - Improving paediatric neurosurgery care. PMID- 23342861 TI - Perioperative nurses celebrate their history. PMID- 23342862 TI - Nurse practitioners urged to shape the future. PMID- 23342863 TI - Controlling infection. PMID- 23342864 TI - Improving hand hygiene rates. PMID- 23342865 TI - Improving New Zealand's health and safety record. PMID- 23342866 TI - Caring and civility go hand-in-hand. PMID- 23342867 TI - Empowering our patients: a vital partnership for nurses and health literacy. PMID- 23342868 TI - [Academic neurology: between science and clinical research]. PMID- 23342869 TI - [Image of the month: rash of H1N1 influenza]. PMID- 23342870 TI - [A left intraventricular mass]. AB - We report the case of a 29-years-old male presenting with a large mass inserted at the hypokinetic apex of the left ventricle. Without any early regression under anticoagulant therapy and taking into account recent neurological manifestations, surgical extraction was decided. The mass corresponded to a chronic thrombus lying on a non-transmural myocardial necrosis. This case gives us the opportunity to review all causes of intracardiac masses. PMID- 23342871 TI - [Onset of Crohn's disease induced by etanercept therapy: a case report]. AB - A 27-year-old-man was diagnosed as having ankylosing spondylitis (AS) in 2003 and received a treatment by etanercept. Typical symptoms of active Crohn's disease (CD) developed 11 months after initiation of etanercept therapy. At colonoscopy, lesions compatible with CD were found endoscopically and histologically. Etanercept was interrupted and CD responded to standard treatment. A switch to infliximab was decided to treat a flare up ofAS. New onset CD may be considered an immune mediated injury induced by etanercept, but the causative role of the latter has not been demonstrated at this stage. PMID- 23342872 TI - [Management of hyperglycaemia in type 2 diabetes: a patient-centered approach]. AB - The pharmacological therapy of type 2 diabetes has become increasingly complex and the goals are now more diverse and, in general, more stringent. The glycaemic target (glycated haemoglobin or HbA1c) and the medications to be prescribed to reach it should be selected according to the individual characteristics of the patient and, if possible, in agreement with him/her. The most relevant criteria to be taken into account are the glucose-lowering efficacy, the risk of hypoglycaemia, the effect on body weight, the side effects and the costs. We summarize here the strategy proposed in the joint "position statement" published in 2012 by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). We will more particularly focus our attention on the practical aspects useful for the clinician. PMID- 23342873 TI - [Presentation of ELISA: a new triage algorithm suitable for emergency department]. AB - Emergency departments are frequently overcrowded due to the imbalance between need and availability of care. It results that influx patients should be regulated by using a triage tool located at the entrance area. This process has been in development for almost 15 years.We propose a new algorithm of triage (ELISA or Liege Scale of severity index at admission) based on a five-score level of emergency from U1 (emergent) to U5 (non urgent). Such a stratification of the state of emergency is associated with a time-delay for the first medical contact (immediate to 120 min) and a corresponding track for providing optimal care (emergency care unit, B sector or bed, A sector or ambulatory and waiting room) which together fit the sorting for the right patient to the right resources in the right place at the right time. Our algorithm has a confident efficiency as evidenced by the comparison between initial score of emergency and patient's follow up (intensive care, hospital recovery and discharge). PMID- 23342874 TI - [Lynch syndrome and microsatellite instability: a review]. AB - Microsatellite instability (MSI) phenotype occurs in approximately 15 to 24% of colorectal cancer (CRC) patients and may be sporadic or hereditary. It reflects a mutator phenotype in the tumor due to a lack of mismatch repair system. MSI is indeed one of the characteristics of CRCs occurring in Lynch syndrome and some sporadic cases. CRCs with MSI have a better prognosis than CRCs with microsatellite stability (MSS). This is explained partly by a more important anti tumor immune response and by apoptosis of tumor cells in which mutations accumulate. However, in some retrospective studies, microsatellite instability in stage II CRCs was associated with no benefit to or even a deleterious effect of 5 FU alone based adjuvant therapy. Nevertheless, results obtained in stage III CRCs with FOLFOX type adjuvant chemotherapy remain favorable in retrospective studies. PMID- 23342875 TI - [Hemolytic uremic syndrome induced by gemcitabine. A poorly recognized complication?]. AB - This report is concerned with the development of an hemolytic uremic syndrome (HUS) in 6 patients (3 males, 3 females, aged 53 to 73) suffering from an advanced cancer and treated by protracted (>= 4 months) infusions of gemcitabine. Over 4 to 14 months, the patients received 13-34 infusions delivering a cumulative dose oscillating between 9 and 29 g/m2. A progressive alteration of renal function preceeded the acute syndrome. After interruption of gemcitabine and symptomatic treatment, the evolution of haemolytic anemia was generally favourable. This was not the case for renal dysfunction: 2 complete and 1 partial resolution of renal insufficiency were noted, but 1 case required chronic dialysis. Based on the authors experience, the frequency of an HUS complication after protracted gemcitabine treatment could be as high as 2.7 %. PMID- 23342876 TI - [Early referral of first line patients suspected of axial spondyloarthritis: the Belgian results of the RADAR study]. AB - Currently, there is a 5 to 7 years gap between the first symptoms and the diagnosis of ankylosing spondylitis. A better patient referral might reduce this gap and accelerate the adequate treatment implementation. The study objective was to compare 2 referral strategies used in first line. In Belgium, 208 referral physicians assigned to 16 rheumatology centres were randomized to refer chronic back pain patients (with onset <45 years) using 1 of the 2 referral strategies: Strategy 1 :1 of 3 criteria (inflammatory back pain, HLA-B27, sacroiliitis on imaging); or Strategy 2: 2 of6 criteria (IBP inflammatory back pain, HLA-B27, sacroiliitis, family history, good response to NSAIDs, extra-articular manifestations). Among the 141 referred patients with strategy 1 and 2, 26.0 and 36.9% respectively were diagnosed with Axial Spondylarthritis (SpA). Inflammatory back pain, sacroiliitis and good respond to NSAIDs were the most frequently used criteria (92.9 %, 36.2 % and 33.3% respectively). This study emphasizes the high prevalence of undiagnosed axial SpA in patients with chronic back pain and stressed the necessity to increase awareness of the disease. PMID- 23342877 TI - [Raynaud's phenomenon]. AB - Raynaud's phenomenon is a vascular acrosyndrome caused by a variety of diseases. There is a distinction between the idiopathic Raynaud's disease, the secondary types and the suspicious idiopathic Raynaud's phenomenon. PMID- 23342878 TI - Assessment of frequency of regression and progression of mild cervical neoplasia- LGSIL in women with positive high-risk HPV DNA test result. AB - OBJECTIVES: Assessment of frequency of regression and progression of mild cervical neoplasia in women positive for types of HPV DNA of high oncogenic potential. MATERIALS AND METHODS: 111 women were studied. One-year-long observation of patients included cervical cytology conducted every three months, and colposcopy conducted every six months. After a period of 12 months all women were evaluated with colposcopy and directed biopsies of abnormal cervical tissue. RESULTS: This study confirms the significant effect of age on both regression and progression of low-grade cervical intraepithelial neoplasia. CONCLUSIONS: In the age group below 26 years, complete regression of LGSIL occurs significantly more frequently than in older women. Whereas in the over 36 age group, progression to HGSIL occurred more frequently during 12 months of follow-up. PMID- 23342879 TI - [Influence of tumor diameter on treatment results in cervical cancer patients]. AB - The impact of the tumor size on treatment outcomes in cervical cancer patients remains a subject of controversy OBJECTIVES: The assessment of prognostic value of pretreatment tumor size in cervical cancer patients. MATERIALS AND METHODS: Patients of Maria Sklodowska - Curie Memorial Cancer Centre in Warsaw, treated between January 1996 and December 2000, were included into the retrospective study. 242 patients were diagnosed with a histologically confirmed squamous cell carcinoma and 42 with adenocarcinoma, FIGO staged IB-IVA, having undergone the clinical assessment and USG examination of the tumor treated with curative intent with surgery and/ or radiotherapy. The widest tumor diameter was adopted as the tumor size. In most cases of adenocarcinoma, the tumors were described as endocervical and the tumor measurement was connected with the risk of mistake, therefore, the analysis of the squamous cell cancer patients only was performed. A multivariate analysis of 242 patients with regard to overall survival (OS) and disease-free survival (DFS), depending on the selected clinico-pathological factors, was performed. The mean potential follow-up time for surviving patients was 50 months (range 8.7-62). The 5-year overall survival (OS) rate was 62%. RESULTS: As the result of the multivariate analysis, the impact of FIGO stage (p=0.002), hemoglobin pretreatment concentration (p=0.031) and tumor size before treatment (p = 0.044) on OS, and FIGO stage (p=0.001), hemoglobin level before treatment (p=0.019) on DFS, was demonstrated. CONCLUSIONS: Tumor diameter before treatment in squamous cell cervical cancer patients provides important prognostic information, regardless of other prognostic factors. PMID- 23342880 TI - Transumbilical single-incision total laparoscopic hysterectomy: technique and initial experience in Turkey. AB - OBJECTIVES: The aim of the study is to determine the results of our initial experience of 32 cases who underwent single incision total laparoscopic hysterectomy MATERIALS AND METHODS: Thirty-two patients who underwent transumbilical single incision total laparoscopic hysterectomy between March 2009 and February 2011 were reviewed retrospectively at the Department of Obstetrics and Gynecology Ege University Faculty of Medicine, Izmir, Turkey Articulating and rigid instruments, 30 degrees 10 mm telescope, SILS port and advanced bipolar and mechanical energy modalities were used during the procedure. Duration of surgery length of hospital stay mean blood loss and postoperative complications were assessed. RESULTS: Mean age of patients and mean operation time were 48 years (ranged 42-55) and 108 minutes (ranged 80-180), respectively. In all cases vaginal cuffs were closed with either intracorporeal or extracorporeal separate sutures. There were no intraoperative complications. All patients were discharged within 48 hours postoperatively The mean length of hospital stay and mean blood loss were as 1.6 days (range 1-2) and 45 ml (range 30-100), respectively CONCLUSIONS: Total laparoscopic hysterectomy performed through transumbilical single incision is technically feasible and safe. Development of advanced flexible instrumentation and visualization platform may facilitate this new operative approach. PMID- 23342881 TI - A randomized comparison of microtip and air-charged catheter for the measurement of maximum urethral closure pressure. AB - BACKGROUND: Measurements of maximum urethral closure pressure (MUCP) are a part of urodynamic investigations preceding an incontinence surgery and a part of urethral function tests. OBJECTIVES: The aim of the study was to compare maximum urethral closure pressure determined by a microtip catheter with those measured by an air-charged catheter. MATERIAL AND METHODS: A prospective randomized study in a tertiary referral centre. 122 female patients with urodynamic stress incontinence were randomly assigned to have their urethral pressure profiles measured at rest by both microtip and air-charged catheters. INTERVENTION AND MEASUREMENTS: Each patient had three measurements taken by each catheter type. Means of the measurements were compared with regard to correlation and repeatability. For statistical analysis, an approach proposed by Bland-Altman was applied to assess the agreement between the two techniques. RESULTS: Correlation coefficient between MUCP by the air-charged and the microtip catheter was r=0.8507 (95% CI 0.7928 - 0.8934; p<0.0001). MUCP by the air-charged catheter was significantly lower than MUCP measured by the microtip catheter. The two-tailed p value was <0.0001, considered extremely significant. (95% CI of the differences; mean difference = -3.033; mean of paired differences -3.730 to -2.335). Discrepancies between measurements of the microtip and the air-charged catheters suggest good agreement between the two catheters since the mean difference was 2.8 cmH2O and the 95% CI of agreement were narrow with -0.03319 to 0.3151. CONCLUSION: Air-charged catheters give lower readings for MUCP than microtip catheters with a good agreement between the two catheters. PMID- 23342882 TI - [Detection of disseminated tumor cells in the bone marrow of breast cancer patients with a new molecular method]. AB - OBJECTIVES: Numerous studies have shown that the presence of clinically occult disseminated tumor cells (DTC) in the bone marrow (BM) of breast cancer patients is associated with an unfavourable clinical outcome. Immunocytochemistry (ICC) remains the gold standard for their detection. Assays based on RT-PCR are available; however so far they have not been used for routine detection of DTC. Therefore, the purpose of this study was to evaluate a newly established molecular method for the detection of DTC. MATERIALS AND METHODS: BM aspirates from 405 patients were examined. Half of the samples were immediately inserted into ICC and the other half was examined with our newly established molecular method based on RT-PCR. Immunocytochemistry was performed according to the Consensus Recommendations of the German, Austrian, and Swiss Societies of Senology and ISHAGE Working Group (A45B-B3 antibody). RT-PCR was conducted as a one-step real-time assay Cytokeratin 19-mRNA was amplified. RESULTS: In 142 of 405 (35%) aspirates disseminated tumor cells were detected by RT-PCR. In 34% of patients DTC were detected by ICC. 48% of the BM samples were positive by at least one method. In 73% of the patients identical results were obtained (p<0,001). CONCLUSION: Our newly established molecular assay for the detection of disseminated tumor cells, and thus minimal residual disease, is sensitive, fast and reproducible, and has a potential to be used as a confirmatory or alternative test for DTC detection. PMID- 23342883 TI - Inherited thrombophilia with recurrent pregnancy loss in Turkish women--a real phenomenon? AB - OBJECTIVES: To determine the prevalence and the role of hereditary thrombophilia caused by Factor V Leiden (G1691A), prothrombin G20210A or methylenetetrahydrofolate reductase (MTHFR) C677T gene mutations in recurrent pregnancy loss. MATERIAL AND METHODS: One hundred and nine patients, who were admitted to the 3rd Obstetrics and Gynecology Outpatient Clinic in Goztepe Training and Research Hospital between 2006 and 2008, were included into the study The study group consisted of fifty-seven patients with a history of 3 miscarriages before 20 weeks of gestation and the control group consisted of forty-seven patients with at least one live birth without any history of miscarriage or pregnancy complications. The maternal blood was evaluated for Factor V Leiden (G1691A), prothrombin G20210A and MTHFR C677T gene mutations. RESULTS: No statistically significant difference was found between the study and the control groups in terms of the prevalence of Factor V Leiden (G1691A), prothrombin G20210A and MTHFR C677T gene mutations (p=0.534/ p=0.452/p=0.656, respectively and p<0.05). Furthermore, the prevalence of multiple gene mutations was not statistically different between the groups (p=0.375 and p<0.05) either. CONCLUSION: Routine screening for Factor V Leiden (G1691A), prothrombin G20210A and MTHFR C677T gene mutations in patients with a history of recurrent pregnancy loss is not recommended in Turkish women. PMID- 23342884 TI - [Is the epidemic of cesarean sections the result of more liberal indications?]. AB - INTRODUCTION: The rate of cesarean sections around the world is steadily rising. The analysis of indications for cesarean section might find the answer to the question whether this trend is a consequence of more liberal indications. OBJECTIVES: The aim of the study was to analyze and compare the changes in the indications for cesarean sections (cs) over the years. MATERIAL AND METHODS: Data regarding cesarean sections performed at the 1st Department of Obstetrics and Gynecology Medical University of Warsaw were analyzed and compared: 559 cs between the years 2000-2001 (G1) and 663 cs in 2010 (G2). RESULTS: The rate of cs was statistically higher in 2010 (30.1% vs. 29.2%; p<0.001), however the rate of preterm cs was lower (25.4% vs. 11.9%; p<0.01). The most frequent indication for cs in 2010 was lack of patient consent for vaginal birth after cs (27.3% vs. 17.9%; p<0.01). Other frequent indications throughout the decade were: fetal distress (G1 18.6% vs. G2 14.2%; p<.01), cervical dystocia (12.3% vs. 11%, respectively), fetal position other than cephalic (12.5% vs. 13.6%) and non obstetrical indications (14.1% vs. 9.4%; p<0.05). CONCLUSIONS: In the last decade the rate of cesarean sections has risen and there are minor differences in the indications for cs. Previous cesareans delivery seems to be the main cause of an increase in the number of cs nowadays. PMID- 23342885 TI - [Uterine carcinosarcoma]. AB - Uterine carcinosarcoma is a rare, metaplastic subtype of endometrial cancer comprised of two distinct malignant components - epithelial and mesenchymal, with phenotypic features. This tumor shows very aggressive behavior including both local recurrence and distant metastases. Surgery consisting of total hysterectomy bilateral salpingo-oophorectomy and dissection of pelvic and para-aortic lymph node, with detailed examination of the entire abdominopelvic cavity and maximal cytoreduction of the lesions, is the principal treatment. The optimal postoperative therapy has not been determined, and is individualized. In a randomized trial a postoperative radiotherapy was shown to improve local control but no survival benefit. High rate of distant metastases suggests a potential role of the systemic therapy However the benefit of postoperative chemotherapy in high-risk patients has not been confirmed in randomized studies. This method, in addition to palliative radiotherapy and surgery is used in recurrent and advanced disease. Currently chemotherapy including the combination of paclitaxel with ifosfamide or carboplatin is considered the most effective regimen, with the latter having a better toxicity profile. PMID- 23342886 TI - [Mode of delivery and eye diseases]. AB - There are many controversies among ophthalmologists and obstetricians regarding indications for caesarean section due to preexisting eye diseases. Many ophthalmologists still believe myopia, retinal detachment, glaucoma or diabetic retinopathy to be indications for a caesarean section. There is a discrepancy between clinical practice and evidence-based medicine, as none of the published trials have reported any retinal changes after vaginal delivery This report provides information on the influence of physiological changes on eye diseases during the final stage of the delivery. We conclude that an eye disease is not an indication for a caesarean section. PMID- 23342887 TI - [Selective intrauterine growth restriction in monochorionic twin pregnancies]. AB - Selective intrauterine growth restriction (sIUGR) is a major complication of monochorionic pregnancies, with potentially high risk of intrauterine fetal death or neurological dysfunction in both fetuses. Diagnostic ultrasound has contributed to the understanding of the pathophysiology of sIUGR and allowed to propose a classification. That, in turn, allows to interpret a wide clinical variety of sIUGR and, depending on the type, to propose a specific clinical management. The introduction of diagnosis based on Doppler studies enables the correct diagnosis of the disorders, fetal monitoring, to determine the prognosis and optimal strategies, and to propose the best therapeutic intervention. PMID- 23342888 TI - [Laparoscopic management of an ectopic pregnancy in a previous caesarean section scar]. AB - Pregnancy in a caesarean section scar is the rarest form of an ectopic pregnancy English language literature up to 2007 reports only about 70 cases, including three cases treated laparoscopically. A 25-year-old woman in the sixth week of pregnancy was admitted to our hospital due to profuse vaginal bleeding. During clinical and ultrasound tests, an unruptured ectopic pregnancy of 6 gestational weeks was found in the caesarean section scar. The treatment plan included two phases. Three days after a Methotrexate injection (80mg), the pregnancy was removed laparoscopically Laparoscopy enabled a successful treatment of the unruptured ectopic pregnancy in a previous caesarean scar and made it possible to preserve the reproductive capability of the patient. PMID- 23342889 TI - Spontaneous rupture of unscarred uterus in the early second trimester: a case report of placenta percreta. AB - BACKGROUND: Prevalence of uterine rupture at delivery has been recently estimated at less than 1 in 2500 deliveries. Spontaneous uterine rupture in the early mid trimester (16 weeks gestation or less), is far less frequent. We report a case of uterine rupture due to placenta percreta in otherwise uncomplicated pregnancy CASE: A 35-year-old, gravida 5, para 5, at 15wk 2d gestation (menstrual age) with negative history of uterine scarring suddenly developed symptoms of incipient hypovolemic shock while being hospitalized for imminent miscarriage. On exploratory laparotomy we found a midline uterine rupture infiltrated by the placenta. Supracervical hysterectomy was performed. Postoperative lab analysis confirmed the elevated serum AFP levels. CONCLUSION: Abnormal placentation and subsequent uterine rupture should be taken into consideration also in women in the second trimester who have no history of uterine instrumentation. PMID- 23342890 TI - [The use of therapeutic whole body cooling in treating hypoxic-ischemic encephalopathy in the newborn--the first case in Poland]. AB - Hypoxic-ischemic encephalopathy (ENN) concerns neonates born after 35 completed weeks of gestation. The incidence rate has been shown to be 1-6/1000 births and can lead to significant permanent neurological damage, cerebral palsy and even death. Until the whole body cooling and selective brain cooling methods have been accepted, the treatment of children with ENN was only symptomatic. The article describes the first case of ENN neonatal treatment with the whole body hypothermia in Poland, which took place at the Department of Neonatology Poznan University of Medical Sciences. Currently both methods--whole body hypothermia and selective brain cooling--offer a chance for a normal neurological development and a better life for children born with ENN. Both methods are accessible in a few centers in Poland. PMID- 23342891 TI - [Statement of the Polish Gynecological Society Expert Group on the use of ellen probiotic tampon]. AB - The group of experts representing the Polish Gynecologic Society has issued this Statement based on the review of available literature on the potential benefits of the use of ellen probiotic tampon. It has been firmly proven that during menstrual bleeding the vaginal flora undergoes profound changes prodisposing to both bacterial and fungal infections. Safety of menstrual tampons has been studied for over 60 years. According to the current state of knowledge, the use of tampons does not lead to any clinically significant change in the vaginal flora. The link between tampon use and Toxic Shock Syndrome (TTS) was revealed in 1978 after introduction of superabsorbent tampons to the United States market. Following the replacement of carboxymethylcellulose and polyester based tampons by the new generation of cotton based tampons, cases of tampon connected TSS are extremely rare in the US. The proper use of modern tampons is considered to be safe. Ellen tampon features dioxin and chlorine free natural fibres treated with the acidic acid producing probiotic Lacto Naturel (LN), which contains a combination of patented benevolent bacteria that can strengthen women's defense against vaginal infections. Both in vivo and in vitro studied have shown that ellen probiotic tampons are able to succesfully colonize vagina with the LN probiotic bacteria which then coexist with endogenous Lactobacilli present in the patients vaginal ecosystem. The ellen probiotic tampon constitutes an innovative solution of the vaginal probiotic application during menses. The use of this product is aimed to maintain natural vaginal flora as well as its pH during menstrual bleeding. According to the available clinical data, the potential benefits of the probiotic tampon use include: prevention of the vaginal/vulval discomfort as a result of frequent swimming poll use, maintaning of the therapeutic effect of antibacterial/antifungal vaginal treatment and prevention of the recurrent infections, prevention of iatrogenic vaginal flora imbalance after an antibiotic treatment. PMID- 23342892 TI - [Genetic variants of endothelial nitric synthase in gestational hypertension and preeclampsia]. AB - INTRODUCTION: Decreased nitric oxide (NO) plasma concentration may be involved in the development of preeclampsia. It has been suggested that genetic variants of endothelial nitric oxide synthase (eNOS) gene may reduce NO plasma levels. AIM OF THE STUDY: To evaluate the correlation of 894G>T (Glu298Asp) and -786T>C polymorphisms of NOS3 gene with the development of preeclampsia (PE) and gestational hypertension (GH). MATERIAL AND METHODS: 110 hypertensive pregnant women (mean age 29.46 +/- 4.54 years, mean gestational age 36.88 +/- 3.50 gw., mean systolic blood pressure 16782 +/- 16.87 mmHg, mean diastolic blood pressure 104.32 +/- 11.62 mmHg) were enrolled into the study group. The whole study group was further subdivided into two subgroups: women with gestational hypertension (GH, n = 69) and with preeclampsia (PE, n = 41). Gestational hypertension and preeclampsia were diagnosed according to the ACOG standards. All patients with multiple pregnancy diabetes, vascular changes and thrombotic complications were excluded from the study. The control group consisted of 150 healthy pregnant women (mean age 28.29 +/- 4.40 years, mean gestational age 39.06 +/- 1.28 gw., mean systolic blood pressure 12.07 +/- 10.75 mmHg, mean diastolic blood pressure 70.62 +/- 9.13 mm Hg). The frequency of investigated genotypes of NOS3 gene polymorphisms was examined by polymerase chain reaction and restriction fragment length polymorphism (PCR/RFLP) method. RESULTS: As far as the 894G>T polymorphism was concerned, a higher frequency of 894TT genotype in the control group in comparison to the whole study group was observed (8.7 vs. 5.4%; WR = 0.61, p = ns). A similar observation was made about the 894T allele (25.4 vs. 30.0%, WR = 0.79, p = ns). The frequency of the 894T allele was also higher in controls in comparison to the PE group (30% vs. 26.8%, p = ns) and GH group (30% vs. 24.6%, p = ns). Analyzing the -786T>C polymorphism no statistically significant differences between the whole study and the control groups was found. The frequency of the mutated -786CC genotype was similar in the entire study group and controls (13.6 vs. 15.3%, p = ns). The frequency of the mutated -786C allele was also similar in both analyzed groups (37.3 vs. 38.0%, p = ns). A statistically significant difference in the frequency of coexistence of mutated homozygotic genotypes 894TT/-786CC between the investigated groups (0.9% in the whole study group vs. 6.7% in the control group, p = 0.019) was observed. Coexistence of 894GT/-786TC genotypes was noted more frequently in the control group (19.1% in the whole study group vs. 24.7% in the control group, p = ns). The frequency of other combinations of investigated genotypes coexistence did not significantly differ between the control group, the entire study group, and the PE and GH groups. In the PE group, a higher systolic blood pressure was noted in patients with -786CC genotype (205.0 +/- 21.2 mmHg) in comparison to patients with -786TT (177.0 +/- 17.8 mmHg) or -786TC (173.4 +/- 13.5 mmHg) genotypes (p = ns). CONCLUSIONS: The presence of the 894TT genotype of the 894G>T (Glu298Asp) polymorphism may play a protective role in the development of preeclampsia. The presence of the -786CC genotype of the -786T>C polymorphism may correlate with the increase of the systolic blood pressure in pregnant women with preeclampsia. PMID- 23342893 TI - [The analysis of selected biochemical parameters concentration in pregnant women with idiopathic edema of the lower limbs--preliminary report]. AB - INTRODUCTION: Pregnancy causes changes in the hormonal balance, musculoskeletal, cardiovascular and lymphatic systems. The swelling of the lower limbs may also be one of the consequences of the enlarging uterus that increases body weight during pregnancy Determination of the serum concentrations of myeloperoxidase - MPO, extracellular matrix metalloproteinase - MMP, and intreleukine-6 - IL-6 allows for the assessment of inflammation. MPO belongs to the group of peroxidase enzymes with strong antibacterial and anti viral action. It is produced and released from the granules of neutrophils in inflammatory reactions, degenerative changes and neoplasmatic diseases. IL-6 is the main mediator of the inflammation in the live organism, released by monocytes and macrophages stimulated by interleukin-1. OBJECTIVE: To assess the levels of inflammatory mediators: MMP MPO and IL-6 in women in the third trimester of pregnancy both healthy and those who experienced idiopathic edema of the lower limbs. MATERIAL AND METHODS: We analyzed the changes in the concentration of biochemical parameters as: MMP-1, MPO and IL-6 in the serum of 20 healthy pregnant women between 36 and 40 weeks of gestation, and 8 pregnant women who developed idiopathic edema of the lower limbs. The R&D Systems Elisa tests were used to perform the measurement. The Quantikine Human IL-6 Immunoassay was used to measure the concentration of IL-6. The concentration was expressed in pg/ml. MMP-1 was measured using The Quantikine Human Pro -MMP-1. The value of MMP-1 concentration was expressed in ng/ml. MPO was measured using The Quantikine Human MPO Immunoassay and expressed in ng/ml. RESULTS: The mean concentration of IL-6 was higher in the group of pregnant women with swelling of the lower limbs (group II) in comparison to healthy pregnant women (group I) and it was approximately 3,01 pg/ml, SD = 2,64, and 2,3 pg/ml, SD = 1,92, respectively. No statistical difference was found (p = 0,436). Parity has no influence on IL-6 concentration. The mean concentration of MPO in group I was 1797,04 ng/ml, SD = 1378,89, in II group it was 1702,54 ng/ml, SD = 1289,64. (p = 0,866). Parity has also no influence on MPO concentration. The mean concentration of MMP-1 in group I was 7,61 ng/ml, SD = 4,6, in group II it was 10,46 ng/ml, SD = 4,03. (p = 0,137). Significantly higher results were observed in primiparas with lower limbs swelling- 11,36 ng/ml when compared to multiparas - 9,57 ng/ml. CONCLUSIONS: 1. There are no significant differences in the concentrations of the studied inflammatory mediators between the groups of healthy pregnant women and those with idiopathic edema observed in the lower limbs. The significance of these differences requires further confirmation. 2. There was a statistically significant difference between the concentrations of MPO in the group of primiparas with a multiparas with lymphatic edema. PMID- 23342894 TI - Internal iliac artery ligation for severe postpartum hemorrhage. AB - OBJECTIVE: To evaluate the outcomes of bilateral internal iliac artery ligation (IIAL) in severe postpartum hemorrhage (PPH). DESIGN: Multi-center retrospective study. METHODS: The study was performed from January 2005 to December 2010, at the Obstetrics and Gynecology Clinic, Dicle University Medical Faculty and Maternity Hospital, Diyarbakir, Turkey. Life-threatening cases of severe postpartum hemorrhage, which could not be controlled with conservative medical and surgical treatments and finally managed with IIAL, were retrospectively evaluated. RESULTS: Totally 53 patients who underwent IIAL procedures were included in the study. All patients were hemodynamically unstable. The mean shock index and transfused units of blood were 1.17 +/- 0.46, 5.49 +/- 3.04, respectively. Uterine atony was the leading cause of severe postpartum hemorrhage and the need for IIAL. Coagulopathy developed in 26 (49.1%) patients during the postoperative follow-up period. Uterus was preserved in 17 (32.0%) cases. Three patients died of complications and/or morbidity associated with hemorrhage. CONCLUSION: Serious PPH is most frequently associated with uterine atony and IIAL should be considered in cases with severe PPH unresponsive to other treatment modalities. If, in the antenatal period, patients have risk factors of postpartum hemorrhage, they must be transferred to appropriate centers to prevent a possibly fatal outcome. PMID- 23342895 TI - [Sonographic evaluation of the levator ani muscle in women with stress urinary incontinence]. AB - Three-dimensional sonography has been used for about 15 years, not only to examine the female genital organs, but also the lower urinary tract and pelvic floor. Three-dimensional sonography offers more information than traditional two dimensional sonography allowing for a dynamic representation of the examined structures and observation at any angle necessary. Translabial sonography is the best way of a sonographic examination of the lower urinary tract, because it does not affect the mutual relationship of any parts in the lower pelvic area, contrary to the transrectal or transvaginal probes. In order to establish proper treatment of the urinary incontinence symptoms, not only a functional examination of the lower urinary tract, but also a very accurate assessment of the statics of the female genital organs and pelvic floor need to be performed. BACKGROUND: The aim of the study was to rate the area and diameters of the limbs of the levator ani muscle using a three-dimensional (3D) translabial sonography in women with stress urinary incontinence without the female genital tract prolapse. MATERIAL AND METHODS: The study group included 100 patients who were examined with the GE Kretz Voluson 730 (GE, Austria), equipped with 6-9 MHz translabial probe. The first group with stress urinary incontinence consisted of 50 women (mean age 56.22 (+/- 10.43) years) and the second group included 50 women without symptoms (mean age 49.40 (+/- 13.22) years). All cases of urinary stress incontinence in the first group were confirm by means of a urodynamic examination. Women in both groups had similar body weight (kilograms), mean (+/- SD): 26.88 (+/- 2.02) and 26.20 (+/- 4,14), respectively. Menopausal status in both groups was not statistically significant and amounted to 7.21 (+/- 8.71) in the group of women with stress urinary incontinence and 4.70 (+/- 6.32) in the group without symptoms. Mean (+/- SD) number of deliveries was significantly higher in the group of women with stress urinary incontinence than in the control group (2.40 (+/- 1.03) and 1.56 (+/- 1.34), respectively). In all cases 3D coronal view of the pelvic diaphragm was obtained and the area and thickness of limbs of the levator ani muscle were measured. All women had about 200 ml urine in the bladder. RESULTS: The results are presented as means +/- SD. Mean measurements of this area in both groups were 8.54 +/- 1.62 cm2 and 10.57 +/- 1.29 cm2, respectively. Mean thickness of the limbs in the groups were: 8.72 +/- 0.64mm and 10.85 +/- 0.89mm on the left side and 8.85 +/- 0.67mm and 10.89 +/- 0.87mm on right side, respectively. The differences between both groups in all measurements were statistically significant (p < 0.001). CONCLUSIONS: There are some differences involving measurements of the thickness and the area of the limbs of the levator ani muscle in women with and without stress urinary incontinence and without the genital tract prolapse in both groups. The observed differences could have implications in physiotherapy of the pelvic floor muscles in women without statics abnormalities. PMID- 23342896 TI - [State of nutrition and diet habits versus estradiol level and its changes in the pre-season preparatory period for the league contest match in female handball and basketball players]. AB - BACKGROUND: Intense exercise is known to induce menstrual disturbances--irregular menstrual cycles, oligomenorrhea and amenorrhea in female athletes. Menstrual disturbances, followed by hypoestrogenism, are associated with infertility decreased bone mineral density high prevalence of stress fractures, and endothelial dysfunction. OBJECTIVES: The aim of the study was to assess the effect of nutrition and diet habits on the estradiol level and its changes in the pre-season preparatory period for the league contest match in female handball and basketball players. MATERIALS AND METHODS: Fifty healthy young female handball and basketball players were enrolled into the study before the opening of the season, after a 2-month holiday period, without regular physical activity and diet restrictions. Serum estradiol was determined at the beginning and after 3 months of moderate aerobic training. Each woman was studied between the 3rd and 5th day of her menstrual cycle. In all subjects, medical history was obtained, together with the anthropometric measurements (body mass and height). The body mass index was calculated according to the standard formula. The use of hormonal contraception in the last 3 months, low-caloric diet in the last 6 months, body mass changes of more than 3 kilograms in the last 6 months, secondary amenorrhea and stress fractures in medical history constituted the exclusion criteria. Informed consent was obtained from each participant and the study protocol was approved by the Ethics Committee of the Medical University of Silesia. Venous blood samples (2 ml) for estradiol levels measurements were taken twice: at the beginning of the preparatory period and after three months of moderate aerobic exercise training (20 hours per week). Blood samples were collected according to the kit manufacturer's recommendations. Serum and plasma samples were stored frozen at -80 degrees C. Serum estradiol was determined by enzyme-linked immunosorbent assay (ELISA) (DRG Instruments GmbH, Marburg, Germany) with a lower limit of sensitivity of 9.714 pg/mL; the intra- and inter-assay coefficients of variation were 4.7% and 7.8%. All statistical analyses were performed with the use of Statistica 8.0 software. The results are presented as means +/- SD. The Wilcoxon rank test was used to compare the before and after exercise measurements. The Mann-Whitney U test was used for subgroups comparisons. The results were considered statistically significant when the p value was less than 0.05. RESULTS: After a 2-month holiday period, without regular physical exercise, p < 0.01) serum estradiol level was significantly lower in the basketball than handball players (48.7 +/- 19.6 vs. 62.3 +/- 18.9 pg/ml, p < 0.01). Although, no body mass changes were noticed (delta = - 0.3 +/- 0.3 kg), after 3 months of moderate aerobic training estradiol level was significantly decreased in the whole study population (58.0 +/- 20.0 vs. 41.4 +/- 18.9 pg/ml, p < 0.001). CONCLUSIONS: Diet habits and nutrition did not correlate with estradiol plasma levels in female handball and basketball players after a 2-month holiday period. Regular exercises correlate with the decrease of serum estradiol level even without body mass changes. PMID- 23342897 TI - [Analysis of BCRP expression in breast cancer patients]. AB - Breast cancer resistance protein (BCRP, ABCG2) is a xenobiotic half-transporter protein. It is a member of the ATP-binding cassette protein family and functions as an energy-dependent efflux pump. BCRP is involved in multidrug resistance. The study aimed at examining BCRP expression in breast cancers and at defining a relationship between activity of this protein and clinical course of the cancer. MATERIALS AND METHODS: We analyzed the expression of BCRP in 101 stage II breast cancer patients. All the patients were diagnosed and treated at the Lower Silesia Oncology Centre (LSOC) between January 1993 and June 1994. After the treatment the patients remained under constant control at LSOC. Mean duration of the observation was 14.2 years (ranging between 9.1 and 16.5 years). Data related to relapse of the disease and deaths were obtained from medical documentation stored in LSOC. The immunohistochemical reactions were performed on paraffin sections of primary tumours, using monoclonal antibodies against BCRP. The intensity of immunohistochemical reactions with BCRP antibody was evaluated using the semi quantitative IRS (ImmunoReactive Score) scale, which took into account the intensity of the colour reaction and percentage of positive cells. Results of the immunohistochemical reactions, pathological and of clinical observations were subjected to statistical analysis. Correlations between these factors and BCRP were analyzed using Spearman and Chi2 tests. In order to estimate the survival rate, we used Kaplan Meier statistics, log-rank tests and Cox proportional hazard regression. RESULTS: In our analysis we observed a positive correlation between the expression of the BCRP protein and grade of tumour advancement (r = 0.2 p = 0.03). We found also a negative correlation between the expression of BCRP and the estrogen (r = 0.24 p = 0.02) and progesteron (r = 0.28 p = 0.02) receptors. In a univariate analysis a significantly shorter disease free survival (DFS) and disease specific survival (DSS) was noted in patients with metastases to the lymph nodes (p = 0.003 and p = 0.0006), over the age of 50 years old ((p = 0.02 and p = 0.04) and clearly statistically significant in patients with a high expression of BCRP (p = 0.00044 and p = 0.00005). Overall survival (OS) was shorter in patients over the age of 50 (p = 0.01), with higher stage of the disease - IIB (p = 0.025), with metastases to the lymph nodes (p = 0.003) and also clearly statistically significant in patients with a high expression of BCRP (p = 0.00004). A multivariate analysis allowed to reveal that only higher expression of BCRP and metastases to lymph nodes were typical for cases of DFS (p = 0.,028 and p = 0.00015), DSS (p = 0.00052 and 0.000017) and OS (p = 0.0018 and p = 0.000007) time. CONCLUSIONS: We demonstrated that high BCRP expression level is associated with poor survival in early stage breast cancer patients. PMID- 23342898 TI - [Modern methods of early screening for preeclampsia and pregnancy-induced hypertension--a review]. AB - Preeclampsia remains to be a serious perinatal complication and early screening for this disease to identify the high risk population before the first symptoms develop constitutes a considerable clinical challenge. Modern methods of screening for preeclampsia and pregnancy-induced hypertension include patients history biochemical serum markers and foetal DNA and RNA in maternal serum. They aid the process of developing an optimal protocol to initiate treatment in early pregnancy and to reduce the rate of complications. Our review presents an overview of the novel methods and techniques used for early screening for preeclampsia and pregnancy-induced hypertension. Most of the research focuses on 11-13 weeks of gestation due to the fact that the first prenatal examination is performed at that time. The most important information seems to be: weight, mass, mean blood pressure, history of pregnancy-induced hypertension or preeclampsia at previous pregnancies as well as the ethnic origin. During an ultrasound scan, pulsatility index of the uterine arteries is measured. Blood samples are obtained during the last part of the examination. At the moment only a few markers seem to be strong predictors of hypertensive disorders during pregnancy: pregnancy associated plasma protein-A (PAPP-A), placental growth factor (PIGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). Also, fetal DNA and RNA in maternal plasma are helpful in the prediction of preeclampsia as they are markers of the trophoblast apoptosis. Researchers aim at identifying the population at high risk of pregnancy-induced hypertension and preeclampsia in order to offer appropriate antenatal care to these women. At the moment many drugs and diet supplements are investigated to reduce the prevalence of hypertensive disorders in pregnancy. These medications are usually administrated in early gestation (up to 16 week of gestation) before the first clinical symptoms present. Low doses of aspirin were found to decrease the risk of preeclampsia in high-risk groups. Moreover, according to some recent research, also essential omega-3 fatty acids reduce the incidence of preeclampsia. None of the other investigated diet supplements or antioxidants were proven to successfully reduce incidents of hypertensive disorders. So far, there is available evidence on the lack of any effect for vitamines C, D or E. Further studies are necessary to define clinical useful markers of gestational hypertension. PMID- 23342899 TI - [Translabial ultrasonography in pelvic floor prolapse and urinary incontinence diagnostics]. AB - Technological advances in the construction of sonographic devices and increasingly universal access to such tests considerably widens the range of diagnostic application of the sonographic examination. This situation also refers to pelvic organs prolapse. At present, sonographic sets used in everyday obstetrical-gynecological practice allow for insight into the structures forming the female pelvic floor, and the obtained images constitute a valuable addition to the physical examination. Positioning the sonographic transducer on a the perineum enables to visualize the three compartments of the female pelvis minor. After freezing the image, it is possible to assess the position of anatomical structures in relation to bones and designated surfaces, establish mutual distances and measure appropriate angles. Most information can be obtained in this manner within the range of the frontal compartment, whose damage is often linked with urinary incontinence. The examination standards developed so far, including the analysis of the quantitative parameters, greatly minimize the potential subjectivity of the assessment of the existing disorders. Apart from its low costs, the main value of the sonographic examination of the pelvic floor is the possibility to dynamically assess the changes in statics which take place during functional testing. Not only does it have a cognitive significance, but also it allows to adjust the scope of the surgical correction to the existing damages. Thus, indirectly it can contribute to the reduction of a number of subsequent remedial surgeries. Three-dimensional sonography allows to thoroughly examine the construction and functioning of the anal levators and to detect their possible damage. It is the trauma to these muscles--occurring, among others, during childbirth--that is one of the major causes of pelvic organs descent and prolapse in women. Sonographic examination also enables to visualize the artificial material, the use of which is increasingly frequent in the surgical treatment of pelvic organs prolapse. The remedial kits currently in use are not visible in classic X-ray examinations and CT however, they can be easily visualized by means of a sonographic test. This way it is possible to locate the positioned tapes or meshes and to establish their orientation towards the urethra, the bladder and the anus. It is also possible to observe the complications (e.g. hematomas) following the surgical procedures via the transvaginal access. Transperineal sonography is a relatively inexpensive method that may be performed in almost every ultrasonographic laboratory Its value, approaching the MRI diagnostic value in the assessment of the pelvic floor defects and its low cost, place ultrasonography on the first place among the methods of imaging the pelvic and uro-genital diaphragm. The results of diagnostics of pelvic organs prolapse obtained by placing the sonographic head on the patient's perineum may also help in establishing the changes of the support apparatus for the uterus and the vagina, bladder urethra and perineum during functional testing and, thus, to verify the clinically established degree of the prolapse. It seems, also, that this method may be used during peri-urethral injections of specific substances and post-application follow-up, an increasingly frequently employed method of urinary incontinence treatment. PMID- 23342900 TI - Testicular adrenal rest tumors (TARTs) as a male infertility factor. Case report. AB - Since testes and adrenal cortex derive from the same urogenital ridge, adrenal tissue with descending gonads may migrate in early embryonic period. Although most often ectopic tissue undergoes atrophy in some cases, when adrenocorticotrophic (ACTH) overstimulation occurs, the adrenal remnants in the testes may become hypertrophic and form testicular adrenal rest tumors (TARTs). The growth of TARTs in the testes leads to obstruction of the seminiferous tubules which can mechanically impair the function of the gonads and cause irreversible azoospermia. We describe a patient suffering since neonatal period from congenital adrenal hyperplasia (CAH), disorder with defected pathway of cortisol production, which leads to increased ACTH production and to overstimulation of adrenal cortex. He had very poor disease control and therefore in late puberty he was diagnosed with TARTs. At the age of 19.5 he was diagnosed with azoospermia, most likely caused by TARTs. It is the first evidence of TARTs in Polish literature. Although not many cases have been published so far the incidence of TARTs seems to be highly underdiagnosed, so it seems reasonable to consider the disease in differential diagnosis of male infertility. PMID- 23342901 TI - Sentinel lymph node detection with the use of SPECT-CT in endometrial cancer- analysis of two cases. AB - On the basis of two cases we discuss the important issues regarding the sentinel lymph node detection biopsy (SLNB) in endometrial cancer with combined cervical administration of the radiocolloid and the subserosal blue dye injection. The first patient (endometrioid adenocarcinoma G2, invasion > 50% myometrium) had 4 SLNs detected. Three were both hot and blue (detected on SPECT-CT). The fourth, paraaortic SLN was blue only. None of the lymph nodes contained metatstases. The second patient (endometrioid adenocarcinoma G1, invasion > 50% myometrium) had 4 SLNs detected. Three were blue (but two of them had also very low radioactivity). The fourth SLN was hot only. Blue only node contained macrometastasis. In the past patients underwent cervical amputation. Diverse distribution of each tracer confirms the advantages of the combined tracers administration in SLNB. The radiotracer is the crucial component--uptake was present in 6 of 8 SLNs. Although the blue dye is more a complimentary method, its suberosal injection significantly increases the safety of the SLNB procedure. In the first case we have detected blue only SLN in paraaortic region which otherwise would be missed using the cervical approach only. More importantly in the second case the tracer uptake was very limited due to the previous surgery and the blue dye administration allowed correct SLNs detection (including the metastatic node). Presented clinical cases confirms that the combined cervical and subserosal tracers administration together with preoperative SPECT-CT constitute an optimal SLN detection method and correctly provides information about the regional lymph node status. PMID- 23342902 TI - [Umbilical cord collision in the first trimester in a monoamniotic twin pregnancy -does it really matter?]. AB - A case of an umbilical cord collision diagnosed in the first trimester of a monochorionic monoamniotic twin pregnancy is presented. An intensive surveillance included ultrasound monitoring with color and spectral Doppler and fetal echocardiography. The first signs of fetal distress were observed at 31 weeks of gestation. The brain sparing effect as well as a periodic appearance of the "notch" in the wave forms obtained from the umbilical artery from the collision region were observed. In the first ultrasound scan there were no abnormalities in twin I. In contrast, in twin II a vascular resistance in the umbilical artery was at the upper limit for the gestational age. Five days later, decreased vascular resistance in the middle cerebral artery, which fluctuated at the lower limit, was noticed in twin II. After the next four days, PI in the middle cerebral artery decreased below the lower limit and tricuspid regurgitation appeared. In twin I the vascular resistance in the umbilical artery increased and remained at the upper limit of the reference ranges. Cardiotocographic records did not reveal signs of fetal distress. After a week the signs of brain sparing effect were visible in both fetuses. However, twin II showed features of umbilical cord clamping in the form of abnormal blood flow waveforms in the umbilical artery ("notch"). Therefore, despite the absence of signs of fetal distress in CTG in monochorionic monoamniotic twins with growth discordance of 20% and exponents of periodical clamping of the umbilical cord in twin II at 34 weeks, the decision to perform a caesarean section was made. The patient gave birth to two daughters (twin I: weight 1780g, Ap 10, pH 7.39, 7.40, BE -3.0, -2.6, and twin II: weight 1860g, Ap 10, pH 7.29, 7.35, BE -1.4, -2.4). During the delivery the umbilical cords collision was found at the region close to the body of twins. This case presents the possibility of using ultrasound and Doppler in the early diagnosis, monitoring and surveillance of pregnancies complicated by umbilical cords collision in monochorionic monoamniotic twins from the first trimester. Application of these methods allowed a safe monitoring of the fetuses and the identification of the onset of the cords collision. This in turn allowed the achievement of fetal maturity at 34 weeks, when both the risk of death and neonatal morbidity are significantly minimized. The use of Doppler blood flow velocimetry allowed the diagnosis of umbilical cords tightening before there were any signs of cardiac dysfunction in the CTG. This enabled to determine the most favorable, earlier time for delivery. The paper presents diagnostic management and surveillance in monochorionic monoamniotic pregnancy complicated by umbilical cord collision since the early pregnancy. PMID- 23342903 TI - [Clinical practice guidelines of the Team of Experts of the Polish Gynecological Society: management of the intrahepatic cholestasis of pregnancy]. AB - Intrahepatic Cholestasis of Pregnancy (ICP) constitutes the most common, reversible liver disease closely connected with pregnancy and spontaneously resolving in puerperium. ICP usually reoccurs in consecutive pregnancies (45 90%), often in a more intensified form. Many compounds (hormones, cytokines, medicines, endotoxins) can impair transport in the hepatocyte, disturb the intracellular transport and increase the permeability of the intercellular connections. As a result, the elements of bile may appear in the peripheral blood. Gestational cholestasis constitutes a classic example of intrahepatic cholestasis. The etiology of ICP is multifactorial with hormonal, genetic and environmental factors participating in the process. The diagnosis is based on the presence of pruritus, elevated values of bile acids in the blood serum and of aminotransferases (aspartic, aminopropionic and gamma-glutamylotranspeptydase (AspAt, AlAt, GGTP)), as well as spontaneous remission in the second or third week after childbirth, of lack of other illnesses causing pruritus and icterus. Clinical and biochemical symptoms of ICP include: pruritus without skin rash (usually after 30 weeks of gestation), mild icterus, steatorrhea etc. Abnormalities in the laboratory tests of the LFT (liver function tests) encompass: an increase in the serum concentration of fatty acids (BA) which can be the first and only laboratory abnormality. Concentrations surpassing 10 micromol/l are considered to be abnormal. Concentration of BA higher than 40 micromol/l allows to recognize a case of severe ICP, connected with the risk of premature delivery presence of the meconium liquor, surgical means of delivery and low APGAR score of the newborn (< 7 pt). In about 80% of pregnant women with ICP, the BA concentration ranges between 10-40 micromol/l, but perinatal results are comparable with uncomplicated pregnancies. Some authors are of the opinion that abnormal AlAt value is the most sensitive test, other authors consider the abnormal values of alkaline phosphatase and bilirubin to be the most pathognomonic factors. Other abnormal tests include: higher activity of alpha hydroxybutyric dehydrogenase correlated with an increase of the alkaline phosphatase and bilirubin; mild metabolic acidosis; dyslipidemia with elevated concentrations of the total lipids, total cholesterol and free LDL cholesterol and apolipoprotein; abnormal glucose tolerance test. ICP constitutes a medical problem that carries a considerable risk for the fetus, resulting from an increased flow of bile acids to the fetal blood circulation (elevated level in the amniotic fluid, in the umbilical blood serum and meconium). The risk of adverse effects for the fetus correlates with the rise of BA concentration in maternal blood serum. Cholestasis increases the risk of premature labor, presence of meconium in the amniotic fluid, fetal bradycardia, intrauterine asphyxia and stillbirth, particularly when the concentration of serum bile acids on an empty stomach is above 40 micromol/l. However, maternal clinical signs and symptoms do not correlate with the fetal outcome. Aspiration of bile acids or their accumulation in the fetal blood circulation are responsible for the increased frequency of RDS appearing in ICP. The aim of the obstetric management of ICP is to reduce maternal symptoms and biochemical disorders and to minimize the risk of premature delivery fetal distress and sudden death. ICP management should include: bed regime, light, low-fat diet, no stress, upper abdomen ultrasound examination, LFT tests and thrombotic tests once a week, monitoring of the fetal well-being with the available biophysical methods, pharmacotherapy and therapeutic termination of pregnancy in case of serious illness and/or the fetal distress. Ursodeoxycholic acid (UDCA) is the basis of the pharmacological treatment of pregnant women and currently constitutes the most promising treatment option of ICP. UDCA is administered orally in the dosage of 10-16 mg/kg/24, what in practice means 250-300 mg/2-3 times a day. PMID- 23342904 TI - How is myogenesis initiated in chordates? AB - Expression of transcriptor factors MyoD, Myf5, myogenin and MRF4 forms the basis of myogenesis. In Acrania, Pisces and Amphibia, as in Aves, myogenesis is initiated by MyoD. In Mammalia expression of Myf5 initiates myogenesis. Signal proteins Wnt and Shh induce the expression of genes encoding for MyoD or Myf5. In fishes and amphibians expression of MyoD starts in non-segmented mesoderm and then in myotomal cells. In birds and mammals expression of MyoD or Myf5 is initiated in the cells of the dermatomyotome. Embryonic myotomes are post mitotic. Proliferating cells Pax3 and Pax7-positive and mesenchymal cells take part in the growth of myotomal muscles. Cells migrating to the limb bud contain regulatory proteins Six4/Six1, Pax3, Lbx1 and c-met. Rectus abdominis develops from cells that contain Pax3 and Lbx1. PMID- 23342905 TI - Number and size of nucleoli in the spermatocytes of chicken and Japanese quail. AB - Nucleoli are the product of nucleolus organizing region activity (NOR) of specific chromosomes. Their basic function is to synthetise ribosomal RNA precursors and promote the maturation and assemblage of preribosomal RNP molecules. Information on rRNA-coding gene activity can be provided by the analysis of the number and size of nucleoli in the prophase of the first meiotic division. The morphology and ultrastructure of a nucleolus depends, among others, on the species and cell growth cycle as well as the physiological and pathological state of an organism. The purpose of this research was to determine the number and size of nucleoli in the spermatocytes of the domestic chicken and the Japanese quail. Diverse numbers and sizes of nucleoli in the cells of the analysed birds were observed. 1-4 nucleoli were identified in chicken cells (1.91 +/- 0.63 on average) and 1-2 in quail cells (1.13 +/- 0.33 on average). For the total of 957 nucleoli observed in Gallus cells, 329 were classified as large and 628 as small. In Coturnix cells, 563 nucleoli were identified (66 large and 497 small ones). An analysis of the numbers and sizes of nucleoli can be performed at the cytogenetic level and serve as an alternative source of information on rRNA encoding gene and nucleolus organising region (NOR) activities. PMID- 23342906 TI - Karyotype of the bird blowfly, Protocalliphora falcozi Seguy, 1928 (Diptera, Calliphoridae). AB - The karyotype structure of Protocalliphora falcozi is described for the first time. The diploid complement comprises 2n = 12, n(male) = 5+XY. Male mitotic plates include four pairs of long (metacentric) and one pair of medium-sized (submetacentric) autosomes. The submetacentric sex chromosomes X and Y are the smallest elements of the set. An achiasmatic meiosis was determined. The heterochromosomes do not form a heterovalent because they occur separately during the first meiotic division. The examined karyotype shows a pericentromeric position of constitutive heterochromatin in all autosomes. The longer arm of the X chromosome is heterochromatic, while the Y is entirely euchromatic. The NORs are active at mitotic prophase and at early meiotic stages. Small, bright signals were observed in the centromeric regions of autosomes after DAPI staining. PMID- 23342907 TI - Chromosome studies of Astyanax jacuhiensis Cope, 1894 (Characidae) from the Tramandai River Basin, Brazil, using in situ hybridization with the 18S rDNA probe, DAPI and CMA3 staining. AB - The genus Astyanax comprises 86 species of fish distributed in Brazilian river basins and is considered of the Incertae sedis group within the family Characidae. This study presents an analysis of 12 specimens of Astyanax jacuhiensis from the Tramandai River Basin, RS Brazil: 6 from the Maquine River and 6 from the Quadros Lagoon. All specimens showed a diploid number equal to 50 chromosomes with different karyotypic formula between the two localities. The population from the Maquine River showed 10m+26sm+6st+8a (FN=92). Fish from the Quadros Lagoon showed 12m+20sm+6st+12a (FN=88). AgNORs were evidenced in the short arm of one acrocentric chromosome pair in both populations, confirmed by FISH with the 18S rDNA probe. CMA3 fluorochrome corresponded with the AgNOR sites, while DAPI staining was negative in these regions. C banding revealed that heterochromatin was weakly distributed, mainly in the pericentromeric and terminal regions in most chromosomes. Analyses of male gonadal tissue were conducted with the objective of characterizing the meiotic chromosome behavior in A. jacuhiensis. The following stages were evidenced: spermatogonial with 50 chromosomes, pachytene and metaphase I with 25 bivalents, and metaphase II with 25 chromosomes, thus confirming the diploid number of the species. Chromosomal abnormalities were not observed. This study shows preliminary data on A. jacuhiensis from the Tramandai River Basin, contributing with more chromosomal information for this group of fish. PMID- 23342908 TI - Sister chromatid exchange in Polish White improved goats (Capra hircus). AB - The study was aimed at evaluating the frequency of spontaneous sister chromatid exchange in Polish White Improved goats (Capra hircus). The mean number of SCEs/cell was 2.73 +/- 1.84. The effect of sex and age on SCE incidence was also investigated. No statistically significant differences in the number of SCEs/cell were observed between the males and females. On the other hand, age was found to significantly influence SCE frequency. A lower SCE frequency was observed in younger goats. A positive correlation between chromosome length and SCE number was identified. The longer the chromosome, the more exchanges occurred. The highest number of SCEs was observed in the interstitial region, the lowest in the distal area. PMID- 23342909 TI - New stands of species of the Paramecium aurelia complex (Ciliophora, Protozoa) in the Mediterranean region (Italy, Greece, Morocco). AB - New stands of species of the Paramecium aurelia complex are presented in the paper, P. primaurelia recorded in Italy (Pisa) and in Morocco (Marrakesh), P. biaurelia in Italy (Calabria), P. triaurelia in Morocco (Ifrane), P. pentaurelia in Greece (Kastorya), and P. dodecaurelia in Italy (Padua). PMID- 23342910 TI - An assessment of the breeding maturity of insemination boars based on ejaculate quality changes. AB - We examined the sexual development and insemination capability of boars representing five breeds used at Polish sow insemination stations. The speed of attaining full breeding maturity by the boars and their insemination usefulness was assessed based on the results of experiments analysing age-related changes in the physical characteristics of the ejaculates. Directly after sampling, the ejaculates were analysed for the following physical parameters: ejaculate volume, sperm concentration and the percentage of progressively motile spermatozoa per ejaculate. The total number of spermatozoa in the ejaculates and the number of insemination doses obtained from one ejaculate were calculated using SYSTEM SUL v. 6.1 software. The sexual development of boars continues during insemination use, leading to improved ejaculatory performance. The physical parameters of the ejaculate change along with the age of the boar. The Duroc and Hampshire boars represent a pattern of sexual development that is different from that of the PLW, PL and Pietrain males, with an evident earlier termination of growth. The American boars (Duroc and Hampshire) acquire top ejaculatory performance approximately 6 months earlier. PMID- 23342911 TI - DNA methylation, histone modifications and behaviour of AKAP95 during mouse oocyte growth and upon nuclear transfer of foreign chromatin into fully grown prophase oocytes. AB - The poor efficiency of mammalian cloning is due to inappropriate/incomplete epigenetic reprogramming of the donor chromatin. As the success in reprogramming of the donor nucleus may require activity of similar mechanisms which reprogram the chromatin in the course of gametogenesis, we decided to follow the status of some epigenetic markers in the late phase of oogenesis in mice, i.e. in prophase oocytes during their growth and after completion of the growth phase. Our analysis reveals an increase in the level of global DNA methylation starting in oocytes with diameters around 60 microm which was further elevated until completion of oocyte growth. A similar increase was observed in respect to the acetylation of histone H4. On the other hand, the methylation of histone H4 Arg3 was constantly high until the end of oocyte growth, although it differed between fully grown oocytes depending on the type of spatial chromatin organization. We have also studied the AKAP95 protein which was abundant at earlier stages but decreased in fully grown oocytes according to changes in their chromatin organization. The nuclear transfer of different types of donor nuclei with hypomethylated DNA into fully grown prophase oocytes did not increase the global level of methylation of transferred foreign chromatin, regardless if the recipient oocyte was devoid of its own nucleus or its nucleus was left intact. This suggests a major problem in the ability of recipient oocytes to modify donor DNA methylation. PMID- 23342912 TI - Analysis of the PPARGC1A gene as a potential marker for productive and reproductive traits in cattle. AB - An association analysis between T19C polymorphism in bovine PPARGC1A and productive and reproductive traits was performed in a population of 620 and 279 Polish Holstein-Friesian cows, respectively. No relationship was found with milk yield and composition. PPARGC1A genotypes had, however, a significant effect on lengths of calving interval and calving to conception interval, and the T allele was demonstrated to have an unfavourable effect on these traits. As the identified associations might result from linkage between the T19C and unknown functional polymorphism, further analysis of the PPARGC1A is necessary to identify the causative gene variation. The first step in searching for new polymorphism was computer analysis of both promoter and 3'UTR gene sequences which resulted in the prediction of binding sites for several transcriptional factors, including CREB. PMID- 23342913 TI - Carcass composition and breast muscle microstructure in guinea fowl (Numida meleagris L.) of different origin. AB - Evaluation of dressing percentage and postmortem traits in 14-week-old white and grey guinea fowl, extended with evaluation of breast muscle microstructure, was the aim of the study. Subjects were two varieties of guinea fowl kept in an environmentally controlled house. Birds received complete commercial feeds. At 14 weeks of rearing, their whole carcasses were dissected postmortem. Diameters and percentages of white (alphaW) and red muscle fibres (betaR) were determined based on histological analysis of the musculus pectoralis superficialis. Similar dressing percentage was found in both guinea fowl varieties. At 14 weeks of age, grey guinea fowl had greater body weight, and weight and proportion of leg muscles and wings compared to white guinea fowl. Females of the white variety had greater weight of breast muscles than males. Breast muscle microstructure showed significantly (P < or = 0.05) greater content and diameter of white fibres in grey guinea fowl, and of red fibres in white guinea fowl. PMID- 23342914 TI - Carcass, meat quality and histochemical traits of m. longissimus lumborum from Zlotnicka Spotted pigs and commercial pigs. AB - Carcass, meat quality and muscle fibre traits of m. longissimus lumborum were studied in 61 Zlotnicka Spotted (ZS) pigs and 35 commercial crossbred (Polish Large White x Polish Landrace) pigs. The animals received organic feed ad libitum and were slaughtered at 210 days of age. The current findings indicate that both slaughter weight and cold carcass weight were significantly lower, and backfat thickness higher for ZS pigs compared to commercial pigs, while the commercial pigs exhibited longer carcasses and greater area, height and width of the loin eye. No significant differences were found in IMF content between the analysed groups. Moreover, the percentage of type I fibres was higher and their diameter was larger in m. longissimus lumborum of ZS compared to commercial pigs, whereas the opposite occurred for type IIB fibre percentage and diameter, and that concurred with markedly higher pigment content and higher pH(u), redness (a*), plasticity values, and significantly lower drip loss, WHC--loose water, and colour lightness (L*) values in ZS pigs than those found in commercial pigs. Also, sensory assessment of raw meat confirmed that m. longissimus lumborum of ZS pigs was characterized by more favourable colour and less exudative meat. PMID- 23342915 TI - Arteries of the brain in wild European rabbit Oryctolagus cuniculus (Linnaeus, 1758). AB - Research into the pattern and variation of brain arteries in wild rabbit involved 43 brains. The main source of blood supply to the brain in rabbit are vertebral arteries and the basilar artery, formed as a result of their anastomosis, as well as internal carotid arteries the branches of which form the arterial circle of the brain. Variation in descent concerns mostly the pattern of descent of middle cerebral arteries, in 36.5% they were multiple vessels. The caudal communicating arteries in wild rabbit constituted a symmetrical anastomosis of internal carotid arteries and caudal cerebral arteries. They stabilized an even blood supply to all parts of the brain. The caudal cerebral arteries constituted the terminal branches of the basilar artery. A comparison of the blood supply to the brain in wild rabbit and domestic rabbit described by WILAND (1968) revealed lower variation in the arteries in the wild form than in the domestic rabbit. PMID- 23342916 TI - Histopathological changes in small and large intestines during hymenolepidosis in rats. AB - The tapeworm Hymenolepis diminuta is a chronic parasite living in the small intestine of rats, mice and humans. The aim of this study was to determine histopathological changes in the rat intestine during experimental hymenolepidosis. Our results showed that in rats infected with H. diminuta slight changes occurred in the length of the villus and crypts in different parts of the digestive tract. The changes were most distinct in the duodenum and jejunum on the 16 days post H. diminuta infection. PMID- 23342917 TI - Changes in estrogen receptor ERalpha and ERbeta expression in chicken (Gallus domesticus) adrenal gland during short-fasting and refeeding. AB - Estrogen receptors have been found in the adrenal gland of rodents, monkeys, mares and sheep, indicating a connection between sex steroids and the activity of the adrenal gland. In the present study, the expression of estrogen receptors alpha (ERalpha) and beta (ERbeta) in the chicken adrenal gland during stress induced by 24 h fasting and after refeeding was determined using reverse transcription and the polymerase chain reaction (RT-PCR). The presence of both ER mRNAs in the adrenal gland of all examined groups was found. The relative expression of ERalpha mRNA was higher than ERbeta mRNA. There were no significant differences in ERalpha mRNA expression among the examined groups. On the contrary, we observed changes in ERbeta expression during stress conditions. These findings indicate different pathways of estrogen action in the avian adrenal gland. Furthermore, changes in ERbeta level suggest that this form of estrogen receptor plays a predominant role for estrogen action in the chicken adrenal gland during stress. PMID- 23342918 TI - Sex- and age-related changes of trabecular bone of tibia in growing domestic geese (Anser domesticus). AB - An analysis of radiological images of the spongious substance of the tibiotarsal bones in domestic goose (120 individuals) was performed for the first time. Based on radiographs obtained from radiological examinations conducted in the region of interest (80 x 90 mm2) of the proximal metaphysis, an analysis of the spongious substance of the tibia was performed with the Trabecula programme in order to construct a map of trabeculae and identify their number, volume and density. The results were evaluated statistically using two-way ANOVA. Changes in the number, volume and density of radiological trabeculae of the tibiotarsal bone (TB) in geese from 4 to 16 weeks old were observed. The lowest number (6.34 per mm2), volume (1.50% mm) and density (33.73%) of radiological trabeculae in the proximal metaphysis of TB was reported in male geese at the age of 6 weeks. Similar tendencies were observed in females as well. It should be noted that the volume and density of radiological trabeculae of the tibiotarsal bone achieved a maximum value in males 12 weeks of age, whereas in females at 8 weeks of age. An inverse relationship between body weight and the number of trabeculae in domestic geese (r = - 0.28; P < or = 0.05) was found. We also found a positive relationship between body weight and the volume of radiological trabeculae in domestic geese (r = 0.43; P < or = 0.05). During posthatching development, from the 4th week to slaughter maturity, a decrease in relative bone mass was observed. Negative changes in the trabecular structure combined with high weight gain could lead to bone deformities and locomotor problems in the studied geese. PMID- 23342919 TI - Independent, non-IGF-I mediated, GH action on estradiol secretion by prehierarchical ovarian follicles in chicken. In vitro study. AB - Information concerning the role of growth hormone (GH) in the local regulation of ovarian activity in birds is limited. Therefore, the aim of the present study was to determine whether in the domestic hen GH influences in vitro estradiol secretion by prehierarchical ovarian follicles. Moreover, the interaction between GH and IGF-I on estradiol secretion was examined. Small white (1-4 mm), large white (4-6 mm) and yellowish (6-8 mm) ovarian follicles were isolated at the stage of 2 h after ovulation. In the first experiment (n = 8 hens), whole follicles (small white, n = 6/dose/ovary; large white, n = 1/dose/ovary and yellowish, n = 1/dose/ovary) were ipcubated for 24 h at 38 degrees C in a medium supplemented with 0 (control), 1, 10 or 100 ng/ml of chicken GH (cGH). In the second experiment (n = 6 hens), follicles were incubated in the same way in a medium with 0 (control), 10 ng/ml cGH, 25 ng/ml human IGF-I or cGH+hIGF-I (10 ng/ml+25 ng/ml). Following incubation the estradiol concentration was determined in media (RIA) and protein in the tissues of the follicular wall (Lowry). The secretion of estradiol was expressed per milligram of protein. The experiments revealed that both cGH and hIGF-I stimulated estradiol secretion by examined chicken ovarian follicles. The simultaneous addition of cGH and hIGF-I increased estradiol secretion by ovarian follicles as compare to the control. These hormones added together did not have an additive effect when compared to their separate actions. The results obtained suggest that both GH and IGF-I are important stimulators of estradiol production in chicken nonhierarchical ovarian follicles. We propose independent, non-IGF-I-mediated GH action on estradiol secretion. PMID- 23342920 TI - Expression of matrix metalloproteinase-2 mRNA in the chicken ovary in relation to follicle remodelling. AB - In the mammalian ovary, matrix metalloproteinase-2 (MMP-2) is thought to be involved in the regulated turnover of the extracellular matrix during the process of follicle development, ovulation and regression. Information concerning the role of MMP-2 in the chicken ovary is scarce. The present investigation was undertaken to determine the distribution of MMP-2 mRNA within the laying hen ovary as well as to define whether the expression of MMP-2 mRNA changes during the ovulatory cycle. Expression of MMP-2 mRNA in ovarian compartments was determined by RT-PCR analysis at two stages of the ovulatory cycle, i.e. at 22 h and 3 h before ovulation. MMP-2 mRNA was detected in the ovarian stroma and follicles: white, yellowish, small yellow, the largest preovulatory (F3-F1) and postovulatory (P1-P5). In the wall of preovulatory follicles MMP-2 mRNA was found in the theca and granulosa layers. Within the ovary the relative expression of MMP-2 mRNA depended on follicular size, the layer of the follicular wall, the stage of the ovulatory cycle and the degree of regression in the postovulatory follicles. The results obtained indicate that in the chicken ovary MMP-2 may take part in the extracellular matrix remodelling required for follicle growth, development and regression. PMID- 23342921 TI - Impact of sex and fishing season on fatty acid profile, fat and cholesterol content in the meat of roach (Rutilus rutilus L.) from Brda River (Poland). AB - The aim of this study was to determine fat and cholesterol content and the fatty acid profile in the meat of roach (Rutilus rutilus L.). Muscle samples for analyses were taken from the large side muscle of the fish body above the lateral line. The study involved 56 individuals caught in fall and spring. Analyses were carried out on 14 females and 14 males caught in each season. The percentage content of fat in the fish meat was determined with the modified method of FOLCH et al. (1957). The cholesterol content was determined with the modified Liebermann-Burchardt colorimetric method using a Shimadzu spectrophotometer (UV VIS-NIR-3100). The fatty acid profile was determined with the gas chromatograph with a flame-ionization detector. Analyses indicated that the percentage content of fat was higher in the meat of roach caught in autumn (0.96% in females and 0.91% in males) than in the tissues of individuals from spring, which was 0.67% and 0.86%, respectively. The content of the total cholesterol was higher in autumn (64.17 mg 100g(-1)) than in spring (56.25 mg 100g(-1)), and these values significantly differed (p < 0.05). Statistical analyses indicated that there were no significant differences in the content of fat and cholesterol between females and males caught in both seasons. The total amounts of SFA, MUFA and PUFA ranged from 30.05% to 33.57%, from 39.53% to 47.64% and from 19.96% to 27.42%, respectively. Analyses of correlations between fatty acids from the n-3 and n-6 group indicated a positive and statistically significant relationship between C20:4 n-6 and C22:4 n-6 (p = 0.000, R = 0.9065) and C20:5 n-3 and C22:6 n-3 (p = 0.000, r = 0.8555). The ratio of n-3/n-6 was highest in the meat of roach caught in spring (0.50-0.81) than in autumn (0.50-0.77). The AI index ranged from 0.35 to 0.46 and the mean values of TI ranged from 0.41 to 0.54. PMID- 23342922 TI - The effect of dietary selenium source on embryonic development in Turkeys. AB - The objective of this study was to determine the effect of dietary selenium source on the growth and development of turkey embryos, and egg hatchability. White broad-breasted BUT Big 6 turkeys (1800 females and 150 males) were placed under optimum management conditions. Turkey diets were supplemented with organic selenium, and in the other with inorganic selenium, in the amount of 0.3 ppm. Eggs intended for incubation and examination were collected in week 2, 10, 18 and 23 of the laying season. The average egg weight was higher (p < or = 0.05) in laying hens fed a diet with organic selenium than in layers receiving inorganic selenium. The rate of yolk sac retraction was faster in embryos from the group fed a diet with inorganic selenium, and it reached 0.59 of the complete yolk sac on day 25 of incubation (p < or = 0.05). Selenium source had no effect on the hatching rates of fertilized eggs, which reached 79.61% and 79.84% in laying hens fed organic and inorganic selenium, respectively. In the flocks fed diets supplemented with organic selenium, dead embryos were more frequently characterized by problems with protein utilization (19.28%) and delayed pipping (10.83%). Embryo death rates at the first mortality peak were higher in layers fed inorganic selenium than in those receiving organic selenium (15% vs. 13.5%). The second embryo mortality peak occurred earlier (day 26) in laying hens fed inorganic selenium than in those fed organic selenium (day 28). PMID- 23342923 TI - Vitamin D3 (cholecalciferol) boosts hydrogen sulfide tissue concentrations in heart and other mouse organs. AB - Vitamin D3 is a crucial co-regulator of bone growth and remodeling, neuromuscular function, inflammation, proliferation, differentiation and apoptosis of cells. Intensive research on endogenous sulfur metabolism has revealed that hydrogen sulfide (H2S) is an important modulator of various physiological processes in mammals. Noteworthy, these compounds are perceived as potential agents in the treatment of numerous disorders, including cardiovascular diseases and different types of cancer. The interaction between vitamin D3 and H2S is unknown. The aim of the study is to assess the influence of cholecalciferol (vitamin D3, calcitriol) on H2S tissue concentrations in mouse brain, heart and kidney. Twenty four SJL mice were given intraperitoneal injections of cholecalciferol at 10000 IU/kg body weight (b.w.) per day (group A, n = 8) or 40000 IU/kg b.w. per day (group B, n = 8). The control group (n = 8) received physiological saline. Free H2S tissue concentrations were measured via the SIEGEL spectrophotometric modified method. There was a significant progressive increase in the H2S concentration along with the rising cholecalciferol doses as compared to the control group in the heart (by 29.6% and by 74.1%, respectively). Higher vitamin D3 dose caused H2S accumulation in the brain (by 10.9%) and in the kidney (by 10.1%). Our study has proven that cholecalciferol affects H2S tissue concentration in different mouse organs. PMID- 23342924 TI - [A clinical study of laparoscopic adrenalectomy for pheochromocytoma--analysis of clinical parameters influencing operative time and intraoperative systolic blood pressure]. AB - PURPOSE: We retrospectively analyzed the preoperative clinical parameters which influence operative time and intraoperative maximum systolic blood pressure in patients undergoing laparoscopic adrenalectomy for pheochromocytoma. MATERIALS AND METHODS: Between January 1992 and September 2010, we performed 28 laparoscopic adrenalectomies for pheochromocytoma at Hamamatsu University School of Medicine. These 28 cases were characterized based on the following parameters: body mass index (BMI), tumor size, history of hypertension, preoperative blood pressure, serum concentration of catecholamine, and 24-h urinary excretion of catecholamine metabolite. We retrospectively analyzed whether or not these parameters influenced operative time or intraoperative maximum systolic blood pressure. RESULTS: All 28 cases of laparoscopic adrenalectomy were performed safely and without intraoperative complications and needed neither blood transfusion nor conversion to laparotomy. The median operative time was 203 minutes, and intraoperative hypertension (systolic blood pressure > 200 mmHg) occurred in 46% (13/28) of cases. Median day of discharge in all patients was post-operative day 5. Significant positive correlation was shown between tumor size and operative time and between intraoperative maximum systolic blood pressure and serum concentration of catecholamine or 24-h urinary excretion of catecholamine metabolite (p < 0.05). CONCLUSION: The lengthened operative time for large tumors and elevated intraoperative blood pressure for tumors with high preoperative catecholamine activity necessitate careful perioperative management in patients receiving laparoscopic adrenalectomy for pheochromocytoma. PMID- 23342925 TI - [Two cases of bowel perforation in patients with metastatic renal cancer treated with a molecularly targeted drug]. AB - (Case 1) An 82-year-old man started immunotherapy with interferon because of lung metastasis 5 years after he had undergone radical nephrectomy. Three years later, he developed multiple metastases, and was started on sorafenib (400 mg/day) and nonsteroidal anti-inflammatory drug (NSAID) orally. As his cancer-related pain worsened with time, he was administered 30 Gy radiation therapy for bone metastasis of L4. He was then admitted to our hospital for pain control because of ineffective radiation therapy. One day, he suddenly had abdominal pain and vomiting, and was diagnosed as bowel perforation based on computed tomography. He was managed conservatively by nasogastric suction and antibiotic course. (Case 2) A 62-year-old man diagnosed as metastatic renal cell cancer began immunotherapy soon after undergoing radical nephrectomy in Dec., 2006. Although he was started on oral sorafenib (800 mg/day) in July, 2008, metastatic foci enlarged after 18 months. He was then changed to sunitinib (50 mg/day). Sunitinib had immediate and long-lasting effect on the cancer for about 10 months, but he was then admitted to our hospital for pleural effusion. While under treatment for thoracic cavity drainage, he experienced upper abdominal pain and was diagnosis as bowel perforation based on computed tomography. He underwent emergency laparotomy. Molecular target drugs such as sorafenib and sunitinib have serious adverse effects. Bowel perforation is rare, but among those adverse effects. It should be remembered that caution is required for long-term use or combined radiation therapy and NSAIDs with molecular target drug. PMID- 23342926 TI - [A case of renal carcinoid with local recurrence and multiple lymph node metastases 4 years after partial nephrectomy]. AB - Primary renal carcinoid is an uncommon tumor. We report a case of local recurrence and multiple lymph node metastases of renal carcinoid 4 years after partial nephrectomy in a 64-year-old man. He was incidentally found to have a mass lesion in the right kidney and right partial nephrectomy was performed 4 years ago. Histological examination including immunohistochemical studies confirmed the diagnosis of the atypical primary renal carcinoid. After 4 years of follow up, abdominal ultrasonography and computed tomography demonstrated a local recurrence and multiple lymph node metastases around the inferior vena cava. He underwent right radical nephrectomy with paraaortic and right renal hilum lymphadenectomy. Histological appearance showed that recurrence of the atypical renal carcinoid. Four of the resected five lymph nodes were positive for metastasis. Unexpectedly, two tiny renal cell carcinomas were also found from the right kidney. The patient remains free from disease recurrence for 2 months post re-operation. This case is the 43rd report of renal carcinoid tumor in Japan. PMID- 23342927 TI - [Ductal adenocarcinoma of the prostate: a report of 7 cases]. AB - Ductal adenocarcinoma of the prostate is a rare subtype of prostatic adenocarcinoma, defined by morphological criteria as one that has papillary or cribriform architecture composed of high columnar cells with pseudostratified nuclei. We clinically evaluated 7 cases of ductal adenocarcinoma of the prostate in our hospital. The median age was 69 years old and median initial serum PSA level was 22.8 ng/ml. Two cases presented with dysuria, two with macrohematuria and one with abnormality on chest radiograph. Five cases were diagnosed on prostate biopsy, one on TUR-P and one on radical prostatectomy. Two had pure ductal adenocarcinoma and five had mixed ductal adenocarcinoma. Four had metastatic disease, and were treated by hormonal therapy. Among three with non metastatic disease, two underwent radical prostatectomy with adjuvant radiotherapy and one underwent external beam radiotherapy with hormonal therapy. Three cases with non-metastatic disease have no biochemical recurrence. Among four with metastatic disease, one underwent chemotherapy of Docetaxel and one had found a new lesion in lung. PMID- 23342928 TI - [Primary carcinoma of the female urethra: report of 4 cases]. AB - We experienced 4 cases of primary carcinoma of the female urethra during 1998 to 2011. All of the cases were diagnosed primary urethral cancer according to tumor biopsy, cystoscopy, and computed tomography (CT) or magnetic resonance imaging (MRI). Patients were between 66 to 92 years of age at the time of presentation. Presenting symptoms included gross hematuria in 1 case, urinary retention in another case, and vulvar bleeding in 2 cases. Pathology showed urothelial carcinoma in 2 cases, adenocarcinoma in 1 case, and squamous cell carcinoma in another case. There were 2 patients with stage D, 1 patient with C, and another with B. Three patients were treated with total cystectomy and ileal conduit. One patient was treated with radiation. Two patients died from urethral cancer, 1 patient is free from disease for 12 months, and another patient became lost during follow-up. PMID- 23342929 TI - Congenital fetal and neonatal visceral chylous effusions: neonatal chylothorax and chylous ascites revisited. A multicenter retrospective study. AB - This retrospective study was carried out at eight Neonatal Intensive Care Units (NICU) Centers worldwide on 33 newborns presenting at birth with pleural, pericardial, or abdominal chylous effusions. Diagnosis of chylous effusion is based on findings of fluid with a milk-like appearance, a concentration of triglycerides in pleural effusion >1.1 mmol/l, and a total cell count >1,000 cells/ml with a predominance of >80% lymphocytes. Thirty-three newborns met the inclusion criteria and were studied. Six subjects who presented at birth with fetal effusion were treated by in-utero pleuro-amniotic shunt. Five of these patients are alive at follow-up. At birth, pleural drainage was performed in 29/33 patients and abdominal drainage was carried out in 3/33. Total parenteral nutrition (TPN) was given to 32/33 patients; 19/23 patients were fed a medium chain triglycerides (MCT). No adverse effects were observed. Eight patients were treated with Octreotide at dosages ranging from 1 to 7 mcg/kg/hour for 8 to 35 days. All patients showed decreased chylous production. Two patients were treated by pleurodesis. Twenty-two babies are alive after at least 6 months follow-up, 9/33 are deceased, and 2 were lost to follow-up. Clinical conditions of survivors are basically good except for lung involvement [chronic lung disease (CLD) or lung lymphangiectasia] and lymphedema. All patients were using a MCT diet at follow-up with good control of chylous effusion. Visceral chylous effusions of the fetus and neonate are rare disorders, and there currently is only partial agreement on decision-making strategies. We suggest the need for an international prospective trial in an effort to establish the efficacy and effectiveness of diagnostic and therapeutic options described in this article. PMID- 23342930 TI - Efficacy of manual lymphatic drainage in preventing secondary lymphedema after breast cancer surgery. AB - This study evaluated the effectiveness of manual lymphatic drainage (MLD) in the prevention of secondary lymphedema after treatment of breast cancer. The study consisted of 67 women, who underwent breast surgery for primary breast cancer. From the second day of surgery, 33 randomly chosen women were given MLD. The control group consisted of 34 women who did not receive MLD. Measurements of the volumes of both the arms were taken before surgery and on days 2, 7, 14, and at 3 and 6 months after surgery. At 6 months after breast cancer surgery, among the women who did not undergo MLD, a significant increase in the arm volume on the operated side was observed (p=0.0033) when compared with the arm volume before surgery. At this time, there was no statistically significant increase in the volume of the upper limb on the operated side in women who underwent MLD. This study demonstrates that regardless of the surgery type and the number of the lymph nodes removed, MLD effectively prevented lymphedema of the arm on the operated side. Even in high risk breast cancer treatments (operation plus irradiation), MLD was demonstrated to be effective against arm volume increase. Even though confirmatory studies are needed, this study demonstrates that MLD administered early after operation for breast cancer should be considered for the prevention of lymphedema. PMID- 23342931 TI - Symptom burden and infection occurrence among individuals with extremity lymphedema. AB - Currently, there is a lack of data related to differences in symptoms and infection across different types and anatomical sites of lymphedema. The objective of this study was to examine differences in symptoms and infection status among individuals with lymphedema of the upper or lower extremities. The National Lymphedema Network initiated an online survey of self-report lymphedema data from March 2006 through January 2010. Descriptive statistics, Mann-Whitney tests, and Chi-square tests were used to analyze data. 723 individuals with upper extremity lymphedema and 1114 individuals with lower extremity lymphedema completed the survey. Individuals with extremity lymphedema experienced high symptom burden and infectious complications. Compared with individuals with upper extremity lymphedema, individuals with lower extremity lymphedema experienced more frequent and more severe symptoms (p<.001), infection episodes (p<.001), and infection-related hospitalizations (p<.001). No statistically significant differences of symptom burden and infection status were identified between individuals with lower extremity primary and secondary lymphedema. Individuals with extremity lymphedema experience substantial symptom burden and infectious complications; however, those with lower extremity lymphedema have more severe symptoms and more infections than those with upper extremity lymphedema. PMID- 23342932 TI - Progressive lipo-lymphedema associated with increased activity of dermal fibroblasts in monoclonal gammopathy of undetermined significance: is there a causal relationship? AB - The pathophysiology of skin diseases associated with monoclonal gammopathies is generally unknown. Our aim was to investigate whether a monoclonal gammopathy could be a causal factor in progressive lymphedema. We describe a 75 year old patient with a rapidly progressive lipo-lymphedema and a monoclonal gammopathy of unknown significance (MGUS) suspected as a key etiological factor. Dermal fibroblasts were cultured from lesional lower leg skin and non-lesional abdominal skin and compared to healthy control fibroblasts. We found 10-fold elevated basic fibroblast growth factor 2 (FGF-2) in the patient's serum and significantly increased basal FGF-2 production of lesional and non-lesional fibroblasts compared to healthy controls. Upon restimulation with patient or healthy control serum, lesional fibroblasts showed significantly increased proliferation rates and FGF-2 production in vitro. Non-lesional abdominal fibroblasts showed an intermediate phenotype between lesional and control fibroblasts. Our findings provide the first evidence that lesional dermal fibroblasts from lipo-lymphedema with plasma cell infiltration show increased proliferation and FGF-2 production and that both local tissue factors and altered FGF-2 serum levels associated with monoclonal gammopathies might contribute to this phenotype. Thus we propose a possible pathophysiologic link between the gammopathy-associated factors and the generation of lymphedema with initial fibrogenesis aggravating pre-existing lipedema. PMID- 23342933 TI - Disturbances of mesenteric lymph flow and in vivo intestinal lymphocyte trafficking during early gut injury induced by ischemia-reperfusion in rats. AB - We sought to define the role of mesenteric lymph in the generation of remote organ damage at the early stage of gut ischemia-reperfusion (I/R) injury. The measurement of mesenteric lymph flow was carried out by cannulation of mesenteric lymphatics. The distribution of in vivo intestinal lymphocyte trafficking was performed by 51Cr labeled lymphocyte and measurement of 51Cr-lymphocytes distribution by gamma-counter. Endotoxin concentration was assayed using the limulus test kit and TNF-alpha level was detected by ELISA. After gut I/R injury, the volumes of lymph flow in mesenteric lymphatics per hour were sharply decreased by 72% and the number of intestinal lymphocytes per milliliter was decreased by 61%, which led to the intestinal lymphocyte output per hour significantly decreased by 90% (predominantly T cells), while the population of 51Cr-lymphocytes in Peyer's patches, small intestine (except Peyer's patches), mesenteric nodes, large intestine, and stomach increased by 87%, 191%, 87%, 266%, 262%, respectively. Meanwhile, endotoxin and TNF-alpha levels in mesenteric lymph were significantly increased. These findings demonstrate the marked disorders of mesenteric lymph flow and in vivo intestinal lymphocytes migration and the accompanying increase of endotoxin and TNF-alpha levels in mesenteric lymph in the early stage of gut I/R injury. PMID- 23342934 TI - A survey of nurses' perceptions of the intensive care delirium screening checklist. AB - OBJECTIVES: Delirium in critically ill patients is common and is associated with increased morbidity and mortality. Routine delirium screening is recommended by the Society of Critical Care Medicine. The Intensive Care Delirium Screening Checklist (ICDSC) is one validated and commonly-used tool, but little is known about nurses'perceptions of using the ICDSC, and of barriers to delirium assessment and treatment. DESIGN: A survey was administered to 189 critical care trained nurses working on four oncology inpatient units, where the ICDSC has been used for greater than five years. RESULTS: Eighty-four nurses (44%) responded to the survey. Respondents indicated that they had knowledge of delirium, confidence in the ICDSC, and that the ICDSC was useful. Respondents perceived that physicians did not value the ICDSC results. Similar to prior nurse surveys for other delirium screening tools, physicians were the most frequently identified barrier to both delirium assessment and treatment, with other frequent barriers being lack of time, feedback on performance, and knowledge of delirium. CONCLUSIONS: The ICDSC is viewed favourably by nurses with experience using the tool. Future delirium screening programs should encourage physician engagement early in the planning process to help address perceived barriers to delirium assessment and treatment. PMID- 23342935 TI - Burnout in critical care nurses: a literature review. AB - Burnout and its development in critical care nurses is a concept that has received extensive study, yet remains a problem in Canada and around the world. Critical care nurses are particularly vulnerable to developing burnout due to the chronic occupational stressors they are exposed to, including high patient acuity, high levels of responsibility, working with advanced technology, caring for families in crisis, and involved in morally distressing situations, particularly prolonging life unnecessarily. The purpose of this article is to explore how the chronic stressors that critical care nurses are exposed to contribute to the development of burnout, and strategies for burnout prevention. A review of the literature between the years 2007 and 2012 was conducted and included the search terms burnout, moral distress, compassion fatigue, intensive care, critical care, and nursing. The search was limited to the adult population, English language, and Western cultures. The results revealed that nurse managers play a crucial role in preventing burnout by creating a supportive work environment for critical care nurses. Strategies for nurse managers to accomplish this include being accessible to critical care nurses, fostering collegial relationships among the different disciplines, and making a counsellor or grief team available to facilitate debriefing after stressful situations, such as a death. In addition, critical care nurses can help prevent burnout by being a support system for each other and implementing self-care strategies. PMID- 23342936 TI - Delirium in the intensive care unit: role of the critical care nurse in early detection and treatment. AB - Critically ill patients are at increased risk of developing delirium, which has been considered one of the most common complications of intensive care unit (ICU) hospitalization. Despite the high occurrence of delirium in the ICU, researchers have shown it is consistently overlooked and often undiagnosed. An understanding of delirium and the three clinical subtypes of hyperactive, hypoactive and mixed type delirium that exist are key to early detection and treatment. Critical care nurses are in the frontline position to detect and monitor for risk factors that contribute to the development of delirium in the ICU. Recognition of predisposing risk factors and the elimination of precipitating risk factors for delirium can prevent the devastating short-term and long-term consequences for the critically ill patient. The importance of the use of validated assessment tools, such as the Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) to detect key features of delirium development is emphasized. Recommendations to improve the practice of critical care nurses include continuing education regarding the causes, risk factors and treatments of delirium, and education sessions on the use of validated assessment tools. Early prevention strategies, such as modification of the ICU environment to promote normal sleep/wake cycles, including reduction of unit noise and nighttime interruptions, are examined as interventions to avoid the development of delirium. PMID- 23342937 TI - The building bridges initiative: learning with, from and about to create an interprofessional end-of-life program. AB - In this paper, the authors outline the rationale, planning, delivery, results, evaluation and knowledge transfer strategies employed in offering an eight-hour education day offered 12 times in 2010, to a total of 200 staff in three Toronto General Hospital (TGH) intensive care units (ICU) at the University Health Network (UHN). The integration of members from the point-of-care staff teams into the planning, development, presentation and attendance was a critical success factor for this initiative. Organizers and participants had the opportunity to build bridges with each other and across teams and programs by engaging in interprofessional learning, sharing narratives and consolidating increasing awareness of resources with facilitation from staff from nursing, medicine, palliative care, bioethics, social work, physiotherapy, respiratory therapy, wellness and spiritual care. The format, which will be outlined with examples and stories of engagement, included an opportunity to explore common elements of ICU work including moral distress, demonstrated wellness and team communication strategies, as well as the introduction of an interprofessional patient/family meeting checklist reviewed and evaluated by participants. An assessment of quality of life in an ICU was explored using a panel, case study and discussion. The results of the evaluation, which included a qualitative reflection on collaborative themes, a program evaluation and an individual learning assessment, will be discussed, as well as sustainability and transferability possibilities specific to interprofessional programming and team development. PMID- 23342938 TI - Applying a multivariate statistical analysis model to evaluate the water quality of a watershed. AB - Multivariate statistics have been applied to evaluate the water quality data collected at six monitoring stations in the Feitsui Reservoir watershed of Taipei, Taiwan. The objective is to evaluate the mutual correlations among the various water quality parameters to reveal the primary factors that affect reservoir water quality, and the differences among the various water quality parameters in the watershed. In this study, using water quality samples collected over a period of two and a half years will effectively raise the efficacy and reliability of the factor analysis results. This will be a valuable reference for managing water pollution in the watershed. Additionally, results obtained using the proposed theory and method to analyze and interpret statistical data must be examined to verify their similarity to field data collected on the stream geographical and geological characteristics, the physical and chemical phenomena of stream self-purification, and the stream hydrological phenomena. In this research, the water quality data has been collected over two and a half years so that sufficient sets of water quality data are available to increase the stability, effectiveness, and reliability of the final factor analysis results. These data sets can be valuable references for managing, regulating, and remediating water pollution in a reservoir watershed. PMID- 23342939 TI - Chemical treatment of chelated metal finishing wastes. AB - This study evaluated two chemical approaches for treatment of commingled cadmium cyanide (Cd-CN) and zinc-nickel (Zn-Ni) wastewaters. The first approach, which involved application of sodium hypochlorite (NaOCl), focused on elimination of chelating substances. The second approach evaluated the use of sodium dimethyldithiocarbamate (DMDTC) to specifically target and precipitate regulated heavy metals. Results demonstrated that by maintaining a pH of 10.0 and an oxidation-reduction potential (ORP) value of +600 mV, NaOCl treatment was effective in eliminating all chelating substances. Cadmium, chromium, nickel, and zinc solution concentrations were reduced from 0.27, 4.44, 0.06, and 0.10 ppm to 0.16, 0.17, 0.03, and 0.06 ppm, respectively. Similarly, a 1% DMDTC solution reduced these same metal concentrations in commingled wastewater to 0.009, 1.142, 0.036, and 0.320 ppm. Increasing the DMDTC concentration to 2% improved the removal of all regulated heavy metals except zinc, the removal of which at high pH values is limited by its amphotericity. PMID- 23342940 TI - The Dynamic Anaerobic Reactor & Integrated Energy System (DARIES) model: model development, validation, and sensitivity analysis. AB - The Dynamic Anaerobic Reactor & Integrated Energy System (DARIES) model has been developed as a biogas and electricity production model of a dairy farm anaerobic digester system. DARIES, which incorporates the Anaerobic Digester Model No. 1 (ADM1) and simulations of both combined heat and power (CHP) and digester heating systems, may be run in either completely mixed or plug flow reactor configurations. DARIES biogas predictions were shown to be statistically coincident with measured data from eighteen full-scale dairy operations in the northeastern United States. DARIES biogas predictions were more accurate than predictions made by the U.S. AgSTAR model FarmWare 3.4. DARIES electricity production predictions were verified against data collected by the NYSERDA DG/CHP Integrated Data System. Preliminary sensitivity analysis demonstrated that DARIES output was most sensitive to influent flow rate, chemical oxygen demand (COD), and biodegradability, and somewhat sensitive to hydraulic retention time and digester temperature. PMID- 23342941 TI - Nitrogen removal in constructed wetlands using nitritation/anammox and nitrification/ denitrification: effects of influent nitrogen concentration. AB - Simultaneous nitritation/anammox and nitrification/denitrification (SNAND) is a promising method to increase nitrogen removal from ammonium- and nitrate-rich wastewater. This study examined the effects of influent nitrogen concentrations on plant assimilation and microbial nitrogen removal via SNAND in three free water surface wetlands. Anammox and denitrification contributed 78 and 22%, respectively, of microbial removal of total inorganic nitrogen (TIN). Nitrogen removal rates increased with influent concentrations in the low ranges of 17 to 105 mg N/L ammonium and 51 to 179 mg N/L TIN. However, nitrogen removal rates appeared to decrease with influent concentrations in the high ranges of 248 to 293 mg N/L ammonium and 348 to 391 mg N/L TIN. Plant growth was negatively affected when influent ammonium concentration exceeded 46 to 76 mg N/L. Plant assimilation contributed 11 to 47% toward TIN removal at low influent ammonium concentrations (42 to 76 mg N/L) and 4% at high influent ammonium concentrations (mean 264 mg N/L). PMID- 23342942 TI - Assessment of nutritional value of single-cell protein from waste-activated sludge as a protein supplement in poultry feed. AB - The amount of protein wasted through sludge in Gauteng, South Africa, amounts to 95 000 metric tonne/yr, with the order of magnitude of the national protein requirement of approximately 145 000 metric tonne/yr. Waste-activated sludge (WAS) from wastewater treatment plants (WWTPs) that treat domestic wastewater contains protein in a ratio of 2:1 against fishmeal. This protein source has not been utilized because of the high content of toxic heavy metals and other potential carcinogenic pollutants in the sludge. In this study, a pretreatment method of modified aqua regia dilute acid wash was used to lower the metal content by approximately 60%. However, this resulted in a 33% loss of amino acids in the acid-washed WAS. A feed substitution test in poultry with different fishmeal-sludge ratios (0%, 25%, 50%, 75%, and 100% WAS as percent substitution of fishmeal) showed no impact of sludge single-cell protein (SCP) on mortality rate. However, sludge substitution in the feed yielded weight gains and cost savings up to 46%. PMID- 23342943 TI - Adsorption kinetic and thermodynamic studies of phosphate onto tantalum hydroxide. AB - Tantalum hydroxide exhibits the ability for the removal of phosphate from aqueous solution. The kinetic study, adsorption isotherm, thermodynamic study, desorption, and foreign anions effect were examined in batch experiments. The kinetic process was very well described by a pseudo-second-order rate model. The adsorption isotherms showed that phosphate uptake fitted with a Langmuir-type model very well, with an increase of PO4(3-) adsorption capacity from 78.5 to 97.0 mg/g when the temperature increased from 298 to 338 K. The negative values of deltaG(0) and the positive values of deltaH(0) indicated that the phosphate adsorption process was spontaneous and endothermic naturally. While the deltaS(0) values obtained were positive, indicating an increase in randomness at the solid liquid interface during the adsorption. Foreign anions tests showed that the presence of competitive ions cause minimal interference with the adsorption of phosphate on tantalum hydroxide. PMID- 23342944 TI - Removal of polyvinylpyrrolidone from wastewater using different methods. AB - Polyvinylpyrrolidone (PVP) is a frequently used polymer in the pharmaceutical and foodstuff industries. Because it is not subject to metabolic changes and is virtually nondegradable, trace concentrations of PVP are often found in community wastewaters. The literature finds that the partial removal of PVP in wastewater treatment plants probably occurs through sorption. The primary objective of this study was to find an effective method to remove PVP from wastewaters. In this regard, the literature indicates the theoretical potential to use specific enzymes (e.g., gamma-lactamases, amidases) to gradually degrade PVP molecules. Polyvinylpyrrolidone biodegradability tests were conducted using suitable heterogeneous cultures (activated sludge) collected from a conventional wastewater treatment plant, treatment plants connected to a pharmaceutical factory, and using select enzymes. Aerobic biodegradation of PVP in a conventional wastewater environment was ineffective, even after adaptation of activated sludge using the nearly identical monomer 1-methyl-2-pyrrolidone. Another potential method for PVP removal involves pretreating the polymer prior to biological degradation. Based on the results (approximately 10 to 15% biodegradation), pretreatment was partially effective, realistically, it could only be applied with difficulty at wastewater treatment plants. Sorption of PVP to an active carbon sorbent (Chezacarb S), which corresponded to the Langmuir isotherm, and sorption to activated sludge, which corresponded to the Freundlich isotherm, were also evaluated. From these sorption tests, it can be concluded that the considerable adsorption of PVP to activated sludge occurred primarily at low PVP concentrations. Based on the test results, the authors recommend the following methods for PVP removal from wastewater: (1) sorption; (2) application of specific microorganisms; and (3) alkaline hydrolysis, which is the least suitable of the three for use in wastewater treatment plants. PMID- 23342945 TI - Effect of black wattle (Acacia mearnsii) extract on blue-green algal bloom control and plankton structure optimization: a field mesocosm experiment. AB - A field mesocosm experiment was conducted at the Three Gorges Reservoir to investigate the utility of black wattle extract in controlling blue algal blooms. The mesocosm experiment was divided into two parts: (1) a short-term test to evaluate how black wattle extract inhibits algal blooms in an emergency and (2) a long-term test to evaluate how black wattle extract maintains water quality and prevents algal blooms over a 1-year period. In the short-term test, the results showed that 3 to 4 mg L(-1) black wattle extract could reduce algal biomass in 1 week, whereas serious algal blooms occurred in the untreated control mesocosm. More importantly, the long-term test suggested that black wattle extract played a significant role in plankton structure optimization at lower concentrations of 1 to 2 mg L(-1). In this test, phytoplankton diversity increased, with the dominant species shifting from cyanobacteria to diatoms and other algae. Meanwhile, as water quality improved through the presence of plant extract treatment, the numbers of smaller zooplankton decreased and larger species increased. Therefore, this investigation founded a novel nature plant agent that not only has good effects on algal bloom control, but also restores the aquatic ecosystem. PMID- 23342946 TI - Of: Effects of temperature on bacterial transport and destruction in bioretention media: field and laboratory evaluations, L. Zhang, E. A. Seagren, A. P. Davis, J. S. Karns, 84, 485-496 (2012). PMID- 23342947 TI - 3-(Dialkoxyphosphoryl)-N-confused phlorin and porphyrin. Synthesis, stereochemistry, and coordination properties. AB - A 3-phosphonated N-confused phlorin 3 was synthesized by the reaction of N confused porphyrin 1 and trimethyl or triethyl phosphite 2 in the presence of acetic acid in good yield. The presence of hydrogen and aryl substituents in one of the meso positions (C5) generates a stereogenic center, resulting in configurationally stable enantiomers. The enantiomers were separated by HPLC and characterized by the circular dichroism method for the first time in the case of phlorin. Further oxidation of 3 by DDQ (2,3-dichloro-5,6-dicyano-1,4 benzoquinone) afforded the achiral 3-phosphonated N-confused porphyrin 4. Chiral chlorozinc 4-Zn and chlorocadmium 4-Cd, as well as achiral nickel(II) complexes 4 Ni were also characterized. For 4-Cd in the solid state, formation of a dimer consisting of heterochiral subunits joined by two H-bonds was established by a single crystal X-ray analysis. For 4-Cd, separation of enantiomers was achieved. Slow racemization of 4-Cd in solution prevented the absolute configuration determination by the X-ray method indicating the labile character of the complex. The relationship between circular dichroism and absolute configuration of 3a and 4-Cd was established on the basis of TD-DFT calculations. PMID- 23342948 TI - Dual patterning of a poly(acrylic acid) layer by electron-beam and block copolymer lithographies. AB - We show the controllable patterning of palladium nanoparticles in both one and two dimensions using electron-beam lithography and reactive ion etching of a thin film of poly(acrylic acid) (PAA). After the initial patterning of the PAA, a monolayer of polystyrene-b-poly-2-vinylpyridine micelles is spun cast onto the surface. A short reactive ion etch is then used to transfer the micelle pattern into the patterned poly(acrylic acid). Finally, PdCl2 is loaded from solution into the patterned poly(acrylic acid) features, and a reactive-ion etching process is used to remove the remaining polymer and form Pd nanoparticles. This method yields location-controlled patches of nanoparticles, including single- and double-file lines and nanoparticle pairs. A locational accuracy of 9 nm or less in one direction was achieved by optimizing the size of the PAA features. PMID- 23342949 TI - Hippurate: the natural history of a mammalian-microbial cometabolite. AB - Hippurate, the glycine conjugate of benzoic acid, is a normal constituent of the endogenous urinary metabolite profile and has long been associated with the microbial degradation of certain dietary components, hepatic function and toluene exposure, and is also commonly used as a measure of renal clearance. Here we discuss the potential relevance of hippurate excretion with regard to normal endogenous metabolism and trends in excretion relating to gender, age, and the intestinal microbiota. Additionally, the significance of hippurate excretion with respect to disease states including obesity, diabetes, gastrointestinal diseases, impaired renal function, psychological disorders and autism, as well as toxicity and parasitic infection, are considered. PMID- 23342950 TI - Effect of helical conformation and side chain structure on gamma-secretase inhibition by beta-peptide foldamers: insight into substrate recognition. AB - Substrate-selective inhibition or modulation of the activity of gamma-secretase, which is responsible for the generation of amyloid-beta peptides, might be an effective strategy for prevention and treatment of Alzheimer's disease. We have shown that helical beta-peptide foldamers are potent and specific inhibitors of gamma-secretase. Here we report identification of target site of the foldamers by using a photoaffinity probe. The photoprobe directly and specifically labeled the N-terminal fragment of presenilin 1, in which the initial substrate docking site is predicted to be located. We also optimized the foldamer structure by preparing a variety of derivatives and obtained two highly potent foldamers by incorporation of a hydrophilic and neutral functional group into the parent structure. The class of side chain functional group and the position of incorporation were both important for gamma-secretase-inhibitory activity. The substrate selectivity of the inhibitory activity was also quite sensitive to the class of side chain group incorporated. PMID- 23342951 TI - Enhanced dipole moments in trimetallic nitride template endohedral metallofullerenes with the pentalene motif. AB - Although not found to date in empty-cage fullerenes, the fused pentagon motifs (pentalenes) are allowed in endohedral metallofullerenes (EMFs). We have found that members of the trimetallic nitride template (TNT) EMF Y3N@C2n (n = 39-44) family that contain pentalene motifs exhibit significant dipole moments. This finding is predicted to be significant for other EMFs with a metal atom orientated toward the pentalene motif. Chromatographic retention data and computational results for Y3N@C2-C78, Y3N@Cs-C82, and Y3N@Cs-C84 are examples that pentalene groups lead to a significant induced dipole moment (~1D). A special case is the Y3N@C2-C78 that contains two pentalenes in a relatively small cage. The (13)C NMR spectrum for Y3N@C2-C78 exhibits strongly deshielded signals for the fullerene cage (155-170 ppm) supporting the presence of the pentalene motif. In addition, a lengthening of the covalent M-N bond in the internal M3N cluster is found for all reported TNT EMFs that contain one or two pentalene motifs. PMID- 23342953 TI - The social-cognitive basis of borderline and antisocial personality disorder: introduction. PMID- 23342952 TI - Serum osteocalcin level and its association with carotid atherosclerosis in patients with type 2 diabetes. AB - OBJECTIVE: To investigate the association of serum osteocalcin with carotid atherosclerosis in patients with type 2 diabetes. METHODS: We performed a cross sectional community-based study in metropolitan area. Serum total osteocalcin was measured by radioimmunoassay in 382 men and 435 postmenopausal women. The carotid artery intima-media thickness (IMT) and carotid plaques (PLQ) were measured by B mode ultrasound. RESULTS: The crude mean of serum osteocalcin concentrations were 4.52+/-2.43 ng/ml for men and 5.75+/-2.92 ng/ml for postmenopausal women (P <0.001), respectively. Osteocalcin levels were associated inversely with age, fasting serum insulin, HOMA-IR, ALT, triglycerides, total cholesterol, LDL- cholesterol, CRP (all P<0.001) and positively with adiponectin and HOMA-B (all P<0.05). After multiple adjustment, the odds ratios (ORs) were substantially higher risk for carotid plaques (OR 1.77 for 1 SD decrease in osteocalcin, 95% CI 1.23-2.76, p=0.005). These associations remained significant after further adjustment for potential confounder. CONCLUSIONS: Serum osteocalcin levels is an independent risk factor for carotid atherosclerosis in patients with type 2 diabetes. PMID- 23342954 TI - Hypermentalizing in adolescent inpatients: treatment effects and association with borderline traits. AB - Sharp et al. (2011) recently demonstrated that in adolescents with borderline traits the loss of mentalization is more apparent in the emergence of unusual alternative strategies (excessive theory of mind or hypermentalizing) than in the loss of the capacity per se (no mentalizing or undermentalizing). This suggests that hypermentalizing could be a worthwhile social-cognitive treatment target in adolescents with borderline traits. The aim of the current study was to examine (1) whether a reduction in excessive theory of mind or hypermentalizing is achieved between admission and discharge for adolescent inpatients; (2) whether the hypothesized reduction is more apparent in adolescents meeting criteria for BPD compared with psychiatric controls; and (3) whether other forms of mentalizing would also be sensitive to and malleable by inpatient treatment in the same way we expected hypermentalizing to be. The "Movie for the Assessment of Social Cognition" Task (Dziobek et al., 2006) was administered to consecutive admissions to an adolescent inpatient setting (n = 164) at admission and discharge, alongside measures of borderline symptomology and interview-based diagnosis of BPD. Results demonstrated that 41% (n = 68) of the sample met full or intermediate criteria for BPD on an interview-based measure of BPD. A relation between borderline traits and hypermentalizing that appears to be independent of internalizing and externalizing problems was demonstrated. Hypermentalizing, but not other forms of social-cognitive reasoning (as measured by the Child Eyes Test, Basic Empathy Scale and the Mentalizing Stories Test for Adolescents), was found to be malleable through a milieu-based inpatient treatment. Clinical implications of the findings for the organization of treatment settings for adolescents are discussed. PMID- 23342955 TI - Reduced sensitivity to emotional facial expressions in borderline personality disorder: effects of emotional valence and intensity. AB - A heightened sensitivity towards negative emotional stimuli has been described for Borderline Personality Disorder (BPD). We investigated whether a faster and more accurate detection of negatively valent information in BPD can be confirmed by means of a visual search task which required subjects to detect a face with an incongruent emotional expression within a crowd of neutral faces. Twenty eight BPD patients and 28 nonpatients were asked to indicate whether a set of schematic neutral faces (3 * 3, 4 * 4 matrices) contained a happy or an angry face. Besides valence, the intensity of the target's emotion was varied in two steps. BPD patients and nonpatients both demonstrated an anger-superiority effect. However, no higher sensitivity towards negative stimuli was observed in BPD compared to nonpatients. BPD patients seem to rely to a stronger extent on controlled, i.e., serial, attention demanding processes when searching more subtle social-emotional information with positive valence. PMID- 23342956 TI - Neither dichotomous nor split, but schema-related negative interpersonal evaluations characterize borderline patients. AB - Cognitive models explain extreme thoughts, affects, and behaviors of patients with Borderline Personality Disorder (BPD) by specific mal-adaptive schemas and dichotomous thinking. Psychodynamic theories ascribe these to splitting. This study expanded the study of Veen and Arntz (2000) and investigated whether extreme evaluations in BPD are (1) dichotomous, negativistic, or split; (2) limited to specific (schema-related) interpersonal situations; and (3) related to traumatic childhood experiences. BPD (n = 18), cluster C personality disorder (n = 16), and nonpatient (n = 17) groups were asked to judge 16 characters portrayed in film fragments in a specific or nonspecific context and with negative, positive, or neutral roles on visual analogue scales. These scales were divided in negative-positive trait opposites related to BPD schemas, negative-positive trait opposites unrelated to BPD schemas, and neutral trait opposites. Interpersonal evaluations of patients with BPD were (1) negativistic; (2) schema related; and (3) partially related to traumatic childhood experiences. Negative evaluations of caring characters in an intimate context particularly characterized BPD. No evidence was found for dichotomous thinking or splitting in BPD. PMID- 23342957 TI - The relationship between adult reactive and proactive aggression, hostile interpretation bias, and antisocial personality disorder. AB - Reactive aggression (RA) refers to angry responses to provocation or frustration, while proactive aggression (PA) denotes nonemotional, instrumental, and unprovoked aggression. The current study examined personality-related and cognitive correlates of both aggressive types. Respectively, the predictive values of antisocial personality disorder (ASPD), and of hostile interpretation bias, which is the tendency to interpret ambiguous stimuli in a hostile manner, were studied. The sample consisted of n = 37 male adult patients with mixed diagnoses and n = 29 male nonpatients that responded to vignettes and pictures of ambiguous situations, using both open and closed answer formats. ASPD was assessed by means of the Structured Clinical Interview for DSM-IV Axis II disorders (SCID-II), and the Reactive Proactive Questionnaire (RPQ) measured RA and PA. Results showed that although both RA and PA types were predicted by ASPD traits, RA was additionally predicted by a hostile interpretation bias. These findings suggest that reducing hostile bias is a promising avenue for clinical treatment of ASPD-patients high in RA. PMID- 23342958 TI - Emotional empathy and psychopathy in offenders: an experimental study. AB - Previous studies associated psychopathy in adults with deficits in empathy but these studies did not directly compare cognitive and emotional facets of empathy. The present study sought to establish whether psychopathy is associated with impairments in emotional empathy among adult offenders. Participants were 90 male offenders scoring low (n = 29), medium (n = 33) or high (n = 28) on the Psychopathy Checklist-Revised (PCL-R) and n = 28 male noncriminal controls. Empathy functioning was assessed through self-report and computerized decision tasks, differentiating between perspective-taking (cognitive empathy) and compassion (emotional empathy). Against expectations, level of psychopathy among the offenders was not associated with either emotional or cognitive empathy. Offenders however had lower scores for both cognitive and emotional components of empathy functioning than controls. Both facets of empathy showed small but significant positive correlations with education level and social desirability. The methods employed to assess differences in empathy functioning may not be sensitive enough to assess differences in forensic samples. PMID- 23342959 TI - Learning-style bias and the development of psychopathy. AB - In accordance with a recently proposed account of amygdala function in psychopathy, it is hypothesized that people with high levels of psychopathic personality traits have a bias in learning style to encode the general valence, and neglect the specific-features, of an outcome. We present a novel learning task designed to operationalize these biases in learning style. The results from pilot samples of healthy adults and children and from a clinical sample of children with conduct problems provide support for the validity of the learning task as a measure of learning style and demonstrate a significant relationship between general-valence style learning and psychopathic personality traits. It is suggested that this relationship may be important for the aetiology of the social cognitive deficits exhibited by psychopaths. These preliminary results suggest that this measure of learning style has the potential to be utilized as a research tool and may assist with the early identification, and treatment, of children with conduct problems and high levels of callous-unemotional traits. PMID- 23342961 TI - The social-cognitive basis of personality disorders: commentary on the special issue. PMID- 23342960 TI - Callous-unemotional traits modulate the neural response associated with punishing another individual during social exchange: a preliminary investigation. AB - The current study examined whether Callous-Unemotional (CU) traits, a core component of psychopathy, modulate neural responses of participants engaged in a social exchange game. In this task, participants were offered an allocation of money and then given the chance to punish the offerer. Twenty youth participated and responses to both offers and the participant's punishment (or not) of these offers were examined. Increasingly unfair offers were associated with increased dorsal anterior cingulate cortex (dACC) activity but this responsiveness was not modulated by CU traits. Increasing punishment of unfair offers was associated with increased dACC and anterior insula activity and this activity was modulated by CU traits. Higher CU trait participants showed a weaker association between activity and punishment level. These data suggest that CU traits are associated with appropriate expectations of other individual's normative behavior but weaker representations of such information when guiding behavior of the self. PMID- 23342962 TI - Posterolateral inter-transverse lumbar fusion in a mouse model. AB - BACKGROUND: Spinal fusion is a common orthopaedic procedure that has been previously modeled using canine, lapine, and rodent subjects. Despite the increasing availability of genetically modified mouse strains, murine models have only been infrequently described. PURPOSE: To present an efficient and minimally traumatic procedure for achieving spinal fusion in a mouse model and determine the optimal rhBMP-2 dose to achieve sufficient fusion mass. METHOD: MicroCT reconstructions of the unfused mouse spine and human spine were compared to design a surgical approach. In phase 1, posterolateral lumbar spine fusion in the mouse was evaluated using 18 animals allocated to three experimental groups. Group 1 received decortication only (n=3), Group 2 received 10 MUg rhBMP-2 in a collagen sponge bilaterally (n=6), and Group 3 received 10 MUg rhBMP-2 + decortication (n=9). The surgical technique was assessed for intra-operative safety, efficacy, access and reproducibility. Spines were harvested for analysis at 3 weeks (Groups 1, 2) and 1, 2, and 3 weeks (Group 3). In phase 2, a dose response study was carried out in an additional 18 animals with C57BL6 mice receiving sponges containing 0, 0.5, 1, 2.5, 5 MUg of rhBMP-2 per sponge bilaterally. RESULTS: The operative procedure via midline access was rapid and reproducible, and fusion of the murine articular processes was found to be analogous to the human procedure. Unlike reports from other species, decortication alone (Group 1) yielded no new bone formation. Addition of rhBMP-2 (Groups 2 and 3) yielded a significant bone mass that bridged the L4-L6 vertebrae. The subsequent dose response experiment revealed that 0.5 MUg rhBMP-2 per sponge was sufficient to create a fusion mass. CONCLUSION: We describe a new approach for mouse lumbar spine fusion that is safe, efficient, and highly reproducible. The technique we employed is analogous to the human midline procedure and may be highly suitable for genetically modified mouse models. PMID- 23342963 TI - Fabrication of low-temperature solid oxide fuel cells with a nanothin protective layer by atomic layer deposition. AB - Anode aluminum oxide-supported thin-film fuel cells having a sub-500-nm-thick bilayered electrolyte comprising a gadolinium-doped ceria (GDC) layer and an yttria-stabilized zirconia (YSZ) layer were fabricated and electrochemically characterized in order to investigate the effect of the YSZ protective layer. The highly dense and thin YSZ layer acted as a blockage against electron and oxygen permeation between the anode and GDC electrolyte. Dense GDC and YSZ thin films were fabricated using radio frequency sputtering and atomic layer deposition techniques, respectively. The resulting bilayered thin-film fuel cell generated a significantly higher open circuit voltage of approximately 1.07 V compared with a thin-film fuel cell with a single-layered GDC electrolyte (approximately 0.3 V). PMID- 23342964 TI - Long-acting injectable antipsychotics in early psychosis: a literature review. AB - AIM: There are sound reasons for considering the use of long-acting injectable antipsychotics early in the course of schizophrenia. We reviewed available literature on the subject. METHOD: We conducted an electronic database search and critically reviewed all studies in which a long-acting injectable antipsychotic was evaluated in early psychosis patients. RESULTS: There is a need for well designed studies as most of those reported were open-label and non-comparative, and samples were frequently small. CONCLUSIONS: The available evidence does suggest that long-acting injectable antipsychotics can be used safely and effectively in early stages of the illness, and that they may be associated with better outcomes than with oral medications. However, this is largely supported by evidence from naturalistic cohort studies and a small number of controlled trials of risperidone long-acting injection. Evidence for olanzapine and paliperidone long-acting injectables in particular is limited. PMID- 23342965 TI - A study of gait acceleration and synchronisation in healthy adult subjects. AB - Accelerometry-based gait analysis is widely recognised as a promising tool in healthcare and clinical settings since it is unobtrusive, inexpensive and capable of providing insightful information on human gait characteristics. In order to expand the application of this technology in daily environments, it is desirable to develop reliable gait measures and their extraction methods from the acceleration signal that can differentiate between normal and atypical gait. Important examples of such measures are gait cycle and gait-induced acceleration magnitude, which are known to be closely related to each other depending on each individual's physical condition. In this study, we derive a model equation with two parameters which captures the essential relationships between gait cycle and gait acceleration based on experiments and physical modelling. We also introduce as a new gait parameter a set of indexes to evaluate the synchronisation behaviour of gait timing. The function and utility of the proposed parameters are examined in 11 healthy subjects during walking under various selected conditions. PMID- 23342966 TI - Image analysis of hyperchromatic crowded cell groups in SurePath cervical cytology. AB - OBJECTIVE: The discrimination of hyperchromatic crowded cell groups (HCCGs) in cervical cytology is a difficult and error-prone interpretive task. While the classic features of dyskaryosis are of undoubted value, the contribution of size, shape and colour intensity of HCCGs is less certain. This study employed morphometric analysis to determine whether HCCG area, shape and colour intensity are useful in categorising them. METHODS: Seventy-five digital images from each of six categories of HCCG were subjected to image analysis. Ten variables relating to HCCG size, shape and colour intensity were assessed by discriminant function analysis. A further 28 cases were employed as a test set to determine the classification accuracy of the discriminant model. All samples were SurePath liquid-based cytology preparations. RESULTS: Nine of the 10 variables contributed significantly to the model (P<0.001) but no single variable had sufficient discriminative ability. Classification accuracy was highest for abnormal endocervical HCCGs and lowest for squamous metaplastic cells (64.0 vs. 17.3% correct classification rate). The accuracy of the model for distinguishing normal and abnormal HCCGs was 70.0%, which was significantly higher than chance (P<0.0001), but this reduced to 64.3% for the test cases, which was no better than chance (P>0.05). CONCLUSIONS: The area, shape and colour intensity of HCCGs, either alone or in combination, have little discriminative value. Practitioners and trainers should focus on the well-established features of dyskaryosis, such as chromatin pattern, nuclear membrane irregularities and group architecture. In terms of morphometric analysis, DNA ploidy and chromatin texture analysis may be more fruitful avenues of investigation. PMID- 23342967 TI - Carbon monoxide form of PEGylated hemoglobin protects myocardium against ischemia/reperfusion injury in diabetic and normal mice. AB - We investigated the pre-clinical utility of carbon monoxide form of PEGylated hemoglobin (PEG-Hb also named SANGUINATE(TM)) in myocardial infarction (MI) and in particular the response of diabetic tissues to superimposed ischemia/reperfusion injury. SANGUINATE(TM) was evaluated in diabetic and normal mice subjected to 30 min of coronary artery ligation followed by either 48 h or 28 days of reperfusion. Our results demonstrate that SANGUINATE(TM) was effective in reducing infarct size when administered either prior to left anterior descending coronary artery (LAD) occlusion or during reperfusion. This finding is an important step in exploring the efficacy of a pharmacoinvasive strategy using SANGUINATE(TM) in patients with acute coronary syndromes. PMID- 23342969 TI - Randomized double-blind placebo-controlled trial of powdered Brassica rapa ethanol extract on alteration of body composition and plasma lipid and adipocytokine profiles in overweight subjects. AB - We evaluated the effects of Brassica rapa ethanol extract (BREE) on body composition and plasma lipid profiles through a randomized, double-blind, and placebo-controlled trial in overweight subjects. Fifty-eight overweight participants (age 20-50 years, body mass index23.0-24.9) were randomly assigned to two groups and served BREE (2 g/day) or placebo (starch, 2 g/day) for 10 weeks. Body compositions, nutrients intake, plasma lipids, adipocytokines, and hepatotoxicity biomarkers were assessed in all subjects at baseline and after 10 weeks of supplementation. The plasma total cholesterol (total-C) concentration was significantly increased after 10 weeks compared to the baseline in both groups. However, BREE supplementation significantly increased the high-density lipoprotein cholesterol (HDL-C) concentration and significantly reduced the total C/HDL-C ratio, free fatty acid, and adipsin levels after 10 weeks. No significant differences were observed in body compositions, fasting blood glucose, plasma adipocytokines except adipsin, and aspartate aminotransferase and alanine aminotransferase activities between before and after trial within groups as well as between the two groups. The supplementation of BREE partially improves plasma lipid metabolism in overweight subjects without adverse effects. PMID- 23342970 TI - Ferulic acid suppresses glutamate release through inhibition of voltage-dependent calcium entry in rat cerebrocortical nerve terminals. AB - This study investigated the effects and possible mechanism of ferulic acid, a naturally occurring phenolic compound, on endogenous glutamate release in the nerve terminals of the cerebral cortex in rats. Results show that ferulic acid inhibited the release of glutamate evoked by the K+ channel blocker 4 aminopyridine (4-AP). The effect of ferulic acid on the evoked glutamate release was prevented by chelating the extracellular Ca2+ ions, but was insensitive to the glutamate transporter inhibitor DL-threo-beta-benzyl-oxyaspartate. Ferulic acid suppressed the depolarization-induced increase in a cytosolic-free Ca2+ concentration, but did not alter 4-AP-mediated depolarization. Furthermore, the effect of ferulic acid on evoked glutamate release was abolished by blocking the Ca(v)2.2 (N-type) and Ca(v)2.1 (P/Q-type) channels, but not by blocking ryanodine receptors or mitochondrial Na+/Ca2+ exchange. These results show that ferulic acid inhibits glutamate release from cortical synaptosomes in rats through the suppression of presynaptic voltage-dependent Ca2+ entry. PMID- 23342971 TI - Soy protein, genistein, and daidzein improve serum paraoxonase activity and lipid profiles in rheumatoid arthritis in rats. AB - In this study, we investigated the effects of genistein, daidzein, and soy protein on paraoxonase and arylesterase activity, malondialdehyde (MDA) levels, and lipid profiles of arthritic rats in vivo and the results were compared with that of dexamethasone. Seventy-two female Sprague-Dawley rats were divided into six groups: healthy control, animals with collagen-induced arthritis (CIA), CIA soy protein (7 g/kg)-treated rats, CIA-genistein (20 mg/kg)-treated animals, CIA daidzein (20 mg/kg)-treated rats, and CIA-dexamethasone (1 mg/kg)-treated rats. Rheumatoid arthritis was induced using collagen type II and the treatments were carried out by daily gavages feedings for 50 days. The paraoxonase activity in serum was measured spectrophotometrically using paraoxon and phenylacetate as substrates. Serum MDA and lipids levels were determined using enzymatic colorimetric methods. Arthritis-induced decreases in paraoxonase and arylesterase activity was restored after treatment with soy protein and isoflavones (P<.05). MDA concentrations were lower after treatment with all tested compounds. However, only soy protein could partially improve the lipid profile. PMID- 23342972 TI - Glutamate metabolism in plant disease and defense: friend or foe? AB - Plant glutamate metabolism (GM) plays a pivotal role in amino acid metabolism and orchestrates crucial metabolic functions, with key roles in plant defense against pathogens. These functions concern three major areas: nitrogen transportation via the glutamine synthetase and glutamine-oxoglutarate aminotransferase cycle, cellular redox regulation, and tricarboxylic acid cycle-dependent energy reprogramming. During interactions with pathogens, the host GM is markedly altered, leading to either a metabolic state, termed "endurance", in which cell viability is maintained, or to an opposite metabolic state, termed "evasion", in which the process of cell death is facilitated. It seems that endurance-natured modulations result in resistance to necrotrophic pathogens and susceptibility to biotrophs, whereas evasion-related reconfigurations lead to resistance to biotrophic pathogens but stimulate the infection by necrotrophs. Pathogens, however, have evolved strategies such as toxin secretion, hemibiotrophy, and selective amino acid utilization to exploit the plant GM to their own benefit. Collectively, alterations in the host GM in response to different pathogenic scenarios appear to function in two opposing ways, either backing the ongoing defense strategy to ultimately shape an efficient resistance response or being exploited by the pathogen to promote and facilitate infection. PMID- 23342973 TI - Iodide as an activating agent for acid chlorides in acylation reactions. AB - Acid chlorides can be activated using a simple iodide source to undergo nucleophilic attack from a variety of relatively weak nucleophiles. These include Friedel-Crafts acylation of N-methylpyrroles, N-acylation of sulfonamides, and acylation reactions of hindered phenol derivatives. The reaction is believed to proceed through a transient acid iodide intermediate. PMID- 23342974 TI - Impact of constitutional copy number variants on biological pathway evolution. AB - BACKGROUND: Inherited Copy Number Variants (CNVs) can modulate the expression levels of individual genes. However, little is known about how CNVs alter biological pathways and how this varies across different populations. To trace potential evolutionary changes of well-described biological pathways, we jointly queried the genomes and the transcriptomes of a collection of individuals with Caucasian, Asian or Yoruban descent combining high-resolution array and sequencing data. RESULTS: We implemented an enrichment analysis of pathways accounting for CNVs and genes sizes and detected significant enrichment not only in signal transduction and extracellular biological processes, but also in metabolism pathways. Upon the estimation of CNV population differentiation (CNVs with different polymorphism frequencies across populations), we evaluated that 22% of the pathways contain at least one gene that is proximal to a CNV (CNV-gene pair) that shows significant population differentiation. The majority of these CNV-gene pairs belong to signal transduction pathways and 6% of the CNV-gene pairs show statistical association between the copy number states and the transcript levels. CONCLUSIONS: The analysis suggested possible examples of positive selection within individual populations including NF-kB, MAPK signaling pathways, and Alu/L1 retrotransposition factors. Altogether, our results suggest that constitutional CNVs may modulate subtle pathway changes through specific pathway enzymes, which may become fixed in some populations. PMID- 23342975 TI - Bilateral radial agenesis with absent thumbs, complex heart defect, short stature, and facial dysmorphism in a patient with pure distal microduplication of 5q35.2-5q35.3. AB - BACKGROUND: A partial duplication of the distal long arm of chromosome 5 (5q35- >qter) is known to be associated with a distinct phenotype referred to as Hunter McAlpine syndrome. Clinical spectrum of this disorder mainly consists of mental retardation, microcephaly, short stature, skeletal anomalies, and craniofacial dysmorphism featuring flat facies, micrognathia, large, low-set dysplastic ears, hypertelorism, almond-shaped, down-slanted palpebral fissures, epicanthal folds, small nose, long philtrum, small mouth, and thin upper lip. Less frequent remarkable findings include craniosynostosis, heart defect, hypoplastic phalanges, preaxial polydactyly, hypospadias, cryptorchidism, and inguinal hernia. In most patients with a partial duplication of 5q the aberration occurred due to an inherited unbalanced translocation, therefore the phenotype was not reflective of pure trisomy 5q. CASE PRESENTATION: We report on a 9.5-year-old boy with some feature of Hunter-McAlpine syndrome including short stature, complex heart defect (dextrocardia, dextroversion, PFO), bilateral cryptorchidism, hypothyroidism, and craniofacial dysmorphism. Additionally, bilateral radial agenesis with complete absence of Ist digital rays, ulnar hypoplasia with bowing, choroidal and retinal coloboma, abnormal biliary vesicle were identified, which have never been noted in 5q trisomy patients. Karyotype analysis, sequencing and MLPA for TBX5 and SALL4 genes were unremarkable. Array comparative genomic hybridization detected a duplication on 5q35.2-5q35.3, resulting from a de novo chromosomal rearrangement. Our proband carried the smallest of all previously reported pure distal 5q trisomies encompassing terminal 5.4-5.6 Mb and presented with the most severe limb malformation attributed to the increased number of distal 5q copies. CONCLUSIONS: We postulate that a terminal distal trisomy of 5q35.2-5q35.3, which maps 1.1 Mb telomeric to the MSX2 gene is causative for both radial agenesis and complex heart defect in our proband. A potential candidate gene causative for limb malformation in our proband could be FGFR4, which maps relatively in the closest position to the chromosomal breakage site (about 1.3 Mb) from all known 5q duplications. Since the limb malformation as well as the underlying genetic defect are distinct from other 5q trisomy patient we propose that a position effect resulting in altered long-range regulation of the FGFR4 (alternatively MSX2) may be responsible for the limb malformation in our proband. PMID- 23342976 TI - Comparative pelvic development of the axolotl (Ambystoma mexicanum) and the Australian lungfish (Neoceratodus forsteri): conservation and innovation across the fish-tetrapod transition. AB - BACKGROUND: The fish-tetrapod transition was one of the major events in vertebrate evolution and was enabled by many morphological changes. Although the transformation of paired fish fins into tetrapod limbs has been a major topic of study in recent years, both from paleontological and comparative developmental perspectives, the interest has focused almost exclusively on the distal part of the appendage and in particular the origin of digits. Relatively little attention has been paid to the transformation of the pelvic girdle from a small unipartite structure to a large tripartite weight-bearing structure, allowing tetrapods to rely mostly on their hindlimbs for locomotion. In order to understand how the ischium and the ilium evolved and how the acetabulum was reoriented during this transition, growth series of the Australian lungfish Neoceratodus forsteri and the Mexican axolotl Ambystoma mexicanum were cleared and stained for cartilage and bone and immunostained for skeletal muscles. In order to understand the myological developmental data, hypotheses about the homologies of pelvic muscles in adults of Latimeria, Neoceratodus and Necturus were formulated based on descriptions from the literature of the coelacanth (Latimeria), the Australian Lungfish (Neoceratodus) and a salamander (Necturus). RESULTS: In the axolotl and the lungfish, the chondrification of the pelvic girdle starts at the acetabula and progresses anteriorly in the lungfish and anteriorly and posteriorly in the salamander. The ilium develops by extending dorsally to meet and connect to the sacral rib in the axolotl. Homologous muscles develop in the same order with the hypaxial musculature developing first, followed by the deep, then the superficial pelvic musculature. CONCLUSIONS: Development of the pelvic endoskeleton and musculature is very similar in Neoceratodus and Ambystoma. If the acetabulum is seen as being a fixed landmark, the evolution of the ischium only required pubic pre-chondrogenic cells to migrate posteriorly. It is hypothesized that the iliac process or ridge present in most tetrapodomorph fish is the precursor to the tetrapod ilium and that its evolution mimicked its development in modern salamanders. PMID- 23342977 TI - Protective effect of montelukast which is cysteinyl-leukotriene receptor antagonist on gentamicin-induced nephrotoxicity and oxidative damage in rat kidney. AB - Nephrotoxicity is a major complication of gentamicin (GEN). We aimed to evaluate the potential protective effect of montelukast (MK) against GEN-induced nephrotoxicity in rats. Thirty-two rats were randomly divided into four groups, each consisting of eight animals as follows: (1) the rats were control; (2) intraperitoneally injected with GEN 14 consecutive days (100 mg/kg/day); (3) treated with GEN plus distilled water via nasogastric gavage for 14 days; and (4) treated with GEN plus MK (10 mg/kg/day) for 14 days. After 15 days, rats were killed and their kidneys were taken and blood analysis was performed. Twenty-four hours urine collections were obtained in standard metabolic cages a day before the rats were killed. Tubular necrosis and interstitial fibrosis scoring were determined histopathologically in a part of kidneys; nitric oxide (NO), malondialdehyde (MDA), and reduced glutathione (GSH) levels were determined in the other part of kidneys. Statistical analyses were made by the chi-square test and analysis of variance. Serum urea and creatinine levels were significantly higher in rats treated with GEN alone, than the rats in control and GEN + MK groups.The GSH levels in renal tissue of only GEN-treated rats were significantly lower than those in control group, and administration of MK to GEN-treated rats significantly increased the level of GSH. The group that was given GEN and MK had significantly lower MDA and NO levels in kidney cortex tissue than those that was given GEN alone. In rats treated with GEN + MK, despite the presence of mild tubular degeneration and tubular necrosis are less severe, and glomeruli maintained a better morphology when compared with GEN group. We can say that MK prevents kidney damage with antioxidant effect, independently of NO. PMID- 23342978 TI - Amphetamine-type medicines: a review of pharmacokinetics, pharmacodynamics, and toxicological aspects. AB - Amphetamine-like drugs are sympathomimetic agents with marked central and peripheral stimulant properties. Despite the street illegal drugs such as amphetamine and ecstasy, some amphetamine-like compounds are also legally marketed under medical prescription in the treatment of attention deficit hyperactivity disorder (methylphenidate) and obesity/overweight (fenproporex and diethylpropione). However, similar with what happens with their illicit analogues, therapeutic amphetamine-like drugs also share important toxicological risks. Although methylphenidate is considered the first choice in the treatment of attention deficit-hyperactivity disorder, its high popularity among teenagers and children is raising concern in the medical community. Regarding weight-loss purposes, the use of amphetamine-like compounds are very controversial, though. Thus, the present review will address pharmacokinetic, pharmacodynamic, and toxicological aspects of amphetamine-like compounds used with therapeutic aims. PMID- 23342979 TI - Molecular decay of enamel matrix protein genes in turtles and other edentulous amniotes. AB - BACKGROUND: Secondary edentulism (toothlessness) has evolved on multiple occasions in amniotes including several mammalian lineages (pangolins, anteaters, baleen whales), birds, and turtles. All edentulous amniote clades have evolved from ancestors with enamel-capped teeth. Previous studies have documented the molecular decay of tooth-specific genes in edentulous mammals, all of which lost their teeth in the Cenozoic, and birds, which lost their teeth in the Cretaceous. By contrast with mammals and birds, tooth loss in turtles occurred in the Jurassic (201.6-145.5 Ma), providing an extended time window for tooth gene degradation in this clade. The release of the painted turtle and Chinese softshell turtle genomes provides an opportunity to recover the decayed remains of tooth-specific genes in Testudines. RESULTS: We queried available genomes of Testudines (Chrysemys picta [painted turtle], Pelodiscus sinensis [Chinese softshell turtle]), Aves (Anas platyrhynchos [duck], Gallus gallus [chicken], Meleagris gallopavo [turkey], Melopsittacus undulatus [budgerigar], Taeniopygia guttata [zebra finch]), and enamelless mammals (Orycteropus afer [aardvark], Choloepus hoffmanni [Hoffmann's two-toed sloth], Dasypus novemcinctus [nine banded armadillo]) for remnants of three enamel matrix protein (EMP) genes with putative enamel-specific functions. Remnants of the AMBN and ENAM genes were recovered in Chrysemys and retain their original synteny. Remnants of AMEL were recovered in both testudines, although there are no shared frameshifts. We also show that there are inactivated copies of AMBN, AMEL and ENAM in representatives of divergent avian lineages including Galloanserae, Passeriformes, and Psittaciformes, and that there are shared frameshift mutations in all three genes that predate the basal split in Neognathae. Among enamelless mammals, all three EMP genes exhibit inactivating mutations in Orycteropus and Choloepus. CONCLUSIONS: Our results highlight the power of combining fossil and genomic evidence to decipher macroevolutionary transitions and characterize the functional range of different loci involved in tooth development. The fossil record and phylogenetics combine to predict the occurrence of molecular fossils of tooth-specific genes in the genomes of edentulous amniotes, and in every case these molecular fossils have been discovered. The widespread occurrence of EMP pseudogenes in turtles, birds, and edentulous/enamelless mammals also provides compelling evidence that in amniotes, the only unique, non-redundant function of these genes is in enamel formation. PMID- 23342981 TI - Cytomegalovirus-induced salivary gland pathology: resistance to kinase inhibitors of the upregulated host cell EGFR/ERK pathway is associated with CMV-dependent stromal overexpression of IL-6 and fibronectin. AB - BACKGROUND: Recently we identified a relationship between human cytomegalovirus (hCMV) and human salivary gland (SG) mucoepidermoid carcinoma (MEC) in over 90% of cases; tumorigenesis in these cases uniformly correlated with active hCMV protein expression and an upregulation of the EGFR -> ERK pathway. Our previously characterized, novel mouse organ culture model of mouse CMV (mCMV)-induced tumorigenesis displays a number of histologic and molecular characteristics similar to human MEC. METHODS: Newborn mouse submandibular glands (SMGs) were incubated with 1 * 105 PFU/ml of lacZ-tagged mCMV RM427+ on day 0 for 24 hours and then cultured in virus-free media for a total of 6 or 12 days with or without EGFR/ERK inhibitors and/or aciclovir. SMGs were collected for histology, immunolocalization (pERK, FN, IL-6), viral distribution, or Western blot analysis (pERK). RESULTS: Here we report: (1) mouse SMG tumors soon exhibit an acquired resistance to EGFR/ERK pathway kinase inhibitors, alone or in combination; (2) long term tumor regression can only be sustained by concurrent inhibitor and antiviral treatment; (3) CMV-dependent, kinase inhibitor resistance is associated with overexpression of fibronectin and IL-6 proteins in abnormal stromal cells. CONCLUSIONS: Acquired resistance to kinase inhibitors is dependent upon CMV dysregulation of alternative pathways with downstream effectors common with the targeted pathway, a phenomenon with important therapeutic implications for human MEC of salivary glands. PMID- 23342982 TI - Alternative approach for mitigation of doxorubicin-induced cardiotoxicity using herbal agents. AB - Doxorubicin (DOX) is an effective and frequently used chemotherapeutic agent for various malignancies. However, its clinical use is hampered due to the development of cardiotoxicity. Investigations have proved that DOX-induced cardiotoxicity occurs through mechanisms other than those mediating its antitumor effect. This theory sheds light on the development of strategies for cardioprotection without altering therapeutic effectiveness of DOX. Bioactive plant constituents of dietary supplements, traditional herbs and foods with potential health benefits can play an important role in therapeutics. This manuscript is an exhaustive review and prospect of herbal and botanical agents against DOX-induced cardiotoxicity with their proposed mechanisms. The activity of herbs evaluated against DOX-induced cardiotoxicity has shown number of mechanisms including apoptosis, antioxidant potential, effect on mitochondria and calcium ion regulation etc. The manuscript reveals that most of the herbal drugs studied are effective through antioxidant mechanism and only few through other major pathways such as apoptosis and iron mediated pathways in DOX-induced cardiotoxicity. Only limited reports are available for the prevention of DOX induced drug resistance using botanicals. Manuscript reports a number of constituents with evident potential in prevention of DOX cardiotoxicity e.g. proanthocyanidins, epigallocatechin-3-gallate, S-allylcysteine, reseveratrol, rutoside etc. In the present communication, several herbal drugs have also been discussed, which can act through mechanisms other than antioxidant and may be evaluated as a combination therapy for prevention of DOX-induced cardiotoxicity in future. PMID- 23342980 TI - A dynamic model of some malaria-transmitting anopheline mosquitoes of the Afrotropical region. I. Model description and sensitivity analysis. AB - BACKGROUND: Most of the current biophysical models designed to address the large scale distribution of malaria assume that transmission of the disease is independent of the vector involved. Another common assumption in these type of model is that the mortality rate of mosquitoes is constant over their life span and that their dispersion is negligible. Mosquito models are important in the prediction of malaria and hence there is a need for a realistic representation of the vectors involved. RESULTS: We construct a biophysical model including two competing species, Anopheles gambiae s.s. and Anopheles arabiensis. Sensitivity analysis highlight the importance of relative humidity and mosquito size, the initial conditions and dispersion, and a rarely used parameter, the probability of finding blood. We also show that the assumption of exponential mortality of adult mosquitoes does not match the observed data, and suggest that an age dimension can overcome this problem. CONCLUSIONS: This study highlights some of the assumptions commonly used when constructing mosquito-malaria models and presents a realistic model of An. gambiae s.s. and An. arabiensis and their interaction. This new mosquito model, OMaWa, can improve our understanding of the dynamics of these vectors, which in turn can be used to understand the dynamics of malaria. PMID- 23342983 TI - Clinical pharmacokinetics of retigabine/ezogabine. AB - BACKGROUND: Retigabine is an antiepileptic drug that reduces neuronal excitability by enhancing potassium channel activity. METHODS: This manuscript summarizes the pharmacokinetic and biopharmaceutical properties of retigabine collated from published and unpublished in vitro and clinical phase I-III studies in healthy volunteers or patients with partial-onset seizures. RESULTS: Retigabine is rapidly absorbed with a median time to C(max) of 0.5-2.0 hours. Thereafter, plasma concentrations decline in a mono-exponential manner, with a median half-life of 6-8 hours. The absolute oral bioavailability of retigabine is ~60%. Retigabine is metabolized extensively by N-acetylation and subsequent N glucuronidation. In vitro and in vivo studies have shown that the drug interaction potential of retigabine is low. The pharmacokinetics of retigabine are linear over the dose range 200-400mg three times daily (tid), with ~ 35-50% between-subject variability. Systemic exposure was not affected by a high fat meal, but C(max) was, ~14% and ~38% higher in the fed versus fasted state for the 200 and 400mg tablets, respectively. Retigabine drug-related material is primarily eliminated renally with unchanged retigabine accounting for ~36%. Retigabine plasma clearance decreased as severity of renal or hepatic impairment increased. Systemic exposure to retigabine is unaffected by gender when normalized for body weight. In elderly patients, retigabine systemic exposure was higher, and half-life was longer than in younger patients. CONCLUSIONS: Retigabine should be administered tid without regard to food. No adjustments required for gender, race, or genetic/polymorphisms. Dosage adjustments are recommended in elderly patients and those with moderate and severe renal or moderate hepatic impairment. PMID- 23342984 TI - Role of aerobic glycolysis in genetically engineered mouse models of cancer. AB - The propensity of cancer cells to convert high levels of glucose to lactate through aerobic glycolysis has been intensively studied in vitro, and is now understood to be a metabolic adaptation that shunts glucose carbons toward building blocks for the growing cell, as well as producing ATP. Much less is known, however, about the role of aerobic glycolysis and glycolytic enzymes in vivo. A paper in Cancer and Metabolism now documents aerobic glycolysis in the proliferating neural progenitors that form the cerebellum in normal newborn mice, as well as in medulloblastoma tumors derived from these cells in transgenic mice. Hexokinase II is demonstrated to be an essential driver of the observed aerobic glycolysis and the malignancy of the tumors. See research article: http://www.cancerandmetabolism.com/content/1/1/2. PMID- 23342985 TI - Prognostic factors for low birthweight repetition in successive pregnancies: a cohort study. AB - BACKGROUND: To identify prognostic factors associated with recurrence of low birthweight (LBW) in successive gestations, a study was carried out with a subsample of mothers enrolled in the 2004 Pelotas Birth Cohort. METHODS: Data were collected by hospital-based interviews. Newborns were weighed and measured. Gestational age was defined according to the date of last menstrual period, ultra sound scan before the 20th week of pregnancy or the Dubowitz method. Mothers who reported at least one LBW newborn in the two previous gestations were included. Prevalence ratios (PR) and 95% confidence intervals were estimated from Poisson Regression. All estimates were adjusted for parity. RESULTS: A total of 4558 births were identified in 2004, and 565 met inclusion criteria, out of which 86 (15.2%) repeated LBW in 2004. Among mothers with two LBW babies before 2004, 47.9% presented LBW recurrence. Belonging to the highest socio-economic stratum (PR 0.89; 0.01-0.46) and gaining >= 10 kg during pregnancy (PR 0.09; 0.01-0.77) were protective against LBW recurrence. Higher risk of LBW recurrence was observed among mothers with higher parity (>=3 previous deliveries; PR=1.93; 95% CI 1.23-3.02); who had given birth to a previous preterm baby (PR=4.01; 2.27 7.10); who delivered a female newborn in current gestation (PR=2.61; 1.45-4.69); and that had not received adequate antenatal care (PR=2.57; 1-37-4.81). CONCLUSION: Improved quality of antenatal care and adequate maternal weight gain during pregnancy may be feasible strategies to prevent LBW repetition in successive pregnancies. PMID- 23342986 TI - Early malperfusion, ischemia reperfusion injury, and respiratory failure in acute complicated type B aortic dissection after thoracic endovascular repair. AB - BACKGROUND: The aim of this study was to determine the early mortality and major complications of acute complicated type B aortic dissection (ACBD) after thoracic endovascular aortic repair (TEVAR). METHODS: Twenty-six consecutive patients with ACBD who underwent TEVAR were included. Clinical indications before TEVAR and in hospital mortality and major complications after TEVAR were analyzed and compared with similar reports. RESULTS: TEVAR was technically successful in all cases. In hospital mortality occurred in four patients (15%), and major complications occurred in an additional four patients (15%). Three of the four (75%) of the deaths were associated with malperfusion and ischemia reperfusion injury (IRI), and 3/4 (75%) of the major complications were caused by respiratory failure (RF). CONCLUSIONS: In-hospital mortality associated strongly with severe end-organ malperfusion and IRI, while major complications associated with RF, during TEVAR. Our results indicate that malperfusion, IRI and respiratory failure during TEVAR should be carefully monitored and aggressively treated. PMID- 23342987 TI - Association mapping of Septoria speckled leaf blotch resistance in U.S. barley breeding germplasm. AB - Septoria speckled leaf blotch (SSLB) is a sporadic but important disease of barley (Hordeum vulgare) in the Upper Midwest region of the United States and Prairie Provinces of Canada that is caused primarily by Septoria passerinii. Most of the widely grown cultivars in the region are susceptible to the disease. To identify and map SSLB resistance loci in U.S. barley breeding germplasm, we employed an association mapping approach using 3,840 breeding lines and cultivars and nearly 3,000 single-nucleotide polymorphism markers previously mapped to the seven barley chromosomes. SSLB infection responses (IRs) were assayed on seedling plants in the greenhouse using a 0-to-5 scale. From the analysis of four yearly panels consisting of 960 lines each, four quantitative trait loci (QTL) for SSLB resistance were identified: one on chromosome 1H (Rsp-qtl-H_12_31144), one on chromosome 3H (Rsp-qtl-3H_12_31488), and two on chromosome 6H (Rsp-qtl 6H_11_21032 and Rsp-qtl-6H_11_10064). Individual resistance QTL reduced the mean IR from 9 to 38% compared with lines lacking any resistance alleles. However, the combination of all four resistance QTL together reduced the mean IR by 83%. The markers found associated with these QTL will be valuable for programs utilizing marker-assisted selection for SSLB resistance. PMID- 23342988 TI - A computational model of amoeboid cell migration. AB - We present a two-dimensional computational model of amoeboid cell migration characterised by cell shape changes due to the formation and extension of protrusions known as blebs. Using this model, we numerically study the deformation of the cell membrane during blebbing, as well as the effects of obstacles, such as protein fibres in the extracellular matrix, on the motion of the blebbing cell. The model is established in the framework of Stokes flow. Cell membrane deformation is coupled to membrane tension, membrane bending, membrane cortex adhesion and cortical activities via the intracellular and extracellular fluid field described by the Stokes equation. By assuming that actin monomers move at constant speed towards the membrane and polymerise when they approach the membrane, our model shows that the cell movement in unconfined space can be sustained. We also study how a migrating cell interacts with obstacles hydrodynamically, allowing us to model cell migration in confined environments and to investigate the effects of confinement on the cell migration speed. Our model can be used to further study how tumour cells move through the extracellular matrix during cancer metastasis. PMID- 23342989 TI - Mid-trimester maternal heart rate is related to neonatal birth weight. AB - OBJECTIVE(S): We sought to establish the relationship between maternal mid trimester heart rate (HR) and neonatal birth weight in women at high a priori risk of preeclampsia. STUDY DESIGN: Ninety-nine women were recruited following second trimester uterine artery Doppler assessment. Maternal blood pressure (BP) and HR were measured between 23(+4) and 30(+5) weeks gestation and neonatal birth weight was expressed as a z-score. The relationship between the parameters was investigated using Pearson's correlation coefficient. RESULTS: There was a significant positive correlation between maternal HR and neonatal birth weight z score, r = 0.22 (95% CI: 0.02-0.40), p = 0.03. An inverse correlation was found between uterine artery Doppler pulsatility index (PI) and maternal HR, r = -0.43 (95% CI: 0.01-0.40), p = 0.0001, and neonatal birth weight, r = -0.3 (95% CI: 0.47 to -0.10), p = 0.004. For neonatal birth weight z-score <-1.65, r = 0.69 (95% CI: 0.15-0.91), p = 0.02. There was no relationship between BP and uterine artery Doppler or neonatal birth weight. CONCLUSION: The finding of a continuous relationship between maternal HR and neonatal birth weight prior to the onset of fetal growth restriction is novel, suggesting that maternal cardiovascular adaptation is reflected by neonatal birth weight. Lower maternal HR is associated with lower neonatal birth weight and vice versa. Further, we confirm the reported associations between uterine artery Doppler PI and both maternal HR and neonatal birth weight. PMID- 23342990 TI - A DFT study of the [3 + 2] versus [4 + 2] cycloaddition reactions of 1,5,6 trimethylpyrazinium-3-olate with methyl methacrylate. AB - The reaction between 1,5,6-trimethylpyrazinium-3-olate and methyl methacrylate (MMA) yielding a lactone-lactam has been studied using the DFT method at the B3LYP/6-31G(d) level. It is concluded that formation of the lactone-lactam is a domino process involving three consecutive reactions: (i) a 1,3-dipolar cycloaddition (13DC) reaction between the pyrazinium-3-olate and MMA yielding a [3 + 2] cycloadduct (CA); (ii) a skeletal rearrangement, which converts the [3 + 2] CA into a formal [4 + 2] CA, possessing a diazabicyclo[2.2.2]octane structure; and finally, (iii) an S(N)2 reaction, promoted by halide anion, with concomitant nucleophilic attack of the created carboxylate anion on an iminium carbon with formation of the lactone ring present in the lactone-lactam. Analysis of the four competitive channels associated with the 13DC reaction indicates that this cycloaddition takes place with complete endo stereoselectivity and 6 regioselectivity, yielding [3 + 2] CA. The subsequent skeletal rearrangement also takes place in an elementary step via a non-concerted mechanism. Electron localization function bonding analysis makes it possible to establish that the bicyclo[2.2.2]octane skeleton present in the lactone-lactam complex structure is not attained via a Diels-Alder reaction between pyrazinium-3-olate and MMA. PMID- 23342991 TI - Hemoglobin-albumin cross-linking with disuccinimidyl suberate (DSS) and/or glutaraldehyde for blood substitutes. AB - Hemoglobin (Hb) derivatization for blood substitute purposes often involves multi step processes including redox reagents such as borohydride and periodate, with possible subsequent side effects. Disuccinimidyl suberate (DSS) allows protein cross-linking without toxic side-products, forming one-step peptide bonds with the lysine residues. Here, we report that Hb polymers were obtained using DSS, making this the first report of a single-step polymerization for blood substitutes. The increase in autooxidation rate incurred by this polymerization is completely reversed when BSA is copolymerized with Hb. Copolymerization of Hb with BSA appears to be beneficial for alleviating pro-oxidant effects, regardless of the polymerizing agent employed. PMID- 23342992 TI - Acquired bartter-like syndrome associated with colistin use in a preterm infant. AB - Acquired Bartter-like syndrome (BLS), characterized by hypokalemic metabolic alkalosis, hypomagnesemia, hypocalcemia, and normal kidney function, can be induced by diuretics or antibiotics. It is a very rare condition and only anecdotal cases mostly in adults were reported. Although tubulopathy associated with colistin was reported in adults, to the best of our knowledge, colistin associated BLS neither in adults nor in children has been reported in the literature. We here report a-28-week, 740 g female preterm infant who developed BLS just after colistin treatment for Acinetobacter baumannii infection and recovered few days after the drug cessation, and discuss the possible association of colistin and tubulopathy. More research on colistin pharmacokinetics and pharmacodynamics in critically ill patients and preterm infants is needed to guide adequate colistin dosing at the least toxicity. PMID- 23342993 TI - Molecular self-assembly: smart design of surface and interface via secondary molecular interactions. AB - The molecular self-assembly of macromolecular species such as polymers, colloids, nano/microparticles, proteins, and cells when they interface with a solid/substrate surface has been studied for many years, especially in terms of molecular interactions, adsorption, and adhesion. Such fundamental knowledge is practically important in designing smart micro- and nanodevices and sensors, including biologically implantable ones. This review gives a brief sketch of molecular self-assembly and nanostructured multifunctional thin films that utilize secondary molecular interactions at surfaces and interfaces. PMID- 23342994 TI - Electrochemically mediated atom transfer radical polymerization on nonconducting substrates: controlled brush growth through catalyst diffusion. AB - Surface initiated atom transfer radical polymerization (SI-ATRP) was triggered after diffusion of a Cu(I)/L activator generated at a working electrode. A stable [Cu(II)L]/[Cu(I)L] ratio gradient was formed at the gap between the working electrode and the initiator terminated substrate due to ion diffusion. The size of the gap can be used to dictate polymer growth kinetics at different gap distances. Gradient polymer brushes were grafted when substrate was placed at a tilting angle along [Cu(II)L]/[Cu(I)L] gradient. PMID- 23342995 TI - Incorporation of amphiphilic cyclodextrins into liposomes as artificial receptor units. AB - In this article, we describe the introduction of amphiphilic beta-cyclodextrins into liposomes to act as artificial receptor units. Using dynamic light scattering, dye encapsulation, and cryogenic transmission electron microscopy, we show that amphiphilic beta-cyclodextrins can be mixed in any proportion with a typical mixture of phospholipids and cholesterol to provide stable, spherical, and unilamellar mixed vesicles. It is also possible to form giant unilamellar vesicles with mixtures of lipids and cyclodextrin. The permeability of the mixed vesicles increases with the percentage of cyclodextrin. The cyclodextrins can act as host molecules for hydrophobic guest molecules, even when they are dispersed at a low percentage in the vesicle membrane. It is shown that mixed vesicles can be decorated with carbohydrate-functionalized guest molecules, with photoresponsive guest molecules, and with dye-functionalized guest molecules. Taken together, it is demonstrated that the host-guest chemistry of amphiphilic cyclodextrins is fully compatible with a liposomal bilayer membrane and the advantages of each can be combined to give superior nanocontainers. PMID- 23342997 TI - Initial predictors of outcome in an early intervention in psychosis service. AB - AIMS: The aims of this study were to determine medium-term outcomes of a cohort of early intervention service users after discharge from the service. Additionally, to establish whether characteristics can be easily identified in the early stages of treatment to predict outcome, aid discharge planning and focus interventions. METHODS: One hundred fifty-five early intervention service users were followed-up for a mean of 4.6 years from the start of early intervention treatment. Patients were divided into good and poor outcome groups and these groups were compared on gender, duration of untreated psychosis, age at first presentation to mental health services, hospital admissions in the first year and time spent on the waiting list. RESULTS: A third of the patients had a good outcome, with a discharge to primary care and no subsequent return to mental health services. Good outcome was associated with a later age of first contact with mental health services and fewer hospital admissions in the first year of treatment. CONCLUSIONS: We would suggest that clinicians working in this and similar services could use these two factors as early as one year into treatment to begin to consider discharge planning, or conversely to focus resources most appropriately on those likely to benefit most or those who have the greatest predicted need. This study supports an optimist view of prognosis for a significant proportion of first-episode psychosis patients. PMID- 23342996 TI - Results from tandem Phase 1 studies evaluating the safety, reactogenicity and immunogenicity of the vaccine candidate antigen Plasmodium falciparum FVO merozoite surface protein-1 (MSP1(42)) administered intramuscularly with adjuvant system AS01. AB - BACKGROUND: The development of an asexual blood stage vaccine against Plasmodium falciparum malaria based on the major merozoite surface protein-1 (MSP1) antigen is founded on the protective efficacy observed in preclinical studies and induction of invasion and growth inhibitory antibody responses. The 42 kDa C terminus of MSP1 has been developed as the recombinant protein vaccine antigen, and the 3D7 allotype, formulated with the Adjuvant System AS02A, has been evaluated extensively in human clinical trials. In preclinical rabbit studies, the FVO allele of MSP142 has been shown to have improved immunogenicity over the 3D7 allele, in terms of antibody titres as well as growth inhibitory activity of antibodies against both the heterologous 3D7 and homologous FVO parasites. METHODS: Two Phase 1 clinical studies were conducted to examine the safety, reactogenicity and immunogenicity of the FVO allele of MSP142 in the adjuvant system AS01 administered intramuscularly at 0-, 1-, and 2-months: one in the USA and, after evaluation of safety data results, one in Western Kenya. The US study was an open-label, dose escalation study of 10 and 50 MUg doses of MSP142 in 26 adults, while the Kenya study, evaluating 30 volunteers, was a double-blind, randomized study of only the 50 MUg dose with a rabies vaccine comparator. RESULTS: In these studies it was demonstrated that this vaccine formulation has an acceptable safety profile and is immunogenic in malaria-naive and malaria experienced populations. High titres of anti-MSP1 antibodies were induced in both study populations, although there was a limited number of volunteers whose serum demonstrated significant inhibition of blood-stage parasites as measured by growth inhibition assay. In the US volunteers, the antibodies generated exhibited better cross-reactivity to heterologous MSP1 alleles than a MSP1-based vaccine (3D7 allele) previously tested at both study sites. CONCLUSIONS: Given that the primary effector mechanism for blood stage vaccine targets is humoral, the antibody responses demonstrated to this vaccine candidate, both quantitative (total antibody titres) and qualitative (functional antibodies inhibiting parasite growth) warrant further consideration of its application in endemic settings. TRIAL REGISTRATIONS: Clinical Trials NCT00666380. PMID- 23342998 TI - Detecting allosteric sites of HIV-1 reverse transcriptase by X-ray crystallographic fragment screening. AB - HIV-1 reverse transcriptase (RT) undergoes a series of conformational changes during viral replication and is a central target for antiretroviral therapy. The intrinsic flexibility of RT can provide novel allosteric sites for inhibition. Crystals of RT that diffract X-rays to better than 2 A resolution facilitated the probing of RT for new druggable sites using fragment screening by X-ray crystallography. A total of 775 fragments were grouped into 143 cocktails, which were soaked into crystals of RT in complex with the non-nucleoside drug rilpivirine (TMC278). Seven new sites were discovered, including the Incoming Nucleotide Binding, Knuckles, NNRTI Adjacent, and 399 sites, located in the polymerase region of RT, and the 428, RNase H Primer Grip Adjacent, and 507 sites, located in the RNase H region. Three of these sites (Knuckles, NNRTI Adjacent, and Incoming Nucleotide Binding) are inhibitory and provide opportunities for discovery of new anti-AIDS drugs. PMID- 23342999 TI - Shift happens: trailing edge contraction associated with recent warming trends threatens a distinct genetic lineage in the marine macroalga Fucus vesiculosus. AB - BACKGROUND: Significant effects of recent global climate change have already been observed in a variety of ecosystems, with evidence for shifts in species ranges, but rarely have such consequences been related to the changes in the species genetic pool. The stretch of Atlantic coast between North Africa and North Iberia is ideal for studying the relationship between species distribution and climate change as it includes the distributional limits of a considerable number of both cold- and warm-water species.We compared temporal changes in distribution of the canopy-forming alga Fucus vesiculosus with historical sea surface temperature (SST) patterns to draw links between range shifts and contemporary climate change. Moreover, we genetically characterized with microsatellite markers previously sampled extinct and extant populations in order to estimate resulting cryptic genetic erosion. RESULTS: Over the past 30 years, a geographic contraction of the southern range edge of this species has occurred, with a northward latitudinal shift of approximately 1,250 km. Additionally, a more restricted distributional decline was recorded in the Bay of Biscay. Coastal SST warming data over the last three decades revealed a significant increase in temperature along most of the studied coastline, averaging 0.214 degrees C/decade. Importantly, the analysis of existing and extinct population samples clearly distinguished two genetically different groups, a northern and a southern clade. Because of the range contraction, the southern group is currently represented by very few extant populations. This southern edge range shift is thus causing the loss of a distinct component of the species genetic background. CONCLUSIONS: We reveal a climate-correlated diversity loss below the species level, a process that could render the species more vulnerable to future environmental changes and affect its evolutionary potential. This is a remarkable case of genetic uniqueness of a vanishing cryptic genetic clade (southern clade). PMID- 23343000 TI - Cystic fibrosis testing in a referral laboratory: results and lessons from a six year period. AB - BACKGROUND: The recent introduction of high throughput sequencing technologies into clinical genetics has made it practical to simultaneously sequence many genes. In contrast, previous technologies limited sequencing based tests to only a handful of genes. While the ability to more accurately diagnose inherited diseases is a great benefit it introduces specific challenges. Interpretation of missense mutations continues to be challenging and the number of variants of uncertain significance continues to grow. RESULTS: We leveraged the data available at ARUP Laboratories, a major reference laboratory, for the CFTR gene to explore specific challenges related to variant interpretation, including a focus on understanding ethnic-specific variants and an evaluation of existing databases for clinical interpretation of variants. In this study we analyzed 555 patients representing eight different ethnic groups. We observed 184 different variants, most of which were ethnic group specific. Eighty-five percent of these variants were present in the Cystic Fibrosis Mutation Database, whereas the Human Mutation Database and dbSNP/1000 Genomes had far fewer of the observed variants. Finally, 21 of the variants were novel and we report these variants and their clinical classifications. CONCLUSIONS: Based on our analyses of data from six years of CFTR testing at ARUP Laboratories a more comprehensive, clinical grade database is needed for the accurate interpretation of observed variants. Furthermore, there is a particular need for more and better information regarding variants from individuals of non-Caucasian ethnicity. PMID- 23343001 TI - Counterintuitive mechanisms of the addition of hydrogen and simple olefins to heavy group 13 alkene analogues. AB - The mechanism of the reaction of olefins and hydrogen with dimetallenes ArMMAr (Ar = aromatic group; M = Al or Ga) was studied by density functional theory calculations and experimental methods. The digallenes, for which the most experimental data are available, are extensively dissociated to gallanediyl monomers, :GaAr, in hydrocarbon solution, but the calculations and experimental data showed also that they react with simple olefins, such as ethylene, as intact ArGaGaAr dimers via stepwise [2 + 2 + 2] cycloadditions due to their considerably lower activation barriers vis-a-vis the gallanediyl monomers, :GaAr. This pathway was preferred over the [2 + 2] cycloaddition of olefin to monomeric :GaAr to form a gallacyclopropane ring with subsequent dimerization to yield the 1,2 digallacyclobutane intermediate and, subsequently, the 1,4-digallacyclohexane product. The calculations showed also that the addition of H(2) to digallene proceeds by a different mechanism involving the initial addition of one equivalent of H(2) to form a 1,2-dihydride intermediate. This reacts with a second equivalent of H(2) to give two ArGaH(2) fragments which recombine to give the observed product with terminal and bridging H-atoms, Ar(H)Ga(MU-H)(2)Ga(H)Ar. The computations agree with the experimental observation that the :GaAr(iPr(8)) (Ar(iPr(8)) = C(6)H-2,6-(C(6)H(3)-2,4,6-(i)Pr(3))(2)-3,5-(i)Pr(2)), which does not associate even in the solid state, does not react with ethylene or hydrogen. Calculations on the reaction of propene with ArAlAlAr show that, in contrast to the digallenes, addition involves an open-shell transition state consistent with the higher singlet diradical character of dialuminenes. PMID- 23343003 TI - Colorimetric Hg2+ sensing in water: from molecules toward low-cost solid devices. AB - A new colorimetric molecular sensor allowing for cheap, fast, sensitive, and highly selective naked-eye detection of Hg(2+) in water is described. This molecule combines a 1,8-diaminoanthraquinone signaling subunit and phosphonic acid esters that confer the water solubility to the dye (R = H). A ready-to-use colorimetric solid sensor was obtained by incorporating an amphiphilic analog (R = OC(12)H(25)) exhibiting similar binding properties and optical responses in an agarose film. PMID- 23343002 TI - An integrated approach to patient-specific predictive modeling for single ventricle heart palliation. AB - In patients with congenital heart disease and a single ventricle (SV), ventricular support of the circulation is inadequate, and staged palliative surgery (usually 3 stages) is needed for treatment. In the various palliative surgical stages individual differences in the circulation are important and patient-specific surgical planning is ideal. In this study, an integrated approach between clinicians and engineers has been developed, based on patient specific multi-scale models, and is here applied to predict stage 2 surgical outcomes. This approach involves four distinct steps: (1) collection of pre operative clinical data from a patient presenting for SV palliation, (2) construction of the pre-operative model, (3) creation of feasible virtual surgical options which couple a three-dimensional model of the surgical anatomy with a lumped parameter model (LPM) of the remainder of the circulation and (4) performance of post-operative simulations to aid clinical decision making. The pre-operative model is described, agreeing well with clinical flow tracings and mean pressures. Two surgical options (bi-directional Glenn and hemi-Fontan operations) are virtually performed and coupled to the pre-operative LPM, with the hemodynamics of both options reported. Results are validated against postoperative clinical data. Ultimately, this work represents the first patient specific predictive modeling of stage 2 palliation using virtual surgery and closed-loop multi-scale modeling. PMID- 23343004 TI - Failure of treatment of impacted canines associated with invasive cervical root resorption. AB - OBJECTIVES: To propose invasive cervical root resorption (ICRR) as an unrecognized and/or overlooked etiologic factor in the failure of response of an impacted tooth to orthodontic traction and to underline the importance of cone beam computerized tomography (CBCT) for early and accurate diagnosis of ICRR. MATERIALS AND METHODS: Fourteen patients (age 13-21 years) with impacted canines (15 canines) that had failed to respond to orthodontic forces and that exhibited ICRR formed the case series for this investigation. The initial diagnosis, treatment, clinical and radiographic expression of failure, and adverse effects on adjacent teeth were analyzed. RESULTS: Initial diagnosis had been performed on plane radiographs. The orthodontist was absent during surgery in 11 patients. Nine canines had been exposed by open procedures. ICRR was not related to the severity of impaction. Its diagnosis was made on existing radiographs, new films, and/or new CBCT. The severity of the lesions was Class 3 or 4, and the teeth were finally extracted. Loss of anchorage characterized 11 patients. Apical resorption of the roots of adjacent teeth was diagnosed in 9 patients. CONCLUSIONS: ICRR is a frequently undiagnosed or unrecognized cause of failure of orthodontic resolution of impacted canines and should be distinguished from replacement resorption. CBCT should be used for its early detection and accurate assessment of potential damage to adjacent anchor teeth. PMID- 23343005 TI - Assessment of the Fe(III)-EDDS complex in Fenton-like processes: from the radical formation to the degradation of bisphenol A. AB - The present work describes, for the first time, the use of a new and strong complexing agent, ethylenediamine-N,N'-disuccinic acid (EDDS) in the homogeneous Fenton process. The effect of H(2)O(2) concentration, Fe(III)-EDDS concentration, pH value, and oxygen concentration on the homogeneous Fenton degradation of bisphenol A (BPA) used as a model pollutant, was investigated. Surprisingly, the performance of BPA oxidation in an EDDS-driven Fenton reaction was found to be much higher at near neutral or basic pH than at acidic pH. Inhibition and probe studies were conducted to ascertain the role of several radicals (e.g., (*)OH, HO(2)(*)/O(2)(*-)) on BPA degradation. This unexpected effect of pH on Fenton reaction efficiency could be due to the formation of HO(2)(*) or O(2)(*-) radicals and to the presence of different forms of the complex Fe(III)-EDDS as a function of pH. Indeed, the reduction of Fe(III)-EDDS to Fe(II)-EDDS is a crucial step that governs the formation of hydroxyl radical, mainly responsible for BPA degradation. In addition to its ability to maintain iron in soluble form, EDDS acts as a superoxide radical-promoting agent, enhancing the generation of Fe(II) (the rate limiting step) and therefore the production of (*)OH radicals. These results are very promising because they offer an important new treatment option at higher range of pH values and more particularly at pHs encountered in natural conditions. PMID- 23343007 TI - Preeclampsia is associated with an elevation of plasma sMet concentrations in the second trimester. AB - OBJECTIVE: The aim of this study was to investigate the association between anti angiogenic factor soluble c-Met (sMet) concentrations in maternal plasma and the risk of preeclampsia. METHODS: The pregnant women included in this study (1) had subsequent preeclampsia (n = 52) and were compared to normal controls (n = 104) at the time of amniocentesis (15-20 weeks); and (2) had preeclampsia (n = 63) and were compared to normal controls (n = 112) at the time of diagnosis of preeclampsia (29-40 weeks). sMet concentrations were measured by ELISA. Non parametric statistics were used for analysis. RESULTS: Maternal plasma sMet concentrations were significantly higher in both women with subsequent preeclampsia (median: 1372.7 ng/ml versus 1100.5 ng/ml; p = 0.036) and women with preeclampsia (median: 1651.9 ng/ml versus 1364.7 ng/ml; p < 0.001) than in the controls. After adjusting for potential confounding factors, the risks of developing preeclampsia were as follows: adjusted odds ratio 2.5 (95% confidence interval, 1.2-5.2; p = 0.016) for second trimester sMet concentration with a cut off value of 1223.5 ng/ml and 4.4 (95% confidence interval, 2.2-9.1; p < 0.001) for third trimester sMet concentration with a cut-off value of 1460.3 ng/ml. CONCLUSION: Elevated maternal plasma sMet concentrations were independently associated with the increased risk of preeclampsia. PMID- 23343006 TI - Basal expression of pluripotency-associated genes can contribute to stemness property and differentiation potential. AB - Pluripotency and stemness is believed to be associated with high Oct-3/4, Nanog, and Sox-2 (ONS) expression. Similar to embryonic stem cells (ESCs), high ONS expression eventually became the measure of pluripotency in any cell. The threshold expression of ONS genes that underscores pluripotency, stemness, and differentiation potential is still unclear. Therefore, we raised a question as to whether pluripotency and stemness is a function of basal ONS gene expression. To prove this, we carried out a comparative study between basal ONS expressing NIH3T3 cells with pluripotent mouse bone marrow mesenchymal stem cells (mBMSC) and mouse ESC. Our studies on cellular, molecular, and immunological biomarkers between NIH3T3 and mBMSC demonstrated stemness property of undifferentiated NIH3T3 cells that was similar to mBMSC and somewhat close to ESC as well. In vivo teratoma formation with all three germ layer derivatives strengthen the fact that these cells in spite of basal ONS gene expression can differentiate into cells of multiple lineages without any genetic modification. Conclusively, our novel findings suggested that the phenomenon of pluripotency which imparts ability for multilineage cell differentiation is not necessarily a function of high ONS gene expression. PMID- 23343008 TI - Hyaluronic acid click hydrogels emulate the extracellular matrix. AB - Hydrogels are used to create 3D microenvironments with properties that direct cell function. The current study demonstrates the versatility of hyaluronic acid (HA)-based hydrogels with independent control over hydrogel properties such as mechanics, architecture, and the spatial distribution of biological factors. Hydrogels were prepared by reacting furan-modified HA with bis-maleimide poly(ethylene glycol) in a Diels-Alder click reaction. Biomolecules were photopatterned into the hydrogel by two-photon laser processing, resulting in spatially defined growth factor gradients. The Young's modulus was controlled by either changing the hydrogel concentration or the furan substitution on the HA backbone, thereby decoupling the hydrogel concentration from mechanical properties. Porosity was controlled by cryogelation, and the pore size distribution, by the thaw temperature. The addition of galactose further influenced the porosity, pore size, and Young's modulus of the cryogels. These HA based hydrogels offer a tunable platform with a diversity of properties for directing cell function, with applications in tissue engineering and regenerative medicine. PMID- 23343009 TI - Phylogenetic and DNA methylation analysis reveal novel regions of variable methylation in the mouse IAP class of transposons. AB - BACKGROUND: Select retrotransposons in the long terminal repeat (LTR) class exhibit interindividual variation in DNA methylation that is altered by developmental environmental exposures. Yet, neither the full extent of variability at these "metastable epialleles," nor the phylogenetic relationship underlying variable elements is well understood. The murine metastable epialleles, Avy and CabpIAP, result from independent insertions of an intracisternal A particle (IAP) mobile element, and exhibit remarkably similar sequence identity (98.5%). RESULTS: Utilizing the C57BL/6 genome we identified 10802 IAP LTRs overall and a subset of 1388 in a family that includes Avy and CabpIAP. Phylogenetic analysis revealed two duplication and divergence events subdividing this family into three clades. To characterize interindividual variation across clades, liver DNA from 17 isogenic mice was subjected to combined bisulfite and restriction analysis (CoBRA) for 21 separate LTR transposons (7 per clade). The lowest and highest mean methylation values were 59% and 88% respectively, while methylation levels at individual LTRs varied widely, ranging from 9% to 34%. The clade with the most conserved elements had significantly higher mean methylation across LTRs than either of the two diverged clades (p = 0.040 and p = 0.017). Within each mouse, average methylation across all LTRs was not significantly different (71%-74%, p > 0.99). CONCLUSIONS: Combined phylogenetic and DNA methylation analysis allows for the identification of novel regions of variable methylation. This approach increases the number of known metastable epialleles in the mouse, which can serve as biomarkers for environmental modifications to the epigenome. PMID- 23343010 TI - Endovascular repair of a type B aortic dissection with a right-sided aortic arch: case report. AB - Right-sided aortic arch is a rare anomaly, and aortic dissection involving a right-sided aortic arch is extremely rare. We report the case of a 65-year-old man with a right-sided aortic arch and a right descending aortic dissection and a stent-graft was accurately deployed without perioperative complications. There were no any complaints and complications after 18 months follow-up. The CTA demonstrated that the false lumen was largely thrombosed only with a mild type II endoleak and a mild descending aortic expansion. We feel that endovascular repair is feasible to patient of type B aortic dissection with a right-sided aortic arch. However, long-term clinical efficacy and safety have yet to be confirmed. PMID- 23343011 TI - Cognitive remediation in schizophrenia: efficacy and effectiveness in patients with early versus long-term course of illness. AB - AIM: We examined the efficacy and effectiveness (transfer to functional competence and everyday functioning) of cognitive remediation in early-course (within 5 years of first episode) and long-term (more than 15 years of illness) schizophrenia. METHODS: Treatment lasted 12 weeks and included computerized exercises, strategic monitoring and methods to transfer cognition to behaviour. Assessments included a standard battery of neurocognition, performance-based measures of social and adaptive competence, and case manager ratings of real world functional behaviour. Changes from baseline to post-treatment were examined with repeated measures analysis of variance and estimated premorbid intelligence and total months in hospital as covariates. RESULTS: The early-course group had larger improvements in measures of processing speed and executive functions, as well as larger improvements in adaptive competence and real-world work skills. Duration of illness was inversely associated with improvement in neurocognition and real-world work skills. CONCLUSIONS: Treatment of cognitive impairments is feasible in both early-course and chronic schizophrenia, but the clinical meaningfulness and generalization to functioning appear to be more substantial when delivered early. Cognitive remediation should be considered a tool for early intervention in schizophrenia. PMID- 23343012 TI - The effect of clinical interventions on hospital readmissions: a meta-review of published meta-analyses. AB - BACKGROUND: The economic impact and ease of measurement of all-cause hospital readmission rates (HRR) have led to the current debate as to whether they are reducible, and whether they should be used as a publicly reported quality indicators of medical care. OBJECTIVE: To assess the efficacy of broad clinical interventions in preventing HRR of patients with chronic diseases METHOD: A meta review of published systematic reviews of randomized controlled trials (RCTs) of clinical interventions that have included HRR among the patients' outcomes of interest. MAIN FINDINGS: Meta-analyses of RCTs have consistently found that, in the community, disease management programs significantly reduced HRR in patients with heart failure, coronary heart disease and bronchial asthma, but not in patients with stroke and in unselected patients with chronic disorders. Inhospital interventions, such as discharge planning, pharmacological consultations and multidisciplinary care, and community interventions in patients with chronic obstructive pulmonary diseases had an inconsistent effect on HRR. MAIN STUDY LIMITATION: Despite their economic impact and ease of measurement, HRR are not the most important outcome of patient care, and efforts aimed at their reduction may compromise patients' health by reducing also justified re admissions. CONCLUSIONS: The efficacy of inhospital interventions in reducing HRR is in need of further study. In patients with heart diseases and bronchial asthma, HRR may be considered as a publicly reported quality indicator of community care, provided that future research confirms that efforts to reduce HRR do not adversely affect other patients' outcomes, such as mortality, functional capacity and quality of life. Future research should also focus on the reasons for the higher efficacy of community interventions in patients with heart diseases and bronchial asthma than in those with other chronic diseases. PMID- 23343015 TI - Placebo effects in therapeutic outcomes. AB - The goal of this review is to address the medical implications of placebos and placebo effects in future medical practice. The applications of placebos have become increasingly relevant due to a recent abundance of clinical research that has been conducted on the mechanisms under which a placebo response is formed. With current research on placebo, the thoughts of using placebo effects as an effective form of co-treatment for patients with disorders such as pain, depression or Parkinson's disease might become a feasible proposition. This review focuses on crucial studies that have been done in this area of research with regard to the physiological and psychological mechanisms that are associated with the formation of a placebo effect, as well as emphasizing the patient clinician relationship and the importance of this relationship for a successful treatment regimen. PMID- 23343016 TI - Patterns of NSAIDs use in Palestinian mid-territories: a prospective study of ambulatory patients in outpatient pharmacies. AB - The out-patient pharmacies in Ramallah and Bethlehem, central Palestine, were evaluated for NSAIDs utilization and pattern of prescribing and dispensing of these commonly used medications across the whole country. In our study for this area that accounts for almost 25% of the inhabitants of all Palestine (459, 761 inhabitants according to 2011 census), we analyzed the use of NSAIDs whether were prescribed for the patient or were obtained without a prescription in the period of Sept 1(st) to Nov. 30, 2011. The number of defined daily doses, DDD/1000 inh/day, and the percentage utilization from total were determined and analyzed using the simple ATC/DDD model which was developed by WHO for assessment of quality prescribing of medications. From these data we calculated DU 90% for the drugs described in this study. Using a scale for GI toxicity and risk determination from a meta- analysis of controlled epidemiological studies, we determined the GI risk of the drugs in the study. Ketoprofen and piroxicam were found to be associated with the highest risk, on the other hand ibuprofen and diclofenac were associated with low risk of GI toxicity. The average Price/DDD was also determined for the purpose of comparison with the prices in other European countries. Our findings were both exciting and interesting with the total consumption of NSAIDs over the period of study was 31.26 DDD/1000 inh/day comparing to 51.02 DDD/1000 inh/day in the European countries included in the study. Only 5 drugs fell within DU 90% which are respectively along with their percentage NSAIDs consumption: (ibuprofen; 26.48%, diclofenac; 23.38%, etoricoxib; 21.24%, meloxiocam; 12.19%, and celecoxib; 7.16%). The drugs were obtained mostly by prescription except for the first 2 agents (ibuprofen and diclofenac) which were almost exclusively bought without a prescription as OTC with the pharmacist greatly influence their use and dispensing. The price of purchasing for the top DU 90% agents was almost twice the price in Europe for the same drugs taking into consideration the limitations of our study in determining the equipotency or the equivalency of the DDD doses in Palestine and Europe. PMID- 23343014 TI - Environmental exposure assessment in European birth cohorts: results from the ENRIECO project. AB - Environmental exposures during pregnancy and early life may have adverse health effects. Single birth cohort studies often lack statistical power to tease out such effects reliably. To improve the use of existing data and to facilitate collaboration among these studies, an inventory of the environmental exposure and health data in these studies was made as part of the ENRIECO (Environmental Health Risks in European Birth Cohorts) project. The focus with regard to exposure was on outdoor air pollution, water contamination, allergens and biological organisms, metals, pesticides, smoking and second hand tobacco smoke (SHS), persistent organic pollutants (POPs), noise, radiation, and occupational exposures. The review lists methods and data on environmental exposures in 37 European birth cohort studies. Most data is currently available for smoking and SHS (N=37 cohorts), occupational exposures (N=33), outdoor air pollution, and allergens and microbial agents (N=27). Exposure modeling is increasingly used for long-term air pollution exposure assessment; biomonitoring is used for assessment of exposure to metals, POPs and other chemicals; and environmental monitoring for house dust mite exposure assessment. Collaborative analyses with data from several birth cohorts have already been performed successfully for outdoor air pollution, water contamination, allergens, biological contaminants, molds, POPs and SHS. Key success factors for collaborative analyses are common definitions of main exposure and health variables. Our review emphasizes that such common definitions need ideally be arrived at in the study design phase. However, careful comparison of methods used in existing studies also offers excellent opportunities for collaborative analyses. Investigators can use this review to evaluate the potential for future collaborative analyses with respect to data availability and methods used in the different cohorts and to identify potential partners for a specific research question. PMID- 23343017 TI - Intestinal transport as a potential determinant of drug bioavailability. AB - Orally administered drugs are generally absorbed by the small intestine and transported either to the lymphatic system or to the hepatic portal system. In general, lipid soluble drugs and vitamins are transported by the small intestine to the lymphatics, and water-soluble drugs are transported to the hepatic portal system. By avoiding the early hepatic first pass effect, the lymphatic transport system may increase drug bioavailability. In addition to its transport systems, the small intestine may affect drug bioavailability through drug uptake, intestinal first pass effect, recruitment of drugs by chylomicrons, formation and secretion of chylomicrons, and enterohepatic circulation. All of these factors should be considered when formulating orally administered lipophilic drugs. Our data also suggest that Caco-2 cells may serve as a valuable in vitro model to study the intestinal transport of orally administered drugs. PMID- 23343018 TI - Application of multicriteria decision making methods to compression ignition engine efficiency and gaseous, particulate, and greenhouse gas emissions. AB - Compression ignition (CI) engine design is subject to many constraints, which present a multicriteria optimization problem that the engine researcher must solve. In particular, the modern CI engine must not only be efficient but must also deliver low gaseous, particulate, and life cycle greenhouse gas emissions so that its impact on urban air quality, human health, and global warming is minimized. Consequently, this study undertakes a multicriteria analysis, which seeks to identify alternative fuels, injection technologies, and combustion strategies that could potentially satisfy these CI engine design constraints. Three data sets are analyzed with the Preference Ranking Organization Method for Enrichment Evaluations and Geometrical Analysis for Interactive Aid (PROMETHEE GAIA) algorithm to explore the impact of (1) an ethanol fumigation system, (2) alternative fuels (20% biodiesel and synthetic diesel) and alternative injection technologies (mechanical direct injection and common rail injection), and (3) various biodiesel fuels made from 3 feedstocks (i.e., soy, tallow, and canola) tested at several blend percentages (20-100%) on the resulting emissions and efficiency profile of the various test engines. The results show that moderate ethanol substitutions (~20% by energy) at moderate load, high percentage soy blends (60-100%), and alternative fuels (biodiesel and synthetic diesel) provide an efficiency and emissions profile that yields the most "preferred" solutions to this multicriteria engine design problem. Further research is, however, required to reduce reactive oxygen species (ROS) emissions with alternative fuels and to deliver technologies that do not significantly reduce the median diameter of particle emissions. PMID- 23343013 TI - Old drugs, old problems: where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMARDs? AB - Methotrexate (MTX) is the central drug in the management of rheumatoid arthritis (RA) and other immune mediated inflammatory diseases. It is widely used either in monotherapy or in association with other synthetic and biologic disease modifying anti-rheumatic drugs (DMARDs). Although comprehensive clinical experience exists for MTX and synthetic DMARDs, to date it has not been possible to preview correctly whether or not a patient will respond to treatment with these drugs. Predicting response to MTX and other DMARDs would allow the selection of patients based on their likelihood of response, thus enabling individualized therapy and avoiding unnecessary adverse effects and elevated costs. However, studies analyzing this issue have struggled to obtain consistent, replicable results and no factor has yet been recognized to individually distinguish responders from nonresponders at treatment start. Variables possibly influencing drug effectiveness may be disease-, patient- or treatment-related, clinical or biological (genetic and nongenetic). In this review we summarize current evidence on predictors of response to MTX and other synthetic DMARDs, discuss possible causes for the heterogeneity observed and address its translation into daily clinical practice. PMID- 23343019 TI - Drinking and driving in the United States: comparing results from the 2007 and 1996 National Roadside Surveys. AB - OBJECTIVES: The objectives of this study were to (a) use data from the 2007 National Roadside Survey (NRS) to determine the characteristics of weekend nighttime drivers with positive blood alcohol concentrations (BACs) on U.S. roads in 2007; (b) determine the relationship of the driving environment and trip characteristics associated with drinking drivers; and (c) compare the findings for the 2007 NRS with those for the 1996 NRS. METHODS: Like the 1996 NRS, the 2007 NRS used a stratified random national roadside survey sample of the contiguous 48 states and collected nighttime data on Fridays and Saturdays between 10 p.m. and 3 a.m. Officers directed 8384 drivers into off-road parking areas where our research team asked them to participate in the survey. RESULTS: Of those approached, 7159 (85.4%) provided a breath test. Results revealed that 12 percent of the nighttime drivers had positive BACs, and of those, 2 percent were higher than the 0.08 BAC illegal limit in the United States. Since the 1996 NRS, we found significant reductions in the percentage of BAC-positive drivers across different demographic groups. Age was among the most significant factors associated with a weekend driver having a positive BAC. The probability that a driver would be drinking peaked in the 21- to 25-year-old age group. Male drivers were more likely than female drivers to be drinking, and Asian and Hispanic drivers were less likely than white drivers to be drinking. Drinking drivers were more likely to be driving short distances (5 or fewer miles) late at night (between 1 and 3 a.m.) and to be coming from a bar or restaurant. Finally, 26 percent of the drivers who reported that they would drive less than 5 miles on the night of the survey had positive BACs, compared to only 16 percent who indicated that they would drive between 6 and 20 miles and 10 percent who planned to drive more than 20 miles. CONCLUSIONS: The 2007 NRS provides another benchmark in the 4-decade record of drinking drivers on American roads and provides a basis for measuring progress in combating driving under the influence during the coming decade. PMID- 23343020 TI - Detecting alcohol and illicit drugs in oral fluid samples collected from truck drivers in the state of Sao Paulo, Brazil. AB - OBJECTIVE: Alcohol and drug use by truck drivers is a current problem in Brazil. Though there is evidence that alcohol consumption is occurring in higher proportions, the use of stimulant drugs to avoid fatigue and to maintain the work schedule has also been reported. The purpose of this study was to estimate the incidence of alcohol and illicit drug use among truck drivers on Sao Paulo state roads. Sao Paulo is the most populous state in Brazil and has the largest industrial park and economic production in the country. METHODS: Data were assessed not only using a questionnaire but also, and more reliably, through toxicological analysis of oral fluid samples. Between the years 2002 and 2008, 1250 oral fluid samples were collected from truck drivers on the roads during morning hours. The samples were tested for the presence of alcohol, cocaine, tetrahydrocannabinol (THC), and amphetamine/methamphetamine. A previously published, validated gas chromatographic (gas chromatography-flame ionization detection and gas chromatography-mass spectrometry) method was applied to the samples for alcohol and drug detection. RESULTS: Of the total analyzed samples, 3.1 percent (n = 39) were positive: 1.44 percent (n = 18) were positive for alcohol, 0.64 percent (n = 8) for amphetamines, 0.56 percent (n = 7) for cocaine, and 0.40 percent (n = 5) for THC. In one case, cocaine and THC were detected. The results are indicative of the extent of alcohol and drug use by truck drivers in the state of Sao Paulo, Brazil. CONCLUSIONS: This research provides evidence that not only alcohol but also illicit drug use is a real problem among professional drivers. The use of these substances should be controlled to better promote safe driving conditions on Brazilian roads. PMID- 23343021 TI - Driver performance while texting: even a little is too much. AB - OBJECTIVE: To examine the impact of text messaging and other in-car behaviors on driving performance under simple and naturalistic road conditions in a driving simulator. METHODS: Data from 28 healthy individuals (12 female) are presented. Participant age ranged from 18 to 28 (mean = 21.0). Average driving experience was 3.8 years (SD = 2.5). Participants completed a baseline loop condition in which they drove normally through a realistic virtual environment. Next, participants drove an identical loop, and at 3 specified points during this drive, participants were required to (1) complete a radio-tuning task; (2) type and send a text message containing "Drexel University"; and (3) type and send "I am driving to the store." Driving performance and task duration was compared between conditions. RESULTS: Across all tasks, both lane management, F(1,27) = 11.1, P = .002, and velocity, F(1,27) = 10.3, P = .003, varied significantly more while task-engaged. Average lane deviation was significantly greater during a text messaging task than during the baseline drive of the same road segment, t(27) = -2.9, P = .007. Comparison of task durations indicated that both texting tasks took significantly longer to complete than the radio task, with the "Drexel University" text (118 s) taking almost twice as long as the radio-tuning task (60 s). Unexpected and novel findings emerged in the evaluation of duration of texting tasks using the varying text-entry methods, with touch-screen modality taking significantly longer than others. CONCLUSIONS: Engaging in secondary tasks while operating a motor vehicle may have deleterious effects on driving performance and increase risk, even under the simplest of driving conditions. Text messaging may constitute a "perfect storm" of risk compared to other in vehicle tasks such as tuning the car radio. The current investigation demonstrated detrimental effects of text messaging on driving behaviors such as lane maintenance, speed maintenance, and shifts of attention, even under relatively ideal and naturalistic driving conditions (e.g., familiar route, good weather, no traffic). PMID- 23343022 TI - Sudden death at the wheel due to a disease attack. AB - PURPOSE: To (1) examine the prevalence of fatal disease attacks while driving, (2) evaluate the potential risk of a driver's acute incapacity to drive, (3) compare the risks related to the driver's incapacity to drive with other major risks related to fatal motor vehicle accidents (fMVAs), and (4) assess how these accidents are reported in official statistics. METHODS: The data consist of information from the Finnish Road Accident Investigation Teams (RAITs) on fMVAs in Finland during 2008-2009, in-depth analyses of accidents in the Uusimaa district in 2008-2009, and data from Statistics of Finland (StatFi) concerning accidents in the Uusimaa district. RESULTS: In 2008-2009 as a whole, 488 fMVAs were encountered in Finland, and 73 of these were in Uusimaa. From fMVAs of the whole country, 55 driver deaths (11%) were due to a disease attack and in 27 (6%) of the cases, the driver was presumed to have fallen asleep. In Uusimaa approximately 25 percent (N = 18/73) of deaths at the wheel were caused by a driver's acute disease attack, but only 20 percent were recorded in the official StatFi. Cardiac and neurological diseases were the most common causes of disease attacks while driving. Additionally, disease attacks contributed as a background reason in at least 6/73 (8%) fMVAs. Speeding was found to be involved in approximately 1/3 (N = 190) of all fMVAs; however, in the absence of other risk factors, it was relatively rare (9%; N = 43). CONCLUSION: A disease attack while driving is a relatively common cause of death on the road. Severe injuries may mask the role of an initial disease attack. This hypothesis is supported by the data collected on sleeping and background accidents. Thus, the drivers' disease attacks might have an even broader impact than initially assumed. Monitoring driver health and recognizing comorbidity problems could play a large role in the promotion of road safety. The current method of monitoring the fitness to drive and producing accident statistics should be reevaluated. PMID- 23343024 TI - Uncertainty analysis of accident notification time and emergency medical service response time in work zone traffic accidents. AB - OBJECTIVE: Taking into account the uncertainty caused by exogenous factors, the accident notification time (ANT) and emergency medical service (EMS) response time were modeled as 2 random variables following the lognormal distribution. METHOD: Their mean values and standard deviations were respectively formulated as the functions of environmental variables including crash time, road type, weekend, holiday, light condition, weather, and work zone type. Work zone traffic accident data from the Fatality Analysis Report System between 2002 and 2009 were utilized to determine the distributions of the ANT and the EMS arrival time in the United States. A mixed logistic regression model, taking into account the uncertainty associated with the ANT and the EMS response time, was developed to estimate the risk of death. RESULTS: The results showed that the uncertainty of the ANT was primarily influenced by crash time and road type, whereas the uncertainty of EMS response time is greatly affected by road type, weather, and light conditions. In addition, work zone accidents occurring during a holiday and in poor light conditions were found to be statistically associated with a longer mean ANT and longer EMS response time. The results also show that shortening the ANT was a more effective approach in reducing the risk of death than the EMS response time in work zones. CONCLUSIONS: To shorten the ANT and the EMS response time, work zone activities are suggested to be undertaken during non-holidays, during the daytime, and in good weather and light conditions. PMID- 23343023 TI - Excessive sleepiness prevalence in public transportation drivers of a developing country. AB - OBJECTIVE: To determine the prevalence of excessive sleepiness (ES) in bus and auto-rickshaw drivers from Lima, Peru. METHODS: We conducted a cross-sectional study of Lima's bus and auto-rickshaw drivers to estimate ES prevalence in this population. Survey sites were private transportation companies, systematically selected with a snowball approach. ES was assessed with the Spanish-validated version of the Epworth sleep questionnaire (ESQ) with a cutoff score >10. We obtained relevant demographic information. RESULTS: Four hundred and thirty-four bus and auto-rickshaw drivers were eligible for analysis. The overall ES prevalence was 32.7 percent (95% confidence interval [CI]: 28-37.2). ES prevalence was higher in bus drivers than in auto-rickshaw drivers, 38 percent (95% CI: 31.7-44.2) and 26.9 percent (95% CI: 20.6-33.1), respectively (P = .01). We used data from all subjects to obtain regression equations for ESQ score with several predictors. Being a bus driver, working additional nighttime hours per week, having depression or anxiety, and alcohol abuse had small but significant associations with ESQ scores. CONCLUSION: ES prevalence in Lima's public transportation drivers is in a medium range as suggested by previous regional studies. PMID- 23343025 TI - Thoracic response to shoulder belt loading: comparison of tabletop and frontal sled tests with PMHS. AB - OBJECTIVE: The recent refinement of high-rate optical tracking allows dramatically detailed thoracic deformation measurements to be taken during postmortem human subject (PMHS) sled tests. These data allow analysis of restraint belt geometry and the 3-dimensional thoracic deformations generated by belt impingement. One consequence of this new capability is a better understanding of complementary thoracic characterization experiments such as tabletop tests and how the thoracic response can be interpreted for applications involving more complex loading mechanisms. METHODS: This article reports a detailed evaluation of the timing, magnitude, and direction of the applied belt forces and the resulting thoracic deformations in 2 previously performed tests series involving frontal sled tests and tabletop belt-loading tests. RESULTS: In the sled tests, the posteriorly directed component (SAE x) of the belt tension (F(B)) was F(Bx) = 0.70 F(B) at the shoulder but only F(Bx) = 0.14 F(B) where the belt engaged the anterolateral torso inferiorly. The corresponding components on the tabletop were F(Bx) = 0.60 F(B) (shoulder) and F(Bx) = 0.48 F(B) (lower). CONCLUSIONS: When these components are cross-plotted with chest deflection, pronounced consequences of thoracic anterior wall deformation patterns due to flexion of the thoracic spine and the internal viscera's inertia can be seen in the effective thoracic stiffness. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file. PMID- 23343026 TI - Investigation of the safety effects of knee bolster air bag deployment in similar real-world crash comparisons. AB - OBJECTIVE: The lower extremity is the most frequently injured body region and knee-thigh-hip (KTH) injuries account for half of these injuries. Knee bolster air bags (KBABs) have been incorporated in some vehicles to serve as an additional restraint for the occupant's knees and reduce KTH injuries. To investigate the safety benefits of KBABs, similar frontal crashes with opposing KBAB deployment were selected from the Crash Injury Research and Engineering Network (CIREN) database. METHODS: An 8-point similarity scoring algorithm was used to quantify crash and occupant similarity and select case comparisons. A total of 183 cases without a KBAB were scored for similarity to 9 KBAB cases. These similarity scores were used to select 31 final case comparisons. The effect of KBAB deployment on occupant injury patterns was investigated with a particular focus on KTH injuries. RESULTS: Over half of the occupants exposed to a KBAB sustained no KTH injuries and a reduction in femur fractures was observed in KBAB occupants (P = .036). However, increases in proximal tibia/fibula and foot/ankle fractures were observed in KBAB occupants (P = .022 and .002, respectively). Mildly significant decreases in pelvic fractures and Abbreviated Injury Scale (AIS) 2+ head injuries were observed in the KBAB occupants, supporting the notion that KBABs reduce forward occupant excursion (P = .094 and .055, respectively). Investigation of each case comparison yielded further insight into the reasons for injury pattern differences between cases with opposing KBAB deployment. In addition to KBAB deployment status, differences in occupant factors (age, height, and weight) and crash factors (delta V and belt use) between the cases for a particular comparison could explain variation in injury patterns. CONCLUSIONS: The current study presents a preliminary in-depth qualitative and quantitative assessment of KBAB safety benefits. However, further investigation is recommended to provide conclusive evidence of KBAB effectiveness. PMID- 23343027 TI - Rebound after rear impacts. AB - OBJECTIVE: A number of field accident studies have found that rebound is a source for occupant injury after rear impacts. Sled tests were run to investigate occupant kinematics and rebound, including head velocity and displacement with 3 different seats, 2 conventional seat designs, and 1 all belts to seat (ABTS). METHODS: Nine rear-end sled tests were run with a belted 50th Hybrid III dummy on a Taurus, Mustang, or Sebring ABTS seat in nominally 16.5, 24.1, and 32.5 km/h rear-end delta Vs. There was no sled braking after the rear acceleration to study rebound from the seat. Dummy kinematics were analyzed from high-speed video and biomechanical responses from triaxial head and chest accelerations, triaxial upper and lower neck loads and moments, and seat belt loads. Peak responses were tabulated during seat back rotation rearward and rebound forward. Ratios of biomechanical and kinematic responses were determined comparing ABTS to conventional seat responses for each delta V. Student's t-test was used to determine significant differences between the ratios of ABTS to conventional seat responses. RESULTS: The rebound velocity of the head varied from 2.9 to 6.8 m/s with respect to the sled. Overall, it was 69 +/- 22 percent higher than the sled delta V. It was greatest with ABTS in the highest severity test where seat back yielding absorbed energy and reduced rebound in the conventional seats. The time to maximum forward excursion was significantly shorter with ABTS compared to the conventional seats with a ratio of 0.54 +/- 0.34 (t = 6.13, df = 5, P < .001). CONCLUSIONS: ABTS seats remain more upright in rear-end crashes and transfer greater load to the occupant during rebound than conventional seats that yield rearward and absorb energy in higher severity crashes. Rebound occurs earlier and at higher velocities with ABTS. This displaces the occupant toward the front interior. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file. PMID- 23343028 TI - Evidence-based review on interventions and determinants of driving performance in teens with attention deficit hyperactivity disorder or autism spectrum disorder. AB - OBJECTIVE: We conducted an evidence-based review of intervention studies and predictor studies related to driving outcomes in teens with attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). METHODS: Ten primary studies were classified using the American Academy of Neurology's criteria (class I-IV, I = highest level of evidence). We provided recommendations including Level A: intervention/factors are effective/predictive or not; Level B: probably effective/predictive or not; Level C: possibly effective/predictive or not; Level U: no recommendations. RESULTS: For the intervention studies we identified 1 Class II and 1 Class III study; for predictor studies, we identified 7 ADHD studies consisting of 1 Class II and 6 Class III studies. Only 1 Class III ASD study was found. In synopsizing the evidence, the following recommendations are made for the intervention studies pertaining to on-road performance in teens with ADHD: a multimodal intervention is possibly effective in improving driving performance (Level C); stimulants possibly do not affect driving negatively (Level C); no recommendations can be made for hazard perception training in ADHD or ASD (Level U). Consider the following recommendations useful for simulated driving performance: Stimulants possibly improve driving performance (Level C); ADHD diagnosis and being unmedicated possibly worsen driving performance (Level C); no recommendations for driving in low-stimulus conditions (Level U). From self-/proxy report, no recommendations can be made related to gender or ADHD subtype affecting adverse driving outcomes (Level U). CONCLUSION: Class I studies with Level A recommendations, currently lacking in the literature, are urgently needed to make clear the mechanism underlying driving performance outcomes in ADHD and ASD. Supplementary materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention for the following supplemental resource: Table: Evidence-based Synopsis of ADHD, ASD and Driving Performance: Variables, Sample, Findings & Rationale. PMID- 23343029 TI - Child restraint safety practices among Arab children in Israel. AB - OBJECTIVE: Because the rate of injury and mortality from car crashes among Arab children is higher than among Jewish children in Israel, this study assesses the patterns of age-appropriate child restraint system (CRS) use in Arab towns in Israel. METHODS: From October 2010 to September 2011, 4396 children ages 0 to 14 were observed while seated in vehicles in 9 Arab towns and villages in Israel. RESULTS: Among infants aged 0 to 1 year old, 31.2 percent were observed in an age appropriate restraint, whereas among children aged 1 to 4 years, only 12.4 percent were age-appropriately restrained. Children aged 5 to 9 were observed to have the lowest levels of age-appropriate restraint use (1.3%). The variation between the various villages was large and dependent on the age of the child. CONCLUSIONS: The low rates of CRS use may explain to some degree the high rates of injury and mortality of Arab children in car crashes. These low rates indicate that previous interventions have not been successful in increasing restraint use in the Arab community in Israel and there is a need to plan targeted interventions specifically for this population. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file. PMID- 23343030 TI - Rear seat child safety in near-side impacts: a modeling study of common sitting positions. AB - OBJECTIVE: The purpose of this study was to evaluate and propose improvements to the injury mitigation systems, in near-side impacts, for 6 common sitting positions of young adolescents using a previously validated model. METHODS: The evaluation was made by using a model of a complete passenger car, including head and thorax-pelvis air bags, which was impacted laterally by a barrier in 2 load cases. The SID-IIs finite element model was used for the evaluations and was seated in 6 different positions in the rear outboard seat: the nominal anthropomorphic test device (ATD) position, 1 inboard position, 3 outboard positions, and 1 braking (forward) position. These positions have previously been identified as common sitting positions in awake and asleep children. The studied dependent variables were head injury criterion (HIC) 36, resultant head linear acceleration, resultant head rotational acceleration, chest viscous criterion, and chest deflection. RESULTS: The lowest head injury measures were seen in the braking positions and in the nominal ATD position, and the highest were seen in the inboard and outboard positions. The lowest chest injury measures were recorded in the inboard and nominal ATD positions, and the highest were recorded in the outboard and braking positions. The occupant in the outboard positions interfered with the air bags during their deployment. The occupant in inboard and braking positions tended to push the curtain air bag over the windowsill. CONCLUSIONS: Studies that investigate the injury mitigation effects in common sitting positions, beyond the nominal ATD position, are essential to highlight means to provide improved and robust safety for child occupants. This study was based on the SID-IIs 5th percentile female, which has very similar anthropometry to a 50th percentile 12-year-old. Therefore, the conclusions of this study are applicable to many 11-year-olds up to young adolescents, as well as to small females. The outboard and inboard positions of this study resulted in the highest head injury measures. Although all of the injury measures were only slightly higher than the nominal position, the trends suggest that, in near-side impacts, these positions should be discouraged. The extensively outboard positions resulted in unfavorable air bag positioning during deployment. The inboard position resulted in head strikes further forward of the nominal one; the curtain air bags need inflated cells at all locations of head strike. PMID- 23343031 TI - Child passenger restraints in relation to other second-row passengers: an analysis of the 2007-2009 National Survey of the Use of Booster Seats. AB - OBJECTIVE: Child restraint systems (CRS) are increasingly being designed to accommodate larger children and to mitigate side impact injuries. Little is known about the impact of CRS on the safety of other vehicle passengers due to limitations of existing crash databases. This study provides the first assessment of the seating positions occupied by child passengers and the relationship between CRS and other second-row passengers in a national sample of vehicles transporting children. METHODS: A secondary analysis was conducted of data from the 2007-2009 National Survey of the Use of Booster Seats (NSUBS), a direct in vehicle observational study of child passenger restraint use. Passengers riding in the same vehicle were identified and passenger position was determined. Vehicles with second-row child passengers were included in analyses of seat positions occupied by child passengers with and without CRS. Frequency counts for the different combinations of CRS and passengers in second rows were calculated. RESULTS: Of the 17,065 vehicles observed in 2007-2009 NSUBS, 14,506 (85%) vehicles contained at least 1 child passenger in a second row that contained no more than 3 total passengers. Of these 14,506 vehicles, 55 percent contained a lone child passenger in the second row. A CRS was in use in 4656 (59%) of the 7949 vehicles with a lone child passenger in the second row compared to 4077 (62%) of the 6557 vehicles with multiple passengers in the second row (P < .001). A passenger was adjacent to a CRS within 1333 (33%) of the 4077 vehicles containing a CRS in the second row. There were 3 second-row passengers in nearly 1 in 5 vehicles containing a CRS in the second row. CONCLUSION: Adults and children not using CRS are frequently seated in vehicle second rows adjacent to a child restrained in a CRS. These findings should be used to inform the regulation, design, and testing of CRS and to determine the risks of larger CRS designs to other passengers seated in the same vehicle row relative to the benefits of the CRS for the passenger it restrains. PMID- 23343032 TI - Evaluation of the heats of formation of corannulene and C60 by means of high level theoretical procedures. AB - In this study, we address the issues associated with predicting usefully accurate heats of formation for moderately-sized molecules such as corannulene and C(60). We obtain a high-level theoretical heat of formation for corannulene through the use of reaction schemes that conserve increasingly larger molecular fragments between the reactants and products. The reaction enthalpies are obtained by means of the high-level, ab initio W1h thermochemical protocol, while accurate experimental enthalpies of formation for the other molecules involved in the reactions are obtained from the Active Thermochemical Tables (ATcT) network. Our best theoretical heat of formation for corannulene (Delta(f)H degrees (298)[C(20)H(10)(g)] = 485.2 +/- 7.9 kJ mol(-1)) differs significantly from the currently accepted experimental value (Delta(f)H degrees (298)[C(20)H(10)(g)] = 458.5 +/- 9.2 kJ mol(-1)), and this suggests that re-examination of the experimental data may be in order. We have used our theoretical heat of formation for corannulene to obtain a predicted heat of formation of C(60) through reactions that involve only corannulene and planar polyacenes. Current experimental values span a range of ~200 kJ mol(-1). Our reaction enthalpies are obtained by means of double-hybrid density functional theory in conjunction with a large quadruple-zeta basis set, while accurate experimental heats of formation (or our theoretical value in the case of corannulene) are used for the other molecules involved. Our best theoretical heat of formation for C(60) (Delta(f)H degrees (298)[C(60)(g)] = 2521.6 kJ mol(-1)) suggests that the experimental value adopted by the NIST thermochemical database (Delta(f)H degrees (298)[C(60)(g)] = 2560 +/- 100 kJ mol(-1)) should be revised downward. PMID- 23343033 TI - Ratiometric fluorescence detection of anions by silanediol-based receptors bearing anthryl and pyrenyl groups. AB - Two silanediol derivatives bearing 9-anthryl (2) and 1-pyrenyl (3) groups have been developed for fluorescence detection of anions. Receptor 3 showed favorable ratiometric response by fluorescence spectroscopy upon the addition of biologically relevant anions, such as acetate and dihydrogen phosphate in acetonitrile. PMID- 23343034 TI - Diagnosis and treatment of a patient with bilateral thoracic outlet syndrome secondary to anterior subluxation of bilateral sternoclavicular joints: a case report. AB - Thoracic outlet syndrome may result from a posterior sternoclavicular (SC) joint subluxation, or an anterior SC joint subluxation after surgical fixation. This case report presents the physical therapy management of a patient with bilateral thoracic outlet syndrome (TOS) secondary to bilateral idiopathic anterior SC joint subluxation. A 16-year-old female presented with a 2-year history of numbness, tingling, and coldness in bilateral upper extremities, and intermittent headaches with occasional vision loss. Ipsilateral upper extremity symptoms were reproduced with cervical rotation and shoulder flexion and abduction from 90 degrees to end of the range. All TOS tests were positive. Passive horizontal abduction, through the plane of scaption, produced anterior subluxation of the ipsilateral SC joint. Sustained posterior glides to the medial clavicle relieved all symptoms during shoulder flexion and the Adson's test. Interventions consisted of manual therapy, therapeutic exercise, and the trial of two orthoses. After 12 treatment sessions, the patient's symptoms resolved and she improved by 10 points on the Upper Extremity Functional Index. She had no reproduction of symptoms with the thoracic outlet special tests. She maintained a static hold for 90 sec at 90 degrees shoulder flexion, 90 degrees shoulder abduction, and full shoulder flexion without symptoms. The outcomes describe a successful intervention for a patient with bilateral TOS secondary to idiopathic bilateral anterior SC joint subluxation. This case suggests that SC joint dysfunction should be considered as a cause of TOS and should be screened during the initial examination. PMID- 23343035 TI - Upper extremity strength and range of motion and their relationship to function in breast cancer survivors. AB - The impact upper extremity impairments (UE) have on UE function in breast cancer survivors (BCS) is unclear. The purpose of this study was to evaluate the associations between upper extremity active range of motion (AROM), passive range of motion (PROM), and strength with self-reported function in BCS. BCS (n = 24) completed the Disabilities of Arm, Shoulder and Hand (DASH) and the Pennsylvania Shoulder Score (PSS). AROM and PROM of shoulder flexion, extension, external rotation (ER) at 0 degrees and 90 degrees of abduction, and internal rotation (IR) at 90 degrees of abduction were measured using a digital inclinometer. Strength was measured using a hand-held dynamometer for scapular abduction and upward rotation, scapular depression and adduction, flexion, IR, ER, scaption, and horizontal adduction. All constructs of AROM, PROM, and strength were correlated with the DASH and PSS. DASH was moderately to highly correlated with 2 of 5 AROM, 2 of 5 PROM, and 6 of 7 shoulder strength measures. PSS was moderately to highly correlated with 2 of 5 AROM, 2 of 5 PROM, and 4 of 7 shoulder strength measures. Regression analysis showed that AROM explained 40% of the DASH scores and strength explained 20% of scores on the PSS. This study characterizes the impact that shoulder motion, flexibility, and strength losses have on shoulder function in BCS. Deficits in AROM and shoulder strength explained the greatest proportion of shoulder disability. Future clinical trials should consider incorporating AROM and strengthening techniques to improve shoulder use after breast cancer treatments. PMID- 23343036 TI - Identification of fidgety movements and prediction of CP by the use of computer based video analysis is more accurate when based on two video recordings. AB - This study evaluates the role of postterm age at assessment and the use of one or two video recordings for the detection of fidgety movements (FMs) and prediction of cerebral palsy (CP) using computer vision software. Recordings between 9 and 17 weeks postterm age from 52 preterm and term infants (24 boys, 28 girls; 26 born preterm) were used. Recordings were analyzed using computer vision software. Movement variables, derived from differences between subsequent video frames, were used for quantitative analysis. Sensitivities, specificities, and area under curve were estimated for the first and second recording, or a mean of both. FMs were classified based on the Prechtl approach of general movement assessment. CP status was reported at 2 years. Nine children developed CP of whom all recordings had absent FMs. The mean variability of the centroid of motion (CSD) from two recordings was more accurate than using only one recording, and identified all children who were diagnosed with CP at 2 years. Age at assessment did not influence the detection of FMs or prediction of CP. The accuracy of computer vision techniques in identifying FMs and predicting CP based on two recordings should be confirmed in future studies. PMID- 23343037 TI - Case records of the Massachusetts General Hospital. Case 4-2013. A 50-year-old man with acute flank pain. PMID- 23343038 TI - Epidemic influenza--responding to the expected but unpredictable. PMID- 23343039 TI - The underside of the silver tsunami--older adults and mental health care. PMID- 23343040 TI - Managing disclosure following recent-onset psychosis: utilizing the individual placement and support model. AB - AIMS: Individual Placement and Support is the most defined and evidence-based approach to supported employment for severe mental illness, including recent onset psychosis. However, there is limited evidence or detailed guidelines informing the management of mental illness disclosure to educators or employers when delivering individual placement and support. In this paper, we describe the initial disclosure preferences of young people with recent-onset psychosis enrolled in individual placement and support and provide guidance for managing disclosure when delivering Individual Placement and Support with this population. METHODS: Drawing from sites in Melbourne, Australia and Los Angeles, USA, clients' initial disclosure preferences were examined. We describe approaches to providing individual placement and support when no disclosure is permitted compared with when disclosure is permitted, including two illustrative case vignettes. RESULTS: No disclosure of mental illness or disability was requested by 54-59% of clients; 41-46% of clients permitted partial or complete disclosure. The 'no disclosure' scenario required the individual placement and support worker to provide support 'behind the scenes', whereas when disclosure was permitted, the individual placement and support worker could have contact with instructors/employers and work 'on the front lines'. The case vignettes illustrate how both approaches can lead to successful vocational outcomes. CONCLUSIONS: We found that Individual Placement and Support can be provided in an educative, flexible, creative and collaborative manner according to client disclosure preferences. We suggest that disclosure preferences do not prevent successful vocational outcomes, although this supposition requires empirical investigation. PMID- 23343041 TI - Human papillomavirus type 16 E6 variants in France and risk of viral persistence. AB - BACKGROUND: Only a small portion of HPV 16 infections persist and can lead to cervical intraepithelial lesions and cancer. Factors that favour HPV persistence versus clearance are still poorly understood, but several studies have suggested that HPV intra-type variants may influence persistence and clinical outcome. The aim of this study was to assess the possible association between HPV 16 variants and the risk for viral persistence in the general population of France. METHODS: One hundred and forty two women infected with HPV 16 with normal cytology, without previous treatment for cervical lesions, and with a valid second follow up visit 4 to 16 months later, were selected from patients participating in routine cervical cancer screening in the Reims HPV Primary Screening Cohort Study. HPV intra-type variants were determined by sequencing the HPV 16 E6 open reading frame, and were compared for viral persistence at the second visit using odds ratios (OR) to estimate relative risk. RESULTS: Although no statistically significant differences in risk for persistence were observed by the HPV 16 variant lineage, European variants containing the polymorphism 350 T (EUR-350 T) appeared to persist more often than those containing 350 G (EUR-350 G) (OR = 1.6, 95% CI = 0.8-3.4). CONCLUSIONS: No strong differences were observed in the risk of viral persistence for the HPV 16 variants that predominate in France. PMID- 23343043 TI - Eating disorders as "brain-based mental illnesses": an antidote to stigma? PMID- 23343042 TI - Genome reannotation of the lizard Anolis carolinensis based on 14 adult and embryonic deep transcriptomes. AB - BACKGROUND: The green anole lizard, Anolis carolinensis, is a key species for both laboratory and field-based studies of evolutionary genetics, development, neurobiology, physiology, behavior, and ecology. As the first non-avian reptilian genome sequenced, A. carolinesis is also a prime reptilian model for comparison with other vertebrate genomes. The public databases of Ensembl and NCBI have provided a first generation gene annotation of the anole genome that relies primarily on sequence conservation with related species. A second generation annotation based on tissue-specific transcriptomes would provide a valuable resource for molecular studies. RESULTS: Here we provide an annotation of the A. carolinensis genome based on de novo assembly of deep transcriptomes of 14 adult and embryonic tissues. This revised annotation describes 59,373 transcripts, compared to 16,533 and 18,939 currently for Ensembl and NCBI, and 22,962 predicted protein-coding genes. A key improvement in this revised annotation is coverage of untranslated region (UTR) sequences, with 79% and 59% of transcripts containing 5' and 3' UTRs, respectively. Gaps in genome sequence from the current A. carolinensis build (Anocar2.0) are highlighted by our identification of 16,542 unmapped transcripts, representing 6,695 orthologues, with less than 70% genomic coverage. CONCLUSIONS: Incorporation of tissue-specific transcriptome sequence into the A. carolinensis genome annotation has markedly improved its utility for comparative and functional studies. Increased UTR coverage allows for more accurate predicted protein sequence and regulatory analysis. This revised annotation also provides an atlas of gene expression specific to adult and embryonic tissues. PMID- 23343044 TI - A comparison of the illness perceptions of North Indian and white British women. AB - BACKGROUND: Treatment seeking by South Asians for depression has been shown to be lower than for white British people. AIMS: This study compared illness perceptions about depression and the help-seeking behaviour of white British (n = 70) and North Indian women (n = 70) living in the UK. Previous studies have used interviews to elicit illness perceptions but have been time-consuming. The shorter Brief Illness Perception Questionnaire (BIPQ) was used instead. METHOD: A cross-sectional survey design was used. Participants were asked to evaluate problems of a vignette character using the BIPQ. RESULTS: Compared with the British group, Indian participants believed treatment would be less beneficial; felt they had less of an understanding of the character's difficulties and that the character's difficulties had less of an effect on her emotionally. Significantly fewer of the Indian sample suggested the character should go to her general practitioner (GP). Consistent with previous findings, Indian women reported themselves to be feeling more distressed when compared with British women. No differences in perceived causes of the vignette character's difficulties were found between the groups which is slightly discrepant with previous studies. CONCLUSIONS: Ethnic differences were found in illness perceptions which could help explain the lower rate of GP consultation amongst Indian women. PMID- 23343045 TI - Age and gender differences of somatic symptoms in children and adolescents*. AB - AIMS: This study provides information about the prevalence of somatic symptoms (Ss) in a population of Spanish children and adolescents and their distribution by age and gender. It also sheds light on which Ss are more associated with depression and anxiety and which are associated with more disability. METHOD: A sample of 2558 school children and adolescents aged 8-16 years old, 1297 girls, completed one questionnaire about Ss, and two about anxiety and depressive symptoms. RESULTS: About 37.6% reported at least one Ss, headache being the most prevalent. In terms of age distribution, 26.8% of children and 52.1% of adolescents reported Ss. Girls reported more Ss than did boys. These gender differences started at 13 years of age and decreased at 15. Headache, stomach ache and muscle pain were the Ss that caused the most impairment. CONCLUSIONS: In general, both anxiety and depressive symptoms were related to all Ss, whereas anxiety symptoms were associated with fatigue and muscle pain [corrected]. PMID- 23343046 TI - Screening for cardiovascular risk in patients with severe mental illness in primary care: a comparison with patients with diabetes. AB - BACKGROUND: People with severe mental illness (SMI) have a higher risk of developing cardiovascular disease (CVD) compared with the general population. Clinical guidelines recommend annual screening for CVD risk factors with appropriate lifestyle counselling. Aims To establish the proportion of patients with SMI being screened for CVD risk factors in their primary care practice compared with those with diabetes and determine whether people with SMI receive lifestyle advice. METHOD DESIGN: a retrospective audit. SETTING: five primary care centres in Northampton, England. PARTICIPANTS: three hundred and eighty-six patients with SMI and 1875 with diabetes. RESULTS: Just over a fifth of patients with SMI received a full CVD screen compared with the 96% of those with diabetes (OR = 90.37; 95% CI = 64.53-126.55, p < 0.01). Fifty-seven per cent of the SMI patients were given smoking advice but only 13% and 14% received guidance regarding diet and exercise, respectively. On average of each patient with SMI received fewer than two (from four) screening interventions and less than one (from three) components of lifestyle advice. CONCLUSIONS: In primary care, the number of people with SMI receiving screening for CVD risk is much lower than those with diabetes. PMID- 23343047 TI - Psychometric properties of a Mental Health Team Development Audit Tool. AB - BACKGROUND: To assist in improving team working in Community Mental Health Teams (CMHTs), the Mental Health Commission formulated a user-friendly but yet-to-be validated 25-item Mental Health Team Development Audit Tool (MHDAT). AIMS: The present study aims to examine the psychometric properties of the MHDAT. METHOD: Based on a sample of clinical psychologists (n = 77) with experience of working in CMHTs, reliability of the MHDAT was explored by means of Cronbach's alpha, intraclass correlation and inter-rater correlation, followed by analysis of face validity, distribution of the total scores, frequency distributions for each item and missing values. In order to identify possible MHDAT subscales, explorative factor analysis with orthogonal and oblique rotation was performed. RESULTS: The MHDAT demonstrated good face validity and internal reliability. Three internally consistent subscales were identified. Cut-off points for level of perceived team working were defined. CONCLUSIONS: The MHDAT meets the criteria for a comprehensive measure of perceived team working in CMHTs. Its use in a team may be repeated at different stages and would be particularly fruitful in moments of transition or review within a team. PMID- 23343048 TI - The case for single-session therapy: does the empirical evidence support the increased prevalence of this service delivery model? AB - BACKGROUND: A significant increase in the number of walk-in counselling clinics offering single-session therapy (SST) prompted this review of the empirical support for the effectiveness of SST. AIMS: The article is intended to (1) increase practitioners' knowledge of the empirical support for the effectiveness of single-session counselling with client populations typically served in community-based mental health and counselling agencies and (2) identify priorities for future research on SST. METHOD: A thorough review of relevant databases was undertaken to locate published studies reporting client outcomes following SST. The focus of the review is research involving clients and presenting problems typically seen in community-based mental health and family counselling agencies. RESULTS: The findings suggest that the majority of clients attending either previously scheduled or walk-in SST find it sufficient and helpful. The studies imply that this model of service delivery leads to perceived improvement in presenting problems in general, and on specific measures of variables such as depression, anxiety, distress level and confidence in parenting skills. CONCLUSIONS: Many of the studies have methodological limitations, and future research requires increased use of standardized measures, control groups and larger and more diverse samples. PMID- 23343051 TI - Interventions for reducing readmissions - are we barking up the right tree? AB - Readmission reduction is at the focus of health care systems worldwide in efforts to improve efficiency across care settings. Yet, setting targets for readmission reduction is complicated due to inconsistencies in evidence pointing to effective organization-wide interventions and because of inverse incentives (such as maintaining high occupancy rates). Nonetheless, readmission reduction is one of the few quality measures that, if implemented properly, can serve as a catalyst for system integration. Appropriate mechanisms should be applied to hospitals as well as ambulatory settings to ensure that accountability is assigned to all stakeholders. PMID- 23343052 TI - Increased activation and cytokine secretion in B cells stimulated with leptin in aged humans. AB - Aging is associated chronic inflammation and autoimmunity, and increased levels of leptin. Increased levels of leptin are associated with inflammation and autoimmunity. We have recently reported that leptin activates B cells to induce secretion of proinflammatory and anti-inflammatory cytokines. Role of B cells and leptin in inflammation associated with aging has not been explored. In this study we demonstrate that leptin activates and induces significantly greater amount of IL-6, TNF-alpha, and IL-10 by B cells from aged humans as compared to young controls. This is associated with increased leptin-induced phosphorylation of STAT3 (signal transducer and activator of transcription-3) in B cells from aged humans as compared to young subjects. These data suggest that leptin-induced B cell-derived proinflammatory cytokines may play a role in chronic inflammation associated with human aging. PMID- 23343053 TI - Preparation methods to optimize the performance of sensor discs for fast chemiluminescence ozone analyzers. AB - Fast ozone (O(3)) measurements (1-50 Hz) in the atmosphere are required for airborne studies and for the measurement of ground-based O(3) fluxes by the eddy covariance technique. Fast response analyzers, based on heterogeneous chemiluminescence, need dye coated sensor discs on which the chemiluminescence is generated. In this study, we present three new preparation methods for those sensor discs. Currently available sensor discs exhibit a fast temporal decay of sensitivity, resulting in short duty times which is troublesome for many field applications. To produce sensor discs that provide more stable signals over time, three dyes and nine energy transfer reagents were tested (as well as different stoichiometric mixtures). The resulting optimal method saves 80% of the solid chemicals and shows a duty ozone dose that is prolonged by a factor of 3.5, revealing the same average sensitivity as currently available discs. In addition, we observed a strong effect of the adsorption matrix on the O(3) sensitivity, although silica discs from the same manufacturer were used. Application of the new sensor discs during field measurements showed that the results are consistent with the laboratory data. PMID- 23343054 TI - Alcohol-specific parenting, adolescent alcohol use and the mediating effect of adolescent alcohol-related cognitions. AB - OBJECTIVES: Previous research indicated that alcohol-specific parenting is an important precursor of adolescent alcohol use, but failed to define the underlying mechanism. Based on social cognitive theory, alcohol-related cognitions such as alcohol refusal self-efficacy and alcohol-related expectancies were hypothesised to mediate this link. DESIGN: A cross-sectional survey included 1349 mothers and their sixth grade (11-12 years old) adolescent offspring. Structural equation modelling was employed to test the association between alcohol-specific parenting and adolescent alcohol use, mediated by adolescent alcohol-related cognitions. MAIN OUTCOME MEASURES: Adolescent alcohol use, drinking refusal self-efficacy and alcohol expectancies. RESULTS: The associations between frequency of communication, maternal alcohol use and adolescent alcohol use were mediated by negative alcohol-related expectancies. The associations between quality of communication, rules and disclosure and adolescent alcohol use were mediated by self-efficacy. CONCLUSIONS: The present study provides a first indication that the underlying mechanism of the association between the most important alcohol-specific parenting practices and adolescent alcohol use can be contributed to the mediating effect of alcohol refusal self-efficacy. PMID- 23343055 TI - End-stage renal disease and low level exposure to lead, cadmium and mercury; a population-based, prospective nested case-referent study in Sweden. AB - BACKGROUND: Cadmium (Cd), lead (Pb), and mercury (Hg) cause toxicological renal effects, but the clinical relevance at low-level exposures in general populations is unclear. The objective of this study is to assess the risk of developing end stage renal disease in relation to Cd, Pb, and Hg exposure. METHODS: A total of 118 cases who later in life developed end-stage renal disease, and 378 matched (sex, age, area, and time of blood sampling) referents were identified among participants in two population-based prospective cohorts (130,000 individuals). Cd, Pb, and Hg concentrations were determined in prospectively collected samples. RESULTS: Erythrocyte lead was associated with an increased risk of developing end stage renal disease (mean in cases 76 MUg/L; odds ratio (OR) 1.54 for an interquartile range increase, 95% confidence interval (CI) 1.18-2.00), while erythrocyte mercury was negatively associated (2.4 MUg/L; OR 0.75 for an interquartile range increase, CI 0.56-0.99). For erythrocyte cadmium, the OR of developing end-stage renal disease was 1.15 for an interquartile range increase (CI 0.99-1.34; mean Ery-Cd among cases: 1.3 MUg/L). The associations for erythrocyte lead and erythrocyte mercury, but not for erythrocyte cadmium, remained after adjusting for the other two metals, smoking, BMI, diabetes, and hypertension. Gender-specific analyses showed that men carried almost all of the erythrocyte lead and erythrocyte cadmium associated risks. CONCLUSIONS: Erythrocyte lead is associated with end-stage renal disease but further studies are needed to evaluate causality. Gender-specific analyses suggest potential differences in susceptibility or in exposure biomarker reliability. PMID- 23343056 TI - Diastereoselective synthesis of beta-heteroaryl syn-alpha-methyl-beta-amino acid derivatives via a double chiral auxiliary approach. AB - The addition of the SuperQuat enolate to five- and six-membered heterocyclic tert butyl sulfinimines led to a high syn-selectivity of up to 99:1 in good to excellent yields. The reaction is tentatively proposed to proceed through an open chain transition state with the presence of an alpha-heteroatom on the sulfinimine leading to high diastereoselectivities. The adducts were derivatized to beta-amino esters and amides in a facile manner. PMID- 23343057 TI - Porcine reproductive and respiratory syndrome virus vaccines: current status and strategies to a universal vaccine. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is the causative agent of PRRS, the most significant infectious disease currently affecting swine industry worldwide. In the United States alone, the economic losses caused by PRRS amount to more than 560 million US dollars every year. Due to immune evasion strategies and the antigenic heterogeneity of the virus, current commercial PRRSV vaccines (killed-virus and modified-live vaccines) are of unsatisfactory efficacy, especially against heterologous infection. Continuous efforts have been devoted to develop better PRRSV vaccines. Experimental PRRSV vaccines, including live attenuated vaccines, recombinant vectors expressing PRRSV viral proteins, DNA vaccines and plant-made subunit vaccines, have been developed. However, the genetic and antigenic heterogeneity of the virus limits the value of almost all of the PRRSV vaccines tested. Developing a universal vaccine that can provide broad protection against circulating PRRSV strains has become a major challenge for current vaccine development. This paper reviews current status of PRRSV vaccine development and discusses strategies to develop a universal PRRSV vaccine. PMID- 23343058 TI - A different model--medical care in Cuba. PMID- 23343059 TI - The future of antibiotics and resistance. PMID- 23343060 TI - Speaking up--when doctors navigate medical hierarchy. PMID- 23343063 TI - 21st-century hazards of smoking and benefits of cessation in the United States. AB - BACKGROUND: Extrapolation from studies in the 1980s suggests that smoking causes 25% of deaths among women and men 35 to 69 years of age in the United States. Nationally representative measurements of the current risks of smoking and the benefits of cessation at various ages are unavailable. METHODS: We obtained smoking and smoking-cessation histories from 113,752 women and 88,496 men 25 years of age or older who were interviewed between 1997 and 2004 in the U.S. National Health Interview Survey and related these data to the causes of deaths that occurred by December 31, 2006 (8236 deaths in women and 7479 in men). Hazard ratios for death among current smokers, as compared with those who had never smoked, were adjusted for age, educational level, adiposity, and alcohol consumption. RESULTS: For participants who were 25 to 79 years of age, the rate of death from any cause among current smokers was about three times that among those who had never smoked (hazard ratio for women, 3.0; 99% confidence interval [CI], 2.7 to 3.3; hazard ratio for men, 2.8; 99% CI, 2.4 to 3.1). Most of the excess mortality among smokers was due to neoplastic, vascular, respiratory, and other diseases that can be caused by smoking. The probability of surviving from 25 to 79 years of age was about twice as great in those who had never smoked as in current smokers (70% vs. 38% among women and 61% vs. 26% among men). Life expectancy was shortened by more than 10 years among the current smokers, as compared with those who had never smoked. Adults who had quit smoking at 25 to 34, 35 to 44, or 45 to 54 years of age gained about 10, 9, and 6 years of life, respectively, as compared with those who continued to smoke. CONCLUSIONS: Smokers lose at least one decade of life expectancy, as compared with those who have never smoked. Cessation before the age of 40 years reduces the risk of death associated with continued smoking by about 90%. PMID- 23343061 TI - Peginesatide in patients with anemia undergoing hemodialysis. AB - BACKGROUND: Peginesatide, a synthetic peptide-based erythropoiesis-stimulating agent (ESA), is a potential therapy for anemia in patients with advanced chronic kidney disease. METHODS: We conducted two randomized, controlled, open-label studies (EMERALD 1 and EMERALD 2) involving patients undergoing hemodialysis. Cardiovascular safety was evaluated by analysis of an adjudicated composite safety end point--death from any cause, stroke, myocardial infarction, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia--with the use of pooled data from the two EMERALD studies and two studies involving patients not undergoing dialysis. In the EMERALD studies, 1608 patients received peginesatide once monthly or continued to receive epoetin one to three times a week, with the doses adjusted as necessary to maintain a hemoglobin level between 10.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 95% confidence interval was -1.0 g per deciliter or higher in the comparison of peginesatide with epoetin. The aim of evaluating the composite safety end point in the pooled cohort was to exclude a hazard ratio with peginesatide relative to the comparator ESA of more than 1.3. RESULTS: In an analysis involving 693 patients from EMERALD 1 and 725 from EMERALD 2, peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, -0.15 g per deciliter; 95% confidence interval [CI], 0.30 to -0.01 in EMERALD 1; and 0.10 g per deciliter; 95% CI, -0.05 to 0.26 in EMERALD 2). The hazard ratio for the composite safety end point was 1.06 (95% CI, 0.89 to 1.26) with peginesatide relative to the comparator ESA in the four pooled studies (2591 patients) and 0.95 (95% CI, 0.77 to 1.17) in the EMERALD studies. The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator ESA in the pooled cohort. CONCLUSIONS: Peginesatide, administered monthly, was as effective as epoetin, administered one to three times per week, in maintaining hemoglobin levels in patients undergoing hemodialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00597753 [EMERALD 1], NCT00597584 [EMERALD 2], NCT00598273 [PEARL 1], and NCT00598442 [PEARL 2].). PMID- 23343065 TI - Clinical practice. Alcohol use in adults. PMID- 23343064 TI - 50-year trends in smoking-related mortality in the United States. AB - BACKGROUND: The disease risks from cigarette smoking increased in the United States over most of the 20th century, first among male smokers and later among female smokers. Whether these risks have continued to increase during the past 20 years is unclear. METHODS: We measured temporal trends in mortality across three time periods (1959-1965, 1982-1988, and 2000-2010), comparing absolute and relative risks according to sex and self-reported smoking status in two historical cohort studies and in five pooled contemporary cohort studies, among participants who became 55 years of age or older during follow-up. RESULTS: For women who were current smokers, as compared with women who had never smoked, the relative risks of death from lung cancer were 2.73, 12.65, and 25.66 in the 1960s, 1980s, and contemporary cohorts, respectively; corresponding relative risks for male current smokers, as compared with men who had never smoked, were 12.22, 23.81, and 24.97. In the contemporary cohorts, male and female current smokers also had similar relative risks for death from chronic obstructive pulmonary disease (COPD) (25.61 for men and 22.35 for women), ischemic heart disease (2.50 for men and 2.86 for women), any type of stroke (1.92 for men and 2.10 for women), and all causes combined (2.80 for men and 2.76 for women). Mortality from COPD among male smokers continued to increase in the contemporary cohorts in nearly all the age groups represented in the study and within each stratum of duration and intensity of smoking. Among men 55 to 74 years of age and women 60 to 74 years of age, all-cause mortality was at least three times as high among current smokers as among those who had never smoked. Smoking cessation at any age dramatically reduced death rates. CONCLUSIONS: The risk of death from cigarette smoking continues to increase among women and the increased risks are now nearly identical for men and women, as compared with persons who have never smoked. Among men, the risks associated with smoking have plateaued at the high levels seen in the 1980s, except for a continuing, unexplained increase in mortality from COPD. PMID- 23343066 TI - Images in clinical medicine. Hemifacial flushing. PMID- 23343062 TI - Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis. AB - BACKGROUND: Peginesatide is a peptide-based erythropoiesis-stimulating agent (ESA) that may have therapeutic potential for anemia in patients with advanced chronic kidney disease. We evaluated the safety and efficacy of peginesatide, as compared with another ESA, darbepoetin, in 983 such patients who were not undergoing dialysis. METHODS: In two randomized, controlled, open-label studies (PEARL 1 and 2), patients received peginesatide once a month, at a starting dose of 0.025 mg or 0.04 mg per kilogram of body weight, or darbepoetin once every 2 weeks, at a starting dose of 0.75 MUg per kilogram. Doses of both drugs were adjusted to achieve and maintain hemoglobin levels between 11.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 97.5% confidence interval was -1.0 g per deciliter or higher. Cardiovascular safety was evaluated on the basis of an adjudicated composite end point. RESULTS: In both studies and at both starting doses, peginesatide was noninferior to darbepoetin in increasing and maintaining hemoglobin levels. The mean differences in the hemoglobin level with peginesatide as compared with darbepoetin in PEARL 1 were 0.03 g per deciliter (97.5% confidence interval [CI], -0.19 to 0.26) for the lower starting dose of peginesatide and 0.26 g per deciliter (97.5% CI, 0.04 to 0.48) for the higher starting dose, and in PEARL 2 they were 0.14 g per deciliter (97.5% CI, -0.09 to 0.36) and 0.31 g per deciliter (97.5% CI, 0.08 to 0.54), respectively. The hazard ratio for the cardiovascular safety end point was 1.32 (95% CI, 0.97 to 1.81) for peginesatide relative to darbepoetin, with higher incidences of death, unstable angina, and arrhythmia with peginesatide. CONCLUSIONS: The efficacy of peginesatide (administered monthly) was similar to that of darbepoetin (administered every 2 weeks) in increasing and maintaining hemoglobin levels. However, cardiovascular events and mortality were increased with peginesatide in patients with chronic kidney disease who were not undergoing dialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00598273 [PEARL 1], NCT00598442 [PEARL 2], NCT00597753 [EMERALD 1], and NCT00597584 [EMERALD 2].). PMID- 23343067 TI - Case records of the Massachusetts General Hospital. Case 3-2013. A 72-year-old woman with abdominal pain and distention after peritoneal dialysis. PMID- 23343068 TI - Anemia treatment in patients with chronic kidney disease. PMID- 23343069 TI - New evidence that cigarette smoking remains the most important health hazard. PMID- 23343070 TI - Neighborhood characteristics and bystander-initiated CPR. PMID- 23343071 TI - Neighborhood characteristics and bystander-initiated CPR. PMID- 23343072 TI - The eyes have it. PMID- 23343073 TI - The eyes have it. PMID- 23343074 TI - The eyes have it. PMID- 23343078 TI - Images in clinical medicine. Perioral myokymia. PMID- 23343079 TI - Changes in glutathione, oxidative stress and mitochondrial membrane potential in apoptosis involving the anticancer activity of cantharidin isolated from redheaded blister beetles, epicauta hirticornis. AB - The present work describes the anticancer activity of cantharidin isolated from red-headed blister beetles, Epicauta hirticornis and its possible mode of action involving induction of apoptosis, oxidative stress and decrease in glutathione against murine ascites Dalton's lymphoma. The structure of isolated compound was confirmed as cantharidin by X-ray diffraction method. Cantharidin treatment showed potent anticancer activity with an increase in life span (~ 87%) of tumor bearing mice. Cantharidin treatment induced apoptosis in Dalton's lymphoma cells and also caused an oxidative stress due to generation of reactive oxygen species (ROS) and an increase in lipid peroxidation. The observed canthardin-mediated decrease in glutathione and glutathione related enzymes activities in the tumor cells may weaken the cellular antioxidant system. Moreover, cantharidin treatment also caused a significant decrease in mitochondrial cytochrome c and simultaneous increase in cytosolic cytochrome c which ultimately facilitates activation of caspase 9 and 3 to augment mitochondrial apoptotic pathway causing cancer cell death. Based on the present findings, it may be suggested that cantharidin mediated anticancer activity could be due to decrease in the protective ability of cancer cells by ROS and subsequent activation of effecter caspases leading to apoptotic cell death. PMID- 23343080 TI - Novel molecular anti-colorectalcancer conjugate:chlorambucil-adipic acid dihydrizide-glutamine. AB - Cancer is one of the most fatal diseases in the world and it has been years that finding new drugs and chemotherapeutic techniques with lowest side effects become one of the most important challenging matters needs really hard efforts. Chlorambucil (CBL), an ancient direct-acting alkylating anticancer agent, is commonly used for initial treatment of some kinds of cancers but the use of CBL is often limited because of the unpleasant side effects due to its lack of specificity for targeting cancer cells. In this research we tried to increase the specificity of CBL by producing a novel conjugate by using glutamine amino acid (Glut). Based on previous studies, poly amines and nitrogen compounds noticeably are used by cancer cells increasingly; therefore we decided to increase the efficiency and specificity of CBL by designing and producing a novel anti cancer conjugate using glutamine amino acid as an uptake enhancer, CBL, and Adipic acid Dihydrazide (ADH) as a spacer and linker. The biological tests were carried out on HT29 colorectal cancer cell line to evaluate its anticancer properties. Biological tests like MTT assay, finding IC50, evaluating the induced mechanism of the death of our novel CBL-Glutamine conjugate on HT29 cells, testing abnormal toxicity of this conjugate on mice in comparison with CBL drug were careid out. We found that not only CBL-Glutamine conjugate preserved its anti cancer property with regard to CBL drug, but also it represent lower abnormal toxicity in mice. Apoptosis was detected as its mechanism of the death. Our present study provides a promising strategy for targeting cancer cells using amino acids nano-conjugate drugs. The future perspectives have also been highlighted in continuing similar and relative researches. PMID- 23343081 TI - From bacteria to antineoplastic: epothilones a successful history. AB - Malignancies are a major cause of morbidity and mortality worldwide. Cancer is a cell disease, characterized by a deviation of the control mechanisms of proliferation and differentiation of cells. Among the treatments available, chemotherapy is often the first choice. Epothilones are a new class of anticancer drugs that act by interacting with cellular microtubules interrupting the proliferation of cancer cells. Many synthetic and semi-synthetic analogues of epothilones have been prepared aiming improvement in effectiveness and tolerability, based on QSAR studies. These analogues have been effective for treatment of tumors resistant to first-line treatments. Six new epothilones are being subjected to clinical trials. Ixabepilone (Ixempra(r)) was approved by FDA in 2007, patupilone is in phase III clinical trial for ovarian and peritoneum cancer. Sagopilone, desoxiepothilone and KOS-1584 are in phase II clinical trials, for the treatment of recurrent glioblastoma and advanced metastatic breast cancer, metastasic breast cancer and metastatic pulmonary cancer, respectively. Desoxiepothilone reached only phase II trials and BMS-310705 reached phase III/IV trials, but were not approved for clinical use due to adverse effects such as neurotoxicity and severe diarrhea, which were dose limiting. Furthermore, the low t1/2 (40h) in comparison with other class analogues, does not recommend the clinical use of this derivative. Some other synthetized epothilones presented antineoplastic activity in vitro, but are not yet submitted to clinical studies. Neuropathies and diarrhea are adverse effects presented by some substances of this class of anticancer drugs. PMID- 23343082 TI - Selection and characterization of human anti-MAGE-A1 scFv and immunotoxin. AB - Melanoma-associated antigen (MAGE) is expressed on the surface of multiple tumor cell types and is a promising target of biotherapeutic drug delivery via the anti MAGE-A1 antibody. In this study, a human single-chain variable fragment (scFv) antibody phage library was generated and applied to recombinant MAGE-A1-coated immunotubes by phage display technology. The soluble anti- MAGE-A1 scFv was expressed and purified by immobilized metal-chelated affinity chromatography (IMAC). The anti-MAGE-A1 scFv could bind native MAGE-A1 confirmed by enzyme linked immunosorbent assay (ELISA), dot blot, and immunoprecipitation (IP) analysis. The immunotoxin was expressed and purified by IMAC successfully. The results indicated that the human anti-MAGE-A1 immunotoxin could provide a valuable drug for clinic cancer therapy. PMID- 23343083 TI - Differential binding preference of methylpheophorbide a and its diboronated derivatives to albumin and low density lipoproteins. AB - The tetrapyrrolic macrocycle and the functional groups at its periphery allow for a variety of modifications aimed at multifunctional therapeutic compounds. In particular, conjugation of boron polyhedra yields dual efficacy antitumor photo/ radiosensitizers. Structural optimization of these agents presumes the identification of macromolecules that bind and transport boronated tetrapyrroles. Using spectroscopic methods we demonstrated that methylpheophorbide a forms complexes with serum albumin and low density lipoproteins (LDL) whereas two diboronated derivatives, 13(2),17(3)-[di(o-carboran-1 yl)methoxycarbonyl]pheophorbide a and 13(2),17(3)-[di(1-carba-closo-dodecaboran-1 yl)methoxycarbonyl]pheophorbide a, were capable of binding to LDL but not to albumin. Molecular modeling showed a mode of interaction of methylpheophorbide a with the amino acid residues in the albumin's hemin binding site. In contrast, for diboronated derivatives such interactions are sterically hindered by boron polyhedra, in line with experimentally determined lack of complex formation with albumin. These data strongly suggest that LDL might be the preferred carrier for polycarborane containing methylpheophorbide a derivatives. PMID- 23343085 TI - Opportunities and obstacles to screening pregnant women for intimate partner violence during antenatal care in Zimbabwe. AB - Pregnancy offers an opportunity for midwives to recognise and respond to women experiencing intimate partner violence (IPV). However, most antenatal care interventions have been conducted in private specialist services in high-income countries and do not address the structural and cultural realities of developing country settings. We report on an exploratory qualitative study conducted in antenatal public health facilities in Harare, Zimbabwe, involving six in-depth interviews with midwives and seven FGDs with 64 pregnant and postpartum women. Recorded interviews were transcribed verbatim and analysed using thematic content analysis. We found that identifying and responding to IPV in antenatal care is hampered by inadequate human, financial and infrastructural resources as well as poor support of gender-based violence training for midwives. Midwives had divergent views of their role, with some perceiving IPV as a non-clinical, social and domestic problem that does not require their attention, while others who had been sensitised to the problem felt that it could easily overwhelm them. A comprehensive response to IPV by midwives would be difficult to achieve in this setting but sensitised midwives could respond to cues to violence and ultimately assist abused women in culturally sensitive and appropriate ways. PMID- 23343084 TI - Suppression of oncoprotein Her-2 and DNA damage after treatment with Flavan-3- ol vitis labrusca extract. AB - Hepatocellular carcinoma and breast cancer are the most prevalent cancers in the world with high morbidity and mortality. Although there are effective drugs for treating advanced stages of liver and breast cancers, the prognosis for patients with liver cancer remains poor, and patients with breast cancer show considerable mortality. Therefore, it is crucial to explore new therapeutic agents for the inhibition of carcinogenesis. This study examined the anti-carcinogenic effect of Vitis labrusca seed extract (VLE), which is a component of winery waste, on liver (HepG2) and breast cancers (MCF-7) cells. The results found in this study demonstrated VLEinduced DNA damage in liver and breast cancer cells. VLE treatment in both cell lines was accompanied by high NO production and upregulation of p53. A significant decrease in total PARP expression was also found in HepG2 cells. In the MCF-7 cell line, VLE treatment increased the expression of Bax and AIF, and decreased total PARP expression. Surprisingly, VLE suppressed Her-2 expression in HepG2 cells and caused a subtle, but significant downregulation of Her-2 in MCF-7 cells. The possible anti-carcinogenic effect of VLE reported in this study suggests the potential of this extract to be used for the development of novel therapeutic agents for the treatment of different kinds of cancers. PMID- 23343086 TI - Poor outcome associated with symptomatic deterioration among help-seeking individuals at risk for psychosis: a naturalistic follow-up study. AB - AIMS: It remains debatable whether early intervention for psychosis is capable of meeting the needs of at-risk subjects. The aims of this study were to describe the actual impact of interventions on subjective difficulties and to explore the factors that may be associated with a poor outcome. METHODS: Participants were help-seeking outpatients at a university hospital who met the Criteria of Prodromal Syndromes. Changes in the symptoms, subjective experience and current insight were assessed using the Scales of Prodromal Symptoms, the Subjective Well being under Neuroleptics, and the Scale to Assess Unawareness of Mental Disorder, respectively. Global functioning, social functioning and subjective quality of life were evaluated using the Global Assessment of Functioning Scale, the Social Functioning Scale, and the WHO-Quality of Life 26, respectively. These measures were assessed both at baseline and after 1 year. RESULTS: Forty-six patients agreed to participate. Of the 27 patients who completed the reassessment at the follow-up point, 13 patients (48%) showed little improvement in their positive/negative symptoms, subjective well-being or awareness of their symptoms. Additionally, less severe negative symptoms, more severe general symptoms and lower subjective well-being at baseline significantly predicted a deterioration of positive/negative symptoms after 1 year. CONCLUSION: Our findings suggest that the current strategy for reducing psychosis risk based on positive symptoms should be reappraised. PMID- 23343087 TI - Managing a case of hypotropia with a positive traction test. PMID- 23343088 TI - Poor vision, deafness, hypotonia . . . with pupillary membranes. PMID- 23343090 TI - Optic nerve appearance in patients with Down syndrome. PMID- 23343091 TI - Retrobulbar optic neuritis and live attenuated influenza vaccine. PMID- 23343093 TI - Vitamin C and the abscisic acid-insensitive 4 transcription factor are important determinants of aphid resistance in Arabidopsis. AB - AIMS: Aphids, like other insects, are probably unable to synthesize vitamin C (ascorbic acid), which is therefore an essential dietary nutrient that has to be obtained from the host plant. Plant responses to aphids involve hormones such as salicylic acid (SA), jasmonic acid (JA), and abscisic acid (ABA), but hormone/redox interactions remain poorly characterized. We therefore investigated hormone/redox signaling in the response of Arabidopsis thaliana to infestation by the aphid Myzus persicae, focusing on the interactions between ascorbic acid and ABA, together with the influence of altered ascorbate and ABA signaling on the SA and JA-dependent pathways. RESULTS: Whole-genome microarray analysis revealed highly dynamic transcriptional responses to aphid infestation with extensive differences between transcript profiles of infested and systemic leaves, revealing aphid-dependent effects on the suites of transcripts involved in the redox, SA, and ABA responses. Central roles for ascorbate, ABA-insensitive 4 (ABI4), and oxidative signal-inducible 1 in plant resistance to aphids were demonstrated by altered fecundity on respective mutants. However, ABA had a negative effect on aphid resistance, as did ABI4 or redox-responsive transcription factor 1. The decrease in aphid fecundity observed in mutants defective in ascorbate accumulation (vtc2) was absent from abi4vtc2 double mutants that are also deficient in ABA signaling (abi4). Aphid-dependent transcriptome responses reveal a role for ascorbate-regulated receptor-like kinases in plant defenses against aphids. INNOVATION: Vitamin C deficiency enhances plant resistance to aphids through redox signaling pathways rather than dietary requirements. CONCLUSION: ABI4 is a linchpin of redox regulation of the innate immune response to aphids. PMID- 23343094 TI - Comparison of similarity-based tests and pooling strategies for rare variants. AB - BACKGROUND: As several rare genomic variants have been shown to affect common phenotypes, rare variants association analysis has received considerable attention. Several efficient association tests using genotype and phenotype similarity measures have been proposed in the literature. The major advantages of similarity-based tests are their ability to accommodate multiple types of DNA variations within one association test, and to account for the possible interaction within a region. However, not much work has been done to compare the performance of similarity-based tests on rare variants association scenarios, especially when applied with different rare variants pooling strategies. RESULTS: Based on the population genetics simulations and analysis of a publicly-available sequencing data set, we compared the performance of four similarity-based tests and two rare variants pooling strategies. We showed that weighting approach outperforms collapsing under the presence of strong effect from rare variants and under the presence of moderate effect from common variants, whereas collapsing of rare variants is preferable when common variants possess a strong effect. We also demonstrated that the difference in statistical power between the two pooling strategies may be substantial. The results also highlighted consistently high power of two similarity-based approaches when applied with an appropriate pooling strategy. CONCLUSIONS: Population genetics simulations and sequencing data set analysis showed high power of two similarity-based tests and a substantial difference in power between the two pooling strategies. PMID- 23343095 TI - Emission, mass balance, and distribution characteristics of PCDD/Fs and heavy metals during cocombustion of sewage sludge and coal in power plants. AB - The emission, mass balance, and distribution characteristics of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) as well as those of heavy metals (Hg, Cd, Pb, Cr, and Cu) were investigated during the cocombustion of 5%, 10%, 15%, and 20% sewage sludge (SS) in a pulverized coal power plant. The PCDD/F emissions increased from 7.00 to 32.72 pg I-TEQ/Nm(3) as the amount of SS in the mixed fuel (MF) increased. High sulfur content and relatively low chlorine levels in MF resulted in lower PCDD/F emissions. SS exhibited a remarkable difference in congener profiles compared with flue gas, bottom ash, and fly ash. The negative dioxin mass balance indicated that the cofiring of SS with coal in power plants was not a source but a sink of dioxins. The concentrations and emission factors of heavy metals in flue gas and bottom ash, as well as fly ash, all exhibited a tendency to increase with increasing input values of heavy metals in MF. The distribution characteristics of the investigated heavy metals were primarily dependent on the evaporative properties of these metals. The availability of chlorine could alter the heavy metal distribution behavior. The emitted pollutants in the power plant were below the legal limits. PMID- 23343097 TI - An evaluation of the ability of Dichelobacter nodosus to survive in soil. AB - BACKGROUND: Dichelobacter nodosus is the causative agent of footrot in sheep. The survival of the bacterium in soil is of importance for the epidemiology of the disease. The investigation evaluates the survival of D. nodosus in soil with and without added hoof powder stored under different temperatures. RESULTS: An experimental setup was used with bacteriological culture and real-time polymerase chain reaction (PCR), and the results indicate that the bacteria can survive in soil for longer time than previously expected. The survival time was found to be dependent on temperature and the addition of hoof powder to the soil, with the longest survival time estimated to be 24 days in soil samples with hoof powder stored at 5 degrees C. CONCLUSION: Our findings indicate that the survival time of D. nodosus and its ability to infect susceptible sheep on pasture under different climatic conditions should be studied further. PMID- 23343096 TI - Association of human papillomavirus type 16 long control region mutation and cervical cancer. AB - BACKGROUND: The variation of human papillomavirus (HPV) genes or HPV variants demonstrates different risks of cervical cancer. Mutation in the long control region (LCR) at YY1-motifs is one of the mechanisms for enhancing viral oncogene expression during the course of cancer cell progression. In Thai women, cervical cancers are almost always associated with HPV16 variant sub-lineage Asian (HPV16As); however, the mechanism involved remains elusive. The aim of this study was to understand further the oncogenic potential of HPV16As. METHODS: A total of 82 HPV16-positive specimens from Thai women were selected from formalin-fixed paraffin-embedded cervical tissues, and the full length E6 gene of each specimen was amplified and sequenced. LCRs of the HPV16As-positive cases were amplified and sequenced to analyze their polymorphisms. Transcriptional activities of the HPV16As LCRs were then compared with sub-lineage European (EUR), sub-lineage Asian-American 1 (AA1) and HPV16 prototype by insertion of the LCRs into the pGL3 Basic vector. RESULTS: The HPV16 DNA sequences were classified as HPV16 prototype (18.3%), Asian (As, 61%), Asian American-1 (AA1, 8.5%), European (EUR, 7.3%), Asian African-2 (AFR2, 3.7%) and Java-135C (J135C, 1.2%). The prevalence of HPV16As was 30% in low-grade squamous intraepithelial lesion (LSIL), while that in high-grade squamous intraepithelial lesion (HSIL) and squamous cell cervical carcinoma (SCC) were 63.9% and 66.7%, respectively, which demonstrates a significant association of HPV16As with the disease severity. LCR polymorphisms from 43 HPV16As positive cases were analyzed by PCR-sequencing. Thirty-eight nucleotide variation positions spanned nucleotide positions 7157-82. Ten new mutations found in the HPV16As LCRs were located predominantly at the enhancer and proximal to the 3'-end of the early promoter. The LCRs of the common HPV16As, EUR and AA1 showed 5, 13 and 23-fold higher activity than the HPV16 prototype LCR, while those of the new nucleotide variations of As showed 19 (As-sv1) and 30 (As-sv14) -fold higher activity than the HPV16 prototype. CONCLUSIONS: HPV16As DNA sequence variation, especially at the proximal to early promoter in the LCR, enhances transcriptional activity. This could be one of the possible mechanisms for HPV16As-associated cervical cancer development. PMID- 23343098 TI - Use of chemical and physical characteristics to investigate trends in biochar feedstocks. AB - Studies have shown that pyrolysis method and temperature are the key factors influencing biochar chemical and physical properties; however, information on the nature of biochar feedstocks is more accessible to consumers, making feedstock a better measure for selecting biochars. This study characterizes physical and chemical properties of commercially available biochars and investigates trends in biochar properties related to feedstock material to develop guidelines for biochar use. Twelve biochars were analyzed for physical and chemical properties. Compiled data from this study and from the literature (n = 85) were used to investigate trends in biochar characteristics related to feedstock. Analysis of compiled data reveals that despite clear differences in biochar properties from feedstocks of algae, grass, manure, nutshells, pomace, and wood (hard- and softwoods), characteristic generalizations can be made. Feedstock was a better predictor of biochar ash content and C/N ratio, but surface area was also temperature dependent for wood-derived biochar. Significant differences in ash content (grass and manure > wood) and C/N ratio (softwoods > grass and manure) enabled the first presentation of guidelines for biochar use based on feedstock material. PMID- 23343099 TI - Validity and feasibility of a satellite imagery-based method for rapid estimation of displaced populations. AB - BACKGROUND: Estimating the size of forcibly displaced populations is key to documenting their plight and allocating sufficient resources to their assistance, but is often not done, particularly during the acute phase of displacement, due to methodological challenges and inaccessibility. In this study, we explored the potential use of very high resolution satellite imagery to remotely estimate forcibly displaced populations. METHODS: Our method consisted of multiplying (i) manual counts of assumed residential structures on a satellite image and (ii) estimates of the mean number of people per structure (structure occupancy) obtained from publicly available reports. We computed population estimates for 11 sites in Bangladesh, Chad, Democratic Republic of Congo, Ethiopia, Haiti, Kenya and Mozambique (six refugee camps, three internally displaced persons' camps and two urban neighbourhoods with a mixture of residents and displaced) ranging in population from 1,969 to 90,547, and compared these to "gold standard" reference population figures from census or other robust methods. RESULTS: Structure counts by independent analysts were reasonably consistent. Between one and 11 occupancy reports were available per site and most of these reported people per household rather than per structure. The imagery-based method had a precision relative to reference population figures of <10% in four sites and 10-30% in three sites, but severely over-estimated the population in an Ethiopian camp with implausible occupancy data and two post-earthquake Haiti sites featuring dense and complex residential layout. For each site, estimates were produced in 2-5 working person days. CONCLUSIONS: In settings with clearly distinguishable individual structures, the remote, imagery-based method had reasonable accuracy for the purposes of rapid estimation, was simple and quick to implement, and would likely perform better in more current application. However, it may have insurmountable limitations in settings featuring connected buildings or shelters, a complex pattern of roofs and multi-level buildings. Based on these results, we discuss possible ways forward for the method's development. PMID- 23343100 TI - Model studies on the first enzyme-catalyzed Ugi reaction. AB - Multicomponent reactions are powerful tools for organic chemistry, and among them, the Ugi reaction provides remarkable improvement in many fields of organic chemistry such us combinatorial chemistry, medicinal chemistry, and peptide chemistry. A new, enzyme-catalyzed example of the Ugi three-component reaction is presented. The studies include the selection of an enzyme as well as determination of the scope and limitations of the newly described reaction. The presented method combines the enzyme promiscuity and multicomponent reaction advantages in the first one-pot formation of dipeptide 1. PMID- 23343101 TI - Eating styles in the morbidly obese: restraint eating, but not emotional and external eating, predicts dietary behaviour. AB - OBJECTIVES: The research explored (1) the relationships between self-reported eating style (restraint, emotional and external eating) and dietary intake and (2) emotional eater status as a moderator of food intake when emotional, in a morbidly obese population. DESIGN: A sample of 57 obese participants (BMI: M = 51.84, SD = 8.66) completed a five-day food diary together with a reflective diary, which assessed eating style and positive and negative affect daily. MAIN OUTCOME MEASURES: A dietician-scored food pyramid analysis of intake. RESULTS: Restraint eating was the only predictor (negative) of overall food intake and the variable most strongly associated with the consumption of top-shelf foods. Emotional and external eating were unrelated to food intake. Emotional eater status did not moderate food intake in response to positive and negative mood states. CONCLUSION: The findings indicated largely analogous relationships between eating style and dietary intake in this obese sample compared with previous results from healthy populations. The lack of predictive validity for emotional eating scales (when emotional) raises questions over people's ability to adequately assess their eating style and consequently, the overall validity of emotional eater scales. PMID- 23343104 TI - The Long-Term Care Insurance Program in Israel: solidarity with the elderly in a changing society. AB - The Long-Term Care Insurance Program (LTCIP) in Israel is a social security program administered by the National Insurance Institute (NII) since 1988. LTCIP focuses on home-based personal care services. Differently from most other programs under the responsibility of the NII, LTCIP benefits are in-kind benefits and are delivered via multiple for-profit and not-for-profit organizations. In recent years LTCIP has been the target of various legal amendments and numerous administrative changes. While many of these changes may have had significant effects on individuals, they have not altered the fundamental principles of the program. Thus, many of the characteristics of beneficiaries have remained quite stable over the years; other characteristics of the population of beneficiaries have changed over the years reflecting the aging of Israeli society. A central issue related to LTCIP is whether benefits are adequate to meet the needs of the growing elderly population of Israel. While the generosity of LTCIP benefits is questionable, economic and political struggles have limited the scope of changes introduced thus far. PMID- 23343105 TI - Health-related quality of life among adolescents: a comparison between subjects at risk for psychosis and other help seekers. AB - AIM: Schizophrenia is a severe illness associated with poor health-related quality of life (HRQoL), and there is some evidence that a risk state for psychosis is associated with decreased HRQoL. The aim of the present study was to investigate group differences in HRQoL in help seekers at risk for psychosis and not at risk for psychosis. METHODS: The data were collected by a Finnish early detection and intervention team at Helsinki University Central Hospital. A total of 202 help-seeking adolescents (110 girls, 92 boys; 11-22 years of age) were assessed with a PROD screen and HRQoL scale of 16D. RESULTS: As the main result, subjects at risk for psychosis had a poorer HRQoL index than other help seekers (P < 0.001). An additional analysis of sub-items for the HRQoL at-risk group had poorer mean scores at a statistically significant level after Bonferroni correction for multiple tests in the following sub-items: vitality (P = 0.016), distress (P = 0.016), physical appearance (P < 0.001), school and hobbies (P = 0.016), friends (P = 0.048), mental function (P < 0.001) and depression (P < 0.001). In a logistic regression analysis of sub-items of the HRQoL scale, lower scores in the sub-item of mental function independently explained the at-risk status for psychosis (P = 0.009). CONCLUSIONS: Adolescents at risk for psychosis have a poorer HRQoL index than other help seekers and they also differ in several sub-items, particularly in the lower scores in mental function. In the future, these findings should be considered in the care of adolescents at risk for psychosis. PMID- 23343106 TI - Stabilization of ruthenium sensitizers to TiO2 surfaces through cooperative anchoring groups. AB - Cooperative binding of a bis(tridentate) ruthenium(II) complex to a TiO(2) surface through carboxylate and phosphonate groups is demonstrated to be an effective method for achieving a robust anchoring motif in aqueous media while maintaining charge transfer from the dye into the semiconductor. The realization of these complementary goals has broad implications for solar cells and (photo)electrocatalytic schemes. PMID- 23343109 TI - Abatement of an aircraft exhaust plume using aerodynamic baffles. AB - The exhaust jet from a departing commercial aircraft will eventually rise buoyantly away from the ground; given the high thrust/power (i.e., momentum/buoyancy) ratio of modern aero-engines, however, this is a slow process, perhaps requiring ~ 1 min or more. Supported by theoretical and wind tunnel modeling, we have experimented with an array of aerodynamic baffles on the surface behind a set of turbofan engines of 124 kN thrust. Lidar and point sampler measurements show that, as long as the intervention takes place within the zone where the Coanda effect holds the jet to the surface (i.e., within about 70 m in this case), then quite modest surface-mounted baffles can rapidly lift the jet away from the ground. This is of potential benefit in abating both surface concentrations and jet blast downstream. There is also some modest acoustic benefit. By distributing the aerodynamic lift and drag across an array of baffles, each need only be a fraction of the height of a single blast fence. PMID- 23343107 TI - Analysis of strain relatedness using high resolution melting in a case of recurrent candiduria. AB - BACKGROUND: Several genotyping protocols have been described to study Candida albicans strains with different sensitivity values. In this study we have analyzed the genetic relatedness and the antifungal susceptibility of several Candida albicans strains isolated from a patient who from suffered recurrent candiduria for a period of five years. Strains were genotyped using Microsatellite Length Polymorphism (MLP) with three microsatellite markers (HIS 3, EF 3 and CDC 3), and a new method based on high resolution melting (HRM) was developed to analyze the microsatellite region. This method was compared with the conventional technique that uses capillary electrophoresis. RESULTS: MICs of the isolates showed the existence of fluconazole susceptible and resistant strains. An inter-colony test using single concentration (8 and 16 mg/l) of fluconazole revealed the coexistence of both fluconazole susceptible and resistant strains. Both genotyping analysis methods showed that all the patient's isolates had a clonal origin. HRM analysis method developed was able to accurately establish strain relatedness and presented a discriminatory power of 0.77. CONCLUSIONS: Although HRM analysis method presented a lower discriminatory power compared to methods based on capillary electrophoresis, it provided a more cost-effective and suitable alternative for genotyping C. albicans in a clinical laboratory. PMID- 23343110 TI - Synthesis and characterization of thermally stable aromatic polyamides and poly(1,3,4-oxadiazole-amide)s nanoparticles containing pendant substituted bezamides. AB - BACKGROUND: The introduction of pendent bulky groups along the polymer backbone results in a less ordered polymer matrix and increases the solubility characteristics without affecting thermal properties. The inclusion of chromogenic chemical moieties in the chains can give rise to the luminescent converter material which permits the preparation of materials with potential applications. Aromatic polymers containing heterocyclic rings in the main chain are known for their high thermal resistance, good hydrolytic stability, low dielectric and tough mechanical properties. There is currently much research directed towards the discovery of new blue light-emitting polymers, with characteristics of high efficiency and high reliability. Herein, we describe the preparation of aromatic polyamides and poly (1,3,4-oxadiazole-amide)s nanoparticles with pendant structures comprised of m- and p-acetoxybenzamide groups, where the acetoxybenzamide groups act as signaling units due to their fluorescent and chromogenic characteristics. RESULTS: Aromatic polyamides and poly(1,3,4-oxadiazole-amide)s nanoparticles with pendant structures comprised of m- and p-acetoxybenzamide groups were successfully prepared and characterized using different analytical methods. Most polyamides were obtained as well separated spherical nanoparticles while aramide containing pyridine produced aggregated particles attributed to the molecular self assembly via H-bond directed organization of molecular precursors. The thermal behavior of all polymers exhibited two major thermal decompositions due to the subsequent breakage of the acetoxy group in the lateral chain and cleavage of the main amide bonds. Photoluminescence studies revealed that the blue emissions for the polyamide derived from benzidine were blue-shifted (shifted to a lower wavelength) compared to that of polyamides containing flexible linkages. CONCLUSIONS: We report the synthesis of aromatic polyamides and poly(1,3,4 oxadiazole-amide)s nanoparticles with pendant structures comprised of m- and p acetoxybenzamide groups. The thermal behavior of all polymers exhibited two major decompositions due to breakage of the acetoxy group in the lateral chain and cleavage of the main amide bonds. Structure- photoluminescence correlation demonstrated an interesting connection between structural modification and optical properties. The blue emissions for the polyamide derived from benzidine, attributed to the highly conjugation system, was blue shifted with the introduction of flexible linkages. The prepared polymers dissolved in warm polar aprotic solvents. Further investigations to obtain films with reasonably good mechanical properties for different applications are in progress. PMID- 23343112 TI - Responding to requests for nondisclosure of medical information, #219. PMID- 23343113 TI - Assessing the financial impact of an inpatient acute palliative care unit in a tertiary care teaching hospital. AB - BACKGROUND: Evidence suggests palliative care consult services yield cost improvements; few studies have examined the impact of an inpatient palliative care unit on hospital costs. OBJECTIVE: This study estimates the cost avoidance of a single hospital's acute palliative care unit (APCU), building upon previous studies (1) by limiting pre-APCU costs to two days pre-APCU transfer, thereby minimizing bias from higher-cost first days of admission, and (2) by not limiting the study to cancer patients or patients who died, thereby presenting more comprehensive APCU costs. DESIGN: This retrospective study compares direct costs of care on an APCU with costs pre-APCU transfer from general medical units, intensive care units (ICU), and the emergency department (ED), and compares the direct costs of APCU patients with those of control patients. The data were entered into an SPSS((r)) 17.0 (SPSS Inc., Chicago, IL) statistical software database. Paired and independent samples t-tests were conducted to test cost differences. SETTING/SUBJECTS: Study patients were admitted or transferred to the APCU from October 2008 through January 2009. Control patients were inpatients during the same time period and met several matching criteria. MEASUREMENTS: The hospital's finance department provided direct costs, case mix index (CMI), and geometric mean length of stay, and the Department of Quality and Resource Management provided patients' demographic and administrative data. RESULTS: Of 209 patients transferred to the APCU, 50% transferred from a medical unit, 32% from an ICU, and 18% from the ED. Annualized, the total cost avoidance realized by transfers to the APCU was $848,556, over half of which came from ICU to APCU transfers. CONCLUSIONS: Cost avoidance is realized when patients transfer to an APCU even when conservative pre-APCU cost measures are used and when patients with varying diagnoses and discharge outcomes are included. This study demonstrates a replicable methodology for estimating the financial impact of an APCU. PMID- 23343114 TI - Assessing the effectiveness of policy interventions to reduce the use of agency or temporary social workers in England. AB - There has been growing concern that English local authorities are over reliant on temporary staff to meet the shortage of social workers. This has been criticised as inefficient and costly while leading to problems of continuity and consistency for people using social work services. Focussing on recent policy and the implementation of new administrative procedures for the procurement and management of temporary or agency staff, this article explores progress being made towards achieving the previous government's policy goal that by 2020 local authorities will no longer need to rely on agency workers to carry out tasks that would normally be carried out by a permanent social worker. The article draws on the findings of an exploratory study (2007-2010) commissioned by the Department of Health which comprised of the following: a survey of local councils in England with adult social services responsibilities; case studies in three different localities; and qualitative interviews with stakeholders (n = 93). The findings suggest that while local authorities have reduced the costs of employing temporary staff through the setting up of intermediary control mechanisms, agency social workers continue to play important roles in teams and services. PMID- 23343115 TI - Excretion of enterovirus 71 in persons infected with hand, foot and mouth disease. AB - BACKGROUND: Hand, foot and mouth disease (HFMD) is a common illness in young children. It also can be seen in adults occasionally. Enterovirus 71 (EV71), a pathogen that causes not only HFMD but also neurological complications and even death, has caused many HFMD outbreaks in China. However, till now the data about the duration of EV71 shedding is very limited. RESULTS: A total of 136 throat swabs and fecal samples were collected from 27 children and 3 adults, which includs 7 close contacts, 9 mild cases and 14 severe cases,. The participants were divided into three groups namely, severe case group, mild case group and close contact group. All the samples were assayed with real-time polymerase chain reaction (PCR). Kruskal-Wallis Test was employed to compare the difference in duration of viral RNA shedding among three groups. The results showed that significant difference in duration of EV71 shedding was found among three groups (P < 0.01). The longest duration of EV71 shedding in fecal samples is 54 days and 30 days in throat swabs. CONCLUSIONS: HFMD is characterized by extended excretion of EV71. Our results suggest that the duration of EV71 shedding is correlated with the severity of the disease. EV71 shedding through feces can persist more than 54 days. Prolonged virus shedding is a potential risk factor of proliferating HFMD epidemic. PMID- 23343116 TI - How does illness severity influence depression, health satisfaction and life satisfaction in patients with cardiovascular disease? The mediating role of illness perception and self-efficacy beliefs. AB - Numerous empirical studies have investigated the relationships between cardiovascular diseases (CVD) and patients' psychological well-being, with a focus almost exclusively on its dark side. Very little is known on the impact of illness severity on both negative and positive indicators of patients' well being, as well as on the psychosocial variables that may mediate this association. Aim of the study was to investigate the impact of illness severity on depression as well as on health satisfaction and life satisfaction of patients undergoing a cardiovascular rehabilitation. It also aimed at testing the mediation of illness perception and self-efficacy beliefs in managing cardiac risk factors. The study involved 172 patients (mean age = 66.43 years; SD = 9.99 years; 76.2% men). Illness severity was measured in terms of left ventricular ejection fraction at discharge from the cardiology department, whereas all psychological dimensions were assessed one week later. Results showed significant relationships among illness severity, depression and health satisfaction that were fully mediated by illness perception and self-efficacy beliefs, but not significant relation between disease severity and life satisfaction (chi2 (1) = 2.30, p = n.s.). Overall, findings underline the importance of working on illness perception and self-efficacy beliefs to contrast depression and to improve health and life satisfaction in patients with CVD. PMID- 23343117 TI - Mechanism for different fluorescence response of a coumarin-amide-dipicolylamine linkage to Zn(II) and Cd(II) in water. AB - A coumarin-amide-dipicolylamine linkage (L) was synthesized and used as a fluorescent receptor for metal cations in water. The receptor dissolved in water with neutral pH shows almost no fluorescence due to the photoinduced electron transfer (PET) from the amide and amine nitrogens to the excited state coumarin moiety. Coordination of Zn(2+) or Cd(2+) with L creates strong fluorescence at 437 or 386 nm, respectively, due to the suppression of PET. In contrast, other metal cations scarcely show fluorescence enhancement. IR, NMR, and potentiometric analysis revealed that both Zn(2+) and Cd(2+) are coordinated with two pyridine N, amine N, and amide O; however, the Zn(2+) center is also coordinated with a hydroxide anion (OH(-)). The structure difference for Zn and Cd complexes results in longer- and shorter-wavelength fluorescence. Ab initio calculations revealed that pi electrons on the excited state Cd complex are delocalized over the molecules and the Cd complex shows shorter-wavelength emission. In contrast, pi electrons of OH(-)-coordinated Zn complex are localized on the coumarin moiety. This increases the electron density of coumarin moiety and shows longer wavelength fluorescence. PMID- 23343119 TI - Imazethapyr enantioselectively affects chlorophyll synthesis and photosynthesis in Arabidopsis thaliana. AB - Imazethapyr (IM) is a chiral herbicide with reported enantioselective biological activities between its enantiomers. This report investigated the effect of enantioselectivity between R- and S-IM in Arabidopsis thaliana on chlorophyll synthesis and photosynthesis. The results suggest that R-IM inhibited the transcription of chlM to a greater extent than S-IM, which reduced chlorophyll synthesis. R-IM also showed a stronger inhibitory effect than S-IM on the transcription of photosynthesis-related genes, affecting linear electron transport and CO(2) fixation. IM stress enantioselectively induced transcriptional upregulation of the ndhH gene, a representative of the NDH complex. In contrast, the expression of pgr5 was downregulated, which demonstrated that IM stress enhanced adenosine 5'-triphosphate (ATP) synthesis by stimulating an NDH-dependent and not ferredoxin (FD)-independent route. This study suggested that R-IM has a greater toxic effect on photosynthesis than S-IM, affecting plant growth through chlorophyll synthesis. PMID- 23343120 TI - Treatment of foot disease in patients with type 2 diabetes mellitus using human umbilical cord blood mesenchymal stem cells: response and correction of immunological anomalies. AB - This study was designed to evaluate the distribution of Tregs/Th17/Th1 cells in type 2 diabetic patients with foot disease before and after human umbilical cord blood mesenchymal stem cell (hUCB-MSCs) transplantation. Fifteen diabetic patients with foot disease under insulin therapy received hUCB-MSC transplantation. The hUCB-MSCs were directly injected into the quadriceps thigh muscles in patients with foot disease (cell quantity at 2 x 106 per point). Physical attributes, blood cytokines, blood glucose and insulin dosage were evaluated before treatment and 1, 2, 4, 8, and 12 weeks thereafter. The ratios of Treg/Th17, Treg/Th1, and Th17/Th1 cells were measured using flow cytometry and their correlation with various cytokines (FoxP3, IL-17, INF-gamma, C-RP, TNF alpha, and VEGF) was scrutinized. Levels of blood glucose and insulin dosage were significantly reduced in all 15 patients following hUCB-MSC transplantation. The ratios of CD4+CD25(hi)FoxP3+ Treg/Th17 and CD4+CD25(hi)FoxP3+ Treg/Th1 cells were significantly increased 4 weeks after transplantation (p < 0.01), while the ratio of Th17/Th1 cells remained unchanged. Serum levels of VEGF peaked at 4 weeks following transplantation. Levels of C-RP and TNF-alpha were significantly reduced 4 weeks after transplantation. Intriguingly, the ratios of Treg/Th17 were positively correlated with VEGF levels, and were inversely correlated with plasma IL-6 levels. Our data indicated that immune disorders are associated with the development of type 2 diabetes and its complications. Levels of blood glucose and required insulin dosage were reduced after hUCB-MSC transplantation accompanied with improved clinical profiles in diabetic patients. These data favor a role for Treg cells in the onset and progression of T2D. PMID- 23343121 TI - Recent advances of diaryl ether family as HIV-1 non-nucleoside reverse transcriptase inhibitors. AB - Diaryl ether family as one of the promising second generation HIV-1 non nucleoside reverse transcriptase inhibitors has attracted considerable attention over the past few years, among which clinical candidate MK-4965 has been advanced into phase II clinical trials. The successful development of diaryl ether family provides valuable avenues in traditional medicinal chemistry, crystallography and computer-aided drug design fields for the design of other novel anti-HIV drug candidates. In this review, the development of diaryl ether family is present including the evolutionary history, design strategies, extensive structural modifications, structure-activity relationship studies and computer-aided molecular simulation of the binding mode in detail. PMID- 23343118 TI - Remote brain network changes after unilateral cortical impact injury and their modulation by acetylcholinesterase inhibition. AB - We explored whether cerebral cortical impact injury (CCI) effects extend beyond direct lesion sites to affect remote brain networks, and whether acetylcholinesterase (AChE) inhibition elicits discrete changes in functional activation of motor circuits following CCI. Adult male rats underwent unilateral motor-sensory CCI or sham injury. Physostigmine (AChE inhibitor) or saline were administered subcutaneously continuously via implanted minipumps (1.6 micromoles/kg/day) for 3 weeks, followed by cerebral perfusion mapping during treadmill walking using [(14)C]-iodoantipyrine. Quantitative autoradiographs were analyzed by statistical parametric mapping and functional connectivity (FC) analysis. CCI resulted in functional deficits in the ipsilesional basal ganglia, with increased activation contralesionally. Recruitment was also observed, especially contralesionally, of the red nucleus, superior colliculus, pedunculopontine tegmental nucleus, thalamus (ventrolateral n., central medial n.), cerebellum, and sensory cortex. FC decreased significantly within ipsi- and contralesional motor circuits and between hemispheres, but increased between midline cerebellum and select regions of the basal ganglia within each hemisphere. Physostigmine significantly increased functional brain activation in the cerebellar thalamocortical pathway (midline cerebellum->ventrolateral thalamus->motor cortex), subthalamic nucleus/zona incerta, and red nucleus and bilateral sensory cortex. In conclusion, CCI resulted in increased functional recruitment of contralesional motor cortex and bilateral subcortical motor regions, as well as recruitment of the cerebellar-thalamocortical circuit and contralesional sensory cortex. This phenomenon, augmented by physostigmine, may partially compensate motor deficits. FC decreased inter-hemispherically and in negative, but not positive, intra-hemispherical FC, and it was not affected by physostigmine. Circuit-based approaches into functional brain reorganization may inform future behavioral or molecular strategies to augment targeted neurorehabilitation. PMID- 23343122 TI - Zamamiphidin A, a new manzamine related alkaloid from an Okinawan marine sponge Amphimedon sp. AB - A manzamine related alkaloid, zamamiphidin A (1), consisting of a new heptacyclic ring system has been isolated from an Okinawan marine sponge Amphimedon sp. The structure of 1 including the relative stereochemistry was elucidated on the basis of the spectroscopic data. Compound 1 showed antibacterial activity against Staphylococcus aureus (MIC, 32 MUg/mL). PMID- 23343124 TI - Association of PPP1R3B polymorphisms with blood lipid and C-reactive protein levels in a Chinese population (PPP1R3B C ). AB - BACKGROUND: Genetic variants of PPP1R3B, a gene encoding a critical protein involved in hepatic glycogen metabolism, were recently reported to be associated with plasma levels of lipids and C-reactive protein (CRP) among populations of mostly European descent. The aim of the present study was to investigate whether the PPP1R3B variants are associated with plasma levels of lipids and inflammation factors in Chinese Han. METHODS: Five single nucleotide polymorphisms (SNPs) of the PPP1R3B gene were genotyped and their associations with plasma lipids and CRP were determined in 1636 Chinese Han from Shanghai. RESULTS: Three SNPs, namely rs2126259, rs9987289, and rs19334, were significantly associated with plasma levels of low-density lipoprotein-cholesterol, and rs2126259 and rs9987289 were further significantly associated with total cholesterol. The remaining two SNPs (rs189798 and rs330919) were significantly associated with plasma CRP levels, but not with plasma lipid levels. CONCLUSION: Genetic polymorphisms of the PPP1R3B gene may contribute to variations in plasma lipids and CRP levels among Chinese Han individuals. PMID- 23343123 TI - Alteration of fatty acid metabolism in the liver, adipose tissue, and testis of male mice conceived through assisted reproductive technologies: fatty acid metabolism in ART mice. AB - BACKGROUND: Lipid metabolism plays important roles in the whole process of pregnancy. Previous studies have demonstrated abnormalities of lipid metabolism in the placentas of pregnancies obtained by assisted reproductive technology (ART). Therefore, we hypothesized that ART micromanipulation may affect lipid metabolism in offspring, and focused on the fatty acid metabolism in ART male offspring in this study. METHODS: The fatty acid metabolism in the liver, adipose tissue and testis was detected. The comparison between naturally conceived (NC), controlled ovarian hyperstimulation (COH), in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) mice was made to analyze the effect of ART on offspring. The mice models in this study included two age groups: adult group and old group. The fatty acid composition and the expression of lipid metabolism-related genes were analyzed by GC-MS and qRT-PCR. RESULTS: The fatty acid composition in the liver and adipose tissue were significantly altered in ART mice, but no significant difference was found in the testis. In adipose tissue, ART mice showed decreased monounsaturated fatty acids (MUFAs) and increased polyunsaturated fatty acids (PUFAs) in both adult and old mice, while the alteration of saturated fatty acids (SFAs) in the adult disappeared in the old. In liver, the changes were much complex in adult mice, while increased MUFAs and decreased PUFAs were found in ART old mice. The activities of fatty acid metabolism-related enzymes and the expression of lipogenic and lipolytic proteins changed in ART groups, with the adult mice and old mice showing inconsistent alterations. Further analysis indicated that SFAs was closely associated with the alterations of fatty acid metabolism-related enzyme activities and the expression of lipogenic and lipolytic proteins. Furthermore, we also found that the effect of separated ART treatments on fatty acid metabolism varied with different ages and tissues. CONCLUSIONS: ART treatments had effect on the fatty acid composition in adipose tissue and liver of male mice. The alteration of SFAs content was crucial for the regulation of fatty acid composition. These changes might have potential effects on the health of ART male offspring which need further investigation. PMID- 23343125 TI - Preservation of immunorecognition by transferring cells from 10% neutral buffered formalin to 70% ethanol. AB - Prolonged fixation of cells and tissues in 10% neutral buffered formalin (NBF) may decrease immunorecognition in some antigen-antibody pairs. Short fixation in 10% NBF followed by transfer to 70% ethanol has been used to overcome these effects, but the effects of this transfer on immunorecognition have not been explored adequately. We used two cell lines, DU145 (prostate cancer) and SKOV3 (ovarian cancer), grew them on coverslips and fixed them with 10% NBF at room temperature for 5 min and 12, 15, 18, 36, 108 and 180 h. Aliquots of the same cells were fixed in 10% NBF for 12 h, then transferred to 70% ethanol for 3, 6, 24, 96 and 168 h. Immunostaining with PCNA, Ki67-MIB-1, cytokeratins AE1/AE3 and EGFr was done concomitantly. In both cell lines, immunorecognition decreased between 18 and 36 h of fixation in 10% NBF for PCNA, Ki67-MIB-1 and cytokeratins AE1/AE3. By 108 to 180 h of 10% NBF exposure, there was complete loss of immunorecognition of PCNA and extensive loss of Ki67-MIB-1 and cytokeratins AE1/AE3. The effects on EGFr immunorecognition were less. Transfer to 70% ethanol after fixation for 12 h in 10% NBF preserved immunorecognition of the antibodies. PMID- 23343126 TI - Object-based neglect in number processing. AB - Recent evidence suggests that neglect patients seem to have particular problems representing relatively smaller numbers corresponding to the left part of the mental number line. However, while this indicates space-based neglect for representational number space little is known about whether and --if so --how object-based neglect influences number processing.To evaluate influences of object-based neglect in numerical cognition, a group of neglect patients and two control groups had to compare two-digit numbers to an internally represented standard. Conceptualizing two-digit numbers as objects of which the left part (i.e., the tens digit should be specifically neglected) we were able to evaluate object-based neglect for number magnitude processing.Object-based neglect was indicated by a larger unit-decade compatibility effect actually reflecting impaired processing of the leftward tens digits. Additionally, faster processing of within- as compared to between-decade items provided further evidence suggesting particular difficulties in integrating tens and units into the place value structure of the Arabic number system.In summary, the present study indicates that, in addition to the spatial representation of number magnitude, also the processing of place-value information of multi-digit numbers seems specifically impaired in neglect patients. PMID- 23343127 TI - Perspectives and concerns of clients at primary health care facilities involved in evaluation of a national mental health training programme for primary care in Kenya. AB - BACKGROUND: A cluster randomised controlled trial (RCT) of a national Kenyan mental health primary care training programme demonstrated a significant impact on the health, disability and quality of life of clients, despite a severe shortage of medicines in the clinics (Jenkins et al. Submitted 2012). As focus group methodology has been found to be a useful method of obtaining a detailed understanding of client and health worker perspectives within health systems (Sharfritz and Roberts. Health Transit Rev 4:81-85, 1994), the experiences of the participating clients were explored through qualitative focus group discussions in order to better understand the potential reasons for the improved outcomes in the intervention group. METHODS: Two ninety minute focus groups were conducted in Nyanza province, a poor agricultural region of Kenya, with 10 clients from the intervention group clinics where staff had received the training programme, and 10 clients from the control group where staff had not received the training during the earlier randomised controlled trial. RESULTS: These focus group discussions suggest that the clients in the intervention group noticed and appreciated enhanced communication, diagnostic and counselling skills in their respective health workers, whereas clients in the control group were aware of the lack of these skills. Confidentiality emerged from the discussions as a significant client concern in relation to the volunteer cadre of community health workers, whose only training comes from their respective primary care health workers. CONCLUSION: Enhanced health worker skills conferred by the mental health training programme may be responsible for the significant improvement in outcomes for clients in the intervention clinics found in the randomised controlled trial, despite the general shortage of medicines and other health system weaknesses. These findings suggest that strengthening mental health training for primary care staff is worthwhile even where health systems are not strong and where the medicine supply cannot be guaranteed. TRIAL REGISTRATION: ISRCTN 53515024. PMID- 23343128 TI - Chirality affects aggregation kinetics of single-walled carbon nanotubes. AB - Aggregation kinetics of chiral-specific semiconducting single-walled carbon nanotubes (SWNTs) was systematically studied through time-resolved dynamic light scattering. Varied monovalent (NaCl) and divalent (CaCl(2)) electrolyte composition was used as background solution chemistry. Suwannee River humic acid (SRHA) was used to study the effects of natural organic matter on chirally separated SWNT aggregation. Increasing salt concentration and introduction of divalent cations caused aggregation of SWNT clusters by suppressing the electrostatic repulsive interaction from the oxidized surfaces. The (6,5) SWNTs, i.e., SG65, with relatively lower diameter tubes compared to (7,6), i.e., SG76, showed substantially higher stability (7- and 5-fold for NaCl and CaCl(2), respectively). The critical coagulation concentration (CCC) values were 96 and 13 mM NaCl in the case of NaCl and 2.8 and 0.6 mM CaCl(2) for SG65 and SG76, respectively. The increased tube diameter for (7,6) armchair SWNTs likely presented with higher van der Waals interaction and thus increased the aggregation propensity substantially. The presence of SRHA enhanced SWNT stability in divalent CaCl(2) environment through steric interaction from adsorbed humic molecules; however showed little or no effects for monovalent NaCl. The mechanism of aggregation-describing favorable interaction tendencies for (7,6) SWNTs-is probed through ab initio molecular modeling. The results suggest that SWNT stability can be chirality dependent in typical aquatic environment. PMID- 23343129 TI - The application of the parallel track model in community health promotion: a literature review. AB - The parallel track model is one of the several models that are used in health promotion programmes that focus on community empowerment. It is unique in that it explicitly incorporates an empowerment approach with a top-down health programme. Since its development in 1999-2000 the model has been used in various health programmes in both developed and developing countries. The aim of this review is to examine the nature and extent of the application of this model and its contribution to promoting health. A review of the literature published between 2000 and 2011 was conducted. Nine results matched the inclusion criteria and revealed that the model has been mostly applied to disadvantaged communities to address health determinants, such as poverty and health literacy. This review found that the model had a positive impact on specific health outcomes such as health literacy and community capacity. We concluded that the parallel track model has the most potential for building capacity for community health promotion and appears to be the least useful for interventions focusing on health behaviour change within a limited time frame. PMID- 23343130 TI - Stigma and hostility towards pregnant smokers: does individuating information reduce the effect? AB - Australia is at the forefront of tobacco control, yet 17% of Australian women smoke during pregnancy. Negative attitudes to smoking are intensified when the smoker is pregnant, consistent with a discourse that encourages surveillance of pregnant women. Such overt anti-smoking attitudes create a context which may make it difficult for pregnant smokers to seek assistance to stop. However, there is little evidence on the extent to which pregnant smokers are stigmatised by community members. We used vignettes to examine the degree of smoking-related stigma expressed by 595 Australian university students who rated a woman, described as a mother who was smoking or not, and pregnant or not. Further, we examined whether provision of individuating information reduced the degree of stigma. Mothers described as smokers were rated more negatively than those not, particularly if they were pregnant: smokers were perceived as unhealthy, and also as bad mothers. Provision of individuating information slightly reduced these effects. These findings support the view that smokers--particularly if pregnant- are subject to negative moral judgement. Our findings contribute to the ethical debate about stigma-inducing tobacco control efforts, and suggest that anti smoking campaigns that contextualise smoking in pregnancy might reduce stigma and assist cessation. PMID- 23343131 TI - Triage of children with moderate and severe traumatic brain injury to trauma centers. AB - Outcomes after pediatric traumatic brain injury (TBI) are related to pre treatment factors including age, injury severity, and mechanism of injury, and may be positively affected by treatment at trauma centers relative to non-trauma centers. This study estimated the proportion of children with moderate to severe TBI who receive care at trauma centers, and examined factors associated with receipt of care at adult (ATC), pediatric (PTC), and adult/pediatric trauma centers (APTC), compared with care at non-trauma centers (NTC) using a nationally representative database. The Kids' Inpatient Database was used to identify hospitalizations for moderate to severe pediatric TBI. Pediatric inpatients ages 0 to 17 years with at least one diagnosis of TBI and a maximum head Abbreviated Injury Scale score of >=3 were studied. Multinomial logistic regression was performed to examine factors predictive of the level and type of facility where care was received. A total of 16.7% of patients were hospitalized at NTC, 44.2% at Level I or II ATC, 17.9% at Level I or II PTC, and 21.2% at Level I or II APTC. Multiple regression analyses showed receipt of care at a trauma center was associated with age and polytrauma. We concluded that almost 84% of children with moderate to severe TBI currently receive care at a Level I or Level II trauma center. Children with trauma to multiple body regions in addition to more severe TBI are more likely to receive care a trauma center relative to a NTC. PMID- 23343132 TI - Love and desire amongst middle-class Gujarati Indians in the UK and India. AB - The paper describes findings from an ethnographic study exploring understandings of love and intimacy amongst young heterosexual middle-class Indians of Gujarati origin in the UK and India. A two-site comparative study was used to enable an understanding of how social and economic contexts shape cultural constructions of intimate relationships and sexuality. Focusing on attitudes to 'love at first sight', this paper shows that, for Indian participants, love based on physical attraction denotes a lesser kind of love. A relationship based on 'physical love' is not expected to last, since it has been formed without regard to family and status concerns. Even couples who meet outside of the arranged marriage system demonstrate the quality of their love by not having sex with one another before marriage. In the UK, however, participants view love as properly spontaneous. Love at first sight is considered desirable and demonstrates how the relationship must be based on love only, without any concern for (for example) material gain. This spontaneous love entails both physical attraction and emotional connection - an early transition to sex, usually before marriage, was seen as both desirable and inevitable. PMID- 23343133 TI - The presentation and diagnosis of laryngomalacia in eighteen children aged over 2 years. PMID- 23343135 TI - How to provide and pay for long term care of an aging population is an international concern. AB - As populations age, most industrialized nations are seeking to review the structure for their long term care programs with the goal of allocating better limited public resources to meet expanding needs. In this Commentary, I examine critical questions that define the way individual nations provide for the long term care needs of their aging populations. As examined by Asiskovitch, Israel's programs appear, in cross-national context, to have a broader reach and rely more heavily on community based services. In the future, the challenge Israel may face involves maintaining aspects of its programs that probably account for its popular support and stability while it identifies better the extent of potential gaps in care for those with greater needs and how best to meet them. PMID- 23343136 TI - Theoretical investigation on monomer and solvent selection for molecular imprinting of nitrocompounds. AB - The aim of this work is to serve as a guideline for the initial selection of monomer and solvent for the synthesis of the nitrocompound-based molecularly imprinted polymers, MIPs. Reported data include evaluation of six systems with the ability to form noncovalently bonded monomer-template complexes. These systems are represented by the following aliphatic and aromatic molecules: acrolein, acrylonitrile, 2,6-bisacrylamide, 4-ethylenebenzoic acid, methyl methacrylate, and 2-vinylpyridine. Cave models for selected monomers are also presented and supported by binding energy analysis under various conditions. Solvent effects on monomer-template binding energy have been studied for four solvents: acetone, acetonitrile, chloroform, and methanol. Additionally, systems such as 2,4-dinitrotoluene (2,4-DNT), 2,6-dinitrotoluene (2,6-DNT), pentachlorophenol (PCP), and 3,6-dichloro-2-methoxybenzoic acid (Dicamba) have been used to study selectivity of acrolein-based MIP toward TNT detection. The density functional theory, DFT, method has been used for all structural, vibrational frequency, and solvent calculations. PMID- 23343134 TI - MAPK signaling pathway regulates cerebrovascular receptor expression in human cerebral arteries. AB - BACKGROUND: Cerebral ischemia results in enhanced expression of contractile cerebrovascular receptors, such as endothelin type B (ET(B)), 5-hydroxytryptamine type 1B (5-HT(1B)), angiotensin II type 1 (AT(1)) and thromboxane (TP) receptors in the cerebral arteries within the ischemic area. The receptor upregulation occurs via activation of the mitogen-activated protein kinases (MAPK) pathway. Previous studies have shown that inhibitors of the MAPK pathway diminished the ischemic area and contractile cerebrovascular receptors after experimental cerebral ischemia. The aim of this study was to examine if the upregulation of contractile cerebrovascular receptors after 48 h of organ culture of human cerebral arteries involves MAPK pathways and if it can be prevented by a MEK1/2 inhibitor. Human cerebral arteries were obtained from patients undergoing intracranial tumor surgery. The vessels were divided into ring segments and incubated for 48 h in the presence or absence of the specific MEK1/2 inhibitor U0126. The vessels were then examined by using in vitro pharmacological methods and protein immunohistochemistry. RESULTS: After organ culture of the cerebral arteries the contractile responses to endothelin (ET)-1, angiotensin (Ang) II and thromboxane (TP) were enhanced in comparison with fresh human arteries. However, 5-carboxamidotryptamine (5-CT) induced decreased contractile responses after organ culture as compared to fresh arteries. Incubation with U0126 diminished the maximum contraction elicited by application of ET-1, Ang II and U46619 in human cerebral arteries. In addition, the MEK1/2 inhibitor decreased the contractile response to 5-CT. Immunohistochemistry revealed that organ culture resulted in increased expression of endothelin ET(A), endothelin ET(B) angiotensin AT(2), 5 hydroxytryptamine 5-HT(1B) and thromboxane A2 receptors, and elevated levels of activated pERK1/2, all localized to the smooth muscle cells of the cerebral arteries. Co-incubation with U0126 normalized these proteins. CONCLUSION: The study demonstrated that there is a clear association between human cerebrovascular receptor upregulation via transcription involving activation of the MAPK pathway after organ culture. Inhibition of the MAPK pathways attenuated the vasoconstriction mediated by ET, AT and TP receptors in human cerebral arteries and the enhanced expression of their receptors. The results indicate that MAPK inhibition might be a novel target for treatment of cerebrovascular disorders. PMID- 23343137 TI - Paradoxical reaction to etanercept: development of pyoderma gangraenosum during therapy of psoriasis arthritis. PMID- 23343140 TI - Remote anionic Fries rearrangement of sulfonates: regioselective synthesis of indole triflones. AB - An unusual NaH-mediated remote anionic 1,5-thia-Fries rearrangement reaction was developed. This method provides an efficient approach for the regioselective synthesis of not only 2-(2-hydroxyphenyl)-3-indole triflones but also related 3 sulfonylindoles. PMID- 23343138 TI - Blood pressure control and treatment adherence in hypertensive patients with metabolic syndrome: protocol of a randomized controlled study based on home blood pressure telemonitoring vs. conventional management and assessment of psychological determinants of adherence (TELEBPMET Study). AB - BACKGROUND: Inadequate blood pressure control and poor adherence to treatment remain among the major limitations in the management of hypertensive patients, particularly of those at high risk of cardiovascular events. Preliminary evidence suggests that home blood pressure telemonitoring (HBPT) might help increasing the chance of achieving blood pressure targets and improve patient's therapeutic adherence. However, all these potential advantages of HBPT have not yet been fully investigated. METHODS/DESIGN: The purpose of this open label, parallel group, randomized, controlled study is to assess whether, in patients with high cardiovascular risk (treated or untreated essential arterial hypertension--both in the office and in ambulatory conditions over 24 h--and metabolic syndrome), long-term (48 weeks) blood pressure control is more effective when based on HBPT and on the feedback to patients by their doctor between visits, or when based exclusively on blood pressure determination during quarterly office visits (conventional management (CM)). A total of 252 patients will be enrolled and randomized to usual care (n = 84) or HBPT (n = 168). The primary study endpoint will be the rate of subjects achieving normal daytime ambulatory blood pressure targets (< 135/85 mmHg) 24 weeks and 48 weeks after randomization. In addition, the study will assess the psychological determinants of adherence and persistence to drug therapy, through specific psychological tests administered during the course of the study. Other secondary study endpoints will be related to the impact of HBPT on additional clinical and economic outcomes (number of additional medical visits, direct costs of patient management, number of antihypertensive drugs prescribed, level of cardiovascular risk, degree of target organ damage and rate of cardiovascular events, regression of the metabolic syndrome). DISCUSSION: The TELEBPMET Study will show whether HBPT is effective in improving blood pressure control and related medical and economic outcomes in hypertensive patients with metabolic syndrome. It will also provide a comprehensive understanding of the psychological determinants of medication adherence and blood pressure control of these patients. TRIAL REGISTRATION: Clinical Trials.gov: NCT01541566. PMID- 23343139 TI - Magnetic core-shell nanoparticles for drug delivery by nebulization. AB - BACKGROUND: Aerosolized therapeutics hold great potential for effective treatment of various diseases including lung cancer. In this context, there is an urgent need to develop novel nanocarriers suitable for drug delivery by nebulization. To address this need, we synthesized and characterized a biocompatible drug delivery vehicle following surface coating of Fe3O4 magnetic nanoparticles (MNPs) with a polymer poly(lactic-co-glycolic acid) (PLGA). The polymeric shell of these engineered nanoparticles was loaded with a potential anti-cancer drug quercetin and their suitability for targeting lung cancer cells via nebulization was evaluated. RESULTS: Average particle size of the developed MNPs and PLGA-MNPs as measured by electron microscopy was 9.6 and 53.2 nm, whereas their hydrodynamic swelling as determined using dynamic light scattering was 54.3 nm and 293.4 nm respectively. Utilizing a series of standardized biological tests incorporating a cell-based automated image acquisition and analysis procedure in combination with real-time impedance sensing, we confirmed that the developed MNP-based nanocarrier system was biocompatible, as no cytotoxicity was observed when up to 100 MUg/ml PLGA-MNP was applied to the cultured human lung epithelial cells. Moreover, the PLGA-MNP preparation was well-tolerated in vivo in mice when applied intranasally as measured by glutathione and IL-6 secretion assays after 1, 4, or 7 days post-treatment. To imitate aerosol formation for drug delivery to the lungs, we applied quercitin loaded PLGA-MNPs to the human lung carcinoma cell line A549 following a single round of nebulization. The drug-loaded PLGA-MNPs significantly reduced the number of viable A549 cells, which was comparable when applied either by nebulization or by direct pipetting. CONCLUSION: We have developed a magnetic core-shell nanoparticle-based nanocarrier system and evaluated the feasibility of its drug delivery capability via aerosol administration. This study has implications for targeted delivery of therapeutics and poorly soluble medicinal compounds via inhalation route. PMID- 23343141 TI - Enzymatic depolymerization of gum tragacanth: bifidogenic potential of low molecular weight oligosaccharides. AB - Gum tragacanth derived from the plant "goat's horn" (Astragalus sp.) has a long history of use as a stabilizing, viscosity-enhancing agent in food emulsions. The gum contains pectinaceous arabinogalactans and fucose-substituted xylogalacturonans. In this work, gum tragacanth from Astragalus gossypinus was enzymatically depolymerized using Aspergillus niger pectinases (Pectinex BE Color). The enzymatically degraded products were divided into three molecular weight fractions via membrane separation: HAG1 < 2 kDa; 2 kDa < HAG2 < 10 kDa; HAG3 > 10 kDa. Compositional and linkage analyses showed that these three fractions also varied with respect to composition and structural elements: HAG1 and HAG2 were enriched in arabinose, galactose, and galacturonic acid, but low in fucose and xylose, whereas HAG3 was high in (terminal) xylose, fucose, and 1,4 bonded galacturonic acid, but low in arabinose and galactose content. The growth stimulating potential of the three enzymatically produced gum tragacanth fractions was evaluated via growth assessment on seven different probiotic strains in single-culture fermentations on Bifidobacterium longum subsp. longum (two strains), B. longum subsp. infantis (three strains), Lactobacillus acidophilus , B. lactis, and on one pathogenic strain of Clostridium perfringens . The fractions HAG1 and HAG2 consistently promoted higher growth of the probiotic strains than HAG3, especially of the three B. longum subsp. infantis strains, and the growth promotion on HAG1 and HAG2 was better than that on galactan (control). HAG3 completely inhibited the growth of the C. perfringens strain. Tragacanth gum is thus a potential source of prebiotic carbohydrates that exert no viscosity effects and which may find use as natural functional food ingredients. PMID- 23343142 TI - W-F substitutions in apomyoglobin increase the local flexibility of the N terminal region causing amyloid aggregation: a H/D exchange study. AB - Myoglobin is an alpha-helical globular protein containing two highly conserved tryptophanyl residues at positions 7 and 14 in the N-terminal region. The simultaneous substitution of the two residues impairs the productive folding of the protein making the polypeptide chain highly prone to aggregate forming amyloid fibrils at physiological pH and room temperature. The role played by tryptophanyl residues in driving the productive folding process was investigated by providing structural details at low resolution of compact intermediate of three mutated apomyoglobins, i.e., W7F, W14F and the amyloid forming mutant W7FW14F. In particular, we followed the hydrogen/deuterium exchange rate of protein segments using proteolysis with pepsin followed by mass spectrometry analysis. The results revealed significant differences in the N-terminal region, consisting in an alteration of the physico-chemical properties of the 7-11 segment for W7F and in an increase of local flexibility of the 12-29 segment for W14F. In the double trypthophanyl substituted mutant, these effects are additive and impair the formation of native-like contacts and favour inter-chain interactions leading to protein aggregation and amyloid formation at physiological pH. PMID- 23343143 TI - The anti-fibrotic hormone relaxin is not reno-protective, despite being active, in an experimental model of type 1 diabetes. AB - The end-point of diabetic renal disease is the accumulation of excess collagen (fibrosis/sclerosis). A number of studies have shown that the hormone relaxin (RLX) ameliorates progression of renal and non-renal fibrosis. This study assessed the anti-fibrotic potential of RLX in streptozotocin (STZ)-treated transgenic mRen-2 rats, an accelerated model of type 1 diabetes. Eight-week old hyperglycaemic (STZ-treated at week-6) and normoglycaemic (STZ-untreated) animals were treated with or without recombinant human gene-2 (H2) RLX for 4-weeks (by osmotic mini-pumps) and assessed for various parameters at 12-weeks of age. Hyperglycaemic mRen-2 rats had elevated kidney weight/body weight ratio, glomerular filtration rate (GFR), albumin excretion rate (AER), interstitial collagen I and glomerulosclerosis (all p<0.05 vs non-diabetic controls). H2 RLX infusion had no effect on any of these parameters. Increased MMP-2 levels in RLX treated rats demonstrated that the hormone was administered and active in this model. The inability of H2 RLX to slow glomerulopathy in diabetic mRen-2 rats could be in part due to the absence of its receptor, RXFP1, in rat mesangial cells, a primary mediator of diabetic glomerulosclerosis and/or the lack of any effect on TGF-beta1/Smad2 signalling, a well described mediator of RLX activity. These findings highlight the cell specific actions of RLX, the dissociation of anti-fibrogenic (collagen synthesis) and antifibrolytic (MMP mediated collagen degradation) properties, and the central involvement of TGF-beta1 in its actions. PMID- 23343144 TI - An adult patient with Henoch-Schonlein purpura and non-occlusive mesenteric ischemia. AB - BACKGROUND: Onset of Henoch-Schonlein purpura (HSP) in middle age is uncommon, and adults with renal or gastrointestinal involvement present with more severe disease than do similar pediatric patients. CASE PRESENTATION: We present the case of a 69-year-old male with HSP who, after treatment with steroids, cyclophosphamide, and continuous intravenous prostaglandin E1 (PGE1), died as a result of severe gastrointestinal involvement with non-occlusive mesenteric ischemia (NOMI). Vascular narrowing associated with the NOMI improved after catheter injection of PGE1 and prednisolone, but the patient died of bleeding from an exposed small vessel. At autopsy there was no active vasculitis in the jejunal submucosa. CONCLUSION: Treatment with PGE1 and prednisolone might improve small-vessel vasculitis associated with NOMI. PMID- 23343145 TI - One year failure rate for de-novo ventriculo-peritoneal shunts in children from a small volume paediatric neurosurgical unit. AB - It is the belief of some that results of shunt surgery for the treatment of hydrocephalus in children are improved if the surgery is performed in high-volume centres. Currently in the UK paediatric neurosurgery is undergoing a service review. As part of this review a set of standards of care are being drafted which state that 1-year failure rates and infection rates for de-novo ventriculo peritoneal shunts in children should be less than 40% and 10%, respectively. Our de-novo shunt infection rate (4.3%) and our 1-year failure rate (28.6%) are well within the standards set by this process and comparable to published literature from much higher volume centres. PMID- 23343146 TI - A narrative review of Men's Sheds literature: reducing social isolation and promoting men's health and well-being. AB - Men's Sheds are community-based organisations that typically provide a space for older men to participate in meaningful occupation such as woodwork. Men's Sheds are considered an exemplar for the promotion of men's health and well-being by health and social policy-makers. The objective of this literature review was to determine the state of the science about the potential for Men's Sheds to promote male health and well-being. Between October 2011 and February 2012, we conducted searches of databases, the grey literature and manual searches of websites and reference lists. In total, we found 5 reports and 19 articles about Men's Sheds. The majority of the literature has emanated from Australian academics and is about older men's learning in community contexts. There is a limited body of research literature about Men's Sheds; the literature consists of either descriptive surveys or small qualitative studies. The range of variables that might contribute towards best practice in Men's Sheds has not yet been adequately conceptualised, measured, tested or understood. Future research should be focussed on the health and well-being benefits of Men's Sheds; it needs to incorporate social determinants of health and well-being within the study designs to enable comparison against other health promotion research. Without this research focus, there is a danger that the potential health and well-being benefits of Men's Sheds as supportive and socially inclusive environments for health will not be incorporated into future male health policy and practice. PMID- 23343147 TI - Impact of lack-of-benefit stopping rules on treatment effect estimates of two-arm multi-stage (TAMS) trials with time to event outcome. AB - BACKGROUND: In 2011, Royston et al. described technical details of a two-arm, multi-stage (TAMS) design. The design enables a trial to be stopped part-way through recruitment if the accumulating data suggests a lack of benefit of the experimental arm. Such interim decisions can be made using data on an available 'intermediate' outcome. At the conclusion of the trial, the definitive outcome is analyzed. Typical intermediate and definitive outcomes in cancer might be progression-free and overall survival, respectively. In TAMS designs, the stopping rule applied at the interim stage(s) affects the sampling distribution of the treatment effect estimator, potentially inducing bias that needs addressing. METHODS: We quantified the bias in the treatment effect estimator in TAMS trials according to the size of the treatment effect and for different designs. We also retrospectively 'redesigned' completed cancer trials as TAMS trials and used the bootstrap to quantify bias. RESULTS: In trials in which the experimental treatment is better than the control and which continue to their planned end, the bias in the estimate of treatment effect is small and of no practical importance. In trials stopped for lack of benefit at an interim stage, the treatment effect estimate is biased at the time of interim assessment. This bias is markedly reduced by further patient follow-up and reanalysis at the planned 'end' of the trial. CONCLUSIONS: Provided that all patients in a TAMS trial are followed up to the planned end of the trial, the bias in the estimated treatment effect is of no practical importance. Bias correction is then unnecessary. PMID- 23343148 TI - Leisure-related injuries at the beach: an analysis of lifeguard incident report forms in New Zealand, 2007-12. AB - From 2007-2012, New Zealand lifeguards provided first aid to almost 9,000 beachgoers, an average of 1,772 cases per annum; more than the average number of rescues (n = 1,343) each year. This study describes the aetiology of non-drowning related injuries occurring at surf beaches patrolled by lifeguards. The study design was that of a retrospective analysis of data collated during five summer seasons from 2007-2012. Cases included individuals who sustained recreational injuries while at a patrolled beach in New Zealand. Incident report forms, routinely completed by lifeguards in New Zealand, were the data source for this study. Of the 8,437 incidents evaluated, 57% of the patients were males, one half (52%) were aged less than 16 years. Most injuries (82%) were minor, almost half (43%) were to the lower limbs. Half (54%) of the injuries were sustained in the water, one third (32%) were attributed to land-based activities. Cuts/abrasions accounted for almost half (47%) of all injuries. First aid responses for both water and land-based incidents are indicative of the nature and extent of recreational injuries sustained at the beach. The diversity and frequency of such incidents suggests that public education promoting beach safety is warranted. PMID- 23343149 TI - Controlled actuation of therapeutic nanoparticles: moving beyond passive delivery modalities. PMID- 23343150 TI - Nanoparticles squeezing across the blood-endothelial barrier via caveolae. PMID- 23343151 TI - Targeted therapy of cancer stem cells: science or fiction. PMID- 23343154 TI - Conference report: 1st Medicon Valley Inhalation Symposium. AB - The 1st Medicon Valley Inhalation Symposium was arranged by the Medicon Valley Inhalation Consortium. It was held at the Medicon Village site, which is the former AstraZeneca site in Lund, Sweden. It was a 1-day symposium focused on inhaled drug delivery and inhalation product development. A total of 90 delegates listened to 15 speakers. The program was organized to follow the value chain of an inhalation product development. The benefits and future opportunities of inhaled drug delivery were discussed together with some new disease areas that can be targeted with inhalation. The pros and cons of the two main formulation types; dry powder and liquid formulations, were discussed by a panel. The different requirements of the drug molecules from a pharmacology, chemical and physical perspective were explained. The modeling of the physics inside an inhaler was demonstrated and the potential strategic benefits of device design were highlighted together with the many challenges of formulation manufacturing. Lung deposition mechanisms and the difficulties of the generic bioequivalence concept were discussed. Using an anatomically correct impactor inlet is a valuable tool in lung deposition predictions and the planning of clinical trials. The management of the biological material generated in clinical studies is key to successful studies. PMID- 23343155 TI - Nanomedicines for HIV therapy. AB - Heterogeneity in response to HIV treatments has been attributed to several causes including variability in pharmacokinetic exposure. Nanomedicine applications have a variety of advantages compared with traditional formulations, such as the potential to increase bioavailability and specifically target the site of action. Our group is focusing on the development of nanoformulations using a closed-loop design process in which nanoparticle optimization (disposition, activity and safety) is a continuous process based on experimental pharmacological data from in vitro and in vivo models. Solid drug nanoparticles, polymer-based drug delivery carriers as well as nanoemulsions are nanomedicine options with potential application to improve antiretroviral deployment. PMID- 23343156 TI - Hydrogels: an interesting strategy for smart drug delivery. AB - Hydrogels are novel delivery systems that have drawn much attention in the current pharmaceutical scenario. Of all the advantages, the most important is their versatility, which makes them optimal for any kind of molecule, adequate to be administered by any administration route and capable to modulate the desired release profile. Current research is managed to solve the limitations of this systems; mainly the low mechanical strength and lack of control of release in time and quantity, and the reversibility of the delivery. Several approaches such as the use of multi-stimuli-sensitive mechanisms, the enhancement of mechanical properties using chemical crosslinkers, development of polyelectrolyte complexes, the increment of interpenetrating networks or composite hydrogels are providing excellent results. These systems represent a promising alternative due to the countless possibilities to offer for modulating drug release. PMID- 23343158 TI - Effervescent redispersion of lyophilized polymeric nanoparticles. AB - BACKGROUND: Freeze-drying is an attractive method for converting nanoparticulate pharmaceutical dispersions into a stable form with a long shelf life. However, practical challenges in translating laboratory practice to the clinic, such as high protectant osmolarity and infeasible reconstitution methods, currently limit lyophilized formulation development of nanoparticle therapeutics. RESULTS: We demonstrate the use of effervescent redispersion for the reconstitution of lyophilized polymeric nanoparticles and we show that a 3:1 mass ratio of effervescent salt produced the optimum redispersibility. With only low-energy hand agitation, reconstitution to sizes less than 600 nm was achieved. Second, the effect of nanoparticle formulation parameters (dispersion concentration, molecular weight of the stabilizing polymer, and physical state of the nanoparticle core) on particle redispersibility were examined. CONCLUSION: This novel freeze-drying and reconstitution method offers a route to producing redispersible dry powders of nanoparticle therapeutics. PMID- 23343157 TI - Nanomedicine for uterine leiomyoma therapy. AB - BACKGROUND: The purpose of this work was to engineer polymeric nanoparticles to encapsulate and deliver 2-methoxyestradiol, a potential antitumor drug for treatment of uterine leiomyoma (fibroids), the most common hormone-dependent pathology affecting women of reproductive age. METHODS/RESULTS: Encapsulation efficiency and drug release from the nanoparticles were monitored by HPLC. Cell morphology and in vitro cytotoxicity experiments were carried out in a human leiomyoma cell line. The nanoparticles displayed high encapsulation efficiency (>86%), which was verified by differential scanning calorimetry and x-ray diffraction. Excellent long-term stability of the nanoparticles and gradual drug release without burst were also observed. Cellular uptake of fluorescent nanoparticles was confirmed by confocal imaging. The drug-loaded poly(lactic acid) and poly(lactic-co-glycolic acid) nanoparticles induced cytotoxicity in human leiomyoma cells to a significantly greater extent than the free drug at 0.35 uM. CONCLUSION: This novel approach represents a potential fertility preserving alternative to hysterectomy. PMID- 23343160 TI - A surrogate for topical delivery in human skin: silicone membranes. AB - We have identified, for any surrogate membrane and human skin in vitro, the maximum flux through the membrane (output) should be measured if a correlation between the two is to be obtained. We also identified from an analysis of the passive permeation process that molecular weight, lipid and aqueous solubilities (which are easily measured) constitute the physicochemical properties of the active (input), upon which prediction of flux through the surrogate membrane and through skin in vitro should be based. Besides providing the bases for predicting flux, changes in these physicochemical properties can be easily implemented by those wishing to optimize new cosmetics or topical products. Maximum flux values through silicone membrane (n = 70) and through human skin in vitro (n = 52) have been collected and a good correlation between the flux through human skin in vitro and flux through silicone membrane (for the same molecules) was found. PMID- 23343159 TI - The role of cytoskeleton networks on lipid-mediated delivery of DNA. AB - BACKGROUND: Lipid-mediated delivery of DNA is hindered by extracellular and intracellular barriers that significantly reduce the transfection efficiency of synthetic nonviral vectors. RESULTS: In this study we investigated the role of the actin and microtubule networks on the uptake and cytoplasmic transport of multicomponent cationic liposome-DNA complexes in CHO-K1 live cells by means of confocal laser scanning microscopy and 3D single particle tracking. Treatment with actin (latrunculin B)- and microtubule-disrupting (nocodazole) reagents indicated that intracellular trafficking of complexes predominantly involves microtubule-dependent active transport. We found that the actin network has a major effect on the initial uptake of complexes, while the microtubule network is mainly responsible for the subsequent active transportation to the lysosomes. CONCLUSION: Collectively, a strategy to improve the efficiency of lipid gene vectors can be formulated. We could find a lipid formulation that allows the nanoparticles to avoid the microtubule pathway to lysosomes. PMID- 23343161 TI - Physicochemical property trends of marketed prodrugs. AB - Many prodrug reviews describe specific examples of the successful application of prodrug technology to produce blockbuster drugs, such as simvastatin, omeprazole, acyclovir and enalapril. These reviews are helpful to understand the previous success stories and case histories of prodrug technology. The aim of the current review seeks to more clearly define quantitative trends in the changes in the physicochemical property parameters between the successful prodrug and the active parent molecule. This information can serve to guide medicinal chemists toward more successful pharmaceutical prodrugs in the future. PMID- 23343163 TI - Drug carriers for oral delivery of peptides and proteins: accomplishments and future perspectives. AB - Effective formulation for peptide and protein delivery through the oral route has always been the critical effort with the advent of biotechnology. Stability, enzymatic degradation and ineffective absorption are common difficulties found for conventional dosage forms. As a result, new drug-delivery approaches are used to circumvent these limitations and enhance effective oral drug delivery. Some of these technologies have reached late stages of clinical trials and promising results will be available in the near future. This review covers, in general, the recent carriers reported in literature. PMID- 23343162 TI - Nanomedicine in chemoradiation. AB - Chemoradiotherapy, the concurrent administration of chemotherapy and radiotherapy, is a treatment paradigm in oncology. It is part of the standard of care and curative treatment of many cancers. Given its importance, one of the primary goals of cancer research has been to identify agents and/or strategies that can improve the therapeutic index of chemoradiation. Recent advances in nanomedicine have provided a unique and unprecedented opportunity for improving chemoradiotherapy. Nanoparticles possess properties that are ideally suited for delivering chemotherapy in the chemoradiation setting. The goal of this review is to examine the role of incorporating nanomedicine into chemoradiation and the potential impact of nanomedicine to chemoradiotherapy. PMID- 23343166 TI - Pattern formation due to fluorination on graphene fragments: structures, hopping behavior, and magnetic properties. AB - Structures and mechanism of pattern formation for the radical fluorination on selected polyaromatic hydrocarbons (PAH) has been studied using density functional theory (DFT) methods. Our study reveals that the F(*) radical addition occurs preferentially at the edges of PAHs followed by the hopping of F(*) to the center due to the fluxional nature of C-F bond. F(*) migrates preferentially over the C-C bonds having a lower barrier than that over the aromatic pi-cloud in cases of monofluorinated PAHs. Addition of a second F radical can stabilize the system, cooperatively. When two F(*) are added to the adjacent C atoms, it forms the minimum energy patterns. However, the addition of two fluorine radicals at the meta position of the same aromatic ring would lead to the stabilization of the triplet state compared to the singlet ground state. Therefore, depending on the sites of F(*) addition, these structures exhibit ferromagnetic/antiferromagnetic ground states. Considering the low barrier heights for the F(*) hopping, these systems are predicted to be in a dynamic equilibrium with their less stable ferromagnetic states. Our study also provides an atomistic understanding of the well-known rate determining state for the fluorine pattern formation in graphene and CNT. PMID- 23343167 TI - Do we really need standard operating procedures in sexual medicine? PMID- 23343164 TI - Development of adenovirus capsid proteins for targeted therapeutic delivery. AB - The outer shell of the adenovirus capsid comprises three major types of protein (hexon, penton base and fiber) that perform the majority of functions facilitating the early stages of adenovirus infection. These stages include initial cell-surface binding followed by receptor-mediated endocytosis, endosomal penetration and cytosolic entry, and intracellular trafficking toward the nucleus. Numerous studies have shown that the penton base contributes to several of these steps and have supported the development of this protein into a delivery agent for therapeutic molecules. Studies revealing that the fiber and hexon bear unexpected properties of cell entry and/or nuclear homing have supported the development of these capsid proteins, as well into potential delivery vehicles. This review summarizes the findings to date of the protein-cell activities of these capsid proteins in the absence of the whole virus and their potential for therapeutic application with regard to the delivery of foreign molecules. PMID- 23343168 TI - Sexuality education in North American medical schools: current status and future directions. AB - INTRODUCTION: Both the general public and individual patients expect healthcare providers to be knowledgeable and approachable regarding sexual health. Despite this expectation there are no universal standards or expectations regarding the sexuality education of medical students. AIMS: To review the current state of the art in sexuality education for North American medical students and to articulate future directions for improvement. METHODS: Evaluation of: (i) peer-reviewed literature on sexuality education (focusing on undergraduate medical students); and (ii) recommendations for sexuality education from national and international public health organizations. MAIN OUTCOME MEASURES: Current status and future innovations for sexual health education in North American medical schools. RESULTS: Although the importance of sexuality to patients is recognized, there is wide variation in both the quantity and quality of education on this topic in North American medical schools. Many sexual health education programs in medical schools are focused on prevention of unwanted pregnancy and sexually transmitted infection. Educational material on sexual function and dysfunction, female sexuality, abortion, and sexual minority groups is generally scant or absent. A number of novel interventions, many student initiated, have been implemented at various medical schools to improve the student's training in sexual health matters. CONCLUSIONS: There is a tremendous opportunity to mold the next generation of healthcare providers to view healthy sexuality as a relevant patient concern. A comprehensive and uniform curriculum on human sexuality at the medical school level may substantially enhance the capacity of tomorrow's physicians to provide optimal care for their patients irrespective of gender, sexual orientation, and individual sexual mores/beliefs. PMID- 23343172 TI - Size-matching effect on inorganic nanosheets: control of distance, alignment, and orientation of molecular adsorption as a bottom-up methodology for nanomaterials. AB - We have been investigating complexes composed of nanolayered materials with anionic charges such as clay nanosheets and dye molecules such as cationic porphyrins. It was found that the structure of dye assembly on the layered materials can be effectively controlled by the use of electrostatic host-guest interaction. The intermolecular distance, the molecular orientation angle, the segregation/integration behavior, and the immobilization strength of the dyes can be controlled in the clay-dye complexes. The mechanism to control these structural factors has been discussed and was established as a size-matching effect. Unique photochemical reactions such as energy transfer through the use of this methodology have been examined. Almost 100% efficiency of the energy transfer reaction was achieved in the clay-porphyrin complexes as a typical example for an artificial light-harvesting system. Control of the molecular orientation angle is found to be useful in regulating the energy-transfer efficiency and in preparing photofunctional materials exhibiting solvatochromic behavior. Through our study, clay minerals turned out to serve as protein-like media to control the molecular position, modify the properties of the molecule, and provide a unique environment for chemical reactions. PMID- 23343170 TI - SOP conservative (medical and mechanical) treatment of erectile dysfunction. AB - INTRODUCTION: Erectile dysfunction (ED) is the most frequently treated male sexual dysfunction worldwide. ED is a chronic condition that exerts a negative impact on male self-esteem and nearly all life domains including interpersonal, family, and business relationships. AIM: The aim of this study is to provide an updated overview on currently used and available conservative treatment options for ED with a special focus on their efficacy, tolerability, safety, merits, and limitations including the role of combination therapies for monotherapy failures. METHODS: The methods used were PubMed and MEDLINE searches using the following keywords: ED, phosphodiesterase type 5 (PDE5) inhibitors, oral drug therapy, intracavernosal injection therapy, transurethral therapy, topical therapy, and vacuum-erection therapy/constriction devices. Additionally, expert opinions by the authors of this article are included. RESULTS: Level 1 evidence exists that changes in sedentary lifestyle with weight loss and optimal treatment of concomitant diseases/risk factors (e.g., diabetes, hypertension, and dyslipidemia) can either improve ED or add to the efficacy of ED-specific therapies, e.g., PDE5 inhibitors. Level 1 evidence also exists that treatment of hypogonadism with total testosterone < 300 ng/dL (10.4 nmol/L) can either improve ED or add to the efficacy of PDE5 inhibitors. There is level 1 evidence regarding the efficacy and safety of the following monotherapies in a spectrum-wide range of ED populations: PDE5 inhibitors, intracavernosal injection therapy with prostaglandin E1 (PGE1, synonymous alprostadil) or vasoactive intestinal peptide (VIP)/phentolamine, and transurethral PGE1 therapy. There is level 2 evidence regarding the efficacy and safety of the following ED treatments: vacuum-erection therapy in a wide range of ED populations, oral L-arginine (3-5 g), topical PGE1 in special ED populations, intracavernosal injection therapy with papaverine/phentolamine (bimix), or papaverine/phentolamine/PGE1 (trimix) combination mixtures. There is level 3 evidence regarding the efficacy and safety of oral yohimbine in nonorganic ED. There is level 3 evidence that combination therapies of PDE5 inhibitors + either transurethral or intracavernosal injection therapy generate better efficacy rates than either monotherapy alone. There is level 4 evidence showing enhanced efficacy with the combination of vacuum erection therapy + either PDE5 inhibitor or transurethral PGE1 or intracavernosal injection therapy. There is level 5 evidence (expert opinion) that combination therapy of PDE5 inhibitors + L-arginine or daily dosing of tadalafil + short acting PDE5 inhibitors pro re nata may rescue PDE5 inhibitor monotherapy failures. There is level 5 evidence (expert opinion) that adding either PDE5 inhibitors or transurethral PGE1 may improve outcome of penile prosthetic surgery regarding soft (cold) glans syndrome. There is level 5 evidence (expert opinion) that the combination of PDE5 inhibitors and dapoxetine is effective and safe in patients suffering from both ED and premature ejaculation. PMID- 23343173 TI - A bottom up approach to on-road CO2 emissions estimates: improved spatial accuracy and applications for regional planning. AB - On-road transportation is responsible for 28% of all U.S. fossil-fuel CO2 emissions. Mapping vehicle emissions at regional scales is challenging due to data limitations. Existing emission inventories use spatial proxies such as population and road density to downscale national or state-level data. Such procedures introduce errors where the proxy variables and actual emissions are weakly correlated, and limit analysis of the relationship between emissions and demographic trends at local scales. We develop an on-road emission inventory product for Massachusetts-based on roadway-level traffic data obtained from the Highway Performance Monitoring System (HPMS). We provide annual estimates of on road CO2 emissions at a 1 * 1 km grid scale for the years 1980 through 2008. We compared our results with on-road emissions estimates from the Emissions Database for Global Atmospheric Research (EDGAR), with the Vulcan Product, and with estimates derived from state fuel consumption statistics reported by the Federal Highway Administration (FHWA). Our model differs from FHWA estimates by less than 8.5% on average, and is within 5% of Vulcan estimates. We found that EDGAR estimates systematically exceed FHWA by an average of 22.8%. Panel regression analysis of per-mile CO2 emissions on population density at the town scale shows a statistically significant correlation that varies systematically in sign and magnitude as population density increases. Population density has a positive correlation with per-mile CO2 emissions for densities below 2000 persons km(-2), above which increasing density correlates negatively with per-mile emissions. PMID- 23343174 TI - High dose cytarabine with rituximab is an effective first-line therapy for mantle cell lymphoma and produces ample stem cell harvest yields after multiple chemotherapy cycles. PMID- 23343175 TI - Prognostic implications and clinical characteristics associated with bone marrow fibrosis in patients with myelofibrosis. PMID- 23343176 TI - Telomere 3' overhang and disease. PMID- 23343177 TI - Preliminary results of radiotherapy for primary intraocular non-Hodgkin lymphoma. AB - This study aimed to retrospectively evaluate the efficacy of radiotherapy for primary intraocular non-Hodgkin lymphoma (PIOL). Between May 1998 and October 2010, 22 immunocompetent patients (four men, 18 women; median age 70 years, range 53-79 years) were diagnosed with PIOL. Magnetic resonance imaging showed no intracranial involvement in any patient. Patients received radiotherapy at a median total dose of 30 Gy (range 30-40 Gy). Three-year overall survival, progression-free survival and local control rates were 89% (95% confidence interval [CI]: 75, 103), 49% (95% CI: 24, 73) and 95% (95% CI: 86, 105) over a median of 36 months of observation, respectively. Twelve patients (55%) had intracranial relapse at a median of 28 months after initiation of radiotherapy. Visual acuity improved or was stable in 81% of treated eyes. The only grade >= 3 toxicity was cataract formation (five patients). Radiotherapy without chemotherapy for PIOL achieved high local control rates with acceptable toxicities. PMID- 23343178 TI - Determination of arsenic metabolites in patients with newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide. AB - The efficacy of arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL) is widely accepted. It is necessary to determine the concentration of arsenic due to its toxicity. The profiles of arsenic speciation in patients with relapsed or refractory APL have been demonstrated in few reports. Arsenic metabolite concentrations in the plasma of patients with newly diagnosed APL during the first course of arsenic remission induction therapy were determined, and the complicated change pattern of these metabolite concentrations in this phase is described for the first time in this study. We demonstrated that the concentration of trivalent inorganic arsenic (As(III)), which is regarded as the most effective and toxic, was much lower than those of other metabolites. Concentrations of the same arsenic metabolites were obviously distinct among various individuals. We infer that determination of the metabolites separately is necessary, and cannot be replaced by total arsenic determination. In addition, the amount of methylated metabolites of arsenic increased during the first course of ATO therapy, and these metabolites might therefore play an increasingly important role. Further research should be carried out to study the relationship between arsenic metabolite concentrations and efficacy, as well as side effects in patients with APL treated with ATO. PMID- 23343179 TI - Protein kinase C expression is deregulated in chronic lymphocytic leukemia. PMID- 23343180 TI - Patterns of use of 18-fluoro-2-deoxy-D-glucose positron emission tomography for initial staging of grade 1-2 follicular lymphoma and its impact on initial treatment strategy in the National Comprehensive Cancer Network Non-Hodgkin Lymphoma Outcomes database. AB - We describe the patterns of use of 18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for the initial staging of patients with newly diagnosed grade 1-2 follicular lymphoma (FL) and its potential impact on treatment. Data were obtained from the National Comprehensive Cancer Network Non-Hodgkin Lymphoma Outcomes database. Patients who presented between 1 January 2001 and 30 September 2009 with newly diagnosed grade 1-2 FL, with at least 6 months of follow-up, were included. We identified 953 eligible patients and 532 (56%) underwent FDG-PET as part of initial staging. Among patients who underwent FDG-PET for initial staging, 438 (82%) received early treatment compared to 259 (61.5%) of those staged without FDG-PET (p < 0.0001). Of all patients with stage I FL (n = 100), 47% were treated with radiotherapy (RT) alone, and the choice of initial treatment strategy for stage I FL did not vary significantly by use of FDG-PET (p = 0.22). The use of FDG-PET for staging of FL is widespread and is associated with a greater proportion of patients receiving early therapy. Given the widespread use and high cost of FDG-PET, its clinical utility in stage I FL should be further evaluated. PMID- 23343181 TI - Kaposi sarcoma after non-myeloablative hematopoietic stem cell transplant: response to withdrawal of immunosuppressant therapy correlated with whole blood human herpesvirus-8 reverse transcriptase-polymerase chain reaction levels. PMID- 23343182 TI - New boys in town: prognostic role of SF3B1, NOTCH1 and other cryptic alterations in chronic lymphocytic leukemia and how it works. AB - B-cell chronic lymphocytic leukemia (B-CLL) is one of the most common leukemias of the elderly. To date, although many prognostic factors are known, none are universal or easily accessible thus allowing for the stratification of patients to slow-go and aggressive-course groups. Recent studies have identified new recurrent mutations in CLL cells, including mutation of the gene encoding one of the spliceosome subunits, SF3B1, mutation or rearrangement of NOTCH1, a gene of well-known tumorigenesis association, and disruption of BIRC3, a member of the inhibitors of apoptosis (IAP) family. This article presents the current state-of the-art findings concerning the prognostic significance of these new alterations, as well as an explanation of the mechanisms underlying their biological impact on CLL lymphocytes. PMID- 23343183 TI - Columnar mesomorphism of fluorescent board-shaped quinoxalinophenanthrophenazine derivatives with donor-acceptor structure. AB - Quinoxalino[2',3':9,10]phenanthro[4,5-abc]phenazine (QPP) dyes have been studied as electron acceptor materials, fluorophores, and building blocks for self organizing organic semiconductors. Condensation of tetraketopyrene with electron rich diamino-terphenylene and -triphenylene derivatives generates new donor acceptor QPP derivatives that display columnar mesomorphism over wide ranges of temperature; are fluorescent in solution, liquid crystal, and solid phases; and have electron acceptor properties. Also reported are the synthesis and properties of the first diamino-(tetraalkoxy)triphenylene as a valuable new synthon. PMID- 23343184 TI - Combined chromatographic and mass spectrometric toolbox for fingerprinting migration from PET tray during microwave heating. AB - A combined chromatographic and mass spectrometric toolbox was utilized to determine the interactions between poly(ethylene terephthalate) (PET) food packaging and different food simulants during microwave heating. Overall and specific migration was determined by combining weight loss measurements with gas chromatography-mass spectrometry (GC-MS) and electrospray ionization mass spectrometry (ESI-MS). This allowed mapping of low molecular weight migrants in the molecular range up to 2000 g/mol. Microwave heating caused significantly faster migration of cyclic oligomers into ethanol and isooctane as compared to migration during conventional heating at the same temperature. This effect was more significant at lower temperature at which diffusion rates are generally lower. It was also shown that transesterification took place between PET and ethanol during microwave heating, leading to formation of diethyl terephthalate. The detected migrants included cyclic oligomers from dimer to hexamer, in most cases containing extra ethylene glycol units, and oxidized Irgafos 168. ESI-MS combined with CID MS-MS was an excellent tool for structural interpretation of the nonvolatile compounds migrating to the food simulants. The overall migration was below the overall migration limit of 10 mg/dm(2) set by the European commission after 4 h of microwave heating at 100 degrees C in all studied food simulants. PMID- 23343186 TI - [(3)H]metyrapol and 4-[(131)i]iodometomidate label overlapping, but not identical, binding sites on rat adrenal membranes. AB - Metyrapone, metyrapol, and etomidate are competitive inhibitors of 11 deoxycorticosterone hydroxylation by 11beta-hydroxylase. [(3)H]Metyrapol and 4 [(131)I]iodometomidate bind with high affinity to membranes prepared from bovine and rat adrenals. Here we report inhibitory potencies of several compounds structurally related to one or both of these adrenostatic drugs, against the binding of both radioligands to rat adrenal membranes. While derivatives of etomidate inhibited the binding of both radioligands with similar potencies, derivatives of metyrapone inhibited the binding of 4-[(131)I]iodometomidate about 10 times weaker than the binding of [(3)H]metyrapol. By X-ray structure analysis the absolute configuration of (+)-1-(2-fluorophenyl)-2-methyl-2-(pyridin-3-yl)-1 propanol [(+)-11, a derivative of metyrapol] was established as (R). We introduce 1-(2-fluorophenyl)-2-methyl-2-(pyridin-3-yl)-1-propanone (9; Ki = 6 nM), 2-(1 imidazolyl)-2-methyl-1-phenyl-1-propanone (13; 2 nM), and (R)-(+)-[1-(4 iodophenyl)ethyl]-1H-imidazole (34; 4 nM) as new high affinity ligands for the metyrapol binding site on 11beta-hydroxylase and discuss our results in relation to a proposed active site model of 11beta-hydroxylase. PMID- 23343185 TI - A population based validation study of self-reported pensions and benefits: the Nord-Trondelag health study (HUNT). AB - BACKGROUND: Measures of disability pensions, sickness certification and long-term health related benefits are often self-reported in epidemiological studies. Few studies have examined these measures, and the validity is yet to be established.We aimed to estimate the validity of self-reported disability pension, rehabilitation benefit and retirement pension and to explore the benefit status and basic characteristics of those not responding to these items.A large health survey (HUNT2) containing self-reported questionnaire data on sickness benefits and pensions was linked to a national registry of pensions and benefits, used as "gold standard" for the analysis. We investigated two main sources of bias in self-reported data; misclassification - due to participants answering questions incorrectly, and systematic missing/selection bias - when participants do not respond to the questions.Sensitivity, specificity, positive (PPV) and negative (NPV) predicative value, agreement and Cohen's Kappa were calculated for each benefit. Co-variables were compared between non-responders and responders. RESULTS: In the study-population of 40,633, 9.2% reported receiving disability pension, 1.4% rehabilitation benefits and 6.1% retirement pension. According to the registry, the corresponding numbers were 9.0%, 1.7% and 5.4%. Excluding non responders, specificity, NPV and agreement were above 98% for all benefits. Sensitivity and PPV were lower. When including non-responders as non-receivers, specificity got higher, sensitivity dropped while the other measures changed less.Between 17.7% and 24.1% did not answer the questions on benefits. Non responders were older and more likely to be female. They reported more anxiety, more depression, a higher number of somatic diagnoses, less physical activity and lower consumption of alcohol (p < 0.001 for all variables). For disability pension and retirement pension, non-responders were less likely to receive benefits than responders (p < 0.001). For each benefit 2.1% or less of non responders were receivers. False positive responses were more prevalent than false negative responses. CONCLUSIONS: The validity of self-reported data on disability pension, rehabilitation benefits and retirement pension is high - it seems that participants' responses can be trusted. Compared to responders, non responders are less likely to be receivers. If necessary, power and validity can be kept high by imputing non-responders as non-receivers. PMID- 23343187 TI - Assessment of causal link between psychological factors and symptom exacerbation in inflammatory bowel disease: a protocol for systematic review of prospective cohort studies. AB - BACKGROUND: Inflammatory bowel disease is an idiopathic chronic disease that affects around 28 million people worldwide. Symptoms are distressing and have a detrimental effect on patients' quality of life. A possible link between exacerbation of symptoms and psychological factors has been suspected but not established. Previous reviews concerned with this link had conceptual and methodological limitations. In this paper we set out a protocol that lays the foundations for a systematic review that will address these shortcomings. The aim of this review is to provide researchers and clinicians with clarity on the role of psychological factors in inflammatory bowel disease symptom exacerbation. METHOD/DESIGN: We will identify all original, published, peer reviewed studies relevant to the topic and published in English from inception to November 2012. The databases MEDLINE, EMBASE, CINAHL and PsychINFO will be systematically searched. The search terms will include: inflammatory bowel disease, Crohn's disease, ulcerative colitis, psychological stress, mental stress, life stress, family stress, hassles, social stress, coping, mood disorders, anxiety and depression in sequential combinations.Studies will be screened according to predetermined inclusion and exclusion criteria by two reviewers. We will include clinical prospective cohort studies of all human participants aged 18 years or over with a diagnosis of inflammatory bowel disease. All eligible papers will be independently and critically appraised using the Critical Appraisal Skills Programme (CASP) tool by two reviewers. Two reviewers will independently extract and synthesise data from the studies using a predefined data extraction sheet. Disagreements will be resolved by discussion between reviewers and a third party will be consulted if agreement is not reached. Synthesised data will be analysed using Bradford Hill criterion for causality. If data permits, meta-analysis will be performed. DISCUSSION: This study will provide the most comprehensive review and synthesis of current evidence around the link between psychological factors and symptom exacerbation in inflammatory bowel disease. Results will inform clinicians in appropriate intervention development for this patient group that would reduce symptom exacerbation and therefore improve patients' quality of life. PMID- 23343188 TI - Incomplete staging surgery as a major predictor of relapse of borderline ovarian tumor. AB - BACKGROUND: Borderline ovarian tumors (BOTs) are a subset of epithelial ovarian tumors with low malignant potential but significant risk of relapse (10% to 30%). Unfortunately, surgical prognostic factors for BOT relapse have not been clearly identified, probably due to the use of heterogeneous surgical definitions and limited follow-up. The aim of this study was to assess potential relapse risk factors using standard surgical definitions and long follow-up. METHODS: All patients diagnosed with BOT for a period of more than 10 years in a single institution were included in the analysis. Complete surgical staging was defined as the set of procedures that follow standard guidelines for staging surgery (except lymphadenectomy), performed either with one or two interventions. Fertility-sparing surgeries that preserved one ovary and the uterus but included all the remaining procedures were classified as complete staging. The relationship between potential risk factors and time to BOT relapse was assessed by log-rank tests corrected for multiple comparisons and Cox regression. RESULTS: Forty-six patients with a median follow-up of 5.4 years were included, of whom 91.3% had been diagnosed as FIGO stage I disease and 45.7% had received complete staging surgery. Five relapses were detected (10.9%), all of them in women who had been diagnosed with stage I disease and had received incomplete staging surgery. Log-rank tests confirmed the association between incomplete staging surgery and shorter time to BOT relapse. CONCLUSIONS: Complete staging surgery should be considered a cornerstone of BOT treatment in order to minimize the risk of relapse. PMID- 23343189 TI - Meta-analysis of randomized controlled trials on magnesium in addition to beta blocker for prevention of postoperative atrial arrhythmias after coronary artery bypass grafting. AB - BACKGROUND: Atrial arrhythmia (AA) is the most common complication after coronary artery bypass grafting (CABG). Only beta-blockers and amiodarone have been convincingly shown to decrease its incidence. The effectiveness of magnesium on this complication is still controversial. This meta-analysis was performed to evaluate the effect of magnesium as a sole or adjuvant agent in addition to beta blocker on suppressing postoperative AA after CABG. METHODS: We searched the PubMed, Medline, ISI Web of Knowledge, Cochrane library databases and online clinical trial database up to May 2012. We used random effects model when there was significant heterogeneity between trials and fixed effects model when heterogeneity was negligible. RESULTS: Five randomized controlled trials were identified, enrolling a total of 1251 patients. The combination of magnesium and beta-blocker did not significantly decrease the incidence of postoperative AA after CABG versus beta-blocker alone (odds ratio (OR) 1.12, 95% confidence interval (CI) 0.86-1.47, P = 0.40). Magnesium in addition to beta-blocker did not significantly affect LOS (weighted mean difference -0.14 days of stay, 95% CI 0.58 to 0.29, P = 0.24) or the overall mortality (OR 0.59, 95% CI 0.08-4.56, P = 0.62). However the risk of postoperative adverse events was higher in the combination of magnesium and beta-blocker group than beta-blocker alone (OR 2.80, 95% CI 1.66-4.71, P = 0.0001). CONCLUSIONS: This meta-analysis offers the more definitive evidence against the prophylactic administration of intravenous magnesium for prevention of AA after CABG when beta-blockers are routinely administered, and shows an association with more adverse events in those people who received magnesium. PMID- 23343190 TI - Effect of doping on the magnetostructural ordered phase of iron arsenides: a comparative study of the resistivity anisotropy in doped BaFe2As2 with doping into three different sites. AB - To unravel the role of doping in iron-based superconductors, we investigated the in-plane resistivity of BaFe(2)As(2) doped at one of the three different lattice sites, Ba(Fe(1-x)Co(x))(2)As(2), BaFe(2)(As(1-x)P(x))(2), and Ba(1 x)K(x)Fe(2)As(2), focusing on the doping effect in the low-temperature antiferromagnetic/orthorhombic (AFO) phase. A major role of doping in the high temperature paramagnetic/tetragonal (PT) phase is known to change the Fermi surface by supplying charge carriers or exerting chemical pressure. In the AFO phase, we found a clear correlation between the magnitude of the residual resistivity and the resistivity anisotropy. This indicates that the resistivity anisotropy originates from anisotropic impurity scattering due to dopant atoms. The magnitude of the residual resistivity was also found to be a parameter controlling the suppression rate of the AFO ordering temperature. Therefore, the dominant role of doping in the AFO phase is to introduce disorder to the system, distinct from that in the PT phase. PMID- 23343191 TI - Potentiation of in vitro and in vivo antitumor efficacy of doxorubicin by cyclin dependent kinase inhibitor P276-00 in human non-small cell lung cancer cells. AB - BACKGROUND: In the present study, we show that the combination of doxorubicin with the cyclin-dependent kinase inhibitor P276-00 was synergistic at suboptimal doses in the non-small cell lung carcinoma (NSCLC) cell lines and induces extensive apoptosis than either drug alone in H-460 human NSCLC cells. METHODS: Synergistic effects of P276-00 and doxorubicin on growth inhibition was studied using the Propidium Iodide (PI) assay. The doses showing the best synergistic effect was determined and these doses were used for further mechanistic studies such as western blotting, cell cycle analysis and RT-PCR. The in vivo efficacy of the combination was evaluated using the H-460 xenograft model. RESULTS: The combination of 100 nM doxorubicin followed by 1200 nM P276-00 showed synergistic effect in the p53-positive and p53-mutated cell lines H-460 and H23 respectively as compared to the p53-null cell line H1299. Abrogation of doxorubicin-induced G2/M arrest and induction of apoptosis was observed in the combination treatment. This was associated with induction of tumor suppressor protein p53 and reduction of anti-apoptotic protein Bcl-2. Furthermore, doxorubicin alone greatly induced COX-2, a NF-kappaB target and Cdk-1, a target of P276-00, which was downregulated by P276-00 in the combination. Doxorubicin when combined with P276-00 in a sequence-specific manner significantly inhibited tumor growth, compared with either doxorubicin or P276-00 alone in H-460 xenograft model. CONCLUSION: These findings suggest that this combination may increase the therapeutic index over doxorubicin alone and reduce systemic toxicity of doxorubicin most likely via an inhibition of doxorubicin-induced chemoresistance involving NF-kappaB signaling and inhibition of Cdk-1 which is involved in cell cycle progression. PMID- 23343192 TI - Development of a solid-phase receptor-based assay for the detection of cyclic imines using a microsphere-flow cytometry system. AB - Biologically active macrocycles containing a cyclic imine were isolated for the first time from aquaculture sites in Nova Scotia, Canada, during the 1990s. These compounds display a "fast-acting" toxicity in the traditional mouse bioassay for lipophilic marine toxins. Our work aimed at developing a receptor-based detection method for spirolides using a microsphere/flow cytometry Luminex system. For the assay, two alternatives were considered as binding proteins, the Torpedo marmorata nicotinic acetylcholine receptor (nAChR) and the Lymnaea stagnalis acetylcholine binding protein (Ls-AChBP). A receptor-based inhibition assay was developed using the immobilization of nAChR or Ls-AChBP on the surface of carboxylated microspheres and the competition of cyclic imines with biotin-alpha bungarotoxin (alpha-BTX) for binding to these proteins. The amount of biotin alpha-BTX bound to the surface of the microspheres was quantified using phycoerythrin (PE)-labeled streptavidin, and the fluorescence was analyzed in a Luminex 200 system. AChBP and nAChR bound to 13-desmethyl spirolide C efficiently; however, the cross-reactivity profile of the nAChR for spirolides and gymnodimine more closely matched the relative toxic potencies reported for these toxins. The nAChR was selected for further assay development. A simple sample preparation protocol consisting of an extraction with acetone yielded a final extract with no matrix interference on the nAChR/microsphere-based assay for mussels, scallops, and clams. This cyclic imine detection method allowed the detection of 13-desmethyl spirolide C in the range of 10-6000 MUg/kg of shellfish meat, displaying a higher sensitivity and wider dynamic range than other receptor based assays previously published. This microsphere-based assay provides a rapid, sensitive, and easily performed screening method that could be multiplexed for the simultaneous detection of several marine toxins. PMID- 23343194 TI - Wnt/beta-catenin signalling: from plasma membrane to nucleus. AB - Wnt/beta-catenin signalling plays essential roles in embryonic development as well as tissue homoeostasis in adults. Thus abnormal regulation of Wnt/beta catenin signalling is linked to a variety of human diseases, including cancer, osteoporosis and Alzheimer's disease. Owing to the importance of Wnt signalling in a wide range of biological fields, a better understanding of its precise mechanisms could provide fundamental insights for therapeutic applications. Although many studies have investigated the regulation of Wnt/beta-catenin signalling, our knowledge remains insufficient due to the complexity and diversity of Wnt signalling. It is generally accepted that the identification of novel regulators and their functions is a prerequisite to fully elucidating the regulation of Wnt/beta-catenin signalling. Recently, several novel modulators of Wnt signalling have been determined through multiple genetic and proteomic approaches. In the present review, we discuss the mechanistic regulation of Wnt/beta-catenin signalling by focusing on the roles of these novel regulators. PMID- 23343193 TI - The dynamic nature of the kinome. AB - Recent advances in proteomics have facilitated the analysis of the kinome 'en masse'. What these studies have revealed is a surprisingly dynamic network of kinase responses to highly selective kinase inhibitors, thereby illustrating the complex biological responses to these small molecules. Moreover these studies have identified key transcription factors, such as c-Myc and FOXO (forkhead box O), that play pivotal roles in kinome reprogramming in cancer cells. Since many kinase inhibitors fail despite a high efficacy of blocking their intended targets, elucidating kinome changes at a more global level will be essential to understanding the mechanisms of kinase inhibitor pharmacology. The development of technologies to study the kinome, as well as examples of kinome resilience and reprogramming, will be discussed in the present review. PMID- 23343195 TI - Molecular determinants of a selective matrix metalloprotease-12 inhibitor: insights from crystallography and thermodynamic studies. AB - The molecular determinants responsible for the potency of the RXP470.1 phosphinic peptide inhibitor toward matrix metalloprotease-12 (MMP-12) remain elusive. To address this issue, structure-activity study, X-ray crystallography, and isothermal titration calorimetry (ITC) experiments were performed. The crystal structure of MMP-12/inhibitor complex (1.15 A) reveals that the inhibitor establishes multiple interactions with the MMP-12 active site, with its long P(1)' side chain filling most of the S(1)' deep cavity. ITC experiments indicate that the binding of this inhibitor to MMP-12 is mostly entropy driven (DeltaG degrees = -13.1 kcal/mol, DeltaH degrees = -2.53 kcal/mol, and -TDeltaS degrees = -10.60 kcal/mol) and involves a proton uptake from the buffer. Comparing phosphinic versus hydroxamate inhibitors reveals that the chelation of the zinc ion is slightly different, leading the inhibitor backbone to adopt a position in which the hydrogen bonding with the MMP-12 active site is less favorable in phosphinic inhibitor while maintaining high affinity. PMID- 23343196 TI - T2 hyperintensity of medial lemniscus: higher threshold application to ROI measurements is more accurate in predicting small vessel disease. AB - BACKGROUND: Medial lemniscus T2 hyperintensity (MLH) has been recently demonstrated as potential imaging marker for small vessel disease (SVD). Our purpose in this study is to improve accuracy of regions of interest (ROI) analysis for this imaging finding. METHODS AND METHODS: Two neuroradiologists retrospectively reviewed 103 consecutive outpatient brain MRI. Medial lemniscus signal in dorsal pons was evaluated; visually on FLAIR and with ROI on T2. Original MRI interpretations were divided into three categories; SVD, multiple sclerosis (MS), and nonspecific WM changes (non). RESULTS: Thirty-seven patients had SVD, 14 patients had MS, 52 had Non. Visual MLH was seen exclusively with SVD and was generally bilateral. Patients with visual MLH belonged to advanced SVD by imaging and clinical parameters. Compared to visual data, ROI analyses of MLH has been known to be compounded by false positives and negatives at low threshold (20% of adjacent to normal brainstem signal). With application of higher ROI threshold (25%), false positives were eliminated but false negatives increased. ROI analyses of MLH by experienced neuroradiologist were more reliable. CONCLUSION: MLH seen on high threshold ROI analysis is a reliable radiologic marker in predicting SVD. ROI analysis of MLH should be performed by an experienced neuroradiologist. PMID- 23343197 TI - Rotterdam Aphasia Therapy Study (RATS)-3: "The efficacy of intensive cognitive linguistic therapy in the acute stage of aphasia"; design of a randomised controlled trial. AB - BACKGROUND: Aphasia is a severely disabling condition occurring in 20 to 25% of stroke patients. Most patients with aphasia due to stroke receive speech and language therapy. Methodologically sound randomised controlled trials investigating the effect of specific interventions for patients with aphasia following stroke are scarce. The currently available evidence suggests that intensive speech and language therapy is beneficial for restoration of communication, but the optimal timing of treatment is as yet unclear.In the Rotterdam Aphasia Therapy Study-3 we aim to test the hypothesis that patients with aphasia due to stroke benefit more from early intensive cognitive-linguistic therapy than from deferred regular language therapy. METHODS/DESIGN: In a single blinded, multicentre, randomised controlled trial, 150 patients with first ever aphasia due to stroke will be randomised within two weeks after stroke to either early intensive cognitive-linguistic therapy (Group A) or deferred regular therapy (Group B). Group A will start as soon as possible, at the latest two weeks after stroke, with a four week period of one hour a day treatment with cognitive-linguistic therapy. In Group B professional speech and language therapy is deferred for four weeks. After this period, patients will follow the conventional procedure of speech and language therapy. Participants will be tested with an extensive linguistic test battery at four weeks, three months and six months after inclusion. Primary outcome measure is the difference in score between the two treatment groups on the Amsterdam-Nijmegen Everyday Language Test, a measure of everyday verbal communication, four weeks after randomisation. TRIAL REGISTRATION: This trial is registered in the Dutch Trial Register (http://www.trialregister.nl), NTR3271. PMID- 23343198 TI - Neurocognitive deficits associated with the hepatitis C virus among incarcerated men. AB - The purpose of this preliminary study was to examine cognitive functioning in inmates with the hepatitis C virus (HCV) and to investigate relationships among performance on the Repeatable Battery for the Assessment of Neuropsychological Status-Form A (RBANS; Randolph, 1998). Data from 43 HCV+ inmates were reviewed retrospectively and compared with a sample of HCV- inmates. Significant differences were found on two of five indices (Attention: U = 537.5, p = .003; r = -.32; Total: U = 643.0, p = .048; r = -.22) and four subtests: Coding (U = 326.0, p <.001, r = -.53), Digit Span (U = 634.0, p = .038, r = -.22), Story Memory (U = 625.5, p = .032, r = -.24), and Story Recall (U = 548.5, p = .004, r = -.31), with the HCV group scoring lower on all significant measures. In this study the RBANS proved to be an efficient measure with clinical utility among an HCV population. Within this incarcerated population patterns of performance were "typical" of current literature, with impaired attention appearing earlier in the disease process, and the study invites further exploration into proposed cognitive deficits among this population where HCV is highly prevalent. PMID- 23343199 TI - Characterization of adipose-derived mesenchymal stem cell combinations for vascularized bone engineering. AB - Since bone repair and regeneration depend on vasculogenesis and osteogenesis, both of these processes are essential for successful vascularized bone engineering. Using adipose-derived stem cells (ASCs), we investigated temporal gene expression profiles, as well as bone nodule and endothelial tubule formation capacities, during osteogenic and vasculogenic ASC lineage commitment. Osteoprogenitor-enriched cell populations were found to express RUNX2, MSX2, SP7 (osterix), BGLAP (osteocalcin), SPARC (osteonectin), and SPP1 (osteopontin) in a temporally specific sequence. Irreversible commitment of ASCs to the osteogenic lineage occurred between days 6 and 9 of differentiation. Endothelioprogenitor enriched cell populations expressed CD34, PECAM1 (CD31), ENG (CD105), FLT1 (Vascular endothelial growth factor [VEGFR1]), and KDR (VEGFR2). Capacity for microtubule formation was evident in as early as 3 days. Functional capacity was assessed in eight coculture combinations for both bone nodule and endothelial tubule formation, and the greatest expression of these end-differentiation phenotypes was observed in the combination of well-differentiated endothelial cells with less-differentiated osteoblastic cells. Taken together, our results demonstrate vascularized bone engineering utilizing ASCs is a promising enterprise, and that coculture strategies should focus on developing a more mature vascular network in combination with a less mature osteoblastic stromal cell. PMID- 23343200 TI - Physically-motivated force fields from symmetry-adapted perturbation theory. AB - We present a general methodology for generating accurate and transferable ab initio force fields, employing the framework of symmetry adapted perturbation theory (SAPT). The resulting force fields are "physically-motivated" in that they contain separate, explicit terms to account for the various fundamental intermolecular interactions, such as exchange, electrostatics, induction, and dispersion, with each term parametrized to a corresponding term in the SAPT energy decomposition. Crucially, the resulting force fields are largely compatible with existing, standard simulation packages, requiring only minimal modifications. We present several novel parametrization techniques that yield robust, physically meaningful atomic parameters that are transferable between molecular environments. We demonstrate the accuracy and generality of our method by validating against experimental second virial coefficients for a variety of small molecules. We then show that the resulting atomic parameters can be combined using physically motivated ansatzes to accurately predict arbitrary heteromolecular interaction energies, with example applications including prediction of gas adsorption in functionalized metal-organic framework materials. PMID- 23343201 TI - Transcervical intralesional vasopressin injection in hysteroscopic myomectomy- description of a new technique. AB - An original technique of transcervical intralesional vasopressin injection that allowed direct infiltration to submucous myomas under hysteroscopic control is described. Five patients with a symptomatic submucous myoma 1.5-5 cm in size scheduled for hysteroscopic myomectomy were recruited. The time required for vasopressin injection was less than 3 minutes in all cases. The time required for myomectomy ranged from 3 to 32 minutes. Four cases had no fluid absorption, whereas 1 had absorption of 1000 mL. The patient with the longest operative time and fluid absorption had multiple submucous myomas, including a large G2 myoma of 5 cm. All cases had complete excision without complication. The surgeons rated the operations as having minimal bleeding and excellent clarity. Transcervical intralesional vasopressin injection is a potentially simple, quick, and feasible method to facilitate complete resection of submucous myomas in hysteroscopic myomectomy. PMID- 23343202 TI - Parapharyngeal space surgery via a transoral approach using a robotic surgical system: transoral robotic surgery. AB - OBJECTIVE: In transoral robotic surgery (TORS), if an endoscopic arm equipped with two integrated cameras is placed close to a lesion, a three-dimensionally magnified view of the operative field can be obtained. More important is that the operation can be performed precisely and bimanually using two instrument arms that can move freely within a limited working space. We performed TORS to treat several diseases that occur in the parapharyngeal space (PPS) and subsequently analyzed the treatment outcomes to confirm the validity of this procedure. PATIENTS AND METHODS: Between February 2009 and February 2012, 11 patients who required surgical treatment for the removal of a parapharyngeal lesion were enrolled in this prospective study. Nine patients received TORS for parapharyngeal tumor resection, and 2 patients with stylohyoid syndrome underwent TORS for resection of an elongated styloid process. The average age of the patients included in this study was 42 years. Five patients were male, and 6 patients were female. RESULTS: TORS was successfully performed in all 11 patients. The average robotic system docking and operation times were 9.9 minutes (range, 5-24 minutes) and 54.2 minutes (range, 26-150 minutes), respectively. Patients were able to swallow normally the day after the operation. The average blood loss during the robotic operation was minimal (11.8 mL). The average hospital stay was 2.6 days. There were no significant complications in the perioperative or postoperative period. All patients were extremely satisfied with their cosmetic outcomes. CONCLUSIONS: PPS surgery via a transoral approach using a robotic surgical system is technically feasible and secures a better cosmetic outcome than the transcervical, transparotid, or transmandibular approach. This new surgical method is safe and effective for benign diseases of the PPS. PMID- 23343203 TI - Characteristic profiles of urinary p-hydroxybenzoic acid and its esters (parabens) in children and adults from the United States and China. AB - Hydroxybenzoic acid esters (parabens) are used as preservatives in foods, cosmetics, and pharmaceuticals, which results in the exposure of humans to these compounds. Parabens and its metabolite, p-hydroxybenzoic acid (p-HB) are excreted from urine in free and conjugated forms. In this study, free and total forms (free plus conjugated) of parabens and their common metabolite, p-HB, were measured in urine samples collected from U.S. children (n = 40), Chinese children (n = 70), and Chinese adults (n = 26). The median concentrations of the sum of 6 parabens (Sigmaparabens) in urine from U.S. and Chinese children were 54.6 and 10.1 ng/mL, respectively. The median concentration of urinary parabens measured for Chinese adults was 33.2 ng/mL, which was lower than that reported for U.S. adults. Elevated concentrations of parabens (1000-10,000 ng/mL) were found in urine from some Chinese adult females. Parabens were present predominantly (>90%) as conjugated species in urine. Among the six parabens analyzed, methyl paraben (MeP) and propyl paraben (PrP) were the predominant compounds, which accounted for 57-98% and 1.4-12%, respectively, of the total concentrations. A significant positive correlation was found between the concentrations of MeP and PrP. The geometric mean (GM) concentration of p-HB was 1380 and 2370 ng/mL for Chinese children and adults, respectively. The GM concentrations of p-HB in urine from U.S. children were 752 ng/mL for girls and 628 ng/mL for boys, which were 2-3 times lower than the concentrations determined for Chinese children. There was a significant difference in the ratios of concentrations of Sigmaparabens and p-HB between demographic groups, which suggested the existence of various exposure routes to parabens. Based on the concentrations of urinary parabens and p-HB, the daily intake (DI) of MeP and PrP was estimated. The GM DI(MeP) estimated for Chinese children was 0.5-0.7 mg/day, which was similar to those determined for U.S. children. The GM DI(PrP) (0.2-0.5 mg/day) estimated for Chinese children was 20- to 50-fold higher than the value determined for U.S. children (0.01 mg/day). The highest exposure to parabens was found for Chinese adult females, with GM DI(MeP) and DI(PrP) of 5.9 and 1.2 mg/day, respectively. Elevated exposure to PrP was found in some Chinese adult females (27 mg/day) and children (11 mg/day). PMID- 23343204 TI - Review on the development of genotyping methods for assessing farm animal diversity. AB - Advances in molecular biotechnology have introduced new generations of molecular markers for use in the genetic improvement of farm animals. Consequently, more accurate genetic information can be obtained to better understand existing animal genetic resources. This review gives a brief summary on the development of genetic markers including both the classical genetic markers and more advanced DNA-based molecular markers. This review will help us better understand the characteristics of different genetic markers and the genetic diversity of animal genetic resources. PMID- 23343206 TI - Photoinduced electron transfer promoted radical ring expansion and cyclization reactions of alpha-(omega-carboxyalkyl) beta-keto esters. AB - Photoinduced electron transfer (PET) promoted decarboxylation of alpha-(omega carboxyalkyl) beta-keto esters undergoes radical ring expansion and cyclization reactions. This mild and environmentally friendly method can provide one-carbon expanded gamma-keto esters and bicyclic alcohols, and the product distribution is strongly dependent on the length of the alkyl chain containing the terminal carboxylate group. PMID- 23343205 TI - Symptomatic cardiac metastases of breast cancer 27 years after mastectomy: a case report with literature review--pathophysiology of molecular mechanisms and metastatic pathways, clinical aspects, diagnostic procedures and treatment modalities. AB - Metastases to the heart and pericardium are rare but more common than primary cardiac tumours and are generally associated with a rather poor prognosis. Most cases are clinically silent and are undiagnosed in vivo until the autopsy. We present a female patient with a 27-year-old history of an operated primary breast cancer who was presented with dyspnoea, paroxysmal nocturnal dyspnoea and orthopnoea. The clinical signs and symptoms aroused suspicion of congestive heart failure. However, the cardiac metastases were detected during a routine cardiologic evaluation and confirmed with computed tomography imaging. Additionally, this paper outlines the pathophysiology of molecular and clinical mechanisms involved in the metastatic spreading, clinical presentation, diagnostic procedures and treatment of heart metastases. The present case demonstrates that a complete surgical resection and systemic chemotherapy may result in a favourable outcome for many years. However, a lifelong medical follow up, with the purpose of a detection of metastases, is highly recommended. We strongly call the attention of clinicians to the fact that during the follow-up of all cancer patients, such heart failure may be a harbinger of the secondary heart involvement. PMID- 23343207 TI - Effect of films on 1,3-dichloropropene and chloropicrin emission, soil concentration, and root-knot nematode control in a raised bed. AB - Soil fumigation is an important component of U.S. agriculture, but excessive emissions can be problematic. The objective of this study was to determine the effects of agricultural films (e.g., tarps) on soil fumigant atmospheric emissions and spatiotemporal distributions in soil, soil temperature, and plant pathogen control in the field using plastic films with various permeabilities and thermal properties. A reduced rate of 70% InLine (60.8% 1,3-dichloropropene (1,3 D) and 33.3% chloropicrin (CP)) was applied via drip line to raised soil beds covered with standard high-density polyethylene film (HDPE), thermic film (Thermic), or virtually impermeable film (VIF). 1,3-D and CP emission rates were determined using dynamic flux chambers, and the concentrations in soil were measured using a gas sampler. The pest control efficacy for the three treatments was determined using bioassay muslin bags containing soil infested with citrus nematodes (Tylenchulus semipenetrans). The results show that the Thermic treatment had the highest emission rates, followed by the HDPE and VIF treatments, and the soil concentrations followed the reverse order. In terms of pest control, covering the beds with thermic film led to sufficient and improved efficacy against citrus nematodes compared to standard HDPE film. Under HDPE, >20% of nematodes survived in the soil at 30 cm depth at day 12. The VIF treatment substantially reduced the emission loss from the bed (2% of the Thermic and 6% of the HDPE treatments) and eliminated plant parasitic nematodes because of its superior ability to entrap fumigant and heat within soils. The findings imply that not only the film permeability but also the synergistic ability to entrap heat should be considered in the development of new improved films for fumigation. PMID- 23343208 TI - A virtual rehabilitation program after amputation: a phenomenological exploration. AB - PURPOSE: This study provides an analysis of bodily experiences of a man with a lower leg amputation who used a virtual rehabilitation program. METHOD: The study reports data from semi-structured interviews with a 32-year veteran who used a virtual environment during rehabilitation. The interviews were analyzed using interpretative phenomenological analysis (IPA). RESULTS: During this rehabilitation program, he initially experienced his body as an object, which he had to handle carefully. As he went along with the training sessions, however, he was more stimulated to react directly without being aware of the body's position. In order to allow himself to react spontaneously, he needed to gain trust in the device. This was fostered by his narrative, in which he stressed how the device mechanically interacts with his movements. CONCLUSION: The use of a virtual environment facilitated the process of re-inserting one's body into the flow of one's experience in two opposite, but complementary ways: (1) it invited this person to move automatically without taking into account his body; (2) it invited him to take an instrumental or rational view on his body. Both processes fostered his trust in the device, and ultimately in his body. IMPLICATIONS FOR REHABILITATION: Providing (more) technological explanation of the technological device (i.e. the virtual environment), may facilitate a rehabilitation process. Providing (more) explicit technological feedback, during training sessions in a virtual environment, may facilitate a rehabilitation process. PMID- 23343209 TI - Comparison of population-averaged and cluster-specific models for the analysis of cluster randomized trials with missing binary outcomes: a simulation study. AB - BACKGROUND: The objective of this simulation study is to compare the accuracy and efficiency of population-averaged (i.e. generalized estimating equations (GEE)) and cluster-specific (i.e. random-effects logistic regression (RELR)) models for analyzing data from cluster randomized trials (CRTs) with missing binary responses. METHODS: In this simulation study, clustered responses were generated from a beta-binomial distribution. The number of clusters per trial arm, the number of subjects per cluster, intra-cluster correlation coefficient, and the percentage of missing data were allowed to vary. Under the assumption of covariate dependent missingness, missing outcomes were handled by complete case analysis, standard multiple imputation (MI) and within-cluster MI strategies. Data were analyzed using GEE and RELR. Performance of the methods was assessed using standardized bias, empirical standard error, root mean squared error (RMSE), and coverage probability. RESULTS: GEE performs well on all four measures -provided the downward bias of the standard error (when the number of clusters per arm is small) is adjusted appropriately--under the following scenarios: complete case analysis for CRTs with a small amount of missing data; standard MI for CRTs with variance inflation factor (VIF) <3; within-cluster MI for CRTs with VIF>=3 and cluster size>50. RELR performs well only when a small amount of data was missing, and complete case analysis was applied. CONCLUSION: GEE performs well as long as appropriate missing data strategies are adopted based on the design of CRTs and the percentage of missing data. In contrast, RELR does not perform well when either standard or within-cluster MI strategy is applied prior to the analysis. PMID- 23343210 TI - Human parvovirus B19 infection in a renal transplant recipient: a case report. AB - BACKGROUND: Parvovirus B19 presents tropism for human erythroid progenitor cells, causing chronic anemia in organ transplant recipients, due to their suppressed humoral and cellular responses. Diagnosis may be achieved through serological tests for detection of anti-B19 antibodies. However, renal transplant recipients are not routinely tested for parvovirus B19 infection, since there is scanty data or consensus on screening for B19 infection, as well as for treatment or preventive management of transplanted patients. CASE PRESENTATION: Herein we report a kidney transplant recipient, who was unresponsive to treatment of severe anemia, and presented hypocellular hematopoietic marrow, megaloblastosis and hypoplasia of erythroid lineage with larger cells with clear nuclei chromatin and eosinophilic nuclear inclusions. This patient was seropositive for Epstein-Barr and Cytomegalovirus infections and negative for anti-parvovirus B19 IgM and IgG antibodies, although symptoms were suggestive of parvoviruses infection. A qualitative polymerase chain reaction testing for B19 in serum sample revealed positive results for B19 virus DNA. CONCLUSION: This case report suggests that the diagnostic process for parvovirus B19 in renal transplant recipients should include a polymerase chain reaction assay to detect B19-DNA, since specific serological tests may be unreliable given their impaired humoral responses. These results also indicate the importance of considering parvovirus B19 infection in the differential diagnosis of persistent anemia in transplanted patients. PMID- 23343211 TI - A population-based study of rates of childbirth in recurrence-free female young adult survivors of non-gynecologic malignancies. AB - BACKGROUND: Fertility is an important issue for long-term survivors of malignancies developing during reproductive years. We designed a population-based study to investigate childbirth in female young adult survivors of non gynecologic malignancies. METHODS: Women 20-34 years diagnosed with non gynecologic malignancies in Ontario from 1992-1999 who lived at least 5 years recurrence-free were identified using the Ontario Cancer Registry and age matched to 5 randomly selected cancer-free women. Childbirth was determined through hospital discharge data. Time-to-childbirth was compared between survivors and controls using Cox proportional hazard regression for all subjects and stratified by prior childbirth and disease site. RESULTS: 3,285 survivors and 15,118 control women had a median of 12 years observation. 1,194 survivors and 6,049 controls experienced childbirth to the end of observation (March 2011). Overall, survivors experienced a longer time to childbirth than controls (HR 0.92, 95% CI 0.87 0.98), however this was limited to survivors with prediagnosis childbirth (HR 0.76, 95% CI 0.66-0.86). Survivors with no prediagnosis childbirth experienced a similar time to childbirth (HR 1.00, 95% CI 0.93-1.08) as control women. Differences between survivors and controls varied by type of malignancy; notably for those with prediagnosis childbirth, survivors of breast cancer (HR 0.45, 95% CI 0.29-0.68) and Hodgkin Disease (HR 0.57, 95% CI 0.36-0.91) had lower rates of postdiagnosis childbirth than controls. CONCLUSIONS: Long-term female young adult survivors of malignancies are less likely than controls to have childbirth after diagnosis; the overall effect is small and is influenced by prediagnosis childbirth and malignancy type. PMID- 23343212 TI - Detained adolescent females' multiple mental health and adjustment problem outcomes in young adulthood. AB - BACKGROUND: Although prior studies have shown that detained females are marked by significant adverse circumstances, little is known about their adult outcomes. METHOD: Prospective follow-up study of 184 (80.4% of original sample of 229) detained adolescent females who were reassessed 4.5 (SD=0.6) years later in young adulthood (mean age=20.0, SD=1.4) on mental health and adjustment outcomes. Associations between these outcomes and detained females' behavior problems and offense history were examined. RESULTS: In the total sample, 59.0% had one or more mental health problems at follow-up, whereas 96.2% were facing at least one adjustment problem. Subjects with a personality disorder (PD) reported more adjustment problems compared to subjects without PD. Mental health and adjustment problems in young adulthood were predicted by detained adolescent females' behavior problems and offense history. CONCLUSION: Detained adolescent females suffered from multiple mental health and adjustment problems in young adulthood. Females who developed PD were most impaired. Results of this study underline the compelling need for continued and gender-specific interventions. The identification of predictors during detention for poor adult outcomes can serve as targets for intervention. PMID- 23343213 TI - Microfluidic screening of electrophoretic mobility shifts elucidates riboswitch binding function. AB - Riboswitches are RNA sensors that change conformation upon binding small molecule metabolites, in turn modulating gene expression. Our understanding of riboswitch regulatory function would be accelerated by a high-throughput, quantitative screening tool capable of measuring riboswitch-ligand binding. We introduce a microfluidic mobility shift assay that enables precise and rapid quantitation of ligand binding and subsequent riboswitch conformational change. In 0.3% of the time required for benchtop assays (3.2 versus 1020 min), we screen and validate five candidate SAM-I riboswitches isolated from thermophilic and cryophilic bacteria. The format offers enhanced resolution of conformational change compared to slab gel formats, quantitation, and repeatability for statistical assessment of small mobility shifts, low reagent consumption, and riboswitch characterization without modification of the aptamer structure. Appreciable analytical sensitivity coupled with high-resolution separation performance allows quantitation of equilibrium dissociation constants (K(d)) for both rapidly and slowly interconverting riboswitch-ligand pairs as validated through experiments and modeling. Conformational change, triplicate mobility shift measurements, and K(d) are reported for both a known and a candidate SAM-I riboswitch with comparison to in-line probing assay results. The microfluidic mobility shift assay establishes a scalable format for the study of riboswitch-ligand binding that will advance the discovery and selection of novel riboswitches and the development of antibiotics to target bacterial riboswitches. PMID- 23343215 TI - Close allies in membrane protein research: cell-free synthesis and nanotechnology. AB - Membrane proteins control fundamental processes that are inherent to nearly all forms of life such as transport of molecules, catalysis, signaling, vesicle fusion, sensing of chemical and physical stimuli from the environment, and cell cell interactions. Membrane proteins are harbored within a non-equilibrium fluid like environment of biological membranes that separate cellular and non-cellular environments, as well as in compartmentalized cellular organelles. One of the classes of membrane proteins that will be specifically treated in this article are transport proteins of plant origin, that facilitate material and energy transfer at the membrane boundaries. These proteins import essential nutrients, export cellular metabolites, maintain ionic and osmotic equilibriums and mediate signal transduction. The aim of this article is to report on the progress of membrane protein functional and structural relationships, with a focus on producing stable and functional proteins suitable for structural and biophysical studies. We interlink membrane protein production primarily through wheat-germ cell-free protein synthesis (WG-CFPS) with the growing repertoire of membrane mimicking environments in the form of lipids, surfactants, amphipathic surfactant polymers, liposomes and nanodiscs that keep membrane proteins soluble. It is hoped that the advancements in these fields could increase the number of elucidated structures, in particular those of plant membrane proteins, and contribute to bridging of the gap between structures of soluble and membrane proteins, the latter being comparatively low. PMID- 23343214 TI - Significance of HE4 estimation in comparison with CA125 in diagnosis of ovarian cancer and assessment of treatment response. AB - BACKGROUND: Human epididymis protein 4 (HE4) is a novel and specific biomarker for ovarian cancer. The aim of this study is to evaluate a new tumor marker, HE4, in comparison with CA125 in diagnosis of epithelial ovarian cancer (EOC) and benign gynecological diseases. METHODS: CA125 and HE4 serum levels were determined in 30 patients with epithelial ovarian cancer (21 serous, 6 endometrioid and 3 mucinous tumors), 20 patients with benign gynecological diseases (8 patients with ovarian cyst, 5 patients with endometriosis, 4 patients with fibroid and 3 patients with pelvic inflammatory disease) and 20 healthy women. CA125 and HE4 cut-offs were 35 U/ml and 150 pmol/l, respectively. RESULTS: Serum HE4 and CA125 concentrations were significantly higher in the ovarian cancer patients compared with those seen in patients with benign disease or in the healthy controls (p = 0.001 and p < 0.001 respectively). In the receiver operating characteristic analysis (ROC), the area under the curve (AUC) values for HE4 was 0.96 (95% confidence interval, 0.9-1.0) and CA125 was 0.82 (95% confidence interval, 0.7-0.94). Compared to CA125, HE4 had higher sensitivity (90% vs. 83.3%), specificity (95% vs. 85%), PPV (93.1% vs. 80.7%) and NPV (92.7% vs. 87.2%), the combination of HE4 + CA125 the sensitivity and PPV reached 96.7% and 97% respectively. CONCLUSION: Measuring serum HE4 concentrations along with CA125 concentrations may provide higher accuracy for detecting epithelial ovarian cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1060413168685759. PMID- 23343216 TI - AFM-based force spectroscopy on polystyrene brushes: effect of brush thickness on protein adsorption. AB - Herein we present a study on nonspecific binding of proteins at highly dense packed hydrophobic polystyrene brushes. In this context, an atomic force microscopy tip was functionalized with concanavalin A to perform single-molecule force spectroscopy measurements on polystyrene brushes with thicknesses of 10 and 60 nm, respectively. Polystyrene brushes with thickness of 10 nm show an almost two times stronger protein adsorption than brushes with a thickness of 60 nm: 72 pN for the thinner and 38 pN for the thicker layer, which is in qualitative agreement with protein adsorption studies conducted macroscopically by fluorescence microscopy. PMID- 23343217 TI - Retraction: progress of genome wide association study in domestic animals. PMID- 23343218 TI - Supporting local planning and budgeting for maternal, neonatal and child health in the Philippines. AB - BACKGROUND: Responsibility for planning and delivery of health services in the Philippines is devolved to the local government level. Given the recognised need to strengthen capacity for local planning and budgeting, we implemented Investment Cases (IC) for Maternal, Neonatal and Child Health (MNCH) in three selected sub-national units: two poor, rural provinces and one highly-urbanised city. The IC combines structured problem-solving by local policymakers and planners to identify key health system constraints and strategies to scale-up critical MNCH interventions with a decision-support model to estimate the cost and impact of different scaling-up scenarios. METHODS: We outline how the initiative was implemented, the aspects that worked well, and the key limitations identified in the sub-national application of this approach. RESULTS: Local officials found the structured analysis of health system constraints helpful to identify problems and select locally appropriate strategies. In particular the process was an improvement on standard approaches that focused only on supply side issues. However, the lack of data available at the local level is a major impediment to planning. While the majority of the strategies recommended by the IC were incorporated into the 2011 plans and budgets in the three study sites, one key strategy in the participating city was subsequently reversed in 2012. Higher level systemic issues are likely to have influenced use of evidence in plans and budgets and implementation of strategies. CONCLUSIONS: Efforts should be made to improve locally-representative data through routine information systems for planning and monitoring purposes. Even with sound plans and budgets, evidence is only one factor influencing investments in health. Political considerations at a local level and issues related to decentralisation, influence prioritisation and implementation of plans. In addition to the strengthening of capacity at local level, a parallel process at a higher level of government to relieve fund channelling and coordination issues is critical for any evidence based planning approach to have a significant impact on health service delivery. PMID- 23343219 TI - Application of land use regression to identify sources and assess spatial variation in urban SVOC concentrations. AB - Land use regression (LUR), a geographic information system (GIS), and measured air concentrations were used to identify potential sources of semivolatile organic contaminants (SVOCs) within an urban/suburban region, using Toronto, Canada as a case study. Regression results suggested that air concentrations of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs), and polycyclic musks (PCMs) were correlated with sources at a scale of <5 km. LUR was able to explain 73-90% of the variability in PCBs and PCMs, and 36-89% of PBDE and PAH variability, suggesting that the latter have more spatially complex emission sources, particularly for the lowest and highest molecular weight compounds/congeners. LUR suggested that ~75% of the PCB air concentration variability was related to the distribution of PCBs in use/storage/building sealants, ~60% of PBDE variability was related to building volume, ~55% of the PAH variability was related to the distribution of transportation infrastructure, and ~65% of the PCM variability was related to population density. Parameters such as population density and household income were successfully used as surrogates to infer sources and air concentrations of SVOCs in Toronto. This is the first application of LUR methods to explain SVOC concentrations. PMID- 23343220 TI - The effectiveness of school mental health literacy programs to address knowledge, attitudes and help seeking among youth. AB - AIM: Conduct a systematic review for the effectiveness of school mental health literacy programs to enhance knowledge, reduce stigmatizing attitudes and improve help-seeking behaviours among youth (12-25 years of age). METHODS: Reviewers independently searched PubMed, PsycINFO, Cochrane Library, CINAHL, ERIC, grey literature and reference lists of included studies. They reached a consensus on the included studies, and rated the risk of bias of each study. Studies that reported three outcomes: knowledge acquisition, stigmatizing attitudes and help seeking behaviours; and were randomized controlled trials (RCTs), cluster RCTs, quasi-experimental studies, and controlled-before-and-after studies, were eligible. RESULTS: This review resulted in 27 articles including 5 RCTs, 13 quasi experimental studies, and 9 controlled-before-and-after studies. Whereas most included studies claimed school-based mental health literacy programs improve knowledge, attitudes and help-seeking behaviour, 17 studies met criteria for high risk of bias, 10 studies for moderate risk of bias, and no studies for low risk of bias. Common limitations included the lack of randomization, control for confounding factors, validated measures and report on attrition in most studies. The overall quality of the evidence for knowledge and help-seeking behaviour outcomes was very low, and low for the attitude outcome. CONCLUSIONS: Research into school-based mental health literacy is still in its infancy and there is insufficient evidence to claim for positive impact of school mental health literacy programs on knowledge improvement, attitudinal change or help-seeking behaviour. Future research should focus on methods to appropriately determine the evidence of effectiveness on school-based mental health literacy programs, considering the values of both RCTs and other research designs in this approach. Educators should consider the strengths and weaknesses of current mental health literacy programs to inform decisions regarding possible implementation. PMID- 23343221 TI - Qualitative screening of undesirable compounds from feeds to fish by liquid chromatography coupled to mass spectrometry. AB - This paper describes the development, validation, and application of a rapid screening method for the detection and identification of undesirable organic compounds in aquaculture products. A generic sample treatment was applied without any purification or preconcentration step. After extraction of the samples with acetonitrile/water 80:20 (0.1% formic acid), the extracts were centrifuged and directly injected in the LC-HRMS system, consisting of ultra-high performance liquid chromatography coupled to hybrid quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). A qualitative validation was carried out for over 70 representative compounds, including antibiotics, pesticides, and mycotoxins, in fish feed and fish fillets spiked at 20 and 100 MUg/kg. At the highest level, the great majority of compounds were detected (using the most abundant ion, typically the protonated molecule) and unequivocally identified (on the basis of the presence of two accurate-mass measured ions). At the 20 MUg/kg level, many contaminants could already be detected, although identification using two ions was not fully reached for some of them, mainly in fish feed due to the complexity of this matrix. Subsequent application of this screening methodology to aquaculture samples made it possible to find several compounds from the target list, such as the antibiotic ciprofloxacin, the insecticide pirimiphos-methyl, and the mycotoxins fumonisin B2 and zearalenone. A retrospective analysis of accurate-mass full-spectrum acquisition data provided by QTOF MS was also made, without either reprocessing or injecting the samples. This allowed the detection and tentative identification of other organic undesirables different from those included in the validated list. PMID- 23343222 TI - Do black (dark) lymph-node metastases in papillary thyroid carcinoma suggest more advanced or aggressive disease? AB - BACKGROUND: In some patients, papillary thyroid carcinoma (PTC) lymph-node metastases are noted to be black (dark) in color at the time of surgical removal. The goal of this project was to determine histological, genetic, and clinical features that are associated with regional black PTC metastasis. METHODS: Fifteen patients with black PTC metastases (black-PTC) were compared to a control cohort of 15 patients with nonblack PTC metastasis (nonblack PTC). Each sample was evaluated for the histological characteristics, BRAF V600E mutational status, and associated patient clinical data. RESULTS: The degree of cystic degeneration (80% vs. 27%, p=0.004), percent hemosiderin deposition (20% vs. 6%, p=0.001), and presence of classical variant (100% vs. 67%, p=0.018) were significantly greater in black PTC than nonblack PTC (alpha=0.05). Other results were not significantly different. CONCLUSION: This study demonstrates that black compared to nonblack metastases have a greater degree of cystic degeneration and hemosiderin deposition leading to discoloration, and a trend toward an increased incidence in BRAF V600E mutations. This study is the first of its kind to describe the clinical, pathological, and genetic features associated with black PTC lymph-node metastasis. PMID- 23343223 TI - A longitudinal assessment of work situation, sick leave, and household income of mothers and fathers of children with cancer in Sweden. AB - BACKGROUND: The diagnosis of childhood cancer often results in an altered life situation for the parents, characterized by difficulties regarding work, family and household demands. Previous research shows that parents' work situation and income are impacted, yet, few studies have explored the issue from a longitudinal perspective. This study sought to increase the knowledge about the socio-economic conditions of parents of children with cancer in Sweden by means of a longitudinal assessment of work situation, sick leave, and household income. MATERIAL AND METHODS: The sample consisted of mothers (n = 139) and fathers (n = 138) of children with cancer recruited from 2002 to 2004. Data was collected by telephone interviews at six time points, ranging from the time of diagnosis to one year after the end of treatment. RESULTS: Findings showed that parents' work situation was most evidently impacted during the child's treatment, when the greatest proportions of non-working and sick-listed parents were found. Compared with the time of diagnosis, fewer mothers worked up to three months after the end of treatment, and more mothers were on sick leave one year after the end of treatment. Although the extent of sick leave among fathers did not differ compared with the time of diagnosis, fewer fathers worked one year after the end of treatment. Household income was significantly reduced during the child's treatment and months thereafter, while income was at an equal level as before the diagnosis for most families one year after the end of treatment. CONCLUSION: The results offer a unique understanding of how mothers' and fathers' work situation and income are impacted in the short- and long-term, and give guidance on how to improve the comprehensive support given to parents of children with cancer. Socio economical issues should be emphasized as these may provide targets for policy interventions aiming to reduce parental strain related to work and finances. PMID- 23343224 TI - The prevalence of immunohistochemically determined oestrogen receptor positivity in primary breast cancer is dependent on the choice of antibody and method of heat-induced epitope retrieval - prognostic implications? AB - BACKGROUND: Oestrogen receptor (ER) status is important for the choice of systemic treatment of breast cancer patients. However, most data from randomised trials on the effect of adjuvant endocrine therapy according to ER status are based on the cytosol methods. Comparisons with immunohistochemical methods have given similar results. The aim of the present study was to examine whether different ER antibodies and heat-induced epitope retrieval (HIER) methods influence the prevalence of ER-positivity in primary breast cancer. MATERIAL AND METHODS: This study is based on patients included in a clinical trial designed to compare the effect of two years of adjuvant tamoxifen versus no adjuvant systemic treatment in premenopausal women. From 1986 to 1991, 564 patients from two study centres in Sweden were enrolled and randomised. Patients were randomised independently of ER status. In the present study, ER status was assessed on tissue microarrays with the three different ER antibody/HIER combinations: 1D5 in citrate pH 6 (n = 390), SP1 in Tris pH 9 (n = 390) and PharmDx in citrate pH 6 (n = 361). RESULTS: At cut-offs of 1% and 10%, respectively, the prevalence of ER positivity was higher with SP1 (75% and 72%) compared with 1D5 (68% and 66%) and PharmDx (66% and 62%). At these cut-offs, patients in the discordant groups (SP1 positive and 1D5-negative) seem to have a prognosis intermediate between those of the double-positive and double-negative groups. Comparison with the ER status determined by the cytosol-based methods in the discordant group also showed an intermediate pattern. The repeatability was good for all antibodies and cut-offs, with overall agreement >= 93%. CONCLUSION: The present study shows that the choice of antibody and HIER method influences the prevalence of ER-positivity. We suggest that this be taken into consideration when choosing a cut-off for clinical decision making. PMID- 23343225 TI - Increasing the efficiency of the transannular Diels-Alder strategy via palladium(II)-catalyzed macrocyclizations. AB - Palladium(II)-catalyzed macrocyclizations of bis(vinylboronate ester) compounds are demonstrated to provide a strategically efficient approach to transannular Diels-Alder reaction substrates. In several systems reported, the macrocycle is preorganized such that cycloaddition at room temperature occurs concomitantly with cyclization. Numerous advantages over palladium(0)-catalyzed cross-coupling approaches are demonstrated. PMID- 23343226 TI - Relationship between the structures of flavonoids and oxygen radical absorbance capacity values: a quantum chemical analysis. AB - Various radical-scavenging activities (RSA) assessment assays are based on discrete mechanisms and on using different radical sources. Few studies have analyzed the structural significance of flavonoids in their peroxyl radical activities in the oxygen radical absorbance capacity (ORAC) assay. In this study, the RSA of 13 flavonoids in two ORAC assays with different probes (fluorescein and pyrogallol red) were investigated. Neither O-H bond dissociation enthalpy nor ionization potential values of flavonoids correlated with ORAC values. The proton affinity (PA) and electron transfer enthalpy (ETE) values, which were obtained via the sequential proton-loss electron-transfer mechanism, were significantly associated with the ORAC(pyrogallol Red) and ORAC(fluorescein) assays, respectively. Thus, PA represented the kinetic aspect of RSA, whereas ETE reflected the RSA extent. The PA values and the most acidic sites of flavonoids were affected by intramolecular electronic interactions, H-bonding, 3-hydroxyl group in the C ring, and conjugation systems. The stability of the deprotonated flavonoid determined the ETE value. Apart from the PA and ETE values in the first oxidation step of flavonoids, the PA and ETE values in the second oxidation step also affected the ORAC values of flavonoids. PMID- 23343227 TI - Assessing risk post intervention for an acute coronary syndrome: a review of the risk assessment tools and their development. AB - Considerable variability in survival rate after an acute myocardial infarction exists and accurate risk stratification is of significant importance. The American College of Cardiology and the American Heart Association has recommended early risk stratification using several clinical risk scoring instruments to identify high risk patients. The aim of this paper is to identify secondary cardiovascular risk scoring instruments that could be utilized at the time of intervention for acute coronary syndromes and compare their psychometric properties as they were developed. A search using Medline, Cumulative Index to Nursing and Allied Health Literature and the Psychology and Behavioral Sciences Collection databases identified studies published between January 1990 and January 2010 used to measure risk after intervention for acute coronary syndrome. Four validated secondary risk prediction scoring instruments were identified for comparison. Secondary risk prediction scoring instruments for the acute coronary syndrome patient population are evidence based, valid and reliable. Use of the instruments by cardiac focused clinicians will aid in the determination of treatment strategies, and estimation of short and long term events and mortality. PMID- 23343228 TI - Goal setting in cardiac rehabilitation: implications for clinical practice. AB - BACKGROUND: Effective goal setting is a vital component of cardiac rehabilitation (CR) programs. OBJECTIVE: The objectives of this study were to investigate the types of goals set by patients attending a CR program in a tertiary teaching hospital and the compatibility of the goals set with the patient's risk factor profile. METHODS: A descriptive, cross sectional, retrospective audit of the medical records of patients who attended the CR program in a tertiary teaching hospital in Sydney NSW between January 2007 and December 2009 was undertaken. The medical records of 355 patients who attended CR within the stipulated time frame were audited. RESULTS: Short and long term goals were set by 104 and 50 patients, respectively. Four themes identified in the analysis of the goal data were reducing behavioural risk factors for further cardiovascular events, improvements in physical symptoms, enhancing mental well being and return to normal life. The majority of the goals related to physical activity (82%). CONCLUSION: Collaborative goal setting and the need to establish goals that are attainable and correspond with the patient's health behaviours and clinical measures that require modification is vital. PMID- 23343229 TI - Reason's accident causation model: application to adverse events in acute care. AB - Adverse events are unintended harm to a patient caused by the health care provided; more than half of all these events have been deemed avoidable. Adverse events are a common problem in acute care and represent a breach in care quality and safety. They are generally not caused by a single mistake or error and although safety barriers exist in health care, patients today are still harmed. Using an accident causation model is a constructive way of identifying the underlying causes of adverse events and to strengthen a study's theoretical underpinnings. Reason's model is recommended as a useful framework for adverse event analysis as it promotes a focus on the conditions or situation in which the clinician was trying to perform, rather than apportioning blame. PMID- 23343230 TI - Reducing time to analgesia in the emergency department using a nurse-initiated pain protocol: a before-and-after study. AB - Suboptimal management of pain in emergency departments (EDs) remains a problem, despite having been first described over two decades ago. A 'before-and-after' intervention study (with a historical control) was undertaken in one Western Australian tertiary hospital ED to test the effect of a 'nurse-initiated pain protocol' (NIPP) intervention. A total of 889 adult patients were included: 144 in the control group and 745 in the intervention group. Patients in the intervention group were: More likely to have a pain score recorded than those in the control group; have reduced median time to the first pain score; and reduced time to analgesia. The statistically significant reduction in both time to pain score and time to analgesia remained, even when adjusted by age and sex. Whilst we demonstrated the safety and efficacy of a NIPP in ED, an unacceptable proportion of patients continued to have inadequate pain relief. PMID- 23343231 TI - Self-efficacy, professional commitment, and job satisfaction of diabetic medical care personnel. AB - The purpose of this study was to investigate the relationships among the self efficacy, professional commitment, and job satisfaction of diabetic health-care personnel. The research design was cross-sectional. Three teaching hospitals, one from each of northern, middle and southern parts of Taiwan, were selected for data collection and used questionnaires to collect data; 202 participants were recruited. The demographic data for job title and job satisfaction were not significantly different (F = 2.13, P = 0.090). Self-efficacy was significantly positively correlated with professional commitment (r = 0.29, P = 0.000) and with job satisfaction (r = 0.14, P = 0.041). A total of 34.1% of the variance in job satisfaction was explained by age, years of service in the medical or nursing field, the actual number of years caring for patients with diabetes, self efficacy, and professional commitment. Understanding the self-efficacy and professional commitment of medical and nursing personnel can help increase job satisfaction and improve the quality of medical and nursing care. PMID- 23343232 TI - Evaluation of reproductive health and sexual behaviors of university students: case study from Istanbul. AB - BACKGROUND: Young people are affected to a higher extent by early and unprotected sexual relations in Turkey. They do not have healthy sexual attitudes, are ignorant about reproductive health and engage in risky practices and behavior. It is therefore necessary to provide effective and confidential reproductive health services to young people. OBJECTIVE: This study was designed to evaluate the reproductive health behaviors of male and female university students. METHODS: This descriptive study was conducted between January and May 2008. The study population was composed of university students from Istanbul University, Florence Nightingale Nursing High School, Faculty of Forestry and Department of Science Teachers' Training, as well as students residing at the Students Dormitory of the Regional Directory of Forestry. Questionnaires were distributed in envelopes during the breaks in the university buildings, cafeterias and in the dormitories. Completed questionnaires were also collected under cover in envelopes. The data were collected by four students from the nursing school. RESULTS: A total of 647 students were enrolled. Among the participants, 75% (N = 490) were female students and 24.3% (N = 157) were male students. The mean age was 21.38 (SD = 1.92). The rate of sexually active participants was 26% (N = 169) and the rate of participants who masturbated was 36% (N = 233). The rate of using a family planning method was determined as 25% (N = 163) and the most frequently used family planning method was use of condoms (67.4%). The rate of pregnancy was determined as 1.5% and the rate of abortion was 1.4%. In 69% of the students, the main source of knowledge on sexuality was the internet. The rate of students stating that sexually transmitted diseases are transmitted by sexual intercourse and via blood was 72.6%, and the percentage of students who were vaccinated against Hepatitis B was 61.8%. CONCLUSION: Twenty-six percent of the students are sexually active and students are unable to reach information on reproduction and sexual health through reliable sources. These results indicate the need for organization of health education programs for university students with regard to reproductive and sexual health. PMID- 23343233 TI - Behind the rhetoric: is palliative care equitably available for all? AB - Disparities in access to health care also extend to the end-of-life care. Despite the general principle that palliative care is equitably available for all in need, it remains underutilised by certain groups in the community. Ethnic minorities, older people and patients with non-cancer diseases are found to be at a greatest risk for underutilisation of palliative care. Barriers to access palliative care by these groups in the community are complex and often overlapping. To overcome these barriers, there is a need to take action on many fronts. This paper discusses these barriers and provides an overview of the strategies that have been implemented to address these issues. PMID- 23343234 TI - Parent satisfaction with early parenting residential services: a telephone interview study. AB - Early parenting residential units provide a child and family health support and education service for parents experiencing parenting difficulties. An ongoing concern of nursing staff and management is whether the parenting knowledge and skills gained are translated into sustainable parenting practices after discharge. This paper explores the response to a post discharge telephone interview about parents' experience of nursing care during their residential stay and their parenting experience since discharge. A descriptive qualitative approach identified four themes in the parents' responses: greater confidence, greater knowledge about their babies, changing expectations of parenting and their infants, and sustainability of parenting skills. PMID- 23343235 TI - Conflict resolution styles in the nursing profession. AB - BACKGROUND: Managers, including those in nursing environments, may spend much of their time addressing employee conflicts. If not handled properly, conflict may significantly affect employee morale, increase turnover, and even result in litigation, ultimately affecting the overall well-being of the organization. A clearer understanding of the factors that underlie conflict resolution styles could lead to the promotion of better management strategies. OBJECTIVE: The aim of this research was to identify the predominant conflict resolution styles used by a sample of Spanish nurses in two work settings, academic and clinical, in order to determine differences between these environments. The effects of employment level and demographic variables were explored as well. DESIGN: Descriptive cross-sectional survey study. PARTICIPANTS: Our sample consisted of professional nurses in Madrid, Spain, who worked in either a university setting or a clinical care setting. Within each of these environments, nurses worked at one of three levels: full professor, assistant professor, or scholarship professor in the academic setting; and nursing supervisor, registered staff nurse, or nursing assistant in the clinical setting. METHODS: Conflict resolution style was examined using the standardized Thomas-Kilmann Conflict Mode Instrument, a dual-choice questionnaire that assesses a respondent's predominant style of conflict resolution. Five styles are defined: accommodating, avoiding, collaborating, competing, and compromising. Participants were asked to give answers that characterized their dominant response in a conflict situation involving either a superior or a subordinate. Descriptive and inferential statistics were used to examine the relationship between workplace setting and conflict resolution style. RESULTS: The most common style used by nurses overall to resolve workplace conflict was compromising, followed by competing, avoiding, accommodating, and collaborating. There was a significant overall difference in styles between nurses who worked in an academic vs. a clinical setting (p = 0.005), with the greatest difference seen for the accommodating style. Of those nurses for whom accommodation was the primary style, 83% worked in a clinical setting compared to just 17% in an academic setting. CONCLUSION: Further examination of the difference in conflict-solving approaches between academic and clinical nursing environments might shed light on etiologic factors, which in turn might enable nursing management to institute conflict management interventions that are tailored to specific work environments and adapted to different employment levels. This research increases our understanding of preferred approaches to handling conflict in nursing organizations. PMID- 23343236 TI - Nursing image: an evolutionary concept analysis. AB - A long-term challenge to the nursing profession is the concept of image. In this study, we used the Rodgers' evolutionary concept analysis approach to analyze the concept of nursing image (NI). The aim of this concept analysis was to clarify the attributes, antecedents, consequences, and implications associated with the concept. We performed an integrative internet-based literature review to retrieve English literature published from 1980-2011. Findings showed that NI is a multidimensional, all-inclusive, paradoxical, dynamic, and complex concept. The media, invisibility, clothing style, nurses' behaviors, gender issues, and professional organizations are the most important antecedents of the concept. We found that NI is pivotal in staff recruitment and nursing shortage, resource allocation to nursing, nurses' job performance, workload, burnout and job dissatisfaction, violence against nurses, public trust, and salaries available to nurses. An in-depth understanding of the NI concept would assist nurses to eliminate negative stereotypes and build a more professional image for the nurse and the profession. PMID- 23343237 TI - Evaluating the effect of self-awareness and communication techniques on nurses' assertiveness and self-esteem. AB - The effect of a course on self-awareness and communication techniques on nursing students' assertiveness and self-esteem was examined. The Rathus Assertiveness Schedule and Coopersmith Self-Esteem Inventory were used to measure assertiveness and self-esteem in second-year students in an undergraduate nursing school. Seventy-nine students completed the course. The study was designed as a pre-test and post-test study. A significant difference between assertiveness and self esteem scores of students in pre-test and post-test measurements was found. There was a positive relationship between assertiveness and self-esteem. The course lasted 14 weeks for a total of 3 h per week. The teaching methods focused mostly on active student participation, demonstration, role play, experience and experience sharing, homework, constructive feedback, and watching films. These educational approaches should be evaluated in future studies and adopted in the curriculum. This study provides a basis for the development of learner-centred teaching methods. PMID- 23343238 TI - Professional nursing governance in a large Australian health service. AB - BACKGROUND: Professional nursing governance refers to the processes and structures that influence nursing practice within an organisation. This study measured the effect of structured meeting communication processes on nurses' perceptions of professional governance. METHOD: The intervention was implemented in eight hospital wards. After 3 months, nurses on the intervention wards and eight matched-control wards completed the Index of Professional Nursing Governance (N = 225). Data were compared with a sample of Magnet((r)) (N = 3) and non-Magnet (N = 46) hospitals. RESULTS: There was substantial variation in nurses' perceptions of governance across the 16 wards, irrespective of the intervention. Compared to non-Magnet hospitals, the overall score and three of the six subscales scores were higher in this study. Magnet hospitals scores, however, were typically higher suggesting greater progress towards shared governance. CONCLUSIONS: Professional nursing governance can be highly variable across individual wards and tailored interventions should be considered. PMID- 23343239 TI - Students' corner: using Te Tiriti O Waitangi to identify and address racism, and achieve cultural safety in nursing. AB - Racism is an idea and belief that some races are superior to others (Harris et al., 2006a). This belief justifies institutional and individual practices that create and reinforce oppressive systems, inequality among racial or ethnic groups, and this creates racial hierarchy in society (Harris et al., 2006a). Recent studies have emphasised the impact of racism on ethnic health inequality (Harris et al., 2006a). In this article we analyse and discuss how nurses can challenge and reduce racism at interpersonal and institutional levels, and improve Maori health outcomes by understanding and using cultural safety in nursing practice and understanding Te Tiriti O Waitangi. PMID- 23343240 TI - The effect of supportive counseling program on the academic performance of nursing and midwifery students. AB - INTRODUCTION: Poor academic performance in universities is a worrying issue, imposing extra finance on the government. This study was conducted to discover if supportive counseling program (SCP) has any effects on the academic performance of students. METHODS: Sixty nursing and midwifery Iranian students with poor academic performance participated in this quasi-experimental semester-long study. They were balanced by gender, major, years of study, and grade average. They were divided into intervention and control groups, the former attended the SCP. Finally the grade averages of the groups before and after the intervention were calculated. RESULTS: An independent t-test revealed a significant difference between the grade averages of the two groups (p = 0.01); similar results were obtained for theoretical courses' grade averages (p = 0.03). Also, a paired t test indicated a significant difference between the grade averages of the intervention group pre and post-intervention (p < 0.0001). CONCLUSION: Findings favored designing and carrying out SCP for students, especially for those with poor academic performance. The effect of SCP on the academic performance of nursing and midwifery students. PMID- 23343241 TI - Flight nurses in Australia: maintaining their midwifery competence - a case study. AB - Flight nurses (FNs) in Australia care for a wide diversity of patients as sole practitioners. No studies could be located regarding how FNs maintain their midwifery competence. The purpose of this study was to investigate how levels of competence in midwifery practice are determined amongst Australian FNs and explore if continuing professional development (CPD) contributes to the maintenance of FN's midwifery clinical skills and knowledge. Data was collected using computer mediated communication and content analysed using a thematic framework. The results of this study showed that the maintenance of current midwifery practice was complex due to the low numbers of midwifery patients cared for by FNs. CPD was identified as essential however this research demonstrated a lack of motivation by this small group of FNs to attend CPD, mainly due to the absence of a programme that recognises the different context and scope of their practice. PMID- 23343242 TI - Effect of pre-transition stimulus duration on acoustic change complex. AB - OBJECTIVE: To investigate the effect of pre-transition duration on acoustic change complex (ACC) for speech and tonal stimulus. DESIGN: Cortical potentials were recorded for consonant-vowel syllable and tonal complex stimuli with varying pre-transition durations. STUDY SAMPLE: Ten individuals (three male and seven female) in the age range from 18 to 26 years, with normal hearing sensitivity, participated in the study. RESULTS: The results revealed that a minimum pre transition duration of 100 ms for tonal stimulus (with spectral change) and 80 ms for consonant-vowel syllable is necessary in order to elicit ACC. The latency of N1(1) and P2(1), which is the response for change within the ongoing stimulus, increased with increase in pre-transition duration. The amplitude of the evoked responses did not show any significant change. CONCLUSIONS: It was found that minimum pre-transition duration required in eliciting ACC for speech and non speech stimulus is not same. The speech stimulus required lesser duration of pre transition than non-speech stimulus. Further studies regarding the acoustic aspects of sound on CAEP in isolation are warranted. PMID- 23343243 TI - Tympanometric measures in ears with negative middle ear pressure, and tests of some common assumptions. AB - OBJECTIVE: To test the assumptions concerning the compensation of middle ear pressure (MEP) in using peak Y(tm) and the tympanogram asymmetry phenomenon, and to address the variability and reliability of 226 Hz tympanometry under negative MEP. DESIGN: (1) Repeated measures in normal ears with experimentally-induced negative MEP; (2) Retrospective analysis of clinical data from ears with negative MEP. STUDY SAMPLE: Experimental data: 57 adult ears. CLINICAL DATA: 200 adult ears. RESULTS: Mean peak Y(tm) significantly increased (~ 0.10 mmhos) under negative MEPs (> - 190 daPa). TW increased, up to ~50 daPa, for MEP <= - 130 daPa. V(ea) decreased when MEP <= - 190 daPa. With increasing negative MEP, peak Y(tm) and tympanogram gradient tended to decrease. The within-subject variation of all measures and difference between normal and negative MEP were small. CONCLUSIONS: The tympanometry procedure increases peak Y(tm )in ears with low to moderate negative MEP, and decreases gradient and V(ea) with high negative MEP. This is referred to as hypercorrection of the admittance and should be accounted for in clinical norms. Results imply that tympanogram asymmetry is due to divergent effects of air pressure on the middle ear. The variability of tympanometry does not increase and reliability not decrease under negative MEP. PMID- 23343244 TI - Clinical association between teeth malocclusions, wrong posture and ocular convergence disorders: an epidemiological investigation on primary school children. AB - BACKGROUND: As the various systems in the body are inter-connected to form a single structural unit, a pathological condition in one area can also affect other areas. There are many known correlations between the visual and motor system. The importance of visual function, particularly the paracentral peripheral field of view, in motor coordination, ambulation and the maintenance of balance has been amply demonstrated.In line with current medical principles, which are moving towards a more holistic view of the human body, this study aims to investigate, in an interdisciplinary manner, the incidence of dental malocclusions together with posture and eye convergence disorders. METHODS: Six hundred and five children attending at the 3rd, 4th and 5th years of seven Genoa primary schools were examined. Each child underwent the following examinations: (i) dental/occlusal; (ii) orthoptic; and (iii) postural. Occlusal data concerned the presence of cross-bite, midline deviation with a mandibular shift, bad habits and deep or open bite.Postural assessment involved frontal and lateral inspection, investigation during trunk flexion and ambulation, and note of any asymmetry in the lower limbs. The recorded orthoptic data included those pertaining to ocular dominance, a cover test, convergence and the Brock string test. RESULTS: A prevalence of cases with an unphysiological gait was found in patients with overjet (14.70%) or overbite (14.87%), while the percentage of patients with normal occlusion that showed an unphysiological gait was 13.08%. Also, about 93.8%-94.2% of children showed normal legs without dysmetry, with no difference in respect to the type of occlusion. Subjects with an open bite or deep bite showed a slightly different distribution of right or left dominant eyes. CONCLUSION: About 13% of children showed a pathological gait and, among them, vertical anomalies of occlusion (deep bite or open bite) were prevalent with respect to the other occlusal defects. The vertical dimension of occlusion revealed a slight relationship with the proper dominant eye. Postural, orthoptic, osteopathic and occlusal variables were often clinically associated, and therefore these disorders appear to request a multidisciplinary medical approach for their treatment. PMID- 23343245 TI - Surveillance of Bungowannah pestivirus in the upper Midwestern USA. AB - Pestiviruses, a genetically and antigenically highly diverse group, include one of the most historically significant swine pathogens, that is, classical swine fever virus. In Australia, investigations into swine outbreaks characterized by neonatal mortality, stillbirths and mummified foetuses resulted in the discovery of a new pestivirus, Bungowannah virus. This finding raised the possibility that Bungowannah virus, or a variant thereof, was circulating in swine herds elsewhere in the World. If so, it raised the possibility of a pestivirus emerging as a new swine disease with unknown consequences for animal health and food safety. Thus, we developed three specific qRT-PCR assays to evaluate tissue samples from undiagnosed cases of abortion or respiratory disease for evidence of Bungowannah virus. Examination of 64 samples collected between the Fall of 2007 and Spring of 2010 tested negative for all three genes examined. We conclude that Bungowannah like pestivirus is unlikely to be present in swine in the upper Midwestern USA. PMID- 23343246 TI - How do anions affect self-assembly and solubility of cetylpyridinium surfactants in water. AB - We report the specific effects of a series of anions (chloride, nitrate, and oxalate) on the solubility and self-assembly of cationic cetylpyridinium surfactants in water. The anion influence on micellization was evidenced by tensiometry and determination of Krafft temperatures. Anions strongly affect these parameters, depending on their position in the lyotropic series as well as on their "bridging" character. Scattering techniques (light, X-rays, and neutrons) were used to characterize the structures of micelles, and by solving a lateral equation of state approach, we show that chaotropic anions can be considered as adsorbed on the pyridinium head groups, inducing a decrease of the surface polarity and a Krafft temperature shift. Mixing different counteranions in various ratios led to a competition with a preferential adsorption at the micellar surface. PMID- 23343247 TI - Diniobium inverted sandwich complexes with MU-eta6:eta6-arene ligands: synthesis, kinetics of formation, and electronic structure. AB - Monometallic niobium arene complexes [Nb(BDI)(N(t)Bu)(R-C(6)H(5))] (2a: R = H and 2b: R = Me, BDI = N,N'-diisopropylbenzene-beta-diketiminate) were synthesized and found to undergo slow conversion into the diniobium inverted arene sandwich complexes [[(BDI)Nb(N(t)Bu)](2)(MU-RC(6)H(5))] (7a: R = H and 7b: R = Me) in solution. The kinetics of this reaction were followed by (1)H NMR spectroscopy and are in agreement with a dissociative mechanism. Compounds 7a-b showed a lack of reactivity toward small molecules, even at elevated temperatures, which is unusual in the chemistry of inverted sandwich complexes. However, protonation of the BDI ligands occurred readily on treatment with [H(OEt(2))][B(C(6)F(5))(4)], resulting in the monoprotonated cationic inverted sandwich complex 8 [[(BDI(#))Nb(N(t)Bu)][(BDI)Nb(N(t)Bu)](MU-C(6)H(5))][B(C(6)F(5))(4)] and the dicationic complex 9 [[(BDI(#))Nb(N(t)Bu)](2)(MU-RC(6)H(5))][B(C(6)F(5))(4)](2) (BDI(#) = (ArNC(Me))(2)CH(2)). NMR, UV-vis, and X-ray absorption near-edge structure (XANES) spectroscopies were used to characterize this unique series of diamagnetic molecules as a means of determining how best to describe the Nb-arene interactions. The X-ray crystal structures, UV-vis spectra, arene (1)H NMR chemical shifts, and large J(CH) coupling constants provide evidence for donation of electron density from the Nb d-orbitals into the antibonding pi system of the arene ligands. However, Nb L(3,2)-edge XANES spectra and the lack of sp(3) hybridization of the arene carbons indicate that the Nb -> arene donation is not accompanied by an increase in Nb formal oxidation state and suggests that 4d(2) electronic configurations are appropriate to describe the Nb atoms in all four complexes. PMID- 23343250 TI - Cost-utility analysis of antihypertensive medications in Nigeria: a decision analysis. AB - BACKGROUND: Many drugs are available for control of hypertension and its sequels in Nigeria but some are not affordable for majority of the populace. This serious pharmacoeconomic question has to be answered by the nation's health economists. The objective of this study was to evaluate the cost-effectiveness of drugs from 4 classes of antihypertensive medications commonly used in Nigeria in management of hypertension without compelling indication to use a particular antihypertensive drug. METHODS: The study employed decision analytic modeling. Interventions were obtained from a meta-analysis. The Markov process model calculated clinical outcomes and costs during a life cycle of 30 years of 1000 hypertensive patients stratified by 3 cardiovascular risk groups, under the alternative intervention scenarios. Quality adjusted life year (QALY) was used to quantify clinical outcome. The average cost of treatment for the 1000 patient was tracked over the Markov cycle model of the alternative interventions and results were presented in 2010 US Dollars. Probabilistic cost-effectiveness analysis was performed using Monte Carlo simulation, and results presented as cost effectiveness acceptability frontiers. Expected value of perfect information (EVPI) and expected value of parameter perfect information (EVPPI) analyses were also conducted for the hypothetical population. RESULTS: Thiazide diuretic was the most cost-effective option across the 3 cardiovascular risk groups. Calcium channel blocker was the second best for Moderate risk and high risk with a willingness to pay of at least 2000$/QALY. The result was robust since it was insensitive to the parameters alteration. CONCLUSIONS: The result of this study showed that thiazide diuretic followed by calcium channel blocker could be a feasible strategy in order to ensure that patients in Nigeria with hypertension are better controlled. PMID- 23343249 TI - Intestinal biopsy is not always required to diagnose celiac disease: a retrospective analysis of combined antibody tests. AB - BACKGROUND: The objective of this study was to compare celiac disease (CD)- specific antibody tests to determine if they could replace jejunal biopsy in patients with a high pretest probability of CD. METHODS: This retrospective study included sera from 149 CD patients and 119 controls, all with intestinal biopsy. All samples were analyzed for IgA and IgG antibodies against native gliadin (ngli) and deamidated gliadin peptides (dpgli), as well as for IgA antibodies against tissue transglutaminase and endomysium. RESULTS: Tests for dpgli were superior to ngli for IgG antibody determination: 68% vs. 92% specificity and 79% vs. 85% sensitivity for ngli and dpgli, respectively. Positive (76% vs. 93%) and negative (72% vs. 83%) predictive values were also higher for dpgli than for ngli. Regarding IgA gliadin antibody determination, sensitivity improved from 61% to 78% with dpgli, while specificity and positive predictive value remained at 97% (P < 0.00001). A combination of four tests (IgA anti-dpgli, IgG anti-dpgli, IgA anti- tissue transglutaminase, and IgA anti-endomysium) yielded positive and negative predictive values of 99% and 100%, respectively and a likelihood ratio positive of 86 with a likelihood ratio negative of 0.00. Omitting the endomysium antibody determination still yielded positive and negative predictive values of 99% and 98%, respectively and a likelihood ratio positive of 87 with a likelihood ratio negative of 0.01. CONCLUSION: Antibody tests for dpgli yielded superior results compared with ngli. A combination of three or four antibody tests including IgA anti-tissue transglutaminase and/or IgA anti- endomysium permitted diagnosis or exclusion of CD without intestinal biopsy in a high proportion of patients (78%). Jejunal biopsy would be necessary in patients with discordant antibody results (22%). With this two-step procedure, only patients with no CD specific antibodies would be missed. PMID- 23343251 TI - Ethnobotanical study of plants used in management of livestock health problems by Afar people of Ada'ar District, Afar Regional State, Ethiopia. AB - BACKGROUND: The great majority of the Afar people of Ethiopia are pastoralists, highly dependent on livestock and livestock products. Livestock productivity is, however, frequently affected by different diseases. Although many districts in the Region have veterinary clinics, they lack basic facilities. As a result, the Afar people are still dependent on local materials, mainly plants, and traditional knowledge to manage livestock health problems. However, there is a serious threat to such local resources mainly due to recurrent drought and influence of modernization. Hence there is a need for proper documentation and evaluation of the existing ethnoveterinary knowledge in the Region. This study was aimed at documenting and analysing ethnoveterinary knowledge of people in Ada'ar District of the Afar Region associated with the use of plants. METHODS: The study involved interviewing selected knowledgeable Afar people in Ada'ar District on the use of plants to manage livestock ailments. Fidelity Level (FL) values were calculated for the reported medicinal plant to estimate their healing potentials. Specimens of reported medicinal plant were collected, identified and deposited at the National Herbarium, Addis Ababa University. RESULTS: The study revealed 49 medicinal plants as being used by the Afar people of Ada'ar District for the treatment of various livestock ailments, the majority of which (67.3%) were shrubs. Highest number of medicinal plants was used to treat blackleg, contagious caprine pleuropneumonia (CCPP), sudden sickness and pneumonia. Leaf was the most frequently sought plant part, accounting for 47% of the reported plants. All the medicnal plants used in the District were uncultivated ones growing in semi-disturbed and disturbed habitats as remnant plants and weeds. Cissus quadrangularis and Solanum incanum were the plants scoring the highest fidelity level values for their use to treat blackleg and respiratory tract problems, respectively. CONCLUSION: The study revealed that there is still rich knowledge of ethnoveterinary medicine in Ada'ar District. There was no habit of cultivating medicinal plants by people in the study area. Efforts, should, therefore, be made to protect these medicinal plants from further depletion, especially those that are scarcely available. Better attention should be given to medicinal plants with the highest fidelity level values as such values could indicate potencies of the plants. PMID- 23343253 TI - Peri-operative physiotherapy. AB - Postoperative pulmonary complications (PPC) are a major cause of morbidity, mortality, prolonged hospital stay, and increased cost of care. Physiotherapy (PT) programs in post-surgical and critical area patients are aimed to reduce the risks of PPC due to long-term bed-rest, to improve the patient's quality of life and residual function, and to avoid new hospitalizations. At this purpose, PT programs apply advanced cost-effective therapeutic modalities to decrease complications and patient's ventilator-dependency. Strategies to reduce PPC include monitoring and reduction of risk factors, improving preoperative status, patient education, smoking cessation, intra-operative and postoperative pulmonary care. Different PT techniques, as a part of the comprehensive management of patients undergoing cardiac, upper abdominal, and thoracic surgery, may prevent and treat PPC such as secretion retention, atelectasis, and pneumonia. PMID- 23343252 TI - Bioluminescence imaging of leukemia cell lines in vitro and in mouse xenografts: effects of monoclonal and polyclonal cell populations on intensity and kinetics of photon emission. AB - BACKGROUND: We investigated the utility of bioluminescence imaging (BLI) using firefly luciferase in monoclonal and polyclonal populations of leukemia cells in vitro and in vivo. METHODS: Monoclonal and polyclonal human lymphoid and myeloid leukemia cell lines transduced with firefly luciferase were used for BLI. RESULTS: Kinetics and dynamics of bioluminescence signal were cell line dependent. Luciferase expression decreased significantly over time in polyclonal leukemia cells in vitro. Transplantation of polyclonal luciferase-tagged cells in mice resulted in inconsistent signal intensity. After selection of monoclonal cell populations, luciferase activity was stable, equal kinetic and dynamic of bioluminescence intensity and strong correlation between cell number and light emission in vitro were observed. We obtained an equal development of leukemia burden detected by luciferase activity in NOD-scid-gamma mice after transplantation of monoclonal populations. CONCLUSION: The use of monoclonal leukemia cells selected for stable and equal luciferase activity is recommended for experiments in vitro and xenograft mouse models. The findings are highly significant for bioluminescence imaging focused on pre-clinical drug development. PMID- 23343254 TI - Structure and physical properties of zein/pluronic f127 composite films. AB - Triblock copolymer Pluronic F127 has been used to form composites with zein, a corn protein and coproduct of the bioethanol industry, to alleviate its natural brittleness. At low F127 loadings (0-35%), the plasticizing effect was dominant, and the elongation at break of zein composite film containing 35% F127 was about 8-fold higher than that of the zein film with 10% F127. At high F127 loadings (50 100%), a large number of lamellae crystals were formed in the film matrix as verified by a combination of differential scanning calorimetry (DSC), atomic force microscopy (AFM), and small-angle X-ray scattering (SAXS). The F127 crystallization surpassed its plasticizing effect, resulting in an increased brittleness of zein film with the further increase of F127 loading. Compared with the flat-on lamellae of pure F127, F127 chains folded into branch-like lamellar structures in the zein composite film containing 50% F127 due to the confinement of amorphous zein. Besides, the crystals in zein films were composed of extended chain integral folding (IF = 0) and once-folded chain (IF = 1) polyethylene oxide (PEO) crystals, and the portion of once-folded chain (IF = 1) PEO crystals increased with F127 loading. Thus, through investigation of the competition of plasticizing effect and crystal formation under different F127 loadings, the optimized F127 loading in zein/F127 composite film with a good overall performance was determined to be at around 35%. PMID- 23343255 TI - Isolation and crystallographic characterization of Sm@C2v(3)-C80 through cocrystal formation with Ni(II)(octaethylporphyrin) or bis(ethylenedithio)tetrathiafulvalene. AB - Sm@C(2v)(3)-C(80) has been separated from the carbon soot produced by electrical arc vaporization of graphite rods doped with Sm(2)O(3) and purified. Its structure has been determined by single crystal X-ray diffraction using cocrystals obtained from either Ni(II)(octaethylporphyrin) (Ni(II)(OEP)) to form Sm@C(2v)(3)-C(80).Ni(II)(OEP).1.68(toluene).0.32(benzene) or bis(ethylenedithio) tetrathiafulvalene (ET) to produce Sm@C(2v)(3)-C(80).ET.0.5(toluene). Thus, this study offers the first opportunity to compare a common endohedral fullerene in two different cocrystals. Both cocrystals provide consistent information on the basic structure of Sm@C(2v)(3)-C(80) but show that the distribution of samarium ion sites inside the carbon cage depends upon whether Ni(II)(OEP) or ET is present. The samarium ion is disordered in both structures, but the prominent sites lie slightly off the 2-fold symmetry axis of the cage. Computational studies at the B3LYP level indicate that Sm@C(2v)(3)-C(80) is more stable than any of the other six isomers of Sm@C(80) that obey the isolated pentagon rule (IPR). The surface electrostatic potential of the interacting components in the cocrystals has been examined to identify factors responsible for the ordering of the fullerene cages. The regions of the Ni(II)(OEP) or ET molecules that are closest to the fullerene display negative potential, while the corresponding regions of the endohedral fullerene show positive potential in a consistent fashion in both cocrystals. PMID- 23343256 TI - The Office for the Advancement of Telehealth. PMID- 23343257 TI - Telehealth at UC Davis--a 20-year experience. AB - Telehealth at the University of California Health System began as a telefetal monitoring connection with a rural hospital in 1992 and evolved to become the Center for Health and Technology (CHT) in 2000. The Center supports the vision of the University of California Davis (UC Davis) Health System-a healthier world through bold innovation. The CHT focuses on the four pillars of the academic health center: clinical services, research and scholarly work, education, and public service. Since 1996, the Center has provided more than 33,000 telemedicine consultation (excluding teleradiology, telepathology, and phone consultations) in over 30 clinical specialties and at more than 90 locations across California. Research and continuous evaluation have played an integral role in shaping the telehealth program, as well as strategic collaborations and partnerships. In an effort to expand the field of telehealth the CHT provides telehealth training for health professionals, technical specialists, and administrators. Furthermore, it also plays an integral role in workforce development through the education of the next generation of community primary care physicians through Rural Programs In Medical Education (Rural PRIME) and continuing educational programs for working health professionals through videoconferencing and Web-based modalities. The Center is supported through a variety of funding sources, and its sustainability comes from a mix of fee-for-service payment, contracts, grants, gifts, and institutional funding. Together with key partners, UC Davis has educated and informed initiatives resulting in legislation and policies that advance telehealth. Looking toward the future, UC Davis is focused on technology-enabled healthcare and supporting synergy among electronic health records, health information exchange, mobile health, informatics, and telehealth. PMID- 23343258 TI - Telemedicine in an academic center--the Arizona Telemedicine Program. AB - This article provides background information on the history of telemedicine in Arizona and the Arizona Telemedicine Program (ATP). Following a brief overview of the growth of the ATP over the past 16 years, special focus is directed toward a description of the ATP business model, sustainability efforts of the Program, and ATP's future directions and goals. The ATP was established by the Arizona State Legislature in 1996 and, today, operates a large university-based statewide telemedicine consortium. It provides a spectrum of telemedicine support services to dozens of independent healthcare organizations throughout Arizona and bordering states. The ATP's backbone is a regional, 160-site dedicated healthcare and education broadband telecommunications network called the Arizona Telemedicine Network (ATN). The ATN is a fixed-cost network operated 24/7 by ATP engineers. In addition to providing access to the ATN, the ATP also provides its member individuals and organizations with benefits including biomedical communications services and expertise, telemedicine training on financial, legal, regulatory, and administrative support aspects, and access to subspecialty telemedicine consultation services. PMID- 23343260 TI - Communication: solute anisotropy effects in hydrated anion and neutral clusters. AB - Specific ion effects in solvation processes are often rationalized in terms of spherically symmetric models involving an ion's size, charge, and polarizability. The effects of permanent charge anisotropy, related to the polyatomic nature of complex solutes, are expected to play a role in solvation but the extent of their importance remains unexplored. In this work, we provide compelling experimental and theoretical evidence that the anisotropic nature of complex polyoxyanion solutes can have a critical influence on the solvation process. Combined photoelectron spectroscopy and theoretical modeling results show that the electron binding energy of IO(3) (-)(H(2)O)(n) (n = 0-12) clusters is characterized by an anomalous drop at n = 10. Such behavior is unprecedented for rigid solute molecules and is related to the anisotropy of the neutral iodate radical that displays a strong selectivity to solvent configurations generated by the charged anion complex. These results highlight the significance of solute anisotropy and its potential impact on ion specificity and selectivity in aqueous environments. PMID- 23343259 TI - Cyberbullying in those at clinical high risk for psychosis. AB - AIM: Several studies suggest an association between experiences of childhood trauma including bullying and the development of psychotic symptoms. The use of communications technology has created a new media for bullying called 'cyberbullying'. Research has demonstrated associations between traditional bullying and cyberbullying. Negative effects of cyberbullying appear similar in nature and severity to the reported effects of traditional bullying. Our aim was to examine the prevalence and correlates of cyberbullying in those at clinical high risk (CHR) for psychosis. METHODS: Fifty young people at CHR for psychosis were administered the Childhood Trauma Questionnaire with added questions about cyberbullying. RESULTS: Cyberbullying was reported in 38% of the sample. Those who experienced cyberbullying also reported experiencing previous trauma. CONCLUSION: It is possible that cyberbullying may be a problem for those at CHR of psychosis, and due to the vulnerable nature of these young people may have longitudinal implications. PMID- 23343261 TI - Communication: structure of magnetic lanthanide clusters from far-IR spectroscopy: Tb(n)+ (n = 5-9). AB - Small lanthanide clusters have interesting magnetic properties, but their structures are unknown. We have identified the structures of small terbium cluster cations Tb(n)(+) (n = 5-9) in the gas phase by analysis of their vibrational spectra. The spectra have been measured via IR multiple photon dissociation of their complexes with Ar atoms in the 50-250 cm(-1) range with an infrared free electron laser. Density functional theory calculations using a 4f in-core effective core potential (ECP) accurately reproduce the experimental far IR spectra. The ECP corresponds to a 4f(8)5d(1)6s(2) trivalent configuration of terbium. The assigned structures are similar to those observed in several other transition metal systems. From this, we conclude that the bonding in Tb clusters is through the interactions between the 5d and 6s electrons, and that the 4f electrons have only an indirect effect on the cluster structures. PMID- 23343262 TI - Optimal scale-free network with a minimum scaling of transport efficiency for random walks with a perfect trap. AB - Average trapping time (ATT) is central in the trapping problem since it is a key indicator characterizing the efficiency of the problem. Previous research has provided the scaling of a lower bound of the ATT for random walks in general networks with a deep trap. However, it is still not well understood in which networks this minimal scaling can be reached. Particularly, explicit quantitative results for ATT in such networks, even in a specific network, are lacking, in spite that such networks shed light on the design for optimal networks with the highest trapping efficiency. In this paper, we study the trapping problem taking place on a hierarchical scale-free network with a perfect trap. We focus on four representative cases with the immobile trap located at the root, a peripheral node, a neighbor of the root with a single connectivity, and a farthest node from the root, respectively. For all the four cases, we obtain the closed-form formulas for the ATT, as well as its leading scalings. We show that for all the four cases of trapping problems, the dominating scalings of ATT can reach the predicted minimum scalings. This work deepens the understanding of behavior of trapping in scale-free networks, and is helpful for designing networks with the most efficient transport process. PMID- 23343263 TI - Reactive adsorption of ammonia and ammonia/water on CuBTC metal-organic framework: a ReaxFF molecular dynamics simulation. AB - We report ReaxFF molecular dynamics simulations for reactive adsorption of NH(3) on dehydrated CuBTC metal-organic framework. If the temperature is moderate (up to 125 degrees C), the dehydrated CuBTC demonstrates a good hydrostatic stability for water concentrations up to 4.0 molecules per copper site. However, if the temperature increases to 550 K, the dehydrated CuBTC will collapse even at a small water concentration, 1.0 H(2)O molecule per copper site. When NH(3) molecules are adsorbed in the channel and micropores of CuBTC, they prefer to chemisorb to the copper sites rather than forming a dimer with another NH(3) molecule. The formation of equimolar Cu(2)(NH(2))(4) and (NH(4))(3)BTC structures is observed at 348 K, which is in good agreement with previous experimental findings. The dehydrated CuBTC framework is partially collapsed upon NH(3) adsorption, while the Cu-Cu dimer structure remains stable under the investigated conditions. Further calculations reveal that the stability of CuBTC is related to the ammonia concentration. The critical NH(3) concentration after which the dehydrated CuBTC starts to collapse is determined to be 1.0 NH(3) molecule per copper site. Depending on whether NH(3) concentration is below or above the critical value, the dehydrated CuBTC can be stable to a higher temperature, 378 K, or can collapse at a lower temperature, 250 K. H(2)O/NH(3) mixtures have also been studied, and we find that although water molecules do not demonstrate a strong interaction with the copper sites of CuBTC, the existence of water molecules can substantially prevent ammonia from interacting with CuBTC, and thus reduce the amount of chemisorbed NH(3) molecules on CuBTC and stabilize the CuBTC framework to some extent. PMID- 23343264 TI - Multicanonical molecular dynamics by variable-temperature thermostats and variable-pressure barostats. AB - Sampling from flat energy or density distributions has proven useful in equilibrating complex systems with large energy barriers. Several thermostats and barostats are presented to sample these flat distributions by molecular dynamics. These methods use a variable temperature or pressure that is updated on the fly in the thermodynamic controller. These methods are illustrated on a Lennard-Jones system and a structure-based model of proteins. PMID- 23343265 TI - Direct determination of exciton couplings from subsystem time-dependent density functional theory within the Tamm-Dancoff approximation. AB - In subsystem time-dependent density functional theory (TDDFT) [J. Neugebauer, J. Chem. Phys. 126, 134116 (2007)] localized excitations are used to calculate delocalized excitations in large chromophore aggregates. We have extended this formalism to allow for the Tamm-Dancoff approximation (TDA). The resulting response equations have a form similar to a perturbative configuration interaction singles (CIS) approach. Thus, the inter-subsystem matrix elements in subsystem TDA can, in contrast to the full subsystem-TDDFT case, directly be interpreted as exciton coupling matrix elements. Here, we present the underlying theory of subsystem TDDFT within the TDA as well as first applications. Since for some classes of pigments, such as linear polyenes and carotenoids, TDA has been reported to perform better than full TDDFT, we also report applications of this formalism to exciton couplings in dimers of such pigments and in mixed bacteriochlorophyll-carotenoid systems. The improved description of the exciton couplings can be traced back to a more balanced description of the involved local excitations. PMID- 23343266 TI - Using fixed-node diffusion Monte Carlo to investigate the effects of rotation vibration coupling in highly fluxional asymmetric top molecules: application to H2D+. AB - A fixed-node diffusion Monte Carlo approach for obtaining the energies and wave functions of the rotationally excited states of asymmetric top molecules that undergo large amplitude, zero-point vibrational motions is reported. The nodal surfaces required to introduce rotational excitation into the diffusion Monte Carlo calculations are obtained from the roots of the asymmetric top rigid rotor wave functions calculated using the system's zero-point, vibrationally averaged rotational constants. Using H(2)D(+) as a model system, the overall accuracy of the methodology is tested by comparing to the results of converged variational calculations. The ability of the fixed-node diffusion Monte Carlo approach to provide insights into the nature and strength of the rotation-vibration coupling present in the rotationally excited states of highly fluxional asymmetric tops is discussed. Finally, the sensitivity of the methodology to the details of its implementation, such as the choice of embedding scheme, is explored. PMID- 23343267 TI - An efficient and near linear scaling pair natural orbital based local coupled cluster method. AB - In previous publications, it was shown that an efficient local coupled cluster method with single- and double excitations can be based on the concept of pair natural orbitals (PNOs) [F. Neese, A. Hansen, and D. G. Liakos, J. Chem. Phys. 131, 064103 (2009)]. The resulting local pair natural orbital-coupled-cluster single double (LPNO-CCSD) method has since been proven to be highly reliable and efficient. For large molecules, the number of amplitudes to be determined is reduced by a factor of 10(5)-10(6) relative to a canonical CCSD calculation on the same system with the same basis set. In the original method, the PNOs were expanded in the set of canonical virtual orbitals and single excitations were not truncated. This led to a number of fifth order scaling steps that eventually rendered the method computationally expensive for large molecules (e.g., >100 atoms). In the present work, these limitations are overcome by a complete redesign of the LPNO-CCSD method. The new method is based on the combination of the concepts of PNOs and projected atomic orbitals (PAOs). Thus, each PNO is expanded in a set of PAOs that in turn belong to a given electron pair specific domain. In this way, it is possible to fully exploit locality while maintaining the extremely high compactness of the original LPNO-CCSD wavefunction. No terms are dropped from the CCSD equations and domains are chosen conservatively. The correlation energy loss due to the domains remains below <0.05%, which implies typically 15-20 but occasionally up to 30 atoms per domain on average. The new method has been given the acronym DLPNO-CCSD ("domain based LPNO-CCSD"). The method is nearly linear scaling with respect to system size. The original LPNO CCSD method had three adjustable truncation thresholds that were chosen conservatively and do not need to be changed for actual applications. In the present treatment, no additional truncation parameters have been introduced. Any additional truncation is performed on the basis of the three original thresholds. There are no real-space cutoffs. Single excitations are truncated using singles specific natural orbitals. Pairs are prescreened according to a multipole expansion of a pair correlation energy estimate based on local orbital specific virtual orbitals (LOSVs). Like its LPNO-CCSD predecessor, the method is completely of black box character and does not require any user adjustments. It is shown here that DLPNO-CCSD is as accurate as LPNO-CCSD while leading to computational savings exceeding one order of magnitude for larger systems. The largest calculations reported here featured >8800 basis functions and >450 atoms. In all larger test calculations done so far, the LPNO-CCSD step took less time than the preceding Hartree-Fock calculation, provided no approximations have been introduced in the latter. Thus, based on the present development reliable CCSD calculations on large molecules with unprecedented efficiency and accuracy are realized. PMID- 23343268 TI - Molecular diffusion between walls with adsorption and desorption. AB - The time dependency of the diffusion coefficient of particles in porous media is an efficient probe of their geometry. The analysis of this quantity, measured, e.g., by nuclear magnetic resonance, can provide rich information pertaining to porosity, pore size distribution, permeability, and surface-to-volume ratio of porous materials. Nevertheless, in numerous if not all practical situations, transport is confined by walls where adsorption and desorption processes may occur. In this article, we derive explicitly the expression of the time-dependent diffusion coefficient between two confining walls in the presence of adsorption and desorption. We show that they strongly modify the time-dependency of the diffusion coefficient, even in this simple geometry. We finally propose several applications, from sorption rates measurements to the use as a reference for numerical implementations for more complex geometries. PMID- 23343269 TI - Multiple population-period transient spectroscopy (MUPPETS) in excitonic systems. AB - Time-resolved experiments with more than one period of incoherent time evolution are becoming increasingly accessible. When applied to a two-level system, these experiments separate homogeneous and heterogeneous contributions to kinetic dispersion, i.e., to nonexponential relaxation. Here, the theory of two dimensional (2D) multiple population-period transient spectroscopy (MUPPETS) is extended to multilevel, excitonic systems. A nonorthogonal basis set is introduced to simplify pathway calculations in multilevel systems. Because the exciton and biexciton signals have different signs, 2D MUPPETS cleanly separates the exciton and biexciton decays. In addition to separating homogeneous and heterogeneous dispersion of the exciton, correlations between the exciton and biexciton decays are measurable. Such correlations indicate shared features in the two relaxation mechanisms. Examples are calculated as both 2D time decays and as 2D rate spectra. The effect of solvent heating (i.e., thermal gratings) is also calculated in multidimensional experiments on multilevel systems. PMID- 23343270 TI - Attachment cross-sections of protonated and deprotonated water clusters. AB - Attachment cross-sections of water molecules onto size selected protonated (H(2)O)(n)H(+) and deprotonated (H(2)O)(n - 1)OH(-) water clusters have been measured in the size range n = 30-140 for 10 eV kinetic energy of the clusters in the laboratory frame. Within our experimental accuracy, the attachment cross sections are found to have the same magnitude and size dependence for both species. It is shown that electrostatic interactions are likely to play a role even for the largest sizes investigated. PMID- 23343271 TI - Velocity effects on the shape of pure H2O isolated lines: complementary tests of the partially correlated speed-dependent Keilson-Storer model. AB - Complementary tests of the partially correlated speed-dependent Keilson-Storer (pCSDKS) model for the shape of isolated transition of pure water vapor [N. H. Ngo et al., J. Chem. Phys. 136, 154310 (2012)] are made using new measurements. The latter have been recorded using a high sensitivity cavity ring down spectrometer, for seven self-broadened H(2)O lines in the 1.6 MUm region at room temperature and for pressures from 0.5 to 15 Torr. Furthermore, the H(2) (18)O spectra of [M. D. De Vizia et al., Phys. Rev. A 83, 052506 (2011)] in the 1.38 MUm region, measured at 273.15 K and for pressures from 0.3 to 3.75 Torr have also been used for comparison with the model. Recall that the pCSDKS model takes into account the collision-induced velocity changes, the speed dependences of the broadening and shifting coefficients as well as the partial correlation between velocity and rotational-state changes. All parameters of the model have been fixed at values previously determined, except for a scaling factor applied to the input speed-dependent line broadening. Comparisons between predictions and experiments have been made by looking at the results obtained when fitting the calculated and measured spectra by Voigt profiles. The good agreement obtained for all considered lines, at different temperature and pressure conditions, confirms the consistency and the robustness of the model. Limiting cases of the model have been then derived, showing the influence of different contributions to the line shape. PMID- 23343272 TI - Hybrid chromophore/template nanostructures: a customizable platform material for solar energy storage and conversion. AB - Challenges with cost, cyclability, and/or low energy density have largely prevented the development of solar thermal fuels, a potentially attractive alternative energy technology based on molecules that can capture and store solar energy as latent heat in a closed cycle. In this paper, we present a set of novel hybrid photoisomer/template solar thermal fuels that can potentially circumvent these challenges. Using first-principles computations, we demonstrate that these fuels, composed of organic photoisomers bound to inexpensive carbon-based templates, can reversibly store solar energy at densities comparable to Li-ion batteries. Furthermore, we show that variation of the template material in combination with the photoisomer can be used to optimize many of the key performance metrics of the fuel-i.e., the energy density, the storage lifetime, the temperature of the output heat, and the efficiency of the solar-to-heat conversion. Our work suggests that the solar thermal fuels concept can be translated into a practical and highly customizable energy storage and conversion technology. PMID- 23343273 TI - Heat capacities of mass selected deprotonated water clusters. AB - Heat capacities of mass selected deprotonated water clusters (H(2)O)(n-1)OH(-) have been measured in the size range n = 48-118, as a function of temperature. We have found that they undergo a melting-like transition in the range 110-130 K. The transition temperature is size dependent with a strong correlation with the dissociation energy around the shell closure at n = 55. PMID- 23343274 TI - A simple but accurate potential for the naphthalene-argon complex: applications to collisional energy transfer and matrix isolated IR spectroscopy. AB - An explicit polarizable potential for the naphthalene-argon complex has been derived assuming only atomic contributions, aiming at large scale simulations of naphthalene under argon environment. The potential was parametrized from dedicated quantum chemical calculations at the CCSD(T) level, and satisfactorily reproduces available structural and energetic properties. Combining this potential with a tight-binding model for naphthalene, collisional energy transfer is studied by means of dedicated molecular dynamics simulations, nuclear quantum effects being accounted for in the path-integral framework. Except at low target temperature, nuclear quantum effects do not alter the average energies transferred by the collision or the collision duration. However, the distribution of energy transferred is much broader in the quantum case due to the significant zero-point energy and the higher density of states. Using an ab initio potential for the Ar-Ar interaction, the IR absorption spectrum of naphthalene solvated by argon clusters or an entire Ar matrix is computed via classical and centroid molecular dynamics. The classical spectra exhibit variations with growing argon environment that are absent from quantum spectra. This is interpreted by the greater fluxional character experienced by the argon atoms due to vibrational delocalization. PMID- 23343275 TI - Non-equivalent carbon atoms in the resonant inelastic soft X-ray scattering map of cysteine. AB - Resonant inelastic soft x-ray scattering (RIXS) was used to study the electronic structure of solid cysteine films. A RIXS map approach, i.e., plotting the x-ray emission intensity as a function of excitation and emission energy, allows us to separate the contributions of the three chemically non-equivalent carbon atoms in cysteine. In particular, we can identify orbitals localized near the photoexcited atoms, as well as orbitals that are delocalized over the entire molecule. PMID- 23343276 TI - Ratchet effect and amplitude dependence of phase locking in a two-dimensional Frenkel-Kontorova model. AB - We demonstrate the ratchet and phase locking effects in a two-dimensional overdamped Frenkel-Kontorova model with a square symmetric periodic substrate when both a longitudinal dc drive and a circular ac drive are applied. Besides the harmonic steps, the large half integer steps can also clearly be seen in the longitudinal (x) direction. These half integer steps are directly correlated to the appearance of positive and negative ratchet effects in the transverse (y) direction due to the symmetry breaking in the combination of the dc and ac drives. The angle between the net displacement and the longitudinal direction is analytically obtained in a single period of the ac drive. In the examination of the amplitude dependence of the ac drive, the maxima decrease monotonically with the amplitude, while the anomalies occur for the critical depinning force and the harmonic steps due to the spatial symmetry breaking of orbits in the presence of the ac drive. PMID- 23343277 TI - A photoelectron spectroscopy and density functional study of di-tantalum boride clusters: Ta2B(x)- (x = 2-5). AB - The structural and electronic properties for di-tantalum boride clusters Ta(2)B(x)(-) (x = 2-5) were investigated using photoelectron spectroscopy and density functional calculations. The photoelectron spectra for Ta(2)B(x)(-) (x = 2-5) are obtained at several photon energies with rich spectral features. Density functional theory calculations are performed at the BP86 level to search for the global minima of both the anionic and neutral clusters. The calculated vertical electron detachment energies for the global minimum and low-lying isomers are compared with the experimental data. Strong boron-boron bonding is found to dominate the lowest energy structures of Ta(2)B(x)(-) and Ta(2)B(x) (x = 2-5), which are shown to be bipyramidal with the boron atoms forming an equatorial belt around the Ta-Ta dimer. Strong Ta-Ta bonding is observed in Ta(2)B(x)(-) and Ta(2)B(x) for x = 2-4, whereas the Ta-Ta distance is increased significantly in Ta(2)B(5)(-) and Ta(2)B(5). PMID- 23343279 TI - Structural study of Al2O3-Na2O-CaO-P2O5 bioactive glasses as a function of aluminium content. AB - Calcium phosphate based biomaterials are extensively used in the context of tissue engineering: small changes in composition can lead to significant changes in properties allowing their use in a wide range of applications. Samples of composition (Al(2)O(3))(x)(Na(2)O)(0.11-x)(CaO)(0.445)(P(2)O(5))(0.445), where x = 0, 0.03, 0.05, and 0.08, were prepared by melt quenching. The atomic-scale structure has been studied using neutron diffraction and solid state (27)Al MAS NMR, and these data have been rationalised with the determined density of the final glass product. With increasing aluminium concentration the density increases initially, but beyond about 3 mol. % Al(2)O(3) the density starts to decrease. Neutron diffraction data show a concomitant change in the aluminium speciation, which is confirmed by (27)Al MAS NMR studies. The NMR data reveal that aluminium is present in 4, 5, and 6-fold coordination and that the relative concentrations of these environments change with increasing aluminium concentration. Materials containing aluminium in 6-fold coordination tend to have higher densities than analogous materials with the aluminium found in 4-fold coordination. Thus, the density changes may readily be explained in terms of an increase in the relative concentration of 4-coordinated aluminium at the expense of 6-fold aluminium as the Al(2)O(3) content is increased beyond 3 mol. %. PMID- 23343278 TI - Collection efficiency of photoelectrons injected into near- and supercritical argon gas. AB - Injection of photoelectrons into gaseous or liquid dielectrics is a widely used technique to produce cold plasmas in weakly ionized systems for investigating the transport properties of electrons. We report measurements of the collection efficiency of photoelectrons injected into dense argon gas for T = 152.7 K, close to the critical temperature T(c) ~ 150.9 K, and for T = 200.0 K. The high-field data agree with the Young-Bradbury model and with previous measurements below T(c) and at an intermediate temperature above T(c). The effective, density dependent electron-atom momentum transfer scattering cross section can be deduced. However, the weak-field data near T(c) show large deviations from the theoretical model. We show that the electron behavior at weak field is influenced by electrostriction effects that are only important near the critical point. PMID- 23343280 TI - Landau-Placzek ratio for heat density dynamics and its application to heat capacity of liquids. AB - Exact relation for contributions to heat capacity of liquids is obtained from hydrodynamic theory. It is shown from analysis of the long-wavelength limit of heat density autocorrelation functions that the heat capacity of simple liquids is represented as a sum of two contributions due to "phonon-like" collective excitations and heat relaxation. The ratio of both contributions being the analogy of Landau-Placzek ratio for heat processes depends on the specific heats ratio. The theory of heat density autocorrelation functions in liquids is verified by computer simulations. Molecular dynamics simulations for six liquids having the ratio of specific heats gamma in the range 1.1-2.3, were used for evaluation of the heat density autocorrelation functions and predicted Landau Placzek ratio for heat processes. The dependence of contributions from collective excitations and heat relaxation process to specific heat on gamma is shown to be in excellent agreement with the theory. PMID- 23343281 TI - Generalized extended Navier-Stokes theory: correlations in molecular fluids with intrinsic angular momentum. AB - The extended Navier-Stokes theory accounts for the coupling between the translational and rotational molecular degrees of freedom. In this paper, we generalize this theory to non-zero frequencies and wavevectors, which enables a new study of spatio-temporal correlation phenomena present in molecular fluids. To discuss these phenomena in detail, molecular dynamics simulations of molecular chlorine are performed for three different state points. In general, the theory captures the behavior for small wavevector and frequencies as expected. For example, in the hydrodynamic regime and for molecular fluids with small moment of inertia like chlorine, the theory predicts that the longitudinal and transverse intrinsic angular velocity correlation functions are almost identical, which is also seen in the molecular dynamics simulations. However, the theory fails at large wavevector and frequencies. To account for the correlations at these scales, we derive a phenomenological expression for the frequency dependent rotational viscosity and wavevector and frequency dependent longitudinal spin viscosity. From this we observe a significant coupling enhancement between the molecular angular velocity and translational velocity for large frequencies in the gas phase; this is not observed for the supercritical fluid and liquid state points. PMID- 23343282 TI - Lattice summations for spread out particles: applications to neutral and charged systems. AB - This work is concerned with the lattice energy of periodic assemblies of mass and charge distributions of the form, exp (-alphap(2)), where alpha is an adjustable positive variable and p() is the vector from the lattice site or average position. The energy of interaction between two distributions is the density weighted integral of the interactions between the volume elements of each distribution. Reciprocal space lattice summation formulas derived for particles represented by gaussian smeared-out density distributions are applied to the gaussian potential and a bounded version of the soft-sphere potential for a range of exponents. Two types of spatial broadening are considered, continuous or physical broadening (PB) and broadening resulting from the time average of point particle positions, so-called "time" broadening (TB). For neutral mass distributions a reciprocal space lattice summation formula is derived which is applied to the bounded soft-sphere potential. For the charged systems, the methodology described in Heyes [J. Chem. Phys. 74, 1924 (1981)] is used, which for the PB case gives the Ewald-like formulas derived by Gingrich and Wilson [Chem. Phys. Lett. 500, 178 (2010)] using a different method. Another expression for the lattice energy of the spread out charge distributions is derived which is cast entirely in terms of a summation over the reciprocal lattice vectors, without the arbitrary charge spreading function used in the Ewald method. The effects of charge spreading on a generalized definition of the Madelung constant (M) for a selection of crystal lattices are shown to be insignificant for route mean square displacements up to values typical of melting of an ionic crystal. When the length scale of the charge distribution becomes comparable to or greater than the mean inter particle spacing, however, the effects of charge broadening on the lattice energy are shown to be significant. In the PB case, M -> 0 for the uniform charge density or alpha -> 0 limit, and M ultimately becomes negative in the TB case for a large enough root mean square displacement (or small enough alpha). PMID- 23343283 TI - Free energy surface of ST2 water near the liquid-liquid phase transition. AB - We carry out umbrella sampling Monte Carlo simulations to evaluate the free energy surface of the ST2 model of water as a function of two order parameters, the density and a bond-orientational order parameter. We approximate the long range electrostatic interactions of the ST2 model using the reaction-field method. We focus on state points in the vicinity of the liquid-liquid critical point proposed for this model in earlier work. At temperatures below the predicted critical temperature we find two basins in the free energy surface, both of which have liquid-like bond orientational order, but differing in density. The pressure and temperature dependence of the shape of the free energy surface is consistent with the assignment of these two basins to the distinct low density and high density liquid phases previously predicted to occur in ST2 water. PMID- 23343284 TI - Distribution of melting times and critical droplet in kinetic Monte Carlo and molecular dynamics. AB - A kinetic Monte Carlo model on a lattice, based on a reaction-like mechanism, is used to investigate the microscopic properties of the homogeneous melting of a metastable crystal. The kinetic Monte Carlo model relies on nearest-neighbors interactions and a few relevant dynamical parameters. To examine the reliability of the model, careful comparison with molecular dynamics simulations of a hard sphere crystal is drawn. A criterion on the critical nature of a microscopic configuration is deduced from the bimodal character of the probability density function of melting time. For kinetic Monte Carlo simulations with dynamical parameter values which fit the molecular dynamics results, the number of liquid sites of the critical droplet is found to be smaller than 300 and the ability of the critical droplet to invade the entire system is shown to be independent of the droplet shape as long as this droplet remains compact. In kinetic Monte Carlo simulations, the size of the critical droplet is independent of the system size. Molecular dynamics evidences a more complex dependence of melting time on system size, which reveals non-trivial finite size effects. PMID- 23343285 TI - Dependence of the width of the glass transition interval on cooling and heating rates. AB - In a preceding paper [J. W. P. Schmelzer, J. Chem. Phys. 136, 074512 (2012)], a general kinetic criterion of glass formation has been advanced allowing one to determine theoretically the dependence of the glass transition temperature on cooling and heating rates (or similarly on the rate of change of any appropriate control parameter determining the transition of a stable or metastable equilibrium system into a frozen-in, non-equilibrium state of the system, a glass). In the present paper, this criterion is employed in order to develop analytical expressions for the dependence of the upper and lower boundaries and of the width of the glass transition interval on the rate of change of the external control parameters. It is shown, in addition, that the width of the glass transition range is strongly correlated with the entropy production at the glass transition temperature. The analytical results are supplemented by numerical computations. Analytical results and numerical computations as well as existing experimental data are shown to be in good agreement. PMID- 23343286 TI - Six-site polarizable model of water based on the classical Drude oscillator. AB - A polarizable water model, SWM6, was developed and optimized for liquid phase simulations under ambient conditions. Building upon the previously developed SWM4 NDP model, additional sites representing oxygen lone-pairs were introduced. The geometry of the sites is assumed to be rigid. Considering the large number of adjustable parameters, simulated annealing together with polynomial fitting was used to facilitate model optimization. The new water model was shown to yield the correct self-diffusion coefficient after taking the system size effect into account, and the dimer geometry is better reproduced than in the SWM4 models. Moreover, the experimental oxygen-oxygen radial distribution is better reproduced, indicating that the new model more accurately describes the local hydrogen bonding structure of bulk phase water. This was further validated by its ability to reproduce the experimental nuclear magnetic shielding and related chemical shift of the water hydrogen in the bulk phase, a property sensitive to the local hydrogen bonding structure. In addition, comparison of the liquid properties of the SWM6 model is made with those of a number of widely used additive and polarizable models. Overall, improved balance between the description of monomer, dimer, clustered, and bulk phase water is obtained with the new model compared to its SWM4-NDP polarizable predecessor, though application of the model requires an approximately twofold increase on computational resources. PMID- 23343287 TI - CO oxidation on h-BN supported Au atom. AB - The mechanism of CO oxidation by O(2) on Au atoms supported on the pristine and defected hexagonal boron nitride (h-BN) surface has been studied theoretically using density functional theory. It is found that O(2) binds stronger than CO on an Au atom supported on the defect free h-BN surface and h-BN surface with nitrogen vacancy (V(N)@h-BN), but weaker than CO on a free Au atom or Au trapped by a boron vacancy (V(B)@h-BN). The excess of the positive or negative charge on Au can considerably change its catalytic properties and enhance activation of the adsorbed O(2). Coadsorption of CO and O(2) on Au, Au/V(N)@h-BN, and Au/V(B)@h-BN results in additional charge transfer to O(2). Various pathways of the CO oxidation reaction by molecular oxygen are studied. We found two different pathways for CO oxidation: a two-step pathway where two CO(2) molecules are formed independently, and a self-promotion pathway where oxidation of the first CO molecule is promoted by the second CO molecule. Interaction of Au with the defect-free and defected h-BN surface considerably affects the CO oxidation reaction pathways and barriers. Therefore, Au supported on the h-BN surface (pristine or defected) cannot be considered as pseudo-free atom and support effects have to be taken into account, even when the interaction of Au with the support is weak. PMID- 23343288 TI - Nondecaying long range effect of surface decoration on the charge state of NV center in diamond. AB - On the basis of density functional theory, stability and electronic structure of nitrogen-vacancy (NV) centers in surface modified diamond have been studied. Surface decoration is traditionally expected to only have influence on those NV centers close to the surface. However, our calculations indicate that its effect to charged NV centers is nondecaying and long-range, where the formation energy of the charged NV center converges to a value typically different for different types of surface decoration. Such a nondecaying long range effect is due to the electrostatic potential shift induced by the surface dipole layer, and it leads to the preference of NV(-) center for oxygen saturated diamond and NV(0) for hydrogenated one. Our work demonstrates that surface functionalization can be used to modify the relative stabilities of differently charged defects in nonmetallic materials. PMID- 23343289 TI - Theoretical evidence for low kinetic overpotentials in Li-O2 electrochemistry. AB - We develop a density functional theory model for the electrochemical growth and dissolution of Li(2)O(2) on various facets, terminations, and sites (terrace, steps, and kinks) of a Li(2)O(2) surface. We argue that this is a reasonable model to describe discharge and charge of Li-O(2) batteries over most of the discharge-charge cycle. Because non-stoichiometric surfaces are potential dependent and since the potential varies during discharge and charge, we study the thermodynamic stability of facets, terminations, and steps as a function of potential. This suggests that different facets, terminations, and sites may dominate in charge relative to those for discharge. We find very low thermodynamic overpotentials (<0.2 V) for both discharge and charge at many sites on the facets studied. These low thermodynamic overpotentials for both discharge and charge are in very good agreement with the low kinetic overpotentials observed in recent experiments. However, there are other predicted paths for discharge/charge that have higher overpotentials, so the phase space available for the electrochemistry opens up with overpotential. PMID- 23343290 TI - Effects of magnesium on phosphorus chemical states and p-type conduction behavior of phosphorus-doped ZnO films. AB - Effects of magnesium on phosphorus chemical states and p-type conduction behavior of phosphorus-doped ZnO (ZnO:P) films were investigated by combining experiment with first-principles calculation. Photoluminescence (PL) spectra show that Mg incorporation increases the amount of V(Zn), which makes more P(Zn)-2V(Zn) complex acceptor formed and background electron density decreased, leading to that MgZnO:P exhibits better p-type conductivity than ZnO:P. The p-type conductivity mainly arises from P(Zn)-2V(Zn) complex acceptor with a shallow acceptor energy of 108 meV. X-ray photoelectron spectroscopy (XPS) spectra reveal that phosphorus has two chemical states of P(Zn)-2V(Zn) complex and isolated P(Zn), with binding energy of P(2p3/2) of 132.81 and 133.87 eV, respectively. The conversion of isolated P(Zn) to P(Zn)-2V(Zn) complex induced by Mg incorporation is observed in XPS, in agreement with the PL results. First-principles calculations suggest that the formation energy of nMg(Zn)-V(Zn) complex decreases with the increasing Mg content, well supporting the experiments from the PL spectra and XPS measurements. PMID- 23343291 TI - Spin-filtering and rectification effects in a Z-shaped boron nitride nanoribbon junction. AB - A Z-shaped junction constructed by a few-nanometer-long armchair-edged boron nitride nanoribbon (ABNNR) sandwiched between two semi-infinite zigzag-edged BNNR electrodes with different hydrogen-passivated edge treatment is proposed, and its spin-dependent electronic transport is studied by ab initio calculations. It is found that a short ABNNR exhibits metallic behavior and can be used as a conduction channel. Interestingly, the spin-filtering and rectification effects exist in the junctions without any edge passivation or with boron-edge passivation. The analysis on the projected density of states and spatial distribution of molecular projected self-consistent Hamiltonian eigenstates gives an insight into the observed results for the system. Our results suggest that a BNNR-based nanodevices with spin-filtering and rectification effects may be synthesized from an hexagonal boron nitride sheet by properly tailoring and edge passivation. PMID- 23343293 TI - Influence of the long-range corrections on the interfacial properties of molecular models using Monte Carlo simulation. AB - We analyze the influence of the long-range corrections, due to the dispersive term of the intermolecular potential energy, on the surface tension using direct simulation of the vapour-liquid interface of different molecular models. Although several calculation methods have been proposed recently to compute the fluid fluid interfacial properties, the truncation of the intermolecular potential or the use of the tail corrections represents a contribution relevant from a quantitative perspective. In this work, a simplified model for methane, namely a spherical Lennard-Jones intermolecular potential, has been considered first, and afterwards other models including rigid non polarizable structures with both Lennard-Jones sites and point electric charges, representing some of the most popular models to describe water (namely the original TIP4P model, and the TIP4P/Ew and TIP4P/2005 versions), and carbon dioxide (MSM, EPM2, TraPPE, and ZD models) have been studied. Our results show that for all cases tested, including those in which the electrostatic interactions may be predominant, an incomplete account of the long-range corrections produces a systematic underestimation of the computed interfacial tension. PMID- 23343292 TI - Probing the hydrogen equilibrium and kinetics in zeolite imidazolate frameworks via molecular dynamics and quasi-elastic neutron scattering experiments. AB - The problem of simulating processes involving equilibria and dynamics of guest sorbates within zeolitic imidazolate frameworks (ZIF) by means of molecular dynamics (MD) computer experiments is of growing importance because of the promising role of ZIFs as molecular "traps" for clean energy applications. A key issue for validating such an atomistic modeling attempt is the possibility of comparing the MD results, with real experiments being able to capture analogous space and time scales to the ones pertained to the computer experiments. In the present study, this prerequisite is fulfilled through the quasi-elastic neutron scattering technique (QENS) for measuring self-diffusivity, by elaborating the incoherent scattering signal of hydrogen nuclei. QENS and MD experiments were performed in parallel to probe the hydrogen motion, for the first time in ZIF members. The predicted and measured dynamics behaviors show considerable concentration variation of the hydrogen self-diffusion coefficient in the two topologically different ZIF pore networks of this study, the ZIF-3 and ZIF-8. Modeling options such as the flexibility of the entire matrix versus a rigid framework version, the mobility of the imidazolate ligand, and the inclusion of quantum mechanical effects in the potential functions were examined in detail for the sorption thermodynamics and kinetics of hydrogen and also of deuterium, by employing MD combined with Widom averaging towards studying phase equilibria. The latter methodology ensures a rigorous and efficient way for post-processing the dynamics trajectory, thereby avoiding stochastic moves via Monte Carlo simulation, over the large number of configurational degrees of freedom a nonrigid framework encompasses. PMID- 23343294 TI - Nonlinear thermal conductance in single-wall carbon nanotubes: negative differential thermal resistance. AB - Nonlinear thermal conductance in single-wall carbon nanotubes (CNTs) is investigated by applying the large temperature difference. From the classical molecular dynamics simulations, we observe the occurrence of negative differential thermal resistance (NDTR) in CNTs, namely, there exist a region of temperature difference, where the heat flux decreases as the applied temperature difference increases. Double NDTRs even occur in some CNTs with special diameters. When the length of CNTs increases, NDTR regime reduces and vanishes in the thermodynamic limit. CNTs with NDTR may be the good candidate materials for designing thermal devices such as thermal transistors, thermal logic gates, and thermal memory. PMID- 23343295 TI - Nernst-Planck model of photo-triggered, pH-tunable ionic transport through nanopores functionalized with "caged" lysine chains. AB - We describe the fabrication of asymmetric nanopores sensitive to ultraviolet (UV) light, and give a detailed account of the divalent ionic transport through these pores using a theoretical model based on the Nernst-Planck equations. The pore surface is decorated with lysine chains having pH-sensitive (amine and carboxylic acid) moieties that are caged with photo-labile 4,5-dimethoxy-2-nitrobenzyl (NVOC) groups. The uncharged hydrophobic NVOC groups are removed using UV irradiation, leading to the generation of hydrophilic "uncaged" amphoteric groups on the pore surface. We demonstrate experimentally that polymer membranes containing single pore and arrays of asymmetric nanopores can be employed for the pH-controlled transport of ionic and molecular analytes. Comparison between theory and experiment allows for understanding the individual properties of the phototriggered nanopores, and provides also useful clues for the design and fabrication of multipore membranes to be used in practical applications. PMID- 23343296 TI - Internal detection of surface plasmon coupled chemiluminescence during chlorination of potassium thin films. AB - The interaction of chlorine with potassium surfaces is a prototype reaction with a strong non-adiabatic energy transfer leading to exoemission and chemiluminescence. Thin film K/Ag/p-Si(111) Schottky diodes with 8 nm potassium on a 5-200 nm thick Ag layer are used as 2pi-photodetectors for the chemiluminescence during chlorination of the K film at 110 K. The observed photocurrent shows a sharp maximum for small exposures and decreases gradually with the increasing chloride layer. The time dependence can be explained by the reaction kinetics, which is governed initially by second-order adsorption processes followed by an electric field-assisted diffusion. The detector current corresponds to a yield of a few percent of elementary charge per reacting chlorine molecule and is orders of magnitude larger than for external detection. The photoyield can be enhanced by increasing the Ag film thickness. For Ag films of 30 and 50 nm, the yield exhibits a maximum indicating surface plasmon coupled chemiluminescence. Surface plasmon polaritons in the Ag layer are excited by the reaction and decay radiatively into Si leading to the observed currents. A model calculation for the reverse process in attenuated total reflection is applied to explain the observed current yield maxima. PMID- 23343297 TI - Deposition of (WO3)3 nanoclusters on the MgO(001) surface: a possible way to identify the charge states of the defect centers. AB - Periodic density functional theory calculations have been performed to study the most stable structure of the (WO(3))(3) nanocluster deposited on the MgO(001) surface with three kinds of F(S) centers (F(S)(0), F(S)(+), and F(S)(2+)). Our results indicate that the configuration of (WO(3))(3) cluster, including the cyclic conformation and the heights of three W atoms, and the oxidation states are sensitive to the charge state of the F(S) center. It is interesting that the electron-riched F(S) (0) vacancy on the MgO(001) surface can act as a promoting site to enhance the W-W interaction and the W(3)O(3) cyclic conformation is maintained, while the skeleton of cluster becomes flexible when (WO(3))(3) is adsorbed on the electron-deficient vacancy (F(S)(+) and F(S)(2+)). Accordingly, three F(S)-centers exhibit different arrangements of X-ray photoelectron spectra, the scanning tunneling microscopy images, and the vibrational spectra after depositing (WO(3))(3) cluster. Present results reveal that the (WO(3))(3) cluster may be used as a probe to identify the different F(S) centers on the MgO(001) surface. PMID- 23343298 TI - Relaxation of surface tension in the free-surface boundary layer of simple Lennard-Jones liquids. AB - In this paper we use molecular dynamics to answer a classical question: how does the surface tension on a liquid/gas interface appear? After defining surface tension from the first principles and performing several consistency checks, we perform a dynamic experiment with a single simple liquid nanodroplet. At time zero, we remove all molecules of the interfacial layer, creating a fresh bare interface with the bulk arrangement of molecules. After that the system evolves towards equilibrium, and the expected surface tension is re-established. We found that the system relaxation consists of three distinct stages. First, the mechanical balance is quickly re-established. During this process the notion of surface tension is meaningless. In the second stage, the surface tension equilibrates, and the density profile broadens to a value which we call "intrinsic" interfacial width. During the third stage, the density profile continues to broaden due to capillary wave excitations, which does not however affect the surface tension. We have observed this scenario for monatomic Lennard Jones (LJ) liquid as well as for binary LJ mixtures at different temperatures, monitoring a wide range of physical observables. PMID- 23343299 TI - Translocation and encapsulation of siRNA inside carbon nanotubes. AB - We report spontaneous translocation of small interfering RNA (siRNA) inside carbon nanotubes (CNTs) of various diameters and chirality using all atom molecular dynamics simulations with explicit solvent. We use umbrella sampling method to calculate the free energy landscape of the siRNA entry and translocation event. Free energy profiles show that siRNA gains free energy while translocating inside CNT, and barrier for siRNA exit from CNT ranges from 40 to 110 kcal/mol depending on CNT chirality and salt concentration. The translocation time tau decreases with the increase of CNT diameter with a critical diameter of 24 A for the translocation. In contrast, double strand DNA of the same sequence does not translocate inside CNT due to large free energy barrier for the translocation. This study helps in understanding the nucleic acid transport through nanopores at microscopic level and may help designing carbon nanotube based sensor for siRNA. PMID- 23343300 TI - Theory of liquid crystalline micelles. AB - A theory is introduced to describe self-assembly of liquid crystalline AB diblock copolymers, consisting of a homopolymer (A) and a side-chain liquid crystalline polymer (B). We derive the free energy of the liquid crystalline micellar solutions and examine the equilibrium solution properties: critical micelle concentration (CMC), nematic-isotropic phase transition (NIT) of the rigid side chains inside the micelle core, and phase separations. It is shown that there is a critical micelle size below which the NIT becomes continuous due to a packing effect. We also find re-entrant micellizations near the NIT temperature. The phase diagrams, including binodal, spinodal, CMC, and NIT curves are also examined on the temperature-concentration plane. PMID- 23343301 TI - On the confinement of semiflexible chains under torsion. AB - The effect of a finite torque on semiflexible polymers in a confined environment is investigated. It is shown how a new length scale appears in the strongly confined limit. The influence of a torque on the extension of biopolymers in nanochannels is also touched upon and it is argued that the presence of a torque has a strong influence on the dimensions of nanochannels needed to prevent hairpins. PMID- 23343302 TI - Dynamics of semiflexible regular hyperbranched polymers. AB - We study the dynamics of semiflexible Vicsek fractals (SVF) following the framework established by Dolgushev and Blumen [J. Chem. Phys. 131, 044905 (2009)], a scheme which allows to model semiflexible treelike polymers of arbitrary architecture. We show, extending the methods used in the treatment of semiflexible dendrimers by Furstenberg et al. [J. Chem. Phys. 136, 154904 (2012)], that in this way the Langevin-dynamics of SVF can be treated to a large part analytically. For this we show for arbitrary Vicsek fractals (VF) how to construct complete sets of eigenvectors; these reduce considerably the diagonalization problem of the corresponding equations of motion. In fact, such eigenvector sets arise naturally from a hierarchical procedure which follows the iterative construction of the VF. We use the obtained eigenvalues to calculate the loss moduli G(")(omega) of SVF for different degrees of stiffness of the junctions. Finally, we compare the results for SVF to those found for semiflexible dendrimers. PMID- 23343303 TI - Adsorption of single polymer molecules in shear flow near a planar wall. AB - Adsorption of homopolymers from a dilute solution to a planar wall in the presence of shear flow is studied using a bead-spring dumbbell model. The bead bead and bead-wall interactions are described by generalized Lennard-Jones potentials. A kinetic theory incorporating bead-wall hydrodynamic interaction is developed in order to obtain an analytical expression for the steady-state dumbbell concentration profile. The concentration profile exhibits an exclusion zone in the immediate vicinity of the wall, is followed by a peak, and finally approaches the bulk concentration far away from the wall. Using the analytical expression, the amount adsorbed and the equivalent film thickness are studied as a function of flow strength and the parameters characterizing the bead-wall interaction potential. Shear flow causes migration of the dumbbells due to bead wall hydrodynamic interaction, which leads to desorption. On increasing the flow strength, the quantity adsorbed and the film thickness decrease until complete desorption occurs. The dependence of the flow strength required for desorption on the model parameters is also studied and a scaling law is derived for the strong interaction limit. Brownian dynamics simulations are performed to verify the predictions from the kinetic theory. Although the theory makes a number of simplifying assumptions, it captures many of the key features seen in the simulations. PMID- 23343304 TI - Computational chemical analysis of unconjugated bilirubin anions and insights into pKa values clarification. AB - The pKa, the negative logarithm of the acid dissociation equilibrium constant, of the carboxylic acid groups of unconjugated bilirubin in water is a discussed issue because there are quite different experimental values reported. Using quantum mechanical calculations we have studied the conformational behavior of unconjugated bilirubin species (in gas phase and in solution modeled implicitly and explicitly) to provide evidence that may clarify pKa values because of its pathophysiological relevance. Our results show that rotation of carboxylate group, which is not restricted, settles it in a suitable place to establish stronger interactions that stabilizes the monoanion and the dianion to be properly solvated, demonstrating that the rationalization used to justify the high pKa values of unconjugated bilirubin is inappropriate. Furthermore, low unconjugated bilirubin (UCB) pKa values were estimated from a linear regression analysis. PMID- 23343305 TI - Exploring the mechanisms of DNA hybridization on a surface. AB - DNA microarrays are a potentially disruptive technology in the medical field, but their use in such settings is limited by poor reliability. Microarrays work on the principle of hybridization and can only be as reliable as this process is robust, yet little is known at the molecular level about how the surface affects the hybridization process. This work uses advanced molecular simulation techniques and an experimentally parameterized coarse-grain model to determine the mechanism by which hybridization occurs on surfaces. The results show that hybridization proceeds through a mechanism where the untethered (target) strand often flips orientation. For evenly lengthed strands, the surface stabilizes hybridization (compared to the bulk system) by reducing the barriers involved in the flipping event. For unevenly lengthed strands, the surface destabilizes hybridization compared to the bulk, but the degree of destabilization is dependent on the location of the matching sequence. Taken as a whole, the results offer an unprecedented view into the hybridization process on surfaces and provide some insights as to the poor reproducibility exhibited by microarrays. PMID- 23343306 TI - Note: network random walk model of two-state protein folding: test of the theory. PMID- 23343307 TI - Treatment of adult femoral shaft fractures using the Perkins traction at addis Ababa Tikur Anbessa University Hospital: the Ethiopian experience. AB - This is a prospective study to evaluate the efficacy of the Perkins traction in the treatment of adult femoral shaft fractures from October 1, 2007, to the present at the Black Lion Hospital in Addis Ababa University Hospital in Ethiopia. All femur fractures admitted to the hospital were reviewed and evaluated for treatment. Black Lion Hospital (Tikur Anbessa) is the university hospital in Addis Ababa and the highest tertiary teaching hospital in a country of 85 million inhabitants. A 67-bed orthopedic department offers the main ground for teaching to the undergraduate medical students. The hospital is also the pivotal center for the formation of the orthopedic residents. Patients from different parts of the country are referred to this institution for orthopedic care. A total of 68 adult (older than 16 years) patients with 69 femoral shaft fractures were considered for treatment during the study period. Consent was obtained and prospective treatment initiated. A standard Perkins traction was applied by an orthopedic team composed of consultants, orthopedic residents, physical therapists, and nurses. A protocol was developed for patients undergoing such traction. The physiotherapists will supervise all individual or group therapy sessions. Progressive knee range of motion to facilitate quadriceps and hamstring muscle strengthening exercises were implemented four times a day and recorded. Demographic information, fracture patterns, duration of traction, thigh circumference leg length discrepancy, and pin sites were routinely monitored and charted. Data were computerized and analyzed weekly, and appropriate adjustments were made accordingly. Clinical evidence of a competent callus and confirmation by radiographic studies will influence the cessation of traction to allow gait training with toe-touch crutch ambulation. Progress will be monitored during the following outpatient visits in the fracture clinic. A total of 68 consecutive patients with 69 femoral shaft fractures were treated with the Perkins traction. There were 60 men (88.2%) and only 8 women (11.8%), for a ratio of 8 men to 1 woman. The age of the cohort patient varied between 18 and 28 years. The mechanisms of injury for most of the fractures were motor vehicle accidents, resulting in an isolated femoral shaft fracture in 49.2% of the patients. Half of the fractures were by means of closed injury (n = 44; 64.7%). One patient with a bilateral femoral shaft fracture was also added to the study. The right side was more often involved, with 41 fractures (60%), than the left, with 28 fractures (40%). Most of the fractures involved the proximal third of the femur (n = 34; 50%), but the most common fracture pattern was transverse (n = 29; 42.6%), followed by a comminuted pattern (n = 18; 26.5%). Three segmental fractures were also encountered. The mean hospital stay was 45 days (33 patients; 48.5%), with the length of time in traction varying from 30 to 40 days. Only 2 patients remained in traction for a period of 60 days. At the end of the traction period, 8 patients (11.8%) showed a decrease in the quadriceps mass, and 7 patients (10.3%) showed stiffness of the knee with a range of motion limited to 0 degrees to 90 degrees . Most patients were discharged after about 8 months of treatment. One patient suffered a nonunion, and one was malunited. Superficial pin care infections were noted in 8 patients (11.8%) and treated appropriately. The conservative treatment of 69 femoral shaft fractures using the Perkins traction at Black Lion University Hospital in Addis Ababa, Ethiopia, has been proven to be a safe and effective method. It should be encouraged in countries like ours where it is a luxury to have a C-Arm in the operating room and where the hardware often is not available to perform a stable stabilization of the long bone fractures. PMID- 23343308 TI - SeDeM expert system a new innovator tool to develop pharmaceutical forms. AB - CONTEXT: The SeDeM expert system is based on the experimental study and quantitative determination of the characterization parameters of powdered substances, the aim being to determine whether a substance is suitable for producing tablets by means of direct compression (DC) technology, thereby reducing the lead time for pre-formulation studies. Additionally, this expert system also provides formulations with a minimum number of excipients. OBJECTIVE: We used this system to analyze suitable formulas for the production of orodispersible ibuprofen tablets. METHOD: Twenty-one disintegrants and ibuprophen were characterized using SeDeM methodology. RESULTS: The results indicated that production of ibuprofen tablets by DC would require improvements in the dimension and compressibility factors of the active pharmaceutical ingredient. The expert system analysis provided the specific percentage of disintegrant needed to blend with ibuprofen and a standardized formula of lubricants in order to obtain a powder mix that would successfully produce tablets by DC. The eight formulas proposed by SeDeM were produced and tested in the laboratory. CONCLUSION: All eight formulas successfully produced tablets by DC, but only four of them could be considered suitable for use as an orodispersible tablet and accomplishes all the pharmaceutical quality parameters. So, in fact, the use of the SeDeM system reduced the time of medicine's development and therefore the cost of the activity. PMID- 23343309 TI - Structures, stabilization energies, and binding energies of quinoxaline...(H2O)(n), quinoxaline dimer, and quinoxaline...Cu complexes: a theoretical study. AB - Quinoxaline is a parent structure for a broad class of N-heteroaromatic compounds, many of which exhibit various biological activities. The interaction of quinoxaline with explicit water molecules or metal ions and the formation of quinoxaline dimer play an important role in many of the biological activities of quinoxaline. This study investigates the structures, stabilization, and binding energies of quinoxaline complexes with water, transition metal ions, and quinoxaline dimer to provide information on the preferred geometries, interaction energies, and type of noncovalent interactions accounting for the stability of the complexes. The investigations are performed in vacuo and in water solution using MP2 and DFT methods. The results of the study on the quinoxaline...(H(2)O)(n) show that the preferred adducts in vacuo involve one, two, or three water molecules hydrogen bonded to the N atom and the neighboring H atom of the C(sp2)-H group. The results in water solution show a preference for water-water clustering. The dimers of quinoxaline are stabilized by either pi-pi stacking or weak C-H...N intermolecular hydrogen bonds. The relative stability of the quinoxaline...Cu complexes depends on the site on which the Cu ion binds and the binding strength depends on both the nature of the cation and the binding site. PMID- 23343310 TI - Autosomal dominant retinitis pigmentosa secondary to pre-mRNA splicing-factor gene PRPF31 (RP11): review of disease mechanism and report of a family with a novel 3-base pair insertion. AB - Several forms of autosomal dominant retinitis pigmentosa (adRP) are caused by mutations in genes encoding proteins that are ubiquitously expressed and involved in the pre-mRNA spliceosome such as PRPF31. This paper provides an overview of the molecular genetics, pathophysiology, and mechanism for incomplete penetrance and retina-specific disease in pedigrees of families who harbor mutations in PRPF31 (RP11). The molecular and clinical features of a family with a novel 3 base insertion, c.914_915insTGT (p.Val305_Asp306insVal) in exon 9 of PRPF31 are described to illustrate the salient clinical features of mutations in this gene. PMID- 23343311 TI - The complete mitochondrial genome of the Bufo tibetanus (Anura: Bufonidae). AB - The total length of the Bufo tibetanus mitochondrial genome sequence is 17,405 bp. It consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and 1 displacement loop (D-loop). Except for eight tRNAs and nd6 genes, all other mitochondrial genes are encoded on the heavy strand (H strand). Most of the 22 tRNA genes can fold into a typical cloverleaf secondary structure by tRNAscan-SE, except for tRNA(Ser). Molecular data presented here provide a useful toll for helping set the stage for further studies and the molecular evolution of the mitochondrial genome. PMID- 23343312 TI - Community-based intervention to improve dietary habits and promote physical activity among older adults: a cluster randomized trial. AB - BACKGROUND: The fastest growing age group globally is older adults, and preventing the need for long-term nursing care in this group is important for social and financial reasons. A population approach to diet and physical activity through the use of social services can play an important role in prevention. This study examined the effectiveness of a social health program for community dwelling older adults aimed at introducing and promoting physical activity in the home at each individual's pace, helping participants maintain good dietary habits by keeping self-check sheets, and determining whether long-standing unhealthy or less-than-ideal physical and dietary habits can be changed. METHOD: This cluster randomized trial conducted at 6 community centers in an urban community involved 92 community-dwelling older adults aged 65-90 years. The intervention group (3 community centers; n = 57) participated in the social health program "Sumida TAKE10!" which is an educational program incorporating the "TAKE10!(r) for Older Adults" program, once every 2 weeks for 3 months. The control group (3 community centers; n=35) was subsequently provided with the same program as a crossover intervention group. The main outcome measures were changes in food intake frequency, food frequency score (FFS), dietary variety score (DVS), and frequency of walking and exercise. The secondary outcome measures were changes in self rated health, appetite, and the Tokyo Metropolitan Institute of Gerontology (TMIG) Index of Competence score. RESULTS: Compared to baseline, post intervention food intake frequency for 6 of 10 food groups (meat, fish/shellfish, eggs, potatoes, fruits, and seaweed), FFS, and DVS were significantly increased in the intervention group, and interaction effects of FFS and DVS were seen between the two groups. No significant differences were observed between baseline and post-intervention in the control group. Frequency of walking and exercise remained unchanged in both groups, and no significant difference in improvement rate was seen between the groups. Self-rated health was significantly increased in the intervention group. Appetite and TMIG Index of Competence score were unchanged in both groups. CONCLUSIONS: The social health program resulted in improved dietary habits, as measured by food intake frequency, FFS, and DVS, and may improve self-rated health among community-dwelling older adults. TRIAL REGISTRATION NUMBER: UMIN000007357. PMID- 23343313 TI - America's childhood obesity crisis and the role of schools. PMID- 23343314 TI - Multiple levels of social disadvantage and links to obesity in adolescence and young adulthood. AB - BACKGROUND: The rise in adolescent obesity has become a public health concern, especially because of its impact on disadvantaged youth. This article examines the role of disadvantage at the family-, peer-, school-, and neighborhood-level, to determine which contexts are related to obesity in adolescence and young adulthood. METHODS: We analyzed longitudinal data from Waves I (1994-1995), II (1996), and III (2001-2002) of the National Longitudinal Study of Adolescent Health, a nationally representative population-based sample of adolescents in grades 7-12 in 1995 who were followed into young adulthood. We assessed the relationship between obesity in adolescence and young adulthood, and disadvantage (measured by low parent education in adolescence) at the family-, peer-, school-, and neighborhood-level using multilevel logistic regression. RESULTS: When all levels of disadvantage were modeled simultaneously, school-level disadvantage was significantly associated with obesity in adolescence for males and females and family-level disadvantage was significantly associated with obesity in young adulthood for females. CONCLUSIONS: Schools may serve as a primary setting for obesity prevention efforts. Because obesity in adolescence tracks into adulthood, it is important to consider prevention efforts at this stage in the life course, in addition to early childhood, particularly among disadvantaged populations. PMID- 23343315 TI - State policies about physical activity minutes in physical education or during school. AB - BACKGROUND: School policies can change practices on a relatively permanent basis. This study investigated adoption and implementation of state-level policies specifying minutes (or percent) of physical activity in physical education (PE) or during school. METHODS: Policies were identified from existing databases and rated as having weak, moderate, or strong wording. Interviews with state-level PE coordinators were conducted to investigate the level of implementation, monitoring, and enforcement of the identified policies. RESULTS: Sixteen states had a policy that met inclusion criteria (19 policies total); 11 states had a policy addressing minutes of physical activity during school, 2 had a policy addressing percent of PE time to be spent in physical activity, and 3 had policies addressing both. None of the 19 policies were rated as having strong wording and 5 were rated as having moderate wording. The range in minutes of physical activity per week addressed in the policies was 60 to 300. Four of the 5 (elementary) and 5 of 5 (middle) policies addressing percent of PE spent physically active specified 50%. The only monitoring efforts reported consisted of schools self-reporting progress to the state. CONCLUSIONS: More states need to adopt school physical activity policies and policy language needs to be more specific to prevent potential loopholes. Monitoring and evaluation strategies, beyond school self-report, are likely needed for these policies to lead to increases in physical activity. PMID- 23343316 TI - Prevalence and prediction of overweight and obesity among elementary school students. AB - BACKGROUND: The high rates of childhood overweight and obesity in the United States have generated interest in schools as sites for monitoring body mass index (BMI) information. This study established baseline values for a 5-year longitudinal assessment of BMI of elementary school children and examined variation across the schools, because little is known about factors that affect the distribution of overweight and obesity within school districts. METHODS: Height and weight measurements were collected on 2317 elementary school children in 1 school district. BMI was calculated using the Centers for Disease Control and Prevention's NutStat program. Child characteristics included gender, age, eligibility for free and reduced lunch (proxy for socioeconomic status [SES]), school, grade, and ethnicity/race. Children were grouped into 2 BMI categories, <85th percentile or >=85th percentile (overweight/obesity). Logistic regression was used to examine potential predictors of overweight/obesity. RESULTS: Prevalence of >=85th percentile was 30.9%, 34.4%, 35.3%, 36.4%, 37.1%, and 44.5% for K-5, respectively. Prevalence of >=85th percentile was highest among Hispanic children. Ethnicity was the strongest predictor of inclusion in the >=85th percentile category followed by grade and free and reduced lunch eligibility. CONCLUSION: The data are consistent with the prevalence of overweight/obesity among American children and Hispanic children in particular. District prevalence of overweight/obesity is higher than available state statistics. Most of the BMI variation is accounted for by ethnicity, SES, and grade. The grade effect and high prevalence of overweight/obesity provide a rationale for BMI screening retention at the schools. PMID- 23343317 TI - VERBTM Summer Scorecard: increasing tween girls' vigorous physical activity. AB - OBJECTIVE: We assessed changes in the frequency of self-reported physical activity (PA) among tween girls exposed and not exposed to the VERBTM Summer Scorecard (VSS) intervention in Lexington, Kentucky, during 2004, 2006, and 2007. METHODS: Girls who reported 0-1 day per week of PA were classified as having little or no PA. Girls who reported 2-3 days of PA were classified as low PA performers; 4-5 days of PA were labeled as moderate performers; and 6-7 days of PA were identified as high performers. Logit regression analysis of survey data from girls identified trends in PA frequency across time. RESULTS: In 2004, participant girls were more likely than girls unfamiliar with VSS (reference group girls) to report high frequency of PA (OR = 1.44, CI = 1.18, 1.70). In 2006, participants were statistically less likely than reference group girls to report low frequency of PA (OR = 1.75, CI = 1.33, 2.21). In 2007, VSS participants were consistently more likely to report moderate frequency (OR = 1.56, CI = 1.35, 1.77) and high frequency of PA (OR = 1.44, CI = 1.24, 1.64) than reference group girls. CONCLUSION: An innovative, community-driven intervention demonstrated promise for increasing PA among tween girls. VSS may have transportability to other communities to help reverse the secular trend of declining PA for this population segment. PMID- 23343318 TI - Impact of a school-based pediatric obesity prevention program facilitated by health professionals. AB - BACKGROUND: This study evaluated a school-based obesity intervention for elementary school children (N = 835) where health professionals assisted teachers with the integration of healthy messages into the school curriculum. METHODS: Schools were randomized into a professional-facilitated intervention (PFI; N = 4) or a self-help (SH; N = 3) condition. Changes in weight-based outcomes were assessed in students enrolled in the second grade from all 7 schools (overall: N = 835 students; PFI: N = 509 students, SH: N = 326 students). Students were between ages 7 and 9 and from diverse ethnic backgrounds (Asian = 25.3%, Black = 23.3%, Hispanic = 23.1%, White = 28.3%). The sample included 321 overweight/obese (BMI >= 85th percentile), 477 normal-weight (BMI >= 5th percentile and <85th percentile), and 37 underweight (BMI < 5th percentile) students. RESULTS: After 2 years, children who were overweight/obese in the PFI condition significantly reduced their standardized BMI (zBMI) compared to children in the SH condition (Wald chi(2) = 28.7, p < .001). End-of-year grades decreased for overweight/obese students in both conditions; however, students in the PFI exhibited a smaller decrease in grades compared to the SH condition (Wald chi(2) = 80.3, p < .001). CONCLUSION: The results indicate that an obesity prevention program where health professionals assist teachers by integrating healthy messages into existing curriculum was effective in reducing zBMI compared to the SH condition. PMID- 23343319 TI - A school nurse-delivered intervention for overweight and obese adolescents. AB - BACKGROUND: Models are needed for implementing weight management interventions for adolescents through readily accessible venues. This study evaluated the feasibility and efficacy of a school nurse-delivered intervention in improving diet and activity and reducing body mass index (BMI) among overweight and obese adolescents. METHODS: Six high schools were randomized to either a 6-session school nurse-delivered counseling intervention utilizing cognitive-behavioral techniques or nurse contact with provision of information. Eighty-four overweight or obese adolescents in grades 9 through 11 completed behavioral and physiological assessments at baseline and 2- and 6-month follow-ups. RESULTS: At 2 months, intervention participants ate breakfast on more days/week (difference = 1.01 days; 95% CI: 0.11, 1.92), and had a lower intake of total sugar (difference = -45.79 g; 95% CI: -88.34, -3.24) and added sugar (difference = -51.35 g; 95% CI: -92.45, -10.26) compared to control participants. At 6 months, they were more likely to drink soda <= one time/day (OR 4.10; 95% CI: 1.19, 16.93) and eat at fast food restaurants <= one time/week (OR 4.62; 95% CI: 1.10, 23.76) compared to control participants. There were no significant differences in BMI, activity, or caloric intake. CONCLUSION: A brief school nurse-delivered intervention was feasible, acceptable, and improved selected obesogenic behaviors, but not BMI. PMID- 23343320 TI - Adapted intervention mapping: a strategic planning process for increasing physical activity and healthy eating opportunities in schools via environment and policy change. AB - BACKGROUND: School environment and policy changes have increased healthy eating and physical activity; however, there has been modest success in translating research findings to practice. The School Environment Project tested whether an adapted version of Intervention Mapping (AIM) resulted in school change. METHODS: Using a pair randomized design, 10 rural elementary schools were assigned to AIM or the School Health Index (SHI). Baseline measures were collected fall 2005, AIM was conducted 2005-2006, and follow-up measures were collected fall 2006 and 2007. Outcome measures included number and type of effective environment and policy changes implemented; process measures included the extent to which 11 implementation steps were used. RESULTS: AIM schools made an average of 4.4 effective changes per school with 90% still in place a year later. SHI schools made an average of 0.6 effective changes with 66% in place a year later. Implementation steps distinguishing AIM from SHI included use of external, trained facilitators; principal involvement; explicitly stating the student behavior goals; identifying effective environment and policy changes; prioritizing potential changes based on importance and feasibility; and developing an action plan. CONCLUSION: The AIM process led to environment and policy changes known to increase healthy eating and physical activity. PMID- 23343321 TI - Elementary school personnel's perceptions on childhood obesity: pervasiveness and facilitating factors. AB - BACKGROUND: Researchers in numerous disciplines have investigated the effects of the school environment on childhood obesity (CHO), one of the greatest current health concerns in the United States. There is a gap in current empirical evidence, however, on school personnel's perspectives of this issue. This study examined school personnel's perceptions of obesity as a problem among school-aged children and their views on factors contributing to obesity. METHODS: Thirty-one semistructured interviews were conducted with elementary school personnel (teachers, administrators, and support staff) from 5 rural schools with a predominantly Hispanic (58.18%) and Black (30.24%) student population. The constant comparison method was used to identify emergent themes. RESULTS: All but one participant considered obesity to be a problem among elementary children. Factors facilitating obesity most frequently cited by school personnel were home environment, poor nutrition, child control of dietary choices, child inactivity, and entertainment electronics. CONCLUSIONS: Child control of dietary choices in both home and school environments was identified as a major contributor to obesity. Further exploration of this control is warranted to understand the complexity of this dynamic and its potential link to CHO. PMID- 23343322 TI - Collaborative school-based obesity interventions: lessons learned from 6 southern districts. AB - BACKGROUND: Although studies have shown that school-based obesity interventions can be effective, little is known about how to translate and implement programs into real-world school settings. METHODS: Semistructured interviews were conducted in spring 2012 with 19 key informants who participated in a multifaceted childhood obesity intervention involving school nurses and wellness coordinators in 6 school districts and over 100 schools. RESULTS: The intervention changed form according to the needs and interests of the school districts. Despite funding support, schools and nurses had little capacity to address childhood obesity without the help of the coordinator. Initiating programs at the beginning of the school year was particularly difficult for schools. Applying for grants from internal and external sources and assisting with planning and logistics for wellness activities were significant activities of the coordinator. Although some school personnel and families preferred a focus on wellness rather than obesity, those working with individual at-risk children and families found the experience especially gratifying. CONCLUSIONS: In contrast to controlled studies, real-world implementation of obesity interventions in schools that are intended to create sustained change requires flexibility in intervention design, timing, and personnel. A single change agent focused on obesity-related activities was essential to success. PMID- 23343323 TI - CHILE: an evidence-based preschool intervention for obesity prevention in Head Start. AB - BACKGROUND: Obesity is a major concern among American Indians and Hispanics. The Child Health Initiative for Lifelong Eating and Exercise (CHILE) is an evidence based intervention to prevent obesity in children enrolled in 16 Head Start (HS) Centers in rural communities. The design and implementation of CHILE are described. METHODS: CHILE uses a socioecological approach to improve dietary intake and increase physical activity. The intervention includes: a classroom curriculum; teacher and food service training; family engagement; grocery store participation; and health care provider support. RESULTS: Lessons learned from CHILE include the need to consider availability of recommended foods; the necessity of multiple training sessions for teachers and food service; the need to tailor the family events to local needs; consideration of the profit needs of grocery stores; and sensitivity to the time constraints of health care providers. CONCLUSIONS: HS can play an important role in preventing obesity in children. CHILE is an example of a feasible intervention that addresses nutrition and physical activity for preschool children that can be incorporated into HS curricula and aligns with HS national performance standards. PMID- 23343324 TI - Ordered nanoscale Archimedean tilings of a templated 3-miktoarm star terpolymer. AB - The directed self-assembly of 3-miktoarm star terpolymer chains (polyisoprene-arm polystyrene-arm-polyferrocenylethylmethylsilane (3 MU-ISF)) into 2D Archimedean tilings is described. A morphological change from (4.8(2)) to (6(3)) tiling is reported in the 3 MU-ISF thin film blended with PS homopolymer when a greater swelling of PI is achieved during the solvent annealing process. Highly oriented (4.8(2)) tilings were produced by templating the self-assembled three colored structures in blended thin films. The use of (4.8(2)) and (6(3)) tilings as nanolithographic masks to transfer square and triangular hole arrays into the substrate is also demonstrated. PMID- 23343325 TI - Effective optical Faraday rotations of semiconductor EuS nanocrystals with paramagnetic transition-metal ions. AB - Novel EuS nanocrystals containing paramagnetic Mn(II), Co(II), or Fe(II) ions have been reported as advanced semiconductor materials with effective optical rotation under a magnetic field, Faraday rotation. EuS nanocrystals with transition-metal ions, EuS:M nanocrystals, were prepared by the reduction of the Eu(III) dithiocarbamate complex tetraphenylphosphonium tetrakis(diethyldithiocarbamate)europium(III) with transition-metal complexes at 300 degrees C. The EuS:M nanocrystals thus prepared were characterized using X ray diffraction (XRD), transmission electron microscopy (TEM), inductively coupled plasma atomic emission spectroanalysis (ICP-AES), and a superconducting quantum interference device (SQUID) magnetometer. Enhanced Faraday rotations of the EuS:M nanocrystals were observed around 550 nm, and their enhanced spin polarization was estimated using electron paramagnetic resonance (EPR) measurements. In this report, the magneto-optical relationship between the Faraday rotation efficiency and spin polarization is discussed. PMID- 23343326 TI - Up-regulation of COX-2/PGE2 by endothelin-1 via MAPK-dependent NF-kappaB pathway in mouse brain microvascular endothelial cells. AB - BACKGROUND: Endothelin-1 (ET-1) is a proinflammatory mediator and elevated in the regions of several brain injury and inflammatory diseases. The deleterious effects of ET-1 on endothelial cells may aggravate brain inflammation mediated through the regulation of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) system in various cell types. However, the signaling mechanisms underlying ET-1-induced COX-2 expression in brain microvascular endothelial cells remain unclear. Herein we investigated the effects of ET-1 in COX-2 regulation in mouse brain microvascular endothelial (bEnd.3) cells. RESULTS: The data obtained with Western blotting, RT-PCR, and immunofluorescent staining analyses showed that ET-1 induced COX-2 expression was mediated through an ETB-dependent transcriptional activation. Engagement of Gi- and Gq-protein-coupled ETB receptors by ET-1 led to phosphorylation of ERK1/2, p38 MAPK, and JNK1/2 and then activated transcription factor NF-kappaB. Moreover, the data of chromatin immunoprecipitation (ChIP) and promoter reporter assay demonstrated that the activated NF-kappaB was translocated into nucleus and bound to its corresponding binding sites in COX-2 promoter, thereby turning on COX-2 gene transcription. Finally, up-regulation of COX-2 by ET-1 promoted PGE2 release in these cells. CONCLUSIONS: These results suggested that in mouse bEnd.3 cells, activation of NF-kappaB by ETB-dependent MAPK cascades is essential for ET-1-induced up-regulation of COX-2/PGE2 system. Understanding the mechanisms of COX-2 expression and PGE2 release regulated by ET 1/ETB system on brain microvascular endothelial cells may provide rationally therapeutic interventions for brain injury or inflammatory diseases. PMID- 23343327 TI - Synchronous high-resolution phenotyping of leaf and root growth in Nicotiana tabacum over 24-h periods with GROWMAP-plant. AB - BACKGROUND: Root growth is highly responsive to temporal changes in the environment. On the contrary, diel (24 h) leaf expansion in dicot plants is governed by endogenous control and therefore its temporal pattern does not strictly follow diel changes in the environment. Nevertheless, root and shoot are connected with each other through resource partitioning and changing environments for one organ could affect growth of the other organ, and hence overall plant growth. RESULTS: We developed a new technique, GROWMAP-plant, to monitor growth processes synchronously in leaf and root of the same plant with a high resolution over the diel period. This allowed us to quantify treatment effects on the growth rates of the treated and non-treated organ and the possible interaction between them. We subjected the root system of Nicotiana tabacum seedlings to three different conditions: constant darkness at 22 degrees C (control), constant darkness at 10 degrees C (root cooling), and 12 h/12 h light-dark cycles at 22 degrees C (root illumination). In all treatments the shoot was kept under the same 12 h/12 h light-dark cycles at 22 degrees C. Root growth rates were found to be constant when the root-zone environment was kept constant, although the root cooling treatment significantly reduced root growth. Root velocity was decreased after light-on and light-off events of the root illumination treatment, resulting in diel root growth rhythmicity. Despite these changes in root growth, leaf growth was not affected substantially by the root-zone treatments, persistently showing up to three times higher nocturnal growth than diurnal growth. CONCLUSION: GROWMAP-plant allows detailed synchronous growth phenotyping of leaf and root in the same plant. Root growth was very responsive to the root cooling and root illumination, while these treatments altered neither relative growth rate nor diel growth pattern in the seedling leaf. Our results that were obtained simultaneously in growing leaves and roots of the same plants corroborate the high sensitivity of root growth to the environment and the contrasting robustness of diel growth patterns in dicot leaves. Further, they also underpin the importance to carefully control the experimental conditions for root growth analysis to avoid or/and minimize artificial complications. PMID- 23343328 TI - Laws of large numbers and langevin approximations for stochastic neural field equations. AB - In this study, we consider limit theorems for microscopic stochastic models of neural fields. We show that the Wilson-Cowan equation can be obtained as the limit in uniform convergence on compacts in probability for a sequence of microscopic models when the number of neuron populations distributed in space and the number of neurons per population tend to infinity. This result also allows to obtain limits for qualitatively different stochastic convergence concepts, e.g., convergence in the mean. Further, we present a central limit theorem for the martingale part of the microscopic models which, suitably re-scaled, converges to a centred Gaussian process with independent increments. These two results provide the basis for presenting the neural field Langevin equation, a stochastic differential equation taking values in a Hilbert space, which is the infinite dimensional analogue of the chemical Langevin equation in the present setting. On a technical level, we apply recently developed law of large numbers and central limit theorems for piecewise deterministic processes taking values in Hilbert spaces to a master equation formulation of stochastic neuronal network models. These theorems are valid for processes taking values in Hilbert spaces, and by this are able to incorporate spatial structures of the underlying model.Mathematics Subject Classification (2000): 60F05, 60J25, 60J75, 92C20. PMID- 23343329 TI - Integrating mobile-phone based assessment for psychosis into people's everyday lives and clinical care: a qualitative study. AB - BACKGROUND: Over the past decade policy makers have emphasised the importance of healthcare technology in the management of long-term conditions. Mobile-phone based assessment may be one method of facilitating clinically- and cost-effective intervention, and increasing the autonomy and independence of service users. Recently, text-message and smartphone interfaces have been developed for the real time assessment of symptoms in individuals with schizophrenia. Little is currently understood about patients' perceptions of these systems, and how they might be implemented into their everyday routine and clinical care. METHOD: 24 community based individuals with non-affective psychosis completed a randomised repeated-measure cross-over design study, where they filled in self-report questions about their symptoms via text-messages on their own phone, or via a purpose designed software application for Android smartphones, for six days. Qualitative interviews were conducted in order to explore participants' perceptions and experiences of the devices, and thematic analysis was used to analyse the data. RESULTS: Three themes emerged from the data: i) the appeal of usability and familiarity, ii) acceptability, validity and integration into domestic routines, and iii) perceived impact on clinical care. Although participants generally found the technology non-stigmatising and well integrated into their everyday activities, the repetitiveness of the questions was identified as a likely barrier to long-term adoption. Potential benefits to the quality of care received were seen in terms of assisting clinicians, faster and more efficient data exchange, and aiding patient-clinician communication. However, patients often failed to see the relevance of the systems to their personal situations, and emphasised the threat to the person centred element of their care. CONCLUSIONS: The feedback presented in this paper suggests that patients are conscious of the benefits that mobile-phone based assessment could bring to clinical care, and that the technology can be successfully integrated into everyday routine. However, it also suggests that it is important to demonstrate to patients the personal, as well as theoretical, benefits of the technology. In the future it will be important to establish whether clinical practitioners are able to use this technology as part of a personalised mental health regime. PMID- 23343330 TI - Clinical outcomes of long-acting risperidone in recent versus long-term diagnosed Belgian schizophrenic patients: results from electronic Schizophrenia Treatment Adherence Registry (e-STAR) and Trial for the Initiation and Maintenance Of REmission in Schizophrenia with risperidone (TIMORES). AB - AIM: Potential differences in psychiatric clinical outcomes and hospitalization rates before and after the initiation of long-acting risperidone among recently and long-term diagnosed schizophrenia patients were studied. METHODS: Data from two observational studies (Trial for the Initiation and Maintenance Of REmission in Schizophrenia with risperidone (TIMORES) and electronic Schizophrenia Treatment Adherence Registry (e-STAR)) were categorized by the recency of their diagnose and compared in several post hoc analyses. Clinical Global Impression of illness Severity (CGI-S) and Global Assessment of Functioning (GAF) scores, as well as symptoms of clinical deterioration (including hospitalization data) at baseline, 12-month (for TIMORES and e-STAR) and 24-month (for e-STAR) follow-up were analysed. Other outcome measures included discontinuation rate, employment status and remission attainment. RESULTS: Statistically significantly differences between recent and long-term diagnosed schizophrenic patients at 12- and 24-month follow-up were found for CGI-S (between P < 0.01 and P <= 0.001) and GAF (P < 0.05) scores. Other differences between both schizophrenic patient groups were found for measures of clinical deterioration, employment status and full symptomatic remission rates at 1 year. Although no consistent difference was found between recent and long-term patient groups for hospitalization parameters, the difference in length of full hospitalization days was statistically significantly different (P < 0.01) between e-STAR 'Early' and 'Late' patient groups at both 12- and 24-month endpoints: the mean change from baseline was significantly greater for e-STAR 'Early' at 12 months, but greater for e-STAR 'Late' at 24 months. CONCLUSIONS: The findings of the post hoc analyses support the significance of pharmacological interventions, such as long-acting risperidone, in addressing discontinuity issues, especially in recently diagnosed patients. PMID- 23343331 TI - Turning on single-molecule magnet behavior in a linear {Mn3} compound. AB - The synthesis, structure, and magnetic properties are reported for a new manganese compound with a mixed-valent {Mn(3)} core arranged in a linear fashion. The previously reported complex 1, [Mn(IV)(3)(dpo)(6)].2MeCN, where H(2)dpo is (E)-1-hydroxy-1,1-diphenylpropan-2-one oxime, served as a starting point for the isolation of a {Mn(3)} compound with an analogous core arrangement through the reaction of Mn(OAc)(2).4H(2)O, H(3)oxol ((E)-2,5-dihydroxy-2,5-dimethylhexan-3 one oxime), and NaOH in MeOH and MeCN. By using these reaction conditions, compound 2, Na[Mn(IV)(2)Mn(III)(Hoxol)(6)](n).MeOH.H(2)O, was successfully isolated revealing a central Mn(III) ion thereby introducing structural and magnetic anisotropy to the system. The structure of 2 reveals linear trinuclear Mn(IV)-Mn(III)-Mn(IV) units connected through Na(+) ions forming a linear one dimensional coordination polymer. The Jahn-Teller axes of each trinuclear unit are aligned parallel within the same chain and form a 75 degrees angle between the two symmetry related chains. Magnetic susceptibility measurements of 1 and 2 in the temperature range 1.9-300 K reveal that only the reduced compound, 2, is a single-molecule magnet (SMM) largely due to the anisotropy introduced by the Jahn Teller distortions on the Mn(III) ions, which effectively induce this magnet behavior. Weak antiferromagnetic interactions along the chains through the Na(+) cations lead to a modulation of the intrinsic properties of the Mn(IV)-Mn(III) Mn(IV) SMMs. PMID- 23343332 TI - Verification of skin autofluorescence values by mass spectrometry in adolescents with type 1 diabetes: brief report. AB - BACKGROUND: Accumulation of advanced glycation end products (AGEs) in tissues is a major risk factor for diabetes-associated complications. Skin autofluorescence (SAF) values measured by a specific noninvasive approach (AGE Reader; DiagnOptics Technologies B.V., Groningen, The Netherlands) reflect the overall AGE exposure in skin. SUBJECTS AND METHODS: In 16 adolescents with type 1 diabetes (age range, 11-18 years) we tested the association between SAF measured with an AGE Reader and the presence of glucuronic acid, 3-indoxyl sulfate, 3-hydroxybutyrate, phenol sulfate, and pentosidine in skin tissue determined with desorption electrospray ionization mass spectrometry (DESI-MS). These compounds are implicated in long term diabetes complications. RESULTS: SAF values significantly correlated with levels of compounds measured by DESI-MS (r>0.9 and P<0.001 for each). CONCLUSIONS: The strong correlation between adolescents' SAF values measured with the AGE Reader and some glycation products measured with DESI-MS indicates that SAF values may be used as surrogate markers of skin exposure to glycemic end products in type 1 diabetes. PMID- 23343333 TI - What we can really expect from telemedicine in intensive diabetes treatment: 10 years later. AB - During the last 10 years many new telematic systems aiming at support of diabetes treatment have been designed and developed. Most systems that were applied in clinical randomized trials used the classical approach, with data transfers from patients performed usually once every few days. In the few available meta analyses of these trials, a significant improvement of the mean hemoglobin A1c was demonstrated in patients using telematic systems. However, the magnitude of this improvement in comparison with the control groups was lower than expected. This conclusion was confirmed by results of the IDEATel study involving more than 1,600 patients over a period of 5 years. It might by hypothesized that in some groups of patients continuous telecare with frequent contacts between patients and the care provider during each day should be required. This hypothesis is confirmed by the results of the clinical trials applying real-time diabetes monitoring systems. However, the increased frequency of the data transfers and checkups requires a new model for technology-supported care. The new model should connect together the ubiquitous data transfer with an automatically selected optimal frequency, the automatic assessment of the data coupled with quicker feedback from the decision support system or from the provider, and selection of the optimal time for the patient's face-to-face visit in the clinic. All this new future implementations together with already confirmed advantages of the telematic support, such as the increase of self-confidence of the patient, will hopefully give real benefits for the patients. PMID- 23343334 TI - Dispersant affects the cellular influences of single-wall carbon nanotube: the role of CNT as carrier of dispersants. AB - The application of carbon nanotube (CNT) as a functional material to engineering and life sciences is advanced. In order to evaluate the cytotoxicity of CNT in vitro, some chemical and biological reagents are used for dispersants. In the present study, the cellular influences of six kinds of chemical or biological reagents used as dispersants were examined. Pluronic F-127, Pluronic F-68, 1,2 dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), pulmonary surfactant preparation Surfacten(r), bovine serum albumin (BSA) and Tween 80 were used in the preparation of CNT-medium dispersants. The influences of each reagent on cell viability in human lung carcinoma A549 cells were small. However, Pluronic F-127, DPPC, Surfacten(r) and Tween 80 induced an increase of intracellular reactive oxygen species (ROS) level. Next, CNT-medium dispersions were prepared, using each reagent as a dispersant and applied to A549 cells. The cellular influences depended on the kind of dispersant. Cells exposed to CNT dispersion including Pluronic(r) F-127, Surfacten(r), DPPC and Tween 80 showed LDH release to the culture supernatant. Induction of intracellular ROS level was observed in cells exposed to CNT dispersion including each reagent except BSA. These results suggest that the adsorbed dispersant reagents on the surface of the CNT affect its cellular influences, particularly the induction of oxidative stress. PMID- 23343335 TI - Medicinal plants used by traditional practitioners of the Kole and Rai tribes of Bangladesh. PMID- 23343336 TI - High-pressure characterization of nitrogen-rich bis-triaminoguanidinium azotetrazolate (TAGzT) by in situ Raman spectroscopy. AB - Compounds rich in nitrogen are attracting significant interest not only because of their high energy content but also because they are potentially more environmentally benign in comparison to conventional energetic materials. Given this interest, it is desirable to understand their molecular composition and structural variations with pressure to derive their stability and determine the conditions in which they transform physically or chemically. In this study, we examine the room-temperature isothermal compression behavior of bis triaminoguanidinium azotetrazolate (TAGzT) by in situ Raman spectroscopy to pressures near 17 GPa. We assign the characteristic vibrational bands and report the effects of pressure on band intensity, line width, and frequency shift. Two prominent peaks near 1370 and 1470 cm(-1) arise from the C-N and N?N symmetric stretches, respectively. Overall, the intensity of these bands and others diminishes with pressure, and their spectral linewidths increase monotonically upon compression. The vibrational frequency modes blue shift linearly upon compression, indicating a generalized stiffening of the bonds as the pressure increases. These results, together with micro Raman spectroscopic analyses of the recovered, decompressed samples, suggest that TAGzT does not undergo any phase transitions within this pressure range. We estimate and report the C-N and N?N intermolecular bond lengths under compression. PMID- 23343337 TI - The complete mitochondrial genome of one band-winged grasshopper, Bryodema luctuosum luctuosum Stoll (Orthoptera: Acridoidea). AB - The complete mitochondrial genome of Bryodema luctuosum luctuosum, which was collected from the Qinghai-Xizang Plateau of China, is reported here. It is 15,946 bp in length and contains 74.9% AT. All B. luctuosum luctuosum protein coding sequences start with a typical ATN codon. The usual termination codon (TAA) and incomplete stop codons (T and TA) were found from 13 protein-coding genes. All tRNA genes could be folded into the typical cloverleaf secondary structure, excluding trnS(AGN) which forms another structure. The sizes of the large and small ribosomal RNA genes are 1316 and 835 bp, respectively. The AT content of the A+T-rich region is 84.8%. PMID- 23343338 TI - Usefulness of steroid administration for diagnosis of IgG4-related sclerosing cholangitis. AB - Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is one of the IgG4 related systemic sclerosing diseases and responds well to steroid therapy. A 58 year-old male was admitted with hilar bile duct stenosis revealed by computed tomography. We performed percutaneous transhepatic right portal vein embolization (PTPE) and scheduled a right hepatectomy because a hilar cholangiocarcinoma was first suspected. However, there was no cytologic evidence of malignancy and serum IgG4 was elevated. Steroid therapy was initiated after PTPE. There was no evidence of bile duct stenosis after 4 weeks. Improving diagnostic technique, IgG4-SC was diagnosed and treated with steroid therapy. In some cases, we couldn't deny the malignancy and performed unnecessary resection. We recommend that steroid administration while waiting for the liver volume to increase after PTPE is useful. The therapy aids in the diagnosis of bile duct stenosis, which has value for a hilar bile duct limit type of IgG4-SC, as in the case reported here. PMID- 23343339 TI - Interfacial study of class II hydrophobin and its mixtures with milk proteins: relationship to bubble stability. AB - Class II hydrophobin (HFBII) is a very promising ingredient for improving food foam stability. Pure HFBII-stabilized bubbles exhibited exceptional stability to disproportionation (dissolution) but were not stable to bubble coalescence induced by a pressure drop. Bubbles stabilized by mixtures of HFBII + sodium caseinate (SC) or beta-lactoglobulin (BL) showed decreased shrinkage rates compared to pure SC or BL and improved the stability to pressure-drop-induced coalescence. Higher bubble stability was more closely correlated with higher surface shear viscosity than the surface dilatational elasticity of the mixed protein systems. Brewster angle microscopy observations and the high shear strength of adsorbed films, including HFBII, even in the presence of hydrophobic and hydrogen-bond-breaking agents, confirm that intermolecular attractive cross links are unlikely to be the origin of the high strength of HFBII films. Possibly the HFBII molecules form a tightly interlocking monolayer of Janus-like particles at the air-water interface. PMID- 23343340 TI - Improving adjustments for older age in pre-hospital assessment and care. AB - Population estimates projects a significant increase in the geriatric population making elderly trauma patients more common. The geriatric trauma patients experience higher incidence of pre-existing medical conditions, impaired age dependent physiologic reserve, use potent drugs and suffer from trauma system related shortcomings that influence outcomes. To improve adjustments for older age in pre-hospital assessment and care, several initiatives should be implemented. Decision-makers should make system revisions and introduce advanced point-of-care initiatives to improve outcome after trauma for the elderly. PMID- 23343341 TI - Maxillary ridge augmentation with custom-made CAD/CAM scaffolds. A 1-year prospective study on 10 patients. AB - Several procedures have been proposed to achieve maxillary ridge augmentation. These require bone replacement materials to be manually cut, shaped, and formed at the time of implantation, resulting in an expensive and time-consuming process. In the present study, we describe a technique for the design and fabrication of custom-made scaffolds for maxillary ridge augmentation, using three-dimensional computerized tomography (3D CT) and computer-aided design/computer-aided manufacturing (CAD/CAM). CT images of the atrophic maxillary ridge of 10 patients were acquired and modified into 3D reconstruction models. These models were transferred as stereolithographic files to a CAD program, where a virtual 3D reconstruction of the alveolar ridge was generated, producing anatomically shaped, custom-made scaffolds. CAM software generated a set of tool-paths for manufacture by a computer-numerical-control milling machine into the exact shape of the reconstruction, starting from porous hydroxyapatite blocks. The custom-made scaffolds were of satisfactory size, shape, and appearance; they matched the defect area, suited the surgeon's requirements, and were easily implanted during surgery. This helped reduce the time for surgery and contributed to the good healing of the defects. PMID- 23343342 TI - Epidemiology and clinical presentation of the four human parainfluenza virus types. AB - BACKGROUND: Human parainfluenza viruses (HPIVs) are important causes of upper respiratory tract illness (URTI) and lower respiratory tract illness (LRTI). To analyse epidemiologic and clinical characteristics of the four types of human parainfluenza viruses (HPIVs), patients with acute respiratory tract illness (ARTI) were studied in Guangzhou, southern China. METHODS: Throat swabs (n=4755) were collected and tested from children and adults with ARTI over a 26-month period, and 4447 of 4755 (93.5%) patients' clinical presentations were recorded for further analysis. RESULTS: Of 4755 patients tested, 178 (3.7%) were positive for HPIV. Ninety-nine (2.1%) samples were positive for HPIV-3, 58 (1.2%) for HPIV 1, 19 (0.4%) for HPIV-2 and 8 (0.2%) for HPIV-4. 160/178 (88.9%) HPIV-positive samples were from paediatric patients younger than 5 years old, but no infant under one month of age was HPIV positive. Seasonal peaks of HPIV-3 and HPIV-1 occurred as autumn turned to winter and summer turned to autumn. HPIV-2 and HPIV 4 were detected less frequently, and their frequency of isolation increased when the frequency of HPIV-3 and HPIV-1 declined. HPIV infection led to a wide spectrum of symptoms, and more "hoarseness" (p=0.015), "abnormal pulmonary breathing sound" (p<0.001), "dyspnoea" (p<0.001), "pneumonia" (p=0.01), and "diarrhoea" (p<0.001) presented in HPIV-positive patients than HPIV-negative patients. 10/10 (100%) HPIV-positive adult patients (>=14 years old) presented with systemic influenza-like symptoms, while 90/164 (54.9%) HPIV-positive paediatric patients (<14 years old) presented with these symptoms (p=0.005). The only significant difference in clinical presentation between HPIV types was "Expectoration" (p<0.001). Co-infections were common, with 33.3%-63.2% of samples positive for the four HPIV types also testing positive for other respiratory pathogens. However, no significant differences were seen in clinical presentation between patients solely infected with HPIV and patients co-infected with HPIV and other respiratory pathogens. CONCLUSIONS: HPIV infection led to a wide spectrum of symptoms, and similar clinical manifestations were found in the patients with four different types of HPIVs. The study suggested pathogenic activity of HPIV in gastrointestinal illness. The clinical presentation of HPIV infection may differ by patient age. PMID- 23343343 TI - Cytoskeletal and membrane dynamics during higher plant cytokinesis. AB - Following mitosis, cytoplasm, organelles and genetic material are partitioned into daughter cells through the process of cytokinesis. In somatic cells of higher plants, two cytoskeletal arrays, the preprophase band and the phragmoplast, facilitate the positioning and de novo assembly of the plant specific cytokinetic organelle, the cell plate, which develops across the division plane and fuses with the parental plasma membrane to yield distinct new cells. The coordination of cytoskeletal and membrane dynamics required to initiate, assemble and shape the cell plate as it grows toward the mother cell cortex is dependent upon a large array of proteins, including molecular motors, membrane tethering, fusion and restructuring factors and biosynthetic, structural and regulatory elements. This review focuses on the temporal and molecular requirements of cytokinesis in somatic cells of higher plants gleaned from recent studies using cell biology, genetics, pharmacology and biochemistry. PMID- 23343344 TI - C3G forms complexes with Bcr-Abl and p38alpha MAPK at the focal adhesions in chronic myeloid leukemia cells: implication in the regulation of leukemic cell adhesion. AB - BACKGROUND: Previous studies by our group and others have shown that C3G interacts with Bcr-Abl through its SH3-b domain. RESULTS: In this work we show that C3G and Bcr-Abl form complexes with the focal adhesion (FA) proteins CrkL, p130Cas, Cbl and Abi1 through SH3/SH3-b interactions. The association between C3G and Bcr-Abl decreased upon Abi1 or p130Cas knock-down in K562 cells, which suggests that Abi1 and p130Cas are essential partners in this interaction. On the other hand, C3G, Abi1 or Cbl knock-down impaired adhesion to fibronectin, while p130Cas silencing enhanced it. C3G, Cbl and p130Cas-SH3-b domains interact directly with common proteins involved in the regulation of cell adhesion and migration. Immunoprecipitation and immunofluorescence studies revealed that C3G form complexes with the FA proteins paxillin and FAK and their phosphorylated forms. Additionally, C3G, Abi1, Cbl and p130Cas regulate the expression and phosphorylation of paxillin and FAK. p38alpha MAPK also participates in the regulation of adhesion in chronic myeloid leukemia cells. It interacts with C3G, CrkL, FAK and paxillin and regulates the expression of paxillin, CrkL and alpha5 integrin, as well as paxillin phosphorylation. Moreover, double knock-down of C3G/p38alpha decreased adhesion to fibronectin, similarly to the single silencing of one of these genes, either C3G or p38alpha. These suggest that C3G and p38alpha MAPK are acting through a common pathway to regulate cell adhesion in K562 cells, as previously described for the regulation of apoptosis. CONCLUSIONS: Our results indicate that C3G-p38alphaMAPK pathway regulates K562 cell adhesion through the interaction with FA proteins and Bcr-Abl, modulating the formation of different protein complexes at FA. PMID- 23343345 TI - Fast translocation of proteins through solid state nanopores. AB - Measurements on protein translocation through solid-state nanopores reveal anomalous (non-Smoluchowski) transport behavior, as evidenced by extremely low detected event rates; that is, the capture rates are orders of magnitude smaller than what is theoretically expected. Systematic experimental measurements of the event rate dependence on the diffusion constant are performed by translocating proteins ranging in size from 6 to 660 kDa. The discrepancy is observed to be significantly larger for smaller proteins, which move faster and have a lower signal-to-noise ratio. This is further confirmed by measuring the event rate dependence on the pore size and concentration for a large 540 kDa protein and a small 37 kDa protein, where only the large protein follows the expected behavior. We dismiss various possible causes for this phenomenon and conclude that it is due to a combination of the limited temporal resolution and low signal-to-noise ratio. A one-dimensional first-passage time-distribution model supports this and suggests that the bulk of the proteins translocate on time scales faster than can be detected. We discuss the implications for protein characterization using solid state nanopores and highlight several possible routes to address this problem. PMID- 23343346 TI - Efficient two-electron reduction of dioxygen to hydrogen peroxide with one electron reductants with a small overpotential catalyzed by a cobalt chlorin complex. AB - A cobalt chlorin complex (Co(II)(Ch)) efficiently and selectively catalyzed two electron reduction of dioxygen (O(2)) by one-electron reductants (ferrocene derivatives) to produce hydrogen peroxide (H(2)O(2)) in the presence of perchloric acid (HClO(4)) in benzonitrile (PhCN) at 298 K. The catalytic reactivity of Co(II)(Ch) was much higher than that of a cobalt porphyrin complex (Co(II)(OEP), OEP(2-) = octaethylporphyrin dianion), which is a typical porphyrinoid complex. The two-electron reduction of O(2) by 1,1'-dibromoferrocene (Br(2)Fc) was catalyzed by Co(II)(Ch), whereas virtually no reduction of O(2) occurred with Co(II)(OEP). In addition, Co(II)(Ch) is more stable than Co(II)(OEP), where the catalytic turnover number (TON) of the two-electron reduction of O(2) catalyzed by Co(II)(Ch) exceeded 30000. The detailed kinetic studies have revealed that the rate-determining step in the catalytic cycle is the proton-coupled electron transfer reduction of O(2) with the protonated Co(II)(Ch) ([Co(II)(ChH)](+)) that is produced by facile electron-transfer reduction of [Co(III)(ChH)](2+) by ferrocene derivative in the presence of HClO(4). The one-electron-reduction potential of [Co(III)(Ch)](+) was positively shifted from 0.37 V (vs SCE) to 0.48 V by the addition of HClO(4) due to the protonation of [Co(III)(Ch)](+). Such a positive shift of [Co(III)(Ch)](+) by protonation resulted in enhancement of the catalytic reactivity of [Co(III)(ChH)](2+) for the two-electron reduction of O(2) with a lower overpotential as compared with that of [Co(III)(OEP)](+). PMID- 23343347 TI - Dynamic PET/CT measurements of induced positron activity in a prostate cancer patient after 50-MV photon radiation therapy. AB - BACKGROUND: The purpose of this work was to reveal the research interest value of positron emission tomography (PET) imaging in visualizing the induced tissue activity post high-energy photon radiation treatment. More specifically, the focus was on the possibility of retrieving data such as tissue composition and physical half-lives from dynamic PET acquisitions, as positron-emitting radionuclides such as 15O, 11C, and 13N are produced in vivo during radiation treatment with high-energy photons (>15 MeV). The type, amount, and distribution of induced positron-emitting radionuclides depend on the irradiated tissue cross section, the photon spectrum, and the possible perfusion-driven washout. METHODS: A 62-year-old man diagnosed with prostate cancer was referred for palliative radiation treatment of the pelvis minor. A total dose of 8 Gy was given using high-energy photon beams (50 MV) with a racetrack microtron, and 7 min after the end of irradiation, the patient was positioned in a PET/computed tomography (CT) camera, and a list-mode acquisition was performed for 30 min. Two volumes of interests (VOIs) were positioned on the dynamic PET/CT images, one in the urinary bladder and the other in the subcutaneous fat. Analysis of the measured relative count rate was performed in order to compute the tissue compositions and physical half-lives in the two regions. RESULTS: Dynamic analysis from the two VOIs showed that the decay constants of activated oxygen and carbon could be deduced. Calculation of tissue composition from analyzing the VOI containing subcutaneous fat only moderately agreed with that of the tabulated International Commission on Radiation Units & Measurements (ICRU) data of the adipose tissue. However, the same analysis for the bladder showed a good agreement with that of the tabulated ICRU data. CONCLUSIONS: PET can be used in visualizing the induced activity post high-energy photon radiation treatment. Despite the very low count rate in this specific application, wherein 7 min after treatment was about 5% of that of a standard 18F-FDG PET scan, the distribution of activated tissue elements (15O and 11C) could be calculated from the dynamic PET data. One possible future application of this method could possibly be to measure and determine the tumor tissue composition in order to identify any hypoxic or necrotic region, which is information that can be used in the ongoing therapy planning process. TRIAL REGISTRATION: The official name of the trial committee of this study is 'Regionala etikprovningsnamnden i Stockholm' (FE 289, Stockholm, SE-17177, Sweden). The unique identifying number is 2011/1789-31/2. PMID- 23343348 TI - Assessing psychotic-like symptoms using the BASC-2: adolescent, parent and teacher agreement. AB - AIM: The aim of the current study was to investigate the psychometric properties of the BASC-2 (Behavior Assessment System for Children, Second Edition) Atypicality subscale in a sample of adolescents receiving mental health services. METHODS: A large sample (n = 1916) of adolescents aged 12-20 years (median = 14.7 years) completed the BASC-2. A parent and teacher also completed the measure for each child. We analyzed internal consistency and interrater reliabilities for the Atypicality subscale, as well as the Depression and Hyperactivity subscales for comparison. Further analyses explored the influence of a participant's subscale scores, gender, and quality of relationships with adults on interrater agreement. RESULTS: All subscales demonstrated good internal consistency; however, interrater agreement was low for all subscales. Gender, Atypicality subscale score, and self-reported quality of relationships with adults could not account for poor interrater agreement. CONCLUSIONS: The Atypicality subscale has strong internal consistency across informants. Low interrater agreement for the Atypicality subscale, as well as other scales, however, presents a challenge when interpreting multi-informant scales. PMID- 23343350 TI - The effects of vitamin C on DDP-induced anemia in rats. AB - The aim of this study was to investigate the effects of vitamin C on cisplatin (DDP)-induced anemia and explore its possible mechanisms in rats. Adult male Sprague-Dawley rats were randomly divided into six groups: control, vitamin C 50, vitamin C 100, DDP, DDP plus vitamin C 50 and DDP plus vitamin C 100-treated groups. DDP was intravenous injected as a single dose and vitamin C was administered by gavage. Serum erythropoietin (Epo), hemoglobin (Hb) and blood urea nitrogen (BUN) concentration were measured 4 and 14 days after DDP treatment. The changes of renal tissue were examined by light microscope. Administration of DDP to rats induced anemia and nephrotoxicity, characterized with a significant decrease in serum Epo and Hb and increase in BUN concentrations. Pathological examination revealed that DDP caused significant renal damage in rats. Vitamin C administration produced amelioration in biochemical indices of anemia and nephrotoxicity and in histological change when compared to group DDP alone; concurrent administration of vitamin C at doses of 100 mg/kg being more effective. Results from this study indicate that the novel natural antioxidant vitamin C might have protective effect against DDP-induced anemia in rats. PMID- 23343351 TI - The age-related change of glutathione antioxidant system in mice liver. AB - Cellular glutathione (GSH) antioxidant system is an important defensive system of the body, which is crucial in the protection against oxidative stress-induced liver injury. The present study was designed to observe the difference of this system in the liver of mice with 1-month- and 12-month-old. Liver reduced GSH level was showed no difference between these two groups of mice. Next, the results showed that liver glutamate-cysteine ligase (GCL) activity was higher in mice of 1-month- than 12-month-old, while glutathione-S-transferase (GST) activity was higher in mice of 12-month- than 1-month-old. Further results showed that the higher activity of liver GCL in 1-month-old mice was due to the higher expression of catalytic subunit of GCL (GCLc) mRNA, while the higher activity of liver GST in 12-month-old mice might be due to the higher expression of GSTA1, GSTA2, GSTP1 and GSTP2 mRNA. Taken together, our results revealed the age-related change of liver GSH antioxidant system in mice, which may be helpful for elucidating some age-related liver injury or diseases. PMID- 23343349 TI - Bovine neonatal pancytopenia--comparative proteomic characterization of two BVD vaccines and the producer cell surface proteome (MDBK). AB - BACKGROUND: Bovine neonatal pancytopenia (BNP) is a disease syndrome in newborn calves of up to four weeks of age, first observed in southern Germany in 2006. By now, cases have been reported in several countries around the globe. Many affected calves die within days due to multiple haemorrhages, thrombocytopenia, leukocytopenia and bone marrow depletion. A certain vaccine directed against Bovine Virus Diarrhoea Virus (BVDV) was recently shown to be associated with BNP pathogenesis. Immunized cows develop alloantibodies that are transferred to newborn calves via colostrum intake. In order to further elucidate BNP pathogenesis, the purpose of this study was to characterize and compare the protein composition of the associated vaccine to another vaccine directed against BVDV not related to BNP and the cell surface proteome of MDBK (Madin-Darby Bovine Kidney) cells, the cell line used for production of the associated vaccine. RESULTS: By SDS-PAGE and mass spectrometry, we were able to detect several coagulation-related and immune modulatory proteins, as well as cellular and serum derived molecules being shared between the associated vaccine and MDBK cells. Furthermore, the number of proteins identified in the BNP related vaccine was almost as high as the number of surface proteins detected on MDBK cells and exceeded the amount of proteins identified in the non-BNP related vaccine over 3.5 fold. The great amount of shared cellular and serum derived proteins confirm that the BNP associated vaccine contained many molecules originating from MDBK cells and vaccine production. CONCLUSIONS: The respective vaccine was not purified enough to prevent the development of alloantibodies. To narrow down possible candidate proteins, those most likely to represent a trigger for BNP pathogenesis are presented in this study, giving a fundament for further analysis in future research. PMID- 23343352 TI - Sildenafil citrate attenuates the deleterious effects of elevated ammonia. AB - Ammonia is a bi-product of protein metabolism in the body. It is able to cross the blood-brain barrier and elevated ammonia levels are toxic to the brain. Rats with hyperammonemia showed impaired learning ability and impaired function of the glutamate-nitric oxide-cyclic guanosine monophosphate (glutamate-NO-cGMP) pathway in the brain. Chronic treatment with sildenafil restored learning ability. We therefore tested the hypothesis that sildenafil has a protective effect on the brains of hyperammonemic rats. Hyperammonemia was induced in male rats by daily intraperitoneal (i.p.) injection of ammonium chloride (100 mg/kg body weight) for 8 weeks. Sildenafil citrate was administered intraperitoneally (10 mg/kg body weight/3 days) for 8 weeks. Treatment with sildenafil resulted in a significant reduction in plasma liver enzymes, lipid profile as well as brain lipid peroxidation and caspase-3 mRNA. Meanwhile, plasma NO as well as cGMP, antioxidants and endothelial nitric oxide synthase (eNOS) gene expression were significantly elevated in the brains of hyperammonemic rats. Our results showed that sildenafil exerts a protective effect on the brain by reversing oxidative stress during hyperammonemia and this could be due to (i) cytoprotective, antioxidant and anti-apoptotic effects (ii) increasing cGMP and enhancing the proper metabolism of fats which could suppress oxygen radical generation and thus preventing oxidative damage in the brain. The exact protective mechanism of sildenafil has to be still investigated and further studies are warranted. Consequently, therapeutic modulation of the NO/cGMP pathway might have important clinical applications to improve brain functions in patients with hyperammonemia or clinical hepatic encephalopathy. PMID- 23343353 TI - Hepatoprotective effects of DL-alpha-lipoic acid and alpha-Tocopherol through amelioration of the mitochondrial oxidative stress in acetaminophen challenged rats. AB - Acetaminophen (APAP) is known to induce liver mitochondrial dysfunction leading to acute hepatotoxicity. Effect of DL-alpha-lipoic acid (LA) and alpha-tocopherol (alpha-Toc) against the APAP-induced liver mitochondrial damage was evaluated in rats. LA (100 mg/kg, p.o.) and alpha-Toc (100 mg/kg, p.o.) were given once daily for 15 d, prior to the APAP administration (3 g/kg, p.o). Hepatic damage was confirmed by determining the activities of serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase and alkaline phosphatase, 4 h after the single dose of APAP. To assess the mitochondrial damage, the activities of antioxidant enzymes, Krebs' cycle dehydrogenases and mitochondrial electron transport chain complexes, and levels of reactive oxygen species (ROS), reduced glutathione, lipid peroxidation (malondialdehyde, MDA) as well as the mitochondrial membrane potential (Deltapsimt) were evaluated. The activities of mitochondrial enzymes and Deltapsimt were significantly (p < 0.01) decreased and the level of ROS and MDA were significantly (p < 0.01) increased due to APAP challenge. LA and alpha-Toc treatment significantly enhanced the activities of mitochondrial enzymes and Deltapsimt than that of control group; whereas the levels of ROS and MDA were decreased. The results of the study concluded that the liver damage induced by APAP was significantly ameliorated by LA and alpha-Toc. LA showed more protection than that of alpha-Toc. The protection can be partially ascribed to their mitochondrial protective effects through their antioxidant activity which could decrease the level of ROS and by direct enhancement of Deltapsimt. PMID- 23343354 TI - Structural and spectroscopic characterization of 17- and 18-electron piano-stool complexes of chromium. Thermochemical analyses of weak Cr-H bonds. AB - The 17-electron radical CpCr(CO)(2)(IMe)(*) (IMe = 1,3-dimethylimidazol-2 ylidene) was synthesized by the reaction of IMe with [CpCr(CO)(3)](2), and characterized by single crystal X-ray diffraction and by electron paramagnetic resonance (EPR), IR, and variable temperature (1)H NMR spectroscopy. The metal centered radical is monomeric under all conditions and exhibits Curie paramagnetic behavior in solution. An electrochemically reversible reduction to 18-electron CpCr(CO)(2)(IMe)(-) takes place at E(1/2) = -1.89(1) V vs Cp(2)Fe(+*/0) in MeCN, and was accomplished chemically with KC(8) in tetrahydrofuran (THF). The salts K(+)(18-crown-6)[CpCr(CO)(2)(IMe)](-).1/2THF and K(+)[CpCr(CO)(2)(IMe)](-).(3)/(4)THF were crystallographically characterized. Monomeric ion pairs are found in the former, whereas the latter has a polymeric structure because of a network of K...O((CO)) interactions. Protonation of K(+)(18-crown-6)[CpCr(CO)(2)(IMe)](-).1/2THF gives the hydride CpCr(CO)(2)(IMe)H, which could not be isolated, but was characterized in solution; a pK(a) of 27.2(4) was determined in MeCN. A thermochemical analysis provides the Cr-H bond dissociation free energy (BDFE) for CpCr(CO)(2)(IMe)H in MeCN solution as 47.3(6) kcal mol(-1). This value is exceptionally low for a transition metal hydride, and implies that the reaction 2 [Cr-H] -> 2 [Cr(*)] + H(2) is exergonic (DeltaG = 9.0(8) kcal mol(-1)). This analysis explains the experimental observation that generated solutions of the hydride produce CpCr(CO)(2)(IMe)(*) (typically on the time scale of days). By contrast, CpCr(CO)(2)(PCy(3))H has a higher Cr-H BDFE (52.9(4) kcal mol(-1)), is more stable with respect to H(2) loss, and is isolable. PMID- 23343355 TI - Beyond NF-kappaB activation: nuclear functions of IkappaB kinase alpha. AB - IkappaB kinase (IKK) complex, the master kinase for NF-kappaB activation, contains two kinase subunits, IKKalpha and IKKbeta. In addition to mediating NF kappaB signaling by phosphorylating IkappaB proteins during inflammatory and immune responses, the activation of the IKK complex also responds to various stimuli to regulate diverse functions independently of NF-kappaB. Although these two kinases share structural and biochemical similarities, different sub-cellular localization and phosphorylation targets between IKKalpha and IKKbeta account for their distinct physiological and pathological roles. While IKKbeta is predominantly cytoplasmic, IKKalpha has been found to shuttle between the cytoplasm and the nucleus. The nuclear-specific roles of IKKalpha have brought increasing complexity to its biological function. This review highlights major advances in the studies of the nuclear functions of IKKalpha and the mechanisms of IKKalpha nuclear translocation. Understanding the nuclear activity is essential for targeting IKKalpha for therapeutics. PMID- 23343356 TI - HIV-infected mental health patients: characteristics and comparison with HIV infected patients from the general population and non-infected mental health patients. AB - OBJECTIVES: HIV-infected patients are at increased risk of developing mental health symptoms, which negatively influence the treatment of the HIV-infection. Mental health problems in HIV-infected patients may affect public health. Psychopathology, including depression and substance abuse, can increase hazardous sexual behaviour and, with it, the chance of spreading HIV. Therefore, it is important to develop an optimal treatment plan for HIV-infected patients with mental health problems. The majority of HIV-infected patients in the Netherlands (almost 60%) are homosexual men.The main objectives of this study were to describe the clinical and demographic characteristics of patients with HIV who seek treatment for their mental health symptoms in the Netherlands. Secondly, we tested whether HIV infected and non-infected homosexual patients with a lifetime depressive disorder differed on several mental health symptoms. METHODS: We compared a cohort of 196 patients who visited the outpatient clinic for HIV and Mental Health with HIV-infected patients in the general population in Amsterdam (ATHENA-study) and with non-HIV infected mental health patients (NESDA-study). DSM-IV diagnoses were determined, and several self-report questionnaires were used to assess mental health symptoms. RESULTS: Depressive disorders were the most commonly occurring diagnoses in the cohort and frequent drug use was common. HIV-infected homosexual men with a depressive disorder showed no difference in depressive symptoms or sleep disturbance, compared with non-infected depressive men. However, HIV-positive patients did express more symptoms like fear, anger and guilt. Although they showed significantly more suicidal ideation, suicide attempts were not more prevalent among HIV-infected patients. Finally, the HIV infected depressive patients displayed a considerably higher level of drug use than the HIV-negative group. CONCLUSION: Habitual drug use is a risk factor for spreading HIV. It is also more often diagnosed in HIV-infected homosexual men with a lifetime depression or dysthymic disorder than in the non-infected population. Untreated mental health problems, such as depressive symptoms and use of drugs can have serious repercussions. Therefore, general practitioners and internists should be trained to recognize mental health problems in HIV-infected patients. PMID- 23343357 TI - Documenting outdoor activity and travel behaviour in persons with neurological conditions using travel diaries and GPS tracking technology: a pilot study in multiple sclerosis. AB - OBJECTIVE: Persons with multiple sclerosis (PwMS) experience several physical and cognitive problems which can influence their travel behaviour. This study aimed to document the number of activities, the activity type and the transport mode of the related trips that are daily made by PwMS. Their outdoor activity and travel behaviour was studied in relation to disease-related disability. METHODS: Thirty six PwMS (Expanded Disability Status Scale, EDSS, 1.5-8.0, age 27-63) and 24 healthy controls (age 25-62) were studied, using activity-related travel diaries and GPS tracking devices. Information about overall disability characteristics was gained by standard clinical tests and questionnaires. PwMS were further divided in three subgroups based on EDSS cut-off scores 4.5 and 6.5. RESULTS: Persons with mild ambulatory dysfunction (EDSS 1.5-4.0, n = 17) showed similar travel characteristics to healthy controls, with few restrictions during travelling. Statistically significant changes in activity and travel behaviour were detected in the moderate (EDSS 4.5-6.5, n = 8) and severe MS subgroups (EDSS > 6.5-8.0, n = 11) compared with healthy controls: driving independently became less frequent, significant more trips were made with company and the duration of performed activities had increased. CONCLUSION: The combination of self-reported travel diaries and objective GPS loggers offered detailed information about the actual outdoor travel behaviour of PwMS, which was significantly changed in PwMS with EDSS greater than 4. Implications for Rehabilitation Activity and travel behaviour changes significantly in persons with multiple sclerosis (MS) with moderate to severe disability (EDSS greater than 4). Behavioural therapy could help to develop better coping and problem-solving skills to overcome anxiety in the making of trips by persons with MS with a mild severity. Enhancing community environments could serve as a promising approach to increase the outdoor participation of persons with (more severe) impairments. PMID- 23343358 TI - Connecting rehabilitation and everyday life--the lived experiences among women with stress-related ill health. AB - PURPOSE: The aim was to describe and understand how connecting rehabilitation experiences and everyday life was characterised in the lived experiences during the rehabilitation in women with stress-related ill health. METHOD: Five women were interviewed on three occasions during a rehabilitation programme and once 3 months later. Data were analysed using the Empirical, Phenomenological and Psychological method. RESULTS: The participants experienced connections between their rehabilitation and their previous, present and future everyday life influencing both rehabilitation and everyday life in a back-and-forth process. These connections were experienced in mind or in doing, mostly targeting the private arena in everyday life. Connecting rehabilitation experiences to their working situations was more challenging and feelings of frustration and being left alone were experienced. CONCLUSIONS: Although the participants described constructive connections between rehabilitation experiences and the private arena in everyday life, they mostly failed to experience connections that facilitated a positive return to work. Recommended support in the return to work process in rehabilitation comprises the provision of practical work-related activities during rehabilitation; being supportive in a constructive dialogue between the participant and the workplace, and continuing this support in follow-ups after the actual rehabilitation period. IMPLICATIONS FOR REHABILITATION: Rehabilitation for persons with stress-related ill health needs to focus on the private arena as well as the work situation in everyday life. Creative activities may enable experiences that inspire connections in mind and connections targeting the private arena in everyday life. The work situation needs to be thoroughly discussed during rehabilitation for enabling the participants to experience a support in the return to work process. Rehabilitation including practical work related activities, support in a constructive dialogue between the participant and the manager at the workplace, and continued support in follow-ups targeting the workplace might be beneficial for successfully return to work. PMID- 23343359 TI - The spinal cord independence measure: how much change is clinically significant for spinal cord injury subjects. AB - PURPOSE: To calculate the clinical significance of the SCIM III according to distribution-based approaches. METHOD: Retrospective review of the charts of 255 patients with registration of the total SCIM and of the four subscales. Clinical significance was calculated per several distribution-based approaches. The calculated clinical significance was compared with improvements by the patients to determine the percentage of patients who achieved significant improvement. RESULTS: An improvement of at least 4 points of the total SCIM is needed to obtain a small significant improvement and of 10 points to obtain a substantial improvement. Based on these results, the percentages of patients who achieved an improvement varied from 60% to 100%. CONCLUSIONS: The results provide benchmarks for clinicians and researchers to interpret whether patients' change score on the SCIM III can be interpreted as true or clinically meaningful and to make clinical judgments about the patients' progress. IMPLICATIONS FOR REHABILITATION: An improvement of at least four points of the total SCIM is needed to obtain a small significant improvement and of 10 points to obtain a substantial improvement. The results provide benchmarks for clinicians and researchers to interpret whether patients' change score on the SCIM III can be interpreted as true or clinically meaningful and to make clinical judgments about the patients' progress. PMID- 23343360 TI - Comprehensive ICF core set for obstructive pulmonary diseases: validation of the activities and participation component through the patient's perspective. AB - PURPOSE: This study aimed to validate the Activities and Participation component of the Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for Obstructive Pulmonary Diseases (OPD) from the patient's perspective. METHODS: A cross-sectional qualitative study was conducted with a convenience sample of outpatients with Chronic Obstructive Pulmonary Disease (COPD). Individual interviews were performed and analysed according to the meaning condensation procedure. RESULTS: Fifty-one participants (70.6% male) with a mean age of 69.5 +/- 10.8 years old were included. Twenty-one of the 24 categories contained in the Activities and Participation component of the Comprehensive ICF Core Set for OPD were identified by the participants. Additionally, seven second-level categories that are not covered by the Core Set were reported: complex interpersonal interactions, informal social relationships, family relationships, conversation, maintaining a body position, eating and preparing meals. CONCLUSIONS: The activities and participation component of the ICF Core Set for OPD was largely supported by the patient's perspective. The categories included in the ICF Core Set that were not confirmed by the participants and the additional categories that were raised need to be further investigated in order to develop an instrument according to the patient's perspective. This will promote a more patient-centred assessments and rehabilitation interventions. Implications for Rehabilitation The Activities and Participation component of the Comprehensive ICF Core Set for OPD is largely supported by the perspective of patients with COPD and therefore could be used in the assessment of patients' individual and social life. The information collected through the Activities and Participation component of the Comprehensive ICF Core Set for OPD could be used to plan and assess rehabilitation interventions for patients with COPD. PMID- 23343361 TI - Community-based rehabilitation in Jordan: challenges to achieving occupational justice. AB - PURPOSE: This paper presents theories of occupational and social justice and applies the theoretical tenets to a community-based rehabilitation (CBR) program in a Palestinian refugee camp in Jordan. METHOD: The example of building a playground for children with disabilities, and other aspects of the social, political and cultural context in Jordan are described in relation to the theory and practice of CBR, occupational and social justice. RESULTS: Key concepts are explained, analyzed and applied, namely occupational justice, social justice, occupational form and occupational deprivation (a strong determinant of occupational injustice), all of which were relevant in the refugee camp where children with disabilities were deprived of resources and chances to play. CONCLUSION: Grounding CBR in an occupational justice framework offers justification and inspiration for occupational therapy in similar settings deprived of resources and opportunities wherein both individuals and communities could benefit. IMPLICATIONS FOR REHABILITATION: Occupational deprivation, such as that seen in refugee camps, is associated with poor mental health and physical frailty. CBR in refugee camps can lead to both occupational justice and social justice for persons with disabilities. Disability laws and legislation must be implemented, not just stated on paper, in order to address the rights of persons with disabilities and social justice. PMID- 23343362 TI - Geographic information systems (GIS): an emerging method to assess demand and provision for rehabilitation services. AB - PURPOSE: To illustrate the application of geographic information systems (GIS) as a tool to assess rehabilitation service delivery by presenting results from research recently conducted to assess demand and provision for community rehabilitation service delivery in Ontario, Canada. METHODS: Secondary analysis of data obtained from existing sources was used to establish demand and provision profiles for community rehabilitation services. These data were integrated using GIS software. RESULTS: A number of descriptive maps were produced that show the geographical distribution of service provision variables (location of individual rehabilitation health care providers and location of private and publicly funded community rehabilitation clinics) in relation to the distribution of demand variables (location of the general population; location of specific populations (i.e., residents age 65 and older) and distribution of household income). CONCLUSIONS: GIS provides a set of tools for describing and understanding the spatial organization of the health of populations and the distribution of health services that can aid the development of health policy and answer key research questions with respect to rehabilitation health services delivery. Implications for Rehabilitation It is important to seek out alternative and innovative methods to examine rehabilitation service delivery. GIS is a computer-based program that takes any data linked to a geographically referenced location and processes it through a software system that manages, analyses and displays the data in the form of a map, allowing for an alternative level of analysis. GIS provides a set of tools for describing and understanding the spatial organization of population health and health services that can aid the development of health policy and answer key research questions with respect to rehabilitation health services delivery. PMID- 23343363 TI - A cluster randomised controlled trial on the efficacy of client-centred occupational therapy in multiple sclerosis: good process, poor outcome. AB - PURPOSE: To assess the efficacy of client-centred occupational therapy (OT) according to a client-centred process framework, as compared to usual care OT, in patients with multiple sclerosis (MS). METHOD: A multicentre cluster randomised controlled trial with the institution (i.e. hospital or rehabilitation centre) as the unit of randomisation was performed. A total of 269 outpatients with MS, 13 hospitals and rehabilitation centres and 29 occupational therapists participated. Primary outcomes included measures of disability, participation and autonomy. Secondary outcomes included fatigue, generic health-related quality of life, quality and evaluation of therapy, therapy compliance and therapy frequency. Measurements were taken at baseline, four months and at eight months follow-up. RESULTS: Primary outcome measures did not show significant differences between the two interventions. Secondary outcomes revealed significant differences in favour of the usual care OT on fatigue (physical scale and total scale) and health-related quality of life (bodily pain and vitality) at four months. After eight months only significant differences on mental health were found. Process outcomes (i.e. the information scale of therapy quality and the client centredness of the organisation) were in favour of the client-centred intervention. CONCLUSION: Because the client-centred intervention resulted in no effects on the primary outcomes and small but negative effects on the secondary functional outcomes, we should seriously reconsider the application of client centred practice. IMPLICATIONS FOR REHABILITATION: An increasing number of interventions claim to incorporate client-centred practice. Client-centred practice is associated with improved satisfaction but the effects on functional health-related outcomes have not been fully evaluated. The findings of this study show that the process outcomes of therapy were in favour of the client-centred intervention, but no effects were found on the primary outcomes and negative effects on the secondary functional health outcomes. It is suggested that the implementation of client-centred practice should be adjusted in order to achieve optimal health outcomes. PMID- 23343365 TI - Impact of geometry optimization on base-base stacking interaction energies in the canonical A- and B-forms of DNA. AB - Base stacking is known to make an important contribution to the stability of DNA and RNA, and accordingly, significant efforts are ongoing to calculate stacking energies using ab initio quantum mechanical methods. To date, impressive improvements have been made in the model chemistries used to perform stacking energy calculations, including extensions that include robust treatments of electron correlation with extended basis sets, as required to treat interactions where dispersion makes a significant contribution. However, those efforts typically use rigid monomer geometries when calculating the interaction energies. To overcome this, in the present work, we describe a novel internal coordinate definition that allows the relative, intermolecular orientation of stacked base monomers to be constrained during geometry optimizations while allowing full optimization of the intramolecular degrees of freedom. Use of the novel reference frame to calculate the impact of full geometry optimization versus constraining the bases to be planar on base monomer stacking energies, combined with density fitted, spin-component scaling MP2 treatment of electron correlation, shows that full optimization makes the average stacking energy more favorable by -3.4 and 1.5 kcal/mol for the canonical A and B conformations of the 16 5' to 3' base stacked monomers. Thus, treatment of geometry optimization impacts the stacking energies to an extent similar to or greater than the impact of current state of the art increases in the rigor of the model chemistry itself used to treat base stacking. Results also indicate that stacking favors the B-form of DNA, though the average difference versus the A-form decreases from -2.6 to -0.6 kcal/mol when the intramolecular geometry is allowed to fully relax. However, stacking involving cytosine is shown to favor the A-form of DNA, with that contribution generally larger in the fully optimized bases. The present results show the importance of allowing geometry optimization, as well as properly treating the appropriate model chemistry, in studies of nucleic acid base stacking. PMID- 23343366 TI - Aspergillosis in Intensive Care Unit (ICU) patients: epidemiology and economic outcomes. AB - BACKGROUND: Few data are available regarding the epidemiology of invasive aspergillosis (IA) in ICU patients. The aim of this study was to examine epidemiology and economic outcomes (length of stay, hospital costs) among ICU patients with IA who lack traditional risk factors for IA, such as cancer, transplants, neutropenia or HIV infection. METHODS: Retrospective cohort study using Premier Inc. PerspectiveTM US administrative hospital database (2005-2008). Adults with ICU stays and aspergillosis (ICD-9 117.3 plus 484.6) who received initial antifungal therapy (AF) in the ICU were included. Patients with traditional risk factors (cancer, transplant, neutropenia, HIV/AIDS) were excluded. The relationship of antifungal therapy and co-morbidities to economic outcomes were examined using Generalized linear models. RESULTS: From 6,424 aspergillosis patients in the database, 412 (6.4%) ICU patients with IA were identified. Mean age was 63.9 years and 53% were male. Frequent co-morbidities included steroid use (77%), acute respiratory failure (76%) and acute renal failure (41%). In-hospital mortality was 46%. The most frequently used AF was voriconazole (71% received at least once). Mean length of stay (LOS) was 26.9 days and mean total hospital cost was $76,235. Each 1 day lag before initiating AF therapy was associated with 1.28 days longer hospital stay and 3.5% increase in costs (p < 0.0001 for both). CONCLUSIONS: Invasive aspergillosis in ICU patients is associated with high mortality and hospital costs. Antifungal timing impacts economic outcomes. These findings underscore the importance of timely diagnosis, appropriate treatment, and consideration of Aspergillus as a potential etiology in ICU patients. PMID- 23343367 TI - Dinuclear bis-propagators for the stereoselective living coordinative chain transfer polymerization of propene. AB - Modulation of steric interactions remote from the active sites within a series of dinuclear bis-propagators derived from racemic 2-4 was used to attenuate the rate of reversible chain transfer between active transition-metal centers and excess equivalents of inactive main-group-metal alkyl species relative to chain growth propagation, as a strategy for achieving the stereoselective living coordinative chain transfer polymerization of propene to provide isotactic stereoblock polypropene. Under identical conditions, the corresponding mononuclear propagator derived from racemic 1 produced only atactic polypropene. PMID- 23343368 TI - Rubisco is a small fraction of total protein in marine phytoplankton. AB - Ribulose 1,5 bisphosphate carboxylase oxygenase (Rubisco) concentrations were quantified as a proportion of total protein in eight species of microalgae. This enzyme has been assumed to be a major fraction of total protein in phytoplankton, as has been demonstrated in plants, potentially constituting a large sink for cellular nitrogen. Representative microalgae were grown in batch and continuous cultures under nutrient-replete, nitrogen (N)-limited, or phosphorus (P)-limited conditions with varying CO(2). Quantitative Western blots were performed using commercially available global antibodies and protein standards. Field incubations with natural populations of organisms from the coast of California were conducted under both nutrient-replete and N-limited conditions with varying CO(2). In all experiments, Rubisco represented < 6% of total protein. In nutrient-replete exponentially growing batch cultures, concentrations ranged from 2% to 6%, while in nutrient-limited laboratory and field cultures, concentrations were < 2.5%. Rubisco generally decreased with increasing CO(2) and with decreasing growth rates. Based on a calculation of maximum Rubisco activity, these results suggest that phytoplankton contain the minimum concentration of enzyme necessary to support observed growth rates. Unlike in plants, Rubisco does not account for a major fraction of cellular N in phytoplankton. PMID- 23343369 TI - Mitochondrial genome of Dasyatis bennettii (Chondrichthyes: Dasyatidae). AB - Dasyatis bennettii is a bottom-dweller that inhabits in the coastal waters of the Indian and Pacific Oceans as well as the freshwaters of Southern China. In this study, we determined the complete mitochondrial genome of this species of stingrays. The results showed that the total length of the mitogenome was 17,668 bp as a circular DNA and contained 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 1 control region. The base composition of the complete mitochondrial DNA was 31.1% A, 28.7% T, 26.7% C, and 13.5% G. All the genes in D. bennettii were distributed on the H-strand, except for the ND6 subunit gene and eight tRNA genes which were encoded on the L-strand. PMID- 23343370 TI - TNF gene polymorphisms in cystic fibrosis patients: contribution to the disease progression. AB - BACKGROUND: It is well known that the disease progression in cystic fibrosis (CF) patients may be diverse in subjects with identical mutation in CFTR gene. It is quite possible that such heterogeneity is associated with TNF-alpha and/or LT alpha gene polymorphisms since their products play a key role in inflammation. The aim of the study was to investigate the possible roles of TNF gene polymorphisms in CF disease phenotype and progression. METHODS: 198 CF patients and 130 control subjects were genotyped for both TNF-alpha-308GA and LT-alpha + 252AG polymorphisms. RESULTS: The carriers of the TNF-alpha-308A allele more frequently had asthma as compared to patients homozygous for the TNF-alpha-308 G allele. In 9 of 108 (8.3%) of LTalpha + 252AA carriers, tuberculosis infection has been documented, whereas there was no case of tuberculosis among patients, either homozygous or heterozygous for LTalpha +252 G alleles (p = 0.01). We never observed virus hepatitis among LTalpha + 252GA carriers. The genotypes TNF-alpha 308GG - LT-alpha + 252AA and TNF-alpha-308GA - LT-alpha + 252AG were unfavorable with regard to liver disease development (both p < 0.05). It was also shown that neutrophil elastase activity was higher in sputum specimens from high TNF producers with genotypes TNF-alpha-308GA or LT-alpha + 252GG. In addition the carriers of such genotypes demonstrated a higher risk of osteoporosis development (p values were 0.011 and 0.017, respectively). CONCLUSIONS: The carriers of genotypes, which are associated with higher TNF-alpha production, demonstrated increased frequency of asthma, higher levels of neutrophil elastase, and decrease of bone density. On the contrary, the carriers of genotypes associated with low TNF-alpha production showed a higher frequency of tuberculosis infection. PMID- 23343371 TI - Release of growth factors and the effect of age, sex, and severity of injury after long bone fracture. A preliminary report. AB - BACKGROUND AND PURPOSE: The systemic response after fracture is regulated by a complex mechanism involving numerous growth factors. In this study, we analyzed the kinetics of key growth factors following lower-limb long bone fracture. MATERIALS AND METHODS: Human serum was isolated from 15 patients suffering from lower-limb long bone fracture (tibia/femur) requiring surgical fixation. The levels of platelet-derived growth factor (PDGF-BB), vascular edothelial growth factor (VEGF), insulin growth factor-I (IGF-I), and transforming growth factor beta1 (TGF-beta1) were assayed by colorimetric ELISA at different time points during the first week after fracture. 10 healthy volunteers made up the control group of the study. Serum levels of the growth factors measured were compared to age, sex, and injury severity score. RESULTS: We found that there was a decline in the levels of PDGF-BB, IGF-I and TGF-beta1 during the first 3 days after fracture. However, VEGF levels remained unchanged. The levels of all the growth factors studied then increased, with the highest concentrations noted at day 7 after surgery. No correlation was found between circulating levels of growth factors and age, injury severity score (ISS), blood loss, or fluid administration. INTERPRETATION: There are systemic mitogenic and osteogenic signals after fracture. Important growth factors are released into the peripheral circulation, but early after surgery it appears that serum levels of key growth factors fall. By 7 days postoperatively, the levels had increased considerably. Our findings should be considered in cases where autologous serum is used for ex vivo expansion of mesenchymal stem cells. There should be further evaluation of the use of these molecules as biomarkers of bone union. PMID- 23343372 TI - Equally good fixation of cemented and uncemented cups in total trapeziometacarpal joint prostheses. A randomized clinical RSA study with 2-year follow-up. AB - BACKGROUND AND PURPOSE: Cup failure is a recognized problem in total trapeziometacarpal (TM) joint prostheses; it may be related to poor fixation, which can be revealed by radiostereometric analysis (RSA). We compared the early implant migration of cemented trapezium cups to that of uncemented screw cups. PATIENTS AND METHODS: In a prospective, parallel-group, randomized patient blinded clinical trial, we included 32 hands in 28 patients (5 males) with a mean age of 58 (40-77) years and with Eaton stage-2 or -3 osteoarthritis of the trapeziometacarpal joint. Patients were randomized to surgery with a cemented DLC all-polyethylene cup (C) (n = 16) or an uncemented hydroxyapatite-coated chrome cobalt Elektra screw cup (UC) (n = 16). Uncemented cups were inserted without threading of the bone. Stereoradiographs for evaluation of cup migration (primary effect size) and DASH and pain scores were obtained during 2 years of follow-up. RESULTS: The 2-year total translation (TT) was similar (p = 0.2): 0.24 mm (SD 0.10) for the C (n = 11) and 0.19 mm (SD 0.16) for the UC (n = 11). Variances were similar (p = 0.4). Judged by RSA, 2 UC cups and 1 C cup became loose (TT > 1 mm). Both UC cups were found to be loose at revision. Grip strength, pain, and DASH scores were similar between groups at all measurement points. INTERPRETATION: Early implant fixation and clinical outcome were equally good with both cup designs. This is the first clinical RSA study on trapezium cups, and the method appears to be clinically useful for detection of loose implants. PMID- 23343373 TI - Risk factors for osteoporosis are common in young and middle-aged patients with femoral neck fractures regardless of trauma mechanism. AB - BACKGROUND AND PURPOSE: There have been few prospective studies examining young and middle-aged patients with hip fracture. We therefore investigated background data, risk factors, and the trauma mechanism in young and middle-aged patients with femoral neck fracture. PATIENTS AND METHODS: 185 patients, 27 young (20-49 years old) and 158 middle-aged (50-69 years old) were prospectively included in a multicenter study lasting 3 years. Background data and risk factors for osteoporosis and fracture were obtained, and the type of injury was classified as low-energy trauma, high-energy trauma, or sports injury. RESULTS: In the young age group, the fracture occurred because of low-energy trauma in two-fifths of patients and because of sport injury in two-fifths of patients. The rest occurred because of high-energy trauma. The corresponding proportions for the middle-aged group were four-fifths, one tenth, and one tenth (p < 0.001). There was a higher proportion of men (19/27) in the young group than in the middle-aged group (69/158) (p = 0.001). One fifth of the young patients were smokers as compared to two-fifths in the middle-age group (p = 0.04). One quarter of the patients reported high-volume alcohol drinking, with no difference between the two groups. Furthermore, three-quarters of the young patients and four-fifths of the middle aged patients had one or more risk factors for osteoporosis and fracture. INTERPRETATION: A minority of patients in each age group had high-energy trauma as the cause of their femoral neck fracture. Lifestyle factors and other non trauma-related risk factors appear to have been important contributors to the occurrence of femoral neck fracture in both age groups. PMID- 23343374 TI - Reliability of patient-reported functional outcome in a joint replacement registry. A comparison of primary responders and non-responders in the Danish Shoulder Arthroplasty Registry. AB - BACKGROUND AND PURPOSE: Patient-reported outcome measures (PROMs) are used by some arthroplasty registries to evaluate results after surgery, but non-response may bias the results. The aim was to identify a potential bias in the outcome scores of subgroups in a cohort of patients from the Danish Shoulder Arthroplasty Registry (DSR) and to characterize non-responders. METHODS: Patient-reported outcome of 787 patients operated in 2008 was assessed 12 months postoperatively using the Western Ontario Osteoarthritis of the Shoulder (WOOS) index. In January 2012, non-responders and incomplete responders were sent a postal reminder. Non responders to the postal reminder were contacted by telephone. Total WOOS score and WOOS subscales were compared for initial responders (n = 509), responders to the postal reminder (n = 156), and responders after telephone contact (n = 27). The predefined variables age, sex, diagnosis, geographical region, and reoperation rate were compared for responding and non-responding cohorts. RESULTS: A postal reminder increased the response rate from 65% (6% incomplete) to 80% (3% incomplete) and telephone contact resulted in a further increase to 82% (2% incomplete). We did not find any statistically significant differences in total WOOS score or in any of the WOOS subscales between responders to the original questionnaire, responders to the postal reminder, and responders after telephone contact. However, a trend of worse outcome for non-responders was found. The response rate was lower in younger patients. INTERPRETATION: Non responders did not appear to bias the overall results after shoulder replacement despite a trend of worse outcome for a subgroup of non-responders. As response rates rose markedly by the use of postal reminders, we recommend the use of reminders in arthroplasty registries using PROMs. PMID- 23343375 TI - A prospective cohort study on the short collum femoris-preserving (CFP) stem using RSA and DXA. Primary stability but no prevention of proximal bone loss in 27 patients followed for 2 years. AB - BACKGROUND AND PURPOSE: Short femoral stems have been introduced in total hip arthroplasty in order to save proximal bone stock. We hypothesized that a short stem preserves periprosthetic bone mineral density (BMD) and provides good primary stability. METHODS: We carried out a prospective cohort study of 30 patients receiving the collum femoris-preserving (CFP) stem. Preoperative total hip BMD and postoperative periprosthetic BMD in Gruen zones 1-7 were investigated by dual-energy x-ray absorptiometry (DXA), stem migration was analyzed by radiostereometric analysis (RSA), and the Harris hip score (HHS) was determined. RESULTS: 2 patients were excluded intraoperatively and 1 patient was revised due to a deep infection, leaving 27 patients for analysis. The mean HHS increased from 49 (24-79) preoperatively to 99 (92-100) after 2 years. DXA after 1 year showed substantial loss of BMD in Gruen zone 7 (-31%), zone 6 (-19%), and zone 2 (-13%, p < 0.001) compared to baseline BMD determined immediately postoperatively. The bone loss in these regions did not recover after 2 years, whereas the more moderate bone loss in Gruen zones 1, 3, and 5 partially recovered. There was a correlation between low preoperative total hip BMD and a higher amount of bone loss in Gruen zones 2, 6 and 7. RSA showed minor micromotion of the stem: mean subsidence was 0.13 (95% CI: -0.28 to 0.01) mm and mean rotation around the longitudinal axis was 0.01o (95% CI: -0.1 to 0.39) after 2 years. INTERPRETATION: We conclude that substantial loss in proximal periprosthetic BMD cannot be prevented by the use of a novel type of short, curved stem, and forces appear to be transmitted distally. However, the stems showed very small migration-a characteristic of stable uncemented implants. PMID- 23343376 TI - The role of the acetabular labrum in hip dysplasia. A literature overview. AB - A periacetabular osteotomy (PAO) is the preferred joint preserving treatment for young adults with symptomatic hip dysplasia and no osteoarthritis. In symptomatic dysplasia of the hip, there is labral pathology in up to 90% of cases. However, no consensus exists as to whether a labral tear should be treated before the periacetabular osteotomy (PAO), treated simultaneously with the PAO, or left alone and only treated if symptoms persist after the PAO. This review is an update of aspects of labral anatomy and function, the etiology of labral tears in hip dysplasia, and diagnostic assessment of labral tears, and we discuss treatment strategies for coexisting labral tears and hip dysplasia. PMID- 23343377 TI - No influence of immigrant background on the outcome of total hip arthroplasty. 140,299 patients born in Sweden and 11,539 immigrants in the Swedish Hip Arthroplasty Register. AB - BACKGROUND AND PURPOSE: Total Hip Replacement (THA) is one of the most successful and cost-effective operations. Despite its benefits, marked ethnic differences in the utilization of THA are well documented. However, very little has been published on the influence of ethnicity on outcome. We investigate whether the outcome-in terms of reoperation within 2 years or revision up to 14 years after the primary operation-varies depending on ethnic background. METHODS: Records of total hip arthroplasties performed between 1992 and 2007 were retrieved from the Swedish Hip Arthropalsty Registry and integrated with data on ethnicity of patients from 2 demographical databases (i.e. Patient Register and Statistics Sweden). The first operated side in patients with THA recorded in the Swedish Hip Arthroplasty Register (SHAR) between 1992 and 2007 were generally included. We excluded patients with 1 Swedish and 1 non-Swedish parent and patients born abroad with 2 Swedish parents. After these exclusions 151,838 patients were left for analysis. There were 11,539 Swedish patients born outside Sweden. We used a Cox regression model including age, sex, diagnosis, type of fixation, whether or not there was comorbidity according to Elixhauser or not, marital status and educational level. RESULTS: The mean age was lowest in the group of patient coming from outside Europe including the former Soviet Union (61 years), and highest in the Swedish population (70 years). Before adjustment, for covariates, patients born in Europe outside the Nordic countries showed a lower risk to undergo early reoperation (HR = 0.73, 95% CI: 0.56-0.97), which increased after adjustment to (HR = 0.76, 95% CI: 0.58-1.01). Before adjustment, patients born in the Nordic countries outside Sweden and those born outside Europe (including the former Soviet Union) showed a higher risk to undergo revision than patients born in Sweden (HR = 1.14, 95% CI: 1.02-1.27; HR = 1.49, 95% CI: 1.2-1.9), but this difference disappeared after adjustment for covariates. CONCLUSION: We did not find any certain differences in reoperation within 2 years, or revision within 14 years, between patients born in Sweden and immigrants. Further studies are needed to determine whether our observations are biased by the attitude of health providers regarding performance of these procedures, or by a reluctance of certain patient groups to seek medical attention should any complications requiring reoperation or revision occur. PMID- 23343378 TI - Shinya Yamanaka's 2012 Nobel Prize and the radical change in orthopedic strategy thanks to his discovery of iPS cells. PMID- 23343379 TI - Childhood femoral fracture can lead to premature knee-joint arthritis. 21-year follow-up results: a retrospective study. AB - BACKGROUND AND PURPOSE: During the past decades, treatment of pediatric femoral fractures in Finland has changed from mostly non-operative to more operative. In this retrospective study, we analyzed the long-term results of treatment. PATIENTS AND METHODS: 74 patients (mean age 7 (0-14) years) with a femoral fracture were treated in Aurora City Hospital in Helsinki during the period 1980 89. 52 of 74 patients participated in this clinical study with a mean follow-up of 21 (16-28) years. Fracture location, treatment mode, time of hospitalization, and fracture alignment at union were assessed. Subjective assessment and range of motion of the hip and knee were evaluated. Leg-length discrepancy and alignment of the lower extremities were measured both clinically and radiographically. RESULTS: Of the 52 children, 28 had sustained a shaft fracture, 13 a proximal fracture, and 11 a distal fracture. 44 children were treated with traction, 5 by internal fixation, and 3 with cast-immobilization. Length of the hospital treatment averaged 58 (3-156) days and the median traction time was 39 (3-77) days. 21 of the 52 patients had angular malalignment of more than 10 degrees at union. 20 patients experienced back pain. Limping was seen in 10 patients and leg length discrepancy of more than 15 mm was in 8 of the 52 patients. There was a positive correlation between angular deformity and knee-joint arthritis in radiographs at follow-up in 6 of 15 patients who were over 10 years of age at the time of injury. INTERPRETATION: Angular malalignment after treatment of femoral fracture may lead to premature knee-joint arthritis. Tibial traction is not an acceptable treatment method for femoral fractures in children over 10 years of age. PMID- 23343380 TI - Broadband focusing flat mirrors based on plasmonic gradient metasurfaces. AB - We demonstrate that metal-insulator-metal configurations, with the top metal layer consisting of a periodic arrangement of differently sized nanobricks, can be designed to function as broadband focusing flat mirrors. Using 50-nm-high gold nanobricks arranged in a 240-nm-period lattice on the top of a 50-nm-thick layer of silicon dioxide deposited on a continuous 100-nm-thick gold film, we realize a 17.3 * 17.3 MUm(2) flat mirror that efficiently reflects (experiment: 14-27%; theory: 50-78%) and focuses a linearly polarized (along the direction of nanobrick size variation) incident beam in the plane of its polarization with the focal length, which changes from ~15 to 11 MUm when tuning the light wavelength from 750 to 950 nm, respectively. Our approach can easily be extended to realize the radiation focusing in two dimensions as well as other optical functionalities by suitably controlling the phase distribution of reflected light. PMID- 23343381 TI - Chemical datuments as scientific enablers. AB - This article is an attempt to construct a chemical datument as a means of presenting insights into chemical phenomena in a scientific journal. An exploration of the interactions present in a small fragment of duplex Z-DNA and the nature of the catalytic centre of a carbon-dioxide/alkene epoxide alternating co-polymerisation is presented in this datument, with examples of the use of three software tools, one based on Java, the other two using Javascript and HTML5 technologies. The implications for the evolution of scientific journals are discussed. PMID- 23343382 TI - Theoretical study of the preferential solvation effect on the solvatochromic shifts of para-nitroaniline. AB - The origin of the nonlinear solvatochromic shift of para-nitroaniline was investigated using a mean-field sequential QM/MM method, with electron transitions computed at the CASPT2/cc-pVDZ level. Experimental data shows that the solvatochromic shift has a strong nonlinear behavior in certain solvent mixtures. We studied the case of cyclohexane-triethylamine mixtures. The results are in good agreement with the experiments and correctly reproduce the nonlinear variation of the solvent shift. Preferential solvation is clearly observed, where the local solvent composition in the neighborhood of the solute is significantly different from the bulk. It is found that even at low triethylamine concentrations a strong hydrogen bond is formed between para-nitroaniline and triethylamine, and cyclohexane is practically absent from the first solvation layer already at a molar fraction of 0.6 in triethylamine. The hydrogen bond formed is sufficiently long-lived to determine an asymmetric environment around the solute molecule. The resulting nonlinear solvent effect is mainly due to this hydrogen bond influence, although there is also a small contribution from dielectric enrichment. PMID- 23343383 TI - Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus. AB - INTRODUCTION: Osteopontin (OPN) has been implicated as a mediator of Th17 regulation via type I interferon (IFN) receptor signaling and in macrophage activity at sites of tissue repair. This study assessed whether increased circulating plasma OPN (cOPN) precedes development of organ damage in pediatric systemic lupus erythematosus (pSLE) and compared it to circulating plasma neutrophil gelatinase-associated lipocalin (cNGAL), a predictor of increased SLE disease activity. METHODS: cOPN and cNGAL were measured in prospectively followed pSLE (n=42) and adult SLE (aSLE; n=23) patients and age-matched controls. Time adjusted cumulative disease activity and disease damage were respectively assessed using adjusted-mean SLE disease activity index (SLEDAI) (AMS) and SLICC/ACR damage index (SDI). RESULTS: Compared to controls, elevated cOPN and cNGAL were observed in pSLE and aSLE. cNGAL preceded worsening SLEDAI by 3-6 months (P=0.04), but was not associated with increased 6-month AMS. High baseline cOPN, which was associated with high IFNalpha activity and expression of autoantibodies to nucleic acids, positively correlated with 6-month AMS (r=0.51 and 0.52, P=0.001 and 0.01 in pSLE and aSLE, respectively) and was associated with SDI increase at 12 months in pSLE (P=0.001). Risk factors for change in SDI in pSLE were cOPN (OR 7.5, 95% CI [2.9-20], P=0.03), but not cNGAL, cumulative prednisone, disease duration, immunosuppression use, gender or ancestry using univariate and multivariate logistic regression. The area under the curve (AUC) when generating the receiver-operating characteristic (ROC) of baseline cOPN sensitivity and specificity for the indication of SLE patients with an increase of SDI over a 12 month period is 0.543 (95% CI 0.347-0.738; positive predictive value 95% and negative predictive value 38%). CONCLUSION: High circulating OPN levels preceded increased cumulative disease activity and organ damage in SLE patients, especially in pSLE, and its value as a predictor of poor outcome should be further validated in large longitudinal cohorts. PMID- 23343385 TI - Mixed metazoan and bacterial infection of the gas bladder of the lined seahorse-a case report. AB - Five wild-caught Lined Seahorses Hippocampus erectus from an aquarium system presented with altered buoyancy and distended upper trunks. Radiography of one specimen revealed a reduced air volume in the gas bladder. Pneumocystocentesis revealed a brown exudate of numerous leukocytes, parasite ova, and Gram- and acid fast-positive bacilli under wet mounts and stains. Necropsies revealed enlarged, friable kidneys and distended gas bladders containing copious purulent exudate, necrotic tissue, and adult digeneans Dictysarca virens. Bacterial isolates from exudate cultures grown on Lowenstein-Jensen medium were identified as Gordonia sp. and Mycobacterium poriferae by high-performance liquid chromatography and 16S ribosomal DNA sequencing. Histopathology demonstrated a histiocytic response in kidney and gas bladder exudate, inflammation of the gas bladder wall, and infection of the gas bladder lumen with parasite ova and acid-fast-positive and Gomori's methenamine silver-positive bacilli. Praziquantel is prescribed for digenean infections but dissolves incompletely in seawater and is toxic to this host. Eradication of intermediate host vectors is a management option. Treatment of Gordonia infection has not been addressed in nonhuman animals, and there is no known effective treatment for Mycobacterium spp. infection in fishes. This is the first case report of digenean infection of the gas bladder in a syngnathid, Gordonia sp. infection in a nonhuman animal, and M. poriferae infection in a fish. PMID- 23343384 TI - Early traumatic experiences in those at clinical high risk for psychosis. AB - AIM: Several lines of evidence suggest a possible association between a history of trauma in childhood and later psychosis or psychotic-like experiences. The purpose of this study was to determine the extent of childhood trauma and bullying in young people at clinical high risk (CHR) of developing psychosis. METHODS: The sample consisted of 360 individuals who were at CHR of developing psychosis and 180 age- and gender-matched healthy controls. All participants were assessed on past trauma and bullying. The CHR participants were also assessed on a range of psychopathology and functioning. RESULTS: Individuals at CHR reported significantly more trauma and bullying than healthy controls. Those who had experienced past trauma and bullying were more likely to have increased levels of depression and anxiety and a poorer sense of self. CONCLUSIONS: These results offer preliminary support for an association between a history of trauma and later subthreshold symptoms. PMID- 23343386 TI - Efficacy of 'Tailored Physical Activity' or 'Chronic Pain Self-Management Program' on return to work for sick-listed citizens: design of a randomised controlled trial. AB - BACKGROUND: Pain affects quality of life and can result in absence from work. Treatment and/or prevention strategies for musculoskeletal pain-related long-term sick leave are currently undertaken in several health sectors. Moreover, there are few evidence-based guidelines for such treatment and prevention. The aim of this study is to evaluate the efficacy of 'Tailored Physical Activity' or 'Chronic Pain Self-Management Program' for sick-listed citizens with pain in the back and/or the upper body. METHODS: This protocol describes the design of a parallel randomised controlled trial on the efficacy of 'Tailored Physical Activity' or a 'Chronic Pain Self-management Program' versus a reference group for sick-listed citizens with complaints of pain in the back or upper body. Participants will have been absent from work due to sick-listing for 3 to 9 weeks at the time of recruitment. All interventions will be performed at the 'Health Care Center' in the Sonderborg Municipality, and a minimum of 138 participants will be randomised into one of the three groups.All participants will receive 'Health Guidance', a (1.5-hour) individualised dialogue focusing on improving ways of living, based on assessments of risk behavior, motivation for change, level of self-care and personal resources. In addition, the experimental groups will receive either 'Tailored Physical Activity' (three 50-minute sessions/week over 10 weeks) or 'Chronic Pain Self-Management Program' (2.5-hours per week over 6 weeks). The reference group will receive only 'Health Guidance'.The primary outcome is the participants' sick-listed status at 3 and 12 months after baseline. The co-primary outcome is the time it takes to return to work. In addition, secondary outcomes include anthropometric measurements, functional capacity and self-reported number of sick days, musculoskeletal symptoms, general health, work ability, physical capacity, kinesiophobia, physical functional status, interpersonal problems and mental disorders. DISCUSSION: There are few evidence-based interventions for rehabilitation programmes assisting people with musculoskeletal pain-related work absence. This study will compare outcomes of interventions on return to work in order to increase the knowledge of evidence based rehabilitation of sick-listed citizens to prevent long-term sick-leave and facilitate return to work. TRIAL REGISTRATION: The trial is registered in the ClinicalTrials.gov, number NCT01356784. PMID- 23343387 TI - Bronchial responsiveness, spirometry and mortality in a cohort of adults. AB - OBJECTIVE: Prospective population studies have reported that pulmonary function, measured by forced expiratory volume in one second (FEV(1)), is an independent predictor for mortality. Besides, several studies found that death from all causes is higher in asthmatics than in non-asthmatics. However, none of these studies examined whether bronchial hyperresponsiveness (BHR), one of the key features in asthma, can be used as a predictor for mortality. Thus, the aim of this study was to analyze the association between BHR, FEV(1), and all-cause mortality in a population-based cohort of adults. METHODS: Within the cross sectional survey ECRHS-I Erfurt (1990-1992), 1162 adults aged 20-65 years performed lung function tests, including spirometry and BHR testing by methacholine inhalation up to a cumulative dose of 2 mg. BHR was assessed from the methacholine dose nebulized at >= 20% fall of FEV(1). After circa 20 years of follow-up, the association between baseline lung function, BHR, and mortality was investigated. RESULTS: A total of 85 individuals (7.3%) died during a mean follow up period of 17.4 years (SD = 2.4). FEV(1), but not forced vital capacity (FVC), was a predictor for mortality. In men, BHR increased the mortality risk (OR = 2.6, 95% CI: 1.3-5.3; adjusted for age and BMI). Additional adjustment for asthma did not change the results (OR = 2.4, 95% CI: 1.2-5.0). However, after an additional adjustment for pack years of cigarette smoking or airway obstruction, the association was not statistically significant anymore (OR = 1.8, 95% CI: 0.8 4.0, OR = 1.9, 95% CI: 0.9-4.3, respectively). CONCLUSIONS: BHR was associated with an increased mortality risk in men. Potential explanatory factors for this association are cigarette smoking, chronic obstructive pulmonary disease (COPD), or asthma. Thus, BHR might be an indirect predictor for all-cause mortality. FEV(1) was an independent predictor for all-cause mortality. PMID- 23343388 TI - Validity and feasibility of a learning style instrument for brain injury rehabilitation. AB - PURPOSE: Identifying learning styles of acquired brain injury (ABI) patients may aid the learning process by tailoring to the patient's learning needs and preferences. Currently, there is no learning style instrument for ABI patients. We therefore determined the validity and feasibility of the Adapted Learning Style Inventory (A-LSI) for patients with ABI. METHOD: We included 99 patients with ABI and 42 healthy controls. Learning styles were determined and subgroups were used to evaluate the validity of the A-LSI. Furthermore, rehabilitation professionals' perceptions on learning style and the A-LSI were evaluated. RESULTS: In the patient group, the A-LSI yielded the following learning styles: 4 doers, 54 observers, 2 deciders and 39 thinkers. A similar distribution was found for the control group (3, 28, 0 and 11, respectively). Spearman correlations revealed moderate internal validity. Content validity of the A-LSI was also moderate; 11 out of 19 patients recognized themselves in their A-LSI learning style. Furthermore, 12 rehabilitation professionals reported positive and negative aspects of the A-LSI and suggestions for using learning style in rehabilitation. CONCLUSIONS: Rehabilitation professionals were generally positive about using learning style in ABI rehabilitation. This study, however, raises doubts about the validity and feasibility of the A-LSI for this population. IMPLICATIONS FOR REHABILITATION: Rehabilitation professionals are generally positive about the assessment and implementation of learning style in rehabilitation. The A-LSI seems to be an inappropriate learning style instrument for individuals with ABI. There is a need for a more practical instrument to assess learning style directly at start of rehabilitation. PMID- 23343389 TI - The role of PPARgamma in carbon nanotube-elicited granulomatous lung inflammation. AB - BACKGROUND: Although granulomatous inflammation is a central feature of many disease processes, cellular mechanisms of granuloma formation and persistence are poorly understood. Carbon nanoparticles, which can be products of manufacture or the environment, have been associated with granulomatous disease. This paper utilizes a previously described carbon nanoparticle granuloma model to address the issue of whether peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear transcription factor and negative regulator of inflammatory cytokines might play a role in granulomatous lung disease. PPARgamma is constitutively expressed in alveolar macrophages from healthy individuals but is depressed in alveolar macrophages of patients with sarcoidosis, a prototypical granulomatous disease. Our previous study of macrophage-specific PPARgamma KO mice had revealed an intrinsically inflammatory pulmonary environment with an elevated pro-inflammatory cytokines profile as compared to wild-type mice. Based on such observations we hypothesized that PPARgamma expression would be repressed in alveolar macrophages from animals bearing granulomas induced by MWCNT instillation. METHODS: Wild-type C57Bl/6 and macrophage-specific PPARgamma KO mice received oropharyngeal instillations of multiwall carbon nanotubes (MWCNT) (100 MUg). Bronchoalveolar lavage (BAL) cells, BAL fluids, and lung tissues were obtained 60 days post-instillation for analysis of granuloma histology and pro inflammatory cytokines (osteopontin, CCL2, and interferon gamma [IFN-gamma] mRNA and protein expression. RESULTS: In wild-type mice, alveolar macrophage PPARgamma expression and activity were significantly reduced in granuloma-bearing animals 60 days after MWCNT instillation. In macrophage-specific PPARgamma KO mice, granuloma formation was more extensive than in wild-type at 60 days after MWCNT instillation. PPARgamma KO mice also demonstrated elevated pro-inflammatory cytokine expression in lung tissue, laser-microdissected lung granulomas, and BAL cells/fluids, at 60 days post MWCNT exposure. CONCLUSIONS: Overall, data indicate that PPARgamma deficiency promotes inflammation and granuloma formation, suggesting that PPARgamma functions as a negative regulator of chronic granulomatous inflammation. PMID- 23343390 TI - Fully convergent chemical synthesis of ester insulin: determination of the high resolution X-ray structure by racemic protein crystallography. AB - Efficient total synthesis of insulin is important to enable the application of medicinal chemistry to the optimization of the properties of this important protein molecule. Recently we described "ester insulin"--a novel form of insulin in which the function of the 35 residue C-peptide of proinsulin is replaced by a single covalent bond--as a key intermediate for the efficient total synthesis of insulin. Here we describe a fully convergent synthetic route to the ester insulin molecule from three unprotected peptide segments of approximately equal size. The synthetic ester insulin polypeptide chain folded much more rapidly than proinsulin, and at physiological pH. Both the D-protein and L-protein enantiomers of monomeric DKP ester insulin (i.e., [Asp(B10), Lys(B28), Pro(B29)]ester insulin) were prepared by total chemical synthesis. The atomic structure of the synthetic ester insulin molecule was determined by racemic protein X-ray crystallography to a resolution of 1.6 A. Diffraction quality crystals were readily obtained from the racemic mixture of {D-DKP ester insulin + L-DKP ester insulin}, whereas crystals were not obtained from the L-ester insulin alone even after extensive trials. Both the D-protein and L-protein enantiomers of monomeric DKP ester insulin were assayed for receptor binding and in diabetic rats, before and after conversion by saponification to the corresponding DKP insulin enantiomers. L-DKP ester insulin bound weakly to the insulin receptor, while synthetic L-DKP insulin derived from the L-DKP ester insulin intermediate was fully active in binding to the insulin receptor. The D- and L-DKP ester insulins and D-DKP insulin were inactive in lowering blood glucose in diabetic rats, while synthetic L-DKP insulin was fully active in this biological assay. The structural basis of the lack of biological activity of ester insulin is discussed. PMID- 23343391 TI - Systematic screening with information and home sampling for genital Chlamydia trachomatis infections in young men and women in Norway: a randomized controlled trial. AB - BACKGROUND: As most genital Chlamydia trachomatis infections are asymptomatic, many patients do not seek health care for testing. Infections remain undiagnosed and untreated. We studied whether screening with information and home sampling resulted in more young people getting tested, diagnosed and treated for chlamydia in the three months following the intervention compared to the current strategy of testing in the health care system. METHOD: We conducted a population based randomized controlled trial among all persons aged 18-25 years in one Norwegian county (41 519 persons). 10 000 persons (intervention) received an invitation by mail with chlamydia information and a mail-back urine sampling kit. 31 519 persons received no intervention and continued with usual care (control). All samples from both groups were analysed in the same laboratory. Information on treatment was obtained from the Norwegian Prescription Database (NorPD). We estimated risk ratios and risk differences of being tested, diagnosed and treated in the intervention group compared to the control group. RESULTS: In the intervention group 16.5% got tested and in the control group 3.4%, risk ratio 4.9 (95% CI 4.5-5.2). The intervention led to 2.6 (95% CI 2.0-3.4) times as many individuals being diagnosed and 2.5 (95% CI 1.9-3.4) times as many individuals receiving treatment for chlamydia compared to no intervention in the three months following the intervention. CONCLUSION: In Norway, systematic screening with information and home sampling results in more young people being tested, diagnosed and treated for chlamydia in the three months following the intervention than the current strategy of testing in the health care system. However, the study has not established that the intervention will reduce the chlamydia prevalence or the risk of complications from chlamydia. PMID- 23343393 TI - Lawsone dimerization in cobalt(III) complexes toward the design of new prototypes of bioreductive prodrugs. AB - Dimerization of lawsone occurs upon reaction with Co(BF(4))(2).6H(2)O and N,N' bis(pyridin-2-ylmethyl)ethylenediamine (py(2)en) to produce the mononuclear complex [Co(III)(bhnq)(py(2)en)]BF(4).H(2)O (1). This complex has been investigated as a prototype of a bioreductive prodrug, where the bhnq(2-) ligand acts as a model for cytotoxic naphthoquinones. Cyclic voltammetry data in aqueous solution have shown a quasi-reversible Co(III)/Co(II) process at E(1/2) = -0.26 V vs Fc/Fc(+). Reactivity studies revealed the dissociation of bhnq(2-) from the complex upon reduction of 1 with ascorbic acid, and a dependence of the reaction rate on the oxygen concentration suggests the occurrence of redox cycling. PMID- 23343392 TI - Partnership for fragility bone fracture care provision and prevention program (P4Bones): study protocol for a secondary fracture prevention pragmatic controlled trial. AB - BACKGROUND: Fractures associated with bone fragility in older adults signal the potential for secondary fracture. Fragility fractures often precipitate further decline in health and loss of mobility, with high associated costs for patients, families, society and the healthcare system. Promptly initiating a coordinated, comprehensive pharmacological bone health and falls prevention program post fracture may improve osteoporosis treatment compliance; and reduce rates of falls and secondary fractures, and associated morbidity, mortality and costs. METHODS/DESIGN: This pragmatic, controlled trial at 11 hospital sites in eight regions in Quebec, Canada, will recruit community-dwelling patients over age 50 who have sustained a fragility fracture to an intervention coordinated program or to standard care, according to the site. Site study coordinators will identify and recruit 1,596 participants for each study arm. Coordinators at intervention sites will facilitate continuity of care for bone health, and arrange fall prevention programs including physical exercise. The intervention teams include medical bone specialists, primary care physicians, pharmacists, nurses, rehabilitation clinicians, and community program organizers.The primary outcome of this study is the incidence of secondary fragility fractures within an 18 month follow-up period. Secondary outcomes include initiation and compliance with bone health medication; time to first fall and number of clinically significant falls; fall-related hospitalization and mortality; physical activity; quality of life; fragility fracture-related costs; admission to a long term care facility; participants' perceptions of care integration, expectations and satisfaction with the program; and participants' compliance with the fall prevention program. Finally, professionals at intervention sites will participate in focus groups to identify barriers and facilitating factors for the integrated fragility fracture prevention program.This integrated program will facilitate knowledge translation and dissemination via the following: involvement of various collaborators during the development and set-up of the integrated program; distribution of pamphlets about osteoporosis and fall prevention strategies to primary care physicians in the intervention group and patients in the control group; participation in evaluation activities; and eventual dissemination of study results. PMID- 23343394 TI - Synthesis of highly active and thermally stable nanostructured Pt/clay materials by clay-mediated in situ reduction. AB - Novel and intriguing one-pot in situ method for the preparation of nanostructured Pt-clay materials under simple conditions is reported. In this synthesis, an inorganic clay mineral such as synthetic hectorite ("Laponite XLG") or natural montmorillonite ("Kunipia F") serves as a mild and effective reducing agent for Pt ions, which is uncommon for such a clay system, and also acts as an outstanding stabilizer for the resulting Pt nanoparticles. In aqueous solution, exfoliated colloidal clay platelets forms complex with Pt ions in the initial stage of mixing. Devoid of any organic dispersants or external reducing agents, subsequently, the Pt nanoparticles (3-6 nm) generated by clay-assisted in situ reduction of Pt ions successfully anchored onto the clay nanoplatelets. The Pt clay material features a very high surface area (312 m(2) g(-1)) and has excellent catalytic activity, as was kinetically evaluated via the reduction of 4 nitrophenol with NaBH(4). After drying, this remarkably stable nanocomposite is completely redispersible in water and displays extreme thermal stability (up to 500 degrees C). On the basis of these results, this synthetic strategy is anticipated to be a very simple, economical, and green approach for the synthesis of nanostructured Pt-clay materials. PMID- 23343396 TI - Mitochondrial genome sequence of the Botia superciliaris (Teleostei, Cypriniformes). AB - The Botia superciliaris is endemic to China and distributed mainly in the upper reaches of the Yangtze River. The complete mitochondrial genome was 16,597 bp in length, which contained 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and 1 displacement loop (D-loop) locus. Except for the ND6 gene and eight tRNA genes, all other mitochondrial genes were encoded on the heavy strand. The overall nucleotide composition was 31.6% A, 25.5% T, 27.2% C and 15.7% G, with an AT content of 57.1%. The gene composition and the structural arrangement of the B. superciliaris complete mtDNA were identical to most of the other vertebrates. The molecular data here we presented could play a useful role to study the evolutionary relationships and population genetics of Cobitidae fish. PMID- 23343395 TI - Issues in women's participation in a phase III community HIV vaccine trial in Thailand. AB - To assess qualities and outcomes of women participating in a large, community based HIV vaccine trial, the present study was conducted among female participants of the RV 144 prime-boost trial in Thailand from 2003 to 2009. Qualities of participation refer to complete vaccination, retention, and status change. Outcomes of participation refer to incident rate, adverse event, and participation impact event. A total of 6,334 (38.6%) women participated in the trial, of whom about 50% were classified as low risk and 11% as high risk. About 85% of participants completed four vaccinations and 76% were included in the per protocol analysis of the on-time vaccination schedule. More women (88%) completed 42 months follow-up compared with men (85%). Women aged 21 and above had more adverse events compared to younger age groups. More women (5%) compared with men (3%) reported participation impact events (PIEs). High-risk women had more PIEs and a higher infection rate compared to the low-risk group. Complete vaccination and retention on last follow-up were more common in married women aged above 21, and being a housewife. Female volunteers showed the same qualities and outcomes of participation as males in the HIV vaccine trial. There was no statistically significant difference in vaccine efficacy between men and women, especially among the high-risk and married women. The study highlighted the important behavioral, social, and cultural issues that could be considered for future HIV vaccine trial designs. PMID- 23343397 TI - Redescription and genetic characterization of Hysterothylacium thalassini Bruce, 1990 (Nematoda: Anisakidae) from marine fishes in the South China Sea. AB - Hysterothylacium thalassini Bruce, 1990, was redescribed using light microscopy and, for the first time, scanning electron microscopy based on newly collected specimens from the marine fishes Priacanthus tayenus Richardson and Pricanthus macracanthus Cuvier (Perciformes: Priacanthidae) in the South China Sea. Previously unreported or inaccurately described morphological features of taxonomic significance are described, including the number and morphology of paracloacal and postcloacal papillae, the morphology of the vulva, and the presence of small phasmids in the both sexes. Moreover, specimens of H. thalassini collected from the 2 hosts were characterized by sequencing and analyzing the internal transcribed spacer (ITS) of the ribosomal DNA. The ITS region of H. thalassini was compared with Hysterothylacium spp. in GenBank, and the results seem to support the validity of the incompletely known species. PMID- 23343399 TI - Orientation of carbon fiber axes in polymer solutions under magnetic field evaluated in terms of orientation distribution of the chain axes of graphite with respect to the carbon fiber axis. AB - Orientation of carbon fiber (CF) axes in poly(vinyl alcohol) (PVA) aqueous solution under magnetic field was evaluated by considering the fact that the c axes (chain axes of graphite) have orientation distribution with respect to their CF axis. This new approach was proposed to resolve the well-known contradiction that the diffraction image from the (002) plane measured by X-ray shows broad arcs indicating dull orientation of the c-axes with respect to the magnetic field, whereas the corresponding orientation of CF axes observed by SEM reveals high predominant orientation. To pursue the quantitative evaluation, the orientation function of CF axes was obtained from the orientation function of the reciprocal lattice vector of the (002) plane by a somewhat coordinate transformation. The real orientation function of the CF axes with respect to the magnetic field direction showed very sharp distribution profile in comparison to the function of the c-axes and it was in good agreement with the orientation of CF axes observed directly by SEM. Furthermore, the orientation of CF axes up to the equilibrium state was estimated by a common diffusion equation. The calculated results predicted time dependence of the preferential orientation behavior of CFs in PVA solution precisely. PMID- 23343398 TI - Reproducibility of rest and exercise stress contrast-enhanced calf perfusion magnetic resonance imaging in peripheral arterial disease. AB - BACKGROUND: The purpose was to determine the reproducibility and utility of rest, exercise, and perfusion reserve (PR) measures by contrast-enhanced (CE) calf perfusion magnetic resonance imaging (MRI) of the calf in normal subjects (NL) and patients with peripheral arterial disease (PAD). METHODS: Eleven PAD patients with claudication (ankle-brachial index 0.67 +/-0.14) and 16 age-matched NL underwent symptom-limited CE-MRI using a pedal ergometer. Tissue perfusion and arterial input were measured at rest and peak exercise after injection of 0.1 mM/kg of gadolinium-diethylnetriamine pentaacetic acid (Gd-DTPA). Tissue function (TF) and arterial input function (AIF) measurements were made from the slope of time-intensity curves in muscle and artery, respectively, and normalized to proton density signal to correct for coil inhomogeneity. Perfusion index (PI) = TF/AIF. Perfusion reserve (PR) = exercise TF/ rest TF. Intraclass correlation coefficient (ICC) was calculated from 11 NL and 10 PAD with repeated MRI on a different day. RESULTS: Resting TF was low in NL and PAD (mean +/- SD 0.25 +/- 0.18 vs 0.35 +/- 0.71, p = 0.59) but reproducible (ICC 0.76). Exercise TF was higher in NL than PAD (5.5 +/- 3.2 vs. 3.4 +/- 1.6, p = 0.04). Perfusion reserve was similar between groups and highly variable (28.6 +/- 19.8 vs. 42.6 +/- 41.0, p = 0.26). Exercise TF and PI were reproducible measures (ICC 0.63 and 0.60, respectively). CONCLUSION: Although rest measures are reproducible, they are quite low, do not distinguish NL from PAD, and lead to variability in perfusion reserve measures. Exercise TF and PI are the most reproducible MRI perfusion measures in PAD for use in clinical trials. PMID- 23343400 TI - Perceived colonoscopy barriers and facilitators among urban African American patients and their medical residents. AB - African Americans suffer from higher colorectal cancer morbidity and mortality than do Whites, yet have the lowest screening rates. To understand barriers and facilitators to colorectal cancer screening, this study used perceptual mapping (multidimensional scaling) methods to compare patients' perceptions of colonoscopy and general preventive health practices to those of their doctors in a general internal medicine clinic in a large urban hospital. African American patients (n = 102) were surveyed about their own screening beliefs; third-year resident physicians (n = 29) were asked what they perceived their patients believed. The perceptual maps showed significant differences between the patients' and physicians' perceptions of barriers, facilitators, and beliefs about screening. Physicians believed logistical lifestyle issues were the greatest screening barriers for their patients whereas fears of complications, pain, and cancer were the most important barriers perceived by patients. Physicians also underestimated patients' understanding of the benefits and importance of screening, doctors' recommendations, and beliefs that faith in God could facilitate screening. Physicians and patients perceived a doctor's recommendation for screening was an important facilitator. Better understanding of patient perceptions can be used to improve doctor-patient communication and to improve medical resident training by incorporating specific messages tailored for use with African American patients. PMID- 23343401 TI - InChI - the worldwide chemical structure identifier standard. AB - Since its public introduction in 2005 the IUPAC InChI chemical structure identifier standard has become the international, worldwide standard for defined chemical structures. This article will describe the extensive use and dissemination of the InChI and InChIKey structure representations by and for the world-wide chemistry community, the chemical information community, and major publishers and disseminators of chemical and related scientific offerings in manuscripts and databases. PMID- 23343402 TI - Synthesis of carbazole-based selenaporphyrin via annulation. AB - Cu(I)-mediated alkoxylation of doubly 1,3-butadiyne-bridged carbazole dimer 1, followed by acid-catalyzed cyclization, provided furan-bridged carbazole dimer 3, while annulation reaction of 1 with selenium in the presence of hydrazine monohydrate provided selenophene-bridged carbazole dimer 5a. Oxidation of isophlorin 5a afforded carbazole-based selenaporphyrin 5b, which possessed distinct aromaticity and produced intensified and red-shifted absorption bands in the near-IR region. PMID- 23343403 TI - CCN4 induces IL-6 production through alphavbeta5 receptor, PI3K, Akt, and NF kappaB singling pathway in human synovial fibroblasts. AB - INTRODUCTION: Osteoarthritis (OA) is the most common degenerative joint disease that is involved in the degradation of articular cartilage. The exact etiology of OA is not completely understood. CCN4 is related to up-regulation in the cartilage of patients with osteoarthritis. Previous studies have shown that CCN4 might be associated with the pathogenesis of OA, but the exact signaling pathways in CCN4-mediated IL-6 expression in synovial fibroblasts (SF) are largely unknown. Therefore, we explored the intracellular signaling pathway involved in CCN4-induced IL-6 production in human synovial fibroblast cells. METHODS: CCN4 induced IL-6 production was assessed with quantitative real-time qPCR and ELISA. The mechanisms of action of CCN4 in different signaling pathways were studied by using Western blotting. Neutralizing antibodies of integrin were used to block the integrin signaling pathway. Luciferase assays were used to study IL-6 and NF kappaB promoter activity. Immunocytochemistry was used to examine the translocation activity of p65. RESULTS: Osteoarthritis synovial fibroblasts (OASFs) showed significant expression of CCN4 and the expression was higher than in normal SFs. OASF stimulation with CCN4 induced concentration- and time dependent increases in IL-6 production. Pretreatment of OASFs with alphavbeta5 but not alpha5beta1 and alphavbeta3 integrin antibodies reduced CCN4-induced IL-6 production. CCN4-mediated IL-6 production was attenuated by PI3K inhibitor (LY294002 and Wortmannin), Akt inhibitor (Akti), and NF-kappaB inhibitor (PDTC and TPCK). Stimulation of cells with CCN4 also increased PI3K, Akt, and NF-kappaB activation. CONCLUSIONS: Our results suggest that CCN4 activates alphavbeta5 integrin, PI3K, Akt, and NF-kappaB pathways, leading to up-regulation of IL-6 production. According to our results, CCN4 may be an appropriate target for drug intervention in OA in the future. PMID- 23343404 TI - The history of childhood trauma among individuals with ultra high risk for psychosis is as common as among patients with first-episode schizophrenia. AB - AIM: Childhood trauma (CT) is more common in patients with psychosis than in general population and is found to be related to the severity of symptoms. The objective of this study was to investigate the severity of CT, and its relationship with clinical features in two different groups: first-episode schizophrenia (FES) and ultra high risk for psychosis (UHR) groups. METHODS: In this cross-sectional study, 83 patients with FES, 41 individuals with UHR and 69 healthy controls were included. Clinical features were evaluated with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms (SAPS). We evaluated CT with the Childhood Trauma Questionnaire (CTQ). UHR group was also assessed with the Calgary Depression Scale for Schizophrenia. RESULTS: The emotional and physical abuse, physical and emotionalneglect subscale scores and CTQ total score of both the UHR group and FES group were higher than the control group. However, the CTQ total score and subscale scores did not differ between FES and UHR groups. UHR group had more Schneiderian symptoms in terms of both number and severity, and severity of sexual abuse was found to be correlated with SAPS scores especially for the 'commenting voices' item. The CTQ emotional abuse and neglect scores were correlated with the severity of depression. FES patients with higher CTQ scores obtained higher total scores on SAPS and higher total scores on Schneiderian items. CONCLUSION: We found that CT is related to the severity of psychotic symptoms in both FES and UHR groups. Therefore, it is possible that interventions aimed at preventing CT in children would reduce the manifestation of psychosis among young people. PMID- 23343405 TI - Joint predictability of health related quality of life and leisure time physical activity on mortality risk in people with diabetes. AB - BACKGROUND: Reduced health related quality of life (HRQOL) has been associated with increased mortality in individuals with diabetes. In contrast, increased leisure time physical activity (LTPA) has been associated with reduced mortality. The aim of this study was to investigate the combined relationship of HRQOL and LTPA on mortality and whether high levels of LTPA are associated with reduced risk of mortality in adults with diabetes and inferior HRQOL. METHODS: We analyzed data from a national sample of adults (18 years or older) with self reported physician-diagnosed diabetes, who participated in the 2001 National Health Interview Survey in Taiwan (N = 797). A total of 701 participants had complete Short Form 36 (SF-36) and LTPA data and were followed from 2002 to 2008. Participants were divided into 3 groups based on their LTPA: (1) a regularly active group who reported 150 or more min/week of moderate-intensity activity; (2) an intermediately active group who reported engaging in LTPA but did not meet the criterion for the "regular" category; and (3) an inactive group who reported no LTPA. The physical component summary (PCS) and mental component summary (MCS) scores were dichotomised at the median (high vs. low) (PCS = 45.11; MCS = 47.91). Cox proportional-hazards models were used to investigate associations between baseline characteristics and mortality. RESULTS: After 4,570 person-years of follow-up, 121 deaths were recorded and the crude mortality rate was 26.5 per 1,000 person-years. Both PCS scores and LTPA were significant predictors of mortality, whereas no significant relationship was observed between MCS and mortality. After adjustment for other factors, participants with low PCS who reported no LTPA had a hazard ratio (HR) for mortality of 4.49 (95% CI = [2.15 9.36]). However, participants with low PCS who were active (including intermediate and regular LTPA) had a HR for mortality of 1.36 (95% CI = [0.64 2.92]). CONCLUSIONS: Our results show a significantly increased mortality risk of diabetes associated with reduced HRQOL in individuals who report no LTPA. Engaging in LTPA may be associated with improved survival in participants with diabetes with poor self-rated physical health status. PMID- 23343406 TI - Cis-trans amide bond rotamers in beta-peptoids and peptoids: evaluation of stereoelectronic effects in backbone and side chains. AB - Non-natural peptide analogs have significant potential for the development of new materials and pharmacologically active ligands. One such architecture, the beta peptoids (N-alkyl-beta-alanines), has found use in a variety of biologically active compounds but has been sparsely studied with respect to folding propensity. Thus, we here report an investigation of the effect of structural variations on the cis-trans amide bond rotamer equilibria in a selection of monomer model systems. In addition to various side chain effects, which correlated well with previous studies of alpha-peptoids, we present the synthesis and investigation of cis-trans isomerism in the first examples of peptoids and beta-peptoids containing thioamide bonds as well as trifluoroacetylated peptoids and beta-peptoids. These systems revealed an increase in the preference for cis amides as compared to their parent compounds and thus provide novel strategies for affecting the folding of peptoid constructs. By using NMR spectroscopy, X-ray crystallographic analysis, and density functional theory calculations, we present evidence for the presence of thioamide-aromatic interactions through C(sp(2)) H...S(amide) hydrogen bonding, which stabilize certain peptoid conformations. PMID- 23343407 TI - Prophylactic vaccination with adjuvant monophosphoryl lipid a prevents Th2 mediated murine asthmatic responses. AB - OBJECTIVE: Asthma is a chronic respiratory disorder characterized by airway hyperreactivity, eosinophilic infiltration, high titer of allergen-specific IgE, and overproduction of T helper 2 (Th2) cytokines. Antigen combined with an appropriate adjuvant and administrated through the proper route can elicit suitable immunological responses to protect humans and animals from diseases. Antigen formulated with monophosphoryl lipid A (MPLA) can produce priming of Th1 mediated immune responses. The purpose of this study was to examine the utility of MPLA as an adjuvant to prevent asthma. METHODS: BALB/c mice were immunized with ovalbumin (OVA) formulated with or without MPLA by intraperitoneal, footpad, or subcutaneous injection. Vaccinated mice were challenged with OVA aerosol to estimate the protective efficacy of MPLA in comparison to Th2-adjuvant aluminum hydroxide (Alum). Airway hyperresponsiveness to methacholine, eosinophilia in bronchoalveolar lavage fluid (BALF), circulating titers of OVA-specific antibodies, and stimulating levels of IFN-gamma and IL-4 cytokines from splenocytes were evaluated. RESULTS: Mice immunized by all injection routes with OVA formulated with MPLA increased the ratio of Th1/Th2 responses compared to mice receiving antigen alone. For prophylactic vaccination purpose, MPLA reduced airway responsiveness and eosinophilic inflammation in the lung, decreased serum OVA-specific IgE level, and increased the serum ratio of OVA-specific IgG2a/IgG1 and the ratio of IFN-gamma/IL4 from OVA-activated splenocytes compared with mice vaccinated with Alum. CONCLUSION: MPLA may be clinically useful in the vaccination of individuals predisposed to asthma. PMID- 23343408 TI - A fast least-squares algorithm for population inference. AB - BACKGROUND: Population inference is an important problem in genetics used to remove population stratification in genome-wide association studies and to detect migration patterns or shared ancestry. An individual's genotype can be modeled as a probabilistic function of ancestral population memberships, Q, and the allele frequencies in those populations, P. The parameters, P and Q, of this binomial likelihood model can be inferred using slow sampling methods such as Markov Chain Monte Carlo methods or faster gradient based approaches such as sequential quadratic programming. This paper proposes a least-squares simplification of the binomial likelihood model motivated by a Euclidean interpretation of the genotype feature space. This results in a faster algorithm that easily incorporates the degree of admixture within the sample of individuals and improves estimates without requiring trial-and-error tuning. RESULTS: We show that the expected value of the least-squares solution across all possible genotype datasets is equal to the true solution when part of the problem has been solved, and that the variance of the solution approaches zero as its size increases. The Least-squares algorithm performs nearly as well as Admixture for these theoretical scenarios. We compare least-squares, Admixture, and FRAPPE for a variety of problem sizes and difficulties. For particularly hard problems with a large number of populations, small number of samples, or greater degree of admixture, least squares performs better than the other methods. On simulated mixtures of real population allele frequencies from the HapMap project, Admixture estimates sparsely mixed individuals better than Least-squares. The least-squares approach, however, performs within 1.5% of the Admixture error. On individual genotypes from the HapMap project, Admixture and least-squares perform qualitatively similarly and within 1.2% of each other. Significantly, the least-squares approach nearly always converges 1.5- to 6-times faster. CONCLUSIONS: The computational advantage of the least-squares approach along with its good estimation performance warrants further research, especially for very large datasets. As problem sizes increase, the difference in estimation performance between all algorithms decreases. In addition, when prior information is known, the least-squares approach easily incorporates the expected degree of admixture to improve the estimate. PMID- 23343409 TI - Immobilized nanorod assemblies: fabrication and understanding of large area surface-enhanced Raman spectroscopy substrates. AB - We describe the fabrication of optimized plasmonic substrates in the form of immobilized nanorod assemblies (INRA) for surface-enhanced Raman spectroscopy (SERS). Included are high-resolution scanning electron micrograph (SEM) images of the surface structures, along with a mechanistic description of their growth. It is shown that, by varying the size of support microspheres, the surface plasmon resonance is tuned between 330 and 1840 nm. Notably, there are predicted optimal microsphere sizes for each of the commonly used SERS laser wavelengths of 532, 633, 785, and 1064 nm. PMID- 23343410 TI - Like cures like: a neuroimmunological model based on electromagnetic resonance. AB - OBJECTIVES: Recent investigations have pointed to the production of characteristic electromagnetic (EM) waves in highly diluted sterile filtrates of different microorganisms and their associated DNA molecules. Analysis of these diluted solutions that are prepared using methods almost identical to the way that homeopathic medicines are prepared has pointed to the existence of nanostructures capable of emitting EM waves. Combining these results with findings that point to the interaction of EM waves with sensory nerves with subsequent activation of homeostatic efferent pathways, we propose a model to describe mechanisms underlying the effects of homeopathic remedies. THE MODEL: Living cells and tissues are capable of generating EM waves in their physiological conditions. When a cell deviates from its physiological state, in addition to normal EM emissions, it starts to produce EM waves with altered characteristics. According to our model, the main cause of the therapeutic effects of homeopathic remedies is the occurrence of resonance between the non physiological EM waves of the patient and extremely low-frequency EM waves produced by nanostructures present in the homeopathic remedy. Resonance occurs if the frequency and amplitude characteristics of the patient's non-physiological EM waves and those produced by nanostructures of the applied homeopathic remedy are similar. Once resonance occurs, stimulation of the patient's sensory neurons, which are sensitized due to inflammation of any origin, leads to triggering of different regulatory mechanisms, including the activation of descending antinociceptive and/or cholinergic anti-inflammatory pathways, which leads to the restoration of homeostasis. PMID- 23343411 TI - Proterometra macrostoma (Trematoda: Azygiidae): location of the redia and emergence path from the snail, Elimia semicarinata (Gastropoda: Pleuroceridae). AB - The objectives of this study were to describe (1) the osmotic environment and precise location of the Proterometra macrostoma redia in its snail intermediate host, (2) where retraction of the distome body into the cercarial tail occurs, and (3) the subsequent emergence path of the cercaria out of the snail. Snails, Elimia semicarinata , were collected from North Elkhorn Creek in Scott County, Kentucky and screened daily for patent infections. Live rediae were extracted from infected snails in either artificial pond water (APW) or artificial snail water (ASW) and monitored for changes in morphology and movement every hour over 5 hr at 22 C. Infected and control snails were simultaneously fixed and decalcified in Cal-Ex II, prepared for routine paraffin sectioning, and serial sections subsequently analyzed for rediae and cercariae location. Significantly (chi(2) = 42.45; 1 df; P = 0.0001) more rediae showed movement in ASW than in APW after 5 hr, suggesting a host compartment separate from the mantle cavity. Histological sections clearly showed rediae developing in close association with the snail digestive tract, within the peri-intestinal sinus of the snail, and isolated from the mantle cavity by a mantle membrane. Retraction of the distome body into the cercarial tail follows the emergence of the cercaria from the redia. Cercariae then enter the mantle cavity and emerge into fresh water through a siphon-like structure formed by the mantle collar of the snail. PMID- 23343412 TI - Interpretable, probability-based confidence metric for continuous quantitative structure-activity relationship models. AB - A great deal of research has gone into the development of robust confidence in prediction and applicability domain (AD) measures for quantitative structure activity relationship (QSAR) models in recent years. Much of the attention has historically focused on structural similarity, which can be defined in many forms and flavors. A concept that is frequently overlooked in the realm of the QSAR applicability domain is how the local activity landscape plays a role in how accurate a prediction is or is not. In this work, we describe an approach that pairs information about both the chemical similarity and activity landscape of a test compound's neighborhood into a single calculated confidence value. We also present an approach for converting this value into an interpretable confidence metric that has a simple and informative meaning across data sets. The approach will be introduced to the reader in the context of models built upon four diverse literature data sets. The steps we will outline include the definition of similarity used to determine nearest neighbors (NN), how we incorporate the NN activity landscape with a similarity-weighted root-mean-square distance (wRMSD) value, and how that value is then calibrated to generate an intuitive confidence metric for prospective application. Finally, we will illustrate the prospective performance of the approach on five proprietary models whose predictions and confidence metrics have been tracked for more than a year. PMID- 23343413 TI - Volatility and high thermal stability in mid-to-late first-row transition-metal complexes containing 1,2,5-triazapentadienyl ligands. AB - Treatment of first-row transition-metal MCl(2) (M = Ni, Co, Fe, Mn, Cr) with 2 equiv of the potassium 1,2,5-triazapentadienyl salts K(tBuNNCHCHNR) (R = tBu, NMe(2)) afforded M(tBuNNCHCHNR)(2) in 18-73% isolated yields after sublimation. The X-ray crystal structures of these compounds show monomeric, tetrahedral molecular geometries, and magnetic moment measurements are consistent with high spin electronic configurations. Complexes with R = tBu sublime between 155 and 175 degrees C at 0.05 Torr and have decomposition temperatures that range from 280 to 310 degrees C, whereas complexes with R = NMe(2) sublime at 105 degrees C at 0.05 Torr but decompose between 181 and 225 degrees C. This work offers new nitrogen-rich ligands that are related to widely used beta-diketiminate and 1,3,5 triazapentadienyl ligands and demonstrates new complexes with properties suitable for use in atomic-layer deposition. PMID- 23343414 TI - The complete mitochondrial genome of the subarctic red king crab, Paralithodes camtschaticus (Decapoda, Anomura). AB - We determined the complete mitochondrial (mt) genome sequence of the red king crab, Paralithodes camtschaticus (Decapoda, Anomura). P. camtschaticus is one of the largest arthropods and the most expensive commercially available gourmet seafood. The genome sequence of P. camtschaticus is 16,720 bp in size and its gene content, gene order, and transcriptional polarity are almost identical to those of the hermit crab Pagurus longicarpus, which is thought to be derived from a common ancestor. However, P. camtschaticus mtDNA showed tRNA translocation in two blocks compared to that of P. longicarpus. Prior to this study, complete mt genomes of only two species of Anomura have been reported. Thus, our genomic data will provide additional information for constructing the decapod phylogeny. PMID- 23343415 TI - Simulated restaurant cook exposure to emissions of PAHs, mutagenic aldehydes, and particles from frying bacon. AB - This study investigated the exposure of cooks to polycyclic aromatic hydrocarbons (PAHs), higher mutagenic aldehydes, total particles, and ultrafine particles during cooking. Experiments were performed by pan frying fresh and smoked bacon on both electric and gas stoves, and with the gas alone. Detailed analyses of PAHs were performed, with analyses of the levels of 32 different PAHs. A TSI-3939 scanning mobility particle sizer system was used to measure the ultrafine particles. The results showed that total PAHs were in the range of 270-300 ng/m(3) air. However, the smoked bacon experiment showed a somewhat different PAH pattern, whereby retene constituted about 10% of the total PAHs, which is a level similar to that of the abundant gas phase constituent phenanthrene. The reason for the elevated retene emissions is unknown. The total cancer risk, expressed as toxic equivalency factors, showed a somewhat higher risk on the electric stove (p < 0.05) compared with the gas stove. Levels of trans, trans-2,4-decadienal were between 34 and 54 MUg/m(3) air. The level of total particles was between 2.2 and 4.2 mg/m(3). Frying on a gas stove caused a statistically significant higher amount of ultrafine particles compared with frying on an electric stove. Large variations in the mobility diameter at peak particle concentration were found (74.4 nm-153.5 nm). The highest mobility diameter was found for frying on an electric stove. The gas flame itself showed a maximum production of 19.5-nm-sized particles and could not be the explanation for the difference between frying on the gas stove and frying on the electric stove. No single indicator for the exposure to cooking fume could be selected. Each compound should be measured independently to provide a comprehensive characterization of the cooking exposure. PMID- 23343416 TI - Long term toxicity and prognostic factors of radiation therapy for secreting and non-secreting pituitary adenomas. AB - BACKGROUND: Radiotherapy is controversially discussed in the management of benign disorders for fear of late sequelae such as tumor induction. This study was initiated to investigate long-term toxicity, treatment outcome and prognostic factors after radiotherapy (RT) in patients with pituitary adenomas. METHODS: 92 patients with pituitary adenomas were included in this analysis. RT was conducted using either 3D conformal (16%) or fractionated stereotactic techniques (83%) in a postoperative adjuvant setting (16%), as second-line treatment for recurring tumors (78%) or as primary treatment (6%). Postoperatively, RT was offered to patients with residual tumor tissue or in case of locally extensive adenomas, in whom early recurrence was deemed likely. Patients were followed for a median time of 152.5 months, and analysed for overall and local progression-free survival (OS and LPFS). Multiple factors were analysed for prognostic impact. Patients were contacted with an institutional questionnaire about qualiy of life (QOL). Statistical analysis was performed using the log-rank test and the Kaplan-Meier method using a software tool (SPSS 19.0). RESULTS: Median follow-up was 152.5 months. Before treatment, 2% of all patients were diagnosed with adenoma-related hypopituitarism. Following surgery, 68% suffered from new pituitary deficits. RT was associated with mild toxicity, including visual deficits (5.4%) and hypopituitarism (10.9%). In particular, no radiation-induced brain necrosis or malignancy was observed. QOL was reported to be stable or improved in 92% of all patients, and RT was perceived to not compromise but increase QOL in the vast majority of patients (95%). OS after RT was 93.3% and 61.0% at 120 and 240 months. LPFS following RT was 90.4 and 75.5% at 120 and 240 months. Early initiation of RT after surgery instead of reserving it for recurring adenomas predisposed for improved outcome. CONCLUSIONS: RT for pituitary adenomas is safe and and self-reported QOL is stable or improved by almost all patients. Hypopituitarism rates are low. Local control appears improved in patients irradiated postoperatively over those undergoing RT for previously resected recurrent tumors. PMID- 23343417 TI - Cognitive insight in individuals at clinical high risk for psychosis. AB - AIM: Reduced cognitive insight has been associated with psychotic symptoms, in particular with the presence of delusions; however, there is little information about whether such reductions are present in at-risk individuals prior to the onset of threshold psychotic symptoms. METHOD: We conducted a cross-sectional comparison of cognitive insight (as indexed by the Beck Cognitive Insight Scale) in 62 help-seeking individuals at clinical high risk for psychosis, Fifty-nine individuals with schizophrenia-spectrum disorders and 37 healthy controls (HC). In patients, we evaluated associations of insight with positive symptoms, including later transition to psychosis in high-risk patients. RESULTS: Individuals with schizophrenia reported significantly higher self-certainty scores than the at-risk patients and HCs, with the at-risk patients scoring intermediate to the individuals with schizophrenia and controls. Similarly, individuals with schizophrenia scored significantly higher on self reflectiveness, with no differences between the at-risk patients and controls. In individuals with schizophrenia, delusions were significantly correlated with self certainty. In at-risk patients, cognitive insight was not associated with positive symptom severity and did not differentiate those at-risk patients who later developed psychosis from those who did not. However, post hoc analyses suggested that at-risk patients with marked unusual thought content (approaching threshold psychosis) had lower self-reflectiveness; whereas those with high suspiciousness had significantly higher self-certainty. CONCLUSIONS: The findings are discussed in the context of normal developmental processes occurring during adolescence, their putative links to neurobiological functioning, and their implications for treatment and future research. PMID- 23343418 TI - Evaluation of Xpert MTB/RIF and MODS assay for the diagnosis of pediatric tuberculosis. AB - BACKGROUND: Tuberculosis (TB) in children is rarely confirmed due to the lack of effective diagnostic tools; only 10 to 15% of pediatric TB is smear positive due to paucibacillary samples and the difficulty of obtaining high-quality specimens from children. We evaluate here the accuracy of Xpert MTB/RIF in comparison with the Micoroscopic observation drug susceptibility (MODS) assay for diagnosis of TB in children using samples stored during a previously reported evaluation of the MODS assay. METHODS: Ninety-six eligible children presenting with suspected TB were recruited consecutively at Pham Ngoc Thach Hospital in Ho Chi Minh City Viet Nam between May to December 2008 and tested by Ziehl-Neelsen smear, MODS and Mycobacterial growth Indicator (MGIT, Becton Dickinson) culture. All samples sent by the treating clinician for testing were included in the analysis. An aliquot of processed sample deposit was stored at -20 degrees C and tested in the present study by Xpert MTB/RIF test. 183 samples from 73 children were available for analysis by Xpert. Accuracy measures of MODS and Xpert were summarized. RESULTS: The sensitivity (%) in detecting children with a clinical diagnosis of TB for smear, MODS and Xpert were 37.9 [95% CI 25.5; 51.6], 51.7 [38.2; 65.0] and 50.0 [36.6; 63.4], respectively (per patient analysis). Xpert was significantly more sensitive than smear (P=0.046). Testing of additional samples did not increase case detection for MODS while testing of a second sputum sample by Xpert detected only two additional cases. The positive and negative predictive values (%) of Xpert were 100.0 [88.0; 100.0] and 34.1 [20.5; 49.9], respectively, while those of MODS were 96.8 [83.3; 99.9] and 33.3 [19.6; 49.5]. CONCLUSION: MODS culture and Xpert MTB/RIF test have similar sensitivities for the detection of pediatric TB. Xpert MTB RIF is able to detect tuberculosis and rifampicin resistance within two hours. MODS allows isolation of cultures for further drug susceptibility testing but requires approximately one week to become positive. Testing of multiple samples by xpert detected only two additional cases and the benefits must be considered against costs in each setting. Further research is required to evaluate the optimal integration of Xpert into pediatric testing algorithms. PMID- 23343419 TI - Filaggrin mutations are strongly associated with contact sensitization in individuals with dermatitis. AB - BACKGROUND: Although heterozygous filaggrin gene (FLG) mutation carriers seem to have an increased risk of atopic, irritant and allergic nickel dermatitis, it remains unclear whether the risk of contact sensitization to allergens other than nickel is also elevated in FLG mutation carriers. OBJECTIVES: We hypothesized that heterozygous FLG mutation carriers who suffer from dermatitis will have strongly reduced or even absent filaggrin levels during episodes of inflammation, potentially increasing the penetration of contact allergens, and hence the risk of becoming sensitized. MATERIALS AND METHODS: During 2006-2008, 3335 randomly invited 18-69-year-old adult Danes participated in a general health examination, filled out a questionnaire, and were genotyped for the R501X and 2282del4 mutations in FLG. RESULTS: A logistic regression analysis restricted to individuals who reported atopic dermatitis and frequent episodes of hand eczema showed a strong association between FLG mutations and contact sensitization to allergens other than nickel (odds ratio 5.71; 95% confidence interval 1.31 24.94). In participants without dermatitis, no association was found between contact sensitization and FLG mutations. CONCLUSION: FLG mutation carriers with self-reported dermatitis have an increased risk of contact sensitization to substances other than nickel, whereas FLG mutations alone may not, or may only slightly, increase the risk of sensitization. PMID- 23343420 TI - L-cysteine-derived ambidextrous gelators of aromatic solvents and ethanol/water mixtures. AB - A series of L-cysteine-derived double hydrocarbon chain amphiphilic gelators L-(3 alkyl-carbamoylsulfanyl)-2-(3-alkylurido)propionic acid with different hydrocarbon chain lengths (C6-C16) was designed and synthesized. These gelators efficiently gelate only aromatic solvents. The gelation ability increased with the increase of chain length up to C14, but then it dropped with further increase of chain length. The C12 and C14 derivatives also gelled ethanol/water mixtures. The gels were characterized by a number of methods, including FT-IR, NMR, and XRD spectroscopy, electron microscopy, and rheology. The amphiphiles were observed to form either flat lamellar or ribbonlike aggregates in aromatic solvents as well as in ethanol/water mixtures. The gelation in all the solvents employed was observed to be thermoreversible. The gel-to-sol transition temperature as well as mechanical strength of the organogels were observed to increase with the hydrocarbon chain length. Both types of gels of C8-C16 amphiphiles have gel-to sol transition temperatures above the physiological temperature (310 K). FT-IR and variable temperature (1)H NMR measurements suggested that van der Waals interactions have major contribution in the gelation process. The gel-to-sol transition temperature and mechanical strength of the organogels in ethanol/water mixtures was observed to be higher than those of benzene organogel. PMID- 23343421 TI - Cluster phases of decorated micellar solutions with macrocyclic ligands. AB - An aqueous self-assembled micellar system (sodium dodecyl sulfate, SDS, decorated with various adhesive sites, cryptand Kryptofix 222 and crown ether 18-Crown-6 molecules) has been investigated by dynamic light scattering (DLS) and small angle x-ray scattering (SAXS) to have insights into the micellar structure, the micellar interactions, and the aggregation properties of the system. DLS demonstrates the existence of populations of aggregates in the submicrometer/micrometer range, while the Guinier analysis of the SAXS curves helps in detailing objects smaller than 30 nm. The aggregates of micelles are here named cluster phases of micelles (CPMs). Considering that SDS micelles in water do not aggregate at low concentration, it is shown that macrocyclic ligands induce the SDS micelle aggregation as a function of the concentration (i.e., investigated ligand/SDS molar ratios are 5.0, 1.5, 1.0, and 0.5) and hydrophobicity of the adhesive sites. The sizes and the percentages of the micelles and the CPMs have been monitored to test the stability and reversibility of the system. DLS results clearly show that the aggregation processes of the decorated micelles are reproducible at time intervals of the order of 1 month, while the stability may not be entirely maintained after a year. As an issue of particular relevance, the higher the ligand/surfactant molar ratio, the larger are the CPMs induced. The K222 ligand results in being more effective in promoting the micellar aggregation than 18C6 as a consequence of the different hydrophobicity. PMID- 23343422 TI - Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models. AB - INTRODUCTION: Targeting receptor tyrosine kinases (RTKs) with kinase inhibitors is a clinically validated anti-cancer approach. However, blocking one signaling pathway is often not sufficient to cause tumor regression and the effectiveness of individual inhibitors is often short-lived. As alterations in fibroblast growth factor receptor (FGFR) activity have been implicated in breast cancer, we examined in breast cancer models with autocrine FGFR activity the impact of targeting FGFRs in vivo with a selective kinase inhibitor in combination with an inhibitor of PI3K/mTOR or with a pan-ErbB inhibitor. METHODS: Using 4T1 or 67NR models of basal-like breast cancer, tumor growth was measured in mice treated with an FGFR inhibitor (dovitinib/TKI258), a PI3K/mTOR inhibitor (NVP-BEZ235) or a pan-ErbB inhibitor (AEE788) individually or in combination. To uncover mechanisms underlying inhibitor action, signaling pathway activity was examined in tumor lysates and transcriptome analysis carried out to identify pathways upregulated by FGFR inhibition. Anti-phosphotyrosine receptor antibody arrays (P Tyr RTK) were also used to screen 4T1 tumors. RESULTS: The combination of dovitinib + NVP-BEZ235 causes tumor stasis and strong down-regulation of the FRS2/Erk and PI3K/Akt/mTOR signaling pathways. P-Tyr RTK arrays identified high levels of P-EGFR and P-ErbB2 in 4T1 tumors. Testing AEE788 in the tumor models revealed that the combination of dovitinib + AEE788 resulted in blockade of the PI3K/Akt/mTOR pathway, prolonged tumor stasis and in the 4T1 model, a significant decrease in lung metastasis. The results show that in vivo these breast cancer models become dependent upon co-activation of FGFR and ErbB receptors for PI3K pathway activity. CONCLUSIONS: The work presented here shows that in the breast cancer models examined, the combination of dovitinib + NVP-BEZ235 or dovitinib + AEE788 results in strong inhibition of tumor growth and a block in metastatic spread. Only these combinations strongly down-regulate the FGFR/FRS2/Erk and PI3K/Akt/mTOR signaling pathways. The resultant decrease in mitosis and increase in apoptosis was consistently stronger in the dovitinib + AEE788 treatment-group, suggesting that targeting ErbB receptors has broader downstream effects compared to targeting only PI3K/mTOR. Considering that sub-classes of human breast tumors co-express ErbB receptors and FGFRs, these results have implications for targeted therapy. PMID- 23343423 TI - Chromosome 18q-syndrome and 1p terminal duplication in a patient with bilateral vesico-ureteral reflux: case report and literature revision. AB - BACKGROUND: Vesico-ureteral reflux (VUR) is a dynamic event in which a retrograde flow of urine is present into the upper tracts. VUR may occur isolated or in association with other congenital abnormalities or as part of syndromic entities. We present a patient with a bilateral primary VUR, syndromic disease caused by a large deletion of 18q (18q21.3-qter) and terminal duplication of 1p (1p36.32 p36.33). CASE REPORT: The patient was 8 years old female with a disease including moderate growth retardation, psychomotor retardation, facial dysmorphism, single umbilical artery, umbilical hernia, urachal remnant, bilateral congenital clubfeet and renal-urinary disease. Chromosomal analysis and Array-CGH revealed two heterozygous chromosomal rearrangements: 1p terminal duplication and de novo 18q terminal deletion. She referred to our clinic to evaluation of bilateral hydronephrosis and right renal cortex thinning. Voiding cystourethrography demonstrated bilateral grade IV VUR and dimercaptosuccinic acid renal scintigraphy confirmed right renal cortex thinning and showed a cortical uptake of 75% of the left kidney and 25% of the right kidney. The patient underwent ureterovesical reimplantation after failure of 3 endoscopic submeatal Deflux injections with VUR resolution. CONCLUSIONS: This is the first report involving a patient with 18q-syndrome and contemporary presence of 1p chromosomal terminal duplication. The coexistence of two chromosomal rearrangements complicates the clinical picture and creates a chimeric disorder (marked by characteristics of both chromosomal anomalies). Kidney problems, primarily VUR is reported in 15% of patients affected by 18-q syndrome and no cases is reported in the literature regarding a correlation between VUR and 1p36 chromosomal duplication. PMID- 23343424 TI - Stereoselective synthesis of 7-epi-incarvilline. AB - The enantioselective synthesis of 7-epi-incarvilline for formal syntheses of (-) incarvilline, (+)-incarvine C, and (-)-incarvillateine is described. The key features of our synthesis involve (1) stereoselective construction of the optically active bicyclic lactone utilizing Pd(0)-catalyzed allylic alkylation, (2) efficient transformation of the bridged bicyclic lactone to the key bicyclic lactam skeleton, and (3) stereoselective elaborations of two stereocenters via a substrate-controlled catalytic hydrogenation and a 1,4-addition. PMID- 23343425 TI - Development of a novel codon-specific polymerase chain reaction for the detection of CXCR4-utilizing HIV type 1 subtype B. AB - Insight concerning the switch in HIV-1 coreceptor use will lead to a better understanding of HIV-1 pathogenesis and host-virus dynamics. Predicting CXCR4 utilization by analyzing HIV-1 envelope consensus sequences is highly specific, but minority variants in the viral population are often missed resulting in low sensitivity. Commercial phenotypic assays are costly, and the development of sensitive in-house phenotypic assays to detect CXCR4-using HIV may not be feasible for some laboratories. A sensitive, inexpensive genotyping assay was developed to detect viral sequences associated with CXCR4-utilizing virus (X4). Codon-specific primer pairs were used to detect X4-associated codons at five positions in the HIV-1 envelope V3 loop (11, 13, 24, 25, and 32). Sixty plasma samples from HIV-1-infected individuals were analyzed by consensus sequencing and codon-specific PCR (CS-PCR). Forty-six of these were also phenotyped by Trofile or Enhanced Sensitivity Trofile (ESTA). CS-PCR detected X4 variants 17% more often than 11/24/25 consensus sequencing alone (n=60), 30% more often than Trofile (n=27), and in a limited data set, 16% more often than ESTA (n=19). CS PCR combined with consensus sequencing had approximately 80% concordance with ESTA. PMID- 23343426 TI - Longitudinal strain from velocity encoded cardiovascular magnetic resonance: a validation study. AB - BACKGROUND: Regional myocardial function is typically evaluated by visual assessment by experienced users, or by methods requiring substantial post processing time. Visual assessment is subjective and not quantitative. Therefore, the purpose of this study is to develop and validate a simple method to derive quantitative measures of regional wall function from velocity encoded cardiovascular magnetic resonance (CMR), and provide associated normal values for longitudinal strain. METHOD: Both fast field echo (FFE) and turbo field echo (TFE) velocity encoded CMR images were acquired in three long axis planes in 36 healthy volunteers (13 women, 23 men), age 35+/-12 years. Strain was also quantified in 10 patients within one week after myocardial infarction. The user manually delineated myocardium in one time frame and strain was calculated as the myocardium was tracked throughout the cardiac cycle using an optimization formulation and mechanical a priori assumptions. A phantom experiment was performed to validate the method with optical tracking of deformation as an independent gold standard. RESULTS: There was an excellent agreement between longitudinal strain measured by optical tracking and longitudinal strain measured with TFE velocity encoding. Difference between the two methods was 0.0025 +/- 0.085 (ns). Mean global longitudinal strain in the 36 healthy volunteers was 0.18 +/- 0.10 (TFE imaging). Intra-observer variability for all segments was 0.00 +/- 0.06. Inter-observer variability was -0.02 +/- 0.07 (TFE imaging). The intra observer variability for radial strain was high limiting the applicability of radial strain. Mean longitudinal strain in patients was significantly lower ( 0.15+/- 0.12) compared to healthy volunteers (p<0.05). Strain (expressed as percentage of normal strain) in infarcted regions was lower compared to remote areas (p<0.01). CONCLUSION: In conclusion, we have developed and validated a robust and clinically applicable technique that can quantify longitudinal strain and regional myocardial wall function and present the associated normal values for longitudinal strain. PMID- 23343427 TI - Efficacy and safety of moxifloxacin in acute exacerbations of chronic bronchitis: a prospective, multicenter, observational study (AVANTI). AB - BACKGROUND: Acute exacerbations of chronic bronchitis (AECB), including chronic obstructive pulmonary disease (AECOPD), represent a substantial patient burden. Few data exist on outpatient antibiotic management for AECB/AECOPD in Eastern/South Eastern Europe, in particular on the use of moxifloxacin (Avelox(r)), although moxifloxacin is widely approved in this region based on evidence from international clinical studies. METHODS: AVANTI (AVelox(r) in Acute Exacerbations of chroNic bronchiTIs) was a prospective, observational study conducted in eight Eastern European countries in patients > 35 years with AECB/AECOPD to whom moxifloxacin was prescribed. In addition to safety and efficacy outcomes, data on risk factors and the impact of exacerbation on daily life were collected. RESULTS: In the efficacy population (N = 2536), chronic bronchitis had been prevalent for > 10 years in 31.4% of patients and 66.0% of patients had concomitant COPD. Almost half the patients had never smoked, in contrast to data from Western Europe and the USA, where only one-quarter of COPD patients are non-smokers. The mean number of exacerbations in the last 12 months was 2.7 and 26.3% of patients had been hospitalized at least once for exacerbation. Physician compliance with the recommended moxifloxacin dose (400 mg once daily) was 99.6%. The mean duration of moxifloxacin therapy for the current exacerbation (Anthonisen type I or II in 83.1%; predominantly type I) was 6.4 +/- 1.9 days. Symptom improvement was reported after a mean of 3.4 +/- 1.4 days. After 5 days, 93.2% of patients reported improvement and, in total, 93.5% of patients were symptom-free after 10 days. In the safety population (N = 2672), 57 (2.3%) patients had treatment-emergent adverse events (TEAEs) and 4 (0.15%) had serious TEAEs; no deaths occurred. These results are in line with the known safety profile of moxifloxacin. CONCLUSIONS: A significant number of patients in this observational study had risk factors for poor outcome, justifying use of moxifloxacin. The safety profile of moxifloxacin and its value as an antibiotic treatment were confirmed. Physicians complied with the recommended 400 mg once daily dose in a large proportion of patients, confirming the advantages of this simple dosing regimen. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00846911. PMID- 23343428 TI - Detecting recurrent gene mutation in interaction network context using multi scale graph diffusion. AB - BACKGROUND: Delineating the molecular drivers of cancer, i.e. determining cancer genes and the pathways which they deregulate, is an important challenge in cancer research. In this study, we aim to identify pathways of frequently mutated genes by exploiting their network neighborhood encoded in the protein-protein interaction network. To this end, we introduce a multi-scale diffusion kernel and apply it to a large collection of murine retroviral insertional mutagenesis data. The diffusion strength plays the role of scale parameter, determining the size of the network neighborhood that is taken into account. As a result, in addition to detecting genes with frequent mutations in their genomic vicinity, we find genes that harbor frequent mutations in their interaction network context. RESULTS: We identify densely connected components of known and putatively novel cancer genes and demonstrate that they are strongly enriched for cancer related pathways across the diffusion scales. Moreover, the mutations in the clusters exhibit a significant pattern of mutual exclusion, supporting the conjecture that such genes are functionally linked. Using multi-scale diffusion kernel, various infrequently mutated genes are found to harbor significant numbers of mutations in their interaction network neighborhood. Many of them are well-known cancer genes. CONCLUSIONS: The results demonstrate the importance of defining recurrent mutations while taking into account the interaction network context. Importantly, the putative cancer genes and networks detected in this study are found to be significant at different diffusion scales, confirming the necessity of a multi scale analysis. PMID- 23343429 TI - Increase of seed germination, growth and membrane integrity of wheat seedlings by exposure to static and a 10-KHz electromagnetic field. AB - There is a large body of experimental data demonstrating various effects of magnetic field (MF) on plants growth and development. Although the mechanism(s) of perception of MF by plants is not yet elucidated, there is a possibility that like other stimuli, MF exerts its effects on plants by changing membrane integrity and conductance of its water channels, thereby influencing growth characteristics. In this study, the seeds of wheat (Triticum aestivum L. cv. Kavir) were imbibed in water overnight and then treated with or without a 30-mT static magnetic field (SMF) and a 10-kHz electromagnetic field (EMF) for 4 days, each 5 h. Water uptake of seeds reduced 5 h of the treatment with EMF but did not show changes in SMF treatment. Exposure to both magnetic fields did not affect germination percent of the seeds but increased the speed of germination, compared to the control group. Treatment with EMF significantly reduced seedling length and subsequently vigor index I, while SMF had no effects on these parameters. Both treatments significantly increased vigor index II, compared to the control group. These treatments also remarkably increased catalase activity and proline contents of seedlings but reduced the activity of peroxidase, the rate of lipid peroxidation and electrolyte leakages of membranes. The results suggest promotional effects of EMFs on membrane integrity and growth characteristics of wheat seedlings. PMID- 23343431 TI - Exercise-induced hypertension: not quite ready for prime time. PMID- 23343432 TI - Freezing of water next to solid surfaces probed by infrared-visible sum frequency generation spectroscopy. AB - Ice formation next to solid surfaces is important in many biological, materials, and geological phenomena and may be a factor in how they impact various technologies. We have used sum frequency generation (SFG) spectroscopy to study the structure of ice as well as the freezing and melting transition temperatures of water in contact with sapphire substrates. We have observed that the structure of ice and water are a function of pH and the surface charge of the sapphire substrate. At low pH, we observed an increase in the SFG signal subsequent to ice formation. Contrary to expectations, at pH 9.8, corresponding to a negatively charged surface, the intensity of the ice SFG signal is about 10 times lower than that of water. Recent simulation studies have suggested that charge transfer is important for the high intensity of the ice peak at the ice-air interface. We believe that the segregation of sodium ions next to the negatively charged sapphire substrate may be responsible for disrupting the charge transfer and stitching bilayer at high pH, providing a plausible explanation for the experimental observations. Even though the structure of water and ice are affected by pH, the freezing and melting transition temperatures are independent of the surface charge. This report offers a unique insight on how ions next to solid surfaces could influence the structure of ice. PMID- 23343433 TI - The economic impact of early intervention in psychosis services for children and adolescents. AB - AIMS: To develop and populate a plausible model of the impact of early intervention (EI) for children and adolescents with psychosis to estimate potential short-term health-related cost savings compared to generic Child and Adolescent Mental Health Services (CAMHS). METHOD: A decision-tree-based model for EI in CAMHS was developed. The model was populated using data relating to the use of inpatient care and EI service activity for people aged under 18 from an area of North East England. Data were abstracted from the National Health Service clinical reporting systems for 2001-2008. Sensitivity analyses were performed to examine costs associated with the model under differing assumptions. RESULTS: EI delivered cost savings of L4814 per patient compared to care provided by generic CAMHS. Cost savings were predominantly a consequence of reduced length of hospital admissions for patients served by the EI team. The findings were robust to sensitivity analyses. CONCLUSIONS: These findings suggest that EI services for children and adolescents with psychosis provide potential direct health cost savings comparable to those observed for working-age adults. PMID- 23343434 TI - Care planning and decision-making in teams in Swedish elderly care: a study of interprofessional collaboration and professional boundaries. AB - In front-line practice, joint working between different professionals in health/social care and rehabilitation is regarded as a means to reach a comprehensive assessment of the needs of the older care recipients, leading to decisions on appropriate care and services. The aim of this study was to examine professional collaboration and professional boundaries in interprofessional care planning teams. Two different care planning teams were studied, one performing care planning in the homes of older individuals and the other performing care planning for older people in hospital wards. The empirical data consisted of audio-recorded care planning meetings and interviews with the professionals in the teams. The integration between the professionals involved was most noticeable in the investigation and assessment phase, while it was lower in the planning phase and almost non-existent in decision-making. The home care planning team tended to work in a more integrated manner than the discharge planning team. The importance of clarifying the roles of all professions concerned with needs assessment and care planning for older people became evident in this study. PMID- 23343435 TI - Automatic identification of emission lines in laser-induced plasma by correlation of model and experimental spectra. AB - We have applied an algorithm to automatically identify emission lines in laser induced breakdown spectrometry (LIBS). A Q-switched Nd:YAG laser at 355 nm was used to ablate a high-alloy stainless steel sample. The algorithm was implemented by three parts: simulation of the set of spectra corresponding to different temperature (T) and electron density (N(e)), searching the best correlated pair of a model spectrum and an experimental one, and attributing the peaks with certain lines. In order to construct the model spectra, we used the parameters of atomic and ionic lines, levels, the mechanisms of the broadening of spectral lines, and the selected parameters of the spectrograph. The highest correlation coefficient between the model and the experimental spectrum was 0.943 for T = 0.675 eV and lg(N(e)) = 16.7 cm(-3). More than 40 emission lines were labeled automatically in the spectral region 393.34-413.04 nm. PMID- 23343436 TI - Computational modeling of the triplet metal-to-ligand charge-transfer excited state structures of mono-bipyridine-ruthenium(II) complexes and comparisons to their 77 K emission band shapes. AB - A computational approach for calculating the distortions in the lowest energy triplet metal to ligand charge-transfer ((3)MLCT = T(0)) excited states of ruthenium(II)-bipyridine (Ru-bpy) complexes is used to account for the patterns of large variations in vibronic sideband amplitudes found in the experimental 77 K emission spectra of complexes with different ancillary ligands (L). Monobipyridine, [Ru(L)(4)bpy](m+) complexes are targeted to simplify analysis. The range of known emission energies for this class of complexes is expanded with the 77 K spectra of the complexes with (L)(4) = bis-acetonylacetonate (emission onset at about 12,000 cm(-1)) and 1,4,8,11-tetrathiacyclotetradecane and tetrakis acetonitrile (emission onsets at about 21,000 cm(-1)); no vibronic sidebands are resolved for the first of these, but they dominate the spectra of the last two. The computational modeling of excited-state distortions within a Franck-Condon approximation indicates that there are more than a dozen important distortion modes including metal-ligand modes (low frequency; lf) as well as predominately bpy modes (medium frequency; mf), and it simulates the observed 77 K emission spectral band shapes of selected complexes very well. This modeling shows that the relative importance of the mf modes increases very strongly as the T(0) energy increases. Furthermore, the calculated metal-centered SOMOs show a substantial bpy-pi-orbital contribution for the complexes with the highest energy T(0). These features are attributed to configurational mixing between the diabatic MLCT and the bpy (3)pipi* excited states at the highest T(0) energies. PMID- 23343437 TI - A mixed integer linear programming model to reconstruct phylogenies from single nucleotide polymorphism haplotypes under the maximum parsimony criterion. AB - BACKGROUND: Phylogeny estimation from aligned haplotype sequences has attracted more and more attention in the recent years due to its importance in analysis of many fine-scale genetic data. Its application fields range from medical research, to drug discovery, to epidemiology, to population dynamics. The literature on molecular phylogenetics proposes a number of criteria for selecting a phylogeny from among plausible alternatives. Usually, such criteria can be expressed by means of objective functions, and the phylogenies that optimize them are referred to as optimal. One of the most important estimation criteria is the parsimony which states that the optimal phylogeny T*for a set H of n haplotype sequences over a common set of variable loci is the one that satisfies the following requirements: (i) it has the shortest length and (ii) it is such that, for each pair of distinct haplotypes hi,hj?H, the sum of the edge weights belonging to the path from hi to hj in T* is not smaller than the observed number of changes between hi and hj. Finding the most parsimonious phylogeny for H involves solving an optimization problem, called the Most Parsimonious Phylogeny Estimation Problem (MPPEP), which is NP-hard in many of its versions. RESULTS: In this article we investigate a recent version of the MPPEP that arises when input data consist of single nucleotide polymorphism haplotypes extracted from a population of individuals on a common genomic region. Specifically, we explore the prospects for improving on the implicit enumeration strategy of implicit enumeration strategy used in previous work using a novel problem formulation and a series of strengthening valid inequalities and preliminary symmetry breaking constraints to more precisely bound the solution space and accelerate implicit enumeration of possible optimal phylogenies. We present the basic formulation and then introduce a series of provable valid constraints to reduce the solution space. We then prove that these constraints can often lead to significant reductions in the gap between the optimal solution and its non-integral linear programming bound relative to the prior art as well as often substantially faster processing of moderately hard problem instances. CONCLUSION: We provide an indication of the conditions under which such an optimal enumeration approach is likely to be feasible, suggesting that these strategies are usable for relatively large numbers of taxa, although with stricter limits on numbers of variable sites. The work thus provides methodology suitable for provably optimal solution of some harder instances that resist all prior approaches. PMID- 23343438 TI - The disease burden of pertussis in adults 50 years old and older in the United States: a retrospective study. AB - BACKGROUND: While the incidence of pertussis has increased in adolescents and adults in recent years in the U.S., little is known about the incidence and economic burden of pertussis in older adults. This study provides evidence of the incidence of pertussis and direct medical charges associated with pertussis episodes of care (PEOCs) in adults aged 50 years and older in the U.S. METHODS: PEOCs were divided into periods before and after the initial pertussis diagnosis was made (i.e., the index date) to capture any conditions immediately preceding the pertussis diagnosis that may have represented misdiagnoses and subsequent conditions that may have represented sequelae. Data were extracted from IMS's recently acquired SDI databases of longitudinal, patient-level practitioner claims and hospital operational billing records collected from private practitioners and hospitals, respectively, across the U.S. Patients 50 years and older with one or more ICD-9-CM diagnoses for pertussis/whooping cough and/or a laboratory test positive for Bordetella pertussis between 1/1/2006 and 10/31/2010 were eligible for study inclusion. Resource utilization and charges (i.e., unadjudicated claims) associated with the patient's physician and hospital care were analyzed. The nationally projected incidence of pertussis was estimated using a subsample of patients with the required data necessary for projection. RESULTS: Estimated incidence of diagnosed pertussis ranged from 2.1-4.6 cases per 100,000 people across the two age groups (50-64 and [greater than or equal to] 65) during the years 2006 to 2010. The analysis of charges included 5,748 patients [greater than or equal to] 50 years of age with pertussis. Average charges across the entire episode of care were $1,835 and $14,428 per patient in the outpatient and inpatient settings, respectively. The average number of outpatient (i.e., private practitioner) visits was 2 per patient in both the pre index and post-index periods. CONCLUSIONS: In the U.S., the incidence of diagnosed pertussis in adults 50 years and older has increased between 2006 and 2010. Healthcare utilization and charges associated with pertussis are substantial, suggesting the need for additional prevention and control strategies and a higher degree of clinical awareness on the part of health care providers. Additional research regarding pertussis in older populations is needed to substantiate these findings. PMID- 23343439 TI - Modeling self-assembly of silica/surfactant mesostructures in the templated synthesis of nanoporous solids. AB - A novel coarse-grained (CG) model to study the self-assembly of silica/surfactant mesostructures during the synthesis of periodic mesoporous silica is reported. Molecular dynamics simulations of hexadecyltrimethylammonium bromide (also called cetyltrimethylammonium bromide, or CTAB) surfactants in water and in aqueous silicate solutions have been performed to understand micelle formation, micelle growth, and their size evolution during the synthesis of surfactant-templated mesoporous materials. Direct comparison of density profiles obtained for preassembled micelles employing an all-atom description, AA, with those calculated with the CG model has been carried out for checking the validity of the latter model. Good agreement between AA and CG approaches was found, demonstrating the potential of the CG approximation for modeling these highly complex systems. The micelle formation and micelle fusion/fission processes were analyzed after performing long CG simulations for surfactant and ionized silica surfactant aqueous solutions. We observed the formation of rodlike micelles in the case of silica-surfactant solutions, while spherical micelles were stable under the same conditions for the CTAB+H(2)O system. This demonstrates that the interaction of anionic silicates with cationic surfactants promotes a sphere-to rod transition in surfactant solutions, a key step in the synthesis of nanoporous silica materials. PMID- 23343440 TI - An update on airborne contact dermatitis: 2007-2011. AB - BACKGROUND: Reviews on irritant and allergic airborne contact dermatitis have been previously reported in the literature. MATERIALS AND METHODS: Here, we present an update based on recently published airborne-induced skin reactions. For this survey, we screened the journals Contact Dermatitis, Dermatitis, and included relevant articles from other journals during the period January 2007 to December 2011. We also present the airborne cases observed in our department during the same time period. RESULTS: This survey provides an updated list of causal agents that have produced airborne allergic contact dermatitis, and briefly mentions some other types of skin reaction induced by airborne exposure. The sources of the reactions are multiple: drugs; plants, natural resins, and wood allergens; plastics, rubbers, and glues; preservatives and other chemicals; and metals. CONCLUSIONS: Airborne contact dermatitis is frequent, and most of the airborne allergens (and irritants) identified are in occupational settings. Drugs and preservatives have recently become more important causes. Dermatologists and occupational physicians need to be aware of them. PMID- 23343441 TI - Critical care resource allocation: trying to PREEDICCT outcomes without a crystal ball. PMID- 23343442 TI - Carbimazole-induced, ANCA-associated, crescentic glomerulonephritis: case report and literature review. AB - Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is a rare complication of antithyroid drug use that was first described with propylthiouracil. We describe an ANCA-associated rapidly progressive glomerulonephritis in a patient treated with carbimazole during 6 months for Graves disease that resulted in end-stage renal disease. A 66-year-old man treated with carbimazole for Graves disease was admitted for macroscopic hematuria and edema of the lower extremities. Laboratory work-up showed elevated serum creatinine (435 MUmol/L), mixed hematuria, nephrotic range proteinuria, and a low positive c-ANCA titer with proteinase-3 specificity. Renal biopsy showed necrotizing, crescentic, pauci-immune glomerulonephritis. Carbimazole was discontinued and hemodialysis was initiated as well as high-dose glucocorticoids and pulses of intravenous cyclophosphamide. Despite immunosuppressive treatment, the patient remained dialysis-dependent at 6 months after diagnosis. Graves disease remained in remission after carbimazole withdrawal. ANCA-associated vasculitis manifesting as glomerulonephritis is a potential adverse effect of all antithyroid drugs. Although prognosis is usually good, end-stage renal disease may ensue in rare cases. Physicians should have a high index of suspicion in patients receiving antithyroid drugs who present with symptoms or signs suggestive of progressive renal disease. PMID- 23343443 TI - Unimolecular reactivity of the [urea-Sr]2+ complex, a metastable dication in the gas phase: an experimental and theoretical perspective. AB - The interactions between urea and Sr(2+) in the gas phase have been investigated by combining electrospray ionization/mass spectrometry techniques and density functional and high-level ab initio molecular orbital calculations. Our theoretical survey indicates that [Sr(urea)](2+) adducts are thermodynamically stable with respect to direct Coulomb explosions. However, after isomerization, some of the local minima of the PES are thermodynamically unstable with respect to the formation of NH(4)(+), but kinetically metastable. The loss of neutral fragments with the concomitant generation of lighter doubly charged fragment ions, namely, [(H(3)N)Sr](2+) and [(HNCO)]Sr(2+), compete with the aforementioned Coulomb explosion processes yielding NH(4)(+) + [(NCO)Sr](+) and [(H(2)N)Sr](+) + [H(2)NCO](+), although the former processes dominate. Hence, both singly and doubly charged species are detected as dissociation products. Quite importantly, the observed eliminations of NH(3) or HNCO lead to the formation of new doubly charged species, which turn out to be thermodynamically stable. PMID- 23343444 TI - Withdrawn PMID- 23343445 TI - Efficacy and safety of long acting injectable atypical antipsychotics: a review. AB - Schizophrenia is a chronic, severe and recurrent brain disorder that requires continuous, long-term treatment with antipsychotic medication to minimize relapse and provide clinical benefit to patients. For patients with schizophrenia, non adherence to medication is a major risk factor for relapse and re hospitalization. Long-acting injectable formulations of second-generation antipsychotics (SGAs-LAIs) provide constant medication delivery and the potential for improved adherence. Currently, three drugs are available for the treatment of schizophrenia, risperidone longacting injectable, olanzapine pamoate and paliperidone palmitate. Several studies have also demonstrated efficacy and safety of such drugs in patients with acute schizophrenia. In the present paper the literature on LAI atypical antipsychotics will be reviewed and practical advice will be given concerning the use of these drugs in the clinical practice. PMID- 23343446 TI - History and therapeutic rationale of long acting antipsychotics. AB - Despite their widespread use, long acting antipsychotics, are often regarded with prejudice, due to fears of punishment, control and insufficient evolution towards psychosocial development of psychotic patients raised by their improper utilization. Another major shortcoming of long-acting antipsychotics is the impossibility of altering their dosage if side-effects appear. However, long acting antipsychotics proved effective in schizophrenia and other severe psychotic disorders as a consequence of stable dose administration, leading to reduction of relapses and increased treatment adherence. Therapeutic opportunities have also risen after introduction of newer long acting second generation antipsychotics in recent years. Newer long-acting antipsychotics were developed to tackle the need for pharmacotherapy enhancing adherence in integrated rehabilitation programmes. This review is an outline of the development and introduction of older and newer long-acting antipsychotics in the treatment of schizophrenia and other psychoses, with considerations on past and present pharmacological and therapeutic issues. PMID- 23343447 TI - The pharmacokinetics of long-acting antipsychotic medications. AB - The depot antipsychotics are synthesized by esterification of the active drug to a long chain fatty acid and the resultant compound is then dissolved in a vegetable oil, with the exception of some molecules of new generation characterized by microcrystalline technologies. The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit 'flip-flop' kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate. The pharmacokinetics of depot antipsychotic medications are such that an intramuscular injection given at intervals from 1 to 4 weeks will produce adequate plasma concentrations that are sufficient to prevent relapse over the dosage interval. Such medication is useful in patients who do not reliably take their oral medication. The pharmacokinetics and clinical actions of various depot formulations of antipsychotic drugs have been extensively studied. The clinical pharmacokinetics of the depot antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol decanoate, bromperidol decanoate, clopenthixol decanoate, flupenthixol decanoate, perphenazine onanthat, pipotiazine undecylenate, pipotiazine palmitate, fluspirilene, long-acting injectable risperidone, olanzapine pamoate, paliperidone palmitate, long-acting iloperidone, long-acting injectable aripiprazole) are reviewed. The proper study of these agents has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma. Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to injectable therapy are discussed. PMID- 23343449 TI - SERS-active silver colloids prepared by reduction of silver nitrate with short chain polyethylene glycol. AB - We report a fast, one-step, facile, and green preparation method that yields very stable and biocompatible silver colloids that are highly active as surface enhanced Raman spectroscopy (SERS) platforms that has a possible application in biomedicine. Reduction of silver nitrate has been carried out using polyethylene glycol (PEG) which acts as both reducing agent and stabilizer. It turned out that the -OH groups provided by the addition of NaOH represent a key element in the successful synthesis of PEG-coated silver nanoparticles (AgNPs). The as-obtained silver colloids have been characterized by UV-visible spectroscopy, transmission electron spectroscopy, and SERS using 532- and 633-nm laser lines on a dispersive Raman spectrometer. Several analytes as methylene blue, p-aminothiophenol, amoxicillin, and Cu(PAR)2 were used to prove SERS enhancement of the obtained silver colloid. It has been found that the PEGylated AgNPs provide SERS signals comparable to those achieved using classical hydroxylamine and citrate-reduced silver colloids, thus demonstrating the ability of this new method to prepare biocompatible silver colloids. PMID- 23343448 TI - HAART-associated dyslipidemia varies by biogeographical ancestry in the multicenter AIDS cohort study. AB - Highly active antiretroviral therapy (HAART) has been successful in delaying the progression to AIDS in HIV-1-infected individuals. Exposure to HAART can result in metabolic side effects, such as dyslipidemia, in a subset of recipients. Longitudinal data and frozen peripheral blood mononuclear cell pellets were obtained from 1,945 men enrolled in the Multicenter AIDS Cohort. Individuals were genotyped for ancestry informative markers (AIMs) and stratified by biogeographical ancestry (BGA). Then serum levels of total cholesterol (TCHOL), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TRIG) were examined controlling for a number of HIV and HAART-related covariates using multivariate mixed-effects linear regression. HIV-1 infection, in the absence of HAART, was associated with altered lipid levels for all phenotypes tested when compared to HIV-negative men. HIV-1 infected men receiving HAART also had significantly different lipid levels compared to HIV-negative men, except for LDL-C. There were statistically significant interactions between BGA and HIV/HAART status for all lipids tested. BGA remained significantly associated with lipid levels after controlling for other HIV and HAART-related covariates. There was low concordance between self reported race (SRR) and BGA in admixed populations. BGA performed better than SRR in our statistical models. Lipid profiles in untreated HIV-1-positive men and HIV 1-positive men receiving HAART differ from HIV-negative men and this effect varies by BGA. BGA performed better in our statistical analysis as a racial classifier but SRR remains a good clinical surrogate for BGA. PMID- 23343450 TI - Pilot programme of modular symptom-specific group cognitive behaviour therapy in a 'Real World' early intervention in psychosis service. AB - AIM: A modular symptom-specific (MSS) programme of early intervention group cognitive behaviour therapy for psychosis might confer additional therapeutic benefits and clinical and financial efficiency, but the approach is empirically untested. Therefore, we devised a novel MSS programme to test - in a culturally diverse 'Real World' early intervention service - its relevancy, feasibility, acceptability and safety. METHOD: The MSS programme comprised six different groups across 33 sessions: Psycho-Education (3), Mood-Management (5), Delusions (8), Auditory Hallucinations (8), Past Auditory Hallucinations (3) and Negative Symptoms (6). All patients were eligible for psycho-education, but other groups required a specific symptom. RESULTS: Patients (n = 166, 37% White) showed wide heterogeneity in the activity, type and number of symptoms, and group-relevant symptoms were common. Eighteen groups have run so far, each type of group at least once, 58/166 (35%) of patients attended across 281/412 (68%) group sessions, 46/58 (79%) of patients re-attended, and the 58 patients attended groups a mean of 4.8 times. Patients were significantly (P < 0.05) more likely to attend the programme if they had a schizophrenia diagnosis, a longer psychotic illness length or one active group-relevant (psychotic/mood) symptom. Diagnostically uncertain psychosis patients were almost significantly (P = 0.05) less likely to attend the programme. duration of untreated psychosis and ethnicity were unrelated to attendance/re-attendance. No group-related risk incidents occurred. CONCLUSION: A MSS programme approach is highly relevant to early intervention symptom heterogeneity and is feasible, culturally acceptable and safe; it also appears particularly efficient. Future research should now test its clinical efficacy. PMID- 23343452 TI - Susceptibility profile of clinical and environmental isolates of Cryptococcus neoformans and Cryptococcus gattii in Uberaba, Minas Gerais, Brazil. AB - Cryptococcus neoformans and C. gattii are the etiologic agents of cryptococcosis, a life-threatening disease in both immunocompromised and immunocompetent hosts. Antifungal resistance has been evaluated using different methods, breakpoints, and sizes of test populations and it is an emerging as a significant issue worldwide. A total of 176 (95 clinical and 81 environmental) C. neoformans and eight clinical C. gattii isolates were evaluated to determine the minimal inhibitory concentration (MIC) according to the Clinical and Laboratory Standards Institute method. A total of 10.5% of the C. neoformans clinical isolates were resistant to amphotericin B (AMB), and 6.2% of the environmental isolates were resistant to fluconazole (FLZ). Environmental and clinical isolates presented epidemiologic cut-off values (ECVs) of 64 and 16 to FLZ and 1 and 2 to AMB, respectively. All of the C. gattii isolates showed high susceptibility to most drugs evaluated. Clinical isolates had lower susceptibility than environmental isolates to AMB and itraconazole whereas environmental isolates had lower susceptibility than the clinical isolates to FLZ, voriconazole, and ketoconazole. However, no difference was found in the susceptibility of the two species. The MICs and ECVs to antifungals can help to select the best therapeutic option for tracking epidemiological resistance among clinical and environmental isolates of Cryptococcus spp. around the world. PMID- 23343451 TI - Plasma membrane events associated with the meiotic divisions in the amphibian oocyte: insights into the evolution of insulin transduction systems and cell signaling. AB - BACKGROUND: Insulin and its plasma membrane receptor constitute an ancient response system critical to cell growth and differentiation. Studies using intact Rana pipiens oocytes have shown that insulin can act at receptors on the oocyte surface to initiate resumption of the first meiotic division. We have reexamined the insulin-induced cascade of electrical and ion transport-related plasma membrane events using both oocytes and intact plasma membranes in order to characterize the insulin receptor-steroid response system associated with the meiotic divisions. RESULTS: [(125)I]Insulin binding (K(d) = 54 +/- 6 nM) at the oocyte plasma membrane activates membrane serine protease(s), followed by the loss of low affinity ouabain binding sites, with a concomitant 3-4 fold increase in high affinity ouabain binding sites. The changes in protease activity and ouabain binding are associated with increased Na(+)/Ca2(+) exchange, increased endocytosis, decreased Na(+) conductance resulting in membrane hyperpolarization, increased 2-deoxy-D-glucose uptake and a sustained elevation of intracellular pH (pHi). Hyperpolarization is largely due to Na(+)-channel inactivation and is the main driving force for glucose uptake by the oocyte via Na(+)/glucose cotransport. The Na(+) sym- and antiporter systems are driven by the Na(+) free energy gradient generated by Na(+)/K(+)-ATPase. Shifts in alpha and/or beta Na(+) pump subunits to caveolar (lipid raft) membrane regions may activate Na/K-ATPase and contribute to the Na(+) free energy gradient and the increase in both Na(+)/glucose co-transport and pHi. CONCLUSIONS: Under physiological conditions, resumption of meiosis results from the concerted action of insulin and progesterone at the cell membrane. Insulin inactivates Na(+) channels and mobilizes fully functional Na(+)-pumps, generating a Na(+) free energy gradient which serves as the energy source for several membrane anti- and symporter systems. PMID- 23343453 TI - Clozapine and visuospatial processing in treatment-resistant schizophrenia. AB - INTRODUCTION: Clozapine, the most widely used option in treatment-resistant schizophrenia, has been shown to be superior to other antipsychotic medications in improving cognitive function in patients. However, the results have not been consistent and the mechanisms underlying this effect have not been elucidated. Thus, the purpose of the present study was to evaluate verbal and nonverbal cognition (using visuospatial processing tests) in patients treated with clozapine (initially treatment resistant) and those treated with other second generation antipsychotics, relative healthy control subjects. Furthermore, we examined neural correlates of visuospatial processing in the three groups. METHODS: Twenty schizophrenia patients treated with clozapine (TR-C group), 23 patients stabilised with atypical antipsychotics other than clozapine (NTR group), and 21 healthy control participants completed a battery of verbal and visuospatial cognitive tests. In addition, participants underwent functional magnetic resonance imaging (fMRI) while performing one of the visuospatial tests (the mental rotation task). The fMRI data were analysed separately in each group using Statistical Parametric Mapping software (SPM5). RESULTS: Overall, schizophrenia patients exhibited deficit on verbal and nonverbal processing relative to the healthy controls, but we observed some interesting differences between the two groups of patients. Specifically, the NTR group performed better than the TR-C group on the Block Design and the Raven's Progressive Matrices. With respect to brain function during mental rotation, the NTR group showed significant activations in regions of the temporal and occipital cortex, whereas the TR-C patients did not. The relative deactivations associated with the task were also more robust in NTR compared to the other group of patients, despite a similar performance. CONCLUSION: Present results suggest better visuospatial processing in the NTR relative to the TR-C group. This difference could be attributed to the treatment resistance itself or a lack of beneficial effect of clozapine relative to other atypical antipsychotics in ameliorating nonverbal abilities. Future studies of the relationship between clozapine and cognition, as well as between treatment resistance and cognition, are warranted. PMID- 23343454 TI - Aluminum in erythropoietin formulations: lyophilized versus liquid forms. AB - BACKGROUND: Erythropoietin (EPO) formulations may comprise aluminum (Al) as a contaminant. Due to the toxicity of Al in chronic kidney disease patients, possible sources of Al were investigated. Since EPO formulations are stored in container-closure systems made of glass and rubber, and both contain Al, formulation ingredients may enable its leaching into the solution during shelf life. METHODS: Individual solutions of formulation ingredients were stored in new glass vials and in contact with the rubber stopper and kept at 4 +/- 2 degrees C. For 12 months, aliquots of each solution were collected for analysis. Fifteen commercial samples of EPO were analyzed for their Al content. Aluminum was determined by atomic absorption spectrometry. RESULTS: Glass and rubber are sources of Al for EPO formulations. Storage assay showed that citrate and phosphate (used as buffers) extracted high amounts of Al from the container/closure parts. The most important difference, however, was found when comparing liquid and lyophilized samples. While in liquid forms the Al level reached 943 MUg/L, in lyophilized forms the level did not exceed 20 MUg/L. The container system was also confirmed as a source of Al in reconstituted lyophilized samples. Al in reconstituted samples stored in their own vials increased 19-fold in 12 months. Lyophilized powders stored for 2 years in glass vials contained less Al than in 1 month after dissolution. CONCLUSION: The difference in the Al measured in liquid forms of EPO and in lyophilized powders suggests that the latter would be the best pharmaceutical form for CKD patients. PMID- 23343455 TI - Raman and ROA spectra of (-)- and (+)-2-Br-hexahelicene: experimental and DFT studies of a pi-conjugated chiral system. AB - The Raman optical activity (ROA) spectra of both enantiomers of 2-Br-hexahelicene in chloroform solution have been measured in the range 1700-300 cm(-1). Density functional theory (DFT) calculations accurately reproduce the observed features. The most intense ROA features are also the most intense Raman features, in the region 1350-1400 cm(-1), and correspond to the so-called D-modes, which play a major role in coronene and other PAHs (polycyclic aromatic hydrocarbons). Together with a detailed analysis of the normal mode structure, the polarizability tensors for the intense Raman features are investigated and related to the principal characteristics of helicene systems, namely, chirality and pi-conjugation. Through electron-phonon coupling analysis, we propose a mechanism that justifies the intense ROA signals. PMID- 23343456 TI - Biomarkers of oxidative damage are elevated among individuals with high cardiovascular risk: refining subject selection strategies for antioxidant trials. AB - The purpose of this study was to evaluate the use of Framingham risk scores (FRRs) to identify high-risk individuals with biochemical evidence of increased oxidative damage, who may benefit from antioxidant therapies. A bimodal change in plasma F2-isoprostane levels was observed with cardiovascular risk categories, while plasma neuroprostanes, 7alpha-hydroxycholesterol, and serum gamma glutamyltransferase levels were higher among individuals at high risk of cardiovascular events (Framingham score, > 36). Total plasma hydroxyeicosatetraenoic acid products (HETEs) and serum high-sensitivity CRP (hsCRP) levels were consistently higher across Framingham risk categories. Multivariable analysis identified plasma 7alpha-hydroxycholesterol (odds ratio (OR), 1.06; 95% confidence interval (CI), 1.03-1.10) and gamma glutamyltransferase (OR, 1.02; 95% CI, 1.01-1.03) as significant predictors of high cardiovascular risk (Framingham score, > 36), accounting for approximately 21% of its variation. Cardiovascular risk scores are useful to identify individuals with high burden of oxidative damage who may benefit from antioxidant therapy. PMID- 23343457 TI - Self-organized cooperative swimming at low Reynolds numbers. AB - Investigations of swimming at low Reynolds numbers (Re < 10(-4)) so far have focused on individual or collectively moving autonomous microswimmers consisting of a single active building unit. Here we show that linear propulsion can also be reproducibly generated in a self-assembled dynamic complex formed from a granular, HCl-releasing particle settled on a charged quartz wall and a swarm of micrometer-sized negatively charged colloids. In isolation, none of the constituents shows motion beyond diffusion. When brought together, they self assemble into a complex capable of directed swimming. It is stabilized by toroidal solvent flow centered about the granular particle. Propulsion is then launched by an asymmetric distribution of the colloids. Motion is self stabilizing and continues for up to 25 min with velocities of 1-3 MUm/s. Although the details of the mechanisms involved pose a formidable experimental and theoretical challenge, our observations offer a conceptually new, well reproduced, versatile approach to swimming and transport at low Reynolds numbers. PMID- 23343458 TI - Oxidative addition versus substitution reactions of group 14 dialkylamino metalylenes with pentafluoropyridine. AB - Dialkylamino compounds of group 14 elements (Si, Ge, Sn) in the +2 oxidation state supported by benzamidinate ligands were synthesized and treated with pentafluoropyridine. Two different modes of reactivity were observed, depending on the metal atom and the basicity of the substituent at the metal. Pentafluoropyridine undergoes oxidative addition reaction at the Si(II) and Ge(II) atoms whereas at the Sn(II) atom substitution of the NMe(2) group by the para fluorine of pentafluoropyridine occurs. The C-F bond activation by the lone pair of germanium is the first report of this kind. The Sn(II) fluoride obtained has an elongated Sn-F bond length and can be used as a good fluorinating agent. The compounds were characterized by multinuclear NMR spectroscopy, mass spectrometry, elemental analysis, and X-ray structural analysis. Single crystal X ray structural analysis of the tin fluoride shows an asymmetric dimer with weak [Formula: see text] interactions. PMID- 23343459 TI - Comparison of RIFLE with and without urine output criteria for acute kidney injury in critically ill patients: a task still not concluded! PMID- 23343460 TI - Lung injury-dependent oxidative status and chymotrypsin-like activity of skeletal muscles in hamsters with experimental emphysema. AB - BACKGROUND: Peripheral skeletal muscle is altered in patients suffering from emphysema and chronic obstructive pulmonary disease (COPD). Oxidative stress have been demonstrated to participate on skeletal muscle loss of several states, including disuse atrophy, mechanical ventilation, and chronic diseases. No evidences have demonstrated the occurance in a severity manner. METHODS: We evaluated body weight, muscle loss, oxidative stress, and chymotrypsin-like proteolytic activity in the gastrocnemius muscle of emphysemic hamsters. The experimental animals had 2 different severities of lung damage from experimental emphysema induced by 20 mg/mL (E20) and 40 mg/mL (E40) papain. RESULTS: The severity of emphysema increased significantly in E20 (60.52 +/- 2.8, p < 0.05) and E40 (52.27 +/- 4.7; crossed the alveolar intercepts) groups. As compared to the control group, there was a reduction on body (171.6 +/- 15.9 g) and muscle weight (251.87 +/- 24.87 mg) in the E20 group (157.5 +/- 10.3 mg and 230.12 +/- 23.52 mg, for body and muscle weight, respectively), which was accentuated in the E40 group (137.4 +/- 7.2 g and 197.87 +/- 10.49 mg, for body and muscle weight, respectively). Additionally, the thiobarbituric acid reactive substances (TBARS), tert-butyl hydroperoxide-initiated chemiluminescence (CL), carbonylated proteins, and chymotrypsin-like proteolytic activity were elevated in the E40 group as compared to the E20 group (p < 0.05 for all comparisons). The severity of emphysema significantly correlated with the progressive increase in CL (r = 0.95), TBARS (r = -0.98), carbonyl proteins (r = -0.99), and chymotrypsin-like proteolytic activity (r = -0.90). Furthermore, augmentation of proteolytic activity correlated significantly with CL (r = 0.97), TBARS (r = 0.96), and carbonyl proteins (r = 0.91). CONCLUSIONS: Taken together, the results of the present study suggest that muscle atrophy observed in this model of emphysema is mediated by increased muscle chymotrypsin-like activity, with possible involvement of oxidative stress in a severity-dependent manner. PMID- 23343461 TI - Refined magic-angle coil spinning resonator for nanoliter NMR spectroscopy: enhanced spectral resolution. AB - The magic-angle coil spinning (MACS) resonator allows a simple approach for nanoliter nuclear magnetic resonance (NMR) detections with enhanced sensitivity and high-resolution under sample magic-angle spinning (MAS). Currently, the spectral resolution acquired with MACS is not efficient for detailed characterization of semisolids like biopsies, where subhertz resolution is necessary. Here, we describe the two sources of line broadening from MACS, sample temperature gradient and anisotropic magnetic susceptibility, and present a refined high-resolution magic-angle coil spinning (HR-MACS) resonator that improves the spectral resolution. We demonstrate with the high quality HR-MACS NMR spectra of micronematodes and tissue biopsy, and illustrate its potential for NMR-based metabolomics of nanoliter tissue samples. PMID- 23343463 TI - Rapid and stereoselective synthesis of spirocyclic ethers via the intramolecular Piancatelli rearrangement. AB - The first example of a Piancatelli rearrangement of alcohols is demonstrated utilizing dysprosium(III) triflate as a catalyst to access oxaspirocycles in a highly diastereoselective manner. The cascade reaction constructs the spirocyclic ether ring system and the tertiary stereocenter in a single operation and is experimentally easy to perform. PMID- 23343464 TI - CO self-promoting oxidation on nanosized gold clusters: triangular Au3 active site and CO induced O-O scission. AB - We have systematically studied the CO oxidation on various nanosized gold clusters with sizes ranging from 0.3 to 0.8 nm on the basis of density functional theory (DFT) calculations. A hitherto unreported trimolecular Langmuir Hinshelwood (LH) mechanism is proposed, which offers new insights into the fundamental mechanism for CO oxidation on nanosized gold clusters. Specifically, we find that the coadsorbed CO molecule at a unique triangular Au(3) active site can act as a promoter for the scission of an O-O bond, leading to the spontaneous formation (due to extremely low energy barrier) of two CO(2) molecules as product. The key step to the O-O bond scission in the OCOO* intermediate is significantly accelerated due to the electrophilic attack of the coadsorbed neighboring CO molecule on the triangular Au(3) site. This new mechanism is called CO self-promoting oxidation, which can be visualized in real time from the trajectory of a Born-Oppenheimer molecular dynamics (BOMD) simulation. We also find that such CO self-promoting oxidation is quite universal, as long as the triangular Au(3) reaction site is available. This is demonstrated in two prototype metal oxide supported gold nanostructure systems: namely, Au(n)/MgO and bilayer-Au/TiO(2). The coadsorbed CO can not only serve as a promoter for its own oxidation but also promote other oxidation reactions such as styrene oxidation through expediting O-O scission on gold nanostructures. PMID- 23343462 TI - The origins of health and disease: the influence of maternal diseases and lifestyle during gestation. AB - According to the Barker hypothesis, the period of pregnancy and the intrauterine environment are crucial to the tendency to develop diseases like hypertension, diabetes, coronary heart disease, metabolic disorders, pulmonary, renal and mental illnesses. The external environment affects the development of a particular phenotype suitable for an environment with characteristics that closely resemble intrauterine conditions. If the extra-uterine environment differs greatly from the intra-uterine one, the fetus is more prone to develop disease. Subsequent studies have shown that maternal diseases like depression and anxiety, epilepsy, asthma, anemia and metabolic disorders, like diabetes, are able to determine alterations in growth and fetal development. Similarly, the maternal lifestyle, particularly diet, exercise and smoking during pregnancy, have an important role in determining the risk to develop diseases that manifest themselves both during childhood and particularly in adulthood. Finally, there are abundant potential sources of pollutants, both indoor and outdoor, in the environment in which the child lives, which can contribute to an increased probability to the development of several diseases and that in some cases could be easily avoided. PMID- 23343465 TI - Assessment of the 9p21.3 locus in severity of coronary artery disease in the presence and absence of type 2 diabetes. AB - BACKGROUND: The 9p21.3 locus is strongly associated with the risk of coronary artery disease (CAD) and with type 2 diabetes (T2D). We investigated the association of 9p21.3 variants with severity of CAD (defined by the number of vessel diseased [VD]) in the presence and absence of T2D. METHODS: We tested 11 9p21.3-variants for association in a white Italian study (N = 2,908), and carried out replication in 2 independent white populations, a German study (N = 2,028) and a Canadian Study (N=950). SNP association and permutation analyses were conducted. RESULTS: We identified two 9p21.3-variants, rs4977574 (P < 4*10(-4)) and rs2383207 (P < 1.5*10(-3)) that were associated with severity of CAD in subjects without T2D. Association of rs4977574 with severity of CAD was confirmed in the Canadian Study. Results from subgroup analysis among patients with T2D showed an interaction between rs10738610 and T2D with P = 4.82*10(-2). Further investigation showed that rs10738610 (P < 1.99*10(-2)) was found to be significantly associated with severity of CAD in subjects with T2D. CONCLUSIONS: The 9p21.3 locus is significantly associated with severity of CAD. The number of associations of 9p21.3 variants with severity of CAD is variable to the presence and absence of T2D. In a CAD-susceptible region of 115 kb, there is only one variant associated with the severity of coronary vessel disease in the presence of type 2 diabetes. PMID- 23343466 TI - Impact of glove occlusion on cumulative skin irritation with or without hand cleanser-comparison in an experimental repeated irritation model. AB - BACKGROUND: Irritant contact dermatitis remains a substantial problem in the food processing industries. Irritants that are weak by themselves, such as glove occlusion and mild detergents, could interact to produce contact dermatitis. OBJECTIVES: To model the irritant action of an antibacterial hand cleanser and glove occlusion, with sodium lauryl sulfate (SLS) as a positive control. The effects of a pre-exposure cream and a post-exposure cream were also investigated. METHODS: A modified repeated short-time occlusive irritation test with 20 healthy volunteers, and application of irritants over 4 days, with pre-exposure and post exposure creams and overnight glove occlusion, was performed. The changes in transepidermal water loss (TEWL) served as a measure of the irritant damage to the epidermal barrier. RESULTS: The antibacterial cleanser and the glove occlusion separately induced only minor increases in TEWL. When combined, the two showed a tandem effect, as the TEWL increase was significantly higher, and was similar to that seen with the positive control, SLS. The pre-exposure and post exposure creams alone significantly mitigated the cumulative irritation, and this effect was strongest when the two creams were combined. CONCLUSIONS: Irritant contact dermatitis may develop through the tandem effects of long-term glove occlusion and the accumulation of barrier damage from hand washing, even when mild hand cleansers are employed. PMID- 23343467 TI - Subtyping first-episode non-affective psychosis using four early-course features: potentially useful prognostic information at initial presentation. AB - AIM: Heterogeneity of symptoms, course and outcomes in primary psychotic disorders complicates prognosis, treatment and diverse aspects of research. This study aimed to identify interpretable subtypes of first-episode non-affective psychosis based on four early-course features (premorbid academic functioning, premorbid social functioning, duration of the prodrome and age at onset of psychosis). METHODS: Data from 200 well-characterized patients hospitalized in public-sector inpatient units for first-episode non-affective psychosis were used in latent profile analyses. Derived subtypes were then compared along a number of clinical dimensions using analyses of variance. RESULTS: Using four early-course features, three classes were derived. A good premorbid/short prodrome subtype was characterized by a lower severity of positive symptoms, better social/occupational/global functioning, and a shorter duration of untreated psychosis; a poor premorbid/early onset subtype demonstrated greater negative and preoccupation symptoms, as well as greater psychosocial problems; and a long prodrome/late onset subtype was characterized by greater dysphoric symptoms. CONCLUSIONS: Findings indicate a need for further research with first-episode samples on the utility of subtyping based on early-course (premorbid, prodromal and onset-related) characteristics. Such efforts could enhance the parsing of heterogeneity, thereby advancing clinical practice and research. PMID- 23343468 TI - Copper(I)-alpha-synuclein interaction: structural description of two independent and competing metal binding sites. AB - The aggregation of alpha-synuclein (alphaS) is a critical step in the etiology of Parkinson's disease. Metal ions such as copper and iron have been shown to bind alphaS, enhancing its fibrillation rate in vitro. alphaS is also susceptible to copper-catalyzed oxidation that involves the reduction of Cu(II) to Cu(I) and the conversion of O(2) into reactive oxygen species. The mechanism of the reaction is highly selective and site-specific and involves interactions of the protein with both oxidation states of the copper ion. The reaction can induce oxidative modification of the protein, which generally leads to extensive protein oligomerization and precipitation. Cu(II) binding to alphaS has been extensively characterized, indicating the N terminus and His-50 as binding donor residues. In this study, we have investigated alphaS-Cu(I) interaction by means of NMR and circular dichroism analysis on the full-length protein (alphaS(1-140)) and on two, designed ad hoc, model peptides: alphaS(1-15) and alphaS(113-130). In order to identify and characterize the metal binding environment in full-length alphaS, in addition to Cu(I), we have also used Ag(I) as a probe for Cu(I) binding. Two distinct Cu(I)/Ag(I) binding domains with comparable affinities have been identified. The structural rearrangements induced by the metal ions and the metal coordination spheres of both sites have been extensively characterized. PMID- 23343469 TI - Decreased semaphorin3A expression correlates with disease activity and histological features of rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease of which the pathogenetic mechanisms are not fully understood. Semaphorin3A (Sema3A) has an immune regulatory role. Neuropilin1 (NRP1), the primary receptor for Sema3A, is also a receptor for vascular endothelial growth factor 165 (VEGF 165). It has been shown that Sema3A competitively antagonizes VEGF 165 signaling. This study investigated whether Sema3A is expressed in synovial tissues, and is associated with disease activity and the histological features of synovial tissues from RA patients. METHODS: Human synovial tissues samples were obtained from RA and osteoarthritis (OA) patients. Disease activity of RA patients was calculated using the 28-joint Disease Activity Score based on C-reactive protein (DAS28 CRP). The histological features of RA synovial tissues were evaluated using Rooney's inflammation scoring system. The localization of Sema3A, VEGF 165 and NRP1 positive cells was immunohistochemically determined in synovial tissues. Expression levels of Sema3A, VEGF-A and NRP1 mRNA were determined using quantitative real-time polymerase chain reaction (qPCR). RESULTS: In OA specimens, Sema3A, VEGF 165 and NRP1 proteins were expressed in the synovial lining and inflammatory cells beneath the lining. Immunohistochemistry revealed the protein expression of Sema3A in synovial lining cells was decreased in RA tissues compared with OA samples. qPCR analysis demonstrated a significant reduction of Sema3A mRNA levels in RA synovial tissue samples than in OA and a significant correlation of the ratio of Sema3A/VEGF-A mRNA expression levels with DAS28-CRP (R = -0.449, p = 0.013). Sema3A mRNA levels also correlated with Rooney's inflammation score, especially in perivascular infiltrates of lymphocytes (R = -0.506, p = 0.004), focal aggregates of lymphocytes (R = -0.501, p = 0.005) and diffuse infiltrates of lymphocytes (R = -0.536, p = 0.002). CONCLUSIONS: Reduction of Sema3A expression in RA synovial tissues may contribute to pathogenesis of RA. PMID- 23343470 TI - Potential contribution of SIM2 and ETS2 functional polymorphisms in Down syndrome associated malignancies. AB - BACKGROUND: Proper expression and functioning of transcription factors (TFs) are essential for regulation of different traits and thus could be crucial for the development of complex diseases. Subjects with Down syndrome (DS) have a higher incidence of acute lymphoblastic leukemia (ALL) while solid tumors, like breast cancer (BC) and oral cancer (OC), show rare incidences. Triplication of the human chromosome 21 in DS is associated with altered genetic dosage of different TFs. V ets erythroblastosis virus E26 oncogene homolog 2 (ETS2) and Single Minded 2 (SIM2) are two such TFs that regulate several downstream genes involved in developmental and neurological pathways. Here we studied functional genetic polymorphisms (fSNP) in ETS2 and SIM2 encoding genes in a group of patients and control subjects to better understand association of these variants with DS phenotypes. METHODS: We employed an in silico approach to identify potential target pathways of ETS2 and SIM2. fSNPs in genes encoding for these two TFs were identified using available databases. Selected sites were genotyped in individuals with DS, their parents, ALL, BC, OC as well as ethnically matched control individuals. We further analyzed these data by population-based statistical methods. RESULTS: Allelic/genotypic association analysis showed significant (P < 0.03) differences of rs2070530, rs1051476, rs11254, rs711 for DS subjects compared to control. rs711 also exhibited significantly different genotypic distribution pattern in parents of DS probands (P < 0.02) and BC patients (P < 0.02). Interaction analysis revealed independent main effect of rs711 in all the groups, while rs11254 exhibited independent main effect in DS subjects only. High entropy values were noticed for rs461155 in the solid tumor groups. Significant interactive effects of rs2070531 with rs1051475, rs1051476, rs11254 were observed in all the groups except DS. CONCLUSIONS: We infer from the present investigation that the difference in frequencies of fSNPs and their independent as well as interactive effects may be the cause for altered expression of SIM2 and ETS2 in DS and malignant groups, which affects different downstream biological pathways. Thus, altered expression of SIM2 and ETS2 could be one of the reasons for variable occurrence of different malignant conditions in DS. PMID- 23343471 TI - Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of alpha-/gamma-tocotrienols and gamma-tocopherol. AB - BACKGROUND: The aim of this study was to evaluate the accuracy of combined structural magnetic resonance imaging (MRI) measures and plasma levels of vitamin E forms, including all eight natural vitamin E congeners (four tocopherols and four tocotrienols) and markers of vitamin E oxidative/nitrosative damage, in differentiating individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects. METHODS: Overall, 81 patients with AD, 86 with MCI and 86 CTL individuals were enrolled from the longitudinal multicentre AddNeuroMed study. MRI and plasma vitamin E data were acquired at baseline. MRI scans were analysed using Freesurfer, an automated segmentation scheme which generates regional volume and cortical thickness measures. Orthogonal partial least squares to latent structures (OPLS), a multivariate data analysis technique, was used to analyse MRI and vitamin E measures in relation to AD and MCI diagnosis. RESULTS: The joint evaluation of MRI and plasma vitamin E measures enhanced the accuracy of differentiating individuals with AD and MCI from CTL subjects: 98.2% (sensitivity 98.8%, specificity 97.7%) for AD versus CTL, and 90.7% (sensitivity 91.8%, specificity 89.5%) for MCI versus CTL. This combination of measures also identified 85% of individuals with MCI who converted to clinical AD at follow-up after 1 year. CONCLUSIONS: Plasma levels of tocopherols and tocotrienols together with automated MRI measures can help to differentiate AD and MCI patients from CTL subjects, and to prospectively predict MCI conversion into AD. Our results suggest the potential role of nutritional biomarkers detected in plasma tocopherols and tocotrienols-as indirect indicators of AD pathology, and the utility of a multimodality approach. PMID- 23343472 TI - Highly enantioselective three-component direct Mannich reactions of unfunctionalized ketones catalyzed by bifunctional organocatalysts. AB - A highly stereoselective three-component direct Mannich reaction between aromatic aldehydes, p-toluenesulfonamide, and unfunctionalized ketones was achieved through an enolate mechanism for the first time with a bifunctional quinidine thiourea catalyst. The corresponding N-tosylated beta-aminoketones were obtained in high yields and excellent diastereo- and enantioselectivities (up to >99:1 dr and >99% ee). PMID- 23343474 TI - Chemisorbed monolayers of corannulene penta-thioethers on gold. AB - Penta(tert-butylthio)corannulene and penta(4-dimethylaminophenylthio)corannulene form highly stable monolayers on gold surfaces, as indicated by X-ray photoelectron spectroscopy (XPS). Formation of these homogeneous monolayers involves multivalent coordination of the five sulfur atoms to gold with the peripheral alkyl or aryl substituents pointing away from the surface. No dissociation of C-S bonds upon binding could be observed at room temperature. Yet, the XPS experiments reveal strong chemical bonding between the thioether groups and gold. Temperature-dependent XPS study shows that the thermal stability of the monolayers is higher than the typical stability of self-assembled monolayers (SAMs) of thiolates on gold. PMID- 23343473 TI - Evolution of microgastropods (Ellobioidea, Carychiidae): integrating taxonomic, phylogenetic and evolutionary hypotheses. AB - BACKGROUND: Current biodiversity patterns are considered largely the result of past climatic and tectonic changes. In an integrative approach, we combine taxonomic and phylogenetic hypotheses to analyze temporal and geographic diversification of epigean (Carychium) and subterranean (Zospeum) evolutionary lineages in Carychiidae (Eupulmonata, Ellobioidea). We explicitly test three hypotheses: 1) morphospecies encompass unrecognized evolutionary lineages, 2) limited dispersal results in a close genetic relationship of geographical proximally distributed taxa and 3) major climatic and tectonic events had an impact on lineage diversification within Carychiidae. RESULTS: Initial morphospecies assignments were investigated by different molecular delimitation approaches (threshold, ABGD, GMYC and SP). Despite a conservative delimitation strategy, carychiid morphospecies comprise a great number of unrecognized evolutionary lineages. We attribute this phenomenon to historic underestimation of morphological stasis and phenotypic variability amongst lineages. The first molecular phylogenetic hypothesis for the Carychiidae (based on COI, 16S and H3) reveals Carychium and Zospeum to be reciprocally monophyletic. Geographical proximally distributed lineages are often closely related. The temporal diversification of Carychiidae is best described by a constant rate model of diversification. The evolution of Carychiidae is characterized by relatively few (long distance) colonization events. We find support for an Asian origin of Carychium. Zospeum may have arrived in Europe before extant members of Carychium. Distantly related Carychium clades inhabit a wide spectrum of the available bioclimatic niche and demonstrate considerable niche overlap. CONCLUSIONS: Carychiid taxonomy is in dire need of revision. An inferred wide distribution and variable phenotype suggest underestimated diversity in Zospeum. Several Carychium morphospecies are results of past taxonomic lumping. By collecting populations at their type locality, molecular investigations are able to link historic morphospecies assignments to their respective evolutionary lineage. We propose that rare founder populations initially colonized a continent or cave system. Subsequent passive dispersal into adjacent areas led to in situ pan-continental or mountain range diversifications. Major environmental changes did not influence carychiid diversification. However, certain molecular delimitation methods indicated a recent decrease in diversification rate. We attribute this decrease to protracted speciation. PMID- 23343476 TI - Preoperative pain treatment in acute abdomen in Osogbo, Nigeria: a randomized double-blind placebo-controlled study. AB - BACKGROUND: Withholding analgesics in acute abdomen for fear of masking clinical features and impairing diagnosis and decision-making is still being practiced despite recent evidence to the contrary. This study assesses the effect of preoperative analgesia on clinical findings, clinical diagnosis, and decision making in patients with non-trauma acute abdomen. METHOD: This is a randomized, double-blind, placebo-controlled study using Tramal, a brand of tramadol, at the ED of LAUTECH Teaching Hospital Osogbo, Nigeria. Ninety-five patients between 18 60 years received Tramal (n = 46) or placebo (n = 49). The pain score, clinical findings, provisional diagnosis, and treatment plan were noted before and 15-20 min after administration of the analgesic or placebo. The final diagnosis arrived at after adequate investigation or operation was considered the gold standard. The pain scores, diagnosis, treatment plan, and decision between the two groups were compared. Statistical analysis was by SPSS 16. Results were considered statistically significant at p < 0.05. RESULTS: Demography and case distribution were similar in both groups. The improvement in pain was greater in the Tramal group (p = 0.001). The abdominal palpation findings were also better in the Tramal group (p = 0.02). There were more changes in the diagnosis after use of Tramal (p = 0.01). There were more changes in the decision in the Tramal group (p = 0.03). Most of the changes in diagnosis and decision in the Tramal group were for the better. CONCLUSION: The preoperative use of Tramal in acute abdomen improved the experience of pain and did not adversely affect the accuracy of the diagnosis or decision-making. PMID- 23343477 TI - Five discrete multinuclear metal-organic assemblies from one ligand: deciphering the effects of different templates. AB - A rigid organic ligand, formed through the subcomponent self-assembly of p toluidine and 6,6'-diformyl-3,3'-bipyridine, was employed in a systematic investigation into the synergistic and competing effects of metal and anion templation. A range of discrete and polymeric metal-organic complexes were formed, many of which represent structure types that have not previously been observed and whose formation would not be predicted on taking into account solely geometric considerations. These complex structures, capable of binding multiple guests within individual binding pockets, were characterized by NMR, ESI-MS, and single-crystal X-ray diffraction. The factors that stabilize individual complexes and lead to the formation of one over another are discussed. PMID- 23343475 TI - High percentage of recent HIV infection among HIV-positive individuals newly diagnosed at voluntary counseling and testing sites in Poland. AB - To gain insight into HIV transmission we estimated the proportion of those recently infected. We examined data from HIV-positive patients and a random 10% sample of HIV-negative patients tested at Voluntary Counseling and Testing sites in Poland in 2006. Archived samples from positive patients were tested by three assays to differentiate recent from long-standing infection. Using logistic regression, we examined the association of recent infection (at least one assay) with age, sex, HIV exposure category, and the interval between self-reported HIV exposure and previous HIV test. Of 13,511 tests, 154 (1.1%) were HIV positive, representing 19.7% (n=783) of new diagnoses in Poland in 2006. Demographic and behavioral data were linked for 95, of whom 45 (47%) were recently infected and 1,001 were HIV negative. New diagnoses were more likely to be injectors (17% vs. 2%), men who have sex with men (MSM) (37% vs. 12%), and less frequent condom users (7.8% vs. 14% always) compared to HIV negatives. The median number of partners during the past 12 months was one and two among positives and negatives, but was higher among MSM-four and three, respectively. Ever injectors were less likely to be recently infected (adjusted OR=0.15, 95%CI=0.03-0.73). Having two or more sexual partners in the past 12 months was an independent predictor of recent infection (4.01, 1.4-11.49). We found no evidence that age or sex predicted recent infection. These data reinforce health education campaigns for safe sex messages, especially among MSM. They also suggest, albeit based on a subset of new diagnoses, that interventions should not be limited to selected age/sex groups. PMID- 23343478 TI - Neutral carotenoid radicals in photoprotection of wild-type Arabidopsis thaliana. AB - The deprotonation of naturally occurring zeaxanthin (Zea) radical cations (Zea(*+)) to form neutral radicals (#Zea(*)) and their involvement in the qE portion of nonphotochemical quenching (NPQ) was examined. The radical cations are weak acids, and readily deprotonate to a long-lived neutral radical (#Zea(*)) that could serve as long-lived quenching sites. When #Zea(*) is eventually neutralized and Zea is reformed in the presence of D2O, the Zea has an opportunity to undergo H/D exchange. This paper examines evidence for H/D exchange specific to qE activity in Arabidopsis thaliana . We demonstrate that Zea(*+) formed chemically via oxidation of Zea by Fe(III) in the presence of D2O undergoes H/D exchange with a significant intensity increase of the M+1 (d1Zea) and M+2 (d2Zea) mass peaks in the mass spectrum. Then leaves from wild-type A. thaliana were infiltrated with either D2O or H2O and exposed to light. The carotenoids were extracted and analyzed via electrospray ionization liquid chromatography/mass spectrometry (LC/MS) to examine the mass peak distribution of Zea. Only leaves exposed to light intensity that triggers qE in A. thaliana (>300 MUE m(-2)s(-1)) showed H/D exchange. This result suggests that #Zea(*) can form by the deprotonation of the weak acid Zea(*+) during qE, and its possible impact on qE must be considered. PMID- 23343479 TI - Maternal filarial infection: association of anti-sheath antibody responses with plasma levels of IFN-gamma and IL-10. AB - Maternal filarial infection influences the risk of acquiring infection and development of immunity in children. Here we have analysed the blood samples of 60 mothers (24 infected and 36 uninfected) and their corresponding cord bloods to assess the impact of maternal infection on the anti-sheath antibodies and cytokine production in neonates born from them. About 69.4% of non-infected mothers and their cord bloods showed the presence of anti-sheath antibodies, while only 16.6% of the cord bloods from infected mothers were positive for it. The IL-10 level was significantly high in cord bloods of infected mothers compared with non-infected mothers. At the same time the IL-10 level was also observed to be remarkably high in cord bloods of both infected and non-infected mothers negative for anti-sheath antibody. In contrast, IFN-gamma levels were significantly high in cord bloods of non-infected mothers compared with infected mothers and the increment was prominent in cord bloods of both infected and non infected mothers positive for anti-sheath antibody. The study reveals that the presence or absence of anti-sheath antibodies in association with cytokines skews the filarial specific immunity to either Th1 or Th2 responses in neonates. This may affect the natural history of filarial infection in early childhood. PMID- 23343480 TI - Eastern equine encephalitis in children, Massachusetts and New Hampshire,USA, 1970-2010. AB - We describe the clinical, laboratory, and radiographic characteristics of 15 cases of eastern equine encephalitis in children during 1970-2010. The most common clinical and laboratory features were fever, headache, seizures, peripheral leukocytosis, and cerebrospinal fluid neutrophilic pleocytosis. Radiographic lesions were found in the basal ganglia, thalami, and cerebral cortex. Clinical outcomes included severe neurologic deficits in 5 (33%) patients, death of 4 (27%), full recovery of 4 (27%), and mild neurologic deficits in 2 (13%). We identify an association between a short prodrome and an increased risk for death or for severe disease. PMID- 23343482 TI - New perspectives on late-life psychosis. PMID- 23343481 TI - Evaluating the translation process of an Internet-based self-help intervention for prevention of depression: a cost-effectiveness analysis. AB - BACKGROUND: Depression is common and treatable with cognitive behavior therapy (CBT), for example. However, access to this therapy is limited. Internet-based interventions have been found to be effective in reducing symptoms of depression. The International Society for Research on Internet Interventions has highlighted the importance of translating effective Internet programs into multiple languages to enable worldwide dissemination. OBJECTIVE: The aim of the current study was to determine if it would be cost effective to translate an existing English-language Internet-based intervention for use in a non-English-speaking country. METHODS: This paper reports an evaluation of a trial in which a research group in Norway translated two English-language Internet-based interventions into Norwegian (MoodGYM and BluePages) that had previously been shown to reduce symptoms of depression. The translation process and estimates of the cost-effectiveness of such a translation process is described. Estimated health effect was found by using quality-adjusted life years (QALY). RESULTS: Conservative estimates indicate that for every 1000 persons treated, 16 QALYs are gained. The investment is returned 9 times and the cost-effectiveness ratio (CER) is 3432. The costs of the translation project totaled to approximately 27% of the estimated original English-language version development costs. CONCLUSIONS: The economic analysis shows that the cost-effectiveness of the translation project was substantial. Hopefully, these results will encourage others to do similar analyses and report cost-effectiveness data in their research reports. PMID- 23343483 TI - Prevalence of negative symptoms and associated factors in older adults with schizophrenia spectrum disorder. AB - OBJECTIVE: To examine the prevalence of negative symptoms and associated factors in older adults with schizophrenia spectrum disorder living in the community. METHODS: The sample consisted of a multiracial sample of 198 persons aged 55 and more with a schizophrenia spectrum disorder that developed the disorder before the age of 45; 39% and 61% lived independently and in supported community residences, respectively. George's Social Antecedent Model of Psychopathology was used to examine 16 predictor variables of negative symptoms, based on scores of 4 or more on any of the PANSS negative symptom items. RESULTS: Forty percent of the sample met the criteria for the presence of negative symptoms, and this decreased to 19% when potential secondary symptoms were excluded. In bivariate analysis, 10 variables were found to be significantly associated with the presence of negative symptoms, but when the model was tested in logistic regression analysis, only 3 variables retained significance: greater positive symptom scores (odds ratio [OR] = 1.26), lower cognitive scores (OR = 0.96), and fewer confidantes (OR = 0.80). CONCLUSION: Negative symptoms do not dominate the clinical picture in later life, and levels of negative symptoms appear to be no higher than in younger schizophrenia populations. The relative paucity of significant variables and their modest effect sizes suggest that treatment for negative symptoms in later life will depend largely on strategies directed specifically at the negative symptoms. PMID- 23343485 TI - Cognitive decline and dementia risk in older adults with psychotic symptoms: a prospective cohort study. AB - OBJECTIVES: To study the temporal association between psychotic symptoms with cognitive decline and incident dementia. DESIGN: Population-based prospective cohort study. SETTING: General population in England and Wales. PARTICIPANTS: A subsample of 2,025 participants of the Medical Research Council Cognitive Function and Ageing Study, representing a study sample of 11,916 nondemented adults age 65 years or older. MEASUREMENTS: Baseline presence of psychotic symptoms was assessed with the Geriatric Mental State. Cognitive decline (Cambridge Cognitive Examination) and incident dementia (Automated Geriatric Examination for Computer Assisted Taxonomy diagnosis) were evaluated at 2, 6, and 10 years from baseline. RESULTS: A total of 330 participants reported baseline symptoms of paranoid delusions, misidentification, or hallucinations, estimated to represent 13.4% of the older general population without dementia. Psychotic symptoms were cross-sectionally associated with worse cognitive functioning, and individuals with psychotic symptoms displayed more rapid cognitive decline from baseline to a 6-year follow-up, especially in nonmemory functions, than people without such symptoms. They further carried an increased overall risk of later dementia (odds ratio = 2.76, 95% confidence interval = 1.75-4.36). The risk increment was observed independently of baseline cognition, depression, anxiety, and vascular risk factors, increased with increasing numbers of psychotic symptoms, and was highest in people age 65-74 years. CONCLUSIONS: Older adults with psychotic symptoms are vulnerable to develop dementia and might be a promising target for indicated prevention strategies. Their neuropsychological functioning should be evaluated on a regular basis. PMID- 23343484 TI - Cognitive performance of individuals with schizophrenia across seven decades: a study using the MATRICS consensus cognitive battery. AB - OBJECTIVES: The objectives of this study were to determine the effect of aging, schizophrenia, and their interaction on cognitive function. DESIGN: Cross sectional controlled study. SETTING: Community living. PARTICIPANTS: A total of 235 subjects with schizophrenia age 19-79 and 333 comparison subjects age 20-81. MEASUREMENTS: The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). RESULTS: Older age was associated with poorer performance on 9 of 10 MCCB tests in both subjects with schizophrenia and comparison subjects. Subjects with schizophrenia were impaired relative to comparison subjects on each of the 10 tests. However, there was no interaction between aging and schizophrenia on any test. Essentially the same results were observed when analyzing performance on the seven MCCB cognitive domains and MCCB global composite score. CONCLUSIONS: Consistent with other reports, schizophrenia appears to be a disorder marked by generalized cognitive dysfunction. However, the rate of cognitive decline appears to be similar to that observed in healthy comparison subjects. They do not experience acceleration in cognitive aging, which supports the hypothesis that schizophrenia is a syndrome of premature aging. Longitudinal studies including very old patients are needed to confirm and extend these findings. PMID- 23343486 TI - The care needs of elderly patients with schizophrenia spectrum disorders. AB - OBJECTIVE: Elderly patients constitute the fastest growing segment of the schizophrenia population. Still, their needs for care are poorly understood. This study aimed to gain insight into the care needs of older patients with schizophrenia spectrum disorders. SETTING AND PARTICIPANTS: Patients, aged 60 years and older, in contact with mental health services within a Dutch psychiatric catchment area, diagnosed with schizophrenia spectrum disorders. MEASUREMENTS: Needs and the extent to which these were met were assessed from the perspective of both patients and staff members. Agreement between patients and staff on the presence of needs was evaluated. In addition, the association between patient characteristics and the number of unmet needs was examined. RESULTS: On average, patients (N = 114, mean age: 69 years) reported 7.6 needs, of which 6.1 were met and 1.5 were unmet. Staff members reported slightly more needs, both met and unmet. Patients and staff showed consensus on the presence of most needs, but discrepancies existed in individual need areas. Psychological and social needs were unmet more often than environmental and physical needs. The number of unmet needs correlated with several patient variables, with the strongest association found for self-reported quality of life. CONCLUSION: In elderly schizophrenia patients, similar to what has been reported in younger patients, psychological and social needs appear to be under serviced. Having more unmet needs was associated with a lower perceived quality of life. PMID- 23343487 TI - PET scanning of brain tau in retired national football league players: preliminary findings. AB - OBJECTIVE: Mild traumatic brain injury due to contact sports may cause chronic behavioral, mood, and cognitive disturbances associated with pathological deposition of tau protein found at brain autopsy. To explore whether brain tau deposits can be detected in living retired players, we used positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F 18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP). METHODS: Five retired National Football League players (age range: 45 to 73 years) with histories of mood and cognitive symptoms received neuropsychiatric evaluations and FDDNP-PET. PET signals in subcortical (caudate, putamen, thalamus, subthalamus, midbrain, cerebellar white matter) and cortical (amygdala, frontal, parietal, posterior cingulate, medial and lateral temporal) regions were compared with those of five male controls of comparable age, education, and body mass index. RESULTS: FDDNP signals were higher in players compared with controls in all subcortical regions and the amygdala, areas that produce tau deposits following trauma. CONCLUSIONS: The small sample size and lack of autopsy confirmation warrant larger, more definitive studies, but if future research confirms these initial findings, FDDNP-PET may offer a means for premorbid identification of neurodegeneration in contact-sports athletes. PMID- 23343489 TI - Patient perspectives on the benefits of psychotherapy for late-life depression. AB - OBJECTIVES: The future of psychotherapy research lies in the development of easy to-use, efficient treatments that target specific characteristics and needs of patients with a given disorder. Meeting this aim will involve understanding why people seek psychotherapy and the therapeutic features that they feel are most helpful in their recovery. Identifying key features of treatment that patients feel lead to improvement may help identify the active ingredients of psychotherapy and further refine treatment. DESIGN: We selected 22 older adults who participated in a larger randomized trial of psychotherapy for late-life depression to participate in individual, semistructured qualitative interviews. SETTING: Interviews took place at the University of California, San Francisco or in the participant's home. PARTICIPANTS: All participants were age 60 years or older with major depression and co-occurring executive dysfunction. MEASUREMENTS: Participants were asked about their depression experience, their expectations for treatment, most and least helpful aspects of treatment, effects of treatment, and recommended improvements to treatment. Data were transcribed, coded, and analyzed using NVivo (QSR International, Cambridge, MA). RESULTS: The most commonly noted causes for seeking treatment were depression related to interpersonal relationships, health conditions, grief/loss, finances, housing, and challenges due to executive dysfunction. Participants had few expectations about treatment and they found support, the problem-solving therapy process, and focus on interpersonal relationships to be the most helpful processes in treatment. CONCLUSION: Suggestions for psychotherapy include increasing the number of sessions, discussing problems in a more proactive way, and considering participant choice in treatment. This research demonstrates the value of mixed methods approaches, in that qualitative approaches assist in contextualizing and interpreting quantitative data. PMID- 23343490 TI - Associations between elevated homocysteine, cognitive impairment, and reduced white matter volume in healthy old adults. AB - OBJECTIVES: Elevated homocysteine has emerged as a risk factor for cognitive impairment even in healthy elderly persons. Reduced brain volume and white matter hyperintensities also occur in healthy elderly as well, but the interrelationships between these have not been well studied. We report these interrelationships in non demented, relatively healthy, community-dwelling older adults from a single East Asian population. METHODS: Two hundred twenty-eight right-handed participants age 55 years and above were evaluated. Persons with medical conditions or neurological diseases other than well-controlled diabetes mellitus and hypertension were excluded. Participants underwent quantitative magnetic resonance imaging of the brain using a standardized protocol and neuropsychological evaluation. Plasma homocysteine, folate, vitamin B(12), and markers for cardiovascular risk: blood pressure, body mass index, fasting blood glucose, and lipid profile were measured. RESULTS: Elevated homocysteine was associated with reduced global cerebral volume, larger ventricles, reduced cerebral white matter volume, and lower cognitive performance in several domains. Elevated homocysteine was associated with reduced white matter volume (beta = 20.80, t = -2.9, df = 223, p = 0.004) and lower speed of processing (beta = 0.38, t = -2.1, df = 223, p = 0.03), even after controlling for age, gender, and education. However, the association between homocysteine and lower speed of processing disappeared after controlling for white matter volume. Elevated homocysteine was not associated with white matter hyperintensity volume or with hippocampal volume. Although homocysteine and folate levels were correlated, their effects on white matter volume were dissociated. CONCLUSION: In non demented, relatively healthy adults, elevated homocysteine is associated with lower cognitive scores and reduced cerebral white matter volume. These effects can be dissociated from those related to white matter hyperintensities or reduced folate level. PMID- 23343488 TI - Neuroticism, extraversion, and motor function in community-dwelling older persons. AB - OBJECTIVE: Personality traits are associated with adverse health outcomes in old age, but their association with motor function is unclear. We tested the hypothesis that neuroticism and extraversion are associated with motor decline in older persons. DESIGN: Prospective, observational cohort study. SETTING: Retirement communities across metropolitan Chicago. PARTICIPANTS: Nine hundred eighty-three older persons without dementia. MEASUREMENTS: At baseline, neuroticism and extraversion were assessed and annual assessment of 18 motor measures were summarized in a composite measure. RESULTS: Average follow-up was 5 years. Separate linear mixed-effects models controlling for age, sex, and education showed that baseline levels of neuroticism and extraversion were associated with the rate of motor decline. For each 7-point (~1 SD) higher neuroticism score at baseline, the average annual rate of motor decline was more than 20% faster. This amount of motor decline was associated with a 10% increased risk of death compared to a participant with an average neuroticism score. Each 6 point (~1 SD) lower extraversion score at baseline was associated with an 8% faster rate of motor decline. This amount of motor decline was associated with about a 9% increased risk of death compared to a participant with an average extraversion score. Neuroticism and extraversion were relatively independently associated with motor decline. These associations were unchanged when controlling for depressive symptoms and current health status but were partially attenuated when controlling for late-life cognitive and social activities. CONCLUSIONS: Higher levels of neuroticism and lower levels of extraversion are associated with more rapid motor decline in old age. PMID- 23343491 TI - Systematic review of the effectiveness of pharmacologic interventions to improve quality of life and well-being in people with dementia. AB - OBJECTIVE: To review systematically, for the first time, the effectiveness of all pharmacologic interventions to improve quality of life and well-being in people with dementia. DESIGN: Systematic review and meta-analysis. METHODS: We systematically reviewed the 15 randomized controlled trials and one review that fitted predetermined criteria. We included studies that reported the outcomes quality of life, well-being, happiness, or pleasure. MEASUREMENTS: We rated the validity of studies using a checklist. We calculated mean differences between intervention and control groups at follow-up. RESULTS: None of the evaluated trials reported a significant benefit to quality of life or well-being for people with dementia when comparing those taking a drug or its comparator at follow-up (pooled weighted mean difference: 0.18 [95% confidence interval: -0.82 to 0.46]). CONCLUSION: We found no consistent evidence that any drug improves quality of life in people with dementia. We recommend that all dementia trials should include quality of life as an outcome, as this is important to patients, and cannot be presumed from improvements in cognition or other symptomatic outcomes, especially if the latter are small. PMID- 23343492 TI - A systematic review and meta-analysis of magnetic resonance imaging studies in late-life depression. AB - Gray matter abnormalities within frontal-subcortical and limbic networks are hypothesized to play a key role in the pathophysiology of late-life depression. In this work, gray matter abnormalities in late-life depression are examined in a systematic review and meta-analysis of magnetic resonance imaging studies. In the systematic review, 27 articles were identified that compared participants with late-life depression with comparison group participants, and 17 studies were suitable for inclusion in meta-analyses of volumes of the whole brain, orbitofrontal cortex, caudate, hippocampus, putamen, and thalamus. Volume reductions were detected in 7 of 15 comparisons of the hippocampus and a meta analysis revealed a significant, but small, effect size. Although examined by fewer studies, meta-analyses also revealed significant volume reductions in the orbitofrontal cortex, putamen, and thalamus. A more systematic and comprehensive analysis of the global distribution of gray matter abnormalities, and an examination of subcortical abnormalities were identified as key areas for future research. PMID- 23343493 TI - Alcohol use disorder in elderly suicide attempters: a comparison study. AB - OBJECTIVES: To compare lifetime prevalence of alcohol use disorder (AUD) in older adults who were hospitalized in connection with a suicide attempt and in a population comparison group, as well as to compare previous suicidal behavior in attempters with and without AUD. DESIGN: Case-comparison. SETTING: Five hospitals in Western Sweden. PARTICIPANTS: Persons 70 years or older, who were treated in a hospital because of a suicide attempt during 2003-2006 were recruited. Of 133 eligible participants, 103 participants were enrolled (47 men, 56 women, mean age 80 years, response rate 77%). Four comparison subjects per case were randomly selected among participants in our late-life population studies. MEASUREMENTS: Lifetime history of AUD in accordance with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, was discerned on the basis of interview data, case record review, and the hospital discharge register. Depression symptoms were rated using the Montgomery-Asberg Rating Scale. RESULTS: AUD was observed in 26% of the cases and in 4% of the comparison group (odds ratio [OR]: 10.5; 95% confidence interval [CI]: 4.9-22.5). Associations were noted in men (OR: 9.5; 95% CI: 4.0-22.8) and women (OR: 12.0; 95% CI: 2.4-59.5). More than half of the cases with AUD and a third of those without AUD had made at least one prior suicide attempt. In these, AUD was associated with a longer interval between the first attempt and the index attempt. CONCLUSIONS: A strong association between AUD and hospital-treated suicide attempts was noted in both sexes in this northern European setting. Given the high rates of suicide worldwide in this fast-growing and vulnerable group, comparison studies in other settings are needed. PMID- 23343494 TI - Predicting 10-year alcohol use trajectories among men age 50 years and older. AB - OBJECTIVE: To describe common 10-year drinking trajectories followed by men age 50 years or older and identify risk factors for those trajectories. DESIGN: Longitudinal data were used to derive a semiparametric group-based model. PARTICIPANTS: Men from the Health and Retirement Study age 50-65 years in 1998 who completed three or more of the six interviews conducted from 1998 to 2008, including our 1998 baseline interview. MEASUREMENTS: Biannual data on number of drinks per drinking day were used to derive drinking trajectories. Risk factors included baseline age, race, ethnicity, education, marital status, retirement, smoking, binge drinking, vigorous exercise, body mass index, depression, pain, self-reported health, and chronic disease. RESULTS: The best-fitting model included consistent infrequent drinkers and nondrinkers (40.6% of cohort), increasing drinkers (5.5%), decreasing drinkers (7.6%), consistent at-risk drinkers (15.6%), and consistent moderate drinkers (30.7%). Adjusted logistic regression models comparing men with similar 1998 drinking levels who subsequently followed different trajectories identified significant risks associated with age, education, smoking, binge drinking, depression, pain, and self-reported health. To illustrate, odds ratios (ORs) and 95% confidence intervals (95% CIs) suggest that baseline infrequent drinkers were less likely to follow an increasing drinkers trajectory if they were older (OR: 0.57, 95% CI: 0.38-0.82) and smoked cigarettes (OR: 0.47, 95% CI: 0.30-0.74). Baseline drinkers were less likely to follow a decreasing trajectory if they reported more than 12 years of education (OR: 0.58, 95% CI: 0.42-0.82) and thought that their health was excellent or very good (OR: 0.54, 95% CI: 0.39-0.76). CONCLUSION: Only 30.7% of older men in this cohort were moderate drinkers throughout the follow-up. Many older men may benefit from brief counseling on the risks and benefits of drinking. PMID- 23343496 TI - Direct access to acylated azobenzenes via Pd-catalyzed C-H functionalization and further transformation into an indazole backbone. AB - Azobenzenes were readily acylated at the 2-position through a Pd-catalyzed C-H functionalization from simple aromatic azo compounds and aldehydes in good yields. The obtained acylated azobenzenes could be efficiently converted into the corresponding indazole derivatives in nearly quantitative yields. PMID- 23343495 TI - TGFbeta signaling regulates lipogenesis in human sebaceous glands cells. AB - BACKGROUND: Sebaceous glands are components of the skin essential for its normal lubrication by the production of sebum. This contributes to skin health and more importantly is crucial for the skin barrier function. A mechanistic understanding of sebaceous gland cells growth and differentiation has lagged behind that for keratinocytes, partly because of a lack of an in vitro model that can be used for experimental manipulation. METHODS: We have developed an in vitro culture model to isolate and grow primary human sebocytes without transformation that display functional characteristics of sebocytes. We used this novel method to probe the effect of Transforming Growth Factor beta (TGFbeta) signaling on sebocyte differentiation, by examining the expression of genes involved in lipogenesis upon treatment with TGFbeta1. We also repressed TGFbeta signaling through knockdown of the TGFbeta Receptor II to address if the effect of TGFbeta activation is mediated via canonical Smad signal transduction. RESULTS: We find that activation of the TGFbeta signaling pathway is necessary and sufficient for maintaining sebocytes in an undifferentiated state. The presence of TGFbeta ligand triggered decreased expression in genes required for the production of characteristics sebaceous lipids and for sebocyte differentiation such as FADS2 and PPARgamma, thereby decreasing lipid accumulation through the TGFbeta RII Smad2 dependent pathway. CONCLUSION: TGFbeta signaling plays an essential role in sebaceous gland regulation by maintaining sebocytes in an undifferentiated state. This data was generated using a novel method for human sebocyte culture, which is likely to prove generally useful in investigations of sebaceous gland growth and differentiation. These findings open a new paradigm in human skin biology with important implications for skin therapies. PMID- 23343497 TI - Laryngeal amyloidosis as a cause of death. PMID- 23343498 TI - Fibrinogen A alpha-chain amyloidosis: report of the first case in Latin America. AB - BACKGROUND: Hereditary fibrinogen A alpha-chain (AFib) amyloidosis affects different organs, especially the kidneys. No case of this disease has been reported in Latin America. CASE REPORT: A 52-year-old previously healthy Brazilian woman presented with a seven-month history of proteinuria in the absence of hematuria. The patient had normal blood pressure and reported no other symptoms. A renal biopsy was obtained and light microscopy revealed the presence of Congo red positive deposits (apple-green birefringence under polarized light) only in the glomerular compartment. These deposits were strongly immunoreactive to fibrinogen in all glomeruli. Electron microscopy showed the presence of organized deposits compatible with AFib. The diagnosis was confirmed by DNA analysis of the AFib gene, which demonstrated a Glu526Val mutation in one allele. CONCLUSION: This first description of hereditary AFib amyloidosis in Latin America highlights the need to include this type of amyloidosis in the differential diagnosis, especially in Brazil where the degree of miscegenation is high. PMID- 23343499 TI - Electrophoresis of a charge-regulated zwitterionic particle: influence of temperature and bulk salt concentration. AB - The influence of temperature on the electrophoretic behavior of a charge regulated zwitterionic particle is investigated by considering a spherical SiO(2) particle in a relatively dilute aqueous NaCl solution of concentration C(NaCl) with its pH adjusted by NaOH and HCl as an example. A complete mobility-pH temperature plot and a mobility-C(NaCl)-temperature plot are prepared for pH, C(NaCl), and temperature ranging from 3 to 9.5, 10(-4) to 10(-2) M, and 293 to 308 K, respectively, for the first time, and empirical correlation relationships are developed. These provide necessary information for both interpreting experimental data and designing electrophoresis devices, where the variation in the temperature can be a factor. In general, the absolute value of the particle mobility increases with T, and that value has a local maximum as pH varies. PMID- 23343500 TI - Animal models of post-ischemic forced use rehabilitation: methods, considerations, and limitations. AB - Many survivors of stroke experience arm impairments, which can severely impact their quality of life. Forcing use of the impaired arm appears to improve functional recovery in post-stroke hemiplegic patients, however the mechanisms underlying improved recovery remain unclear. Animal models of post-stroke rehabilitation could prove critical to investigating such mechanisms, however modeling forced use in animals has proven challenging. Potential problems associated with reported experimental models include variability between stroke methods, rehabilitation paradigms, and reported outcome measures. Herein, we provide an overview of commonly used stroke models, including advantages and disadvantages of each with respect to studying rehabilitation. We then review various forced use rehabilitation paradigms, and highlight potential difficulties and translational problems. Lastly, we discuss the variety of functional outcome measures described by experimental researchers. To conclude, we outline ongoing challenges faced by researchers, and the importance of translational communication. Many stroke patients rely critically on rehabilitation of post stroke impairments, and continued effort toward progression of rehabilitative techniques is warranted to ensure best possible treatment of the devastating effects of stroke. PMID- 23343501 TI - Impact of pre-therapy viral load on virological response to modern first-line HAART. AB - BACKGROUND: We tested whether pre-HAART viraemia affects the achievement and maintenance of virological success in HIV-1-infected patients starting modern first-line therapies. METHODS: A total of 1,430 patients starting their first HAART (genotype-tailored) in 2008 (median; IQR: 2006-2009) were grouped according to levels of pre-HAART viraemia (<= 30,000, 30,001-100,000, 100,001-300,000, 300,001-500,000 and > 500,000 copies/ml). The impact of pre-therapy viraemia on the time to virological success (viraemia <= 50 copies/ml) and on the time to virological rebound (first of two consecutive viraemia values > 50 copies/ml after virological success) were evaluated by Kaplan-Meier curves and Cox regression analyses. RESULTS: Median pre-HAART viraemia was 5.1 log10 copies/ml (IQR 4.5-5.5), and 53% of patients had viraemia > 100,000 copies/ml. By week 48, the prevalence of patients reaching virological success was > 90% in all pre HAART viraemia ranges, with the only exception of range > 500,000 copies/ml (virological success = 83%; P < 0.001). Higher pre-HAART viraemia was tightly correlated with longer median time to achieve virological success. Cox multivariable estimates confirmed this result: patients with pre-HAART viraemia > 500,000 copies/ml showed the lowest hazard of virological undetectability after adjusting for age, gender, pre-HAART CD4+ T-cell count, transmitted drug resistance, calendar year and third drug administered (adjusted hazard ratio [95% CI]: 0.27 [0.21, 0.35]; P < 0.001). Pre-HAART viraemia > 500,000 copies/ml was also associated with higher probability of virological rebound compared with patients belonging to lower viraemia strata at weeks 4, 12 and 24 (P = 0.050). CONCLUSIONS: At the time of modern HAART, and even though an average > 90% of virological success, high pre-HAART viraemia remains an independent factor associated with delayed and decreased virological success. Patients starting HAART with > 500,000 copies/ml represent a significant population that may deserve special attention. PMID- 23343502 TI - The sympatric occurrence of two genetically divergent lineages of sucking louse, Polyplax arvicanthis (Phthiraptera: Anoplura), on the four-striped mouse genus, Rhabdomys (Rodentia: Muridae). AB - Within southern Africa, the widely distributed four-striped mouse genus (Rhabdomys) is parasitized by, amongst others, the specific ectoparasitic sucking louse, Polyplax arvicanthis. Given the presence of significant geographically structured genetic divergence in Rhabdomys, and the propensity of parasites to harbour cryptic diversity, the molecular systematics of P. arvicanthis was investigated. Representatives of P. arvicanthis were sampled from Rhabdomys at 16 localities throughout southern Africa. Parsimony and Bayesian gene trees were constructed for the mitochondrial COI, 12S rRNA, 16S rRNA and nuclear CAD genes. Our findings support the existence of 2 genetic groups within P. arvicanthis separated by at least 25% COI sequence divergence, which is comparable to that observed among recognized Polyplax species. We therefore propose that these 2 genetic lineages probably represent distinct species and that the apparent absence of clear morphological differences may point to cryptic speciation. The 2 taxa have sympatric distributions throughout most of the sampled host range and also occasionally occur sympatrically on the same host individual. The co occurrence of these genetically distinct lineages probably resulted from parasite duplication via host-associated allopatric divergence and subsequent reciprocal range expansions of the 2 parasite taxa throughout southern Africa. PMID- 23343503 TI - Quantifying short-term dynamics of Parkinson's disease using self-reported symptom data from an Internet social network. AB - BACKGROUND: Parkinson's disease (PD) is an incurable neurological disease with approximately 0.3% prevalence. The hallmark symptom is gradual movement deterioration. Current scientific consensus about disease progression holds that symptoms will worsen smoothly over time unless treated. Accurate information about symptom dynamics is of critical importance to patients, caregivers, and the scientific community for the design of new treatments, clinical decision making, and individual disease management. Long-term studies characterize the typical time course of the disease as an early linear progression gradually reaching a plateau in later stages. However, symptom dynamics over durations of days to weeks remains unquantified. Currently, there is a scarcity of objective clinical information about symptom dynamics at intervals shorter than 3 months stretching over several years, but Internet-based patient self-report platforms may change this. OBJECTIVE: To assess the clinical value of online self-reported PD symptom data recorded by users of the health-focused Internet social research platform PatientsLikeMe (PLM), in which patients quantify their symptoms on a regular basis on a subset of the Unified Parkinson's Disease Ratings Scale (UPDRS). By analyzing this data, we aim for a scientific window on the nature of symptom dynamics for assessment intervals shorter than 3 months over durations of several years. METHODS: Online self-reported data was validated against the gold standard Parkinson's Disease Data and Organizing Center (PD-DOC) database, containing clinical symptom data at intervals greater than 3 months. The data were compared visually using quantile-quantile plots, and numerically using the Kolmogorov Smirnov test. By using a simple piecewise linear trend estimation algorithm, the PLM data was smoothed to separate random fluctuations from continuous symptom dynamics. Subtracting the trends from the original data revealed random fluctuations in symptom severity. The average magnitude of fluctuations versus time since diagnosis was modeled by using a gamma generalized linear model. RESULTS: Distributions of ages at diagnosis and UPDRS in the PLM and PD-DOC databases were broadly consistent. The PLM patients were systematically younger than the PD-DOC patients and showed increased symptom severity in the PD off state. The average fluctuation in symptoms (UPDRS Parts I and II) was 2.6 points at the time of diagnosis, rising to 5.9 points 16 years after diagnosis. This fluctuation exceeds the estimated minimal and moderate clinically important differences, respectively. Not all patients conformed to the current clinical picture of gradual, smooth changes: many patients had regimes where symptom severity varied in an unpredictable manner, or underwent large rapid changes in an otherwise more stable progression. CONCLUSIONS: This information about short term PD symptom dynamics contributes new scientific understanding about the disease progression, currently very costly to obtain without self-administered Internet-based reporting. This understanding should have implications for the optimization of clinical trials into new treatments and for the choice of treatment decision timescales. PMID- 23343504 TI - Lessons and challenges for measles control from unexpected large outbreak, Malawi. AB - Despite high reported coverage for routine and supplementary immunization, in 2010 in Malawi, a large measles outbreak occurred that comprised 134,000 cases and 304 deaths. Although the highest attack rates were for young children (2.3%, 7.6%, and 4.5% for children <6, 6-8, and 9-11 months, respectively), persons >15 years of age were highly affected (1.0% and 0.4% for persons 15-19 and >19 years, respectively; 28% of all cases). A survey in 8 districts showed routine coverage of 95.0% for children 12-23 months; 57.9% for children 9-11 months; and 60.7% for children covered during the last supplementary immunization activities in 2008. Vaccine effectiveness was 83.9% for 1 dose and 90.5% for 2 doses. A continuous accumulation of susceptible persons during the past decade probably accounts for this outbreak. Countries en route to measles elimination, such as Malawi, should improve outbreak preparedness. Timeliness and the population chosen are crucial elements for reactive campaigns. PMID- 23343505 TI - Psychoanalysis and empirical research: the example of alexithymia. AB - An extensive body of research on the alexithymia construct is reviewed to show how various empirical methodologies can be used to evaluate the validity and increase our understanding of theoretical and clinically derived psychoanalytic concepts. The historical background of alexithymia and the theoretical framework in which the construct was formulated are presented, after which measurement- and experiment-based approaches to construct validation are described. This is followed by a review of empirical investigations that have yielded evidence that alexithymia is a dimensional personality trait associated with several illnesses of interest to psychoanalysts. Empirical research also supports clinical observations and impressions that individuals with high degrees of alexithymia principally employ primitive defenses, have a limited capacity for empathy, exhibit deficits in mentalization, and do not respond well to traditional interpretive psychotherapies. Also reviewed is empirical research that implicates genetic and environmental/developmental factors in the etiology of alexithymia, in particular childhood trauma and insecure attachments, factors generally associated with deficits in affect development and affect regulation. The clinical relevance of the empirical research findings is discussed in the final section. PMID- 23343506 TI - Phosphine-catalyzed synthesis of 3,3-spirocyclopenteneoxindoles from gamma substituted allenoates: systematic studies and targeted applications. AB - The phosphine-promoted [3 + 2] cyclizations between gamma-substituted allenoates and arylideneoxindoles have been applied to the stereoselective synthesis of spiro(cyclopentene)oxindoles with trisubstituted cyclopentene units. It has been demonstrated that PPh(3) operates a very efficient control of the relative stereochemistry of the three stereogenic centers of the final spiranic products. Focused experiments have been carried out then so as to access carbocyclic analogues of an important series of anticancer agents inhibiting MDM2-p53 interactions. PMID- 23343507 TI - Prevalence of hepatitis C infection among children with beta-thalassaemia major in Mid Delta, Egypt: a single centre study. AB - BACKGROUND: Transfusion dependant patients are at a higher risk of acquiring bloodborne infections even under conditions of safe transfusion. This study was designed to determine sero-prevalence of hepatitis C infection and possible associated risk factors in thalassaemic children. METHODS: One hundred and twenty five children with beta thalassaemia major (beta-TM) were recruited from the Haematology/Oncology Unit, Paediatric Department, Tanta University Hospital, Egypt, between April 2010 and October 2011. Patients underwent history taking, full clinical examination, routine investigations and venous blood sampling. Serum was stored at -20 degrees C till tested for hepatitis C (HCV Ab) and B (HBsAg) by ELISA. HCV Ab positive cases were confirmed by PCR. RESULTS: All patients were HBsAg negative. HCV Ab ELISA was positive in 76%, negative in 20% and equivocal in 4%. Fifty patients (40%) had positive PCR for HCV. PCR showed low viraemia in 78%, moderate viraemia in 20% and high viraemia in 2%. A positive family history of HCV, history of minor operative intervention and/or dental procedures were significantly associated with higher frequency of HCV infection in thalassaemic children, while amount and frequency of transfused blood, age at transfusion and chelation state were not. CONCLUSION: HCV infection is highly prevalent in children with beta-TM in Egypt despite strict pre-transfusion blood testing. This should arouse the attention for environmental and community acquired factors. Quality management to insure infection control in minor operative procedures and adding more sensitive tests for blood screening are recommended. PMID- 23343508 TI - Evaluation of the fully automated hematological analyzer Sysmex XE-5000 for flow cytometric analysis of peritoneal fluid. AB - Although microscopy still represents the gold standard for cytometric analysis of peritoneal fluids, automated flow cytometry may improve throughput and accuracy. We evaluated the performance of total nucleated cell (TNC), white blood cell (WBC), polymorphonuclear cell (PMN), and mononuclear cell (MONO) counts of Sysmex XE-5000 on peritoneal fluids. The imprecision was excellent, being always lower than 11%, whereas linearity studies yielded correlation coefficients of 1.00 for all parameters. The carryover was always lower than 0.2%. The comparison between XE-5000 and microscopic analysis of 117 ascitic fluids yielded correlation coefficients always greater than 0.96, with mean biases <11/uL. The diagnostic accuracy versus manual microscopy was greater than that of XE-2100, especially at thresholds for septic ascites (100 versus 98% for >=500 WBC/uL; 98 versus 93% for >=250 PMN/uL). The correlation with manual microscopy for macrophages and mesothelial cell count was also higher for XE-5000 than for XE-2100 (0.63 versus 0.55). The results of this evaluation show optimal performance of XE-5000 for routine analysis of ascitic fluids, which are combined with the advantages of automated analysis such as high throughout, shortened turnaround time, no need of sample preparation and trained staff, reduced sample volume, and less likelihood of transcriptional errors. PMID- 23343509 TI - Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways. AB - Experimental studies have indicated that endothelial cells play an important role in maintaining vascular homeostasis. We previously reported that human coronary artery endothelial cells (HCAECs) express the glucagon-like peptide 1 (GLP1) receptor and that the stable GLP1 mimetic exendin-4 is able to activate the receptor, leading to increased cell proliferation. Here, we have studied the effect of exendin-4 and native GLP1 (7-36) on lipoapoptosis and its underlying mechanisms in HCAECs. Apoptosis was assessed by DNA fragmentation and caspase-3 activation, after incubating cells with palmitate. Nitric oxide (NO) and reactive oxidative species (ROS) were analyzed. GLP1 receptor activation, PKA-, PI3K/Akt-, eNOS-, p38 MAPK-, and JNK-dependent pathways, and genetic silencing of transfection of eNOS were also studied. Palmitate-induced apoptosis stimulated cells to release NO and ROS, concomitant with upregulation of eNOS, which required activation of p38 MAPK and JNK. Exendin-4 restored the imbalance between NO and ROS production in which ROS production decreased and NO production was further augmented. Incubation with exendin-4 and GLP1 (7-36) protected HCAECs against lipoapoptosis, an effect that was blocked by PKA, PI3K/Akt, eNOS, p38 MAPK, and JNK inhibitors. Genetic silencing of eNOS also abolished the anti apoptotic effect afforded by exendin-4. Our results support the notion that GLP1 receptor agonists restore eNOS-induced ROS production due to lipotoxicity and that such agonists protect against lipoapoptosis through PKA-PI3K/Akt-eNOS-p38 MAPK-JNK-dependent pathways via a GLP1 receptor-dependent mechanism. PMID- 23343510 TI - An integrated study of thermal treatment effects on the microstructure and magnetic properties of Zn-ferrite nanoparticles. AB - The evolution of the magnetic state, crystal structure and microstructure parameters of nanocrystalline zinc-ferrite, tuned by thermal annealing of ~4 nm nanoparticles, was systematically studied by complementary characterization methods. Structural analysis of neutron and synchrotron x-ray radiation data revealed a mixed cation distribution in the nanoparticle samples, with the degree of inversion systematically decreasing from 0.25 in an as-prepared nanocrystalline sample to a non-inverted spinel structure with a normal cation distribution in the bulk counterpart. The results of DC magnetization and Mossbauer spectroscopy experiments indicated a superparamagnetic relaxation in ~4 nm nanoparticles, albeit with different freezing temperatures T(f) of 27.5 K and 46 K, respectively. The quadrupole splitting parameter decreases with the annealing temperature due to cation redistribution between the tetrahedral and octahedral sites of the spinel structure and the associated defects. DC magnetization measurements indicated the existence of significant interparticle interactions among nanoparticles ('superspins'). Additional confirmation for the presence of interparticle interactions was found from the fit of the T(f)(H) dependence to the AT line, from which a value of the anisotropy constant of K(eff) = 5.6 * 10(5) erg cm(-3) was deduced. Further evidence for strong interparticle interactions was found from AC susceptibility measurements, where the frequency dependence of the freezing temperature T(f)(f) was satisfactory described by both Vogel-Fulcher and dynamic scaling theory, both applicable for interacting systems. The parameters obtained from these fits suggest collective freezing of magnetic moments at T(f). PMID- 23343511 TI - Genomic homeostasis is dysregulated in favour of apoptosis in the colonic epithelium of the azoxymethane treated rat. AB - BACKGROUND: The acute response to genotoxic carcinogens in rats is an important model for researching cancer initiation events. In this report we define the normal rat colonic epithelium by describing transcriptional events along the anterior-posterior axis and then investigate the acute effects of azoxymethane (AOM) on gene expression, with a particular emphasis on pathways associated with the maintenance of genomic integrity in the proximal and distal compartments using whole genome expression microarrays. RESULTS: There are large transcriptional changes that occur in epithelial gene expression along the anterior-posterior axis of the normal healthy rat colon. AOM administration superimposes substantial changes on these basal gene expression patterns in both the distal and proximal rat colonic epithelium. In particular, the pathways associated with cell cycle and DNA damage and repair processes appear to be disrupted in favour of apoptosis. CONCLUSIONS: The healthy rats' colon exhibits extensive gene expression changes between its proximal and distal ends. The most common changes are associated with metabolism, but more subtle expression changes in genes involved in genomic homeostasis are also evident. These latter changes presumably protect and maintain a healthy colonic epithelium against incidental dietary and environmental insults. AOM induces substantial changes in gene expression, resulting in an early switch in the cell cycle process, involving p53 signalling, towards cell cycle arrest leading to the more effective process of apoptosis to counteract this genotoxic insult. PMID- 23343512 TI - Lessons from the history of quarantine, from plague to influenza A. AB - In the new millennium, the centuries-old strategy of quarantine is becoming a powerful component of the public health response to emerging and reemerging infectious diseases. During the 2003 pandemic of severe acute respiratory syndrome, the use of quarantine, border controls, contact tracing, and surveillance proved effective in containing the global threat in just over 3 months. For centuries, these practices have been the cornerstone of organized responses to infectious disease outbreaks. However, the use of quarantine and other measures for controlling epidemic diseases has always been controversial because such strategies raise political, ethical, and socioeconomic issues and require a careful balance between public interest and individual rights. In a globalized world that is becoming ever more vulnerable to communicable diseases, a historical perspective can help clarify the use and implications of a still valid public health strategy. PMID- 23343513 TI - Selective anti-herpesvirus agents. AB - This review article focuses on the anti-herpesvirus agents effective against herpes simplex virus, varicella-zoster virus and cytomegalovirus, which have either been licensed for clinical use (idoxuridine, trifluridine, brivudin, acyclovir, valaciclovir, valganciclovir, famciclovir and foscarnet) or are under clinical development (CMX001 [the hexadecyloxypropyl prodrug of cidofovir], the helicase-primase inhibitor BAY 57-1293 [now referred to as AIC316], FV-100 [the valine ester of Cf 1743] and the terminase inhibitor letermovir [AIC246]). PMID- 23343514 TI - Interpretation of left ventricular diastolic dysfunction in children with cardiomyopathy by echocardiography: problems and limitations. AB - BACKGROUND: Left ventricular diastolic dysfunction (DD) is a key determinant of outcomes in pediatric cardiomyopathy (CM), but remains very challenging to diagnose and classify. Adult paradigms and guidelines relating to DD are currently applied in children. However, it is unknown whether these are applicable to children with CM. We investigated the assessment of DD in children with CM using adult and pediatric echocardiographic criteria and tested whether recent adult guidelines are applicable to this population. METHODS AND RESULTS: Three investigators independently classified diastolic function in 4 study groups: controls, dilated, hypertrophic, and restrictive CM. Agreement among investigators, failure to classify DD, and the reasons for diagnostic failure were determined. The usefulness of individual echo parameters to diagnose and classify DD was assessed. One hundred seventy-five children (aged 0-18 years) were studied. DD diagnostic criteria were discrepant in the majority of patients. Delayed relaxation was diagnosed in only 14% of hypertrophic CM patients and never in dilated CM and restrictive CM, with 50% of those patients having coexisting findings of elevated filling pressures. Many key parameters, such as mitral and pulmonary venous Doppler, were not informative. Agreement among investigators for grading of DD was poor (36% of CM patients). CONCLUSIONS: Assessment of DD in childhood CM seems inadequate using current guidelines. The large range of normal pediatric reference values allows diagnosis of DD in only a small proportion of patients. Key echo parameters to assess DF are not sufficiently discriminatory in this population, and discrepancies between criteria within individuals prevent further classification and result in poor interobserver agreement. PMID- 23343515 TI - Selective in vivo visualization of immune-cell infiltration in a mouse model of autoimmune myocarditis by fluorine-19 cardiac magnetic resonance. AB - BACKGROUND: The goal of this study was to characterize the performance of fluorine-19 ((19)F) cardiac magnetic resonance (CMR) for the specific detection of inflammatory cells in a mouse model of myocarditis. Intravenously administered perfluorocarbons are taken up by infiltrating inflammatory cells and can be detected by (19)F-CMR. (19)F-labeled cells should, therefore, generate an exclusive signal at the inflamed regions within the myocardium. METHODS AND RESULTS: Experimental autoimmune myocarditis was induced in BALB/c mice. After intravenous injection of 2*200 uL of a perfluorocarbon on day 19 and 20 (n=9) after immunization, in vivo (19)F-CMR was performed at the peak of myocardial inflammation (day 21). In 5 additional animals, perfluorocarbon combined with FITC (fluorescein isothiocyanate) was administered for postmortem immunofluorescence and flow-cytometry analyses. Control experiments were performed in 9 animals. In vivo (19)F-CMR detected myocardial inflammation in all experimental autoimmune myocarditis-positive animals. Its resolution was sufficient to identify even small inflammatory foci, that is, at the surface of the right ventricle. Postmortem immunohistochemistry and flow cytometry confirmed the presence of perfluorocarbon in macrophages, dendritic cells, and granulocytes, but not in lymphocytes. The myocardial volume of elevated (19)F signal (rs=0.96; P<0.001), the (19)F signal-to-noise ratio (rs=0.92; P<0.001), and the (19)F signal integral (rs=0.96; P<0.001) at day 21 correlated with the histological myocarditis severity score. CONCLUSIONS: In vivo (19)F-CMR was successfully used to visualize the inflammation specifically and robustly in experimental autoimmune myocarditis, and thus allowed for an unprecedented insight into the involvement of inflammatory cells in the disease process. PMID- 23343516 TI - Contribution of silver ions to the inhibition of infectivity of Schistosoma japonicum cercariae caused by silver nanoparticles. AB - Blockage of pathogen transmission through water decontamination is considered an important strategy for the prevention of schistosome infection. Many believe that this strategy is feasible, but it has yet to be achieved. Silver has a long history of use as a disinfectant. With the emergence of nanotechnology, silver can be shaped into nanoparticles which have been found to possess superb antimicrobial activities. In this light, we investigated the effects of silver nanoparticles (AgNPs) on Schistosoma japonicum cercariae. AgNPs rapidly induced cercarial tail-shedding, agitated behaviour and a decrease in cercarial secretion in a dose-dependent manner. Prolonged treatment was found to be cercariocidal, which nevertheless might be attributable to AgNP-induced cercarial tail loss rather than to toxicity. Higher concentrations of AgNPs (125 MUg mL-1 and above) completely blocked cercarial infectivity. Despite decreased infectivity, cercariae exposed to lower concentrations of AgNPs for 30 min were still found capable of infecting hosts even without their tails, suggesting that tail loss does not necessarily signify a total loss of infective ability. We also found that silver ions (Ag+) were heavily involved in the observed cercarial responses of AgNPs. Our observations provide insight into the interactions between the larvae of helminth parasites and nanoparticles. PMID- 23343517 TI - Embryonic stem cells facilitate the isolation of persistent clonal cardiovascular progenitor cell lines and leukemia inhibitor factor maintains their self-renewal and myocardial differentiation potential in vitro. AB - Compelling evidence for the existence of somatic stem cells in the heart of different mammalian species has been provided by numerous groups; however, so far it has not been possible to maintain these cells as self-renewing and phenotypically stable clonal cell lines in vitro. Thus, we sought to identify a surrogate stem cell niche for the isolation and persistent maintenance of stable clonal cardiovascular progenitor cell lines, enabling us to study the mechanism of self-renewal and differentiation in these cells. Using postnatal murine hearts with a selectable marker as the stem cell source and embryonic stem cells and leukemia inhibitory factor (LIF)-secreting fibroblasts as a surrogate niche, we succeeded in the isolation of stable clonal cardiovascular progenitor cell lines. These cell lines self-renew in an LIF-dependent manner. They express both stemness transcription factors Oct4, Sox2, and Nanog and early myocardial transcription factors Nkx2.5, GATA4, and Isl-1 at the same time. Upon LIF deprivation, they exclusively differentiate to functional cardiomyocytes and endothelial and smooth muscle cells, suggesting that these cells are mesodermal intermediates already committed to the cardiogenic lineage. Cardiovascular progenitor cell lines can be maintained for at least 149 passages over 7 years without phenotypic changes, in the presence of LIF-secreting fibroblasts. Isolation of wild-type cardiovascular progenitor cell lines from adolescent and old mice has finally demonstrated the general feasibility of this strategy for the isolation of phenotypically stable somatic stem cell lines. PMID- 23343518 TI - Robust inter-beat interval estimation in cardiac vibration signals. AB - Reliable and accurate estimation of instantaneous frequencies of physiological rhythms, such as heart rate, is critical for many healthcare applications. Robust estimation is especially challenging when novel unobtrusive sensors are used for continuous health monitoring in uncontrolled environments, because these sensors can create significant amounts of potentially unreliable data. We propose a new flexible algorithm for the robust estimation of local (beat-to-beat) intervals from cardiac vibration signals, specifically ballistocardiograms (BCGs), recorded by an unobtrusive bed-mounted sensor. This sensor allows the measurement of motions of the body which are caused by cardiac activity. Our method requires neither a training phase nor any prior knowledge about the morphology of the heart beats in the analyzed waveforms. Instead, three short-time estimators are combined using a Bayesian approach to continuously estimate the inter-beat intervals. We have validated our method on over-night BCG recordings from 33 subjects (8 normal, 25 insomniacs). On this dataset, containing approximately one million heart beats, our method achieved a mean beat-to-beat interval error of 0.78% with a coverage of 72.69%. PMID- 23343519 TI - Synthesis, structural elucidation, and biochemical analysis of immunoactive glucuronosyl diacylglycerides of mycobacteria and corynebacteria. AB - Glucuronosyl diacylglycerides (GlcAGroAc2) are functionally important glycolipids and membrane anchors for cell wall lipoglycans in the Corynebacteria. Here we describe the complete synthesis of distinct acyl-isoforms of GlcAGroAc2 bearing both acylation patterns of (R)-tuberculostearic acid (C19:0) and palmitic acid (C16:0) and their mass spectral characterization. Collision-induced fragmentation mass spectrometry identified characteristic fragment ions that were used to develop "rules" allowing the assignment of the acylation pattern as C19:0 (sn-1), C16:0 (sn-2) in the natural product from Mycobacterium smegmatis, and the structural assignment of related C18:1 (sn-1), C16:0 (sn-2) GlcAGroAc2 glycolipids from M. smegmatis and Corynebacterium glutamicum. A synthetic hydrophobic octyl glucuronoside was used to characterize the GDP-mannose dependent mannosyltransferase MgtA from C. glutamicum that extends GlcAGroAc2. This enzyme is an Mg(2+)/Mn(2+)-dependent metalloenzyme that undergoes dramatic activation upon reduction with dithiothreitol. PMID- 23343520 TI - Cutaneous manifestations in patients with Wiskott-Aldrich syndrome submitted to haematopoietic stem cell transplantation. AB - INTRODUCTION: Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by a mutation of the WAS protein gene. This protein actively participates in important cellular processes, and its presence is related to diverse clinical manifestations, including cutaneous alterations. The classical triad of WAS consists of recurrent infections, thrombocytopaenia with small platelets and atopic dermatitis (AD)-like lesions. OBJECTIVE: To evaluate the frequencies of cutaneous manifestations in patients with WAS prior to haematopoietic stem cell transplantation (HSCT). RESULTS: Twenty-four boys diagnosed with WAS and treated with HSCT between 1992 and 2007 were included. The characteristic triad of WAS occurred in 46% of patients. Before HSCT, the most frequent cutaneous manifestations included eczema similar to AD (71%), followed by petechiae and/or ecchymosis (58%) and cutaneous infections (17%). CONCLUSIONS: Cutaneous manifestations in patients with WAS are frequent, especially those similar to the eczema found in AD. PMID- 23343521 TI - A patient survey for emergency care designed by children, for children. PMID- 23343522 TI - Childhood epilepsy recorded in primary care in the UK. AB - OBJECTIVE: To examine temporal trends in the incidence of epilepsy recorded in UK primary care and to evaluate the impact of recent efforts to improve the specificity of diagnosis in children. DESIGN: Birth cohort study using primary care data from The Health Improvement Network, which includes a representative sample of the UK population of approximately 5%. METHODS: We identified epilepsy recorded in primary care using relatively specific through to relatively sensitive indicators to identify epilepsy. Incidence estimates were based on 344 718 children aged 0-14 years with 1 447 760 years' follow-up between 1994 and 2008. Trends in cumulative incidence were explored with stratified analysis by year-of-birth. Trends in annual incidence were investigated using Poisson regression with adjustment for age, gender and deprivation. RESULTS: Cumulative incidence of recorded epilepsy at age 5 years ranged from 0.38% to 0.68% and annual incidence ranged from 71 to 116/100 000 person-years-at-risk, depending on the indicator used to identify epilepsy. With the most specific indicator for epilepsy, cumulative incidence was 33% lower among children born in 2003-2005 than in children born in 1994-1996, and annual incidence declined by 4% per annum between 2001 and 2008, after adjusting for age, gender and deprivation. Using a more sensitive indicator for epilepsy, the equivalent declines were 47% in cumulative incidence and 9% in annual incidence. CONCLUSIONS: The decline since the mid-1990s in epilepsy recorded in primary care may be due to more specific diagnosis, cessation of treatment for some forms of epilepsy, reduced exposure to risk factors or all of these factors. PMID- 23343523 TI - in silico surveillance: evaluating outbreak detection with simulation models. AB - BACKGROUND: Detecting outbreaks is a crucial task for public health officials, yet gaps remain in the systematic evaluation of outbreak detection protocols. The authors' objectives were to design, implement, and test a flexible methodology for generating detailed synthetic surveillance data that provides realistic geographical and temporal clustering of cases and use to evaluate outbreak detection protocols. METHODS: A detailed representation of the Boston area was constructed, based on data about individuals, locations, and activity patterns. Influenza-like illness (ILI) transmission was simulated, producing 100 years of in silico ILI data. Six different surveillance systems were designed and developed using gathered cases from the simulated disease data. Performance was measured by inserting test outbreaks into the surveillance streams and analyzing the likelihood and timeliness of detection. RESULTS: Detection of outbreaks varied from 21% to 95%. Increased coverage did not linearly improve detection probability for all surveillance systems. Relaxing the decision threshold for signaling outbreaks greatly increased false-positives, improved outbreak detection slightly, and led to earlier outbreak detection. CONCLUSIONS: Geographical distribution can be more important than coverage level. Detailed simulations of infectious disease transmission can be configured to represent nearly any conceivable scenario. They are a powerful tool for evaluating the performance of surveillance systems and methods used for outbreak detection. PMID- 23343524 TI - Human infection with Rickettsia sibirica mongolitimonae, Spain, 2007-2011. AB - Human infection with Rickettsia sibirica mongolitimonae was initially reported in 1996, and reports of a total of 18 cases have been published. We describe 6 additional cases that occurred in the Mediterranean coast region of Spain during 2007-2011. Clinicians should consider this infection in patients who have traveled to this area. PMID- 23343525 TI - Anisotropically oriented electrospun matrices with an imprinted periodic micropattern: a new scaffold for engineered muscle constructs. AB - Engineered muscle constructs provide a promising perspective on the regeneration or substitution of irreversibly damaged skeletal muscle. However, the highly ordered structure of native muscle tissue necessitates special consideration during scaffold development. Multiple approaches to the design of anisotropically structured substrates with grooved micropatterns or parallel-aligned fibres have previously been undertaken. In this study we report the guidance effect of a scaffold that combines both approaches, oriented fibres and a grooved topography. By electrospinning onto a topographically structured collector, matrices of parallel-oriented poly(epsilon-caprolactone) fibres with an imprinted wavy topography of 90 um periodicity were produced. Matrices of randomly oriented fibres or parallel-oriented fibres without micropatterns served as controls. As previously shown, un-patterned, parallel-oriented substrates induced myotube orientation that is parallel to fibre direction. Interestingly, pattern addition induced an orientation of myotubes at an angle of 24 degrees (statistical median) relative to fibre orientation. Myotube length was significantly increased on aligned micropatterned substrates in comparison to that on aligned substrates without pattern (436 +/- 245 um versus 365 +/- 212 um; p < 0.05). We report an innovative, yet simple, design to produce micropatterned electrospun scaffolds that induce an unexpected myotube orientation and an increase in myotube length. PMID- 23343526 TI - Expanding the domain of the understandable in psychiatric illness: an updating of the Jasperian framework of explanation and understanding. AB - Jaspers famously argued that psychiatry has two distinct ways of knowing about psychiatric illness: explanation - which utilizes natural sciences, and objective and empirical methods; and understanding - which reflects our subjective, empathic appreciation of our patients' experiences. He saw a clear division between these two approaches and considered a number of psychotic symptoms to be fundamentally un-understandable. We here argue for an updating of Jasper's view that includes the possibility, due to advances in neuroscience and neuropsychology, for explanation-aided understanding. We describe two scientific explanatory models for kinds of psychotic symptoms deemed un-understandable by Jaspers that illustrate this process. The first describes how dysfunction of the brain dopamine salience system may produce ideas of reference. The second demonstrates that symptoms of made-actions may be caused by abnormalities in the feed-forward motor control system. Both of these models begin at a biological level describing pathological brain processes in neuroscience language but then utilize neuropsychology to 'translate' from brain dysfunction into the mental. Both models break down the pathological pathways into individual subjective elements (particularly misattributing meaning to environmental stimuli and having body parts moved by others) that are understandable because they are common to nearly all of us. The neuropsychology provides hypotheses about the functional and physiological structures underlying familiar subjective experiences. Analyses of disorders of those structures thus provide a scaffold for expanding our empathic understanding of the subjective experiences of those suffering from psychiatric illness. PMID- 23343527 TI - Desert hedgehog promotes ischemia-induced angiogenesis by ensuring peripheral nerve survival. AB - RATIONALE: Blood vessel growth and patterning have been shown to be regulated by nerve-derived signals. Desert hedgehog (Dhh), one of the Hedgehog family members, is expressed by Schwann cells of peripheral nerves. OBJECTIVE: The purpose of this study was to investigate the contribution of Dhh to angiogenesis in the setting of ischemia. METHODS AND RESULTS: We induced hindlimb ischemia in wild type and Dhh(-/-) mice. First, we found that limb perfusion is significantly impaired in the absence of Dhh. This effect is associated with a significant decrease in capillary and artery density in Dhh(-/-). By using mice in which the Hedgehog signaling pathway effector Smoothened was specifically invalidated in endothelial cells, we demonstrated that Dhh does not promote angiogenesis by a direct activation of endothelial cells. On the contrary, we found that Dhh promotes peripheral nerve survival in the ischemic muscle and, by doing so, maintains the pool of nerve-derived proangiogenic factors. Consistently, we found that denervation of the leg, immediately after the onset of ischemia, severely impairs ischemia-induced angiogenesis and decreases expression of vascular endothelial growth factor A, angiopoietin 1, and neurotrophin 3 in the ischemic muscle. CONCLUSIONS: This study demonstrates the crucial roles of nerves and factors regulating nerve physiology in the setting of ischemia-induced angiogenesis. PMID- 23343528 TI - Is franchising in health care valuable? A systematic review. AB - BACKGROUND: Franchising is an organizational form that originates from the business sector. It is increasingly used in the healthcare sector with the aim of enhancing quality and accessibility for patients, improving the efficiency and competitiveness of organizations and/or providing professionals with a supportive working environment. However, a structured overview of the scientific evidence for these claims is absent, whereas such an overview can be supportive to scholars, policy makers and franchise practitioners. METHODS: This article provides a systematic review of literature on the outcomes of franchising in health care. Seven major databases were systematically searched. Peer-reviewed empirical journal articles focusing on the relationship between franchising and outcomes were included. Eventually, 15 articles were included and their findings were narratively synthesized. The level of evidence was rated by using the Grading of Recommendations Assessment, Development, and Evaluation scale. RESULTS: The review shows that outcomes of franchising in health care have primarily been evaluated in low- and middle-income countries in the reproductive health/family planning sector. Articles about high-income countries are largely absent, apart from three articles evaluating pharmacy franchises. Most studies focus on outcomes for customers/clients and less on organizations and professionals. The evidence is primarily of low quality. Based on this evidence, franchising is predominantly positively associated with client volumes, physical accessibility and some types of quality. Findings regarding utilization, customer loyalty, efficiency and results for providers are mixed. CONCLUSIONS: We conclude that franchising has the potential to improve outcomes in healthcare practices, but the evidence base is yet too weak for firm conclusions. Extensive research is needed to further determine the value of healthcare franchising in various contexts. We advocate more research in other healthcare sectors in both low- and middle-income countries and high-income countries, on more types of outcomes with attention to trade-offs, and on what factors produce those outcomes. PMID- 23343529 TI - Erythrocyte swelling and membrane hole formation in hypotonic media as studied by conductometry. AB - Hypoosmotic swelling of erythrocytes and the formation of membrane holes were studied by measuring the dc conductance (G). In accordance with the theoretical predictions, these processes are manifested by a decrease in G followed by its increase. Thus, unlike the conventional osmotic fragility test, the proposed methodological approach allows investigations of both the kinetics of swelling and the erythrocyte fragility. It is shown that the initial rate of swelling and the equilibrium size of the cells are affected by the tonicity of a hypotonic solution and the membrane rheological properties. Because the rupture of biological membranes is a stochastic process, a time-dependent increase in the conductance follows an integral distribution function of the membrane lifetime. The main conclusion which stems from reported results is that information about rheological properties of red blood cell (RBC) membranes and the resistivity of RBCs to a certain osmotic shock may be extracted from conductance signals. PMID- 23343530 TI - Evidence for specific genotype-dependent immune priming in the lophotrochozoan Biomphalaria glabrata snail. AB - Historically, the prevailing view in the field of invertebrate immunity was that invertebrates that do not possess acquired adaptive immunity rely on innate mechanisms with low specificity and no memory. Several recent studies have shaken this paradigm and suggested that the immune defenses of invertebrates are more complex and specific than previously thought. Mounting evidence has shown that at least some invertebrates (mainly Ecdysozoa) show high levels of specificity in their immune responses to different pathogens, and that subsequent reexposure may result in enhanced protection (recently called 'immune priming'). Here, we investigated immune priming in the Lophotrochozoan snail species Biomphalaria glabrata, following infection by the trematode pathogen Schistosoma mansoni. We confirmed that snails were protected against a secondary homologous infection whatever the host strain. We then investigated how immune priming occurs and the level of specificity of B. glabrata immune priming. In this report we confirmed that immune priming exists and we identified a genotype-dependent immune priming in the fresh-water snail B. glabrata. PMID- 23343531 TI - Esterified dendritic TAM radicals with very high stability and enhanced oxygen sensitivity. AB - In this work, we have developed a new class of dendritic TAM radicals (TG, TdG, and dTdG) through a convergent method based on the TAM core CT-03 or its deuterated analogue dCT-03 and trifurcated Newkome-type monomer. Among these radicals, dTdG exhibits the best EPR properties with sharpest EPR singlet and highest O(2) sensitivity due to deuteration of both the ester linker groups and the TAM core CT-03. Like the previous dendritic TAM radicals, these new compounds also show extremely high stability toward various reactive species owing to the dendritic encapsulation. The highly charged nature of these molecules resulting from nine carboxylate groups prevents concentration-dependent EPR line broadening at physiological pH. Furthermore, we demonstrate that these TAM radicals can be easily derivatized (e.g., PEGylation) at the nine carboxylate groups and the resulting PEGylated analogue dTdG-PEG completely inhibits the albumin binding, thereby enhancing suitability for in vivo applications. These new dendritic TAM radicals show great potential for in vivo EPR oximetric applications and provide insights on approaches to develop improved and targeted EPR oximetric probes for biomedical applications. PMID- 23343532 TI - Ebola virus antibodies in fruit bats, bangladesh. AB - To determine geographic range for Ebola virus, we tested 276 bats in Bangladesh. Five (3.5%) bats were positive for antibodies against Ebola Zaire and Reston viruses; no virus was detected by PCR. These bats might be a reservoir for Ebola or Ebola-like viruses, and extend the range of filoviruses to mainland Asia. PMID- 23343533 TI - Effective tuning of ligand incorporation and mechanical properties in visible light photopolymerized poly(ethylene glycol) diacrylate hydrogels dictates cell adhesion and proliferation. AB - Cell behavior is guided by the complex interplay of matrix mechanical properties as well as soluble and immobilized biochemical signals. The development of synthetic scaffolds that incorporate key functionalities of the native extracellular matrix (ECM) for support of cell proliferation and tissue regeneration requires that stiffness and immobilized concentrations of ECM signals within these biomaterials be tuned and optimized prior to in vitro and in vivo studies. A detailed experimental sensitivity analysis was conducted to identify the key polymerization conditions that result in significant changes in both elastic modulus and immobilized YRGDS within visible light photopolymerized poly(ethylene glycol) diacrylate hydrogels. Among the polymerization conditions investigated, single as well as simultaneous variations in N-vinylpyrrolidinone and precursor concentrations of acryl-PEG3400-YRGDS resulted in a broad range of the hydrogel elastic modulus (81-1178 kPa) and YRGDS surface concentration (0.04 1.72 pmol cm(-2)). Increasing the YRGDS surface concentration enhanced fibroblast cell adhesion and proliferation for a given stiffness, while increases in the hydrogel elastic modulus caused decreases in cell adhesion and increases in proliferation. The identification of key polymerization conditions is critical for the tuning and optimization of biomaterial properties and the controlled study of cell-substrate interactions. PMID- 23343534 TI - A case study of nurse practitioner role implementation in primary care: what happens when new roles are introduced? AB - BACKGROUND: At the time of this study (2009) the role of the nurse practitioner was new to the province of British Columbia. The provincial government gave the responsibility for implementing the role to health authorities. Managers of health authorities, many of whom were unfamiliar with the role, were responsible for identifying the need for the NP role, determining how the NP would function, and gaining team members' acceptance for the new role. METHOD: The purpose of the study was to explain the process of nurse practitioner role implementation as it was occurring and to identify factors that could enhance the implementation process. An explanatory, single case study with embedded units of analysis was used. The technique of explanation building was used in data analysis. Three primary health care settings in one health authority in British Columbia were purposively selected. Data sources included semi-structured interviews with participants (n=16) and key documents. RESULTS: The results demonstrate the complexity of implementing a new role in settings unfamiliar with it. The findings suggest that early in the implementation process and after the nurse practitioner was hired, team members needed to clarify intentions for the role and they looked to senior health authority managers for assistance. Acceptance of the nurse practitioner was facilitated by team members' prior knowledge of either the role or the individual nurse practitioner. Community health care providers needed to be involved in the implementation process and their acceptance developed as they gained knowledge and understanding of the role. CONCLUSION: The findings suggest that the interconnectedness of the concepts of intention, involvement and acceptance influences the implementation process and how the nurse practitioner is able to function in the setting. Without any one of the three concepts not only is implementation difficult, but it is also challenging for the nurse practitioner to fulfill role expectations. Implications for research, policy, practice and education are discussed. PMID- 23343535 TI - Calcium-calmodulin-dependent protein kinase II isoforms differentially impact the dynamics and structure of the actin cytoskeleton. AB - Calcium-calmodulin-dependent protein kinase II (CaMKII) has been implicated in a wide variety of cellular processes, which include a critical regulatory role in actin cytoskeletal assembly. CaMKII is ubiquitous in cells, expressed as one of four isoforms termed alpha, beta, gamma, and delta. Characterization of the CaMKII-actin interaction has mainly focused on the beta isoform, which has been shown to bundle actin filaments and sequester actin monomers in an activity dependent manner. Much less is known about the interactions of other CaMKII isoforms with actin. In this work, isoform specific interactions of CaMKII with actin are described and reveal that the delta isoform of CaMKII bundles F-actin filaments like the beta isoform while the gamma isoform induces a novel layered structure in filaments. Using electron tomography, CaMKII holoenzymes are clearly identified in the complexes bridging the actin filaments, allowing direct visualization of the interactions between CaMKII isoforms and actin. In addition, we determined the isoform specificity of CaMKII-mediated inhibition of actin polymerization and discovered that all isoforms inhibit polymerization to varying degrees: beta > gamma ~ delta > alpha (from most to least effective). Ca(2+)/CaM activation of all kinase isoforms produced a robust increase in actin polymerization that surpassed the rates of polymerization in the absence of kinase inhibition. These results indicate that diversity exists between the types of CaMKII-actin interactions mediated by the different isoforms and that the CaMKII isoform composition differentially impacts the formation and maintenance of the actin cytoskeleton. PMID- 23343536 TI - Family psychiatric morbidity of acute and transient psychotic disorders and their relationship to schizophrenia and bipolar disorder. AB - BACKGROUND: Although transient psychotic disorders are currently classified as a category separate from schizophrenia (SZ) and affective disorders, their distinctive features remain uncertain. This study examines the family psychiatric morbidity of the ICD-10 category of 'acute and transient psychotic disorders' (ATPDs), pointing out differences from SZ and bipolar disorder (BD). METHOD: From a cohort of 2.5 million persons, we identified all patients enrolled in the Danish Psychiatric Register who were ever admitted with ATPDs (n=2537), SZ (n = 10639) and BD disorder (n=5292) between 1996 and 2008. The relative risk (RR) of ATPDs, SZ and BD associated with psychiatric morbidity in first-degree relatives (FDRs) was calculated as the incidence rate ratio using Poisson regression. RESULTS: The RR of ATPDs [1.93, 95% confidence interval (CI) 1.76-2.11] was higher if patients with ATPDs had at least one FDR admitted with any mental disorder than patients without family psychiatric antecedents. An additional risk arose if they had FDRs admitted not only with ATPDs (RR 1.60, 95% CI 1.33-1.92) but also with SZ (RR 2.06, 95% CI 1.70-2.50) and/or BD (RR 1.55, 95% CI 1.23 1.96). Despite some overlap, the risk of SZ (RR 2.80, 95% CI 2.58-3.04) and BD (RR 3.68, 95% CI 3.29-4.12) was markedly higher if patients with SZ and BD had FDRs admitted with the same condition. CONCLUSIONS: These findings suggest that family psychiatric predisposition has a relatively modest impact on ATPDs and argue against a sharp differentiation of ATPDs from SZ and BD. PMID- 23343540 TI - Entropy of uremia and dialysis technology. AB - The second law of thermodynamics applies with local exceptions to patient history and therapy interventions. Living things preserve their low level of entropy throughout time because they receive energy from their surroundings in the form of food. They gain their order at the expense of disordering the nutrients they consume. Death is the thermodynamically favored state: it represents a large increase in entropy as molecular structure yields to chaos. The kidney is an organ dissipating large amounts of energy to maintain the level of entropy of the organism as low as possible. Diseases, and in particular uremia, represent conditions of rapid increase in entropy. Therapeutic strategies are oriented towards a reduction in entropy or at least a decrease in the speed of entropy increase. Uremia is a process accelerating the trend towards randomness and disorder (increase in entropy). Dialysis is a factor external to the patient that tends to reduce the level of entropy caused by kidney disease. Since entropy can only increase in closed systems, energy and work must be spent to limit the entropy of uremia. This energy should be adapted to the system (patient) and be specifically oriented and personalized. This includes a multidimensional effort to achieve an adequate dialysis that goes beyond small molecular weight solute clearance. It includes a biological plan for recovery of homeostasis and a strategy towards long-term rehabilitation of the patient. Such objectives can be achieved with a combination of technology and innovation to answer specific questions that are still present after 60 years of dialysis history. This change in the individual bioentropy may represent a local exception to natural trends as the patient could be considered an isolated universe responding to the classic laws of thermodynamics. PMID- 23343541 TI - Vascular calcifications, arterial aging and arterial remodeling in ESRD. AB - BACKGROUND: Accelerated arterial aging and inadequate outward arterial remodeling are observed in end-stage renal disease (ESRD) patients. Whether these changes could be closely associated with arterial calcifications has never been investigated. METHODS: 155 ESRD patients and 105 age-, sex-, and blood pressure matched control subjects were included. Common carotid artery (CCA) pressure, diameter, intima-media thickness, elastic modulus, and presence of calcified plaques were measured ultrasonographically. Carotid artery stiffness was determined from simultaneously recorded CCA diameter and stroke changes in diameter and CCA pressure waveforms, obtained by applanation tonometry. RESULTS: Compared with control subjects, ESRD patients had increased CCA systolic and pulse pressures (p < 0.001), larger CCA diameter (p < 0.001) and CCA intima-media thickness (p < 0.01) and similar CCA relative wall thickness. In ESRD patients the arterial remodeling was associated with increased CCA elastic modulus/stiffness (p < 0.001). In ESRD patients the association between CCA elastic modulus and age was characterized by a steeper slope (p = 0.03), but after separation of uremic patients according to the presence of calcifications, the accelerated aging was observed only in calcified subjects. Despite higher CCA systolic and pulse pressures, the CCA relative wall thickness was similar to controls indicating an inadequate pressure-associated remodeling. Moreover, the positive systolic pressure/relative thickness correlation observed in control subjects was lost with paradoxical negative correlation in calcified ESRD patients (p = 0.03). CONCLUSION: These results indicate that, in ESRD patients, accelerated arterial aging and inadequate arterial hypertrophy are closely associated with the calcifications of arterial walls. Inadequate hypertrophy is responsible for high circumferential stress applied on the vessels. PMID- 23343542 TI - Dietary protein restriction and preservation of kidney function in chronic kidney disease. AB - Dietary protein augmentation elicits an increase in single nephron glomerular filtration rate (GFR) and increased transglomerular pressure. This is similar to the hemodynamic response to reduction in renal mass. Among patients and experimental animals with proteinuric renal disease, these changes also cause an increase in glomerular permselectivity, which in experimental animals accelerates loss of renal function. A meta-analysis of a group of prospective randomized trials including over 2,000 patients found a significant effect on reducing dietary protein decreasing the risk of end-stage renal disease or death (defined as renal death). This differs somewhat in the outcomes of clinical trials using intermediate outcomes, such as the Modification of Diet in Renal Disease study that used change in GFR in part because of the initial hemodynamic effect of reduction in GFR mediated by dietary protein restriction. PMID- 23343543 TI - Is lipid management effective for all stages of CKD?. AB - Patients with chronic kidney disease (CKD) suffer from high rates of cardiovascular morbidity and mortality. The general approach to traditional cardiovascular risk factor modification via dyslipidemia control has not been thoroughly tested in patients with all stages of CKD. In this article, we review the evidence for statin therapy in patients at various stages of CKD, including patients with CKD on dialysis and patients with kidney transplants. PMID- 23343545 TI - The MONitoring Dialysis Outcomes (MONDO) initiative. AB - BACKGROUND: Systematic collection and analysis of global hemodialysis patient data may help to improve patient outcomes. METHODS: The MONitoring Dialysis Outcomes (MONDO) initiative comprises data from eight dialysis providers worldwide. Data are combined into one repository. Extensive procedures are employed to merge data across countries and providers. RESULTS: The MONDO database comprises longitudinal data of currently 128,000 hemodialysis patients from 26 countries on five continents. Here we report data from 62,345 incident hemodialysis patients. We found lower catheter rates in South-East Asia and Australia, lower hemoglobin levels in South-East Asia, and a higher prevalence of diabetes in North America. Longitudinal analyses suggest that there is a decline in interdialytic weight gain and serum phosphorus and an increasing neutrophil-to lymphocyte ratio before death in all regions studied. CONCLUSIONS: While organizationally lean and low-cost, MONDO is the largest global dialysis database initiative to date, with a particular focus on high longitudinal data density and geographical diversity. PMID- 23343544 TI - Reasons for the lack of salutary effects of cholesterol-lowering interventions in end-stage renal disease populations. AB - Cardiovascular disease (CVD) is the main cause of premature death in patients with chronic kidney disease (CKD). The underlying mechanisms of CVD in patients with mild to moderate CKD are different from those with end-stage renal disease (ESRD). While serum cholesterol is frequently elevated and contributes to atherosclerosis in many CKD patients, particularly those with nephrotic proteinuria, it is usually normal, even subnormal, in most ESRD patients receiving hemodialysis. CVD in the ESRD population is primarily driven by oxidative stress, inflammation, accumulation of the oxidation-prone intermediate density lipoproteins, chylomicron remnants and small dense low-density lipoprotein particles as well as high-density lipoprotein deficiency and dysfunction, hypertension, vascular calcification, and arrhythmias. Only a minority of hemodialysis patients have hypercholesterolemia which is most likely due to genetic or unrelated factors. In addition, due to peritoneal losses of proteins which simulate nephrotic syndrome, peritoneal dialysis patients often exhibit hypercholesterolemia. Clearly when present, hypercholesterolemia contributes to CVD in the CKD and ESRD population and justifies cholesterol lowering therapy. However, the majority of ESRD patients and a subpopulation of CKD patients with minimal proteinuria have normal or subnormal serum cholesterol levels and do not benefit from and can be potentially harmed by statin therapy. In fact the lack of efficacy of statins in hemodialysis patients has been demonstrated in several randomized clinical trials. This review is intended to provide an overview of the mechanisms responsible for the failure of statins to reduce cardiovascular morbidity and mortality in most ESRD patients and to advocate the adoption of individualized care principles in the management of dyslipidemia in this population. PMID- 23343546 TI - Prevention of sudden cardiac death in dialysis patients: drugs, defibrillators or what else. AB - Death from cardiovascular disease in general and sudden cardiac arrest (SCA) in particular are exponentially proportional to declining renal function and are a major cause of mortality among those with chronic kidney disease (CKD). The greatest risk, however, is reserved for those patients on chronic dialysis. These individuals have an extraordinarily high rate of death, with cardiac disease accounting for 45% and SCA responsible for 25% of all-cause mortality. Once cardiac arrest occurs, survival is extremely poor. Thus, reducing mortality from cardiovascular disease and SCA in dialysis patients is a global health challenge. The main objectives of this review are to elucidate the nature of SCA in the dialysis population, describe possible mechanisms and risk factors, and discuss options for prevention. PMID- 23343547 TI - Emerging clinical evidence on online hemodiafiltration: does volume of ultrafiltration matter?. AB - Online hemodiafiltration (OL-HDF), first described in 1985, is today a widely prescribed treatment modality for end-stage chronic kidney disease (CKD) patients. Other than in the United States, prescription of the treatment modality is widespread with a steady increase since its inception. Indeed, in Western Europe, more CKD patients receive OL-HDF than peritoneal dialysis, hitherto the second most prescribed therapy after conventional hemodialysis. The rise and success of OL-HDF can be attributed to diverse clinical advantages that have been documented over the last two decades. Numerous publications attest to the beneficial effects of OL-HDF in terms of removal of a broad spectrum of uremic toxin, anemia control, phosphate reduction, increased hemodynamic stability and blood pressure control and less dialysis-related amyloidosis, to mention just a few. Significantly, the improvement in these conditions is considered to contribute to improved patient outcomes. Despite the extended worldwide clinical experience, elaborate scientific validation of the principles of the therapy and technical innovations that facilitate its prescription, a point of contention is whether OL-HDF leads to a reduction of mortality rates. A number of observational and retrospective analyses have indicated a survival benefit, while prospective investigations involving small numbers of patients but nevertheless specifically addressing survival have further supplied evidence of improved survival with OL HDF. The quest for large-scale, multicenter prospective randomized controlled trials examining patient survival led to the CONTRAST and the Turkish OL-HDF trials. Both trials have been concluded and published recently. In this chapter, we document and assess the key investigations that have examined the impact of OL HDF on patient outcome and survival. Based on the findings of previous analyses and of the two recently concluded trials, it appears that the volume of convection appears to be decisive towards the survival benefit accredited to OL HDF. We consider the implications of this new evidence. PMID- 23343548 TI - Absolute blood volume in hemodialysis patients: why is it relevant, and how to measure it?. AB - Intradialytic hypotension (IDH) is the most common complication during hemodialysis and is associated with significant morbidity. It occurs as a consequence of a reduction in blood volume during ultrafiltration. Today, devices for monitoring relative blood volume (i.e. the intradialytic blood volume as a fraction of the blood volume at the start of the dialysis treatment) are routinely available and have been used to analyze the relationship between changes in relative blood volume and the occurrence of IDH in an attempt to derive critical thresholds that, when observed, would help avoid hypotensive episodes during the treatment. However, the results have been unsatisfactory in many patients. Here we illustrate the importance of absolute blood volume in hemodialysis patients, summarize the acute physiologic mechanisms involved in the preservation of adequate circulation during ultrafiltration, and outline why hemodialysis patients are often particularly vulnerable to reductions in blood volume. We then discuss the shortcomings of relative blood volume measurements, make a case for the superiority of absolute blood volume measurements, and introduce the reader to a mathematical concept that allows relative blood volume devices to be used for the estimation of absolute blood volume. Finally, we discuss the implications of absolute blood volume beyond IDH and propose a paradigm shift in the approach to dry weight attainment. PMID- 23343549 TI - New hemodialysis access system. AB - A new blood access system for hemodialysis (HD) addresses the major shortcomings of current accessing techniques and helps overcome patient adversity with available choices. The system uses new methods, devices and compositions comprising several novel elements: (1) totally implanted port, elementally simple in design, small and robust with improved safety features, (2) engineered transcutaneous tissue tract (TTT) to precisely guide a tubular conduit to engage the implanted port, (3) viscoelastic gel prophylaxis for internal passages and surface interfaces of the port and TTT, (4) the tool kit aligns the TTT with the port and initiates TTT formation at the time of port placement, (5) an integrated external bloodline circuit comprising the interface between the implanted port and HD machine which can be reused for several treatment sessions. The system provides bloodless, painless, and fail-safe connections with redundant sealing along the complete blood path. It is substantially more robust than current access options and more convenient to use. TTT construct is durable, permanently aligned and fixed to the port enabling non-compromised tissue integrity during access penetration. A bullet-pointed tubular assembly enters and passes through the TTT confining the tubular device to advance towards the port and entering it to engage a solid tactually sensed stop indicating the correct position. The system may be used within a few days of port placement. The access is unobtrusive and preserves patient self-image. PMID- 23343550 TI - Peritoneal dialysis in the pediatric intensive care unit setting: techniques, quantitations and outcomes. AB - Acute kidney injury (AKI) is a common complication in pediatric and neonatal intensive care units (ICU). Renal replacement therapy (RRT) is frequently needed in children in whom supportive therapy is not enough to satisfy their metabolic demands or to be able to provide adequate nutrition. The decision to begin dialysis should not be delayed since experience in infants shows that the shorter the time from the insult to the beginning of dialysis, the higher the survival rate. As the use of continuous RRT in pediatric patients in the ICU has almost tripled, the use of peritoneal dialysis (PD) and intermittent hemodialysis has markedly decreased. The patient's age seems to be the most important factor influencing the decision on the choice of dialysis modality. PD is still the most common modality used in patients younger than 6 years of age. The relatively low cost, technical simplicity, no need for anticoagulation or placement of central venous catheters, and excellent tolerance in hemodynamically unstable patients are among the most significant advantages of PD. Much controversy exists regarding the adequacy of PD in hypercatabolic patients in the ICU. Nonetheless, when Kt/V has been applied to acutely ill children, it has been shown that PD can provide adequate clearances for most infants. The outcomes of critically ill patients with AKI treated with PD are comparable to other dialysis modalities. Therefore, the decision about dialysis modality should be based on local expertise, resources available, and patient's clinical status. PMID- 23343551 TI - New diagnostic tests and new therapies for glomerular diseases. AB - There has recently been considerable progress in our understanding of the pathology and mechanisms of a number of primary glomerulopathies. However, without parallel advancement in both our diagnostic skills and treatment methods, such advances cannot be translated into clinical progress. Fortunately, a number of new promising diagnostic tests are being evaluated in patients with a variety of primary glomerulopathies including focal segmental glomerulosclerosis membranous nephropathy, IgA nephropathy, and C3 glomerulopathies. Likewise, a number of new therapeutic interventions are available to treat these entities, including the pituitary hormone ACTH, the monoclonal antibody rituximab, and the monoclonal blocker of the fifth component of complement, eculizumab. All three are already FDA-approved for at least one glomerular disease. This article will discuss these newer diagnostic tests and therapies as well as their potential roles in patients with glomerular diseases and where they fit in with the rest of our therapeutic armamentarium in treating patients with glomerular diseases. PMID- 23343552 TI - Multifaceted hemolytic uremic syndrome in pediatrics. AB - Hemolytic uremic syndromes can have devastating consequences in childhood. The common feature of a microangiopathic hemolytic anemia and thrombocytopenia associated with varying degrees of renal injury often creates diagnostic confusion. The inability to arrive at a definitive diagnosis quickly can lead to a delay in initiating renal-preserving and sometimes life-saving treatment. Currently, both the treatment plan and the prognosis vary substantially according to the presumed diagnosis. The availability of anti-complement therapy makes differentiating the cause of the hemolytic uremic syndrome particularly critical. Therefore, it is imperative that consideration be given to each of the possible syndromes at presentation in order to facilitate correct diagnosis and development of an appropriate treatment strategy for both the acute phase and for the long-term care of the patient. PMID- 23343553 TI - How can we improve the solute and fluid transport prescriptions in hemodialysis to improve patient outcomes?. AB - Improvements in the dialysis prescription can only be achieved by changes in solute and water transport which provide better control of the metabolic uremic abnormalities that are amenable to dialysis. The key abnormalities identified here are protein catabolites, fluid and electrolyte balance, calcium and phosphorus balance and bone metabolism and acid-base balance. The history of the dialysis prescription is reviewed and changes which might improve the control of these metabolic systems are described. This review concludes there is no support for the recommendation of the routine application of long treatment time and routine use of hemodiafiltration. PMID- 23343554 TI - Effects of dialysate flow configurations in continuous renal replacement therapy on solute removal: computational modeling. AB - BACKGROUND/AIMS: Continuous renal replacement therapy (CRRT) is commonly used for critically ill patients with acute kidney injury. During treatment, a slow dialysate flow rate can be applied to enhance diffusive solute removal. However, due to the lack of the rationale of the dialysate flow configuration (countercurrent or concurrent to blood flow), in clinical practice, the connection settings of a hemodiafilter are done depending on nurse preference or at random. METHODS: In this study, we investigated the effects of flow configurations in a hemodiafilter during continuous venovenous hemodialysis on solute removal and fluid transport using computational fluid dynamic modeling. We solved the momentum equation coupling solute transport to predict quantitative diffusion and convection phenomena in a simplified hemodiafilter model. RESULTS: Computational modeling results showed superior solute removal (clearance of urea: 67.8 vs. 45.1 ml/min) and convection (filtration volume: 29.0 vs. 25.7 ml/min) performances for the countercurrent flow configuration. Countercurrent flow configuration enhances convection and diffusion compared to concurrent flow configuration by increasing filtration volume and equilibrium concentration in the proximal part of a hemodiafilter and backfiltration of pure dialysate in the distal part. In clinical practice, the countercurrent dialysate flow configuration of a hemodiafilter could increase solute removal in CRRT. Nevertheless, while this configuration may become mandatory for high-efficiency treatments, the impact of differences in solute removal observed in slow continuous therapies may be less important. Under these circumstances, if continuous therapies are prescribed, some of the advantages of the concurrent configuration in terms of simpler circuit layout and simpler machine design may overcome the advantages in terms of solute clearance. CONCLUSION: Different dialysate flow configurations influence solute clearance and change major solute removal mechanisms in the proximal and distal parts of a hemodiafilter. Advantages of each configuration should be balanced against the overall performance of the treatment and its simplicity in terms of treatment delivery and circuit handling procedures. PMID- 23343555 TI - Purity and stability of online-prepared hemodiafiltration fluid after storage. AB - BACKGROUND/AIMS: Previous studies have suggested that online hemodiafiltration (OL-HDF) fluid can be used as dialysate for continuous renal replacement therapies, and thus HDF costs can be reduced. The aims of this study were to determine the purity of OL-HDF fluid and to verify the stability of the electrolyte composition and acid-base balance during its storage. METHODS: OL-HDF fluid was collected in 70 individual bags and stored for up to 7 days. The following tests were performed daily in 10 bags: natural visible precipitation (macrocrystallization), sample collection for chemical analysis and fluid culture, limulus amebocyte lysate endotoxin test, standard culture of NALGENE(r) filters after passing of the fluid, and molecular analysis of bacterial DNA. RESULTS: The values of pH and pCO(2) showed a significant change starting at 24 h (p < 0.001); after 72 h, their values were beyond the measurable range. Coefficient of variation for pCO(2) was as high as 25.7%. Electrolyte composition (Na(+), K(+), Cl(-), Ca(2+) and glucose) showed a statistically significant difference over time (p < 0.05); however, their coefficients of variation were low (1.7, 1.4, 0.6, 2.3 and 0.9%, respectively), which might not be considered clinically significant. Negative results were obtained at all points by fluid and filter cultures, endotoxin test and molecular analysis. No macrocrystallization was observed at any time point. CONCLUSIONS: We demonstrate the microbiological purity of OL-HDF fluid stored for up to 7 days. The electrolyte composition was stable, except for a relevant change in pCO(2) and consequently in pH (first noted at 24 h), emphasizing the need to reassess the acid-base balance in multilayer plastic bags in future studies. PMID- 23343556 TI - Effect of percutaneous ventricular assist devices on renal function. AB - Ventricular assist devices (VADs) are used to improve the systemic circulation and to decrease ventricular loading in patients with hemodynamic instability that is refractory to pharmacologic therapies. During an acute critical event, percutaneous devices are preferred because of their rapid deployment, since implantable devices require more extensive procedures. Implantable devices are used for patients with established end-stage heart failure as a bridge to heart transplantation, recovery or destination therapy. This report reviews mechanical principles and clinical studies regarding percutaneous VAD to address their potential renal effects. Since the focus of this study is set on devices that are dedicated to cardiac support only, extracorporeal membrane oxygenation systems are not included. PMID- 23343557 TI - Hydrodynamic analysis of the miniaturized hemofilter for a wearable ultrafiltration device. AB - BACKGROUND/AIMS: Using a small wearable hemofiltration device, heart failure (HF) patients may have the possibility of eliminating acute hemodynamic changes and the freedom from spending many hours attached to a large stationary treatment system. METHODS: We developed a miniaturized hemofilter for a vest-type wearable ultrafiltration device for the treatment of overhydration and congestive HF. In this study, we investigated the feasibility of the newly developed hemofilter based on dynamic CT imaging and in vitro evaluation of hydrodynamic properties. RESULTS: The dynamic CT imaging technique showed development of uniform flow distribution and effective bubble removal in the hemofilter. Hydrodynamic performance of the hemofilter was also acceptable with a stable pressure drop in the blood compartment and ultrafiltration profiles in the intended operating ranges for the treatment of congestive HF patients. CONCLUSIONS: The newly developed miniaturized hemofilter for a wearable ultrafiltration device meets the technical requirements of wearable medical devices and its structural design enables uniform blood flow distribution and stable hydrodynamics during operation. PMID- 23343558 TI - Clinical evaluation of a model for prediction of end-dialysis systemic ionized calcium concentration in citrate hemodialysis. AB - BACKGROUND/AIM: Citrate anticoagulation in hemodialysis (HD) is increasingly drawing attention in the nephrology community. One of the major deterrents to a more widespread use are the monitoring requirements for fear of systemic calcium derangements. Means of accurately predicting systemic ionized calcium (iCa) may help to overcome this challenge. We have previously presented a mathematical model of regional citrate anticoagulation (RCA) to address this need. Here, we present a refined model and show results in an independent validation cohort of maintenance HD patients on Citrasate(r), a calcium- and citrate-containing dialysate. METHODS: A hybrid RCA model was developed, comprising the previously published 'native' RCA model and a statistical correction based on levels of alkaline phosphatase as a marker of bone turnover. The model was validated in 120 patients on Citrasate, a dialysate containing 0.8 mmol/l citrate and 1.125 mmol/l calcium. Systemic iCa was measured at the beginning and end of one HD treatment in each subject. Serum iCa predictions were compared between our previously published model and the new hybrid model. RESULTS: On average, the hybrid model predicted end-HD systemic iCa with an error (predicted - measured) of 0.028 mmol/l, compared to -0.051 mmol/l with the previously published model. There were only 4 subjects out of the 120 analyzed in whom the prediction error was <-0.1 mmol/l, and only 6 in whom the error was >+0.1 mmol/l (max: +0.13 mmol/l). CONCLUSION: This study demonstrates that the novel hybrid model is an improvement over the previously published model and that it is capable of predicting end dialysis systemic iCa levels with improved accuracy and precision even in a citrate dialysis setting which was much different from the original derivation cohort. PMID- 23343559 TI - Genomics and biological activity of neutrophil gelatinase-associated lipocalin in several clinical settings. AB - Recent literature has shown that neutrophil gelatinase-associated lipocalin (NGAL) is one of the most interesting and promising biomarkers in case of acute kidney injury. However, several studies indicated that this protein may be applied beyond the boundaries of renal pathophysiology and may be used in other pathophysiological settings since it is also expressed in neutrophils, and respiratory, bowel and prostate epithelia. In this review, we report NGAL genomics and biology and its possible use in several clinical settings. In particular, we review the genomic organization of the NGAL gene, the lipocalin family structure, the interaction between NGAL and ligands, and the induction and expression of NGAL in different conditions. PMID- 23343561 TI - Role of PRRT2 in common paroxysmal neurological disorders: a gene with remarkable pleiotropy. AB - Mutations in the gene PRRT2 encoding proline-rich transmembrane protein 2 have recently been identified as the cause of three clinical entities: benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis (ICCA) syndrome, and paroxysmal kinesigenic dyskinesia (PKD). Patients with ICCA have both BFIE and PKD and families with ICCA may contain individuals who exhibit all three phenotypes. These three phenotypes were all mapped by linkage analyses to the pericentromeric region of chromosome 16, and were hypothesised to have the same genetic basis due to the co-occurrence of the disorders in some families. Despite considerable effort, the gene or genes for BFIE, ICCA, and PKD were not identified for many years after the linkage region was identified. Mutations in the gene PRRT2 were identified in several Chinese families with PKD, suggesting that the gene may also be responsible for ICCA and BFIE in families linked to the chromosome 16 locus. This was demonstrated to be the case, with the majority of families with ICCA and BFIE found to have PRRT2 mutations. The vast majority of these mutations are truncating and are predicted to lead to haploinsufficiency. PRRT2 is a largely uncharacterised protein. It is expressed in the brain and has been demonstrated to interact with SNAP-25, a component of the molecular machinery involved in the release of neurotransmitters at the presynaptic membrane. Therefore, the PRRT2 protein may play a role in this process. However, the molecular mechanisms underlying the remarkable pleiotropy associated with PRRT2 mutations have still to be determined. PMID- 23343562 TI - TBC1D24 truncating mutation resulting in severe neurodegeneration. AB - BACKGROUND: Recessive TBC1D24 gene mutations have been described in two families: an Italian family afflicted with familial infantile myoclonic epilepsy, and an Arab family with focal epilepsy and intellectual disability syndrome. The patients in the Italian family were compound heterozygous for two mutations, whereas those in the Arab family were homozygotes. All three mutations were missense and were determined to be loss of function. We conducted a gene search in a family we previously reported with a severe, lethal epileptic encephalopathy mapping at 16pter-p13.3. METHODS: Exome sequencing and subsequent Sanger sequencing of TBC1D24 exons were conducted. Sanger sequencing was used to determine the structures of novel mRNA isoforms. The abundance of mRNA isoforms was assessed via real-time quantitative PCR. RESULTS: A homozygous two-base pair deletion leading to premature termination and two novel TBC1D24 transcript isoforms were identified. Isoform 1 is predominant in the brain whereas isoform 2 is predominant in non-neural tissues, except for muscle. CONCLUSIONS: The very severe phenotype in our patients can be attributed to mutation severity; however, the mutation does not affect isoform 2, whereas the three previously reported mutations do. These findings expand the spectrum of the TBC1D24 mutation phenotype and the transcript isoforms. PMID- 23343563 TI - Obstructive sleep apnea screening by integrating snore feature classes. AB - Obstructive sleep apnea (OSA) is a serious sleep disorder with high community prevalence. More than 80% of OSA suffers remain undiagnosed. Polysomnography (PSG) is the current reference standard used for OSA diagnosis. It is expensive, inconvenient and demands the extensive involvement of a sleep technologist. At present, a low cost, unattended, convenient OSA screening technique is an urgent requirement. Snoring is always almost associated with OSA and is one of the earliest nocturnal symptoms. With the onset of sleep, the upper airway undergoes both functional and structural changes, leading to spatially and temporally distributed sites conducive to snore sound (SS) generation. The goal of this paper is to investigate the possibility of developing a snore based multi-feature class OSA screening tool by integrating snore features that capture functional, structural, and spatio-temporal dependences of SS. In this paper, we focused our attention to the features in voiced parts of a snore, where quasi-repetitive packets of energy are visible. Individual snore feature classes were then optimized using logistic regression for optimum OSA diagnostic performance. Consequently, all feature classes were integrated and optimized to obtain optimum OSA classification sensitivity and specificity. We also augmented snore features with neck circumference, which is a one-time measurement readily available at no extra cost. The performance of the proposed method was evaluated using snore recordings from 86 subjects (51 males and 35 females). Data from each subject consisted of 6-8 h long sound recordings, made concurrently with routine PSG in a clinical sleep laboratory. Clinical diagnosis supported by standard PSG was used as the reference diagnosis to compare our results against. Our proposed techniques resulted in a sensitivity of 93+/-9% with specificity 93+/-9% for females and sensitivity of 92+/-6% with specificity 93+/-7% for males at an AHI decision threshold of 15 events/h. These results indicate that our method holds the potential as a tool for population screening of OSA in an unattended environment. PMID- 23343564 TI - Stepwise screening of atrial fibrillation in a 75-year-old population: implications for stroke prevention. AB - BACKGROUND: Atrial fibrillation (AF) is a frequent source of cardiac emboli in patients with ischemic stroke. AF may be asymptomatic and therefore undiagnosed. Screening for silent AF seems suitable in risk populations, however little is known on the yield and cost-effectiveness of such screening. METHODS AND RESULTS: All inhabitants in the municipality of Halmstad, Sweden aged 75 to 76 years were invited to a stepwise screening program for AF. As a first step, participants recorded a 12-lead ECG and reported their relevant medical history. Those with sinus rhythm on 12-lead ECG, no history of AF, and >=2 risk factors according to CHADS(2) were invited to a 2-week recording period using a hand-held ECG and asked to record 20 or 30 seconds twice daily and if palpitations occurred. One thousand, three hundred thirty inhabitants were invited, of whom 848 (64%) participated. Previously undiagnosed silent AF was found in 10 (1%) among 848 individuals who recorded 12-lead ECG. Among 81 patients with known AF, 35 (43%) were not on oral anticoagulation treatment. Among 403 persons with >=2 risk factors for stroke, who completed the hand-held ECG event recording, 30 (7.4%) were diagnosed with paroxysmal AF. Thus 75/848 (9%) of the screened population were candidates for new oral anticoagulation treatment, of those 57 actually started oral anticoagulation treatment. CONCLUSIONS: Stepwise risk factor stratified AF screening in a 75-year-old population yields a large share of candidates for oral anticoagulation treatment on AF indication. PMID- 23343565 TI - Binary diffusion coefficients for mixtures of ionic liquids [EMIM][N(CN)2], [EMIM][NTf2], and [HMIM][NTf2] with acetone and ethanol by dynamic light scattering (DLS). AB - Mutual diffusivities for binary mixtures of the ionic liquids (ILs) [EMIM][N(CN)2] (1-ethyl-3-methylimidazolium dicyanimide), [EMIM][NTf2] (1-ethyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide), and [HMIM][NTf2] (1-hexyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide) with acetone and ethanol were studied in dependence on composition in the temperature range from 283.15 to 323.15 K, applying dynamic light scattering (DLS). The influence of experimental parameters on the achievable uncertainties was analyzed to ensure the acquisition of accurate data in adequate measurement times. For all probed systems, increasing binary diffusion coefficients were found for increasing temperatures. The systematic variation of anion and cation of the investigated ILs as well as a comparison with the literature data demonstrates the considerable influence of different ions on the resulting binary diffusion coefficients. Mutual diffusivities were found to be lower for the mixtures with ethanol than for those with acetone, which could be related to the formation of hydrogen bonds between ethanol and the ions. Most of the investigated IL solvent mixtures show increasing binary diffusion coefficients with increasing solvent concentration. For the mixtures of [EMIM][NTf2] with ethanol, however, a minimum of the mutual diffusivities was found in the ethanol mole fraction range from 0.7 to 0.8, which may hint at the vicinity of a critical demixing point. The viscosity of the pure ILs turned out to be no reliable indicator for the mutual diffusivity in mixtures with the same solvent. PMID- 23343566 TI - 3-Fluoro-4-hexylthiophene as a building block for tuning the electronic properties of conjugated polythiophenes. AB - 3-Fluoro-4-hexylthiophene has been prepared by a synthetic route involving perbromination of 3-hexylthiophene followed by protection of the 2- and 5 positions of thiophene by trimethylsilyl groups and bromine/fluorine exchange. As expected, 3-hexyl-4-fluorothiophene oxidizes at a higher potential than 3 hexylthiophene; however, all attempts to electropolymerize this new thiophenic monomer have remained unsuccessful. Three terthienyls containing 3 hexylthiophene, 3-fluoro-4-hexylthiophene, and 3-bromo-4-hexylthiophene as the median group have been synthesized and used as substrates for electropolymerization. The electronic properties of the starting terthienyls and the resulting polymers have been analyzed by cyclic voltammetry and UV-vis spectroscopy, and the effects of substitution of the median thiophene ring are discussed. PMID- 23343567 TI - Large pancreatic mucinous cystic neoplasm during pregnancy: what should be done?. AB - Pancreatic mucinous cystic neoplasms are uncommon and their occurrence in pregnancy is extremely rare. The authors report the unique case of a newborn weighing 3,620 g, delivered vaginally with no complications by a patient with a large 'silent' pancreatic mucinous cystic neoplasms, and analyze the very few other reports. With no available protocol, this case highlights an interesting dilemma on the management of pregnancy and delivery as well on the timing of pancreatic surgery. Despite its limitations, MRI remains the most accurate investigation either for differentiating the mucinous from nonmucinous cysts or for evaluating the malignancy, but echography is also very useful. Without symptoms, all low-grade malignant potential tumors, independent of the moment of their diagnosis during pregnancy, should be resected 2-3 months after delivery and we believe that the best option is a term vaginal birth, even in the presence of a large cyst and large fetus. On the contrary, all high-grade malignant potential tumors, discovered in the first two trimesters of pregnancy should be resected during the second trimester, and followed by a vaginal delivery at term. If high-grade malignant potential tumor is diagnosed in the third trimester, an early vaginal delivery followed by surgery is recommended. Finally, the patient's preference is crucial. PMID- 23343568 TI - Regulatory light chain mutants linked to heart disease modify the cardiac myosin lever arm. AB - Myosin is the chemomechanical energy transducer in striated heart muscle. The myosin cross-bridge applies impulsive force to actin while consuming ATP chemical energy to propel myosin thick filaments relative to actin thin filaments in the fiber. Transduction begins with ATP hydrolysis in the cross-bridge driving rotary movement of a lever arm converting torque into linear displacement. Myosin regulatory light chain (RLC) binds to the lever arm and modifies its ability to translate actin. Gene sequencing implicated several RLC mutations in heart disease, and three of them are investigated here using photoactivatable GFP tagged RLC (RLC-PAGFP) exchanged into permeabilized papillary muscle fibers. A single-lever arm probe orientation is detected in the crowded environment of the muscle fiber by using RLC-PAGFP with dipole orientation deduced from the three spatial dimension fluorescence emission pattern of the single molecule. Symmetry and selection rules locate dipoles in their half-sarcomere, identify those at the minimal free energy, and specify active dipole contraction intermediates. Experiments were performed in a microfluidic chamber designed for isometric contraction, total internal reflection fluorescence detection, and two-photon excitation second harmonic generation to evaluate sarcomere length. The RLC-PAGFP reports apparently discretized lever arm orientation intermediates in active isometric fibers that on average produce the stall force. Disease-linked mutants introduced into RLC move intermediate occupancy further down the free energy gradient, implying lever arms rotate more to reach stall force because mutant RLC increases lever arm shear strain. A lower free energy intermediate occupancy involves a lower energy conversion efficiency in the fiber relating a specific myosin function modification to the disease-implicated mutant. PMID- 23343569 TI - In vitro evaluation of biomimetic chitosan-calcium phosphate scaffolds with potential application in bone tissue engineering. AB - This work reports on the physicochemical properties and in vitro cytotoxicity assessment of chitosan-calcium phosphate (Cs-CP) scaffolds for bone tissue engineering, which were synthesized by a novel biomimetic co-precipitation method. X-ray diffraction (XRD) along with scanning electron microscopy (SEM) analysis confirmed the porous morphology of the scaffolds and the amorphous nature of the inorganic phase with different crystallite sizes and the formation of various forms of calcium phosphate. Compressive mechanical testing revealed that the Young's modulus of the biomaterials is in the range of human trabecular bone. In vitro tests were performed on the biomaterials for up to 14 days to study the behavior of the osteoblast-like human cell line (MG63), primary human osteoblasts (HOS) and human dermal microvascular endothelial cells (HDMEC). The cytotoxicity was evaluated by the MTS assay for cell metabolism and the detection of membrane integrity (lactate dehydrogenase-LDH release). An expression of the vascular endothelial growth factor (VEGF) in the cell supernatants was quantified by ELISA. Cell viability gave values close to untreated controls for MG63 and HOS, while in the case of HDMEC the viability after 2 weeks in the cell culture was between 80-90%. The cytotoxicity induced by the Cs-CP scaffolds on MG63, HOS and HDMEC in vitro was evaluated by the amount of LDH released, which is a sensitive and accurate marker for cellular toxicity. The increased levels of VEGF obtained in the osteoblast culture highlights its important role in the regulation of vascularization and bone remodeling. The biological responses of the Cs-CP scaffolds demonstrate a similar proliferation and differentiation characteristics of the cells comparable to the controls. These results reveal that biomimetic Cs-CP composite scaffolds are promising biomaterials for bone tissue engineering; their in vivo response remains to be tested. PMID- 23343570 TI - Kyasanur Forest disease, India, 2011-2012. AB - To determine the cause of the recent upsurge in Kyasanur Forest disease, we investigated the outbreak that occurred during December 2011-March 2012 in India. Male patients >14 years of age were most commonly affected. Although vaccination is the key strategy for preventing disease, vaccine for boosters was unavailable during 2011, which might be a reason for the increased cases. PMID- 23343571 TI - Computational evaluation of the Traceback Method. AB - Several models of language acquisition have emerged in recent years that rely on computational algorithms for simulation and evaluation. Computational models are formal and precise, and can thus provide mathematically well-motivated insights into the process of language acquisition. Such models are amenable to robust computational evaluation, using technology that was developed for Information Retrieval and Computational Linguistics. In this article we advocate the use of such technology for the evaluation of formal models of language acquisition. We focus on the Traceback Method, proposed in several recent studies as a model of early language acquisition, explaining some of the phenomena associated with children's ability to generalize previously heard utterances and generate novel ones. We present a rigorous computational evaluation that reveals some flaws in the method, and suggest directions for improving it. PMID- 23343573 TI - Outcome of cervical cancer patients with single-node compared with no nodal involvement treated with radical hysterectomy and pelvic lymphadenectomy. AB - OBJECTIVE: To evaluate disease-free survival (DFS) after radical hysterectomy and pelvic lymphadenectomy (RHPL) among early-stage cervical cancer patients with single-node involvement versus patients with no nodal involvement. METHODS: A retrospective review was conducted of the medical records of 843 patients undergoing RHPL at Chiang Mai University Hospital, Thailand, between January 1, 2002, and December 31, 2008. Neoadjuvant chemotherapy was administered when the operative schedule was more than 1 month after diagnosis and adjuvant chemoradiation was administered to high-risk patients. Five subgroups were defined on the basis of pelvic node involvement: group A (0 nodes; n=706), group B (1 node; n=65), group C (2 nodes; n=38), group D (3 nodes; n=13), and group E (>=4 nodes; n=21). RESULTS: The 5-year DFS was comparable for groups A and B (94.3% versus 92.1%; P=0.454). In groups C, D, and E, the 5-year DFS was 85.9%, 75.0%, and 61.8%, respectively. The survival outcomes for groups A and B were significantly different from those of the other 3 groups (P<0.001). CONCLUSION: Cervical cancer patients with single-node involvement had comparable survival outcomes to those without nodal metastases; however, patients with multiple node involvement had reduced DFS. PMID- 23343574 TI - Interaction of human synovial phospholipase A2 with mixed lipid bilayers: a coarse-grain and all-atom molecular dynamics simulation study. AB - Human secreted phospholipase A2s have been shown to promote inflammation in mammals by catalyzing the first step of the arachidonic acid pathway by breaking down phospholipids, producing fatty acids, including arachidonic acid. They bind to the membrane water interface to access their phospholipid substrates from the membrane. Their binding modes on membrane surfaces are regulated by diverse factors, including membrane charge, fluidity, and heterogeneity. The influence of these factors on the binding modes of the enzymes is not well understood. Here we have studied several human synovial phospholipase A2 (hs-PLA2)/mixed bilayer systems through a combined coarse-grain and all-atom molecular dynamics simulation. It was found that hydrophobic residues Leu2, Val3, Ala18, Leu19, Phe23, Gly30, and Phe63 that form the edge of the entrance of the hydrophobic binding pocket in hs-PLA2 tend to penetrate into the hydrophobic area of lipid bilayers, and more than half of the total amino acid residues make contact with the lipid headgroups. Each enzyme molecule forms 19-38 hydrogen bonds with the bilayer to which it binds, most of which are with the phosphate groups. Analysis of the root-mean-square deviation (rmsd) shows that residues Val30-Thr40, Tyr66 Gln80, and Lys107-Arg118 have relatively large rmsds during all-atom molecular dynamics simulations, in accordance with the observation of an enlarged entrance region of the hydrophobic binding pocket. The amino acid sequences forming the entrance of the binding pocket prefer to interact with lipid molecules that are more fluid or negatively charged, and the opening of the binding pocket would be larger when the lipid components are more fluid. PMID- 23343572 TI - HIV testing and care in Burkina Faso, Kenya, Malawi and Uganda: ethics on the ground. AB - BACKGROUND: The ethical discourse about HIV testing has undergone a profound transformation in recent years. The greater availability of antiretroviral therapy (ART) has led to a global scaling up of HIV testing and counseling as a gateway to prevention, treatment and care. In response, critics raised important ethical questions, including: How do different testing policies and practices undermine or strengthen informed consent and medical confidentiality? How well do different modalities of testing provide benefits that outweigh risks of harm? To what degree do current testing policies and programs provide equitable access to HIV services? And finally, what lessons have been learned from the field about how to improve the delivery of HIV services to achieve public health objectives and protections for human rights? This article reviews the empirical evidence that has emerged to answer these questions, from four sub-Saharan African countries, namely: Burkina Faso, Kenya, Malawi and Uganda. DISCUSSION: Expanding access to treatment and prevention in these four countries has made the biomedical benefits of HIV testing increasingly clear. But serious challenges remain with regard to protecting human rights, informed consent and ensuring linkages to care. Policy makers and practitioners are grappling with difficult ethical issues, including how to protect confidentiality, how to strengthen linkages to care, and how to provide equitable access to services, especially for most at risk populations, including men who have sex with men. SUMMARY: The most salient policy questions about HIV testing in these countries no longer address whether to scale up routine PITC (and other strategies), but how. Instead, individuals, health care providers and policy makers are struggling with a host of difficult ethical questions about how to protect rights, maximize benefits, and mitigate risks in the face of resource scarcity. PMID- 23343575 TI - Production of zinc substituted hydroxyapatite using various precipitation routes. AB - Substituted hydroxyapatites have been investigated for use as bone grafts and have been investigated for many years. Zinc is of interest due to its potential to reduce bone resorption and antibacterial properties. However, it has proven problematic to substitute biologically significant levels of zinc into the crystal structure through wet chemical routes, whilst retaining the high temperature phase stability required for processing. The aim of this study is to investigate two different precipitation routes used to synthesize zinc substituted hydroxyapatite and to explore the effects of ammonia used in the reactions on the levels of zinc substituted into the crystal lattice. It was found that considerable amounts of ammonia are required to maintain a pH sufficiently high for the production of stoichiometric hydroxyapatite using a reaction between calcium nitrate, zinc nitrate and ammonium phosphate. X-ray fluorescence analysis showed that a significant proportion of the zinc added did not substitute into the hydroxyapatite lattice. Fourier transform infrared spectroscopy revealed the existence of a zinc-ammonia complex that, it is proposed, inhibits zinc substitution for calcium. It was found that by reacting orthophosphoric acid with calcium nitrate and zinc nitrate, the volume of ammonia required in the reaction was reduced and higher levels of zinc substitution were achieved, with up to 0.58 wt% incorporated into the hydroxyapatite lattice. The resulting products were found to be stoichiometric hydroxyapatite and did not appear to contain any extraneous calcium phosphate phases after heat treatment up to 1100 degrees C. X-ray diffraction and Rietveld analysis revealed that the effect of substituting zinc into the HA lattice was to decrease the a-lattice parameter whilst increasing the c-lattice. Transmission electron microscopy also showed that the incorporation of zinc reduced both the length and width of the precipitated crystals. PMID- 23343576 TI - Complementary charge trapping and ionic migration in resistive switching of rare earth manganite TbMnO3. AB - Perovskite rare-earth manganites like TbMnO3 exhibit rich magnetic and electric phases, providing opportunities for next-generation multifunctional devices. Here, we report the nonvolatile bipolar switching of resistance and capacitance in TbMnO3 thin films grown on conducting Nb:SrTiO3 substrates. The device shows an ON/OFF resistance ratio of ~1 * 104, and the resistive switching is accompanied by a frequency-dependent capacitance switching. Detailed analysis of the conduction mechanisms reveals that the migration of oxygen vacancies and the charge trapping/detrapping at the heterojunction interface play important and complementary roles in the switching behaviors. Our results suggest that both electronic and ionic processes should be considered in order to elucidate the conduction mechanisms and the switching behaviors in such heterostructures made of complex oxides. PMID- 23343577 TI - In utero hematopoietic stem cell transplantation in canines: exploring the gestational age window of opportunity to maximize engraftment. AB - OBJECTIVE: In utero hematopoietic stem cell transplantation (IUHSCT) is a promising therapy for a variety of congenital disorders. Our objective was to determine the optimal time in gestation for IUHSCT in a canine model. METHODS: IUHSCT was performed in day 31-50 (term 63) fetal canines with CD34+ cells isolated from paternal bone marrow at doses of 0.09-3.4 * 109 CD34+ cells/kg and T cells (CD3+/CD5+) from paternal blood at 0.11-1.1 * 109 cells/kg. Engraftment was assayed using PCR-based chimerism analysis (SRY gene detection for female recipients, and unique microsatellite loci for both sexes). RESULTS: Microchimerism and chimerism were present in multiple recipients across most gestational ages at transplant. Maximal engraftment was obtained in hematopoietic tissues in transplants performed at 42 days. At extremes of recipient gestational age, minimal to no engraftment was seen. CONCLUSION: Fetal age at the time of IUHSCT plays an important role in achieving engraftment in our canine model. PMID- 23343578 TI - Gastroduodenal major haemorrhages in critical patients: an original surgical technique. AB - AIM: Upper gastrointestinal bleeding represents today a serious pathology with two important problems: mortality and correct management. Our study is a review of recent and past licterature about causes, diagnosis and treatment of upper gastrointestinal bleeding. PERSONAL EXPERIENCE: The Authors describe an original surgical technique in treating patients with gastroduodenal haemorrhages and critical circulatory-coagulative conditions. Any surgical resective procedure could be absolutely inacceptable for the rates in morbility and mortality in these absolutely instable patients. We approached the problem with a control damage surgery by endoluminal packing of the stomach or the duodenum. PMID- 23343579 TI - Are modern contraceptives acceptable to people and where do they source them from across Nigeria? AB - BACKGROUND: Understanding the extent that different modern contraceptives are acceptable to different populations groups and where they get the commodities from will help in developing specific interventions that will help to scale-up the availability of the contraceptives. METHODS: The study took place in urban and rural sites in six states across Nigeria. Data on acceptability and sources of the contraceptives was collected from at least 770 randomly selected mostly female householders from each state respectively using a questionnaire. Acceptability of the different contraceptives was scored by the respondents on a scale of 1 (lowest) to 10 (highest). The relationships between acceptability and sources of the contraceptives with socio-economic status and geographic location of the respondents were examined. RESULTS: The use of modern contraceptives in general was acceptable to 87% of the respondents. Male condom was the most acceptable means of contraceptive with an average score of 5.0. It was followed by implants with and oral contraceptive pill with average scores of 4.0, whilst IUD was the least acceptable with an average score of 2.9. The private sector was the major source of contraceptives to different population groups. Both male and female condoms were mostly procured from patent medicine dealers (PMD) and pharmacy shops. Intra Uterine Devices (IUDs) and implants were mostly sourced from public and private hospitals in the urban areas, whilst injectibles were mostly sourced from private hospitals. Oral contraceptives were mostly sourced from pharmacy shops and patent medicine dealers. There were SES and geographic differences for both acceptability and sources of the contraceptives. Also, the sources of different contraceptives depended on the type of the contraceptive. CONCLUSION: The different contraceptives were acceptable to the respondents and the major source of the contraceptives was the private sector. Hence, public private partnership arrangements should be explored so that universal coverage with contraceptives could be easily achieved. Interventions should be developed to eliminate the inequities in both acceptability and sources of different contraceptives. The acceptability of all the contraceptives should be enhanced with relevant behaviour change communication interventions especially in areas with the lowest levels of acceptability. PMID- 23343580 TI - West Nile virus lineage 2 in Sardinian wild birds in 2012: a further threat to public health. AB - West Nile virus (WNV) strains belonging to lineage 2 were detected and isolated from the tissues of a goshawk and two carrion crows in Sardinia in August 2012. According to NS3 sequence analysis, the Sardinian isolates shared a high level of similarity with those of Italian lineage 2 strains which circulated in 2011 and with the homologous sequence of the 2004 Hungarian isolate. Following the human fatality reported in 2011 in Olbia, this study is the first to report the spread and enzootic circulation of WNV lineage 2 in Sardinia. PMID- 23343581 TI - Genetic variants of echovirus 13, northern India, 2010. AB - Nonpolio acute flaccid paralysis is increasing in India. To determine viral causes, we conducted cell culture and molecular analysis identification of nonpolio human enteroviruses associated with acute flaccid paralysis during March August 2010 in northern India. The predominant nonpolio enterovirus found was echovirus 13, a serotype rarely isolated in India. PMID- 23343582 TI - [Complementary therapies in the German guidelines for the treatment of fibromyalgia syndrome--update 2012]. PMID- 23343583 TI - BCQ-: A Body Constitution Questionnaire to assess Yin-Xu. Part II: evaluation of reliability and validity. AB - BACKGROUND: Based on the Traditional Chinese Medicine (TCM) theory and guided by the principles of modern medicine (MM), we aimed to develop an effective and reliable diagnostic tool using self-reported data in order to assess the Yin-Xu body constitution. In this study, we further evaluated a provisional 22-item version of the Yin-Xu Body Constitution Questionnaire (BCQ-) previously derived from the Delphi process. METHODS: A total of 1,272 eligible participants aged between 20 and 60 years was recruited. The participants had received health examination in teaching hospitals and had not shown any disease onset in the prior month. The factor structure of the BCQ- was explored, and the reliability and validity of each derived factor (scale) were evaluated. RESULTS: Exploratory factor analysis revealed 5 factors corresponding to the manifestations of the diminishing Yin-Xu level in 5 different body areas: head, 4 limbs, gastrointestinal tract, body surface, and abdominal cavity. 3 items with low factor loading (<0.4) were dropped, resulting in a 19-item BCQ-. Cronbach's alpha ranged from 0.57 to 0.85, and the intra-class correlation coefficients were greater than 0.7 for most items. The diagnoses of Yin-Xu by both the BCQ- and experienced TCM doctors were consistent. The concurrent validity showed that higher Yin-Xu scores were associated with lower hemoglobin. CONCLUSIONS: The final BCQ- measures the Yin-Xu constitution of 5 different body areas. The questionnaire is a reliable, valid, and potentially useful instrument for evaluating the Yin-Xu constitution in clinical research and practice. PMID- 23343584 TI - Prescribing pattern of Bryophyllum preparations among a network of anthroposophic physicians. AB - BACKGROUND: The use of preparations from Bryophyllum pinnatum for tocolysis (or to arrest labor) is supported by observations obtained mainly at empirical level, but also by preclinical experiments performed with uterus strips and myometrium cell lines. Furthermore, a retrospective matched-pair study revealed good tolerability and effectiveness. In anthroposophic medicine, however, Bryophyllum species are used for a broad spectrum of diagnoses. Here, we characterize the prescribing pattern of Bryophyllum preparations in a network of anthroposophic physicians in Germany. METHODS: 38 primary-care physicians in Germany participated in the EvaMed network, a multi-center observational study. They documented anonymized prescriptions, diagnoses and demographic data (age and gender) for each consecutive patient between 01.01.2004 and 01.01.2010. Diagnoses were coded according to the 10th revision of the International Classification of Diseases (ICD-10). In the present analysis, all prescriptions of any Bryophyllum preparation in the resulting data bank were identified and the corresponding diagnoses were analyzed retrospectively. RESULTS: A total of 4,038 prescriptions of Bryophyllum preparations were identified in the EvaMed data bank. A variety of preparations could be found, 77.7% of which were prepared from Bryophyllum plants exclusively and 22.5% were combinations. Bryophyllum preparations were often prescribed to treat 'mental and behavioral disorders' (ICD-10 F00-F99, 35.7%) and 'diseases of the skin and subcutaneous tissue' (L00-L99, 16.0%), followed by 'symptoms, signs, and abnormal clinical and laboratory findings, not elsewhere classified diseases' (R00-R99, 15.2%) and 'diseases of the nervous system' (G00- G99, 9.7%). CONCLUSION: By revealing the use of Bryophyllum preparations in so many other indications than preterm delivery, our data clearly show the urgent need to conduct additional clinical trials. PMID- 23343585 TI - A pilot feasibility study of a questionnaire to determine European Union-wide CAM use. AB - BACKGROUND: No questionnaire specifically measuring the core components of complementary and alternative medicine (CAM) use has been validated for use across European Union (EU) countries. We aimed to determine the face validity, acceptability and the participants' comprehension of a pre-existing questionnaire designed to measure 'CAM use', to provide a comparative, standardised questionnaire for use by health care providers, policy makers and purchasers throughout Europe. METHODS: Established procedures were employed to translate the questionnaire into 4 EU languages. The translated questionnaires were piloted on 50 healthy adults from each country who may never have used CAM. 10 participants per country also took part in audio-recorded think aloud interviews about the questionnaire. The interviews were transcribed and analysed in the language in which they were conducted; findings were summarised in English. Questionnaire data were pooled across countries, and patterns of completion and missing data were analysed. RESULTS: The questionnaire was translated into Italian, Spanish, Dutch and Romanian. The mean age of the participants was 43.6 years. 34% were male, 87.4% were either light or heavy CAM users, and 12.6% were non-users. Qualitative analysis identified common problems across countries including a 'hard-to-read' layout, misunderstood terminology and uncertainty in choosing response options. Quantitative analysis confirmed that a substantial minority of respondents failed to follow questionnaire instructions and that some questions had substantial rates of missing data. CONCLUSIONS: The I-CAM-Q has low face validity and low acceptability, and is likely to produce biased estimates of CAM use if applied in England, Romania, Italy, The Netherlands or Spain. Further work is required to develop the layout, terms, some response options and instructions for completion before it can be used across the EU. PMID- 23343586 TI - Ethical implications of the increasing use of complementary and alternative medicine. AB - BACKGROUND: The increasing demand for complementary and alternative medicine (CAM) raises ethical questions about specific aspects of both CAM and conventional medicine (COM). METHODS: The present article provides a critical survey of the most important ethical aspects in the current debate about CAM. RESULTS: The relevant ethical issues arise mainly in 4 main areas: 1) patient information, 2) research ethics, 3) cost, and 4) education. Most of the contributions used for our purpose are based upon the implicit assumption that, in principle, the ethics of CAM and COM have to be identical because of the same underlying doctor-patient relationship. This premise is shared by the author. CONCLUSIONS: Substantial efforts on various levels will have to be made in order to create the conditions necessary for CAM to be ethically justified. But the ethical implications for COM also have to be considered. PMID- 23343587 TI - Survey of students regarding their attitudes toward complementary and alternative medicine in oncology. PMID- 23343588 TI - Asking the right questions about nutrient control in aquatic ecosystems. PMID- 23343589 TI - Electronic transport between quantum Hall states and quantum anomalous Hall states in a graphene nanoribbon based heterojunction. AB - We theoretically investigate the electronic transport between quantum Hall states and quantum anomalous Hall states in a zigzag edged graphene nanoribbon based two terminal heterojunction. The electrical conductance of the system is calculated by the method of the non-equilibrium Green's function and Landauer-Buttiker formula. We find perfect transmission through the junction when the propagation direction of the charge carriers is the same at the same edge in both regions. However, when the propagation direction at the same edge is the opposite, the electrical conductance is smaller than the quantized value. In this case, snake states at the interface are responsible for the transmission. The results are explained with the aid of the local density of states near the interface. For higher magnetic field in the quantum Hall region or larger ribbon width, the edge states are better realized and quantized electrical conductance is strengthened. Finally, the effects of Anderson disorder and dephasing on the transmission are discussed. PMID- 23343590 TI - Utility of Prehospital Quantitative End Tidal CO2? AB - INTRODUCTION: End tidal CO2 (ETCO2) has been established as a standard for confirmation of an airway, but its role is expanding. In certain settings ETCO2 closely approximates the partial pressure of arterial CO2 (PaCO2) and has been described as a tool to optimize a patient's ventilatory status. ETCO2 monitors are increasingly being used by EMS personnel to guide ventilation in the prehospital setting. Severely traumatized and burn patients represent a unique population to which this practice has not been validated. HYPOTHESIS: The sole use of ETCO2 to monitor ventilation may lead to avoidable respiratory acidosis. METHODS: A consecutive series of patients with burns or trauma intubated in the prehospital setting over a 24-month period were evaluated. Prehospital arrests were excluded. Absence of ETCO2 transport data and patients without an arterial blood gas (ABG) within 15 minutes of arrival were also excluded. Data collected included demographics, place and time of intubation, service performing intubation, ETCO2 maintained en-route to hospital, and ABG upon arrival. Further data included length of stay, mortality, and injury severity scores. RESULTS: One hundred sixty patients met the inclusion criteria. Prehospital ETCO2 did not correlate with measured PaCO2 (R2 = 0.08). Mean ETCO2 was significantly lower than mean PaCO2 (34 mmHg vs 44 mmHg, P < .005). Patients arriving acidotic were more likely to die. Mean pH on arrival for survivors and decedents was 7.32 and 7.19 respectively (P < .001). Mortality, acidosis, higher base deficits, and more severe injury patterns were all predictors for a worse correlation between ETCO2 and PaCO2 and increased mean difference between the two values. Decedents and patients presenting with a pH <7.2 demonstrated the greatest discrepancy between ETCO2 and PaCO2. The data suggest that patients may be hypoventilated by prehospital providers in order to obtain a prescribed ETCO2. CONCLUSION: ETCO2 is an inadequate tool for predicting PaCO2 or optimizing ventilation in severely injured patients. Adherence to current ETCO2 guidelines in the prehospital setting may contribute to acidosis and increased mortality. Consideration should be given to developing alternate protocols to guide ventilation of the severely injured in the prehospital setting. PMID- 23343591 TI - Suspected spinocellular carcinoma of the inferior eyelid resulted multiple chalazion. AB - Chalazion is a subacute granulomatous inflammation of the eyelid caused by retention of tarsal gland secretions and it's the most common inflammatory lesion of the eyelid. In cases of doubtful clinical presentation the diagnosis with a biopsy and a histopathological examination is important because it can orientate an appropriate surgical treatment. We report a case of a 64-years-old diabetic man, suspected for a spinocellular lesion of the inferior eyelid of the left eye, it resulted unexpectedly a chalazion. PMID- 23343592 TI - Risk perceptions for avian influenza virus infection among poultry workers, China. AB - To determine risk for avian influenza virus infection, we conducted serologic surveillance for H5 and H9 subtypes among poultry workers in Beijing, China, 2009 2010, and assessed workers' understanding of avian influenza. We found that poultry workers had considerable risk for infection with H9 subtypes. Increasing their knowledge could prevent future infections. PMID- 23343593 TI - HIV-related CD8+ cutaneous pseudolymphoma: efficacy of methotrexate. AB - Human immunodeficiency virus (HIV)-related CD8+ cutaneous pseudolymphoma (CD8+ cytotoxic T cell skin infiltrative disease) is an inflammatory process resulting from a massive infiltration of the skin by activated, oligoclonal, HIV-specific, cytotoxic T lymphocytes. Usually, CD8+ cutaneous pseudolymphoma affects patients with a deep immunosuppression, and is rare in patients with mild immunosuppression. In deeply immunocompromised patients, highly active antiretroviral therapy (HAART) is considered as the first-line treatment. In contrast, the choice of therapy in moderately immunocompromised patients and/or patients already receiving HAART remains nonconsensual. We report a case of HIV related CD8+ cutaneous pseudolymphoma in a moderately immunocompromised patient who was successfully and safely treated with methotrexate. We review the literature on HIV-related CD8+ pseudolymphoma and the use of methotrexate in HIV positive patients. PMID- 23343594 TI - Reducing plasma cholesterol is not the end of the quest. PMID- 23343595 TI - Weight change by baseline BMI from three-year observational data: findings from the Worldwide Schizophrenia Outpatient Health Outcomes Database. AB - The aim was to explore weight and body mass index (BMI) changes by baseline BMI in patients completing three years of monotherapy with various first- and second generation antipsychotics in a large cohort in a post hoc analysis of three-year observational data. Data were analyzed by antipsychotic and three baseline BMI bands: underweight/normal weight (BMI <25 kg/m2), overweight (25-30 kg/m2) and obese (>30 kg/m2). Baseline BMI was associated with subsequent weight change irrespective of the antipsychotic given. Specifically, a smaller proportion of patients gained >=7% baseline bodyweight, and a greater proportion of patients lost >=7% baseline bodyweight with increasing baseline BMI. For olanzapine (the antipsychotic associated with highest mean weight gain in the total drug cohort), the percentage of patients gaining >=7% baseline weight was 45% (95% CI: 43-48) in the underweight/normal weight BMI cohort and 20% (95% CI: 15-27) in the obese BMI cohort; 7% (95% CI: 6-8) of the underweight/normal cohort and 19% (95% CI: 13 27) of the obese cohort lost >=7% baseline weight. BMI has an association with the likelihood of weight gain or loss and should be considered in analyses of antipsychotic weight change. PMID- 23343597 TI - Effects of acute systemic administration of cannabidiol on sleep-wake cycle in rats. AB - Cannabidiol (CBD) is one of the main components of Cannabis sativa and has a wide spectrum of action, including effects in the sleep-wake cycle. OBJECTIVE: The objective of this paper is to assess the effects on sleep of acute systemic administration of CBD. METHOD: Adult male Wistar rats were randomly distributed into four groups that received intraperitoneal injections of CBD 2.5 mg/kg, CBD 10 mg/kg, CBD 40 mg/kg or vehicle (n=seven animals/group). Sleep recordings were made during light and dark periods for four days: two days of baseline recording, one day of drug administration (test), and one day after drug (post-test). RESULTS: During the light period of the test day, the total percentage of sleep significantly increased in the groups treated with 10 and 40 mg/kg of CBD compared to placebo. REM sleep latency increased in the group injected with CBD 40 mg/kg and was significantly decreased with the dose of 10 mg/kg on the post test day. There was an increase in the time of SWS in the group treated with CBD 40 mg/kg, although this result did not reach statistical significance. CONCLUSION: The systemic acute administration of CBD appears to increase total sleep time, in addition to increasing sleep latency in the light period of the day of administration. PMID- 23343598 TI - Generic legislation of new psychoactive drugs. AB - New psychoactive drugs (NPDs, new psychoactive substances) enter the market all the time. However, it takes several months to ban these NPDs and immediate action is generally not possible. Several European countries and drug enforcement officers insist on a faster procedure to ban NPDs. Introduction of generic legislation, in which clusters of psychotropic drugs are banned in advance, has been mentioned as a possible solution. Here we discuss the pros and cons of such an approach. First, generic legislation could unintentionally increase the expenditures of enforcement, black market practices, administrative burden and health risks for users. Second, it may have a negative impact on research and the development of new treatments. Third, due to the complexity of generic legislation, problems in the enforcement are anticipated due to lack of knowledge about the chemical nomenclature. Finally, various legal options are already available to ban the use, sale and trade of NPDs. We therefore conclude that the currently used scientific benefit-risk evaluation should be continued to limit the adverse health effects of NPDs. Only in emergency cases, where fatal incidents (may) occur, should this approach be overruled. PMID- 23343596 TI - Personality and the acute subjective effects of d-amphetamine in humans. AB - There is evidence that subjective responses to psychoactive drugs are related to personality traits. Here, we extend previous findings by examining personality measures in relation to acute responses to d-amphetamine (AMPH) in a large sample of healthy volunteers. Healthy adults (n=286) completed the Multidimensional Personality Questionnaire Brief Form (MPQ-BF) and participated in four sessions during which they received oral AMPH (0, 5, 10, 20 mg), under double-blind conditions. Subjective responses to the drug were measured using the Profile of Mood States, Addiction Research Center Inventory, and Drug Effects Questionnaire. Drug responses were reduced via principal components analysis to three higher order factors ('Euphoria', 'Arousal', 'Dysphoria'). Participants were rank ordered on selected MPQ-BF scales; the top and bottom third on each trait were compared on the drug response factors. High trait physical fearlessness was significantly associated with greater amphetamine-related Arousal, and high trait reward sensitivity was significantly associated with greater Euphoria. In addition, high trait impulsivity was significantly associated with greater Arousal and Euphoria. These results provide further evidence that individual differences in the subjective effects of AMPH are partially explained by differences in personality, and are consistent with the idea that both personality and responses to stimulants depend upon shared neurochemical systems. PMID- 23343599 TI - The maximum tolerated dose of gamma radiation to the optic nerve during gamma knife radiosurgery in an animal study. AB - BACKGROUND: The safety of gamma knife radiosurgery should be considered when treating pituitary adenomas. OBJECTIVES: To determine the maximum tolerated dose of radiation delivered by gamma knife radiosurgery to optic nerves. METHODS: An animal model designed to establish prolonged balloon compression of the optic chiasm and parasellar region was developed to mimic the optic nerve compression caused by pituitary adenomas. Twenty cats underwent surgery to place a balloon for compression effect and 20 cats in a sham operation group received microsurgery without any treatment. The effects of gamma knife irradiation at 10 13 Gy on normal (sham operation group) and compressed (optic nerve compression group) optic nerves were investigated by pattern visual evoked potential examination and histopathology. RESULTS: Gamma knife radiosurgery at 10 Gy had almost no effect. At 11 Gy, P100 latency was significantly prolonged and P100 amplitude was significantly decreased in compressed optic nerves, but there was little change in the normal optic nerves. Doses of 11 Gy and higher induced significant electrophysiological variations and degeneration of the myelin sheath and axons in both normal and compressed optic nerves. CONCLUSIONS: Compressed optic nerves are more sensitive to gamma knife radiosurgery than normal optic nerves. The minimum dose of gamma knife radiosurgery that causes radiation injury in normal optic nerves is 12 Gy; however, the minimum dose is 11 Gy in compressed optic nerves. PMID- 23343601 TI - Comparative genomic insights into the biosynthesis and regulation of mycobacterial siderophores. AB - Iron is essential for nearly all biological events. Siderophores are indispensable for most organisms to obtain iron from iron-limiting milieus. This holds particularly true for pathogens such as the causative agent of tuberculosis - Mycobacterium tuberculosis. The categories of mycobacterial siderophores, their biosynthesis and regulation are summarized here. The siderophore biosynthesis and regulation differences between the pathogenic and non-pathogenic mycobacteria are highlighted from comparative genomic perspective, with an aim to find clues for drug or drug target within siderophore metabolism. PMID- 23343600 TI - Joint analysis for integrating two related studies of different data types and different study designs using hierarchical modeling approaches. AB - BACKGROUND: A chronic disease such as asthma is the result of a complex sequence of biological interactions involving multiple genes and pathways in response to a multitude of environmental exposures. However, methods to model jointly all factors are still evolving. Some of the current challenges include how to integrate knowledge from different data types and different disciplines, as well as how to utilize relevant external information such as gene annotation to identify novel disease genes and gene-environment inter-actions. METHODS: Using a Bayesian hierarchical modeling framework, we developed two alternative methods for joint analysis of an epidemiologic study of a disease endpoint and an experimental study of intermediate phenotypes, while incorporating external information. RESULTS: Our simulation studies demonstrated superior performance of the proposed hierarchical models compared to separate analysis with the standard single-level regression modeling approach. The combined analyses of the Southern California Children's Health Study and challenge study data suggest that these joint analytical methods detected more significant genetic main and gene environment interaction effects than the conventional analysis. CONCLUSION: The proposed prior framework is very flexible and can be generalized for an integrative analysis of diverse sources of relevant biological data. PMID- 23343603 TI - Phase stability and elastic properties of Cr-V alloys. AB - V is the only element in the periodic table that forms a complete solid solution with Cr and thus is particularly important in alloying strategy to ductilize Cr. This study combines first-principles density functional theory calculations and experiments to investigate the phase stability and elastic properties of Cr-V binary alloys. The cluster expansion study reveals the formation of various ordered compounds at low temperatures that were not previously known. These compounds become unstable due to the configurational entropy of bcc solid solution as the temperature is increased. The elastic constants of ordered and disordered compounds are calculated at both T = 0 K and finite temperatures. The overall trends in elastic properties are in agreement with measurements using the resonant ultrasound spectroscopy method. The calculations predict that addition of V to Cr decreases both the bulk modulus and the shear modulus, and enhances the Poisson's ratio, in agreement with experiments. Decrease in the bulk modulus is correlated to decrease in the valence electron density and increase in the lattice constant. An enhanced Poisson's ratio for bcc Cr-V alloys (compared to pure Cr) is associated with an increased density of states at the Fermi level. Furthermore, the difference charge density in the bonding region in the (110) slip plane is highest for pure Cr and decreases gradually as V is added. The present calculation also predicts a negative Cauchy pressure for pure Cr, and it becomes positive upon alloying with V. The intrinsic ductilizing effect from V may contribute, at least partially, to the experimentally observed ductilizing phenomenon in the literature. PMID- 23343604 TI - SwarmDock: a server for flexible protein-protein docking. AB - Protein-protein interactions are central to almost all biological functions, and the atomic details of such interactions can yield insights into the mechanisms that underlie these functions. We present a web server that wraps and extends the SwarmDock flexible protein-protein docking algorithm. After uploading PDB files of the binding partners, the server generates low energy conformations and returns a ranked list of clustered docking poses and their corresponding structures. The user can perform full global docking, or focus on particular residues that are implicated in binding. The server is validated in the CAPRI blind docking experiment, against the most current docking benchmark, and against the ClusPro docking server, the highest performing server currently available. PMID- 23343605 TI - A novel mutation in COQ2 leading to fatal infantile multisystem disease. AB - Coenzyme Q10 (ubiquinone or CoQ10) serves as a redox carrier in the mitochondrial oxidative phosphorylation system. The reduced form of this lipid-soluble antioxidant (ubiquinol) is involved in other metabolic processes as well, such as preventing reactive oxygen species (ROS) induced damage from the mitochondrial membrane. Primary coenzyme Q10 deficiency is a rare, autosomal recessive disorder, often presenting with neurological and/or muscle involvement. Until now, five patients from four families have been described with primary coenzyme Q10 deficiency due to mutations in COQ2 encoding para-hydroxybenzoate polyprenyl transferase. Interestingly, four of these patients showed a distinctive renal involvement (focal segmental glomerular sclerosis, crescentic glomerulonephritis, nephrotic syndrome), which is only very rarely seen in correlation with mitochondrial disorders. The fifth patient deceases due to infantile multi organ failure, also with renal involvement. Here we report a novel homozygous mutation in COQ2 (c.905C>T, p.Ala302Val) in a dizygotic twin from consanguineous Turkish parents. The children were born prematurely and died at the age of five and six months, respectively, after an undulating disease course involving apneas, seizures, feeding problems and generalized edema, alternating with relative stable periods without the need of artificial ventilation. There was no evidence for renal involvement. We would like to raise awareness for this potentially treatable disorder which could be under diagnosed in patients with fatal neonatal or infantile multi-organ disease. PMID- 23343606 TI - A new approach to evaluating statistical significance of spectral identifications. AB - While nonlinear peptide natural products such as Vancomycin and Daptomycin are among the most effective antibiotics, the computational techniques for sequencing such peptides are still in their infancy. Previous methods for sequencing peptide natural products are based on Nuclear Magnetic Resonance spectroscopy and require large amounts (milligrams) of purified materials. Recently, development of mass spectrometry-based methods has enabled accurate sequencing of nonlinear peptide natural products using picograms of material, but the question of evaluating statistical significance of Peptide Spectrum Matches (PSM) for these peptides remains open. Moreover, it is unclear how to decide whether a given spectrum is produced by a linear, cyclic, or branch-cyclic peptide. Surprisingly, all previous mass spectrometry studies overlooked the fact that a very similar problem has been successfully addressed in particle physics in 1951. In this work, we develop a method for estimating statistical significance of PSMs defined by any peptide (including linear and nonlinear). This method enables us to identify whether a peptide is linear, cyclic, or branch-cyclic, an important step toward identification of peptide natural products. PMID- 23343608 TI - RT-PCR- and MALDI-TOF mass spectrometry-based identification and discrimination of isoforms homologous to pufferfish saxitoxin- and tetrodotoxin-binding protein in the plasma of non-toxic cultured pufferfish (Takifugu rubripes). AB - Four genes of Takifugu rubripes, tentatively designated Tr1-Tr4, encoding homologs of pufferfish saxitoxin- and tetrodotoxin-binding protein, were identified by BLAST search and 3'-RACE. RT-PCR and MALDI-TOF mass spectrometry allowed the identification and discrimination of Tr isoforms from the non toxically cultured specimens. The expression of Tr1 and Tr3 mRNAs exclusively in the liver and the presence of their products as 120-kDa plasma proteins were confirmed. PMID- 23343607 TI - Identification of novel host-targeted compounds that protect from anthrax lethal toxin-induced cell death. AB - Studying how pathogens subvert the host to cause disease has contributed to the understanding of fundamental cell biology. Bacillus anthracis, the causative agent of anthrax, produces the virulence factor lethal toxin to disarm host immunity and cause pathology. We conducted a phenotypic small molecule screen to identify inhibitors of lethal toxin-induced macrophage cell death and used an ordered series of secondary assays to characterize the hits and determine their effects on cellular function. We identified a structurally diverse set of small molecules that act at various points along the lethal toxin pathway, including inhibitors of endocytosis, natural product inhibitors of organelle acidification (e.g., the botulinum neurotoxin inhibitor, toosendanin), and a novel proteasome inhibitor, 4MNB (4-methoxy-2-[2-(5-methoxy-2-nitrosophenyl)ethyl]-1 nitrosobenzene). Many of the compounds, including three drugs approved for use in humans, also protected against the related Clostridium difficile toxin TcdB, further demonstrating their value as novel tools for perturbation and study of toxin biology and host cellular processes and highlighting potential new strategies for intervening on toxin-mediated diseases. PMID- 23343610 TI - Seroprevalence of dengue in American Samoa, 2010. PMID- 23343609 TI - Radially branched deployment for more efficient cell transplantation at the scale of the human brain. AB - BACKGROUND: In preclinical studies, cell transplantation into the brain has shown great promise for the treatment of a wide range of neurological diseases. However, the use of a straight cannula and syringe for cell delivery to the human brain does not approximate cell distribution achieved in animal studies. This technical deficiency may limit the successful clinical translation of cell transplantation. OBJECTIVE: To develop a stereotactic device that effectively distributes viable cells to the human brain. Our primary aims were to (1) minimize the number of transcortical penetrations required for transplantation, (2) reduce variability in cell dosing and (3) increase cell survival. METHODS: We developed a modular cannula system capable of radially branched deployment (RBD) of a cell delivery catheter at variable angles from the longitudinal device axis. We also developed an integrated catheter-plunger system, eliminating the need for a separate syringe delivery mechanism. The RBD prototype was evaluated in vitro and in vivo with subcortical injections into the swine brain. Performance was compared to a 20G straight cannula with dual side ports, a device used in current clinical trials. RESULTS: RBD enabled therapeutic delivery in a precise 'tree like' pattern branched from a single initial trajectory, thereby facilitating delivery to a volumetrically large target region. RBD could transplant materials in a radial pattern up to 2.0 cm from the initial penetration tract. The novel integrated catheter-plunger system facilitated manual delivery of small and precise volumes of injection (1.36 +/- 0.13 ul per cm of plunger travel). Both dilute and highly concentrated neural precursor cell populations tolerated transit through the device with high viability and unaffected developmental potential. While reflux of infusate along the penetration tract was problematic with the use of the 20G cannula, RBD was resistant to this source of cell dose variability in agarose. RBD enabled radial injections to the swine brain when used with a modern clinical stereotactic system. CONCLUSIONS: By increasing the total delivery volume through a single transcortical penetration in agarose models, RBD strategy may provide a new approach for cell transplantation to the human brain. Incorporation of RBD or selected aspects of its design into future clinical trials may increase the likelihood of successful translation of cell based therapy to the human patient. PMID- 23343611 TI - Rapid downregulation of innate immune cells, interleukin-12 and interleukin-23 in generalized pustular psoriasis with infliximab in combination with acitretin. AB - BACKGROUND: Generalized pustular psoriasis (GPP) is a severe inflammatory disease characterized by recurrent eruptions of sterile pustules on erythematous skin. Although tumor necrosis factor (TNF) antagonists may lead to a rapid resolution of GPP, the mechanism of action of these agents remains to be investigated. Here, we sought to evaluate markers of immune response in the skin of a patient who experienced a rapid amelioration of GPP after treatment with infliximab and acitretin. METHODS: A skin biopsy was obtained before and 72 h after initiation of treatment. Immunohistochemical stainings were performed to characterize alterations of the infiltrates, the apoptosis marker caspase 3 and key cytokines like TNFalpha, interleukin (IL)-12, IL-23 and the chemokine CXCL8/IL-8. RESULTS: Parallel with clinical improvement, a striking decline of neutrophils, myeloid and plasmacytoid dendritic cells, M1 macrophages and partly of CD4+ T cells was observed. There was no evidence of increased apoptosis mediated through the caspase-3 pathway. A marked reduction particularly of IL-12 and IL-23 and, to a lesser degree, of TNFalpha and CXCL8/IL-8 was observed. CONCLUSION: A swift clinical improvement of GPP by infliximab and acitretin is associated with a marked reduction particularly of innate and partially of the acquired immune cells as well as IL-12 and IL-23. PMID- 23343612 TI - In the summertime when the weather is fine. PMID- 23343614 TI - Efficacy of medical expulsive treatment with doxazosin in pediatric patients. AB - OBJECTIVE: To evaluate the possible efficacy of an alpha1 blocker (doxazosin) therapy on the management and disease course in pediatric patients with distal ureteral stones. MATERIALS AND METHODS: A total of 45 patients (24 boys and 21 girls) with a single lower ureteral stone were included in the study program. Their age range was 3-15 years (mean 6.65 +/- 3.78). The children were randomized into 2 main groups: group 1 (n = 21), who received only ibuprofen 20 mg/kg/d divided into 2 equal doses for pain control during follow-up; and group 2 (n = 24), who received, in addition to ibuprofen, 0.03 mg/kg/d doxazosin once daily, before bed. RESULTS: The stone expulsion rate was 28.5% (6 of 21) in group 1 and 70.8% (17 of 24) in group 2 (P = .001). The number of daily colic attacks and stone expulsion time clearly demonstrated the advantage of doxazosin, with a statistically significant diminished number of pain attacks (P = .04) and shorter stone expulsion period (P = .001). Stones <5 mm were expulsed at greater rates than stones 5-10 mm in group 2 (P = .046). Also children aged <6 years passed the stones with significantly greater rates than children aged >=7 years (P = .008). CONCLUSION: The use of alpha-adrenergic blocker agents could have certain advantages in attempts to render children stone free within a shorter period, which would inevitably diminish the number of colic attacks and the need for analgesic usage. PMID- 23343613 TI - Short-term systemic effects of nose-only cigarette smoke exposure in mice: role of oxidative stress. AB - BACKGROUND/AIMS: Long-term cigarette smoking (CS) is a major risk factor for respiratory and cardiovascular diseases, and is also known to adversely affect other organs. However, data on the systemic effects of short-term CS exposure (STCSE) are scarce. Presently, using a nose-only exposure system, we evaluated the systemic effects of STCSE in mice. METHODS: We assessed the effects of CS generated by 9 consecutive cigarettes per day for 4 days in a nose-only exposure system on cardiovascular, hepatic and renal endpoints evaluated on day 5 in mice. Control mice were exposed to air only. RESULTS: CS significantly increased systolic blood pressure and decreased total nitric oxide plasma concentration. Circulating platelets and erythrocyte numbers were also increased. However, STCSE did not significantly increase thrombosis in pial arterioles and venules. STCSE significantly raised plasma alanine aminotransferase and gamma glutamyl transpeptidase activities, but did not affect urea or creatinine concentrations. Interestingly, while STCSE enhanced the production of reactive oxygen species in heart and kidney and lipid peroxidation in heart, liver and kidneys, it also enhanced the antioxidant activity of superoxide dismutase, probably indicating that STCSE causes adaptive reactions to counterbalance the potentially damaging action of oxygen radicals induced by STCSE. CONCLUSION: These results suggest that STCSE causes blood pressure increase, hepatotoxicity and oxidative stress in the heart, liver and the kidneys. These data provide information on the initial steps leading to the systemic effects of STCSE, a stage at which the diseases may likely be reversed. PMID- 23343615 TI - The Turin pouch: a new technique of ileocecal cutaneous continent urinary diversion. AB - OBJECTIVE: To evaluate the functional results of a new cutaneous continent reservoir, the Turin pouch (TP), consisting of an ileocolonic pouch with an innovative efferent channel (EC). METHODS: Since 2006, we have performed the TP on 14 patients in whom the appendix was absent. The distal ileum (10 cm) and right colon (40 cm) were isolated. The cecum and right colon were folded to obtain a U-shaped pouch through a stapler detubularization. An artificial EC was created by separating with a stapler a 5-cm tubularized flap of colonic wall and anastomosing this to the umbilicus. RESULTS: After a mean follow-up of 45 months (range, 12-72 months), 13 patients were alive and 1 died of bladder cancer progression. Early and late complications occurred in 3 and 4 patients, respectively. Daytime continence was 100% and nighttime continence was 93%. No patient has reported stenosis or difficulties in catheterization. Urodynamic studies (12 months postoperatively) showed a mean maximal pouch capacity of 520 mL (range, 360-720 mL), mean end-filling pressure of 23 cm H2O (range, 18-30 cm H2O), and mean EC closing pressure of 65 cm H2O (range, 52-75 cm H2O). CONCLUSION: The TP offers good functional results and could be applied in patients undergoing continent, heterotopic, urinary diversion. PMID- 23343616 TI - Dependence of the structural, transport and magnetic properties of Tl(1-y)Fe(2 z)(Se(1-x)S(x))2 with isovalent substitution of Se by S. AB - The effect of selenium substitution by sulfur in the Tl(1-y)Fe(2-z)Se(2) antiferromagnet was studied by x-ray and electron diffraction, magnetization and transport measurements. Tl(0.8)Fe(1.5)(Se(1-x)S(x))(2) (nominal composition) solid solution was synthesized in the full x range (0 <= x(S) <= 1) using the sealed tube technique. No superconductivity was found down to 4.2 K in the series despite the fact that the optimal crystallographic parameters, determined by Rietveld refinements, are reached in the series (i.e. the Fe-(Se, S) interplane height and (Se, S)-Fe-(Se, S) angle for which the critical superconducting transition T(c) is usually maximal in pnictides). A quasi-full Tl site (y ~ 0.05) compared to significant alkaline deficiency (y = 0.2-0.3) in analogous A(1-y)Fe(2 z)Se(2) (A = K, Rb, Cs), and the resulting differences in iron valency, density of states and doping, are suggested as an explanation for this absence of superconductivity. Transmission electron microscopy confirmed the existence of an ordered iron vacancies network in the samples of the Tl(0.8)Fe(1.5)(Se(1 x)S(x))(2) series in the form of the tetragonal ?5a * ?5a * c superstructure (I4/m). The Neel temperature (T(N)) indicating the onset of antiferromagnetism order in this ?5a * ?5a * c supercell is found to decrease from 450 K in the selenide (x = 0) to 330 K in the sulfide (x = 1). Finally, we demonstrate a direct linear relationship between T(N) and the Fe-(Se, S) bond length (or Fe (Se, S) height). PMID- 23343617 TI - Effect of subthalamic nucleus or globus pallidus interna stimulation on oculomotor function in patients with Parkinson's disease. AB - BACKGROUND: Deep brain stimulation (DBS) of either the globus pallidus interna (GPi) or subthalamic nucleus (STN) is similarly effective for treating somatomotor manifestations of Parkinson's disease (PD), but differences in how stimulation of each target affects oculomotor function are poorly understood. OBJECTIVE: We sought to determine if stimulation of the STN, but not the GPi, affects oculomotor function in PD patients. METHODS: Nineteen PD patients with DBS implants (8 bilateral GPi, 9 bilateral STN and 2 unilateral STN) were studied. Testing was performed with stimulation on, then off. Somatomotor function was tested using the Unified Parkinson's Disease Rating Scale (UPDRS) motor exam. For oculomotor testing, patients performed pro- and antisaccade tasks while monitored with an infrared eye tracker. Saccadic latency, saccadic intrusions, and square-wave jerks (SWJs) were measured for each trial. RESULTS: As expected, UPDRS motor scores improved with both GPi and STN stimulation. With GPi stimulation, there was no significant difference in oculomotor function with stimulation on or off. However, with STN stimulation on, there was a significant increase in the mean number of SWJs/s, as well as a significant decrease in latency for both pro- and antisaccade tasks. CONCLUSION: Stimulation of either GPi or STN had similar effects on somatomotor function, but only STN stimulation significantly altered oculomotor function. PMID- 23343618 TI - Product life trade-offs: what if products fail early? AB - Increasing product life allows the embodied emissions in products to be spread across a longer period but can mean that opportunities to improve use-phase efficiency are foregone. In this paper, a model that evaluates this trade-off is presented and used to estimate the optimal product life for a range of metal intensive products. Two strategies that have potential to save emissions are explored: (1) adding extra embodied emissions to make products more sturdy, increasing product life, and (2) increasing frequency of use, causing early product failure to take advantage of improvements in use-phase efficiency. These strategies are evaluated for two specific case studies (long-life washing machines and more frequent use of vehicles through car clubs) and for a range of embodied and use-phase intensive products under different use-phase improvement rate assumptions. Particular emphasis is placed on the fact that products often fail neither at their design life nor at their optimal life. Policy recommendations are then made regarding the targeting of these strategies according to product characteristics and the timing of typical product failure relative to optimal product life. PMID- 23343619 TI - Activation of AMP-activated protein kinase by a plant-derived dihydroisosteviol in human intestinal epithelial cell. AB - Our previous study has shown that dihydroisosteviol (DHIS), a derivative of stevioside isolated from Stevia rebaudiana (Bertoni), inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated transepithelial chloride secretion across monolayers of human intestinal epithelial (T84) cells and prevents cholera toxin-induced intestinal fluid secretion in mouse closed loop models. In this study, we aimed to investigate a mechanism by which DHIS inhibits CFTR activity. Apical chloride current measurements in Fisher rat thyroid cells stably transfected with wild-type human CFTR (FRT-CFTR cells) and T84 cells were used to investigate mechanism of CFTR inhibition by DHIS. In addition, effect of DHIS on AMP-activated protein kinase (AMPK) activation was investigated using Western blot analysis. Surprisingly, it was found that DHIS failed to inhibit CFTR-mediated apical chloride current in FRT-CFTR cells. In contrast, DHIS effectively inhibited CFTR-mediated apical chloride current induced by a cell permeable cAMP analog CPT-cAMP and a direct CFTR activator genistein in T84 cell monolayers. Interestingly, this inhibitory effect of DHIS on CFTR was significantly (p<0.05) reduced by pretreatment with compound C, an AMPK inhibitor. AICAR, a known AMPK activator, was able to inhibit CFTR activity in both FRT-CFTR and T84 cells. Western blot analysis showed that DHIS induced AMPK activation in T84 cells, but not in FRT-CFTR cells. Our results indicate that DHIS inhibits CFTR-mediated chloride secretion in T84 cells, in part, by activation of AMPK activity. DHIS therefore represents a novel candidate of AMPK activators. PMID- 23343620 TI - The Adolescent Girls' Anaemia Control Programme: a decade of programming experience to break the inter-generational cycle of malnutrition in India. AB - OBJECTIVE: To document the scale-up of India's Adolescent Girls' Anaemia Control Programme following a knowledge-centred framework for scaling up nutrition interventions and to identify the critical elements of and lessons learned from a decade of programme experience for the control of anaemia in adolescent girls. DESIGN: We reviewed all articles, programme and project reports, and baseline and endline assessments published between 1995 and 2012 regarding the control of anaemia through intermittent iron and folic acid supplementation; key programme specialists and managers were interviewed to complete or verify information wherever needed. SETTING: India. SUBJECTS: Adolescent girls. RESULTS: The scale up of India's Adolescent Girls' Anaemia Control Programme followed a knowledge centred programme cycle comprising five phases: Evidence, Innovation, Evaluation, Replication and Universalization. By the end of 2011, the programme was being rolled out in thirteen states and was reaching 27.6 million adolescent girls of whom 16.3 million were school-going girls and 11.3 million were out-of-school girls. Building on the critical elements of and lessons learned from the programme, the Government of India launched in 2012 the national Weekly Iron and Folic Acid Supplementation (WIFS) programme to universalize the benefits of anaemia control to the overall population of Indian adolescents. CONCLUSIONS: The Adolescent Girls' Anaemia Control Programme in India provides a good example of how a knowledge-centred approach can successfully guide the scaling up of public health nutrition interventions and facilitate intersectoral convergence among different government departments and development partners to break the inter generational cycle of undernutrition and deprivation. PMID- 23343621 TI - Microfluidic validation of diagnostic protein markers for spontaneous cerebrospinal fluid rhinorrhea. AB - Cerebrospinal fluid (CSF) rhinorrhea is a potentially dangerous condition identified by CSF leakage into the nasal cavity. This malady stands to benefit from rapid and noninvasive screening diagnostics to complement low-throughput imaging based methods currently in use. To address this gap, we demonstrate on chip immunosubtraction to accelerate biomarker validation and immunoassay development for a putative CSF rhinorrhea diagnostic marker, transthyretin, by combining high-specificity immunoaffinity capture with subsequent polyacrylamide gel electrophoresis (PAGE). We demonstrate the on-chip assay using photopatterned polyacrylamide immunofilters. The filter consists of polymer with controlled pore sizes to size-exclude (i.e., "subtract") large antibody-target immune complexes from downstream PAGE separation. A control PAGE separation is also performed for comparison without immunoaffinity capture (i.e., no antibody present). We compare on-chip immunosubtraction to Western blotting and ELISA to validate CSF rhinorrhea biomarkers from nasal surgery samples. For samples representative of spontaneous rhinorrhea, the 5 min on-chip assay achieved clinical specificity of 100%, compared to 50% for ELISA which required 6 h. On-chip immunosubtraction also generated results for clinical samples not assayable via ELISA due to matrix protein spurious signals. The pilot study suggests the capability of a rapid on chip validation tool to expedite scrutiny of putative protein markers for new clinical assays. PMID- 23343622 TI - Non-pro-vitamin A and pro-vitamin A carotenoids in atopy development. AB - Carotenoids are important derivatives of the human diet and occur in high concentrations in the human organism. Various carotenoids are also present in human breast milk and are transferred to breast-fed children. The alternative to breastfeeding is supplementation with an infant milk formula, but these formulas contain only a limited variety of carotenoids. Our question is: 'What is the function of various carotenoids in human nutrition with a special emphasis on child development and the development of atopy?' In this review, the mechanisms of action of the most important non-pro-vitamin A and pro-vitamin A carotenoids: alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, lycopene and retinoids are discussed. In summary, the combination of carotenoids, especially lycopene, seems to be of great importance, and exclusive usage of beta carotene in infant formula may yield in an increased atopy prevalence mediated in various target organs like the skin, lungs and immune competent cells. We conclude that the determination of novel bioactive metabolites of various carotenoids, at various stages in different organs during atopy development, might be the key to understanding the potential importance of carotenoids on atopy development. PMID- 23343623 TI - Streptococcus suis and porcine reproductive and respiratory syndrome, Vietnam. PMID- 23343624 TI - Mechanisms responsible for the trophic effect of beta-adrenoceptors on the I(to) current density in type 1 diabetic rat cardiomyocytes. AB - BACKGROUND/AIMS: In diabetic ventricular myocytes, transient outward potassium current (Ito) amplitude is severely reduced because of the impaired catecholamine release that characterizes diabetic autonomic neuropathy. Sympathetic nervous system exhibits a trophic effect on Ito since incubation of myocytes with noradrenaline restores current amplitude via beta-adrenoceptor (betaAR) stimulation. Here, we investigate the intracellular signalling pathway though which incubation of diabetic cardiomyocytes with the betaAR agonist isoproterenol recovers Ito amplitude to normal values. METHODS: Experiments were performed in ventricular myocytes isolated from streptozotocin-diabetic rats. Ito current was recorded by using the patch-clamp technique. Kv4 channel expression was determined by immunofluorescence. Protein-protein interaction was determined by coimmunoprecipitation. RESULTS: Stimulation of betaAR activates first a Galphas protein, adenylyl cyclase and Protein Kinase A. PKA-phosphorylated receptor then switches to the Galphai protein. This leads to the activation of the betaAR Kinase-1 and further receptor phosphorylation and arrestin dependent internalization. The internalized receptor-arrestin complex recruits and activates cSrc and the MAPK cascade, where Ras, c-Raf1 and finally ERK1/2 mediate the increase in Kv4.2 and Kv4.3 protein abundance in the plasma membrane. CONCLUSION: beta2AR stimulation activates a Galphas and Galphai protein dependent pathway where the ERK1/2 modulates the Ito current amplitude and the density of the Kv4.2 and Kv4.2 channels in the plasma membrane upon sympathetic stimulation in diabetic heart. PMID- 23343625 TI - Health education materials for Arab patients: content and design preferences. AB - OBJECTIVE: To investigate the content and design preferences of printed health education leaflets among Arab patients. MATERIALS AND METHODS: A survey questionnaire to 17 subjects (women: n = 8, men: n = 9; age range 17-70 years) and three focus-group discussions (total 16 participants) were used to assess preferences by showing samples of Arabic health education materials. The questionnaire was administered by interviewers. For the focus-group discussions, the sessions were conducted by a trained interviewer, audio recorded and analyzed thematically. The subjects' educational level was from no formal schooling to university level. RESULTS: In survey component, all patients preferred photographs over clipart. Typeface ('font') preferences were for Simplified Arabic in 8 subjects (47%) and Mudir MT in 7 (41%); the 16-point font size was favored by 14 (82%) patients. In the three focus-group discussions, themes that participants expressed included use of standard Arabic with local dialects, short sentences, and culturally appropriate advice with practical and quantifiable examples. CONCLUSIONS: The participants preferred health education materials to be color trifold brochures illustrated with pictures and not clipart and written in Arabic using the Simplified Arabic font in 16-point size. PMID- 23343626 TI - Piscine reovirus encodes a cytotoxic, non-fusogenic, integral membrane protein and previously unrecognized virion outer-capsid proteins. AB - Piscine reovirus (PRV) is a tentative new member of the family Reoviridae and has been linked to heart and skeletal muscle inflammation in farmed Atlantic salmon (Salmo salar L.). Recent sequence-based evidence suggests that PRV is about equally related to members of the genera Orthoreovirus and Aquareovirus. Sequence similarities have also suggested that PRV might encode a fusion-associated small transmembrane (FAST) protein, which in turn suggests that PRV might be the prototype of a new genus with syncytium-inducing potential. In previous support of this designation has been the absence of identifiable PRV-encoded homologues of either the virion outer-clamp protein of ortho- and aquareoviruses or the virion outer-fibre protein of most orthoreoviruses. In the current report, we have provided experimental evidence that the putative p13 FAST protein of PRV lacks the defining feature of the FAST protein family - the ability to induce syncytium formation. Instead, p13 is the first example of a cytosolic, integral membrane protein encoded by ortho- or aquareoviruses, and induces cytotoxicity in the absence of cell-cell fusion. Sequence analysis also identified signature motifs of the outer-clamp and outer-fibre proteins of other reoviruses in two of the predicted PRV gene products. Based on these findings, we conclude that PRV does not encode a FAST protein and is therefore unlikely to be a new fusogenic reovirus. The presence of a novel integral membrane protein and two previously unrecognized, essential outer-capsid proteins has important implications for the biology, evolution and taxonomic classification of this virus. PMID- 23343628 TI - Providence virus (family: Carmotetraviridae) replicates vRNA in association with the Golgi apparatus and secretory vesicles. AB - Providence virus (PrV) is the sole member of the family Carmotetraviridae (formerly Tetraviridae) sharing the characteristic T=4 capsid architecture with other tetravirus families. Despite significant structural similarities, PrV differs from other tetraviruses in terms of genome organization, non-structural protein sequence and regulation of gene expression. In addition, it is the only tetravirus that infects tissue culture cells. Previous studies showed that in persistently infected Helicoverpa zea MG8 cells, the PrV replicase associates with detergent-resistant membranes in punctate cytosolic structures, which is similar to the distribution of an alpha-like tetravirus replicase (Helicoverpa armigera stunt virus). Here, we demonstrate that the site of PrV vRNA replication coincides with the presence of PrV p40/p104 proteins in infected cells and that these replication proteins associate with the Golgi apparatus and secretory vesicles in transfected cells. PMID- 23343627 TI - Host microRNA molecular signatures associated with human H1N1 and H3N2 influenza A viruses reveal an unanticipated antiviral activity for miR-146a. AB - While post-transcriptional regulation of gene expression by microRNAs (miRNAs) has been shown to be involved in influenza virus replication cycle, only a few studies have further investigated this aspect in a human cellular model infected with human influenza viruses. In this study, we performed miRNA global profiling in human lung epithelial cells (A549) infected by two different subtypes of human influenza A viruses (H1N1 and H3N2). We identified a common miRNA signature in response to infection by the two different strains, highlighting a pool of five miRNAs commonly deregulated, which are known to be involved in the innate immune response or apoptosis. Among the five miRNA hits, the only upregulated miRNA in response to influenza infection corresponded to miR-146a. Based on a previously published gene expression dataset, we extracted inversely correlated miR-146a target genes and determined their first-level interactants. This functional analysis revealed eight distinct biological processes strongly associated with these interactants: Toll-like receptor pathway, innate immune response, cytokine production and apoptosis. To better understand the biological significance of miR 146a upregulation, using a reporter assay and a specific anti-miR-146a inhibitor, we confirmed that infection increased the endogenous miR-146a promoter activity and that inhibition of miR-146a significantly increased viral propagation. Altogether, our results suggest a functional role of miR-146a in the outcome of influenza infection, at the crossroads of several biological processes. PMID- 23343629 TI - Pseudovirion-binding and neutralizing antibodies to cutaneous human papillomaviruses (HPV) correlated with the presence of HPV DNA in skin. AB - Whereas the antibody response to the anogenital human papillomaviruses (HPVs) is known to be mainly type-specific, correlated with the presence of viral DNA and mainly directed to conformational epitopes of the virion, it is not known if this applies also to the antibody response to cutaneous HPVs. For 434 non immunosuppressed patients with skin lesions (squamous cell carcinoma and basal cell carcinoma of the skin, actinic keratosis and benign skin lesions), we compared HPV DNA status with seroreactivity to HPV pseudovirions (PsV) and to GST L1 fusion proteins from HPV types -5, -6, -15, -16, -32 and -38. Biopsies from the skin lesions were tested for the presence of HPV DNA using three different PCR methods, with typing by sequencing. Serum samples from subjects with HPV DNA positive biopsies and randomly selected serum samples from subjects with HPV DNA negative biopsies were also tested with neutralization assays with HPV5, -38 and 76 PsV. Agreement of the three serological methods varied from poor to moderate. Type-specific seroprevalences among patients positive for the same type of HPV DNA (sensitivity of serology) was improved with the PsV-based method (mean of 40%, maximum 63%) compared with the GST-L1 method (mean of 20%, maximum of 25%). Neutralization was the most sensitive assay for HPV38 (50%). In summary, cutaneous HPVs also appear to induce a type-specific antibody response that correlates with the presence of HPV DNA and that can be detected with improved sensitivity using PsV-based serology. PMID- 23343630 TI - Characterization of the polydnaviral 'T. rostrale virus' (TrV) gene family: TrV1 expression inhibits in vitro cell proliferation. AB - Tranosema rostrale ichnovirus (TrIV) is a polydnavirus (PDV) transmitted by the endoparasitic wasp T. rostrale to its host Choristoneura fumiferana during oviposition. PDV genes are expressed in infected caterpillars, causing physiological disturbances that promote the survival of the developing endoparasite. The previously sequenced genome of TrIV contains ~86 genes organized in multigene families and distributed on multiple segments of circular dsDNA. Among these, the 'T. rostrale virus' (TrV) family comprises seven genes that are absent in other PDV genomes examined to date and whose function(s) remain(s) unknown. Here, we initiated a functional analysis of the TrV family using qPCR, transfection and RNAi approaches. TrV family genes were weakly expressed in wasp ovaries, but some displayed high transcript abundance in parasitized caterpillars. Whilst TrV1 was the most highly transcribed TrV gene in infected caterpillars, transcript levels for TrV5 and TrV6 were nearly undetectable, indicating that they may be pseudogenes. Temporal and tissue specific patterns of transcript abundance were similar for all expressed TrV family genes, indicative of an apparent lack of difference in function or tissue specificity. Infection of Cf-203 and Sf-21 insect cells with TrIV led to a dose dependent inhibition of cell proliferation with no sign of apoptosis. Whilst similar inhibition was observed following transfection of cells with a cloned genome segment carrying the TrV1 gene, RNA interference targeting TrV1 largely restored cell growth in TrIV-infected cells, indicating that TrV1 expression was responsible for the observed inhibition. We suggest that TrV genes may contribute to host developmental disruption by interfering with host-cell proliferation during parasitism. PMID- 23343631 TI - The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate. AB - The biodegradable polymer medium chain length polyhydroxyalkanoate (mclPHA), produced by Pseudomonas putida CA-3, was depolymerised and the predominant monomer (R)-3-hydroxydecanoic acid (R10) purified. R10 was conjugated to a d peptide DP18 and its derivatives. All peptides conjugated with R10 exhibited greater anti-cancer activity compared to the unconjugated peptides. Unconjugated and conjugated peptides were cytocidal for cancer cells. Conjugation of R10 to peptides was essential for enhanced anti-proliferation activity, as unconjugated mixes did not result in enhancement of anti-cancer activity. The conjugation of R10 resulted in more rapid uptake of peptides into HeLa and MiaPaCa cells compared to unconjugated peptide. Both unconjugated and R10 conjugated peptides localized to the mitochondria of HeLa and MiaPaCa cells and induced apoptosis. Peptide conjugated with a terminally hydroxylated decanoic acid (omega hydroxydecanoic acid) exhibited 3.3 and 6.3 fold higher IC(50) values compared to R10 conjugated peptide indicating a role for the position of the hydroxyl moiety in enhancement of anti-cancer activity. Conjugation of decanoic acid (C10) to peptides resulted in similar or higher IC(50) values compared to R10 conjugates but C10 conjugates did not exhibit any cancer selectivity. Combination studies showed that R10DP18L exhibited synergy with cisplatin, gemcitabine, and taxotere with IC(50) values in the nanomolar range. PMID- 23343633 TI - Bone regeneration in a canine cranial model using allogeneic adipose derived stem cells and coral scaffold. AB - Adipose tissue derived stem cells (ASCs) based therapies for the repair and regeneration of various tissues have been widely investigated recently because of their multilineage potential and self-renewal capability. Our previous study demonstrated that autologous ASCs loaded onto natural coral scaffolds could repair cranial critical-sized defects (CSDs) in a canine model. The objective of this study was to determine whether the use of allogeneic ASCs could heal the same defect without the use of immunosuppressive therapy. The pedigree mismatch, mixed lymphocyte reaction assays (MLRs) and allogeneic skin graft experiments were performed to confirm unrelated ASC donors and recipients. A total of 12 adult Beagle dogs were enrolled in this study and divided into two groups. Bilateral cranial CSDs were created in each animal. The right-side defect was treated with allogeneic ASCs delivered onto a coral scaffold, and the left defect was either filled with an autologous ASC/coral composite (Group 1, n = 5) or with one coral scaffold alone (Group 2, n = 5). The systematic immune response and bone healing were evaluated postoperatively. The results showed that allogeneic ASC transplantation did not induce a systemic immune response by the hosts, and allogeneic ASCs could repair the cranial CSDs in an analogous way to that of the autologous cells. Moreover, both the green fluorescently labeled allogeneic and autologous ASCs were detected within the lacunae of newly formed bone in the defect site at 24 weeks, illustrating that the grafted ASCs contributed directly to bone regeneration in vivo. Thus, we concluded that allogeneic ASCs have the capacity to regenerate bone within craniofacial defects, providing an alternative source of seed cells for bone tissue engineering. PMID- 23343632 TI - Affibody modified and radiolabeled gold-iron oxide hetero-nanostructures for tumor PET, optical and MR imaging. AB - A highly monodispersed hetero-nanostructure with two different functional nanomaterials (gold (Au) and iron oxide (Fe(3)O(4,) IO)) within one structure was successfully developed as Affibody based trimodality nanoprobe (positron emission tomography, PET; optical imaging; and magnetic resonance imaging, MRI) for imaging of epidermal growth factor receptor (EGFR) positive tumors. Unlike other regular nanostructures with a single component, the Au-IO hetero-nanostructures (Au-IONPs) with unique chemical and physical properties have capability to combine several imaging modalities together to provide complementary information. The IO component within hetero-nanostructures serve as a T(2) reporter for MRI; and gold component serve as both optical and PET reporters. Moreover, such hetero nanoprobes could provide a robust nano-platform for surface-specific modification with both targeting molecules (anti-EGFR Affibody protein) and PET imaging reporters (radiometal (64)Cu chelators) in highly efficient and reliable manner. In vitro and in vivo study showed that the resultant nanoprobe provided high specificity, sensitivity, and excellent tumor contrast for both PET and MRI imaging in the human EGFR-expressing cells and tumors. Our study data also highlighted the EGFR targeting efficiency of hetero-nanoparticles and the feasibility for their further theranostic applications. PMID- 23343634 TI - pDNA-loaded Bubble liposomes as potential ultrasound imaging and gene delivery agents. AB - We have developed polyethyleneglycol (PEG)-modified liposomes (Bubble liposomes; BLs) that entrap ultrasound (US) contrast gas, and we have reported that the combination of BLs and US exposure was an effective tool for delivering pDNA and siRNA in vitro and in vivo. In this study, we prepared pDNA-loaded BLs using three types of cationic lipids to enhance the US imaging effect and the transfection efficiency via systemic injection. We investigated the US imaging abilities of these BLs, their protective effects on pDNA from serum component, and their transfection effects in vitro and in vivo. As a result, we demonstrated that the US imaging ability and transfection effect varied with lipid component and that p-BLs containing DSDAP could be the most stable and effective tool the among three types of p-BLs. Indeed, in ischemic muscle, p-BLs containing DSDAP could be detected using diagnostic US and could deliver bFGF-expressing pDNA using therapeutic US, leading to the induction of angiogenic factors and the improvement of blood flow. These results suggest that combining p-BLs with US exposure may be useful for stable US imaging and efficient gene delivery and may lead to the establishment of a theranostic approach, which is a combination of disease diagnosis and therapy. PMID- 23343635 TI - Injectable intratumoral hydrogel as 5-fluorouracil drug depot. AB - The effectiveness of systemically administered anticancer treatments is limited by difficulties in achieving therapeutic doses within tumors, a problem that is complicated by dose-limiting side effects to normal tissue. To increase the efficacy and reduce the toxicity of systemically administered anticancer 5 fluorouracil (5-Fu) treatments in patients, intratumoral administration of an injectable hydrogel has been evaluated in the current work. The MPEG-b-(PCL-ran PLLA) diblock copolymer (MCL) containing 5-Fu existed in an emulsion-sol state at room temperature and rapidly gelled in vivo at the body temperature. MCL acted as in vivo biodegradable drug depot over a defined experimental period. A single injection of 5-Fu-loaded MCL solution resulted in significant suppression of tumor growth, compared with repeated injection of free 5-Fu as well as saline and MCL alone. For both repeated injections of free 5-Fu and single injection of 5-Fu loaded MCL, most of the 5-Fu was found in the tumor, indicating the maintenance of therapeutic concentrations of 5-Fu within the target tumor tissue and the prevention of systemic toxicity associated with 5-Fu in healthy normal tissues. In conclusion, this work demonstrated that intratumoral injection of 5-Fu-loaded MCL may induce significant suppression of tumor growth through effective accumulation of 5-Fu in the tumor. PMID- 23343636 TI - Nutrition as a new treatment target in chronic heart failure. PMID- 23343637 TI - Constant face pain in typical trigeminal neuralgia and response to gamma knife radiosurgery. AB - BACKGROUND/AIMS: Constant pain, especially if prominent, is sometimes considered incompatible with a diagnosis of typical idiopathic trigeminal neuralgia. This study aims to clarify the frequency of patient-reported constant pain in patients with medically intractable, typical, idiopathic trigeminal neuralgia as diagnosed with standard clinical parameters and confirmed by the response to a modified McGill questionnaire, a 'hold-still' test that eliminated triggers and the response to Gamma Knife radiosurgery. METHOD: Forty consecutive patients with typical trigeminal neuralgia were given questionnaires prior to Gamma Knife radiosurgery. Those with constant pain were further tested by being advised to hold completely still for up to 3 min. Final pain relief was evaluated after Gamma Knife radiosurgery. RESULTS: Twenty of forty patients indicated on a questionnaire that they had constant face pain. Pain decreased on the 'hold still' test on all 12 patients who were tested. Following Gamma Knife radiosurgery, there was no significant difference in pain relief in those without or with constant pain. CONCLUSION: Patients with typical idiopathic trigeminal neuralgia frequently report that 50% or more of their pain is constant. This constant pain is markedly decreased if the patient holds completely still for a few minutes and does not affect the outcome of Gamma Knife radiosurgery. PMID- 23343638 TI - Single-crystal growth and thermoelectric properties of Ge(Bi,Sb)4Te7. AB - The thermoelectric properties between 10 and 300 K and the growth of single crystals of n-type and p-type GeBi(4)Te(7), GeSb(4)Te(7) and Ge(Bi(1 x)Sb(x))(4)Te(7) solid solution are reported. Single crystals were grown by the modified Bridgman method, and p-type behavior was achieved by the substitution of Bi by Sb in GeBi(4)Te(7). The thermopower in the Ge(Bi(1-x)Sb(x))(4)Te(7) solid solution ranges from -117 to +160 MUV K(-1). The crossover from n-type to p-type is continuous with increasing Sb content and is observed at x ~0.15. The highest thermoelectric efficiencies among the tested n-type and p-type samples are Z(n)T = 0.11 and Z(p)T = 0.20, respectively. For an optimal n-p couple in this alloy system the composite figure of merit is Z(np)T = 0.17 at room temperature. PMID- 23343639 TI - Neglected infectious diseases: are push and pull incentive mechanisms suitable for promoting drug development research? AB - Infectious diseases are among the main causes of death and disability in developing countries, and they are a major reason for the health disparity between rich and poor countries. One of the reasons for this public health tragedy is a lack of lifesaving essential medicines, which either do not exist or badly need improvements. In this article, we analyse which of the push and pull mechanisms proposed in the recent literature may serve to promote research into neglected infectious diseases. A combination of push programmes that subsidise research inputs through direct funding and pull programmes that reward research output rather than research input may be the appropriate strategy to stimulate research into neglected diseases. On the one hand, early-stage (basic) research should be supported through push mechanisms, such as research grants or publicly financed research institutions. On the other hand, pull mechanisms, such as prize funds that link reward payments to the health impacts of effective medicines, have the potential to stimulate research into neglected diseases. PMID- 23343640 TI - Time to achieve first blood pressure control after diagnosis among hypertensive patients at primary health care clinics: a preliminary study. AB - This study aimed to examine the duration to achieve first blood pressure (BP) control after the diagnosis of hypertension. This was a retrospective cohort study on 195 hypertensive patients' (age >=18 years) records from a primary health care clinic. The median time to achieve first BP control was 7.2 months (95% confidence interval [CI] = 4.99-9.35). Cox proportional hazards regression results showed female patients were 1.5 times more likely to achieve BP control when compared with male patients (hazard ratio [HR] = 1.50, 95% CI 1.09-2.09, P = .013). Those with monotherapy were 2 times more likely (HR = 2.09, 95% CI = 1.39 3.13, P < 0.001) and those on 2 drugs were 3.5 times more likely (HR = 3.49, 95% CI = 1.65-7.40, P = .001) to achieve BP control than those with nonpharmacological treatment. The median time to achieve BP control was longer than the recommended time. Doctors may need to consider starting the pharmacological treatment early and be more aggressive in hypertensive management for male patients. PMID- 23343641 TI - Sex work and its associations with alcohol and methamphetamine use among female bar and spa workers in the Philippines. AB - To assess the prevalence of sex work and its associations with substance use among female bar/spa workers in the Philippines (N = 498), workers from 54 bar or spa venues in Metro Manila (2009-2010) were surveyed on demographics, drug/alcohol use, abuse history, and sex work. Their median age was 23 years and 35% engaged in sex work. Sex work was independently associated with methamphetamine use (19% vs 4%; adjusted odds ratio [AOR] =2.9, 95% confidence interval [CI] = 1.3-6.2), alcohol use with patrons (49% vs. 27%; AOR = 1.9, 95% CI = 1.1-3.4), and alcohol intoxication during sex (50% vs. 24%; AOR = 2.0, 95% CI = 1.2-3.5), but inversely associated with daily alcohol use (13% vs. 16%; AOR = 0.2, 95% CI = 0.1-0.5). Additional significant covariates included sexual abuse history, younger age, and not having a higher education. Findings suggest that interventions with sex workers in bars and spas should focus on methamphetamine use, alcohol use contexts, and violence victimization, to better meet the needs of this population. PMID- 23343642 TI - Spatial analysis of dengue fever in Guangdong Province, China, 2001-2006. AB - Guangdong Province is the area most seriously affected by dengue fever in China. In this study, we describe the spatial distribution of dengue fever in Guangdong Province from 2001 to 2006 with the objective of informing priority areas for public health planning and resource allocation. Annualized incidence at a county level was calculated and mapped to show crude incidence, excess hazard, and spatial smoothed incidence. Geographic information system-based spatial scan statistics was conducted to detect the spatial distribution pattern of dengue fever incidence at the county level. Spatial scan cluster analyses suggested that counties around Guangzhou City and Chaoshan Region were at increased risk for dengue fever (P < .01). Some spatial clusters of dengue fever were found in Guangdong Province, which allowed intervention measures to be targeted for maximum effect. PMID- 23343643 TI - Risk-adjusted resource allocation: using Taiwan's National Health Insurance as an example. AB - OBJECTIVES: To determine if access to medical services differed by regions and to demonstrate the extent of the differences of adopting a claims-based risk adjustment system versus a demographic model for regional resource allocation. METHODS: The claims of a 1% random sample of Taiwan's National Health Insurance enrollees (N = 173 175) in 2002 was used. The number of visits and morbidity adjusted resource consumption were calculated individually then collapsed regionally. Regional expected resource allocation was compared with actual consumption. RESULTS: After controlling for diagnosis-based health measures, the average numbers of visits were stable across regions. Two models were consistent in showing over- or underutilization; the overall difference between two models in resource allocation was 5.8% at the district level. We observed strong urban overutilization and rural underutilization. CONCLUSIONS: Access to medical services is similar across regions. The adoption of a diagnosis-based model over a demographic-adjusted budgeting method would affect resource allocation considerably. PMID- 23343644 TI - The childhood sexual abuse among youth in three Asian cities: Taipei, Shanghai, and Hanoi. AB - The article describes the prevalence and risk factors of childhood sexual abuse (CSA) among youth in Hanoi, Shanghai, and Taipei. Data used in this study are from the Three-City Asian Study of Adolescents and Youth, 2006-2007. Descriptive analysis and logistic regression models were used. The self-reported lifetime prevalence of CSA was 5.2% in Taipei, 1.3% in Shanghai, and 0.5% in Hanoi. The overall prevalence was 2.2% for females and 1.7% for males. The average age of first CSA was 10.5 years. Household instability, migration before age 14, and low maternal warmth were found to be positively associated with CSA, whereas discussing problems with father and being close to mother were negatively associated with CSA, after adjusting for sociodemographic characteristics. Our findings suggested the importance of prevention programs for preteen aged children, public education to raise awareness, and further prospective studies to identify various risk markers for CSA in Asia. PMID- 23343645 TI - Occupational versus leisure-time physical activity in reducing cardiovascular risks and mortality among ethnic Chinese adults in Taiwan. AB - The aim of the study was to investigate the associations of occupational physical activity (OPA) and leisure-time physical activity (LTPA) with the risk of cardiovascular disease (CVD) and mortality. Physical activity data from the Baeck questionnaire was available for 1706 participants. During a follow-up period, there were 215 cases of CVD and 438 deaths. With the lowest tertile as the reference, the hazard ratios (HRs) for CVD and mortality in the highest tertiles of LTPA were 0.65 (95% confidence interval [CI] = 0.46-0.92) and 0.73 (95% CI = 0.58-0.92). In contrast, the HRs for CVD and mortality in the highest tertiles of OPA were 1.75 (95% CI = 1.10-2.80) and 1.53 (95% CI = 1.06-2.22). The association between OPA and the risk of CVD and mortality was significant in men but not in women. Our findings suggest that high OPA imposes harmful effects on the risk of CVD and mortality, particularly among men. PMID- 23343646 TI - Mapping risk of Nipah virus transmission across Asia and across Bangladesh. AB - Nipah virus is a highly pathogenic but poorly known paramyxovirus from South and Southeast Asia. In spite of the risks that it poses to human health, the geography and ecology of its occurrence remain little understood-the virus is basically known from Bangladesh and peninsular Malaysia, and little in between. In this contribution, I use documented occurrences of the virus to develop ecological niche-based maps summarizing its likely broader occurrence-although rangewide maps could not be developed that had significant predictive abilities, reflecting minimal sample sizes available, maps within Bangladesh were quite successful in identifying areas in which the virus is predictably present and likely transmitted. PMID- 23343647 TI - Coxiella burnetii in ticks, Argentina. PMID- 23343648 TI - Comparison of GLUT1, GLUT2, GLUT4 and SGLT1 mRNA expression in the salivary glands and six other organs of control, streptozotocin-induced and Goto-Kakizaki diabetic rats. AB - BACKGROUND/AIMS: The expression and localization of several distinct glucose transporters (GLUT1, GLUT2, GLUT4, and SGLT1) was recently characterized in the parotid gland of normal rats by quantitative real-time PCR analysis, immunohistochemistry and Western blotting. The major aims of the present study was to compare the mRNA expression of these glucose transporters in both the parotid gland and submaxillary gland of control rats, streptozotocin-induced diabetic rats and hereditarily diabetic Goto-Kakizaki rats. METHODS: Quantitative real-time PCR analysis was performed in the parotid and submaxillary salivary glands and, for purpose of comparison, also in the heart, kidney, liver, lung, muscle and pancreas from control animals and either streptozotocin-treated or Goto-Kakizaki rats. RESULTS: The expression of GLUT4, but not GLUT1 or SGLT1, mRNA was decreased in the diabetic rats. The results also allow comparing both the mRNA expression level of the four glucose transporters in salivary glands and six other organs, and the diabetes-induced changes in such an expression in distinct locations. CONCLUSION: The mRNA expression of the insulin-dependent GLUT4 transporter was the sole to be significantly decreased in the salivary glands of diabetic animals. The possible consequence of such a decrease in terms of the control of salivary glucose concentration requires further investigation. PMID- 23343649 TI - A practical tranexamic acid dosing scheme based on population pharmacokinetics in children undergoing cardiac surgery. AB - BACKGROUND: Pediatric cardiac surgery patients are at high risk for bleeding, and the antifibrinolytic drug tranexamic acid (TA) is often used to reduce blood loss. However, dosing schemes remain empirical as a consequence of the absence of pharmacokinetic study in this population. The authors' objectives were thus to investigate the population pharmacokinetics of TA in pediatric cardiac surgery patients during cardiopulmonary bypass (CPB). METHODS: Twenty-one patients were randomized to receive TA either continuously (10 mg/kg followed by an infusion of 1 mg . kg . h(-1) throughout the operation, and 10 mg/kg into the CPB) or discontinuously (10 mg/kg, then 10 mg/kg into the CPB and 10 mg . kg . h(-1) at the end of CPB). Serum concentrations were measured at eight time points with chromatography-mass spectrometry and the data were modeled using Monolix (Lixoft, Orsay, France). RESULTS: Tranexamic acid pharmacokinetics was ascribed to a two compartment open model. The main covariate effects were body weight and CPB. Representative pharmacokinetic parameters adjusted to a 70-kg body weight were as follows: systemic clearance, 2.45 l/h; volume of distribution in the central compartment, 14.1 l; intercompartmental clearance, 5.74 l/h; and peripheral volume, 32.8 l. In accordance with this model, the authors proposed a weight adjusted dosing scheme to maintain effective TA concentrations in children during surgery, consisting of one loading dose followed by a continuous infusion. CONCLUSIONS: The authors report for the first time the pharmacokinetics of TA in children undergoing cardiac surgery with CPB, and propose a dosing scheme for optimized TA administration in those children. PMID- 23343651 TI - 2012 Emery A. Rovenstine Memorial Lecture: the genesis, development, and future of the American Society of Anesthesiologists evidence-based practice parameters. PMID- 23343650 TI - Anesthetic techniques for fetal surgery: effects of maternal anesthesia on intraoperative fetal outcomes in a sheep model. AB - BACKGROUND: Use of high-dose inhalational anesthesia during open fetal surgery may induce maternal-fetal hemodynamic instability and fetal myocardial depression. The authors' preliminary human retrospective study demonstrated less fetal bradycardia and left ventricular systolic dysfunction with lower dose desflurane supplemented with propofol and remifentanil IV anesthesia (SIVA). In this animal study, the authors compare maternal-fetal effects of high-dose desflurane anesthesia (HD-DES) and SIVA. METHODS: Of 26 instrumented midgestational ewes, data from 11 animals exposed to both SIVA and HD-DES in random sequences and six animals exposed to HD-DES while maternal normotension was maintained were analyzed. Maternal electroencephalography was used to guide comparable depths of anesthesia in both techniques. Hemodynamic parameters, blood gas, and fetal cardiac function from echocardiography were recorded. RESULTS: Compared with SIVA, HD-DES resulted in significant maternal hypotension (mean arterial pressure difference, 19.53 mmHg; 95% CI, 17.6-21.4; P < 0.0001), fetal acidosis (pH 7.11 vs. 7.24 at 150 min, P < 0.001), and decreased uterine blood flow. In the HD-DES group with maternal normotension, uterine blood flow still declined and fetal acidosis persisted, with no statistically significant difference from the group exposed to HD-DES that had maternal hypotension. There was no statistically significant difference in fetal cardiac function. CONCLUSION: In sheep, SIVA affects maternal hemodynamics less and provides better fetal acid/base status than high-dose desflurane. Fetal echocardiography did not reflect myocardial dysfunction in this model. PMID- 23343652 TI - Nasal high-mobility group box-1 protein in children with allergic rhinitis. AB - BACKGROUND: Allergic rhinitis (AR) is characterized by an inflammatory reaction. High-mobility group box-1 protein (HMGB1) has many characteristics similar to classic proinflammatory cytokines. No study has yet investigated its role in AR. The aim of this study was to measure HMGB1 levels in the fluid recovered from nasal lavage in children with untreated AR and in control subjects. MATERIALS: The study was conducted on 104 AR subjects (48 males and 56 females, median age 10.3 +/- 3.4 years) and 97 healthy children (42 males and 55 females) who were age-matched (median age 9.8 +/- 4.1 years). Total serum immunoglobulin E, peripheral eosinophils and nasal symptoms assessed by visual analog scale (VAS) were considered. HMGB1 was measured using an ELISA assay. RESULTS: HMGB1 levels in nasal lavage fluid were higher in AR children than in the control group (96.9 +/- 19.3 vs. 9.27 +/- 4.01 ng/ml; p < 0.001). There was a very strong relationship between HMGB1 levels and VAS values in AR children (r = 0.919). Considering the symptom severity assessed by VAS, there was a relationship between HMGB1 and VAS in all AR subgroups: more evident in the severe subgroup (r = 0.727). CONCLUSIONS: Nasal HMGB1 has significantly increased in children with AR and is significantly related to symptom severity. PMID- 23343653 TI - Oral administration of Ag suppresses Ag-induced allergic conjunctivitis in mice: critical timing and dose of Ag. AB - BACKGROUND/AIMS: To investigate the effect of Ag doses and administration time points on oral tolerance induction in experimental allergic conjunctivitis (EAC). METHODS: BALB/c mice were actively sensitised twice with ovalbumin (OVA) in alum, and then challenged twice with OVA in eye drops. Twenty minutes after the last challenge, the clinical appearance was evaluated. Twenty-four hours later, the conjunctivas, spleens and blood were collected for histological analyses, cytokine production assays, and measurement of serum Ig levels, respectively. The mice were fed with a high or low dose of OVA before sensitisation (prophylactic treatment). To assess the effect of therapeutic treatment, the high-dose Ag was administered after sensitisation. Control groups received phosphate-buffered saline without OVA. To determine the role of interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) in prophylactic low-dose oral tolerance, mice were injected intraperitoneally with neutralising antibodies during the entire experimental period. To assess the role of regulatory T cells, neonatally thymectomised mice were injected with depleting anti-CD25 monoclonal antibodies before the low-dose prophylactic treatment. RESULTS: OVA-feeding was suppressive even when the mice were treated soon after Ag sensitisation. Both the low and high doses of oral OVA suppressed EAC. High-dose treatment significantly suppressed EAC-related cytokine production and serum Ig levels. IL-10 and TGF beta were less likely to be involved in prophylactic low-dose oral tolerance induction but regulatory T cells played a role. CONCLUSIONS: Prophylactic and early therapeutic treatment of OVA feeding suppressed EAC. Both high and low doses of oral OVA induced oral tolerance but with different mechanisms. PMID- 23343654 TI - Grey and white matter changes in children with monocular amblyopia: voxel-based morphometry and diffusion tensor imaging study. AB - AIMS: To investigate the potential morphological alterations of grey and white matter in monocular amblyopic children using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). METHODS: A total of 20 monocular amblyopic children and 20 age-matched controls were recruited. Whole-brain MRI scans were performed after a series of ophthalmologic exams. The imaging data were processed and two-sample t-tests were employed to identify group differences in grey matter volume (GMV), white matter volume (WMV) and fractional anisotropy (FA). RESULTS: After image screening, there were 12 amblyopic participants and 15 normal controls qualified for the VBM analyses. For DTI analysis, 14 amblyopes and 14 controls were included. Compared to the normal controls, reduced GMVs were observed in the left inferior occipital gyrus, the bilateral parahippocampal gyrus and the left supramarginal/postcentral gyrus in the monocular amblyopic group, with the lingual gyrus presenting augmented GMV. Meanwhile, WMVs reduced in the left calcarine, the bilateral inferior frontal and the right precuneus areas, and growth in the WMVs was seen in the right cuneus, right middle occipital and left orbital frontal areas. Diminished FA values in optic radiation and increased FA in the left middle occipital area and right precuneus were detected in amblyopic patients. CONCLUSIONS: In monocular amblyopia, cortices related to spatial vision underwent volume loss, which provided neuroanatomical evidence of stereoscopic defects. Additionally, white matter development was also hindered due to visual defects in amblyopes. Growth in the GMVs, WMVs and FA in the occipital lobe and precuneus may reflect a compensation effect by the unaffected eye in monocular amblyopia. PMID- 23343655 TI - Initial treatment of Pseudomonas aeruginosa contact lens-associated keratitis with topical chloramphenicol, and effect on outcome. AB - AIM: To determine whether initial empiric treatment of cases with Pseudomonas aeruginosa contact lens-associated keratitis (CLAK) with chloramphenicol had an adverse effect on outcome. METHODS: We retrospectively reviewed 139 cases of culture-proven P. aeruginosa CLAK seen between 2007 and 2009. We recorded chloramphenicol use prior to the prescription of a fluoroquinolone, the visual acuity (VA) when the fluoroquinolone was started and at final follow-up, complications and duration of follow-up. RESULTS: 46 patients (33.1%) had used chloramphenicol before they were prescribed a fluoroquinolone. When we compared this group with patients who had initial treatment with a fluoroquinolone, the ulcer size was larger when a fluoroquinolone was started (Mann-Whitney, p=0.018). Although the initial VA was also worse in the chloramphenicol group (p=0.02), and complications more frequent (p=0.016), the final VA in both groups was similar (p=0.29). The chloramphenicol group had a longer median follow-up of 37 days (IQR: 9-310 days) compared with 21 days (IQR: 6-80 days) for the non chloramphenicol group (p=0.09). CONCLUSIONS: Chloramphenicol 0.5% eye drops are available in the UK without prescription. Chloramphenicol had been used in one third of cases of P. aeruginosa CLAK prior to the use of a broad-spectrum antimicrobial, which was associated with more complications and a longer interval to resolution, but with no adverse effect on final VA. PMID- 23343657 TI - Simultaneous inactivation of the p16, p15 and p14 genes encoding cyclin-dependent kinase inhibitors in canine T-lymphoid tumor cells. AB - The p16, p15 and p14 genes are widely known as tumor suppressor genes in human medicine. Although a large number of genetic and epigenetic aberrations in these genes have been reported in human malignancies, canine malignancies have not been well analyzed on the aberrations of these genes. In this study, the full-length complementary DNA (cDNA) of the canine p16 gene was cloned using the 5' and 3' rapid amplification of cDNA ends methods. Based on the sequence data, primers specific for p16, p15 and p14 were designed. Using these primers, the expression of p16, p15 and p14 mRNAs could be individually evaluated by reverse transcriptase polymerase chain reaction. Genomic aberrations were also examined using genomic polymerase chain reaction. Two of the 6 canine lymphoid tumor cell lines did not express detectable levels of p16, p15 and p14 mRNAs, and wide ranging deletions in the p15-p14-p16 genomic locus were suspected. Wide-ranging deletions were also speculated in 2 of 14 dogs with T-cell lymphoid tumors. On the other hand, similar failure of amplification suggesting wide-ranging deletions were not observed in any of the 14 dogs with B-cell lymphoma. Deletion of the p15-p14-p16 genomic locus could be one of the molecular aberrations in canine lymphoid tumor cells. PMID- 23343658 TI - Inhibitory effects of psychotropic drugs on the acetylcholine receptor-operated potassium current (IK.ACh) in guinea-pig atrial myocytes. AB - Influences of psychotropic drugs, six antipsychotics and three antidepressants, on acetylcholine receptor-operated potassium current (IK.ACh) were examined by a whole-cell patch clamp method in freshly isolated guinea-pig atrial myocyte. IK.ACh was induced by a superfusion of carbachol (CCh) or by an intracellular application of guanosine 5'-[thio] triphosphate (GTPgammaS). To elucidate mechanism for anticholinergic action, IC50 ratio, the ratio of IC50 for GTPgammaS activated IK.ACh to CCh-induced IK.ACh, was calculated. Antipsychotics and antidepressants inhibited CCh-induced IK.ACh in a concentration-dependent manner. The IC50 values were as follows; chlorpromazine 0.53 MUM, clozapine 0.06 MUM, fluphenazine 2.69 MUM, haloperidol 2.66 MUM, sulpiride 42.3 MUM, thioridazine 0.07 MUM, amitriptyline 0.03 MUM, imipramine 0.22 MUM and maprotiline 1.81 MUM. The drugs, except for sulpiride, inhibited GTPgammaS-activated IK.ACh with following IC50 values; chlorpromazine 1.71 MUM, clozapine 14.9 MUM, fluphenazine 3.55 MUM, haloperidol 2.73 MUM, thioridazine 1.90 MUM, amitriptyline 7.55 MUM, imipramine 7.09 MUM and maprotiline 5.93 MUM. The IC50 ratio for fluphenazine and haloperidol was close to unity. The IC50 ratio for chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine and maprotiline was much higher than unity. The present findings suggest that the psychotropics studied suppress IK.ACh. Chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine, maprotiline and sulpiride are preferentially acting on muscarinic receptor. Fluphenazine and haloperidol may act on G protein and/or potassium channel. PMID- 23343659 TI - Force application during handcycling and handrim wheelchair propulsion: an initial comparison. AB - The aim of the study was to evaluate the external applied forces, the effectiveness of force application and the net shoulder moments of handcycling in comparison with handrim wheelchair propulsion at different inclines. Ten able bodied men performed standardized exercises on a treadmill at inclines of 1%, 2.5% and 4% with an instrumented handbike and wheelchair that measured three dimensional propulsion forces. The results showed that during handcycling significantly lower mean forces were applied at inclines of 2.5% (P < .001) and 4% (P < .001) and significantly lower peak forces were applied at all inclines (1%: P = .014, 2.5% and 4%: P < .001). At the 2.5% incline, where power output was the same for both devices, total forces (mean over trial) of 22.8 N and 27.5 N and peak forces of 40.1 N and 106.9 N were measured for handbike and wheelchair propulsion. The force effectiveness did not differ between the devices (P = .757); however, the effectiveness did increase with higher inclines during handcycling whereas it stayed constant over all inclines for wheelchair propulsion. The resulting peak net shoulder moments were lower for handcycling compared with wheelchair propulsion at all inclines (P < .001). These results confirm the assumption that handcycling is physically less straining. PMID- 23343662 TI - Grants and contracts, JIM 61-2. PMID- 23343656 TI - Clinical errors and medical negligence. AB - This paper discusses the definition, nature and origins of clinical errors including their prevention. The relationship between clinical errors and medical negligence is examined as are the characteristics of litigants and events that are the source of litigation. The pattern of malpractice claims in different specialties and settings is examined. Among hospitalized patients worldwide, 3 16% suffer injury as a result of medical intervention, the most common being the adverse effects of drugs. The frequency of adverse drug effects appears superficially to be higher in intensive care units and emergency departments but once rates have been corrected for volume of patients, comorbidity of conditions and number of drugs prescribed, the difference is not significant. It is concluded that probably no more than 1 in 7 adverse events in medicine result in a malpractice claim and the factors that predict that a patient will resort to litigation include a prior poor relationship with the clinician and the feeling that the patient is not being kept informed. Methods for preventing clinical errors are still in their infancy. The most promising include new technologies such as electronic prescribing systems, diagnostic and clinical decision-making aids and error-resistant systems. PMID- 23343663 TI - Efficiency improvements of public hospitals under a capitation payment scheme. AB - In a context of cost containment and demands for better quality in public health care, payment systems are used as an instrument to promote efficiency improvements in service providers. Andalusia has adopted an original type of risk adjusted capitation payment mechanism to reimburse public hospitals. This paper presents the main characteristics of the reimbursement mechanism of the Andalusian Health Service highlighting some differences with the mechanisms adopted in other parts of Europe. The paper also explores the evolution of the efficiency and quality of the hospitals after its implementation using the Malmquist index. Results indicate that hospitals have slightly improved their efficiency, particularly urban hospitals, and these improvements are not significantly related to a negative evolution of quality. However, it is not possible to assert to what extent, improvements are the consequence of the new payment system. The organisation of the Servicio Andaluz de Salud and the limited competition between hospitals reduce the effectiveness of the reform. PMID- 23343664 TI - Omnidirectional suppression of Anderson localization of light in disordered one dimensional photonic superlattices. AB - The omnidirectional suppression of Anderson localization of light in a disordered one-dimensional normal-metamaterial photonic superlattice is thoroughly investigated. Analytical conditions relating to the electric-permittivity and magnetic-permeability responses of each slab of the heterostructure are established for the omnidirectional divergence of the localization length of the normal-metamaterial superlattice. The robustness of such conditions with respect to the degree of disorder of the superlattice is also analyzed. PMID- 23343665 TI - Differential and better response to deep brain stimulation of chorea compared to dystonia in Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominant and progressive neurodegenerative syndrome characterized by motor, cognitive and psychiatric manifestations. Chorea and dystonia are features that may be troublesome to some patients and may potentially prove unresponsive to pharmacological treatments. There are several reports on the results of globus pallidus internus deep brain stimulation (DBS) surgery for HD. In these published cases, DBS was utilized mainly to treat disabling chorea. We report our experience with 2 HD cases treated with DBS. The cases illustrate a differential response with a better outcome in the choreic presentation compared to the dystonic presentation. Additionally, DBS worsened gait features in both cases. PMID- 23343666 TI - Deep venous thrombosis after repair of nonruptured abdominal aneurysm. AB - OBJECTIVE: To examine venous thromboembolism (VTE) rates, timing, and risk factors after nonruptured open or endoluminal abdominal aortic aneurysm (AAA) repair. METHODS: We queried The American College of Surgeons National Surgery Quality Improvement Program dataset from 2005 to 2009 for open or endoluminal AAA repairs using Current Procedural Terminology and International Classification of Diseases, 9th Edition, codes. Operations performed emergently or for ruptured AAA were excluded. VTE was defined as either deep venous thrombosis or pulmonary embolism requiring treatment within 30 days of operation. VTE was classified as occurring in-hospital or postdischarge. Univariate and multivariable analyses of VTE were performed relative to preoperative and operative risks, including type of repair. RESULTS: Query of the dataset yielded 12,469 patients: 8502 endoluminal (68.2%) and 3967 (31.8%) open repairs. Mean patient age was 73.2 +/- 8.7 (standard deviation) years, and 19.8% of patients were women. The 30-day VTE rate was 1.1% (n = 135). Of VTE cases, 30% (40/135) were diagnosed after discharge from the surgical hospitalization. The postdischarge VTE rate was 0.3% after both open and endoluminal repairs. The in-hospital VTE rate was higher in the open group (1.6% vs 0.4%; P < .001), as was median length of stay (7 days vs 2 days; P < .001). Independent preoperative predictors of in-hospital VTE were dyspnea, serum albumin (protective), and history of peripheral vascular disease. With preoperative risk adjustment, in-hospital VTE risk increased with duration of operation and number of units of blood transfused. Open repairs were associated with higher risk for VTE than endoluminal repairs (odds ratio, 1.91; 95% confidence interval, 1.10-3.33; P = .022). VTE was associated with increased 30-day mortality from 1.9% (232/12,102) in patients without VTE to 4.4% (6/135) in patients with VTE (chiP = .035). CONCLUSIONS: VTE after AAA repair was infrequent but was associated with higher mortality, and one-third of VTEs were diagnosed after discharge. Open AAA repair increased risk for in-hospital VTE compared with endoluminal repair. Patients with the identified risk factors may benefit from pharmacologic thromboprophylaxis after AAA repair. Pharmacologic thromboprophylaxis may be unnecessary after endoluminal repair. PMID- 23343667 TI - Bifurcated coronary stents for infrapopliteal angioplasty in critical limb ischemia. AB - OBJECTIVE: The goal of this article is to report the preliminary results of infrapopliteal percutaneous transluminal angioplasty stenting with the Nile Croco coronary bifurcated stent (Minvasys, Gennevilliers, France) for selected patients with critical limb ischemia (CLI). METHODS: From October 2006 to December 2010, 31 patients with CLI with below-the-knee TransAtlantic Inter-Society Consensus C and D lesions at the popliteal (n = 17, 54.8%) and distal tibioperoneal trunk (n = 14, 45.2%) bifurcations, with suboptimal primary percutaneous transluminal angioplasty results (residual stenosis >30%, elastic recoiling, or dissection), with at least two-vessel runoff to the foot (present or after percutaneous transluminal angioplasty), free of aortoiliac arterial disease, and at high surgical risk (more than three risk factors) were treated with the Nile Croco coronary bifurcated stent. Study end points included technical success, immediate and midterm primary and secondary patency rates, clinical improvement, and limb salvage. RESULTS: Technical success was achieved in all patients (100%) without any intraoperative complications. Early complications included an acute stent occlusion and an acute compartment syndrome for a collateral arterial branch perforation. Median follow-up was 12.1 months (range, 1-32). Primary and secondary patency rates were 96.7% and 86.2% (95% confidence interval [CI], 67.2% 94.6%) at 30 days and and 100% and 96.6% (95% CI, 78.0%-99.5%) at 1 year, respectively. Clinical improvement (an upward shift of at least two Rutherford categories) was achieved in 28 patients (90.3%). A major amputation was required in one patient (3.2%). The overall limb salvage rate at 1 year was 96.7% (95% CI, 78.6%-99.5%). CONCLUSIONS: Preliminary data suggest that the Nile Croco bifurcated stent for below-the-knee angioplasty in selected patients with CLI is associated with high rates of technical success, early and midterm patency, and clinical improvement. Limb salvage rates are acceptable for this technically highly challenging anatomy, yet further studies with larger patient populations are necessary to validate these results. PMID- 23343668 TI - Pathogenesis and etiology of recurrent varicose veins. AB - BACKGROUND: Recurrent varicose veins (RVV) occur in 13% to 65% of patients following treatment, and remain a debilitating and costly problem. RVV were initially thought largely to be due to inadequate intervention, however, more recently neovascularization and other factors have been implicated. This review aims to provide an overview of the current understanding of the etiology and pathogenesis of RVV. METHODS: A systematic search of the PubMed database was performed using the search terms including "recurrent," "varicose veins," and "neovascularization." RESULTS: Three types of RVV have been reported, namely residual veins, true RVV, and new varicose veins, although the definitions varied between studies. RVV are attributable to causes including inadequate treatment, disease progression, and neovascularization. Using duplex ultrasonography, neovascularization has been observed in 25% to 94% of RVV. These new vessels appear in various size, number, and tortuosity, and they reconnect previously treated diseased veins to the lower limb venous circulation. Histologically, these vessels appear primitive with incomplete vein wall formation, decreased elastic component, and lack of valves and accompanying nerves. Although the rate of RVV following open surgery and endovenous treatment appears similar, neovascularization seems less common following endothermal ablation. Other causes of RVV following endovenous treatment include recanalization and opening of collaterals. CONCLUSIONS: Recurrence remains poorly understood following treatment of varicose veins. Neovascularization is an established and common cause of RVV, although other factors may contribute. PMID- 23343669 TI - Habitual dietary intake is associated with stool microbiota composition in monozygotic twins. AB - The impact of diet on the gut microbiota has usually been assessed by subjecting people to the same controlled diet and thereafter following the shifts in the microbiota. In the present study, we used habitual dietary intake, clinical data, quantitative polymerase chain reaction, and denaturing gradient gel electrophoresis (DGGE) to characterize the stool microbiota of Finnish monozygotic twins. The effect of diet on the numbers of bacteria was described through a hierarchical linear mixed model that included the twin individuals, stratified by body mass index, and their families as random effects. The abundance and diversity of the bacterial groups studied did not differ between normal-weight, overweight, and obese individuals with the techniques used. Intakes of energy, monounsaturated fatty acids, n3 polyunsaturated fatty acids (PUFAs), n6 PUFAs, and soluble fiber had significant associations with the stool bacterial numbers (e.g., increased energy intake was associated with reduced numbers of Bacteroides spp.). In addition, co-twins with identical energy intake had more similar numbers and DGGE-profile diversities of Bacteroides spp. than did the co-twins with different intake. Moreover, the co-twins who ingested the same amounts of saturated fatty acids had very similar DGGE profiles of Bacteroides spp., whereas the co-twins with similar consumption of fiber had a very low bifidobacterial DGGE-profile similarity. In conclusion, our findings confirm that the diet plays an important role in the modulation of the stool microbiota, in particular Bacteroides spp. and bifidobacteria. PMID- 23343670 TI - Higher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE Consortium Studies. AB - Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [beta = -0.009 mmol/L (95% CI: -0.013, -0.005), P < 0.0001] and insulin [ 0.020 ln-pmol/L (95% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted. PMID- 23343672 TI - Cash and in-kind transfers lead to excess weight gain in a population of women with a high prevalence of overweight in rural Mexico. AB - There is a growing concern that food or cash transfer programs may contribute to overweight and obesity in adults. We studied the impact of Mexico's Programa de Apoyo Alimentario (PAL), which provided very poor rural households with cash or in-kind transfers, on women's body weight. A random sample of 208 rural communities in southern Mexico was randomly assigned to 1 of 4 groups: food basket with or without health and nutrition education, cash with education, or control. The impact on women's weight was estimated in a cohort of 3010 women using a difference-in-difference model. We compared the impact between the food basket and cash groups and evaluated whether the impact was modified by women's BMI status at baseline. With respect to the control group, the program increased women's weight in the food basket (550 +/- 210 g; P = 0.004) and the cash group (420 +/- 230 g; P = 0.032); this was equivalent to 70 and 53% increases in weight gain, respectively, over that observed in the control group in a 23-mo time period. The greatest impact was found in already obese women: 980 +/- 290 g in the food basket group (P = 0.001) and 670 +/- 320 g in the cash group (P = 0.019). Impact was marginally significant in women with a preprogram BMI between 25 and 30 kg/m2: 490 +/- 310 g (P = 0.055) and 540 +/- 360 g (P = 0.067), respectively. No program impact was found in women with a BMI <25 kg/m2. Providing households with a considerable amount of unrestricted resources led to excess weight gain in an already overweight population. Research is needed to develop cost-effective behavior change communication strategies to complement cash and in-kind transfer programs such as PAL and to help beneficiaries choose healthy diets that improve the nutritional status of all family members. PMID- 23343671 TI - Protein blend ingestion following resistance exercise promotes human muscle protein synthesis. AB - High-quality proteins such as soy, whey, and casein are all capable of promoting muscle protein synthesis postexercise by activating the mammalian target of rapamycin (mTORC1) signaling pathway. We hypothesized that a protein blend of soy and dairy proteins would capitalize on the unique properties of each individual protein and allow for optimal delivery of amino acids to prolong the fractional synthetic rate (FSR) following resistance exercise (RE). In this double-blind, randomized, clinical trial, 19 young adults were studied before and after ingestion of ~19 g of protein blend (PB) or ~18 g whey protein (WP) consumed 1 h after high-intensity leg RE. We examined mixed-muscle protein FSR by stable isotopic methods and mTORC1 signaling with western blotting. Muscle biopsies from the vastus lateralis were collected at rest (before RE) and at 3 postexercise time points during an early (0-2 h) and late (2-4 h) postingestion period. WP ingestion resulted in higher and earlier amplitude of blood branched-chain amino acid (BCAA) concentrations. PB ingestion created a lower initial rise in blood BCAA but sustained elevated levels of blood amino acids later into recovery (P < 0.05). Postexercise FSR increased equivalently in both groups during the early period (WP, 0.078 +/- 0.009%; PB, 0.088 +/- 0.007%); however, FSR remained elevated only in the PB group during the late period (WP, 0.074 +/- 0.010%; PB, 0.087 +/- 0.003%) (P < 0.05). mTORC1 signaling similarly increased between groups, except for no increase in S6K1 phosphorylation in the WP group at 5 h postexercise (P < 0.05). We conclude that a soy-dairy PB ingested following exercise is capable of prolonging blood aminoacidemia, mTORC1 signaling, and protein synthesis in human skeletal muscle and is an effective postexercise nutritional supplement. PMID- 23343673 TI - Plasma ferritin and soluble transferrin receptor concentrations and body iron stores identify similar risk factors for iron deficiency but result in different estimates of the national prevalence of iron deficiency and iron-deficiency anemia among women and children in Cameroon. AB - Available iron status indicators reflect different aspects of metabolism. We compared the prevalence and distribution of iron deficiency (ID) and iron deficiency anemia (IDA) among Cameroonian women and children, as measured by plasma ferritin, and soluble transferrin receptor concentrations, body iron stores (BIS), and hemoglobin, and evaluated the impact of adjustments for inflammation on these measures. In a nationally representative survey, we randomly selected 30 clusters in each of 3 zones (north, south, and large cities) and 10 households/ cluster, each with a child aged 12-59 mo and a woman 15-49 y. Ferritin and BIS were mathematically adjusted for inflammation, using plasma C reactive protein and alpha(1)-acid glycoprotein both as continuous and categorical variables. Inflammation was present in 48.0% of children and 20.8% of women and anemia was diagnosed in 57.6% of children and 38.8% of women. Depending on the iron status indicator applied, the prevalence of ID ranged from 14.2 to 68.4% among children and 11.5 to 31.8% among women, and the prevalence of IDA ranged from 12.0 to 47.4% among children and 9.0 to 19.4% among women; the proportion of anemia associated with ID ranged from 20.8 to 82.3% among children and 23.2 to 50.0% among women. The different iron indicators generally identified similar groups at greatest risk of deficiency, using both conventional and derived cutoffs: younger children, pregnant women, and women and children in the north and rural areas. Research is needed to clarify the relationships between iron status indicators, particularly in the presence of inflammation, to harmonize global data on prevalence of ID. PMID- 23343674 TI - Factor analysis is more appropriate to identify overall dietary patterns associated with diabetes when compared with Treelet transform analysis. AB - Treelet transform (TT) is a proposed alternative to factor analysis for deriving dietary patterns. Before applying this method to nutrition data, further analyses are required to assess its validity in nutritional epidemiology. We aimed to compare dietary patterns from factor analysis and TT and their associations with diabetes incidence. Complete data were available for 7349 women (50-55 y at baseline) from the Australian Longitudinal Study on Women's Health. Exploratory factor analysis and TT were performed to obtain patterns by using dietary data collected from an FFQ. Generalized estimating equations analyses were used to examine associations between dietary patterns and diabetes incidence. Two patterns were identified by both methods: a prudent and a Western dietary pattern. Factor analysis factors are a linear combination of all food items, whereas TT factors also include items with zero loading. The Western pattern identified by factor analysis showed a significant positive association with diabetes [highest quintile: OR = 1.94 (95% CI: 1.25, 3.00); P-trend = 0.001). Both factor analysis and TT involve different assumptions and subjective decisions. TT produces clearly interpretable factors accounting for almost as much variance as factors from factor analysis. However, TT patterns include food items with zero loading and therefore do not represent overall dietary patterns. The different dietary pattern loading structures identified by both methods result in different conclusions regarding the relationship with diabetes. Results from this study indicate that factor analysis might be a more appropriate method for identifying overall dietary patterns associated with diabetes compared with TT. PMID- 23343675 TI - Sweet bing cherries lower circulating concentrations of markers for chronic inflammatory diseases in healthy humans. AB - A limited number of studies have demonstrated that some modulators of inflammation can be altered by the consumption of sweet cherries. We have taken a proteomics approach to determine the effects of dietary cherries on targeted gene expression. The purpose was then to determine changes caused by cherry consumption in the plasma concentrations of multiple biomarkers for several chronic inflammatory diseases in healthy humans with modestly elevated C-reactive protein (CRP; range, 1-14 mg/L; mean, 3.5 mg/L; normal, <1.0 mg/L). Eighteen men and women (45-61 y) supplemented their diets with Bing sweet cherries (280 g/d) for 28 d. Fasting blood samples were taken before the start of consuming the cherries (study d 7), 28 d after the initiation of cherry supplementation (d 35), and 28 d after the discontinuation (d 63). Of the 89 biomarkers assessed, cherry consumption for 28 d altered concentrations of 9, did not change those of 67, and the other 13 were below the detection limits. Cherry consumption decreased (P < 0.05) plasma concentrations of extracellular newly identified ligand for the receptor for advanced glycation end products (29.0%), CRP (20.1%), ferritin (20.3%), plasminogen activator inhibitor-1 (19.9%), endothelin-1 (13.7%), epidermal growth factor (13.2%), and IL-18 (8.1%) and increased that of IL-1 receptor antagonist (27.9%) compared with corresponding values on study d 7. The ferritin concentration continued to decrease between d 35 and 63 and it was significantly lower on d 63 than on d 7. Because the participants in this study were healthy, no clinical pathology end points were measured. However, results from the present study demonstrate that cherry consumption selectively reduced several biomarkers associated with inflammatory diseases. PMID- 23343677 TI - High-fat diet is associated with obesity-mediated insulin resistance and beta cell dysfunction in Mexican Americans. AB - Consumption of energy-dense, nutrient-poor foods has contributed to the rising incidence of obesity and may underlie insulin resistance and beta-cell dysfunction. Macronutrient intake patterns were examined in relation to anthropometric and metabolic traits in participants of BetaGene, a family-based study of obesity, insulin resistance, and beta-cell dysfunction in Mexican Americans. Dietary intake, body composition, insulin sensitivity (SI), and beta cell function [Disposition Index (DI)] were assessed by food-frequency questionnaires, dual-energy X-ray absorptiometry, and intravenous glucose tolerance tests, respectively. Patterns of macronutrient intake were identified by using a K-means model based on the proportion of total energy intake per day attributable to carbohydrate, fat, and protein and were tested for association with anthropometric and metabolic traits. Among 1150 subjects aged 18-65 y (73% female), tertiles of fat intake were associated with greater adiposity and lower SI, after adjustment for age, sex, and daily energy intake. Moreover, 3 distinct dietary patterns were identified: "high fat" (35% fat, 44% carbohydrate, 21% protein; n = 238), "moderate fat" (28% fat, 54% carbohydrate, 18% protein; n = 520), and "low fat" (20% fat, 65% carbohydrate, 15% protein; n = 392). Compared with the low-fat group, the high-fat group had higher age- and sex-adjusted mean body mass index, body fat percentage, and trunk fat and lower SI and DI. Further adjustment for daily energy intake by matching individuals across dietary pattern groups yielded similar results. None of the observed associations were altered after adjustment for physical activity; however, associations with SI and DI were attenuated after adjustment for adiposity. These findings suggest that high-fat diets may contribute to increased adiposity and concomitant insulin resistance and beta-cell dysfunction in Mexican Americans. PMID- 23343676 TI - Addition of carbohydrate or alanine to an essential amino acid mixture does not enhance human skeletal muscle protein anabolism. AB - In humans, essential amino acids (EAAs) stimulate muscle protein synthesis (MPS) with no effect on muscle protein breakdown (MPB). Insulin can stimulate MPS, and carbohydrates (CHOs) and insulin decrease MPB. Net protein balance (NB; indicator of overall anabolism) is greatest when MPS is maximized and MPB is minimized. To determine whether adding CHO or a gluconeogenic amino acid to EAAs would improve NB compared with EAA alone, young men and women (n = 21) ingested 10 g EAA alone, with 30 g sucrose (EAA+CHO), or with 30 g alanine (EAA+ALA). The fractional synthetic rate and phenylalanine kinetics (MPS, MPB, NB) were assessed by stable isotopic methods on muscle biopsies at baseline and 60 and 180 min following nutrient ingestion. Insulin increased 30 min postingestion in all groups and remained elevated in the EAA+CHO and EAA+ALA groups for 60 and 120 min, respectively. The fractional synthetic rate increased from baseline at 60 min in all groups (P < 0.05; EAA = 0.053 +/- 0.018 to 0.090 +/- 0.039% . h(-1); EAA+ALA = 0.051 +/- 0.005 to 0.087 +/- 0.015% . h(-1); EAA+CHO = 0.049 +/- 0.006 to 0.115 +/- 0.024% . h(-1)). MPS and NB peaked at 30 min in the EAA and EAA+CHO groups but at 60 min in the EAA+ALA group and NB was elevated above baseline longer in the EAA+ALA group than in the EAA group (P < 0.05). Although responses were more robust in the EAA+CHO group and prolonged in the EAA+ALA group, AUCs were similar among all groups for fractional synthetic rate, MPS, MPB, and NB. Because the overall muscle protein anabolic response was not improved in either the EAA+ALA or EAA+CHO group compared with EAA, we conclude that protein nutritional interventions to enhance muscle protein anabolism do not require such additional energy. PMID- 23343678 TI - White button mushrooms increase microbial diversity and accelerate the resolution of Citrobacter rodentium infection in mice. AB - The effect of feeding C57BL/6 mice white button (WB) mushrooms or control (CTRL) diets for 6 wk was determined on the bacterial microflora, urinary metabolome, and resistance to a gastrointestinal (GI) pathogen. Feeding mice a diet containing 1 g WB mushrooms/100 g diet resulted in changes in the microflora that were evident at 2 wk and stabilized after 4 wk of WB feeding. Compared with CTRL fed mice, WB feeding (1 g/100 g diet) increased the diversity of the microflora and reduced potentially pathogenic (e.g., Clostridia) bacteria in the GI tract. Bacteria from the Bacteroidetes phylum increased and the Firmicutes phylum decreased in mushroom-fed mice compared with CTRL. The changes in the microflora were also reflected in the urinary metabolome that showed a metabolic shift in the WB-fed compared with the CTRL-fed mice. The WB feeding and changes in the microbiome were associated with fewer inflammatory cells and decreased colitis severity in the GI mucosa following Citrobacter rodentium infection compared with CTRL. Paradoxically, the clearance of C. rodentium infection did not differ even though Ifn-gamma and Il-17 were higher in the colons of the WB-fed mice compared with CTRL. Adding modest amounts of WB mushrooms (1 g/100 g diet) to the diet changed the composition of the normal flora and the urinary metabolome of mice and these changes resulted in better control of inflammation and resolution of infection with C. rodentium. PMID- 23343679 TI - beta-1,4-mannobiose stimulates innate immune responses and induces TLR4-dependent activation of mouse macrophages but reduces severity of inflammation during endotoxemia in mice. AB - beta-1,4-Mannobiose (MNB) has been shown to exert prebiotic activity and modulate mucosal gene expression. In this study, the immune-modulating effect of MNB in healthy and endotoxemic mice and its role in Toll-like receptor (TLR) 2/4 mediated macrophage activation were investigated. Mice were supplemented daily with MNB (0, 5, 10, or 25 mg/kg) for 14 d. To examine the effect of MNB during endotoxemia, mice were supplemented with or without MNB (25 mg/kg) for 14 d, followed by challenge with intraperitoneal LPS or saline. MNB induced expression of both T helper (Th) 1- and Th2-type cytokines in the ileum (P < 0.05) and increased fecal IgA production and splenic NK cell activity (P < 0.05) in healthy mice. In endotoxemic mice, MNB reduced the expression of Tnfa, Il-6, iNos (P < 0.05), and Il-10 (P < 0.05), and reduced LPS-induced weight loss but increased Ifng, Il-12p40, Il-5, and Ifna expression (P < 0.05) and NK cell activity relative to positive control (LPS) mice. Treatment of RAW 264.7 macrophages with MNB induced TNF-alpha and IL-6 secretion (P < 0.05), and this effect was abrogated by inhibiting TLR4, but not TLR2, signaling. Pretreatment of RAW 264.7 cells with MNB induced tolerance to TLR2 and TLR4 agonists, reducing TNF-alpha production (P < 0.05) upon secondary stimulation with LPS or lipoteichoic acid. These results indicate that MNB can modulate intestinal and systemic immune responses in healthy and endotoxemic mice and prevent LPS-induced immune suppression, as well as directly stimulating innate immune mechanisms in vitro as a TLR4 agonist. PMID- 23343680 TI - Maternal diet supplementation with methyl donors and increased parity affect the incidence of craniofacial defects in the offspring of twisted gastrulation mutant mice. AB - Diets rich in methyl-donating compounds, including folate, can provide protection against neural tube defects, but their role in preventing craniofacial defects is less clear. Mice deficient in Twisted gastrulation (TWSG1), an extracellular modulator of bone morphogenetic protein signaling, manifest both midline facial defects and jaw defects, allowing study of the effects of methyl donors on various craniofacial defects in an experimentally tractable animal model. The goal of this study was to examine the effects of maternal dietary supplementation with methyl donors on the incidence and type of craniofacial defects among Twsg1( /-) offspring. Nulliparous and primiparous female mice were fed an NIH31 standard diet (control) or a methyl donor supplemented (MDS) diet (folate, vitamin B-12, betaine, and choline). Observed defects in the pups were divided into those derived mostly from the first branchial arch (BA1) (micrognathia, agnathia, cleft palate) and midline facial defects in the holoprosencephaly spectrum (cyclopia, proboscis, and anterior truncation). In the first pregnancy, offspring of mice fed the MDS diet had lower incidence of BA1-derived defects (12.8% in MDS vs. 32.5% in control; P = 0.02) but similar incidence of midline facial defects (6.4% in MDS vs. 5.2% in control; P = 1.0). Increased maternal parity was independently associated with increased incidence of craniofacial defects after adjusting for diet (from 37.7 to 59.5% in control, P = 0.04 and from 19.1 to 45.3% in MDS, P = 0.045). In conclusion, methyl donor supplementation shows protective effects against jaw defects, but not midline facial defects, and increased parity can be a risk factor for some craniofacial defects. PMID- 23343681 TI - Regulation of renin release via cyclic ADP-ribose-mediated signaling: evidence from mice lacking CD38 gene. AB - BACKGROUND/AIMS: Despite extensive studies, the intracellular regulatory mechanism of renin production and release is still poorly understood. The present study was designed to test whether CD38-ADP-ribosylcyclase signaling pathway contributes to the regulation of renin production and release, and to examine whether CD38 gene knockout (CD38(-/-)) can change this important renal endocrinal function. METHODS: ADP-ribosylcyclase activity was estimated utilizing HPLC, cADPR levels from western blot, plasma renin activity from RIA kit, urinary sodium and potassium excretion from fame photometry. RESULTS: The expression of CD38 and the activity of ADP-ribosylcyclase to produce cyclic ADP-ribose (cADPR) were nearly abolished in the kidney from CD38(-/-) mice, indicating that CD38 gene is a major enzyme responsible for the generation of cADPR in vivo. Mice lacking CD38 gene showed increased plasma renin activity (PRA) in either conscious or anesthetized status (P<0.05). Low salt intake significantly increased, but high salt intake significantly decreased renin release in both CD38(+/+) and CD38(-/-) mice. In acute experiments, it was demonstrated that plasma renin activity (PRA) significantly increased upon isoprenaline infusion in CD38(-/-) mice compared to CD38(+/+) mice. Accompanied with such increase in PRA, glomerular filtration rate (GFR), renal blood flow (RBF), urine volume (UV) and sodium excretion (UNaV) more significantly decreased in CD38(-/-) than CD38(+/+) mice. Similarly, more increases in PRA but more decreases in GFR, RBF, UV and UNaV were observed in CD38(-/-) than CD38(+/+) mice when they had a low renal perfusion pressure (RPP). CONCLUSION: CD38-cADPR-mediated signaling may importantly contribute to the maintenance of low PRA and participate in the regulation of renal hemodynamics and excretory function in mice. PMID- 23343682 TI - Fibrosis and cardiac function in obesity: a randomised controlled trial of aldosterone blockade. AB - OBJECTIVES: As myocardial fibrosis might be an important contributor to the association of obesity with left ventricular (LV) dysfunction and heart failure, we investigated the effects of spironolactone on LV function and serological fibrosis markers (procollagen type III N-terminal propeptide (PIIINP) and procollagen type I C-terminal propeptide (PICP)) in patients with obesity and abnormal LV performance. DESIGN: A prospective, randomised, double-blind, placebo controlled study. SETTING: A university hospital. PATIENTS AND INTERVENTION: 113 patients (mean+/-SD age 58+/-8 years) with body mass index>=30, without any comorbidities, with impaired early diastolic mitral annular velocity, randomised to spironolactone 25 mg/day or placebo for 6 months. MAIN OUTCOME MEASURES: Echocardiographically derived indices of LV systolic (strain and strain rate) and diastolic (E velocity, tissue e' and E/e' ratio) function, myocardial reflectivity (calibrated integrated backscatter (IB)), and serum PICP and PIIINP. RESULTS: In the spironolactone group, significant improvements in myocardial deformation, peak early diastolic velocity (Em), E/e' and IB were noted with a simultaneous decrease in PICP and PIIINP. No corresponding alterations were found with placebo. Improvement in LV systolic function (increase in strain) was independently associated with baseline strain (beta=-0.43, p<0.001), change in IB (beta=0.26, p<0.02) and baseline PICP (beta=0.24, p<0.04). Among the independent determinants of LV diastolic improvement were for increase in Em - baseline Em (beta=-0.44, p<0.001) and baseline PICP (beta=0.35, p<0.002), and for decrease in E/e' - baseline E/e' (beta=-0.35, p<0.005) and change in PICP (beta=0.25, p<0.04). CONCLUSIONS: In patients with obesity without other comorbidities, aldosterone antagonism improves LV function and myocardial acoustic properties, and reduces circulating procollagen levels. Beneficial changes in cardiac performance are independently predicted by baseline LV dysfunction and baseline disturbances, as well as treatment-induced improvements in fibrosis markers. CLINICAL TRIAL REGISTRATION: http://www.anzctr.org.au ACTRN12609000655246. PMID- 23343683 TI - Is C reactive protein expression affected by local microenvironment? PMID- 23343684 TI - Saphenous vein graft patency: 33 year angiographic finding of a pristine vein graft to the left anterior descending artery. PMID- 23343685 TI - Feeling the squeeze: an unusual cause of atrial fibrillation. PMID- 23343686 TI - Effects of coronary sinus occlusion on myocardial ischaemia in humans: role of coronary collateral function. AB - OBJECTIVE: This study tested the hypotheses that intermittent coronary sinus occlusion (iCSO) reduces myocardial ischaemia, and that the amount of ischaemia reduction is related to coronary collateral function. DESIGN: Prospective case control study with intraindividual comparison of myocardial ischaemia during two 2-min coronary artery balloon occlusions with and without simultaneous iCSO by a balloon-tipped catheter. SETTING: University Hospital. PATIENTS: 35 patients with chronic stable coronary artery disease. INTERVENTION: 2-min iCSO. MAIN OUTCOME MEASURES: Myocardial ischaemia as assessed by intracoronary (i.c.) ECG ST shift at 2 min of coronary artery balloon occlusion. Collateral flow index (CFI) without iCSO, that is, the ratio between mean distal coronary occlusive (Poccl) and mean aortic pressure (Pao) both minus central venous pressure. RESULTS: I.c. ECG ST segment shift (elevation in all) at the end of the procedure with iCSO versus without iCSO was 1.33+/-1.25 mV versus 1.85+/-1.45 mV, p<0.0001. Regression analysis showed that the degree of i.c. ECG ST shift reduction during iCSO was related to CFI, best fitting a Lorentzian function (r(2)=0.61). Ischaemia reduction with iCSO was greatest at a CFI of 0.05-0.20, whereas in the low and high CFI range the effect of iCSO was absent. CONCLUSIONS: ICSO reduces myocardial ischaemia in patients with chronic coronary artery disease. Ischaemia reduction by iCSO depends on coronary collateral function. A minimal degree of collateral function is necessary to render iCSO effective. ICSO cannot manifest an effect when collateral function prevents ischaemia in the first place. PMID- 23343687 TI - Identifying excellence in contemporary cardiology practice: transparency, professionalism and the role of the professional society. PMID- 23343688 TI - Predictors for efficacy of percutaneous mitral valve repair using the MitraClip system: the results of the MitraSwiss registry. AB - BACKGROUND: Percutaneous mitral valve repair (MVR) using the MitraClip system has become a valid alternative for patients with severe mitral regurgitation (MR) and high operative risk. OBJECTIVE: To identify clinical and periprocedural factors that may have an impact on clinical outcome. DESIGN: Multi-centre longitudinal cohort study. SETTING: Tertiary referral centres. PATIENTS: Here we report on the first 100 consecutive patients treated with percutaneous MVR in Switzerland between March 2009 and April 2011. All of them had moderate-severe (3+) or severe (4+) MR, and 62% had functional MR. 82% of the patients were in New York Heart Association (NYHA) class III/IV, mean left ventricular ejection fraction was 48% and the median European System for Cardiac Operative Risk Evaluation was 16.9%. INTERVENTIONS: MitraClip implantation performed under echocardiographic and fluoroscopic guidance in general anaesthesia. MAIN OUTCOME MEASURES: Clinical, echocardiographic and procedural data were prospectively collected. RESULTS: Acute procedural success (APS, defined as successful clip implantation with residual MR grade <=2+) was achieved in 85% of patients. Overall survival at 6 and 12 months was 89.9% (95% CI 81.8 to 94.6) and 84.6% (95% CI 74.7 to 91.0), respectively. Univariate Cox regression analysis identified APS (p=0.0069) and discharge MR grade (p=0.03) as significant predictors of survival. CONCLUSIONS: In our consecutive cohort of patients, APS was achieved in 85%. APS and residual discharge MR grade are important predictors of mid-term survival after percutaneous MVR. PMID- 23343689 TI - The role of uric acid in the pathogenesis of human cardiovascular disease. AB - Hyperuricaemia is common in subjects with cardiovascular disease, but is not commonly considered a true risk factor. Recent studies suggest that uric acid is biologically active and can stimulate oxidative stress, endothelial dysfunction, inflammation and vasoconstriction. Epidemiological studies have found that uric acid can independently predict the development of hypertension, as well as stroke and heart failure. Experimentally raising uric acid in animals increases blood pressure, and pilot studies suggest that lowering uric acid in humans can reduce blood pressure in hypertensive individuals. Uric acid may also have emerging roles in the pathogenesis of kidney disease, metabolic syndrome and diabetes. More studies need to be performed on the pathophysiology and clinical consequences of hyperuricaemia in cardiovascular disease. PMID- 23343690 TI - Operator exposure to x-ray in left and right radial access during percutaneous coronary procedures: OPERA randomised study. AB - OBJECTIVE: Left radial access (LRA) and right radial access (RRA) have been shown to be safe and effective for coronary arteries catheterisation. However, the differences between the two approaches in terms of radiation exposure are still unclear. The aim of the present investigation is to evaluate in a randomised study, the dose of radiation absorbed by operators using either LRA or RRA. DESIGN: Randomised, prospective, double arm, single centre study. SETTING: University Hospital. PATIENTS: Male or female subjects with stable, unstable angina and silent ischaemia. INTERVENTIONS: The present study is a comparison of LRA and RRA for coronary artery catheterisation in terms of operators' radiation exposure. MAIN OUTCOME MEASURES: The primary outcome measure was the radiation dose absorbed by operators; secondary outcome measures were fluoroscopy time, dose-area product and contrast delivered. RESULTS: A total of 413 patients were enrolled; 209 were randomly selected to undergo diagnostic procedures with RRA and 204 with LRA. The operator's radiation exposure was significantly lower in the left radial group (LRA 33+/-37 MUSv vs RRA 44+/-32 MUSv, p=0.04). No significant differences were observed in fluoroscopy time (LRA 349+/-231s vs RRA 370+/-246 s p=0.09) and dose-area product (LRA 7011.42+/-3617.30 MUGym(2) vs RRA 7382.38+/-5226.61 MUGym(2), p=0.80), even though in both there was a trend towards a lower level in the LRA. No differences were observed in contrast medium delivered (LRA 89.92+/-32.55 ml vs RRA 88.88+/-35.35 ml, p=0.45). CONCLUSIONS: The LRA was associated in the present report with a lower radiation dose absorbed by the operator during coronary angiography. PMID- 23343691 TI - Clinical characteristics of gastric cancer in patients with familial adenomatous polyposis. AB - Familial adenomatous polyposis is an autosomal dominant hereditary disease leading to the development of numerous colorectal polyps with malignant potential. Extra-colonic neoplasms are observed often in patients with familial adenomatous polyposis, but clinical characteristics of gastric cancer associated with familial adenomatous polyposis are not well understood. We studied the clinical characteristics of five Japanese patients who developed gastric cancer after undergoing colectomy for familial adenomatous polyposis. Gastric cancer was found on gastroduodenal endoscopy performed during postoperative follow-up in all five patients. Mean ages at the time of colectomy and at the time of diagnosis of gastric cancer were 39.2 and 58 years, respectively. Importantly, gastric fundic gland polyps were undetectable in these five patients. The mean duration between colectomy and diagnosis of gastric cancer was more than 20 years in three of five patients (mean: 19 years and 1 month). Cancers were multiple in three of five patients. Two patients developed metachronous gastric cancer in the gastric remnant. All five patients presented with well to moderately differentiated adenocarcinoma; four of the five patients were stage IA. Characteristics of the gastric cancer with familial adenomatous polyposis include a long duration between occurrence of gastric cancer and colectomy, metachronous cancers, multicentric lesions, and a high rate of well to moderately differentiated adenocarcinoma. Long-term and periodic gastroduodenal surveillance endoscopy is recommended for patients with FAP who underwent colectomy. PMID- 23343692 TI - Inconclusive evidence for or against positive antigen selection in the shaping of human immunoglobulin E repertoires: a call for new approaches. AB - BACKGROUND: The mechanisms driving the development of immunoglobulin E (IgE) antibody repertoires are a matter of debate. Alternatives to the classical view on antibody development, involving somatic mutation and antigen-driven selection of high-affinity variants in germinal centers, have been proposed. METHODS: We have re-analyzed the pattern of mutations in previously isolated and characterized human clonally unrelated IgE-encoding transcripts using the validated focused binomial methodology to find evidence in such genes of antigen specific selection. RESULTS: As expected there is a selection against replacement mutations in IgE framework regions. In contrast, in all examined cases but one (assessing IgE repertoires of parasite-infected individuals) there was no evidence in favor of either positive or negative selection in complementarity determining regions. Importantly, however, the validated method also failed to detect selection for replacement mutations in two, non-IgE, hypermutated antibody populations targeting tetanus toxoid and vaccinia virus, respectively. CONCLUSIONS: Current methodology is unable to define with certainty, using commonly assessed IgE repertoire sizes, whether antigen selection is or is not a major driving force in the establishment of human IgE. New approaches are needed to address this matter. PMID- 23343693 TI - Fusaric acid, a mycotoxin, and its influence on blood coagulation and platelet function. AB - The current study intended to explore the effect of fusaric acid on blood coagulation including plasma coagulation and platelet aggregation. Fusaric acid exhibited biphasic effects on citrated human plasma recalcification time. At concentrations below 50 ng, fusaric acid decreased the clotting time of plasma dose-dependently from 130 +/- 3s control value to 32 +/- 3s; however, above 50 ng, fusaric acid increased the clotting time from 32 +/- 3s and reached a maximum of 152 s at 100 ng and remained unaltered thereafter for the increased dose of fusaric acid. Fusaric acid without damaging red blood cells and platelets, inhibited agonists such as collagen, ADP, thrombin, and epinephrine-induced aggregation of both platelet-rich plasma (PRP) and washed platelets preparations of human. Interestingly, fusaric acid showed biphasic effects only in thrombin induced platelet aggregation of washed platelets, and at lower concentration (below 900 ng) it activated platelet aggregation; however, in increased concentration (above 900 ng) it inhibited the platelet aggregation of washed platelets. In addition, fusaric acid also inhibited the agonist ADP-induced platelet aggregation of washed platelet suspension but did not show biphasic effect. Further, fusaric acid did not induce the platelets to generate reactive oxygen species (ROS) that clearly suggests that the induction of platelet function could be the result of the fusaric acid-mediated receptor interaction but not through the morphological shape change. PMID- 23343694 TI - Antithrombin activity and outcomes in patients undergoing cardiac surgery with cardiopulmonary bypass. AB - We recently reported prospective results from a cohort of patients scheduled for elective cardiac surgery with cardiopulmonary bypass (CPB) in which most baseline clinical parameters of patients and surgery outcomes failed to demonstrate relationships with post-CPB antithrombin (AT) activity. In this extension study, a larger sample size (250 patients) was analyzed following general linear models. Patients' sociodemographic and pre-CPB clinical data as well as pre/post-CPB AT activity and outcomes were collected. There was a significant decrease of post CPB AT activity (95.6 +/- 13.7-64.6 +/- 12.1%; P < 0.001). Univariate and multivariate analyses revealed that a decrease of approximately 1% post-CPB AT activity may be expected per 3 years increase in patient's age. Univariate analysis showed that post-CBP AT activity was inversely related to the need for transfusions, acute renal failure and occurrence of any complication (re intervention, low cardiac output, arrhythmia, lung dysfunction, stroke, acute renal failure, mesenteric ischemia and re-hospitalization; P < 0.05). Multivariate analysis adjusted for age and pre-CPB AT did not show statistical significance. Odds ratio (OR) less than 1 was observed in most outcomes (0.8 on average), which suggested a reduction of the probability for an increase of 10% in post-CBP AT. Our results confirm the role of low postsurgery AT activity influencing outcomes in patients undergoing CPB. PMID- 23343695 TI - Temporal trends in genital warts among individuals covered by the public prescription drug insurance plan in the province of Quebec, Canada, from 1998 to 2007. AB - OBJECTIVE: We assessed temporal trend in the incidence and prevalence of genital warts (GWs) in the province of Quebec, Canada, between 1998 and 2007 as a baseline for future assessment of the impact of Quebec human papillomavirus vaccination program. MATERIALS AND METHODS: Data on GWs were obtained from the linkage of the physician service claims and the public insurance drug plan databases. Genital warts were identified through a prescription of podofilox, a medical procedure code specific to GWs or a diagnosis code for viral warts followed by a prescription of imiquimod or fluorouracil within 2 weeks. An episode was considered incident if it was preceded by a 12-month interval period free of GWs care. RESULTS: During the study period, a total of 27,138 episodes of GWs occurred among 24,267 individuals. The age-standardized incidence rate increased over time in men and women. The highest incidence was observed in women aged 20 to 24 years (391.9/100,000) and in men aged 25 to 29 years (383.3/100,000). Similar trends in prevalence were observed. CONCLUSIONS: The incidence and prevalence of GWs has increased among the population covered by the public insurance drug plan in Quebec. PMID- 23343696 TI - Cervical epithelial brightness by optical coherence tomography can determine histological grades of cervical neoplasia. AB - OBJECTIVE: The study aimed to determine if the difference in cervical epithelium brightness, as measured by optical coherence tomography (OCT), has potential as a distinguishing characteristic of normal, low-grade, high-grade (cervical intraepithelial neoplasia 2+), and cancer histological findings. MATERIALS AND METHODS: Information from 476 women was available for analysis. Demographic information was collected through in-person interview. All participants were human papillomavirus positive and/or had abnormal cytological finding and underwent colposcopy or unaided visual inspection and examination by OCT by quadrant. All women had a minimum of 4 OCT-matched cervical biopsies and endocervical curettage. Two sample t tests were used to measure differences in OCT image brightness by histological grades. RESULTS: Mean OCT image brightness differed significantly between each preinvasive histological grade and invasive cancer (p < .01 for all comparisons). Brightness as measured by OCT was also able to differentiate between squamous metaplasia and cervical intraepithelial neoplasia 3/cancer; p values were .004 and .003, respectively. CONCLUSIONS: Epithelial brightness is an important component of cervical epithelium diagnosis by OCT, and we plan to add it to our diagnostic mathematical algorithm in all future versions of OCT software. PMID- 23343697 TI - Pityriasis rosea-like drug eruption due to nortriptyline in a patient with vulvodynia. AB - BACKGROUND: Nortriptyline and other tricyclic antidepressants are widely used in the treatment of depression. They are also used in chronic pain syndromes such as vulvodynia. We report a case of pityriasis rosea (PR)-like eruption in a young woman who was treated with oral nortriptyline for vulvodynia. CASE REPORT: The patient presented with photosensitivity and erythematous, well-defined, oval papules and patches, with fine collarettes of scale on the dorsal hands, upper arms, and trunk. She showed a complete resolution of her rash with discontinuation of nortriptyline, thereby supporting the diagnosis of a drug induced reaction. COMMENT: Pityriasis rosea-like drug eruptions have been associated with numerous medications, including angiotensin-converting enzyme inhibitors, antirheumatic drugs, lithium, and, more recently, biologics such as imatinib, adalimumab, and etanercept. A literature review did not reveal an association between PR-like drug eruptions and tricyclic antidepressants such as nortriptyline. We report a case of PR-like drug reaction to nortriptyline for clinical interest. PMID- 23343698 TI - Extramammary Paget disease: epidemiology and association to cancer in a Quebec based population. AB - OBJECTIVE: This study aimed to further characterize the epidemiology, clinical manifestations, pathology, immunopathology, outcome from therapy, and associated underlying malignancy in extramammary Paget disease (EMPD). MATERIALS AND METHODS: We conducted a retrospective review of patients treated for EMPD in our tertiary care center during a 23-year period ranging from 1985 to 2008. RESULTS: Sixty-four cases of EMPD were diagnosed during this period. Mean age at diagnosis was 66.8 years. Of the patients, 79.7% were female. Tumors were mostly localized on the vulvoperineal region. Associated cancers were found in 30% of the patients and included breast cancer and urogenital cancers. Of the patients, 42% had a least 1 recurrence. The risk of recurrence could only be associated to tumor location on the vulvoperineal region. The limitations of this study include its retrospective nature and sample size. CONCLUSIONS: Extramammary Paget disease is more commonly found on the vulva of older women and frequently recurs. Recurrence was not associated to margin status, which would support a more conservative therapeutic approach. PMID- 23343699 TI - Self-sampling in the diagnosis of recurrent vulvovaginal candidosis. AB - OBJECTIVE: This study aimed to determine the accuracy and feasibility of self sampling in patients suspected of having recurrent vulvovaginal candidosis (RVC). MATERIALS AND METHODS: Of 441 patients with symptoms suggestive of RVC presenting during an 8-year period (January 2000 to December 2007) at a dermatology clinic, 277 were instructed to perform weekly vaginal self-sampling for a period of up to 8 weeks. Demographic charactervistics, medical history, physical examination, culture results, and therapeutic efficacy were analyzed with Fisher exact, chi test, or Student t test. RESULTS: When only considering the results of the culture taken at consultation, 17.1% (20/117) of RVC cases could be confirmed. Positive cultures from self-sampling confirmed another 97 cases of RVC (82.9%). The sensitivity of a single Candida culture ranged from 18% to 53%, depending on the cutoff level of growth intensity of the yeast recovered. Specificity ranged from 97% to 100%, and the positive predictive value ranged from 92% to 100%. The number of positive cultures obtained was not associated with the duration of earlier vaginal complaints or with the efficacy of prophylactic treatment. Prophylactic treatment was equally effective in patients taking fluconazole once (8/13, 61.5%) or twice (48/74, 64.9%) a month, but treatment regimes were not randomized. CONCLUSIONS: The diagnosis of RVC can be improved dramatically by self-sampling, enabling a sooner start of adequate treatment. Multiple positive cultures were not associated with disease of longer duration or more severe disease and did not influence the response to prophylactic treatment. PMID- 23343700 TI - Use of electronic medical record-based tools to improve compliance with cervical cancer screening guidelines: effect of an educational intervention on physicians' practice patterns. AB - OBJECTIVE: This study aimed to determine whether electronic medical record (EMR) based tools influence providers' compliance with guidelines for cervical cancer screening in adolescent (<21 y) patients. MATERIALS AND METHODS: Three EMR-based tools to educate providers on cervical cancer screening guidelines were implemented midyear in 2010. Charts of adolescents with Pap and/or human papillomavirus results from January to December 2010 were reviewed. Physicians' demographic data were collected. Appropriateness of the index Pap and follow-up were determined using American Society for Colposcopy and Cervical Pathology guidelines. RESULTS: A total of 380 Pap tests were completed on 374 adolescents. Fewer Pap tests were done after the EMR interventions (229 vs 151, p < .0005). The proportion of Pap tests ordered by primary care providers was significantly higher than obstetrician-gynecologists (Ob/Gyns) (70% vs 30%, p < .0005). The number of Pap tests done by Ob/Gyns decreased 60% after EMR interventions (from 82 to 33, p < .0005) and that done by primary care physicians decreased 20% (from 147 to 118, p = .08). Indicated Pap tests were more often ordered by Ob/Gyn than by primary care, especially after EMR changes (31.4% vs 7.6%, p < .0005). Reflex human papillomavirus testing (if atypical squamous cells of undetermined significance) was high (74%) and did not improve after the EMR changes (72% vs 76%). The rate of co-testing in adolescents decreased in the primary care department after the EMR changes (13% vs 6%, p = .049). CONCLUSIONS: Electronic medical record prompts improved compliance with cervical cytology guidelines for adolescents, suggesting that EMR may be an important tool to enhance compliance with changing recommendations. PMID- 23343701 TI - Prevalence of high-risk cervical human papillomavirus and squamous intraepithelial lesion in Nigeria. AB - OBJECTIVE: The prevalence of cervical cancer and high-risk human papillomavirus (HPV) in Nigerian women remains poorly studied. Our objective was to estimate the prevalence of high-risk HPV and associated squamous intraepithelial lesions (SILs) in Nigeria. METHODS: After institutional review board approval, data collection was performed by volunteers of FaithCare, Inc, between 2004 and 2008 in 3 regions of Nigeria (Okene, Katari, and Abuja). Demographic data and ThinPrep Pap smears (Cytyc, Marlborough, MA) were collected from 410 women. Pap smears were analyzed for both the presence of SIL and HPV DNA. RESULTS: The prevalence of high-risk HPV and SIL was 15.6% and 6.8%, respectively. Of the 28 abnormal Pap tests, 42.9% had atypical squamous cells of undetermined significance, 39.3% had low-grade SIL, 14.3% had high-grade SIL, and 3.6% had atypical glandular cells. There was a strong association between high-risk HPV and SIL in both the combined (p < .001) and individual group data (p < .001, p = .013, and p < .001 for Okene, Abuja, and Katari, respectively). However, there were no statistically significant correlations between either high-risk HPV or presence of SIL and known risk factors including age, history of sexually transmitted disease, and the number of sexual partners. There was also no statistical difference in the prevalence of high-risk HPV and SIL among the 3 locations. CONCLUSIONS: A strong association exists between high-risk HPV and SIL. The prevalence of cervical high risk HPV and SIL, however, did not vary in the 3 different locations and is consistent with reports from other regions in Africa. PMID- 23343702 TI - Comparative risk of high-grade histopathology diagnosis after a CIN 1 finding in endocervical curettage versus cervical biopsy. AB - OBJECTIVE: No evidence-based clinical management recommendations exist for women with an endocervical curettage (ECC) cervical intraepithelial neoplasia grade 1 (CIN 1) result when the concurrent cervical biopsy is not high-grade. For women with these pathologic findings, we assessed their short-term risk of high-grade histopathologic diagnosis in the Calgary Health Region where ECC was routinely performed. MATERIALS AND METHODS: We analyzed pathology and colposcopy reports from 1,902 referral colposcopies where both ECC and biopsies were normal or CIN 1. We calculated the short-term risk of CIN 2 or more severe (CIN 2+) detected 12 to 24 months after colposcopy. Pearson chi tests or Fisher exact tests were used to compare risks of a CIN 2+ diagnosis between combinations of test results and strata of risk factors. RESULTS: The short-term risk of CIN 2+ was the same after a CIN 1 biopsy and CIN 1 ECC (4.9% of 1,389 vs 5.0% of 359, respectively, p = .37). Compared with low-grade referral cytology, the risk of CIN 2+ after high grade cytology was elevated significantly for CIN 1 ECC (13.3% vs 3.3%, p < .01) and nonsignificantly for CIN 1 biopsy (7.1% vs 4.6%, p = .12). CONCLUSIONS: After low-grade cytology, the short-term risk of a high-grade histologic diagnosis in women with either CIN 1 ECC or biopsy is equivalent, suggesting similar management. A CIN 1 ECC may warrant different management in the context of high grade referral cytology. PMID- 23343703 TI - Recurrent vulvar melanoma in 35-year-old pregnant women. AB - Vulvar melanoma represents between 3% and 10% of vulvar neoplasms. We present a case of a 34-year-old pregnant woman presenting with a pigmented lesion on the left labium majus; she reported no family history of melanoma. The histological diagnosis was malignant melanoma, superficial spreading type, with Breslow thickness of 0.9 mm; the excision was complete. Eight months before, an atypical genital nevus was completely excised from a nearby location. The pregnancy was finished by cesarean delivery at term, and 3 months later, another pigmented lesion was noticed near but not within the scars. Partial right vulvectomy was performed, and histological diagnosis was malignant melanoma of superficial spreading type, with Breslow thickness of 0.7 mm. The specimen obtained in the first operation was reviewed, and although histological examination was diagnostic for atypical genital nevus, Vysis Melanoma Fluorescence in situ hybridization Probe Kit revealed increased copy numbers of RREB1, which could be consistent with a diagnosis of malignant melanoma. PMID- 23343704 TI - Vestibulodynia: synergy between palmitoylethanolamide + transpolydatin and transcutaneous electrical nerve stimulation. AB - OBJECTIVE: The study aimed to assess the effect of palmitoylethanolamide + transpolydatin combination in patients with vestibulodynia undergoing transcutaneous electrical nerve stimulation (TENS) therapy and to confirm the effectiveness of TENS also in a domiciliary protocol. The study is based on the premise that palmitoylethanolamide + transpolydatin combination may contribute to a down-regulation of mast cell hyperactivity, which is believed to be responsible for the proliferation and sprouting of vestibular pain fibers and the associated hyperalgesia and allodynia. MATERIALS AND METHODS: Twenty women with vestibulodynia were randomly assigned to receive oral palmitoylethanolamide (PEA) 400 mg and transpolydatin 40 mg or placebo, twice daily for 60 days. All patients underwent TENS therapy in a self-administered home protocol. Visual analogue scale (VAS), Marinoff score for dyspareunia, and current perception threshold obtained from the vulvar vestibule were assessed at baseline and at the end of treatment. RESULTS: The patients received a mean of 26.7 TENS sessions. All scores in the 2 groups improved significantly, although the level of improvement was similar between the groups (VAS, p < .57; dyspareunia, p < .38). Nevertheless, the analysis of regression of symptoms related to the duration of disease revealed the therapy to be more effective when PEA + transpolydatin is included in cases with more recent disease onset, as compared with the placebo group (PEA: VAS, p < .01; dyspareunia, p < .01) (placebo: VAS, p = nonsignificant; dyspareunia, p = nonsignificant). CONCLUSIONS: This study confirms that TENS is of significant benefit in the management of vestibulodynia, also in a home environment. PEA + transpolydatin can be a value-added treatment adjunct when the onset of vestibulodynia is more recent or when the disease relapses. PMID- 23343705 TI - Vulval skin conditions: disease activity and quality of life. AB - OBJECTIVE: Chronic vulval skin conditions are known to cause a significant reduction in the quality of life. Validated scales exist to measure the disease impact of general dermatologic conditions; however, none have been specifically derived to assess vulval disease. This study aimed to identify what symptoms and aspects of their lives are important for women with vulval skin conditions and to assess their usefulness in developing an assessment measure for monitoring disease activity and quality of life in women with vulval skin conditions. MATERIALS AND METHODS: Participants were female patients attending a specialist vulval dermatology clinic at a tertiary referral center. Ten patients with a variety vulval skin conditions were interviewed to gain their experiences of living with a vulval skin condition. Using qualitative semistructured interviews, patients were asked open-ended questions about aspects of their disease that have affected them. These included the following: daily activities and social activities, physical functions, sexual activities, mobility, relationships, and an understanding of their vulval condition. Data was recorded, transcribed, and then analyzed thematically with all aspects regarding quality of life and symptoms identified. RESULTS: Results are presented according to common themes identified, specifically physical symptoms, body image, the impact of the condition on sexual and physical function, issues affecting daily activities, and the journey traveled when accessing medical care. CONCLUSIONS: This qualitative study adds to the evidence that chronic vulval conditions are distressing and cause significant morbidity. It highlights further the need to devise a validated questionnaire which can be used in clinical practice looking specifically at disease impact and quality of life. It can only enhance the clinical consultation and facilitate discussion which is disease and person specific. PMID- 23343706 TI - Bakri balloon in vaginal-perineal hematomas complicating vaginal delivery: a new therapeutic approach. AB - OBJECTIVE: The study aimed to evaluate the effectiveness of Bakri balloon as a hemostatic device in severe postpartum hemorrhage due to complicated vaginal perineal hematoma not responsive to standard surgical treatments. MATERIALS AND METHODS: The article discusses an effective and minimally invasive technique for resolving a case of massive vaginal-perineal bleeding after vaginal delivery complicated by ischiorectal fossa hematoma. A 36-year-old primipara white woman, 41 weeks 1 day pregnant, was admitted to our unit for beginning of labor. She experienced a precipitous delivery of a healthy male baby (3.72 kg, 51 cm in length), and spontaneous complete afterbirth of placenta and membranes. The intervention involved positioning of an hemostatic Bakri balloon device in the vagina, to compress the vaginal wall, ensuring that the draining apex was well positioned into the uterine cervix. RESULTS: The patient was discharged after having a puerperal course without further complications. CONCLUSIONS: Vaginal hemostatic Bakri balloon device shows hemostatic efficacy immediately assessable, is promptly removable, not interfering with subsequent surgical or radiological procedures, does not increase the risk of infections as other compressive procedures, allows flow of lochia, does not cause pain or discomfort in women, and permits adjustable compression when a drainage is placed during surgery. Despite the high cost, it does not show disadvantages. PMID- 23343707 TI - Human papillomavirus-unrelated gastric type of cervical adenocarcinoma presenting with a metastatic ovarian tumor: report of a case. AB - OBJECTIVE: Gastric type of adenocarcinoma (GAC) is a newly reported, morphologically distinct, mucinous subtype of cervical adenocarcinoma and is distinguished by aggressiveness and fatal outcomes. The association between human papillomavirus (HPV) and cervical carcinoma is well known; however, GAC is almost always HPV negative. MATERIALS AND METHODS: We report an unusual case of cervical GAC in a 41-year-old woman with a metastatic ovarian mass. The histological morphology of both tumors consisted of irregular glands lined by mucous cells with mild to moderate nuclear atypia and containing abundant cytoplasmic mucin. RESULTS: Immunohistochemical studies of the tumor cells revealed positive reactivity for CK7 and carcinoembryonic antigen but negative reactivity for p16 and HPV DNA usually expressed in cervical adenocarcinoma. Further staining for mucin with monoclonal antibody HIK1083 showed positive reactivity in both cervical and ovarian tumors. A gastric type of cervical carcinoma is considered. The patient is free of detectable disease at a 12-month follow-up. CONCLUSIONS: P16 staining and HPV DNA test result are usually positive in usual mucinous type of cervical adenocarcinoma, but they are negative in GAC. HIK1083 is becoming more commonly used for the diagnosis of GAC. Differentiation of GAC from usual mucinous type of cervical adenocarcinoma is important because GAC was related to a significant risk of recurrence and decreased 5-year disease-specific survival. We suggest applying HIK1083 in the diagnosis of cervical adenocarcinoma, especially in a small biopsy specimen. PMID- 23343708 TI - Joint torques and joint reaction forces during squatting with a forward or backward inclined Smith machine. AB - We developed a biomechanical model to determine the joint torques and loadings during squatting with a backward/forward-inclined Smith machine. The Smith squat allows a large variety of body positioning (trunk tilt, foot placement, combinations of joint angles) and easy control of weight distribution between forefoot and heel. These distinctive aspects of the exercise can be managed concurrently with the equipment inclination selected to unload specific joint structures while activating specific muscle groups. A backward (forward) equipment inclination decreases (increases) knee torque, and compressive tibiofemoral and patellofemoral forces, while enhances (depresses) hip and lumbosacral torques. For small knee flexion angles, the strain-force on the posterior cruciate ligament increases (decreases) with a backward (forward) equipment inclination, whereas for large knee flexion angles, this behavior is reversed. In the 0 to 60 degree range of knee flexion angles, loads on both cruciate ligaments may be simultaneously suppressed by a 30 degree backward equipment inclination and selecting, for each value of the knee angle, specific pairs of ankle and hip angles. The anterior cruciate ligament is safely maintained unloaded by squatting with backward equipment inclination and uniform/forward foot weight distribution. The conditions for the development of anterior cruciate ligament strain forces are clearly explained. PMID- 23343709 TI - Magnetoencephalography reveals a unique neurophysiological profile of focal-onset epileptic spasms. AB - Epilepsy is defined as a disorder of the brain characterized by an enduring predisposition to experience epileptic seizures and the neurobiological, cognitive, psychological, and social difficulties relating to the condition. An epileptic spasm (ES) is a type of seizure characterized by clusters of short contractions involving axial muscles and proximal segments. However, the precise mechanism of ESs remains unknown. Despite the potential of magnetoencephalography (MEG) as a tool for investigating the neurophysiological mechanism of ESs, it has been difficult to use this methodology due to magnetic artifacts attributable to patient movement. We report on an 8-year-old girl suffering from intractable epileptic spasms from the age of 7 months. She was diagnosed with possible Aicardi syndrome [corrected] (AGS), characterized by the triad of callosal agenesis, infantile spasms, and chorioretinal lacunae. She is now intellectually delayed and suffers from intractable ES. We used both MEG and electroencephalography to investigate her epilepsy. The recording captured two series of spasm clusters. Spikes were clearly identified with MEG in about four fifths of all spasms but were identified poorly or not at all in the remainder. MEG findings support previous studies that used intracranial electrodes to analyze patients with ESs and that showed variability in ES-associated spikes in terms of manner of cortical involvement and magnitude. Given the limitations of intracranial electrodes, such as sampling restrictions and invasiveness, MEG may be a helpful tool for non-invasively investigating the unique pathophysiological profile of focal-onset ESs. PMID- 23343710 TI - Bed bug saliva causes release of monocytic inflammatory mediators: plausible cause of cutaneous bite reactions. AB - Bed bugs may cause mild to severe cutaneous reactions. We studied the ability of bed bug salivary extract (SGE) to induce inflammatory reactions responsible for cutaneous manifestations and found that SGE stimulated the production of several potent chemokines and cytokines from macrophages. Chemokines induced by SGE included those known to recruit eosinophils (eotaxin), attract neutrophils [interleukin (IL)-8] or induce their survival and proliferation (granulocyte colony-stimulating factor). Cytokines involved in cell-mediated immunity, including IL-7, IL-10 and IL-12, were also induced. Saliva of bed bugs contains protein and non-protein molecules that have pleotropic effects on macrophages, orchestrating the immune response in the skin after bed bug bites. PMID- 23343711 TI - Female gender and reproductive factors affecting risk, relapses and progression in multiple sclerosis. AB - Multiple sclerosis (MS), a chronic inflammatory demyelina-ting and degenerative disease of the central nervous system, is a frequent cause of neurological disability in young adults. Female predominance has increased over the last decades. Although female gender carries a higher risk of developing relapsing remitting MS, being female and at child-bearing age also appears to provide some protection against cognitive decline and against progressive onset MS, an adverse predictive factor when considering long-term disability in MS. The risk of MS in women has been associated with an earlier age at menarche. In most studies, parity did not impact MS risk. However, the recently published association of higher parity and offspring number with a reduced risk of a first demyelinating event suggests a potential suppressive effect. Pregnancy in MS patients has been associated with a reduced relapse rate and a reduction of neurological symptoms, especially in the third trimester. Despite the increased relapse risk in the postpartum period, there is no indication of an adverse effect of childbirth on the long-term course of MS. Fertility treatment in MS has been associated with an increased relapse risk in the following 3-month period, especially when the procedure did not result in pregnancy and gonadotrophin-releasing hormone agonists were used. Altogether, there is substantial evidence to support a regulatory role of sex steroid hormones in MS. In the absence of correlations with single hormone blood levels, we can only speculate about the underlying mechanisms. In conclusion, the increased MS risk in women and the changes in relapse and progression risk in association with reproductive events suggest significant and complex interactions between immune, neuroendocrine and reproductive systems in MS. PMID- 23343712 TI - Arthroscopic management of primary synovial chondromatosis of the hip. AB - PURPOSE: We evaluated clinical outcomes after hip arthroscopy in patients with primary synovial chondromatosis (SC). METHODS: We retrospectively assessed 11 patients who underwent hip arthroscopy for primary SC at a mean follow-up of 22 months (range, 12 to 36 months). Clinical preoperative and postoperative evaluation was performed with the Harris hip score. The preoperative evaluation included plain radiographs and magnetic resonance (MR) scanning to detect number and positioning of intra-articular radiopaque loose bodies. The osteochondral damage was graded using the Kellgren-Lawrence classification. The chondral surfaces of both the acetabulum and femoral head were graded according to the Outerbridge scale. RESULTS: The clinical score improved postoperatively. There were statistically significant differences between preoperative and postoperative Harris hip scores (P < .05). Outcomes were rated as very satisfactory and satisfactory in 3 and 5 of 11 patients, respectively. The osteochondral damage ranged between stages 1 and 2. No complications related to surgical procedures were observed. CONCLUSIONS: Hip arthroscopy for the treatment of patients with primary SC showed good clinical results without any complications related to the surgical procedure. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23343713 TI - The diagnostic value of clinical tests, magnetic resonance imaging, and instrumented laxity in the differentiation of complete versus partial anterior cruciate ligament tears. AB - PURPOSE: To evaluate the question of whether different arthroscopically confirmed anterior cruciate ligament (ACL) injury patterns have distinctive preoperative findings on clinical examination, instrumented laxity, and magnetic resonance imaging (MRI). METHODS: Three hundred consecutive ACL-deficient patients with isolated ACL tears were evaluated with the Lachman test (LT), the pivot-shift test (PST), stress radiographs using the Telos Stress Device (Metax, Hungen, Germany), and MRI. After arthroscopic confirmation of the ACL injury, we grouped patients into 4 different ACL tear types (complete, partial anteromedial [AM] bundle intact, posterolateral [PL] bundle intact, and posterior cruciate ligament [PCL] healing), and partial tears were further evaluated for mechanical integrity and functionality of the remaining fibers. RESULTS: PST grades of +2 and +3 were consistent with complete ACL tears (86%; P < .00001), whereas PST grades of 0 or +1 were strongly related to partial tears (76%; P < .00001). Instrumented laxity results showed a significant difference in side-to-side difference (SSD) of anterior tibial translation in complete tears (9.1 +/- 3.4 mm) versus partial tears (5.2 +/- 2.9 mm; P < .0001). Most PL-intact cases were "functional" (67%), with lower instrumented laxity values (SSD, 4.3 +/- 2.3 mm) than the "nonfunctional" cases (SSD, 6.7 +/- 2.9 mm; P < .001). The contrary was not observed for AM-intact cases (17% functional). Partial ACL tears with functional remaining fibers had PST grades of 0 or +1 and less than a 4 mm SSD in stress radiographs (sensitivity, 0.76; specificity, 0.90). Partial ACL tears with nonfunctional fibers had positive PST results and an SSD of anterior tibial displacement from 4 to 9 mm (sensitivity, 0.56; specificity, 0.92). Positive PST results and an SSD greater than 9 mm was recorded in complete ACL tears (sensitivity, 0.88; specificity, 0.96). MRI analysis revealed overlapping results between complete and partial tears. CONCLUSIONS: Preoperative evaluation of different ACL tear types showed differences between complete and partial ACL tears with functional fibers in clinical examination and instrumented laxity tests. The combination of clinical tests and stress radiographs produced threshold values that distinguished complete from partial ACL tears, which may help the surgeon in the early identification of the presence of remaining functional fibers. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 23343714 TI - Effect of posterolateral bundle graft fixation angles on graft tension curves and load sharing in double-bundle anterior cruciate ligament reconstruction using a transtibial drilling technique. AB - PURPOSE: To evaluate the effect of posterolateral bundle (PLB) graft fixation angles on graft tension curves and load sharing between the anteromedial bundle (AMB) and the PLB in double-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: Twenty-four patients who underwent double-bundle ACL reconstruction were included in this study. AMB and PLB were provisionally fixed to a graft tensioning system during surgery. The graft fixation settings were as follows: (1) AMB at 20 degrees and PLB at 0 degrees (A20P0), (2) AMB at 20 degrees and PLB at 20 degrees (A20P20), and (3) AMB at 20 degrees and PLB at 45 degrees (A20P45). Bundle tension was recorded during knee flexion-extension and in response to anterior or rotatory loads. A pivot-shift test, as well as factors affecting the residual pivot-shift, was also evaluated. RESULTS: A20P45 created reciprocal tension curves and load sharing, in which the tension in both bundles was equivalent during flexion-extension and during each loading test at 30 degrees . In A20P0, the tension of the AMB was constantly higher than that of the PLB. Seven patients showed grade 1 pivot-shift phenomenon in A20P0, whereas no patient showed a positive pivot-shift at other settings. Larger tension reduction of the PLB between 0 degrees and 30 degrees and smaller load sharing of the PLB were significant factors affecting residual pivot-shift. CONCLUSIONS: In double-bundle ACL reconstruction, fixation of the AMB at 20 degrees and the PLB at 45 degrees created reciprocal tension curves and load sharing between the bundles. Fixation of the AMB at 20 degrees and the PLB at 0 degrees led to insufficient tension in the PLB, resulting in a residual pivot-shift phenomenon in 7 of 24 patients. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23343715 TI - MiR-138 inhibits tumor growth through repression of EZH2 in non-small cell lung cancer. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) play important roles in tumorigenesis. We investigated the roles and mechanisms of miR-138 in human non-small cell lung cancer (NSCLC). METHODS: The expression of miR-138 was first examined in NSCLC cell lines and tumour tissues by real-time PCR The in vitro and in vivo functional effect of miR-138 was examined further. A luciferase reporter assay was conducted to confirm target association between miR-138 and the enhancer of zeste homolog 2 (EZH2). RESULTS: miR-138 was frequently downregulated in NSCLC cells and tissues. Overexpression of miR-138 inhibited proliferation of NSCLC cells in vitro and tumor growth in vivo. The EZH2 oncogene, which is often overexpressed in various human cancers and acts as an important regulator of cell growth and tumor invasion, was identified as a novel target of miR-138. miR-138 can bind to the 3' untranslated region (3' UTR) of EZH2 and suppress the expression of EZH2 at both mRNA and protein levels. Furthermore, knockdown of EZH2 phenocopied the tumor suppressive effects of miR-138 in cell models, whereas ectopic expression of EZH2 rescued the suppressive effects of miR-138. CONCLUSION: These findings define a tumor suppressor function for miR-138 in NSCLC and further suggest that miR-138 may represent a potential therapeutic target for NSCLC patients. PMID- 23343716 TI - Low p14ARF expression in neuroblastoma cells is associated with repressed histone mark status, and enforced expression induces growth arrest and apoptosis. AB - The TP53 tumor suppressor pathway is abrogated by TP53 mutations in the majority of human cancers. Increased levels of wild-type TP53 in aggressive neuroblastomas appear paradox but are tolerated by tumor cells due to co-activation of the TP53 ubiquitin ligase, MDM2. The role of the MDM2 antagonist, p14(ARF), in controlling the TP53-MDM2 balance in neuroblastoma is unresolved. In the present study, we show that conditional p14(ARF) expression substantially suppresses viability, clonogenicity and anchorage-independent growth in p14(ARF)-deficient or MYCN amplified neuroblastoma cell lines. Furthermore, ectopic 14(ARF) expression induced accumulation of cells in the G1 phase and apoptosis, which was paralleled by accumulation of TP53 and its targets. Comparative genomic hybridization analysis of 193 primary neuroblastomas detected one homozygous deletion of CDKN2A (encoding both p14(ARF) and p16(INK4A)) and heterozygous loss of CDKN2A in 22% of tumors. Co-expression analysis of p14(ARF) and its transactivator, E2F1, in a set of 68 primary tumors revealed only a weak correlation, suggesting that further regulatory mechanisms govern p14(ARF) expression in neuroblastomas. Intriguingly, analyses utilizing chromatin immunoprecipitation revealed different histone mark defined epigenetic activity states of p14(ARF) in neuroblastoma cell lines that correlated with endogenous p14(ARF) expression but not with episomal p14(ARF) promoter reporter activity, indicating that the native chromatin context serves to epigenetically repress p14(ARF) in neuroblastoma cells. Collectively, the data pinpoint p14(ARF) as a critical factor for efficient TP53 response in neuroblastoma cells and assign p14(ARF) as a neuroblastoma suppressor candidate that is impaired by genomic loss and epigenetic repression. PMID- 23343717 TI - Would they dope? Revisiting the Goldman dilemma. AB - BACKGROUND/AIM: Discussions of doping often report Goldman's sensational results that half of the elite athletes asked would take a drug that guaranteed sporting success which would also result in their death in 5 years' time. There has never been any effort to assess the properties of the 'Goldman dilemma' or replicate the results in the post World Anti-Doping Agency context. This research evaluated the dilemma with contemporary elite athletes. METHODS: Participants at an elite level track and field meet in North America were segregated into an interview or online response. After basic demographics, participants were presented with three variant 'Goldman' dilemmas counter-balanced for presentation order. RESULTS: Only 2 out of 212 samples (119 men, 93 women, mean age 20.89) reported that they would take the Faustian bargain offered by the original Goldman dilemma. However, if there were no consequences to the (illegal) drug use, then 25/212 indicated that they would take the substance (no death condition). Legality also changes the acceptance rate to 13/212 even with death as a consequence. Regression modelling showed that no other variable was significant (gender, competitive level, type of sport) and there was no statistical difference between the interview and online collection method. CONCLUSIONS: Goldman's results do not match our sample. A subset of athletes is willing to dope and another subset is willing to sacrifice their life to achieve success, although to a much lesser degree than that observed by Goldman. A larger scale online survey is now viable to answer important questions such as variation across sports. PMID- 23343718 TI - Ensuring implementation success: how should coach injury prevention education be improved if we want coaches to deliver safety programmes during training sessions? AB - Coaches play a major role in encouraging and ensuring that participants of their teams adopt appropriate safety practices. However, the extent to which the coaches undertake this role will depend upon their attitudes about injury prevention, their perceptions of what the other coaches usually do and their own beliefs about how much control they have in delivering such programmes. Fifty-one junior netball coaches were surveyed about incorporating the teaching of correct (safe) landing technique during their delivery of training sessions to junior players. Overall, >94% of coaches had strongly positive attitudes towards teaching correct landing technique and >80% had strongly positive perceptions of their own control over delivering such programmes. Coaches' ratings of social norms relating to what others think about teaching safe landing were more positive (>94%) than those relating to what others actually do (63-74%). In conclusion, the junior coaches were generally receptive towards delivering safe landing training programmes in the training sessions they led. Future coach education could include role modelling by prominent coaches so that more community-level coaches are aware that this is a behaviour that many coaches can, and do, engage in. PMID- 23343719 TI - Transformational leadership: unleashing the potential. PMID- 23343720 TI - Enhancing communication between night shift RNs and hospitalists: an opportunity for performance improvement. AB - In a rapid cycle quality improvement project, the creation of a nurse-physician task force defined guidelines for nurse-physician communication between hospitalists and night shift nurses. Benefits include creating a structured presentation of patient information, reduced nonurgent pager interruptions, and formation of a collaborative team to smooth future communication concerns. PMID- 23343721 TI - Improving care transitions through meaningful use stage 2: continuity of care document. AB - In this department, Drs Murphy, Wilson, and Newhouse highlight hot topics in nursing outcomes, research, and evidence-based practice relevant to the nurse administrator. The goal is to discuss the practical implications for nurse leaders in diverse healthcare settings. Content includes evidence-based projects and decision making, locating measurement tools for quality improvement and safety projects, using outcome measures to evaluate quality, practice implications of administrative research, and exemplars of projects that demon strate innovative approaches to organizational problems. In this article, the authors describe the elements of continuity of care documentation, how sharing information can improve the quality and safety of care transitions and the implications for nurse executives. PMID- 23343722 TI - Influencing collaborative leadership: an interview with Dean Terry Fulmer. Interview by Jeffrey M. Adams. AB - This department highlights nursing leaders who have demonstrated a commitment to innovation and patient care leadership in practice, policy, research, education and theory. This interview profiles Terry Fulmer, PhD, RN, FAAN, chairperson of the Robert Wood Johnson Executive Nurse Fellows Advisory Committee and dean of the Bouve College of Health Sciences at Northeastern University. PMID- 23343723 TI - Lewin's Theory of Planned Change as a strategic resource. AB - This department highlights change management strategies that may be successful in strategically planning and executing organizational change initiatives. With the goal of presenting practical approaches helpful to nurse leaders advancing organizational change, content includes evidence-based projects, tools, and resources that mobilize and sustain organizational change initiatives. In this article, the author explores the use of the Lewin's Theory of Planned Change as a strategic resource to mobilize the people side of change. An overview of the theory is provided along with a discussion of its strengths, limitations, and targeted application. PMID- 23343724 TI - Creative approaches to increasing hospital-based nursing research. AB - Magnet-designated and aspiring hospitals use research and evidence-based practice initiatives to demonstrate new knowledge and innovation, a key component of the Magnet Recognition Program. Four creative approaches to supporting and conducting institutional nursing research and the implementation of evidence-based care are illustrated, along with examples of successful nurse staff-led projects. PMID- 23343725 TI - How differing shift lengths relate to quality outcomes in pediatrics. AB - OBJECTIVE: The aims of this study were to describe the shift lengths of pediatric nurses and to measure the association of shift length with nurse job outcomes, nurse-reported patient outcomes, and nurse-assessed safety and quality of care in hospitals. BACKGROUND: Long work hours have been linked with poor patient outcomes in adult patient populations, but little is known about the relationship in pediatric settings. METHODS: A secondary analysis of cross-sectional nurse survey data was conducted. Our analysis focused on 3710 registered nurses who worked in 342 acute care hospitals that treated children. RESULTS: Most pediatric nurses worked 12-hour shifts, especially in intensive care settings. Nurses who worked extended shifts of more than 13 hours reported worse job outcomes and lower quality and safety for patients compared with nurses who worked 8-hour shifts. CONCLUSIONS: Allocating resources to nursing to improve working hours may be a productive strategy for administrators to improve the health and well-being of pediatric patients and nurses. PMID- 23343726 TI - Development of a hospital-based integrative healthcare program. AB - Public demand for complementary and alternative medicine (CAM) therapies, often referred to as integrative health (IH), continues to grow. Health systems are now pursing the integration of these therapies with conventional medical care. This article describes the development and evolution of 1 nursing-led model for the integration of CAM services in an inpatient setting and to provide lessons learned for nursing administrators or others interested in developing hospital based IH programs. PMID- 23343727 TI - The professional appearance of registered nurses: an integrative review of peer refereed studies. AB - BACKGROUND: There is a paucity of research examining the impact of standardized uniform style and color for registered nurses (RNs). OBJECTIVE: The aim of this study was to appraise published peer-refereed studies on the effect of a standardized uniform style and color for RNs. METHODS: Seven peer-refereed studies exploring standardized uniforms for RNs were identified. Using the Oxford Centre for Evidence-Based Medicine evidence hierarchy, each study was assigned a level of evidence and overall rating. RESULTS: Data suggest that patients felt that RNs appeared professional and were easily identified by a standardized uniform style and color. No strong evidence supports a patient's preference for a specific style and color of uniform. CONCLUSIONS: Findings are inconsistent but demonstrate that a standardized uniform style and color increased the perception of professionalism and recognition of RNs among patients. PMID- 23343728 TI - Business case for Magnet(r) in a small hospital. AB - There is minimal evidence related to Magnet(r) designation and the benefits in small hospitals. A business strategy for small hospitals (<100 beds) to achieve Magnet designation is presented, including a cost-benefit analysis, outcome measures, and financial impact data. PMID- 23343729 TI - [A woman with abdominal striae]. AB - Bleomycin can cause very specific hyperpigmentation, which occurs mainly on the trunk and the proximal extremities. The lesions are mostly asymptomatic, although in some cases may itch. The exact mechanism of flagellate pigmentation is still unclear. The lesions are harmless and resolve spontaneously after discontinuation of bleomycin. PMID- 23343730 TI - [Guideline 'Overweight' for child health care]. AB - The '5th National Growth Study' indicates that the percentage of overweight children in the Netherlands has risen from 9-12% in 1997 to 13-15% in 2009. Child Health Care is a unique setting for promotion of development, growth and behaviour of children, in which tailored prevention can be offered. Detection of overweight in children and intervention by Child Health Care takes place in a multidisciplinary setting linking general practitioners, paediatricians, dieticians, teachers, physiotherapists, pedagogues and psychologists. For overweight children, a change plan is created based on exercise, playing outside, having breakfast every day, as little as possible sweetened beverages and fast food, and less time spent in front of the television or computer, with fewer energy-rich snacks. As recommended in the Dutch CBO guideline 'Obesity', obese children are referred to a general practitioner or paediatrician. PMID- 23343731 TI - [A woman with palpitations and dysphagia]. AB - A 55-year-old female experienced palpitations and thoracic pain. Coronary angiography showed a right sided aorta. The patient was diagnosed with a Kommerell's diverticulum that compressed the esophagus and trachea. During follow up she developed dysphagia and she underwent a transposition of the left subclavian artery to the left common carotid artery followed by endovascular treatment of the distal aortic arch and thereby excluding the diverticulum. PMID- 23343732 TI - [Is anaesthesia detrimental to brain development?]. AB - Many experimental studies in mammals, and increasingly also in primates, have shown that almost all anaesthetic agents when administered during a young animal's brain-development phase cause increased neuroapoptosis and changes in dendritic morphology at short term, and later, learning disorders. These findings are being confirmed in increasing numbers of retrospective cohort studies in humans. However, these retrospective cohort studies are considerably influenced by confounding. A current prospective randomized clinical trial comparing general and locoregional (spinal) anaesthesia for hernia repair could provide some clinical evidence. These study results will only provide information on relatively short procedures and will not be available until the first reliable neuropsychological evaluation at age 5 in 2018. Pending this additional data, we should discuss with our surgical colleagues the indications, timing and duration of surgery and - if possible - postpone elective surgery until the child is more mature. PMID- 23343733 TI - [Drug interactions between coumarin derivatives and antimycotics: also with topical antifungal agents]. AB - The imidazole derivative miconazole is often used to treat fungal infections of the skin, mouth and gastrointestinal tract. Used concomitantly with coumarin derivatives, it may enhance their anticoagulant effects by inhibiting the CYP2C9 isoenzyme; an interaction which has been well described for oral and vaginal administrations of miconazole. In daily practice, however, cutaneous formulations can also cause clinically relevant drug interactions after having been absorbed through the skin. We describe 4 patients in whom topically applied miconazole enhanced the effect of coumarin derivatives. These cases concern reports received by the Netherlands Pharmacovigilance Centre Lareb between April 2001 and April 2012. PMID- 23343734 TI - [Introducing new surgical techniques: stricter surveillance is needed]. AB - Surgical mesh products and instruments may be used in patients in daily practice, when they have proven to do what they aim to do. This practice can lead to situations in which data on the clinical application of the new technology/instrument is still uncertain, which does not inherently mean that patient safety is at risk; however, it could lead to additional healthcare expenditures. Introducing new technology in healthcare is not simple. There might be pressure from both the commercial arena, as well as from patients, to have the new technique applied, which obliges surgeons to implement these immediately. Nevertheless, the evidence-based background data are sometimes not even available. By means of the recently introduced IDEAL model, therefore, a plea is made to introduce and implement new techniques and technologies in the field of surgery in a way that is safe for the patient. PMID- 23343735 TI - [A woman with a "bruise" on the face]. AB - A 95-year-old woman presented with a progressive purple blue asymptomatic tumorous plaque on her forehead, extending as a macula to the upper face, possibly arisen after a fall. Histology showed atypical epitheloid cells with vascular-lumen formation. The patient was diagnosed with cutaneous angiosarcoma. She was treated palliatively with radiotherapy. PMID- 23343736 TI - [Boerhaave and his syndrome]. AB - Herman Boerhaave (1668-1738), professor of botany, medicine and chemistry at the University of Leyden, attracted students from across Europe, thanks to his didactic qualities, reinforced by bedside teaching. His published writings, often unauthorised, were mainly theoretical and systematic. The more remarkable is the extensive and 'atrocious' case history he published about the 51-year-old nobleman Jan Gerrit van Wassenaer. As courtier and admiral of the Dutch fleet Van Wassenaer was a regular attendant at copious banquets, but at home he used to eat sparingly and sometimes he resorted to emetics. One day, having taken several bowls with an extract of Blessed Thistle (Carduus benedictus) and trying to vomit, he was seized by excruciating pain in the chest. The pain continued unabated until his death, the next day. Boerhaave, called to his bedside in the middle of the night, was unable to make a diagnosis from the history and physical examination. Post mortem examination showed the oesophagus had been torn off in the chest. Later generations have linked Boerhaave's name with spontaneous rupture of the oesophagus. PMID- 23343737 TI - [Instrumental variable analysis]. AB - Instrumental variable analysis is a recently propagated method to deal with confounding and to estimate therapeutic effects in observational studies. An instrumental variable is a factor which affects treatment but is not related to patient prognosis. A theoretical advantage of a well-chosen instrumental variable is that both measured and unmeasured confounders do not influence the effect estimator. Examples of instrumental variables previously used are regional differences in treatment and physician prescribing preference. Application of instrumental variable analysis seems most suited to large patient registries with considerable expected residual confounding in case standard analytical methods are applied. PMID- 23343738 TI - [Therapy resistant diabetes mellitus and lipodystrophy: leptin therapy leads to improvement]. AB - Lipodystrophy is a congenital or acquired disorder characterized by complete or partial absence of subcutaneous fat tissue, often accompanied by insulin resistance, diabetes mellitus (DM), hypertriglyceridemia and hepatic steatosis. A decrease in both number and function of adipocytes leads to ectopic fat depositions and decreased production of adipokines such as leptin. We present 2 patients with inadequately regulated DM, hypertriglyceridemia and hepatic steatosis who were eventually diagnosed with lipodystrophy: 1 with congenital generalized lipodystrophy (Berardinelli-Seip syndrome) and 1 with congenital partial lipodystrophy (Dunnigan syndrome). Both received recombinant human leptin therapy (methionylleptin, available on a compassionate-use basis). This resulted in improved plasma levels of triglyceride, glucose and HbA1c and a decrease in liver size. In addition, hepatic triglyceride content decreased from 19.3% to 1.3% in the first patient and from 20.6% to 12.4% in the second. Leptin therapy is an effective and safe treatment for therapy-resistant diabetes and hypertriglyceridemia in patients with congenital lipodystrophy. PMID- 23343739 TI - [Pertussis in young infants: a dangerous disease with non-specific signs]. AB - Pertussis, or whooping cough, caused by Bordetella pertussis, still occurs despite vaccination. Most of the cases occurring in adolescents and adults are mild or have a subclinical course, but these patients can be a source of transmission to unvaccinated or partially vaccinated infants. Symptoms of infant pertussis are often not specific, but pertussis can be fatal. In this article, we present one case of unvaccinated twins who each presented with initial signs of a viral respiratory disease. Within a few days, each developed rapidly progressive respiratory failure complicated by refractory pulmonary hypertension due to malignant pertussis. Both patients died eventually. It is important for paediatricians, general practitioners, midwives and gynaecologists to be alert to coughing in their patients. More efficient vaccination strategies should be discussed to prevent both the transmission of B. pertussis and the occurrence of severe and fatal pertussis in young infants. PMID- 23343740 TI - [The presence of medications in the water cycle]. AB - Medications and radiographic contrast dyes are sometimes detected in surface waters, ground water and drinking water; these have proven detrimental effects on organisms living in such waters The concentration of medications found in drinking water is at least a thousand times below their minimum therapeutic dosages. In humans, the long-term effects of daily exposure to low dosages of medications and 'mixture toxicity' is not known; based on the concentrations and substance toxicity, it is presumed that the risk is nil.. Physicians can play their part in controlling the problem of medications becoming part of the water cycle by taking this into account when prescribing medications. Users can make a difference by handling their medications with care and by returning all unused portions to the pharmacy. The pharmaceutical industry can also do its part by taking degradability, options for removal and the environmental effects of medications into account during their stages of development. PMID- 23343741 TI - [The globalization of medical education]. AB - With reference to a recently published research article on the applicability and effectiveness of problem-based learning (PBL) in non-Western medical schools, this commentary explores the assumption that a set of shared values is the common denominator of the globalisation of medical education. The use and effectiveness of PBL are not isolated from the cultural and social structural context in which it is applied; critical differences in values and in views on education underlie what educators and students perceive to be effective locally. The globalisation of medical education is more than the import of instructional designs, and includes Western models of social organisation that require deep reflection and adaptation for success; hence, instead of spreading models for medical education across the globe, more effort should be put into the support of 'home-grown' equivalents and alternatives. PMID- 23343742 TI - [No quetiapine for sleeping disorders]. AB - The prescribing of low doses of quetiapine for the treatment of sleeping disorders appears to be widespread. Recently, in a systematic literature review on low-dose quetiapine use for the treatment of sleeping disorders, it was concluded that evidence for its efficacy is currently lacking. Furthermore, quetiapine is probably associated with potentially severe adverse effects, also at low doses. In conclusion, sufficient scientific evidence that justifies the current practice of off-label prescribing of low-dose quetiapine for the treatment of sleeping disorders is insufficient; further research into its efficacy and safety is needed. PMID- 23343743 TI - Influence of N-H-O hydrogen bonds on the structure and properties of (K(1 x)(NH4)(x)H2PO4) proton glasses: a single crystal neutron diffraction study. AB - It has been known for quite some time now that proton dynamics plays a key role in the structural ferroelectric (FE)/antiferroelectric (AFE) phase transition in the crystals belonging to the potassium dihydrogen phosphate crystal family. Mixed crystals belonging to this family having the composition M(1 x)(NW(4))(x)W(2)AO(4), where M = K, Rb, Cs, W = H, D, and A = P, As, exhibit proton glass behavior due to frustration between FE and AFE ordering; these proton glasses do not undergo any structural phase change but retain their room temperature structure down to very low temperatures. Single crystal neutron diffraction investigations of four mixed crystals with composition (K(1 x)(NH(4))(x)H(2)PO(4)), where x = 0.0, 0.29, 0.67 1.0, were undertaken with the intention to investigate the effect of the local structural deviations on the overall average structure of the crystals and correlate these structural changes to the presence or absence of a structural phase transition in these crystals. Hydrogen bonding is shown to play a key role in the changing nature of the mixed crystals as the composition varies from the potassium rich ferroelectric region to the proton glass region to the ammonium rich antiferroelectric region. PMID- 23343744 TI - A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies. AB - To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and they must be predictive of future health status. In 2009, the Nutrition and Immunity Task Force of the International Life Sciences Institute, European Branch, organized an expert group to attempt to identify robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population. Inflammation is a normal process and there are a number of cells and mediators involved. These markers are involved in, or are produced as a result of, the inflammatory process irrespective of its trigger and its location and are common to all inflammatory situations. Currently, there is no consensus as to which markers of inflammation best represent low-grade inflammation or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses. There are a number of modifying factors that affect the concentration of an inflammatory marker at a given time, including age, diet and body fatness, among others. Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative compared with data related to the concentration change in response to a challenge. A number of inflammatory challenges have been described. However, many of these challenges are poorly standardised. Patterns and clusters may be important as robust biomarkers of inflammation. Therefore, it is likely that a combination of multiple inflammatory markers and integrated readouts based upon kinetic analysis following defined challenges will be the most informative biomarker of inflammation. PMID- 23343745 TI - Controllable atomic scale patterning of freestanding monolayer graphene at elevated temperature. AB - We show that by operating a scanning transmission electron microscope (STEM) with a 0.1 nm 300 kV electron beam, one can sculpt free-standing monolayer graphene with close-to-atomic precision at 600 degrees C. The same electron beam that is used for destructive sculpting can be used to image the sculpted monolayer graphene nondestructively. For imaging, a scanning dwell time is used that is about 1000 times shorter than for the sculpting. This approach allows for instantaneous switching between sculpting and imaging and thus fine-tuning the shape of the sculpted lattice. Furthermore, the sculpting process can be automated using a script. In this way, free-standing monolayer graphene can be controllably sculpted into patterns that are predefined in position, size, and orientation while maintaining defect-free crystallinity of the adjacent lattice. The sculpting and imaging processes can be fully computer-controlled to fabricate complex assemblies of ribbons or other shapes. PMID- 23343746 TI - Down-regulation of MTA1 protein leads to the inhibition of migration, invasion, and angiogenesis of non-small-cell lung cancer cell line. AB - Metastasis-associated protein 1 (MTA1) high expression has been detected in a wide variety of human aggressive tumors and plays important roles in the malignant biological behaviors such as invasion, metastasis, and angiogenesis. However, the specific roles and mechanisms of MTA1 protein in regulating the malignant behaviors of non-small-cell lung cancer (NSCLC) cells still remain unclear. To elucidate the detailed functions of MTA1 protein, we down-regulated the MTA1 protein expression in NSCLC cell line by RNA interference (RNAi) in vitro, and found that down-regulation of MTA1 protein significantly inhibited the migration and invasion potentials of 95D cells. Further research revealed that down-regulation of MTA1 protein significantly decreased the activity of matrix metalloproteinase-9, which could be the mechanism responsible for the inhibition of 95D cells migration and invasion. In addition, the tube formation assay demonstrated that the number of complete tubes induced by the conditioned medium of MTA1-siRNA 95D cells was significantly smaller than that of 95D cells. These findings demonstrate that MTA1 protein plays important roles in regulating the migration, invasion, and angiogenesis potentials of 95D cells, suggesting that MTA1 protein down-regulation by RNAi might be a novel therapeutic approach to inhibit the progression of NSCLC. PMID- 23343747 TI - Experimental implementation of a polyenergetic statistical reconstruction algorithm for a commercial fan-beam CT scanner. AB - PURPOSE: To present a framework for characterizing the data needed to implement a polyenergetic model-based statistical reconstruction algorithm, Alternating Minimization (AM), on a commercial fan-beam CT scanner and a novel method for assessing the accuracy of the commissioned data model. METHODS: The X-ray spectra for three tube potentials on the Philips Brilliance CT scanner were estimated by fitting a semi-empirical X-ray spectrum model to transmission measurements. Spectral variations due to the bowtie filter were computationally modeled. Eight homogeneous cylinders of PMMA, Teflon and water with varying diameters were scanned at each energy. Central-axis scatter was measured for each cylinder using a beam-stop technique. AM reconstruction with a single-basis object-model matched to the scanned cylinder's composition allows assessment of the accuracy of the AM algorithm's polyenergetic data model. Filtered-backprojection (FBP) was also performed to compare consistency metrics such as uniformity and object-size dependence. RESULTS: The spectrum model fit measured transmission curves with residual root-mean-square-error of 1.20%-1.34% for the three scanning energies. The estimated spectrum and scatter data supported polyenergetic AM reconstruction of the test cylinders to within 0.5% of expected in the matched object-model reconstruction test. In comparison to FBP, polyenergetic AM exhibited better uniformity and less object-size dependence. CONCLUSIONS: Reconstruction using a matched object-model illustrate that the polyenergetic AM algorithm's data model was commissioned to within 0.5% of an expected ground truth. These results support ongoing and future research with polyenergetic AM reconstruction of commercial fan-beam CT data for quantitative CT applications. PMID- 23343748 TI - Autophagy regulates inflammation following oxidative injury in diabetes. AB - T1D (type 1 diabetes) is an autoimmune disease characterized by lymphocytic infiltration, or inflammation in pancreatic islets called 'insulitis.' Comparatively speaking, T2D (type 2 diabetes) is traditionally characterized by insulin resistance and islet beta cell dysfunction; however, a number of studies have clearly demonstrated that chronic tissue inflammation is a key contributing factor to T2D. The NLR (Nod-like receptor) family of innate immune cell sensors such as the NLRP3 inflammasome are implicated in leading to CASP1 activation and subsequent IL1B (interleukin 1, beta) and IL18 secretion in T2D. Recent developments reveal a crucial role for the autophagy pathway under conditions of oxidative stress and inflammation. Increasingly, research on autophagy has begun to focus on its role in interacting with inflammatory processes, and thereby how it potentially affects the outcome of disease progression. In this review, we explore the pathophysiological pathways associated with oxidative stress and inflammation in T2D. We also explore how autophagy influences glucose homeostasis by modulating the inflammatory response. We will provide here a perspective on the current research between autophagy, inflammation and T2D. PMID- 23343749 TI - Antitumor effect of everolimus in preclinical models of high-grade gastroenteropancreatic neuroendocrine carcinomas. AB - BACKGROUND/AIMS: While the range of therapeutic options for well-differentiated gastroenteropancreatic neuroendocrine tumors has recently increased with the emergence of targeted therapies, such as mTOR inhibitors, there is no recent progress in the treatment of poorly differentiated neuroendocrine carcinomas (PDNECs). Since PDNECs have been shown to strongly express mTOR pathway components, the aim of the present study was to assess the antitumor effect of the mTOR inhibitor everolimus in preclinical models of PDNECs. METHODS: The expression of mTOR pathway components and their response to everolimus were assessed in two neuroendocrine cell lines: STC-1 and GluTag. A xenograft model of intrahepatic dissemination in the nude mouse, based on the intrasplenic injection of either STC-1 and GluTag tumor cells, was used. Animals were started on everolimus treatment 3 days after injection. The effects of treatment on tumor growth, proliferative capacities, apoptosis and in situ expression of mTOR pathway components were assessed. RESULTS: The expression of mTOR pathway components was comparable in STC-1 and GluTag cells and in human PDNECs and could be inhibited in vitro by everolimus. In vivo, the tumor volume of STC-1 and GluTag xenografts was significantly reduced in treated animals (6.05 +/- 1.84% as compared to 21.76 +/- 3.88% in controls). Everolimus treatment also induced a significant decrease in Ki67 index and in the phosphorylation levels of the two major effectors of mTOR, p70S6K and 4E-BP1. CONCLUSION: Our experimental data suggest that mTOR inhibition could be considered a therapeutic option for high grade gastroenteropancreatic neuroendocrine tumors. PMID- 23343750 TI - Pulmonary artery involvement in Takayasu arteritis. PET/CT versus CT angiography. AB - OBJECTIVES: To report a patient with Takayasu arteritis in whom 18F Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computerised tomography (CT) failed to demonstrate pulmonary artery involvement. METHODS: A patient with Takayasu arteritis underwent PET/CT and CT angiography before and one year after immunosuppressive treatment. RESULTS: Before treatment, PET/CT showed increased FDG uptake in the aortic arch and epiaortic arteries; pulmonary arteries were not visualised. Follow-up PET/CT one year later demonstrated resolution of abnormal vascular FDG uptake. CT angiography of the chest/abdomen prior to treatment revealed circumferential thickening of the ascending aorta, aortic arch, supra-aortic branches, and left inferior intralobar pulmonary artery with normal lumen diameter (27 mm). After therapy, CT angiography revealed decreased aortic wall thickening with complete resolution of intralobar wall thickening. However, the lumen of the central pulmonary artery was increased (32 mm). CONCLUSIONS: PET/CT is very sensitive in depicting active vasculitis, but cannot visualise the pulmonary arteries, presumably because their diameter is below the power of detection of PET/CT. CT angiography or magnetic resonance angiography is required to evaluate pulmonary artery abnormalities. PMID- 23343751 TI - Influence of center of pressure estimation errors on 3D inverse dynamics solutions during gait at different velocities. AB - The aim of this study was to investigate the effect of errors in the location of the center of pressure (5 and 10 mm) on lower limb joint moment uncertainties at different gait velocities (1.0, 1.5, and 2.0 m/s). Our hypotheses were that the absolute joint moment uncertainties would be gradually reduced from distal to proximal joints and from higher to lower velocities. Joint moments of five healthy young adults were calculated by inverse dynamics using the bottom-up approach, depending on which estimate the uncertainty propagated. Results indicated that there is a linear relationship between errors in center of pressure and joint moment uncertainties. The absolute moment peak uncertainties expressed on the anatomic reference frames decreased from distal to proximal joints, confirming our first hypothesis, except for the abduction moments. There was an increase in moment uncertainty (up to 0.04 N m/kg for the 10 mm error in the center of pressure) from the lower to higher gait velocity, confirming our second hypothesis, although, once again, not for hip or knee abduction. Finally, depending on the plane of movement and the joint, relative uncertainties experienced variation (between 5 and 31%), and the knee joint moments were the most affected. PMID- 23343752 TI - Right-to-left ventricular differences in the expression of mitochondrial hexokinase and phosphorylation of Akt. AB - BACKGROUND/AIMS: Hexokinase (HK) is a key glycolytic enzyme which promotes the maintenance of glucose homeostasis in cardiomyocytes. HK1 isoform is predominantly bound to the outer mitochondrial membrane and highly supports oxidative phosphorylation by increasing the availability of ADP for complex V of the respiratory chain. HK2 isoform is under physiological conditions predominantly localized in the cytosol and upon stimulation of PI3K/ Akt pathway associates with mitochondria and thus can prevent apoptosis. The purpose of this study was to investigate expression and subcellular localization of both HK isoforms in left (LV) and right (RV) heart ventricles of adult male Wistar rats. METHODS: Real-Time RT-PCR, Western blotting, and quantitative immunofluorescence microscopy were used. RESULTS: Our results showed a significantly higher expression of both HK1 and HK2 at mRNA and protein levels in the RV compared to the LV. These findings were corroborated by immunofluorescence staining which revealed substantially higher fluorescence signals of both HKs in the RV than in the LV. The ratios of phospho-Ser473-Akt/non-phospho-Akt and phospho-Thr308 Akt/non-phospho-Akt were also markedly higher in the RV than in the LV. CONCLUSION: These results suggest that the RV has a higher activity of aerobic glycolytic metabolism and may be able to respond faster and more powerfully to stressful stimuli than the LV. PMID- 23343753 TI - Phenotypic correlations between monocytes and CD4+ T cells in allergic patients. AB - Despite widely acknowledged contributions of innate and adaptive immune systems to the pathogenesis of allergic diseases, mutual interactions occurring in vivo between components of those two systems have not been studied in sufficient detail. Here, we wished to investigate whether phenotypic features of monocytes and CD4+ T cells in allergic patients are reciprocally related. Therefore, we recruited 50 untreated house dust mite-sensitive allergic rhinitis patients and 29 non-atopic healthy individuals and performed comprehensive simultaneous flow cytometric analysis of mutual correlations between levels of CD14, CD16, CD163, CD206, CD124 (IL-4R), CD210 (IL-10R) and CD25, CD124, CD127 (IL-7R), CD210, ICOS expression on monocytes and CD4+ T cells, respectively. We found that CD163 monocyte expression in allergic but not healthy subjects is positively correlated with monocyte IL-10R, and, to a lesser extent, CD206, but not IL-4R expression. Levels of CD163 expression were not related to frequencies of CD14++CD16-, CD14++CD16+, and CD14+CD16++ monocyte subsets. In contrast to healthy controls, intensities of monocyte IL-10R in allergic individuals were significantly correlated with monocyte CD206 and IL-4R expression. In addition, levels of monocyte IL-4R and IL-10R monocyte expression were positively correlated to expression of IL-4R and IL-10R on CD4+ T cells in both groups of studied subjects. Interestingly, we demonstrated a significant positive correlation between levels of monocyte CD206 expression and levels of IL-10R and IL-4R expression on CD4+ T cells in allergic but not healthy individuals. In summary, we conclude that allergic rhinitis is associated with a number of phenotypic alterations of circulating monocytes and CD4+ T cells. PMID- 23343754 TI - Placentas from pregnancies conceived by IVF/ICSI have a reduced DNA methylation level at the H19 and MEST differentially methylated regions. AB - STUDY QUESTION: Does IVF/ICSI have an effect on the epigenetic regulation of the human placenta? SUMMARY ANSWER: We found a reduced DNA methylation level at the H19 and MEST differentially methylated regions (DMRs), and an increased RNA expression of H19 in placentas from pregnancies conceived by IVF/ICSI when compared with placentas from spontaneous conception. WHAT IS KNOWN ALREADY: Changes in fetal environment are associated with adverse health outcomes. The placenta is pivotal for intrauterine environment. Animal studies show that epigenetic regulation plays an important role in these environment-induced phenotypic effects. Also, the preimplantation embryo environment affects birthweight as well as the risk of chronic adult diseases. Epigenetic processes are sensitive to the environment, especially during the period around conception. STUDY DESIGN AND PARTICIPANTS: Placental tissue was collected from 35 spontaneously conceived pregnancies and 35 IVF/ICSI (5 IVF, 30 ICSI) derived pregnancies. We quantitatively analysed the DNA methylation patterns of a number of consecutive CpGs in the core regions of DMRs and other regulatory regions of imprinted genes, since these are involved in placental and fetal growth and development. METHODS: By using pyrosequencing, the DNA methylation at seven germline-derived primary DMRs was analysed quantitatively. Five of these are maternally methylated (MEST isoform alpha and beta, PEG3, KCNQ1OT1 and SNRPN) and two are paternally methylated [H19 DMR and the intergenic region between DLK1 and MEG3 (IG-DMR)]. The post-fertilization-derived secondary DMRs, IGF2 (DMR0 and 2) and IG-DMR (CG7, also called MEG3 DMR), and the MEG3 promoter region were examined as well. In case of differential methylation between the two groups, the effect on gene expression was assessed by quantitative real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE: Both the promoter region of MEST isoform alpha and beta and the 6th CTCF binding site within the H19 DMR were significantly hypomethylated in the IVF/ICSI group. The phenomenon was consistently observed over all CpG sites analysed and not restricted to single CpG sites. The other primary and secondary DMRs were not affected. Expression of H19 was increased in the IVF/ICSI group, while that of IGF2 and MEST remained similar. LIMITATIONS, REASONS FOR CAUTION: In the IVF/ICSI group, mostly ICSI pregnancies were investigated. The ICSI technique or male subfertility could be a confounding factor. Therefore, our results are less generalizable to IVF pregnancies. WIDER IMPLICATIONS OF THE FINDINGS: The clinical effects of the observed placental hypomethylations on the developmental programming of the IVF/ICSI progeny, if any, are as yet unknown. Whether the hypomethylation is an adaptation of the placenta to maintain fetal supply and ameliorate the effects of environmental cues, or whether it is a deregulation leading to deranged developmental programming with or without increased vulnerability for disease, consistent with the developmental origins of health and disease hypothesis, needs further investigation. STUDY FUNDING/COMPETING INTEREST(S): Partly funded by an unrestricted research grant by Organon BV (now MSD BV) without any role in study design, data collection and analysis, or preparation of the manuscript. No conflict of interests to declare. TRIAL REGISTRATION NUMBER: Dutch Trial Registry (NTR) number 1298. PMID- 23343755 TI - Development and a pilot test of an internet-based cardiovascular risk reduction program for Korean male workers with metabolic syndrome. AB - An Internet-based, Best Exerciser Super Trainer program for risk reduction among Korean male workers with metabolic syndrome was developed, and a pilot test was conducted. The Best Exerciser Super Trainer program was designed to be delivered via the Internet to promote the initiation and maintenance of behavioral lifestyle modification using a transtheoretical model. Stage-matched psychobehavioral strategies were derived from the main constructs of a transtheoretical model and matched to each individual's stage of readiness for physical activity/weight control using the cardiovascular risk assessment. A simulated version of Best Exerciser Super Trainer was evaluated by an expert group (n=8). Eighteen male workers participated in an 8-week pilot test of the program. The Best Exerciser Super Trainer Web site consisted of an introduction, main, and administrator components. A majority of the expert group (87.5%) either strongly agreed or agreed with the contents on the Web site. Significant changes in cardiovascular disease risk reduction over the study period among the participants included decreased cardiovascular risk (-2.4%), waist circumference (-2.9 cm), diastolic blood pressure (-9.9 mm Hg), and fasting plasma glucose ( 16.7 mg/dL). The findings of this pilot study provide evidence that the Best Exerciser Super Trainer program may be useful for conducting Web surveys and delivering an intervention. PMID- 23343756 TI - Nurses' information appraisal within the clinical setting. AB - Limited discussion in nursing literature exists regarding how nurses appraise information. In the absence of information appraisal skills, nurses cannot safely and effectively apply evidence in practice. The research study used an interpretive description design to define and describe the process of information appraisal in the clinical setting. This study represented a sample of 44 RNs employed at a medical center in the Southeastern US. Based on the descriptions offered by participants, information appraisal contains three dimensions: gathering, analysis, and application. In addition, nurses perform information appraisal by way of an unspoken algorithm, incorporating two major decision points: first situational urgency, then familiarity with information sources. In most cases, the trusted resource served as a proxy for evaluating the information that was provided by the resource. Findings suggest that information appraisal is described in a number of ways by nurses, resulting in an unclear definition for the process. Understanding the perceptions of this sample has given insight into how nurses describe and perform information evaluation. Knowledge gained from this study may be used by nurse educators in the academic and clinical setting as they work to deliver relevant information that facilitates providing the highest quality care. PMID- 23343757 TI - On the Landau theory of phase transitions: a hierarchical dynamic model. AB - The Landau theory of phase transitions has been re-examined under the framework of a modified mean field theory in ferroelectrics. By doing so, one can see that there are two atomic movements involved in the ferroelectric phase transition; the first corresponds to the vibration of the crystalline lattice, which will render phonon mode softening at the critical point, and the second represents the slow evolution of a partially ordered nematic phase formed by the cooperative behavior of high-temperature structure precursors. In this hierarchical dynamic structure, the former fast dynamics could be significantly modulated by the latter slow dynamics in the vicinity of the Curie temperature; it then turns out that it is the behavior of the nematic phase on approaching the critical point that makes the Landau theory deviate from experimental observations. PMID- 23343758 TI - Survival advantage and PaO2 threshold in severe traumatic brain injury. AB - BACKGROUND: Hypoxemia can adversely affect outcome after traumatic brain injury (TBI). However, the effect of high PaO2 on TBI outcomes is controversial. The primary aim of this study was to identify the optimal PaO2 range early after severe TBI. METHODS: In this single-center retrospective study conducted at a level-1 trauma center, patients with severe TBI (head Abbreviated Injury Scale score >3, admission Glasgow Coma Scale score <=8) were included. The crude and adjusted (including chest injuries and acute respiratory distress syndrome) effects of 50 mm Hg incremental PaO2 thresholds during the first 72 hours on discharge survival were examined. RESULTS: Data from 193 patients (44+/-18 y; 77% male; admission Glasgow Coma Scale score 4+/-2) were reviewed. Overall survival was 57%. PaO2 thresholds in increments of 50 mm Hg between 250 and 486 mm Hg (68%) were associated with discharge survival in patients with severe TBI compared with PaO2 60 mm Hg=250 mm Hg during the first 72 hours, in-hospital hypoxemia was common (24%) and was associated with mortality (survival adjusted odds ratio 0.46; 95% confidence interval, 0.22-0.95). CONCLUSIONS: In this series, a PaO2 threshold between 250 and 486 mm Hg during the first 72 hours after injury was associated with improved all-cause survival in patients with severe TBI, independent of hypocarbia or hypercarbia. PMID- 23343759 TI - Coat colour in mouse populations selected for weight gain: support for hitchhiking, not pleiotropy. AB - With many molecular markers in many species, research efforts in quantitative genetics have focused on dissecting these traits and understanding the importance of factors such as correlated response due to hitchhiking or pleiotropy. Here, in an examination of long-term selection experiments in mice, the evidence strongly supports the primary importance of hitchhiking on the coat colour loci brown and dilute in mice selected for high weight gain. First, the amount of observed change in coat colour allele frequency could not be explained by genetic drift alone, implying that selection was of high importance. Second, the allele frequency changes included reversals in the direction change, but there were still positive correlations in the early generations with differences in weight gain between the phenotypes. Third, the correlation between the change in allele frequencies and phenotypic difference in weight gain declined over time, consistent with the decay expected from linkage associations. Fourth, the changes at both loci in a short-term selection experiment for low weight gain were in the opposite direction than the changes in the contemporaneous related population selected for high weight gain. PMID- 23343760 TI - Epidemiology of mammalian hepatitis E virus infection. AB - Mammalian hepatitis E virus (HEV), the etiological agent of hepatitis E in humans, is a recently discovered infectious agent. It was identified for the first time in 1983 using electron microscopy on a faecal specimen of a person infected with non-A, non-B enterically-transmitted hepatitis. Based on retrospective and prospective studies, HEV was long described as one of the leading causes of acute viral hepatitis in tropical and subtropical countries, whereas in developed countries hepatitis E was considered an imported disease from HEV hyperendemic countries. Data from studies conducted during the past decade have greatly shifted our knowledge on the epidemiology and clinical spectrum of HEV. Recently, it has been shown that contrary to previous beliefs, hepatitis E is also an endemic disease in several developed countries, particularly in Japan and in Europe, as evidenced by reports of high anti-HEV immunoglobulin G prevalence in healthy individuals and an increasing number of non-travel-related acute hepatitis E cases. Moreover, a porcine reservoir and growing evidence of zoonotic transmission have been reported in these countries. This review summarizes the current knowledge on the epidemiology and prevention of transmission of mammalian HEV. PMID- 23343761 TI - In-plane coassembly route to atomically thick inorganic-organic hybrid nanosheets. AB - Control over the anisotropic assembly of small building blocks into organized structures is considered an effective way to design organic nanosheets and atomically thick inorganic nanosheets with nonlayered structure. However, there is still no available route so far to control the assembly of inorganic and organic building blocks into a flattened hybrid nanosheet with atomic thickness. Herein, we highlight for the first time a universal in-plane coassembly process for the design and synthesis of transition-metal chalcogenide-alkylamine inorganic-organic hybrid nanosheets with atomic thickness. The structure, formation mechanism, and stability of the hybrid nanosheets were investigated in detail by taking the Co9S8-oleylamine (Co9S8-OA) hybrid nanosheets as an example. Both experimental data and theoretical simulations demonstrate that the hybrid nanosheets were formed by in-plane connection of small two-dimensional (2D) Co9S8 nanoplates via oleylamine molecules adsorbed at the side surface and corner sites of the nanoplates. X-ray absorption fine structure spectroscopy study reveals the structure distortion of the small 2D Co9S8 nanoplates that endows structural stability of the atomically thick Co9S8-OA hybrid nanosheets. The brand new atomically thick nanosheets with inorganic-organic hybrid network nanostructure will not only enrich the family of atomically thick 2D nanosheets but also inspire more interest in their potential applications. PMID- 23343762 TI - p53-Dependent regulation of metabolic function through transcriptional activation of pantothenate kinase-1 gene. AB - It is well established that the p53 tumor suppressor plays a crucial role in controlling cell proliferation and apoptosis upon various types of stress. There is increasing evidence showing that p53 is also critically involved in various metabolic pathways, both in tumor and normal cells. Here, we have identified a novel p53 metabolic target pantothenate kinase-1 (PANK1) via ChIP-on-chip. PanK1 catalyzes the rate-limiting step for CoA synthesis and, therefore, controls intracellular CoA content; Pank1-knockout mice exhibit defect in beta-oxidation and gluconeogenesis in the liver after starvation due to insufficient CoA levels. We demonstrated that PANK1 gene is a direct transcriptional target of p53. Although DNA damage-induced p53 upregulates PanK1 expression, depletion of PanK1 expression does not affect p53-dependent growth arrest or apoptosis. Interestingly, upon glucose starvation, PanK1 expression is significantly reduced in HCT116 p53 (-/-) but not in HCT116 p53 (+/+) cells, suggesting that p53 is required to maintain PanK1 expression under metabolic stress conditions. Moreover, by using p53-mutant mice, we observed that, similar to the case in Pank1-knockout mice, gluconeogenesis is partially impaired in p53-null mice. Together, our findings show that p53 plays an important role in regulating energy homeostasis through transcriptional control of PANK1, independent of its canonical functions in apoptosis and cell cycle arrest. PMID- 23343763 TI - Deficiency in spliceosome-associated factor CTNNBL1 does not affect ongoing cell cycling but delays exit from quiescence and results in embryonic lethality in mice. AB - CTNNBL1 is an armadillo-repeat protein that associates with the CDC5L/Prp19 complex of the spliceosome. Unlike the majority of spliceosomal proteins (and despite having no obvious homologs), CTNNBL1 is inessential for cell viability as revealed by studies in both vertebrate B cell lines and in fission yeast. Here, however, we show that ablation of CTNNBL1 in the mouse germline results in mid gestation embryonic lethality but that lineage-specific CTNNBL1 ablation in early B cell precursors does not affect the production and abundance of mature B lymphocytes. However, CTNNBL1-deficient resting B lymphocytes show sluggish exit from quiescence on cell activation, although once entry into cycle has initiated, proliferation and differentiation in response to mitogenic stimuli continue largely unaffected. A similar sluggish exit from quiescence is also observed on reprovision of nutrients to nitrogen-starved CTNNBL1-deficient yeast. The results indicate that, whereas other RNA splicing-associated factors have been connected to cell cycle progression, CTNNBL1 plays no essential role in cycling cells but does fulfill an evolutionarily conserved function in helping cells to undergo efficient exit from quiescence following activation. PMID- 23343764 TI - Testosterone replacement therapy improves QTaVI in hypogonadal men with spinal cord injury. AB - AIM: To determine the effect of a 12-month intent-to-treat testosterone (T) replacement therapy (TRT) trial on QTa interval variability (QTaVI) in hypogonadal (HG) men with spinal cord injury (SCI). METHOD: A prospective, controlled 12-month TRT trial was completed in 22 healthy, chronic, nonambulatory men with SCI. Based on serum T concentration, subjects were designated as HG (<= 11.3 nmol/l) or eugonadal (EG >= 11.4 nmol/l). Digital 3-lead electrocardiograms were performed. Heart rate (RR), heart rate variability [including total power (TPRR), low frequency (LFRR) and high frequency (HFRR)], QTa, QTe, and RT intervals, QTC (Bazett formula), QTVN, and QTaVI were calculated and evaluated at baseline and at 12 months. Lipoprotein profiles (triglycerides, total cholesterol, low-density and high-density lipoproteins) were obtained at the respective time points. RESULTS: Based on serum T concentration, 13 subjects were designated as HG and 11 as EG. During the trial, there were no group differences for RR, QTa, QTe or RT intervals, QTC, TPRR, HFRR, or lipoproteins. The HG group was older (p < 0.05) and their LFRR was lower (p < 0.05) at baseline. At baseline, QTaVI was significantly greater in the HG group compared to the EG group [-0.17 (0.92) vs. -1.07 (0.90); p < 0.05]. After TRT, this group difference was no longer present [-0.44 (0.87) vs. -0.65 (0.85)] and the change in the HG group was significant (p < 0.05). CONCLUSION: Hypogonadism in men with SCI was associated with elevated QTaVI at baseline. After 12 months of physiological TRT, the QTaVI improved in association with raising T into the normal range. These findings occurred independently of the prolongation of the QT interval. PMID- 23343765 TI - Prognostic value of LIPC in non-small cell lung carcinoma. AB - Non-small cell lung carcinoma (NSCLC) is the most common form of lung cancer and is associated with a high mortality rate worldwide. The majority of individuals bearing NSCLC are treated with surgery plus adjuvant cisplatin, an initially effective therapeutic regimen that, however, is unable to prevent relapse within 5 years after tumor resection in an elevated proportion of patients. The factors that predict the clinical course of NSCLC and its sensitivity to therapy remain largely obscure. One notable exception is provided by pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. PDXK has recently been shown to be required for optimal cisplatin responses in vitro and in vivo and to constitute a bona fide prognostic marker in the NSCLC setting. Together with PDXK, 84 additional factors were identified that influence the response of NSCLC cells to cisplatin, in vitro including the hepatic lipase LIPC. Here, we report that the intratumoral levels of LIPC, as assessed by immunohistochemistry in two independent cohorts of NSCLC patients, positively correlate with disease outcome. In one out of two cohorts studied, the overall survival of NSCLC patients bearing LIPChigh lesions was unaffected, if not slightly worsened, by cisplatin-based adjuvant therapy. Conversely, the overall survival of patients with LIPClow lesions was prolonged by post-operative cisplatin. Pending validation in appropriate clinical series, these results suggest that LIPClow NSCLC patients would be those who mainly benefit from adjuvant cisplatin therapy. Thus, the expression levels of LIPC appear to have an independent prognostic value (and perhaps a predictive potential) in the setting of NSCLC. If these findings were confirmed by additional studies, LIPC expression levels might allow not only for NSCLC patient stratification, but also for the implementation of personalized therapeutic approaches. PMID- 23343766 TI - ATM-dependent phosphorylation of heterogeneous nuclear ribonucleoprotein K promotes p53 transcriptional activation in response to DNA damage. AB - Previous work has established that heterogeneous nuclear ribonucleoprotein K (hnRNP K) is stabilized in an ATM-dependent manner in response to DNA damage and acts as a cofactor for p53-mediated transcription. Here, we show that in response to DNA damage caused by ionizing radiation, hnRNP K is phosphorylated in an ATM dependent manner. Furthermore, our data indicate that ATM-dependent hnRNP K phosphorylation is required for its stabilization and its function as a p53 transcriptional cofactor in response to DNA damage. These findings thereby establish hnRNP K as an ATM target and help define how ATM orchestrates p53 dependent transcriptional responses in response to genotoxic stress. PMID- 23343767 TI - The impact of trisomy 21 on early human hematopoiesis. PMID- 23343768 TI - Body temperature cycles: gatekeepers of circadian clocks. PMID- 23343769 TI - Target search dynamics during post-replicative mismatch repair. PMID- 23343770 TI - Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. AB - The term "mitochondrial permeability transition" (MPT) refers to an abrupt increase in the permeability of the inner mitochondrial membrane to low molecular weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate mitochondrial outer membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade as well as of caspase-independent cell death mechanisms. MPT appears to be mediated by the opening of the so-called "permeability transition pore complex" (PTPC), a poorly characterized and versatile supramolecular entity assembled at the junctions between the inner and outer mitochondrial membranes. In spite of considerable experimental efforts, the precise molecular composition of the PTPC remains obscure and only one of its constituents, cyclophilin D (CYPD), has been ascribed with a crucial role in the regulation of cell death. Conversely, the results of genetic experiments indicate that other major components of the PTPC, such as voltage-dependent anion channel (VDAC) and adenine nucleotide translocase (ANT), are dispensable for MPT-driven MOMP. Here, we demonstrate that the c subunit of the FO ATP synthase is required for MPT, mitochondrial fragmentation and cell death as induced by cytosolic calcium overload and oxidative stress in both glycolytic and respiratory cell models. Our results strongly suggest that, similar to CYPD, the c subunit of the FO ATP synthase constitutes a critical component of the PTPC. PMID- 23343771 TI - Essential role of Cenexin1, but not Odf2, in ciliogenesis. AB - Primary cilia are microtubule-based solitary sensing structures on the cell surface that play crucial roles in cell signaling and development. Abnormal ciliary function leads to various human genetic disorders, collectively known as ciliopathies. Outer dense fiber protein 2 (Odf2) was initially isolated as a major component of sperm-tail fibers. Subsequent studies have demonstrated the existence of many splicing variants of Odf2, including Cenexin1 (Odf2 isoform 9), which bears an unusual C-terminal extension. Strikingly, Odf2 localizes along the axoneme of primary cilia, whereas Cenexin1 localizes to basal bodies in cultured mammalian cells. Whether Odf2 and Cenexin1 contribute to primary cilia assembly by carrying out either concerted or distinct functions is unknown. By taking advantage of odf2-/- cells lacking endogenous Odf2 and Cenexin1, but exogenously expressing one or both of these proteins, we showed that Cenexin1, but not Odf2, was necessary and sufficient to induce ciliogenesis. Furthermore, the Cenexin1 dependent primary cilia assembly pathway appeared to function independently of Odf2. Consistently, Cenexin1, but not Odf2, interacted with GTP-loaded Rab8a, localized to the distal/subdistal appendages of basal bodies, and facilitated the recruitment of Chibby, a centriolar component that is important for proper ciliogenesis. Taken together, our results suggest that Cenexin1 plays a critical role in ciliogenesis through its C-terminal extension that confers a unique ability to mediate primary cilia assembly. The presence of multiple splicing variants hints that the function of Odf2 is diversified in such a way that each variant has a distinct role in the complex cellular and developmental processes. PMID- 23343773 TI - Is myofascial pain in temporomandibular disorder patients a manifestation of delayed-onset muscle soreness? AB - OBJECTIVE: In a study to the possible role of overuse of the jaw muscles in the pathogenesis of jaw muscle pain, we used a protocol involving concentric and eccentric muscle contractions to provoke a state of delayed-onset muscle soreness (DOMS) in the jaw muscles of healthy individuals. We tested whether the accompanying signs and symptoms would yield the temporary diagnosis of myofascial pain according to the research diagnostic criteria for temporomandibular disorders (RDC/TMD) in these individuals. METHODS: Forty persons (mean age+/ SD=27.7+/-7.5 y) performed six, 5-minute bouts of eccentric and concentric jaw muscle contractions. Before and immediately after the exercise, and 24 hours, 48 hours, and 1 week later, self-reported muscle fatigue and pain, pain-free maximum mouth opening, pressure-pain thresholds, and the number of painful jaw muscle palpation sites were recorded. RESULTS: Significant signs and symptoms of DOMS in the jaw muscles were found, which all had resolved after 1 week. In 31 (77.5%) of the participants, these signs and symptoms also gave rise to a temporary diagnosis of myofascial pain according to the RDC/TMD. CONCLUSIONS: The results of this study demonstrate that an experimental protocol involving concentric and eccentric muscle contractions can provoke DOMS in the jaw muscles and the temporary diagnosis of myofascial pain according to the RDC/TMD. The results observed strengthen the supposition that the myofascial pain in TMD patients may be a manifestation of DOMS in the jaw muscles. PMID- 23343772 TI - Phospho-DeltaNp63alpha/microRNA feedback regulation in squamous carcinoma cells upon cisplatin exposure. AB - Our previous reports showed that the cisplatin exposure induced the ATM-dependent phosphorylation of DeltaNp63a, which is subsequently involved in transcriptional regulation of gene promoters encoding mRNAs and microRNAs in squamous cell carcinoma (SCC) cells upon cisplatin-induced cell death. We showed that phosphorylated (p)-DeltaNp63a plays a role in upregulation of pro-apoptotic proteins, while non-p-DeltaNp63a is implicated in pro-survival signaling. In contrast to non-p-DeltaNp63a, p-DeltaNp63a modulated expression of specific microRNAs in SCC cells exposed to cisplatin. These microRNAs were shown to attenuate the expression of several proteins involved in cell death/survival, suggesting the critical role for p-DeltaNp63a in regulation of tumor cell resistance to cisplatin. Here, we studied the function of DeltaNp63a in transcriptional activation and repression of the specific microRNA promoters whose expression is affected by cisplatin treatment of SCC cells. We quantitatively studied chromatin-associated proteins bound to tumor protein (TP) p63-responsive element, we found that p-DeltaNp63a along with certain transcription coactivators (e.g., CARM1, KAT2B, TFAP2A, etc.) necessary to induce gene promoters for microRNAs (630 and 885-3p) or with transcription corepressors (e.g., EZH2, CTBP1, HDACs, etc.) needed to repress promoters for microRNAs (181a 5p, 374a-5p and 519a-3p) in SCC cells exposed to cisplatin. PMID- 23343774 TI - Pathways to renal biopsy and diagnosis among patients with ANCA small-vessel vasculitis. AB - OBJECTIVES: Antineutrophil cytoplasmic antibody small-vessel vasculitis (ANCA SVV) is an autoimmune systemic process increasingly recogniSed since the advent of antibody testing for the disease. Prompt diagnosis and institution of immunosuppressive therapy has been shown to improve patient outcome. The goal of this study was to better understand how patients navigate the health care system from symptom presentation to biopsy diagnosis, and to study the effects of prompt versus delayed diagnosis. METHODS: Disease symptoms and number of physicians seen prior to renal biopsy were assessed for 127 ANCA-SVV patients. Direct, delayed, and quest pathways to diagnosis and treatment of vasculitis were defined for both patients and providers. Kruskal-Wallis and Fisher exact tests were used to evaluate continual measures and compare categorical variables across pathways. RESULTS: Among patients who sought direct care, physician delay in referral to a nephrologist was common (49/127, 71%, p=0.0023). Patients who delayed seeking care also experienced a delayed diagnosis 57% of the time (p=0.0023). Patients presenting with prodromal flu or upper respiratory involvement were more likely to have a delay/quest patient pathway (56% and 55%, respectively) than a direct patient pathway (44%, p=0.033 and 45%, p=0.019, respectively). There was a trend for patients with more severe loss of renal function to have a more direct referral to a nephrologist. CONCLUSIONS: Delay in diagnosis of ANCA SVV may be due to lack of or non-specific symptoms, especially in patients who present with non-renal manifestations of disease. Better algorithms are needed to identify extra-renal manifestations, expedite diagnosis and improve patient outcomes. PMID- 23343775 TI - Increased cortical excitability after selective REM sleep deprivation in healthy humans: a transcranial magnetic stimulation study. AB - BACKGROUND: REM sleep has antiepileptogenic properties whereas, its loss is known to have a proconvulsive role. However, the mechanisms underlying the proepileptogenic effects of REM sleep deprivation are yet not fully understood. The aim of our study was to evaluate the effects of selective REM sleep deprivation (SRD) on cortical excitability in healthy subjects by means of transcranial magnetic stimulation (TMS). METHODS: Ten normal subjects underwent three TMS sessions: (1) in baseline condition (BL), (2) after SRD by awakening them at each REM sleep onset and (3) after non-rapid eye movement sleep awakenings (NREM-A) as control for potential non-specific effects of interruptions. The TMS investigation included two protocols: (a) the evaluation of motor evoked potentials (MEPs) and silent period (SP) parameters, recorded in response to single pulse magnetic stimulation; (b) the evaluation of the time course of intracortical motor activity tested with paired-pulse TMS applied at inter-stimulus intervals of 1-10 ms. RESULTS: After SRD the principal finding observed using single pulse TMS was a significant reduction in the duration of SP whereas, a reduction of intracortical inhibition was found, using the paired pulse TMS. TMS parameters did not show significant changes after NREM-A with respect to BL. CONCLUSIONS: SRD may influence cortical excitability with a reduction of inhibitory intracortical mechanisms, thus supporting the proconvulsant role of REM loss. PMID- 23343776 TI - Revealing the impact of catalyst phase transition on carbon nanotube growth by in situ Raman spectroscopy. AB - The physical state of the catalyst and its impact on the growth of single-walled carbon nanotubes (SWNTs) is the subject of a long-standing debate. We addressed it here using in situ Raman spectroscopy to measure Fe and Ni catalyst lifetimes during the growth of individual SWNTs across a wide range of temperatures (500 1400 degrees C). The temperature dependence of the Fe catalyst lifetimes underwent a sharp increase around 1100 degrees C due to a solid-to-liquid phase transition. By comparing experimental results with the metal-carbon phase diagrams, we prove that SWNTs can grow from solid and liquid phase-catalysts, depending on the temperature. PMID- 23343777 TI - MicroRNA expression and JAK2 allele burden in bone marrow trephine biopsies of polycythemia vera, essential thrombocythemia and early primary myelofibrosis. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) play an important role in cellular differentiation and cancer pathogenesis. However, their role in promoting the malignant phenotype of myeloproliferative diseases and their importance for differential diagnosis of early-stage chronic myeloproliferative diseases (CMPDs) remains widely obscure. METHODS: In this study, we systematically evaluated the differential expression of miRNAs previously described to be associated with myelopoiesis and myeloproliferative pathogenesis by quantitative RT-PCR in polycythemia vera, essential thrombocythemia, early primary myelofibrosis (PMF) and normal hematopoiesis. Our goal was to establish certain miRNAs as potential markers for CMPDs to facilitate the differentiation between these diseases and to further investigate molecular differences between the subtypes of myeloproliferative neoplasia. RESULTS: An aberrant expression of miRNAs 10a and 150 could be demonstrated for essential thrombocythemia and PMF as well as for polycythemia vera and PMF, respectively. The expression of miR-150 could further be shown to correlate with both JAK2 allele burden and peripheral blood counts. CONCLUSION: Thus, the miRNAs investigated in this study seem to be potential marker oncomiRs in the differential diagnosis of CMPDs and possibly hold potential for the elucidation of a JAK2-independent mechanism of pathogenesis. PMID- 23343778 TI - Relationships among neurocognition, symptoms, and functioning in treatment resistant depression. AB - Treatment-resistant depression (TRD) refers to a condition where individuals with major depressive disorder have inadequate or no response to treatment. Although functional disability is a prominent and costly feature of treatment resistance, very little is known about the factors that contribute to and maintain functional impairment in TRD. This is the first study to report the neurocognitive profile of TRD and the relationships among neurocognition, symptoms, and functioning in this syndrome. Results indicated that patients with TRD (N = 33) exhibit mildly reduced performance across all neurocognitive domains with a superimposed moderate impairment in verbal working memory. Neurocognition was associated with functional competence (what one can do), whereas depressive symptoms were associated with functional performance (what one actually does). Understanding the psychological mechanisms related to functioning may help us move toward recovery in this chronically ill group. PMID- 23343779 TI - Specific antibody responses against Neospora caninum recombinant rNcGRA7, rNcSAG4, rNcBSR4 and rNcSRS9 proteins are correlated with virulence in mice. AB - The intraspecific diversity of Neospora caninum is a determinant for in vivo parasite virulence and in vitro parasite behaviour. The relationship between isolate virulence and specific antibody responses against key parasite proteins has not been well characterized. The response kinetics and the differences in specific anti-rNcGRA7, -rNcSAG4, -rNcBSR4 and -rNcSRS9 antibody levels were analysed by recombinant protein-based ELISA in groups of mice inoculated with 10 different N. caninum isolates that differ in their virulence. The majority of the virulence parameters analysed correlated with the specific antibody levels against the 4 recombinant proteins. The antibodies developed against the highly immunogenic protein NcGRA7 were significantly higher in mice inoculated with high virulence isolates than in those inoculated with low-to-moderate virulence isolates in both non-pregnant and pregnant mouse models. Moreover, these levels were correlated with the anti-N. caninum IgG1 and IgG2a responses and the in vitro tachyzoite yield at 56 h. The antibodies directed against the bradyzoite specific proteins were not detected in a non-pregnant mouse model. However, some seropositive mice were found in groups inoculated with high virulence isolates in a pregnant mouse model. NcGRA7 and NcSAG4 are proteins clearly correlated with virulence, and to a lesser extent NcBSR4 and NcSRS9 proteins. Moreover, antibodies to bradyzoite-specific proteins appear to also be related to virulence in mice. Further analyses should be performed in order to verify the usefulness of these proteins as predictive markers for virulence in an experimental bovine model of neosporosis. PMID- 23343780 TI - Characterization of candidate anti-allergic probiotic strains in a model of th2 skewed human peripheral blood mononuclear cells. AB - BACKGROUND: Pre-clinical and clinical studies have evaluated the efficacy of probiotics in allergy. However, predictive in vitro systems for rational strain selection are still missing. METHODS: We developed a novel in vitro screening system for the characterization of probiotics with anti-allergic potential. In this model, human peripheral blood mononuclear cells (PBMC) from healthy donors (n = 68) were skewed towards a Th2 cytokine phenotype by culture with IL-4 and anti-CD40, to resemble cells from allergic donors. Th2-skewed cells were then co cultured with probiotics; a total of 35 strains were tested. Levels of IFN-gamma, IL-10, IL-5 and 7 additional cytokines in culture supernatants were determined by ELISA or multiplex assay. Gene expression was assessed by real-time PCR. For validation, splenocytes from ovalbumin-primed mice and PBMC from grass-allergic donors were restimulated with respective antigen and co-cultured with probiotics, and cytokine profiles were correlated. RESULTS: Culture with IL-4 and anti-CD40 antibody induced secretion of IL-5 from PBMC, indicative of induction of a Th2 phenotype. Cytokine profiles induced by probiotics were strain specific even though species- and genus-specific clustering was observed for many strains by principal component analysis. This was paralleled by mRNA levels of the corresponding genes such as increased Tbet and reduced GATA-3 gene expression. Cytokine profiles induced by probiotics in PBMC stimulated with IL-4 and anti CD40 correlated with those obtained from allergen-stimulated murine splenocytes or human PBMC from grass-allergic donors. CONCLUSIONS: Cytokine profiling of probiotic strains with IL-4-/anti-CD40-stimulated PBMC allowed to determine the effect of probiotics on Th2-skewed cells and thus to classify probiotic strains with anti-allergic potential. PMID- 23343781 TI - Polymorphisms near interleukin 28B gene are not associated with hepatitis B virus clearance, hepatitis B e antigen clearance and hepatocellular carcinoma occurrence. AB - BACKGROUND: Polymorphisms near the IL28B gene have been proposed to be strongly associated with treatment response and the rate of spontaneous clearance of hepatitis C virus infection, and treatment response of hepatitis B virus (HBV) infection. In this study, we aimed to determine whether these polymorphisms could affect natural courses of HBV infection. METHODS: Genetic variations were identified through direct DNA sequencing using TaqMan assay in 1,439 patients with past or present HBV infection. Subjects included 404 spontaneously recovered patients, 313 chronic hepatitis B (CHB) patients, 305 liver cirrhosis (LC) patients and 417 hepatocellular carcinoma (HCC) patients. Three polymorphisms near the IL28B gene, rs8099917T>G, rs12979860C>T and rs12980275A>G, were identified. Associations between these polymorphisms and HBV clearance, hepatitis B e antigen (HBeAg) clearance as well as HCC occurrence among patients were analyzed using logistic regression analyses adjusted for age and gender. RESULTS: There were no significant associations between these polymorphisms and the HBV clearance both in CHB and LC groups. Similarly, these polymorphisms showed no significant associations with HBeAg clearance and the occurrence of HCC either. DISCUSSION: No significant association was identified between polymorphisms near the IL28B gene and the natural courses of chronic HBV infection, including the HBV clearance and HCC occurrence. PMID- 23343782 TI - Isokinetic testing of evertor and invertor muscles in patients with chronic ankle instability. AB - Ankle sprains are among the most common sport-related injuries and can lead to chronic ankle instability. Impaired sensorimotor function of the ankle musculature is often suggested as a cause. The current study sought to assess and compare the isokinetic performance and electromyographic patterns of evertor and invertor muscles in patients with chronic ankle instability and in a control group. Twelve patients with chronic ankle instability and twelve healthy subjects were included. Isokinetic eccentric and concentric testing at various angular velocities was performed for eversion and inversion movements. The corresponding myoelectric activities of the fibularis longus and tibialis anterior muscles were quantified from surface electromyographic recordings by computing average root mean square values. Patients had lower myoelectric activity of the evertor and invertor muscles than controls did; this difference could account for the eccentric weakness associated with ankle instability. Functional strength ratios revealed a dynamic strength imbalance in unstable ankle patients and that may contribute to recurrent injury. Our findings suggest that rehabilitation programs for unstable ankle patients must be focused on the motor control of eccentric contractions of the ankle evertors and invertors, to boost these muscles' contribution to ankle stabilization. PMID- 23343783 TI - A wake-up call for nutrition labelling. PMID- 23343784 TI - Scattering theory of nonlinear thermoelectricity in quantum coherent conductors. AB - We construct a scattering theory of weakly nonlinear thermoelectric transport through sub-micron scale conductors. The theory incorporates the leading nonlinear contributions in temperature and voltage biases to the charge and heat currents. Because of the finite capacitances of sub-micron scale conducting circuits, fundamental conservation laws such as gauge invariance and current conservation require special care to be preserved. We do this by extending the approach of Christen and Buttiker (1996 Europhys. Lett. 35 523) to coupled charge and heat transport. In this way we write relations connecting nonlinear transport coefficients in a manner similar to Mott's relation between the linear thermopower and the linear conductance. We derive sum rules that nonlinear transport coefficients must satisfy to preserve gauge invariance and current conservation. We illustrate our theory by calculating the efficiency of heat engines and the coefficient of performance of thermoelectric refrigerators based on quantum point contacts and resonant tunneling barriers. We identify, in particular, rectification effects that increase device performance. PMID- 23343785 TI - Overlap of ACA-positive systemic sclerosis and Sjogren's syndrome: a distinct clinical entity with mild organ involvement but at high risk of lymphoma. AB - OBJECTIVES: We aimed to assess the prevalence of patients with either primary Sjogren's syndrome (pSS) and positive anticentromere antibodies (ACA) and secondary Sjogren's syndrome (sSS) and limited cutaneous ACA positive-systemic sclerosis (SSc) in two large cohorts of patients with pSS and SSc and also to compare the clinical features of these two subsets with those of patients affected by 'ACA-positive SSc without sicca symptoms' and 'pSS'. METHODS: In this retrospective monocentric study, the case records of 'overlap' patients fulfilling both the classification criteria for SS and the LeRoy criteria for early SSc were identified from two datasets of patients with limited cutaneous ACA positive SSc (209 subjects) and with pSS (402 subjects) who attended our Rheumatology Unit in the years between 1989 and 2011. Control groups were represented by SSc subjects without sicca symptoms ('SSc group') and ACA negative Pss patients ('pSS group'). SSc patients with sicca symptoms ('Sicca-SSc group') who did not complete the diagnostic algorithm for SS were excluded from the analysis. Demographic, clinical and immunological data of the patients enrolled were collected cumulatively over the entire follow up period. Statistical analysis was performed using SPSS 13 (SPSS Inc., Chicago IL, USA). RESULTS: Out of the two datasets 41 'overlap' patients were selected. The control groups were represented by 102/209 SSc subjects without sicca symptoms ('SSc group') and 387/402 pSS patients ('pSS group'). Eighty-one 'sicca-SSc' with an incomplete work-up for SS were excluded from the analysis. The prevalence of ACA positive pSS patients among pSS was 3.7% (15/402), while the frequency of patients with definite sSS in the SSc cohort was 20% (26/128). No differences were detected between 'overlap' patients and control groups, relatively to demographic characteristics. 'Overlap patients' were characterised by a milder SSc disease (i.e. lower frequency of sclerodactily, negative evolution of the capillaroscopy pattern or absence of severe systemic involvement) whereas, as far as the SS related manifestations were concerned, although often lacking in specific autoantibodies (i.e. rheumatoid factor, anti-Ro/SSA, anti-La/SSB), the 'overlap patients' displayed a full blown SS phenotype with recurrent salivary gland enlargement, purpura, fatigue, arthralgias, and leukocytopenia. It is noteworthy that the prevalence of non-Hodgkin's lymphoma in the 'overlap patients' was higher than in pSS. CONCLUSIONS: Taken together, the results of our work emphasise the existence of a novel distinct clinical entity which might tentatively be called 'ACA-positive limited scleroderma/SS overlap syndrome' characterised by a benign SSc clinical course but at a high risk of non-Hodgkin's lymphoma. PMID- 23343786 TI - Dural puncture-induced intracranial hypotension causing diplopia. AB - BACKGROUND: Diplopia that occurs after an epidural spinal catheter has been placed for pain control has been attributed to sixth nerve palsy nerve palsy induced by intracranial hypotension. There is sparse information about the factors that confound diagnosis in this setting. METHODS: Review of 6 cases examined over a period of 5 years at a single tertiary care medical center. RESULTS: Six confounders to diagnosis were identified: 1) lack of awareness that an epidural spinal catheter was or had been in place; 2) delayed reporting of diplopia; 3) mild or inapparent ductional deficits; 4) lack of postural headache; 5) clinical features that suggested an alternative diagnosis; 6) neuroimaging features that did not allow exclusion of pachymeningitis. CONCLUSION: Clinicians should be aware of features that confound a diagnosis of dural puncture-induced intracranial hypotension as a cause of diplopia in the post-operative period when an epidural pain control system is or has been deployed. If these confounders are recognized and the correct diagnosis is reached, radiologists will be less likely to diagnose pachymeningitis and clinicians will be able to avoid lumbar puncture, which may exacerbate the condition. PMID- 23343787 TI - The impact on quality of life for people with brain tumours of entering a research trial involving new anti-cancer agents. AB - PURPOSE: The intention of this study was to offer an alternative perspective to the quantitative findings of larger randomised controlled trials by using a phenomenological approach to explore the impact on Quality of Life (QoL) for people with brain tumours of entering a research trial involving new anti-cancer agents. METHOD: Given the subjective nature of the proposed topic, a phenomenological approach was adopted. Sample size was limited to five participants. A semi-structured interview technique was used. Interviews were digitally audio recorded with permission from those involved. In order to guide data analysis for this study, Colaizzi's framework was utilised. RESULTS: As a result of data analysis, two major themes were identified. These were 'Hope and optimism' and 'The therapeutic relationship'. Three minor themes were also found. These were 'A complex symptom profile', 'The importance of non-medical coping strategies' and 'Impressions of the QoL tools used'. CONCLUSIONS: This phenomenological study has highlighted key themes relating to QoL which are not addressed in some of the widely used assessment tools such as the EORTC QLQ C30 and BN20. They generally focus on health status, and do not capture issues identified in this study as being of significant importance to the QoL of participants such as hope and optimism, and the importance of the therapeutic relationship. They also omit reference to coping and management strategies. PMID- 23343789 TI - Enigmatic pregnancy. PMID- 23343788 TI - Validation of the Distress Thermometer in a Swedish population of oncology patients; accuracy of changes during six months. AB - PURPOSE: To validate the Swedish version of the Distress Thermometer (DT) against the Hospital Anxiety and Depression Scale (HADS) for screening of distress and to explore how well DT measures changes of distress during six months in a population of heterogeneous oncology patients. METHODS: The DT was translated into Swedish according to the forward- and back-translation procedure. HADS total score >=15 was used as gold standard. Consecutive patients were invited to participate at their first visit to the Oncology department. The HADS and the DT were completed at baseline and after 1, 3 and 6 months. RESULTS: 462 baseline and 321 six-month assessments were completed. The patients had a variety of cancer diagnoses (n = 42). Most patients (95%) received active treatment. The DT compared favourably with the HADS. The area under the curve was 0.86 (95% CI, 0.82-0.90). DT >= 4 showed a sensitivity of 87%, a specificity of 73%, a positive predictive value (PPV) of 52% and a negative predictive value (NPV) of 95% at baseline. The results from the 1, 3 and 6 months assessments were equivalent baseline results. The DT means changed in the same direction as HADS at all points of assessment. Patients with distress reported statistically significantly more problems in all categories on the associated 'Problem List' compared to non distressed patients. CONCLUSION: The Swedish version of the DT with a score >=4 is valid for screening of distress in heterogeneous oncology patients. Its ability to measure changes in distress over time is comparable to HADS. PMID- 23343790 TI - Home improvement. PMID- 23343791 TI - Art and reproductive science: celebrating a glorious marriage. PMID- 23343792 TI - A national study of the provision of oncofertility services to female patients in Canada. PMID- 23343793 TI - Fetal movement monitoring: how are we doing as educators? AB - OBJECTIVE: When decreased fetal movement is noticed, delay in seeking care is associated with poor perinatal outcomes, including stillbirth. Health care providers are responsible for educating women about normal fetal movement and the appropriate actions they should take if it decreases. This study aimed to demonstrate our pregnant population's understanding of normal fetal movement and responses to decreased fetal movement, and to potentially guide educational interventions to improve perinatal outcomes. METHODS: We surveyed 304 pregnant women (over 26 weeks' gestation) during clinic visits at the IWK Health Centre, Halifax, NS. Information collected in the survey included demographics, knowledge about normal fetal movement, monitoring techniques, and response to decreased fetal movement. RESULTS: Eighteen percent of women (55/298) demonstrated knowledge of normal fetal movement and fetal monitoring, indicating that they would seek assessment promptly if they experienced decreased fetal movement. Although 54.7% of participants (164/300) would contact a health care professional if they noticed decreased fetal movement, approximately two thirds of participants were unable to describe normal fetal movement or monitoring techniques. Almost 30% of participants (90/304) did not identify daily fetal movement as normal, and 37.5% (114/304) reported it may be normal for fetal movement to stop around their due date. Written and verbal communication regarding fetal movement from a health care provider significantly increased the likelihood of appropriate intended self-management in the context of decreased fetal movement. CONCLUSION: Education influences the anticipated behaviour of pregnant women regarding decreased fetal movement. Specific areas of misinformation which may guide future education strategies are identified. There is room for improvement in this area of patient education. PMID- 23343794 TI - Measuring quality in maternal-newborn care: developing a clinical dashboard. AB - Pregnancy, birth, and the early newborn period are times of high use of health care services. As well as opportunities for providing quality care, there are potential missed opportunities for health promotion, safety issues, and increased costs for the individual and the system when quality is not well defined or measured. There has been a need to identify key performance indicators (KPIs) to measure quality care within the provincial maternal-newborn system. We also wanted to provide automated audit and feedback about these KPIs to support quality improvement initiatives in a large Canadian province with approximately 140 000 births per year. We therefore worked to develop a maternal-newborn dashboard to increase awareness about selected KPIs and to inform and support hospitals and care providers about areas for quality improvement. We mapped maternal-newborn data elements to a quality domain framework, sought feedback via survey for the relevance and feasibility of change, and examined current data and the literature to assist in setting provincial benchmarks. Six clinical performance indicators of maternal-newborn quality care were identified and evidence-informed benchmarks were set. A maternal-newborn dashboard with "drill down" capacity for detailed analysis to enhance audit and feedback is now available for implementation. While audit and feedback does not guarantee individuals or institutions will make practice changes and move towards quality improvement, it is an important first step. Practice change and quality improvement will not occur without an awareness of the issues. PMID- 23343795 TI - Pregnancy outcomes in women with spinal cord lesions. AB - OBJECTIVE: Women with spinal cord lesions present special challenges during pregnancy. We studied their pregnancy outcomes with regard to medical, obstetrical, and social concerns. METHODS: We reviewed the records of pregnant women with spinal cord injury who attended our institution between 1999 and 2009. RESULTS: Thirty-two women with a total of 37 pregnancies were identified. Most were nulliparous (65%) with either thoracic or lumbar spinal cord lesions due to neural tube defects (69%), trauma (19%), tumours (9%), or iatrogenic injury (3%). Most had undergone orthopedic surgery (63%) or neurosurgery (53%). The most common medical conditions were neurogenic bladder (53%), anemia (16%), autonomic hyperreflexia (9%), and elevated BMI > 30 (6%). Recurrent urinary tract infection occurred in 32%. Antibiotic suppression against bacteriuria was used in 35%. Antenatal hospitalization occurred in 46%, most often because of threatened preterm labour (19%). There were 33 live births and two stillbirths (6%). Preterm birth < 37 weeks occurred in 24%. Vaginal birth occurred in 33%. CONCLUSION: Pregnant women with spinal cord lesions generally have successful pregnancy outcomes. However, their pregnancies are at significant risk for preterm birth, infection, and Caesarean section. Coordinated multidisciplinary care is recommended for optimal management of these pregnancies. PMID- 23343796 TI - The role of appendectomy in gynaecologic surgery: a canadian retrospective case series. AB - OBJECTIVE: To review the indications for, and the associated pathology and complications of, appendectomy performed during gynaecologic surgery in a tertiary academic health sciences centre. METHODS: We performed a retrospective review of appendectomy cases performed from September 2007 to December 2011 in a tertiary level gynaecologic surgical practice. Cases were reviewed using a standardized intake sheet with surgical reports, history, and pathologic findings. RESULTS: A total of 71 appendectomies were performed during gynaecologic surgery in the study period. All cases were primary gynaecologic surgical cases; the most common diagnoses were endometriosis, pelvic pain, and pelvic mass. Overall, 42 (59%) of the study cases had abnormal histopathology in the appendix. Of the 44 women with a primary diagnosis of endometriosis, 28 (64%) had positive appendiceal pathology. In women with chronic pelvic pain, three of eight (38%) had pathology within their appendix. Of all appendixes removed that appeared normal on gross inspection, irrespective of diagnosis, 44% had positive pathology. CONCLUSION: When a structured approach is taken towards assessment of the appendix during gynaecologic surgical cases, with removal when indicated, a high rate of pathology may be found. In this series, there were no complications directly related to the appendectomy, providing support for the contention that appropriately trained gynaecologists can safely perform appendectomy. The findings in this Canadian series are in keeping with previous reports and support the need for evaluation and removal of the appendix when indicated at the time of gynaecological surgery. PMID- 23343797 TI - Optimal cytoreduction with neutral argon plasma energy in selected patients with ovarian and primitive peritoneal cancer. AB - INTRODUCTION: Epithelial ovarian cancer (EOC) is a deadly disease for which optimal cytoreduction to microscopic disease has shown the best correlation with survival. Electrically neutral argon plasma technology is a novel surgical tool to allow aggressive cytoreduction in selected patients with EOC, primary peritoneal cancer, and tubal cancer. METHODS: We conducted a prospective feasibility study of the use of neutral argon plasma technology to complete cytoreductive surgery in order to assess its ability to obtain optimal cytoreduction. RESULTS: Six patients had their surgery completed with the neutral argon plasma device. None of the patients would have had optimal surgery unless the device had been available. All patients had cytoreduction to less than 5 mm to 10 mm without additional morbidity. One patient had complete cytoreduction, and two had residual disease of less than 2 mm. CONCLUSION: Electrically neutral plasma argon technology is a useful technology to maximize cytoreduction and to reduce tumour burden in selected cases of EOC. PMID- 23343798 TI - Efficacy of botulinum toxin a intradetrusor injections for non-neurogenic urinary urge incontinence: a randomized double-blind controlled trial. AB - OBJECTIVE: To determine the efficacy of intradetrusor injections of botulinum toxin A for non-neurogenic urinary urge incontinence. METHODS: We conducted a six month, randomized, double-blind controlled trial involving women with urinary urge incontinence. Participants received intradetrusor injections of either botulinum toxin (100U in 10 mL) via cystoscopy or a placebo control (saline injection). The primary outcome was maximum bladder capacity at cystoscopy. Secondary outcomes included quality-of-life measures, 24-hour leakage rate, patients' subjective assessment, and safety data. RESULTS: There were 21 participants: 11 in the botulinum toxin (treated) group and 10 in the placebo (control) group. There were no significant differences between the groups at baseline. After six months the mean maximum bladder capacity at cystoscopy was 161.6 mL greater in the treated group than in the control group (P = 0.018). There were no differences in diary data or quality-of-life measures. The 24-hour pad test (a measure of leakage) after three months showed significant improvement in the treated group (difference 272.12g, P = 0.016); treated subjects also showed subjective benefit at three months (difference 1.29, P = 0.007) and at six months (difference 1.16, P = 0.01). There was no significant difference in rates of urinary tract infection between groups. There was one serious adverse event (a perioperative cardiac event) in the botulinum toxin group. CONCLUSION: Botulinum toxin increased bladder capacity at cystoscopy and reduced urinary incontinence on 24-hour pad testing in adult females with urinary urge incontinence. There was one adverse event in the group treated with botulinum toxin. PMID- 23343799 TI - Dose-dense paclitaxel with carboplatin for advanced ovarian cancer: a feasible treatment alternative. AB - OBJECTIVE: Epithelial ovarian cancer is the leading cause of death from gynaecologic cancers in the Western world. If possible, initial cytoreductive surgery is the treatment of choice, followed by adjuvant chemotherapy, usually with a platinum/taxane combination. Increased survival has been recently reported in women who were given adjuvant chemotherapy weekly rather than at three-week intervals, which has been the standard. At our centre, we have been treating patients with advanced ovarian cancer with a dose-dense protocol since March 2010. Treatment is given in an outpatient setting on days 1, 8, and 15 of a 21 day cycle for six cycles. Carboplatin for an AUC of 5 mg/mL/min and paclitaxel 80mg/m2 are given on day 1, followed by paclitaxel 80mg/m2 on days 8 and 15. Our objective was to determine whether this protocol is a feasible alternative treatment in our population and whether or not the toxicity profile is acceptable. METHODS: We performed a chart review of 46 patients undergoing treatment with dose-dense chemotherapy for advanced ovarian cancer. Demographic information, patient characteristics, adverse events, and treatment endpoints were recorded. RESULTS: Sixty-one percent of women completed the six-cycle protocol as planned with minimal interruption, which is comparable to the only previously reported trial using this regimen. The most common side effects of treatment were fatigue, neuropathy, and neutropenia. Supplementation with regular magnesium and granulocyte colony-stimulating factor reduced delays. CONCLUSION: Dose-dense paclitaxel with carboplatin chemotherapy for the treatment of advanced ovarian cancer shows promise in terms of progression-free and overall survival. We have shown this protocol to be practical and feasible in our population. PMID- 23343800 TI - Increase in transaminase levels following the use of raltegravir in a woman with a high HIV viral load at 35 weeks of pregnancy. AB - BACKGROUND: Despite the efficacy of raltegravir in reducing viral load in HIV infected patients, evidence for its safety in late pregnancy is lacking. A high rate of placental transfer was recently demonstrated. CASE: A treatment-naive 34 year-old HIV-1-positive woman of African origin began treatment with zidovudine/lamivudine, lopinavir/ritonavir, and raltegravir at 35 weeks of pregnancy. After 11 days of treatment with raltegravir, a substantial reduction in viral load was achieved. Concurrently, she had a 23-fold increase in serum alanine aminotransferase and a 10-fold increase in serum aspartate aminotransferase, both of which returned to normal when raltegravir treatment was discontinued. A healthy boy was delivered at term. The infant's tests for HIV were negative at five months, and he had no health problems at eight months. CONCLUSION: This is the first case report, to our knowledge, of increased maternal serum transaminase levels following the use of raltegravir in a woman at a late stage of pregnancy. PMID- 23343801 TI - Fundamentals of knowledge translation. PMID- 23343802 TI - Toxoplasmosis in pregnancy: prevention, screening, and treatment. AB - BACKGROUND: One of the major consequences of pregnant women becoming infected by Toxoplasma gondii is vertical transmission to the fetus. Although rare, congenital toxoplasmosis can cause severe neurological or ocular disease (leading to blindness), as well as cardiac and cerebral anomalies. Prenatal care must include education about prevention of toxoplasmosis. The low prevalence of the disease in the Canadian population and limitations in diagnosis and therapy limit the effectiveness of screening strategies. Therefore, routine screening is not currently recommended. OBJECTIVE: To review the prevention, diagnosis, and management of toxoplasmosis in pregnancy. OUTCOMES: OUTCOMES evaluated include the effect of screening on diagnosis of congenital toxoplasmosis and the efficacy of prophylaxis and treatment. EVIDENCE: The Cochrane Library and Medline were searched for articles published in English from 1990 to the present related to toxoplasmosis and pregnancy. Additional articles were identified through references of these articles. VALUES: The quality of evidence is rated and recommendations made according to guidelines developed by the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS: Guideline implementation should assist the practitioner in developing an approach to screening for and treatment of toxoplasmosis in pregnancy. Patients will benefit from appropriate management of this condition. SPONSOR: The Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS: 1. Routine universal screening should not be performed for pregnant women at low risk. Serologic screening should be offered only to pregnant women considered to be at risk for primary Toxoplasma gondii infection. (II-3E) 2. Suspected recent infection in a pregnant woman should be confirmed before intervention by having samples tested at a toxoplasmosis reference laboratory, using tests that are as accurate as possible and correctly interpreted. (II-2B) 3. If acute infection is suspected, repeat testing should be performed within 2 to 3 weeks, and consideration given to starting therapy with spiramycin immediately, without waiting for the repeat test results. (II-2B) 4. Amniocentesis should be offered to identify Toxoplasma gondii in the amniotic fluid by polymerase chain reaction (a) if maternal primary infection is diagnosed, (b) if serologic testing cannot confirm or exclude acute infection, or (c) in the presence of abnormal ultrasound findings (intracranial calcification, microcephaly, hydrocephalus, ascites, hepatosplenomegaly, or severe intrauterine growth restriction). (II-2B) 5. Amniocentesis should not be offered for the identification of Toxoplasma gondii infection at less than 18 weeks' gestation and should be offered no less than 4 weeks after suspected acute maternal infection to lower the occurrence of false-negative results. (II-2D) 6. Toxoplasma gondii infection should be suspected and screening should be offered to pregnant women with ultrasound findings consistent with possible TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes, and other) infection, including but not limited to intracranial calcification, microcephaly, hydrocephalus, ascites, hepatosplenomegaly, or severe intrauterine growth restriction. (II-2B) 7. Each case involving a pregnant woman suspected of having an acute Toxoplasma gondii infection acquired during gestation should be discussed with an expert in the management of toxoplasmosis. (III-B) 8. If maternal infection has been confirmed but the fetus is not yet known to be infected, spiramycin should be offered for fetal prophylaxis (to prevent spread of organisms across the placenta from mother to fetus). (I-B) 9. A combination of pyrimethamine, sulfadiazine, and folinic acid should be offered as treatment for women in whom fetal infection has been confirmed or is highly suspected (usually by a positive amniotic fluid polymerase chain reaction). (I-B) 10. Anti-toxoplasma treatment in immunocompetent pregnant women with previous infection with Toxoplasma gondii should not be necessary. (I-E) 11. Women who are immunosuppressed or HIV-positive should be offered screening because of the risk of reactivation and toxoplasmosis encephalitis. (I-A) 12. A non-pregnant woman who has been diagnosed with an acute Toxoplasma gondii infection should be counselled to wait 6 months before attempting to become pregnant. Each case should be considered separately in consultation with an expert. (III-B) 13. Information on prevention of Toxoplasma gondii infection in pregnancy should be made available to all women who are pregnant or planning a pregnancy. (III-C). PMID- 23343803 TI - Surgical safety checklist in obstetrics and gynaecology. AB - OBJECTIVE: To provide guidance on the implementation of a surgical safety checklist in the practice of obstetrics and gynaecology. OUTCOMES: OUTCOMES evaluated include the impact of the surgical safety checklist on surgical morbidity and mortality. EVIDENCE: Medline databases were searched for articles on subjects related to "surgical safety checklist" published in English from January 2001 to January 2011. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated in the guideline to January 2012. VALUES: The quality of evidence was rated with use of the criteria described by the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described by the Task Force (Table). BENEFITS, HARMS, AND COSTS: Implementation of the guideline recommendations will improve the health and well-being of women undergoing obstetrical or gynaecologic surgery. Summary Statements and Recommendations Summary Statements 1. Surgery may account for up to 40% of all hospital adverse events. (II-2) 2. Good communication is essential for safer surgical care, as communication failure is common in the operating room. (III) 3. The concept of a surgical safety checklist has been studied globally, and there have been decreases in complications and mortality when the checklist has been implemented. (II-1) 4. Emergency cases such as a "crash" Caesarean section will require a modified approach that is centre- and situation-dependent. (III) 5. The SOGC endorses the adoption of the surgical safety checklist in obstetrics and gynaecology. (III) Recommendations 1. The surgical safety checklist should be adopted by all surgical care providers and their respective institutions to improve patient safety. (II-1A) 2. Surgeons should be familiar with, advocate for the use of, and participate in all 3 parts of the surgical safety checklist. (II-1A) 3. The surgical safety checklist may be modified and adapted for use in surgical obstetrics cases. (II-2A). PMID- 23343804 TI - Clinical and ultrastructural effects of different liners/restorative materials on deep carious dentin: a randomized clinical trial. AB - We evaluated the effect of calcium hydroxide cement (CHC) and glass ionomer cement (GIC) on carious dentin and bacterial infections after partial caries removal and sealing. Sixty permanent teeth with deep lesions underwent partial caries removal, the application of CHC, GIC or wax, i.e. negative control (NC), and were then sealed for 3-4 months. After the partial caries removal and the sealing period, the dentin was clinically assessed (colour and consistency) and analysed by scanning electron microscopy to assess dentin organization and bacterial infections. The effect of the treatment in each group was assessed by the Wilcoxon and chi2 tests, differences among groups by the Kruskal-Wallis test and the correlations between variables by Spearman correlation. No clinical symptoms or radiographic signals of pulpits or pulp necrosis were observed during the study. Dentin darkening was observed after the sealing period in the CHC and NC groups (p < 0.05). However, there was no difference in the colour after treatment among the 3 groups (p > 0.05). Dentin hardening occurred in all groups after treatment (p < 0.05), also with no differences (p > 0.05). Dentin samples showed better organization after the sealing period than after partial caries removal, with total or partial obliteration of dentinal tubules (CHC p < 0.03, GIC p < 0.05, NC p < 0.01) and a reduction of bacterial infections (CHC p < 0.03, GIC p < 0.05, NC p < 0.03). No differences were observed. Correlations between the different criteria, except for colour and bacterial infection, were detected in all cases. Partial caries removal and sealing resulted in dentin hardening, decreased bacterial numbers and dentin reorganization, irrespective of the dentin protection used. PMID- 23343805 TI - Editor's note. PMID- 23343806 TI - Ventriculoperitoneal shunt infections in adult patients. PMID- 23343808 TI - Serotonin syndrome: recognition and treatment. PMID- 23343810 TI - Advanced practice nursing scope of practice for hospitals, acute care/critical care, and ambulatory care settings: a primer for clinicians, executives, and preceptors. PMID- 23343811 TI - Collaboration: a key component of excellence. PMID- 23343812 TI - Pediatric brain death: updated guidelines. AB - Logan, a 5-year-old boy, was riding his bike with his 7-year-old brother when he was struck from behind by a car traveling at approximately 40 mph. The driver indicated that she did not see the riders until she hit Logan, who was not wearing a helmet at the time of the accident. Logan was thrown from his bike and was found at the side of the road, unresponsive and posturing. Although he was uninjured, Logan's brother witnessed the incident.Emergency medical services arrived and placed Logan on a backboard with a c-collar. Because he was not protecting his airway, he was intubated and then given sodium chloride fluids and brought to the pediatric emergency department. Upon arrival, his Glasgow Coma Scale score was 5, and his right pupil was 6 mm and not reactive.Logan's initial head computed tomographic scan showed diffuse brain edema, with early downward transtentorial brain herniation. The pediatric neurosurgeon determined that no operative management was appropriate for Logan. Besides a small laceration on his forehead, Logan had no other injuries. At this time, he was taking a few spontaneous respirations and had occasional posturing of his extremities. PMID- 23343813 TI - Preventing ventilator-associated pneumonia through oral care, product selection, and application method: a literature review. AB - OBJECTIVE: Review the literature to identify the most effective method of oral hygiene to reduce the incidence of ventilator-associated pneumonia (VAP). BACKGROUND: Ventilator-associated pneumonia is the most common nosocomial infection in patients being treated with mechanical ventilation. METHOD: This study is a systematic literature review. The databases searched included Web of Science, Cumulative Index to Nursing and Allied Health Literature, Ovid, and MEDLINE. RESULTS: Implementation of oral care protocols and nurse education programs reduced VAP. Although chlorhexidine was the most popular oral care product, no consensus emerged on concentration or protocols for oral care. CONCLUSION: No consensus on best practice for oral hygiene in patients being treated with mechanical ventilation was found. Chlorhexidine was the most popular oral care product. Implementation of an oral care protocol, ongoing nurse education, and evaluation were important in reducing the incidence of VAP. Future research should analyze chlorhexidine concentration, application techniques, and frequency of oral care, to optimize VAP prevention. PMID- 23343814 TI - Early metabolic/cellular-level resuscitation following terminal brain stem herniation: implications for organ transplantation. AB - Patients with terminal brain stem herniation experience global physiological consequences and represent a challenging population in critical care practice as a result of multiple factors. The first factor is severe depression of consciousness, with resulting compromise in airway stability and lung ventilation. Second, with increasing severity of brain trauma, progressive brain edema, mass effect, herniation syndromes, and subsequent distortion/displacement of the brain stem follow. Third, with progression of intracranial pathophysiology to terminal brain stem herniation, multisystem consequences occur, including dysfunction of the hypothalamic-pituitary axis, depletion of stress hormones, and decreased thyroid hormone bioavailability as well as biphasic cardiovascular state. Cardiovascular dysfunction in phase 1 is a hyperdynamic and hypertensive state characterized by elevated systemic vascular resistance and cardiac contractility. Cardiovascular dysfunction in phase 2 is a hypotensive state characterized by decreased systemic vascular resistance and tissue perfusion. Rapid changes along the continuum of hyperperfusion versus hypoperfusion increase risk of end-organ damage, specifically pulmonary dysfunction from hemodynamic stress and high-flow states as well as ischemic changes consequent to low-flow states. A pronounced inflammatory state occurs, affecting pulmonary function and gas exchange and contributing to hemodynamic instability as a result of additional vasodilatation. Coagulopathy also occurs as a result of consumption of clotting factors as well as dilution of clotting factors and platelets consequent to aggressive crystalloid administration. Each consequence of terminal brain stem injury complicates clinical management within this patient demographic. In general, these multisystem consequences are managed with mechanism-based interventions within the context of caring for the donor's organs (liver, kidneys, heart, etc.) after death by neurological criteria. These processes begin far earlier in the continuum of injury, at the moment of terminal brain stem herniation. As such, aggressive, mechanism-based care, including hormonal replacement therapy, becomes clinically appropriate before formal brain death declaration to support cardiopulmonary stability following terminal brain stem herniation. PMID- 23343815 TI - Monitoring the quality of clinical inquiry projects. PMID- 23343816 TI - Principled moral outrage: an antidote to moral distress? PMID- 23343817 TI - Measurement and rate correction of the QT interval. PMID- 23343818 TI - The relationship between hamstring muscle extensibility and spinal postures varies with the degree of knee extension. AB - The aim was to determine the relationship between hamstring muscle extensibility and sagittal spinal curvatures and pelvic tilt in cyclists while adopting several postures. A total of 75 male cyclists were recruited for this study (34.79 +/- 9.46 years). Thoracic and lumbar spine and pelvic tilt were randomly measured using a Spinal Mouse. Hamstring muscle extensibility was determined in both legs by a passive knee extension test. Low relationships were found between hamstring muscle extensibility and spinal parameters (thoracic and lumbar curvature, and pelvic tilt) in standing, slumped sitting, and on the bicycle (r = .19; P > .05). Significant but low relationships were found in maximal trunk flexion with knees flexed (r = .29; P < .05). In addition, in the sit-and-reach test, low and statistically significant relationships were found between hamstring muscle extensibility for thoracic spine (r = -.23; P = .01) and (r = .37; P = .001) for pelvic tilt. In conclusion, hamstring muscle extensibility has a significant relationship in maximal trunk flexion postures with knees flexed and extended, but there are no relationships while standing or on the bicycle postures. PMID- 23343819 TI - GSTT1 null genotype is associated with an increased risk of prostate cancer in caucasians: a meta-analysis. AB - BACKGROUND: Many studies have investigated the association between glutathione S transferase T1 (GSTT1) null genotype and the risk of prostate cancer (PCa), but the impact of GSTT1 null genotype on PCa risk in Caucasians is still unclear owing to the inconsistency of such studies. The present study aimed to quantify the strength of association between GSTT1 null genotype and the risk of PCa in Caucasians. METHODS: We searched the PubMed, Embase and Web of Science databases for studies assessing the association between GSTT1 null genotype and the risk of PCa in Caucasians. We estimated the summary odds ratio (OR) with the corresponding 95% confidence interval (95% CI) to assess the association. RESULTS: 16 case-control studies with 11,648 subjects were included in this meta analysis. Meta-analysis of a total of 16 studies showed GSTT1 null genotype was significantly associated with an increased risk of PCa in Caucasians (random effects OR 1.30, 95% CI 1.10-1.53, p = 0.002). After adjustment for heterogeneity, GSTT1 null genotype was still associated with an increased risk of PCa in Caucasians (fixed-effects OR 1.33, 95% CI 1.17-1.52, p < 0.001). The cumulative meta-analyses of all 16 studies showed a trend of more obvious association as information accumulated by year. CONCLUSIONS: Meta-analysis of available data suggests the GSTT1 null genotype is significantly associated with an increased risk of PCa in Caucasians. PMID- 23343820 TI - Different frequencies of Tc17/Tc1 and Th17/Th1 cells in chronic spontaneous urticaria. AB - BACKGROUND: Chronic urticaria is associated with an immune dysregulation usually mediated by T lymphocytes. Recently, Th17 and Tc17 have been implicated in autoimmune diseases; however, their role in urticaria is not clear yet. METHODS: For the study we recruited 20 patients [10 of them had autoreactive chronic spontaneous urticaria (positive autologous intradermal serum test response, ASST+), and the other 10 were nonautoreactive chronic spontaneous urticaria patients (ASST-)] and 17 healthy age- and gender-matched controls (HG). The frequency and functional activity of Th17/Tc17 and Th1/Tc1 cells were evaluated by flow cytometry and type 2 cytokine mRNA by real-time PCR. RESULTS: Our results demonstrated a significant decrease in Th17 frequency in both chronic urticaria groups compared to HG; regarding the amount of IL-17, at the single cell level, it was reduced in ASST- compared to HG. Concerning the Th1 and Th17 cells producing IFN-gamma, IL-2, and TNF-alpha, a lower frequency was noted in chronic urticaria patients compared to HG. In contrast, a significantly increased frequency of Tc1 cells producing these cytokines was noted in ASST+ compared to HG and ASST-. Also, the frequency of Tc17 cells producing TNF-alpha was increased in ASST+ compared to HG; however, with respect to the amount of TNF-alpha, at the single cell level, we found a decrease in ASST+ compared to HG. Regarding type 2 cytokine mRNA, a higher expression was verified in ASST+ compared to HG. CONCLUSION: Our data suggest a probable involvement of cytotoxic T cells, mainly the Tc1 and Tc17 subsets, in chronic urticaria, particularly in the ASST+ group. PMID- 23343821 TI - Explaining variability in parasite aggregation levels among host samples. AB - Aggregated distributions among individual hosts are a defining feature of metazoan parasite populations. Heterogeneity among host individuals in exposure to parasites or in susceptibility to infection is thought to be the main factor generating aggregation, with properties of parasites themselves explaining some of the variability in aggregation levels observed among species. Here, using data from 410 samples of helminth parasites on fish hosts, I tested the contribution of (i) within-sample variation in host body size, taken as a proxy for variability in host susceptibility, and (ii) parasite taxon and developmental stage, to the aggregated distribution of parasites. Log-transformed variance in numbers of parasites per host was regressed against log mean number across all samples; the strong relationship (r2= 0.88) indicated that aggregation levels are tightly constrained by mean infection levels, and that only a small proportion of the observed variability in parasite aggregation levels remains to be accounted for by other factors. Using the residuals of this regression as measures of 'unexplained' aggregation, a mixed effects model revealed no significant effect of within-sample variation in host body size or of parasite taxon or stage (i.e. juvenile versus adult) on parasite aggregation level within a sample. However, much of the remaining variability in parasite aggregation levels among samples was accounted for by the number of individual hosts examined per sample, and species-specific and study-specific effects reflecting idiosyncrasies of particular systems. This suggests that with most differences in aggregation among samples already explained, there may be little point in seeking universal causes for the remaining variation. PMID- 23343823 TI - Re: Techniques, rationale, and outcomes of internal limiting membrane peeling. PMID- 23343822 TI - Optical coherence tomography-guided facedown positioning for macular hole surgery. AB - PURPOSE: To use spectral domain optical coherence tomography-guided duration of facedown positioning to study anatomical macular hole closure rates. METHODS: Retrospective review of patients with macular holes undergoing 23-gauge pars plana vitrectomy and intraocular gas tamponade. Spectral domain optical coherence tomography imaging was done on postoperative Day 1. Patients remained facedown for 2 more days if the macular hole was closed or 6 more days facedown if the macular hole was open or indeterminate. RESULTS: There were 8 Stage 2, 12 Stage 3, and 12 Stage 4 macular holes. On postoperative Day 1, 24 holes were closed by spectral domain optical coherence tomography and instructed to remain facedown for two more days. Twenty-three of 24 holes remained closed during the postoperative period. Eight holes were open or indeterminate on postoperative Day 1 and remained facedown for 6 more days. Six of 8 holes (75%) were closed at their last follow-up. The overall closure rate was 29/32 (90.6%). Average follow up was 334 days. CONCLUSION: Confirming early closure of macular holes with spectral domain optical coherence tomography imaging can serve as an important guide to significantly shorten the duration of prone positioning while maintaining high closure rates. PMID- 23343824 TI - Reply: To PMID 22105502. PMID- 23343825 TI - Acute promyelocytic leukemia-associated thrombosis. AB - Patients with acute promyelocytic leukemia (APL) are prone to both bleeding and thrombosis. The bleeding complications are well known. In contrast, APL associated thrombosis is relatively underappreciated. We aimed to explore the issue of APL-associated thrombosis events. In the past 20 years, 127 cases with APL were found in our hospital database. We collected their coagulation laboratory profiles, including leukemia burdens, white blood cell and platelet counts, prothrombin time, activated partial thromboplastin time, fibrinogen levels, and disseminated intravascular coagulation scores. Data were compared between patients with or without thrombosis. Clinical outcomes and potential risk factors were obtained for analysis. Ten cases with APL-associated thrombosis were found. The incidence of thrombosis was 7.9% in our cohort. Five patients had cerebral infarction, 5 had catheter-related thrombosis and 1 had acute myocardial infarction. No laboratory data were associated with clinical thrombosis. Three patients died during the induction phase but thrombosis was not the direct cause of death for any of them. We conclude that patients with APL are susceptible to thrombosis in addition to bleeding. Laboratory coagulation parameters did not predict thrombosis in our series. Ischemic stroke and catheter-related thrombosis were the most common events in our Taiwanese cohort. Such a thrombosis pattern is unique and worth further investigation. PMID- 23343826 TI - Structural and magnetic properties of Ba2LuMoO6: a valence bond glass. AB - We report here the synthesis of the site ordered double perovskite Ba(2)LuMoO(6). Rietveld refinement of room temperature powder x-ray diffraction measurements indicates that it crystallizes in the cubic space group Fm3m, with a = 8.3265(1) A. Powder neutron diffraction data indicate that, unusually, this cubic symmetry is maintained down to 2 K, with [Formula: see text], Mo(5+) ions situated on the frustrated face-centred cubic lattice. Despite dc-susceptibility measurements showing Curie-Weiss behaviour with strong antiferromagnetic interactions at T >= 200 K, there is no evidence of long range magnetic ordering at 2 K. At T <= 50 K, susceptibility measurements indicate a loss in moment to ~18% of the expected value, and there is a corresponding loss in the magnitude of the magnetic exchange. The structural and magnetic properties of this compound are compared with the related compound Ba(2)YMoO(6), which is a valence bond glass. PMID- 23343827 TI - Outcomes of nails versus plates for humeral shaft fractures: a Medicare cohort study. AB - OBJECTIVES: This study was performed to determine (1) the incidence of humeral shaft fractures within the Medicare noncancer population, (2) the trends in utilization of humeral shaft fixation techniques by plate-and-screw devices and intramedullary nails, (3) differences in procedure times, and (4) the outcomes of individuals as measured by rate of secondary operations and 1-year mortality. DESIGN/SETTING: Retrospective comparative cohort analysis. A cancer-free Medicare part B claims sample derived from a 5% sample from the years 1993 to 2007 was analyzed. PATIENTS/INTERVENTION: Our cohorts were generated by diagnostic and procedural codes for humeral shaft fractures. MAIN OUTCOME MEASUREMENT: The incidence of humeral shaft fracture and trend in operative fixation were evaluated for all years of data. Surgical times were assessed by anesthesia Current Procedural Terminology codes. Outcomes and complications were assessed by Current Procedural Terminology codes. The proportion of individuals experiencing complications and 1-year mortality were compared by proportion hazards. RESULTS: We identified 1385 claims for humeral shaft fractures over 15 years, with an adjusted rate of between 12.0 and 23.4 fractures per 100,000 beneficiaries. We identified 511 individuals who received surgical treatment for humeral shaft fractures, 451 of whom had complete 1-year follow-up data. Nail fixation was more prevalent than plate fixation most years and had shorter anesthesia time by 27.1 minutes (P < 0.0001). There were no significant differences in the complication rates between the 2 groups as measured by incidence of secondary operations and 1 year mortality. CONCLUSIONS: Intramedullary nails are used for the majority of operative humeral shaft fractures among Medicare beneficiaries. Nailing has a shorter mean operative time. The 2 surgical techniques had no significant differences in terms of risk of secondary procedures and 1-year mortality. LEVEL OF EVIDENCE: : Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 23343828 TI - Complex proximal humerus fractures treated with locked plating utilizing an extended deltoid split approach with a shoulder strap incision. AB - OBJECTIVES: The goal of the study is to analyze the outcome and complications after locked plating of proximal humerus fractures with the extended deltoid split approach though a shoulder strap incision. DESIGN: Prospective. SETTING: Tertiary care referral center. PATIENTS: Fifty-two adult patients with a displaced 3 or 4 part proximal humerus fracture or fracture dislocation. INTERVENTIONS: Open reduction and locked plate osteosynthesis through an extended deltoid split approach using a strap incision. OUTCOME MEASUREMENTS: Electrophysiological assessment of axillary nerve function at 6 weeks and at 3, 6, and 12 months postoperatively in those patients in whom an abnormality was detected postoperatively. Functional outcome measurement using normalized Constant scores at 6 and 12 months. Other measures include radiological assessment and complications. RESULTS: Traction injury to the anterior part of the axillary nerve was electrically evident but not clinically apparent in 4 patients. The normalized Constant score continued to show significant improvement 1 year post surgery, 67.3 +/- 11.3 at 6 months and 80.2 +/- 7.7 at 1 year (P = 0.001)). Union was obtained in all patients. Varus/valgus/tuberosity malreductions were seen in 8 patients. Loss of reduction was seen in 2 patients. Two patients had radiological evidence of avascular necrosis at 1-year follow-up. CONCLUSIONS: Locked plating of proximal humerus fractures through an extended deltoid split approach using a shoulder strap incision provides satisfactory outcomes. Axillary nerve injury is the only limitation of the approach and can be minimized with careful identification and protection of the nerve throughout the procedure. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 23343829 TI - Lidocaine analgesia for removal of wound vacuum-assisted closure dressings: a randomized double-blinded placebo-controlled trial. AB - OBJECTIVES: Wound vacuum-assisted closure (VAC) is a technique used frequently by orthopedic surgeons to facilitate wound closure. Bedside VAC removal can be a source of great pain for patients, which we hypothesize can be decreased by topical lidocaine application. DESIGN: This was a prospective randomized double blinded, placebo-controlled trial (registered on clinicaltrials.gov), utilizing the crossover intervention technique. SETTING: The study was carried out at a level 1 trauma center. PATIENTS/PARTICIPANTS: Nondiabetic, adult patients requiring at least 2 extremity wound VAC dressing changes were involved. INTERVENTION: In a double-blinded fashion, topical lidocaine (1%) was compared with topical normal saline (0.9% NaCl) after injection into the VAC sponge. The crossover intervention technique, wherein each patient received an independent VAC change with lidocaine and saline, served to control for all possible patient characteristics. Randomization determined which sample was given first or second. MAIN OUTCOME MEASUREMENTS: The patients were evaluated for visual analog pain scores, narcotic requirement, and wound characteristics. RESULTS: : A total of 11 patients were enrolled for a total of 21 VAC changes (mean wound size 133 cm); 1 patient withdrew after his first VAC dressing was changed with saline. Controlling for pre-VAC change pain, the lidocaine intervention was associated with 2.4 points less on the 0-10 visual analog scale for pain (P value <0.001, 3.0 to -1.7) and 1.7 mg less morphine-equivalents administered (P value <0.001, 2.3 to -1.1) during the VAC sponge removal. CONCLUSIONS: The patients undergoing an extremity wound VAC dressing removal at the bedside should be pretreated with topical lidocaine because it decreases pain and narcotic requirements. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 23343830 TI - Recent advances in the management of therapy-related myelodysplastic syndromes and acute myeloid leukemia. AB - PURPOSE OF REVIEW: Therapy-related myelodysplastic syndromes and acute myelogenous leukemia (t-MDS/AML) comprise an increasingly common, poor-risk disease cohort without standard treatment options. This review describes available treatments and recent advances that may influence the clinical management of t-MDS/AML. RECENT FINDINGS: Multiple retrospective studies have identified poor-risk cytogenetics, chemotherapy resistance, comorbidities from prior cancer and therapy, and persistence of the primary malignancy as factors that contribute to poor clinical outcomes of t-MDS/AML. Recent analyses show that t-MDS/AML can respond to standard therapy, but responses are less durable. In most cases, cure is made more likely with allogeneic stem cell transplantation. These findings suggest that improved survival may result from earlier, low intensity nontransplant therapy, and aggressive pursuit of reduced-intensity transplant approaches in eligible individuals coupled with posttransplant relapse prevention strategies. Molecular characterization of t-MDS/AML may aid future clinical management decisions and identify targets for therapy. SUMMARY: Data emerging from recent t-MDS/AML studies are shedding light on factors that contribute to disease biology and poor clinical outcomes. These findings can be used to develop strategies to improve the treatment and survival of patients with t-MDS/AML. PMID- 23343831 TI - Anticentromere (ACA)-positive Sjogren's syndrome: a disease entity? PMID- 23343833 TI - Red blood cells mediate the onset of thrombosis in the ferric chloride murine model. AB - Application of ferric chloride (FeCl(3)) to exposed blood vessels is widely used to initiate thrombosis in laboratory mice. Because the mechanisms by which FeCl(3) induces endothelial injury and subsequent thrombus formation are little understood, we used scanning electron and brightfield intravital microscopy to visualize endothelial damage and thrombus formation occurring in situ. Contrary to generally accepted belief, FeCl(3) does not result in appreciable subendothelial exposure within the time frame of thrombosis. Furthermore, the first cells to adhere to FeCl(3)-treated endothelial surfaces are red blood cells (RBCs) rather than platelets. Energy dispersive x-ray spectroscopy demonstrated that ferric ions predominantly localize to endothelial-associated RBCs and RBC derived structures rather than to the endothelium. With continuing time points, RBC-derived structures rapidly recruit platelets, resulting in large complexes that subsequently enlarge and coalesce, quickly covering the endothelial surface. Further studies demonstrated that neither von Willebrand factor nor platelet glycoprotein Ib-alpha receptor (GPIb-alpha) is required for RBCs to adhere to the endothelium, and that deficiency of GPIb-alpha greatly abrogated the recruitment of platelets to the endothelial-associated RBC material. These findings illuminate the mechanisms of FeCl(3)-mediated thrombosis and reveal a previously unrecognized ability of RBCs to participate in thrombosis by mediating platelet adhesion to the intact endothelial surface. PMID- 23343832 TI - CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. AB - CD30, originally identified as a cell-surface marker of Reed-Sternberg and Hodgkin cells of classical Hodgkin lymphoma, is also expressed by several types of non-Hodgkin lymphoma, including a subset of diffuse large B-cell lymphoma (DLBCL). However, the prognostic and biological importance of CD30 expression in DLBCL is unknown. Here we report that CD30 expression is a favorable prognostic factor in a cohort of 903 de novo DLBCL patients. CD30 was expressed in ~14% of DLBCL patients. Patients with CD30(+) DLBCL had superior 5-year overall survival (CD30(+), 79% vs CD30(-), 59%; P = .001) and progression-free survival (P = .003). The favorable outcome of CD30 expression was maintained in both the germinal center B-cell and activated B-cell subtypes. Gene expression profiling revealed the upregulation of genes encoding negative regulators of nuclear factor kappaB activation and lymphocyte survival, and downregulation of genes encoding B cell receptor signaling and proliferation, as well as prominent cytokine and stromal signatures in CD30(+) DLBCL patients, suggesting a distinct molecular basis for its favorable outcome. Given the superior prognostic value, unique gene expression signature, and significant value of CD30 as a therapeutic target for brentuximab vedotin in ongoing successful clinical trials, it seems appropriate to consider CD30(+) DLBCL as a distinct subgroup of DLBCL. PMID- 23343835 TI - A simple method of aortic valve reconstruction with fixed pericardium in children. AB - Aortic valve reconstruction with fixed pericardium may occasionally be very useful when treating children with aortic valve disease. This is because diseased aortic valves in children are sometimes too dysmorphic for simple repair without the addition of material, their annulus may be too small for a prosthesis, and the Ross operation may be precluded due to other congenital anomalies such as pulmonary valvar or coronary malformations. Such reconstruction is usually technically demanding and requires much precision. We describe a simple alternative method, which we have carried out in 3 patients, aged 1 week, 3 years and 12 years, respectively, with good early results. PMID- 23343834 TI - Integrin activation by P-Rex1 is required for selectin-mediated slow leukocyte rolling and intravascular crawling. AB - Integrin activation is essential for the function of leukocytes. Impaired integrin activation on leukocytes is the hallmark of the leukocyte adhesion deficiency syndrome in humans, characterized by impaired leukocyte recruitment and recurrent infections. In inflammation, leukocytes collect different signals during the contact with the microvasculature, which activate signaling pathways leading to integrin activation and leukocyte recruitment. We report the role of P Rex1, a Rac-specific guanine nucleotide exchanging factor, in integrin activation and leukocyte recruitment. We find that P-Rex1 is required for inducing selectin mediated lymphocyte function-associated antigen-1 (LFA-1) extension that corresponds to intermediate affinity and induces slow leukocyte rolling, whereas P-Rex1 is not involved in the induction of the high-affinity conformation of LFA 1 obligatory for leukocyte arrest. Furthermore, we demonstrate that P-Rex1 is involved in Mac-1-dependent intravascular crawling. In vivo, both LFA-1-dependent slow rolling and Mac-1-dependent crawling are defective in P-Rex1(-/-) leukocytes, whereas chemokine-induced arrest and postadhesion strengthening remain intact in P-Rex1-deficient leukocytes. Rac1 is involved in E-selectin mediated slow rolling and crawling. In vivo, in an ischemia-reperfusion-induced model of acute kidney injury, abolished selectin-mediated integrin activation contributed to decreased neutrophil recruitment and reduced kidney damage in P Rex1-deficient mice. We conclude that P-Rex1 serves distinct functions in LFA-1 and Mac-1 activation. PMID- 23343836 TI - Unexpected extensions of non-small-cell lung cancer diagnosed during surgery: revisiting exploratory thoracotomies and incomplete resections. AB - OBJECTIVES: Only patients with a complete resection of non-small-cell lung cancer (NSCLC) may expect long-term survival. Despite the recent progress in imaging and induction therapy, a thoracotomy may remain exploratory or with incomplete resection (R2). Our purpose was to revisit these situations. METHODS: A total of 5305 patients who underwent surgery for NSCLC between 1980 and 2009 were reviewed. We compared the epidemiology, pathology, causes and prognosis characteristics of exploratory thoracotomy (ET) and R2 resections. RESULTS: ET and R2 resections were observed in 223 (4%) and 197 (4%) patients, respectively. The frequency of ET decreased with time, while the frequency of R2 resection remained almost stable. The indications for ET and R2 resections were not significantly different. In comparison with ET, R2 resections were characterized by a significantly higher frequency of induction therapy (22 vs 17%, P < 10(-3)), adenocarcinomas (49 vs 15%, P < 10(-6)), T1-T2 (53 vs 29%, P < 10(-6)) and N0-N1 extension (67 vs 42%, P = 10(-6)). R2 resections were also characterized by a higher rate of postoperative complications (19.1 vs 9.9%, P = 0.014), with no significant difference in postoperative mortality (6.9 vs 4.9%, P = non significant). R2 resections resulted in a higher 5-year survival compared with ET (11.1 vs 1.2%, P = 10(-3)). There was no long-term survivor after ET, except during the last decade. CONCLUSIONS: ET and R2 remain unavoidable. In comparison with ET, R2 resection is associated with a higher rate of postoperative complications, but a higher long-term survival. PMID- 23343837 TI - Elder abuse: a systematic review of risk factors in community-dwelling elders. AB - OBJECTIVE: to undertake a systematic literature review of risk factors for abuse in community-dwelling elders, as a first step towards exploring the clinical utility of a risk factor framework. Search strategy and selection criteria: a search was undertaken using the MEDLINE, CINAHL, EMBASE and PsycINFO databases for articles published in English up to March 2011, to identify original studies with statistically significant risk factors for abuse in community-dwelling elders. Studies concerning self-neglect and persons aged under 55 were excluded. RESULTS: forty-nine studies met the inclusion criteria, with 13 risk factors being reproducible across a range of settings in high-quality studies. These concerned the elder person (cognitive impairment, behavioural problems, psychiatric illness or psychological problems, functional dependency, poor physical health or frailty, low income or wealth, trauma or past abuse and ethnicity), perpetrator (caregiver burden or stress, and psychiatric illness or psychological problems), relationship (family disharmony, poor or conflictual relationships) and environment (low social support and living with others except for financial abuse). CONCLUSIONS: current evidence supports the multifactorial aetiology of elder abuse involving risk factors within the elder person, perpetrator, relationship and environment. PMID- 23343838 TI - Adrenocortical carcinoma: clinicopathological features, prognostic factors and outcome. AB - OBJECTIVE: The purpose of this study was to investigate the clinicopathological characteristics and treatment outcomes of patients with adrenocortical carcinoma (AC). METHODS: Twenty-four patients (10 females and 14 males) diagnosed with AC between 1998 and 2009 were evaluated. Clinical features and outcomes were reviewed. RESULTS: Median age was 46.5 years. One (4%) patient was classified as stage I, 10 (42%) were classified as stage II, 8 (33%) were classified as stage III and 5 (21%) were classified as stage IV. Tumor sizes ranged from 3 to 22 cm with a mean diameter of 11 cm. Five patients were locally inoperable at initial diagnosis. In addition to surgery, 2 of 19 patients were treated with an adjuvant cisplatin plus etoposide regimen. Sixteen patients were treated with chemotherapy after recurrence. Median survival time was 18 months. The 1- and 5-year overall survival estimates were 73 and 48%, respectively. Mean survival times for male and female patients were 58 and 12 months, respectively (p = 0.046). Early T stage (p = 0.04), lymph node negativity (p < 0.001), the absence of distant metastases (p < 0.001) and early stage (p < 0.001) were correlated with overall survival. CONCLUSION: AC is a rare disease with a poor prognosis. There are correlations between gender, stage and survival. PMID- 23343839 TI - The relationship between facilitators' questions and the level of reflection in postsimulation debriefing. AB - INTRODUCTION: Simulation-based education is a learner-active method that may enhance teamwork skills such as leadership and communication. The importance of postsimulation debriefing to promote reflection is well accepted, but many questions concerning whether and how faculty promote reflection remain largely unanswered in the research literature. The aim of this study was therefore to explore the depth of reflection expressed in questions by facilitators and responses from nursing students during postsimulation debriefings. METHODS: Eighty-one nursing students and 4 facilitators participated. The data were collected in February and March 2008, the analysis being conducted on 24 video recorded debriefings from simulated resuscitation teamwork involving nursing students only. Using Gibbs' reflective cycle, we graded the facilitators' questions and nursing students' responses into stages of reflection and then correlated these. RESULTS: Facilitators asked most evaluative and fewest emotional questions, whereas nursing students answered most evaluative and analytic responses and fewest emotional responses. The greatest difference between facilitators and nursing students was in the analytic stage. Only 23 (20%) of 117 questions asked by the facilitators were analytic, whereas 45 (35%) of 130 students' responses were rated as analytic. Nevertheless, the facilitators' descriptive questions also elicited student responses in other stages such as evaluative and analytic responses. CONCLUSION: We found that postsimulation debriefings provide students with the opportunity to reflect on their simulation experience. Still, if the debriefing is going to pave the way for student reflection, it is necessary to work further on structuring the debriefing to facilitate deeper reflection. Furthermore, it is important that facilitators consider what kind of questions they ask to promote reflection. We think future research on debriefing should focus on developing an analytical framework for grading reflective questions. Such research will inform and support facilitators in devising strategies for the promotion of learning through reflection in postsimulation debriefings. PMID- 23343840 TI - The effect of an olfactory and visual cue on realism and engagement in a health care simulation experience. AB - INTRODUCTION: Fidelity has been identified as an important element in a subject's perception of realism and engagement in learning during a simulation experience. The purpose of this study was to determine whether an isolated visual and olfactory sensory change to the simulation environment affects the subjects' perceptions of realism during simulation cases. METHODS: Using an electrosurgical unit applied to bovine muscle tissue, we created a model to simulate the characteristic operating room smoke and burning odor that occur during many procedures. Anesthesiologist subjects were randomly assigned to an intervention group that participated in a simulation involving the characteristic smoke and odor or a control group whose simulation involved no smoke or odor. Subjects completed a 7-question survey on the fidelity of the simulation, their perception of realism, and their learning engagement. RESULTS: We enrolled 103 subjects over 22 simulation courses in our study (intervention, n = 52; control, n = 51). The subjects' reactions to the physical (P = 0.73), conceptual (P = 0.34), and emotional (P = 0.12) fidelity and their perception of realism (P = 0.71) did not differ between the intervention and control groups. DISCUSSION: In a high fidelity simulation environment, a visual and olfactory increment to physical fidelity did not affect subjects' overall ratings of fidelity, perceptions of realism, and engagement in the learning experience. PMID- 23343841 TI - A systematic review of simulation for multidisciplinary team training in operating rooms. AB - SUMMARY STATEMENT: Current simulation training initiatives predominantly occur in uniprofessional silos and do little to integrate different disciplines working in the operating room (OR). The objective of this review was to determine the current status of work describing simulation for full OR multidisciplinary teams including barriers to conducting OR multidisciplinary team training and factors contributing to successful courses. We found a total of 18 articles from 10 research groups. Various scenarios and simulators were used, and training sessions were generally perceived as realistic and beneficial by participants despite rudimentary integration of surgical and anesthetic models. Measures of performance involved a variety of both technical and nontechnical ratings of the simulations. Challenges to conducting the simulations included recruitment, model realism, and financial costs. Future work should focus on how best to overcome the barriers to implementation of team training interventions for full OR teams, particularly on how to engage senior staff to aid recruitment. PMID- 23343842 TI - Case and commentary: using simulation to address hierarchy issues during medical crises. AB - SUMMARY STATEMENT: Medicine is hierarchical, and both positive and negative effects of this can be exposed and magnified during a crisis. Ideally, hierarchies function in an orderly manner, but when an inappropriate directive is given, the results can be disastrous unless team members are empowered to challenge the order. This article describes a case that uses misdirection and the possibility of simulated "death" to facilitate learning among experienced clinicians about the potentially deadly effects of an unchallenged, inappropriate order. The design of this case, however, raises additional questions regarding both ethics and psychological safety. The ethical concerns that surround the use of misdirection in simulation and the psychological ramifications of incorporating patient death in this context are explored in the commentary. We conclude with a discussion of debriefing strategies that can be used to promote psychological safety during potentially emotionally charged simulations and possible directions for future research. PMID- 23343843 TI - Acidulated phosphate fluoride application changes the protein composition of human acquired enamel pellicle. AB - We evaluated, by proteomic analysis, whether the chemical changes provoked on enamel by acidulated phosphate fluoride (APF) application alter the protein composition of acquired enamel pellicle. Enamel slabs, pretreated with distilled water (negative control), phosphoric acid (active control) or APF solution, were immersed in human saliva for pellicle formation. The adsorbed proteins were extracted and analyzed by liquid chromatography-mass spectrometry/mass spectrometry. Fifty-six proteins were identified, 12 exclusive to APF and 11 to phosphoric acid. APF decreased the concentration of histatin-1, but increased the concentration of S100-A9, which is confirmed by immunoblotting. The findings suggest that APF application changes the acquired enamel pellicle composition. PMID- 23343855 TI - Mortality and renal outcome of primary glomerulonephritis in Korea: observation in 1,943 biopsied cases. AB - BACKGROUND: Previous epidemiological studies have focused on the prevalence of primary glomerulonephritis (GN), but few have explored long-term patient outcomes. This study was conducted to investigate the long-term patient and renal outcomes of primary GN. METHODS: A total of 1,943 biopsy-proven primary GN patients were included. The outcomes were mortality and end-stage renal disease (ESRD) progression. The relative mortality rate was expressed by the standardized mortality ratio (SMR) and the 95% confidence interval (CI). RESULTS: During the median follow-up of 90 months, 325 (16.7%) patients progressed to ESRD and 164 (8.4%) patients died. Patients with minimal change disease exhibited the best renal and patient outcomes, whereas those with membranoproliferative GN had the worst. IgA nephropathy patients appeared to have a good survival rate in spite of their considerable progression to ESRD, and focal segmental glomerulosclerosis patients showed poor renal and patient outcomes. Mortality was 67% higher in primary GN patients than in the age- and sex-matched general population (SMR, 1.67; 95% CI, 1.42-1.95). The difference was more prominent in women (SMR, 2.95; 95% CI, 2.27-3.77) than in men (SMR, 1.31; 95% CI, 1.07-1.60). Renal risk factors, e.g. hypertension, proteinuria and initial renal dysfunction, were all associated with higher mortality, and the relative mortality rate increased with the number of risk factors. CONCLUSIONS: In patients with primary GN, mortality is significantly higher than in the age-/sex-matched general population, especially in women. Moreover, the presence of renal risk factors is positively associated with both relative mortality and progression to ESRD. PMID- 23343857 TI - Shift work and cancer research: can chronotype predict susceptibility in night shift and rotating-shift workers? PMID- 23343856 TI - Nightshift work and risk of ovarian cancer. AB - OBJECTIVES: Animal evidence suggests that circadian disruption may be associated with ovarian cancer, though very little epidemiological work has been done to assess this potential association. We evaluated the association between self reported nightshift work, a known circadian disruptor, and ovarian cancer in a population-based case-control study. METHODS: The study included 1101 women with invasive epithelial ovarian cancer, 389 women with borderline epithelial ovarian tumours and 1832 controls and was conducted in western Washington state. Shift work data were collected as part of inperson interviews. RESULTS: Working the nightshift was associated with an increased risk of invasive (OR=1.24, 95% CI 1.04 to 1.49) and borderline (OR=1.48, 95% CI 1.15 to 1.90) tumours; however, we observed little evidence that risks increased with increasing cumulative duration of nightshift work, and risks were not elevated in the highest duration category (>7 nightshift work-years). Increased risks were restricted to women who were 50 years of age and older and to serous and mucinous histologies of invasive and borderline tumours. There was suggestive evidence of a decreased risk of ovarian cancer among women reporting a preference for activity during evenings rather than mornings. CONCLUSIONS: We found evidence suggesting an association between shift work and ovarian cancer. This observation should be followed up in future studies incorporating detailed assessments of diurnal preference (ie, chronotype) in addition to detailed data on shift schedules. PMID- 23343858 TI - Environmental risk factors for cancers of the brain and nervous system: the use of ecological data to generate hypotheses. AB - BACKGROUND: There is a public health need to balance timely generation of hypotheses with cautious causal inference. For rare cancers this is particularly challenging because standard epidemiological study designs may not be able to elucidate causal factors in an early period of newly emerging risks. Alternative methodologies need to be considered for generating and shaping hypotheses prior to definitive investigation. OBJECTIVES: To evaluate whether open-access databases can be used to explore links between potential risk factors and cancers at an ecological level, using the case study of brain and nervous system cancers as an example. METHODS: National age-adjusted cancer incidence rates were obtained from the GLOBOCAN 2008 resource and combined with data from the United Nations Development Report and the World Bank list of development indicators. Data were analysed using multivariate regression models. RESULTS: Cancer rates, potential confounders and environmental risk factors were available for 165 of 208 countries. 2008 national incidences of brain and nervous system cancers were associated with continent, gross national income in 2008 and Human Development Index Score. The only exogenous risk factor consistently associated with higher incidence was the penetration rate of mobile/cellular telecommunications subscriptions, although other factors were highlighted. According to these ecological results the latency period is at least 11-12 years, but probably more than 20 years. Missing data on cancer incidence and for other potential risk factors prohibit more detailed investigation of exposure-response associations and/or explore other hypotheses. CONCLUSIONS: Readily available ecological data may be underused, particularly for the study of risk factors for rare diseases and those with long latencies. The results of ecological analyses in general should not be overinterpreted in causal inference, but equally they should not be ignored where alternative signals of aetiology are lacking. PMID- 23343860 TI - Shift-related sleep problems vary according to work schedule. AB - OBJECTIVES: Shift-related sleep and sleepiness problems may be due to characteristics of both shifts (ie, day, evening and night shifts) and work schedules (ie, permanent vs rotational schedules). The Bergen Shift Work Sleep Questionnaire (BSWSQ) was used to investigate associations between shift-related sleep problems and work schedules. METHODS: 1586 nurses completed the BSWSQ. Participants who, in relation to a shift, 'often' or 'always' experienced both a sleep problem and a tiredness/sleepiness problem were defined as having shift related insomnia (separate for day, evening and night shifts and rest-days). Logistic regression analyses were conducted for day, evening, night, and rest-day insomnia with participants on both permanent and rotational schedules. RESULTS: Shift-related insomnia differed between the work schedules. The evening shift insomnia was more prevalent in the two-shift rotation schedule than the three shift rotation schedule (29.8% and 19.8%, respectively). Night shift insomnia showed higher frequencies among three-shift rotation workers compared with permanent night workers (67.7% and 41.7%, respectively). Rest-day insomnia was more prevalent among permanent night workers compared with two- and three-shift rotations (11.4% compared with 4.2% and 3.6%, respectively). CONCLUSIONS: The prevalences of shift-related insomnia differed between the work schedules with higher frequencies for three-shift rotations and night shifts. However, sleep problems were present in all shifts and schedules. This suggests that both shifts and work schedules should be considered in the study of shift work-related sleep problems. PMID- 23343861 TI - The world at work: hotel cleaners. PMID- 23343862 TI - Time trends in the incidence of work-related mental ill-health and musculoskeletal disorders in the UK. AB - OBJECTIVES: To determine UK trends (from 1996 to 2009) in incidence of work related mental ill-health and musculoskeletal disorders, for all industry as well as for health and social care employees. Second, to investigate whether there may have been a recent shift from a physical to psychological perspective in how patients present their illness by comparing reporting trends for back pain and 'other work stress'. METHODS: Multilevel models were used to investigate changes in incidence of work-related illness, as diagnosed by specialist physicians. The dependent variable comprised case reports to The Health and Occupation Research network. Comparisons were made between medical specialties, industry (health and social care vs all other employees), gender and diagnosis. RESULTS: Trends for Occupational Physicians' (OP) reporting mental ill-health (average annual increase +3.7% (95% CI +2.2% to +5.2%)) differed significantly (p<0.001) from psychiatrists' reporting over the same time period (-5.9% (95% CI -7.6% to 4.2%)). For OPs' reporting, the rate of increase was greater for females and for health and social care employees. A fall in incidence of musculoskeletal disorders for OPs of -5.8% (95% CI -7.3% to -4.3%) and rheumatologists' reporting -6.6% (95% CI -8.3% to -4.8%) was found, with little variation by gender or industry. Within health and social care, an increase in incidence of 'other work stress' was accompanied by a similar decrease in 'spine/back pain'. CONCLUSIONS: The evidence presented is consistent with a shift in the presentation of ill health from a physical to psychological perspective, although changes in hazards, prevention measures and physician awareness should also be considered as explanations. PMID- 23343859 TI - Work activities and risk of prematurity, low birth weight and pre-eclampsia: an updated review with meta-analysis. AB - OBJECTIVES: We assessed the evidence relating preterm delivery (PTD), low birth weight, small for gestational age (SGA), pre-eclampsia and gestational hypertension to five occupational exposures (working hours, shift work, lifting, standing and physical workload). We conducted a systematic search in Medline and Embase (1966 to 2011), updating a previous search with a further 6 years of observations. METHODS: As before, combinations of keywords and medical subject headings were used. Each relevant paper was assessed for completeness of reporting and potential for important bias or confounding, and its effect estimates abstracted. Where similar definitions of exposure and outcome existed we calculated pooled estimates of relative risk (RR) in meta-analysis. RESULTS: Analysis was based on 86 reports (32 cohort investigations, 57 with usable data on PTD, 54 on birth weight and 11 on pre-eclampsia/gestational hypertension); 33 reports were new to this review. For PTD, findings across a substantial evidence base were generally consistent, effectively ruling out large effects (eg, RR>1.2). Larger and higher quality studies were less positive, while meta estimates of risk were smaller than in previous analyses and best estimates pointed to modest or null effects (RR 1.04 to 1.18). For SGA, the position was similar but meta-estimates were even closer to the null (eight of nine RRs <= 1.07). For pre-eclampsia/gestational hypertension the evidence base remains insufficient. CONCLUSIONS: The balance of evidence is against large effects for the associations investigated. As the evidence base has grown, estimates of risk in relation to these outcomes have become smaller. PMID- 23343864 TI - Exposure of sweepers to volatile organic compounds using urinary biological exposure index. AB - BACKGROUND: Evaluation of exposition to Volatile Organic Compounds (VOC) and compare urinary level of urinary biological exposure index in sweepers in West of Iran. METHODS: This study was carried out on 40 street sweepers and 40 non exposed as control group living in Hamadan City, west of Iran. VOC was analyzed using gas chromatography equipped with a Flame Ionization Detector (FID). The urinary biological exposure index (BEI) was analyzed with High performance Liquid Chromatography (HPLC) equipped with an ultraviolet (UV) detector. The concentration of benzene , toluene, m & p-xylene o-xylene and ethyl benzene was 39.01, 121.60, 27.12, 12.30, and 10.21 (mg/m3), respectively. RESULTS: No difference in the levels of hippuric acid in urine was found in sweepers compared with the control group. Significance differences in the level of o-cresol in urine were found in sweepers compared to control group (P< 0.005). The poor correlation coefficient was seen between xylenes concentration and urinary MHA for drivers. CONCLUSION: High VOC are emitted inside of cities at Iran. O-cresol could separate the exposed to toluene from the non-exposed in sweepers. Hippuric acid, methyl hippuric acid and muconic acid arenot suitable biomarkers for occupations such as sweepers exposure to VOC in low concentration. PMID- 23343863 TI - Mild improvement in symptoms and pulmonary function in a long-term follow-up of patients with toluene diisocyanate-induced asthma. AB - BACKGROUND: Long-term follow-up of diisocyanate-induced occupational asthma has been occasionally reported. METHODS: We studied the outcome of toluene diisocyanate (TDI)-induced asthma in 46 patients at diagnosis and after a follow up of 11 +/- 3.6 years. Symptoms, anti-asthma therapy, forced expiratory volume in 1 s (FEV1) and bronchial hyperresponsiveness to methacholine were assessed. RESULTS: A significant improvement in FEV1 (% predicted) and PD20FEV1 methacholine was observed at follow-up in comparison with diagnosis. Anti-asthma treatment was performed by 42% of patients at diagnosis and by 70% at follow-up. At the time of follow-up, 32 subjects had been removed from exposure for 6.0 +/- 6.9 years, whereas 14 subjects continued to work with reduced exposure to TDI. There was a significant reduction in the prevalence of attacks of shortness of breath and dyspnoea at follow-up, but only in unexposed patients. PD20FEV1 was significantly improved only in patients with a lower FEV1 at diagnosis and in those who have ceased work. Logistic regression analysis, using different models with some independent variables, showed that there were no significant determinants of improvement in FEV1 at follow-up, while a shorter duration of symptoms before diagnosis was a significant predictor of improvement in PD20FEV1 at follow-up. CONCLUSIONS: Asthma-like symptoms, bronchial hyperresponsiveness and airway obstruction improved, but did not normalize, after a long-term follow up with cessation or reduction in TDI exposure, mainly in subjects with an early diagnosis of occupational asthma and in patients with a lower baseline FEV1 no longer exposed to TDI. PMID- 23343865 TI - Behavioral Intention to Avoid Drug Abuse Works as Protective Factor among Adolescent. AB - BACKGROUND: Young people engage in risky behaviors unintentionally and these behaviors might be reduced or inhibited by preventative behaviors. Although adolescents' risky behaviors are known as unplanned or unintentional, preventative behaviors are intentional. The aim of the present study was to assess students' behavior intentions to avoid drug abuse. METHODS: This study was a cross sectional design that male high school students (n= 176) in Tehran, Iran completed a questionnaire assessing behavior intentions to avoid drug abuse, self control, selfefficacy, perceived susceptibility, and negative attitudes toward drug abuse, peer resistance skills and substance abuse related behaviors. RESULTS: Peer resistance skills, negative attitude toward drugs, perceived self- efficacy, and high selfcontrol were four predictors on intention against drug abuse. Moreover, students' educational status, interested in school and truancy and spending with friends were other predictors for intention against drug abuse. CONCLUSION: Healthy behaviors are intentional. As a result improving behavior intentions to avoid drug abuse would act as a protective factor for preventing drug abuse among adolescents as well as preventing high-risk behaviors. PMID- 23343867 TI - Tobacco smoking and oral cancer: a meta-analysis. AB - BACKGROUND: Several epidemiological studies suggest that tobacco smoking increases the risk of oral cancer. No systematic review, however, has been reported to examine how consistent the evidence is across the studies. We undertook a meta-analysis of epidemiological studies investigating the magnitude relationship between tobacco smoking and oral cancer. METHODS: Primary studies were identified through a computerized literature search of Medline. Articles abstracted were all epidemiological studies published as original articles in English during 1990-2007 provided the summary estimates of odds ratios (OR) of tobacco smoking for oral cancer compared to that of non-smokers. A total of 15 case-control studies were used for this meta-analysis. Summary of OR was calculated based on random effects model. RESULTS: The combined odds ratio for tobacco smoking related to oral cancer was 4.65 (95%CI, 3.19-6.77). Also, the highest combined odds ratio was belong to America continents (OR= 7.65; 95%CI, 5.11-11.45) and the lowest was in Asia (OR= 1.88; 95%CI, 0.95-3.71). There was heterogeneity in the pooled OR estimate across the studies. CONCLUSION: Our results clearly indicate that tobacco smokers are at increased risk of oral cancer. The cancer risk can be reduced by controlling of tobacco smoking in different countries. PMID- 23343866 TI - Road traffic noise model. AB - BACKGROUND: The recognition of road traffic noise as one of the main sources of environmental pollution has led to develop models that enable to predict noise level from fundamental variables. Traffic noise prediction models are required as aids for designing roads and highways. In addition, sometimes are used in the assessment of existing or envisaged changes in traffic noise conditions. In this paper a statistical modelling approach has been used for predicting road traffic noise in Iranian road conditions. METHODS: The study was performed during 2005 2006 in Hamadan city, in the west of Iran. The data set consisted of 282 noise measurements. The entire data set was utilized to develop a new model for Iranian condition using regression analysis. RESULTS: The developed model has twelve explanatory variables in order to achieve a proper fit for measured values of Leq (r2= 0.913). CONCLUSION: The proposed road traffic noise model can be effectively used as a decision support tools for prediction of traffic noise index of Leq(30min), in Iran's cities. PMID- 23343868 TI - Pattern of complementary and alternative medicine use in urban population. AB - BACKGROUND: To determine the prevalence and patterns of Complementary and Alternative Medicine (CAM) use in urban population in Isfahan. METHODS: In a crossa?"sectional study through two-stage sampling methods, 870 individuals were selected from Isfahan Province, center of Iran. We selected 20 clusters randomly and chose one household from each cluster by chance then 24 households were included consequently. Subsequently a resident of each household aged 18 years or older was selected randomly. We assessed the rate of use, types of alternative medicine, and conditional disease during recent two years. RESULTS: The overall use of at least one method of complementary and alternative medicine was 62.5%. The most common problems were as follows: digestive problem, obesity and hyperlipidemia, as well as anxiety and depression. Herbal medicine and bless therapy were the most common methods that people chose. CONCLUSION: Regarding to high prevalence of complementary and alternative medicine use, more attention to complementary and alternative medicine is mandate for physicians and health system managers. Health authorities' supervision and training of traditional practitioner is important not only for its economic impact and postponement of seeking treatment, but also for its untoward side-effects either alone or in combination with orthodox medicines. PMID- 23343869 TI - Integrated health, safety, environment and ergonomic management systems for industry. AB - BACKGROUND: Conventional health, safety and environment (HSE) are a widely used approach to enhance availability and efficiency of complex systems. The integrated HSEE system is defined however as integration of conventional HSE with ergonomics approach. The presented HSEE system introduces a unique, effective and systemic mechanism, which integrates the structure of the human and organizational systems with conventional HSE system. It is utilized to enhance reliability, availability, maintainability and safety through the proposed integrated framework of this study. METHODS: The integrated HSEE is developed by integration of conventional HSE with job systems by re-engineering organizational structures and teamwork through electronic data interchange (EDI). To show the need for and superiority of HSEE over conventional HSE to gas Treatment Company was studied and questionnaires were collected and examined with respect to distinct components of HSEE. RESULTS: The main result of this study is a framework for development of integrated intelligent human engineering environment in complex critical systems. CONCLUSION: The presented HSEE system introduces a unique, effective and systemic mechanism, which integrates the structure of the human and organizational systems with conventional HSE system. PMID- 23343870 TI - L-carnitine level in seminal plasma of fertile and infertile men. AB - BACKGROUND: To determine any correlation between infertility and semen quality with concentrations of L-carnitine in human seminal plasma. METHODS: This case control study performed in Fatemieh Hospital in Hamadan, Iran. Seminal plasma of 72 infertile men and 80 men with proved fertility as a control group was investigated and L-carnitine level was determined using UV enzymatic test at 340 nm. RESULTS: The concentration of L-carnitine was significantly lower in the infertile group compared with control group (80.59+/-56.43 mg/l versus 108.43+/ 42.26 mg/l; P= 0.0009). There was also a statistically significant positive correlation between seminal plasma L-carnitine concentration, total sperm count, and the percentage of motile sperm (P= 0.0009, and P= 0.0000, respectively). CONCLUSION: These finding suggest that the determination of seminal plasma L carnitine level may be a useful test in evaluation of male infertility. PMID- 23343871 TI - Frequency of typhoidal and non-typhoidal salmonella species and detection of their drugs resistance patterns. AB - BACKGROUND: To determine the prevalence of typhoidal and non-typhoidal Salmonella species in Hamadan City, west of Iarn and detection of antibiotic susceptibility patterns of isolates. METHODS: In a cross-sectional descriptive study, 296 Salmonella species including 192 strains of typhoidal Salmonella and 104 strains of non- typhoidal Salmonella were examined for serotyping and determining of antibiotic susceptibility. The strains were collected from patients referred to cilinical centers in Hamadan during 2001 to 2004. They were serotyped and then tested for their antibiotic susceptibility patterns, using Stokes disc diffusion method for 8 antibiotics. RESULTS: Among 296 samples, 64.8% were typhoidal and 35.2% were non-typhoidal Salmonella species. Typhoidal Salmonella species were as follows: S. typhi 45.6%, S. paratyphi B 8.1%, S. paratyphi C 7.1% and S. paratyphi a 4.7%. Non-typhoidal Salmonella species were as follows: S.typhimurium 21.2%, S.enteritidis 4.4%, S. species 2.1%, S. cholerasuis 1.7%, S. arizona 1.3%, S. agona 1.1%, S. thompson 0.7%, S.muenchen, S.lexington and S. hirschfeldii 0.35%. A proportion of strains ( > 60%) were resistance to cefotaxime and ampicillin. Resistance to ciprofloxacin and amikacin was very low ( < 15%). S.typhimurim (100%), S. typhi (95.7%) S. paratyphi B (89.2%) and S. enteitidis (60%) showed multi-drug resistance. CONCLUSION: S. typhi and S. typhimurium were the most predominant serotypes in this area. Most of the Salmonella species isolated from patients were resistant to beta-lactam antibiotics and co trimoxazole, whereas, most of them were sensitive to ciprofloxacin, gentamicin and amikacin. As the prevalence of multidrug-resistant serovar Typhi increases, newer, more expensive, and less readily available antimicrobial agents will be required for the treatment of typhoid. PMID- 23343872 TI - [Don't see, don't hear, and don't speak: the silence as an obstacle to the caring process. Phenomenological investigation among health staff working in an emergency department]. AB - Many health professionals show their concerns about the "professional misconduct"committed by their colleagues. Such concerns are sometimes referred to colleagues or superiors, but they are rarely communicated directly to the persons concerned. Starting from these assumptions we wanted to investigate whether in the setting of italian intensive care unit, you have the same perception. A phenomenological study was performed, aiming at collecting the experiences of health care professionals about the professional mistake question. As a means of detection we used a semi-structured, audio-recorded and transcribed in full interview. The analysis was done using the Giorgi method. Six units of meaning have been identified, expression of the most important and recurring experiences. They are: the climate / alliance and sense of belonging, the meaning of mistake: tolerable and not tolerable, the incident, the emotions / feelings; the mistakes / reasons; communication. The research highlights that the "culture of silence" is not widespread so when a mistake occurs the professional is usually faced by a colleague However, there are two exceptions:when the mistake is not serious, or when the professional to be faced is higher in the hierarchy. Those who committed a mistake, usually don't admit it because they don't want to damage their "image" or because they are afraid of the consequences. PMID- 23343873 TI - [Socio-cultural dynamics in health care: communication as a step in the curing process]. AB - A "pilot" training course entitled "Communication as a step in cure " was organized by the University Hospital of Bari and other organs with the aim of improving and increasing knowledge of the techniques , instruments and information involved in good communication and was articulated in several meetings. At the end of the course, participants were asked to assess the results obtained: some critical points were identified and suggestions were made to improve the level of communication between health professional and patients. PMID- 23343874 TI - [Methodology for determining the index of caring complexity (ICC):prospective observational study in a stroke unit]. AB - The method for determining the value of the index of caring complexity (ICC) is a multi-dimensional capable of resolving the problem of assessing the complexity of care. The fields of application of ICC methodology are multidisciplinary. The ICC method was applied in hospitals and territorial services and could also be useful for free professionals. Methodology is part and parcel of the caring process and does not therefore require specific data collection for classifying patients but the "scores " derive directly from the data flow obtained during the caring process. PMID- 23343875 TI - [Safety culture of nursing staff. A descriptive study in a Piedmont Hospital]. AB - Assessing safety culture is the first step towards a responsible and wary system to the errors and to the quality of the performance. The aim of the study was to assess nurses' safety culture, in order to identify improvement's priorities. A survey of nursing staff, using a questionnaire was carried out in a Piedmont hospital. Of 1056 health care workers, 707 participated (67%). The staff's perception of patient safety was positive: the results of the domains "Information and communication", "Suggestions and development" and "Safety guarantees" tend to be fair, while "Teamwork" was sufficient. The weakest areas were related to involvement (Items: "We are consulted when choosing equipment and devices to be used", 25.9% agreement, "At the end of the year we discuss together activities carried out and results" 31,8%), and "Work organization (shifts, workload) doesn't cause overload and stress", 25.3% agreement, "When an error occurs we know how to communicate with the patient as we have a guideline to lead us" 35.8% agreement. The study shows that, even if the safety culture is overall positive, there are some critical aspects that lead to distress and uncertainty between nursing staff. Improvement strategies may include: staff training to improve teamwork skills and staff involvement, increasing opportunities for discussion, organizing systematic multi-professional audit, to reflect in a structured way on clinical practice. PMID- 23343876 TI - [Collaboration between nurses and auxiliary staff: cognitive study on behaviour in a hospital environment]. AB - The aim of this study was to analyze collaboration between nurses and auxiliary staff and it was implemented at the Santa Maria Nuova Hospital of Reggio Emilia. Although this topic is of great interest for the health structures, so far few studies dealing specifically with the interactions between these two categories have been published. The international scenario offers an extremely varied picture of the staff employed in such tasks : in fact, only Italy has a single national legislation which establishes that auxiliary staff are figures supporting the health professions in both a social and healty context. The study assessed the areas susceptible to improvement in terms of nursing-auxiliary staff collaboration , thus improving the quality of care, by promoting negotiation and confrontation between the two categories. In the literture the Jefferson Scale of Attitude Toward Physician Nurse Collaboration was used. Results identified that the priority areas of intervention regarded how the patient was received on hospital entry and during his stay and the safety of the patient throught hospitalization. PMID- 23343877 TI - [Construction and implementation of an experimental instrument for assessing and monitoring oncological pain to use in professional nursing care]. AB - In this study the construction and experimentation of an instrument for assessing and monitoring oncological pain is described with the aim of controlling pain in at least 90% of cases, training the nurses involved to acquire the competencies necessary. The study was observational and based on a questionnaire filled in on admission and updated daily . The patient population consisted of 97 patients with lung cancer admitted to the San Camillo Hospital of Rome during the last 3 months of 2010. On discharge pain was absent in 31,5%, mild in 59,3%, moderate in 3,7% and severe in 5,5%. The incidence of breakthrough pain was 6.8%. The percentage of patients without pain at discharge was judged satisfactory and, when added to the percentage of mild pain, brought the total number of patients in whom the quality of life improved to 90.8%. PMID- 23343878 TI - The use of complementary therapies for chronic pain in Italian hospices. AB - PURPOSE: Although there has been an increase in the use of CT (Complementary Therapy) in Europe, little is known about CT available in Italian hospices. The present study is aimed at assessing the diffusion and typologies of CT used to treat chronic pain in Italian hospices. METHODS. An online survey was e-mailed to a regional sample of 16 hospices, which included questions on common CT used to treat malignant or nonmalignant chronic pain, and the barriers to their utilization. RESULTS: The response rate was 81%. Only 5 hospices (38%) offered CT with conventional treatment. Massage therapy was the most common type of CT used, followed by naturopathy, nurturing touch, hypnotherapy, guided imagery, and aromatherapy. Barriers to the delivery of CT included insufficient knowledge of CT by staff, limited knowledge, and lack of funding. CONCLUSIONS: Although limited to Lazio hospices, this survey shows a partial use of CT for the treatment of chronic pain, caused by economic and cultural barriers. PMID- 23343879 TI - Care seeking for pain in young adults with sickle cell disease. AB - In individuals with sickle cell disease (SCD), recognizing the cues to an acute pain episode and responding appropriately are important. The purpose of this mixed-methods pilot study is to identify preliminary factors that influence care seeking for pain in young adults with SCD. Responses were received from 69 young adults with SCD, age 18-35 years. The majority of respondents (88%) wait until the pain intensity is an average of 8.7 (+/- 1.2) on a scale of 1 to 10 before seeking care. Prominent themes influencing care seeking for pain include: trying to treat pain at home, avoiding the emergency department because of past treatment experiences, the desire to avoid admission to the hospital, and the importance of time in the lives of the young adults with SCD. Young adults with SCD need additional support from family and healthcare providers in order to make timely, appropriate decisions regarding care seeking. PMID- 23343880 TI - When they don't bite, we smell money: understanding malaria bednet misuse. AB - Insecticide-treated nets (ITNs) are a major tool to control malaria. Over recent years increased ITN coverage has been associated with decreased malaria transmission. However, ITN 'misuse' has been increasingly reported and whether this emergent behaviour poses a threat to successful malaria control and elimination is an open question. Here, we use a game theory mathematical model to understand the possible roles of poverty and malaria infection protection by individual and emerging 'community effects' on the 'misuse' of malaria bednets. We compare model predictions with data from our studies in Lake Victoria Islands (LVI), Kenya and Aneityum, Vanuatu. Our model shows that alternative ITN use is likely to emerge in impoverished populations and could be exacerbated if ITNs become ineffective or when large 'community effects' emerge. Our model predicted patterns of ITN use similar to the observed in LVI, where 'misuse' is common and the high ITN use in Aneityum, more than 20 years after malaria elimination in 1990. We think that observed differences in ITN use may be shaped by different degrees of economic and social development, and educational components of the Aneityum elimination, where traditional cooperative attitudes were strengthened with the malaria elimination intervention and post-elimination surveillance. PMID- 23343881 TI - Arresting the Culprit: Targeted Antagomir Delivery to Sequester Oncogenic miR-221 in HCC. PMID- 23343882 TI - Molecular Therapy's New Open-access Sibling. PMID- 23343883 TI - Antisense Oligonucleotide (AON)-based Therapy for Leber Congenital Amaurosis Caused by a Frequent Mutation in CEP290. AB - Leber congenital amaurosis (LCA) is the most severe form of inherited retinal degeneration, with an onset in the first year of life. The most frequent mutation that causes LCA, present in at least 10% of individuals with LCA from North American and Northern-European descent, is an intronic mutation in CEP290 that results in the inclusion of an aberrant exon in the CEP290 mRNA. Here, we describe a genetic therapy approach that is based on antisense oligonucleotides (AONs), small RNA molecules that are able to redirect normal splicing of aberrantly processed pre-mRNA. Immortalized lymphoblastoid cells of individuals with LCA homozygously carrying the intronic CEP290 mutation were transfected with several AONs that target the aberrant exon that is incorporated in the mutant CEP290 mRNA. Subsequent RNA isolation and reverse transcription-PCR analysis revealed that a number of AONs were capable of almost fully redirecting normal CEP290 splicing, in a dose-dependent manner. Other AONs however, displayed no effect on CEP290 splicing at all, indicating that the rescue of aberrant CEP290 splicing shows a high degree of sequence specificity. Together, our data show that AON-based therapy is a promising therapeutic approach for CEP290-associated LCA that warrants future research in animal models to develop a cure for this blinding disease. PMID- 23343884 TI - Formulation of Small Activating RNA Into Lipidoid Nanoparticles Inhibits Xenograft Prostate Tumor Growth by Inducing p21 Expression. AB - Application of RNA interference (RNAi) in the clinic has improved with the development of novel delivery reagents (e.g., lipidoids). Although RNAi promises a therapeutic approach at silencing gene expression, practical methods for enhancing gene production still remain a challenge. Previously, we reported that double-stranded RNA (dsRNA) can activate gene expression by targeting promoter sequence in a phenomenon termed RNA activation (RNAa). In the present study, we investigate the therapeutic potential of RNAa in prostate cancer xenografts by using lipidoid-based formulation to facilitate in vivo delivery. We identify a strong activator of gene expression by screening several dsRNAs targeting the promoter of tumor suppressor p21(WAF1/ Cip1) (p21). Chemical modification is subsequently implemented to improve the medicinal properties of the candidate duplex. Lipidoid-encapsulated nanoparticle (LNP) formulation is validated as a delivery vehicle to mediate p21 induction and inhibit growth of prostate tumor xenografts grown in nude mice following intratumoral injection. We provide insight into the stepwise creation and analysis of a putative RNAa-based therapeutic with antitumor activity. Our results provide proof-of-principle that RNAa in conjunction with lipidioids may represent a novel approach for stimulating gene expression in vivo to treat disease. PMID- 23343885 TI - A DFT + U study of (Rh, Nb)-codoped rutile TiO2. AB - A systematic study of electronic structure and band gap states is conducted to analyze the monodoping and charge compensated codoping of rutile TiO(2) with Rh and Nb, using the DFT + U approach. Doping of rutile TiO(2) with Rh atoms induces hybridized O 2p and Rh 4d band gap states leading to a red shift of the optical absorption edge, consistent with previous experimental studies. Since Rh monodoping may induce recombination centers, charge compensated codoping with Rh and Nb is also explored. This codoping induces an electron transfer from Nb induced states to Rh 4d states, which suppresses the formation of Rh(4+), thereby leading to a reduction in recombination centers and to the formation of more stable Rh(3+). A combination of band gap reduction by 0.5 eV and the elimination of band gap states that account for recombination centers makes (Rh, Nb)-codoped TiO(2) a more efficient and stable photocatalyst. PMID- 23343886 TI - Epidemiology of acute transfusions in major orthopaedic trauma. AB - OBJECTIVES: The orthopaedic trauma-related blood product usage is largely unknown. Aim of this study was to describe the epidemiology of early (<24 hours of arrival) blood component use in major orthopaedic trauma. DESIGN: 12-month prospective observational study. SETTING: John Hunter Hospital, Level 1 Trauma Center, New South Wales, Australia. PATIENTS: 64 consecutive trauma admissions identified, who had an orthopaedic injury and required at least 1 unit of packed red blood cells (PRBC) <24 hours of arrival. INTERVENTION: Epidemiological study. MAIN OUTCOME MEASURES: Demographics, orthopaedic injury type, procedure type, injury severity score, timing, place of first unit of transfusion, and blood component volumes were collected. Activation of the massive transfusion protocol was recorded. Primary outcome measures were intensive care unit admission and mortality. RESULTS: From 965 major trauma admissions, 64 had one or more orthopaedic injuries and were transfused <24 hours. Forty-eight percent (31/64) required massive transfusion protocol activation. Average age was 41 +/- 21 years, 73% (47/64) men. Eighty-four percent (54/64) required emergent orthopaedic intervention, 41% (22/54) having multiple procedures. Overall mortality was 13% (8/64). Twenty-five percent (16/64) required >=10 units of PRBC. Average PRBC use was 7.2 +/- 6.6 units and fresh frozen plasma use 4.3 +/- 5.2 units. Thirty-nine percent (25/64) had a pelvic ring injury or acetabular fracture. Thirty-seven percent (24/64) had at least one femoral shaft fracture. Twenty patients had a total of 23 tibia fractures. CONCLUSIONS: Orthopaedic trauma patients consume the majority of the blood products <24 hours among blunt trauma patients. This resource-intensive group requires frequent urgent surgical interventions and intensive care unit admission. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 23343887 TI - Impact of scabies in resource-poor communities. AB - PURPOSE OF REVIEW: Features of endemic scabies are specific in resource-poor and underprivileged communities, with implications for control measures on the community level. In this review, these special aspects are addressed. RECENT FINDINGS: Scabies is endemic in many resource-poor communities, with a prevalence of 20% and higher. Transmission is influenced by social attitudes, migration, access to healthcare services, housing conditions, hygiene conditions, and crowding. Endemic scabies occurs with severe infestations, complications, and sequels, mainly in children. Sleep loss as a result of scabies-related itching is common. Complications include secondary infections by group A streptococci and acute poststreptococcal glomerulonephritis. Shame, restriction of leisure activities, and stigmatization are common. Treatment of scabies includes a variety of topical compounds, but control on the community level is not an easy task. As ivermectin kills a variety of other parasites, this oral drug is increasingly used for mass treatment. Intervention should address socioemotional aspects using an integrated approach with professionals from different areas, and the community. SUMMARY: Scabies is a neglected disease and needs to be perceived as an important public health problem causing morbidity in many resource-poor communities. Future work on epidemiology, clinical aspects, transmission dynamics, socioeconomic aspects, and sustainable control in resource-poor communities is needed. PMID- 23343888 TI - The development of risky attitudes from pre-driving to fully-qualified driving. AB - BACKGROUND: Young drivers are at increased crash risk as a result of adopting risky driving styles. The present work examines the development of risky attitudes from pre-driving to fully-qualified driving, focussing on speed related attitudes. METHODS: Data were drawn from a UK longitudinal study of adolescent behaviour development in the general population (the G1219 study). At baseline (modal age 17 years) there were 1596 participants, only 18% of whom were fully qualified drivers. At follow-up (modal age 20 years) 64% were fully-qualified drivers. Attitudes to driving violations, particularly speeding, were measured in all participants at both assessments. Self-reported driving violations, also related to speeding, were measured in fully-qualified drivers at follow-up. RESULTS: Attitudes became riskier with driver training/experience. Baseline attitudes measured in pre-drivers did not independently predict violations in those that had become fully-qualified drivers at follow-up. The attitudes of learner and fully-qualified drivers at baseline independently predicted violations at follow-up. CONCLUSIONS: These results indicate that the driver training period offers a promising opportunity for interventions to develop safer driving attitudes. PMID- 23343889 TI - Three-dimensional angioultrasonography for the prediction of malignancy in ovarian masses. AB - OBJECTIVE: To determine the efficacy of the angiographic indexes of 3D power Doppler angiography (3D-PDA) for the diagnosis of malignancy in complex ovarian masses. METHODS: A prospective, observational study of 72 patients with complex adnexal mass. RESULTS: In the morphological study, 3D ultrasound showed sensitivity, specificity, PPV, NPV, PLHR and NLHR of 84.6%, 81.9%, 85.1%, 81.8%, 4.65 and 0.19. No differences in vascular indexes (VI, FI, VFI) between malignant and benign masses were found: VI 5.38 (CI 95% 3.06-7.7) vs. 6.29 (CI 95% 4.41 8.17) (p = 0.53); FI 29.6 (CI 95% 25.17-34.08) vs. 33.8 (CI 95% 30.03-37.3) (p = 0.15); VFI 1.68 (CI 95% 0.94-2.42) vs. 2.37 (CI 95% 1.49-3.25) (p = 0.24). When analysed according to different stages, VI was higher in patients with more advanced stages of disease; 4.34 (95% CI 2.21-6.47) vs. 7.38 (95% CI 4.7-10.06) (p = 0.11). FI was significantly lower in patients with early stages of disease; FI 29.07 (95% CI 21.49-36.68) vs. 36.46 (95% CI 32.31-40.62) (p = 0.04). For VFI, differences were not significant, although there was a strong trend; VFI 1.47 (95% CI 0.67-2.28) vs. 2.86 (95% CI 1.57-4.16) (p = 0.11). 3D-PDA indexes were significantly higher in patients with positive adenopathies. CONCLUSION: 3D-PDA values increase progressively, but not significantly, with the stage of the disease. PMID- 23343890 TI - Imaging the response of the retina to electrical stimulation with genetically encoded calcium indicators. AB - Epiretinal implants for the blind are designed to stimulate surviving retinal neurons, thus bypassing the diseased photoreceptor layer. Single-unit or multielectrode recordings from isolated animal retina are commonly used to inform the design of these implants. However, such electrical recordings provide limited information about the spatial patterns of retinal activation. Calcium imaging overcomes this limitation, as imaging enables high spatial resolution mapping of retinal ganglion cell (RGC) activity as well as simultaneous recording from hundreds of RGCs. Prior experiments in amphibian retina have demonstrated proof of principle, yet experiments in mammalian retina have been hindered by the inability to load calcium indicators into mature mammalian RGCs. Here, we report a method for labeling the majority of ganglion cells in adult rat retina with genetically encoded calcium indicators, specifically GCaMP3 and GCaMP5G. Intravitreal injection of an adeno-associated viral vector targets ~85% of ganglion cells with high specificity. Because of the large fluorescence signals provided by the GCaMP sensors, we can now for the first time visualize the response of the retina to electrical stimulation in real-time. Imaging transduced retinas mounted on multielectrode arrays reveals how stimulus pulse shape can dramatically affect the spatial extent of RGC activation, which has clear implications in prosthetic applications. Our method can be easily adapted to work with other fluorescent indicator proteins in both wild-type and transgenic mammals. PMID- 23343891 TI - Responses to pulsatile subretinal electric stimulation: effects of amplitude and duration. AB - In working to improve the quality of visual percepts elicited by retinal prosthetics, considerable effort has been made to understand how retinal neurons respond to electric stimulation. Whereas responses arising from direct activation of retinal ganglion cells have been well studied, responses arising through indirect activation (e.g., secondary to activation of bipolar cells) are not as well understood. Here, we used cell-attached, patch-clamp recordings to measure the responses of rabbit ganglion cells in vitro to a wide range of stimulus-pulse parameters (amplitudes: 0-100 MUA; durations: 0.1-50 ms), applied to a 400-MUm diameter, subretinal-stimulating electrode. The indirect responses generally consisted of multiple action potentials that were clustered into bursts, although the latency and number of spikes within a burst were highly variable. When different parameter pairs representing identical charge levels were compared, the shortest pulse durations generally elicited the most spikes. In addition, latencies were shortest, and jitter was lowest for short pulses. These findings suggest that short pulses are optimum for activation of presynaptic neurons, and therefore, short pulses are more effective for both direct as well as indirect activation. PMID- 23343892 TI - Intrinsic physiological properties of the five types of mouse ganglion-cell photoreceptors. AB - In the mammalian retina, some ganglion cells express the photopigment melanopsin and function as photoreceptors. Five morphological types of these intrinsically photosensitive retinal ganglion cells (ipRGCs), M1-M5, have been identified in mice. Whereas M1 specializes in non-image-forming visual functions and drives such behaviors as the pupillary light reflex and circadian photoentrainment, the other types appear to contribute to image-forming as well as non-image-forming vision. Recent work has begun to reveal physiological diversity among some of the ipRGC types, including differences in photosensitivity, firing rate, and membrane resistance. To gain further insights into these neurons' functional differences, we conducted a comprehensive survey of the electrophysiological properties of all five morphological types. Compared with the other types, M1 had the highest membrane resistance, longest membrane time constant, lowest spike frequencies, widest action potentials, most positive spike thresholds, smallest hyperpolarization-activated inwardly-rectifying current-induced "sagging" responses to hyperpolarizing currents, and the largest effects of voltage-gated K(+) currents on membrane potentials. M4 and M5 were at the other end of the spectrum for most of these measures, while M2 and M3 tended to be in the middle of this spectrum. Additionally, M1 and M2 cells generated more diverse voltage gated Ca(2+) currents than M3-M5. In conclusion, M1 cells are significantly different from all other ipRGCs in most respects, possibly reflecting the unique physiological requirements of non-image-forming vision. Furthermore, the non-M1 ipRGCs are electrophysiologically heterogeneous, implicating these cells' diverse functional roles in both non-image-forming vision and pattern vision. PMID- 23343893 TI - Alignment to natural and imposed mismatches between the senses. AB - Does the nervous system continuously realign the senses so that objects are seen and felt in the same place? Conflicting answers to this question have been given. Research imposing a sensory mismatch has provided evidence that the nervous system realigns the senses to reduce the mismatch. Other studies have shown that when subjects point with the unseen hand to visual targets, their end points show visual-proprioceptive biases that do not disappear after episodes of visual feedback. These biases are indicative of intersensory mismatches that the nervous system does not align for. Here, we directly compare how the nervous system deals with natural and imposed mismatches. Subjects moved a hand-held cube to virtual cubes appearing at pseudorandom locations in three-dimensional space. We alternated blocks in which subjects moved without visual feedback of the hand with feedback blocks in which we rendered a cube representing the hand-held cube. In feedback blocks, we rotated the visual feedback by 5 degrees relative to the subject's head, creating an imposed mismatch between vision and proprioception on top of any natural mismatches. Realignment occurred quickly but was incomplete. We found more realignment to imposed mismatches than to natural mismatches. We propose that this difference is related to the way in which the visual information changed when subjects entered the experiment: the imposed mismatches were different from the mismatch in daily life, so alignment started from scratch, whereas the natural mismatches were not imposed by the experimenter, so subjects are likely to have entered the experiment partly aligned. PMID- 23343894 TI - Extrasynaptic glutamate and inhibitory neurotransmission modulate ganglion cell participation during glutamatergic retinal waves. AB - During the first 2 wk of mouse postnatal development, transient retinal circuits give rise to the spontaneous initiation and lateral propagation of depolarizations across the ganglion cell layer (GCL). Glutamatergic retinal waves occur during the second postnatal week, when GCL depolarizations are mediated by ionotropic glutamate receptors. Bipolar cells are the primary source of glutamate in the inner retina, indicating that the propagation of waves depends on their activation. Using the fluorescence resonance energy transfer-based optical sensor of glutamate FLII81E-1MU, we found that retinal waves are accompanied by a large transient increase in extrasynaptic glutamate throughout the inner plexiform layer. Using two-photon Ca(2+) imaging to record spontaneous Ca(2+) transients in large populations of cells, we found that despite this spatially diffuse source of depolarization, only a subset of neurons in the GCL and inner nuclear layer (INL) are robustly depolarized during retinal waves. Application of the glutamate transporter blocker dl-threo-beta-benzyloxyaspartate (25 MUM) led to a significant increase in cell participation in both layers, indicating that the concentration of extrasynaptic glutamate affects cell participation in both the INL and GCL. In contrast, blocking inhibitory transmission with the GABAA receptor antagonist gabazine and the glycine receptor antagonist strychnine increased cell participation in the GCL without significantly affecting the INL. These data indicate that during development, glutamate spillover provides a spatially diffuse source of depolarization, but that inhibitory circuits dictate which neurons within the GCL participate in retinal waves. PMID- 23343895 TI - Early postnatal development of GABAergic presynaptic inhibition of Ia proprioceptive afferent connections in mouse spinal cord. AB - Sensory feedback is critical for normal locomotion and adaptation to external perturbations during movement. Feedback provided by group Ia afferents influences motor output both directly through monosynaptic connections and indirectly through spinal interneuronal circuits. For example, the circuit responsible for reciprocal inhibition, which acts to prevent co-contraction of antagonist flexor and extensor muscles, is driven by Ia afferent feedback. Additionally, circuits mediating presynaptic inhibition can limit Ia afferent synaptic transmission onto central neuronal targets in a task-specific manner. These circuits can also be activated by stimulation of proprioceptive afferents. Rodent locomotion rapidly matures during postnatal development; therefore, we assayed the functional status of reciprocal and presynaptic inhibitory circuits of mice at birth and compared responses with observations made after 1 wk of postnatal development. Using extracellular physiological techniques from isolated and hemisected spinal cord preparations, we demonstrate that Ia afferent-evoked reciprocal inhibition is as effective at blocking antagonist motor neuron activation at birth as at 1 wk postnatally. In contrast, at birth conditioning stimulation of muscle nerve afferents failed to evoke presynaptic inhibition sufficient to block functional transmission at synapses between Ia afferents and motor neurons, even though dorsal root potentials could be evoked by stimulating the neighboring dorsal root. Presynaptic inhibition at this synapse was readily observed, however, at the end of the first postnatal week. These results indicate Ia afferent feedback from the periphery to central spinal circuits is only weakly gated at birth, which may provide enhanced sensitivity to peripheral feedback during early postnatal experiences. PMID- 23343896 TI - Healthy and dystonic children compensate for changes in motor variability. AB - Successful reaching requires that we plan movements to compensate for variability in motor output. Previous studies have shown that healthy adults optimally incorporate estimates of motor variability when planning a pointing task. Children with dystonia have increased variability compared with healthy children. It is not known whether they are able to compensate appropriately for the increased variability and whether this compensation leads to changes in reaching behavior. We examined healthy children and those with increased motor variability due to secondary dystonia. Using a simple virtual display, children performed a motor task where the variability of their movements was manipulated. Results showed that both subject groups changed their movement strategies in response to changes in the level of perceived motor variability. Both groups changed their strategy in a way that improved performance relative to the perceived motor variability. Importantly, dystonic children faced with decreased motor variability adapted their movement strategy to perform better and more similarly to healthy children. These findings show that both healthy and dystonic children are able to respond to changes in motor variability and alter their movement strategies. PMID- 23343897 TI - Sensorimotor adaptation changes the neural coding of somatosensory stimuli. AB - Motor learning is reflected in changes to the brain's functional organization as a result of experience. We show here that these changes are not limited to motor areas of the brain and indeed that motor learning also changes sensory systems. We test for plasticity in sensory systems using somatosensory evoked potentials (SEPs). A robotic device is used to elicit somatosensory inputs by displacing the arm in the direction of applied force during learning. We observe that following learning there are short latency changes to the response in somatosensory areas of the brain that are reliably correlated with the magnitude of motor learning: subjects who learn more show greater changes in SEP magnitude. The effects we observe are tied to motor learning. When the limb is displaced passively, such that subjects experience similar movements but without experiencing learning, no changes in the evoked response are observed. Sensorimotor adaptation thus alters the neural coding of somatosensory stimuli. PMID- 23343898 TI - Up states are rare in awake auditory cortex. AB - The dynamics of subthreshold membrane potential provide insight into the organization of activity in neural circuits. In many brain areas, membrane potential is bistable, transiting between a relatively hyperpolarized down state and a depolarized up state. These up and down states, which have been proposed to play a number of computational roles, have mainly been studied in anesthetized and in vitro preparations. Here, we have used intracellular recordings to characterize the dynamics of membrane potential in the auditory cortex of awake rats. We find that long up states are rare in the awake auditory cortex, with only 0.4% of up states >500 ms. Most neurons displayed only brief up states (bumps) and spent on average ~1% of recording time in up states >500 ms. We suggest that the near absence of long up states in awake auditory cortex may reflect an adaptation to the rapid processing of auditory stimuli. PMID- 23343899 TI - Multimodal representation of limb endpoint position in the posterior parietal cortex. AB - Understanding the neural representation of limb position is important for comprehending the control of limb movements and the maintenance of body schema, as well as for the development of neuroprosthetic systems designed to replace lost limb function. Multiple subcortical and cortical areas contribute to this representation, but its multimodal basis has largely been ignored. Regarding the parietal cortex, previous results suggest that visual information about arm position is not strongly represented in area 5, although these results were obtained under conditions in which animals were not using their arms to interact with objects in their environment, which could have affected the relative weighting of relevant sensory signals. Here we examined the multimodal basis of limb position in the superior parietal lobule (SPL) as monkeys reached to and actively maintained their arm position at multiple locations in a frontal plane. On half of the trials both visual and nonvisual feedback of the endpoint of the arm were available, while on the other trials visual feedback was withheld. Many neurons were tuned to arm position, while a smaller number were modulated by the presence/absence of visual feedback. Visual modulation generally took the form of a decrease in both firing rate and variability with limb vision and was associated with more accurate decoding of position at the population level under these conditions. These findings support a multimodal representation of limb endpoint position in the SPL but suggest that visual signals are relatively weakly represented in this area, and only at the population level. PMID- 23343900 TI - Augmented P2X response and immunolabeling in dorsal root ganglion neurons innervating skeletal muscle following femoral artery occlusion. AB - The responsiveness of sensory neurons to muscle metabolites is altered under the conditions of insufficient limb blood supply in some diseases, such as peripheral artery disease. The purpose of this study was to examine ATP-induced current with activation of purinergic P2X subtypes P2X3 and P2X2/3 in dorsal root ganglion (DRG) neurons of control limbs and limbs with 24 h of femoral artery occlusion using whole cell patch-clamp methods. Also, dual-labeling immunohistochemistry was employed to determine existence of P2X3 expression in DRG neurons of thin fiber afferents. DRG neurons from 4- to 6-wk-old rats were labeled by injecting the fluorescence tracer DiI into the hindlimb muscles 4-5 days before the recording experiments. Transient (P2X3), mixed (P2X3 and P2X2/3), and sustained (P2X2/3) current responses to alpha,beta-methylene ATP (a P2X receptor agonist) are observed in small and medium DRG neurons, and size distribution of DRG neurons is similar in control and occluded limbs. However, the peak current amplitude of DRG neuron induced by stimulation of P2X3 and/or P2X2/3 is larger in occluded limbs than that in control limbs. Moreover, the percentage of DRG neurons with P2X3 transient currents is greater after arterial occlusion compared with control. In addition, a rapid desensitization was observed in DRG neurons with transient currents, but not with sustained currents in control and occluded groups. Furthermore, results from immunofluorescence experiments show that femoral artery occlusion primarily augments P2X3 expression within DRG neurons projecting C-fiber afferents. Overall, these findings suggest that 1) greater ATP induced currents with activation of P2X3 and P2X2/3 are developed when hindlimb arterial blood supply is deficient under ischemic conditions and 2) increased P2X3 expression is largely observed in C-fibers of DRG neurons after hindlimb vascular insufficiency. PMID- 23343901 TI - Multiple serotonergic paths to antidepressant efficacy. AB - Depression is a leading cause of disability worldwide. Brain mechanisms underlying the clinical antidepressant efficacy of selective serotonin reuptake inhibitors (SSRI), currently the first-line treatment, remain poorly understood. Recent animal studies have implicated multiple serotonin receptor subtypes in SSRI response, opening new therapeutic perspectives. PMID- 23343903 TI - Silent synapses persist into adulthood in layer 2/3 pyramidal neurons of visual cortex in dark-reared mice. AB - Immature excitatory synapses often have NMDA receptors but not AMPA receptors in central neurons, including visual cortical pyramidal neurons. These synapses, called silent synapses, are converted to functional synapses with AMPA receptors by NMDA receptor activation during early development. It is likely that this process underlies the activity-dependent refinement of neuronal circuits and brain functions. In the present study, we investigated postnatal development of excitatory synapses, focusing on the role of visual inputs in the conversion of silent to functional synapses in mouse visual cortex. We analyzed presumably unitary excitatory postsynaptic currents (EPSCs) between a pair of layer 2/3 pyramidal neurons, using minimal stimulation with a patch pipette attached to the soma of one of the pair. The proportion of silent synapses was estimated by the difference in the failure rate between AMPA- and NMDA-EPSCs. In normal development, silent synapses were present abundantly before eye opening, decreased considerably by the critical period of ocular dominance plasticity, and almost absent in adulthood. This decline in silent synapses was prevented by dark rearing. The amplitude of presumably unitary AMPA-EPSCs increased with age, but this increase was suppressed by dark rearing. The quantal amplitude of AMPA-EPSCs and paired-pulse ratio of NMDA-EPSCs both remained unchanged during development, independent of visual experience. These results indicate that visual inputs are required for the conversion of silent to functional synapses and this conversion largely contributes to developmental increases in the amplitude of presumably unitary AMPA-EPSCs. PMID- 23343904 TI - Frequency-specific adaptation in human auditory cortex depends on the spectral variance in the acoustic stimulation. AB - In auditory cortex, activation and subsequent adaptation is strongest for regions responding best to a stimulated tone frequency and less for regions responding best to other frequencies. Previous attempts to characterize the spread of neural adaptation in humans investigated the auditory cortex N1 component of the event related potentials. Importantly, however, more recent studies in animals show that neural response properties are not independent of the stimulation context. To link these findings in animals to human scalp potentials, we investigated whether contextual factors of the acoustic stimulation, namely, spectral variance, affect the spread of neural adaptation. Electroencephalograms were recorded while human participants listened to random tone sequences varying in spectral variance (narrow vs. wide). Spread of adaptation was investigated by modeling single-trial neural adaptation and subsequent recovery based on the spectro-temporal stimulation history. Frequency-specific neural responses were largest on the N1 component, and the modeled neural adaptation indices were strongly predictive of trial-by-trial amplitude variations. Yet the spread of adaption varied depending on the spectral variance in the stimulation, such that adaptation spread was broadened for tone sequences with wide spectral variance. Thus the present findings reveal context-dependent auditory cortex adaptation and point toward a flexibly adjusting auditory system that changes its response properties with the spectral requirements of the acoustic environment. PMID- 23343905 TI - An electroolfactogram study of odor response patterns from the mouse olfactory epithelium with reference to receptor zones and odor sorptiveness. AB - Olfactory sensory neuron (OSN) responses to odors, measured at the population level, tend to be spatially heterogeneous in the vertebrates that have been studied. These response patterns vary between odors but are similar across subjects for a given stimulus. However, few species have been studied making functional interpretation of these patterns problematic. One proximate explanation for the spatial heterogeneity of odor responses comes from evidence that olfactory receptor (OR) genes in rodents are expressed in OSN populations that are spatially restricted to a few zones in the olfactory epithelium (OE). A long-standing functional explanation for response anisotropy in the OE posits that it is the signature of a supplementary mechanism for quality coding, based on the sorptive properties of odor molecules. These theories are difficult to assess because most mapping studies have utilized few odors, provided little replication, or involved but a single species (rat). In fact, to our knowledge, a detailed olfactory response "map" has not been reported for mouse, the species used in most studies of gene localization. Here we report the results of a study of mouse OE response patterns using the electroolfactogram (EOG). We focused on the medial aspect of olfactory turbinates that are accessible in the midsagittal section. This limited approach still allowed us to test predictions derived from the zonal distribution of OSN types and the sorption hypothesis. In 3 separate experiments, 290 mice were used to record EOGs from a set of standard locations along each of 4 endoturbinates utilizing 11 different odors resulting in over 4,400 separate recordings. Our results confirmed a marked spatial heterogeneity in odor responses that varied with odor, as seen in other species. However, no discontinuities were found in the odor-specific response patterns across the OE as might have been predicted given the existence of classical receptor zones nor did we find clear support for the hypothesis that OE response patterns, presumably a reflection of OSN distribution, have been shaped through natural selection by the relative sorptive properties of odors. We propose that receptor zones may be an epiphenomenon of a contingent evolutionary process. In this formulation, constraints on developmental programs for distributing OSN classes within the OE may be minimally related to the odor ligands of specific class members. Further, we propose that odor sorptiveness, which appears to be correlated with the inherent response patterns in the OE of larger species, may be of minimal effect in mice owing to scaling issues. PMID- 23343902 TI - Somatosensory responses in a human motor cortex. AB - Somatic sensory signals provide a major source of feedback to motor cortex. Changes in somatosensory systems after stroke or injury could profoundly influence brain computer interfaces (BCI) being developed to create new output signals from motor cortex activity patterns. We had the unique opportunity to study the responses of hand/arm area neurons in primary motor cortex to passive joint manipulation in a person with a long-standing brain stem stroke but intact sensory pathways. Neurons responded to passive manipulation of the contralateral shoulder, elbow, or wrist as predicted from prior studies of intact primates. Thus fundamental properties and organization were preserved despite arm/hand paralysis and damage to cortical outputs. The same neurons were engaged by attempted arm actions. These results indicate that intact sensory pathways retain the potential to influence primary motor cortex firing rates years after cortical outputs are interrupted and may contribute to online decoding of motor intentions for BCI applications. PMID- 23343906 TI - Tacrolimus versus cyclophosphamide in steroid-dependent or steroid-resistant focal segmental glomerulosclerosis: a randomized controlled trial. AB - BACKGROUND: The efficacy and safety of tacrolimus (TAC) and cyclophosphamide (CTX) were prospectively examined in steroid-dependent or steroid-resistant primary focal segmental glomerulosclerosis (FSGS). METHODS: Patients with biopsy proven FSGS were enrolled and randomly divided into two groups: CTX and TAC. Patients treated with CTX (0.5-0.75 g/m(2).month, i.v.) received prednisone at 0.8 mg/kg.day, while patients treated with TAC (0.1 mg/kg.day) received prednisone at 0.5 mg/kg.day. The plasma concentration of TAC was monitored and maintained at 5-10 ng/ml. After a 6-month treatment the patients were evaluated. Patients with complete remission (CR) and partial remission (PR) continued the treatment for 12 months with the dose tapered, whereas the patients with no response were excluded from the study and underwent an alternative treatment. RESULTS: A total of 33 patients were recruited and 27 completed the 12-month follow-up. The TAC-treated patients (n = 15) showed a quick remission. The initial remission time averaged 1.23 +/- 0.21 versus 2.21 +/- 0.77 months in the CTX group (n = 18), but no significant difference was achieved (p > 0.05). At 6 months, the two groups showed a similar outcome. Ten patients from each group showed remission (7 CR and 3 PR). At 12 months, the CTX group had 9 CR and 3 PR while the TAC group had 6 CR and 5 PR. Remission rates in TAC tended to be higher than that in CTX, but there was no difference. CTX patients had a high prevalence of infections (50.0 vs. 13.3% in TAC, p < 0.05). In contrast, TAC-treated patients showed a high incidence of hyperglycemia (26.7 vs. 0.0% in CTX, p < 0.05). CONCLUSION: These results suggest that CTX and TAC had a similar efficacy in steroid-dependent and steroid-resistant FSGS as manifested by reduced proteinuria, improved serum albumin level and renal function. PMID- 23343907 TI - Benefits of fidelity: does host specialization impact nematode parasite life history and fecundity? AB - The range of hosts used by a parasite is influenced by macro-evolutionary processes (host switching, host-parasite co-evolution), as well as 'encounter filters' and 'compatibility filters' at the micro-evolutionary level driven by host/parasite ecology and physiology. Host specialization is hypothesized to result in trade-offs with aspects of parasite life history (e.g. reproductive output), but these have not been well studied. We used previously published data to create models examining general relationships among host specificity and important aspects of life history and reproduction for nematodes parasitizing animals. Our results indicate no general trade-off between host specificity and the average pre-patent period (time to first reproduction), female size, egg size, or fecundity of these nematodes. However, female size was positively related to egg size, fecundity, and pre-patent period. Host compatibility may thus not be the primary determinant of specificity in these parasitic nematodes if there are few apparent trade-offs with reproduction, but rather, the encounter opportunities for new host species at the micro-evolutionary level, and other processes at the macro-evolutionary level (i.e. phylogeny). Because host specificity is recognized as a key factor determining the spread of parasitic diseases understanding factors limiting host use are essential to predict future changes in parasite range and occurrence. PMID- 23343908 TI - Deletion of podocyte STAT3 mitigates the entire spectrum of HIV-1-associated nephropathy. AB - OBJECTIVE: HIV-1 gene expression in kidney epithelial cells is thought to be responsible for the pathogenesis of HIV-1-associated nephropathy (HIVAN). Signal transducer and activator of transcription (STAT) 3 signaling is activated in podocytes of patients with HIVAN and drives the dedifferentiation and proliferation of podocytes in culture. We confirm here that deletion of podocyte STAT3 is sufficient to mitigate the glomerular as well as tubulointerstitial findings of HIVAN. METHODS: To demonstrate the functional role of podocyte STAT3 in the pathogenesis of HIVAN we compared the development of HIVAN in Tg26 HIV transgenic mice with and without deletion of STAT3 in the podocyte. RESULTS: Tg26 mice with podocyte-specific STAT3 deletion developed significantly less weight loss, albuminuria, and renal function impairment compared to Tg26 mice without STAT3 deletion. Tg26 mice with podocyte STAT3 deletion also had significantly less glomerular collapse, sclerosis, epithelial cell hyperplasia, podocyte dedifferentiation, and proinflammatory STAT3 target gene expression; and tubulointerstitial changes of HIVAN, including tubular atrophy, degeneration, apoptosis, and lymphocyte infiltration, were also significantly reduced compared to Tg26 mice without STAT3 deletion. CONCLUSION: Development of glomerular as well as tubulointerstitial injuries in the Tg26 HIVAN model is dependent on podocyte STAT3 expression. Inhibition of STAT3 could be a potential adjunctive therapy for the treatment of HIVAN. PMID- 23343909 TI - Incident tuberculosis and risk factors among HIV-infected children in Tanzania. AB - OBJECTIVE: To describe the burden of pediatric tuberculosis (TB) in a HIV infected population and explore the demographic and clinical factors associated with the occurrence of pediatric TB. DESIGN: Longitudinal analysis of a cohort of HIV-infected children. METHODS: The endpoint of the study was clinically diagnosed TB. Cox proportional hazard regression was used to explore the predictors of incident TB among HIV-infected children under age 15 years after enrollment into the HIV program. RESULTS: The cohort comprised of 5040 children [median age: 5 years, interquartile range (IQR) 1-9 years]. During a median follow-up of 0.8 (IQR 0.1-2.5) years, 376 out of 5040 children met the case definition for TB. The overall incidence of TB was 5.2/100 person-years. In multivariate analyses, older age at enrollment [relative risk (RR) 1.7, 95%, confidence interval (CI) 1.5-1.8], severe wasting (RR 1.8, 95% CI 1.3-2.5), severe immune suppression (RR 2.6, 95% CI 1.8-3.8), anemia (RR 1.4, 95% CI 1.0 1.9) and WHO stage IV (RR 4.5, 95% CI 2.4-8.5) were all independently associated with a higher risk of TB. In addition, the use of antiretroviral drugs for more than 180 days reduced the risk of TB by 70% (RR 0.3, 95% CI 0.2-0.4). CONCLUSIONS: Antiretroviral therapy (ART) use is strongly associated with a reduced risk of tuberculosis among HIV-infected children, and should therefore be included in HIV care and treatment programs. Trials of interventions designed to improve the nutritional and hematologic status of these children should also be performed. PMID- 23343910 TI - Cross-group neutralization of HIV-1 and evidence for conservation of the PG9/PG16 epitopes within divergent groups. AB - OBJECTIVE: HIV-1 has been classified into four groups: M, N, O and P. The aim of this study was to revisit the cross-group neutralization using a highly diverse panel of primary isolates. DESIGN: The panel of viruses included nine HIV-1 group O primary isolates, one recombinant M/O primary isolate, one group N primary isolates, one group P primary isolate, two group M (subtype B) primary isolates and the HIV-1 group M adapted strain MN. METHODS: All the viruses were tested for neutralization in TZM-bl cells, using sera issued from patients infected by viruses of group M (n = 11), O (n = 12) and P (n = 1), and a panel of nine human monoclonal broadly neutralizing antibodies (HuMo bNAbs). RESULTS: Although the primary isolates displayed a wide spectrum of sensitivity to neutralization by the human sera, cross-group neutralization was clearly observed. In contrast, the bNAbs did not show any cross-group neutralization, except PG9 and PG16. Interestingly, the group N prototype strain YBF30 was highly sensitive to neutralization by PG9 (IC50: 0.28 MUg/ml) and PG16 (IC50: < 0.12 MUg/ml). The interaction between PG9 and key residues of YBF30 was confirmed by molecular modeling. CONCLUSION: The conservation of the PG9 and PG16 epitopes within groups M and N provides an argument for their relevance as components of a potentially efficient HIV vaccine immunogen. PMID- 23343911 TI - B-cell subset alterations and correlated factors in HIV-1 infection. AB - OBJECTIVES: During HIV-1 infection, the development, phenotype, and functionality of B cells are impaired. Transitional B cells and aberrant B-cell populations arise in blood, whereas a declined percentage of resting memory B cells is detected. Our study aimed at pinpointing the demographic, immunological, and viral factors driving these pathological findings, and the role of antiretroviral therapy in reverting these alterations. DESIGN: B-cell phenotype and correlating factors were evaluated. METHODS: Variations in B-cell subsets were evaluated by flow cytometry in HIV-1-infected individuals naive to therapy, elite controllers, and patients treated with antiretroviral drugs (virological control or failure). Multivariable analysis was performed to identify variables independently associated with the B-cell alterations. RESULTS: Significant differences were observed among patients' groups in relation to all B-cell subsets. Resting memory B cells were preserved in patients naive to therapy and elite controllers, but reduced in treated patients. Individuals naive to therapy and experiencing multidrug failure, as well as elite controllers, had significantly higher levels of activated memory B cells compared to healthy controls. In the multivariate analysis, plasma viral load and nadir CD4 T cells independently correlated with major B-cell alterations. Coinfection with hepatitis C but not hepatitis B virus also showed an impact on specific B-cell subsets. Successful protracted antiretroviral treatment led to normalization of all B-cell subsets with exception of resting memory B cells. CONCLUSION: Our results indicate that viremia and nadir CD4 T cells are important prognostic markers of B-cell perturbations and provide evidence that resting memory B-cell depletion during chronic infection is not reverted upon successful antiretroviral therapy. PMID- 23343912 TI - Increasing HIV testing among male partners. AB - OBJECTIVE: Couple-oriented posttest HIV counselling (COC) provides pregnant women with tools and strategies to invite her partner to HIV counselling and testing. We conducted a randomized trial of the efficacy of COC on partner HIV testing in low/medium HIV prevalence settings (Cameroon, Dominican Republic, Georgia, India). METHODS: Pregnant women were randomized to receive standard posttest HIV counselling or COC and followed until 6 months postpartum. Partner HIV testing events were notified by site laboratories, self-reported by women or both combined. Impact of COC on partner HIV testing was measured in intention-to-treat analysis. Socio-behavioural factors associated with partner HIV testing were evaluated using multivariable logistic regression. RESULTS: Among 1943 pregnant women enrolled, partner HIV testing rates (combined indicator) were 24.7% among women from COC group versus 14.3% in standard posttest HIV counselling group in Cameroon [odds ratio (OR) = 2.0 95% CI (1.2-3.1)], 23.1 versus 20.3% in Dominican Republic [OR = 1.2 (0.8-1.8)], 26.8 versus 1.2% in Georgia [OR = 29.6 (9.1-95.6)] and 35.4 versus 26.6% in India [OR = 1.5 (1.0-2.2)]. Women having received COC did not report more conjugal violence or union break-ups than in the standard posttest HIV counselling group. The main factors associated with partner HIV testing were a history of HIV testing among men in Cameroon, Dominican Republic and Georgia and the existence of couple communication around HIV testing in Georgia and India. CONCLUSION: A simple prenatal intervention taking into account the couple relationship increases the uptake of HIV testing among men in different socio-cultural settings. COC could contribute to the efforts towards eliminating mother-to-child transmission of HIV. PMID- 23343913 TI - Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AB - INTRODUCTION: Since 2002, the WHO has recommended either nevirapine (NVP) or efavirenz (EFV) as part of first-line antiretroviral therapy. These two drugs are known to have differing toxicity profiles, but the risk of these toxicities overall is not well established. METHODS: We systematically reviewed adverse events among treatment-naive HIV-positive adults and children receiving either NVP or EFV as part of first-line antiretroviral therapy. The primary outcome was drug discontinuation as a result of any adverse event; specific toxicities were evaluated as secondary outcomes. Point estimates and 95% confidence intervals (95% CIs) were calculated and proportions and odds ratios (ORs) pooled using fixed-effects meta-analysis. RESULTS: We reviewed data on 26,446 adults and 3975 children from eight randomized trials and 26 prospective cohorts. Overall, adults on NVP were more than two times more likely to discontinue treatment due to any adverse event compared to patients on EFV (OR 2.2, 95% CI 1.9-2.6). Severe hepatotoxicity (OR 3.3, 95% CI 2.5-4.2), severe skin toxicity (OR 3.9, 95% CI 2.5 5.4), and severe hypersensitivity reactions (OR 2.4, 95% CI 1.9-2.9) were more likely to occur among patients on NVP. Patients receiving EFV were more likely to experience severe central nervous system events (OR 3.4, 95% CI 2.1-5.4). Similar associations were seen in children. DISCUSSION: Compared to NVP, EFV is associated with a lower frequency of severe adverse events, in particular treatment discontinuations. This finding supports a move toward EFV-based therapy as the preferred first-line treatment regimen for HIV treatment within a public health approach. PMID- 23343915 TI - Spatiotemporal dynamics of the HIV-1 CRF06_cpx epidemic in Western Africa. AB - OBJECTIVE: To investigate the origin and spatiotemporal dynamics of dissemination of the HIV-1 CRF06_cpx clade in western Africa. DESIGN: A total of 180 HIV-1 CRF06_cpx-like pol sequences isolated from 12 different countries from west and west-central Africa over a period of 16 years (1995-2010) were analyzed. METHODS: Evolutionary, phylogeographic and demographic parameters were jointly estimated from sequence data using a Bayesian coalescent-based method and combined with molecular epidemiology and spatial accessibility data. RESULTS: The CRF06_cpx most probably emerged in Burkina Faso in 1979 (1970-1985). From Burkina Faso, the virus was first disseminated to Mali and Nigeria during the 1980s and later to other countries from west and west-central Africa. Demographic reconstruction indicates that the CRF06_cpx epidemic grew exponentially during the 1980s, with a median growth rate of 0.82 year (0.60-1.09 year), and after stabilize. We found a negative correlation between CRF06_cpx prevalence and the geographical distance to Burkina Faso's capital. Regional accessibility information agrees with the overall geographical range of the CRF06_cpx, but not fully explains the highly heterogeneous distribution pattern of this CRF at regional level. CONCLUSION: The CRF06_cpx epidemic in western Africa probably emerged at the late 1970s and grew during the 1980s at a rate comparable to the HIV-1 epidemics in the United States and Europe. Burkina Faso seems to be the most important epicenter of dissemination of the HIV-1 CRF06_cpx strain at regional level. The explanation for the current geographical distribution of CRF06_cpx is probably multifactorial. PMID- 23343914 TI - Serum albumin and short-term risk for mortality and cardiovascular disease among HIV-infected veterans. AB - OBJECTIVE: We examined the short-term and long-term associations of serum albumin with mortality and cardiovascular disease among HIV-infected veterans. DESIGN: Retrospective cohort analysis using a national database of US veterans with HIV infection. METHODS: This analysis evaluated all HIV-infected veterans in the Department of Veterans Affairs HIV Clinical Case Registry (CCR), a national database consisting of demographic, clinical, laboratory, pharmaceutical, and viral status data. There were 25 522 patients enrolled between 1986 and 2007. We evaluated the associations of baseline and time-updated serum albumin levels with all-cause mortality, atherosclerotic cardiovascular disease, and heart failure by multivariate proportional hazards models. RESULTS: Over 21 years, there were 10 869 deaths; the cumulative mortality was 73.2 per 1000 person-years. After multivariate adjustment for covariates measured at baseline, the lowest category of serum albumin (<2.5 g/dl) was associated with a higher mortality risk compared with the highest category (>4 g/dl; hazard ratio 3.00; 2.67-3.37). When analyzed as a time-dependent model, the association strengthened substantially (15.1; 14.0 16.4). Findings were similar for atherosclerotic cardiovascular disease and heart failure. We stratified the baseline mortality model by year of follow-up and found that albumin was more strongly associated with deaths that occurred within 1 year of baseline (9.29; 7.85-11.0) than in the second (1.66; 1.18-2.33) or third (1.22; 0.77-1.96) year after measurement. CONCLUSION: Among ambulatory HIV infected patients, lower serum albumin levels are strongly predictive of mortality risk, particularly within 1 year. PMID- 23343916 TI - International Journal of Environmental Research and Public Health Best Paper Award 2013. AB - With the start of 2013, International Journal of Environmental Research and Public Health is instituting an annual award to recognize outstanding papers related to environmental health sciences and public health that meet the aims, scope and high standards of this journal. We are pleased to announce the first "International Journal of Environmental Research and Public Health Best Paper Award" for 2013. Nominations were solicited from the Editorial Board members, with all papers published in 2009 eligible for consideration. PMID- 23343917 TI - Fibroblast growth factors in neurodevelopment and psychopathology. AB - In psychiatric disorders, the effect of genetic and environmental factors may converge on molecular pathways and brain circuits related to growth factor functioning. In this review, we describe how disturbances in fibroblast growth factors (FGFs) and their receptors influence behavior by affecting brain development. Recently, several studies reported associations of members of the FGF family with psychiatric disorders. FGFs are key candidates to modulate the impact of environmental factors, such as stress. Mutant mice for FGF receptor 1 show schizophrenia-like behaviors that are related to general loss of neurons and postnatal glia dysfunction. Mice lacking FGF2, a FGFR1 ligand, show similar reductions in brain volume and hyperactivity, as well as increased anxiety behaviors. FGFR2 and FGF17 are involved in the development of frontal brain regions and impairments in cognitive and social behaviors, respectively. Moreover, treatment with FGF2 was beneficial for depressive and cognitive measures in several animal studies and one human study. These findings indicate the importance of the FGF system with respect to developing novel etiology directed treatments for psychopathology. PMID- 23343918 TI - Modeling an integrated health, safety and ergonomics management system: application to power plants. AB - BACKGROUND: This study presents a framework for development of integrated health, safety and ergonomic (HSE) in complex critical systems. Total ergonomics model considers conventional ergonomics factors as well as management and organizational factors. METHODS: Control room operation and maintenance department of a thermal power plant was chosen as the case of our study. To achieve the above objectives, an integrated approach based on total ergonomics factors was developed. Second, it was applied to the thermal power plant and the advantages of total ergonomics approach were discussed. Third, the impacts of total ergonomics factors on local factors were examined through non-parametric statistical analysis. Moreover, the importance and impacts of total ergonomics factors were shown through statistical tests. RESULTS: It is shown that total ergonomics model is much more beneficial than conventional approach. It should be noted that the traditional ergonomics methodology is not capable of locating the findings of total ergonomics model. CONCLUSION: The distinguished aspect of this study is the employment of a total system approach based on integration of the conventional ergonomics factors with HSE factors. PMID- 23343919 TI - Some biomarkers in acute myocardial infarction. AB - BACKGROUND: Several changes in serum biochemical factors occur in acute myocardial infarction (AMI). Recently alterations in serum levels of homocysteine (Hcy), sialic acid (SA) and high sensitive C-reactive protein (HS-CRP) has been attended as risk factors and index for prediction. This study was aimed to show the alterations in these factors and their relationships in AMI. METHODS: Thirty four patients with AMI were enrolled in this case-control study. Also 51 apparently healthy individuals were selected as control group. Serum was prepared from all subjects in fasting state. Hcy and HS-CRP were measured using ELISA and SA was determined by Erlich method. RESULTS: Serum levels of Hcy, SA and HS-CRP in AMI patients were 14.35A+/-2.55I1/4mol/l, 73.54A+/-2.82 mg/dl, and 17.32A+/ 3.45 mg/l, respectively and in the control group they were 8.31A+/-2.66 I1/4mol/l, 59.82A+/-2.70 mg/dl and 2.77A+/-1.98 mg/l, respectively. Statistical analysis of data showed that serum level of Hcy, SA, and HS-CRP in the patients with AMI was significantly higher than those of control (P < 0.001). Also significant correlation was observed between Hcy-HS-CRP (r= 0.63), SA- Hcy (r= 0.73), and SA - CRP (r= 0.75) (P < 0.05 for all items). CONCLUSION: Our findings showed increased level of HS-CRP, SA, and Hcy in AMI patients. Also obtained data indicated a direct and significant correlation between HS-CRP as an inflammation index and Hcy and SA. Hence these two factors can be used as biomarkers in this disease. PMID- 23343920 TI - A Study on the Prevalence of Cryptosporidium in HIV Positive Patients. AB - BACKGROUND: AIDS is acquired by infection with HIV (human immuno-deficiency virus). It leaves the host susceptible to malignant and unusual infections especially opportunistic ones. Most of AIDS patients infected with opportunistic parasitic infections die because of chronic diarrhea and deaths due to Cryptosporidium diarrhea in AIDS patients are considerable in the recent two decades. The aim of this study is to find Cryptosporidium parasite in AIDS patients referring to the center of Diseases consultation in Kermanshah province and to determine the frequency of infection in those patients. METHODS: In this study stool and blood samples were collected from 75 AIDS patients referring regularly to the Center of Diseases Consultation in Kermanshah and the gathered information were filled in the questionnaires together with their personal information regarding their names, sex and etc. Stool samples were tested using direct and formalin ether methods and then the smears that were dyed using modified acid fast staining were examined. Peripheral blood samples were used to determine the CD4 counts. RESULTS: The results showed that the frequency of infection with Cryptosporidium in AIDS patients was 26.7% (20 cases). CONCLUSION: According to the study, as the number of CD4 decreased in the patients, the probability of infection with opportunistic parasites increased and increase in the number CD4 that is normally accompanied with strengthening the body immune system resulted in the decrease in the frequency of infection with Cryptosporidium. PMID- 23343921 TI - Application of the Trans-Theoretical Model (TTM) to Exercise Behavior among Female College Students. AB - BACKGROUND: This study examined the applicability of trans-theoretical model (TTM) to understand exercise behavior among female college students in Hamadan University of Medical Sciences, Iran in 2007. METHODS: A cross-sectional descriptive study was conducted. The dependent variables analyzed were exercise efficacy expectation, decisional balance (pros and cons). The independent variable was stage of exercise behavior change. Five hundred and ninety female students representing various disciplines on campus completed a valid and reliable questionnaire (r = 0.78) during regularly scheduled classes. More than seventy-three percent of sample were sedentary (pre-contemplation, contemplation, or preparation) whereas 24.6% were in the action stage (regularly active < 6 months) and 2.2% were in the maintenance stage (regularly active > 6 months). RESULTS: All of the TTM constructs differed significantly across exercise stages. Students in pre-contemplation scored the lowest and those in maintenance stage scored highest on efficacy expectation and pros and reversed on cons. CONCLUSION: Results supported the use of the entire TTM in examining exercise behavior among female college students. PMID- 23343922 TI - IUD Survival and Its Determinants; a Historical Cohort Study. AB - BACKGROUND: IUD is one of the safest and most widely used reversible methods of contraception. The purpose of this study was to determine IUD survival and reasons for early discontinuation in Bandar Abbas, south of Iran. METHODS: Probability of IUD continuation rate and factors associated with discontinuation were assessed in a historical cohort study of 400 women records from March 2002 to February 2004. Data were collected from documents in health centers and interview with subjects. Life tables, Kaplan- Meier, log-rank test and cox regression model were used for data analysis. RESULTS: The continuation rate of using IUD at 6, 12, 18, 24, 30, 36, 42 and 48 month were 92%, 87%, 81%, 75%, 69%, 62%, 56% and 50%, respectively. Counseling and desire to becoming pregnant were associated with continuation rate (P< 0.03). Furthermore the most important reasons for IUD discontinuation were side effects of IUD followed by pregnancy tendency, health concerns, expulsion, and unsatisfied with the method. CONCLUSION: This study suggested that women should be fully informed about side effects of IUD before inserting it as well as during its using. PMID- 23343923 TI - Depression in menopaused and nonmenopaused women. AB - BACKGROUND: This cross-sectional investigation compared the depressive condition between menopaused and nonmenopasued women in the age of 45-55 in Yazd city in Yazd Province in center of Iran. METHODS: The samples were divided into two groups (70 menopaused women and 70 nonmenopaused women) , and were selected by cluster sampling from the city of Yazd. The depressive tendency of participants was examined with the Beck depression inventory. RESULTS: About 72% of women were free of any depressive tendency, or very minor depression. Thirty women (21.4%) suffered from intermediate depression and 9 women (6.4%) suffered from sever depression. More than 27% of subjects were suffered from some forms of depression. There was no significant difference between the depression and condition of menopause of women. CONCLUSION: It is a need to know the women's condition of depression and counseling as well as guiding them on basis of their needs to prevent any disorders. PMID- 23343924 TI - Management development in health care setting: a training model for hospital managers. AB - BACKGROUND: This study was conducted to design an on job-training model for the managers of the Iranian Social Security Organization (ISSO) hospitals and any other similar setting. METHODS: A five dimensional model (i.e. knowledge, ability, managerial skills, personality attributes and attitudes) with 187 components was designed. The model was validated through seeking the view of experts and a field test. For the field test, a survey was done on 31 ISSO hospital managers to explore their views on the structure of the model and its components. The managers were asked to score each component on a five- point Likert scale as they thought it would affect their job performance. RESULTS: The model with 5 dimensions and 165 components was verified in the field test, and 104 out of 165 components of this model got high, 52 medium and nine low mean scores for influencing job performance of the managers. These findings reveal that most of the components selected in this project are justified to be included in the model. It also reflects the managers' needs for any formal and informal training program in future. CONCLUSION: The needs of hospital managers at work go far beyond the knowledge and skills, which they have gained, via formal education in school. Therefore, in designing a training program for this group of professionals one should consider a multi-dimensional model in which "knowledge, ability, managerial skills, personality, and attitude dimensions" are all taken under consideration. PMID- 23343925 TI - Needlestick Injuries among Nurses. AB - BACKGROUND: Needlestick injuries (NSIs) are among the most important occupational injuries for health care workers (HCWs). In Iran, the problem of exposure to contaminated blood among nursing personnels has not well documented. The aim of this study was to determine the incidence of needlestick injuries in population of nurses in Shahroud Imam Hossein Hospital, northern Iran. METHODS: A self administrated questionnaire was completed by 180 nurses in September and October 2005 for their NSIs experience in the past year. In this study, needlestick injury was defined as percutaneous injury caused by hollow-borne needles, suturing needles, scalpel blades and lancets. RESULTS: The case incidence of NSIs was 63.3% (114/180). The total number of episodes of NSIs among respondents was 220 (range: 1-5 episodes) with incidence rate of episodes i.e. 1.2 per person/year. 12.8% of nurses had not been vaccinated against hepatitis B virus (HBV). The causal devices in 105 cases (92.1%) were hollow-borne needles and the main causes of percutaneous injuries with hollow-bore needles were recapping (32.4%) and manipulating needles in patients (18.1%). The majority (51.8%) of injuries occurred after use and before disposal of the objects. CONCLUSION: Nurses working in Imam Hossein Hospital are frequently exposed to blood-borne infection. NSIs were highly prevalent in these nurses therefore more intensive education programs should be directed at nurses to increase their awareness of and compliance with universal precautions (UP). We recommend a surveillance system and a center for managing injured persons. PMID- 23343926 TI - Association between Alcohol Consumption and Gastric Cancer: A Meta-Analysis. AB - BACKGROUND: Gastric cancer is the second most common cause of death from cancer. As conflicting studies have recently been published, we aimed to evaluate the magnitude of the epidemiological evidence for an association between alcohol consumption and gastric cancer. METHODS: This study is a meta-analysis of case control studies which have been performed during 1989 to 2007. We systematically reviewed the literature on the association between alcohol consumption and gastric cancer. Published case-control studies were identified in Pub Med and reference lists. Random effects meta-analysis was used to pool effects from twenty studies. RESULTS: The odds ratio (OR) for the overall association between alcohol and gastric cancer was 1.77 (95%CI: 1.46-2.15). The pooled OR for alcohol consumption related to gastric cancer for men was 2.17 (95%CI: 1.67-2.83). The odds ratio of beer or liquor was 1.16 which is not statistically related to gastric cancer risk (P> 0.05). Whereas, the odds ratio of vodka, wine and other types of alcohol intake related to gastric cancer were respectively 3.26, 1.69, and 1.77 (P< 0.01). CONCLUSION: Overall, based on the results of pooled analysis, it is reassuring that this meta-analysis shows a direct effect of alcohol associated with gastric cancer. Knowledge on the level of exposure to different alcohol constituents provides a deeper understanding of the real role of alcohol on cancer risk and ultimately allows the design of safer beverages. PMID- 23343927 TI - Chemically Modified Oligonucleotides Modulate an Epigenetically Varied and Transient Form of Transcription Silencing of HIV-1 in Human Cells. AB - Small noncoding RNAs (ncRNAs) have been shown to guide epigenetic silencing complexes to target loci in human cells. When targeted to gene promoters, these small RNAs can lead to long-term stable epigenetic silencing of gene transcription. To date, small RNAs have been shown to modulate transcriptional gene silencing (TGS) of human immunodeficiency virus type 1 (HIV-1) as well as several other disease-related genes, but it has remained unknown as to what extent particular chemistries can be used to generate single-stranded backbone modified oligonucleotides that are amenable to this form of gene targeting and regulation. Here, we present data indicating that specific combinations of backbone modifications can be used to generate single-stranded antisense oligonucleotides that can functionally direct TGS of HIV-1 in a manner that is however, independent of epigenetic changes at the target loci. Furthermore, this functionality appears contingent on the absence of a 5' phosphate in the oligonucleotide. These data suggest that chemically modified oligonucleotide based approaches could be implemented as a means to regulate gene transcription in an epigenetically independent manner. PMID- 23343928 TI - Deep Sequencing Analyses of DsiRNAs Reveal the Influence of 3' Terminal Overhangs on Dicing Polarity, Strand Selectivity, and RNA Editing of siRNAs. AB - 25/27 Base duplex RNAs that are substrates for Dicer have been demonstrated to enhance RNA interference (RNAi) potency and efficacy. Since the target sites are not always equally susceptible to suppression by small interfering RNA (siRNA), not all 27-mer duplexes that are processed into the corresponding conventional siRNAs show increased potency. Thus random designing of Dicer-substrate siRNAs (DsiRNAs) may generate siRNAs with poor RNAi due to unpredictable Dicer processing. Previous studies have demonstrated that the 3'-overhang affects dicing cleavage site and the orientation of Dicer entry. Moreover, an asymmetric 27-mer duplex having a 3' two-nucleotide overhang and 3'-DNA residues on the blunt end has been rationally designed to obtain greater efficacy. This asymmetric structure directs dicing to predictably yield a single primary cleavage product. In the present study, we analyzed the in vitro and intracellular dicing patterns of chemically synthesized duplex RNAs with different 3'-overhangs. Consistent with previous studies, we observed that Dicer preferentially processes these RNAs at a site 21-22 nucleotide (nt) from the two base 3'-overhangs. We also observed that the direction and ability of human Dicer to generate siRNAs can be partially or completely blocked by DNA residues at the 3'-termimi. To examine the effects of various 3'-end modifications on Dicer processing in cells, we employed Illumina Deep sequencing analyses to unravel the fates of the asymmetric 27-mer duplexes. To validate the strand selection process and knockdown capabilities we also conducted dual-luciferase psiCHECK reporter assays to monitor the RNAi potencies of both the "sense" (S) and "antisense" (AS) strands derived from these DsiRNAs. Consistent with our in vitro Dicer assays, the asymmetric duplexes were predictably processed into desired primary cleavage products of 21-22-mers in cells. We also observed the trimming of the 3' end, especially when DNA residues were incorporated into the overhangs and this trimming ultimately influenced the Dicer-cleavage site and RNAi potency. Moreover, the observation that the most efficacious strand was the most abundant revealed that the relative frequencies of each "S" or "AS" strand are highly correlated with the silencing activity and strand selectivity. Collectively, our data demonstrate that even though the only differences between a family of DsiRNAs was the 3' two-nuclotide overhang, dicing polarity and strand selectivity are distinct depending upon the sequence and chemical nature of this overhang. Thus, it is possible to predictably control dicing polarity and strand selectivity via simply changing the 3'-end overhangs without altering the original duplex sequence. These optimal design features of 3'-overhangs might provide a facile approach for rationally designing highly potent 25/27-mer DsiRNAs. PMID- 23343929 TI - DNA damage response pathway and replication fork stress during oligonucleotide directed gene editing. AB - Single-stranded DNA oligonucleotides (ODNs) can be used to direct the exchange of nucleotides in the genome of mammalian cells in a process known as gene editing. Once refined, gene editing should become a viable option for gene therapy and molecular medicine. Gene editing is regulated by a number of DNA recombination and repair pathways whose natural activities often lead to single- and double stranded DNA breaks. It has been previously shown that introduction of a phosphorotioated ODN, designed to direct a gene-editing event, into cells results in the activation of gammaH2AX, a well-recognized protein biomarker for double stranded DNA breakage. Using a single copy, integrated mutant enhanced green fluorescent protein (eGFP) gene as our target, we now demonstrate that several types of ODNs, capable of directing gene editing, also activate the DNA damage response and the post-translational modification of proliferating cell nuclear antigen (PCNA), a signature modification of replication stress. We find that the gene editing reaction itself leads to transient DNA breakage, perhaps through replication fork collapse. Unmodified specific ODNs elicit a lesser degree of replication stress than their chemically modified counterparts, but are also less active in gene editing. Modified phosphothioate oligonucleotides (PTOs) are detrimental irrespective of the DNA sequence. Such collateral damage may prove problematic for proliferation of human cells genetically modified by gene editing. PMID- 23343930 TI - Delivery of Quantum Dot-siRNA Nanoplexes in SK-N-SH Cells for BACE1 Gene Silencing and Intracellular Imaging. AB - The fluorescent quantum dots (QDs) delivered small interfering RNAs (siRNAs) targeting beta-secretase (BACE1) to achieve high transfection efficiency of siRNAs and reduction of beta-amyloid (Abeta) in nerve cells. The CdSe/ZnS QDs with the conjugation of amino-polyethylene glycol (PEG) were synthesized. Negatively charged siRNAs were electrostatically adsorbed to the surface of QDs to develop QD-PEG/siRNA nanoplexes. The QD-PEG/siRNAs nanoplexes significantly promote the transfection efficiency of siRNA, and the siRNAs from non-packaged nanoplexes were widely distributed in cell bodies and processes and efficiently silenced BACE1 gene, leading to the reduction of Abeta. The biodegradable PEG polymer coating could protect QDs from being exposed to the intracellular environment and restrained the release of toxic Cd2(+). Therefore, the QD PEG/siRNA nanoplexes reported here might serve as ideal carriers for siRNAs. We developed a novel method of siRNA delivery into nerve cells. We first reported that the QD-PEG/siRNA nanoplexes were generated by the electrostatic interaction and inhibited the Alzheimer's disease (AD)-associated BACE1 gene. We also first revealed the dynamics of QD-PEG/siRNAs within nerve cells via confocal microscopy and the ultrastructural evidences under transmission electron microscopy (TEM). This technology might hold promise for the treatment of neurodegenerative diseases such as AD. PMID- 23343931 TI - MMP expression in rheumatoid inflammation: the rs11568818 polymorphism is associated with MMP-7 expression at an extra-articular site. AB - Matrix metalloproteinases (MMPs) contribute to the joint damage in rheumatoid arthritis (RA). Less is known of the involvement of MMPs at extra-articular sites of rheumatoid inflammation. We assessed the relative contribution from MMP-1, MMP 3, MMP-7 and MMP-12 to joint and extra-articular tissue destruction and inflammation by comparing gene expression in joint synovia and subcutaneous rheumatoid nodules from RA patients. Expression of MMP-1 and MMP-3 predominated in synovia, whereas MMP-12 expression was significantly higher in rheumatoid nodules. Markedly higher MMP-7 expression distinguished a subgroup of nodules that featured infiltrating monocyte/macrophage-producing MMP-7 protein. The high MMP-7 expression in nodules was associated with the single-nucleotide polymorphism (SNP) rs11568818 (-181A>G, MMP-7 promoter) and more active inflammation within the nodule lesions. Patients with such nodules had significantly earlier age of RA onset. Our findings indicate that the expression of MMP-1 and MMP-3 occurs relatively independent of the tissue microenvironment with substantial expression also at extra-articular sites. MMP-12 expression reflects the involvement of monocyte/macrophages in rheumatoid inflammation. Evidence for the association between the rs11568818 SNP and increased MMP-7 expression is restricted to nodules, which indicates that consequences of the MMP 7 polymorphism are likely to manifest within aspects of immune/inflammatory activity that are monocyte/macrophage-mediated. PMID- 23343932 TI - Lack of nonspecific protection against all-cause nonrotavirus gastroenteritis by vaccination with orally administered rotavirus vaccine. AB - OBJECTIVES: Acute gastroenteritis (AGE) is recognized as a global, common threat to child survival, especially in developing countries. Rotavirus, in particular, has been implicated as a leading cause of severe AGE; however, there are numerous other pathogens that also cause AGE. Several studies have demonstrated that oral vaccination against rotavirus has generated the unanticipated benefit of protecting against AGE caused by nonrotavirus pathogens. METHODS: Safety and efficacy of the pentavalent bovine-human reassortant rotavirus vaccine were studied in multiple populations, including children of the Navajo and White Mountain Apache tribes in the southwestern United States. Stool specimens were collected from children with AGE and tested for rotavirus using an enzyme immunoassay. Analyses were conducted to detect the presence or absence of a vaccine effect on incidence, severity, and duration of AGE in which rotavirus was not detected. RESULTS: The majority of AGE (N = 558: 472 nonrotavirus vs 86 rotavirus) occurred between August 2002 and March 2004 among children ranging from ages 4 to 23 months. The incidence of nonrotavirus AGE was similar by vaccine groups with an incidence rate ratio of 1.07 (incidence rate ratio = vaccinated/unvaccinated, 95% confidence interval 0.89-1.29). The hazards of first, second, third, or any AGE in which rotavirus was not detected differed little by vaccination status (P > 0.05). Duration of symptoms and severity of nonrotavirus AGE were similar by vaccine group. CONCLUSIONS: There was no vaccine effect on frequency or severity of nonrotavirus AGE. PMID- 23343933 TI - Characterization of esophageal motility following esophageal atresia repair using high-resolution esophageal manometry. AB - BACKGROUND: Esophageal dysmotility, a considerable issue following esophageal atresia (EA) repair, has been reported but has not been precisely described and characterized. Using high-resolution esophageal manometry (HREM), we characterized the esophageal motility patterns in children with repaired EA and compared these patterns of dysmotility with symptomatology. METHODS: HREM was performed as an outpatient procedure in patients with repaired EA. The tracings were analyzed using the software provided by the company and were then reviewed visually. Charts were reviewed for medical/surgical histories and symptoms were assessed by a standardized questionnaire. RESULTS: Forty patients (25 boys, 15 girls) with a median age of 8 years (11 months-18 years) underwent an HREM. Thirty-five patients had type C EA and 5 had type A EA. Only 7 patients were asymptomatic at the time of the examination. HREM results were abnormal in all of the patients. Three different esophageal motility patterns were derived from HREM tracing analysis: aperistalsis (15 patients, 38%), pressurization (6 patients, 15%), and distal contractions (19 patients, 47%). Distal contractions pattern was found exclusively in type C EA. Dysphagia was encountered in the 3 groups. Gastroesophageal reflux disease-related symptoms predominated in the aperistalsis group. CONCLUSIONS: HREM improves our understanding and allows precise characterization of esophageal dysmotility in patients who have undergone EA repair. PMID- 23343934 TI - GLP-2 delays but does not prevent the onset of necrotizing enterocolitis in preterm pigs. AB - OBJECTIVES: Necrotizing enterocolitis (NEC) is complex disease thought to occur as a result of an immaturity of the gastrointestinal tract of preterm infants. Intestinal dysfunction induced by total parental nutrition (TPN) may increase the risk for NEC upon introduction of enteral feeding. We hypothesized that the intestinal trophic and anti-inflammatory actions previously ascribed to the gut hormone, glucagon-like peptide-2 (GLP-2), would reduce the incidence of NEC when given in combination with TPN in preterm piglets. METHODS: Preterm, newborn piglets were nourished by TPN and infused continuously with either human GLP-2 (100 MUg . kg-1 . day-1) or control saline for 2 days (n = 12/group). On day 3, TPN was discontinued and pigs were given orogastric formula feeding every 3 hours, and continued GLP-2 or control treatment until the onset of clinical signs of NEC for an additional 96 hours and tissue was collected for molecular and histological endpoints. RESULTS: GLP-2 treatment delayed the onset of NEC but was unable to prevent a high NEC incidence (~70%) and severity that occurred in both groups. GLP-2-treated pigs had less histological injury and increased proximal intestinal weight and mucosal villus height, but not crypt depth or Ki-67 positive cells. Inflammatory markers of intestinal myeloperoxidase were unchanged and serum amyloid A levels were higher in GLP-2-treated pigs. CONCLUSIONS: GLP-2 did not prevent NEC and a proinflammatory response despite some reduction in mucosal injury and increased trophic effect. PMID- 23343935 TI - Calcium ameliorates diarrhea in immunocompromised children. AB - Treatment of infectious diarrheas remains a challenge, particularly in immunocompromised patients in whom infections usually persist and resultant diarrhea is often severe and protracted. Children with infectious diarrhea who become dehydrated are normally treated with oral or intravenous rehydration therapy. Although rehydration therapy can replace the loss of fluid, it does not ameliorate diarrhea. Thus, during the last decades, there has been continuous effort to search for ways to safely stop diarrhea. Herein, we report 3 immunocompromised children who developed severe and/or protracted infectious diarrhea. Their diarrheas were successfully "halted" within 1 to 2 days following the administration of calcium. PMID- 23343936 TI - Intussusception associated with adenovirus. PMID- 23343937 TI - Near-infrared spectroscopy measurements of splanchnic tissue oxygenation during continuous versus intermittent feeding method in preterm infants. AB - OBJECTIVES: The aim of the present study was to compare the effects of continuous and intermittent bolus milk feeding on splanchnic regional oxygenation (rSO2S) in small-for-gestational age (SGA) and appropriate-for-gestational age (AGA) preterm infants. METHODS: Infants with gestational age <32 weeks were prospectively studied by near-infrared spectroscopy. Each infant was given a milk bolus in ~10 minutes (intermittent feeding) followed after 3 hours by a 3-hour continuous feeding. rO2S and splanchnic fractional oxygen extraction ratio (FOES [S = splanchnic]) were recorded 30 minutes before (T0) and 30 minutes after the beginning of bolus feeding (T1), 30 minutes before (T2), at the end (T3), and 30 minutes after the continuous feeding period (T4). RESULTS: rSO2S increased at T1 in both AGA and SGA groups, whereas FOES did not vary during the study period. Moreover, we found that rSO2S was higher and FOES was lower at T1 and T3 in the AGA than in the SGA group. CONCLUSIONS: Bolus milk feeding increases splanchnic oxygenation in both AGA and SGA infants, whereas continuous feeding does not. Splanchnic oxygenation is higher in AGA than in SGA infants both during bolus and continuous feeding. Continuous enteral feeding could help to limit the risk of hypoxic-ischemic gut damage in preterm infants in critical condition, especially in AGA infants. PMID- 23343938 TI - Lithophagia in iron-deficient patient with celiac disease. PMID- 23343939 TI - Intact choledochal cyst with spontaneous common hepatic duct perforation: a spectrum of congenital biliary canal defects? PMID- 23343940 TI - Autologous intestinal reconstructive surgery to reduce bowel dilatation improves intestinal adaptation in children with short bowel syndrome. AB - OBJECTIVES: Intestinal failure (IF) is a common consequence of neonatal small bowel pathology. In our experience, bowel dilatation is often responsible for the IF state in patients who fail to adapt despite adequate residual bowel length. The aim of the present study was to investigate the role of surgery to reduce bowel dilatation, and thus favour PN independence, for these children. METHODS: Data were collected prospectively for all of the patients referred to our unit for a 7-year period (2004-2011). Eight patients (2 congenital atresia, 2 gastroschisis with atresia, 1 simple gastroschisis, 3 necrotising enterocolitis) with gut dilatation who failed adaptation despite a bowel length >40 cm were identified. Preoperatively, all patients were totally dependent on parenteral nutrition (PN). Patients were managed by longitudinal intestinal lengthening and tailoring (n = 3), serial transverse enteroplasty (n = 2), or tapering enteroplasty (n = 3). RESULTS: Median age at time of surgery was 273 days (103 1059). Mean gut length increased from 51 (35-75) to 73 cm (45-120) following surgery (P = 0.02). Incidence of sepsis (P = 0.01) and peak serum bilirubin levels (P = 0.005) were reduced postoperatively. PN was discontinued after a median of 110 days (35-537) for 7 patients; 1 patient remains on PN 497 days after surgery. CONCLUSIONS: These data indicate that reconstructive surgery to reduce bowel diameter may be an effective technique for treating IF in patients with short bowel syndrome, without sacrificing intestinal length. We suggest that this technique may reduce the need for bowel transplantation in this group of patients. PMID- 23343942 TI - The diagnosis of the burden and distribution of undernutrition in the global context is clear, although the solutions may not be intuitively clear. PMID- 23343943 TI - Global burden of maternal and child undernutrition and micronutrient deficiencies. AB - Maternal and child undernutrition and micronutrient deficiencies affect approximately half of the world's population. These conditions include intrauterine growth restriction (IUGR), low birth weight, protein-energy malnutrition, chronic energy deficit of women, and micronutrient deficiencies. Although the rates of stunting or chronic protein-energy malnutrition are increasing in Africa, the absolute numbers of stunted children are much higher in Asia. The four common micronutrient deficiencies include those of iron, iodine, vitamin A, and zinc. All these conditions are responsible directly or indirectly for more than 50% of all under-5 deaths globally. According to more recent estimates, IUGR, stunting and severe wasting are responsible for one third of under-5 mortality. About 12% of deaths among under-5 children are attributed to the deficiency of the four common micronutrients. Despite tremendous progress in different disciplines and unprecedented improvement with many health indicators, persistently high undernutrition rates are a shame to the society. Human development is not possible without taking care to control undernutrition and micronutrient deficiencies. Poverty, food insecurity, ignorance, lack of appropriate infant and young child feeding practices, heavy burden of infectious illnesses, and poor hygiene and sanitation are factors responsible for the high levels of maternal and child undernutrition in developing countries. These factors can be controlled or removed by scaling up direct nutrition interventions and eliminating the root conditions including female illiteracy, lack of livelihoods, lack of women's empowerment, and poor hygiene and sanitation. PMID- 23343944 TI - Global nutrition epidemiology and trends. AB - In the year 2011, 6.9 million children under the age of 5 years died worldwide, one third of them related to increased susceptibility to illnesses due to undernutrition. An estimated 178 million children under 5 years are stunted, 55 million are wasted, and 19 million of these are severely affected and are at a higher risk of premature death, the vast majority being from sub-Saharan Africa and South-Central Asia. Globally, over 2 billion people are at risk for vitamin A, iodine, and/or iron deficiency. Other micronutrient deficiencies of public health concern include zinc, folate, and the B vitamins. The risk factors for undernutrition include low birth weight, inadequate breastfeeding, improper complementary feeding, and recurrent infections. Infectious diseases often coexist with micronutrient deficiencies and exhibit complex interactions leading to the vicious cycle of malnutrition and infections. Diarrhea along with the poor selection and intake of complementary food are the major contributors to undernutrition. Possible strategies to combat malnutrition include promotion of breastfeeding, dietary supplementation of micronutrients, prevention of protein energy malnutrition, and improvement in the standard of preparation and hygiene of available weaning foods. The universal coverage with the full package of these proven interventions at observed levels of program effectiveness could prevent about one quarter of child deaths under 36 months of age and reduce the prevalence of stunting at 36 months by about one third. The median coverage rate of interventions along the continuum of care for Countdown countries has however been >=80% for vaccination and vitamin A supplementation. However, for several interventions, including early initiation and exclusive breastfeeding below 6 months of age and case management of childhood illnesses, the median coverage rate hovers at or below 50%. This suggests that interventions requiring strong health systems or behavior change appear to be stalled and need to be re-examined to find more effective ways of delivery. PMID- 23343945 TI - Global dietary patterns and diets in childhood: implications for health outcomes. AB - This article provides an overview of child feeding recommendations and how these relate to actual practice and dietary adequacy, primarily in developing countries. From birth to 6 months, recommendations focus on optimal breastfeeding practices, although these are still suboptimal in about one third of infants in developing countries. From 6 months of age, breast milk can no longer meet all the nutrient requirements of the child, so from 6 months through at least 24 months, the recommendation is to continue breastfeeding but gradually introduce complementary foods. In poorer populations, the available foods for complementary feeding are primarily cereals and legumes, to which small amounts of fruits and vegetables are added, and even less animal source foods. Based on intake data from infants and preschoolers, it is evident that usual diets typically fall far short of supplying micronutrient needs. By adding more fruits, vegetables, and animal source foods the diet can be improved. Intervention studies show that increasing animal source food intake improves growth, muscle mass, and cognitive function of school children. Milk and dairy product intakes are correlated with greater child growth in many studies, even in industrialized countries. However, for many families, substantially improving children's diets by providing higher quality foods is often financially unrealistic. Newer approaches to home fortification of children's foods using micronutrient powders or lipid-based nutrient supplements hold great potential to prevent micronutrient deficiencies at reasonable cost, thus preventing the adverse consequences of these deficiencies for child development. PMID- 23343946 TI - Interaction of nutrition and infections globally: an overview. AB - The interaction of nutrition and infections is known by experience by generations of medical doctors. Before the era of antibiotics, diet was an integral part of the management of infections. Now, it is necessary to take a fresh look at this interaction as the understanding of immune response has expanded considerably. Comparatively little research has addressed the impact of nutrition interventions on the management of infectious diseases. Most observations of the interaction between nutrition and infections are epidemiological in character. This holds especially true for measles as well as for tuberculosis. In AIDS, the deterioration of the nutritional status is an indicator of disease progression. Infections in undernourished children are a common cause of death, and taking this finding into account helps to reduce the case fatality rate in severely malnourished patients. Regarding the immune response, cellular as well as soluble components are affected by deficiencies of single nutrients or general undernutrition. The immunosuppressive effect of undernutrition starts during intrauterine life already: maternal nutrition status has been shown to impact on immune function in adult animals. Recent research suggests that not only undernutrition but also caloric overnutrition impacts on immune response to infections and immunization. This is partly due to the chronic inflammatory activity of the adipose tissue and partly due to neuroendocrine alterations. Infectious diseases also impact on the nutritional status, either specifically or through unspecific mechanisms, such as anorexia, tachypnea, and vomiting. PMID- 23343947 TI - Fusarium keratitis: genotyping, in vitro susceptibility and clinical outcomes. AB - PURPOSE: To determine differences in the clinical characteristics and antifungal susceptibility patterns among molecularly characterized ocular Fusarium sp isolates. METHODS: Fifty-eight isolates of Fusarium sp obtained from 52 eyes of 52 patients were retrieved from the Ocular Microbiology Laboratory of the Bascom Palmer Eye Institute and grown in pure culture. These isolates were characterized based on DNA sequence analysis of the ITS1/2 and ribosomal deoxyribonucleic acid regions. Antifungal susceptibilities were determined for each isolate using broth microdilution methods, and the corresponding medical records were reviewed to determine the clinical outcomes. RESULTS: Fusarium solani isolates had significantly higher values of minimum inhibitory concentration for 90% isolates (MIC90) with voriconazole than F. non-solani organisms (16 and 4 MUg/mL, respectively). Isolates of F. solani also exhibited a significantly longer time to cure (65 vs. 40.5 days), a worse follow-up best-corrected visual acuity (20/118 vs. 20/36), and an increased need for urgent surgical management (7 vs. 0 penetrating keratoplasties) when compared with those of F. non-solani. CONCLUSIONS: This is the first report to examine the correlation between ocular genotyped Fusarium sp and clinical outcomes. It supports the overall worse prognosis of F. solani versus F. non-solani isolates, including higher voriconazole resistance by the former. The clinical implementation of molecular based diagnostics and antifungal efficacy testing may yield important prognostic and therapeutic information that could improve the management of fungal ocular infections. PMID- 23343948 TI - Acidic/neutral amino acid residues substitution in NH2 terminal of plasminogen kringle 5 exerts enhanced effects on corneal neovascularization. AB - PURPOSE: Recent results showed that plasminogen kringle 5 (K5) has improved inhibitory effect on human umbilical vein endothelial cells (HUVECs) viability when 5 acidic amino acids in NH2 terminal outside kringle domain were replaced by 5 serine residues (mutant K5, mK5). This study was designed to identify the enhanced antiangiogenic activity of mK5 in corneal neovascularization (CNV). METHODS: Alkali burn-induced CNV was induced and treated with K5 and mK5 for 11 days. CNV and inflammation were evaluated by the CNV area and the inflammatory index, respectively. At the end of treatment, the corneas were removed for terminal deoxynucleotidyl transferase dUTP nick end labeling detection and immunohistochemistry. The effects of mK5 and K5 on HUVECs apoptosis were tested by MTT, BrdU, and flow cytometry. The expression levels of pigment epithelium derived factor (PEDF) and vascular endothelial growth factor (VEGF) were detected by Western blot. RESULTS: In a rat model of CNV induced by alkali, topical treatment with mK5 significantly decreased the neovascular area and inflammation compared with the wild-type K5-treated group. Meanwhile, mK5 and K5 specifically inhibited the HUVECs proliferation and induced vascular endothelial cell apoptosis in vitro and in vivo, and mK5 exerted higher apoptosis induction. Toward the mechanism of action, both mK5 and K5 significantly upregulated the expression of PEDF and mildly downregulated the expression of VEGF. The elevation of PEDF/VEGF ratio induced by mK5 was higher than that by K5. CONCLUSIONS: These findings suggest that mK5 has more effective therapeutic potential in CNV than wild-type K5. PMID- 23343950 TI - Descemet membrane endothelial keratoplasty: why does the donor tissue roll? PMID- 23343949 TI - Corneal thickness as a predictor of corneal transplant outcome. AB - PURPOSE: To assess corneal thickness (CT) and correlation with graft outcome after penetrating keratoplasty in the Cornea Donor Study. METHODS: A total of 887 subjects with a corneal transplant for a moderate-risk condition (principally Fuchs dystrophy or pseudophakic corneal edema) had postoperative CT measurements throughout a 5-year follow-up time. Relationships between baseline (recipient, donor, and operative) factors and CT were explored. Proportional hazards models were used to assess the association between CT and graft failure. Relationship between CT and cell density was assessed with a longitudinal repeated measures model and Spearman correlation estimates. RESULTS: Higher longitudinal CT measurements were associated with the following: diagnosis of pseudophakic or aphakic corneal edema (P < 0.001), intraocular pressure >25 mm Hg during the first postoperative month (P = 0.003), white (non-Hispanic) donor race (P = 0.002), and respiratory causes of donor death (P < 0.001). Among those without graft failure within the first postoperative year, the 5-year cumulative incidence (+/- 95% confidence interval) of graft failure was 5% +/- 5% in those with a 1-year CT <= 500 MUm, 5% +/- 3% for CT 501 to 550 MUm, 7% +/- 4% for CT 551 to 600 MUm, and 20% +/- 11% for CT >600 MUm. In a multivariate analysis, both 1-year CT and cell density were associated with subsequent graft failure (P = 0.002 and 0.009). CT increase was modestly associated with endothelial cell loss during follow-up (r = -0.29). CONCLUSIONS: During the first 5 years after penetrating keratoplasty, CT can serve as a predictor of graft survival. However, CT is not a substitute for cell density measurement because both measures were independently predictive of graft failure. PMID- 23343951 TI - Pterygium extended removal followed by extended conjunctival transplant: but on which eye? AB - PURPOSE: To assess the cosmetic result after pterygium extended removal followed by extended conjunctival transplant. METHODS: A web-based program was used by graders to select from a series of pairs of photographic images which eye of each pair had had pterygium surgery and which eye had the better appearance. A total of 395 pairs of eyes in which 1 eye had had pterygium surgery with the opposite eye acting as the control were assessed. Graders were asked the question "which eye has had surgery?" in sections 1 and 2, and then asked which "was the better looking eye?" for each pair, first at real-life size and then with magnified images in sections 3 and 4. Analysis was undertaken on the correlation of the selection of the eye that was thought to have had surgery with the eye that had actually had the surgery, and correlation between the eyes selected for the better appearance with the eyes that had had surgery. RESULTS: Thirteen graders completed the study and most graders correctly selected the operative eye in fewer than 50% of the pairs of eyes in sections 1 and 2. In addition, the operated eye was selected as the "better looking eye" in almost 40% of the pairs of eyes in sections 3 and 4. CONCLUSIONS: Pterygium extended removal followed by extended conjunctival transplant results in an appearance that is indistinguishable from a normal eye. PMID- 23343952 TI - Prognostic value of microvessel density and p53 expression on the locoregional metastasis and survival of the patients with head and neck squamous cell carcinoma. AB - Cancer cells need to develop microvessels in order to grow and to establish metastatic foci. A role for the p53 protein in the regulation of the angiogenic process is suggested. This study aimed to investigate the relationship between immunohistochemical expression of microvessel density (MVD), measured by CD31 staining, and p53 protein with clinicopathologic factors, and survival in head and neck squamous cell carcinoma (n=70). Tumor angiogenesis was estimated by determining MVD in areas with the highest number of stained microvessels (hot spots). Clinicopathologic factors and immunohistochemical data were evaluated by chi statistical test and were submitted to binary logistic regression to analyze the risk of presence of lymph node metastasis. Factors that might predict survival were investigated using Cox proportional hazards tests. Differences were considered statistically significant when P<0.05. The percentage of p53-positive cells showed no association with clinicopathologic parameters and MVD. Patients with locoregional metastasis presented statistically significant higher MVD (P=0.043). Individuals presenting head and neck squamous cell carcinoma in posterior sites (P=0.022; OR=3.644) and higher MVD (P=0.039; OR=3.247) had a significant increase in risk of metastasis occurrence. Multivariate analysis showed that presence of lymph node metastasis was statistically significant for overall survival of head and neck carcinoma patients (P=0.006; OR =2.917). The present data suggest that MVD represents a promising diagnostic tool to identify individuals with increased risk for the development of metastatic disease, which is very indicative of poor prognosis. PMID- 23343953 TI - Identification and characterization of 2 testicular germ cell markers, Glut3 and CyclinA2. AB - Testicular germ cell tumors (TGCT) are the most common type of testicular tumor and encompass different histologic types that greatly influence treatment and prognosis. Immunohistochemical studies may be required for accurate classification, particularly when these tumors present at extragonadal sites, and to aid in distinguishing histologic types. Traditional markers for identifying and distinguishing TGCT include PLAP, CD117, AFP, and CD30. More recently, the addition of OCT3/4 and SALL4 has increased sensitivity for immunohistochemical detection of germ cell tumors. We examined gene expression data from a previously published microarray study that compared normal testis mRNA expression to various TGCT. We also performed a search of the literature to identify less well characterized markers. Glut3 and cyclinA2 showed promise as TGCT markers. Therefore, we evaluated expression of glut3 and cyclinA2 by immunohistochemistry using tissue microarrays (TMAs). Of 66 seminomas included in the TMA, 64 (97%) showed positive nuclear staining for cyclinA2 and 58 (88%) were strongly positive. Strong positive staining for cyclinA2 was also seen in the spermatocytic seminoma. All 20 of the embryonal carcinomas stained positively with cyclinA2, and 19 (95%) displayed strong nuclear staining for cyclinA2. Twenty of the 20 embryonal carcinomas stained for glut3 in a strong membranous pattern. Of 8 yolk sac tumors, 100% stained with glut3. We also evaluated glut3 and cyclinA2 staining on a general TMA containing 486 samples representing 156 different tumors. CyclinA2 stained a number of other tumor types, but the majority of these were weak or focal staining. Glut3 was rarely positive in other tumors; interestingly, most of these were of ovarian origin. We conclude that glut3 is a sensitive (96%) and specific (92%) marker for embryonal carcinomas and yolk sac tumors. Although cyclinA2 is a sensitive marker of seminomas and embryonal carcinomas (98%), its specificity is lower if focal and weak staining of nongerm cell tumors is considered positive. The sensitivity and specificity of glut3 are comparable with that seen for SALL4. PMID- 23343954 TI - A comparative study of 2 computer-assisted methods of quantifying brightfield microscopy images. AB - Immunohistochemistry continues to be a powerful tool for the detection of antigens. There are several commercially available software packages that allow image analysis; however, these can be complex, require relatively high level of computer skills, and can be expensive. We compared 2 commonly available software packages, Adobe Photoshop CS6 and ImageJ, in their ability to quantify percentage positive area after picrosirius red (PSR) staining and 3,3'-diaminobenzidine (DAB) staining. On analysis of DAB-stained B cells in the mouse spleen, with a biotinylated primary rat anti-mouse-B220 antibody, there was no significant difference on converting images from brightfield microscopy to binary images to measure black and white pixels using ImageJ compared with measuring a range of brown pixels with Photoshop (Student t test, P=0.243, correlation r=0.985). When analyzing mouse kidney allografts stained with PSR, Photoshop achieved a greater interquartile range while maintaining a lower 10th percentile value compared with analysis with ImageJ. A lower 10% percentile reflects that Photoshop analysis is better at analyzing tissues with low levels of positive pixels; particularly relevant for control tissues or negative controls, whereas after ImageJ analysis the same images would result in spuriously high levels of positivity. Furthermore comparing the 2 methods by Bland-Altman plot revealed that these 2 methodologies did not agree when measuring images with a higher percentage of positive staining and correlation was poor (r=0.804). We conclude that for computer-assisted analysis of images of DAB-stained tissue there is no difference between using Photoshop or ImageJ. However, for analysis of color images where differentiation into a binary pattern is not easy, such as with PSR, Photoshop is superior at identifying higher levels of positivity while maintaining differentiation of low levels of positive staining. PMID- 23343955 TI - Expression of cytokeratin subtypes: MMP-9, p53, and alphaSMA to differentiate basaloid squamous cell carcinoma from other basaloid tumors of the oral cavity. AB - Basaloid squamous cell carcinoma (BSCC) is rare variant of oral squamous cell carcinoma (OSCC) with predilection for upper aerodigestive tract. Although it is characterized by distinct histologic features it is often confused with conventional OSCC and other basaloid tumors. The study aims to establish differentiating features of BSCC with oral basaloid tumors using immunohistochemical (IHC) markers. This retrospective study included 34 cases, including BSCC, OSCC, and basaloid tumors. IHC staining was performed with primary antibodies against cytokeratin (CK) 19, 14, 8/18, alpha-smooth muscle actin (alphaSMA), p53, and MMP-9. A prominent CK 19, 14, and 8/18 expression was observed in BSCC as compared with basaloid tumors suggesting of basal cell origin with undifferentiated type of tumor cells. Expression of alphaSMA was intense in tumor cells of myoepithelial differentiation but lacked in BSCC. The intense expression of p53 and MMP-9 was noted in all basaloid malignancies. Considering standard histologic criteria in diagnosing BSCC, when in confusion with other basaloid tumors, IHC markers gain importance. Hence, enhanced expression of CK 19, 8/18, and 14 and coexistence of p53 and MMP-9 expression and negativity for alphaSMA suggest an accurate diagnosis of BSCC. PMID- 23343956 TI - No evidence for BRAF-V600E mutations in gastroeosophageal tumors: results from a high-throughput analysis of 534 cases using a mutation-specific antibody. AB - BACKGROUND: BRAF-V600E mutations are found in a broad spectrum of cancer types and can be successfully targeted by specific therapeutic compounds. Little data on the prevalence of BRAF-V600E mutations in tumors of the upper gastrointestinal tract are available. MATERIALS AND METHODS: We constructed tissue microarrays of formalin-fixed and paraffin-embedded specimens of 534 gastroesophageal tumors (119 squamous cell cancers and 72 adenocarcinomas of the esophagus, 63 cancers of the gastroesophageal junction/cardia, 199 gastric cancers of the corpus or antrum, 81 gastric gastrointestinal stromal tumors) and performed anti-BRAF-V600E immunostaining using the mutation-specific antibody VE1. As control tissue we used 3 melanoma cases with confirmed BRAF-V600E mutation and distinct VE1 immunostaining. RESULTS: None of the gastroesophageal tumor cases showed a positive immunostaining signal. CONCLUSIONS: BRAF-V600E mutation is not a relevant oncogenic driver in gastroesophageal tumors. Immunohistochemical analysis using mutation-specific antibodies on tissue microarrays is a feasible, time-efficient and cost-efficient approach to high-throughput screening for specific mutations in large tumor series. PMID- 23343957 TI - Major histocompatibility complex class I and II expression in idiopathic inflammatory myopathy. AB - INTRODUCTION: We sought to study the intensity and pattern of major histocompatibility complex (MHC) I and II expression in muscle from patients with biopsy-proven idiopathic inflammatory myositis (IIM) including the subgroups, polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). METHODS: A total of 120 muscle biopsies (61 PM, 14 DM, and 45 IBM) were immunostained for MHC I and II. Staining was graded as follows. 0: no staining, 1+: <=10% fibers, 2+: 10% to 25%, 3+: 25% to 50%, 4+: 50% to 99%, and 5+ 100%. RESULTS: All IIM biopsies showed MHC I positivity; 93% showed MHC II positivity. The proportion of patients with MHC II score >=3+ was higher in IBM than DM or PM. In DM, MHC I expression showed a perifascicular pattern. All IBM biopsies were immunopositive for MHC I and II; 30/45 were scored 5+. DISCUSSION: Immunostaining for MHC I and II is a useful adjunctive test in diagnosis and subclassification of IIM. PMID- 23343958 TI - Expression of SHP2 and related markers in non-small cell lung cancer: a tissue microarray study of 80 cases. AB - The purpose of this study was to assess the relationships between the expression of SHP2 and VEGF, VEGFR-1, VEGFR-2, MMP-2, MMP-9, TIMP-1, TIMP-2, and microvessel density (MVD), as well as the clinicopathologic parameters of these markers in non-small cell lung cancer (NSCLC). Using a tissue microarray, the expression of these 8 markers in 80 NSCLC cases was detected by immunohistochemistry. The expression of the markers was higher in cancer tissues when compared with the surrounding tissues. The MVD was lower in the CD34-positive cancer tissues than in the surrounding tissues. Significantly higher positive rates of expression for SHP2, MMP-9, and MMP-2 were observed in patients with lymph node metastases. The later the clinical stage was, the higher the expression of MMP-9 and MMP-2. The expression of VEGF in patients with lung squamous cell carcinomas was significantly higher than in patients with lung adenocarcinomas. The positive expression of SHP2 correlated significantly with that of VEGFR-2 and the MVD and a survival disadvantage was noted in the patients with SHP2-positive tumors. Therefore, our data suggest that the expression of SHP2 in NSCLC has high specificity and sensitivity and is closely related to lymph node metastasis and the expression of VEGFR-2 and the MVD in patients with NSCLC. SHP2 expression may promote the invasion and metastasis of NSCLC through angiogenesis and the lymphatic system. PMID- 23343959 TI - Expression and prognostic significance of livin, caspase-3, and ki-67 in the progression of human ampullary carcinoma. AB - Livin is a new member of the inhibitor of apoptosis proteins family of proteins that interacts with downstream caspases, such as caspase-3, caspase-7, and caspase-9, however, its role in human ampullary carcinoma has not been clearly defined. Immunohistochemistry was used to evaluate tissue samples from patients with ampullary carcinomas (n=71) using antibodies against livin, Ki-67 (a proliferation marker), and caspase-3. Livin was detected in 33/71 cases (in the cytoplasm of all and in the nucleus of only 2 cases). High livin expression correlated with cell differentiation, tumor-node-metastasis stage, and lymph node metastasis (P=0.001, P<0.001, and P=0.028, respectively). Caspase-3 and Ki-67 expression were significantly associated with differentiation (P<0.001, P=0.008, respectively). There was a significant negative correlation between livin and caspase-3 (r=-0.575, P<0.001), and a positive correlation between livin and Ki-67 (r=0.308, P=0.009). Survival of patients with high livin expression was shorter compared with that of patients with low livin expression (P=0.001). Expression of caspase-3 was not associated with overall survival in this cohort (P=0.335). Livin expression was an independent prognostic factor (hazard ratio 2.693, P=0.017), as was lymph node metastasis (hazard ratio 4.959; P<0.001). In this study livin expression significantly correlated with the proliferation marker Ki 67, but was negatively correlated with caspase-3 expression. These data suggest that livin may be a valuable prognostic factor for human ampullary carcinoma. PMID- 23343960 TI - Lead-position dependent regular oscillations and random fluctuations of conductance in graphene quantum dots. AB - Quantum interference causes a wavefunction to have sensitive spatial dependence, and this has a significant effect on quantum transport. For example, in a quantum dot system, the conductance can depend on the lead positions. We investigate, for graphene quantum dots, the conductance variations with the lead positions. Since for graphene the types of boundaries, e.g., zigzag and armchair, can fundamentally affect the quantum transport characteristics, we focus on rectangular graphene quantum dots, for which the effects of boundaries can be systematically studied. For both zigzag and armchair horizontal boundaries, we find that changing the positions of the leads can induce significant conductance variations. Depending on the Fermi energy, the variations can be either regular oscillations or random conductance fluctuations. We develop a physical theory to elucidate the origin of the conductance oscillation/fluctuation patterns. In particular, quantum interference leads to standing-wave-like-patterns in the quantum dot which, in the absence of leads, are regulated by the energy-band structure of the corresponding vertical graphene ribbon. The observed 'coexistence' of regular oscillations and random fluctuations in the conductance can be exploited for the development of graphene-based nanodevices. PMID- 23343962 TI - Impact of inflammation-metaplasia-adenocarcinoma sequence and prevention in surgical rat models. AB - The incidence of esophageal cancer continues to rise in the Western world. Prior studies have suggested that gastroduodenal content reflux from gastroesophageal reflux disease induces the inflammation-mediated progression from hyperplasia to metaplasia, and to adenocarcinoma. We further investigated the sequential development of esophageal adenocarcinoma (EADC) with the use of an established surgical rat model. The present paper will describe the impact of the inflammation-metaplasia-adenocarcinoma sequence and chemoprevention in surgical rat models. A clinically relevant rat reflux model was used to investigate the cause of carcinogenesis, the sequential development of adenocarcinoma and chemoprevention with the use of a proton pump inhibitor. We found that duodenal reflux plays an important role in the inflammation-induced transformation of esophageal mucosa to adenocarcinoma. We were able to inhibit this transformation with rabeprazole, a proton pump inhibitor. Duodenal reflux promotes inflammation in the esophagus. The inflammation-metaplasia-adenocarcinoma sequence is important in the progression and development of EADC. Carcinogenesis can be prevented with chemoprevention agents such as rabeprazole. These results will need to be validated in clinical trials. PMID- 23343963 TI - Cyclooxygenase, cancer stem cells and DNA methylation play important roles in colorectal carcinogenesis. AB - Many effective anticancer therapies against colorectal cancer have been developed, but chemoresistance and recurrence are still inevitable problems and their counter measures are urgently needed. Recently, cancer stem cells have been indicated to play a pivotal role in chemoresistance and recurrence and have gained attention as a novel target. On the other hand, both aberrant hyper- and hypomethylation have been shown to be involved in carcinogenesis and the simultaneous amendment is indispensable. Cyclooxygenase-2 (COX-2) has already been reported to play an important role in carcinogenesis. Our latest study indicates that COX-2 inhibitors remedy aberrant methylation and beat cancer stemness, suggesting that COX-2 inhibitors hold great promise for cancer prevention and therapy. PMID- 23343964 TI - Usefulness of transnasal argon plasma coagulation for esophageal varices compared with the peroral method: a randomized and prospective clinical study. AB - BACKGROUND: Argon plasma coagulation (APC) is very useful as a consolidation treatment for reducing the recurrence of esophageal varices (EVs). However, repeated sedation in endoscopic treatment has the risk of prolonging hepatic encephalopathy and affects the respiratory state of liver cirrhosis (LC) patients, in whom pulmonary arteriovenous shunts are observed. We evaluated prospectively whether transnasal endoscopic APC without sedation is more effective than peroral endoscopic APC with sedation. PATIENTS AND METHODS: LC patients (n = 101), treated by endoscopic injection sclerotherapy to eradicate EVs, were randomly divided into a transnasal APC group (n = 50) and a peroral APC group (n = 51). The primary efficacy endpoint was the cumulative recurrence rate of EVs. The secondary endpoints were blood pressure (BP), heart rate, oxygen saturation during APC and complications. RESULTS: There was no significant difference in the cumulative recurrence rate of EVs at 36 months between the transnasal APC and peroral APC groups (35.0 vs. 40.8%, p = 0.39, log-rank test), indicating that transnasal APC is not inferior to peroral APC. The transnasal APC group showed more stable intraoperative BP and oxygen saturation values, and a lower incidence of epigastralgia (56.0 vs. 74.5%, p = 0.04). CONCLUSION: The efficacy of reducing the recurrence of EVs in the transnasal APC group was not significantly different from that in the peroral APC group. Transnasal APC caused less distress and required no sedation. Therefore, this method was more advantageous for LC patients at risk of suffering from prolongation of hepatic encephalopathy. PMID- 23343965 TI - Predictive factors associated with the success of pneumatic dilatation in Japanese patients with primary achalasia: a study using high-resolution manometry. AB - BACKGROUND/AIMS: A new classification of achalasia using high-resolution manometry (HRM) has recently been suggested. Pneumatic dilatation (PD) is a common treatment for primary achalasia. The usefulness of the new classification and HRM for the treatment and follow-up of patients after PD is unknown. The aim of this study was to evaluate the PD effectiveness and the predictive factors of success in Japanese patients with achalasia using HRM and the new classification of achalasia. METHODS: Twenty-five patients were diagnosed with primary achalasia using HRM and treated by PD in our hospital. We evaluated symptom scores and esophageal manometry 6 and 12 months after the first PD. RESULTS: After the first PD treatment, remission occurred in 24 out of 25 (96.0%) patients at 6 months and in 19 out of 25 (76.0%) patients at 12 months. With the new classification of achalasia, the success rates were 83.3, 80.0 and 50% for types I, II and III, respectively, 12 months after PD. The median age of the successful group was significantly greater than that of the failure group (47.1 vs. 37.0 years, p < 0.05). The median residual lower esophageal sphincter (LES) pressure 6 months after PD in the successful group was significantly lower than that of the failure group (9.0 vs. 15.5 mm Hg, p < 0.05). CONCLUSION: Good predictors of PD success were old age (>40 years) and residual LES pressures less than 15 mm Hg 6 months after PD. PMID- 23343966 TI - Comparison of the clinicopathological characteristics and results of endoscopic submucosal dissection for esophagogastric junction and non-junctional cancers. AB - BACKGROUND: Esophagogastric junction (EGJ) cancers are not only located in regions anatomically difficult for endoscopic submucosal dissection (ESD), but they also have higher clinicopathological malignant potential than non-junctional gastric cancers (NJC). Despite this, no ESD-based comparative studies of junctional cancer (JC) and NJC have been conducted to date. The aims of this study were to clarify the clinicopathological characteristics of EGJ cancers and the short- and long-term outcomes after ESD. METHODS: Between April 2005 and December 2010, ESD was performed on 1,463 lesions that were divided into the following three groups: Barrett's adenocarcinoma (BA; n = 25); JC (n = 103), and NJC (n = 1,335). They were assessed for short-term outcomes, clinicopathological malignancy and long-term outcomes. RESULTS: Rates of complete and curative resection were significantly lower for BA than for JC and NJC (64.0 vs. 96.1 and 96.0%; and 48.0 vs. 80.6 and 85.8%, respectively). The perforation rate was significantly higher for BA than for JC and NJC (20.0 vs. 2.9 and 2.7%). Clinicopathologically, submucosal invasion rates were higher in BA and JC than in NJC (32.0 and 30.1 vs. 13.6%), and positive rates of lymphatic and/or vascular invasion were remarkably higher in BA and JC versus NJC (24.0 vs. 9.7 vs. 4.8%, respectively). The 5-year survival rate in all patients with curative resection was 100%. CONCLUSION: This study confirmed the technical and theoretical validity of ESD for EGJ as a diagnostic treatment. However, we have to pay attention to the high rates of submucosal and lymphovascular invasive malignant potential of these cancers. PMID- 23343967 TI - Comparison of gastric relaxation and sensory functions between functional dyspepsia and healthy subjects using novel drinking-ultrasonography test. AB - BACKGROUND: Functional dyspepsia (FD) is a heterogeneous disease characterized by various upper abdominal symptoms. The major mechanism of FD includes impaired fundic accommodation, delayed gastric emptying and visceral hypersensitivity. We developed a novel drinking-ultrasonography test to combine a drink test with ultrasonography to assess gastric motility and sensory function of FD patients. METHOD: Subjects were 20 healthy volunteers and 26 successive FD patients according to the Rome III criteria. The subjects ingested 200 ml of water at 2 min intervals 4 times (total 800 ml) through a straw. The maximum cross section of the proximal stomach was visualized before water intake, after each water intake, and 5 and 10 min after the completion of drinking using extracorporeal ultrasonography. Abdominal symptoms were evaluated using the visual analog scale (VAS) a total of 5 times. RESULTS: The mean cross-sectional area of the fornix after 800 ml of water intake was significantly lower in the FD group compared with the control group. In the FD group, marked abdominal symptoms developed immediately after initiation of water intake, and VAS score differed significantly (p < 0.01) between the control and FD groups at each time point. CONCLUSION: We developed the novel drinking-ultrasonography test which revealed abnormalities in gastric accommodation and sensation in patients with FD compared with healthy controls. This approach can be readily performed and allows the simultaneous evaluation of gastric accommodation, emptying and sensation. PMID- 23343968 TI - Hemorrhagic ulcers after Great East Japan Earthquake and Tsunami: features of post-disaster hemorrhagic ulcers. AB - BACKGROUND: We investigated the characteristic features and treatment of hemorrhagic peptic ulcers after the Great East Japan Earthquake, which occurred on 11 March 2011. METHODS: Clinical data of patients with hemorrhagic peptic ulcers were retrospectively collected during the 3 months after the earthquake from seven major hospitals in the middle of the stricken area, and were compared with those during the same period of the previous year. RESULTS: After the earthquake, the number of hemorrhagic ulcers increased 2.2 fold as compared with the previous year, and gastric ulcers were significantly more frequent compared with duodenal ulcers (p < 0.05) and more often presented multiple forms (p < 0.05). Nonetheless, the proportion of re-bleeding cases after hemostasis treatment (8% in 2010 vs. 5% in 2011) or total mortality rate (2.5% in 2010 vs. 1.2% in 2011) was rather lower after the earthquake compared with that of the previous year. CONCLUSION: We clarified that post-disaster hemorrhagic ulcers existed frequently in the stomach, often as multiple ulcers at the same time. The Great East Japan Earthquake and Tsunami caused many cases of hemorrhagic ulcer. However, because of the high success rate of endoscopic hemostasis, the mortality remained as low as in the previous year. Our present study provides important information for large-scale disasters which can occur anywhere. PMID- 23343969 TI - Long-term follow-up outcome of imatinib mesylate treatment for recurrent and unresectable gastrointestinal stromal tumors. AB - BACKGROUND: The follow-up study of up to 71 months of a randomized phase II B2222 trial has demonstrated a long-term survival in patients with recurrent or unresectable gastrointestinal stromal tumors (GISTs). One subset of the patients (17.7%) has been alive for over 9 years with continuous imatinib mesylate (imatinib) treatment. Here, we report the retrospective analysis of recurrent or unresectable GIST patients with imatinib treatment at our institution. METHODS: We summarized the data of 20 patients with recurrent or unresectable GIST treated with imatinib. RESULTS: Patients were followed for a median of 40 months (range 2.5-103) under imatinib treatment. The median progression-free survival (PFS) was 89 months and overall survival for 8 years was 67%. Fifteen patients showed continuous partial response or stable disease with imatinib treatment. The median PFS was 45 months and the median size of the primary tumor was 7.6 cm (range 2.8 18). Four patients showed progressive disease. The median PFS was 56 months and the median size of the primary tumor was 11.9 cm (range 6.7-19). Grade 3 or 4 adverse events occurred in neutropenia (10%), anemia (15%) and renal dysfunction (5%). However, all patients were well managed by supportive treatment and none were discontinued from imatinib treatment due to toxicity or adverse events. CONCLUSION: Imatinib had a high efficacy in patients with unresectable and recurrent GIST during long-term follow-up. All patients were well managed by supportive treatment against adverse events and they were able to take imatinib without discontinuation. The management of adverse events was a key factor for achieving a long-term survival. In addition, the potential risk of imatinib resistant GISTs tends to depend on the size of the primary GISTs. PMID- 23343970 TI - Relationship between narrow-band imaging magnifying observation and pit pattern diagnosis in colorectal tumors. AB - BACKGROUND/AIM: The aim of this study was to examine the relationship between narrow-band imaging (NBI) magnifying observation using the surface pattern as the main evaluation criterion and pit pattern diagnosis on the basis of magnifying observation using a dye in relation to the characteristics of colorectal tumors according to their morphologies. METHODS: In this study, NBI observation and pit pattern diagnosis using a dye with magnifying observation were simultaneously performed in our hospital, and the consecutive 786 cases of colorectal lesions (hyperplasia, adenomata and early carcinomas) that had been endoscopically or surgically resected were retrospectively analyzed. NBI magnifying observation was in conformance with the Hiroshima classification and pit pattern diagnosis was in conformance with the Kudo and Tsuruta classification. The relationship between NBI magnifying observation and pit pattern diagnosis and that between NBI magnifying observation and the histological type/invasion depth were examined in relation to colorectal tumor morphology. RESULTS: Type A corresponded to the type II pit pattern, type B corresponded to the type III(S), type III(L) and type IV regular pit patterns, type C1 corresponded to the type V(I) slightly irregular pit pattern, type C2 corresponded to the type V(I) highly irregular pit pattern and type C3 corresponded to the type V(N) pit pattern. In the protruded type, the irregularity of type C1 or C2 lesions agreed with the type V(I) slightly or highly irregular pit pattern, respectively, in 114 cases (64.0%). Moreover, the irregularity was higher with NBI magnifying observation than with pit pattern diagnosis in 58 cases (32.6%). In the superficial type, the irregularity of type C1 or C2 lesions agreed with the type V(I) slightly or highly irregular pit pattern, respectively, in 63 cases (71.6%). Moreover, the irregularity was higher with NBI magnifying observation than with pit pattern diagnosis in 19 cases (21.6%). In the case of type C1 or C2 lesions, the irregularity tended to be higher with NBI magnifying observation than with pit pattern diagnosis in the protruded type compared to the superficial type (p = 0.087). CONCLUSION: The surface pattern, which was visible in NBI magnifying observation, differed from the pit pattern findings obtained by magnifying endoscopic observation using a dye. Findings were more detailed in pit pattern diagnosis using a dye than in NBI magnifying observation. PMID- 23343971 TI - Retrospective study as first-line chemotherapy combined anti-VEGF antibody with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer. AB - BACKGROUND/AIM: Combination chemotherapies of oxaliplatin or irinotecan with fluoropyrimidine and molecular target drug were reported to be active in several clinical studies and so regarded as a first-line standard therapy for unresectable or metastatic colorectal cancer. However, the incidence of adverse events is not so low. We investigated the efficacy and safety of chemotherapy combined bevacizumab with fluoropyrimidine as a first-line treatment for frail patients. METHODS: Twenty-six patients with unresectable or metastatic colorectal cancer who were treated with first-line chemotherapy combined bevacizumab with S 1 or 5FU/LV (modified Roswell Park Memorial Institute regimen) at our hospital between October 2007 and December 2010 were retrospectively investigated. RESULTS: The median age was 72 years (range 66-84). Performance status was 0, 1 and 2 in 8, 17 and 1 patient, respectively. The primary lesion was located in the colon in 14 patients and in the rectum in 12. Twenty patients were with resection of the primary lesion and 6 were without, 8 were with postoperative adjuvant chemotherapy and 18 were without. The number of metastasized organs was 1, 2 and 3 in 17, 9 and 0 patients, respectively. The liver, lung, lymph node and peritoneum were metastasized in 9, 9, 11 and 5 patients, respectively. The KRAS gene was wild in 11, mutated in 7 and unknown in 8 patients. Bevacizumab with S-1 was used in 17 patients and bevacizumab with 5FU/LV was used in 9. Response and disease control rates were 50 and 100%, respectively. The median duration of progression-free survival was 9.1 months and the median time to treatment failure was 9.0 months. The incidences of all grades of neutropenia and hypertension were 31%, those of grade 3 or severer were 12%, and those of other adverse events were low. Grade 3 cerebral hemorrhage, grade 4 pulmonary embolism and grade 5 febrile neutropenia each occurred in 1 patient. CONCLUSION: The first-line chemotherapy combined bevacizumab with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer in Japan was comparable to the safety and efficacy of combination therapy reported previously in Western countries. PMID- 23343972 TI - Role of alcohol drinking pattern in type 2 diabetes in Japanese men: the Toranomon Hospital Health Management Center Study 11 (TOPICS 11). AB - BACKGROUND: Findings of past studies on the effect of drinking patterns on diabetes risk have been inconsistent. OBJECTIVE: We aimed to investigate the role of drinking frequency and usual quantity consumed in the development of type 2 diabetes. DESIGN: Enrolled were 1650 Japanese men without diabetes (diabetes: fasting plasma glucose >=7.0 mmol/L, glycated hemoglobin >=6.5%, or self-reported clinician-diagnosed diabetes). Average alcohol consumption and 12 combinations of frequency and usual quantity per drinking occasion were assessed at the baseline examination. The absolute risk and HR for the development of diabetes were calculated. RESULTS: During a mean follow-up period of 10.2 y, 216 individuals developed diabetes. Lifetime abstainers (n = 153) had a relatively low incidence of diabetes (9.1/1000 person-years), similar to moderate consumers (99-160 g ethanol/wk; 9.0/1000 person-years). Increasingly higher quantities of alcohol usually consumed per occasion increased the risk of diabetes regardless of drinking frequency. The lowest incidence rate of diabetes (8.5/1000 person-years) was associated with the consumption of <1 drink (<23 g ethanol) per occasion over >=6 times/wk. Binge drinking (>=3 drinks per occasion) significantly increased the risk of future diabetes regardless of frequency (HR: 1.79; 95% CI: 1.17, 2.74) compared with <1 drink per occasion. CONCLUSIONS: Among current drinkers, a drinking pattern of <1 drink per occasion regularly over 6 times within a week was associated with the lowest risk of developing diabetes. Usual quantity per drinking occasion was a more important determinant than was weekly drinking frequency in the association between alcohol consumption and risk of diabetes in Japanese men. PMID- 23343973 TI - Physiologic basis for understanding quantitative dehydration assessment. AB - Dehydration (body water deficit) is a physiologic state that can have profound implications for human health and performance. Unfortunately, dehydration can be difficult to assess, and there is no single, universal gold standard for decision making. In this article, we review the physiologic basis for understanding quantitative dehydration assessment. We highlight how phenomenologic interpretations of dehydration depend critically on the type (dehydration compared with volume depletion) and magnitude (moderate compared with severe) of dehydration, which in turn influence the osmotic (plasma osmolality) and blood volume-dependent compensatory thresholds for antidiuretic and thirst responses. In particular, we review new findings regarding the biological variation in osmotic responses to dehydration and discuss how this variation can help provide a quantitative and clinically relevant link between the physiology and phenomenology of dehydration. Practical measures with empirical thresholds are provided as a starting point for improving the practice of dehydration assessment. PMID- 23343974 TI - Cell permeable fluorescent receptor for detection of H2PO4(-) in aqueous solvent. AB - A new colorimetric fluorescent receptor for H(2)PO(4)(-) is reported in this communication. The receptor can detect dihydrogen phosphates optically by developing a color change from yellow to green. Acute spectral responses to H(2)PO(4)(-) in HEPES buffer (DMSO-HEPES 1:9) have been observed. The selectivity zone in terms of pH of the receptor for H(2)PO(4)(-) is attributed to the fitness in the acidity (pK(a)) of receptor with H(2)PO(4)(-). Hydrogen bonding plays the key role here which is confirmed by (1)H NMR titration. The receptor also has good potential for bio-imaging. The mode of interaction has also been established by ab initio calculation. PMID- 23343977 TI - A model for efficient, semiconductor-free solar cells via supersensitized electron transfer cascades in photogalvanic devices. AB - A mathematical model for a photosynthesis-inspired regenerative photogalvanic device, for transient rather than exclusively steady-state conditions, based on molecular electrochemistry rather than electron transfer processes involving semiconductors, is considered within this work and which is adapted from an experimental system previously developed (J. E. Halls and J. D. Wadhawan, Energy Environ. Sci., 2012, 5, 6541). Computational simulations suggest that pragmatically achievable systems behave as middle-of-the-range photo-rechargeable electrochemical capacitors for light-to-electrical energy storage; in contrast the system performance as a light-to-electrical energy convertor (viz., solar cell), for cells constructed from electrochemically reversible redox couples with fast photo-induced electron transfer reactions is critically dependent on the concentration of the supersensitiser; maximum power conversion efficiency of ca. 6.5% under 500 nm light, 2.4 mW cm(-2) intensity for typical experimental parameters, neglecting Ohmic losses, and employing galvanostatic discharge, with a power conversion efficiency that is capable of being increased by a factor of five (to ca. 34%) when the supersensitizer concentration increases by an order of magnitude (from 5.0 to 50.0 mM). Under an AM 2.0 solar spectrum, numerical simulations suggest that one potentially pragmatically achievable embodiment of this regenerative system is able to perform with a solar-to-electrical power conversion efficiency of 4.5% - an attractive realistic single cell value. PMID- 23343978 TI - Awareness of and attitudes towards heat waves within the context of climate change among a cohort of residents in Adelaide, Australia. AB - Heat waves are a public health concern in Australia and unprecedented heat waves have been recorded in Adelaide over recent years. The aim of this study was to examine the perception and attitudes towards heat waves in the context of climate change among a group of residents in Adelaide, an Australian city with a temperate climate. A cross-sectional study was conducted in the summer of 2012 among a sample of 267 residents. The results of the survey found that television (89.9%), radio (71.2%), newspapers (45.3%) were the main sources from which respondents received information about heat waves. The majority of the respondents (73.0%) followed news about heat waves very or somewhat closely. About 26.6% of the respondents were extremely or very concerned about the effects of heat waves on them personally. The main issues that were of personal concern for respondents during a heat wave were their personal comfort (60.7%), their garden (48.7%), and sleeping well (47.6%). Overall, respondents were more concerned about the impacts of heat waves to the society than on themselves. There was a significant association between gender (chi2 = 21.2, df = 3, p = 0.000), gross annual household income (p = 0.03) and concern for the societal effects of heat waves. Less than half (43.2%) of the respondents believed that heat waves will extremely or very likely increase in Adelaide according to climate projections. Nearly half (49.3%) believed that the effects of heat waves were already being felt in Adelaide. These findings may inform the reframing and communication strategies for heat waves in Adelaide in the context of climate change. PMID- 23343979 TI - Arsenic contaminated groundwater and its treatment options in Bangladesh. AB - Arsenic (As) causes health concerns due to its significant toxicity and worldwide presence in drinking water and groundwater. The major sources of As pollution may be natural process such as dissolution of As-containing minerals and anthropogenic activities such as percolation of water from mines, etc. The maximum contaminant level for total As in potable water has been established as 10 ug/L. Among the countries facing As contamination problems, Bangladesh is the most affected. Up to 77 million people in Bangladesh have been exposed to toxic levels of arsenic from drinking water. Therefore, it has become an urgent need to provide As-free drinking water in rural households throughout Bangladesh. This paper provides a comprehensive overview on the recent data on arsenic contamination status, its sources and reasons of mobilization and the exposure pathways in Bangladesh. Very little literature has focused on the removal of As from groundwaters in developing countries and thus this paper aims to review the As removal technologies and be a useful resource for researchers or policy makers to help identify and investigate useful treatment options. While a number of technological developments in arsenic removal have taken place, we must consider variations in sources and quality characteristics of As polluted water and differences in the socio-economic and literacy conditions of people, and then aim at improving effectiveness in arsenic removal, reducing the cost of the system, making the technology user friendly, overcoming maintenance problems and resolving sludge management issues. PMID- 23343976 TI - Targeted drug delivery to treat pain and cerebral hypoxia. AB - Limited drug penetration is an obstacle that is often encountered in treatment of central nervous system (CNS) diseases including pain and cerebral hypoxia. Over the past several years, biochemical characteristics of the brain (i.e., tight junction protein complexes at brain barrier sites, expression of influx and efflux transporters) have been shown to be directly involved in determining CNS permeation of therapeutic agents; however, the vast majority of these studies have focused on understanding those mechanisms that prevent drugs from entering the CNS. Recently, this paradigm has shifted toward identifying and characterizing brain targets that facilitate CNS drug delivery. Such targets include the organic anion-transporting polypeptides (OATPs in humans; Oatps in rodents), a family of sodium-independent transporters that are endogenously expressed in the brain and are involved in drug uptake. OATP/Oatp substrates include drugs that are efficacious in treatment of pain and/or cerebral hypoxia (i.e., opioid analgesic peptides, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors). This clearly suggests that OATP/Oatp isoforms are viable transporter targets that can be exploited for optimization of drug delivery to the brain and, therefore, improved treatment of CNS diseases. This review summarizes recent knowledge in this area and emphasizes the potential that therapeutic targeting of OATP/Oatp isoforms may have in facilitating CNS drug delivery and distribution. Additionally, information presented in this review will point to novel strategies that can be used for treatment of pain and cerebral hypoxia. PMID- 23343980 TI - Effect of magnetic nanoparticles on tobacco BY-2 cell suspension culture. AB - Nanomaterials are structures whose exceptionality is based on their large surface, which is closely connected with reactivity and modification possibilities. Due to these properties nanomaterials are used in textile industry (antibacterial textiles with silver nanoparticles), electronics (high-resolution imaging, logical circuits on the molecular level) and medicine. Medicine represents one of the most important fields of application of nanomaterials. They are investigated in connection with targeted therapy (infectious diseases, malignant diseases) or imaging (contrast agents). Nanomaterials including nanoparticles have a great application potential in the targeted transport of pharmaceuticals. However, there are some negative properties of nanoparticles, which must be carefully solved, as hydrophobic properties leading to instability in aqueous environment, and especially their possible toxicity. Data about toxicity of nanomaterials are still scarce. Due to this fact, in this work we focused on studying of the effect of magnetic nanoparticles (NPs) and modified magnetic nanoparticles (MNPs) on tobacco BY-2 plant cell suspension culture. We aimed at examining the effect of NPs and MNPs on growth, proteosynthesis - total protein content, thiols - reduced (GSH) and oxidized (GSSG) glutathione, phytochelatins PC2-5, glutathione S-transferase (GST) activity and antioxidant activity of BY-2 cells. Whereas the effect of NPs and MNPs on growth of cell suspension culture was only moderate, significant changes were detected in all other biochemical parameters. Significant changes in protein content, phytochelatins levels and GST activity were observed in BY-2 cells treated with MNPs nanoparticles treatment. Changes were also clearly evident in the case of application of NPs. Our results demonstrate the ability of MNPs to negatively affect metabolism and induce biosynthesis of protective compounds in a plant cell model represented by BY-2 cell suspension culture. The obtained results are discussed, especially in connection with already published data. Possible mechanisms of NPs' and MNPs' toxicity are introduced. PMID- 23343981 TI - Biomarkers of maternal and fetal exposure to organochlorine pesticides measured in pregnant Hispanic women from Brownsville, Texas. AB - Biomarkers of organochlorine pesticides were measured in both venous and umbilical cord blood from 35 pregnant Hispanic women living in Brownsville, Texas, USA. Gas chromatography with an electron capture detector was used to analyze specimens for 30 individual pesticides or their metabolites. Results indicate that blood concentrations were relatively low for most individual compounds, but that high-end (upper 10th percentile) values for total DDT were comparatively high. Although health effects associated with measured blood concentrations are uncertain, there is concern that fetal exposure to low levels of these OC compounds, either individually or in combination, might contribute to subsequent health problems, including neurodevelopmental effects, cancer, endocrine disruption, obesity and diabetes. PMID- 23343975 TI - Individual differences and social influences on the neurobehavioral pharmacology of abused drugs. AB - The interaction of drugs with biologic targets is a critical area of research, particularly for the development of medications to treat substance use disorders. In addition to understanding these drug-target interactions, however, there is a need to understand more fully the psychosocial influences that moderate these interactions. The first section of this review introduces some examples from human behavioral pharmacology that illustrate the clinical importance of this research. The second section covers preclinical evidence to characterize some of the key individual differences that alter drug sensitivity and abuse vulnerability, related primarily to differences in response to novelty and impulsivity. Evidence is presented to indicate that critical neuropharmacological mechanisms associated with these individual differences involve integrated neurocircuits underlying stress, reward, and behavioral inhibitory processes. The third section covers social influences on drug abuse vulnerability, including effects experienced during infancy, adolescence, and young adulthood, such as maternal separation, housing conditions, and social interactions (defeat, play, and social rank). Some of the same neurocircuits involved in individual differences also are altered by social influences, although the precise neurochemical and cellular mechanisms involved remain to be elucidated fully. Finally, some speculation is offered about the implications of this research for the prevention and treatment of substance abuse. PMID- 23343983 TI - Transfer of multidrug-resistant bacteria between intermingled ecological niches: the interface between humans, animals and the environment. AB - The use of antimicrobial agents has been claimed to be the driving force for the emergence and spread of microbial resistance. However, several studies have reported the presence of multidrug-resistant bacteria in populations exposed to low levels of antimicrobial drugs or even never exposed. For many pathogens, especially those organisms for which asymptomatic colonization typically precedes infection (e.g., Enterococcus spp. and Escherichia coli), the selective effects of antimicrobial use can only be understood if we considerer all biological and environmental pathways which enable these bacteria, and the genes they carry, to spread between different biomes. This ecological framework provides an essential perspective for formulating antimicrobial use policies, precisely because it encompasses the root causes of these problems rather than merely their consequences. PMID- 23343984 TI - Exploring the role of the food environment on food shopping patterns in Philadelphia, PA, USA: a semiquantitative comparison of two matched neighborhood groups. AB - Increasing research has focused on the built food environment and nutrition related outcomes, yet what constitutes a food environment and how this environment influences individual behavior still remain unclear. This study assesses whether travel mode and distance to food shopping venues differ among individuals in varying food environments and whether individual- and household level factors are associated with food shopping patterns. Fifty neighbors who share a traditionally defined food environment (25 in an unfavorable environment and 25 in a favorable environment) were surveyed using a mix of close- and open ended survey questions. Food shopping patterns were mapped using Geographic Information Systems (GIS). Stores visited were beyond the 0.5-mile (805 meters) radius traditionally used to represent the extent of an individual's food environment in an urban area. We found no significant difference in shopping frequency or motivating factor behind store choice between the groups. No differences existed between the two groups for big food shopping trips. For small trips, individuals in the favorable food environment traveled shorter distances and were more likely to walk than drive. Socioeconomic status, including car ownership, education, and income influenced distance traveled. These findings highlight the complexities involved in the study and measurement of food environments. PMID- 23343985 TI - Cancer risk in diagnostic radiation workers in Korea from 1996–2002. AB - This study was aimed to examine the association between the effective radiation dose of diagnostic radiation workers in Korea and their risk for cancer. A total of 36,394 diagnostic radiation workers (159,189 person-years) were included in this study; the effective dose and cancer incidence were analyzed between the period 1996 and 2002. Median (range) follow-up time was 5.5 (0.04-7) years in males and 3.75 (0.04-7) years in females. Cancer risk related to the average annual effective dose and exposure to more than 5 mSv of annual radiation dose were calculated by the Cox proportional hazard model adjusted for occupation and age at the last follow-up. The standardized incidence ratio of cancer in radiation workers showed strong healthy worker effects in both male and female workers. The relative risk of all cancers from exposure of the average annual effective dose in the highest quartile (upper 75% or more of radiation dose) was 2.14 in male workers (95% CI: 1.48-3.10, p-trend: <0.0001) and 4.43 in female workers (95% CI: 2.17-9.04, p-trend: <0.0001), compared to those in the lower three quartiles of radiation exposure dose (less than upper 75% of radiation dose). Cancer risks of the brain (HR: 17.38, 95% CI: 1.05-287.8, p-trend: 0.04) and thyroid (HR: 3.88, 95% CI: 1.09-13.75, p-trend: 0.01) in female workers were significantly higher in the highest quartile group of radiation exposure compared to those in the lower three quartiles, and the risk of colon and rectum cancers in male workers showed a significantly increasing trend according to the increase of the average annual radiation dose (HR: 2.37, 95% CI: 0.99-5.67, p-trend: 0.02). The relative risk of leukemia in male workers and that of brain cancer in female workers were significantly higher in the group of people who had been exposed to more than 5 mSv/year than those exposed to less than 5 mSv/year (HR: 11.75, 95% CI: 1.08-128.20; HR: 63.11, 95% CI: 3.70-1,075.00, respectively). Although the present study involved a relatively young population and a short follow-up time, statistically significant increased risks of some cancers in radiation workers were found, which warrants a longer follow-up study and more intensive protective measures in this population. PMID- 23343982 TI - Nature, nurture and evolution of intra-species variation in mosquito arbovirus transmission competence. AB - Mosquitoes vary in their competence or ability to transmit arthropod-borne viruses (arboviruses). Many arboviruses cause disease in humans and animals. Identifying the environmental and genetic causes of variation in mosquito competence for arboviruses is one of the great challenges in public health. Progress identifying genetic (nature) and environmental (nurture) factors influencing mosquito competence for arboviruses is reviewed. There is great complexity in the various traits that comprise mosquito competence. The complex interactions between environmental and genetic factors controlling these traits and the factors shaping variation in Nature are largely unknown. The norms of reaction of specific genes influencing competence, their distributions in natural populations and the effects of genetic polymorphism on phenotypic variation need to be determined. Mechanisms influencing competence are not likely due to natural selection because of the direct effects of the arbovirus on mosquito fitness. More likely the traits for mosquito competence for arboviruses are the effects of adaptations for other functions of these competence mechanisms. Determining these other functions is essential to understand the evolution and distributions of competence for arboviruses. This information is needed to assess risk from mosquito-borne disease, predict new mosquito-arbovirus systems, and provide novel strategies to mitigate mosquito-borne arbovirus transmission. PMID- 23343986 TI - Ecological risk assessment of land use change in the Poyang Lake Eco-economic Zone, China. AB - Land use/land cover change has been attracting increasing attention in the field of global environmental change research because of its role in the social and ecological environment. To explore the ecological risk characteristics of land use change in the Poyang Lake Eco-economic Zone of China, an eco-risk index was established in this study by the combination of a landscape disturbance index with a landscape fragmentation index. Spatial distribution and gradient difference of land use eco-risk are analyzed by using the methods of spatial autocorrelation and semivariance. Results show that ecological risk in the study area has a positive correlation, and there is a decreasing trend with the increase of grain size both in 1995 and 2005. Because the area of high eco-risk value increased from 1995 to 2005, eco-environment quality declined slightly in the study area. There are distinct spatial changes in the concentrated areas with high land use eco-risk values from 1995 to 2005. The step length of spatial separation of land use eco-risk is comparatively long - 58 km in 1995 and 11 km in 2005 - respectively. There are still nonstructural factors affecting the quality of the regional ecological environment at some small-scales. Our research results can provide some useful information for land eco-management, eco environmental harnessing and restoration. In the future, some measures should be put forward in the regions with high eco-risk value, which include strengthening land use management, avoiding unreasonable types of land use and reducing the degree of fragmentation and separation. PMID- 23343987 TI - Evaluation of full-facepiece respirator fit on fire fighters in the municipality of Jeddah, Saudi Arabia. AB - The purpose of this study was to assess the effect of personal variables on the fit of the respirators used by firefighters and workers in highly polluted environments. However, resistance from many plants managers was met to conduct the study on their workers. Therefore, we were forced to limit the study on firefighters who were found very cooperative. Forty volunteer firefighters from different departments participated in the study. They were subjected to a daily leak rate measurement using a Control Negative Pressure (CNP) fit tester for five consecutive days. Two types of respirators were used for each volunteer: the Drager type and the MSA. At the end of the study, the association between face shape and presence of beard with the respirator leak rates was investigated. A significant difference in the leak rate was detected between the two types of respirators used, with the Drager respirator having higher leak rates. The presence of a beard increased dramatically the leak rate whatever the face shape was. The oval shape was the best fitting to the respirators, followed by the rounded and finally the rectangular face. The study recommends that personal variables like face shape must be taken into consideration and fit testing must be carried out periodically, to specify the respirator that best fits each firefighter. Having beard must be absolutely prohibited, since it can be life threatening in environmental dangerous conditions such those encountered during extinguishing fires and overhaul situations. PMID- 23343988 TI - Application of solid phase extraction on multiwalled carbon nanotubes of some heavy metal ions to analysis of skin whitening cosmetics using ICP-AES. AB - A novel and highly sensitive method for the determination of some heavy metals in skin whitening cosmetics creams using multiwalled carbon nanotubes MWCNTs as solid phase extraction sorbent for the preconcentration of these heavy metals prior to their determination by inductively coupled plasma atomic emission spectrometry is described. Different practical parameters have been thoroughly investigated and the optimum experimental conditions were employed. The developed method was then applied for the determination of arsenic, bismuth, cadmium, mercury, lead and titanium in samples of skin whitening cosmetics. The detection limits under these conditions for As, Bi, Cd, Pb, Hg and Ti were 2.4, 4.08, 0.3, 2.1, 1.8, and 1.8 ng.mL-1, respectively. The relative standard deviations (RSDs) were found to be less than 2.0%. For validation, a certified reference material of NIST SRM 1570a spinach leaves was analyzed and the determined values were in good agreement with the certified values. The recoveries for spiked samples were found to be in the range of 89.6-104.4%. PMID- 23343989 TI - Job stress across gender: the importance of emotional and intellectual demands and social support in women. AB - This study aims to analyse whether any differences exist between the genders with respect to the effect of perceived Job Demands, Control and Support (JDCS model) on how individuals reach high levels of job stress. To do this, the perceived risk of suffering an illness or having an accident in the workplace is used as an outcome measure. The study is based on the First Survey on Working Conditions in Andalusia, which has a sample of 5,496 men and 2,779 women. We carry out a multi sample analysis with structural equation models, controlling for age and sector. The results show that the generation of job stress has a different pattern in men and women. In the case of men, the results show that only one dimension of the job demands stressor is significant (quantitative demands), whose effect on job stress is weakened slightly by the direct effects of control and support. With women, in contrast, emotional and intellectual aspects (qualitative demands) are also statistically significant. Moreover, social support has a greater weakening effect on the levels of job stress in women than in men. These results suggest that applying the JDCS model in function of the gender will contribute to a greater understanding of how to reduce the levels of job stress in men and women, helping the design of more effective policies in this area. PMID- 23343990 TI - The effectiveness of cultural competence programs in ethnic minority patient centered health care--a systematic review of the literature. AB - PURPOSE: To examine the effectiveness of patient-centered care (PCC) models, which incorporate a cultural competence (CC) perspective, in improving health outcomes among culturally and linguistically diverse patients. DATA SOURCES: The search included seven EBSCO-host databases: Academic Search Complete, Academic Search Premier, CINAHL with Full Text, Global Health, MEDLINE with Full Text, PsycINFO PsycARTICLES, PsycEXTRA, Psychology and Behavioural Sciences Collection and Pubmed, Web of Knowledge and Google Scholar. STUDY SELECTION: The review was undertaken following the preferred reporting items for systematic reviews and meta-analyses, and the critical appraisals skill program guidelines, covering the period from January 2000 to July 2011. Data extraction Data were extracted from the studies using a piloted form, including fields for study research design, population under study, setting, sample size, study results and limitations. RESULTS OF DATA SYNTHESIS: The initial search identified 1450 potentially relevant studies. Only 13 met the inclusion criteria. Of these, 11 were quantitative studies and 2 were qualitative. The conclusions drawn from the retained studies indicated that CC PCC programs increased practitioners' knowledge, awareness and cultural sensitivity. No significant findings were identified in terms of improved patient health outcomes. CONCLUSION: PCC models that incorporate a CC component are increased practitioners' knowledge about and awareness of dealing with culturally diverse patients. However, there is a considerable lack of research looking into whether this increase in practitioner knowledge translates into better practice, and in turn improved patient-related outcomes. More research examining this specific relationship is, thus, needed. PMID- 23343991 TI - The Comparison of Educational Intervention Effect Using BASNEF and Classic Models on Improving Assertion Skill Level. AB - BACKGROUND: To compare the effectiveness of BASNEF and Classic educational models to improve the assertion skill level of high school boy students. METHODS: The 60 high school male students from Shiraz City, Fars Province Iran, were participated in this study. They were randomly divided in two groups (groups A and B). The group A attended in designed educational planning based on BASNEF model and group B attended in classic educational program. The both groups had participated in six session educational activity (2 hours each session) during the four weeks. The data collected using questionnaire before and after one-month intervention. RESULTS: The mean score of knowledge, attitude, enabling factors, social norms, and Rathus Assertion Test were not significant statistically between two groups before and after intervention. However, the mean scores of all mentioned variables in group A and only knowledge and assertion variables in group B changed significantly after intervention. In addition, the comparison of the mean scores and the means of scores difference of all variables changed significantly between two groups after intervention. DISCUSSION: Performing BASNEF educational model, in accordance with its main parts (knowledge, attitude, social norms, and enabling factors) is more effective than performing classic educational model to improve high school boy students' assertion. PMID- 23343992 TI - Effects of velocity and particles load on efficiency of cyclone in the stone crushing units at azendarian area. AB - BACKGROUND: The traditional cyclone has been developed for the removal of airborne silica particles from local exhaust ventilation (LEV). The objective of this research was to evaluate the effects of velocity and particles load on efficiency of cyclone in the Stone Crushing Units at Azendarian Area. METHODS: After the designing and installing the traditional cyclone, downstream and upstream samples of the apparatus were obtained. The mass of all samples collected was determined gravimetrically using EPA method with cascade Impactor. RESULTS: The relation between inlet total and respirable dust concentration to cyclone and cyclone overall efficiency is statistically significant (P= 0.005) and the relation between inlet air velocity to cyclone and cyclone pressure loss is statistically significant (P= 0.002). There was a significant correlation between the inlet concentration loaded to cyclone and the efficiency of cyclone. CONCLUSION: Increase of respirable dust concentration and also total concentration cause to increase efficiency of cyclone. PMID- 23343993 TI - Removal of water turbidity by the electrocoagulation method. AB - BACKGROUND: Electrocoagulation is a technique involving the electrolytic addition of coagulating metal ions directly from sacrificial electrodes. These ions coagulate with turbidity agents in the water, in a similar manner to the addition of coagulating chemicals such as alum and ferric chloride, and allow the easier removal of the pollutants. Purpose of this study was to conduct experimental investigation of water turbidity removal using the electrocoagulation method. METHODS: Removal of turbidity from raw water in batch system was investigated by different voltage (10, 15, 20, 25, 30V), electrodes (Al, Fe and St) and electrolyzes time (0 to 40 min.), electrodes distance 2 cm and pH=7.5. RESULTS: The experimental results showed that the removal efficiency depends on the electrolyze time, types of electrodes and the applied current. From the experiments carried out at 20V, it was found that in 20 minutes the removal efficiency for Al, Fe and St electrodes was 93, 91 and 51 percent respectively. Based on turbidity removal efficiency, Al is prior to Fe and St as sacrificial electrode material. CONCLUSION: In an era when environmental phenomena attract a great attention, electrocoagulation methods can be said to be a promising cleaning and purifying method for water treatment. PMID- 23343994 TI - Case-Control Study of acute diarrhea in Children. AB - BACKGROUND: To determine the risk factor for acute diarrhea disease in children. METHODS: In the survey, 220 cases and 220 controls were involved. Cases were children with loose watery feces, pathologically diagnosed as acute diarrhea by the physician, and enrolled from the Emergency Ward as the Incident Cases in Dr. Sheykh Hospital, Mashhad, northeast of Iran. Control group too, was enrolled from the same cases and the members were children whose risk factors disease were not the risk factor for acute diarrhea, and were enrolled from emergency ward of burn patients, accidents, acute respiratory diseases and eligible patients. RESULTS: By using univariate logistic regression models, variables consisting used milk up to 6 months age, antibiotic usage during the last 15 days, mother's employment, mother's acquaintance with ORS, occupancy, and water slack during the week before illness, were significantly related with acute diarrhea. In a multiple logistic regression, the relationship between the said factors as the independent variables and acute diarrhea was studied. Use of formulas before 6 month age with (95% CI 1.77- 5.79) OR=3.21, and tenantry with (95% CI 1.24-2.71) OR=1.83, and mother's employment with (95%CI 1.2-5.06) OR= 2.48 were factors affecting acute diarrhea which remained in the multiple logistic model and had significant relationship with the disease. CONCLUSION: During this study, important environmental risk factors were recognized. Endangered groups and mothers with children under 5 years old should be aware of these risk factors in order to prevent their children's diseases. Prevention of acute diarrhea in children can reduce massive detriments to health system. PMID- 23343995 TI - The application of human factors engineering for evaluation of overall performance. AB - BACKGROUND: Total system design (TSD) factors are design factors, which have impact on overall performance of the power plants in context of total human engineering or macroergonomic. The evaluation of the impact of TSD factors was the main goal of this study. The main objective was human factors engineering on human performance in a power plant. METHODS: The systems being studied are the control rooms and maintenance departments of a 2000 MW thermal power plant in IRAN. By non-parametric correlation analysis and Kruskal-Wallis test of means, we can achieve between TSD factors and human performance. RESULTS: The selected TSD factors are related to procedures, work assessment, teamwork, selforganization, information exchange and communication. In a way we can say that various factors influence on human performance in the power plant is TSD factors such as organizational and safety procedures, teamwork, self-organization, job design and information exchange. CONCLUSION: The best way to increase human performance is TSD factors must be considered, designed and tested concurrently with the engineering factors at the design phase of the system developmental cycle. PMID- 23343996 TI - Predicting Factors in Iron Supplement Intake among Pregnant Women in Urban Care Setting. AB - BACKGROUND: The world health organization estimates that 58% of pregnant women in developing countries are anemic. In spite of the fact that most ministries of health in developing countries have policies to provide pregnant women with iron supplementation, prevalence of maternal anemia has not declined significantly. The aim of this study was to assess adherence to the current recommendation in the local population and to describe factors associated with taking iron supplementation during pregnancy. METHODS: A questionnaire assessing the use of prenatal iron supplementation was distributed among women recently having delivered in Urmia, west Azerbaijan Province, northwest Iran. The questionnaire consisted of two sections. The first included demographic information and the second part covered questions regarding duration of iron supplementation, awareness of per partum anemia and management including benefits and side effects of iron supplementation. SPSS version 10 was used for statistical analysis; data were analyzed by Chi-Square and logistic regression. RESULTS: Eighty seven percent of participants took iron supplements for at least 4 months. Training during pregnancy was associated with longer duration of iron use. In logistic regression analysis nuliparity was the only variable, which remained in the model .Knowledge of participants on anemia, was obviously poor. Health care stuffs were the main source of information. CONCLUSION: The compliance was rather high but knowledge of subjects was low. Therefore, increasing effort is required to mobilize health workers to distribute information on anemia prevention and using iron supplements properly. PMID- 23343997 TI - Estimation of illuminance on the South facing surfaces for clear skies in iran. AB - BACKGROUND: Daylight availability data are essential for designing effectively day lighted buildings. In respect to no available daylight availability data in Iran, illuminance data on the south facing vertical surfaces were estimated using a proper method. METHODS: An illuminance measuring set was designed for measuring vertical illuminances for standard times over 15 days at one hour intervals from 9 a.m. to 3 p.m. at three measuring stations (Hamadan, Eshtehard and Kerman). Measuring data were used to confirm predicted by the IESNA method. RESULTS: Measurement of respective illuminances on the south vertical surfaces resulted in minimum values of 10.5 KLx, mean values of 33.59 KLx and maximum values of 79.6 KLx. CONCLUSION: In this study was developed a regression model between measured and calculated data of south facing vertical illuminance. This model, have a good linear correlation between measured and calculated values (r= 0.892). PMID- 23343998 TI - Fruit and Vegetable Intakes among Elementary Schools' Pupils: Using Five-A-Day Educational Program. AB - BACKGROUND: Low fruit and vegetable intake is a major risk factor for cancer, coronary heart disease and stroke. The recommended intake of five portions per day would reduce death rates from these causes by 20%. In order to have reach fruit and vegetables in daily diet among students, this study examines a brief preventive intervention as for embedding schools action and students role for keeping and promoting fruit and vegetables consumption. METHODS: To promote increased fruit and vegetable consumption, this quasi-experimental study, was conducted among forth and fifth grade students (228 students: Intervention and control groups) in Hamadan, Iran from October 2007 to February 2008. The intervention consisted of behavioral curriculum in classrooms, serving fruit in the school, and parental support plus involvement. 24-hour and 1-week food recalls measured food consumption. RESULTS: Compared with controls, the intervention group significantly increased their knowledge of the 5-a-day optimum (P< 0.001) and also it was found visible improvement for consumption of fruit and vegetables but it was not significant based on adjusted by the Holmes- Bonfereroni procedure. CONCLUSION: School-based interventions can produce important changes in knowledge of and access to fruit and vegetables among students. However, educational programs need to advocacy for providing fruit and vegetables in each community. PMID- 23343999 TI - Increased intestinal absorption in the era of teduglutide and its impact on management strategies in patients with short bowel syndrome-associated intestinal failure. AB - Short bowel syndrome-associated intestinal failure (SBS-IF) as a consequence of extensive surgical resection of the gastrointestinal (GI) tract results in a chronic reduction in intestinal absorption. The ensuing malabsorption of a conventional diet with associated diarrhea and weight loss results in a dependency on parenteral nutrition and/or intravenous fluids (PN/IV). A natural compensatory process of intestinal adaptation occurs in the years after bowel resection as the body responds to a lack of sufficient functional nutrient processing intestinal surface area. The adaptive process improves bowel function but is a highly variable process, yielding different levels of symptom control and PN/IV independence among patients. Intestinal rehabilitation is the strategy of maximizing the absorptive capacity of the remnant GI tract. The approaches for achieving this goal have been limited to dietary intervention, antidiarrheal and antisecretory medications, and surgical bowel reconstruction. A targeted pharmacotherapy has now been developed that improves intestinal absorption. Teduglutide is a human recombinant analogue of glucagon-like peptide 2 that promotes the expansion of the intestinal surface area and increases the intestinal absorptive capacity. Enhanced absorption has been shown in clinical trials by a reduction in PN/IV requirements in patients with SBS-IF. This article details the clinical considerations and best-practice recommendations for intestinal rehabilitation, including optimization of fluids, electrolytes, and nutrients; the integration of teduglutide therapy; and approaches to PN/IV weaning. PMID- 23344000 TI - Specific inhibition of SRC kinase impairs malignant glioma growth in vitro and in vivo. AB - Malignant glioma is a severe cancer with a poor prognosis. Local occurrence and rare metastases of malignant glioma make it a suitable target for gene therapy. Several studies have demonstrated the importance of Src kinase in different cancers. However, these studies have focused mainly on Src-deficient mice or pharmacological inhibitors of Src. In this study we have used Src small hairpin RNAs (shRNAs) in a lentiviral backbone to mimic a long-term stable treatment and determined the role of Src in tumor tissues. Efficacy of Src shRNAs was confirmed in vitro demonstrating up to 90% target gene inhibition. In a mouse malignant glioma model, Src shRNA tumors were almost 50-fold smaller in comparison to control tumors and had significantly reduced vascularity. In a syngenic rat intracranial glioma model, Src shRNA-transduced tumors were smaller and these rats had a survival benefit over the control rats. In vivo treatment was enhanced by chemotherapy and histone deacetylase inhibition. Our results emphasise the importance of Src in tumorigenesis and demonstrate that it can be efficiently inhibited in vitro and in vivo in two independent malignant glioma models. In conclusion, Src is a potential target for RNA interference-mediated treatment of malignant glioma. PMID- 23344001 TI - An RNA alternative to human transferrin: a new tool for targeting human cells. AB - The transferrin receptor, CD71, is an attractive target for drug development because of its high expression on a number of cancer cell lines and the blood brain barrier. To generate serum-stabilized aptamers that recognize the human transferrin receptor, we have modified the traditional aptamer selection protocol by employing a functional selection step that enriches for RNA molecules which bind the target receptor and are internalized by cells. Selected aptamers were specific for the human receptor, rapidly endocytosed by cells and shared a common core structure. A minimized variant was found to compete with the natural ligand, transferrin, for receptor binding and cell uptake, but performed ~twofold better than it in competition experiments. Using this molecule, we generated aptamer targeted siRNA-laden liposomes. Aptamer targeting enhanced both uptake and target gene knockdown in cells grown in culture when compared to nonmodified or nontargeted liposomes. The aptamer should prove useful as a surrogate for transferrin in many applications including cell imaging and targeted drug delivery. PMID- 23344002 TI - Cholesterol-lowering Action of BNA-based Antisense Oligonucleotides Targeting PCSK9 in Atherogenic Diet-induced Hypercholesterolemic Mice. AB - Recent findings in molecular biology implicate the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in low-density lipoprotein receptor (LDLR) protein regulation. The cholesterol-lowering potential of anti-PCSK9 antisense oligonucleotides (AONs) modified with bridged nucleic acids (BNA-AONs) including 2',4'-BNA (also called as locked nucleic acid (LNA)) and 2',4'-BNA(NC) chemistries were demonstrated both in vitro and in vivo. An in vitro transfection study revealed that all of the BNA-AONs induce dose-dependent reductions in PCSK9 messenger RNA (mRNA) levels concomitantly with increases in LDLR protein levels. BNA-AONs were administered to atherogenic diet-fed C57BL/6J mice twice weekly for 6 weeks; 2',4'-BNA-AON that targeted murine PCSK9 induced a dose-dependent reduction in hepatic PCSK9 mRNA and LDL cholesterol (LDL-C); the 43% reduction of serum LDL-C was achieved at a dose of 20 mg/kg/injection with only moderate increases in toxicological indicators. In addition, the serum high-density lipoprotein cholesterol (HDL-C) levels increased. These results support antisense inhibition of PCSK9 as a potential therapeutic approach. When compared with 2',4' BNA-AON, 2',4'-BNA(NC)-AON showed an earlier LDL-C-lowering effect and was more tolerable in mice. Our results validate the optimization of 2',4'-BNA(NC)-based anti-PCSK9 antisense molecules to produce a promising therapeutic agent for the treatment of hypercholesterolemia. PMID- 23344003 TI - Small RNA-Mediated Epigenetic Myostatin Silencing. AB - Myostatin (Mstn) is a secreted growth factor that negatively regulates muscle mass and is therefore a potential pharmacological target for the treatment of muscle wasting disorders such as Duchenne muscular dystrophy. Here we describe a novel Mstn blockade approach in which small interfering RNAs (siRNAs) complementary to a promoter-associated transcript induce transcriptional gene silencing (TGS) in two differentiated mouse muscle cell lines. Silencing is sensitive to treatment with the histone deacetylase inhibitor trichostatin A, and the silent state chromatin mark H3K9me2 is enriched at the Mstn promoter following siRNA transfection, suggesting epigenetic remodeling underlies the silencing effect. These observations suggest that long-term epigenetic silencing may be feasible for Mstn and that TGS is a promising novel therapeutic strategy for the treatment of muscle wasting disorders. PMID- 23344004 TI - Natural Antisense Makes Sense for Gene-specific Activation in Brain. PMID- 23344007 TI - Verrucous cutaneous sarcoidosis: case report and review of this unusual variant of cutaneous sarcoidosis. AB - Sarcoidosis is a multisystem disorder of unknown origin, characterized by the accumulation of lymphocytes and mononuclear histiocytes inducing the formation of noncaseating "naked" epithelioid granulomas. The lungs, lymphatic system, and skin are most often affected, but sarcoidosis may affect any organ. Cutaneous involvement of sarcoidosis is often the sentinel sign of the disease, with the skin sometimes being exclusively affected. We present a case of a 54-year-old African American woman with long-standing history of pulmonary sarcoidosis that presented with multiple verrucous cutaneous lesions on the upper and lower extremities mimicking carcinoma. The initial cutaneous biopsy was superficial in nature, and the pathologist raised the consideration of a possible keratoacanthoma. A deeper skin shave biopsy was performed, and the histopathology showed verrucous pseudoepitheliomatous epidermal hyperplasia with scattered noncaseating granulomas in the superficial dermis. Stains (acid-fast bacillus, Periodic acid-Schiff, and Gomori-Grocott methenamine silver stains) were negative for microorganisms. Given the clinical setting and histomorphology of the cutaneous lesions, the diagnosis of verrucous sarcoidosis was rendered. Verrucous sarcoidosis is a rare cutaneous manifestation of sarcoidosis that could be easily misdiagnosed if it is not appropriately biopsied. This hinders the precise evaluation of the histological specimen, overall clinical picture, and administration of appropriate therapy. PMID- 23344005 TI - Estimating the burden of total knee replacement in the United States. AB - BACKGROUND: In the last decade, the number of total knee replacements performed annually in the United States has doubled, with disproportionate increases among younger adults. While total knee replacement is a highly effective treatment for end-stage knee osteoarthritis, total knee replacement recipients can experience persistent pain and severe complications. We are aware of no current estimates of the prevalence of total knee replacement among adults in the U.S. METHODS: We used the Osteoarthritis Policy Model, a validated computer simulation model of knee osteoarthritis, and data on annual total knee replacement utilization to estimate the prevalence of primary and revision total knee replacement among adults fifty years of age or older in the U.S. We combined these prevalence estimates with U.S. Census data to estimate the number of adults in the U.S. currently living with total knee replacement. The annual incidence of total knee replacement was derived from two longitudinal knee osteoarthritis cohorts and ranged from 1.6% to 11.9% in males and from 2.0% to 10.9% in females. RESULTS: We estimated that 4.0 million (95% confidence interval [CI]: 3.6 million to 4.4 million) adults in the U.S. currently live with a total knee replacement, representing 4.2% (95% CI: 3.7% to 4.6%) of the population fifty years of age or older. The prevalence was higher among females (4.8%) than among males (3.4%) and increased with age. The lifetime risk of primary total knee replacement from the age of twenty-five years was 7.0% (95% CI: 6.1% to 7.8%) for males and 9.5% (95% CI: 8.5% to 10.5%) for females. Over half of adults in the U.S. diagnosed with knee osteoarthritis will undergo a total knee replacement. CONCLUSIONS: Among older adults in the U.S., total knee replacement is considerably more prevalent than rheumatoid arthritis and nearly as prevalent as congestive heart failure. Nearly 1.5 million of those with a primary total knee replacement are fifty to sixty-nine years old, indicating that a large population is at risk for costly revision surgery as well as possible long-term complications of total knee replacement. PMID- 23344008 TI - Combined trichoblastoma and melanocytic nevus: report of 2 cases widening the spectrum of hair follicle-derived tumors combined with melanocytic nevus. PMID- 23344009 TI - Melanocytic tumors express connexin 43 but not 26: immunohistochemical analysis with potential significance in melanocytic oncogenesis. AB - Connexins (Cx) are structural proteins that form gap junctions, which are vital to cell-cell communication and help to regulate cell division. The purpose of this study was to evaluate if there are diagnostically important differences in immunostaining for connexins 43 (Cx43) and 26 (Cx26) in melanoma compared with nevi. Formalin-fixed paraffin-embedded sections of 34 histologically well characterized melanocytic lesions, 17 primary malignant melanomas (MM), and 17 nevi were stained with a polyclonal antibody to Cx43 and a polyclonal antibody to Cx26. Immunoreactivity in tumor cells was evaluated semiquantitatively based on extent (1%-100%) and intensity (0-3) of reactivity. A score of 0-300 was generated by the product of the extent and intensity readings in each case. Significantly higher Cx43 immunoreactivity was detected in MM (mean intensity score = 253.5; 95% confidence interval, 227.9-279.2; P = 0.002) compared with nevi (mean intensity score = 152.4; 95% confidence interval, 104.9-199.8). In contrast, Cx26 immunoreactivity was less than 5% or entirely absent in all melanocytic tumors (n = 34). The significantly higher Cx43 staining in MM when compared with nevi suggests an oncogenic role for this protein in melanocytic tumor progression. Consequently, the evaluation of immunohistochemical staining for Cx43 in conjunction with other ancillary stains and tumor histology may be helpful in distinguishing MM from nevi, although positive Cx26 reactivity suggests that a cutaneous neoplasm is of nonmelanocytic origin. PMID- 23344010 TI - Routine use of ex vivo dermoscopy with "derm dotting" in dermatopathology. PMID- 23344011 TI - In response. PMID- 23344012 TI - Castrate-resistant prostate cancer: postdocetaxel management. AB - PURPOSE OF REVIEW: Prior to 2010, docetaxel was the only treatment shown to prolong survival in metastatic castrate-resistant prostate cancer (CRPC). In the past 3 years, several therapeutic agents have demonstrated survival improvements for CRPC after the receipt of prior docetaxel, leading to multiple approvals by the US Food and Drug Administration. RECENT FINDINGS: The development of these novel agents, each with a distinct mechanism of action, is the fruition of sedulous preclinical research and well designed clinical trials. Cabazitaxel, a next generation taxane, was the first Food and Drug Administration-approved drug for the postdocetaxel setting. The recognition of sustained androgen dependence of CRPC has led to the identification of more potent and selective inhibitors of androgen synthesis and androgen-receptor signaling, such as abiraterone and enzalutamide, respectively. Radium-223, an alpha-emitting radionuclide still under regulatory review, recently showed a significant survival benefit for CRPC. Finally, sipuleucel-T, a form of immunotherapy, may benefit a subset of patients in the postdocetaxel setting. SUMMARY: Post-docetaxel management of CRPC has undergone a dramatic yet welcome paradigm change in the past 3 years. With multiple life-prolonging agents available, it now becomes imperative to coordinate how and when these new therapies should be used and sequenced to achieve optimal patient outcomes. PMID- 23344013 TI - Vitamin B(12) intake and status in early pregnancy among urban South Indian women. AB - AIM: To evaluate the vitamin B(12) status of South Indian women in early pregnancy and its relationship with sociodemographic, anthropometry and dietary intake. METHODS: Cross-sectional study among 366 pregnant urban South Indian women <=14 weeks of gestation with outcome variables defined as low vitamin B(12) blood concentration (<150 pmol/l) and impaired vitamin B(12) status [low vitamin B(12) plus elevated methylmalonic acid (MMA) >0.26 umol/l)]. RESULTS: Low plasma vitamin B(12) concentration was observed in 51.1% of the women, while 42.4% had impaired B(12) status. Elevated MMA, elevated homocysteine (>10 umol/l) and low erythrocyte folate (<283 nmol/l) were observed among 75.8, 43.3 and 22.2% of the women, respectively. The median (25th, 75th percentile) dietary intake of vitamin B(12) was 1.25 (0.86, 1.96) ug/day. Lower maternal body weight was associated with higher vitamin B(12) concentration [prevalence ratios (PR) (95% CI) 0.57 (0.39, 0.84)]. The predictors of impaired vitamin B(12) status were no consumption of yoghurt [PR (95% CI) 1.63 (1.03, 2.58)] or fish [PR (95% CI) 1.32 (1.01, 1.71)] and primiparity [PR (95% CI) 1.41 (1.05, 1.90)]. CONCLUSION: A high prevalence of vitamin B(12) deficiency in early pregnancy among urban South Indian women was related to primiparity and to a low consumption of yoghurt and fish. PMID- 23344014 TI - Photobleaching of quantum dots by non-resonant light. AB - Core-shell quantum dots suffer from photobleaching by light at wavelengths longer than their emission wavelengths. That is, QD photobleaching can be triggered by photons with low energies that are insufficient to pump electrons into the conduction band. The most probable reason is that electrons are pumped into a surface state and then nonradiatively decayed as in conventional photobleaching. PMID- 23344015 TI - Electronic structure of alpha-SrB4O7: experiment and theory. AB - The investigation of valence band structure and electronic parameters of constituent element core levels of alpha-SrB(4)O(7) has been carried out with x ray photoemission spectroscopy. Optical-quality crystal alpha-SrB(4)O(7) has been grown by the Czochralski method. Detailed photoemission spectra of the element core levels have been recorded from the powder sample under excitation by nonmonochromatic Al Kalpha radiation (1486.6 eV). The band structure of alpha SrB(4)O(7) has been calculated by ab initio methods and compared to XPS measurements. It has been found that the band structure of alpha-SrB(4)O(7) is weakly dependent on the Sr-related states. PMID- 23344016 TI - Quantification of ovarian cancer markers with integrated microfluidic concentration gradient and imaging nanohole surface plasmon resonance. AB - Nanohole array-based biosensors integrated with a microfluidic concentration gradient generator were used for imaging detection and quantification of ovarian cancer markers. Calibration curves based on controlled concentrations of the analyte were created using a microfluidic stepped diffusive mixing scheme. Quantification of samples with unknown concentration of analyte was achieved by image-intensity comparison with the calibration curves. The biosensors were first used to detect the immobilization of ovarian cancer marker antibodies, and subsequently applied for the quantification of the ovarian cancer marker r-PAX8 (with a limit of detection of about 5 nM and a dynamic range from 0.25 to 9.0 MUg.mL(-1)). The proposed biosensor demonstrated the ability of self-generating calibration curves on-chip in an integrated microfluidic platform, representing a further step towards the development of comprehensive lab-on-chip biomedical diagnostics based on nanohole array technology. PMID- 23344017 TI - Cantharidin and its anhydride-modified derivatives: relation of structure to insecticidal activity. AB - Cantharidin is a natural compound of novel structure with ideal insecticidal activity. However, the relationship of structure to insecticidal activity of cantharidin and its derivatives has not been ever clarified. To explore what determines the insecticidal activity structurally of cantharidin-related compounds, two series target compounds 6 and 7 were synthesized by replacing the anhydride ring of norcantharidin with an aromatic amine or fatty amine with different electron density, respectively. The structures of these compounds were characterized by 1H NMR, 13C NMR and HRMS-ESI. A bioassay showed that compounds 6 (a-m) lacked any larvicidal activity against Plutella xylostella; whereas their ring-opened partners 7 (a-m) provided a variety of larvicidal activities against P. xylostella, and compound 7f indicated the highest larvicidal activity with LC(50) value of 0.43 mM. The present work demonstrated that the form of the compound (cyclic or ring-opened) or their ability to hydrolyze facilely was the key to determine whether it exhibits larvicidal activity. Moreover, it revealed that the improvement of insecticidal activity required a reasonable combination of both aliphatic amide and aromatic amide moieties, and the type of substituent Y on the aniline ring was critical. PMID- 23344018 TI - Characterization of a polyamine microsphere and its adsorption for protein. AB - A novel polyamine microsphere, prepared from the water-in-oil emulsion of polyethylenimine, was characterized. The investigation of scanning electron microscopy showed that the polyamine microsphere is a regular ball with a smooth surface. The diameter distribution of the microsphere is 0.37-4.29 MUm. The isoelectric point of the microsphere is 10.6. The microsphere can adsorb proteins through the co-effect of electrostatic and hydrophobic interactions. Among the proteins tested, the highest value of adsorption of microsphere, 127.8 mg.g-1 microsphere, was obtained with lipase. In comparison with other proteins, the hydrophobic force is more important in promoting the adsorption of lipase. The microsphere can preferentially adsorb lipase from an even mixture of proteins. The optimum temperature and pH for the selective adsorption of lipase by the microsphere was 35 degrees C and pH 7.0. PMID- 23344020 TI - Immunological effects of Oenothein B, an ellagitannin dimer, on dendritic cells. AB - Oenothein B is a unique macrocyclic ellagitannin dimer that has been found in various medicinal plants belonging to Onagraceae, Lythraceae, and Myrtaceae, with diverse biological activities. The immunological effects of tannins in terms of cytokine-release from macrophages and monocytes have been discussed, while the effects on other immunocompetent cells have been the subject of minimal investigation. We evaluated the immunomodulatory effects induced by tannin treatment in human dendritic cells (DCs), which play a critical role in the initial immune response, by measuring the changes in cytokine production, cell differentiation, and cell viability. Oenothein B showed significant down regulation of the expression of cell surface molecules, CD1a and CD83, suggesting the inhibition of DC differentiation and/or maturation. The suppressive effect on DCs was associated with the induction of apoptosis without the activation of caspase-3/7, 8, and 9, and this was supported by the morphological features indicating significant nuclear condensation. Oenothein B also markedly suppressed the production of inflammatory cytokines, such as IL-1beta and IL-6, in a dose dependent manner. These data may, in part, be able to explain the traditional use of tannin-containing medicinal plants for the treatment of a variety of inflammatory diseases, including inflammatory bowel disease, celiac disease, and rheumatoid arthritis. PMID- 23344019 TI - Novel molecular targets for the treatment of gastroenteropancreatic endocrine tumors: answers and unsolved problems. AB - As more knowledge on molecular alterations favoring carcinogenesis and spreading of gastroenteropancreatic endocrine tumors has become available, a number of targeted agents interfering with key growth and angiogenic pathways have been explored in preclinical and clinical studies. The mTOR inhibitor Everolimus, and the multi-target antiangiogenetic agent Sunitinib, have been shown to be effective and thus have been approved by the FDA for treatment of pancreatic endocrine tumors. However, there is little data on the primary resistance to targeted agents on these tumors. The goals of the present review are to elucidate the possible advantage of combined treatments in overcoming induced resistances, and to identify biomarkers able to predict clinical efficacy. Moreover, the role of interesting targets for which a strong biological rationale exists, and specific inhibitors are available, such as the Src Family Kinases and the Hedgehog Pathway, are discussed. There is now need for more preclinical studies on cell lines and animal models to provide a stronger preclinical background in this field, as well as clinical trials specifically comparing one targeted therapy with another or combining different targeted agents. PMID- 23344021 TI - Chromosome-specific DNA repeats: rapid identification in silico and validation using fluorescence in situ hybridization. AB - Chromosome enumeration in interphase and metaphase cells using fluorescence in situ hybridization (FISH) is an established procedure for the rapid and accurate cytogenetic analysis of cell nuclei and polar bodies, the unambiguous gender determination, as well as the definition of tumor-specific signatures. Present bottlenecks in the procedure are a limited number of commercial, non-isotopically labeled probes that can be combined in multiplex FISH assays and the relatively high price and effort to develop additional probes. We describe a streamlined approach for rapid probe definition, synthesis and validation, which is based on the analysis of publicly available DNA sequence information, also known as "database mining". Examples of probe preparation for the human gonosomes and chromosome 16 as a selected autosome outline the probe selection strategy, define a timeline for expedited probe production and compare this novel selection strategy to more conventional probe cloning protocols. PMID- 23344022 TI - Spatial regulation of epidermal growth factor receptor signaling by endocytosis. AB - Signaling by cell surface receptors appears to be relatively straight-forward: ligand binds to the extracellular domain of the receptor and biochemical changes are communicated into the cell. However, this process is more complex than it first seems due to the various mechanisms that regulate signaling. In order to effectively target these receptors for pharmacological purposes, a more complete understanding of how their signaling is regulated is needed. Here, how the endocytic pathway regulates receptor signaling is discussed, using the epidermal growth factor receptor (EGFR) as a model. In particular, the spatial regulation of signaling is examined. Areas of discussion include: how endocytic trafficking affects biology/pathology, varying approaches for studying the relationship between receptor endocytosis and signaling, and developments in how the endocytic pathway controls EGFR:effector communication and EGFR-mediated cell biology. PMID- 23344023 TI - The role of the VEGF-C/VEGFRs axis in tumor progression and therapy. AB - Vascular endothelial growth factor C (VEGF-C) has been identified as a multifaceted factor participating in the regulation of tumor angiogenesis and lymphangiogenesis. VEGF-C is not only expressed in endothelial cells, but also in tumor cells. VEGF-C signaling is important for progression of various cancer types through both VEGF receptor-2 (VEGFR-2) and VEGF receptor-3 (VEGFR-3). Likewise, both receptors are expressed mainly on endothelial cells, but also expressed in tumor cells. The dimeric VEGF-C undergoes a series of proteolytic cleavage steps that increase the protein binding affinity to VEGFR-3; however, only complete processing, removing both the N- and C-terminal propeptides, yields mature VEGF-C that can bind to VEGFR-2. The processed VEGF-C can bind and activate VEGFR-3 homodimers and VEGFR-2/VEGFR-3 heterodimers to elicit biological responses. High levels of VEGF-C expression and VEGF-C/VEGFRs signaling correlate significantly with poorer prognosis in a variety of malignancies. Therefore, the development of new drugs that selectively target the VEGF-C/VEGFRs axis seems to be an effective means to potentiate anti-tumor therapies in the future. PMID- 23344025 TI - Modulation of P1 and EGF expression by Baicalin. AB - Mycoplasma pneumoniae (M. pneumoniae) is increasingly recognized as a major cause of acute respiratory tract infections. Today, macrolides are used in the primary treatment of M. pneumoniae infection. However, with the increasing prevalence of strains resistant to macrolides, as well as reports of toxicity and adverse side effects, it is necessary to develop an alternative therapeutic agent. A compound recipe - Qinbaiqingfei pellets (Qinbai) - have already been approved in China as the first effective traditional Chinese medicine to be used against M. pneumoniae. Herein, we characterize the mechanism by which Qinbai interacts with M. pneumoniae and lung epithelial cells. The fact that Baicalin is the key component of Qingbai leads us to believe its study is important to elucidating the mechanism of the action of Qinbai. In this study, we describe the complex impact of Baicalin on the adhesin protein P1 of M. pneumoniae and on the expression of epidermal growth factor (EGF) in BALB/c mice and A549 cells infected with M. pneumonia. We draw the conclusion that Baicalin not only cured M. pneumoniae infection by inhibiting P1 expression, but also enhanced the repair of lung epithelial cells by upregulating EGF. Finally, we demonstrate that Baicalin plays a role in Qinbai treatment. PMID- 23344026 TI - A potential daidzein derivative enhances cytotoxicity of epirubicin on human colon adenocarcinoma Caco-2 cells. AB - In this study, we evaluated the effects of 8-hydroxydaidzein (8HD), an isoflavone isolated from fermented soy germ koji, and epirubicin (Epi), an antineoplastic agent, on the production of reactive oxygen species (ROS). We subsequently correlated the ROS levels to the anticancer mechanisms of Epi and 8HD in human colon adenocarcinoma Caco-2 cells. 8HD enhanced cytotoxicity of Epi and generated a synergistic effect. Epi and/or 8HD treatments increased the hydrogen peroxide( )and( )superoxide levels. Combined treatment markedly decreased mRNA expression levels of multidrug resistance protein 1 (MDR1), MDR-associated protein (MRP) 1, and MRP2. 8HD significantly intensified Epi intracellular accumulation in Caco-2 cells. 8HD and/or Epi-induced apoptosis, as indicated by the reduced mitochondrial membrane potential and increased sub-G1 phase in cell cycle. Moreover, 8HD and Epi significantly enhanced the mRNA expressions of Bax, p53, caspases-3, -8, and -9. To our best knowledge, this study verifies for the first time that 8HD effectively circumvents MDR in Caco-2 cells through the ROS dependent inhibition of efflux transporters and p53-mediated activation of both death receptor and mitochondrial pathways of apoptosis. Our findings of 8HD shed light on the future search for potential biotransformed isoflavones to intensify the cytotoxicity of anticancer drugs through simultaneous reversal of pump and nonpump resistance. PMID- 23344024 TI - Mechanisms of resistance to endocrine therapy in breast cancer: focus on signaling pathways, miRNAs and genetically based resistance. AB - Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERalpha-positive breast cancer. Alone or combined with chemotherapy, tamoxifen significantly reduces disease progression and is associated with more favorable impact on survival in patients. Unfortunately, endocrine resistance occurs, either de novo or acquired during the course of the treatment. The mechanisms that contribute to hormonal resistance include loss or modification in the ERalpha expression, regulation of signal transduction pathways, altered expression of specific microRNAs, balance of co-regulatory proteins, and genetic polymorphisms involved in tamoxifen metabolic activity. Because of the clinical consequences of endocrine resistance, new treatment strategies are arising to make the cells sensitive to tamoxifen. Here, we will review the current knowledge on mechanisms of endocrine resistance in breast cancer cells. In addition, we will discuss novel therapeutic strategies to overcome such resistance. Undoubtedly, circumventing endocrine resistance should help to improve therapy for the benefit of breast cancer patients. PMID- 23344027 TI - Changes in translational control after pro-apoptotic stress. AB - In stressed cells, a general decrease in the rate of protein synthesis occurs due to modifications in the activity of translation initiation factors. Compelling data now indicate that these changes also permit a selective post-transcriptional expression of proteins necessary for either cell survival or completion of apoptosis when cells are exposed to severe or prolonged stress. In this review, we summarize the modifications that inhibit the activity of the main canonical translation initiation factors, and the data explaining how certain mRNAs encoding proteins involved in either cell survival or apoptosis can be selectively translated. PMID- 23344028 TI - The role of photolabile dermal nitric oxide derivates in ultraviolet radiation (UVR)-induced cell death. AB - Human skin is exposed to solar ultraviolet radiation comprising UVB (280-315 nm) and UVA (315-400 nm) on a daily basis. Within the last two decades, the molecular and cellular response to UVA/UVB and the possible effects on human health have been investigated extensively. It is generally accepted that the mutagenic and carcinogenic properties of UVB is due to the direct interaction with DNA. On the other hand, by interaction with non-DNA chromophores as endogenous photosensitizers, UVA induces formation of reactive oxygen species (ROS), which play a pivotal role as mediators of UVA-induced injuries in human skin. This review gives a short overview about relevant findings concerning the molecular mechanisms underlying UVA/UVB-induced cell death. Furthermore, we will highlight the potential role of cutaneous antioxidants and photolabile nitric oxide derivates (NODs) in skin physiology. UVA-induced decomposition of the NODs, like nitrite, leads not only to non-enzymatic formation of nitric oxide (NO), but also to toxic reactive nitrogen species (RNS), like peroxynitrite. Whereas under antioxidative conditions the generation of protective amounts of NO is favored, under oxidative conditions, less injurious reactive nitrogen species are generated, which may enhance UVA-induced cell death. PMID- 23344029 TI - Expression and functional studies on the noncoding RNA, PRINS. AB - PRINS, a noncoding RNA identified earlier by our research group, contributes to psoriasis susceptibility and cellular stress response. We have now studied the cellular and histological distribution of PRINS by using in situ hybridization and demonstrated variable expressions in different human tissues and a consistent staining pattern in epidermal keratinocytes and in vitro cultured keratinocytes. To identify the cellular function(s) of PRINS, we searched for a direct interacting partner(s) of this stress-induced molecule. In HaCaT and NHEK cell lysates, the protein proved to be nucleophosmin (NPM) protein as a potential physical interactor with PRINS. Immunohistochemical experiments revealed an elevated expression of NPM in the dividing cells of the basal layers of psoriatic involved skin samples as compared with healthy and psoriatic uninvolved samples. Others have previously shown that NPM is a ubiquitously expressed nucleolar phosphoprotein which shuttles to the nucleoplasm after UV-B irradiation in fibroblasts and cancer cells. We detected a similar translocation of NPM in UV-B irradiated cultured keratinocytes. The gene-specific silencing of PRINS resulted in the retention of NPM in the nucleolus of UV-B-irradiated keratinocytes; suggesting that PRINS may play a role in the NPM-mediated cellular stress response in the skin. PMID- 23344030 TI - The controversial role of retinoic acid in fibrotic diseases: analysis of involved signaling pathways. AB - Fibrotic diseases, such as liver, pulmonary and renal fibrosis, are common end stage conditions and represent a major global health problem. Furthermore, effective therapeutic measures are presently unavailable. Extracellular matrix accumulation is the most prominent characteristic in the pathogenesis of fibrotic disease. Retinoic acid, including all-trans retinoic acid, 9-cis and 13-cis retinoic acid, play important roles in various physiological processes, such as in embryonic development, reproduction, vision, cell growth, differentiation, apoptosis and inflammation. Present studies report that retinoic acid treatment may affect various processes involved in the onset and progression of fibrotic disease. However, the therapeutic effects of retinoic acid in such diseases remain controversial. Several reports indicate that retinoic acid positively affects the progression of fibrosis and alleviates the accumulation of the extracellular matrix, whereas other studies report the opposite; that retinoic acid exacerbates fibrosis and induces extracellular matrix accumulation. Signaling pathways might be an important influencing factor and differences in signaling events might be responsible for the contradictory role of retinoic acid in fibrotic diseases. Since there was no review available that investigated the role of retinoic acid and the signaling pathways involved, we retrospectively studied the literature and provide a comprehensive analysis of retinoic acid's role in fibrotic diseases, and provide an overview of the signal transduction pathways involved in its pathogenesis. PMID- 23344031 TI - Nano size effects of TiO2 nanotube array on the glioma cells behavior. AB - In order to investigate the interplay between the cells and TiO(2) nanotube array, and to explore the ability of cells to sense the size change in nano environment, we reported on the behavior of glioma C6 cells on nanotube array coatings in terms of proliferation and apoptosis. The behavior of glioma C6 cells was obviously size-dependent on the coatings; the caliber with 15 nm diameter provided effective spacing to improve the cells proliferation and enhanced the cellular activities. C6 cells' biological behaviors showed many similar tendencies to many phorocytes; the matching degree of geometry between nanotube and integrin defined that a spacing of 15 nm was optimal for inducing signals to nucleus, which results in achieving maximum activity of glioma cells. In addition, the immune behavior of cells was studied, a variety of inflammatory mediator's gene expression levels were controlled by the nanoscale dimension, the expressions of IL-6 and IL-10 were higher on 30 nm than on 15 nm nanotube. PMID- 23344032 TI - Role of carnitine acetyl transferase in regulation of nitric oxide signaling in pulmonary arterial endothelial cells. AB - Congenital heart defects with increased pulmonary blood flow (PBF) result in pulmonary endothelial dysfunction that is dependent, at least in part, on decreases in nitric oxide (NO) signaling. Utilizing a lamb model with left-to right shunting of blood and increased PBF that mimics the human disease, we have recently shown that a disruption in carnitine homeostasis, due to a decreased carnitine acetyl transferase (CrAT) activity, correlates with decreased bioavailable NO. Thus, we undertook this study to test the hypothesis that the CrAT enzyme plays a major role in regulating NO signaling through its effect on mitochondrial function. We utilized the siRNA gene knockdown approach to mimic the effect of decreased CrAT activity in pulmonary arterial endothelial cells (PAEC). Our data indicate that silencing the CrAT gene disrupted cellular carnitine homeostasis, reduced the expression of mitochondrial superoxide dismutase-and resulted in an increase in oxidative stress within the mitochondrion. CrAT gene silencing also disrupted mitochondrial bioenergetics resulting in reduced ATP generation and decreased NO signaling secondary to a reduction in eNOS/Hsp90 interactions. Thus, this study links the disruption of carnitine homeostasis to the loss of NO signaling observed in children with CHD. Preserving carnitine homeostasis may have important clinical implications that warrant further investigation. PMID- 23344033 TI - Antitumor effects of rapamycin in pancreatic cancer cells by inducing apoptosis and autophagy. AB - Rapamycin (Rapa), an inhibitor of mammalian target of Rapamycin (mTOR), is an immunosuppressive agent that has anti-proliferative effects on some tumors. This study aims to investigate the effects of Rapa suppressing proliferation of pancreatic carcinoma PC-2 cells in vitro and its molecular mechanism involved in antitumor activities. MTT assays showed that the inhibition of proliferation of PC-2 cells in vitro was in a time- and dose-dependent manner. By using transmission electron microscopy, apoptosis bodies and formation of abundant autophagic vacuoles were observed in PC-2 cells after Rapa treatment. Flow cytometry assays also showed Rapa had a positive effect on apoptosis. MDC staining showed that the fluorescent density was higher and the number of MDC labeled particles in PC-2 cells was greater in the Rapa treatment group than in the control group. RT-PCR revealed that the expression levels of p53, Bax and Beclin 1 were up-regulated in a dose-dependent manner, indicating that Beclin 1 was involved in Rapa induced autophagy and Rapa induced apoptosis as well as p53 up-regulation in PC-2 cells. The results demonstrated that Rapa could effectively inhibit proliferation and induce apoptosis and autophagy in PC-2 cells. PMID- 23344035 TI - Purification and properties of an insecticidal metalloprotease produced by Photorhabdus luminescens strain 0805-P5G, the entomopathogenic nematode symbiont. AB - A total of 13 Photorhabdus luminescens strains were screened for proteolytic activity. The P. luminescens strain 0805-P5G had the highest activity on both skim milk and gelatin plates. The protease was purified to electrophoretical homogeneity by using a two-step column chromatographic procedure. It had a molecular weight of 51.8 kDa, as determined by MALDI-TOF mass spectrometry. The optimum pH, temperature, as well as pH and thermal stabilities were 8, 60 degrees C, 5-10, and 14-60 degrees C, respectively. It was completely inhibited by EDTA and 1,10-phenanthroline. Bioassay of the purified protease against Galleria mellonella by injection showed high insecticidal activity. The protease also showed high oral toxicity to the diamondback moth (Plutella xylostella) of a Taiwan field-collected strain, but low toxicity to an American strain. To our knowledge, this is the first report to demonstrate that the purified protease of P. luminescens has direct toxicity to P. xylostella and biopesticide potentiality. PMID- 23344034 TI - Quantitative profiling of DNA damage and apoptotic pathways in UV damaged cells using PTMScan Direct. AB - Traditional methods for analysis of peptides using liquid chromatography and tandem mass spectrometry (LC-MS/MS) lack the specificity to comprehensively monitor specific biological processes due to the inherent duty cycle limitations of the MS instrument and the stochastic nature of the analytical platform. PTMScan Direct is a novel, antibody-based method that allows quantitative LC MS/MS profiling of specific peptides from proteins that reside in the same signaling pathway. New PTMScan Direct reagents have been produced that target peptides from proteins involved in DNA Damage/Cell Cycle and Apoptosis/Autophagy pathways. Together, the reagents provide access to 438 sites on 237 proteins in these signaling cascades. These reagents have been used to profile the response to UV damage of DNA in human cell lines. UV damage was shown to activate canonical DNA damage response pathways through ATM/ATR-dependent signaling, stress response pathways and induce the initiation of apoptosis, as assessed by an increase in the abundance of peptides corresponding to cleaved, activated caspases. These data demonstrate the utility of PTMScan Direct as a multiplexed assay for profiling specific cellular responses to various stimuli, such as UV damage of DNA. PMID- 23344036 TI - Synthesis and self-organization of fluorene-conjugated bisimidazolylporphyrin and its optical properties. AB - A conjugated-bisimidazolylporphyrin bridged by bis(ethynylfluorene) was synthesized and organized into linear polymer through self-coordination having mean molecular weights, M(w) and M(n), of ~2.1 * 105 Da and ~1.6 * 105 Da, respectively. A large two-photon absorption cross section value of 3.4 * 105 GM (per dimer unit) was observed. This value was comparable to that of the previously reported self-assembled linear polymer consisting of butadiyne-bridged imidazolylporphyrins. The two-photon absorption properties could be controlled by tuning the wavelength and absorption intensity of the one-photon absorption. PMID- 23344038 TI - Overlapping ATP2C1 and ASTE1 genes in human genome: implications for SPCA1 expression? AB - The ATP2C1 gene encodes for the secretory pathway calcium (Ca2+)-ATPase pump (SPCA1), which localizes along the secretory pathway, mainly in the trans-Golgi. The loss of one ATP2C1 allele causes Hailey-Hailey disease in humans but not mice. Examining differences in genomic organization between mouse and human we speculate that the overlap between ATP2C1 and ASTE1 genes only in humans could explain this different response to ATP2C1 dysregulation. We propose that ASTE1, overlapping with ATP2C1 in humans, affects alternative splicing, and potentially protein expression of the latter. If dysregulated, the composition of the SPCA1 isoform pool could diverge from the physiological status, affecting cytosolic Ca2+-signaling, and in turn perturbing cell division, leading to cell death or to neoplastic transformation. PMID- 23344037 TI - Ovarian cancer: in search of better marker systems based on DNA repair defects. AB - Ovarian cancer is the fifth most common female cancer in the Western world, and the deadliest gynecological malignancy. The overall poor prognosis for ovarian cancer patients is a consequence of aggressive biological behavior and a lack of adequate diagnostic tools for early detection. In fact, approximately 70% of all patients with epithelial ovarian cancer are diagnosed at advanced tumor stages. These facts highlight a significant clinical need for reliable and accurate detection methods for ovarian cancer, especially for patients at high risk. Because CA125 has not achieved satisfactory sensitivity and specificity in detecting ovarian cancer, numerous efforts, including those based on single and combined molecule detection and "omics" approaches, have been made to identify new biomarkers. Intriguingly, more than 10% of all ovarian cancer cases are of familial origin. BRCA1 and BRCA2 germline mutations are the most common genetic defects underlying hereditary ovarian cancer, which is why ovarian cancer risk assessment in developed countries, aside from pedigree analysis, relies on genetic testing of BRCA1 and BRCA2. Because not only BRCA1 and BRCA2 but also other susceptibility genes are tightly linked with ovarian cancer-specific DNA repair defects, another possible approach for defining susceptibility might be patient cell-based functional testing, a concept for which support came from a recent case-control study. This principle would be applicable to risk assessment and the prediction of responsiveness to conventional regimens involving platinum based drugs and targeted therapies involving poly (ADP-ribose) polymerase (PARP) inhibitors. PMID- 23344039 TI - A molecular-modeling toolbox aimed at bridging the gap between medicinal chemistry and computational sciences. AB - In the current era of high-throughput drug discovery and development, molecular modeling has become an indispensable tool for identifying, optimizing and prioritizing small-molecule drug candidates. The required background in computational chemistry and the knowledge of how to handle the complex underlying protocols, however, might keep medicinal chemists from routinely using in silico technologies. Our objective is to encourage those researchers to exploit existing modeling technologies more frequently through easy-to-use graphical user interfaces. In this account, we present two innovative tools (which we are prepared to share with academic institutions) facilitating computational tasks commonly utilized in drug discovery and development: (1) the VirtualDesignLab estimates the binding affinity of small molecules by simulating and quantifying their binding to the three-dimensional structure of a target protein; and (2) the MD Client launches molecular dynamics simulations aimed at exploring the time dependent stability of ligand-protein complexes and provides residue-based interaction energies. This allows medicinal chemists to identify sites of potential improvement in their candidate molecule. As a case study, we present the application of our tools towards the design of novel antagonists for the FimH adhesin. PMID- 23344040 TI - The voltage-dependent anion channel 1 (AtVDAC1) negatively regulates plant cold responses during germination and seedling development in Arabidopsis and interacts with calcium sensor CBL1. AB - The voltage-dependent anion channel (VDAC), a highly conserved major mitochondrial outer membrane protein, plays crucial roles in energy metabolism and metabolite transport. However, knowledge about the roles of the VDAC family in plants is limited. In this study, we investigated the expression pattern of VDAC1 in Arabidopsis and found that cold stress promoted the accumulation of VDAC1 transcripts in imbibed seeds and mature plants. Overexpression of VDAC1 reduced tolerance to cold stress in Arabidopsis. Phenotype analysis of VDAC1 T DNA insertion mutant plants indicated that a vdac1 mutant line had faster germination kinetics under cold treatment and showed enhanced tolerance to freezing. The yeast two-hybrid system revealed that VDAC1 interacts with CBL1, a calcium sensor in plants. Like the vdac1, a cbl1 mutant also exhibited a higher seed germination rate. We conclude that both VDAC1 and CBL1 regulate cold stress responses during seed germination and plant development. PMID- 23344041 TI - Molecular eigensolution symmetry analysis and fine structure. AB - Spectra of high-symmetry molecules contain fine and superfine level cluster structure related to J-tunneling between hills and valleys on rovibronic energy surfaces (RES). Such graphic visualizations help disentangle multi-level dynamics, selection rules, and state mixing effects including widespread violation of nuclear spin symmetry species. A review of RES analysis compares it to that of potential energy surfaces (PES) used in Born-Oppenheimer approximations. Both take advantage of adiabatic coupling in order to visualize Hamiltonian eigensolutions. RES of symmetric and D(2) asymmetric top rank-2 tensor Hamiltonians are compared with O(h) spherical top rank-4-tensor fine structure clusters of 6-fold and 8-fold tunneling multiplets. Then extreme 12 fold and 24-fold multiplets are analyzed by RES plots of higher rank tensor Hamiltonians. Such extreme clustering is rare in fundamental bands but prevalent in hot bands, and analysis of its superfine structure requires more efficient labeling and a more powerful group theory. This is introduced using elementary examples involving two groups of order-6 (C(6) and D(3)~C(3v)), then applied to families of O(h) clusters in SF(6) spectra and to extreme clusters. PMID- 23344042 TI - A model of interaction between nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and apocynin analogues by docking method. AB - Some apocynin analogues have exhibited outstanding inhibition to NADPH oxidase. In this study, the key interactions between apocynin analogues and NADPH oxidase were analyzed by the docking method. The potential active site was first identified by the SiteID program combining with the key residue CYS378. Afterwards, the compounds in the training set were docked into NADPH oxidase (1K4U) under specific docking constraints to discuss the key interactions between ligands and the receptor. These key interactions were then validated by the consistence between the docking result and the experimental result of the test set. The result reveals that the Pi interaction between apocynin analogues and NADPH oxidase has a direct contribution to inhibition activities, except for H bond formation and docking score. The key interactions might be valuable to discover and screen apocynin analogues as potent inhibitors of NADPH oxidase. PMID- 23344043 TI - Ameliorating effects of exogenously applied proline on seed composition, seed oil quality and oil antioxidant activity of maize (Zea mays L.) under drought stress. AB - This study was carried out to appraise whether or not the exogenous application of a potential osmoprotectant, proline, could ameliorate the adverse effects of drought stress on maize seed and seed oil composition, as well as oil antioxidant activity. Water stress reduced the kernel sugar, oil, protein and moisture contents and most of the seed macro- and micro-elements analyzed in both maize cultivars but it increased the contents of seed fiber and ash. Water stress increased the oil oleic acid content with a subsequent decrease in the amount of linoleic acid, resulting in an increased oil oleic/linoleic ratio for both maize cultivars. However, no variation was observed in oil stearic and palmitic acids content due to water stress. A considerable drought induced an increase in seed oil alpha-, gamma-, delta- and total tocopherols and flavonoids were observed in both maize cultivars. However, oil phenolic and carotenoid content as well as 1,1 diphenyl-2-picryl-hydrazyl (DPPH) free radical scavenging activity decreased. Foliar-applied proline significantly increased the content of seed sugar, oil, protein, moisture, fiber and ash in both maize cultivars under well irrigated and water deficit conditions. Furthermore, exogenous application of proline increased the oil oleic and linoleic acid contents. The concentrations of antioxidant compounds namely phenolics, carotenoids, flavonoids and tocopherols estimated in the seed oil increased due to foliar-applied proline under water deficit conditions that was positively correlated with the enhanced oil DPPH free radical scavenging activity. Moreover, the increase in the contents of these antioxidant compounds and oil antioxidant activity due to the foliar application of proline was noted to be more pronounced under water deficit conditions. PMID- 23344044 TI - Pharmacokinetics of dibutyl phthalate (DBP) in the rat determined by UPLC-MS/MS. AB - Dibutyl phthalate (DBP) is commonly used to increase the flexibility of plastics in industrial products. However, several plasticizers have been illegally used as clouding agents to increase dispersion of aqueous matrix in beverages. This study thus develops a rapid and validated analytical method by ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) for the evaluation of pharmacokinetics of DBP in free moving rats. The UPLC-MS/MS system equipped with positive electrospray ionization (ESI) source in multiple reaction monitoring (MRM) mode was used to monitor m/z 279.25->148.93 transitions for DBP. The limit of quantification for DBP in rat plasma and feces was 0.05 ug/mL and 0.125 ug/g, respectively. The pharmacokinetic results demonstrate that DBP appeared to have a two-compartment model in the rats; the area under concentration versus time (AUC) was 57.8 +/- 5.93 min MUg/mL and the distribution and elimination half-life (t(1/2,alpha) and t(1/2,beta)) were 5.77 +/- 1.14 and 217 +/- 131 min, respectively, after DBP administration (30 mg/kg, i.v.). About 0.18% of the administered dose was recovered from the feces within 48 h. The pharmacokinetic behavior demonstrated that DBP was quickly degraded within 2 h, suggesting a rapid metabolism low fecal cumulative excretion in the rat. PMID- 23344045 TI - Apoptosis is induced in cancer cells via the mitochondrial pathway by the novel xylocydine-derived compound JRS-15. AB - The novel compound JRS-15 was obtained through the chemical modification of xylocydine. JRS-15 exhibited much stronger cytotoxic and pro-apoptotic activity than its parent compound in various cancer cell lines, with IC(50) values in HeLa, HepG2, SK-HEP-1, PC-3M and A549 cells ranging from 12.42 to 28.25 uM. In addition, it is more potent for killing cancer than non-cancerous cells. Mechanistic studies showed that JRS-15 treatment arrested cell cycle at the G1/S phase, which further triggered the translocation of Bax and Bak to the mitochondria, resulting in mitochondrial membrane potential (MMP) depolarization and the subsequent release of cytochrome c and the second mitochondria-derived activator of caspase (Smac). The sequential activation of caspase-9 and caspase 3/7 and the cleavage of poly (ADP-ribose) polymerase (PARP) were observed following these mitochondrial events. Caspase-8, an initiator caspase that is required to activate the membrane receptor-mediated extrinsic apoptosis pathway was not activated in JRS-15-treated cells. Further analysis showed that the levels of the anti-apoptotic proteins Bcl-xL and XIAP were significantly reduced upon JRS-15 treatment. Furthermore, the caspase-9 inhibitor z-LEHD-fmk, the pan caspase inhibitor z-VAD-fmk, and Bcl-xL or XIAP overexpression all effectively prevented JRS-15-induced apoptosis. Taken together, these results indicate that JRS-15 induces cancer cell apoptosis by regulating multiple apoptosis-related proteins, and this compound may therefore be a good candidate reagent for anticancer therapy. PMID- 23344046 TI - Potential applications of carbohydrases immobilization in the food industry. AB - Carbohydrases find a wide application in industrial processes and products, mainly in the food industry. With these enzymes, it is possible to obtain different types of sugar syrups (viz. glucose, fructose and inverted sugar syrups), prebiotics (viz. galactooligossacharides and fructooligossacharides) and isomaltulose, which is an interesting sweetener substitute for sucrose to improve the sensory properties of juices and wines and to reduce lactose in milk. The most important carbohydrases to accomplish these goals are of microbial origin and include amylases (alpha-amylases and glucoamylases), invertases, inulinases, galactosidases, glucosidases, fructosyltransferases, pectinases and glucosyltransferases. Yet, for all these processes to be cost-effective for industrial application, a very efficient, simple and cheap immobilization technique is required. Immobilization techniques can involve adsorption, entrapment or covalent bonding of the enzyme into an insoluble support, or carrier-free methods, usually based on the formation of cross-linked enzyme aggregates (CLEAs). They include a broad variety of supports, such as magnetic materials, gums, gels, synthetic polymers and ionic resins. All these techniques present advantages and disadvantages and several parameters must be considered. In this work, the most recent and important studies on the immobilization of carbohydrases with potential application in the food industry are reviewed. PMID- 23344047 TI - Anticancer effects of bufalin on human hepatocellular carcinoma HepG2 cells: roles of apoptosis and autophagy. AB - The traditional Chinese medicine bufalin, extracted from toad's skin, has been demonstrated to exert anticancer activities in various kinds of human cancers. The mechanisms of action lie in its capacity to induce apoptosis, or termed type I programmed cell death (PCD). However, type II PCD, or autophagy, participates in cancer proliferation, progression, and relapse, as well. Recent studies on autophagy seem to be controversial because of the dual roles of autophagy in cancer survival and death. In good agreement with previous studies, we found that 100 nM bufalin induced extensive HepG2 cell apoptosis. However, we also noticed bufalin triggered autophagy and enhanced Beclin-1 expression, LC3-I to LC3-II conversion, as well as decreased p62 expression and mTOR signaling activation in HepG2 cells. Blockage of autophagy by selective inhibitor 3-MA decreased apoptotic ratio in bufalin-treated HepG2 cells, suggesting a proapoptotic role of bufalin-induced autophagy. Furthermore, we investigated the underlying mechanisms of bufalin-induced autophagy. Bufalin treatment dose-dependently promoted AMPK phosphorylation while AMPK inhibition by compound C significantly attenuated bufalin-induced autophagy. Taken together, we report for the first time that bufalin induces HepG2 cells PCD, especially for autophagy, and the mechanism of action is, at least in part, AMPK-mTOR dependent. PMID- 23344048 TI - Role of the blood-brain barrier in the formation of brain metastases. AB - The majority of brain metastases originate from lung cancer, breast cancer and malignant melanoma. In order to reach the brain, parenchyma metastatic cells have to transmigrate through the endothelial cell layer of brain capillaries, which forms the morphological basis of the blood-brain barrier (BBB). The BBB has a dual role in brain metastasis formation: it forms a tight barrier protecting the central nervous system from entering cancer cells, but it is also actively involved in protecting metastatic cells during extravasation and proliferation in the brain. The mechanisms of interaction of cancer cells and cerebral endothelial cells are largely uncharacterized. Here, we provide a comprehensive review on our current knowledge about the role of junctional and adhesion molecules, soluble factors, proteolytic enzymes and signaling pathways mediating the attachment of tumor cells to brain endothelial cells and the transendothelial migration of metastatic cells. Since brain metastases represent a great therapeutic challenge, it is indispensable to understand the mechanisms of the interaction of tumor cells with the BBB in order to find targets of prevention of brain metastasis formation. PMID- 23344049 TI - Shear stress inhibits apoptosis of ischemic brain microvascular endothelial cells. AB - As a therapeutic strategy for ischemic stroke, to restore or increase cerebral blood flow (CBF) is the most fundamental option. Laminar shear stress (LS), as an important force generated by CBF, mainly acts on brain microvascular endothelial cells (BMECs). In order to study whether LS was a protective factor in stroke, we investigated LS-intervented ischemic apoptosis of rat BMECs (rBMECs) through PE Annexin V/7-AAD, JC-1 and Hoechst 33258 staining to observe the membranous, mitochondrial and nuclear dysfunction. Real-time PCR and western blot were also used to test the gene and protein expressions of Tie-2, Bcl-2 and Akt, which were respectively related to maintain membranous, mitochondrial and nuclear norm. The results showed that LS could be a helpful stimulus for ischemic rBMECs survival. Simultaneously, membranous, mitochondrial and nuclear regulation played an important role in this process. PMID- 23344050 TI - Buckwheat (Fagopyrum esculentum M.) sprout treated with methyl jasmonate (MeJA) improved anti-adipogenic activity associated with the oxidative stress system in 3T3-L1 adipocytes. AB - Buckwheat sprouts contain various bioactive compounds including rutin which have a number of biological activities. We have previously shown that buckwheat sprouts (TBWE) treated with methyl jasmonate (MeJA) significantly increased the amount of phenolics and the antioxidant activity. The aim of this study was to demonstrate the effect of TBWE on anti-adipogenesis and pro-oxidant enzyme in 3T3 L1 adipocytes. We also evaluated the anti-oxidative activity of TBWE in adipocytes by using the nitroblue tetrazolium assay. Our data showed that TBWE markedly inhibited adipocyte differentiation and ROS production in 3T3-L1 cells compared with control groups. Moreover, TBWE has strongly shown the inhibition of adipogenic transcription factor as well as pro-oxidant enzymes. Together, we demonstrate that the MeJA treatment significantly increased the amount of phenolic compound, resulting in the suppression of adipogenesis and ROS production in the 3T3-L1 cells. These findings indicate that TBWE has the potential for anti-adipogenesis activity with anti-oxidative properties. PMID- 23344051 TI - Quantitative structure-activity relationships predicting the antioxidant potency of 17beta-estradiol-related polycyclic phenols to inhibit lipid peroxidation. AB - The antioxidant potency of 17beta-estradiol and related polycyclic phenols has been well established. This property is an important component of the complex events by which these types of agents are capable to protect neurons against the detrimental consequences of oxidative stress. In order to relate their molecular structure and properties with their capacity to inhibit lipid peroxidation, a marker of oxidative stress, quantitative structure-activity relationship (QSAR) studies were conducted. The inhibition of Fe3+-induced lipid peroxidation in rat brain homogenate, measured through an assay detecting thiobarbituric acid reactive substances for about seventy compounds were correlated with various molecular descriptors. We found that lipophilicity (modeled by the logarithm of the n-octanol/water partition coefficient, logP) was the property that influenced most profoundly the potency of these compounds to inhibit lipid peroxidation in the biological medium studied. Additionally, the important contribution of the bond dissociation enthalpy of the phenolic O-H group, a shape index, the solvent accessible surface area and the energy required to remove an electron from the highest occupied molecular orbital were also confirmed. Several QSAR equations were validated as potentially useful exploratory tools for identifying or designing novel phenolic antioxidants incorporating the structural backbone of 17beta-estradiol to assist therapy development against oxidative stress associated neurodegeneration. PMID- 23344052 TI - Role of oxidative stress in refractory epilepsy: evidence in patients and experimental models. AB - Oxidative stress, a state of imbalance in the production of reactive oxygen species and nitrogen, is induced by a wide variety of factors. This biochemical state is associated with systemic diseases, and diseases affecting the central nervous system. Epilepsy is a chronic neurological disorder with refractoriness to drug therapy at about 30%. Currently, experimental evidence supports the involvement of oxidative stress in seizures, in the process of their generation, and in the mechanisms associated with refractoriness to drug therapy. Hence, the aim of this review is to present information in order to facilitate the handling of this evidence and determine the therapeutic impact of the biochemical status for this pathology. PMID- 23344053 TI - Folate-equipped nanolipoplexes mediated efficient gene transfer into human epithelial cells. AB - Since recombinant viral vectors have been associated with serious side effects, such as immunogenicity and oncogenicity, synthetic delivery systems represent a realistic alternative for achieving efficacy in gene therapy. A major challenge for non-viral nanocarriers is the optimization of transgene expression in the targeted cells. This goal can be achieved by fine-tuning the chemical carriers and the adding specific motifs to promote cellular penetration. Our study focuses on the development of novel folate-based complexes that contain varying quantities of folate motifs. After controlling for their physical properties, neutral folate-modified lipid formulations were compared in vitro to lipoplexes leading to comparable expression levels. In addition, no cytotoxicity was detected, unlike what was observed in the cationic controls. Mechanistically, the delivery of the transgene appeared to be, in part, due to endocytosis mediated by folate receptor targeting. This mechanism was further validated by the observation that adding free folate into the medium decreased luciferase expression by 50%. In vivo transfection with the folate-modified MM18 lipid, containing the highest amount of FA-PEG(570)-diether co-lipid (w:w; 90:10), at a neutral charge ratio, gave luciferase transgene expression. These studies indicate that modification of lipids with folate residues could enhance non toxic, cell-specific gene delivery. PMID- 23344054 TI - Anthocyanins downregulate lipopolysaccharide-induced inflammatory responses in BV2 microglial cells by suppressing the NF-kappaB and Akt/MAPKs signaling pathways. AB - Anthocyanins are naturally occurring polyphenols that impart bright color to fruits, vegetables and plants and have a variety of protective properties, which have generally been attributed to their antioxidant capacity. However, little is known about the molecular mechanisms underlying anti-inflammatory effects of anthocyanins related to neurodegenerative diseases. Therefore, we determined whether anthocyanins isolated from black soybean seed coats would inhibit pro inflammatory mediators and cytokines in lipopolysaccharide (LPS)-stimulated murine BV2 microglial cells. Our results showed that anthocyanins significantly inhibited LPS-induced pro-inflammatory mediators, such as nitric oxide (NO) and prostaglandin E(2), and pro-inflammatory cytokines including tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, without significant cytotoxicity. Anthocyanins also downregulated excessive expression of inducible NO synthase, cyclooxygenase-2, TNF-alpha, and IL-1beta in LPS-stimulated BV2 cells. Moreover, anthocyanins inhibited nuclear translocation of nuclear factor-kappa B (NF kappaB) by reducing inhibitor of NF-kappaB alpha degradation as well as phosphorylating extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and Akt. These findings suggest that anthocyanins may offer substantial therapeutic potential for treating inflammatory and neurodegenerative diseases accompanied by microglial activation. PMID- 23344056 TI - Aqueous self-sorting in extended supramolecular aggregates. AB - Self-organization and self-sorting processes are responsible for the regulation and control of the vast majority of biological processes that eventually sustain life on our planet. Attempts to unveil the complexity of these systems have been devoted to the investigation of the binding processes between artificial molecules, complexes or aggregates within multicomponent mixtures, which has facilitated the emergence of the field of self-sorting in the last decade. Since, artificial systems involving discrete supramolecular structures, extended supramolecular aggregates or gel-phase materials in organic solvents or-to a lesser extent-in water have been investigated. In this review, we have collected diverse strategies employed in recent years to construct extended supramolecular aggregates in water upon self-sorting of small synthetic molecules. We have made particular emphasis on co-assembly processes in binary mixtures leading to supramolecular structures of remarkable complexity and the influence of different external variables such as solvent and concentration to direct recognition or discrimination processes between these species. The comprehension of such recognition phenomena will be crucial for the organization and evolution of complex matter. PMID- 23344055 TI - Role of RNA interference (RNAi) in the Moss Physcomitrella patens. AB - RNA interference (RNAi) is a mechanism that regulates genes by either transcriptional (TGS) or posttranscriptional gene silencing (PTGS), required for genome maintenance and proper development of an organism. Small non-coding RNAs are the key players in RNAi and have been intensively studied in eukaryotes. In plants, several classes of small RNAs with specific sizes and dedicated functions have evolved. The major classes of small RNAs include microRNAs (miRNAs) and small interfering RNAs (siRNAs), which differ in their biogenesis. miRNAs are synthesized from a short hairpin structure while siRNAs are derived from long double-stranded RNAs (dsRNA). Both miRNA and siRNAs control the expression of cognate target RNAs by binding to reverse complementary sequences mediating cleavage or translational inhibition of the target RNA. They also act on the DNA and cause epigenetic changes such as DNA methylation and histone modifications. In the last years, the analysis of plant RNAi pathways was extended to the bryophyte Physcomitrella patens, a non-flowering, non-vascular ancient land plant that diverged from the lineage of seed plants approximately 450 million years ago. Based on a number of characteristic features and its phylogenetic key position in land plant evolution P. patens emerged as a plant model species to address basic as well as applied topics in plant biology. Here we summarize the current knowledge on the role of RNAi in P. patens that shows functional overlap with RNAi pathways from seed plants, and also unique features specific to this species. PMID- 23344057 TI - RUNX1: A microRNA hub in normal and malignant hematopoiesis. AB - Hematopoietic development is orchestrated by gene regulatory networks that progressively induce lineage-specific transcriptional programs. To guarantee the appropriate level of complexity, flexibility, and robustness, these networks rely on transcriptional and post-transcriptional circuits involving both transcription factors (TFs) and microRNAs (miRNAs). The focus of this review is on RUNX1 (AML1), a master hematopoietic transcription factor which is at the center of miRNA circuits necessary for both embryonic and post-natal hematopoiesis. Interference with components of these circuits can perturb RUNX1-controlled coding and non-coding transcriptional programs in leukemia. PMID- 23344058 TI - Reconstitution of membrane proteins into model membranes: seeking better ways to retain protein activities. AB - The function of any given biological membrane is determined largely by the specific set of integral membrane proteins embedded in it, and the peripheral membrane proteins attached to the membrane surface. The activity of these proteins, in turn, can be modulated by the phospholipid composition of the membrane. The reconstitution of membrane proteins into a model membrane allows investigation of individual features and activities of a given cell membrane component. However, the activity of membrane proteins is often difficult to sustain following reconstitution, since the composition of the model phospholipid bilayer differs from that of the native cell membrane. This review will discuss the reconstitution of membrane protein activities in four different types of model membrane - monolayers, supported lipid bilayers, liposomes and nanodiscs, comparing their advantages in membrane protein reconstitution. Variation in the surrounding model environments for these four different types of membrane layer can affect the three-dimensional structure of reconstituted proteins and may possibly lead to loss of the proteins activity. We also discuss examples where the same membrane proteins have been successfully reconstituted into two or more model membrane systems with comparison of the observed activity in each system. Understanding of the behavioral changes for proteins in model membrane systems after membrane reconstitution is often a prerequisite to protein research. It is essential to find better solutions for retaining membrane protein activities for measurement and characterization in vitro. PMID- 23344059 TI - UV-Induced cell death in plants. AB - Plants are photosynthetic organisms that depend on sunlight for energy. Plants respond to light through different photoreceptors and show photomorphogenic development. Apart from Photosynthetically Active Radiation (PAR; 400-700 nm), plants are exposed to UV light, which is comprised of UV-C (below 280 nm), UV-B (280-320 nm) and UV-A (320-390 nm). The atmospheric ozone layer protects UV-C radiation from reaching earth while the UVR8 protein acts as a receptor for UV-B radiation. Low levels of UV-B exposure initiate signaling through UVR8 and induce secondary metabolite genes involved in protection against UV while higher dosages are very detrimental to plants. It has also been reported that genes involved in MAPK cascade help the plant in providing tolerance against UV radiation. The important targets of UV radiation in plant cells are DNA, lipids and proteins and also vital processes such as photosynthesis. Recent studies showed that, in response to UV radiation, mitochondria and chloroplasts produce a reactive oxygen species (ROS). Arabidopsis metacaspase-8 (AtMC8) is induced in response to oxidative stress caused by ROS, which acts downstream of the radical induced cell death (AtRCD1) gene making plants vulnerable to cell death. The studies on salicylic and jasmonic acid signaling mutants revealed that SA and JA regulate the ROS level and antagonize ROS mediated cell death. Recently, molecular studies have revealed genes involved in response to UV exposure, with respect to programmed cell death (PCD). PMID- 23344060 TI - Biopolymer-based nanoparticles for drug/gene delivery and tissue engineering. AB - There has been a great interest in application of nanoparticles as biomaterials for delivery of therapeutic molecules such as drugs and genes, and for tissue engineering. In particular, biopolymers are suitable materials as nanoparticles for clinical application due to their versatile traits, including biocompatibility, biodegradability and low immunogenicity. Biopolymers are polymers that are produced from living organisms, which are classified in three groups: polysaccharides, proteins and nucleic acids. It is important to control particle size, charge, morphology of surface and release rate of loaded molecules to use biopolymer-based nanoparticles as drug/gene delivery carriers. To obtain a nano-carrier for therapeutic purposes, a variety of materials and preparation process has been attempted. This review focuses on fabrication of biocompatible nanoparticles consisting of biopolymers such as protein (silk, collagen, gelatin, beta-casein, zein and albumin), protein-mimicked polypeptides and polysaccharides (chitosan, alginate, pullulan, starch and heparin). The effects of the nature of the materials and the fabrication process on the characteristics of the nanoparticles are described. In addition, their application as delivery carriers of therapeutic drugs and genes and biomaterials for tissue engineering are also reviewed. PMID- 23344062 TI - Nanostructured surfaces of dental implants. AB - The structural and functional fusion of the surface of the dental implant with the surrounding bone (osseointegration) is crucial for the short and long term outcome of the device. In recent years, the enhancement of bone formation at the bone-implant interface has been achieved through the modulation of osteoblasts adhesion and spreading, induced by structural modifications of the implant surface, particularly at the nanoscale level. In this context, traditional chemical and physical processes find new applications to achieve the best dental implant technology. This review provides an overview of the most common manufacture techniques and the related cells-surface interactions and modulation. A Medline and a hand search were conducted to identify studies concerning nanostructuration of implant surface and their related biological interaction. In this paper, we stressed the importance of the modifications on dental implant surfaces at the nanometric level. Nowadays, there is still little evidence of the long-term benefits of nanofeatures, as the promising results achieved in vitro and in animals have still to be confirmed in humans. However, the increasing interest in nanotechnology is undoubted and more research is going to be published in the coming years. PMID- 23344063 TI - Neuroprotective effects of ultra-low-molecular-weight heparin on cerebral ischemia/reperfusion injury in rats: involvement of apoptosis, inflammatory reaction and energy metabolism. AB - Previous experiments showed that ultra-low-molecular-weight heparin (ULMWH) reduced the infarct and neurologic deficit in rats followed by transient cerebral ischemia, but the mechanisms of its neuroprotective effect are unclear. This study reported the effect of ULMWH on energy metabolism, inflammatory reaction and neuronal apoptosis. Male Wistar rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 24 h. ULMWH (0.5, 1 mg/kg, i.v.) was administered after the MCAO and reperfusion. 24 h after the reperfusion, Spectrophotometric assay was used to determine the activity of ATPase and the content of lactic acid in the brain. The ICAM-1 and Caspase-3 genes were investigated by RT-PCR. Furthermore, the apoptotic percentage of cells in hippocampus was quantified by flow cytometry. Compared with the model group, ULMWH significantly decreased lactic acid content and increased ATPase activity in ischemic brain. At the same time, ULMWH inhibited the neural apoptosis and decreased the expressions of ICAM-1 and Caspase-3 mRNA in hippocampus. These findings suggest that ULMWH exhibits a neuroprotective effect against cerebral ischemia/reperfusion injury, partly through improving energy metabolism, inhibiting apoptosis and attenuating inflammatory reaction. PMID- 23344064 TI - Resveratrol down-regulates Myosin light chain kinase, induces apoptosis and inhibits diethylnitrosamine-induced liver tumorigenesis in rats. AB - Hepatocellular carcinoma (HCC) is a serious healthcare problem worldwide because of its increasing morbidity and high mortality rates. However, our understanding of the mechanism of liver tumorigenesis remains incomplete. We report the expression of myosin light chain kinase (MLCK) in the livers of rats with diethylnitrosamine (DENA)-induced HCC and investigated the correlation between MLCK and liver tumorigenesis by observing the expression of MLCK in a rat model of HCC. HCC was induced in rats by an intraperitoneal injection of DENA, and resveratrol-treated rats were orally administered resveratrol with 50 mg/kg body weight/day. The livers of rats were excised after 20 weeks and immersed in 10% formaldehyde prior to immunohistochemical and Western blot analyses for determining the level of MLCK expression. These analyses indicated that the MLCK expression was higher in the livers of HCC rats than in normal and resveratrol treated rats. High level of MLCK expression was responsible for proliferation and anti-apoptotic effects. However, resveratrol down-regulated the expression of MLCK, which induced cell apoptosis and inhibited liver tumorigenesis in rats with DENA-induced HCC. Our results suggest that the over expression of MLCK may be related to the development of liver tumorigenesis. PMID- 23344061 TI - Neuroprotection for ischemic stroke: moving past shortcomings and identifying promising directions. AB - The translation of neuroprotective agents for ischemic stroke from bench-to bedside has largely failed to produce improved treatments since the development of tissue plasminogen activator (tPA). One possible reason for lack of translation is the failure to acknowledge the greatest risk factor for stroke, age, and other common comorbidities such as hypertension, obesity, and diabetes that are associated with stroke. In this review, we highlight both mechanisms of studying these factors and results of those that have been addressed. We also discuss the potential role of other lifestyle factors associated with an increased stroke risk such as sleep fragmentation and/or deprivation. Furthermore, many proposed therapeutic agents have targeted molecular mechanisms occurring soon after the onset of ischemia despite data indicating delayed patient presentation following ischemic stroke. Modulating inflammation has been identified as a promising therapeutic avenue consistent with preliminary success of ongoing clinical trials for anti-inflammatory compounds such as minocycline. We review the role of inflammation in stroke and in particular, the role of inflammatory cell recruitment and macrophage phenotype in the inflammatory process. Emerging evidence indicates an increasing role of neuro-immune crosstalk, which has led to increased interest in identification of peripheral biomarkers indicative of neural injury. It is our hope that identification and investigation of factors influencing stroke pathophysiology may lead to improved therapeutics. PMID- 23344066 TI - Novel electric power-driven hydrodynamic injection system for gene delivery: safety and efficacy of human factor IX delivery in rats. AB - The development of a safe and reproducible gene delivery system is an essential step toward the clinical application of the hydrodynamic gene delivery (HGD) method. For this purpose, we have developed a novel electric power-driven injection system called the HydroJector-EM, which can replicate various time pressure curves preloaded into the computer program before injection. The assessment of the reproducibility and safety of gene delivery system in vitro and in vivo demonstrated the precise replication of intravascular time-pressure curves and the reproducibility of gene delivery efficiency. The highest level of luciferase expression (272 pg luciferase per mg of proteins) was achieved safely using the time-pressure curve, which reaches 30 mm Hg in 10 s among various curves tested. Using this curve, the sustained expression of a therapeutic level of human factor IX protein (>500 ng ml(-1)) was maintained for 2 months after the HGD of the pBS-HCRHP-FIXIA plasmid. Other than a transient increase in liver enzymes that recovered in a few days, no adverse events were seen in rats. These results confirm the effectiveness of the HydroJector-EM for reproducible gene delivery and demonstrate that long-term therapeutic gene expression can be achieved by automatic computer-controlled hydrodynamic injection that can be performed by anyone. PMID- 23344067 TI - Gravimetric and analytical evaluation of welding fume in an automobile part manufacturing factory. AB - BACKGROUND: Welding is one of the most exercised industrial processes which welders are exposed to chemical and physical Hazardous agents. This study was conducted to evaluate occupational and environmental exposures to aerosols generated by welding processes in a factory. METHODS: A total of 28 samples of aerosols were collected at 4 different locations including indoor, outdoor, source of welding and the stacks using a high volume pump with a volumetric flow rate of 112 lit/min calibrated with a dry gas meter. The samples were collected on round 110 mm fiber glass filters, measured gravimetrically, extracted using nitric acid and analyzed with atomic absorption spectroscopy method for heavy metals including Fe, Mn, Ni, Cr3+, Cr+6, Co, and Zn. RESULTS: Gravimetric measuring has shown the mean values of indoor air: 1.33 mg/m3, breathing zone of the welders using coated electrodes and CO2: 7.25 mg/m3 and 6.45 mg/m3 respectively and in ventilation exhausts: 95.07 mg/m3. The mean values of Fe, Mn, and Ni were 0.8, 0.041, and 0.00 mg/m3 in indoor air, 2.7, 0.18, and 0.15 mg/m3 in breathing zone of welders used coated electrodes, and 1.75, 0.08, and 0.22 mg/m3 in breathing zone of welders used CO2 welding respectively. The concentrations of Cr3+, Cr+6, Co, and Zn were too low to be detected. CONCLUSION: The welders were exposed to high concentration of metallic fumes, which raise the risk of pulmonary dysfunction and other health disorders. Using suitable respiratory masks and Appling the effective local ventilation system may improve the working condition. PMID- 23344068 TI - A Practical Method for School Furniture Design to Prevent Musculoskeletal Disorders among Pupils. AB - BACKGROUND: Design of school furniture is one of the contributing factors to back pain among pupils. Research has implicated that mismatch between school furniture and body size may be regarded as a causative factor for muculoskeletal disorders amongst pupils. To investigate the fitness between school furniture and pupils this study was designed and implemented in Hamadan City, west of Iran. METHODS: This descriptive study was done on 1580 pupils from 11 to 18 years old including both genders, using cluster sampling. Anthropometrical dimensions including height and weight were measured and demographic data collected. RESULTS: According to ISO 5970 procedure, all studied pupils, divided into four groups. In the first group, including both genders in first grade of secondary school, size 3 was purposed for redesign of school furniture. In the second group, including boys in second and third grade of secondary school, size 4 was purposed for redesign of school furniture. Accordingly, in the third group including girls from second grade of secondary school to end of high school, size 4 was purposed for redesign of school furniture. In forth group including high school boys, size 5 was purposed for redesign of school furniture. CONCLUSION: Current design of school furniture is not compatible with the purposed dimensions. In most cases, the same size furniture was in use from secondary schools to high schools. PMID- 23344069 TI - Application of a hazard and operability study method to hazard evaluation of a chemical unit of the power station. AB - BACKGROUND: The aim of this study was to identify the hazards, evaluate their risk factors and determine the measure for promotion of the process and reduction of accidents in the chemical unit of the power station. METHODS: In this case and qualitative study, HAZOP technique was used to recognize the hazards and problems of operations on the chemical section at power station. Totally, 126 deviations were documented with various causes and consequences. RESULTS: Ranking and evaluation of identified risks indicate that the majority of deviations were categorized as "acceptable" and less than half of that were "unacceptable". The highest calculated risk level (1B) related to both the interruption of acid entry to the discharge pumps and an increased density of the acid. About 27% of the deviations had the lowest risk level (4B). CONCLUSION: The identification of hazards by HAZOP indicates that it could, systemically, assess and criticize the process of consumption or production of acid and alkali in the chemical unit of power plant. PMID- 23344065 TI - Retinal gene therapy with a large MYO7A cDNA using adeno-associated virus. AB - Usher 1 patients are born profoundly deaf and then develop retinal degeneration. Thus they are readily identified before the onset of retinal degeneration, making gene therapy a viable strategy to prevent their blindness. Here, we have investigated the use of adeno-associated viruses (AAVs) for the delivery of the Usher 1B gene, MYO7A, to retinal cells in cell culture and in Myo7a-null mice. MYO7A cDNA, under control of a smCBA promoter, was packaged in single AAV2 and AAV5 vectors and as two overlapping halves in dual AAV2 vectors. The 7.9-kb smCBA MYO7A exceeds the capacity of an AAV vector; packaging of such oversized constructs into single AAV vectors may involve fragmentation of the gene. Nevertheless, the AAV2 and AAV5 single vector preparations successfully transduced photoreceptor and retinal pigment epithelium cells, resulting in functional, full-length MYO7A protein and correction of mutant phenotypes, suggesting successful homologous recombination of gene fragments. With discrete, conventional-sized dual AAV2 vectors, full-length MYO7A was detected, but the level of protein expression was variable, and only a minority of cells showed phenotype correction. Our results show that MYO7A therapy with AAV2 or AAV5 single vectors is efficacious; however, the dual AAV2 approach proved to be less effective. PMID- 23344070 TI - A Rapid Method for Estimating of Noise Exposure in Work-places. AB - BACKGROUND: Noise pollution is one of the important issues of pollutant in workplaces and is almost one of the harmful agents for workers. At present, instrumental based inspections for determining the index levels of noise in workshops is performed. This method is requiring a time consuming and ex-pensive in large scale inspection for workplaces. Classification of workplaces based on noise pollution is one of the necessaries for macro programming view of monitoring and controlling of noise. The Propose of this study was to submit a simply scientifically screening method for inspection of noise pollution in workplaces. METHODS: In this experimental study, the results of instrument based and checklist based of noise in-vestigation was compared. For designing of proposed screening checklist and instrumental measuring based, 30 workplaces with more than 20 workers in Hamadan industrial area (west of Iran) were stud-ied. The suggested screening checklist containing a 3*10 matrix can use for recognition step of noise assessment in a large scale investigations. RESULTS: Comparison of the results of the noise screening test with the outcome of a noise measurement by sound level meter, gave a sensitivity of 50% and specificity of 85%. CONCLUSION: The screening test will be useable, if we only want to estimate the global noise pollution in workplaces. PMID- 23344071 TI - An Integrated and Multivariate Model along with Designing Experiments Approach for Assessment of Micro- and Macro- Ergonomic Factors: The Case of a Gas Refinery. AB - BACKGROUND: The objectives of this paper are three folds. First, an integrated framework for designing and development of the integrated health, safety and environment (HSE) model is presented. Second, it is implemented and tested for a large gas refinery in Iran. Third, it is shown whether the total ergonomics model is superior to the conventional ergonomics approach. This study is among the first to examine total ergonomics components in a manufacturing system. METHODS: This study was conducted in Sarkhoon & Qeshm Gas refinery- Iran in 2006. To achieve the above objectives, an integrated approach based on total ergonomics factors was developed. Second, it is applied to the refinery and the advantages of total ergonomics approach are discussed. Third, the impacts of total ergonomics factors on local factors are examined through non-parametric statistical analysis. RESULTS: It was shown that total ergonomics model is much more beneficial than conventional approach. It should be noted that the traditional ergonomics methodology is not capable of locating the findings of total ergonomics model. CONCLUSION: The distinguished aspect of this study is the employment of a total system approach based on integration of the conventional ergonomics factors with HSE factors. PMID- 23344072 TI - Quality Management in Health Systems of Developed and Developing Countries: Which Approaches and Models are Appropriate? AB - BACKGROUND: Quality Management is one of the most effective strategies for improving the health systems performance in developed and developing countries. The main goal of this study was identifying the most important aspects of quality management and preparing an appropriate model for health system. METHOD: This research was a comparative study on quality management models in the health systems of different countries. We have selected, as a sample, different countries in Asia, Africa, North America, Europe, and South America having a background in using various samples of total quality models in their health units. The studies also included the experiences of World Health Organization in different countries. RESULTS: The main goals for promoting quality in the countries are being studied includes service efficiency increase, promoting services delivery, promoting quality of working life, and changing organizational culture. Total approaches used for the countries studied include quality Assurance, Cultural change, ISO 9001, TQM and improving services quality. There are not generally outcomes criteria in 22 cases of the studies done in the developing countries. The most important problems revealed in establishing the quality management, organizational resistance against the change, lack of senior management commitments, lack of strategic planning and lack of required resources. CONCLUSION: The models for quality management should pay attention to the cultural change strategies, staff participation, strategic vision and Strategic planning. Strategic total quality management is the appropriate model in this regard. PMID- 23344073 TI - Comparison between Intravenous and Intramuscular Administration of Prostaglandin E2 on Management of Missed Abortion. AB - BACKGROUND: To compare the efficacy of two routes of prostaglandin E2 administration (Intravenous and Intramuscular) for treatment of missed abortion this study was conducted. Regarding the pilot cases of missed abortion admitted for termination of pregnancy intravenous administration of PGE2 that had higher efficacy compare to intramuscular route, investigators designed this study. METHODS: In a randomized clinical trail, 50 women with confirmed missed abortion received 250-500 I1/4g prostaglandins E2 either intravenously or intramuscularly. Evacuation time set from drug injection to complete empting of uterus. Complete uterine evacuation was defined as empting of uterus from pregnancy materials without the need for surgical intervention and partial evacuation defined as incomplete empting of uterus that need further surgical management. Data were analyzed using SPSS, version 13. All the data extracted with a checklist and compare by descriptive statistics and X2 and t-tests. RESULTS: There was no statistically difference between the results of two administration routes. The mean of evacuation time in intravenous administration routes was significantly lower in compare to intramuscular administration routes (P< 0.5). There was no statistically significant difference in the demographic data in two groups. CONCLUSION: There was no preference between two administration routes except for evacuation time that occurred more rapidly in intravenous administration of PG E2. PMID- 23344074 TI - Investigation of Photocatalytic Degradation of Phenol by UV/TiO2 Process in Aquatic Solutions. AB - BACKGROUND: The main objective of this research was to study photocatalytic oxidation of phenol in aquatic solutions by using of UV, TiO2 and the combination of them. Phenol compounds are widely used in industries and other daily life. Highly toxicity and carcinogenicity of these compounds can causal considerable adverse effects on the aquatic ecosystems and human health. METHODS: The study was an experimental research and carried out by phenol 100 mg L-1 solution and contact time, pH and amount of TiO2 were considered in photocatalytic system as the basic variables affecting removal efficiencies. Phenol concentration in inlet and outlet samples was detected by spectrophotometery at 500nm. RESULTS: Combination of UV and TiO2 can cause higher efficiencies of phenol removal. The removal efficiencies of UV, TiO2 and UV/TiO2 photocatalytic oxidation system with various operation conditions had a range of 1.8%-19.64%, 2.38%-17.8% and 34.65% 82.91%, respectively. It was found that increasing of TiO2 concentration and contact time and pH , increasing the amount of phenol that oxidized in combined system and maximum removal coefficients obtained in pH=11, 9 h contact time and 0.2 gr of TiO2. CONCLUSION: Combinated UV/TiO2 process may be applied as an effective process for the removal of phenol from aquatic solutions such as industrial wastewaters and polluted water resources. PMID- 23344075 TI - Environmental exposure to xylenes in drivers and petrol station workers by urinary methylhippuric Acid. AB - BACKGROUND: The aims of this study were evaluation of exposed to xylenes in low concentration and compare urinary level of methyl hippuric acid in taxi drivers and petrol stations workers in West of Iran. METHODS: This observation study was carried out on samples of the exposed men to xylenes in two occupational groups in Hamadan City (west of Iran) from March 2003 to March 2004. Subjects included 45 taxi drivers and 25 petrol station workers. The study group was selected from 54 workers at petrol stations and 300 drivers by simple random sampling. Xylenes was analyzed using gas chromatography equipped with a Flame Ionization Detector (FID). The urinary methyl hippuric acid (MHA) was analyzed with High performance Liquid Chromatography (HPLC) equipped with an ultraviolet (UV) detector. RESULTS: Total xylene exposure was 1.05+/-0.55 ppm (mean+/-SD) with a range of 0.20-2.55 ppm that was about 4 times more than taxi drivers' exposure. The poor correlation coefficient was seen between xylenes concentration and urinary MHA for drivers (r2= 0.09 to 0.42) but significant associations were noted between urinary MHA and xylene in the breathing zone of petrol station workers (r2= 0.69 to 0.77; P< 0.05). CONCLUSION: High xylenes levels are emitted in petrol stations at Iran. Urinary MHA level has a poor correlation with exposure to xylenes in drivers but has good correlation in petrol station workers. PMID- 23344076 TI - Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. AB - CONTEXT: Evidence for symptomatic convergence of schizophrenia and N-methyl-D aspartate glutamate receptor (NMDA-R) encephalitis highlights the need for an assessment of antibody prevalence and specificity for distinct disease mechanisms in patients with a diagnosis of schizophrenia among glutamatergic pathophysiologic abnormalities in psychiatric disorders. OBJECTIVES: To compare the specificity and prevalence of NMDA-R antibodies in schizophrenia (DSM-IV criteria) with those of other psychiatric diagnoses and to determine whether antibody subtypes characterize overlap with and distinction from those in NMDA-R encephalitis. DESIGN: Serum from 459 patients admitted with acute schizophrenia, major depression (MD), and borderline personality disorder (BLPD) or individuals serving as matched controls was obtained from our scientific blood bank. To explore epitope specificity and antibody subtype, IgA/IgG/IgM NMDA-R (NR1a or NR1a/NR2b) and alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPA-R) (GluR1/GluR2) serum antibodies were determined. PARTICIPANTS: Two hundred thirty matched healthy controls were compared with patients (unmedicated for at least 6 weeks) with schizophrenia (n = 121), MD (n = 70), or BLPD (n = 38). MAIN OUTCOME MEASURES: The primary outcome was the overall number of seropositive cases for NMDA-R and AMPA-R antibodies; the secondary outcome was disease specificity of IgA/IgG/IgM antibodies and epitope specificity for clinical subgroups. RESULTS: Diverse NMDA-R antibodies were identified in 15 subjects, primarily those with an initial schizophrenia diagnosis (9.9%), opposed to MD (2.8%), BLPD (0), and controls (0.4%). Retrospectively, 2 patients initially classified as having catatonic or disorganized schizophrenia were reclassified as having misdiagnosed NMDA-R encephalitis (presence of specific serum and cerebrospinal fluid IgG NR1a antibodies). In all other seropositive cases, the antibodies consisted of classes IgA and/or IgM or were directed against NR1a/NR2b (not against NR1a alone). None of the patients or controls had antibodies against AMPA-R. CONCLUSIONS: Acutely ill patients with an initial schizophrenia diagnosis show an increased prevalence of NMDA-R antibodies. The repertoire of antibody subtypes in schizophrenia and MD is different from that with NMDA-R encephalitis. The latter disorder should be considered as a differential diagnosis, particularly in young females with acute disorganized behavior or catatonia. PMID- 23344077 TI - A continuous perfusion microplate for cell culture. AB - We describe a 96-well microplate with fluidically connected wells that enables the continuous fluid perfusion between wells without the need for external pumping. A single unit in such a perfusion microplate consists of three wells: a source well, a sample (cell culture) well in the middle and a waste well. Fluid perfusion is achieved using a combination of the hydrostatic pressure generated by different liquid levels in the wells and the fluid wicking through narrow strips of a cellulose membrane connecting the wells. There is an excellent correspondence between the observed perfusion flow dynamics and the flow simulations based on Darcy's Law. Hepatocytes (C3A cells) cultured for 4 days in the perfusion microplate with no media exchange in the cell culture well had the same viability as hepatocytes exposed to a daily exchange of media. EOC 20 cells that require media conditioned by LADMAC cells were shown to be equally viable in the adjacent cell culture well of the perfusion microplate with LADMAC cells cultured in the source well. Tegafur, a prodrug, when added to primary human hepatocytes in the source well, was metabolized into a cytotoxic metabolite that kills colon cancer cells (HCT 116) cultured in the adjacent cell culture well; no toxicity was observed when only medium was in the source well. These results suggest that the perfusion microplate is a useful tool for a variety of cell culture applications with benefits ranging from labor savings to enabling in vivo like toxicity studies. PMID- 23344078 TI - HIV-1 Escape From RNAi Antivirals: Yet Another Houdini Action? PMID- 23344080 TI - Response to "HIV Escape From RNAi Antivirals: Yet Another Houdini Action?". PMID- 23344081 TI - AON-mediated Exon Skipping Restores Ciliation in Fibroblasts Harboring the Common Leber Congenital Amaurosis CEP290 Mutation. AB - Leber congenital amaurosis (LCA) is a severe hereditary retinal dystrophy responsible for congenital or early-onset blindness. The most common disease causing mutation (>10%) is located deep in intron 26 of the CEP290 gene (c.2991+1655A>G). It creates a strong splice donor site that leads to insertion of a cryptic exon encoding a premature stop codon. In the present study, we show that the use of antisense oligonucleotides (AONs) allow an efficient skipping of the mutant cryptic exon and the restoration of ciliation in fibroblasts of affected patients. These data support the feasibility of an AON-mediated exon skipping strategy to correct the aberrant splicing. PMID- 23344079 TI - Peptide-mediated Cell and In Vivo Delivery of Antisense Oligonucleotides and siRNA. PMID- 23344082 TI - Quantitative analysis of survivin protein expression and its therapeutic depletion by an antisense oligonucleotide in human lung tumors. AB - RNA-directed antisense and interference therapeutics are a promising treatment option for cancer. The demonstration of depletion of target proteins within human tumors in vivo using validated methodology will be a key to the application of this technology. Here, we present a flow cytometric-based approach to quantitatively determine protein levels in solid tumor material derived by fiber optic brushing (FOB) of non-small cell lung cancer (NSCLC) patients. Focusing upon the survivin protein, and its depletion by an antisense oligonucleotide (ASO) (LY2181308), we show that we can robustly identify a subpopulation of survivin positive tumor cells in FOB samples, and, moreover, detect survivin depletion in tumor samples from a patient treated with LY2181308. Survivin depletion appears to be a result of treatment with this ASO, because a tumor treated with conventional cytotoxic chemotherapy did not exhibit a decreased percentage of survivin positive cells. Our approach is likely to be broadly applicable to, and useful for, the quantification of protein levels in tumor samples obtained as part of clinical trials and studies, facilitating the proof of-principle testing of novel targeted therapies. PMID- 23344083 TI - The Cellular Processing Capacity Limits the Amounts of Chimeric U7 snRNA Available for Antisense Delivery. AB - Many genetic diseases are induced by mutations disturbing the maturation of pre mRNAs, often affecting splicing. Antisense oligoribonucleotides (AONs) have been used to modulate splicing thereby circumventing the deleterious effects of mutations. Stable delivery of antisense sequences is achieved by linking them to small nuclear RNA (snRNAs) delivered by viral vectors, as illustrated by studies where therapeutic exon skipping was obtained in animal models of Duchenne muscular dystrophy (DMD). Yet, clinical translation of these approaches is limited by the amounts of vector to be administered. In this respect, maximizing the amount of snRNA antisense shuttle delivered by the vector is essential. Here, we have used a muscle- and heart-specific enhancer (MHCK) to drive the expression of U7 snRNA shuttles carrying antisense sequences against the human or murine DMD pre-mRNAs. Although antisense delivery and subsequent exon skipping were improved both in tissue culture and in vivo, we observed the formation of additional U7 snRNA by-products following gene transfer. These included aberrantly 3' processed as well as unprocessed species that may arise because of the saturation of the cellular processing capacity. Future efforts to increase the amounts of functional U7 shuttles delivered into a cell will have to take this limitation into account. PMID- 23344084 TI - Gene polymorphisms as clinical tools in chronic glomerulopathies: a prospective study. AB - BACKGROUND/AIMS: Studies have proposed various polymorphisms of genes implicated in the physiopathology of chronic kidney disease as risk factors of progression and potential clinical tools. We sought to validate and simultaneously compare their predictive value in a prospective cohort of chronic glomerulopathies receiving recommended antihypertensive and antiproteinuric therapies. METHODS: Using PubMed, we identified 9 polymorphisms previously associated with progression. These were mostly of the renin-angiotensin-aldosterone and inflammation pathways: MCP-1 A2518G, TGF-beta1 T869C and C-509T, ACE I/D, AGT M235T, AT1R A1166C, TSC-22 A-396G, eNOS 4b/a and CYP11beta2 C-344T. We hypothesized that their determination would identify individuals at higher risk of progression. RESULTS: We recruited 93 predominantly male and Caucasian patients with a mean age of 63 and baseline eGFR of 33 ml/min/1.73 m(2) followed prospectively over a median of 36 months. 61% of patients had diabetic nephropathy, almost all received RAA blockade (90%) and none immunosuppressive therapy. The average blood pressure during follow-up was 140/72 mm Hg, the urinary protein to creatinine ratio 0.15 g/mmol and the rate of renal function decline -3.2 +/- 4.1 ml/min/1.73 m(2)/year. Proteinuria and blood pressure strongly predicted progression. However, under recommended therapy, none of the proposed polymorphisms predicted renal function decline. In addition, none showed simple or partial correlations with the severity of proteinuria or blood pressure. Finally, summation variable of risk polymorphisms did not predict progression. CONCLUSION: This study does not validate the use of these 9 polymorphisms as individual clinical tools in patients with chronic glomerulopathies on recommended antihypertensive and antiproteinuric therapies. PMID- 23344085 TI - Cytokine removal under hemodiafiltration with endogenous reinfusion in acute kidney injury secondary to angioimmunoblastic T-cell lymphoma: a case report. AB - Angioimmunoblastic T-cell lymphoma shows a high release of cytokines. Different blood purification techniques are employed to control hypercytokinemia. Here we investigated the effects of intermittent supra-hemodiafiltration with endogenous reinfusion on cytokine removal in a patient presenting with acute kidney injury. After the first day of chemotherapy for angioimmunoblastic T-cell lymphoma, a 78 year-old male patient developed acute kidney injury and systemic inflammatory response syndrome due to massive release of inflammatory cytokines. Three sessions of supra-hemodiafiltration were performed. Blood samples for evaluation of renal function and inflammatory mediators were collected at the beginning and the end of each dialytic session. A marked improvement of clinical state and renal function was associated to a significant reduction of inflammatory markers. Our results suggest that renal replacement therapy with supra-hemodiafiltration may remove a wide spectrum of inflammatory mediators and uremic toxins involved in acute kidney injury and systemic inflammatory response syndrome. PMID- 23344087 TI - Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer. AB - BACKGROUND: Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is markedly sensitive to the ALK inhibitor crizotinib. However, acquired resistance to crizotinib is inevitable through several mechanisms. Therefore, this study was conducted to identify genetic alterations associated with crizotinib resistance. METHODS: Tumor samples were derived from seven ALK positive NSCLC patients who showed acquired resistance to crizotinib, and these patients were analyzed for ALK, EGFR, and KRAS mutations and ALK and EGFR gene amplifications. In vitro cytotoxicity of crizotinib and ALK downstream signals were compared between crizotinib-naive and -resistant NSCLC cells. RESULTS: After a median duration of 6 months (range, 4-12 months), seven ALK-positive NSCLC patients developed acquired resistance to crizotinib. Three patients harbored secondary ALK mutations, including one patient with both mutations: L1196M (n = 2) and G1269A (n = 2). Of note, one patient displayed ALK gene copy number gain (4.1-fold increase compared with the pre-crizotinib specimen) and EGFR L858R mutation with high polysomy. The amphiregulin concentration was high in the supernatant fluid from five patients with malignant pleural effusion (116.4 18934.0 pg/ml). SNU-2535 cells derived from a patient who harbored the G1269 mutation were resistant to crizotinib treatment similar to H3122 CR1 cells. L1196M and G1269A mutant clones were less sensitive to crizotinib and ALK downstream signals were ineffectively suppressed in these clones. CONCLUSIONS: Genetic changes associated with crizotinib resistance are heterogeneous in ALK rearranged NSCLC patients who respond to crizotinib and subsequently develop resistance. PMID- 23344089 TI - Effects of Zingiber officinale on the plasma pharmacokinetics and lung penetrations of ciprofloxacin and isoniazid. AB - The study was carried out to determine the effect of ginger on the plasma pharmacokinetics of ciprofloxacin and Isoniazid in a rat model in phase 1. The effects of the herb on the penetration of ciproflacin and Isoniazid into the lung tissues were also determined in phase 2. In phase 1, Albino rats of both sexes (n = 20) were divided into 4 groups of 5 rats per group. Two groups received oral ciprofloxacin (20 mg/kg) and isoniazid (15 mg/kg). Other groups were fed with ginger (5 mg/kg) for 10 days followed by the drug administration on the 11th day. Blood samples were collected from each group at 0-, 0.5-, 1-, 2-, 5-, 8-, 12-, and 24-hour intervals. Plasma concentrations of the drugs were determined by a spectrophotometric method and the pharmacokinetic parameters determined using noncompartmental method as implemented in the winNonlin program. In phase 2, where the effects of the herb on the penetration of the drugs were determined, the concentrations of ciprofloxacin and isoniazid attained in the lung fluid of rats in the presence and absence of the herb were compared after a single oral dose of the drugs used in the same dose range as in phase 1. In the first phase, treatment with ginger significantly increased the area under the concentration time curve of ciprofloxacin, whereas Vz and Cl were decreased. Ginger significantly decreased the area under the concentration-time curve of isoniazid, whereas Vz and Cl were increased. Ginger enhanced the penetration of ciprofloxacin and Isoniazid into the lung tissues; however, their rates of penetration were delayed. PMID- 23344090 TI - Delayed elevation in carbamazepine concentrations after overdose: a retrospective poison center study. AB - An initial carbamazepine concentration may initially be supratherapeutic, therapeutic, or even subtherapeutic only to persist to rise over time. The aim of this study was to report the frequency of toxic carbamazepine concentrations continuing to rise and to estimate how often an initially therapeutic or subtherapeutic concentration misrepresents the potential toxicity of an acute carbamazepine overdose. An 8-year retrospective search of all carbamazepine exposures reported to the Illinois Poison Center (January 1, 2001 through December 31, 2008) was reviewed. Inclusion criteria were acute poisonings with a documented carbamazepine concentration of >12 MUg/mL at any time. Those with initial concentrations of >12 MUg/mL that subsequently increased over time were recorded. Additionally, those cases that initially had therapeutic (4-12 MUg/mL) or subtherapeutic (<4 MUg/mL) concentration were identified. Descriptive statistics were used to analyze the data. A total of 1424 cases were reported. Of the 523 patients with documented concentrations of >12 MUg/mL, 93 patients (17.8%) had initial carbamazepine concentrations >12 MUg/mL and continued to rise. Sixteen patients (3.5%) had initial carbamazepine concentrations that were therapeutic (4-12 MUg/mL) and 7 patients (1.3%) had initial carbamazepine concentrations <4 MUg/mL before rising >12 MUg/mL. Certain patients had progressive decreases in level of consciousness corresponding to increasing carbamazepine concentrations. Additionally, several patients with initial levels of therapeutic or subtherapeutic concentration later became comatose and required ventilator management. Initial serum carbamazepine concentrations can be misleading. Serial measurements documenting a declining carbamazepine concentration or prolonged observation are recommended when managing these overdoses. PMID- 23344091 TI - Angioplasty alone versus angioplasty and stenting for subclavian artery stenosis- a systematic review and meta-analysis. AB - Subclavian artery stenosis has long been treated with great success with bypass surgery. Percutaneous intervention, often used in combination with stent placement, has come into vogue for the past few years as a safe and effective therapeutic modality. This study aimed to compare angioplasty alone with angioplasty followed by stent placement by combining available data. The objective of this study was to perform a review of the available literature to compare the efficacy of percutaneous transluminal angioplasty (PTA) alone with PTA followed by stent placement for proximal subclavian artery stenosis. Successful recanalization was defined as patency at the end of 1 year, and reocclusions and restenoses were noted as events for the purpose of pooling the data. The authors searched the Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, PubMed, EMBASE, and CINAHL databases for relevant trials/studies comparing PTA and PTA with stenting. Review authors independently assessed the methodological quality of studies (focusing on the adequacy of the randomization process, allocation concealment, blinding, completeness of follow-up, and intention-to-treat analysis) and selected studies for inclusion. All retrospective observational studies were also included in the analysis in the absence of double-blinded randomized trials for increasing sample size. All analyses were done using RevMan 5.0. Odds ratio was calculated using Mantel-Haenszel test with a fixed effect model. All included studies were assessed by all authors for potential sources of bias. Eight studies were included in the analysis having 544 participants. Stenting after PTA was significantly superior to angioplasty alone for treatment of subclavian artery stenosis and maintenance of patency at 1 year, as indicated by absence of events (P = 0.004; 95% confidence interval, odds ratio 2.37 [1.32 4.26]) without significant complication rates for either procedure. There is evidence in favor of stent placement after angioplasty for successful recanalization of stenosed subclavian arteries and long-term maintenance of patency without significant increase in risk for major complications in subjects. PMID- 23344092 TI - Therapeutic advances in understanding pathophysiology and treatment of cerebral venous sinus thrombosis. AB - Cerebral venous sinus thrombosis is an important cause of stroke in young population. A thorough understanding of its pathophysiology, clinical, and radiological features is needed for an early and timely diagnosis to initiate appropriate treatment before the disease becomes worse and difficult to manage. In this study, the recent advances in the therapeutics of cerebral venous thrombosis with brief overview of epidemiology, clinical features, and imaging modalities were reviewed. With emerging imaging modalities and therapeutic options, there has been a progress in ease of ability to diagnose and treat cerebral venous thrombosis, but because of the lack of a much-needed randomized controlled trial, there is deficiency of a standardized algorithm/protocol for treatment of cerebral sinus thrombosis, which remains mostly at the discretion of experiences of treating physicians. In this study, the presently available treatment and diagnostic modalities with pros and cons of each of them were reviewed. PMID- 23344093 TI - Therapeutic potential of a low-cost device for wound healing: a study of three cases of healing after lower-extremity amputation in patients with diabetes. AB - Diabetic foot ulcers constitute a tremendous challenge for patients, caregivers, and health care systems. The high incidence and high financial costs associated with their treatment have transformed them in a health and economic worldwide problem. The increase in population life expectancy and lifestyle changes have facilitated the spreading of diabetes, rising diabetic foot ulcer incidence. Only 60%-80% of the patients achieve healing of ulcers, and the incidence of a second ulcer, in the same or different site of the foot that has had a previous ulcer, is approximately 50% in 2-5 years. In addition, ulcers with duration longer than 4 weeks are commonly associated with bad results in healing and an increased risk of amputation. Three patients with type 2 diabetes mellitus have been subjected to treatment with NL.1.2, a low-cost, biocompatible solid device that presented pro-angiogenic properties. The selected patients had undergone amputation, and their wounds, classified as Wagner II, did not show a significant progress in healing after a period of 2-5 months before treatment with NL.1.2. Complete closure of their wounds was achieved in 42-60 days. PMID- 23344094 TI - Association of inflammatory and oxidative stress biomarkers in subjects with cardiovascular risk. AB - Cardiovascular disease is originated in the vascular endothelium, which controls the homeostasis and the filtration and diffusion of molecules from blood to the tissues. The classical cardiovascular risk factors (CRFs) act directly on the endothelium through an increase in the production of reactive oxygen species, promoting an endothelial activation mediated by the expression of adhesion and proinflammatory molecules, which lead to endothelial dysfunction, the progression of the atherosclerotic plaque, and the onset of cardiovascular disease. The objective of this study was to analyze the association of superoxide dismutase, catalase, gluthatione peroxidase, and lipoperoxidation with fibrinogen, interleukin (IL)-6, tumor necrosis factor-alpha, and vascular cell adhesion molecule (VCAM)-1 in subjects with cardiovascular risk (CVR) and CRF. This was a cross-sectional study of 114 individuals; oxidative stress (superoxide dismutase, catalase, gluthatione peroxidase, and lipoperoxidation) and inflammatory (fibrinogen, IL-6, tumor necrosis factor-alpha, and VCAM-1) biomarkers were measured; a CVR score (Framingham) and its CRF were taken into consideration to classify the participants. Twenty-nine subjects out of a total of 114 had high CVR. Smokers and subjects with diabetes (43 subjects) were excluded from the low CVR group. Significant decreases in lipoperoxidation, IL-6, and VCAM-1 and an increase in SOD were found in the high CVR group (P <= 0.05). Individual analysis of each CRF in the 114 subjects revealed a different pattern in the biomarkers' statistical differences. Concluding that the biomarkers show statistical differences in each CRF, especially IL-6, VCAM-1, and SOD; therefore, these are highly recommended to be used as biomarkers of the oxidative stress and inflammatory status in CVR. PMID- 23344095 TI - Painful boney metastases. AB - Up to 90% of patients with metastatic or advanced stage cancer will experience significant cancer-related pain. Approximately half or more of patients diagnosed with cancer may experience bone pain. It has been estimated that tumor metastases to the skeleton affects roughly 400,000 US citizens annually. Carcinoma from breast, lung, and prostate cancers account for approximately 80% of secondary metastatic bone disease. Bone metastases may cause devastating clinical complications associated with dramatic reductions in quality of life, mobility, and independence, as well as excruciating refractory pain. Associated complications from osseous metastases also present a substantial economic burden. Currently, there are still a significantly high number of patients suffering with unrelieved pain from osseous metastases. Treatments for painful osseous metastases may not only diminish pain but also may improve quality of life and independence/mobility, and reduce skeletal morbidity, potential pathologic fractures, spinal cord compression, and other "skeletal-related events." Treatment strategies for painful osseous metastases include the following: systemic analgesics, intrathecal analgesics, glucocorticoids, radiation (external beam radiation, radiopharmaceuticals), ablative techniques (radiofrequency ablation and cryoablation), bisphosphonates, chemotherapeutic agents, inhibitors of RANKL-RANK interaction (eg, denosumab), hormonal therapies, interventional techniques (eg, kyphoplasty), and surgical approaches. Although the mechanisms underlying the development of bone metastases remain incompletely understood, there appears to be important bi-directional interactions between the tumor and the bone microenvironment. A greater understanding of the pathophysiology of painful osseous metastases may lead to better and more selective targeted analgesic therapy. Additionally, potential future therapeutic approaches to painful osseous metastases may revolutionize approaches to analgesia for this condition, leading to optimal outcomes with maximal pain relief and minimal adverse effects. PMID- 23344096 TI - Time trends of gender-based differences in lipid goal attainments during secondary prevention of coronary artery disease: results of a 5-year survey. AB - Coronary artery disease is the leading cause of death in both men and women worldwide. Little is known about gender-based differences in lipid goal attainment during secondary prevention of coronary artery disease. We conducted this study to analyze gender differences in low-density lipoprotein cholesterol target attainment in secondary prevention after acute myocardial infarction over a 5-year period. In this retrospective study, the electronic database of lipid clinic at a single center was used as the data source. Temporal trends and gender differences in demographics, lipid profile, and medication use were determined. Goal low-density lipoprotein (LDL) was defined per National Cholesterol Education Program ATP III guidelines.A total of 1365 patients (823 males, 542 females) constituted the study sample. Patients in 2007 were older than those in 2003 (females 68.6 +/- 14 vs. 70.7 +/- 11.7 years; males 63.6 +/- 12 vs. 65.8 +/- 11 years; P < 0.05) and had a higher body mass index (females 27.8 +/- 1 vs. 28.6 +/ 1 kg/m; males 27.6 +/- 1 vs. 28.1 +/- 1 kg/m, in 2003 and 2007 respectively, P < 0.05). Mean LDL decreased significantly overtime in both males and females. No gender difference in lipid-lowering therapy was observed. Females had a higher LDL than did males in 2003 (115.3 +/- 12.3 vs. 99.7 +/- 12.5 mg/dL; P < 0.05), and this difference persisted through 2007 (102.2 +/- 11.7 vs. 91.3 +/- 11.2 mg/dL; P < 0.05). Overall rate of achieving goal LDL improved from 76.5% (2003) to 83.02% (2007), P < 0.05, but remained lower for females than for males both in 2003 and 2007 [69.8% vs. 80.1% (2003), P < 0.05, and 77.9% vs. 85.6% (2007), P < 0.05].The trend over a recent 5-year period shows that females are less likely to achieve goal LDL than males are, and it indicates the need for more aggressive lipid-lowering strategies in females. PMID- 23344097 TI - The toxic trio: valproic acid, lithium, and carbamazepine. AB - Patients with altered mental status and seizure or psychiatric disease often present with an unclear medication history. Commonly prescribed medications include valproic acid (VPA), lithium (Li), or carbamazepine (CZN) of which the regional poison center (RPC) often recommends obtaining these serum concentrations. Regularly ruling out supratherapeutic concentrations without a known history of ingestion may help direct care. Cases from the RPC coded as VPA, Li, and CZN, from January 1, 2006 to December 31, 2008, were searched. All patients with supratherapeutic concentrations (VPA >100 MUg/mL, Li >1.2 mEq/L, and CZN >12 MUg/mL) were evaluated for the following criteria: (1) those with altered mental status and an unclear history of seizure or psychiatric disorder and (2) a mediation profile not including VPA, Li, or CZN. Twenty-six patients met the inclusion criteria: 8 patients in the VPA group (113-247 MUg/mL; mean, 158), 9 patients in the Li group (1.9-5.2 mEq/L; mean, 2.9), and 9 patients in the CZN group (13.4-38.8 MUg/mL; mean, 23.2). All patients survived and were treated with supportive care; however, 1 patient had a Li level of 5.2 mEq/L and received hemodialysis. In altered patients potentially being treated for seizure or psychiatric disorders and unknown ingestions or medication lists, obtaining concentrations of VPA, Li, and CZN may help direct care and provide clinically relevant information. The RPC detected 26 patients with supratherapeutic VPA, Li, or CZN concentrations in patients with potential indications for the agent but no available history of drug ingested or medication list. A prospective study is warranted to evaluate the usefulness of obtaining these concentrations in this patient population. PMID- 23344098 TI - Acute aortic dissection in a patient receiving gemcitabine and cisplatin. AB - Acute aortic dissection is often a fatal condition with in-hospital mortality rates of 27%. The incidence of acute aortic dissection is low at around 3 cases per 100,000 person-years. There is a strong relationship between hypertension and aortic dissection. 72% of patients in the International Registry of Acute Aortic Dissection had a history of hypertension. The inciting event is an intimal tear extending into the media with resultant dissection of blood along the laminar planes of the media. Cisplatin, a commonly used platinum-based chemotherapy drug, is associated with the development of hypertension on long-term follow up studies. This knowledge should prompt clinicians to screen for the development of hypertension and to be aware of its potential complications in patients treated with cisplatin-containing chemotherapy. Despite the known vascular complications of chemotherapy, there is a paucity of data on the association of aortic dissection with active cancer or chemotherapy. We present an unusual case of an extensive, acute aortic dissection in a relatively young male patient receiving gemcitabine and cisplatin for advanced metastatic pancreatic adenocarcinoma. PMID- 23344099 TI - Golimumab may induce exacerbation of inflammatory bowel disease when it is used for the treatment of ankylosing spondylitis: a case report with a review of literature. AB - Golimumab is a human IgG monoclonal antibody specific for human tumor necrosis factor alpha. Golimumab has been approved for use in rheumatological conditions; however, its use in inflammatory bowel disease is still being evaluated in clinical trials. We report a case of an exacerbation of ulcerative proctitis after starting on golimumab for ankylosing spondylitis. PMID- 23344101 TI - Efficacy of corticosteroid therapy in severe decompensation of chronic obstructive pulmonary disease requiring mechanical ventilation. AB - The purpose of this study was to analyze the efficacy of corticosteroids in severe acute decompensation of chronic obstructive pulmonary disease requiring mechanical ventilation and intensive care unit (ICU) admission. Pairwise retrospective case-control study with 1:1 matching. Patients were defined as cases when they received corticosteroids and as controls when they did not received any steroids. Patients were matched according to age, severity factors at admission represented by the PaO2/FiO2 ratio, and simplified acute physiology score. Thirty-four patients were included. There were 17 patients in the case group and 17 patients in the control group. There were 27 men (80%) and 7 women (20%). The mean age (+/-SD) was 70 +/- 9 years with a range of 40-85 years. Thirty-two patients (94 %) were older than 60 years. The comparison between the 2 groups showed that they had the same epidemiological, clinical, and biological findings on ICU admission. Homodynamic parameters were also not significantly different between the 2 groups. Moreover, there is the same proportion of invasive mechanical ventilation use in 2 groups. Concomitant drugs used were also not significantly different between the 2 groups. Finally, the comparison of outcome between the steroid and steroid-free groups showed that mortality rate was not significantly different (64% vs. 58%, P = 0.72). However, systemic corticosteroid therapy was associated with a significant increase in a reduction in the duration of mechanical ventilation (P = 0.004) and a trend toward a shorter length of ICU stay (P = 0.053). Although the authors detected no significant difference in mortality rate at the time of discharge between steroid and streroid-free patients, this study confirms that systemic corticosteroid therapy in patients with chronic obstructive pulmonary disease exacerbations requiring mechanical ventilation is associated with a significant reduction in the duration of mechanical ventilation. Other studies are needed on this subject. PMID- 23344100 TI - 61-year-old man with sudden onset of gross hematuria: a case report. AB - A 61-year-old man with a medical history of gastroesophageal reflux disease presented with complaints of gross hematuria for 2 days and occasional epistaxis for 1 week. The medication list included only ranitidine. Laboratory data showed significantly elevated prothrombin time and international normalized ratio. The liver panel was normal. On inspection, the patient's bottle of ranitidine, which was refilled 20 days before, contained 5-mg tablets of warfarin. The international normalized ratio and prothrombin time were reversed with FFP, vitamin K, and Novoseven. PMID- 23344102 TI - Safety of desirudin in thrombosis prevention after total knee arthroplasty: the DESIR-ABLE study. AB - Desirudin, administered 30 minutes before total hip arthroplasty is superior to enoxaparin in preventing proximal deep vein thrombosis (DVT) and pulmonary embolism (PE) with similar bleeding. The purpose of this study was to determine the safety of desirudin in patients undergoing elective total knee arthroplasty (TKA) when the first dose of desirudin was administered the evening after surgery. This is a case series of patients undergoing TKA who received desirudin 15 mg every 12 hours subcutaneously for an average of 5 days with the first dose administered postoperatively. The primary endpoint was major bleeding; secondary endpoints included wound outcomes (oozing and infection) and new symptomatic DVT or PE. Desirudin has a favorable safety profile when administered postoperatively in patients undergoing TKA with no reports of major bleeding, wound ooze, or infection. No patients experienced symptomatic DVT, but 2 patients had PE detected by computed tomography after experiencing atypical symptoms. The safety profile of desirudin is improved when administered postoperatively. Bleeding and wound outcomes seem to occur less frequently than historical desirudin and enoxaparin controls. PMID- 23344103 TI - Pharmaceutical R&D performance by firm size: approval success rates and economic returns. AB - The R&D productivity of pharmaceutical firms has become an increasingly significant concern of industry, regulators, and policymakers. To address an important aspect of R&D performance, public and private data sources were used to estimate clinical phase transition and clinical approval probabilities for the pipelines of the 50 largest pharmaceutical firms (by sales) by 3 firms size groups (top 10 firms, top 11-20 firms, and top 21-50 firms). For self-originated compounds, the clinical approval success rates were 14.3%, 16.4%, and 18.4% for top 10 firms, top 11-20 firms, and top 21-50 firms, respectively. The results showing higher success rates for smaller firms were largely driven by outcomes for the small-molecule drugs. Adjustments for the relatively small differences in therapeutic class distributions across the firm size groups showed that the success rate for small-molecule self-originated drugs was 6% below average for top 10 firms and 17% above average for top 21-50 firms. Although success rates for small firms were higher, this advantage was offset to some degree by lower returns on approved drugs, suggesting different strategic objectives with regard to risk and reward by firm size. PMID- 23344104 TI - Resolution of whipple disease-induced pulmonary hypertension following antibiotic therapy. AB - Whipple disease is a disorder caused by Tropheryma whipplei, a ubiquitous Gram positive bacillus. In addition to gastrointestinal manifestations, many other systems may be involved in Whipple disease. Pulmonary hypertension (PH) is a rare manifestation of Whipple disease, and its clinical course is not well established. We report a case of a 45-year-old woman who presented with typical gastrointestinal manifestations of Whipple disease, which was diagnosed by duodenal biopsy. She was also noted to have elevated pulmonary arterial pressures on transthoracic echocardiography. There was no evidence of left-sided valvular disease, hypertrophy, or dyskinesis, and there was no evidence of endocarditis. The patient was started on intravenous ceftriaxone for 6 weeks and then transitioned to oral trimethoprim-sulfamethoxazole for a year. The patient demonstrated clinical improvement, endoscopic and histologic improvement, and also resolution of PH. This is the third reported case of PH that is convincingly secondary to Whipple disease that resolved after appropriate antibiotic therapy. PMID- 23344105 TI - Antiangiogenic drugs and cardiogenic shock: a case report. AB - A 56-year-old man attended the emergency room with respiratory failure, deteriorated general status, fatigue, and diarrhea. His clinical history included a liver transplant because of alcoholic cirrhosis, which developed to hepatocellular carcinoma. Initial immunosuppression consisted of corticosteroids, tacrolimus, and mycophenolate mofetil. Examination of the explant revealed vascular invasion, and tacrolimus was replaced with everolimus. The patient presented recurrence of the carcinoma with peritoneal implants, and treatment with sorafenib was started. He was admitted to the gastroenterology department and, after withdrawal of sorafenib, the patient improved clinically. However, 6 days later, he was admitted to the intensive care unit with acute respiratory failure and metabolic acidosis. The final diagnosis was cardiogenic shock. Although cardiogenic shock is not mentioned in the summaries of product characteristics of sorafenib or everolimus, there are reports of a relationship between cardiotoxicity and antiangiogenic therapy that inhibits the proliferation of vascular smooth muscle cells, as is the case with these drugs. We believe that there is a relationship between sorafenib (especially when combined with everolimus) and cardiogenic shock. Application of the Karch and Lasagna algorithm to assess the causality of the reaction induced by the combination of sorafenib and everolimus revealed the relationship to be probable. PMID- 23344107 TI - Anesthetic management of the patient with low ejection fraction. AB - The number of patients with heart failure presenting for surgery continues to rise, and anesthesiologists are increasingly being called upon to provide quality, safe care in the operating room for patients with low ejection fraction (EF). Perioperative goals in the management of these patients include maintaining forward flow, promoting inotropy without inducing or exacerbating ischemia, and returning patients to their preoperative level of function after surgery. Oftentimes, these goals can be met with pharmacologic support, including the use of calcium channel blockers, phosphodiesterase inhibitors, and novel agents, such as nesiritide and levosimendan. Many patients with diminished EF have implantable cardioverter-defibrillators (ICDs) in place. These devices can be complex to manage, and concern often arises regarding electromagnetic interference from monopolar cautery. Although simply placing a magnet on the device will often disable the antitachycardia interventions of an ICD, this is not always the case. The safest way to manage an ICD in the perioperative period is to interrogate and reprogram the device before and after surgery. Another helpful device in dealing with patients with low EF, particularly those in acute cardiogenic shock, is the intra-aortic balloon pump. These devices can serve a critical role in managing patients who have inadequate responses to pharmacologic therapy or in whom vasopressor and inotropic support are suboptimal because of concerns for increasing myocardial work. With full understanding of available pharmacologic agents, and an appreciation of the capabilities of ICDs and intra-aortic balloon pumps, anesthesiologists will be better equipped to meet the perioperative needs of the patient with low EF. PMID- 23344106 TI - Estimation of potential cost savings associated with reduced rates of cardiovascular hospitalization among atrial fibrillation/flutter patients treated with dronedarone in the ATHENA trial. AB - The aim of this study was to estimate, from a US payer perspective, potential cost savings resulting from the reduction in cardiovascular (CV) hospitalizations obtained with dronedarone in the ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from any Cause in PatiENts with Atrial Fibrillation/Atrial Flutter) trial. ATHENA randomized atrial fibrillation/flutter patients to dronedarone (n=2301) or placebo (n=2327) plus standard care. Dronedarone significantly reduced first CV hospitalization/all cause mortality over 12-30 months of follow-up. CV hospitalization costs (2008 values) from a US cohort of ATHENA-like atrial fibrillation/flutter patients with Medicare supplemental insurance (n=10,200) and diagnosis-related group costs of adverse event-related hospitalizations were applied to hospitalizations occurring in ATHENA. The impact of cost variation was assessed using Monte Carlo simulation. In ATHENA, dronedarone reduced the overall CV hospitalization rate (vs. placebo) by 29% over the first 12 months (33.36 vs. 47.19 events per 100 patients) and by 25% over the full study (51.15 vs. 68.55 events per 100 patients). Adverse event-related hospitalization rates (dronedarone vs. placebo) were low (0.48 vs. 0.21 and 0.56 vs. 0.26 events per 100 patients over 12 months and the full study, respectively). Overall hospitalization cost savings were estimated at $1329 and $1763 per patient over 12 months and the full study, respectively. Cost savings were relatively stable [mean (95% confidence interval): $1330 ($994-$1676) for the first 12 months and $1763 ($1369-$2184) for the full study] over 10,000 cycles of random variation. PMID- 23344108 TI - Evaluation of factors associated with achieving glycemic control in a pharmacist managed diabetes clinic. AB - The aim of this study was to identify factors that are associated with patients achieving goal A1c after 6 months in a pharmacist-managed diabetes clinic. This study is a descriptive, retrospective chart review of patients with type 2 diabetes enrolled in a pharmacist-managed diabetes clinic. The primary endpoint was the odds of each identified factor being associated with achievement of goal A1c after 6 months of enrollment. The factors were also evaluated within 2 subgroups: those with a baseline A1c >7% and those with a baseline A1c >9%. Of 112 patients enrolled, 58 were included in the analysis. There was a positive association with reaching goal for patients who had <1 failure to show (FTS) to office visits in 6 months [odds ratio (OR) 8.10, 95% confidence interval (CI) 1.47-58.65], had canceled or FTS to <50% of office visits (OR 10.0, 95% CI 1.8 72.79), and brought >75% of blood glucose logs to their office visits (OR 7.36, 95% CI 1.87-30.88). There was a negative association with reaching the goal for patients with documented social worker involvement (OR 0.22, 95% CI 0.04-0.99) and noninsulin or insulin dose increases at >50% of office visits (OR 0.10, 95% CI 0.01-0.55). Overall, this analysis found that patients who had <1 FTS, had canceled or FTS to <50% of office visits, or who brought >75% logs to office visits were more likely to achieve goal A1c, whereas patients with social work assistance or dose increases at >50% of office visits were less likely to reach goal A1c. PMID- 23344109 TI - A rare case of acyclovir-induced thrombocytopenia. AB - Acyclovir is used for its potent antiviral properties for the mucocutaneous herpes, herpes zoster, herpes encephalitis, and genital herpes simplex. The drug has a very wide distribution involving almost every organ of the body, with excretion into the urine. Urine analysis, kidney function, liver function, and complete blood counts are some of the monitoring parameters. The active triphosphate form of the drug inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA. Because the drug is only absorbed by the cells that are virus infected, acyclovir has minimal side effects at therapeutic doses. However, at high intravenous infusions, severe central nervous system (malaise), gastrointestinal (nausea/vomiting), renal (elevated blood urea nitrogen/creatinine), hepatic (elevated liver enzymes), and skin dyscrasias have been found to occur. There have been few case reports of bone marrow suppression and only one case report so far of acyclovir-related isolated thrombocytopenia. Whether there is any further association between acyclovir and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome is the next dilemma if such an association is established. Here, the authors present a case report of a 58-year old man with acquired immune deficiency syndrome on highly active antiretroviral therapy who went into severe thrombocytopenia on starting acyclovir. PMID- 23344111 TI - Changes in mean arterial blood pressure during sildenafil use in neonates with meconium aspiration syndrome or sepsis. AB - The aim of this study was to evaluate changes in mean blood pressure (MBP) in late preterm and term newborns with meconium aspiration syndrome (MAS) or sepsis who, in addition to inhaled nitric oxide (iNO), received enteral sildenafil for treatment of persistent pulmonary hypertension of the newborn. Data on sildenafil dosing, MBP, and vasopressor/inotrope use were collected for 72 hours after initiation of sildenafil. Groups were compared between "low dose" (<3 mg.kg.d) versus "high dose" (>= 3 mg.kg.d) and "early" (<7 postnatal days) versus "late" (>= 7 postnatal days) administration of sildenafil. Seventeen patients were identified. Ten and 7 patients received "low-dose" and "high-dose" sildenafil, respectively, and 8 and 9 patients were started on sildenafil "early" and "late," respectively. At the doses used, sildenafil treatment of infants with MAS and sepsis was not associated with changes in MBP. In addition, vasopressor/inotropic support was weaned in all groups. During the first 72 hours of enteral sildenafil administration in neonates with pulmonary hypertension of the newborn secondary to MAS or sepsis, no significant decrease in MBP or increase in vasopressor/inotrope requirement occurred. PMID- 23344110 TI - Tumor necrosis factor inhibitor-induced serositis. AB - A 46-year-old man with a history of asthma and psoriatic arthritis on adalimumab presented with fever, tachycardia, and hypoxia. He was diagnosed with pleural effusion and started on antibiotics, as it was noted to be an exudative effusion. Patient failed to improve on multiple courses of antibiotics, and his blood and pleural fluid cultures were negative. He was then started on prednisone 1 mg/kg and showed remarkable recovery. He was diagnosed with adalimumab-induced serositis. PMID- 23344112 TI - Uptake and processing of semiconductor quantum dots in living cells studied by fluorescence lifetime imaging microscopy (FLIM). AB - Carboxylate-terminated and dopamine-conjugated CdSe-ZnS quantum dots (QDs) are imaged in living fibroblasts using fluorescence lifetime imaging microscopy. Changes in lifetime are observed as the QDs are processed in the cells, and are consistent with lifetime measurements in bulk solution using buffers compositions that correspond to different cellular regions. PMID- 23344113 TI - Bioactivity and applications of sulphated polysaccharides from marine microalgae. AB - Marine microalgae have been used for a long time as food for humans, such as Arthrospira (formerly, Spirulina), and for animals in aquaculture. The biomass of these microalgae and the compounds they produce have been shown to possess several biological applications with numerous health benefits. The present review puts up-to-date the research on the biological activities and applications of polysaccharides, active biocompounds synthesized by marine unicellular algae, which are, most of the times, released into the surrounding medium (exo- or extracellular polysaccharides, EPS). It goes through the most studied activities of sulphated polysaccharides (sPS) or their derivatives, but also highlights lesser known applications as hypolipidaemic or hypoglycaemic, or as biolubricant agents and drag-reducers. Therefore, the great potentials of sPS from marine microalgae to be used as nutraceuticals, therapeutic agents, cosmetics, or in other areas, such as engineering, are approached in this review. PMID- 23344114 TI - Quorum sensing inhibition by Asparagopsis taxiformis, a marine macro alga: separation of the compound that interrupts bacterial communication. AB - The majority of the marine algal species, though completing their life cycle in seawater, are rarely susceptible to fouling, making them an important source of quorum sensing (QS) inhibitory substances. The separation and characterization of QS inhibitors are crucial for any potential application. Thirty marine macroalgae were tested for QS inhibition activity by using Chromobacterium violaceum CV026 as the reporter strain, and among them, Asparagopsis taxiformis showed antibacterial, as well as antiquorum, sensing activities. Cinnamaldehyde (75 mM) and methanol were used as positive and negative controls, respectively. The antiquorum sensing activity of A. taxiformis was further confirmed using the sensor strain, Serratia liquefaciens MG44, having green fluorescent protein (gfp). Methanolic extract of the alga was fractionated by solid phase extraction (SPE), and each fraction was tested for QS inhibition. Two types of activities were observed-zone of clearance (antibacterial activity) and zone of inhibition with or without finger-like projections (QS inhibition). Out of five SPE cartridges, Bond Elut PH showed clear separation of these two fractions. The Ion Cyclotron Resonance Fourier Transformation Mass Spectrometer (ICR-FT/MS) analysis of the fractions further supported the bioassay results. The presence of strong QS inhibitory compound in A. taxiformis indicates its potential use in antifouling preparations. PMID- 23344115 TI - Isolation and purification of a peptide from Bullacta exarata and its impaction of apoptosis on prostate cancer cell. AB - Bullacta exarata was hydrolyzed with trypsin to prepare peptides; Hydrolysates were isolated by ultrafiltration and purified using G-25 gel filtration. The purity of the Bullacta exarata was demonstrated by HPLC and its peptide sequence analysis was detected. The effects of BEPT II and BEPT II-1 on the proliferation of PC-3 cells were examined using a MTT assay. BEPT II and BEPT II-1 significantly inhibited the proliferation of PC-3 cells in a time- and dose dependent manner. Annexin V/PI double staining studies showed exposing PC-3 cells to 5, or 15 mg/mL BEPT II-1 for 24 h increased the percentage of the early stage of apoptotic cells from 11.22% to 22.09%. In addition, typical morphologic changes were observed in the cells with acridine orange/ethidium bromide staining. These data support that BEPT II-1 has anticancer properties and merits further investigation to understand the mechanisms of BEPT II-1-induced apoptosis in PC-3 cells. PMID- 23344116 TI - Orthotic variations in the management of infantile tibia vara and the results of treatment. AB - BACKGROUND: Infantile tibia vara is an acquired form of tibial deformity associated with tibial varus and internal torsion. Several methods have been described for orthotics treatment. The purpose of this study was to determine the effectiveness of orthotics treatment in infantile tibia vara. STUDY DESIGN: Controlled trial. OBJECTIVE: The aim of this study was to compare the effect of different types of orthoses and correction methods on decreasing the curve in children with severe genu varum. METHODS: Three different types of knee-ankle foot orthoses were applied to 35 lower extremities of 22 pediatric participants who were 19-38 months of age. The same orthotic design principles were used to correct the femur, while different designs were applied to correct the tibia. The orthoses used on 20 participants were evaluated for differences among them and their effects on the treatment process. In addition, methods used in the treatment, problems encountered, production of different types of orthoses, convenience of application of the orthoses, and degree of patients satisfaction are discussed in this article. RESULTS: The mean duration of treatment of the participants until completion of treatment was 25.3 +/- 9.7 weeks with a minimum of 9 weeks and a maximum of 41 weeks. No statistically significant correlation was found between the duration of orthotic use in patients with a successful outcome and percentile height and percentile weight. When the duration of treatment using the different types of orthoses was analyzed, significant differences were found between Type 1 and Type 2, and Type 1 and Type 3 orthoses (p < 0.05), while no difference was observed between Type 2 and Type 3 orthoses (p > 0.05). CONCLUSION: We found that bracing is an effective form of treatment for infantile tibia vara up to 38 months of age. We conclude that full-time use of knee-ankle-foot orthoses exerting corrective forces from five points along the full length of the limb was effective. PMID- 23344117 TI - Kinematics of lower limbs of healthy Chinese people sitting cross-legged. AB - BACKGROUND: Sitting cross-legged as an activity of daily living and its kinematics have significantly different demands on the arthroplasty of hip and knee, which can be referred in the design of joint arthroplasty. OBJECTIVES: The purpose of this study was to obtain the kinematics of the lower limb in Chinese people during cross-legged sitting. STUDY DESIGN: This study identified the necessary requirements for joint arthroplasty to carry out sitting cross-legged activity. METHODS: A total of 40 healthy Chinese participants (average age = 23.8 years) performed six cross-legged sitting trials per person. Three-dimensional kinematic data of ankle, knee, and hip joints were collected; the means of the three-dimensional angles of these three joints were calculated. RESULTS: At the hip, the range of motion of the flexion was 101.7 degrees , the abduction reached 43.2 degrees , and the range of motion of the external rotation was 36.4 degrees . At the knee, the range of motion of the flexion was 131.9 degrees and the range of motion of the internal rotation reached 32.4 degrees . At the ankle, the range of motion in three planes was not great. CONCLUSIONS: Such motion ranges were likely to result in prosthetic dislocation. The results would provide valuable references for prosthesis design in the Chinese population. PMID- 23344118 TI - Normal curvature of glenoid surface can be restored when performing an inlay osteochondral allograft: an anatomic computed tomographic comparison. AB - PURPOSE: The purpose of this study was to quantitatively measure the morphology of the glenoid and to assess feasibility of using the medial tibial plateau surface as a donor for osteoarticular allograft reconstruction of the glenoid. METHODS: Using computed tomography (CT), 10 tibias and 10 scapular models from our database (5 males and 5 females in each group) were randomly selected. Commercial software (Mimics, Materialize, Inc., Plymouth, MI) was used to extract the bone contours from the CT images and to reconstruct the 3-dimensional (3D) geometry of the scapula and tibia. By utilizing the software Creo Elements/Pro 5.0 (Parametric Technology Corp., Needham, MA), mean length and width of both the glenoid and medial tibial plateau were calculated. Radius of curvature was then measured in each 3D CT model at three intermediate segment points that were established within the length line at 25, 50, and 75 percent from superior to inferior in the glenoid and from posterior to anterior in the medial tibial plateau. Statistical analysis was performed and determined to be significant for P < 0.05. RESULTS: The mean (+/- SD) radius of curvature values at the established 25, 50, and 75 percent segments of the glenoid were 47.4 +/- 17.5 mm, 51.2 +/- 12.4 mm, and 45.9 +/- 17.0 mm, respectively. For the medial tibial plateau, the radius of curvature at 25, 50, and 75 percent were 43.5 +/- 9.7 mm, 37.4 +/- 14.3 mm and 52.3 +/- 21.5 mm, respectively. Values of the glenoid length were 34.0 +/- 2.9 mm, and width values were 24.4 +/- 2.3 mm. For the medial tibial plateau, the length was 42.6 +/- 2.7 mm, and the width was 23.3 +/- 4.3 mm. There was no statistical difference in the radius of curvature and dimensional surface area between the glenoid and medial tibial plateau surfaces. CONCLUSION: The 3D CT-based anatomic study found that there is a statistically similar relationship in the radius of curvature of the glenoid and the medial tibial plateau surface. This concept may allow the medial tibial plateau to be used as a donor for osteoarticular allograft reconstruction of the glenoid, especially in young patients where previous studies have demonstrated that the success rate in shoulder replacements is not as good as in older patients. PMID- 23344119 TI - Anatomic and histologic analysis of the mid-substance and fan-like extension fibres of the anterior cruciate ligament during knee motion, with special reference to the femoral attachment. AB - PURPOSE: The purpose of this study is to evaluate the morphology of the mid substance and fan-like extension fibres of ACL during knee motion with reference to the femoral attachment. METHODS: This study used six fresh-frozen cadaveric knees and 22 embalmed cadaveric knees to macroscopically evaluate morphological changes in the ACL attachment during knee motion. Three embalmed specimens fixed at knee extension and another three specimens fixed at 120 degrees flexion were used for histologic observations. RESULTS: The fan-like extension fibres were adhered to the bone surface and the fibre location and orientation in relation to the femoral surface did not change, regardless of the knee flexion angle, while the orientation of the mid-substance fibres in relation to the femur did change during knee motion. During knee flexion, a fold in the ACL femoral attachment was observed at the border between the mid-substance and the fan-like extension fibres. The attachment of the mid-substance fibres was significantly smaller than the attachment of the fan-like extension fibres. CONCLUSION: The present study clarified anatomic and histologic character of the mid-substance fibres and fan like extension fibres, and provided critical information for future clinical and biomechanical studies concerning both two different fibres. Specifically for ACL reconstruction, it is difficult to reconstruct the natural fan-like extension fibres by creating a tunnel at the femoral and tibial ends of each fibre bundle, although the mid-substance fibres can be reconstructed by such procedures. PMID- 23344120 TI - Legitimate division of large data sets, salami slicing and dual publication, where does a fraud begin? PMID- 23344121 TI - Microarray analysis of gene expression profiles in the rat kidney demonstrates a local inflammatory response induced by cardiopulmonary bypass. AB - CONTEXT: Cardiopulmonary bypass (CPB) is a commonly used technique in cardiac surgery but is associated with acute, transient, renal dysfunction that has a negative impact on long-term survival. OBJECTIVE: To unravel the molecular pathogenesis of renal injury following CPB. DESIGN: To obtain insight into the pathogenesis of renal dysfunction following CPB, we performed a microarray analysis of renal gene expression in the rat. SETTING: University Medical Centre Groningen. INTERVENTION: Rats underwent CPB or a sham procedure for 60 min and were sacrificed at 60 min, 1 and 5 days after the procedure. MAIN OUTCOME MEASURES: Renal gene expression profile as determined by microarray analysis. RESULTS: Expression of 420 genes was significantly altered in CPB compared to the sham procedure, and in 407 genes, this was evident in the acute phase (60 min) following CPB. Gene ontology analysis revealed 28 of these genes were involved in inflammatory responses, with high expression of genes downstream of mitogen activated protein-kinase (MAP-kinase) signalling pathways. Potent inducers identified are from the interleukin-6 cytokine family that consists of interleukin-6 and oncostatin M (OSM), which signal through the gp130-cytokine receptor complex. The plasma concentration of interleukin-6 was hugely increased by CPB as measured by ELISA. Expression of genes downstream of these signalling pathways that lead to production of chemokines, adhesion molecules and molecules involved in coagulative pathways, was upregulated. CONCLUSION: CPB induces an acute and local inflammatory response in the kidney, which might contribute to renal injury. The signalling pathways involved identified by gene expression analysis may represent pharmacological targets to limit renal injury following CPB. PMID- 23344122 TI - Incidence, predictors and outcomes of postoperative coma: an observational study of 858,606 patients. AB - CONTEXT: Coma is a state of profound unresponsiveness that can occur as a serious perioperative complication. The study of risk factors for, and sequelae of, postoperative coma has been limited due to the rarity of the event. OBJECTIVE: To determine the incidence, risk factors and impact of postoperative coma in a large patient population. DESIGN: Observational study using a prospectively gathered national dataset. PATIENTS: Data from 858 606 patients were analysed. MAIN OUTCOME MEASURES: The incidence of postoperative coma of more than 24-h duration was identified. Logistic regression was used to identify independent predictors and develop a risk model of postoperative coma in derivation and validation cohorts; 30-day mortality was also analysed. RESULTS: The incidence of postoperative coma was 0.06%. Multivariate analysis revealed the following independent predictors: liver disease, systemic sepsis, age at least 63 years, renal disease, emergency operation, cardiac disease, hypertension, prior neurological disease, diabetes mellitus and BMI 25 to 29.99 kg m (protective). These predictors were incorporated into a risk index classification; odds ratios for postoperative coma increased from 2.5 with one risk factor to 18.4 with three. Coma was associated with 74.2% all-cause mortality; coma associated with cardiac arrest had a 1.9-fold higher mortality. CONCLUSION: This is the largest study of postoperative coma ever reported and will be useful for determining risk of coma of more than 24 h duration when evaluating an unresponsive patient following surgery. Data on prognosis will aid medical and ethical decision-making for the comatose surgical patient. PMID- 23344123 TI - Incidence of postoperative residual neuromuscular blockade in the postanaesthesia care unit: an observational multicentre study in Portugal. AB - CONTEXT: Residual neuromuscular blockade still presents despite the use of intermediate duration muscle relaxants and is a risk factor for postoperative morbidity. OBJECTIVE: To determine the incidence of incomplete postoperative neuromuscular recovery from anaesthesia in a postanaesthesia care unit. DESIGN: Multicentre observational study. SETTING: Public Portuguese hospitals. PATIENTS: Adult patients scheduled for elective surgery requiring general anaesthesia with neuromuscular blocking agents. MAIN OUTCOME MEASURES: An independent anaesthesiologist measured neuromuscular transmission by the TOF-Watch SX acceleromyograph. Train-of-four ratios at least 0.9 and less than 0.9 were assessed as complete and incomplete neuromuscular recovery following general anaesthesia, respectively. RESULTS: The study population consisted of 350 patients [134 men and 216 women, mean (SD) age 54.3 (15.9) years]. Ninety-one patients had a train-of-four ratio less than 0.9 on arrival in the postanaesthesia care unit, an incidence of residual neuromuscular blockade of 26% [95% confidence interval (CI) 21 to 31%]. The most frequent neuromuscular blockers were rocuronium (44.2%) and cisatracurium (32%). A neuromuscular block reversal agent was used in 66.6% of the patients (neostigmine in 97%). The incidence of residual neuromuscular blockade in patients receiving reversal agents was 30% (95% CI 25 to 37%). There were no statistically significant differences in the occurrence of residual blockade relating to the neuromuscular blocker used, although higher percentages were observed for cisatracurium (32.4%) and vecuronium (32%) compared with atracurium (23.6%) and rocuronium (20.8%). Incomplete neuromuscular recovery was significantly more frequent among patients who had received a reversal agent (30.5 vs. 17.1%, P = 0.01). Incomplete neuromuscular recovery was more frequent in patients given propofol than in those exposed to sevoflurane (26.2 vs. 14.3%). CONCLUSION: The incidence of incomplete neuromuscular recovery of 26% confirms that it is relatively frequent in the postoperative period and calls attention to the dimension of this problem in Portugal. PMID- 23344124 TI - The effect of deep vs. awake extubation on respiratory complications in high-risk children undergoing adenotonsillectomy: a randomised controlled trial. AB - CONTEXT: There is ongoing debate regarding the optimal timing for tracheal extubation in children at increased risk of perioperative respiratory adverse events, particularly following adenotonsillectomy. OBJECTIVE: To assess the occurrence of perioperative respiratory adverse events in children undergoing elective adenotonsillectomy extubated under deep anaesthesia or when fully awake. DESIGN: Prospective, randomised controlled trial. SETTING: Tertiary paediatric hospital. PATIENTS: One hundred children (<16 years), with at least one risk factor for perioperative respiratory adverse events (current or recent upper respiratory tract infection in the past 2 weeks, eczema, wheezing in the past 12 months, dry nocturnal cough, wheezing on exercise, family history of asthma, eczema or hay fever as well as passive smoking). INTERVENTION: Deep or awake extubation. MAIN OUTCOME MEASURE: The occurrence of perioperative respiratory adverse events (laryngospasm, bronchospasm, persistent coughing, airway obstruction, desaturation <95%). RESULTS: There were no differences between the two groups with regard to age, medical and surgical parameters. The overall incidence of complications did not differ between the two groups; tracheal extubation in fully awake children was associated with a greater incidence of persistent coughing (60 vs. 35%, P = 0.028), whereas the incidence of airway obstruction relieved by simple airway manoeuvres in children extubated while deeply anaesthetised was greater (26 vs. 8%, P = 0.03). There was no difference in the incidence of oxygen desaturation lasting more than 10 s. CONCLUSION: There was no difference in the overall incidence of perioperative respiratory adverse events. Both extubation techniques may be used in high-risk children undergoing adenotonsillectomy provided that the child is monitored closely in the postoperative period. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000387224. PMID- 23344125 TI - Seasonal variation in metabolism: evidence for the role of circannual rhythms in metabolism? PMID- 23344126 TI - The association between methylenetetrahydrofolate reductase C677T polymorphism and pre-eclampsia risk: appraisal of a recent meta-analysis. PMID- 23344127 TI - During winter the body resists insulin. PMID- 23344128 TI - Are peripheral arterial changes during enhanced external counterpulsation necessary for and/or evidence of an adequate cardiovascular response? PMID- 23344129 TI - Urinary prostasin in normotensive individuals: correlation with the aldosterone to renin ratio and urinary sodium. AB - Prostasin, a glycosylphosphatidylinositol (GPI)-anchored serine protease, activates the epithelial sodium (Na) channel (ENaC), and prostasin is released in extracellular fluids, including urine. Previous data have suggested a direct association between urinary prostasin and the activation of an aldosterone-driven pathway, but a quantitative association has never been demonstrated in normotensive subjects. Similarly, physiological relationships with natriuresis or possible gender- or female hormone-related changes in urinary prostasin concentrations have never been investigated. We measured urinary prostasin by enzyme-linked immunosorbent assay in 43 healthy normotensive subjects of similar age presenting different urinary Na levels and in 15 women during the menstrual cycle and after oral estro-progestinic contraceptive (OC) therapy. Exosomal urinary prostasin was also estimated by western blotting of samples from six healthy subjects twice during the morning. Urinary prostasin presented a wide range of values (from 0.5 to 18.9 nM) without gender differences. It was positively correlated with the aldosterone to renin ratio (ARR) but not with circulating aldosterone or renin individually. Urinary prostasin was directly correlated with U-Na levels (up to 200 nmol Na), whereas it decreased for higher Na concentrations. In women, no significant changes of prostasin concentration were observed during menstrual phases. After OC therapy, prostasin increased (from 2.37+/-1.27 to 4.85+/-5.28 nM), although the increase was not statistically different (P=0.07). Prostasin was detectable in urinary exosomes and displayed a pattern similar to urinary prostasin in relation to urinary Na. In conclusion, urinary prostasin correlates with the ARR, and it is physiologically modulated by natriuresis in normotensive individuals. PMID- 23344130 TI - Asymmetrical limbs arterial pressures: a new marker of atherosclerosis. PMID- 23344131 TI - Ambulatory and home blood pressure monitoring in children and adolescents: diagnosis of hypertension and assessment of target-organ damage. AB - The prevalence of elevated blood pressure in children and adolescents is more common than previously believed and often represents the early onset of essential hypertension, particularly in adolescents. The definition of hypertension in children is based on distribution criteria and normalcy tables that provide blood pressure percentiles for each measurement method (office, ambulatory and home) according to the individual's age, gender and body size. Owing to the white coat and masked hypertension phenomena, ambulatory blood pressure monitoring is indispensable for the diagnosis of hypertension in children. Home blood pressure monitoring in children has been less well studied, and at present, treatment decisions should not be based solely on such measurements. Hypertension-induced preclinical target-organ damage (mainly echocardiographic left ventricular hypertrophy) is not uncommon in children and should be evaluated in all hypertensive children. Other indices of target-organ damage, such as carotid intima-media thickness, pulse wave velocity and microalbuminuria, remain under investigation in pediatric hypertension. PMID- 23344132 TI - Increased mean arterial pressure response to dynamic exercise in normotensive subjects with multiple metabolic risk factors. AB - Metabolic syndrome (MS) may influence vascular reactivity and might cause an excessive increase in blood pressure (BP) during dynamic exercise. We examined this hypothesis in 698 normotensive men (mean age: 43 years) free of cardiovascular disease, diabetes mellitus and renal disease. The response of BP to exercise was assessed by the mean arterial pressure (MAP) during bicycle ergometry. The MAP values were expressed as z-scores normalized to the relative increases in heart rate. High-normal BP, dyslipidemia and hyperglycemia were diagnosed according to the Japan-specific MS criteria. The z-score of MAP was significantly higher in subjects with high-normal BP (+0.57, P<0.001), dyslipidemia (+0.18, P<0.001) and hyperglycemia (+0.24, P<0.001) than in those without MS component (-0.38). In the high-normal BP subjects, the addition of dyslipidemia and/or hyperglycemia was associated with a progressive increase in the z-score of exercise MAP, whereas no such association was observed in the normal-BP subjects (P=0.033, two-way ANOVA). Multivariate regression analysis revealed that a greater number of MS components (beta=0.102, P=0.010) was an independent determinant of increased MAP z-score after adjustment for potential confounders, including age (beta=0.123, P<0.001), body mass index (beta=0.145, P<0.001) and high-normal BP (beta=0.410, P<0.001). These results suggest that accumulation of MS components may alter vascular structure and function and lead to the significant elevation of MAP during dynamic exercise even before clinical manifestation of arterial hypertension. PMID- 23344133 TI - Asleep blood pressure: relevance to the proper definition of isolated-office and masked hypertension. PMID- 23344134 TI - A meta-analysis of randomized trials of telmisartan vs. valsartan therapy for blood pressure reduction. AB - A previous meta-analysis of six randomized head-to-head trials suggests that the blood pressure (BP)-lowering capabilities of telmisartan may be comparable to those of valsartan. We performed an updated meta-analysis of telmisartan vs. valsartan therapy for the reduction of BP in hypertensive patients. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched through August 2012 using web-based search engines (PubMed, OVID). Eligible studies were prospective randomized controlled trials examining telmisartan vs. valsartan therapy and reporting clinic BP as an outcome. For each study, the data regarding changes from baseline to final clinic systolic BP (SBP) and diastolic BP (DBP) in both the telmisartan and valsartan groups were used to generate mean differences (MDs) and 95% confidence intervals (CIs). Of the 62 potentially relevant articles initially screened, 17 reports about prospective randomized controlled clinical trials of telmisartan vs. valsartan therapy, including a total of 5422 patients with hypertension, were identified and included. Pooled analysis suggested significant differences in BP reductions among the patients randomized to telmisartan vs. valsartan therapy (MD for SBP, -2.04 mm Hg; 95% CI, -2.80 to -1.28 mm Hg; P<0.00001; MD for DBP, -1.08 mm Hg; 95% CI, -1.55 to -0.62 mm Hg; P<0.00001). When data from the monotherapy and combination therapy (with hydrochlorothiazide) trials were pooled separately, telmisartan therapy was associated with a statistically significant difference in BP reductions relative to valsartan therapy in both the monotherapy and combination therapy groups. In conclusion, telmisartan therapy appears to reduce BP more than valsartan therapy in patients with hypertension. PMID- 23344135 TI - Effectiveness of a selective, personality-targeted prevention program for adolescent alcohol use and misuse: a cluster randomized controlled trial. AB - CONTEXT: Selective school-based alcohol prevention programs targeting youth with personality risk factors for addiction and mental health problems have been found to reduce substance use and misuse in those with elevated personality profiles. OBJECTIVES: To report 24-month outcomes of the Teacher-Delivered Personality Targeted Interventions for Substance Misuse Trial (Adventure trial) in which school staff were trained to provide interventions to students with 1 of 4 high risk (HR) profiles: anxiety sensitivity, hopelessness, impulsivity, and sensation seeking and to examine the indirect herd effects of this program on the broader low-risk (LR) population of students who were not selected for intervention. DESIGN: Cluster randomized controlled trial. SETTING: Secondary schools in London, United Kingdom. PARTICIPANTS: A total of 1210 HR and 1433 LR students in the ninth grade (mean [SD] age, 13.7 [0.33] years). INTERVENTION: Schools were randomized to provide brief personality-targeted interventions to HR youth or treatment as usual (statutory drug education in class). MAIN OUTCOME MEASURES: Participants were assessed for drinking, binge drinking, and problem drinking before randomization and at 6-monthly intervals for 2 years. RESULTS: Two-part latent growth models indicated long-term effects of the intervention on drinking rates (beta = -0.320, SE = 0.145, P = .03) and binge drinking rates (beta = 0.400, SE = 0.179, P = .03) and growth in binge drinking (beta = -0.716, SE = 0.274, P = .009) and problem drinking (beta = -0.452, SE = 0.193, P = .02) for HR youth. The HR youth were also found to benefit from the interventions during the 24-month follow-up on drinking quantity (beta = -0.098, SE = 0.047, P = .04), growth in drinking quantity (beta = -0.176, SE = 0.073, P = .02), and growth in binge drinking frequency (beta = -0.183, SE = 0.092, P = .047). Some herd effects in LR youth were observed, specifically on drinking rates (beta = -0.259, SE = 0.132, P = .049) and growth of binge drinking (beta = -0.244, SE = 0.073, P = .001), during the 24-month follow-up. CONCLUSIONS: Findings further support the personality-targeted approach to alcohol prevention and its effectiveness when provided by trained school staff. Particularly novel are the findings of some mild herd effects that result from this selective prevention program. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00776685. PMID- 23344136 TI - Interim FDG PET/CT as a prognostic factor in diffuse large B-cell lymphoma. AB - PURPOSE: Interim (18)F-FDG PET performed early during the course of therapy in diffuse large B-cell lymphoma (DLBCL) is a good predictor of outcome. However, interpretation criteria for interim PET for the evaluation of tumour response are still not clearly defined. The study aim was to assess whether interim PET can predict overall survival (OS) and progression-free survival (PFS) in DLBCL patients following three different sets of parameters, two qualitative (visual) methods and one semiquantitative. METHODS: A total of 50 newly diagnosed DLBCL patients were prospectively enrolled in this study. All patients had a PET/CT scan at diagnosis and an interim PET/CT scan after the second or third cycle of chemotherapy. Three methods of evaluation for the interim PET/CT were used: a qualitative three-point scoring (3-PS) method, a qualitative 5-PS method and a semiquantitative method (DeltaSUVmax). The degree of correlation between therapy response seen on FDG PET and PFS and OS was determined. RESULTS: The analysis of the visual 3-PS method showed no statistically significant difference in PFS and OS. The estimated 5-year PFS and OS were 79 % and 92 %, respectively, in patients with an interim PET scan showing uptake not greater than in the liver versus 50 % in patients with uptake greater than in the liver, and this difference was statistically significant. The optimal cut-off value of DeltaSUVmax that could predict the PFS and OS difference in patients with DLBCL was 76 % (95 % CI 62.7 89.2 %) and 75 % (95 % CI, 54.6-95.4 %), respectively. CONCLUSION: Our results support the use of liver uptake as an indicator in the qualitative evaluation of interim PET, or a DeltaSUVmax greater than 75 % in semiquantitative analysis. Interim PET may predict PFS and OS and could be considered in the prognostic evaluation of DLBCL. PMID- 23344139 TI - Photocatalytic Disinfection of Coliform Bacteria Using UV/TiO2. AB - BACKGROUND: There are great interests in photocatalytic oxidation of contaminants using titanium dioxide in recent years. The main objective of this research was to study photocatalytic disinfection of Coliform bacteria as water microbial pollution index using TiO2 and a low pressure UV lamp in a batch reactor. METHODS: The polluted water was prepared by adding a colony of Coliform in raw water and in separate stages was contacted with UV, TiO2 and combination of them and various parameters such as contact time, pH and amount of TiO2 were studied in terms of their effect on reaction progress. RESULTS: The results showed that in simultaneous presence of both UV ray and TiO2, there was the most effective disinfection of Coliform. This study showed that 100% of Coliform was killed by irradiation for 60-75 min. in the presence of 0.8 gr l-1 TiO2 in pH=7.0. CONCLUSION: Based on the results, UV/TiO2 process may be effectively applied for disinfection of polluted water and can be suggested as a effective purifying method for water disinfection. PMID- 23344137 TI - Performance evaluation of small-animal multipinhole MUSPECT scanners for mouse imaging. AB - PURPOSE: We compared the performance of three commercial small-animal MUSPECT scanners equipped with multipinhole general purpose (GP) and multipinhole high resolution (HR) collimators designed for imaging mice. METHODS: Spatial resolution, image uniformity, point source sensitivity and contrast recovery were determined for the U-SPECT-II (MILabs), the NanoSPECT-NSO (BioScan) and the X SPECT (GE) scanners. The pinhole diameters of the HR collimator were 0.35 mm, 0.6 mm and 0.5 mm for these three systems respectively. A pinhole diameter of 1 mm was used for the GP collimator. To cover a broad field of imaging applications three isotopes were used with various photon energies: (99m)Tc (140 keV), (111)In (171 and 245 keV) and (125)I (27 keV). Spatial resolution and reconstructed image uniformity were evaluated in both HR and a GP mode with hot rod phantoms, line sources and a uniform phantom. Point source sensitivity and contrast recovery measures were additionally obtained in the GP mode with a novel contrast recovery phantom developed in-house containing hot and cold submillimetre capillaries on a warm background. RESULTS: In hot rod phantom images, capillaries as small as 0.4 mm with the U-SPECT-II, 0.75 mm with the X-SPECT and 0.6 mm with the NanoSPECT NSO could be resolved with the HR collimators for (99m)Tc. The NanoSPECT-NSO achieved this resolution in a smaller field-of-view (FOV) and line source measurements showed that this device had a lower axial than transaxial resolution. For all systems, the degradation in image resolution was only minor when acquiring the more challenging isotopes (111)In and (125)I. The point source sensitivity with (99m)Tc and GP collimators was 3,984 cps/MBq for the U-SPECT-II, 620 cps/MBq for the X-SPECT and 751 cps/MBq for the NanoSPECT-NSO. The effects of volume sensitivity over a larger object were evaluated by measuring the contrast recovery phantom in a realistic FOV and acquisition time. For 1.5-mm rods at a noise level of 8 %, the contrast recovery coefficient (CRC) was 42 %, 37 % and 34 % for the U-SPECT-II, X-SPECT and NanoSPECT-NSO, respectively. At maximal noise levels of 10 %, a CRCcold of 70 %, 52 % and 42 % were obtained for the U-SPECT II, X-SPECT and NanoSPECT-NSO, respectively. When acquiring (99m)Tc with the GP collimators, the integral/differential uniformity values were 30 %/14 % for the U SPECT-II, 50 %/30 % for the X-SPECT and 38 %/25 % for the NanoSPECT-NSO. When using the HR collimators, these uniformity values remained similar for U-SPECT-II and X-SPECT, but not for the NanoSPECT-NSO for which the uniformity deteriorated with larger volumes. CONCLUSION: We compared three MUSPECT systems by acquiring and analysing mouse-sized phantoms including a contrast recovery phantom built in house offering the ability to measure the hot contrast on a warm background in the submillimetre resolution range. We believe our evaluation addressed the differences in imaging potential for each system to realistically image tracer distributions in mouse-sized objects. PMID- 23344140 TI - Evaluation of Injuries among a Manufacturing Industry Staff in Iran. AB - BACKGROUND: Occupational injury is related to personal characteristics. This phenomenon is a controversial issue. This paper presents the relationships of certain occupational and individual characteristics with frequency of occupational injuries. METHODS: A standardized injury questionnaire was completed for 199 employees in a big Iranian industrial company (MAPNA Group) by the researcher in the presence of the subjects. The data were analyzed using zero inflated Poisson regression with random effects. RESULTS: We demonstrated a significant relation between the marital status (P< 0.001) and score of injures (P < 0.001) with number of injuries by employees. Technicians and supervisors have high chance of "not to be injured at all" relative to workers (P< 0.05). Technicians and supervisors have less number of injuring than workers have (P< 0.05). In addition, increasing assessment score decreases the number of injuring of employees (P< 0.001). CONCLUSION: Due to being aware of the risks and remedial measures, married employees and workers should be assisted by occupational specialists. PMID- 23344138 TI - PET imaging of CD105/endoglin expression with a 61/64Cu-labeled Fab antibody fragment. AB - PURPOSE: The goal of this study was to generate and characterize the Fab fragment of TRC105, a monoclonal antibody that binds with high affinity to human and murine CD105 (i.e., endoglin), and investigate its potential for PET imaging of tumor angiogenesis in a small-animal model after (61/64)Cu labeling. METHODS: TRC105-Fab was generated by enzymatic papain digestion. The integrity and CD105 binding affinity of TRC105-Fab was evaluated before NOTA (1,4,7-triazacyclononane 1,4,7-triacetic acid) conjugation and (61/64)Cu labeling. Serial PET imaging and biodistribution studies were carried out in the syngeneic 4T1 murine breast cancer model to quantify tumor targeting efficiency and normal organ distribution of (61/64)Cu-NOTA-TRC105-Fab. Blocking studies with unlabeled TRC105 were performed to confirm CD105 specificity of the tracer in vivo. Immunofluorescence staining was also conducted to correlate tracer uptake in the tumor and normal tissues with CD105 expression. RESULTS: TRC105-Fab was produced with high purity through papain digestion of TRC105, as confirmed by SDS-PAGE, HPLC analysis, and mass spectrometry. (61/64)Cu labeling of NOTA-TRC105-Fab was achieved with about 50 % yield (specific activity about 44 GBq/MUmol). PET imaging revealed rapid uptake of (64)Cu-NOTA-TRC105-Fab in the 4T1 tumor (3.6 +/- 0.4, 4.2 +/- 0.5, 4.9 +/- 0.3, 4.4 +/- 0.7, and 4.6 +/- 0.8 %ID/g at 0.5, 2, 5, 16, and 24 h after injection, respectively; n = 4). Since tumor uptake peaked soon after tracer injection, (61)Cu-labeled TRC105-Fab was also able to provide tumor contrast at 3 and 8 h after injection. CD105 specificity of the tracer was confirmed with blocking studies and histological examination. CONCLUSION: We report PET imaging of CD105 expression using (61/64)Cu-NOTA-TRC105-Fab, which exhibited prominent and target-specific uptake in the 4T1 tumor. The use of a Fab fragment led to much faster tumor uptake (which peaked at a few hours after tracer injection) compared to radiolabeled intact antibody, which may be translated into same-day immunoPET imaging for clinical investigation. PMID- 23344141 TI - An annual survey of successful suicide incidence in hamadan, Western iran. AB - BACKGROUND: Suicide has constituted a critical public health problem for many decades. The number of completed suicide is traditionally high in Iran. The objective of the present study was to describe the patterns of methods of suicide among registered deaths due to suicide in Hamada, western Iran. METHODS: In this cross-sectional study, all completed suicide cases (n=146) were included from March 2004 through March 2005 based on Hamadan's Forensic center registered deaths because of suicide. Supplementary data were gauged through a questionnaire from the attemptersa?TM relatives. All statistical analyses were performed using version 13 of the statistical software package SPSS and an alpha level of .05 for all statistical tests. RESULTS: Prevalence of completed suicide was 8.3 per 100,000 in Hamadan, Iran. From 146 cases, the male-to-female ratio was 7.1:1. Average age of cases was 33.9 yr (Min=10, Max=94) across all age groups, males show consistently higher completed suicide rates than females. Of the 69.2% were from urban population versus 30.8% form rural population. The most common method of suicide was hanging (78.1 %). Other common methods were poisoning (11.6%), and self-burning (6.2%). CONCLUSION: Suicide rate in Hamadan is high among males through hanging which can be due tosubstance dependency and unemployment. PMID- 23344142 TI - The Relationship between the Worker's Safety Attitude and the Registered Accidents. AB - BACKGROUND: Millions of workers are the victims of different kinds of accidents every year throughout the world. The purpose of this study was to investigate the relationships between safety attitude and occurrence of the occupational accidents. METHODS: This investigation was a cross-sectional study performed in a gas refinery in south of Iran in 2008. Sample size of this study was 176 people. To determine the value of worker's safety attitude a validated 5 degrees questionnaire was used. Different statistic analyses including Chi-square, t-test and Logistic Regression were used by Spss11.5 to analyze the data. The Cronbachs alpha coefficient was found to be 0.97 in this investigation. RESULTS: In the study population, the average age was 31.67(+/- 5.89), the average work experience was 5.65 (+/- 4.29) and the average of the safety attitude was 188.52(+/- 14.84) and only 28.7% were injured through accidents. The relationship between safety attitude of the workers and the accidents occurred was significant (P< 0.0001). CONCLUSION: The relationship between safety attitude of the workers and the accidents occurred was significant, although the relation was not significant for graduate workers. No significant relationship was found between safety attitude and accident in accordance with worker's age and work experience. PMID- 23344143 TI - Occupational Stress among Rural Health Workers in Mashhad District, Northeast Iran. AB - BACKGROUND: This study explores the level of Occupational Stress and main sources of occupational and personal stress among Rural Health Workers (RHW) of the health network of Mashhad district. METHODS: The first part of the Occupational Stress Inventory (OSI) (called the Occupational Roles Questionnaire (ORQ)) was used to measure the Rural Health Workers occupational stress (N=172). A number of extra questions were also added to measure their specific sources of stress. The questionnaires were distributed among RHW in a meeting held in the Health District Center in the city of Mashhad. RESULTS: The mean score of stress for the investigated subjects on OSI and all of its dimensions was within the normal range. On some dimensions such as role overload and role ambiguity however, about 40% of the Health Workers had middle to sever stress. Type of employment, distance of the village to the nearest city, number and combination of Health Workers in rural health clinics showed to have a significant impact on the RHW stress as well. CONCLUSION: As the RHW Job is concerned, role overload and role ambiguity are the main sources of stress, which may have an adverse effect on the quality of their services. Type of employment, distance of the village to the nearest city, number and combination of Health Workers at the health center also put pressure on RHW that need to be taken under consideration in planning for improving RHW quality of work Life. PMID- 23344144 TI - Safety Cultural Assessment among Management, Supervisory and Worker Groups in a Tar Refinery Plant. AB - BACKGROUND: This study investigated the relationship between people's attitudes towards the safety culture and comparing its perceptions among three levels of refinery Personnel: top management, supervisory staff and frontline workers by conducting safety culture survey. METHODS: A questionnaire comprising general information and 59-safety attitude statement were distributed among 237 workers, 53 supervisors and 12 managers in Isfahan Tar Refinery in Iran. RESULTS: The 10 testable factors, including organizational and management commitment to safety and communication, Rule breaking, Training and competence, Pressure for production and safety, Communication, Personal involvement in health and safety, Accident/Incidents/Near misses, Organizational/management commitment to health and safety, Supervisors/Immediate bosses/Line managers, Health and safety procedures/Instructions/rules, Workforce view on state of safety culture, have high inter-correlations and the three groups of respondents hold quite different attitudes regarding safety culture. CONCLUSION: These findings can give invaluable indication to the managers to have better understanding of safety culture in this industry. PMID- 23344145 TI - Relationships between Locus of Control and Adherence to Diabetes Regimen. AB - BACKGROUND: Adequate self-care in diabetes causes quality of life promotion and decreases the number of inpatient cases. The health locus of control theory is used to assess adherence to diabetes regimen in some studies in developed countries. The purpose of this study was to determine the status of diabetes locus of control in a sample of diabetic patients in Iran and investigation of it's relationship to adherence to diabetes regimen. METHODS: This analytical and cross-sectional study was carried out on 120 patients referred to Yazd Diabetes Research Center. The Iranian versions of Diabetes Locus of Control scale and Diabetes Selfcare Activities scale were used for data collection. RESULTS: Men were more internal locus of control and women were more chance locus of control. The attributions of external locus of control increased by age, while the internal locus of control increased by education level and chance locus of control decreased by education level. A positive association between internal locus of control and adherence to diabetes regimen was found and there was a negative association between chance locus of control and adherence to diabetes regimen. CONCLUSION: Findings suggest that interventions aimed at improving internal locus of control may improve adherence to diabetes regimen but different diabetic patients have different attribution styles and interventional programs to enhance diabetes self-care will be more successful if patient's locus of control is addressed. PMID- 23344146 TI - The Prevalence of Pediculosis capitis in Primary School Students in Bahar, Hamadan Province, Iran. AB - BACKGROUND: Head lice infestation caused by Pediculus humanus var capitis (Pediculus capitis) is a worldwide public health concern that affects mostly school aged children. This descriptive, analytical study was carried out in 2008 to determine the prevalence of pediculosis capitis and some risk factors among primary-school pupils in Bahar, Hamadan Province, Iran. METHODS: We selected 900 pupils (50% girls and 50% boys) from 18 primary schools by multistage, systematic random sampling. Their hair was examined for head louse infestation. The results and demographic information recorded in the questionnaire and then were analyzed by SPSS software. RESULTS: Twelve students (1.3%) were infected with lice, 10 (2.2%) girls and 2 (0.44%) boys. The rate of infection was 0.66% in urban and 1.66% in rural areas. The results showed significant variations in head lice infestation, and factors such as sex, level of parent education and habitat (P 0.05). CONCLUSIONS: The prevalence of pediculosis was less than average percentages observed in other students inside and outside Iran. We recommend that the parents and teachers should receive training about the danger of infection and its distribution in family and school in order to prevent it. PMID- 23344147 TI - Analysis of hospitalized burned patients in bandar abbass, iran. AB - This study was conducted to determine the causes and outcomes of burn in patients referred to Shahid Mohammadi Hospital in Bandar Abbass, southern Iran, in which 212 burned patients were assessed from March 2007 to March 2008 .Mean age of patients was 22.14 yr. Heat contact was the main cause of burn with 92.5%. 49.1% of total burns occurred among less than 20 yr old people. Mortality rate was 10.4%. Most of burns occurred at home. An educational program is necessary to prevent thermal burning at home. PMID- 23344148 TI - Nonviral direct conversion of primary mouse embryonic fibroblasts to neuronal cells. AB - Transdifferentiation, where differentiated cells are reprogrammed into another lineage without going through an intermediate proliferative stem cell-like stage, is the next frontier of regenerative medicine. Wernig et al. first described the direct conversion of fibroblasts into functional induced neuronal cells (iNs). Subsequent reports of transdifferentiation into clinically relevant neuronal subtypes have further endorsed the prospect of autologous cell therapy for neurodegenerative disorders. So far, all published neuronal transdifferentiation protocols rely on lentiviruses, which likely precludes their clinical translation. Instead, we delivered plasmids encoding neuronal transcription factors (Brn2, Ascl1, Myt1l) to primary mouse embryonic fibroblasts with a bioreducible linear poly(amido amine). The low toxicity and high transfection efficiency of this gene carrier allowed repeated dosing to sustain high transgene expression levels. Serial 0.5 ug cm(-2) doses of reprogramming factors delivered at 48-hour intervals produced up to 7.6% Tuj1(+) (neuron-specific class III beta tubulin) cells, a subset of which expressed MAP2 (microtubule-associated protein 2), tau, and synaptophysin. A synapsin-red fluorescent protein (RFP) reporter helped to identify more mature, electrophysiologically active cells, with 24/26 patch-clamped RFP(+) cells firing action potentials. Some non-virally induced neuronal cells (NiNs) were observed firing multiple and spontaneous action potentials. This study demonstrates the feasibility of nonviral neuronal transdifferentiation, and may be amenable to other transdifferentiation processes. PMID- 23344149 TI - Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol. AB - Increased DNA repair activity in cancer cells is one of their primary mechanisms of resistance to current radio- and chemotherapies. The molecule coDbait is the first candidate in a new class of drugs that target the double-strand DNA break repair pathways with the aim of overcoming these resistances. coDbait is a 32 base pair (bp) double-stranded DNA molecule with a cholesterol moiety covalently attached to its 5'-end to facilitate its cellular uptake. We report here the preclinical pharmacokinetic and toxicology studies of subcutaneous coDbait administration in rodents and monkeys. Maximum plasma concentration occurred between 2 to 4 hours in rats and at 4 hours in monkeys. Increase in mean AUC0-24h was linear with dose reaching 0.5 mg.h/ml for the highest dose injected (32 mg) for both rats and monkeys. No sex-related differences in maximum concentration (Cmax) nor AUC0-24h were observed. We extrapolated these pharmacokinetic results to humans as the subcutaneous route has been selected for evaluation in clinical trials. Tri-weekly administration of coDbait (from 8 to 32 mg per dose) for 4 weeks was overall well tolerated in rats and monkeys as no morbidity/mortality nor changes in clinical chemistry and histopathology parameters considered to be adverse effects have been observed. PMID- 23344150 TI - A report of renal artery embolization for hematuria facilitating neoadjuvant chemotherapy in an unresectable malignant renal rhabdoid tumor. AB - Malignant rhabdoid tumor (MRT) of the kidney is a rare pediatric tumor characterized by its aggressive nature and chemoresistance. Our patient had MRT of the right kidney with tumor thrombus in the renal vein, inferior vena cava, and right atrium. He developed transfusion-resistant hematuria. This was successfully controlled with right renal artery embolization allowing completion of his neoadjuvant chemotherapy. He then underwent complete resection of the tumor and thrombus avoiding cardiopulmonary bypass. PMID- 23344151 TI - To drain or not to drain: an analysis of abscess drains in the treatment of appendicitis with abscess. AB - BACKGROUND/PURPOSE: Perforated appendicitis is associated with abscess formation before or after appendectomy. Many abscesses are not amenable to drainage due to size or location. In this study, we compare patients who had a drain placed for an abscess to those who were treated without a drain. METHODS: Data were retrospectively collected from January 2000 to March 2011. Abscess before or after appendectomy was assessed. CT scans were reviewed and abscess size was estimated using the product of the greatest anteroposterior and lateral dimensions from an axial image. Patients with abscess smaller than 5 cm(2) were excluded. Patients treated with a drain were compared to those without using t test for continuous variables and Fisher's exact for categorical variables. RESULTS: Of 217 patients, those with drains had significantly more CT scans, total healthcare visits and larger abscess size. When match controlled for size, drain patients accrued more CT scans and healthcare visits. In a subset analysis of aspiration versus antibiotics only, there were more CT scans but no difference between length of stay, total healthcare visits, abscess size, recurrence, or complications. CONCLUSIONS: Appendicitis-associated abscesses may be treated with antibiotics alone based on size, which improves resource utilization with fewer CT scans and healthcare visits. PMID- 23344152 TI - A surgical approach to Wilms' tumour with retrohepatic vena caval extension. AB - PURPOSE: Wilms' tumours (WT) with retrohepatic vascular extension traditionally requires cardiac bypass for complete excision. We share our experience of these complex cases. METHODS: A retrospective review was performed of children with WT with retrohepatic vascular extension presenting to two UK children's hospitals. Tumour stage, chemotherapy, level of vascular extension, operative details and complication data were analysed. RESULTS: Ten children were identified. Mean age 6.6 years (range 3.3-8.2 years); tumour side 6 right, 2 left, 2 bilateral. Level of tumour extension was to the right atrium in two, diaphragm in two, hepatic vein (HV) level in four and retrohepatic inferior vena cava (IVC) in one patient. Following chemotherapy it reduced to hepatic veins (5) or below (4). Surgery involved radical nephrectomy and complete mobilisation of the liver off the IVC, which was then clamped, opened and the thrombus excised. There were no intraoperative complications. Mean hospital stay was 9.77 days (7-20 days). Histology showed viable tumour thrombus in six patients. One patient died after 1 year from metastatic disease. CONCLUSION: Retrohepatic extension of WT can be managed without bypass using pre-operative chemotherapy and by complete liver mobilisation. The tumour was always adherent to IVC and required sharp dissection. PMID- 23344153 TI - Quantitative MRI analysis of the brain after twenty-two years of neuromyelitis optica indicates focal tissue damage. AB - BACKGROUND: The long-term effect of neuromyelitis optica (NMO) on the brain is not well established. METHODS: After 22 years of NMO, a patient's brain was examined by quantitative T1- and T2-weighted mono- and biexponential diffusion and proton spectroscopy. It was compared to 3 cases with short-term NMO and 20 healthy subjects. RESULTS: Although routine T1- and T2-weighted images appeared to be normal, quantitative T1-, T2- and diffusion-weighted magnetic resonance imaging identified areas with high diffusivity and altered relaxation time in 'normal appearing white matter' (NAWM). In such abnormal NAWM regions, biexponential diffusion analysis and quantitative spectroscopy indicated extracellular edema and axonal loss, respectively. Repeated analysis 6 months later identified the same alterations. Such patchy alterations were not detectable in the NAWM of the 3 cases with short-term NMO, and they were also not quantitatively different from the controls. CONCLUSION: After NMO of 22-year duration, metabolic changes, altered diffusivity and magnetic resonance relaxation features of patchy brain areas may suggest tissue damage in NAWM that persist for at least 6 months. PMID- 23344154 TI - Diversity of peptides produced by Nodularia spumigena from various geographical regions. AB - Cyanobacteria produce a great variety of non-ribosomal peptides. Among these compounds, both acute toxins and potential drug candidates have been reported. The profile of the peptides, as a stable and specific feature of an individual strain, can be used to discriminate cyanobacteria at sub-population levels. In our work, liquid chromatography-tandem mass spectrometry was used to elucidate the structures of non-ribosomal peptides produced by Nodularia spumigena from the Baltic Sea, the coastal waters of southern Australia and Lake Iznik in Turkey. In addition to known structures, 9 new congeners of spumigins, 4 aeruginosins and 12 anabaenopeptins (nodulapeptins) were identified. The production of aeruginosins by N. spumigena was revealed in this work for the first time. The isolates from the Baltic Sea appeared to be the richest source of the peptides; they also showed a higher diversity in peptide profiles. The Australian strains were characterized by similar peptide patterns, but distinct from those represented by the Baltic and Lake Iznik isolates. The results obtained with the application of the peptidomic approach were consistent with the published data on the genetic diversity of the Baltic and Australian populations. PMID- 23344155 TI - Steroidal carboxylic acids from soft coral Paraminabea acronocephala. AB - Three new steroidal carboxylic acids, paraminabic acids A-C (1-3) were isolated from a Formosan soft coral Paraminabea acronocephala. The structures of these compounds were established by extensive spectroscopic analysis and chemical methods. Application of the PGME method allowed the establishment of the absolute configurations at C-25 and C-24 for 1 and 2, respectively. Compound 3 showed potent cytotoxicity toward Hep3B, MDA-MB-231, MCF-7, and A-549 cancer cell lines, with IC(50) values ranging from 2.05 to 2.83 MUg/mL. Compounds 2 and 3 were found to inhibit the accumulation of the pro-inflammatory iNOS protein. PMID- 23344156 TI - Beneficial effects of marine algal compounds in cosmeceuticals. AB - The name "cosmeceuticals" is derived from "cosmetics and pharmaceuticals", indicating that a specific product contains active ingredients. Marine algae have gained much importance in cosmeceutical product development due to their rich bioactive compounds. In the present review, marine algal compounds (phlorotannins, sulfated polysaccharides and tyrosinase inhibitors) have been discussed toward cosmeceutical application. In addition, atopic dermatitis and the possible role of matrix metalloproteinase (MMP) in skin-related diseases have been explored extensively for cosmeceutical products. The proper development of marine algae compounds will be helpful in cosmeceutical product development and in the development of the cosmeceutical industry. PMID- 23344159 TI - Tumor-infiltrating lymphocyte response in cutaneous melanoma in the elderly predicts clinical outcomes. AB - Tumor-infiltrating lymphocytes (TILs) and regression are manifestations of the host immune response to tumor, but their influence on outcome remains undefined. There is a paucity of data on the elderly who represent a growing proportion of melanoma patients. The aim of this study was to evaluate the influence of TILs and regression as an indirect measure of immunity on outcome in elderly patients with melanoma. From a prospective database, we identified 250 consecutive cutaneous melanoma patients aged at least 65 years at the time of diagnosis. Data were verified by record review. Within the primary melanoma, a brisk TIL response was present in 66 (31%), nonbrisk TILs in 36 (17%), and absent in 111 (52%). The presence of a brisk infiltrate conferred a three-fold increased risk of sentinel lymph node (SLN) metastasis (P=0.02). Despite this, nonbrisk or absent TILs were associated with a five-fold increased risk of recurrence (P=0.0001). In multivariate analysis, nonbrisk or absent TILs were independently associated with recurrence (P<0.0001), diminished 5-year disease-free survival (76 vs. 91%, P=0.0006), and 5-year melanoma-specific survival (82 vs. 95%, P=0.0008). Regression was not an independent predictor of SLN metastasis, disease-free survival, or melanoma-specific survival. Our study demonstrates that an active antitumor immune response exists in elderly melanoma patients that, paradoxically, predicts both SLN metastasis and improved melanoma-specific outcomes. Further investigation to characterize this lymphocytic infiltrate and to confirm its clinical significance as a predictor of nodal status, patient outcome, and response to immunotherapy in elderly melanoma patients appears warranted. PMID- 23344158 TI - The pan-Aurora kinase inhibitor, PHA-739358, induces apoptosis and inhibits migration in melanoma cell lines. AB - Treatment of metastatic melanoma has long been a challenge because of its resistance to traditional chemotherapeutics, leading to the search for alternative strategies. Aurora kinases are key mitotic regulators that are frequently overexpressed in various cancers including melanoma, making them ideal targets for drug development. Several Aurora kinase inhibitors have been developed and tested preclinically and clinically. PHA-739358 is currently one of the most advanced clinical compounds being tested in phase II clinical trials; however, its antitumor effect has not been tested in melanoma. In this study, the antiproliferative and anti-invasive effects of PHA-739358 were investigated in melanoma cell lines. The results demonstrated that PHA-739358 produces a time dependent and dose-dependent inhibition of cell proliferation, induction of apoptosis, and inhibition of cell migration. Downregulation of matrix metalloproteinase-2 by the inhibition of NFkappaB-signaling pathway may contribute to PHA-739358-induced inhibition of migration. Furthermore, PHA-739358 enhanced temozolomide and Plx4032-induced apoptosis. This study suggests that Aurora kinase inhibitors may provide a new strategy for the treatment of advanced melanoma. PMID- 23344160 TI - Increased endothelin-1 responsiveness in human coronary artery smooth muscle cells exposed to 1,25-dihydroxyvitamin D(3). AB - Low blood concentrations of 25-hydroxyvitamin D(3) are associated with increased mortality, while some studies suggest improved cardiovascular outcomes with vitamin D(3) supplementation in chronic kidney disease. However, the physiological effects of vitamin D(3) on the cardiovascular system remain poorly understood making it difficult to determine whether vitamin D(3) supplementation might provide cardiovascular benefit or even cause harm. Thus here we investigated the effects of chronic 1,25-dihydroxyvitamin D(3) treatment on intracellular signaling in human coronary artery smooth muscle cells (HCASMCs) and found that 1,25-dihydroxyvitamin D(3) significantly potentiated endothelin (ET-1) signaling. Specifically, 1,25-dihydroxyvitamin D(3) (24-h pretreatment) caused a more than threefold enhancement in both ET-1-induced intracellular calcium mobilization and extracellular signal-regulated kinase (ERK) activation. This 1,25-dihydroxyvitamin D(3)-elicited signaling enhancement was not observed for either vasopressin or carbachol. With the use of endothelin receptor (ETR) isoform-selective antagonists, ETRA was found to be primarily responsible for the 1,25-dihydroxyvitamin D(3)-induced ET-1 responsiveness and yet ETRA mRNA expression and protein abundance were unaltered following 1,25-dihydroxyvitamin D(3) treatment. While there was an increase in ETRB mRNA expression in response to 1,25-dihydroxyvitamin D(3), the protein abundance of ETRB was again unchanged. Finally, ETRA/ETRB heterodimerization was not detected in HCASMCs in either the absence or presence of 1,25-dihydroxyvitamin D(3). Together, these data show for the first time that 1,25-dihydroxyvitamin D(3) enhances endothelin responsiveness in HCASMCs and that the effect is mediated through ETRA. PMID- 23344162 TI - Side effects of multiculturalism: the interaction effect of a multicultural ideology and authoritarianism on prejudice and diversity beliefs. AB - We studied the influence of right-wing authoritarianism (RWA) on the relationship between a multicultural ideology and attitudes about ethnic diversity and immigrants. We hypothesized that a multicultural ideology poses a threat to authoritarian individuals, which leads to a decrease in positive diversity beliefs and an increase in prejudice toward immigrants. On the basis of representative survey-data from 23 European countries, we showed that the negative relationship between RWA and positive diversity beliefs was stronger the more a country engages in multiculturalism (Study 1). In addition, in two experiments we demonstrated that RWA moderated the relationship between a video promoting multiculturalism (Study 2) or a picture showing a multicultural group (Study 3) and attitudes toward immigrants and diversity. As expected, for high RWAs, both stimuli led to an increase in prejudice. In Study 3, perceived threat mediated the relationship between a multicultural norm and prejudice for people high in RWA. PMID- 23344161 TI - Redox artifacts in electrophysiological recordings. AB - Electrophysiological techniques make use of Ag/AgCl electrodes that are in direct contact with cells or bath. In the bath, electrodes are exposed to numerous experimental conditions and chemical reagents that can modify electrode voltage. We examined voltage offsets created in Ag/AgCl electrodes by exposure to redox reagents used in electrophysiological studies. Voltage offsets were measured in reference to an electrode separated from the solution by an agar bridge. The reducing reagents Tris-2-carboxyethly-phosphine, dithiothreitol (DTT), and glutathione, as well as the oxidizing agent H(2)O(2) used at experimentally relevant concentrations reacted with Ag in the electrodes to produce voltage offsets. Chloride ions and strong acids and bases produced offsets at millimolar concentrations. Electrolytic depletion of the AgCl layer, to replicate voltage clamp and sustained use, resulted in increased sensitivity to flow and DTT. Offsets were sensitive to electrode silver purity and to the amount and method of chloride deposition. For example, exposure to 10 MUM DTT produced a voltage offset between 10 and 284 mV depending on the chloride deposition method. Currents generated by these offsets are significant and dependent on membrane conductance and by extension the expression of ion channels and may therefore appear to be biological in origin. These data demonstrate a new source of artifacts in electrophysiological recordings that can affect measurements obtained from a variety of experimental techniques from patch clamp to two electrode voltage clamp. PMID- 23344163 TI - Enhanced hydrogen storage properties under external electric fields of N-doped graphene with Li decoration. AB - In this article, the imposition of an external electric field is proposed as an effective means to improve the hydrogen storage properties of a promising medium. To demonstrate the feasibility of this concept, the geometric stability and hydrogen capacity of Li functionalized N-doped graphene were investigated in the presence of an electric field using density functional theory (DFT) calculations. For Li decorated pristine and graphitic structures, the binding energy of the Li atom on the surface sheets exceeded the cohesive energy of the Li metal bulk under a positive electric field. From these results, Li adatom dispersion with atomic accuracy is expected for these two unstable structures. Furthermore, the hydrogen adsorption behavior of the pyridinic and pyrrolic structures was changed by the applied electric field in the range of 0.14-0.27 eV. It is therefore anticipated that the adsorption and desorption processes can be easily controlled using suitable field strength and direction. PMID- 23344164 TI - How curved is too curved? The severity of penile deformity may predict sexual disability among men with Peyronie's disease. AB - Peyronie's disease (PD) is caused by progressive fibrotic scarring of the tunica albuginea resulting in curvature or other deformities of the erect penis. The severity of penile curvature or other deformity may contribute to a man's inability to have intercourse (sexual disability), due to difficulty with penetration, partner pain or emotional stress. To determine whether the degree of curvature or type of penile deformity predicts sexual disability among men with PD. This cross-sectional analysis of consecutive men evaluated for PD at a single tertiary referral center used a PD-specific questionnaire to evaluate risk factors for sexual disability in men with PD, who did not have erectile dysfunction (ED). Multivariate logistic regression was used to determine the clinical predictors of sexual disability. Sexual disability as defined by the inability to have penetrative intercourse. A total of 202 men were evaluated and 88 men with ED were excluded. Sexual disability was associated with relationship problems, penile curvature and penile length loss in bivariate, but not multivariate analysis. We found that although many of the demographic, medical and sexual function domains were significant predictors of inability to have sex, the only significant predictor of sexual disability in multivariate analysis was curvature>60 degrees (odds ratio 3.23 95%CI 1.08-9.67). PD can be sexually disabling in many men without ED. Severe penile curvature is a robust independent predictor of the ability to have intercourse. Other penile deformities fail to predict sexual disability. This is important for counseling patients with newly diagnosed PD and those who are considering medical or surgical intervention. PMID- 23344165 TI - Quality of delivered care for people with type 2 diabetes: a new patient-centred model. AB - BACKGROUND: The quality of care from the perspective of people with Type 2 diabetes using a new model (CQMH) including three dimensions of quality in health care (Technical, Service and Customer Quality) was assessed. METHODS: A cross sectional survey with a sample of 577 people with Type 2 diabetes was conducted. Measures were self-reported adherence to national guidelines for technical quality, the Netherlands Institute for Health Services Research questionnaire for service quality and the short form of the Patient Activation Measure for Customer Quality. RESULTS: There was a significant gap in technical quality between what diabetes care the patients reported receiving and what was recommended in the guideline, particularly for management and lifestyle aspects. For service quality, the lowest scores were for choice of care provider and accessibility of care. The mean Customer Quality score was 64.5 (meaning higher score indicating better quality). A positive relationship was demonstrated between higher technical, service and customer quality scores, and better diabetes control status as well as maintaining continuity of care. The average Quality Index was 70.0 of a 0-100 scale. CONCLUSIONS: Customer Quality appears to be a useful third dimension in conceptualising quality in health care, particularly in the context of chronic disease, where good self-management can improve the outcomes of care. A high proportion of Queensland adults with Type 2 diabetes reported receiving suboptimal care in the majority aspects of provided care services as reflected in the overall Quality Index score indicating substantial room for quality improvement. PMID- 23344166 TI - The evaluation of importance of safety behaviors in a steel manufacturer by entropy. AB - BACKGROUND: This study aimed to evaluate the workers safety behavior and to determine the importance of each unsafe behavior in an Iranian steel manufacturing company. METHODS: This study was conducted in Mobareke steel manufacturing company, which is located in the middle of Iran, in 2007. The methodology was based on the safety behavior sampling (SBS) technique and entropy. After specifying the unsafe behaviors and with reference to the results of a pilot study a sample of 3248 was determined, with a sampling accuracy of 5% and confidence level of 95%. RESULTS: The results indicated that 41.8% of workers behaviors were unsafe. The most frequent unsafe behaviors were inappropriate use of personal protective equipments (PPEs) with 32% of total unsafe behaviors. The results also notified a significant relationship between age, job experience and educational level on unsafe behaviors (P< 0.05). The highest weight, which is obtained by entropy, belongs to using inappropriate tools with weight of 0.1425. The ultimate findings of the study showed that a considerable number of workers' behaviors were unsafe, which is one of the main antecedents of industrial accidents. CONCLUSION: Considering catastrophic consequences of accidents in steel manufacturing industry, the results emphasize on diminishing unsafe behaviors and recommends applying behavior based safety principles. PMID- 23344167 TI - Assessment of marhame-mafasel pomade effect on knee osteoarthritis with non compliance. AB - BACKGROUND: Osteoarthritis is the most prevalent chronic non-infective joint arthritis. In the present study, the effect of new herbal pomade (Marhame Mafasel) on knee osteoarthritis was investigated in a randomized trial. The objective of this study was to assess efficacy of Marhame- Mafasel pomade, which was consisted of several medic herbs like Arnebia euchroma and Martricaria chamomilla in pri-mary osteoarthritis of the knee with non-compliance. METHODS: The 2*2 crossover trial enrolled 42 osteoarthritis patients (Marhame-Mafasel versus pla-cebo) in 2006. The instrument of data collection was Western Ontario and McMaster Universities (WOMAC) LK3.1 standard questionnaires. We used conditional estimation to adjust non-compliance effect. RESULTS: The participants in each group were 21 patients. About 30 (71.4%) were female. The partici-pants were between 40-76 years old. Positive analgesic effect of herbal pomade "Marhame Mafasel" on knee osteoarthritis severity was considerable (P < 0.01). After adjusting results to compliance level, the estimators were sharper than crude results. CONCLUSION: Herbal joint pomade "Marhame-Mafasel" has significant positive analgesic effect on pri-mary knee osteoarthritis. PMID- 23344168 TI - Evaluation of chemical quality in 17 brands of Iranian bottled drinking waters. AB - BACKGROUND: The purpose of study was to evaluate and compare chemical quality of Iranian bottled drinking water reported on manufacturer's labeling and standards. METHODS: This study was a cross-sectional descriptive study and done during July to December 2008. The bottled mineral water collected from shops randomly were analyzed for all parameters address on manufacturer's labeling and the results were compared with the manufacturer's labeling data, WHO Guideline Values, USEPA Maximum Contaminant Levels and the maximum contaminant levels of drinking water imposed by the Iranian legislation. Statistical analysis on data was done with the Kolmogorov-Smirnov test for normal distribution, the paired t-test to compare the data with manufacturer's labeling and the one-sample t-test to compare with standard and MCL values at P 0.05). In addition, pH and calcium values were significantly higher than their proposed values indicated by Iranian National Legislation and international MCLs (P< 0.05). CONCLUSION: Our results are extremely important for the health supervisory agencies such as Ministry of Health and Institute of Standards & Industrial Research of Iran to have more effective controls on bottled water industries, and to improve periodical the proposed standard values. PMID- 23344169 TI - Wife abuse prevalence and predisposing factors in women. AB - BACKGROUND: Spouse abuse so called intimate partner violence (IPV) is a common problem in the world. This survey was conducted to identify IPV prevalence and related factors in district health centers in Hamadan, western Iran, in hope that, by identifying risk factors, preventive guidelines could be understood. METHODS: In this descriptive analytic cross sectional study, 600 married women from six district health centers in Hamadan, western Iran were randomly enrolled in 2007. For gathering information we used a questionnaire which included demographic and specific questions about IPV, based on WHO guidelines. For increasing validity of results, questionnaires were nameless and participants were ensured about concealment of their identities. Finally data analyzed by SPSS software (version15). RESULTS: Wife abuse was identified in 34.2% of participants. For understanding IPV risk factors, we used logistic regression method and 27 variables were enrolled in the equation and finally 4 variables were statistically significant to wife abuse (P< 0.05). These variables were: weak religious believe of men, history of wife abuse in participant's mothers, men's criminal history and finally men's alcoholic abuse CONCLUSION: Wife abuse was prevalent in this survey, so that 1 from 3 women was abused by their husbands. Other similar investigations in different countries also verify this result. Because of so many women who disclaim violence due to cultural texture and religious believe, it is believed that, intimate partner violence is more than those being reported. PMID- 23344170 TI - Catastrophic health expenditures in kermanshah, west of iran: magnitude and distribution. AB - BACKGROUND: Health policy makers are concerned about protecting people from catastrophic health expenditures and subsequent impoverishment. This study aimed to describe the magnitude and distribution of catastrophic health expenditures in Kermanshah western Iran. METHODS: In this descriptive study, during May 2008, 189 households were chosen by "Systematic Random sampling" among the community of Maskan in Maskan Center for Population. After getting the informed consent forms signed, data ere collected using a questionnaire by interviewing the head of the families. The cut-off point for catastrophic expenditure was defined as health expenditures over 40% of household's capacity to pay. RESULTS: From a total of 189 households, 22.2% (42) households (95% CI 16.3%- 28.1%) incurred catastrophic health expenditures. Out of 42 households, for 11.9%, the head of family was female. 40.5 % had one member younger than 12 years old, 26.2% had one member older than sixty years old, and 9.5% were households with at least one member with chronic condition. In addition, 19% were uninsured. In addition, because of financial burden of health expenditures 21.4% of the households sold their jewels, 16.7% used up their savings and 47.6% were in debt. CONCLUSION: Compared to 2% of general population facing catastrophic health expenditure, 22.2% was a high proportion. Our study revealed the importance of protecting households against the cost of ill-health. PMID- 23344171 TI - Acidity rate and fluoride content of consumed beverages in kerman/iran. AB - BACKGROUND: High consumption of nonalcoholic beverages is one of the causes of dental erosion. Annual consumption of beverages in Iran is 48 LPCY (Lit per capita per year) that is equal to 144 bottles per capita in year and is relatively a high rate. Taking this into consideration, the present study was planned to determine the pH and fluoride content of beverages consumed in Kerman, south east of Iran. METHODS: In a descriptive cross-sectional study during 2006 2007, samples of any type of beverages in Kerman were taken once every 4 months and each sample was examined for its acidity and fluoride content in ambient and refrigerator temperatures. A total of 744 experiments were conducted on 62 brands of beverages with different colors to determine the acidity and on 31 brands of beverages to determine their fluoride content. Acidity was determined by pH-meter in the ambient temperature and refrigerator temperature (+4?C). Fluoride content was determined using specific electrode method. Data analysis was done by SPSS software package. RESULTS: Mean acidity of the consumed beverages in Kerman was 2.55 and 2.78 mg/L in the ambient temperature and refrigerator temperature, respectively. Mean fluoride concentration in the temperature of the ambient and refrigerator were 1.13 and 1.27 mg/L respectively. Therefore beverages consumption in Kerman had a higher acidity than national standard. CONCLUSION: Since some of the consumed beverages in Kerman are distributed and consumed in other parts of Iran as well, necessary precautions for controlling dental erosion especially in Kerman residents should be taken. PMID- 23344172 TI - Identification of leishmania species isolated from human cutaneous leishmaniasis using PCR method. AB - BACKGROUND: To determine the epidemiological status of cutaneous leishmaniasis outbreak, isolation and identification of the agent parasite, Leishmania, using PCR method in Gonbad-e Qabus County, north Iran, during 2006-2007. METHODS: Data were collected on the prevalence of scars and ulcers over a period of 3 months among 6990 inhabitants of five villages around Gonbad-e Qabus County, north Iran, during 2006-2007. Cultured promastigotes were identified using PCR technique. Its1 and its2 of Non Coding Transcribed region at ribosomal DNA of 46 Leishmania isolates were amplified and the PCR products were separated by electrophoresis in 1.5% agarose gel (200 mA, 140 V), visualized by staining with ethidium bromide, and photographed. RESULTS: Among 6990 inhabitants of 5 villages, 62.9% were identified as scars and 1.5% as active lesions. Individuals 11 to 20 years were the most highly infected age group. All the parasite isolates were Leishmania major. CONCLUSION: Cutaneous leishmaniasis due to L. major is endemic in Gonbad-e Qabus County, north Iran. PMID- 23344173 TI - Granulocyte-colony stimulating factor as treatment option in patients with recurrent miscarriage. AB - In 1-5% of patients during childbearing years recurrent miscarriages (RM) occur. There are established risk factors like anatomical, endocrine and hemostatic disorders as well as immunological changes in the maternal immune system. Nevertheless, further elucidation of the pathogenesis remains a matter of debate. In addition, there are no standardized immunological treatment strategies. Recent studies indicate possible effects of tumor necrosis factor alpha blocker and granulocyte-colony stimulating factor (G-CSF) concerning live birth rate (LBR) in RM patients. Therefore, we performed a retrospective cohort study in patients undergoing assisted reproductive treatment (ART) with known RM analysing the possible benefits of G-CSF application. From January 2002 to December 2010, 127 patients (199 cylces) with RM (at least 2 early miscarriages) 49 (72 cycles) receiving G-CSF and 78 (127 cycles) controls receiving either no medication (subgroup 1) or Cortisone, intravenous immunoglobulins or low molecular weight heparin (subgroup 2) undergoing ART for in vitro fertilisation/intracytoplasmic sperm injection were analysed. G-CSF was administered weekly once (34 Mill) in 11 patients, 38 patients received 2 * 13 Mill G-CSF per week until the 12th week of gestation. Statistical analysis was performed with SPSS for Windows (19.0), p < 0.05 significant. The mean age of the study population was 37.3 +/- 4.4 years (mean +/- standard deviation) and differed not significantly between patients and subgroups. However, the number of early miscarriages was significantly higher in the G-CSF group as compared to the subgroups (G-CSF 2.67 +/- 1.27, subgroup 1 0.85 +/- 0.91, subgroup 2 0.64 +/- 0.74) and RM patients receiving G-CSF had significantly more often a late embryo transfer (day 5) (G-CSF 36.7%, subgroup 1 12.1%, subgroup 2 8.9%). The LBR of patients and the subgroups differed significantly (G-CSF 32%, subgroup 1 13%, subgroup 2 14%). Side effects were present in less than 10% of patients, consisting of irritation at the injection side, slight leukocytosis, rise of the temperature (<38 degrees C), mild bone pain and hyperemesis gravidarum. None of the newborn showed any kind of malformations. According to our data, G-CSF seems to be a safe and promising immunological treatment option for RM patients. However, with regard to the retrospective setting and the possible bias of a higher rate of late embryo transfers in the G-CSF group additional studies are needed to further strengthen our results. PMID- 23344174 TI - Microsolvation of dimethylphosphate: a molecular model for the interaction of cell membranes with water. AB - We present an exhaustive stochastic search of the quantum conformational spaces of the (CH(3)O)(2)PO(2)(-) + nH(2)O (n = 1,2,3) systems. We uncover structural, conformational and energetic features of the problem. As in the isolated species, clusters containing the gauche-gauche (gg) conformation of dimethylphosphate (DMP(-)) are energetically preferred, however, contributions from hydrated gauche anti (ga) and anti-anti (aa) monomers cannot be neglected because such structures are quite common and because they are close in energy to those containing the gg monomer. At least seven distinct types of O???H-O-H contacts lead to DMP(-) <-> water interactions that are always stabilizing, but not strong enough to induce significant changes in the geometries of either DMP(-) or water units. Our results lead us to postulate DMP(-) to be a suitable model to study explicit and detailed aspects of microsolvation of cell membranes. PMID- 23344175 TI - Taking a break from huntingtin. PMID- 23344176 TI - MicroRNA-181a* Targets Nanog in a Subpopulation of CD34(+) Cells Isolated From Peripheral Blood. AB - Exploiting the properties of stem cells by microRNA (miRNA) profiling offers an attractive approach to identify new regulators of stem cell fate. Although numerous miRNA have been screened from hematopoietic stem cells (HSC), the targets corresponding to many of these miRNA have not yet been fully elucidated. By miRNA profiling in a subpopulation of CD34+ cells isolated from peripheral blood, we have identified eight clusters of miRNA that were differentially expressed. Further analysis of one of the clusters by bioinformatics revealed that a miRNA, miR-181a*, which is highly expressed in the adherent CD34+ cells, affects the expression levels of Nanog, a stem cell surrogate marker. We show specifically by reporter assay and mutational analysis that miR-181a* targets a seedless 3' compensatory site in the 3'UTR of Nanog and affects gene expression. We demonstrate that inhibiting miR-181a* upregulates the Nanog expression level, in addition to an increase in alkaline phosphatase activity. Our studies suggest that miR-181a* may be important in controlling the expression level of Nanog in a subpopulation of CD34+ cells. PMID- 23344178 TI - Rolling Circle Transcription of Tandem siRNA to Generate Spherulitic RNA Nanoparticles for Cell Entry. PMID- 23344177 TI - Gene Expression Profile Changes After Short-activating RNA-mediated Induction of Endogenous Pluripotency Factors in Human Mesenchymal Stem Cells. AB - It is now recognized that small noncoding RNA sequences have the ability to mediate transcriptional activation of specific target genes in human cells. Using bioinformatics analysis and functional screening, we screened short-activating RNA (saRNA) oligonucleotides designed to target the promoter regions of the pluripotency reprogramming factors, Kruppel-like factor 4 (KLF4) and c-MYC. We identified KLF4 and c-MYC promoter-targeted saRNA sequences that consistently induced increases in their respective levels of nascent mRNA and protein expression in a time- and dose-dependent manner, as compared with scrambled sequence control oligonucleotides. The functional consequences of saRNA-induced activation of each targeted reprogramming factor were then characterized by comprehensively profiling changes in gene expression by microarray analysis, which revealed significant increases in mRNA levels of their respective downstream pathway genes. Notably, the microarray profile after saRNA-mediated induction of endogenous KLF4 and c-MYC showed similar gene expression patterns for stem cell- and cell cycle-related genes as compared with lentiviral vector mediated overexpression of exogenous KLF4 and c-MYC transgenes, while divergent gene expression patterns common to viral vector-mediated transgene delivery were also noted. The use of promoter-targeted saRNAs for the activation of pluripotency reprogramming factors could have broad implications for stem cell research. PMID- 23344179 TI - Microfluidic Synthesis of Highly Potent Limit-size Lipid Nanoparticles for In Vivo Delivery of siRNA. AB - Lipid nanoparticles (LNP) are the leading systems for in vivo delivery of small interfering RNA (siRNA) for therapeutic applications. Formulation of LNP siRNA systems requires rapid mixing of solutions containing cationic lipid with solutions containing siRNA. Current formulation procedures employ macroscopic mixing processes to produce systems 70-nm diameter or larger that have variable siRNA encapsulation efficiency, homogeneity, and reproducibility. Here, we show that microfluidic mixing techniques, which permit millisecond mixing at the nanoliter scale, can reproducibly generate limit size LNP siRNA systems 20 nm and larger with essentially complete encapsulation of siRNA over a wide range of conditions with polydispersity indexes as low as 0.02. Optimized LNP siRNA systems produced by microfluidic mixing achieved 50% target gene silencing in hepatocytes at a dose level of 10 ug/kg siRNA in mice. We anticipate that microfluidic mixing, a precisely controlled and readily scalable technique, will become the preferred method for formulation of LNP siRNA delivery systems. PMID- 23344180 TI - Pip6-PMO, A New Generation of Peptide-oligonucleotide Conjugates With Improved Cardiac Exon Skipping Activity for DMD Treatment. AB - Antisense oligonucleotides (AOs) are currently the most promising therapeutic intervention for Duchenne muscular dystrophy (DMD). AOs modulate dystrophin pre mRNA splicing, thereby specifically restoring the dystrophin reading frame and generating a truncated but semifunctional dystrophin protein. Challenges in the development of this approach are the relatively poor systemic AO delivery and inefficient dystrophin correction in affected non-skeletal muscle tissues, including the heart. We have previously reported impressive heart activity including high-splicing efficiency and dystrophin restoration following a single administration of an arginine-rich cell-penetrating peptide (CPPs) conjugated to a phosphorodiamidate morpholino oligonucleotide (PMO): Pip5e-PMO. However, the mechanisms underlying this activity are poorly understood. Here, we report studies involving single dose administration (12.5 mg/kg) of derivatives of Pip5e PMO, consecutively assigned as Pip6-PMOs. These peptide-PMOs comprise alterations to the central hydrophobic core of the Pip5e peptide and illustrate that certain changes to the peptide sequence improves its activity; however, partial deletions within the hydrophobic core abolish its efficiency. Our data indicate that the hydrophobic core of the Pip sequences is critical for PMO delivery to the heart and that specific modifications to this region can enhance activity further. The results have implications for therapeutic PMO development for DMD. PMID- 23344181 TI - Expression analysis in multiple muscle groups and serum reveals complexity in the microRNA transcriptome of the mdx mouse with implications for therapy. AB - MicroRNAs (miRNAs) are a class of small RNAs that regulate gene expression and are implicated in wide-ranging cellular processes and pathological conditions including Duchenne muscular dystrophy (DMD). We have compared differential miRNA expression in proximal and distal limb muscles, diaphragm, heart and serum in the mdx mouse relative to wild-type controls. Global transcriptome analysis revealed muscle-specific patterns of differential miRNA expression as well as a number of changes common between tissues, including previously identified dystromirs. In the case of miR-31 and miR-34c, upregulation of primary-miRNA transcripts, precursor hairpins and all mature miRNAs derived from the same transcript or miRNA cluster, strongly suggests transcriptional regulation of these miRNAs. The most striking differences in differential miRNA expression were between muscle tissue and serum. Specifically, miR-1, miR-133a, and miR-206 were highly abundant in mdx serum but downregulated or modestly upregulated in muscle, suggesting that these miRNAs are promising disease biomarkers. Indeed, the relative serum levels of these miRNAs were normalized in response to peptide-phosphorodiamidate morpholino oligonucleotide (PMO) mediated dystrophin restoration therapy. This study has revealed further complexity in the miRNA transcriptome of the mdx mouse, an understanding of which will be valuable in the development of novel therapeutics and for monitoring their efficacy. PMID- 23344182 TI - Manipulation of Cell Physiology Enables Gene Silencing in Well-differentiated Airway Epithelia. AB - The application of RNA interference-based gene silencing to the airway surface epithelium holds great promise to manipulate host and pathogen gene expression for therapeutic purposes. However, well-differentiated airway epithelia display significant barriers to double-stranded small-interfering RNA (siRNA) delivery despite testing varied classes of nonviral reagents. In well-differentiated primary pig airway epithelia (PAE) or human airway epithelia (HAE) grown at the air-liquid interface (ALI), the delivery of a Dicer-substrate small-interfering RNA (DsiRNA) duplex against hypoxanthine-guanine phosphoribosyltransferase (HPRT) with several nonviral reagents showed minimal uptake and no knockdown of the target. In contrast, poorly differentiated cells (2-5-day post-seeding) exhibited significant oligonucleotide internalization and target knockdown. This finding suggested that during differentiation, the barrier properties of the epithelium are modified to an extent that impedes oligonucleotide uptake. We used two methods to overcome this inefficiency. First, we tested the impact of epidermal growth factor (EGF), a known enhancer of macropinocytosis. Treatment of the cells with EGF improved oligonucleotide uptake resulting in significant but modest levels of target knockdown. Secondly, we used the connectivity map (Cmap) database to correlate gene expression changes during small molecule treatments on various cells types with genes that change upon mucociliary differentiation. Several different drug classes were identified from this correlative assessment. Well-differentiated epithelia treated with DsiRNAs and LY294002, a PI3K inhibitor, significantly improved gene silencing and concomitantly reduced target protein levels. These novel findings reveal that well-differentiated airway epithelia, normally resistant to siRNA delivery, can be pretreated with small molecules to improve uptake of synthetic oligonucleotide and RNA interference (RNAi) responses.Molecular Therapy - Nucleic Acids (2012) 1, e41; doi:10.1038/mtna.2012.36; published online 28 August 2012. PMID- 23344183 TI - Effect of white matter hyperintensity on medial temporal lobe atrophy in Alzheimer's disease. AB - BACKGROUND: Medial temporal atrophy (MTA) is a recognized marker of Alzheimer's disease (AD), and white matter hyperintensities (WMH) are frequently observed on MRI of AD. The purpose of this study was to understand the role of WMH in MTA. METHODS: Subjects were 94 probable AD patients and 51 cognitively normal subjects. WMH was assessed based on the severity of deep WMH (DWMH) and periventricular WMH (PWMH). Each structural volume was evaluated using the Individual Brain Atlases from the Statistical Parametric Mapping Toolbox. RESULTS: There were no significant differences between subjects with and without WMH in terms of general cognitive function scales. Subjects with AD with WMH had decreased volume in the bilateral orbital frontal gyrus, frontal rectus gyrus, and olfactory gyrus, but not in the medial temporal lobes. After correcting for differences in DWMH, age and Clinical Dementia Rating Scale (CDR), AD with PWMH showed decreased volumes in the bilateral hippocampi. AD with PWMH showed worse scores on the Clinical Dementia Rating-Sum of Boxes and Barthel-ADL, and some frontal executive function tests. Those with DWMH did not show any reductions in the medial temporal lobes. CONCLUSION: WMH in AD is not associated with medial temporal lobe atrophy, but PWMH is independently correlated with hippocampal volume reduction. PMID- 23344184 TI - The feedback regulation of PI3K-miR-19a, and MAPK-miR-23b/27b in endothelial cells under shear stress. AB - Mechanical stimulation regulates endothelial cell (EC) functions through the modulation of signaling networks and gene expression. Our recent studies have identified that shear stress regulation of microRNAs (miRs)-19a, 23b and 27b, led to the modulation of EC proliferation. However, the underlying molecular mechanisms by which shear stress regulates these miRs have not been explored. Previous studies showed that shear stress activates multiple signaling pathways, including phosphatidylinositol 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK). In this work we demonstrate that inhibition of the PI3K pathway attenuated the shear-induced miR-19a, and inhibition of the MAPK pathway attenuated miR-23b, 27b. The knockdown of miR-19a using antagomir-19a oligonucleotide (AM19a) decreased the shear-induced PI3K activation; whereas AM 23b, 27b reduced the shear-induced MAPK activation. Furthermore, the overexpression of miR-19a overrode the suppressive effects of PI3K inhibitors on shear-induced PI3K activation; the overexpression of miR-23b, 27b had similar effects on ERK activations, but had little effect on P38 and JNK activation. Our findings suggest a positive feedback loop whereby PI3K and MAPK mediate the shear regulation of miR expression, which in turn modulates the shear-regulated PI3K/MAPK signaling events in ECs. PMID- 23344185 TI - An N-linked bidentate phosphoramidite ligand (N-Me-BIPAM) for rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to alpha,beta-unsaturated ketones. AB - A new bidentate phosphoramidite (N-Me-BIPAM) based on Shibasaki's N-linked BINOL was synthesized. This ligand appears to be highly effective for rhodium-catalyzed asymmetric conjugated addition of arylboronic acids to alpha,beta-unsaturated enones. The reaction of ortho-substituted arylboronic acid with acyclic and cyclic enones provides the corresponding products in good yields and enantioselectivities. PMID- 23344186 TI - Tripolyphosphate cross-linked macromolecular composites for the growth of shape- and size-controlled apatites. AB - Bioactive composites that enable the formation of calcium phosphates have received increased attention over the last decade, in the development of osteoconductive biomaterials for orthopaedic applications. In this work, tripolyphosphate (TPP)-cross-linked chitosan/gelatin composites (TPP-CG) were prepared for the growth of shape- and size-controlled calcium phosphates on/in the composites. The mineralization pattern of the composites, after soaking in the Ca(OH)(2) aqueous solution, clearly demonstrated oriented, needle-like nanocrystallites of calcium phosphates in the matrix with especially high Ca/P molar ratio (3.98) as detected by energy dispersive X-ray spectroscopy (EDX) analysis. Subsequent to mineralization in a simulated body fluid (SBF), the mineralized composites showed micro-scaled spherical aggregates deposited on the surface and granule-like nanocrystallites grew in the matrix. The Ca/P molar ratio (1.72) and X-ray diffraction pattern of the nanocrystallites grown in the composites were similar to those of hydroxyapatite (HAp). Osteoblastic differentiation of ROS cells cultured on the mineralized composites allowed an enhanced expression of the chosen osteogenic marker (alkaline phosphatase, ALPase). These results indicated that the composites mineralized with micro- and nano-scaled calcium phosphates with various structural features make them attractive for bone tissue engineering applications. PMID- 23344187 TI - Anti-inflammatory lignans from the fruits of Acanthopanax sessiliflorus. AB - A new lignan, named acanthosessilin A (1), as well as eight known lignan and lignan glycosides 2-9 were isolated from an ethanolic extract of Acanthopanax sessiliflorus fruits. The chemical structures were determined by spectroscopic methods, including HR-EIMS, 1D NMR (1H, 13C, DEPT), 2D NMR (gCOSY, gHSQC, gHMBC, NOESY), and IR spectroscopy. All isolated compounds were tested for the ability to inhibit LPS-induced nitric oxide production in RAW264.7 macrophages. PMID- 23344189 TI - Bronsted acidic ionic liquid accelerated halogenation of organic compounds with N Halosuccinimides (NXS). AB - The Bronsted-acidic ionic liquid 1-methyl-3-(4-sulfobutyl)imidazolium triflate [BMIM(SO(3)H)][OTf] was demonstrated to act efficiently as solvent and catalyst for the halogenation of activated organic compounds with N-halosuccinimides (NXS) under mild conditions with short reaction times. Methyl aryl ketones were converted into alpha-halo and alpha,alpha-dihaloketones, depending on the quantity of NXS used. Ketones with activated aromatic rings were selectively halogenated, however in some cases mixtures of alpha-halogenated ketone and ring halogenated ketones were obtained. Activated aromatics were regioselectively ring halogenated to give mono- and dihalo-substituted products. The [BMIM(SO(3)H)][OTf] ionic liquid (IL-A) was successfully reused eight times in a representative monohalogenation reaction with no noticeable decrease in efficiency. An effective halogenation scale-up in this IL is also presented. The reactivity trend and the observed chemo- and regioselectiivities point to an ET process in these IL-promoted halofunctionalization reactions. PMID- 23344188 TI - Synthesis of new optically active 2-pyrrolidinones. AB - A new class of optically active 2-pyrrolidinones was synthesized, starting from S pyroglutamic acid, a well known natural chiral synthon. The synthetic design followed led to the insertion of various substituents at positions 1 and 5 of the 2-pyrrolidinone ring, including the imidazole moiety. Some of them possess two or three stereogenic centers, the configuration of which was retained under the mild conditions used. The new compounds also carry an imidazole moiety, which, along with the 2-pyrrolidinone template, may prove pivotal to several biological processes. PMID- 23344190 TI - Synthesis and promising in vitro antiproliferative activity of sulfones of a 5 nitrothiazole series. AB - The synthesis in water of new sulfone derivatives under microwave irradiation is described. This eco-friendly process leads to the expected products in good yields by reaction of various substituted sulfinates (commercially available or obtained by reduction of the corresponding sulfonyl chlorides) with 4 chloromethyl-2-methyl-5-nitro-1,3-thiazole. In order to evaluate the antiproliferative effect of these compounds, several sulfone derivatives are also dichlorinated on the Calpha next to the sulfonyl group. An evaluation on different cancer cell lines reveals promising selective in vitro antiproliferative activity toward HepG2 human cell lines by dihydrogenated sulfones, suggesting further research should be to explore their anticancer potential in the treatment of liver cancer. PMID- 23344191 TI - Chemical constituents of three Allium species from Romania. AB - The aim of this work was to study the chemical composition of Allium obliquum L., A. senescens L. subsp. montanum (Fries) Holub, and A. schoenoprasum L. subsp. schoenoprasum. Sulphur-containing compounds analysis was performed by an LC-MS method, the identification and quantification of polyphenolic compounds through a HPLC-UV-MS method, and the presence of five sterols was simultaneously assessed by HPLC-MS-MS. Alliin was identified only in A. obliquum and A. senescens subsp. montanum extracts, whilst allicin was present in all extracts, with higher amounts in A. schoenoprasum and A. obliquum. The pattern of phenol carboxylic acids shows the presence of p-coumaric and ferulic acids in all species. Isoquercitrin was identified in A. obliquum and A. schoenoprasum, and rutin in A. senescens subsp. montanum and A. schoenoprasum. Luteolin and apigenin were identified only in A. obliquum. All three species contain glycosides of kaempferol and quercetol. beta-Sitosterol and campesterol were identified in all species. The results obtained showed significant differences in the composition of the three Allium species. PMID- 23344192 TI - Cytotoxic and antioxidant compounds from the stem bark of Goniothalamus tapisoides Mat Salleh. AB - Eleven compounds:goniomicin A (1), goniomicin B (2), goniomicin C (3), goniomicin D (4), tapisoidin (5), goniothalamin (6), 9-deoxygoniopypyrone (7), pterodondiol (8), liriodenine (9), benzamide (10) and cinnamic acid (11), were isolated from the stem bark of Goniothalamus tapisoides. All compounds were identified by spectroscopic analysis and, for known compounds, by comparison with published data. Goniothalamin (6) exhibited mild cytotoxic activity towards a colon cancer cell line (HT-29), with an IC(50)value of 64.17 +/- 5.60 uM. Goniomicin B (2) give the highest antioxidant activity in the DPPH assay among all compounds tested, with an IC(50) of 0.207 uM. PMID- 23344193 TI - Inhibitory evaluation of sulfonamide chalcones on β-secretase and acylcholinesterase. AB - The action of beta-secretase (BACE1) is strongly correlated with the onset of Alzheimer's disease (AD). Aminochalcone derivatives were examined for their ability to inhibit BACE1. Parent aminochalcones showed two digit micromolar IC(50)s against BACE1. Potency was enhanced 10-fold or more by introducing benzenesulfonyl derivatives to the amino group: 1 (IC(50) = 48.2 MUM) versus 4a (IC(50) = 1.44 MUM) and 2 (IC(50) = 17.7 MUM) versus 5a (IC(50) = 0.21 MUM). The activity was significantly influenced by position and number of hydroxyl groups on the chalcone B-ring: 3,4-dihydroxy 5a (IC(50) = 0.21 MUM) > 4-hydroxy 4a (IC(50) = 1.44 MUM) > 2,4-dihydroxy 6 (IC(50) = 3.60 MUM) > 2,5-dihydroxy 7 (IC(50) = 16.87 MUM) > des hydroxy 4b (IC(50) = 168.7 MUM). Lineweaver-Burk and Dixon plots and their secondary replots indicate that compound 5a was a mixed inhibitor with reversible and time-dependent behavior. Potent BACE1 inhibitors 4a,c,f, 5a-c showed moderate inhibition against two other enzymes implicated in AD pathogenesis, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC(50)s ranging between 56.1 ~ 95.8 MUM and 19.5 ~ 79.0 MUM, respectively. PMID- 23344194 TI - Investigation on the interaction between cyclophosphamide and lysozyme in the presence of three different kind of cyclodextrins: determination of the binding mechanism by spectroscopic and molecular modeling techniques. AB - The interactions between cyclophosphamide (CYC) and lysozyme (LYZ) in the presence of different cyclodextrins (CDs) were investigated by UV absorption, fluorescence spectroscopy, circular dichroism (CD), and molecular modeling techniques under imitated physiological conditions. The UV absorption results showed the formation of complexes between CYC and LYZ in the presence of different CDs. Fluorescence data show that CYC has a stronger quenching effect on LYZ, and the red shifts suggested that the microenvironment of Trp residues was changed and became more hydrophilic. The interaction of CYC with LYZ and quenching properties of the complexes caused strong static fluorescence quenching in binary and ternary systems. The binding affinities as well as the number of binding sites were obtained from interaction between CYC and LYZ in the presence of different CDs as binary and ternary systems by modified Stern-Volmer plots. The Resonance Light Scattering (RLS) technique was utilized to investigate the effect of drug and CDs on conformational changes of LYZ as separate and simultaneous. The results suggested that the enhancement of RLS intensity was attributed to the formation of a complex between drug and protein in absence and presence of CDs. The effect of CYC and cyclodextrins on the conformation of LYZ was analyzed using synchronous fluorescence spectroscopy. Our results revealed that the fluorescence quenching of LYZ originated from the Trp and Tyr residues, and demonstrated conformational changes of LYZ with the addition of CYC and CDs. The molecular distances between the donor (LYZ) and acceptor (CYC and CDs) in binary and ternary systems were estimated according to Forster's theory and showed static quenching for protein with CYC in the presence of CDs. The CD spectra indicated that the binding of the CYC induced secondary structural changes in LYZ in binary and ternary systems. Molecular modeling suggested the binding sites of CYC in the ternary systems differ from those in the binary systems. estimated the distance between CYC and Trp residues in binary and ternary systems in the presence of CDs and confirmed the experimental results. PMID- 23344195 TI - 'One-pot' synthesis of dihydrobenzo[4,5][1,3]oxazino[2,3-a] isoquinolines via a silver(I)-catalyzed cascade approach. AB - An efficient approach for the synthesis of biologically interesting fused tetracyclic isoquinolines in high yields and with a broad substrate scope has been developed. The strategy features an AgNO(3) catalyzed 'one-pot' cascade process involving formation of two new C-N bonds and one new C-O bond. PMID- 23344196 TI - Synthesis and antibacterial evaluation of novel heterocyclic compounds containing a sulfonamido moiety. AB - Aiming for the synthesis of new heterocyclic compounds containing a sulfonamido moiety suitable for use as antibacterial agents, the precursor ethyl {[4-N-(4,6 dimethylpyrimidin-2-yl)sulfamoyl]phenylazo}cyanoacetate was reacted with a variety of active methylene compounds producing pyran, pyridine and pyridazine derivatives. Also, the reactivity of the precursor hydrazone towards hydrazine derivatives to give pyrazole and oxazole derivatives was studied. On the other hand, treatment of the same precursor with urea, thiourea and/or guanidine hydrochloride furnished pyrimidine and thiazine derivatives, respectively. The newly synthesized compounds were tested for antibacterial activity, whereby eight compounds were found to have high activities. PMID- 23344197 TI - Chamaejasmine arrests cell cycle, induces apoptosis and inhibits nuclear NF kappaB translocation in the human breast cancer cell line MDA-MB-231. AB - In this study, the anticancer activity of chamaejasmine was characterized in the human breast cancer cell line, MDA-MB-231. Cell viability and cell cycle distribution were determined by MTT assay and flow cytometry, respectively. Western blotting was performed to determine changes in levels of various proteins. Results showed that treatment with chamaejasmine (4-16 MUM) inhibited cell proliferation, which correlated with G2/M phase arrest and apoptosis in MDA MB-231 cells. Chamaejasmine treatment of MDA-MB-231 cells resulted in induction of WAF1/p21 and KIP1/p27, decrease in cyclins A and cyclins B1. Cyclin-dependent kinase (cdk) 2 and cdc2 was also decreased after chamaejasmine treatment. Moreover, inhibition of nuclear translocation, phosphorylation of NF-kappaB, activation of IKKalpha and IKKbeta, inhibition of phosphorylation and degradation of IkappaBalpha were also detected in this work. Our findings suggested that chamaejasmine could be explored as a preventive and perhaps as a chemotherapeutic agent in the management of breast cancer. PMID- 23344198 TI - Structural characterization of de novo designed L5K5W model peptide isomers with potent antimicrobial and varied hemolytic activities. AB - In an effort to develop short antimicrobial peptides with simple amino acid compositions, we generated a series of undecapeptide isomers having the L(5)K(5)W formula. Amino acid sequences were designed to be perfectly amphipathic when folded into a helical conformation by converging leucines onto one side and lysines onto the other side of the helical axis. The single tryptophans, whose positions were varied in the primary structures, were located commonly at the critical amphipathic interface in the helical wheel projection. Helical conformations and the tryptophanyl environments of the 11 L(5)K(5)W peptides were confirmed and characterized by circular dichroism, fluorescence and nuclear magnetic resonance spectroscopy. All of the isomers exhibited a potent, broad spectrum of antibacterial activity with just a slight variance in individual potency, whereas their hemolytic activities against human erythrocytes were significantly diversified. Interestingly, helical dispositions and fluorescence blue shifts of the peptides in aqueous trifluoroethanol solutions, rather than in detergent micelles, showed a marked linear correlation with their hemolytic potency. These results demonstrate that our de novo design strategy for amphipathic helical model peptides is effective for developing novel antimicrobial peptides and their hemolytic activities can be estimated in correlation with structural parameters. PMID- 23344199 TI - Synthesis, crystal structure, vibration spectral, and DFT studies of 4 aminoantipyrine and its derivatives. AB - Three compounds derived from 4-aminoantipyrine (AA) were synthesized and their structures confirmed by melting point, elemental analysis, FT-IR, and 1H-NMR. The molecular structures of the four compounds were characterized by single-crystal X ray diffraction and calculated by using the density functional theory (DFT) method with 6-31G (d) basis set. The calculated molecular geometries and the vibration frequencies of the AA derivatives in the ground state have been compared with the experimental data. The results show that the optimized geometries can reproduce well the crystal structural parameters, and the theoretical vibration frequencies show good agreement with the experimental data, although the experimental data are different from the theoretical ones due to the intermolecular forces. Besides, the molecular electrostatic potential (MEP) and the frontier molecular orbital (FMO) analysis of the compounds were investigated by theoretical calculations. PMID- 23344200 TI - Dibenzo[1,2,5]thiadiazepines are non-competitive GABAA receptor antagonists. AB - A new process for obtaining dibenzo[c,f][1,2,5]thiadiazepines (DBTDs) and their effects on GABA(A) receptors of guinea pig myenteric neurons are described. Synthesis of DBTD derivatives began with two commercial aromatic compounds. An azide group was obtained after two sequential reactions, and the central ring was closed via a nitrene to obtain the tricyclic sulfonamides (DBTDs). Whole-cell recordings showed that DBTDs application did not affect the holding current but inhibited the currents induced by GABA (I(GABA)), which are mediated by GABA(A) receptors. These DBTDs effects reached their maximum 3 min after application and were: (i) reversible, (ii) concentration-dependent (with a rank order of potency of 2c = 2d > 2b), (iii) mediated by a non-competitive antagonism, and (iv) only observed when applied extracellularly. Picrotoxin (which binds in the channel mouth) and DBTDs effects were not modified when both substances were simultaneous applied. Our results indicate that DBTD acted on the extracellular domain of GABA(A) channels but independent of the picrotoxin, benzodiazepine, and GABA binding sites. DBTDs used here could be the initial model for synthesizing new GABA(A) receptor inhibitors with a potential to be used as antidotes for positive modulators of these receptors or to induce experimental epilepsy. PMID- 23344201 TI - Synthesis of 5alpha-androstane-17-spiro-delta-lactones with a 3-keto, 3-hydroxy, 3-spirocarbamate or 3-spiromorpholinone as inhibitors of 17beta-hydroxysteroid dehydrogenases. AB - We synthesized two series of androstane derivatives as inhibitors of type 3 and type 5 17beta-hydroxysteroid dehydrogenases (17beta-HSDs). In the first series, four monospiro derivatives at position C17 were prepared from androsterone (ADT) or epi-ADT. After the protection of the alcohol at C3, the C17-ketone was alkylated with the lithium acetylide of tetrahydro-2-(but-3-ynyl)-2-H-pyran, the triple bond was hydrogenated, the protecting groups hydrolysed and the alcohols oxidized to give the corresponding 3-keto-17-spiro-lactone derivative. The other three compounds were generated from this keto-lactone by reducing the ketone at C3, or by introducing one or two methyl groups. In the second series, two dispiro derivatives at C3 and C17 were prepared from epi-ADT. After introducing a spiro delta-lactone at C17 and an oxirane at C3, an aminolysis of the oxirane with L isoleucine methyl ester provided an amino alcohol, which was treated with triphosgene or sodium methylate to afford a carbamate- or a morpholinone androstane derivative, respectively. These steroid derivatives inhibited 17beta HSD3 (14-88% at 1 MUM; 46-94% at 10 MUM) and 17beta-HSD5 (54-73% at 0.3 MUM; 91 92% at 3 MUM). They did not produce any androgenic activity and did not bind steroid (androgen, estrogen, glucocorticoid and progestin) receptors, suggesting a good profile for prostate cancer therapy. PMID- 23344202 TI - Total flavonoids of Scutellaria barbata inhibit invasion of hepatocarcinoma via MMP/TIMP in vitro. AB - Metastasis is the major cause of cancer-related deaths. Targeting the process of metastasis has been proposed as a strategy to fight cancer. Scutellaria barbata D. Don (S. barbata), a traditional Chinese medicine, is used for treatment of many diseases, including cancer. This study aimed to determine the anti metastatic effect of total flavonoids of S. barbata (TF-SB) using the human hepatocarcinoma MHCC97H cell line with high metastatic potential. Our results show that TF-SB could significantly inhibit the proliferation and invasion of MHCC97H cells in a dose-dependent manner. MMP-2 and MMP-9 expression were obviously decreased after TF-SB treatment at both the mRNA and protein level. TIMP-1 and TIMP-2 expression were simultaneously increased. The present study indicates that TF-SB could reduce the metastatic capability of MHCC97H cell, probably through decrease of the MMP expression, and simultaneous increase of the TIMP expression. PMID- 23344203 TI - Investigating the antioxidant and acetylcholinesterase inhibition activities of Gossypium herbaceam. AB - Our previous research showed that standardized extract from the flowers of the Gossypium herbaceam labeled GHE had been used in clinical trials for its beneficial effects on brain functions, particularly in connection with age related dementia and Alzheimer's disease (AD). The aim of this work was to determine the components of this herb and the individual constituents of GHE. In order to better understand this herb for AD treatment, we investigated the acetylcholinesterase (AChE) inhibition and antioxidant activity of GHE as well as the protective effects to PC12 cells against cytotoxicity induced by tertiary butyl hydroperoxide (tBHP) using in vitro assays. The antioxidant activities were assessed by measuring their capabilities for scavenging 1,1-diphenyl-2 picylhydrazyl (DPPH) and 2-2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radical as well as in inhibiting lipid peroxidation. Our data showed that GHE exhibited certain activities against AChE and also is an efficient free radical scavenger, which may be helpful in preventing or alleviating patients suffering from AD. PMID- 23344204 TI - Chemical composition and antibacterial activity of essential oils from different parts of Leonurus japonicus Houtt. AB - The herb and fruits of Leonurus japonicus Houtt., named "Yimucao" and "Chongweizi", respectively, in Chinese, have been widely used in China as gynecological medicines. The components of the essential oils obtained by hydrodistillation were investigated by GC-MS. The antibacterial activity of the essential oils was determined by micro-dilution assay. The results showed large variations in the chemical composition and antibacterial activity of the oils. The oil of "Yimucao" showed antibacterial activity against various Gram-positive bacteria and consisted mainly of sesquiterpenes and diterpenes, with phytone, phytol, caryophyllene oxide and beta-caryophyllene being the most significant constituents, whereas the oil of "Chongweizi", mainly made up of bornyl acetate and aliphatic hydrocarbons, was inactive in the antibacterial assay. Further study of the main compounds in "Yimucao oil" showed that beta-caryophyllene had wide-spectrum activity against Gram-positive bacteria. PMID- 23344205 TI - Comparative ANNs with different input layers and GA-PLS study for simultaneous spectrofluorimetric determination of melatonin and pyridoxine HCl in the presence of melatonin's main impurity. AB - Melatonin (MLT) has many health implications, therefore it is important to develop specific analytical methods for the determination of MLT in the presence of its main impurity, N-{2-[1-({3-[2-(acetylamino)ethyl]-5-methoxy-1H-indol-2 yl}methyl)-5-methoxy-1H-indol-3-yl]ethyl}acetamide (DMLT) and pyridoxine HCl (PNH) as a co-formulated drug. This work describes simple, sensitive, and reliable four multivariate calibration methods, namely artificial neural network preceded by genetic algorithm (GA-ANN), principal component analysis (PCA-ANN) and wavelet transform procedures (WT-ANN) as well as partial least squares preceded by genetic algorithm (GA-PLS) for the spectrofluorimetric determination of MLT and PNH in the presence of DMLT. Analytical performance of the proposed methods was statistically validated with respect to linearity, accuracy, precision and specificity. The proposed methods were successfully applied for the assay of MLT in laboratory prepared mixtures containing up to 15% of DMLT and in commercial MLT tablets with recoveries of no less than 99.00%. No interference was observed from common pharmaceutical additives and the results compared favorably with those obtained by a reference method. PMID- 23344206 TI - Diastereoselective synthesis of 5-hydroxy-8-methoxy-1-oxaspiro[5,5]undeca-7,10 diene-9-one. AB - A short five steps synthesis of the title compound from vanillin is described. The racemic spiroether 7 was obtained in 61% yield and in >99% diastereomeric excess (by 1H-NMR) from the corresponding phenolic derivative 3 by oxidation with lead (IV) acetate. PMID- 23344207 TI - Two cerebrosides isolated from the seeds of Sterculia lychnophora and their neuroprotective effect. AB - Two cerebrosides named 1-O-b-D-glucopyranosyl-(2S,3R,4E,8Z)-2-[(2 hydroxyoctadecanoyl)amido]-4,8-octadecadiene-1,3-diol (1) and soya-cerebroside I (2) were isolated from the seeds of Sterculia lychnophora for the first time. Their structures were completely characterized by spectroscopic methods including IR, MS and NMR. Compound 1 exhibited moderate neuroprotective effect against SH SY5Y cell damage induced by hydrogen peroxide. PMID- 23344208 TI - Suzuki-miyaura cross-coupling in acylation reactions, scope and recent developments. AB - Since the first report and due to its handiness and wide scope, the Suzuki Miyaura (SM) cross coupling reaction has become a routine methodology in many laboratories worldwide. With respect to other common transition metal catalyzed cross couplings, the SM reaction has been so far less exploited as a tool to introduce an acyl function into a specific substrate. In this review, the various approaches found in the literature will be considered, starting from the direct SM acylative coupling to the recent developments of cross coupling between boronates and acyl chlorides or anhydrides. Special attention will be dedicated to the use of masked acyl boronates, alkoxy styryl and alkoxy dienyl boronates as coupling partners. A final section will be then focused on the acyl SM reaction as key synthetic step in the framework of natural products synthesis. PMID- 23344209 TI - Protective effect of ginsenoside Rb1 against lung injury induced by intestinal ischemia-reperfusion in rats. AB - Intestinal ischemia-reperfusion (I/R) is a critical event in the pathogenesis of multiple organ dysfunction syndromes (MODS). The lungs are some of the most vulnerable organs that are impacted by intestinal I/R. The aim of this study is to investigate whether ginsenoside Rb1 can ameliorate remote lung injury induced by intestinal I/R. Adult male Wistar rats were randomly divided into four groups: (1) a control, sham-operated group (sham group); (2) an intestinal I/R group subjected to 1 h intestinal ischemia and 2 h reperfusion (I/R group); (3) a group treated with 20 mg/kg ginsenoside Rb1 before reperfusion (Rb1-20 group); and (4) a group treated with 40 mg/kg ginsenoside Rb1 before reperfusion (Rb1-40 group). Intestinal and lung histology was observed. The malondialdehyde (MDA) levels in intestinal tissues were measured. Myeloperoxidase (MPO), TNF-alpha, MDA levels, wet/dry weight ratio and immunohistochemical expression of intracellular adhesion molecule-1 (ICAM-1) in lung tissues were assayed. In addition, a western blot of lung NF-kB was performed. Results indicated that intestinal I/R induced intestinal and lung injury, which was characterized by increase of MDA levels and pathological scores in intestinal tissues and MPO, TNF-alpha , MDA levels, wet/dry weight ratio and ICAM-1, NF-kB expression in the lung tissues. Ginsenoside Rb1 (20, 40 mg/kg) ameliorated intestinal and lung injury, decreased MPO, TNF-alpha, MDA levels, wet/dry weight ratio, ICAM-1 and NF-kB expression in lung tissues. In conclusion, ginsenoside Rb1 ameliorated the lung injuries by decreasing the NF-kB activation-induced inflammatory response. PMID- 23344210 TI - Breastfeeding, previous Epstein-Barr virus infection, Enterovirus 71 infection, and rural residence are associated with the severity of hand, foot, and mouth disease. AB - Severe hand, foot, and mouth disease (HFMD) is likely to develop critical complications such as brainstem encephalitis, acute pulmonary edema, and circulatory failure, which cause child mortality during outbreaks. This study aims to investigate factors that predict the severity of HFMD. One hundred sixteen in-patient children with severe HFMD and 202 with mild HFMD were retrospectively enrolled. Potential factors were collected for each child including sex, age, residence, modes of delivery, birth weight, virus types causing HFMD, and virus exposure history. Univariate and multivariable logistic regression were used to determine which factors were associated with HFMD severity. In the univariate analysis, breastfeeding (OR 0.514, 95 % CI 0.309 0.856), rural residence (OR 1.971, 95 % CI 1.239-3.137), current Enterovirus 71 (EV71) infection (OR 2.539, 95 % CI 1.504-4.287), and previous Epstein-Barr virus (EBV) exposure (OR 3.136, 95 % CI 1.863-5.278) were each associated with the severity of HFMD. In the multivariate model, breastfeeding (OR 0.570, 95 % CI 0.332-0.980), rural residence (OR 1.973, 95 % CI 1.202-3.237), current EV71 infection (OR 2.290, 95 % CI 1.315-3.987), and previous EBV exposure (OR 2.550, 95 % CI 1.470-4.422) remained independently associated with the severity of HFMD. In conclusion, previous EBV exposure, EV71 infection, and rural residence are risk factors for severe HFMD; breastfeeding is a protective factor. PMID- 23344211 TI - Genetic admixture and risk of hypertensive disorders of pregnancy among Latinas in Los Angeles County. AB - BACKGROUND: Latinos are a heterogeneous population in terms of demographics, culture, and genetic admixture from three racial groups (white, African, and Native American). This study examines the role of genetic ancestry and environmental risk factors in the risk of hypertensive disorder of pregnancy among Latinas in Los Angeles County. METHODS: Gestational hypertension, preeclampsia, eclampsia, or hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome cases (n = 125), plus unaffected controls (n = 161), were recruited from Los Angeles County + University of Southern California Women's and Children's Hospital from 1999 through 2008. Diagnoses were confirmed with extensive chart review. Personal information, demographics, and biospecimens were collected from all participants. Ancestry informative markers were used to estimate genetic ancestry proportions. RESULTS: After adjusting for European ancestry and key risk factors, African ancestry was positively associated with hypertensive disorders of pregnancy risk for the highest vs. the lowest quartiles of African ancestry (odds ratio = 2.6 [95% confidence interval = 1.1-6.1]). This association was stronger among women born in Mexico with parents born in Mexico (4.3 [1.4-13]). The results from generalized additive models showed a positive association between joint European/African ancestry and hypertensive disorders of pregnancy risk and an inverse association between Native American ancestry and risk. These associations were stronger among women of Mexican origin. CONCLUSION: Our findings suggest that higher Native American ancestry among Latinas may protect against hypertensive disorders of pregnancy. Further studies are needed to determine whether this protective effect is driven by specific alleles present in this population or by other risk factors that correlate with Native American ancestry. PMID- 23344212 TI - Cancer mortality of workers exposed to styrene in the U.S. Reinforced plastics and composite industry. AB - BACKGROUND: Epidemiologic studies have reported increased risk of lymphohematopoietic cancers, lung cancer, and pancreatic cancer after exposure to styrene, although findings across studies are not consistent. METHODS: We update a large study of reinforced plastic industry workers with relatively high exposures to styrene, examining cancer risks associated with exposure levels. The study includes 15,826 workers who were exposed between 1948 and 1977 with vital status follow-up from 1948 to 2008. We examine mortality rates associated with cumulative exposure, duration of exposure, peak exposures, average exposure, and time since first exposure to styrene. Exposure estimates were truncated starting in 1977, the period with the lowest exposures, leaving 27% of the study group with incomplete work histories. RESULTS: The standardized mortality ratios were 0.84 (95% confidence interval = 0.69-1.02) for all lymphatic and hematopoietic cancers combined, 0.72 (0.50-1.00) for non-Hodgkin lymphoma, and 0.84 (0.60-1.14) for leukemia. There was no trend with either cumulative exposure to styrene or number of peaks. Pancreatic cancer deaths were at expected levels (0.96 [0.73 1.22]). There were more lung cancer deaths than expected (1.34 [1.23-1.46]), although with a marked inverse trend with cumulative exposure. CONCLUSION: We found no coherent evidence that styrene exposure increases risk from cancers of the lymphatic and hematopoietic tissue, pancreas, or lung. PMID- 23344213 TI - A fluorescent probe for the 3'-overhang of telomeric DNA based on competition between two interstrand G-quadruplexes. AB - A 6-mer oligonucleotide containing a fluorescent (Bod)U moiety has been used as a novel fluorescent probe for the 3'-overhang of telomeric DNA based on competition between non-fluorescent tetramolecular and fluorescent (3+1) intermolecular G quadruplexes. PMID- 23344215 TI - The VEGF/VEGF-R axis in sporadic vestibular schwannomas correlates with irradiation and disease recurrence. AB - BACKGROUND/AIMS: The molecular mechanisms downstream of mutated neurofibromatosis type 2 (NF2) gene resulting in the growth and development of vestibular schwannoma (VS) are controversial. Several lines of evidence suggest the involvement of the vascular endothelial growth factor (VEGF) pathway in VS development. Given that recent studies of VEGF blockade in patients with NF2 associated VS showed positive effects on VS growth control, we initiated this comprehensive study of the VEGF pathway in sporadic VS. METHODS: A tissue microarray analysis of 182 sporadic VS was conducted. The expression of VEGF and its receptors as well as the proliferative activity of the tumors were quantified. The expression data were correlated to tumor volumes and diameters as well as to tumor recurrence and previous irradiation. RESULTS: All studied tumors expressed VEGF and its receptors. Proliferative activity was related to the growth characteristics of the tumors. Moreover, we found significantly higher VEGF levels in recurrent tumors (p = 0.0387) and in preoperatively irradiated tumors (p = 0.0213). CONCLUSION: Our data suggest a relevant role of the VEGF pathway in VS growth and therapy outcome. Therefore, targeting this pathway using antiangiogenic compounds might be beneficial for patients with sporadic VS, especially those with recurrent or irradiated tumors. PMID- 23344216 TI - Single port laparoscopic sacrohysteropexy in a young patient presenting with grade III uterine prolapse and rectocele. AB - INTRODUCTION: Uterine preservation in patients with uterine prolapse is a common practice in the last decade and the reconstructive pelvic operation can be done either by vaginal, abdominal or laparoscopic approach. In young patients, uterine preservation is a legitimate option and one of the proposed operations is sacro hystero-pexy. Single Port Laparoscopy (SPL) is a relatively new technique. This is a case of a young patient presented with grade III uterine prolapse and rectocele. METHODS: The video presents the surgical technique of sacro-hystero pexy as was described in 2001 by von Theobald, adapted specifically for the SPL technique. CONCLUSIONS: The Single Port laparoscopy is an advanced laparoscopic technique. This video demonstrate that scaro-hystero-pexy can be done safely and efficacy with Single Port Laparoscopy without prolonging the operation time significantly. PMID- 23344218 TI - Botulinum toxin for conditions of the female pelvis. AB - INTRODUCTION AND HYPOTHESIS: Botulinum toxin has recently been approved by the Food and Drug Administration (FDA) for the treatment of urinary incontinence associated with neurogenic detrusor overactivity. However, it has also been used off-label for a multitude of other conditions in the female pelvis, including urological, gynecological, and colorectal. This article reviews the most recent data regarding its efficacy and safety, and administration techniques for those conditions. METHODS: A literature review of the most relevant reports published between 1985 and 2012. RESULTS: Urinary incontinence related to neurogenic detrusor overactivity is currently the only approved indication in the female pelvis. Other supported off-label uses include: idiopathic detrusor overactivity, interstitial cystitis/bladder pain syndrome, detrusor sphincter dyssynergia, high tone pelvic floor dysfunction, anal fissure, anismus, and functional anal pain. CONCLUSIONS: Botulinum toxin may effectively and safely be used in many conditions of the female pelvis. More high quality research is needed to better clarify its role in the therapeutic algorithm for those indications. PMID- 23344219 TI - [Early detection and prevention of elder abuse and neglect in family care giving: development of the PURFAM assessment]. AB - The purpose of the PURFAM ("potentials and risk factors of family caregiving for older people") project is to support staff members of home care services in preventing elder abuse by facilitating an assessment instrument for early recognition and a standard for action. During a pilot phase of the project nursing staff of home services were presented with training sessions in which the use of the PURFAM assessment was introduced using concrete examples from routine daily work. The article describes the development of the PURFAM assessment and its first evaluation by staff members of nursing home services. The preliminary results indicate a high practicability und acceptance of the instrument by staff members. The sustainability of PURFAM is yet to be tested using the data of the still ongoing main part of the evaluation. PMID- 23344220 TI - [Psychotherapy of depression in old age]. AB - Depression in old age is common and also dangerous due to somatic comorbidity and suicide; however, it is often not recognized and not adequately treated. Psychotherapy is almost never offered to the elderly. However, clinical experience, single-case studies and some controlled trials show effectiveness--at least to the age of 75. The psychotherapist must be aware of unusual transference and countertransference between a younger therapist and elderly patient. Psychotherapy in old age requires some modifications, especially concerning special interest in biography and history, strong empathy, "container function", and focusing. In the future, psychotherapy for the elderly should be both investigated and educated more. In addition, it is hoped that psychotherapists offer to treat elderly people with depression and that more older patients accept this professional help. PMID- 23344221 TI - [Neurobiological subtypes of geriatric depression. Their importance for diagnosis and treatment]. AB - With age, increasing biological constraints on functioning are often aggravated by increases in multimorbidity. These effects, however, not only have an impact on somatic, but also psychological processes. In geriatric depression, for instance, there are both effects of recurrent depressive episodes on the neurobiology of the disorder as well as effects of cardiovascular comorbidity that interact with brain areas associated with the perception and regulation of emotions. These biobehavioral interactions have strong implications for both the differential diagnosis and treatment of geriatric depression. PMID- 23344222 TI - [Depression in late life]. PMID- 23344223 TI - APNs taking the next step: disseminating practice information via effective poster presentations. AB - Advanced practice nurses (APNs) have a responsibility to share information from projects and research with other professionals. Poster presentations offer a way to visually share the information to a wide audience. Key elements include title, objective/purpose, data collection, results, analysis, implications for nursing, and appropriate references. PMID- 23344224 TI - A primer on Medicare and changes resulting from the Patient Protection and Affordable Care Act. PMID- 23344225 TI - Leprosy: when to raise suspicion. PMID- 23344228 TI - How insulin analogues can benefit patients. AB - Primary care providers offer diabetes care for many patients in the United States. Primary care nurse practitioners can benefit from an understanding of effective administration of insulin therapy. This review will outline suggestions for the effective use of insulin analogues in clinical practice. PMID- 23344230 TI - Leptin receptor antagonist treatment ameliorates the effects of long-term maternal hypoxia on adrenal expression of key steroidogenic genes in the ovine fetus. AB - We previously reported elevated adipose leptin expression, plasma leptin concentrations, and adrenocortical leptin receptor expression in the long-term hypoxic (LTH) ovine fetus. This study addressed whether leptin antagonist (LA) administration to LTH fetal sheep altered expression of key genes governing cortisol synthesis. Ewes were maintained at high altitude (3,820 meters) from 40 to 130 days gestation (dG), returned to Loma Linda University, and implanted with a maternal tracheal catheter. Reduced Po2 was maintained by nitrogen infusion. On 132 dG, LTH (n = 11) and age-matched, normoxic control (n = 11) fetuses underwent vascular catheter implantation. At 138 dG, fetuses were continuously infused with either saline or the LA (1.5 mg.kg(-1).day(-1)) for 4 days and samples collected for blood gases, ACTH, and cortisol. Fetal adrenal cortex was collected for determination of steriodogenic acute regulatory protein (StAR), ACTH, and leptin receptor, cholesterol side-chain cleavage (CYP11A1), cytochrome P-450 11beta hydroxylase (CYP11B1), 17alpha-hydroxylase (CYP17), 21-hydroxylase (CYP21), signal transducer and activator of transcription 3 (STAT3), pSTAT3, and 17beta hydroxysteroid dehydrogenase (HSD3B) expression. In the saline-infused LTH fetuses, StAR, ACTH receptor, CYP11A1, and CYP17 expression was significantly lower compared with control (P < 0.05), whereas levels of CYP11B1, CYP21, and HSD3B mRNA were similar between groups. LA infusion restored expression of StAR, pSTAT3, CYP11A1, and CYP17, but not ACTH receptor, to normal ontogenic levels in the LTH group while having no effect on control fetuses. Neither fetal plasma ACTH nor cortisol concentrations were altered by LA infusion. We speculate that while leptin plays a role in governing expression of key enzymes and StAR in response to LTH, other factors play a role in modulating cortisol synthesis in these fetuses. PMID- 23344232 TI - Anti-inflammatory effect of quinoline alkaloid skimmianine isolated from Ruta graveolens L. AB - OBJECTIVE: The present study evaluates the anti-inflammatory effect of the quinoline alkaloid skimmianine (SKM), isolated from Ruta graveolens L., against carrageenan-induced acute inflammation. METHODS: SKM at a dose of 5.0 mg/kg body weight was found to be the minimal concentration for maximal edema inhibition. Carrageenan suspension was administered into the sub-plantar tissue of the right hind paw 1 h after SKM and diclofenac (20 mg/kg) administration (i.p.). Paw edema was determined 3 h after carrageenan administration. The rats were then killed and mRNA expressions of TNF-alpha and IL-6, levels of PGE2 and TBARS, activities of COX-2, 5-LOX, SOD, catalase, glutathione peroxidase (GPx) and myeloperoxidase (MPO) and the level of nitrite were measured. RESULTS: SKM treatment resulted in a decrease in the mRNA levels of TNF-alpha and IL-6, which are upstream events of the inflammatory cascade. The levels of PGE2 and NO and the activities of COX-2 and 5-LOX were also significantly reduced after SKM treatment. Neutrophil infiltration, lipid peroxidation and associated oxidative stress in the paw tissue were reduced following SKM treatment. CONCLUSION: These results support the anti-inflammatory properties of skimmianine and its multi-targeted mechanism of action, suggesting its potential therapeutic efficacy in various inflammatory diseases. PMID- 23344233 TI - Patterns of subarachnoid hemorrhage admissions in England, 2008-2011. AB - BACKGROUND: To investigate hospital admissions for subarachnoid hemorrhage (SAH) across regions in England in recent years, with the hypothesis that deprived areas have higher admissions. METHODS: Hospital episode statistics between July 2008 and June 2011 were retrieved. Hospital admissions by geographic and seasonal variations were examined. Data on prevalence of deprivation were extracted from the English Indices of Deprivation. Comparisons were made by using linear regression models to test associations between deprivation and classical risk contributors and SAH admissions at the area level. RESULTS: SAH admissions were observed to be higher in warm months and lower in cold months. There was not much variation in SAH admissions across regions. Areas with higher prevalence of risk contributors had higher SAH admissions (all p < 0.05), but no relation with deprivation was found. Additionally, over the last 13 years, SAH admissions have decreased (beta: -0.011, 95% CI: -0.015 to -0.008, p < 0.001) annually, but the proportion of male patient admissions has increased (beta: 0.022, 95% CI: 0.008 0.036, p = 0.005). CONCLUSION: SAH admissions varied across seasons but not geographically. Additionally, they were correlated with known risk contributors. Policies attending to lifestyle change are suggested in reducing this disease. PMID- 23344231 TI - A novel murine model of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) induced by immunization with a spermine binding protein (p25) peptide. AB - The pathophysiology of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is poorly understood. Inflammatory and autoimmune mechanisms may play a role. We developed a murine model of experimental autoimmune prostatitis (EAP) that mimics the human phenotype of CP/CPPS. Eight-week-old mice were immunized subcutaneously with prostate-specific peptides in an emulsion of complete Freund's adjuvant. Mice were euthanized 10 days after immunization, and lymph node cells were isolated and assessed for recall proliferation to each peptide. P25 99-118 was the most immunogenic peptide. T-cell and B-cell immunity and serum levels of C reactive protein and nitrate/nitrite levels were evaluated over a 9-wk period. Morphometric studies of prostate, 24-h micturition frequencies, and urine volume per void were evaluated. Tactile referred hyperalgesia was measured using von Frey filaments to the pelvic region. The unpaired Student's t-test was used to analyze differences between EAP and control groups. Prostates from p25 99-118 immunized mice demonstrated elevated gene expression levels of TNF-alpha, IL-17A, IFN-gamma, and IL-1beta, not observed in control mice. Compared with controls, p25 99-118-immunized mice had significantly higher micturition frequency and decreased urine output per void, and they demonstrated elevated pelvic pain response. p25 99-118 immunization of male SWXJ mice induced prostate-specific autoimmunity characterized by prostate-confined inflammation, increased micturition frequency, and pelvic pain. This autoimmune prostatitis model provides a useful tool for exploring the pathophysiology and new treatments. PMID- 23344234 TI - Specific Jak3 Downregulation in Lymphocytes Impairs gammac Cytokine Signal Transduction and Alleviates Antigen-driven Inflammation In Vivo. AB - Jak3, one of the four members comprising the Jak family of cytosolic tyrosine kinases, has emerged as a promising target for nontoxic immunotherapies. Although a number of Jak inhibitors has already demonstrated efficacy, they suffer from secondary effects apparently associated to their pan-Jak activity. However, whether selective Jak3 inhibition would afford therapeutic efficacy remains unclear. To address this question we have investigated the immunosuppressive potential of selective Jak3 intervention in lymphocytes using RNA interference (RNAi) technology in vitro and in vivo. Using synthetic small interference RNA (siRNA) sequences we achieved successful transfections into human and mouse primary T lymphocytes. We found that Jak3 knockdown was sufficient to impair not only interleukin-2 (IL-2) and T cell receptor (TCR)-mediated cell activation in vitro, but also antigen-triggereds welling, inflammatory cell infiltration, and proinflammatory cytokine raise in vivo. Furthermore, Jak1 (which mediates gammac cytokine signaling in conjunction with Jak3) cosilencing did not provide higher potency to the aforementioned immunosuppressant effects. Our data provides direct evidences indicating that Jak3 protein plays an important role in gammac cytokine and antigen-mediated T cell activation and modulates Th1-mediated inflammatory disorders, all in all highlighting its potential as a target in immunosuppressive therapies.Molecular Therapy - Nucleic Acids (2012) 1, e42; doi:10.1038/mtna.2012.37; published online 04 September 2012. PMID- 23344235 TI - Antisense 2'-Deoxy, 2'-Fluroarabino Nucleic Acids (2'F-ANAs) Oligonucleotides: In Vitro Gymnotic Silencers of Gene Expression Whose Potency Is Enhanced by Fatty Acids. AB - Gymnosis is the process of the delivery of antisense oligodeoxynucleotides to cells, in the absence of any carriers or conjugation, that produces sequence specific gene silencing. While gymnosis was originally demonstrated using locked nucleic acid (LNA) gapmers, 2'-deoxy-2'fluroarabinonucleic acid (2'F-ANA) phosphorothioate gapmer oligonucleotides (oligos) when targeted to the Bcl-2 and androgen receptor (AR) mRNAs in multiple cell lines in tissue culture, are approximately as effective at silencing of Bcl-2 expression as the iso-sequential LNA congeners. In LNCaP prostate cancer cells, gymnotic silencing of the AR by a 2'F-ANA phosphorothioate gapmer oligo led to downstream silencing of cellular prostate-specific antigen (PSA) expression even in the presence of the androgenic steroid R1881 (metribolone), which stabilizes cytoplasmic levels of the AR. Furthermore, gymnotic silencing occurs in the absence of serum, and silencing by both LNA and 2'F-ANA oligos is augmented in serum-free (SF) media in some cell lines when they are treated with oleic acid and a variety of omega-6 polyunsaturated fatty acids (omega-6 PUFAs), but not by an aliphatic (palmitic) fatty acid. These results significantly expand our understanding of and ability to successfully manipulate the cellular delivery of single-stranded DNA molecules in vitro.Molecular Therapy - Nucleic Acids (2012) 1, e43; doi:10.1038/mtna.2012.35; advance online publication 18 September 2012. PMID- 23344236 TI - Long-term Exon Skipping Studies With 2'-O-Methyl Phosphorothioate Antisense Oligonucleotides in Dystrophic Mouse Models. AB - Antisense-mediated exon skipping for Duchenne muscular dystrophy (DMD) is currently tested in phase 3 clinical trials. The aim of this approach is to modulate splicing by skipping a specific exon to reframe disrupted dystrophin transcripts, allowing the synthesis of a partly functional dystrophin protein. Studies in animal models allow detailed analysis of the pharmacokinetic and pharmacodynamic profile of antisense oligonucleotides (AONs). Here, we tested the safety and efficacy of subcutaneously administered 2'-O-methyl phosphorothioate AON at 200 mg/kg/week for up to 6 months in mouse models with varying levels of disease severity: mdx mice (mild phenotype) and mdx mice with one utrophin allele (mdx/utrn(+/-); more severe phenotype). Long-term treatment was well tolerated and exon skipping and dystrophin restoration confirmed for all animals. Notably, in the more severely affected mdx/utrn(+/-) mice the therapeutic effect was larger: creatine kinase (CK) levels were more decreased and rotarod running time was more increased. This suggests that the mdx/utrn(+/-) model may be a more suitable model to test potential therapies than the regular mdx mouse. Our results also indicate that long-term subcutaneous treatment in dystrophic mouse models with these AONs is safe and beneficial.Molecular Therapy-Nucleic Acids (2012) 1, e44; doi:10.1038/mtna.2012.38; published online 4 September 2012. PMID- 23344237 TI - Development of a 2',4'-BNA/LNA-based siRNA for Dyslipidemia and Assessment of the Effects of Its Chemical Modifications In Vivo. AB - Recent advances in RNA interference (RNAi)-based drug development have partially allowed systemic administration of these agents in vivo with promising therapeutic effects. However, before chemically modified small-interfering RNAs (siRNAs) can be applied clinically, their in vivo effects should be thoroughly assessed. And while many studies have assessed the effects of chemically modified siRNAs in vitro, there has been no comprehensive assessment of their effects in vivo. Here, we aimed to elucidate the effects of administering chemically modified siRNAs in vivo and to propose a 2',4'-bridged nucleic acid (BNA)/locked nucleic acid (LNA)-based siRNA candidate for dyslipidemia. A potentially therapeutic siRNA, siL2PT-1M, was modified with phosphorothioate (PS) and 2',4' BNA/LNA in its sense strand and with 2'-methoxy (2'-OMe) nucleotides in its immunostimulatory motif; administration of siL2PT-1M resulted in sustained reductions in serum total cholesterol (TC) (24 days) and a concomitant apolipoprotein B (apoB) mRNA reduction in liver without adverse effects. The 2',4'-BNA/LNA modification in the sense strand was greatly augmented the duration of the RNAi effect, whereas cholesterol conjugation shortened the duration. Cholesterol-conjugated immunostimulatory siRNA (isRNA) induced higher serum interferon-alpha (IFN-alpha) levels than did nonmodified isRNA, indicating that the immune reaction was facilitated by cholesterol conjugation. Our results indicated that modification of the adenosine residues complementary to the immunostimulatory motif and of central 5'-UG-3' in the sense strand would ameliorate the negative immune response.Molecular Therapy - Nucleic Acids (2012) 1, e45; doi:10.1038/mtna.2012.32; published online 18 September 2012. PMID- 23344238 TI - Targeted siRNA Delivery and mRNA Knockdown Mediated by Bispecific Digoxigenin binding Antibodies. AB - Bispecific antibodies (bsAbs) that bind to cell surface antigens and to digoxigenin (Dig) were used for targeted small interfering RNA (siRNA) delivery. They are derivatives of immunoglobulins G (IgGs) that bind tumor antigens, such as Her2, IGF1-R, CD22, and LeY, with stabilized Dig-binding variable domains fused to the C-terminal ends of the heavy chains. siRNA that was digoxigeninylated at its 3'end was bound in a 2:1 ratio to the bsAbs. These bsAb siRNA complexes delivered siRNAs specifically to cells that express the corresponding antigen as demonstrated by flow cytometry and confocal microscopy. The complexes internalized into endosomes and Dig-siRNAs separated from bsAbs, but Dig-siRNA was not released into the cytoplasm; bsAb-targeting alone was thus not sufficient for effective mRNA knockdown. This limitation was overcome by formulating the Dig-siRNA into nanoparticles consisting of dynamic polyconjugates (DPCs) or into lipid-based nanoparticles (LNPs). The resulting complexes enabled bsAb-targeted siRNA-specific messenger RNA (mRNA) knockdown with IC(50) siRNA values in the low nanomolar range for a variety of bsAbs, siRNAs, and target cells. Furthermore, pilot studies in mice bearing tumor xenografts indicated mRNA knockdown in endothelial cells following systemic co-administration of bsAbs and siRNA formulated in LNPs that were targeted to the tumor vasculature.Molecular Therapy - Nucleic Acids (2012) 1, e45; doi:10.1038/mtna.2012.39; published online 18 September 2012. PMID- 23344239 TI - Structure Activity Relationships of alpha-L-LNA Modified Phosphorothioate Gapmer Antisense Oligonucleotides in Animals. AB - We report the structure activity relationships of short 14-mer phosphorothioate gapmer antisense oligonucleotides (ASOs) modified with alpha-L-locked nucleic acid (LNA) and related modifications targeting phosphatase and tensin homologue (PTEN) messenger RNA in mice. alpha-L-LNA represents the alpha-anomer of enantio LNA and modified oligonucleotides show LNA like binding affinity for complementary RNA. In contrast to sequence matched LNA gapmer ASOs which showed elevations in plasma alanine aminotransferase (ALT) levels indicative of hepatotoxicity, gapmer ASOs modified with alpha-L-LNA and related analogs in the flanks showed potent downregulation of PTEN messenger RNA in liver tissue without producing elevations in plasma ALT levels. However, the alpha-L-LNA ASO showed a moderate dose-dependent increase in liver and spleen weights suggesting a higher propensity for immune stimulation. Interestingly, replacing alpha-L-LNA nucleotides in the 3'- and 5'-flanks with R-5'-Me-alpha-L-LNA but not R-6'-Me- or 3'-Me-alpha-L-LNA nucleotides, reversed the drug induced increase in organ weights. Examination of structural models of dinucleotide units suggested that the 5'-Me group increases steric bulk in close proximity to the phosphorothioate backbone or produces subtle changes in the backbone conformation which could interfere with recognition of the ASO by putative immune receptors. Our data suggests that introducing steric bulk at the 5'-position of the sugar-phosphate backbone could be a general strategy to mitigate the immunostimulatory profile of oligonucleotide drugs. In a clinical setting, proinflammatory effects manifest themselves as injection site reactions and flu-like symptoms. Thus, a mitigation of these effects could increase patient comfort and compliance when treated with ASOs.Molecular Therapy - Nucleic Acids (2012) 1, e47; doi:10.1038/mtna.2012.34; published online 18 September 2012. PMID- 23344240 TI - Genomic island genes in a coastal marine Synechococcus strain confer enhanced tolerance to copper and oxidative stress. AB - Highly variable regions called genomic islands are found in the genomes of marine picocyanobacteria, and have been predicted to be involved in niche adaptation and the ecological success of these microbes. These picocyanobacteria are typically highly sensitive to copper stress and thus, increased copper tolerance could confer a selective advantage under some conditions seen in the marine environment. Through targeted gene inactivation of genomic island genes that were known to be upregulated in response to copper stress in Synechococcus sp. strain CC9311, we found two genes (sync_1495 and sync_1217) conferred tolerance to both methyl viologen and copper stress in culture. The prevalence of one gene, sync_1495, was then investigated in natural samples, and had a predictable temporal variability in abundance at a coastal monitoring site with higher abundance in winter months. Together, this shows that genomic island genes can confer an adaptive advantage to specific stresses in marine Synechococcus, and may help structure their population diversity. PMID- 23344241 TI - Host-released dimethylsulphide activates the dinoflagellate parasitoid Parvilucifera sinerae. AB - Parasitoids are a major top-down cause of mortality of coastal harmful algae, but the mechanisms and strategies they have evolved to efficiently infect ephemeral blooms are largely unknown. Here, we show that the generalist dinoflagellate parasitoid Parvilucifera sinerae (Perkinsozoa, Alveolata) is activated from dormancy, not only by Alexandrium minutum cells but also by culture filtrates. We unequivocally identified the algal metabolite dimethylsulphide (DMS) as the density-dependent cue of the presence of potential host. This allows the parasitoid to alternate between a sporangium-hosted dormant stage and a chemically-activated, free-living virulent stage. DMS-rich exudates of resistant dinoflagellates also induced parasitoid activation, which we interpret as an example of coevolutionary arms race between parasitoid and host. These results further expand the involvement of dimethylated sulphur compounds in marine chemical ecology, where they have been described as foraging cues and chemoattractants for mammals, turtles, birds, fish, invertebrates and plankton microbes. PMID- 23344242 TI - Bacterial colonization of Hydra hatchlings follows a robust temporal pattern. AB - Animals are colonized by complex bacterial communities. The processes controlling community membership and influencing the establishment of the microbial ecosystem during development are poorly understood. Here we aimed to explore the assembly of bacterial communities in Hydra with the broader goal of elucidating the general rules that determine the temporal progression of bacterial colonization of animal epithelia. We profiled the microbial communities in polyps at various time points after hatching in four replicates. The composition and temporal patterns of the bacterial communities were strikingly similar in all replicates. Distinct features included high diversity of community profiles in the first week, a remarkable but transient adult-like profile 2 weeks after hatching, followed by progressive emergence of a stable adult-like pattern characterized by low species diversity and the preponderance of the Betaproteobacterium Curvibacter. Intriguingly, this process displayed important parallels to the assembly of human fecal communities after birth. In addition, a mathematical modeling approach was used to uncover the organizational principles of this colonization process, suggesting that both, local environmental or host-derived factor(s) modulating the colonization rate, as well as frequency-dependent interactions of individual bacterial community members are important aspects in the emergence of a stable bacterial community at the end of development. PMID- 23344243 TI - Epidemiological risk factors in microscopic colitis: a prospective case-control study. AB - BACKGROUND: The cause of collagenous colitis (CC) and lymphocytic colitis (LC) is unknown and epidemiological risk factors for CC and LC are not well studied. The aim was to evaluate in a case-control study epidemiological risk factors for CC and LC. METHODS: In all, 120 patients with CC, 70 with CL, and 128 controls were included. For all cases and controls information was prospectively recorded. A binary logistic regression analysis was performed separately for CC and LC. RESULTS: Independent associations observed with the diagnosis of CC were: current smoking (odds ratio [OR], 2.4), history of polyarthritis (OR, 20.8), and consumption of lansoprazole (OR, 6.4), low-dose aspirin (OR, 3.8), beta-blockers (OR, 3.6), and angiotensin II receptor antagonists (OR 0.20). In the case of LC they were: current smoking (OR, 3.8), associated autoimmune diseases (OR, 8), and consumption of sertraline (OR, 17.5), omeprazole (OR 2.7), low-dose aspirin (OR, 4.7), and oral antidiabetic drugs (OR, 0.14). CONCLUSIONS: The consumption of drugs, current smoking, and associated autoimmune diseases were independently associated with the risk of microscopic colitis. PMID- 23344244 TI - First-principles vdW-DF investigation on the interaction between the oxazepam molecule and C60 fullerene. AB - The interaction between oxazepam and C60 fullerene was explored using first principles vdW-DF calculations. It was found that oxazepam binds weakly to the fullerene cage via its carbonyl group. The binding of oxazepam to C60 is affected drastically by nonlocal dispersion interactions, while vdW forces affect the corresponding geometries only a little. Furthermore, aqueous solution affects the geometries of the oxazepam approaching to fullerene slightly, while oxazepam binds slightly farther away from the nanocage. The results presented provide evidence for the applicability of the vdW-DF method and serve as a practical benchmark for the investigation of host-guest interactions in biological systems. PMID- 23344245 TI - Trivalent cations switch the selectivity in nanopores. AB - In this letter, we study the effect of cation charge on anion selectivity in the pore using grand canonical Monte Carlo simulations. The mechanism of anion selectivity inside nanopores was found to be primarily a consequence of the screening of negative charges by the cations. In the case of monovalent cations, screening was not very effective and anions were rejected. We found an 'off state' at high pH and an 'on-state' at low pH. When there are divalent cations, screening is good and there is no rejection of the anion. The concentration of anions at high pH is similar to that at low pH. The system is always in an 'on state'. Trivalent cations show an inverse selectivity mechanism: at high pH the concentration is higher than at low pH, i.e., the pore is in the 'on-state' at high pH and in the 'off-state' at low pH. PMID- 23344246 TI - Zwitterion L-cysteine adsorbed on the Au20 cluster: enhancement of infrared active normal modes. AB - The study reported herein addressed the structure, adsorption energy and normal modes of zwitterion L-cysteine (Z-cys) adsorbed on the Au20 cluster by using density functional theory (DFT). It was found that four Z-cys are bound to the Au20 apexes preferentially through S atoms. Regarding normal modes, after adsorption of four Z-cys molecules, a more intense infrared (IR) peak is maintained around 1,631.4 cm(-1) corresponding with a C=O stretching mode, but its intensity is enhanced approximately six times. The enhancement in the intensity of modes between 0 to 300 cm(-1) is around 4.5 to 5.0 times for normal modes that involve O-C=O and C-S bending modes. Other two normal modes in the range from 300 to 3,500 cm(-1) show enhancements of 6.0 and 7.4 times. In general, four peaks show major intensities and they are related with normal modes of carboxyl and NH3 groups of Z-cys. PMID- 23344247 TI - Livestock trypanosomosis in Uganda: parasite heterogeneity and anaemia status of naturally infected cattle, goats and pigs. AB - The prevalence and pathogenic effects of trypanosomosis were determined in cattle, goats and pigs reared in Kasese, Jinja and Rakai districts, Uganda; presence of trypanosomes was detected by buffy coat technique (BCT). The overall prevalence of trypanosomosis in cattle was 7.6% (144/1,891), 0.7% in goats (4/573) and 2.3% in pigs (9/386). Internal transcribed spacer 1 (ITS1) of ribosomal DNA polymerase chain reaction was utilised to identify trypanosomes to species level and revealed infections in 108 of the 144 trypanosome-positive cattle while all infected goats and pigs gave amplicons. Trypanosoma vivax was the most prevalent trypanosome species in cattle in single and mixed infections compared to infections involving Trypanosoma congolense and Trypanosoma brucei; in pigs, eight were mixed infections with one single T. vivax infection. No predominant trypanosome species was detected in goats. Anaemia, the main trypanosomosis pathological feature, was investigated by determining packed cell volume (PCV). Mean PCV values by t test in infected individuals were significantly lower than non-infected individuals (P<0.05) for all animal species. However, the proportion of anaemic animals was not significantly different in infected and non-infected individuals. In addition, the percent of infected animals by Fisher's exact test depended on district of origin and species but not sex. These findings show that trypanosomosis is a major cause of anaemia in livestock in endemic areas. Cattle were the major animal species affected by trypanosomosis; similar genotypes of trypanosomes were detected in the three animal species. BCT was more effective than ITS1 rDNA detecting trypanosomes in naturally infected cattle. PMID- 23344248 TI - Timing of peak blood glucose after breakfast meals of different glycemic index in women with gestational diabetes. AB - This study aims to determine the peak timing of postprandial blood glucose level (PBGL) of two breakfasts with different glycemic index (GI) in gestational diabetes mellitus (GDM). Ten women with diet-controlled GDM who were between 30 and 32 weeks of gestation were enrolled in the study. They consumed two carbohydrate controlled, macronutrient matched bread-based breakfasts with different GI (low vs. high) on two separate occasions in a random order after an overnight fast. PBGLs were assessed using a portable blood analyser. Subjects were asked to indicate their satiety rating at each blood sample collection. Overall the consumption of a high GI breakfast resulted in a greater rise in PBGL (mean +/- SEM peak PBGL: low GI 6.7 +/- 0.3 mmol/L vs. high GI 8.6 +/- 0.3 mmol/L; p < 0.001) and an earlier peak PBGL time (16.9 +/- 4.9 min earlier; p = 0.015), with high variability in PBGL time between subjects. There was no significant difference in subjective satiety throughout the test period. In conclusion, the low GI breakfast produced lower postprandial glycemia, and the peak PBGL occurred closer to the time recommended for PBGL monitoring (i.e., 1 h postprandial) in GDM than a macronutrient matched high GI breakfast. PMID- 23344249 TI - Evaluation of antioxidant potential of "maltese mushroom" (Cynomorium coccineum) by means of multiple chemical and biological assays. AB - Cynomorium coccineum is an edible, non-photosynthetic plant widespread along the coasts of the Mediterranean Sea. The medicinal properties of Maltese mushroom - one of the oldest vernacular names used to identify this species - have been kept in high regard since ancient times to the present day. We evaluated the antioxidant potential of fresh specimens of C. coccineum picked in Sardinia, Italy. Both aqueous and methanolic extracts were tested by using multiple assay systems (DPPH, FRAP, TEAC, ORAC-PYR). Total phenolics and flavonoids were also determined. Gallic acid and cyanidin 3-O-glucoside were identified as the main constituents and measured. Both extracts showed antioxidant capacities; ORAC-PYR assay gave the highest antioxidant value in both cases. The methanolic extract was further investigated with in vitro biological models of lipid oxidation; it showed a significant activity in preventing cholesterol degradation and exerted protection against Cu2+-mediated degradation of the liposomal unsaturated fatty acids. Results of the present study demonstrate that the extracts of C. coccineum show a significant total antioxidant power and also exert an in vitro protective effect in different bio-assays of oxidative stress. Therefore, Maltese mushroom can be considered a valuable source of antioxidants and phytochemicals useful in the preparation of nutraceuticals and functional foods. PMID- 23344251 TI - Effects of collagen and collagen hydrolysate from jellyfish umbrella on histological and immunity changes of mice photoaging. AB - Jellyfish collagen (JC) was extracted from jellyfish umbrella and hydrolyzed to prepare jellyfish collagen hydrolysate (JCH). The effects of JC and JCH on UV induced skin damage of mice were evaluated by the skin moisture, microscopic analyses of skin and immunity indexes. The skin moisture analyses showed that moisture retention ability of UV-induced mice skin was increased by JC and JCH. Further histological analysis showed that JC and JCH could repair the endogenous collagen and elastin protein fibers, and could maintain the natural ratio of type I to type III collagen. The immunity indexes showed that JC and JCH play a role in enhancing immunity of photoaging mice in vivo. JCH showed much higher protective ability than JC. These results suggest that JCH as a potential novel antiphotoaging agent from natural resources. PMID- 23344252 TI - Diet-microbiota interactions and their implications for healthy living. AB - It is well established that diet influences the health of an individual and that a diet rich in plant-based foods has many advantages in relation to the health and well-being of an individual. What has been unclear until recently is the large contribution of the gut microbiota to this effect. As well as providing basic nutritional requirements, the long-term diet of an animal modifies its gut microbiota. In adults, diets that have a high proportion of fruit and vegetables and a low consumption of meat are associated with a highly diverse microbiota and are defined by a greater abundance of Prevotella compared to Bacteroides, while the reverse is associated with a diet that contains a low proportion of plant-based foods. Furthermore, it is becoming increasingly clear that the effect of the microbial ecology of the gut goes beyond the local gut immune system and is implicated in immune-related disorders, such as IBS, diabetes and inflamm ageing. In this review, we investigate the evidence that a balanced diet leads to a balanced, diverse microbiota with significant consequences for healthy ageing by focusing on conditions of interest. PMID- 23344254 TI - Cariporide, a specific Na/H(+) exchanger 1 blocker, inhibits neointimal proliferation induced by advanced glycation end products in a balloon injury rat model. AB - AIMS: The association between diabetes and neointimal expansion after vascular injury has been attributed to the accumulation of advanced glycation end products (AGEs). Here we investigated the inhibitory effect of cariporide, a specific Na(+)/H(+) exchanger 1 blocker, on neointimal proliferation induced by AGEs in a balloon injury model. METHODS: Expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase (MMP) was monitored by reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR. The level of reactive oxygen species (ROS) was determined by specific fluorescent probe. The phosphorylation of the nuclear factor-KB (NF-KB) system was studied by Western blot. RESULTS: Cariporide significantly suppressed AGE-induced neointimal hyperplasia, vascular smooth muscle cell (VSMC) proliferation, COX-2, MMP-2 and MMP-9 expression. In addition, cariporide decreased AGE-induced ROS, malondiadehyde level and increased the superoxide dismutase and glutathione peroxidase activity. We also found that cariporide blocked AGE-induced NF-KB activation and inhibitor-KB degradation. CONCLUSIONS: The results indicated that cariporide inhibited AGE-induced neointimal formation by suppressing the VSMC proliferation and the up-regulation of COX-2, MMP-2, MMP-9 via inhibiting ROS and NF-KB activation. PMID- 23344250 TI - Nutrition of the critically ill — a 21st-century perspective. AB - Health care-induced diseases constitute a fast-increasing problem. Just one type of these health care-associated infections (HCAI) constitutes the fourth leading cause of death in Western countries. About 25 million individuals worldwide are estimated each year to undergo major surgery, of which approximately 3 million will never return home from the hospital. Furthermore, the quality of life is reported to be significantly impaired for the rest of the lives of those who, during their hospital stay, suffered life-threatening infections/sepsis. Severe infections are strongly associated with a high degree of systemic inflammation in the body, and intimately associated with significantly reduced and malfunctioning GI microbiota, a condition called dysbiosis. Deranged composition and function of the gastrointestinal microbiota, occurring from the mouth to the anus, has been found to cause impaired ability to maintain intact mucosal membrane functions and prevent leakage of toxins - bacterial endotoxins, as well as whole bacteria or debris of bacteria, the DNA of which are commonly found in most cells of the body, often in adipocytes of obese individuals or in arteriosclerotic plaques. Foods rich in proteotoxins such as gluten, casein and zein, and proteins, have been observed to have endotoxin-like effects that can contribute to dysbiosis. About 75% of the food in the Western diet is of limited or no benefit to the microbiota in the lower gut. Most of it, comprised specifically of refined carbohydrates, is already absorbed in the upper part of the GI tract, and what eventually reaches the large intestine is of limited value, as it contains only small amounts of the minerals, vitamins and other nutrients necessary for maintenance of the microbiota. The consequence is that the microbiota of modern humans is greatly reduced, both in terms of numbers and diversity when compared to the diets of our paleolithic forebears and the individuals living a rural lifestyle today. It is the artificial treatment provided in modern medical care - unfortunately often the only alternative provided - which constitute the main contributors to a poor outcome. These treatments include artificial ventilation, artificial nutrition, hygienic measures, use of skin-penetrating devices, tubes and catheters, frequent use of pharmaceuticals; they are all known to severely impair the microbiomes in various locations of the body, which, to a large extent, are ultimately responsible for a poor outcome. Attempts to reconstitute a normal microbiome by supply of probiotics have often failed as they are almost always undertaken as a complement to - and not as an alternative to - existing treatment schemes, especially those based on antibiotics, but also other pharmaceuticals. PMID- 23344255 TI - Dystrophin deficiency leads to disturbance of LAMP1-vesicle-associated protein secretion. AB - Duchenne muscular dystrophy results from loss of the protein dystrophin, which links the intracellular cytoskeletal network with the extracellular matrix, but deficiency in this function does not fully explain the onset or progression of the disease. While some intracellular events involved in the degeneration of dystrophin-deficient muscle fibers have been well characterized, changes in their secretory profile are undescribed. To analyze the secretome profile of mdx myotubes independently of myonecrosis, we labeled the proteins of mdx and wild type myotubes with stable isotope-labeled amino acids (SILAC), finding marked enrichment of vesicular markers in the mdx secretome. These included the lysosomal-associated membrane protein, LAMP1, that co-localized in vesicles with an over-secreted cytoskeletal protein, myosin light chain 1. These LAMP1/MLC1-3 positive vesicles accumulated in the cytosol of mdx myotubes and were secreted into the culture medium in a range of abnormal densities. Restitution of dystrophin expression, by exon skipping, to some 30 % of the control value, partially normalized the secretome profile and the excess LAMP1 accumulation. Together, our results suggest that a lack of dystrophin leads to a general dysregulation of vesicle trafficking. We hypothesize that disturbance of the export of proteins through vesicles occurs before, and then concurrently with, the myonecrotic cascade and contributes chronically to the pathophysiology of DMD, thereby presenting us with a range of new potential therapeutic targets. PMID- 23344256 TI - GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis. AB - High-grade gliomas are the most common primary brain tumors. Their malignancy is promoted by the complex crosstalk between different cell types in the central nervous system. Microglia/brain macrophages infiltrate high-grade gliomas and contribute to their progression. To identify factors that mediate the attraction of microglia/macrophages to malignant brain tumors, we established a glioma cell encapsulation model that was applied in vivo. Mouse GL261 glioma cell line and human high-grade glioma cells were seeded into hollow fibers (HF) that allow the passage of soluble molecules but not cells. The glioma cell containing HF were implanted into one brain hemisphere and simultaneously HF with non-transformed fibroblasts (controls) were introduced into the contralateral hemisphere. Implanted mouse and human glioma- but not fibroblast-containing HF attracted microglia and up-regulated immunoreactivity for GFAP, which is a marker of astrogliosis. In this study, we identified GDNF as an important factor for microglial attraction: (1) GL261 and human glioma cells secret GDNF, (2) reduced GDNF production by siRNA in GL261 in mouse glioma cells diminished attraction of microglia, (3) over-expression of GDNF in fibroblasts promoted microglia attraction in our HF assay. In vitro migration assays also showed that GDNF is a strong chemoattractant for microglia. While GDNF release from human or mouse glioma had a profound effect on microglial attraction, the glioma-induced astrogliosis was not affected. Finally, we could show that injection of GL261 mouse glioma cells with GDNF knockdown by shRNA into mouse brains resulted in reduced tumor expansion and improved survival as compared to injection of control cells. PMID- 23344257 TI - Monitoring time interval for pQCT-derived bone outcomes in postmenopausal women. AB - Evidence of measurement precision, annual changes and monitoring time interval is essential when designing and interpreting longitudinal studies. Despite the precise measures, small annual changes in bone properties led to monitoring time intervals (MTIs) of 2-6 years in peripheral quantitative computed tomography (pQCT)-derived radial and tibial bone area, density, and estimated strength in postmenopausal women. INTRODUCTION: The purpose of the study was to determine the precision error, annual change, and MTI in bone density, area, and strength parameters in postmenopausal women. METHODS: Postmenopausal women (n = 114) from the Saskatoon cohort of the Canadian Multicentre Osteoporosis Study had annual pQCT scans of the distal and shaft sites of the radius and tibia for 2 years. Median annualized rates of percent change and the MTI were calculated for bone density, area, and strength parameters. Root mean squared coefficients of variation (CV%) were calculated from duplicate scans in a random subgroup of 35 postmenopausal women. RESULTS: CV% ranged from 1.4 to 6.1 % at the radius and 0.7 to 2.1 % at the tibia. MTIs for the distal radius were 3 years for total bone density (ToD) and 4 years for total bone cross sectional area (ToA), trabecular area, and bone strength index. At the diaphyseal radius, MTI was 3 years for ToA, 5 years for cortical density, and 6 years for polar stress strain index (SSIp). Similarly, MTI for total and trabecular density was 3 years at the distal tibia. At the diaphyseal tibia, MTI for ToA was 3 years and SSIp 4 years. CONCLUSION: MTI for longitudinal studies in older postmenopausal women should be at least 2-6 years at the radius and tibia, with specific monitoring of the total and trabecular area, total density, and bone strength at the radius and total and trabecular density, total area, and bone strength at the tibia. PMID- 23344258 TI - The discriminatory capacity of BMD measurements by DXA and dual X-ray and laser (DXL) at the calcaneus including clinical risk factors for detecting patients with vertebral fractures. AB - Osteoporotic fracture risk depends on bone mineral density (BMD) and clinical risk factors (CRF). Five hundred and eighty-eight untreated female and male outpatient subjects were evaluated, 160 with vertebral fractures. BMD was measured both by using calcaneal dual X-ray and laser (DXL) and dual-energy X-ray absorptiometry (DXA), and CRF were evaluated. Detection frequencies for different BMD methods with or without CRF are presented. INTRODUCTION: Osteoporotic fracture risk depends on bone mineral density and clinical risk factors. DXA of the spine/hip is considered a gold standard for BMD assessment, but due to degenerative conditions, particularly among the older population, assessment of BMD at the lumbar spine has been shown to be of limited significance. Portable calcaneal dual X-ray technology and laser can be an easily obtainable alternative. METHODS: Vertebral fractures were evaluated in a baseline analysis of 588 females and males (median age 64.4, range 17.6-93.1 years), comparing BMD measurements by using DXL and DXA and CRF with/without BMD. One hundred and sixty subjects had radiological verified vertebral fractures. Area under receiver operating characteristic curves (AUROCC) and univariate and multiple logistic regressions were calculated. RESULTS: AUROCC for detection of vertebral fractures was comparable for DXL at calcaneus and DXA at femoral neck (DXL 0.665 and DXA 0.670). Odds ratio for prevalent vertebral fracture was generally weak for DXA femoral neck (0.613) and DXL (0.521). Univariate logistic regression among CRF without BMD revealed age, prevalent fragility fracture, and body mass index significantly associated with prevalent vertebral fracture (AUROCC = 0.805). Combining BMD and CRF, a prognostic improvement in case of DXA at femoral neck (AUROCC 0.869, p = 0.02), DXL at calcaneus (AUROCC 0.869, p = 0.059), and DXA at total hip (AUROCC 0.861, p = 0.06) was observed. CONCLUSIONS: DXL was similarly sensitive compared with DXA for identification of subjects with vertebral fragility fractures, and combination of CRF with BMD by DXL or DXA further increased the discriminatory capacity for detection of patients susceptible to vertebral fracture. PMID- 23344259 TI - Adrenal gland abnormality detection using random forest classification. AB - Adrenal abnormalities are commonly identified on computed tomography (CT) and are seen in at least 5 % of CT examinations of the thorax and abdomen. Previous studies have suggested that evaluation of Hounsfield units within a region of interest or a histogram analysis of a region of interest can be used to determine the likelihood that an adrenal gland is abnormal. However, the selection of a region of interest can be arbitrary and operator dependent. We hypothesize that segmenting the entire adrenal gland automatically without any human intervention and then performing a histogram analysis can accurately detect adrenal abnormality. We use the random forest classification framework to automatically perform a pixel-wise classification of an entire CT volume (abdomen and pelvis) into three classes namely right adrenal, left adrenal, and background. Once we obtain this classification, we perform histogram analysis to detect adrenal abnormality. The combination of these methods resulted in a sensitivity and specificity of 80 and 90 %, respectively, when analyzing 20 adrenal glands seen on volumetric CT datasets for abnormality. PMID- 23344260 TI - Using the Microsoft Kinect for patient size estimation and radiation dose normalization: proof of concept and initial validation. AB - Monitoring patients' imaging-related radiation is currently a hot topic, but there are many obstacles to accurate, patient-specific dose estimation. While some, such as easier access to dose data and parameters, have been overcome, the challenge remains as to how accurately these dose estimates reflect the actual dose received by the patient. The main parameter that is often not considered is patient size. There are many surrogates-weight, body mass index, effective diameter-but none of these truly reflect the three-dimensional "size" of an individual. In this work, we present and evaluate a novel approach to estimating patient volume using the Microsoft KinectTM, a combination RGB camera-infrared depth sensor device. The goal of using this device is to generate a three dimensional estimate of patient size, in order to more effectively model the dimensions of the anatomy of interest and not only enable better normalization of dose estimates but also promote more patient-specific protocoling of future CT examinations. Preliminary testing and validation of this system reveals good correlation when individuals are standing upright with their arms by their sides, but demonstrates some variation with arm position. Further evaluation and testing is necessary with multiple patient positions and in both adult and pediatric patients. Correlation with other patient size metrics will also be helpful, as the ideal measure of patient "size" may in fact be a combination of existing metrics and newly developed techniques. PMID- 23344262 TI - Changing the way we do business: recommendations to accelerate biomarker development in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma is the most aggressive of all epithelial malignancies. In contrast to the favorable trends seen in most other common malignancies, the five-year survival of patients with this disease remains only 6%, a statistic that has changed minimally for decades. Only two drugs have been approved by the U.S. Food and Drug Administration (FDA) for use in pancreatic cancer in the last 15 years, and there are no established strategies for early detection. PMID- 23344261 TI - Identification of FGFR4 as a potential therapeutic target for advanced-stage, high-grade serous ovarian cancer. AB - PURPOSE: To evaluate the prognostic value of fibroblast growth factor receptor 4 (FGFR4) protein expression in patients with advanced-stage, high-grade serous ovarian cancer, delineate the functional role of FGFR4 in ovarian cancer progression, and evaluate the feasibility of targeting FGFR4 in serous ovarian cancer treatment. EXPERIMENTAL DESIGN: Immunolocalization of FGFR4 was conducted on 183 ovarian tumor samples. The collected FGFR4 expression data were correlated with overall survival using Kaplan-Meier and Cox regression analyses. The effects of FGFR4 silencing on ovarian cancer cell growth, survival, invasiveness, apoptosis, and FGF1-mediated signaling pathway activation were evaluated by transfecting cells with FGFR4-specific siRNAs. An orthotopic mouse model was used to evaluate the effect of injection of FGFR4-specific siRNAs and FGFR4 trap protein encapsulated in nanoliposomes on ovarian tumor growth in vivo. RESULTS: Overexpression of FGFR4 protein was significantly associated with decreased overall survival durations. FGFR4 silencing significantly decreased the proliferation, survival, and invasiveness and increased apoptosis of ovarian cancer cells. Also, downregulation of FGFR4 significantly abrogated the mitogen activated protein kinase (MAPK), nuclear factor-kappaB (NF-kappaB), and WNT signaling pathways, which are activated by FGF1. Targeting FGFR4 with the FGFR4 specific siRNAs and FGFR4 trap protein significantly decreased ovarian tumor growth in vivo. CONCLUSIONS: FGFR4 is a prognostic marker for advanced-stage, high-grade serous ovarian carcinoma. Silencing FGFR4 and inhibiting ligand receptor binding significantly decrease ovarian tumor growth both in vitro and in vivo, suggesting that targeting ovarian cancer cells with high levels of FGFR4 protein expression is a new therapeutic modality for this disease and will improve survival of it. PMID- 23344263 TI - Caspase-independent cell death is involved in the negative effect of EGF receptor inhibitors on cisplatin in non-small cell lung cancer cells. AB - PURPOSE: Results of multiple clinical trials suggest that EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) exhibit negative effects on platinum-based chemotherapy in patients with lung cancer with wild-type (WT) EGFR, but the underlying molecular mechanisms are still uncertain. Studies that identify the mechanism of how TKIs negatively affect patients with WT EGFR are important for future development of effective strategies to target lung cancer. Thus, we returned to in vitro study to investigate and determine a possible explanation for this phenomenon. EXPERIMENTAL DESIGN: We investigated the effects of TKIs and cisplatin on caspase-independent cell death (CID) and the role of CID in the efficacy of each drug and the combination. Furthermore, we studied the mechanism by which EGFR signaling pathway is involved in CID. Finally, on the basis of the identified mechanism, we tested the combinational effects of cisplatin plus suberoylanilide hydroxamic acid (SAHA) or erastin on CID. RESULTS: We found that gefitinib inhibited cisplatin-induced CID but not caspase-dependent apoptotic cell death. In WT EGFR cells, gefitinib not only inhibited CID but also failed to induce apoptosis, therefore compromising the efficacy of cisplatin. Inhibition of EGFR-ERK/AKT by gefitinib activates FOXO3a, which in turn reduces reactive oxygen species (ROS) and ROS-mediated CID. To overcome this, we showed that SAHA and erastin, the inducers of ROS-mediated CID, strongly enhanced the effect of cisplatin in WT EGFR cells. CONCLUSION: TKI-mediated inhibition of CID plays an important role in the efficacy of chemotherapy. Moreover, FOXO3a is a key factor in the negative effects of TKI by eliminating cisplatin-induced ROS. PMID- 23344264 TI - DNA-Mutation Inventory to Refine and Enhance Cancer Treatment (DIRECT): a catalog of clinically relevant cancer mutations to enable genome-directed anticancer therapy. AB - PURPOSE: Tumor gene mutation status is becoming increasingly important in the treatment of patients with cancer. A comprehensive catalog of tumor gene-response outcomes from individual patients is needed, especially for actionable mutations and rare variants. We created a proof-of-principle database [DNA-mutation Inventory to Refine and Enhance Cancer Treatment (DIRECT)], starting with lung cancer-associated EGF receptor (EGFR) mutations, to provide a resource for clinicians to prioritize treatment decisions based on a patient's tumor mutations at the point of care. METHODS: A systematic search of literature published between June 2005 and May 2011 was conducted through PubMed to identify patient level, mutation-drug response in patients with non-small cell lung cancer (NSCLC) with EGFR mutant tumors. Minimum inclusion criteria included patient's EGFR mutation, corresponding treatment, and an associated radiographic outcome. RESULTS: A total of 1,021 patients with 1,070 separate EGFR tyrosine kinase inhibitor therapy responses from 116 different publications were included. About 188 unique EGFR mutations occurring in 207 different combinations were identified: 149 different mutation combinations were associated with disease control and 42 were associated with disease progression. Four secondary mutations, in 16 different combinations, were associated with acquired resistance. CONCLUSIONS: As tumor sequencing becomes more common in oncology, this comprehensive electronic catalog can enable genome-directed anticancer therapy. DIRECT will eventually encompass all tumor mutations associated with clinical outcomes on targeted therapies. Users can make specific queries at http://www.mycancergenome.org/about/direct to obtain clinically relevant data associated with various mutations. PMID- 23344266 TI - Review of drug interactions with telaprevir and antiretrovirals. AB - HCV infection is a major cause of mortality worldwide. HCV-related deaths also represent a leading cause of mortality in HIV-coinfected individuals. Telaprevir is an NS3/4A protease inhibitor approved for the treatment of chronic HCV genotype 1 infection in adults in combination with pegylated interferon and ribavirin. Telaprevir-based treatment has been shown to increase rates of sustained viral response in HCV genotype-1-monoinfected patients, and studies in HCV-HIV-coinfected patients are ongoing. Drug-drug interactions of telaprevir with antiretroviral drugs were investigated in a series of studies in healthy subjects. This review summarizes the results of interaction studies with low-dose ritonavir, ritonavir-boosted HIV protease inhibitors (atazanavir, darunavir, fosamprenavir and lopinavir), efavirenz, etravirine, rilpivirine, tenofovir disoproxil fumarate and raltegravir. PMID- 23344265 TI - B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. AB - PURPOSE: Multiple myeloma is a usually incurable malignancy of plasma cells. New therapies are urgently needed for multiple myeloma. Adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a promising new therapy for hematologic malignancies, but an ideal target antigen for CAR-expressing T-cell therapies for multiple myeloma has not been identified. B-cell maturation antigen (BCMA) is a protein that has been reported to be selectively expressed by B lineage cells including multiple myeloma cells. Our goal was to determine if BCMA is a suitable target for CAR-expressing T cells. EXPERIMENTAL DESIGN: We conducted an assessment of BCMA expression in normal human tissues and multiple myeloma cells by flow cytometry, quantitative PCR, and immunohistochemistry. We designed and tested novel anti-BCMA CARs. RESULTS: BCMA had a restricted RNA expression pattern. Except for expression in plasma cells, BCMA protein was not detected in normal human tissues. BCMA was not detected on primary human CD34(+) hematopoietic cells. We detected uniform BCMA cell-surface expression on primary multiple myeloma cells from five of five patients. We designed the first anti BCMA CARs to be reported and we transduced T cells with lentiviral vectors encoding these CARs. The CARs gave T cells the ability to specifically recognize BCMA. The anti-BCMA-CAR-transduced T cells exhibited BCMA-specific functions including cytokine production, proliferation, cytotoxicity, and in vivo tumor eradication. Importantly, anti-BCMA-CAR-transduced T cells recognized and killed primary multiple myeloma cells. CONCLUSIONS: BCMA is a suitable target for CAR expressing T cells, and adoptive transfer of anti-BCMA-CAR-expressing T cells is a promising new strategy for treating multiple myeloma. PMID- 23344268 TI - Magnesium sulfate, cerebral palsy prevention, and medical protocols. PMID- 23344269 TI - "Do ask, do provide" contraception for women in the u.s. Military. PMID- 23344270 TI - Payment reform: why is it happening and what will it mean for you? PMID- 23344272 TI - Unintended pregnancy among active-duty women in the United States military, 2008. AB - OBJECTIVE: To estimate unintended pregnancy rates among a representative sample of 7,225 active-duty women in the U.S. military in 2008 and to compare these rates with 2005 and with the U.S. population. METHODS: Cross-sectional data came from the 2008 Department of Defense Survey of Health Related Behaviors among Active Duty Military Personnel (Health Related Behaviors Survey). For all women and by key subgroups, unintended pregnancy rates per 1,000 women were calculated and compared with rates reported in the 2005 Health Related Behaviors Survey. Univariable and multivariable logistic regression to test for associations between unintended pregnancy and key subgroups was also performed. Finally, an age-standardized unintended pregnancy rate was calculated to adjust for differences in age composition between the military and U.S. populations for better comparison with the general U.S. rate. RESULTS: Eleven percent of women reported an unintended pregnancy in the prior 12 months. The 2008 self-reported unintended pregnancy rate was 105 per 1,000 women, an increase from 2005 (97/1,000 women). Younger, less educated, nonwhite, and married or cohabitating women had significantly higher rates of unintended pregnancy compared with their counterparts. Rates did not differ between women deployed in the prior 12 months and nondeployed women. The age-standardized rate was 78 per 1,000 women (95% confidence interval 77-79), which is 50% higher than the general U.S. population (52/1,000 women). CONCLUSION: Unintended pregnancy rates in the military are high and have increased in most key subgroups since the 2005 survey. Efforts are needed to help servicewomen prevent unintended pregnancy, including during deployment. LEVEL OF EVIDENCE: II. PMID- 23344271 TI - Evaluation of the clinical use of magnesium sulfate for cerebral palsy prevention. AB - OBJECTIVE: Clinical trials support the efficacy and safety of magnesium sulfate for cerebral palsy prevention. We evaluated the implementation of a clinical protocol for the use of magnesium for cerebral palsy prevention in our large women's hospital, focusing on uptake, indications, and safety. METHODS: We performed a review of selected gravidas with threatened or planned delivery before 32 weeks of gestation from October 2007 to February 2011. The primary study outcome was the change in the rate of predelivery administration of magnesium sulfate over this time period. RESULTS: Three hundred seventy-three patients were included. In 2007, before guideline implementation, 20% of eligible gravidas (95% confidence interval [CI] 9.1-35.6%) received magnesium before delivery compared with 93.9% (95% CI 79.8-99.3%) in the final 2 months of the study period (P<.001). Dosing did not vary significantly over the 4 study years: the median number of treatments was one, the total predelivery median dose ranged from 15 to 48 g, and the median duration of therapy ranged from 3 to 12 hours. After 3 years, magnesium administration was almost universal among patients diagnosed with preeclampsia, preterm labor, or preterm premature rupture of membranes (95.4%), whereas patients delivered preterm for fetal growth restriction were significantly less likely to receive predelivery magnesium (44%, P<.001). No maternal or perinatal magnesium-attributable morbidity was noted. Among patients eligible for the protocol who received magnesium, 84.2% delivered before 32 weeks of gestation. CONCLUSION: It is feasible to implement a magnesium sulfate cerebral palsy prevention protocol into clinical practice. LEVEL OF EVIDENCE: III. PMID- 23344273 TI - Immediate compared with delayed oxytocin after amniotomy labor induction in parous women: a randomized controlled trial. AB - OBJECTIVE: To compare immediate with delayed (4 hours) oxytocin infusion after amniotomy on vaginal delivery within 12 hours and patient satisfaction with the birth process. METHODS: Parous women with favorable cervixes after amniotomy for labor induction were randomized to immediate titrated oxytocin or placebo intravenous infusion in a double-blind noninferiority trial. After 4 hours, study infusions were stopped, the women were assessed, and open-label oxytocin was started if required. Maternal satisfaction with the birth process was assessed with a 10-point visual numerical rating scale (lower score, greater satisfaction). RESULTS: Vaginal delivery rates at 12 hours were 91 of 96 (94.8%) compared with 91 of 94 (96.8%) (relative risk 0.98, 95% confidence interval [CI] 0.92-1.04, P=.72), and maternal satisfaction on a visual numerical rating scale (median [interquartile range]) was 3 [3-4] compared with 3 [3-5], P=.36 for immediate compared with delayed arm, respectively). Cesarean delivery, maternal fever, postpartum hemorrhage, uterine hyperactivity, and adverse neonatal outcome rates were similar between arms. The immediate oxytocin arm had a shorter amniotomy-to-delivery interval of 5.3+/-3.1 compared with 6.9+/-2.9 hours (P<.001) and lower epidural analgesia rate of 2.9% compared with 9.9% (relative risk 0.3, 95% CI 0.1-1.0, P=.046), but fetal heart rate abnormalities on cardiotocogram were higher, 28.6% compared with 16.8% (relative risk 1.7 95% CI 1.0-2.9, P=.048). In the delayed arm, oxytocin infusion was avoided by 35.6%. CONCLUSIONS: Immediate or delayed oxytocin infusions are reasonable options after amniotomy for labor induction in parous women with favorable cervixes. The choice should take into account local resources and the woman's wish. CLINICAL TRIAL REGISTRATION: ISRCTN Register, http://isrctn.org, ISRCTN51476259. LEVEL OF EVIDENCE: I. PMID- 23344274 TI - Rate of change in cervical length in women with vaginal bleeding during pregnancy. AB - OBJECTIVE: To evaluate whether women with known risk factors for preterm birth will manifest different rates of cervical shortening preceding a spontaneous preterm birth. METHODS: We conducted a secondary analysis of data from the Maternal--Fetal Medicine Units Network Preterm Prediction Study. Known risk factors for preterm birth were recorded. Cervical lengths were measured between 22+0 weeks and 24+6 weeks, and again 4 weeks later. Cervical slope was defined as the change in cervical length between these visits divided by time (millimeters per week). Preterm birth was defined as preterm premature rupture of membranes or spontaneous preterm labor leading to delivery before 37 weeks of gestation. We analyzed the data for 2,584 women using logistic regression and tested for interaction between risk factors in the model to determine whether cervical shortening preceded preterm births in all variable groups. RESULTS: Cervical slope was not significantly associated with preterm birth (P=.9) in women with vaginal bleeding. Cervical slope was significantly associated with preterm birth in women without a history of vaginal bleeding (odds ratio 1.2, 95% confidence interval 1.1-1.4). CONCLUSIONS: Pregnancies without vaginal bleeding have a 20% increase in the risk of preterm birth for each additional millimeter per week increase in cervical slope. Pregnancies with vaginal bleeding are at risk for preterm birth but do not appear to undergo progressive cervical shortening. This suggests that women with vaginal bleeding undergo a different mechanism leading to preterm birth. LEVEL OF EVIDENCE: II. PMID- 23344275 TI - Effects of changes in prenatal aneuploidy screening policies in an integrated health care system. AB - OBJECTIVES: To estimate changes in rates of prenatal testing for aneuploidy over a 5-year period in a large integrated health care system. METHODS: Data from the Kaiser Permanente Northern California cytogenetics laboratory and Regional Prenatal Screening Program were used to estimate rates of prenatal aneuploidy screening and diagnostic testing in females of all ages during 2006-2010. We estimated the number of chromosome abnormalities detected and the proportion of abnormal cytogenetic results. Dichotomous variables were compared using chi tests. Rates of use and aneuploidy detection rates were compared for trend using a linear repeated-measures model. RESULTS: Annual deliveries decreased during this period, from 36,276 to 34,314, whereas births to women aged 35 years or older increased from 21.8% to 22.7% (P=.004). The rate of aneuploidy screening decreased minimally from 76.1% to 75.4% (P=.04). Among women 35 years or older, the rate of screening increased from 53.1% in 2006 to 63.7% in 2010 (P<.001), whereas the percentage having diagnostic testing decreased from 40.9% to 26.8% (P<.001). Among women younger than 35 years old, the rate of screening decreased from 82.5% in 2006 to 78.9% in 2010 and the rate of diagnostic testing decreased from 4.1% to 2.8% (P<.001). Abnormal diagnostic test results increased from 5.9% to 8.2% (P<.001); the number of chromosome abnormalities identified overall was 7.2 per 1,000 births in 2006 and 6.7 per 1,000 births in 2010 (P=.43). CONCLUSIONS: Offering comprehensive aneuploidy testing options to all pregnant women in an integrated health care system resulted in lower use and higher yield of diagnostic testing. LEVEL OF EVIDENCE: II. PMID- 23344276 TI - Incontinence outcomes in women undergoing primary and repeat midurethral sling procedures. AB - OBJECTIVE: To assess stress urinary incontinence (SUI) and other lower urinary tract symptom outcomes in women undergoing repeat midurethral sling procedures compared with those undergoing primary midurethral sling procedures. METHODS: Cure was defined as responses of "not at all" or "somewhat" to both questions of the SUI subscale of the Urogenital Distress Inventory-6; symptom effect was assessed using the Incontinence Impact Questionnaire-7. Multivariable models were created controlling for baseline Medical Epidemiologic and Social Aspects of Aging questionnaire urge score and Urogenital Distress Inventory-6 stress subscale score. RESULTS: One thousand three hundred sixteen patients had charts available for review: 135 of 1,316 (10.2%) had undergone prior midurethral sling procedures; 799 of 1,316 (61%) questionnaires were returned, with 92 from those having undergone prior midurethral sling procedures. Median follow-up time was 36.4 months with a range of 11.4-71.5 months. Cure rates were 71% (95% confidence interval [CI] 67.7-74.3%) in the primary midurethral sling group and 54% (95% CI 43.8-64.2%) in the repeat midurethral sling group (P<.001). Women undergoing repeat midurethral sling procedures experienced significantly greater improvement in symptom-specific quality of life (QOL) compared with those undergoing primary midurethral sling procedures (-28.87+/-37.6 compared with -18.42+/-32.73, P=.01). Multivariable analyses revealed that women in the repeat midurethral sling group had increased risk of SUI failure (odds ratio 1.7, 95% CI 1.1-2.8). CONCLUSION: Women undergoing repeat midurethral sling procedures had almost two times the odds of SUI treatment failure but greater improvement in symptom effect on QOL than did those undergoing a primary midurethral sling procedure. This information can help counsel patients regarding their expectations of repeat midurethral sling surgery for recurrent SUI . LEVEL OF EVIDENCE: II. PMID- 23344277 TI - Obliterative LeFort colpocleisis in a large group of elderly women. AB - OBJECTIVE: To report on anatomical and functional outcomes, patient satisfaction, and associated morbidity and mortality in patients undergoing LeFort colpocleisis. METHODS: This was a retrospective case series of LeFort colpocleisis performed from January 2000 to October 2011. Data obtained from a urogynecologic database included demographics, comorbidities, medications, and urinary and bowel symptoms. Prolapse was quantified using the pelvic organ prolapse quantification (POP-Q) examination. Operative characteristics were recorded. All patients underwent pelvic examination and POP-Q assessment at follow-up visits. Patients also were asked about urinary and bowel symptoms as well as overall satisfaction. All intraoperative and postoperative surgical complications were recorded. RESULTS: Three hundred twenty-five patients underwent LeFort colpocleisis. Fifteen patients were excluded from the analysis because of incomplete data. The mean age was 81.3+/-5.3 years. Comorbidities were common, with 74.1% of the patients having at least one concomitant medical condition. The procedure was performed under spinal anesthesia in 67%. Additional procedures at the time of colpocleisis included incontinence procedures (79%) and dilation and curettage (46%). Mean follow-up was 45 (range 2-392) weeks. Anatomical success rate was 98.1% and patients were highly satisfied, with 92.9% reported being "cured" or "greatly improved." Complication and mortality rates were 15.2% and 1.3%, respectively. CONCLUSION: Colpocleisis is an effective and low-risk procedure with high anatomical success rates and patient satisfaction. Associated morbidity and mortality related to the procedure are low. Colpocleisis remains an excellent surgical option for the elderly patient with advanced pelvic organ prolapse. LEVEL OF EVIDENCE: III. PMID- 23344278 TI - Preventing L5-S1 discitis associated with sacrocolpopexy. AB - OBJECTIVE: To further characterize the anatomy of the fifth lumbar to first sacral (L5-S1) disc space and to provide anatomic landmarks that can be used to predict the locations of the disc, sacral promontory, and surrounding structures during sacrocolpopexy. METHODS: The lumbosacral anatomy was examined in 25 female cadavers and 100 computed tomography (CT) studies. Measurements were obtained using the midpoint of the sacral promontory as a reference. Data were analyzed using Pearson chi, unpaired Student's t test, and analysis of covariance. RESULTS: The average height of the L5-S1 disc was 1.8+/-0.3 cm (range 1.3-2.8 cm) in cadavers and 1.4+/-0.4 cm (0.3-2.3) on CT (P<.001). The average angle of descent between the anterior surfaces of L5 and S1 was 60.5+/-9 degrees (39.5 80.5 degrees) in cadavers and 65.3+/-8 degrees (42.6-88.6 degrees) on CT (P=.016). The average shortest distance between the S1 foramina was 3.4+/-0.4 cm in cadavers and 3.0+/-0.4 cm on CT (P<.001). The average height of the first sacral vertebra (S1) was 3.0+/-0.2 cm in cadavers and 3.0+/-0.3 on CT (P=.269). CONCLUSION: In the supine position, the most prominent structure in the presacral space is the L5-S1 disc, which extends approximately 1.5 cm cephalad to the "true" sacral promontory. During sacrocolpopexy, awareness of a 60-degree average drop between the anterior surfaces of L5 and S1 vertebra should assist with intraoperative localization of the sacral promontory and avoidance of the L5-S1 disc. The first sacral nerve can be expected approximately 3 cm from the upper surface of the sacrum and 1.5 cm from the midline. LEVEL OF EVIDENCE: II. PMID- 23344279 TI - Contamination rates of three urine-sampling methods to assess bacteriuria in pregnant women. AB - OBJECTIVE: To estimate and compare contamination rates of three different urine sampling methods in pregnant women to assess bacteriuria. METHODS: In this cross sectional study, 113 pregnant women collected three different midstream urine samples consecutively: morning (first void); midstream (void without further instructions); and clean-catch sample (void after cleaning). The following end points were considered contaminants: epithelial cells, Gram-positive rods or mixed bacteria in the Gram stain, and mixed growth or skin flora in the urine culture. Intraindividual variability in contaminants was quantified with Fleiss Cohen's weighted kappa statistic. Differences between samples were assessed using generalized estimating equations. RESULTS: Mainly low numbers of Gram-positive rods were more likely to be present in Gram stains of midstream samples compared with clean-catch samples (77.7% compared with 66.7%, P=.022). Morning samples showed more mixed growth compared with midstream samples (6.2% compared with 0.9%, P=.050). No consistency in quantity of contaminants was found in midstream samples compared with morning and clean-catch samples. No differences were found between the other end points in all three urine samples (P>.05). The study could detect an odds ratios of 2.0 for differences in urine-sampling methods with 80% power and 5% significance for most end points. CONCLUSION: In pregnant women, the contamination rate of midstream samples is comparable with the contamination rates of morning and clean-catch samples. The quantity of contaminants varied among the three samples collected by one woman. These results show that more complex, unpractical, and time-consuming morning and clean-catch samples are not superior. Therefore, we recommend a midstream sample to assess bacteriuria in pregnant women. LEVEL OF EVIDENCE: II. PMID- 23344280 TI - Neonatal outcomes after gestational exposure to nitrofurantoin. AB - OBJECTIVE: To estimate whether first-trimester exposure to nitrofurantoin is associated with increased malformation rates and, secondarily, to estimate whether exposure to nitrofurantoin is associated with increased rates of negative pregnancy outcomes and perinatal complications. METHODS: We conducted a population-based cohort study using the Norwegian Prescription Database linked to data on all live births, stillbirths, and induced abortions after 12 weeks of gestation from The Medical Birth Registry of Norway. The study population consisted of 180,120 pregnancies in 2004-2008. The pregnancy outcomes of women who were dispensed nitrofurantoin during pregnancy were compared with the outcomes of women who were dispensed pivmecillinam (disease comparison group) and unexposed women. RESULTS: In all, 5,794 (3.2%) filled prescriptions for nitrofurantoin during pregnancy, 1,334 women (0.7%) in the first trimester and 979 women (0.5%) in the last 4 weeks of pregnancy. Dispensing nitrofurantoin during the first trimester was not associated with increased risk of major malformations (31 of 1,334 [2.3%]) compared with disease controls (162 of 5,800 [2.8%], odds ratio [OR] 0.79, 95% confidence interval [CI] 0.51-1.23). No increased risk for secondary adverse pregnancy outcomes was observed when compared with the disease comparison group. Dispensing nitrofurantoin the last 30 days before delivery was associated with increased risk of neonatal jaundice (103 of 959 [10.8%]) compared with unexposed women (10,336 of 127,507 [8.1%], OR 1.31, 95% CI 1.02-1.70). CONCLUSION: The results from this large, population-based study suggest that the teratogenic potential of nitrofurantoin is low. LEVEL OF EVIDENCE: II. PMID- 23344282 TI - Clinical significance of serum anti-human papillomavirus 16 and 18 antibodies in cervical neoplasia. AB - OBJECTIVE: To estimate the clinical significance of serum anti-human papillomavirus (HPV) antibodies and high-risk cervical HPV DNA in cervical neoplasia. METHODS: The study population comprised patients who were histopathologically diagnosed with cervical intraepithelial neoplasia (CIN) 1 (n=64), CIN 2 and 3 (n=241), cervical cancer (n=170), and normal control participants (n=975). Cervical HPV DNA tests were performed through nucleic acid hybridization assay tests, and serum anti-HPV 16 and 18 antibodies were measured by competitive immunoassay. The associations of HPV DNA and anti-HPV antibodies were evaluated with demographic characteristics and compared according to the levels of disease severity. Anti-HPV antibodies were also investigated with clinicopathologic parameters, including survival data. RESULTS: Among various demographic characteristics, factors involving sexual behavior had a higher tendency of HPV DNA positivity and HPV seropositivity. Human papillomavirus DNA mean titer and positivity were both increased in patients with cervical neoplasia compared with those with normal control participants, but there was no statistical difference among types of cervical neoplasia. Serum anti-HPV 16 antibodies were also able to differentiate cervical neoplasia from a normal control participant and furthermore distinguished CIN 1 from CIN 2 and 3 (odd ratio 2.87 [1.43-5.78], P=.002). In cervical cancer, HPV 16 seropositivity was associated with prolonged disease-free survival according to the univariable analysis (hazard ratio=0.12 [0.01-0.94], P=.044). CONCLUSION: Serum anti-HPV 16 antibodies can distinguish cervical neoplasia from a normal control and has the advantage of identifying high-grade CIN. Moreover, in cervical cancer, HPV 16 seropositivity may be associated with a more favorable prognosis. LEVEL OF EVIDENCE: II. PMID- 23344281 TI - Effect of maternal body mass index on serum magnesium levels given for seizure prophylaxis. AB - OBJECTIVE: To estimate the effect of body mass index (BMI) on magnesium levels for eclampsia prophylaxis. METHODS: This is a retrospective study from 2004 to 2011, examining magnesium levels in women receiving seizure prophylaxis. Women received 6 g and then 2 g/h. Women had 4-hour and 12-hour levels drawn. Levels were considered subtherapeutic at less than 4.9 mg/dL, therapeutic from 4.9 to 8.4 mg/dL, and supratherapeutic at 8.5 mg/dL or more. If the 4-hour value was not therapeutic, the dose was adjusted and a 12-hour level was drawn. Levels at 4 and 12 hours were compared among the women with different BMI classifications and clinical characteristics. RESULTS: During the study period,106,265 women delivered, and 7,799 (7.4%) had preeclampsia diagnosed and received magnesium sulfate for seizure prophylaxis. A total of 5,304 (68%) of these women had a recorded BMI. At 4 hours, 2,698 (51%) were subtherapeutic. These women were more likely to be older, parous, undergo cesarean delivery, have a higher systolic blood pressure, and have central nervous system manifestations. At 12 hours, 2,342 (90%) of therapeutic women remained therapeutic, and 5% became subtherapeutic (n=118) or supratherapeutic (n=140). Using logistic regression, we were able to predict being subtherapeutic in women with greater BMI and to predict being supratherapeutic if women had labor longer than 12 hours and worsening severity of preeclampsia. CONCLUSION: Women receiving seizure prophylaxis with a BMI of more than 30 may benefit from routine serum magnesium evaluation 4 hours after the loading dose. LEVEL OF EVIDENCE: III. PMID- 23344283 TI - Factors associated with 12-month discontinuation among contraceptive pill, patch, and ring users. AB - OBJECTIVE: To examine factors associated with discontinuation of the oral contraceptive pill (OCP), patch, and ring. METHODS: We included 1,452 female participants from the Contraceptive CHOICE Project who selected the OCP, patch, or ring and completed 12 months of follow-up for this analysis. We defined discontinuation as stopping the contraceptive method for longer than 1 month during a follow-up survey. Participants who stopped their method as a result of pregnancy or to attempt pregnancy or who were lost to follow-up were censored. We examined demographic, behavioral, and method-related factors in the Cox proportional hazard models. RESULTS: Patch users had a higher 1-year discontinuation rate (58%) than OCP (47%; P=.03) and ring users (49%; P=.02). Women were more likely to discontinue the OCP, patch, or ring if they were black (adjusted hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.02-1.44), no longer married (adjusted HR 1.83, 95% CI 1.27-2.65), or received public assistance (adjusted HR 1.30, 95% CI 1.08-1.57). Women who reported difficulty obtaining the method were more than twice as likely to discontinue (adjusted HR 2.43, 95% CI 1.81-3.27). Women who were certain they would continue despite side effects (adjusted HR 0.57, 95% CI 0.43-0.77) were less likely to discontinue. CONCLUSION: Despite selecting their method and obtaining it at no cost, almost half of OCP and ring users and a majority of patch users discontinued their method by 12 months. Experiencing difficulty obtaining the method contributes to high rates of discontinuation. LEVEL OF EVIDENCE: II. PMID- 23344284 TI - Platinum derivatives during pregnancy in cervical cancer: a systematic review and meta-analysis. AB - OBJECTIVE: Cervical cancer is the most common solid carcinoma diagnosed during pregnancy; obviously, pregnancy adds complexity to treatment recommendations. We synthesized all available data and evaluated the efficacy and safety of the administration of platinum derivatives during pregnancy in cervical cancer. DATA SOURCES: Eligible articles were identified by a search of MEDLINE and ClinicalTrials.gov databases for the period up to September 7, 2012; the algorithm comprised a predefined combination of the terms "cervical," "cancer," "cisplatin," carboplatin," and "pregnancy." METHODS OF STUDY SELECTION: Two investigators, working independently, searched the literature and extracted data from all studies that examined the efficacy and safety of platinum derivatives administered during pregnancy in cervical cancer. All cases in which therapeutic abortion was scheduled were excluded. Moreover, quantitative synthesis of the published articles was performed. TABULATION, INTEGRATION, AND RESULTS: Overall, 24 studies (48 pregnancies, 48 newborns [one twin pregnancy and one miscarriage]) were eligible. In relation to cisplatin, 47 pregnancies were identified, whereas regarding carboplatin administration, only one pregnancy was retrieved. Cisplatin was administered either as monotherapy or combined with bleomycin, 5 fluorouracil, paclitaxel, vincristine, and bleomycin, whereas carboplatin was given in combination with paclitaxel. In most cases (67.4%), a completely healthy neonate was born; all children were healthy with a median follow-up of 12.5 months. The mean delivery weight of newborns was 2,213 g. Complete and partial response was achieved in 10% and 63.4% of patients with cervical cancer, respectively, whereas stabilization and progression of the disease occurred in 23.3% and 3.3% of women in the case group. In the majority of women in the case group, chemotherapy was well tolerated. The median progression-free survival was 48.5 months. CONCLUSION: Cisplatin may play a significant role in the management of patients with cervical cancer during the second and third trimesters. PMID- 23344285 TI - Classification of diabetes in pregnancy: time to reassess the alphabet. AB - The White classification is a system of alphabetically designated categories of diabetes in pregnancy based on age at onset, duration of disease, and the presence or absence of vascular complications. The original classification system underwent several revisions, each progressively increasing in detail and complexity. Individual authors and institutions have modified the classes, resulting in identically lettered classes having different definitions. Some publications make reference to the class of diabetes by letter without providing a reference defining that class. Despite a 1994 American College of Obstetricians and Gynecologists Bulletin, which suggested that the White classification system was less helpful, publications still appear using lettered designations with and without modifications and with and without attendant definitions of terms. A clinically useful system of disease classification should consist of clearly defined, mutually exclusive, easily remembered categories. The current American Diabetes Association classification of diabetes fulfills these requirements and is applicable to diabetes during pregnancy. Adoption of such a system by the obstetrics community in verbal and written medical communication will likely enhance patient care and facilitate accurate data collection and comparison. PMID- 23344287 TI - Surgical treatment of vaginal apex prolapse. AB - Pelvic organ prolapse is a common problem in women that increases with age and adversely affects quality of life and sexual function. If conservative treatments fail, surgery becomes the main option for symptom abatement. For uterovaginal prolapse, treatment with or without hysterectomy can be offered, and operations must include a specific apical support procedure to be effective. Operations for apical prolapse include transvaginal, open, and laparoscopic or robotic options; few clinical trials have compared the effectiveness and risk of these various surgeries. Grafts can be used selectively for apical suspensions and may improve cure rates but also increase risk of some complications. Slings should be added selectively to reduce postoperative stress incontinence. For women interested in future sexual activity who require apical prolapse surgery, we suggest using transvaginal apical repairs for older patients, those with primary or less severe prolapse, and those at increased surgical risk. We recommend sacral colpopexy with polypropylene mesh (preferably by minimally invasive route) in younger women, those with more severe prolapse or recurrences after vaginal surgery, and women with prolapsed, short vaginas. In older women with severe prolapse who are not interested in sexual activity, obliterative operations are very effective and have high satisfaction rates. An interactive consent process is mandatory, because many decisions-about route of surgery; use of hysterectomy, slings, and grafts; and vaginal capacity for sexual intercourse-require an informed patient's input. Selective referral to specialists in Female Pelvic medicine and Reconstructive Surgery can be considered for complex and recurrent cases. PMID- 23344288 TI - What is new in placenta accreta?: best articles from the past year. AB - This month, we focus on current research in placenta accreta. Dr. Lorenz discusses five recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 23344286 TI - Pravastatin for the prevention of preeclampsia in high-risk pregnant women. AB - Preeclampsia complicates approximately 3-5% of pregnancies and remains one of the major causes of maternal and neonatal morbidity. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Attempts at prevention of preeclampsia using various supplements and classes of medications have failed or had limited success, and they were not convincing enough to lead to widespread adoption of any particular strategy. Contrary to the experience with preeclampsia, prevention of cardiovascular mortality and other cardiovascular events in nonpregnant patients using 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, or statins, is widely accepted. Pravastatin and other statins have been shown to reverse various pathophysiologic pathways associated with preeclampsia, such as angiogenic imbalance, endothelial injury, inflammation, and oxidative stress. These beneficial effects are likely to contribute substantially to preventing preeclampsia and provide biological plausibility for the use of pravastatin in this setting. Pravastatin has favorable safety and pharmacokinetic profiles. In addition, animal studies and human pregnancy exposure data do not support teratogenicity claims for pravastatin. Therefore, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network started a pilot trial to collect maternal--fetal safety data and to evaluate pravastatin pharmacokinetics when used as a prophylactic daily treatment in high risk pregnant women (identifier NCT01717586, clinicaltrials.gov). PMID- 23344289 TI - Pregnancy outcomes in women with and without gestational diabetes mellitus according to the international association of the diabetes and pregnancy study groups criteria. PMID- 23344290 TI - In reply: pregnancy outcomes in women. PMID- 23344291 TI - Practicing pelvic examinations by medical students on women under anesthesia: why not ask first? PMID- 23344292 TI - Chlorhexidine-alcohol compared with povidone-iodine for surgical-site antisepsis in cesarean deliveries. PMID- 23344293 TI - In reply: chlorhexidine-alcohol. PMID- 23344294 TI - Pelvic muscle strength after childbirth. PMID- 23344295 TI - In reply: pelvic muscle. PMID- 23344296 TI - Risk factors for developing endometrial cancer after benign endometrial sampling. PMID- 23344297 TI - Risk factors for developing endometrial cancer after benign endometrial sampling. PMID- 23344298 TI - In reply: risk factors for developing endometrial cancer. PMID- 23344299 TI - Peripartum cardiomyopathy: population-based birth prevalence and 7-year mortality. PMID- 23344300 TI - In reply: peripartum cardiomyopathy. PMID- 23344305 TI - ACOG Practice bulletin no. 133: benefits and risks of sterilization. AB - Female and male sterilization are both safe and effective methods of permanent contraception used by more than 220 million couples worldwide . Approximately 600,000 tubal occlusions and 200,000 vasectomies are performed in the United States annually . For women seeking permanent contraception, sterilization obviates the need for user-dependent contraception throughout their reproductive years and provides an excellent alternative for those with medical contraindications to reversible methods. The purpose of this document is to review the evidence for the safety and effectiveness of female sterilization in comparison with male sterilization and other forms of contraception. PMID- 23344306 TI - ACOG Committee opinion no. 553: multifetal pregnancy reduction. AB - Fertility treatments have contributed significantly to the increase in multifetal pregnancies. The first approach to the problem of multifetal pregnancies should be prevention, and strategies to limit multifetal pregnancies, especially high order multifetal pregnancies, should be practiced by all physicians who treat women for infertility. Incorporating the ethical frameworks presented in this Committee Opinion will help physicians counsel and guide patients when making decisions regarding multifetal pregnancy reduction. In cases of high-order multifetal pregnancies, counseling should include the availability of multifetal pregnancy reduction. Fellows should be knowledgeable about the medical risks of multifetal pregnancy, the possible medical benefits of multifetal pregnancy reduction, and the complex ethical issues inherent in decisions regarding the use of multifetal pregnancy reduction. Physicians should not be required to act in ways that conflict with their value systems but should be prepared to react in a professional and ethical manner to patient requests for both information and intervention. PMID- 23344307 TI - ACOG Committee opinion no. 554: reproductive and sexual coercion. AB - Reproductive and sexual coercion involves behavior intended to maintain power and control in a relationship related to reproductive health by someone who is, was, or wishes to be involved in an intimate or dating relationship with an adult or adolescent. This behavior includes explicit attempts to impregnate a partner against her will, control outcomes of a pregnancy, coerce a partner to have unprotected sex, and interfere with contraceptive methods. Obstetrician gynecologists are in a unique position to address reproductive and sexual coercion and provide screening and clinical interventions to improve health outcomes. Because of the known link between reproductive health and violence, health care providers should screen women and adolescent girls for intimate partner violence and reproductive and sexual coercion at periodic intervals such as annual examinations, new patient visits, and during obstetric care (at the first prenatal visit, at least once per trimester, and at the postpartum checkup). Interventions include education on the effect of reproductive and sexual coercion and intimate partner violence on patients' health and choices, counseling on harm-reduction strategies, and prevention of unintended pregnancies by offering long-acting methods of contraception that are less detectable to partners. PMID- 23344308 TI - Recognition and management of psychosis and schizophrenia in children and young people: summary of NICE guidance. PMID- 23344310 TI - Preparing for the next pandemic. PMID- 23344309 TI - Women's views on overdiagnosis in breast cancer screening: a qualitative study. AB - OBJECTIVE: To elicit women's responses to information about the nature and extent of overdiagnosis in mammography screening (detecting disease that would not present clinically during the woman's lifetime) and explore how awareness of overdiagnosis might influence attitudes and intentions about screening. DESIGN: Qualitative study using focus groups that included a presentation explaining overdiagnosis, incorporating different published estimates of its rate (1-10%, 30%, 50%) and information on the mortality benefit of screening, with guided group discussions SETTING: Sydney, Australia PARTICIPANTS: Fifty women aged 40-79 years with no personal history of breast cancer and with varying levels of education and participation in screening. RESULTS: Prior awareness of breast cancer overdiagnosis was minimal. Women generally reacted with surprise, but most came to understand the issue. Responses to overdiagnosis and the different estimates of its magnitude were diverse. The highest estimate (50%) made some women perceive a need for more careful personal decision making about screening. In contrast, the lower and intermediate estimates (1-10% and 30%) had limited impact on attitudes and intentions, with many women remaining committed to screening. For some women, the information raised concerns, not about whether to screen but whether to treat a screen detected cancer or consider alternative approaches (such as watchful waiting). Information preferences varied: many women considered it important to take overdiagnosis into account and make informed choices about whether to have screening, but many wanted to be encouraged to be screened. CONCLUSIONS: Women from a range of socioeconomic backgrounds could comprehend the issue of overdiagnosis in mammography screening, and they generally valued information about it. Effects on screening intentions may depend heavily on the rate of overdiagnosis. Overdiagnosis will be new and counterintuitive for many people and may influence screening and treatment decisions in unintended ways, underscoring the need for careful communication. PMID- 23344311 TI - Vaccination against H1N1 looks safer than influenza during pregnancy. PMID- 23344312 TI - Donor faeces for recurrent Clostridium difficile diarrhoea? PMID- 23344313 TI - ART sooner rather than later for adults with HIV. PMID- 23344314 TI - Harms from breast cancer screening outweigh benefits if death caused by treatment is included. PMID- 23344315 TI - Trials of mobile technologies fail to deliver. PMID- 23344316 TI - What are the rates of readmission in the US. PMID- 23344317 TI - Minister denies that screening and immunisation will be weakened under changes to NHS. PMID- 23344318 TI - Government sets up new service to tackle long term sickness absence. PMID- 23344320 TI - Breast cancer screening: what does the future hold? PMID- 23344321 TI - The Indonesian archipelago: an ancient genetic highway linking Asia and the Pacific. AB - Indonesia, an island nation linking mainland Asia with the Pacific world, hosts a wide range of linguistic, ethnic and genetic diversity. Despite the complexity of this cultural environment, genetic studies in Indonesia remain surprisingly sparse. Here, we report mitochondrial DNA (mtDNA) and associated Y-chromosome diversity for the largest cohort of Indonesians examined to date-2740 individuals from 70 communities spanning 12 islands across the breadth of the Indonesian archipelago. We reconstruct 50 000 years of population movements, from mitochondrial lineages reflecting the very earliest settlers in island southeast Asia, to Neolithic population dispersals. Historic contacts from Chinese, Indians, Arabs and Europeans comprise a noticeable fraction of Y-chromosome variation, but are not reflected in the maternally inherited mtDNA. While this historic immigration favored men, patterns of genetic diversity show that women moved more widely in earlier times. However, measures of population differentiation signal that Indonesian communities are trending away from the matri- or ambilocality of early Austronesian societies toward the more common practice of patrilocal residence today. Such sex-specific dispersal patterns remain even after correcting for the different mutation rates of mtDNA and the Y chromosome. This detailed palimpsest of Indonesian genetic diversity is a direct outcome of the region's complex history of immigration, transitory migrants and populations that have endured in situ since the region's first settlement. PMID- 23344322 TI - Association of lipoprotein lipase polymorphism rs2197089 with serum lipid concentrations and LPL gene expression. AB - Many single-nucleotide polymorphisms (SNPs) have been reported to be associated with lipid concentrations in recent genome-wide association studies. The aim of this study was to validate the associations of rs2197089 in the lipoprotein lipase (LPL) gene with serum lipid concentrations and gene expression levels in the Chinese Han population and examine the potential interactions. A total of 9339 participants were recruited and genotyped for rs2197089. Gene expression levels of LPL in blood cells of 309 participants were evaluated by real-time PCR. We observed significant associations between rs2197089 and decreased triglycerides (TG) (P=0.0006), but not high-density lipoprotein cholesterol (HDL C) concentration (P=0.0881). However, weak evidence of interaction between cigarette smoking and rs2197089 was detected (P=0.0362). In smokers, significant association between rs2197089 and increased HDL-C concentration was found (P=0.0068). Participants with the minor allele A had higher expression levels of LPL (P=0.0243). The results of our study indicated that rs2197089 was significantly associated with TG but it was associated with HDL-C only in smokers. This SNP seemed to have influence on the expression level of LPL. PMID- 23344323 TI - Ensuring health in universal health coverage. PMID- 23344334 TI - Greenland defied ancient warming. PMID- 23344335 TI - Work resumes on lethal flu strains. PMID- 23344336 TI - Researchers debate oil-spill remedy. PMID- 23344337 TI - International aid projects come under the microscope. PMID- 23344338 TI - Fresh bid to see exo-Earths. PMID- 23344339 TI - Japan's stimulus package showers science with cash. PMID- 23344341 TI - Social evolution: The ritual animal. PMID- 23344340 TI - Mapping brain networks: Fish-bowl neuroscience. PMID- 23344342 TI - Computing: A vision for data science. PMID- 23344343 TI - Energy policy: The rebound effect is overplayed. PMID- 23344347 TI - Graphics: Chance thrown by inaccurate dice. PMID- 23344348 TI - Grant applications: Undo NIH policy to ease effect of cuts. PMID- 23344349 TI - Public opinion: Science petitions are a facade of numbers. PMID- 23344350 TI - Obesity: Appetite hormone weighs in. PMID- 23344351 TI - Obesity: Multiple factors contribute. PMID- 23344352 TI - Natural history: Small collections make a big impact. PMID- 23344353 TI - Neuroscience: Strength in numbers. PMID- 23344355 TI - Solar physics: Towards ever smaller length scales. PMID- 23344356 TI - Palaeontology: Gritting their teeth. PMID- 23344357 TI - Cancer: The to and fro of tumour spread. PMID- 23344359 TI - Energy release in the solar corona from spatially resolved magnetic braids. AB - It is now apparent that there are at least two heating mechanisms in the Sun's outer atmosphere, or corona. Wave heating may be the prevalent mechanism in quiet solar periods and may contribute to heating the corona to 1,500,000 K (refs 1-3). The active corona needs additional heating to reach 2,000,000-4,000,000 K; this heat has been theoretically proposed to come from the reconnection and unravelling of magnetic 'braids'. Evidence favouring that process has been inferred, but has not been generally accepted because observations are sparse and, in general, the braided magnetic strands that are thought to have an angular width of about 0.2 arc seconds have not been resolved. Fine-scale braiding has been seen in the chromosphere but not, until now, in the corona. Here we report observations, at a resolution of 0.2 arc seconds, of magnetic braids in a coronal active region that are reconnecting, relaxing and dissipating sufficient energy to heat the structures to about 4,000,000 K. Although our 5-minute observations cannot unambiguously identify the field reconnection and subsequent relaxation as the dominant heating mechanism throughout active regions, the energy available from the observed field relaxation in our example is ample for the observed heating. PMID- 23344360 TI - Laser cooling of a semiconductor by 40 kelvin. AB - Optical irradiation accompanied by spontaneous anti-Stokes emission can lead to cooling of matter, in a phenomenon known as laser cooling, or optical refrigeration, which was proposed by Pringsheim in 1929. In gaseous matter, an extremely low temperature can be obtained in diluted atomic gases by Doppler cooling, and laser cooling of ultradense gas has been demonstrated by collisional redistribution of radiation. In solid-state materials, laser cooling is achieved by the annihilation of phonons, which are quanta of lattice vibrations, during anti-Stokes luminescence. Since the first experimental demonstration in glasses doped with rare-earth metals, considerable progress has been made, particularly in ytterbium-doped glasses or crystals: recently a record was set of cooling to about 110 kelvin from the ambient temperature, surpassing the thermoelectric Peltier cooler. It would be interesting to realize laser cooling in semiconductors, in which excitonic resonances dominate, rather than in systems doped with rare-earth metals, where atomic resonances dominate. However, so far no net cooling in semiconductors has been achieved despite much experimental and theoretical work, mainly on group-III-V gallium arsenide quantum wells. Here we report a net cooling by about 40 kelvin in a semiconductor using group-II-VI cadmium sulphide nanoribbons, or nanobelts, starting from 290 kelvin. We use a pump laser with a wavelength of 514 nanometres, and obtain an estimated cooling efficiency of about 1.3 per cent and an estimated cooling power of 180 microwatts. At 100 kelvin, 532-nm pumping leads to a net cooling of about 15 kelvin with a cooling efficiency of about 2.0 per cent. We attribute the net laser cooling in cadmium sulphide nanobelts to strong coupling between excitons and longitudinal optical phonons (LOPs), which allows the resonant annihilation of multiple LOPs in luminescence up-conversion processes, high external quantum efficiency and negligible background absorption. Our findings suggest that, alternatively, group-II-VI semiconductors with strong exciton-LOP coupling could be harnessed to achieve laser cooling and open the way to optical refrigeration based on semiconductors. PMID- 23344361 TI - Interface-engineered templates for molecular spin memory devices. AB - The use of molecular spin state as a quantum of information for storage, sensing and computing has generated considerable interest in the context of next generation data storage and communication devices, opening avenues for developing multifunctional molecular spintronics. Such ideas have been researched extensively, using single-molecule magnets and molecules with a metal ion or nitrogen vacancy as localized spin-carrying centres for storage and for realizing logic operations. However, the electronic coupling between the spin centres of these molecules is rather weak, which makes construction of quantum memory registers a challenging task. In this regard, delocalized carbon-based radical species with unpaired spin, such as phenalenyl, have shown promise. These phenalenyl moieties, which can be regarded as graphene fragments, are formed by the fusion of three benzene rings and belong to the class of open-shell systems. The spin structure of these molecules responds to external stimuli (such as light, and electric and magnetic fields), which provides novel schemes for performing spin memory and logic operations. Here we construct a molecular device using such molecules as templates to engineer interfacial spin transfer resulting from hybridization and magnetic exchange interaction with the surface of a ferromagnet; the device shows an unexpected interfacial magnetoresistance of more than 20 per cent near room temperature. Moreover, we successfully demonstrate the formation of a nanoscale magnetic molecule with a well-defined magnetic hysteresis on ferromagnetic surfaces. Owing to strong magnetic coupling with the ferromagnet, such independent switching of an adsorbed magnetic molecule has been unsuccessful with single-molecule magnets. Our findings suggest the use of chemically amenable phenalenyl-based molecules as a viable and scalable platform for building molecular-scale quantum spin memory and processors for technological development. PMID- 23344358 TI - Eemian interglacial reconstructed from a Greenland folded ice core. AB - Efforts to extract a Greenland ice core with a complete record of the Eemian interglacial (130,000 to 115,000 years ago) have until now been unsuccessful. The response of the Greenland ice sheet to the warmer-than-present climate of the Eemian has thus remained unclear. Here we present the new North Greenland Eemian Ice Drilling ('NEEM') ice core and show only a modest ice-sheet response to the strong warming in the early Eemian. We reconstructed the Eemian record from folded ice using globally homogeneous parameters known from dated Greenland and Antarctic ice-core records. On the basis of water stable isotopes, NEEM surface temperatures after the onset of the Eemian (126,000 years ago) peaked at 8 +/- 4 degrees Celsius above the mean of the past millennium, followed by a gradual cooling that was probably driven by the decreasing summer insolation. Between 128,000 and 122,000 years ago, the thickness of the northwest Greenland ice sheet decreased by 400 +/- 250 metres, reaching surface elevations 122,000 years ago of 130 +/- 300 metres lower than the present. Extensive surface melt occurred at the NEEM site during the Eemian, a phenomenon witnessed when melt layers formed again at NEEM during the exceptional heat of July 2012. With additional warming, surface melt might become more common in the future. PMID- 23344363 TI - Synthesis and biological evaluation of radioiodinated quinacrine-based derivatives for SPECT imaging of Abeta plaques. AB - The aim of the present study was to characterize the binding property of quinacrine-based acridine derivatives for Abeta plaques and to evaluate this series of compounds as Abeta imaging probes. Quinacrine clearly stained Abeta plaques in the brain sections of Abeta deposition model transgenic mice (Tg2576 mice). Similarly, the quinacrine analog, 2-methoxy-9-(4-(dimethyl-1-methyl) -N butyl) amino-6-iodo acridine (5), labeled Abeta plaques in the brain slices of Tg2576 mice. In addition, [(125)I]5 showed modest affinity for Abeta(1-42) aggregates with a K(d) value of 48 nM. Biodistribution studies using normal mice demonstrated that [(125)I]5 displayed poor initial brain uptake. Next, (125)I labeled acridines without aliphatic amino groups were synthesized and characterized. Similar to quinacrine and 5, these compounds could detect Abeta plaques in the brain sections of Tg2576 mice. It should be noted that the acridines showed much higher binding affinity for Abeta aggregates and greater in vivo blood brain barrier permeability than [(125)I]5. Among them, 13 (6-Iodo-2 methoxy-9-methylaminoacridine) and 25 (2,9-Dimethoxy-6-iodo acridine) exhibited high affinity for the Abeta aggregates with K(i) values of 14 and 29 nM, respectively. In the in vivo studies, [(125)I]13 and [(125)I]25 showed excellent initial brain uptake (3.0 and 4.4% dose/g, respectively, at 2 min) with fast washout from the brain (0.33 and 0.37% dose/g, respectively, at 60 min). These acridine derivatives are demonstrated to be promising SPECT imaging probes for amyloid in the living brain. PMID- 23344364 TI - Cysteine proteases: mode of action and role in epidermal differentiation. AB - Desquamation or cell shedding in mammalian skin is known to involve serine proteases, aspartic proteases and glycosidases. In addition, evidence continues to accumulate that papain-like cysteine proteases and an inhibitor cystatin M/E largely confined to the cutaneous epithelia also play key roles in the process. This involves the complete proteolysis of cell adhesive structures of the stratum corneum, the corneodesmosomes and notably of the desmogleins. Continual cell replacement in the epidermis is the result of the balance between the loss of the outer squames and mitosis of the cells in the basal cell layer. This article provides a brief account of the salient features of the characteristics and catalytic mechanism of cysteine proteases, followed by a discussion of the relevant epidermal biology. The proteases include the asparaginyl endopeptidase legumain, which exerts a strict specificity for the hydrolysis of asparaginyl bonds, cathepsin-V and cathepsin-L. The control of these enzymes by cystatin M/E regulates the processing of transglutaminases and is crucial in the biochemical pathway responsible for regulating the cross-linking and desquamation of the stratum corneum. In addition, caspase-14 has now been shown to play a major part in epidermal maturation. Uncontrolled proteolytic activity leads to abnormal hair follicle formation and deleterious effects on the skin barrier function. PMID- 23344365 TI - Netherton syndrome: skin inflammation and allergy by loss of protease inhibition. AB - Netherton syndrome (NS) is a rare autosomal recessive skin disease with severe skin inflammation and scaling, a specific hair shaft defect and constant allergic manifestations. NS is caused by loss-of-function mutations in SPINK5 (serine protease inhibitor of kazal type 5) encoding LEKTI-1 (lympho-epithelial kazal type related inhibitor type 5) expressed in stratified epithelia. In vitro and in vivo studies in murine models and in NS patients have cast light on the pathogenesis of the disease and shown that LEKTI deficiency results in unopposed kallikrein-related peptidase 5 (KLK5) and KLK7 activities and to the overactivity of a new epidermal protease, elastase 2 (ELA2). Two main cascades initiated by KLK5 activity have emerged. One results in desmoglein 1 degradation and desmosome cleavage leading to stratum corneum detachment. KLK5 also activates KLK7 and ELA2, which contribute to a defective skin barrier. This facilitates allergen and microbe penetration and generates danger signals leading to caspase 1 activation and the production of active interleukin-1beta. In parallel, KLK5 activates a specific cascade of allergy and inflammation by activating protease-activated receptor-2 (PAR-2) receptors. PAR-2 activation triggers the production of the major pro-Th2 cytokine TSLP (thymic stromal lymphopoietin) and several inflammatory cytokines, including tumour necrosis factor-alpha. Levels of thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) also contribute to allergy in a PAR-2-independent manner. Patient investigations have confirmed these abnormalities and revealed a wide spectrum of disease expression, sometimes associated with residual LEKTI expression. These results have demonstrated that the tight regulation of epidermal protease activity is essential for skin homeostasis and identified new targets for therapeutic intervention. They also provide a link with atopic dermatitis through deregulated protease activity, as recently supported by functional studies of the E420K LEKTI variant. PMID- 23344366 TI - Minimally invasive ridge augmentation using xenogenous bone blocks in an atrophied posterior mandible: a clinical and histological study. AB - PURPOSE: Although various techniques for the treatment of an atrophic alveolar ridge have been described in the literature, these procedures have increased the morbidity and discomfort for the patient. The purpose of this study was to evaluate histological and clinical results in 9 patients who underwent a subperiosteal tunneling procedure with a Bio-Oss block onlay graft in an atrophic area of the mandible. PATIENTS AND METHODS: Nine months after grafting, at the time of dental implantation, biopsy samples were taken from the grafted areas of 9 patients and were analyzed histologically. RESULTS: New bone formation through the bovine bone block was observed consistently in the 9 cases. There was direct deposition of bone on the surface of the graft material. CONCLUSION: The results of this study indicated that ridge augmentation using a subperiosteal tunneling procedure with Bio-Oss bone blocks might be useful for implant placement in the atrophic alveolar ridges. PMID- 23344367 TI - Morphology of bone particles after harvesting with 4 different devices. AB - INTRODUCTION: Autogenous bone is routinely used for regeneration of osseous defects around teeth and implants, and different instruments are available for bone harvesting. OBJECTIVES: The purpose of this study was to describe the morphology of bone particles after harvesting with 4 different instruments. MATERIALS AND METHODS: Bone particles were harvested from fresh cow ribs with 2 different types of back action chisels, a safescraper and a sonic device. The samples were examined morphologically using light microscopy and scanning electron microscopy. RESULTS: The bone particles after the back action chisel I had an appearance similar to "pencil shavings." With the back action chisel II, they were like thin paper with an "accordion bellows" appearance. After removal with the safescraper, they had an irregular shape (with an irregular surface) resembling "crushed stone." Finally, the appearance of the bone particles obtained with the sonic device was homogenous, condensed and continuous, and had a "seaweed" appearance. CONCLUSIONS: Harvesting of bone particles with 4 different devices produce distinctly difference sizes and shapes, which may influence the results of grafting procedures. PMID- 23344368 TI - A histological and histomorphometrical evaluation of retrieved human implants with a wettable, highly hydrophilic, hierarchically microstructured surface: a retrospective analysis of 14 implants. AB - PURPOSE: Analysis of human-retrieved implants provides a unique opportunity to evaluate osseointegration processes. There is evidence that faster bone apposition is present at textured surfaces, with a very high success percentage. Aim of the present retrospective analysis was an evaluation of 14 human retrieved from humans implants with a wettable, highly hydrophilic, microstructured surface. MATERIALS AND METHODS: The archives of the Implant Retrieval Center of the Dental School, University of Chieti-Pescara, Italy, were searched, and a total of 14 implants FRIADENT plus surface (Dentsply Implants Manufacturing GmbH, Mannheim, Germany) retrieved after a loading period comprised between 4 and 8 weeks were found. RESULTS: Around all implants, newly formed bone was found in direct contact with the implant surface, with no connective fibrous tissue found at the interface. In all implants, no epithelial downgrowth was present. A very high bone-to-implant contact percentage was found. CONCLUSIONS: The efficacy of dental implants is related to biological and biomechanical stability and to the integration between the bone and the implant. This integration plays the key role in the fixation and anchoring of the implants. PMID- 23344370 TI - Investigation of a passive sensor array for diagnosis of loosening of endoprosthetic implants. AB - Currently, imaging methods are used to diagnose loosening of endoprosthetic implants, but fail to achieve 100% accuracy. In this study, a passive sensor array which is based on the interaction between magnetic oscillators inside the implant and an excitation coil outside the patient was investigated. The excited oscillators produce sound in the audible range, which varies according to the extent of loosening. By performing several experimental tests, the sensor array was optimized to guarantee reproducible and selective excitation of the sound emission. Variation in the distance between the oscillators demonstrated a definite influence on the quality of the generated sound signal. Furthermore, a numerical design analysis using the boundary element method was generated for consideration of the magnetic field and the selectivity of the oscillators during excitation. The numerical simulation of the coil showed the higher selectivity of a coil with a C-shape compared to a cylindrical coil. Based on these investigations, the passive sensor system reveals the potential for detection of implant loosening. Future aims include the further miniaturization of the oscillators and measurements to determine the sensitivity of the proposed sensor system. PMID- 23344371 TI - Mobile devices for community-based REDD+ monitoring: a case study for Central Vietnam. AB - Monitoring tropical deforestation and forest degradation is one of the central elements for the Reduced Emissions from Deforestation and Forest Degradation in developing countries (REDD+) scheme. Current arrangements for monitoring are based on remote sensing and field measurements. Since monitoring is the periodic process of assessing forest stands properties with respect to reference data, adopting the current REDD+ requirements for implementing monitoring at national levels is a challenging task. Recently, the advancement in Information and Communications Technologies (ICT) and mobile devices has enabled local communities to monitor their forest in a basic resource setting such as no or slow internet connection link, limited power supply, etc. Despite the potential, the use of mobile device system for community based monitoring (CBM) is still exceptional and faces implementation challenges. This paper presents an integrated data collection system based on mobile devices that streamlines the community-based forest monitoring data collection, transmission and visualization process. This paper also assesses the accuracy and reliability of CBM data and proposes a way to fit them into national REDD+ Monitoring, Reporting and Verification (MRV) scheme. The system performance is evaluated at Tra Bui commune, Quang Nam province, Central Vietnam, where forest carbon and change activities were tracked. The results show that the local community is able to provide data with accuracy comparable to expert measurements (index of agreement greater than 0.88), but against lower costs. Furthermore, the results confirm that communities are more effective to monitor small scale forest degradation due to subsistence fuel wood collection and selective logging, than high resolution remote sensing SPOT imagery. PMID- 23344372 TI - Fiber loop ringdown sensor for potential real-time monitoring of cracks in concrete structures: an exploratory study. AB - A fiber loop ringdown (FLRD) concrete crack sensor is described for the first time. A bare single mode fiber (SMF), without using other optical components or chemical coatings, etc., was utilized to construct the sensor head, which was driven by a FLRD sensor system. The performance of the sensor was evaluated on concrete bars with dimensions 20 cm * 5 cm * 5 cm, made in our laboratory. Cracks were produced manually and the responses of the sensor were recorded in terms of ringdown times. The sensor demonstrated detection of the surface crack width (SCW) of 0.5 mm, which leads to a theoretical SCW detection limit of 31 MUm. The sensor's response to a cracking event is near real-time (1.5 s). A large dynamic range of crack detection ranging from a few microns (MUm) to a few millimeters is expected from this sensor. With the distinct features, such as simplicity, temperature independence, near real-time response, high SCW detection sensitivity, and a large dynamic range, this FLRD crack sensor appears promising for detections of cracks when embedded in concrete. PMID- 23344373 TI - Flow cell design for effective biosensing. AB - The efficiency of three different biosensor flow cells is reported. All three flow cells featured a central channel that expands in the vicinity of the sensing element to provide the same diameter active region, but the rate of channel expansion and contraction varied between the designs. For each cell the rate at which the analyte concentration in the sensor chamber responds to a change in the influent analyte concentration was determined numerically using a finite element model and experimentally using a flow-fluorescence technique. Reduced flow cell efficiency with increasing flow rates was observed for all three designs and was related to the increased importance of diffusion relative to advection, with efficiency being limited by the development of regions of recirculating flow (eddies). However, the onset of eddy development occurred at higher flow rates for the design with the most gradual channel expansion, producing a considerably more efficient flow cell across the range of flow rates considered in this study. It is recommended that biosensor flow cells be designed to minimize the tendency towards, and be operated under conditions that prevent the development of flow recirculation. PMID- 23344374 TI - Foreign object detection by sub-terahertz quasi-Bessel beam imaging. AB - Food quality monitoring, particularly foreign object detection, has recently become a critical issue for the food industry. In contrast to X-ray imaging, terahertz imaging can provide a safe and ionizing-radiation-free nondestructive inspection method for foreign object sensing. In this work, a quasi-Bessel beam (QBB) known to be nondiffracting was generated by a conical dielectric lens to detect foreign objects in food samples. Using numerical evaluation via the finite difference time-domain (FDTD) method, the beam profiles of a QBB were evaluated and compared with the results obtained via analytical calculation and experimental characterization (knife edge method, point scanning method). The FDTD method enables a more precise estimation of the beam profile. Foreign objects in food samples, namely crickets, were then detected with the QBB, which had a deep focus and a high spatial resolution at 210 GHz. Transmitted images using a Gaussian beam obtained with a conventional lens were compared in the sub terahertz frequency experimentally with those using a QBB generated using an axicon. PMID- 23344375 TI - A protein concentration measurement system using a flexural plate-wave frequency shift readout technique. AB - A protein concentration measurement system with two-port flexural plate-wave (FPW) biosensors using a frequency-shift readout technique is presented in this paper. The proposed frequency-shift readout method employs a peak detecting scheme to measure the amount of resonant frequency shift. The proposed system is composed of a linear frequency generator, a pair of peak detectors, two registers, and a subtractor. The frequency sweep range of the linear frequency generator is limited to 2 MHz to 10 MHz according to the characteristics of the FPW biosensors. The proposed frequency-shift readout circuit is carried out on silicon using a standard 0.18 MUm CMOS technology. The sensitivity of the peak detectors is measured to be 10 mV. The power consumption of the proposed protein concentration measurement system is 48 mW given a 0.1 MHz system clock. PMID- 23344376 TI - Influence of cobalt on the properties of load-sensitive magnesium alloys. AB - In this study, magnesium is alloyed with varying amounts of the ferromagnetic alloying element cobalt in order to obtain lightweight load-sensitive materials with sensory properties which allow an online-monitoring of mechanical forces applied to components made from Mg-Co alloys. An optimized casting process with the use of extruded Mg-Co powder rods is utilized which enables the production of magnetic magnesium alloys with a reproducible Co concentration. The efficiency of the casting process is confirmed by SEM analyses. Microstructures and Co-rich precipitations of various Mg-Co alloys are investigated by means of EDS and XRD analyses. The Mg-Co alloys' mechanical strengths are determined by tensile tests. Magnetic properties of the Mg-Co sensor alloys depending on the cobalt content and the acting mechanical load are measured utilizing the harmonic analysis of eddy-current signals. Within the scope of this work, the influence of the element cobalt on magnesium is investigated in detail and an optimal cobalt concentration is defined based on the performed examinations. PMID- 23344377 TI - GPS-supported visual SLAM with a rigorous sensor model for a panoramic camera in outdoor environments. AB - Accurate localization of moving sensors is essential for many fields, such as robot navigation and urban mapping. In this paper, we present a framework for GPS supported visual Simultaneous Localization and Mapping with Bundle Adjustment (BA SLAM) using a rigorous sensor model in a panoramic camera. The rigorous model does not cause system errors, thus representing an improvement over the widely used ideal sensor model. The proposed SLAM does not require additional restrictions, such as loop closing, or additional sensors, such as expensive inertial measurement units. In this paper, the problems of the ideal sensor model for a panoramic camera are analysed, and a rigorous sensor model is established. GPS data are then introduced for global optimization and georeferencing. Using the rigorous sensor model with the geometric observation equations of BA, a GPS supported BA-SLAM approach that combines ray observations and GPS observations is then established. Finally, our method is applied to a set of vehicle-borne panoramic images captured from a campus environment, and several ground control points (GCP) are used to check the localization accuracy. The results demonstrated that our method can reach an accuracy of several centimetres. PMID- 23344378 TI - Probabilistic evaluation of three-dimensional reconstructions from X-ray images spanning a limited angle. AB - An important part of computed tomography is the calculation of a three dimensional reconstruction of an object from series of X-ray images. Unfortunately, some applications do not provide sufficient X-ray images. Then, the reconstructed objects no longer truly represent the original. Inside of the volumes, the accuracy seems to vary unpredictably. In this paper, we introduce a novel method to evaluate any reconstruction, voxel by voxel. The evaluation is based on a sophisticated probabilistic handling of the measured X-rays, as well as the inclusion of a priori knowledge about the materials that the object receiving the X-ray examination consists of. For each voxel, the proposed method outputs a numerical value that represents the probability of existence of a predefined material at the position of the voxel while doing X-ray. Such a probabilistic quality measure was lacking so far. In our experiment, false reconstructed areas get detected by their low probability. In exact reconstructed areas, a high probability predominates. Receiver Operating Characteristics not only confirm the reliability of our quality measure but also demonstrate that existing methods are less suitable for evaluating a reconstruction. PMID- 23344379 TI - About Non-Line-Of-Sight satellite detection and exclusion in a 3D map-aided localization algorithm. AB - Reliable GPS positioning in city environment is a key issue: actually, signals are prone to multipath, with poor satellite geometry in many streets. Using a 3D urban model to forecast satellite visibility in urban contexts in order to improve GPS localization is the main topic of the present article. A virtual image processing that detects and eliminates possible faulty measurements is the core of this method. This image is generated using the position estimated a priori by the navigation process itself, under road constraints. This position is then updated by measurements to line-of-sight satellites only. This closed-loop real-time processing has shown very first promising full-scale test results. PMID- 23344380 TI - Hybrid radar emitter recognition based on rough k-means classifier and relevance vector machine. AB - Due to the increasing complexity of electromagnetic signals, there exists a significant challenge for recognizing radar emitter signals. In this paper, a hybrid recognition approach is presented that classifies radar emitter signals by exploiting the different separability of samples. The proposed approach comprises two steps, namely the primary signal recognition and the advanced signal recognition. In the former step, a novel rough k-means classifier, which comprises three regions, i.e., certain area, rough area and uncertain area, is proposed to cluster the samples of radar emitter signals. In the latter step, the samples within the rough boundary are used to train the relevance vector machine (RVM). Then RVM is used to recognize the samples in the uncertain area; therefore, the classification accuracy is improved. Simulation results show that, for recognizing radar emitter signals, the proposed hybrid recognition approach is more accurate, and presents lower computational complexity than traditional approaches. PMID- 23344381 TI - Sensing performance of precisely ordered TiO2 nanowire gas sensors fabricated by electron-beam lithography. AB - In this study, electron beam lithography, rather than the most popular method, chemical synthesis, is used to construct periodical TiO(2) nanowires for a gas sensor with both robust and rapid performance. The effects of temperature on the sensing response and reaction time are analyzed at various operation temperatures ranging from 200 to 350 degrees C. At the optimized temperature of 300 degrees C, the proposed sensor repeatedly obtained a rise/recovery time (DeltaR: 0.9 R(0) to 0.1 R(0)) of 3.2/17.5 s and a corresponding sensor response (DeltaR/R(0)) of 21.7% at an ethanol injection mass quantity of 0.2 MUg. PMID- 23344382 TI - Deciphering the crowd: modeling and identification of pedestrian group motion. AB - Associating attributes to pedestrians in a crowd is relevant for various areas like surveillance, customer profiling and service providing. The attributes of interest greatly depend on the application domain and might involve such social relations as friends or family as well as the hierarchy of the group including the leader or subordinates. Nevertheless, the complex social setting inherently complicates this task. We attack this problem by exploiting the small group structures in the crowd. The relations among individuals and their peers within a social group are reliable indicators of social attributes. To that end, this paper identifies social groups based on explicit motion models integrated through a hypothesis testing scheme. We develop two models relating positional and directional relations. A pair of pedestrians is identified as belonging to the same group or not by utilizing the two models in parallel, which defines a compound hypothesis testing scheme. By testing the proposed approach on three datasets with different environmental properties and group characteristics, it is demonstrated that we achieve an identification accuracy of 87% to 99%. The contribution of this study lies in its definition of positional and directional relation models, its description of compound evaluations, and the resolution of ambiguities with our proposed uncertainty measure based on the local and global indicators of group relation. PMID- 23344383 TI - Evaluation of a 433 MHz band body sensor network for biomedical applications. AB - Body sensor networks (BSN) are an important research topic due to various advantages over conventional measurement equipment. One main advantage is the feasibility to deploy a BSN system for 24/7 health monitoring applications. The requirements for such an application are miniaturization of the network nodes and the use of wireless data transmission technologies to ensure wearability and ease of use. Therefore, the reliability of such a system depends on the quality of the wireless data transmission. At present, most BSNs use ZigBee or other IEEE 802.15.4 based transmission technologies. Here, we evaluated the performance of a wireless transmission system of a novel BSN for biomedical applications in the 433MHz ISM band, called Integrated Posture and Activity NEtwork by Medit Aachen (IPANEMA) BSN. The 433MHz ISM band is used mostly by implanted sensors and thus allows easy integration of such into the BSN. Multiple measurement scenarios have been assessed, including varying antenna orientations, transmission distances and the number of network participants. The mean packet loss rate (PLR) was 0.63% for a single slave, which is comparable to IEEE 802.15.4 BSNs in the proximity of Bluetooth or WiFi networks. Secondly, an enhanced version is evaluated during on body measurements with five slaves. The mean PLR results show a comparable good performance for measurements on a treadmill (2.5%), an outdoor track (3.4%) and in a climate chamber (1.5%). PMID- 23344384 TI - Characterization of a new heat dissipation matric potential sensor. AB - Soil moisture sensors can help to reduce the amount of water needed for irrigation. In this paper we describe the PlantCare soil moisture sensor as a new type of heat dissipation sensor, its calibration and the correction for temperature changes. With the PlantCare sensor it is possible to measure the matric potential indirectly to monitor or control irrigation. This sensor is based on thermal properties of a synthetic felt. After a defined heating phase the cooling time to a threshold temperature is a function of the water content in the synthetic felt. The water content in this porous matrix is controlled by the matric potential in the surrounding soil. Calibration measurements have shown that the sensor is most sensitive to -400 hPa and allows lower sensitivity measurements to -800 hPa. The disturbing effect of the temperature change during the measurement on the cooling time can be corrected by a linear function and the differences among sensors are minimized by a two point calibration. PMID- 23344388 TI - A wireless sensor network-based portable vehicle detector evaluation system. AB - In an upcoming smart transportation environment, performance evaluations of existing Vehicle Detection Systems are crucial to maintain their accuracy. The existing evaluation method for Vehicle Detection Systems is based on a wired Vehicle Detection System reference and a video recorder, which must be operated and analyzed by capable traffic experts. However, this conventional evaluation system has many disadvantages. It is inconvenient to deploy, the evaluation takes a long time, and it lacks scalability and objectivity. To improve the evaluation procedure, this paper proposes a Portable Vehicle Detector Evaluation System based on wireless sensor networks. We describe both the architecture and design of a Vehicle Detector Evaluation System and the implementation results, focusing on the wireless sensor networks and methods for traffic information measurement. With the help of wireless sensor networks and automated analysis, our Vehicle Detector Evaluation System can evaluate a Vehicle Detection System conveniently and objectively. The extensive evaluations of our Vehicle Detector Evaluation System show that it can measure the traffic information such as volume counts and speed with over 98% accuracy. PMID- 23344390 TI - Supramolecular design for two-component hydrogels with intrinsic emission in the visible region. AB - We report, for the first time, an in situ formation of two-component hydrogels from pyridine derivatives of poly(aryl ether) dendrons and tartaric acid. The two component system (dendron + acid) undergoes J-type aggregation, leading to fibrillar type self-assembly in THF-water mixture along with blue (470 nm) and green (500 nm) intrinsic emissions. PMID- 23344389 TI - [Current value of 3D echocardiography in international guidelines]. AB - Real-time 3D echocardiography is one of the most important developments in the field of non-invasive cardiac imaging within the last years. To investigate whether this new technology can be considered as a standard method the current guidelines and recommendations were reviewed. In the field of left ventricular function assessment, evaluation of mitral valve pathologies and peri interventional monitoring of percutaneous valve repair procedures 3D echocardiography plays a major role. For other clinical applications, such as right heart assessment, congenital heart disease and stress echocardiography, a high potential is seen but evidence is currently too weak for general recommendations. However, in the near future no echo laboratory will be working without 3D modalities. PMID- 23344391 TI - Three-dimensional evaluation of thoracic aorta enlargement and unfolding in hypertensive men using non-contrast computed tomography. AB - Aging produces a simultaneous thoracic aorta (TA) enlargement and unfolding. We sought to analyze the impact of hypertension on these geometric changes. Non contrast computed tomography images were obtained from coronary artery calcium scans, including the entire aortic arch, in 200 normotensive and 200 hypertensive asymptomatic men. An automated algorithm reconstructed the vessel in three dimensions, estimating orthogonal aortic sections along the whole TA pathway, and calculated several geometric descriptors to assess TA morphology. Hypertensive patients were older with respect to normotensive (P<0.001). Diameter and volume of TA ascending, arch and descending segments were higher in hypertensive patients with respect to normotensive (P<0.001) and differences persisted after adjustment for age. Hypertension produced an accelerated unfolding effect on TA shape. We found increments in aortic arch width (P<0.001), radius of curvature (P<0.001) and area under the arch curve (P<0.01) with a concomitant tortuosity decrease (P<0.05) and no significant change in aortic arch height. Overall, hypertension produced an equivalent effect of 2-7-years of aging. In multivariate analysis adjusted for age and hypertension treatment, diastolic pressure was more associated to TA size and shape changes than systolic pressure. These data suggest that hypertension accelerates TA enlargement and unfolding deformation with respect to the aging effect. PMID- 23344393 TI - Reversible binding of water, methanol, and ethanol to a five-coordinate ruthenium(II) complex. AB - The known green, five-coordinate, square-pyramidal trans-RuCl(2)(P-N)(PPh(3)) complex reversibly binds water, MeOH and EtOH in the vacant coordination site in the solid state and in CH(2)Cl(2) solution to give pink adducts (P-N = o diphenylphosphino-N,N'-dimethylaniline). The adducts are well characterized, including X-ray analysis of the aqua complex, trans-RuCl(2)(P-N)(PPh(3))(H(2)O), which crystallizes in two different benzene-solvated forms. Comparison of the structural data with those determined previously for the binding of H(2)S, thiols, and H(2), which form cis-RuX(2)(P-N)(PPh(3))L products (X = Cl, Br; L = a S-ligand or H(2)) reveals the trans-influence trend P > H(2)S ~ thiols > H(2) > Cl ~ Br > H(2)O. Thermodynamic data for the binding of water were estimated in solution by UV-Vis spectroscopy, and DeltaH(o) data for the aqua and alcohol adducts in the solid state were obtained by differential scanning calorimetry. Inclusion of published data for the S-ligand adducts reveals the thermal stability trend of the solid complexes as MeSH > MeOH > H(2)S > H(2)O > EtSH > EtOH. PMID- 23344392 TI - Analysis of indoleamine 2-3 dioxygenase (IDO1) expression in breast cancer tissue by immunohistochemistry. AB - INTRODUCTION: The immunosuppressive enzyme, indoleamine 2,3 dioxygenase (IDO), is overexpressed in many different tumor types including breast cancer. IDO inhibitors synergize with chemotherapy in breast cancer murine models. Characterizing IDO expression in breast cancer could define which patients receive IDO inhibitors. This study analyzed IDO protein expression in 203 breast cancer cases. The relationship between IDO, overall survival (OS), disease specific survival (DSS), clinicopathologic, molecular, and immune tumor infiltrate factors was evaluated. METHODS: Expression of IDO, estrogen receptor (ER), progesterone receptor (PR), human epithelial receptor 2, cytokeratin 5/6, epithelial growth factor receptor, phosphorylated AKT, neoangiogenesis, nitrogen oxide synthetase 2 (NOS2), cyclooxygenase 2 (COX2), FoxP3, CD8, and CD11b on archival breast cancer tissue sections was evaluated by immunohistochemistry. Associations between IDO and these markers were explored by a univariate and multivariate analysis. Survival was analyzed using Kaplan-Meier (OS) and Wilcoxon two-sample (DSS) tests. RESULTS: IDO expression was higher in ER+ tumors compared to ER- tumors. IDO was lower in those with higher neoangiogenesis. OS was better in ER+ patients with high IDO expression. DSS was better in node-positive patients with high IDO expression. IDO activity positively correlates with NOS2. COX2 as positively correlated with IDO on univariate but not multivariate analysis. There was a trend toward greater numbers of CD11b+ cells in IDO-low tumors. CONCLUSIONS: IDO protein expression is lower in ER- breast tumors with greater neoangiogenesis. Future clinical trials evaluating the synergy between IDO inhibitors and chemotherapy should take this finding into account and stratify for ER status in the trial design. PMID- 23344394 TI - Cesarean delivery for refractory status asthmaticus. PMID- 23344395 TI - Uterine bleeding during high-dose chemotherapy and hematopoietic stem cell transplantation: a perfect storm. PMID- 23344396 TI - Cesarean delivery for life-threatening status asthmaticus. AB - BACKGROUND: Asthma remains a common chronic illness in pregnancy with the potential for catastrophic complications. Most women with asthma exacerbation can be treated with medical management and continuation of pregnancy. However, refractory cases may necessitate delivery for fetal or maternal indications. CASE: We report a case of status asthmaticus at 33 weeks of gestation with significant maternal respiratory acidosis and difficulty with ventilation necessitating delivery by cesarean delivery in the medical intensive care unit. The patient was unresponsive to standard medical therapies. Delivery resulted in immediate improvement in maternal ventilation parameters. CONCLUSION: In cases of life-threatening status asthmaticus refractory to standard medical and ventilatory therapies in the third trimester, cesarean delivery should be considered as a final effort to increase tidal volumes and improve maternal gas exchange. PMID- 23344397 TI - Management of uterine bleeding during hematopoietic stem cell transplantation. AB - BACKGROUND: Hematopoietic stem cell transplant is an effective treatment strategy for a variety of hematologic disorders, but patients are at risk for dysfunctional coagulation and abnormal bleeding. Gynecologists are often consulted before transplant for management of abnormal uterine bleeding, which may be particularly challenging in this context. CASE: A premenopausal woman with MonoMAC (a rare adult-onset immunodeficiency syndrome characterized by monocytopenia and Mycobacterium avium complex infections resulting from mutations in GATA2, a crucial gene in early hematopoiesis) presented with pancytopenia, evolving leukemia, and recent strokes, necessitating anticoagulation. During preparation for hematopoietic stem cell transplant, she experienced prolonged menorrhagia requiring transfusions. Surgical therapy was contraindicated, and medical management was successful only when combined with balloon tamponade. CONCLUSION: Balloon tamponade may be a potentially life-saving adjunct to medical therapy for control of uterine hemorrhage before hematopoietic stem cell transplant. PMID- 23344398 TI - A true cornual (interstitial) pregnancy resulting in a viable fetus. AB - BACKGROUND: Interstitial ectopic pregnancies are known for their dangerous implantation location and high risk of rupture. CASE: We report an interstitial pregnancy that was not ruptured at the time of cesarean delivery. Hysterectomy was not necessary and a viable fetus was delivered with a neonatal intensive care unit stay compatible to any neonate of his gestational age. CONCLUSION: In very rare circumstances, interstitial pregnancies can result in a viable fetus, and careful inspection of second-trimester ultrasonogram can lead to proper management of complicated ectopic pregnancies. PMID- 23344399 TI - Pyomyoma after uterine artery embolization. AB - BACKGROUND: Pyomyoma (suppurative leiomyoma of the uterus) is a rare condition resulting from infarction and infection of a leiomyoma. It can lead to sepsis and death unless treated with antibiotics and aggressive surgical intervention. CASE: A 47-year-old multigravid woman with symptomatic uterine leiomyomas presented with fever, pelvic pain, and leukocytosis after uncomplicated uterine artery embolization. Pyomyoma was suspected after computed tomography scan demonstrated an enlarged, heterogeneous uterus containing copious myometrial air. She underwent supracervical hysterectomy, lysis of adhesions, and right salpingo oophorectomy. CONCLUSION: Surgical management of pyomyoma may be necessary early in the management of pyomyoma after uterine artery embolization. PMID- 23344400 TI - Short bowel syndrome causing bleeding diathesis and profound vitamin deficiency in pregnancy. AB - BACKGROUND: Extensive bowel resection may lead to a state of inadequate nutrient absorption and malnutrition known as short bowel syndrome. Deficiencies in fat soluble vitamins may occur from this condition, with sequelae such as a bleeding diathesis. Maternal vitamin deficiencies also have been associated with fetal anomalies. CASE: A young gravid patient with a history of neonatal bowel resection presented with bleeding diathesis. She subsequently was found to have profound vitamin deficiencies and delivered a newborn with multiple anomalies. CONCLUSION: Preconceptional counseling, nutritional status evaluation, and concomitant management with a gastroenterologist are essential to optimize pregnancy outcome for patients with a history of extensive bowel resection. PMID- 23344401 TI - Autologous graft for treatment of midurethral sling exposure without mesh excision. AB - BACKGROUND: The midurethral sling is an effective treatment for stress urinary incontinence. Mesh exposure is a known complication of this procedure, with an associated rate of approximately 4%. Other than sling excision, there is minimal information on other options that may help to preserve an effective sling when an exposure has occurred. CASE: A patient presented with a mesh exposure 9 weeks after a retropubic midurethral sling. Conservative treatment with vaginal estrogen failed, as did primary reclosure in the operating room. She was then successfully treated with a full-thickness autologous vaginal epithelium graft. CONCLUSION: We report an alternative surgical option to mesh excision, which may help preserve an otherwise effective midurethral sling complicated by mesh exposure. PMID- 23344402 TI - Endoscopic transurethral resection of urethral mesh erosion with the use of a pediatric nasal speculum. AB - BACKGROUND: A rare but challenging complication of midurethral slings is erosion of mesh tape through the urethral wall. CASES: In this report, we describe two cases in which a pediatric nasal speculum provided exposure for transurethral resection of eroded mesh. Exposure was sufficient for complete mesh resection endoscopically as well as with use of traditional surgical instruments. Since having surgery there has been no recurrence of mesh erosion and the irritative voiding symptoms have resolved. CONCLUSION: Urethral mesh erosion can be managed from a transurethral approach. Furthermore, use of a pediatric nasal speculum improves visualization and efficiency. PMID- 23344403 TI - Selective arterial embolization as a first-line treatment for postpartum hematomas. AB - BACKGROUND: Postpartum hematomas are a potentially serious obstetric complication for which management options are not standardized. We report successful treatment of a large postpartum hematoma using arterial embolization as primary approach. CASE: A 29-year-old woman at term gestation underwent vacuum-assisted vaginal delivery. Two hours later, marked rectal pain developed. Examination revealed a large left vaginal hematoma and no obvious bleeding sites. Computed tomography demonstrated a 10-cm supralevator hematoma and extrauterine arterial bleeding. Angiography revealed contrast extravasation from a branch of the left internal pudendal artery. Selective embolization of this branch stopped the bleeding. The patient was discharged on the third postpartum day. Eight weeks after delivery, there was no evidence of the hematoma. CONCLUSION: Arterial embolization can be used as a first-line treatment for large postpartum hematomas. PMID- 23344404 TI - Oxidized regenerated cellulose imitating pelvic abscess. AB - BACKGROUND: Oxidized regenerated cellulose is a topical hemostatic agent that is used commonly in abdominal and pelvic surgery. Although oxidized regenerated cellulose mimicking an abscess has been reported after different operations, little is known about its side effects after gynecologic surgery. CASES: Two women were diagnosed with postoperative abscess and intra-abdominal oxidized regenerated cellulose was identified as an abscess or as part of an abscess on computed tomography imaging. Both women recovered after treatment with antibiotics with and without drainage. CONCLUSION: Oxidized regenerated cellulose may be mistaken for an abscess or as part of an abscess on imaging studies. It is important to reveal information about oxidized regenerated cellulose use to the imaging department. PMID- 23344405 TI - Indigo carmine extravasation to upper limb after pelvic reconstructive surgery. AB - BACKGROUND: The use of dyes during cystoscopy to visualize the ureters adequately is prevalent in gynecologic surgery. Observing ureteral patency after procedures such as a hysterectomy or pelvic reconstruction is important for identifying injury to the upper urinary tract. Indigo carmine is commonly used. Knowing the possible adverse effects and being aware of unusual presentations with the use of indigo carmine are important in managing and counseling patients. CASE: We present a case in which a patient developed indigo carmine extravasation to her upper limb after pelvic reconstructive surgery. The blue discoloration disappeared after 1 day. CONCLUSION: Indigo carmine extravasation to other parts of the body can occur without long-term complications. It takes 24-48 hours for the dye to clear subcutaneously. PMID- 23344406 TI - Intra-amniotic fluconazole therapy for Candida albicans intra-amniotic infection. AB - BACKGROUND: The consequences of intra-amniotic Candida infection can be devastating. Currently, standard management includes delivery. We identified only one previous case reporting intrauterine antifungal therapy, which used transcervical amphotericin B. We present two cases of intra-amniotic Candida infection treated with intra-amniotic fluconazole instilled before membrane rupture. CASES: Two patients presented with intra-amniotic Candida albicans infection that was diagnosed during previability. Both underwent cerclage placement before culture results were available. Aggressive antifungal therapy was instituted using oral, vaginal, and intra-amniotic fluconazole instilled through serial amniocenteses. Both fetuses survived without sequelae. CONCLUSION: Intra-amniotic Candida infection is associated with preterm rupture of membranes, preterm labor, severe neonatal infection, and fetal death. Early diagnosis and treatment is essential. PMID- 23344407 TI - Utility of antimullerian hormone level obtained for infertility assessment for alerting to ovarian tumor. AB - BACKGROUND: Antimullerian hormone is a marker of ovarian reserve and is now routinely measured in women seeking infertility treatment. CASE: A 42-year-old woman, gravida 1, abortus 1, presented with secondary infertility. Obtained originally for assessment of ovarian reserve, an antimullerian hormone of more than 160 ng/mL raised suspicion for a granulosa cell tumor. A laparoscopic right salpingo-oophorectomy, pelvic washings, dilation and curettage, and peritoneal and omental biopsies were performed. A well-differentiated granulosa cell tumor confined to the right ovary was consistent with stage 1A disease. CONCLUSION: As the use of antimullerian hormone becomes more common for ovarian reserve testing, providers need to maintain an awareness for neoplastic disease with abnormal values. PMID- 23344408 TI - Pregnancy in a woman with chronic neutrophilic leukemia. AB - BACKGROUND: Chronic neutrophilic leukemia is a rare myeloproliferative disorder in women of reproductive age. CASE: A pregnant woman with an established diagnosis of chronic neutrophilic leukemia presented at 26 weeks of gestation with splenomegaly, thrombocytopenia, leukocytosis, and anemia. Thrombocytopenia was refractory to medical treatment and, in part, was attributed to splenic sequestration. She delivered a healthy neonate at 35 weeks of gestation by repeat cesarean delivery under general anesthesia. Her preoperative platelet count was 30,000/mL and she was transfused platelets throughout the perioperative period. Her postpartum course was complicated by intraabdominal hemorrhage and severe preeclampsia. She recovered with intensive medical and surgical management. CONCLUSION: Chronic neutrophilic leukemia poses difficult challenges during pregnancy and requires a multidisciplinary approach. PMID- 23344409 TI - Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer. AB - BACKGROUND: Cowden syndrome is an autosomal-dominant condition associated with mutations in the tumor suppressor gene PTEN. Gynecologic malignancies are common with a 5-10% risk of endometrial cancer and 25-50% risk of breast cancer. CASE: A 37-year-old woman with a history of breast cancer, other neoplasms, and multiple skin lesions was diagnosed with Cowden syndrome after a germline PTEN mutation was identified. The endometrium had high glucose uptake on positron emission tomography scan and was irregularly thickened on ultrasonography; biopsy revealed endometrial polyps and simple hyperplasia. Fifteen months later, hysteroscopy again confirmed numerous benign endometrial polyps. CONCLUSION: Recurrent, multiple endometrial polyps portend a high risk of endometrial cancer in women with Cowden syndrome. Monitoring for malignancy and consideration of hysterectomy after childbearing is completed is warranted. PMID- 23344410 TI - Unsuccessful planned conservative resection of placental site trophoblastic tumor. AB - BACKGROUND: Placental site trophoblastic tumor is a rare subtype of gestational trophoblastic neoplasia affecting women of reproductive age. The preferred method of treatment is surgical resection. CASE: A 33-year-old woman, gravida 3 para 1111, was incidentally diagnosed with placental site trophoblastic tumor during an evaluation for infertility. As a result of persistent pathologic evidence of disease, she underwent a hysterectomy. The site of disease on pathologic review of the hysterectomy specimen was widely discordant from the preoperative imaging and hysteroscopic evaluations. CONCLUSION: Wedge resection of the uterus has been suggested as an acceptable alternative to hysterectomy in women with placental site trophoblastic tumor who wish to preserve future fertility. However, this case demonstrated that preoperative imaging may not correlate with the tumor site, making wedge resection treatment ineffective. PMID- 23344411 TI - Ectopic production of human chorionic gonadotropin by synovial sarcoma of the hip. AB - BACKGROUND: Human chorionic gonadotropin (hCG) is a marker of pregnancy and a tumor marker for some gynecologic malignancies, including germ cell tumors and gestational trophoblastic neoplasia. Rarely, hCG is secreted by nongynecologic tumors, confounding the diagnosis. CASE: A 45-year-old woman was evaluated for a persistently elevated beta-hCG. Diagnosis of her primary malignancy, synovial sarcoma of the hip, was delayed as more common etiologies were considered, including ectopic pregnancy and gestational trophoblastic neoplasm. The workup eventually led to the diagnosis using imaging studies but ultimately resulted in a 3-month delay and unnecessary medical and surgical treatments. CONCLUSION: This case highlights the importance of nongynecologic malignancies when evaluating patients with a persistent beta-hCG. PMID- 23344412 TI - Maternal hemolysis after intravenous immunoglobulin treatment in fetal and neonatal alloimmune thrombocytopenia. AB - BACKGROUND: Intravenous immunoglobulin (IVIG) is a therapeutic agent used to prevent fetal thrombocytopenia in those pregnancies identified to be at risk for fetal and neonatal alloimmune thrombocytopenia. Although generally considered a safe medication, hemolytic anemia is a known side effect of IVIG treatment that may result in maternal medical complications. CASES: We present three cases of IVIG-induced maternal anemia from separate institutions that occurred during treatment for fetal and neonatal alloimmune thrombocytopenia and resolved after discontinuation or alteration of therapy. None of the treated fetuses had thrombocytopenia at birth. CONCLUSION: There is a potential for hemolysis when prescribing IVIG. We recommend laboratory monitoring for hemolytic anemia and suggest options for management including drug modification or cessation of therapy. PMID- 23344413 TI - Severe thrombocytopenia after contrast infusion in pregnancy. AB - BACKGROUND: Intravenous contrast-induced thrombocytopenia is a rare but potentially life-threatening complication in pregnancy. CASE: A 22-year-old woman, gravida 2 para 1, at 33 2/7 weeks of gestation presented with chest pain, shortness of breath, and tachycardia. A computed tomography angiogram was pursued to evaluate for pulmonary embolus. During contrast infusion the woman experienced facial flushing, throat tightening, and worsening dyspnea. Her platelet count was noted to decrease precipitously to 4,000/microliter several hours after the imaging study. With medical management and observation, the woman's platelet count steadily recovered without further exacerbation of thrombocytopenia during gestation. CONCLUSION: Prompt recognition and therapy for intravenous contrast induced thrombocytopenia during pregnancy are essential to optimize maternal fetal outcome. PMID- 23344414 TI - Recurrent exophytic meningioma in pregnancy. AB - BACKGROUND: Meningiomas are slow-growing tumors that may present in pregnancy because of accelerated growth. We present the case of a recurrent meningioma in two separate pregnancies in the same woman. CASE: A 35-year-old woman presented at 30 weeks of gestation with limb weakness, vomiting, and a progressive decreased level of consciousness with an enlarging forehead mass. Imaging revealed a massive extra-axial exophytic tumor. An emergency craniotomy was performed, complicated by massive blood loss. Final pathology showed a grade I meningioma positive for progesterone receptors. Maternal-fetal outcome was good, with return of normal neurologic status and elective delivery at 38 weeks of gestation. CONCLUSION: Pregnancy is associated with accelerated meningioma growth and recurrence. Treatment during pregnancy is possible and requires a multidisciplinary approach. PMID- 23344415 TI - Technical challenges of a term delivery in a separated ischiopagus twin. AB - BACKGROUND: Conjoined twins occur in one in 100,000 live births. Successful term pregnancy in a separated conjoined twin is rare. CASE: We present a 27-year-old woman, gravida 2 para 0, former ischiopagus conjoined twin with successful separation at 12 days of life. We report a successful term gestation delivered by cesarean without complications. CONCLUSION: Term pregnancy is possible in a previous conjoined twin patient having undergone surgical separation. We recommend a multidisciplinary approach with close evaluation of maternal anatomy to achieve a successful pregnancy outcome while minimizing the risk of complications. PMID- 23344416 TI - Embolization of renal hemorrhage in pregnancy. AB - BACKGROUND: Selective embolization in pregnancy for treatment of renal hemorrhage has been reported infrequently in the literature; the possibility of minimizing radiation dose to the fetus by using dose-sparing fluoroscopy techniques is not commonly appreciated by the obstetric community. CASE: We describe performing partial renal embolization with the use of all available radiation dose-sparing techniques. The patient had no further complications, and she and her newborn were well postpartum. A dose reconstruction indicated that the fetal dose from the procedure was less than 5 mGy. CONCLUSION: When faced with a symptomatic renal hemorrhage in pregnancy, a renal angiogram and embolization by an experienced interventional radiologist are effective treatment options that can be performed with minimal fetal radiation risk. PMID- 23344417 TI - Rupture of an unscarred uterus in a quadruplet pregnancy. AB - BACKGROUND: Uterine rupture of an unscarred uterus is a rare complication in a quadruplet pregnancy. CASE: A 30-year-old woman, gravida 4 para 0030, with a quadruplet pregnancy and no previous uterine surgeries presented with moderate vaginal bleeding at 32 4/7 weeks of gestation. Fetal testing was reassuring, and the cervix showed no signs of preterm labor. A decision was made to proceed with cesarean delivery because of the amount of vaginal bleeding, with surgical findings of uterine rupture superior to the lower uterine segment. CONCLUSION: High-order gestations may be an independent risk factor for uterine rupture. PMID- 23344418 TI - Spontaneous rupture of solid pseudopapillary neoplasm of the pancreas during pregnancy. AB - BACKGROUND: Spontaneous rupture of solid pseudopapillary neoplasm of the pancreas is an unusual complication during pregnancy. CASE: At 19 weeks of gestation, a 29 year-old woman presented with a pancreatic mass and upper abdominal pain radiating to the back. On the third day of admission, shock and peritoneal signs developed. Exploratory laparotomy and subsequent subtotal pancreatectomy were performed for a bleeding tumor. Solid pseudopapillary neoplasm was confirmed by pathological examination. The patient delivered a healthy full-term girl vaginally. Eight months postoperatively, the clinical courses of both mother and infant have been uneventful. CONCLUSION: Ruptured solid pseudopapillary neoplasms can cause an acute abdomen during pregnancy. The expression of progesterone receptors in solid pseudopapillary neoplasm is a possible cause of this potentially devastating event. PMID- 23344419 TI - Nonsurgical management of heterotopic abdominal pregnancy. AB - BACKGROUND: Heterotopic abdominal pregnancies with coexisting intrauterine pregnancies pose unique therapeutic challenges, and management options, particularly nonsurgical approaches, are limited. CASE: We present a case in which selective reduction of a heterotopic abdominal pregnancy during the second trimester using fetal intracardiac injection with potassium chloride enabled subsequent vaginal delivery of the intrauterine pregnancy at term. In addition, we summarize nine cases of nonsurgical management of heterotopic abdominal pregnancies, four of which involve potassium chloride selective reduction. Our case is unique in that the abdominal fetus remained as a stable lithopedion, allowing the uncomplicated conception and vaginal delivery of a second intrauterine pregnancy without need for surgical intervention. CONCLUSION: Our case report and literature review demonstrate the use of selective potassium chloride reduction in managing heterotopic abdominal pregnancy nonsurgically. PMID- 23344420 TI - Peripheral subcutaneous vulvar stimulation in the management of severe and refractory vulvodynia. AB - BACKGROUND: Vulvodynia is a complex and multifactorial clinical condition with severe pain that occurs in the absence of visible infectious, inflammatory, neoplastic, or neurological findings. CASE: A 35-year-old woman with 3 years of dysesthetic vulvodynia tried conventional and interventional medical treatment with inadequate relief. She was offered peripheral subcutaneous vulvar field stimulation and underwent implantation of two vulvar subcutaneous electrodes. At 15 days after treatment and during 1-year follow-up, the patient scored 1 out of 15 on Friedrich scale, 1 out of 10 on the visual analog scale, and 1 out of 10 on the tampon test. The patient no longer requires oral medication. CONCLUSION: Stimulation with subcutaneous electrodes provided relief from vulvodynia to a patient in whom all previous therapeutic approaches had failed. PMID- 23344421 TI - Recurrent severe oligohydramnios and fetal pulmonary hypoplasia associated with ErbB4 mutation. AB - BACKGROUND: Pulmonary hypoplasia resulting from oligohydramnios or anhydramnios can cause severe respiratory compromise in newborn patients. We report a case of recurrent oligohydramnios in a mother with an ErbB4 mutation and speculate that the effects on the placenta through decreased vascularization contributed to oligohdyramnios and subsequent pulmonary hypoplasia in the newborn. CASE: The pregnant mother in this case had two subsequent term pregnancies complicated by severe oligohydramnios. Both pregnancies resulted in live born female neonates with pulmonary hypoplasia, pneumothoraces, and pulmonary hypertension. The mother and second newborn, who died, were found to have the ErbB4 mutation. Examination of the placenta with that pregnancy showed decreased vascularity. CONCLUSION: ErbB4 may have important effects on placental development and hydramnios that also may affect neonatal pulmonary hypoplasia. PMID- 23344422 TI - Nanosilver: application and novel aspects of toxicology. AB - Nanomaterials are a challenge to toxicology. The high diversity of novel materials and products will require extensive expertize for evaluation and regulatory efforts. Nanomaterials are of substantial scientific and economic potential. Here, we will focus on nanosilver, a material not only with medical applications, but a rapidly increasing use in surprisingly many products. Consequently, toxicological evaluation has to cover an increasing range of complex topics. The toxicology of nanosilver is advancing rapidly; regulatory efforts by Federal Drug Agency and European Environment Protection Agencies are substantial. Current toxicological data, ranging from in vitro studies with cell lines to rodent experiments and ecological evaluation, are numerous, and many groups are providing continuously new data. However, standard classification based on nanosize only is neglecting nanoshape, which adds another level of complexity to the analysis of biological effects. A surprising neglect in nanosilver toxicology so far is the analysis of effects of nanosilver on amyloidosis. Amyloid diseases are widespread in humans and a severe health hazard. The known potential of silver to stimulate amyloidosis in rodents will require a timely and balanced evaluation of nanosilvers. PMID- 23344423 TI - Arthroscopic transtibial single-bundle posterior cruciate ligament reconstruction using patellar tendon graft compared with hamstring tendon graft. AB - PURPOSE: The purpose of this study was to compare the outcomes of arthroscopic transtibial single-bundle posterior cruciate ligament reconstruction using autologous patellar tendon and hamstring tendon grafts. METHODS: From 1998 to 2007, 59 patients with symptomatic isolated posterior cruciate ligament injury were included in this retrospective study. Twenty-five knees were reconstructed using bone-patellar tendon-bone graft, and 34 knees were reconstructed using hamstring graft. In both groups, surgical techniques were similar, except material of fixation screws. Patients were evaluated pre-operatively and post operatively at the latest follow-up with several parameters, including symptoms, physical examination, outcome satisfaction, functional scores, radiography and complications. RESULTS: Average follow-up period was 51.6 months in patellar tendon group and 51.1 months in hamstring tendon group. Significantly more kneeling pain (32 vs. 3 %), squatting pain (24 vs. 3 %), anterior knee pain (36 vs. 3 %), posterior drawer laxity and osteoarthritic change were shown in patellar tendon group than in hamstring tendon group post-operatively. No significant differences were found in other parameters between both groups. CONCLUSIONS: Several shortcomings, including anterior knee pain, squatting pain, kneeling pain and osteoarthritic change, have to be concerned when using patellar tendon autograft. In conclusion, hamstring tendon autograft may be a better choice for transtibial tunnel PCL reconstruction. PMID- 23344424 TI - Hypertrophied facial fat in an HIV-1-infected patient after autologous transplantation from 'buffalo hump' retains a partial brown-fat-like molecular signature. AB - BACKGROUND: Facial lipoatrophy, a common alteration among HIV-1-infected, antiretroviral-treated patients, is often corrected using autologous transplantation. In some cases, especially when enlarged adipose tissue from the dorso-cervical area (that is, a 'buffalo hump') is used as a source of fat for transplantation, the transplanted fat develops progressive hypertrophy. To gain insight into the molecular basis of this phenomenon, we evaluated the cell morphology and gene expression in this hypertrophied facial fat. METHODS: Quantitative real-time PCR was used to examine the expression of various marker genes in a sample of facial fat that underwent hypertrophy after autologous transplantation. The results were compared with gene expression data from 'buffalo hump' fat and subcutaneous fat from healthy controls. Optical and electron microscopic analyses were used to determine cell morphology. RESULTS: The enlarged facial adipose tissue did not exhibit the overt microscopic morphology of brown adipose tissue but (similar to 'buffalo hump' fat) it contained adipocytes heterogeneous in size. The enlarged facial fat retained the partial molecular signature of a distorted brown-to-white adipocyte phenotype, including expression of uncoupling protein-1 (UCP1) transcript, and showed unaltered adipogenesis and inflammation that are characteristic of 'buffalo hump' fat. CONCLUSIONS: Despite being implanted in a former lipoatrophic area, facially grafted 'buffalo hump' tissue appears to retain the altered phenotype of dorso cervical adipose cells, thus accounting for its progressive enlargement. These results argue that caution should be exercised when considering 'buffalo hump' fat depots as a fat source for autologous transplantation. PMID- 23344425 TI - Sustained silent reading: an outcome that matters. PMID- 23344426 TI - Radiocesium fallout in the grasslands on Sakhalin, Kunashir and Shikotan Islands due to Fukushima accident: the radioactive contamination of soil and plants in 2011. AB - The accident at the Fukushima Dai-ichi Nuclear Power Plant has resulted in radioactive contamination of environmental media and food in the Far East of Russia, particularly in the Sakhalin Region. To obtain the knowledge about the (134)Cs and (137)Cs spatial distribution in the Sakhalin Region, soil samples were collected at 31 representative grassland sites on Sakhalin, Kunashir and Shikotan islands (43.80 degrees -46.40 degrees N and 142.73 degrees -146.84 degrees E) in the middle of May and around the end of September to early October 2011. In the autumn, vegetation samples (mixed grass/forb crop and bamboo, Sasa sp.) were collected together with soil samples. Maximum measured activity concentrations (on dry weight) of (134)Cs and (137)Cs in soil were 30 Bq kg(-1) and 210 Bq kg(-1), respectively. Within soil profile, (134)Cs activity concentrations declined rapidly with depth. Although for both sampling occasions (in the spring and autumn) the radionuclide was completely retained in the upper 3-4 cm of soil, a deeper penetration of the contaminant into the ground was observed in the autumn. In contrast with (134)Cs, activity concentrations of (137)Cs demonstrated a broad range of the vertical distribution in soil; at most sites, the radionuclide was found down to a depth of 20 cm. This resulted from interfering the aged pre-accidental (137)Cs and the new Fukushima-borne (137)Cs. To calculate contribution of these sources to the inventory of (137)Cs, the (134)Cs:(137)Cs activity ratio of 1:1 in Fukushima fallout (the reference date 15 March 2011) was used. The maximum deposition density of Fukushima-derived (137)Cs was found on Shikotan and Kunashir Islands with average density of 0.124 +/- 0.018 kBq m(-2) and 0.086 +/- 0.026 kBq m(-2), respectively. Sakhalin Island was less contaminated by Fukushima-derived (137)Cs of 0.021 +/- 0.018 kBq m(-2). For the south of Sakhalin Island, the reference inventory of pre-Fukushima (137)Cs was calculated as 1.93 +/- 0.25 kBq m(-2) (reference date 15 March 2011). For Shikotan and Kunashir Islands, the pre-Fukushima reference levels of (137)Cs ground contamination appeared to be higher: on average, 2.81 +/- 0.35 kBq m(-2). Maximum measured activity concentrations (on wet weight) of (134)Cs and (137)Cs in the vegetation were 5 Bq kg(-1) and 18 Bq kg(-1), respectively. Soil-to-plant aggregated transfer factors, T(ag)s, for (134)Cs were more than an order of magnitude higher than those for (137)Cs. For the above-ground biomass density of 1 kg per m(2) (wet weight), plant contamination may contribute approximately 2% and 0.1% to the ground deposition of Fukushima-derived and pre-accidental (137)Cs, respectively. PMID- 23344427 TI - Food availability determines the response to pond desiccation in anuran tadpoles. AB - Food availability and pond desiccation are two of the most studied factors that condition amphibian metamorphosis. It is well known that, when food is abundant, organisms undergo metamorphosis early and when they are relatively large. The capability of anurans to accelerate their developmental rate in response to desiccation is also common knowledge. These two variables must act together in nature, since we know that, as a pond dries, the per capita resources decrease. We conduct an experiment to evaluate the effects of desiccation and food availability separately and in combination in tadpoles of the painted frog (Discoglossus pictus). We demonstrate that food deprivation leads to slow growth rates, which delay metamorphosis and produce smaller size and weight. The capability to accelerate metamorphosis when facing a drying pond is also confirmed, but, nevertheless, with factor interaction (when the pool is drying and resources are scarce) the capacity to respond to desiccation is lost. In addition, slow drying rates are shown to be stressful situations, but not enough to provoke a shortening of the larval period; in fact, the larval period becomes longer. We also demonstrate that the interaction of these factors changes the allometric relationship of different parts of the hind limb, which has implications for the biomechanics of jumping. Due to low mortality rates and an adequate response to both environmental factors, we expect D. pictus to have a great invasive potential in its new Mediterranean distribution area, where lots of temporary and ephemeral ponds are present. PMID- 23344428 TI - Mechanochemistry: Demonstrated leverage. PMID- 23344430 TI - Sulfur as a selective 'soft' oxidant for catalytic methane conversion probed by experiment and theory. AB - Developing efficient catalytic processes to convert methane into useful feedstocks relies critically upon devising new coupling processes that use abundant, thermodynamically 'mild' oxidants together with selective catalysts. We report here on elemental sulfur as a promising 'soft' oxidant for selective methane conversion to ethylene over MoS(2), RuS(2), TiS(2), PdS and Pd/ZrO(2) catalysts. Experiments and density functional theory reveal that methane conversion is directly correlated with surface metal-sulfur bond strengths. Surfaces with weakly bound sulfur are more basic and activate methane C-H bonds more readily. In contrast, experimental and theoretical selectivities scale inversely with surface metal-sulfur bond strengths, and surfaces with the strongest metal-sulfur bonds afford the highest ethylene selectivities. High CH(4)/S ratios, short contact times and the provision of a support maximizes the coupling of CH(x) intermediates and selectivity to ethylene, because these conditions yield surfaces with stronger metal-sulfur bonding (for example, Pd(16)S(7)), which suppresses the over-oxidation of methane. PMID- 23344429 TI - Synthetic cascades are enabled by combining biocatalysts with artificial metalloenzymes. AB - Enzymatic catalysis and homogeneous catalysis offer complementary means to address synthetic challenges, both in chemistry and in biology. Despite its attractiveness, the implementation of concurrent cascade reactions that combine an organometallic catalyst with an enzyme has proven challenging because of the mutual inactivation of both catalysts. To address this, we show that incorporation of a d(6)-piano stool complex within a host protein affords an artificial transfer hydrogenase (ATHase) that is fully compatible with and complementary to natural enzymes, thus enabling efficient concurrent tandem catalysis. To illustrate the generality of the approach, the ATHase was combined with various NADH-, FAD- and haem-dependent enzymes, resulting in orthogonal redox cascades. Up to three enzymes were integrated in the cascade and combined with the ATHase with a view to achieving (i) a double stereoselective amine deracemization, (ii) a horseradish peroxidase-coupled readout of the transfer hydrogenase activity towards its genetic optimization, (iii) the formation of L pipecolic acid from L-lysine and (iv) regeneration of NADH to promote a monooxygenase-catalysed oxyfunctionalization reaction. PMID- 23344431 TI - A backbone lever-arm effect enhances polymer mechanochemistry. AB - Mechanical forces along a polymer backbone can be used to bring about remarkable reactivity in embedded mechanically active functional groups, but little attention has been paid to how a given polymer backbone delivers that force to the reactant. Here, single-molecule force spectroscopy was used to directly quantify and compare the forces associated with the ring opening of gem-dibromo and gem-dichlorocyclopropanes affixed along the backbone of cis-polynorbornene and cis-polybutadiene. The critical force for isomerization drops by about one third in the polynorbornene scaffold relative to polybutadiene. The root of the effect lies in more efficient chemomechanical coupling through the polynorbornene backbone, which acts as a phenomenological lever with greater mechanical advantage than polybutadiene. The experimental results are supported computationally and provide the foundation for a new strategy by which to engineer mechanochemical reactivity. PMID- 23344432 TI - Bond-strengthening pi backdonation in a transition-metal pi-diborene complex. AB - Transition-metal catalysis is founded on the principle that electron donation from a metal to a ligand is accepted by an antibonding orbital of the ligand, thereby weakening one of the bonds in the ligand. Without this, the initial step of bond activation in many catalytic processes would simply not occur. This concept is enshrined in the well-accepted Dewar-Chatt-Duncanson model of transition-metal bonding. We present herein experimental and computational evidence for the first true violation of the Dewar-Chatt-Duncanson bonding model, found in a pi-diborene complex in which an electron-rich group 10 metal donates electrons into an empty bonding pi orbital on the ligand, and thereby strengthens the bond. The complex is also the first transition-metal complex to contain a bound diborene, a species not isolated before, either in its free form or bound to a metal. PMID- 23344440 TI - Fluorescent imaging: Shining a light into live cells. PMID- 23344433 TI - A divergent approach to the synthesis of the yohimbinoid alkaloids venenatine and alstovenine. AB - The yohimbinoid alkaloids continue to receive considerable attention from the synthetic community because of their interesting chemical structures and varied biological activity. Although there are several elegant syntheses of certain members of this group of alkaloids, a truly unified approach has yet to be developed. In short, general approaches to this compound class are hampered by a lack of complete control in setting the C(3) stereocentre at a late stage. Herein, we report that a functionalized hydrindanone enables a divergent strategy that builds on existing precedent to address this long-standing challenge. Utilizing an aminonitrile intermediate, the stereochemistry at C(3) of the yohimbinoid skeleton can be controlled effectively in a Pictet-Spengler reaction. We applied this approach to the first total syntheses of the C(3) epimeric natural products venenatine and alstovenine. PMID- 23344441 TI - Air/water interface: Two sides of the acid-base story. PMID- 23344442 TI - Burgenstock 2012: Reflections on stereochemistry. PMID- 23344443 TI - Main group chemistry: metal-reinforced bonding. PMID- 23344444 TI - Gas separation: Trapdoors in zeolites. PMID- 23344445 TI - Methane activation: Oxidation goes soft. PMID- 23344446 TI - A supramolecular approach to combining enzymatic and transition metal catalysis. AB - The ability of supramolecular host-guest complexes to catalyse organic reactions collaboratively with an enzyme is an important goal in the research and discovery of synthetic enzyme mimics. Herein we present a variety of catalytic tandem reactions that employ esterases, lipases or alcohol dehydrogenases and gold(I) or ruthenium(II) complexes encapsulated in a Ga(4)L(6) tetrahedral supramolecular cluster. The host-guest complexes are tolerated well by the enzymes and, in the case of the gold(I) host-guest complex, show improved reactivity relative to the free cationic guest. We propose that supramolecular encapsulation of organometallic complexes prevents their diffusion into the bulk solution, where they can bind amino-acid residues on the proteins and potentially compromise their activity. Our observations underline the advantages of the supramolecular approach and suggest that encapsulation of reactive complexes may provide a general strategy for carrying out classic organic reactions in the presence of biocatalysts. PMID- 23344447 TI - Catalytic transformation of alcohols to carboxylic acid salts and H2 using water as the oxygen atom source. AB - The oxidation of alcohols to carboxylic acids is an important industrial reaction used in the synthesis of bulk and fine chemicals. Most current processes are performed by making use of either stoichiometric amounts of toxic oxidizing agents or the use of pressurized dioxygen. Here, we describe an alternative dehydrogenative pathway effected by water and base with the concomitant generation of hydrogen gas. A homogeneous ruthenium complex catalyses the transformation of primary alcohols to carboxylic acid salts at low catalyst loadings (0.2 mol%) in basic aqueous solution. A consequence of this finding could be a safer and cleaner process for the synthesis of carboxylic acids and their derivatives at both laboratory and industrial scales. PMID- 23344448 TI - A near-infrared fluorophore for live-cell super-resolution microscopy of cellular proteins. AB - The ideal fluorescent probe for bioimaging is bright, absorbs at long wavelengths and can be implemented flexibly in living cells and in vivo. However, the design of synthetic fluorophores that combine all of these properties has proved to be extremely difficult. Here, we introduce a biocompatible near-infrared silicon rhodamine probe that can be coupled specifically to proteins using different labelling techniques. Importantly, its high permeability and fluorogenic character permit the imaging of proteins in living cells and tissues, and its brightness and photostability make it ideally suited for live-cell super resolution microscopy. The excellent spectroscopic properties of the probe combined with its ease of use in live-cell applications make it a powerful new tool for bioimaging. PMID- 23344449 TI - A sustainable catalytic pyrrole synthesis. AB - The pyrrole heterocycle is a prominent chemical motif and is found widely in natural products, drugs, catalysts and advanced materials. Here we introduce a sustainable iridium-catalysed pyrrole synthesis in which secondary alcohols and amino alcohols are deoxygenated and linked selectively via the formation of C-N and C-C bonds. Two equivalents of hydrogen gas are eliminated in the course of the reaction, and alcohols based entirely on renewable resources can be used as starting materials. The catalytic synthesis protocol tolerates a large variety of functional groups, which includes olefins, chlorides, bromides, organometallic moieties, amines and hydroxyl groups. We have developed a catalyst that operates efficiently under mild conditions. PMID- 23344451 TI - Barium bright and heavy. PMID- 23344452 TI - Obstructive sleep apnea and heart rate asymmetry microstructure during sleep. AB - PURPOSE: Heart rate decelerations and accelerations have unequal input to heart rate variability (HRV) and patterns created by consecutive cardiac cycles-this phenomenon is known as heart rate asymmetry (HRA). The analysis of monotonic runs of heart rate decelerations and accelerations provides a detailed insight into the HRA microstructure and thus of HRV. AIM: To evaluate the relation between the severity of obstructive sleep apnea (OSA) and the HRA microstructure during sleep. METHODS: Seventy-eight patients with suspected OSA underwent overnight polysomnography. The 300-min ECGs from the polysomnography were selected and analyzed. The HRA microstructure was quantified by measuring (1) the contribution of monotonic runs of decelerations or accelerations of different lengths to the number of all sinus beats, and (2) the length of the longest deceleration and acceleration runs. RESULTS: There were 19 patients with no/mild OSA (Apnea/Hypopnea Index (AHI) 5.1 +/- 2.5/h), 18 with moderate OSA (AHI 21.8 +/- 4.0/h) and 41 with severe OSA (AHI 42.8 +/- 17.4/h). Patients with severe OSA had significantly reduced deceleration and acceleration runs of length 1 compared to the moderate OSA group, and compared to patients with no/mild OSA they had an increased number of longer runs (from 5 to 10 for accelerations and from 5 to 8 for decelerations; p < 0.05 for all comparisons). The longest acceleration runs were significantly longer in severe OSA group (p < 0.05) than in subjects with no/mild OSA. CONCLUSIONS: HRA microstructure is related with OSA severity. An increased number of longer deceleration and acceleration runs is more common in severe OSA patients. PMID- 23344453 TI - First evidence of placental transfer of ochratoxin A in horses. AB - Ochratoxin A (OTA) is a renal mycotoxin and transplacental genotoxic carcinogen. The aim of this study was to evaluate the natural occurrence of OTA in equine blood samples and its placental transfer. For the assessment of OTA levels, serum samples were collected from 12 stallions, 7 cycling mares and 17 pregnant mares. OTA was found in 83% of serum samples (median value = 121.4 pg/mL). For the assessment of placental transfer, serum samples were collected from the 17 mares after delivery and from the umbilical cords of their foals, after foaling. Fourteen serum samples from pregnant mares contained OTA (median value = 106.5 pg/mL), but only 50% of their foals were exposed (median values = 96.6 pg/mL). HPLC analysis carried out on four serum samples (collected from two mares and their respective foals) supported the ELISA results on OTA placental transfer. This is the first report on the natural occurrence of OTA in horse serum samples and placental transfer in horses. PMID- 23344454 TI - Influence of botulinum toxin therapy on postural control and lower limb intersegmental coordination in children with spastic cerebral palsy. AB - Botulinum toxin injections may significantly improve lower limb kinematics in gait of children with spastic forms of cerebral palsy. Here we aimed to analyze the effect of lower limb botulinum toxin injections on trunk postural control and lower limb intralimb (intersegmental) coordination in children with spastic diplegia or spastic hemiplegia (GMFCS I or II). We recorded tridimensional trunk kinematics and thigh, shank and foot elevation angles in fourteen 3-12 year-old children with spastic diplegia and 14 with spastic hemiplegia while walking either barefoot or with ankle-foot orthoses (AFO) before and after botulinum toxin infiltration according to a management protocol. We found significantly greater trunk excursions in the transverse plane (barefoot condition) and in the frontal plane (AFO condition). Intralimb coordination showed significant differences only in the barefoot condition, suggesting that reducing the degrees of freedom may limit the emergence of selective coordination. Minimal relative phase analysis showed differences between the groups (diplegia and hemiplegia) but there were no significant alterations unless the children wore AFO. We conclude that botulinum toxin injection in lower limb spastic muscles leads to changes in motor planning, including through interference with trunk stability, but a combination of therapies (orthoses and physical therapy) is needed in order to learn new motor strategies. PMID- 23344455 TI - Difference in F-actin depolymerization induced by toxin B from the Clostridium difficile strain VPI 10463 and toxin B from the variant Clostridium difficile serotype F strain 1470. AB - Clostridium difficile toxin A (TcdA) and toxin B (TcdB) are the causative agent of the C. difficile-associated diarrhea (CDAD) and its severe form, the pseudomembranous colitis (PMC). TcdB from the C. difficile strain VPI10463 mono glucosylates (thereby inactivates) the small GTPases Rho, Rac, and Cdc42, while Toxin B from the variant C. difficile strain serotype F 1470 (TcdBF) specifically mono-glucosylates Rac but not Rho(A/B/C). TcdBF is related to lethal toxin from C. sordellii (TcsL) that glucosylates Rac1 but not Rho(A/B/C). In this study, the effects of Rho-inactivating toxins on the concentrations of cellular F actin were investigated using the rhodamine-phalloidin-based F-actin ELISA. TcdB induces F-actin depolymerization comparable to the RhoA-inactivating exoenzyme C3 from C. limosum (C3-lim). In contrast, the Rac-glucosylating toxins TcdBF and TcsL did not cause F-actin depolymerization. These observations led to the conclusion that F-actin depolymerization depends on the toxin's capability of glucosylating RhoA. Furthermore, the integrity of focal adhesions (FAs) was analyzed using paxillin and p21-activated kinase (PAK) as FA marker proteins. Paxillin dephosphorylation was observed upon treatment of cells with TcdB, TcdBF, or C3-lim. In conclusion, the Rho-inactivating toxins induce loss of cell shape by either F-actin depolymerization (upon RhoA inactivation) or the disassembly of FAs (upon Rac1 inactivation). PMID- 23344456 TI - Bacillus anthracis protective antigen kinetics in inhalation spore-challenged untreated or levofloxacin/ raxibacumab-treated New Zealand white rabbits. AB - Inhaled Bacillus anthracis spores germinate and the subsequent vegetative growth results in bacteremia and toxin production. Anthrax toxin is tripartite: the lethal factor and edema factor are enzymatic moieties, while the protective antigen (PA) binds to cell receptors and the enzymatic moieties. Antibiotics can control B. anthracis bacteremia, whereas raxibacumab binds PA and blocks lethal toxin effects. This study assessed plasma PA kinetics in rabbits following an inhaled B. anthracis spore challenge. Additionally, at 84 h post-challenge, 42% of challenged rabbits that had survived were treated with either levofloxacin/placebo or levofloxacin/raxibacumab. The profiles were modeled using a modified Gompertz/second exponential growth phase model in untreated rabbits, with added monoexponential PA elimination in treated rabbits. Shorter survival times were related to a higher plateau and a faster increase in PA levels. PA elimination half-lives were 10 and 19 h for the levofloxacin/placebo and levofloxacin/raxibacumab groups, respectively, with the difference attributable to persistent circulating PA-raxibacumab complex. PA kinetics were similar between untreated and treated rabbits, with one exception: treated rabbits had a plateau phase nearly twice as long as that for untreated rabbits. Treated rabbits that succumbed to disease had higher plateau PA levels and shorter plateau duration than surviving treated rabbits. PMID- 23344458 TI - A reusable biosensor for detecting mercury(II) at the subpicomolar level based on "turn-on" resonance light scattering. AB - A reusable sensing strategy employing magnetic nanoparticles and thymine containing aptamers was developed to detect Hg(2+) in real water samples based on "turn-on" resonance light scattering. The LOD was as low as 500 fM (S/N = 3), and the present sensor can be repeatedly used for at least seven cycles. PMID- 23344457 TI - Bioinformatic analysis of benzo-alpha-pyrene-induced damage to the human placental insulin-like growth factor-1 gene. AB - INTRODUCTION: Intrauterine growth restriction (IUGR) has been associated with exposure to polyaromatic hydrocarbons (PAHs) which are released in the combustion of oil, fuel, gas, garbage, and tobacco. Pregnant women exposed to PAHs are at risk of the effects of these environmental toxins; for example, benzo-alpha pyrene (BalphaP) is able to enter the blood stream and could contribute to IUGR or other developmental abnormalities via effects on the placental cells. Since IUGR has been associated with decreased cord blood concentrations of immunoreactive insulin-like growth factor 1 (ir-IGF-1) and IUGR has been associated with disordered development and fetal programming, we tested the effects of BalphaP on human placental trophoblast cells in culture. EXPERIMENTAL: IGF-1 expression and activation was studied using an immortalized human placental trophoblast cell line (HTR-8). The cells were treated with vehicle control or 1 umol/L BalphaP, or 5 umol/L BalphaP for 12 hours. RNA was extracted and the exons of IGF-1 were amplified using reverse transcriptase-polymerase chain reaction (RT PCR). The ir-IGF-1 expression levels were compared using gel electrophoresis. The PCR products were sequenced, and levels of mutation were measured with comparative sequence analysis. A computational protein analysis (computer simulation) was performed in order to assess the potential impact of BalphaP associated mutation on IGF-1 protein function. RESULTS: The IGF-1 expression decreased considerably in BalphaP-treated cells relative to untreated controls (P < .05), also in a dose-dependent manner. Comparative sequence analysis indicated that the level of BalphaP exposure correlated with the percentage of base pair mutations in IGF-1 nucleotide sequences for both treatment groups (P < .05). Shifts were observed in the open reading frame, indicating a possible change in the IGF-1 start codon. Protein folding simulation analysis indicated that the base pair changes induced by BalphaP weakened IGF-1-IGF binding protein (IGFBP) interaction. CONCLUSIONS: In concordance with the previous findings, exposure of human placental trophoblast cells to BalphaP exposure results in reduction of IGF 1 expression and base pair mutations. The direct action of BalphaP on the placenta indicates that it may not be necessary for BalphaP to access other maternal tissues in order for gene abnormalities to occur. Given that PAHs are known to work through aryl hydrocarbon hydrolase (AHH), these results are likely due to the presence of AHH in HTR cells. Computational modeling of BalphaP actions on IGF1, substrate-ligand binding, supports the biological premise of this work and underlines the need to determine actual biological effects rather than equating immune to bioactivity of IGF1. PMID- 23344459 TI - The pathogenetic role of IL-1beta in severe epidermolysis bullosa simplex. PMID- 23344460 TI - Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas. AB - Vemurafenib (PLX4032), a selective inhibitor of Braf, has been approved by the US Food and Drug Administration for the treatment of unresectable or metastatic melanoma in patients with Braf(V600E) mutations. Many patients treated with vemurafenib initially display dramatic improvement, with decreases in both risk of death and tumor progression. Acquired resistance, however, rapidly arises in previously sensitive cells. We attempted to overcome this resistance by targeting the signal transducer and activator of transcription 3 (STAT3)-paired box homeotic gene 3 (PAX3)-signaling pathway, which is upregulated, owing to fibroblast growth factor 2 (FGF2) secretion or increased kinase activity, with the Braf(V600E) mutation. We found that activation of Stat3 or overexpression of PAX3 induced resistance to vemurafenib in melanoma cells. In addition, PAX3 or Stat3 silencing inhibited the growth of melanoma cells with acquired resistance to vemurafenib. Furthermore, treatment with the Stat3 inhibitor, WP1066, resulted in growth inhibition in both vemurafenib-sensitive and -resistant melanoma cells. Significantly, vemurafenib stimulation induced FGF2 secretion from keratinocytes and fibroblasts, which might uncover, at least in part, the mechanisms underlying targeting Stat3-PAX3 signaling to overcome the acquired resistance to vemurafenib. Our results suggest that Stat3-targeted therapy is a new therapeutic strategy to overcome the acquired resistance to vemurafenib in the treatment of melanoma. PMID- 23344461 TI - Photosensitizing agents and the risk of non-melanoma skin cancer: a population based case-control study. AB - It is well-known that UV light exposure and a sun-sensitive phenotype are risk factors for the development of non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). In this New Hampshire population-based case-control study, we collected data from 5,072 individuals, including histologically confirmed cases of BCC and SCC, and controls via a personal interview to investigate possible associations between photosensitizing medication use and NMSC. After adjustment for potentially confounding factors (e.g., lifetime number of painful sunburns), we found a modest increase in risk of SCC (odds ratio (OR)=1.2, 95% confidence interval (CI)=1.0-1.4) and BCC (OR=1.2, 95% CI=0.9-1.5), in particular early-onset BCC, (<= 50 years of age) (OR=1.5, 95% CI=1.1-2.1) associated with photosensitizing medication use. For SCC the association was strongest among those with tendency to sunburn rather than tan. We also specifically found associations with BCC, and especially early-onset BCC, and photosensitizing antimicrobials. In conclusion, certain commonly prescribed photosensitizing medications may enhance the risk of developing SCC, especially in individuals with a sun-sensitive phenotype, and may increase the risk of developing BCC and incidence of BCC at a younger age. PMID- 23344462 TI - Trigeminal melanoma metastasis. AB - We present the case of a 70-year-old patient presented to our institution for paresthesia of the right hemiface associated with dysarthria in aggravation since 1 year. He was diagnosed with right trigeminal melanoma metastasis. This case is characterized by a thickening of the right trigeminal nerve from his cisternal segment to his mandibular branch V3. MRI demonstrated an intensive perineural spread by a melanotic melanoma. PMID- 23344463 TI - Ongoing HIV replication in cerebrospinal fluid under successful monotherapy. AB - We report a case of an HIV-infected patient who was successfully treated with ritonavir/lopinavir (r/LPV) monotherapy for several years. He presented with neurological symptoms and high HIV RNA levels in cerebrospinal fluid (CSF). Sequencing of the HIV from the CSF revealed mutations in the protease gene reflecting resistance against most protease inhibitors, that is, lopinavir and ritonavir. His regimen was switched and after 2 months the HIV RNA viral load was again undetectable in both plasma as well as in CSF. Monotherapy with r/LPV may not be sufficient to fully suppress viral replication in the central nervous system in all individuals and may lead to compartimentalization and the selection of resistant mutations of HIV in the central nervous system. PMID- 23344464 TI - Medical surgery leagues. AB - Medical plastic surgery league is a group of medical students interested in plastic surgery and a professional volunteer in the area willing to share and produce knowledge. Students define their direction, and are coordinated by an board certified plastic surgeon. Students should be aware that the league is an opportunity to learn, to seek knowledge, to develop clinical and scientific reasoning, and stimulate its interaction with the community. It means strengthening and enhancement of expertise in different levels of learning. Even if they do not become plastic surgeons, students build skills that can be adapted to other conditions and situations in the future. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23344465 TI - Cutaneous idiopathic hyperchromia of the orbital region (CIHOR): a histopathological study. AB - BACKGROUND: Dark circles under or around the eyes is a cosmetic problem for a large number of people. It is a condition of unknown etiology characterized by the darkening of the eyelids and periorbital skin. The aim of this study was to determine histopathological changes associated with cutaneous idiopathic hyperchromia of the orbital region (CIHOR). METHODS: Twenty-eight adult patients with CIHOR were consecutively selected for the study. Biopsy specimens were taken from the darkened skin of the eyelid and from the normal retroauricular skin as a control. RESULTS: Hemosiderin was absent in all cases. The increase in melanin content in the papillary dermis was slight in mild clinical cases and moderate in both the moderate and severe clinical cases of CIHOR. Mild dilation of blood vessels was observed in the papillary dermis at the different clinical levels of CIHOR severity, while in the reticular dermis, blood vessels showed moderate dilation and few melanophages were found. CONCLUSION: An increase in melanin content was the most marked histological change in specimens of darkened skin. Dilation of dermal blood vessels may contribute to the severity of CIHOR. Hemosiderin was not observed in any case. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23344466 TI - Minimizing surgical skin incision scars with a latex surgical glove. AB - BACKGROUND: The current trend in minimally invasive surgery is to make a small surgical incision. However, the excessive tensile stress applied by the retractors to the skin surrounding the incision often results in a long wound healing time and extensive scarring. To minimize these types of wound problems, the authors evaluated a simple and cost-effective method to minimize surgical incision scars based on the use of a latex surgical glove. METHODS: The tunnel shaped part of a powder-free latex surgical glove was applied to the incision and the dissection plane. It was fixed to the full layer of the dissection plane with sutures. The glove on the skin surface then was sealed with Ioban (3 M Health Care, St. Paul, MN, USA) to prevent movement. The operation proceeded as usual, with the retractor running through the tunnel of the latex glove. RESULTS: It was possible to complete the operation without any disturbance of the visual field by the surgical glove, and the glove was neither torn nor separated by the retractors. The retractors caused traction and friction during the operation, but the extent of damage to the postoperative skin incision margin was remarkably less than when the operation was performed without a glove. CONCLUSION: This simple and cost-effective method is based on the use of a latex surgical glove to protect the surgical skin incision site and improve the appearance of the postoperative scar. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23344467 TI - A case series study on complications after breast augmentation with MacrolaneTM. AB - BACKGROUND: The use of MacrolaneTM seems to have several advantages compared to the other standard methods for breast augmentation: it is faster, less invasive, and requires only local anesthesia. Nevertheless, various complications associated with the use of MacrolaneTM have been described, e.g., encapsulated lumps in breast tissue, infection, and parenchymal fibrosis. We report the results of our case series study on the clinical and imaging evaluations of patients who came to our attention after breast augmentation with MacrolaneTM injection and evaluate the effect of this treatment on breast cancer screening procedures. METHODS: Between September 2009 and July 2010, seven patients, treated elsewhere with intramammary MacrolaneTM injection for cosmetic purposes, presented to our institution complaining of breast pain. In all patients, MacrolaneTM had been injected under local anesthesia in the retromammary space through a surgical cannula. RESULTS: On mammography, nodules appeared as gross lobulated radiopacities with polycyclic contours. On breast ultrasound, the nodules showed hypo-anaechogenic cystlike features. In all cases, image analysis by the radiologist was hindered by the presence of the implanted substance, which did not allow the complete inspection of the whole breast tissue. CONCLUSIONS: From our experience, although safe in other areas, injection of MacrolaneTM into breast tissue cannot be recommended at this time. Our study, along with other reports, supports the need to start a clinical trial on the use of injectable fillers in the breast to validate their safety and effectiveness. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23344468 TI - Evaluation of intraoperative bleeding during an endoscopic surgery of nasal polyposis after a pre-operative single dose versus a 5-day course of corticosteroid. AB - Nasal polyps are associated with the inflammation of the nasal cavity and the sinus mucosa. When medical treatment cannot solve a patient's problem, a functional endoscopic sinus surgery may be indicated. Bleeding impairs the surgery field during operation and increases the operation risk and time. Pre operative corticosteroids can reduce bleeding during surgery. In this study, we have evaluated the effect of pre-operative single-dose prednisolone (1 mg/Kg/dose 24 h before surgery) versus 5-day prednisolone (1 mg/Kg/day before operation) on the bleeding volume and the surgery field quality during FESS. In this mono blind randomized clinical trial, 80 patients with bilateral nasal polyps were randomly assigned in two groups. The first group (A) received a single dose of 1 mg/Kg/dose prednisolone on the day before the surgery. The second group (B) received 1 mg/Kg/day prednisolone for 5 days before the operation. The patients were operated on under general anesthesia through the same protocol. The mean arterial blood pressure was 70-80 mm Hg in both groups. The surgeons were not aware of the patients' group. The bleeding volume and the surgeons' opinion about the surgery field quality were recorded at the end of the procedure and analyzed by Chi-square and t test. The two groups were not significantly different in their overall demographic and clinical characteristics. The mean bleeding volume during the operation was 266.5 +/- 96.31 ml in group A and 206 +/- 52.81 ml in group B; there was a significant difference between the groups (P value = 0.038). There was no significant difference between the groups in the surgeons' opinion about the surgery field quality (P value = 0.09). In conclusion, unlike a single dose (1 mg/kg/dose), treatment with 5-day prednisolone (1 mg/kg/day) can reduce blood loss during FESS more efficiently and may improve the surgery field quality slightly. But this difference is not clinically significant. PMID- 23344469 TI - Systematic review and meta-analysis of the relation between body mass index and short-term donor outcome of laparoscopic donor nephrectomy. AB - In this era of organ donor shortage, live kidney donation has been proven to increase the donor pool; however, it is extremely important to make careful decisions in the selection of possible live donors. A body mass index (BMI) above 35 is generally considered as a relative contraindication for donation. To determine whether this is justified, a systematic review and meta-analysis were carried out to compare perioperative outcome of live donor nephrectomy between donors with high and low BMI. A comprehensive literature search was performed in MEDLINE, Embase, and CENTRAL (the Cochrane Library). All aspects of the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement were followed. Of 14 studies reviewed, eight perioperative donor outcome measures were meta analyzed, and, of these, five were not different between BMI categories. Three found significant differences in favor of low BMI (29.9 and less) donors with significant mean differences in operation duration (16.9 min (confidence interval (CI) 9.1-24.8)), mean difference in rise in serum creatinine (0.05 mg/dl (CI 0.01 0.09)), and risk ratio for conversion (1.69 (CI 1.12-2.56)). Thus, a high body mass index (BMI) alone is no contraindication for live kidney donation regarding short-term outcome. PMID- 23344470 TI - Dietary sodium restriction prevents kidney damage in high fructose-fed rats. AB - Sodium depletion has a protective effect on target-organ damage in hypertension independent of blood pressure. Here we tested whether chronic dietary sodium restriction may prevent the development of renal alterations associated with insulin resistance by reducing the inflammatory and oxidant state. Rats were fed normal-salt-60% fructose, low-salt-60% fructose, or control normal-salt diet for 12 weeks. Insulin resistance induced by high-fructose diet was associated with an increase in albuminuria, tubular and glomerular hypertrophy, and inflammation of kidney and adipose tissue. The low-salt diet improved insulin sensitivity and prevented kidney damage. These beneficial effects of sodium depletion were associated with a decrease in renal inflammation (macrophage infiltration, IL-6, TNF-alpha) and oxidative stress (NADPH oxidase activity), and a prevention of histologic changes in retroperitoneal fat induced by high fructose. Thus, dietary salt depletion has beneficial effects on renal and metabolic alterations associated with a high-fructose diet in rats. PMID- 23344471 TI - Leukocyte-derived MMP9 is crucial for the recruitment of proinflammatory macrophages in experimental glomerulonephritis. AB - Matrix metalloproteinase 9 (MMP9) is a conditionally expressed enzyme and is upregulated in glomerulonephritis. Its function in these diseases, however, remains to be fully elucidated. The induction of nephrotoxic serum nephritis (NTN) in wild-type mice resulted in an upregulation of MMP9, followed by leukocyte infiltration, albuminuria, and subsequent renal failure. MMP9 deficiency ameliorated the course of NTN as indicated by reduced histological injury and reduced infiltration of proinflammatory macrophages. The chemotaxis of MMP9-deficient macrophages in vitro was impaired. Intrarenal macrophages isolated from the kidneys of nephritic MMP9 knockout mice still displayed the typical features of a proinflammatory phenotype and were indistinguishable from wild type derived cells. Bone marrow transplantation restored renal tissue injury and macrophage recruitment when wild type-derived donor cells were transplanted onto MMP9-deficient mice prior to the induction of NTN. Thus, leukocyte-derived MMP9 mediates the recruitment of proinflammatory macrophages into kidneys during experimental crescentic glomerulonephritis. PMID- 23344472 TI - Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels. AB - Uromodulin (UMOD) genetic variants cause familial juvenile hyperuricemic nephropathy, characterized by hyperuricemia with decreased renal excretion of UMOD and uric acid, suggesting a role for UMOD in the regulation of plasma uric acid. To determine this, we screened common variants across the UMOD locus in one community-based Chinese population of 1000 individuals and the other population from 642 American twins and siblings of European and Hispanic ancestry. Transcriptional activity of promoter variants was estimated in luciferase reporter plasmids transfected into HEK-293 cells and mIMCD3 cells. In the primary Chinese population, we found that carriers of the GCC haplotype had higher plasma uric acid, and three promoter variants were associated with plasma uric acid. UMOD promoter variants displayed reciprocal effects on urine uric acid excretion and plasma uric acid concentration, suggesting a primary effect on renal tubular handling of urate. These UMOD genetic marker-on-trait associations for uric acid were replicated in the independent American cohort. Site-directed mutagenesis at trait-associated UMOD promoter variants altered promoter activity in transfected luciferase reporter plasmids. Thus, UMOD promoter variants seem to initiate a cascade of transcriptional and biochemical changes influencing UMOD secretion, leading to altered plasma uric acid levels. PMID- 23344473 TI - Urine neutrophil gelatinase-associated lipocalin levels do not improve risk prediction of progressive chronic kidney disease. AB - Novel biomarkers may improve our ability to predict which patients with chronic kidney disease (CKD) are at higher risk for progressive loss of renal function. Here, we assessed the performance of urine neutrophil gelatinase-associated lipocalin (NGAL) for outcome prediction in a diverse cohort of 3386 patients with CKD in the Chronic Renal Insufficiency Cohort study. In this cohort, the baseline mean estimated glomerular filtration rate (eGFR) was 42.4 ml/min per 1.73 m(2), the median 24-h urine protein was 0.2 g/day, and the median urine NGAL concentration was 17.2 ng/ml. Over an average follow-up of 3.2 years, there were 689 cases in which the eGFR was decreased by half or incident end-stage renal disease developed. Even after accounting for eGFR, proteinuria, and other known CKD progression risk factors, urine NGAL remained a significant independent risk factor (Cox model hazard ratio 1.70 highest to lowest quartile). The association between baseline urine NGAL levels and risk of CKD progression was strongest in the first 2 years of biomarker measurement. Within this time frame, adding urine NGAL to a model that included eGFR, proteinuria, and other CKD progression risk factors led to net reclassification improvement of 24.7%, but the C-statistic remained nearly identical. Thus, while urine NGAL was an independent risk factor of progression among patients with established CKD of diverse etiology, it did not substantially improve prediction of outcome events. PMID- 23344474 TI - Effect of frequent hemodialysis on residual kidney function. AB - Frequent hemodialysis can alter volume status, blood pressure, and the concentration of osmotically active solutes, each of which might affect residual kidney function (RKF). In the Frequent Hemodialysis Network Daily and Nocturnal Trials, we examined the effects of assignment to six compared with three-times per-week hemodialysis on follow-up RKF. In both trials, baseline RKF was inversely correlated with number of years since onset of ESRD. In the Nocturnal Trial, 63 participants had non-zero RKF at baseline (mean urine volume 0.76 liter/day, urea clearance 2.3 ml/min, and creatinine clearance 4.7 ml/min). In those assigned to frequent nocturnal dialysis, these indices were all significantly lower at month 4 and were mostly so at month 12 compared with controls. In the frequent dialysis group, urine volume had declined to zero in 52% and 67% of patients at months 4 and 12, respectively, compared with 18% and 36% in controls. In the Daily Trial, 83 patients had non-zero RKF at baseline (mean urine volume 0.43 liter/day, urea clearance 1.2 ml/min, and creatinine clearance 2.7 ml/min). Here, treatment assignment did not significantly influence follow-up levels of the measured indices, although the range in baseline RKF was narrower, potentially limiting power to detect differences. Thus, frequent nocturnal hemodialysis appears to promote a more rapid loss of RKF, the mechanism of which remains to be determined. Whether RKF also declines with frequent daily treatment could not be determined. PMID- 23344475 TI - Dietary vitamin K and therapeutic warfarin alter the susceptibility to vascular calcification in experimental chronic kidney disease. AB - The leading cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease, with vascular calcification being a key modifier of disease progression. A local regulator of vascular calcification is vitamin K. This gamma-glutamyl carboxylase substrate is an essential cofactor in the activation of several extracellular matrix proteins that inhibit calcification. Warfarin, a common therapy in dialysis patients, inhibits the recycling of vitamin K and thereby decreases the inhibitory activity of these proteins. In this study, we sought to determine whether modifying vitamin K status, either by increasing dietary vitamin K intake or by antagonism with therapeutic doses of warfarin, could alter the development of vascular calcification in male Sprague Dawley rats with adenine-induced CKD. Treatment of CKD rats with warfarin markedly increased pulse pressure and pulse wave velocity, as well as significantly increased calcium concentrations in the thoracic aorta (3-fold), abdominal aorta (8-fold), renal artery (4-fold), and carotid artery (20-fold). In contrast, treatment with high dietary vitamin K1 increased vitamin K tissue concentrations (10-300-fold) and blunted the development of vascular calcification. Thus, vitamin K has an important role in modifying mechanisms linked to the susceptibility of arteries to calcify in an experimental model of CKD. PMID- 23344476 TI - Selective estrogen receptor modulation attenuates proteinuria-induced renal tubular damage by modulating mitochondrial oxidative status. AB - Proteinuria is an independent risk factor for progressive renal diseases because it initiates or aggravates tubulointerstitial injury. Clinically, females are less susceptible to progression of chronic kidney disease; however, the mechanisms underlying the renoprotective effect of estrogen receptor stimulation have yet to be clarified. Recently, inflammasome-dependent inflammatory responses were shown to be triggered by free fatty acids, and mitochondria-derived reactive oxygen species were shown to be required for this response. Albumin-bound free fatty acids trigger inflammasome activation through mitochondrial reactive oxygen species production in human proximal tubule epithelial cells in vitro, an effect inhibited by raloxifene. Female ICR-derived glomerulonephritic mice (mice with hereditary nephritic syndrome) were ovariectomized and treated with raloxifene, a selective estrogen receptor modulator. Ovariectomized mice showed activation of tubular inflammasomes and elevated levels of inflammasome-dependent cytokines. Raloxifene attenuated these changes ameliorating tubulointerstitial damage, reduced production of reactive oxygen species, averted morphological changes, and improved respiratory function in mitochondria. The expression of genes that encode rate-limiting enzymes in the mitochondrial beta-oxidation pathway was reduced by ovariectomy but enhanced by raloxifene. Thus, inflammasomes may be a novel and promising therapeutic target for proteinuria-induced renal injury. PMID- 23344477 TI - Change in the estimated glomerular filtration rate over time and risk of all cause mortality. AB - Using a community-based cohort we studied the association between changes in the estimated glomerular filtration rate (eGFR) over time and the risk of all-cause mortality. We identified 529,312 adults who had at least three outpatient eGFR measurements over a 4-year period from a provincial laboratory repository in Alberta, Canada. Two indices of change in eGFR were evaluated: the absolute annual rate of change (in ml/min per 1.73 m(2) per year) and the annual percentage change (percent/year). The adjusted mortality risk associated with each category of change in eGFR was assessed, using stable eGFR (no change) as the reference. Over a median follow-up of 2.5 years there were 32,372 deaths. Compared to the reference participants, those with the greatest absolute annual decline less than or equal to 5 ml/min per 1.73 m(2) per year had significantly increased mortality (hazard ratio of 1.52) adjusted for covariates and kidney function at baseline (last eGFR measurement). Participants with the greatest increase in eGFR of 5 ml/min per 1.73 m(2) per year or more also had significantly increased mortality (adjusted hazard ratio of 2.20). A similar pattern was found when change in eGFR was quantified as an annual percentage change. Thus, both declining and increasing eGFR were independently associated with mortality and underscore the importance of identifying change in eGFR over time to improve mortality risk prediction. PMID- 23344478 TI - Role of pCeMT, a putative metallothionein from Colocasia esculenta, in response to metal stress. AB - Metallothioneins (MTs) play a major role in metal homeostasis and/or detoxification in plants. In this study, a novel gene, pCeMT, was isolated from Colocasia esculenta and characterized. Our results indicate that Escherichia coli cells expressing pCeMT exhibited enhanced Cd, Cu, and Zn tolerance and accumulation compared with control cells. Furthermore, pCeMT-overexpressing tobacco seedlings displayed better growth under Cd, Cu, and Zn stresses and accumulated more Cd and Zn compared with the wild type. Interestingly, transgenic tobacco displayed markedly decreased hydrogen peroxide (H(2)O(2)) and lipid peroxidation levels under Cd, Cu, and Zn treatments. These results suggest that pCeMT could play an important role in the protection of plant cells from oxidative stress by reactive oxygen species (ROS) scavenging and in the detoxification of free metals by metal binding, leading to improved plant metal tolerance. PMID- 23344481 TI - The need for a national total joint registry. PMID- 23344482 TI - Response from the authors. PMID- 23344483 TI - The cycle of comorbidities: potential risks with delayed joint replacement. AB - Joint replacement is an option that has demonstrated significant improvement in the quality of life for individuals with severe arthritis. However, it is often delayed either in an attempt to avoid future revision surgeries or for other personal reasons. Increasing disability leads to inactivity, chronic pain, and sleep disruption, each of which cycles into significant comorbid risks, many of which are life-threatening. A beginning conceptual framework identified as the cycle of comorbidities is presented to identify these risks and help guide both the patient and the provider in the decision-making process associated with joint replacement surgery. PMID- 23344485 TI - Finding the evidence to support evidence-based practice. AB - Practicing from an evidence-based paradigm requires the practitioner to integrate best available evidence with the patient's preference and values, the clinical context, and the practitioner's clinical expertise. However, the clinician is often at a loss for where to access best evidence. The 6S Model of evidence acquisition can guide the busy practitioner in efficient searching for best available evidence. The article explains the 6S model and the strengths and weaknesses of different types of evidence, while guiding readers with their role as clinicians in ensuring trustworthiness of evidence and relevance to their particular clinical context and patient population. PMID- 23344487 TI - Osteoarthritis: detection, pathophysiology, and current/future treatment strategies. AB - Osteoarthritis (OA) is a disease of the joint, and age is the major risk factor for its development. Clinical manifestation of OA includes joint pain, stiffness, and loss of mobility. Currently, no pharmacological treatments are available to treat this specific joint disease; only symptom-modifying drugs are available. Improvement in imaging technology, identification of biomarkers, and increased understanding of the molecular basis of OA will aid in detecting the early stages of disease. Yet the development of interventional strategies remains elusive and will be critical for effective prevention of OA-associated joint destruction. The potential of cell-based therapies may be applicable in improving joint function in mild to more advanced cases of OA. Ongoing studies to understand the basis of this disease will eventually lead to prevention and treatment strategies and will also be a key in reducing the social and economic burden of this disease. Nurses are advised to provide an integrative approach of disease assessment and management in OA patients' care with a focus on education and implementation. Knowledge and understanding of OA and how this affects the individual patient form the basis for such an integrative approach to all-round patient care and disease management. PMID- 23344489 TI - Patients' experiences of pain in the 48 hours following total knee arthroplasty. AB - BACKGROUND: Previous research indicates that both pain severity and interference caused by pain should be addressed in the recovery period following total knee arthroplasty. PURPOSE: This research describes the range of pain severity of patients in the first 48 hours postoperation, ways in which pain interferes with activities, and the observed differences in pain experience by patients' age, level of education, race, and gender, using the Brief Pain Inventory. ANALYSIS: Descriptive statistics and multivariate analysis were used to assess the data. FINDINGS: Of the participants, 12% reported severe pain and 35% reported severe interference with general activities. Pain interfered most with walking, activities, and physical therapy. There were no differences by race, gender, or education. Older participants reported less pain and less interference. Participants reporting nonsurgical pain reported more interference with mood, walking, relationships with other people, and sleep. RECOMMENDATIONS: Pain evaluation should include an assessment of pain unrelated to the surgical procedure. Additional research exploring the impact of nonpostoperative surgical pain during the postoperative period is needed. PMID- 23344490 TI - Your client has multiple sclerosis: understanding the challenge. AB - Multiple sclerosis (MS) is an autoimmune inflammatory disease that causes muscle weakness or spasticity, balance incoordination, sensory deficit, and fatigue. Any of these effects of MS can increase the risk for orthopaedic injury that places individuals with MS in an orthopaedic care setting. Nurses with an understanding of MS and the effect of MS on the body will be better prepared to educate peers about MS, act as advocates for individuals with MS in the orthopaedic setting, and offer optimum care that addresses the patient's MS as well as the orthopaedic problem. The following discussion addresses MS, its effect on the body, and various approaches to managing the disease, including a brief look at the current disease-modifying agents available to reduce or slow the neurologic damage caused by MS. PMID- 23344493 TI - Acute quadriceps tendon rupture. PMID- 23344496 TI - Tumorigenesis: All together now. PMID- 23344497 TI - Increased serum and urinary microRNAs in children with idiopathic nephrotic syndrome. AB - BACKGROUND: MicroRNAs (miRNAs) are present in body fluids and may have the potential to serve as disease biomarkers. This study explored the clinical value of miRNAs in serum and urine as biomarkers for idiopathic childhood nephrotic syndrome (NS). METHODS: We obtained serum samples from 159 NS children (24 steroid resistant and 135 steroid sensitive), 109 age/sex-matched healthy controls and 44 children with other kidney diseases. Serum miRNAs were analyzed with the TaqMan Low Density Array and then validated with a quantitative reverse transcription PCR assay with 126 individual samples. Moreover, we collected paired serum samples from 50 patients before and after treatment to determine the value of these miRNAs for condition assessment. In addition, urine samples from these patients were examined for candidate miRNAs. RESULTS: The concentrations of serum miR-30a-5p, miR-151-3p, miR-150, miR-191, and miR-19b were highly increased in NS children compared with controls (P < 0.0001). The urinary miR-30a-5p concentration was also increased in NS (P = 0.001). The area under the ROC curve and the odds ratio for the combined 5 serum miRNAs were 0.90 (95% CI, 0.86-0.94; P < 0.0001) and 40.7 (95% CI, 6.06-103; P < 0.0001), respectively. Moreover, the concentrations of the 5 serum miRNAs and urinary miR-30a-5p markedly declined with the clinical improvement of the patients. CONCLUSIONS: We determined that 5 distinct serum miRNAs and urinary miR-30a-5p were increased in NS children. These circulating or urinary miRNAs may represent potential diagnostic and prognostic biomarkers for idiopathic pediatric NS. PMID- 23344498 TI - Quantification of 5-methylcytosine and 5-hydroxymethylcytosine in genomic DNA from hepatocellular carcinoma tissues by capillary hydrophilic-interaction liquid chromatography/quadrupole TOF mass spectrometry. AB - BACKGROUND: 5-Methylcytosine (5-mC) is an important epigenetic modification involved in development and is frequently altered in cancer. 5-mC can be enzymatically converted to 5-hydroxymethylcytosine (5-hmC). 5-hmC modifications are known to be prevalent in DNA of embryonic stem cells and neurons, but the distribution of 5-hmC in human liver tumor and matched control tissues has not been rigorously explored. METHODS: We developed an online trapping/capillary hydrophilic-interaction liquid chromatography (cHILIC)/in-source fragmentation/tandem mass spectrometry system for quantifying 5-mC and 5-hmC in genomic DNA from hepatocellular carcinoma (HCC) tumor tissues and relevant tumor adjacent tissues. A polymer-based hydrophilic monolithic column was prepared and used for the separation of 12 nucleosides by cHILIC coupled with an online trapping system. Limits of detection and quantification, recovery, and imprecision of the method were determined. RESULTS: Limits of detection for 5-mC and 5-hmC were 0.06 and 0.19 fmol, respectively. The imprecision and recovery of the method were determined, with the relative SDs and relative errors being <14.9% and 15.8%, respectively. HCC tumor tissues had a 4- to 5-fold lower 5-hmC content compared to tumor-adjacent tissues. In addition, 5-hmC content highly correlated with tumor stage (tumor-nodes-metastasis, P = 0.0002; Barcelona Clinic liver cancer, P = 0.0003). CONCLUSIONS: The marked depletion of 5-hmC may have profound effects on epigenetic regulation in HCC and could be a potential biomarker for the early detection and prognosis of HCC. PMID- 23344500 TI - Enhancement of Streptomyces transglutaminase activity and pro-peptide cleavage efficiency by introducing linker peptide in the C-terminus of the pro-peptide. AB - Streptomyces transglutaminase (TGase) has been widely used in food, pharmaceutical and textile industries. Streptomyces TGase is naturally synthesized as zymogen (pro-TGase), which is then processed to produce active enzyme by removing its N-terminal pro-peptide. Although the pro-peptide is essential for TGase folding and secretion, few studies have been reported on improving the properties of TGase by pro-peptide engineering. In this study, we developed a new approach to improve the properties of TGase based on pro-peptide engineering. When the alpha-helix(37G-42S) in pro-peptide was substituted with three glycines and three alanines respectively, the mutants exhibited higher specific activity and the efficiency of pro-peptide cleavage was enhanced. To further improve the properties of TGase, relevant mutations were constructed by introducing linker peptides in the C-terminus of the pro-peptide. Mutants with GS (GGGGS) and PT (PTPPTTPT) linker peptide exhibited 1.28 fold and 1.5 fold higher specific activity than the wild-type enzyme, respectively. This new method could be used to improve the properties of TGase by pro-peptide modification, which is a promising technology for creating unique TGase with various beneficial properties. PMID- 23344499 TI - Apoptosis in pneumovirus infection. AB - Pneumovirus infections cause a wide spectrum of respiratory disease in humans and animals. The airway epithelium is the major site of pneumovirus replication. Apoptosis or regulated cell death, may contribute to the host anti-viral response by limiting viral replication. However, apoptosis of lung epithelial cells may also exacerbate lung injury, depending on the extent, the timing and specific location in the lungs. Differential apoptotic responses of epithelial cells versus innate immune cells (e.g., neutrophils, macrophages) during pneumovirus infection can further contribute to the complex and delicate balance between host defense and disease pathogenesis. The purpose of this manuscript is to give an overview of the role of apoptosis in pneumovirus infection. We will examine clinical and experimental data concerning the various pro-apoptotic stimuli and the roles of apoptotic epithelial and innate immune cells during pneumovirus disease. Finally, we will discuss potential therapeutic interventions targeting apoptosis in the lungs. PMID- 23344501 TI - Construction of lactose-consuming Saccharomyces cerevisiae for lactose fermentation into ethanol fuel. AB - Two lactose-consuming diploid Saccharomyces cerevisiae strains, AY-51024A and AY 51024M, were constructed by expressing the LAC4 and LAC12 genes of Kluyveromyces marxianus in the host strain AY-5. In AY-51024A, both genes were targeted to the ATH1 and NTH1 gene-encoding regions to abolish the activity of acid/neutral trehalase. In AY-51024M, both genes were respectively integrated into the MIG1 and NTH1 gene-encoding regions to relieve glucose repression. Physiologic studies of the two transformants under anaerobic cultivations in glucose and galactose media indicated that the expression of both LAC genes did not physiologically burden the cells, except for AY-51024A in glucose medium. Galactose consumption was initiated at higher glucose concentrations in the MIG1 deletion strain AY 51024M than in the corresponding wild-type strain and AY-51024A, wherein galactose was consumed until glucose was completely depleted in the mixture. In lactose medium, the Sp. growth rates of AY-51024A and AY-51024M under anaerobic shake-flasks were 0.025 and 0.067 h(-1), respectively. The specific lactose uptake rate and ethanol production of AY-51024M were 2.50 g lactose g CDW(-1) h( 1) and 23.4 g l(-1), respectively, whereas those of AY-51024A were 0.98 g lactose g CDW(-1) h(-1) and 24.3 g lactose g CDW(-1) h(-1), respectively. In concentrated cheese whey powder solutions, AY-51024M produced 63.3 g l(-1) ethanol from approximately 150 g l(-1) initial lactose in 120 h, conversely, AY-51024A consumed 63.7 % of the initial lactose and produced 35.9 g l(-1) ethanol. Therefore, relieving glucose repression is an effective strategy for constructing lactose-consuming S. cerevisiae. PMID- 23344502 TI - Raman-on-chip device and detection fibres with fibre Bragg grating for analysis of solutions and particles. AB - An all-fibre based Raman-on-chip setup is introduced which enables analysis of solutions and trapped particles without microscopes or objectives. Beside the novel quartz microfluidic chip, innovative multi-core single-mode fibres with integrated fibre Bragg gratings are used for detection. The limit of quantitation is 7.5 mM for urea and 2.5 mM for nicotine with linear Raman spectroscopy. This is an improvement of more than two orders of magnitude compared with previous fibre-based microfluidic Raman detection schemes. Furthermore, our device was combined with optical traps to collect Raman-on-chip spectra of spherical polymer beads. PMID- 23344503 TI - Thoracoscopic lung metastasectomies: a 10-year, single-center experience. AB - INTRODUCTION: The ideal surgical treatment for pulmonary metastasectomy remains controversial. Minimally invasive surgery may offer advantages for quality of life outcomes, with equivalent oncologic long-term results. The purpose of our study was to confirm the validity of the thoracoscopic approach for pulmonary metastasectomy. METHODS: We retrospectively reviewed 164 patients who underwent 212 lung metastasectomies from January 2000 to December 2010. Complete curative pulmonary resections were performed in 159 (96.95 %) cases; 126 patients developed lung metastases from epithelial tumors: 28 from sarcoma, 7 from melanoma, and 3 from germ cell tumors. The mean disease-free interval (DFI) was 38.75 months. Fifty-four patients underwent a major VATS resection (53 thoracoscopic lobectomies and 1 pneumonectomy), and 110 patients underwent a wedge resection/segmentectomy. Lymph node sampling was performed in 117 cases. RESULTS: After a mean follow-up of 38 months, 87 patients (53 %) had died. All resection margins were tumor-free at final pathological examination. Multivariate analysis not confirmed in our series a better prognosis for patients with a particular histologic type and also DFI, age, number of metastases, and type of surgery did not statistically influence long-term survival. CONCLUSIONS: Thoracoscopic surgery is an acceptable procedure, safe and efficacious, with a 5 year overall survival that is equivalent to open surgery. PMID- 23344504 TI - Sleeve gastrectomy in older obese patients. AB - BACKGROUND: With global aging, obesity will increasingly affect the older population with higher risks of morbidity and mortality, yet full consensus has been obtained for the role of sleeve gastrectomy (SG) in the older obese. OBJECTIVE: The aim of this study is to report the outcomes of SG in the older obese. SETTING: Bariatric department, large teaching hospital, The Netherlands. METHODS: Between August 2006 and December 2011, 135 patients aged 55 years or older underwent SG. Outcomes in terms of perioperative complications, weight loss, remission of comorbidities, and revision were extracted from our prospectively held database. A subanalysis was done comparing three age groups: 55-59 years, 60-64 years, and 65 years and older. RESULTS: During mean follow-up of 14.6 months, short-term mortality was 0 %. The 30-day complication rate was 11.1 %, without significant differences between age groups. Late complications occurred in 4.4 %. In 14 patients, revisions were performed because of development of reflux disease or dysphagia. Significant reduction of comorbidities was found in all age groups, except for sleep apnea. Among the total cohort, excellent weight loss was achieved during follow-up. CONCLUSIONS: Laparoscopic sleeve gastrectomy (LSG) as a primary treatment modality for the older morbidly obese is an effective and relatively safe procedure in terms of weight loss and remission of comorbidities with an acceptable low complication rate. PMID- 23344505 TI - Benefit-risk paradigm for clinical trial design of obesity devices: FDA proposal. PMID- 23344506 TI - Analysis of laparoscopic dissection skill by instrument tip force measurement. AB - BACKGROUND: When comparing a single-stroke dissection maneuver among surgeons with differing experience levels, there are major differences in the force applied to the instrument tip. It is difficult to explain to surgeons in training the appropriate force and for the surgeons to ascertain the force intuitively. We quantified the force pattern during single-stroke laparoscopic dissection maneuvers to reveal the factors related to expertise. METHODS: We recorded the force pattern of a single maneuver and measured the magnitude of vertical (VF) and horizontal forces (HF) on the instrument tip using a box trainer (ex vivo). We compared VF and HF among surgeons: experts (n = 10), intermediates (n = 10), and novices (n = 10). The dissection time of a single stroke (T), magnitude of the VF and HF, and the timing of the peak vertical force (TPV) and horizontal force (TPH) were evaluated as performance parameters. RESULTS: The dissection time of a single stroke (T) was shortest in the expert group (p < 0.05). The average maximum magnitude of VF and HF was smallest in the expert group. TPV occurred significantly earlier than TPH in all three groups (p < 0.05). TPV in the expert group occurred earlier than in the intermediate and novice groups (p < 0.05). With increasing experience, TPV occurred earlier. CONCLUSIONS: Expert surgeons apply the most efficient vertical forces to make an initial dissection point and then change to the horizontal direction to separate surrounding tissues from the target organ. Measuring instrument tip force could help in understanding and improving the safety margin in laparoscopic surgical dissection. PMID- 23344507 TI - The impact of body habitus on the surgical outcomes of transaxillary single incision robotic thyroidectomy in papillary thyroid carcinoma patients. AB - BACKGROUND: Robotic applications have achieved safe and precise thyroidectomy with notable cosmetic and functional benefits. This study was designed to document the influence of body habitus on robotic thyroidectomy in papillary thyroid carcinoma (PTC) patients. METHODS: From July 2009 to February 2010, 352 patients underwent robotic thyroidectomy using a gasless, transaxillary single incision approach at Yonsei University Health System. Body habitus was described using body mass index category (normal weight, overweight, obese), neck length, shoulder width, and shoulder width to neck length ratios. The impact of body habitus on surgical outcomes was analyzed with respect to operation time, number of retrieved central nodes, bleeding amount, and postoperative complications. RESULTS: Of the 352 patients, 217 underwent less than total thyroidectomy and 135 underwent total thyroidectomy. Operative variables (i.e. operation times, bleeding amounts, and numbers of retrieved central nodes) showed no significant differences between three BMI groups for less than total thyroidectomy. However, total operation and working space times were longer for obese patients during total thyroidectomy. In particular, shoulder width was positively correlated with total operation time, working space time, console time, and number of retrieved central nodes. On the other hand, postoperative complications were not significantly different in the three BMI groups and showed no significant correlation with the other indices of body habitus. CONCLUSIONS: Standardized robotic thyroidectomy can be performed safely and feasibly in patients with a large body habitus despite longer operation times. PMID- 23344508 TI - A review of the current status of endoluminal therapy as a primary approach to obesity management. AB - Gastroenterologists are expected to play a pivotal role in the management of the global obesity epidemic in coming years as novel endoscopic approaches become more widely available, safe, and effective. This review focuses on the recent advances in the field of endoluminal therapy as a primary approach to obesity management with the aim of providing the interventional endoscopist an overview of currently available evidence along with an insight into upcoming devices and techniques. The intragastric balloon appears to be safe and effective in the short term, especially as a bridge to bariatric surgery. Although early trials support the safety and feasibility of endoscopic gastroplasty, it is technically demanding and staple-line dehiscence continues to be a problem. Moreover, with ongoing technical innovations, most devices that have been used in published trials are no longer manufactured and results of studies using newer endoscopic suturing systems are currently awaited. The duodenojejunal bypass sleeve mimics the physiology of intestinal bypass and shares the metabolic advantages of intestinal diversion. A high rate of premature device withdrawal has been its major limiting factor. Therapeutic endoscopy may be the next paradigm of bariatric care. Combining restrictive and barrier endoscopic techniques can potentially improve efficacy and should be evaluated in the setting of appropriate clinical trials. PMID- 23344509 TI - Effect of pre-emptive pregabalin on pain intensity and postoperative morphine consumption after laparoscopic cholecystectomy. AB - BACKGROUND: Postoperative pain is the dominant complaint and the most common cause of delayed discharge after laparoscopic cholecystectomy. The aim of this study is to evaluate the potential of preoperative administration of pregabalin to reduce postoperative pain and opioid consumption. METHODS: Fifty American Society of Anesthesiologists (ASA) I and II adult patients with symptomatic gallstone disease scheduled for elective laparoscopic cholecystectomy were randomized into two groups: group I patients (n = 25) were given 600 mg pregabalin per os divided in two doses, the night before surgery and 1 h preoperatively, respectively, while group II patients (n = 25) received a matching to pregabalin placebo at the same scheme. Postoperative pain, morphine consumption, and complications were compared between the two groups. RESULTS: Postoperative pain (static and dynamic assessment) was significantly less at 0, 1, 8, 16, and 24 h (p < 0.001) after the procedure for group I (pregabalin) compared with the placebo group. Postoperative patient-controlled morphine consumption during hospital stay was also significantly less in the pregabalin group compared with the placebo group. Side-effects were similar in both groups expect for dizziness, which was significantly higher (p < 0.0001) in the pregabalin group. CONCLUSIONS: Administration of 600 mg pregabalin per os, divided in two preoperative doses, significantly reduces postoperative pain as well as opioid consumption in patients undergoing laparoscopic cholecystectomy, at the cost of increased incidence of dizziness. PMID- 23344510 TI - Ten-year outcome after minilaparotomy versus laparoscopic cholecystectomy: a prospective randomised trial. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) and minilaparotomy cholecystectomy (MC) are the two most commonly performed mini-invasive surgical techniques for the treatment of symptomatic gallstone disease, but the long-term outcome after these two procedures has not been compared in prospective clinical trials. We therefore investigated the outcome after LC and MC in 127 patients operated at Kuopio University Hospital. PATIENTS AND METHODS: Initially 157 patients with uncomplicated symptomatic gallstones were randomised to MC (n = 85) or LC (n = 72) over a 5-year period (1998-2004), and 127 of them (81 %), 69/85 with MC and 58/72 with LC, were reached for a follow-up interview 10.5 (7.3-13.6) years after the surgery. RESULTS: Baseline and surgical parameters were similar in the two groups; 3/69 MCs and 2/58 LCs were converted to open laparotomy. The prevalence of chronic post-surgical pain 10 years after procedure was similar in the two groups: 5/69 (7 %) in the MC group and 1/58 (2 %) in the LC group (p = 0.14). Residual abdominal symptoms were common, but less frequent in the MC group (14/69; 20 %) than in the LC group (21/58 patients; 36 %) (p = 0.039). In the MC group 63/69 (91 %) and 57/58 (98 %) in the LC group (p = 0.059) were satisfied with the cosmetic outcome. CONCLUSION: Our results suggest a relatively similar long-term outcome after MC and LC. PMID- 23344512 TI - Minimally invasive surgery using intraoperative real-time capsule endoscopy for small bowel lesions. AB - BACKGROUND: The small bowel has been considered the "black box" of gastroenterology. Identifying the exact site of small bowel hemorrhage is often difficult, thus complicating surgical treatment. We report two cases of small bowel bleeding lesions that were successfully managed by intraoperative real-time capsule endoscopy and minimally invasive surgery. METHODS: We developed a double lumen tube similar to, but thinner and longer than, the Miller-Abbott tube. We insert the tube nasally, 3 or 4 days preoperatively, such that its balloon tip reaches the anus by the operative day. During surgery, the endoscopic capsule is connected to the balloon tip of the tube that protrudes from the anus. An assistant pulls on the nasal end of the tube, bringing the balloon tip and capsule back into the bowel. Capsule endoscopic images are displayed in a real time video format. RESULTS: We employed this procedure in two patients with repeated melena. Various examinations including gastroendoscopy and total colonoscopy showed bleeding confined to the small bowel, but the exact lesion site was unknown. Minimally invasive surgery was successfully performed in both patients: open minilaparotomy in one and laparoscopy in the other. The small bowel and capsule endoscope were easily controlled during minilaparotomy, and real-time capsule endoscopic images clearly identified the bleeding lesion. Control of the small bowel was more difficult in the laparoscopic case; however, real-time capsule endoscopic images identified a small tumor that was successfully resected. CONCLUSIONS: Intraoperative capsule endoscopy combined with the tube provides surgeons real-time images indicating the exact site of lesions. The tube also helps surgeons control the position of the capsule endoscope and enables suction of intraluminal fluid or inflation of the lumen to allow clearer views during the operation. We conclude that combined use of capsule endoscopy and the tube facilitates management of bleeding lesions in the small bowel. PMID- 23344511 TI - Laparoscopic totally extraperitoneal versus open preperitoneal mesh repair for inguinal hernia recurrence: a decision analysis based on net health benefits. AB - BACKGROUND: The aim of this study is to evaluate the most cost-effective treatment strategy using preperitoneal mesh for patients with recurrent inguinal hernia. Currently, the issue of cost-effectiveness is entirely unresolved. METHODS: A decision analysis was carried out based on the results of a systematic literature review of articles concerning recurrent inguinal hernia repair that were published between 1979 and 2011. A virtual cohort was programmed to undergo three different treatment procedures: (1) laparoscopic totally extraperitoneal hernia repair (TEP), (2) open preperitoneal mesh repair according to Stoppa, and (3) open preperitoneal mesh repair according to Nyhus. We carried out a base-case analysis and varied all variables over a broad range of reasonable hypotheses in multiple one-way and two-way sensitivity analyses. RESULTS: The average cost effectiveness ratio of Nyhus, Stoppa, and TEP per quality-adjusted life year was US $ ($)1,942, $1,948, and $2,011, respectively. In terms of the incremental cost effectiveness ratio (ICER), Stoppa was dominated. The choice between TEP or Nyhus procedure depends on the combination of a specific center's rates of recurrence and morbidity as disclosed by three-way sensitivity analysis. CONCLUSIONS: Nyhus and TEP repairs are possible optimal choices depending primarily on the institution's rates of recurrence and morbidity. Based on our net benefit-related decision analysis, a hypothetical "fixed budget trade-off" suggests potential annual incremental health system cost savings of $200,000 attained by shifting care for 1,000 patients from TEP to Nyhus repair (depending on clinical end points, which is a decisive factor). PMID- 23344513 TI - A unique magnesium-based 3D MOF with nanoscale cages and temperature dependent selective gas sorption properties. AB - A porous Mg-based 3D metal-organic framework with unique nanoscale cages and two fold interpenetrating pcu nets has been synthesized and characterized. It shows gas-uptake capacities for N(2), H(2), O(2) and CO(2) at low temperatures and selective adsorption of CO(2) over O(2) and N(2) at room temperature. PMID- 23344514 TI - Magnetic resonance-guided shielding of prefocal acoustic obstacles in focused ultrasound therapy: application to intercostal ablation in liver. AB - OBJECTIVES: The treatment of liver cancer is a major public health issue because the liver is a frequent site for both primary and secondary tumors. Rib heating represents a major obstacle for the application of extracorporeal focused ultrasound to liver ablation. Magnetic resonance (MR)-guided external shielding of acoustic obstacles (eg, the ribs) was investigated here to avoid unwanted prefocal energy deposition in the pathway of the focused ultrasound beam. MATERIALS AND METHODS: Ex vivo and in vivo (7 female sheep) experiments were performed in this study. Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) was performed using a randomized 256-element phased-array transducer (f~1 MHz) and a 3-T whole-body clinical MR scanner. A physical mask was inserted in the prefocal beam pathway, external to the body, to block the energy normally targeted on the ribs. The effectiveness of the reflecting material was investigated by characterizing the efficacy of high-intensity focused ultrasound beam reflection and scattering on its surface using Schlieren interferometry. Before high-intensity focused ultrasound sonication, the alignment of the protectors with the conical projections of the ribs was required and achieved in multiple steps using the embedded graphical tools of the MR scanner. Multiplanar near real-time MR thermometry (proton resonance frequency shift method) enabled the simultaneous visualization of the local temperature increase at the focal point and around the exposed ribs. The beam defocusing due to the shielding was evaluated from the MR acoustic radiation force impulse imaging data. RESULTS: Both MR thermometry (performed with hard absorber positioned behind a full-aperture blocking shield) and Schlieren interferometry indicated a very good energy barrier of the shielding material. The specific temperature contrast between rib surface (spatial average) and focus, calculated at the end point of the MRgHIFU sonication, with protectors vs no protectors, indicated an important reduction of the temperature elevation at the ribs' surface, typically by 3.3 +/- 0.4 in vivo. This was translated into an exponential reduction in thermal dose by several orders of magnitude. The external shielding covering the full conical shadow of the ribs was more effective when the protectors could be placed close to the ribs' surface and had a tendency to lose its efficiency when placed further from the ribs. Hepatic parenchyma was safely ablated in vivo using this rib-sparing strategy and single focus independent sonications. CONCLUSIONS: A readily available, MR-compatible, effective, and cost-competitive method for rib protection in transcostal MRgHIFU was validated in this study, using specific reflective strips. The current approach permitted safe intercostal ablation of small volumes (0.7 mL) of liver parenchyma. PMID- 23344515 TI - Free breathing real-time cardiac cine imaging with improved spatial resolution at 3 T. AB - OBJECTIVES: The aim of this study was to evaluate free-breathing single-shot real time cine imaging for functional cardiac imaging at 3 T with increased spatial resolution. Special emphasis of this study was placed on the influence of parallel imaging techniques. MATERIALS AND METHODS: Gradient echo phantom images were acquired with GRAPPA and modified SENSE reconstruction using both integrated and separate reference scans as well as TGRAPPA and TSENSE. In vivo measurements were performed for GRAPPA reconstruction with an integrated and a separate reference scan, as well as TGRAPPA using balanced steady-state free precession protocols. Three clinical protocols, rtLRInt (Tres = 51.3 milliseconds; voxel, 2.5 * 5.0 * 10 mm3), rtMRSep (Tres = 48.8 milliseconds; voxel, 1.9 * 3.1 * 10 mm3), and rtHRSep (Tres = 48.3 milliseconds; voxel, 1.6 * 2.6 * 10 mm), were investigated on 20 volunteers using GRAPPA reconstruction with internal as well as separate reference scans. End-diastolic volume, end-systolic volume, ejection fraction, peak ejection rate, peak filling rate, and myocardial mass were evaluated for the left ventricle and compared with an electrocardiogram-triggered segmented readout cine protocol used as standard of reference. All studies were performed at 3 T. RESULTS: Phantom and in vivo data demonstrate that the combination of GRAPPA reconstruction with a separate reference scan provides an optimal compromise of image quality as well as spatial and temporal resolution. Functional values (P values) for the standard of reference, rtLRInt, rtMRSep, and rtHRSep end-diastolic volume were 141 +/- 24 mL, 138 +/- 21 mL, 138 +/- 19 mL, and 128 +/- 33 mL, respectively (P = 0.7, 0.7, 0.4); end-systolic volume, 55 +/- 15 mL, 61 +/- 14 mL, 58 +/- 12 mL, and 55 +/- 20 mL, respectively (P = 0.23, 0.43, 0.62); ejection fraction, 61% +/- 5%, 57% +/- 5%, 58% +/- 4%, and 56% +/- 8%, respectively (P = 0.01, 0.11, 0.06); peak ejection rate, 481 +/- 73 mL/s, 425 +/- 62 mL/s, 434 +/- 67 mL/s, and 381 +/- 86 mL/s, respectively (P = 0.03, 0.04, 0.01); peak filling rate, 555 +/- 80 mL/s, 480 +/- 70 mL/s, 500 +/- 70 mL/s, and 438 +/- 108 mL/s, respectively (P= 0.007, 0.05, 0.004); and myocardial mass, 137 +/- 26 g, 141 +/- 25 g, 141 +/- 23 g, and 130 +/- 31 g, respectively (P = 0.62, 0.54, 0.99). CONCLUSIONS: Using a separate reference scan and high acceleration factors up to R = 6, single-shot real-time cardiac imaging offers adequate temporal and spatial resolution for accurate assessment of global left ventricular function in free breathing with short examination times. PMID- 23344516 TI - In vivo visualization of polymer-based mesh implants using conventional magnetic resonance imaging and positive-contrast susceptibility imaging. AB - PURPOSE: Polymer-based textile meshes for abdominal hernia treatment are invisible by conventional imaging methods, including magnetic resonance imaging (MRI). Integration of iron particles in the mesh base material allows MRI visualization of meshes. Positive-contrast susceptibility imaging (PCSI) was implemented to separate susceptibility-induced voids from proton-deficient voids. The purpose of this study was to compare PCSI with conventional gradient echo and turbo spin echo (TSE) sequences for the in vivo assessment of superparamagnetic iron oxide particle-loaded surgical meshes in an animal model. METHODS AND MATERIALS: Iron-loaded polymer meshes were implanted into the abdominal wall of 10 rabbits. At days 1, 30, and 90 after surgery, conventional gradient echo, TSE, and PCSI were performed at 1.5 T in the sagittal and axial planes. Images were scored by 2 radiologists with respect to mesh visibility, delineation of the surrounding tissue, differentiation from other structures, and overall diagnostic use, on a 4-point scale ranging from 1 (insufficient) to 4 (excellent). The results were compared using Wilcoxon signed-rank tests. The mesh shape, possible deformation or fracture, and possible mesh migration were evaluated on the different pulse sequences and compared with the results at surgery and autopsy. RESULTS: The iron-loaded meshes appeared as hypointense signal voids on gradient echo sequences, as a hyperintense line on PCSI, and as a very thin dark line on TSE images. In all animals, a precise depiction of the mesh location and its spatial configuration and integrity was possible by MRI and confirmed by surgical and autopsy results. In all 4 categories and at all 3 time points of imaging, image quality scores were significantly higher for gradient echo imaging (range, 3.60-3.80) compared with PCSI (range, 3.12-3.42) and TSE (range, 1.64-1.89). At day 90, the image quality ratings of gradient echo and PCSI were comparable. In 2 cases, the complete delineation of mesh borders was impossible because of signal voids of adjacent anatomical structures, whereas PCSI helped achieve this differentiation. CONCLUSION: In this rabbit model of iron-loaded implanted abdominal meshes, standard gradient echo imaging was best suitable to assess implant location, integrity, and configuration. In 2 of 10 animals, PCSI helped achieve a complete delineation of mesh borders. PMID- 23344517 TI - Model-based iterative reconstruction technique for ultralow-dose chest CT: comparison of pulmonary nodule detectability with the adaptive statistical iterative reconstruction technique. AB - PURPOSE: The purpose of this study was to evaluate whether model-based iterative reconstruction (MBIR) enables dose reduction over adaptive iterative reconstruction (ASIR) while maintaining diagnostic performance. METHODS: In this institutional review board-approved and Health Insurance Portability and Accountability Act-compliant study, 59 patients (mean [SD] age, 64.7 [13.4] years) gave informed consent to undergo reference-, low-, and ultralow-dose chest computed tomography (CT) with 64-row multidetector CT. The reference- and low dose CT involved the use of automatic tube current modulation with fixed noise indices (31.5 and 70.44 at 0.625 mm, respectively) and were reconstructed with 50% ASIR-filtered back projection blending. The ultralow-dose CT was acquired with a fixed tube current-time product of 5 mA s and reconstructed with MBIR. Two radiologists evaluated 2.5- and 0.625-mm-slice-thick axial images from low-dose ASIR and ultralow-dose MBIR, recorded the pattern of each nodule candidate, and assigned each a confidence score. A reference standard was established by a consensus panel of 2 different radiologists, who identified 84 noncalcified nodules with diameters of 4 mm or greater on reference-dose ASIR (ground-glass opacity, n = 18; partly solid, n = 11; solid, n = 55). Sensitivity in nodule detection was assessed using the McNemar test. Jackknife alternative free response receiver operating characteristic (JAFROC) analysis was applied to assess the results including confidence scores. RESULTS: Compared with the low dose CT, a 78.1% decrease in dose-length product was seen with the ultralow-dose CT. No significant differences were observed between the low-dose ASIR and the ultralow-dose MBIR for overall nodule detection in sensitivity (P = 0.48-0.69) or the JAFROC analysis (P = 0.57). Likewise, no significant differences were seen for ground-glass opacity, partly solid, or solid nodule detection in sensitivity (P = 0.08-0.65) or the JAFROC analysis (P = 0.21-0.90). CONCLUSIONS: Model-based iterative reconstruction enables nearly an 80% reduction in radiation dose for chest CT from a low-dose level to an ultralow-dose level, without affecting nodule detectability. PMID- 23344518 TI - Effect of x-ray tube parameters and iodine concentration on image quality and radiation dose in cerebral pediatric and adult CT angiography: a phantom study. AB - OBJECTIVES: The aim of the present phantom study was to investigate the effect of x-ray tube parameters and iodine concentration on image quality and radiation dose in cerebral computed tomographic (CT) angiographic examinations of pediatric and adult individuals. MATERIALS AND METHODS: Four physical anthropomorphic phantoms that represent the average individual as neonate, 1-year-old, 5-year old, and 10-year-old children and the RANDO phantom that simulates the average adult individual were used. Cylindrical vessels were bored along the brain equivalent plugs of each physical phantom. To simulate the brain vasculature, vessels of 0.6, 1, 2, and 3 mm in diameter were created. These vessels were filled with contrast medium (CM) solutions at different iodine concentrations, that is, 5.6, 4.2, 2.7, and 1.4 mg I/mL. The phantom heads were scanned at 120, 100, and 80 kV. The applied quality reference tube current-time product values ranged from a minimum of 45 to a maximum of 680. The CT acquisitions were performed on a 16-slice CT scanner using the automatic exposure control system. Image quality was evaluated on the basis of image noise and contrast-to-noise ratio (CNR) between the contrast-enhanced iodinated vessels and the unenhanced regions of interest. Dose reduction was calculated as the percentage difference of the CT dose index value at the quality reference tube current-time product and the CT dose index at the mean modulated tube current-time product. RESULTS: Image noise that was measured using the preset tube current-time product settings varied significantly among the different phantoms (P < 0.0001). Hounsfield unit number of iodinated vessels was linearly related to CM concentration (r2 = 0.907) and vessel diameter (r2 = 0.918). The Hounsfield unit number of iodinated vessels followed a decreasing trend from the neonate phantom to the adult phantom at all kilovoltage settings. For the same image noise level, a CNR improvement of up to 69% and a dose reduction of up to 61% may be achieved when CT acquisition is performed at 80 kV compared with 120 kV. For the same CNR, a reduction by 25% of the administered CM concentration may be achieved when CT acquisition is performed at 80 kV compared with 120 kV. CONCLUSIONS: In cerebral CT angiographic studies, appropriate adjustment of the preset tube current-time product settings is required to achieve the same image noise level among participants of different age. Cerebral CT angiography at 80 kV significantly improves CNR and significantly reduces radiation dose. Moreover, at 80 kV, a considerable reduction of the administered amount of the CM may be reached, thus reducing potential risks for contrast-induced nephropathy. PMID- 23344519 TI - Assessment of image quality on effects of varying tube voltage and automatic tube current modulation with hybrid and pure iterative reconstruction techniques in abdominal/pelvic CT: a phantom study. AB - OBJECTIVES: The objective of this study was to compare image quality on abdominal/pelvic computed tomographic images acquired with filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), and novel model-based iterative reconstruction (MBIR) techniques with varying levels of automatic tube current modulation and tube voltages. METHODS: A 2-phase study was performed. In phase 1, a torso phantom was scanned at 17 different noise levels of automatic current modulation (selected using noise index [NI]) at 120 kilovolt (peak) (kVp). Images reconstructed with FBP, ASIR, and MBIR underwent objective analysis. In phase 2, additional scans were performed at 3 different kVp (80, 100, and 120 kVp at 3 different NIs (33, 50, and 70). Objective and subjective image qualities were assessed. Computed tomography dose index and dose-length products were recorded. RESULTS: The objective image analysis supports significant noise reduction with MBIR compared with ASIR and FBP (P < 0.05) at all 17 NI tested at 120 kVp. When lowering the kVp, the subjective image quality was improved, but when this is performed in conjunction with increasing NI, image quality was maintained only at moderately high NI of 50 but was degraded at higher NIs despite improving contrast-to-noise ratio. CONCLUSIONS: Our results represent the first exploration in the utility of MBIR technique with alteration of kVp in conjunction with tube current modulation in comparison with traditional methods. Objective image noise for MBIR is superior. Subjective image quality is only moderately improved. Scanning at low kVp and moderately high NI with MBIR can ensure that a balance of improved image noise and contrast can be achieved as well as reducing dose. PMID- 23344520 TI - [Strategies to avoid antibiotic resistance]. AB - Antibiotics are used very frequently in critically ill patients as a causal and often life-saving treatment; however, the high density of use of broad spectrum antibiotics contributes to a further deterioration in resistance trends, which makes a rational prescription behavior mandatory. This particularly includes measures which lead to the reduction of antibiotic use, i.e. rigorous indications, targeted de-escalation and limited duration. For optimal efficacy of a necessary treatment the integration of pharmacokinetic and pharmacodynamic principles can be helpful. PMID- 23344521 TI - [A manual for physiotherapists]. PMID- 23344522 TI - Outcome of various treatments for posttransplant hepatitis B virus recurrence. AB - BACKGROUND: Currently, no treatment guidelines are available for posttransplant hepatitis B virus (HBV) recurrence. We retrospectively evaluated the rate of clearance of hepatitis B surface antigen (HBsAg) from serum according to various treatment regimens in two large Korean liver transplantation centers. METHODS: Between 1996 and 2008, HBV recurred in 59 patients among 933 HBV liver recipients (6.3 %). Patients with HBV recurrence were divided into four groups according to their treatment: group L (lamivudine-based therapy n = 21) and group N [new nucleos(t)ide analogue (NA)-based therapy, n = 38]. Intravenous hepatitis B immunoglobulin (ivHBIG) had been simultaneously administered to 10 patients in group L and 26 patients in group N. The mean posttransplant follow-up duration and time to HBV recurrence were 69 (14-152) months and 37 (3-120) months. RESULTS: Overall, 22 patients (37.3 %) showed seronegative conversion of HBsAg for a median 8 months after treatment (range 1-15 months). The seroclearance rate was significantly higher in group N (n = 20, 52.6 %) than in group L (n = 2, 9.5 %) (p < 0.000). The time to seroconversion did not differ between group L (7 months, range 5-16) and group N (7 months, range 1-15) (p = 0.428). Subgroup analysis showed that the HBsAg seroconversion rate was much higher for patients given combined ivHBIG and new NAs (15/26 patients, 58.0 %) than the others (p = 0.006). CONCLUSIONS: Seroclearance of HBsAg could be achieved using new NAs in half of the patients after posttransplant HBV recurrence. Combined ivHBIG may add a synergistic effect to new NAs for clearing HBsAg. PMID- 23344523 TI - beta3-adrenoceptors: a drug target in ophthalmology? PMID- 23344524 TI - The mechanism of hydralazine-induced collagen biosynthesis in cultured fibroblasts. AB - The finding that hydralazine (HYD) affects collagen metabolism led us to investigate the mechanism of its action on collagen biosynthesis, prolidase expression and activity, expression of alpha2beta1 integrin, insulin-like growth factor-I receptor (IGF-IR), focal adhesion kinase (FAK), mitogen-activated protein (MAP) kinases (ERK1, ERK2), and transcription factors hypoxia-inducible factor-1alpha (HIF-1alpha) and nuclear factor-kappaB p65 (NF-kappaB p65) in human dermal fibroblasts. Confluent fibroblasts were treated with micromolar concentrations (50-500 MUM) of HYD for 24 h. HYD had no influence on cell viability. It was found that HYD-dependent increase in collagen biosynthesis was accompanied by a parallel increase in prolidase activity and expression, HIF 1alpha expression, and decrease in DNA biosynthesis, compared to untreated cells. Since collagen biosynthesis and prolidase activity are regulated by a signal induced by activated alpha2beta1 integrin receptor as well as IGF-IR, the expression of these receptors was measured by Western immunoblot analysis. The exposure of the cells to HYD contributed to the increase in IGF-IR expression without any effect on alpha2beta1 integrin receptor and FAK expressions. It was accompanied by a decrease in expression of MAP kinases and NF-kappaB p65, the known inhibitor of collagen gene expression. The data suggest that the HYD dependent increase of collagen biosynthesis in cultured human skin fibroblasts results from activation of IGF-IR expression and prolidase activity and downregulation of NF-kappaB p65. PMID- 23344525 TI - TGF-beta1 T869C polymorphism may affect susceptibility to idiopathic pulmonary fibrosis and disease severity. AB - BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) is a key cytokine that plays a critical role in idiopathic pulmonary fibrosis (IPF). The genotypes of T869C polymorphism may be associated with the susceptibility to fibrotic lung disease. METHODS: We investigated a single-nucleotide polymorphism at exon 1 nucleotide position 29 (T -> C) of the TGF-beta1 gene. Eighty-five healthy controls and 85 subjects with surgically confirmed IPF were investigated using polymerase chain reaction and restriction enzyme fragment length polymorphism techniques. RESULTS: The IPF patients consisted of 55 men and 30 women. The mean age was 61 +/- 8 years. Fifty-one (60 %) of the 85 IPF patients were smokers and 34 were nonsmokers. The distribution of genotypes between IPF patients and controls was significantly different (IPF: TT 43.5 % and TC or CC 56.5 %; controls: TT 27.1 % and TC or CC 72.9 %, p = 0.037). TT genotype was significantly associated with decreased PaO2 and increased D(A-a)O2 upon initial diagnosis (p = 0.006 and 0.009, respectively). There was a positive association between TT genotype and IPF development (odds ratio [OR] = 2.1, 95 % confidence interval [CI] = 1.1-4.0, p = 0.028). CONCLUSIONS: This study suggests that the TGF-beta1 gene T869C polymorphism may affect susceptibility to IPF in Koreans. Larger studies are required to confirm the genetic association of TGF-beta1 gene polymorphism and IPF. PMID- 23344526 TI - Hypoxia-inducible factor (HIF)-1alpha suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction. AB - Hypoxia-inducible transcription factor-1 (HIF-1alpha) is overexpressed in multiple myeloma (MM) cells within the hypoxic microenvironment. Herein, we explored the effect of persistent HIF-1alpha inhibition by a lentivirus short hairpin RNA pool on MM cell growth either in vitro or in vivo and on the transcriptional and pro-angiogenic profiles of MM cells. HIF-1alpha suppression did not have a significant impact on MM cell proliferation and survival in vitro although, increased the antiproliferative effect of lenalidomide. On the other hand, we found that HIF-1alpha inhibition in MM cells downregulates the pro angiogenic genes VEGF, IL8, IL10, CCL2, CCL5 and MMP9. Pro-osteoclastogenic cytokines were also inhibited, such as IL-7 and CCL3/MIP-1alpha. The effect of HIF-1alpha inhibition was assessed in vivo in nonobese diabetic/severe combined immunodeficiency mice both in a subcutaneous and an intratibial MM model. HIF 1alpha inhibition caused a dramatic reduction in the weight and volume of the tumor burden in both mouse models. Moreover, a significant reduction of the number of vessels and vascular endothelial growth factors (VEGFs) immunostaining was observed. Finally, in the intratibial experiments, HIF-1alpha inhibition significantly blocked bone destruction. Overall, our data indicate that HIF 1alpha suppression in MM cells significantly blocks MM-induced angiogenesis and reduces MM tumor burden and bone destruction in vivo, supporting HIF-1alpha as a potential therapeutic target in MM. PMID- 23344529 TI - Magnitude representation in sequential comparison of two-digit numbers is not holistic either. AB - There is accumulating evidence suggesting that two-digit number magnitude is represented in a decomposed fashion into tens and units rather than holistically as one integrated entity. However, recently, it has been claimed that this property does not hold for the case when two to-be-compared numbers are presented sequentially. In the present study, we pursued this issue in two experiments by evaluating perceptual as well as strategic aspects arising for sequential stimulus presentation in a magnitude comparison task. We observed reliable unit decade compatibility effects indicating decomposed processing of tens and units in a magnitude comparison task with sequential presentation of the to-be-compared numbers. In particular, we found that both confounding low-level perceptual features and stimulus set characteristics determining cue validity of the units influenced the compatibility effect. Taken together, our results clearly indicate that decomposed representations of tens and units seem to be a general characteristic of multi-digit number magnitude processing, rather than an exception occurring under very specific conditions only. Implications of these results for the understanding of number magnitude representations are discussed. PMID- 23344530 TI - Priming the mental time-line: effects of modality and processing mode. AB - The notion of a mental time-line (i.e., past corresponds to left and future corresponds to right) supports the conceptual metaphor view assuming that abstract concepts like "time" are grounded in cognitively more accessible concepts like "space." In five experiments, we further investigated the relationship between temporal and spatial representations and examined whether or not the spatial correspondents of time are unintentionally activated. We employed a priming paradigm, in which visual or auditory prime words (i.e., temporal adverbs such as yesterday, tomorrow) preceded a colored square. In all experiments, participants discriminated the color of this square by responding with the left or the right hand. Although the temporal reference of the priming adverb was task irrelevant in Experiment 1, visually presented primes facilitated responses to the square in correspondence with the direction of the mental time line. This priming effect was absent in Experiments 2, 3, and 5, in which the primes were presented auditorily and the temporal reference of the words could be ignored. The effect, however, emerged when attention was oriented to the temporal content of the auditory prime words in Experiment 4. The results suggest that task demands differentially modulate the activation of the mental time-line within the visual and auditory modality and support a flexible association between conceptual codes. PMID- 23344531 TI - Acute cholecystitis in the late phase of severe acute pancreatitis: a neglected problem. AB - OBJECTIVE: This study aimed to evaluate the incidence and risk factors for acute cholecystitis (AC) in the late phase of severe acute pancreatitis (SAP). METHODS: A review of patients with SAP from January 2008 to December 2009 was performed. Clinical characteristics were compared between patients with AC in the late phase and those without. Risk factors for AC were analyzed using a logistic regression analysis. Receiver operating characteristic curve was used to estimate the predictive value of the risk factors. RESULTS: A total of 269 cases were included. Twenty-seven episodes of AC in the late phase were identified. Patients with AC had higher computed tomography severity index and Acute Physiology and Chronic Health Evaluation (APACHE) II score, as well as higher rate of intraabdominal hypertension, infective pancreatic necrosis (IPN) of the pancreas head, fistula, abdominal bleeding, mechanical ventilation, and prolonged enteral nutrition (EN) via jejunal tube. Independent risk factors for AC, based on the results of logistic regression analysis, included higher APACHE II score, prolonged EN via jejunal tube, and IPN of the pancreas head. CONCLUSIONS: Approximately 10% of patients with SAP will develop AC in the late phase. Risk factors include higher APACHE II score, prolonged EN via jejunal tube, and IPN of the pancreas head. PMID- 23344532 TI - Genetic alterations of K-ras, p53, c-erbB-2, and DPC4 in pancreatic ductal adenocarcinoma and their correlation with patient survival. AB - OBJECTIVES: The objective of this study was to evaluate genetic alterations of K ras, p53, c-erbB-2, and deleted in pancreatic cancer, locus 4 (DPC4) genes in pancreatic ductal adenocarcinoma and correlate these changes with patients' overall survival. METHODS: Between April 2004 and December 2008, 272 patients with pancreatic ductal adenocarcinoma underwent surgical resection at a single institute. Genetic analyses and immunohistochemical stains were reviewed retrospectively. RESULTS: Alterational rates of each gene were as follows: K-ras, 53.8%; p53, 38.2%; c-erbB-2, 7.3%; DPC4, 81.6%. Subtypes of K-ras gene were as follows: GGT (wild type), 46.2%; GAT, 31.2%; GTT, 14.5%; CGT, 5.6%; TGT, 1.7%; CTG, 0.4%; AGT, 0.4%. K-ras mutation (especially GAT subtype) and DPC4 inactivation resulted in a reduction of postresection survival (P = 0.001 and P = 0.047). Univariate analysis revealed 8 factors affecting to the survival, and multivariate analysis revealed that 6 of them were independently responsible for poor survival of patients: presence of lymphovascular tumor emboli, DPC4 inactivation, poorly differentiated carcinoma, K-ras mutation, presence of lymph node metastasis, and elevated CA-19-9 (>37 U/mL). CONCLUSIONS: This study may help to understand the genetic feature of pancreatic cancer and its survival effect in our population. This shows that additional genetic insights would contribute to the improvement of patients' prognosis. PMID- 23344533 TI - Metastasis: Polarizing metastasis. PMID- 23344534 TI - Microenvironment: Secreted DNA damage? PMID- 23344535 TI - Metabolism: Sensitivity to serine starvation. PMID- 23344537 TI - Apoptosis: Refined and lethal. PMID- 23344542 TI - Regulatory networks defining EMT during cancer initiation and progression. AB - Epithelial to mesenchymal transition (EMT) is essential for driving plasticity during development, but is an unintentional behaviour of cells during cancer progression. The EMT-associated reprogramming of cells not only suggests that fundamental changes may occur to several regulatory networks but also that an intimate interplay exists between them. Disturbance of a controlled epithelial balance is triggered by altering several layers of regulation, including the transcriptional and translational machinery, expression of non-coding RNAs, alternative splicing and protein stability. PMID- 23344544 TI - p63 steps into the limelight: crucial roles in the suppression of tumorigenesis and metastasis. AB - The role of p63 in cancer has been an area of intense debate and controversy. Is TP63 (which encodes p63) a tumour suppressor gene or an oncogene? This debate is partly due to the complexity of the gene. There are several p63 isoforms - some with tumour suppressive functions and others with oncogenic functions. In this Opinion article, we focus on the recent advances in understanding p63 biology and its roles in cancer. In this regard, we discuss the role of p63 in multiple stem cell compartments, ageing, in the response to DNA damage and in DNA repair. Finally, we highlight the importance of understanding the interactions between all three p53 family members and the potential impact of this knowledge on cancer therapy and regenerative medicine. PMID- 23344543 TI - Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a highly lethal cancer, with increasing worldwide incidence, that is mainly associated with chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections. There are few effective treatments partly because the cell- and molecular-based mechanisms that contribute to the pathogenesis of this tumour type are poorly understood. This Review outlines pathogenic mechanisms that seem to be common to both viruses and which suggest innovative approaches to the prevention and treatment of HCC. PMID- 23344545 TI - High viral load and elevated angiogenic markers associated with increased risk of preeclampsia among women initiating highly active antiretroviral therapy in pregnancy in the Mma Bana study, Botswana. AB - BACKGROUND: Risk factors associated with preeclampsia in HIV-infected women remain largely unknown. Systemic angiogenic imbalance contributes to preeclampsia in HIV-uninfected women, but changes in angiogenic markers after highly active antiretroviral therapy (HAART) initiation have not been studied. METHODS: The Mma Bana study randomized 560 HIV-infected, HAART-naive pregnant women with CD4 counts >= 200 cells per cubic millimeter between 26 and 34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine or abacavir/zidovudine/lamivudine. Another 170 participants with CD4 counts less than 200 cells per cubic millimeter initiated nevirapine/zidovudine/lamivudine between 18 and 34 weeks gestation. Characteristics of 11 women who developed preeclampsia were compared with the remaining 722 Mma Bana participants who delivered using logistic regression. Plasma samples drawn at HAART initiation and 1 month later from 60 women without preeclampsia and at HAART initiation for all 11 preeclamptic women were assayed for placental growth factor (PlGF) and soluble FMS toll-like tyrosine kinase-1 (sFlt-1). RESULTS: Pre-HAART viral load greater than 100,000 copies per milliliter was associated with preeclampsia (odds ratio: 5.8, 95% confidence interval: 1.8 to 19.4, P = 0.004). Median pre-HAART PlGF level was lower and sFlt 1 was higher in women who developed preeclampsia vs those who did not (130 vs 992 pg/mL, P = 0.001; 17.5 vs 9.4 pg/mL, P = 0.03, respectively). In multivariate analysis, PlGF and viral load remained significantly associated with preeclampsia. No significant changes in angiogenic factors were noted after 1 month of HAART treatment among non-preeclamptic women. CONCLUSIONS: Pre-HAART viral load greater than 100,000 copies per milliliter and PlGF predicted preeclampsia among women starting HAART in pregnancy. Among non-preeclamptic women, HAART treatment did not significantly alter levels of PlGF or sFlt-1 after 1 month of treatment. PMID- 23344546 TI - Antibody-dependent cell-mediated virus inhibition antibody activity does not correlate with risk of HIV-1 superinfection. AB - Previous studies of HIV-infected women with high-risk behavior have indicated that neither neutralizing antibody nor cellular immunity elicited by an initial HIV-1 infection is associated with protection against superinfection with a different HIV-1 strain. Here, we measured antibody-dependent cell-mediated virus inhibition (ADCVI) antibody activity in the plasma of 12 superinfected cases and 36 singly infected matched controls against 2 heterologous viruses. We found no association between plasma ADCVI activity and superinfection status. ADCVI antibody activity against heterologous virus elicited by the original infection may not contribute to preventing a superinfecting HIV-1. PMID- 23344548 TI - Journalistic licence. PMID- 23344549 TI - Coca-Cola launches antiobesity advertisements. PMID- 23344547 TI - CD4 count slope and mortality in HIV-infected patients on antiretroviral therapy: multicohort analysis from South Africa. AB - BACKGROUND: In many resource-limited settings monitoring of combination antiretroviral therapy (cART) is based on the current CD4 count, with limited access to HIV RNA tests or laboratory diagnostics. We examined whether the CD4 count slope over 6 months could provide additional prognostic information. METHODS: We analyzed data from a large multicohort study in South Africa, where HIV RNA is routinely monitored. Adult HIV-positive patients initiating cART between 2003 and 2010 were included. Mortality was analyzed in Cox models; CD4 count slope by HIV RNA level was assessed using linear mixed models. RESULTS: About 44,829 patients (median age: 35 years, 58% female, median CD4 count at cART initiation: 116 cells/mm) were followed up for a median of 1.9 years, with 3706 deaths. Mean CD4 count slopes per week ranged from 1.4 [95% confidence interval (CI): 1.2 to 1.6] cells per cubic millimeter when HIV RNA was <400 copies per milliliter to -0.32 (95% CI: -0.47 to -0.18) cells per cubic millimeter with >100,000 copies per milliliter. The association of CD4 slope with mortality depended on current CD4 count: the adjusted hazard ratio (aHRs) comparing a >25% increase over 6 months with a >25% decrease was 0.68 (95% CI: 0.58 to 0.79) at <100 cells per cubic millimeter but 1.11 (95% CI: 0.78 to 1.58) at 201-350 cells per cubic millimeter. In contrast, the aHR for current CD4 count, comparing >350 with <100 cells per cubic millimeter, was 0.10 (95% CI: 0.05 to 0.20). CONCLUSIONS: Absolute CD4 count remains a strong risk for mortality with a stable effect size over the first 4 years of cART. However, CD4 count slope and HIV RNA provide independently added to the model. PMID- 23344550 TI - US vaccination schedule is safe and effective, says Institute of Medicine. PMID- 23344551 TI - Does computational biology help us to understand the molecular phylogenetics and evolution of cluster of differentiation (CD) proteins? AB - Cluster of differentiation (CD) is a group of proteins with highly immunological and medical importance, and some are established therapeutics. These membrane proteins are used to investigate of cell surface molecules of blood cells especially WBC. We selected a population of fifteen members with most medical importance, which includes CD2, CD4, CD5, CD6, CD7, CD9, CD14, CD16, CD19, CD22, CD28, CD33, CD36, CD38, and CD44 and performed in silico analysis using algorithm analysis and mathematical models. The results suggest that LEU (L) is well aligned. CD16 is rooted with CD22 and likewise, CD4 is closely related to CD44. Notably, highest number of highly conserved amino acids is recorded in CD22. WebLogo were formed up to 350 amino acid position and Met (M) is found to be tallest logo. Our results would be useful for upcoming researchers to obtain fundamental idea about the particular regions CD proteins which is having the structural and functional significance related to the evolutionary biology. PMID- 23344552 TI - The blind kidney: disorders affecting kidneys and eyes. AB - There are many disorders that can affect both the kidneys and the eyes. Awareness of the ocular manifestations of kidney disorders is important as it can guide the diagnosis and facilitate the choice of a specific treatment. Conversely, ophthalmologists need to be aware of potential renal manifestations in disorders presenting initially with visual failure. We review disorders affecting both of these organ systems, based upon cases from our clinical practice to highlight the importance of interdisciplinary collaboration. PMID- 23344553 TI - Increased impulsive choice for saccharin during PCP withdrawal in female monkeys: influence of menstrual cycle phase. AB - BACKGROUND: In previous studies with male and female rhesus monkeys, withdrawal of access to oral phencyclidine (PCP) self-administration reduced responding for food under a high fixed-ratio (FR) schedule more in males than females, and with a delay discounting (DD) task with saccharin (SACC) as the reinforcer impulsive choice for SACC increased during PCP withdrawal more in males than females. OBJECTIVES: The goal of the present study was to examine the effect of PCP (0.25 or 0.5 mg/ml) withdrawal on impulsive choice for SACC in females during the follicular and luteal phases of the menstrual cycle. MATERIALS AND METHODS: In component 1, PCP and water were available from two drinking spouts for 1.5 h sessions under concurrent FR 16 schedules. In component 2, a SACC solution was available for 45 min under a DD schedule. Monkeys had a choice of one immediate SACC delivery (0.6 ml) or six delayed SACC deliveries, and the delay was increased by 1 s after a response on the delayed lever and decreased by 1 s after a response on the immediate lever. There was then a 10-day water substitution phase, or PCP withdrawal, that occurred during the mid-follicular phase (days 7 11) or the late luteal phase (days 24-28) of the menstrual cycle. Access to PCP and concurrent water was then restored, and the PCP withdrawal procedure was repeated over several follicular and luteal menstrual phases. RESULTS: PCP deliveries were higher during the luteal (vs follicular) phase. Impulsive choice was greater during the luteal (vs follicular) phase during withdrawal of the higher PCP concentration. CONCLUSIONS: PCP withdrawal was associated with elevated impulsive choice for SACC, especially in the luteal (vs follicular) phase of the menstrual cycle in female monkeys. PMID- 23344554 TI - The inositol monophosphatase inhibitor L-690,330 affects pilocarpine-behavior and the forced swim test. AB - RATIONALE: Lithium has been a standard pharmacological treatment for bipolar disorder over the last 60 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. Attenuation of the phosphatidylinositol signal transduction pathway as a consequence of inhibition of inositol monophosphatase (IMPase) has been proposed as one of the possible mechanisms for lithium-induced mood stabilization. OBJECTIVES: The objective was to study the behavioral effect of the specific competitive IMPase inhibitor L 690,330 in mice in the lithium-sensitive pilocarpine-induced seizures paradigm and the forced swim test (FST). METHODS: The inhibitor was administered intracerebroventricularly in liposomes. RESULTS: L-690,330 increased the sensitivity to subconvulsive doses of pilocarpine and decreased immobility time in the FST. CONCLUSIONS: It is possible that the behavioral effects of lithium in the pilocarpine-induced seizures and in the FST are mediated through the inhibition of IMPase, but reversal of the inhibitor's effect with intracerebroventricular inositol would be an important further step in proof. PMID- 23344555 TI - Varenicline and cytisine: two nicotinic acetylcholine receptor ligands reduce ethanol intake in University of Chile bibulous rats. AB - RATIONALE: Neuronal nicotinic acetylcholine receptors (nAChRs) are pharmacological targets that have recently been implicated in the reinforcing effects of many drugs of abuse, including ethanol. Varenicline and cytisine are nAChR partial agonists in clinical use as smoking cessation aids. However, their efficacies to reduce alcohol consumption have not been fully studied. OBJECTIVES: This study aims to compare the effects of varenicline and cytisine on ethanol consumption by rats bred for many generations as high ethanol drinkers (UChB). RESULTS: Repeated dosing (0.5 or 1.0 mg/kg/day i.p.) of varenicline or cytisine, for three consecutive days, to male UChB rats pre-exposed to 10 % (v/v) ethanol and water 24 h/day for 4 weeks, significantly reduced alcohol intake and preference of ethanol over water during 1- and 24-h ethanol access periods. This effect was specific for ethanol intake and was not observed for 0.2 % saccharin or water consumption. Varenicline appears to be more effective than cytisine, probably due to its more favorable pharmacokinetic and pharmacodynamic properties. Long-term use of both nAChRs ligands for more than 8-10 days induced tolerance to their effects on ethanol consumption. CONCLUSIONS: This preclinical study in UChB rats demonstrated that both varenicline and cytisine reduce alcohol intake, with varenicline producing a greater and longer-lasting reduction than cytisine. However, dose adjustment will have to be considered as a possible way to counter tolerance arising after continued use. PMID- 23344556 TI - Atypical antipsychotics and diabetic ketoacidosis: a review. AB - RATIONALE: Atypical antipsychotics have been linked to weight gain and type 2 diabetes, but are also associated with diabetic ketoacidosis (DKA), which can occur more acutely and in the absence of weight gain. OBJECTIVES: Our aim was to review current case reports of DKA in the context of atypical antipsychotic treatment to better understand (a) the scope of the problem, (b) its relationship to different atypical agents, (c) risk factors, (d) long-term outcome, and (e) putative mechanisms of action. METHOD: Searches in PubMed/Medline, as well as the University of Toronto's Scholar Portal, were performed for all relevant articles/abstracts in English. RESULTS: Sixty reports, yielding 69 cases, affirm that DKA is a rare but serious risk with almost all atypical antipsychotics; however, liability seems to vary between agents, at least partially mirroring risk of weight gain. Mean age of onset was 36.9 years (range 12-80), with 68 % of cases occurring in males, and 41 % in individuals of African American or African Caribbean descent. Over one third of cases present with either no weight gain or weight loss, and 61 % of these require ongoing treatment for glycemic control. Death occurred in 7.25 % of cases. CONCLUSION: While the underlying mechanisms are not well understood, antipsychotic-related DKA can occur soon after treatment onset and in the absence of weight gain. Although rare, clinicians must remain vigilant given its acute onset and potential lethality. PMID- 23344557 TI - Nicotine derived from the electronic cigarette improves time-based prospective memory in abstinent smokers. AB - RATIONALE: It is well established that nicotine improves, and deprivation impairs, cognitive performance and mood in smokers. Prospective memory (PM), remembering to execute a delayed intention at a given time point, is under explored in smokers. Whilst a handful of studies have shown improved PM with nicotine, the effects of nicotine delivered via the electronic cigarette (e cigarette) have not been investigated. OBJECTIVE: This study explores whether, by comparison with placebo, nicotine delivered via the e-cigarette can improve PM, tobacco withdrawal symptoms and desire to smoke in abstinent smokers. METHODS: Twenty smokers, abstinent for 8-10 h, each completed two experimental sessions under nicotine (18 mg) and placebo (0 mg) e-cigarette conditions. Participants completed a single-item desire-to-smoke scale and the Mood and Physical Symptoms Scale. PM was measured using the Cambridge Prospective Memory Test. RESULTS: Compared with placebo, the nicotine e-cigarette reduced the desire to smoke and tobacco withdrawal symptoms, and improved time-based but not event-based PM. There was a moderate, marginally significant negative correlation between PM performance during abstinence and nicotine dependence. CONCLUSIONS: This is the first study to show that nicotine derived via e-cigarette can improve PM in abstinent smokers, suggesting efficient nicotine delivery. The finding that the effect of nicotine was restricted to time-based rather than event-based PM is consistent with the view that nicotine acts to improve performance on strategic (effortful) rather than automatic processing. These findings add to the growing body of evidence that the e-cigarette can replace some of the effects of nicotine derived from tobacco smoking, thus highlighting its potential for smoking cessation. PMID- 23344558 TI - Molecular mechanisms of HIV immune evasion of the innate immune response in myeloid cells. AB - The expression of intrinsic antiviral factors by myeloid cells is a recently recognized mechanism of restricting lentiviral replication. Viruses that enter these cells must develop strategies to evade cellular antiviral factors to establish a productive infection. By studying the cellular targets of virally encoded proteins that are necessary to infect myeloid cells, a better understanding of cellular intrinsic antiviral strategies has now been achieved. Recent findings have provided insight into how the lentiviral accessory proteins, Vpx, Vpr and Vif counteract antiviral factors found in myeloid cells including SAMHD1, APOBEC3G, APOBEC3A, UNG2 and uracil. Here we review our current understanding of the molecular basis of how cellular antiviral factors function and the viral countermeasures that antagonize them to promote viral transmission and spread. PMID- 23344559 TI - A genetic approach to the development of new therapeutic phages to fight pseudomonas aeruginosa in wound infections. AB - Pseudomonas aeruginosa is a frequent participant in wound infections. Emergence of multiple antibiotic resistant strains has created significant problems in the treatment of infected wounds. Phage therapy (PT) has been proposed as a possible alternative approach. Infected wounds are the perfect place for PT applications, since the basic condition for PT is ensured; namely, the direct contact of bacteria and their viruses. Plenty of virulent ("lytic") and temperate ("lysogenic") bacteriophages are known in P. aeruginosa. However, the number of virulent phage species acceptable for PT and their mutability are limited. Besides, there are different deviations in the behavior of virulent (and temperate) phages from their expected canonical models of development. We consider some examples of non-canonical phage-bacterium interactions and the possibility of their use in PT. In addition, some optimal approaches to the development of phage therapy will be discussed from the point of view of a biologist, considering the danger of phage-assisted horizontal gene transfer (HGT), and from the point of view of a surgeon who has accepted the Hippocrates Oath to cure patients by all possible means. It is also time now to discuss the possible approaches in international cooperation for the development of PT. We think it would be advantageous to make phage therapy a kind of personalized medicine. PMID- 23344560 TI - Approaches for identification of HIV-1 entry inhibitors targeting gp41 pocket. AB - The hydrophobic pocket in the HIV-1 gp41 N-terminal heptad repeat (NHR) domain plays an important role in viral fusion and entry into the host cell, and serves as an attractive target for development of HIV-1 fusion/entry inhibitors. The peptide anti-HIV drug targeting gp41 NHR, T-20 (generic name: enfuvirtide; brand name: Fuzeon), was approved by the U.S. FDA in 2003 as the first HIV fusion/entry inhibitor for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, because T20 lacks the pocket-binding domain (PBD), it exhibits low anti-HIV-1 activity and short half-life. Therefore, several next-generation HIV fusion inhibitory peptides with PBD have been developed. They possess longer half-life and more potent antiviral activity against a broad spectrum of HIV-1 strains, including the T-20-resistant variants. Nonetheless, the clinical application of these peptides is still limited by the lack of oral availability and the high cost of production. Thus, development of small molecule compounds targeting the gp41 pocket with oral availability has been promoted. This review describes the main approaches for identification of HIV fusion/entry inhibitors targeting the gp41 pocket and summarizes the latest progress in developing these inhibitors as a new class of anti-HIV drugs. PMID- 23344561 TI - Lysogenic conversion and phage resistance development in phage exposed Escherichia coli biofilms. AB - In this study, three-day old mature biofilms of Escherichia coli were exposed once to either a temperate Shiga-toxin encoding phage (H-19B) or an obligatory lytic phage (T7), after which further dynamics in the biofilm were monitored. As such, it was found that a single dose of H-19B could rapidly lead to a near complete lysogenization of the biofilm, with a subsequent continuous release of infectious H-19B particles. On the other hand, a single dose of T7 rapidly led to resistance development in the biofilm population. Together, our data indicates a profound impact of phages on the dynamics within structured bacterial populations. PMID- 23344563 TI - Residual tumour volumes and grey zones after external beam radiotherapy (with or without chemotherapy) in cervical cancer patients. A low-field MRI study. AB - BACKGROUND: Grey zones, which are defined as tissue with intermediate signal intensity in the area of primary hyperintense tumour extension, can be seen during radiation with or without chemotherapy on the T2-weighted MRI in patients with cervical cancer. The purpose of this study was to systematically measure the tumour volume at the time of diagnosis and the residual tumour volume at the time of brachytherapy without and with consideration of the grey zones and to estimate tumour regression during external beam radiotherapy (EBRT). MATERIAL AND METHODS: T2-weighted MRI datasets of 175 patients with locally advanced cervical cancer (FIGO stage IB-IVA), who underwent combined external beam radiotherapy and brachytherapy with or without concomitant chemotherapy were available for this study. The gross tumour volume at the time of diagnosis (GTV(init)) and at the time of first brachytherapy without (GTV(res)) and with (GTV(res)+ GZ) consideration of grey zones were measured for each patient. A descriptive statistical analysis was performed and tumour regression rates without (R) and with consideration of grey zones (R(GZ)) were calculated. Further, the role of prognostic factors on GTV(init), GTV(res), GTV(res)+ GZ and tumour regression rates was investigated. RESULTS: The median GTV(init), GTV(res), GTV(res)+ GZ in all patients were 44.4 cm(3), 8.2 cm(3), 20.3 cm(3), respectively. The median R was 78.5% and the median R(GZ) was 50.1%. The histology and FIGO staging showed a significant impact on GTV(init), GTV(res) and GTV(res)+ GZ. CONCLUSION: Grey zones represent a substantial proportion of the residual tumour volume at the time of brachytherapy. Differentiation of high signal intensity mass and surrounding intermediate signal intensity grey zones may be reasonable. PMID- 23344564 TI - Cremated human remains: is measurement of the lateral angle of the meatus acusticus internus a reliable method of sex determination? AB - The purpose of this study was to evaluate the lateral angle (LA) method-based on the measurement of the angle at which the internal acoustic canal opens up to the surface of the petrous bone-for sex determination in cremated skeletal remains of Italians. The sample consisted of 160 adult individuals of known age and sex who had recently died and were cremated in the crematorium of Ferrara (northern Italy). Several studies have demonstrated that the petrous portion of the temporal bone may be a valuable tool for sex diagnosis in unburned skeletal remains. Since petrous bones are usually preserved after cremation, this method could be of particular interest in the case of burned skeletal remains. The repeatability of intra- and inter-observer measurements was good. The results indicated that male and female lateral angles were significantly different but that the values did not differ among age-groups. There was no bilateral difference in LA. However, neither the 45 degrees angle, proposed in earlier studies as the sectioning point for this variable from male and female data distributions, nor another angular value allowed satisfactory discrimination between the sexes in our sample. The influence of the "age" factor (about 82 % of females were of >= 75 years of age) on the results is critically discussed. The results of this study suggest that the LA method is not sufficiently reliable to assess the sex of elderly Italian individuals from their burned remains and thus should only be used in conjunction with other sexing techniques. PMID- 23344562 TI - Arenavirus variations due to host-specific adaptation. AB - Arenavirus particles are enveloped and contain two single-strand RNA genomic segments with ambisense coding. Genetic plasticity of the arenaviruses comes from transcription errors, segment reassortment, and permissive genomic packaging, and results in their remarkable ability, as a group, to infect a wide variety of hosts. In this review, we discuss some in vitro studies of virus genetic and phenotypic variation after exposure to selective pressures such as high viral dose, mutagens and antivirals. Additionally, we discuss the variation in vivo of selected isolates of Old World arenaviruses, particularly after infection of different animal species. We also discuss the recent emergence of new arenaviruses in the context of our observations of sequence variations that appear to be host-specific. PMID- 23344565 TI - Markers of inflammation in the prefrontal cortex of individuals with schizophrenia. PMID- 23344571 TI - Retention of fetuin-A in renal tubular lumen protects the kidney from nephrocalcinosis in rats. AB - The serum glycoprotein fetuin-A is an important inhibitor of extraosseous calcification. The importance of fetuin-A has been confirmed in fetuin-A null mice, which develop widespread extraosseous calcification including the kidney. However, the mechanism how fetuin-A protects kidneys from nephrocalcinosis remains uncertain. Here, we demonstrate that intratubular fetuin-A plays a role in the prevention of nephrocalcinosis in the proximal tubules. Although normal rat kidney did not express mRNA for fetuin-A, we found punctate immunohistochemical staining of fetuin-A mainly in the S1 segment of the proximal tubules. The staining pattern suggested that fetuin-A passed through the slit diaphragm, traveled in the proximal tubular lumen, and was introduced into proximal tubular cells by megalin-mediated endocytosis. To test this hypothesis, we inhibited the function of megalin by intravenous injection of histidine-tagged soluble receptor-associated protein (His-sRAP), a megalin inhibitor. His-sRAP injection diminished fetuin-A staining in the proximal tubules and led to urinary excretion of fetuin-A. We further analyzed the role of fetuin-A in nephrocalcinosis. Continuous injection of parathyroid hormone (PTH) 1-34 induced nephrocalcinosis mainly in the proximal tubules in rats. His-sRAP retained fetuin A in renal tubular lumen and thereby protected the kidneys of PTH-treated rats from calcification. Our findings suggest that tubular luminal fetuin-A works as a natural inhibitor against calcification in the proximal tubules under PTH-loaded condition. PMID- 23344570 TI - Sex differences in the enhanced responsiveness to acute angiotensin II in growth restricted rats: role of fasudil, a Rho kinase inhibitor. AB - This study tested the hypothesis that Rho kinase contributes to the enhanced pressor response to acute angiotensin II in intact male growth-restricted and gonadectomized female growth-restricted rats. Mean arterial pressure (MAP) and renal function were determined in conscious animals pretreated with enalapril (250 mg/l in drinking water) for 1 wk to block the endogenous renin-angiotensin system and normalize blood pressure (baseline). Blood pressure and renal hemodynamics did not differ at baseline. Acute Ang II (100 ng.kg(-1).min(-1)) induced a greater increase in MAP and renal vascular resistance and enhanced reduction in glomerular filtration rate in intact male growth-restricted rats compared with intact male controls (P < 0.05). Cotreatment with the Rho kinase inhibitor fasudil (33 MUg.kg(-1).min(-1)) significantly attenuated these hemodynamic changes (P < 0.05), but it did not abolish the differential increase in blood pressure above baseline, suggesting that the impact of intrauterine growth restriction on blood pressure in intact male growth-restricted rats is independent of Rho kinase. Gonadectomy in conjunction with fasudil returned blood pressure back to baseline in male growth-restricted rats, and yet glomerular filtration rate remained significantly reduced (P < 0.05). Thus, these data suggest a role for enhanced renal sensitivity to acute Ang II in the developmental programming of hypertension in male growth-restricted rats. However, inhibition of Rho kinase had no effect on the basal or enhanced increase in blood pressure induced by acute Ang II in the gonadectomized female growth restricted rat. Therefore, these studies suggest that Rho kinase inhibition exerts a sex-specific effect on blood pressure sensitivity to acute Ang II in growth-restricted rats. PMID- 23344572 TI - Parathyroid hormone (PTH) decreases sodium-phosphate cotransporter type IIa (NpT2a) mRNA stability. AB - The acute inhibitory effects of parathyroid hormone (PTH) on proximal tubule Na(+)-K(+)-ATPase (Na-K) and sodium-dependent phosphate (NaPi) transport have been extensively studied, while little is known about the chronic effects of PTH. Patients with primary hyperparathyroidism, a condition characterized by chronic elevations in PTH, exhibit persistent hypophosphatemia but not significant evidence of salt wasting. We postulate that chronic PTH stimulation results in differential desensitization of PTH responses. To address this hypothesis, we compared the effects of chronic PTH stimulation on Na-P(i) cotransporter (Npt2a) expression and Na-K activity and expression in Sprague Dawley rats, transgenic mice featuring parathyroid-specific cyclin D1 overexpression (PTH-D1), and proximal tubule cell culture models. We demonstrated a progressive decrease in brush-border membrane (BBM) expression of Npt2a from rats treated with PTH for 6 h or 4 days, while Na-K expression and activity in the basolateral membranes (BLM) exhibited an initial decrease followed by recovery to control levels by 4 days. Npt2a protein expression in PTH-D1 mice was decreased relative to control animals, whereas levels of Na-K, NHERF-1, and PTH receptor remained unchanged. In PTH-D1 mice, NpT2a mRNA expression was reduced by 50% relative to control mice. In opossum kidney proximal tubule cells, PTH decreased Npt2a mRNA levels. Both actinomycin D and cycloheximide treatment prevented the PTH-mediated decrease in Npt2a mRNA, suggesting that the PTH response requires transcription and translation. These findings suggest that responses to chronic PTH exposure are selectively regulated at a posttranscriptional level. The persistence of the phosphaturic response to PTH occurs through posttranscriptional mechanisms. PMID- 23344573 TI - Limited capacity of proximal tubular proteolysis in mice with proteinuria. AB - Albuminuria is associated with the additional loss in the urine of small molecular weight proteins normally degraded by the proximal convoluted tubule (PCT), and competition for binding to the megalin/cubilin reuptake system has been considered the likely cause. We have previously reported that deficiency of the intrinsic lysosomal protein Limp-2 causes tubular proteinuria due to reduced fusion of endosomes with lysosomes in the PCT leading to inadequate proteolysis. To determine whether this mechanism also contributes to the tubular proteinuria induced by albumin overload in normal mice, wild-type (WT) mice received daily BSA injections intraperitoneally for 10 days, using untreated Limp-2(-/-) mice as positive controls for inadequate proteolysis. BSA overload induced significant urinary loss of megalin and cubilin ligands in WT mice. Tubular uptake of Alexa conjugated BSA, administered by intravenous injection, was not reduced in the PCT of mice receiving intraperitoneal BSA. Expression of the tubular protein receptor megalin was also unchanged. There was a delay in proteolysis of reabsorbed proteins in WT mice receiving BSA, evidenced by an increased quantity of retinol binding protein (RBP) in the kidney cortex, increased basal distribution of endocytosed RBP in cells of the PCT, and persistence of exogenous Alexa conjugated BSA and RBP after injection. Upregulation of cathepsin L and normal fusion of lysosomes with endosomes were apparently not sufficient to maintain normal clearance of endocytosed proteins. The data suggest that in the presence of competition from albumin overload, reabsorption of filtered proteins is limited by the capacity of lysosomal degradation rather than receptor-mediated endocytosis. PMID- 23344575 TI - 5-Hydroxytryptamine-induced bladder hyperactivity via the 5-HT2A receptor in partial bladder outlet obstruction in rats. AB - We investigated the effects of partial bladder outlet obstruction (BOO) on the function and gene expression of 5-hydroxytryptamine (5-HT) receptor subtypes in rat bladder. Isometric contractions of the isolated bladders from sham-operated control and BOO rats were examined. The contractile responses to 5-HT were significantly increased in BOO rat bladder strips, while the responses to KCl, carbachol, or phenylephrine were not different from the control. The 5-HT-induced hypercontraction in BOO rat bladder strips was inhibited by ketanserin, a 5 HT(2A) receptor antagonist. The contractile responses to 5-HT in bladder strips were not affected by urothelium removal from the intact bladder. The gene expression of 5-HT receptor subtypes in the bladders was analyzed by RT-PCR. The mRNA expression of the 5-HT(2A), 5-HT(2B), 5-HT(2C), 5-HT(4), and 5-HT(7) receptors was detected in both the control and BOO rat bladders. Quantitative RT PCR analysis showed there was a significant increase of 5-HT(2A) receptor mRNA in the BOO rat bladder compared with the control bladder. On the other hand, the gene expression of the 5-HT(4) receptor was not changed in the BOO rat bladder. These results suggest that the increased contractile responses to 5-HT in BOO rat bladder may be partly caused by 5-HT(2A) receptor upregulation in the detrusor smooth muscles. PMID- 23344576 TI - Tn6198, a novel transposon containing the trimethoprim resistance gene dfrG embedded into a Tn916 element in Listeria monocytogenes. AB - OBJECTIVES: To characterize Tn6198, a novel conjugative transposon from the clinical Listeria monocytogenes strain TTH-2007, which contains the tetracycline and trimethoprim resistance genes tet(M) and dfrG, respectively, and to assess its transferability in vitro and in situ. METHODS: The complete sequence of Tn6198 was determined using a primer walking strategy. Horizontal gene transfer studies were performed by filter matings, as well as on the surface of smear ripened cheese and smoked salmon. The presence of Tn916-like circular intermediates was determined by PCR. Antibiotic resistance was determined by the broth microdilution method and microarray hybridization. RESULTS: Sequencing of Tn6198 revealed that a 3.3 kb fragment containing dfrG was integrated between open reading frames 23 and 24 of Tn916. Furthermore, an additional copy of Tn916 was present in L. monocytogenes TTH-2007. Both elements were transferred simultaneously and separately in vitro to recipients L. monocytogenes 10403S and Enterococcus faecalis JH2-2 by conjugation, resulting in either tetracycline- and trimethoprim-resistant or solely tetracycline-resistant transconjugants. On the surface of cheese and salmon, only L. monocytogenes 10403S transconjugants were detected. CONCLUSIONS: This study reports the first Tn916-like element associated with a trimethoprim resistance gene, as well as the first fully characterized transposon conferring multidrug resistance in L. monocytogenes. This is of concern, as trimethoprim is administered to listeriosis patients with beta-lactam allergy and as Tn6198 has a large potential for dissemination, indicated by both intra-species and inter-genus transfer. PMID- 23344574 TI - Increased biological response to 1,25(OH)(2)D(3) in genetic hypercalciuric stone forming rats. AB - Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (U) calcium (Ca) excretion, have increased intestinal Ca absorption and bone Ca resorption and reduced renal Ca reabsorption, leading to increased UCa compared with the Sprague-Dawley (SD) rats. GHS rats have increased vitamin D receptors (VDR) at each of these sites, with normal levels of 1,25(OH)(2)D(3) (1,25D), indicating that their VDR is undersaturated with 1,25D. We tested the hypothesis that 1,25D would induce a greater increase in UCa in GHS rats by feeding both strains ample Ca and injecting 1,25D (25 ng . 100 g body wt(-1) . day(-1)) or vehicle for 16 days. With 1,25D, UCa in SD increased from 1.7 +/- 0.3 mg/day to 24.4 +/- 1.2 (Delta = 22.4 +/- 1.5) and increased more in GHS from 10.5 +/- 0.7 to 41.9 +/- 0.7 (Delta = 29.8 +/- 1.8; P = 0.003). To determine the mechanism of the greater increase in UCa in GHS rats, we measured kidney RNA expression of components of renal Ca transport. Expression of transient receptor potential vanilloid (TRPV)5 and calbindin D(28K) were increased similarly in SD + 1,25D and GHS + 1,25D. The Na(+)/Ca(2+) exchanger (NCX1) was increased in GHS + 1,25D. Klotho was decreased in SD + 1,25D and GHS + 1,25D. TRPV6 was increased in SD + 1,25D and increased further in GHS + 1,25D. Claudin 14, 16, and 19, Na/K/2Cl transporter (NKCC2), and secretory K channel (ROMK) did not differ between SD + 1,25D and GHS + 1,25D. Increased UCa with 1,25D in GHS exceeded that of SD, indicating that the increased VDR in GHS induces a greater biological response. This increase in UCa, which must come from the intestine and/or bone, must exceed any effect of 1,25D on TRPV6 or NCX1-mediated renal Ca reabsorption. PMID- 23344577 TI - Combined effects of the siderophore monosulfactam BAL30072 and carbapenems on multidrug-resistant Gram-negative bacilli. AB - OBJECTIVES: Carbapenem resistance in Gram-negative bacteria, mediated by restricted net influx and carbapenem-hydrolysing beta-lactamases, is a growing problem. The monosulfactam antibiotic BAL30072 is stable to most carbapenemases, suggesting that it could be complementary to carbapenems. We have investigated the antimicrobial activity of BAL30072 combined with imipenem, meropenem and doripenem. METHODS: The in vitro activities of the combinations were evaluated using broth microdilution susceptibility and agar disc diffusion tests, broth dilution chequerboard titration and time-kill studies, using strains of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter with carbapenem MICs >= 2 mg/L. RESULTS: The combinations were effective against 70%-80% of the isolates tested in the presence of 1 mg/L of each antibiotic, whereas the carbapenems were ineffective and BAL30072 alone was effective against 20%-40% of the strains. Synergistic effects were observed with many Enterobacteriaceae and P. aeruginosa, but were less common among the Acinetobacter, although additive effects, where the activity of one partner compensated for lack of activity of the other, were common. None of the combinations exhibited an antagonistic effect in all tests, in contrast to other beta-lactams where negative interactions were frequently observed. Animal models of septicaemia demonstrated that the synergy observed in vitro with BAL30072 and meropenem can translate into greater in vivo efficacy. CONCLUSIONS: BAL30072/carbapenem combinations were effective against a broader range of multidrug-resistant Gram-negative bacteria than either of the single agents. Additive and synergistic effects were observed in Enterobacteriaceae and P. aeruginosa, and this enhanced activity was frequently associated with suppression of resistance development. The in vitro activity translated into improved in vivo efficacy. PMID- 23344578 TI - Expression of the adeB gene and responsiveness to 1-(1-naphthylmethyl)-piperazine and phenylalanyl-arginyl-beta-naphthylamide in clinical isolates of Acinetobacter baumannii. PMID- 23344579 TI - Wilms' tumor 1 protein and estrogen receptor beta expression are associated with poor outcomes in uterine carcinosarcoma. AB - BACKGROUND: Uterine carcinosarcoma (CS) is an aggressive malignancy. Increased expression of Wilms' tumor 1 (WT1) protein and estrogen receptor beta (ER-beta) protein is associated with worse outcomes in gynecologic cancers; therefore, we sought to assess this association in CS patients. METHODS: A retrospective analysis was conducted for women diagnosed with uterine CS from departmental databases. WT1/ER-beta expression was determined by immunohistochemical staining and scoring of specimens. Univariate and multivariate models were used to correlate progression-free survival (PFS) and overall survival (OS) with WT1/ER beta expression and clinicopathologic factors. RESULTS: Ninety four patients had mean follow-up of 27 months. Postoperative treatments included chemotherapy for 52 (55 %) subjects and radiotherapy for 25 (27 %). Sixty-four (68 %) and 74 (79 %) tumor samples expressed WT1 and ER-beta by immunohistochemistry, respectively. On univariate analysis, stage (p = .02) and lower uterine segment invasion (LUSI) (p = .001) were associated with decreased PFS. Only stage (p = .003) was linked to OS. In the total sample, increased WT1 expression was marginally associated with impaired PFS (p = .07) and OS (p = .09) but ER-beta expression was not associated with PFS (p = .89) or OS (p = .30). WT1 and ER-beta concurrent expression was associated with impaired OS (p = .02) and PFS (p = .02). On multivariate analysis, LUSI was a significant prognostic factor for PFS [hazard ratio (HR) 2.21, 95 % confidence interval (CI) = 1.12-4.32, p = .03] and stage for OS (HR 3.20, 95 % CI = 1.23-8.35, p = .02). Increased WT1/ER-beta expression was associated with impaired OS (HR 1.31, 95 % CI = 1.02-1.69, p = .04). CONCLUSIONS: Concurrent increased WT1 and ER-beta expression impairs prognosis for women with uterine CS. Further research is warranted to define how relevant pathways interact and whether targeting these pathways improves OS. PMID- 23344580 TI - Population-based outcome of stage IA-IIA resected gastric adenocarcinoma: who should get adjuvant treatment? AB - BACKGROUND: The benefit of adjuvant treatment in gastric adenocarcinoma was demonstrated by randomized, controlled trials of patients with locally advanced tumors. Thus, its role for stage IIB-IIIC disease is widely accepted. We aimed to identify patients with stage IA-IIA gastric adenocarcinoma who have a poor prognosis and thus may benefit from adjuvant treatment. METHODS: Patients with gastric adenocarcinoma who underwent surgical resection with pathological evaluation of >=15 lymph nodes and had available disease-specific survival (DSS) data were identified from the Surveillance Epidemiology and End Results Registry. Survival differences were evaluated with the log-rank test and Cox multivariate analysis. RESULTS: Stage and TN grouping strongly predicted DSS (P < 0.001, P < 0.001). Stage IA tumors had an excellent outcome: 91 +/- 1.2 % 5-year DSS. The TN groupings of stages IB and IIA had the next best outcomes with 5-year DSS from 66 +/- 4.6 % to 81 +/- 2.3 %. Older age (P < 0.001), higher grade (P = 0.004), larger tumor size (P < 0.001), and proximal tumor location (P < 0.001) were independent predictors of worse DSS in stage IB-IIA tumors. We devised a risk stratification scheme for stage IB-IIA tumors where 1 point was assigned for age >60 years, tumor size >5 cm, proximal tumor location, and grade other than well differentiated. Five-year DSS was 100 % for patients with 0 points; 86 +/- 4.3 %, 1 point; 76 +/- 3 %, 2 points; 72 +/- 2.8 %, 3 points; and 48 +/- 4.9 %, 4 points (P < 0.001). CONCLUSIONS: Patients with stage IB-IIA gastric adenocarcinoma and >=2 adverse features (age >60 years, tumor size >5 cm, proximal location, and high-grade) have 5-year DSS <=76 %. Adjuvant therapy may be warranted for these patients. PMID- 23344581 TI - Influence of CYP2B6 genetic variants on plasma and urine concentrations of bupropion and metabolites at steady state. AB - BACKGROUND: Bupropion, an antidepressant and smoking cessation medication, is metabolized to hydroxybupropion (HB), an active metabolite, primarily by CYP2B6. OBJECTIVES: To compare plasma concentrations of bupropion and metabolites at steady state in healthy volunteers with and without CYP2B6 genetic variants. METHODS: In a genotype-guided study of 42 healthy individuals, we measured the plasma and urine concentrations of bupropion and its metabolites, HB, threohydrobupropion, and erythrohydrobupropion after 7 days of sustained-release bupropion dosing. RESULTS: CYP2B6*6 and *18 gene variants were associated with ~33% reduced concentrations of HB, with no effects on concentrations of bupropion or other metabolites. We could account for 50% of the variation in HB concentrations in a model including genotype and sex. CONCLUSION: As HB is active and its steady-state concentrations are more than 10 times higher than bupropion, CYP2B6 variants are likely to affect pharmacological activity. Because of the large individual variation within the genotype group, the use of therapeutic drug monitoring for dose optimization may be necessary. PMID- 23344583 TI - This is a good title. PMID- 23344584 TI - [Difficult drug reimbursement system for pain patients]. PMID- 23344585 TI - [Self elected menstruation]. PMID- 23344588 TI - [Lack of confidence in the pharmacies?]. PMID- 23344589 TI - [Electronic prescriptions and cooperation]. PMID- 23344590 TI - [K.A. Olsen replies]. PMID- 23344591 TI - [Uncertainty about unnecessary admissions]. PMID- 23344592 TI - [There is not enough research being done!]. PMID- 23344593 TI - [D. Bratlid & T.W. Ruud Hansen replies]. PMID- 23344594 TI - Videobased emergency medical interaction. PMID- 23344595 TI - Virtual crisis management: an alternative to one single public emergency number and joint operation centres. PMID- 23344597 TI - [Potentially addictive drugs on reimbursable prescription for chronic severe pain]. AB - BACKGROUND: Changes in the Norwegian drug reimbursement system in 2008 included the establishment of a new reimbursement code (-71) which authorises coverage of expenditures for potentially addictive drugs in patients with severe, predominantly non-malignant, chronic pain. This reform has hitherto not been evaluated. MATERIAL AND METHOD: We assessed national data on drug reimbursements in accordance with code -71 for the period 2008-2011, and anonymised copies of all confirmation letters granting reimbursements according to code -71 in Central Norway (three counties) for 2010. Approximately 1300 individual applicants' gender and age, diagnosis, potentially addictive drug applied for, drug dose, and identity and specialty of the prescribing physician, were recorded. RESULTS: From the time of establishment, reimbursement code -71 has been utilised by an increasing number of individuals, encompassing close to 10,000 subjects in 3rd quarter 2011. Almost one-third of the approved applications were for pregabalin, and the rest were for various opioids. The diagnoses were most often derived from the musculoskeletal and nervous systems, and were often nonspecific. A considerable number of treatment regimens were not in accordance with current principles for the management of chronic non-malignant pain, and drug doses were at times remarkably high. INTERPRETATION: Aspects of this drug reimbursement regulation should be closely monitored, and may be in need of changes. PMID- 23344598 TI - [Drug-related claims in the Norwegian system of compensation to patients]. AB - BACKGROUND: Patients subjected to drug-related injuries can, in accordance with Norwegian legislation, seek compensation from the Norwegian System of Patient Injury Compensation (NPE). The aim of this study was to examine what drugs and injuries instigate claims against NPE, and how these cases are resolved. MATERIAL AND METHODS: We have assessed anonymised summaries of 992 consecutive indemnity applications received and evaluated by NPE over the period 2003-2009. We recorded the age and gender of applicants, treatment diagnosis, drugs implicated, outcome, and NPE's decision in each case. RESULTS: A total of 964 claims were included. The most commonly implicated drugs were those affecting the nervous system (34.6%) and the musculoskeletal system (26.1%). Rofecoxib at 18.9% was the predominant single drug implicated. In two-thirds of the cases, adverse effects were given as the reason for the claim, whereas the last one-third consisted of claims for medication errors. The most common injuries were related to cardiovascular diseases (28.7%) or non-specific conditions (17.5%). 8.4% of the cases related to fatalities. In all, 26.3% of the claims resulted in compensations. INTERPRETATION: Few patients made use of the NPE. Most of the compensation claims in the years 2003-2009 involved rofecoxib and psychoactive drugs, and the majority of claims were rejected. PMID- 23344599 TI - [Iron deficiency anaemia--interpretation of biochemical and haematological findings]. AB - BACKGROUND: Iron deficiency and iron deficiency anaemia are frequent problems in both the primary and the specialist health services. It is important to detect iron deficiency and to determine the causal relationship because iron deficiency may be secondary to a serious disease. The diagnosis of iron deficiency is largely based on biochemical and haematological laboratory findings, but there is no standardisation or consensus on the interpretation of these findings. METHOD: Non-systematic search in the PubMed database with a discretionary selection of articles, based on the authors' knowledge of the field. RESULTS: Ferritin measurement is the most important analysis in the study of iron deficiency, but there is no consensus on the diagnostic cut-off. It is usual in Norway today to use a ferritin level of < 12-20 MUg/L, but at this low level the sensitivity for detecting iron deficiency is very low. A number of studies show that if the diagnostic cut-off is increased to the order of 30 MUg/L the sensitivity is significantly higher for only a small reduction in specificity. INTERPRETATION: When studying iron deficiency as a cause of anaemia, the diagnostic cut-off for detecting deficiency should be higher than that used today. The ferritin level increases with inflammation and ought in practice to be considered in conjunction with the CRP level. The level of transferrin receptor in plasma increases with iron deficiency without being influenced by inflammation and is therefore a good supplement to ferritin measurement. Measurement of iron, transferrin and transferrin saturation provides little information additional to that provided by ferritin in iron deficiency studies. PMID- 23344600 TI - Uncommon adverse effect of a common medication. PMID- 23344601 TI - [Drug induced displacement of menstruation]. PMID- 23344602 TI - [Neurography for diagnosing carpal tunnel syndrome]. AB - BACKGROUND: A number of evidence-based guidelines now recommend that a nerve conduction study should be used to confirm the existence of carpal tunnel syndrome before any surgery takes place. METHOD: The article is based on a search in PubMed, a personal literature archive (1980-2011) and long clinical experience of neurological and neurophysiological diagnostics. RESULTS: Both motor and sensory nerve fascicles must be tested after adequate warming up. An extended nerve conduction study with supplementary tests to compare velocities and latencies in median and ulnar nerves, increases the diagnostic precision. Given normal or mild findings, surgery can usually be avoided as the first choice of treatment, because many patients with mild carpal tunnel syndrome recover spontaneously. INTERPRETATION: The gold standard for diagnosis of carpal tunnel syndrome should be a combination of a clinical examination and a nerve conduction study. PMID- 23344603 TI - [Electromyography (EMG) and neurography in patients with severe neuromuscular diseases]. AB - BACKGROUND: Many neuromuscular diseases are potentially severe, and EMG and neurography are methods used in the assessment of these conditions. METHOD: The article is based on the authors' knowledge and experience, with special emphasis on the use of these methods in the assessment of severe diseases affecting striated muscle and peripheral nerves. A PubMed search was performed with the cut off fifteen years back in time, and in addition a discretionary selection was made of articles known to the authors. RESULTS: EMG is the most valuable method for assessing myopathy, and neurography provides most information about neuropathy, but the methods are complementary. These examinations are the most sensitive for diagnosing some conditions (for example myasthaenia) A high level of expertise is necessary for diagnosing these conditions. INTERPRETATION: EMG and neurography are important and often necessary means of assessing patients with severe neuromuscular disease. PMID- 23344604 TI - [Small-fibre neuropathy]. AB - BACKGROUND: Small-fibre neuropathy is a neuropathy that mainly affects the small nerve fibres. Owing to doctors' inadequate knowledge of the condition and limited diagnostic methods, this type of neuropathy is probably under-diagnosed. Small fibre neuropathy has many causes, but the symptoms are often relatively similar. This review article is intended to give doctors insight into the clinical expressions and diagnosis of the condition. METHOD: The article is based on literature searches in PubMed and the authors' clinical and scientific experience of the subject. RESULTS: Small-fibre neuropathy generates a characteristic distribution of symptoms, particularly pain, and is associated with a number of common illnesses. Specific tests for small fibre neuropathy, such as skin biopsy and thermal testing, can be used to confirm the diagnosis. The treatment targets the symptoms, but complete pain relief is often difficult to achieve. INTERPRETATION: The clinical neurological examination will not generally be able to detect small-fibre neuropathy, but will contribute primarily to excluding a more general polyneuropathy. Supplementary tests are often necessary to make a final diagnosis. PMID- 23344605 TI - [Diet, cholesterol and carbohydrates]. PMID- 23344606 TI - [Exchange of health personnel between Bergen and Zanzibar]. PMID- 23344607 TI - [Living in a body that lacks proprioception]. PMID- 23344608 TI - [The sixth sense]. PMID- 23344609 TI - [Interview in judicial observation]. PMID- 23344610 TI - [Fan charts]. PMID- 23344613 TI - Phylogenetic and pathogenic analyses of two virulent Newcastle disease viruses isolated from Crested Ibis (Nipponia nippon) in China. AB - The crested ibis is one of the most endangered birds in the world, found only in Shaanxi Province in Central China, and it has been reintroduced in Sadogashima in Japan. Two Newcastle disease virus (NDV) isolates were collected from sick crested ibises, and their pathogenic and phylogenetic characteristics were investigated. The results showed that they are virulent, with intracerebral pathogenicity indices of 1.46-1.83 and a mean time of death of 54.4-84.4 h. They shared the same virulent motif (112)-R-R-Q-K-R-F-(117) at the F protein cleavage site. The phylogenetic analysis revealed that both isolates were clustered with class II NDVs, with one in genotype VIId and another in a novel genotype (provisionally designated as VIi). The two isolates shared high homology with the strains isolated from poultry flocks in the same region from 2006 to 2010. We first isolated and characterised the NDV isolates from crested ibises, one of which showed new genetic characteristics and formed a new subgenotype with isolates from pigeons and ostriches in the same area. These data are useful for further epidemiological studies on NDV and the protection of crested ibises. PMID- 23344614 TI - Relationship between serum gamma-glutamyltransferase levels and acute exacerbation of chronic obstructive pulmonary disease. AB - INTRODUCTION: gamma-glutamyltransferase (GGT) is a plasma membrane enzyme, which is involved in antioxidant glutathione resynthesis. OBJECTIVES: The aim of the study was to compare the serum levels of GGT (which is considered a novel marker of oxidative stress) between patients with stable chronic obstructive pulmonary disease (COPD) and those with acute exacerbation of COPD, and the relationship of GGT with inflammation. PATIENTS AND METHODS: The study involved 132 patients with exacerbated COPD and normal function of the liver and biliary tract (mean age, 66.6 +/-10.1 years; men, 88.6%) and 147 patients with stable COPD (mean age, 65.4 +/-8.8 years; men, 87.1%). Serum GGT and C-reactive protein (CRP) levels were measured and compared between the groups. RESULTS: Serum GGT levels in patients with exacerbated COPD were significantly higher than in those with stable COPD (30 U/l; interquartile range [IQR], 18.8 vs. 25 U/l; IQR, 16; P <0.001]. Serum CRP levels were significantly higher in patients with exacerbated COPD compared with those with stable COPD (34 mg/l; IQR, 58.3 vs. 16 mg/l; IQR, 24.6; P <0.001). A significant positive correlation was observed between GGT activity and CRP levels (r = 0.27, P = 0.002). The GGT level of 29 U/l was set as a cutoff value of acute exacerbation with the specificity of 70.1% and sensitivity of 62.8% (95% confidence interval, 0.6-0.71; area under the curve, 0.66; standard error, 0.032; P <0.001). CONCLUSIONS: Our study indicates that serum GGT levels as the marker of oxidative stress increase during exacerbated COPD and correlate with CRP levels. The measurement of GGT activity may be useful in the evaluation of exacerbated COPD. PMID- 23344615 TI - Lateral compression open cap splint with circummandibular wiring for management of pediatric mandibular fractures: a retrospective audit of 10 cases. AB - INTRODUCTION: Mandibular fractures are relatively less frequent in children when compared to adults. Pediatric patients present a unique challenge to maxillofacial surgeons in terms of their treatment planning and in their functional needs. We currently describe our experience with lateral compression open cap splint with circummandibular wiring as a treatment modality which involves fewer risks in treating pediatric symphysis/parasymphysis/body mandibular fractures. MATERIALS AND METHODS: A retrospective analysis of pediatric patients with mandibular symphysis/parasymphysis/body fractures operated from January 2007 to January 2012 was performed. Clinical photographs and orthopantomogram assessment at the time of presentation, after treatment, and at 6 months postoperatively were evaluated. RESULTS: All the 10 patients were followed up until the period of 6 months, and none of them had any major complications. Postoperatively, there was satisfactory healing and union of fracture fragments in all the patients. Only one patient developed infection at submental region. The 6-month follow-up showed good occlusion, without interference in teeth eruption and no signs of temporomandibular joint problems. CONCLUSIONS: Lateral compression open cap splints for treatment of pediatric mandibular symphysis/parasymphysis/body fractures are reliable treatment modalities with regard to occlusion-guided fracture reduction. PMID- 23344616 TI - Intraoral schwannoma: a case report. AB - Schwannoma (neurilemmona) is a benign nerve sheath composed of Schwann cells. This tumor represents 1% of all benign tumor, usually observed in the head and neck region, and in, rare cases, this lesion may be observed in oral cavity. They are usually asymptomatic, do not recur, and malignant transformation is rare. We presented a case report of schwannoma in the lower lips. PMID- 23344617 TI - An unusual cause of epistaxis in a young patient: the supernumerary nasal tooth. AB - Eruption of supernumerary teeth into the nasal cavity is a rare pathological condition. Identification of such teeth is important as they can sometimes cause significant morbidity. This report describes a young female patient with a complaint of epistaxis from the right nasal cavity. The diagnosis of a supernumerary nasal tooth was confirmed by computed tomography and the tooth was removed endoscopically with minimal morbidity. PMID- 23344618 TI - Oligonucleotide delivery to the lung: waiting to inhale. PMID- 23344619 TI - Virus-mediated Genetic Surgery: Homologous Recombination With a Little "Helper" From My Friends. PMID- 23344620 TI - Targeting DNA With Fingers and TALENs. PMID- 23344622 TI - siRNA-optimized Modifications for Enhanced In Vivo Activity. AB - Current modifications used in small interfering RNAs (siRNAs), such as 2'-methoxy (2'-OMe) and 2'-fluoro (2'-F), improve stability, specificity or immunogenic properties but do not improve potency. These modifications were previously designed for use in antisense and not siRNA. We show, for the first time, that the siRNA-optimized novel 2'-O modifications, 2'-O-benzyl, and 2'-O-methyl-4 pyridine (2'-O-CH2Py(4)), are tolerated at multiple positions on the guide strand of siRNA sequences in vivo. 2'-O-benzyl and 2'-O-CH2Py(4) modifications were tested at each position individually along the guide strand in five sequences to determine positions that tolerated the modifications. The positions were combined together and found to increase potency and duration of siRNAs in vivo compared to their unmodified counterparts when delivered using lipid nanoparticles. For 2'-O benzyl, four incorporations were tolerated with similar activity to the unmodified siRNA in vivo, while for 2'-O-CH2Py(4) six incorporations were tolerated. Increased in vivo activity was observed when the modifications were combined at positions 8 and 15 on the guide strand. Understanding the optimal placement of siRNA-optimized modifications needed for maximal in vivo activity is necessary for development of RNA-based therapeutics. PMID- 23344621 TI - Systemic RNAi-mediated Gene Silencing in Nonhuman Primate and Rodent Myeloid Cells. AB - Leukocytes are central regulators of inflammation and the target cells of therapies for key diseases, including autoimmune, cardiovascular, and malignant disorders. Efficient in vivo delivery of small interfering RNA (siRNA) to immune cells could thus enable novel treatment strategies with broad applicability. In this report, we develop systemic delivery methods of siRNA encapsulated in lipid nanoparticles (LNP) for durable and potent in vivo RNA interference (RNAi) mediated silencing in myeloid cells. This work provides the first demonstration of siRNA-mediated silencing in myeloid cell types of nonhuman primates (NHPs) and establishes the feasibility of targeting multiple gene targets in rodent myeloid cells. The therapeutic potential of these formulations was demonstrated using siRNA targeting tumor necrosis factor-alpha (TNFalpha) which induced substantial attenuation of disease progression comparable to a potent antibody treatment in a mouse model of rheumatoid arthritis (RA). In summary, we demonstrate a broadly applicable and therapeutically relevant platform for silencing disease genes in immune cells. PMID- 23344623 TI - Targeting LDL Cholesterol With LNA. PMID- 23344624 TI - Defined Folate-PEG-siRNA Conjugates for Receptor-specific Gene Silencing. AB - Gene silencing mediated by small interfering RNA (siRNA) is a novel approach in the development of new cancer therapeutics. Polycations used for nucleic acid delivery still remain heterogeneous compounds, despite continuous progress in polymer synthetic technologies. Here we report the development of a structural defined folic acid polyethylene glycol (PEG) siRNA conjugate accessible via click chemistry yielding a monodisperse ligand-PEG-siRNA conjugate. The folic acid targeting ligand was synthesized by solid phase supported peptide chemistry. The conjugate was shown to be specifically internalized into folic acid receptor expressing cells. When combined with a structurally defined polycation, again synthesized with the precision of solid phase chemistry, efficient receptor specific gene silencing is achieved. PMID- 23344625 TI - Oswald Bumke (1877-1950). PMID- 23344626 TI - Is there a difference in gastric emptying between myotonic dystrophy type 1 patients with and without gastrointestinal symptoms? AB - Gastrointestinal symptoms are frequent complaints in patients with myotonic dystrophy type 1 (MyD1) and may be associated with reduced gastrointestinal motility caused by smooth muscle dysfunction. Although previous studies have found delayed gastric emptying (GE) in MyD1 patients, the relationship between GE and symptoms has been unclear. We investigated GE in 23 MyD1 patients and 20 healthy volunteers using the 13C-acetate breath test. The MyD1 patients were divided into two groups: those with gastrointestinal symptoms (n = 9) and those without gastrointestinal symptoms (n = 14). The GE function was estimated using the 13C-acetate breath test as half-emptying time (HET) and peak time of the 13C %-dose-excess curve (T max). GE (HET and T max) was more significantly delayed in patients with MyD1 than in the controls. The GE in MyD1 patients with gastrointestinal symptoms was significantly delayed compared to those without gastrointestinal symptoms. The GE in MyD1 patients with gastrointestinal symptoms was more significantly delayed than in the controls. The GE was significantly delayed in MyD1 patients with gastrointestinal symptoms for >5 years as compared to those with the disease for <5 years, while GE of MyD1 patients without gastrointestinal symptoms did not correlate with the duration of the disease. The GE in MyD1 patients did not correlate with the muscular disability rating scale. These findings suggest that impairment of GE evolves over time and that the progression of delayed GE and skeletal muscle impairment are independent. Smooth muscle impairment may be affected at an earlier stage in MyD1. PMID- 23344627 TI - Dielectric properties of MSWI bottom ash for non-invasive monitoring of moisture. AB - The dielectric procperties of MSWI bottom ash as a function of volumetric water content (VWC) are reported in this paper. The objective was to aid the development of microwave based non-invasive emission monitoring and control system for various bottom ash applications. The dielectric measurements were made, on a 1.5-year-old bottom ash, with an electrical network analyzer in microwave range (300 MHz-1.5 GHz). The VWC of the samples ranged between 0.05 and 0.40 m(3) m(-3). The relationship between the dielectric permittivity and the VWC was modeled with an empirical model and a physically based Birchak model (BM). The results showed that a linear relationship existed between the permittivity and the VWC at higher water contents (>0.25 m(3) m(-3)). However, at lower water contents (<0.25 m(3) m(-3)), the relationship between the permittivity and the WVC was affected by the composition of the bottom ash. The permittivity measurement, with the current method, was not affected by high salt concentrations (10 and 20 dS/m). The empirical model, as compared to BM, provided the best fit between the actual and the predicted water content. The root mean square error (RMSE) values were 0.008-0.010 and 0.06-0.09 m(3) m(-3) for the empirical and the Birchak model, respectively. PMID- 23344628 TI - Addressing statistical and operational challenges in designing large-scale stream condition surveys. AB - Implementing a statistically valid and practical monitoring design for large scale stream condition monitoring and assessment programs can be difficult due to factors including the likely existence of a diversity of ecosystem types such as ephemeral streams over the sampling domain; limited resources to undertake detailed monitoring surveys and address knowledge gaps; and operational constraints on effective sampling at monitoring sites. In statistical speak, these issues translate to defining appropriate target populations and sampling units; designing appropriate spatial and temporal sample site selection methods; selection and use of appropriate indicators; and setting effect sizes with limited ecological and statistical information about the indicators of interest. We identify the statistical and operational challenges in designing large-scale stream condition surveys and discuss general approaches for addressing them. The ultimate aim in drawing attention to these challenges is to ensure operational practicality in carrying out future monitoring programs and that the resulting inferences about stream condition are statistically valid and relevant. PMID- 23344629 TI - Integration in bioanalysis: technologies for point-of-care testing. AB - Biosensors, Lab-on-Chip technologies, and sensor-actor molecules are steps towards the integration of bioanalysis into small devices that will help in providing analysis where it is needed: the point-of-care. This article gives a brief overview of recent achievements and future prospects. PMID- 23344631 TI - Trust plans to slash one in three consultant posts. PMID- 23344630 TI - Analysis of the dynamic relationships between the lingual artery and lingual markers in patients with obstructive sleep apnea. AB - PURPOSE: To determine the relationships between the lingual artery and the lingual markers in tongue resting and extended positions in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) for the clinical application of functional tongue surgery. METHOD: Computed tomography angiography (CTA) of the lingual artery was performed on 30 OSAHS patients using a 16-slice spiral CT scanner. The anatomical relationships between the lingual artery and the lingual markers were analyzed with the tongue in resting and extended positions using the CTA images. RESULTS: The course of the lingual artery resembled the configuration of the Big Dipper constellation when the tongue was in a resting position. When the tongue was in a full-extended position, the majority of the lingual artery moved forward and upward with the hyoid and formed a "?" fashion. The positions of the tip of the greater horn of the hyoid changed with the tongue positions. While the relationship between the main lingual artery and the tip of the greater horn of the hyoid, as well as the distances between bilateral lingual arteries, remained constant in both tongue positions. CONCLUSIONS: In conditions of dynamic tongue movement, the tip of the great horn of the hyoid and the lingual midline are constant anatomical markers to indicate the course of the lingual artery. PMID- 23344632 TI - Correlates and geographic patterns of knowledge that physical activity decreases cancer risk. AB - While many lifestyle-related cancer risk factors including tobacco use, poor diet, and sun exposure are well recognized by the general public, the role of physical activity in decreasing cancer risk is less recognized. Studies have demonstrated gender-, race/ethnicity-, and age-based disparities in cancer risk factor knowledge; however, beliefs and geographic factors that may be related to knowledge are under-examined. In this study, we analyzed data from the 2008 Health Information National Trends Survey to determine correlates of knowledge of the relationship between physical activity and reduced cancer risk in the adult US population. We generated geographic information system maps to examine the geographic distribution of this knowledge. Results revealed that there is confusion among US adults about the relationship between physical activity and cancer risk: Respondents who believed that cancer is not preventable had significantly lower odds of knowing that physical activity reduces cancer risk (p < .001) whereas respondents who believed that cancer is caused by one's behavior had almost two times the odds of knowing that physical activity reduces cancer risk (p < .001). Those who were aware of current physical activity guidelines were also significantly more likely to know that physical activity reduces cancer risk (p < .01). Observed geographic variability in knowledge was consistent with geographic trends in obesity and physical inactivity. Correlates of cancer risk factor knowledge point to opportunities for targeted interventions. PMID- 23344636 TI - A family-based association study of PRSS12 and mental retardation in the Qinba mountain region of China. PMID- 23344633 TI - It's Your Game...Keep It Real: can innovative public health prevention research thrive within a comparative effectiveness research framework? AB - The federal comparative effectiveness research (CER) initiative is designed to evaluate best practices in health care settings where they can be disseminated for immediate benefit to patients. The CER strategic framework comprises four categories (research, human and scientific capital, data infrastructure, and dissemination) with three crosscutting themes (conditions, patient populations, and types of intervention). The challenge for the field of public health has been accommodating the CER framework within prevention research. Applying a medicine based, research-to-practice CER approach to public health prevention research has raised concerns regarding definitions of acceptable evidence (an evidence challenge), effective intervention dissemination within heterogeneous communities (a dissemination and implementation challenge), and rewards for best practice at the cost of other promising but high-risk approaches (an innovation challenge). Herein, a dynamic operationalization of the CER framework is described that is compatible with the development, evaluation, and dissemination of innovative public health prevention interventions. An effective HIV, STI, and pregnancy prevention program, It's Your Game...Keep It Real, provides a case study of this application, providing support that the CER framework can compatibly coexist with innovative, community-based public health prevention research. PMID- 23344637 TI - Association study on tardive dyskinesia and polymorphisms in COMT and MAOA in Chinese population. PMID- 23344638 TI - Dibenzo-p-dioxins and dibenzofurans in human breast milk collected in the area of Taranto (Southern Italy): first case study. AB - We report on the content of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in 15 breast milk samples of nursing women living in the city of Taranto (Southern, Italy) or nearby. Breast milk samples were collected over the 2008-2009 period and analyzed by gas chromatography coupled with high-resolution mass spectrometry (GC-HRMS) upon accelerated solvent extraction (ASE) using acetone/n-hexane mixture 1:1 (v/v). The method was validated demonstrating good performing features. Profiles of PCDD/PCDF congeners in breast milk samples exhibited a prevalence of PCDFs compared to PCDDs. Toxic equivalents (TEQs in picogram per gram fat) of four breast milk were far above the legal limit for human consumption of 3.0 pg/g; their estimated daily and weekly dietary intake were almost 5-20 and 10-40 times higher, respectively, than the tolerable intake values established by the World Health Organization. PMID- 23344639 TI - Shrub clearing adversely affects the abundance of Ixodes ricinus ticks. AB - In order to get a better understanding of the importance of vertical forest structure as a component of Ixodes ricinus tick habitat, an experiment was set up in a coniferous forest on sandy soils in northern Belgium. Ticks were sampled in six control and six treatment plots on various sampling occasions in 2008-2010. In the course of the study period, a moderate thinning was carried out in all plots and shrub clearing was performed in the treatment plots. Thinning had no effect on tick abundance, while shrub clearing had an adverse affect on the abundance of all three life stages (larva, nymph, adult) up to 2 years post clearing. Our findings are especially relevant in the light of the ongoing efforts to improve vertical forest structure in Belgium and many other parts of Europe, which might create suitable habitats for ticks and change the epidemiology of tick-borne diseases. Also, our results indicate that shrub clearing could be applied as a tick control measure in recreational areas where there is a high degree of human-tick contact. PMID- 23344640 TI - In vitro activities of plant extracts from the Brazilian Cerrado and Pantanal against Rhipicephalus (Boophilus) microplus (Acari: Ixodidae). AB - A total of 73 ethanol extracts from different anatomical parts of 44 plant species belonging to 24 families, native to the Mid-Western region of Brazil, were assessed in vitro for their effect on the reproductive cycle of engorged females of the cattle tick Rhipicephalus (Boophilus) microplus, using the adult immersion test. All extracts were evaluated at the concentration of 0.2 % and, among the extracts tested, the one obtained from the fruits of Guarea kunthiana (Meliaceae) proved to be highly efficacious, showing 99.1 % of product effectiveness. Extracts from other three species were shown to be moderately active, namely Nymphaea amazonum trunk (Nymphaeaceae) [51.7 %], Strychnos pseudoquina trunk (Loganiaceae) [48 %] [corrected] and Ocotea lancifolia leaves (Lauraceae) [34.5 %], while the remaining extracts were shown to be weakly active or inactive. This is the first report on the bioactivity of these species on egg production by engorged females of R. microplus. PMID- 23344642 TI - Medical care of pregnant women with type 1 diabetes: current guidelines and clinical practice. AB - The prevalence of all types of diabetes mellitus is increasing worldwide. Diabetes is a common metabolic complication of pregnancy. For many years, pregnancy complicated by type 1 diabetes was associated with a particularly poor prognosis, and while this has changed dramatically over the last 2 decades, a lot has yet to be done. The continuous relationship between the maternal glucose level and the prevalence of pregnancy complications is well-documented. The list of outcomes includes congenital malformations, stillbirths, neonatal mortality, macrosomia, hypoglycemia, and many others. Several new therapeutic and monitoring tools have become available over the recent years, for example, short- and long acting insulin analogs, personal pumps, and continuous glucose monitoring systems. Interestingly, pregnancy planning and preconception education proved to be particularly effective in improving glycemic control in type 1 diabetic women and achieving therapeutic goals recommended by clinical guidelines. This resulted in the reduction of some maternal and neonatal pregnancy outcomes reported from various populations, but despite this remarkable progress the prevalence of the most common complication, neonatal macrosomia, is still substantially higher than in the newborns of mothers without diabetes. The likely causes of this phenomenon are short episodes of hyperglycemia, particularly postprandial ones, liberal diet, maternal obesity, and substantial weight gain during pregnancy - these potential reasons should be addressed in clinical practice. In the future, new therapeutic devices, such as close-loop insulin pumps, may help further improve the prognosis in pregnant women with type 1 diabetes. PMID- 23344641 TI - SyM-BBB: a microfluidic Blood Brain Barrier model. AB - Current techniques for mimicking the Blood-Brain Barrier (BBB) largely use incubation chambers (Transwell) separated with a filter and matrix coating to represent and to study barrier permeability. These devices have several critical shortcomings: (a) they do not reproduce critical microenvironmental parameters, primarily anatomical size or hemodynamic shear stress, (b) they often do not provide real-time visualization capability, and (c) they require a large amount of consumables. To overcome these limitations, we have developed a microfluidics based Synthetic Microvasculature model of the Blood-Brain Barrier (SyM-BBB). The SyM-BBB platform is comprised of a plastic, disposable and optically clear microfluidic chip with a microcirculation sized two-compartment chamber. The chamber is designed in such a way as to permit the realization of side-by-side apical and basolateral compartments, thereby simplifying fabrication and facilitating integration with standard instrumentation. The individually addressable apical side is seeded with endothelial cells and the basolateral side can support neuronal cells or conditioned media. In the present study, an immortalized Rat Brain Endothelial cell line (RBE4) was cultured in SyM-BBB with a perfusate of Astrocyte Conditioned Media (ACM). Biochemical analysis showed upregulation of tight junction molecules while permeation studies showed an intact BBB. Finally, transporter assay was successfully demonstrated in SyM-BBB indicating a functional model. PMID- 23344643 TI - Pathways of infusate loss during convection-enhanced delivery into the putamen nucleus. AB - BACKGROUND: New strategies aiming to treat Parkinson's disease, such as delivery of trophic factors via protein infusion or gene transfer, depend upon localized intracerebral infusion, mainly into the putamen nucleus. Convection-enhanced delivery (CED) has been proposed as a method to improve intracerebral distribution of therapies. Yet analysis of controversial results during the clinical translation of these strategies suggests that intracerebral misdistribution of infusate may have affected the outcomes by limiting the amount of treatment into the target region. OBJECTIVES: This study aimed to identify possible pathways of infusate loss and their relative impact in the success of targeted CED into the postcommissural ventral putamen nucleus. METHODS: Thirteen adult macaque monkeys received intraputaminal CED infusions of 100 ul of 2.0 mM gadoteridol and bromophenol blue (0.16 mg/ml) solution at a rate of 1.0 ul/min under intraoperative magnetic resonance imaging (MRI) guidance. Quantitative maps of infusate concentration were computed at 10-min intervals throughout the procedure in a 3-Tesla MRI scanner. The fraction of tracer lost from the putamen as well as the path of loss were evaluated and quantified for each infusion. RESULTS: All injections (total 22) were successfully placed in the ventral postcommissural putamen nucleus. Four major paths of infusate loss from the putamen were observed: overflow across putamen boundaries, perivascular flow along large blood vessels, backflow along the inserted catheter and catheter tract leakage into the vacated catheter tract upon catheter removal. Overflow loss was observed within the first 30 ul of infusion in all cases. Measurable tracer loss following the path of an artery out of the putamen was observed in 15 cases, and in 8 of these cases, the loss was greater than 10% of infusate. Backflow that exited the putamen was observed in 4 cases and led to large loss of infusate (80% in 1 case) into the corona radiata. Loss into the vacated catheter tract amounted only to a few microliters. CONCLUSIONS: Our analysis demonstrates that after controlling for targeting, catheter type, infusion rate and infusate, the main issues during surgical planning are the identification of appropriate infusate volume that matches the target area, as well as mapping the regional vasculature as it may become a pathway for infusate loss. Most importantly, these results underscore the significance of presurgical planning for catheter placement and infusion, and the value of imaging guidance to ensure targeting accuracy. PMID- 23344644 TI - [Off-label use of drugs in pediatric emergencies: limitations and grey areas of drug approval]. AB - In the medical treatment of children drugs are frequently used outside the boundaries of the approved licensing and use under the terms of off-label use is possible. However, this requires critical reasoning and experience with the drug involved. With help of a traffic light colored spreadsheet this article illustrates the limitations, problems and possibilities of pharmacotherapy in pediatric emergencies or pediatric anesthesia. Of the 45 emergency drugs listed in this article most can be used in childhood, at least under specific conditions. Licensing restrictions occur especially in the newborn period and infancy resulting in frequent off-label use. Severe pitfalls, such as the propofol infusion syndrome after long-term sedation with propofol under the age of 16 years, emphasize the need for serious reflection on the substances involved. Decisions regarding pharmaceutical therapy should be based on the current standard of medical knowledge. When official recommendations from pharmaceutical companies are missing, treatment decisions for off-label use can be based on guidelines, study and literature databases or recommendations in medical journals. PMID- 23344645 TI - Increased promyelocytic-derived microparticles: a novel potential factor for coagulopathy in acute promyelocytic leukemia. AB - The frequent serious bleeding and thrombotic complications in acute promyelocytic leukemia (APL) are major causes of early mortality, but the complex mechanisms causing the bleeding have not been completely elucidated. Because microparticles (MPs) are known to be elevated in thromboembolic disorders, we hypothesized a role for MPs in the pathogenesis of coagulopathy in APL. MPs were isolated from 30 APL patients and 20 healthy subjects and from cultured NB4/APL cells. The morphology of the MPs was examined, and they were quantified and analyzed for their thrombin-generating potential. We confirmed the existence of promyelocytic derived MPs by morphology using transmission electron microscopy and laser scanning confocal microscopy. Counts of MPs in APL were elevated and were typically from promyelocytic cells (CD33(+) TF(+) MPs). Importantly, the CD33(+) MPs strongly correlated with patient leukocyte count (R = 0.64, p = 0.002) and D dimer (R = 0.51, p = 0.0038). Moreover, the MPs from patients with APL decreased the coagulation times and induced thrombin generation. APL MP-associated thrombin generation was reduced by 54 % when the extrinsic pathway was blocked using an anti-human tissue factor (TF) antibody. However, neither anti-factor XI nor anti tissue factor pathway inhibitor had any significant inhibitory effect. Our results show that the procoagulant state in APL is partially due to the TF dependent procoagulant properties of circulating promyelocytic-derived MPs. TF(+) MPs may be a novel potential risk factor for coagulopathy in APL. PMID- 23344646 TI - Cooperation between general practitioners and occupational health physicians in Germany: how can it be optimised? A qualitative study. AB - PURPOSE: General practitioners (GPs) and occupational health physicians (OPs) have several overlapping work fields, such as important functions in prevention, rehabilitation and reintegration into the workplace. In Germany, however, cooperation between GP and OP is often lacking or suboptimal. In this article, we analysed the suggestions for optimisation of cooperation. METHODS: Three focus groups were interviewed: GP, OP and medical doctors working in both fields. A qualitative content analysis was performed. RESULTS: Categories of suggestions could be assigned to five issues: the "Systemic View" concerning the state and/or employer (e.g. the system of remuneration for GPs), "Inter-collegial Contact" (e.g. fostering "friendly exchanges" between both groups), "Medical Education" (e.g. introducing joint quality circles), "Contents of both Specialities" (e.g. necessity of communicating respective contents and competences), and "Patient centred Care" (e.g. reintegration into workplace after longer periods of illness). The optimisation of cooperation was considered necessary by the OPs, whereas its necessity was sometimes questioned in the GPs' group. CONCLUSION: In many aspects, the present data agree with results of studies from other countries addressing the cooperation between GPs and OPs and/or other specialists. Many suggestions obtained in this study are practical and could be implemented into daily routine. Future quantitative research is required to better assess the relative weight of the suggestions presented here. PMID- 23344647 TI - SAM-like arrangement of thiolated graphene nanoribbons: decoupling the edge state from the metal substrate. AB - Density functional theory calculations have been used to analyze the electronic and magnetic properties of ultrathin zigzag graphene nanoribbons (ZGNRs) with different edge saturations. We have compared a symmetric hydrogen saturation of both edges with an asymmetric saturation in which one of the edges is saturated with sulphur atoms or thiol groups, while the other one is kept hydrogen saturated. The adsorption of such partially thiolated ZGNRs on Au(111) has also been explored. We have considered vertical and tilted adsorption configurations of the ribbons, reminiscent of those found for thiolated organic molecules in self-assembled monolayers (SAM) on gold substrates. We have found that saturation with sulphur atoms or thiol groups removes the corresponding edge state from the Fermi energy and kills the accompanying spin polarization. However, this effect is so local that the electronic and magnetic properties of the mono-hydrogenated edge (H-edge) remain unaffected. Thus, the system develops a spin moment mainly localized at the H-edge. This property is not modified when the partially thiolated ribbon is attached to the gold substrate, and is quite independent of the width of the ribbon. Therefore, the upright adsorption of partially thiolated ZGNRs can be an effective way to decouple the spin-polarized channel provided by the H-edge from an underlying metal substrate. These observations might open a novel route to build spin-filter devices using ZGNRs on gold substrates. PMID- 23344648 TI - Targeted exon skipping to address "leaky" mutations in the dystrophin gene. AB - Protein-truncating mutations in the dystrophin gene lead to the progressive muscle wasting disorder Duchenne muscular dystrophy, whereas in-frame deletions typically manifest as the milder allelic condition, Becker muscular dystrophy. Antisense oligomer-induced exon skipping can modify dystrophin gene expression so that a disease-associated dystrophin pre-mRNA is processed into a Becker muscular dystrophy-like mature transcript. Despite genomic deletions that may encompass hundreds of kilobases of the gene, some dystrophin mutations appear "leaky", and low levels of high molecular weight, and presumably semi-functional, dystrophin are produced. A likely causative mechanism is endogenous exon skipping, and Duchenne individuals with higher baseline levels of dystrophin may respond more efficiently to the administration of splice-switching antisense oligomers. We optimized excision of exons 8 and 9 in normal human myoblasts, and evaluated several oligomers in cells from eight Duchenne muscular dystrophy patients with deletions in a known "leaky" region of the dystrophin gene. Inter-patient variation in response to antisense oligomer induced skipping in vitro appeared minimal. We describe oligomers targeting exon 8, that unequivocally increase dystrophin above baseline in vitro, and propose that patients with leaky mutations are ideally suited for participation in antisense oligomer mediated splice-switching clinical studies.Molecular Therapy - Nucleic Acids (2012) 1, e48; doi:10.1038/mtna.2012.40; published online 16 October 2012. PMID- 23344649 TI - Epigenetic modification of the repair donor regulates targeted gene correction. AB - Optimizing design of vectors is critical to effective gene therapy. In targeted gene correction (TGC), cleavage of chromosomal DNA near a mutation stimulates homology-directed repair of a target gene using a donor provided in trans. We have systematically addressed epigenetic parameters of donor design, using a flow based assay to quantify correction frequencies and expression levels of a green fluorescent protein (GFP) reporter gene in a human cell line. We show that active transcription of the donor increased correction frequency by threefold, establishing that a proximal promoter enhances donor use. Conversely, CpG methylation of the donor diminished correction frequency and reduced expression of the repaired gene. However, bisulfite sequencing of the target revealed no transfer of methylation marks during repair with a methylated donor. Treatment with histone deacetylase (HDAC) inhibitors can partially compensate for epigenetic inactivation, suggesting a role for class I and II HDACs in regulation of donor use. These results establish that epigenetic status of a trans-donor determines both the efficiency and outcome of gene correction, and identify and clarify parameters that should guide donor design for targeted gene therapy.Molecular Therapy - Nucleic Acids (2012) 1, e49; doi:10.1038/mtna.2012.42; published online 23 October 2012. PMID- 23344650 TI - A Hyperactive Transposase Promotes Persistent Gene Transfer of a piggyBac DNA Transposon. AB - Nonviral vector systems are used increasingly in gene targeting and gene transfer applications. The piggyBac transposon represents an alternative integrating vector for in vivo gene transfer. We hypothesized that this system could achieve persistent gene transfer to the liver when administered systemically. We report that a novel hyperactive transposase generated higher transposition efficiency than a codon-optimized transposase in a human liver cell line. Hyperactive transposase-mediated reporter gene expression persisted at levels twice that of codon-optimized transposase in the livers of mice for the 6-month study. Of note, expression persisted in mice following partial hepatectomy, consistent with expression from an integrated transgene. We also used the hyperactive transposase to deliver the human alpha(1)-antitrypsin gene and achieved stable expression in serum. To determine the integration pattern of insertions, we performed large scale mapping in human cells and recovered 60,685 unique hyperactive transposase mediated insertions. We found that a hyperactive piggyBac transposase conferred an altered pattern of integration from that of insect piggyBac transposase, with a decreased frequency of integration near transcription start sites than previously reported. Our results support that the piggyBac transposon combined with the hyperactive transposase is an efficient integrating vector system for in vitro and in vivo applications.Molecular Therapy - Nucleic Acids (2012) 1, e50; doi:10.1038/mtna.2012.12; published online 16 October 2012. PMID- 23344651 TI - Thermal Stability of siRNA Modulates Aptamer- conjugated siRNA Inhibition. AB - Oligonucleotide aptamer-mediated in vivo cell targeting of small interfering RNAs (siRNAs) is emerging as a useful approach to enhance the efficacy and reduce the adverse effects resulting from siRNA-mediated genetic interference. A current main impediment in aptamer-mediated siRNA targeting is that the activity of the siRNA is often compromised when conjugated to an aptamer, often requiring labor intensive and time consuming design and testing of multiple configurations to identify a conjugate in which the siRNA activity has not been significantly reduced. Here, we show that the thermal stability of the siRNA is an important parameter of siRNA activity in its conjugated form, and that siRNAs with lower melting temperature (T(m)) are not or are minimally affected when conjugated to the 3' end of 2'F-pyrimidine-modified aptamers. In addition, the configuration of the aptamer-siRNA conjugate retains activity comparable with the free siRNA duplex when the passenger strand is co-transcribed with the aptamer and 3' overhangs on the passenger strand are removed. The approach described in this paper significantly reduces the time and effort necessary to screening siRNA sequences that retain biological activity upon aptamer conjugation, facilitating the process of identifying candidate aptamer-siRNA conjugates suitable for in vivo testing.Molecular Therapy - Nucleic Acids (2012) 1, e51; doi:10.1038/mtna.2012.41; published online 16 October 2012. PMID- 23344652 TI - Concurrent and prospective analyses of peer, television and social media influences on body dissatisfaction, eating disorder symptoms and life satisfaction in adolescent girls. AB - The degree to which media contributes to body dissatisfaction, life satisfaction and eating disorder symptoms in teenage girls continues to be debated. The current study examines television, social media and peer competition influences on body dissatisfaction, eating disorder symptoms and life satisfaction in a sample of 237 mostly Hispanic girls. 101 of these girls were reassessed in a later 6-month follow-up. Neither television exposure to thin ideal media nor social media predicted negative outcomes either concurrently nor prospectively with the exception of a small concurrent correlation between social media use and life satisfaction. Social media use was found to contribute to later peer competition in prospective analysis, however, suggesting potential indirect but not direct effects on body related outcomes. Peer competition proved to be a moderate strong predictor of negative outcomes both concurrently and prospectively. It is concluded that the negative influences of social comparison are focused on peers rather than television or social media exposure. PMID- 23344653 TI - More than just fun and games: the longitudinal relationships between strategic video games, self-reported problem solving skills, and academic grades. AB - Some researchers have proposed that video games possess good learning principles and may promote problem solving skills. Empirical research regarding this relationship, however, is limited. The goal of the presented study was to examine whether strategic video game play (i.e., role playing and strategy games) predicted self-reported problem solving skills among a sample of 1,492 adolescents (50.8 % female), over the four high school years. The results showed that more strategic video game play predicted higher self-reported problem solving skills over time than less strategic video game play. In addition, the results showed support for an indirect association between strategic video game play and academic grades, in that strategic video game play predicted higher self reported problem solving skills, and, in turn, higher self-reported problem solving skills predicted higher academic grades. The novel findings that strategic video games promote self-reported problem solving skills and indirectly predict academic grades are important considering that millions of adolescents play video games every day. PMID- 23344655 TI - Women's perceptions of their involvement in treatment decision making for early stage breast cancer. AB - PURPOSE: This study aimed to describe the perceptions of women with early stage breast cancer regarding their involvement in treatment decision making (TDM). METHODS: Eligible women with early stage breast cancer were recruited immediately after their first consultation with a specialist. Semistructured personal interviews were held prior to treatment. Interviews were audiotaped, transcribed, and analyzed. RESULTS: Nineteen women with early stage breast cancer considering surgery (n = 6) or adjuvant therapy (n = 13) participated. Women described being involved in various stages of TDM and interacting with informal networks and specialists. Women's descriptions suggest that (1) the concept of involvement in TDM may have a broader meaning for patients than strictly their decisional role and (2) inclusion of significant others in TDM contributes to the patient's sense of involvement. CONCLUSIONS: Conceptualization and measurement of patient involvement in TDM have often been framed within the context of the medical encounter and the patient's perceived or actual role in this process. Our findings raise questions about what involvement means to patients with early stage breast cancer and suggest that the focus on patient involvement in TDM within the medical encounter may be too narrow to capture the meaning of involvement from the patient's perspective. PMID- 23344656 TI - Palliative care needs, symptoms, and treatment intensity along the disease trajectory in medical oncology outpatients: a retrospective chart review. AB - BACKGROUND: Early integration of palliative care into cancer disease management is beneficial for patients with advanced tumors. However, little is known about the association of palliative care interventions with symptom burden and treatment aggressiveness at the end of life (EoL). METHODS: To assess determinants of symptom burden and treatment intensity at the EoL, a retrospective chart review was conducted in university cancer clinic outpatients who died between July 2009 and June 2011. The objective was the correlation of place of death, palliative care utilization, prior EoL discussion, and social background (determinant variables) with symptom burden and treatment intensity (outcome variables). RESULTS: Ninety-six patients (61 men and 35 women) died; the mean age at death was 62.4 years (range 24-83). Mean duration of treatment was 17.9 months (range 1-129). Data on the last 14 days (3) of life were available for 62 (44) patients. Forty-seven patients received aggressive EoL care which was strongly associated with hospital death (p = 0.000, chi2 test). The 15 patients having used palliative care services or dying in a palliative care unit (PCU) had fewer symptoms (p = 0.006, t test) and interventions (p = 0.000, t test) at the EoL. Having addressed EoL issues was correlated with fewer procedures during the last 3 days (p = 0.035, t test). CONCLUSIONS: Most cancer patients receive aggressive EoL care interfering with quality of life. Despite limitations by small sample size and missing data, the results suggest that palliative care utilization is associated with reduced symptom burden and intensity of treatment at the EoL. Timely discussion of EoL issues may reduce the number of unnecessary interventions and facilitate referral to the PCU. PMID- 23344658 TI - Correction. PMID- 23344657 TI - Chromosome painting of Z and W sex chromosomes in Characidium (Characiformes, Crenuchidae). AB - Some species of the genus Characidium have heteromorphic ZZ/ZW sex chromosomes with a totally heterochromatic W chromosome. Methods for chromosome microdissection associated with chromosome painting have become important tools for cytogenetic studies in Neotropical fish. In Characidium cf. fasciatum, the Z chromosome contains a pericentromeric heterochromatin block, whereas the W chromosome is completely heterochromatic. Therefore, a probe was produced from the W chromosome through microdissection and degenerate oligonucleotide-primed polymerase chain reaction amplification. FISH was performed using the W probe on the chromosomes of specimens of this species. This revealed expressive marks in the pericentromeric region of the Z chromosome as well as a completely painted W chromosome. When applying the same probe on chromosome preparations of C. cf. gomesi and Characidium sp., a pattern similar to C. cf. fasciatum was found, while C. cf. zebra, C. cf. lagosantense and Crenuchus spilurus species showed no hybridization signals. Structural changes in the chromosomes of an ancestral sexual system in the group that includes the species C. cf. gomesi, C. cf. fasciatum and Characidium sp., could have contributed to the process of speciation and could represent a causal mechanism of chromosomal diversification in this group. The heterochromatinization process possibly began in homomorphic and homologous chromosomes of an ancestral form, and this process could have given rise to the current patterns found in the species with sex chromosome heteromorphism. PMID- 23344659 TI - Bivariate and multivariate analyses of the influence of blood variables of patients submitted to Roux-en-Y gastric bypass on the stability of erythrocyte membrane against the chaotropic action of ethanol. AB - The stability of the erythrocyte membrane, which is essential for the maintenance of cell functions, occurs in a critical region of fluidity, which depends largely on its composition and the composition and characteristics of the medium. As the composition of the erythrocyte membrane is influenced by several blood variables, the stability of the erythrocyte membrane must have relations with them. The present study aimed to evaluate, by bivariate and multivariate statistical analyses, the correlations and causal relationships between hematologic and biochemical variables and the stability of the erythrocyte membrane against the chaotropic action of ethanol. The validity of this type of analysis depends on the homogeneity of the population and on the variability of the studied parameters, conditions that can be filled by patients who undergo bariatric surgery by the technique of Roux-en-Y gastric bypass since they will suffer feeding restrictions that have great impact on their blood composition. Pathway analysis revealed that an increase in hemoglobin leads to decreased stability of the cell, probably through a process mediated by an increase in mean corpuscular volume. Furthermore, an increase in the mean corpuscular hemoglobin (MCH) leads to an increase in erythrocyte membrane stability, probably because higher values of MCH are associated with smaller quantities of red blood cells and a larger contact area between the cell membrane and ethanol present in the medium. PMID- 23344660 TI - Amniotic lamellar body count and congenital diaphragmatic hernia in humans and in a rat model. AB - BACKGROUND: We examined the extent of fetal lung hypoplasia and lung maturation using the amniotic lamellar body count (LBC) in congenital diaphragmatic hernia (CDH). METHODS: We obtained 30 amniotic fluid samples from human CDH cases during cesarean section. We assessed LBC, magnetic resonance imaging (MRI), and ultrasound findings for predicting the prognosis of CDH. We collected newborn amniotic fluid and lung tissue at embryonic day (E)21 from normal and nitrofen induced CDH rats (administered 100 mg orally at E9). Amniotic LBCs in rats were measured using light microscopy. RESULTS: In human CDH, LBC was significantly higher in the surviving than in the deceased group (P < 0.01). A significant positive correlation was observed between LBC and percentage of fetal lung volume on MRI (P < 0.001; r = 0.716). In rats, LBC was significantly higher in controls than in CDH rats (P < 0.01) and correlated with fetal lung weight. CONCLUSION: We conclude that LBC is useful for predicting lung hypoplasia in human CDH after 35 gestational weeks and in a rat model of nitrofen-induced CDH. PMID- 23344661 TI - Integrins alpha4 and alphaM, collagen1A1, and matrix metalloproteinase 7 are upregulated in acute Kawasaki disease vasculopathy. AB - BACKGROUND: Kawasaki disease (KD) can result in fatal coronary artery (CA) aneurysms, especially if left untreated. Our recent studies of its vascular pathology revealed subacute/chronic vasculitis that begins early in the illness with the proliferation of smooth muscle cell-derived myofibroblasts in a complex extracellular matrix (ECM). We hypothesized that a dysregulation of specific ECM and adhesion molecules occurs in KD CAs. METHODS: Gene expression profiling for ECM and adhesion molecules was performed on six acute KD and eight control CAs using a targeted real-time PCR array approach. RESULTS: Integrins alpha4 and alphaM (ITGA4, ITGAM), collagen type I, alpha1 (COL1A1), and matrix metalloproteinase 7 (MMP7) were significantly upregulated in KD CAs as compared with controls. Immunohistochemistry with anti-ITGAM antibodies revealed expression on inflammatory cells within the CA wall in patients with KD but not in controls. CONCLUSION: Integrins ITGA4 and ITGAM are upregulated in KD vasculopathy, probably promoting inflammatory recruitment that stimulates smooth muscle cell transition to myofibroblasts and their proliferation. MMP7 probably enhances myofibroblast proliferation and luminal lesion expansion, and overexpression of COL1A1 may lead to CA stenosis. Identification of the molecular pathogenesis of KD vasculopathy may lead to the development of circulating biomarkers and to directed therapeutic interventions. PMID- 23344662 TI - Does kidney disease cause hypertension? AB - Hypertension complicates most cases of chronic kidney disease. While the prevalence and severity of hypertension increase as glomerular filtration rate falls, hypertension is often observed in patients with structural kidney disease while renal function is normal, in particular those with polycystic kidney disease or proteinuric glomerular diseases. On the other hand, even severe reductions in renal function may not result in hypertension, especially if there is effective control of extracellular fluid volume. Recent clinical and experimental data indicate that proteinuria may mediate sodium retention and hypertension via plasmin-mediated activation of the epithelial sodium channel. Current evidence supports the notion that chronic kidney disease is a cause of chronic hypertension, even in the absence of detectable changes in glomerular filtration rate. PMID- 23344663 TI - Platinum compounds sensitize ovarian carcinoma cells to ABT-737 by modulation of the Mcl-1/Noxa axis. AB - Ovarian cancer is the leading cause of death from gynecological cancer. The anti apoptotic protein Bcl-x(L) is frequently overexpressed in ovarian carcinoma which correlates with chemotherapy resistance. It has been demonstrated that Bcl-x(L) cooperates with another anti-apoptotic protein, Mcl-1, to protect ovarian cancer cells against apoptosis, and that their concomitant inhibition induces massive cell death. Here, we examined the interest of ABT-737, a potent BH3-mimetic molecule targeting Bcl-x(L), both alone and in combination with Mcl-1 modulators, in ovarian cancer cell lines. As a single agent, ABT-737 was ineffective at promoting cell death in the four cell lines we tested in vitro. However, the specific inhibition of Mcl-1 by siRNA dramatically increased the sensitivity of chemoresistant cells to ABT-737. Platinum compounds also sensitize to ABT-737 by dose-dependently decreasing Mcl-1 expression or by increasing the expression of pro-apoptotic BH3-only proteins Noxa and, to a lower extent, Bim. Furthermore, we demonstrated that Noxa accumulation was involved in apoptosis occurring in response to the combination of ABT-737 and platinum compounds, since cells were protected from apoptosis by its silencing. Moreover, the combination was also highly cytotoxic ex vivo in sliced SKOV3 tumor nodes. However we observed in these slices a strong basal expression of Noxa and apoptotic cell death in response to ABT-737 alone. Therefore, we have revealed that the modulation of the Mcl-1/Noxa axis by platinum compounds results in a strong sensitization of chemoresistant ovarian carcinoma cells to ABT-737, which could constitute a promising therapeutic in these cancers. PMID- 23344665 TI - Planning target volume assessment in lung tumors during 3D conformal radiotherapy by means of an aSi electronic portal imaging device in cine mode. AB - PURPOSE: The major uncertainties in treating lung cancer are the repositioning errors and respiratory lung tumor motion. Typically, margins are added to the clinical target volume (CTV) to obtain a planning target volume (PTV) allowing the accommodation of such uncertainties. We want to test a new technique to assess the adequacy of the chosen PTV using an aSi electronic portal imaging device (EPID). METHODS: Four patients affected by lung cancer and treated by radical 3D conformal radiotherapy (3DRT) were studied. During treatment the EPID was used in cine mode acquisition: acquired images were used to the aim. RESULTS AND CONCLUSIONS: Treatment monitoring with an EPID in cine mode is shown to be a clinically feasible and useful tool. PMID- 23344666 TI - Recent advances in the diagnosis and treatment of systemic sclerosis. AB - Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by widespread vascular injury and progressive fibrosis of the skin and internal organs. The involvement of internal organs results in significant morbidity and mortality of SSc patients with cardiopulmonary involvement being the leading cause of SSc-related deaths. The management of SSc patients remains a challenge because therapeutic options are rather limited and no therapy has definitively shown a disease-modifying effect. A significant progress that has recently been made in the understanding of the SSc pathogenesis contributed to the introduction of new therapeutic options. Preliminary clinical studies have yielded promising results for mycophenolate mofetil, anti-CD20 antibodies, and stem-cell in the treatment of SSc. Multicenter cohort studies help understand the natural history of SSc, which leads to improvement in the care of SSc patients. The major objective of those studies is to establish the screening strategies for early diagnosis and, subsequently, to introduce appropriate management concerning specific organ involvement in SSc as well as to formulate specific treatment recommendations. PMID- 23344664 TI - Nanoemulsions and nanoparticles for non-melanoma skin cancer: effects of lipid materials. AB - Basal cell carcinomas and squamous cell carcinomas are non-melanoma skin cancers reported to be among the most common malignancies, being responsible for high human morbidity. Conventional chemotherapy applied to these conditions shows non specific targeting, thus severe adverse side effects are also commonly reported. New therapeutic strategies based on nanoparticulates technology have emerged as alternatives for site specific chemotherapy. Among the different types of nanoparticulates, lipid nanoemulsions and nanoparticles have several advantages for topical delivery of poorly soluble chemotherapeutics. These particles show sustained drug release and protection of loaded drugs from chemical degradation. This technology is promising to enhance the intracellular concentration of drugs and consequently reduce the cytotoxicity of skin chemotherapy. PMID- 23344667 TI - Mesh fixation with fibrin sealant during endoscopic totally extraperitoneal inguinal hernia approach: a review of 640 repairs. AB - PURPOSE: Endoscopic repair of inguinal hernia can decrease the incidence of chronic groin pain. Staple mesh fixation is the surgical technique preferentially used but may also cause residual pain. Although a substantial number of specialists advocate no mesh fixations, concerns are that this could lead to an increase in recurrence rates. This study aimed to assess the safety and the effectiveness of fibrin sealant, as an alternative technique to staple mesh fixation after totally extraperitoneal (TEP) inguinal hernia repair. METHODS: A total of 472 patients underwent elective TEP inguinal hernia repair between February 2005 and July 2011. Mesh fixation was achieved using fibrin sealant. Patients were reviewed postoperatively at Week 2, Week 6, and Month 6. Patient satisfaction was assessed in a subgroup of 116 patients using a comprehensive scoring system designed for hernia repairs, and pain was assessed using a standard Visual Analog pain Scale. RESULTS: No conversion to open surgery was observed. There were two cases of major morbidities and no mortality. Three months after surgery, only three patients (0.6 %) experienced chronic groin or testicular discomfort. At Week 6, 98.9 % of the patients were either satisfied or very satisfied with their outcome, and 96.8 % denied any residual pain. Finally, only six hernia recurrences (0.9 %) were reported, of which five occurred during the first months of the study. CONCLUSIONS: Fibrin sealant is safe and reliable for mesh fixation of inguinal hernia during TEP repair with a very high satisfaction index and limited risk of developing chronic pain. PMID- 23344668 TI - Comparative study of shrinkage, inflammatory response and fibroplasia in heavyweight and lightweight meshes. AB - PURPOSE: In this manuscript, the authors describe an animal study comparing shrinkage, inflammatory response and fibroplasia in heavyweight (HW-PP) and lightweight polypropylene (LW-PP) meshes. METHODS: Both meshes were fixed on abdominal fascia of 25 Wistar rats (epifascial onlay placement). They were killed at 7, 28 and 90 days to measure the prostheses. Histological analysis was performed with hematoxylin-eosin for cellular counting and immunohistochemistry to measure collagen types I and III. RESULTS: The authors found that the LW-PP mesh presented greater median shrinkage than HW-PP mesh at 7 (P = .036), 28 (P = .674) and 90 days (P = .038) postoperatively. There were more neutrophils on LW PP mesh (P = .008) at 7 days, gradually diminishing in both prostheses. Lymphocytes were similar between the implants at 7 days, diminishing about 50 % on LW-PP mesh (P < .001) at 90 days. Macrophages and giant cells diminished on LW PP and increased on HW-PP meshes (P < .001). Collagen I/III ratio presented a progressive, almost fivefold rise at 90 days, on both mesh types (P < .001). The collagen I/III ratio was similar between LW-PP and HW-PP meshes at the three times studied. CONCLUSIONS: It is concluded that LW-PP showed more shrinkage than HW-PP mesh at 7 and 90 days, despite the fact that HW-PP presented more lately foreign body reaction. The collagen I/III ratio was similar between the prostheses and increased during the postimplant period. PMID- 23344669 TI - [Epidemiology of anaphylaxis]. AB - Anaphylaxis is the most severe manifestation of a mast cell dependent hypersensitivity reaction. Recent data on epidemiology indicate that food and drug induced anaphylaxis has increased within the last years. The epidemiological data on anaphylaxis vary throughout the world as the overall incidence and also relevant elicitors depend on different endogenous, but also exogenous factors (e.g. ICD-code, life style, comorbidities). Data from the anaphylaxis registry has shown that venom, drugs and foods are the most frequent elicitors for anaphylaxis within German-speaking countries, while the ranking of the elicitors is age-dependent. Risk factors for anaphylaxis are comorbidities like asthma or mastocytosis or other circumstances, which can increase either the relative risk or the severity. Further risk factors are age, gender and the concomitant intake of drugs like ACE inhibitors or acetylsalicylic acid but also exercise. Data on the clinical epidemiology of anaphylaxis are essential to follow up the most frequent elicitors and risk factors over time and accumulate data about diagnostic and therapeutic procedures in patients suffering from a potential fatal manifestation of an IgE-dependent disease. The anaphylaxis registry within the German-speaking area achieved to provide data of the most frequent elicitors, risk factors and the medical treatment from affected individuals to optimize the management of patients with anaphylaxis. PMID- 23344670 TI - Neuromuscular fatigue induced by whole-body vibration exercise. AB - The aim of this study was to examine the magnitude and the origin of neuromuscular fatigue induced by half-squat static whole-body vibration (WBV) exercise, and to compare it to a non-WBV condition. Nine healthy volunteers completed two fatiguing protocols (WBV and non-WBV, randomly presented) consisting of five 1-min bouts of static half-squat exercise with a load corresponding to 50 % of their individual body mass. Neuromuscular fatigue of knee and ankle muscles was investigated before and immediately after each fatiguing protocol. The main outcomes were maximal voluntary contraction (MVC) torque, voluntary activation, and doublet peak torque. Knee extensor MVC torque decreased significantly (P < 0.01) and to the same extent after WBV (-23 %) and non-WBV (-25 %), while knee flexor, plantar flexor, and dorsiflexor MVC torque was not affected by the treatments. Voluntary activation of knee extensor and plantar flexor muscles was unaffected by the two fatiguing protocols. Doublet peak torque decreased significantly and to a similar extent following WBV and non WBV exercise, for both knee extensors (-25 %; P < 0.01) and plantar flexors (-7 %; P < 0.05). WBV exercise with additional load did not accentuate fatigue and did not change its causative factors compared to non-WBV half-squat resistive exercise in recreationally active subjects. PMID- 23344671 TI - SnO(2)-ZnSn(OH)(6): a novel binary affinity probe for global phosphopeptide detection. AB - ZnSn(OH)(6) and binary-component SnO(2)-ZnSn(OH)(6) were introduced as affinity probes for phosphopeptide enrichment for the first time. Two strategies, either ZnSn(OH)(6) and SnO(2) serial enrichment or binary-component SnO(2)-ZnSn(OH)(6) enrichment in a single run, were proposed to enhance multi-phosphopeptide enrichment and to significantly improve global phosphopeptide detection. PMID- 23344672 TI - Phosphine-containing Lewis base catalyzed cyclization of benzofuranone type electron-deficient alkenes with allenoates: a facile synthesis of spirocyclic benzofuranones. AB - A regioselective [3 + 2] cycloaddition of benzofuranone type active olefins with allenoates catalyzed by trivalent phosphines has been developed, which provided an easy access to enriched functionalized spirocyclic benzofuranones. The reactions accommodated a number of benzofuranone type electron-deficient olefins and allenoates to give the desired 3-spirocyclopentane benzofuran-2-ones or 2 spirocyclopentane benzofuran-3-ones with moderate to excellent yields (up to 99%) and moderate to good regioselectivities (up to 11:1). PMID- 23344673 TI - What is a psychiatric disability? AB - This article aims to clarify the notion of a psychiatric disability. The article uses conceptual analysis, examining and applying established definitions of (general) disability to psychiatric disabilities. This analysis reveals that disability as inability to perform according to expectations or norms is related to impairment as deviation from the (statistical) norm, while disability as inability to achieve (personal) goals is related to impairment as deviation from the (personal) ideal. These two views of impairment and disability are distinct from the self-organization view of impairment as disrupted self-creation or disrupted self-repair and of disability as disrupted whole person self compensation (in relation to an impairment). All these three views of disability pertain to psychiatric disability. Although there is nothing necessarily psychiatric about psychiatric disability other than the psychiatric impairment related to it, the life course and life circumstances typical of many people with (severe) psychiatric disorders may lead to disability and may thus confer some (psychiatric) specificity on this disability. This analysis may facilitate research on specific psychiatric disabilities and a broader scope for psychiatric rehabilitation. PMID- 23344674 TI - From needs to health care needs. AB - One generally considered plausible way to allocate resources in health care is according to people's needs. In this paper I focus on a somewhat overlooked issue, that is the conceptual structure of health care needs. It is argued that what conceptual understanding of needs one has is decisive in the assessment of what qualifies as a health care need and what does not. The aim for this paper is a clarification of the concept of health care need with a starting point in the general philosophical discussion about needs. I outline three approaches to the concept of need and argue that they all share the same conceptual underpinnings. The concept of need is then analyzed in terms of a subject x needing some object y in order to achieve some goal z. I then discuss the relevant features of the object y and the goal z which make a given need qualify as a health care need and not just a need for anything. PMID- 23344675 TI - Neglected intussusception presenting as transanal prolapse of small bowel. PMID- 23344676 TI - Abstracts of Acute Leukemias XIV : Biology and Treatment Strategies. February 24- 27, 2013. Munich, Germany. PMID- 23344677 TI - Conditional loss of kidney microRNAs results in congenital anomalies of the kidney and urinary tract (CAKUT). AB - MicroRNAs have emerged as essential regulators of gene expression and may play important roles in a variety of human disorders. To understand the role of microRNA-mediated gene regulation in the kidney, we deleted the microRNA processing enzyme Dicer in developing renal tubules and parts of the ureteric bud in mice. Genetic deletion of Dicer resulted in renal failure and death of the animals at 4-6 weeks of age. Interestingly, the kidneys of microRNA-deficient animals were small due to a reduced number of nephrons and showed massive hydronephrosis due to ureteropelvic junction obstruction. This phenotype is reminiscent of congenital anomalies of the kidney and urinary tract (CAKUT), an important group of human disorders characterized by a combination of renal hypoplasia with congenital abnormalities of the urinary tract. We used metanephric kidney cultures to examine the developmental defects underlying these pathologies. Dicer knockout kidneys showed a significant reduction of tubular branching explaining renal hypoplasia. Moreover, the ureters of these kidneys showed an altered morphology and impaired motility. These functional changes went along with altered expression of smooth muscle actin implying a defect in the differentiation of ureteric smooth muscle cells. In addition, we show the polycystic kidney disease gene Pkd1 to be a target of miR-20 implying that this interaction may contribute to the molecular basis for the cystogenesis in our model. In conclusion, these data demonstrate an essential role for microRNA dependent gene regulation in mammalian kidney development and suggest that deregulation of microRNAs may underlie CAKUT, the most important group of renal disorders in humans. PMID- 23344678 TI - Genetic associations with neonatal thyroid-stimulating hormone levels. AB - BACKGROUND: Elevations or deficits in thyroid hormone levels are responsible for a wide range of neonatal and adult phenotypes. Several genome-wide, candidate gene, and meta-analysis studies have examined thyroid hormones in adults; however, to our knowledge, no genetic association studies have been performed with neonatal thyroid levels. METHODS: A population of Iowa neonates, term (n = 827) and preterm (n = 815), were genotyped for 45 single-nucleotide polymorphisms (SNPs). Thyroid-stimulating hormone (TSH) values were obtained from the Iowa Neonatal Metabolic Screening Program. ANOVA was performed to identify genetic associations with TSH concentrations. RESULTS: The strongest association was rs4704397 in the PDE8B gene (P = 1.3 * 10(-4)), followed by rs965513 (P = 6.4 * 10(-4)) on chromosome 9 upstream of the FOXE1 gene. Both of these SNPs met statistical significance after correction for multiple testing. Six other SNPs were marginally significant (P < 0.05). CONCLUSION: We demonstrated for the first time two genetic associations with neonatal TSH levels that replicate findings with adult TSH levels. These SNPs should be considered early predictors of risk for adult diseases and conditions associated with thyroid hormone levels. Furthermore, this study provides a better understanding of the thyroid profile and potential risk for thyroid disorders in newborns. PMID- 23344679 TI - A comparison of combination dopamine and epinephrine treatment with high-dose dopamine alone in asphyxiated newborn piglets after resuscitation. AB - BACKGROUND: When asphyxiated neonates require additional cardiovascular support to moderate doses of dopamine infusion, controversy exists on the differential hemodynamic effects of two approaches (adding a second inotrope vs. increasing dopamine dosage). We hypothesized that high-dose dopamine (HD) would be detrimental to systemic and regional perfusion as compared with dopamine and epinephrine (D + E) combination therapy using a swine model of neonatal hypoxia reoxygenation (H-R). METHODS: Twenty-seven piglets (1-4 d, 1.5-2.5 kg) were used for continuous monitoring of systemic arterial pressure (mean arterial pressure, MAP) and pulmonary arterial pressure (PAP), cardiac output (cardiac index, CI), and carotid (carotid artery flow index, CAFI), superior mesenteric (superior mesenteric artery flow index), and renal arterial flows. H-R piglets underwent 2 h of hypoxia followed by 2 h of reoxygenation before drug infusion (2 h). RESULTS: The hemodynamics of H-R piglets deteriorated gradually after reoxygenation. HD and D + E infusions improved CI similarly (both groups vs. control; P < 0.05). Both regimens increased MAP (P < 0.05) but not PAP, with decreased PAP/MAP ratio in D + E piglets. Both regimens improved CAFI and superior mesenteric artery flow index, with decreased mesenteric vascular resistance in HD-treated piglets. No significant effect on renal perfusion was observed. CONCLUSION: In H-R newborn piglets treated with a moderate dose of dopamine, adding epinephrine or further increasing dopamine improved systemic hemodynamics similarly; these treatments have differential effects on the pulmonary and mesenteric circulations. PMID- 23344680 TI - Prevalence of undiagnosed abnormal glucose tolerance in adult patients cared for by general practitioners in Hungary. Results of a risk-stratified screening based on FINDRISC questionnaire. AB - BACKGROUND: The prevalence of type 2 diabetes mellitus is rapidly increasing, worldwide and also in Hungary. Timely diagnosis and early treatment could be aided by targeted screening. Recognizing this, the Hungarian Diabetes Association initiated a risk-stratified screening with the involvement of primary care physicians. MATERIAL/METHODS: In the first phase of screening, the FINDRISC questionnaire was completed, followed by an oral glucose tolerance test (OGTT) for those with a score of >=12. Between September 1, 2010 and March 31, 2011, 70,432 non-diabetic adults, who visited their general practitioners for any reason, were involved in the screening. Of these, 68,476 questionnaires proved to be suitable for processing. RESULTS: From the questionnaires, 28,077 (41.0%) had a score of >=12. A valid OGTT was performed in 22,846 cases; of this group 3,217 subjects (14.1%) had elevated fasting glucose levels, 5,663 (24.8%) had impaired glucose tolerance, and 1,750 (7.6%) had manifest, previously undiagnosed, diabetes mellitus. Overall, from the valid OGTT group, 46.5% subjects had some degree of glucose intolerance. CONCLUSIONS: Based on the FINDRISC questionnaire, the risk-stratified screening for diabetes mellitus proved to be simple and cost effective method for the early detection of carbohydrate metabolism disorders. Using this method, the prevalence rate of previously undiagnosed abnormal glucose tolerance was high in adult patients cared for by general practitioners in Hungary. PMID- 23344681 TI - Intraoperative spinal cord monitoring during the surgical correction of scoliosis due to cerebral palsy and other neuromuscular disorders. AB - PURPOSE: Patients with neuromuscular scoliosis are at increased risk of neurological deficit post-operatively, but are a difficult population on whom to perform neurophysiological monitoring. We look here at a 7-year sample of our practice in the monitoring of neuromuscular patients. METHODS: A retrospective chart review was performed for 109 patients who underwent correction of neuromuscular scoliosis within our institution between 2005 and 2011. RESULTS: Of 109 patients who were identified, intraoperative monitoring was attempted in 66 cases. In eight cases (13 %), no reliable monitoring could be achieved and was therefore abandoned. On nine occasions, there was a significant drop in at least one modality intraoperatively. None of these nine suffered any clinically observable neurological deficit post-operatively. Of the 109 patients, 2 had clinically detectable deficits post-operatively, both of whom had undergone normal intraoperative monitoring. CONCLUSIONS: The two patients with observable deficit had their instrumentation left in situ after discussion with them and/or parents. Spinal cord monitoring in this population is possible but potentially unreliable. Surgeons will need to carefully consider the use of monitoring in their management of this challenging population. PMID- 23344682 TI - Variations in the origin of the vertebral artery and its level of entry into the transverse foramen diagnosed by CT angiography. AB - INTRODUCTION: The origin of the vertebral artery (VA) varies, though most VAs enter the transverse foramen (TF) of the sixth cervical vertebra. On computed tomography (CT) angiographic images, we evaluated the prevalence of variations of both VA origin and its level of entry into the TF. METHODS: We retrospectively reviewed CT angiographic images of 2,287 patients obtained using either of two 64 slice multidetector CT scanners. All patients were Japanese and underwent scanning from the aortic arch to the intracranial region; most had or were suspected of having cerebrovascular diseases. RESULTS: The left VA (LVA) arose from the aorta between the left common carotid artery and left subclavian artery in 94 patients (4.1 %) and in other variations in 44 patients (1.9 %). The right VA (RVA) arose from the extreme proximal segment of the right subclavian artery in 72 patients (3.1 %) and in other variations in 14 patients (0.6 %). The LVA entered the sixth TF in 2,127 patients (93.0 %), and the RVA entered the sixth TF in 2,146 patients (93.8 %). Anomalous origin and anomalous entry level into the TF correlated strongly. CONCLUSIONS: The total prevalence of variation in the origin of the LVA was 6.0 % and of the RVA, 3.8 %. The total prevalence of variation in entry level into the TF was 7.0 % for the LVA and 6.2 % for the RVA. Recognition and reporting of these variations is important in interpreting CT angiography to prevent complications during surgery of the aortic arch or lower neck. PMID- 23344683 TI - Conservative nephron-sparing treatment of upper-tract tumors. AB - While radical nephroureterectomy represents the gold standard for managing upper tract urothelial carcinoma, nephron-sparing approaches have increasingly been utilized in the elective setting. Such considerations are accentuated by contemporary studies highlighting sequelae related to chronic kidney disease following nephrectomy. Kidney sparing treatments including segmental ureteral resection and endoscopic ablation may therefore be appropriate in select patients with small, solitary, low-grade upper-tract tumors. Bladder and ipsilateral upper tract recurrences are frequent after nephron-sparing treatments for UTUC, thereby underscoring the need to maintain strict radiographic and endoscopic surveillance protocols in patients amenable to this rigorous compliance program. PMID- 23344684 TI - The role of systemic chemotherapy in management of upper tract urothelial cancer. AB - Upper tract urothelial cancer (UTUC) accounts for roughly 5 % of all urothelial cancers. At presentation, 30 % of patients demonstrate invasive and/or locally advanced disease, 30-40 % have regional lymph node involvement, and 20 % harbor metastatic disease. Systemic recurrence and progression rates after surgery for patients with advanced disease range between 45-60 %. Five-year cancer specific survival rates for pT2 and pT3 tumors are 73 % and 40 %, respectively. Median survival for patients with pT4 disease is approximately 6 months. Nonetheless, there is a lack of improvement in the rates of systemic recurrence and progression in patients with advanced UTUC. Extrapolating evidence obtained from experience with multi-modal therapy of patients with urothelial bladder cancer, additional improvements in oncological outcomes for patients with UTUC can be achieved through integration of effective systemic chemotherapy with local tumor control. We provide an overview of the rationale and utilization strategies of peri-operative systemic chemotherapy in patients with UTUC. PMID- 23344685 TI - Evaluation of renal masses with contrast-enhanced ultrasound. AB - The clinical need for characterising small renal masses (SRMs) is increasing due to their rising incidental detection. This increase is especially seen in younger and older generations and concerns mainly SRMs. Diagnostics is mainly made by contrast-enhanced CT or MRI. However, these imaging methods fail to accurately distinguishing benign from malignant SRMs. Other disadvantages of CT or MRI are high costs, the use of ionizing radiation, nephrotoxicity induced by iodine contrast agents or nephrogenic systemic fibrosis (NSF) induced by gadolinium contrast agents. Contrast-enhanced ultrasound (CEUS) is based on ultrasonography and microbubbles to real-time visualize the renal blood flow without the use of nephrotoxic agents or ionizing radiation. This comprehensive review evaluates the capabilities of CEUS in the diagnostics of benign (angiomyolipomas, cysts, oncocytomas, pseudotumors) and malignant masses (renal cell carcinomas), and focuses on possible future treatment. PMID- 23344686 TI - Low occurrence of digital ulcers in scleroderma patients treated with bosentan for pulmonary arterial hypertension: a retrospective case-control study. AB - Digital ulcers (DU) are one of the most common and debilitating manifestations of vasculopathy in systemic sclerosis (SSc). Their prevention is important in order to improve patients' outcome and as a result of the economic impact they have on society. Randomised controlled studies have demonstrated that bosentan, an endothelin receptor antagonist, reduces the appearance of new DU. The aim of this retrospective study was to evaluate the occurrence of DU in a group of patients receiving long-term bosentan treatment for pulmonary arterial hypertension associated with SSc (PAH-SSc). Patients with PAH-SSc and treated with bosentan for at least 6 months (n = 30) were evaluated. Thirty patients with SSc not treated with bosentan, but matched for sex, age, disease duration and cutaneous form of SSc, were considered as a control group. The occurrence of DU, defined as loss of tissue of varying degrees in the epidermis, dermis and subcutaneous tissue, was determined in the bosentan-treated and untreated groups. Mean duration of bosentan treatment was 3.6 years. DU were detected in six patients in the bosentan-treated group (20.0 %) and 16 patients (53.3 %) in the untreated group (p = 0.0015). There were no significant differences in demographic or clinical characteristics between patients with or without DU at study end. The occurrence of DU in patients with PAH-SSc receiving long-term bosentan treatment was significantly lower than in untreated patients. The results from this long term observational study provide valuable information on management of patients with PAH-SSc. PMID- 23344687 TI - Antibodies to citrullinated peptides in tuberculosis. AB - Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetric polyarthritis, rheumatoid factor (RF) positivity, and bone erosions. Recently, research has been conducted on anti-citrullinated peptide antibodies (ACPAs) to which there are greater sensitivity and specificity than RF. However, these antibodies have also been described in infectious diseases, particularly tuberculosis (TB), placing the high specificity of the test in doubt. The aim of this research was to study the prevalence of ACPAs in TB, RA, and healthy controls. Patients with bacteriologically confirmed pulmonary tuberculosis, RA (ACR criteria), in addition to healthy controls were included. ACPAs were researched by: anti-cyclic citrullinated peptide (CCP), anti-modified citrullinated vimentin (MCV), and RF by ELISA. The study was conducted in 50 TB patients, 50 with RA, and 20 controls. Anti-CCP antibodies were found in 39 (78 %) of the RA patients (median titer, 128 U), whereas anti-MCV antibodies were found in 25 (50 %). Of the patients with TB, two (4 %) had positivity for anti CCP and anti-MCV and no patient in the control group tested positive for these antibodies. Sensitivity of anti-CCP for RA was 78 % (confidence interval (CI), 63 to 88 %) and specificity was 97 % (CI, 89 to 99 %) while the sensitivity of anti MCV was 50 % (CI, 35-64 %) and specificity was 97 % (CI, 89 to 99 %). RF was positive in 40 samples (80 %) of RA, in 30 (60 %) of TB, and in 1 (5 %) of the controls. Our findings showed high sensitivity of anti-CCP and high specificity of both anti-CCP and anti-MCV antibodies for RA, even in a population with high incidence of tuberculosis. The higher frequency of positivity of ACPA in TB observed in previous studies may be attributed to methodological factors. PMID- 23344688 TI - Molecular cloning and expression analysis of the starch-branching enzyme III gene from common wheat (Triticum aestivum ). AB - The starch-branching enzyme (SBE) catalyzes the formation of branch points by cleaving the alpha-1,4 linkage in polyglucans and reattaching the chain via an alpha-1,6 linkage. Three types of SBE isoforms (SBEI, SBEII, and SBEIII) exist in higher plants, with the number of SBE isoforms being species-specific. This study isolated the SBEIII cDNA sequence (3,780 bp), designated TaSBEIII (accession no. JQ346193), from common wheat (Triticum aestivum L.) using the RACE method, revealing that the SBEIII gene exists in common wheat. The open reading frame of TaSBEIII was 2,748 bp. The predicted protein of 916 amino acids contained the specific characteristics of the SBEIII protein: four highly conserved regions and a central (alpha/beta)(8) barrel domain. The SBE activity of the protein expressed in Escherichia coli (BL21) was also measured and verified. During the wheat grain filling period, TaSBEIII was constitutively expressed. The role of the TaSBEIII gene in starch synthesis is discussed. PMID- 23344691 TI - A sterically demanding organo-superbase avoids decomposition of a naked trifluoromethyl carbanion directly generated from fluoroform. AB - A simple strategy avoiding the decomposition of a naked trifluoromethyl anion to difluorocarbene by a sterically very demanding organo-superbase without the help of a trifluoromethyl anion reservoir such as DMF is reported. The direct non metallic trifluoromethylation of carbonyl compounds using fluoroform in the presence of t-Bu-P4 base afforded trifluoromethyl alcohols in high yields. PMID- 23344690 TI - Modulation of crucial adenosinetriphosphatase activities due to U-74389G administration in a porcine model of intracerebral hemorrhage. AB - Spontaneous intracerebral hemorrhage (ICH) represents a partially-understood cerebrovascular disease of high incidence, morbidity and mortality. We, herein, report the findings of our study concerning the role of two important adenosinetriphosphatases (ATPases) in a porcine model of spontaneous ICH that we have recently developed (by following recent references as well as previously established models and techniques), with a focus on the first 4 and 24 h following the lesion's induction, in combination with a study of the effectiveness of the lazaroid antioxidant U-74389G administration. Our study demonstrates that the examined ICH model does not cause a decrease in Na(+),K(+) ATPase activity (the levels of which are responsible for a very large part of neuronal energy expenditure) in the perihematomal basal ganglia territory, nor a change in the activity of Mg(2+)-ATPase. This is the first report focusing on these crucial ATPases in the experimental setting of ICH and differs from the majority of the findings concerning the behavior of these (crucial for central nervous system cell survival) enzymes under stroke-related ischemic conditions. The administration of U-74389G (an established antioxidant) in this ICH model revealed an injury specific type of behavior, that could be considered as neuroprotective provided that one considers that Na(+),K(+)- and Mg(2+)-ATPase inhibition might in this case diminish the local ATP consumption. PMID- 23344692 TI - Pharmacokinetic model of myocardial (99m)Tc-sestamibi washout. AB - OBJECTIVES: Technetium-99m sestamibi ((99m)Tc-MIBI) scintigraphy has been reported to be a functional imaging tool for in vivo detection of mitochondrial dysfunction in myocardium and multidrug resistance-associated protein expression in tumors. The purpose of this study was to propose a clinically applicable pharmacokinetic model with metabolic equilibrium of (99m)Tc-MIBI and to evaluate the accuracy of the model. METHODS: For this study, eight healthy men received (99m)Tc-MIBI scintigraphy. The planar images were obtained at 0.25, 0.5, 1, 2, 3, 4, 5, and 6 h after (99m)Tc-MIBI injection. The measured time series (99m)Tc-MIBI counts were fitted to our model by nonlinear regression analysis. The predictive performance of the model was determined by comparing the residuals between measured and predicted values. RESULTS: We obtained a good regression by fitting data from 0.25 to 6 h after (99m)Tc-MIBI injection, with excellent correlation between measured and predicted (99m)Tc-MIBI counts (R(2) = 0.9792) and a slope near unity. The 95% confidence interval of the mean prediction error included 0, which means that the prediction was not significantly biased. The precision of the prediction was also excellent. CONCLUSIONS: Our model shows good predictive capacity, with favorable bias and accuracy. By comparing the predictive values of this model with measured values, mitochondrial (99m)Tc-MIBI washout can be quantified. (99m)Tc-MIBI washout rates are reported to be a promising method for evaluating cardiac function in patients with cardiac diseases and P-glycoprotein expression in tumor cells. Therefore, this quantification could be useful for mitochondrial functional imaging, especially in patients with cardiac diseases or tumors. PMID- 23344693 TI - A donor-acceptor type organic dye connected with a quinoidal thiophene for dye sensitized solar cells. AB - A donor-acceptor type organic dye connected with a quinoidal thiophene as a pi conjugated chain, cyano-[5'-(4''-(N,N-dimethylamino)benzylidene)-5H-thiophen-2' ylidene]acetic acid, was synthesized and applied to dye-sensitized solar cells (DSSCs). The absorption band of this quinoidal thiophene dye appeared at longer wavelengths than those of dyes with similar pi-conjugation length, indicating the effective pi-conjugation through the quinoidal structure. Although the excited state of the quinoidal thiophene dye is deactivated within several picoseconds even in solution, the DSSCs using the quinoidal thiophene dye showed incident photon to current conversion efficiency (IPCE) values of more than 90%, demonstrating the fast and efficient electron injection from the excited dye to TiO(2). By optimizing the fabrication conditions, the DSSC using this dye afforded a photoelectric conversion efficiency of 5.2%, without enlarging the molecular size. PMID- 23344694 TI - [Arthroscopically controlled screw placement for osteosynthesis of acetabular fractures]. AB - In the surgical treatment of acetabular fractures via a ventral approach the hip joint is not visible. Hip arthroscopy can be an alternative tool instead of 3-D fluoroscope-based navigation to exclude intra-articular perforation of the screws. PMID- 23344695 TI - [Multidirectional locking volar plate in distal radius fractures. Secondary loss of reduction--correct implantation is essential]. AB - In recent years a trend has evolved from unidirectional to multidirectional locking plates. Different technical solutions have been developed and the quality of the angle stability of all methods has been described as sufficient. Published trials describing the necessary shearing forces are rarely published. We report two cases with loss of reduction after the use of a variable angle locking implant used in distal radius fractures. PMID- 23344696 TI - Surveillance for foodborne disease outbreaks--United States, 2009-2010. AB - Known pathogens cause an estimated 9.4 million foodborne illnesses annually in the United States. CDC collects data on foodborne disease outbreaks submitted by all states, the District of Columbia, and Puerto Rico through CDC's Foodborne Disease Outbreak Surveillance System. Data reported for each outbreak include the number of illnesses, hospitalizations, and deaths; the etiologic agent; the implicated food vehicle; and other factors involved in food preparation and consumption. During 2009-2010, a total of 1,527 foodborne disease outbreaks (675 in 2009 and 852 in 2010) were reported, resulting in 29,444 cases of illness, 1,184 hospitalizations, and 23 deaths. Among the 790 outbreaks with a single laboratory-confirmed etiologic agent, norovirus was the most commonly reported, accounting for 42% of outbreaks. Salmonella was second, accounting for 30% of outbreaks. Among the 299 outbreaks attributed to a food composed of ingredients from one of 17 predefined, mutually exclusive food commodities, those most often implicated were beef (13%), dairy (12%), fish (12%), and poultry (11%). The commodities in the 299 outbreaks associated with the most illnesses were eggs (27% of illnesses), beef (11%), and poultry (10%). Public health, regulatory, and food industry professionals can use this information when creating targeted control strategies along the farm-to-table continuum for specific agents, specific foods, and specific pairs of agents and foods. This information also supports efforts to promote safe food-handling practices among food workers and the public. PMID- 23344697 TI - Progress in immunization information systems--United States, 2011. AB - Immunization information systems (IIS) are confidential, computerized, population based systems that collect and consolidate vaccination data from vaccination providers and provide important tools for designing and sustaining effective immunization strategies. A Healthy People 2020 objective (IID-18) is to increase to 95% the proportion of children aged <6 years whose immunization records are in fully operational, population-based IIS. The National Vaccine Advisory Committee (NVAC) has published goals for IIS, including required and optional core data elements for which IIS should collect information. Two of the required core data elements are vaccine manufacturer and vaccine lot number. To monitor progress toward achieving these and other program goals, CDC annually surveys 56 immunization program grantees using the IIS Annual Report (IISAR). Results from the 2011 IISAR (completed by 54 grantees) indicate that 84% (19.2 million) of U.S. children aged <6 years participated in IIS, as defined by having at least two recorded vaccinations, an increase from 82% (18.8 million) in 2010. Grantees reported that an average of 63% of vaccination records for these children contained data in the field for vaccine manufacturer and 60% contained data in the field for lot number. A new project under way to capture vaccine product information, expiration date, and lot number on two-dimensional (2D) barcodes on vaccine vials might increase completeness, accuracy, and availability of these data elements in patient medical records and IIS, which in turn might enhance vaccine safety and support vaccine inventory management. PMID- 23344698 TI - Infant meningococcal vaccination: Advisory Committee on Immunization Practices (ACIP) recommendations and rationale. AB - At its October 2012 meeting, the Advisory Committee on Immunization Practices (ACIP) voted to recommend vaccination against meningococcal serogroups C and Y for children aged 6 weeks through 18 months at increased risk for meningococcal disease. Meningococcal groups C and Y and Haemophilus b tetanus toxoid conjugate vaccine (Hib-MenCY-TT [MenHibrix, GlaxoSmithKline Biologicals]) is licensed for active immunization for prevention of invasive disease caused by Haemophilus influenzae type b (Hib) and meningococcal serogroups C and Y. Hib-MenCY-TT is not indicated for prevention of disease caused by meningococcal serogroup B, the most common serogroup causing disease in infants, or serogroups W135 or A, which are represented in quadrivalent meningococcal vaccines. Before licensure of Hib-MenCY TT, no meningococcal conjugate vaccine was licensed for infants aged 2 through 8 months. MenACWY-D (Menactra, Sanofi Pasteur) is licensed as a 2-dose series for infants and toddlers aged 9 through 23 months, and MenACWY-D and MenACWY-CRM (Menveo, Novartis Vaccines) are licensed for persons aged 2 through 55 years as a single dose. These vaccines are recommended routinely for persons aged 11 through 18 years and persons aged 2 through 55 years at increased risk for meningococcal disease (and persons aged 9 months through 55 years for MenACWY-D). This report summarizes the deliberations of ACIP, the rationale for its decision, and recommendations for use of Hib-MenCY-TT in infants at increased risk for meningococcal disease. PMID- 23344699 TI - Emergence of new norovirus strain GII.4 Sydney--United States, 2012. AB - Noroviruses are the leading cause of epidemic gastroenteritis, including foodborne outbreaks, in the United States. Hospitalization and mortality associated with norovirus infection occur most frequently among elderly persons, young children, and immunocompromised patients. Noroviruses belong to the family Caliciviridae and can be grouped into five genogroups (GI through GV), which are further divided into at least 34 genotypes. Human disease primarily is caused by GI and GII noroviruses, with most outbreaks caused by GII.4 strains. During the past decade, new GII.4 strains have emerged every 2-3 years, replacing previously predominant GII.4 strains. Emergence of these new norovirus strains has often, but not always, led to increased outbreak activity. For example, the previously dominant GII.4 New Orleans strain was not associated with increased norovirus outbreak activity in the United States. CDC collects information on norovirus strains associated with outbreaks in the United States through an electronic laboratory surveillance network called CaliciNet. This report documents the recent emergence of a new GII.4 strain, GII.4 Sydney, which caused most (53%) of the norovirus outbreaks reported through CaliciNet during September-December 2012. Continued surveillance will enable further assessment of the public health implications and significance of this new strain. PMID- 23344700 TI - Emergency department visits and hospitalizations for buprenorphine ingestion by children--United States, 2010-2011. AB - Buprenorphine (Subutex) and buprenorphine/naloxone (Suboxone) received Food and Drug Administration approval in 2002 for the treatment of opioid dependence. Introduction of these drugs expanded the availability of opioid-dependence treatment options to reduce the morbidity and mortality associated with opioid abuse, and buprenorphine has become an increasingly prescribed component of office-based treatment. However, unsupervised ingestion of buprenorphine containing products by children is a growing concern. PMID- 23344701 TI - Prevalence and function of non-suicidal self-injury (NSSI) in a community sample of adolescents, using suggested DSM-5 criteria for a potential NSSI disorder. AB - Previous prevalence rates of non-suicidal self-injury (NSSI) in adolescents have varied considerably. In the present cross-sectional study, prevalence rates, characteristics and functions of NSSI were assessed in a large randomized community sample consisting of 3,060 (50.5 % female) Swedish adolescents aged 15 17 years. The suggested criteria for NSSI disorder in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, (DSM-5) were used to assess prevalence rates with the aim of arriving at a more precise estimate. Out of the whole sample, 1,088 (35.6 %) adolescents (56.2 % female) reported at least one episode of NSSI during the last year, of which 205 (6.7 %) met suggested DSM-5 criteria for a potential NSSI disorder diagnosis. The NSSI disorder diagnosis was significantly more common in girls (11.1 % vs. 2.3 %, chi (2) (1, N = 3046) = 94.08, p < 0.001, cOR = 5.43, 95 % CI [3.73, 7.90]). The NSSI disorder group consisted of significantly more smokers and drug users compared to adolescents with NSSI that did not meet DSM-5 criteria for NSSI disorder, and also differed concerning demographic variables. A confirmatory factor analysis (CFA) was conducted on reported functions of NSSI, with the aim of validating Nock and Prinstein's (Journal of Consulting and Clinical Psychology 72:885-890, 2004, Journal of Abnormal Psychology 114:140-146, 2005) four-factor model on a Swedish community sample, resulting in a close to acceptable fit. A two-factor model (social and automatic reinforcement) resulted in a slightly better fit. The most frequently reported factors were positive and negative automatic reinforcement. A majority of functions were significantly more often reported by girls than boys. The implications of the suggested DSM-5 criteria and reported functions are discussed. PMID- 23344702 TI - The Eating Attitudes Test-26 revisited using exploratory structural equation modeling. AB - Most previous studies have failed to replicate the original factor structure of the 26-item version of the Eating Attitudes Test (EAT-26) among community samples of adolescents. The main objective of the present series of four studies (n = 2178) was to revisit the factor structure of this instrument among mixed gender community samples of adolescents using both exploratory structural equation modeling (ESEM) and confirmatory factor analysis (CFA). First, results from the ESEM analyses provided satisfactory goodness-of-fit statistics and reliability coefficients for a six-factor model of the EAT with 18 items (EAT-18) closely corresponding to the original seven-factor structure proposed for the 40-item version of the EAT. Second, these analyses were satisfactorily replicated among a new sample of community adolescents using CFA. The results confirmed the factor loading and intercept invariance of this model across gender and age groups (i.e., early and late adolescence), as well as the complete invariance of the EAT 18 measurement model between ethnicities (i.e., European versus African origins) and across weight categories (i.e., underweight, normal weight and overweight). Finally, the last study provided support for convergent validity of the EAT-18 with the Eating Disorder Inventory and with instruments measuring global self esteem, physical appearance, social physique anxiety and fear of negative appearance evaluation. PMID- 23344703 TI - Bullies, victims, and antipathy: the feeling is mutual. AB - In this study we consider whether bullies and victims are disliked by most of their classmates, or whether antipathy is concentrated among the occupants of these roles. Antipathy nominations were collected from a community sample of 699 Finnish adolescents (14 to 17 years of age), who described their own bullying and victimization, as well as problem behaviors and school engagement. Victimization was associated with antipathy, but the strength of the association differed according to characteristics of the nominator. Victimization was related to antipathy when the nominator was high on bullying but not low. Similarly, bullying was related to antipathy when the nominator was high on victimization, but not low. The findings indicate that although bullies and victims have elevated mean levels of rejection, they are not disliked by most peers but rather by those who report themselves to be high on these attributes. PMID- 23344704 TI - Management of patients with unprovoked venous thromboembolism: an evidence-based and practical approach. AB - OPINION STATEMENT: The management of patients with unprovoked venous thromboembolism is a common and challenging clinical problem. Although the initial antithrombotic management is well-established, there is uncertainty about the optimal long-term anticoagulant management, specifically whether patients should receive a short (i.e., 3- to 6-month) duration of anticoagulant therapy or indefinite anticoagulation. Factors that may be considered to estimate patients' risk for recurrent thromboembolism include the mode of initial clinical presentation, as deep vein thrombosis or pulmonary embolism, patient sex, antecedent hormonal therapy use, thrombophilia, D-dimer levels, and residual vein occlusion in patients with deep vein thrombosis. Many of these factors have been integrated into clinical prediction guides which stratify patients with unprovoked venous thromboembolism according to their risk for disease recurrence and, thereby, can assist clinicians in decisions about the duration of anticoagulation. The objective of this review is to consider the evidence relating to the clinical significance of purported risk factors and provide a practical case-based approach to guide decisions on duration of anticoagulation for patients with unprovoked venous thromboembolism. PMID- 23344705 TI - Pseudotyped retroviruses for infecting axolotl in vivo and in vitro. AB - Axolotls are poised to become the premiere model system for studying vertebrate appendage regeneration. However, very few molecular tools exist for studying crucial cell lineage relationships over regeneration or for robust and sustained misexpression of genetic elements to test their function. Furthermore, targeting specific cell types will be necessary to understand how regeneration of the diverse tissues within the limb is accomplished. We report that pseudotyped, replication-incompetent retroviruses can be used in axolotls to permanently express markers or genetic elements for functional study. These viruses, when modified by changing their coat protein, can infect axolotl cells only when they have been experimentally manipulated to express the receptor for that coat protein, thus allowing for the possibility of targeting specific cell types. Using viral vectors, we have found that progenitor populations for many different cell types within the blastema are present at all stages of limb regeneration, although their relative proportions change with time. PMID- 23344706 TI - Analysis of RNA-Seq data reveals involvement of JAK/STAT signalling during leg regeneration in the cricket Gryllus bimaculatus. AB - In the cricket Gryllus bimaculatus, missing distal parts of the amputated leg are regenerated from the blastema, a population of dedifferentiated proliferating cells that forms at the distal tip of the leg stump. To identify molecules involved in blastema formation, comparative transcriptome analysis was performed between regenerating and normal unamputated legs. Components of JAK/STAT signalling were upregulated more than twofold in regenerating legs. To verify their involvement, Gryllus homologues of the interleukin receptor Domeless (Gb'dome), the Janus kinase Hopscotch (Gb'hop) and the transcription factor STAT (Gb'Stat) were cloned, and RNAi was performed against these genes. Gb'dome(RNAi), Gb'hop(RNAi) and Gb'Stat(RNAi) crickets showed defects in leg regeneration. Blastema expression of Gb'cyclinE was decreased in the Gb'Stat(RNAi) cricket compared with that in the control. Hyperproliferation of blastema cells caused by Gb'fat(RNAi) or Gb'warts(RNAi) was suppressed by RNAi against Gb'Stat. The results suggest that JAK/STAT signalling regulates blastema cell proliferation during leg regeneration. PMID- 23344707 TI - Notch regulates blastema proliferation and prevents differentiation during adult zebrafish fin regeneration. AB - Zebrafish have the capacity to regenerate several organs, including the heart and fins. Fin regeneration is epimorphic, involving the formation at the amputation plane of a mass of undifferentiated, proliferating mesenchymal progenitor-like cells, called blastema. This tissue provides all the cell types that form the fin, so that after damage or amputation the fin pattern and structure are fully restored. How blastema cells remain in this progenitor-like state is poorly understood. Here, we show that the Notch pathway plays an essential role during fin regeneration. Notch signalling is activated during blastema formation and remains active throughout the regeneration process. Chemical inhibition or morpholino-mediated knockdown of Notch signalling impairs fin regeneration via decreased proliferation accompanied by reduced expression of Notch target genes in the blastema. Conversely, overexpression of a constitutively active form of the Notch1 receptor (N1ICD) in the regenerating fin leads to increased proliferation and to the expansion of the blastema cell markers msxe and msxb, as well as increased expression of the proliferation regulator aldh1a2. This blastema expansion prevents regenerative fin outgrowth, as indicated by the reduction in differentiating osteoblasts and the inhibition of bone regeneration. We conclude that Notch signalling maintains blastema cells in a plastic, undifferentiated and proliferative state, an essential requirement for fin regeneration. PMID- 23344708 TI - Foxc1 controls the growth of the murine frontal bone rudiment by direct regulation of a Bmp response threshold of Msx2. AB - The mammalian skull vault consists of several intricately patterned bones that grow in close coordination. The growth of these bones depends on the precise regulation of the migration and differentiation of osteogenic cells from undifferentiated precursor cells located above the eye. Here, we demonstrate a role for Foxc1 in modulating the influence of Bmp signaling on the expression of Msx2 and the specification of these cells. Inactivation of Foxc1 results in a dramatic reduction in skull vault growth and causes an expansion of Msx2 expression and Bmp signaling into the area occupied by undifferentiated precursor cells. Foxc1 interacts directly with a Bmp responsive element in an enhancer upstream of Msx2, and acts to reduce the occupancy of P-Smad1/5/8. We propose that Foxc1 sets a threshold for the Bmp-dependent activation of Msx2, thus controlling the differentiation of osteogenic precursor cells and the rate and pattern of calvarial bone development. PMID- 23344710 TI - Early cell lineage specification in a marsupial: a case for diverse mechanisms among mammals. AB - Early cell lineage specification in eutherian mammals results in the formation of a pluripotent inner cell mass (ICM) and trophoblast. By contrast, marsupials have no ICM. Here, we present the first molecular analysis of mechanisms of early cell lineage specification in a marsupial, the tammar wallaby. There was no overt differential localisation of key lineage-specific transcription factors in cleavage and early unilaminar blastocyst stages. Pluriblast cells (equivalent to the ICM) became distinguishable from trophoblast cells by differential expression of POU5F1 and, to a greater extent, POU2, a paralogue of POU5F1. Unlike in the mouse, pluriblast-trophoblast differentiation coincided with a global nuclear-to cytoplasmic transition of CDX2 localisation. Also unlike in the mouse, Hippo pathway factors YAP and WWTR1 showed mutually distinct localisation patterns that suggest non-redundant roles. NANOG and GATA6 were conserved as markers of epiblast and hypoblast, respectively, but some differences to the mouse were found in their mode of differentiation. Our results suggest that there is considerable evolutionary plasticity in the mechanisms regulating early lineage specification in mammals. PMID- 23344709 TI - FGF signaling induces mesoderm in the hemichordate Saccoglossus kowalevskii. AB - FGFs act in vertebrate mesoderm induction and also play key roles in early mesoderm formation in ascidians and amphioxus. However, in sea urchins initial characterizations of FGF function do not support a role in early mesoderm induction, making the ancestral roles of FGF signaling and mechanisms of mesoderm specification in deuterostomes unclear. In order to better characterize the evolution of mesoderm formation, we have examined the role of FGF signaling during mesoderm development in Saccoglossus kowalevskii, an experimentally tractable representative of hemichordates. We report the expression of an FGF ligand, fgf8/17/18, in ectoderm overlying sites of mesoderm specification within the archenteron endomesoderm. Embryological experiments demonstrate that mesoderm induction in the archenteron requires contact with ectoderm, and loss-of-function experiments indicate that both FGF ligand and receptor are necessary for mesoderm specification. fgf8/17/18 gain-of-function experiments establish that FGF8/17/18 is sufficient to induce mesoderm in adjacent endomesoderm. These experiments suggest that FGF signaling is necessary from the earliest stages of mesoderm specification and is required for all mesoderm development. Furthermore, they suggest that the archenteron is competent to form mesoderm or endoderm, and that FGF signaling from the ectoderm defines the location and amount of mesoderm. When considered in a comparative context, these data support a phylogenetically broad requirement for FGF8/17/18 signaling in mesoderm specification and suggest that FGF signaling played an ancestral role in deuterostome mesoderm formation. PMID- 23344711 TI - Lin28 proteins are required for germ layer specification in Xenopus. AB - Lin28 family proteins share a unique structure, with both zinc knuckle and cold shock RNA-binding domains, and were originally identified as regulators of developmental timing in Caenorhabditis elegans. They have since been implicated as regulators of pluripotency in mammalian stem cells in culture. Using Xenopus tropicalis, we have undertaken the first analysis of the effects on the early development of a vertebrate embryo resulting from global inhibition of the Lin28 family. The Xenopus genome contains two Lin28-related genes, lin28a and lin28b. lin28a is expressed zygotically, whereas lin28b is expressed both zygotically and maternally. Both lin28a and lin28b are expressed in pluripotent cells of the Xenopus embryo and are enriched in cells that respond to mesoderm-inducing signals. The development of axial and paraxial mesoderm is severely abnormal in lin28 knockdown (morphant) embryos. In culture, the ability of pluripotent cells from the embryo to respond to the FGF and activin/nodal-like mesoderm-inducing pathways is compromised following inhibition of lin28 function. Furthermore, there are complex effects on the temporal regulation of, and the responses to, mesoderm-inducing signals in lin28 morphant embryos. We provide evidence that Xenopus lin28 proteins play a key role in choreographing the responses of pluripotent cells in the early embryo to the signals that regulate germ layer specification, and that this early function is probably independent of the recognised role of Lin28 proteins in negatively regulating let-7 miRNA biogenesis. PMID- 23344712 TI - A randomized, double-blind, placebo-controlled study to evaluate the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors. AB - PURPOSE: As tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer. METHODS: This double blind, placebo-controlled, parallel-group study randomized patients (N = 96) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800 mg/day (fasted) on Days 2-8 and 1,600 mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms. RESULTS: Sixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6 ms (90% confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800 mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4 ms (90% CI: -2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval. CONCLUSIONS: Pazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval. PMID- 23344713 TI - All-oral combination of vinorelbine and capecitabine as first-line treatment in HER2/Neu-negative metastatic breast cancer. AB - PURPOSE: To evaluate the efficacy and safety of an all-oral vinorelbine and capecitabine combination therapy in anthracycline- +/- taxane-pretreated HER2/Neu negative metastatic breast cancer (MBC). METHODS: A phase 2 trial including women >18 years with HER2/Neu-negative MBC previously exposed to anthracycline- +/- taxane-based chemotherapy in the adjuvant or neoadjuvant setting. Enrolled patients received oral vinorelbine 60 mg/m(2) on days 1 and 8 and oral capecitabine 1,000 mg/m(2) twice daily on days 1-14 on a 3 weekly schedule. Patients with progressive disease after 3 cycles discontinued the study, while the remaining patients continued treatment for a maximum of 6 cycles. RESULTS: From January 2007 to March 2011, 30 patients were enrolled in this study (median age 47 years). In the 28 evaluable patients, the overall response rate was 57.1 % (95 % CI 30-67 %), including 3 complete (10.7 %) and 13 partial (46.4 %) responses. Six (21.4 %) patients suffered from disease progression. With a median follow-up time of 13 months, the median time to disease progression was 8.6 months (95 % CI 6.2-10.6 months) and the median survival time was 27.2 months. Treatment-related adverse events were manageable, and no World Health Organization grade 4 toxicities were noted. Neutropenia observed in 6 (21.4 %) patients was the main grade 3 toxicity. Grade 3 nausea and vomiting were reported in 2 (7.1 %) and 3 (10.7 %) patients, respectively. Two (7.1 %) patients developed grade 3 hand and foot syndrome. CONCLUSION: These results show that the combination of oral vinorelbine and capecitabine is an effective and well tolerated first-line regimen for HER2/Neu-negative MBC patients pretreated with anthracyclines +/- taxanes. PMID- 23344714 TI - Asymmetric functional divergence of young, dispersed gene duplicates in Arabidopsis thaliana. AB - One prediction of the classic Ohno model of gene duplication predicts that new genes form from the asymmetric functional divergence of a newly arisen, redundant duplicate locus. In order to understand the mechanisms which give rise to functional divergence of newly formed dispersed duplicates, we assessed the expression and molecular evolutionary divergence of a suite of 19 highly similar dispersed duplicates in Arabidopsis thaliana. These duplicates have a K sil equal to or less than 5 % and are specific to the A. thaliana lineage; thus, they predictably represent some of the youngest duplicates in the A. thaliana genome. We found that the majority of young duplicate loci exhibit asymmetric expression patterns, with the daughter locus exhibiting reduced expression across all tissues analyzed relative to the progenitor locus or simply not expressed. Furthermore, daughter loci, on the whole, have significantly more nonsynonymous substitutions than the progenitor loci. We also identified four pairs of loci which exhibit significant (P < 0.05) evolutionary rate asymmetry, three of which exhibit elevated dN/dS in the duplicate copy. We suggest, based on these data, that functional diversification initially takes the form of asymmetric regulatory divergence that can be a direct consequence of the mode of duplication. The reduced and/or absence of expression in the daughter copy relaxes functional constraint on its protein coding sequence leading to the asymmetric accumulation of nonsynonymous mutations. Thus, our data both affirm Ohno's prediction while explaining the mechanism by which functional divergence initially occurs following duplication for dispersed gene duplicates. PMID- 23344715 TI - An alternative look at code evolution: using non-canonical codes to evaluate adaptive and historic models for the origin of the genetic code. AB - The canonical code has been shown many times to be highly robust against point mutations; that is, mutations that change a single nucleotide tend to result in similar amino acids more often than expected by chance. There are two major types of models for the origin of the code, which explain how this sophisticated structure evolved. Adaptive models state that the primitive code was specifically selected for error minimization, while historic models hypothesize that the robustness of the code is an artifact or by-product of the mechanism of code evolution. In this paper, we evaluated the levels of robustness in existing non canonical codes as well as codes that differ in only one codon assignment from the standard code. We found that the level of robustness of many of these codes is comparable or better than that of the standard code. Although these results do not preclude an adaptive origin of the genetic code, they suggest that the code was not selected for minimizing the effects of point mutations. PMID- 23344716 TI - Clinical trials with new oral anticoagulants. Additive value of indirect comparisons also named network meta-analyses. AB - To compare the efficacy and safety of the new oral anticoagulants (NOAC), ideally head-to-head clinical trials should be performed. Given the expense of such an undertaking, it is highly unlikely that such a comparison would be performed. Therefore, there is a need for an unbiased comparative assessment of the benefits and risks of the NOACs, based on the available trial data. Indirect or mixed treatment comparisons may be an useful tool to overcome these limitations also known as network meta-analysis (NMA). The aim of this paper is to give an overview on published NMAs for dabigatran, rivaroxaban and apixaban, each assessed against warfarin in patients with atrial fibrillation, and against enoxaparin in patients undergoing total knee and total hip replacement surgery, in order to obtain insights into the comparability of the adopted methodological techniques. PMID- 23344718 TI - Implicit chaining in cotton-top tamarins (Saguinus oedipus) with elements equated for probability of reinforcement. AB - Three experiments examined the implicit learning of sequences under conditions in which the elements comprising a sequence were equated in terms of reinforcement probability. In Experiment 1 cotton-top tamarins (Saguinus oedipus) experienced a five-element sequence displayed serially on a touch screen in which reinforcement probability was equated across elements at .16 per element. Tamarins demonstrated learning of this sequence with higher latencies during a random test as compared to baseline sequence training. In Experiments 2 and 3, manipulations of the procedure used in the first experiment were undertaken to rule out a confound owing to the fact that the elements in Experiment 1 bore different temporal relations to the intertrial interval (ITI), an inhibitory period. The results of Experiments 2 and 3 indicated that the implicit learning observed in Experiment 1 was not due to temporal proximity between some elements and the inhibitory ITI. The results taken together support two conclusion: First that tamarins engaged in sequence learning whether or not there was contingent reinforcement for learning the sequence, and second that this learning was not due to subtle differences in associative strength between the elements of the sequence. PMID- 23344719 TI - Prevalence of yeasts in English full blood mares. AB - The aim of the study was a quantitative and qualitative analysis of microflora, presentation of current data about prevalence of the microflora on the skin and mucous membranes, and determination of its possible effect on reproduction of English full blood horses bred in Poland. The material for analyses was sampled from the skin and mucous membranes (385 samples) of 55 English full blood mares. Taking into account reproduction traits, the mares were classified into three groups. Six yeast-like species, including five species from the genus Candida (C. albicans, C. guiliermondii, C. lusitaniae, C. sp., and C. tropicalis) and Trichomonascus ciferrii, were detected on the skin and mucous membranes in the English full blood mares. Growth of yeasts was observed in more than half of the samples taken from mares that had foaled and approximately 46 % of non-conceiving and barren mares. The high prevalence of various yeast strains in the mouth, nostrils, and collateral groove may suggest widespread occurrence of the microflora in the breeding environment. The results obtained indicate that the yeasts isolated in this study may be components of the normal microflora of the skin and mucous membranes in horses. The analysis results do not indicate unambiguously that the isolated microflora affects reproduction in mares, although this cannot be excluded. PMID- 23344720 TI - Impact of subcortical white matter lesions on dopamine transporter SPECT. AB - Subcortical arteriosclerotic encephalopathy (SAE) can affect the nigrostriatal system and presumably cause vascular parkinsonism (VP). However, in patients with SAE, the differentiation of VP from idiopathic Parkinson's disease (IPS) is challenging. The aim of the present study was to examine the striatal dopamine transporter (DAT) density in patients with parkinsonism and SAE. Fifteen consecutive patients with parkinsonian symptoms displayed SAE, as detected by magnetic resonance imaging (MRI). Fifteen retrospectively chosen, matched patients with diagnosis of IPS without any abnormalities in MRI served as a reference group. DAT SPECT was performed using the tracer 123I-FP-CIT. Scans were acquired on a triple-head SPECT system (Multispect 3, Siemens) and analysed using the investigator-independent BRASSTM software (HERMES). In the SAE group, a DAT deficit was observed in 9/15 patients. In contrast, all patients from the IPS group showed a reduced DAT binding (p = 0.008). The specific binding ratios (BR) of putamen contralateral to the side of the more affected limb versus occipital lobe were in trend higher in patients with SAE versus patients in the IPS-group (p = 0.053). Indices for putaminal asymmetry (p = 0.036) and asymmetry caudate-to putamen (p = 0.026) as well as the ratio caudate-to-putamen (p = 0.048) were significantly higher in IPS patients having no SAE. DAT deficit was less pronounced in patients with SAE and parkinsonism than in patients with IPS without any abnormalities in the MRI. A potential role of DAT SPECT in the differential diagnosis of VP and IPS requires more assessments within prospective studies. PMID- 23344721 TI - miR-1289 and "Zipcode"-like Sequence Enrich mRNAs in Microvesicles. AB - Despite intensive studies, the molecular mechanisms by which the genetic materials are uploaded into microvesicles (MVs) are still unknown. This is the first study describing a zipcode-like 25 nucleotide (nt) sequence in the 3' untranslated region (3'UTR) of mRNAs, with variants of this sequence present in many mRNAs enriched in MVs, as compared to their glioblastoma cells of origin. When this sequence was incorporated into the 3'UTR of a reporter message and expressed in a different cell type, it led to enrichment of the reporter mRNA in MVs. Critical features of this sequence are both a CUGCC core presented on a stem loop structure and a miRNA-binding site, with increased levels of the corresponding miRNA in cells further increasing levels of mRNAs in MVs. PMID- 23344722 TI - Optimized in vivo transfer of small interfering RNA targeting dermal tissue using in vivo surface electroporation. AB - Electroporation (EP) of mammalian tissue is a technique that has been used successfully in the clinic for the delivery of genetic-based vaccines in the form of DNA plasmids. There is great interest in platforms which efficiently deliver RNA molecules such as messenger RNA and small interfering RNA (siRNA) to mammalian tissue. However, the in vivo delivery of RNA enhanced by EP has not been extensively characterized. This paper details the optimization of electrical parameters for a novel low-voltage EP method to deliver oligonucleotides (both DNA and RNA) to dermal tissue in vivo. Initially, the electrical parameters were optimized for dermal delivery of plasmid DNA encoding green fluorescent protein (GFP) using this novel surface dermal EP device. While all investigated parameters resulted in visible transfection, voltage parameters in the 10 V range elicited the most robust signal. The parameters optimized for DNA, were then assessed for translation of successful electrotransfer of siRNA into dermal tissue. Robust tagged-siRNA transfection in skin was detected. We then assessed whether these parameters translated to successful transfer of siRNA resulting in gene knockdown in vivo. Using a reporter gene construct encoding GFP and tagged siRNA targeting the GFP message, we show simultaneous transfection of the siRNA to the skin via EP and the concomitant knockdown of the reporter gene signal. The siRNA delivery was accomplished with no evidence of injection site inflammation or local tissue damage. The minimally invasive low-voltage EP method is thus capable of efficiently delivering both DNA and RNA molecules to dermal tissue in a tolerable manner. PMID- 23344723 TI - The Business of RNAi Therapeutics in 2012. PMID- 23344724 TI - Intracerebral Infusion of Antisense Oligonucleotides Into Prion-infected Mice. AB - Mice deficient for the cellular prion protein (PrP(C)) do not develop prion disease; accordingly, gene-based strategies to diminish PrP(C) expression are of interest. We synthesized a series of chemically modified antisense oligonucleotides (ASOs) targeted against mouse Prnp messenger RNA (mRNA) and identified those that were most effective in decreasing PrP(C) expression. Those ASOs were also evaluated in scrapie-infected cultured cells (ScN2a) for their efficacy in diminishing the levels of the disease-causing prion protein (PrP(Sc)). When the optimal ASO was infused intracerebrally into FVB mice over a 14-day period beginning 1 day after infection with the Rocky Mountain Laboratory (RML) strain of mouse prions, a prolongation of the incubation period of almost 2 months was observed. Whether ASOs can be used to develop an effective therapy for patients dying of Creutzfeldt-Jakob disease remains to be established. PMID- 23344725 TI - Cornelius Celsus--ancient encyclopedist, surgeon-scientist, or master of surgery? AB - PURPOSE: The Roman nobleman Cornelius Celsus (25 BC-AD 50) wrote a general encyclopedia (De Artibus) dealing with several subjects, among which some had medical content (De Medicina), an eight-volume compendium, including two books about surgery (VII + VIII). It is the most significant medical document following the Hippocratic writings. In 1443, Pope Nicolas V rediscovered the work of Cornelius Celsus, despite it having been forgotten for several centuries, and it was the first medical and surgical book to be printed (AD 1478). Up until the nineteenth century, 60 editions were published in Latin as well as numerous translations in European languages, the last of which was a French translation in 1876. While Celsus' work is the best account of Roman medicine as practiced in the first century of the Christian era and its influence persisted until the nineteenth century, there is controversy as to whether Cornelius Celsus himself actually practiced as a surgeon or was only an encyclopedist who collected in the Latin language the medical knowledge available at that time. METHODS: The detailed analysis of the surgical techniques described by Celsus, the modifications tailored to the findings, possible complications, detailed description of pre- and postsurgical activities, give the general impression that he himself practiced surgery at least within his family and among his dependents. In addition, his descriptions give a clear insight into the astonishingly high standard of surgical knowledge available at the time of Celsus. RESULTS: His work thus reflects the state of knowledge of his time, which is why he also assumed the role of teacher and scientist. As such, his meets the modern criteria addressed to a surgeon-scientist, who apart from the practical surgical activity, also had a role as teacher of surgery and scientist. Whether Cornelius Celsus had inaugurated a new surgical technique and was the first to describe that, and as such can be described as a master of surgery, cannot be corroborated. CONCLUSION: Cornelius Celsus deserves a firm place in the history of surgery because with his publication De Medicina, Book VII + VIII, he has preserved Roman surgical knowledge in the first century of the Christian era and, thanks to the use of Latin in medicine and surgery, this continues to be retained up till the present day. PMID- 23344726 TI - Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects. AB - AIMS/HYPOTHESIS: Muscle insulin resistance, one of the earliest defects associated with type 2 diabetes, involves changes in the phosphoinositide 3 kinase/Akt network. The relative contribution of obesity vs insulin resistance to perturbations in this pathway is poorly understood. METHODS: We used phosphospecific antibodies against targets in the Akt signalling network to study insulin action in muscle from lean, overweight/obese and type 2 diabetic individuals before and during a hyperinsulinaemic-euglycaemic clamp. RESULTS: Insulin-stimulated Akt phosphorylation at Thr309 and Ser474 was highly correlated with whole-body insulin sensitivity. In contrast, impaired phosphorylation of Akt substrate of 160 kDa (AS160; also known as TBC1D4) was associated with adiposity, but not insulin sensitivity. Neither insulin sensitivity nor obesity was associated with defective insulin-dependent phosphorylation of forkhead box O (FOXO) transcription factor. In view of the resultant basal hyperinsulinaemia, we predicted that this selective response within the Akt pathway might lead to hyperactivation of those processes that were spared. Indeed, the expression of genes targeted by FOXO was downregulated in insulin-resistant individuals. CONCLUSIONS/INTERPRETATION: These results highlight non-linearity in Akt signalling and suggest that: (1) the pathway from Akt to glucose transport is complex; and (2) pathways, particularly FOXO, that are not insulin-resistant, are likely to be hyperactivated in response to hyperinsulinaemia. This facet of Akt signalling may contribute to multiple features of the metabolic syndrome. PMID- 23344727 TI - The association of alanine aminotransferase within the normal and mildly elevated range with lipoproteins and apolipoproteins: the Insulin Resistance Atherosclerosis Study. AB - AIMS/HYPOTHESIS: Markers of liver injury, such as alanine aminotransferase (ALT), have been associated with atherogenic lipoprotein changes. We examined the extent to which this association was explained by insulin resistance, adiposity, glucose tolerance and chronic inflammation. METHODS: In this analysis we included 824 non diabetic participants (age 40-69 years) in the Insulin Resistance Atherosclerosis Study. No participants reported excessive alcohol intake or treatment with lipid lowering medications. Lipoproteins and apolipoproteins were measured by conventional methods and lipoprotein heterogeneity by nuclear magnetic resonance (NMR) spectroscopy. RESULTS: ALT had a positive relationship with triacylglycerols, LDL-to-HDL-cholesterol ratio and apolipoprotein B (ApoB) after adjusting for demographic variables (p < 0.001 for all three relationships). ALT was also associated with the following NMR lipoproteins: positively with large VLDL (p < 0.001), intermediate-density lipoprotein (IDL) (p < 0.001) and small LDL subclass particles (p < 0.001), and VLDL particle size (p < 0.001); and negatively with large LDL subclass particles (p < 0.05) and LDL (p < 0.001) and HDL particle sizes (p < 0.01). ALT remained associated with IDL and small LDL subclass particles and ApoB after adjusting for glucose tolerance, adiposity, directly measured insulin sensitivity and C-reactive protein. CONCLUSIONS/INTERPRETATION: ALT is associated with a wide range of atherogenic lipoprotein changes, which are partially explained by insulin resistance, adiposity, glucose tolerance and chronic inflammation. Because of the significant variability in the relationship between ALT and liver fat, further studies are needed to assess the extent of the lipoprotein changes using a direct measure of liver fat. PMID- 23344728 TI - Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis. AB - AIMS/HYPOTHESIS: The aim of this work was to compare the glucose-lowering efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors between Asian and non-Asian patients with type 2 diabetes. METHODS: We searched MEDLINE, EMBASE, LILACS, CENTRAL, ClinicalTrials.gov and conference proceedings. Studies were eligible if they were randomised controlled trials with a treatment duration of at least 12 weeks, compared a DPP-4 inhibitor with a placebo as either monotherapy or oral combination therapy, had information on ethnicity and HbA1c values and were published or described in English. A systematic review and meta-analysis with a meta-regression analysis was conducted. RESULTS: Among 809 potentially relevant studies, 55 trials were included. A meta-analysis revealed that DPP-4 inhibitors lowered HbA1c to a greater extent in studies with >=50% Asian participants (weighted mean difference [WMD] -0.92%; 95% CI -1.03, -0.82) than in studies with <50% Asian participants (WMD -0.65%; 95% CI -0.69, -0.60). The between-group difference was -0.26% (95% CI -0.36, -0.17, p < 0.001). The baseline BMI significantly correlated with the HbA1c-lowering efficacy of DPP-4 inhibitors. The RR of achieving the goal of HbA1c <7.0% (53.0 mmol/mol) was higher in studies with >=50% Asian participants (3.4 [95% CI 2.6, 4.7] vs 1.9 [95% CI 1.8, 2.0]). The fasting plasma glucose-lowering efficacy was higher with monotherapy in the Asian-dominant studies, but the postprandial glucose-lowering efficacy and changes in body weight were comparable between the two groups. CONCLUSIONS/INTERPRETATION: DPP-4 inhibitors exhibit a better glucose-lowering efficacy in Asians than in other ethnic groups; this requires further investigation to understand the underlying mechanism, particularly in relation to BMI. PMID- 23344729 TI - The permissive effects of glucose on receptor-operated potentiation of insulin secretion from mouse islets: a role for ERK1/2 activation and cytoskeletal remodelling. AB - AIMS/HYPOTHESIS: Glucose plays two distinct roles in regulating insulin secretion from beta cells--an initiatory role, and a permissive role enabling receptor operated secretagogues to potentiate glucose-induced insulin secretion. The molecular mechanisms underlying the permissive effects of glucose on receptor operated insulin secretion remain uncertain. We have investigated the role of extracellular signal-regulated kinase 1/2 (ERK1/2) activation and consequent cytoskeletal remodelling in this process. METHODS: Insulin release was measured from groups of isolated mouse islets using static incubation experiments and subsequent radioimmunoassay of samples. ERK1/2 activation was measured by western blotting of islet protein samples for both phosphorylated and total ERK1/2. Rhodamine-phalloidin staining was used to measure filamentous actin in dispersed primary beta cells. RESULTS: Inhibition of ERK1/2 blocked potentiation of glucose induced insulin release by the receptor-operated secretagogues kisspeptin, A568, exendin-4 and JWH015, although the agonists alone had minimal effects on ERK1/2 activation, suggesting a permissive rather than causal role for ERK1/2 activation in receptor-operated insulin release. Following pharmacological activation of ERK1/2 all agonists caused a significant increase in insulin release from islets incubated with sub-stimulatory levels of glucose. ERK1/2 inhibition significantly reduced the glucose-dependent decreases in filamentous actin observed in primary beta cells, while pharmacological dissociation of actin filaments enabled all receptor-operated secretagogues tested to significantly stimulate insulin release from islets at a sub-stimulatory glucose concentration. CONCLUSIONS/INTERPRETATION: Glucose-induced ERK1/2 activation in beta cells mediates the permissive effects of stimulatory glucose concentrations on receptor operated insulin secretagogues, at least in part through effects on actin depolymerisation and cytoskeletal remodelling. PMID- 23344730 TI - Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice. AB - AIMS/HYPOTHESIS: Enterovirus (e.g. Coxsackie B virus serotypes [CVBs]) infections may be associated with development of type 1 diabetes. Studies conducted in several European countries have, however, shown an inverse correlation between the incidence of type 1 diabetes and the prevalence of enterovirus infections. These findings could in part be explained by an extension of the poliovirus hypothesis, suggesting that the absence of maternally transferred antibodies protecting offspring from early infection increases the risk for diabetes development. Experimental evidence supporting this hypothesis in type 1 diabetes is, however, lacking. As maternally transferred protection from infection is a crucial component of the extended poliovirus hypothesis, we here tested the hypothesis that previously infected females transfer protection against infection and diabetes to offspring. METHODS: The induction of CVB-specific maternal antibodies and transfer of protection from virus infection, replication and development of virus-induced diabetes to offspring was assessed using NOD and Socs1-transgenic NOD mice. RESULTS: Infected mice produced neutralising antibodies to CVB. Offspring from infected females were positive for neutralising antibodies and were strongly protected from both infection and experimental diabetes. CONCLUSIONS/INTERPRETATION: Our study shows that maternally transferred antibodies protect offspring from enterovirus infection and virus-induced diabetes. This suggests that the absence of maternally provided protection increases the risk for severe outcomes after an enterovirus infection in offspring. Moreover, our findings may have implications for the design of prospective studies aimed at investigating the possible role of enterovirus infections in the aetiology of human type 1 diabetes. PMID- 23344731 TI - Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes. AB - AIMS/HYPOTHESIS: The small, highly conserved vasoactive peptide urotensin II (UII) is upregulated in atherosclerosis. However, its effects in diabetes associated atherosclerosis have not been assessed. METHODS: Endothelial cells were grown in normal- and high-glucose (5 and 25 mmol/l) media with and without UII (10-8 mol/l) and/or the UII receptor antagonist, SB-657510 (10-8 mol/l). Apoe knockout (KO) mice with or without streptozotocin-induced diabetes were treated with or without SB-657510 (30 mg kg-1 day-1; n = 20 per group) and followed for 20 weeks. Carotid endarterectomy specimens from diabetic and non-diabetic humans were also evaluated. RESULTS: In high (but not normal) glucose medium, UII significantly increased CCL2 (encodes macrophage chemoattractant protein 1 [MCP 1]) gene expression (human aortic endothelial cells) and increased monocyte adhesion (HUVECs). UII receptor antagonism in diabetic Apoe KO mice significantly attenuated diabetes-associated atherosclerosis and aortic staining for MCP-1, F4/80 (macrophage marker), cyclooxygenase-2, nitrotyrosine and UII. UII staining was significantly increased in carotid endarterectomies from diabetic compared with non-diabetic individuals, as was staining for MCP-1. CONCLUSIONS/INTERPRETATION: This is the first report to demonstrate that UII is increased in diabetes-associated atherosclerosis in humans and rodents. Diabetes associated plaque development was attenuated by UII receptor antagonism in the experimental setting. Thus UII may represent a novel therapeutic target in the treatment of diabetes-associated atherosclerosis. PMID- 23344733 TI - MPTinR: analysis of multinomial processing tree models in R. AB - We introduce MPTinR, a software package developed for the analysis of multinomial processing tree (MPT) models. MPT models represent a prominent class of cognitive measurement models for categorical data with applications in a wide variety of fields. MPTinR is the first software for the analysis of MPT models in the statistical programming language R, providing a modeling framework that is more flexible than standalone software packages. MPTinR also introduces important features such as (1) the ability to calculate the Fisher information approximation measure of model complexity for MPT models, (2) the ability to fit models for categorical data outside the MPT model class, such as signal detection models, (3) a function for model selection across a set of nested and nonnested candidate models (using several model selection indices), and (4) multicore fitting. MPTinR is available from the Comprehensive R Archive Network at http://cran.r-project.org/web/packages/MPTinR/ . PMID- 23344732 TI - Y chromosome microdeletions in infertile men: prevalence, phenotypes and screening markers for the Indian population. AB - PURPOSE: Yq microdeletions are the leading genetic cause of male infertility and its detection is clinically relevant for appropriate genetic counseling. We aimed to determine the prevalence and type of Yq microdeletions, the associated seminal phenotypes and the STS markers that are relevant for its testing in Indian population. METHODS: Yq microdeletion analysis was carried out in 1,636 infertile cases in our centers. Additional data was collected from published studies in Indian population leading to a total of 3,647 cases. RESULTS: In our cohort, 3.4 % (56/1,636) of infertile men had Yq microdeletions. Combining the data from other published studies identified 215/3,647 (5.8 %) infertile individuals to harbor Yq microdeletions; with 6.4 % in azoopsermia, 5.8 % in oligozoospermia and 3.2 % in oligoasthenozoospermia and teratozoospermia cases. No significant differences in the deletion frequencies were observed between idiopathic vs non idiopathic cases (5.8 vs 8.6 % respectively). Deletions of AZFc were at highest frequency (46.6 %) with double deletions most commonly observed in azoospermic subjects. With respect to the STS markers, screening with the six European Academy of Andrology (EAA) markers would miss 3.1 % of cases; additional non EAA markers that would contribute significantly to screening are sY746, sY82, sY121, sY128, sY130, sY143, sY145 & sY160. INTERPRETATIONS AND CONCLUSIONS: The frequency of Yq microdeletions is lower in Indian population as compared to Western counterparts. There is no major association of Yq microdeletions with seminal parameters or cause of infertility. Clinically it will be necessary to offer Yq microdeletion testing to all the classes of infertile men. The EAA markers may not be adequate to detect microdeletions in Indian infertile men. PMID- 23344734 TI - SPSS and SAS programs for comparing Pearson correlations and OLS regression coefficients. AB - Several procedures that use summary data to test hypotheses about Pearson correlations and ordinary least squares regression coefficients have been described in various books and articles. To our knowledge, however, no single resource describes all of the most common tests. Furthermore, many of these tests have not yet been implemented in popular statistical software packages such as SPSS and SAS. In this article, we describe all of the most common tests and provide SPSS and SAS programs to perform them. When they are applicable, our code also computes 100 * (1 - alpha)% confidence intervals corresponding to the tests. For testing hypotheses about independent regression coefficients, we demonstrate one method that uses summary data and another that uses raw data (i.e., Potthoff analysis). When the raw data are available, the latter method is preferred, because use of summary data entails some loss of precision due to rounding. PMID- 23344735 TI - Recurrence quantification analysis of eye movements. AB - Recurrence quantification analysis (RQA) has been successfully used for describing dynamic systems that are too complex to be characterized adequately by standard methods in time series analysis. More recently, RQA has been used for analyzing the coordination of gaze patterns between cooperating individuals. Here, we extend RQA to the characterization of fixation sequences, and we show that the global and local temporal characteristics of fixation sequences can be captured by a small number of RQA measures that have a clear interpretation in this context. We applied RQA to the analysis of a study in which observers looked at different scenes under natural or gaze-contingent viewing conditions, and we found large differences in the RQA measures between the viewing conditions, indicating that RQA is a powerful new tool for the analysis of the temporal patterns of eye movement behavior. PMID- 23344736 TI - Investigating eye movement acquisition and analysis technologies as a causal factor in differential prevalence of crossed and uncrossed fixation disparity during reading and dot scanning. AB - Previous studies examining binocular coordination during reading have reported conflicting results in terms of the nature of disparity (e.g. Kliegl, Nuthmann, & Engbert (Journal of Experimental Psychology General 135:12-35, 2006); Liversedge, White, Findlay, & Rayner (Vision Research 46:2363-2374, 2006). One potential cause of this inconsistency is differences in acquisition devices and associated analysis technologies. We tested this by directly comparing binocular eye movement recordings made using SR Research EyeLink 1000 and the Fourward Technologies Inc. DPI binocular eye-tracking systems. Participants read sentences or scanned horizontal rows of dot strings; for each participant, half the data were recorded with the EyeLink, and the other half with the DPIs. The viewing conditions in both testing laboratories were set to be very similar. Monocular calibrations were used. The majority of fixations recorded using either system were aligned, although data from the EyeLink system showed greater disparity magnitudes. Critically, for unaligned fixations, the data from both systems showed a majority of uncrossed fixations. These results suggest that variability in previous reports of binocular fixation alignment is attributable to the specific viewing conditions associated with a particular experiment (variables such as luminance and viewing distance), rather than acquisition and analysis software and hardware. PMID- 23344738 TI - Establishing normative data for repeated cognitive assessment: a comparison of different statistical methods. AB - Serial cognitive assessment is conducted to monitor changes in the cognitive abilities of patients over time. At present, mainly the regression-based change and the ANCOVA approaches are used to establish normative data for serial cognitive assessment. These methods are straightforward, but they have some severe drawbacks. For example, they can only consider the data of two measurement occasions. In this article, we propose three alternative normative methods that are not hampered by these problems-that is, multivariate regression, the standard linear mixed model (LMM), and the linear mixed model combined with multiple imputation (LMM with MI) approaches. The multivariate regression method is primarily useful when a small number of repeated measurements are taken at fixed time points. When the data are more unbalanced, the standard LMM and the LMM with MI methods are more appropriate because they allow for a more adequate modeling of the covariance structure. The standard LMM has the advantage that it is easier to conduct and that it does not require a Monte Carlo component. The LMM with MI, on the other hand, has the advantage that it can flexibly deal with missing responses and missing covariate values at the same time. The different normative methods are illustrated on the basis of the data of a large longitudinal study in which a cognitive test (the Stroop Color Word Test) was administered at four measurement occasions (i.e., at baseline and 3, 6, and 12 years later). The results are discussed and suggestions for future research are provided. PMID- 23344737 TI - The semantic priming project. AB - Speeded naming and lexical decision data for 1,661 target words following related and unrelated primes were collected from 768 subjects across four different universities. These behavioral measures have been integrated with demographic information for each subject and descriptive characteristics for every item. Subjects also completed portions of the Woodcock-Johnson reading battery, three attentional control tasks, and a circadian rhythm measure. These data are available at a user-friendly Internet-based repository ( http://spp.montana.edu ). This Web site includes a search engine designed to generate lists of prime target pairs with specific characteristics (e.g., length, frequency, associative strength, latent semantic similarity, priming effect in standardized and raw reaction times). We illustrate the types of questions that can be addressed via the Semantic Priming Project. These data represent the largest behavioral database on semantic priming and are available to researchers to aid in selecting stimuli, testing theories, and reducing potential confounds in their studies. PMID- 23344739 TI - General knowledge norms: updated and expanded from the Nelson and Narens (1980) norms. AB - The Nelson and Narens (Journal of Verbal Learning and Verbal Behavior 19:338-368, 1980) general knowledge norms have been valuable to researchers in many fields. However, much has changed over the 32 years since the 1980 norms. For example, in 1980, most people knew the answer to the question "What is the name of the Lone Ranger's Indian sidekick?" (answer: Tonto), whereas in 2012, few people know this answer. Thus, we updated the 1980 norms and expanded them by providing new measures. In particular, we report two new metacognitive measures (confidence judgments and peer judgments) and provide a detailed report of commission errors. Each of these measures will be valuable to researchers, and together they are likely to facilitate future research in a number of fields, such as research investigating memory illusions, metamemory processes, and error correction. The presence of substantial generational shifts from 1980 to 2012 necessitates the use of updated norms. PMID- 23344740 TI - A visual object naming task standardized for the Croatian language: a tool for research and clinical practice. AB - The aim of the present study was to provide normative data for the Croatian language using 346 visually presented objects (Cycowicz, Friedman, Rothstein, & Snodgrass Journal of Experimental Child Psychology 65:171-237, 1997; Roach, Schwartz, Martin, Grewal, & Brecher Clinical Aphasiology 24:121-133, 1996; Snodgrass & Vanderwart Journal of Experimental Psychology: Human Learning and Memory 6:174-215, 1980). Picture naming was standardized according to seven variables: naming latency, name agreement, familiarity, visual complexity, word length, number of syllables, and word frequency. The descriptive statistics and correlation pattern of the variables collected in the present study were consistent with normative studies in other languages. These normative data for pictorial stimuli named by young healthy Croatian native speakers will be useful in studies of perception, language, and memory, as well as for preoperative and intraoperative mapping of speech and language brain areas. PMID- 23344741 TI - Italian multicentre observational study of the prevalence of CCSVI in multiple sclerosis (CoSMo study): rationale, design, and methodology. AB - Chronic cerebro-spinal venous insufficiency (CCSVI) has been proposed as a "congenital malformation" implicated in the pathogenesis of multiple sclerosis (MS). However, numerous studies failed to confirm its presence in MS patients. This paper presents the rationale, design, and methodology adopted in the CoSMo study, conducted with the aim of verifying whether or not CCSVI is linked to MS. The primary endpoint of the CoSMo study is to compare the prevalence of CCSVI in patients with MS versus patients affected by other neurodegenerative diseases (OND) and healthy volunteers. CoSMo is a multicenter, blinded, prevalence study recruiting 2,000 adult subjects, involving 43 MS centers across Italy. Assessment of the presence or absence of CCSVI is performed by color-coded duplex (CCD) sonography and two out of the five criteria according to Zamboni are necessary for the diagnosis of CCSVI. Local CCD examination carried out by a certified sonologist and the central image readings performed by experts in the field are blinded. An advanced protocol is also described in this paper. The application of a rigorous methodological design will definitively confirm whether an association exists between CCSVI and MS. Should an association be observed, this study also further examines the link between CCSVI and the severity of MS. The addition of subgroups without MS and OND also provides information on whether CCSVI is specific to MS only. Results from the CoSMo study will play a crucial role in the possible studies concerning the potential treatment of CCSVI in MS. PMID- 23344742 TI - Shenfu injection attenuates neonatal hypoxic-ischemic brain damage in rat. AB - Perinatal hypoxia-ischemia remains the most important cause of brain injury in the newborn. However, there is still no effective cure for neonatal hypoxic ischemic brain damage (HIBD). In the present study, we aimed to examine the neuroprotective effects of Shenfu injection (SFI) on HIBD of neonatal rat. Sprague-Dawley rats were divided randomly into three groups (n = 8): S group: the rats were sham operated; C group: the rats were operated for HIBD modeling and received intraperitoneal injection of saline; SFI group: the rats were operated for HIBD modeling and received intraperitoneal injection of SFI (10 ml/kg days) for 7 days. Flow cytometry analysis showed that apoptosis rate of neuron in hippocampal CAI region in SFI group was significantly less than in NC group at 3 and 7 days after HI insult (P < 0.05). Immunohistochemical staining demonstrated that Bcl-2 expression was markedly higher while Bax expression was significantly lower in SFI group than in the C group at 24, 72 h and 7 days after HI insult (P < 0.05). Our findings suggest that SFI exhibits neuroprotective effects for neonatal hypoxic-ischemic brain injury by preventing neuron apoptosis and has potential to be used in the clinical for the treatment of perinatal hypoxia ischemia. PMID- 23344743 TI - Possible anticipation associated with a novel splice site mutation in episodic ataxia type 2. AB - Anticipation is a phenomenon characterized by decreasing age at onset and increasing severity of symptoms of a disease in successive generations within a pedigree. Anticipation mostly occurs in neurodegenerative diseases with expansion of unstable trinucleotide repeats. However, it has not been previously pointed out in episodic ataxia type 2 (EA2). Clinical and genetic analyses were performed in nine members from three consecutive generations of a Korean family with EA2. We performed a polymerase chain reaction (PCR)-based direct sequence analysis of all coding regions of CACNA1A using genomic DNA. The clinically affected family members showed recurrent vertigo, interictal nystagmus, and childhood epilepsy. There is a decrease in the age onset (possible genetic anticipation) in three succeeding generations of the family. Genetic analysis identified a splice site mutation (p.Val1465Glyfs13X) and normal trinucleotide repeats in CACNA1A in all clinically affected and one unaffected members. Recognizing anticipation would aid in genetic counseling in EA2. PMID- 23344744 TI - Reversible myoclonus in a patient undergoing transcervical hysteroscopic surgery. AB - We describe a 58-year-old woman who underwent hysteroscopic myomectomy to treat a large submucosal leiomyoma. A hypotonic glycine solution was instilled to distend the uterus. At one hour after the distending medium infusion started for hysteroscopic resection an electrolytic imbalance developed. One hour later myoclonus developed predominantly involving the bilateral sternocleidomastoidei and abdominal muscles. The patient was alert and cooperative; jerks were spontaneous and triggered by sensory stimuli. The electroencephalographic and brain computed tomography was normal. The clinical characteristics of her myoclonus resemble reticular reflex myoclonus, a form of subcortical myoclonus originating from the lower brainstem reticular formation. Given her severe hyponatremia we conjecture that she had symptomatic metabolic myoclonus caused by electrolytic disturbance. The case report we present underlines the need to detect in time and promptly treat neurological symptoms such as myoclonus suggesting resorption syndrome, an uncommon event complicating transcervical hysteroscopic surgery and urologic procedures. PMID- 23344745 TI - Pitfalls in the diagnosis of Neuro-Behcet presenting with psychiatric symptoms at onset: a case report! PMID- 23344747 TI - Aortic valve regurgitation and ventricular septal defect diagnosed 5 years after penetrating cardiac injury. AB - Despite high mortality rates for penetrating heart injuries, developments in transport, diagnosis, and surgical interventions have increased survival rates. In some cases, life-threatening complications may be misdiagnosed or remain asymptomatic and lead to loss of life. Herein, we report a patient with aortic valve regurgitation because of noncoronary cusp perforation and ventricular septal defect that remained asymptomatic and diagnosed 5 years after a penetrating heart injury. PMID- 23344746 TI - Single-channel biophysical and pharmacological characterizations of native human large-conductance calcium-activated potassium channels in freshly isolated detrusor smooth muscle cells. AB - Recent studies have demonstrated the importance of large-conductance Ca(2+) activated K(+) (BK) channels in detrusor smooth muscle (DSM) function in vitro and in vivo. However, in-depth characterization of human native DSM single BK channels has not yet been provided. Here, we conducted single-channel recordings from excised patches from native human DSM cells. Inside-out and outside-out recordings in high K(+) symmetrical solution (containing 140 mM KCl and ~300 nM free Ca(2+)) showed single-channel conductance of 215-220 pS, half-maximum constant for activation of ~+75 to +80 mV, and low probability of opening (P o) at +20 mV that increased ~10-fold at +40 mV and ~60-fold at +60 mV. Using the inside-out configuration at +30 mV, reduction of intracellular [Ca(2+)] from ~300 nM to Ca(2+)-free decreased the P o by ~85 %, whereas elevation to ~800 nM increased P o by ~50-fold. The BK channel activator NS1619 (10 MUM) enhanced the P o by ~10-fold at +30 mV; subsequent application of the selective BK channel inhibitor paxilline (500 nM) blocked the activity. Changes in intracellular [Ca(2+)] or the addition of NS1619 did not significantly alter the current amplitude or single-channel conductance. This is the first report to provide biophysical and pharmacological profiles of native human DSM single BK channels highlighting their importance in regulating human DSM excitability. PMID- 23344748 TI - Chronic calcific constrictive pericarditis complicating Churg-Strauss syndrome: first reported case. AB - Churg-Strauss syndrome is a necrotizing systemic vasculitis characterized by extravascular granulomas and eosinophilic infiltrates of small vessels. Although cardiac complications are considered to be relatively common, no case of constrictive calcified pericarditis has ever been previously described in this setting. In this report, we present the case of a 46-year-old man with Churg Strauss syndrome, in whom we were able to document the development of symptomatic calcific constrictive pericarditis during a 10-year period despite long-term corticosteroid therapy. PMID- 23344749 TI - Parasternal mass revealing as a postvaccinal Bacillus Calmette-Guerin (BCG) elicited sternal osteomyelitis. AB - Although osteomyelitis is a very rare complication of Bacillus Calmette-Guerin (BCG) vaccination, sternal osteomyelitis as a late complication of BCG vaccination diagnosed by polymerase chain reaction (PCR) in a child is described.We might consider BCG osteomyelitis in the case of osteomyelitis without bacterial isolation within a year after BCG vaccination, the absence of pulmonary foci, and a contact to the patient with tuberculosis. PMID- 23344750 TI - Successful treatment of pure aortic insufficiency with transapical implantation of the JenaValve. AB - Transcatheter aortic valve implantation was predominantly developed for patients with severe calcified aortic stenosis, as most devices are designed to anchor within the native valve calcium. We report on a patient with pure insufficiency of a non-calcified aortic valve, in whom an anatomically oriented catheter valve was implanted successfully. The design of the prosthesis with position feelers engaging the native aortic valve leaflets proved to be suitable for the treatment of pure aortic insufficiency. PMID- 23344751 TI - Giant pulmonary artery aneurysm: 12 years of follow-up. case report and review of the literature. AB - Pulmonary artery aneurysm (PAA) is defined as pulmonary artery diameter of greater than 4 cm. PAA is not frequently encountered in clinical practice. There is a rare report in giant low-pressure PAA in terms of long-term follow-up. Herein, we sought to report a case of idiopathic PAA that was followed for 12 years in view of its learning points and to review the current literature for PAA. Herein we observed learning points according to long-term follow-up of PAA case as follows. PAA progressed dramatically after reaching a diameter greater than 6 cm and resulted in 7.87 cm in 2 years according to our case observation. Pericardial effusion may develop after a dramatic increase of PAA diameter. The reason for pericardial effusion is not always dissection or rupture; the presence of pericardial effusion possibly stemmed from the impairment of lymphatic drainage because of pressure effect on lymphatic circulation. Progressive increase of dilatation may lead to cough, as in our case. PMID- 23344752 TI - Pulmonary vein aneurysm secondary to mitral regurgitation: rare and confusing lesion. AB - A 54-year-old woman was referred to our institution suffering from severe dyspnea and asthenia due to progressive heart failure. Multidetector computed tomography angiography revealed biatrial enlargement with an image of pulmonary vein aneurysm. She underwent valvuloplasty for mitral and tricuspid valves, ligation of left atrial appendage, and left atrial reduction plasty concomitant with minimaze procedure using radiofrequency ablation but no intervention for aneurysm. PMID- 23344753 TI - Simultaneous surgical correction of pectus excavatum and cardiac disease in two adults. AB - Thoracic reconstruction in patients with pectus excavatum with concomitant cardiac or aortic surgery poses a major clinical challenge. The report describes two cases of adult patients undergoing simultaneous surgical correction of cardiac disease and sternal deformity using one of two different techniques: a sterno-turnover method preserving the rectus muscle or a sternal elevation method with A-O plates. PMID- 23344754 TI - Late consequences of traumatic rupture of the diaphragm. AB - A 54-year-old man was admitted to our clinic due to elevated gamma glutamyltransferase, without any clinical symptoms. About 25 years ago, he had undergone blunt abdominal and thoracic trauma during an accident. No diagnostic measures or therapy had been performed at that time. Serum bilirubin was normal, but the values for alanine transaminase, aspartate transaminase, and alkaline phosphatase were slightly above the reference range. Sonography of the abdomen revealed dilated intrahepatic bile ducts up to 3 mm in diameter and steatosis of the liver grade I. CT scan and MRI of the thorax and abdomen showed a giant hiatal hernia with transposition of upper abdominal organs into the chest. As the patient presented clinically completely asymptomatic, without dyspnea, dysfunction of phonation or ingestion, we decided a conservative treatment with Ursodesoxycholic acid. The liver values resolved with this regimen gradually. At follow-up examination 1 year later, they had normalized. Spirometry showed a reduced lung capacity (3.44 L; 64.4% of the desired value) and a reduced FEV1 (forced expiratory volume in one second) of 2.84 L (70.2% of the desired value). Further diagnostics revealed normal otorhinolaryngological and phoniatric findings including stroboscopy of the vocal folds and voice range profile. PMID- 23344755 TI - Partial inferior sternotomy and deep hypothermic circulatory arrest for rescue of a failed TAVI case: what does constitute 'inoperable'? AB - A 65-year-old male patient was considered inoperable by conventional means for a previous triple coronary artery bypass grafting with a patent in situ right internal mammary artery graft to the left anterior descending artery crossing the thorax at midline directly behind the sternum. Transcatheter aortic valve implantation failed due to loss of the prosthetic device in the left ventricular outflow tract. Mandatory conversion was accomplished by an inferior partial T shape sternotomy and extracorporeal circulation draining from the right atrium and feeding into the right femoral artery. A conventional 27-mm aortic valve bioprosthesis was successfully implanted during deep hypothermic circulatory arrest. The patient recovered normally exhibiting no neurological or cardiocirculatory complications. PMID- 23344756 TI - Anomalous pulmonary vein drainage is not a contraindication for VATS lobectomy. AB - This is a case report on a 26-year-old woman with metastatic mandibular osteosarcoma to the lung. A video-assisted thorascopic surgery (VATS) completion left upper lobe lobectomy was attempted, but was converted to a thoracotomy when anomalous pulmonary vein drainage (APVD) was identified. There were no other anomalies found and the lobectomy was completed as planned. To our knowledge, this is the first reported case of an attempted VATS lobectomy for patients with APVD. This case demonstrates that APVD tends not to be associated with any other anatomic abnormalities in the lung and should not be a contraindication for VATS lobectomy. PMID- 23344757 TI - Surgery for fulminant prosthetic valve endocarditis after transapical transcatheter aortic valve-in-valve implantation. AB - We report the clinical course of a patient with a history of transapical aortic "valve-in-valve" transcatheter aortic valve implantation (TAVI), actually suffering from prosthetic valve endocarditis. The patient now underwent cardiac surgery as a salvage procedure. The procedure itself was uneventful, but the patient died several days postoperative due to persisting sepsis. The present case raises the question, how to deal with high-risk patients, once considered unsuitable for cardiac surgery in presence of prosthetic valve infection? Up to now, there exists only insufficient knowledge about incidence, clinical course, and effectiveness of treatment strategies for prosthetic valve endocarditis after TAVI. A review of the available literature is given. PMID- 23344758 TI - Severe bacterial superinfection based on influenza A (H1N1) pneumonia in a heart lung transplant recipient. AB - A 47-year-old heart-lung transplant recipient presented to our outpatient transplant clinic with respiratory infection. Her nose and throat swabs for influenza A (H1N1) infection were negative. Broncheoalveolar lavage showed a positive result for H1N1 infection. Antiviral therapy was initiated. Because of superinfection with Pseudomonas aeruginosa and Aspergillus terreus, her clinical condition worsened. The clinical condition of the patient improved with antibiotic and antifungal treatment. Negative nose and throat swab results cannot rule out H1N1 infection safely. We therefore advocate to routinely perform broncheoalveolar lavage. PMID- 23344760 TI - Morcellation in semi-exteriorized pouch in thoracoscopic surgery. AB - Extraction of small specimens such as excised blebs through trocar site is a simple procedure. However, working thoracotomy is mandatory for removal of large solid intrathoracic tumors. We have used an instrument to morcellate a specimen in semi-exteriorized pouch during video-assisted thoracoscopic surgery. Morcellation has provided the solution for removing large solid benign tumors without a working thoracotomy. PMID- 23344759 TI - Successful management of a massive residual space empyema using intrathoracic vacuum-assisted instillation. AB - There is no universally accepted single line treatment for residual space empyema. Recently, the vacuum-assisted instillation therapy was applied for wounds in different anatomical positions. However, it has not yet been applied as an intrathoracic management. Herein, we describe the first experience of intrathoracic vacuum-assisted instillation therapy for residual space empyema after extended thoracic surgery. It appears to be an attractive treatment option for patients with large contaminated pleural cavities in preparation for reconstructive surgery. PMID- 23344761 TI - Bilateral cerebral perfusion via right axillary artery cannulation alone in aortic arch surgery. AB - Several methods have been proposed to avoid cerebral damage during aortic arch surgery. Antegrade, bilateral, selective cerebral perfusion is probably the most efficient one, although it has some drawbacks, such as air or particulate embolism risk, limitation in operative field visibility, and interactions with surgical maneuvers. We describe a surgical technique that provides bilateral antegrade perfusion to the brain, via the right axillary artery, with no need of additional arterial lines or shunting devices. PMID- 23344762 TI - Continuing aspirin causes higher drainage even under full protection with antifibrinolytics. AB - BACKGROUND: The purpose of this study was to assess the impact of continuation of aspirin on bleeding complications following coronary artery bypass grafting (CABG) surgery operated by a single surgeon. METHODS: A total of 109 patients underwent isolated, primary, on-pump surgery performed over a 17-month period. These patients were divided into two groups: group 1 (n = 51) received aspirin (81 mg daily) to within 7 days of surgery and group 2 (n = 58) in which aspirin was discontinued > 7 days before surgery. All patients received antifibrinolytic agents. Both groups had identical preoperative characteristics. RESULTS: The aspirin group had significant more drainage and consumed more blood products than the nonaspirin group during the first 12 postoperative hours. However, both groups were similar in terms of: (1) re-exploration rate, (2) requirements for blood transfusion, (3) drop in hemoglobin levels and platelet counts, and (4) length of intensive care unit and hospital stay. CONCLUSION: Continuing aspirin before CABG is associated with increased blood loss even when used in small doses and under full cover of antifibrinolytic agents. However, this blood loss is not harmful and does not negatively affect the patient's clinical progress. PMID- 23344763 TI - Hemodynamic effects of left upper extremity arteriovenous fistula on ipsilateral internal mammary coronary artery bypass graft. AB - OBJECTIVE: Arteriovenous fistula (AVF) in patients undergoing hemodialysis (HD) may cause coronary left internal mammary artery (IMA) steal. This phenomenon was demonstrated by few prospective studies with limited number of patients and case reports. We aimed to demonstrate with a relatively larger patient population that the AVF may cause ipsilateral IMA steal. METHODS: We included 22 prospective patients undergoing HD who had left IMA to left anterior descending artery graft and left upper limb AVF. Right IMA was taken as control. Flows were assessed by using color Doppler ultrasonography. RESULTS: The mean age was 57.8 +/- 9 years. Statistically nonsignificant increases in AVF flow and decreases in left IMA flow were observed during HD compared with pre-HD. Moreover, fistula localization did not affect median left IMA flows (for peak systolic velocity [PSV] 43.7 versus 70 cm/s, respectively; p = 0.7, and for end diastolic velocity [EDV] 3.4 versus 6.5 cm/s, respectively; p = 0.7). We have not detected significant difference in left IMA flows during HD (median values of PSV 58.4 versus 68.4 cm/s, respectively; p = 0.1, and EDV 6.4 versus 4.4 cm/s, respectively; p = 0.08). Only three patients experienced dialysis-induced reduction of ipsilateral IMA flow that was accompanied by evidence of hypokinesia of the anterior left ventricular wall without clinical angina. CONCLUSIONS: Hemodynamically affected left IMA flow by ipsilateral upper extremity AVF may cause steal phenomenon. Hemodynamic differences between left and right IMAs in patients undergoing HD via left wrist and brachial fistulae are limited. PMID- 23344764 TI - Coagulation disorders do not increase the risk for bleeding during percutaneous dilatational tracheotomy. AB - BACKGROUND: Percutaneous dilatational tracheotomy (PDT) is a common procedure. Coagulation disorders represent a relative contraindication for PDT and, therefore, normalization of hemostasis parameters is recommended. Especially patients undergoing cardiac surgery after valve replacement and with any kind of assist device need to require an adequate anticoagulation. This study investigated the impact of impaired hemostasis as a risk factor for bleeding complications retrospectively. METHODS: Patients who underwent PDT (November 2007 to November 2010) were stratified into a high-risk (HR) and low-risk (LR) group in regard to bleeding complications. The following determining factors activated partial thromboplastin time (aPTT > 50 seconds, prothrombin time (PT < 50%), international normalized ratio (INR > 1.4), and platelet count (< 50,000/uL) were assessed. RESULTS: A total of 213 patients underwent PDT (HR = 5/85; LR = 8/128). There was no difference in demographics or intraoperative data. Patients of both groups showed mild bleeding without the need for surgical intervention or transfusion (p = 0.957). There were no severe bleeding nor other procedure related complications. CONCLUSION: Percutaneous tracheotomy is a safe and feasible procedure in patients with coagulation disorders. Therefore, discontinuation of anticoagulation treatment or normalization of hemostasis prior to the procedure is not necessary. PMID- 23344765 TI - Perioperative and long-term development of anxiety and depression in CABG patients. AB - BACKGROUND: The high incidence of symptomatic anxiety and depression in coronary artery bypass graft (CABG) patients may lead to impaired quality of life and increased morbidity and mortality. This prospective longitudinal study on CABG patients should provide data for future preoperative and postoperative psychotherapeutic interventions. METHODS: From 2009 to 2010, 135 consecutive patients who were able and prepared were consulted by one interviewer immediately before 1 week (early) and 6 months (late) after surgery to complete the "Hospital Anxiety and Depression Scale" questionnaire. RESULTS: Compared with the standard population, anxiety scores (AS) were preoperatively elevated in 39.3% of the patients. Early and late after surgery, AS had decreased to 34.4% (not significant [n.s.]) and 28.9% (p < 0.01). Before surgery, depression scores (DS) were elevated in 20.7%. Early and late after surgery, DS further increased to 24.0% (n.s.) and 28.0% (n.s.).Preoperative elevated DS appeared to correlate with increased complications. Mortality was not associated with elevated AS or DS. Both scores were not affected by on- or off-pump surgery. CONCLUSION: Remarkably high AS and elevated DS late postoperatively require psychotherapeutic support even after seemingly successful CABG. PMID- 23344766 TI - Hypothermic circulatory arrest using antegrade cerebral perfusion is safe for elective aortic arch surgery. AB - BACKGROUND: We hypothesized that hypothermic circulatory arrest (HCA) can be performed with a low operative risk and does not add to the morbidity in elective procedures. METHODS: A total of 178 patients with a mean (+/- SD) age of 62 (+/- 10) years underwent HCA for elective aortic surgery from April 2008 to September 2011. Pre- and postoperative clinical data were collected prospectively. RESULTS: Hemiarch replacement was performed in 97% patients. Mean logistic Euroscore I was 17% (+/- 15). HCA was performed at 26 degrees C bilateral tympanic temperature. Mean HCA duration was 17 (+/-) min. Mean cross-clamp time was 106 (+/- 39) min. Overall 30-day mortality was 2% and stroke occurred in 4% of patients. Overall 6 month survival was 96%. Cox regression analysis for 6-month survival revealed four variables with significant influence: the logistic Euroscore I (p = 0.008), age (p = 0.04), cross-clamp time (p = 0.008), and reoperation for bleeding complications (p = 0.04). CONCLUSIONS: HCA with open distal anastomosis for elective aortic repair can be performed with low operative mortality, even in the elderly, and seems not to add to the morbidity of the procedure. PMID- 23344767 TI - Echocardiography alone allows the determination of heart failure stages in rats with pressure overload. AB - BACKGROUND: There is currently no standard for the assessment of contractile function in animals. We aimed to determine whether transthoracic echocardiography in rats with chronic pressure overload allows determining the stage of hypertrophy and heart failure (HF). METHODS: Pressure overload was created by placement of a metal clip around the thoracic aorta at a weight of 40 to 50 g. After 1, 2, 6, 10, and 20 weeks, we performed echocardiography according to the American Heart Association guidelines (n = 26, four to six rats for each time point). We also obtained heart, lung, and body weights and regularly evaluated clinical signs of HF. RESULTS: : Pressure overload caused significant hypertrophy within 1 week. Contractile function was normal until 6 weeks when diastolic dysfunction appeared. After 10 weeks of pressure overload, systolic function decreased. At 20 weeks, hearts were dilated and cardiac index was decreased. These findings correlated with increased lung-to-body weight ratio after 6 weeks and clinical signs of HF after 20 weeks. CONCLUSION: Echocardiography alone allows the reproducible determination of HF stages after aortic constriction in rats. PMID- 23344768 TI - Reversed C sternotomy versus conventional sternotomy in cardiac surgery. AB - BACKGROUND: In this study, cardiac surgery with minimally invasive reversed C sternotomy was compared with conventional sternotomy in patients undergoing valve replacement or septal defect repair. METHODS: In this prospective randomized study, 35 patients were assigned into one of two groups for elective cardiac surgery under general anesthesia: Group A (reversed C sternotomy group) and Group B (conventional sternotomy group). Intraoperative variables, intubation time, postoperative drainage volume, pulmonary function tests, sleep quality and quality of life, and requirement for blood transfusion were compared. RESULTS: A significant difference between the two groups was found in blood transfusion requirement, extubation time, and drainage volume. Forced expiratory volume in one second and functional vital capacity were significantly lower in Group B than in Group A at postoperative Month 1. Total sleep component score of Pittsburg Sleep Quality Index in Group B patients was significantly worse at postoperative Month 1. Postoperative assessment of quality of life (physical and mental) also showed a significant difference between the two groups. CONCLUSION: These preliminary findings suggest that creating an access point without compromising the integrity of the sternum seems to be an advantageous and appropriate technique for suitable patients undergoing cardiac surgery. PMID- 23344769 TI - Effects of delivering recombinant tissue plasminogen activator on a new infusion system during endovascular intervention in patients with lower limb ischemia. AB - BACKGROUND: To evaluate the feasibility and effects of recombinant tissue plasminogen activator (rt-PA) delivered by a new infusion system during endovascular intervention therapy in patients who had limb ischemia within 6 months. METHODS: From November 2006 to December 2010, 103 consecutive patients were randomly distributed in two groups. 10 mg (group A) and 5 mg (group B) bolus of rt-PA was respectively injected into the proximal occlusive lesion by a new infusion system. Subsequently, additional rt-PA of 10 mg (group A) and 5 mg (group B) was injected into the thrombotic occlusion, respectively. Significant underlying lesions were treated by endovascular intervention or surgery. Rates of major and minor complication, procedural success, and clinical success were evaluated statistically. RESULTS: Rates of complete lysis and partial lysis success were 12.6% (13 of 103) and 87.4% (90 of 103), respectively. To treat underlying lesions, 84.5% (84 of 103) patients received balloon angioplasty/stent implantation and 4.9% (5 of 103) patients received surgical correction. After final definitive treatment, procedural success rate was up to 99% (102 of 103) and clinical success rate was 100%. Comorbidity conditions and patient characteristics did not statistically influence the rates of success and complication. During the follow-up period of 30-day, 6-, 12- month, there was no statistical difference in the amputation-free survival rates between these two groups. CONCLUSION: It is safe and effective to treat lower limb ischemia by combining adjunctive endovascular intervention with bolus of rt-PA (10 to 20 mg) given by a new infusion system. But long-term effects of thrombolysoangioplasty therapy in treating lower limb ischemia must be confirmed by large-scale population studies before routine use. PMID- 23344770 TI - Feasibility of systematic transesophageal endoscopic mediastinoscopy. AB - Thoracoscopy and mediastinoscopy are common procedures with painful incisions and prominent scars. Transesophageal endoscopic mediastinoscopy could reduce pain, improve cosmesis, and provide better access to the posterior mediastinal compartment, especially in patients with a complex mediastinum because of previous mediastinoscopy or with tracheostoma. We describe a new way to access the mediastinum through a natural orifice that provides excellent visualization of mediastinal structures. PMID- 23344771 TI - Hook wire localization of pulmonary pure ground-glass opacities for video assisted thoracoscopic surgery. AB - OBJECTIVE: We compared the success of preoperative hook wire localization of pulmonary pure ground-glass opacities (pGGOs) with intraoperative palpation during video-assisted thoracoscopic (VAT) surgery and examined the safety of the preoperative hook wire method. METHODS: A total of 39 patients with 41 pulmonary pGGOs less than 2 cm in diameter underwent preoperative hook wire localization guided by DSA Innova CT before VAT lesion resection. The relationship between localization, as determined by finger palpation or hook wire, and clinicopathological factors was analyzed retrospectively. Complications resulting from hook wire localization are summarized. RESULTS: Twelve lesions (29.3%) were successfully identified by palpation, whereas 39 (95.1%) were successfully identified by hook wire (p < 0.01). The hook wire was dislodged in three cases (7.3%). No correlation was found between the positive rate of finger palpation or hook wire localization and the size, depth, position, or pathological grade of the lesion. Following surgery, five patients (12.8%) had asymptomatic minimal pneumothoraces, two patients (5.2%) had minimal hemothorax, and one patient (2.6%) had serious chest pain. CONCLUSIONS: Preoperative localization of pulmonary pGGOs is necessary for VATS when the lesions are less than 2 cm in diameter. Preoperative hook wire localization is safe and more successful than palpation for localization of pGGOs. PMID- 23344772 TI - Predictive procedure for compensatory hyperhidrosis before sympathectomy: preliminary findings. AB - OBJECTIVE: Compensatory hyperhidrosis is one of the most common and serious adverse effects following sympathectomy. We performed a local anesthetic procedure that predicts the occurrence and severity of compensatory hyperhidrosis, and evaluated the feasibility, safety, and efficacy of the procedure. METHODS AND METHODS: From July 2009 to July 2010, 20 patients with severe primary palmar hyperhidrosis underwent predictive procedures. A sympathetic nerve block was obtained via thoracoscopic approach under local anesthesia. The patients were evaluated for compensatory hyperhidrosis 1 week after the procedure before deciding whether to proceed with sympathectomy. RESULTS: Of the 20 patients, 17 patients proceeded with sympathectomy and 3 refused the final procedure. Following sympathectomy, the occurrence and severity of compensatory hyperhidrosis in the remaining 17 patients were statistically analyzed with two tailed paired t test, and there is no significant difference between the predictive and final procedures (t = 1.69, df = 16, p > 0.1). CONCLUSION: Predictive procedure using local anesthesia to detect compensatory hyperhidrosis before sympathectomy may be useful for helping patients to decide whether to undergo the operation. PMID- 23344773 TI - Presurgical planning using a three-dimensional pulmonary model of the actual anatomy of patient with primary lung cancer. AB - OBJECTIVES: Video-assisted thoracoscopic surgery (VATS) for both lobectomy and segmentectomy has been used widely for early stage nonsmall cell lung cancer (NSCLC). The objective of this study was to investigate the clinical feasibility of surgical planning using patient's actual three-dimensional (3D) pulmonary model for the thoracoscopic surgical treatment of early stage NSCLC. METHODS: We examined 57 patients with stage IA NSCLC <= 2 cm in diameter. Based on patient's actual 3D pulmonary model created by using a homemade software program called CTTRY (Tokyo Women's Medical University, Tokyo, Japan), both the location of and extent of tumor invasion were assessed, and a suitable type of VATS lung resection for an individual was selected. RESULTS: By the 3D models, tumors in 47 patients were localized within one segment, and other tumors (10 patients, 18%) were involved in multiple segments. VATS lung resections consisted of a single segmentectomy were performed in 25 patients; upper division resections, 9; lingulectomy, 5; extended segmentectomy, 7; single subsegmentectomy, 6; and multiple subsegmentectomy, 5. All 57 patients underwent successful VATS lung resection without massive bleeding. CONCLUSION: Presurgical planning based on patient's actual 3D pulmonary model is useful for patients with stage IA NSCLC <= 2 cm in diameter and for selecting an appropriate VATS lung resection for an individual. PMID- 23344774 TI - 1913: Annus mirabilis of esophageal surgery. AB - Although Sir Ronald Belsey once called the year 1904 "annus mirabilis," it is actually the year 1913 that stands out as the true milestone in esophageal surgery. Within a year, Torek performed the first transpleural resection for cancer in the thoracic esophagus, Zaaijer successfully resected the distal esophagus through the transpleural route, Heller performed the first myotomy for achalasia, and it was also the year of Ach's pioneering transmediastinal esophagectomy. Previously, in 1912, after a series of animal experiments by Beck and Jianu, Roepke successfully used the greater curvature of the stomach as a presternal conduit. Other previous approaches included reconstruction with jejunum (Roux-1907), colon (Kelling-1911), and skin tube (Bircher-1907). Several technical advances made these operations possible, most of all were the giant leaps in the perioperative medicine. PMID- 23344775 TI - Elastofibroma dorsi: clinicopathological analysis of 71 cases. AB - INTRODUCTION: Elastofibroma dorsi (ELD) is a rare soft tissue benign tumor of the chest wall. So far, only a few large series have been reported in the English literature and, to the best of our knowledge, radiological assessment and clinical management remain without consensus. The aim of this study is to provide, on the basis of a single-institutional, homogeneous and large experience, ample evidences to support etiological and "clinical-usefulness grade" classification hypotheses. MATERIALS AND METHODS: We report observational information on 71 ELD cases and, on the basis of these, we discuss the clinical onset features, radiological and surgical characteristics, as well as pathological and immunohistochemical evidences. RESULTS: In the period between January 1994 and September 2009, 71 consecutive patients (23 male and 48 female; mean age: 60.2 years; standard deviation [SD] +/- 8.3 years) with ELD diagnosis were surgically treated at our institution. ELD was right sided in 34 patients (47.9%), left in 25 (35.2%), and bilateral in 12 (16.9%). In nine patients, ELD were diagnosed synchronously and three metachronously. Thirty-eight patients (53.5%) had no significant symptoms; 33 (46.5%) reported a clunking sensation or a localized scapular swelling during the shoulder movements. Sixty-six (93%) patients underwent surgical excision with radical intent while in five patients, a biopsy-only procedure was undertaken. Mean hospital stay was 3.0 days (SD +/- 1.2 days) with a morbidity of 10.6% (one case of major postoperative bleeding requested a surgical revision of the hemostasis). At the univariate analysis, the probability of occurrence of morbidity increases with tumor size. All operated patients are alive and well at follow-up with no sign of recurrence and complete resolution of the symptomatology. CONCLUSIONS: ELD is relatively uncommon, benign, and well controlled by radical surgery. PMID- 23344776 TI - Spectroscopy of BODIPY in solid phase: crystal and nanoparticles. AB - We compare the absorption and fluorescence spectra of single crystals and suspensions of nanoparticles with the prediction of the Frenkel theory. The single crystals of a novel synthesized fluorescent BODIPY derivative dye, adamantyl mesityl BODIPY (4,4-difluoro-3,5-di-(adamantyl)-8-mesityl-4-bora-3a,4a diaza-s-indacene), have been prepared. Their birefringence and dichroism have been studied. The X-ray crystallography shows a monoclinic crystal with all transition moments parallel to one common plane. The refractive indices along the two neutral axes have been measured for a wavelength from 530 to 700 nm, with a difference, Deltan equal to 0.11. The Frenkel exciton theory was used here to describe the coupling of the electronic excited states in the crystals. The coupling estimated by the dipolar approximation was compared with the excited state splitting calculated by TDDFT in dimers. A perfect crystal absorption spectrum is predicted. The spectral broadening that occurs at room temperature is also taken into account. The absorption spectrum of the monocrystal is reproduced without adjustable parameters. But we had to take into account the presence of optical leaks in our microspectrophotometer before comparing experiment and theory. The controlled size nanoparticles (NPs) produced by our 3D hydrodynamic focusing microfluidic system exhibit molecule like absorption. We could reproduce their absorption and fluorescence spectra assuming a strong disorder in the Frenkel model. We conclude that the nanoparticles are amorphous. PMID- 23344777 TI - Surface proteins of C6/36 cells involved in dengue virus 4 binding and entry. AB - Dengue virus (DENV) is the causative agent of the most important mosquito-borne viral disease, which is endemic to over 100 countries in tropical and subtropical areas of the world. It is transmitted to humans by Aedes mosquitoes. The first step in the viral infection of host cells is virion attachment to the plasma membrane, which is mediated by specific surface molecules. There are several molecules that participate in DENV infection of mosquitoes, but only a few have been identified. In this work, we co-purified 4 proteins from C6/36 cells using a recombinant DENV 4 E protein and identified them as 70 kDa Heat Shock and 70 kDa Heat Shock cognate proteins (HSP70/HSc70), Binding immunoglobulin protein (BiP), Thioredoxin/protein disulphide isomerase (PDI), and 44 kDa Endoplasmic reticulum resident protein (ERp44) via matrix-assisted laser desorption/ionisation time of flight (Maldi-ToF) analysis. Using immunofluorescence and flow cytometry assays, we observed re-localisation of HSP70/HSc70 and, to a lesser extent, BiP to the plasma membrane under stress conditions, such as during DENV infection. By performing binding and infection assays independently, we found that all 4 proteins participate in both processes, but to differing extents: HSP70/HSc70 is the most critical component, while ERp44 is less important. Viral infection was not inhibited when the cells were incubated with antibodies against all of the surface proteins after virus binding, which suggests that DENV entry to C6/36 cells is mediated by these proteins at the same step and not sequentially. PMID- 23344778 TI - Finding the missing millions - the impact of a locally enhanced service for COPD on current and projected rates of diagnosis: a population-based prevalence study using interrupted time series analysis. AB - BACKGROUND: Many patients with chronic obstructive pulmonary disease (COPD) are not identified until their condition is relatively advanced and there is a considerable gap between the modelled and diagnosed prevalence of the disease. We have previously shown that, in the first year after the introduction of a locally enhanced service (LES) for COPD in 2008, there was a significant step-up in the diagnosed prevalence. AIMS: To investigate whether this initial increase in prevalence was sustained, and the impact of this increase on future projected rates of COPD diagnosis. METHODS: Using data from 2005-2011, we compared the prevalence of diagnosed COPD in the LES Primary Care Trust (LES-PCT) before and after it was introduced. Data were compared with a neighbouring PCT, the London Strategic Health Authority, and England. The true prevalence of COPD was estimated based on data from the Health Survey for England. Trends were extrapolated to estimate the proportion of patients that would be diagnosed in 2017. RESULTS: The introduction of the LES was associated with a significant acceleration in the annual increase in diagnosed COPD (p<0.0001). By 2011 the prevalence was 1.17% in the LES-PCT compared with a predicted value of 0.91% (95% CI 0.86% to 0.95%) based on the pre-LES trend. There was no change in the rate of increase in COPD prevalence for the neighbouring PCT or for London as a whole. The LES-PCT would be expected to diagnose 55.6% of COPD patients by 2017 compared with only 27.3% without the LES, and only 33.3% would be diagnosed in the neighbouring PCT. CONCLUSIONS: These data suggest that, with appropriate incentives, it is possible to achieve a sustained improvement in COPD case finding in primary care and that such policies need to be implemented systematically. PMID- 23344779 TI - Exhaled nitric oxide measures allergy not symptoms in children with allergic rhinitis in primary care: a prospective cross-sectional and longitudinal cohort study. AB - BACKGROUND: Allergic rhinitis (AR) and asthma are both inflammatory diseases and are often associated. Relationships between fractional exhaled nitric oxide (FeNO) and asthma, atopy, and quality of life have been shown. AIMS: This study aimed to determine whether FeNO in children with AR (n=158) or combined AR and asthma (n=93) was associated with clinical symptoms, house dust mite (HDM) specific IgE, and rhinitis-specific quality of life, both cross-sectionally and longitudinally. METHODS: Children with AR aged 6-18 years (n=251) in primary care were assessed for FeNO, nasal symptom scores, asthma symptom scores, quality of life, and HDM-specific IgE at baseline and 2 years later. RESULTS: We found similarly elevated FeNO in children with only AR and in those with combined AR and asthma. No correlations were found between FeNO and nasal or asthma symptoms and rhinitis-related quality of life. Longitudinal correlations were strongest for HDM-specific IgE (r=0.91, p<0.0001). CONCLUSIONS: FeNO was similar in a selected group of children with AR with and without asthma in primary care and was unrelated to symptoms or quality of life in both groups. FeNO is unlikely to be a useful biomarker of the clinical severity of upper or lower airway disease in primary care. PMID- 23344780 TI - The quality of reporting of randomised controlled trials in asthma: systematic review protocol. PMID- 23344782 TI - Mood instability, mental illness and suicidal ideas: results from a household survey. AB - PURPOSE: There is weak and inconsistent evidence that mood instability (MI) is associated with depression, post traumatic stress disorder (PTSD) and suicidality although the basis of this is unclear. Our objectives were first to test whether there is an association between depression and PTSD, and MI and secondly whether MI exerts an independent effect on suicidal thinking over and above that explained by common mental disorders. METHODS: We used data from the Adult Psychiatric Morbidity Survey 2007 (N = 7,131). Chi-square tests were used to examine associations between depression and PTSD, and MI, followed by regression modelling to examine associations between MI and depression, and with PTSD. Multiple logistic regression analyses were used to assess the independent effect of MI on suicidal thinking, after adjustment for demographic factors and the effects of common mental disorder diagnoses. RESULTS: There are high rates of MI in depression and PTSD and the presence of MI increases the odds of depression by 10.66 [95% confidence interval (CI) 7.51-15.13] and PTSD by 8.69 (95% CI 5.90 12.79), respectively, after adjusting for other factors. Mood instability independently explained suicidal thinking, multiplying the odds by nearly five (odds ratio 4.82; 95% CI 3.39-6.85), and was individually by some way the most important single factor in explaining suicidal thoughts. CONCLUSIONS: MI is strongly associated with depression and PTSD. In people with common mental disorders MI is clinically significant as it acts as an additional factor exacerbating the risk of suicidal thinking. It is important to enquire about MI as part of clinical assessment and treatment studies are required. PMID- 23344783 TI - Parenting and risk for mood, anxiety and substance use disorders: a study in population-based male twins. AB - BACKGROUND: Previous studies consistently identified a relationship between parenting behavior and psychopathology. In this study, we extended prior analyses performed in female twins to a large sample of twins from male-male pairs. METHODS: We used interview data on 2,609 adult male twins from a population-based twin registry. We examined the association between three retrospectively reported parenting dimensions (coldness, protectiveness, and authoritarianism) and lifetime history of seven common psychiatric and substance use disorders. Using univariate structural equation modeling, we also examined the influence of the genetic and environmental factors on parenting. RESULTS: Examined individually, coldness was consistently associated with risk for a broad range of adult psychopathology. Averaged odds of psychiatric disorders associated with parenting were increased between 26 and 36 %. When the three parenting dimensions were examined together, coldness remained significant for major depression, phobia, and generalized anxiety disorder. Controlling for other disorders, the associations between the parenting dimensions and psychopathology were non specific. Twin fitting model demonstrated that modest heritability accounted for parenting, whereas most variance resulted from the non-shared environment. CONCLUSIONS: Based on our current and prior findings, there is broad similarity in the impact of parenting on adult psychopathology between men and women. PMID- 23344784 TI - 2-Deoxy-2-[18F]fluoro-D-glucose positron emission tomography demonstrates target inhibition with the potential to predict anti-tumour activity following treatment with the AKT inhibitor AZD5363. AB - PURPOSE: The phosphatidyl inositol 3 kinase, AKT and mammalian target of rapamycin are frequently deregulated in human cancer and are among one of the most promising targets for cancer therapy. AZD5363 (AstraZeneca) is an AKT inhibitor in phase 1 clinical trials. Given its utility in assessing glucose metabolism, we investigated the role of 2-Deoxy-2-[18F]fluoro-D-glucose (18F-FDG) positron emission tomography (PET) as a biomarker to demonstrate target inhibition and its potential to predict and demonstrate the anti-tumour activity of AZD5363. METHODS: 18F-FDG PETscans were performed in nude mice in a number of xenograft models (U87-MG glioblastoma, BT474C breast carcinoma and Calu-6 lung). Mice were fasted prior to imaging, and either static or dynamic 18F-FDG PET imaging was performed. RESULTS: We have shown that 18F-FDG uptake in tumour xenografts was reduced by 39% reduction compared to vehicle after a single dose of AZD5363, demonstrating activation of the AKT pathway after only 4 h of dosing. Multiple doses of AZD5363 showed an anti-tumour volume effect and a reduction in 18F-FDG uptake (28% reduction compared to vehicle), highlighting the potential of 18F-FDG PET as an efficacy biomarker. Furthermore, the degree of inhibition of 18F-FDG uptake corresponded with the sensitivity of the tumour model to AZD5363. The use of dynamic 18F-FDG PET and a two-compartmental analysis identified the mechanism of this change to be due to a change in cellular uptake of 18F-FDG following administration of AZD5363. CONCLUSIONS: We conclude that 18F-FDG PET is a promising pharmacodynamic biomarker of AKT pathway inhibition, with potential to predict and demonstrate anti-tumour activity. It is a biomarker that may stop ineffective drug schedules, helping to make early stop decisions and identify responding subsets of patients, resulting in improved clinical decision making both during drug development and patient management. PMID- 23344781 TI - Neutrophils, IL-1beta, and gout: is there a link? AB - Gout is a prototype crystal-induced inflammatory disorder, characterized by neutrophil infiltration into inflamed joints. The identification of the role of NLRP3 inflammasome in the recognition of monosodium urate crystals and the subsequent release of IL-1beta was a milestone in the elucidation of the pathogenesis of this disorder. IL-1beta signaling is considered nowadays as the initiatory event that induces gouty inflammation and promotes the recruitment of vast numbers of neutrophils at the sites of inflammation. Crystal-induced neutrophil activation results in apoptosis inhibition, degranulation, superoxide production, cytokine release and, as recently described, formation of neutrophil extracellular traps, further amplifying the inflammatory process. Finally, neutrophil apoptosis and uptake of apoptotic material by macrophages drive the resolution of acute inflammation. In this review, we discuss the recent experimental data regarding the crosstalk between IL-1beta and neutrophils in the pathogenesis of acute gout. PMID- 23344786 TI - Gallium(III) complexes with 2-acetylpyridine-derived thiosemicarbazones: antimicrobial and cytotoxic effects and investigation on the interactions with tubulin. AB - Complexes [Ga(2Ac4pFPh)(2)]NO(3) (1), [Ga(2Ac4pClPh)(2)]NO(3) (2), [Ga(2Ac4pIPh)(2)]NO(3) (3), [Ga(2Ac4pNO(2)Ph)(2)]NO(3).3H(2)O (4) and [Ga(2Ac4pT)(2)]NO(3) (5) were obtained with 2-acetylpyridine N(4)-para fluorophenyl-(H2Ac4pFPh), 2-acetylpyridine N(4)-para-chlorophenyl-(H2Ac4pClPh), 2 acetylpyridine N(4)-para-iodophenyl-(H2Ac4pIPh), 2-acetylpyridine N(4)-para nitrophenyl-(H2Ac4pNO(2)Ph) and 2-acetylpyridine N(4)-para-tolyl-(H2Ac4pT) thiosemicarbazone. 1-5 presented antimicrobial and cytotoxic properties. Coordination to gallium(III) proved to be an effective strategy for activity improvement against Pseudomonas aeruginosa and Candida albicans. The complexes were highly cytotoxic against malignant glioblastoma and breast cancer cells at nanomolar concentrations. The compounds induced morphological changes characteristic of apoptotic death in tumor cells and showed no toxicity against erythrocytes. 2 partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization, but this does not appear to be the main mechanism of cytotoxic activity. PMID- 23344787 TI - Glioma infiltration of the corpus callosum: early signs detected by DTI. AB - The most frequent primary brain tumors, anaplastic astrocytomas (AA) and glioblastomas (GBM): tend to invasion of the surrounding brain. Histopathological studies found malignant cells in macroscopically unsuspicious brain parenchyma remote from the primary tumor, even affecting the contralateral hemisphere. In early stages, diffuse interneural infiltration with changes of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) is suspected. The purpose of this study was to investigate the value of DTI as a possible instrument of depicting evidence of tumor invasion into the corpus callosum (CC). Preoperatively, 31 patients with high-grade brain tumors (8 AA and 23 GBM) were examined by MRI at 3 T, applying a high-resolution diffusion tensor imaging (DTI) sequence. ADC- and FA-values were analyzed in the tumor-associated area of the CC as identified by fiber tracking, and were compared to matched healthy controls. In (MR-)morphologically normal appearing CC the ADC values were elevated in the tumor patients (n = 22; 0.978 * 10(-3) mm2/s) compared to matched controls (0.917 * 10(-3) mm2/s, p < 0.05), and the corresponding relative FA was reduced (rFA: 88 %, p < 0.01). The effect was pronounced in case of affection of the CC visible on MRI (n = 9; 0.978 * 10(-3) mm2/s, p < 0.05; rFA: 72 %, p < 0.01). Changes in diffusivity and anisotropy in the CC can be interpreted as an indicator of tumor spread into the contralateral hemisphere not visible on conventional MRI. PMID- 23344788 TI - Pre- and post-contrast three-dimensional double inversion-recovery MRI in human glioblastoma. AB - Fluid attenuated inversion recovery (FLAIR) MRI sequences have become an indispensible tool for defining the malignant boundary in patients with brain tumors by nulling the signal contribution from cerebrospinal fluid allowing both regions of edema and regions of non-enhancing, infiltrating tumor to become hyperintense on resulting images. In the current study we examined the utility of a three-dimensional double inversion recovery (DIR) sequence that additionally nulls the MR signal associated with white matter, implemented either pre-contrast or post-contrast, in order to determine whether this sequence allows for better differentiation between tumor and normal brain tissue. T1- and T2-weighted, FLAIR, dynamic susceptibility contrast (DSC)-MRI estimates of cerebral blood volume (rCBV), contrast-enhanced T1-weighted images (T1+C), and DIR data (pre- or post-contrast) were acquired in 22 patients with glioblastoma. Contrast-to-noise (CNR) and tumor volumes were compared between DIR and FLAIR sequences. Line profiles across regions of tumor were generated to evaluate similarities between image contrasts. Additionally, voxel-wise associations between DIR and other sequences were examined. Results suggested post-contrast DIR images were hyperintense (bright) in regions spatially similar those having FLAIR hyperintensity and hypointense (dark) in regions with contrast-enhancement or elevated rCBV due to the high sensitivity of 3D turbo spin echo sequences to susceptibility differences between different tissues. DIR tumor volumes were statistically smaller than tumor volumes as defined by FLAIR (Paired t test, P = 0.0084), averaging a difference of approximately 14 mL or 24 %. DIR images had approximately 1.5* higher lesion CNR compared with FLAIR images (Paired t test, P = 0.0048). Line profiles across tumor regions and scatter plots of voxel-wise coherence between different contrasts confirmed a positive correlation between DIR and FLAIR signal intensity and a negative correlation between DIR and both post-contrast T1-weighted image signal intensity and rCBV. Additional discrepancies between FLAIR and DIR abnormal regions were also observed, together suggesting DIR may provide additional information beyond that of FLAIR. PMID- 23344789 TI - Discriminating radiation necrosis from tumor progression in gliomas: a systematic review what is the best imaging modality? AB - Differentiating post radiation necrosis from progression of glioma and pseudoprogression poses a diagnostic conundrum for many clinicians. As radiation therapy and temozolomide chemotherapy have become the mainstay of treatment for higher-grade gliomas, radiation necrosis and post treatment changes such as pseudoprogression have become a more relevant clinical problem for neurosurgeons and neurooncologists. Due to their radiological similarity to tumor progression, accurate recognition of these findings remains paramount given their vastly different treatment regimens and prognoses. However, no consensus has been reached on the optimal technique to discriminate between these two lesions. In order to clarify the types of imaging modalities for recurrent enhancing lesions, we conducted a systematic review of case reports, case series, and prospective studies to increase our current understanding of the imaging options for these common lesions and their efficacy. In particular, we were interested in distinguishing radiation necrosis from true tumor progression. A PubMed search was performed to include all relevant studies where the imaging was used to differentiate between radiation necrosis and recurrent gliomas with post radiation enhancing lesions. After screening for certain parameters in our study, seventeen articles with 435 patients were included in our analysis including 10 retrospective and 7 prospective studies. The average time from the end of radiation therapy to the onset of a recurrent enhancing lesion was 13.2 months. The most sensitive and specific imaging modality was SPECT with a sensitivity of 87.6 % and specificity of 97.8 %. Based on our review, we conclude that certain imaging modalities may be preferred over other less sensitive/specific techniques. Overall, tests such as SPECT may be preferable in differentiating TP (tumor progression) from RN (radiation necrosis) due to its high specificity, while nonspecific imaging such as conventional MRI is not ideal. PMID- 23344791 TI - A sensitivity analysis of the modified chi-square ratio statistic for equivalence testing of aerodynamic particle size distribution. AB - Demonstration of equivalence in aerodynamic particle size distribution (APSD) is one key component for establishing bioequivalence of orally inhaled drug products. We previously proposed a modified version of the Chi-square ratio statistic (mCSRS) for APSD equivalence testing and demonstrated that the median of the distribution of the mCSRS (MmCSRS) is a robust metric when test (T) and reference (R) cascade impactor (CI) profiles are identical. Here, we systematically evaluate the behavior of the MmCSRS when T and R CI profiles differ from each other in their mean deposition and variability on a single and multiple sites. All CI profiles were generated by Monte-Carlo simulations based upon modified actual CI data. Twenty thousand sets of 30 T and 30 R CI profiles were simulated for each scenario, and the behavior of the MmCSRS was correlated to metrics that characterize the difference between T and R product in mean deposition and variability. The two key findings were, first, that the MmCSRS is more sensitive to difference between T and R CI profiles on high deposition sites, and second, that a cut-off value for APSD equivalence testing based on the MmCSRS needs to be scaled on the variability of the R product. The former is considered as beneficial for equivalence testing of CI profiles as it decreases the likelihood of failing identical CI profiles by chance, in part, due to increasing analytical variability associated with lower deposition sites. The latter is expected to be important for consistently being able to discriminate equivalent from inequivalent CI profiles. PMID- 23344790 TI - A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam. AB - The use of physiologically based pharmacokinetic (PBPK) models in the field of pediatric drug development has garnered much interest of late due to a recent Food and Drug Administration recommendation. The purpose of this study is to illustrate the developmental processes involved in creation of a pediatric PBPK model incorporating existing adult drug data. Lorazepam, a benzodiazepine utilized in both adults and children, was used as an example. A population-PBPK model was developed in PK-Sim v4.2(r) and scaled to account for age-related changes in size and composition of tissue compartments, protein binding, and growth/maturation of elimination processes. Dose (milligrams per kilogram) requirements for children aged 0-18 years were calculated based on simulations that achieved targeted exposures based on adult references. Predictive accuracy of the PBPK model for producing comparable plasma concentrations among 63 pediatric subjects was assessed using average-fold error (AFE). Estimates of clearance (CL) and volume of distribution (V(ss)) were compared with observed values for a subset of 15 children using fold error (FE). Pediatric dose requirements in young children (1-3 years) exceeded adult levels on a linear weight-adjusted (milligrams per kilogram) basis. AFE values for model-derived concentration estimates were within 1.5- and 2-fold deviation from observed values for 73% and 92% of patients, respectively. For CL, 60% and 80% of predictions were within 1.5 and 2 FE, respectively. Comparatively, predictions of V(ss) were more accurate with 80% and 100% of estimates within 1.5 and 2 FE, respectively. Using the presented workflow, the developed pediatric model estimated lorazepam pharmacokinetics in children as a function of age. PMID- 23344792 TI - The interaction of fatty acid amide hydrolase (FAAH) inhibitors with an anandamide carrier protein using (19)F-NMR. AB - It has been reported that the endocannabinoid anandamide (AEA) binds to a class of fatty acid-binding proteins and serum albumin which can serve as carrier proteins and potentiate the cellular uptake of AEA and its intracellular translocation. Here, we employed (19)F nuclear magnetic resonance spectroscopy to study the interactions of serum albumin with two inhibitors of fatty acid amide hydrolase (FAAH), the enzyme involved in the deactivation of anandamide. We found that, for both inhibitors AM5206 and AM5207, the primary binding site on serum albumin is drug site 1 located at subdomain IIA. Neither inhibitor binds to drug site 2. While AM5207 binds exclusively to drug site 1, AM5206 also interacts with other fatty acid-binding sites on serum albumin. Additionally, AM5206 has an affinity for serum albumin approximately one order of magnitude higher than that of AM5207. The data suggest that interactions of FAAH inhibitors with albumin may provide added advantages for their ability to modulate endocannabinoid levels for a range of applications including analgesia, antiemesis, and neuroprotection. PMID- 23344794 TI - Educational differences in completed fertility: a behavioral genetic study of Finnish male and female twins. AB - Despite the large body of research on educational differences in fertility, how genetic and environmental influences may contribute to educational differences in completed fertility is not well understood. This study examines the association between educational level and completed fertility in a sample of Finnish male and female twins born between 1950 and 1957 with register-based fertility follow-up until 2009. The results show that poorly educated men and highly educated women are least likely to have any children and have lower completed fertility in general. Behavioral genetics analysis suggests that the association between education and having any children in both sexes is influenced by factors shared by co-twins and that these factors are genetic rather than common environmental. No evidence of a causal pathway between education and having any children independent of these shared influences is found. These findings suggest that familial factors may play a role in the process through which educational differences in completed fertility are formed. PMID- 23344795 TI - Educational homogamy and gender-specific earnings: Sweden, 1990-2009. AB - Several studies have shown strong educational homogamy in most Western societies, although the trends over time differ across countries. In this article, we study the connection between educational assortative mating and gender-specific earnings in a sample containing the entire Swedish population born 1960-1974; we follow this sample from 1990 to 2009. Our empirical strategy exploits a longitudinal design, using distributed fixed-effects models capturing the impact of partner education on postmarital earnings, relating it to the income development before union formation. We find that being partnered with someone with more education (hypergamy) is associated with higher earnings, while partnering someone with less education (hypogamy) is associated with lower earnings. However, most of these differences in earnings emerge prior to the time of marriage, implying that the effect is explained by marital selection processes rather than by partner education affecting earnings. The exception is hypogamy among the highly educated, for which there are strong indications that in comparison with homogamy and hypergamy, earnings grow slower after union formation. PMID- 23344793 TI - Drug discovery and regulatory considerations for improving in silico and in vitro predictions that use Caco-2 as a surrogate for human intestinal permeability measurements. AB - There is a growing need for highly accurate in silico and in vitro predictive models to facilitate drug discovery and development. Results from in vitro permeation studies across the Caco-2 cell monolayer are commonly used for drug permeability screening in industry and are also accepted as a surrogate for human intestinal permeability measurements by the US FDA to support new drug applications. Countless studies carried out in this cell line with published permeability measurements have enabled the development of many in silico prediction models. We identify several common cases that illustrate how using Caco-2 permeability measurements in these in silico and in vitro predictive models will not correlate with human intestinal permeability and will further lead to inaccuracies in these models. We provide guidelines and recommendations for improving these models to more accurately predict clinically relevant information, thereby enhancing the drug discovery, development, and regulatory approval processes. PMID- 23344796 TI - Organic anion transporter 3 interacts selectively with lipophilic beta-lactam antibiotics. AB - Transporters are major determinants of the disposition of xenobiotics and endogenous chemicals in the body. Organic anion transporter 3 (Oat3) functions in the kidney and brain to remove metabolic waste, toxins, and drugs, and thus transports diverse chemicals. Some beta-lactam antibiotics interact with Oat3, and penicillin G exhibits a strong dependence on Oat3 for renal elimination. However, over 80 beta-lactams exist, and many have not been assessed for an interaction with Oat3. Moreover, beta-lactams continue to receive U.S. Food and Drug Administration approval. This study identified new beta-lactam-Oat3 interactions, provided a head-to-head comparison with Oat1, and characterized the physicochemical determinants of affinity for Oat3. Cells expressing mouse Oat3 (mOat3) and Oat1 (mOat1), and human OAT3 (hOAT3) were used to test inhibitors, and high-performance liquid chromatography (HPLC) was used to measure transport. Of 26 beta-lactams tested, 12 were clear inhibitors of Oat3, and 14 exhibited poor interactions. Inhibitors exhibited a nearly identical rank-order of potency against mOat3 and hOAT3. Oat1 demonstrated a poor interaction with most beta lactams. The majority of Oat3 inhibitors were substrates, and there were clear physicochemical differences between inhibitors and noninhibitors. That is, inhibitors had nearly 40% fewer hydrogen bond donors (P < 0.001), a lower total polar surface area (P < 0.05), and greater lipophilicity (LogP of inhibitors, +1.41; noninhibitors, -1.54; P < 0.001). Pharmacophore mapping revealed a prohibitive hydrogen bond donor group in noninhibitors adjacent to a hydrophobic moiety that was important for binding to Oat3. These findings indicate that Oat3 recognizes lipophilic beta-lactams more readily. Moreover, this study has potential implications for designing beta-lactams to avoid renal accumulation or brain efflux via Oat3. PMID- 23344797 TI - Anaplastic oligodendroglioma: advances and treatment options. AB - OPINION STATEMENT: The optimal treatment strategy for anaplastic oligodendroglial (AO) tumors is evolving. Molecular profiling of oligodendrogliomas have shown distinctive genetic patterns characterized by combined deletions of chromosome arms 1p and 19q, O(6)-methylguanine methyltransferase (MGMT) methylation, and isocitrate dehydrogenase 1 (IDH1) mutations; they are all prognostic factors for patients with AO. In addition, a strong association has also been found between the CpG island hypermethylation phenotype (CIMP) status and MGMT promoter methylation. Long term follow up data of the Radiation Therapy Oncology Group (RTOG) 9402 and the European Organisation for Research and Treatment of Cancer (EORTC) 26951 studies demonstrate clear evidence that for patients with codeleted 1p19q AO, early chemotherapy with radiation offers a significant improvement in overall survival compared with early radiation, even with salvage chemotherapy at tumor relapse, and thus establishes the 1p19q allelic loss as a predictive marker distinct from tumors without the chromosome change. Radiotherapy alone is no longer considered an adequate treatment for this patient population. In cases with no 1p19q deletion, most neuro-oncologists recommend incorporating radiotherapy into the upfront treatment strategy. However, there are still unanswered questions regarding whether upfront chemotherapy, omitting/deferring radiotherapy, in the desire to avoid late neurocognitive toxicity of radiotherapy should be the initial therapy for AO tumors with codeleted 1p19q, or whether temozolomide, an oral agent with a better toxicity profile, can be substituted for procarbazine, lomustine, and vincristine (PCV). Further studies are warranted and the increasing understanding of molecular pathways involved may lead to more selective therapeutic targets in the future. PMID- 23344798 TI - Immunohistochemical evaluation of cell proliferation and apoptosis markers in ovarian surface epithelial cells of cladribine-treated rats. AB - Cladribine has been used in the treatment of hairy cell leukemia for about 30 years. In addition, the number of indications for the application of 2-CdA is constantly increasing. The treatment with cladribine, of younger persons and even children, appears to be a major factor stimulating the more exact recognition of its activities. However, till now, little has been known about the impact of cladribine on the reproductive system. The aim of the study was to evaluate the immunohistochemical expression of cell proliferation and apoptosis markers in ovarian surface epithelial (OSE) cells. In our study, ten rats were placed into two equal groups. The study group received daily subcutaneous injections of cladribine in a dose of 0.10 mg/kg of weight/day for one cycle lasting 7 days. The control group received only saline injections. The rats were sacrificed 24 h after the last injection, and their ovaries were extracted. The sections were immunohistochemically stained with cell proliferation marker Ki-67 and the apoptosis marker caspase 3. The expressions of the markers were evaluated using a light microscope. An analysis was made using an image analysis system and the CellAD software. The results were then statistically explored by way of the Mann Whitney U test. The proliferative index (Ki-67) of ovarian surface epithelial cells was significantly lower in the study group than in the control group (p < 0.05). These results suggest that cladribine treatment has a potential to inhibit the OSE cell proliferation in rats. The apoptosis marker demonstrated a significant increase after the cladribine treatment. These suggest that cladribine induces apoptosis in OSE cells. PMID- 23344799 TI - Milestones for a college and journal. PMID- 23344800 TI - William Siegfried Dawson: a pioneering Australasian psychiatrist. AB - OBJECTIVE: The purpose of this paper was to consider the life and contribution of Professor William Siegfried Dawson (1891-1975) by examination of school, university and hospital reports and journal articles. CONCLUSIONS: Professor Dawson made a major contribution, through his academic and professional roles and leadership, to the firm establishment of psychiatry, psychiatric scholarship and psychiatric organisations in Australia. PMID- 23344801 TI - Ball or aerosol? Sin, soap and the pharmaceutical industry. AB - OBJECTIVE: The purpose of this paper is to provoke careful and continuing reconsideration of the relationship between psychiatrists and the pharmaceutical industry through historical analysis of trends in the promotion of psychotropic drugs. CONCLUSIONS: Psychiatrists remain concerned about the relationship of the profession with the pharmaceutical industry. From examination of my own extended experience of that relationship (including as a former Royal Australian and New Zealand College of Psychiatrists General Councilor and chair of the Clinical Practice Advisory and Ethical Practice Committees), attention is drawn to the influence of the industry on the categorization and naming of drugs, attempts to propose target disorders and the obsolescence of established agents. Caution in accepting the role of 'opinion leader' is recommended but it remains important for psychiatrists to continue to ethically engage with the industry. PMID- 23344802 TI - Impact of the mining industry on the mental health of landholders and rural communities in southwest Queensland. AB - OBJECTIVE: We aimed to ascertain the extent of mental health problems in rural communities of southwest Queensland. METHODS: Twelve workshops were conducted within this region, asking community members about the issues which were affecting their mental health, the gaps in services and facilities, and suggestions as to how to strengthen their capacity to deal with mental health problems. RESULTS: The participants highlighted the higher cost of living through increased rental and goods and services costs. Non-resident workforces, putting a strain on housing availability and succession planning, were among key concerns. The rapid increase in population has also put strains on health services within these communities, highlighting the need for mental health resources and a greater clarification and coordination of available health services. CONCLUSIONS: The rural communities in this region are under sustained stress resulting from the incursion of the mining and coal seam gas industries. This has an impact on community mental health and wellbeing. PMID- 23344803 TI - Malariotherapy at Mont Park: the earliest surviving movie of psychiatric treatment in Australia. AB - OBJECTIVE: A movie on malariotherapy for neurosyphilis made at Mont Park and filmed by Reg Ellery in 1926 is believed to be the oldest surviving movie of psychiatric treatment in Australia. The objective is to review the movie and discuss the background and context of the film, which shows the conditions of patients in a psychiatric hospital in the 1920s. CONCLUSION: Movie film is a guide to a psychiatric past that is rapidly being forgotten. The Ellery movie is an incentive to collect surviving footage before it is too late. PMID- 23344804 TI - Evidence-based medicine: a position statement is needed. PMID- 23344805 TI - Monitoring of long-term cardiac complications in patients receiving clozapine. PMID- 23344806 TI - Collaborative quality improvement: consumers, carers and mental health service providers working together in service co-design. PMID- 23344819 TI - Pen microfluidics: rapid desktop manufacturing of sealed thermoplastic microchannels. AB - A unique technique for the rapid fabrication of thermoplastic microfluidic chips is described. The method enables the realization of fully-sealed microchannels in around one hour while requiring only minimal infrastructure by taking advantage of a solvent swelling mechanism that allows raised features to be patterned on the surface of homogeneous thermoplastic materials. Patterning is achieved without photolithography by simply drawing the desired microchannel pattern onto the polymer surface using a suitable ink as a masking layer, either manually or under robotic control, followed by timed exposure to solvent vapor to yield a desired depth for the masked channel features. The channels are then permanently sealed through solvent bonding of the microchannel chip to a mating thermoplastic substrate. The process is demonstrated using cyclic olefin copolymer as a thermoplastic material, with fully operational microfluidic devices fabricated following a true desktop manufacturing model suitable for rapid prototyping. PMID- 23344820 TI - Biochemical modulation of cell energy by 2-deoxyglucose and malonate in 7,12 dimethylbenz(a)anthracene-induced carcinogenesis in rats. AB - The goal of this study was to explore the impact of 2-deoxglucose or malonate individually or in combination on the level of cell energy (adenosine-5' triphosphate) and oxidative stress in 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary proliferation in rats. A total of 60 adult female Sprague Dawley rats were randomly divided into five groups (12 rats each): group I serves as the control group. Rats in groups (II-V) were administrated intragastrically a single dose of 50 mg/kg body weight (bw) of DMBA. A day after DMBA administration, rats in group III were injected intraperitoneally (ip) with 100 mg 2-deoxyglucose (2 DG)/kg bw daily. Rats in group IV were injected ip with 10 mg sodium malonate/kg bw daily. Rats in group V were injected ip with 100 mg 2-DG/kg bw and 10 mg sodium malonate/kg bw (treatment for 90 days). The results obtained showed that DMBA induced oxidative stress by decreasing the activities of glutathione reductase (GRase) and superoxide dismutase (SOD), glutathione peroxidase (GPx) and elevating the levels of malondialdehyde (MDA) and nitric oxide (NO) in mammary tissues when compared with control. The combined treatment protected against the previous deleterious changes by a significant elevation in the activities of GRase and SOD, GPx and lowering the levels of MDA and NO more potentially when compared with individual treatment. Apoptosis, as indicated by a significant release of cytochrome c from mitochondria into the cytosol, observed in DMBA-injected rats was positively significantly correlated with the elevation of the level of NO. These data explained the possible additive effect of 2-DG and malonate by depleting the cell energy by their protective effects against the earlier stages of carcinogenesis. PMID- 23344821 TI - Oxidative stress and alteration of biochemical markers in liver and kidney by malathion in rat pups. AB - The present study was undertaken to determine the effects of malathion exposure through maternal milk on oxidative stress, functional an metabolic parameters in kidney and liver of rat pups. We found that lactational exposure to malation (200 mg/kg, body weight (bw)) induced an oxidative stress status assessed by an increase in malondialdhyde (MDA) content, reflecting lipoperoxidation, a decrease in thiol groups' content as well as depletion of enzyme activities as a superoxide dismutase (SOD) and catalase (CAT) on postnatal days (Pnds) 21 and 51. Moreover, the current study showed that malathion induced liver and kidney dysfunctions demonstrated by considerable increase in phosphatase alkaline (PAL), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities as well as total and direct bilirubin, creatinine urea and acid uric contents. We also observed an increase in triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and a decrease in high-density lipoprotein cholesterol (HDL-C) in the plasma of treated rat pups. These findings evidenced that malathion exposure during lactation through maternal milk of rats pups induced kidney and liver oxidative stress as well as functional and metabolic disorders that play a role in the development of others pathologies as cardiovascular diseases and cancers. PMID- 23344823 TI - RETRACTED: Median lethal concentration of two pesticides, diazinon and deltamethrin, on tra catfish Pangasius hypophthalmus (Siluroidei, Pangasiidae). PMID- 23344822 TI - Interleukin-10 involvement in exposure to low dose of benzene. AB - OBJECTIVE: To establish if serum levels of interleukin-10 (IL-10) in subjects exposed to benzene are connected with age, working years, and employment age. METHODS: We evaluated serum levels of IL-10 in 51 employees working in oil refinery (group A) and in 16 office workers who resided in the same area (group B). RESULTS: There was no statistically significant difference between serum concentrations of IL-10 in groups A and B. There was a statistically significant dependent relationship in group A between age, working years, and serum concentration of IL-10. There was a statistically significant and positive dependent relationship in group A between serum concentration of IL-10 and employment age. CONCLUSIONS: The role played by IL-10 in benzene immune suppression may be relevant and attention should be directed toward assessment of age, working years, and employment age in benzene-exposed populations. PMID- 23344824 TI - Phytotoxicity evaluation and phytochemical analysis of three medicinally important plants from Pakistan. AB - This work examines the crude methanolic extracts of three medicinally important plants native to Pakistan for potent phytotoxic activities and important phytochemicals. These plants include Euphorbia wallichii, Bergenia ciliata and Phytolacca latbenia. The phytotoxic effects were checked at 10,000, 1000, and 100 ug/ml against two economically important standard target species, Triticum aestivum (monocot representative) and Brassica napus (dicot representative). The phytotoxicity effects on seed germination, seedling growth and seedling weight were checked. A simple, cost-effective in vitro phytotoxicity assay (that uses petri plates) was used to evaluate the allelopathic properties of crude extracts. At highest concentration, extracts from all the three plants showed phytotoxic activities such that P. latbenia > E. wallichii > B. ciliata. In seedling growth, root length was affected more than shoot length, whereas among the target species B. napus was found to be more sensitive towards extracts when compared with T. aestivum. Phytochemical analysis showed that P. latbenia is rich in saponins and terpenoids, while E. wallichii and B. ciliata are rich in tannins, terpenoids and cardiac glycoside. P. latbenia also carries a moderate amount of cardiac glycosides. PMID- 23344825 TI - Heavy metals accumulation in crab and shrimps from Pulicat lake, north Chennai coastal region, southeast coast of India. AB - The accumulation of heavy metals such as lead (Pb), iron (Fe), zinc (Zn), cadmium (Cd), and chromium (Cr) was examined in crab (Scylla serrata) and shrimps (Penaeus semisulcatus, Penaeus indicus, and Penaeus monodon) collected from Pulicat lake that receives effluents from industries located in north Chennai, southeast coast of India. The results showed limited difference between crab and prawns as well as significant variations between the organs. Pb is the highly accumulated metal in both crab and shrimps, except P. monodon. The highest metal concentration was mostly found in the liver followed by other organs. The concentration of metals in edible parts (muscle) was within the permissible level and safe for consumption. However, the results of the study clearly indicate the biomagnification of metals in Pulicat lake. PMID- 23344826 TI - Systemic sclerosis: demographic, clinical and serological features in 100 Iranian patients. AB - To evaluate demographic, clinical and laboratory features associated with scleroderma-specific auto-antibodies. Sera of 100 patients with systemic sclerosis (SSc) were analyzed by an indirect immunofluorescence technique with HEp-2 cells as a substrate. Specific ANA such as anti-centromere antibodies (ACA), anti-topoisomerase (TOPO), anti-RNA polymerase III (Pol 3), anti-U3-RNP (U3-RNP), anti-Th/To (Th/To) and anti-PM/Scl (PM/Scl) were detected by line immunoassay and anti-U1-RNP (U1-RNP) by ELISA. Frequency of clinical features associated with a specific antibody group was reported cumulatively over the follow-up period. Frequency of specific clinical features was compared across the two disease subtype including limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc) as well as the auto-antibody groups. Ninety-four percent of patients were ANA positive with significant higher skin score, Raynauds and digital ulcer/gangrene. Anti-TOPO was detected in 71% of all patients, in 90.5% of dcSSC and in 65.8% of lcSSc. Anti-TOPO was significantly associated with dcSSc, higher skin score, digital ulcer/gangrene, pulmonary fibrosis, DLCO <70%. U1-RNP antibody was associated with lower fibrosis in lung. ACA was positive in 7% of patients and exclusively in those with lcSSc. We did not find association between gender and presence of auto-antibodies. Anti-TOPO antibody had a high prevalence in contrast to low prevalence of ACA antibody. There were no differences in clinical subtypes of the disease in patients with positive anti-TOPO and positive ACA. Differences in prevalence of auto-antibodies are suggestive of further genetic study. PMID- 23344827 TI - Impact of multidrug resistance on Pseudomonas aeruginosa ventilator-associated pneumonia outcome: predictors of early and crude mortality. AB - The prevalence of multidrug-resistant (MDR) Pseudomonas aeruginosa has increased over the past decade and a significant rise in these isolates in ventilator associated pneumonia (VAP) has been observed. However, the impact of MDR on VAP outcome has not been analysed in depth. We investigated the risk factors for early and crude mortality in a retrospective study of microbiologically and clinically documented VAP. Ninety-one VAP episodes in 83 patients were included, 31 caused by susceptible P. aeruginosa and 60 by MDR strains, of which 42 (70 %) were extensively drug-resistant (XDR) P. aeruginosa. Thirteen episodes concomitantly presented P. aeruginosa bacteraemia, in seven of which the origin was the respiratory tract. Whereas susceptible P. aeruginosa episodes were more likely than MDR episodes to receive adequate empirical (68 % vs. 30 %; p < 0.001) and definitive antimicrobial therapy (96 % vs. 50 %; p < 0.001), susceptible P. aeruginosa VAP presented a trend towards early mortality (29 % vs. 15 %; p = 0.06). A logistic regression model with early mortality as the dependent variable identified multiorgan dysfunction syndrome (MODS) [odds ratio (OR) 10.4; 95 % confidence interval (CI) 1.7-63.5; p = 0.01] and inadequate antibiotic therapy (OR 4.27; 95 % CI 0.98-18.4; p = 0.052) as independent risk factors for early mortality. A similar analysis identified MODS (OR 4.31; 95 % CI 1.14-16.2; p = 0.03) as the only independent predictor of crude mortality. The severity of acute illness clinical presentation was the main predictor of mortality. Despite adequate antibiotic therapy, susceptible P. aeruginosa seems to cause major early mortality. Although adequate therapy is essential to treat VAP, the severity of acute illness is a more important factor than drug resistance. PMID- 23344828 TI - CBCT assessment of upper airway changes and treatment outcomes of obstructive sleep apnoea: a systematic review. AB - PURPOSE: The aim of this study was to review studies using cone beam computed tomography (CBCT) to assess dimensional changes in the upper airway after appliance or surgical therapy in subjects with obstructive sleep apnoea and to correlate CBCT findings with treatment outcome. METHOD: Several electronic databases were searched. Studies that met selection criteria were evaluated using a customized evaluation tool. RESULTS: Study parameters were met in seven articles. Fifty adults were assessed using CBCT 1.6-10 months after appliance therapy or maxillary mandibular advancement surgery with or without genial tubercle advancement. Airway parameters measured were linear, cross-sectional (CS) area, volume or airway function. In only two validated surgical case reports, airway volume increased by 6.5-9.7 cm(3) (>80 %) and minimum CS area by 0.1-1.2 cm(2) (21 and 269 %). CONCLUSION: The available published studies show evidence of CBCT measured anatomic airway changes with surgery and dental appliance treatment for OSA. There is insufficient literature pertaining to the use of CBCT to assess treatment outcomes to reach a conclusion. High-quality evidence level studies, with statistically appropriate sample sizes and cross validated clinically, are needed to determine if CBCT airway dimensional changes are suitable for assessment of treatment outcome. PMID- 23344829 TI - Polygraphic respiratory events during sleep with noninvasive ventilation in children: description, prevalence, and clinical consequences. AB - PURPOSE: The optimal monitoring during sleep with noninvasive positive pressure ventilation (NPPV) has not been validated in children. The aim of the study was to describe on polygraphic (PG) recordings the respiratory events and associated autonomic arousals (AA) and/or 3 % desaturations (DS3%) during nocturnal NPPV. METHODS: This was a prospective descriptive study performed in the pulmonology unit of a pediatric university hospital. Consecutive patients admitted for routine follow-up of long-term NPPV were enrolled. Nocturnal PG during sleep with NPPV was performed. A second PG was performed after adjustment of the ventilatory settings when a respiratory event occurred more than 50 times/h. RESULTS: The PG tracings of 39 patients (age range 1-18 years) were analyzed. Underlying diagnoses included neuromuscular disease (n = 13), obstructive sleep apnea (n = 15), and lung disease (n = 11). Unintentional leaks, patient-ventilator asynchronies, decrease in ventilatory drive, upper airway obstruction with or without reduction of ventilatory drive, and mixed events were observed in 27, 33, 10, 11, 12, and 3 % of the patients, respectively. A predominant respiratory event was observed in all patients. The mean duration spent with respiratory events was 32 +/- 30 % (range 3-96 %) of total recording time. Unintentional leaks were the most frequently associated with AA, whereas patient-ventilator asynchronies were rarely associated with AA or DS3%. In eight re-evaluated patients, a decrease in the main event was observed (p = 0.005). CONCLUSION: Respiratory events during sleep with NPPV are common in children treated with long-term NPPV. Consequences of respiratory events vary according to the type of event with unintentional leaks being associated preferentially with AA. PMID- 23344830 TI - Sonographic evaluation of the diaphragm in critically ill patients. Technique and clinical applications. AB - The use of ultrasonography has become increasingly popular in the everyday management of critically ill patients. It has been demonstrated to be a safe and handy bedside tool that allows rapid hemodynamic assessment and visualization of the thoracic, abdominal and major vessels structures. More recently, M-mode ultrasonography has been used in the assessment of diaphragm kinetics. Ultrasounds provide a simple, non-invasive method of quantifying diaphragmatic movement in a variety of normal and pathological conditions. Ultrasonography can assess the characteristics of diaphragmatic movement such as amplitude, force and velocity of contraction, special patterns of motion and changes in diaphragmatic thickness during inspiration. These sonographic diaphragmatic parameters can provide valuable information in the assessment and follow up of patients with diaphragmatic weakness or paralysis, in terms of patient-ventilator interactions during controlled or assisted modalities of mechanical ventilation, and can potentially help to understand post-operative pulmonary dysfunction or weaning failure from mechanical ventilation. This article reviews the technique and the clinical applications of ultrasonography in the evaluation of diaphragmatic function in ICU patients. PMID- 23344831 TI - Vasopressin and copeptin levels in children with sepsis and septic shock. AB - PURPOSE: Levels of vasopressin and its precursor copeptin in pediatric sepsis and septic shock are not well defined. The main aim of this study is to compare the serum levels of vasopressin and copeptin in children with septic shock or sepsis and in healthy children. We hypothesized that vasopressin and copeptin levels are elevated in early and late stages of pediatric septic shock. METHODS: Three groups were included: healthy children, children with clinical diagnosis of sepsis, and children admitted to the pediatric intensive care unit (PICU) with diagnosis of sepsis shock. Blood samples were drawn from children in all groups within 24 h of admission. For the septic shock group, additional samples at 24-h intervals were drawn up to 120 h after PICU admission. We used competitive immunoassays to determine vasopressin and copeptin levels. RESULTS: There were 70 children in the control group, 53 children in the sepsis group, and 13 in the septic shock group. At baseline, there was a difference in median vasopressin levels [60.9 (Interquartile range: 32.3, 138.0) vs. 141.1 (45.2, 542) vs. 326 (55.6, 399) pg/mL, p < 0.05], but there was no difference in copeptin levels [1.2 (0.8, 1.8) vs. 1.5 (1.0, 2.2) vs. 0.9 (0.8, 1.2) ng/mL, p = 0.14] between the three groups. There was no difference in vasopressin and copeptin levels in early and late stages of pediatric septic shock. CONCLUSIONS: Baseline vasopressin levels were different between the three groups. In pediatric septic shock, vasopressin and copeptin levels are not robust markers for severity and clinical outcomes. PMID- 23344832 TI - Effect of different seated positions on lung volume and oxygenation in acute respiratory distress syndrome. AB - RATIONALE: Lung volume available for ventilation is markedly decreased during acute respiratory distress syndrome. Body positioning may contribute to increase lung volume and partial verticalization is simple to perform. This study evaluated whether verticalization had parallel effects on oxygenation and end expiratory lung volume (EELV). METHODS: Prospective multicenter study in 40 mechanically ventilated patients with ALI/ARDS in five university hospital MICUs. We evaluated four 45-min successive trunk position epochs (supine slightly elevated at 15 degrees ; semi recumbent with trunk elevated at 45 degrees ; seated with trunk elevated at 60 degrees and legs down at 45 degrees ; back to supine). Arterial blood gases, EELV measured using the nitrogen washin/washout, and static compliance were measured. Responders were defined by a PaO2/FiO2 increase >20 % between supine and seated position. Results are median [25th-75th percentiles]. RESULTS: With median PEEP = 10 cmH2O, verticalization increased lung volume but only responders (13 patients, 32 %) had a significant increase in EELV/PBW (predicted body weight) compared to baseline. This increase persisted at least partially when patients were positioned back to supine. Responders had a lower EELV/PBW supine [14 mL/kg (13-15) vs. 18 mL/kg (15-27) (p = 0.005)] and a lower compliance [30 mL/cmH2O (22-38) vs. 42 (30-46) (p = 0.01)] than non responders. Strain decreased with verticalization for responders. EELV/PBW increase and PaO2/FiO2 increase were not correlated. DISCUSSION: Verticalization is easily achieved and improves oxygenation in approximately 32 % of the patients together with an increase in EELV. Nonetheless, effect of verticalization on EELV/PBW is not predictable by PaO2/FiO2 increase, its monitoring may be helpful for strain optimization. PMID- 23344835 TI - Cerebral oximetry to adjust cerebral and systemic circulation after cardiac arrest. PMID- 23344834 TI - Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study. AB - PURPOSE: To ascertain the relationship among early (first 48 h) deep sedation, time to extubation, delirium and long-term mortality. METHODS: We conducted a multicentre prospective longitudinal cohort study in 11 Malaysian hospitals including medical/surgical patients (n = 259) who were sedated and ventilated >=24 h. Patients were followed from ICU admission up to 28 days in ICU with 4 hourly sedation and daily delirium assessments and 180-day mortality. Deep sedation was defined as Richmond Agitation Sedation Score (RASS) <=-3. RESULTS: The cohort had a mean (SD) age of 53.1 (15.9) years and APACHE II score of 21.3 (8.2) with hospital and 180-day mortality of 82 (31.7%) and 110/237 (46.4%). Patients were followed for 2,657 ICU days and underwent 13,836 RASS assessments. Midazolam prescription was predominant compared to propofol, given to 241 (93%) versus 72 (28%) patients (P < 0.0001) for 966 (39.6%) versus 183 (7.5%) study days respectively. Deep sedation occurred in (182/257) 71% patients at first assessment and in 159 (61%) patients and 1,658 (59%) of all RASS assessments at 48 h. Multivariable Cox proportional hazard regression analysis adjusting for a priori assigned covariates including sedative agents, diagnosis, age, APACHE II score, operative, elective, vasopressors and dialysis showed that early deep sedation was independently associated with longer time to extubation [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.89-0.97, P = 0.003], hospital death (HR 1.11, 95% CI 1.05-1.18, P < 0.001) and 180-day mortality (HR 1.09, 95% CI 1.04-1.15, P = 0.002), but not time to delirium (HR 0.98, P = 0.23). Delirium occurred in 114 (44%) of patients. CONCLUSION: Irrespective of sedative choice, early deep sedation was independently associated with delayed extubation and higher mortality, and thus was a potentially modifiable risk in interventional trials. PMID- 23344836 TI - Carbon dioxide elimination and cardiac output changes. PMID- 23344838 TI - Number of supervised studies required to reach competence in advanced critical care transesophageal echocardiography. AB - PURPOSE: To determine the minimum number of supervised transesophageal echocardiography (TEE) that intensivists should perform to reach competence in performing and interpreting a comprehensive hemodynamic assessment in ventilated intensive care unit patients. METHODS: Prospective and multicentric study. Skills of 41 intensivists (trainees) with no (level 0) or little (level 1) experience in echocardiography was evaluated over a 6-month period, using a previously validated skills assessment score (/40 points). Trainees were evaluated at 1 (M1), 3 (M3) and 6 months (M6) by their tutor while performing 2 TEE examinations in ventilated patients. Competence was a priori defined by a skills assessment score >35/40 points. RESULTS: No difference in the score was observed between level 0 and level 1, except at M1 (22.2 +/- 6.2 vs. 25.9 +/- 4.4 points, p = 0.03). After 6 months, trainees performed a mean of 31 +/- 9 supervised TEE. The score gradually increased from M1 to M6 (24 +/- 6, 32 +/- 3, and 35 +/- 3 points, p < 0.001), regardless of trainees' initial level. A correlation was found between the number of supervised TEE and the skills assessment score (r (2) = 0.60; p < 0.001). The number of supervised TEE examinations which best predicted a score >35/40 points was 25, with a sensitivity of 81 % and a specificity of 93 % (area under the ROC curve: 0.91 +/- 0.04). A number of 31 supervised TEE examinations predicted a score >35/40 points with a specificity close to 100 %. CONCLUSION: The performance of at least 31 supervised examinations over 6 months is required to reach competence in TEE driven hemodynamic evaluation of ventilated patient. PMID- 23344839 TI - From SDD to a risk- and CIRCO-diagnosis-based approach for treatment and prophylaxis of intestinal bacterial overgrowth in critically ill patients. PMID- 23344833 TI - Macrolide-based regimens in absence of bacterial co-infection in critically ill H1N1 patients with primary viral pneumonia. AB - PURPOSE: To determine whether macrolide-based treatment is associated with mortality in critically ill H1N1 patients with primary viral pneumonia. METHODS: Secondary analysis of a prospective, observational, multicenter study conducted across 148 Intensive Care Units (ICU) in Spain. RESULTS: Primary viral pneumonia was present in 733 ICU patients with pandemic influenza A (H1N1) virus infection with severe respiratory failure. Macrolide-based treatment was administered to 190 (25.9 %) patients. Patients who received macrolides had chronic obstructive pulmonary disease more often, lower severity on admission (APACHE II score on ICU admission (13.1 +/- 6.8 vs. 14.4 +/- 7.4 points, p < 0.05), and multiple organ dysfunction syndrome less often (23.4 vs. 30.1 %, p < 0.05). Length of ICU stay in survivors was not significantly different in patients who received macrolides compared to patients who did not (10 (IQR 4-20) vs. 10 (IQR 5-20), p = 0.9). ICU mortality was 24.1 % (n = 177). Patients with macrolide-based treatment had lower ICU mortality in the univariate analysis (19.2 vs. 28.1 %, p = 0.02); however, a propensity score analysis showed no effect of macrolide-based treatment on ICU mortality (OR = 0.87; 95 % CI 0.55-1.37, p = 0.5). Moreover, the sensitivity analysis revealed very similar results (OR = 0.91; 95 % CI 0.58-1.44, p = 0.7). A separate analysis of patients under mechanical ventilation yielded similar results (OR = 0.77; 95 % CI 0.44-1.35, p = 0.4). CONCLUSION: Our results suggest that macrolide-based treatment was not associated with improved survival in critically ill H1N1 patients with primary viral pneumonia. PMID- 23344841 TI - Fluorescence molecular tomography of an animal model using structured light rotating view acquisition. AB - In recent years, an increasing effort has been devoted to the optimization of acquisition and reconstruction schemes for fluorescence molecular tomography (FMT). In particular, wide-field structured illumination and compression of the measured images have enabled significant reduction of the data set and, consequently, a decrease in both acquisition and processing times. FMT based on this concept has been recently demonstrated on a cylindrical phantom with a rotating-view scheme that significantly increases the reconstruction quality. In this work, we generalize the rotating-view scheme to arbitrary geometries and experimentally demonstrate its applicability to murine models. To the best of our knowledge this is the first time that FMT based on a rotating-view scheme with structured illumination and image compression has been applied to animals. PMID- 23344840 TI - A microfabricated platform for establishing oxygen gradients in 3-D constructs. AB - Oxygen gradients are increasingly implicated in a number of biological processes, including stem cell differentiation and cancer metastasis. Unfortunately, the current in vitro tools designed to mimic conditions found in vivo lack application flexibility, simplicity in operation, and precise spatial control that most researchers require for widespread dissemination. The novel microfluidic-based device presented here addresses all the above concerns, offering a simple platform for enhanced control over the oxygen microenvironment exposed to three-dimensional cell-seeded constructs. The device utilizes an oxygen diffusion membrane approach to establish a gradient across a construct sandwiched between two continually perfused microfluidic networks. The device is capable of forming steady-state gradients at both the conditions tested-0 % to 5 % O2 and 0 % to 21 % O2-but a wide variety of profiles within the construct are possible. Cell viability with two model cell lines was also tested, with no adverse effects relative to the control. PMID- 23344843 TI - Fetal head entrapment through a spontaneous chorionic septostomy in a first trimester dichorionic diamniotic twin pregnancy: a case report. PMID- 23344844 TI - Mercury in the body of the most commonly occurring European game duck, the mallard (Anas platyrhynchos L. 1758), from northwestern Poland. AB - The aim of this study was to determine the concentration of mercury (Hg) in liver (L), kidney (K), breast muscle [BM (musculus pectoralis major)], breast feathers (BF), and stomach contents (SC) of mallard (Anas platyrhynchos L. 1758). Among the edible parts of mallard, the greatest concentrations of Hg were observed in K and L, although they did not exceed 1.5 mg/kg dry weight (dw). Average concentrations in K, L, and BM were 0.27, 0.25, and 0.13 mg/kg dw, respectively. Significant correlations were observed between Hg concentrations in BM and K and in BM and L (r s = 0.92) as well as between Hg concentrations in these tissues and BF. In addition, we found significant correlations between Hg concentrations in SC and BM (r s = 0.72) and in L and K (r s = 0.55). In conclusion, mallard exhibits a measurable response to environmental Hg pollution and meets the requirements of a bioindicator. PMID- 23344845 TI - Effect of pollution history on immunological responses and organ histology in the marine mussel Mytilus edulis exposed to cadmium. AB - The effect of previous toxicant exposure (i.e., exposure history) on an organism's response to re-exposure to the toxicant is of considerable interest. The marine mussel Mytilus edulis was collected from reference and polluted sites in southwest England, and groups of mussels from each site were exposed to 20 MUg/L CdCl2 for 0, 1, 4, and 8 days and compared with unexposed controls. End points evaluated were tissue metal and electrolyte concentrations, haemolymph chemistry, haemocyte characteristics [counts, neutral red uptake (NRU), and phagocytosis], histology, and expression of metallothionein gene (mt10) expression in digestive glands. Field-collected animals differed by collection site for some end points at time zero, at which time tissue Fe and Pb concentrations were greater and NRU and condition index lower in mussels from the polluted site. Subsequent exposure to cadmium (Cd) in the laboratory caused Cd accumulation mainly in digestive gland, but there were no site-specific effects on tissue trace-metal concentrations. NRU, phagocytosis, and haemolymph Na(+) and K(+) concentrations differed among sites and Cd treatment, but there were no clear trends. Exposure to Cd resulted in lower Ca(2+) concentrations in gill, digestive gland, and haemolymph in animals from the polluted site compared with controls (Kruskal-Wallis, p <= 0.05). Lesions, including necrosis, inflammation, and neoplasia, were observed in animals from the polluted site, but the frequency of these lesions appeared to decrease unexpectedly after Cd exposure. Expression of mt10 increased 3-fold in Cd-exposed animals from the polluted site compared with all other groups (Kruskal-Wallis, p = 0.01). We conclude that Cd exposure affected some immune responses in M. edulis, but pre-exposure history influenced toxicological outcomes of Cd exposure in the laboratory. PMID- 23344846 TI - Malpractice: Problems and solutions. PMID- 23344847 TI - 50 years ago in CORR: Synovial sarcoma. Kirk J. Anderson, MD and Orliss Wildermuth, MD CORR 1961;29:55-70. PMID- 23344848 TI - CORR InsightsTM: Is limited incision better than standard total hip arthroplasty? A meta-analysis. AB - This CORR InsightsTM is a commentary on the article "Is Limited Incision Better Than Standard Total Hip Arthroplasty? A Meta-analysis" by Joseph T. Moskal MD and Susan G. Capps PhD available at DOI 10.1007/s11999-012-2717-5 . PMID- 23344849 TI - Outcomes after volar plate fixation of low-grade open and closed distal radius fractures are similar. AB - BACKGROUND: Low-grade (Gustilo and Anderson Type I or II) open distal radius fractures (DRFs) have been treated by volar locking plate fixation. However, it is unclear whether the outcomes after volar locking plate fixation for low-grade open DRFs are comparable to those for closed DRFs. QUESTIONS/PURPOSES: We asked whether low-grade open DRFs had worse DASH scores and higher infection rates than closed DRFs when the DRFs were treated by volar plate fixation. METHODS: Twenty consecutive patients treated by volar locking plate fixation for low-grade open DRFs constituted the open fracture group, and 40 patients were selected from among the total number of patients treated by volar, locking plate fixation for closed DRFs as the closed fracture group. Complications including infection were recorded. Clinical outcomes and radiographic assessments were performed postoperatively at 3 months and 1 year. RESULTS: At 3 postoperative months, wrist flexion and extension, grip strengths, and DASH scores were better in the closed fracture group; however, no difference was observed postoperatively between the two groups in terms of any functional outcome measure at 1 year. Any of the radiographic parameters were not different between the groups. There were no differences in infection rate and in any other complication rate between the groups. CONCLUSIONS: Although functional outcomes of open DRFs were inferior to those of closed DRFs at 3 months, at 1 year, outcomes of low-grade open DRFs were found to be comparable to those of closed DRFs when volar plate fixation was used. PMID- 23344850 TI - Editorial: Limb preservation: past and present. PMID- 23344851 TI - Urinary exosomes and diabetic nephropathy: a proteomic approach. AB - Urinary exosomes (UE) are nanovesicles released by every epithelial cell facing the urinary space and they are considered a promising source of molecular markers for renal dysfunction and structural injury. Exosomal proteomics has emerged as a powerful tool for understanding the molecular composition of exosomes and has potential to accelerate biomarker discovery. We employed this strategy in the study of diabetic nephropathy (DN) and the consequent end stage renal disease, which represent the dramatic evolution of diabetes, often leading the patients to dialysis or kidney transplantation. The identification of DN biomarkers is likely to help monitoring the disease onset and progression. A label free LC-MS/MS approach was applied to investigate the alteration of the proteome of urinary exosomes isolated from the Zucker diabetic fatty rats (ZDF), as a model of type 2 DN. We collected 24 hour urine samples from 7 ZDF and from 7 control rats at different ages (6, 12 and 20 weeks old) to monitor the development of DN. Exosomes were isolated by ultracentrifugation and their purity assessed by immunoblotting for known exosomal markers. Exosomal proteins from urine samples of 20 week old rats were pooled and analyzed by nLC-ESI-UHR-QToF-MS/MS after pre filtration and tryptic digestion, leading to the identification and label free quantification of 286 proteins. Subcellular localization and molecular functions were assigned to each protein by UniprotKB, showing that the majority of identified proteins were membrane-associated or cytoplasmic and involved in transport, signalling and cellular adhesion, typical functions of exosomal proteins. We further validated label free mass spectrometry results by immunoblotting, as exemplified by: Xaa-Pro dipeptidase, Major Urinary Protein 1 and Neprilysin, which resulted increased, decreased and not different, respectively, in exosomes isolated from diabetic urine samples compared to controls, by both techniques. In conclusion we show the potential of exosome proteomics for DN biomarker discovery. PMID- 23344852 TI - Intrathecal epigallocatechin gallate treatment improves functional recovery after spinal cord injury by upregulating the expression of BDNF and GDNF. AB - This study aimed to investigate the therapeutic effects of epigallocatechin-3 gallate (EGCG) administered by subarachnoid injection following spinal cord injury (SCI) in rats and to explore the underlying mechanism. Sprague-Dawley rats were randomly divided into four groups of 12 as follows: a sham group (laminectomy only); a control group; a 10 mg/kg EGCG-treated group; and a 20 mg/kg EGCG-treated group. SCI was induced in the rats using the modified weight drop method (10 g * 4 cm) at the T10 (10th thoracic vertebral) level. EGCG (10 or 20 mg/kg) or vehicle as control was administered by subarachnoid injection at lumbar level 4 immediately after SCI. Locomotor functional recovery was assessed during the four weeks post-operation using open-field locomotor tests and inclined-plane tests. At the end of the study, the segments of spinal cord encompassing the injury site were removed for histopathological analysis. Immunohistochemical and Western blot analyses were performed to observe the expression of: the B cell CLL/lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). The results showed that the EGCG-treated animals had significantly better recovery of locomotor function, less myelin loss, greater Bcl-2 expression and attenuated Bax expression. In addition, the EGCG treatment significantly increased the expression of BDNF and GDNF after SCI. These findings suggest that EGCG treatment can significantly improve locomotor recovery, and this neuroprotective effect may be related to the up-regulation of BDNF and GDNF, and the inhibition of apoptosis-related proteins. Therefore, EGCG may be a promising therapeutic agent for SCI. PMID- 23344853 TI - Good Cascade Impactor Practice (GCIP) and considerations for "in-use" specifications. AB - The multi-stage cascade impactor (CI) is widely used to determine aerodynamic particle size distributions (APSDs) of orally inhaled products. Its size fractionating capability depends primarily on the size of nozzles of each stage. Good Cascade Impactor Practice (GCIP) requires that these critical dimensions are linked to the accuracy of the APSD measurement based on the aerodynamic diameter size scale. Effective diameter (Deff) is the critical dimension describing any nozzle array, as it is directly related to stage cut-point size (d50). d50 can in turn be determined by calibration using particles of known aerodynamic diameter, providing traceability to the international length standard. Movements in Deff within manufacturer tolerances for compendial CIs result in the worst case in shifts in d50 of <+/-10%. Stage mensuration therefore provides satisfactory control of measurement accuracy. The accurate relationship of Deff to d50 requires the CI system to be leak-free, which can be checked by sealing the apparatus at the entry to the induction port and isolating it from the vacuum source and measuring the rate of pressure rise before each use. Mensuration takes place on an infrequent basis compared with the typical interval between individual APSD determinations. Measurement of stage flow resistance (pressure drop; DeltaPstage) could enable the user to know that the CI stages are fit for use before every APSD measurement, by yielding an accurate measure of Deff. However, more data are needed to assess the effects of wear and blockage before this approach can be advocated as part of GCIP. PMID- 23344854 TI - A novel preparation method for organogels: high-speed homogenization and micro irradiation. AB - The aim of this work was to prepare organogels of Carbopol 974P NF (C974) in PEG 400 by using a novel technique, high-speed homogenization followed by microwave heating. Triclosan (TCS) was used as a model drug. C974, at concentrations ranging between 2% and 4%, was dispersed in 25 ml of PEG 400, and the dispersion was homogenised for 5 min at 24,000 rpm. The dispersion was either heated at 80 degrees C in water bath under mechanic stirring at 200 rpm or exposed to micro irradiation (1,200 W/1 h) for 2 min. The formulations prepared with both methods performed a well-structured gel matrix characteristic at 3% and 4% of C974 concentrations. As the concentrations of the polymer increased, the elastic properties also increased. The viscosity profiles indicated a shear-thinning system. DSC data revealed that TCS was dissolved in gel. Skin accumulation ability of TCS had been improved by these novel organogels regardless of the preparation method. TCS was still microbiologically effective after the microwave process was applied. It was determined that microwave heating is a suitable method to obtain C974 organogels. This novel production technique developed might be promising especially in industrial scale when the dramatic reduction in the preparation time and energy were considered. PMID- 23344855 TI - Theoretical design and experimental implementation of Ag/Au electrodes for the electrochemical reduction of nitrate. AB - The current imbalance in the biogeochemical cycle of nitrogen is as serious as that of carbon. One way to mitigate this problem is through the electrochemical reduction of nitrates under mild conditions, which is an appealing though not fully understood process. Therefore, deeper insight into the electrocatalytic reaction mechanism is needed to optimize this process. Here we thoroughly analyse the adsorption energy of nitrate with DFT calculations on various surface facets of pure Au, Ag, and their near-surface and surface alloys, as the adsorption and subsequent reduction of nitrate are thought to be rate limiting in the electrocatalytic reaction. The observed systematic trends allow prediction of the surface with highest electrocatalytic activity for the reduction of nitrate. This prediction was verified experimentally by depositing sub-monolayer amounts of Ag on polycrystalline Au electrodes. We observe a well-defined volcano curve which correlates the amount of Ag deposited on the surface with the current density at a fixed potential, with the peak activity around 2/3 ML Ag surface coverage. The electrocatalytic activity and stability of the bimetallic Ag-Au systems, found through the interplay of theoretical modelling and empirical observations, serve as a clear example for the rational design of novel catalytic materials and confirm the key role that the adsorption of nitrate plays in the overall nitrate reduction rate. PMID- 23344856 TI - Tissue accumulation and species-specific metabolism of technical pentabrominated diphenyl ether (DE-71) in two predator fish. AB - The tissue-specific accumulation and species-specific metabolism of polybrominated diphenyl ethers (PBDEs) in two predator fish species (redtail catfish and oscar fish) feeding on the same prey (tiger barb) that was exposed to technical pentabrominated diphenyl ether (DE-71) in the laboratory were investigated. The trends in the wet-weight tissue concentration of PBDEs in two predatory fish species suggested that the tissue distribution of PBDEs occurs through a series of events involving passive diffusion to the lipid compartment. A comparison of the fugacities of PBDEs in various tissues and in the serum revealed that the liver, gill, and perivisceral adipose tissue readily achieved equilibrium with the serum, but the muscle, kidney, and intestine exhibited the potential to accumulate PBDEs. The lower fugacities of PBDEs in the intestine may have significance in the transportation of PBDEs from prey to predatory fish. No tissue-specific differences in PBDE congener profiles were found, while interspecies differences in PBDE profiles were evident. The difference in profiles between two species could be attributed to species-specific debromination of PBDE. No metabolic debromination of PBDE was observed in redtail catfish, but extensive debromination of PBDEs occurred in oscar fish. Several hydroxylated PBDEs (OH-PBDEs) were detected in serum samples from the two fish species, but no methoxylated PBDEs were found. The similarities in the OH-PBDE congener profile and the ratio of OH-PBDEs to total PBDEs between the two fish species indicated that the hydroxylation of PBDEs might not be species-specific. PMID- 23344858 TI - Studying the differential co-expression of microRNAs reveals significant role of white matter in early Alzheimer's progression. AB - MicroRNAs (miRNAs) are a class of short non-coding RNAs, which show tissue specific regulatory activity on genes. Expression profiling of miRNAs is an important step for understanding the pathology of Alzheimer's disease (AD), a neurodegenerative disorder originating in the brain. Recent studies highlight that miRNAs enriched in gray matter (GM) and white matter (WM) of AD brains show differential expression. However, no in-depth study has yet been conducted on analysing the differential co-expression of pairs of miRNAs over GM and WM. Two genes (or miRNAs) are said to be co-expressed if their expression profiles change similarly over a number of samples. A pair of co-expressed genes under a condition type (or phenotype) may not remain co-expressed, or get contra expressed, under another condition. Such pairs of genes are referred to as differentially co-expressed. Such an investigation in the early stage of AD is reported in this article. A network of differentially co-expressed miRNAs in GM and WM is first built. Analysis of the differential co-expression property reveals that such a network can not have any cycle. We use the notion of switching to distinguish two distinct types of differential co-expression patterns - a pair of miRNAs that are highly co-expressed in GM but does not remain so in WM, and vice versa. Based on this, we find the substructures, referred to as differentially co-expressed switching tree (DCST), that throughout have similar pattern of switching. The miR-423-5p emerges as a hub of the network. We extract subtrees of these DCSTs that have similar switching pattern throughout. These substructures are found to be both statistically and biologically significant. A large number of miRNAs obtained from the DCSTs are found to have association with AD, most of which are enriched in WM. This computational study therefore indicates a significant role of WM in early AD progression, a hitherto less acknowledged fact. PMID- 23344857 TI - OsMPK3 positively regulates the JA signaling pathway and plant resistance to a chewing herbivore in rice. AB - KEY MESSAGE : Silencing OsMPK3 decreased elicited JA levels, which subsequently reduced levels of herbivore-induced trypsin protease inhibitors (TrypPIs) and improved the performance of SSB larvae, but did not influence BPH. Mitogen activated protein kinases (MPKs) are known to play an important role in plant defense by transferring biotic and abiotic signals into programmed cellular responses. However, their functions in the herbivore-induced defense response in rice remain largely unknown. Here, we identified a MPK3 gene from rice, OsMPK3, and found that its expression levels were up-regulated in response to infestation by the larvae of the striped stem borer (SSB) (Chilo suppressalis), to mechanical wounding and to treatment with jasmonic acid (JA), but not to infestation by the brown planthopper (BPH) Nilaparvata lugens or to treatment with salicylic acid. Moreover, mechanical wounding and SSB infestation induced the expression of OsMPK3 strongly and quickly, whereas JA treatment induced the gene more weakly and slowly. Silencing OsMPK3 (ir-mpk3) reduced the expression of the gene by 50 70 %, decreased elicited levels of JA and diminished the expression of a lipoxygenase gene OsHI-LOX and an allene oxide synthase gene OsAOS1. The reduced JA signaling in ir-mpk3 plants decreased the levels of herbivore-induced trypsin protease inhibitors (TrypPIs) and improved the performance of SSB larvae, but did not influence BPH. Our findings suggest that the gene OsMPK3 responds early in herbivore-induced defense and can be regulated by rice plants to activate a specific and appropriate defense response to different herbivores. PMID- 23344859 TI - Metal binding sites of human H-chain ferritin and iron transport mechanism to the ferroxidase sites: a molecular dynamics simulation study. AB - We study via all atom classical molecular dynamics (MD) simulation the process of uptake of ferrous ions (Fe(2+)) into the human ferritin protein and the catalytic ferroxidase sites via pores ("channels") in the interior of the protein. We observe that the three-fold hydrophilic channels serve as the main entrance pathway for the Fe(2+) ions. The binding sites along the ion pathway are investigated. Two strong binding sites, at the Asp131 and Glu134 residues and two weak binding sites, at the His118 and Cys130 are observed inside the three-fold channel. We also identify an explicit pathway for an ion exiting the channel into the central core of the protein as it moves to the ferroxidase site. The diffusion of an Fe(2+) ion from the inner opening of the channel to a ferroxidase site located in the interior region of the protein coat is assisted by Thr135, His136 and Tyr137. The Fe(2+) ion binds preferentially to site A of the ferroxidase site. PMID- 23344860 TI - Early post-operative results after repair of traumatic brachial plexus palsy. AB - AIM: Treatment options for traumatic brachial plexus injuries include nerve grafting, or neurotization. The type of lesion and the reconstructive procedures affect functional results and postoperative pain relief. MATERIAL AND METHODS: A total number of twenty five patients suffering from post-traumatic brachial plexus injury were included in the study. The patients underwent exploration and primary repair of the affected plexus, based on case by case policy. RESULTS: Spinal accessory nerve transfer to suprascapular nerve procedure regained 78.95% of functional muscle power, 10.50% of non functional muscle power and only 10.5 % of non innervated muscle. The Oberlin procedure regained 83.33% with elbow flexion muscle power, 16.67% with non functional muscle power. Intercostal nerve transfer to musculocutaneous nerve regained 62.5% with functional muscle power, 25% with non functional muscle power and only 12.5 % with non innervated muscle. The shoulder, elbow and wrist extension functions were significantly improved early post-operatively. In addition, the post-operative improvement of shoulder, elbow and wrist extension functions had significant negative correlations with the pre operative elapsed time, and accompanied by a significant positive correlation with post-operative follow up period. CONCLUSION: Early intervention for traumatic brachial plexus palsy is recommended to get good results with pain relief. PMID- 23344861 TI - Human brain arteriovenous malformations are associated with interruptions in elastic fibers and changes in collagen content. AB - AIM: We hypothesized that the loss of structural integrity in vessels of brain arteriovenous malformations (bAVM) is associated with abnormal expression of collagen subtypes. MATERIAL AND METHODS: We retrospectively obtained the nidus tissue specimens from 24 bAVM patients and structurally normal cerebral cortex from six surgical epilepsy patients. The samples were paraffin-embedded and stained with Victoria blue and picrosirius red and examined by light microscopy. RESULTS: Light microscopy showed that collagen fibers became disorganized, and the internal elastic lamina was duplicated or interrupted in the arteries from the nidus tissue of bAVM. In some vessels in the nidus, Col I was the only collagen component and the interstitial tissue was mainly comprised of Col I. bAVM patients showed significantly higher Col I levels (86.25% +/-13.92) and lower Col III levels (13.75% +/-13.92) in the vasculature in the nidus tissue than those of otherwise normal surgical epilepsy patients (Col I, 80.78% +/ 18.03; Col III, 19.22% +/-18.03) (p < 0.001). Additionally, bAVM patients showed a higher Col I / Col III ratio (24.71+/-40.47) than that of normal controls (16.04 +/-31.28) (p < 0.001). CONCLUSION: bAVM patients exhibit changes in the Col I/Col III ratio and elastic fibers in the vasculature, which may compromise the structural integrity of cerebral vessels. PMID- 23344863 TI - Endovascular embolization of ruptured and unruptured posterior circulation aneurysms. A multi-factor analysis. AB - AIM: Complete aneurysm obliteration reduces the risk of rebleeding and is an important goal of the aneurysm treatment. MATERIAL AND METHODS: A retrospective analysis of 63 patients undergoing endovascular treatment of posterior circulation aneurysms. The occlusion rate was stratified to three groups: complete, incomplete and partial. In the analysis compared the influence of the selected characteristics: age, sex, WFNS grade, aneurysm location, size of the aneurysm dome and neck, neck to dome ratio, on the effectiveness of embolization in each group. A multi-factor analysis with probit model and linear regression was applied to assess the impact of all characteristics on the complete occlusion. RESULTS: In the series of 63 single aneurysms, 51 were ruptured and 12 unruptured aneurysms. Complete occlusion was achieved in 36 (57.1%), incomplete in 15 (23.8%), partial in 12 (19%) patients. In patients with the neck size of 1-2 mm the complete occlusion was in 75% (24/32) incomplete in 12,5% (4/32), while when the neck size was 2-4 mm these rates were 38.7% (12/31) and 29% (9/31) respectively. The predictor of total occlusion in probit and linear regression model was only one independent variable, the narrow-neck size. CONCLUSION: Multi-factor analysis found that the strongest predictor of the complete occlusion is the aneurysm neck size. PMID- 23344862 TI - Evaluation of the neurotoxicity of the polyethylene glycol hydrogel dural sealant. AB - AIM: Although polyethylene glycol (PEG) is a neutral, biocompatible hydrophilic polymer recognized for its lack of interaction with biological barrier, its neurotoxicity has not been clearly identified in neurosurgery. This study is constructed to evaluate the possible neurotoxicity of a PEG hydrogel dural sealant. MATERIAL AND METHODS: After a burrhole was opened in the left parietal bone of the twenty five Wistar albino rats, the dura mater and cerebral cortex were incised and the experimental material (activated polyethylene glycol and polyethylene imine) was sprayed into the burrhole. Then brain tissues were harvested for histopathological and biochemical studies at 72 hours to investigate the acute stage changes and on 15th day to evaluate the chronic stage changes. RESULTS: There were statistically significant differences among the groups regarding the comparison of the values of the PMNL cell infiltration grades, gliosis and congestion in both acute and chronic stages. However, the values of the MNL cell infiltration grades, edema and fibrin formation, lipid peroxidation levels of harvested brain tissues were similar in all groups. CONCLUSION: Although this study did not present the detailed histopathological and biochemical evaluation results, it indicated that the application of the PEG-based hydrogel sealant was not associated with neurotoxicity, delayed healing, or degenerative changes. PMID- 23344864 TI - Management of intraneural fibro-lipoma of the median nerve and the role of Pressure-Specified Sensory Device (PSSD) for the patient's motor and sensorial evaluations. AB - AIM: The intraneural fibro-lipoma is a benign, uncommon tumor which is characterised with infiltration of the epineurium and perineurium by fibrofatty tissue. The preoperative diagnosis is difficult. However, the Pressure Specified Sensory Device (PSSD) may support identifying the earliest stages of intraneural fibro-lipoma when traditional electrodiagnostic testing will not be able to detect a change in peripheral nerve function. MATERIAL AND METHODS: Five patients (3 male, 2 female, age 23-53; mean 41 years) with intraneural fibro-lipoma were operated on. Grip strength, pinch strength and sensorial functions were assessed in all patients before surgery and at the end of the follow-up period by PSSD. RESULTS: The patients were followed-up for 7 to 24 months (mean; 12 month). All patient's condition improved dramatically following the operation and all patients had total relief of pain and paresthesia. CONCLUSION: The decompression of intraneural fibro-lipoma of the nerve with limited excision and epineurotomy without sacrificing the main nerve and its branches is the ideal surgical procedure. We recommend the use of PSSD in the investigation of patients with peripheral nerve compression, and chronic unusual volar forearm and wrist swelling. PSSD is an important tool for pre-operative evaluation and diagnosis of intraneural fibro-lipoma. PMID- 23344865 TI - Effects of intracisternal dexmedetomidine on cerebral neuronal cells in rat: a preliminary study. AB - AIM: The aim was to investigate whether dexmedetomidine had a toxic effect on cerebral neurons when it was administered centrally into the cerebrospinal fluid by the intracisternal route. MATERIAL AND METHODS: Eighteen rats were anesthetized and the right femoral artery was cannulated. Mean arterial pressures, heart rates, arterial carbon dioxide tension, arterial oxygen tension, and blood pH were recorded. When the free cerebrospinal fluid flow was seen, 0.1 ml normal saline (Group SIC, n=6) or 9 MUg/kg diluted dexmedetomidine in 0.1 ml volume (Group DIC, n=6) was administered into the cisterna magna of rats. After 24 hours, the whole body blood was collected for measurement of plasma lipid peroxidation (LPO) levels. The hippocampal formations used for histopathological examination and measurement of tissue LPO levels. RESULTS: There was a statistically significant difference between the DIC/SIC groups and DIC/CONTROL groups regarding the brain LPO levels (p=0.002, p < 0.001, respectively). Plasma LPO levels were statistically different between the CONTROL/DIC groups, CONTROL/SIC groups, DIC/ SIC groups (p=0.002, p=0.047, p=0.025, respectively), The picnotic neuron counts were different between the CONTROL/SIC groups, CONTROL/ DIC groups, DIC/SIC groups (p < 0.001, p=0.001, p=0.024, respectively). CONCLUSION: In conclusion, dexmedetomidine had a toxic effect on cerebral neurons when it was administered centrally into the cerebrospinal fluid by the intracisternal route. PMID- 23344866 TI - Neuroprotective effect of acute interferon-beta 1B treatment after spinal cord injury. AB - AIM: The purpose of this trial was to investigate the effect of a well known immunomodulator -interferon beta- on traumatized spinal cord in terms of biochemical and histopathological features. MATERIAL AND METHODS: Twenty-four rats were used in this trial. The rats were divided into 3 groups. In the first group of rats, spinal cord injury was created by the weight drop method and interferon beta was administered. In the second group, physiological saline was administered. Third group was used as control. Rats were sacrificed 24 hours following trauma. Heat shock protein 70 levels were measured in the spinal cord samples and the samples were examined histopathologically. RESULTS: When the rats in the physiological saline and control groups were compared to rats treated with interferon beta 1b, those treated with interferon beta 1b revealed significant increases in the heat shock protein 70 levels in tissues, and histopathological examination revealed decreases in polymorphonuclear leucocyte infiltration, haemorrhage, oedema and necrosis. CONCLUSION: Although, the results of the study indicated that interferon beta might have some healing effects via increasing the cellular heat shock protein 70 on spinal cord injuries, more studies are needed. PMID- 23344867 TI - Modified twist drill technique in the management of chronic subdural hematoma. AB - AIM: Burr-hole craniostomy is the most efficient and safe choice for surgical drainage of chronic subdural hematoma (CSDH). Although the twist-drill drainage is also relatively safe and time-saving, it carries the risk of inadequate drainage, brain penetration and hematoma formation. Our modified technique helps in avoiding bleeding and brain penetration. MATERIAL AND METHODS: The preferred sites for twist drill were the most curved parts on the cranium. Normal drilling at about 90 degree angle was done on the most curved surfaces while it was at about 60 degree angles on flat surface. This angled drilling and the curved guide wire (hooked in the distal blind end of infant feeding tube), helped to guide infant feeding tube in the hematoma cavity. Dura matter was coagulated using insulated wire. RESULTS: There was no procedure related hematoma, brain penetration and mortality in any of the 50 patients managed by the modified technique. Infant feeding tube was properly positioned in all the cases. Burr hole evacuation was done in 7 cases (14%) due to inadequate evacuation of the hematoma after TDC. CONCLUSION: Our modified technique of twist drill drainage is inexpensive, simple, safe and effective alternative technique in the treatment of CSDH. PMID- 23344868 TI - Immunohistochemical expression of ErbB2 in adamantinomatous craniopharyngiomas: a possible target for immunotherapy. AB - AIM: To determine the immunohistochemical expression of ErbB2 in adamantinomatous craniopharyngiomas (ACP) and to assess its relationship with nuclear expression of beta-catenin in surgically resected human ACP tissue sections and to estimate whether these tumors could be candidates for anti-ErbB2 therapy. MATERIAL AND METHODS: The ErbB2 and beta-catenin immunostaining was performed on paraffin embedded tissue sections of 20 ACP using avidin biotin-peroxidase complex method. ErbB2 immunoreactivity was interpreted according to the American Society of Clinical Oncology/ College of American Pathologists criterions for breast carcinoma. RESULTS: Foci of nuclear reactivity for beta-catenin was observed in all ACP tissue specimens mainly concentrated in whorl like arrays of the epithelial cells. Two (10%) of the cases were score 3+ for ErbB2 as demonstrated by strong complete membrane staining. However, the localization of 3+ ErbB2 cells was different from those with nuclear beta-catenin immunoreactivity. CONCLUSION: Our preliminary data demonstrate score 3+ staining for ErbB2 in 10% of ACP and different localization of 3+ ErbB2 cells and cells with nuclear beta-catenin immunoreactivity. However, because of the small number of cases, further studies with larger samples should be conducted to verify and validate our preliminary data and to determine the effect of ErbB2 protein in ACP cell growth, survival and differentiation. PMID- 23344869 TI - Laparoscopic revision of the distally obstructed ventriculoperitoneal shunt. AB - AIM: Evaluation of the laparoscopic assisted revision of the ventriculoperitoneal shunt as an alternative technique to the traditional laparotomy. MATERIAL AND METHODS: Out of 1181 elective neurosurgical procedures have been done from January 2009 to December 2010. There are 98 (8.2%) ventriculoperitoneal shunt procedures. New shunt insertion was performed 41 times (41.9%) and shunt revision performed 57 times (58.1%). Shunt-related infection was detected in 11 cases (11.22%) while mechanical failure was found in 46 cases (46.9%), proximal obstruction was diagnosed in 26 cases (26.5 %) while 20 patients (20.4%) suffered from distal obstruction. Out of the 20 patients with distal obstruction, 12 patients were treated with laparoscopic assisted revision of the peritoneal end. RESULTS: Intra operative finding revealed peritoneal adhesion in 83.3% of cases and cerebrospinal fluid pseudo cyst in 16.6% while extra peritoneal tube was found in one case. Intraoperative management included adhesiolysis in 10 patient, evacuation and marsupialization of the cyst in two cases in addition to tube repositioning in all cases. There was no procedure-related complications. CONCLUSION: Laparoscopic assisted revision of the peritoneal catheter is an alternative technique to traditional laparotomy in the revision of ventriculoperitoneal shunt. PMID- 23344870 TI - The effects of splenectomy on lipid peroxidation and neuronal loss in experimental spinal cord ischemia/reperfusion injury. AB - AIM: The aim of this study is to investigate the effects of prior splenectomy on oxidative stress and neuronal loss following spinal cord ischemia and reperfusion injury. MATERIAL AND METHODS: Twenty-one Sprague Dawley rats were randomly divided into three groups as sham laparatomy (n=7), spinal cord ischemia/reperfusion (SCIR) injury (n=7) and splenectomy+spinal cord ischemia/reperfusion (SSCIR) injury (n=7). In the latter group, splenectomy was performed 3 days before the SCIR injury. The activity of lipid peroxidation in the spinal cord was assessed by malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities. The difference between the 3 groups was compared using Kruskal-Wallis test. The histological differences were assessed by counting the viable neurons. RESULTS: SCIR injury resulted in a decrease of tissue lipid peroxidation activities. There was statistically significance between the three groups (p < 0.05), but there was not any significance between the SCIR and SSCIR injury groups (p > 0.05). The number of viable neurons was higher in SSCIR group when comparing with SCIR group (p < 0.05). CONCLUSION: SCIR injury affects lipid peroxidation in rats. Prior splenectomy does not attenuate lipid peroxidation, but prevents neuronal loss after SCIR injury. PMID- 23344871 TI - Assessment of physical activity in patients with chronic low back or neck pain. AB - AIM: To investigate physical activity level in patients with chronic low back and neck pain. MATERIAL AND METHODS: 32 preoperative patients, 32 outpatients with low back or neck pain and 32 healthy controls were included in study. The physical activity level of the participants was evaluated with the International Physical Activity Questionnaire. The Oswestry Disability Index and Neck Pain Disability Index, Short Form-36, Pittsburgh Sleep Quality Index and Beck Depression Inventory were used for assessment of disability, quality of life, sleep quality and depression. RESULTS: Statistical significant differences was found in disability, sleep quality, depression, physical activity level and quality of life scores between three groups (p < 0.05). All scores of preoperative patients were significantly lower than outpatients except sleep parameter (p < 0.05). Sleep quality, disability and depression scores of patients with chronic neck pain were significantly lower and physical activity level and quality of life scores were significantly higher than patients' with chronic low back pain (p < 0.05). CONCLUSION: Physical activity modification was found in patients with chronic low back and neck pain. Physical activity level, disability, sleep, depression and quality of life scores of preoperative patients with low back pain more affected than neck patients. PMID- 23344872 TI - CT-guided percutaneous cordotomy for intractable pain in what is more than a disease: lung malignancies. AB - AIM: Lung cancer is the leading cause of cancer-related mortality worldwide. Pain is a common problem in these patients, yet inadequate or dissatisfactory management is prevalent. MATERIAL AND METHODS: Between 1987 and 2012, 224 patients with intractable pain were treated with computerized tomography (CT)- guided cordotomy. Among them, 210 had intractable pain due to malignancies. The majority of the cases were diagnosed as pulmonary malignancies (108 patients). Sixty-seven were pulmonary carcinoma, 26 mesothelioma and 15 Pancoast tumors. RESULTS: After cordotomy, 98.13% of cancer patients reported initial pain relief. Minimum and maximum preoperative scores of the Karnofsky Performance Scale were 20 and 70, versus postoperative scores of 40 and 90 (p < 0.001). The median preoperative VAS score was 8 (6-9). On the first postoperative day, the score dropped sharply to 0 (0-8) (p < 0.001). In this selected series of 108 percutaneous cordotomy procedures, as well as in the total series of 224 patients, there was no mortality or major morbidity. CONCLUSION: CT-guided percutaneous cordotomy is an effective procedure that should be used in the treatment of cancer-related pain problems. We suggest that cordotomy should be preferred as soon as possible in patients who fail to respond to the classic analgesic therapy. PMID- 23344873 TI - Concomitant tubercular and fungal cerebellar abscess in an immunocompromised girl. AB - Concomitant tubercular and fungal cerebellar abscess is rare and we report the first concomitant recurrent multi-lobulated tubercular and fungal cerebellar abscess in an immunocompromised girl with Histiocytosis-X. She presented with cerebellar abscess history diagnosed during the ongoing treatment for tuberculous meningitis. The abscess was drained. Upon the detection of cerebellar abscess recurrence and pulmonary infection, she was referred to our clinic five weeks after the first surgical intervention. Patient was conscious, co-operating but confused. She had severe cachexia, stiff neck and fever. Fundus examination showed bilateral papilledema. Cranial MR images revealed multiple lobulated lesions. Suboccipital craniectomy was performed and abscess was evacuated in toto. Lesion was multi-lobulated. Thick, yellow-gray purulent material was drained. Histopathological examinations yielded Langhans giant cells,budding and branching fungal structures. Fungal infection was identified. We emphasize that posterior decompression and total resection should be considered first in the management of lesions with mass effect in the posterior fossa. Also the presence of concomitant fatal fungal abscess highlights that although the clinic and former diagnoses of the patient may direct the clinician to a certain pathogen, unusual resistant organisms should not be. PMID- 23344874 TI - Unusual magnetic resonance imaging appearance of multiple cystic lesions in glioblastoma multiforme. AB - The differential diagnosis of multiple ring-enhancing intraaxial lesions includes neoplastic, infectious, inflammatory, demyelinating and vascular lesions. We report a case of a 41-year-old man who presented with a brief history of left lower extremity weakness and sensory loss. Magnetic resonance imaging demonstrated multiple ring-enhancing lesions in the right frontal and parietal lobes. Neuroradiology interpretation was felt to be unlikely for a neoplastic process. The patient underwent stereotactic brain biopsy, which was diagnostic for glioblastoma multiforme. This case demonstrates the importance of histological confirmation of intraaxial brain lesions whenever feasible. The course of his disease and treatment are discussed and the literature reviewed. PMID- 23344875 TI - Primary Ewings sarcoma of cavernous sinus in an infant: a case report and review of literature. AB - Ewing's / peripheral primitive neuroectodermal tumor (pPNET) of the cavernous sinus are extremely uncommon. We present clinical, radiological, pathological findings of Ewing's / pPNET involving the cavernous sinus in an eleven-month-old infant presenting with proptosis and 6th nerve palsy. MRI Contrast scans showed a well-defined, homogenously enhancing mass involving the right cavernous sinus location. Histopathology and immunohistochemical features were consistent with Ewing's/pPNET. The patient succumbed to disease in spite of starting chemotherapy. The clinical, radiological and pathological findings of previously reported cases of Ewing's sarcoma / pPNET involving the cavernous sinus are summarized. The histological differential diagnosis of primary intracranial Ewing's sarcoma / pPNET are discussed. PMID- 23344876 TI - Bilateral globus pallidus internus deep brain stimulation in Parkinson's disease with periodic limb movement disorder. AB - Deep brain stimulation for Parkinson's disease is a well-established therapeutic intervention for refractory disease. The main nuclear targets are the subthalamic nucleus and the globus pallidus internus. Periodic limb movements are often an associated condition in patients with Parkinson's disease. Both conditions can respond to dopaminergic agents. The case of a 57-year-old man with severe Parkinson's disease and periodic limb movement who underwent bilateral globus pallidus deep brain stimulation surgery for his Parkinson's disease is presented and discussed. Intraoperatively the patient's periodic limb movements responded to voltage stimulation higher than those required for improvement of his parkinsonian symptoms. The immediate and reversible improvement in these symptoms contralateral to the stimulation site suggests pallidal stimulation may directly ameliorate periodic limb movement symptoms. PMID- 23344877 TI - Application of an antibiotic crescent-shaped polymethylmethacrylate strut in thoracic vertebral tuberculosis. AB - Spinal tuberculosis accounts for up to 50% of all cases with musculoskeletal tuberculosis. In patients needing surgical treatment, the use of anterior instrumentation offers the theoretical advantage of more complete debridement and decompression, safer mobilization and reliable deformity correction. However, the placement of instrumentation in an infected area remains a matter of debate. We present a patient with thoracic vertebral tuberculosis using an antibiotic crescent-shaped PMMA strut for spinal reconstruction and fusion. The patient recovered satisfactory and no complication was observed in the follow-up. The antibiotic crescent-shaped PMMA strut can be used as a carrier for antibiotic drug and an ideal alternative for anterior spinal reconstruction. However, long-term outcome in this case requires further evaluation. PMID- 23344878 TI - Nerve sheath myxoma (neurothekeoma) of cerebellopontine angle: case report of a rare tumor with brief review of literature. AB - Nerve sheath myxoma (neurothekeoma) are rare benign nerve sheath tumors, usually arising in the skin of the head and neck region and upper extremities in young females. To the best of author's knowledge only two cases of intracranial neurothekeoma have been published in the English literature. These tumors were located in the parasellar area and in middle cranial fossa. This is the first case report of cerebellopontine angle neurothekeoma and third case report of intracranial neurothekeoma. This patient, a 45-year-old female, presented to us with complaints of right side progressive hearing loss for 12 months and swaying during walking for 8 months. Histologically the tumor had lobular appearance with spindle or stellate cells embedded in abundant myxoid background. The tumor cells were diffusely positive for S100. The patient was symptom free at eight month follow up. PMID- 23344879 TI - Acquired cerebral hemiatrophy: Dyke-Davidoff-Masson Syndrome - a case report. AB - A rare syndrome, Dyke-Davidoff-Masson Syndrome (DDMS), with a diagnostic conundrum, and the way it was solved is presented. A 13-year-old boy presented with recurrent seizures for the past 10 years. He had been treated with anticonvulsant medication which was satisfactory at first but later the seizures recurred. Recently, the frequency of the seizures increased with preictal dizziness and postictal drowsiness. Physical examination revealed mild left hemiparesis and left deviated gait irregularity. He was mentally alert but had not achieved all the developmental milestones as compared to normal child of his age. CT and MRI scan of the head showed hemiatrophic cerebral parenchyma with prominent sulci and encephalomalacia. 24-hour intensive video EEG monitoring revealed suppression of alpha rhythm and local slow wave activity on the side of the atrophic hemisphere. PET-CT showed highly functional left cerebral hemisphere and less functional right cerebral hemisphere. The patient underwent functional hemispherectomy under neurophysiological monitoring and the nonfunctional brain tissues were resected while selectively preserving the functional areas detected by fMRI and PET-CT scan. During follow up, the patient was seizure free as well as without difficulties in performing his daily activities and communications. Functional hemispherectomy for DDMS patient has a good prognosis. PMID- 23344880 TI - Primary writing tremor responds to unilateral thalamic deep brain stimulation. AB - Primary writing tremor is a task associated tremor which occurs during and interferes with handwriting. Considered in most cases to be a nonprogressive disorder, a number of patients are significantly debilitated by the disease. The pathophysiology of the disorder is not fully understood, but felt to represent a variant of either essential tremor or dystonia versus a separate entity. Treatment has been limited to medications, writing devices and botulinum toxin type A for most patients. Recently, deep brain stimulation has been reported in a few patients as an effective option for those patients with medically refractory symptoms. We report our experience in a patient with primary writing tremor who underwent successful thalamic deep brain stimulation, discuss the current theories on the pathophysiology of the disorder and review the current literature of deep brain stimulation for refractory primary writing tremor. PMID- 23344881 TI - Pallidal deep brain stimulation in a 5-year-old child with dystonic storm: case report. AB - A 5-year-old child had a medical history of epilepsy and a newly presented mental retardation with a life-threatening dystonic storm. Neuroimagings showed bilateral calcification of the pallidum. Several treatment modalities were performed, but the symptoms showed no significant improvement. The patient was operated on in order to place a deep brain stimulation (DBS) targeting bilateral globus pallidum internus (GPi). The dystonia showed a remarkable improvement after surgery, with 81% reduction of dystonia severity after 15 months. To our best knowledge, this is the youngest patient mentioned in the literature to be treated with DBS, which was also life-saving in this case. PMID- 23344882 TI - A quantitative analysis of spontaneous isoaspartate formation from N-terminal asparaginyl and aspartyl residues. AB - The formation of isoaspartate (isoAsp) from asparaginyl or aspartyl residues is a spontaneous post-translational modification of peptides and proteins. Due to isopeptide bond formation, the structure and possibly function of peptides and proteins is altered. IsoAsp modifications within the peptide chain have been reported for many cytosolic proteins. Amyloid peptides (Abeta) deposited in Alzheimer's disease may carry an N-terminal isoAsp-modification. Here, we describe a quantitative investigation of isoAsp-formation from N-terminal Asn and Asp using model peptides similar to the Abeta N-terminus. The study is based on a newly developed separation of peptides using capillary electrophoresis (CE). 1H NMR was employed to validate the basic finding of N-terminal isoAsp-formation from Asp and Asn. Thereby, the isomerization of Asn at neutral pH (0.6 day(-1), peptide NGEF) is approximately six times faster than that within the peptide chain (AANGEF). The difference in velocity between Asn and Asp isomerization is approximately 50-fold. In contrast to N-terminal Asn, Asp isomerization is significantly accelerated at acidic pH. The kinetic solvent isotope (kD2O/kH2O) effect of 2.46 suggests a rate-limiting proton transfer in isoAsp-formation. The proton inventory is consistent with transfer of one proton in the transition state, supporting the previous notion of rate-limiting deprotonation of the peptide backbone amide during succinimide-intermediate formation. The study provides evidence for a spontaneous N-terminal isoAsp-formation within peptides and might explain the accumulation of N-terminal isoAsp in amyloid deposits. PMID- 23344883 TI - Interaction proteomics of the AMPA receptor: towards identification of receptor sub-complexes. AB - AMPA receptors (AMPAR) are the main ligand-gated ion channels responsible for the fast excitatory synaptic transmission in the mammalian brain. Whereas a number of proteins that interact with AMPAR are known to be involved in the trafficking and localization of the receptor and/or the regulation of receptor channel properties, the protein composition of the AMPAR supra-complexes are largely unclear. Recent interaction proteomics report the presence of up to 34 proteins as high-confidence constituents of the AMPAR. It was proposed that the inner core of the receptor complex consists of the GluA tetramer and four auxiliary proteins comprising transmembrane AMPA receptor regulatory proteins and/or cornichons. The other AMPAR interactors, present in lower amount, may form the outer shell of the AMPAR with a range in size and variability. PMID- 23344884 TI - Coffee, but not caffeine, has positive effects on cognition and psychomotor behavior in aging. AB - The complex mixture of phytochemicals in fruits and vegetables provides protective health benefits, mainly through additive and/or synergistic effects. The presence of several bioactive compounds, such as polyphenols and caffeine, implicates coffee as a potential nutritional therapeutic in aging. Moderate (three to five cups a day) coffee consumption in humans is associated with a significant decrease in the risk of developing certain chronic diseases. However, the ability of coffee supplementation to improve cognitive function in aged individuals and the effect of the individual components in coffee, such as caffeine, have not been fully evaluated. We fed aged rats (19 months) one of five coffee-supplemented diets (0, 0.165, 0.275, 0.55, and 0.825% of the diet) for 8 weeks prior to motor and cognitive behavior assessment. Aged rats supplemented with a 0.55% coffee diet, equivalent to ten cups of coffee, performed better in psychomotor testing (rotarod) and in a working memory task (Morris water maze) compared to aged rats fed a control diet. A diet with 0.55% coffee appeared to be optimal. The 0.165% coffee-supplemented group (three cups) showed some improvement in reference memory performance in the Morris water maze. In a subsequent study, the effects of caffeine alone did not account for the performance improvements, showing that the neuroprotective benefits of coffee are not due to caffeine alone, but rather to other bioactive compounds in coffee. Therefore, coffee, in achievable amounts, may reduce both motor and cognitive deficits in aging. PMID- 23344885 TI - A laboratory model of a prebiotic, spontaneous, and continuous enantiomeric enrichment process. AB - Construction and operation of a laboratory model, which combines the lately discovered enantioenrichment method of the author (2007) with the sun-powered evaporative pumping process of Hsu and Siegenthaler (Sedimentology 12:11-25 1969), is described. The model operated continuously for 120 days before it was intentionally shut down, even though it could have continued. During that time it raised the enantiomeric excess of the test material by a factor of 3.6. Implications of these results on the origin of biohomochirality are discussed. PMID- 23344886 TI - A ribonucleotide Origin for Life--fluctuation and near-ideal reactions. AB - Oligoribonucleotides are potentially capable of Darwinian evolution - they may replicate and can express an independent chemical phenotype, as embodied in modern enzymatic cofactors. Using quantitative chemical kinetics on a sporadically fed ribonucleotide pool, unreliable supplies of unstable activated ribonucleotides A and B at low concentrations recurrently yield a replicating AB polymer with a potential chemical phenotype. Self-complementary replication in the pool occurs during a minority (here ~ 35 %) of synthetic episodes that exploit coincidental overlaps between 4, 5 or 6 spikes of arbitrarily arriving substrates. Such uniquely productive synthetic episodes, in which near-ideal reaction sequences recur at random, account for most AB oligonucleotide synthesis, and therefore underlie the emergence of net replication under realistic primordial conditions. Because overlapping substrate spikes are unexpectedly frequent, and in addition, complex spike sequences appear disproportionately, a sporadically fed pool can host unexpectedly complex syntheses. Thus, primordial substrate fluctuations are not necessarily a barrier to Darwinism, but instead can facilitate early evolution. PMID- 23344887 TI - The CXCL12/CXCR4/CXCR7 ligand-receptor system regulates neuro-glio-vascular interactions and vessel growth during human brain development. AB - This study investigates glio-vascular interactions in human fetal brain at midgestation, specifically examining the expression and immunolocalization of the CXCL12/CXCR4/CXCR7 ligand-receptor axis and its possible role in the vascular patterning of the developing brain. At midgestation, the telencephalic vesicles are characterized by well developed radial glia cells (RGCs), the first differentiated astrocytes and a basic vascular network mainly built of radial vessels. RGCs have been recognized to contribute to cerebral cortex neuro vascular architecture and have also been demonstrated to act as a significant source of neural cells (Rakic, Brain Res 33:471-476, 1971; Malatesta et al, Development 127:5253-5263, 2000). According to our hypothesis CXCL12, a potent migration and differentiation chemokine released by RGCs, may act as a linking factor coordinating neuroblast migration with vessel growth and patterning through the activation of different ligand/receptor axes. The obtained results support this hypothesis showing that together with CXCR4/CXCR7-reactive neuroblasts, which migrate in close association with CXCL12 RGCs, layer-specific subsets of CXCL12 RGCs and astrocytes specifically contact the microvessel wall. Moreover, the CXCL12/CXCR4/CXCR7 system appears to be directly involved in microvessel growth, its members being differentially expressed in angiogenically activated microvessels and vascular sprouts. PMID- 23344888 TI - High risk of primary liver cancer in a cohort of 179 patients with Acute Hepatic Porphyria. AB - BACKGROUND/AIMS: Previous studies have indicated a high risk of hepatocellular carcinoma in acute hepatic porphyrias. In this retrospective study we present the incidence of primary liver cancer and clinical characteristics in a cohort of 179 acute porphyria patients above the age of 50 years. METHODS: Twenty-three cases with primary liver cancer were found either by a surveillance program or due to clinical suspicion. Standardized rate ratio was used to estimate the relative risk of primary liver cancer after indirect standardization. Survival data were calculated using the Kaplan-Meier method. RESULTS: The mean age at diagnosis was 69 years. Hepatocellular carcinoma was found in 19 patients while four patients had cholangiocarcinoma or a combination of the two. Four patients had underlying cirrhosis. Mean tumour size was 4.3 cm in the surveillance group and 10.3 cm in the non-surveillance group (p = 0.01). The overall relative risk of primary liver cancer was 86 above the age of 50: 150 for women and 37 for men. Mean survival time was 5.7 years. CONCLUSION: Acute hepatic porphyria carries a high risk of primary liver cancer above the age of 50 which warrants ultrasound surveillance. Sex distribution and frequency of cirrhosis differs from more common aetiologies of primary liver cancer. PMID- 23344889 TI - Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexia. AB - BACKGROUND: Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. Inhibiting the signaling of the transcription factor nuclear factor kappa B (NF-kappaB) largely prevents cancer-induced muscle wasting in murine models. We have previously shown the utility of Compound A, a highly selective novel NF-kappaB inhibitor that targets the IkappaB kinase complex, to provide clinical benefit in cancer-induced skeletal muscle and cardiac atrophy. METHODS: Using a metabolomics approach, we describe the changes found between cachectic and noncachectic gastrocnemius muscles before and after Compound A treatment at various doses. RESULTS: Of the 234 metabolites in the gastrocnemius, cachexia-induced changes in gastrocnemius metabolism reset the steady-state abundances of 42 metabolites (p < 0.05). These changes, not evenly distributed across biochemical categories, are concentrated in amino acids, peptides, carbohydrates and energetics intermediates, and lipids. The gastrocnemius glycolytic pathway is markedly altered-changes consistent with tumor Warburg physiology. This is the first account of a Warburg effect that is not exclusively restricted to cancer cells or rapidly proliferating nonmalignant cells. Cachectic gastrocnemius also displays tricarboxylic acid cycle disruptions, signs of oxidative stress, and impaired redox homeostasis. Compound A only partially rescues the phenotype of the cachectic gastrocnemius, failing to restore the gastrocnemius' baseline metabolic profile. CONCLUSIONS: The findings in the present manuscript enumerate the metabolic consequences of cachexia in the gastrocnemius and demonstrate that NF-kB targeted treatment only partly rescues the cachectic metabolic phenotype. These data strengthen the previous findings from metabolomic characterization of serum in cachectic animals, suggesting that many of the metabolic alterations observed in the blood originate in the diseased muscle. These findings provide significant insight into the complex pathophysiology of cancer cachexia and provide objective criteria for evaluating future therapeutics. PMID- 23344890 TI - Large-scale isolation of human skeletal muscle satellite cells from post-mortem tissue and development of quantitative assays to evaluate modulators of myogenesis. AB - BACKGROUND: During aging, there is a decreased ability to maintain skeletal muscle mass and function (sarcopenia). Such changes in skeletal muscle are also co-morbidities of diseases including cancer, congestive heart failure and chronic obstructive pulmonary disease. The loss of muscle mass results in decreased strength and exercise tolerance and reduced ability to perform daily activities. Pharmacological agents addressing these pathologies could have significant clinical impact, but their identification requires understanding of mechanisms driving myotube formation (myogenesis) and atrophy and provision of relevant assays. The aim of this study was to develop robust in vitro methods to study human myogenesis. METHODS: Satellite cells were isolated by digestion of post mortem skeletal muscle and selection using anti-CD56 MicroBeads. CD56(+) cell derived myotubes were quantified by high content imaging of myosin heavy chains. TaqMan-polymerase chain reaction arrays were used to quantify expression of 41 selected genes during differentiation. The effects of activin receptor agonists and tumour necrosis factor alpha (TNFalpha) on myogenesis and gene expression were characterised. RESULTS: Large-scale isolation of CD56(+) cells enabled development of a quantitative myogenesis assay with maximal myotube formation 3 days after initiating differentiation. Gene expression analysis demonstrated expression of 19 genes changed substantially during myogenesis. TNFalpha and activin receptor agonists inhibited myogenesis and downregulated gene expression of muscle transcription factors, structural components and markers of oxidative phenotype, but only TNFalpha increased expression of pro-inflammatory markers. CONCLUSIONS: We have developed methods for large-scale isolation of satellite cells from muscle and quantitative assays for studying human myogenesis. These systems may prove useful as part of a screening cascade designed to identify therapeutic agents for improving muscle function. PMID- 23344891 TI - Ultrastructural pathology and interorganelle cross talk in hepatotoxicity. AB - Mitochondria, endoplasmic reticulum (ER), cytoplasmic lipid droplets (CLD), and Golgi vesicles use cross talk to control hepatocyte metabolism, growth, and stress. Interpretation of ultrastructural change requires knowledge of how cross talk pathways function, how differential activation of hepatocellular signals influences organelle structure, and how organelles position themselves to become central hubs for stress responses. Mitochondria, by coupling energy production to pathways for protection, form critical platforms for innate signaling. Mitochondrial outer and inner membranes activate channels and signals to translocate peptides that drive oxidative phosphorylation, beta-oxidation of fatty acids, and calcium ion (Ca(2+)) flux. In cell stress, mitochondrial signals initiate fusion and fission, reactive oxygen species (ROS) control, autophagy, apoptosis, and senescence. Specialized tethering proteins tie mitochondria to ER to support translocation of metabolites. For Ca(2+) translocation, ER pores are connected to mitochondrial voltage-dependent anion channels, and for mitochondrial fission, unique membrane proteins pull ER to mitochondria. In toxic injury, cytosolic cytokines translocate to alter metabolism. Toxic effects on ER lipid synthesis lead to Golgi vesicle reduplication and transport of perilipin and other protein cargos into CLDs. How cellular proteostasis, oxidative homeostasis, and ion balance are maintained depend upon the effectiveness of mitochondrial ROS defense responses, unfolded protein responses in mitochondria and ER, and other organelle defenses. PMID- 23344893 TI - Reference values of aortic flow velocity integral in 1193 healthy infants, children, and adolescents to quickly estimate cardiac stroke volume. AB - The aortic velocity time integral (VTI) is an echocardiographic tool used to estimate cardiac output (CO) by multiplying it with the aortic valve (AV) area and heart rate (HR). Inaccurate measurement of AV diameter will lead to squared miscalculation of CO. The aortic VTI itself can serve as a left-ventricular (LV) output parameter. The normal range of aortic VTI in adulthood is relatively stable, compared with childhood, but reference data are lacking. The aim of this study was to establish reference values of VTI in infants, children, and adolescents. A retrospective analysis of 1223 echocardiographic examinations of healthy children (age 0-20 years, body surface area [BSA] 0.11-2.23 m(2)) was performed. Data were correlated with age, BSA, and HR, and age subgroups with normal distribution were determined. Interobserver and intraobserver variability was calculated. Aortic VTI ranged from mean 13.8 cm (10.0-18.4 cm 5-95th percentile) in neonates to 25.1 cm (19.6-32.8 cm 5-95th percentile) in children >17 years of age and had a positive correlation with age (r = 0.685, p < 0.001), BSA (r = 0.645, p < 0.001) and a negative correlation with HR (r = -0.710, p < 0.001). Interobserver and intraobserver variability were excellent (3.9 +/- 3.1 and 4.6 +/- 3.7 %, respectively). Calculated mean values and percentile charts for the different age groups can serve as reference data to easily judge LV output in patients with or without congenital heart disease without enlargement or dysfunction of the AV. PMID- 23344894 TI - Infant cardiac magnetic resonance imaging using oscillatory ventilation: safe and effective. AB - Cardiac magnetic resonance imaging (CMR) for infants and young children typically requires sedation. General anesthesia with controlled ventilation can eliminate motion artifact with breath-holds during imaging to limit respiratory artifact, but these may lead to atelectasis or other complications. High-frequency oscillatory ventilation (HFOV) provides ventilation with near-constant mean airway pressure and minimal movement of chest wall and diaphragm, thus obviating the need for breath-holding. Clinical data were collected for 8 infants who underwent CMR with HFOV and 8 controls who underwent CMR with conventional ventilator and breath-hold technique. Data included demographic information, adverse events, and scan-acquisition time. Studies were reviewed for image quality by two cardiologists who were blinded to type of ventilation. There were no significant differences in patient characteristics between the two groups. There was no significant difference in average image quality for cine short-axis or black blood imaging. Total CMR scan time was not significantly different between groups, but the short-axis cine stack was acquired more quickly in the HFOV group (1.8 +/- 0.8 vs. 5.0 +/- 3.6 min). There were no adverse events in the HFOV group, but scans were terminated early for two patients in the conventional ventilator group. HFOV during CMR is feasible and well tolerated. Image quality is equivalent to that obtained with conventional ventilation with breath-holding technique and allows shorter cine scan times for some sequences. PMID- 23344895 TI - Subclinical hypothyroidism as a risk factor for the development of cardiovascular disease in obese adolescents with nonalcoholic fatty liver disease. AB - No data are available on the relationship between subclinical hypothyroidism and risk factors for the development of cardiovascular disease in obese adolescents with nonalcoholic fatty liver disease (NAFLD). This study aimed to determine whether an association exists between subclinical hypothyroidism and risk factors for the development of cardiovascular disease in obese adolescents with NAFLD. The study enrolled 111 obese adolescents and 42 lean subjects. The obese subjects were divided into two subgroups based on the presence or absence of fatty liver with high transaminases: a NAFLD group and a non-NAFLD group. Subclinical hypothyroidism was defined as a thyroid-stimulating hormone (TSH) level higher than 4 mIU/l and a normal free-thyroxine level (0.6-1.8 ng/dl). Insulin resistance was calculated by the homeostasis model assessment (HOMA-IR). Left ventricular mass (LVM), LVM index measurements, carotid intima media thickness (IMT), and HOMA-IR values were higher in the NAFLD obese group with TSH levels higher than 4 mIU/l than in the NAFLD obese group with TSH levels lower than 4 mIU/l. Elevated TSH values in the NAFLD obese group were positively correlated with most of the metabolic and cardiovascular risk parameters such as total cholesterol (r = 0.606, p = 0.001), triglycerides (r = 0.476, p = 0.016), low density lipoprotein cholesterol (r = 0.461, p = 0.004), insulin (r = 0.607, p = 0.001), HOMA-IR (r = 0.596, p = 0.002), carotid IMT (r = 0.894, p < 0.0001), and LVM (r = 0.563, p = 0.003). The findings demonstrated that the obese adolescents with NAFLD and subclinical hypothyroidism had a more adverse cardiovascular risk profile and a higher carotid IMT and LVM. PMID- 23344896 TI - Women and men with stable coronary artery disease: different risk factors but similar outcomes! PMID- 23344898 TI - Synthesis, characterisation and in vitro anticancer activity of hexanuclear thiolato-bridged arene ruthenium metalla-prisms. AB - Hexanuclear thiolato-bridged arene ruthenium metalla-prisms of the general formula [(p-cymene)(6)Ru(6)(SR)(6)(tpt)(2) ](6+) (R=CH(2)Ph, CH(2)C(6)H(4)-p-tBu, CH(2)CH(2)Ph; tpt=2,4,6-tris(4-pyridyl)-1,3,5-triazine), obtained from the dinuclear precursors [(p-cymene)(2)Ru(2)(SR)(2)Cl(2)], AgCF(3)SO(3) and tpt, have been isolated and fully characterised as triflate salts. The metalla-prisms are highly cytotoxic against human ovarian cancer cells, especially towards the cisplatin-resistant cell line A2780cisR (IC(50) <0.25 MUM). PMID- 23344899 TI - Metal dichalcogenide nanosheets: preparation, properties and applications. AB - Two-dimensional (2D) nanomaterials have received much attention in recent years, because of their unusual properties associated with their ultra-thin thickness and 2D morphology. Besides graphene which has aroused tremendous research interest, other types of 2D nanomaterials such as metal dichalcogenides have also been studied and applied in various applications including electronics, optoelectronics, energy storage devices, and so on. In this tutorial review, we will take MoS(2) as a typical example to introduce the latest research development of 2D inorganic nanomaterials with emphasis on their preparation methods, properties and applications. PMID- 23344900 TI - Network analysis of genomic alteration profiles reveals co-altered functional modules and driver genes for glioblastoma. AB - The heterogeneity of genetic alterations in human cancer genomes presents a major challenge to advancing our understanding of cancer mechanisms and identifying cancer driver genes. To tackle this heterogeneity problem, many approaches have been proposed to investigate genetic alterations and predict driver genes at the individual pathway level. However, most of these approaches ignore the correlation of alteration events between pathways and miss many genes with rare alterations collectively contributing to carcinogenesis. Here, we devise a network-based approach to capture the cooperative functional modules hidden in genome-wide somatic mutation and copy number alteration profiles of glioblastoma (GBM) from The Cancer Genome Atlas (TCGA), where a module is a set of altered genes with dense interactions in the protein interaction network. We identify 7 pairs of significantly co-altered modules that involve the main pathways known to be altered in GBM (TP53, RB and RTK signaling pathways) and highlight the striking co-occurring alterations among these GBM pathways. By taking into account the non-random correlation of gene alterations, the property of co alteration could distinguish oncogenic modules that contain driver genes involved in the progression of GBM. The collaboration among cancer pathways suggests that the redundant models and aggravating models could shed new light on the potential mechanisms during carcinogenesis and provide new indications for the design of cancer therapeutic strategies. PMID- 23344901 TI - Heaven can wait. How religion modulates temporal discounting. AB - Evidence suggests that religious systems have specific effects on attentional and action control processes. The present study investigated whether religions also modulate choices that involve higher-order knowledge and the delay of gratification in particular. We tested Dutch Calvinists, Italian Catholics, and Atheists from both countries/cultures using an intertemporal choice task where participants could choose between a small immediate and a larger delayed monetary reward. Based on the Calvinist theory of predestination and the Catholic concept of a cycle of sin-confession-expiation, we predicted a reduced delay tolerance, i.e., higher discount rate, for Italian Catholics than for Dutch Calvinists, and intermediate rates for the two atheist groups. Analyses of discount rates support our hypotheses. We also found a magnitude effect on temporal discounting and faster responses for large than for small rewards across religions and countries/cultures. We conclude that temporal discounting is specifically modulated by religious upbringing rather than by generic cultural differences. PMID- 23344902 TI - Temporal characteristics of the effects of visual pattern redundancy on encoding and storage processes: evidence from rapid serial visual presentation. AB - Pattern redundancy is a key concept for representing the amount of internal mental load (encoding efficiency) needed for pattern perception/recognition. The present study investigated how pattern redundancy influences encoding and memory processes in the visual system using a rapid serial visual presentation (RSVP) paradigm. With RSVP, it is well known that participants often fail to detect repetitions of words (repetition blindness, RB). We used this phenomenon as an index of the encoding and storage of visual patterns. In three experiments, we presented patterns with higher and lower redundancy, as defined by Garner's equivalent set size (ESS). The results showed that RB occurred more frequently for higher redundancy patterns when the temporal distance between the targets was less than 500 ms; this tendency was reversed with longer temporal distances of over 500 ms. Our results suggest that pattern redundancy modulates both the early encoding and subsequent memory processes of a representation. PMID- 23344903 TI - "Deafness" effects in detecting alterations to auditory feedback during sequence production. AB - Past research has shown that when discrete responses are associated with a perceptual goal, performers may have difficulty detecting stimuli that are commensurate with that goal. Three experiments are reported here that test whether such effects extend to sequence production. In Experiment 1, participants performed 8-note melodies repeatedly, and on each trial a single tone could be altered with respect to its pitch and/or synchrony with actions. Results suggested a selective deficit of detection when feedback pitch was unchanged and the event was slightly delayed. Experiment 2 showed that this "deafness" to feedback is limited to rhythmic motor tasks that require sequencing, in that similar effects did not emerge when participants produced pitch sequences by tapping a single key repeatedly. A third experiment demonstrated similar results to Experiment 1 when the mapping of keys to pitches on the keyboard was reversed. Taken together, results suggest a selective deafness to response-congruent delayed feedback, consistent with the idea that performers suppress previously planned events during production. PMID- 23344904 TI - Monolignol pathway 4-coumaric acid:coenzyme A ligases in Populus trichocarpa: novel specificity, metabolic regulation, and simulation of coenzyme A ligation fluxes. AB - 4-Coumaric acid:coenzyme A ligase (4CL) is involved in monolignol biosynthesis for lignification in plant cell walls. It ligates coenzyme A (CoA) with hydroxycinnamic acids, such as 4-coumaric and caffeic acids, into hydroxycinnamoyl-CoA thioesters. The ligation ensures the activated state of the acid for reduction into monolignols. In Populus spp., it has long been thought that one monolignol-specific 4CL is involved. Here, we present evidence of two monolignol 4CLs, Ptr4CL3 and Ptr4CL5, in Populus trichocarpa. Ptr4CL3 is the ortholog of the monolignol 4CL reported for many other species. Ptr4CL5 is novel. The two Ptr4CLs exhibited distinct Michaelis-Menten kinetic properties. Inhibition kinetics demonstrated that hydroxycinnamic acid substrates are also inhibitors of 4CL and suggested that Ptr4CL5 is an allosteric enzyme. Experimentally validated flux simulation, incorporating reaction/inhibition kinetics, suggested two CoA ligation paths in vivo: one through 4-coumaric acid and the other through caffeic acid. We previously showed that a membrane protein complex mediated the 3-hydroxylation of 4-coumaric acid to caffeic acid. The demonstration here of two ligation paths requiring these acids supports this 3 hydroxylation function. Ptr4CL3 regulates both CoA ligation paths with similar efficiencies, whereas Ptr4CL5 regulates primarily the caffeic acid path. Both paths can be inhibited by caffeic acid. The Ptr4CL5-catalyzed caffeic acid metabolism, therefore, may also act to mitigate the inhibition by caffeic acid to maintain a proper ligation flux. A high level of caffeic acid was detected in stem-differentiating xylem of P. trichocarpa. Our results suggest that Ptr4CL5 and caffeic acid coordinately modulate the CoA ligation flux for monolignol biosynthesis. PMID- 23344905 TI - Enhanced reactive oxygen species scavenging by overproduction of superoxide dismutase and catalase delays postharvest physiological deterioration of cassava storage roots. AB - Postharvest physiological deterioration (PPD) of cassava (Manihot esculenta) storage roots is the result of a rapid oxidative burst, which leads to discoloration of the vascular tissues due to the oxidation of phenolic compounds. In this study, coexpression of the reactive oxygen species (ROS)-scavenging enzymes copper/zinc superoxide dismutase (MeCu/ZnSOD) and catalase (MeCAT1) in transgenic cassava was used to explore the intrinsic relationship between ROS scavenging and PPD occurrence. Transgenic cassava plants integrated with the expression cassette p54::MeCu/ZnSOD-35S::MeCAT1 were confirmed by Southern-blot analysis. The expression of MeCu/ZnSOD and MeCAT1 was verified by quantitative reverse transcription-polymerase chain reaction and enzymatic activity analysis both in the leaves and storage roots. Under exposure to the ROS-generating reagent methyl viologen or to hydrogen peroxide (H2O2), the transgenic plants showed higher enzymatic activities of SOD and CAT than the wild-type plants. Levels of malondialdehyde, chlorophyll degradation, lipid peroxidation, and H2O2 accumulation were dramatically reduced in the transgenic lines compared with the wild type. After harvest, the storage roots of transgenic cassava lines show a delay in their PPD response of at least 10 d, accompanied by less mitochondrial oxidation and H2O2 accumulation, compared with those of the wild type. We hypothesize that this is due to the combined ectopic expression of Cu/ZnSOD and CAT leading to an improved synergistic ROS-scavenging capacity of the roots. Our study not only sheds light on the mechanism of the PPD process but also develops an effective approach for delaying the occurrence of PPD in cassava. PMID- 23344906 TI - CT coronary angiography at an ultra-low radiation dose (<0.1 mSv): feasible and viable in times of constraint on healthcare costs. AB - Computed tomography coronary angiography (CTCA) has reached very high standards both in terms of diagnostic performance and radiation dose reduction. This commentary follows a report on CTCA using less than 0.1 mSv in selected patients. This is an extraordinary accomplishment, both for technology and for medicine. The difficult task is now to implement this tool in clinical practice so it can play the best possible role. CTCA can improve diagnostic pathways, can save money for healthcare systems and could even improve pharmacological therapy. All of this may happen, but it will require the combined effort of all the experienced operators in this field, including the referring clinicians. In times of financial constraint, CTCA may also help to restrict ineffective medical expenses. PMID- 23344907 TI - Delivery systems and local administration routes for therapeutic siRNA. AB - With the increasing number of studies proposing new and optimal delivery strategies for the efficacious silencing of gene-related diseases by the local administration of siRNAs, the present review aims to provide a broad overview of the most important and latest developments of non-viral siRNA delivery systems for local administration. Moreover, the main disease targets for the local delivery of siRNA to specific tissues or organs, including the skin, the lung, the eye, the nervous system, the digestive system and the vagina, were explored. PMID- 23344908 TI - Preclinical pharmacokinetic/pharmacodynamic models to predict schedule-dependent interaction between erlotinib and gemcitabine. AB - PURPOSE: To investigate the pharmacological effects of different erlotinib (ER) and gemcitabine (GM) combination schedules by in vitro and in vivo experiments and PK/PD models in non-small cell lung cancer cells. METHODS: H1299 cells were exposed to different ER combined with GM schedules. Cell growth inhibition was analyzed to evaluate these schedules. A preclinical in vivo study was then conducted to compare tumor suppression effects of different schedules in H1299 xenografts. PK/PD models were developed to quantify the anti-tumor interaction of ER and GM. RESULTS: Synergism was observed when ER preceded GM, but other sequences showed antagonism. The optimal in vitro schedule, or interval schedule, was applied to the animal study, which showed greater anti-tumor effect than simultaneous group. PK/PD models implied that interaction of the two drugs was additive in simultaneous treatment but synergistic in interval schedule. The simulation results showed that interval schedule can delay tumor growth for a longer time, and demonstrated more evident anti-tumor effect compared with simultaneous group if the treatment duration was longer. CONCLUSIONS: Interval schedule of the two drugs can achieve synergistic anti-tumor effect, and is superior to simultaneous treatment. PMID- 23344910 TI - Cardiac CT and MRI for congenital heart disease in Asian countries: recent trends in publication based on a scientific database. AB - In the past 12 years, during the process of imaging congenital heart disease (CHD), Asian doctors have not only made every effort to adhere to established magnetic resonance imaging (MRI) protocols as in Western countries, but also have developed Computed tomography (CT) as an alternative problem-solving technique. Databases have shown that Asian doctors were more inclined to utilize CT than MRI in evaluating CHD. Articles in the literature focusing on CT have been cited more frequently than articles on MRI. Additionally, several repeatedly cited CT articles have become seminal papers in this field. The database reflects a trend suggesting that Asian doctors actively adapt to new techniques and flexibly develop unique strategies to overcome limitations caused by the relatively limited resources often available to them. PMID- 23344909 TI - Magnetic nanoparticles for tumor imaging and therapy: a so-called theranostic system. AB - In this review, we discussed the establishment of a so-called "theranostic" system by instituting the basic principles including the use of: [1] magnetic iron oxide nanoparticles (MION)-based drug carrier; [2] intra-arterial (I.A.) magnetic targeting; [3] macromolecular drugs with unmatched therapeutic potency and a repetitive reaction mechanism; [4] cell-penetrating peptide-mediated cellular drug uptake; and [5] heparin/protamine-regulated prodrug protection and tumor-specific drug re-activation into one single drug delivery system to overcome all possible obstacles, thereby achieving a potentially non-invasive, magnetic resonance imaging-guided, clinically enabled yet minimally toxic brain tumor drug therapy. By applying a topography-optimized I.A. magnetic targeting to dodge rapid organ clearance of the carrier during its first passage into the circulation, tumor capture of MION was enriched by >350 folds over that by conventional passive enhanced permeability and retention targeting. By adopting the prodrug strategy, we observed by far the first experimental success in a rat model of delivering micro-gram quantity of the large beta-galactosidase model protein selectively into a brain tumor but not to the ipsi- or contra-lateral normal brain regions. With the therapeutic regimens of most toxin/siRNA drugs to fully (>99.9%) eradicate a tumor being in the nano-molar range, the prospects of reaching this threshold become practically accomplishable. PMID- 23344911 TI - Clusterin expression in elastofibroma dorsi. AB - BACKGROUND: Elastofibroma dorsi is a benign soft tissue lesion composed of abnormal elastic fibers. Degenerated elastic fibers in skin and liver are associated with clusterin, an apoprotein that shares functional properties with small heat shock proteins. We evaluated the staining pattern and possible role of clusterin in elastofibroma dorsi. MATERIAL AND METHODS: Twenty-one subcutaneous elastofibromas from the scapular region were evaluated with Elastica van Gieson and Orcein stains, immunohistochemically with antibodies to clusterin, smooth muscle actin, S-100, vimentin and CD34 and correlated with clinical data with respect to physical trauma. RESULTS: Clusterin correlated with the staining pattern of Elastica van Gieson and labelled abnormal broad coarse fibrillar and globular elastic fibers in all elastofibromas. Orcein stains additionally identified fine oxytalan fibers which were not stained by clusterin. Clusterin staining was observed only on the outside of the elastin fibers, while the cores of fibers and globules were unstained. 4/21 elastofibromas showed cellular nodules with a myxoid/collagenous stroma. The round to oval cells showed cytoplasmic staining with vimentin and clusterin; CD34 labelled mostly cell membranes. The cells lacked SMA and S-100 expression. The central areas of the nodules were devoid of elastic fibers, but the periphery contained coarse fibers and globules. 9/ 11 patients, for whom clinical data were available, reported trauma to the scapular region. CONCLUSION: Many investigated ED were associated with trauma, which supports a reactive/degenerative etiology of ED. The abnormal large elastic fibers in all ED were enveloped by clusterin. Clusterin deposition may protect elastic fibers from degradation and thus contribute indirectly to the tumor-like presentation of ED. PMID- 23344912 TI - Safety and efficacy of fimasartan in patients with arterial hypertension (Safe KanArb study): an open-label observational study. AB - BACKGROUND: Angiotensin II receptor blockers (ARBs) play a key role in hypertension therapy. Recently, fimasartan, the ninth ARB, was developed, but its safety and efficacy have not been well established. OBJECTIVE: The objective of this study was to determine whether age, sex, concomitant disease, and current antihypertensive medications affect the safety and efficacy of fimasartan in patients with arterial hypertension. METHODS: This was a large-scale, open-label observational study to determine the safety and efficacy of fimasartan in patients with hypertension. Patients who were treated for more than 2 months with fimasartan (60 or 120 mg, once daily) were recruited, and the data were systematically collected using electronic case report forms. Written informed consent forms were obtained from all patients. RESULTS: A total of 14,151 patients (50.7 % males; mean age 59 +/- 12 years) were evaluated, of whom 37.9 % were never treated with fimasartan, 53.5 % were switched to fimasartan, and 8.5 % had fimasartan added to their treatment. Overall, fimasartan reduced systolic blood pressure (SBP) from 145.4 +/- 18.1 to 126.8 +/- 12.6 mmHg and diastolic blood pressure (DBP) from 88.7 +/- 11.8 to 79.0 +/- 8.7 mmHg (all p < 0.001). The pulse rate decreased from 74.4 +/- 10.3 to 71.9 +/- 9.2 beats/min in comparison with before treatment (p < 0.001). The reductions were similar between sexes, age groups, and patients with and without co-morbidities, and were not dependent on prior or concomitant treatment with other antihypertensive drugs. Adverse events were reported in 3.31 % (treatment-emergent) and 2.35 % (drug-related) of patients; there were no dose differences for adverse events. The most frequent adverse events were dizziness (1.55 %) and headache (0.52 %); other adverse events were rare. The responder rate (DBP to <90 mmHg or a reduction of >=10 mmHg) and the goal rate (combined SBP/DBP <140/90 mmHg) were 85.0 and 75.6 %, respectively. Global drug compliance was rated as excellent, very good, good, and poor in 68.1, 26.9, 3.4, and 1.7 % of patients, respectively. CONCLUSION: The safety, efficacy, and compliance of fimasartan were found to be excellent in a large patient population that included patients potentially at higher risk for adverse events. PMID- 23344913 TI - The Inventory of Callous and Unemotional Traits: a construct-validational analysis in an at-risk sample. AB - The Inventory of Callous and Unemotional Traits (ICU), developed to assess callous/unemotional (CU) traits, has recently experienced increased attention in light of the proposal to add a CU specifier to the conduct disorder diagnosis in DSM-5. In a sample of 70 at-risk adolescents (ages 13-17 years) in the foster care system who received a contemplative intervention program, the present study placed the ICU within a nomological network of correlates, including anxiety, depression, hopefulness, loneliness, and physiological measures of stress (e.g., cortisol). The findings offered some support for the ICU's construct validity, including significant negative associations with measures of compassion toward others. Nevertheless, unexpected substantial positive correlations emerged with multiple measures of psychological distress, raising questions concerning other aspects of the ICU's construct validity. Taken together, results of the current study suggest that rather than assessing a dearth of all major emotions as implied by its name and some previous descriptions, the ICU may be heavily saturated with negative emotionality and global maladjustment. PMID- 23344914 TI - The validity of the MSI-BPD among inpatient adolescents. AB - Although the McLean Screening Instrument for Borderline Personality Disorder (MSI BPD) has shown validity in adult samples, only one study has explored its validity in adolescents and, to our knowledge, the measure has not been validated with inpatient adolescents. The aim of the current study was to evaluate the reliability, and convergent and criterion validity, of the MSI-BPD in an effort to establish the clinical utility of the MSI-PBD as a screening measure for BPD in inpatient adolescents. A total of 121 adolescents from an acute care inpatient unit were recruited for the study. Convergent validity was examined with established measures of BPD in adolescents, including the use of receiver operating characteristics analyses to establish a clinical cutoff score for the MSI-BPD in predicting a diagnosis of BPD. Criterion validity was examined by using this clinical cutoff to investigate group differences in suicidal ideation and Axis I symptoms, known correlates of BPD. Findings demonstrated support for validity of the MSI-BPD when used among inpatient adolescents, and established a clinical cutoff of 5.5. Taken together, this study demonstrates adequate validity for the MSI-BPD, and suggests it is a valuable screening measure for BPD in adolescent inpatients. PMID- 23344915 TI - Biophysical mechanism of spike threshold dependence on the rate of rise of the membrane potential by sodium channel inactivation or subthreshold axonal potassium current. AB - Spike threshold filters incoming inputs and thus gates activity flow through neuronal networks. Threshold is variable, and in many types of neurons there is a relationship between the threshold voltage and the rate of rise of the membrane potential (dVm/dt) leading to the spike. In primary sensory cortex this relationship enhances the sensitivity of neurons to a particular stimulus feature. While Na+ channel inactivation may contribute to this relationship, recent evidence indicates that K+ currents located in the spike initiation zone are crucial. Here we used a simple Hodgkin-Huxley biophysical model to systematically investigate the role of K+ and Na+ current parameters (activation voltages and kinetics) in regulating spike threshold as a function of dVm/dt. Threshold was determined empirically and not estimated from the shape of the Vm prior to a spike. This allowed us to investigate intrinsic currents and values of gating variables at the precise voltage threshold. We found that Na+ nactivation is sufficient to produce the relationship provided it occurs at hyperpolarized voltages combined with slow kinetics. Alternatively, hyperpolarization of the K+ current activation voltage, even in the absence of Na+ inactivation, is also sufficient to produce the relationship. This hyperpolarized shift of K+ activation allows an outward current prior to spike initiation to antagonize the Na+ inward current such that it becomes self-sustaining at a more depolarized voltage. Our simulations demonstrate parameter constraints on Na+ inactivation and the biophysical mechanism by which an outward current regulates spike threshold as a function of dVm/dt. PMID- 23344917 TI - Gloomy forecast for the prophets of apocalypse and bright forecast for chemists. PMID- 23344916 TI - Detection of pulmonary nodules at paediatric CT: maximum intensity projections and axial source images are complementary. AB - BACKGROUND: Maximum intensity projection (MIP) images might be useful in helping to differentiate small pulmonary nodules from adjacent vessels on thoracic multidetector CT (MDCT). OBJECTIVE: The aim was to evaluate the benefits of axial MIP images over axial source images for the paediatric chest in an interobserver variability study. MATERIALS AND METHODS: We included 46 children with extra pulmonary solid organ malignancy who had undergone thoracic MDCT. Three radiologists independently read 2-mm axial and 10-mm MIP image datasets, recording the number of nodules, size and location, overall time taken and confidence. RESULTS: There were 83 nodules (249 total reads among three readers) in 46 children (mean age 10.4 +/- 4.98 years, range 0.3-15.9 years; 24 boys). Consensus read was used as the reference standard. Overall, three readers recorded significantly more nodules on MIP images (228 vs. 174; P < 0.05), improving sensitivity from 67% to 77.5% (P < 0.05) but with lower positive predictive value (96% vs. 85%, P < 0.005). MIP images took significantly less time to read (71.6 +/- 43.7 s vs. 92.9 +/- 48.7 s; P < 0.005) but did not improve confidence levels. CONCLUSION: Using 10-mm axial MIP images for nodule detection in the paediatric chest enhances diagnostic performance, improving sensitivity and reducing reading time when compared with conventional axial thin-slice images. Axial MIP and axial source images are complementary in thoracic nodule detection. PMID- 23344918 TI - Separating different polymers using an interacting nanopore: a Monte Carlo study. AB - Translocation of a multi-polymer system containing two kinds of polymers, polymer A and polymer B, through an interacting nanopore is studied using dynamic Monte Carlo method. Polymer A and polymer B have different polymer-pore interactions. The probability of one kind of polymer first translocating through a nanopore is dependent on the polymer-pore interactions and the magnitude of driving force for monomers inside the nanopore. At weak driving, there are separation regions where one kind of polymer translocates through the pore always before another kind of polymer. A phase diagram containing separation regions and mixed region is presented. At last, the first-in first-out rule for the polymer translocation is investigated. PMID- 23344919 TI - Enantioselective construction of 2,5-dihydropyrrole skeleton with quaternary stereogenic center via catalytic asymmetric 1,3-dipolar cycloaddition involving alpha-arylglycine esters. AB - A catalytic asymmetric construction of synthetically and biologically important 2,5-dihydropyrrole scaffolds with concomitant creation of multiple chiral carbon centers including one quaternary stereogenic center in high yields (up to 99%) and excellent enantioselectivities (up to 99% ee) has been established via an organocatalytic 1,3-dipolar cycloaddition using alpha-arylglycine esters as azomethine precursors. Moreover, a detailed investigation has been performed on the catalytic asymmetric 1,3-dipolar cycloadditions of alpha-arylglycine ester generated azomethine ylides with alkynes, providing an efficient way to simultaneously access both 2,5-dihydropyrrole diastereomers in good enantioselectivities. PMID- 23344920 TI - The rationale for platelet transfusion during cardiopulmonary bypass: an observational study. AB - PURPOSE: Platelet transfusion in cardiac surgery is often empiric as no established point-of-care tests are available for clear guidance of blood product administration, and there are many variables that can potentially increase the risk of bleeding during cardiopulmonary bypass. The objectives of this study were to determine the factors that influenced physicians' decisions to transfuse platelets perioperatively and to determine whether these factors coincide with characteristics using chart abstraction. METHODS: This study was conducted at three university affiliated hospitals using focused physician questionnaires to assess factors influencing decisions to transfuse platelets and data abstraction to determine characteristics of patients receiving platelet transfusion during cardiac surgery. RESULTS: Seventy-six physicians participated in the questionnaire; 41% identified bleeding and 22% identified both bleeding and the platelet count as the most significant factors influencing their decision to transfuse platelets. Of the 629 patients included in the study, 24.5% received a platelet transfusion intraoperatively and 4.5% received the transfusion postoperatively. The following factors were identified with the highest odds of receiving a platelet transfusion intraoperatively: combined bypass and valvular surgery (odds ratio [OR] 3.94; 95% confidence interval [CI] 1.94 to 8.00) and the presence of liver disease (OR 6.43; 95% CI 1.17 to 35.37). CONCLUSION: The use of focused physician questionnaires identified relevant aspects of patient care not apparent in the chart review that influenced the decision to transfuse platelets. The identification of bleeding, thrombocytopenia, more complex surgery, and the presence of liver disease highlights the requirement for standardized measures to assess the need for platelet transfusions in bleeding patients. PMID- 23344921 TI - Comparison of the effects of dexmedetomidine, ketamine, and placebo on emergence agitation after strabismus surgery in children. AB - BACKGROUND: Children undergoing strabismus surgery under sevoflurane anesthesia often experience emergence agitation (EA) and postoperative vomiting (POV). This study compared the effects of intraoperative dexmedetomidine, ketamine, and placebo on postoperative EA and POV. METHODS: Eighty-four children (aged two to seven years) undergoing elective strabismus surgery under sevoflurane anesthesia were randomly assigned to one of three groups (n = 28 each). Intraoperatively, the placebo, dexmedetomidine, and ketamine groups received normal saline, dexmedetomidine 1 MUg.kg(-1) iv plus a 1 MUg.kg(-1).hr(-1) infusion, and ketamine 1 mg.kg(-1) iv plus a 1 mg.kg(-1).hr(-1) infusion, respectively. Agitation scores (Pediatric Anesthesia Emergence Delirium [PAED] scale) and POV were assessed in the postanesthetic care unit (PACU) and for 24 hr on the ward. Pain scores and times to laryngeal mask airway (LMATM) removal, resumption of mental orientation, and discharge from the PACU were also assessed. RESULTS: Seventy-eight children completed the study. Peak PAED scores for EA were lower in the dexmedetomidine (P < 0.001) and ketamine (P = 0.002) groups than in the placebo group. Incidence of POV was lower in the dexmedetomidine group (15%) than in the ketamine (44%; P = 0.02) or placebo (45.8%; P = 0.02) groups. Pain scores on the ward were lower in the dexmedetomidine (P < 0.001) and ketamine (P < 0.001) groups than in the placebo group. Time to LMA removal was similar in all groups. Time for resumption of mental orientation and time to discharge from PACU were longer in the dexmedetomidine and ketamine groups than in the placebo group. CONCLUSIONS: Dexmedetomidine and ketamine appear to prevent postoperative agitation and pain after sevoflurane anesthesia for pediatric strabismus surgery. Dexmedetomidine also prevents POV. PMID- 23344922 TI - Ephedrine delays rocuronium recovery. PMID- 23344923 TI - Operating room fire using an alcohol-based skin preparation but without electrocautery. PMID- 23344926 TI - The historical development of mechanochemistry. AB - This paper reviews the history of mechanochemistry. It begins with prehistoric times, when reactions could be initiated during grinding and rubbing accidentally, and follows the main developments until recent results and current trends. There are very few records on mechanochemistry until the first systematic investigations by Spring and Lea at the end of the 19th century. For the next decades, mechanochemistry developed slowly; minerals, inorganic compounds, and polymers were the main subjects of investigation. The area became more organized in the 1960s, when several large groups were established and the first dedicated conferences were held. Mechanical alloying was invented in 1966 independently and it became a subject of intense research. Interaction between the two topics was established in the 1990s. In recent years, the mechanochemical synthesis of organic compounds was added to the main subjects and the invention of the atomic force microscope provided new ways to manipulate atoms and molecules by direct mechanical action. The theoretical explanation of mechanochemical phenomena is difficult, as the mechanism is system specific and several length and time scales are involved. Thiessen proposed the first theory, the magma-plasma model, in 1967, and deeper insight is being obtained by computer modelling combined with empirical work. Practical applications have been an important motivation throughout the history of mechanochemistry. It is used alone or in combination with other steps in an increasing number of technologies. PMID- 23344924 TI - Bone morphogenic protein-2 (BMP-2) loaded hybrid coating on porous hydroxyapatite scaffolds for bone tissue engineering. AB - In this study, a silica xerogel-chitosan hybrid is utilized as a coating material to incorporate bone morphogenic protein-2 (BMP-2) on a porous hydroxyapatite (HA) scaffold for bone tissue engineering. BMP-2 is known as a therapeutic agent for improving bone regeneration and repair. Silica xerogel-chitosan hybrids have been used for the delivery of a growth factor as well as osteoconductive coatings. The biological properties of the hybrid coating incorporated with BMP-2 were evaluated in terms of the BMP-2 release behavior, osteoblastic cellular responses and in vivo performance. BMP-2 was continuously released from the hybrid coating layer on the porous HA scaffold for up to 6 weeks. The hybrid coating containing BMP-2 showed significantly enhanced osteoblastic cell responses in comparison with the hybrid coating and HA substrate. Consequently, new bone formation was significantly increased within the hybrid coating containing BMP-2. These results reveal that the hybrid coating containing BMP-2 has the potential to be used as a bone implant, whose osteogenic properties are promoted by the release of BMP-2 in a controlled manner for a prolonged period of time. PMID- 23344925 TI - Dr. Robert E. Scully: a tribute. PMID- 23344927 TI - Regulation of sodium and calcium in Daphnia magna exposed to silver nanoparticles. AB - The toxicity of manufactured silver nanoparticles (AgNPs) has been widely studied, but the influence of AgNPs on the major ions (such as sodium [Na] and calcium [Ca]) regulations are unknown. In the present study, a freshwater cladoceran Daphnia magna was exposed to commercial AgNPs coated with polyvinylpyrrolidone. After 48 h, the Na body content was significantly reduced by AgNO3 exposure, but the Ca body content was significantly increased under AgNO3 and AgNP exposures, respectively. No effect was observed on the body concentrations of Na and Ca at 50 to 500 ug/L AgNPs with 1-uM cysteine addition. Exposure of AgNO3 and AgNPs inhibited the Na influx and elevated the Na efflux. In contrast, their exposure increased the Ca influx, but did not affect the Ca efflux. The results of the present study demonstrated the significant influences of AgNO3 and AgNPs (without cysteine) on Na and Ca regulations. Such effect of AgNPs on Na and Ca regulation disappeared after cysteine addition, indicating that the soluble Ag released from AgNPs played a major role in the ionoregulatory dysfunction. PMID- 23344928 TI - Antiviral activity of diarylheptanoid stereoisomers against respiratory syncytial virus in vitro and in vivo. AB - We previously showed that (5S)-5-hydroxy-7-(4-hydroxyphenyl)-1-phenylhept-3-one (AO-0011) and (5S)-5-methoxy-1,7-diphenylhept-3-one (AO-0016) isolated from Alpinia officinarum exhibited stronger anti-influenza virus activity and anti respiratory syncytial virus (RSV) activity, respectively, than the other isolated diarylheptanoids. In this study, we synthesized an enantiomer (AO-0503) and racemate (AO-0504) of AO-0011 and an enantiomer (AO-0514) of AO-0016. The anti RSV activities of the three stereoisomers (AO-0503, AO-0504, and AO-0514) and AO 0011 were examined in vitro and in vivo to evaluate the stereoisomeric effect on anti-RSV activity. In a plaque reduction assay using human epidermoid carcinoma cells, all four diarylheptanoids significantly exhibited anti-RSV activity, and AO-0514 and AO-0016 exhibited stronger anti-RSV activity than AO-0503, AO-0504, and AO-0011. In a murine RSV infection model, all four diarylheptanoids with anti RSV activity in vitro were also significantly effective in reducing virus titers in the lungs of RSV-infected mice. In the histopathological analysis of RSV infected lungs, the oral administration of even AO-0514, which showed the lowest reduction of virus titers in the lungs, was significantly effective in reducing the infiltration of lymphocytes and in reducing the interferon-gamma level, which is a marker of severity of pneumonia due to RSV infection, in bronchoalveolar lavage fluids prepared from RSV-infected mice. Although the stereoisomeric effects of diarylheptanoids on anti-RSV activity varied moderately, all four diarylheptanoids examined were suggested to ameliorate pneumonia and have a potential anti-RSV activity in vivo. They are possibly mother compounds for the development of an anti-RSV drug in the future. PMID- 23344929 TI - Liposomal amiodarone augments anti-arrhythmic effects and reduces hemodynamic adverse effects in an ischemia/reperfusion rat model. AB - PURPOSE: Although amiodarone is recognized as the most effective anti-arrhythmic drug available, it has negative hemodynamic effects. Nano-sized liposomes can accumulate in and selectively deliver drugs to ischemic/reperfused (I/R) myocardium, which may augment drug effects and reduce side effects. We investigated the effects of liposomal amiodarone on lethal arrhythmias and hemodynamic parameters in an ischemia/reperfusion rat model. METHODS AND RESULTS: We prepared liposomal amiodarone (mean diameter: 113 +/- 8 nm) by a thin-film method. The left coronary artery of experimental rats was occluded for 5 min followed by reperfusion. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads accumulated in the I/R myocardium. Amiodarone was measurable in samples from the I/R myocardium when liposomal amiodarone, but not amiodarone, was administered. Although the intravenous administration of amiodarone (3 mg/kg) or liposomal amiodarone (3 mg/kg) reduced heart rate and systolic blood pressure compared with saline, the decrease in heart rate or systolic blood pressure caused by liposomal amiodarone was smaller compared with a corresponding dose of free amiodarone. The intravenous administration of liposomal amiodarone (3 mg/kg), but not free amiodarone (3 mg/kg), 5 min before ischemia showed a significantly reduced duration of lethal arrhythmias (18 +/- 9 s) and mortality (0 %) during the reperfusion period compared with saline (195 +/- 42 s, 71 %, respectively). CONCLUSIONS: Targeting the delivery of liposomal amiodarone to ischemic/reperfused myocardium reduces the mortality due to lethal arrhythmia and the negative hemodynamic changes caused by amiodarone. Nano-size liposomes may be a promising drug delivery system for targeting I/R myocardium with cardioprotective agents. PMID- 23344930 TI - Protective effects of hydrogen sulfide against chronic alcohol intake-induced left ventricular remodeling in rats. AB - PURPOSE: To investigate the protective effects of hydrogen sulfide (H(2)S) against chronic alcohol intake-induced left ventricular remodeling and explore the potential mechanisms involved. METHODS: Rats were randomly divided into 4 groups: alcohol group, NaHS group, alcohol + NaHS group, and control group. The echocardiographic and morphometric studies were performed to assess left ventricular remodeling. Oxidative stress was evaluated by detecting MDA, GSH-Px, Tot-SOD, CuZn-SOD and Mn-SOD in the supernatant. Cardiomyocyte apoptotic rate was determined by flow cytometry with Annexin V/PI staining. Western blotting was conducted to detect the expression of Bcl-2 family of apoptosis regulator proteins. RESULTS: The echocardiographic and morphometric data indicated that H(2)S has protective effects against chronic alcohol intake-induced left ventricular remodeling. Our findings showed a significant increase in MDA level and decreases in GSH-Px, Tot-SOD, CuZn-SOD and Mn-SOD activities in the alcohol group compared to the control group, while in the alcohol + NaHS group, a significant decrease in MDA level and increases in GSH-Px, Tot-SOD, CuZn-SOD and Mn-SOD activities were found compared to the alcohol group. The apoptotic rate in the alcohol group was significantly higher than in the control group, whereas apoptotic rate in the alcohol + NaHS group was significantly lower than in the alcohol group. In addition, Bcl-2 and Bcl-xL expression was upregulated and Bax expression was downregulated in the alcohol + NaHS group compared to the alcohol group. CONCLUSIONS: Our study demonstrates that H(2)S protects against chronic alcohol intake-induced left ventricular remodeling via attenuating oxidative stress and apoptosis. PMID- 23344931 TI - Radiological outcome analyses of transtrochanteric posterior rotational osteotomy for osteonecrosis of the femoral head at a mean follow-up of 11 years. AB - BACKGROUND: This study investigated the radiological factors that correlated with progression of collapse and joint space narrowing after transtrochanteric posterior rotational osteotomy (PRO) for osteonecrosis of the femoral head. METHODS: This study reviewed 51 hips in 47 patients with a mean follow-up of 11 years (5-20). The subjects included 29 males and 18 females with a mean age of 34 years (12-54) at the time of surgery. The 51 hips were divided into two groups based on the radiological outcome (group I: evidence of progression of collapse and/or joint space narrowing, group II: no evidence of either progression of collapse or joint space narrowing). Both clinical and radiological factors were analyzed by both univariate and multivariable analyses. RESULTS: Six hips were categorized as group I and 45 hips were categorized as group II. The postoperative intact ratio and preoperative stage were significantly correlated with the radiological outcome in both univariate (P < 0.0001, P = 0.006) and multivariate (P = 0.0014, P = 0.0039) analysis. The cutoff point for the postoperative intact ratio (the minimum ratio required to prevent both progression of collapse and joint space narrowing) was 36.8 %. CONCLUSIONS: The results of this study indicate that the postoperative intact ratio is one of the main influences on progression of collapse and/or joint space narrowing after PRO, and should be at least 36.8 %. An increased awareness of this critical ratio would be useful for planning the optimal use of this procedure. PMID- 23344933 TI - A predictive model for disability in patients with lumbar disc herniation. AB - BACKGROUND: Lumbar disc herniation may influence patients' daily activities and social interactions; however, no predictive models of disability could be found for patients with lumbar disc herniation. We aimed to explore predictive factors for disability in patients with lumbar disc herniation. METHODS: The sample included 216 patients recruited from the orthopedic outpatient clinics at a medical center in northern Taiwan. Data were collected on patients' pain, fatigue, depression, disability, and demographics. Hierarchical multiple regression analysis was used in model verification. Path analysis was used to investigate causal relationships between disability and other factors. RESULTS: In path analysis, the most influential factor affecting the disability level was the pain level (standardized regression coefficient, b = 0.746), followed by the fatigue level (b = 0.138) and depression level (b = 0.100). The depression level was directly affected by the fatigue level (b = 0.416) and the pain level (b = 0.367), the fatigue level was directly affected by the pain level (b = 0.538), and the pain level was directly affected by age (b = 0.140) and previous surgery (b = 0.260). CONCLUSIONS: We recommend that health-care providers regularly assess and treat pain and depression to reduce/prevent disability among patients with lumbar disc herniation, even among those who are apparently functioning well in the community. PMID- 23344932 TI - Adipose-derived stem cells and rabbit bone regeneration: histomorphometric, immunohistochemical and mechanical characterization. AB - BACKGROUND: In the last few years, several attempts have been made to treat large bone loss, including the use of tissue engineering with osteoinductive scaffolds and cells. This study highlights the role of mesenchymal stem cells from adipose tissue (ASCs; adipose-derived stem cells) in a rabbit bone regeneration model. METHODS: We compared the neoformed bone tissues achieved by treating critical tibial defects with either hydroxyapatite alone (HA, group I) or hydroxyapatite autologous ASC constructs (ASCs-HA, group II), investigating their histomorphometric, immunohistochemical and biomechanical properties. RESULTS: After eight weeks of follow-up, we observed advanced maturation and a spatial distribution of new bone that was more homogeneous in the inner parts of the pores in group II, not just along the walls (as seen in group I). The new tissue expressed osteogenic markers, and biomechanical tests suggested that the newly formed bone in group II had a higher mineral content than that in group I. Although variability in differentiation was observed among the different cell populations in vitro, no differences in bone healing were observed in vivo; the variability seen in vitro was probably due to local microenvironment effects. CONCLUSIONS: Tibial defects treated with rabbit ASCs-HA showed an improved healing process when compared to the process that occurred when only the scaffold was used. We suggest that implanted ASCs ameliorate the bone reparative process either directly or by recruiting resident progenitor cells. PMID- 23344934 TI - Systematic synthesis of ZnO nanostructures. AB - In this study, we report a simple solution-phase method to prepare ZnO nanostructures with controllable morphologies. By using oleylamine (OAm) and dodecanol (DDL) as solvents, zinc oxide nanocrystals with tunable sizes and diverse shapes (hexagonal pyramids, bulletlike, and pencil-like shapes) have been obtained under mild conditions. At the same time, the introduction of presynthesized gold nanocrystals can also lead to the hybrid nanostructures of gold-zinc oxide hexagonal nanopyramids. In addition, the possible formation mechanism of the as-prepared ZnO nanostructures has been investigated. Notably, the unique optical properties of the ZnO nanostructures with different sizes and shapes have also been discussed. We hope that this strategy will be a general and effective method for fabricating other metal oxide nanocrystals. PMID- 23344935 TI - Beyond the ligand-binding pocket: targeting alternate sites in nuclear receptors. AB - Nuclear receptors (NRs) are a family of ligand-modulated transcription factors with significant therapeutic relevance from metabolic disorders and inflammation to cancer, neurodegenerative, and psychiatric disorders. Drug discovery efforts are typically concentrated on modulating the natural ligand action within the ligand-binding pocket (LBP) in the C-terminal ligand-binding domain (LBD). Drawbacks of LBP-based strategies include physiological alterations due to disruption of ligand binding and difficulties in achieving tissue specificity. Furthermore, the lack of a "pure" and predictable mechanism of action predisposes such intervention toward drug resistance. Recent outstanding progress in our understanding of NR biology has shifted the focus of drug discovery efforts from inside to outside the LBP, affording consideration to the interaction between NRs and coactivator proteins, the interaction between NRs and DNA and the NRs' ligand independent functions. This review encompasses such currently available NR non LBP-based interventions and their potential application in therapy or as specific tools to probe NR biology. PMID- 23344938 TI - Copper-catalyzed aerobic intramolecular dehydrogenative cyclization of N,N disubstituted hydrazones through C(sp(3)-H functionalization. AB - An aerobic activity: The title reaction proceeds through an oxidation/cyclization/aromatization sequence under an atmosphere of O(2) (see scheme; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DCE=1,2-dichloroethane, DMS=dimethylsulfide). This coupling reaction is the first to proceed via an iminium intermediate for a C(sp(3)-H bond-functionalization process, and provides an environmentally friendly and atom-efficient access to substituted pyrazoles. PMID- 23344939 TI - Characterization of a heavy metal translocating P-type ATPase gene from an environmental heavy metal resistance Enterobacter sp. isolate. AB - Heavy metals are common contaminants found in polluted areas. We have identified a heavy metal translocating P-type ATPase gene (hmtp) via fosmid library and in vitro transposon mutagenesis from an Enterobacter sp. isolate. This gene is believed to participate in the bacterium's heavy metal resistance traits. The complete gene was identified, cloned, and expressed in a suitable Escherichia coli host cell. E. coli W3110, RW3110 (zntA::Km), GG48 (DeltazitB::Cm zntA::Km), and GG51 (DeltazitB::Cm) were used to study the possible effects of this gene for heavy metal (cadmium and zinc in particular) resistance. Among the E. coli strains tested, RW3110 and GG48 showed more sensitivity to cadmium and zinc compared to the wild-type E. coli W3110 and strain GG51. Therefore, strains RW3110 and GG48 were chosen for the reference hosts for further evaluation of the gene's effect. The results showed that expression of this heavy metal translocating P-type ATPase gene could increase the ability for zinc and cadmium resistance in the tested microorganisms. PMID- 23344940 TI - Optimized fed-batch fermentation of Scheffersomyces stipitis for efficient production of ethanol from hexoses and pentoses. AB - Scheffersomyces stipitis was cultivated in an optimized, controlled fed-batch fermentation for production of ethanol from glucose-xylose mixture. Effect of feed medium composition was investigated on sugar utilization and ethanol production. Studying influence of specific cell growth rate on ethanol fermentation performance showed the carbon flow towards ethanol synthesis decreased with increasing cell growth rate. The optimum specific growth rate to achieve efficient ethanol production performance from a glucose-xylose mixture existed at 0.1 h(-1). With these optimized feed medium and cell growth rate, a kinetic model has been utilized to avoid overflow metabolism as well as to ensure a balanced feeding of nutrient substrate in fed-batch system. Fed-batch culture with feeding profile designed based on the model resulted in high titer, yield, and productivity of ethanol compared with batch cultures. The maximal ethanol concentration was 40.7 g/L. The yield and productivity of ethanol production in the optimized fed-batch culture was 1.3 and 2 times higher than those in batch culture. Thus, higher efficiency ethanol production was achieved in this study through fed-batch process optimization. This strategy may contribute to an improvement of ethanol fermentation from lignocellulosic biomass by S. stipitis on the industrial scale. PMID- 23344941 TI - Recombinant expression and characterization of an organic-solvent-tolerant alpha amylase from Exiguobacterium sp. DAU5. AB - The enzyme from halophilic microorganisms often has unique properties such as organic-solvent-tolerance. In this study, a novel organic-solvent-tolerant alpha amylase gene was cloned from the mild halophile Exiguobacterium sp. DAU5. The open reading frame (ORF) of the enzyme consisted of 1,545 bp and encoded 514 amino acids, the primary sequence revealed that it belongs to the glycoside hydrolase (GH) family 13. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) showed an AmyH monomer of 57 kDa. The enzyme exhibited maximal activity at 40 degrees C in pH 8.5 glycine-NaOH buffer, and the activity was strongly inhibited by Zn(2+), Cu(2+), and Fe(2+). The alpha-amylase AmyH exhibited high hydrolysis activity toward soluble starch, and the major hydrolysis products were maltose, maltotriose, and maltopentaose; the AmyH could not efficiently hydrolyze oligosaccharides smaller than maltoheptaose, nor could it act on the beta-1,4 or alpha-1,6 glucosidic bonds in xylan or pullulan, respectively. In addition, the alpha-amylase exhibited better tolerance to organic solvents, as it was stable in the presence of dimethylsulfoxide (DMSO), methanol, ethanol, and acetone. Base on all of these results, the enzyme could be useful for practical application in the bakery industry and in biotechnological processes that occur in the presence of organic solvents. PMID- 23344942 TI - Recombinant production of crab antimicrobial protein scygonadin expressed as thioredoxin and SUMO fusions in Escherichia coli. AB - Scygonadin is an antimicrobial protein isolated from the mud crab, Scylla serrate. The mature protein comprises 102 amino acids and has a theoretical molecular weight of 11,272 Da. The protein's specific expression pattern strongly suggests that it plays a role in reproductive immunity. In this study, I developed a protocol for producing recombinant scygonadin in Escherichia coli. The target protein was expressed as both thioredoxin and SUMO fusions, and released by TEV and SUMO protease-mediated cleavages, respectively. In either case, the liberated scygonadin was separated from its carrier using a HisTrap HP column. From thioredoxin and SUMO fusion constructs, 32.7 and 29.2 mg target protein per liter of culture was obtained, respectively. The described protocol provides an effective means for producing scygonadin in relatively large quantities, which facilities its further characterization. PMID- 23344943 TI - Prediction of optimal pH in hydrolytic reaction of beta-glucosidase. AB - This is the continuation of our studies to use very basic information on enzyme to predict optimal reaction parameters in enzymatic reactions because the gap between available enzyme sequences and their available reaction parameters is widening. In this study, 23 features selected from 540 plus features of individual amino acid as well as a feature combined whole protein information were screened as independents in a 20-1 feedforward backpropagation neural network for predicting optimal pH in beta-glucosidase's hydrolytic reaction because this enzyme drew attention recently due to its role in biofuel industry. The results show that 11 features can be used as independents for the prediction, while the feature of amino acid distribution probability works better than the rest independents for the prediction. Our study paves a way to predict the optimal reaction parameters of enzymes based on the amino acid features of enzyme sequences. PMID- 23344944 TI - Linking performance with microbial community characteristics in an anaerobic baffled reactor. AB - The performance and microbial community characteristics of a laboratory scale anaerobic baffled reactor (ABR) with four compartments (C1-C4) treating sugar refinery wastewater were investigated. The COD removal was 94.8 % with a CH4 yield of 0.21 L g(-1) CODremoved at total organic loading rate (OLR) of 5.33 kg COD/m(-3) day(-1). Fermentative bacteria were dominant in C1 and C2, while syntrophic acetogens and methanogens were dominant in C3 and C4. Some acid tolerant methanogens were enriched in acidogenic phase. The present of the acid tolerant methanogens could improve the efficiency and stability of the ABR as the most of the methanogens are vulnerable to low pH. In addition, high functional redundancy of the fermentative bacteria implicated that the microbial communities in acidogenic phase were stable functionally and allowed the ABR to balance perturbation. It was also found that syntrophic acetogenesis might be a weakness in the ABR as syntrophic acetogens were poor as compared with fermentative bacteria and methanogens. PMID- 23344945 TI - Secretory phospholipase A2 in dromedary tears: a host defense against staphylococci and other gram-positive bacteria. AB - The best known physiologic function of secreted phospholipase A2 (sPLA2) group IIA (sPLA2-IIA) is defense against bacterial infection through hydrolytic degradation of bacterial membrane phospholipids. In fact, sPLA2-IIA effectively kills Gram-positive bacteria and to a lesser extent Gram-negative bacteria and is considered a major component of the eye's innate immune defense system. The antibacterial properties of sPLA2 have been demonstrated in rabbit and human tears. In this report, we have analyzed the bactericidal activity of dromedary tears and the subsequently purified sPLA2 on several Gram-positive bacteria. Our results showed that the sPLA2 displays a potent bactericidal activity against all the tested bacteria particularly against the Staphylococcus strains when tested in the ionic environment of tears. There is a synergic action of the sPLA2 with lysozyme when added to the bacteria culture prior to sPLA2. Interestingly, lysozyme purified from dromedary tears showed a significant bactericidal activity against Listeria monocytogene and Staphylococcus epidermidis, whereas the one purified from human tears displayed no activity against these two strains. We have also demonstrated that Ca(2+) is crucial for the activity of dromedary tear sPLA2 and to a less extent Mg(2+) ions. Given the presence of sPLA2 in tears and intestinal secretions, this enzyme may play a substantial role in innate mucosal and systemic bactericidal defenses against Gram-positive bacteria. PMID- 23344946 TI - Selection of potential therapeutic human single-chain Fv antibodies against cholecystokinin-B/gastrin receptor by phage display technology. AB - BACKGROUND AND OBJECTIVE: Gastric/gastrointestinal cancers are associated with high mortality worldwide. G-protein coupled receptor (GPCR) superfamily members such as gastrin/cholecystokinin-B receptor (CCK-BR) are involved in progression of gastric tumors, thus CCK-BR is considered as a potential target for immunotherapy. However, production of functional monoclonal antibodies (mAbs) against GPCR seems to be very challenging, in part due to its integration in cell membranes and inaccessibility for selection. To tackle this problem, we implemented phage display technology and a solution-phase biopanning (SPB) scheme for production of mAbs specific to the native conformation of CCK-BR. METHODS: To perform the SPB process, we utilized a synthetic biotinylated peptide corresponding to the second extracellular loop (ECL2) of CCK-BR and a semi synthetic phage antibody library. After enzyme-linked immunosorbent assay (ELISA) screening, the CCK-BR specificity of the selected single-chain variable fragments (scFvs) were further examined using immunoblotting, whole-cell ELISA, and flow cytometry assays. RESULTS: After performing four rounds of selection, we identified nine antibody clones which showed positive reactivity with the CCK-BR peptide in an ELISA assay. Of these, eight clones were unique scFv antibodies and one was a V(L) single domain antibody. Specificity analysis of the selected scFvs revealed that five of the selected scFvs recognized a denatured form of CCK-BR, while the majority of the selected scFvs were able to recognize the native conformation of CCK-BR on the surface of human gastric adenocarcinoma cells and cervical carcinoma HeLa cells. CONCLUSION: For the first time, we report on the establishment of a diverse panel of scFv antibody fragments that are specific to the native conformation of CCK-BR. Based on these results, we suggest the selected scFv antibody fragments as potential agents for diagnosis, imaging, targeting, and/or immunotherapy of cancers that overexpress CCK-BR. PMID- 23344947 TI - Stimulus change detection in phasic auditory units in the frog midbrain: frequency and ear specific adaptation. AB - Neural adaptation, a reduction in the response to a maintained stimulus, is an important mechanism for detecting stimulus change. Contributing to change detection is the fact that adaptation is often stimulus specific: adaptation to a particular stimulus reduces excitability to a specific subset of stimuli, while the ability to respond to other stimuli is unaffected. Phasic cells (e.g., cells responding to stimulus onset) are good candidates for detecting the most rapid changes in natural auditory scenes, as they exhibit fast and complete adaptation to an initial stimulus presentation. We made recordings of single phasic auditory units in the frog midbrain to determine if adaptation was specific to stimulus frequency and ear of input. In response to an instantaneous frequency step in a tone, 28% of phasic cells exhibited frequency specific adaptation based on a relative frequency change (delta-f=+/-16%). Frequency specific adaptation was not limited to frequency steps, however, as adaptation was also overcome during continuous frequency modulated stimuli and in response to spectral transients interrupting tones. The results suggest that adaptation is separated for peripheral (e.g., frequency) channels. This was tested directly using dichotic stimuli. In 45% of binaural phasic units, adaptation was ear specific: adaptation to stimulation of one ear did not affect responses to stimulation of the other ear. Thus, adaptation exhibited specificity for stimulus frequency and lateralization at the level of the midbrain. This mechanism could be employed to detect rapid stimulus change within and between sound sources in complex acoustic environments. PMID- 23344948 TI - Glucagon regulation of oxidative phosphorylation requires an increase in matrix adenine nucleotide content through Ca2+ activation of the mitochondrial ATP-Mg/Pi carrier SCaMC-3. AB - It has been known for a long time that mitochondria isolated from hepatocytes treated with glucagon or Ca(2+)-mobilizing agents such as phenylephrine show an increase in their adenine nucleotide (AdN) content, respiratory activity, and calcium retention capacity (CRC). Here, we have studied the role of SCaMC 3/slc25a23, the mitochondrial ATP-Mg/Pi carrier present in adult mouse liver, in the control of mitochondrial AdN levels and respiration in response to Ca(2+) signals as a candidate target of glucagon actions. With the use of SCaMC-3 knock out (KO) mice, we have found that the carrier is responsible for the accumulation of AdNs in liver mitochondria in a strictly Ca(2+)-dependent way with an S0.5 for Ca(2+) activation of 3.3 +/- 0.9 MUm. Accumulation of matrix AdNs allows a SCaMC 3-dependent increase in CRC. In addition, SCaMC-3-dependent accumulation of AdNs is required to acquire a fully active state 3 respiration in AdN-depleted liver mitochondria, although further accumulation of AdNs is not followed by increases in respiration. Moreover, glucagon addition to isolated hepatocytes increases oligomycin-sensitive oxygen consumption and maximal respiratory rates in cells derived from wild type, but not SCaMC-3-KO mice and glucagon administration in vivo results in an increase in AdN content, state 3 respiration and CRC in liver mitochondria in wild type but not in SCaMC-3-KO mice. These results show that SCaMC-3 is required for the increase in oxidative phosphorylation observed in liver mitochondria in response to glucagon and Ca(2+)-mobilizing agents, possibly by allowing a Ca(2+)-dependent accumulation of mitochondrial AdNs and matrix Ca(2+), events permissive for other glucagon actions. PMID- 23344949 TI - Alteration of plasma membrane organization by an anticancer lysophosphatidylcholine analogue induces intracellular acidification and internalization of plasma membrane transporters in yeast. AB - The lysophosphatidylcholine analogue edelfosine is a potent antitumor lipid that targets cellular membranes. The underlying mechanisms leading to cell death remain controversial, although two cellular membranes have emerged as primary targets of edelfosine, the plasma membrane (PM) and the endoplasmic reticulum. In an effort to identify conditions that enhance or prevent the cytotoxic effect of edelfosine, we have conducted genome-wide surveys of edelfosine sensitivity and resistance in Saccharomyces cerevisiae presented in this work and the accompanying paper (Cuesta-Marban, A., Botet, J., Czyz, O., Cacharro, L. M., Gajate, C., Hornillos, V., Delgado, J., Zhang, H., Amat-Guerri, F., Acuna, A. U., McMaster, C. R., Revuelta, J. L., Zaremberg, V., and Mollinedo, F. (January 23, 2013) J. Biol. Chem. 288,), respectively. Our results point to maintenance of pH homeostasis as a major player in modulating susceptibility to edelfosine with the PM proton pump Pma1p playing a main role. We demonstrate that edelfosine alters PM organization and induces intracellular acidification. Significantly, we show that edelfosine selectively reduces lateral segregation of PM proteins like Pma1p and nutrient H(+)-symporters inducing their ubiquitination and internalization. The biology associated to the mode of action of edelfosine we have unveiled includes selective modification of lipid raft integrity altering pH homeostasis, which in turn regulates cell growth. PMID- 23344950 TI - Unique requirements for mono- and polyubiquitination of the peroxisomal targeting signal co-receptor, Pex20. AB - In Pichia pastoris, the peroxisomal targeting signal 2 (PTS2)-dependent peroxisomal matrix protein import pathway requires the receptor, Pex7, and its co receptor Pex20. A conserved lysine (Lys(19)) near the N terminus of Pex20 is required for its polyubiquitination and proteasomal degradation, whereas a conserved cysteine (Cys(8)) is essential for its recycling. In this study, we found that Cys(8) is required for the DTT-sensitive mono- and diubiquitination of Pex20. We also show that the PTS2 cargo receptor, Pex7, is required for Pex20 polyubiquitination. Pex4, the E2 ubiquitin-conjugation enzyme, is required for monoubiquitination of Pex20. However, it is also necessary for polyubiquitination of Pex20, making its behavior distinct from the ubiquitination described for other PTS receptors. Unlike the roles of specific RING peroxins in Pex5 ubiquitination, we found that all the RING peroxins (Pex2, Pex10, and Pex12) are required as E3 ubiquitin ligases for Pex20 mono- and polyubiquitination. A model for Pex20 ubiquitination is proposed based on these observations. This is the first description of the complete ubiquitination pathway of Pex20, which provides a better understanding of the recycling and degradation of this PTS2 cargo co receptor. PMID- 23344951 TI - Hyperplasia of pancreatic beta cells and improved glucose tolerance in mice deficient in the FXYD2 subunit of Na,K-ATPase. AB - Restoration of the functional potency of pancreatic islets either through enhanced proliferation (hyperplasia) or increase in size (hypertrophy) of beta cells is a major objective for intervention in diabetes. We have obtained experimental evidence that global knock-out of a small, single-span regulatory subunit of Na,K-ATPase, FXYD2, alters glucose control. Adult Fxyd2(-/-) mice showed significantly lower blood glucose levels, no signs of peripheral insulin resistance, and improved glucose tolerance compared with their littermate controls. Strikingly, there was a substantial hyperplasia in pancreatic beta cells from the Fxyd2(-/-) mice compared with the wild type littermates, compatible with an observed increase in the level of circulating insulin. No changes were seen in the exocrine compartment of the pancreas, and the mice had only a mild, well-adapted renal phenotype. Morphometric analysis revealed an increase in beta cell mass in KO compared with WT mice. This appears to explain a phenotype of hyperinsulinemia. By RT-PCR, Western blot, and immunocytochemistry we showed the FXYD2b splice variant in pancreatic beta cells from wild type mice. Phosphorylation of Akt kinase was significantly higher under basal conditions in freshly isolated islets from Fxyd2(-/-) mice compared with their WT littermates. Inducible expression of FXYD2 in INS 832/13 cells produced a reduction in the phosphorylation level of Akt, and phosphorylation was restored in parallel with degradation of FXYD2. Thus we suggest that in pancreatic beta cells FXYD2 plays a role in Akt signaling pathways associated with cell growth and proliferation. PMID- 23344952 TI - The molecular basis of iron-induced oligomerization of frataxin and the role of the ferroxidation reaction in oligomerization. AB - The role of the mitochondrial protein frataxin in iron storage and detoxification, iron delivery to iron-sulfur cluster biosynthesis, heme biosynthesis, and aconitase repair has been extensively studied during the last decade. However, still no general consensus exists on the details of the mechanism of frataxin function and oligomerization. Here, using small-angle x-ray scattering and x-ray crystallography, we describe the solution structure of the oligomers formed during the iron-dependent assembly of yeast (Yfh1) and Escherichia coli (CyaY) frataxin. At an iron-to-protein ratio of 2, the initially monomeric Yfh1 is converted to a trimeric form in solution. The trimer in turn serves as the assembly unit for higher order oligomers induced at higher iron-to protein ratios. The x-ray crystallographic structure obtained from iron-soaked crystals demonstrates that iron binds at the trimer-trimer interaction sites, presumably contributing to oligomer stabilization. For the ferroxidation deficient D79A/D82A variant of Yfh1, iron-dependent oligomerization may still take place, although >50% of the protein is found in the monomeric state at the highest iron-to-protein ratio used. This demonstrates that the ferroxidation reaction controls frataxin assembly and presumably the iron chaperone function of frataxin and its interactions with target proteins. For E. coli CyaY, the assembly unit of higher order oligomers is a tetramer, which could be an effect of the much shorter N-terminal region of this protein. The results show that understanding of the mechanistic features of frataxin function requires detailed knowledge of the interplay between the ferroxidation reaction, iron-induced oligomerization, and the structure of oligomers formed during assembly. PMID- 23344953 TI - BMP induces cochlin expression to facilitate self-renewal and suppress neural differentiation of mouse embryonic stem cells. AB - BMP4 maintains self-renewal of mouse embryonic stem cells (ESCs) in collaboration with LIF. Here, we report the identification of a novel key BMP target gene, cochlin (Coch) in mouse ESCs. Coch can be significantly up-regulated by BMP4 specifically in ESCs but not in somatic differentiated cells, and this up regulation is dependent on the BMP signaling mediators Smad1/5 and Smad4. Overexpression of Coch can partially substitute BMP4 to promote self-renewal of mouse ESCs together with LIF, whereas knockdown of Coch impairs self-renewal marker gene expression even in the presence of both BMP4 and LIF. Further studies showed that COCH could mimic BMP4 in repressing neural differentiation of mouse ESCs upon LIF withdrawal and the inhibitory effect of BMP4 on neural differentiation is compromised by Coch knockdown. Taken together, our data suggest that COCH is a part of the downstream target network of BMP signaling and serves as another important effector to fine-tune mouse ESC fates. PMID- 23344954 TI - BRCA1-Ku80 protein interaction enhances end-joining fidelity of chromosomal double-strand breaks in the G1 phase of the cell cycle. AB - Quality control of DNA double-strand break (DSB) repair is vital in preventing mutagenesis. Non-homologous end-joining (NHEJ), a repair process predominant in the G1 phase of the cell cycle, rejoins DSBs either accurately or with errors, but the mechanisms controlling its fidelity are poorly understood. Here we show that BRCA1, a tumor suppressor, enhances the fidelity of NHEJ-mediated DSB repair and prevents mutagenic deletional end-joining through interaction with canonical NHEJ machinery during G1. BRCA1 binds and stabilizes Ku80 at DSBs through its N terminal region, promotes precise DSB rejoining, and increases cellular resistance to radiation-induced DNA damage in a G1 phase-specific manner. These results suggest that BRCA1, as a central player in genome integrity maintenance, ensures high fidelity repair of DSBs by not only promoting homologous recombination repair in G2/M phase but also facilitating fidelity of Ku80 dependent NHEJ repair, thus preventing deletional end-joining of chromosomal DSBs during G1. PMID- 23344955 TI - alpha-Synuclein membrane association is regulated by the Rab3a recycling machinery and presynaptic activity. AB - alpha-Synuclein is an abundant presynaptic protein and a primary component of Lewy bodies in Parkinson disease. Although its pathogenic role remains unclear, in healthy nerve terminals alpha-synuclein undergoes a cycle of membrane binding and dissociation. An alpha-synuclein binding assay was used to screen for vesicle proteins involved in alpha-synuclein membrane interactions and showed that antibodies directed to the Ras-related GTPase Rab3a and its chaperone RabGDI abrogated alpha-synuclein membrane binding. Biochemical analyses, including density gradient sedimentation and co-immunoprecipitation, suggested that alpha synuclein interacts with membrane-associated GTP-bound Rab3a but not to cytosolic GDP-Rab3a. Accumulation of membrane-bound alpha-synuclein was induced by the expression of a GTPase-deficient Rab3a mutant, by a dominant-negative GDP dissociation inhibitor mutant unable to recycle Rab3a off membranes, and by Hsp90 inhibitors, radicicol and geldanamycin, which are known to inhibit Rab3a dissociation from membranes. Thus, all treatments that inhibited Rab3a recycling also increased alpha-synuclein sequestration on intracellular membranes. Our results suggest that membrane-bound GTP-Rab3a stabilizes alpha-synuclein on synaptic vesicles and that the GDP dissociation inhibitor.Hsp90 complex that controls Rab3a membrane dissociation also regulates alpha-synuclein dissociation during synaptic activity. PMID- 23344956 TI - Depletion of molecular chaperones from the endoplasmic reticulum and fragmentation of the Golgi apparatus associated with pathogenesis in Pelizaeus Merzbacher disease. AB - Missense mutations in the proteolipid protein 1 (PLP1) gene cause a wide spectrum of hypomyelinating disorders, from mild spastic paraplegia type 2 to severe Pelizaeus-Merzbacher disease (PMD). Mutant PLP1 accumulates in the endoplasmic reticulum (ER) and induces ER stress. However, the link between the clinical severity of PMD and the cellular response induced by mutant PLP1 remains largely unknown. Accumulation of misfolded proteins in the ER generally leads to up regulation of ER chaperones to alleviate ER stress. Here, we found that expression of the PLP1-A243V mutant, which causes severe disease, depletes some ER chaperones with a KDEL (Lys-Asp-Glu-Leu) motif, in HeLa cells, MO3.13 oligodendrocytic cells, and primary oligodendrocytes. The same PLP1 mutant also induces fragmentation of the Golgi apparatus (GA). These organelle changes are less prominent in cells with milder disease-associated PLP1 mutants. Similar changes are also observed in cells expressing another disease-causing gene that triggers ER stress, as well as in cells treated with brefeldin A, which induces ER stress and GA fragmentation by inhibiting GA to ER trafficking. We also found that mutant PLP1 disturbs localization of the KDEL receptor, which transports the chaperones with the KDEL motif from the GA to the ER. These data show that PLP1 mutants inhibit GA to ER trafficking, which reduces the supply of ER chaperones and induces GA fragmentation. We propose that depletion of ER chaperones and GA fragmentation induced by mutant misfolded proteins contribute to the pathogenesis of inherited ER stress-related diseases and affect the disease severity. PMID- 23344957 TI - Ca2+/S100 proteins act as upstream regulators of the chaperone-associated ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein). AB - The U-box E3 ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein) binds Hsp90 and/or Hsp70 via its tetratricopeptide repeat (TPR), facilitating ubiquitination of the chaperone-bound client proteins. Mechanisms that regulate the activity of CHIP are, at present, poorly understood. We previously reported that Ca(2+)/S100 proteins directly associate with the TPR proteins, such as Hsp70/Hsp90-organizing protein (Hop), kinesin light chain, Tom70, FKBP52, CyP40, and protein phosphatase 5 (PP5), leading to the dissociation of the interactions of the TPR proteins with their target proteins. Therefore, we have hypothesized that Ca(2+)/S100 proteins can interact with CHIP and regulate its function. GST pulldown assays indicated that Ca(2+)/S100A2 and S100P bind to the TPR domain and lead to interference with the interactions of CHIP with Hsp70, Hsp90, HSF1, and Smad1. In vitro ubiquitination assays indicated that Ca(2+)/S100A2 and S100P are efficient and specific inhibitors of CHIP-mediated ubiquitination of Hsp70, Hsp90, HSF1, and Smad1. Overexpression of S100A2 and S100P suppressed CHIP chaperone complex-dependent mutant p53 ubiquitination and degradation in Hep3B cells. The association of the S100 proteins with CHIP provides a Ca(2+)-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway. PMID- 23344958 TI - Membrane association via an amino-terminal amphipathic helix is required for the cellular organization and function of RNase II. AB - The subcellular localization of the exoribonuclease RNase II is not known despite the advanced biochemical characterization of the enzyme. Here we report that RNase II is organized into cellular structures that appear to coil around the Escherichia coli cell periphery and that RNase II is associated with the cytoplasmic membrane by its amino-terminal amphipathic helix. The helix also acts as an autonomous transplantable membrane binding domain capable of directing normally cytoplasmic proteins to the membrane. Assembly of the organized cellular structures of RNase II required the RNase II amphipathic membrane binding domain. Co-immunoprecipitation of the protein from cell extracts indicated that RNase II interacts with itself. The RNase II self-interaction and the ability of the protein to assemble into organized cellular structures required the membrane binding domain. The ability of RNase II to maintain cell viability in the absence of the exoribonuclease polynucleotide phosphorylase was markedly diminished when the RNase II cellular structures were lost due to changes in the amphipathicity of the amino-terminal helix, suggesting that membrane association and assembly of RNase II into organized cellular structures play an important role in the normal function of the protein within the bacterial cell. PMID- 23344959 TI - Ca2+ signals generated by CatSper and Ca2+ stores regulate different behaviors in human sperm. AB - [Ca(2+)]i signaling regulates sperm motility, enabling switching between functionally different behaviors that the sperm must employ as it ascends the female tract and fertilizes the oocyte. We report that different behaviors in human sperm are recruited according to the Ca(2+) signaling pathway used. Activation of CatSper (by raising pHi or stimulating with progesterone) caused sustained [Ca(2+)]i elevation but did not induce hyperactivation, the whiplash like behavior required for progression along the oviduct and penetration of the zona pellucida. In contrast, penetration into methylcellulose (mimicking penetration into cervical mucus or cumulus matrix) was enhanced by activation of CatSper. NNC55-0396, which abolishes CatSper currents in human sperm, inhibited this effect. Treatment with 5 MUm thimerosal to mobilize stored Ca(2+) caused sustained [Ca(2+)]i elevation and induced strong, sustained hyperactivation that was completely insensitive to NNC55-0396. Thimerosal had no effect on penetration into methylcellulose. 4-Aminopyridine, a powerful modulator of sperm motility, both raised pHi and mobilized Ca(2+) stored in sperm (and from microsomal membrane preparations). 4-Aminopyridine-induced hyperactivation even in cells suspended in Ca(2+)-depleted medium and also potentiated penetration into methylcellulose. The latter effect was sensitive to NNC55-039, but induction of hyperactivation was not. We conclude that these two components of the [Ca(2+)]i signaling apparatus have strikingly different effects on sperm motility. Furthermore, since stored Ca(2+) at the sperm neck can be mobilized by Ca(2+) induced Ca(2+) release, we propose that CatSper activation can elicit functionally different behaviors according to the sensitivity of the Ca(2+) store, which may be regulated by capacitation and NO from the cumulus. PMID- 23344960 TI - The N-terminal 45-kDa domain of Dna2 endonuclease/helicase targets the enzyme to secondary structure DNA. AB - The removal of initiating primers from the 5'-ends of each Okazaki fragment, required for the generation of contiguous daughter strands, can be catalyzed by the combined action of DNA polymerase delta and Fen1. When the flaps generated by displacement of DNA synthesis activity of polymerase delta become long enough to bind replication protein A or form hairpin structures, the helicase/endonuclease enzyme, Dna2, becomes critical because of its ability to remove replication protein A-coated or secondary structure flaps. In this study, we show that the N terminal 45-kDa domain of Dna2 binds hairpin structures, allowing the enzyme to target secondary structure flap DNA. We found that this activity was essential for the efficient removal of hairpin flaps by the endonuclease activity of Dna2 with the aid of its helicase activity. Thus, the efficient removal of hairpin structure flaps requires the coordinated action of all three functional domains of Dna2. We also found that deletion of the N-terminal 45-kDa domain of Dna2 led to a partial loss of the intra-S-phase checkpoint function and an increased rate of homologous recombination in yeast. We discuss the potential roles of the N terminal domain of Dna2 in the maintenance of genomic stability. PMID- 23344964 TI - Identification of radiolytic products of [C4mim][NTf2] and their effects on the Sr2+ extraction. AB - The trace water-soluble radiolytic products of neat 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C(4)mim][NTf(2)]) were identified by analysing water-washed samples of gamma-ray irradiated ionic liquids. CF(3)SO(2)OH, CF(3)SOOH, CF(3)SO(2)NH(2), HF and H(2)SO(3) were confirmed as main radiolytic products of [C(4)mim][NTf(2)], and the total radiation chemical yields of the water-soluble radiolytic products (0.35 MUmol J(-1)) and that of hydrogen ions (0.46 +/- 0.02 MUmol J(-1)) were determined by using ion chromatography and neutralization titration, respectively. It was found that the water-soluble radiolytic products of [C(4)mim][NTf(2)] greatly reduced the extraction efficiency of Sr(2+) from water to irradiated [C(4)mim][NTf(2)], while the water insoluble radiolytic products of [C(4)mim][NTf(2)] had a slight influence on the Sr(2+) extraction. PMID- 23344962 TI - Full diffusion characterization implicates regionally disparate neuropathology in mild cognitive impairment. AB - Diffusion tensor imaging (DTI) is used to detect tissue pathology. In Alzheimer's disease (AD) research, DTI has been used to elucidate differences in disease stages and to track progression over time and clinical severity. Many of these studies have identified the fornix as particularly vulnerable in the early stages of pathology associated with memory decline in prodromal AD. Emerging research suggests principal tensor components, axial (DA) and radial (DR) diffusivity, are more sensitive to underlying tissue pathology than are mean diffusivity (MD) and fractional anisotropy (FA). Given the established regionally specific tissue decline in MCI, we examined components of the full diffusion tensor (MD, FA, DR, and DA) for sensitivity to regional pathology associated with specific memory deficits in 18 individuals with MCI. We investigated multiple regions of interest, including fornix, temporal stem, and control regions for association with severity of impairment on multiple memory measures, including a type of neuropsychological task shown to be particularly sensitive to early memory decline in MCI. Better paired associate learning was selectively associated with lower DA (beta = -0.663, p = 0.003), but not with DR, MD, or FA of the temporal stems. Conversely, better paired associate learning was associated with lower DR (beta = -0.523, p = 0.026), higher FA (beta = 0.498, p = 0.036), and lower MD (beta = -0.513, p = 0.030), but not DA in the fornix. No association was found for control regions, or for control cognitive measures. These findings suggest disparate pathology of temporal stems and fornix white matter in association with early memory impairment in MCI. Further, they highlight the methodological importance of evaluating the full tensor, rather than only summative metrics in research using DTI. PMID- 23344961 TI - Topoisomerase IIbeta deficiency enhances camptothecin-induced apoptosis. AB - Camptothecin (CPT), a topoisomerase (Top) I-targeting drug that stabilizes Top1 DNA covalent adducts, can induce S-phase-specific cytotoxicity due to the arrest of progressing replication forks. However, CPT-induced non-S-phase cytotoxicity is less well characterized. In this study, we have identified topoisomerase IIbeta (Top2beta) as a specific determinant for CPT sensitivity, but not for many other cytotoxic agents, in non-S-phase cells. First, quiescent mouse embryonic fibroblasts (MEFs) lacking Top2beta were shown to be hypersensitive to CPT with prominent induction of apoptosis. Second, ICRF-187, a Top2 catalytic inhibitor known to deplete Top2beta, specifically sensitized MEFs to CPT. To explore the molecular basis for CPT hypersensitivity in Top2beta-deficient cells, we found that upon CPT exposure, the RNA polymerase II large subunit (RNAP LS) became progressively depleted, followed by recovery to nearly the original level in wild type MEFs, whereas RNAP LS remained depleted without recovery in Top2beta deficient cells. Concomitant with the reduction of the RNAP LS level, the p53 protein level was greatly induced. Interestingly, RNAP LS depletion has been well documented to lead to p53-dependent apoptosis. Altogether, our findings support a model in which Top2beta deficiency promotes CPT-induced apoptosis in quiescent non-S-phase cells, possibly due to RNAP LS depletion and p53 accumulation. PMID- 23344965 TI - Size-selective encapsulation of hydrophobic guests by self-assembled M4L6 cobalt and nickel cages. AB - Subtle differences in metal-ligand bond lengths between a series of [M(4)L(6)](4 ) tetrahedral cages, where M = Fe(II), Co(II), or Ni(II), were observed to result in substantial differences in affinity for hydrophobic guests in water. Changing the metal ion from iron(II) to cobalt(II) or nickel(II) increases the size of the interior cavity of the cage and allows encapsulation of larger guest molecules. NMR spectroscopy was used to study the recognition properties of the iron(II) and cobalt(II) cages towards small hydrophobic guests in water, and single-crystal X ray diffraction was used to study the solid-state complexes of the iron(II) and nickel(II) cages. PMID- 23344966 TI - Monocarboxylate 4 mediated butyrate transport in a rat intestinal epithelial cell line. AB - BACKGROUND: Short chain fatty acids (SCFA) are absorbed by carrier mediated uptake in the small intestine by pH-dependent SCFA/HCO3 (-) exchangers on the apical membrane of epithelial cells. Conventional assumption is that MCT1 mediates SCFA/HCO3 (-) exchange in the intestine. Further, due to the presence of multiple such anion exchangers, the identity of the intestinal SCFA/HCO3 (-) has been controversial. AIMS: The aim of this study was to determine the identities of the butyrate transporter in the intestinal epithelial cells (IEC-18). METHODS: IEC-18 cells were treated with specific siRNAs for MCT1 and MCT4, and butyrate and lactate uptake studies were performed. RESULTS: Alpha-cyano-4-hydroxycinnamic acid inhibited lactate uptake but not butyrate uptake in IEC-18 cells, indicating that these two substrates are transported via two different transporter systems. MCT1 siRNA treatment abolished both MCT1 mRNA by more than 95 % and protein expression by 83 % as evidenced by RTQ-PCR and western blotting experiments. However, MCT1 siRNA treatment inhibited butyrate uptake upto 24 %, whereas it inhibited lactate uptake significantly by 70 %. Treatment with MCT4 siRNA inhibited MCT4 mRNA expression by 75 % and protein expression by 85 % in these cells. MCT4 siRNA inhibited butyrate uptake by 40 %. Further, several non steroidal anti-inflammatory drugs (NSAIDs) are transported by the butyrate transporter. Finally, MCT4 siRNA inhibited salicylate uptake by 27 % indicating direct evidence for the transport of salicylate by MCT4. CONCLUSIONS: These data indicate that MCT1 is the high affinity lactate transporter and MCT4 is the high affinity butyrate transporter in the intestinal epithelial cell line IEC-18. PMID- 23344967 TI - Alginate hydrogel as a potential alternative to hyaluronic acid as submucosal injection material. AB - BACKGROUND: Sodium alginate is currently used in medical products, including drugs and cosmetic materials. It can also be used as a submucosal injection material due to its excellent water retention ability. Alginate with a high water retention ability is called alginate hydrogel (AH). The aim of this study was to investigate the usefulness of AH as a submucosal injection material. METHODS: To investigate the optimal viscosity of AH as a submucosal injection material, we observed the changes in submucosal height from the initial submucosal height in the stomachs of six miniature pigs for each injection material tested (0.3 % AH, 0.5 % hyaluronic acid, glycerol). All submucosal heights were compared serially over time (3, 5, 10, 20, and 30 min). Both immediate and 1-week delayed tissue reactions were investigated endoscopically in the same living pigs. Histological analyses were performed after the animals had been sacrificed. RESULTS: In a preliminary study, we determined that 0.3 % sodium alginate mixed with BaCl2 (400 MUl) was the optimal viscosity of AH as an injection material. Our comparison of submucosal height changes over time showed that there was a significant decrease in submucosal height just 3 min following the injection of hyaluronic acid and glycerol, but that following the injection of AH a significant decrease in submucosal height was observed only after 10 min (p < 0.05). The histological analyses revealed that there were mild capillary dilations with congestion and mild fibrotic changes with some lymphocytic infiltration at the AH injection site. CONCLUSION: Alginate hydrogel demonstrated long-lasting maintenance of submucosal elevation, safety, and cost-effectiveness in a pig model, which makes it a potential alternative to hyaluronic acid. PMID- 23344968 TI - Biodiversity of Actinomycetes associated with Caribbean sponges and their potential for natural product discovery. AB - Marine actinomycetes provide a rich source of structurally unique and bioactive secondary metabolites. Numerous genera of marine actinomycetes have been isolated from marine sediments as well as several sponge species. In this study, 16 different species of Caribbean sponges were collected from four different locations in the coastal waters off Puerto Rico in order to examine diversity and bioactive metabolite production of marine actinomycetes in Caribbean sponges. Sediments were also collected from each location, in order to compare actinomycete communities between these two types of samples. A total of 180 actinomycetes were isolated and identified based on 16S rRNA gene analysis. Phylogenetic analysis revealed the presence of at least 14 new phylotypes belonging to the genera Micromonospora, Verruscosispora, Streptomyces, Salinospora, Solwaraspora, Microbacterium and Cellulosimicrobium. Seventy-eight of the isolates (19 from sediments and 59 from sponges) shared 100 % sequence identity with Micromonospora sp. R1. Despite having identical 16S rRNA sequences, the bioactivity of extracts and subsequent fractions generated from the fermentation of both sponge- and sediment-derived isolates identical to Micromonospora sp. R1 varied greatly, with a marked increase in antibiotic metabolite production in those isolates derived from sponges. These results indicate that the chemical profiles of isolates with high 16S rRNA sequence homology to known strains can be diverse and dependent on the source of isolation. In addition, seven previously reported dihydroquinones produced by five different Streptomyces strains have been purified and characterized from one Streptomyces sp. strain isolated in this study from the Caribbean sponge Agelas sceptrum. PMID- 23344972 TI - CyClus: a fast, comprehensive cylindrical interface approximation clustering/reranking method for rigid-body protein-protein docking decoys. AB - We propose a fast clustering and reranking method, CyClus, for protein-protein docking decoys. This method enables comprehensive clustering of whole decoys generated by rigid-body docking using cylindrical approximation of the protein proteininterface and hierarchical clustering procedures. We demonstrate the clustering and reranking of 54,000 decoy structures generated by ZDOCK for each complex within a few minutes. After parameter tuning for the test set in ZDOCK benchmark 2.0 with the ZDOCK and ZRANK scoring functions, blind tests for the incremental data in ZDOCK benchmark 3.0 and 4.0 were conducted. CyClus successfully generated smaller subsets of decoys containing near-native decoys. For example, the number of decoys required to create subsets containing near native decoys with 80% probability was reduced from 22% to 50% of the number required in the original ZDOCK. Although specific ZDOCK and ZRANK results were demonstrated, the CyClus algorithm was designed to be more general and can be applied to a wide range of decoys and scoring functions by adjusting just two parameters, p and T. CyClus results were also compared to those from ClusPro. PMID- 23344971 TI - Yeast-expressed human membrane protein aquaporin-1 yields excellent resolution of solid-state MAS NMR spectra. AB - One of the biggest challenges in solid-state NMR studies of membrane proteins is to obtain a homogeneous natively folded sample giving high spectral resolution sufficient for structural studies. Eukaryotic membrane proteins are especially difficult and expensive targets in this respect. Methylotrophic yeast Pichia pastoris is a reliable producer of eukaryotic membrane proteins for crystallography and a promising economical source of isotopically labeled proteins for NMR. We show that eukaryotic membrane protein human aquaporin 1 can be doubly ((13)C/(15)N) isotopically labeled in this system and functionally reconstituted into phospholipids, giving excellent resolution of solid-state magic angle spinning NMR spectra. PMID- 23344973 TI - Application of two segmentation protocols during the processing of virtual images in rapid prototyping: ex vivo study with human dry mandibles. AB - OBJECTIVES: The aim of this study was to evaluate the accuracy of virtual three dimensional (3D) reconstructions of human dry mandibles, produced from two segmentation protocols ("outline only" and "all-boundary lines"). MATERIALS AND METHODS: Twenty virtual three-dimensional (3D) images were built from computed tomography exam (CT) of 10 dry mandibles, in which linear measurements between anatomical landmarks were obtained and compared to an error probability of 5 %. RESULTS: The results showed no statistically significant difference among the dry mandibles and the virtual 3D reconstructions produced from segmentation protocols tested (p = 0,24). CONCLUSIONS: During the designing of a virtual 3D reconstruction, both "outline only" and "all-boundary lines" segmentation protocols can be used. CLINICAL RELEVANCE: Virtual processing of CT images is the most complex stage during the manufacture of the biomodel. Establishing a better protocol during this phase allows the construction of a biomodel with characteristics that are closer to the original anatomical structures. This is essential to ensure a correct preoperative planning and a suitable treatment. PMID- 23344975 TI - Differential gene expression and bioinformatics analysis of copper resistance gene afe_1073 in Acidithiobacillus ferrooxidans. AB - Copper resistance of acidophilic bacteria is very significant in bioleaching of copper ore since high concentration of copper are harmful to the growth of organisms. Copper resistance gene afe_1073 was putatively considered to be involved in copper homeostasis in Acidithiobacillus ferrooxidans ATCC23270. In the present study, differential expression of afe_1073 in A. ferrooxidans strain DY26 and DC was assessed with quantitative reverse transcription polymerase chain reaction. The results showed the expression of afe_1073 in two strains increased with the increment of copper concentrations. The expression of DY26 was lower than that of DC at the same copper concentration although A. ferrooxidans strain DY26 possessed higher copper resistance than strain DC. In addition, bioinformatics analysis showed AFE_1073 was a typical transmembrane protein P1b1 ATPase, which could reduce the harm of Cu(+) by pumping it out from the cell. There were two mutation sites in AFE_1073 between DY26 and DC and one may change the hydrophobicity of AFE_1073, which could enhance the ability of DY26 to pump out Cu(+). Therefore, DY26 needed less gene expression of afe_1073 for resisting copper toxicity than that of DC at the same copper stress. Our study will be beneficial to understanding the copper resistance mechanism of A. ferrooxidans. PMID- 23344974 TI - Using a fragment-based approach to target protein-protein interactions. AB - The ability to identify inhibitors of protein-protein interactions represents a major challenge in modern drug discovery and in the development of tools for chemical biology. In recent years, fragment-based approaches have emerged as a new methodology in drug discovery; however, few examples of small molecules that are active against chemotherapeutic targets have been published. Herein, we describe the fragment-based approach of targeting the interaction between the tumour suppressor BRCA2 and the recombination enzyme RAD51; it makes use of a screening pipeline of biophysical techniques that we expect to be more generally applicable to similar targets. Disruption of this interaction in vivo is hypothesised to give rise to cellular hypersensitivity to radiation and genotoxic drugs. We have used protein engineering to create a monomeric form of RAD51 by humanising a thermostable archaeal orthologue, RadA, and used this protein for fragment screening. The initial fragment hits were thoroughly validated biophysically by isothermal titration calorimetry (ITC) and NMR techniques and observed by X-ray crystallography to bind in a shallow surface pocket that is occupied in the native complex by the side chain of a phenylalanine from the conserved FxxA interaction motif found in BRCA2. This represents the first report of fragments or any small molecule binding at this protein-protein interaction site. PMID- 23344976 TI - Increased clinical symptoms of acromegalic arthropathy in patients with long-term disease control: a prospective follow-up study. AB - Arthropathy is an invalidating complication of acromegaly. This arthropathy deteriorates radiographically despite long-term disease control. However, the clinical course and its relationship to the radiographic course are currently unknown. We aimed to investigate the clinical course of arthropathy during follow up and its relationship to radiographic progression in long-term controlled acromegaly patients. Prospective follow-up study. We studied 58 patients (mean age 62 years, women 41 %) with controlled acromegaly for a mean of 17.6 years. Clinical progression of joint disease was defined at baseline and after 2.6 years, by the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and Australian/Canadian Osteoarthritis Index (AUSCAN) questionnaires for lower limb and hand OA, respectively, and performance tests. Potential risk factors for progression were assessed. The clinical course of arthropathy was related to the radiographic course. On average, hand and lower limb function deteriorated during follow-up, despite large interindividual variations. Joint pain was stable over time. High levels of pain and functional impairment at baseline were related to clinical progression of hand pain and functional limitations. High baseline BMI was a risk factor for functional deterioration in the lower limb. The changes in symptoms and radiographic progression during follow-up were not related. In treated acromegaly patients, joint function deteriorates during prolonged follow up, despite biochemical disease control, although there was interindividual variation. Clinical and radiographic course of arthropathy were not related. Therefore, in clinical practice, a combination of clinical and radiographic assessment is necessary to evaluate the course of acromegalic arthropathy. PMID- 23344977 TI - Mixed pituitary adenoma/craniopharyngioma: clinical, morphological, immunohistochemical and ultrastructural study of a case, review of the literature, and pathogenetic and nosological considerations. AB - Mixed pituitary adenoma/craniopharyngiomas are very rare tumors. Their pathogenesis is still unclear and it is not known whether they are collision tumors derived from independent stem cells or whether they originate from a single stem cell undergoing divergent differentiation. The latter hypothesis is supported by the close commixture between the two tumor components with transition areas that has been previously described. However, "hybrid" cells with both pituitary adenoma and craniopharyngioma features have never been described. In this paper we report a case of mixed pituitary adenoma/craniopharyngioma observed in a 75-year-old woman presenting with diplopia and slight increase of serum prolactin, who underwent endoscopic endonasal trans-sphenoidal tumor resection. Histologically, the tumor was composed of a typical pituitary silent subtype 2 ACTH cell adenoma admixed with islands of adamantinomatous craniopharyngioma. Electron microscopy showed that, in addition to distinct silent subtype 2 ACTH and craniopharyngioma cells, there were "hybrid" cells, showing characteristics of both pituitary adenoma and craniopharyngioma, consisting of small dense secretory granules, bundles of cytoplasmic filaments, and desmosomes. This ultrastructural finding was also confirmed by the presence of cells showing nuclear p40 expression and chromogranin A immunoreactivity. The close commixture between the two components and the ultrastructural and immunohistochemical findings demonstrate a common histogenesis of the two components and support the classification of the neoplasm as a mixed tumor. The patient completely recovered and, 10 months after surgery, head MR confirmed the complete resection of the lesion. PMID- 23344978 TI - Purulent pericarditis caused by a bad tooth. PMID- 23344980 TI - Double-chambered right ventricle in adults: an 'uncommon' entity, new ways of imaging. PMID- 23344979 TI - Long-term outcomes of fractional flow reserve-guided vs. angiography-guided percutaneous coronary intervention in contemporary practice. AB - AIMS: Fractional flow reserve (FFR) is the reference standard for the assessment of the functional significance of coronary artery stenoses, but is underutilized in daily clinical practice. We aimed to study long-term outcomes of FFR-guided percutaneous coronary intervention (PCI) in the general clinical practice. METHODS AND RESULTS: In this retrospective study, consecutive patients (n = 7358), referred for PCI at the Mayo Clinic between October 2002 and December 2009, were divided in two groups: those undergoing PCI without (PCI-only, n = 6268) or with FFR measurements (FFR-guided, n = 1090). The latter group was further classified as the FFR-Perform group (n = 369) if followed by PCI, and the FFR-Defer group (n = 721) if PCI was deferred. Clinical events were compared during a median follow-up of 50.9 months. The Kaplan-Meier fraction of major adverse cardiac events at 7 years was 57.0% in the PCI-only vs. 50.0% in the FFR guided group (P = 0.016). Patients with FFR-guided interventions had a non significantly lower rate of death or myocardial infarction compared with those with angiography-guided interventions [hazard ratio (HR): 0.85, 95% CI: 0.71 1.01, P = 0.06]; the FFR-guided deferred-PCI strategy was independently associated with reduced rate of myocardial infarction (HR: 0.46, 95% CI: 0.26 0.82, P = 0.008). After excluding patients with FFR of 0.75-0.80 and deferring PCI, the use of FFR was significantly associated with reduced rate of death or myocardial infarction (HR: 0.80, 95% CI: 0.66-0.96, P = 0.02). CONCLUSION: In the contemporary practice, an FFR-guided treatment strategy is associated with a favourable long-term outcome. The current study supports the use of the FFR for decision-making in patients undergoing cardiac catheterization. PMID- 23344981 TI - Clinical pharmacokinetics of drugs in patients with heart failure: an update (part 1, drugs administered intravenously). AB - Heart failure is one of the leading causes of death in developed countries, and its prevalence is expected to increase further in the coming years. While the pharmacokinetic changes observed in patients with heart failure have been reviewed twice in Clinical Pharmacokinetics, approximately a quarter century has passed since the latest article was published in 1988. Since then, many important classes of agents (e.g. ACE inhibitors, angiotensin receptor antagonists and inotropes) have been introduced for the treatment of heart failure. The aim of the present article is to update the information regarding the pharmacokinetics of these drugs. For this purpose we have made a systematic survey of literature using MEDLINE, EMBASE and Japan Centra Revuo Medicina (in Japanese) and found a total of 111 relevant publications for 58 drugs. Heart failure is a pathophysiological state where the damaged heart, from whatever causes, no longer pumps enough blood for the needs of body tissues at rest or during the normal daily activities. The spectrum of heart failure ranges from acute decompensated heart failure (including circulatory shock) to chronic compensated or decompensated heart failure. Because hypoperfusion of organs may influence drug absorption from the gastrointestinal tract, distribution into tissues and elimination either by the liver or kidneys, it is conceivable that the pharmacokinetics of many drugs may be altered in patients with heart failure. The pharmacokinetic changes of drugs in these patients in the light of a physiologically based pharmacokinetic model are discussed, since this model can interpret altered pharmacokinetics in terms of changes in the binding of drugs in plasma and tissue, blood flow to drug-eliminating organs and intrinsic activity of drug elimination. Pharmacokinetic changes of drugs after intravenous administration are described here in Part 1 and those after oral administration will be discussed in Part 2 in a later issue of the Clinical Pharmacokinetics. Reviewing the retrieved data, it was considered that patients with asymptomatic or compensated chronic heart failure seem to have no or minimal alterations in the pharmacokinetics of parenterally administered drugs as long as there was no concurrent liver and/or kidney dysfunction. In contrast, it was found that the systemic clearance of at least six drugs (i.e. milrinone, carperitide, molsidomine, theophylline, ciclosporin and hydralazine) was reduced after intravenous administration by 50 % or more in patients with acute decompensated heart failure or chronic severe heart failure (New York Heart Association class III or IV) as compared with healthy subjects. Because there is a paucity of information regarding the pharmacokinetics of drugs in patients with severe heart failure, close attention should be paid to monitoring the efficacy of these agents and their associated adverse effects. PMID- 23344982 TI - Quantitative prediction of the impact of drug interactions and genetic polymorphisms on cytochrome P450 2C9 substrate exposure. AB - BACKGROUND AND OBJECTIVE: Cytochrome P450 (CYP) 2C9 is the most common CYP2C enzyme and makes up approximately onethird of total CYP protein content in the liver. It metabolises more than 100 drugs. The exposure of drugs mainly eliminated by CYP2C9 may be dramatically modified by drug-drug interactions (DDIs) and genetic variations. The objective of this study was to develop a modelling approach to predict the impact of genetic polymorphisms and DDIs on drug exposure in drugs metabolised by CYP2C9. We then developed dosing recommendations based on genotypes and compared them to current Epar/Vidal dosing guidelines. METHODS: We created two models. The genetic model was designed to predict the impact of CYP2C9 polymorphisms on drug exposure. It links the area under the concentration-time curve (AUC) ratio (mutant to wild-type patients) to two parameters: the fractional contribution of CYP2C9 to oral clearance in vivo (i.e. CR or contribution ratio), and the fractional activity of the allele combination with respect to the homozygous wild type (i.e. FA or fraction of activity). Data were available for 77 couples (substrate, genotype). We used a three-step approach: (1) initial estimates of CRs and FAs were calculated using a first bibliographic dataset; (2) external validation of these estimates was then performed through the comparison between the AUC ratios predicted by the model and the observed values, using a second published dataset; and (3) refined estimates of CRs and FAs were obtained using Bayesian orthogonal regression involving the whole dataset and initial estimates of CRs and FAs. Posterior distributions of AUC ratios, CRs and FAs were estimated using Monte-Carlo Markov chain simulation. The drug interaction model was designed to predict the impact of DDIs on drug exposure. It links the AUC ratio (ratio of drug given in combination to drug given alone) to several parameters: the CR, the inhibition ratio (IR) of an inhibitor, and the increase in clearance (IC) due to an inducer. Data were available for 80 DDIs. IRs and ICs were calculated using the interaction model and an external validation was performed. Doses adjustments were calculated in order to obtain equal values for drug exposure in extensive and poor metabolisers and then compared to Epar/Vidal dosing guidelines. RESULTS: CRs were assessed for 26 substrates, FAs for five genotype classes including CYP2C9*2 and *3 allelic variants, IRs for 27 inhibitors and ICs for two inducers. For the genetic model, the mean prediction error of AUC ratios was -0.01, while the mean prediction absolute error was 0.36. For the drug interaction model, the mean prediction error of AUC ratios was 0.01, while the mean prediction absolute error was 0.22. Of the 26 substrates and CYP2C9*2 and *3 variants investigated, 30 couples (substrate, genotype) lead to a dose adjustment, as opposed to only ten couples identified in the Epar/Vidal recommendations. CONCLUSION: These models were already used for CYP2D6. They are accurate at predicting the impact of drug interactions and genetic polymorphisms on CYP2C9 substrate exposure. This approach will contribute to the development of personalized medicine, i.e. individualized drug therapy with specific dosing recommendations based on CYP genotype or drug associations. PMID- 23344983 TI - Expression of immunoregulatory genes and its relationship to lead exposure and lead-mediated oxidative stress in wild ungulates from an abandoned mining area. AB - Lead (Pb) is a highly toxic metal that can induce oxidative stress and affect the immune system by modifying the expression of immunomodulator-related genes. The aim of the present study was to investigate the association between Pb exposure and the transcriptional profiles of some cytokines, as well as the relationship between Pb exposure and changes in oxidative stress biomarkers observed in the spleen of wild ungulates exposed to mining pollution. Red deer and wild boar from the mining area studied had higher spleen, liver, and bone Pb levels than controls, indicating a chronic exposure to Pb pollution. Such exposure caused a depletion of spleen glutathione levels in both species and disrupted the activity of antioxidant enzymes, suggesting the generation of oxidative stress conditions. Deer from the mining area also showed an induced T-helper (Th )-dependent immune response toward the Th 2 pathway, whereas boar from the mining area showed a cytokine profile suggesting an inclination of the immune response toward the Th 1 pathway. These results indicate that environmental exposure to Pb may alter immune responses in wild ungulates exposed to mining pollution. However, evidence of direct relationships between Pb-mediated oxidative stress and the changes detected in immune responses were not found. Further research is needed to evaluate the immunotoxic potential of Pb pollution, also considering the prevalence of chronic infectious diseases in wildlife in environments affected by mining activities. PMID- 23344984 TI - From demand curves to public policy: introduction to the special issue on behavioral economics. PMID- 23344985 TI - How many impulsivities? A discounting perspective. AB - People discount the value of delayed and uncertain outcomes, and how steeply individuals discount is thought to reflect how impulsive they are. From this perspective, steep discounting of delayed outcomes (which fails to maximize long term welfare) and shallow discounting of probabilistic outcomes (which fails to adequately take risk into account) reflect the same trait of impulsivity. Despite the fact that a hyperboloid function describes the discounting of both delayed and probabilistic outcomes, there is considerable evidence that the two kinds of discounting involve different processes as well as separate impulsivity traits. Several manipulations differentially affect delay and probability discounting, and correlational studies show that how steeply one discounts delayed rewards is relatively independent of how steeply one discounts probabilistic rewards. Moreover, people's discounting of delayed money and health outcomes are uncorrelated as are discounting of real, consumable rewards and hypothetical money. These results suggest that even within delay discounting, there may be multiple 'impulsivities,' each of which may be important for understanding a different aspect of decision making. Taken together, the pattern of findings reviewed here argues for a more nuanced view of impulsivity than that which is usually assumed in discounting research. PMID- 23344986 TI - Integrating behavioral economics and behavioral genetics: delayed reward discounting as an endophenotype for addictive disorders. AB - Delayed reward discounting is a behavioral economic index of impulsivity, referring to how much an individual devalues a reward based on its delay in time. As a behavioral process that varies considerably across individuals, delay discounting has been studied extensively as a model for self-control, both in the general population and in clinical samples. There is growing interest in genetic influences on discounting and, in particular, the prospect of discounting as an endophenotype for addictive disorders (i.e., a heritable mechanism partially responsible for conferring genetic risk). This review assembles and critiques the evidence supporting this hypothesis. Via numerous cross-sectional studies and a small number of longitudinal studies, there is considerable evidence that impulsive discounting is associated with addictive behavior and appears to play an etiological role. Moreover, there is increasing evidence from diverse methodologies that impulsive delay discounting is temporally stable, heritable, and that elevated levels are present in nonaffected family members. These findings suggest that impulsive discounting meets the criteria for being considered an endophenotype. In addition, recent findings suggest that genetic variation related to dopamine neurotransmission is significantly associated with variability in discounting preferences. A significant caveat, however, is that the literature is modest in some domains and, in others, not all the findings have been supportive or consistent. In addition, important methodological considerations are necessary in future studies. Taken together, although not definitive, there is accumulating support for the hypothesis of impulsive discounting as an endophenotype for addictive behavior and a need for further systematic investigation. PMID- 23344988 TI - Towards a general model of temporal discounting. AB - Psychological models of temporal discounting have now successfully displaced classical economic theory due to the simple fact that many common behavior patterns, such as impulsivity, were unexplainable with classic models. However, the now dominant hyperbolic model of discounting is itself becoming increasingly strained. Numerous factors have arisen that alter discount rates with no means to incorporate the different influences into standard hyperbolic models. Furthermore, disparate literatures are emerging that propose theoretical constructs that are seemingly independent of hyperbolic discounting. We argue that, although hyperbolic discounting provides an eminently useful quantitative measure of discounting, it fails as a descriptive psychological model of the cognitive processes that produce intertemporal preferences. Instead, we propose that recent contributions from cognitive neuroscience indicate a path for developing a general model of time discounting. New data suggest a means by which neuroscience-based theory may both integrate the diverse empirical data on time preferences and merge seemingly disparate theoretical models that impinge on time preferences. PMID- 23344987 TI - Changing delay discounting in the light of the competing neurobehavioral decision systems theory: a review. AB - Excessively devaluing delayed reinforcers co-occurs with a wide variety of clinical conditions such as drug dependence, obesity, and excessive gambling. If excessive delay discounting is a trans-disease process that underlies the choice behavior leading to these and other negative health conditions, efforts to change an individual's discount rate are arguably important. Although discount rate is often regarded as a relatively stable trait, descriptions of interventions and environmental manipulations that successfully alter discount rate have begun to appear in the literature. In this review, we compare published examples of procedures that change discount rate and classify them into categories of procedures, including therapeutic interventions, direct manipulation of the executive decision-making system, framing effects, physiological state effects, and acute drug effects. These changes in discount rate are interpreted from the perspective of the competing neurobehavioral decision systems theory, which describes a combination of neurological and behavioral processes that account for delay discounting. We also suggest future directions that researchers could take to identify the mechanistic processes that allow for changes in discount rate and to test whether the competing neurobehavioral decision systems view of delay discounting is correct. PMID- 23344989 TI - Change detection, multiple controllers, and dynamic environments: insights from the brain. AB - Foundational studies in decision making focused on behavior as the most accessible and reliable data on which to build theories of choice. More recent work, however, has incorporated neural data to provide insights unavailable from behavior alone. Among other contributions, these studies have validated reinforcement learning models by demonstrating neural signals posited on the basis of behavioral work in classical and operant conditioning. In such models, the values of actions or options are updated incrementally based on the difference between expectations and outcomes, resulting in the gradual acquisition of stable behavior. By contrast, natural environments are often dynamic, including sudden, unsignaled shifts in reinforcement contingencies. Such rapid changes may necessitate frequent shifts in behavioral mode, requiring dynamic sensitivity to environmental changes. Recently, we proposed a model in which cingulate cortex plays a key role in detecting behaviorally relevant environmental changes and facilitating the update of multiple behavioral strategies. Here, we connect this framework to a model developed to handle the analogous problem in motor control. We offer a tentative dictionary of control signals in terms of brain structures and highlight key differences between motor and decision systems that may be important in evaluating the model. PMID- 23344990 TI - Social discounting and the prisoner's dilemma game. AB - Altruistic behavior has been defined in economic terms as "...costly acts that confer economic benefits on other individuals" (Fehr & Fischbacher, 2003). In a prisoner's dilemma game, cooperation benefits the group but is costly to the individual (relative to defection), yet a significant number of players choose to cooperate. We propose that people do value rewards to others, albeit at a discounted rate (social discounting), in a manner similar to discounting of delayed rewards (delay discounting). Two experiments opposed the personal benefit from defection to the socially discounted benefit to others from cooperation. The benefit to others was determined from a social discount function relating the individual's subjective value of a reward to another person and the social distance between that individual and the other person. In Experiment 1, the cost of cooperating was held constant while its social benefit was varied in terms of the number of other players, each gaining a fixed, hypothetical amount of money. In Experiment 2, the cost of cooperating was again held constant while the social benefit of cooperating was varied by the hypothetical amount of money earned by a single other player. In both experiments, significantly more participants cooperated when the social benefit was higher. PMID- 23344991 TI - Behavioral economics and empirical public policy. AB - The application of economics principles to the analysis of behavior has yielded novel insights on value and choice across contexts ranging from laboratory animal research to clinical populations to national trends of global impact. Recent innovations in demand curve methods provide a credible means of quantitatively comparing qualitatively different reinforcers as well as quantifying the choice relations between concurrently available reinforcers. The potential of the behavioral economic approach to inform public policy is illustrated with examples from basic research, pre-clinical behavioral pharmacology, and clinical drug abuse research as well as emerging applications to public transportation and social behavior. Behavioral Economics can serve as a broadly applicable conceptual, methodological, and analytical framework for the development and evaluation of empirical public policy. PMID- 23344992 TI - Editorial: an anniversary and an inaugural issue. PMID- 23344993 TI - Targeting therapy to the fibrin-mediated pathophysiology of acute coronary syndrome. AB - Acute coronary syndrome (ACS) encompasses a spectrum of diseases, ranging from ST elevation myocardial infarction to non-ST-elevation myocardial infarction and unstable angina. A key initiating event in the pathology of ACS is atheromatous plaque disruption, in which the exposure of thrombogenic material triggers simultaneous activation of primary and secondary hemostatic pathways. Targeting platelet-mediated thrombus formation with dual antiplatelet therapy comprising acetylsalicylic acid and a P2Y12 antagonist is the current mainstay for management of ACS. However, a significant proportion of patients remain at risk of cardiovascular events. Fibrin is an important contributor to thrombogenesis and may account for the residual event rates. This review examines evidence for the role of the coagulation cascade in thrombus formation in ACS, which provides a rationale for the use of anticoagulation therapy. The current status of research with novel oral anticoagulants in combination with dual antiplatelet therapy for the secondary prevention of ACS is also discussed. PMID- 23344994 TI - Platelet Reactivity and Intramyocardial Hemorrhage in Patients With ST-Segment Elevation Myocardial Infarction. AB - The aim of the study was to analyze the relation between platelet reactivity and intramyocardial hemorrhage (IMH) in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. Platelet reactivity was measured in 49 patients with means of impedance aggregometry (Multiplate) before reperfusion and repeated in the subacute phase of STEMI. Cardiovascular magnetic resonance was used to detect IMH, which was found in 16 (33%) patients. There were no differences in platelet reactivity between patients with and without IMH before reperfusion. Reassessment in the subacute phase of STEMI demonstrated that patients with IMH had lower thrombin receptor activating peptide (TRAP)-induced platelet aggregation (P = .004) and trends toward lower values of ristocetin and collagen-induced platelet aggregation (P = .09 and P = .07). The TRAP-induced platelet aggregation and initial perfusion grade were the factors independently associated with IMH. Intramyocardial hemorrhage is related to more potent inhibition of platelet aggregation in the subacute phase of STEMI. PMID- 23344995 TI - Higher neutrophil to lymhocyte ratio in patients with metabolic syndrome. PMID- 23344996 TI - Relation of neutrophil to lymphocyte ratio with the presence and severity of stable coronary artery disease. AB - OBJECTIVES: We examined the association between neutrophil to lymphocyte ratio (NLR) and the complexity of coronary artery disease assessed by SYNTAX score (SS). METHODS: The study population included patients with chest pain who had undergone coronary angiography for stable angina pectoris. Patients were classified depending on whether the SS was 0 or SS > 0. RESULTS: Left ventricular ejection fraction, estimated glomerular filtration rate, and NLR were found to be the independent predictors of high SS in multivariate analysis. The area under the receiver-operating curve of NLR was 0.72 (0.65-0.80, P < .001) for predicting high SS. The optimal cutoff value of NLR to predict high SS was 2.7 (sensitivity of 72% and a specificity of 61%). There was a significant correlation between NLR ratio and continuous SS (r = .552, P < .001). CONCLUSION: The NLR is a readily measurable systemic inflammatory marker and is associated with both the presence and the complexity of coronary artery disease. PMID- 23344997 TI - Aerobic transformation of zinc into metal sulfide by photosynthetic microorganisms. AB - Industrial activity over the last two centuries has increased heavy metal contamination worldwide, leading to greater human exposure. Zinc is particularly common in industrial effluents and although an essential nutrient, it is highly toxic at elevated concentrations. Photoautotrophic microbes hold promise for heavy metal bioremediation applications because of their ease of culture and their ability to produce sulfide through metabolic processes that in turn are known to complex with the metal ion, Hg(II). The green alga Chlamydomonas reinhardtii, the red alga Cyanidioschyzon merolae, and the cyanobacterium Synechococcus leopoliensis were all able to synthesize sulfide and form zinc sulfide when exposed to Zn(II). Supplementation of their respective media with sulfite and cysteine had deleterious effects on growth, although ZnS still formed in Cyanidioschyzon cells to the same extent as in unsupplemented cells. The simultaneous addition of sulfate and Zn(II) had similar effects to that of Zn(II) alone in all three species, whereas supplying sulfate prior to exposure to Zn(II) enhanced metal sulfide production. The coupled activities of serine acetyltransferase and O-acetylserine(thiol)lyase (SAT/OASTL) did not increase significantly in response to conditions in which enhanced ZnS formation occurred; sulfate added prior to and simultaneously with Zn(II). However, even low activity could provide sufficient sulfate assimilation over this relatively long-term study. Because the extractable activity of cysteine desulfhydrase was elevated in cells that produced higher amounts of zinc sulfide, cysteine is the probable source of the sulfide in this aerobic process. PMID- 23344999 TI - Synthesis of soluble poly-yne polymers containing zirconium and silicon and corresponding conversion to nanosized ZrC/SiC composite ceramics. AB - Soluble organometallic polymers containing zirconium and silicon were synthesized by a salt metathesis reaction. The molecular weight of the polymers was measured by GPC and the corresponding structures were identified by (13)C NMR and FT-IR. After heat treatment of the polymers under argon at 1400 degrees C for 2 h, ZrC/SiC composites with different molar ratios of crystalline phases were obtained and characterized by XRD, elemental analysis, SEM and Raman spectroscopy. The crystalline size of the composites was approximately 100 nm-200 nm and the elements were well distributed at the different sites in the ceramics. The Raman results indicated that the ceramic residue could be considered as ZrC/SiC/C ternary composites. PMID- 23344998 TI - Comparative functional genomics to reveal the molecular basis of phenotypic diversities and guide the genetic breeding of industrial yeast strains. AB - An understanding of the genetic basis underlying the phenotypic variations of yeast strains would guide the breeding of this useful microorganism. Here, comparative functional genomics (CFG) of two bioethanol Saccharomyces cerevisiae strains (YJS329 and ZK2) with different stress tolerances and ethanol fermentation performances were performed. Our analysis indicated that different patterns of gene expression in the central carbon metabolism, antioxidative factors, and membrane compositions of these two strains are the main contributors to their various traits. Some of the differently expressed genes were directly caused by the genomic structural variations between YJS329 and ZK2. Moreover, CFG of these two strains also led to novel insights into the mechanism of stress tolerance in yeast. For example, it was found that more oleic acid in the plasma membrane contributes to the acetic acid tolerance of yeast. Based on the genetic information particular to each strain, strategies to improve their adaptability and ethanol fermentation performances were designed and confirmed. Thus, CFG could not only help reveal basis of phenotypic diversities but also guide the genetic breeding of industrial microorganisms. PMID- 23345000 TI - Phase I study of oral CP-4126, a gemcitabine derivative, in patients with advanced solid tumors. AB - CP-4126 is a gemcitabine (2',2'-difluorodeoxycytidine; dFdC) 5' elaidic acid ester. The purpose of this dose-escalating study was to assess safety, pharmacokinetics (PK) and preliminary antitumor activity of the oral formulation and to determine the recommended dose (RD) for phase II studies. The study had a two-step design: a non-randomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II that compared oral CP-4126 with dFdC i.v.. CP-4126 was given on days 1,8,15 in a 4-week schedule with increasing doses until the RD was established. 26 patients with different solid tumours were enrolled in step I at seven dose levels (100-3,000 mg/day). The most frequent drug-related AEs were fatigue and dysgeusia, the majority being grade 1-2. One patient experienced a dose limiting toxicity after one dose of CP-4126 at 1,300 mg/day (ASAT grade 3). PK of CP-4126 could not be determined. The metabolites dFdC and dFdU obeyed dose-dependent pharmacokinetics. Exposures to dFdC were about ten-fold lower compared to exposures after comparable doses of dFdC i.v.. Nine patients reached stable disease as best response, whereby in one patient with vaginal carcinoma a 25 % reduction of tumor volume was reached. This study demonstrates that CP-4126 can be safely administered orally to patients up to 3,000 mg/day in a d1,8,15 q4w schedule with a tolerable safety profile. CP-4126 acts as a prodrug for dFdC when given orally, but because of the poor absorption and the rapid pre-systemic metabolism the study was terminated early and no RD could be determined. PMID- 23345001 TI - The risk of hand-foot skin reaction to axitinib, a novel VEGF inhibitor: a systematic review of literature and meta-analysis. AB - Axitinib is a potent, selective vascular endothelial growth factor receptor (VEGFR) inhibitor. We have performed a systematic analysis to investigate the risk of hand-foot skin reaction (HFSR) to axitinib and compare the differences in incidences between sorafenib, sunitinib, pazopanib and axitinib. Relevant studies were identified from PubMed (1998-2012). Eligible studies were limited to prospective Phase II-III clinical trials in which cancer patients were treated with axitinib monotherapy at a starting dose of 5 mg orally twice daily. Incidence, relative risk (RR), and 95 % confidence intervals were calculated using random-effects or fixed-effects models based on heterogeneity of included studies. A total of 984 patients from 6 prospective clinical trials were included in the analysis. The overall incidence of all-grade and high-grade HFSR was 29.2 % (95 % CI: 14.0-51.1 %) and 9.6 % (95 % CI: 4.2-20.7 %), respectively. The relative risks of all-grade and high-grade HFSR to axitinib compared to sorafenib were decreased for all-grade (RR=0.54, 95 % CI: 0.44-0.65, p<0.001) and high grade HFSR (RR=0.31, 95 % CI: 0.19-0.52, p<0.001). The risk of all-grade and high grade HFSR to axitinib, sunitinib and sorafenib was significantly higher as compared to pazopanib (RR=6.49, 95 % CI: 4.65-9.05, p<0.001; RR=6.40, 95 % CI: 3.60-11.37, p<0.001, and RR=4.20, 95 % CI: 3.07-5.75, p<0.001; RR=3.67, 95 % CI: 2.15-6.24, p<0.001, and RR=7.51, 95 % CI: 5.5-10.3, p<0.001; RR=5.93, 95 % CI: 3.5-10.0, p<0.001, respectively). Similar to sorafenib and sunitinib, axitinib is associated with a significant risk of HFSR, despite having an increased specificity for VEGF receptors. These findings underscore the importance of supportive dermatologic care in patients treated with axitinib, in order to maintain quality of life, adherence, and persistence to therapy. PMID- 23345002 TI - Synthesis of monodisperse hollow carbon nanocapsules by using protective silica shells. AB - Monodisperse hollow carbon nanocapsules (<200 nm) with mesoporous shells were synthesized by coating their outer shells with silica to prevent aggregation during their high-temperature annealing. Monodispersed silica nanoparticles were used as starting materials and octadecyltrimethoxysilane (C18TMS) was used as a carbon source to create core-shell nanostructures. These core-shell nanoparticles were coated with silica on their outer shell to form a second shell layer. This outer silica shell prevented aggregation during calcination. The samples were characterized by TEM, SEM, dynamic light scattering (DLS), UV/Vis spectroscopy, and by using the Brunauer-Emmett-Teller (BET) method. The as-synthesized hollow carbon nanoparticles exhibited a high surface area (1123 m(2) g(-1)) and formed stable dispersions in water after the pegylation process. The drug-loading and drug-release properties of these hollow carbon nanocapsules were also investigated. PMID- 23345003 TI - Alpha-tocopherol ameliorates oxidative renal insult associated with spinal cord reperfusion injury. AB - Ischemic-reperfusion procedures targeting a specific organ often results in remote multiple organ injuries mediated possibly by heightened oxidative stress levels. As the kidney is one of the most vulnerable organs for ischemic oxidative stress, the aim of the present study was to confirm the occurrence of renal complication secondary to spinal cord ischemic-reperfusion injury (SC-IRI) induced by aortic clamping. The study also investigated the possible prophylactic effect of long-term administration of alpha-tocopherol (alpha-TOL) against high level of renal oxidative stress and inflammatory processes induced by SC-IRI. In this study, a total of 60 male Sprague-Dawley rats were randomly divided into five equal groups: C group underwent no surgery; CE group received alpha-TOL 600 mg/kg intramuscular twice weekly for 6 weeks; S group were subjected to laparotomy without clamping of the aorta; SE group were handled as S group and treated with alpha-TOL as group CE; SC-IRI group were subjected to laparotomy with clamping of the aorta just above the bifurcation of the aorta for 45 min, then the clamp was released for 48 h for reperfusion. SC-IRIE group was subjected to IRI as in group SC-IRI and was injected with alpha-TOL in the same dose and route as alpha-TOL-treated control group. SC-IRI resulted in increases in serum creatinine, blood urea nitrogen, plasma nitrite/nitrate level, serum tumor necrosis factor alpha, renal tissue homogenate level for malondialdehyde, superoxide dismutase and prostaglandin E2. Long-term prophylactic treatment with alpha-TOL resulted in amelioration of the renal functional disturbances and all measured parameters of oxidative stress and inflammation. Ischemic reperfusion injury of the spinal cord induced some remote renal functional disturbances although some of the observed changes may have resulted from decreased renal blood flow due to the hypotension induced during the procedure. Prophylactic long term alpha-TOL administration guards against the renal function disturbances an effect that can be attributed, at least partially, to improvement of the renal pro-oxidant/antioxidant balance and inhibition of the inflammatory processes. PMID- 23345005 TI - Formation and properties of a hybrid organosilica with a p-phenylene vinylene polymer partially grafted to the walls. AB - The present manuscript reports a mesoporous organosilica (mpSiO(2)) containing a p-phenylene vinylene (PPV) co-polymer partially grafted to the walls of the hybrid material (PPV?mpSiO(2)). This material was obtained by using a bis silylated 2,5-bis(chloromethylphenylene) as the silicon precursor in combination with tetraethyl orthosilicate (TEOS) and cetyltrimethylammonium bromide (CTABr) as the surfactant. The final polymer was formed by adding appropriate amounts of 2,2'-{[2,5-bis(chloromethyl)-1,4-phenylene]bis(oxy)}diethanol as the co-monomer and KtBuO as the base. The resulting PPV?mpSiO(2) was characterized by XRD, SEM, TEM, FTIR spectroscopy, and magic angle spinning (29) Si NMR spectroscopy; all spectroscopic data were in agreement with the presence of a conducting polymer. The resulting PPV?mpSiO(2) material exhibits electrical conductivity, particularly after I(2) doping, an electrochemical response, and electroluminescence. Laser flash photolysis studies of PPV?mpSiO(2) indicate that this material can form PPV(.+) polarons that could be responsible for the electrochemical and electroluminescent response. PMID- 23345004 TI - Efficient and selective formation of macrocyclic disubstituted Z alkenes by ring closing metathesis (RCM) reactions catalyzed by Mo- or W-based monoaryloxide pyrrolide (MAP) complexes: applications to total syntheses of epilachnene, yuzu lactone, ambrettolide, epothilone C, and nakadomarin A. AB - The first broadly applicable set of protocols for efficient Z-selective formation of macrocyclic disubstituted alkenes through catalytic ring-closing metathesis (RCM) is described. Cyclizations are performed with 1.2-7.5 mol% of a Mo- or W based monoaryloxide pyrrolide (MAP) complex at 22 degrees C and proceed to complete conversion typically within two hours. Utility is demonstrated by synthesis of representative macrocyclic alkenes, such as natural products yuzu lactone (13-membered ring: 73% Z) epilachnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanced precursor to epothilones C and A (16-membered ring: up to 97% Z), and nakadomarin A (15-membered ring: up to 97% Z). We show that catalytic Z-selective cyclizations can be performed efficiently on gram-scale with complex molecule starting materials and catalysts that can be handled in air. We elucidate several critical principles of the catalytic protocol: 1) The complementary nature of the Mo catalysts, which deliver high activity but can be more prone towards engendering post-RCM stereoisomerization, versus W variants, which furnish lower activity but are less inclined to cause loss of kinetic Z selectivity. 2) Reaction time is critical to retaining kinetic Z selectivity not only with MAP species but with the widely used Mo bis(hexafluoro-tert-butoxide) complex as well. 3) Polycyclic structures can be accessed without significant isomerization at the existing Z alkenes within the molecule. PMID- 23345006 TI - Low frequency pulsed electromagnetic field affects proliferation, tissue-specific gene expression, and cytokines release of human tendon cells. AB - Low frequency pulsed electromagnetic field (PEMF) has proven to be effective in the modulation of bone and cartilage tissue functional responsiveness, but its effect on tendon tissue and tendon cells (TCs) is still underinvestigated. PEMF treatment (1.5 mT, 75 Hz) was assessed on primary TCs, harvested from semitendinosus and gracilis tendons of eight patients, under different experimental conditions (4, 8, 12 h). Quantitative PCR analyses were conducted to identify the possible effect of PEMF on tendon-specific gene transcription (scleraxis, SCX and type I collagen, COL1A1); the release of pro- and anti inflammatory cytokines and of vascular endothelial growth factor (VEGF) was also assessed. Our findings show that PEMF exposure is not cytotoxic and is able to stimulate TCs' proliferation. The increase of SCX and COL1A1 in PEMF-treated cells was positively correlated to the treatment length. The release of anti inflammatory cytokines in TCs treated with PEMF for 8 and 12 h was significantly higher in comparison with untreated cells, while the production of pro inflammatory cytokines was not affected. A dramatically higher increase of VEGF-A mRNA transcription and of its related protein was observed after PEMF exposure. Our data demonstrated that PEMF positively influence, in a dose-dependent manner, the proliferation, tendon-specific marker expression, and release of anti inflammatory cytokines and angiogenic factor in a healthy human TCs culture model. PMID- 23345007 TI - Risk stratification of cardiac autonomic neuropathy based on multi-lag Tone Entropy. AB - Cardiac autonomic neuropathy (CAN) is an irreversible condition affecting the autonomic nervous system, which leads to abnormal functioning of the visceral organs and affects critical body functions such as blood pressure, heart rate and kidney filtration. This study presents multi-lag Tone-Entropy (T-E) analysis of heart rate variability (HRV) at multiple lags as a screening tool for CAN. A total of 41 ECG recordings were acquired from diabetic subjects with definite CAN (CAN+) and without CAN (CAN-) and analyzed. Tone and entropy values of each patient were calculated for different beat sequence lengths (len: 50-900) and lags (m: 1-8). The CAN- group was found to have a lower mean tone value compared to that of CAN+ group for all m and len, whereas the mean entropy value was higher in CAN- than that in CAN+ group. Leave-one-out (LOO) cross-validation tests using a quadratic discriminant (QD) classifier were applied to investigate the performance of multi-lag T-E features. We obtained 100 % accuracy for tone and entropy with len = 250 and m = {2, 3} settings, which is better than the performance of T-E technique based on lag m = 1. The results demonstrate the usefulness of multi-lag T-E analysis over single lag analysis in CAN diagnosis for risk stratification and highlight the change in autonomic nervous system modulation of the heart rate associated with cardiac autonomic neuropathy. PMID- 23345008 TI - Parameterisation of multi-scale continuum perfusion models from discrete vascular networks. AB - Experimental data and advanced imaging techniques are increasingly enabling the extraction of detailed vascular anatomy from biological tissues. Incorporation of anatomical data within perfusion models is non-trivial, due to heterogeneous vessel density and disparate radii scales. Furthermore, previous idealised networks have assumed a spatially repeating motif or periodic canonical cell, thereby allowing for a flow solution via homogenisation. However, such periodicity is not observed throughout anatomical networks. In this study, we apply various spatial averaging methods to discrete vascular geometries in order to parameterise a continuum model of perfusion. Specifically, a multi-compartment Darcy model was used to provide vascular scale separation for the fluid flow. Permeability tensor fields were derived from both synthetic and anatomically realistic networks using (1) porosity-scaled isotropic, (2) Huyghe and Van Campen, and (3) projected-PCA methods. The Darcy pressure fields were compared via a root-mean-square error metric to an averaged Poiseuille pressure solution over the same domain. The method of Huyghe and Van Campen performed better than the other two methods in all simulations, even for relatively coarse networks. Furthermore, inter-compartment volumetric flux fields, determined using the spatially averaged discrete flux per unit pressure difference, were shown to be accurate across a range of pressure boundary conditions. This work justifies the application of continuum flow models to characterise perfusion resulting from flow in an underlying vascular network. PMID- 23345009 TI - Comparison of real beat-to-beat signals with commercially available 4 Hz sampling on the evaluation of foetal heart rate variability. AB - Evaluation of foetal heart rate (FHR) variability is an essential part of foetal monitoring, but a precise quantification of this parameter depends on the quality of the signal. In this study, we compared real FHR beat-to-beat signals with 4 Hz sampling provided by commercial foetal monitors on linear and nonlinear indices and analysed their clinical implications. Simultaneous acquisition of beat-to beat signals and their 4 Hz sampling rate counterparts was performed using a scalp electrode, during the last hour of labour in 21 fetuses born with an umbilical artery blood (UAB) pH >= 7.20 and 6 born with an UAB pH < 7.20. For each case, the first and last 10 min segments were analysed, using time and frequency domain linear, and nonlinear FHR indices, namely mean FHR, low frequency, high frequency, approximate, sample and multiscale entropy. Significant differences in variability indices were found between beat-to-beat and 4 Hz sampled signals, with a lesser effect seen with 2 Hz sampling. These differences did not affect physiological changes observed during labour progression, such as decreased entropy and linear time domain indices, and increased frequency domain indices. However, significant differences were found in the discrimination between fetuses born with different UAB pHs, with beat-to beat sampling providing better results in linear indices and 4 Hz sampling better results in entropy indices. In conclusion, different FHR sampling frequencies can significantly affect the quantification of variability indices. This needs to be taken into account in the interpretation of FHR variability and in the development of new equipment. PMID- 23345010 TI - Thermodesulfobacterium geofontis sp. nov., a hyperthermophilic, sulfate-reducing bacterium isolated from Obsidian Pool, Yellowstone National Park. AB - A novel sulfate-reducing bacterium designated OPF15(T) was isolated from Obsidian Pool, Yellowstone National Park, Wyoming. The phylogeny of 16S rRNA and functional genes (dsrAB) placed the organism within the family Thermodesulfobacteriaceae. The organism displayed hyperthermophilic temperature requirements for growth with a range of 70-90 degrees C and an optimum of 83 degrees C. Optimal pH was around 6.5-7.0 and the organism required the presence of H2 or formate as an electron donor and CO2 as a carbon source. Electron acceptors supporting growth included sulfate, thiosulfate, and elemental sulfur. Lactate, acetate, pyruvate, benzoate, oleic acid, and ethanol did not serve as electron donors. Membrane lipid analysis revealed diacyl glycerols and acyl/ether glycerols which ranged from C14:0 to C20:0. Alkyl chains present in acyl/ether and diether glycerol lipids ranged from C16:0 to C18:0. Straight, iso- and anteiso-configurations were found for all lipid types. The presence of OPF15(T) was also shown to increase cellulose consumption during co-cultivation with Caldicellulosiruptor obsidiansis, a fermentative, cellulolytic extreme thermophile isolated from the same environment. On the basis of phylogenetic, phenotypic, and structural analyses, Thermodesulfobacterium geofontis sp. nov. is proposed as a new species with OPF15(T) representing the type strain. PMID- 23345011 TI - Circumstances and efforts: how important is their correlation for the measurement of inequality of opportunity in health? AB - The way to treat the correlation between circumstances and effort is a central, yet largely neglected issue in the applied literature on inequality of opportunity. This paper adopts three alternative normative ways of treating this correlation championed by Roemer, Barry and Swift and assesses their empirical relevance using survey data. We combine regression analysis with the natural decomposition of the variance to compare the relative contributions of circumstances and efforts to overall health inequality according to the different normative principles. Our results suggest that, in practice, the normative principle on the way to treat the correlation between circumstances and effort makes little difference on the relative contributions of circumstances and efforts to explained health inequality. PMID- 23345012 TI - Longitudinal relationships of executive cognitive function and parent influence to child substance use and physical activity. AB - Considered a set of neuro-cognitive skills, executive cognitive function (ECF) may serve to protect children from initiating substance use, although its role relative to other protective influences that parents and physical activity might provide is not known. As part of a large multiple health risk behavior trial for prevention of substance use and obesity, Pathways, the present study evaluated the relative impact of ECF on lifetime substance use (tobacco and alcohol) and physical activity in a panel of fourth grade children over a 6-month period (N = 1005; 51 % female; 25 % on free/reduced lunch; 60 % Hispanic/Latino or multi racial; 28 elementary schools). A self-report survey included measures of ECF, lifetime tobacco and alcohol use, out-of-school physical activity, exercising with parents, and parent rules about food/sedentary behavior, monitoring, and arguing, was adapted for use with children. A path analysis demonstrated that ECF was the major predictor of lower substance use and higher physical activity and exercising with parents. Physical activity and exercising with parents showed reciprocal positive relationships. Findings suggest that promoting ECF skills should be a major focus of child health promotion and substance use prevention programs, although the potential protective effects of physical activity and exercise with parents on substance use in this young age group are not yet clear. PMID- 23345013 TI - Substrate-shielding and hydrolytic reaction in hydrolases. AB - In general, transferases undergo large structural changes and sequester substrate molecules, to shield them from water. By contrast, hydrolases exhibit only small structural changes, and expose substrate molecules to water. However, some hydrolases deeply bury their substrates within the proteins. To clarify the relationship between substrate-shielding and enzymatic functions, we investigated 70 representative hydrolase structures, and examined the relative accessible surface areas of their substrates. As compared to the hydrolases employing the single displacement reaction, the hydrolases employing the double displacement reaction bury the substrate within the proteins. The exo hydrolases display significantly more substrate-shielding from water than the endo hydrolases. It suggests that the substrate-shielding is related to the chemical reaction mechanism of the hydrolases and the substrate specificity. PMID- 23345014 TI - Adenosine induces cell cycle arrest and apoptosis via cyclinD1/Cdk4 and Bcl-2/Bax pathways in human ovarian cancer cell line OVCAR-3. AB - Adenosine is a regulatory molecule with widespread physiological effects in almost every cells and acts as a potent regulator of cell growth. Adenosine has been shown to inhibit cell growth and induce apoptosis in the several cancer cells via caspase activation and Bcl-2/Bax pathway. The present study was designed to understand the mechanism underlying adenosine-induced apoptosis in the OVCAR-3 human ovarian cancer cells. MTT viability, BrdU and cell counting assays were used to study the cell proliferation effect of adenosine in presence of adenosine deaminase inhibitor and the nucleoside transporter inhibitor. Cell cycle analysis, propidium iodide and annexin V staining, caspase-3 activity assay, cyclinD1, Cdk4, Bcl-2 and Bax protein expressions were assessed to detect apoptosis. Adenosine significantly inhibited cell proliferation in a concentration-dependent manner in OVCAR-3 cell line. Adenosine induced cell cycle arrest in G0/G1 phase via Cdk4/cyclinD1-mediated pathway. Adenosine induced apoptosis, which was determined by Annexin V-FITC staining and increased sub-G1 population. Moreover, down-regulation of Bcl-2 protein expression, up-regulation of Bax protein expression and activation of caspase-3 were observed in response to adenosine treatment. The results of this study suggest that extracellular adenosine induced G1 cell cycle arrest and apoptosis in ovarian cancer cells via cyclinD1/ Cdk4 and Bcl-2/Bax pathways and caspase-3 activation. These data might suggest that adenosine could be used as an agent for the treatment of ovarian cancer. PMID- 23345015 TI - BMI, apolipoprotein B/apolipoprotein A-I ratio, and insulin resistance in patients with prolactinomas: a pilot study in a Chinese cohort. AB - Deranged metabolic profiles and insulin resistance (IR) have been documented in patients with prolactinomas. Few data are yet available on the apolipoprotein (apo) B/apoA-I ratio and its relationship with IR in patients with prolactinomas. This study was aimed to evaluate the level of apoB/apoA-I ratio and its association with IR in a Chinese subgroup with prolactinomas. Twenty-three prolactinoma patients and 20 healthy controls were enrolled in this study. The clinical anthropometric parameters and laboratory evaluation were collected. Insulin sensitivity was estimated using homeostatic model assessment [homeostasis model assessment of insulin resistance (HOMA-IR)]. Waist circumference and body weight index (BMI) were significantly higher in patients with prolactinomas than those in the controls (p < 0.05). Meanwhile, the prevalence of general and abdominal obesity seemed more pronounced in male patients compared to that in healthy subjects (57.14 vs. 0 % and 71.43 vs. 16.7 %, respectively). Furthermore, fasting glucose, insulin, HOMA-IR, triglyceride, and apoB/apoA-I ratio were also significantly higher in prolactinoma patients, but with lower level of apoA-I (p < 0.05). Univariate regression analysis revealed that prolactin, waist circumference, BMI, and presence of hypogonadism were significantly associated with IR (p < 0.05). However, only BMI [odds ratio (OR) = 1.937, 95 % confidence interval (CI) 1.112-3.375, p = 0.02] and prolactin (OR = 5.173, 95 % CI 1.073 24.94, p = 0.041) were shown to be independent predictors for the presence of IR in multivariate logistic analysis. This study confirmed the altered metabolic profile, including body weight gain, IR, disordered lipids, and apolipoproteins in prolactinoma patients. Prolactin and BMI were independently associated with IR. The effect of apoB/apoA-I ratio on IR is warranted to be determined in further studies. PMID- 23345016 TI - Surgical treatment of tentorial dural arteriovenous fistulae located around the tentorial incisura. AB - Tentorial dural arteriovenous fistulae (DAVF) are relatively uncommon and are the most dangerous type of DAVF. Because of a high incidence of hemorrhage and subsequent neurological deficits, treatment is mandatory. A consecutive series of nine surgically treated patients with symptomatic tentorial DAVF were analyzed in this study. All lesions were located around the tentorial incisura and were treated microsurgically using a subtemporal approach in eight cases and a supracerebellar approach in one case. The dural bases of the lesions were located adjacent to the tentorial edge in six patients and the tentorial apex in three patients. Complete obliteration was achieved in all treated tentorial DAVF. In one patient, the torcular fistula remained untreated without cortical venous reflux. Postoperative asymptomatic temporal lobe hemorrhage was diagnosed in one patient with a tentorial apex DAVF; however, no new neurological symptoms were present after surgical treatment. The subtemporal approach for unilateral tentorial DAVF is a favorable and direct approach for the highly skilled surgeon. Perimesencephalic venous dilatation or varix is an important finding on MRI to help localize tentorial DAVF in the tentorial edge or apex. PMID- 23345017 TI - Chronic encapsulated expanding hematoma in nonfunctioning pituitary adenoma. AB - The diagnosis and treatment of pituitary macroadenomas with entire hematoma fluid accumulation are problematic. Such lesions are often difficult to completely resect, and recurrence is not uncommon. We present five cases of pituitary macroadenomas entirely composed of hematoma fluid and investigated their histopathology to clarify the mechanism of the hematoma fluid accumulation. Five patients with pituitary adenoma and significant intra-tumor hematoma underwent transsphenoidal resection and were retrospectively reviewed for their clinical status, findings on magnetic resonance imaging (MRI), intraoperative findings, and histopathology. The specific surgical techniques used to address these cases were also reviewed. All patients were diagnosed with nonfunctioning pituitary adenomas by histopathological examination. MRI showed all tumors extended to the cavernous sinus. Histopathology showed tumor tissues were located between the thick granulation tissue and the pseudocapsule of the tumor. The thick granulation tissues were composed of collagenous layers, neovascular vessels, and necrotic red blood cells, indicating repeat hemorrhage from the granulation tissues. The boundary between adenoma and normal pituitary gland was identified during surgical removal in four patients and was not identified in the other patient who showed a recurrence 2 years later. Clinical and histopathological findings indicate hematoma fluid accumulation in the present cases is caused by repeat hemorrhage from the reactive granulation tissues and can be regarded as a chronic encapsulated expanding hematoma. In these cases, the boundary between adenoma and normal pituitary gland should be identified before puncturing the hematoma fluid to minimize the risk of tumor recurrence. PMID- 23345018 TI - Copper-catalyzed synthesis of alpha-hydroxy phosphonates from H-phosphonates and alcohols or ethers. PMID- 23345019 TI - History of microsurgery: curiosities from the sixties and seventies. PMID- 23345020 TI - Institutional experience of endoscopic suprasellar arachnoid cyst fenestration. AB - INTRODUCTION: Suprasellar arachnoid cysts can differ from other arachnoid cysts in several ways, making a separate analysis of these cysts worthwhile. Herein, we present the outcome and perform volumetric analysis of six children with suprasellar arachnoid cysts treated with endoscopic ventriculocystocisternostomy in order to evaluate the long-term outcomes. PATIENTS AND METHODS: Operative and postoperative data were retrospectively reviewed for six patients harboring suprasellar arachnoid cysts. Imaging was then used to follow success of surgical intervention. RESULTS: Six patients with suprasellar arachnoid cysts underwent ventriculocystocisternostomy. Presenting symptoms were headaches in three patients, developmental delay in another, and an incidental finding in the remaining patients. All patients had enlarged lateral and third ventricles on initial imaging. Average age at presentation was 145.7 months (65.4-250.2). Follow-up was an average of 46.5 months (3-84). The average cyst size was 153.96 cm(3) (42.98-369.20) preoperatively and an average of 39.92 cm(3) (3.20-101.47) at follow-up. CONCLUSIONS: Based on our experience, suprasellar arachnoid cyst treatment with ventriculocystocisternostomy is an adequate surgical intervention. Suprasellar and third ventricular size does respond to the surgical intervention at long-term follow-up. PMID- 23345021 TI - Nanoadhesion on rigid methyl-terminated biphenyl thiol monolayers: a high-rate dynamic force spectroscopy study. AB - Nanoadhesion on a self-assembled monolayer of 4-methyl-4'-mercaptobiphenyl is measured using a modified atomic force microscope. The dependence of the adhesion force on the loading rate is analyzed with the Dudko-Hummer-Szabo model, and the kinetic and interaction potential parameters for a single terminal group are extracted. The energy and location of the activation barrier suggest that the adhesion is dominated by van der Waals dispersion forces. The humidity effect on the nanoadhesion is also studied. The results are compared with previously measured values for methyl-terminated alkane thiols and the influence of the thiol rigidity on the adhesion force is discussed. PMID- 23345022 TI - A prospective examination of the impact of a supported employment program and employment on health-related quality of life, handicap, and disability among Veterans with SCI. AB - PURPOSES: To investigate impact of participation in a supported employment program and impact of employment itself on health-related quality of life (HRQOL), disability, and handicap among Veterans with spinal cord injury (SCI). METHODS: We used a prospective, randomized, controlled, multi-site trial of supported employment (SE) versus treatment as usual (TAU) for vocational issues. Subjects were 157 Veterans with SCI who received either SE or TAU for vocational issues. Outcomes were examined in terms of type of vocational treatment received and whether competitive employment was obtained. Outcomes investigated were HRQOL as measured by the Veterans RAND 36-item health survey (VR-36), handicap as measured by the Craig Handicap Assessment and Reporting Technique (CHART), and disability as measured by the functional independence measure (FIM). Subjects were assessed at baseline and at 3, 6, 9, and 12 months. RESULTS: There were no significant differences between Veterans who participated in SE compared to those who received TAU in study measures. Participants obtaining competitive employment demonstrated significantly higher scores on the Social Integration, Mobility, and Occupation dimensions of the CHART. There were no observed differences in VR-36 scores or FIM scores for those obtaining competitive employment. CONCLUSION(S): This study suggests that employment has a positive effect on an individual's ability to participate in social relationships, move about their home and community, and spend time in productive and usual roles. Inability to detect differences across other domains of handicap or any changes in HRQOL may have been due to several factors including level and intensity of employment, insufficient follow-up period, or measurement limitations. PMID- 23345023 TI - Contribution of taking part in sport to the association between physical activity and quality of life. AB - PURPOSE: The purpose of this study was to investigate the contribution of sport to the association between physical activity (PA) and quality of life (QoL). METHODS: Cross-sectional data were gathered on 4,909 subjects (age 15-69) from the French National Barometer 2005 survey. The International Physical Activity Questionnaire (IPAQ) and the abbreviated version of the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) were administered. An additional question was used to assess sporting activity. All analyses used linear regression models and were adjusted on variables associated with QoL in a general population. RESULTS: The mean age of the participants (both men and women) decreased with increasing PA level. Sport was positively associated with QoL among men (beta range from 4.2 [95 % CI 3.1-5.4] for physical health to 2.4 [95 % CI 1.1-3.8] for social relationship domains) and women (beta range from 3.6 [95 % CI 2.6-4.5] for physical health to 1.6 [95 % CI 0.6-2.8] for social relationship domains). The association between sport and QoL was greater for low or high PA levels rather than moderate PA for men (physical and psychological health) and women (physical health only). For women, there was a dose-response association with psychological health and social relationships (contribution of sport to QoL increased with PA level). CONCLUSIONS: These results showed that sport was nearly always associated with better QoL, even more so for people who had low or high PA levels (physical and psychological health for men and physical health for women). Prospective studies are necessary to confirm these findings. PMID- 23345024 TI - Diet-induced obesity has a differential effect on adipose tissue and macrophage inflammatory responses of young and old mice. AB - Obesity and aging are both associated with increased inflammation in adipose tissue. In this study, we investigated effect of diet-induced obesity on inflammatory status in young and old mice. Young (2 months) and old (19 months) C57BL/6 mice were fed a low-fat (10%, LF) or high-fat (60%, HF) diet for 4.5 months. Adipose tissue from old/LF mice expressed higher levels of IL-1beta, IL 6, TNFalpha, and cyclooxygenase-2 mRNA compared with young/LF mice. HF diet upregulated expression of all these inflammatory markers in young mice to the levels seen in the aged. Adipocytes, but not stromal vascular cells, from old/LF mice produced more IL-6, TNFalpha, and prostaglandin (PG)E2 than those from young/LF mice. HF diet resulted in an increase of all these markers produced by adipocytes in young, but only TNFalpha in old mice. PGE2 produced by peritoneal macrophages (Mphi's) was upregulated with aging, and HF diet induced more IL-6, TNFalpha, and PGE2 production in young but not in old mice. Thus, HF diet/obesity induces an inflammatory state in both visceral fat cells and peritoneal Mphi's of young mice, but not so in old mice. Together, these results suggest that HF diet induced obesity may speed up the aging process as characterized by inflammatory status. This study also indicates that animals have a differential response, depending on their ages, to HF diet-induced obesity and inflammation. This age related difference in response to HF diet should be considered when using inflammation status as a marker in investigating adverse health impacts of HF diet and obesity. PMID- 23345025 TI - Presence of anti-proteinase 3 antineutrophil cytoplasmic antibodies (anti-PR3 ANCA) as serologic markers in inflammatory bowel disease. AB - Anti-proteinase 3 anti-neutrophil cytoplasmic antibodies (anti-PR3 ANCA) represent an established serologic marker of active granulomatosis with polyangiitis, but their role as a serologic marker in inflammatory bowel disease (IBD) remains uncertain. This study evaluates the presence of anti-PR3 ANCA and their validity as a serologic marker to aid in the diagnosis of IBD. Retrospectively, 142 serum samples obtained at early stages of the disease were analyzed with a new chemiluminiscent assay for the measurement of anti-PR3 ANCA. The results were correlated to the diagnosis, clinical, and therapeutic data, and ANCA and anti-Saccharomyces cerevisiae antibody (ASCA) measurements available from routine clinical practice. Anti-PR3 ANCA were significantly more prevalent (p < 0.0001) and their titers significantly higher (p < 0.0001) among ulcerative colitis compared with Crohn's disease patients. Receiver operating characteristic curve analysis performed with anti-PR3 ANCA titers to assess the diagnostic accuracy of the assay gave an area under the curve of 0.81 (95 % CI (0.76-0.89); p < 0.0001), with a cut-off titer of 11.8 chemiluminescent units displaying 52.1 % sensitivity and 97.3 % specificity for ulcerative colitis. Combining anti-PR3 ANCA positivity with IgA ASCA negativity as the diagnostic parameter demonstrated highest diagnostic utility, with a sensitivity and specificity of 47.5 % and 98.2 %, respectively. In our cohort, anti-PR3 ANCA was significantly more prevalent in ulcerative colitis than in Crohn's disease patients, which suggests a possible role of anti-PR3 ANCA as a serologic marker to aid in the diagnosis of IBD. PMID- 23345027 TI - Immunolocalization of water channel aquaporins in human knee articular cartilage with intact and early degenerative regions. AB - Aquaporins (AQPs), a family of water channel proteins expressed in various cells and tissues, serve as physiological pathways of water and small solute transport. Articular cartilage is avascular tissue with unique biomechanical structure, a major component of which is "water". Our objective is to investigate the immunolocalization and expression pattern changes of AQPs in articular cartilage with normal and early degenerative regions in the human knee joint, which is the joint most commonly involved in osteoarthritis (OA). Two isoforms (AQPs 1 and 3) of AQPs were examined by immunohistochemical analyses using isoform-specific antibodies with cartilage samples from OA patients undergoing total knee arthroplasty. AQP 1 and AQP 3 were expressed in human knee articular cartilage and were localized in chondrocytes, both in the intact and early degenerative cartilage regions. Compared to the intact cartilage, both AQP 1 and AQP 3 immunopositive cells were observed at the damaged surface area in the degenerative region. These findings suggest that these AQPs play roles in metabolic water regulation in articular cartilage of load bearing joints and that they are responsible for OA onset. PMID- 23345028 TI - A neonate with neck swelling and fever. PMID- 23345026 TI - Novel mechanisms of action of the biologicals in rheumatic diseases. AB - Biological drugs targeting pro-inflammatory or co-stimulatory molecules or depleting lymphocyte subsets made a revolution in rheumatoid arthritis (RA) treatment. Their comparable efficacy in clinical trials raised the point of the heterogeneity of RA pathogenesis, suggesting that we are dealing with a syndrome rather than with a single disease. Several tumor necrosis factor-alpha (TNF alpha) blockers are available, and a burning question is whether they are biosimilar or not. The evidence of diverse biological effects in vitro is in line with the fact that a lack of efficacy to one TNF-alpha agent does not imply a non response to another one. As proteins, biologicals are potentially immunogenic. It has been recently raised that anti-drug antibodies (ADA) may affect their bioavailability and eventually the clinical efficacy through local formation of immune complexes and directly by preventing the interaction between the drug and TNF-alpha. Regular monitoring of drug and ADA levels appears the best way to tailor anti-TNF-alpha therapies. Owing to the pleiotropic characteristics of the target, anti-TNF-alpha blockers may affect several mechanisms beyond rheumatoid synovitis. As TNF-alpha plays a pivotal role in the induction of early atherosclerosis, treatment with TNF-inhibitors may modulate cholesterol handling, in particular, cholesterol efflux from macrophages. Side effects are a major issue because of the systemic TNF-alpha blocking action. The efficacy of an anti C5 monoclonal antibody fused to a peptide targeting inflamed synovia in experimental arthritis opened the way for new strategies: Homing to the synovium of molecules neutralizing TNF would allow to maximize the therapeutic action avoiding the side effects. PMID- 23345029 TI - A revisited strategy for antiepileptic drug development in children: designing an initial exploratory step. AB - BACKGROUND: Randomized controlled trials (RCTs) in refractory paediatric epilepsy usually involve the two main types of epilepsy shared by children and adults, focal epilepsy and Lennox-Gastaut syndrome (LGS). Most other epilepsy syndromes, specifically paediatric, are excluded from drug development. In order to identify among them the candidate(s) for dedicated RCTs with a new drug, the European Medicine Agency (EMA) recently recommended proceeding in two steps: (1) an exploratory (prospective-observational) trial (POT) including a large variety of paediatric epilepsy syndromes and (2) a subsequent RCT in each of those that disclose a signal for possible efficacy. OBJECTIVE: Our objective was to address the three following issues that have not been addressed by the EMA: (1) to determine a minimal threshold for this signal; (2) to establish a list of epilepsies to evaluate; and (3) to estimate the number of patients to include in such POTs. METHODS: We extensively reviewed the POTs (including various syndromes) and RCTs reported in paediatric patients with uncontrolled epilepsy using MEDLINE (from 1990 to 2011) and the Cochrane library. We determined the threshold as the lowest percentage of responders observed in a POT with a positive corresponding RCT. The syndromes that reached this threshold in a POT were those to evaluate in an RCT. The minimal number of patients to include for each syndrome for a POT with a new antiepileptic drug was estimated in order to reach at least this threshold of responders with a 95 % confidence interval. RESULTS: We found the minimal responder threshold to be 25 %. We identified eight epilepsy types/syndromes reaching this threshold and estimated for each of them the minimal sample needed: refractory focal epilepsy (n = 40), Lennox-Gastaut syndrome (n = 32), infantile spasms (n = 50), Dravet syndrome (n = 32), childhood absence epilepsy (n = 12), other symptomatic generalized epilepsy (n = 38), epileptic encephalopathy with continuous spikes and waves during sleep (n = 7) and epilepsy with myoclonic-astatic seizures (n = 4) [the two last samples may be underestimated due to the lack of RCTs in these conditions]. CONCLUSION: Among the eight epilepsy types/syndromes that we recommend to systematically include in exploratory trials using the POT procedure, we assume that, for the minimal sample given above, a responder threshold of 25 % will provide a reliable efficacy signal, to be confirmed by a dedicated RCT. This strategy should avoid missing new therapeutic possibilities for children with epilepsy and reduce the off-label use of drugs in paediatric neurology. PMID- 23345030 TI - Newly initiated opioid treatment and the risk of fall-related injuries. A nationwide, register-based, case-crossover study in Sweden. AB - BACKGROUND: There is growing epidemiological evidence that opioids may increase the risk of unintentional injuries and it is plausible that the time of initiation is most critical in that respect. Studies on fall-related injuries remain few, limited and mostly focused on specific groups of elderly patients. OBJECTIVE: The objective of this study was to assess the short-term effects of newly prescribed opioids on the risk of fall-related injuries in the general adult population. METHODS: A case-crossover design was applied on national register data linking, at the individual level, fall-injury information involving adults aged 18 years and above identified in the Swedish National Inpatient Register (during the period 1 May 2006 to 31 December 2009) and dispensed drugs from the Swedish Prescribed Drug Register (n=167,257 cases with a first fall related injury). All types of opioid substances were considered, classified according to the Anatomical Therapeutic Chemical (ATC) classification system. We investigated newly dispensed opioids 28 days preceding the injury, compared with an earlier, and equally long, control period following a 3-month washout period. Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI). The analyses were also conducted stratified by age group, by type of fall and for each period of 1 week during the 28-day period. RESULTS: From among the fall-injured patients, 7,450 patients (4.5%) had a new opioid dispensation within 28 days prior to the injury, of which the most frequent types were tramadol (2.0%) and codeine (1.1%). Consistently increased risks of fall-related injuries associated with a new prescription of any opioid were found and they were most pronounced among young adults, 18-29 years of age (OR, 7.17; 95% CI 5.04-10.2). The closer the dispensation date to the injury, the higher the odds: an OR of 5.14 (95% CI 4.76-5.55) during the first week of opioid treatment and 1.23 (95% CI 1.10-1.38) for the fourth week. Of the documented falls, the risk was most pronounced for falls from 'another, high level' (OR, 5.33; 95% CI 3.99-7.10). CONCLUSIONS: Newly prescribed opioids may trigger injurious falls. The effect lowers over time and is less pronounced with increasing age. The risk is also higher for fall from height. PMID- 23345031 TI - Structure and function of an acetyl xylan esterase (Est2A) from the rumen bacterium Butyrivibrio proteoclasticus. AB - Butyrivibrio proteoclasticus is a significant component of the microbial population of the rumen of dairy cattle. It is a xylan-degrading organism whose genome encodes a large number of open reading frames annotated as fiber-degrading enzymes. We have determined the three-dimensional structure of Est2A, an acetyl xylan esterase from B. proteoclasticus, at 2.1 A resolution, along with the structure of an inactive mutant (H351A) at 2.0 A resolution. The structure reveals two domains-a C-terminal SGNH domain and an N-terminal jelly-roll domain typical of CE2 family structures. The structures are accompanied by experimentally determined enzymatic parameters against two model substrates, para nitrophenyl acetate and para-nitrophenyl butyrate. The suite of fiber-degrading enzymes produced by B. proteoclasticus provides a rich source of new enzymes of potential use in industrial settings. PMID- 23345032 TI - Differentiating isobaric steroid hormone metabolites using multi-stage tandem mass spectrometry. AB - Steroid hormones and their metabolites are currently undergoing clinical trials as potential therapeutics for traumatic brain injury (TBI). To support this work, it is necessary to develop improved procedures for differentiating isobaric species in this compound class. Equilin sulfate (E-S), estrone sulfate (E1-S), 17alpha-dihydroequilin sulfate (ADHE-S), and 17beta-dihydroequilin sulfate (BDHE S) are primary constituents in hormone replacement therapies, such as Premarin, which are among pharmaceuticals being investigated for TBI treatment. The latter three compounds are isomers and can be difficult to differentiate in trace analytical determinations. In this work, a systematic study of the fragmentation of ADHE-S, BDHE-S, E1-S, and E-S under different stages of higher order tandem mass spectrometry (MS(n)) and variation of collision energy, allowed optimization of conditions for distinguishing the isomeric structures. For epimeric variants (e.g., ADHE-S versus BDHE-S; alpha- versus beta-stereoisomerization in the C-17 position), differentiation was achieved at MS(4) and fragmentation was demonstrated through MS(5). Computational analysis was performed to further explore differences in the fragmentation pathways due to changes in stereochemistry. PMID- 23345033 TI - Comparison of the reactivity of the three distonic isomers of the pyridine radical cation toward tetrahydrofuran in solution and in the gas phase. AB - The reactivity of the three distonic isomers of the pyridine radical cation toward tetrahydrofuran is compared in solution and in the gas phase. In solution, the distonic ions were generated by UV photolysis at 300 nm from iodo-precursors in acidic 50:50 tetrahydrofuran/water solutions. In the gas phase, the ions were generated by collisionally activated dissociation (CAD) of protonated iodo precursors in an FT-ICR mass spectrometer, as described in the literature. The same major reaction, hydrogen atom abstraction, was observed in solution and in the gas phase. Attempts to cleave the iodine atom from the 2-iodopyridinium cation in the gas phase and in solution yielded the 2-pyridyl cation in addition to the desired 2-dehydropyridinium cation. In the gas phase, this ion was ejected prior to the examination of the desired ion's chemical properties. This was not possible in solution. This study suggests that solvation effects are not significant for radical reactions of charged radicals. On the other hand, the even-electron ion studied, the 2-pyridyl cation, shows substantial solvation effects. For example, in solution, the 2-pyridyl cation forms a stable adduct with tetrahydrofuran, whereas in the gas phase, only addition/elimination reactions were observed. PMID- 23345035 TI - Hyperbaric oxygen and cancer: more complex than we expected. PMID- 23345034 TI - Cytokines associated with toxicity in the treatment of recurrent glioblastoma with aflibercept. AB - Plasma profiling of patients treated with antiangiogenic agents may identify markers that correlate with toxicity. Objectives were to correlate changes in cytokine and angiogenic factors as potential markers of toxicity to aflibercept. Circulating cytokine and angiogenic factors were measured in 28 patients with recurrent glioblastoma in a single-arm phase II study of aflibercept. Plasma samples were analyzed at baseline, 24 h, and 28 days using multiplex assays or ELISA. We evaluated log-transformed baseline biomarker expressions with Cox proportional hazard regression models to assess the effect of markers on any grade II-IV (Gr II-IV) toxicity, on-target toxicity (hypertension, proteinuria, thromboembolism), and fatigue. All tests were two sided with a statistical significance level of p = 0.05. Among 28 pts, there were 116 Gr II-IV events. Changes in IL-13 from baseline to 24 h predicted on-target toxicities. Increases in IL-1b, IL-6, and IL-10 at 24 h were significantly associated with fatigue. Progression-free survival was 14.9 months for patients in the all-toxicity group and 9.0 months for patients in the on-target toxicity group compared to 4.3 months for those who did not develop any Gr II-IV toxicity (p = 0.002 and p = 0.045, respectively). Toxicity from antiangiogenic therapy remains an important cause of antiangiogenic treatment discontinuation and patient morbidity. Changes in IL6, IL10, and IL13 were repeatedly correlated with toxicity. Profiling of IL 13 as a surrogate for endothelial dysfunction could individualize patients at risk during antiangiogenic therapy, as could identifying those at higher risk for fatigue using IL-6 and IL-10. PMID- 23345036 TI - Dendrimers as Nd3+ ligands: effect of generation on the efficiency of the sensitized lanthanide emission. AB - We have designed two novel dendrimers with cyclam cores with appended poly(amido amine) (PAMAM) dendrons, decorated at the periphery with four and eight dansyl chromophores, respectively. The photophysical properties of the dendrimers and their Nd(3+) complexes have been investigated. The energy-transfer efficiency to the lanthanide ions from these dendrimers has been studied as a function of the generation. It has been observed that an increase in the dendrimer generation as well as the number of amide units enhances the energy transfer to the lanthanide ion. PMID- 23345037 TI - Two-staged hindfoot reconstruction with vascularized fibula graft for calcaneal osteomyelitis caused by methicillin-resistant Staphylococcus aureus: a case report. AB - Hindfoot reconstruction after calcaneal osteomyelitis is a challenging procedure designed to restore the weight bearing function of the heel and to allow a functional reconstruction of the Achilles tendon. Some patients require subtalar arthrodesis after primary calcaneal osteosyntesis or hindfoot reconstruction due to the considerable pain associated with weight-bearing caused by the irregular surface of the subtalar joint. To date, no reports have shown a case of hindfoot reconstruction with subtalar arthrodesis using a pedicled vascularized fibula graft. We report a case of a 24-year-old woman who presented with calcaneal methicillin-resistant Staphylococcus aureus osteomyelitis after open comminuted fracture due to a fall. Radical debridement of bone and soft tissue was repeated six times in combination with negative pressure wound therapy, followed by hindfoot reconstruction with pedicled vascularized fibula and subtalar arthrodesis. Good functional restoration had been achieved by the final follow-up 18 months after surgery. PMID- 23345038 TI - The boron conundrum: which principles underlie the formation of large hollow boron cages? AB - Extensive optimisation calculations are performed for the B(80) isomers in order to find out which principles underlie the formation of large hollow boron cages. Our analysis shows that the most stable isomers contain triangular B(10) or rhombohedral B(16) building blocks. The lowest-energy isomer has C(3v) symmetry and is characterised by a belt of three interconnected B(16) units and two separate B(10) units. At the B3LYP/6-31G(d) level of theory, this newly discovered isomer is 2.29, 1.48, and 0.54 eV below the leapfrog B(80) of Szwacki et al., the T(h) -B(80) of Wang, and the D(3d) -B(80) of Pochet et al., respectively. Our C(3v) isomer is therefore identified as the most stable hollow cage isomer of B(80) presently known. Its HOMO-LUMO gap of 1.6 eV approaches that of the leapfrog B(80). The leapfrog principle still remains a reliable scheme for producing boron cages with larger HOMO-LUMO gaps, whereas the thermodynamically most stable B(80) cages are formed when all pentagonal faces are capped. We show that large hollow cages of boron retain a preference for fullerene frames. The additional capping is in accordance with the following rules: preference for capping of pentagonal faces, formation of B(10) and/or B(16) units, homogeneous distribution of the hexagonal caps, and hole density approaching 1/9. Although our most stable B(80) isomer still remains higher in energy than the B(80) core shell structure, we show that by applying the bonding principles to larger structures it is possible to construct boron cages with higher stabilisation energy per boron atom than the core-shell structure; a prototypical example is B(160). This clearly shows the continuous competition between the two suggested construction schemes, namely, the formation of multiple-shell structures and hollow cages. PMID- 23345039 TI - Modeling sample/patient-specific structural and diffusional responses of cartilage using DT-MRI. AB - We propose a new 3D biphasic constitutive model designed to incorporate structural data on the sample/patient-specific collagen fiber network. The finite strain model focuses on the load-bearing morphology, that is, an incompressible, poroelastic solid matrix, reinforced by an inhomogeneous, dispersed fiber fabric, saturated with an incompressible fluid at constant electrolytic conditions residing in strain-dependent pores of the collagen-proteoglycan solid matrix. In addition, the fiber network of the solid influences the fluid permeability and an intrafibrillar portion that cannot be 'squeezed out' from the tissue. We implement the model into a finite element code. To demonstrate the utility of our proposed modeling approach, we test two hypotheses by simulating an indentation experiment for a human tissue sample. The simulations use ultra-high field diffusion tensor magnetic resonance imaging that was performed on the tissue sample. We test the following hypotheses: (i) the through-thickness structural arrangement of the collagen fiber network adjusts fluid permeation to maintain fluid pressure (Biomech. Model. Mechanobiol. 7:367-378, 2008); and (ii) the inhomogeneity of mechanical properties through the cartilage thickness acts to maintain fluid pressure at the articular surface (J. Biomech. Eng. 125:569-577, 2003). For the tissue sample investigated, both through-thickness inhomogeneities of the collagen fiber distribution and of the material properties serve to influence the interstitial fluid pressure distribution and maintain fluid pressure underneath the indenter at the cartilage surface. Tissue inhomogeneity appears to have a larger effect on fluid pressure retention in this tissue sample and on the advantageous pressure distribution. PMID- 23345040 TI - Colorectal natural orifice transluminal endoscopic surgery (NOTES) and transvaginal/transrectal specimen extraction. AB - Advancements in minimally invasive surgery have both revolutionized laparoscopy and set the stage for the advancement of endoscopic surgery to the forefront of modern medicine. Natural orifice transluminal endoscopic surgery (NOTES) has now become a subject of great interest to surgeons worldwide who wish to reduce the morbidity associated with abdominal operations. However, the application of NOTES to colorectal surgery has thus far been limited due to the complex dissection, anastomosis and specimen extraction typically required when operating on the large bowel. For this reason, laparoscopic-assisted natural orifice surgery has been the means by which most surgeons have begun to incorporate natural orifice surgery into their established practices. Transanal endoscopic surgery, transvaginal-assisted laparoscopy and transrectal specimen extraction are all emerging techniques that may be currently employed, in a hybrid manner, with traditionally accepted laparoscopic operations in order to transition toward less invasive surgery and even pure NOTES. To this end, the vagina appears to be the most practical and widely used site of specimen extraction and adjunct access site for laparoscopic hybrid operations. An accompanying video demonstrates the authors' preferred technique for transvaginal and transrectal specimen extraction. PMID- 23345041 TI - Laparoscopic ventral rectopexy: a prospective long-term evaluation of functional results and quality of life. AB - BACKGROUND: Laparoscopic ventral rectopexy for rectal prolapse combines the advantages of a minimally invasive approach with the low recurrence rate observed after abdominal procedures. To date, only a few long-term functional studies and no quality of life assessment are available. The aim of this study was to assess long-term functional outcomes and quality of life after laparoscopic ventral rectopexy. METHODS: Between January 2007 and December 2008, patients who underwent laparoscopic ventral rectopexy for full-thickness external rectal prolapse and/or rectocele were prospectively included. Fecal incontinence and constipation were scored (Wexner score and Rome II criteria). Quality of life was assessed using the gastrointestinal quality of life form (GIQLI). RESULTS: Thirty three patients were included and 30 (91 %) completed all the questionnaires. There was no morbidity or mortality. The mean length of hospital stay was 5 +/- 1 days (range 3-7 days). After a mean follow-up of 42 +/- 7 months (range 32-52 months), recurrence of rectocele was observed in two patients (6 %). At the end of follow-up, constipation was improved in 13/18 patients (72 %) and two patients (7 %) presented de novo constipation. The patients' Wexner score improved between preoperative status and end of follow-up (12 +/- 7 vs. 4 +/- 3, p = 0.002). Compared to the preoperative score, quality of life significantly improved over time: 77 +/- 21 preoperatively versus 107 +/- 17 at 1 year versus 109 +/- 18 at the end of follow-up (p < 0.001). CONCLUSIONS: This prospective study showed that laparoscopic ventral rectopexy was associated with excellent postoperative outcomes and a low long-term recurrence rate. Long-term functional results were excellent in terms of continence, with significant improvement of quality of life and without worsening constipation. PMID- 23345042 TI - Comparison of three medication adherence measures in patients taking warfarin. AB - In order to improve warfarin adherence, we must first know the rate of non adherence and the reasons for it. Assessment of warfarin adherence is important in improving patients' warfarin-taking behavior and International Normalized Ratio (INR) control. This study aimed to compare three medication adherence measures in patients taking warfarin: the 8-item Morisky Medication Adherence Scale (MMAS), the 100-point Visual Analogue Scale (VAS) and medication refill adherence (MRA). A cross-sectional observational study was conducted in a convenience sample of 174 patients taking warfarin at an anticoagulation clinic. A survey questionnaire that included the MMAS, VAS, and demographic and warfarin related clinical questions was administered to patients in English or Chinese depending on their preferences. The MRA and INR values were retrieved from hospital electronic databases. Most participants were adherent to warfarin as indicated by the three measures. A weak association was found between the MMAS and the other two adherence measures. The MMAS and MRA were associated with the percentage of INRs within range in the past 2 weeks. Moreover, the MRA was weakly associated with time within the therapeutic INR range in the past 3 months and 2 weeks. The findings provide insights into the differences among three medication adherence measures and may assist healthcare providers to select the most suitable measure for the assessment of warfarin adherence. PMID- 23345043 TI - Mean platelet volume as a predictor for long-term outcome after percutaneous coronary intervention. AB - Mean platelet volume (MPV) is a value that is available from standard blood count. Increased MPV is associated with increased platelet reactivity and it has been correlated with adverse cardiac outcomes in patients with acute coronary syndromes (ACS). However, there is limited information about the prognostic value of baseline MPV in a large heterogenous patient population which undergoes percutaneous coronary intervention (PCI). To examine whether baseline MPV is predictive of clinical outcomes in patients who undergo PCI. Included were consecutive patients who underwent PCI during 2004-2010 (n = 7,585, mean age 67.7 +/- 12.1 years, 76.0% males) with a median follow-up period of 4 years. Baseline MPV before angiography and long-term clinical outcomes were assessed. The mean MPV was higher in women as compared to men (8.6 +/- 1.2 vs. 8.5 +/- 1.1 fL, p = 0.02), in diabetic versus non-diabetic patients (8.6 +/- 1.2 vs. 8.4 +/- 1.1 fL, p < 0.001) and in patients who were admitted with ACS (n = 4,961) compared to patients who underwent an elective PCI (8.6 +/- 1.1 vs. 8.5 +/- 1.1 fL, p = 0.001). On multivariate analysis, MPV was associated with mortality (HR 1.18, 95% CI 1.12-1.23, p < 0.001) and with a composite end-point of death, MI and target vessel revascularization (HR 1.09, 95% CI 1.04-1.13, p < 0.001). Baseline MPV was associated with mortality in patients undergoing an elective PCI as well as in urgent PCI (HR 1.30, 95% CI 1.20-1.40, p < 0.001 and HR 1.13, 95% CI 1.07-1.20, p < 0.001, respectively). In patients undergoing either an elective or urgent PCI, an elevated MPV is a significant predictor of cardiovascular adverse events including death. PMID- 23345044 TI - Two novel mutations in CYP11B1 and modeling the consequent alterations of the translated protein in classic congenital adrenal hyperplasia patients. AB - Mutations in the 11beta-hydroxylase (CYP11B1) gene are the second leading cause of congenital adrenal hyperplasia (CAH), an autosomal recessive disorder characterized by adrenal insufficiency, virilization of female external genitalia, and hypertension with or without hypokalemic alkalosis. Molecular analysis of CYP11B1 gene in CAH patients with 11beta-hydroxylase deficiency was performed in this study. Cycle sequencing of 9 exons in CYP11B1 was performed in 5 unrelated families with 11beta-hydroxylase deficient children. Three dimensional models for the normal and mutant proteins and their affinity to their known substrates were examined. Analysis of the CYP11B1 gene revealed two novel mutations, a small insertion in exon 7 (InsAG393) and a small deletion in exon 2 (DelG766), and three previously known missense mutations (T318M, Q356X, and R427H). According to docking results, the affinity of the protein to its substrates is highly reduced by these novel mutations. DelG766 has more negative impact on the protein in comparison to InsAG393. The novel mutations, InsAG393 and DelG766, change the folding of the protein and disrupt the enzyme's active site as it was measured in the protein modeling and substrate binding analysis. Molecular modeling and sequence conservation were predictive of clinical severity of the disease and correlated with the clinical diagnosis of the patients. PMID- 23345045 TI - Long wavelength fluorescence ratiometric zinc biosensor. AB - A protein-based emission ratiometric fluorescence biosensor is described that exhibits sensitivity to free zinc ion in solution down to picomolar concentrations. Ratiometric measurements are widely used to assure accurate quantitation, and emission ratios are preferred for laser scanning microscopes such as confocal fluorescence microscopes. The relatively long emission wavelengths used are well suited to studies in tissues and other matrices which exhibit significant fluorescence background, and the apo-carbonic anhydrase moiety recognizes zinc ion with high and controllable specificity. PMID- 23345046 TI - Adsorption and folding dynamics of MPER of HIV-1 gp41 in the presence of DPC micelle. AB - Membrane-proximal ectodomain region (MPER) of HIV-1 gp41 is known to have several epitopes of monoclonal antibodies. It also plays an important role in the membrane fusion process that is well-evidenced, though not well-elucidated. There are also disputes over the true structure of MPER. In this study, MPER NMR structure in the presence of dodecylphosphatidylcholine micelle is used in the molecular dynamic simulation to elucidate structural dynamics and adsorption to model MPER interaction in a membrane environment. Polarized protein-specific charge derived from its NMR structure is found to better preserve the helical structure found in the NMR structure compared to AMBER03 calculation. The preserved helical structure also adsorb to the micelle using the hydrophobic side chains, consistent to the NMR structure. Ab initio folding of MPER predicts a structure quite in well agreement with the NMR structure (RMSd 3.9 A) and shows that the micelle plays a role in the folding process. PMID- 23345047 TI - Cyanomethylbenzoic acid: an acceptor for donor-pi-acceptor chromophores used in dye-sensitized solar cells. AB - Sensing the sun: Incorporation of a cyanomethyl benzoic acid electron acceptor into donor-pi-acceptor sensitizers for dye-sensitized-solar cell is shown to lead to devices with improved conversion efficiency when compared with more widely used cyanoacetic acid acceptor. PMID- 23345048 TI - Application of nested PCR for diagnosis of histoplasmosis. AB - Histoplasmosis is a fungal infection that, although not endemic in Japan, has seen a rise in the number of Japanese cases since the mid-1980s. Diagnosis of the disease is not straightforward, and the main method of detection, fungal culture (which has biosafety-related issues), is of low sensitivity in general. Alternative methods that depend on antibody or antigen detection have had limited use. We have developed a histoplasmosis detection method based on PCR amplification of the Histoplasma capsulatum M antigen gene. We compared this method with fungal culture and serological diagnostic techniques. Among five cases that were finally diagnosed as histoplasmosis, the fungal culture method was only successful in identifying one such case. Although the presence of anti H. capsulatum antibodies was confirmed in three cases, our PCR method identified four of five cases of histoplasmosis. The performance of our PCR method could not be compared with the antigen detection method, which is used in the United States but is not routinely used in Japan. However, the PCR method was shown to have high sensitivity and specificity for H. capsulatum. Although the number of histoplasmosis cases examined in this study was small, our data suggest that the molecular diagnosis technique has potential for increasing the reliability of histoplasmosis diagnosis when used in combination with established methods. PMID- 23345049 TI - Preferable timing of therapeutic drug monitoring in patients with impaired renal function treated with once-daily administration of vancomycin. AB - The aim of this study was to investigate the timing of therapeutic drug monitoring (TDM) in patients with impaired renal function treated with once-daily administration of vancomycin (VCM). Once-daily administration was selected for patients whose creatinine clearance (Ccr) was <80 ml/min. TDM was conducted on day 3 or on day 4. Adult patients whose VCM dosage was not altered according to initial C min and for whom subsequent follow-up TDM was performed within 1 week were entered into the study. Patients whose renal function deteriorated at follow up TDM were excluded. One hundred sixty-five patients were eligible for analysis. Among patients with once-daily dosing, relative increases of C min at follow-up TDM compared with initial TDM were 34.5 +/- 39.2 % in TDM on day 3 and 16.6 +/- 20.6 % in TDM on day 4 (P = 0.016). In contrast, there was no significant difference in the relative increase of C min between TDM on days 3 and 4 (26.1 +/ 39.6 vs. 18.4 +/- 25.6 %, P = 0.551) in the twice-daily regimen. On multivariate analysis, TDM on day 3 alone (odds ratio, 4.93; 95 % confidence interval, 1.71 14.2) was selected as an independent risk factor associated with a relative increase of C min by >30 % in the once-daily regimen. Steady-state VCM serum concentration was not achieved on day 3 in the once-daily regimen in patients with impaired renal function, and TDM on day 3 caused underestimation of C min. PMID- 23345050 TI - Prospective randomized comparison study of piperacillin/tazobactam and meropenem for healthcare-associated pneumonia in Japan. AB - Healthcare-associated pneumonia (HCAP) may have a more severe course than community-acquired pneumonia (CAP); hence, it is more likely to be caused by drug resistant bacterial pathogens and anaerobes involved in aspiration pneumonia. We compared the efficacy and safety of initial empiric therapy with piperacillin/tazobactam (PIPC/TAZ, 13.5 g/day) with that of meropenem (MEPM, 1.5 g/day) as single broad-spectrum regimens with gram-negative and anaerobic coverage in patients with HCAP in Japan. The clinical cure rate was 75.9 % (22/29 cases) in the PIPC/TAZ group and 64.3 % (18/28 cases) in the MEPM group. The clinical efficacy rate was 87.9 % (29/33 cases) in the PIPC/TAZ group and 74.2 % (23/31 cases) in the MEPM group. The bacteriological eradication rate was 94.4 % (17/18) in the PIPC/TAZ group and 87.5 % (14/16) in the MEPM group. Adverse drug reactions were seen in 22.4 % (11/49 cases) of patients in the PIPC/TAZ group and 17.4 % (8/46 cases) of patients in the MEPM group. Although not statistically different, the PIPC/TAZ group had a slightly higher efficacy rate than the MEPM group. Both treatment regimens are tolerable and might be appropriate to use as initial empiric therapy for HCAP in Japan. To investigate the differences in efficacy profiles of those two regimens, a further confirmatory study with a larger cohort as determined by a power analysis is recommended. PMID- 23345051 TI - Free sensate medial plantar flap for contralateral plantar forefoot reconstruction with flap reinnervation using end-to-side neurorrhaphy: a case report and literature review. AB - Reconstruction of weight-bearing plantar defects remains a challenge due to the unique characteristics of the plantar skin and thus the limited available options. The medial plantar flap, either pedicled or free, represents an ideal option, but its use as sensate flap for forefoot defects has been scarcely reported. We present a case of plantar forefoot reconstruction with a free sensate medial plantar flap, with end-to-side coaptation of the cutaneous sensory fascicles of the flap to the medial plantar nerve of the recipient. Last follow up, at 2 years post-op, verified a very good functional and aesthetic outcome, indicating that the suggested approach may prove the treatment of choice in selected cases of plantar forefoot reconstruction. PMID- 23345052 TI - Extent of pancreatic fibrosis as a determinant of symptom resolution after the Frey procedure: a clinico-pathologic analysis. AB - OBJECTIVE: The aim of this study was to evaluate the association of histopathologic features of chronic pancreatitis and pain relief after the Frey procedure. DESIGN: We retrospectively analyzed 35 patients who underwent the Frey procedure for chronic pancreatitis over a 5-year period (November 2005 to February 2011). SETTING: Thirty-five patients with varied etiologies of chronic pancreatitis and persistent symptoms were referred to a multi-disciplinary pancreatitis clinic where a consensus decision to recommend surgery was established. The Frey procedure was then performed. MAIN OUTCOME MEASURES: We compared symptomatic outcomes with the degree of pancreatic fibrosis, duct dilatation, and presence of pancreatic duct stones based on a blinded evaluation of resected pancreatic tissue. RESULTS: Symptom resolution was associated with severe or extensive (>75 %) fibrosis and absence of symptom resolution was associated with mild or minimal (<25 %) fibrosis (chi-squared, p value < 0.05). Symptom resolution was associated with pancreatic duct >4 mm and absence of symptom resolution was associated with pancreatic duct <=4 mm (chi-squared, p value < 0.05). There was no difference in outcomes for patients with and without pancreatic duct stones. CONCLUSION: Symptom resolution after the Frey procedure is more likely in the setting of severe or extensive fibrosis due to chronic pancreatitis. PMID- 23345053 TI - Negligible effect of perioperative epidural analgesia among patients undergoing elective gastric and pancreatic resections. AB - BACKGROUND: There are conflicting data regarding improvements in postoperative outcomes with perioperative epidural analgesia. We sought to examine the effect of perioperative epidural analgesia vs. intravenous narcotic analgesia on perioperative outcomes including pain control, morbidity, and mortality in patients undergoing gastric and pancreatic resections. METHODS: We evaluated 169 patients from 2007 to 2011 who underwent open gastric and pancreatic resections for malignancy at a university medical center. Emergency, traumatic, pediatric, enucleations, and disseminated cancer cases were excluded. Clinicopathologic data were reviewed among epidural (E) and non-epidural (NE) patients for their association with perioperative endpoints. RESULTS: One hundred twenty patients (71 %) received an epidural and 49 (29 %) did not. There were no significant differences (P > 0.05) in mean pain scores at each of the four days (days 0-3) among the E (3.2 +/- 2.7, 3.2 +/- 2.3, 2.3 +/- 1.9, and 2.1 +/- 1.9, respectively) and NE patients (3.7 +/- 2.7, 3.4 +/- 1.9, 2.9 +/- 2.1, and 2.4 +/- 1.9, respectively). Within each of the E and NE patient groups, there were significant differences (P < 0.0001) in mean pain scores from day 0 to day 3 (P < 0.0001). Of the E patients, 69 % also received intravenous patient-controlled analgesia (PCA). Ileus (13 % E vs. 8 % NE), pneumonia (12 % E vs. 8 % NE), venous thromboembolism (6 % E vs. 4 % NE), length of stay [11.0 +/- 12.1 (8, 4-107) E vs. 12.2 +/- 10.7 (7, 3-54) NE], overall morbidity (36 % E vs. 39 % NE), and mortality (4 % E vs. 2 % NE) were not significantly different. CONCLUSIONS: Routine use of epidurals in this group of patients does not appear to be superior to PCA. PMID- 23345054 TI - Automatic tracking of labeled red blood cells in microchannels. AB - The current study proposes an automatic method for the segmentation and tracking of red blood cells flowing through a 100- MUm glass capillary. The original images were obtained by means of a confocal system and then processed in MATLAB using the Image Processing Toolbox. The measurements obtained with the proposed automatic method were compared with the results determined by a manual tracking method. The comparison was performed by using both linear regressions and Bland Altman analysis. The results have shown a good agreement between the two methods. Therefore, the proposed automatic method is a powerful way to provide rapid and accurate measurements for in vitro blood experiments in microchannels. PMID- 23345055 TI - Provision of genetics services on Guam. AB - Guam's geographic isolation and lack of community resources have resulted in unique healthcare needs. In 2006, the Western States Genetic Services Collaborative (WSGSC) conducted a genetics needs assessment and found that professional development is limited, families lack access to genetic services, and improved coverage of genetic testing is needed. With funding from the WSGSC, a Guam genetics outreach clinic was established and staffed by genetic counselors and a medical geneticist from Hawaii. Four clinics have been held to date. Although several challenges have been encountered, including minimal coverage of genetic testing by Guam insurance companies, limited referrals for families with private insurance, and inappropriate referral indications, the outreach clinic has been successful at increasing access to genetic services and improving professional development. With more collaborative work by staff from Guam, Hawaii, and the WSGSC, provision and reimbursement of genetic services and testing will continue to improve. PMID- 23345056 TI - Comparison of the screening practices of unaffected noncarriers under 40 and between 40 and 49 in BRCA1/2 families. AB - This study aimed to 1) compare the cancer screening practices of unaffected noncarrier women under 40 and those aged 40 to 49, following the age-based medical screening guidelines, and 2) consider the way the patients justified their practices of screening or over-screening. For this study, 131 unaffected noncarriers-77 women under age 40 and 54 between 40 and 49, all belonging to a BRCA1/2 family-responded to a questionnaire on breast or ovarian cancer screenings they had undergone since receiving their negative genetic test results, their motives for seeking these screenings, and their intentions to pursue these screenings in the future. Unaffected noncarriers under age 40 admitted practices that could be qualified as over-screening. Apart from mammogram and breast ultrasounds, which the women under 40 reported seeking less often, these women's screening practices were comparable to those of women between 40 and 49. Cancer prevention and a family history of cancer were the two most frequently cited justifications for pursuing these screenings. We suggest that health care professionals discuss with women under 50 the ineffectiveness of breast and ovarian cancer screenings so that they will adapt their practices to conform to medical guidelines and limit their exposure to the potentially negative impacts of early cancer screening. PMID- 23345057 TI - The role of religious and existential well-being in families with Lynch syndrome: prevention, family communication, and psychosocial adjustment. AB - This study explored the role of religious (RWB) and existential well-being (EWB) on psychosocial factors, support network characteristics, and screening practices in families with Lynch syndrome, also referred to as hereditary nonpolyposis colon cancer (HNPCC). Participants were individuals with Lynch syndrome associated cancers and their first-degree relatives at risk of inheriting an identified deleterious mutation. Analyses considered both family RWB and EWB norms and individual deviations from that norm. Analyses controlled for age, gender, cancer diagnosis, number of respondents, and network size. Higher family RWB was associated with increased depressive symptoms (p < .05) and avoidant cognitions (p < .05). Higher family EWB was related to decreased depression symptoms (p < .001). Higher family EWB was associated with fecal occult blood testing (p < .01), and family communication about genetic counselling and testing (p < .01). Analyses pointed to individual effects of EWB above and beyond family level effects. Individuals with lower EWB than their family had lower perceived risk for colorectal cancer (p < .05), communicated disease risk information to less family members (p < .05), and were less likely to undergo recent colonoscopies (p < .05). Participants with lower EWB than their family also had higher cancer worry (p < .01) and increased depressive symptoms (p < .001). Findings indicate the importance of assessing individuals within the context of their family network and being aware of family characteristics which may impact individual adjustment to disease risk. Interventions considering family-level factors may provide efficient pathways to improving psychosocial factors, screening practices, communication about disease risk and genetic testing, and cancer prevention. PMID- 23345058 TI - Complexation of C60 fullerene with aromatic drugs. AB - The contributions of various physical factors to the energetics of complexation of aromatic drug molecules with C(60) fullerene are investigated in terms of the calculated magnitudes of equilibrium complexation constants and the components of the net Gibbs free energy. Models of complexation are developed taking into account the polydisperse nature of fullerene solutions in terms of the continuous or discrete (fractal) aggregation of C(60) molecules. Analysis of the energetics has shown that stabilization of the ligand-fullerene complexes in aqueous solution is mainly determined by intermolecular van der Waals interactions and, to lesser extent, by hydrophobic interactions. The results provide a physicochemical basis for a potentially new biotechnological application of fullerenes as modulators of biological activity of aromatic drugs. PMID- 23345059 TI - High-definition differential ion mobility spectrometry with resolving power up to 500. AB - As the resolution of analytical methods improves, further progress tends to be increasingly limited by instrumental parameter instabilities that were previously inconsequential. This is now the case with differential ion mobility spectrometry (FAIMS), where fluctuations of the voltages and gas pressure have become critical. A new high-definition generator for FAIMS compensation voltage reported here provides a stable and accurate output than can be scanned with negligible steps. This reduces the spectral drift and peak width, thus improving the resolving power (R) and resolution. The gain for multiply-charged peptides that have narrowest peaks is up to ~40%, and R ~400-500 is achievable using He/N(2) or H(2)/N(2) gas mixtures. PMID- 23345060 TI - The (un)certainty of selectivity in liquid chromatography tandem mass spectrometry. AB - We developed a procedure to determine the "identification power" of an LC-MS/MS method operated in the MRM acquisition mode, which is related to its selectivity. The probability of any compound showing the same precursor ion, product ions, and retention time as the compound of interest is used as a measure of selectivity. This is calculated based upon empirical models constructed from three very large compound databases. Based upon the final probability estimation, additional measures to assure unambiguous identification can be taken, like the selection of different or additional product ions. The reported procedure in combination with criteria for relative ion abundances results in a powerful technique to determine the (un)certainty of the selectivity of any LC-MS/MS analysis and thus the risk of false positive results. Furthermore, the procedure is very useful as a tool to validate method selectivity. PMID- 23345062 TI - Intramyocardial injection of heart tissue-derived extracellular matrix improves postinfarction cardiac function in rats. AB - AIMS: We determined whether implantation of heart tissue-derived decellularized matrix, which contains native biochemical and structural matrix composition, could thicken the infarcted left ventricular (LV) wall and improve LV function in a rat myocardial infarction model. METHODS AND RESULTS: Myocardial infarction was induced by left coronary ligation in Fischer rats. One week later, saline (75 MUL, n = 17) or matrix (75 MUL, n = 19) was directly injected into the infarcted area. At 6 weeks after injection, cardiac function was assessed by left ventriculogram, echocardiography, and Millar catheter. The hearts were pressure fixed to measure postmortem LV volume and processed for histology. Left ventriculogram demonstrated that LV ejection fraction (EF) was significantly greater in the matrix-treated (56.7% +/- 1.4%) than in the saline-treated group (52.4% +/- 1.5%; P = .043), and paradoxical LV systolic bulging was significantly reduced in the matrix-treated group (6.2% +/- 1.6% of the LV circumference) compared to the saline-treated group (10.3% +/- 1.3%; P = .048). Matrix implantation significantly increased the thickness of infarcted LV wall (0.602 +/ 0.029 mm) compared to the saline-treated group (0.484 +/- 0.03 mm; P = .0084). Infarct expansion index was significantly lower in the matrix-treated group (1.053 +/- 0.051) than in the saline-treated group (1.382 +/- 0.096, P = .0058). Blood vessel density and c-kit positive staining cells within the infarct area were comparable between the 2 groups. CONCLUSIONS: Implantation of heart tissue derived decellularized matrix thickens the LV infarcted wall, prevents paradoxical LV systolic bulging, and improves LV EF after myocardial infarction in rats. This benefit was not dependent on the enhanced angiogenesis or the recruitment of endogenous stem cells to the injury site. PMID- 23345061 TI - Deletion of the NMDA-NR1 receptor subunit gene in the mouse nucleus accumbens attenuates apomorphine-induced dopamine D1 receptor trafficking and acoustic startle behavior. AB - The nucleus accumbens (Acb) contains subpopulations of neurons defined by their receptor content and potential involvement in sensorimotor gating and other behaviors that are dysfunctional in schizophrenia. In Acb neurons, the NMDA NR1 (NR1) subunit is coexpressed not only with the dopamine D1 receptor (D1R), but also with the u-opioid receptor (u-OR), which mediates certain behaviors that are adversely impacted by schizophrenia. The NMDA-NR1 subunit has been suggested to play a role in the D1R trafficking and behavioral dysfunctions resulting from systemic administration of apomorphine, a D1R and dopamine D2 receptor agonist that impacts prepulse inhibition to auditory-evoked startle (AS). Together, this evidence suggests that the NMDA receptor may regulate D1R trafficking in Acb neurons, including those expressing u-OR, in animals exposed to auditory startle and apomorphine. We tested this hypothesis by combining spatial-temporal gene deletion technology, dual labeling immunocytochemistry, and behavioral analysis. Deleting NR1 in Acb neurons prevented the increase in the dendritic density of plasma membrane D1Rs in single D1R and dual (D1R and u-OR) labeled dendrites in the Acb in response to apomorphine and AS. Deleting NR1 also attenuated the decrease in AS induced by apomorphine. In the absence of apomorphine and startle, deletion of Acb NR1 diminished social interaction, without affecting novel object recognition, or open field activity. These results suggest that NR1 expression in the Acb is essential for apomorphine-induced D1R surface trafficking, as well as auditory startle and social behaviors that are impaired in multiple psychiatric disorders. PMID- 23345063 TI - Immune responses elicited by apoB-100-derived peptides in mice. AB - Peptides derived from apolipoprotein B (apoB)-100 have been previously used in vaccine preparations to treat atherosclerosis. Such vaccines have been shown to reduce atherosclerotic plaque development by 50 % in experimental animals, and this effect is associated with induction of T helper (Th)2 immune responses. In this study we immunised apolipoprotein E-deficient (apoE(-/-)) mice with apoB-100 derived peptides P2, P45 and P210. Animals received BSA-conjugated peptides or peptide-loaded bone marrow-derived dendritic cells (DCs). We used enzyme-linked immunosorbent assays to assess the synthesis of anti-peptide-specific IgG1 and IgG2a as well as the levels of interleukin (IL-)10 and interferon gamma (IFN gamma) in plasma of immunised animals. We also measured the effect of immunisation on the number of spleen-derived CD4(+) and CD8(+) regulatory T cells (Tregs) in these animals. Peptide and peptide-loaded DC immunisation significantly increased the levels of peptide-specific immunoglobulins and the number of Tregs in apoE(-/-) mice. This was accompanied by a significant increase in the secretion of IL-10 with no effect on IFN-gamma levels. The results also show that the peptides can modulate the homing properties of DCs. Altogether, this study provides novel evidence for the immune mechanisms excerpted by apoB 100-derived peptides and their effect on Tregs and DCs relevant to their use in vaccine preparations. PMID- 23345064 TI - Effect of feeding of calcium hydroxide-treated or vitamin E-supplemented cottonseed meal on plasma gossypol levels, blood parameters, and performance of Bikaneri lambs. AB - To study the effect of feeding calcium hydroxide-treated or vitamin E supplemented cottonseed meal (CSM) incorporated diets on plasma gossypol, blood parameters and animal performance, 24 male Bikaneri lambs of 6-7 months of age and of uniform body weight were divided into four groups of six animals each in a completely randomized design and respectively fed isonitrogenous and isocaloric concentrate mixtures containing 20% soybean meal (CON) or 40% raw CSM (RCSM), 40% raw CSM supplemented with 500 IU of vitamin E per head per day (ERCSM), and 40%, 1.5% calcium hydroxide-treated CSM (CaCSM) along with ad libitum wheat straw throughout 510 days of experimental feeding. The lambs on all the diets grew linearly throughout the experimental period. The total weight gain, in turn the average daily gain (ADG), was not affected by dietary variations. The daily intake of dry matter, crude protein (CP), digestible crude protein (DCP) and total digestible nutrients (TDN) were found comparable among lambs of all the groups. Though total gossypol intake was similar in RCSM, ECSM and CaCSM groups, however, free gossypol intake was significantly higher (P < 0.01) in RCSM, ECSM groups as compared to CaCSM group. Serum iron and blood hemoglobin levels were significantly (P < 0.05) lower in RCSM group as compared to CaCSM and CON groups, and ALT activity was significantly (P < 0.05) higher on RCSM group as compared to other groups. Plasma gossypol and osmotic fragility of erythrocytes were significantly (P < 0.05) increased in RCSM group as compared to CaCSM and ERCSM groups. However, there was no significant difference in the concentration of other blood/serum biochemical constituents among the lambs on different groups. Based on the results, it may be concluded that feeding of 40% CSM in the concentrate mixture of the diet in Bikaneri lambs did not have any major adverse effect in blood parameters and animal performance. Either calcium hydroxide treatment or vitamin E supplementation did not produce any major additional benefits. PMID- 23345065 TI - Assessing carcass and meat characteristics of Damara, Dorper and Australian Merino lambs under restricted feeding. AB - Seasonal weight loss (SWL) is the most pressing constraint in ruminant production systems in tropical climates. SWL is controlled using supplementation, which is costly and difficult to implement in extensive systems, or using breeds adapted to tropical hot dry climates, like the Damara and Dorper. Albeit 15 years in Australia, little is known on how these sheep compare to Australian Merino. Here, the responses of the Damara, Dorper and Merino breeds to nutritional stress were compared. Seventy-two 6-month-old ram lambs, 24 from each breed, were allocated to growth (gaining 100 g/day) or restricted diets (losing 100 g/day, 85% of maintenance needs). Animals were weighed and carcass and meat characteristics determined. Results point out to the existence of important differences between the three genotypes, in particular between the Merino and the Southern African breeds. Additionally, Merino ram lambs seem to have been more influenced by SWL than the other two, with consequences on meat characteristics. PMID- 23345066 TI - Habitual diet and ascorbic acid status in Sudanese camels. AB - There is suggestive evidence that a low status of ascorbic acid in camels enhances their risk for infectious diseases. This study was carried out to find clues as to the role of diet in affecting ascorbic acid status. In a crossover trial with feeding periods of 3 weeks each, six camels (Camelus dromedarius) were fed either a composite of their habitual diet or alfalfa. The simulated habitual diet contained grass (hummra), Acacia mellifera and Blepharis persica. The habitual diet significantly lowered ascorbic acid concentrations in plasma and leukocytes. It is concluded that camels kept on natural desert vegetation may not have optimal disease resistance due to a diet-induced low ascorbic acid status. PMID- 23345067 TI - Electrocatalytic hydrogenation and deoxygenation of glucose on solid metal electrodes. AB - This Full Paper addresses the electrocatalytic hydrogenation of glucose to sorbitol or 2-deoxysorbitol on solid metal electrodes in neutral media. Combining voltammetry and online product analysis with high-performance liquid chromatography (HPLC), provides both qualitative and quantitative information regarding the reaction products as a function of potential. Three groups of catalysts clearly show affinities toward: (1) hydrogen formation [on early transition metals (Ti, V, Cr, Mn, Zr, Nb, Mo, Hf, Ta, We, and Re) and platinum group metals (Ru, Rh, Ir, and Pt)], (2) sorbitol formation [on late transition metals (Fe, Co, Ni, Cu, Pd, Au, and Ag) and Al (sp metal)], and (3) sorbitol and 2-deoxysorbitol formation [on post-transition metals (In, Sn, Sb, Pb, and Bi), as well as Zn and Cd (d metals)]. Ni shows the lowest overpotential for the onset of sorbitol formation (-0.25 V) whereas Pb generates sorbitol with the highest yield (<0.7 mM cm(-2) ). Different from a smooth Pt electrode, a large-surface-area Pt/C electrode hydrogenates glucose to sorbitol from -0.21 V with relatively low current. This emphasizes the importance of the active sites and the surface area of the catalyst. The mechanism to form 2-deoxysorbitol from glucose and/or fructose is discussed according to the observed reaction products. The yield and selectivity of hydrogenated products are highly sensitive to the chemical nature and state of the catalyst surface. PMID- 23345068 TI - Perforator flap from adjacent thigh skin to improve the repair of the donor site of the anterolateral thigh flap. PMID- 23345069 TI - Albuminuria is an independent predictor of all-cause and cardiovascular mortality in the Japanese population: the Takahata study. AB - BACKGROUND: Albuminuria is a known risk factor for cardiovascular events and premature deaths. However, the association between urinary albumin excretion and mortality is unknown in the Japanese population. To clarify this, we conducted a community-based longitudinal study. METHODS: This study included 3,445 registered Japanese subjects (mean age 62.6 years), with a 7-year follow-up. Albuminuria was defined as a urine albumin-creatinine ratio (ACR) >=30 mg/g in the morning spot urine. RESULTS: Subjects with albuminuria (n = 514, 14.9 %) were older and showed a higher prevalence of hypertension, obesity, and diabetes and lower values of estimated glomerular filtration rate (eGFR) than those without albuminuria (n = 2931, 85.1 %). During the follow-up, 138 subjects died. A Kaplan-Meier analysis showed that all-cause mortality significantly increased along with the increase in urine albumin excretion (log-rank test, P < 0.001). The subjects with albuminuria showed a significantly higher mortality rate than those without albuminuria (7.4 vs. 3.4 %; log-rank test, P < 0.001). A Cox proportional hazard model analysis after adjusting for possible confounders showed that albuminuria was an independent risk factor for all-cause and cardiovascular mortality (hazard ratio [HR] 1.69, 95 % confidence interval [CI] 1.12-2.56 and HR 2.27, 95 % CI 1.10-4.70, respectively) but not for noncardiovascular mortality. These associations were preserved after excluding subjects with high ACR (>=300 mg/g). CONCLUSIONS: Albuminuria was a risk factor for all-cause and cardiovascular mortality in the Japanese population. To detect subjects with a high risk for premature death, measuring urinary albumin excretion might be useful. PMID- 23345070 TI - Effect of low-osmolar contrast medium iopromide and iso-osmolar iodixanol on DNA fragmentation in renal tubular cell culture. AB - BACKGROUND: Intravascular administration of iodinated contrast media continues to be a common cause of hospital-acquired acute kidney injury. Accumulating evidence suggests that radiocontrast agent-induced nephrotoxicity is associated with increased oxidative stress, which leads to renal tissue damage with DNA fragmentation. We therefore tested whether an iso-osmolar contrast medium (iodixanol) causes less oxidative DNA damage to renal tubular cells than a low osmolar contrast medium (iopromide). METHODS: HK-2 cells (human proximal renal tubular cell line) were incubated at different time points (10 min-2 h) with increasing concentrations (20-120 mg/ml iodine) of iodixanol or of iopromide. Oxidative DNA damage to renal tubular cells was measured by alkaline comet assay (single-cell gel electrophoresis). RESULTS: Both iso- and low-osmolar contrast agents induced time- and concentration-dependent DNA fragmentation. DNA fragmentation was maximal at 2 h with 120 mg/ml iodine for iopromide (32 +/- 27 tail moments) and iodixanol (46 +/- 41 tail moments); both were significantly different from the control value with 3.15 +/- 1.6 tail moments (Student's t test; p < 0.001). After 1 and 2 h and for all concentrations, iodixanol produced significantly higher DNA fragmentation than iopromide (ANOVA for 1 h p = 0.039 and 2 h p = 0.025, respectively). CONCLUSION: We were able to demonstrate for the first time that an iso-osmolar contrast medium induced even greater oxidative stress and DNA damage than a low-osmolar agent in HK-2 cells. This could provide an explanation for the nephrotoxicity that also is observed with iodixanol in clinical practice. PMID- 23345071 TI - Verigene(r) gram-positive blood culture nucleic acid test. AB - Bloodstream infections (BSIs) are a major cause of morbidity and mortality worldwide, and impose considerable costs on healthcare systems. A key predictor of clinical outcomes in patients with BSIs is the early initiation of appropriate targeted antimicrobial therapy. However, with conventional blood culture methods, the gold standard, there is a significant time delay of approximately 2-3 days before clinical results are available, with many patients receiving inappropriate and/or unnecessary antimicrobial therapy in the interim. During the past two decades, the use of in vitro assays that utilize nucleic acid amplification-based detection of pathogen-associated molecular patterns has led to a significant reduction in the time (hours vs. days with blood culture) to detection and identification of several of the causative pathogens of BSIs and, potentially, earlier initiation of targeted antimicrobial therapy. This review focuses on the properties and clinical use of one of these molecular diagnostic assays, the Verigene((r)) Gram-Positive Blood Culture Nucleic Acid Test (BC-GP), which detects many of the potentially pathogenic Gram-positive bacteria associated with BSIs, including Staphylococcus spp., Streptococcus spp., Listeria spp., and Enterococcus spp., and specific resistance markers (mecA, vanA, and vanB). Based on more than 1,600 samples, there was a high degree of agreement between BC-GP test results and those obtained using conventional blood culture and assay methods, irrespective of whether samples were fresh or frozen, and a high degree of agreement for identification of mecA-mediated meticillin resistance in S. aureus and S. epidermidis organisms and vanA- or vanB-mediated vancomycin resistance in E. faecalis and E. faecium organisms. PMID- 23345072 TI - Independent contribution of A1C, systolic blood pressure, and LDL cholesterol control to risk of cardiovascular disease hospitalizations in type 2 diabetes: an observational cohort study. AB - BACKGROUND: Cardiovascular disease (CVD) prevention in diabetes requires broad based treatment of dyslipidemia, hypertension, and hyperglycemia. The independent contribution of all combinations of risk factor control to CVD risk has not been evaluated. OBJECTIVE: To estimate the independent association of control of glycosylated hemoglobin (A1C), systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) with risk of cardiovascular disease hospitalization. DESIGN: Non-concurrent longitudinal cohort study. PATIENTS: The study included 26,636 patients with type 2 diabetes who were members of an integrated group model HMO with multiple A1C, SBP, and LDL-C measurements. MAIN MEASURES: Patients were followed for a mean (SD) of 5.6 (2.5) years until they died or disenrolled, or until 31 December 2010. The outcome was a first-observed CVD hospitalization. Using the mean of all A1C, SBP, and LDL-C measures during follow-up, we created dichotomous categories of A1C control (< 7 %), SBP control (< 130 mmHg), and LDL-C control (< 100 mg/dL) to estimate the incidence rate of CVD hospitalization associated with all combinations of risk factor control adjusting for demographic and clinical characteristics. KEY RESULTS: Patients with no controlled risk factors (18.2/1,000 person-years, 95 % CI 16.5-20.2) or with only A1C in control (16.9, 15.0-19.0) had the highest rate of CVD hospitalization, whereas those with all three risk factors controlled (7.2, 6.2 8.4) or with SBP and LDL-C in control (6.1, 5.1-7.2) had the lowest rates. Those with only SBP or LDL-C in control, A1C and SBP controlled, or A1C and LDL-C controlled had statistically similar incidence between the highest and lowest rates. CONCLUSIONS: Maintaining SBP < 130 mmHg or LDL-C < 100 mg/dL was significantly associated with reduced CVD hospitalization risk, especially when both risk factors were well controlled. Maintaining A1C < 7 % was not independently associated with reduced CVD hospitalization risk. PMID- 23345073 TI - Adverse events rates and risk factors in adults undergoing cardiac catheterization at pediatric hospitals--results from the C3PO. AB - OBJECTIVE: Determine the frequency and risk factors for adverse events (AE) for adults undergoing cardiac catheterization at pediatric hospitals. BACKGROUND: Adult catheterization AE rates at pediatric hospitals are not well understood. The Congenital Cardiac Catheterization Project on Outcomes (C3PO) collects data on all catheterizations at eight pediatric institutions. METHODS: Adult (>= 18 years) case characteristics and AE were reviewed and compared with those of pediatric (<18 years) cases. Cases were classified into procedure risk categories from 1 to 4 based on highest risk procedure/intervention performed. AE were categorized by level of severity. Using a multivariate model for high severity AE (HSAE), standardized AE rates (SAER) were calculated by dividing the observed rates of HSAE by the expected rates. RESULTS: 2,061 cases (15% of total) were performed on adults and 11,422 cases (85%) were performed on children. Adults less frequently underwent high-risk procedure category cases than children (19% vs. 30%). AE occurred in 10% of adult cases and 13% of pediatric cases (P < 0.001). HSAE occurred in 4% of adult and 5% of pediatric cases (P = 0.006). Procedure-type risk category (Category 2, 3, 4 OR = 4.8, 6.0, 12.9) and systemic ventricle end diastolic pressure >= 18 mm Hg (OR 3.1) were associated with HSAE, c statistic 0.751. There were no statistically significant differences in SAER among institutions. CONCLUSIONS: Adults undergoing catheterization at pediatric hospitals encountered AE less frequently than children did. The congenital heart disease adjustment for risk method for adults with congenital heart disease is a new tool for assessing procedural risk in adult patients. PMID- 23345074 TI - The Alzheimer's disease-8 and Montreal Cognitive Assessment as screening tools for neurocognitive impairment in HIV-infected persons. AB - The diagnosis of human immunodeficiency virus (HIV)-associated neurocognitive impairment is time-intensive and often omitted in busy outpatient settings. Brief screening tools are needed. The Montreal Cognitive Assessment (MoCA) and the Alzheimer's disease (AD)-8 have been used in neurodegenerative disorders. We evaluated the sensitivity and specificity of these brief screening tools in HIV infected persons. The AD-8, MoCA, and formal neuropsychological testing were administered to 200 HIV-infected patients who were followed at a single institution. Normalized scores on formal neuropsychological testing were used to define neurocognitive impairment. The sensitivity and specificity of the MoCA and AD-8 were assessed to diagnose the impairment. Neurocognitive impairment was highly prevalent in this cohort: 127 persons (64 %) were diagnosed with neurocognitive impairment based on formal testing. Using the AD-8 and MoCA, 113 (57 %) and 101 (51 %) persons were identified with neurocognitive impairment, respectively. The sensitivity and specificity of MoCA were 63 % and 71 %, respectively. The sensitivity and specificity of AD-8 were 61 % and 51 %, respectively. Our findings highlight that brief screening tools correlate with formal neuropsychological testing. However, the sensitivities of these screening tools are lower than desired. Nevertheless, given their ease in administration, these tools could assist as a first line for identifying individuals who may subsequently require formal neuropsychological testing. PMID- 23345075 TI - Involvement of dynorphin and kappa opioid receptor in yohimbine-induced reinstatement of heroin seeking in rats. PMID- 23345076 TI - Hemodynamics analysis of patient-specific carotid bifurcation: a CFD model of downstream peripheral vascular impedance. AB - The study of cardiovascular models was presented in this paper based on medical image reconstruction and computational fluid dynamics. Our aim is to provide a reality platform for the purpose of flow analysis and virtual intervention outcome predication for vascular diseases. By connecting two porous mediums with transient permeability at the downstream of the carotid bifurcation branches, a downstream peripheral impedance model was developed, and the effect of the downstream vascular bed impedance can be taken into consideration. After verifying its accuracy with a healthy carotid bifurcation, this model was implemented in a diseased carotid bifurcation analysis. On the basis of time averaged wall shear stress, oscillatory shear index, and the relative residence time, fractions of abnormal luminal surface were highlighted, and the atherosclerosis was assessed from a hemodynamic point of view. The effect of the atherosclerosis on the transient flow division between the two branches because of the existence of plaque was also analysed. This work demonstrated that the proposed downstream peripheral vascular impedance model can be used for computational modelling when the outlets boundary conditions are not available, and successfully presented the potential of using medical imaging and numerical simulation to provide existing clinical prerequisites for diagnosis and therapeutic treatment. PMID- 23345077 TI - First clinical experience with intranasal cooling for hyperthermia in brain injured patients. AB - INTRODUCTION: Hyperthermia is common in brain-injured patients and associated with a worse outcome. As brain rather than body temperature reduction, theoretically, is the most important in cerebral protection, there is logic in targeting cooling at the brain. Selective brain cooling can, in theory, be obtained by cooling the skull or by heat loss from the upper airways. In this preliminary safety and efficacy study, we report clinical data from brain-injured patients who because of hyperthermia were treated with intranasal cooling. METHODS: Nine intubated brain-injured patients with hyperthermia were treated using a prototype intranasal balloon system perfused with cold saline. Temperature in the cerebrum, esophagus, and bladder was monitored together with intracranial pressure. RESULTS: In only two of nine patients, normothermia was reached in the esophagus and in only four of nine patients it was reached in the bladder. When normothermia was reached, the time to normothermia was delayed. In the brain, normothermia was reached in two of five patients after approximately 72 h. Median temperature curves from the first 72 h of cooling showed that normothermia was not reached in any of the three compartments. The temperature in the brain and bladder were on average 0.6 and 0.5 degrees C higher than in the esophagus. ICP increased with increasing brain temperature. We found no signs of clinical important injury to the nasal mucosa from the cold saline or pressure in the balloons. CONCLUSION: In brain-injured patients with hyperthermia, cooling with a prototype intranasal balloon system was clinically inadequate as the effect was delayed and not brain selective. PMID- 23345078 TI - The transverse musculocutaneous gracilis flap for chest wall reconstruction in male patients with Poland's syndrome. AB - Poland's syndrome represents a congenital unilateral deformity of the breast, chest wall, and upper limb with extremely variable manifestations. In most cases, the problem is mainly cosmetic, and the reconstruction of the chest wall should use a method designed to be performed easily and to achieve minimal scarring and donor site morbidity. We describe using a transverse musculocutaneous gracilis (TMG) flap for chest wall and anterior maxillary fold reconstruction in three male patients. In two patients, only the pectoralis major muscle was missing. In the third case, the ipsilateral latissimus dorsi muscle was also absent. The indication for surgical treatment was purely cosmetic. In all patients, a free TMG flap was performed to reconstruct the anterior axillary fold and the soft tissue defect. There was no flap loss, and all three patients had a clearly improved appearance of the chest wall. In this article, we demonstrate our experience with the use of a TMG flap for chest wall reconstruction in male patients with Poland's syndrome. PMID- 23345079 TI - Towards photo-rechargeable textiles integrating power conversion and energy storage functions: can we kill two birds with one stone? AB - Wearable power supplies: Photo-rechargeable devices integrating power conversion and energy storage functions are useful for supplying power to portable electronics. A recent report introduces a facile method to fabricate flexible dual-functional devices on a single metal wire which paves the way for wearable fabric power supplies. PMID- 23345080 TI - A spontaneous deletion of alpha-synuclein is associated with an increase in CB1 mRNA transcript and receptor expression in the hippocampus and amygdala: effects on alcohol consumption. AB - alpha-Synuclein (alpha-syn) protein and endocannabinoid CB1 receptors are primarily located in presynaptic terminals. An association between alpha-syn and CB1 receptors has recently been established in Parkinson's disease, but it is completely unknown whether there is an association between these two proteins in alcohol addiction. Therefore, we aimed to examine the alpha-syn mRNA transcript and protein expression levels in the prefrontal cortex, striatum, amygdala and hippocampus. These brain regions are the most frequently implicated in alcohol and other drug addiction. In these studies, we used C57BL/6 mice carrying a spontaneous deletion of the alpha-syn gene (C57BL/6(Snca-/-) ) and their respective controls (C57BL/6(Snca) (+/) (+) ). These animals were monitored for spontaneous alcohol consumption (3-10%) and their response to a hypnotic-sedative dose of alcohol (3 g kg(-1) ) was also assessed. Compared with the C57BL/6(Snca+/+) mice, we found that the C57BL/6(Snca-/-) mice exhibited a higher expression level of the CB1 mRNA transcript and CB1 receptor in the hippocampus and amygdala. Furthermore, C57BL/6(Snca-/-) mice showed an increase in alcohol consumption when offered a 10% alcohol solution. There was no significant difference in sleep time after the injection of 3 g/kg alcohol. These results are the first to reveal an association between alpha-syn and the CB1 receptor in the brain regions that are most frequently implicated in alcohol and other drug addictions. PMID- 23345081 TI - Ac-cel, a novel antioxidant, protects against hydrogen peroxide-induced injury in PC12 cells via attenuation of mitochondrial dysfunction. AB - Oxidative stress has been implicated in pathophysiology of many neurodegenerative diseases (ND) and increased oxidative stress is closely associated with mitochondrial dysfunction. As a result, looking for potent antioxidants, especially those targeting mitochondria, has become an attractive strategy in ND therapy. In this study, we explored protective effects and potential mechanism of Ac-cel, a novel compound, against hydrogen peroxide (H(2)O(2))-induced injury in PC12 cells. Pretreatment of PC12 cells with Ac-cel prior to 24 h of H(2)O(2) exposure markedly attenuated cytotoxicity induced by H(2)O(2) as evidenced by morphological changes and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Ac-cel also exhibited potent antiapoptotic effect demonstrated by results of annexin V and PI staining. The above beneficial effects of Ac-cel were accompanied by improved mitochondrial function, reduced caspase-3 cleavage as well as upregulated ratio of Bcl-2/Bax protein expression. Moreover, Ac-cel pretreatment markedly reversed intracellular reactive oxygen species (ROS) accumulation following 30 min of H(2)O(2) exposure in PC12 cells. Further, subcellular investigation indicated that Ac-cel significantly reduced production of mitochondrial ROS in isolated rat cortical mitochondria. Taken together, the present study, for the first time, reports that Ac-cel pretreatment inhibits H(2)O(2)-stimulated early accumulation of intracellular ROS possibly via reducing mitochondrial ROS production directly and leads to subsequent preservation of mitochondrial function. These results indicate that Ac-cel is a potential drug candidate for treatment of oxidative stress-associated ND. PMID- 23345082 TI - Cellular prion protein participates in the regulation of inflammatory response and apoptosis in BV2 microglia during infection with Mycobacterium bovis. AB - The cellular prion protein (PrP(C)) is a glycoprotein anchored by glycosylphosphatidylinositol to the cell surface and is abundantly expressed in the central nervous system. A previous study has shown that PrP(C) contributes to the establishment of infections with intracellular bacteria in macrophages. In the present work, we investigated the role of PrP(C) in the response of BV2 microglia to Mycobacterium bovis infection. For this purpose, we examined the mRNA expression of prion protein gene (PRNP) upon M. bovis infection and analyzed the effect of siRNA-mediated disruption of PRNP on different parameters of microglial activation and apoptosis in M. bovis-infected microglia. We found that M. bovis infection induced a gradual increase in PRNP mRNA level and that siRNA mediated silencing of PRNP in M. bovis-infected microglia reduced M. bovis induced upregulation of pro-inflammatory factors, increased the rate of apoptosis in infected microglia, promoted the intrinsic apoptotic pathway, and downregulated the extrinsic apoptotic pathway. We conclude that PrP(C) participates in the regulation of the response of microglia to M. bovis infection through the upregulation of pro-inflammatory cytokines and the modulation of apoptosis by interference with the intrinsic apoptotic pathway. PMID- 23345083 TI - Hypoxia increases Abeta-induced tau phosphorylation by calpain and promotes behavioral consequences in AD transgenic mice. AB - Chronic hypoxia has been reported to contribute to the development of Alzheimer's disease (AD). However, the mechanism of hypoxia in the pathogenesis of AD remains unclear. The purpose of this study was to investigate the effects of chronic hypoxia treatment on beta-amyloid, tau pathologies, and the behavioral consequences in the double transgenic (APP/PS1) mice. Double transgenic mice (APP/PS1 mice) were treated with hypoxia, and spatial learning and memory abilities of mice were assessed in the Morris water maze. beta-amyloid level and plaque level in APP/PS1 double transgenic mice were detected by immunohistochemistry. Protein tau, p35/p25, cyclin-dependent kinase 5 (CDK5), and calpain were detected by western blotting analysis. Chronic hypoxia treatment decreased memory and cognitive function in AD mice. In addition, chronic hypoxia treatment resulted in increased senile plaques, accompanying with increased tau phosphorylation. The hypoxia-induced increase in the tau phosphorylation was associated with a significant increase in the production of p35 and p25 and upregulation of calpain, suggesting that hypoxia induced aberrant CDK5/p25 activation via upregulation of calpain. Our results showed that chronic hypoxia exposure accelerates not only amyloid pathology but also tau pathology via calpain-mediated tau hyperphosphorylation in an AD mouse model. These pathological changes possibly contribute to the hypoxia-induced behavioral change in AD mice. PMID- 23345084 TI - Novel insights into protein misfolding diseases revealed by ion mobility-mass spectrometry. AB - Amyloid disorders incorporate a wide range of human diseases arising from the failure of a specific peptide or protein to adopt, or remain in, its native functional conformational state. These pathological conditions, such as Parkinson's disease, Alzheimer's disease and Huntington's disease are highly debilitating, exact enormous costs on both individuals and society, and are predicted to increase in prevalence. Consequently, they form the focus of a topical and rich area of current scientific research. A major goal in attempts to understand and treat protein misfolding diseases is to define the structures and interactions of protein species intermediate between fully folded and aggregated, and extract a description of the aggregation process. This has proven a difficult task due to the inability of traditional structural biology approaches to analyze structurally heterogeneous systems. Continued developments in instrumentation and analytical approaches have seen ion mobility-mass spectrometry (IM-MS) emerge as a complementary approach for protein structure determination, and in some cases, a structural biology tool in its own right. IM-MS is well suited to the study of protein misfolding, and has already yielded significant structural information for selected amyloidogenic systems during the aggregation process. This review describes IM-MS for protein structure investigation, and provides a summary of current research highlighting how this methodology has unequivocally and unprecedentedly provided structural and mechanistic detail pertaining to the oligomerization of a variety of disease related proteins. PMID- 23345085 TI - Professional conduct and making decisions for minors. PMID- 23345086 TI - Bioethics and its gatekeepers: does institutional racism exist in leading bioethics journals? AB - Who are the gatekeepers in bioethics? Does editorial bias or institutional racism exist in leading bioethics journals? We analyzed the composition of the editorial boards of 14 leading bioethics journals by country. Categorizing these countries according to their Human Development Index (HDI), we discovered that approximately 95 percent of editorial board members are based in (very) high-HDI countries, less than 4 percent are from medium-HDI countries, and fewer than 1.5 percent are from low-HDI countries. Eight out of 14 leading bioethics journals have no editorial board members from a medium- or low-HDI country. Eleven bioethics journals have no board members from low-HDI countries. This severe underrepresentation of bioethics scholars from developing countries on editorial boards suggests that bioethics may be affected by institutional racism, raising significant questions about the ethics of bioethics in a global context. PMID- 23345087 TI - Moral distress in uninsured health care. PMID- 23345088 TI - Invasive hemodynamic evaluation in patients with mechanical aortic valves. AB - Invasive hemodynamic evaluation in the patient with a mechanical aortic valve has in the past required transseptal or apical left ventricular puncture in order to obtain left ventricular pressure measurements. Over the last few years, several case reports have described the feasibility of using a coronary pressure-sensing guidewire to cross mechanical prosthetic aortic valves. In the current manuscript, we report four cases in which the use of a pressure-sensing guidewire was utilized for invasive hemodynamic diagnostic evaluation in patients with mechanical aortic valves. Furthermore, we present a detailed description of the technical approach to this technique and the limitations of this approach. PMID- 23345089 TI - Regional accent variation in the shadowing task: evidence for a loose perception action coupling in speech. AB - We investigated the relation between action and perception in speech processing, using the shadowing task, in which participants repeat words they hear. In support of a tight perception-action link, previous work has shown that phonetic details in the stimulus influence the shadowing response. On the other hand, latencies do not seem to suffer if stimulus and response differ in their articulatory properties. The present investigation tested how perception influences production when participants are confronted with regional variation. Results showed that participants often imitate a regional variation if it occurs in the stimulus set but tend to stick to their variant if the stimuli are consistent. Participants were forced or induced to correct by the experimental instructions. Articulatory stimulus-response differences do not lead to latency costs. These data indicate that speech perception does not necessarily recruit the production system. PMID- 23345091 TI - Improved dynamic ID-based authentication scheme for telecare medical information systems. AB - In order to protect users' identity privacy, Chen et al. proposed an efficient dynamic ID-based authentication scheme for telecare medical information systems. However, Chen et al.'s scheme has some weaknesses. In Chen et al.'s scheme, an attacker can track a user by a linkability attack or an off-line identity guessing attack. Chen et al.'s scheme is also vulnerable to an off-line password guessing attack and an undetectable on-line password guessing attack when user's smart card is stolen. In server side, Chen et al.'s scheme needs large computational load to authentication a legal user or reject an illegal user. To remedy the weaknesses in Chen et al.'s scheme, we propose an improved smart card based password authentication scheme. Our analysis shows that the improved scheme can overcome the weaknesses in Chen et al.'s scheme. PMID- 23345092 TI - On the security of a dynamic ID-based authentication scheme for telecare medical information systems. AB - Telecare medical information systems (TMISs) are increasingly popular technologies for healthcare applications. Using TMISs, physicians and caregivers can monitor the vital signs of patients remotely. Since the database of TMISs stores patients' electronic medical records (EMRs), only authorized users should be granted the access to this information for the privacy concern. To keep the user anonymity, recently, Chen et al. proposed a dynamic ID-based authentication scheme for telecare medical information system. They claimed that their scheme is more secure and robust for use in a TMIS. However, we will demonstrate that their scheme fails to satisfy the user anonymity due to the dictionary attacks. It is also possible to derive a user password in case of smart card loss attacks. Additionally, an improved scheme eliminating these weaknesses is also presented. PMID- 23345093 TI - Pathogenesis of prediabetes: role of the liver in isolated fasting hyperglycemia and combined fasting and postprandial hyperglycemia. AB - CONTEXT: People with prediabetes are at high risk of developing diabetes. OBJECTIVE: The objective of this study was to determine the pathogenesis of fasting and postprandial hyperglycemia in prediabetes. DESIGN: Glucose production, gluconeogenesis, glycogenolysis, and glucose disappearance were measured before and during a hyperinsulinemic clamp using [6,6-(2)H2]glucose and the deuterated water method corrected for transaldolase exchange. SETTING: The study was conducted at the Mayo Clinic Clinical Research Unit. PARTICIPANTS: Subjects with impaired fasting glucose (IFG)/normal glucose tolerance (NGT) (n = 14), IFG/impaired glucose tolerance (IGT) (n = 18), and normal fasting glucose (NFG)/NGT (n = 16) were studied. INTERVENTION: A hyperinsulinemic clamp was used. OUTCOME MEASURES: Glucose production, glucose disappearance, gluconeogenesis, and glycogenolysis were measured. RESULTS: Fasting glucose production was higher (P < .0001) in subjects with IFG/NGT than in those with NFG/NGT because of increased rates of gluconeogenesis (P = .003). On the other hand, insulin-induced suppression of glucose production, gluconeogenesis, glycogenolysis, and stimulation of glucose disappearance all were normal. Although fasting glucose production also was increased (P = .0002) in subjects with IFG/IGT, insulin induced suppression of glucose production, gluconeogenesis, and glycogenolysis and stimulation of glucose disappearance were impaired (P = .005). CONCLUSIONS: Fasting hyperglycemia is due to excessive glucose production in people with either IFG/NGT or IFG/IGT. Both insulin action and postprandial glucose concentrations are normal in IFG/NGT but abnormal in IFG/IGT. This finding suggests that hepatic and extrahepatic insulin resistance causes or exacerbates postprandial glucose intolerance in IFG/IGT. Elevated gluconeogenesis in the fasting state in IFG/NGT and impaired insulin-induced suppression of both gluconeogenesis and glycogenolysis in IFG/IGT suggest that alteration in the regulation of these pathways occurs early in the evolution of type 2 diabetes. PMID- 23345094 TI - Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the Thyroid Epidemiology, Audit, and Research Study (TEARS). AB - OBJECTIVE: The aim of the study was to examine the association of tested TSH with age, gender, and diabetes in a large population-based cohort without evidence of thyroid disease. DESIGN: Record-linkage technology was used retrospectively to identify people without evidence of thyroid disease in the general population of Tayside, Scotland, from July 1, 2003, to December 31, 2009. COHORT: All Tayside residents who had thyroid function tests performed were identified. Using a unique patient identifier, data linkage enabled a cohort without thyroid disease to be identified by excluding anyone with thyroid or antithyroid prescription, thyroid-related admission or surgery, treatment with radioactive iodine and/or positive thyroid antibodies. Cases below 18 years of age were also excluded. OUTCOME MEASURES: We measured TSH distribution among different age groups and by gender. RESULTS: We identified the latest TSH measurements in 153127 people from the reference population after applying the exclusion criteria. There was a significant increase in median TSH (1.58 mU/L at 31-40 y to 1.86 mU/L at >90 y; P < .001) and 97.5th centile TSH (3.98 to 5.94 mU/L, respectively) with increasing age. The 2.5th centile decreased with age (0.51 to 0.31 mU/L). Patients with diabetes had marginally higher TSH concentration (1.80 vs 1.70 mU/L; P < .001). CONCLUSION: The use of these age-specific reference intervals for TSH, especially in those over 70 years old, would result in the reclassification of many TSH results from "abnormal" to "normal" (within the 95th centile reference interval) and avoid unnecessary treatment. PMID- 23345095 TI - DNA copy number variations characterize benign and malignant thyroid tumors. AB - CONTEXT: Fine-needle aspiration (FNA) is the best diagnostic tool for preoperative evaluation of thyroid nodules but is often inconclusive as a guide for surgical management. OBJECTIVE: Our hypothesis was that thyroid tumor subtypes may show characteristic DNA copy number variation (CNV) patterns, which may further improve the preoperative classification. DESIGN: Our study cohorts included benign follicular adenomas (FAs), classic papillary thyroid carcinomas (PTCs), and follicular variant PTCs (FVPTCs), the three subtypes most commonly associated with inconclusive preoperative cytopathology. SETTING: Tissue and FNA samples were obtained at an academic tertiary referral center. PATIENTS: Cases were identified that underwent partial or complete thyroidectomy for malignant or indeterminate thyroid lesions between 2000 and 2008 and had adequate snap-frozen tissue. INTERVENTIONS: Pairs of tumor tissue and matching normal thyroid tissue derived DNA were compared using 550K single-nucleotide polymorphism arrays. MAIN OUTCOME MEASURE: Statistically significant differences in CNV patterns between tumor subtypes were identified. RESULTS: Segmental amplifications in chromosomes (Ch) 7 and 12 were more common in FAs than in PTCs or FVPTCs. Additionally, a subset of FAs and FVPTCs showed deletions in Ch22. We identified the 5 CNV associated genes best at discriminating between FAs and PTCs/FVPTCs, which correctly classified 90% of cases. These 5 Ch12 genes were validated by quantitative genomic PCR and gene expression array analyses on the same patient cohort. The 5-gene signature was then successfully validated against an independent test cohort of benign and malignant tumor samples. Finally, we performed a feasibility study on matched FA-derived intraoperative FNA samples and were able to correctly identify FAs harboring the Ch12 amplification signature, whereas FAs without amplification showed a normal Ch12 signature. CONCLUSIONS: Thyroid tumor subtypes possess characteristic genomic profiles that may further our understanding of structural genetic changes in thyroid tumor subtypes and may lead to the development of new diagnostic biomarkers in FNA samples. PMID- 23345096 TI - Clinical review: Parathyroid localization and implications for clinical management. AB - CLINICAL CONTEXT: The prevalence of hyperparathyroidism, especially primary hyperparathyroidism, has increased in recent decades due to improvements in diagnostic techniques with a corresponding surge in parathyroid surgery, leading to the development of focused, minimally invasive surgical approaches. Focused parathyroidectomy is predicated on preoperative localization of suspected parathyroid pathology. As a result, there has been a proliferation of parathyroid imaging modalities and protocols, resulting in confusion about their indications and applications. EVIDENCE ACQUISITION: Bibliographies from clinical trials and review articles published since 2000 were reviewed and supplemented with targeted searches using biomedical databases. We also employed our extensive clinical experience. EVIDENCE SYNTHESIS: The best-studied modalities for parathyroid localization are nuclear scintigraphy and sonography and are widely applied as initial studies. Multiple variations exist, and several additional noninvasive imaging techniques, such as computed tomography and magnetic resonance, are described. The exquisite anatomical detail of 4-dimensional computed tomography must be balanced with significant radiation exposure to the thyroid gland. Invasive venous PTH sampling and parathyroid arteriography have important roles in remedial cases. Due to considerable heterogeneity in imaging, multidisciplinary collaboration between endocrinologists, surgeons, and radiologists is beneficial. CONCLUSIONS: Parathyroid localization is indicated in surgical candidates. Crucial considerations when selecting an imaging study include availability, cost, radiation exposure, local expertise, and accuracy. Additional factors include the patient's anticipated pathology and whether it is de novo or refractory disease. An approach to imaging for patients with primary hyperparathyroidism is presented. PMID- 23345097 TI - Thyroglobulin is a sensitive measure of both deficient and excess iodine intakes in children and indicates no adverse effects on thyroid function in the UIC range of 100-299 MUg/L: a UNICEF/ICCIDD study group report. AB - CONTEXT: The median urinary iodine concentration (UIC) is a biomarker of iodine intake. According to the World Health Organization, a median UIC in the range 100 199 MUg/L indicates adequate and 200-299 MUg/L more than adequate intake. Thyroglobulin (Tg) may be a promising functional biomarker of both iodine deficiency and excess. OBJECTIVES: Using a standardized dried blood spots-Tg assay in children, we evaluated the Tg response to both low- and high-iodine intake and estimated the population cutoff point for iodine deficiency or excess. Also, we compared thyroid functions within the UIC ranges of 100-199 vs 200-299 MUg/L. DESIGN AND SETTING: We conducted a cross-sectional study in primary schools in 12 countries. SUBJECTS: SUBJECTS were 6 to 12 years old (n = 2512). MAIN OUTCOME MEASURES: We measured UIC, TSH, total T4, Tg, and thyroid antibodies. RESULTS: Over a range of iodine intakes from severely deficient to excessive, Tg concentrations showed a clear U-shaped curve. Compared with iodine sufficient children, there was a significantly higher prevalence of elevated Tg values in children with iodine deficiency (UIC <100 MUg/L) and iodine excess (UIC >300 MUg/L). There was no significant change in the prevalence of elevated Tg, TSH, T4, or thyroid antibodies comparing children within the UIC ranges of 100 199 vs 200-299 MUg/L. CONCLUSIONS: In school-aged children, 1) Tg is a sensitive indicator of both low and excess iodine intake; 2) a median Tg of <13 MUg/L and/or <3% of Tg values >40 MUg/L indicates iodine sufficiency in the population; 3) the acceptable range of median UIC in monitoring iodized salt programs could be widened to a single category of sufficient iodine intake from 100 to 299 MUg/L. PMID- 23345099 TI - Risk factors for subtrochanteric and diaphyseal fractures: the study of osteoporotic fractures. AB - CONTEXT: Patients on long-term bisphosphonate therapy may have an increased incidence of low-energy subtrochanteric and diaphyseal (SD) femoral fractures. However, the incidence and risk factors associated with these fractures have not been well defined. OBJECTIVE: The objective of the study was to determine the incidence of and risk factors for low-energy SD fractures in the Study of Osteoporotic Fractures (SOF). DESIGN: Low-energy SD fractures were identified from a review of radiographic reports obtained between 1986 and 2010 in women in the SOF. Among the SD fractures, pathological, periprosthetic, and traumatic fractures were excluded. We assessed risk factors for SD fractures as well as risk factors for femoral neck (FN) and intertrochanteric (IT) hip fractures using both age-adjusted and multivariate time-dependent proportional hazards models. During this follow-up, only a small minority had ever used bisphosphonates. RESULTS: Forty-five women sustained low-energy subtrochanteric/diaphyseal femoral fractures over a total follow-up of 140 000 person-years. The incidence of SD fracture was 3.2 per 10 000 person-years compared with a total hip fracture incidence of 110 per 10 000 person-years. A total of about 12% of women reported bisphosphonate use at 1 or more visits. In multivariate analyses, age, total hip bone mineral density (BMD), bisphosphonate use, and history of diabetes emerged as independent risk factors for SD fractures. Risk factors for FN and IT fractures included age, BMD, and history of falls or prior fractures. Bisphosphonate use was protective against FN fractures, whereas there was an increased risk of SD fractures (hazard ratio 2.58, P = .049) with bisphosphonate use after adjustment for other risk factors for fracture. CONCLUSIONS: In SOF, low-energy SD fractures were rare occurrences, far outnumbered by FN and IT fractures. Typical risk factors were associated with FN and IT fractures, whereas only age, total hip BMD, and history of diabetes were independent risk factors for SD fractures. In addition, bisphosphonate use was a marginally significantly predictor although the SOF study has limited ability to assess this association. PMID- 23345100 TI - Medical treatment of Cushing's disease. AB - CONTEXT: Cushing's disease (CD) is associated with serious morbidity and, when suboptimally treated, an increased mortality. Although surgery is the first-line treatment modality for CD, hypercortisolism persists or recurs in an important subset of patients. Considering the deleterious effects of uncontrolled CD, there is a clear need for effective medical therapy. OBJECTIVE: In this review, we discuss molecular targets for medical therapy, efficacy, and side effects of the currently used drugs to treat hypercortisolism and focus on recent developments resulting from translational and clinical studies. EVIDENCE ACQUISITION: Selection of publications related to the study objective was performed via a PubMed search using relevant keywords and search terms. MAIN FINDINGS: Medical therapy for CD can be classified into pituitary-directed, adrenal-blocking, and glucocorticoid receptor-antagonizing drugs. Recent studies demonstrate that somatostatin receptor subtype 5 (sst(5)) and dopamine receptor subtype 2 (D(2)) are frequently (co-)expressed by corticotroph adenomas. Pituitary-directed therapy with pasireotide and cabergoline, targeting sst(5) and D(2), respectively, is successful in approximately 25-30% of patients. Adrenal-blocking drugs can be effective by inhibiting steroidogenic enzyme activity. Finally, the glucocorticoid receptor antagonist mifepristone induces clinical and metabolic improvement in the majority of patients. Each drug can have important side effects that may impair long-term treatment. Generally, patients with moderate to severe hypercortisolism need combination therapy to normalize cortisol production. CONCLUSION: Medical therapy for CD can be targeted at different levels and should be tailored in each individual patient. Future studies should examine the optimal dose and combination of medical treatment modalities for CD. PMID- 23345101 TI - Efficacy of 'indigenous vaccine' using native 'Indian bison type' genotype of Mycobacterium avium subspecies paratuberculosis for the control of clinical Johne's disease in an organized goat herd. AB - Therapeutic efficacy of a new 'Indigenous vaccine' prepared from native highly pathogenic 'Indian Bison Type' genotype of Mycobacterium avium subspecies paratuberculosis (MAP) of goat origin has been evaluated with respect to control of clinical Johne's disease in naturally infected Mehsana breed of goat in North Gujarat. Fifty goats from Sheep and Goats Research Station, Sardarkrushinagar Dantiwada Agricultural University, Sardarkrushinagar, were randomly divided into 2 groups viz.,'Vaccinated'(n = 35) and 'Control'(n = 15). After vaccination, goats were monitored for physical condition, morbidity, mortality, body weights, shedding of MAP in feces, internal condition, gross lesions and humoral immune responses up to 120 days (at each interval of 30 days). At the end of 120 days trial, there was marked overall improvement in physical condition and body weights of vaccinated goats as compared to 'Control' goats. Vaccinated goats gained significantly (P < 0.05) higher body weights, hardly exhibited any lesions characteristic of JD, had significantly higher (P < 0.01) antibody titers and shedding of MAP was significantly (P < 0.01) reduced. Few of the vaccinated goats were positive for MAP DNA in faecal PCR and blood PCR before vaccination. However, all were found as negative at 120 days post vaccination (DPV). Overall vaccine exhibited effective in restriction of MAP infection and significant improvement in production parameters and reduction in mortality and morbidity due to JD. The trial in the herd will be continued. PMID- 23345102 TI - Preoperative identification of perforator vessels by combining MDCT, doppler flowmetry, and ICG fluorescent angiography. AB - BACKGROUND: The position of perforator vessels varies between individuals. In this report, we present our experience on the use of combining multidetector-row computed tomography (MDCT), Doppler flowmetry, and indocyanine green (ICG) fluorescent angiography to identify perforator vessels of flaps for reconstruction. We evaluated the advantages, disadvantages, and chose the necessary examination, depending on characteristics of the flap. METHODS: The combination of MDCT, Doppler flowmetry, and ICG fluorescent angiography examinations to identify perforators was performed in 50 patients before reconstructive surgery. The patients first underwent MDCT of the prospective flap donor region. Perforators were then marked for this site by using Doppler flowmetry in the neighborhood of the points identified by MDCT. After placing the patient in the intraoperative posture, ICG fluorescent angiography was performed to confirm the intensity and position of the perforators. RESULTS: In all 50 patients examined by using this approach, perforators were intraoperatively identified near the preoperatively determined sites. Flap harvesting was possible in all patients with the identified perforators as the vascular pedicle. But it was difficult to identify the perforators on the MDCT in the patients who had a flap thickness of less than 8 mm and the identification of the perforators was difficult on ICG fluorescent angiography in the patients with a flap thickness greater than 20 mm. The transferred free flaps survived in all patients without complications. CONCLUSION: On the basis of the results, selection of the most suitable mode of examination depending on the characteristics of flap is recommended. PMID- 23345098 TI - Prospective safety surveillance of GH-deficient adults: comparison of GH-treated vs untreated patients. AB - CONTEXT: In clinical practice, the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown. OBJECTIVE: The objective of this study was to compare adverse events (AEs) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement. DESIGN AND SETTING: This was a prospective observational study in the setting of US clinical practices. PATIENTS AND OUTCOME MEASURES: AEs were compared between GH-treated (n = 1988) and untreated (n = 442) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate. The standardized mortality ratio was calculated using US mortality rates. RESULTS: After a mean follow-up of 2.3 years, there was no significant difference in rates of death, cancer, intracranial tumor growth or recurrence, diabetes, or cardiovascular events in GH-treated compared with untreated patients. The standardized mortality ratio was not increased in either group. Unexpected AEs (GH-treated vs untreated, P <= .05) included insomnia (6.4% vs 2.7%), dyspnea (4.2% vs 2.0%), anxiety (3.4% vs 0.9%), sleep apnea (3.3% vs 0.9%), and decreased libido (2.1% vs 0.2%). Some of these AEs were related to baseline risk factors (including obesity and cardiopulmonary disease), higher GH dose, or concomitant GH side effects. CONCLUSIONS: In GH-deficient adults, there was no evidence for a GH treatment effect on death, cancer, intracranial tumor recurrence, diabetes, or cardiovascular events, although the follow-up period was of insufficient duration to be conclusive for these long-term events. The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement. PMID- 23345103 TI - Specific anti-integrase abzymes from HIV-infected patients: a comparison of the cleavage sites of intact globular HIV integrase and two 20-mer oligopeptides corresponding to its antigenic determinants. AB - HIV-infected patients possess anti-integrase (IN) IgGs and IgMs that, after isolation by chromatography on IN-Sepharose, unlike canonical proteases, specifically hydrolyze only IN but not many other tested proteins. Hydrolysis of intact globular IN first leads to formation of many long fragments of protein, while its long incubation with anti-IN antibodies, especially in the case of abzymes (Abzs) with a high proteolytic activity, results in the formation of short and very short oligopeptides (OPs). To identify all sites of IgG-mediated proteolysis corresponding to known AGDs of integrase, we have used a combination of reverse-phase chromatography, matrix-assisted laser desorption/ionization spectrometry, and thin-layer chromatography to analyze the cleavage products of two 20-mer OPs corresponding to these AGDs. Both OPs contained 9-10 mainly clustered major, medium, and minor sites of cleavage. The main superficial cleavage sites of the AGDs in the intact IN and sites of partial or deep hydrolysis of the peptides analyzed do not coincide. The active sites of anti-IN Abzs are localized on their light chains, whereas the heavy chains are responsible for the affinity of protein substrates. Interactions of intact globular proteins with both light and heavy chains of Abzs provide high specificity of IN hydrolysis. The affinity of anti-IN Abzs for intact integrase was ~1000-fold higher than for the OPs. The data suggest that both OPs interact mainly with the light chains of different monoclonal Abzs of the total pool of IgGs, which possesses lower affinity for substrates; and therefore, depending on the oligopeptide sequences, their hydrolysis may be less specific and remarkably different in comparison with the cleavage of intact globular IN. PMID- 23345104 TI - Recognition of specific and nonspecific DNA by human lactoferrin. AB - The general principles of recognition of nucleic acids by proteins are among the most exciting problems of molecular biology. Human lactoferrin (LF) is a remarkable protein possessing many independent biological functions, including interaction with DNA. In human milk, LF is a major DNase featuring two DNA binding sites with different affinities for DNA. The mechanism of DNA recognition by LF was studied here for the first time. Electrophoretic mobility shift assay and fluorescence measurements were used to probe for interactions of the high affinity DNA-binding site of LF with a series of model-specific and nonspecific DNA ligands, and the structural determinants of DNA recognition by LF were characterized quantitatively. The minimal ligands for this binding site were orthophosphate (K(i) = 5 mM), deoxyribose 5'-phosphate (K(i) = 3 mM), and different dNMPs (K(i) = 0.56-1.6 mM). LF interacted additionally with 9-12 nucleotides or nucleotide pairs of single- and double-stranded ribo- and deoxyribooligonucleotides of different lengths and sequences, mainly through weak additive contacts with internucleoside phosphate groups. Such nonspecific interactions of LF with noncognate single- and double-stranded d(pN)(10) provided ~6 to ~7.5 orders of magnitude of the enzyme affinity for any DNA. This corresponds to the Gibbs free energy of binding (DeltaG(0)) of -8.5 to -10.0 kcal/mol. Formation of specific contacts between the LF and its cognate DNA results in an increase of the DNA affinity for the enzyme by approximately 1 order of magnitude (K(d) = 10 nM; DeltaG(0) ~ -11.1 kcal/mol). A general function for the LF affinity for nonspecific d(pN)(n) of different sequences and lengths was obtained, giving the K(d) values comparable with the experimentally measured ones. A thermodynamic model was constructed to describe the interactions of LF with DNA. PMID- 23345105 TI - Salt bridge exchange binding mechanism between streptavidin and its DNA aptamer- thermodynamics and spectroscopic evidences. AB - Protein-nucleic acids binding driven by electrostatic interactions typically are characterized by the release of counter ions, and the salt-inhibited binding association constant (K(a)) and the magnitude of exothermic binding enthalpy (DeltaH). Here, we report a non-classical thermodynamics of streptavidin (SA) aptamer binding in NaCl (140-350 mM) solutions near room temperatures (23-27 degrees C). By using isothermal titration calorimetry (ITC) and circular dichroism (CD)/fluorescence spectroscopy, we found that the binding was enthalpy driven with a large entropy cost (DeltaH -20.58 kcal mol(-1), TDeltaS -10.99 kcal mol(-1), and K(a) 1.08 * 10(7) M(-1) at 140 mM NaCl 25 degrees C). With the raise of salt concentrations, the DeltaH became more exothermic, yet the K(a) was almost unchanged (DeltaH -26.29 kcal mol(-1) and K(a) 1.50 * 10(7) M(-1) at 350 mM NaCl 25 degrees C). The data suggest that no counter Na(+) was released in the binding. Spectroscopy data suggest that the binding, with a stoichiometry of 2, was accompanied with substantial conformational changes on SA, and the changes were insensitive to the variation of salt concentrations. To account for the non classical results, we propose a salt bridge exchange model. The intramolecular binding-site salt bridge(s) of the free SA and the charged phosphate group of aptamers re-organize to form the binding complex by forming a new intermolecular salt bridge(s). The salt bridge exchange binding process requires minimum amount of counter ions releasing but dehydration of the contacting surface of SA and the aptamer. The energy required for dehydration is reduced in the case of binding solution with higher salt concentration and account for the higher binding exothermic mainly. PMID- 23345109 TI - Emerging applications of superhydrophilic-superhydrophobic micropatterns. AB - Water on superhydrophilic surfaces spreads or is absorbed very quickly, and exhibits water contact angles close to zero. We encounter superhydrophilic materials in our daily life (e.g., paper, sponges, textiles) and they are also ubiquitous in nature (e.g., plant and tree leaves, Nepenthes pitcher plant). On the other hand, water on completely non-wettable, superhydrophobic surfaces forms spherical droplets and rolls off the surface easily. One of the most well-known examples of a superhydrophobic surface is the lotus leaf. Creating novel superhydrophobic surfaces has led to exciting new properties such as complete water repellency, self-cleaning, separation of oil and water, and antibiofouling. However, combining these two extreme states of superhydrophilicity and superhydrophobicity on the same surface in precise two-dimensional micropatterns opens exciting new functionalities and possibilities in a wide variety of applications from cell, droplet, and hydrogel microarrays for screening to surface tension confined microchannels for separation and diagnostic devices. In this Progress Report, we briefly describe the methods for fabricating superhydrophilic-superhydrophobic patterns and highlight some of the newer and emerging applications of these patterned substrates that are currently being explored. We also give an outlook on current and future applications that would benefit from using such superhydrophilic-superhydrophobic micropatterns. PMID- 23345110 TI - Radial incision and cutting method for refractory stricture after nonsurgical treatment of esophageal cancer. AB - Strictures remaining after nonsurgical treatment for esophageal cancer are generally more refractory to endoscopic balloon dilation (EBD) when compared with anastomotic strictures. The aim of the present study was to evaluate the efficacy and safety of a radial incision and cutting (RIC) method for the treatment of refractory strictures after nonsurgical treatment of esophageal cancer. All subjects complained of grade 2 or worse dysphagia, even after at least 10 sessions of EBD. Between August 2009 and May 2012, eight consecutive patients with refractory esophageal stricture after nonsurgical treatments, including chemoradiotherapy (CRT) alone (n = 3), CRT followed by salvage endoscopic treatment (n = 3), or endoscopic submucosal dissection (ESD; n = 2), underwent the RIC procedure. After the RIC procedure, dysphagia in all the patients dramatically improved to grade 1 or 0 without any major complications; however, the long-term efficacy was unfavorable as only 37.5 % (3 /8) demonstrated adequate lumen patency at 3 months, and re-intervention was necessary in six patients (75 %). PMID- 23345111 TI - Optimization and validation of spectrofluorimetric method for determination of cefadroxile and cefuroxime sodium in pharmaceutical formulations. AB - A simple, accurate, precise and validated spectrofluorimetric method is proposed for the determination of two cephalosporins, namely, cefadroxile (cefa) and cefuroxime sodium (cefu) in pharmaceutical formulations. The method is based on a reaction between cephalosporins with 1,2-naphthoquinone-4-sulfonate in alkaline medium, to form fluorescent derivatives that are extracted with chloroform and subsequently measured at 610 and 605 nm after excitation at 470 and 460 nm for cefa and cefu respectively. The optimum experimental conditions have been studied. Beer's law is obeyed over the concentrations of 20-70 ng/mL and 15-40 ng/mL for cefa and cefu, respectively. The detection limits were 4.46 ng/mL and 3.02 ng/mL with a linear regression correlation coefficient of 0.9984 and 0.998, and recoveries ranging 97.50-109.96% and 95.73-98.89% for cefa and cefu, respectively. The effects of pH, temperature, reaction time, 1,2-naphthoquinone-4 sulfonic concentration and extraction solvent on the determination of cefa and cefu, have been examined. The proposed method can be applied for the determination of cefa and cefu in pharmaceutical formulations in quality control laboratories. PMID- 23345112 TI - Non-invasive continuous blood pressure monitoring: a review of current applications. AB - Blood pressure monitoring has come a long way from the initial observations made by Reverend Hales in the 18th century. There are none that deny the importance of monitoring perioperative blood pressure; however, the limited ability of the current prevalent technology (oscillometric blood pressure monitoring) to offer continuous blood pressure measurements leaves room for improvement. Invasive monitoring is able to detect beat-to-beat blood pressure measurement, but the risks inherent to the procedure make it unsuitable for routine use except when this risk is outweighed by the benefits. This review focuses on the discoveries which have led up to the current blood pressure monitoring technologies, and especially the creation of those offering non-invasive but continuous blood pressure monitoring capabilities, including their methods of measurement and limitations. PMID- 23345113 TI - Primary hypertrophic osteoarthropathy: an update. AB - Digital clubbing, which has been recognized as a sign of systemic disease, is one of the most ancient diseases. However, the pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood. The study of a clinically indistinguishable idiopathic form (primary hypertrophic osteoarthropathy, PHO) provides an opportunity to understand the pathogenesis of hypertrophic osteoarthropathy. Current advances in the study of PHO are discussed. The impaired metabolism of prostaglandin E2 (PGE2) plays a central role in its pathogenesis. PMID- 23345114 TI - The usefulness of hydrazine derivatives for mass spectrometric analysis of carbohydrates. AB - Over the last years, extensive studies have evaluated glycans from different biological samples and validated the importance of glycosylation as one of the most important post-translational modifications of proteins. Although a number of new methods for carbohydrate analysis have been published and there has been significant progress in their identification, the development of new approaches to study these biomolecules and understand their role in living systems are still vivid challenges that intrigue glycobiologists. In the last decade, the success in analyses of oligosaccharides has been driven mainly by the development of innovative, highly sensitive mass spectrometry techniques. For enhanced mass spectrometry detection, carbohydrate molecules are often derivatized. Besides, the type of labeling can influence the fragmentation pattern and make the structural analysis less complicated. In this regard, in 2003 we introduced the low scale, simple non-reductive tagging of glycans employing phenylhydrazine (PHN) as the derivatizing reagent. PHN-labeled glycans showed increased detection and as reported previously they can be analyzed by HPLC, ESI, or MALDI immediately after derivatization. Under tandem mass spectrometry conditions, PHN derivatives produced useful data for the structural elucidation of oligosaccharides. This approach of analysis has helped to reveal new isomeric structures for glycans of known/unknown composition and has been successfully applied for the profiling of N-glycans obtained from serum samples and cancer cells. The efficacy of this labeling has also been evaluated for different substituted hydrazine reagents. This review summarizes all types of reducing-end labeling based on hydrazone-linkage that have been used for mass spectrometric analyses of oligosaccharides. This review is also aimed at correcting some past misconceptions or interpretations reported in the literature. PMID- 23345115 TI - Decreased expression of light chain 3 (LC3) increased the risk of distant metastasis in triple-negative breast cancer. AB - The aim of this study was to evaluate the prognostic value of light chain 3 (LC3) expression in triple-negative breast cancer (TNBC) and describe the association of LC3 expression with the occurrence of metastasis. LC3 expression in tissue microarray was evaluated by immunohistochemistry in 163 patients with TNBC. The prognostic value of LC3 expression was assessed by a Cox regression model adjusted for clinical characteristics. Low LC3 expression in TNBC was observed in 56 (34.4 %) of 163 TNBC. Low LC3 expression significantly correlated with a higher risk of distant metastasis, rather than locoregional relapse. The 10-year distant metastases-free survival for LC3-negative and LC3-positive patients was 57.2 and 95.1 %, respectively (p < 0.0001). Accordingly, a significant correlation was found between LC3 expression and disease-free survival (DFS) and overall survival (OS). Multivariate analysis indicated that LC3 negative was a significant independent prognostic factor of DFS (p = 0.019), but not for OS (p = 0.545) in all patients. Our results suggested that expression of LC3 in TNBC was associated with higher distant metastases. This finding could open new avenues for the development of novel therapy strategies to TNBC. PMID- 23345116 TI - Prognostic factors and clinical outcome of patients with Ewing's sarcoma family of tumors in adults: multicentric study of the Anatolian Society of Medical Oncology. AB - The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with Ewing sarcoma family of tumors (ESFT). Data of patients with ESFTs followed up at different cancer centers in Turkey between 2001 and 2010 were retrospectively analyzed. The median age of 114 patients was 26 years (range 14-66). The median follow-up was 20 months (range 1-118 months). Tumor size was between 1.5 and 14 cm (median 8 cm). Eighty-six percent of patients had localized disease at presentation, and 14 % had metastatic disease. Local therapy was surgery alone in 31 % of patients, surgery combined with radiotherapy in 41 % and radiotherapy alone in 18 %. Approximately 70 % of patients were treated with vincristine, doxorubicin, cyclophosphamide and actinomycin-D, alternating with ifosfamide and etoposide every 3 weeks. In patients with localized disease at presentation, the 5-year disease-free survival and overall survival were 60 and 65 %, respectively. At univariate analysis, patients with tumor size >= 8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size <= 8 cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. ESFTs are aggressive tumors with a high incidence of local recurrence and distant metastasis. Multimodality treatment consisting of adequate surgical resection, aggressive chemotherapy (VAC alternating with IE) and radiotherapy is recommended for patients with ESFTs. PMID- 23345117 TI - Association of LAPTM4B gene polymorphism with nasopharyngeal carcinoma susceptibility in a Chinese population. AB - Lysosome-associated protein transmembrane-4 beta (LAPTM4B) is a novel cancer related gene. It has two alleles designated LAPTM4B 1 and LAPTM4B 2. Previous studies have revealed that LAPTM4B polymorphisms contribute to the risk of many cancers. The aim of this study was to investigate the association between different LAPTM4B alleles and the risk of nasopharyngeal carcinoma (NPC), one of the most common cancers in southern China. Using polymerase chain reaction (PCR) in a case-control study, we detected the LAPTM4B genotype in peripheral blood samples from 134 patients with NPC and 327 control subjects. The chi-square test was used to analyze differences of categorical variables and Hardy-Weinberg equilibrium. Odds ratios and 95 % CI were computed using an unconditional logistic regression model. The frequency of allele 2 was 26.87 % in the NPC group, which was not significantly different from that of the control group (27.98 %, P = 0.867). Using the LAPTM4B 1/1 genotype as a reference, we found that the 1/2, 2/2 and 1/2 + 2/2 genotype were also not associated with the risk of NPC. No association was observed between LAPTM4B gene polymorphisms and the risk of NPC adjusted by gender and age. The results of our study indicated that the polymorphism of LAPTM4B gene did not influence the susceptibility of NPC in the Chinese population. Large-scale studies are needed to confirm our findings. PMID- 23345118 TI - Working memory differences in illusory recollection of critical lures. AB - In the present experiments, we explored the relationship between individual differences in working memory (WM) capacity and susceptibility to false recognitions and their accompanying subjective experiences. Deese/Roediger McDermott (DRM) associative lists were used to elicit false memories, and remember/know judgments were used to measure the recollective experiences accompanying recognition decisions. We found that WM capacity was related to false recognitions of nonpresented critical lures and to the proportion of remember responses given to critical lures, such that higher WM capacity was associated with lower false-recognition rates and with lower proportions of remember responses. Importantly, these WM differences were only found when participants were forewarned about the nature of the DRM task prior to encoding (Exp. 1). When the forewarning was absent, WM capacity was not related to false recognitions or to the proportion of remember responses given to critical lures (Exp. 2). These results support the controlled-attention view of WM and suggest that subjective experiences of falsely recognized lures fluctuate as a function of WM capacity. PMID- 23345119 TI - Primary healthcare professionals' experiences of the sick leave process: a focus group study in Sweden. AB - PURPOSE: The aim of this study was to explore primary healthcare (PHC) professionals' experiences of the sick leave process. METHODS: This is an explorative study using data from four semi-structured focus group discussions with a purposeful sample of PHC professionals in Ostergotland County, Sweden. Content analysis with an inductive approach was used in the analysis. RESULTS: Four key themes emerged from the analysis; priority to the sick leave process, handling sickness certifications, collaboration within PHC and with other stakeholders, and work ability assessments. Patients' need for sick leave was handled from each professional group's perspective. Collaboration was considered important, but difficult to achieve and all the competencies available at the PHC centre were not used for work ability assessments. There was insufficient knowledge of patients' work demands and contact with an employer was rare, and the strained relationship with the social insurance officers affected the collaboration. CONCLUSIONS: This study highlights the challenges physicians and other PHC professionals face when handling the need for sick leave, especially when encountering patients with symptom-based diagnoses, and the influence of non medical factors. Hindrances to good practice were increased demands, collaboration, and role responsibility. The challenges in the sick leave process concerned both content and consequences related to poor collaboration within PHC and with representatives from various organizations, primarily employers and social insurance officers. Further research on how to develop a professional approach for handling the sick leave process is needed. PMID- 23345120 TI - Objective preoperative estimation of the ability of primary closure on anterolateral thigh free flap donor site: circumference and area ratios of deep tissue to thigh. AB - PURPOSE: The purpose of this study was to consider the relationship between the ratio of deep tissue including muscle to thigh at donor sites and the possibility of performing primary closure of donor site. METHODS: The subjects were 74 patients who had harvesting of anterolateral thigh (ALT) free flap from June 2005 to June 2011. Primary closure was possible for 65 but not possible for 9. All received CT angiography of lower extremity before their operations. We measured circumference and cross-sectional area of thigh and deep tissue including muscle at the reference point. Using the measured data, we examined the ratio of circumference as well as cross-sectional area of deep tissue including muscles to thighs. RESULTS: For whom primary closure was possible, the ratio of deep tissue including muscle's circumference to thigh's at the reference point was 0.83 +/- 0.07 on average, and the ratio of cross-sectional area was 0.68 +/- 0.11. For whom primary closure was not possible, the ratio of circumference was 0.89 +/- 0.06 on average, and the cross-section areas was 0.8 +/- 0.07. The average width of flap for those with primary closure was 64.9 mm and without primary closure was 84.4 mm. There was statistical significance in ratios of circumference and cross-sectional area between primary closure and without primary closure. CONCLUSION: Primary closure of donor site when performing ALT free flap gets increasingly difficult as the ratio of deep tissue including muscle in the thighs increased. Such information prior to the procedure will be helpful in determining flap design and finalizing the operation plan. PMID- 23345121 TI - Coupled finite difference and boundary element methods for fluid flow through a vessel with multibranches in tumours. AB - A mathematical model and a numerical solution procedure are developed to simulate flow field through a 3D permeable vessel with multibranches embedded in a solid tumour. The model is based on Poisseuille's law for the description of the flow through the vessels, Darcy's law for the fluid field inside the tumour interstitium, and Starling's law for the flux transmitted across the vascular walls. The solution procedure is based on a coupled method, in which the finite difference method is used for the flow in the vessels and the boundary element method is used for the flow in the tumour. When vessels meet each other at a junction, the pressure continuity and mass conservation are imposed at the junction. Three typical representative structures within the tumour vasculature, symmetrical dichotomous branching, asymmetrical bifurcation with uneven radius of daughter vessels and trifurcation, are investigated in detail as case studies. These results have demonstrated the features of tumour flow environment by the pressure distributions and flow velocity field. PMID- 23345123 TI - Editorial--Resistance 2011. PMID- 23345122 TI - High-yield membrane protein expression from E. coli using an engineered outer membrane protein F fusion. AB - Obtaining high yields of membrane proteins necessary to perform detailed structural study is difficult due to poor solubility and variability in yields from heterologous expression systems. To address this issue, an Escherichia coli based membrane protein overexpression system utilizing an engineered bacterial outer membrane protein F (pOmpF) fusion has been developed. Full-length human receptor activity-modifying protein 1 (RAMP1) was expressed using pOmpF, solubilized in FC15 and purified to homogeneity. Using circular dichroism and fluorescence spectroscopy, purified full-length RAMP1 is composed of approximately 90% alpha-helix, and retains its solubility and structure in FC15 over a wide range of temperatures (20-60 degrees C). Thus, our approach provides a useful, complementary approach to achieve high-yield, full-length membrane protein overexpression for biophysical studies. PMID- 23345124 TI - Incidence of pyrethroid-resistant oilseed rape pests in Germany. AB - BACKGROUND: Failures in pollen beetle control using pyrethroids since 2005 indicated pyrethroid resistance in Germany. Therefore, resistance monitoring using bioassays was established in Germany for oilseed rape pest insects. RESULTS: The spread and intensity of pyrethroid resistance of Meligethes aeneus increased from 2005 onwards, with no sensitive samples left in any region of Germany in 2011. Sensitivity also declined for the newly introduced actives bifenthrin, etofenprox (both class-I pyrethroids) and tau-fluvalinate; all three claimed to be less affected by resistance, although there was no clear cross resistance to lambda-cyhalothrin (class-II pyrethroid). In the German region with the longest tradition and high intensity of oilseed rape production, pyrethroid resistance of Psylliodes chrysocephala and Ceutorhynchus obstrictus, with resistance factors of up to 81 and 140 respectively, was detected. CONCLUSION: The intensive use of only one mode of action for many years is risky, because even pest insects with a low intrinsic resistance risk may develop resistance. Therefore, resistance strategies need to include several control options for pest insects needing regular treatments. PMID- 23345125 TI - Conjugated oligoelectrolytes increase power generation in E. coli microbial fuel cells. AB - A series of conjugated oligoelectrolytes with structural variations is used to stain E. coli. By taking advantage of a high-throughput screening platform that incorporates gold anodes, it is found that MFCs with COE-modified E. coli generate significantly higher power densities, relative to unmodified E. coli. These findings highlight the potential of using water-soluble molecules inspired by the work on organic semiconductors to improve electrode/microbe interfaces. PMID- 23345129 TI - Surface area control and photocatalytic activity of conjugated microporous poly(benzothiadiazole) networks. PMID- 23345130 TI - A 19F NMR label to substitute polar amino acids in peptides: a CF3-substituted analogue of serine and threonine. PMID- 23345131 TI - Functionalizing alphavbeta3- or alpha5beta1-selective integrin antagonists for surface coating: a method to discriminate integrin subtypes in vitro. PMID- 23345132 TI - Androgen synthesis in patients with congenital adrenal hyperplasia due to 21 hydroxylase deficiency. AB - A hallmark of severe congenital adrenal hyperplasia due to 21-hydroxylase deficiency is pre- and postnatal virilization. The most characteristic biochemical abnormality is the elevation of 17alpha-hydroxyprogesterone, which is metabolized to the most potent androgen receptor agonist dihydrotestosterone. 17alpha-Hydroxyprogesterone can be metabolized to dihydrotestosterone via 4 androstenedione through the classical Delta4-pathway or via 17alpha hydroxypregnenolone and dehydroepiandrosterone through the classical Delta5 pathway, as well as through an alternative route, called the 'backdoor pathway', that bypasses dehydroepiandrosterone, 4-androstenedione, and testosterone as intermediates. This review article will summarize recent advances in the understanding of the activities of androgen synthesis pathways in patients with 21-hydroxylase deficiency obtained by urinary steroid metabolomics based on gas chromatography-mass spectrometry. Compared with healthy controls, the relative activities of the backdoor and Delta4-pathways increase in patients with congenital adrenal hyperplasia during neonatal age and infancy, whereas the activity of the Delta5-pathway remains unchanged. Thereafter, the activity of the Delta5-pathway dominates, whereas a decreasing 5alpha-reductase activity leads to a diminished role of the backdoor pathway for androgenic steroid production. Beside the backdoor pathway, the Delta4-pathway seems to be responsible for increased androgen generation in patients with 21-hydroxylase deficiency before the onset of adrenarche, whereas the Delta5-pathway might contribute to the increased androgen formation in those patients only after the onset of adrenarche. PMID- 23345135 TI - Preparation of reactive three-dimensional microstructures via direct laser writing and thiol-ene chemistry. AB - Three-dimensional microstructures are fabricated employing the direct laser writing process and radical thiol-ene polymerization. The resin system consists of a two-photon photoinitiator and multifunctional thiols and olefins. Woodpile photonic crystals with 22 layers and a rod distance of 2 MUm are fabricated. The structures are characterized via scanning electron microscopy and focused ion beam milling. The thiol-ene polymerization during fabrication is verified via infrared spectroscopy. The structures are grafted in a subsequent thiol-Michael addition reaction with different functional maleimides. The success of the grafting reaction is evaluated via laser scanning microscopy and X-ray photoelectron spectroscopy. The grafting density is calculated to be close to 200 molecules MUm(-2) . PMID- 23345133 TI - Oligodendrocyte N-methyl-D-aspartate receptor signaling: insights into its functions. AB - Myelination by oligodendrocytes facilitates rapid nerve conduction. Loss of oligodendrocytes and failure of myelination lead to nerve degeneration and numerous demyelinating white matter diseases. N-methyl-D-aspartate (NMDA) receptors, which are key regulators on neuron survival and functions, have been recently identified to express in oligodendrocytes, especially in the myelin sheath. NMDA receptor signaling in oligodendrocytes plays crucial roles in energy metabolism and myelination. In the present review, we highlight the subcellular location-specific impairment of excessive NMDA receptor signaling on oligodendrocyte energy metabolism in soma and myelin, and the mechanisms including Ca(2+) overload, acidotoxicity, mitochondria dysfunction, and impairment of respiratory chains. Conversely, physiological NMDA receptor signaling regulates differentiation and migration of oligodendrocytes. How can we use above knowledge to treat excitotoxic oligodendrocyte loss, congenital myelination deficiency, or postnatal demyelination? A thorough understanding of NMDA receptor signaling-mediated cellular events in oligodendrocytes at the pathophysiological level will no doubt aid in exploring effective therapeutic strategies for demyelinating white matter diseases. PMID- 23345134 TI - G proteins, p60TRP, and neurodegenerative diseases. AB - Alzheimer's disease (AD) is a complex brain disorder of the limbic system and association cortices. The disease is characterized by the production and deposition of the amyloid beta-peptide (Abeta) in the brain, and the neuropathological mechanisms involved must be deciphered to gain further insights into the fundamental aspects of the protein biology responsible for the development and progression of this disease. Abeta is generated by the intramembranous cleavage of the beta-amyloid precursor protein, which is mediated by the proteases beta- and gamma-secretase. Accumulating evidence suggests the importance of the coupling of this cleavage mechanism to G protein signaling. Heterotrimeric G proteins play pivotal roles as molecular switches in signal transduction pathways mediated by G protein-coupled receptors (GPCRs). Extracellular stimuli activate these receptors, which in turn catalyze guanosine triphosphate-guanosine diphosphate exchange on the G protein alpha-subunit. The activation-deactivation cycles of G proteins underlie their crucial functions as molecular switches for a vast array of biological responses. The novel transcription regulator protein p60 transcription regulator protein and its related GPCR signaling pathways have recently been described as potential targets for the development of alternative strategies for inhibiting the early signaling mechanisms involved in neurodegenerative diseases such as AD. PMID- 23345136 TI - Augmented Lagrange methods for quasi-incompressible materials--applications to soft biological tissue. AB - Arterial walls in the healthy physiological regime are characterized by quasi incompressible, anisotropic, hyperelastic material behavior. Polyconvex material functions representing such materials typically incorporate a penalty function to account for the incompressibility. Unfortunately, the penalty will affect the conditioning of the stiffness matrices. For high penalty parameters, the performance of iterative solvers will degrade, and when direct solvers are used, the quality of the solutions will deteriorate. In this paper, an augmented Lagrange approach is used to cope with the quasi-incompressibility condition. Here, the penalty parameter can be chosen much smaller, and as a consequence, the arising linear systems of equations have better properties. An improved convergence is then observed for the finite element tearing and interconnecting dual primal domain decomposition method, which is used as an iterative solver. Numerical results for an arterial geometry obtained from ultrasound imaging are presented. PMID- 23345137 TI - The spectrophotometric sulfo-phospho-vanillin assessment of total lipids in human meibomian gland secretions. AB - Human meibomian gland secretions (meibum) are the major lipid component of the human preocular tear film. The predominant lipid classes found in meibum include waxes (WE), cholesteryl esters (CE), and varying amounts of cholesterol (Chl). The classical sulfo-phospho-vanillin assay (SPVA), adapted for a microplate reader, was used to quantitate lipids in meibum. To account for varying reactivities of different lipids in SPVA, a model meibomian lipid mixture (MMx) that approximated the WE/CE/Chl composition of meibum was developed and used to quantitate meibomian lipids. The overall SPV responses of MMx and meibum were found to be close, with similar intermediate and final reaction products for both. Saturated WE that had not been expected to be reactive were found to be SPV positive. A reaction mechanism for these compounds in SPVA which involves the formation of alkenyl ethers is proposed and discussed. Tested proteins were non reactive in SPVA. Thus, by comparing the results of gravimetric analyses of meibum samples with the results of a properly calibrated SPVA, it was estimated that the SPV-reactive lipid content of dry meibum in tested samples was about 78 % (w/w). The SPV method can also be adopted for analyzing other types of complex lipids secretions, such as sebum, as well as whole lipid extracts from other lipid-enriched organs and tissues, if proper standards are chosen. PMID- 23345138 TI - Advanced techniques for constrained internal coordinate molecular dynamics. AB - Internal coordinate molecular dynamics (ICMD) methods provide a more natural description of a protein by using bond, angle, and torsional coordinates instead of a Cartesian coordinate representation. Freezing high-frequency bonds and angles in the ICMD model gives rise to constrained ICMD (CICMD) models. There are several theoretical aspects that need to be developed to make the CICMD method robust and widely usable. In this article, we have designed a new framework for (1) initializing velocities for nonindependent CICMD coordinates, (2) efficient computation of center of mass velocity during CICMD simulations, (3) using advanced integrators such as Runge-Kutta, Lobatto, and adaptive CVODE for CICMD simulations, and (4) cancelling out the "flying ice cube effect" that sometimes arises in Nose-Hoover dynamics. The Generalized Newton-Euler Inverse Mass Operator (GNEIMO) method is an implementation of a CICMD method that we have developed to study protein dynamics. GNEIMO allows for a hierarchy of coarse grained simulation models based on the ability to rigidly constrain any group of atoms. In this article, we perform tests on the Lobatto and Runge-Kutta integrators to determine optimal simulation parameters. We also implement an adaptive coarse-graining tool using the GNEIMO Python interface. This tool enables the secondary structure-guided "freezing and thawing" of degrees of freedom in the molecule on the fly during molecular dynamics simulations and is shown to fold four proteins to their native topologies. With these advancements, we envision the use of the GNEIMO method in protein structure prediction, structure refinement, and in studying domain motion. PMID- 23345139 TI - Unskilled and optimistic: overconfident predictions despite calibrated knowledge of relative skill. AB - Those who are less skilled tend to overestimate their abilities more than do those who are more skilled-the so-called Dunning-Kruger effect. Less-skilled performers presumably have less of the knowledge needed to make informed guesses about their relative performance. If so, the Dunning-Kruger effect should vanish when participants do have access to information about their relative ability and performance. Competitive bridge players predicted their results for bridge sessions before playing and received feedback about their actual performance following each session. Despite knowing their own relative skill and showing unbiased memory for their performance, they made overconfident predictions consistent with a Dunning-Kruger effect. This bias persisted even though players received accurate feedback about their predictions after each session. The finding of a Dunning-Kruger effect despite knowledge of relative ability suggests that differential self-knowledge is not a necessary precondition for the Dunning Kruger effect. At least in some cases, the effect might reflect a different form of irrational optimism. PMID- 23345140 TI - Weak Te,Te interactions through the looking glass of NMR spin-spin coupling. AB - Across the bay: J((125)Te, (125)Te) spin-spin coupling is a highly sensitive probe into the electronic and geometric structure of 1,8-peri-substituted naphthalene tellurium derivatives. The coupling is related to the onset of multicenter bonding in these systems. PMID- 23345141 TI - Solvent-induced delamination of a multifunctional two dimensional coordination polymer. AB - A coordination polymer is fully exfoliated by solvent-assisted interaction only. The soft-delamination process results from the structure of the starting material, which shows a layered structure with weak layer-to-layer interactions and cavities with the ability to locate several solvents in an unselective way. These results represent a significant step forward towards the production of structurally designed one-molecule thick 2D materials with tailored physico chemical properties. PMID- 23345142 TI - [Klinische monatsblatter 150 years side by side with the ophthalmologist]. PMID- 23345143 TI - [Highlights from the past from Klinische Monatsblatter fur Augenheilkunde]. PMID- 23345144 TI - [Highlights from the past from Klinische Monatsblatter fur Augenheilkunde]. PMID- 23345145 TI - [Editorial]. PMID- 23345146 TI - [Reconstructions after periorbital burn injuries]. AB - Nowadays burn patients who also have periocular symptoms are usually treated by reconstructive surgeons and the role of the ophthalmic surgeon has decreased.Although periocular complications occur in a minority of burned patients, they pose a greater challenge in surgical and non-surgical treatment. Chemical, electrical and thermal burns can lead to disfiguring scar formations and delayed treatment can lead to devastating ocular complications. Achieving a successful reconstruction requires a comprehensive approach, entailing many advanced techniques with an emphasis on preserving function and balancing intricate aesthetic requirements. The theory is illustrated in this article with clinical examples. PMID- 23345147 TI - [Surgical treatment of upper lid entropion -- selected aspects]. AB - The upper lid entropion is a rare eyelid malposition in which the external lid margin turns inward against the ocular surface. It may be classified as congenital (tarsal malformation, hypoplasia of tarsus, eyelid hyperlaxity) but is more commonly an acquired condition (traumatic, immunopathological, inflammation, involutional forms). Surgery is the treatment of choice for correction of upper lid entropion. Appropriate surgical techniques are available for the respective conditions. This article gives an overview of the most commonly used treatment strategies including non-surgical and surgical procedures. Transcutaneous and intermarginal access routes have proven to be safe methods for minimal or moderate upper lid entropion. Combined surgical procedures (e.g., rotation of tarsoconjunctiva, posterior lamellar graft, everting sutures and autologous cultivated oral mucosal epithelial transplantation and so on) should be applied as treatment strategies for severe upper lid entropion with cicatricial changes in the tarsoconjunctival layer, shortage of posterior lamella and severe ocular surface disease. PMID- 23345148 TI - [Eyelid nevi: differential diagnosis and surgical treatment]. AB - Congenital nevi are very rare. Acquired nevi belong to the most common group of skin tumours. Eyelid nevi occur frequently in a great variety. They are treated for cosmetic reasons or due to the risk of malignant transformation. This contribution explains the differential diagnosis of various types of nevus and the surgical techniques of resection and plastic reconstruction. PMID- 23345149 TI - [Development of oculoplastic surgery in Kinshasa (capital of Democratic Republic of Congo)]. AB - The partnership between Saint Joseph Hospital in Kinshasa (Capital city of DRC) and University Eye Clinic Rostock, Germany exists since 2000. The ophthalmologists from Rostock University performed 12 visits of St. Josef Hospital with the aim to perform oculoplastic surgery in complicated cases as well as to teach the local ophthalmologists. There they performed about 150 surgeries (entropion, ectropion, ptosis, repair of lid injuries, eye lid reconstruction and tumour management, lacrimal surgery) in joint teams. The programme of on-site training was established during this time. Meanwhile, the Kinshasa colleagues are able to perform the basic techniques by themselves. Two colleagues have obtained advanced training in oculoplastics in Rostock. The fruitful cooperation enabled the development of oculoplastic surgery in St. Josef Hospital in Kinshasa. The further education and training proccesses will support the continuous advancement in ophthalmological health care in DRC. PMID- 23345150 TI - [The modern body image as ethical device for biomedical enhancement]. AB - Ovid's "De medicamine faciei feminae" contains the astonishing sentence "Culta placent - all that is artificial is beautiful". In his "Eloge du maquillage" Baudelaire, buidling on Ovid's argument, states that first culture as picture and construction of beauty brings forth the truth of Nature and claims that cosmetics that allow errors of beauty to disappear artificially produce the true fulfillment of human nature. The present article looks into the historical roots of the body images that have emerged in modern times and attempts to derive structural devices for an ethical assessment of the potential we have to enhance human nature. PMID- 23345151 TI - [Pathological conditions of the ocular surface -- a clinical and confocal laser scanning microscopy study]. AB - Confocal in vivo laser scanning microscopy is an established technique to visualise morphology of the cornea and conjunctiva, whereby the image interpretation needs experience. We report about changes of the ocular surface in the pathological conditions of infectious, metabolic and traumatic genesis and discuss their relevance. The micromorphology of the corneal epithelium and stroma in respect to pathogens (bacterial, fungal) is discussed. Metabolic disease induces multifaceted corneal alterations which can be visualised and used for assessment of the disease progression. Follow-up microscopic investigations allow for an assessment of the wound healing dynamics and enable a prognosis to be made for corneal recurrence. Taken together, confocal in vivo microscopy allows a non invasive microscopy on the cellular level and thus complements clinical diagnostics. PMID- 23345153 TI - A look at recent improvements in the durability of tissue valves. AB - BACKGROUND: The various uses of biological valves for either aortic or mitral valve replacement have recently increased because of the growing proportion of elderly patients requiring surgery. RESULTS: The durability of recent xenografts has been reported to be over 90 % at 10 years after aortic or mitral valve replacement for elderly patients more than 65 years of age, and therefore the guidelines now recommend the use of bioprostheses for patients over 65 years of age. Bioprostheses are also recommended for valve replacement of the right side of the heart by several authors; however, no clear guidelines are available. Trans-catheter aortic valve replacement and percutaneous pulmonary valve implantation are promising procedures for high-risk patients, although evaluation of the long-term durability of these valves is mandatory. CONCLUSIONS: This article will review the development of the tissue valve for valve surgery. PMID- 23345154 TI - Epithelioid inflammatory myofibroblastic sarcoma arising in the pleural cavity. AB - A 57-year-old Japanese man presented with massive right pleural effusion, and a huge tumor arising in the pleural cavity was detected by chest computed tomography. A thoracoscopic tumor biopsy revealed that the tumor protruded extensively into the pleural cavity, and its gross appearance was cystic and glossy. Microscopically, the tumor cells were rounded and epithelioid in shape. Prominent and abundant myxoid stroma was also present together with an inflammatory infiltrate, and the tumor was anaplastic lymphoma kinase (ALK) immunopositive. Fluorescence in situ hybridization revealed that the Ran-binding protein 2-ALK fusion gene was present. Taken together, these findings supported the diagnosis of epithelioid inflammatory myofibroblastic sarcoma (EIMS), which is a variant of an inflammatory myofibrobrastic tumor. This is the first reported case of an EIMS arising in the pleural cavity. PMID- 23345155 TI - Message passing interface and multithreading hybrid for parallel molecular docking of large databases on petascale high performance computing machines. AB - A mixed parallel scheme that combines message passing interface (MPI) and multithreading was implemented in the AutoDock Vina molecular docking program. The resulting program, named VinaLC, was tested on the petascale high performance computing (HPC) machines at Lawrence Livermore National Laboratory. To exploit the typical cluster-type supercomputers, thousands of docking calculations were dispatched by the master process to run simultaneously on thousands of slave processes, where each docking calculation takes one slave process on one node, and within the node each docking calculation runs via multithreading on multiple CPU cores and shared memory. Input and output of the program and the data handling within the program were carefully designed to deal with large databases and ultimately achieve HPC on a large number of CPU cores. Parallel performance analysis of the VinaLC program shows that the code scales up to more than 15K CPUs with a very low overhead cost of 3.94%. One million flexible compound docking calculations took only 1.4 h to finish on about 15K CPUs. The docking accuracy of VinaLC has been validated against the DUD data set by the re-docking of X-ray ligands and an enrichment study, 64.4% of the top scoring poses have RMSD values under 2.0 A. The program has been demonstrated to have good enrichment performance on 70% of the targets in the DUD data set. An analysis of the enrichment factors calculated at various percentages of the screening database indicates VinaLC has very good early recovery of actives. PMID- 23345156 TI - Hyoid osteoradionecrosis associated with carotid rupture: report of 2 cases. AB - BACKGROUND: Osteoradionecrosis (ORN) of the hyoid bone is a rare but reported complication of head and neck irradiation. Here we describe 2 cases in which carotid rupture was associated with hyoid ORN. METHODS: This study was conducted through a retrospective chart review and case reports of 2 patients. RESULTS: Both patients had a history of radiation therapy for head and neck cancer; 1 patient had undergone previous surgical resection. Both patients had a history of painful swelling in the neck preceding presentation with hemorrhage. Acute hemorrhage was controlled in all patients using a combination of techniques including embolization, stent grafting, and vessel ligation. CONCLUSION: ORN of the hyoid can be associated with life-threatening carotid rupture. In patients with a history of head and neck irradiation who present with painful swelling in the region of the hyoid, this entity should be considered. Early intervention may prevent subsequent rupture of the carotid artery and hemorrhage. PMID- 23345157 TI - Proton conduction in metal-organic frameworks and related modularly built porous solids. AB - Proton-conducting materials are an important component of fuel cells. Development of new types of proton-conducting materials is one of the most important issues in fuel-cell technology. Herein, we present newly developed proton-conducting materials, modularly built porous solids, including coordination polymers (CPs) or metal-organic frameworks (MOFs). The designable and tunable nature of the porous materials allows for fast development in this research field. Design and synthesis of the new types of proton-conducting materials and their unique proton conduction properties are discussed. PMID- 23345158 TI - Cleaved iron oxide nanoparticles as T2 contrast agents for magnetic resonance imaging. AB - Iron oxide nanoparticles as contrast agents are reported to effectively improve magnetic resonance imaging of tissues and cells. In this work, cleaved iron oxide nanoparticles (CIONPs) were generated from hydrophobic FeO nanoparticles (HIONPs) by coating their surfaces with PEG-phospholipids, oxidizing them under water, and slowly removing the residual FeO phase in phthalate buffer. The synthesized CIONPs showed good r2 values of up to 258 s(-1) mM(-1). Thus, the CIONPs can be employed as vectors for drug delivery due to their unique structure with an empty inner space, which enables their use in a wide range of applications. PMID- 23345159 TI - Patient-specific computational biomechanics of the brain without segmentation and meshing. AB - Motivated by patient-specific computational modelling in the context of image guided brain surgery, we propose a new fuzzy mesh-free modelling framework. The method works directly on an unstructured cloud of points that do not form elements so that mesh generation is not required. Mechanical properties are assigned directly to each integration point based on fuzzy tissue classification membership functions without the need for image segmentation. Geometric integration is performed over an underlying uniform background grid. The verification example shows that, while requiring no hard segmentation and meshing, the proposed model gives, for all practical purposes, equivalent results to a finite element model. PMID- 23345160 TI - Multimodal elucidation of choline metabolism in a murine glioma model using magnetic resonance spectroscopy and 11C-choline positron emission tomography. AB - The metabolites, transporters, and enzymes involved in choline metabolism are regarded as biomarkers for disease progression in a variety of cancers, but their in vivo detection is not ideal. Both magnetic resonance spectroscopy [MRS using chemical shift imaging (CSI) total choline (tCho)] and C-choline positron emission tomography (PET) can probe this pathway, but they have not been compared side by side. In this study, we used the spontaneous murine astrocytoma model SMA560 injected intracranially into syngeneic VM/Dk mice, analyzing animals at various postimplantation time points using dynamic microPET imaging and CSI MRS. We observed an increase in tumor volume and C-choline uptake between days 5 and 18. Similarly, tCho levels decreased at days 5 to 18. We found a negative correlation between the tCho and PET results in the tumor and a positive correlation between the tCho tumor-to-brain ratio and choline uptake in the tumor. PCR results confirmed expected increases in expression levels for most of the transporters and enzymes. Using MRS quantification, a good agreement was found between CSI and C-choline PET data, whereas a negative correlation occurred when CSI was not referenced. Thus, C-choline PET and MRS methods seemed to be complementary in strengths. While advancing tumor proliferation caused an increasing C-choline uptake, gliosis and inflammation potentially accounted for a high peritumoral tCho signal in CSI, as supported by histology and secondary ion mass spectrometry imaging. Our findings provide definitive evidence of the use of MRS, CSI, and PET for imaging tumors in vivo. PMID- 23345161 TI - LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. AB - Tumor metastasis is a highly complex, dynamic, and inefficient process involving multiple steps, yet it accounts for more than 90% of cancer-related deaths. Although it has long been known that fibrotic signals enhance tumor progression and metastasis, the underlying molecular mechanisms are still unclear. Identifying events involved in creating environments that promote metastatic colonization and growth are critical for the development of effective cancer therapies. Here, we show a critical role for lysyl oxidase (LOX) in establishing a milieu within fibrosing tissues that is favorable to growth of metastastic tumor cells. We show that LOX-dependent collagen crosslinking is involved in creating a growth-permissive fibrotic microenvironment capable of supporting metastatic growth by enhancing tumor cell persistence and survival. We show that therapeutic targeting of LOX abrogates not only the extent to which fibrosis manifests, but also prevents fibrosis-enhanced metastatic colonization. Finally, we show that the LOX-mediated collagen crosslinking directly increases tumor cell proliferation, enhancing metastatic colonization and growth manifesting in vivo as increased metastasis. This is the first time that crosslinking of collagen I has been shown to enhance metastatic growth. These findings provide an important link between ECM homeostasis, fibrosis, and cancer with important clinical implications for both the treatment of fibrotic disease and cancer. PMID- 23345162 TI - Heterogeneity of neoplastic stem cells: theoretical, functional, and clinical implications. AB - Accumulating evidence suggests that human cancers develop through a step-wise, but nonlinear process of cellular diversification and evolution. Recent mutational analyses indicate that this process is more complex and diverse than anticipated before whole-genome sequencing methods were readily available. Examples are also emerging now of genetically abnormal clones of cells that have acquired mutations with known oncogenic potential but, nevertheless, may show no manifestations of malignant change for many years. To accommodate these diverse realities, we suggest the term neoplastic refer to clones of cells that have any type of somatic aberrancy associated with an increased propensity to become malignant, and the derivative term neoplastic stem cell be adopted to identify the cells responsible for the long-term maintenance of such clones. Neoplastic clones would thus include those that never evolve further, as well as those that eventually give rise to fully malignant populations, and all stages in between. The term cancer stem cells would then be more appropriately restricted to cells generating subclones that have established malignant properties. More precise molecular understanding of the different stem cell states thus distinguished should contribute to the development of more effective prognostic and therapeutic tools for cancer diagnosis and treatment. PMID- 23345163 TI - Natural human plasmacytoid dendritic cells induce antigen-specific T-cell responses in melanoma patients. AB - Vaccination against cancer by using dendritic cells has for more than a decade been based on dendritic cells generated ex vivo from monocytes or CD34(+) progenitors. Here, we report on the first clinical study of therapeutic vaccination against cancer using naturally occurring plasmacytoid dendritic cells (pDC). Fifteen patients with metastatic melanoma received intranodal injections of pDCs activated and loaded with tumor antigen-associated peptides ex vivo. In vivo imaging showed that administered pDCs migrated and distributed over multiple lymph nodes. Several patients mounted antivaccine CD4(+) and CD8(+) T-cell responses. Despite the limited number of administered pDCs, an IFN signature was observed after each vaccination. These results indicate that vaccination with naturally occurring pDC is feasible with minimal toxicity and that in patients with metastatic melanoma, it induces favorable immune responses. PMID- 23345164 TI - Modelling the impact of old and new mechanisms of entry and selection to medical school in Ireland: who gets in? AB - BACKGROUND: Several changes to entry and selection to medical school in Ireland were introduced in 2009 including the addition of a specialised admission test the Health Professionals Admissions Test (HPAT-Ireland). AIMS: We wished to determine the impact of each aspect of the reforms by modelling outcomes if old and new mechanism had prevailed, the extent to which applicants and entrants repeated the leaving certificate, and leaving certificate and HPAT-Ireland scores of successful candidates. METHODS: The leaving certificate and HPAT scores of all medical school applicants and entrants in 2009 and 2010 were analysed. RESULTS: Data were available for 2,913 applicants in 2009 and 3,292 applicants in 2010. In 2009, over 33% of students admitted to medicine would not have been admitted if the decision was based solely on their leaving certificate. The corresponding figure for 2010 was 44%. In 2009, if entry had been based on the combined HPAT Ireland and an un-moderated leaving certificate score, this would have affected the outcomes in 5% of applicants or 25% of those who secured a medical school place. The corresponding figures for 2010 are 6 and 24%, respectively. Since 2009 applicants and entrants are far less likely to repeat the leaving certificate examination. HPAT-Ireland entry scores appear relatively stable while leaving certificate scores have varied in an upward direction. CONCLUSIONS: All of the reforms to medical school admission have contributed significantly in determining outcomes. The addition of the HPAT-Ireland adjunct admission test equates with the impact of moderation of leaving certificate points. PMID- 23345165 TI - Transepithelial transport of a natural cholinesterase inhibitor, huperzine A, along the gastrointestinal tract: the role of ionization on absorption mechanism. AB - During recent years there has been increasing interest in the Lycopodium alkaloid huperzine A as a potential therapeutic agent for neurodegenerative diseases. This study aimed to characterize huperzine A's permeability across the enterocyte barrier along the gastrointestinal tract with an emphasis on the effect of ionization on the drug absorption. Intestinal permeability of huperzine A was evaluated by in vitro Caco-2 and parallel artificial membrane permeation assay models and by the ex vivo Ussing chamber model. The permeability rate was strongly dependent on the degree of ionization and increased with elevation of the donor medium pH in all studied models. The transport of the unionized fraction was similar to the permeability of the markers for passive transcellular diffusion. Addition of the paracellular permeability modulator palmitoylcarnitine in the Caco-2 model led to significant enhancement in the permeability of the ionized huperzine A fraction. No evidence of active transport of huperzine A was detected in this study. The Ussing chamber model experiments showed similar drug permeability along the entire rat intestine. In conclusion, huperzine A permeates the intestinal border mainly by passive transcellular diffusion whereas some fraction, dependent on the degree of huperzine A ionization, is absorbed by the paracellular route. Huperzine A's permeability characteristics pave the way to the development of its oral extended release dosage form. The specific population of the potential users of huperzine A and the high potency of this molecule support the rationale for such a delivery. PMID- 23345166 TI - Isolation and synthesis of melodamide A, a new anti-inflammatory phenolic amide from the leaves of Melodorum fruticosum. AB - Together with twelve known compounds (2-13), melodamide A (1), a new phenolic amide possessing p-quinol moiety, was purified and characterized from the methanolic extracts of the leaves of Melodorum fruticosum. The structure of melodamide A (1) was established with a combination of 2D NMR experiments, HR-ESI MS and X-ray analyses. The other known compounds were identified by comparison of their spectroscopic and physical data with those reported in the literature. Moreover, some isolated compounds were examined for their inhibitory activity towards superoxide anion generation and elastase release in human neutrophils. Among the tested compounds, 1, 3, and 5 exhibited strong inhibition of superoxide anion generation with IC50 values ranging from 5.25 to 8.65 uM. Furthermore, synthesis and biological evaluation of melodamide A (1) and its analogs (14a-p) were described. PMID- 23345167 TI - Characterisation of Nox4 inhibitors from edible plants. AB - NADPH oxidases transport electrons from cytosolic NADPH through biological membranes to generate reactive oxygen species. NADPH oxidase 4, broadly expressed in humans, is an interesting pharmacological target, since its activity is deregulated in several diseases, including pulmonary fibrosis, diabetic nephropathy, and cardiac hypertrophy. Whereas several candidate NADPH oxidase 4 inhibitors were recently described, most of these compounds are either unspecific or toxic. Here we set out to identify new NADPH oxidase 4 inhibitors from edible plants, in an attempt to decrease the number of hits with toxic side effects. We screened a compound library prepared from edible plants for new bioactives with the ability to inhibit the activity of NADPH oxidase 4. Using both cell-based and cell-free assays, we identified several compounds with significant inhibitory activity towards NADPH oxidase 4. For selected compounds, the activity profile towards NADPH oxidase 2 and NADPH oxidase 5 was established, and controls were carried out to exclude general reactive oxygen species scavengers. A number of promising NADPH oxidase 4 inhibitors from edible plants was identified and characterised. Several new chemical entities are disclosed which act as NADPH oxidase 4 inhibitors, and the efficacies of our best hits, in particular several diarylheptanoids and lignans, are comparable to the best available pharmacological NADPH oxidase 4 inhibitors. These findings will provide valuable tools to study mechanisms of NADPH oxidase inhibition. PMID- 23345168 TI - Blocking the proliferation of human tumor cell lines by peptidase inhibitors from Bauhinia seeds. AB - In cancer tumors, growth, invasion, and formation of metastasis at a secondary site play a pivotal role, participating in diverse processes in the development of the pathology, such as degradation of extracellular matrix. Bauhinia seeds contain relatively large quantities of peptidase inhibitors, and two Bauhinia inhibitors were obtained in a recombinant form from the Bauhinia bauhinioides species, B. bauhinoides cruzipain inhibitor, which is a cysteine and serine peptidase inhibitor, and B. bauhinioides kallikrein inhibitor, which is a serine peptidase inhibitor. While recombinant B. bauhinoides cruzipain inhibitor inhibits human neutrophil elastase cathepsin G and the cysteine proteinase cathepsin L, recombinant B. bauhinioides kallikrein inhibitor inhibits plasma kallikrein and plasmin. The effects of recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor on the viability of tumor cell lines with a distinct potential of growth from the same tissue were compared to those of the clinical cytotoxic drug 5-fluorouracil. At 12.5 uM concentration, recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor were more efficient than 5-fluorouracil in inhibiting MKN-28 and Hs746T (gastric), HCT116 and HT29 (colorectal), SkBr-3 and MCF-7 (breast), and THP-1 and K562 (leukemia) cell lines. Additionally, recombinant B. bauhinoides cruzipain inhibitor inhibited 40 % of the migration of Hs746T, the most invasive gastric cell line, while recombinant B. bauhinioides kallikrein inhibitor did not affect cell migration. Recombinant B. bauhinioides kallikrein inhibitor and recombinant B. bauhinoides cruzipain inhibitor, even at high doses, did not affect hMSC proliferation while 5-fluorouracil greatly reduced the proliferation rates of hMSCs. Therefore, both recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor might be considered for further studies to block peptidase activities in order to target specific peptidase-mediated growth and invasion characteristics of individual tumors, mainly in patients resistant to 5 fluorouracil chemotherapy. PMID- 23345169 TI - 5-Geranyloxy-7-methoxycoumarin inhibits colon cancer (SW480) cells growth by inducing apoptosis. AB - For the first time, three coumarins were isolated from the hexane extract of limes (Citrus aurantifolia) and purified by flash chromatography. The structures were identified by NMR (1D, 2D) and mass spectral analyses as 5-geranyloxy-7 methoxycoumarin, limettin, and isopimpinellin. These compounds inhibited human colon cancer (SW-480) cell proliferation, with 5-geranyloxy-7-methoxycoumarin showing the highest inhibition activity (67 %) at 25 uM. Suppression of SW480 cell proliferation by 5-geranyloxy-7-methoxycoumarin was associated with induction of apoptosis, as evidenced by annexin V staining and DNA fragmentation. In addition, 5-geranyloxy-7-methoxycoumarin arrested cells at the G0/G1 phase, and induction of apoptosis was demonstrated through the activation of tumour suppressor gene p53, caspase8/3, regulation of Bcl2, and inhibition of p38 MAPK phosphorylation. These findings suggest that 5-geranyloxy-7-methoxycoumarin has potential as a cancer preventive agent. PMID- 23345170 TI - p16 expression in carcinoma of unknown primary: diagnostic indicator and prognostic marker. AB - BACKGROUND: Carcinoma of unknown primary (CUP) of the neck are heterogeneous tumors in their clinical and biological characteristics, and a preoperative prognostic marker is desirable to optimize staging and therapy and to improve outcome and survival. For CUP syndrome, no optimized diagnostic and treatment strategy or biomarker have yet been determined. METHODS: Forty-seven patients presenting with CUP syndrome were analyzed after thorough standard diagnostic staging procedures. All patients were surgically treated with tonsillectomy, neck dissection of the diseased neck, as well as adjuvant chemoradiation. The tissue of lymph node metastases (and, if found, of the primary tumor) was analyzed regarding expression of p16, epidermal growth factor receptor (EGFR), and presence of human papillomavirus (HPV) DNA. RESULTS: In 39% of all cases (20 of 47), the primary cancer was found during diagnostic workup. If HPV DNA was detected in the neck lymph node metastasis, the primary cancer was significantly more frequently found in the oropharynx (p = .002). Patients with a p16-positive tumor had a significantly higher 5-year overall survival (OS; 33% vs 69%; p = .045, disease-free survival [DSF] 77% vs 89%; p = not significant [NS]). Patients with p16-positive neck metastasis and no detectable primary cancer had a better prognosis. Expression of EGFR in this series did not have a significant effect on prognosis. CONCLUSION: In patients presenting with CUP syndrome, p16 immunohistochemistry can serve to locate the primary cancer in the oropharynx. It is a positive prognostic indicator in patients with those heterogeneous cancers. PMID- 23345171 TI - Adjustment of Born-Oppenheimer electronic wave functions to simplify close coupling calculations. AB - Technical problems connected with use of the Born-Oppenheimer clamped-nuclei approximation to generate electronic wave functions, potential energy surfaces (PES), and associated properties are discussed. A computational procedure for adjusting the phases of the wave functions, as well as their order when potential crossings occur, is presented which is based on the calculation of overlaps between sets of molecular orbitals and configuration interaction eigenfunctions obtained at neighboring nuclear conformations. This approach has significant advantages for theoretical treatments describing atomic collisions and photo dissociation processes by means of ab initio PES, electronic transition moments, and nonadiabatic radial and rotational coupling matrix elements. It ensures that the electronic wave functions are continuous over the entire range of nuclear conformations considered, thereby greatly simplifying the process of obtaining the above quantities from the results of single-point Born-Oppenheimer calculations. The overlap results are also used to define a diabatic transformation of the wave functions obtained for conical intersections that greatly simplifies the computation of off-diagonal matrix elements by eliminating the need for complex phase factors. PMID- 23345172 TI - Structural accelerating effect of chloride on copper electrodeposition. AB - Under the microscope: In situ, video-rate scanning-tunneling-microscopy imaging during Cu electrodeposition reveals a profound structural accelerating effect of Cl(-) on the deposition process. This effect could be present in systems with different metals and different additives. The structural accelerating effect is important for the fundamental understanding of electrodeposition phenomena and for applications in industry. PMID- 23345173 TI - Supramolecular polymerization of C3-symmetric organogelators: cooperativity, solvent, and gelation relationship. AB - A systematic study of the influence of solvent and the size of C(3)-symmetric discotics on their supramolecular polymerization mechanism is presented. The cooperativity of the self-assembly of the reported compounds is directly related to their gelation ability. The two series of C(3)-symmetric discotics investigated herein are based on benzene-1,3,5-tricarboxamides (BTAs) and oligo(phenylene ethynylene)-based tricarboxamides (OPE?TAs) that are peripherally decorated with achiral (1a and 2a) or chiral N-(2-aminoethyl)-3,4,5 trialkoxybenzamide units (1b and 2b). The supramolecular polymerization of compounds 1a,b and 2a,b has been exhaustively investigated in a number of solvents and by using various techniques: variable-temperature circular dichroism (VT-CD) spectroscopy, concentration-dependent (1)H NMR spectroscopy, and isothermal titration calorimetry (ITC). The supramolecular polymerization mechanism of compounds 2 is highly cooperative in solvents such as methylcyclohexane and toluene and is isodesmic in CHCl(3). Unexpectedly, chiral compound 1b is practically CD-silent, in contrast with previously reported BTAs. ITC measurements in CHCl(3) demonstrated that the supramolecular polymerization of BTA 1a is isodesmic. These results confirm the strong influence of the pi surface of the central aromatic core of the studied discotic and the branched nature of the peripheral side chains on the supramolecular polymerization. The gelation ability of these organogelators is negated in CHCl(3), in which the supramolecular polymerization mechanism is isodesmic. PMID- 23345174 TI - Influence of bypass angles on extracardiac Fontan connections: a numerical study. AB - The extracardiac Fontan connection (EFC) is an effective treatment for congenital single ventricle heart defects. Numerous studies have sought to optimize the EFC design. However, the optimal design of EFC remains uncertain. This study aims to examine the influence of bypass angles between the inferior vena cava (IVC) and right pulmonary artery (RPA), and the angles between the IVC and superior vena cava (SVC), on hemodynamics. Furthermore, this study demonstrates a methodology for cardiovascular surgical planning. First, a three-dimensional anatomical geometry was reconstructed from the medical images of a patient with single ventricle heart defects. Second, based on haptic deformations, six computational models were virtually generated. Third, numerical simulations were conducted using computational fluid dynamics through the finite volume method. Finally, hemodynamic parameters were obtained and evaluated. The hemodynamic parameters, including the flow patterns, streamlines, and swirling flow, were obtained. Meanwhile, the energy loss and flow distributions of vena cava blood were calculated. First, the hepatic artery blood distribution to two lungs and the flow ratio of the left pulmonary artery to RPA are sensitive to the angle between the IVC and RPA and not to that between the IVC and SVC. Second, energy dissipation is mainly sensitive to the angle between the IVC and SVC and not to that between the IVC and RPA. Third, an appropriate increase in the angle between the IVC and RPA or that between the IVC and SVC may lead to optimal options. This study is useful for surgeons in evaluating optimal Fontan options. PMID- 23345175 TI - Complex pectus excavatum in adults: which is the best solution? PMID- 23345176 TI - Currently, children with congenital heart disease are not limited in their submaximal exercise performance. AB - OBJECTIVES: In several former studies, adolescents and adults with congenital heart disease (CHD) had a reduced exercise capacity even with defects considered to be simple. Currently, children might get better medical management and less restrictions concerning an active lifestyle or sports activities. The exercise performance of this new generation of children with CHD has to be evaluated. METHODS: In the year 2010, 88 children (12.7 years, 52 males), 11-14 years old, with various CHD performed a cardiopulmonary exercise test in our institution. These children were matched for age and gender with healthy subjects who underwent the same procedure at a school survey. RESULTS: In comparison with healthy controls, children with CHD had a diminished peak oxygen uptake (CHD: 35.5 ml/min/kg vs controls: 42.4 ml/min/kg; P < 0.001) corresponding to 87.1% (CHD) and 99.5% (Controls) of the reference value, respectively. Peak oxygen uptake decreased with the severity of the heart defect (r = -0.410; P < 0.001). However, there was no difference in oxygen uptake at the ventilatory threshold (CHD: 20.6 ml/min/kg vs controls: 21.5 ml/min/kg; P = 0.68). CONCLUSIONS: Currently, children with CHD are not limited in their submaximal exercise performance. However, there is still a reduction in peak oxygen uptake. PMID- 23345177 TI - Secondary mitral regurgitation in patients undergoing aortic valve replacement. PMID- 23345178 TI - Management of moderate secondary mitral regurgitation at the time of aortic valve surgery. AB - OBJECTIVES: To define the impact of surgical strategy [concomitant mitral valve surgery or isolated aortic valve replacement (AVR)] in patients with moderate secondary mitral regurgitation (MR) at the time of AVR. METHODS: From January 1999 to December 2009, 3339 patients underwent AVR of whom 255 had secondary MR >2+ and constituted the study population. Patients were stratified into two groups, with (Group A, n = 94, 36.8%) and without concomitant mitral valve surgery (Group B, n = 161, 63.2%). Follow-up up to 12 years (1076 patient-years) was analysed for survival, valve-related events and persistent MR. Predictors of late mortality and persistent MR were further analysed. A case-match analysis [age, gender, New York Heart Association (NYHA) and left ventricular ejection fraction] was performed, excluding patients with coronary artery disease (CAD). RESULTS: The mean age of the population was 67.0 +/- 11.7 years, 63.5% male and 64.7% in NYHA III-IV. Group B patients were significantly older and had higher incidence of coronary disease, hypertension and mitral calcification. They also had a higher ejection fraction and transaortic gradients, and lower MR grade (mean MR: 2.8 vs 3.2) and pulmonary artery pressure. Mitral surgery consisted mainly of annuloplasty procedures (96%). Only 2 patients from the entire cohort were reoperated on/for the mitral valve. Thirty-day mortality rate was 0.3%. There was no difference in long-term survival and valve-related complications, even after case-matched analysis. CAD, history of cerebrovascular accident, permanent atrial fibrillation, renal failure and persistence of MR emerged as independent predictors of late mortality (P < 0.05). MR improved in 67.4% of patients from Group B against 82.3% from Group A (P = 0.011). Atrial fibrillation (AF) and higher MR grade at discharge were the only independent predictors for persistent MR (P < 0.05). Patients with persistent MR early after AVR had decreased late survival (hazard ratio: 4.9, P = 0.001). CONCLUSIONS: Secondary MR improves after AVR even without mitral surgery. Concomitant mitral surgery was significantly associated with greater improvement of postoperative MR, but had no significant impact on survival. However, patients who did not improve immediately after AVR had compromised survival. Patients in AF should have mitral valve repair at the time of surgery. PMID- 23345179 TI - Bilateral lobar lung transplantation and size mismatch by pTLC-ratio. PMID- 23345180 TI - Transapical transcatheter aortic valve implantation vs conventional aortic valve replacement in high-risk patients with previous cardiac surgery: a propensity score analysis. AB - OBJECTIVES: The present analysis compared clinical and mid-term outcomes of patients with previous cardiac surgery undergoing transapical transcatheter aortic valve implantation (TAVI) with propensity-matched patients undergoing conventional redo aortic valve replacement (cAVR). METHODS: Since 2008, 508 patients were treated with TAVI. Fifty-three of these patients presented with a history of cardiac surgery and underwent transapical TAVI using the Edwards SAPIEN bioprosthesis. A propensity-matched control group of 53 patients receiving cAVR was generated out of the hospital's database. The mean age for all the patients was 77.8 +/- 4.5 years. The logistic EuroSCORE was 28.4 +/- 13.6% in mean, and mean EuroSCORE II was 8.56 +/- 3.93%. The mean follow-up time was 245 +/- 323 days, which equated to a total of 700 patient-months. RESULTS: The observed hospital mortality did not differ significantly between TAVI and cAVR (TAVI: 9.4% and cAVR: 5.7%; P = 0.695). Six-month survival was 83.0% for the TAVI and 86.8% for the cAVR patients (P = 0.768). Postoperative bleedings (TAVI: 725 +/- 1770 ml and cAVR: 1884 +/- 6387; P = 0.022), the need for transfusion (TAVI: 1.7 +/- 5.3 vs cAVR: 6.2 +/- 13.7 units packed red blood cells (PRBC); P = 0.030), consecutive rethoracotomy (TAVI: 1.9% vs cAVR: 16.9%; P = 0.002) and postoperative delirium (TAVI: 11.5% vs cAVR: 28.3%; P = 0.046) were more common in the cAVR patients. The TAVI patients suffered more frequently from respiratory failure (TAVI: 11.3% vs cAVR: 0.0%; P = 0.017) and mean grade of paravalvular regurgitation (TAVI: 0.8 +/- 0.2 vs cAVR: 0.0; P = 0.047). Although primary ventilation time (P = 0.020) and intensive care unit stay (P = 0.022) were shorter in the TAVI patients, mean hospital stay did not differ significantly (P = 0.108). CONCLUSIONS: Transapical TAVI as well as surgical aortic valve replacement provided good clinical results. The pattern of postoperative morbidity and mortality was different for both entities, but the final clinical outcome did not differ significantly. Both techniques can be seen as complementary approaches by means of developing a tailor-made and patient orientated surgery. PMID- 23345181 TI - Editorial comment: Ventricular assist devices for advanced heart failure: evidence that cannot be ignored. PMID- 23345182 TI - Use of the model for end-stage liver disease score for guiding clinical decision making in the selection of patients for emergency cardiac transplantation. AB - OBJECTIVES: The outcomes of emergency cardiac transplantation remain controversial, but recipient selection is essential for success. With a shortage of organs, it is essential to determine an objective method, such as a risk score, for choosing patients who are at too great a risk to undergo cardiac transplantation. In this study, we analysed the model for end-stage liver disease in terms of predicting operative mortality after emergency cardiac transplantation. METHODS: We analysed the Nancy University database of heart transplantation and selected all patients who underwent emergency heart transplantation between January 2005 and January 2012. The calibration and discriminatory power were evaluated to determine the model for end-stage liver disease (MELD) score. Preoperative and peri-operative variables regarding the prediction of operative mortality were analysed by univariate and multivariate logistic regression models. RESULTS: Forty-three patients underwent emergency cardiac transplantation. The operative mortality was 20.9% (n = 9). The Hosmer Lemeshow test demonstrated a calibrated model for predicting operative mortality (P = 0.15), and the MELD score presented an excellent discrimination between survivors and non-survivors (AUC: 0.89 +/- 0.05; 95% CI: 0.79-0.99). In the univariate analysis, an MELD score of >= 16 and bilirubin concentration were predictive markers of operative mortality. Multivariate logistic regression tested the contribution of the univariate risk predictors (P < 0.15) and confirmed that an MELD score of >= 16 was predictive of operative mortality. CONCLUSIONS: The MELD score appears to be adequate for predicting operative mortality among patients who undergo heart transplantation. The MELD score could therefore be used to guide clinical decision-making for emergency transplantation. PMID- 23345183 TI - Prediction of in-hospital mortality following pulmonary resections: improving on current risk models. AB - OBJECTIVES: Using a large, prospectively collected and independently validated thoracic database, we created a risk-prediction tool for in-hospital mortality with the aim of improving on the accuracy of Thoracoscore. METHODS: A prospectively collected and independently validated database containing lung resections was utilized, N = 2574. Logistic regression analysis with bootstrapping, and by the use of a random training and test set was utilized. Comparisons against the Thoracoscore, ESOS.01 and the Society of Thoracic Surgeons (STS) models were performed. RESULTS: A logistic model identified age [odds ratio (OR) 1.1, 95% confidence interval (CI) 1.0-1.2, P = 0.0002], sex (OR 0.34, 95% CI 0.14-0.83, P = 0.02), predicted postoperative FEV1 (OR 0.96, 95% CI 0.94-0.99, P = 0.002), emphysema (OR 3.2, 95% CI 1.0-9.9, P = 0.04), excess alcohol consumption (OR 1.0, 95% CI 1.0-1.0, P = 0.04), pre-existing renal disease (OR 4.3, 95% CI 1.1-17.1, P = 0.04), predicted in-hospital mortality with an receiver operating curve (ROC) of 0.81 and a Hosmer-Lemeshow test of 0.9. Bootstrap analysis confirmed the above risk factors (ROC 0.82 and Hosmer-Lemeshow 0.2). Comparisons between Thoracoscore, ESOS.01 and the STS risk models demonstrated that none was very accurate, as all had low ROC values of 0.69, 0.70 and 0.61, respectively. The STS risk model does not apply to our population (ROC 0.61, Hosmer-Lemeshow, P = 0.004), and the ESOS.01 has poor predictive power (Hosmer-Lemeshow, P < 0.0001). CONCLUSIONS: Logistic regression based on age, sex, predicted postoperative FEV1, alcohol consumption and pre-existing renal disease predicts in-hospital mortality with improved accuracy compared with the use of Thoracoscore, ESOS.01 and the STS risk model. PMID- 23345184 TI - Use of centrifugal left ventricular assist device as a bridge to candidacy in severe heart failure with secondary pulmonary hypertension. AB - OBJECTIVES: Raised pulmonary artery pressure (PAP), trans-pulmonary gradient (TPG) and pulmonary vascular resistance (PVR) are risk factors for poor outcomes after heart transplant in patients with secondary pulmonary hypertension (PH) and may contraindicate transplant. Unloading of the left ventricle with an implantable left ventricular assist device (LVAD) may reverse these pulmonary vascular changes. We studied the effect of implanting centrifugal LVADs in a cohort of patients with secondary PH as a bridge to candidacy. METHODS: Pulmonary haemodynamics on patients implanted with centrifugal LVADs at a single unit between May 2005 and December 2010 were retrospectively reviewed. RESULTS: Twenty nine patients were implanted with centrifugal LVADs (eight HeartWare ventricular assist device (HVAD), HeartWare International, USA and 21 VentrAssist, Ventracor Ltd., Australia). Seventeen were ineligible for transplant by virtue of high TPG/PVR. All the patients were optimized with inotrope/balloon pump followed by LVAD insertion. Four required temporary right VAD support. Thirty-day mortality post-LVAD was 3.4% (1 of 29) with a 1-year survival of 85.7% (24 of 28). Thirteen patients have been transplanted to date: 30-day mortality was 7.7% (1 of 13) and 1-year survival was 91% (10 of 11). Baseline and post-VAD pulmonary haemodynamics were significantly improved: systolic PAP (mmHg), mean PAP, TPG (mmHg) of 57 +/- 9.5, 42 +/- 4.4 and 14 +/- 3.9 reduced to 32 +/- 7.5, 18 +/- 5.5 and 9 +/- 3.3, respectively. PVR reduced from 5 +/- 1.5 to 2.1 +/- 0.5 Wood units (P < 0.05). CONCLUSIONS: In selected heart failure patients with secondary PH, use of centrifugal LVAD results in significant reductions in PAP, TPG and PVR, which are observed within 1 month, reaching a nadir by 3 months. Such patients bridged to candidacy have post-transplant survival comparable with those having a heart transplant as primary treatment. PMID- 23345185 TI - Editorial comment: Surgery for aneurysms of the ascending aorta: keep it simple, safe and straightforward. PMID- 23345186 TI - One-year multicentre outcomes of transapical aortic valve implantation using the SAPIEN XTTM valve: the PREVAIL transapical study. AB - OBJECTIVES: The study aimed to evaluate 1-year outcomes of the multicentre PREVAIL transapical (TA) study of TA-aortic valve implantation (AVI) in high-risk patients. METHODS: From September 2009 to August 2010, a total of 150 patients, aged 81.6 +/- 5.8 years, 40.7% female, were included at 12 European TA-AVI experienced sites. Patients received 23 (n = 36), 26 (n = 57) and 29 mm (n = 57) second-generation SAPIEN XTTM (Edwards Lifesciences, Irvine, CA, USA) valves. The mean logistic EuroSCORE was 24.3 +/- 7.0, and mean Society Thoracic Surgeons score was 7.5 +/- 4.4%. RESULTS: Survival was 91.3% at 30 days and 77.9% at 1 year. Subgroup analysis revealed survivals of 91.7/88.9, 86.0/70.2, 96.55/91.2% for patients receiving 23-, 26- and 29-mm valves at 30 days and at 1 year, respectively. Transthoracic echocardiography revealed preserved left ventricular ejection fraction and low gradients. Aortic incompetence was none in 41/48, trace 30/36, mild 22/12 and moderate in 7/4% at discharge and 1 year. Walking distance increased from 221 (postimplant) to 284 m (at 1 year, P = 0.0004). Three patients required reoperation due to increasing aortic incompetence during follow-up. Causes of mortality at 1 year were cardiac (n = 7), stroke (n = 1) and others (n = 5). CONCLUSIONS: The European PREVAIL multicentre trial demonstrates good functionality and good outcomes for TA-AVI using the second-generation SAPIEN XT prosthesis and the ASCENDRA-II delivery system. The 29-mm SAPIEN XT valve was successfully introduced and showed excellent results. PMID- 23345187 TI - Reply to Actis Dato et al. PMID- 23345188 TI - [Drug-drug-interactions in psychiatry]. AB - OBJECTIVE: In daily practice of psycho-pharmacotherapy most patients are under polypharmacy which may result in potentially harmful drug-drug interactions. Therefore, we investigated if the risk of drug-drug interactions can be reduced by a consultant clinical pharmacist for the physicians on psychiatric wards. METHODS: Drug-drug-interactions and adverse drug reactions of patients on 2 psychiatric intensive care units were investigated retrospectively in 2008 and 2009. Before the second investigation period, a special training was performed and during this period a pharmacist supported the physicians regarding drug therapy. RESULTS: After the introduction of a pharmacist on the ward and 2 teaching lessons relevant drug interactions were reduced by 78 % (p < 0.001), the number of all interactions by 44 % (p < 0.001). The total number of drug interactions decreased by the training sessions, which were offered shortly before starting the second observation period, from 3.4 interactions/patients in 2008 to 2.2 interactions/patients in 2009 (p < 0.04). CONCLUSION: A clinical pharmacist on the ward can contribute to a higher drug therapy safety in psychiatric wards. An interdisciplinary approach can relieve the physicians' daily work. The drug therapy can be improved by continuous teaching sessions about drug interactions. PMID- 23345189 TI - [Statutory duties of German psychiatric outpatient clinics and their real care conditions]. AB - OBJECTIVE: This study examines whether psychiatric outpatient clinics fulfill their statutory role of providing psychiatric services for patients with severe mental disorders. METHODS: A retrospective cross-sectional study on 1,672 patients of a psychiatric outpatient clinic for the year 2010, based on 30 variables. Associations between variables were explored by means of robust multivariate regression models and polynomial regression plots. RESULTS: The patients' average CGI value was found to be 5.98, the mean GAF-score 47.3, and the mean duration of illness 13.8 years. A third of the sample attempted suicide in the past. Metabolic comorbidity was found in 23.1 % of the sample. Results of regression analyses reveal positive effects of the disease severity and functional impairment on the use of psychiatric care. Patients with affective and schizophrenic disorders received more units of care and caused more costs. Patients living in nursing homes received less in- and outpatient care but caused more medication costs. CONCLUSIONS: Study results support the assumption that German psychiatric outpatient clinics fulfill their statutory duties by treating severely chronically mentally ill patients. The patients' use of care is positively related to the disease severity and their functional impairment. However, results of the regression analyses suggest that patients living in nursing homes received less psychiatric care than patients who live more independently. PMID- 23345191 TI - QMX: a versatile environment for hybrid calculations applied to the grafting of Al2Cl3Me3 on a silica surface. AB - We present a new software to easily perform QM:MM and QM:QM' calculations called QMX. It follows the subtraction scheme and it is implemented in the Atomic Simulation Environment (ASE). Special attention is paid to couple molecular calculations with periodic boundaries approaches. QMX inherits the flexibility and versatility of the ASE package: any combination of methods namely force field, semiempirical, first principle, and ab initio, can be used as hybrid potential energy surface (PES). Its ease of use is demonstrated by considering the adsorption of Al2Cl3Me3 on silica surface and by combining different levels of theory (from standard DFT to MP2 calculations) for the so-called High Level cluster with standard PW91 density functional theory calculations for the Low Level environment. It is shown that the High Level cluster must contain the silanol group close to the aluminum atoms. The bridging adsorption is favored by 58 kJ mol(-1) at the MP2:PW91 level with respect to the terminal position. Using large clusters at the MP2:PW91 level, it is shown that PW91 calculations are sufficient for structure optimization but that embedded methods are required for accurate energy profiles. PMID- 23345192 TI - Electronic properties of p-xylylene and p-phenylene chains subjected to finite bias voltages: a new highly conducting oligophenyl structure. AB - Recently, experimental and theoretical determination of electric currents induced by finite bias voltages in p-xylylene chains attached to gold contacts revealed higher conductance of these systems in comparison with p-phenylene homologous chains. To gain more insight into the conducting properties of these oligophenyl structures, ab initio studies were carried out on the electronic properties of two different p-xylylene-like chains (pX1 and pX2) and the p-phenylene (pP) chain attached to gold contacts, with molecular formulas AuCH2 (C6 H4 )n CH2 Au (n=1 5), Au2 C(C6 H4 )n CAu2 (n=1-5), and Au(C6 H4 )n Au (n=1-5), respectively. The molecules were subjected to finite bias voltages ranging from 0 to 5 V. Analysis of the intramolecular electron transfer and electron delocalization revealed a completely opposite response to electric perturbation of pX2 in comparison with pX1 and pP. Thus, in pX2 the applied voltage causes an increase in the electron delocalization within the rings together with a large electron transfer and energetic stabilization. On the contrary, the same voltages partially destroy the electron delocalization in pX1 and pP, produce a large local electron polarization in the benzene rings, and a smaller energetic stabilization. These differences can be rationalized in terms of the role played by polarized valence bond structures in the total wave function. Theoretical estimation of the I/V profiles indicates that pX2 chains are much better electronic conductors than pX1 and pP. PMID- 23345190 TI - Postprandial hypertriglyceridemia and cardiovascular disease: current and future therapies. AB - Exaggerated postprandial hypertriglyceridemia is a risk factor for cardiovascular disease. This metabolic abnormality is principally due to overproduction and/or decreased catabolism of triglyceride-rich lipoproteins (TRLs) and is a consequence of pathogenic genetic variations and other coexistent medical conditions, particularly obesity and insulin resistance. Accumulation of TRL in the postprandial state promotes the formation of small, dense low-density lipoproteins, as well as oxidative stress, inflammation, and endothelial dysfunction, all of which compound the risk of cardiovascular disease. The cardiovascular benefits of lifestyle modification (weight loss and exercise) and conventional lipid-lowering therapies (statins, fibrates, niacin, ezetimibe, and n-3 fatty acid supplementation) could involve their favorable effects on TRL metabolism. New agents, such as dual peroxisome-proliferator-activated receptor alpha/delta agonists, diacylglycerol, inhibitors of diacylglycerol acyltransferase 1 and microsomal triglyceride transfer protein, antisense oligonucleotides for apolipoprotein B-100 and apolipoprotein C-III, and incretin based therapies, may enhance the treatment of postprandial lipemia, but their efficacy needs to be tested in clinical end point trials. Further work is required to develop a simple clinical protocol for investigating postprandial lipemia, as well as internationally agreed management guidelines for this type of dyslipidemia. PMID- 23345193 TI - Synthesis and structure of tetraarylcumulenes: characterization of bond-length alternation versus molecule length. PMID- 23345194 TI - Tracheo-innominate artery fistula: Diagnosis and surgical management. AB - BACKGROUND: Tracheo-innominate artery fistula (TIF) is a rare and fatal complication after tracheostomy. The diagnosis, treatment, and possible prevention of this disease are discussed in this study. METHODS: From 1976 to 2008, 14 patients with TIF were studied retrospectively. RESULTS: All patients underwent open surgical tracheostomy. Before TIF, herald events occurred in 10 patients (8 had slight hemoptysis and 2 had innominate artery exposure). When TIF occurred, bedside aid was administered, and 5 patients lived long enough to reach the operating room. Four patients accepted median sternotomy and ligation of innominate arteries. After surgery, mediastinal infection caused the rebleeding and death of 3 patients. In conducting follow-up for 11 months, the last patient was still alive without neurological complications. The survival rate was only 7.1%. CONCLUSION: Prompt diagnosis and surgical intervention can save the life of a patient with TIF. Prevention is vital because of the high mortality of this disease. PMID- 23345195 TI - Reduction of the impact of multiple uncertain conductivity values on EEG dipole source analysis. AB - It is well known that the uncertain knowledge of the conductivity values of the head tissues has an important impact upon the accuracy of the electroencephalogram source reconstruction. Assuming a certain value of the conductivity often leads to high reconstruction error values when solving the inverse problem. It is possible to quantify the impact of multiple uncertain conductivity values on the localization accuracy. We propose an approach that reduces the impact of these multiple uncertainties on the reconstruction accuracy of the dipole parameters. This paper elaborates the numerical method and shows results of localization accuracy in a five-shell spherical head model. Sensitivity analysis, when considering multiple layers in the head model, shows the different scales of the influence of the various uncertain conductivity values on the potential values. We propose a cost function that reduces the impact of multiple uncertainties of the conductivity value on the electroencephalogram dipole reconstruction and two strategies for selecting potential values on the basis of the sensitivity analysis. Numerical simulations, when considering multiple uncertainties in the model, provide results with higher reconstruction accuracy compared with the case where only a single uncertainty is taken into account. PMID- 23345196 TI - Postnatal phenotype according to prenatal ultrasound features of Noonan syndrome: a retrospective study of 28 cases. AB - OBJECTIVE: Noonan syndrome is a frequent genetic disorder with autosomal dominant transmission. Classically, it combines postnatal growth restriction with dysmorphic and malformation syndromes that vary widely in expressivity. Lymphatic dysplasia induced during the embryonic stage might interfere with tissue migration. Our hypothesis is that the earlier the edema, the more severe postnatal phenotype. METHOD: This retrospective study analyzed data from all 32 cases of Noonan syndrome diagnosed in the Medical Genetics Department of Hautepierre Hospital in Strasbourg, France, between 1995 and 2011. The postnatal evolution of Noonan syndrome was compared according to the presence of at least one prenatal ultrasound feature of lymphatic dysplasia. RESULTS: The most frequent prenatal ultrasound features found were increased nuchal translucency, cystic hygroma and polyhydramnios; their global prevalence was 46.4%. The presence of these features was not significantly associated with the postnatal phenotype of Noonan syndrome. CONCLUSION: The results of our study indicate that prenatal ultrasound features of lymphatic dysplasia do not predict an unfavorable postnatal prognosis for Noonan syndrome. PMID- 23345197 TI - Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. AB - BACKGROUND: Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) are known to cause CHI. AIM: To characterise the clinical and molecular aspects of a large cohort of patients with CHI. METHODOLOGY: Three hundred patients were recruited and clinical information was collected before genotyping. ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1, HADH, GCK and HNF4A genes were sought in patients with diazoxide responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A). RESULTS: Mutations were identified in 136/300 patients (45.3%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations in ABCC8/KCNJ11 (n=15), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3). CONCLUSIONS: A genetic diagnosis was made for 45.3% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms. PMID- 23345198 TI - The role of community health workers in diabetes: update on current literature. AB - Community health worker (CHW) interventions have been found to be a promising strategy for improving diabetes outcomes, especially among low-income and racial and ethnic minority populations. This review serves as an update of the literature published since 2011 on CHWs' role in diabetes care. In our review of the most current literature, we noted several key areas of advancement. These areas include community-based participatory research approaches to intervention development and evaluation, analyses of the cost effectiveness of CHW interventions, evaluation of sustainability through integrated team-based approaches, thorough descriptions of characteristics and training of CHWs, and delineation of the scope of practice and most effective roles for CHWs. PMID- 23345199 TI - Conducting organic frameworks based on a main-group metal and organocyanide radicals. AB - Reactions of the main-group cation Tl(I) with anions of 2,5-derivatives of TCNQ (TCNQ = 7,7,8,8-tetracyanoquinodimethane) have led to the isolation of a family of unprecedented semiconducting main-group-metal-organic frameworks, namely, [Tl(TCNQX(2))], (X = H, Cl, Br, I). A comparison of single-crystal and powder X ray diffraction data revealed the existence of a third polymorph of the previously reported material Tl(TCNQ)] and two distinct polymorphs of [Tl(TCNQCl(2))], whereas only one phase was identified for [Tl(TCNQBr(2))] and [Tl(TCNQI(2))]. These new results are described in the context of the structures of other known binary metal-TCNQ frameworks that display a variety of coordination environments for the central cation, namely, four-, six-, and eight coordinate, and different arrangements of the adjacent TCNQ radicals-parallel versus perpendicular-in the stacked columns. The halogen substituents affect the structures and the properties of these compounds, owing to both steric and electronic effects as evidenced by the semiconducting properties of crystals of [Tl(TCNQCl(2))] phase I, [Tl(TCNQBr(2))], and [Tl(TCNQI(2))], which correlate well with the distances of adjacent TCNQ radicals in the columns. 1D infinite Huckel model simulations of the band structures of [Tl(TCNQCl(2))] phase I, [Tl(TCNQBr(2))], and [Tl(TCNQI(2))] were conducted with and without consideration of the Tl(I) cations, the results of which indicate that the charge mobility does not strictly occur in one dimension. The modulations of the band structures with various assumptions of the energy difference (Delta) between the Tl(I) 6s orbital and the TCNQ LUMO orbital were calculated and are discussed in light of the observed properties. PMID- 23345201 TI - Selectivity of CO(2) reduction on copper electrodes: the role of the kinetics of elementary steps. AB - On the right path: Based on DFT calculations (incorporating the role of water solvation) of the activation barriers of elementary steps, a new path that leads to methane and ethylene for CO(2) electroreduction on Cu(111) was identified. Methane formation proceeds through reduction of CO to COH (path II, see picture), which leads to CH(x) species that can produce both methane and ethylene, as observed experimentally. PMID- 23345200 TI - ACR guidance document on MR safe practices: 2013. AB - Because there are many potential risks in the MR environment and reports of adverse incidents involving patients, equipment and personnel, the need for a guidance document on MR safe practices emerged. Initially published in 2002, the ACR MR Safe Practices Guidelines established de facto industry standards for safe and responsible practices in clinical and research MR environments. As the MR industry changes the document is reviewed, modified and updated. The most recent version will reflect these changes. PMID- 23345202 TI - On the influence of patient-specific material properties in computational simulations: a case study of a large ruptured abdominal aortic aneurysm. AB - Patient-specific modelling of abdominal aortic aneurysm has been shown to have clinical potential. This paper examines a large ruptured abdominal aortic aneurysm where the tissue from the diseased wall and the intraluminal thrombus was excised during open surgical repair and experimentally characterised. The mechanical data were used to develop material parameters that were incorporated into finite element models with measured nonuniform wall thickness. Implementation of the material data into the numerical model increased peak wall stress by 67%, wall strain by 320% and displacement by 177%, when compared with simulations based on material properties available in the literature. Distributions of numerical results were similar for both material data. Magnitudes of numerical results can differ significantly when using patient specific material properties and therefore, care should be taken when interpreting numerical results derived from population-based data. PMID- 23345203 TI - 8p23.1 duplication syndrome; common, confirmed, and novel features in six further patients. AB - The 8p23.1 duplication syndrome is a relatively rare genomic condition that has been confirmed with molecular cytogenetic methods in only 11 probands and five family members. Here, we describe another prenatal and five postnatal patients with de novo 8p23.1 duplications analyzed with oligonucleotide array comparative genomic hybridization (oaCGH). Of the common features, mild or moderate developmental delays and/or learning difficulties have been found in 11/12 postnatal probands, a variable degree of mild dysmorphism in 8/12 and congenital heart disease (CHD) in 4/5 prenatal and 3/12 postnatal probands. Behavioral problems, cleft lip and/or palate, macrocephaly, and seizures were confirmed as additional features among the new patients, and novel features included neonatal respiratory distress, attention deficit hyperactivity disorder (ADHD), ocular anomalies, balance problems, hypotonia, and hydrocele. The core duplication of 3.68 Mb contains 31 genes and microRNAs of which only GATA4, TNKS, SOX7, and XKR6 are likely to be dosage sensitive genes and MIR124-1 and MIR598 have been implicated in neurocognitive phenotypes. A combination of the duplication of GATA4, SOX7, and related genes may account for the variable penetrance of CHD. Two of the duplications were maternal and intrachromosomal in origin with maternal heterozygosity for the common inversion between the repeats in 8p23.1. These additional patients and the absence of the 8p23.1 duplications in published controls, indicate that the 8p23.1 duplication syndrome may now be considered a pathogenic copy number variation (pCNV) with an estimated population prevalence of 1 in 58,000. PMID- 23345204 TI - Decoding the contents of visual working memory: evidence for process-based and content-based working memory areas? PMID- 23345205 TI - Disinhibition of histaminergic neurons: lack of effect on arousal switch following propofol hypnosis. PMID- 23345206 TI - Glial cells decipher synaptic competition at the mammalian neuromuscular junction. AB - It is now accepted that glial cells actively interact with neurons and modulate their activity in many regions of the nervous system. Importantly, modulation of synaptic activity by glial cells depends on the proper detection and decoding of synaptic activity. However, it remains unknown whether glial cells are capable of decoding synaptic activity and properties during early postdevelopmental stages, in particular when different presynaptic nerve terminals compete for the control of the same synaptic site. This may be particularly relevant because a major determinant of the outcome of synaptic competition process is the relative synaptic strength of competing terminals whereby stronger terminals are more likely to occupy postsynaptic territory and become stabilized while weaker terminals are often eliminated. Hence, because of their ability to decode synaptic activity, glial cells should be able to integrate neuronal information of competing terminals. Using simultaneous glial Ca(2+) imaging and synaptic recordings of dually innervated mouse neuromuscular junctions, we report that single glial cells decipher the strength of competing nerve terminals. Activity of single glial cells, revealed by Ca(2+) responses, reflects the synaptic strength of each competing nerve terminal and the state of synaptic competition. This deciphering is mediated by functionally segregated purinergic receptors and intrinsic properties of glial cells. Our results indicate that glial cells decode ongoing synaptic competition and, hence, are poised to influence its outcome. PMID- 23345207 TI - Distal dendritic inputs control neuronal activity by heterosynaptic potentiation of proximal inputs. AB - Synapses onto distal dendritic tufts are believed to function by modulating time locked proximal inputs; however, the role of these synapses when proximal inputs are asynchronous or silent is unknown. Surprisingly, we found that activation of apical tuft synapses alone resulted in heterosynaptic potentiation of proximal synapses. In mouse adult hippocampal CA1 pyramidal neurons, we show that activation of distal inputs from the entorhinal cortex (EC) specifically strengthens proximal synapses projecting from CA3. This slow AMPA receptor mediated potentiation is accompanied by increased synaptic GluN2B-containing NMDA receptors, which are normally restricted to juvenile animals. These two synaptic modifications interact to generate striking bidirectional metaplastic changes. Heterosynaptically potentiated synapses become resistant to subsequent long-term potentiation (LTP) as the two forms of AMPA receptor-mediated potentiation occlude. However, this is only true when the LTP induction protocol is relatively weak. When it is strong and repeated, the magnitude of LTP after heterosynaptic plasticity is greatly increased, specifically through the activation of GluN2B containing NMDA receptors. Thus, CA1 neurons expressing heterosynaptic potentiation induced by external sensory input from the EC become more strongly driven by internally generated environmental representations from CA3. Furthermore, subsequent SC LTP in this ensemble is shifted to potentiate only strongly activated CA3 inputs, while endowing these synapses with enhanced potentiation. These results show that one set of inputs can exert long-lasting heterosynaptic control over another, allowing the coupling of two functionally and spatially distinct pathways, thereby greatly expanding the repertoire of cellular and network plasticity. PMID- 23345208 TI - Cortical adaptation to a chronic micro-electrocorticographic brain computer interface. AB - Brain-computer interface (BCI) technology decodes neural signals in real time to control external devices. In this study, chronic epidural micro electrocorticographic recordings were performed over primary motor (M1) and dorsal premotor (PMd) cortex of three macaque monkeys. The differential gamma band amplitude (75-105 Hz) from two arbitrarily chosen 300 MUm electrodes (one located over each cortical area) was used for closed-loop control of a one dimensional BCI device. Each monkey rapidly learned over a period of days to successfully control the velocity of a computer cursor. While both cortical areas contributed to success on the BCI task, the control signals from M1 were consistently modulated more strongly than those from PMd. Additionally, we observe that gamma-band power during active BCI control is always above resting brain activity. This suggests that purposeful gamma-band modulation is an active process that is obtained through increased cortical activation. PMID- 23345209 TI - The occipital place area is causally and selectively involved in scene perception. AB - Functional magnetic resonance imaging has revealed a set of regions selectively engaged in visual scene processing: the parahippocampal place area (PPA), the retrosplenial complex (RSC), and a region around the transverse occipital sulcus (previously known as "TOS"), here renamed the "occipital place area" (OPA). Are these regions not only preferentially activated by, but also causally involved in scene perception? Although past neuropsychological data imply a causal role in scene processing for PPA and RSC, no such evidence exists for OPA. Thus, to test the causal role of OPA in human adults, we delivered transcranial magnetic stimulation (TMS) to the right OPA (rOPA) or the nearby face-selective right occipital face area (rOFA) while participants performed fine-grained perceptual discrimination tasks on scenes or faces. TMS over rOPA impaired discrimination of scenes but not faces, while TMS over rOFA impaired discrimination of faces but not scenes. In a second experiment, we delivered TMS to rOPA, or the object selective right lateral occipital complex (rLOC), while participants performed categorization tasks involving scenes and objects. TMS over rOPA impaired categorization accuracy of scenes but not objects, while TMS over rLOC impaired categorization accuracy of objects but not scenes. These findings provide the first evidence that OPA is causally involved in scene processing, and further show that this causal role is selective for scene perception. Our findings illuminate the functional architecture of the scene perception system, and also argue against the "distributed coding" view in which each category-selective region participates in the representation of all objects. PMID- 23345210 TI - Uncovering the mechanisms of conscious face perception: a single-trial study of the n170 responses. AB - When a face is flashed to an observer, a large negative component is elicited in the occipitotemporal cortex at ~170 ms from the onset of presentation (N170). Previous studies have shown that the average N170 is correlated with conscious face perception; however, the single-trial mechanisms underlying such modulation remain largely unexplored. Here, we studied in human subjects the average and the single-trial N170 responses to briefly flashed faces, coupled with backward masking and varying degrees of Gaussian noise. In the average evoked responses we observed that, at fixed levels of noise, supraliminal faces exhibited significantly larger N170 amplitudes than subliminal faces. Moreover, the average N170 amplitude decreased with noise level both for the perceived and the nonperceived faces. At the single-trial level, the N170 amplitude was modulated by conscious recognition, which allowed predicting the subjects' perceptual responses above chance. In contrast, the single-trial N170 amplitudes were not modulated by the amount of noise and the effect found in the average responses was due to different latency jitters, as confirmed with latency-corrected averages. Altogether, these results suggest that conscious face perception is correlated with a boost in the activity of face-selective neural assemblies, whereas the stimulus uncertainty introduced by the added noise decreases the timing consistency (but not the amplitude) of this activation. PMID- 23345211 TI - Differential balance of prefrontal synaptic activity in successful versus unsuccessful cognitive aging. AB - Normal aging is associated with a variable decline in cognitive functions. Among these, executive function, decision-making, and working memory are primarily associated with the prefrontal cortex. Although a number of studies have examined the structural substrates of cognitive decline associated with aging within this cortical area, their functional correlates remain poorly understood. To fill this gap, we aimed to identify functional synaptic substrates of age-associated frontal-dependent deficits in layer 2/3 pyramidal neurons of medial prefrontal cortex of 3-, 9-, and >= 23-month-old Fischer 344 rats. We combined, in the same animals, novelty recognition and exploratory behavioral tasks with assessment of structural and functional aspects of prefrontal synaptic properties. We found that subsets of aged animals displayed stereotyped exploratory behavior or memory deficits. Despite an age-dependent dendritic spine loss, patch-clamp recording of synaptic activity revealed an increase in miniature EPSC frequency restricted to aged animals with preserved exploratory behavior. In contrast, we found a strong positive relationship between miniature IPSC frequency and the occurrence of both stereotyped exploratory behavior and novelty-related memory deficits. The enhanced miniature inhibitory tone was accompanied by a deficit in activity driven inhibition, also suggesting an impaired dynamic range for modulation of inhibition in the aged, cognitively impaired animals. Together, our data indicate that differential changes in the balance of inhibitory to excitatory synaptic tone may underlie distinct trajectories in the evolution of cognitive performance during aging. PMID- 23345212 TI - Declines in Drp1 and parkin expression underlie DNA damage-induced changes in mitochondrial length and neuronal death. AB - Maintaining proper mitochondrial length is essential for normal mitochondrial function in neurons. Mitochondrial fragmentation has been associated with neuronal cell death caused by a variety of experimental toxic stressors. Despite the fact that oxidative stress is a hallmark of neurodegenerative conditions and aging and the resulting activation of p53 is believed to contribute to the neuropathology, little is still known regarding changes in mitochondrial morphology in p53-dependent neuronal death. Therefore, we specifically addressed the relationship between genotoxic stress, p53 activation, and the regulation of mitochondrial morphology in neurons. In cultured postnatal mouse cortical neurons, treatment with the DNA-damaging agent camptothecin (CPT) resulted in elongated mitochondria, in contrast to fragmented mitochondria observed upon staurosporine and glutamate treatment. In fibroblasts, however, CPT resulted in fragmented mitochondria. CPT treatment in neurons suppressed expression of the mitochondrial fission protein Drp1 and the E3 ubiquitin ligase parkin. The presence of elongated mitochondria and the declines in Drp1 and parkin expression occurred before the commitment point for apoptosis. The CPT-induced changes in Drp1 and parkin were not observed in p53-deficient neurons, while p53 overexpression alone was sufficient to reduce the expression of the two proteins. Elevating Drp1 or parkin expression before CPT treatment enhanced neuronal viability and restored a normal pattern of mitochondrial morphology. The present findings demonstrate that genotoxic stress in neurons results in elongated mitochondria in contrast to fission induced by other forms of stress, and p53 dependent declines in Drp1 and parkin levels contribute to altered mitochondrial morphology and cell death. PMID- 23345214 TI - Spatiotemporal dynamics of functional clusters of neurons in the mouse motor cortex during a voluntary movement. AB - Functional clustering of neurons is frequently observed in the motor cortex. However, it is unknown if, when, and how fine-scale (<100 MUm) functional clusters form relative to voluntary forelimb movements. In addition, the implications of clustering remain unclear. To address these issues, we conducted two-photon calcium imaging of mouse layer 2/3 motor cortex during a self initiated lever-pull task. In the imaging session after 8-9 days of training, head-restrained mice had to pull a lever for ~600 ms to receive a water drop, and then had to wait for >3 s to pull it again. We found two types of task-related cells in the mice: cells whose peak activities occurred during lever pulls (pull cells) and cells whose peak activities occurred after the end of lever pulls. The activity of pull cells was strongly associated with lever-pull duration. In ~40% of imaged fields, functional clusterings were temporally detected during the lever pulls. Spatially, there were ~70-MUm-scale clusters that consisted of more than four pull cells in ~50% of the fields. Ensemble and individual activities of pull cells within the cluster more accurately predicted lever movement trajectories than activities of pull cells outside the cluster. This was likely because clustered pull cells were more often active in the individual trials than pull cells outside the cluster. This higher fidelity of activity was related to higher trial-to-trial correlations of activities of pairs within the cluster. We propose that strong recurrent network clusters may represent the execution of voluntary movements. PMID- 23345213 TI - Serotonergic neurosecretory synapse targeting is controlled by netrin-releasing guidepost neurons in Caenorhabditis elegans. AB - Neurosecretory release sites lack distinct postsynaptic partners, yet target to specific circuits. This targeting specificity regulates local release of neurotransmitters and modulation of adjacent circuits. How neurosecretory release sites target to specific regions is not understood. Here we identify a molecular mechanism that governs the spatial specificity of extrasynaptic neurosecretory terminal (ENT) formation in the serotonergic neurosecretory-motor (NSM) neurons of Caenorhabditis elegans. We show that postembryonic arborization and neurosecretory terminal targeting of the C. elegans NSM neuron is dependent on the Netrin receptor UNC-40/DCC. We observe that UNC-40 localizes to specific neurosecretory terminals at the time of axon arbor formation. This localization is dependent on UNC-6/Netrin, which is expressed by nerve ring neurons that act as guideposts to instruct local arbor and release site formation. We find that both UNC-34/Enabled and MIG-10/Lamellipodin are required downstream of UNC-40 to link the sites of ENT formation to nascent axon arbor extensions. Our findings provide a molecular link between release site development and axon arborization and introduce a novel mechanism that governs the spatial specificity of serotonergic ENTs in vivo. PMID- 23345215 TI - Ataxia with cerebellar lesions in mice expressing chimeric PrP-Dpl protein. AB - Mutations within the central region of prion protein (PrP) have been shown to be associated with severe neurotoxic activity similar to that observed with Dpl, a PrP-like protein. To further investigate this neurotoxic effect, we generated lines of transgenic (Tg) mice expressing three different chimeric PrP-Dpl proteins. Chi1 (amino acids 1-57 of Dpl replaced by amino acids 1-125 of PrP) and Chi2 (amino acids 1-66 of Dpl replaced by amino acids 1-134 of PrP) abrogated the pathogenicity of Dpl indicating that the presence of a N-terminal domain of PrP (23-134) reduced the toxicity of Dpl, as reported. However, when the amino acids 1-24 of Dpl were replaced by amino acids 1-124 of PrP, Chi3 Tg mice, which express the chimeric protein at a very low level, start developing ataxia at the age of 5-7 weeks. This phenotype was not counteracted by a single copy of full length-PrP(c) but rather by its overexpression, indicating the strong toxicity of the chimeric protein Chi3. Chi3 Tg mice exhibit severe cerebellar atrophy with a significant loss of granule cells. We concluded that aa25 to aa57 of Dpl, which are not present in Chi1 and Chi2 constructs, confer toxicity to the protein. We tested this possibility by using the 25-57 Dpl peptide in primary culture of mouse embryo cortical neurons and found a significant neurotoxic effect. This finding identifies a protein domain that plays a role in mediating Dpl-related toxicity. PMID- 23345216 TI - Prestimulus oscillatory activity over motor cortex reflects perceptual expectations. AB - When perceptual decisions are coupled to a specific effector, preparatory motor cortical activity may provide a window into the dynamics of the perceptual choice. Specifically, previous studies have observed a buildup of choice selective activity in motor regions over time reflecting the integrated sensory evidence provided by visual cortex. Here we ask how this choice-selective motor activity is modified by prior expectation during a visual motion discrimination task. Computational models of decision making formalize decisions as the accumulation of evidence from a starting point to a decision bound. Within this framework, expectation could change the starting point, rate of accumulation, or the decision bound. Using magneto-encephalography in human observers, we specifically tested for changes in the starting point in choice-selective oscillatory activity over motor cortex. Inducing prior expectation about motion direction biased subjects' perceptual judgments as well as the choice-selective motor activity in the 8-30 Hz frequency range before stimulus onset; the individual strength of these behavioral and neural biases were correlated across subjects. In the absence of explicit expectation cues, spontaneous biases in choice-selective activity were evident over motor cortex. These also predicted eventual perceptual choice and were, at least in part, induced by the choice on the previous trial. We conclude that both endogenous and explicitly induced perceptual expectations bias the starting point of decision-related activity, before the accumulation of sensory evidence. PMID- 23345217 TI - Persistent reversal of enhanced amphetamine intake by transient CaMKII inhibition. AB - Amphetamine exposure transiently increases Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) alpha expression in the nucleus accumbens (NAcc) shell and this persistently increases local GluA1 S831 phosphorylation and enhances behavioral responding to the drug. Here we assessed whether transiently interfering with CaMKII signaling using a dominant-negative CaMKIIalpha mutant delivered to the NAcc shell with herpes simplex viral vectors could reverse these long-lasting biochemical and behavioral effects observed following exposure to amphetamine. As expected, transient expression of CaMKIIalpha K42M in the NAcc shell produced a corresponding transient increase in CaMKIIalpha and decrease in pCaMKIIalpha (T286) protein levels in this site. Remarkably, this transient inhibition of CaMKII activity produced a long-lasting reversal of the increased GluA1 S831 phosphorylation levels in NAcc shell and persistently blocked the enhanced locomotor response to and self-administration of amphetamine normally observed in rats previously exposed to the drug. Together, these results indicate that even transient interference with CaMKII signaling may confer long-lasting benefits in drug-sensitized individuals and point to CaMKII and its downstream pathways as attractive therapeutic targets for the treatment of stimulant addiction. PMID- 23345218 TI - Visual input enhances selective speech envelope tracking in auditory cortex at a "cocktail party". AB - Our ability to selectively attend to one auditory signal amid competing input streams, epitomized by the "Cocktail Party" problem, continues to stimulate research from various approaches. How this demanding perceptual feat is achieved from a neural systems perspective remains unclear and controversial. It is well established that neural responses to attended stimuli are enhanced compared with responses to ignored ones, but responses to ignored stimuli are nonetheless highly significant, leading to interference in performance. We investigated whether congruent visual input of an attended speaker enhances cortical selectivity in auditory cortex, leading to diminished representation of ignored stimuli. We recorded magnetoencephalographic signals from human participants as they attended to segments of natural continuous speech. Using two complementary methods of quantifying the neural response to speech, we found that viewing a speaker's face enhances the capacity of auditory cortex to track the temporal speech envelope of that speaker. This mechanism was most effective in a Cocktail Party setting, promoting preferential tracking of the attended speaker, whereas without visual input no significant attentional modulation was observed. These neurophysiological results underscore the importance of visual input in resolving perceptual ambiguity in a noisy environment. Since visual cues in speech precede the associated auditory signals, they likely serve a predictive role in facilitating auditory processing of speech, perhaps by directing attentional resources to appropriate points in time when to-be-attended acoustic input is expected to arrive. PMID- 23345219 TI - Bradykinin-induced chemotaxis of human gliomas requires the activation of KCa3.1 and ClC-3. AB - Previous reports demonstrate that cell migration in the nervous system is associated with stereotypic changes in intracellular calcium concentration ([Ca(2+)](i)), yet the target of these changes are essentially unknown. We examined chemotactic migration/invasion of human gliomas to study how [Ca(2+)](i) regulates cellular movement and to identify downstream targets. Gliomas are primary brain cancers that spread exclusively within the brain, frequently migrating along blood vessels to which they are chemotactically attracted by bradykinin. Using simultaneous fura-2 Ca(2+) imaging and amphotericin B perforated patch-clamp electrophysiology, we find that bradykinin raises [Ca(2+)](i) and induces a biphasic voltage response. This voltage response is mediated by the coordinated activation of Ca(2+)-dependent, TRAM-34-sensitive K(Ca)3.1 channels, and Ca(2+)-dependent, 4,4'-diisothiocyanato-stilbene-2,2' disulfonic acid (DIDS)-sensitive and gluconate-sensitive Cl(-) channels. A significant portion of these Cl(-) currents can be attributed to Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activation of ClC-3, a voltage-gated Cl(-) channel/transporter, because pharmacological inhibition of CaMKII or shRNA-mediated knockdown of ClC-3 inhibited Ca(2+)-activated Cl(-) currents. Western blots show that K(Ca)3.1 and ClC-3 are expressed in tissue samples obtained from patients diagnosed with grade IV gliomas. Both K(Ca)3.1 and ClC-3 colocalize to the invading processes of glioma cells. Importantly, inhibition of either channel abrogates bradykinin-induced chemotaxis and reduces tumor expansion in mouse brain slices in situ. These channels should be further explored as future targets for anti-invasive drugs. Furthermore, these data elucidate a novel mechanism placing cation and anion channels downstream of ligand-mediated [Ca(2+)](i) increases, which likely play similar roles in other migratory cells in the nervous system. PMID- 23345220 TI - Amygdala beta-noradrenergic receptors modulate delayed downregulation of dopamine activity following restraint. AB - Stress, which involves a heightened arousal and excitability, triggers important adaptive responses to maintain homeostasis and prepare a response. In the current studies, we administered a psychological stressor of 2 h acute restraint on rats, and found that 24 h after the cessation of the restraint session, there was a significant decrease in ventral tegmental area dopaminergic (DA) neuron population activity and a significant attenuation in amphetamine-induced locomotor activity. Systemic or intra-basolateral nuclei of the amygdala administration of the beta-noradrenergic receptor antagonist, propranolol, reversed the decrease, suggesting that the delayed attenuation of DA neuron firing following a stressor depends on a noradrenaline-mediated mechanism. This alteration in DA activity may adaptively prepare the individual to avoid the stressor, or in the extreme, may be a factor that contributes to pathological changes in behavior or physiological responses. PMID- 23345221 TI - Receptive field properties of color opponent neurons in the cat lateral geniculate nucleus. AB - Most nonprimate mammals possess dichromatic ("red-green color blind") color vision based on short-wavelength-sensitive (S) and medium/long-wavelength sensitive (ML) cone photoreceptor classes. However, the neural pathways carrying signals underlying the primitive "blue-yellow" axis of color vision in nonprimate mammals are largely unexplored. Here, we have characterized a population of color opponent (blue-ON) cells in recordings from the dorsal lateral geniculate nucleus of anesthetized cats. We found five points of similarity to previous descriptions of primate blue-ON cells. First, cat blue-ON cells receive ON-type excitation from S-cones, and OFF-type excitation from ML-cones. We found no blue-OFF cells. Second, the S- and ML-cone-driven receptive field regions of cat blue-ON cells are closely matched in size, consistent with specialization for detecting color contrast. Third, the receptive field center diameter of cat blue-ON cells is approximately three times larger than the center diameter of non-color opponent receptive fields at any eccentricity. Fourth, S- and ML-cones contribute weak surround inhibition to cat blue-ON cells. These data show that blue-ON receptive fields in cats are functionally very similar to blue-ON type receptive fields previously described in macaque and marmoset monkeys. Finally, cat blue-ON cells are found in the same layers as W-cells, which are thought to be homologous to the primate koniocellular system. Based on these data, we suggest that cat blue ON cells are part of a "blue-yellow" color opponent system that is the evolutionary homolog of the blue-ON division of the koniocellular pathway in primates. PMID- 23345222 TI - Aging-induced Nrf2-ARE pathway disruption in the subventricular zone drives neurogenic impairment in parkinsonian mice via PI3K-Wnt/beta-catenin dysregulation. AB - Aging and exposure to environmental toxins including MPTP (1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine) are strong risk factors for developing Parkinson's disease (PD), a common neurologic disorder characterized by selective degeneration of midbrain dopaminergic (DAergic) neurons and astrogliosis. Aging and PD impair the subventricular zone (SVZ), one of the most important brain regions for adult neurogenesis. Because inflammation and oxidative stress are the hallmarks of aging and PD, we investigated the nature, timing, and signaling mechanisms contributing to aging-induced SVZ stem/neuroprogenitor cell (NPC) inhibition in aging male mice and attempted to determine to what extent manipulation of these pathways produces a functional response in the outcome of MPTP-induced DAergic toxicity. We herein reveal an imbalance of Nrf2-driven antioxidant/anti-inflammatory genes, such as Heme oxygenase1 in the SVZ niche, starting by middle age, amplified upon neurotoxin treatment and associated with an exacerbated proinflammatory SVZ microenvironment converging to dysregulate the Wingless-type MMTV integration site (Wnt)/beta-catenin signaling, a key regulatory pathway for adult NPCs. In vitro experiments using coculture paradigms uncovered aged microglial proinflammatory mediators as critical inhibitors of NPC proliferative potential. We also found that interruption of PI3K (phosphatidylinositol3-kinase)/Akt and the Wnt/Fzd/beta-catenin signaling cascades, which switch glycogen synthase kinase 3beta (GSK-3beta) activation on and off, were causally related to the impairment of SVZ-NPCs. Moreover, a synergy between dysfunctional microglia of aging mice and MPTP exposure further inhibited astrocyte proneurogenic properties, including the expression of key Wnts components. Last, pharmacological activation/antagonism studies in vivo and in vitro suggest the potential that aged SVZ manipulation is associated with DAergic functional recovery. PMID- 23345223 TI - Glutamatergic neurotransmission between the C1 neurons and the parasympathetic preganglionic neurons of the dorsal motor nucleus of the vagus. AB - The C1 neurons are a nodal point for blood pressure control and other autonomic responses. Here we test whether these rostral ventrolateral medullary catecholaminergic (RVLM-CA) neurons use glutamate as a transmitter in the dorsal motor nucleus of the vagus (DMV). After injecting Cre-dependent adeno-associated virus (AAV2) DIO-Ef1alpha-channelrhodopsin2(ChR2)-mCherry (AAV2) into the RVLM of dopamine-beta-hydroxylase Cre transgenic mice (DbetaH(Cre/0)), mCherry was detected exclusively in RVLM-CA neurons. Within the DMV >95% mCherry immunoreactive(ir) axonal varicosities were tyrosine hydroxylase (TH)-ir and the same proportion were vesicular glutamate transporter 2 (VGLUT2)-ir. VGLUT2 mCherry colocalization was virtually absent when AAV2 was injected into the RVLM of DbetaH(Cre/0);VGLUT2(flox/flox) mice, into the caudal VLM (A1 noradrenergic neuron-rich region) of DbetaH(Cre/0) mice or into the raphe of ePet(Cre/0) mice. Following injection of AAV2 into RVLM of TH-Cre rats, phenylethanolamine N-methyl transferase and VGLUT2 immunoreactivities were highly colocalized in DMV within EYFP-positive or EYFP-negative axonal varicosities. Ultrastructurally, mCherry terminals from RVLM-CA neurons in DbetaH(Cre/0) mice made predominantly asymmetric synapses with choline acetyl-transferase-ir DMV neurons. Photostimulation of ChR2-positive axons in DbetaH(Cre/0) mouse brain slices produced EPSCs in 71% of tested DMV preganglionic neurons (PGNs) but no IPSCs. Photostimulation (20 Hz) activated PGNs up to 8 spikes/s (current-clamp). EPSCs were eliminated by tetrodotoxin, reinstated by 4-aminopyridine, and blocked by ionotropic glutamate receptor blockers. In conclusion, VGLUT2 is expressed by RVLM-CA (C1) neurons in rats and mice regardless of the presence of AAV2, the C1 neurons activate DMV parasympathetic PGNs monosynaptically and this connection uses glutamate as an ionotropic transmitter. PMID- 23345224 TI - Laminar transformation of frequency organization in auditory cortex. AB - The mammalian neocortex is a six-layered structure organized into radial columns. Within sensory cortical areas, information enters in the thalamorecipient layer and is further processed in supragranular and infragranular layers. Within the neocortex, topographic maps of stimulus features are present, but whether topographic patterns of active neurons change between laminae is unknown. Here, we used in vivo two-photon Ca(2+) imaging to probe the organization of the mouse primary auditory cortex and show that the spatial organization of neural response properties (frequency tuning) within the thalamorecipient layer (L3b/4) is more homogeneous than in supragranular layers (L2/3). Moreover, stimulus-related correlations between pairs of neurons are higher in the thalamorecipient layer, whereas stimulus-independent trial-to-trial covariance is higher in supragranular neurons. These findings reveal a transformation of sensory representations that occurs between layers within the auditory cortex, which could generate sequentially more complex analysis of the acoustic scene incorporating a broad range of spectrotemporal sound features. PMID- 23345225 TI - R7 photoreceptor axon growth is temporally controlled by the transcription factor Ttk69, which inhibits growth in part by promoting transforming growth factor beta/activin signaling. AB - Work on axon growth has classically focused on understanding how extrinsic cues control growth cone dynamics independent of the cell body. However, more recently, neuron-intrinsic transcription factors have been shown to influence both normal and regenerative axon growth, suggesting that understanding their mechanism of action is of clinical importance. We are studying axon targeting in the Drosophila visual system and here show that the BTB/POZ zinc-finger transcription factor Tramtrack69 (Ttk69) plays an instructive role in inhibiting the growth of R7 photoreceptor axon terminals. Although ttk69 mutant R7 axons project to the correct medullar target layer, M6, their terminals fail to remain retinotopically restricted and instead grow laterally within M6. This overgrowth is not caused by an inability to be repelled by neighboring R7 axons or by an inability to recognize and initiate synapse formation with postsynaptic targets. The overgrowth is progressive and occurs even if contact between ttk69 mutant R7 axons and their normal target layer is disrupted. Ttk69 is first expressed in wild-type R7s after their axons have reached the medulla; ttk69 mutant R7 axon terminal overgrowth begins shortly after this time point. We find that expressing Ttk69 prematurely in R7s collapses their growth cones and disrupts axon extension, indicating that Ttk69 plays an instructive role in this process. A TGF beta/Activin pathway was shown previously to inhibit R7 axon terminal growth. We find that Ttk69 is required for normal activation of this pathway but that Ttk69 likely also inhibits R7 axon growth by a TGF-beta/Activin-independent mechanism. PMID- 23345226 TI - Covariance-based synaptic plasticity in an attractor network model accounts for fast adaptation in free operant learning. AB - In free operant experiments, subjects alternate at will between targets that yield rewards stochastically. Behavior in these experiments is typically characterized by (1) an exponential distribution of stay durations, (2) matching of the relative time spent at a target to its relative share of the total number of rewards, and (3) adaptation after a change in the reward rates that can be very fast. The neural mechanism underlying these regularities is largely unknown. Moreover, current decision-making neural network models typically aim at explaining behavior in discrete-time experiments in which a single decision is made once in every trial, making these models hard to extend to the more natural case of free operant decisions. Here we show that a model based on attractor dynamics, in which transitions are induced by noise and preference is formed via covariance-based synaptic plasticity, can account for the characteristics of behavior in free operant experiments. We compare a specific instance of such a model, in which two recurrently excited populations of neurons compete for higher activity, to the behavior of rats responding on two levers for rewarding brain stimulation on a concurrent variable interval reward schedule (Gallistel et al., 2001). We show that the model is consistent with the rats' behavior, and in particular, with the observed fast adaptation to matching behavior. Further, we show that the neural model can be reduced to a behavioral model, and we use this model to deduce a novel "conservation law," which is consistent with the behavior of the rats. PMID- 23345227 TI - On high-frequency field oscillations (>100 Hz) and the spectral leakage of spiking activity. AB - Recent reports converge to the idea that high-frequency oscillations in local field potentials (LFPs) represent multiunit activity. In particular, the amplitude of LFP activity above 100 Hz-commonly referred to as "high-gamma" or "epsilon" band-was found to correlate with firing rate. However, other studies suggest the existence of true LFP oscillations at this frequency range that are different from the well established ripple oscillations. Using multisite recordings of the hippocampus of freely moving rats, we show here that high frequency LFP oscillations can represent either the spectral leakage of spiking activity or a genuine rhythm, depending on recording location. Both spike-leaked, spurious activity and true fast oscillations couple to theta phase; however, the two phenomena can be clearly distinguished by other key features, such as preferred coupling phase and spectral signatures. Our results argue against the idea that all high-frequency LFP activity stems from spike contamination and suggest avoiding defining brain rhythms solely based on frequency range. PMID- 23345228 TI - The upregulation of translocator protein (18 kDa) promotes recovery from neuropathic pain in rats. AB - At present, effective drug for treatment of neuropathic pain is still lacking. Recent studies have shown that the ligands of translocator protein (TSPO, 18 kDa), a peripheral receptor for benzodiazepine, modulate inflammatory pain. Here, we report that TSPO was upregulated in astrocytes and microglia in the ipsilateral spinal dorsal horn of rats following L5 spinal nerve ligation (L5 SNL), lasting until the vanishing of the behavioral signs of neuropathic pain (~50 d). Importantly, a single intrathecal injection of specific TSPO agonists Ro5-4864 or FGIN-1-27 at 7 and 21 d after L5 SNL depressed the established mechanical allodynia and thermal hyperalgesia dramatically, and the effect was abolished by pretreatment with AMG, a neurosteroid synthesis inhibitor. Mechanically, Ro5-4864 substantially inhibited spinal astrocytes but not microglia, and reduced the production of tumor necrosis factor-alpha (TNF-alpha) in vivo and in vitro. The anti-neuroinflammatory effect was also prevented by AMG. Interestingly, TSPO expression returned to control levels or decreased substantially, when neuropathic pain healed naturally or was reversed by Ro5 4864, suggesting that the role of TSPO upregulation might be to promote recovery from the neurological disorder. Finally, the neuropathic pain and the upregulation of TSPO by L5 SNL were prevented by pharmacological blockage of Toll like receptor 4 (TLR4). These data suggested that TSPO might be a novel therapeutic target for the treatment of neuropathic pain. PMID- 23345229 TI - Interglomerular lateral inhibition targeted on external tufted cells in the olfactory bulb. AB - Lateral inhibition between neurons occurs in many different sensory systems, where it can perform such functions as contrast enhancement. In the olfactory bulb, lateral inhibition may occur between odorant receptor-specific glomeruli that are linked anatomically by GABAergic granule cells (GCs) and cells within the glomerular layer, although evidence supporting lateral inhibition at a functional level is modest. Here, we used patch-clamp, imaging, and glutamate uncaging methods in rat olfactory bulb slices to test for the presence of interglomerular lateral inhibition, as well as its underlying mechanisms. We found that a conditioning stimulus applied at one or a small group of glomeruli could suppress stimulus-evoked excitation of output mitral cells (MCs) at another glomerulus for interstimulus intervals of 20-50 ms and glomerular separations of up to 600 MUm. The observed lateral inhibition was entirely dependent on circuitry within the glomerular layer, rather than GCs, and it involved GABAergic synaptic inputs that were targeted mainly onto tufted cells, which act as intermediaries in the excitation between olfactory sensory neurons and MCs. The key cell type responsible for mediating lateral interactions between glomeruli were GABAergic short-axon cells. These results suggest a functional segregation of GABAergic cells within the bulb, with one set located in the glomerular layer mediating suppression of MC spiking across glomeruli, and a second set, the GCs, synchronizing different glomeruli. PMID- 23345230 TI - Selective ablation of pillar and deiters' cells severely affects cochlear postnatal development and hearing in mice. AB - Mammalian auditory hair cells (HCs) are inserted into a well structured environment of supporting cells (SCs) and acellular matrices. It has been proposed that when HCs are irreversibly damaged by noise or ototoxic drugs, surrounding SCs seal the epithelial surface and likely extend the survival of auditory neurons. Because SCs are more resistant to damage than HCs, the effects of primary SC loss on HC survival and hearing have received little attention. We used the Cre/loxP system in mice to specifically ablate pillar cells (PCs) and Deiters' cells (DCs). In Prox1CreER(T2)+/-;Rosa26(DTA/+) (Prox1DTA) mice, Cre estrogen receptor (CreER) expression is driven by the endogenous Prox1 promoter and, in presence of tamoxifen, removes a stop codon in the Rosa26(DTA/+) allele and induces diphtheria toxin fragment A (DTA) expression. DTA produces cell autonomous apoptosis. Prox1DTA mice injected with tamoxifen at postnatal days 0 (P0) and P1 show significant DC and outer PC loss at P2-P4, that reaches ~70% by 1 month. Outer HC loss follows at P14 and is almost complete at 1 month, while inner HCs remain intact. Neural innervation to the outer HCs is disrupted in Prox1DTA mice and auditory brainstem response thresholds in adults are 40-50 dB higher than in controls. The hearing deficit correlates with loss of cochlear amplification. Remarkably, in Prox1DTA mice, the auditory epithelium preserves the ability to seal the reticular lamina and spiral ganglion neuron counts are normal, a key requirement for cochlear implant success. In addition, our results show that cochlear SC pools should be appropriately replenished during HC regeneration strategies. PMID- 23345232 TI - Presenilin1 regulates histamine neuron development and behavior in zebrafish, danio rerio. AB - Modulatory neurotransmitters, including the histaminergic system, are essential in mediating cognitive functions affected in Alzheimer's disease (AD). The roles of disease genes associated with AD, most importantly the presenilin1 gene (psen1), are poorly understood. We studied the role of psen1 in plasticity of the brain histaminergic system using a novel psen1 mutant zebrafish, Danio rerio. We found that in psen1(-/-) zebrafish, the histaminergic system is altered throughout life. At 7 d postfertilization (dpf) the histamine neuron number was reduced in psen1(-/-) compared with wild-type (WT) fish; at 2 months of age the histamine neuron number was at the same level as that in WT fish. In 1-year-old zebrafish, the histamine neuron number was significantly increased in psen1(-/-) fish compared with WT fish. These changes in histamine neuron number were accompanied by changes in histamine-driven behaviors. Treatment with DAPT, a gamma-secretase inhibitor, similarly interfered with the development of the histaminergic neurons. We also assessed the expression of gamma-secretase regulated Notch1a mRNA and beta-catenin at different time points. Notch1a mRNA level was reduced in psen1(-/-) compared with WT fish, whereas beta-catenin was slightly upregulated in the hypothalamus of psen1(-/-) compared with WT fish at 7 dpf. The results reveal a life-long brain plasticity in both the structure of the histaminergic system and its functions induced by altered Notch1a activity as a consequence of psen1 mutation. The new histaminergic neurons in aging zebrafish brain may arise as a result of phenotypic plasticity or represent newly differentiated stem cells. PMID- 23345231 TI - Central amygdala GluA1 facilitates associative learning of opioid reward. AB - GluA1 subunits of AMPA glutamate receptors are implicated in the synaptic plasticity induced by drugs of abuse for behaviors of drug addiction, but GluA1 roles in emotional learning and memories of drug reward in the development of drug addiction remain unclear. In this study of the central nucleus of the amygdala (CeA), which is critical in emotional learning of drug reward, we investigated how adaptive changes in the expression of GluA1 subunits affected the learning process of opioid-induced context-reward association (associative learning) for the acquisition of reward-related behavior. In CeA neurons, we found that CeA GluA1 expression was significantly increased 2 h after conditioning treatment with morphine, but not 24 h after the conditioning when the behavior of conditioned place reference (CPP) was fully established in rats. Adenoviral overexpression of GluA1 subunits in CeA accelerated associative learning, as shown by reduced minimum time of morphine conditioning required for CPP acquisition and by facilitated CPP extinction through extinction training with no morphine involved. Adenoviral shRNA-mediated downregulation of CeA GluA1 produced opposite effects, inhibiting the processes of both CPP acquisition and CPP extinction. Adenoviral knockdown of CeA GluA2 subunits facilitated CPP acquisition, but did not alter CPP extinction. Whole-cell recording revealed enhanced electrophysiological properties of postsynaptic GluA2-lacking AMPA receptors in adenoviral GluA1-infected CeA neurons. These results suggest that increased GluA1 expression of CeA AMPA receptors facilitates the associative learning of context-drug reward, an important process in both development and relapse of drug-seeking behaviors in drug addiction. PMID- 23345233 TI - Target-specific IPSC kinetics promote temporal processing in auditory parallel pathways. AB - The acoustic environment contains biologically relevant information on timescales from microseconds to tens of seconds. The auditory brainstem nuclei process this temporal information through parallel pathways that originate in the cochlear nucleus from different classes of cells. Although the roles of ion channels and excitatory synapses in temporal processing have been well studied, the contribution of inhibition is less well understood. Here, we show in CBA/CaJ mice that the two major projection neurons of the ventral cochlear nucleus, the bushy and T-stellate cells, receive glycinergic inhibition with different synaptic conductance time courses. Bushy cells, which provide precisely timed spike trains used in sound localization and pitch identification, receive slow inhibitory inputs. In contrast, T-stellate cells, which encode slower envelope information, receive inhibition that is eightfold faster. Both types of inhibition improved the precision of spike timing but engage different cellular mechanisms and operate on different timescales. Computer models reveal that slow IPSCs in bushy cells can improve spike timing on the scale of tens of microseconds. Although fast and slow IPSCs in T-stellate cells improve spike timing on the scale of milliseconds, only fast IPSCs can enhance the detection of narrowband acoustic signals in a complex background. Our results suggest that target-specific IPSC kinetics are critical for the segregated parallel processing of temporal information from the sensory environment. PMID- 23345235 TI - Sustained transcription of the immediate early gene Arc in the dentate gyrus after spatial exploration. AB - After spatial exploration in rats, Arc mRNA is expressed in ~2% of dentate gyrus (DG) granule cells, and this proportion of Arc-positive neurons remains stable for ~8 h. This long-term presence of Arc mRNA following behavior is not observed in hippocampal CA1 pyramidal cells. We report here that in rats ~50% of granule cells with cytoplasmic Arc mRNA, induced some hours previously during exploration, also show Arc expression in the nucleus. This suggests that recent transcription can occur long after the exploration behavior that elicited it. To confirm that the delayed nuclear Arc expression was indeed recent transcription, Actinomycin D was administered immediately after exploration. This treatment resulted in inhibition of recent Arc expression both when evaluated shortly after exploratory behavior as well as after longer time intervals. Together, these data demonstrate a unique kinetic profile for Arc transcription in hippocampal granule neurons following behavior that is not observed in other cell types. Among a number of possibilities, this sustained transcription may provide a mechanism that ensures that the synaptic connection weights in the sparse population of granule cells recruited during a given behavioral event are able to be modified. PMID- 23345236 TI - Affective and sensorimotor components of emotional prosody generation. AB - Although advances have been made regarding how the brain perceives emotional prosody, the neural bases involved in the generation of affective prosody remain unclear and debated. Two models have been forged on the basis of clinical observations: a first model proposes that the right hemisphere sustains production and comprehension of emotional prosody, while a second model proposes that emotional prosody relies heavily on basal ganglia. Here, we tested their predictions in two functional magnetic resonance imaging experiments that used a cue-target paradigm, which allows distinguishing affective from sensorimotor aspects of emotional prosody generation. Both experiments show that when participants prepare for emotional prosody, bilateral ventral striatum is specifically activated and connected to temporal poles and anterior insula, regions in which lesions frequently cause dysprosody. The bilateral dorsal striatum is more sensitive to cognitive and motor aspects of emotional prosody preparation and production and is more strongly connected to the sensorimotor speech network compared with the ventral striatum. Right lateralization during increased prosodic processing is confined to the posterior superior temporal sulcus, a region previously associated with perception of emotional prosody. Our data thus provide physiological evidence supporting both models and suggest that bilateral basal ganglia are involved in modulating motor behavior as a function of affective state. Right lateralization of cortical regions mobilized for prosody control could point to efficient processing of slowly changing acoustic speech parameters in the ventral stream and thus identify sensorimotor processing as an important factor contributing to right lateralization of prosody. PMID- 23345234 TI - Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior. AB - Serotonin (5-hydroxytryptamine; 5-HT) signaling through the 5-HT(2C) receptor (5 HT(2C)R) is essential in normal physiology, whereas aberrant 5-HT(2C)R function is thought to contribute to the pathogenesis of multiple neural disorders. The 5 HT(2C)R interacts with specific protein partners, but the impact of such interactions on 5-HT(2C)R function is poorly understood. Here, we report convergent cellular and behavioral data that the interaction between the 5 HT(2C)R and protein phosphatase and tensin homolog (PTEN) serves as a regulatory mechanism to control 5-HT(2C)R-mediated biology but not that of the closely homologous 5-HT(2A)R. A peptide derived from the third intracellular loop of the human 5-HT(2C)R [3L4F (third loop, fourth fragment)] disrupted the association, allosterically augmented 5-HT(2C)R-mediated signaling in live cells, and acted as a positive allosteric modulator in rats in vivo. We identified the critical residues within an 8 aa fragment of the 3L4F peptide that maintained efficacy (within the picomolar range) in live cells similar to that of the 3L4F peptide. Last, molecular modeling identified key structural features and potential interaction sites of the active 3L4F peptides against PTEN. These compelling data demonstrate the specificity and importance of this protein assembly in cellular events and behaviors mediated by 5-HT(2C)R signaling and provide a chemical guidepost to the future development of drug-like peptide or small-molecule inhibitors as neuroprobes to study 5-HT(2C)R allostery and therapeutics for 5 HT(2C)R-mediated disorders. PMID- 23345237 TI - Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy. AB - Neuronal network hyperexcitability underlies the pathogenesis of seizures and is a component of some degenerative neurological disorders such as Alzheimer's disease (AD). Recently, the microtubule-binding protein tau has been implicated in the regulation of network synchronization. Genetic removal of Mapt, the gene encoding tau, in AD models overexpressing amyloid-beta (Abeta) decreases hyperexcitability and normalizes the excitation/inhibition imbalance. Whether this effect of tau removal is specific to Abeta mouse models remains to be determined. Here, we examined tau as an excitability modifier in the non-AD nervous system using genetic deletion of tau in mouse and Drosophila models of hyperexcitability. Kcna1(-/-) mice lack Kv1.1-delayed rectifier currents and exhibit severe spontaneous seizures, early lethality, and megencephaly. Young Kcna1(-/-) mice retained wild-type levels of Abeta, tau, and tau phospho Thr(231). Decreasing tau in Kcna1(-/-) mice reduced hyperexcitability and alleviated seizure-related comorbidities. Tau reduction decreased Kcna1(-/-) video-EEG recorded seizure frequency and duration as well as normalized Kcna1(-/ ) hippocampal network hyperexcitability in vitro. Additionally, tau reduction increased Kcna1(-/-) survival and prevented megencephaly and hippocampal hypertrophy, as determined by MRI. Bang-sensitive Drosophila mutants display paralysis and seizures in response to mechanical stimulation, providing a complementary excitability assay for epistatic interactions. We found that tau reduction significantly decreased seizure sensitivity in two independent bang sensitive mutant models, kcc and eas. Our results indicate that tau plays a general role in regulating intrinsic neuronal network hyperexcitability independently of Abeta overexpression and suggest that reducing tau function could be a viable target for therapeutic intervention in seizure disorders and antiepileptogenesis. PMID- 23345238 TI - Retinoic acid induces blood-brain barrier development. AB - The blood-brain barrier (BBB) is crucial in the maintenance of a controlled environment within the brain to safeguard optimal neuronal function. The endothelial cells (ECs) of the BBB possess specific properties that restrict the entry of cells and metabolites into the CNS. The specialized BBB endothelial phenotype is induced during neurovascular development by surrounding cells of the CNS. However, the molecular differentiation of the BBB endothelium remains poorly understood. Retinoic acid (RA) plays a crucial role in the brain during embryogenesis. Because radial glial cells supply the brain with RA during the developmental cascade and associate closely with the developing vasculature, we hypothesize that RA is important for the induction of BBB properties in brain ECs. Analysis of human postmortem fetal brain tissue shows that the enzyme mainly responsible for RA synthesis, retinaldehyde dehydrogenase, is expressed by radial glial cells. In addition, the most important receptor for RA-driven signaling in the CNS, RA-receptor beta (RARbeta), is markedly expressed by the developing brain vasculature. Our findings have been further corroborated by in vitro experiments showing RA- and RARbeta-dependent induction of different aspects of the brain EC barrier. Finally, pharmacologic inhibition of RAR activation during the differentiation of the murine BBB resulted in the leakage of a fluorescent tracer as well as serum proteins into the developing brain and reduced the expression levels of important BBB determinants. Together, our results point to an important role for RA in the induction of the BBB during human and mouse development. PMID- 23345239 TI - Appetitive learning requires the alpha1-like octopamine receptor OAMB in the Drosophila mushroom body neurons. AB - Associative learning is a fundamental form of behavioral plasticity. Octopamine plays central roles in various learning types in invertebrates; however, the target receptors and underlying mechanisms are poorly understood. Drosophila provides a powerful system to uncover the mechanisms for learning and memory. Here, we report that OAMB in the mushroom body neurons mediates the octopamine's signal for appetitive olfactory learning. The octopamine receptor OAMB has two isoforms (OAMB-K3 and OAMB-AS), differing in the third cytoplasmic loop and downstream sequence. The activation of each OAMB isoform increases intracellular Ca(2+) similar to the alpha1 adrenergic receptor, while OAMB-K3 additionally stimulates cAMP production. The oamb-null mutants showed severely impaired learning in appetitive olfactory conditioning that tests flies' capacity to learn and remember the odor associated with sugar reward. This deficit was also seen in the hypomorphic mutant with reduced OAMB expression in the mushroom bodies, the brain structure crucial for olfactory conditioning. Consistently, the oamb mutant's learning phenotype was fully rescued by conditional expression of either OAMB isoform in the mushroom body alphabeta and gamma neurons. These results indicate that the OAMB receptor is a key molecule mediating the octopamine's signal for appetitive olfactory learning and its functional site is the mushroom body alphabeta and gamma neurons. This study represents a critical step forward in understanding the cellular mechanism and neural circuit mediating reward learning and memory. PMID- 23345240 TI - Target selectivity of feedforward inhibition by striatal fast-spiking interneurons. AB - The striatal microcircuitry consists of a vast majority of projection neurons, the medium spiny neurons (MSNs), and a small yet diverse population of interneurons. To understand how activity is orchestrated within the striatum, it is essential to unravel the functional connectivity between the different neuronal types. Fast-spiking (FS) interneurons provide feedforward inhibition to both direct and indirect pathway MSNs and are important in sculpting their output to downstream basal ganglia nuclei. FS interneurons are also interconnected with each other via electrical and chemical synapses; however, whether and how they inhibit other striatal interneuron types remains unknown. In this study we combined multineuron whole-cell recordings with optogenetics to determine the target selectivity of feedforward inhibition by striatal FS interneurons. Using transgenic and viral approaches we directed expression of channelrhodopsin 2 (ChR2) to FS interneurons to study their connectivity within the mouse striatal microcircuit. Optogenetic stimulation of ChR2-expressing FS interneurons generated strong and reliable GABA(A)-dependent synaptic inputs in MSNs. In sharp contrast, simultaneously recorded neighboring cholinergic interneurons did not receive any synaptic inputs from photostimulated FS cells, and a minority of low threshold spiking (LTS) interneurons responded weakly. We further tested the synaptic connectivity between FS and LTS interneurons using paired recordings, which showed only sparse connectivity. Our results show that striatal FS interneurons form a feedforward inhibitory circuit that is target selective, inhibiting projection neurons while avoiding cholinergic interneurons and sparsely contacting LTS interneurons, thus supporting independent modulation of MSN activity by the different types of striatal interneurons. PMID- 23345241 TI - Gating of sensory input by spontaneous cortical activity. AB - The activity of neural populations is determined not only by sensory inputs but also by internally generated patterns. During quiet wakefulness, the brain produces spontaneous firing events that can spread over large areas of cortex and have been suggested to underlie processes such as memory recall and consolidation. Here we demonstrate a different role for spontaneous activity in sensory cortex: gating of sensory inputs. We show that population activity in rat auditory cortex is composed of transient 50-100 ms packets of spiking activity that occur irregularly during silence and sustained tone stimuli, but reliably at tone onset. Population activity within these packets had broadly consistent spatiotemporal structure, but the rate and also precise relative timing of action potentials varied between stimuli. Packet frequency varied with cortical state, with desynchronized state activity consistent with superposition of multiple overlapping packets. We suggest that such packets reflect the sporadic opening of a "gate" that allows auditory cortex to broadcast a representation of external sounds to other brain regions. PMID- 23345242 TI - Stream-related preferences of inputs to the superior colliculus from areas of dorsal and ventral streams of mouse visual cortex. AB - Previous studies of intracortical connections in mouse visual cortex have revealed two subnetworks that resemble the dorsal and ventral streams in primates. Although calcium imaging studies have shown that many areas of the ventral stream have high spatial acuity whereas areas of the dorsal stream are highly sensitive for transient visual stimuli, there are some functional inconsistencies that challenge a simple grouping into "what/perception" and "where/action" streams known in primates. The superior colliculus (SC) is a major center for processing of multimodal sensory information and the motor control of orienting the eyes, head, and body. Visual processing is performed in superficial layers, whereas premotor activity is generated in deep layers of the SC. Because the SC is known to receive input from visual cortex, we asked whether the projections from 10 visual areas of the dorsal and ventral streams terminate in differential depth profiles within the SC. We found that inputs from primary visual cortex are by far the strongest. Projections from the ventral stream were substantially weaker, whereas the sparsest input originated from areas of the dorsal stream. Importantly, we found that ventral stream inputs terminated in superficial layers, whereas dorsal stream inputs tended to be patchy and either projected equally to superficial and deep layers or strongly preferred deep layers. The results suggest that the anatomically defined ventral and dorsal streams contain areas that belong to distinct functional systems, specialized for the processing of visual information and visually guided action, respectively. PMID- 23345243 TI - Neural integration of risk and effort costs by the frontal pole: only upon request. AB - Rewards in real life are rarely received without incurring costs and successful reward harvesting often involves weighing and minimizing different types of costs. In the natural environment, such costs often include the physical effort required to obtain rewards and potential risks attached to them. Costs may also include potential risks. In this study, we applied fMRI to explore the neural coding of physical effort costs as opposed to costs associated with risky rewards. Using an incentive-compatible valuation mechanism, we separately measured the subjective costs associated with effortful and risky options. As expected, subjective costs of options increased with both increasing effort and increasing risk. Despite the similar nature of behavioral discounting of effort and risk, distinct regions of the brain coded these two cost types separately, with anterior insula primarily processing risk costs and midcingulate and supplementary motor area (SMA) processing effort costs. To investigate integration of the two cost types, we also presented participants with options that combined effortful and risky elements. We found that the frontal pole integrates effort and risk costs through functional coupling with the SMA and insula. The degree to which the latter two regions influenced frontal pole activity correlated with participant-specific behavioral sensitivity to effort and risk costs. These data support the notion that, although physical effort costs may appear to be behaviorally similar to other types of costs, such as risk, they are treated separately at the neural level and are integrated only if there is a need to do so. PMID- 23345244 TI - Complexin activates exocytosis of distinct secretory vesicles controlled by different synaptotagmins. AB - Complexins are SNARE-complex binding proteins essential for the Ca(2+)-triggered exocytosis mediated by synaptotagmin-1, -2, -7, or -9, but the possible role of complexins in other types of exocytosis controlled by other synaptotagmin isoforms remains unclear. Here we show that, in mouse olfactory bulb neurons, synaptotagmin-1 localizes to synaptic vesicles and to large dense-core secretory vesicles as reported previously, whereas synaptotagmin-10 localizes to a distinct class of peptidergic secretory vesicles containing IGF-1. Both synaptotagmin-1 dependent synaptic vesicle exocytosis and synaptotagmin-10-dependent IGF-1 exocytosis were severely impaired by knockdown of complexins, demonstrating that complexin acts as a cofactor for both synaptotagmin-1 and synaptotagmin-10 despite the functional differences between these synaptotagmins. Rescue experiments revealed that only the activating but not the clamping function of complexins was required for IGF-1 exocytosis controlled by synaptotagmin-10. Thus, our data indicate that complexins are essential for activation of multiple types of Ca(2+)-induced exocytosis that are regulated by different synaptotagmin isoforms. These results suggest that different types of regulated exocytosis are mediated by similar synaptotagmin-dependent fusion mechanisms, that particular synaptotagmin isoforms confer specificity onto different types of regulated exocytosis, and that complexins serve as universal synaptotagmin adaptors for all of these types of exocytosis independent of which synaptotagmin isoform is involved. PMID- 23345245 TI - Indian hedgehog B function is required for the specification of oligodendrocyte progenitor cells in the zebrafish CNS. AB - A subset of ventral spinal cord precursors, known as pMN precursor cells, initially generate motor neurons and then oligodendrocyte progenitor cells (OPCs), which migrate and differentiate as myelinating oligodendrocytes in the developing neural tube. The switch between motor neuron and oligodendrocyte production by the pMN neural precursors is an important step in building a functional nervous system. However, the precise mechanism that orchestrates the sequential generation of motor neurons and oligodendrocytes within the common population of pMN precursors is still unclear. The current study demonstrates that Indian Hedgehog b (Ihhb), previously known as Echidna Hedgehog, begins to be expressed in the floor plate cells of the ventral spinal cord at the time of OPC specification in zebrafish embryos. Ihhb loss-of-function analysis revealed that Ihhb function is required for OPC specification from pMN precursors by negatively regulating the proliferation of neural precursors. Finally, results showed that Sonic Hedgehog (Shh) could not replace Ihhb function in OPC specification, suggesting that Ihhb and Shh play separate roles in OPC specification. Altogether, data from the present study suggested a novel mechanism, mediated by Ihhb, for the sequential generation of motor neurons and oligodendrocytes from pMN precursors in the ventral spinal cord of zebrafish embryos. PMID- 23345246 TI - MicroRNA-182 regulates amygdala-dependent memory formation. AB - De novo protein synthesis supports long-lasting functional and structural plasticity and is a molecular requirement for new memory formation. Recent evidence has suggested that microRNAs may be involved in regulating the molecular mechanisms underlying neural plasticity. MicroRNAs are endogenous, noncoding RNAs capable of post-transcriptional repression of their mRNA targets. To explore the potential for microRNA-mediated regulation of amygdala-dependent memory formation, we performed expression profiling of microRNAs in the lateral amygdala of rats 1 h after auditory fear conditioning. Microarray analysis revealed that over half of all known microRNAs are endogenously expressed in the lateral amygdala, with 7 microRNAs upregulated and 32 downregulated by auditory fear training. Bioinformatic analysis identified several of the downregulated microRNAs as potential repressors of actin-regulating proteins known to be involved in plasticity and memory. Downregulation of one of these microRNAs by auditory fear conditioning, miR-182, was confirmed by quantitative real-time PCR. Overexpression of miR-182 within the lateral amygdala resulted in decreased expression of the protein but not mRNA of two synapse-enriched regulators of actin known to modulate structural plasticity, cortactin and Rac1. The overexpression of miR-182 also disrupted long-term but not short-term auditory fear memory. These data indicate that learning-induced suppression of miR-182, a microRNA previously uncharacterized in the brain, supports long-term memory formation in the amygdala and suggests it does so, at least in part, through the derepression of key actin-regulating proteins. These findings further indicate that microRNAs may represent a previously underappreciated mechanism for regulating protein synthesis during memory consolidation. PMID- 23345247 TI - Calcium channel agonists protect against neuromuscular dysfunction in a genetic model of TDP-43 mutation in ALS. AB - TAR DNA binding protein (TDP-43, encoded by the TARDBP gene) has recently been shown to be associated with amyotrophic lateral sclerosis (ALS), but the early pathophysiological deficits causing impairment in motor function are unknown. Here we expressed the wild-type human gene (wtTARDBP) or the ALS mutation G348C (mutTARDBP) in zebrafish larvae and characterized their motor (swimming) activity and the structure and function of their neuromuscular junctions (NMJs). Of these groups only mutTARDBP larvae showed impaired swimming and increased motoneuron vulnerability with reduced synaptic fidelity, reduced quantal transmission, and more orphaned presynaptic and postsynaptic structures at the NMJ. Remarkably, all behavioral and cellular features were stabilized by chronic treatment with either of the L-type calcium channel agonists FPL 64176 or Bay K 8644. These results indicate that expression of mutTARDBP results in defective NMJs and that calcium channel agonists could be novel therapeutics for ALS. PMID- 23345248 TI - Predicting infections in high-risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: a retrospective multicenter study. AB - Hypomethylating agents have become the standard therapy for patients with high risk myelodysplastic syndrome (MDS). In Israel, azacitidine (AZA) is routinely used. Yet, infectious complications are common during AZA therapy. The current study was aimed to evaluate the incidence and predisposing risk factors for infections in AZA-treated patients. This retrospective study included patients treated with AZA in 18 Israeli medical institutions between 2008 and 2011. Data on 184 patients [157 high-risk MDS and 27 acute myeloid leukemia (AML)], with a median age of 71.6 (range 29-92) were recorded. Overall, 153 infectious events were reported during 928 treatment cycles (16.5%) administered to 100 patients. One hundred fourteen, 114/153 (75%) events required hospitalization and 30 (19.6%) were fatal. In a univariate analysis, unfavorable cytogenetics, low neutrophil, hemoglobin (Hb) and platelet (PLT) counts were found to be associated with infections (24.4% vs. 12.9%, P < 0.0001; 27% vs. 13.5%, P < 0.0001; 20.4% vs. 11%, P < 0.0001 and 29.2% vs. 14.2%, P < 0.0001, respectively). In multivariate analysis, only low Hb level, low PLT count, and unfavorable cytogenetics remained significant. Prior to therapy, poor cytogenetics, PLT count below 20 * 109/L and neutrophil count below 0.5 * 109/L were predictive of the risk of infection during the first two cycles of therapy. In conclusion, patients with unfavorable cytogenetics, presenting with low neutrophil and PLT counts, are susceptible to infections. Evaluation of infection risk should be repeated prior to each cycle. Patients with poor cytogenetics in whom AZA is prescribed despite low PLT count are particularly at high risk for infections and infection prophylaxis may be considered. PMID- 23345249 TI - A pH-sensitive lasso-based rotaxane molecular switch. AB - The synthesis of a pH-sensitive two-station [1]rotaxane molecular switch by self entanglement of a non-interlocked hermaphrodite molecule, containing an anilinium and triazole moieties, is reported. The anilinium was chosen as the best template for the macrocycle benzometaphenylene[25]crown-8 (BMP25C8) and allowed the self entanglement of the molecule. The equilibrium between the hermaphrodite molecule and the pseudo[1]rotaxane was studied by (1)H NMR spectroscopy: the best conditions of self-entanglement were found in the less polar solvent CD(2)Cl(2) and at high dilution. The triazole moiety was then benzylated to afford a benzyltriazolium moiety, which then played a dual role. On one hand, it acts as a bulky gate to trap the BMP25C8, thus to avoid any self-disentanglement of the molecular architecture. On another hand, it acts as a second molecular station for the macrocycle. At acidic pH, the BMP25C8 resides around the best anilinium molecular station, displaying the lasso [1]rotaxane in a loosened conformation. The deprotonation of the anilinium molecular station triggers the shuttling of the BMP25C8 around the triazolium moiety, therefore tightening the lasso. PMID- 23345250 TI - Interrelating sentinel event alert #38 with the ACR guidance document on MR safe practices: 2013. An MRI accreditation safety review tool. AB - When, in 2008, the Joint Commission released its Sentinel Event Alert #38 regarding MRI safety, it joined the ACR's Guidance Document on MR Safe Practices as one of two radiology best-practice documents establishing MR safety protections. However, particularly for MR providers who held both modality-level accreditation from the ACR, and enterprise-level accreditation from the Joint Commission, there has been confusion about which institution's standard takes precedence, or whether there are inherent conflicts between the two. With the release of the 2013 update to the ACR Guidance Document on MR Safe Practices, the authors have cross-referenced the performance criteria of both MR safety standards, and correlated the ACR Guidance Document performance criteria with the Joint Commission's Environment of Care standards. PMID- 23345251 TI - Micelle-like molecular capsules with anthracene shells as photoactive hosts. PMID- 23345252 TI - Treatment planning for a TCPC test case: a numerical investigation under rigid and moving wall assumptions. AB - The hemodynamics in patients with total cavopulmonary connections (TCPC) is generally very complex and characterized by patient-to-patient variability. To better understand its effect on patients' outcome, CFD models are widely used, also to test and optimize surgical options before their implementation. These models often assume rigid geometries, despite the motion experienced by thoracic vessels that could influence the hemodynamics predictions. By improving their accuracy and expanding the range of simulated interventions, the benefit of treatment planning for patients is expected to increase. We simulate three types of intervention on a patient-specific 3D model, and compare their predicted outcome with baseline condition: a decrease in pulmonary vascular resistance obtainable with medications; a surgical revision of the connection design; the introduction of a fenestration in the TCPC wall. The simulations are performed both with rigid wall assumption and including patient-specific TCPC wall motion, reconstructed from a 4DMRI dataset. The results show the effect of each option on clinically important metrics and highlight the impact of patient-specific wall motion. The largest differences between rigid and moving wall models are observed in measures of energetic efficiency of TCPC as well as in hepatic flow distribution and transit time of seeded particles through the connection. PMID- 23345253 TI - Positive effects of short course androgen therapy on the neurodevelopmental outcome in boys with 47,XXY syndrome at 36 and 72 months of age. AB - The effects of early androgen treatment on neurodevelopmental performance in pre pubertal boys with 47,XXY have not been well investigated. The influence of hormones on brain development in humans suggests that a positive effect on neurodevelopmental outcome in young boys with XXY may be plausible with hormone replacement therapy. The aim of the study was to investigate retrospectively if an early course of androgen treatment (three injections of testosterone enanthate, 25 mg, each) had an impact on specific domains of neurodevelopmental function in boys with 47,XXY at 36 and 72 months of age. One hundred one boys with a karyotype of 47,XXY had neurodevelopmental assessments. The retrospective chart review resulted in one group (n = 34) who had received androgen treatment during infancy and the second group was untreated (N = 67). Statistical analysis was completed to determine if there was a positive effect from treatment observed at 36 and at 72 months on multiple domains of development. There were significant differences in multiple cognitive domains in the group who received androgen treatment, including multiple measures of language, intellectual, and neuromotor skills. Improved function was observed in neurodevelopmental outcome in boys with 47,XXY at 36 and 72 months who had been treated with a short course of androgen treatment in infancy. Continued research is underway to expand our understanding of the relationship of androgen, brain function, and neurobehavioral and neurodevelopmental outcome in boys with 47,XXY. PMID- 23345255 TI - Graphene nanoplatelets: electrochemical properties and applications for oxidation of endocrine-disrupting chemicals. AB - In most graphene-based electrochemical applications, graphene nanoplatelets (GNPs) have been applied. Now, for the first time, electrochemical properties of GNPs, namely, its electrochemical activity, potential window, and double-layer capacitance, have been investigated. These properties are compared with those of carbon nanotubes (CNTs). GNP- and CNT-coated electrodes were then applied for electrochemical oxidation of endocrine-disrupting chemicals. The GNP-coated electrode was characterized by atomic force microscopy and electrochemical techniques. Compared with the CNT-coated electrode, higher peak current for the oxidation of 4-nonylphenol is achieved on the GNP-coated electrode, together with lower capacitive current. Electrochemical oxidation of 2,4-dichlorophenol, bisphenol A, and octylphenol in the absence or presence of 4-nonylphenol was studied on the GNP-coated electrode. The results suggest that GNPs have better electrochemical performance than CNTs and are thus more promising for electrochemical applications, for example, electrochemical detection and removal of endocrine-disrupting chemicals. PMID- 23345254 TI - Allogeneic hematopoietic stem cell transplantation versus hypomethylating agents in patients with myelodysplastic syndrome: a retrospective case-control study. AB - Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative treatment for myelodysplastic syndrome (MDS). Recently, hypomethylating agents (HMAs) have been shown to improve survival in patients with high-risk MDS. We conducted a retrospective case-control study to compare survival with these treatment modalities in patients with untreated MDS. Controls were identified using a departmental database and transplant patients were matched in at least three of the following five criteria: year of diagnosis, age, blast percentage, International Prognostic Scoring System cytogenetic risk, and time from diagnosis to treatment. Median overall survival (OS) was 26 and 25 months for, respectively, allo-SCT [(n = 53); range, 2-210 months] and HMA [(n = 40); range, 2-98 months] (P = 0.89). Four-year survival rates were 24 and 23% for allo-SCT patients and the nontransplant cohort, respectively. Patients undergoing allo-SCT after 2000 had longer median OS compared with those transplanted before 2000 (41 versus 7 months, P=0.001). These results would suggest that prospective studies are needed to delineate the timing and efficacy of allo-SCT in the HMA era. PMID- 23345256 TI - Real-time 3D echocardiography and tissue Doppler echocardiography in the assessment of right ventricle systolic function in patients with right ventricular myocardial infarction. AB - AIMS: Knowledge of right ventricular (RV) function may be crucial in diagnosis and proper management of patients with suspected acute myocardial infarction (MI). Standard echocardiography has several drawbacks, tissue Doppler echocardiography (TDE) and real-time three-dimensional echocardiography (RT3DE) could be used for evaluation of the RV performance. The purpose of this study was to assess RV function in patients with inferior wall acute MI with both TDE and RT3DE. METHODS AND RESULTS: Study group consisted of 85 patients in the acute phase of MI complicated with right ventricular myocardial infarction (RVMI) admitted for primary coronary intervention (PCI). Control group was formed from 85 patients with isolated inferior wall infarction matched to RVMI group. Before PCI all of the patients underwent echocardiographic examination with the assessment of RV function by TDE and RT3DE. TDE derived peak systolic velocity ', peak early diastolic velocity of RV free wall differed significantly between groups. Three-dimensional reconstruction and calculation of the right ventricular ejection fraction (RVEF) showed that in RVMI patients RVEF values were lower than in the controls (41.7 +/- 6.03 vs. 52.7 +/- 2.3%, respectively). RVEF < 51% allowed diagnosis of RVMI with sensitivity 91% and specificity 80%. CONCLUSION: Three-dimensional echocardiography is a useful method in the estimation of RVEF, however does not perform better than TDE in diagnosis of RVMI. Threshold of RVEF < 51% may be used for diagnosing of RVMI with adequate sensitivity and specificity. PMID- 23345257 TI - Biomechanical responses of a pig head under blast loading: a computational simulation. AB - A series of computational studies were performed to investigate the biomechanical responses of the pig head under a specific shock tube environment. A finite element model of the head of a 50-kg Yorkshire pig was developed with sufficient details, based on the Lagrangian formulation, and a shock tube model was developed using the multimaterial arbitrary Lagrangian-Eulerian (MMALE) approach. These two models were integrated and a fluid/solid coupling algorithm was used to simulate the interaction of the shock wave with the pig's head. The finite element model-predicted incident and intracranial pressure traces were in reasonable agreement with those obtained experimentally. Using the verified numerical model of the shock tube and pig head, further investigations were carried out to study the spatial and temporal distributions of pressure, shear stress, and principal strain within the head. Pressure enhancement was found in the skull, which is believed to be caused by shock wave reflection at the interface of the materials with distinct wave impedances. Brain tissue has a shock attenuation effect and larger pressures were observed in the frontal and occipital regions, suggesting a greater possibility of coup and contrecoup contusion. Shear stresses in the brain and deflection in the skull remained at a low level. Higher principal strains were observed in the brain near the foramen magnum, suggesting that there is a greater chance of cellular or vascular injuries in the brainstem region. PMID- 23345258 TI - Synthesis of single-chain sugar arrays. PMID- 23345259 TI - Immunodeficiency in patients with 49,XXXXY chromosomal variation. AB - Boys affected with 49,XXXXY sex chromosomal variation have been described to have high incidence of recurrent otitis media and asthma, the cause of which is unknown. We hypothesized that primary immunodeficiency occurs in patients with XXXXY aneuploidy. To investigate this, 31 boys with known 49,XXXXY were evaluated through a multidisciplinary clinic. Screening history was performed using the "10 Warning Signs of primary immunodeficiency" (Jeffrey Modell Foundation), as well as by history of atopic and autoimmune conditions. Of the 31 boys, 20 had at least two warning signs of primary immunodeficiency, and five had four or more signs. Sixteen had history of recurrent pneumonia, and 15 carried the diagnosis of asthma. Of the 10 who underwent immunologic screening, eight showed some evidence of impaired antibody responses to polysaccharide antigens, and one was diagnosed with specific antibody deficiency. These preliminary results suggest a high incidence of both atopy and antibody deficiency in boys with 49,XXXXY. PMID- 23345260 TI - Selective arylation and vinylation at the alpha position of vinylarenes. AB - In intermolecular Heck reactions of styrene and vinylarenes, the aryl and vinyl groups routinely insert at the beta position. However, selective insertion at the alpha position has been very rare. Herein, we provide a missing piece in the palette of Heck reaction, which gave >20:1 alpha selectivity. The key to our success is a new ferrocene 1,1'-bisphosphane (dnpf) that carries 1-naphthyl groups. Our mechanistic studies revealed that the high alpha selectivity is partly attributable to the steric effect of dnpf. The rigid and bulky 1-naphthyl groups of dnpf sterically disfavor beta insertion. PMID- 23345261 TI - A black-box decomposition approach for coupling heterogeneous components in hemodynamics simulations. AB - This work presents a generic and efficient black-box approach for the strong iterative coupling of dimensionally heterogeneous flow models in computational hemodynamics. A heterogeneous model of the cardiovascular system is formed by several vascular black-box components, which are connected through coupling equations. The associated system of equations is solved using the Broyden algorithm. In addition, a multiple time-stepping strategy is introduced to meet different component requirements. The proposed algorithm is employed to split a 3D-1D-0D closed-loop model of the cardiovascular system into corresponding black box components standing for the 3D (specific vessels), 1D (systemic arteries/peripheral vessels), and 0D (venous/cardiac/pulmonary circulation) components. Examples of application are presented showing the robustness and suitability of this novel approach. PMID- 23345262 TI - 47,XXY Klinefelter syndrome: clinical characteristics and age-specific recommendations for medical management. AB - 47,XXY (Klinefelter syndrome) is the most frequent sex chromosomal disorder and affects approximately one in 660 newborn boys. The syndrome is characterized by varying degrees of cognitive, social, behavioral, and learning difficulties and in adulthood additionally primary testicular failure with small testes, hypergonadotropic hypogonadism, tall stature, and eunuchoid body proportions. The phenotype is variable ranging from "near-normal" to a significantly affected individual. In addition, newborns with Klinefelter syndrome generally present with a normal male phenotype and the only consistent clinical finding in KS is small testes, that are most often not identified until after puberty. Decreased awareness of this syndrome among health professionals and a general perception that all patients with 47,XXY exhibit the classic textbook phenotype results in a highly under-diagnosed condition with up to 75% of the patients left undetected. Typically, diagnosis is delayed with the majority of patients identified during fertility workup in adulthood, and only 10% of patients diagnosed prior to puberty. Early detection of this syndrome is recommended in order to offer treatment and intervention at the appropriate ages and stages of development for the purpose of preventing osteopenia/osteoporosis, metabolic syndrome, and other medical conditions related to hypogonadism and to the XXY as well as minimizing potential learning and psychosocial problems. The aim of this review is to present the clinical aspects of XXY and the age-specific recommendations for medical management. (c) 2013 Wiley Periodicals, Inc. PMID- 23345263 TI - Muscle insulin resistance resulting from impaired microvascular insulin sensitivity in Sprague Dawley rats. AB - AIMS: Enhanced microvascular perfusion of skeletal muscle is important for nutrient exchange and contributes ~40% insulin-mediated muscle glucose disposal. High fat-fed (36% fat wt./wt.) rats are a commonly used model of insulin resistance that exhibit impairment of insulin-mediated microvascular recruitment and muscle glucose uptake, which is accompanied by myocyte insulin-resistance. Distinguishing the contribution of impaired microvascular recruitment and impaired insulin action in the myocyte to decreased muscle glucose uptake in these high-fat models is difficult. It is unclear whether microvascular and myocyte insulin-resistance develop simultaneously. To assess this, we used a rat diet model with a moderate increase (two-fold) in dietary fat. METHODS AND RESULTS: Sprague Dawley rats fed normal (4.8% fat wt./wt., 5FD) or high (9.0% fat wt./wt., 9FD) fat diets for 4 weeks were subject to euglycaemic hyperinsulinemic clamp (10 mU/min/kg insulin or saline) or isolated hindlimb perfusion (1.5 or 15 nM insulin or saline). Body weight, epididymal fat mass, and fasting plasma glucose were unaffected by diet. Fasting plasma insulin and non-esterified fatty acid concentrations were significantly elevated in 9FD. Glucose infusion rate and muscle glucose uptake were significantly impaired during insulin clamps in 9FD. Insulin-stimulated microvascular recruitment was significantly blunted in 9FD. Insulin-mediated muscle glucose uptake between 5FD and 9FD were not different during hindlimb perfusion. CONCLUSIONS: Impaired insulin-mediated muscle glucose uptake in vivo can be the direct result of reduced microvascular blood flow responses to insulin, and can result from small (two-fold) increases in dietary fat. Thus, microvascular insulin-resistance can occur independently to the development of myocyte insulin-resistance. PMID- 23345265 TI - Reversibility of T-tubule remodelling in heart failure: mechanical load as a dynamic regulator of the T-tubules. AB - The T-tubule system in ventricular cardiomyocytes is essential for synchronous Ca(2+) handling, and, therefore, efficient contraction. T-tubular remodelling is a common feature of heart disease. In this review, we discuss whether t-tubular remodelling can be reversed and which factors may be implicated in this process. In particular, we focus on the interaction between mechanical load variation and T-tubule structure and function. What is the evidence of this relationship? What is the role of different degrees and durations of mechanical load variation? In what settings might mechanical load variation have detrimental or beneficial effects on T-tubule structure and function? What are the molecular determinants of this interaction? Ultimately this discussion is used to address the question of whether mechanical load variation can provide an understanding to underpin attempts to induce recovery of the T-tubule system. In reviewing these questions, we define what remains to be discovered in understanding T-tubule recovery. PMID- 23345266 TI - A computationally efficient framework for the simulation of cardiac perfusion using a multi-compartment Darcy porous-media flow model. AB - We present a method to efficiently simulate coronary perfusion in subject specific models of the heart within clinically relevant time frames. Perfusion is modelled as a Darcy porous-media flow, where the permeability tensor is derived from homogenization of an explicit anatomical representation of the vasculature. To account for the disparity in length scales present in the vascular network, in this study, this approach is further refined through the implementation of a multi-compartment medium where each compartment encapsulates the spatial scales in a certain range by using an effective permeability tensor. Neighbouring compartments then communicate through distributed sources and sinks, acting as volume fluxes. Although elegant from a modelling perspective, the full multi compartment Darcy system is computationally expensive to solve. We therefore enhance computational efficiency of this model by reducing the N-compartment system of Darcy equations to N pressure equations, and N subsequent projection problems to recover the Darcy velocity. The resulting 'reduced' Darcy formulation leads to a dramatic reduction in algebraic-system size and is therefore computationally cheaper to solve than the full multi-compartment Darcy system. A comparison of the reduced and the full formulation in terms of solution time and memory usage clearly highlights the superior performance of the reduced formulation. Moreover, the implementation of flux and, specifically, impermeable boundary conditions on arbitrarily curved boundaries such as epicardium and endocardium is straightforward in contrast to the full Darcy formulation. Finally, to demonstrate the applicability of our methodology to a personalized model and its solvability in clinically relevant time frames, we simulate perfusion in a subject-specific model of the left ventricle. PMID- 23345264 TI - Spatial control of the betaAR system in heart failure: the transverse tubule and beyond. AB - The beta1-adrenoceptors (beta(1)AR) and beta-2 (beta(2)AR) adrenoceptors represent the predominant pathway for sympathetic control of myocardial function. Diverse mechanisms have evolved to translate signalling via these two molecules into differential effects on physiology. In this review, we discuss how the functions of the betaAR are organized from the level of secondary messengers to the whole heart to achieve this. Using novel microscopy and bio-imaging methods researchers have uncovered subtle organization of the control of cyclic adenosine monophosphate (cAMP), the predominant positively inotropic pathway for the betaAR. The beta(2)AR in particular is demonstrated to give rise to highly compartmentalized, spatially confined cAMP signals. Organization of beta(2)AR within the T-tubule and caveolae of cardiomyocytes concentrates this receptor with molecules which buffer and shape its cAMP signal to give fine control. This situation is undermined in various forms of heart failure. Human and animal models of heart failure demonstrate disruption of cellular micro-architecture which contributes to the change in response to cardiac betaARs. Loss of cellular structure has proved key to the observed loss of confined beta(2)AR signalling. Some pharmacological and genetic treatments have been successful in returning failing cells to a more structured phenotype. Within these cells it has been possible to observe the partial restoration of normal beta(2)AR signalling. At the level of the organ, the expression of the two betaAR subtypes varies between regions with the beta(2)AR forming a greater proportion of the betaAR population at the apex. This distribution may contribute to regional wall motion abnormalities in Takotsubo cardiomyopathy, a syndrome of high sympathetic activity, where the phosphorylated beta(2)AR can signal via Gi protein to produce negatively inotropic effects. PMID- 23345268 TI - HoBi-like viruses: an emerging group of pestiviruses. AB - The genus Pestivirus is composed of 4 important pathogens of livestock: Bovine viral diarrhea virus 1 and 2 (BVDV-1 and BVDV-2), Classical swine fever virus (CSFV), and Border disease virus of sheep (BDV). BVDV are major pathogens of cattle, and infection results in significant economic loss worldwide. A new putative pestivirus species, tentatively called "HoBi-like," "BVDV-3," or "atypical pestiviruses," was first identified in Europe in fetal bovine serum (FBS) imported from Brazil. HoBi-like viruses are related to BVDV at the genetic and antigenic levels. Further, the disease caused by these new viruses resembles clinical presentations historically associated with BVDV infection, including growth retardation, reduced milk production, respiratory disease, reduced reproductive performance, and increased mortality among young stock. Current BVDV diagnostic tests may fail to detect HoBi-like viruses or to differentiate between BVDV and HoBi-like viruses. Further, commercial tests for BVDV exposure, based on serological response, do not reliably detect HoBi-like virus exposure, and cross protection against HoBi-like viruses conferred by current BVDV vaccines is likely limited. As many HoBi-like viruses, characterized to date, were isolated from FBS originating from Brazil, it is assumed that the agent is probably widespread in Brazilian herds. Nevertheless, reports of natural infection in Southeast Asia and Europe demonstrate that these viruses are not restricted to South America. Increased demand for FBS has led to widespread distribution of FBS originating in HoBi-like virus endemic regions. The contamination of such FBS with HoBi-like viruses may lead to spread of this virus to other regions. PMID- 23345269 TI - Molecular characterization and phylogenetic analysis of Murray Valley encephalitis virus and West Nile virus (Kunjin subtype) from an arbovirus disease outbreak in horses in Victoria, Australia, in 2011. AB - Virus was detected in the central nervous system (CNS) tissue of 11 horses from Victoria that died displaying neurological symptoms during an outbreak of disease in Australia in 2011. Five horses were identified as being infected with Murray Valley encephalitis virus (MVEV) and 6 as being infected with West Nile virus subtype Kunjin (WNV(KUN)). Analysis of partial sequence information from the NS5 and E genes indicated that the MVEVs within the samples were highly homogenous and all belonged to lineage I, which is enzootic to the tropical regions of northern Australia. Likewise, analysis of partial NS5 and E gene and full genome sequences indicated that the WNV(KUN) within the samples were also highly homogenous and clustered with WNV lineage 1, clade b, which is consistent with other WNV(KUN) isolates. Full genomes of 1 MVEV isolate and 2 WNV(KUN) isolates were sequenced and characterized. The genome sequences of Victorian WNV(KUN) are almost identical (3 amino acid differences) to that of the recently sequenced WNV isolate WNV(NSW2011). Metagenome sequencing directly from CNS tissue identified the presence of WNV(KUN) and MVEV within infected CNS tissue. PMID- 23345270 TI - Cerebrospinal fluid eosinophilia is a sensitive and specific test for the diagnosis of Parelaphostrongylus tenuis in camelids in the northeastern United States. AB - Aberrant migration of Parelaphostrongylus tenuis in camelids results in neurologic deficits, recumbency, and sometimes death. An antemortem diagnosis of P. tenuis in camelids is typically based upon the presence of characteristic asymmetric neurologic deficits, known exposure to white-tailed deer, cerebrospinal fluid (CSF) eosinophilia, and response to treatment. The diagnostic accuracy of CSF eosinophil percentage for the diagnosis of P. tenuis in camelids has not been critically examined. The objective of the current study was to determine the sensitivity (Se) and specificity (Sp) of CSF eosinophil percentage, CSF eosinophil concentration, total nucleated cell concentration, and protein concentration for the antemortem diagnosis of P. tenuis. Medical records of camelids admitted to Cornell University with clinical signs of neurologic disease, CSF analysis, and necropsy were examined from January 2000 through December 2009. Se and Sp were determined by receiver operating characteristic curves in camelids diagnosed with P. tenuis (n = 13) or other conditions (n = 24) based on postmortem examination. More than 17% of eosinophils in CSF had a Se of 85% and Sp of 92% for P. tenuis diagnosis (area under the curve [AUC]: 0.87; SE AUC: 0.07; P < 0.0001; 95% confidence interval [CI] AUC: 0.72-0.96), and >1.4 eosinophils/ul of CSF had a Se of 85% and Sp of 96% (AUC: 0.9; SE AUC: 0.06; P < 0.0001; 95% CI AUC: 0.76-0.97). Cerebrospinal fluid eosinophil percentage and concentration are sensitive and specific methods for diagnosing P. tenuis antemortem in camelids residing in regions endemic to white-tailed deer. PMID- 23345271 TI - A multiplex real-time polymerase chain reaction assay with two internal controls for the detection of Brucella species in tissues, blood, and feces from marine mammals. AB - Brucellosis has emerged as a disease of concern in marine mammals in the last 2 decades. Molecular detection techniques have the potential to address limitations of other methods for detecting infection with Brucella in these species. Presented herein is a real-time polymerase chain reaction (PCR) method targeting the Brucella genus-specific bcsp31 gene. The method also includes a target to a conserved region of the eukaryotic mitochondrial 16S ribosomal RNA gene to assess suitability of extracted DNA and a plasmid-based internal control to detect failure of PCR due to inhibition. This method was optimized and validated to detect Brucella spp. in multiple sample matrices, including fresh or frozen tissue, blood, and feces. The analytical limit of detection was low, with 95% amplification at 24 fg, or an estimated 7 bacterial genomic copies. When Brucella spp. were experimentally added to tissue or fecal homogenates, the assay detected an estimated 1-5 bacteria/ul. An experiment simulating tissue autolysis showed relative persistence of bacterial DNA compared to host mitochondrial DNA. When used to screen 1,658 field-collected marine mammal tissues in comparison to microbial culture, diagnostic sensitivity and specificity were 70.4% and 98.3%, respectively. In addition to amplification in fresh and frozen tissues, Brucella spp. were detected in feces and formalin-fixed, paraffin-embedded tissues from culture-positive animals. Results indicate the utility of this real-time PCR for the detection of Brucella spp. in marine species, which may have applications in surveillance or epidemiologic investigations. PMID- 23345272 TI - Comparison of three immunoglobulin G assays for the diagnosis of failure of passive transfer of immunity in neonatal alpacas. AB - Measurement of serum immunoglobulin G (IgG) is used for the assessment of passive transfer of immunity in neonatal crias, with an IgG concentration <10 g/l being suggestive of failure of passive transfer (FPT). The purpose of the current study was to determine whether 3 commercially available immunologic assays yielded comparable results for IgG in alpacas. Serum samples from 91 alpacas were used and were stored frozen until batch analysis on the same day with the 3 assays. Immunoglobulin G was measured by radial immunodiffusion (RID) and 2 immunoturbidimetric (IT) assays (IT1, configured for automated chemistry analyzers; IT2, a point-of-care test). Median IgG concentrations were significantly different between the 3 assays, with the RID (median: 15 g/l) and IT1 (median: 16 g/l) assays, which used the same standard, yielding significantly higher IgG values than IT2 (median: 11 g/l). Results indicated a diagnostic discordance in 1-17% of samples at an IgG threshold of 10 g/l. Protein electrophoresis revealed that the RID and IT1 standard contained mostly albumin (>60%), whereas the IT2 standard consisted of beta and gamma globulins. The discrepant results between assays IT1 and IT2 were eliminated when the same standard was used (IT1: median 11 g/l; IT2: 10 g/l; n = 19 and 17, respectively). The IT1 assay had the highest precision, while the RID assay had the lowest. The results indicate that camelid IgG measurement is highly dependent on the assay standard and is not directly comparable between assays, potentially resulting in underdiagnosis of FPT in some crias. PMID- 23345273 TI - A novel gammaherpesvirus found in oral squamous cell carcinomas in sun bears (Helarctos malayanus). AB - A novel herpesvirus was detected in sun bears (Helarctos malayanus) with oral squamous cell carcinoma. Five captive sun bears from 4 institutions in the United States presented with oral lesions ranging from erythema and mild erosions to nodular, ulcerated masses. All 5 were diagnosed with squamous cell carcinoma. The tumors were treated with surgical resection but recurrence, local extension, or appearance of new lesions was noted in all cases. Intralesional chemotherapy was administered in 2 cases, and the nonsteroidal anti-inflammatory drug piroxicam was administered in 3 cases. Virus was detected in 4 of the 5 bears' tissue samples using a consensus herpesvirus polymerase chain reaction. Nucleotide sequencing and phylogenetic analysis showed that this herpesvirus is in the subfamily Gammaherpesvirinae and distinct from other known herpesviruses. The association between the herpesvirus and squamous cell carcinoma is unknown. The current study presents a novel gammaherpesvirus within the order Ursidae, with the name Ursid herpesvirus 1 proposed. PMID- 23345274 TI - Development of a real-time polymerase chain reaction assay for single nucleotide polymorphism genotyping codons 136, 154, and 171 of the prnp gene and application to Brazilian sheep herds. AB - Scrapie is a transmissible spongiform encephalopathy of sheep and goats and is associated with the deposition of an abnormal isoform of prion protein (PrP(sc)). This isoform presents an altered conformation that leads to its aggregation in the host's central nervous and lymphoreticular systems. A predisposition to the prion-agent infection can be influenced by specific genotypes that are related to polymorphisms in the ovine prnp gene. The most characterized polymorphisms occur at codons 136, 154, and 171, with genotype VRQ being the most susceptible and ARR the most resistant. In the current study, a real-time quantitative polymerase chain reaction (qPCR) technique based on allele-specific TaqMan probes was developed to identify single nucleotide polymorphisms in the prnp gene from Brazilian herds. Specific primers and TaqMan probes were designed for all 3 codons of interest. Samples from a total of 142 animals were analyzed by qPCR, followed by DNA sequencing of the amplicons. All of the genotypes determined by qPCR were in agreement with the data determined by DNA sequencing. In all 3 of the analyzed breeds, the majority of the animals were AA homozygous for the 136 codon. The most frequent genotype for codon 154 was RR, and genotypes QQ and QR were the most frequent for codon 171. The results are discussed in relation to establishing scrapie control measures and breeding programs for Brazilian herds. PMID- 23345275 TI - Serological evidence and risk factors associated with Caprine herpesvirus 1 in dairy goat flocks in a semiarid region of northeastern Brazil. AB - A cross-sectional study was carried out to determine the flock-level seroprevalence of Caprine herpesvirus 1 (CpHV-1) and Bovine herpesvirus 1 (BoHV 1) and 2 (BoHV-2) and risk factors associated with CpHV-1 in dairy goat flocks from a semiarid region of northeastern Brazil. A total of 1,034 serum samples from 110 flocks were collected from March 2009 through March 2010. A structured questionnaire focusing on variables related to risk factors for CpHV-1 infection was given to each farmer at the time of blood collection. Antibodies against CpHV 1, BoHV-1, and BoHV-2 were detected by neutralization tests. The flock-level prevalences of CpHV-1, BoHV-1, and BoHV-2 were 89.1% (98/110; 95% confidence interval [CI]: 81.7-94.2), 80% (88/110; 95% CI: 71.3-87), and 4.5% (5/110; 95% CI: 1.5-10.3), respectively. Frequencies of seropositive animals were 36.6% (379/1,034), 25.8% (267/1,034), and 0.6% (6/1,034) for CpHV-1, BoHV-1, and BoHV 2, respectively. The use of natural mating was identified as a risk factor associated with CpHV-1 flock-level prevalence (P = 0.001). It is suggested that adoption of veterinary services and active surveillance of the at-risk flocks in the study region should be initiated to reduce the prevalence of herpesvirus infections. PMID- 23345276 TI - Intracoelomic anaplastic sarcoma in an intersex Madagascar tree boa (Sanzinia madagascariensis). AB - An adult Madagascar tree boa (Sanzinia madagascariensis) underwent coeliotomy for investigation of a coelomic mass. At surgery, a large mass originating from the peri-pancreatic adipose tissue and involving the gall bladder was removed. The snake did not recover from general anesthesia. A complete postmortem was performed, and samples were submitted to the University of Glasgow for histopathology. On histological examination, the mass was composed of adipose tissue infiltrated with a poorly demarcated spindle cell neoplasm. The neoplastic cells were highly pleomorphic with abundant cytoplasm and frequent clear cytoplasmic vacuoles, suggestive of adipocyte origin. Immunohistochemical characterization of the mass was inconclusive. Metastatic neoplastic cells were present within vessels in the liver, lungs, and brain. As an incidental finding, the gonads contained both maturing ovarian follicles and seminiferous tubules with intact germinal epithelium and evidence of spermatogenesis, along with other features of male and female gonad anatomy. The current report describes a rare neoplasm in snakes within an intersex Madagascar tree boa. PMID- 23345278 TI - Engineering the mesopores of Fe3O4@mesosilica core-shell nanospheres through a solvothermal post-treatment method. AB - A solvothermal post-treatment method was developed to synthesize Fe(3)O(4)@mesosilica core-shell nanospheres (CSNs) with a well-preserved morphology, mesoporous structure, and tunable large pore diameters (2.5-17.6 nm) for the first time. N,N-Dimethylhexadecylamine (DMHA), which was generated in situ during the heat-treatment process, was mainly responsible for this pore-size enlargement, as characterized by NMR spectroscopy. This pore-size expansion can be strengthened with the aid of hexamethyldisilazane (HMDS), whilst the nature of the surface of the Fe(3)O(4)@mesosilica CSNs can be easily modified with trimethylsilyl groups during the pore-size-expansion process. The hydrophobicity of the Fe(3)O(4)@mesosilica CSNs increased for the enlarged mesopores and the adsorption capacity of these CSNs for benzene (up to 1.5 g g(-1)) is the highest ever reported for Fe(3)O(4)@mesosilica CSNs. The resultant Fe(3)O(4)@mesosilica CSNs (pore size: 10 nm) showed a 3.6-times higher adsorption capacity of lysozyme than those without the pore expansion (pore size: 2.5 nm), thus making them a good candidate for loading large molecules. PMID- 23345279 TI - Numerical investigation of axonal cargo rerouting in a dendrite: a three kinetic state model. AB - The purpose of this paper is to develop a three-kinetic state model to investigate axonal cargo rerouting in a dendrite. It is assumed that axonal cargos are transported by kinesin motors; they can enter dendrites riding on plus end-out microtubules (MTs). If this happens, cargos are rerouted by dissociating from these MTs and associating with minus-end-out MTs. The same kinesin motors then move axonal cargos out of the dendrite. The model predicts how far axonal cargos can penetrate into the dendrite, concentrations of various populations of axonal cargos, and cargo fluxes. PMID- 23345281 TI - Volume-dependent effect of perihaematomal oedema on outcome for spontaneous intracerebral haemorrhages. AB - INTRODUCTION: It is still unknown whether subsequent perihaematomal oedema (PHE) formation further increases the odds of an unfavourable outcome. METHODS: Demographic, clinical, radiographic and outcome data were prospectively collected in a single large academic centre. A multiple logistic regression model was then developed to determine the effect of admission oedema volume on outcome. RESULTS: 133 patients were analysed in this study. While there was no significant association between relative PHE volume and discharge outcome (p=0.713), a strong relationship was observed between absolute PHE volume and discharge outcome (p=0.009). In a multivariate model incorporating known predictors of outcome, as well as other factors found to be significant in our univariate analysis, absolute PHE volume remained a significant predictor of poor outcome only in patients with intracerebral haemorrhage (ICH) volumes <=30 cm(3) (OR 1.123, 95% CI 1.021 to 1.273, p=0.034). An increase in absolute PHE volume of 10 cm(3) in these patients was found to increase the odds of poor outcome on discharge by a factor of 3.19. CONCLUSIONS: Our findings suggest that the effect of absolute PHE volume on functional outcome following ICH is dependent on haematoma size, with only patients with smaller haemorrhages exhibiting poorer outcome with worse PHE. Further studies are needed to define the precise role of PHE in driving outcome following ICH. PMID- 23345280 TI - The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease. AB - Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD. PMID- 23345282 TI - Memory outcome after hippocampus sparing resections in the temporal lobe. AB - BACKGROUND AND OBJECTIVE: Epilepsy surgery within the temporal lobe of the language dominant hemisphere bears the risk of postoperative verbal memory decline. As surgical procedures have become more tailored, the question has arisen, which type of resection within the temporal lobe is more favourable for memory outcome. Since the hippocampus (HC) is known to play an essential role for long-term memory, we examined whether HC sparing resections help to preserve verbal memory functions. METHODS: We retrospectively analysed neuropsychological data (prior to and 1 year after surgery) of patients undergoing either HC sparing resections (HC-S, N=65) or resections including the hippocampus (HC-R, N=62). RESULTS: Prior to surgery, the HC-R group showed worse memory performance as compared to HC-S patients. Both patient groups revealed further deterioration over time, but in verbal learning HC-R patients demonstrated a stronger decline. Predictors for verbal learning decline were left-sided surgery, better preoperative performance, higher age at surgery, hippocampus resection, and lower preoperative IQ. In patients with spared HC, resection of the left-sided parahippocampal gyrus was rather accompanied by a decline in verbal learning performance. For visual memory, better preoperative performance best predicted deterioration after surgery. Seizure outcome was comparable between the two groups (HC-S: 66%, HC-R: 65% Engel 1a). CONCLUSIONS: Temporal lobe resections within the language dominant hemisphere can be accompanied by a decline in verbal memory performance, even if the HC is spared. Yet, HC sparing surgery is associated with a benefit in verbal learning performance. These results can help when counselling patients prior to epilepsy surgery. PMID- 23345283 TI - Endoscopic versus microscopic pituitary surgery. PMID- 23345285 TI - Iron-catalyzed synthesis of 2-vinylquinolines via sp3 C-H functionalization and subsequent C-N cleavage. PMID- 23345284 TI - Recurrent transient ischaemic attack and early risk of stroke: data from the PROMAPA study. AB - BACKGROUND: Many guidelines recommend urgent intervention for patients with two or more transient ischaemic attacks (TIAs) within 7 days (multiple TIAs) to reduce the early risk of stroke. OBJECTIVE: To determine whether all patients with multiple TIAs have the same high early risk of stroke. METHODS: Between April 2008 and December 2009, we included 1255 consecutive patients with a TIA from 30 Spanish stroke centres (PROMAPA study). We prospectively recorded clinical characteristics. We also determined the short-term risk of stroke (at 7 and 90 days). Aetiology was categorised using the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. RESULTS: Clinical variables and extracranial vascular imaging were available and assessed in 1137/1255 (90.6%) patients. 7-Day and 90-day stroke risk were 2.6% and 3.8%, respectively. Large artery atherosclerosis (LAA) was confirmed in 190 (16.7%) patients. Multiple TIAs were seen in 274 (24.1%) patients. Duration <1 h (OR=2.97, 95% CI 2.20 to 4.01, p<0.001), LAA (OR=1.92, 95% CI 1.35 to 2.72, p<0.001) and motor weakness (OR=1.37, 95% CI 1.03 to 1.81, p=0.031) were independent predictors of multiple TIAs. The subsequent risk of stroke in these patients at 7 and 90 days was significantly higher than the risk after a single TIA (5.9% vs 1.5%, p<0.001 and 6.8% vs 3.0%, respectively). In the logistic regression model, among patients with multiple TIAs, no variables remained as independent predictors of stroke recurrence. CONCLUSIONS: According to our results, multiple TIAs within 7 days are associated with a greater subsequent risk of stroke than after a single TIA. Nevertheless, we found no independent predictor of stroke recurrence among these patients. PMID- 23345286 TI - Development of a panel of recombinase polymerase amplification assays for detection of biothreat agents. AB - Syndromic panels for infectious disease have been suggested to be of value in point-of-care diagnostics for developing countries and for biodefense. To test the performance of isothermal recombinase polymerase amplification (RPA) assays, we developed a panel of 10 RPAs for biothreat agents. The panel included RPAs for Francisella tularensis, Yersinia pestis, Bacillus anthracis, variola virus, and reverse transcriptase RPA (RT-RPA) assays for Rift Valley fever virus, Ebola virus, Sudan virus, and Marburg virus. Their analytical sensitivities ranged from 16 to 21 molecules detected (probit analysis) for the majority of RPA and RT-RPA assays. A magnetic bead-based total nucleic acid extraction method was combined with the RPAs and tested using inactivated whole organisms spiked into plasma. The RPA showed comparable sensitivities to real-time RCR assays in these extracts. The run times of the assays at 42 degrees C ranged from 6 to 10 min, and they showed no cross-detection of any of the target genomes of the panel nor of the human genome. The RPAs therefore seem suitable for the implementation of syndromic panels onto microfluidic platforms. PMID- 23345287 TI - Sequence conservation of the region targeted by the Abbott RealTime HBV viral load assay in clinical specimens. AB - The Abbott RealTime HBV assay targets the N-terminal region of the S gene. Here we analyzed the sequence variability of the assay target region from >2,100 clinical specimens. Thermodynamic modeling of the percentage of bound primer/probe at the assay annealing temperature was performed to assess the potential effect of sequence variability. PMID- 23345288 TI - Culture-based method with performance comparable to that of PCR-based methods for detection of group B Streptococcus in screening samples from pregnant women. AB - We compared five approaches for group B streptococcus (GBS) detection: three culture-based methods and two methods using broth-enhanced real-time PCR. Carrot broth-enhanced subculture to GBS Detect (Hardy Diagnostics, Santa Maria, CA) exhibited sensitivity and specificity comparable to carrot broth- and LIM broth enhanced real-time PCRs. PMID- 23345289 TI - Short-term storage does not affect the quantitative yield of Mycobacterium tuberculosis in sputum in early-bactericidal-activity studies. AB - Early-bactericidal-activity (EBA) studies measure the change in mycobacterial load in sputum over time to evaluate antituberculosis drugs. We investigated whether a delay in sputum processing influences the quantitative results of sputum mycobacterial culture. We identified pretreatment smear-positive sputum samples collected overnight and processed at a single laboratory. Sputum volume, time from sputum collection to processing, CFU counts/ml of sputum, and time to culture positivity (TTP) data were retrieved. We obtained 817 TTP and 794 CFU results from a total of 844 sputum samples. Contamination did not occur more frequently with prolonged storage (TTP, 2.0%; CFU, 2.4%). Sample volumes were <5 ml in 5%, 5 to 10 ml in 46%, and >10 ml in 49%. Delays to processing were 0, 1, 2, and 3 days in 696 (43.2%), 722 (44.8%), 128 (7.9%), and 65 (4.0%) samples, respectively. TTP and CFU did not significantly differ between days of delay to processing (P = 0.098 and P = 0.908, respectively), but there was a nonsignificant trend toward a prolonged TTP over time (P = 0.052, Jonckheere Terpstra trend test). Sputa of <5 ml in volume showed a significantly prolonged TTP compared to sputum of >5 ml (113 h versus 99 h; P < 0.01) but no significant decrease in CFU. Sputum can be stored under refrigerated conditions for deferred processing for at least 3 days. This means that central laboratories can be used for quantitative mycobacterial study endpoints when delays to processing are not expected to exceed a few days. Care should be taken to collect sputum of sufficient volume. PMID- 23345290 TI - Rapid and simultaneous detection of genes encoding Klebsiella pneumoniae carbapenemase (blaKPC) and New Delhi metallo-beta-lactamase (blaNDM) in Gram negative bacilli. AB - We present a duplex, real-time PCR assay for detection of Klebsiella pneumoniae carbapenemase (blaKPC) and New Delhi metallo-beta-lactamase (blaNDM) genes. Accuracy was assessed with 158 Gram-negative bacillary isolates, including 134 carbapenemase producers. The assay had 100% sensitivity and specificity compared with reference methods and a turnaround time of 90 min. PMID- 23345291 TI - Multilocus sequence analysis of Streptococcus canis confirms the zoonotic origin of human infections and reveals genetic exchange with Streptococcus dysgalactiae subsp. equisimilis. AB - Streptococcus canis is an animal pathogen that occasionally causes human infections. Isolates recovered from infections of animals (n = 78, recovered from 2000 to 2010 in three European countries, mainly from house pets) and humans (n = 7, recovered from 2006 to 2010 in Portugal) were identified by phenotypic and genotypic methods and characterized by antimicrobial susceptibility testing, multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), and emm typing. S. canis isolates presented considerable variability in biochemical profiles and 16S rRNA. Resistance to antimicrobial agents was low, with the most significant being tet(M)- and tet(O)-mediated tetracycline resistance. MLST analysis revealed a polyclonal structure of the S. canis population causing infections, where the same genetic lineages were found infecting house pets and humans and were disseminated in distinct geographic locations. Phylogenetic analysis indicated that S. canis was a divergent taxon of the sister species Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis and found evidence of acquisition of genetic material by S. canis from S. dysgalactiae subsp. equisimilis. PFGE confirmed the MLST findings, further strengthening the similarity between animal and human isolates. The presence of emm-like genes was restricted to a few isolates and correlated with some MLST based genetic lineages, but none of the human isolates could be emm typed. Our data show that S. canis isolates recovered from house pets and humans constitute a single population and demonstrate that isolates belonging to the main genetic lineages identified have the ability to infect the human host, providing strong evidence for the zoonotic nature of S. canis infection. PMID- 23345292 TI - Worrisome trend of new multiple mechanisms of linezolid resistance in staphylococcal clones diffused in Italy. AB - In order to assess the frequency of clinically relevant linezolid-resistant staphylococcal isolates, and the role of linezolid in maintaining and coselecting multiple resistance mechanisms (cfr, 23S rRNA, L3/L4 mutations), a prospective Italian study was performed from 2010 to 2011 to confirm the diffusion of three major multidrug-resistant clones (ST2, ST5, ST23). PMID- 23345293 TI - Catalase-negative Staphylococcus lugdunensis strain with a novel point mutation in the catalase gene isolated from a patient with chronic suppurative otitis media. AB - This report describes the results of the sequence analysis of a methicillin susceptible strain of catalase-negative Staphylococcus lugdunensis. Molecular characterization of the deduced sequence revealed a novel point mutation in the catalase gene. To our knowledge, this is the first report of a catalase-negative S. lugdunensis strain, although catalase-negative isolates of Staphylococcus aureus and Staphylococcus epidermidis have been previously reported. PMID- 23345294 TI - Invasive sino-orbital mycosis in an aplastic anemia patient caused by Neosartorya laciniosa. AB - We report the first case of Neosartorya laciniosa invasive sinusitis involving the orbit in an immunocompromised male with aplastic anemia. Treatment included surgical debridement with enucleation of the eye and combination voriconazole and micafungin therapy followed by voriconazole alone. The fungus was identified using sequencing of partial benA and calmodulin genes. PMID- 23345295 TI - Comparison of multiple-locus variable-number tandem-repeat analysis with pulsed field gel electrophoresis typing of Acinetobacter baumannii in China. AB - A panel of seven variable-number tandem-repeat (VNTR) markers was selected for Acinetobacter baumannii typing analysis (MLVA-7). Compared with pulsed-field gel electrophoresis (PFGE), MLVA-7 provided greater discrimination. We modified the criteria for MLVA complex assignments proposed previously, and a remarkable congruence between MLVA-7- and PFGE-based strain clustering was observed. PMID- 23345296 TI - Microplate alamarBlue assay for Paracoccidioides susceptibility testing. AB - CLSI method M27-A3 is not available for use with dimorphic fungi, such as those of the Paracoccidioides genus. In this study, we developed a microdilution method and added the alamarBlue reagent to test the responses of Paracoccidioides brasiliensis and Paracoccidioides lutzii against amphotericin B and itraconazole antifungals. The test proved to be sensitive, practical, and inexpensive and can be used to monitor the activity of low-growth microorganisms and their response to various drugs. PMID- 23345298 TI - A genomic day in the life of a clinical microbiology laboratory. AB - Next-generation sequencing technology is available to many clinical laboratories; however, it is not yet widely used in routine microbiology practice. To demonstrate the feasibility of using whole-genome sequencing in a routine clinical microbiology workflow, we sequenced the genome of every organism isolated in our laboratory for 1 day. PMID- 23345297 TI - Evaluation of the sensitivity of a pLDH-based and an aldolase-based rapid diagnostic test for diagnosis of uncomplicated and severe malaria caused by PCR confirmed Plasmodium knowlesi, Plasmodium falciparum, and Plasmodium vivax. AB - Plasmodium knowlesi can cause severe and fatal human malaria in Southeast Asia. Rapid diagnosis of all Plasmodium species is essential for initiation of effective treatment. Rapid diagnostic tests (RDTs) are sensitive for detection of uncomplicated and severe falciparum malaria but have not been systematically evaluated in knowlesi malaria. At a tertiary referral hospital in Sabah, Malaysia, we prospectively evaluated the sensitivity of two combination RDTs for the diagnosis of uncomplicated and severe malaria from all three potentially fatal Plasmodium species, using a pan-Plasmodium lactate dehydrogenase (pLDH)-P. falciparum histidine-rich protein 2 (PfHRP2) RDT (First Response) and a pan Plasmodium aldolase-PfHRP2 RDT (ParaHIT). Among 293 hospitalized adults with PCR confirmed Plasmodium monoinfection, the sensitivity of the pLDH component of the pLDH-PfHRP2 RDT was 74% (95/129; 95% confidence interval [CI], 65 to 80%), 91% (110/121; 95% CI, 84 to 95%), and 95% (41/43; 95% CI, 85 to 99%) for PCR confirmed P. knowlesi, P. falciparum, and P. vivax infections, respectively, and 88% (30/34; 95% CI, 73 to 95%), 90% (38/42; 95% CI, 78 to 96%), and 100% (12/12; 95% CI, 76 to 100%) among patients tested before antimalarial treatment was begun. Sensitivity in severe malaria was 95% (36/38; 95% CI, 83 to 99), 100% (13/13; 95% CI, 77 to 100), and 100% (7/7; 95% CI, 65 to 100%), respectively. The aldolase component of the aldolase-PfHRP2 RDT performed poorly in all Plasmodium species. The pLDH-based RDT was highly sensitive for the diagnosis of severe malaria from all species; however, neither the pLDH- nor aldolase-based RDT demonstrated sufficiently high overall sensitivity for P. knowlesi. More sensitive RDTs are needed in regions of P. knowlesi endemicity. PMID- 23345299 TI - Comparison of a multiplex real-time PCR assay with a multiplex Luminex assay for influenza virus detection. AB - We describe the development of a multiplex reverse transcription-PCR (RT-PCR) with Luminex microarray hybridization for detection of influenza virus subtypes (FLULUM). Performance of FLULUM was evaluated by comparing it to our real-time RT PCR influenza virus assay on samples collected during two influenza seasons. Both assays targeted the matrix genes of influenza virus A (FluA M) and influenza virus B (FluB M) and the hemagglutinin genes of seasonal H3N2 (H3) and H1N1 (H1) and 2009 pandemic H1N1 (2009 H1). We evaluated FLULUM on both the Luminex LX200 and the Luminex MagPix instruments. Compared to real-time PCR, FLULUM tested on 259 specimens submitted in the 2010-2011 season showed sensitivities of 97.3% for FluA M, 90.5% for 2009 H1, 96.9% for H3, and 88.9% for FluB M. No specimens were positive for seasonal H1. FLULUM tested on 806 specimens submitted in the 2011 2012 season showed a sensitivity of 100% for FluA M, 89.9% for 2009 H1, 96.4% for H3, and 95.6% for FluB M. No cross-reactivity was observed for other respiratory viruses. Analytical sensitivity was assessed by testing dilutions of specimens with high viral loads. The limits of detection of FLULUM were comparable to those of the real-time PCR assay for FluA M, FluB M, and H3. The limits of detection for seasonal H1 and 2009 H1 were 10-fold higher for the FLULUM assay compared to real-time PCR. The FLULUM is an economic assay with high clinical sensitivity and specificity. It is particularly suited to high-volume detection of influenza viruses. PMID- 23345300 TI - An unusual cause of false-positive results with the BD GeneOhm Cdiff assay. PMID- 23345301 TI - Bordetella holmesii, an emerging cause of septic arthritis. AB - Bordetella holmesii is a well-described pathogen in asplenic and immunocompromised patients. Here we report the first two published cases of septic arthritis caused by B. holmesii documented in apparently immunocompetent patients and unaccompanied by bacteremia. PMID- 23345302 TI - Inactivation of HNSCC cells by 90Y-labeled cetuximab strictly depends on the number of induced DNA double-strand breaks. AB - Radioimmunotherapy is considered to have great potential for efficient and highly specific treatment of tumors. The aim of this study was to determine the efficacy of radioimmunotherapy when using (90)Y-labeled cetuximab and to determine to what degree induction and repair of DNA double-strand breaks (DSBs) are decisive for this approach. METHODS: This study was performed with 9 cell lines of squamous cell carcinoma of the head and neck (HNSCC) differing strongly in epidermal growth factor receptor (EGFR) expression. The radionuclide (90)Y was coupled by the chelator trans-cyclohexyl-diethylene-triamine-pentaacetic acid (CHX-A" DTPA)/linker construct to the EGFR-directed antibody cetuximab to yield (90)Y-Y CHX-A"-DTPA-cetuximab with a specific activity of approximately 1.2 GBq/mg. EGFR expression was determined by immunofluorescence and Western blotting, cetuximab binding by fluorescence-activated cell sorter analysis, the number of DSBs by immunofluorescence staining gammaH2AX/53BP1-positive repair foci, and cell survival by colony formation. RESULTS: For the 9 HNSCC cell lines, cetuximab binding correlated with the amount of EGFR present in the cell membrane (r(2) = 0.967, P < 0.001). When cells were exposed to (90)Y-Y-CHX-A"-DTPA-cetuximab, the number of induced DSBs increased linearly with time (r(2) = 0.968, P = 0.016). This number was found to correlate with the amount of membranous EGFR (r(2) = 0.877, P = 0.006). Most DSBs were repaired during incubation at 37 degrees C, but the small number of remaining DSBs still correlated with the amount of membranous EGFR (24 h: r(2) = 0.977, P < 0.001; 48 h: r(2) = 0.947, P < 0.001). Exposure to (90)Y-Y-CHX-A"-DTPA-cetuximab also resulted in efficient cell killing, whereby the extent of cell killing correlated strongly with the respective number of remaining DSBs (r(2) = 0.989, P < 0.001) and with the amount of membranous EGFR (r(2) = 0.967, P < 0.001). No cell killing was observed for UTSCC15 cells with low EGFR expression, in contrast to the strong reduction of 86% measured for UTSCC14 cells showing a strong overexpression of EGFR. CONCLUSION: (90)Y-Y-CHX-A" DTPA-cetuximab affected cell survival through the induction of DSBs. This treatment was especially efficient for HNSCC cells strongly overexpressing EGFR, whereas no effect was seen for cells with low levels of EGFR expression. Therefore, EGFR-directed radioimmunotherapy using (90)Y-Y-CHX-A"-DTPA-cetuximab appears to be a powerful tool that can be used to inactivate tumors with strong EGFR overexpression, which are often characterized by a pronounced radioresistance. PMID- 23345303 TI - 18F-FLT PET during radiotherapy or chemoradiotherapy in head and neck squamous cell carcinoma is an early predictor of outcome. AB - This prospective study used sequential PET with the proliferation tracer 3'-deoxy 3'-(18)F-fluorothymidine ((18)F-FLT) to monitor the early response to treatment of head and neck cancer and evaluated the association between PET parameters and clinical outcome. METHODS: Forty-eight patients with head and neck cancer underwent (18)F-FLT PET/CT before and during the second and fourth weeks of radiotherapy or chemoradiotherapy. Mean maximum standardized uptake values for the hottest voxel in the tumor and its 8 surrounding voxels in 1 transversal slice (SUVmax(9)) of the PET scans were calculated, as well as PET-segmented gross tumor volumes using visual delineation (GTVVIS) and operator-independent methods based on signal-to-background ratio (GTVSBR) and 50% isocontour of the maximum signal intensity (GTV50%). PET parameters were evaluated for correlations with outcome. RESULTS: (18)F-FLT uptake decreased significantly between consecutive scans. An SUVmax(9) decline >= 45% and a GTVVIS decrease >= median during the first 2 treatment weeks were associated with better 3-y disease-free survival (88% vs. 63%, P = 0.035, and 91% vs. 65%, P = 0.037, respectively). A GTVVIS decrease >= median in the fourth treatment week was also associated with better 3-y locoregional control (100% vs. 68%, P = 0.021). These correlations were most prominent in the subset of patients treated with chemoradiotherapy. Because of low (18)F-FLT uptake levels during treatment, GTVSBR and GTV50% were unsuccessful in segmenting primary tumor volume. CONCLUSION: In head and neck cancer, a change in (18)F-FLT uptake early during radiotherapy or chemoradiotherapy is a strong indicator for long-term outcome. (18)F-FLT PET may thus aid in personalized patient management by steering treatment modifications during an early phase of therapy. PMID- 23345304 TI - Small-sample behavior of novel phase I cancer trial designs. AB - BACKGROUND: Novel dose-finding designs for Phase I cancer clinical trials, using estimation to assign the best estimated Maximum Tolerated Dose (MTD) at each point in the experiment, most prominently via Bayesian techniques, have been widely discussed and promoted since 1990. PURPOSE: To examine the small-sample behavior of these 'Bayesian Phase I' designs, and also of non-Bayesian designs sharing the same main 'Long-Memory' traits of using likelihood estimation and assigning the estimated MTD to the next patient. METHODS: Data from several recently published experiments are presented and discussed, and Long-Memory designs' operating principles are explained. Simulation studies compare the small sample behavior of Long-Memory designs with short-memory 'Up-and-Down' designs. RESULTS: In simulation, Long-Memory and Up-and-Down designs achieved similar success rates in finding the MTD. However, for all Long-Memory designs examined, the number n (*) of cohorts treated at the true MTD was highly variable between simulated experiments drawn from the same toxicity-threshold distribution. Further investigation using the same set of thresholds in permuted order indicates that this Long-Memory behavior is driven by sensitivity to the order in which participants enter the experiment. This sensitivity is related to Long Memory designs' 'winner-takes-all' dose-assignment rule, which grants the early cohorts a disproportionately large influence, and causes many experiments to settle early on a specific dose. Additionally for the Bayesian Long-Memory designs, the prior-predictive distribution over the dose levels has a substantial impact upon MTD-finding performance, long into the experiment. LIMITATIONS: While the numerical evidence for Long-Memory designs' order sensitivity is broad, and plausible explanations for it are provided, we do not present a theoretical proof of the phenomenon. CONCLUSIONS: Method developers, analysts, and practitioners should be aware of Long-Memory designs' order sensitivity and related phenomena. In particular, they should be informed that settling on a single dose does not guarantee that this dose is the MTD. Presently, Up-and-Down designs offer a simpler and more robust alternative for the sample sizes of 10-40 patients used in most Phase I trials. Future designs might benefit from combining the two approaches. We also suggest that the field's paradigm change from dose-selection to dose-estimation. PMID- 23345305 TI - Discussion of 'small-sample behavior of novel phase I cancer trial designs' by Assaf P Oron and Peter D Hoff. PMID- 23345306 TI - Commentary on 'Small-sample behavior of novel phase I cancer trial designs'. PMID- 23345308 TI - A systematic review of on-site monitoring methods for health-care randomised controlled trials. AB - BACKGROUND: Monitoring the conduct of clinical trials is recommended by International Conference of Harmonisation Good Clinical Practice (ICH GCP) guidelines and is integral to trial quality assurance. On-site monitoring, that is, visiting trial sites, is one part of this process but little is known about the procedures that are performed in practice. PURPOSE: To examine and summarise published on-site monitoring methods for health-care clinical trials, including evaluations of their benefits and costs to trials. METHODS: A systematic literature review identified all articles reporting the methods and practices of on-site monitoring of randomised controlled trials (RCTs). Articles were categorised into (1) reports from research groups and organisations, (2) reports from individual RCTs, (3) randomised trials of on-site monitoring interventions, (4) cost simulations, or (5) surveys of trial staff and monitors. Data were extracted on the characteristics of the trials and groups reporting on-site monitoring (e.g., geographical origin, sponsor, and trial focus). Information from articles in categories (1)-(3) was summarised on the frequency and scope of site monitoring visits, monitoring team size and composition, activities during site visits, and reporting structures. Evaluations of the benefits and disadvantages of on-site monitoring were examined for all included articles. RESULTS: In total, 57 articles were identified, comprising 21 articles about the on-site monitoring practices of 16 research groups, 30 articles from 26 RCTs, 1 on-site monitoring intervention RCT, 2 cost simulations, and 3 surveys. Publications in categories (1)-(3), mostly originated from the United States (33/52, 63%) or Europe (15/52, 29%), were predominantly describing non-commercial organisations or trials (45/52, 87%), with heart disease (9/26, 35%) or cancer (5/26, 19%) the commonest focus of individual RCTs. The frequency of visits ranged from every 6-8 weeks up to once every 3 years, with mostly all trial sites visited. The number of monitors visiting a site varied between 1 and 8. The most common on-site monitoring activity was verifying source data and consent forms, with a focus on data accuracy. Only six articles evaluated their on-site monitoring process, with improvements observed in recruitment rates and protocol adherence but with direct costs and staff time viewed as the major disadvantages. The on-site monitoring RCT ended prematurely so preventing full assessment. LIMITATIONS: Trialists and organisations may utilise additional unpublished on site monitoring systems. The varied terminology used to describe monitoring may have limited identification of some relevant articles. CONCLUSIONS: This review demonstrated that on-site monitoring is utilised in trials worldwide but systems vary considerably with little evidence to support practice. These on-site monitoring practices need to be evaluated empirically, including costs, to provide robust evidence for the contribution of site visits to trial performance and quality. PMID- 23345309 TI - Clinician-trialist rounds: 14. ways to advance your career by saying 'no' - part 2: when to say 'no', and why. PMID- 23345311 TI - Development of a checklist of quality indicators for clinical trials in resource limited countries: the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) experience. AB - BACKGROUND: Since 1994, the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) has funded research sites in resource-limited countries (RLCs). These sites implement research on human immunodeficiency virus (HIV) infection and Hepatitis C. In parallel, international regulations and recommendations for clinical trials have evolved and proliferated. However, little guidance exists on how these should be interpreted and applied within academic trials and in the context of RLCs. After developing a specific Ethical Charter for research in developing countries in 2002, ANRS developed a set of quality indicators (QIs) as a monitoring tool for assessing compliance to international guidelines. PURPOSE: We describe here the development process, QIs adopted, and areas for improvement. METHODS: In 2008, a group of experts was convened that included a researcher representing each ANRS site (Cote d'Ivoire, Senegal, Cameroun, Burkina Faso, Egypt, and Cambodia). Our structuring interaction development process combined evidence and expert opinion in two nominal group meetings to identify (1) clinical trial processes involved, (2) issues specific to RLCs in terms of Good Clinical Practice (GCP) and the application of ethical recommendations, and (3) checklists of QIs adapted to clinical trials conducted in RLCs. RESULTS: The trial process reviewed and proposed for RLCs was mostly similar to the one produced in wealthier countries. The scheme generated by our work group added two further processes: 'drug management' and 'biological investigations'. Specific issues regarding trial management in RLCs were therefore described for eight trial steps (1) protocol conception and seeking authorizations, (2) participant enrollment and follow-up, (3) site monitoring, (4) drug management, (5) biological investigations, (6) record management, (7) data management, and (8) site closeout. A total of 58 indicators were identified with at least one indicator for each trial process. LIMITATIONS: Some trial activities require further consideration, that is, in the case of vulnerable participants (children, pregnant women). Proposed indicators are the result of expert consensus and reflect their experience in the HIV field. Relevance to existing trials and extrapolation to other fields must be assessed. CONCLUSIONS: This innovative program allowed ANRS sites located in RLCs to share their GCP implementation experiences in order to build a list of relevant indicators for clinical trials. The next step is to collect data from ongoing HIV and hepatitis C trials in these settings and will assess the relevance of these indicators to document current quality of performance among trials in resource-limited settings. PMID- 23345312 TI - Distal intestinal obstruction syndrome: a mimic of acute appendicitis. PMID- 23345313 TI - Manchester Triage System version II and resource utilisation in the emergency department. AB - Emergency department (ED) triage systems aim to direct the best clinical assistance to those who are in the greatest urgency and guarantee that resources are efficiently applied. The study's purpose was to determine whether the Manchester Triage System (MTS) second version is a useful instrument for determining the risk of hospital admission, intrahospital death and resource utilisation in ED and to compare it with the MTS first version. This was a prospective study of patients that attended the ED at a large hospital. It comprised a total of 25,218 cases that were triaged between 11 July and 13 October 2011. The MTS codes were grouped into two clusters: red and orange into a 'high acuity/priority' (HP) cluster, and yellow, green and blue into a 'low acuity/priority' cluster. The risk of hospital admission in the HP cluster was 4.86 times that of the LP cluster for both admission route and ages. The percentage of patient hospital admission between medical and surgical specialties, in high and low priority clusters, was similar. We found the risk of death in the HP cluster to be 5.58 times that of the risk of the low acuity/priority cluster. The MTS had an inconsistent association relative to the utilisation of x-ray, while it seemed to portray a consistent association between ECG and laboratory utilisation and MTS cluster. There were no differences between medical and surgical specialities risk of admission. This suggests that improvements were made in the second version of MTS, particularly in the discriminators of patients triaged to surgical specialties, because this was not true for the first version of MTS. PMID- 23345314 TI - Emergency medical admissions, deaths at weekends and the public holiday effect. Cohort study. AB - OBJECTIVES: To assess whether mortality of patients admitted on weekends and public holidays was higher in a district general hospital whose consultants are present more than 6 h per day on the acute medical unit with no other fixed clinical commitments. DESIGN: Cohort study. SETTING: Secondary care. PARTICIPANTS: All emergency medical admissions to Dumfries and Galloway Royal Infirmary between 1 January 2008 and 31 December 2010. METHODS: We examined 7 and 30 day mortality for all weekend and for all public holiday admissions, using all weekday and non-public holiday admissions, respectively, as comparators. We adjusted mortality for age, gender, comorbidity, deprivation, diagnosis and year of admission. RESULTS: 771 (3.8%) of 20 072 emergency admissions died within 7 days of admission and 1780 (8.9%) within 30 days. Adjusted weekend mortality in the all weekend versus all other days analysis was not significantly higher at 7 days (OR 1.10, 95% CI 0.92 to 1.31; p=0.312) or at 30 days (OR 1.07, 95% CI 0.94 to 1.21; p=0.322). By contrast, adjusted public holiday mortality in the all public holidays versus all other days analysis was 48% higher at 7 days (OR 1.48, 95% CI 1.12 to 1.95; p=0.006) and 27% higher at 30 days (OR 1.27, 95% CI 1.02 to 1.57; p=0.031). Interactions between the weekend variable and the public holiday variable were not statistically significant for mortality at either 7 or 30 days. CONCLUSIONS: Patients admitted as emergencies to medicine on public holidays had significantly higher mortality at 7 and 30 days compared with patients admitted on other days of the week. PMID- 23345315 TI - Developing a multidisciplinary approach within the ED towards domestic violence presentations. AB - AIM: To improve the detection and quality of care of patients who attend the emergency department (ED) with confirmed or suspected domestic abuse (DA). DESIGN: A quality improvement report on the design, implementation and evaluation of a specialised service and structured training programme to detect and manage DA presentations within an emergency medicine department. SETTING: The study was set in the ED at the Northern General Hospital, Sheffield, UK. KEY MEASURES FOR IMPROVEMENT: Key measures for improvement included introducing a service within the ED to help staff manage DA and coordinate responses; improve staff confidence in detecting DA; develop a structured and consistent process by which to manage DA presentations. STRATEGIES FOR CHANGE: An Independent Domestic Violence Advocate service was introduced into the department in July 2011 through a multiagency agreement. A structured training and education programme was delivered to ED staff. A 'communications form' was developed for DA risk assessment and case management. The process was reviewed quarterly. RESULTS: One hundred and seventy-two referrals were made to the service (121 distinct clients) over a 12-month period. Staff reported greater confidence in detecting DA, and community partners highlighted the role the service had in improving DA detection and care quality within the city. CONCLUSIONS: Strong leadership and prioritising the issue within the department has facilitated the development of the process and contributed substantially to its success. Support from community partners has been invaluable in tailoring the service and education programme to the needs of staff and patients within the department. PMID- 23345316 TI - Prehospital anaesthesia performed in a rural and suburban air ambulance service staffed by a physician and paramedic: a 16-month review of practice. AB - INTRODUCTION: This paper describes the first 16-months experience of prehospital rapid sequence intubation (RSI) in a rural and suburban helicopter-based doctor paramedic service after the introduction of a standard operating procedure (SOP) already proven in an urban trauma environment. METHOD: A retrospective database review of all missions between October 2010 and January 2012 was carried out. Any RSI or intubation carried out was included, regardless of age or indication. Patients who were intubated by Ambulance Service personnel prior to the arrival of the East Anglian Air Ambulance (EAAA) team were excluded. RESULTS: The team was activated 1156 times and attended 763 cases. A total of 88 RSIs occurring within the study period were identified as having been carried out by the EAAA team and meeting inclusion criteria for review. There were no failed intubations that required a rescue surgical airway or the placement of a supraglottic airway device. For road traffic collisions (RTCs), the overall on-scene time for patients who required an RSI was 40 min (range 15-72 min). For all other trauma, the average on-scene time was 48 min (range 25-77 min), and for medical patients, the average time spent at scene was 41 min (range 15-94 min). CONCLUSIONS: We have demonstrated the successful introduction of a prehospital care SOP, already tested in the urban trauma environment, to a rural and suburban air ambulance service operating a fulltime doctor-paramedic model. We have shown a zero failed intubation rate over 16 months of practice during which time over 750 missions were flown, with 11.5% of these resulting in an RSI. PMID- 23345317 TI - Use of prothrombin complex concentrates: 4-year experience of a national aeromedical retrieval service servicing remote and rural areas. AB - INTRODUCTION: Prothrombin complex concentrates (PCCs) are recommended as first line treatment for acquired or congenital factor II, VII, IX and X deficiencies in situations of major haemorrhage. The Emergency Medical Retrieval Service (EMRS) provides critical care and aeromedical retrieval to patients in remote and rural Scotland. It has an important role in the care of these patients. METHOD: We sought to determine the incidence of haemorrhage requiring PCC administration in our cohort of patients, and to assess compliance with current national guidelines regarding their storage and use. We searched our database for all patients that received PCCs, or met current guidelines for their administration, and followed them through to hospital discharge. We also conducted a telephone survey of all hospitals served by the EMRS to determine compliance with national standards. RESULTS: During the 42-month study period, 1170 retrieval missions were conducted. Twenty-six retrieved patients had a congenital or acquired clotting factor deficiency and seven met criteria for PCC administration. Of these, only three received PCCs prior to transfer to definitive care. Telephone survey revealed that all the rural general hospitals were served by the EMRS stock PCCs, but only one out of 15 GP-led community hospitals had access to PCCs. CONCLUSIONS: In the remote and rural setting where access to definitive care may be limited or delayed, timely administration of PCCs in appropriate patients may improve outcomes. As many rural hospitals do not have access to PCCs, the ability of the EMRS to provide this treatment may improve patient care. PMID- 23345318 TI - Evolved design makes ThoraQuik safe and user friendly in the management of pneumothorax and pleural effusion. AB - BACKGROUND: We have previously described the utility of ThoraQuik, a device designed to be fit for purpose for aspirations of pneumothorax and pleural effusions. We evaluated the safety, efficacy and operator handling of the evolved prototype, ThoraQuik II, which has a lesser profile and a spring loaded Veres needle for added safety. METHODS: A prospective, observational clinical trial with ethics and MHRA approval was conducted in a single centre. Patients with diagnosed pneumothorax (including tension pneumothorax) and pleural effusion were consented and recruited. The ease of device introduction, penetration and ease of use were evaluated. Clinical and radiological improvements were the clinical endpoints and operator feedback was analysed. RESULTS: 20 procedures were performed on patients (mean age: 63.4 years (range: 30-90 years) with 75% male subjects) recruited between September 2008 and August 2009. Nine patients had pneumothorax (tension pneumothorax n=4) and 11 had pleural effusions. 19 patients completed the study with symptomatic and radiological resolution. One patient was withdrawn due to poor pain threshold disproportionate to the procedure. No complications were encountered. 68% had complete clinical and radiological resolution and 32% had partial resolution (these patients needed a definitive drain and hence were not aspirated to completion). The operator feedback in the study rated the device as very good or excellent in 90% patients. CONCLUSIONS: Our study found the use of ThoraQuik II to be safe and easy in draining pneumothorax and pleural effusions. The changes to ThoraQuik II made it more user friendly. PMID- 23345319 TI - Origins and diversity of eukaryotic CO2-concentrating mechanisms: lessons for the future. AB - The importance of the eukaryotic algal CO(2)-concentrating mechanism (CCM) is considered in terms of global productivity as well as molecular phylogeny and diversity. The three major constituents comprising the CCM in the majority of eukaryotes are described. These include: (i) likely plasma- and chloroplast membrane inorganic carbon transporters; (ii) a suite of carbonic anhydrase enzymes in strategic locations; and usually (iii) a microcompartment in which most Rubisco aggregates (the chloroplast pyrenoid). The molecular diversity of known CCM components are set against the current green algal model for their probable operation. The review then focuses on the kinetic and cystallographic interactions of Rubisco, which permit pyrenoid formation and CCM function. Firstly, we consider observations that surface residues of the Rubisco small subunit directly condition Rubisco aggregation and pyrenoid formation. Secondly, we reanalyse the phylogenetic progression in green Rubisco kinetic properties, and suggest that Rubisco substrate selectivity (the specificity factor, S(rel), and affinity for CO(2), K(c)) demonstrate a systematic relaxation, which directly relates to the origins and effectiveness of a CCM. Finally, we consider the implications of eukaryotic CCM regulation and minimum components needed for introduction into higher plants as a possible means to enhance crop productivity in the future. PMID- 23345320 TI - Time preferences, socioeconomic status and smokers' behaviour, attitudes and risk awareness. AB - BACKGROUND: Tobacco control policies have succeeded in reducing tobacco use, but the negative correlation between smoking prevalence and socioeconomic status (SES) has increased. This study focused on the relationships between time preferences, SES, and smoking behaviour, attitudes and risk awareness. METHODS: A cross-sectional telephone survey was conducted in France in 2008 on a representative national sample of people aged 18-75 (N = 2000, including 621 smokers) years. Two scales measuring planning horizon and impulsivity and various indicators of SES were introduced into the logistic regressions performed on smoking status and smokers' attitudes to anti-smoking campaigns, quitting attempts, attempts to quit or smoke less, fear of smoking-related cancer and risk perception. RESULTS: Indicators of lower SES and smoking status were correlated with present time orientation and impulsivity. On modelling smoking status, time orientation and lower SES were found to be significant predictors. Among smokers, lower SES and present time orientation were predictive of smoking-related outcomes: little personal concern with anti-tobacco campaigns, not reporting recent behavioural changes, not expressing personal fear of smoking-related cancer and low risk awareness. When time-related preferences were introduced into the analysis, the effects of several lower SES indicators (especially a low educational level) became non-significant. CONCLUSION: The relationship between SES and smoking behaviour, attitudes and beliefs may be partly mediated by time preferences. Time preference is strongly correlated with smoking status, risk perceptions and attitudes towards anti-smoking campaigns. Tobacco control policies should include messages targeting present time-oriented smokers and/or interventions designed to enhance more future-oriented attitudes among smokers. PMID- 23345321 TI - Is there an emergency of tobacco smoking among health professionals in the European region? PMID- 23345322 TI - Doctors and medical students as non-smoking role models? Using the right arguments. PMID- 23345323 TI - Enhancing gamma-aminobutyric acid content in germinated brown rice by repeated treatment of soaking and incubation. AB - Gamma-aminobutyric acid (GABA), commonly produced by germination of brown rice grain, is a free amino acid which could help relieving or preventing non communicable diseases in human. Several research works have been conducted on GABA production from germinated brown rice. However, the yielded GABA (10.1-69.2 mg/100 g germinated brown rice) was comparatively low; thus the amount was insufficient to be used as active ingredients in functional foods. The objective of this study was to explore alternative methods in order to gain higher yield of GABA. A new process of repeated soaking (in tap water at 35 degrees C, 3 h) and incubation (at 37 degrees C, 21 h) during germination was developed. The amount of GABA produced was highest at 116.88 +/- 9.24 mg/100 g germinated brown rice (dry basis). However, an unpleasant odour was generated by some microorganisms during long germination. Lactic acid was applied at soaking step to overcome this problem; whereby 0.5% lactic acid solution (vol./vol.) could effectively control the microorganisms without impairing GABA producing ability and sensory qualities. PMID- 23345324 TI - Changes on image texture features of breakfast flakes cereals during water absorption. AB - Normally breakfast cereal flakes are consumed by pouring them into a bowl and covering them with fresh or cold milk. During this process the liquid uptake causes changes in the surface and internal matrix of breakfast cereals that influence texture and integrity. Some breakfast cereal as flakes have a translucent structure that could provide information about the solid matrix and air cells and how they change during liquid absorption. The objective of the study was to assess the image texture changes of corn flakes and frosted flakes during water absorption at 5, 15 and 25 degrees C, employing 11 image feature textures extracted from grey-level co-occurrence matrix and grey-level run length matrix (at three directions) and to relate the fractal dimension (FD) of images with rupture force (RF) reduction during soaking of both flakes at 5 degrees C. The most relevant result from principal component analysis calculated with a matrix of 54 (soaking times) * 22 (texture features), shows that it was possible to distinguish an isolated group consisting of different soaking times at the same water temperature in each breakfast cereal flakes evaluated, corroborating that superficial liquid imbibition is important during the liquid absorption process when flakes are soaked. Furthermore, standardized FD could be related to RF in the period when samples tend to search for an equilibrium state. PMID- 23345325 TI - Characterisation of a highly saturated Irvingia gabonensis seed kernel oil with unusual linolenic acid content. AB - The search for new sources of oil with improved characteristics has focused our attention on the characterisation of Irvingia gabonensis seed kernel oil. Physicochemical analysis have revealed the following assets: refractive index (1.42 +/- 0.00), free fatty acids (2.3 +/- 0.8%), peroxide value (3.33 +/- 0.57 meq O(2)/kg), iodine value (32.43 +/- 1.22 g I(2)/100 g), saponification value (233.75 +/- 2.60 mg KOH/g), unsaponifiable matter (1.5 +/- 0.02%), carotenoids (63 +/- 0.01 mg beta-carotene/100 g) and phospholipids (2.1 +/- 0.01%). Absorbance of this oil decreased abruptly in the range of UV-B and UV-A wavelengths. Gas chromatography analysis showed that the major fatty acids were saturated, being mainly composed of lauric (C12:0, 39.35 +/- 0.01%) and myristic acids (C14:0, 20.54 +/- 0.01%). Nevertheless, an unusually high amount (6.44 +/- 0.02%) of linolenic acid was also noted. Mass spectrometer analysis of volatile compounds highlighted the presence of various aromatic and aliphatic organic compounds. I. gabonensis seed kernel oil also showed oxidative stability at 60 degrees C after 12 days of storage with maximum peroxide value of 34.66 meq O(2)/kg. In view of these interesting characteristics, I. gabonensis seed kernel could be used as an alternative source of oil for lipid industries. PMID- 23345326 TI - Producing children in the 21st century: a critical discourse analysis of the science and techniques of monitoring early child development. AB - The purpose of this article is to identify the implications of commonly held ideologies within theories of child development. Despite critiques to doing so, developmental theory assumes that children's bodies are unitary, natural and material. The recent explosion of neuroscience illustrates the significance of historical, social and cultural contexts to portrayals of brain development, offering the opportunity for a critical departure in thinking. Instead, this neuroscience research has been taken up in ways that align with biomedical traditions and neoliberal values. This article uses a critical discursive approach, supported by Haraway's ideas of technoscience, to analyse a population based early child development research initiative. This initiative organises a large-scale surveillance of children's development, operating from the premise that risks to development are best captured early to optimise children's potential. The analysis in this article shows an intermingling of health and economic discourses and clarifies how the child is a figure of significant contemporary social and political interests. In a poignant example of technobiopolitics, the collusion between health research, technologies and the state enrols health professionals to participate in the production of children as subjects of social value, figured as human capital, investments in the future, or alternatively, as waste. The analysis shows how practices that participate in what has become a developmental enterprise also participate in the marginalisation of the very children they intend to serve. Hence, there is the need to rethink practices critically and move towards innovative conceptualisations of child development that hold possibilities to resist these figurations. PMID- 23345327 TI - Human NK cells selective targeting of colon cancer-initiating cells: a role for natural cytotoxicity receptors and MHC class I molecules. AB - Tumor cell populations have been recently proposed to be composed of two compartments: tumor-initiating cells characterized by a slow and asymmetrical growth, and the "differentiated" cancer cells with a fast and symmetrical growth. Cancer stem cells or cancer-initiating cells (CICs) play a crucial role in tumor recurrence. The resistance of CICs to drugs and irradiation often allows them to survive traditional therapy. NK cells are potent cytotoxic lymphocytes that can recognize tumor cells. In this study, we have analyzed the NK cell recognition of tumor target cells derived from the two cancer cell compartments of colon adenocarcinoma lesions. Our data demonstrate that freshly purified allogeneic NK cells can recognize and kill colorectal carcinoma-derived CICs whereas the non CIC counterpart of the tumors (differentiated tumor cells), either autologous or allogeneic, is less susceptible to NK cells. This difference in the NK cell susceptibility correlates with higher expression on CICs of ligands for NKp30 and NKp44 in the natural cytotoxicity receptor (NCR) group of activating NK receptors. In contrast, CICs express lower levels of MHC class I, known to inhibit NK recognition, on their surface than do the "differentiated" tumor cells. These data have been validated by confocal microscopy where NCR ligands and MHC class I molecule membrane distribution have been analyzed. Moreover, NK cell receptor blockade in cytotoxicity assays demonstrates that NCRs play a major role in the recognition of CIC targets. This study strengthens the idea that biology-based therapy harnessing NK cells could be an attractive opportunity in solid tumors. PMID- 23345329 TI - Cutting edge: antibody-dependent memory-like NK cells distinguished by FcRgamma deficiency. AB - Because NK cells lack gene-recombination machinery and are thought to be relatively short-lived, it is unclear whether NK cells can mount long-term effective recall responses to reinfections by diverse pathogens. In this article, we report that FcRgamma-deficient NK cells, which we recently identified and termed g(-)NK cells, possess distinct memory features directed by FcR-mediated Ab dependent target recognition. The presence of g(-)NK cells was associated with prior human CMV (HMCV) infection, yet g(-)NK cell responses were not restricted to HCMV-infected target cells. In the presence of virus-specific Abs, g(-)NK cells had greatly enhanced functional capabilities, superior to conventional NK cells, and were highly responsive to cells infected with either HCMV or HSV-1. Remarkably, the g(-)NK cell subset persisted long-term at nearly constant levels in healthy individuals. Therefore, FcRgamma deficiency distinguishes an Ab dependent memory-like NK cell subset with enhanced potential for broad antiviral responses. PMID- 23345328 TI - Activated invariant NKT cells control central nervous system autoimmunity in a mechanism that involves myeloid-derived suppressor cells. AB - Invariant NKT (iNKT) cells are a subset of T lymphocytes that recognize glycolipid Ags presented by the MHC class I-related protein CD1d. Activation of iNKT cells with glycolipid Ags, such as the marine sponge-derived reagent alpha galactosylceramide (alpha-GalCer), results in the rapid production of a variety of cytokines and activation of many other immune cell types. These immunomodulatory properties of iNKT cells have been exploited for the development of immunotherapies against a variety of autoimmune and inflammatory diseases, but mechanisms by which activated iNKT cells confer disease protection have remained incompletely understood. In this study, we demonstrate that glycolipid-activated iNKT cells cooperate with myeloid-derived suppressor cells (MDSCs) in protecting mice against the development of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model for multiple sclerosis. We show that alpha-GalCer induced the expansion and immunosuppressive activities of MDSCs in the spleen of mice induced for development of EAE. Disease protection in these animals also correlated with recruitment of MDSCs to the CNS. Depletion of MDSCs abrogated the protective effects of alpha-GalCer against EAE and, conversely, adoptive transfer of MDSCs from alpha-GalCer-treated mice ameliorated passive EAE induced in recipient animals. The cytokines GM-CSF, IL-4, and IFN-gamma, produced by activated iNKT cells, and inducible NO synthase, arginase-1, and IL-10 produced by MDSCs, contributed to these effects. Our findings have revealed cooperative immunosuppressive interactions between iNKT cells and MDSCs that might be exploited for the development of improved immunotherapies for multiple sclerosis and other autoimmune and inflammatory diseases. PMID- 23345330 TI - Sox4 is required for the survival of pro-B cells. AB - The development of mature B cells from hematopoietic stem cells is a strictly orchestrated process involving multiple regulatory genes. The transcription factor Sox4 is required for this process, but its role has not been systematically studied, and the underlying mechanisms remain unknown. To determine when and how Sox4 functions in the stepwise process of B cell development, we used mice harboring conditional null alleles for Sox4 and a Cre transgene. Sox4 deletion in hematopoietic stem cells almost entirely eliminated pro-B cells in both fetal livers and adult bone marrow, resulting in a severe deficiency in later stage B cells, including circulating mature B cells. Sox4 deficient pro-B cells, particularly those expressing the stem cell factor receptor c-Kit, readily underwent apoptosis, and even more so when c-Kit activity was inhibited by imatinib. C-Kit-expressing pro-B cells showed decreased activation of the c-Kit downstream protein Src upon Sox4 deletion. Likewise, the level of the anti-apoptotic Bcl2 protein was decreased in residual pro-B cells, and its restoration using a Bcl2 transgene allowed not only partial rescue of pro B cell survival but also B cell maturation in the absence of Sox4. Our findings indicate that Sox4 is required for the survival of pro-B cells and may functionally interact with c-Kit and Bcl2. PMID- 23345331 TI - Vitronectin inhibits efferocytosis through interactions with apoptotic cells as well as with macrophages. AB - Effective removal of apoptotic cells, particularly apoptotic neutrophils, is essential for the successful resolution of acute inflammatory conditions. In these experiments, we found that whereas interaction between vitronectin and integrins diminished the ability of macrophages to ingest apoptotic cells, interaction between vitronectin with urokinase-type plasminogen activator receptor (uPAR) on the surface of apoptotic cells also had equally important inhibitory effects on efferocytosis. Preincubation of vitronectin with plasminogen activator inhibitor-1 eliminated its ability to inhibit phagocytosis of apoptotic cells. Similarly, incubation of apoptotic cells with soluble uPAR or Abs to uPAR significantly diminished efferocytosis. In the setting of LPS-induced ALI, enhanced efferocytosis and decreased numbers of neutrophils were found in bronchoalveolar lavage obtained from vitronectin-deficient (vtn(-/-)) mice compared with wild type (vtn(+/+)) mice. Furthermore, there was increased clearance of apoptotic vtn(-/-) as compared with vtn(+/+) neutrophils after introduction into the lungs of vtn(-/-) mice. Incubation of apoptotic vtn(-/-) neutrophils with purified vitronectin before intratracheal instillation decreased efferocytosis in vivo. These findings demonstrate that the inhibitory effects of vitronectin on efferocytosis involve interactions with both the engulfing phagocyte and the apoptotic target cell. PMID- 23345332 TI - Proteasomal degradation of herpes simplex virus capsids in macrophages releases DNA to the cytosol for recognition by DNA sensors. AB - The innate immune system is important for control of infections, including herpesvirus infections. Intracellular DNA potently stimulates antiviral IFN responses. It is known that plasmacytoid dendritic cells sense herpesvirus DNA in endosomes via TLR9 and that nonimmune tissue cells can sense herpesvirus DNA in the nucleus. However, it remains unknown how and where myeloid cells, such as macrophages and conventional dendritic cells, detect infections with herpesviruses. In this study, we demonstrate that the HSV-1 capsid was ubiquitinated in the cytosol and degraded by the proteasome, hence releasing genomic DNA into the cytoplasm for detection by DNA sensors. In this context, the DNA sensor IFN-gamma-inducible 16 is important for induction of IFN-beta in human macrophages postinfection with HSV-1 and CMV. Viral DNA localized to the same cytoplasmic regions as did IFN-gamma-inducible 16, with DNA sensing being independent of viral nuclear entry. Thus, proteasomal degradation of herpesvirus capsids releases DNA to the cytoplasm for recognition by DNA sensors. PMID- 23345333 TI - Inhibition of TLR4 signaling by TRAM-derived decoy peptides in vitro and in vivo. AB - Toll/IL-1R (TIR) domain-containing adapter-inducing IFN-beta (TRIF)-related adapter molecule (TRAM) serves as a bridging adapter that enables recruitment of TRIF to activated TLR4 and thereby mediates the induction of TRIF-dependent cytokines. A library of cell-permeating decoy peptides derived from TRAM TIR domain has been screened for the ability of individual peptides to inhibit TLR4 signaling in primary murine macrophages. Peptides derived from TRAM TIR BB loop (TM4) and C helix (TM6) inhibited the LPS-induced activation of MyD88-dependent and TRIF-dependent cytokines, as well as MAPK activation. TM4 and TM6 did not block macrophage activation induced by TLR2, TLR9, or retinoic acid-inducible gene 1-like receptor agonists. Both TM4 and TM6 blocked coimmunoprecipitation of TRAM and TLR4 ectopically expressed in HEK293T cells. Both peptides also blocked the LPS-induced recruitment of MyD88 to TLR4 in primary murine macrophages. In vivo examination of TRAM-derived peptides demonstrated that all peptides that were inhibitory in vitro profoundly suppressed systemic inflammatory response elicited in mice by a sublethal LPS dose, and protected mice against a lethal LPS challenge. This research identifies novel TLR inhibitors effective in vitro and in vivo and validates the approach taken in this study as a rational way for development of signaling inhibitors and lead therapeutics. PMID- 23345335 TI - Family health history communication networks of older adults: importance of social relationships and disease perceptions. AB - Older individuals play a critical role in disseminating family health history (FHH) information that can facilitate disease prevention among younger family members. This study evaluated the characteristics of older adults and their familial networks associated with two types of communication (have shared and intend to share new FHH information with family members) to inform public health efforts to facilitate FHH dissemination. Information on 970 social network members enumerated by 99 seniors (aged 57 years and older) at 3 senior centers in Memphis, Tennessee, through face-to-face interviews was analyzed. Participants shared FHH information with 27.5% of the network members; 54.7% of children and 24.4% of siblings. Two-level logistic regression models showed that participants had shared FHH with those to whom they provided emotional support (odds ratio [OR] = 1.836) and felt close to (OR = 1.757). Network-members were more likely to have received FHH from participants with a cancer diagnosis (OR = 2.617) and higher familiarity with (OR = 1.380) and importance of sharing FHH with family (OR = 1.474). Participants intended to share new FHH with those who provide tangible support to (OR = 1.804) and were very close to them (OR = 2.112). Members with whom participants intend to share new FHH were more likely to belong to the network of participants with higher perceived severity if family members encountered heart disease (OR = 1.329). Many first-degree relatives were not informed of FHH. Perceptions about FHH and disease risk as well as quality of social relationships may play roles in whether seniors communicate FHH with their families. Future studies may consider influencing these perceptions and relationships. PMID- 23345334 TI - Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis. AB - IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL 35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity. PMID- 23345336 TI - Are physicians and patients in agreement? Exploring dyadic concordance. AB - Dyadic concordance in physician-patient interactions can be defined as the extent of agreement between physicians and patients in their perceptions of the clinical encounter. The current research specifically examined two types of concordance: informational concordance-the extent of agreement in physician and patient responses regarding patient information (education, self-rated health, pain); and interactional concordance-the extent of physician-patient agreement regarding the patient's level of confidence and trust in the physician and the perceived quality of explanations concerning diagnosis and treatment. Using a convenience sample of physicians and patients (N = 50 dyads), a paired survey method was tested, which measured and compared physician and patient reports to identify informational and interactional concordances. Factors potentially related to dyadic concordance were also measured, including demographic characteristics (patient race, gender, age, and education) and clinical factors (whether this was a first visit and physician specialty in family medicine or oncology). The paired survey showed informational discordances, as physicians tended to underestimate patients' pain and overestimate patient education. Interactional discordances included overestimating patients' understanding of diagnosis and treatment explanations and patients' level of confidence and trust. Discordances were linked to patient dissatisfaction with physician listening, having unanswered questions, and feeling the physician had not spent enough time. The paired survey method effectively identified physician-patient discordances that may interfere with effective medical practice; this method may be used in various settings to identify potential areas of improvement in health communication and education. PMID- 23345337 TI - The relationship between self-efficacy and help evasion. AB - OBJECTIVE: To examine the relationship between self-efficacy and not wanting help to change health behaviors. METHOD: All employees in the Danish police department were invited to respond to an electronic questionnaire. All respondents expressing a desire to change health behaviors in relation to smoking (n = 845), alcohol (n = 684), eating (n = 4431), and physical activity (n = 5179) and who subsequently responded to questions on self-efficacy were included. RESULTS: Both the bivariate and multiple regression analyses showed that all four specific self efficacy scores were positively related to reporting that one did not want help. CONCLUSION: A high belief in one's own ability to change lifestyle behaviors in relation to smoking, alcohol, eating, and physical activity may lead to avoidance of help offers in a workplace setting. PMID- 23345338 TI - The days are long and the years are short: a year in the shoes of a SOPHE president. AB - Among the most memorable lessons I learned from my father was based on a comment he often made when I was young: "The days are long and the years are short." During a year as President of the Society for Public Health Education (SOPHE), there were many days that seemed to go on forever; but in retrospect, the entire year seems to have flown by in the blink of an eye. During this year, SOPHE has accomplished much for its members through its annual meetings, publications, and social media presence. Perhaps as important, SOPHE has continued to make an indelible mark on the profession of health education. Whether by launching new initiatives through its cooperative agreements with the U.S. Centers for Disease Control and Prevention, ensuring ongoing training for in-service health educators or by continuing to work on unification of the profession in negotiations with the American Association for Health, Physical Education, Recreation, and Dance, SOPHE continues to innovate. There remains much to be done; the challenges continue; and the opportunities are rich for the future of health education. PMID- 23345340 TI - Motivating factors for small and midsized businesses to implement worksite health promotion. AB - OBJECTIVE: This study explores the decision-making process, including motivating factors, for small and midsized businesses in the Midwest to implement health promotion initiatives. METHOD: This a replication of a study conducted in the Pacific Northwest. Semistructured qualitative interviews were conducted with key informants from 12 Midwestern metropolitan employers with fewer than 1,000 employees. Informants were interviewed regarding their companies' policies and practices around workplace health promotion programming adoption and valuation. RESULTS: Workplace health promotion adoption at these small and midsized businesses was motivated by three goals: to lower health care costs, to address human relations objectives, and to improve productivity. Low upfront cost was the most frequently considered criterion in choosing which workplace health promotion program to offer. Barriers to implementation included lack of employee buy-in, prohibitive costs, and personnel or time constraints. Aids to implementation included employee buy-in and affordability. CONCLUSIONS: This study suggests that cost considerations predominate in the workplace health promotion decision-making process at small to midsized businesses. Furthermore, employee buy-in cannot be underestimated as a factor in successful program implementation or longevity. Employees, along with executives and human resources management, must be appropriately targeted by health promotion practitioners in workplace health promotion efforts. PMID- 23345339 TI - Human papillomavirus clearance among males is associated with HIV acquisition and increased dendritic cell density in the foreskin. AB - BACKGROUND: The association between human papillomavirus (HPV) infection and the risk of human immunodeficiency virus (HIV) seroconversion is unclear, and the genital cellular immunology has not been evaluated. METHODS: A case-control analysis nested within a male circumcision trial was conducted. Cases consisted of 44 male HIV seroconverters, and controls were 787 males who were persistently negative for HIV. The Roche HPV Linear Array Genotype Test detected high-risk HPV (HR-HPV) and low-risk HPV (LR-HPV) genotypes. Generalized estimating equations logistic regression was used to estimate adjusted odds ratios (aORs) of HIV seroconversion. In addition, densities of CD1a(+) dendritic cells, CD4(+) T cells, and CD8(+) T cells were measured using immunohistochemistry analysis in foreskins of 79 males randomly selected from participants in the circumcision trial. RESULTS: HR-HPV or LR-HPV acquisition was not significantly associated with HIV seroconversion, after adjustment for sexual behaviors. However, HR-HPV and LR-HPV clearance was significantly associated with HIV seroconversion (aOR, 3.25 [95% confidence interval {CI}, 1.11-9.55] and 3.18 [95% CI, 1.14-8.90], respectively). The odds of HIV seroconversion increased with increasing number of HPV genotypes cleared (P < .001, by the test for trend). The median CD1a(+) dendritic cell density in the foreskin epidermis was significantly higher among males who cleared HPV (72.0 cells/mm(2) [interquartile range {IQR}, 29.4-138.3 cells/mm(2)]), compared with males who were persistently negative for HPV (32.1 cells/mm(2) [IQR, 3.1-96.2 cells/mm(2)]; P = .047), and increased progressively with the number of HPV genotypes cleared (P = .05). CONCLUSIONS: HPV clearance was associated with subsequent HIV seroconversion and also with increased epidermal dendritic cell density, which potentially mediates HIV seroconversion. PMID- 23345343 TI - Section editor's notebook: Technical advances in women's imaging and the "digital native". PMID- 23345342 TI - Job satisfaction of program directors in radiology: a survey of current program directors. AB - OBJECTIVE: Informal conversations and anecdotal evidence suggest that the job turnover rate among radiology residency program directors is disproportionately high. The purpose of our study was to assess the characteristics of current program directors and determine factors that may be affecting overall job satisfaction and job turnover rate. SUBJECTS AND METHODS: A survey that combined facet-specific measurements and global assessment was sent to current program directors in Accreditation Council for Graduate Medical Education (ACGME) approved diagnostic radiology programs. An optional free response section was included. Results were collected over 4 weeks. RESULTS: Most of the program directors responded. The mean tenure of current program directors was 6.9 +/- 6.7 years (range, 0.5-30 years). Fifty-three percent rated global job satisfaction high, and 6% reported low satisfaction. Sixty-four percent of the respondents were not considering resignation, compared with 13% who were definitely resigning. Program directors in larger programs reported a higher level of satisfaction. Positive interactions with residents and feeling valued by colleagues increased job satisfaction. The greatest source of dissatisfaction from all respondents seemed to be ACGME regulations, which were considered excessive and to change too frequently. The changing format of the board examination and structure of a residency were not the major factors in determining job satisfaction. CONCLUSION: The job satisfaction rate among current program directors is high, likely owing to feelings of fulfillment in working with residents and feeling valued by colleagues. The major source of dissatisfaction appears to stem from ACGME oversight, which is perceived as excessive and having requirements that change too frequently. PMID- 23345344 TI - New MR techniques in gynecologic cancer. AB - OBJECTIVE: Functional MR techniques report on a variety of biologic features of tumors: dynamic contrast-enhanced, diffusion-weighted, and intrinsic susceptibility-weighted MRI and MR spectroscopy reflect, at a simplistic level, vascularity, cellularity, hypoxic status, and metabolism, respectively. This article reviews the evidence for each of the functional MR readouts to determine these clinical end points and thus influence the management of ovarian, endometrial, and cervical cancer. CONCLUSION: These techniques may be implemented in gynecologic malignancies to detect, characterize, and stage tumors as well as potentially to predict the outcome and measure response to treatment. PMID- 23345345 TI - Pearls and pitfalls in MRI of gynecologic malignancy with diffusion-weighted technique. AB - OBJECTIVE: Developments in MRI techniques have increased the role of MRI in assessment of the pelvis in women. The aims of this review are a short overview of pelvic MRI with an emphasis on diffusion-weighted MRI (DWI) and presentation of a practical approach that includes the pearls and pitfalls of DWI. CONCLUSION: DWI provides indispensable information in the evaluation of gynecologic malignancies. Prudent application of this technique requires knowledge of the optimal protocols and pitfalls in interpretation. PMID- 23345346 TI - Observer study of a prototype clinical decision support system for breast cancer diagnosis using dynamic contrast-enhanced MRI. AB - OBJECTIVE: The purpose of this article is to evaluate the performance of radiologists using a prototype clinical decision support system to diagnose and manage patients with breast cancer based on dynamic contrast-enhanced MRI studies. MATERIALS AND METHODS: The study was conducted with three breast radiologists and two breast imaging fellows who gave patient treatment recommendations and confidence ratings, both without and with computer aid. The computer aid presented similar cases from a retrieval database of 192 lesions (96 malignant and 96 benign) for a test set of 97 mass lesions (46 malignant and 51 benign). The performance of each observer was quantified by receiver operating characteristic analysis. The radiologists' confidence in their recommendations was analyzed with respect to the query case pathologic diagnosis, perceived usefulness of the similar cases, and the accuracy of the computer in retrieving cases of the correct diagnosis. The statistical significance in the performance measure differences was determined by using a two-tailed Student t test for paired data. RESULTS: For each observer, the area under the receiver operating characteristic curve did not change significantly with the use of the computer aid (from a mean of 0.8 to a mean of 0.8; p = 0.61). The average confidence of three of the five observers increased significantly with the computer aid (from 5.9 to 6.3 [p < 0.001], from 7.0 to 7.2 [p = 0.04], and from 4.4 to 5.4 [p < 0.001], respectively). The confidence change of the radiologists was more frequent and larger for malignant lesions where the computer was correct. However, for benign lesions, even when the computer was correct, the confidence of the radiologists did not necessarily change. CONCLUSION: The presentation of similar cases reinforced radiologists' confidence rating in the diagnosis of malignant lesions; however, it did not change their confidence rating for benign lesions or reduce the number of unnecessary biopsies in managing patients with breast cancer using dynamic contrast-enhanced MRI under the limited study conditions. PMID- 23345347 TI - Assessing the role of ultrasound in predicting the biological behavior of breast cancer. AB - OBJECTIVE: The purpose of this article is to correlate various ultrasound features of breast cancer with tumor grade, and with estrogen, progesterone, and ERRB2 (formerly HER2) receptor status as well as to assess the predictive value of these features. MATERIALS AND METHODS: The features of breast cancers found by using ultrasound between January 2010 and June 2011 were reviewed for tumor size, margins, and posterior acoustic features. The tumor margins were classified into spiculated, angular, indistinct, lobulated or microlobulated, and circumscribed. The posterior acoustic features were classified into shadowing, enhancement, mixed pattern, and no change. The individual features were correlated with the estrogen receptor (ER)-progesterone receptor (PR) and ERRB2 receptor status and tumor grade. RESULTS: Among 160 patients with breast cancer, 102 (63.8%) were ER positive/PR-positive, 32 (20.0%) were ER-positive/PR-negative, and 26 (16.3%) were ER-negative/PR-negative (22 were triple-negative). Tumors with posterior shadowing have greater than nine times the odds of having ER-positive findings (95% CI, 2.09-40.81; p = 0.011) and greater than 13 times the odds of having a lower-grade tumor (I or II vs III; 95% CI, 4.90-36.54; p < 0.001) than those without posterior shadowing. Tumors with posterior enhancement have greater than eight times the odds of having at least one negative receptor (95% CI, 3.97 18.11; p < 0.001) and 24 times the odds of having a high-grade tumor (95% CI, 9.91-58.14; p < 0.001) than those without posterior enhancement. CONCLUSION: The presence of posterior shadowing is strongly associated with an ER-positive and low-grade tumor, whereas the presence of posterior enhancement is strongly associated with a high-grade tumor and with moderate risk of being receptor negative. PMID- 23345348 TI - Can digital breast tomosynthesis replace conventional diagnostic mammography views for screening recalls without calcifications? A comparison study in a simulated clinical setting. AB - OBJECTIVE: This study evaluated digital breast tomosynthesis (DBT) as an alternative to conventional diagnostic mammography in the workup of noncalcified findings recalled from screening mammography in a simulated clinical setting that incorporated comparison mammograms and breast ultrasound results. SUBJECTS AND METHODS: One hundred forty-six women, with 158 abnormalities, underwent diagnostic mammography and two-view DBT. Three radiologists viewed the abnormal screening mammograms, comparison mammograms, and DBT images and recorded a DBT BI RADS category and confidence score for each finding. Readers did not view the diagnostic mammograms. A final DBT BI-RADS category, incorporating ultrasound results in some cases, was determined and compared with the diagnostic mammography BI-RADS category using kappa statistics. Sensitivity and specificity were calculated for DBT and diagnostic mammography. RESULTS: Agreement between DBT and diagnostic mammography BI-RADS categories was excellent for readers 1 and 2 (kappa = 0.91 and kappa = 0.84) and good for reader 3 (kappa = 0.68). For readers 1, 2, and 3, sensitivity and specificity of DBT for breast abnormalities were 100%, 100%, and 88% and 94%, 93%, and 89%, respectively. The clinical workup averaged three diagnostic views per abnormality and ultrasound was requested in 49% of the cases. DBT was adequate mammographic evaluation for 93-99% of the findings and ultrasound was requested in 33-55% of the cases. CONCLUSION: The results of this study suggest that DBT can replace conventional diagnostic mammography views for the evaluation of noncalcified findings recalled from screening mammography and achieve similar sensitivity and specificity. Two-view DBT was considered adequate mammographic evaluation for more than 90% of the findings. There was minimal change in the use of ultrasound with DBT compared with diagnostic mammography. PMID- 23345349 TI - Large rodlike calcifications at mammography: analysis of morphologic features. AB - OBJECTIVE: The purpose of this article is to prospectively determine the prevalence and morphologic features of typically benign large rodlike calcifications at mammography and to provide evidence-based data for this descriptor in a future version of the BI-RADS lexicon. SUBJECTS AND METHODS: In the 1-year period of 2011, large rodlike calcifications were detected in 239 of 7935 (3%) consecutive women undergoing screening or diagnostic mammography. Analysis of morphologic features was performed in 165 of the 239 women (69%; mean age, 71.1 years; range, 39-86 years), who had a minimum number of six calcific particles and in whom benignity was assessed by lack of suspicious change compared with prior mammograms. Two of the 165 women had undergone a mastectomy previously. RESULTS: The mean length of the longest calcification was 4.2 (SD, 2.4) mm (median, 3.5 mm; range, 1-14 mm). The mean width of the widest calcification was 0.6 (SD, 0.5) mm (median, 0.5 mm; range 0.2-3 mm). Bilaterality was found in 131 of 163 women (80.4%) with two breasts, periductal calcifications were found in 18 of 165 women (10.9%), and branching calcifications were found in another 18 women (10.9%). One hundred fifty-five of 165 women (93.9%) had almost entirely fat or scattered areas of fibroglandular tissue; 10 women (6.1%) had heterogeneously dense or extremely dense tissue. CONCLUSION: Our results partially contradict the current description (size, diameter, and bilaterality versus unilaterality) of large rodlike calcifications in the BI-RADS lexicon. Content for this descriptor should be modified in a future version of the lexicon. PMID- 23345350 TI - Preoperative breast MRI can reduce the rate of tumor-positive resection margins and reoperations in patients undergoing breast-conserving surgery. AB - OBJECTIVE: In breast cancer patients eligible for breast-conserving surgery, we evaluated whether the information provided by preoperative MRI of the breast would result in fewer tumor-positive resection margins and fewer reoperations. SUBJECTS AND METHODS: The study group consisted of 123 consecutive patients diagnosed with either breast cancer or ductal carcinoma in situ eligible for breast-conserving surgery between April 2007 and July 2010. For these patients, a first plan for breast-conserving surgery was made on the basis of clinical examination and conventional imaging. The final surgical plan was made with knowledge of the preoperative breast MRI. The rates of tumor-positive resection margins and reoperations were compared with those of a historical control group consisting of 119 patients who underwent 123 breast-conserving procedures between January 2005 and December 2006. The percentage of change in the surgical plan was recorded. RESULTS: Preoperative breast MRI changed the surgical plan to more extensive surgery in 42 patients (34.1%), mainly to mastectomy (29 patients, 23.6%). Ninety-four patients underwent 95 breast-conserving procedures. Significantly fewer patients had tumor-positive resection margins than in the control group (15.8%, 15/95 versus 29.3%, 36/123; p < 0.01). Patients in the study group underwent significantly fewer reoperations compared with the historical control group (18.9%, 18/95 vs 37.4%, 46/123; p < 0.01). CONCLUSION: Preoperative breast MRI can substantially decrease the rate of tumor-positive resection margins and reoperations in breast cancer patients eligible for breast conserving surgery. PMID- 23345351 TI - Histogram-based apparent diffusion coefficient analysis: an emerging tool for cervical cancer characterization? AB - OBJECTIVE: Numerous prior studies have shown the utility of apparent diffusion coefficient values in cervical cancer assessment, particularly in differentiation from benign cervix. This article will discuss histogram-based analysis for detection of adverse histologic features of cervical cancer. CONCLUSION: The study by Downey et al. in this issue investigates histogram-based analysis for detection of adverse histologic features of cervical cancer, including subtype and grade. This approach offers a more complete assessment of tumor texture and heterogeneity. Given the potential utility suggested by the results of this study, additional larger studies are warranted. PMID- 23345352 TI - Relationship between imaging biomarkers of stage I cervical cancer and poor prognosis histologic features: quantitative histogram analysis of diffusion weighted MR images. AB - OBJECTIVE: The purpose of this study was to determine whether histogram analysis of apparent diffusion coefficient (ADC) values from diffusion-weighted MRI can be used to differentiate cervical tumors according to their histologic characteristics. SUBJECTS AND METHODS: Sixty patients with International Federation of Gynecology stage I cervical cancer underwent MRI at 1.5 T with a 37 mm-diameter endovaginal coil. T2-weighted images (TR/TE, 2000-2368/90) followed by diffusion-weighted images (TR/TE, 2500/69; b values, 0, 100, 300, 500, and 800 s/mm(2)) were acquired. An expert observer drew regions of interest around a histologically confirmed tumor on ADC maps by referring to the T2-weighted images. Pixel-by-pixel ADCs were calculated with a monoexponential fit of data from b values of 100-800 s/mm(2), and ADC histograms were obtained from the entire tumor volume. An independent samples Student t test was used to compare differences in ADC percentile values, skew, and kurtosis between squamous cell carcinoma and adenocarcinoma, well or moderately differentiated and poorly differentiated tumors, and absence and presence of lymphovascular space invasion. RESULTS: There was no statistically significant difference in ADC percentiles between squamous cell carcinoma and adenocarcinoma, but the median was significantly higher in well or moderately differentiated tumors (50th percentile, 1113 +/- 177 * 10(-6) mm(2)/s) compared with poorly differentiated tumors (50th percentile, 996 +/- 184 * 10(-6) mm(2)/s) (p = 0.049). Histogram skew was significantly less positive for adenocarcinoma compared with squamous cell carcinoma (p = 0.016) but did not differ between tumor grades. There was no significant difference between any parameter with regard to lymphovascular space invasion. CONCLUSION: Median ADC is lower in poorly compared with well or moderately differentiated tumors, while lower histogram-positive skew in adenocarcinoma compared with squamous cell carcinoma is likely to reflect the glandular content of adenocarcinoma. PMID- 23345353 TI - Breast imaging of the pregnant and lactating patient: imaging modalities and pregnancy-associated breast cancer. AB - OBJECTIVE: The purpose of this article is to review key clinical, histologic, and imaging features of pregnancy-associated breast cancer. A discussion of imaging modalities, including mammography, ultrasound, and MRI, and imaging-based interventions available for evaluating this population is provided. CONCLUSION: Successful detection of pregnancy-associated breast cancer requires knowledge of key clinical and imaging features of pregnancy-associated breast carcinoma and selection of the appropriate imaging workup and intervention. PMID- 23345354 TI - Breast imaging of the pregnant and lactating patient: physiologic changes and common benign entities. AB - OBJECTIVE: The purpose of this article is to review key clinical, histologic, and imaging features of expected physiologic changes within the breast and common benign breast disease in the pregnant and lactating patient. CONCLUSION: A thorough understanding of expected physiologic changes and common benign breast abnormalities of pregnancy and lactation is required to differentiate these entities from pregnancy-associated breast cancer and to appropriately guide patient management. PMID- 23345355 TI - Resting cardiac 64-MDCT does not reliably detect myocardial ischemia identified by radionuclide imaging. AB - OBJECTIVE: CT myocardial perfusion imaging is an emerging diagnostic modality that is under intensive study but not yet widely used in clinical practice. The purpose of this study is to evaluate the performance of resting 64-MDCT in revealing ischemia identified on radionuclide myocardial perfusion imaging (MPI). MATERIALS AND METHODS: We retrospectively identified 35 patients (20 women and 15 men; mean age, 52 years) with myocardial ischemia found on MPI who underwent retrospectively gated CT within 90 days of MPI. Myocardial perfusion on CT was evaluated using both a visual (n = 35) and an automated (n = 34) method. For the visual method, myocardial segments were evaluated qualitatively in systole and diastole. For the automated method, subendocardial perfusion of the standard 17 American Heart Association segments was measured using a commercially available tool in both systole and diastole. Differences between systolic and diastolic perfusion were computed. RESULTS: Five hundred eighty myocardial segments were evaluated, 152 of which were ischemic on MPI. Visual analysis had a sensitivity of 16% (24/152), specificity of 92% (393/428), positive predictive value of 40% (24/60), and negative predictive value of 75% (392/520) in systole, and a sensitivity of 18% (27/152), specificity of 89% (382/428), positive predictive value of 37% (27/73), and negative predictive value of 75% (382/507) in diastole, as compared with MPI. There was no significant difference in subendocardial perfusion between ischemic and nonischemic segments by the automated method. There was no significant difference in CT perfusion between patients with and without obstructive coronary artery disease on CT angiography using the visual or automated methods. CONCLUSION: Resting 64-MDCT is unsuitable for clinical use in revealing ischemia seen on MPI. PMID- 23345356 TI - Diagnosis and management of cystic pancreatic lesions. AB - OBJECTIVE: The purpose of this review is to outline the management guidelines for the care of patients with cystic pancreatic lesions. CONCLUSION: The guidelines are as follows: Annual imaging surveillance is generally sufficient for benign serous cystadenomas smaller than 4 cm and for asymptomatic lesions. Asymptomatic thin-walled unilocular cystic lesions smaller than 3 cm or side-branch intraductal papillary mucinous neoplasms should be followed up with CT or MRI at 6 and 12 months interval after detection. Cystic lesions with more complex features or with growth rates greater than 1 cm/year should be followed more closely or recommended for resection if the patient's condition allows surgery. Symptomatic cystic lesions, neoplasms with high malignant potential, and lesions larger than 3 cm should be referred for surgical evaluation. Endoscopic ultrasound with fine-needle aspiration (FNA) biopsy can be used preoperatively to assess the risk of malignancy. PMID- 23345357 TI - Incidental neuroendocrine tumors of the pancreas: MDCT findings and features of malignancy. AB - OBJECTIVE: The objective of our study was to evaluate the MDCT features of incidentally detected neuroendocrine tumors (NETs) of the pancreas, identify features that can predict tumor biology or aggressiveness and long-term outcome, and determine the incidence of "nonbenign" behavior. MATERIALS AND METHODS: In this retrospective study, 60 histologically verified pancreatic NETs incidentally detected with contrast-enhanced MDCT were included. Various MDCT features such as size, morphology, enhancement, and presence of calcifications were evaluated and were correlated with tumor biology on histopathology. The sensitivity, specificity, predictive values, and accuracy were calculated for MDCT features in predicting nonbenign biology and risk of recurrence. RESULTS: A total of 32 of 60 (53%) NETs were nonbenign: most were large (mean, 29.1 mm) with a solid or complex pattern. NET size of 3 cm or larger yielded a positive predictive value of 61% for nonbenign tumors and 100% when calcification was present. In 12 patients with recurrence, 92% of NETs were nonbenign. The presence of calcification, local invasion, main pancreatic duct dilatation, vascular invasion, and lymph node enlargement along with angioinvasion and a Ki-67 index greater than 2% on histology were associated with a nonbenign diagnosis and a higher risk of recurrence. CONCLUSION: Approximately 50% of incidental NETs show uncertain or malignant behavior. Solid tumors 3 cm or larger are commonly nonbenign; however, about 30% of tumors smaller than that size cutoff can be malignant. Nonbenign tumors and those with invasive features on MDCT have a higher incidence of recurrence. PMID- 23345358 TI - Acute cholecystitis: do sonographic findings and WBC count predict gangrenous changes? AB - OBJECTIVE: The purpose of our study was to determine, first, if gallbladder wall striations in patients with sonographic findings suspicious for acute cholecystitis are associated with gangrenous changes and certain histologic features; and, second, if WBC count or other sonographic findings are associated with gangrenous cholecystitis. MATERIALS AND METHODS: Sixty-eight patients who underwent cholecystectomies within 48 hours of sonography comprised the study group. Sonograms and reports were reviewed for wall thickness, striations, Murphy sign, pericholecystic fluid, wall irregularity, intraluminal membranes, and luminal short-axis diameter. Medical records were reviewed for WBC count and pathology reports for the diagnosis. Histologic specimens were reviewed for pathologic changes. Statistical analyses tested for associations between nongangrenous and gangrenous cholecystitis and sonographic findings and for associations between wall striations and histologic features. RESULTS: Ten patients had gangrenous cholecystitis and 57, nongangrenous cholecystitis. One had cholesterolosis. Thirty patients had wall striations: 60% had gangrenous and 42% nongangrenous cholecystitis. There was no association with the pathology diagnosis (p = 0.32). There was no association between any histologic feature and wall striations (p >= 0.19). A Murphy sign was reported in 70% of patients with gangrenous cholecystitis and in 82% with nongangrenous cholecystitis; there was no association with the pathology diagnosis (p = 0.39). Wall thickness and WBC count were greater in patients with gangrenous cholecystitis than in those with nongangrenous cholecystitis (p <= 0.04). CONCLUSION: Gallbladder wall thickening and increased WBC counts were associated with gangrenous cholecystitis; however, there was considerable overlap between the two groups. Wall striations and a negative Murphy sign were not associated with gangrenous cholecystitis. PMID- 23345359 TI - Pheochromocytoma: the range of appearances on ultrasound, CT, MRI, and functional imaging. AB - OBJECTIVE: Pheochromocytomas are relatively rare neuroendocrine tumors of the adrenal medulla. Their variable clinical presentation and biologic behavior often make accurate diagnosis challenging. A variable spectrum of imaging appearances- some of which may also mimic other diseases--has been recognized. This article reviews the epidemiology; associations; and clinical, biochemical, pathologic, and multimodality imaging features of pheochromocytomas including diagnostic pearls and pitfalls. CONCLUSION: Pheochromocytomas are often considered the great mimicker of other adrenal tumors. Because of their varied clinical, imaging, and pathologic appearances, accurate diagnosis can be challenging. The various imaging appearances on ultrasound, CT, MRI, and functional imaging can be complementary and have features that are useful for differentiating pheochromocytoma from other lesions of the adrenal. PMID- 23345360 TI - Radiology fellowship with a focus on musculoskeletal imaging: current challenges and future directions. AB - OBJECTIVE: Many musculoskeletal fellowships are nonaccredited, leading to heterogeneity of educational experiences. There is no governing body for these nonaccredited fellowships, leaving program content and rules to the program directors' discretion. In addition, imaging fellowships in general currently face many external pressures that challenge their capacity to provide a high-quality education. Federal cuts to Medicare, diminished reimbursement to radiology departments, and pressure for increased accountability exerted by insurance companies and hospitals all place additional stress on fellowship training programs. CONCLUSION: Only those fellowships providing the highest-quality educational experience will continue to thrive. PMID- 23345361 TI - Seesaw balancing radiation dose and i.v. contrast dose: evaluation of a new abdominal CT protocol for reducing age-specific risk. AB - OBJECTIVE: The purpose of this study was to evaluate an abdominal CT protocol in which radiation dose was reduced and i.v. contrast dose increased for young patients and radiation dose was increased and i.v. medium dose decreased for elderly patients. The hypothesis was that these adjustments would result in constant image quality and a reduction in age-specific risk. MATERIALS AND METHODS: Patients were divided into four age groups of 25 patients each: group 1, 16-25 years; group 2, 26-50 years; group 3, 51-75 years; and group 4, older than 75 years. The quality reference tube load ranged from 100 to 300 mAs, and the i.v. contrast dose ranged from 600 to 350 mg I/kg. Group 3 was the reference group. Signal-to-noise and contrast-to-noise ratios for a hypothetical hypovascular liver metastatic lesion were calculated. Subjective image quality was evaluated by visual grading characteristic analysis in which four readers assessed the reproduction of seven image-quality criteria. RESULTS: Radiation dose was reduced 57% in the youngest group, and the i.v. contrast dose was reduced 18% in elderly patients. There were no statistically significant differences between the groups with respect to signal-to-noise and contrast-to noise ratios. Subjective image quality was graded significantly lower for four criteria in group 1 compared with group 3. No significant difference was found in comparisons of groups 2 (except for one criterion) and 4 with group 3. CONCLUSION: It is possible to balance radiation dose and contrast dose against each other and maintain signal-to-noise and contrast-to-noise ratios. Subjective image quality was affected by increased noise level on the images but was judged acceptable in all groups except the one with the lowest radiation dose. PMID- 23345362 TI - Cam and pincer femoroacetabular impingement: CT findings of features resembling femoroacetabular impingement in a young population without symptoms. AB - OBJECTIVE: The purpose of this study was to use CT to determine the presence of radiologic parameters associated with cam and pincer femoroacetabular impingement (FAI) in a young population without symptoms. MATERIALS AND METHODS: A retrospective review of 50 patients (age range, 20-40 years) with no current or previous hip disorder who underwent CT of the abdomen and pelvis was conducted. Multiplanar images were reformatted with a soft-tissue and bone algorithm and assessed for the presence of parameters associated with FAI; alpha angle greater than 55 degrees , femoral head-neck offset less than 8 mm, angle of acetabular version less than 15 degrees , lateral center edge angle greater than 40 degrees , acetabular index less than 0 degrees , pistol-grip deformity, acetabular crossover, and prominent posterior wall signs. RESULTS: At least one abnormal parameter was present in 66% of joints, and two or more abnormal parameters were present in 29% of joints. In seven patients the findings were bilateral. Parameters of mixed morphologic characteristics (cam and pincer) were found in 22% of joints. In side-by-side comparison, high alpha angles were seen in 36 joints measured in the radial plane compared with only three joints measured in the axial oblique plane. CONCLUSION: The CT finding of FAI-like features was made with high frequency in a young symptom-free population. Cutoff values for defining morphologic abnormalities associated with FAI may have been set too low in the current literature. Alpha angle measurements in the radial plane may be a more accurate quantitative assessment of asphericity of the femoral head-neck junction than are measurements in the axial oblique plane. PMID- 23345363 TI - CT assessment of bone remodeling in the otic capsule in chronic renal failure: association with hearing loss. AB - OBJECTIVE: Hearing loss (HL) is common in patients with chronic renal failure (CRF), but its cause is controversial. The aim of this study was to determine the effect of CRF on the bone density of the otic capsule using densitometric measurements with MDCT and to evaluate the relationship between changes in the otic capsule density and HL in patients with CRF. MATERIALS AND METHODS: The study included 34 patients with nonsyndromic CRF undergoing hemodialysis and 35 healthy control subjects. A CT was obtained, for a variety of reasons, in control subjects who did not have CRF or HL, but patients with trauma and infection were excluded. Control subjects were chosen on the basis of a normal CT and pure tone audiometry findings. Densitometric measurements were made using CT in the region anterior to the oval window and anterior to the internal auditory canal. These measurements were compared between patients and control subjects. Pure tone audiometry was performed to detect HL. The average levels of parathyroid hormone in the previous 6 months and the duration of hemodialysis in patients were documented. The association between the levels of parathyroid hormone, the duration of hemodialysis, and the region-of-interest density values in the patient groups were evaluated using the Pearson correlation coefficient. RESULTS: HL was found in 40 of 68 ears (58.8%) in the patient group. A significant difference in the otic capsule density was found between the ears with and without HL. There was a strong negative correlation between the parathyroid hormone level and the densitometric measurement of the otic capsule. CONCLUSION: There is osseous remodeling of the otic capsule in CRF with loss of bone density, and this is associated with HL in CRF. PMID- 23345364 TI - Intracranial hypotension: improved MRI detection with diagnostic intracranial angles. AB - OBJECTIVE: Intracranial hypotension is an uncommon cause of headaches that is often misdiagnosed. The classic MRI features of intracranial hypotension can be variable and subjective. The purpose of this study was to provide objective criteria in the MRI evaluation of intracranial hypotension by quantifying normal values for the pontomesencephalic angle, mamillopontine distance, and lateral ventricular angle. MATERIALS AND METHODS: A retrospective review of patients with the clinical diagnosis of intracranial hypotension and a control group was performed with measurements of the pontomesencephalic angle, mamillopontine distance, and lateral ventricular angle. Qualitative evaluation of other MRI findings included dural enhancement, venous engorgement, subdural collections, brainstem slumping, and tonsillar herniation. RESULTS: In 29 patients with intracranial hypotension, the mean pontomesencephalic angle, mamillopontine distance, and lateral ventricular angle were 41.2 degrees (SD, +/- 17.4 degrees ), 4.4 mm (SD, +/- 1.8), and 130.1 degrees (SD, +/- 9.8 degrees ), respectively. In the control group, the mean pontomesencephalic angle, mamillopontine distance, and lateral ventricular angle were 65 degrees (SD, +/- 9.9 degrees ), 7.0 mm (SD, +/- 1.3), and 132.2 degrees (SD, +/- 5.7 degrees ), respectively. The differences in the pontomesencephalic angle and mamillopontine distance values for the intracranial hypotension group versus the control group were statistically significant (p < 0.01). The difference in the lateral ventricular angle measurements was not statistically significant (p = 0.37). Cutoff points of a 5.5-mm mamillopontine distance and 50 degrees pontomesencephalic angle were estimated using receiver operating characteristic curves. CONCLUSION: In patients with the clinical suspicion of intracranial hypotension, we found that cutoff values of 5.5 mm or less for the mamillopontine distance and 50 degrees or less for the pontomesencephalic angle were sensitive and specific in strengthening the qualitative MRI findings. Therefore, quantitative assessments may provide a more accurate diagnosis. PMID- 23345365 TI - Dual-time-point FDG PET/CT for the evaluation of pediatric tumors. AB - OBJECTIVE: The utility of dual-time-point (18)F-FDG PET/CT in differentiating benign from malignant processes in pediatric patients was assessed. SUBJECTS AND METHODS: Twenty-one patients (13 girls and eight boys; age range, 1-17 years) with suspected malignancy underwent dual-time-point FDG PET/CT. Scan 1 was performed at approximately 60 minutes after i.v. injection of 5.18 MBq/kg of FDG, and scan 2 was performed at 121 +/- 43 minutes after the first scan. Regions of interest were overlaid onto each non-attenuated-corrected image, and semiquantitative analysis was performed using the standardized uptake value (SUV) obtained from early and delayed images. A retention index was calculated according to the following equation: [(delayed SUV - early SUV) / early SUV] * 100. Results were compared prospectively in relation to pathologic examination or other conventional radiologic imaging or clinical follow-up. A retention index of 10% or higher was chosen as a cutoff for differentiating malignant from benign entities. RESULTS: For patients with malignant disease, the average SUV increased from 7.3 +/- 1.2 to 10.9 +/- 2.7 between the two time points, whereas the SUV changed from 4.5 +/- 0.8 to 4.2 +/- 1.0 for patients with benign lesions. The average retention index was 37.1% +/- 10.8% for patients with malignant lesions versus -9.9% +/- 7.1% for benign lesions (p < 0.01). With a cutoff value of 10% or higher for the retention index, the sensitivity and specificity of dual-time point FDG PET/CT were 77% and 80%, respectively. CONCLUSION: These data show that dual-time-point FDG PET/CT is useful in distinguishing malignant from benign processes in pediatric patients. PMID- 23345366 TI - Vascular anomalies: hemangiomas and beyond--part 1, Fast-flow lesions. AB - OBJECTIVE: The purpose of this study was to review the medical literature and the current classification of vascular anomalies to clarify common misconceptions and provide guidance for imaging and treatment. In this first article of a two-part series, we focus on the fast-flow vascular anomalies. CONCLUSION: Nonuniformity of terminology across the medical literature hampers understanding of the vascular anomalies. A familiarity with the classification and biology on which this terminology is based is essential for accurate and precise diagnosis. PMID- 23345367 TI - Vascular anomalies: hemangiomas and beyond--part 2, Slow-flow lesions. AB - OBJECTIVE: The purpose of this article is to review the medical literature and the current classification of the vascular anomalies to clarify common misconceptions and provide guidance for imaging and treatment. In this second article of a two-part series, we focus on slow-flow vascular anomalies. CONCLUSION: Nonuniformity of terminology across the medical literature hampers understanding of vascular anomalies. A familiarity with the classification and biology on which it is based are essential for accurate and precise diagnosis. PMID- 23345368 TI - Utility of salivagram in pulmonary aspiration in pediatric patients: comparison of salivagram and chest radiography. AB - OBJECTIVE: The purpose of our study was to correlate the results of the radionuclide salivagram with the corresponding chest radiography findings on patients being evaluated for salivary aspiration to determine the utility of the salivagram. MATERIALS AND METHODS: We identified 222 patients younger than 21 years who underwent salivagram and chest radiography within 3 months of each other. Salivagrams were blindly interpreted by two readers and chest radiographs were blindly interpreted by two other readers. The kappa coefficient with 95% CI was used to measure the level of interobserver agreement. Multivariate logistic regression was applied to determine whether age, sex, and neurologic diagnosis were predictors of a positive salivagram, with the odds ratio used to estimate association. RESULTS: Interobserver agreement on salivagram interpretation was excellent (kappa = 0.988; p < 0.0001; 95% CI, 0.968-1.000). Interobserver agreement on chest radiography interpretation was excellent (kappa = 0.905; p < 0.0001; 95% CI, 0.845-0.965). The salivagram was positive for aspiration in 55 patients (25%). Chest radiography was positive in 54 patients (24%). When the interpretations of the salivagram (normal or abnormal) were compared with interpretations of the chest radiograph (normal or abnormal), there were 213 agreements and nine disagreements (intermethod agreement kappa = 0.891; p < 0.0001; 95% CI, 0.831-0.952). Independent of age (p = 0.80) and sex (p = 0.31), patients with a neurologic diagnosis had odds of a positive salivagram 5.6 times higher than other diagnoses (odds ratio = 5.6; 95% CI, 2.5-13.1; p < 0.0001). CONCLUSION: Infants with abnormal findings on salivagrams also had a high rate of abnormal findings on chest radiographs, which may indicate that some of the lung disease may be due to aspirated saliva. Salivagrams may be useful in children at risk of aspiration to identify those in whom intervention may help minimize the consequences of aspiration. PMID- 23345369 TI - Improved delineation of the anterior spinal artery with model-based iterative reconstruction in CT angiography: a clinical pilot study. AB - OBJECTIVE: The purpose of this study was to investigate the utility of model based iterative reconstruction (MBIR) for improving delineation of the anterior spinal artery (ASA) during routine-dose CT angiography. MATERIALS AND METHODS: For imaging of 10 patients (six men, four women; mean age, 73.9 +/- 7.5 years) consecutively undergoing CT angiography of the whole aorta with a 12-HU noise index, we used filtered back projection with a standard kernel, adaptive statistical iterative reconstruction of 40% with a detail kernel, and MBIR to reconstruct axial and oblique coronal multiplanar reformation images to delineate the ASA. We measured objective noise in the spinal cord and contrast-to-noise ratio (CNR) between the aorta and spinal cord on axial images at the T12 level. Two radiologists independently graded subjective noise and ASA delineation on the multiplanar reformation images from 1 (poor) to 4 (excellent). We compared results among the three reconstructions using one-way analysis of variance and Tukey-Kramer significance tests. RESULTS: Objective noise, CNR, and subjective image noise and ASA delineation improved significantly with MBIR. Image noise was 18.4 +/- 3.6 HU and CNR, 23.4 +/- 8.6 (reader 1 scores, 3.9 +/- 0.3 and 3.7 +/- 0.5; reader 2, 3.9 +/- 0.3 and 3.5 +/- 0.7). With filtered back projection, image noise was 34.7 +/- 8.3 HU and CNR 12.1 +/- 4.0 (reader 1 scores, 2.0 +/- 0.0 and 2.2 +/- 0.4; reader 2, 2.2 +/- 0.4 and 2.5 +/- 0.7), and with ASIR, 33.0 +/- 8.1 HU and 12.7 +/- 4.3 (reader 1 scores, 2.0 +/- 0.0 and 2.2 +/- 0.4; reader 2, 2.2 +/- 0.4 and 2.5 +/- 0.7) (p < 0.05). Results between filtered back projection and adaptive statistical iterative reconstruction were comparable. CONCLUSION: Use of MBIR can improve delineation of the ASA during CT angiography. PMID- 23345370 TI - Percutaneous screw fixation of acetabular roof fractures by radiologists under CT and fluoroscopy guidance. AB - OBJECTIVE: The aim of this study was to evaluate CT- and fluoroscopy-guided percutaneous screw fixation by radiologists in the management of acetabular roof fractures. SUBJECTS AND METHODS: Fifty-two consecutive adult patients with a nondisplaced and isolated acetabular roof fracture were prospectively treated by an interventional radiologist who made a percutaneous screw fixation under CT and fluoroscopy guidance. All these procedures were performed under local anesthesia. The postoperative follow-up ranged from 36 to 48 months. RESULTS: For each patient, two 6.5-mm Asnis III screws were inserted to fix the roof acetabular fracture. The mean procedure time was 45 minutes (range, 30-90 minutes). No complications were observed. Follow-up CT showed evidence of fracture healing. No evidence of secondary displacement, degenerative changes, or screw failure was noted. Using the rating system of D'Aubigne and Postel, all patients had excellent results. CONCLUSION: The results of our study showed that nondisplaced acetabular roof fractures could be successfully treated by a minimally invasive technique with an excellent long-term outcome. PMID- 23345371 TI - Endoleak detection after endovascular repair of thoracic aortic aneurysm using dual-source dual-energy CT: suitable scanning protocols and potential radiation dose reduction. AB - OBJECTIVE: The objective of our study was to evaluate the diagnostic performance of dual-source dual-energy CT (DECT) in the detection of endoleaks after thoracic endovascular aortic repair for thoracic aortic aneurysm and to investigate if a double-phase (arterial and dual-energy late delayed phase) or a single-phase (dual-energy late delayed phase) acquisition can replace the standard triphasic protocol. MATERIALS AND METHODS: All DECT examinations performed for evaluation after thoracic endovascular aortic repair during a 30-month period were retrospectively reviewed. An initial single-source unenhanced acquisition was followed by a single-source arterial phase acquisition and a dual-energy 300 second late delayed phase acquisition. "Virtual noncontrast images" were generated from the dual-energy acquisition. Two independent and blinded radiologists evaluated the cases during three reading sessions: session A (triphasic protocol: standard unenhanced, arterial phase, and late delayed phase), session B (virtual noncontrast and late delayed phase), and session C (virtual noncontrast, arterial phase, and late delayed phase). The diagnostic accuracies of sessions B and C were calculated using session A as the reference standard. Contrast-to-noise ratios and effective radiation doses were calculated. RESULTS: Forty-eight patients (mean age, 66 years; age range, 19-84 years) underwent 74 triple-phase CT examinations. The single-phase studies (session B) were characterized by 85.7% sensitivity, 100% specificity, 100% negative predictive value (NPV), and 94.6% positive predictive value (PPV). The dual-phase study (session C) revealed 100% sensitivity, 100% specificity, 100% NPV, and 100% PPV. The use of the dual-phase protocol and single-phase protocol resulted in a radiation exposure reduction of 19.5% and 64.1%, respectively. CONCLUSION: Virtual noncontrast and late delayed phase images reconstructed from a single DECT acquisition can replace the standard triphasic protocol in follow-up examinations after thoracic endovascular aortic repair, thereby providing a significant dose reduction. PMID- 23345372 TI - Percutaneous ablation of renal masses measuring 3.0 cm and smaller: comparative local control and complications after radiofrequency ablation and cryoablation. AB - OBJECTIVE: The purpose of this article is to compare the efficacy and complication rates of percutaneous radiofrequency ablation (RFA) and cryoablation in the treatment of renal masses measuring 3.0 cm and smaller. MATERIALS AND METHODS: A retrospective review was performed of 385 patients with 445 tumors measuring 3.0 cm or smaller treated with thermal ablation from 2000 through 2010. Two hundred fifty-six tumors in 222 patients were treated with RFA (mean [+/- SD] tumor size, 1.9 +/- 0.5 cm), and 189 tumors in 163 patients were treated with cryoablation (mean tumor size, 2.3 +/- 0.5 cm). Major complications and efficacy as measured by technical success and local tumor recurrence rates were recorded. RESULTS: There were five (1.1%) technical failures, including one (0.4%) among tumors treated with RFA and four (2.1%) among tumors treated with cryoablation (p = 0.17). Of the 218 tumors treated with RFA and with follow-up beyond 3 months, seven (3.2%) developed local tumor recurrence, at a mean of 2.8 years after treatment (range, 1.2-4.1 years). Of the 145 tumors treated with cryoablation and with follow-up beyond 3 months, four (2.8%) developed local tumor recurrence at a mean of 0.9 years after treatment (range, 0.3-1.6 years). For biopsy-proven renal cell carcinoma, estimated local recurrence-free survival rates at 1, 3, and 5 years after RFA were 100%, 98.1%, and 98.1%, respectively, compared with 97.3%, 90.6%, and 90.6%, respectively, after cryoablation (p = 0.09). Major complications occurred after 4.3% (10/232) of RFAs and 4.5% (8/176) of cryoablation procedures (p = 0.91). CONCLUSION: RFA and cryoablation are both effective in the treatment of renal masses measuring 3 cm or smaller. Major complications with either procedure are infrequent. PMID- 23345373 TI - Treatment of unresectable pancreatic cancer. PMID- 23345374 TI - Pulmonary hyperlucency in adults. PMID- 23345375 TI - The "misty mesentery": mesenteric panniculitis and its mimics. PMID- 23345376 TI - Radiology on the Africa Mercy, the largest private floating hospital ship in the world. AB - OBJECTIVE: The Africa Mercy, a rehabilitated Danish ferry, is the largest private hospital ship in the world, devoted to providing medical and surgical care to the residents of West Africa, one of the poorest regions on the globe. CONCLUSION: There is a small radiology department on board, along with six operating rooms and a small ICU and inpatient wards, and the former is described in this report, as well as opportunities for humanitarian work by volunteer radiologists. PMID- 23345377 TI - Imaging-pathologic correlation of diseases in the axilla. AB - OBJECTIVE: This article reviews the imaging and histopathologic findings of various axillary diseases and suggests management guidelines for radiologists based on imaging findings with clinical correlation. CONCLUSION: Although axillary diseases may reveal nonspecific imaging findings, a knowledge of the characteristic radiologic manifestations of specific diseases according to anatomic origin (nodal, accessory breast, adipocytic, fibrous, nerve, vascular, stromal, and dermal) and postsurgical lesions aids in establishing an appropriate differential diagnosis and determining whether intervention is necessary. PMID- 23345378 TI - Imaging of postpartum complications: a multimodality review. AB - OBJECTIVE: The purpose of this article is to review common and uncommon complications of postpartum and posttermination patients and their imaging findings. A variety of imaging modalities, including ultrasound, CT, MRI, and angiography, will be presented. Knowledge of the spectrum of normal and abnormal imaging findings as well as recognition of the common and uncommon complications are essential for accurate diagnosis. CONCLUSION: Obstetric complications are a common source of morbidity and mortality for women of reproductive age. Imaging, particularly with ultrasound, is often supplementary to the clinical history and examination in assessing and treating women during the postpartum period. Radiologists should be familiar with the common abnormalities that present in this period and their imaging findings, as well as the wide range of normal appearances the postpartum uterus can assume. PMID- 23345379 TI - Effect of sampling frequency on perfusion values in perfusion CT of lung tumors. AB - OBJECTIVE: The purpose of this study was to assess as a potential means of limiting radiation exposure the effect on perfusion CT values of increasing sampling intervals in lung perfusion CT acquisition. SUBJECTS AND METHODS: Lung perfusion CT datasets in patients with lung tumors (> 2.5 cm diameter) were analyzed by distributed parameter modeling to yield tumor blood flow, blood volume, mean transit time, and permeability values. Scans were obtained 2-7 days apart with a 16-MDCT scanner without intervening therapy. Linear mixed-model analyses were used to compare perfusion CT values for the reference standard sampling interval of 0.5 second with those of datasets obtained at sampling intervals of 1, 2, and 3 seconds, which included relative shifts to account for uncertainty in preenhancement set points. Scan-rescan reproducibility was assessed by between-visit coefficient of variation. RESULTS: Twenty-four lung perfusion CT datasets in 12 patients were analyzed. With increasing sampling interval, mean and 95% CI blood flow and blood volume values were increasingly overestimated by up to 14% (95% CI, 11-18%) and 8% (95% CI, 5-11%) at the 3 second sampling interval, and mean transit time and permeability values were underestimated by up to 11% (95% CI, 9-13%) and 3% (95% CI, 1-6%) compared with the results in the standard sampling interval of 0.5 second. The differences were significant for blood flow, blood volume, and mean transit time for sampling intervals of 2 and 3 seconds (p <= 0.0002) but not for the 1-second sampling interval. The between-visit coefficient of variation increased with subsampling for blood flow (32.9-34.2%), blood volume (27.1-33.5%), and permeability (39.0 42.4%) compared with the values in the 0.5-second sampling interval (21.3%, 23.6%, and 32.2%). CONCLUSION: Increasing sampling intervals beyond 1 second yields significantly different perfusion CT parameter values compared with the reference standard (up to 18% for 3 seconds of sampling). Scan-rescan reproducibility is also adversely affected. PMID- 23345380 TI - Dual-source 256-MDCT for diagnosis of anomalous pulmonary venous drainage in pediatric population. AB - OBJECTIVE: The purpose of this study is to describe the MDCT findings of anomalous pulmonary venous drainage (APVD) in a pediatric population using a 256 MDCT dual-source scanner with a high-pitch protocol. CONCLUSION: MDCT is a fast and noninvasive technique that allows detailed and comprehensive visualization of APVD characteristics in a pediatric population. High-pitch acquisitions with scanners using a high volume of coverage permit low radiation doses and are an accurate modality for assessing these patients. PMID- 23345381 TI - Dynamic contrast-enhanced MRI in determining disease activity in perianal fistulizing Crohn disease: a pilot study. AB - OBJECTIVE: The objective of our study was to perform a semiquantitative analysis of dynamic contrast-enhanced MRI for the evaluation of disease activity and therapeutic response in patients with perianal fistulizing Crohn disease. SUBJECTS AND METHODS: Sixteen consecutively registered patients with perianal Crohn disease underwent pelvic MRI. A dynamic contrast-enhanced sequence was performed at 3 T (temporal resolution, 4.2 seconds) during i.v. contrast injection. Maximum enhancement, initial slope of increase, volume transfer constant (K(trans)), and the extravascular space fractional volume (x028B;(e)) were calculated in a region of interest drawn around the fistula. Perianal disease activity index, C-reactive protein concentration, and an MRI-based activity score were calculated as reference standards. Six patients underwent a second MRI examination 6 weeks after starting treatment with anti-tumor necrosis factor alpha (anti-TNF-alpha). RESULTS: Perianal disease activity index moderately correlated with maximum enhancement (r = 0.67, p = 0.005), initial slope of increase (r = 0.58, p = 0.018), and volume of enhancing pixels (r = 0.79, p < 0.001) but not with K(trans) or x028B;(e). Volume of enhancing pixels also correlated with C-reactive protein concentration and the MRI-based score (r = 0.52, p = 0.041; r = 0.79, p < 0.001). The K(trans) values had decreased significantly 6 weeks after the start of anti-TNF-alpha therapy. CONCLUSION: Maximum enhancement and initial slope of increase correlate with disease activity in perianal Crohn disease. K(trans) may be an indicator of the effect of therapy on patients starting anti-TNF-alpha treatment. PMID- 23345382 TI - Renal epithelioid angiomyolipoma: imaging characteristics in nine cases with radiologic-pathologic correlation and review of the literature. AB - OBJECTIVE: The purpose of this study was to describe the imaging features of renal epithelioid angiomyolipoma (EAML), a rare subtype of angiomyolipoma, with clinical and pathologic correlation. MATERIALS AND METHODS: This study was a retrospective review of nine cases from a single institution in which total resection and preoperative imaging were performed and the diagnosis of EAML was made. Imaging included CT (nine cases), MRI (five cases), and ultrasound (one case), and the images were reviewed in consensus by two radiologists. Patient demographics, disease associations, presentation, and outcomes were determined by chart review. RESULTS: The patients were nine women and one man (mean age, 42 years). Two patients had tuberous sclerosis complex. The size of the nine EAMLs ranged from 1.4 to 22 cm (mean, 7.8 cm). Six lesions had minor components of fat identifiable at imaging. The contrast enhancement pattern was heterogeneous in eight lesions, five of which contained cysts, necrosis, and hematoma. Four presentations were acute hemorrhage, with ruptured EAML in three of the four. Five tumors extended into the renal sinus. Two tumors were locally invasive. One patient had metastatic disease at presentation with epithelioid tumor identified in a single lymph node. The follow-up periods ranged from 0 to 89 months, and there was one case of suspected but not yet proved recurrence. CONCLUSION: Renal EAML can have a range of imaging appearances and can be indistinguishable from renal cell carcinoma and angiomyolipoma with minimal fat. EAML can be considered when a mass is found that has small foci of macroscopic fat without calcification or when acute hemorrhage of a renal mass occurs. PMID- 23345383 TI - Tumoral hypoxia in osteosarcoma in rats: preliminary study of blood oxygenation level-dependent functional MRI and 18F-misonidazole PET/CT with diffusion weighted MRI correlation. AB - OBJECTIVE: The prognostic implication of oxygen concentration as a factor in recurrence of solid tumors has been proved. Hypoxic osteosarcoma, imaged with (18)F-misonidazole PET/CT, is the most frequent primary malignant bone tumor. The aim of our study was to determine the role of blood oxygenation level-dependent (BOLD) functional MRI in an osteosarcoma rodent model by comparison of oxygenation levels in BOLD functional MRI and (18)F-misonidazole PET/CT and correlating the findings with those of diffusion-weighted MRI (DWI). MATERIALS AND METHODS: After validation of a hypoxic rodent model, 3-T MRI of osteosarcoma grafted in eight rats, including anatomic, DWI, and BOLD sequences in ambient air and after 2 and 3 minutes of impregnation of 8 L/min of oxygen, was performed on days 10, 17, and 24 after tumor grafting. (18)F-misonidazole PET/CT was performed on day 26, and the rats were sacrificed on day 27 for specific screening of markers of hypoxia. We measured BOLD signal intensity in tumors and normal tissue and compared these results with those on apparent diffusion coefficient maps and (18)F-misonidazole uptake according to maximum standardized uptake value ratio between tumor and healthy spongy bone. RESULTS: Hypoxia was confirmed by histologic study in all cases. We found a significant difference (day 17, p = 0.0038; day 24, p = 0.0051) in the decrease in signal intensity of hypoxic tumor in the presence of oxygen compared with ambient air without relation to duration of oxygen impregnation (p = 0.06). We found a significant correlation (p = 0.003) between BOLD signal intensity and maximum standardized uptake value at (18)F misonidazole PET/CT. We found no correlation between the decrease in BOLD signal intensity and apparent diffusion coefficient (p = 0.07). CONCLUSION: BOLD functional MRI may be a promising tool for noninvasive functional imaging of bone tumors, but additional developments are necessary to permit its use in clinical practice. PMID- 23345384 TI - Limb-sparing surgery for distal femoral and proximal tibial bone lesions: imaging findings with intraoperative correlation. AB - OBJECTIVE: Our purpose is to present normal and abnormal imaging findings associated with endoprosthetic reconstruction after limb-salvage surgery. CONCLUSION: Endoprosthetic reconstruction varies with the location and size of the tumor, implant designs, and complications. Radiologists need to be aware of associated imaging findings seen in postoperative infection, tumor recurrence, and hardware failure. With a thorough understanding of the normal postoperative radiographic findings after complex reconstructions, subsequent abnormalities are readily identified and timely diagnosis can be obtained. PMID- 23345385 TI - Pediatric and adolescent breast masses: a review of pathophysiology, imaging, diagnosis, and treatment. AB - OBJECTIVE: Pediatric breast masses are relatively rare and most are benign. Most are either secondary to normal developmental changes or neoplastic processes with a relatively benign behavior. To fully understand pediatric breast disease, it is important to have a firm comprehension of normal development and of the various tumors that can arise. Physical examination and targeted history (including family history) are key to appropriate patient management. When indicated, ultrasound is the imaging modality of choice. The purpose of this article is to review the benign breast conditions that arise as part of the spectrum of normal breast development, as well as the usually benign but neoplastic process that may develop within an otherwise normal breast. Rare primary carcinomas and metastatic lesions to the pediatric breast will also be addressed. The associated imaging findings will be reviewed, as well as treatment strategies for clinical management of the pediatric patient with signs or symptoms of breast disease. CONCLUSION: The majority of breast abnormalities in the pediatric patient are benign, but malignancies do occur. Careful attention to patient presentation, history, and clinical findings will help guide appropriate imaging and therapeutic decisions. PMID- 23345386 TI - Medicolegal: Malpractice and ethical issues in radiology: Should radiologists perform interventional procedures in the absence of clinical backup? PMID- 23345387 TI - Medicolegal: Malpractice and ethical issues in radiology: Adding to a referring physician's order without permission. PMID- 23345388 TI - ACR appropriateness criteria for follow-up of renal cell carcinoma. PMID- 23345389 TI - A brief review of the combined use of T2-weighted MRI and diffusion-weighted imaging for prostate cancer diagnosis. PMID- 23345390 TI - Do all individuals with sleep apnea suffer from daytime sleepiness? A preliminary investigation. AB - We derived descriptive characteristics related to habitual sleep duration and insomnia for individuals newly diagnosed with sleep apnea/hypopnea syndrome and evaluated how sleep apnea/hypopnea syndrome, insomnia, depression, and sleep duration relate to sleepiness and fatigue. In total, 100 participants were divided into three sleep groups: short (<7 hours), long (>= 8 hours), and midrange (7-7.9 hours). Polysomnography, insomnia, sleepiness, fatigue, depression, and gender were assessed. Half of the participants were short sleepers. They were more likely to have insomnia than midrange or long sleepers and they were more likely to be sleepy than midrange or long sleepers, regardless of insomnia. PMID- 23345391 TI - Adjusting for unrecorded consumption in survey and per capita sales data: quantification of impact on gender- and age-specific alcohol-attributable fractions for oral and pharyngeal cancers in Great Britain. AB - AIMS: Large discrepancies are typically found between per capita alcohol consumption estimated via survey data compared with sales, excise or production figures. This may lead to significant inaccuracies when calculating levels of alcohol-attributable harms. Using British data, we demonstrate an approach to adjusting survey data to give more accurate estimates of per capita alcohol consumption. METHODS: First, sales and survey data are adjusted to account for potential biases (e.g. self-pouring, under-sampled populations) using evidence from external data sources. Secondly, survey and sales data are aligned using different implementations of Rehm et al.'s method [in (2010) Statistical modeling of volume of alcohol exposure for epidemiological studies of population health: the US example. Pop Health Metrics 8, 1-12]. Thirdly, the impact of our approaches is tested by using our revised survey dataset to calculate alcohol attributable fractions (AAFs) for oral and pharyngeal cancers. RESULTS: British sales data under-estimate per capita consumption by 8%, primarily due to illicit alcohol. Adjustments to survey data increase per capita consumption estimates by 35%, primarily due to under-sampling of dependent drinkers and under-estimation of home-poured spirits volumes. Before aligning sales and survey data, the revised survey estimate remains 22% lower than the revised sales estimate. Revised AAFs for oral and pharyngeal cancers are substantially larger with our preferred method for aligning data sources, yielding increases in an AAF from the original survey dataset of 0.47-0.60 (males) and 0.28-0.35 (females). CONCLUSION: It is possible to use external data sources to adjust survey data to reduce the under-estimation of alcohol consumption and then account for residual under estimation using a statistical calibration technique. These revisions lead to markedly higher estimated levels of alcohol-attributable harm. PMID- 23345392 TI - Sphingosine-1-phosphate suppresses TLR-induced CXCL8 secretion from human T cells. AB - T cells produce a number of cytokines and chemokines upon stimulation with TLR agonists in the presence or absence of TCR signals. Here, we show that secretion of neutrophil chemoattractant CXCL8 from human T cell line Jurkat in response to stimulation with TLR agonists is reduced when cell stimulation is carried out in presence of serum. Serum does not, however, inhibit TCR-activated secretion of CXCL8 nor does it down-regulate TLR-costimulated IL-2 secretion from activated T cells. The molecule that can mimic the ability to bring about suppression in CXCL8 from TLR-activated T cells is serum-borne bioactive lipid, S1P. Serum and S1P-mediated inhibition require intracellular calcium. S1P also suppresses CXCL8 secretion from peripheral blood-derived human T cells activated ex vivo with various TLR ligands. Our findings reveal a previously unrecognized role for S1P in regulating TLR-induced CXCL8 secretion from human T cells. PMID- 23345393 TI - Interaction of members of the heat shock protein-70 family with the macrophage mannose receptor. AB - The macrophage MR has been the subject of investigation for over 20 years, and several important physiological functions have been described. However, the molecular mechanisms that regulate MR signaling and trafficking during these processes still remain elusive. The focus of the current paper was to identify potential cellular MR-interacting proteins. An initial screen of binding proteins in MR-expressing cells was performed using coimmunoprecipitation, followed by identification of matching peptide sequences using proteomics and MS. The major class of binding proteins identified belonged to the heat shock family of proteins. The specific interaction of the MR with HSP70 family members was validated by Western blot analysis, ligand binding assays, and intracellular colocalization using confocal microscopy. Additional studies indicated that inhibition of the HSP BiP by treatment of cells with EGCG reduced BiP interaction with and surface expression of the MR. Studies of possible motifs within the cytoplasmic tail of the receptor suggested that a juxtamembrane dibasic sequence may contribute to the interaction with BiP. These findings suggest that the molecular association of the MR with HSP70 family members via the receptor cytoplasmic tail may contribute to MR trafficking in macrophages. PMID- 23345394 TI - The Shc family protein adaptor, Rai, acts as a negative regulator of Th17 and Th1 cell development. AB - Rai, a Shc adapter family member, acts as a negative regulator of antigen receptor signaling in T and B cells. Rai(-/-) mice develop lupus-like autoimmunity associated to the spontaneous activation of self-reactive lymphocytes. Here, we have addressed the potential role of Rai in the development of the proinflammatory Th1 and Th17 subsets, which are centrally implicated in the pathogenesis of a number of autoimmune diseases, including lupus. We show that Rai(-/-) mice display a spontaneous Th1/Th17 bias. In vitro polarization experiments on naive and effector/memory CD4(+) T cells demonstrate that Rai(-/-) favors the development and expansion of Th17 but not Th1 cells, indicating that Rai modulates TCR signaling to antagonize the pathways driving naive CD4(+) T cell differentiation to the Th17 lineage, while indirectly limiting Th1 cell development in vivo. Th1 and Th17 cell infiltrates were found in the kidneys of Rai(-/-) mice, providing evidence that Rai(-/-) contributes to the development of lupus nephritis, not only by enhancing lymphocyte activation but also by promoting the development and expansion of proinflammatory effector T cells. Interestingly, T cells from SLE patients were found to have a defect in Rai expression, suggesting a role for Rai in disease pathogenesis. PMID- 23345395 TI - Coupling of septins to the axial landmark by Bud4 in budding yeast. AB - Cells of the budding yeast Saccharomyces cerevisiae select a site for polarized growth in a specific pattern that depends on their cell type. Haploid a and alpha cells bud in the axial budding pattern, which requires assembly of a landmark that includes the Bud4 protein. To understand how an axial bud site is established, we performed a structure-function analysis of Bud4. Bud4 contains DUF1709 (domain of unknown function), which is similar to a part of the anillin homology domain, and a putative Pleckstrin homology (PH) domain near to its C terminus. Although its localization depends on septins, a conserved family of GTP binding proteins, Bud4 is necessary for the stable inheritance of septin rings during cell division. Although some anillins interact directly with septins, we find that neither DUF1709 nor the PH domain is necessary for targeting Bud4 to the mother-bud neck. Instead, this C-terminal region is crucial for association of Bud4 with Bud3 and other components of the axial landmark. Remarkably, septins colocalize with Bud4 mutant proteins that lack these C-terminal domains, forming an arc or a single ring instead of a double ring during and after cytokinesis. Interestingly, overexpression of Bud4 also induces formation of extra Bud4 rings and arcs that are associated with septins. Analyses of a series of bud4 truncation mutants suggest that at least two domains in the central region play a redundant role in targeting Bud4 to the mother-bud neck and are thus likely to interact with septins. Taken together, these results indicate that Bud4 functions as a platform that links septins to the axial landmark. PMID- 23345396 TI - p62/SQSTM1 regulates cellular oxygen sensing by attenuating PHD3 activity through aggregate sequestration and enhanced degradation. AB - The hypoxia-inducible factor (HIF) prolyl hydroxylase PHD3 regulates cellular responses to hypoxia. In normoxia the expression of PHD3 is low and it occurs in cytosolic aggregates. SQSTM1/p62 (p62) recruits proteins into cytosolic aggregates, regulates metabolism and protein degradation and is downregulated by hypoxia. Here we show that p62 determines the localization, expression and activity of PHD3. In normoxia PHD3 interacted with p62 in cytosolic aggregates, and p62 was required for PHD3 aggregation that was lost upon transfer to hypoxia, allowing PHD3 to be expressed evenly throughout the cell. In line with this, p62 enhanced the normoxic degradation of PHD3. Depletion of p62 in normoxia led to elevated PHD3 levels, whereas forced p62 expression in hypoxia downregulated PHD3. The loss of p62 resulted in enhanced interaction of PHD3 with HIF-alpha and reduced HIF-alpha levels. The data demonstrate p62 is a critical regulator of the hypoxia response and PHD3 activity, by inducing PHD3 aggregation and degradation under normoxia. PMID- 23345397 TI - COUP-TFII orchestrates venous and lymphatic endothelial identity by homo- or hetero-dimerisation with PROX1. AB - Endothelial cell (EC) identity is in part genetically predetermined. Transcription factor NR2F2 (also known as chicken ovalbumin upstream promoter transcription factor II, COUP-TFII) plays a key role in EC fate decision making; however, many of the underlying mechanisms remain enigmatic. In the present study, we demonstrate that NR2F2 differentially regulates gene expression of venous versus lymphatic ECs (LECs) and document a novel paradigm whereby NR2F2 homodimers induce a venous EC fate, while heterodimers with the LEC-specific transcription factor PROX1 instruct LEC lineage specification. NR2F2 homodimers inhibit arterial differentiation in venous ECs through direct binding to the promoter regions of the Notch target genes HEY1 and HEY2 (HEY1/2), whereas NR2F2/PROX1 heterodimers lack this inhibitory effect, resulting at least in part in non-canonical HEY1/2 expression in LECs. Furthermore, NR2F2/PROX1 heterodimers actively induce or are permissive for the expression of a major subset of LEC specific genes. In addition to NR2F2/PROX1 heterodimerisation, the expression of HEY1 and some of these LEC-specific genes is dependent on PROX1 DNA binding. Thus, NR2F2 homodimers in venous ECs and NR2F2/PROX1 heterodimers in LECs differentially regulate EC subtype-specific genes and pathways, most prominently the Notch target genes HEY1/2. This novel mechanistic insight could pave the way for new therapeutic interventions for vascular-bed-specific disorders. PMID- 23345399 TI - Direct binding between BubR1 and B56-PP2A phosphatase complexes regulate mitotic progression. AB - BubR1 is a central component of the spindle assembly checkpoint that inhibits progression into anaphase in response to improper kinetochore-microtubule interactions. In addition, BubR1 also helps stabilize kinetochore-microtubule interactions by counteracting the Aurora B kinase but the mechanism behind this is not clear. Here we show that BubR1 directly binds to the B56 family of protein phosphatase 2A (PP2A) regulatory subunits through a conserved motif that is phosphorylated by cyclin-dependent kinase 1 (Cdk1) and polo-like kinase 1 (Plk1). Two highly conserved hydrophobic residues surrounding the serine 670 Cdk1 phosphorylation site are required for B56 binding. Mutation of these residues prevents the establishment of a proper metaphase plate and delays cells in mitosis. Furthermore, we show that phosphorylation of serines 670 and 676 stimulates the binding of B56 to BubR1 and that BubR1 targets a pool of B56 to kinetochores. Our data suggest that BubR1 counteracts Aurora B kinase activity at improperly attached kinetochores by recruiting B56-PP2A phosphatase complexes. PMID- 23345398 TI - Cdc25A activity is required for the metaphase II arrest in mouse oocytes. AB - Mammalian oocytes are arrested in metaphase of second meiosis (MII) until fertilization. This arrest is enforced by the cytostatic factor (CSF), which maintains the M-phase promoting factor (MPF) in a highly active state. Although the continuous synthesis and degradation of cyclin B to maintain the CSF-mediated MII arrest is well established, it is unknown whether cyclin-dependent kinase 1 (Cdk1) phosphorylations are involved in this arrest in mouse oocytes. Here, we show that a dynamic equilibrium of Cdk1 phosphorylation is required to maintain MII arrest. When the Cdc25A phosphatase is downregulated, mouse oocytes are released from MII arrest and MPF becomes inactivated. This inactivation occurs in the absence of cyclin B degradation and is dependent on Wee1B-mediated phosphorylation of Cdk1. Thus, our data demonstrate that Cdk1 activity is maintained during MII arrest not only by cyclin turnover but also by steady state phosphorylation. PMID- 23345400 TI - Occludin is required for TRPV1-modulated paracellular permeability in the submandibular gland. AB - Occludin plays an important role in maintaining tight junction barrier function in many types of epithelia. We previously reported that activation of transient receptor potential vanilloid subtype 1 (TRPV1) in rabbit submandibular gland promoted salivary secretion, partly by an increase in paracellular permeability. We have now explored the role of occludin in TRPV1-modulated paracellular permeability in a rat submandibular gland cell line SMG-C6. Both TRPV1 and occludin were expressed in SMG-C6 cells, and capsaicin induced redistribution of occludin, but not claudin-3, claudin-4 or E-cadherin, from the cell membrane into the cytoplasm. Capsaicin also decreased transepithelial electrical resistance (TER) and increased the Trypan Blue and FITC-dextran flux. Capsazepine (CPZ), a TRPV1 antagonist, inhibited the capsaicin-induced occludin redistribution and TER decrease. Moreover, occludin knockdown by shRNA suppressed, whereas occludin re expression restored, the TER response to capsaicin. Mechanistically, TRPV1 activation increased ERK1/2 and MLC2 phosphorylation. PD98059, an ERK1/2 kinase inhibitor, abolished the capsaicin-induced MLC2 phosphorylation, whereas ML-7, an MLC2 kinase inhibitor, did not affect ERK1/2 phosphorylation, suggesting that ERK1/2 is the upstream signaling molecule of MLC2. Capsaicin also induced F-actin reorganization, which was abolished by CPZ, PD98059 and ML-7, indicating that TRPV1 activation altered F-actin organization in an ERK1/2- and MLC2-dependent manner. Furthermore, either PD98059 or ML-7 could abolish the capsaicin-induced TER response and occludin redistribution, whereas knockdown of ERK1/2 further confirmed that the TRPV1-modulated paracellular permeability was ERK1/2 dependent. Taken together, these results identified a crucial role of occludin in submandibular epithelial cells, and more importantly, demonstrated that occludin was required to mediate TRPV1-modulated paracellular permeability. PMID- 23345401 TI - APLP2 regulates neuronal stem cell differentiation during cortical development. AB - Expression of amyloid precursor protein (APP) and its two paralogues, APLP1 and APLP2 during brain development coincides with key cellular events such as neuronal differentiation and migration. However, genetic knockout and shRNA studies have led to contradictory conclusions about their role during embryonic brain development. To address this issue, we analysed in depth the role of APLP2 during neurogenesis by silencing APLP2 in vivo in an APP/APLP1 double knockout mouse background. We find that under these conditions cortical progenitors remain in their undifferentiated state much longer, displaying a higher number of mitotic cells. In addition, we show that neuron-specific APLP2 downregulation does not impact the speed or position of migrating excitatory cortical neurons. In summary, our data reveal that APLP2 is specifically required for proper cell cycle exit of neuronal progenitors, and thus has a distinct role in priming cortical progenitors for neuronal differentiation. PMID- 23345402 TI - PCM1 recruits Plk1 to the pericentriolar matrix to promote primary cilia disassembly before mitotic entry. AB - Primary cilia, which emanate from the cell surface, exhibit assembly and disassembly dynamics along the progression of the cell cycle. However, the mechanism that links ciliary dynamics and cell cycle regulation remains elusive. In the present study, we report that Polo-like kinase 1 (Plk1), one of the key cell cycle regulators, which regulate centrosome maturation, bipolar spindle assembly and cytokinesis, acts as a pivotal player that connects ciliary dynamics and cell cycle regulation. We found that the kinase activity of centrosome enriched Plk1 is required for primary cilia disassembly before mitotic entry, wherein Plk1 interacts with and activates histone deacetylase 6 (HDAC6) to promote ciliary deacetylation and resorption. Furthermore, we showed that pericentriolar material 1 (PCM1) acts upstream of Plk1 and recruits the kinase to pericentriolar matrix (PCM) in a dynein-dynactin complex-dependent manner. This process coincides with the primary cilia disassembly dynamics at the onset of mitosis, as depletion of PCM1 by shRNA dramatically disrupted the pericentriolar accumulation of Plk1. Notably, the interaction between PCM1 and Plk1 is phosphorylation dependent, and CDK1 functions as the priming kinase to facilitate the interaction. Our data suggest a mechanism whereby the recruitment of Plk1 to pericentriolar matrix by PCM1 plays a pivotal role in the regulation of primary cilia disassembly before mitotic entry. Thus, the regulation of ciliary dynamics and cell proliferation share some common regulators. PMID- 23345403 TI - Using multifocal plane microscopy to reveal novel trafficking processes in the recycling pathway. AB - A major outstanding issue in cell biology is the lack of understanding of the contribution of tubulovesicular transport carriers (TCs) to intracellular trafficking pathways within 3D cellular environments. This is primarily due to the challenges associated with the use of microscopy techniques to track these highly motile, small compartments. In the present study we have used multifocal plane microscopy with localized photoactivation to overcome these limitations. Using this approach, we have characterized individual components constituting the recycling pathway of the receptor FcRn. Specifically, several different pathways followed by TCs that intersect with larger, relatively static sorting endosomes have been defined. These pathways include a novel 'looping' process in which TCs leave and return to the same sorting endosome. Significantly, TCs with different itineraries can be identified by associations with distinct complements of Rab GTPases, APPL1 and SNX4. These studies provide a framework for further analyses of the recycling pathway. PMID- 23345404 TI - Gbx2, a LIF/Stat3 target, promotes reprogramming to and retention of the pluripotent ground state. AB - Activation of signal transducer and activator of transcription 3 (Stat3) by leukemia inhibitory factor (LIF) maintains mouse embryonic stem cell (mESC) self renewal and also facilitates reprogramming to ground state pluripotency. Exactly how LIF/Stat3 signaling exerts these effects, however, remains elusive. We identified gastrulation brain homeobox 2 (Gbx2) as a LIF/Stat3 downstream target that, when overexpressed, allows long-term expansion of undifferentiated mESCs in the absence of LIF/Stat3 signaling. Elevated Gbx2 expression also enhanced reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells. Moreover, overexpression of Gbx2 was sufficient to reprogram epiblast stem cells to ground state ESCs. Our results reveal a novel function of Gbx2 in mESC reprogramming and LIF/Stat3-mediated self-renewal. PMID- 23345405 TI - Amyloid-beta signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease. AB - Normally post-mitotic neurons that aberrantly re-enter the cell cycle without dividing account for a substantial fraction of the neurons that die in Alzheimer's disease (AD). We now report that this ectopic cell cycle re-entry (CCR) requires soluble amyloid-beta (Abeta) and tau, the respective building blocks of the insoluble plaques and tangles that accumulate in AD brain. Exposure of cultured wild type (WT) neurons to Abeta oligomers caused CCR and activation of the non-receptor tyrosine kinase, fyn, the cAMP-regulated protein kinase A and calcium-calmodulin kinase II, which respectively phosphorylated tau on Y18, S409 and S416. In tau knockout (KO) neurons, Abeta oligomers activated all three kinases, but failed to induce CCR. Expression of WT, but not Y18F, S409A or S416A tau restored CCR in tau KO neurons. Tau-dependent CCR was also observed in vivo in an AD mouse model. CCR, a seminal step in AD pathogenesis, therefore requires signaling from Abeta through tau independently of their incorporation into plaques and tangles. PMID- 23345406 TI - CALHM1 controls the Ca2+-dependent MEK, ERK, RSK and MSK signaling cascade in neurons. AB - Calcium homeostasis modulator 1 (CALHM1) is a Ca(2+) channel controlling neuronal excitability and potentially involved in the pathogenesis of Alzheimer's disease (AD). Although strong evidence indicates that CALHM1 is required for neuronal electrical activity, its role in intracellular Ca(2+) signaling remains unknown. In the present study, we show that in hippocampal HT-22 cells, CALHM1 expression led to a robust and relatively selective activation of the Ca(2+)-sensing kinases ERK1/2. CALHM1 also triggered activation of MEK1/2, the upstream ERK1/2 activating kinases, and of RSK1/2/3 and MSK1, two downstream effectors of ERK1/2 signaling. CALHM1-mediated activation of ERK1/2 signaling was controlled by the small GTPase Ras. Pharmacological inhibition of CALHM1 permeability using Ruthenium Red, Zn(2+), and Gd(3+), or expression of the CALHM1 N140A and W114A mutants, which are deficient in mediating Ca(2+) influx, prevented the effect of CALHM1 on the MEK, ERK, RSK and MSK signaling cascade, demonstrating that CALHM1 controlled this pathway via its channel properties. Importantly, expression of CALHM1 bearing the natural P86L polymorphism, which leads to a partial loss of CALHM1 function and is associated with an earlier age at onset in AD patients, showed reduced activation of ERK1/2, RSK1/2/3, and MSK1. In line with these results obtained in transfected cells, primary cerebral neurons isolated from Calhm1 knockout mice showed significant impairments in the activation of MEK, ERK, RSK and MSK signaling. The present study identifies a previously uncharacterized mechanism of control of Ca(2+)-dependent ERK1/2 signaling in neurons, and further establishes CALHM1 as a critical ion channel for neuronal signaling and function. PMID- 23345407 TI - The signalling factor PI3K is a specific regulator of the clathrin-independent dynamin-dependent endocytosis of IL-2 receptors. AB - Receptor-mediated endocytosis is an essential process used by eukaryotic cells to internalise many molecules. Several clathrin-independent endocytic routes exist, but the molecular mechanism of each pathway remains to be uncovered. The present study focuses on a clathrin-independent dynamin-dependent pathway used by interleukin 2 receptors (IL-2R), essential players of the immune response. Ras related C3 botulinum toxin substrate (Rac1) and its targets, the p21-activated kinases (Pak), are specific regulators of this pathway, acting on cortactin and actin polymerization. The present study reveals a dual and specific role of phosphatidylinositol 3-kinase (PI3K) in IL-2R endocytosis. Inhibition of the catalytic activity of PI3K strongly affects IL-2R endocytosis, in contrast to transferrin (Tf) uptake, a marker of the clathrin-mediated pathway. Moreover, Vav2, a GTPase exchange factor (GEF) induced upon PI3K activation, is specifically involved in IL-2R entry. The second action of PI3K is through its regulatory subunit, p85alpha, which binds to and recruits Rac1 during IL-2R internalisation. Indeed, the overexpression of a p85alpha mutant missing the Rac1 binding motif leads to the specific inhibition of IL-2R endocytosis. The inhibitory effect of this p85alpha mutant could be rescued by the overexpression of either Rac1 or the active form of Pak, indicating that p85alpha acts upstream of the Rac1-Pak cascade. Finally, biochemical and fluorescent microscopy techniques reveal an interaction between p85alpha, Rac1 and IL-2R that is enhanced by IL-2. In summary, our results indicate a key role of class I PI3K in IL-2R endocytosis that creates a link with IL-2 signalling. PMID- 23345408 TI - Meaningful measurement: developing a measurement system to improve blood pressure control in patients with chronic kidney disease. AB - OBJECTIVES: To develop an electronic registry of patients with chronic kidney disease (CKD) treated in a nephrology practice in order to provide clinically meaningful measurement and population management to improve rates of blood pressure (BP) control. METHODS: We combined data from multiple electronic sources: the billing system, structured fields in the electronic health record (EHR), and free text physician notes using natural language processing (NLP). We also used point-of-care worksheets to capture clinical rationale. RESULTS: Nephrologist billing accurately identified patients with CKD. Using an algorithm that incorporated multiple BP readings increased the measured rate of control (130/80 mm Hg) from 37.1% to 42.3%. With the addition of NLP to capture BP readings from free text notes, the rate was 52.6%. Data from point-of-care worksheets indicated that in 52% of visits in which patients were identified as not having controlled BP, patients were actually at goal based on BP readings taken at home or on that day in the office. CONCLUSIONS: Building a method for clinically meaningful continuous performance measurement of BP control is possible, but will require data from multiple sources. Electronic measurement systems need to grow to be able to capture and process performance data from patients as well as in real-time from physicians. PMID- 23345409 TI - Pharmacogenomics in the pocket of every patient? A prototype based on quick response codes. AB - A sizable fraction of patients experiences adverse drug events or lack of drug efficacy. A part of this variability in drug response can be explained by genetic differences between patients. However, pharmacogenomic data as well as computational clinical decision support systems for interpreting such data are still unavailable in most healthcare settings. We address this problem by introducing the medicine safety code (MSC), which captures compressed pharmacogenomic data in a two-dimensional barcode that can be carried in a patient's wallet. We successfully encoded data about 385 genetic polymorphisms in MSC and were able to decode and interpret MSC quickly with common mobile devices. The MSC could make individual pharmacogenomic data and decision support available in a wide variety of healthcare settings without the set up of large-scale infrastructures or centralized databases. PMID- 23345410 TI - Cardiac-specific overexpression of perilipin 5 provokes severe cardiac steatosis via the formation of a lipolytic barrier. AB - Cardiac triacylglycerol (TG) catabolism critically depends on the TG hydrolytic activity of adipose triglyceride lipase (ATGL). Perilipin 5 (Plin5) is expressed in cardiac muscle (CM) and has been shown to interact with ATGL and its coactivator comparative gene identification-58 (CGI-58). Furthermore, ectopic Plin5 expression increases cellular TG content and Plin5-deficient mice exhibit reduced cardiac TG levels. In this study we show that mice with cardiac muscle specific overexpression of perilipin 5 (CM-Plin5) massively accumulate TG in CM, which is accompanied by moderately reduced fatty acid (FA) oxidizing gene expression levels. Cardiac lipid droplet (LD) preparations from CM of CM-Plin5 mice showed reduced ATGL- and hormone-sensitive lipase-mediated TG mobilization implying that Plin5 overexpression restricts cardiac lipolysis via the formation of a lipolytic barrier. To test this hypothesis, we analyzed TG hydrolytic activities in preparations of Plin5-, ATGL-, and CGI-58-transfected cells. In vitro ATGL-mediated TG hydrolysis of an artificial micellar TG substrate was not inhibited by the presence of Plin5, whereas Plin5-coated LDs were resistant toward ATGL-mediated TG catabolism. These findings strongly suggest that Plin5 functions as a lipolytic barrier to protect the cardiac TG pool from uncontrolled TG mobilization and the excessive release of free FAs. PMID- 23345411 TI - Cardiomyocyte-specific perilipin 5 overexpression leads to myocardial steatosis and modest cardiac dysfunction. AB - Presence of ectopic lipid droplets (LDs) in cardiac muscle is associated to lipotoxicity and tissue dysfunction. However, presence of LDs in heart is also observed in physiological conditions, such as when cellular energy needs and energy production from mitochondria fatty acid beta-oxidation are high (fasting). This suggests that development of tissue lipotoxicity and dysfunction is not simply due to the presence of LDs in cardiac muscle but due at least in part to alterations in LD function. To examine the function of cardiac LDs, we obtained transgenic mice with heart-specific perilipin 5 (Plin5) overexpression (MHC Plin5), a member of the perilipin protein family. Hearts from MHC-Plin5 mice expressed at least 4-fold higher levels of plin5 and exhibited a 3.5-fold increase in triglyceride content versus nontransgenic littermates. Chronic cardiac excess of LDs was found to result in mild heart dysfunction with decreased expression of peroxisome proliferator-activated receptor (PPAR)alpha target genes, decreased mitochondria function, and left ventricular concentric hypertrophia. Lack of more severe heart function complications may have been prevented by a strong increased expression of oxidative-induced genes via NF-E2 related factor 2 antioxidative pathway. Perilipin 5 regulates the formation and stabilization of cardiac LDs, and it promotes cardiac steatosis without major heart function impairment. PMID- 23345412 TI - Regulation of integrin alphaV subunit expression by sulfatide in hepatocellular carcinoma cells. AB - Integrin is important in migration and metastasis of tumor cells. Changes of integrin expression and distribution will cause an alteration of cellular adhesion and migration behaviors. In this study, we investigated sulfatide regulation of the integrin alphaV subunit expression in hepatoma cells and observed that either exogenous or endogenous sulfatide elicited a robust upregulation of integrin alphaV subunit mRNA and protein expression in hepatoma cells. This regulatory effect occurred with a corresponding phosphorylation (T739) of the transcription factor Sp1. Based on the electrophoretic mobility shift assay, sulfatide enhanced the integrin alphaV promoter activity and strengthened the Sp1 complex super-shift. The results of chromatin immunoprecipitation analysis also indicated that sulfatide enhanced Sp1 binding to the integrin alphaV promoter in vivo. Silence of Sp1 diminished the stimulation of integrin alphaV expression by sulfatide. In the early stage of sulfatide stimulation, phosphorylation of Erk as well as c-Src was noted, and inhibition of Erk activation with either U0126 or PD98059 significantly suppressed Sp1 phosphorylation and integrin alphaV expression. We demonstrated that sulfatide regulated integrin alphaV expression and cell adhesion, which was associated with Erk activation. PMID- 23345413 TI - Visual attention and flexible normalization pools. AB - Attention to a spatial location or feature in a visual scene can modulate the responses of cortical neurons and affect perceptual biases in illusions. We add attention to a cortical model of spatial context based on a well-founded account of natural scene statistics. The cortical model amounts to a generalized form of divisive normalization, in which the surround is in the normalization pool of the center target only if they are considered statistically dependent. Here we propose that attention influences this computation by accentuating the neural unit activations at the attended location, and that the amount of attentional influence of the surround on the center thus depends on whether center and surround are deemed in the same normalization pool. The resulting form of model extends a recent divisive normalization model of attention (Reynolds & Heeger, 2009). We simulate cortical surround orientation experiments with attention and show that the flexible model is suitable for capturing additional data and makes nontrivial testable predictions. PMID- 23345414 TI - Higher order color mechanisms: evidence from noise-masking experiments in cone contrast space. AB - This study addresses a fundamental question concerning the number of cortical, i.e., higher order mechanisms in color vision. The initial subcortical stages in color vision can be described by three cone mechanisms, S, M, L, and three pairs of second-stage mechanisms (achromatic L + M and -L - M, chromatic S - (L + M) and -S + (L + M), and chromatic L - M and M - L). The further mechanistic description of cortical color vision is controversial. On the one hand, numerous studies that defined their stimuli in a color-opponent Derrington-Krauskopf Lennie (DKL) color space found evidence for higher order mechanisms. On the other hand, some studies that defined their stimuli in cone contrast (CC) space failed to find such evidence. Here we show that this failure was due to a restricted choice of stimuli. We used a noise-masking paradigm to measure discrimination thresholds for textured patterns modulated along chromatic directions in CC space. Unlike previous studies we defined noise directions in DKL space and converted them to CC space. When the noise contrast was sufficiently high we found selective masking, but this did not occur when the noise contrast was low. Selective masking indicates higher order mechanisms, since so far no alternative model has been proposed. Previous studies in CC space failed to find selective masking due to the low contrast of the noise and due to the restricted choice of perceptually highly similar noise directions that mainly stimulated the second stage mechanisms. We conclude that cortical color vision is governed by higher order mechanisms. PMID- 23345415 TI - Polymorphism at genes involved in salt tolerance in Arabidopsis thaliana (Brassicaceae). AB - PREMISE OF THE STUDY: Genes involved in relevant functions for environmental adaptation can be considered primary candidates for their variation having been shaped by natural selection. Detecting recent selective events through their footprint on nucleotide variation constitutes a challenging task in species with a complex demographic history such as Arabidopsis thaliana. We have surveyed nucleotide variation in this species at nine genes involved in salt tolerance. The available genomewide information for this species has allowed us to contrast the levels and patterns of variation detected at the candidate genes with empirical distributions obtained from noncandidate regions. METHODS: We sequenced nine genes involved in salt tolerance (~32 kb) in 20 ecotypes of A. thaliana and analyzed polymorphism and divergence at the individual gene and multilocus levels. KEY RESULTS: Variation at the nine genes studied was characterized by a generalized skew toward polymorphisms with low-frequency variants. Except for genes RCD1 and NHX8, this pattern was similar to that generally detected in the A. thaliana genome and could thus be primarily explained by the species demographic history. The more extreme deviation at the NHX8 gene and its excess of polymorphism relative to divergence points to the recent action of selection on this gene. CONCLUSIONS: The analysis of nucleotide polymorphism and divergence at nine genes involved in salt tolerance provided little evidence for the recent action of positive selection. Only the signals detected at NHX8 from both polymorphism and divergence were suggestive of the putative contribution of this gene to local adaptation. PMID- 23345416 TI - Does retained-seed priming drive the evolution of serotiny in drylands? An assessment using the cactus Mammillaria hernandezii. AB - PREMISE OF THE STUDY: Serotinous plants retain their seeds for a long time. In deserts, retained seeds undergo hydration-dehydration cycles and thus may become primed. Priming enhances germination and seedling vigor. We test the hypothesis that serotiny evolves because it provides a site protected from predators in which seeds can become primed. Rainfall-cued dispersal of primed seeds may enhance this effect. METHODS: We tested this hypothesis with Mammillaria hernandezii through protein-content analyses; field and laboratory germination experiments with primed, unprimed, and retained seeds; and fitness estimations from demographic models. KEY RESULTS: Hydration-dehydration cycles induced priming, enhancing germination. Artificial priming and retention in the parent plant for 1 yr induced similar changes in seed protein patterns, suggesting that priming occurs naturally while seeds are retained. Under field conditions, germination of seeds retained for 1 yr more than doubled that of seeds of the same cohort that were not primed or that remained buried for 1 yr. The first seeds to germinate died rapidly. Serotinous plants whose seeds underwent priming had higher fitness than those whose seeds were in the soil seed bank or that did not experience priming. CONCLUSIONS: Priming in soil seed banks may be costly because of high predation, so seed protection during priming is sufficient to promote the evolution of serotiny. Bet hedging contributes to this process. Rapid germination of primed seeds that respond to brief rainfall events is disadvantageous because such rainfall is insufficient for seedling survival. Serotinous species counteract this cost by cueing dispersal with heavy precipitation. PMID- 23345417 TI - Xylem vessel relays contribute to radial connectivity in grapevine stems (Vitis vinifera and V. arizonica; Vitaceae). AB - PREMISE OF THE STUDY: Xylem network connections play an important role in water and nutrient transport in plants, but also facilitate the spread of air embolisms and xylem-dwelling pathogens. This study describes the structure and function of vessel relays found in grapevine xylem that form radial and tangential connections between spatially discrete vessels. METHODS: We used high-resolution computed tomography, light microscopy, scanning electron microscopy, and single vessel dye injections to characterize vessel relays in stems and compare their distributions and structure in two Vitis species. KEY RESULTS: Vessel relays were composed of 1-8 narrow diameter (~25 um) vessel elements and were oriented radially, connecting vessels via scalariform pitting within a xylem sector delineated by rays. The functional connectedness of vessels linked by vessel relays was confirmed with single-vessel dye injections. In 4.5-cm sections of stem tissue, there were 26% more vessel relays in V. vinifera compared with V. arizonica. * CONCLUSIONS: Because of their spatial distribution within Vitis xylem, vessel relays increase the connectivity between vessels that would otherwise remain isolated. Differences in vessel relays between Vitis species suggest these anatomical features could contribute to disease and embolism resistance in some species. PMID- 23345418 TI - So many manuscripts, so little space! How does an associate editor choose what articles are sent for review? PMID- 23345419 TI - Estrogen receptor-alpha in osteocytes is important for trabecular bone formation in male mice. AB - The bone-sparing effect of estrogen in both males and females is primarily mediated via estrogen receptor-alpha (ERalpha), encoded by the Esr1 gene. ERalpha in osteoclasts is crucial for the trabecular bone-sparing effect of estrogen in females, but it is dispensable for trabecular bone in male mice and for cortical bone in both genders. We hypothesized that ERalpha in osteocytes is important for trabecular bone in male mice and for cortical bone in both males and females. Dmp1-Cre mice were crossed with ERalpha(flox/flox) mice to generate mice lacking ERalpha protein expression specifically in osteocytes (Dmp1-ERalpha(-/-)). Male Dmp1-ERalpha(-/-) mice displayed a substantial reduction in trabecular bone volume (-20%, P < 0.01) compared with controls. Dynamic histomorphometry revealed reduced bone formation rate (-45%, P < 0.01) but the number of osteoclasts per bone surface was unaffected in the male Dmp1-ERalpha(-/-) mice. The male Dmp1 ERalpha(-/-) mice had reduced expression of several osteoblast/osteocyte markers in bone, including Runx2, Sp7, and Dmp1 (P < 0.05). Gonadal intact Dmp1-ERalpha( /-) female mice had no significant reduction in trabecular bone volume but ovariectomized Dmp1-ERalpha(-/-) female mice displayed an attenuated trabecular bone response to supraphysiological E2 treatment. Dmp1-ERalpha(-/-) mice of both genders had unaffected cortical bone. In conclusion, ERalpha in osteocytes regulates trabecular bone formation and thereby trabecular bone volume in male mice but it is dispensable for the trabecular bone in female mice and the cortical bone in both genders. We propose that the physiological trabecular bone sparing effect of estrogen is mediated via ERalpha in osteocytes in males, but via ERalpha in osteoclasts in females. PMID- 23345420 TI - Mechanism of action and initial evaluation of a membrane active all-D-enantiomer antimicrobial peptidomimetic. AB - Development of therapy against infections caused by antibiotic-resistant pathogens is a major unmet need in contemporary medicine. In previous work, our group chemically modified an antimicrobial peptidomimetic motif for targeted applications against cancer and obesity. Here, we show that the modified motif per se is resistant to proteolytic degradation and is a candidate antiinfective agent. We also show that the susceptibility of microorganisms to the drug is independent of bacterial growth phase. Moreover, this peptidomimetic selectively interferes with the integrity and function of the microbial surface lipid bilayer, data indicative that bacterial death results from membrane disruption followed by dissipation of membrane potential. Finally, we demonstrate two potential translational applications: use against biofilms and synergy with antibiotics in use. In summary, we introduce the mechanism of action and the initial evaluation of a prototype drug and a platform for the development of D enantiomer antimicrobial peptidomimetics that target bacterial membranes of certain gram-negative problem pathogens with promising translational applications. PMID- 23345421 TI - Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial-mesenchymal transition in liver injury. AB - In many organs, myofibroblasts play a major role in the scarring process in response to injury. In liver fibrogenesis, hepatic stellate cells (HSCs) are thought to transdifferentiate into myofibroblasts, but the origins of both HSCs and myofibroblasts remain elusive. In the developing liver, lung, and intestine, mesothelial cells (MCs) differentiate into specific mesenchymal cell types; however, the contribution of this differentiation to organ injury is unknown. In the present study, using mouse models, conditional cell lineage analysis has demonstrated that MCs expressing Wilms tumor 1 give rise to HSCs and myofibroblasts during liver fibrogenesis. Primary MCs, isolated from adult mouse liver using antibodies against glycoprotein M6a, undergo myofibroblastic transdifferentiation. Antagonism of TGF-beta signaling suppresses transition of MCs to mesenchymal cells both in vitro and in vivo. These results indicate that MCs undergo mesothelial-mesenchymal transition and participate in liver injury via differentiation to HSCs and myofibroblasts. PMID- 23345422 TI - Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. AB - Although it has been hypothesized that some of the somatic mutations found in tumors may occur before tumor initiation, there is little experimental or conceptual data on this topic. To gain insights into this fundamental issue, we formulated a mathematical model for the evolution of somatic mutations in which all relevant phases of a tissue's history are considered. The model makes the prediction, validated by our empirical findings, that the number of somatic mutations in tumors of self-renewing tissues is positively correlated with the age of the patient at diagnosis. Importantly, our analysis indicates that half or more of the somatic mutations in certain tumors of self-renewing tissues occur before the onset of neoplasia. The model also provides a unique way to estimate the in vivo tissue-specific somatic mutation rates in normal tissues directly from the sequencing data of tumors. Our results have substantial implications for the interpretation of the large number of genome-wide cancer studies now being undertaken. PMID- 23345423 TI - Profile of James A. Birchler. Interview by Farooq Ahmed. PMID- 23345424 TI - Perturbation of cell cycle regulation triggers plant immune response via activation of disease resistance genes. AB - The Arabidopsis gene OSD1 (Omission of the Second Division) and its homolog UVI4 (UV-B-Insensitive 4) are negative regulators of anaphase-promoting complex/cyclosome (APC/C), a multisubunit ubiquitin E3 ligase that regulates the progression of cell cycles. Here we report the isolation of an activation tagging allele of OSD1 as an enhancer of a mutant of BON1 (BONZAI1), a negative regulator of plant immunity. Overexpression of OSD1 and UVI4 each leads to enhanced immunity to a bacterial pathogen, which is associated with increased expression of disease resistance (R) genes similar to the animal NOD1 receptor-like immune receptor genes. In addition, the reduction of function of one subunit of the APC complex APC10 exhibited a similar phenotype to that of overexpression of OSD1 or UVI4, indicating that altered APC function induces immune responses. Enhanced immune response induced by OSD1 overexpression is dependent on CYCB1;1, which is a degradation target of APC/C. It is also associated with up-regulation of R genes and is dependent on the R gene SNC1 (Suppressor of npr1-1, constitutive 1). Taken together, our findings reveal an unexpected link between cell cycle progression and plant immunity, suggesting that cell cycle misregulation could have an impact on expression of genes, including R genes, in plant immunity. PMID- 23345425 TI - Role of 53BP1 oligomerization in regulating double-strand break repair. AB - Tumor suppressor p53-binding protein 1 (53BP1) regulates the repair of dysfunctional telomeres lacking the shelterin protein TRF2 by promoting their mobility, their nonhomologous end-joining (NHEJ), and, as we show here, by blocking 5' resection by CtIP. We report that these functions of 53BP1 required its N-terminal ATM/ATR target sites and its association with H4K20diMe, but not the BRCT domain, the GAR domain, or the binding of 53BP1 to dynein. A mutant lacking the oligomerization domain (53BP1(oligo)) was only modestly impaired in promoting NHEJ of dysfunctional telomeres and showed no defect with regard to the repression of CtIP. This 53BP1(oligo) allele was previously found to be unable to support class switch recombination or to promote radial chromosome formation in PARP1 inhibitor-treated Brca1-deficient cells. The data therefore support two conclusions. First, the requirements for 53BP1 in mediating NHEJ at dysfunctional telomeres and in class switch recombination are not identical. Second, 53BP1 dependent repression of CtIP at double-strand breaks (DSBs) is unlikely to be sufficient for the generation of radial chromosomes in PARP1 inhibitor-treated Brca1-deficient cells. PMID- 23345426 TI - Contribution of Thy1+ NK cells to protective IFN-gamma production during Salmonella typhimurium infections. AB - IFN-gamma is critical for immunity against infections with intracellular pathogens, such as Salmonella enterica. However, which of the many cell types capable of producing IFN-gamma controls Salmonella infections remains unclear. Using a mouse model of systemic Salmonella infection, we observed that only a lack of all lymphocytes or CD90 (Thy1)(+) cells, but not the absence of T cells, Retinoic acid-related orphan receptor (ROR)-gammat-dependent lymphocytes, (NK)1.1(+) cells, natural killer T (NKT), and/or B cells alone, replicated the highly susceptible phenotype of IFN-gamma-deficient mice to Salmonella infection. A combination of antibody depletions and adoptive transfer experiments revealed that early protective IFN-gamma was provided by Thy1-expressing natural killer (NK) cells and that these cells improved antibacterial immunity through the provision of IFN-gamma. Further analysis of NK cells producing IFN-gamma in response to Salmonella indicated that less mature NK cells were more efficient at mediating antibacterial effector function than terminally differentiated NK cells. Inspired by recent reports of Thy1(+) NK cells contributing to immune memory, we analyzed their role in secondary protection against otherwise lethal WT Salmonella infections. Notably, we observed that a newly generated Salmonella vaccine strain not only conferred superior protection compared with conventional regimens but that this enhanced efficiency of recall immunity was afforded by incorporating CD4(-)CD8(-)Thy1(+) cells into the secondary response. Taken together, these findings demonstrate that Thy1-expressing NK cells play an important role in antibacterial immunity. PMID- 23345427 TI - Compromised fidelity of endocytic synaptic vesicle protein sorting in the absence of stonin 2. AB - Neurotransmission depends on the exocytic fusion of synaptic vesicles (SVs) and their subsequent reformation either by clathrin-mediated endocytosis or budding from bulk endosomes. How synapses are able to rapidly recycle SVs to maintain SV pool size, yet preserve their compositional identity, is poorly understood. We demonstrate that deletion of the endocytic adaptor stonin 2 (Stn2) in mice compromises the fidelity of SV protein sorting, whereas the apparent speed of SV retrieval is increased. Loss of Stn2 leads to selective missorting of synaptotagmin 1 to the neuronal surface, an elevated SV pool size, and accelerated SV protein endocytosis. The latter phenotype is mimicked by overexpression of endocytosis-defective variants of synaptotagmin 1. Increased speed of SV protein retrieval in the absence of Stn2 correlates with an up regulation of SV reformation from bulk endosomes. Our results are consistent with a model whereby Stn2 is required to preserve SV protein composition but is dispensable for maintaining the speed of SV recycling. PMID- 23345428 TI - GABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2. AB - Hematopoietic stem cells (HSCs) are the source of all blood lineages, and HSCs must balance quiescence, self-renewal, and differentiation to meet lifelong needs for blood cell development. Transformation of HSCs by the breakpoint cluster region-ABL tyrosine kinase (BCR-ABL) oncogene causes chronic myelogenous leukemia (CML). The E-twenty six (ets) transcription factor GA binding protein (GABP) is a tetrameric transcription factor complex that contains GABPalpha and GABPbeta proteins. Deletion in bone marrow of Gabpa, the gene that encodes the DNA-binding component, caused cell cycle arrest in HSCs and profound loss of hematopoietic progenitor cells. Loss of Gabpalpha prevented development of CML, although mice continued to generate BCR-ABL-expressing Gabpalpha-null cells for months that were serially transplantable and contributed to all lineages in secondary recipients. A bioinformatic screen identified the serine-threonine kinase protein kinase D2 (PRKD2) as a potential effector of GABP in HSCs. Prkd2 expression was markedly reduced in Gabpalpha-null HSCs and progenitor cells. Reduced expression of PRKD2 or pharmacologic inhibition decreased cell cycling, and PRKD2 rescued growth of Gabpalpha-null BCR-ABL-expressing cells. Thus, GABP is required for HSC cell cycle entry and CML development through its control of PRKD2. This offers a potential therapeutic target in leukemia. PMID- 23345429 TI - UV light phototransduction activates transient receptor potential A1 ion channels in human melanocytes. AB - Human skin is constantly exposed to solar ultraviolet radiation (UVR), the most prevalent environmental carcinogen. Humans have the unique ability among mammals to respond to UVR by increasing their skin pigmentation, a protective process driven by melanin synthesis in epidermal melanocytes. The molecular mechanisms used by melanocytes to detect and respond to long-wavelength UVR (UVA) are not well understood. We recently identified a UVA phototransduction pathway in melanocytes that is mediated by G protein-coupled receptors and leads to rapid calcium mobilization. Here we report that in human epidermal melanocytes physiological doses of UVR activate a retinal-dependent current mediated by transient receptor potential A1 (TRPA1) ion channels. The TRPA1 photocurrent is UVA-specific and requires G protein and phospholipase C signaling, thus contributing to UVA-induced calcium responses to mediate downstream cellular effects and providing evidence for TRPA1 function in mammalian phototransduction. Remarkably, TRPA1 activation is required for the UVR-induced and retinal dependent early increase in cellular melanin. Our results show that TRPA1 is essential for a unique extraocular phototransduction pathway in human melanocytes that is activated by physiological doses of UVR and results in early melanin synthesis. PMID- 23345430 TI - Depletion of cellular polyamines, spermidine and spermine, causes a total arrest in translation and growth in mammalian cells. AB - The polyamines, putrescine, spermidine, and spermine, are essential polycations, intimately involved in the regulation of cellular proliferation. Although polyamines exert dynamic effects on the conformation of nucleic acids and macromolecular synthesis in vitro, their specific functions in vivo are poorly understood. We investigated the cellular function of polyamines by overexpression of a key catabolic enzyme, spermidine/spermine N(1)-acetyltransferase 1 (SAT1) in mammalian cells. Transient cotransfection of HeLa cells with GFP and SAT1 vectors suppressed GFP protein expression without lowering its mRNA level, an indication that the block in GFP expression was not at transcription, but at translation. Fluorescence single-cell imaging also revealed specific inhibition of endogenous protein synthesis in the SAT1 overexpressing cells, without any inhibition of synthesis of DNA or RNA. Overexpression of SAT1 using a SAT1 adenovirus led to rapid depletion of cellular spermidine and spermine, total inhibition of protein synthesis, and growth arrest within 24 h. The SAT1 effect is most likely due to depletion of spermidine and spermine, because stable polyamine analogs that are not substrates for SAT1 restored GFP and endogenous protein synthesis. Loss of polysomes with increased 80S monosomes in the polyamine-depleted cells suggests a direct role for polyamines in translation initiation. Our data provide strong evidence for a primary function of polyamines, spermidine and spermine, in translation in mammalian cells. PMID- 23345431 TI - Immunoglobulins drive terminal maturation of splenic dendritic cells. AB - Nature and physiological status of antigen-presenting cells, such as dendritic cells DCs, are decisive for the immune reactions elicited. Multiple factors and cell interactions have been described that affect maturation of DCs. Here, we show that DCs arising in the absence of immunoglobulins (Ig) in vivo are impaired in cross-presentation of soluble antigen. This deficiency was due to aberrant cellular targeting of antigen to lysosomes and its rapid degradation. Function of DCs could be restored by transfer of Ig irrespective of antigen specificity and isotype. Modulation of cross-presentation by Ig was inhibited by coapplication of mannan and, thus, likely to be mediated by C-type lectin receptors. This unexpected dependency of splenic DCs on Ig to cross-present antigen provides insights into the interplay between cellular and humoral immunity and the immunomodulatory capacity of Ig. PMID- 23345432 TI - Functional redundancy between the XLF and DNA-PKcs DNA repair factors in V(D)J recombination and nonhomologous DNA end joining. AB - Classical nonhomologous end joining (C-NHEJ) is a major mammalian DNA double strand break (DSB) repair pathway that is required for assembly of antigen receptor variable region gene segments by V(D)J recombination. Recombination activating gene endonuclease initiates V(D)J recombination by generating DSBs between two V(D)J coding gene segments and flanking recombination signal sequences (RS), with the two coding ends and two RS ends joined by C-NHEJ to form coding joins and signal joins, respectively. During C-NHEJ, recombination activating gene factor generates two coding ends as covalently sealed hairpins and RS ends as blunt 5'-phosphorylated DSBs. Opening and processing of coding end hairpins before joining by C-NHEJ requires the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). However, C-NHEJ of RS ends, which do not require processing, occurs relatively normally in the absence of DNA-PKcs. The XRCC4-like factor (XLF) is a C-NHEJ component that is not required for C-NHEJ of chromosomal signal joins or coding joins because of functional redundancy with ataxia telangiectasia mutated kinase, a protein that also has some functional overlap with DNA-PKcs in this process. Here, we show that XLF has dramatic functional redundancy with DNA-PKcs in the V(D)J SJ joining process, which is nearly abrogated in their combined absence. Moreover, we show that XLF functionally overlaps with DNA-PKcs in normal mouse development, promotion of genomic stability in mouse fibroblasts, and in IgH class switch recombination in mature B cells. Our findings suggest that DNA-PKcs has fundamental roles in C-NHEJ processes beyond end processing that have been masked by functional overlaps with XLF. PMID- 23345433 TI - Engineering allosteric control to an unregulated enzyme by transfer of a regulatory domain. AB - Allosteric regulation of protein function is a critical component of metabolic control. Its importance is underpinned by the diversity of mechanisms and its presence in all three domains of life. The first enzyme of the aromatic amino acid biosynthesis, 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase, shows remarkable variation in allosteric response and machinery, and both contemporary regulated and unregulated orthologs have been described. To examine the molecular events by which allostery can evolve, we have generated a chimeric protein by joining the catalytic domain of an unregulated 3-deoxy-D-arabino-heptulosonate 7 phosphate synthase with the regulatory domain of a regulated enzyme. We demonstrate that this simple gene fusion event on its own is sufficient to confer functional allostery to the unregulated enzyme. The fusion protein shares structural similarities with its regulated parent protein and undergoes an analogous major conformational change in response to the binding of allosteric effector tyrosine to the regulatory domain. These findings help delineate a remarkably facile mechanism for the evolution of modular allostery by domain recruitment. PMID- 23345434 TI - Nek1 kinase associates with ATR-ATRIP and primes ATR for efficient DNA damage signaling. AB - The master checkpoint kinase ATR (ATM and Rad3-related) and its partner ATRIP (ATR-interacting protein) exist as a complex and function together in the DNA damage response. Unexpectedly, we found that the stability of the ATR-ATRIP complex is regulated by an unknown kinase independently of DNA damage. In search for this regulator of ATR-ATRIP, we found that a single member of the NIMA (never in mitosis A)-related kinase family, Nek1, is critical for initiating the ATR response. Upon DNA damage, cells lacking Nek1 failed to efficiently phosphorylate multiple ATR substrates and support ATR autophosphorylation at threnine 1989, one of the earliest events during the ATR response. The ability of Nek1 to promote ATR activation relies on the kinase activity of Nek1 and its interaction with ATR ATRIP. Importantly, even in undamaged cells, Nek1 is required for maintaining the levels of ATRIP, the association between ATR and ATRIP, and the basal kinase activity of ATR. Thus, as an ATR-associated kinase, Nek1, enhances the stability and activity of ATR-ATRIP before DNA damage, priming ATR-ATRIP for a robust DNA damage response. PMID- 23345435 TI - Retrograde bilin signaling enables Chlamydomonas greening and phototrophic survival. AB - The maintenance of functional chloroplasts in photosynthetic eukaryotes requires real-time coordination of the nuclear and plastid genomes. Tetrapyrroles play a significant role in plastid-to-nucleus retrograde signaling in plants to ensure that nuclear gene expression is attuned to the needs of the chloroplast. Well known sites of synthesis of chlorophyll for photosynthesis, plant chloroplasts also export heme and heme-derived linear tetrapyrroles (bilins), two critical metabolites respectively required for essential cellular activities and for light sensing by phytochromes. Here we establish that Chlamydomonas reinhardtii, one of many chlorophyte species that lack phytochromes, can synthesize bilins in both plastid and cytosol compartments. Genetic analyses show that both pathways contribute to iron acquisition from extracellular heme, whereas the plastid localized pathway is essential for light-dependent greening and phototrophic growth. Our discovery of a bilin-dependent nuclear gene network implicates a widespread use of bilins as retrograde signals in oxygenic photosynthetic species. Our studies also suggest that bilins trigger critical metabolic pathways to detoxify molecular oxygen produced by photosynthesis, thereby permitting survival and phototrophic growth during the light period. PMID- 23345436 TI - Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases. AB - The balance between excitatory and inhibitory synaptic inputs, which is governed by multiple synapse organizers, controls neural circuit functions and behaviors. Slit- and Trk-like proteins (Slitrks) are a family of synapse organizers, whose emerging synaptic roles are incompletely understood. Here, we report that Slitrks are enriched in postsynaptic densities in rat brains. Overexpression of Slitrks promoted synapse formation, whereas RNAi-mediated knockdown of Slitrks decreased synapse density. Intriguingly, Slitrks were required for both excitatory and inhibitory synapse formation in an isoform-dependent manner. Moreover, Slitrks required distinct members of the leukocyte antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family to trigger synapse formation. Protein tyrosine phosphatase sigma (PTPsigma), in particular, was specifically required for excitatory synaptic differentiation by Slitrks, whereas PTPdelta was necessary for inhibitory synapse differentiation. Taken together, these data suggest that combinatorial interactions of Slitrks with LAR-RPTP family members maintain synapse formation to coordinate excitatory-inhibitory balance. PMID- 23345437 TI - Hydrogel drug delivery system with predictable and tunable drug release and degradation rates. AB - Many drugs and drug candidates are suboptimal because of short duration of action. For example, peptides and proteins often have serum half-lives of only minutes to hours. One solution to this problem involves conjugation to circulating carriers, such as PEG, that retard kidney filtration and hence increase plasma half-life of the attached drug. We recently reported an approach to half-life extension that uses sets of self-cleaving linkers to attach drugs to macromolecular carriers. The linkers undergo beta-eliminative cleavage to release the native drug with predictable half-lives ranging from a few hours to over 1 y; however, half-life extension becomes limited by the renal elimination rate of the circulating carrier. An approach to overcoming this constraint is to use noncirculating, biodegradable s.c. implants as drug carriers that are stable throughout the duration of drug release. Here, we use beta-eliminative linkers to both tether drugs to and cross-link PEG hydrogels, and demonstrate tunable drug release and hydrogel erosion rates over a very wide range. By using one beta eliminative linker to tether a drug to the hydrogel, and another beta-eliminative linker with a longer half-life to control polymer degradation, the system can be coordinated to release the drug before the gel undergoes complete erosion. The practical utility is illustrated by a PEG hydrogel-exenatide conjugate that should allow once-a-month administration, and results indicate that the technology may serve as a generic platform for tunable ultralong half-life extension of potent therapeutics. PMID- 23345438 TI - Pattern and synchrony of gene expression among sympatric marine microbial populations. AB - Planktonic marine microbes live in dynamic habitats that demand rapid sensing and response to periodic as well as stochastic environmental change. The kinetics, regularity, and specificity of microbial responses in situ, however, are not well described. We report here simultaneous multitaxon genome-wide transcriptome profiling in a naturally occurring picoplankton community. An in situ robotic sampler using a Lagrangian sampling strategy enabled continuous tracking and repeated sampling of coherent microbial populations over 2 d. Subsequent RNA sequencing analyses yielded genome-wide transcriptome profiles of eukaryotic (Ostreococcus) and bacterial (Synechococcus) photosynthetic picoplankton as well as proteorhodopsin-containing heterotrophs, including Pelagibacter, SAR86-cluster Gammaproteobacteria, and marine Euryarchaea. The photosynthetic picoplankton exhibited strong diel rhythms over thousands of gene transcripts that were remarkably consistent with diel cycling observed in laboratory pure cultures. In contrast, the heterotrophs did not cycle diurnally. Instead, heterotrophic picoplankton populations exhibited cross-species synchronous, tightly regulated, temporally variable patterns of gene expression for many genes, particularly those genes associated with growth and nutrient acquisition. This multitaxon, population-wide gene regulation seemed to reflect sporadic, short-term, reversible responses to high-frequency environmental variability. Although the timing of the environmental responses among different heterotrophic species seemed synchronous, the specific metabolic genes that were expressed varied from taxon to taxon. In aggregate, these results provide insights into the kinetics, diversity, and functional patterns of microbial community response to environmental change. Our results also suggest a means by which complex multispecies metabolic processes could be coordinated, facilitating the regulation of matter and energy processing in a dynamically changing environment. PMID- 23345439 TI - Arl1p regulates spatial membrane organization at the trans-Golgi network through interaction with Arf-GEF Gea2p and flippase Drs2p. AB - ADP ribosylation factors (Arfs) are the central regulators of vesicle trafficking from the Golgi complex. Activated Arfs facilitate vesicle formation through stimulating coat assembly, activating lipid-modifying enzymes and recruiting tethers and other effectors. Lipid translocases (flippases) have been implicated in vesicle formation through the generation of membrane curvature. Although there is no evidence that Arfs directly regulate flippase activity, an Arf-guanine nucleotide-exchange factor (GEF) Gea2p has been shown to bind to and stimulate the activity of the flippase Drs2p. Here, we provide evidence for the interaction and activation of Drs2p by Arf-like protein Arl1p in yeast. We observed that Arl1p, Drs2p and Gea2p form a complex through direct interaction with each other, and each interaction is necessary for the stability of the complex and is indispensable for flippase activity. Furthermore, we show that this Arl1p-Drs2p Gea2p complex is specifically required for recruiting golgin Imh1p to the Golgi. Our results demonstrate that activated Arl1p can promote the spatial modulation of membrane organization at the trans-Golgi network through interacting with the effectors Gea2p and Drs2p. PMID- 23345440 TI - Alignment of cellular motility forces with tissue flow as a mechanism for efficient wound healing. AB - Recent experiments have shown that spreading epithelial sheets exhibit a long range coordination of motility forces that leads to a buildup of tension in the tissue, which may enhance cell division and the speed of wound healing. Furthermore, the edges of these epithelial sheets commonly show finger-like protrusions whereas the bulk often displays spontaneous swirls of motile cells. To explain these experimental observations, we propose a simple flocking-type mechanism, in which cells tend to align their motility forces with their velocity. Implementing this idea in a mechanical tissue simulation, the proposed model gives rise to efficient spreading and can explain the experimentally observed long-range alignment of motility forces in highly disordered patterns, as well as the buildup of tensile stress throughout the tissue. Our model also qualitatively reproduces the dependence of swirl size and swirl velocity on cell density reported in experiments and exhibits an undulation instability at the edge of the spreading tissue commonly observed in vivo. Finally, we study the dependence of colony spreading speed on important physical and biological parameters and derive simple scaling relations that show that coordination of motility forces leads to an improvement of the wound healing process for realistic tissue parameters. PMID- 23345441 TI - Kin recognition within a seed and the effect of genetic relatedness of an endosperm to its compatriot embryo on maize seed development. AB - As one of two sexual products resulting from double fertilization in angiosperms, the endosperm nourishes its compatriot embryo during seed development and/or germination and ultimately dies. Theoretical studies suggest that the genetic relatedness of an endosperm to its embryo in the same seed might determine the amount of resources ultimately available for the embryo during seed development. We took advantage of the phenomenon of heterofertilization in cultivated maize to empirically test whether genetic relatedness between a triploid embryo-nourishing endosperm and its compatriot diploid embryo impacts the process of resource allocation between these two sexually produced entities. We used genetically distinct maize inbred lines to perform two crossing experiments. Dry weights of dissected embryos and endosperms of mature heterofertilized and adjacent homofertilized kernels were compared. Embryo weight of heterofertilized kernels was significantly less than that of embryos of homofertilized kernels, whereas there was no significant difference in endosperm weight between the two types of kernels. Our results suggest that the degree of genetic relatedness of an endosperm to its compatriot embryo affects seed development and specifically the amount of maternal resources allocated to an endosperm that are eventually turned over to an embryo. The lower the coefficient of relatedness of an endosperm to its compatriot embryo, the smaller the embryo. Thus, the endosperm of a heterofertilized seed appears to behave less cooperatively with respect to resource transfer toward its less closely related embryo compared with the endosperm of a homofertilized seed. PMID- 23345442 TI - Biomimetic, synthetic HDL nanostructures for lymphoma. AB - New therapies that challenge existing paradigms are needed for the treatment of cancer. We report a nanoparticle-enabled therapeutic approach to B-cell lymphoma using synthetic high density lipoprotein nanoparticles (HDL-NPs). HDL-NPs are synthesized using a gold nanoparticle template to control conjugate size and ensure a spherical shape. Like natural HDLs, biomimetic HDL-NPs target scavenger receptor type B-1, a high-affinity HDL receptor expressed by lymphoma cells. Functionally, compared with natural HDL, the gold NP template enables differential manipulation of cellular cholesterol flux in lymphoma cells, promoting cellular cholesterol efflux and limiting cholesterol delivery. This combination of scavenger receptor type B-1 binding and relative cholesterol starvation selectively induces apoptosis. HDL-NP treatment of mice bearing B-cell lymphoma xenografts selectively inhibits B-cell lymphoma growth. As such, HDL-NPs are biofunctional therapeutic agents, whose mechanism of action is enabled by the presence of a synthetic nanotemplate. HDL-NPs are active in B-cell lymphomas and potentially, other malignancies or diseases of pathologic cholesterol accumulation. PMID- 23345443 TI - Rate of hydrolysis in ATP synthase is fine-tuned by alpha-subunit motif controlling active site conformation. AB - Computer-designed artificial enzymes will require precise understanding of how conformation of active sites may control barrier heights of key transition states, including dependence on structure and dynamics at larger molecular scale. F(o)F(1) ATP synthase is interesting as a model system: a delicate molecular machine synthesizing or hydrolyzing ATP using a rotary motor. Isolated F(1) performs hydrolysis with a rate very sensitive to ATP concentration. Experimental and theoretical results show that, at low ATP concentrations, ATP is slowly hydrolyzed in the so-called tight binding site, whereas at higher concentrations, the binding of additional ATP molecules induces rotation of the central gamma subunit, thereby forcing the site to transform through subtle conformational changes into a loose binding site in which hydrolysis occurs faster. How the 1-A scale rearrangements are controlled is not yet fully understood. By a combination of theoretical approaches, we address how large macromolecular rearrangements may manipulate the active site and how the reaction rate changes with active site conformation. Simulations reveal that, in response to gamma-subunit position, the active site conformation is fine-tuned mainly by small alpha-subunit changes. Quantum mechanics-based results confirm that the sub-Angstrom gradual changes between tight and loose binding site structures dramatically alter the hydrolysis rate. PMID- 23345444 TI - Detection of iodine monoxide in the tropical free troposphere. AB - Atmospheric iodine monoxide (IO) is a radical that catalytically destroys heat trapping ozone and reacts further to form aerosols. Here, we report the detection of IO in the tropical free troposphere (FT). We present vertical profiles from airborne measurements over the Pacific Ocean that show significant IO up to 9.5 km altitude and locate, on average, two-thirds of the total column above the marine boundary layer. IO was observed in both recent deep convective outflow and aged free tropospheric air, suggesting a widespread abundance in the FT over tropical oceans. Our vertical profile measurements imply that most of the IO signal detected by satellites over tropical oceans could originate in the FT, which has implications for our understanding of iodine sources. Surprisingly, the IO concentration remains elevated in a transition layer that is decoupled from the ocean surface. This elevated concentration aloft is difficult to reconcile with our current understanding of iodine lifetimes and may indicate heterogeneous recycling of iodine from aerosols back to the gas phase. Chemical model simulations reveal that the iodine-induced ozone loss occurs mostly above the marine boundary layer (34%), in the transition layer (40%) and FT (26%) and accounts for up to 20% of the overall tropospheric ozone loss rate in the upper FT. Our results suggest that the halogen-driven ozone loss in the FT is currently underestimated. More research is needed to quantify the widespread impact that iodine species of marine origin have on free tropospheric composition, chemistry, and climate. PMID- 23345445 TI - Eriocalyxin B ameliorates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells. AB - Eriocalyxin B (EriB), a diterpenoid isolated from Isodon eriocalyx, was previously reported to have antitumor effects via multiple pathways, and these pathways are related to immune responses. In this study, we demonstrated that EriB was efficacious in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Treatment with EriB led to amelioration of EAE, which correlated with reduced spinal cord inflammation and demyelination. EriB treatment abolished encephalitogenic T-cell responses to myelin oligodendrocyte glycoprotein in an adoptive transfer EAE model. The underlying mechanism of EriB-induced effects involved inhibition of T helper (Th) 1 and Th17 cell differentiation through Janus Kinase/Signal Transducer and Activator Of Transcription and Nuclear factor-kappaB signaling pathways as well as elevation of reactive oxygen species. These findings indicate that EriB exerts potent antiinflammatory effects through selective modulation of pathogenic Th1 and Th17 cells by targeting critical signaling pathways. The study provides insights into the role of EriB as a unique therapeutic agent for the treatment of autoimmune diseases. PMID- 23345446 TI - Deep sequencing reveals abundant noncanonical retroviral microRNAs in B-cell leukemia/lymphoma. AB - Viral tumor models have significantly contributed to our understanding of oncogenic mechanisms. How transforming delta-retroviruses induce malignancy, however, remains poorly understood, especially as viral mRNA/protein are tightly silenced in tumors. Here, using deep sequencing of broad windows of small RNA sizes in the bovine leukemia virus ovine model of leukemia/lymphoma, we provide in vivo evidence of the production of noncanonical RNA polymerase III (Pol III) transcribed viral microRNAs in leukemic B cells in the complete absence of Pol II 5'-LTR-driven transcriptional activity. Processed from a cluster of five independent self-sufficient transcriptional units located in a proviral region dispensable for in vivo infectivity, bovine leukemia virus microRNAs represent ~40% of all microRNAs in both experimental and natural malignancy. They are subject to strong purifying selection and associate with Argonautes, consistent with a critical function in silencing of important cellular and/or viral targets. Bovine leukemia virus microRNAs are strongly expressed in preleukemic and malignant cells in which structural and regulatory gene expression is repressed, suggesting a key role in tumor onset and progression. Understanding how Pol III dependent microRNAs subvert cellular and viral pathways will contribute to deciphering the intricate perturbations that underlie malignant transformation. PMID- 23345447 TI - Human cortical sensorimotor network underlying feedback control of vocal pitch. AB - The control of vocalization is critically dependent on auditory feedback. Here, we determined the human peri-Sylvian speech network that mediates feedback control of pitch using direct cortical recordings. Subjects phonated while a real time signal processor briefly perturbed their output pitch (speak condition). Subjects later heard the same recordings of their auditory feedback (listen condition). In posterior superior temporal gyrus, a proportion of sites had suppressed responses to normal feedback, whereas other spatially independent sites had enhanced responses to altered feedback. Behaviorally, speakers compensated for perturbations by changing their pitch. Single-trial analyses revealed that compensatory vocal changes were predicted by the magnitude of both auditory and subsequent ventral premotor responses to perturbations. Furthermore, sites whose responses to perturbation were enhanced in the speaking condition exhibited stronger correlations with behavior. This sensorimotor cortical network appears to underlie auditory feedback-based control of vocal pitch in humans. PMID- 23345448 TI - Using data to attribute episodes of warming and cooling in instrumental records. AB - The observed global-warming rate has been nonuniform, and the cause of each episode of slowing in the expected warming rate is the subject of intense debate. To explain this, nonrecurrent events have commonly been invoked for each episode separately. After reviewing evidence in both the latest global data (HadCRUT4) and the longest instrumental record, Central England Temperature, a revised picture is emerging that gives a consistent attribution for each multidecadal episode of warming and cooling in recent history, and suggests that the anthropogenic global warming trends might have been overestimated by a factor of two in the second half of the 20th century. A recurrent multidecadal oscillation is found to extend to the preindustrial era in the 353-y Central England Temperature and is likely an internal variability related to the Atlantic Multidecadal Oscillation (AMO), possibly caused by the thermohaline circulation variability. The perspective of a long record helps in quantifying the contribution from internal variability, especially one with a period so long that it is often confused with secular trends in shorter records. Solar contribution is found to be minimal for the second half of the 20th century and less than 10% for the first half. The underlying net anthropogenic warming rate in the industrial era is found to have been steady since 1910 at 0.07-0.08 degrees C/decade, with superimposed AMO-related ups and downs that included the early 20th century warming, the cooling of the 1960s and 1970s, the accelerated warming of the 1980s and 1990s, and the recent slowing of the warming rates. Quantitatively, the recurrent multidecadal internal variability, often underestimated in attribution studies, accounts for 40% of the observed recent 50 y warming trend. PMID- 23345449 TI - Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone. AB - Here, we evaluate an alternative approach of preconditioning pancreatic islets before transplantation using a potent agonist of growth-hormone-releasing hormone (GHRH) to promote islet viability and function, and we explore the adrenal gland as an alternative transplantation site for islet engraftment. The endocrine microenvironment of the adrenal represents a promising niche with the unique advantages of exceptional high oxygen tension and local anti-inflammatory and immunosuppressive properties. GHRH agonists have been shown to promote islet graft survival and function, which may help to reduce the islet mass necessary to reverse diabetes. In the present study, the most potent GHRH agonist MR403 was tested on insulinoma cells, isolated rat islets, and adrenal beta-cell cocultures in vitro. GHRH receptor is expressed on both adrenal cells and islets. MR403 caused a significant increase in cell viability and proliferation and revealed an antiapoptotic effect on insulinoma cells. Viability of rat islets was increased after treatment with the agonist and in coculture with adrenal cells. Rat islets were transplanted into diabetic mice to the intraadrenal transplant site and compared with the classical transplants underneath the kidney capsule. Graft function and integration were tested by metabolic follow-up and immunohistochemical staining of intraadrenal grafts. A rapid decrease occurred in blood glucose levels in both models, and all animals reached normoglycemia within the first days after transplantation. Our studies demonstrated that the adrenal may be an attractive site for islet transplantation and that GHRH analogs might allow reduction of the islet mass needed to reverse a diabetic status. PMID- 23345450 TI - Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise. AB - Age-related hearing loss and noise-induced hearing loss are major causes of human morbidity. Here we used genetics and functional studies to show that a shared cause of these disorders may be loss of function of the ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) that is expressed in sensory and supporting cells of the cochlea. Genomic analysis of dominantly inherited, progressive sensorineural hearing loss DFNA41 in a six-generation kindred revealed a rare heterozygous allele, P2RX2 c.178G > T (p.V60L), at chr12:133,196,029, which cosegregated with fully penetrant hearing loss in the index family, and also appeared in a second family with the same phenotype. The mutation was absent from more than 7,000 controls. P2RX2 p.V60L abolishes two hallmark features of P2X(2) receptors: ATP-evoked inward current response and ATP stimulated macropore permeability, measured as loss of ATP-activated FM1-43 fluorescence labeling. Coexpression of mutant and WT P2X(2) receptor subunits significantly reduced ATP-activated membrane permeability. P2RX2-null mice developed severe progressive hearing loss, and their early exposure to continuous moderate noise led to high-frequency hearing loss as young adults. Similarly, among family members heterozygous for P2RX2 p.V60L, noise exposure exacerbated high-frequency hearing loss in young adulthood. Our results suggest that P2X(2) function is required for life-long normal hearing and for protection from exposure to noise. PMID- 23345451 TI - Total cellular glycomics allows characterizing cells and streamlining the discovery process for cellular biomarkers. AB - Although many of the frequently used pluripotency biomarkers are glycoconjugates, a glycoconjugate-based exploration of novel cellular biomarkers has proven difficult due to technical difficulties. This study reports a unique approach for the systematic overview of all major classes of oligosaccharides in the cellular glycome. The proposed method enabled mass spectrometry-based structurally intensive analyses, both qualitatively and quantitatively, of cellular N- and O linked glycans derived from glycoproteins, glycosaminoglycans, and glycosphingolipids, as well as free oligosaccharides of human embryonic stem cells (hESCs), induced pluripotent stem cells (hiPSCs), and various human cells derived from normal and carcinoma cells. Cellular total glycomes were found to be highly cell specific, demonstrating their utility as unique cellular descriptors. Structures of glycans of all classes specifically observed in hESCs and hiPSCs tended to be immature in general, suggesting the presence of stem cell-specific glycosylation spectra. The current analysis revealed the high similarity of the total cellular glycome between hESCs and hiPSCs, although it was suggested that hESCs are more homogeneous than hiPSCs from a glycomic standpoint. Notably, this study enabled a priori identification of known pluripotency biomarkers such as SSEA-3, -4, and -5 and Tra-1-60/81, as well as a panel of glycans specifically expressed by hESCs and hiPSCs. PMID- 23345452 TI - Coordinated regulation of synthesis and stability of RNA during the acute TNF induced proinflammatory response. AB - Steady-state gene expression is a coordination of synthesis and decay of RNA through epigenetic regulation, transcription factors, micro RNAs (miRNAs), and RNA-binding proteins. Here, we present bromouride labeling and sequencing (Bru Seq) and bromouridine pulse-chase and sequencing (BruChase-Seq) to assess genome wide changes to RNA synthesis and stability in human fibroblasts at homeostasis and after exposure to the proinflammatory tumor necrosis factor (TNF). The inflammatory response in human cells involves rapid and dramatic changes in gene expression, and the Bru-Seq and BruChase-Seq techniques revealed a coordinated and complex regulation of gene expression both at the transcriptional and posttranscriptional levels. The combinatory analysis of both RNA synthesis and stability using Bru-Seq and BruChase-Seq allows for a much deeper understanding of mechanisms of gene regulation than afforded by the analysis of steady-state total RNA and should be useful in many biological settings. PMID- 23345453 TI - Mushroom phenological changes: a role for resource availability? PMID- 23345454 TI - Clever crows or unbalanced birds? PMID- 23345455 TI - Chemical and metabolomic screens identify novel biomarkers and antidotes for cyanide exposure. AB - Exposure to cyanide causes a spectrum of cardiac, neurological, and metabolic dysfunctions that can be fatal. Improved cyanide antidotes are needed, but the ideal biological pathways to target are not known. To understand better the metabolic effects of cyanide and to discover novel cyanide antidotes, we developed a zebrafish model of cyanide exposure and scaled it for high-throughput chemical screening. In a screen of 3120 small molecules, we discovered 4 novel antidotes that block cyanide toxicity. The most potent antidote was riboflavin. Metabolomic profiling of cyanide-treated zebrafish revealed changes in bile acid and purine metabolism, most notably by an increase in inosine levels. Riboflavin normalizes many of the cyanide-induced neurological and metabolic perturbations in zebrafish. The metabolic effects of cyanide observed in zebrafish were conserved in a rabbit model of cyanide toxicity. Further, humans treated with nitroprusside, a drug that releases nitric oxide and cyanide ions, display increased circulating bile acids and inosine. In summary, riboflavin may be a novel treatment for cyanide toxicity and prophylactic measure during nitroprusside treatment, inosine may serve as a biomarker of cyanide exposure, and metabolites in the bile acid and purine metabolism pathways may shed light on the pathways critical to reversing cyanide toxicity. PMID- 23345456 TI - Perinatal bisphenol A exposure promotes hyperactivity, lean body composition, and hormonal responses across the murine life course. AB - The development of adult-onset diseases is influenced by perinatal exposure to altered environmental conditions. One such exposure, bisphenol A (BPA), has been associated with obesity and diabetes, and consequently labeled an obesogen. Using an isogenic murine model, we examined the effects of perinatal exposure through maternal diet to 50 ng (n=20), 50 MUg (n=21), or 50 mg (n=18) BPA/kg diet, as well as controls (n=20) on offspring energy expenditure, spontaneous activity, and body composition at 3, 6, and 9 mo of age, and hormone levels at 9 and 10 mo of age. Overall, exposed females and males exhibited increased energy expenditure (P<0.001 and 0.001, respectively) throughout the life course. In females, horizontal and vertical activity increased (P=0.07 and 0.06, respectively) throughout the life course. Generally, body composition measures were not different throughout the life course in exposed females or males (all P>0.44), although body fat and weight decreased in exposed females at particular ages (all P<0.08). Milligram-exposed females had improved glucose, insulin, adiponectin, and leptin profiles (all P<0.10). Thus, life-course analysis illustrates that BPA is associated with hyperactive and lean phenotypes. Variability across studies may be attributable to differential exposure duration and timing, dietary fat and phytoestrogen content, or lack of sophisticated phenotyping across the life course. PMID- 23345457 TI - Genome evolution and phylogenomic analysis of Candidatus Kinetoplastibacterium, the betaproteobacterial endosymbionts of Strigomonas and Angomonas. AB - It has been long known that insect-infecting trypanosomatid flagellates from the genera Angomonas and Strigomonas harbor bacterial endosymbionts (Candidatus Kinetoplastibacterium or TPE [trypanosomatid proteobacterial endosymbiont]) that supplement the host metabolism. Based on previous analyses of other bacterial endosymbiont genomes from other lineages, a stereotypical path of genome evolution in such bacteria over the duration of their association with the eukaryotic host has been characterized. In this work, we sequence and analyze the genomes of five TPEs, perform their metabolic reconstruction, do an extensive phylogenomic analyses with all available Betaproteobacteria, and compare the TPEs with their nearest betaproteobacterial relatives. We also identify a number of housekeeping and central metabolism genes that seem to have undergone positive selection. Our genome structure analyses show total synteny among the five TPEs despite millions of years of divergence, and that this lineage follows the common path of genome evolution observed in other endosymbionts of diverse ancestries. As previously suggested by cell biology and biochemistry experiments, Ca. Kinetoplastibacterium spp. preferentially maintain those genes necessary for the biosynthesis of compounds needed by their hosts. We have also shown that metabolic and informational genes related to the cooperation with the host are overrepresented amongst genes shown to be under positive selection. Finally, our phylogenomic analysis shows that, while being in the Alcaligenaceae family of Betaproteobacteria, the closest relatives of these endosymbionts are not in the genus Bordetella as previously reported, but more likely in the Taylorella genus. PMID- 23345460 TI - A cross-platform analysis of 14,177 expression quantitative trait loci derived from lymphoblastoid cell lines. AB - Gene expression levels can be an important link DNA between variation and phenotypic manifestations. Our previous map of global gene expression, based on ~400K single nucleotide polymorphisms (SNPs) and 50K transcripts in 400 sib pairs from the MRCA family panel, has been widely used to interpret the results of genome-wide association studies (GWASs). Here, we more than double the size of our initial data set with expression data on 550 additional individuals from the MRCE family panel using the Illumina whole-genome expression array. We have used new statistical methods for dimension reduction to account for nongenetic effects in estimates of expression levels, and we have also included SNPs imputed from the 1000 Genomes Project. Our methods reduced false-discovery rates and increased the number of expression quantitative trait loci (eQTLs) mapped either locally or at a distance (i.e., in cis or trans) from 1534 in the MRCA data set to 4452 (with <5% FDR). Imputation of 1000 Genomes SNPs further increased the number of eQTLs to 7302. Using the same methods and imputed SNPs in the newly acquired MRCE data set, we identified eQTLs for 9000 genes. The combined results identify strong local and distant effects for transcripts from 14,177 genes. Our eQTL database based on these results is freely available to help define the function of disease-associated variants. PMID- 23345461 TI - Gender differences in diabetes self-management among African American adults. AB - The rising incidence of diabetes complications among African Americans is a major health concern. Few studies have addressed gender differences in diabetes self management in this population. The purpose of this study was to determine whether gender differences in facilitators and barriers to self-management exist among African American adults with type 2 diabetes. Thirty-eight participants were recruited from community agencies and each participated in one of seven audio recorded focus group sessions. Regular health care visits, positive outlook, prioritization of health, and independence facilitated self-management behaviors in men, whereas acceptance of diabetes was a facilitator for women. Lack of time at work, lack of family support, and lack of knowledge were barriers for men, whereas lack of finances, embarrassment, negative outlook, perceived lack of disease control, and adverse effects of medications were barriers for women. Further research is necessary to design and test gender-specific tailored interventions to improve diabetes self-management in this population. PMID- 23345459 TI - Getting leukocytes to the site of inflammation. AB - There is no "response" in either the innate or adaptive immune response unless leukocytes cross blood vessels. They do this through the process of diapedesis, in which the leukocyte moves in ameboid fashion through tightly apposed endothelial borders (paracellular transmigration) and in some cases through the endothelial cell itself (transcellular migration). This review summarizes the steps leading up to diapedesis, then focuses on the molecules and mechanisms responsible for transendothelial migration. Surprisingly, many of the same molecules and mechanisms that regulate paracellular migration also control transcellular migration, including a major role for membrane from the recently described lateral border recycling compartment. A hypothesis that integrates the various known mechanisms of transmigration is proposed. PMID- 23345462 TI - Liver disease as a cause of thrombocytopenia. AB - BACKGROUND: Liver disease is frequently missed as the cause for a patient's thrombocytopenia. AIM: To evaluate the role of liver disease in causing thrombocytopenia within a tertiary hospital. DESIGN: A hospital-based retrospective study. METHODS: Analysis of medical records of outpatients and inpatients with a platelet count <100 * 10(9)/l seen at St Mary's Hospital, London in October 2011, was conducted. Cause for thrombocytopenia was determined in each case and patients with liver disease were analysed further looking at factors associated with their low platelet count. RESULTS: In total, 223 patients were included in this study, 109 of them were outpatients and 114 were inpatients. The mean age was 57.1 years (range 22-106), 64% male and 36% female. Liver disease was the cause for thrombocytopenia in 58% of outpatients. Overall, 92 patients with liver disease were identified; cirrhosis and/or splenomegaly were present in 78%, a further 8% were on interferon therapy. Thrombocytopenia was not explained by the extent of liver disease in 8%, significantly more in hepatitis C than other causes of liver disease (P < 0.05). Factors correlating with low platelet count in patients with liver disease were spleen size (P < 0.05) and serum bilirubin (P < 0.001). There were none, or mild abnormalities only in liver function tests in 19 patients with liver disease-associated thrombocytopenia. CONCLUSION: Liver disease should be considered in all patients with an unknown cause of thrombocytopenia. Advanced liver disease does not have to be present for thrombocytopenia to develop. All patients with unexplained thrombocytopenia should be evaluated to see if liver disease is present, even when liver function tests are normal. PMID- 23345463 TI - Cerebral tuberculoma. PMID- 23345464 TI - Disseminated tuberculosis presenting as rapidly progressive dementia. PMID- 23345465 TI - A hook in the esophagus. PMID- 23345466 TI - Treatment of progressive multifocal leukoencephalopathy. PMID- 23345467 TI - Primary hypothyroidism masquerading as hepatocellular necrosis. PMID- 23345468 TI - Acute kidney injury: outcomes and quality of care. AB - BACKGROUND: Deficiencies in management have been highlighted as contributory factors in the death of many patients with acute kidney injury (AKI). However, there is little evidence addressing the quality of care provided to patients with milder AKI. AIM: The aim of this study is to evaluate the quality of care provided to a non-select cohort of patients with AKI and evaluate discrepancies in causation, recognition and management. DESIGN: Retrospective inception cohort study. METHODS: Demographic data were collected for all 1577 patients admitted to a University Teaching Hospital during a 1-month period. Baseline, admission and peak creatinine were correlated with mortality and length of hospital admission. AKI was classified according to Kidney Disease Improving Global Outcomes criteria. A retrospective case note review of all patients with AKI was carried out to evaluate quality of documentation and clinical management of AKI. Multivariate analysis was undertaken to determine risk factors for AKI. RESULTS: Incidence of AKI on admission was 4.6%. A further 10.3% developed AKI while in hospital. All cause mortality was 4-fold higher among patients with AKI compared with those without (19 vs. 3.8%; P < 0.001). Mortality was significantly higher in those patients who developed AKI while an in-patient compared with those with AKI on admission (27.3 vs. 11.8%; P < 0.001). Diabetes, clinician perception of frailty, age and treatment with angiotensin-converting enzyme inhibitor prior to admission were found to be independent risk factors for AKI. AKI was unrecognized in 23.5% of patients, two-thirds of whom were discharged without resolution of renal function. Significant weaknesses in management were poorly kept fluid balance charts (48.2%), failure to withhold nephrotoxic drugs (38.8%) and failure to act upon abnormal biochemistry (41%) in a timely fashion. CONCLUSION: AKI is common in hospitalized patients and associated with a significant increase in hospital stay and mortality. AKI is often found in conjunction with other organ failure and in many cases is not preventable. Nevertheless clinicians need to be more vigilant of small creatinine rises to permit early intervention particularly among elderly and frail patients. PMID- 23345469 TI - Iatrogenic tracheal stenosis presenting as persistent asthma. AB - Although the incidence of post-intubation tracheal stenosis has markedly decreased with the advent of large volume, low pressure endotracheal tube cuffs, it still occurs, commonly in patients after prolonged intubation. We report a case of tracheal stenosis that developed after a brief period of endotracheal intubation, and that was misdiagnosed and treated as asthma and panic attacks. PMID- 23345470 TI - Bronchoscopic lung volume reduction for pulmonary emphysema: preliminary experience with endobronchial occluder. AB - OBJECTIVE: To describe the self-expanding endobronchial occluder, as utilized in bronchoscopic lung volume reduction, with a 36 month follow-up procedure. METHODS: Twenty-three subjects with severe emphysema were recruited and underwent flexible bronchoscopic placement of self-expanding endobronchial occluders. Outcomes were assessed at 1 week, 1-month, 3-, 6-, 12-, 24-, and 36-month intervals. Feasibility, safety, and efficacy were analyzed by means of pulmonary function testing, 6-min walk test, dyspnea score, BODE (body mass index, air-flow obstruction, dyspnea, and exercise capacity) index, and St George's Respiratory Questionnaire. RESULTS: Fifty-eight self-expanding endobronchial occluders were implanted into 23 lobes previously selected. No displacement was found during the follow-up. Five subjects experienced postoperative complications of cough, and 6 subjects had lobar pneumonia, which were not located in any of the blocked segments. The FEV1 in 18 subjects was improved by > 15%, compared with baselines (P < .001), and the mean first efficacy time and maximal efficacy time were 5.65 +/- 1.51 months and 6.35 +/- 3.08 months, respectively. No significant changes were observed in FVC or the ratio of residual volume to TLC. The 6-min walk distance, dyspnea score, and St George's Respiratory Questionnaire total score were improved in 22 subjects over a 24-month period, and a minority of subjects continued to improve through to the end of the study. Mean baseline BODE index had improved during follow-up, but not at the study's conclusion. CONCLUSIONS: This preliminary study demonstrates early significant improvements in pulmonary function, 6-min walk distance, dyspnea score, BODE index, and quality of life after placement of the self-expanding endobronchial occluder in bronchoscopic lung volume reduction. Its placement also proved both easy and safe. However, the initial improvements were maintained long-term for only a minority of subjects. PMID- 23345472 TI - Symptomatic sclerosing haemangioma: a rare case of solitary pulmonary nodule in a young girl. AB - Sclerosing haemangioma (SH) is a rare benign lung tumour with distinctive variety of histological patterns. SH typically presents as asymptomatic peripheral, solitary well-circumscribed lesion in women with median age at diagnosis in the fifth decade. Preoperative diagnosis of this tumour is difficult, and sometimes even intraoperative frozen sections cannot differentiate it from malignant tumours. Here, we present our experiences in investigating its characteristics. We report a case of a 19-year-old girl who presented with chest pain, cough and sputum and off and on haemoptysis for 6 months. Anti-tubercular treatment was given but provided no relief. CT chest showed a well-defined hypodense solid mass lesion with a soft tissue alternation. Lobectomy was performed. Microscopy revealed a tumour comprising of two distinct populations of cells surface and stromal cells which disposed in papillary, solid, sclerotic and haemorrhagic growth patterns. Histology and immunohistochemistry confirmed the diagnosis of SH of the lung. PMID- 23345471 TI - Effects of inhaled corticosteroids on pneumonia severity and antimicrobial resistance. AB - BACKGROUND: Limited information is available regarding the impact of prior use of inhaled corticosteroids (ICS) in patients subsequently developing community acquired pneumonia (CAP). We assessed the effects of prior ICS use on severity of illness and microbiology in CAP hospitalized patients. METHODS: A retrospective cohort study of subjects with CAP (by the International Classification of Diseases, 9th Revision, Clinical Modification) was conducted over a 4-year period at 2 tertiary teaching hospitals. Subjects were considered to be ICS users if they received ICS prior to admission. Primary outcomes were severity of illness and microbiology at admission. RESULTS: Data were abstracted on 664 subjects: 89 prior ICS users (13.4%) and 575 non-users (86.6%). Prior ICS users had higher severity of illness at admission: mean +/- SD Pneumonia Severity Index 100.8 +/- 31.4 vs 68.8 +/- 33.4, P = .001, and CURB-65 (confusion, urea nitrogen, respiratory rate, blood pressure, >= 65 years of age) score 1.56 +/- 1.02 vs 1.19 +/- 1.02, P = .002. Prior ICS use was independently associated with antimicrobial resistant pathogens: 11.2% vs 5.9%, odds ratio 2.6, 95% CI 1.1-6.1, P = .04. CONCLUSIONS: Prior ICS use was associated with higher severity of illness at admission and higher incidence of antimicrobial-resistant pathogens in CAP hospitalized patients. PMID- 23345473 TI - Successful rechallenge with clozapine following 'red alert'. AB - A case is presented of a 23-year-old lady with treatment-resistant schizoaffective disorder who had responded well to treatment with clozapine. Fifteen months after satisfactory use of clozapine she had 'red alerts' from routine haematological monitoring indicating neutropenia. Clozapine was discontinued and she was admitted to the psychiatric hospital to manage the aftermath of discontinuing clozapine and start alternative treatment with other antipsychotics. Her mental health rapidly deteriorated. Adequate trials with amisulpride, haloperidol, olanzapine and flupenthixol decanoate yielded little improvement in her clinical state. After 9 months of non-response to other antipsychotic medications, she was rechallenged with clozapine, followed by improvement in her mental state. She was eventually discharged home after 14 months of hospitalisation in a stable mental state. She remained mentally stable in the community on clozapine for 18 months after rechallenge, with no further red alerts. PMID- 23345474 TI - Osteogenesis imperfecta and congenital diaphragmatic hernia. AB - Osteogenesis imperfecta and congenital diaphragmatic hernia are both conditions that can occur due to genetic mutation. We present the first case to be reported of a child with both osteogenesis imperfecta and congenital diaphragmatic hernias, showing that the incidence of this presentation may be more than chance. PMID- 23345475 TI - An unexpected CT finding in a patient with abdominal pain. AB - A fit and well 16-year-old girl presented to the emergency department with signs and symptoms suggestive of appendicitis. A transabdominal ultrasound scan revealed a normal appendix but there was significant free fluid in the pelvis. Consequently, a CT scan of her abdomen was performed which showed mucosal oedema and inflammation involving virtually the entire length of her large bowel (the 'accordion sign'). Clostridium difficile colitis was thus suspected; however, the toxin was not detected in her stool. The patient was treated conservatively with intravenous fluids and antibiotics and had an uneventful recovery. She was subsequently discharged home 3 days later with a full recovery. In this case, the radiological appearance of the accordion sign which is traditionally known to be pathognomonic of pseudomembranous colitis, reveals that it may also be indicative of severe colonic luminal inflammation. PMID- 23345476 TI - A foreign body masquerading as a tumour. AB - A 29-year-old man presented to his local orthopaedic service with a mass in the medial aspect of his left thigh, present for 1 year. It had not changed in size, although he complained of increasing tightness in the region. He denied any systemic symptoms or history of local trauma. Extensive imaging performed at his local hospital was thought suggestive of a musculoskeletal tumour. The patient was referred to our tertiary centre musculoskeletal tumour clinic. Review of external imaging and further investigations revealed a fluid-filled intramuscular mass containing an echogenic focus consistent with foreign body. Ultrasound guided aspiration yielded fluid which grew Staphylococcus aureus. Only when presented with this information did the patient vaguely recall sitting on a wooden kebab stick 30 months previously. At surgery, a thick-walled abscess with a central foreign body was identified and drained. At follow-up 1 month later, he was well with no recurrent problems. PMID- 23345477 TI - Three cases of septic arthritis following a recent arthroscopic procedure. AB - We report three cases of septic arthritis in patients who presented with a painful, swollen and supurative knee joint following a recent arthroscopic procedure, 8-15 days prior to attendance. In all three cases, patients presented with pain and swelling of the affected knee joint with discharge from the port sites. All were sent for washout of the affected joint and received intravenous antibiotic cover. Any patient presenting within 1 month of a recent arthroscopic procedure with pain and swelling of that joint should be presumed to have septic arthritis until proven otherwise. They must have urgent treatment in the form of joint washout and intravenous antibiotics, and receive 6 weeks oral antibiotics on discharge. PMID- 23345479 TI - NGS identifies TAZ mutation in a family with X-linked dilated cardiomyopathy. AB - We reported a family with two male siblings affected with infantile dilated cardiomyopathy (DCM). Extensive evaluation failed to identify the underlying cause for the DCM. Next generation sequencing (NGS) with targeted enrichment identified a hemizygous variant c.718G>C (p.Gly240Arg) in the TAZ gene. This variant has been reported in three other families with X linked infantile DCM and is therefore likely pathogenic. NGS allows efficient screening of a large number of uncommon genes in complex disorders like DCM, in which there is substantial genetic and phenotypic heterogeneity. The identification of TAZ mutation has major impact on their medical care as the surveillance needs to be expanded to cover for the Barth syndrome, a severe metabolic phenotype also caused by TAZ mutation, in addition to DCM. PMID- 23345478 TI - Rituximab seems a promising therapeutic option in granulomatosis with polyangiitis with intestinal perforation: a case report and literature review. AB - Granulomatosis with polyangiitis (Wegener's) (GPA) is a chronic disease of unknown aetiology that leads to necrotising vasculitis in small and medium-sized vessels characterised by respiratory system and kidney involvement. Intestinal involvement is rare and perforation is even rarer in GPA. In this study, we are presenting a literature review of related cases, and a 29-year-old man referred from the emergency department with a multiple distal ileal perforation that was diagnosed with GPA, and successfully treated with rituximab. PMID- 23345480 TI - Two cross-linked porcine dermal implants in a single patient undergoing hernia repair. AB - A 50-year-old woman with a history of multiple recurrent incisional hernias and multiple comorbidities received two different porcine dermal implants during the same procedure due to the availability of products in stock. At 3.5 months following this procedure, the patient developed a secondary hernia inferior and lateral to the site of previous surgery. Both the implants were biopsied and sent for pathological evaluation. One implant was compliant and well integrated while the other was non-compliant and exhibited extensive foreign body reaction. In this case report, we examine the differences between the two porcine implants that may have caused them to react so differently in the same subject under the same conditions. PMID- 23345481 TI - Atypical presentation of Lemierre syndrome: role of imaging. AB - A 51-year-old male patient presented with breathlessness for 10 days. Chest radiograph revealed bilateral moderate pleural effusion. Ultrasound-guided diagnostic pleural aspirate revealed sterile transudative fluid. CT thorax revealed bilateral moderate pleural effusion with partial collapse of both lower lobes and thrombus in right brachiocephalic vein. Two-dimensional-echo revealed circumferential pericardial effusion with mild pericardial thickening and moderate tricuspid regurgitation. Cardiolipin antibodies were within normal limits. d-Dimer assay and C reactive protein were markedly raised. During the period of investigations, the patient had developed mild swelling and pain in right upper limb for which colour Doppler ultrasonography of his right upper limb and neck regions were done. Thrombi in right internal jugular, subclavian and brachiocephalic veins were noted. CT angiography, CT abdomen and chest confirmed the above findings. However, extent of the thrombus and lung lesions was better delineated by CT angiography. We have highlighted the pathognomonic imaging findings of Lemierre syndrome. PMID- 23345482 TI - An instant rare complication: a fractured metallic pyloric stent. AB - Metallic pyloric stenting (also termed as metallic enteral stenting) performed endoscopically, stands as first-line treatment for malignant gastric outlet obstruction. With reported evidence, these self-expandable metallic stents (SEMS) re-enable oral food intake, preventing patients having to face invasive techniques such as surgical gastroenterostomy. We report a patient having received a covered pyloric SEMS insertion following a tumour growth causing stenosis in the gastric antropyloric region. After 3 weeks, the patient presented with a fracture of the pyloric SEMS, a rare complication, resulting in a second pyloric SEMS insertion. PMID- 23345483 TI - Late-occurring coil migration into the duodenum. PMID- 23345484 TI - Salmonella sternoclavicular osteomyelitis in a patient with Crohn's disease. AB - We describe a 73-year-old man with Crohn's disease and previous sternotomies, who developed Salmonella sternoclavicular osteomyelitis subsequent to a Salmonella enteritidis sepsis and closed fracture of his clavicle. We include evidence from several cases related to sternoclavicular osteomyelitis, and Salmonella osteomyelitis. We continue by summarising the aetologies of these diseases, and risk factors that predispose to them. PMID- 23345485 TI - Road traffic accidents: more than just whiplash? AB - Following a minor road traffic accident (RTA) a 55-year-old woman developed a new onset of whole body tremor and abnormal gait. This was in the context of significant previous depressive episodes and a traumatic background relating to RTAs. After extensive investigation, no organic causes were identified. The patient was subsequently referred to psychiatry and diagnosed with conversion disorder. Subsequently, various treatments including mirtazepine, venlafaxine, clonazepam, diazepam and lithium have been tried. Currently, the patient remains on mirtazepine 15 mg nocte, diazepam 2 mg twice daily, venlafaxine 225 mg and recently has been started on lithium 400 mg nocte. The patient has also been seen regularly by a psychologist for mindfulness therapy. There has been a significant improvement after seven sessions of mindfulness therapy and the patient has long periods without a tremor and is now able to walk normally. In addition, this case highlights the importance of communication skills with our patients in diagnostic uncertainty. PMID- 23345486 TI - Plantaris rupture: why is it important? AB - Plantaris muscle is accessory plantar flexor of calf, a vestigial muscle of triceps surae complex. Its importance lies in the fact that its rupture cans mimic deep vein thrombosis (DVT). Sometimes when there is rupture of Achilles tendon, intact plantaris can still cause plantar flexion at ankle presenting a confusing picture. We present one such case of plantaris rupture confused by radiology resident with DVT. A 51-year-old man had a feeling as if kicked in back of calf along with a snapping sound and severe pain while playing tennis. On seeing fluid between muscle plane and a hypoechoic structure radiology resident labelled it DVT. MRI suggested ruptured plantaris as fluid and muscle stump were seen between gastronemius and soleus. Patient was treated conservatively with rest, ice compression and elevated leg and showed significant reduction in pain and swelling. PMID- 23345487 TI - Duodenal adenocarcinoma masked by acute cholecystitis and peptic ulcer disease. AB - We report a case of duodenal adenocarcinoma, who presented to the emergency ward, with features of acute cholecystitis and peptic ulcer disease. Ultrasonography and upper gastrointestinal (GI) endoscopy failed to pick up duodenal pathology, previously two times. Only third time endoscopy showed circumferential thickening of first and second part of the duodenum. On diagnosis laparoscopy mass at the D1/2 junction with apparent involvement of head of pancreas was noted. Pancreatoduodenectomy was performed. Histopathological examination showed it to be primary duodenal adenocarcinoma with extension in to head of pancreas. His postoperative course was uneventful. After 4-month follow-up the patient remained well. PMID- 23345488 TI - Gitelman or Bartter type 3 syndrome? A case of distal convoluted tubulopathy caused by CLCNKB gene mutation. AB - A 32-year-old woman with no significant medical history was sent to our consultation due to hypokalaemia (<3.0 mmol/l). Her main complaints were longstanding polyuria and nocturia. Physical examination was normal. Basic investigations showed normal renal function, low serum potassium (2.7 mmol/l) and magnesium (0.79 mmol/l), metabolic alkalosis (pH 7.54; bicarbonate 32.5 mmol/l), elevated urinary potassium (185 mmol/24 h) and normal urinary calcium (246 mg/24 h). Thiazide test revealed blunted response. Chronic vomiting and the abuse of diuretics were excluded. Genetic tests for SLC12A3 gene mutation described in Gitelman syndrome (GS) came negative. CLCNKB gene mutation analysis present in both GS and Bartter (BS) type 3 syndromes was positive. The patient is now being treated with potassium and magnesium oral supplements, ramipril and spironolactone with stable near-normal potassium and magnesium levels. This article presents the case of a patient with hypokalaemia caused by CLCNKB gene mutation hard to categorise as GS or BS type 3. PMID- 23345489 TI - Acute exacerbation of restless legs due to cervical spinal cord ischaemia. AB - We present a 60-year-old male patient with an acute exacerbation of restless legs due to cervical spinal cord ischaemia. This case supports the hypothesis that interruption of spinal cord pathways are part of the aetiology of restless legs syndrome. PMID- 23345490 TI - Clozapine-induced ischaemic colitis. AB - Ischaemic colitis is a rare side effect of antipsychotics, especially phenothiazines and atypical antipsychotics. The colitis may be precipitated secondary to the anticholinergic effects of such medication rather than a direct cytotoxic effect of the drugs themselves. A 32-year-old man with a history of schizophrenia was admitted to the hospital with a history of diffuse abdominal pain and vomiting. His bloods showed leucocytosis. Sigmoidoscopy demonstrated rectal sparing acute colitis, confirmed on biopsy findings. A CT scan also showed similar findings. After careful drug review, it was decided that clozapine was the cause of colitis and promptly stopped. The patient was managed conservatively on intravenous fluids and antibiotics and made a full recovery. Any patient starting antipsychotics should be counselled on their anticholinergic side effects. Drugs should always be considered as a cause of ischaemic colitis; although an uncommon complication of antipsychotics, it can have a potentially fatal outcome. PMID- 23345491 TI - Illustrative cases of false positive biopsies after stereotactic body radiation therapy for lung cancer based on abnormal FDG-PET-CT imaging. AB - Stereotactic body radiation therapy (SBRT) for early stage lung cancer has made significant strides as an alternative to surgery.1 We present two cases of non small cell lung cancer treated with SBRT and then followed serially with imaging in which suspicion of recurrence led to biopsies. PMID- 23345492 TI - Contiguous haemangioblastomas of the brain and spine in a patient of Von Hippel Lindau disease. AB - Von Hippel-Lindau (VHL) disease is an inherited, autosomal-dominant syndrome caused by heterozygous germline mutations in the VHL gene, and predisposing to the development of benign and malignant tumours and cysts in multiple organ systems involving eyes, kidneys, pancreas, liver and central nervous system. The responsible tumour suppressor gene for VHL disease is in chromosome 3p25. We are presenting a case of a patient with both cerebellar as well as spinal haemangioblastoma in addition to polycystic pancreas. We operated on both the spinal and the cerebellar haemangioblastomas and the patient had made a very good recovery. We present this case for its rarity along with the literature review. PMID- 23345493 TI - Prosthodontic management of an albinism patient-dental implications and management. AB - Albinism is a congenital hypopigmentary disorder. Albinism is due to the dysfunction of the melanin-producing cells (melanocytes) resulting in defective production of melanin from tyrosine through a complex pathway of metabolic reactions. Little is known about the varied dental features that albinism presents with. This case report summarises the features encountered in albinism, the different oral findings available in the literature and also presents a case of an albinism patient treated with fixed partial denture and the precautions to be exercised for such patients. PMID- 23345494 TI - Pseudohypoparathyroidism: a rare but important cause of hypocalcaemia. AB - We present a 46-year-old Caucasian lady with symptomatic hypocalcaemia. Investigations revealed markedly raised parathyroid hormone (PTH) levels with vitamin D deficiency. A number of conditions causing secondary hyperparathyroidism were ruled out from her medical history and initial investigations. The main differential diagnoses were vitamin D deficiency and PTH resistance (pseudohypoparathyroidism, PHP). With high-normal serum phosphate and normal alkaline phosphatase, and a lack of symptoms associated with osteomalacia, vitamin D deficiency alone was unlikely to be the cause of hypocalcaemia. Given a normal physical appearance, genetic testing was arranged and confirmed the diagnosis of PHP type Ib. She is currently taking activated vitamin D to maintain calcium homeostasis. PTH resistance is the hallmark of PHP, a rare complex genetic disorder, which can be easily missed resulting in potentially serious consequences. PMID- 23345495 TI - Simultaneous hypertensive intracerebral haemorrhages: what are the odds? AB - The simultaneous development of two (or more) spontaneous, hypertensive, non traumatic intraparenchymal cerebral haemorrhages is rare and constitutes less than 5.6% of all hypertensive cerebral haemorrhages. In addition to having a high early mortality, these haemorrhages carry a considerable morbidity figure in patients who survive the event. We report a 68-year-old hypertensive and diabetic woman who presented with a sudden onset of headache, vomiting, and dense right sided weakness. In less than an hour, she became obtunded. An urgent non-contrast CT brain scan revealed two left-sided supratentorial hemispheric haemorrhages; putamenal and thalamic. PMID- 23345496 TI - Cricopharyngeal myotomy for cricopharyngeus stricture in an inclusion body myositis patient with hiatus hernia: a learning experience. AB - Inclusion body myositis is a chronic progressive myopathy which tends not to respond to steroids and immunosuppressive treatments. Dysphagia is more common in this group than other inflammatory myopathies like polymyositis and dermatomyositis. Otolaryngologists are involved in the management of dysphagia in inclusion body myositis. They usually use a combination of cricopharyngeal myotomy, upper oesophageal dilation or botulinum injection to help with the symptoms. Cricopharyngeus myotomy is the preferred treatment in this group and patients tend to be discharged after a short stay in the hospital. However, our experience was completely different from what we expected as a relatively straightforward procedure led to severe morbidity and prolonged hospital admission due to continuous acid reflux and aspiration. We believe that the presence of hiatus hernia led to this problem as the patient's problem resolved completely after her hernia was treated. PMID- 23345497 TI - Old drugs: new complications. AB - This is a case of acute splenic and bilateral renal infarction in a patient with non-small cell lung carcinoma during chemotherapy with gemcitabine and cisplatin. Till date, bilateral renal infarction following gemcitabine and cisplatin has been reported only once in the past. The case that is being reported has had acute splenic and bilateral renal infarct and has not been reported previously. Splenic and renal infarction should be considered in the differential diagnosis of excruciating abdominal pain and backache in a patient on gemcitabine-based and cisplatin-based chemotherapy. PMID- 23345499 TI - Intravesical migration of intrauterine device. PMID- 23345498 TI - Lithium-induced sinus node dysfunction at therapeutic levels. AB - Lithium is used as an antimanic and mood-stabilising drug. It can cause various adverse effects such as nausea, vomiting, polyuria, fine tremors, myocarditis and arrhythmias. We are describing a case of lithium induced sinus-node dysfunction in a patient with serum lithium levels in therapeutic range. PMID- 23345500 TI - Cobb's collar: a rare cause of urinary retention. AB - Cobb's collar is a membranous stricture of the bulbar urethra, often misdiagnosed, potentially leading to acute urinary retention, upper urinary tract dilations, enuresis, infectious diseases, poor streaming and haematuria. A 14 year-old boy with a history of previous hospitalisations came to our attention. A Cobb's collar was diagnosed and successfully managed with a videoendoscopic one step approach. Although extremely uncommon, paediatric urologists must be aware of this congenital anomaly. A correct and timely diagnosis and endoscopic management may affect positively the clinical onset of these patients avoiding major urethral surgery and preserving renal and bladder function. PMID- 23345501 TI - Pseudomembranous colitis due to Clostridium difficile as a cause of perineal necrotising fasciitis. AB - Although rare, pseudomembranous colitis may be a cause of perineal necrotising fasciitis in a context of immunosuppression, as in the case we report. This origin must be quickly identified because the therapeutic management, especially surgery, is unlikely to be the same as usual. Similarly, antibiotic treatment is also a matter of discussion due to the potential deleterious role of antibiotics in pseudomembranous colitis. PMID- 23345502 TI - Pleural tuberculosis following lung cancer chemotherapy: a report of two cases proven pathologically by pleural biopsy. AB - Malignancy per se and cytotoxic chemotherapy given for its treatment both are recognised risk factors for the development of tuberculosis (TB). However, individual case descriptions of pleural tuberculosis (TB-PE) following chemotherapy for lung cancer (LC) have not been published previously. We herein report the first two cases of histopathologically proven TB-PE following LC chemotherapy. The first patient was a 38-year-old man with stage IV non-small cell LC (adenocarcinoma) who developed TB-PE following four cycles of chemotherapy (pemetrexed-cisplatin). The second patient was a 49-year-old man with extensive disease small cell LC who developed TB-PE after six cycles of chemotherapy (irinotecan-cisplatin). In both patients, diagnosis of TB-PE was established by demonstration of granulomatous inflammation, caseous necrosis and positive stain for acid-fast bacilli in pleural biopsy specimens. Both cases responded to standard four-drug antitubercular therapy. These cases highlight the importance of carrying out an extensive evaluation for exudative pleural effusions in LC patients receiving chemotherapy, especially in countries with high TB prevalence. Attributing such pleural effusions to disease progression, without histopathological confirmation, may be associated with disastrous consequences. PMID- 23345503 TI - Massive pulmonary embolism and thrombophilia. AB - A 32-year-old man presented overnight to the accident and emergency unit with mild breathlessness on exertion. He was found to be hypoxic on room air and his chest x-ray revealed areas of patchy lung consolidation. He was given intravenous antibiotics for presumed community-acquired pneumonia. Unfortunately his condition deteriorated and he remained significantly hypoxic despite high-flow oxygen with ECG evidence of right heart strain. Further questioning revealed a history of protein S deficiency and a strong family history of venous thromboembolic disease. An urgent CT pulmonary angiogram showed an evidence of massive pulmonary embolism and the patient was successfully thrombolysed. PMID- 23345504 TI - Bilateral taurodontism in primary dentition with hypodontia. AB - Taurodontism is a rare dental anomaly in which there is an enlarged pulp chamber at the expense of roots with apical displacement of the pulpal floor, giving it a rectangular shape. It is caused by the failure of Hertwig's epithelial root sheath to invaginate at the proper horizontal level. Taurodontism has been reported as an intraoral feature of several syndromes like Down syndrome, Klinefelter syndrome, Smith-Magenis syndrome, Hurler syndrome, etc. Association of taurodontism with hypodontia in permanent dentition has also been reported. Taurodontism in primary dentition and its association with hypodontia is very rarely reported in the literature. The present case illustrates bilateral taurodontism of primary mandibular molars with hypodontia in maxilla. PMID- 23345505 TI - An overlooked cause of back pain and stiffness. PMID- 23345506 TI - Getting rid of MPO-ANCA: a matter of disease subtype. PMID- 23345507 TI - One size does not fit all. PMID- 23345508 TI - Diversity of ubiquitin and ISG15 specificity among nairoviruses' viral ovarian tumor domain proteases. AB - Nairoviruses are responsible for numerous diseases that affect both humans and animal. Recent work has implicated the viral ovarian tumor domain (vOTU) as a possible nairovirus virulence factor due to its ability to edit ubiquitin (Ub) bound to cellular proteins and, at least in the case of Crimean-Congo hemorrhagic fever virus (CCHFV), to cleave the Ub-like protein interferon-stimulated gene 15 (ISG15), a protein involved in the regulation of host immunity. The prospective roles of vOTUs in immune evasion have generated several questions concerning whether vOTUs act through a preserved specificity for Ub- and ISG15-conjugated proteins and where that specificity may originate. To gain insight into the substrate specificity of vOTUs, enzymological studies were conducted on vOTUs from Dugbe, CCHFV, and Erve nairoviruses. These studies revealed that vOTUs originating from different nairoviruses display a significant divergence in their preference toward Ub and ISG15. In addition, a recently identified vOTU from turnip yellow mosaic tymovirus was evaluated to elucidate any possible similarities between vOTUs originating from different viral families. Although possessing a similar preference for certain polymeric Ub moieties, its activity toward Ub in general was significantly less then those of nairoviruses. Lastly, the X-ray crystallographic structure of the vOTU from the Dugbe nairovirus was obtained in complex with Ub to reveal structural commonalities of vOTUs originating from nairoviruses. The structure suggests that divergences between nairovirus vOTUs specificity originate at the primary structural level. Comparison of this structure to that originating from CCHFV identified key residues that infer the substrate specificity of vOTUs. PMID- 23345509 TI - Prostate-specific antigen-retargeted recombinant newcastle disease virus for prostate cancer virotherapy. AB - Oncolytic virus (OV) therapies of cancer are based on the use of replication competent, tumor-selective viruses with limited toxicity. Newcastle disease virus (NDV), an avian paramyxovirus, is a promising OV and is inherently tumor selective and cytotoxic only to tumor cells. Replication is restricted in normal cells. Despite encouraging phase I/II clinical trials with NDV, further refinements for tumor-specific targeting are needed to enhance its therapeutic index. Systemically delivered NDV fails to reach solid tumors in therapeutic concentrations and also spreads poorly within the tumors due to barriers including complement, innate immunity, and the extracellular matrix. Overcoming these hurdles is paramount to realizing the exceptional oncolytic efficacy of NDV. We engineered the F protein of NDV and generated a recombinant NDV (rNDV) whose F protein is cleavable exclusively by prostate-specific antigen (PSA). The rNDV replicated efficiently and specifically in prostate cancer (CaP) cells and 3 dimensional prostaspheres but failed to replicate in the absence of PSA. Induction of intracellular PSA production by a synthetic androgen analog (R1881) enhanced fusogenicity in androgen-responsive CaP cells. Further, PSA-cleavable rNDV caused specific lysis of androgen-independent and androgen responsive/nonresponsive CaP cells and prostaspheres, with a half-maximal effective concentration (EC50) ranging from a multiplicity of infection of 0.01 to 0.1. PSA-retargeted NDV efficiently lysed prostasphere tumor mimics, suggesting efficacy in vivo. Also, PSA-cleavable NDV failed to replicate in chicken embryos, indicating no pathogenicity for chickens. Prostate-specific antigen targeting is likely to enhance the therapeutic index of rNDV owing to tumor-restricted replication and enhanced fusogenicity. PMID- 23345510 TI - Enhanced autointegration in hyperstable simian immunodeficiency virus capsid mutants blocked after reverse transcription. AB - After entering a host cell, retroviruses such as simian immunodeficiency virus (SIV) uncoat, disassembling the viral capsid. Rates of uncoating that are too high and too low can be detrimental to the efficiency of infection. Rapid uncoating typically leads to blocks in reverse transcription, but the basis for replication defects associated with slow uncoating is less clear. Here we characterize the phenotypes of two SIVmac239 mutants with changes, A87E and A87D, in the helix 4/5 loop of the capsid protein. These mutant viruses exhibited normal capsid morphology but were significantly attenuated for infectivity. The infectivity of wild-type and mutant SIVmac239 was not decreased by aphidicolin induced growth arrest of the target cells. In the cytosol of infected cells, the A87E and A87D capsids remained in particulate form longer than the wild-type SIVmac239 capsid, suggesting that the mutants uncoat more slowly than the wild type capsid. Both mutants exhibited much higher levels of autointegrated DNA forms than wild-type SIVmac239. Thus, some changes in the helix 4/5 loop of the SIVmac239 capsid protein result in capsid hyperstability and an increase in autointegration. PMID- 23345511 TI - Ebola virus exploits a monocyte differentiation program to promote its entry. AB - Antigen-presenting cells (APCs) are critical targets of Ebola virus (EBOV) infection in vivo. However, the susceptibility of monocytes to infection is controversial. Studies indicate productive monocyte infection, and yet monocytes are also reported to be resistant to EBOV GP-mediated entry. In contrast, monocyte-derived macrophages and dendritic cells are permissive for both EBOV entry and replication. Here, freshly isolated monocytes are demonstrated to indeed be refractory to EBOV entry. However, EBOV binds monocytes, and delayed entry occurs during monocyte differentiation. Cultured monocytes spontaneously downregulate the expression of viral entry restriction factors such as interferon inducible transmembrane proteins, while upregulating the expression of critical EBOV entry factors cathepsin B and NPC1. Moreover, these processes are accelerated by EBOV infection. Finally, ectopic expression of NPC1 is sufficient to rescue entry into an undifferentiated, normally nonpermissive monocytic cell line. These results define the molecular basis for infection of APCs and suggest means to limit APC infection. PMID- 23345512 TI - Susceptibility of human iris stromal cells to herpes simplex virus 1 entry. AB - Ocular herpes simplex virus 1 (HSV-1) infection can lead to multiple complications, including iritis, an inflammation of the iris. Here, we use human iris stroma cells as a novel in vitro model to demonstrate HSV-1 entry and the inflammatory mediators that can damage the iris. The upregulated cytokines observed in this study provide a new understanding of the intrinsic immune mechanisms that can contribute to the onset of iritis. PMID- 23345513 TI - Identification of a hydrophobic domain in varicella-zoster virus ORF61 necessary for ORF61 self-interaction, viral replication, and skin pathogenesis. AB - The varicella-zoster virus (VZV) ORF61 protein is necessary for normal replication in vitro and virulence in human skin xenografts in the severe combined immunodeficiency mouse model in vivo. These experiments identify a hydrophobic domain that mediates ORF61 self-interaction. While not needed to inhibit host cell defenses, disruption of this domain (residues 250 to 320) severely impairs VZV growth, transactivation of the immediate early 63 and glycoprotein E genes, and the pathogenesis of VZV skin infection in vivo. PMID- 23345514 TI - Identification of a role for the trans-Golgi network in human papillomavirus 16 pseudovirus infection. AB - Human papillomavirus 16 (HPV16) enters its host cells by a process that most closely resembles macropinocytosis. Uncoating occurs during passage through the endosomal compartment, and the low pH encountered in this environment is essential for infection. Furin cleavage of the minor capsid protein, L2, and cyclophilin B-mediated separation of L2 and the viral genome from the major capsid protein, L1, are necessary for escape from the late endosome (LE). Following this exodus, L2 and the genome are found colocalized at the ND10 nuclear subdomain, which is essential for efficient pseudogenome expression. However, the route by which L2 and the genome traverse the intervening cytoplasm between these two subcellular compartments has not been determined. This study extends our understanding of this phase in PV entry in demonstrating the involvement of the Golgi complex. With confocal microscopic analyses involving 5 ethynyl-2'-deoxyuridine (EdU)-labeled pseudogenomes and antibodies to virion and cellular proteins, we found that the viral pseudogenome and L2 travel to the trans-Golgi network (TGN) following exit from the LE, while L1 is retained. This transit is dependent upon furin cleavage of L2 and can be prevented pharmacologically with either brefeldin A or golgicide A, inhibitors of anterograde and retrograde Golgi trafficking. Additionally, Rab9a and Rab7b were determined to be mediators of this transit, as expression of dominant negative versions of these proteins, but not Rab7a, significantly inhibited HPV16 pseudovirus infection. PMID- 23345515 TI - In vitro modeling of human bocavirus 1 infection of polarized primary human airway epithelia. AB - Human bocavirus 1 (HBoV1) is an emerging human-pathogenic respiratory virus. We characterized two important features of HBoV1 infection in polarized primary human airway epithelia (HAE). Apical HBoV1 infection of HAE at a low multiplicity of infection causes disruption of the tight junction barrier, loss of cilia, and epithelial cell hypertrophy, which are hallmarks of the airway epithelial damage caused by HBoV1 infection. HBoV1 also infects HAE from the basolateral surface productively, although less efficiently, and this also leads to the characteristic airway epithelial damage. PMID- 23345516 TI - The HIV-1 gp120 major variable regions modulate cold inactivation. AB - HIV-1 entry involves the viral envelope glycoproteins (Env gps) and receptors on the target cell. Receptor binding channels the intrinsic high potential energy of Env into the force required to fuse the membranes of virus and target cell. For some HIV-1 strains, prolonged incubation on ice decreases Env potential energy and results in functional inactivation. By characterizing chimeras between two primary clade C HIV-1 strains that differ in sensitivities to cold, soluble CD4, and neutralizing antibodies, we found that these properties were largely determined by discrete elements within the gp120 variable regions V1V2 and V3. PMID- 23345517 TI - Activity and mechanism of action of HDVD, a novel pyrimidine nucleoside derivative with high levels of selectivity and potency against gammaherpesviruses. AB - A novel nucleoside analogue, 1-[(2S,4S-2-(hydroxymethyl)-1,3-dioxolan-4-yl]5 vinylpyrimidine-2,4(1H,3H)-dione, or HDVD, was evaluated against a wide variety of herpesviruses and was found to be a highly selective inhibitor of replication of the gammaherpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). HDVD had also a pronounced inhibitory activity against murine herpesvirus 68 (MHV-68) and herpes simplex virus 1 (HSV-1). In contrast, replication of herpesvirus saimiri (HVS), HSV-2, and varicella-zoster virus (VZV) was weakly inhibited by the compound, and no antiviral activity was determined against human cytomegalovirus (HCMV) and rhesus rhadinovirus (RRV). The HDVD resistant virus phenotype contained point mutations in the viral thymidine kinase (TK) of HSV-1, MHV-68, and HVS isolates. These mutations conferred cross resistance to other TK-dependent drugs, with the exception of an MHV-68 mutant (E358D) that exhibited resistance only to HDVD. HSV-1 and HVS TK-mutants isolated under selective pressure with bromovinyldeoxyuridine (BVDU) also showed reduced sensitivity to HDVD. Oral treatment with HDVD and BVDU was assessed in an intranasal model of MHV-68 infection in BALB/c mice. In contrast to BVDU treatment, HDVD-treated animals showed a reduction in viral DNA loads and diminished viral gene expression during acute viral replication in the lungs in comparison to levels in untreated controls. The valyl ester prodrug of HDVD (USS 02-71-44) suppressed the latent infection in the spleen to a greater extent than HDVD. In the present study, HDVD emerged as a highly potent antiviral with a unique spectrum of activity against herpesviruses, in particular, gammaherpesviruses, and may be of interest in the treatment of virus-associated diseases. PMID- 23345518 TI - Characteristics of viruses derived from nude mice with persistent measles virus infection. AB - Measles virus (MV) isolates from patients with subacute sclerosing panencephalitis (SSPE) differ from wild-type MV virologically. However, few animal models have reported viruses with characteristics of the SSPE virus. The MV Edmonston strain was inoculated into the subarachnoid space of nude mice. All nude mice displayed weight loss and required euthanasia, with a mean survival duration of 73.2 days. The viral load in the brain was 4- to 400-fold higher than the inoculated load, and brain infection was confirmed by immunostaining. Gene sequencing of the viruses revealed that amino acid mutations occurred more frequently in matrix proteins. The most common mutation was a uridine-to-cytosine transition. The virus exhibited lower free virus particle formation ability than the Edmonston strain. When nude mice were challenged with 2 * 10(2) PFU of the brain-derived virus, the mean survival duration was 34.7 days, which was significantly shorter than that of the mice challenged with 4 * 10(4) PFU of the Edmonston strain (P < 0.01). This study indicated that MV in a nude mouse model of persistent infection exhibited characteristics of the SSPE virus. This model may prove useful in elucidating the pathogenic mechanism of SSPE and developing potential therapeutics. PMID- 23345519 TI - Trivalent live attenuated influenza-simian immunodeficiency virus vaccines: efficacy and evolution of cytotoxic T lymphocyte escape in macaques. AB - There is an urgent need for a human immunodeficiency virus (HIV) vaccine that induces robust mucosal immunity. CD8(+) cytotoxic T lymphocytes (CTLs) apply substantial antiviral pressure, but CTLs to individual epitopes select for immune escape variants in both HIV in humans and SIV in macaques. Inducing multiple simian immunodeficiency virus (SIV)-specific CTLs may assist in controlling viremia. We vaccinated 10 Mane-A1*08401(+) female pigtail macaques with recombinant influenza viruses expressing three Mane-A1*08401-restricted SIV specific CTL epitopes and subsequently challenged the animals, along with five controls, intravaginally with SIV(mac251). Seroconversion to the influenza virus vector resulted and small, but detectable, SIV-specific CTL responses were induced. There was a boost in CTL responses after challenge but no protection from high-level viremia or CD4 depletion was observed. All three CTL epitopes underwent a coordinated pattern of immune escape during early SIV infection. CTL escape was more rapid in the vaccinees than in the controls at the more dominant CTL epitopes. Although CTL escape can incur a "fitness" cost to the virus, a putative compensatory mutation 20 amino acids upstream from an immunodominant Gag CTL epitope also evolved soon after the primary CTL escape mutation. We conclude that vaccines based only on CTL epitopes will likely be undermined by rapid evolution of both CTL escape and compensatory mutations. More potent and possibly broader immune responses may be required to protect pigtail macaques from SIV. PMID- 23345520 TI - Enterovirus 71 infection cleaves a negative regulator for viral internal ribosomal entry site-driven translation. AB - Far-upstream element-binding protein 2 (FBP2) is an internal ribosomal entry site (IRES) trans-acting factor (ITAF) that negatively regulates enterovirus 71 (EV71) translation. This study shows that EV71 infection cleaved FBP2. Live EV71 and the EV71 replicon (but not UV-inactivated virus particles) induced FBP2 cleavage, suggesting that viral replication results in FBP2 cleavage. The results also showed that virus-induced proteasome, autophagy, and caspase activity co contribute to EV71-induced FBP2 cleavage. Using FLAG-fused FBP2, we mapped the potential cleavage fragments of FBP2 in infected cells. We also found that FBP2 altered its function when its carboxyl terminus was cleaved. This study presents a mechanism for virus-induced cellular events to cleave a negative regulator for viral IRES-driven translation. PMID- 23345521 TI - Identification of common mechanisms by which human and mouse cytomegalovirus seven-transmembrane receptor homologues contribute to in vivo phenotypes in a mouse model. AB - The mouse cytomegalovirus chemokine receptor homologue (CKR) M33 is required for salivary gland tropism and efficient reactivation from latency, phenotypes partially rescued by the human cytomegalovirus CKR US28. Herein, we demonstrate that complementation of salivary gland tropism is mediated predominantly by G protein-dependent signaling conserved with that of M33; in contrast, both G protein-dependent and -independent pathways contribute to the latency phenotypes. A novel M33-dependent replication phenotype in cultured bone marrow macrophages is also described. PMID- 23345522 TI - The orchestrated functions of innate leukocytes and T cell subsets contribute to humoral immunity, virus control, and recovery from secondary poxvirus challenge. AB - A pivotal role for antigen-specific recall responses to secondary virus infection is well established, but the contribution of innate immune cells to this process is unknown. Recovery of mice from a primary orthopoxvirus (ectromelia virus [ECTV]) infection requires the function of natural killer (NK) cells, granulocytes, plasmacytoid dendritic cells (pDC), T cells, and B cells. However, during a secondary challenge, resolution of infection is thought to be dependent on antibody but not T cell function. We investigated the contribution of NK cells, granulocytes, and pDC to virus control during a secondary virus challenge in mice that had been primed with an avirulent, mutant strain of ECTV. Mice depleted of NK cells, granulocytes, or pDC effectively controlled virus, as did mice depleted of both CD4 and CD8 T cell subsets. However, mice concurrently depleted of all three innate cell subsets had elevated virus load, but this was significantly exacerbated in mice also depleted of CD4 and/or CD8 T cells. Increased viral replication in mice lacking innate cells plus CD4 T cells was associated with a significant reduction in neutralizing antibody. Importantly, in addition to T-dependent neutralizing antibody responses, the function of CD8 T cells was also clearly important for virus control. The data indicate that in the absence of innate cell subsets, a critical role for both CD4 and CD8 T cells becomes apparent and, conversely, in the absence of T cell subsets, innate immune cells help contain infection. PMID- 23345523 TI - Promotion of Hendra virus replication by microRNA 146a. AB - Hendra virus is a highly pathogenic zoonotic paramyxovirus in the genus Henipavirus. Thirty-nine outbreaks of Hendra virus have been reported since its initial identification in Queensland, Australia, resulting in seven human infections and four fatalities. Little is known about cellular host factors impacting Hendra virus replication. In this work, we demonstrate that Hendra virus makes use of a microRNA (miRNA) designated miR-146a, an NF-kappaB responsive miRNA upregulated by several innate immune ligands, to favor its replication. miR-146a is elevated in the blood of ferrets and horses infected with Hendra virus and is upregulated by Hendra virus in human cells in vitro. Blocking miR-146a reduces Hendra virus replication in vitro, suggesting a role for this miRNA in Hendra virus replication. In silico analysis of miR-146a targets identified ring finger protein (RNF)11, a member of the A20 ubiquitin editing complex that negatively regulates NF-kappaB activity, as a novel component of Hendra virus replication. RNA interference-mediated silencing of RNF11 promotes Hendra virus replication in vitro, suggesting that increased NF kappaB activity aids Hendra virus replication. Furthermore, overexpression of the IkappaB superrepressor inhibits Hendra virus replication. These studies are the first to demonstrate a host miRNA response to Hendra virus infection and suggest an important role for host miRNAs in Hendra virus disease. PMID- 23345525 TI - Doing the "talk": disclosure of a diagnosis of cerebral palsy. AB - The disclosure to a family of a child's cerebral palsy is an important transformative event that has potential lasting implications. This article highlights specific challenges, the results of research into the disclosure process and what attributes should be sought for in this encounter by health care providers. Illustrative case vignettes are presented to concretely demonstrate the "dos and don'ts" of the disclosure. Suggestions will also be provided to improve the disclosure process. PMID- 23345524 TI - Rearrangements within human spliceosomes captured after exon ligation. AB - In spliceosomes, dynamic RNA/RNA and RNA/protein interactions position the pre mRNA substrate for the two chemical steps of splicing. Not all of these interactions have been characterized, in part because it has not been possible to arrest the complex at clearly defined states relative to chemistry. Previously, it was shown in yeast that the DEAD/H-box protein Prp22 requires an extended 3' exon to promote mRNA release from the spliceosome following second-step chemistry. In line with that observation, we find that shortening the 3' exon blocks cleaved lariat intron and mRNA release in human splicing extracts, which allowed us to stall human spliceosomes in a new post-catalytic complex (P complex). In comparison to C complex, which is blocked at a point following first step chemistry, we detect specific differences in RNA substrate interactions near the splice sites. These differences include extended protection across the exon junction and changes in protein crosslinks to specific sites in the 5' and 3' exons. Using selective reaction monitoring (SRM) mass spectrometry, we quantitatively compared P and C complex proteins and observed enrichment of SF3b components and loss of the putative RNA-dependent ATPase DHX35. Electron microscopy revealed similar structural features for both complexes. Notably, additional density is present when complexes are chemically fixed, which reconciles our results with previously reported C complex structures. Our ability to compare human spliceosomes before and after second-step chemistry has opened a new window to rearrangements near the active site of spliceosomes, which may play roles in exon ligation and mRNA release. PMID- 23345526 TI - Dominantly inherited nonprogressive cerebellar hypoplasia identified in utero: a note of doubt. PMID- 23345527 TI - Dominantly inherited nonprogressive cerebellar hypoplasia identified in utero: no doubt. PMID- 23345530 TI - Tricuspid valve thrombus causing acute pulmonary embolism. AB - The development of thrombus on the tricuspid valve is very rare in adulthood and it needs special attention in clinical practice as it can be confused with vegetation or a tumour. Embolisation due to thrombus may have an acute and unexpected course with a detrimental prognosis and a high death rate during the first 24 h after diagnosis. In this report, we presented a case of mobile tricuspid valve thrombus detected by transthoracic echocardiography that led to recurrent pulmonary embolism. PMID- 23345531 TI - Fever of unknown origin, with a twist. AB - The authors present a case of an 81-year-old man with fever of unknown origin. The case report is illustrated with the images which clarified the diagnosis in this challenging case. The cardiac MR images were of critical importance in arriving at a diagnosis of aortic root mycotic pseudoaneurysm with rupture into the right ventricle. PMID- 23345532 TI - Marcus Gunn jaw winking synkinesis: report of two cases. AB - Marcus Gunn jaw winking synkinesis (MGJWS) is caused by congenital miswiring of a branch of the fifth cranial nerve into the branch of the third cranial nerve supplying the levator muscle. It has been observed in 2-13% of patients with congenital ptosis. Although bilateral cases were reported, most were unilateral and occurred more frequently on the left side than the right. We report two cases of children who presented with ptosis and were diagnosed with MGJWS. PMID- 23345533 TI - Synovial osteochondroma originating from the synovium of the anterior cruciate ligament. AB - Primary synovial osteochondromatosis is a rarely seen disorder of the synovium in any joints. Among reported cases of knee osteochondromatosis, those originating from the anterior cruciate ligament (ACL) are very rare. We report an unusual case of primary synovial osteochondromatosis. A 27-year-old woman complained of a restricted range of right-knee motion and pain when walking. With locking symptoms similar to those associated with a meniscus bucket handle tear. Although plain radiograph and MRI showed normal appearance, diagnostic arthroscopy revealed the curious appearance of a huge mass seated on ACL. In addition, the sign of proliferation of synovium and cartilaginous tissues were apparent. The ACL mass has been removed while preserving the ACL fibres. Histological examination confirmed a diagnosis of osteochondromatosis. To the best of our knowledge, this is the first report to describe synovial osteochondromatosis originating from ACL fibres and has been resected while preserving the ACL. PMID- 23345534 TI - Rapid evolution of troglomorphic characters suggests selection rather than neutral mutation as a driver of eye reduction in cave crabs. AB - This study asked whether reductive traits in cave organisms evolve at a slower pace (suggesting neutral evolution under relaxed selection) than constructive changes, which are likely to evolve under directional selection. We investigated 11 subterranean and seven surface populations of Sundathelphusa freshwater crabs on Bohol Island, Philippines, and examined constructive traits associated with improved food finding in darkness (increased leg and setae length) and reductive traits (reduced cornea size and eyestalk length). All changes occurred rapidly, given that the age of the most recent common ancestor was estimated to be 722-271 ka based on three mitochondrial markers. In order to quantify the speed of character change, we correlated the degree of morphological change with genetic distances between surface and subterranean individuals. The temporal pattern of character change following the transition to subterranean life was indistinguishable for constructive and reductive traits, characterized by an immediate onset and rapid evolutionary change. We propose that the evolution of these reductive traits-just like constructive traits-is most likely driven by strong directional selection. PMID- 23345535 TI - beta-catenin is required in odontoblasts for tooth root formation. AB - The tooth root is an important part of the tooth that works together with the surrounding periodontium to maintain the tooth in the alveolar socket. The root develops after crown morphogenesis. While the molecular and cellular mechanisms of early tooth development and crown morphogenesis have been extensively studied, little is known about the molecular mechanisms controlling tooth root formation. Here, we show that beta-catenin is strongly expressed in odontoblast-lineage cells and is required for root formation. Tissue-specific inactivation of beta catenin in developing odontoblasts produced molars lacking roots and aberrantly thin incisors. At the beginning of root formation in the mutant molars, the cervical loop epithelium extended apically to form Hertwig's epithelial root sheath (HERS), but root odontoblast differentiation was disrupted and followed by the loss of some HERS inner layer cells. However, the outer layer of the HERS extended without the root, and the mutant molars finally erupted. The periodontal tissues extensively invaded the dental pulp. These results indicate that there is a cell-autonomous requirement for Wnt/beta-catenin signaling in the dental mesenchyme for root formation. PMID- 23345536 TI - Tooth eruption without roots. AB - Root development and tooth eruption are very important topics in dentistry. However, they remain among the less-studied and -understood subjects. Root development accompanies rapid tooth eruption, but roots are required for the movement of teeth into the oral cavity. It has been shown that the dental follicle and bone remodeling are essential for tooth eruption. So far, only limited genes have been associated with root formation and tooth eruption. This may be due to the difficulties in studying late stages of tooth development and tooth movement and the lack of good model systems. Transgenic mice with eruption problems and short or no roots can be used as a powerful model for further deciphering of the cellular, molecular, and genetic mechanisms underlying root formation and tooth eruption. Better understanding of these processes can provide hints on delivering more efficient dental therapies in the future. PMID- 23345537 TI - Proteomic profiling of Mycobacterium tuberculosis identifies nutrient-starvation responsive toxin-antitoxin systems. AB - In order to successfully enter the latent stage, Mycobacterium tuberculosis must adapt to conditions such as nutrient limitation and hypoxia. In vitro models that mimic latent infection are valuable tools for describing the changes in metabolism that occur when the bacterium exists in a non-growing form. We used two complementary proteomic approaches, label-free LC-MS/MS analysis and two dimensional difference gel electrophoresis, to determine the proteome profile of extracellular proteins from M. tuberculosis cultured under nutrient starvation. Through the label-free LC-MS/MS analysis of fractionated samples, 1176 proteins were identified from culture filtrates of log phase and nutrient-starved cultures, and the protein levels of 230 proteins were increased in nutrient starved culture filtrates, whereas those of 208 proteins were decreased. By means of Gene Ontology clustering analysis, significant differences in the overall metabolism during nutrient starvation were detected. Notably, members of the toxin-antitoxin systems were present in larger quantities in nutrient-starved cultures, supporting a role for these global modules as M. tuberculosis switches its metabolism into dormancy. Decreased abundance of proteins involved in amino acid and protein synthesis was apparent, as well as changes in the lipid metabolism. Further analysis of the dataset identified increased abundance of lipoproteins and decreased abundance of ESAT-6 family proteins. Results from the two-dimensional difference gel electrophoresis proteomics demonstrated overall agreement with the LC-MS/MS data and added complementary insights about protein degradation and modification. PMID- 23345538 TI - Glycoproteomic analysis of the secretome of human endothelial cells. AB - Previous proteomics studies have partially unraveled the complexity of endothelial protein secretion but have not investigated glycosylation, a key modification of secreted and membrane proteins for cell communication. In this study, human umbilical vein endothelial cells were kept in serum-free medium before activation by phorbol-12-myristate-13 acetate, a commonly used secretagogue that induces exocytosis of endothelial vesicles. In addition to 123 secreted proteins, the secretome was particularly rich in membrane proteins. Glycopeptides were enriched by zwitterionic hydrophilic interaction liquid chromatography resins and were either treated with PNGase F and H2(18)O or directly analyzed using a recently developed workflow combining higher-energy C trap dissociation (HCD) with electron-transfer dissociation (ETD) for a hybrid linear ion trap-orbitrap mass spectrometer. After deglycosylation with PNGase F in the presence of H2(18)O, 123 unique peptides displayed (18)O-deamidation of asparagine, corresponding to 86 proteins with a total of 121 glycosylation sites. Direct glycopeptide analysis via HCD-ETD identified 131 glycopeptides from 59 proteins and 118 glycosylation sites, of which 41 were known, 51 were predicted, and 26 were novel. Two methods were compared: alternating HCD-ETD and HCD-product dependent ETD. The former detected predominantly high-intensity, multiply charged glycopeptides, whereas the latter preferentially selected precursors with complex/hybrid glycans for fragmentation. Validation was performed by means of glycoprotein enrichment and analysis of the input, the flow-through, and the bound fraction. This study represents the most comprehensive characterization of endothelial protein secretion to date and demonstrates the potential of new HCD ETD workflows for determining the glycosylation status of complex biological samples. PMID- 23345539 TI - Urinary angiostatin--a novel putative marker of renal pathology chronicity in lupus nephritis. AB - There is a critical need to identify biomarkers for Systemic Lupus Erythematosus (SLE) which has a high prevalence of renal failure. When urine from patients with lupus nephritis was recently screened for the levels of ~280 molecules using an exploratory array-based proteomic platform, elevated angiostatin levels were noted. Angiostatin is a bioactive fragment of plasminogen, and has been known to have modulatory function in angiogenesis and inflammation. The significant elevation in urinary angiostatin was next validated in an independent cohort of SLE patients (n = 100) using ELISA. Among patients with SLE, urine angiostatin was significantly increased in active SLE compared with inactive SLE, correlating well with the SLEDAI disease activity index and SLICC renal activity score (r = 0.66, p < 0.0001). ROC curve analysis further confirmed that urinary angiostatin had the capacity to discriminate patients with active SLE from those with inactive disease. Patients with Class IV lupus nephritis exhibited the highest levels of urinary angiostatin. Immunohistochemistry staining localized angiostatin expression to the renal tubular cells in these patients. Finally, when paired urine-kidney samples procured concurrently from patients with LN were next examined, urine angiostatin levels correlated strongly with the renal pathology chronicity index, but not with the activity index. Given that Class IV lupus nephritis and renal pathology chronicity changes forebode poor renal and patient survival, urinary angiostatin emerges as a novel noninvasive marker of renal disease in SLE. Longitudinal studies are in progress to further assess the disease-predictive potential of urinary angiostatin. PMID- 23345542 TI - Soft tissue reconstruction of the thumb with the dorsoradial forearm flap. AB - The dorsoradial flap is a recently described cutaneous flap, which is harvested from the distal forearm and indicated for covering dorsal soft tissue defects of the hand and thumb. Vascularization of the flap is assured by a cutaneous branch of the radial artery, which arises at the level of the first intermetacarpal space and supplies the skin of the distal quarter of the forearm dorsum. This area corresponds to the skin island of the dorsoradial flap. We report our clinical experience on seven patients where this flap was used for covering post traumatic defects of the thumb. Dimensions of the defect varied from 18 to 28 cm(2). The donor site was skin grafted. All flaps survived and provided satisfactory coverage of the defect. Based on a secondary vascular axis, the flap has a large skin paddle and a wide rotation arc that allows soft tissue reconstruction of the dorsal and radiopalmar areas of the thumb. PMID- 23345541 TI - Morphological development and cytochrome c oxidase activity in Streptomyces lividans are dependent on the action of a copper bound Sco protein. AB - Copper has an important role in the life cycle of many streptomycetes, stimulating the developmental switch between vegetative mycelium and aerial hyphae concomitant with the production of antibiotics. In streptomycetes, a gene encoding for a putative Sco-like protein has been identified and is part of an operon that contains two other genes predicted to handle cellular copper. We report on the Sco-like protein from Streptomyces lividans (Sco(Sl)) and present a series of experiments that firmly establish a role for Sco(Sl) as a copper metallochaperone as opposed to a role as a thiol-disulphide reductase that has been assigned to other bacterial Sco proteins. Under low copper concentrations, a Deltasco mutant in S. lividans displays two phenotypes; the development switch between vegetative mycelium and aerial hyphae stalls and cytochrome c oxidase (CcO) activity is significantly decreased. At elevated copper levels, the development and CcO activity in the Deltasco mutant are restored to wild-type levels and are thus independent of Sco(Sl). A CcO knockout reveals that morphological development is independent of CcO activity leading us to suggest that Sco(Sl) has at least two targets in S. lividans. We establish that one Sco(Sl) target is the dinuclear Cu(A) domain of CcO and it is the cupric form of Sco(Sl) that is functionally active. The mechanism of cupric ion capture by Sco(Sl) has been investigated, and an important role for a conserved His residue is identified. PMID- 23345540 TI - Plasticity within the alphabeta+CD4+ T-cell lineage: when, how and what for? AB - Following thymic output, alphabeta+CD4+ T cells become activated in the periphery when they encounter peptide-major histocompatibility complex. A combination of cytokine and co-stimulatory signals instructs the differentiation of T cells into various lineages and subsequent expansion and contraction during an appropriate and protective immune response. Our understanding of the events leading to T-cell lineage commitment has been dominated by a single fate model describing the commitment of T cells to one of several helper (T(H)), follicular helper (T(FH)) or regulatory (T(REG)) phenotypes. Although a single lineage-committed and dedicated T cell may best execute a single function, the view of a single fate for T cells has recently been challenged. A relatively new paradigm in alphabeta+CD4+ T-cell biology indicates that T cells are much more flexible than previously appreciated, with the ability to change between helper phenotypes, between helper and follicular helper, or, most extremely, between helper and regulatory functions. In this review, we comprehensively summarize the recent literature identifying when T(H) or T(REG) cell plasticity occurs, provide potential mechanisms of plasticity and ask if T-cell plasticity is beneficial or detrimental to immunity. PMID- 23345543 TI - Lymph node ratio predicts recurrence in papillary thyroid cancer. AB - BACKGROUND: Lymph node metastasis occurs in 20%-50% of patients presenting for initial treatment of papillary thyroid cancer (PTC). The significance of lymph node metastases remains controversial, and the aim of this study is to determine how the lymph node ratio (LNR) may predict the likelihood of disease recurrence. METHODS: We conducted a retrospective review of patients undergoing total thyroidectomy for PTC at our institution from 2005 to 2010. A total LNR (positive nodes to total nodes) and central lymph node ratio (cLNR) was calculated. Regression was used to determine a threshold LNR that best predicted recurrence. Multivariate logistic regression then determined the influence of LNR on recurrence while accounting for other known predictors of recurrence. Kaplan Meier analysis and the log-rank test were used to compare differences in disease free survival. RESULTS: Of the 217 patients undergoing total thyroidectomy for PTC, 69 patients had concomitant neck dissections. Sixteen (23.2%) patients developed disease recurrence. When disease-free survival functions were compared, we found that patients with a total LNR >=0.7 (p < .01) or a cLNR >=0.86 (p = .04) had significantly worse disease-free survival rates than patients with ratios below these threshold values. Considering other known predictors of recurrence, we found that LNR was significantly associated with recurrence (odds ratio: 19.5, 95% confidence interval: 4.1-22.9; p < .01). CONCLUSIONS: Elevated total LNR and cLNR are strongly associated with recurrence of PTC after initial operation. LNR in PTC is a tool that can be used to determine the likelihood of the patient developing recurrent disease and inform postoperative follow-up. PMID- 23345544 TI - Cancer risk for patients using thiazolidinediones for type 2 diabetes: a meta analysis. AB - OBJECTIVE: To clarify and quantify the effect of thiazolidinediones (TZDs; e.g., pioglitazone, rosiglitazone) on the risk of bladder cancer, other selected cancers, and overall cancer in patients with type 2 diabetes, we performed a systematic review and meta-analysis of observational studies. METHODS: A PubMed/MEDLINE search was conducted for studies published in English up to June 30, 2012. Random-effect models were fitted to estimate summary relative risks (RR). RESULTS: Seventeen studies satisfying inclusion criteria (3 case-control studies and 14 cohort studies) were considered. Use of TZDs was not associated to the risk of cancer overall (summary RR: 0.96; 95% confidence interval [CI]: 0.91 1.01). A modest excess risk of bladder cancer was reported in pioglitazone (RR: 1.20; 95% CI: 1.07-1.34 from six studies) but not in rosiglitazone (RR: 1.08; 95% CI: 0.95-1.23 from three studies) users. The RRs of bladder cancer were higher for longer duration (RR: 1.42 for >2 years) and higher cumulative dose of pioglitazone (RR: 1.64 for >28,000 mg). Inverse relations were observed with colorectal cancer (RR: 0.93; 95% CI: 0.90-0.97 from six cohort studies) and liver cancer (RR: 0.65; 95% CI: 0.48-0.89 from four studies), whereas there was no association with pancreatic, lung, breast, and prostate cancers. CONCLUSIONS: Adequate evidence excludes an overall excess cancer risk in TZD users within a few years after starting treatment. However, there is a modest excess risk of bladder cancer, particularly with reference to pioglitazone. Assuming that this association is real, the potential implications on the risk-benefit analysis of TZD use should be evaluated. PMID- 23345545 TI - A patient-centered approach to counseling patients with head and neck cancer undergoing human papillomavirus testing: a clinician's guide. AB - The International Agency for Research on Cancer and the National Cancer Institute have acknowledged human papillomavirus (HPV)-16 as an independent risk factor for oropharyngeal cancer (OPC). HPV-positive oropharyngeal cancer (HPVOPC) is a sexually transmitted entity that is on the rise; within the next 10 years, the annual number of HPV-associated OPC cases is projected to exceed the annual number of cervical cancer cases in the United States. Recognition of HPV status in OPC has broad implications beyond the traditional oncological concerns of timely diagnosis, accurate staging, and appropriate treatment of cancer patients. The National Comprehensive Cancer Network recommends testing the tumor site for HPV-status during OPC management; it is likely this will become a standard component of care for patients with high-probability tumors of the oropharynx. As the practice of HPV testing becomes more common, it behooves providers to be able to adequately address the concerns of patients with HPVOPC. Although there are currently few relevant studies focusing on this population, existing literature on HPV-infected women and patients with cervical cancer strongly supports the concept that patients with HPVOPC need education to optimally address concerns such as self-blame, guilt, intimacy, and interpersonal relationships. When HPV testing is done, it should be accompanied by evidence-driven and patient-centered counseling to best minimize negative psychosocial outcomes and ensure optimum health promotion. Based on the current state of the literature, this article is intended to be a reference for physicians to effectively manage psychosocial outcomes when diagnosing patients with HPV-associated OPC. PMID- 23345546 TI - The role of MET receptor tyrosine kinase in non-small cell lung cancer and clinical development of targeted anti-MET agents. AB - A better understanding of the pathophysiology and evolution of non-small cell lung cancer (NSCLC) has identified a number of molecular targets and spurred development of novel targeted therapeutic agents. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are implicated in tumor cell proliferation, migration, invasion, and angiogenesis in a broad spectrum of human cancers, including NSCLC. Amplification of MET has been reported in approximately 5%-22% of lung tumors with acquired resistance to small-molecule inhibitors of the epidermal growth factor receptor (EGFR). Resistance to EGFR inhibitors is likely mediated through downstream activation of the phosphoinositide 3-kinase /AKT pathway. Simultaneous treatment of resistant tumors with a MET inhibitor plus an EGFR inhibitor can abrogate activation of downstream effectors of cell growth, proliferation, and survival, thereby overcoming acquired resistance to EGFR inhibitors. Development and preclinical testing of multiple agents targeting the HGF-MET pathway, including monoclonal antibodies targeting HGF or the MET receptor and small-molecule inhibitors of the MET tyrosine kinase, have confirmed the crucial role of this pathway in NSCLC. Several agents are now in phase III clinical development for the treatment of NSCLC. This review summarizes the role of MET in the pathophysiology of NSCLC and in acquired resistance to EGFR inhibitors and provides an update on progress in the clinical development of inhibitors of MET for treatment of NSCLC. PMID- 23345547 TI - Treatment of splenic marginal zone lymphoma with rituximab monotherapy: progress report and comparison with splenectomy. AB - BACKGROUND: Treatment of splenic marginal zone lymphoma (SMZL) patients is not standardized. Recent data suggest that rituximab is highly effective and could be considered as initial therapy. AIM: To assess the efficacy of rituximab monotherapy in a large series of patients with SMZL and compare these results with splenectomy results. METHODS: The studied population included 85 patients. Fifty-eight received rituximab at a dose of 375 mg/m2 per week for 6 weeks as induction followed by maintenance at the same dose every 2 months for 1-2 years, whereas 27 patients were treated using splenectomy only. RESULTS: The overall response rate to rituximab 2 months after the end of induction was 95% (complete response [CR], 45%; unconfirmed CR, 26%; partial response, 24%). The median times to hematologic and clinical response were 2 weeks and 3 weeks, respectively. Forty-three of 55 patients already completed the maintenance phase: 28 sustained their initial response, 14 improved their response, and one progressed. Eighty five percent of splenectomized patients responded, and two were treated with rituximab as consolidation after splenectomy and achieved a CR. The 5-year overall and progression-free survival (PFS) rates for rituximab-treated and splenectomized patients were 92% and 77% (p = .09) and 73% and 58% (p = .06), respectively. Furthermore, maintenance therapy with rituximab resulted in a longer duration of response (at 5 years, PFS was 84% for patients receiving maintenance and 36% for patients without maintenance, p <.0001). CONCLUSIONS: Rituximab is a very effective and well-tolerated therapy and may be substituted for splenectomy as the first-line treatment of choice for patients with SMZL. PMID- 23345548 TI - Metabolic adaptation of two pig muscles to cold rearing conditions. AB - Cold environment represents an external stress modulating animal growth and energy use. At muscle level, adaptation to cold conditions potentially involves energy homeostasis regulation gauged by the adenosine monophosphate (AMP) activated protein kinase (AMPK). Our study aimed at evaluating the bare effects of short- and long-term cold exposure on growth performance, carcass traits, and metabolic characteristics of the oxidative semispinalis (SS) muscle and glycolytic LM and to evaluate the reversibility of short-term effects, with a special emphasis on AMPK activity. A total of 84 pigs fed ad libitum and individually housed were submitted after weaning to either Cold (from 23 +/- 1 to 15 +/- 3 degrees C) or thermoneutral (T; from 28 +/- 1 to 23 +/- 1 degrees C) temperature up to 24.7 +/- 1.6 kg BW (25 BW). Twelve Cold and 12 T piglets were then slaughtered the same day. Eighteen remaining Cold piglets were reared at 12 +/- 2 degrees C (CC) whereas 18 Cold and 24 T piglets were reared at 23 +/- 4 degrees C (CT and TT, respectively) and slaughtered at 114.3 +/- 5.9 kg (115 BW). The LM and SS samples were analyzed to determine glycolytic potential (GP), activities of lactate dehydrogenase (LDH), citrate synthase (CS), and beta hydroxy-acyl-CoA dehydrogenase (HAD) and to quantify AMPK phosphorylation Threonine 172 phosphorylated form of AMPK alpha1+alpha2 isoforms (pAMPK) / total AMPK alpha1+alpha2 isoforms (AMPK). Despite a greater ADFI (P < 0.001), Cold piglets exhibited less ADG (P < 0.001) and body fatness (P < 0.03) attesting an acute adaptation to a short-term cold exposure. A long-term cold adaptation evaluated on 115 BW pigs increased ADFI (P < 0.001) but did not influence ADG and carcass lean meat content. Cold environment influenced the dynamic of muscle metabolism in a muscle type dependent manner corresponding to an earlier and acute adaptation in SS from 8 kg onward and a belated adaptation in LM from 25 BW to 115 BW. Cold exposure was associated with a progressive increase of muscle oxidative capacity, first in the SS with greater HAD (P = 0.002) and CS activities (P = 0.03) at 25 BW and then both in SS and LM at 115 BW (P < 0.001). Conversely, in LM of CC pigs, increased GP (P < 0.001) and LDH activity (P = 0.03) were observed in addition to increased CS and HAD activities, highlighting the ability of LM to increase both its glycolytic and oxidative metabolism and to diversify its energy substrates. Pigs from CC group exhibited also less pAMPK/AMPK (P < 0.01) specifically in red SS muscle, denoting a reduced metabolic stress of this muscle after a long-term cold adaptation. PMID- 23345549 TI - Effect of zilpaterol hydrochloride on feedlot performance, nutrient intake, and digestibility in hair-breed sheep. AB - Twelve Dorper * Pelibuey wether lambs (26.8 +/- 1.6 kg initial BW, 5 mo of age) were used to evaluate effects of zilpaterol hydrochloride (ZH) on feedlot performance, and effects of ZH and ZH supplementation period (15 and 30 d) on nutrient intake and digestibility. Lambs were blocked by initial BW, and assigned randomly within BW blocks to 1 of 2 treatments: i) control (no ZH), and ii) supplemented with ZH (10 mg ZH/wether lamb daily). Measurements of intake and digestibility were performed on d 9 to 15 and 24 to 30. Feedlot performance data were analyzed as a randomized complete block design, and nutrient intake and digestibility data were analyzed as a randomized complete block design with a 2 * 2 factorial arrangement of treatments. Final BW, ADG, total BW gain, and G:F were greater (P <= 0.04) for ZH than for control lambs. No treatment * feeding duration interaction for nutrient intake and apparent total tract digestibility were observed (P > 0.05). Intake of DM, OM, CP, and GE were less (P <= 0.03) for ZH than for control. Lambs fed for 30 d had greater (P <= 0.04) NDF and GE intake compared with those fed for 15 d. Total tract digestibility of DM, OM, CP, EE, and ADF (P <= 0.03) was less for ZH than control. Furthermore, calculated DE, ME, and TDN intake decreased (P < 0.01) with ZH supplementation. Also, DM, CP, and ether extract(EE) digestibility were greater (P < 0.01) for 30 d than for 15 d. Additionally, greater (P <= 0.01) DE, ME, and TDN intake was observed for 30 d compared with 15 d. In conclusion, ZH supplementation of wether lambs consuming feedlot diets resulted in improved feedlot performance and reduced the intake and digestibility of some nutrients. PMID- 23345550 TI - Accuracies of direct genomic breeding values in Hereford beef cattle using national or international training populations. AB - The objective of this study was to estimate accuracies of direct genomic breeding values (DGV) for nationally evaluated traits of 1,081 American (AMH), 100 Argentine (ARH), 75 Canadian (CAH), and 395 Uruguayan (URH) Hereford animals genotyped using the Illumina BovineSNP50 BeadChip. Deregressed EBV (DEBV) were used as observations in a weighted analysis to derive DGV using BayesB and BayesC methods. The AMH animals were clustered into 4 groups, using either K-means or random clustering. Cross validation was performed with the group not used in training providing validation of the accuracies of estimated DGV. Genomic predictions were also evaluated for AMH animals by training on older animals and validating on younger animals. Bivariate animal models were used for each trait to estimate genetic correlations between DEBV and DGV. Genomic predictions were separately evaluated for foreign animals from each country using marker estimates from training on AMH or pooled international data. Pedigree estimated breeding values were developed for AMH animals, using traditional, pedigree-based BLUP (PBLUP) for comparison purposes. Using BayesB (BayesC) method, the average simple correlations between DGV and DEBV in AMH animals was 0.24 (0.21), 0.39 (0.36), and 0.32 (0.30) when training and validation sets were formed by K-means clustering, random allocation or year of birth of the animals, respectively. Genetic correlations between DEBV and DGV ranged from 0.20 (0.18) to 0.52 (0.45) in AMH animals. The DGV from BayesB were more accurate than from BayesC for most traits in AMH animals. Genomic predictions for foreign animals were less accurate than those obtained in AMH animals. Among foreign animals, genomic predictions were more accurate for CAH animals, which reflect the greater use of AMH sires in CAH in comparison with ARH and URH populations. Small changes in accuracies of DGV were observed for foreign animals by using admixed training populations. On average, genomic predictions across countries were more accurate for CAH and URH animals using BayesB. On average, accuracies of genomic predictions using BayesB (BayesC) method were 66% (55%) greater than those obtained from PBLUP. These results demonstrate the feasibility of developing DGV for American Hereford beef cattle. However, foreign breeders, especially South American Hereford breeders, need to genotype more animals to obtain more accurate genomic predictions. PMID- 23345551 TI - Weaning management of newly received beef calves with or without continuous exposure to a persistently infected bovine viral diarrhea virus pen mate: effects on rectal temperature and serum proinflammatory cytokine and haptoglobin concentrations. AB - Exposure to animals persistently infected (PI) with bovine viral diarrhea virus (BVDV) results in immunomodulation in cohorts. It is hypothesized that the extent of modulation differs for low-risk, preconditioned (PC) vs. high-risk, auction market (AM) beef cattle. Our objective was to compare immune responses of PC or AM calves in the presence (PI) or absence (CON) of a PI-BVDV pen mate. Crossbred PC steers (n = 27) from a single ranch origin were weaned, dewormed, vaccinated against respiratory and clostridial pathogens, tested for PI-BVDV, and kept on the ranch for 61 d. Subsequently, PC steers were transported to a receiving unit (RU), weighed, stratified by d -1 BW, and assigned randomly to treatment (PCPI or PCCON) with no additional processing. Simultaneously, crossbred AM calves (n = 27) were assembled from regional auction markets and transported to the RU. The AM calves were weighed, stratified by gender and d -1 BW, processed under the same regimen used for PC steers at their origin ranch, except bull calves were castrated, then assigned randomly to treatment (AMPI or AMCON). Treatment pens were arranged spatially so that PI did not have fence line contact with CON. Blood samples were collected on d 0, 1, 3, 7, and 14 to determine serum concentrations of haptoglobin (Hp), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-4, and IL-6. Rectal temperature (RT) was recorded concurrent with blood sampling. In AM calves, RT and Hp increased (management effect; P < 0.001) sharply on d 1; however, exposure to a PI-BVDV pen mate did not affect either variable (P >= 0.79) during the 14-d evaluation period. Serum concentrations of TNF-alpha tended to increase (P = 0.09) for the PI cohort. A treatment * day interaction (P <= 0.05) was observed for IFN-gamma on d 7 and 14 and IL-6 on d 14; these indices were greatest for AMPI. Results indicate weaning management and PI-BVDV exposure alter the immune status of newly received beef cattle. These main effects may be additive because proinflammatory cytokine concentrations were greatest for AMPI. Therefore, results further indicate that potential health or growth consequences in cohorts exposed to a PI BVDV pen mate are impacted by previous management and health history. PMID- 23345552 TI - Relationship between hair fatty acid profile, reproduction, and milk performance in Holstein Friesian cows. AB - The aim of this study was to analyze the relationship between the fatty acid profiles of hair of first parity cows and their reproduction and milk performance. Hair samples from 46 German Holstein cows, 50 to 62 d postpartum, were analyzed to assess the relationship. All cows were fed the same diet. The lipid composition of hair was determined by gas chromatography. The fat content in the hair was 0.86%. Hair lipids contributed 75.14% SFA, 15.81% MUFA, and 9.92% PUFA. Cows were classified into a high and a low performance group according to their a) length of the interval from calving to first insemination (CFI), b) 100 d protein yield (100-d PY), and c) length of the interval from calving to conception (CC) and 100-d PY. Cows with short CFI or high 100-d PY or short CC and high 100-d PY had significantly greater proportions of de novo synthesized C12:0 (P < 0.05) compared with the corresponding low performing groups. Increased proportions of C12:0 in the hair were associated with shorter CFI (r = -0.32, P = 0.033) and greater 100-d PY (r = 0.34, P = 0.021). Furthermore, a discriminant analysis with C12:0 as a variable best predicted short CC and high 100-d PY (error rate 33.5%). Greater proportions of de novo synthesized fatty acids in the hair, in particular C12:0, are likely to reflect a sufficient energy availability that is required for fatty acid synthesis in ruminants. PMID- 23345553 TI - Administration of a GnRH analog on day 9 of a 14-day controlled internal drug release insert with timed artificial insemination in lactating beef cows. AB - Many estrus synchronization protocols aim to induce a new follicular wave to improve response and enhance pregnancy rate. Our objectives were to determine the effectiveness of GnRH analog administered d 0 and 9 during an extended controlled internal drug release (CIDR) protocol to produce 2 follicular waves, induce cyclicity in anestrus cows, and evaluate the efficacy of a single 50-mg dose of PGF2alpha to initiate luteal regression on CIDR removal. Lactating beef cows (n = 779) at 3 locations (n = 247, location 1; n = 395, location 2; n = 137, location 3) were randomly assigned to 1 of 3 treatments. Cows in the 14-d 50 PG treatment received a CIDR (1.38 g progesterone) with 100 MUg GnRH analog intramuscularly (i.m.) on d 0, 100 MUg GnRH analog i.m. on d 9, and CIDR removal concurrent with 50 mg PGF2alpha i.m. on d 14. Cows in the 14-d 6-h PG treatment were assigned the same protocol as the 14-d 50 PG treatment except that 25 mg PGF2alpha i.m. was given on d 14 plus 25 mg PGF2alpha i.m. 6 +/- 1 h later. Cows in the control treatment, 5-d CO-Synch + CIDR (5-d CO-Synch), received a CIDR concurrent with 100 MUg GnRH analog i.m. on d 9, CIDR removal concurrent with 25 mg PGF2alpha i.m. on d 14, and 25 mg PGF2alpha i.m. 6 +/- 1 h after first F2alpha injection. Cows in all treatments received 100 MUg GnRH analog i.m. and timed AI (TAI) 72 +/ 3 h after CIDR removal. Pregnancy status to TAI was determined by ultrasonography 37 to 40 d after TAI. Averaged over all locations, pregnancy rates to TAI for 14-d 50 PG, 14-d 6-h PG, and 5-d CO-Synch treatments were 58.2%, 46.8%, and 41.9%, respectively. Pregnancy rates to TAI were greater (P < 0.05) in 14-d 50 PG treatment than 14-d 6-h PGF2alpha and 5-d CO-Synch treatments. Cycling status at 2 locations (n = 243, location 1; n = 391, location 2) was determined from blood collected on d -7 and 0; cows with serum progesterone concentrations >1 ng/mL at either (or both) bleeding date were considered cyclic. Averaged over the 2 locations, there was a tendency (P = 0.06) for a greater number of cyclic animals to become pregnant to TAI in the 14-d 50 PG treatment (64.4%) than 5-d CO Synch treatment (50.2%). The 14-d CIDR with GnRH analog on d 0 and 9 and a single 50-mg dose of PG i.m. at CIDR removal was a more efficacious protocol to maximize TAI pregnancy rates than the standard 5-d CO-Synch. PMID- 23345554 TI - Differences in exterior conformation between primitive, Half-bred, and Thoroughbred horses: anatomic-breeding approach. AB - The study included 249 horses belonging to 3 horse breeds. Konik horses, comprising the first group, is an example of a breed similar to the extinct Tarpan. In our study, these horses were taken to be a primitive anatomical model of the horse body. The other groups comprised the Polish Half-bred horse and Thoroughbred horse. The biometric characteristics of the horses were compared based on 24 indices. The aim of the paper was to find a reduced set of indices that can be used to determine group membership of the horses. To do this, we used statistical methods to find the most important indices that best discriminate breeds from each other. Chi-squared statistics, linear discriminant analysis, logistic regression, and 1-way ANOVA showed that the discrimination among groups of horses is connected with these 5 indices: scapula, smaller trunk (distance between tubercle of humerus and coxal tuber), greater trunk (distance between tubercle of humerus and ischial tuberosity), metacarpus circumference, and hind autopodium-smaller trunk. Thoroughbred and Half-bred horses are clearly different in exterior conformation from Konik horses. The differences between Thoroughbred and Half-bred horses are more subtle. The conformation of Thoroughbreds is jointly determined by relatively small differences in a range of features. PMID- 23345555 TI - Digestive physiology of the pig symposium: detection of dietary glutamate via gut brain axis. AB - Gustatory and visceral stimulation from food regulates digestion and nutrient use. Free L-glutamate (Glu) release from digested protein is responsible for umami taste perception in the gut. Moreover, monosodium Glu (MSG) is widely used as a flavor enhancer to add umami taste in various cuisines. Recent studies indicate that dietary Glu sensors and their signal transduction system exist in both gut mucosa and taste cells. Oral Glu sensing has been well studied. In this review, we focus on the role of Glu on digestion and absorption of food. Infusion of Glu into the stomach and intestine increase afferent nerve activity of the gastric and the celiac branches of the vagus nerve, respectively. Luminal Glu also evokes efferent nerve activation of the abdominal vagus nerve branches simultaneously. Additionally, intragastric infusion of Glu activates the insular cortex, limbic system, hypothalamus, nucleus tractus solitaries, and amygdala, as determined by functional magnetic resonance imaging, and is able to induce flavor preference learning as a result of postingestive effects in rats. These results indicate that Glu signaling via gustatory and visceral pathways plays an important role in the processes of digestion, absorption, metabolism, and other physiological functions via activation of the brain. PMID- 23345556 TI - Characterization of the effects of Enterococcus faecium on intestinal epithelial transport properties in piglets. AB - Probiotics have been shown to have positive effects on growth performance traits and the health of farm animals. The objective of the study was to examine whether the probiotic strain Enterococcus faecium NCIMB 10415 (E. faecium) changes the absorptive and secretory transport and barrier properties of piglet jejunum in vitro and thereby to verify tendencies observed in a former feeding trial with E. faecium. Further aims were to assess a potential mechanism of probiotics by testing effects of IL-alpha, which is upregulated in the peripheral blood mononuclear cells of E. faecium-supplemented piglets, and to test the hypothesis that IL-1alpha induces a change in ion transport. Sows and their piglets were randomly assigned to a control group and a probiotic group supplemented with E. faecium. The sows received the probiotic supplemented feed from d 28 before parturition and the piglets from d 12 after birth. Piglets were killed at the age of 12 +/- 1, 26 +/- 1, 34 +/- 1, and 54 +/- 1 d. Ussing chamber studies were conducted with isolated mucosae from the mid jejunum. Samples were taken for mRNA expression analysis of sodium-glucose-linked transporter 1 (SGLT1) and cystic fibrosis transmembrane conductance regulator (CFTR). The Na(+)/glucose cotransport was increased in the probiotic group compared with the control group at 26 (P = 0.04) and 54 d of age (P = 0.01). The PGE2-induced short circuit current (Isc) was greater at 54 d of age in the probiotic group compared with the control group (P = 0.03). In addition, effects of age on the absorptive (P < 0.01) and secretory (P < 0.01) capacities were observed. Neither SGLT1 nor CFTR mRNA expression was changed by probiotic supplementation. Mannitol flux rates as a marker of paracellular permeability decreased in both groups with increasing age and were less in the probiotic group at the 26 d of age (P = 0.04), indicating a tighter intestinal barrier. The DeltaIsc induced by IL-1alpha was inhibited by bumetanide (P < 0.01), indicating an induction of Cl(-) secretion. Thus, in this experimental setup, E. faecium increased the absorptive and secretory capacity of jejunal mucosae and enhanced the intestinal barrier. Furthermore, the results indicated that IL-1alpha induces bumetanide-sensitive chloride secretion. The effects of cytokines as potential mediators of probiotic effects should, therefore, be the subject of further studies. PMID- 23345557 TI - Cell Biology Symposium: genetics of feed efficiency in dairy and beef cattle. AB - Increasing food production for the growing human population off a constraining land base will require greater efficiency of production. Genetic improvement of feed efficiency in cattle, which is cumulative and permanent, is one likely vehicle to achieving efficiency gains. The objective of this review is to summarize genetic parameters for feed efficiency traits in dairy and beef cattle and also to address some of the misconceptions associated with feed efficiency in these sectors, as well as discuss the potential use of feed efficiency in breeding programs. A meta-analysis of up to 39 scientific publications in growing cattle clearly showed that genetic variation in feed efficiency exists with a pooled heritability for residual feed intake (RFI) and feed conversion efficiency of 0.33 +/- 0.01 (range of 0.07 to 0.62) and 0.23 +/- 0.01 (range of 0.06 to 0.46), respectively. Heritability estimates for feed efficiency in cows were lower; a meta-analysis of up to 11 estimates revealed heritability estimates for gross feed efficiency and RFI of 0.06 +/- 0.010 and 0.04 +/- 0.008, respectively. Meta-analysis of genetic correlations between feed intake, feed efficiency and other performance traits are presented, and selection index theory is used to calculate the proportion of genetic variation in feed intake that can be explained by easy to measure, and often already collected, data. A large proportion of the genetic variation in feed intake could be explained in both growing animals and lactating animals using up to 5 predictor traits, including BW, growth rate, milk yield, body composition, and linear type traits reflecting body size and muscularity. Knowledge of genetic merit for feed intake can be used, along with estimates of genetic merit for energy sinks, to calculate genetic merit for feed efficiency. Therefore, the marginal benefit of collecting actual feed intake data, using the genetic parameters used in this study, appears to be low. There is now sufficient information available to develop a road map on how best to direct research to ensure long-term food security for a growing human population. Gaps in knowledge are identified here, and possibilities to address these gaps are discussed. PMID- 23345559 TI - Effect of increasing distillers grains inclusion on performance and carcass characteristics of early-weaned steers. AB - Dried distillers grains with solubles (DDGS) contain elevated concentrations of CP, oil, and S, which can negatively impact performance and carcass characteristics in steers weaned at 205 d of age. Early weaned (EW) cattle, however, consume less DM and require increased CP. Furthermore, the energy required to dispose of excess N may actually decrease excessive fat accumulation, which can occur in EW cattle. Thus, we hypothesized that feeding diets with increased concentrations of DDGS to EW steers for the first 99 d would decrease fat thickness and increase harvest weights, and would not inhibit performance or marbling deposition. To test this hypothesis, 90 Angus * Simmental steers (199.7 +/- 12.2 kg) were weaned at 134 d of age (EW) and allotted to 3 high concentrate diets (20% corn silage) containing either 0%, 30%, or 60% DDGS (15.7%, 15.8% and 21.7% CP, respectively). Dietary treatments were fed for 99 d, after which steers were placed on a common diet containing no DDGS (12.9% CP) until harvest at a common weight of 599 kg. Concentration of dietary DDGS did not affect ADG, DMI, or G:F during the growing phase (P > 0.41), did not produce any carryover effects on ADG, DMI, or G:F during the finishing phase (P > 0.26), and resulted in similar overall performance (P > 0.52). Dressing percentage (P < 0.05), HCW (P = 0.06), fat thickness (P = 0.10), and % KPH (P = 0.08) responded quadratically to early DDGS supplementation, increasing from 0 to 30% DDGS inclusion and decreasing from 30 to 60% DDGS inclusion, respectively. Marbling score was not affected (P > 0.46) by DDGS inclusion, but there was a tendency (P = 0.08) for the ratio of subcutaneous (SC) to intramuscular (IM) fat to be altered by DDGS inclusion. The ratio of IM to SC fat decreased from 0 to 30% DDGS inclusion and increased from 30 to 60% DDGS inclusion. These data suggest that inclusion of increased concentrations of dietary DDGS early in the feedlot phase does not negatively impact growth and performance of EW cattle, but does partition energy from carcass to noncarcass components. However, increased concentrations of DDGS did not negatively impact IM fat deposition. Utilization of energy for disposal of excess N may be responsible for changes in carcass weight and SC fat deposition. PMID- 23345558 TI - Digestive physiology of the pig symposium: involvement of gut chemosensing in the regulation of mucosal barrier function and defense mechanisms. AB - Meal ingestion is followed by release of numerous hormones from enteroendocrine cells interspersed among the epithelial cells lining the intestine. Recently, the de-orphanization of G protein-coupled receptor (GPCR)-type nutrient receptors, expressed on the apical membranes of enteroendocrine cells, has suggested a plausible mechanism whereby luminal nutrients trigger the release of gut hormones. Activation of nutrient receptors triggers intracellular signaling mechanisms that promote exocytosis of hormone-containing granules into the submucosal space. Hormones released by foregut enteroendocrine cells include the glucagon-like peptides (GLP) affecting glycemic control (GLP-1) and releasing pro proliferative, hypertrophy-inducing growth factors (GLP-2). The foregut mucosa, being exposed to pulses of concentrated HCl, is protected by a system of defense mechanisms, which includes epithelial bicarbonate and mucus secretion and augmentation of mucosal blood flow. We have reported that luminal co-perfusion of AA with nucleotides in anesthetized rats releases GLP-2 into the portal vein, associated with increased bicarbonate and mucus secretion and mucosal blood flow. The GLP-2 increases bicarbonate secretion via release of vasoactive intestinal peptide (VIP) from myenteric nerves. Luminal bile acids also release gut hormones due to activation of the bile-acid receptor known as G Protein-Coupled Receptor (GPR) 131, G Protein Bile Acid Receptor (GPBAR) 1, or Takeda G Protein-Coupled Receptor (TGR) 5, also expressed on enteroendocrine cells. The GLP are metabolized by dipeptidyl peptidase IV (DPPIV), an enzyme of particular interest to pharmaceutical, because its inhibition increases plasma concentrations of GLP 1 to treat diabetes. We have also reported that DPPIV inhibition enhances the secretory effects of nutrient-evoked GLP-2. Understanding the release mechanism and the metabolic pathways of gut hormones is of potential utility to the formulation of feedstuff additives that, by increasing nutrient absorption due to increased mucosal mass, can increase yields. PMID- 23345560 TI - Triennial Reproduction Symposium: the obstacle course to successful establishment of pregnancy in domestic livestock species. AB - The 2012 Triennial Reproduction Symposium (TRS), "Impediments to Fertility in Domestic Animals," was held immediately before the Joint Annual Meeting of the American Society of Animal Science, American Dairy Science Association, Canadian Society of Animal Science, Western Section of the American Society of Animal Science, and the Asociacion Mexicana de Produccion Animal in Phoenix, AZ, in July, 2012. The theme of the symposium highlighted key impediments or opportunities in the process of creating a pregnancy, beginning with male and female gametes and ending with a viable fetus. The 2012 TRS was designed to focus on areas of current and exciting investigation across a variety of species and to include 8 presentations from a mix of established and early-career scientists. The TRS was also the venue for presentation of the 2012 L. E. Casida Award for Graduate Education; the recipient was R. D. Randel (Texas A&M University). The symposium provided an excellent opportunity for reproductive biologists to consider the broad spectrum of factors that limit fertility in domestic species and contemplate the current status of knowledge relative to several of the significant obstacles to pregnancy. PMID- 23345561 TI - Rumen morphometrics and the effect of digesta pH and volume on volatile fatty acid absorption. AB - The effects of rumen digesta volume and pH on VFA absorption and its relation to rumen wall morphology were evaluated. Nine rumen cannulated cows formed 3 groups based on desired variation in rumen morphology: The High group was formed by Holsteins yielding 25.9 kg milk/d and fed on a high-grain total mixed ration (TMR); the Medium group by Holstein-Zebu crossbreds yielding 12.3 kg milk/d and fed on corn silage, tropical pasture, and a commercial concentrate; and the Dry group by nonlactating grazing Jerseys fed exclusively on tropical pasture. Within each group, a sequence of 3 ruminal conditions was induced on each cow in 3 * 3 Latin Squares, with 7-d periods: high digesta volume and high pH (HVHP), low volume and high pH (LVHP), and low volume and low pH (LVLP). Rumen mucosa was biopsied on the first day of Period 1. Ruminal morphometric variables evaluated were mitotic index, absorptive surface and papillae number per square centimeter of wall, area per papillae, papillae area as a percentage of absorptive surface, and epithelium, keratinized layer, and nonkeratinized layer thickness. There was marked variation in rumen morphology among the groups of cows. Grazing Jerseys had decreased rumen wall absorptive surface area and basal cells mitotic index, and increased thickness of the epithelium and of the keratin layer compared with cows receiving concentrates. Mean rumen pH throughout the 4 h sampling period was: 6.78 for HVHP, 7.08 for LVHP, and 5.90 for LVLP (P < 0.01). The capacity of the rumen wall to absorb VFA was estimated by the Valerate/CrEDTA technique. The fractional exponential decay rate for the ratio of valeric acid to Cr (k Val/Cr) was determined by rumen digesta sampling at 20-min intervals during 4 h, after the mixing of markers and the return of the evacuated ruminal content. The k Val/Cr values for treatments HVHP, LVHP, and LVLP were, respectively: 19.6, 23.9, and 35.0 %/h (SEM = 2.01; P = 0.21 for contrast HVHP vs. LVHP and P < 0.01 for contrast LVHP vs. LVLP). The k Val/Cr was faster under low pH, but decreasing digesta volume under high pH did not elicit such a response. The correlation between the absorptive surface area per square centimeter of rumen wall and the mean of the 3 k Val/Cr values of each cow was 0.90 (P < 0.01). Cows capable of maintaining a less-acidic rumen environment had greater inflow of water into the digestive cavity, had a more developed rumen mucosa, and were more efficient VFA absorbers. PMID- 23345562 TI - Brazilian beef cattle feedlot manure management: a country survey. AB - No information regarding the management of manure from beef cattle feedlots is available for Brazil. To fill this knowledge gap, a survey of 73 feedlots was conducted in 7 Brazilian states. In this survey, questions were asked regarding animal characteristics, their diets, and manure handling management from generation to disposal. These feedlots finished 831,450 animals in 2010. The predominant breed fed was Nellore, with average feeding periods of 60 to 135 d. Corn was the primary source of grain used in the feedlot diets (76% of surveyed animals) with concentrate inclusion levels ranging from 81 to 90% (38% of surveyed animals). The most representative manure management practice was the removal of manure from pens only at the end of the feeding period. Subsequently, the manure was stored in mounds before being applied to crop and pasture lands. Runoff, mainly from rainwater, was collected in retention ponds and used for agriculture. However, the quantity of runoff was not known. Manure was composted for only 20% of the animals in the survey and was treated in anaerobic digesters for only 1% of the animals. Manure from 59% of the cattle surveyed was used as fertilizer, providing a cost savings over the use of synthetic fertilizers. Overall, chemical analysis of the manure before application to fields was conducted for the manure of 56% of the surveyed animals, but the exact quantity applied (per hectare) was unknown for 48%. Feedlots representing 48% of the surveyed animals noted similar or greater crop and pasture yields when using manure, rather than synthetic fertilizers. In addition, 32% mentioned an increase in soil organic matter. Feedlots representing 88% of the surveyed cattle indicated that information concerning management practices that improve manure use efficiency is lacking. Feedlots representing 93% of the animals in the survey reported having basic information regarding the generation of energy and fertilizer with anaerobic digesters. However, only 1 feedlot implemented this technology. In conclusion, the manure management evaluated in this study represents an important indirect economic benefit that was represented by decreased use of synthetic fertilizers in crops. However, little attention was given to the specific treatments and environmental impacts of handling manure. This survey provides information that should assist in the development of better research practices and broader application of future models. PMID- 23345563 TI - Effects of vaccination on the acute-phase protein response and measures of performance in growing beef calves. AB - Two experiments were conducted to evaluate the influence of vaccination on the acute-phase protein (APP) reaction (Exp. 1 and 2) and measures of performance (Exp. 2) in growing beef calves. In Exp. 1, the APP reaction was assessed in newly weaned steers administered 1 of 3 treatments (n = 8 steers/treatment), consisting of 1) Mannheimia haemolytica vaccine (One Shot; Pfizer Inc., New York, NY), 2) Clostridium vaccine (UltraBac 7; Pfizer, Inc.), or 3) saline-injected control. Blood samples for the evaluation of APP concentrations were collected on d 0, 1, 3, 5, 7, 10, and 14 and steer BW measured on d 0 and 21 relative to treatment administration. Plasma concentrations of haptoglobin (Hp) increased (P < 0.05) in vaccinated but not control calves and reached a peak on d 3 and 5 for steers receiving Mannheimia haemolytica and Clostridium vaccine, respectively. Plasma concentrations of ceruloplasmin (Cp) and fibrinogen (Fb) increased (P < 0.05) in all calves after treatment administration and Fb concentrations were greatest (P < 0.01) in calves receiving Mannheimia haemolytica vaccine on d 3 and 5 compared with the other treatments. There were no treatment effects (P = 0.44) on 21-d steer ADG (0.43 kg/d; SEM = 0.082). In Exp. 2, 23 heifers were randomly assigned to 2 treatments: 1) vaccinated (Mannheimia haemolytica vaccine (One Shot; n = 12) and 2) saline control (n = 11). After vaccination, blood samples were collected for determination of APP concentrations on d 0, 3, 6, 9, 12, and 15. During this period, individual heifer DMI was measured using an automated feed intake measuring system (Model 4000E; GrowSafe Systems Ltd., Airdrie, Alberta, Canada). Initial and final shrunk BW did not differ (P > 0.36) among treatments. On d 1, plasma Cp concentrations increased (P < 0.01) sharply in vaccinated heifers but not control heifers and were greater (P < 0.05) in vaccinated vs. control heifers on d 3, 6, 9, and 12 relative to injection. Daily DMI did not differ (P = 0.66) among treatments (average = 9.1 kg/d; SEM = 0.34); however, ADG and G:F were greater (P <= 0.05) for control vs. vaccinated heifers (1.14 vs. 0.87 kg/d and 0.13 and 0.10 kg, respectively; SEM = 0.064 and 0.011). These data indicate that within a 2 wk period after vaccination, beef calves experience an acute-phase protein response, which may result in reduced ADG and feed efficiency. PMID- 23345564 TI - Meta-analysis of the effects of essential oils and their bioactive compounds on rumen fermentation characteristics and feed efficiency in ruminants. AB - The present study aimed at investigating the effects of essential oils and their bioactive compounds (EOBC) on rumen fermentation in vivo as well as animal performance and feed efficiency in different ruminant species, using a meta analysis approach. Ruminant species were classified into 3 classes consisting of beef cattle, dairy cattle, and small ruminants. Two datasets (i.e., rumen fermentation and animal performance) were constructed, according to the available dependent variables within each animal class, from 28 publications (34 experiments) comprising a total of 97 dietary treatments. In addition, changes in rumen fermentation parameters relative to controls (i.e., no EOBC supplementation) of all animal classes were computed. Data were statistically analyzed within each animal class to evaluate the EOBC dose effect, taking into account variations of other variables across experiments (e.g., diet, feeding duration). The dose effect of EOBC on relative changes in fermentation parameters were analyzed across all animal classes. The primary results were that EOBC at doses <0.75 g/kg diet DM acted as a potential methane inhibitor in the rumen as a result of decreased acetate to propionate ratio. These responses were more pronounced in beef cattle (methane, P = 0.001; acetate to propionate ratio, P = 0.005) than in small ruminants (methane, P = 0.068; acetate to propionate ratio, P = 0.056) and in dairy cattle (P > 0.05), respectively. The analysis of relative changes in rumen fermentation variables suggests that EOBC affected protozoa numbers (P < 0.001) but only high doses (>0.20 g/kg DM) of EOBC had an inhibitory effect on this variable whereas lower doses promoted the number. For performance data, because numbers of observations in beef cattle and small ruminants were small, only those of dairy cattle (DMI, milk yield and milk composition, and feed efficiency) were analyzed. The results revealed no effect of EOBC dose on most parameters, except increased milk protein percentage (P< 0.001) and content (P = 0.006). It appears that EOBC supplementation can enhance rumen fermentation in such a way (i.e., decreased acetate to propionate ratio) that may favor beef production. High doses of EOBC do not necessarily modify rumen fermentation or improve animal performance and feed efficiency. Furthermore, additional attention should be paid to diet composition and supplementation period when evaluating the effects of EOBC in ruminants. PMID- 23345565 TI - Gas alternatives to carbon dioxide for euthanasia: a piglet perspective. AB - The search for alternative methods to euthanize piglets is critical to address public concern that current methods are not optimal. Scientific evidence supports that blunt force trauma is humane when performed correctly, but most people find it visually difficult to accept. The use of CO2 is often recommended; at the same time, it is criticized as being aversive to pigs. This research sought to 1) identify a method of scientifically determining if piglets find a gas aversive, using an approach-avoidance test, which relies on the perspective of the piglet, and 2) test different gas mixtures to determine if they are effective and humane for neonatal piglet euthanasia. Pigs were allowed to walk freely between 1 chamber filled with air and another chamber either gradually filled with gas mixtures (Exp. 1) or prefilled with gas mixtures (Exp. 2). Experiment 1 tested CO2 (90%) and air (10%), N2O (60%) and CO2 (30%), Ar (60%) and CO2 (30%), and N2 (60%) and CO2 (30%). Because piglets had to be removed when they started to flail, the test was shortest (P < 0.01) for the pigs in the CO2 treatment compared with pigs in the N2O/CO2, Ar/CO2, and N2/CO2 treatments, 3.1 +/- 0.2, 8.5 +/- 0.6, 9.6 +/- 0.4, and 9.9 +/- 0.1 min, respectively. Nonetheless, all gas mixtures adversely affected the pigs, causing the pigs to leave the test chamber. In Exp. 2, piglets were allowed to enter a chamber prefilled with N2/CO2 or N2O/CO2 (both 60/30%). Pigs exposed to the prefill chambers started to flail in fewer than 20 s, much faster in comparison with the gradual fill method, which supports that this method was more aversive. In Exp. 3, piglets were euthanized using a 2-step procedure. Pigs were first placed in a gradual fill chamber with 1 of 4 gas mixtures: 90% CO2, N2/CO2, N2O/CO2, or N2O/O2 (the last 3 mixtures at 60/30%) followed by placement into a 90% CO2 prefill chamber when the pigs started to flail or were anesthetized. All 3 gas treatments that contained CO2 killed pigs more quickly than N2O/O2 (P < 0.05). However, N2O/O2 was the only treatment that anesthetized the pigs instead of causing squeals or flailing although requiring about 12 min longer. Although longer, a 2-step procedure in which pigs are anesthetized with a mixture of N2O and O2 before being euthanized by immersion in CO2 may prove to be more humane than CO2 alone. PMID- 23345566 TI - Effect of time of cutting and maceration on nutrient flow, microbial protein synthesis, and digestibility in dual-flow continuous culture. AB - Maceration and evening-cutting are 2 forage management techniques that have independently improved forage quality and nutrient utilization in ruminants, but have not been evaluated in combination. Using a dual-flow continuous culture fermenter system, this preliminary study was designed to evaluate the individual and combined effects of time of cutting and maceration on in vitro ruminal digestion, nutrient flows, and microbial protein synthesis. Forages were harvested as hay from a timothy (Phleum pratense L.)-birdsfoot trefoil (Lotus corniculatus L.) stand in the morning (AM) or evening (PM). Half of each morning- and evening-cut treatment was macerated (AM-M, PM-M). The chemical composition (DM, OM, CP, NDF, ADF), including nonstructural carbohydrates (NSC) and water soluble carbohydrates (WSC), was determined for each of the 4 treatments (AM, AM M, PM, PM-M). Forages were ground to 2 mm and allocated to separate fermenters at 60 g of DM/d in a 4 * 4 Latin square design. Fermenters were operated over four 10-d periods with the first 7 d for adaptation followed by 3 d of sampling. Evening-cutting enhanced the apparent digestibility of NDF (P = 0.02) and ADF (P = 0.006), with a tendency (P < 0.10) for improved true DM digestibility and microbial protein synthesis. Molar proportions of individual VFA were not affected (P > 0.10) by time of cutting, though evening-cutting increased (P = 0.02) total concentration of VFA. Maceration had no effect (P > 0.10) on true nutrient digestibility or microbial protein synthesis. An interaction of time of cutting and maceration (P < 0.05) was observed whereby maceration decreased true DM and OM digestibilities in evening-cut treatments, but had no effect in morning cut treatments. Similarly, maceration reduced total N supply (P < 0.001) and molar proportions of acetate (P = 0.04) and increased molar proportions of propionate (P = 0.01) in evening-cut treatments with no effect on morning-cut treatments. These results indicate that independent use of evening cutting increased fiber digestibility and total VFA concentration, and independent use of maceration shifted molar proportions of VFA toward glucogenic fermentation. The combined use of these management techniques afforded no improvement for in vitro digestibility or metabolism when applied to morning-cut hay, and decreased nutrient digestibility when applied to evening-cut hay. Due to inherent limitations of in vitro systems, the results of this study should be interpreted with caution. Further in vivo studies are needed to support our conclusions. PMID- 23345568 TI - Effects of forage species or concentrate finishing on animal performance, carcass and meat quality. AB - Angus-cross steers (n = 128; initial BW = 270 +/- 3.8 kg) were used in a 3-yr study to assess effects of forage species grazed before slaughter versus concentrate finishing on carcass and meat quality. At the completion of the stockering phase, steers were randomly allotted to mixed pasture (MP; n = 36/yr) or corn-silage concentrate (CON; n = 12/yr) finishing treatments. At 40 d before harvest, MP steers were randomly divided into 3 forage species treatments: alfalfa (AL), pearl millet (PM), or mixed pasture (MP). Average daily BW gain was greater (P = 0.001) for CON than for forage-finished (FOR) steers during the early and overall finishing phase. During the late finishing phase when FOR steers were grazing difference forage species, ADG was greater (P = 0.03) for PM than MP or AL. Harvest weight and HCW were greater (P < 0.001) for CON than FOR due to the differences in animal performance. Total fat percentage of the 9th to 11th rib section was 46% less(P = 0.028) for FOR than CON due to reductions (P < 0.001) in the percentage of subcutaneous fat. Warner-Bratzler shear force (WBS) values at 14 d and 28 d of aging did not differ (P > 0.78) between CON and FOR and were not altered (P > 0.40) by forage species. Trained sensory panel juiciness, initial tenderness, and overall tenderness scores did not differ (P > 0.17) by finishing treatment or forage species. Beef flavor intensity was greater (P < 0.001) for CON than FOR. Beef flavor intensity was greater (P < 0.02) for AL and PM than MP. Off-flavor intensity was greater (P < 0.001) for all forage-fed steaks, regardless of forage species, than CON. Finishing on forages reduced (P = 0.003) total lipid content by 61% for the LM compared with CON finished cattle. Forage species grazed before harvest did not alter (P > 0.05) total lipid content of the LM. Oleic acid concentration and total MUFA of the LM were 21% and 22% less (P = 0.001) for FOR than CON. Concentrations of all individual [linolenic acid, eicosapentaenoic (EPA), docosapentaenoic (DPA), and docosadexaenoic (DHA) acids] and total n-3 fatty acids were greater (P < 0.001) for FOR than CON. Finishing on AL increased (P = 0.017) the concentration of linolenic acid compared with MP or PM. The ratio of n-6 to n-3 fatty acids was greater (P = 0.001) for CON than FOR and did not differ (P = 0.88) by forage species. Concentrate finishing increases carcass weight with same time endpoints and accelerates deposition of MUFA in comparison with FOR, which reduces carcass weight and fat deposition but maintains high concentrations of n-3 and CLA fatty acids. Finishing system or forage species grazed 40 d before slaughter did not alter beef tenderness but FOR had greater off-flavors according to both trained and descriptive sensory panelists. PMID- 23345569 TI - A study of consent for participation in a non-therapeutic study in the pediatric intensive care population. AB - OBJECTIVE: To document the legal guardian-related barriers to consent procurement, and their stated reasons for non-participation in a paediatric critical care research study. STUDY DESIGN: A multicentre, prospective, cohort study. PARTICIPANTS: Legal guardians of children who participated in a multicentre study on adrenal insufficiency in paediatric critical illness. Data were collected on all consent encounters in the main study. METHODS: Screening data, reasons for consent not being obtained, paediatric risk of mortality (illness severity) scores and age were collected on all 1707 patients eligible for participation in the Adrenal Insufficiency Study. RESULTS: The main barriers to approaching legal guardians for consent were lack of availability of the legal guardians (321/1707) and language barriers (84/1707). Legal guardians of 917 patients were approached with an overall consent rate of 42% (range 14-56% across the seven sites). 81% of the 528 legal guardians who declined consent provided an unsolicited reason for refusal. The three most commonly stated reasons were: being overwhelmed (117/429), not wanting anything else done to their child (63/429) and not wanting an additional medication (53/429). In addition, 14.2% cited research-related concerns as the reason for their non-participation. CONCLUSIONS: Barriers to consent procurement in a non-therapeutic paediatric critical care study appear to occur at many levels with lack of availability of legal guardians, and legal guardians feeling overwhelmed, being the most commonly recorded reasons. Further research into the impact of these findings on the validity and generalisability of the results of such studies is necessary prior to the development and study of future consent models. PMID- 23345570 TI - Dual use opportunity and public health infrastructure. PMID- 23345571 TI - Sexual identity group differences in child abuse and neglect. AB - Childhood abuse and neglect are pervasive problems among girls and young women that have numerous health consequences. Research suggests that sexual minority women are more likely than heterosexual women to report childhood abuse and neglect, but little is known about which sexual minority women are at greatest risk for these early adverse experiences. Using data from a pooled sample of women in a national probability study and in a large community-based study of sexual minority women designed to replicate the national study's methodology (pooled n = 953), we investigated rates and characteristics of childhood sexual abuse, physical abuse, and neglect among women from five sexual identity groups. As predicted, heterosexual women reported significantly less childhood abuse and neglect than did women who identified as mostly heterosexual, bisexual, mostly lesbian, or lesbian. We found considerable variability across the sexual minority subgroups, including severity of abuse, highlighting the need for research that distinguishes among these groups. To the extent that differences reported by women in the sample reflect the actual prevalence and severity of abuse experiences, sexual identity group differences in childhood abuse have important clinical and public health implications. PMID- 23345573 TI - Idiopathic pulmonary fibrosis: is all-cause mortality a practical and realistic end-point for clinical trials? PMID- 23345572 TI - What's age got to do with it? Partner age difference, power, intimate partner violence, and sexual risk in urban adolescents. AB - Adolescent girls with older male main partners are at greater risk for adverse sexual health outcomes than other adolescent girls. One explanation for this finding is that low relationship power occurs with partner age difference. Using a cross-sectional, descriptive design, we investigated the effect of partner age difference between an adolescent girl and her male partner on sexual risk behavior through the mediators of sexual relationship power, and physical intimate partner violence (IPV), and psychological IPV severity. We chose Blanc's framework to guide this study as it depicts the links among demographic, social, economic, relationship, family and community characteristics, and reproductive health outcomes with gender-based relationship power and violence. Urban adolescent girls (N = 155) completed an anonymous computer-assisted self interview survey to examine partner and relationship factors' effect on consistent condom use. Our sample had an average age of 16.1 years with a mean partner age of 17.8 years. Partners were predominantly African American (75%), non-Hispanic (74%), and low-income (81%); 24% of participants reported consistent condom use in the last 3 months. Descriptive, correlation, and multiple mediation analyses were conducted. Partner age difference was negatively associated with consistent condom use (-.4292, p < .01); however, the indirect effects through three proposed mediators (relationship power, physical IPV, or psychological IPV severity) were not statistically significant. Further studies are needed to explore alternative rationale explaining the relationship between partner age differences and sexual risk factors within adolescent sexual relationships. Nonetheless, for clinicians and researchers, these findings underscore the heightened risk associated with partner age differences and impact of relationship dynamics on sexual risk behavior. PMID- 23345574 TI - Prospective evaluation of respiratory exacerbations in children with cystic fibrosis from newborn screening to 5 years of age. AB - BACKGROUND: Newborn screening allows novel treatments for cystic fibrosis (CF) to be trialled in early childhood before irreversible lung injury occurs. As respiratory exacerbations are a potential trial outcome variable, we determined their rate, duration and clinical features in preschool children with CF; and whether they were associated with growth, lung structure and function at age 5 years. METHODS: Respiratory exacerbations were recorded prospectively in Australasian CF Bronchoalveolar Lavage trial subjects from enrolment after newborn screening to age 5 years, when all participants underwent clinical assessment, chest CT scans and spirometry. RESULTS: 168 children (88 boys) experienced 2080 exacerbations, at an average rate of 3.66 exacerbations per person-year; 80.1% were community managed and 19.9% required hospital admission. There was an average increase in exacerbation rate of 9% (95% CI 4% to 14%; p<0.001) per year of age. Exacerbation rate differed by site (p<0.001) and was 26% lower (95% CI 12% to 38%) in children receiving 12 months of prophylactic antibiotics. The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores. Ever having a hospital-managed exacerbation was associated with bronchiectasis (OR 2.67, 95% CI 1.13 to 6.31) in chest CT scans, and lower weight z scores at 5 years of age (coefficient -0.39, 95% CI -0.74 to -0.05). CONCLUSIONS: Respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group. PMID- 23345575 TI - Urinary oxytocin and social bonding in related and unrelated wild chimpanzees. AB - Animals that maintain cooperative relationships show gains in longevity and offspring survival. However, little is known about the cognitive or hormonal mechanisms involved in cooperation. Indeed, there is little support for a main hypothesis that non-human animals have the cognitive capacities required for bookkeeping of cooperative exchanges. We tested an alternative hypothesis that cooperative relationships are facilitated by an endocrinological mechanism involving oxytocin, a hormone required for bonding in parental and sexual relationships across mammals. We measured urinary oxytocin after single bouts of grooming in wild chimpanzees. Oxytocin levels were higher after grooming with bond partners compared with non-bond partners or after no grooming, regardless of genetic relatedness or sexual interest. We ruled out other possible confounds, such as grooming duration, grooming direction or sampling regime issues, indicating that changes in oxytocin levels were mediated by social bond strength. Oxytocin, which is thought to act directly on neural reward and social memory systems, is likely to play a key role in keeping track of social interactions with multiple individuals over time. The evolutionary linkage of an ancestral hormonal system with complex social cognition may be the primary mechanism through which long-term cooperative relationships develop between both kin and non-kin in mammals. PMID- 23345576 TI - Fractal geometry of a complex plumage trait reveals bird's quality. AB - Animal coloration is key in natural and sexual selection, playing significant roles in intra- and interspecific communication because of its linkage to individual behaviour, genetics and physiology. Simple animal traits such as the area or the colour intensity of homogeneous patches have been profusely studied. More complex patterns are widespread in nature, but they escape our understanding because their variation is difficult to capture effectively by standard, simple measures. Here, we used fractal geometry to quantify inter-individual variation in the expression of a complex plumage trait, the heterogeneous black bib of the red-legged partridge (Alectoris rufa). We show that a higher bib fractal dimension (FD) predicted better individual body condition, as well as immune responsiveness, which is condition-dependent in our study species. Moreover, when food intake was experimentally reduced during moult as a means to reduce body condition, the bib's FD significantly decreased. Fractal geometry therefore provides new opportunities for the study of complex animal colour patterns and their roles in animal communication. PMID- 23345577 TI - Major histocompatibility complex peptide ligands as olfactory cues in human body odour assessment. AB - In many animal species, social communication and mate choice are influenced by cues encoded by the major histocompatibility complex (MHC). The mechanism by which the MHC influences sexual selection is a matter of intense debate. In mice, peptide ligands of MHC molecules activate subsets of vomeronasal and olfactory sensory neurons and influence social memory formation; in sticklebacks, such peptides predictably modify the outcome of mate choice. Here, we examine whether this evolutionarily conserved mechanism of interindividual communication extends to humans. In psychometric tests, volunteers recognized the supplementation of their body odour by MHC peptides and preferred 'self' to 'non-self' ligands when asked to decide whether the modified odour smelled 'like themselves' or 'like their favourite perfume'. Functional magnetic resonance imaging indicated that 'self'-peptides specifically activated a region in the right middle frontal cortex. Our results suggest that despite the absence of a vomeronasal organ, humans have the ability to detect and evaluate MHC peptides in body odour. This may provide a basis for the sensory evaluation of potential partners during human mate choice. PMID- 23345578 TI - Dark survival in a warming world. AB - Most algae regularly experience periods of darkness ranging from a few hours to a few days. During this time, they are unable to photosynthesize, and so must consume stored energy products. However, some organisms such as polar algae and some microalgal cysts and spores are exposed to darkness for months to years, and these must use alternative strategies to survive. Some taxa, such as dinoflagellates, form cysts and become dormant. Others use physiological methods or adopt mixotrophy. The longest documented survival of more than a century was for dinoflagellates buried in sediments in a Norwegian fjord. Seasonal changes in daylight hours are naturally unaffected by climate change. This means that polar microalgae will in the future need to survive the same period of seasonal darkness but at higher temperatures, and this will require a greater drawdown of stored energy. Recent experimental work has shown that both Arctic and Antarctic phytoplankton are able to survive increases of up to 6 degrees C in the dark. PMID- 23345579 TI - Mass spectrometry method to identify aging pathways of Sp- and Rp-tabun adducts on human butyrylcholinesterase based on the acid labile P-N bond. AB - The phosphoramidate nerve agent tabun inhibits butyrylcholinesterase (BChE) and acetylcholinesterase by making a covalent bond on the active site serine. The adduct loses an alkyl group in a process called aging. The mechanism of aging of the tabun adduct is controversial. Some studies claim that aging proceeds through deamination, whereas crystal structure studies show aging by O-dealkylation. Our goal was to develop a method that clearly distinguishes between deamination and O dealkylation. We began by studying the tetraisopropyl pyrophosphoramide adduct of BChE because this adduct has two P-N bonds. Mass spectra showed that the P-N bonds were stable during trypsin digestion at pH 8 but were cleaved during pepsin digestion at pH 2. The P-N bond in tabun was also acid labile, whereas the P-O bond was stable. A scheme to distinguish aging by deamination from aging by O dealkylation was based on the acid labile P-N bond. BChE was inhibited with Sp- and Rp-tabun thiocholine nerve agent model compounds to make adducts identical to those of tabun with known stereochemistry. After aging and digestion with pepsin at pH 2, peptide FGES198AGAAS from Sp-tabun thiocholine had a mass of 902.2 m/z in negative mode, indicating that it had aged by deamination, whereas peptide FGES198AGAAS from Rp-tabun thiocholine had a mass of 874.2 m/z in negative mode, indicating that it had aged by O-dealkylation. BChE inhibited by authentic, racemic tabun yielded both 902.2 and 874.2 m/z peptides, indicating that both stereoisomers reacted with BChE and aged either by deamination or dealkylation. PMID- 23345580 TI - Blueprints of signaling interactions between pattern recognition receptors: implications for the design of vaccine adjuvants. AB - Innate immunity activation largely depends on recognition of microorganism structures by Pattern Recognition Receptors (PRRs). PRR downstream signaling results in production of pro- and anti-inflammatory cytokines and other mediators. Moreover, PRR engagement in antigen-presenting cells initiates the activation of adaptive immunity. Recent reports suggest that for the activation of innate immune responses and initiation of adaptive immunity, synergistic effects between two or more PRRs are necessary. No systematic analysis of the interaction between the major PRR pathways were performed to date. In this study, a systematical analysis of the interactions between PRR signaling pathways was performed. PBMCs derived from 10 healthy volunteers were stimulated with either a single PRR ligand or a combination of two PRR ligands. Known ligands for the major PRR families were used: Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), and RigI-helicases. After 24 h of incubation, production of tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL 1beta), IL-6, and IL-10 was measured in supernatants by enzyme-linked immunosorbent assay (ELISA). The consistency of the PRR interactions (both inhibitory and synergistic) between the various individuals was assessed. A number of PRR-dependent signaling interactions were found to be consistent, both between individuals and with regard to multiple cytokines. The combinations of TLR2 and NOD2, TLR5 and NOD2, TLR5 and TLR3, and TLR5 and TLR9 acted as synergistic combinations. Surprisingly, inhibitory interactions between TLR4 and TLR2, TLR4 and Dectin-1, and TLR2 and TLR9 as well as TLR3 and TLR2 were observed. These consistent signaling interactions between PRR combinations may represent promising targets for immunomodulation and vaccine adjuvant development. PMID- 23345581 TI - Safety and immunogenicity of DNA prime and modified vaccinia ankara virus-HIV subtype C vaccine boost in healthy adults. AB - A randomized, double-blind, placebo-controlled phase I trial was conducted in 32 HIV-uninfected healthy volunteers to assess the safety and immunogenicity of 3 doses of DNA vaccine (Advax) plus 1 dose of recombinant modified vaccinia virus Ankara (MVA) (TBC-M4) or 3 doses of TBC-M4 alone (groups A and B, respectively). Both vaccine regimens were found to be safe and well tolerated. Gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot (ELISPOT) assay responses were detected in 1/10 (10%) individuals in group A after three Advax primes and in 9/9 individuals (100%) after the MVA boost. In group B, IFN-gamma ELISPOT responses were detected in 6/12 (50%) and 7/11 (64%) individuals after the second and third MVA vaccinations, respectively. Responses to all vaccine components, but predominantly to Env, were seen. The breadth and magnitude of the T cell response and viral inhibition were greater in group A than in group B, indicating that the quality of the T-cell response was enhanced by the DNA prime. Intracellular cytokine staining indicated that the T-cell responses were polyfunctional but were skewed toward Env with a CD4(+) phenotype. At 2 weeks after the last vaccination, HIV-specific antibody responses were detected in all (100%) group B and 1/11 (9.1%) group A vaccinees. Vaccinia virus-specific responses were detected in all (100%) group B and 2/11 (18.2%) group A vaccinees. In conclusion, HIV-specific T-cell responses were seen in the majority of volunteers in groups A and B but with a trend toward greater quality of the T-cell response in group A. Antibody responses were better in group B than in group A. PMID- 23345582 TI - Unusual patterns of IgG avidity in some young children following two doses of the adjuvanted pandemic H1N1 (2009) influenza virus vaccine. AB - During the 2009-2010 H1N1 influenza pandemic, an adjuvanted monovalent vaccine containing ~25% of the normal antigen dose and AS03 adjuvant was widely used in Canada. This vaccine was found to be well-tolerated and immunogenic in young children (D. W. Scheifele et al., Pediatr. Infect. Dis. J. 30:402-407, 2011). We report here additional analyses to further characterize the humoral response to this vaccine. We measured standard hemagglutination inhibition (HAI) and microneutralization (MN) titers, as well as influenza virus-specific IgG avidity and subclass distribution by enzyme-linked immunosorbent assay in 73 subjects. Sera were collected before (day 0) and 3 weeks after each dose of vaccine (days 21 and 42). Most children (55/73) had undetectable HAI and MN titers at day 0 (presumed to be antigen naive) and mounted good responses at days 21 and 42. The majority of these children (43/55) had the expected pattern of an increasing IgG avidity index (AI) after each dose of vaccine (not detected [ND], 0.30, and 2.97 at days 0, 21, and 42, respectively). The avidity responses in the remaining children (12/55) were quite different, with AIs increasing abruptly after the first dose and then declining after the second dose of vaccine (ND, 8.83, and 7.15, respectively). These children also had higher concentrations of influenza virus-specific IgG1 and IgG3 antibodies at day 21. Although the antibody titers were similar, some antigen-naive children demonstrated an unusual pattern of avidity maturation after two immunizations with AS03-adjuvanted, low-dose influenza virus vaccine. These data suggest the presence of subtle differences in the quality of the antibodies produced by some subjects in response to this vaccine. PMID- 23345583 TI - Seropositivity rates for measles, mumps, and rubella IgG and costs associated with testing and revaccination. AB - Retrospective analysis of IgG test results and patterns for measles, mumps, and rubella revealed generally high seropositivity rates, with that of mumps being the lowest. A simplified cost analysis shows that when there is a suspicion of nonimmunity, serological testing may be cheaper than vaccination. PMID- 23345584 TI - Development of whole-virus multiplex luminex-based serological assays for diagnosis of infections with kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 homologs in macaques. AB - Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 is a tumorigenic rhadinovirus that is associated with all forms of Kaposi's sarcoma. Current serological detection of KSHV is based on enzyme-linked immunosorbent or immunofluorescence assays that suffer from a variety of problems, including the lack of defined standards for test comparison. While KSHV is the only known human rhadinovirus, two lineages of KSHV-like rhadinoviruses are found in Old World primates: the RV1 lineage includes KSHV and retroperitoneal fibromatosis herpesvirus (RFHV) in macaques, and the RV2 lineage includes RRV and MneRV2 from different macaque species. To develop animal models of KSHV-associated diseases, we developed quantitative multiplex bead-based serological assays to detect antibodies against rhadinovirus antigens. Proteins from KSHV (RV1) and MneRV2 (RV2) virions were coupled to spectrally distinct fluorescent beads and used in Luminex flow cytometry-based assays to detect immune responses in macaques. Both assays showed large dynamic ranges with high levels of seroreactivity to both KSHV and MneRV2 proteins. A large set of macaque serum samples from the Washington National Primate Research Center was screened, and most of the samples (82%) were positive in both assays, consistent with the high level of RV1-RV2 coinfection detected by PCR. The macaque sera showed broad, variable, and unique serological responses to the different viral antigens, allowing an initial seroprevalence to be determined for the macaque viruses. The Luminex assays offer a novel multiplexed approach to assess rhadinovirus infection patterns in both humans and nonhuman primates. This will help advance our understanding of rhadinovirus biology and associated host immunological responses. PMID- 23345585 TI - Performance of the Elecsys Rubella IgG assay in the diagnostic laboratory setting for assessment of immune status. AB - Rubella in early pregnancy bears a high risk for congenital defects (e.g., cataracts, hearing loss, and heart disease) and for long-term sequelae in the newborn. Despite implementation of vaccination programs in many regions, the threat of devastating consequences from congenital rubella virus infection remains and careful screening of maternal immune status before and during pregnancy helps to reduce the risk. This study compared the performance of the Elecsys Rubella IgG assay with that of other assays routinely used for screening. Samples from 1,090 women undergoing routine antenatal care were tested using the Elecsys and Enzygnost Rubella IgG assays and the hemagglutination inhibition test. Samples with hemagglutination inhibition titers of <32 (n = 148) were additionally tested using the Vidas, AxSYM, Liaison, and Architect Rubella IgG assays. Agreement of qualitative results from the Elecsys, Enzygnost, and hemagglutination inhibition assays was good in all samples. All assays showed 100.0% specificity. In samples with hemagglutination inhibition titers of <32, the Elecsys, AxSYM, and Enzygnost assays showed higher sensitivity (>90.0%) than the other immunoassays (78.6 to 82.4%). The Elecsys assay reported significantly higher rubella virus IgG levels than the other immunoassays across the whole set of 1,090 samples, with the largest bias and deviation from limits of agreement in Bland-Altman analysis. In conclusion, the Elecsys assay is highly sensitive and specific with regard to qualitative results and suitable for routine automated screening. However, given the considerable variation between quantitative results from different immunoassays, testing methods should be documented and the same assay used throughout an individual's antenatal follow-up wherever possible. PMID- 23345586 TI - Enzyme-linked immunosorbent assay using recombinant SAG1 antigen to detect Toxoplasma gondii-specific immunoglobulin G antibodies in human sera and saliva. AB - Serologic detection of Toxoplasma gondii IgG antibodies is widely accepted as a means to determine immune status and susceptibility to Toxoplasma infection during pregnancy. However, current commercial kits present some drawbacks, such as a requirement for whole-parasite antigen preparation or interassay variability. To address these problems, the purpose of this study was to produce a whole sequence of the recombinant T. gondii SAG1 antigen (rSAG1) to assess its diagnostic performance in Toxoplasma IgG screening and to explore a saliva-based method as a noninvasive alternative to serum-based testing. rSAG1 was expressed in recombinant bacteria as inclusion bodies, purified through one-step affinity chromatography, and refolded in native form by dialysis. A large amount was obtained, and the specific antigen immunoreactivity was confirmed by immunoblotting. Two rSAG1-based enzyme-linked immunosorbent assays (ELISAs) applied to paired serum and saliva samples were designed. The rSAG1-based ELISA evaluation consisted of testing intrinsic sensitivity and specificity of 49 serum samples from patients immune to toxoplasmosis and 42 serum samples from nonimmune controls identified by routinely used kits. To assess agreement between serum based and saliva-based tests, the positive percent agreement (PPA) and negative percent agreement (NPA) between the 2 tests were estimated. The rSAG1 serum-based ELISA detected specific IgG with 100% sensitivity and specificity. The PPA and NPA between the serum-based and saliva-based tests varied according to the selected optical density threshold in saliva. Thus, for a selected cutoff of 0.14, the PPA was 100% and the NPA was 88.1%, whereas for a selected cutoff of 0.29, the PPA was 67.3% and the NPA was 100%. PMID- 23345588 TI - Effect of an educational intervention on requesting behaviour by a medical admission unit. AB - BACKGROUND: Previous studies have shown that of all the tests requested of hospital laboratories, 25-40% are thought to be unnecessary. Our hospital laboratory observed that a significant number of requests from the medical admissions unit (MAU) were probably inappropriate. In an attempt to improve requesting behaviour this observation was investigated and an educational intervention employed. METHODS: We performed a survey of requesting behaviour by the MAU and a local protocol was designed as an audit standard. The influence of the educational intervention on requesting behaviour was audited. RESULTS: The generation of local guidelines and an educational intervention to promote them, significantly changed requesting behaviour. The main effect was the reduction in requesting of thyroid function tests, lipid profiles and coagulation screens. CONCLUSIONS: This process highlighted inappropriate requesting behaviour from the MAU which, following a process of investigation and education, resulted in a significant change with an associated cost benefit. PMID- 23345587 TI - Identification of VAR2CSA domain-specific inhibitory antibodies of the Plasmodium falciparum erythrocyte membrane protein 1 using a novel flow cytometry assay. AB - VAR2CSA, a member of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family, is a leading candidate for use in vaccines to protect first-time mothers from placental malaria (PM). VAR2CSA, which is comprised of a series of six Duffy binding-like (DBL) domains, binds chondroitin sulfate A (CSA) on placental syncytiotrophoblast. Several recombinant DBL domains have been shown to bind CSA. In order to identify and develop recombinant proteins suitable for clinical development, DBL2X and DBL3X, as well as their respective third subdomain (S3) from the FCR3 parasite clone, were expressed in Escherichia coli, refolded, and purified. All but DBL3X-S3 recombinant proteins bound to CSA expressed on Chinese hamster ovary (CHO)-K1 cells but not to CHO-pgsA745 cells, which are CSA negative as determined by flow cytometry. All but DBL3X-S3 bound to CSA on chondroitin sulfate proteoglycan (CSPG) as determined by surface plasmon resonance (SPR) analysis. Purified IgG from rats and rabbits immunized with these four recombinant proteins bound homologous and some heterologous parasite infected erythrocytes (IE). Using a novel flow cytometry inhibition-of-binding assay (flow-IBA), antibodies against DBL3X-S3 inhibited 35% and 45% of IE binding to CSA on CHO-K1 cells compared to results for soluble CSA (sCSA) and purified multigravida (MG) IgG, respectively, from areas in Tanzania to which malaria is endemic. Antibodies generated against the other domains provided little or no inhibition of IE binding to CSA on CHO-K1 cells as determined by the flow cytometry inhibition-of-binding assay. These results demonstrate for the first time the ability to identify antibodies to VAR2CSA DBL domains and subdomains capable of inhibiting VAR2CSA parasite-IE binding to CSA by flow cytometry. The flow cytometry inhibition-of-binding assay was robust and provided an accurate, reproducible, and reliable means to identify blocking of IE binding to CSA and promises to be significant in the development of a vaccine to protect pregnant women. PMID- 23345589 TI - Myosin phosphatase is inactivated by caspase-3 cleavage and phosphorylation of myosin phosphatase targeting subunit 1 during apoptosis. AB - In nonapoptotic cells, the phosphorylation level of myosin II is constantly maintained by myosin kinases and myosin phosphatase. During apoptosis, caspase-3 activated Rho-associated protein kinase I triggers hyperphosphorylation of myosin II, leading to membrane blebbing. Although inhibition of myosin phosphatase could also contribute to myosin II phosphorylation, little is known about the regulation of myosin phosphatase in apoptosis. In this study, we have demonstrated that, in apoptotic cells, the myosin-binding domain of myosin phosphatase targeting subunit 1 (MYPT1) is cleaved by caspase-3 at Asp-884, and the cleaved MYPT1 is strongly phosphorylated at Thr-696 and Thr-853, phosphorylation of which is known to inhibit myosin II binding. Expression of the caspase-3 cleaved form of MYPT1 that lacked the C-terminal end in HeLa cells caused the dissociation of MYPT1 from actin stress fibers. The dephosphorylation activity of myosin phosphatase immunoprecipitated from the apoptotic cells was lower than that from the nonapoptotic control cells. These results suggest that down-regulation of MYPT1 may play a role in promoting hyperphosphorylation of myosin II by inhibiting the dephosphorylation of myosin II during apoptosis. PMID- 23345590 TI - Energy metabolism regulates clathrin adaptors at the trans-Golgi network and endosomes. AB - Glucose is a master regulator of cell behavior in the yeast Saccharomyces cerevisiae. It acts as both a metabolic substrate and a potent regulator of intracellular signaling cascades. Glucose starvation induces the transient delocalization and then partial relocalization of clathrin adaptors at the trans Golgi network and endosomes. Although these localization responses are known to depend on the protein kinase A (PKA) signaling pathway, the molecular mechanism of this regulation is unknown. Here we demonstrate that PKA and the AMP-regulated kinase regulate adaptor localization through changes in energy metabolism. We show that genetic and chemical manipulation of intracellular ATP levels cause corresponding changes in adaptor localization. In permeabilized cells, exogenous ATP is sufficient to induce adaptor localization. Furthermore, we reveal distinct energy-dependent steps in adaptor localization: a step that requires the ADP ribosylation factor ARF, an ATP-dependent step that requires the phosphatidyl inositol-4 kinase Pik1, and third ATP-dependent step for which we provide evidence but for which the mechanism is unknown. We propose that these energy dependent mechanisms precisely synchronize membrane traffic with overall proliferation rates and contribute a crucial aspect of energy conservation during acute glucose starvation. PMID- 23345591 TI - Rab25 regulates integrin expression in polarized colonic epithelial cells. AB - Rab25 is a tumor suppressor for colon cancer in humans and mice. To identify elements of intestinal polarity regulated by Rab25, we developed Caco2-BBE cell lines stably expressing short hairpin RNA for Rab25 and lines rescuing Rab25 knockdown with reexpression of rabbit Rab25. Rab25 knockdown decreased alpha2-, alpha5-, and beta1-integrin expression. We observed colocalization and direct association of Rab25 with alpha5beta1-integrins. Rab25 knockdown also up regulated claudin-1 expression, increased transepithelial resistance, and increased invasive behavior. Rab25-knockdown cells showed disorganized brush border microvilli with decreases in villin expression. All of these changes were reversed by reintroduction of rabbit Rab25. Rab25 knockdown altered the expression of 29 gene transcripts, including the loss of alpha5-integrin transcripts. Rab25 loss decreased expression of one transcription factor, ETV4, and overexpression of ETV4 in Rab25-knockdown cells reversed losses of alpha5beta1-integrin. The results suggest that Rab25 controls intestinal cell polarity through the regulation of gene expression. PMID- 23345592 TI - GOLPH3L antagonizes GOLPH3 to determine Golgi morphology. AB - GOLPH3 is a phosphatidylinositol-4-phosphate (PI4P) effector that plays an important role in maintaining Golgi architecture and anterograde trafficking. GOLPH3 does so through its ability to link trans-Golgi membranes to F-actin via its interaction with myosin 18A (MYO18A). GOLPH3 also is known to be an oncogene commonly amplified in human cancers. GOLPH3L is a GOLPH3 paralogue found in all vertebrate genomes, although previously it was largely uncharacterized. Here we demonstrate that although GOLPH3 is ubiquitously expressed in mammalian cells, GOLPH3L is present in only a subset of tissues and cell types, particularly secretory tissues. We show that, like GOLPH3, GOLPH3L binds to PI4P, localizes to the Golgi as a consequence of its PI4P binding, and is required for efficient anterograde trafficking. Surprisingly, however, we find that perturbations of GOLPH3L expression produce effects on Golgi morphology that are opposite to those of GOLPH3 and MYO18A. GOLPH3L differs critically from GOLPH3 in that it is largely unable to bind to MYO18A. Our data demonstrate that despite their similarities, unexpectedly, GOLPH3L antagonizes GOLPH3/MYO18A at the Golgi. PMID- 23345593 TI - COX19 mediates the transduction of a mitochondrial redox signal from SCO1 that regulates ATP7A-mediated cellular copper efflux. AB - SCO1 and SCO2 are metallochaperones whose principal function is to add two copper ions to the catalytic core of cytochrome c oxidase (COX). However, affected tissues of SCO1 and SCO2 patients exhibit a combined deficiency in COX activity and total copper content, suggesting additional roles for these proteins in the regulation of cellular copper homeostasis. Here we show that both the redox state of the copper-binding cysteines of SCO1 and the abundance of SCO2 correlate with cellular copper content and that these relationships are perturbed by mutations in SCO1 or SCO2, producing a state of apparent copper overload. The copper deficiency in SCO patient fibroblasts is rescued by knockdown of ATP7A, a trans Golgi, copper-transporting ATPase that traffics to the plasma membrane during copper overload to promote efflux. To investigate how a signal from SCO1 could be relayed to ATP7A, we examined the abundance and subcellular distribution of several soluble COX assembly factors. We found that COX19 partitions between mitochondria and the cytosol in a copper-dependent manner and that its knockdown partially rescues the copper deficiency in patient cells. These results demonstrate that COX19 is necessary for the transduction of a SCO1-dependent mitochondrial redox signal that regulates ATP7A-mediated cellular copper efflux. PMID- 23345594 TI - Analysis of turnover dynamics of the submembranous actin cortex. AB - The cell cortex is a thin network of actin, myosin motors, and associated proteins that underlies the plasma membrane in most eukaryotic cells. It enables cells to resist extracellular stresses, perform mechanical work, and change shape. Cortical structural and mechanical properties depend strongly on the relative turnover rates of its constituents, but quantitative data on these rates remain elusive. Using photobleaching experiments, we analyzed the dynamics of three classes of proteins within the cortex of living cells: a scaffold protein (actin), a cross-linker (alpha-actinin), and a motor (myosin). We found that two filament subpopulations with very different turnover rates composed the actin cortex: one with fast turnover dynamics and polymerization resulting from addition of monomers to free barbed ends, and one with slow turnover dynamics with polymerization resulting from formin-mediated filament growth. Our data suggest that filaments in the second subpopulation are on average longer than those in the first and that cofilin-mediated severing of formin-capped filaments contributes to replenishing the filament subpopulation with free barbed ends. Furthermore, alpha-actinin and myosin minifilaments turned over significantly faster than F-actin. Surprisingly, only one-fourth of alpha-actinin dimers were bound to two actin filaments. Taken together, our results provide a quantitative characterization of essential mechanisms under-lying actin cortex homeostasis. PMID- 23345595 TI - Mge1, a nucleotide exchange factor of Hsp70, acts as an oxidative sensor to regulate mitochondrial Hsp70 function. AB - Despite the growing evidence of the role of oxidative stress in disease, its molecular mechanism of action remains poorly understood. The yeast Saccharomyces cerevisiae provides a valuable model system in which to elucidate the effects of oxidative stress on mitochondria in higher eukaryotes. Dimeric yeast Mge1, the cochaperone of heat shock protein 70 (Hsp70), is essential for exchanging ATP for ADP on Hsp70 and thus for recycling of Hsp70 for mitochondrial protein import and folding. Here we show an oxidative stress-dependent decrease in Mge1 dimer formation accompanied by a concomitant decrease in Mge1-Hsp70 complex formation in vitro. The Mge1-M155L substitution mutant stabilizes both Mge1 dimer and Mge1 Hsp70 complex formation. Most important, the Mge1-M155L mutant rescues the slow growth phenomenon associated with the wild-type Mge1 strain in the presence of H2O2 in vivo, stimulation of the ATPase activity of Hsp70, and the protein import defect during oxidative stress in vitro. Furthermore, cross-linking studies reveal that Mge1-Hsp70 complex formation in mitochondria isolated from wild-type Mge1 cells is more susceptible to reactive oxygen species compared with mitochondria from Mge1-M155L cells. This novel oxidative sensor capability of yeast Mge1 might represent an evolutionarily conserved function, given that human recombinant dimeric Mge1 is also sensitive to H2O2. PMID- 23345596 TI - Validation of the systemic lupus erythematosus responder index for use in juvenile-onset systemic lupus erythematosus. AB - OBJECTIVES: This study tested the concurrent validity of the systemic lupus erythematosus responder index (SRI) in assessing improvement in juvenile-onset systemic lupus erythematosus (jSLE). METHODS: The SRI considers changes in the SELENA-SLEDAI, BILAG and a 3-cm visual analogue scale of physician-rated disease activity (PGA) to determine patient improvement. Using prospectively collected data from 760 unique follow-up visit intervals of 274 jSLE patients, we assessed the sensitivity and specificity of the SRI using these external standards: physician-rated improvement (MD-change), patient/parent-rated major improvement of wellbeing (patient-change) and decrease in prescribed systemic corticosteroids (steroid-change). Modifications of the SRI that considered different thresholds for the SELENA-SLEDAI, BILAG and 10-cm PGA were explored and agreement with the American College of Rheumatology/PRINTO provisional criteria for improvement of jSLE (PCI) was examined. RESULTS: The sensitivity/specificity in capturing major improvement by the MD-change were 78%/76% for the SRI and 83%/78% for the PCI, respectively. There was fair agreement between the SRI and PCI (kappa=0.35, 95% CI 0.02 to 0.73) in capturing major improvement by the MD-change. Select modified versions of the SRI had improved accuracy overall. All improvement criteria tested had lower sensitivity when considering patient-change and steroid-change as external standards compared to MD-change. CONCLUSIONS: The SRI and its modified versions based on meaningful changes in jSLE have high specificity but at most modest sensitivity for capturing jSLE improvement. When used as an endpoint of clinical trials in jSLE, the SRI will provide a conservative estimate regarding the efficacy of the therapeutic agent under investigation. PMID- 23345597 TI - MRI comes of age in RA clinical trials. AB - The success of modern rheumatoid arthritis (RA) therapies and treatment strategies has led to extended placebo phases being unethical in RA randomised controlled trials (RCTs). Modern trials therefore increasingly involve active comparator designs, and this together with some technical issues has meant difficulties in differentiating structural progression using traditional radiographic outcome measures. Magnetic resonance imaging (MRI) has been demonstrated to assess damage more sensitively than radiographs, but importantly it can measure the upstream drivers of erosions and cartilage loss, synovitis and osteitis. An increasing number of recent RCTs using the RA MRI scoring system (RAMRIS) have demonstrated the ability of MRI to discriminate progression and treatment effect. Consistency of erosion progression determination was seen across the majority of these studies. In most studies, MRI demonstrated reduction in synovitis and osteitis at early (12 week) timepoints, and MRI predicted subsequent radiographic findings. Often small numbers of patients were required to demonstrate such changes. The time is right for regulatory authorities to include MRI as an alternative to radiographic data in support of claims of inhibition of progression of structural damage in RA trials. PMID- 23345598 TI - Quantitative measurement of syndesmophyte volume and height in ankylosing spondylitis using CT. AB - OBJECTIVE: Syndesmophyte growth in ankylosing spondylitis can be difficult to measure using radiographs because of poor visualisation and semiquantitative scoring methods. We developed and tested the reliability and validity of a new computer-based method that fully quantifies syndesmophyte volumes and heights on CT scans. METHODS: In this developmental study, we performed lumbar spine CT scans on 38 patients and used our algorithm to compute syndesmophyte volume and height in four intervertebral disk spaces. To assess reliability, we compared results between two scans performed on the same day in nine patients. To assess validity, we compared computed measures to visual ratings of syndesmophyte volume and height on both CT scans and radiographs by two physician readers. RESULTS: Coefficients of variation for syndesmophyte volume and height, based on repeat scans, were 2.05% and 2.40%, respectively. Based on Bland-Altman analysis, an increase in syndesmophyte volume of more than 4% or in height of more than 0.20 mm represented a change greater than measurement error. Computed volumes and heights were strongly associated with physician ratings of syndesmophyte volume and height on visual examination of both the CT scans (p<0.0001) and plain radiographs (p<0.002). Syndesmophyte volumes correlated with the Schober test (r= 0.48) and lateral thoracolumbar flexion (r=-0.60). CONCLUSIONS: This new CT-based method that fully quantifies syndesmophytes in three-dimensional space had excellent reliability and face and construct validity. Given its high precision, this method shows promise for longitudinal clinical studies of syndesmophyte development and growth. PMID- 23345599 TI - Low-dose aspirin use and recurrent gout attacks. AB - OBJECTIVE: To examine the association between cardioprotective use of low-dose aspirin and the risk of recurrent gout attacks among gout patients. METHODS: We conducted an online case-crossover study of individuals with gout over 1 year. The following information was obtained during gout attacks: the onset dates, symptoms and signs, medications, and exposure to potential risk factors, including daily aspirin use and dosage, during the 2-day hazard period prior to the gout attacks. The same exposure information was also obtained over 2-day control periods. RESULTS: Of the 724 participants analysed, 40.5% took aspirin <=325 mg/day during either a hazard or a control period. Compared with no aspirin use, the adjusted OR of gout attacks increased by 81% (OR=1.81, 95% CI 1.30 to 2.51) for <=325 mg/day of aspirin use on two consecutive days. The corresponding ORs were stronger with lower doses (eg, OR=1.91 for <=100 mg, 95% CI 1.32 to 2.85). These associations persisted across subgroups by sex, age, body mass index categories and renal insufficiency status. Concomitant use of allopurinol nullified the detrimental effect of aspirin. CONCLUSIONS: Our findings suggest that the use of low-dose aspirin on two consecutive days is associated with an increased risk of recurrent gout attacks. Recommended serum urate monitoring with concomitant use and dose adjustment of a urate-lowering therapy among patients with gout may be especially important to help avoid the risk of gout attacks associated with low-dose aspirin. PMID- 23345600 TI - Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tocilizumab therapy. AB - OBJECTIVES: We assessed the impact of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following administration of the 23-valent pneumococcal polysaccharide vaccine (PPV23). METHODS: A total of 190 patients with rheumatoid arthritis (RA) received PPV23. Patients were classified into TCZ (n=50), TCZ + methotrexate (MTX) (n=54), MTX (n=62) and RA control (n=24) groups. We measured serotype-specific IgG concentrations of pneumococcal serotypes 6B and 23F using ELISA and functional antibody activity using a multiplexed opsonophagocytic killing assay, reported as the opsonisation indices (OIs), before and 4-6 weeks after vaccination. Positive antibody response was defined as a 2-fold or more increase in the IgG concentration or as a >=10-fold or more increase in the OI. RESULTS: IgG concentrations and OIs were significantly increased in all treatment groups in response to vaccination. The TCZ group antibody response rates were comparable with those of the RA control group for each serotype. MTX had a negative impact on vaccine efficacy. Multivariate logistic analysis confirmed that TCZ is not associated with an inadequate antibody response to either serotype. No severe adverse effect was observed in any treatment group. CONCLUSIONS: TCZ does not impair PPV23 immunogenicity in RA patients, whereas antibody responses may be reduced when TCZ is used as a combination therapy with MTX. PMID- 23345601 TI - Randomised, controlled trial of avocado-soybean unsaponifiable (Piascledine) effect on structure modification in hip osteoarthritis: the ERADIAS study. AB - OBJECTIVE: To assess the ability of avocado-soybean unsaponifiable-Expanscience (ASU-E) to slow radiographic progression in symptomatic hip osteoarthritis (OA). METHODS: Prospective, randomised, double blind, parallel group, placebo controlled 3 year trial. Patients with symptomatic (painful >=1 year, Lequesne Index between 3 and 10) hip OA (American College of Rheumatology criteria) and a minimum joint space width (JSW) of the target hip between 1 and 4 mm on a pelvic radiograph were randomly assigned to 300 mg/day ASU-E or placebo. Standing pelvis, target hip anteroposterior (AP) and oblique views were taken annually. The primary outcome was JSW change at year 3, measured at the narrowest point on pelvic or target hip AP view (manual measure using a 0.1 mm graduated magnifying glass). The full analysis dataset (FAS) included all patients having at least two successive radiographs. An analysis of covariance Mixed Model for Repeated Measurements with Missing at Random (for missing data) was performed to compare adjusted 3 year JSW changes (primary outcome) and the percentages of 'progressors' (JSW loss>=0.5 mm) between groups. RESULTS: 399 patients were randomised (345 kept in the FAS), aged 62 (35-84) years, 54% women, mean body mass index 27 (SD 4) kg/m(2), mean symptom duration 4 (SD 5) years, 0-100 normalised Lequesne Index 30 (SD 9) and global pain visual analogue scale 37 (SD 23) mm. Mean baseline JSW was 2.8 (0.9) mm. There was no significant difference on mean JSW loss (-0.638 mm vs -0.672 mm, p=0.72, in the ASU-E and placebo groups, respectively) but there were 20% less progressors in the ASU-E than in the placebo group (40% vs 50%, respectively, p=0.040). No difference was observed on clinical outcomes. Safety was excellent. CONCLUSIONS: 3 year treatment with ASU-E reduces the percentage of JSW progressors, indicating a potential structure modifying effect in hip OA to be confirmed, and the clinical relevance requires further assessment. PMID- 23345602 TI - International comparisons of the consultation prevalence of musculoskeletal conditions using population-based healthcare data from England and Sweden. AB - OBJECTIVES: To assess the consultation prevalence of musculoskeletal (MSK) conditions as presented in different healthcare systems, and to determine the feasibility of comparing prevalence figures between nations. METHODS: The settings were an English regional database (Consultations in Primary Care Archive (CiPCA)) and the Swedish Skane County Health Care Register. Case definitions, data extraction and analysis procedures were harmonised. The number of people consulting per 10 000 registered population in primary care, and in primary or secondary care, in the year 2010 (annual consultation prevalence) were determined for doctor-diagnosed osteoarthritis (OA), rheumatoid arthritis (RA), low back pain, and spondyloarthritis including psoriatic arthritis and ankylosing spondylitis (AS). Seven-year period consultation prevalences were also determined. RESULTS: Combining primary and secondary care, annual consultation prevalences of any MSK condition (2143 vs 1610/10 000) and low back pain (587 vs 294/10 000) were higher in England than in Sweden, but higher for RA, spondyloarthritis and psoriatic arthritis in Sweden. Annual primary care prevalence figures for OA (176 vs 196/10 000), RA (25 vs 26/10 000), spondyloarthritis (both 8/10 000) and psoriatic arthritis (5 vs 3/10 000) were similar between England and Sweden. AS was rarely recorded in Swedish primary care. These patterns were also observed for 7-year period consultation prevalences. CONCLUSIONS: A rigorous methodological approach allowed feasible comparison of MSK consultation prevalence between England and Sweden. Differences in prevalence of inflammatory and unspecific pain conditions may be partially explained by known variations in healthcare systems and recording practice. Routine healthcare data offers potential for investigating variations in occurrence and outcome of MSK conditions between nations. PMID- 23345603 TI - Transmission studies resume for avian flu. PMID- 23345604 TI - Neurotransmitter substance P mediates pancreatic cancer perineural invasion via NK-1R in cancer cells. AB - Pancreatic cancer significantly affects the quality of life due to the severe abdominal pain. However, the underlying mechanism is not clear. This study aimed to determine the relationship between Substance P (SP) and pancreatic cancer perineural invasion (PNI) as well as the mechanism of SP mediating pancreatic cancer PNI, which causes pain in patients with pancreatic cancer. Human pancreatic cancer cells and newborn dorsal root ganglions (DRG) were used to determine the expression of SP or NK-1R in pancreatic cancer cells and DRGs cells by QT-PCR and Western blotting. The effects of SP on pancreatic cancer cell proliferation and invasion were analyzed using MTT assay and Transwell Matrigel invasion assay, respectively. Alterations in the neurotropism of pancreatic cancer cells were assessed by coculture system, which mimics the interaction of tumor/neuron in vivo. SP is not only widely distributed in the neurite outgrowth from newborn DRGs but also expressed in MIA PaCa-2 and BxPC-3 cells. NK-1R is found to be overexpressed in the pancreatic cancer cell lines examined. SP induces cancer cell proliferation and invasion as well as the expression of matrix metalloproteinase (MMP)-2 in pancreatic cancer cells, and NK-1R antagonists inhibit these effects. Furthermore, SP promotes neurite outgrowth and the migration of pancreatic cancer cell cluster to the DRGs, which is blocked by NK-1R antagonists in the coculture model. Our results suggest that SP plays an important role in the development of pancreatic cancer metastasis and PNI, and blocking the SP/NK-1R signaling system is a novel strategy for the treatment of pancreatic cancer. PMID- 23345606 TI - Culture of impact: faculty as mentors for student entrepreneurs. PMID- 23345605 TI - Acquisition of the metastatic phenotype is accompanied by H2O2-dependent activation of the p130Cas signaling complex. AB - Reactive oxygen species (ROS) have emerged as cellular signaling molecules and are implicated in metastatic disease by their ability to drive invasion and migration. Here, we define the signaling adaptor protein p130Cas (Crk-associated substrate) as a key redox-responsive molecular trigger that is engaged in highly invasive metastatic bladder tumor cell lines. Endogenous shifts in steady-state hydrogen peroxide (H2O2) that accompany the metastatic phenotype increase p130Cas phosphorylation, membrane recruitment and association with the scaffolding protein Crk, and subsequent Rac1 activation and actin reorganization. Both enzymatic and nonenzymatic scavenging of H2O2 abrogates p130Cas-dependent signaling and the migratory and invasive activity of the metastatic bladder tumor cells. Disruption of p130Cas attenuates both invasion and migration of the metastatic variant (253J-BV). 253J-BV cells displayed an increase in global thiol oxidation and a concomitant decrease in total phosphatase activity, common target proteins of active-site cysteine oxidation. The dependence of phosphatases on regulation of p130Cas was highlighted when depletion of PTPN12 enhanced p130cas phosphorylation and the migratory behavior of a noninvasive parental bladder tumor control (253J). These data show that the metastatic phenotype is accompanied by increases in steady-state H2O2 production that drive promigratory signaling and suggest that antioxidant-based therapeutics may prove useful in limiting bladder tumor invasiveness. PMID- 23345607 TI - A splicing twist on metastasis. AB - An oncogenic splice variant of the transcription factor KLF6 is associated with metastasis and poor survival in node-negative breast cancer patients and promotes the epithelial-to-mesenchymal transition by regulating Twist. PMID- 23345608 TI - DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases. AB - Human cancers almost ubiquitously harbor epigenetic alterations. Although such alterations in epigenetic marks, including DNA methylation, are potentially heritable, they can also be dynamically altered. Given this potential for plasticity, the degree to which epigenetic changes can be subject to selection and act as drivers of neoplasia has been questioned. We carried out genome-scale analyses of DNA methylation alterations in lethal metastatic prostate cancer and created DNA methylation "cityscape" plots to visualize these complex data. We show that somatic DNA methylation alterations, despite showing marked interindividual heterogeneity among men with lethal metastatic prostate cancer, were maintained across all metastases within the same individual. The overall extent of maintenance in DNA methylation changes was comparable to that of genetic copy number alterations. Regions that were frequently hypermethylated across individuals were markedly enriched for cancer- and development/differentiation-related genes. Additionally, regions exhibiting high consistency of hypermethylation across metastases within individuals, even if variably hypermethylated across individuals, showed enrichment for cancer-related genes. Whereas some regions showed intraindividual metastatic tumor heterogeneity in promoter methylation, such methylation alterations were generally not correlated with gene expression. This was despite a general tendency for promoter methylation patterns to be strongly correlated with gene expression, particularly at regions that were variably methylated across individuals. These findings suggest that DNA methylation alterations have the potential for producing selectable driver events in carcinogenesis and disease progression and highlight the possibility of targeting such epigenome alterations for development of longitudinal markers and therapeutic strategies. PMID- 23345609 TI - Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock. AB - Shock, sepsis, and multiorgan failure are associated with inflammation, morbidity, and high mortality. The underlying pathophysiological mechanism is unknown, but evidence suggests that pancreatic enzymes in the intestinal lumen autodigest the intestine and generate systemic inflammation. Blocking these enzymes in the intestine reduces inflammation and multiorgan dysfunction. We investigated whether enzymatic blockade also reduces mortality after shock. Three rat shock models were used here: hemorrhagic shock, peritonitis shock induced by placement of cecal material into the peritoneum, and endotoxin shock. One hour after initiation of hemorrhagic, peritonitis, or endotoxin shock, animals were administered one of three different pancreatic enzyme inhibitors--6-amidino-2 naphtyl p-guanidinobenzoate dimethanesulfate, tranexamic acid, or aprotinin--into the lumen of the small intestine. In all forms of shock, blockade of digestive proteases with protease inhibitor attenuated entry of digestive enzymes into the wall of the intestine and subsequent autodigestion and morphological damage to the intestine, lung, and heart. Animals treated with protease inhibitors also survived in larger numbers than untreated controls over a period of 12 weeks. Surviving animals recovered completely and returned to normal weight within 14 days after shock. The results suggest that the active and concentrated digestive enzymes in the lumen of the intestine play a central role in shock and multiorgan failure, which can be treated with protease inhibitors that are currently available for use in the clinic. PMID- 23345611 TI - Cellular dynamics: seeing is believing. PMID- 23345612 TI - A comparison of support needs between rural and urban family caregivers providing palliative care. AB - The present study examined the support needs for urban and rural family caregivers of a palliative family member using a cross-sectional telephone survey in northeastern Ontario, Canada (n = 140; 70 urban, 70 rural). Support needs identified as most important by both the groups were informational. Rural caregivers reported greater unmet needs in tangible support (P = .01). No differences were observed between the groups for emotional or informational support needs (P = .25 and P = .35, respectively). Rural and urban caregivers perceived care for care recipients as accessible (mean accessibility score 1.9, standard deviation [SD] = 0.09 and 1.7, SD = 0.7, respectively, P = .20); the majority indicated that when needed, services were easily and quickly obtained. Although there are similarities in the formal care experiences, rural caregivers experience greater unmet needs in receiving support for instrumental activities. PMID- 23345610 TI - KLF6-SV1 drives breast cancer metastasis and is associated with poor survival. AB - Metastasis is the major cause of cancer mortality. A more thorough understanding of the mechanisms driving this complex multistep process will aid in the identification and characterization of therapeutically targetable genetic drivers of disease progression. We demonstrate that KLF6-SV1, an oncogenic splice variant of the KLF6 tumor suppressor gene, is associated with increased metastatic potential and poor survival in a cohort of 671 lymph node-negative breast cancer patients. KLF6-SV1 overexpression in mammary epithelial cell lines resulted in an epithelial-to-mesenchymal-like transition and drove aggressive multiorgan metastatic disease in multiple in vivo models. Additionally, KLF6-SV1 loss-of function studies demonstrated reversion to an epithelial and less invasive phenotype. Combined, these findings implicate KLF6-SV1 as a key driver of breast cancer metastasis that distinguishes between indolent and lethal early-stage disease and provides a potential therapeutic target for invasive breast cancer. PMID- 23345613 TI - Use of intravenous fentanyl against morphine tolerance in breakthrough cancer pain: a case series and literature review. AB - Palliative care physicians are accustomed to using transdermal fentanyl patch for cancer pain control but not so familiar with its intravenous administration. Historically, fentanyl has been used to treat breakthrough pain because it is a very potent analgesic with a rapid onset and short duration of action. Although several formulations of fentanyl have been recently developed for breakthrough cancer pain, these are unavailable or too expensive in some countries. Also, all opioids can induce tolerance potentially and different opioids cause significantly different degrees of tolerance. Therefore, sequential opioid trials may be a reasonable approach in patients with poor analgesic effect after dose escalation. Here, we present 2 morphine-tolerant patients with cancer in whom the intravenous fentanyl was effectively used for their refractory breakthrough pain. PMID- 23345614 TI - The use of pentobarbital in cases of severe delirium: a case series. AB - Delirium is a common syndrome present at the end of life and causes significant distress for patients and families. Sleep disruption is a common precipitating factor for delirium and restoration of sleep may be instrumental in attenuating symptoms. In this cases series, we present three patients who were unresponsive to escalating doses of standard delirium medications, but whose delirium resolved once improved sleep was achieved using Pentobarbital. In a fourth patient, delirium was successfully treated where neuroleptics were contraindicated. Pentobarbital has been shown to reduce the time to sleep onset, decrease the number of body movements during sleep and spontaneous awakenings and increase the total sleep time. Pentobarbital may provide an additional treatment option for patients whose delirium is refractory to standard management approaches. PMID- 23345615 TI - Prevalent coordination of mitochondrial DNA transcription and initiation of replication with the cell cycle. AB - Nuclear (nDNA) and mitochondrial DNA (mtDNA) communication is essential for cell function, but it remains unclear whether the replication of these genomes is linked. We inspected human cells with a novel fluorescence in situ hybridization protocol (mitochondrial Transcription and Replication Imaging Protocol) that identifies mitochondrial structures engaged in initiation of mtDNA replication and unique transcript profiles, and reconstruct the temporal series of mitochondrial and nuclear events in single cells during the cell cycle. We show that mtDNA transcription and initiation of replication are prevalently coordinated with the cell cycle, preceding nuclear DNA synthesis, and being reactivated towards the end of S-phase. This coordination is achieved by modulating the fraction of mitochondrial structures that intiate mtDNA synthesis and/or contain transcript at a given time. Thus, although replication of the mitochondrial genome is active through the entire cell cycle, but in a limited fraction of mitochondrial structures, peaks of these activities are synchronized with nDNA synthesis. After release from blockage of mtDNA replication with either nocodazole or double thymidine treatment, prevalent mtDNA and nDNA synthesis occurred simultaneously, indicating that mitochondrial coordination with the nuclear phase can be adjusted in response to physiological alterations. These findings will help redefine other nuclear-mitochondrial links in cell function. PMID- 23345616 TI - Histone H4 lysine 20 methylation: key player in epigenetic regulation of genomic integrity. AB - Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. Nuclear DNA is packaged into chromatin, and thus genome maintenance can be influenced by distinct chromatin environments. In particular, post-translational modifications of histones have emerged as key regulators of genomic integrity. Intense research during the past few years has revealed histone H4 lysine 20 methylation (H4K20me) as critically important for the biological processes that ensure genome integrity, such as DNA damage repair, DNA replication and chromatin compaction. The distinct H4K20 methylation states are mediated by SET8/PR-Set7 that catalyses monomethylation of H4K20, whereas SUV4-20H1 and SUV4-20H2 enzymes mediate further H4K20 methylation to H4K20me2 and H4K20me3. Disruption of these H4K20-specific histone methyltransferases leads to genomic instability, demonstrating the important functions of H4K20 methylation in genome maintenance. In this review, we explain molecular mechanisms underlying these defects and discuss novel ideas for furthering our understanding of genome maintenance in higher eukaryotes. PMID- 23345617 TI - Insight into centromere-binding properties of ParB proteins: a secondary binding motif is essential for bacterial genome maintenance. AB - ParB proteins are one of the three essential components of partition systems that actively segregate bacterial chromosomes and plasmids. In binding to centromere sequences, ParB assembles as nucleoprotein structures called partition complexes. These assemblies are the substrates for the partitioning process that ensures DNA molecules are segregated to both sides of the cell. We recently identified the sopC centromere nucleotides required for binding to the ParB homologue of plasmid F, SopB. This analysis also suggested a role in sopC binding for an arginine residue, R219, located outside the helix-turn-helix (HTH) DNA-binding motif previously shown to be the only determinant for sopC-specific binding. Here, we demonstrated that the R219 residue is critical for SopB binding to sopC during partition. Mutating R219 to alanine or lysine abolished partition by preventing partition complex assembly. Thus, specificity of SopB binding relies on two distinct motifs, an HTH and an arginine residue, which define a split DNA-binding domain larger than previously thought. Bioinformatic analysis over a broad range of chromosomal ParBs generalized our findings with the identification of a non HTH positively charged residue essential for partition and centromere binding, present in a newly identified highly conserved motif. We propose that ParB proteins possess two DNA-binding motifs that form an extended centromere-binding domain, providing high specificity. PMID- 23345618 TI - A non-catalytic role of DNA polymerase eta in recruiting Rad18 and promoting PCNA monoubiquitination at stalled replication forks. AB - Trans-lesion DNA synthesis (TLS) is a DNA damage-tolerance mechanism that uses low-fidelity DNA polymerases to replicate damaged DNA. The inherited cancer propensity syndrome xeroderma pigmentosum variant (XPV) results from error-prone TLS of UV-damaged DNA. TLS is initiated when the Rad6/Rad18 complex monoubiquitinates proliferating cell nuclear antigen (PCNA), but the basis for recruitment of Rad18 to PCNA is not completely understood. Here, we show that Rad18 is targeted to PCNA by DNA polymerase eta (Poleta), the XPV gene product that is mutated in XPV patients. The C-terminal domain of Poleta binds to both Rad18 and PCNA and promotes PCNA monoubiquitination, a function unique to Poleta among Y-family TLS polymerases and dissociable from its catalytic activity. Importantly, XPV cells expressing full-length catalytically-inactive Poleta exhibit increased recruitment of other error-prone TLS polymerases (Polkappa and Poliota) after UV irradiation. These results define a novel non-catalytic role for Poleta in promoting PCNA monoubiquitination and provide a new potential mechanism for mutagenesis and genome instability in XPV individuals. PMID- 23345619 TI - IS200/IS605 family single-strand transposition: mechanism of IS608 strand transfer. AB - Transposase, TnpA, of the IS200/IS605 family member IS608, catalyses single strand DNA transposition and is dimeric with hybrid catalytic sites composed of an HUH motif from one monomer and a catalytic Y127 present in an alpha-helix (alphaD) from the other (trans configuration). alphaD is attached to the main body by a flexible loop. Although the reactions leading to excision of a transposition intermediate are well characterized, little is known about the dynamic behaviour of the transpososome that drives this process. We provide evidence strongly supporting a strand transfer model involving rotation of both alphaD helices from the trans to the cis configuration (HUH and Y residues from the same monomer). Studies with TnpA heterodimers suggest that TnpA cleaves DNA in the trans configuration, and that the catalytic tyrosines linked to the 5' phosphates exchange positions to allow rejoining of the cleaved strands (strand transfer) in the cis configuration. They further imply that, after excision of the transposon junction, TnpA should be reset to a trans configuration before the cleavage required for integration. Analysis also suggests that this mechanism is conserved among members of the IS200/IS605 family. PMID- 23345621 TI - Online haemodiafiltration: definition, dose quantification and safety revisited. AB - The general objective assigned to the EUropean DIALlysis (EUDIAL) Working Group by the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) was to enhance the quality of dialysis therapies in Europe in the broadest possible sense. Given the increasing interest in convective therapies, the Working Group has started by focusing on haemodiafiltration (HDF) therapies. Several reports suggest that those therapies potentially improve the outcomes for end-stage renal disease patients. Europe is the leader in the field, having introduced the concept of ultra-purity for water and dialysis fluids and with notified bodies of the European Community having certified water treatment systems and online HDF machines. The prevalence of online HDF-treated patients is steadily increasing in Europe, averaging 15%. A EUDIAL consensus conference was held in Paris on 13 October 2011 to revisit terminology, safety and efficacy of online HDF. This is the first report of the expert group arising from that conference. PMID- 23345620 TI - Development of bis-locked nucleic acid (bisLNA) oligonucleotides for efficient invasion of supercoiled duplex DNA. AB - In spite of the many developments in synthetic oligonucleotide (ON) chemistry and design, invasion into double-stranded DNA (DSI) under physiological salt and pH conditions remains a challenge. In this work, we provide a new ON tool based on locked nucleic acids (LNAs), designed for strand invasion into duplex DNA (DSI). We thus report on the development of a clamp type of LNA ON-bisLNA-with capacity to bind and invade into supercoiled double-stranded DNA. The bisLNA links a triplex-forming, Hoogsteen-binding, targeting arm with a strand-invading Watson Crick binding arm. Optimization was carried out by varying the number and location of LNA nucleotides and the length of the triplex-forming versus strand invading arms. Single-strand regions in target duplex DNA were mapped using chemical probing. By combining design and increase in LNA content, it was possible to achieve a 100-fold increase in potency with 30% DSI at 450 nM using a bisLNA to plasmid ratio of only 21:1. Although this first conceptual report does not address the utility of bisLNA for the targeting of DNA in a chromosomal context, it shows bisLNA as a promising candidate for interfering also with cellular genes. PMID- 23345623 TI - Length polymorphisms of heme oxygenase-1 determine the effect of far-infrared therapy on the function of arteriovenous fistula in hemodialysis patients: a novel physicogenomic study. AB - BACKGROUND: The objective of this study was to evaluate the interaction between the length polymorphism of the guanosine thymidine repeat [(GT)n] in the heme oxygenase-1 (HO-1) gene and far-infrared (FIR) therapy on access flow (Qa) and arteriovenous fistula (AVF) patency in hemodialysis (HD) patients. METHODS: A total of 280 HD patients were randomized into a control group (n = 141) and the FIR group (n = 139) who received 40 min of FIR therapy three times weekly for a year during the study period from May 2005 to December 2007. Access flow was measured during HD. The [(GT)n] was determined with the definition of long (L) allele as [(GT)n] >= 30 and short (S) allele as [(GT)n] < 30. RESULTS: The Qa decreased from S/S to S/L and further to the L/L group but increased by FIR therapy with the highest Qa increase in the S/S group. The incidence of AVF malfunction decreased both from the L/L, S/L to S/S group (32.4 versus 17.2 versus 10.9%, P = 0.007) and from the control group to FIR group (27.5 versus 12.6%, P = 0.004). Significant associations were found between AVF malfunction and the following factors (hazard ratio, P-value): a past history of AVF malfunction (2.45, P = 0.044), FIR therapy (0.369, P = 0.03) and L/L genotypes of HO-1 (2.531 versus S/S + S/L genotypes). The 1-year unassisted patency decreased from 91.9 and 77.6% in S/S and S/L subgroups with and without FIR therapy to 75.8 and 60% for L/L subgroup with and without FIR therapy, respectively (P < 0.001). CONCLUSIONS: FIR therapy improves Qa and patency of AVF in HD patients, with the best protective effect in those with S/S genotype of HO-1. PMID- 23345622 TI - A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats. AB - BACKGROUND: Anemia is a common complication of chronic kidney disease (CKD) that negatively impacts the quality of life and is associated with numerous adverse outcomes. Excess levels of the iron regulatory hormone hepcidin are thought to contribute to anemia in CKD patients by decreasing iron availability from the diet and from body stores. Adenine treatment in rats has been proposed as an animal model of anemia of CKD with high hepcidin levels that mirrors the condition in human patients. METHODS: We developed a modified adenine-induced kidney disease model with a higher survival rate than previously reported models, while maintaining persistent kidney disease and anemia. We then tested whether the small molecule bone morphogenetic protein (BMP) inhibitor LDN-193189, which was previously shown to lower hepcidin levels in rodents, mobilized iron into the plasma and improved iron-restricted erythropoiesis in this model. RESULTS: Adenine-treated rats exhibited increased hepatic hepcidin mRNA, decreased serum iron, increased spleen iron content, low hemoglobin (Hb) and inappropriately low erythropoietin (EPO) levels relative to the degree of anemia. LDN-193189 administration to adenine-treated rats lowered hepatic hepcidin mRNA, mobilized stored iron into plasma and increased Hb content of reticulocytes. CONCLUSIONS: Our data suggest that hepcidin lowering agents may provide a new therapeutic strategy to improve iron availability for erythropoiesis in CKD. PMID- 23345624 TI - Improved survival among sickle cell kidney transplant recipients in the recent era. AB - BACKGROUND: Studies from older cohorts of kidney recipients have observed that recipients with sickle cell disease (SCD) have lower patient survival compared with age- and race-matched controls. We examined whether survival has improved among SCD recipients in the current era. METHODS: Using Organ Procurement and Transplantation Network/United Network for Organ Sharing data, all black/African American kidney recipients were stratified according to transplant year into an early (1988-99) and recent era (2000-11). Patient and allograft survival among SCD recipients and those with other diagnoses were compared (early era: SCD n = 67, others n = 20 694; recent era: SCD n = 106, others n = 34 428). A secondary matched cohort analysis compared patient and allograft survival between SCD recipients matched to recipients with other diagnoses based on recipient and donor age, gender and donor type (deceased versus living). RESULTS: Patient survival at 6 years was lower among SCD recipients in the early era compared with other diagnoses (55.7 versus 78.0%; P < 0.001). Six-year patient survival among sickle cell recipients improved in the recent era (69.8%; P versus early era = 0.04), although still trended toward lower survival compared with other diagnoses (80.0%; P = 0.07). Multivariate Cox proportional hazard models revealed an increased mortality risk with SCD in both eras [early: hazard ratio (HR) = 3.12; 95% confidence interval (CI): 2.15-4.54; recent: HR: 2.03; 95% CI: 1.31-3.16]. Patient survival among matched SCD recipients in the recent era was comparable to diabetic recipients (SCD: 73.1%, diabetes: 74.1%; P = 0.44). CONCLUSIONS: Patient survival has improved among contemporary sickle cell recipients compared with an earlier cohort and is comparable to a matched cohort of diabetic kidney recipients. Appropriately selected SCD patients may receive kidney transplants with reasonable survival outcome. PMID- 23345625 TI - Thalidomide suppresses inflammation in adenine-induced CKD with uraemia in mice. AB - BACKGROUND: Persistent systemic inflammation has been widely recognized in patients with chronic kidney disease (CKD), and is associated with increased risk of morbidity and mortality. Intervention therapies aiming for the blockade of inflammatory cytokines are considered attractive approaches for CKD patients with signs of chronic inflammation. In this context, thalidomide, due to its potent anti-inflammatory and immunomodulatory properties, may represent an alternative strategy of treatment. In the present study, we developed an experimental model of CKD with uraemia in mice, induced by a diet rich in adenine, which causes progressive renal dysfunction, resembling the human uraemic features. Inflammatory parameters were analysed in this model of CKD and the potential beneficial effects of thalidomide as an anti-inflammatory drug was also investigated. METHODS: C57/BL-6 mice were fed with an adenine-containing diet during a period of 6 weeks. Thirty mice were divided into three groups: Control group (animals receiving normal diet), ADE group (mice receiving adenine containing diet) and ADE + TLD group (CKD mice receiving thalidomide, 30 mg/kg/day, by gavage). Besides biochemical and histopathological changes, local and systemic inflammatory parameters were also analysed, including expression of cytokines interleukin (IL)-1beta, tumour necrosis factor-alpha, IL-6, IL-4 and IL 10 in kidney samples by real-time RT-PCR and quantification of serum levels of cytokines. Finally, the electrophoretic mobility shift assay (EMSA) for NF-kappaB was also examined. RESULTS: Adenine-fed mice developed advanced CKD characterized by a marked increase in serum urea, creatinine, phosphorus and intact parathyroid hormone (iPTH) levels. In addition, histological changes of tubulointerstitial injury, characterized by deposition of crystals in the kidney, accompanied by tubular dilatation, degeneration of proximal tubular epithelium with loss of the brush border, inflammatory cellular infiltration, foreign-body granuloma formation and interstitial fibrosis were also evident. By immunohistochemistry, Mac-2- and alpha-SMA-positive cells were identified in the tubulointerstitial compartment. Treatment with thalidomide significantly reduced serum urea, creatinine, phosphorus and iPTH levels and protected against tubulointerstitial injury. Local and systemic inflammation in the mice model of adenine-induced CKD was confirmed by the findings of significantly high expression of cytokine mRNA levels and NF-kappaB activation in the kidney tissue as well as marked increased serum levels of inflammatory cytokines. Thalidomide treatment significantly reduced gene expression of these cytokines and the activation of the NF-kappaB in the renal tissue and the circulating levels of cytokines. CONCLUSIONS: Dietary adenine caused advanced CKD with uraemia in mice providing a useful experimental model to study molecular and morphological changes associated with this disease. The negative impact of inflammation in this CKD model was overcome by the marked anti-inflammatory effects of thalidomide, promoting renal protection. PMID- 23345626 TI - Associations of marital status with mortality from all causes and mortality from cardiovascular disease in Japanese haemodialysis patients. AB - BACKGROUND: Marital status is an important social factor associated with increased mortality from cardiovascular disease (CVD) and all causes. However, there has been no study on the association of marital status with mortality in haemodialysis patients. METHODS: We analysed data from a 5-year prospective cohort study of 1064 Japanese haemodialysis patients aged 30 years or older. Marital status was classified into three groups: married, single and divorced/widowed. Cox's regression was used to estimate multivariate hazard ratios (HRs) [95% confidence intervals (CIs)] for all-cause mortality and CVD mortality according to marital status after adjusting for age, sex, duration of haemodialysis, cause of renal failure, body mass index, systolic blood pressure, total cholesterol, high density lipoprotein-cholesterol, albumin, high sensitivity C-reactive protein, co-morbid conditions, smoking, alcohol consumption, education levels and job status. RESULTS: Single patients had higher risks than married patients for mortality from all causes (HR = 1.51, 95% CI: 1.06-2.16) and mortality from CVD (HR = 1.68, 95% CI: 1.03-2.76), and divorced/widowed patients had a higher risk than married patients for mortality from CVD (HR = 1.73, 95% CI: 1.15-2.60). After stratification by age, single patients aged 30-59 years had significantly higher risks for all-cause mortality and CVD mortality. CONCLUSIONS: The findings suggest that single status is a significant predictor for all-cause mortality and CVD mortality and that divorced/widowed status is a significant predictor for CVD mortality in haemodialysis patients. PMID- 23345627 TI - Lupus nephritis in children and adolescents: results of the Italian Collaborative Study. AB - BACKGROUND: Lupus nephritis (LN) strongly affects the outcome in children with systemic lupus erythematosus (SLE). Many patients, however, have renal disease at onset, but lack a sufficient number of criteria to be diagnosed as SLE and develop delayed symptoms over time (d-SLE). Data on the clinical course, long term outcome and predictors of disease progression in children with LN are scant. METHODS: The Italian Collaborative Study included 161 paediatric patients with LN who were followed up for a mean of 96 months (range 6-296) in seven paediatric nephrology units. Cox-Mantel regression models were used to identify predictors of disease remission, relapse and progression. RESULTS: At 1 year, the proportion of patients in remission was 83.2% (partial) and 53.5% (complete). Renal flares occurred in >50% of patients within 10 years. The intensity of induction treatment correlated significantly with the achievement of remission, while d SLE, class IV LN and younger age were associated with poor response to treatment and/or with progression to chronic renal failure. CONCLUSIONS: The current study provides outcome data on a large paediatric population with LN and underlines the importance of prescribing appropriate induction treatment to all children, regardless of the presence of enough SLE criteria, which may develop several years after the initial diagnosis. PMID- 23345628 TI - The utility of cone beam volume CT in the evaluation of thrombosed intracranial aneurysms in subarachnoid hemorrhage. AB - Thrombosed aneurysms are difficult to visualize with digital subtraction angiography. We report a case of subarachnoid hemorrhage from a thrombosed ruptured aneurysm which was undetected on digital subtraction angiography but was visualized with cone beam volume CT. To our knowledge, this is the first report highlighting the utility of cone beam volume CT in identifying such aneurysms. PMID- 23345629 TI - Percutaneous sacroplasty using CT guidance for pain palliation in sacral insufficiency fractures. AB - BACKGROUND AND OBJECTIVE: Sacroplasty has emerged as a treatment option for patients with painful osteoporotic sacral insufficiency fractures. We report short-term outcomes in a consecutive cohort of patients treated with sacroplasty. METHODS: We retrospectively reviewed 57 patients treated with sacroplasty for painful osteoporotic sacral fractures at our institution between 2004 and 2011. An 11-point numerical rating scale pain score was recorded at rest and at activity pre- and post-procedure. Opioids prescribed to the patient both pre- and post-procedure were recorded. RESULTS: Mean duration of pain prior to sacroplasty was 3 weeks (IQR 2-5). Procedural complications were minimal. Median post procedure follow-up time was 2.5 weeks (IQR 1-5) among 45 patients with available data. Thirty-seven (82%) of the 45 patients experienced a numerical or descriptive decrease from initial pain at follow-up. Median activity pain scores collected from 13 patients decreased from 10 (IQR 8.5-10) pre-procedure to 6 (IQR 4-6.8) post-procedure (p<0.0001), and median rest pain scores collected from 29 patients decreased from 7 (IQR 4-8.5) to 2 (IQR 1-3.5)(p<0.0001). Twenty-two (76%) of 29 patients had at least a 30% decrease in rest pain scores. The median number of opioids prescribed per patient decreased from 1 (IQR 1-2) pre-procedure to 0 (IQR 0-1) post-procedure (p<0.0001). Thirty-four of 57 patients (60%) had decreased opioid usage, 15 (26%) patients had unchanged usage and 8 (14%) had increased usage. CONCLUSIONS: Our series demonstrates that sacroplasty is a safe and effective treatment in patients with painful osteoporotic insufficiency fractures. PMID- 23345630 TI - Treatment of recurrent intracranial aneurysms with the Pipeline Embolization Device. AB - BACKGROUND: The treatment of recurrent aneurysms after previous surgery or embolization is challenging. Little is known regarding the use of the Pipeline Embolization Device (PED) for recurrent aneurysms. OBJECTIVE: To analyze the safety and results of PED therapy for recurrent aneurysms. METHODS: Fifteen patients with recurrent intracranial aneurysms after previous embolization or surgical clipping were treated with the PED at our institution between 2011 and 2012. Procedural complications and clinical and angiographic outcomes were analyzed. RESULTS: Median aneurysm size was 12 mm. Previous aneurysm treatment consisted of coiling in eight patients, stent coiling in four, a telescoping stent technique in two and surgical clipping in one. Major procedural complications (leaving significant morbidity) occurred in one patient (6.7%) and minor procedural or technical complications (no or minor morbidity) occurred in four patients (26.7%). Fourteen of the 15 patients (93.3%) had a favorable outcome (modified Rankin Scale score 0-2). Of 14 patients with angiographic follow-up, nine (64.3%) had complete aneurysm occlusion (100%), four (28.6%) had near-complete occlusion (>=90%) and only one (7.1%) had incomplete occlusion (<90%). Four of the five patients with less than 100% occlusion at follow-up had a previous stent in situ. CONCLUSIONS: Treatment of recurrent aneurysms with the PED appears to be effective, but patients with a previous stent in situ may achieve lower obliteration rates. The morbidity rate associated with PED therapy may be higher than with more standard endovascular techniques using historical data. Larger studies are needed to assess this question better. PMID- 23345631 TI - The history of INSTOR. PMID- 23345632 TI - Provocation of migraine with aura using natural trigger factors. AB - OBJECTIVE: It is well-known that migraine attacks can be precipitated by various stimuli. More than 50% of patients with migraine with aura (MA) know of at least one stimulus that always or often triggers their MA attacks. The objective of this study was to expose patients with MA to their self-reported trigger factors in order to assess the causal relation between trigger factors and attacks. METHODS: We recruited 27 patients with MA who reported that bright or flickering light or strenuous exercise would trigger their migraine attacks. The patients were experimentally provoked by different types of photo stimulation, strenuous exercise, or a combination of these 2 factors. During and following provocation, the patients would report any aura symptoms or other migraine-related symptoms. RESULTS: Of 27 provoked patients with MA, 3 (11%) reported attacks of MA following provocation. An additional 3 patients reported migraine without aura attacks. Following exercise, 4 out of 12 patients reported migraine, while no patients developed attacks following photo stimulation. CONCLUSION: Experimental provocation using self-reported natural trigger factors causes MA only in a small subgroup of patients with MA. Prospective confirmation is important for future studies of migraine trigger factors and in the clinical management of patients with migraine. PMID- 23345633 TI - Large-vessel correlates of cerebral small-vessel disease. AB - OBJECTIVE: Our aim was to investigate the relationship of carotid structure and function with MRI markers of cerebral ischemic small-vessel disease. METHODS: The study comprised 1,800 participants (aged 72.5 +/- 4.1 years, 59.4% women) from the 3C-Dijon Study, a population-based, prospective cohort study, who had undergone quantitative brain MRI and carotid ultrasound. We used multivariable logistic and linear regression adjusted for age, sex, and vascular risk factors. RESULTS: Presence of carotid plaque and increasing carotid lumen diameter (but not common carotid artery intima-media thickness) were associated with higher prevalence of lacunar infarcts: odds ratio (OR) = 1.60 (95% confidence interval [CI]: 1.09-2.35), p = 0.02 and OR = 1.24 (95% CI: 1.02-1.50), p = 0.03 (by SD increase). Carotid plaque was also associated with large white matter hyperintensity volume (WMHV) (age-specific top quartile of WMHV distribution): OR = 1.32 (95% CI: 1.04-1.67), p = 0.02, independently of vascular risk factors. Increasing Young elastic modulus and higher circumferential wall stress, reflecting augmented carotid stiffness, were associated with increasing WMHV (effect estimate [beta] +/- standard error: 0.0003 +/- 0.0001, p = 0.024; beta +/ standard error: 0.005 +/- 0.002, p = 0.008). Large WMHV was also associated with increasing Young elastic modulus (OR = 1.22 [95% CI: 1.04-1.42], p = 0.01) and with decreasing distensibility coefficient (OR = 0.83 [95% CI: 0.69-0.99], p = 0.04), independently of vascular risk factors. Associations of carotid lumen diameter with lacunar infarcts and of carotid stiffness markers with WMHV were independent of carotid plaque. CONCLUSIONS: In addition to and independently of carotid plaque, increasing carotid lumen diameter and markers of carotid stiffness were associated with increasing prevalence of lacunar infarcts and increasing WMHV, respectively. PMID- 23345634 TI - The THRombolysis and STatins (THRaST) study. AB - OBJECTIVE: To assess the impact on stroke outcome of statin use in the acute phase after IV thrombolysis. METHODS: Multicenter study on prospectively collected data of 2,072 stroke patients treated with IV thrombolysis. Outcome measures of efficacy were neurologic improvement (NIH Stroke Scale [NIHSS] <= 4 points from baseline or NIHSS = 0) and major neurologic improvement (NIHSS <= 8 points from baseline or NIHSS = 0) at 7 days and favorable (modified Rankin Scale [mRS] <= 2) and excellent functional outcome (mRS <= 1) at 3 months. Outcome measures of safety were 7-day neurologic deterioration (NIHSS >= 4 points from baseline or death), symptomatic intracerebral hemorrhage type 2 with NIHSS >= 4 points from baseline or death within 36 hours, and 3-month death. RESULTS: Adjusted multivariate analysis showed that statin use in the acute phase was associated with neurologic improvement (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.26-2.25; p < 0.001), major neurologic improvement (OR 1.43, 95% CI 1.11-1.85; p = 0.006), favorable functional outcome (OR 1.63, 95% CI 1.18 2.26; p = 0.003), and a reduced risk of neurologic deterioration (OR: 0.31, 95% CI 0.19-0.53; p < 0.001) and death (OR 0.48, 95% CI 0.28-0.82; p = 0.007). CONCLUSION: Statin use in the acute phase of stroke after IV thrombolysis may positively influence short- and long-term outcome. PMID- 23345635 TI - Rivastigmine for HIV-associated neurocognitive disorders: a randomized crossover pilot study. AB - OBJECTIVE: To assess the efficacy and safety of rivastigmine for the treatment of HIV-associated neurocognitive disorders (HAND) in a cohort of long-lasting aviremic HIV+ patients. METHODS: Seventeen aviremic HIV+ patients with HAND were enrolled in a randomized, double-blind, placebo-controlled, crossover study to receive either oral rivastigmine (up to 12 mg/day for 20 weeks) followed by placebo (20 weeks) or placebo followed by rivastigmine. Efficacy endpoints were improvement on rivastigmine in the Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog) and individual neuropsychological scores of information processing speed, attention/working memory, executive functioning, and motor skills. Measures of safety included frequency and nature of adverse events and abnormalities on laboratory tests and on plasma concentrations of antiretroviral drugs. Analyses of variance with repeated measures were computed to look for treatment effects. RESULTS: There was no change on the primary outcome ADAS-Cog on drug. For secondary outcomes, processing speed improved on rivastigmine (trail making test A: F(1,13) = 5.57, p = 0.03). One measure of executive functioning just failed to reach significance (CANTAB spatial working memory [strategy]: F(1,13) = 3.94, p = 0.069). No other change was observed. Adverse events were frequent, but not different from those observed in other populations treated with rivastigmine. No safety issues were recorded. CONCLUSIONS: Rivastigmine in aviremic HIV+ patients with HAND seemed to improve psychomotor speed. A larger trial with the better tolerated transdermal form of rivastigmine is warranted. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that rivastigmine is ineffective for improving ADAS-Cog scores, but is effective in improving some secondary outcome measures in aviremic HIV+ patients with HAND. PMID- 23345636 TI - Shoulder taping reduces injury and pain in stroke patients: randomized controlled trial. AB - OBJECTIVES: We aimed to study the effectiveness of shoulder taping and conventional treatment vs sham taping and conventional treatment in prevention of shoulder injuries in patients with acute stroke. METHODS: This study was a multicenter, interventional, prospective, randomized, outcome-blinded trial (PROBE design). All first-ever stroke patients were included within 48 hours of stroke onset (August 2009-October 2011). The treatment group included shoulder taping and conventional treatment, and the control group received sham taping and conventional treatment. Primary outcomes were changes in visual analog scale (VAS) and shoulder pain and disability index (SPADI), and secondary outcomes were changes in shoulder range of motion (flexion and abduction) at days 14 and 30. Clinical trials registration no. NCT 01062308. RESULTS: There were 80 patients in the treatment arm and 82 in the control arm. There was a better reduction of VAS (on day 14: mean difference 3.7 mm, p = 0.45; on day 30: 11.9 mm, p = 0.03) and SPADI scores (on day 14: mean difference 3.5, p = 0.33; on day 30: 9.3, p = 0.04) in the treatment arm. CONCLUSIONS: Although there was a trend toward pain reduction and functional improvement associated with shoulder taping for 2 weeks after acute stage of stroke, this did not reach statistical significance. The long-term effects of taping need to be studied in large trials. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that tri-pull shoulder taping was ineffective in significantly reducing shoulder pain in patients with acute stoke. PMID- 23345637 TI - Prognostic factors of motor impairment, disability, and quality of life in newly diagnosed PD. AB - OBJECTIVE: In Parkinson disease (PD), the rate of clinical progression is highly variable. To date, there are conflicting findings concerning the prognostic factors influencing the rate of progression. Methodologic issues such as the use of selected patients from therapeutic trials, and short durations of follow-up probably underlie this problem. We therefore designed a prospective follow-up study of a cohort of newly diagnosed patients with PD. METHODS: A cohort of 129 patients with newly diagnosed PD was assessed at baseline, and 1, 2, 3, and 5 years later. The rate of progression and its prognostic factors on the level of motor impairments, disability, and quality of life were investigated using linear mixed-model analysis. RESULTS: Annual increase of motor impairments measured with the Unified Parkinson's Disease Rating Scale-Motor Examination was estimated to be 2.46 points (95% confidence interval: 2.05-2.88). The main determinants of faster increase of motor impairments were male sex and cognitive dysfunction at the time of diagnosis. The main determinants of faster increase of disability were higher age at onset, cognitive dysfunction, and the presence of levodopa nonresponsive motor symptoms at the time of diagnosis. No clinically relevant determinants were found for the decrease in quality of life. CONCLUSION: This study shows the importance of nondopaminergic symptoms at the time of diagnosis, because these symptoms are the main determinants of increased disability in the first 5 years of the disease. PMID- 23345638 TI - ALS dysphagia pathophysiology: differential botulinum toxin response. AB - OBJECTIVES: This study looked at the effect of botulinum toxin type A (BoTox-A) in patients with amyotrophic lateral sclerosis (ALS) with dysphagia due to isolated upper motor neuron (UMN) involvement or combined UMN/lower motor neuron (LMN) impairment associated with oral phase or oropharyngeal muscles involvement. Establishing whether different pathophysiologic mechanisms underlie different responses to BoTox-A treatment may have important implications for patient management. PATIENTS AND METHODS: We screened 35 patients with sporadic ALS with dysphagia and included in the study 20 out of 35 with upper esophageal sphincter (UES) hyperactivity. We divided these 20 patients into 2 groups, based on the presence or absence of LMN impairment. Irrespective of the groups, we treated all 20 patients with BoTox-A injected into the UES. The study outcome was dysphagia severity scored using the Penetration/Aspiration Scale (PAS), measured before and 2, 4, and 20 weeks after injection. RESULTS: Significant mean PAS reduction was noted at weeks 2 and 4. The botulinum-dependent PAS reduction was entirely associated with the variability shown by the group of patients with no sign of LMN impairment (group 2) and was not observed in group 1. CONCLUSIONS: The significant improvement observed in patients with isolated UES dysfunction suggests that a different pathophysiology of ALS dysphagia predisposes patients to a different response to treatment with BoTox-A. This treatment may represent an alternative treatment to percutaneous endoscopic gastrostomy (PEG) or prolong PEG-free time. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that botulinum is more effective at 2 and 4 weeks in improving dysphagia in patients with ALS with UES hyperactivity without LMN involvement (vs those with LMN involvement). PMID- 23345640 TI - Migraine triggers: harnessing the messages of clinical practice. PMID- 23345639 TI - A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury. AB - OBJECTIVE: To assess the efficacy and tolerability of pregabalin for the treatment of central neuropathic pain after spinal cord injury (SCI). METHODS: Patients with chronic, below-level, neuropathic pain due to SCI were randomized to receive 150 to 600 mg/d pregabalin (n = 108) or matching placebo (n = 112) for 17 weeks. Pain was classified in relation to the neurologic level of injury, defined as the most caudal spinal cord segment with normal sensory and motor function, as above, at, or below level. The primary outcome measure was duration adjusted average change in pain. Key secondary outcome measures included the change in mean pain score from baseline to end point, the percentage of patients with >=30% reduction in mean pain score at end point, patient global impression of change scores at end point, and the change in mean pain-related sleep interference score from baseline to end point. Additional outcome measures included the medical outcomes study-sleep scale and the Hospital anxiety and depression scale. RESULTS: Pregabalin treatment resulted in statistically significant improvements over placebo for all primary and key secondary outcome measures. Significant pain improvement was evident as early as week 1 and was sustained throughout the treatment period. Adverse events were consistent with the known safety profile of pregabalin and were mostly mild to moderate in severity. Somnolence and dizziness were most frequently reported. CONCLUSIONS: This study demonstrates that pregabalin is effective and well tolerated in patients with neuropathic pain due to SCI. CLASSIFICATION OF EVIDENCE: This study provides class I evidence that pregabalin, 150 to 600 mg/d, is effective in reducing duration-adjusted average change in pain compared with baseline in patients with SCI over a 16-week period (p = 0.003, 95% confidence interval = 0.98, -0.20). PMID- 23345641 TI - Functional disturbance of the locomotor network in progressive supranuclear palsy. AB - OBJECTIVE: To determine pathologic regulations and potential compensatory mechanisms in the supraspinal locomotor network of patients with progressive supranuclear palsy (PSP) by investigation of brain activation during walking and correlation to gait performance. METHODS: Twelve patients with PSP were scanned with [18F]-FDG-PET during walking and at rest as has been described earlier. Results were compared to age-matched healthy controls (n = 12). RESULTS: The major results were as follows. (1) At rest, the regional cerebral glucose metabolism (rCGM) in the supraspinal locomotor centers, i.e., the prefrontal cortex, the subthalamic nucleus, and the pedunculopontine/cuneiform nucleus complex, was reduced in PSP. (2) Severity of gait impairment, measured by gait velocity, step length, and progressive supranuclear palsy rating scales/gait, correlated with decrease of rCGM in the prefrontal cortex and subthalamic nucleus. (3) Accordingly, during walking functional activation of the prefrontal cortex, the subthalamic nucleus, the pedunculopontine/cuneiform nucleus complex, and the thalamus was reduced in patients with PSP compared to controls. (4) The precentral gyrus and the vermal cerebellum were activated more strongly during locomotion in PSP. CONCLUSIONS: Gait impairment in PSP is especially associated with dysfunction of the indirect, modulatory prefrontal-subthalamic pedunculopontine loop of locomotor control. The direct, stereotyped locomotor loop from the primary motor cortex to the spinal cord with rhythmic cerebellar drive shows increased activity in PSP. The latter can be interpreted as an attempt of compensation, but may also contribute to a stereotyped gait pattern in PSP. PMID- 23345643 TI - Photo quiz. 21-Year-old male trauma patient with skin and liver lesions, hepatitis, and coagulopathy. PMID- 23345645 TI - NHC-Based Self-Assembled Monolayers on Solid Gold Substrates. AB - Thin films of 1,3-diethylbenzimidazol-2-ylidene (BIEt) were fabricated from THF solution on solid gold substrates and characterised by high-resolution X-ray photoelectron and near-edge X-ray absorption fine structure spectroscopy. The surface-analytical data are in accord with the formation of self-assembled monolayers of BIEt molecules exhibiting an approximately vertical orientation on the substrate. The crystal structure of (BIEt)(2) was also determined. PMID- 23345646 TI - Suppression of Chaos in a One-dimensional Mapping. AB - The suppression of chaos in an one-dimensional model of malignant tumor growth is presented. As a result, a steady-state and differentperiodic motions, embedded in the chaotic attractor, arestabilized. PMID- 23345647 TI - Detailed analysis of a nonlinear prey-predator model. AB - A model of competition between populations of two species, describedby a two dimensional map, is analytically and numerically studied. A rich dynamics is observed. PMID- 23345648 TI - Sscillatory Cortical Activity during Visual Hallucinations. AB - From a theoretical point of view we investigate cortical activity patterns causing dynamic visual hallucinations. For this reason we analyze an oscillatory instability of the dynamics ofthe activator-inhibitor model of Ermentrout and Cowan.Such an oscillatory instability occurs as a result of several disease mechanisms.We explicitly derive the order parameter equation. By means of the averaging theorem, we obtain the averaged order parameter equation.The latter enables us to determine stable and unstable bifurcating cortical activity patterns analytically in lowest order.Depending on model parameters as well as on initial conditions two types of cortical activity patterns occur: travelling waves and 'blinking rolls', i.e.standing waves oscillating with the same frequency and with a phase shift of pi/2. In contrast to cortical activitypatterns caused by non-oscillatory instabilitiesanalyzed by Ermentrout and Cowan and by the author the travelling waves and the blinking rolls lead to a variety of dynamic visual hallucinations which are discussed indetail. PMID- 23345649 TI - An electrical model for the cytoplasmic calcium wave in fertilized eggs. AB - The calcium wave subsequent to fertilization of the egg is analyzed interms of an electrical equivalent circuit. The circuit consists of aswitch, capacitor, an inductor, and a resistor. The switch symbolizes aseries of chemical reactions initiated by the sperm the lead to thedevelopment of the calcium wave. Its closure signifies the onset of thecalcium wave. The capacitor and inductor represent the endoplasmicreticulum. The capacitive component of the endoplasmic reticulum controlsthe release of calcium ions while the inductive component regulates thesequestration of clacium ions. The resistor represents the inductor andcytoplasm and has very low resistance. The analysis of the circuit showsthat the period of the calcium oscillations is proportional to the size ofthe egg. It agrees with the measurements on various types of eggs. PMID- 23345650 TI - Phase grating from ordered polymer lattices for optica image preprocessing. AB - The 'inverted' retina of the human eye can beemulated by multilayer gratings from polymer latexparticles located in the image plane of opticalsystems. This so called OPTO-RETINA provides v. Laueinterference patterns in visible light with atrichromatic characteristic containing,simultaneously, local spatiotemporal direction anddistance information, which are relevant to 3Dspatial vision and 4D spatiotemporal Fouriercorrelator-optical preprocessing in shape andmotion analysis.As a first step in the realization of OPTO-RETINAproperties the formation of hexagonally orderedmonolayers of polystyrene latex sphereswith diameters in the~MUm range is reported and firstresults of diffraction and dispersion of white lightby these layers obtained by conoscopical opticalmicroscopy are presented. PMID- 23345651 TI - Synaptic vesicle dynamics: a simple model of phasic release. AB - We present a simple model of phasic neurotransmitter release whichreproduces the salient features of chemical neurotransmission. The synapticvesicle cycle has been modelled as a set of biochemical reactionsrepresented by a system of coupled differential equations. These equationshave been solved analytically to obtain the time dependent behaviour of thesystem on perturbation from the steady state. The scheme of the synapticvesicle network has been emphasized and its role in determining some of themajor experimentally observed properties of synaptic transmission has beendiscussed, which includes the biphasic decay of the rate neurotransmitterrelease even under sustained stimulation. Another interesting outcome ofthis theoretical exercise is the saturation of total release with thecalcium dependent rate constant. The theoretically calculated values oftotal release fit very well into a sigmoidal saturating function with afourth order cooperativity exponent similar to the empiricalDodge-Rahamimoff equation. It appears that the synaptic vesiclenetwork itself is responsible for some of the major properties associatedwith chemical neurotransmission. PMID- 23345652 TI - Extension of Gatlin's Informational Divergence to Markovian Stochastic Processes. AB - In the information theoretic framework, to some extent, the complexity ofa system can be measured by its informational divergence which is thedifference between the maximum possible value of its entropy and theactual value of the latter. In her analysis of the DNA chain, Gatlinput in evidence two different divergences. One which drops the mutualdependences between the bases (A, C, G, T) and the other one whichexplicitly refers to this dependence via conditional entropies, and thus,provides a measure of the structural complexity of the system. One showshow the explicit form of this structural divergence can be obtained fordiscrete and continuous Markovian stochastic processes, and in the lattercase, as expected, this divergence is invariant under a transformation ofvariables. PMID- 23345653 TI - A Description of Reverse Osmosis using Practical Kedem-Katchalsky Equations. AB - The work is concerned with an analytical description of reverseosmosis using the Kedem-Katchalsky equations.The process has been considered for well-mixed solutions.We have obtained formulas describing the concentration of a solution(purified by reverse osmosis) as a function of the transportparameters of a membrane, concentration of the initial solution, andthe mechanical pressures on the membrane.The formulae are illustrated by numerical computations.Our results may be applicable to biophysical studies concerningreverse osmosis in biological membrane systems. PMID- 23345654 TI - Effect of fibrin polymerzation on flow properties of coagulating blood. AB - The evolution of stress in coagulating blood is described by aMaxwell-like constitutive model. The evolution is essentiallyaffected by conversion of fibrinogen to fibrin monomer, fibrinpolymerization and its crosslinking. The modifying effects of theprocess result from the active constituents of blood plasma,blood cell concentration and intensity of flow. Interrelationof stress evolution and the kinetics of polymerization species these effects in terms of the order of the kinetics ofpolymerization and degree of fibrin polymerization and values of the constitutive coefficients. The results are presented for a normal blood, averaging the effect of blood constituents and blood platelets on coagulation. PMID- 23345655 TI - Resolving linear and non-linear interactive kinetic mechanisms for ions in membrane channels. AB - Thallous ion in gramicidin channels displays the anomalous molefraction effect and other behavior that suggests its permeationmechanism might be more complicated than the mechanisms for sodiumor potassium ion permeation. The permeation is modeled by eithermultistate first order kinetics where the number of states and therate constants are modified to fit the data or an ion displacementmechanism that requires higher order rate terms. Although the twoclasses of mechanism are difficult to distinguish usingcurrent-voltage data, the two classes give different responses toa modulated transmembrane potential with frequency comparable tothe rate constants for intrachannel ion transitions. Themultistate first order kinetics give currents only at themodulation frequency. Information is transmitted in the phase andamplitude of the observed current. The non-linear iondisplacement mechanism produces harmonic frequencies. A detailedspectral analysis then distinguishes the two classes of mechanismand provides a range of frequency and phase data that permitsdetermination of the appropriate rate constants. PMID- 23345656 TI - Selective interaction model and photoreceptor cell membrane. AB - A mathematical model is proposed in order to describe, from the thermodynamic point of view, the changes in the photoreceptorcell membrane induced by light stimuli. The phenomenologicalbackground is the increase of the fly microvillar membrane ionicconductivity as a consequence of Ca(++-)Na(+) affinity modification under light action. On the basis of the analogywith the model of protein interaction in mixed solvents, themodel is focused on the selective interaction between ionchannels gates and two ionic ligands. Three possible theoretical cases are examined. PMID- 23345657 TI - Influence of medium and long range interactions in different structural classes of globular proteins. AB - An analysis of the dependence known three dimensional structure ofglobular proteins on their residue contacts and their interactions providesmuch information about their folding and stability. In this work, we analysethe residue-residue contacts and the role of medium and long rangeinteractions in globular proteins belonging to different structural classes.The results show that while medium range interactions predominate in allalpha class proteins, long range interactions predominate in all beta class.The residues Pro and Gly are found to have lowest medium range contacts,probably due to their helix breaking tendency. The hydrophobic residues Ile,Val and Tyr have higher long range contacts, and hence may serve as goodnucleation centres. Further, the role of charged residues and disulfidebridges in these interactions are also discussed. PMID- 23345658 TI - Boltzmann entropy: generalization and applications. AB - The object of the paper is to generalize Boltzmann entropy to takeaccount of the subjective nature of a system. The generalized entropyor relative entropy so obtained has been applied to an ecologicalsystem leading to some interesting new results in violation ofexisting physical laws. The entropy was further developed to derive ageneralized macroscopic measure of relative entropy which plays asignificant role in the study of stability and evolution ofecological and chemical reaction systems. PMID- 23345659 TI - Vibrations in microtubules. AB - Vibrations in microtubules and actin filaments are analysed using amethod similar to that employed for description of lattice vibrationsin solid state physics. The derived dispersion relations show thatvibrations in microtubules can have optical and acoustical branches.The highest frequency of vibrations in microtubules and in actinfilaments is of the order of 10(8) Hz. Vibrations are polar andinteraction with surroundings is mediated by the generatedelectromagnetic field. Supply of energy from hydrolysis of guanosinetriphosphate (GTP) in microtubules and of adenosine triphosphate(ATP) in actin filaments may excite the vibrations. PMID- 23345660 TI - The Investigation of Time-dependent Solute Transport through Horizontally Situated Membrane: The Effect of Configuration Membrane System. AB - This paper presents an experimental and theoretical investigation ofsolute transport through a horizontally situated membrane. Theexperimental investigation was carried out by the laserinterferometric method in association with a computer system ofinterference image analysis. On the basis of this analysis thicknessof near-membrane layers, solution concentration drops on these layersas well as diffusion fluxes of diluted substance are determined.Different fluxes of the soluble substance are observed depending onthe configuration of the system. The results of the experimental andtheoretical investigation of diffusion fluxes are conformable inrespect of measurement error, with one adjustment parameter, i.e. thesolute partition coefficient. PMID- 23345661 TI - Ion regulation of the kinetics of potential-dependent potassium channels. AB - We apply a theoretical approach developed earlier. The interaction ofions that permeate a channel with slowly relaxing charged channel-forminggroups (ion conformational interaction - ICI) is addressed by thisapproach. One can describe the ion concentration influence (ion regulation)on channel functioning in this manner. A patch-clamp method in a'whole-cell' configuration is used to study the ICI. For this purpose theinfluence of an external concentration of potassium ions on thepotential-dependent potassium current (I(A)) in the externalmembrane of GH(3) cells was studied. The increase of[K(+) (out)] from 5 mM to 100 mM causes anon-monotonous shift of current-voltage dependencies. The dependence of bothan activation time constant tgr(n) and a steady-state activation(n(infinity)) on [K(+)](out) have a minimum andmaximum respectively. The analysis of the results suggests that the observedeffects are caused by ICI. A physical model is developed to describe thedependence of the potassium channel kinetics on the external concentrationof the ions and the membrane potential. The 'deformation' of the closedstate of the gate and the corresponding energy shifts cause the observednon-monotonous dependencies due to ICI. Thus, the general theoreticalapproach has an experimental confirmation and is applied to concreteexamples. Formulas for concentrational dependencies of the channel kineticsare given for practical uses. PMID- 23345662 TI - Influence of Medium and Long Range Interactions in (alpha/beta)(8) Barrel Proteins. AB - The residue-residue contacts and the role of medium and long rangeinteractions in 36 (alpha/beta)(8) barrel proteins have beenanalysed. The influence of long range contacts in the formation ofphysico-chemically similar clusters, and the preference of amino acidresidues towards long range contacts have also been studied. Theresults reveal a nearly uniform level of medium and long rangecontacts in most of the proteins. The residues Gln and Ala havehighest medium range contacts and the residue Pro has the lowestmedium range contacts. The residue Cys has the highest long rangecontact followed by other hydrophobic residues namely Val, Ile andLeu. In the physico-chemically similar clusters identified in theseproteins, 25-40 percent residues are influenced by long rangecontacts, and the residues Cys, Ile, Val and Met are the mostpreferred ones. PMID- 23345663 TI - Time evolution of the action potential in plant cells. AB - In this paper we extend and reconsider a solitonic model of the actionpotential in biological membranes for the case of plant cells. Aiming togive at least a qualitative description of the K(+),Cl(-) and Ca(2+) driven process of propagation ofthe action potential along plant cells we put forward the hypothesis ofthree scalar fields phi(i) (X), i = 1, 2, 3 which representK(+), Cl( ) and Ca(2+) ions,respectively. The modulus squared of these fields carries the usualquantum-mechanical (probabilistic) interpretation of the wave function. Onthe other hand, the fields are described themselves by the Lagrangiandensities L[Formula: see text]. Moreover, the interaction and self-interaction term L[Formula: see text] between thefields is considered. The Lagrangian densities L[Formula: see text]include a double-well potential (which is proportional tosigma(4) (i)) that leads to spontaneous symmetrybreaking which may produce structures with non-zero topological charge, e.g.longitudinal solitons. In order to describe the transversal motion of theions of concern we need to assume only non-uniform solutions of the system of equation of motion. Hence we seek for solutions (travelling waves) whichpreserve the shape and which move without dissipation and in this way wereconstruct the main dynamical features of the action potential in plants. PMID- 23345664 TI - Correlation Relation for the Membrane Transport ParametersL(p), sigma, and omega. AB - We derive a formula for the correlation of the three practical transportparameters L(p), sigma, and omega appearing in Kedem Katchalskyequations. It has a form omega = KL(p)/v(s)(1-sigma), where K = 0.0306 is a universal constant independent ofthe choice of a membrane and a solute. It can be used to calculate the valueof any of these parameters, provided the other two and the molar volume[Formula: see text] of the solute are known. The formula couldbe very useful, in particular when measurements of the parameters aredifficult or even impossible. PMID- 23345665 TI - A Frictional Interpretation of the Phenomenological Coefficients of Membrane Permeability for Multicomponent Non-ionic Solutions. AB - This paper presents the physical interpretation of phenomenologicalcoefficients of transmembrane transport for single and neutral membrane andmulticomponent non ionic solutions. In the framework of this model theexpressions linking the permeability parameters of the membrane(L(p), sigma, omega(ik)) with friction coefficients(f(ik)) for n-component, binary and ternary solutions and themethod of calculation of friction coefficients for binary and ternarynon-electrolytes are also presented. PMID- 23345666 TI - Effects of mutual influence of photoinduced electron transitions and slow structural rearrangements in bacterial photosynthetic reaction centers. AB - We describe the phenomenon of light-induced structural transformations in the reaction centers (RC) of photosynthetic bacteria which makes self-regulation of the RC charge separation efficiency possible. The nature of the effect is that the light-driven electron transfer (ET) between the RC redox-cofactors causes structural changes in the protein-cofactors system and this in turn affects the ET kinetics. If the electron-conformation interaction is strong enough, then such self-regulation gives birth to a new RC conformational state of enhanced charge separation efficiency. We show experimental results of stationary and kinetic absorbance change characteristics under different photoexcitation conditions, indicating structural rearrangements on a rather long (minutes) time scale, mainly within the secondary acceptor binding pocket. To simplify the description, in constructing a theory of structure-function reorganization in the RC we employ the adiabatic approach. Final expressions enable us to make qualitative comparison with experimentally observed kinetics of the fast and slow stages of 'free' and 'structurally controlled' electron relaxation, respectively. PMID- 23345667 TI - Influence of electromagnetic radiation on molecular solitons. AB - The soliton model of charge and energy transport in biological macromolecules is used to suggest one of the possible mechanisms for electromagnetic radiation influence on biological systems. The influence of the electromagnetic field (EMF) on molecular solitons is studied both analytically and numerically. Numerical simulations prove the stability of solitons for fields of large amplitude, and allow the study of emission of phonons. It is shown that in the spectra of biological effects of radiation there are two characteristic frequencies of EMFs, one of which is connected with the most intensive energy absorption and emission of sound waves by the soliton, and the other of which is connected with the soliton photodissociation into a delocalized state. PMID- 23345668 TI - The possibilities of modeling neural networks in the framework of the thermodynamics of genetically disordered systems (glasses). AB - Non-spin glasses possess a number of specific features which, in structural and dynamic aspects, are close to conditions necessary for neural networks to function. In a disordered network there exists a plurality of structural parameters and a number of two-level states defined by double-well potentials. Their characteristics are specified by the conditions of glass formation, i.e. by genesis. The thermodynamic description of glass as a self-organizing system (that does not require introducing an interacting potential model) leads to an unambiguous conclusion that its frequency spectrum is predetermined by the structure, which is characterized by zero-point entropy. Glass is a natural system of oscillators which form a disordered network. In this sense, glass conforms to a known model of a disordered neural network formed by interconnected oscillators. If one assumes that in living organisms the structure of a neural network (the brain) is inherited according to a genetic mechanism, the quickness of learning and recognition of patterns, the stability of associative memory and other capabilities have to be inherited genetically. The more ordered a neural network formed by distinguishable neurons, the better its capabilities. PMID- 23345669 TI - A model equations of the volume transport of multicomponent and heterogeneous non ionic solutions in double-membrane system. AB - The volume flows model equation for a double-membrane system, in which two membranes separate three compartments (l,m,r) containing the heterogeneous, non ionic n-component solutions is elaborated. In this system the solution concentrations fulfill the condition Clk > Cmk > Crk. The inter-membrane compartment (m) consists of the infinitesimal layer of solution. The volume of compartment m and external compartments (l and r) fulfill the conditions Vm-> 0 and Vl =Vr->infinity respectively. The linear dependences of the volume flux on concentration differences in binary solutions and nonlinear - in ternary solutions, were obtained. This model for binary and ternary non-electrolyte solutions is discussed. It is shown, that the double-membrane system has rectifying and amplifying properties for osmotic transport and mechanical pressure. PMID- 23345670 TI - Holger kantz and Thomas schreiber, nonlinear time series analysis. PMID- 23345671 TI - Results and limitations of the soliton theory of DNA transcription. AB - It has been suggested by several authors that nonlinear excitations, in particular solitary waves, could play a fundamental functional role in the process of DNA transcription, effecting the opening of the double chain needed for RNA Polymerase to be able to copy the genetic code. Some models have been proposed to model the relevant DNA dynamics in terms of a reduced number of effective degrees of freedom. Here I discuss advantages and disadvantages of such an approach, and discuss in more detail one of the models, i.e. the one proposed by Yakushevich. PMID- 23345672 TI - A twist opening model for DNA. AB - The real mechanisms of several biological processes involving DNA are not yet understood. We discuss here some aspects of the initiation of transcription, in particular the formation of the open complex and the activation mechanism associated to enhancer binding proteins. Transcription activation seems to be governed by underlying dynamical mechanisms related to several distortions of the double chain structure: a dynamical approach on a mesoscopic description level could then allow a deeper understanding of this complex process. Starting from the Peyrard Bishop (PB) model, that considers only the hydrogen bond stretching of each base pair, we describe here an extended DNA model, proposed in [1], that allows a rather good representation of the double helix geometry and of its structural features by the introduction of angular variables related to the twist angle. Using a generalized multiple scale expansion for the case of vectorial lattices derived elsewhere [2], we derive analytically small amplitude approximate solutions of the model which are movable and spatially localized: we present here the results of this calculation and show how the special shape of the solutions is in good agreement with what can be expected for coupled angular radial distortions in the real molecule. PMID- 23345673 TI - Statistical mechanical theory of DNA denaturation. AB - Thermodynamic quantities of a coupled sine-lattice chain, which is a simplified model of DNA (rotator model) are calculated for both in low and high temperature regions. In the high temperature region those quantities are expressed as a series expansion in terms of modified Bessel functions of an integer order. The results of numerical calculations are presented in connection with DNA denaturation (melting). PMID- 23345674 TI - Dynamical form-factor of neutron scattering by DNA solitons. AB - Method of scattering of slow neutrons has been considered in recent years as a rather perspective way to study the nonlinear DNA dynamics. In this paper we present the results of theoretical calculations of the dynamical form-factor of the scattering. The calculations were made on the basis of the nonlinear mathematical model which takes into account rotational motions of bases around the sugar-phosphate chains. The results of the calculations are considered as predictions for further neutron scattering experiments. PMID- 23345675 TI - Melting of DNA oligomers: dynamical models and comparison with experimental results. AB - We compare experimental melting curves of short heterogeneous DNA oligomers with theoretical curves derived from statistical mechanics. Partition functions are computed with the one-dimensional Peyrard-Bishop (PB) Hamiltonian, already used in the study of the melting of long DNA chains. Working with short chains we take into account, in the computations, not only the breaking of the interstrand hydrogen bonds, but also the complete dissociation of the double helix into separate single strands. Since this dissociation equilibrium is of general relevance, independent of the particular microscopic model, we give some details of its treatment. We discuss how the non bonded three-dimensional interactions, not explicitly considered in the one-dimensional PB model, are taken into account through the treatment of the dissociation equilibrium. We also evaluate the relevance of the dissociation as a function of the chain length. PMID- 23345676 TI - Complex Formation of E. coli RNA Polymerase with Bacteriophage T2 DNA: Long-Range Effects in DNA. AB - Conformation behavior of phase T2 DNA in the process of its interaction with it E. coli RNA polymerase was studied using spin labeling technique. T2 DNA was modified by the spin-labeled imidazole at OH-groups of glucosylated cytidine residues. It was shown that the binding of RNA polymerase under the conditions favoring the formation of open promoter complexes induces specific conformational changes in the spin-labeled DNA. The observed conformational changes encompass not only the promoter regions of DNA which are involved in direct contacts with RNA polymerase molecules but extend over remote DNA sites (long-range effect). In relation to this effect, current theoretical models of DNA dynamics are discussed. PMID- 23345677 TI - On Spectral Identification of DNA-Base Pairs Polymorphism. AB - The results of MNDO-PM3 theoretical study of H-bonds liability of watson-crick base pairs are discussed. Some microwave and IR spectral criteria are suggested for identification of hidden polymorphism of DNA base pairing. PMID- 23345678 TI - Supersonic vibron solitons and their possible existence in polypeptides. AB - Nonlinear interactions of vibrons with lattice solitons due to the soft cubic nonlinearity in a quasi-one-dimensional lattice yield supersonic vibron solitons. Their binding energy is larger than those of the conventional Davydov solitons and vibron solitons, and their propagation velocity is uniquely determined in contrast to the latter two. Examination of parameters in the model Hamiltonian for polypeptides leads to the result that the supersonic vibron solitons obtained here are more likely to be realizable than the Davydov solitons and the conventional vibron solitons in alpha-helical proteins. PMID- 23345679 TI - Mechanism of nonlinear photoinduced anisotropy in bacteriorhodopsin and its derivatives. AB - Polymer films made with photosensitive chromophore protein bacteriorhodopsin (BR) from the extreme halophile Halobacterium salinarium as well as films made with BR derivatives exhibit a nonlinear photoinduced anisotropy. Two different methods can be used to induce anisotropy in polymer BR films. The first method is based on the anisotropic properties of the initial form of the photocycle, BR570 (B type anisotropy). Another method is based on the anisotropic properties of the longest-lived photocycle intermediate M412 (M-type anisotropy). CW gas lasers were employed to induce a reversible anisotropy in polymer BR films. Nonlinear photoinduced anisotropy is discussed in the context of a model for the anisotropic photoselection of BR molecules under linearly polarized light. A comparison of the experimental dependencies of nonlinear photoinduced anisotropy on laser intensity with similar calculated dependencies enables one to determine the molecular dichroism of BR and its derivatives not only for the initial form of the photocycle, B but also for the longest-lived intermediate M. Here we present the data showing the correlation between the laser induced nonlinear anisotropic properties and chromophore/protein interactions in BR. The effect of polymer binder on the nonlinear photoanisotropic properties of polymer BR films is also described. PMID- 23345680 TI - Backbone Dynamics of Triple-helical Collagen-like Structure. AB - Some details of the backbone dynamics in the collagen-like triple helix is discussed and the role of backbone dynamics in functioning collagen proteins is illustrated. On a series of oligotripeptides synthetic analogs of collagen formation of high-frequency vibrational backbone dynamics and low-frequency nonlinear backbone dynamics upon stepwise elongation of peptide chain have been described using infrared spectroscopy and hydrogen-exchange method. In the fully completed triple helix the level of high-frequency backbone dynamics is regulated firstly by contact interactions of adjacent atoms and chemical bounded groups, while the level of low-frequency large-amplitude backbone dynamics depends mainly on cooperative interactions attributed by conjugation of interpeptide hydrogen bonds. In native collagens the nonlinear large-amplitude dynamics following by non-denaturational micro-unfolding of the triple-helical structure appears to be under the natural selection control delivering an optimal condition for formation, functioning and utilization of collagen fibrils. PMID- 23345681 TI - Electromagnetic radiation influence on nonlinear charge and energy transport in biosystems. AB - The influence of electromagnetic radiation (EMR) on charge and energy transport processes in biological systems is studied in the light of the soliton model. It is shown that in the spectrum of biological effects of EMR there are two frequency resonances corresponding to qualitatively different frequency dependent effects of EMR on solitons. One of them is connected with the quasiresonance dynamic response of solitons to the EMR. At EMR frequencies close to the dynamic resonance frequency the solitons absorb energy from the field and generate intensive vibrational modes in the macromolecule. The second EMR resonance is connected with soliton decay due to the quantum mechanical transition of the system from the bound soliton state into the excited unbound states. PMID- 23345682 TI - Role of Bisolitons and their Correlations in Charge Transfer Processes. AB - The charge transport processes in biological macromolecules are studied within the nonlinear electrosoliton mechanism. The interaction between few electrosolitons in a one-dimensional electron-phonon system is investigated. It is shown that in a singlet state the minimum of energy corresponds to a bisoliton. In a triplet state the autolocalized state is described by two electrosolitons which are separated from one another by some finite distance determined by the nonadiabatic terms of the Hamiltonian. PMID- 23345683 TI - Superexchange coupling and electron transfer in globular proteins via polaron excitations. AB - The polaron approach is used to treat long-range electron transfers between globular proteins. A rate expression for the polaron transfer model is given along with a description of appropriate conditions for its use. Assuming that electrons transfer via a superexchange coupling due to a polaron excitation, we have estimated the distance dependence of the rate constant for the self-exchange reactions between globular proteins in solutions. The distance dependence of the polaron coupling and solvent reorganization energy are provided as a basis for understanding and interpreting a long-range electron transfer experiment. The difficulties and problems of the polaron treatment of long-range electron transfers are discussed, and suggestions for new experiments are made. PMID- 23345684 TI - Models of assembly and disassembly of individual microtubules: stochastic and averaged equations. AB - In this paper we present solutions of the master equations for the microtubule length and show that the local probability for rescues or catastrophes can lead to bell-shaped length histograms. Conversely, as already known, non-local probabilities for these events result in exponential length histograms. We also derive master equations for a stabilizing cap and obtain a new boundary condition which provides an explanation of the results obtained in dilution and cutting experiments. PMID- 23345685 TI - Non-linear bifurcation analysis of reaction-diffusion activator-inhibator system. AB - The paper first deals with the linear stability analysis of an activator inhibitor reaction diffusion system to determine the nature of the bifurcation point of the system. The non-linear bifurcation analysis determining the steady state solution beyond the critical point enables us to determine characteristic features of the spatial inhomogeneous pattern formation arising out of the bifurcation of the state of the system. PMID- 23345686 TI - Amplitude hierarchy of vesicle shapes. AB - Shapes of fluid lipid vesicles are governed by the bending elasticity of their membrane as described by the Area-Difference-Elasticity (ADE) model. These shapes can be quantified using a suitable modal representation of the vesicle contour. Prolate vesicles are characterized by a hierarchy in their shape amplitudes. Experimentally, we find an ordering of the amplitudes with mode number both in large (100 nm) as well as giant (10 MUm) unilamellar vesicles. Mean shapes are found only within the small energetically stable region of the prolate phase. Our study demonstrates that bending energy concepts may be quantitatively used on cellular length scales ranging from the size of organelles to the plasma membrane. PMID- 23345687 TI - Models for energy and charge transport and storage in biomolecules. AB - Two models for energy and charge transport and storage in biomolecules are considered. A model based on the discrete nonlinear Schrodinger equation with long-range dispersive interactions (LRI's) between base pairs of DNA is offered for the description of nonlinear dynamics of the DNA molecule. We show that LRI's are responsible for the existence of an interval of bistability where two stable stationary states, a narrow, pinned state and a broad, mobile state, coexist at each value of the total energy. The possibility of controlled switching between pinned and mobile states is demonstrated. The mechanism could be important for controlling energy storage and transport in DNA molecules. Another model is offered for the description of nonlinear excitations in proteins and other anharmonic biomolecules. We show that in the highly anharmonic systems a bound state of Davydov and Boussinesq solitons can exist. PMID- 23345688 TI - On the problem of asymptotic positivity of solutions for dissipative partial differential equations. AB - The objective of this paper aims to prove positivity of solutions for the following semilinear partial differential equationu[Formula: see text]. This equation represents a generalised model of the so-called porous medium equation. It arises in a variety of meaningful physical situations including gas flows, diffusion of an electron-ion plasma and the dynamics of biological populations whose mobility is density dependent. In all these situations the solutions of the equation must be positive functions. PMID- 23345689 TI - Modeling of nonlinear chemical reaction systems and two-parameter stochastic resonance. AB - The idea of stochastic resonance (SR) is extended to two-parameter dynamical systems based on the Oregonator model of the Belousov-Zhabotinsky (BZ) reaction. The first case presents the photosensitivity of the reaction, and light flux and a flow rate are the two control parameters. The second case presents the effect of temperature on the oscillatory behaviors, and temperature and a flow rate are the control parameters. Stochastic resonance is demonstrated in the first case in which a signal and noise are applied to the different inputs, respectively. The scenario and novel aspects of SR in two-parameter systems are discussed, and the possibility of the analogous SR in biological systems is also pointed out. PMID- 23345690 TI - Propagation of curved activation fronts in anisotropic excitable media. AB - We study theoretical and numerical propagation of autowave fronts in excitable two-variable (activator-inhibitor) systems with anisotropic diffusion. A general curvature-velocity relation is derived for the case that the inhibitor diffusion is neglected. This relation predicts the break of an activation front when the front curvature exceeds a critical value, which is corroborated by computer simulations of a particular reaction-diffusion model. Some qualitative effects associated with the inhibitor diffusion are studied numerically. It is found that the critical value of curvature decreases with an increase in the inhibitor diffusion coefficient. The core of a spiral wave increases in size and turns through an angle which depends on the inhibitor diffusion coefficient. PACS Numbers: 05.50. +q, 05.70. Ln., 82.40. -g, 87.10. +e. PMID- 23345691 TI - Effects of shear flows on nonlinear waves in excitable media. AB - If an excitable medium is moving with relative shear, the waves of excitation may be broken by the motion. We consider such breaks for the case of a constant linear shear flow. The mechanisms and conditions for the breaking of solitary waves and wavetrains are essentially different: the solitary waves require the velocity gradient to exceed a certain threshold, whilst the breaking of repetitive wavetrains happens for arbitrarily small velocity gradients. Since broken waves evolve into new spiral wave sources, this leads to spatio-temporal irregularity. PMID- 23345692 TI - Resonant drift of spiral waves in the complex ginzburg-landau equation. AB - Weak periodic external perturbations of an autowave medium can cause large distance directed motion of the spiral wave. This happens when the period of the perturbation coincides with, or is close to the rotation period of a spiral wave, or its multiple. Such motion is called resonant or parametric drift. It may be used for low-voltage defibrillation of heart tissue. Theory of the resonant drift exists, but so far was used only qualitatively. In this paper, we show good quantitative agreement of the theory with direct numerical simulations. This is done for Complex Ginzburg-Landau Equation, one of the simplest autowave models. PMID- 23345693 TI - Drift of large-core spiral waves in inhomogeneous excitable media. AB - Spiral waves in excitable media may drift due to interaction with medium inhomogeneities. We describe this drift asymptotically, within the kinematic (eikonal) approximation. PMID- 23345694 TI - Soliton-like regimes and excitation pulse reflection (echo) in homogeneous cardiac purkinje fibers: results of numerical simulations. AB - On the basis of numerical simulations of the partial McAllister-Noble-Tsien equations quantitatively describing the dynamics of electrical processes in conductive cardiac Purkinje fibers we reveal unusual - soliton-like - regimes of interaction of nonlinear excitation pulses governing the heart contraction rhythm: reflection of colliding pulses instead of their annihilation. The phenomenological mechanism of the reflection effects is that in a narrow (but finite) range of the system parameters the traveling pulse presents a doublet consisting of a high-amplitude leader followed by a low-amplitude subthreshold wave. Upon collisions of pulses the leaders are annihilated, but subthreshold waves summarize becoming superthreshold and initiating two novel echo-pulses traveling in opposite directions. The phenomenon revealed presents an analogy to the effect of reflection of colliding nerve pulses, predicted recently, and can be of use in getting insight into the mechanisms of heart rhythm disturbances. PMID- 23345695 TI - The mechanism of fractal-like structure formation by bacterial populations. AB - Three types of population growth and development of chemotaxic motile bacteria Escherichia coli on semi-solid nutrient media are investigated: a) stable development - circular symmetrical waves; b) bursts; c) fractal-like self organization. Experimental investigation of the burst formation is presented. The microscopic analysis of growing, fractal-like structures is carried out, and a mechanism for such structure formation is suggested. It is supposed that fractal like bacterial structures growth is based on the principle of successively forming multiple micro-bursts. A mathematical model has been suggested to reproduce the experimental results. The structures obtained by numerical modeling of population growth in the parameter space 'substrate concentration - bacterial movement rate' reproduce the corresponding experimental structures in the space 'nutrient concentration in the media - the density of the media'. PMID- 23345696 TI - Kinetic mechanisms of biological regulation in photosynthetic organisms. AB - Principles of regulation on different levels of photosynthetic apparatus are discussed. Mathematical models of isolated photosynthetic reaction centers and general system of energy transduction in chloroplast are developed. A general approach to model these complex metabolic systems is suggested. Regulatory mechanisms in plant cell are correlated with the different patterns of fluorescence induction curve at different internal physiological states of the cells and external (environmental) conditions. Light regulation inside photosynthetic reaction centers, diffusion processes in thylakoid membrane, generation of transmembrane electrochemical potential, coupling with processes of CO(2) fixation in Calvin Cycle are considered as stages of control of energy transformation in chloroplasts in their connection with kinetic patterns of fluorescence induction curves and other spectrophotometric data. PMID- 23345698 TI - Non-markovian gating of ca(2+)-activated k(+) channels in cultured kidney cells vero. Rescaled range analysis. AB - Using the patch-voltage clamp technique and the rescaled range method, activity of single large conductance Ca(2+)-activated K(+) channels (K(Ca) channels) was studied. For the sequences of alternating open and shut time intervals, the dependence R/S vs. N(tau) in the double logarithmic coordinates presented a curve with two slopes, H(1) =0.60 +/- 0.04, and H(2) = 0.88 +/- 0.21, where H(1) and H(2) characterized the Hurst exponents for shot and long time ranges, respectively. Similar results were obtained for reduced data sets consisting of only open or only shut intervals. Randomization of the experimental data resulted in a single slope, H, of 0.52 +/- 0.02. Simulations were performed with eight state Markovian model without memory. The calculated Hurst exponent presented in average 0.54 +/- 0.02. The results suggest that the activity of single Ca(2+) activated K(+) channel exhibits two regimes, with slight positive correlation at short time ranges (H(1) =0.6), and strong positive correlation at long time ranges (H(2) = 0.88); therefore the channel gating as a whole is not a steady state Markovian process. PMID- 23345697 TI - Model analysis of nonlinear modification of neutrophil calcium homeostasis under the influence of modulated electromagnetic radiation of extremely high frequencies. AB - The problem of resonance effects of electromagnetic radiation (EMR) on biological objects remained unsolved till now. Previously we demonstrated that low-intensity amplitude-modulated EMR of extremely high frequencies (EHF) modified the activity of mouse neutrophils in the synergistic reaction of calcium ionophore A23187 and phorbol ester PMA. The EHF EMR influence on the neutrophils was significant at the carrier frequencies of radiation within a narrow range of 41.8-42.05 GHz and at the modulation frequency of 1 Hz. The purpose of the work was the analysis of frequency-dependent modification of intracellular free calcium concentration ([Ca(2+)](i)) by modulated EHF EMR on the basis of a special model for [Ca(2+)](i) oscillations in the neutrophils. The calcium channels of plasma membrane were chosen as the action target of external modulation in the model. The computer simulation demonstrated the rise in [Ca(2+)](i) at the influence of the external field with a threshold dependence on the modulation amplitude. The effect depended heavily on a sequence of delivery of the chemical and electromagnetic stimuli. The narrow-band rise in [Ca(2+)](i) had a phase frequency dependence. With the modulation amplitudes exceeding the threshold value, the rise in [Ca(2+)](i) of more than 50% of the initial level was observed at the frequency of about 1 Hz and in the phase range of 0.3-2.5 radians. The results of the model analysis are in good correspondence with the experimental data obtained before, namely, with the resonance modification of the neutrophil activity at the modulation frequency of 1 Hz and with the presence of the effect only at high concentrations of calcium ionophore. PMID- 23345699 TI - Nonlinear neurodynamics in representation of a rhythm of speech. AB - The mathematical model is offered to describe an algorithm for functioning of a speech rhythm. The duration of a speech signal is divided into the numbered sequence of durations of voice and voiceless segments. All elements of this sequence will be considered as values normalized on the maximum element. We determine this sequence of the elements as a speech rhythm. 1) The model describes a speech rhythm as the recurrent relations between elements of a rhythm. 2) The model permits use of the concept of information entropy. 3) The model explains experimental findings obtained by our research group during comparative investigation of a rhythm in normal speech and stuttering. In particular, the model explains the existence of two classes of stutterers with various rhythms of speech. PMID- 23345700 TI - Nonlinear pharmacological modulation of conditioning in the neocortex. AB - The conditioned defence reflex was elaborated by pair combination of direct stimulation of the motor cortex and electrocutaneous stimulation in awake nonimmobilized rabbit. This conditioning was organized mainly in the cortical part close to the stimulating electrode in the cortex. Influence of modulation of functional state on the observed phenomenon by means of application of GABA solution on the hypothetical place of the formation of the conditioning was examined. S-shaped dependence of effects on concentration of GABA solution was found. The hypothesis of the simultaneous modulation of processes of excitement and inhibition was used to analyse empirical dependences. Saturation effects (100% appearance of same alterations) were took into account. The model was suitable for description of the discovered nonlinear pharmacological modulation of physiological processes. PMID- 23345701 TI - Molecular dynamics investigation of bond ordering of unsaturated lipids in monolayers. AB - Molecular dynamics simulations of three model lipid monolayers of 2,3-diacyl-D glycerolipids, that contained stearoyl (18:0) in the position 3 and oleoyl (18:omega9cis), linoleoyl (18:2omega6cis), or linolenoyl (18:3omega3cis) in the position 2, have been carried out. The simulation systems consisted of 24 lipid molecules arranged in a rectangular simulation cell, with periodic boundary conditions in the surface plane. 1 nanosecond simulations were performed at T = 295 K. C-C and C-H bond order parameter profiles and the bond orientation distributions about the monolayer normal have been calculated. The relation of the distributions to the order parameters was analyzed in terms of maxima and widths of the distributions. The cis double bond order parameter is found to be higher than those of adjacent single C-C bonds. The widths of the two distributions of C-H bonds of the cis double bond segment in di- and triunsaturated molecules are much smaller than that obtained for methylene group located between the double bonds. The bond orientation distribution function widths depend on both the segment location in the chain and the segment chemical structure. PMID- 23345702 TI - Induction of the SOS Response in Ultraviolet-Irradiated Escherichia coli Analyzed by Dynamics of LexA, RecA and SulA Proteins. AB - The SOS response in Escherichia coli is induced after DNA-damaging treatments including ultraviolet light. Regulation of the SOS response is accomplished through specific interaction of the two SOS regulator proteins, LexA and RecA. In ultraviolet light-treated cells, nucleotide excision repair is the major system that removes the induced lesions from the DNA. Here, induction of the SOS response in Escherichia coli with normal and impaired excision repair function is studied by simulation of intracellular levels of regulatory LexA and RecA proteins, and SulA protein. SulA protein is responsible for SOS-inducible cell division inhibition. Results of the simulations show that nucleotide excision repair influences time-courses of LexA, RecA and SulA induction by modulating the dynamics of RecA protein distribution between its normal and SOS-activated forms. PMID- 23345703 TI - Pattern formation by competition: a biological example. AB - We present a simple model based on a reaction-diffusion equation to explain pattern formation in a multicellular bacterium (Streptomyces). We assume competition for resources as the basic mechanism that leads to pattern formation; in particular we are able to reproduce the spatial pattern formed by bacterial aerial mycelium in the case of growth in minimal (low resources) and maximal (large resources) culture media. PMID- 23345704 TI - Thermodynamic model equations for heterogeneous multicomponent non-ionic solution transport in a multimembrane system. AB - Non-equilibrium thermodynamic model equations for non-ionic and heterogeneous n component solution transport in a m-membrane system are presented. This model is based on two equations. The first one describes the volume transport of the solution and the second the transport of the solute. Definitions of the hydraulic permeability, reflection and diffusive permeability coefficients of the m membrane system and relations between the coefficients of the m-membrane system and the respective membranes of the system are also given. The validity of this model for binary and ternary solutions was verified, using a double-membrane cell with a horizontally mounted membrane. In the cell, volume and solute fluxes were measured as a function of concentration and gravitational configuration. PMID- 23345705 TI - Temporal duration and event size distribution at the epidemic threshold. AB - The epidemic event, seen as a nonequilibrium dynamic process, is studied through a simple stochastic system reminiscent of the classical SIR model. The system is described in terms of global and local variables and was mainly treated by means of Monte Carlo simulation; square lattices N*N, with N=23, 51, 100, 151, and 211 were used. Distinct extensive runs were performed and then classified as corresponding to epidemic or non-epidemic phase. They were examined with detail through the analysis of the event duration and event size; illustrations, such as density-like plots in the space of the model's parameters, are provided. The epidemic/non-epidemic phase presents smaller/larger relative fluctuations, whereas closer to the threshold the uncertainty reaches its highest values. Far enough from the threshold, the distribution phi(t) of the events time duration t shows a step-like appearance. However at the threshold line it shows an exponential behavior of the form phi (t) ~ exp (-omegat); the same behavior is observed for the event size distribution. These results help to explain why the approach to epidemic threshold would be hard to anticipate with standard census data. PMID- 23345706 TI - Nonmonotonous Changes in Metabolic Parameters of Tissues and Cells under Action of Ionizing Radiation on Animal. AB - A nonmonotonous relationship between changes of metabolic parameters of tissues and cells of animal and radiation dose were discussed. Under acute irradiation of animals the nonmonotonous dose-response curve for metabolic parameters of tissues and cells were found. The nonmonotonous dose-response curves of metabolic and functional tissues and cells parameters were also revealed upon chronic irradiation of animals at a low dose-rate. The nonmonotonous shape of dose response curves may be explained on the basis of nonmonotonous kind of the time course of metabolic response after irradiation. Living cells were supposed to possess a fundamental property in response to action of different stress agents by nonmonotonous changes of cell metabolism. This response was damping in time oscillation of the value of metabolic parameters around the normal level. Amplitudes and periods of oscillations in these changes of metabolic parameters could be observed. In case of chronic irradiation at a low dose-rate the metabolic and functional parameters showed some modified oscillation during irradiation. The nonmonotonous type of changes in metabolic and functional parameters of tissue and cell by chronic low dose-rate irradiation threw some new light on the peculiarities of biological effects of chronic irradiation. PMID- 23345707 TI - Screening hypochromism in molecular aggregates and biopolymers. AB - An improved model of the screening effect is suggested. Mutual ?shielding? of chromophores from light due to competition for the incident photon can take place in molecular aggregates and macromolecules. From a common point of view, it could be interpreted as in ?interaction? of the absorption dipol moment transitions. Screening leads to a decrease in the extinction coefficient. The largest decrease is observed in the maximum of the absorption band. This is demonstrated with chromophores of adenine, tyrosine, tryptophan, retinol, porphyrin and anthracene. The model enables prediction of hypochromic spectra or evaluation of the quantity of chromophores in an aggregate or macromolecule. PMID- 23345708 TI - A Landau-Ginzburg Model of the Co-existence of Free Tubulin and Assembled Microtubules in Nucleation and Oscillations Phenomena. AB - A link is shown between reaction-diffusion kinetics for microtubuleassembly and time-dependent Landau-Ginzburg phenomenology. In the latter,microtubule assembly is treated as a first-order phase transition using apostulated Landau-Ginzburg free energy expansion. The results establish aconnection between the oscillations observed in experiment and the phasediagram for microtubule assembly. The model also predicts a specific heatbehavior which could be verified experimentally. PMID- 23345709 TI - Non-normal Statistics of DNA Sequences of Prokaryotes. AB - The ? n-rule of Schrodinger in his discussion of DNA is based onnormal statistics and equilibrium physics. Herein the kurtosis is used tomeasure the deviation from normality of the stistics of non-equilibrium DNAsequences. A pattern for this deviation from normality is identified andthis signature is found in prokaryotes. The signature is explained by atheory of DNA sequences that involves finite length DNA walks withdynamically generated long-range correlations. PMID- 23345710 TI - Synergetics of the Membrane Self-Assembly: A Micelle-to-Vesicle Transition. AB - A model approach is developed to study intermediate steps and transientstructures in a course of the membrane self-assembly. The approach isbased on investigation of mixed lipid/protein-detergent systems capable ofthe temperature induced transformation from a solubilized micellar stateto closed membrane vesicles. We performed a theoretical analysis ofself-assembling molecular structures formed in binary mixtures ofdimyristoylphosphatidylcholine (DMPC) and sodium cholate (NaC). Thetheoretical model is based on the Helfrich theory of curvature elasticity,which relates geometrical shapes of the structures to their free energy inthe Ginzburg-Landau approximation. The driving force for the shapetransformation is spontaneous curvature of amphiphilic aggregates which isnonlinearly dependent on the lipid/detergent composition. An analysis ofthe free energy in the regular solution approximation shows that theformation of mixed structures of different shapes (discoidal micelles,rod-like micelles, multilayer membrane structures and vesicles) ispossible in a certain range of detergent/lipid ratios. A transition fromthe flat discoidal micelles to the rod like cylindrical micelles isinduced by curvature instabilities resulting from acyl chain melting andinsertion of detergent molecules into the lipid phase. Nonideal mixing ofthe NaC and DMPC molecules results in formation of nonideal cylindricalaggregates with elliptical cross section. Further dissolution of NaCmolecules in DMPC may be accompanied with a change of their orientation inthe lipid phase and leads to temperature-induced curvature instabilitiesin the highly curved cylindrical geometry. As a result the rod-likemicelles fuse into less curved bilayer structures which transformeventually to the unilamellar and multilamellar membrane vesicles. Thetheoretical analysis performed shows that a sequence of shapetransformations in the DMPC/NaC mixed systems is determined by thesynergism of four major factors: detergent/lipid ratio, temperature (acylchain melting), DMPC and NaC mixing, and reorientation of NaC molecules inmixed aggregates. PMID- 23345711 TI - Structure based sequence dependent stiffness scale for trinucleotides: a direct method. AB - A new set of stiffness parameters for all the 32trinucleotide units has been set up directly from thethree dimensional structures of DNA molecules. It wasobserved that GAC/GTC is the stiffest trinucleotideand ACC/GGT is the most flexible one. The averagestiffness values computed for a set of operatorsequences using the new parameters correlate very wellwith the protein-DNA binding specificity and bindingfree energy change of 434 repressor and Cro repressor,respectively. The new structure based stiffness scalecan explain the protein-DNA binding specificity to thelevel of 0.92. PMID- 23345712 TI - Parity violation of electroweak force in phase transitions of single crystals of d- and L-alanine and valine. AB - Three kinds of experiments have been designed in attempting to observe theparity violation of electroweak force at the phase transition of singlecrystals of D- and L-alanine and valine.(1) An obvious lambda phasetransition at 270 +/- 1 K was shown in the specific heat measurement ofalanine and valine enantiomers by differential scanning calorimetry. Thebiologically dominant L-enantiomer was found to have lower energy. (2)Magnetization of single crystals of D- and L alanine and D-valine weremeasured as a function of temperature using the SQUID magnetometer. Thedifference of the mass susceptibility chi(rho) ~ T curve between theD-alanine and L-alanine is attributable to the variation of intramoleculargeometry of chirality density, which is related to the parity violationenergy shift of a chiral molecule and is a consequence of the short rangeof the weak interaction between the nuclei and electrons. (3) Laser Ramanspectra of D- and L-alanine at different low temperatures (100 K, 250 K,260 K, 270 K, 280 K and 290 K) showed that the second order Calpha-Hdeformation modes at 2606 cm(-1), 2724 cm(-1) of D-alanine vanishedat 270 K but reappeared at 100 K. In the same method, L-alanine has nosuch phenomenon. An obvious decrease in the scattering intensity of themethyne group C(alpha)-H stretching mode at 2964 cm(-1) in D-alanineoccurs at the lambda transition temperature. We present our experimentsinvolving the possible relevance of Z(0) force with Salam's putativephase transition in the origin of homochirality. PMID- 23345713 TI - Nonlinear relationships in the patterns of neuronal spiking in cortical neurons. AB - The pattern of neuronal spiking of cortical neurons was investigated in an awake nonimmobilized rabbit. Thecharacteristics of the interspike intervals (total numberof intervals, mean interval, mean-square deviation) and of the burst (group) activity (burst number, mean spikefrequency in a burst, mean spike number for a burst, meanburst duration) were considered. Nonlinear relationshipbetween the values of mean interspike intervals and thenumber of spike bursts was found. A number of functionswere applied to describe the observed phenomena. On thebasis of regression analysis two populations of corticalneurons with distinct neuronal spiking patterns wereidentified. Bursts occur at a higher rate in one populationthan the other, although both populations exhibit burstsand are otherwise indistinguishable. PMID- 23345714 TI - Turbulence under the microscope. AB - Our objective was to observe a new form of turbulence caused bybiological effects - biological micro-turbulence and explore itsprocess and controlling factors. The methods used were proteusmirabilis CGCs micro-cultured to render the occurrence of the specific movement on micro-organic suspension and its controllingfactors were determined by comparison with the control trials.The results showed that turbulence under the microscope was generally in a mass but partially regular. It was also confirmedthat the turbulence under the microscope exhibited hollow effect,temperature-dependent switching on of occurrence and self-controlof suspension quantity. It is clarified that this new form ofturbulence is a spontaneous and self-control process, which providesan experimental model with controllable conditions for studies ofturbulence and a new way for researches on the mechanism andphysiological functions of the flow of body liquid. PMID- 23345715 TI - Parametric stabilization of biological coordination: a theoretical model. AB - In human coordination studies information from the environment may not only pace rhythmic behavior, but also contribute to the observed dynamics, e.g. aphenomenon known as anchoring in the literature. For the paradigmatic caseof bimanual coordination we study these contributions mathematically and develop a model of the interaction between the limb's intrinsic dynamics and environmental signals from a metronome in terms of oscillator equations. We discuss additive versus multiplicative metronomeimpact and show the latter to be more appropriate.Our model describes single limb-metronome interaction, as well as multilimb-metronome interaction. We establish a parametricstabilization term which preserves the characteristicsof bimanual coordination and additionally explains the varyingstability of movement under different metronome conditions, the frequency dependence of the amplitudes of finger movements, anchoring phenomena andgeometries of phase space trajectories. Predictions of our model are tested against experimental observations. PMID- 23345716 TI - Stochastic and reduced biophysical models of synaptic transmission. AB - Stochastic and reduced biophysical models of synaptictransmission are formulated and evaluated. Thesynaptic transmission involves presynapticfacilitation of neurotransmitter release, depletionand recovery of the presynaptic pool of readilyreleasable vesicles containing neurotransmittermolecules and saturation of postsynaptic receptors ofboth fast non-NMDA and slow NMDA types. The models areshown to display the principal dynamicalcharacteristics experimentally observed of synaptictransmission. The two main types of neural coding,i.e. rate and temporal coding, can be distinguished bymeans of different dynamical properties of synaptictransmission determined by initial neurotransmitterrelease probability and presynaptic firing rate. Fromthe temporal evolution of the postsynaptic membranepotential response to a train of presynaptic actionpotentials at a sustained firing rate, in particularthe steady-state amplitude and steady-state averagelevel of postsynaptic membrane potentials aredetermined as functions of both initial releaseprobability and presynaptic firing rate. The modelsare applicable to studies of the primary stages oflearning processes and can be extended to incorporateshort-term and long-term potentiation in memoryconsolidation processes. PMID- 23345717 TI - Soliton-like Solutions and Electron Transfer in DNA. AB - We consider various mechanisms of long-range electron transfer in DNAwhich enable us to explain recent controversial experiments. We show thatcontinuous super exchange theory can explain the values of electron rateconstants in short fragments of DNA. The soliton-type electron transfer inlong segments of DNA is also dealt with. PMID- 23345718 TI - Gravitational effects in a passive transmembrane transport: the flux graviosmotic and gravidiffusive effects in non-electrolytes. AB - In this paper the classification ofthe gravitational effects in a passive transmembranetransport is presented. Among these effects there arethe flux and force gravitational effects (fluxgraviosmotic effect, osmotic pressure graviosmoticeffect, flux gravidiffusive effect, osmotic pressuregravidiffusive effect, voltage gravielectric effectand current gravielectric effect). The volume fluxgraviosmotic and solute flux gravidiffusive effectsmodel equations for a single-membrane system areelaborated. These models for binary and ternarynon electrolyte solutions have been verified using anexperimental data volume and solute fluxes forosmotic-diffusion cell with horizontally mountedmembrane. In the experimental set-up, water was placedon one side of the membrane. The opposite side of themembrane was exposed to binary or ternary solutions ofdensities greater than that of water (aqueous glucoseor glucose-0.2 mole/l aqueous ethanol) and binary andternary solutions of densities larger than that ofwater (aqueous ethanol or ethanol-0.05 mole/l aqueousglucose). These experimental results are interpretedin terms of the convective instability that increasesthe diffusive permeability coefficient of junction:boundary layer/membrane/boundary layer. PMID- 23345719 TI - Superexchange coupling and electron transfer in globular proteins via polaron excitations. AB - The polaron approach is used to treat long-range electron transfersbetween globular proteins. A rate expression for the polaron transfer model is given along with a description of appropriate conditions forits use. Assuming that electrons transfer via a superexchange couplingdue to a polaron excitation, we have estimated the distance dependenceof the rate constant for the self-exchange reactions between globularproteins in solutions. The distance dependence of the polaron coupling andsolvent reorganization energy are provided as a basis forunderstanding and interpreting a long-range electron transfer experiment.The difficulties and problems of the polaron treatment of long-rangeelectron transfers are discussed, and suggestions for new experimentsare made. PMID- 23345720 TI - Slow relaxation process in DNA at different levels of hydration. AB - There are many speculations about the dynamic transition observed in hydrated bio polymers at temperatures T ~ 200 - 230 K being an important factor for enabling of their functions. The transition shows up as a sharp increase of atomic mean squared displacements above this temperature. The nature of the dynamic transition is not yet clear. Using inelastic neutron scattering we show in this Note that the transition in DNA is related to the appearance of a slow relaxation process. Decrease in the hydration level suppresses the process and the dynamic transition. It is found that, in terms of dynamics, the decrease in water content is similar in effect to a decrease in temperature. The obtained results support the idea that the dynamic transition is mediated by the water of hydration since bulk water has a dynamic transition around the same temperature. PMID- 23345721 TI - Random stride intervals with memory. AB - The stride interval in normal human gait is not strictly constant, butfluctuates from step to step in a random manner. Herein we show thatcontrary to the traditional assumption of uncorrelated random errors,these fluctuations have long time memory. However, rather than being amonofractal process as found earlier, there exists a multiplicative timescale that characterizes the process in addition to the fractal dimension.Further, these long-time correlations are interpreted in terms of anallometric control process. PMID- 23345722 TI - Role of mg2+ in chromomycin a3 - DNA interaction: a molecular modeling study. AB - Chromomycin A(3) (CHR) is an antitumor antibiotic that inhibits macromolecular biosynthesis by reversibly binding to double stranded DNA via the minor groove, with GC-base specificity. At and above physiological pH when CHR is anionic, interaction of CHR with DNA requires the presence of divalent metal ions like Mg(2+). However, at acidic pHthe molecule is neutral and it binds DNA even in absence of Mg(2+). Molecular dynamics simulation studies at 300K of neutral CHR and 1:1 CHR:Mg(2+) complexes formed at pH 5.2 and 8.0 show that hydrophobicity of CHR:Mg(2+) complex formed with the neutral drug is greater than that of the two other species. Interactions of CHR with DNA in presence and absence of Mg(2+) have been studied by simulated annealing to understand the role of Mg(2+) in the DNA binding potential of CHR. This shows that the antibiotic has the structural potential to bind to DNA even in the absence of metal ion. Evaluation of the direct interaction energy between the ligand and DNA does not explain the observed GC-base specificity of the antibiotic. When energy contributions from structural alteration of the interacting ligand and DNA as a sequel to complex formation are taken into account, atrue picture of the theoretical binding propensity emerges. This implies that DNA and/or the ligand undergo significant structural alterations during the process of association, particularly in presence of Mg(2+). Accessible surface area calculations give idea about the entropy contribution to the binding free energy which is found to be different depending upon the presence and absence of Mg(2+). PMID- 23345723 TI - A statistical mechanics model for receptor clustering. AB - We introduce and study a simple lattice statistical mechanics modelfor the clustering of tumor necrosis factor receptor I (TNFR1).Our model explains clustering under over-expression of the cytoplasmicsignal transducer as well as the clustering induced via extracellularligand binding; also we explain why the loss of transducer leads to arapid break-up of the clusters. The basic mechanism at work is a first-order(cooperative) phase transition caused by the multimeric binding capability ofthe receptor-transducer complex. Using cooperativity of this type, the cellsare found to have an enhanced sensitivity and robustness. In general, ourmethod can be applied to other receptor-clustering related signaling system. PMID- 23345724 TI - Study of the solute flows of multicomponent and heterogeneous non-ionic solutions in double-membrane system. AB - The solute flows were studied in a double-membrane osmotic-diffusive cell, in which two membranes mounted in horizontal planes separate three compartments (l,m,r) containing the non-homogeneous, non-electrolytic binary and ternary solutions. The volume of inter-membrane compartment (m), which is the infinitesimally layer of solution, and volume of external compartments (l and r) fulfill the conditions V(m)-> 0 and V(l) =V(r)-> infinity, respectively. In an initial moment, the solution concentrations satisfy the condition (C(o) (s))(l) < (C(o) (s))(m) >(C(o) (s))(r). The double-membrane osmotic-diffusive cell is composed of two complexes: boundary layer/membrane/boundary layer, mounted in horizontal planes. In the cell, solute flux was measured as a function of concentration and gravitational configuration. The linear dependencies of the solute flux on concentration difference in binary solutions and nonlinear - in ternary solutions were obtained. It was shown that the double-membrane osmotic diffusive cell has rectifying and amplifying properties of solute flows. PMID- 23345725 TI - Viscous damping of vibrations in microtubules. AB - Pokorny et al. have recently suggested that metabolic processes drivemicrotubules in a cell to vibrate at Megahertz frequencies, but the theorydoes not explicitly consider dissipative effects which will tend to damp outthe vibrations. To examine the effects of viscous damping on the structure,we determine viscous forces and rate of energy loss in a cylinderundergoing longitudinal oscillations in water. A nondimensional expressionis obtained for the viscous drag on the cylinder. When applied to amicrotubule, the results indicate that viscous damping is several orders ofmagnitude too large to allow resonant vibrations. PMID- 23345726 TI - A coupled oscillatory model mimicking avian circadian regulatory systems. AB - Much evidence indicates that the pineal gland and thesuprachiasmatic nucleus (SCN) are the primary pacemakers in the housesparrow, Passer domesticus. The interactions between the pineal andSCN predicted by the neuroendocrine loop model indicates that uncouplingwould cause the two oscillators to damp out in constant darkness. Basedupon the original neuroendocrine loop model, a mathematical frameworkof the house sparrow circadian regulatory organization that incorporatesdamping and co-inhibitory coupling has been formulated. The proposedmodel clearly indicates that two coupled oscillators must be 180( degrees )out of the phase for sustaining oscillations. From damping coefficients,which can be determined from experimental data, other parameters suchas external stimuli (interaction coefficient) and characteristicfrequencies can then be computed. Based upon earlier studies and simulations,we conclude that the sparrow pineal gland dampens more rapidly than does theSCN, suggesting that the SCN are probably more important in sparrowsthan previously thought. The model also provides the explanations ofendogenous circadian period (tau) alteration. Finally, we extend this modelto other avian and to mammalian circadian systems. We suggest that avianand mammalian circadian systems may differ in damping coefficients ofpineal glands and the degree of SCN dominance. PMID- 23345727 TI - Scaling of folding properties in go models of proteins. AB - Insights about scaling of folding properties of proteins are obtained bystudying folding in heteropolymers described by Go-like Hamiltonians. Bothlattice and continuum space models are considered. In the latter case, themonomer-monomer interactions correspond to the Lennard-Jones potential.Several statistical ensembles of the two- and three-dimensional targetnative conformations are considered. Among them are maximally compactconformations which are confined to a lattice and those which are obtainedeither through quenching or annealing of homopolymers to their compactlocal energy minima. Characteristic folding times are found to grow aspower laws with the system size. The corresponding exponents are notuniversal. The size related deterioration of foldability is found to beconsistent with the scaling behavior of the characteristic temperatures:asymptotically, the folding temperature becomes much lower than thetemperature at which glassy kinetics become important. The helicalconformations are found to have the lowest overall scaling exponent andthe best foldability among the classes of conformations studied. Thescaling properties of the Go-like models of the protein conformationsstored in the Protein Data Bank suggest that proteins are not optimizedkinetically. PMID- 23345728 TI - Experimental study of the hydration properties of homologous disaccharides. AB - To get some insight into the hydration mechanisms of homologousdisaccharides, we report measurements on trehalose, maltose, and sucroseaqueous solutions. The interest on these systems is mainly due to theextraordinary properties of disaccharides and especially of trehalose, themost effective bio-protector against freezing and dehydration. To carry outthis study we have investigated the volumetric properties of the threedisaccharide solutions, by performing density and ultrasonic velocitymeasurements at different concentration and temperature values. Whatemerges from these studies is that trehalose shows, in comparison withmaltose and sucrose, the greatest structural sensitivity to temperaturechanges and the smallest values of the partial molar volume in all theinvestigated temperature range, this circumstance being indicative of a morepacked conformational arrangement. PMID- 23345729 TI - Membrane Transport Generated by the Osmotic and Hydrostatic Pressure. Correlation Relation for Parameters L(p), sigma, and omega. AB - Standard approach to membrane transport generated by osmotic andhydrostatic pressures, developed by Kedem and Katchalsky, is based onprinciples of thermodynamics of irreversible processes. In this paper wepropose an alternative technique. We derive transport equations from fewfairly natural assumptions and a mechanistic interpretation of the flows.In particular we postulate that a sieve type membrane permeability isdetermined by the pore sizes and these are random within certain range.Assuming that an individual pore is either permeable or impermeable tosolute molecules, the membrane reflection coefficient depends on the ratioof permeable and impermeable pores. Considering flows through permeableand impermeable pores separately, we derive equations for the total volumeflux, solute flux and the solvent flux across the membrane. Comparing themechanistic equations to the Kedem-Katchalsky equations we find the formereasier to interpret physically. Based on the mechanistic equations we alsoderive a correlation relation for the membrane transport parameters L(p),sigma, and omega. This relation eliminates the need for experimentaldetermination of all three phenomenological parameters, which in somecases met with considerable difficulties. PMID- 23345730 TI - Electronic Excited States of the CP29 Antenna Complex of Green Plants: A Model Based on Exciton Calculations. AB - We have suggested a model for the electronic excited states of the minorplant antenna, CP29, by incorporating a considerable part of the currentinformation offered by structure determination, site-directed mutagenesis,and spectroscopy in the modeling.We have assumed that the electronic excited states of the complex havebeen decided by the chlorophyll-chlorophyll (Chl) and Chl-proteininteractions and have modeled the Coulombic interaction between a pairof Chls in the point dipole approximation and the Chl-protein interactionsare treated as empirical fit parameters.We have suggested the Q(y) dipole moment orientations and the siteenergies for all the chlorophylls in the complex through a simultaneoussimulation of the absorption and linear dichroism spectra.The assignments proposed have been discussed to yield a satisfactoryreproduction of all prominent features of the absorption, linear and circulardichroism spectra as well as the key spectral and temporal characteristics ofthe energy transfer processes among the chlorophylls.The orientations and the spectral assignments obtained by relatively simpleexciton calculations have been necessary to provide a good point ofdeparture for more detailed treatments of structure-function relationship inCP29. Moreover, it has been discussed that the CP29 model suggested canguide the studies for a better understanding of the structure functionrelationship in the major plant antenna, LHCII. PMID- 23345731 TI - Crystalizing the genetic code. AB - New developments are presented in the framework of the model introduced bythe authors in References [1, 2] and in which nucleotides as well ascodons are classified in crystal bases of the quantum group U(q)(sl(2) ? sl (2)) in the limit q -> 0. An operator whichgives the correspondence between the amino-acids and the codons isobtained for any known genetic code. The free energy released by basepairing of dinucleotides as well as the relative hydrophilicity andhydrophobicity of the dinucleosides are also computed. For the vertebrateseries, a universal behaviour in the ratios of codon usage frequencies isput in evidence and is shown to fit nicely in our model. Then a firstattempt to represent the mutations relative to the deletion of apyrimidine by action of a suitable crystal spinor operator is proposed.Finally recent theoretial descriptions are reviewed and compared with ourmodel.PACS number: 87.10.+e, 02.10.-v. PMID- 23345732 TI - Steady flow visualization in a rigid model of the aortic bifurcation: application to atherosclerosis. AB - Hemodynamics have long been implicated in atherogenesis. The studiesreported here seek to explain the mechanisms for the formation ofatherosclerotic plaque in an aortic bifurcation. Flow studies were made ina model constructed from plexiglass to represent an aortic bifurcation. Under steady flow conditions at inflow Reynolds numbers of 80-1250,the streamline flow patterns and the boundary layer separation zones wereinvestigated in relation to the location of atherosclerotic plaques clinicallyfound at regions in the human aortic bifurcation. The streamline flowswere visualized by a slow injection of dye over the cross section of the tubeentrance and along the tube walls. The studies revealed a complex flowfield where secondary flows, induced by the centrifugal and viscous forces,cause the fluid to move towards the inner walls of the aortic bifurcation. The effect was more clearly seen with increasing Reynolds number. Boundary layer separation zones were observed to occur at the outercorners of the branching. The nature of the separation zone formed wasfound to be dependent on Reynolds number. The residence time of fluidparticles within such a separation zone was estimated by measuring thewashout time of a bolus of dye injected at strategic locations along the tubewalls. The residence time was found to decrease exponentially withincreasing Reynolds number. These observations provide strong support forthe role of flow separation in the accumulation of LDL and plateletaggregation within the aortic bifurcation. PMID- 23345733 TI - Size of Unfolded and Dissociated Subunits versus that of Native Multimeric Proteins. AB - Two factors, unfolding and dissociation, act in opposition indetermining the size of the unfolded state of multimeric proteins. Ananalysis has been presented to correlate relative expansion of the unfoldedmonomers in absence of disulfide bridges over the native state of differenthomomultimeric proteins of varying molecular weights. The Stoke's radii ofabout 70 proteins of Mw between 6 kDa to 4000 kDa and ranging frommonomers to dodecamers were calculated both under native anddenatured condition induced by 8 M urea or 6 M guanidinium,HClaccording to relations derived by Uversky [Biochemistry32 (1993), 13288-13298]. Stoke's radii of monomeric proteins were foundto increase by 1.6-2.2 times after denaturation as compared with the nativestate while that of the subunits of dimeric and tetrameric proteins wereincreased by factors 1.1-2.2 under the same conditions. For hexamericproteins this factor lies between 0.96-1.2. In each set the relativeincrement of the Stoke's radii followed a logarithmic relation with molecularweight and reached a minimum limiting value when Stoke's radii of nativeprotein became almost equal to that of the unfolded monomer. PMID- 23345734 TI - Role of co-solute in biomolecular stability: glucose, urea and the water structure. AB - We have studied the action of urea and glucose on the stability of DNAand micelles. We measured the melting temperature of aqueous solutionsof DNA with urea or glucose as a co-solute; we have also measured thechanges in the critical micelle concentrations (cmc) of Sodium DodecylSulfate and Triton X-100 by addition of urea and glucose. Ourexperimental results show that glucose increases the melting temperature ofDNA and decreases the cmc, while urea acts in the contrary direction. The effects of urea and glucose on the stability of DNA and micelles canbe explained by the weakening and enhancement of hydrophobicinteractions, respectively. These effects on hydrophobic interactions arediscussed in this paper. PMID- 23345735 TI - Novel Cholesteric Phase in Dispersions of Nucleic Acids due to Polymeric Chelate Bridges. AB - Physics, Moscow, RussiaWe consider cholesteric liquid-crystalline DNA dispersions, and show thatpolymeric (Dau-Cu) complexes, the so-called bridges, between pairs of DNA molecules may generate a super liquid-crystalline structure (BR-phase), charachterized by a soliton lattice of the spatial distribution of theorder parameter. The BR-phase could have a layered spatial structure andan abnormal optical activity that could have a bearing upon the intenseCD-band observed in DNA-dispersions. PMID- 23345736 TI - Editorial. PMID- 23345737 TI - A comparison of experimental and computational methods for mapping the interactions present in the transition state for folding of FKBP12. AB - The folding pathway of FKBP12, a 107 residue alpha/beta protein, has been characterised in detail using a combination of experimental and computational techniques. FKBP12 follows a two-state model of folding in which only the denatured and native states are significantly populated; no intermediate states are detected. The refolding rate constant in water is 4 s(-1) at 25 degrees C. Two different experimental strategies were employed for studying the transition state for folding. In the first case, a non-mutagenic approach was used and the unfolding and refolding of the wild-type protein measured as a function of experimental conditions such as temperature, denaturant, ligand and trifluoroethanol (TFE) concentration. These data suggest a compact transition state relative to the unfolded state with some 70% of the surface area buried. The ligand-binding site, whichis mainly formed by two long loops, is largely unstructured in the transition state. TFE experiments suggest that the alpha helix may be formed in the transition state. The second experimental approach involved using protein engineering techniques with phi-value analysis. Residue specific information on the structure and energetics of the transition state can be obtained by this method. 34 mutations were made at sites throughout the protein to probe the extent of secondary and tertiary structure in the transition state. In contrast to some other proteins of this size, no element of structure is fully formed in the transition state, instead, the transition state is similar to that found for smaller, single-domain proteins, such as chymotrypsin inhibitor 2 and the SH3 domainfrom alpha-spectrin. For FKBP12, the central three strands of the beta-sheet (2, 4 and 5), comprise the most structured region of the transition state. In particular Val 101, which is one of the most highly buried residues and located in the middle of the central beta-strand,makes approximately 60% of its native interactions. The outer beta-strands, and the ends of the central beta-strands are formed to a lesser degree. The short alpha-helix is largely unstructured in the transition state as are the loops. The data are consistent with a nucleation-condensation model of folding, the nucleus of which is formed by side chains within beta-strands 2, 4 and 5 and the C-terminus of the alpha-helix. These residues are distant in the primary sequence, demonstrating the importance of tertiary interactions in the transition state. High-temperature molecular dynamic simulations on the unfoldingpathway of FKBP12 are in good agreement with the experimental results. PMID- 23345738 TI - Early aggregated States in the folding of interleukin-1beta. AB - Kinetic data measured from folding of the protein interleukin-1beta fits best to three exponential phases when studied with tryptophan fluorescence but only two exponential phases when measured using other methods. The technique of ANS fluorescence was used to determine whether the additional phase observed in tryptophan fluorescence was also detected with ANS dye binding. Unlike trytophan fluorescence, the ANS fluorescence was highly dependent on the concentration of protein present during the folding experiment. Experimental controls provide evidence that ANS binds to protein aggregates, present at higher concentrations and absent at lower concentrations. Protein concentration-dependent folding studies demonstrate that, at lower interleukin-1beta concentrations, tryptophan fluorescence kinetics can be fit adequately with a two exponential fit. This study indicates that (1) measured interleukin-1beta folding kinetics fit to a 2 phase model and (2) at higher protein concentrations, transient association of IL 1beta may result in a kinetic fit of 3 phases. PMID- 23345739 TI - The role of solvent in protein folding and in aggregation. AB - We discuss features of the effect of solvent on protein folding andaggregation, highlighting the physics related to the particulate nature and the peculiar structure of the aqueous solvent, and the biological significance of interactions between solvent and proteins. To this purpose we use a generalized energy landscape of extended dimensionality. A closer look at the properties of solvent induced interactions and forces proves useful for understanding the physical grounds of 'ad hoc' interactions and for devising realistic ways of accounting for solvent effects. The solvent has long been known to be a crucially important part of biological systems, and times appear mature for it to be adequately accounted for in the protein folding problem. Use of the extended dimensionality energy landscape helpseliciting the possibility of coupling among conformational changes and aggregation, such as proved by experimental data in the literature. PMID- 23345740 TI - Energy profile of the space of model protein sequences. AB - A numerical study of the energy landscape of the space of model proteinsequences is carried out. As a consequence of the heterogeneity of thecontact energies among amino acids, the energy landscape displays a veryrough profile, a behaviour typical of frustrated systems. This givesraise to a hierarchical clustering of low-energy sequences and can have evolutionary consequences. PMID- 23345741 TI - Predicting the tertiary structure of a lattice designed model protein from its primary structure. AB - Through systematic studies of lattice Monte Carlo simulations of thefolding of designed heteropolymers, we have identified a hierarchy ofspecific elementary phenomena which control the way single domain proteinfold: a) formation of few, local elementary structures, b) creation ofthe (post-critical) folding nucleus through the assemblage together ofthe local elementary structures, c) relaxation of the remaining aminoacids to the native conformation. These results, which are consistentwith a two-state kinetics of the folding of small, single domain proteins,where the local elementary structures and the folding nucleus can be viewedas hidden intermediates along the reaction pathway, provide the basis fora strategy to read the tertiary structure of a protein from its aminoacid sequence. PMID- 23345742 TI - Hydrogen bonds, hydrophobicity forces and the character of the collapse transition. AB - We study the thermodynamic behavior of a model protein with 54 amino acidsthat is designed to form a three-helix bundle in its native state. The model contains three types of amino acids and five to six atoms per amino acid, and has the Ramachandran torsion angles as its only degrees of freedom.The force field is based on hydrogen bonds and effective hydrophobicity forces. We study how the character of the collapse transition depends on the strengths of these forces. For a suitable choice of these two parameters, it is found that the collapse transition is first-order-like and coincides with the folding transition. Also shown is that the corresponding one- and two-helix segments make less stable secondary structure than the three-helix sequence. PMID- 23345743 TI - A dynamical approach to protein folding. AB - In this paper we show that a dynamical description of the protein folding process provides an effective representation of equilibrium properties and it allows for a direct investigation of the mechanisms ruling the approach towards the native configuration. The results reported in this paper have been obtained fora two dimensional toy-model of aminoacid sequences, whosenative configurations were previously determined byMonte Carlo techniques.The somewhat controversial scenario emerging from the comparison among different thermodynamical indicators is definitely better resolved with the help of a truly dynamical description. In particular,we are able to identify the metastable states visited during the folding process by monitoring the temporal evolution of the 'long-range' potentialenergy. Moreover, the resulting dynamical scenario is consistent with the picture arising from a reconstruction of the energy landscape in the vicinity of the global minimum. This suggests that the introduction of efficient 'static' indicators too should properly account for the complex 'orography' of the landscape. PMID- 23345744 TI - Assessment of the quality of energy functions for protein folding by using a criterion derived with the help of the noisy go model. AB - We propose a simple criterion based on the Z-scoreto assess the quality of energy functions for protein folding: one should obtain Z>-10 for the equilibrium ensembleat about native conditions. We derive this criterionby studying a Go model with random errors added to the native interactions. The dependence of the Z-score on the thermodynamic parameters,including the noise, can be precisely obtained in this case,as the ground state of the model is known exactly.We apply this criterion to rapidly rule out two otherwise promisingpairwise energy approximations.The advantage of adopting the present criterionis that it is not necessary to know the ground state of an energy function to assess its quality. It is sufficient to compute the Z-scorefrom a single equilibrium simulation at around the folding temperature. PMID- 23345745 TI - Hydration water, charge transport and protein dynamics. AB - The hydration water of proteins is essential to biological activity but its properties are not yet fully understood. A recent study of dielectric relaxation of hydrated proteins [A. Levstik et al., Phys. Rev E.60 7604 (1999)] has found a behavior typical of a proton glass, with a glass transition of about 268 K. In order to analyze these results, we investigate the statistical mechanics and dynamics of a model of 'two-dimensional water' which describes the hydrogen bonding scheme of bounded water molecules. We discuss the connection between the dynamics of bound water and charge transport on the protein surface as observed in the dielectric measurements. PMID- 23345746 TI - Cold and warm denaturation of proteins. AB - We introduce a simplified protein model where the water degrees of freedom appear explicitly (although in an extremely simplified fashion). Using thismodel we are able to recover both the warm and the cold protein denaturation within a single framework, while addressing important issues about the structure of model proteins. PMID- 23345747 TI - Modeling hydration water and its role in polymer folding. AB - The hydrophobic effect is the dominant force which drives a proteintowards its native state, but its physics has not been thoroughlyunderstood yet. We introduce an exactly solvable model of the solvation ofnon-polar molecules in water, which shows that the reduced number ofallowed configurations of water molecules when the solute is present isenough to give rise to hydrophobic behaviour. We apply our model to anon-polar homopolymer in aqueous solution, obtaining a clear evidence ofboth 'cold' and 'warm' collapse transitions that recall those of proteins.Finally we show how the model can be adapted to describe the solvation ofaromatic and polar molecules. PMID- 23345748 TI - Structural Complexity of Early Embryos: A Study on the Nematode Caenorhabditis elegans. AB - For analytical studies on the dynamics of gene expression, gene expressioncontrol and cellular interactions, the nematode Caenorhabditis elegans[C. elegans] is at present one of the best suited models [1-4].In this organism the genetic map and sequence is known [5], moreover theconstancy of its lineage tree allows a complete description of cellularclones giving rise to embryos. These characteristics have fostered detailedstudies on several aspects of development for this organism. Quantitativestudies of cellular movement, through time lapse cinematography of gastrulation, allows the description of cellular migrations giving rise to the final embryonic structure. In perspective, these studies coupledwith: genetic analysis, patterns of gene expression obtained throughmolecular techniques or other methods, open up the possibility of dynamicalstudies at the organismic scale. This possibility implies, first of all,a study of partitioning of space, and raise several problems in order todefine basic conceptual tools to be used in such studies. One of the mainproblems to handle in this respect is the definition of embryonic structurein a quantitative way. We will show that this aspect is a more generalcase of distance geometry approaches, as defined in protein folding studies.In this paper we discuss measures of the complexity for embryonal body plans,at the end of grastrulation. These can be applied to studies on the dynamicsof gene expression and phylogenetic studies with further experiments orsimulations. PMID- 23345749 TI - Temporary Changes in the dc ElectricalConductivity of MX (3-Chloro 4(Dichloromethyl)-5-Hydroxy-2(5H)-Furanone) Treated Collagen. AB - The influence of MX(3-Chloro-4(Dichloromethyl)-5-Hydroxy-2(5H)- Furanone), a stronglymutagenic compound, on the temperature dependence of the dcelectrical conductivity of collagen as a function of time was studied.Collagen was immersed in MX solution, next dried and pressed intotablets. The MX concentration was measured by HPLC analysis.The reduction of MX concentration to 10% of the initial value wasobserved in the presence of collagen in the solution, whereas in thecontrol solution concentration of MX decreased to 70% of the initialvalue. Measurements of electrical conductivity were performed for thetemperature range 295-453K and activation energies for the chargeconduction process were calculated. Within the temperature range295-340K, the presence of MX decreased electrical conductivity ofcollagen. Calculated activation energies were typical for dry proteins.Within the temperature range 295-320K activation energy decreasedwith time, probably due to the stronger interactions in thecollagen water-MX system. For temperatures between 320-410 and430-450K the activation energy was not time dependent and theapplication of MX did not change the structure of the collagenmacromolecule. The temporary changes occurring at the lowertemperatures being due solely to changes in the collagen-waterinteractions. PMID- 23345750 TI - Synchronization of metabolic oscillations:two cells and ensembles of adsorbed cells. AB - We treat synchronization of metabolic oscillations in two cellsand in ensembles of cells adsorbed at the liquid-solid interface.(i) Synchronization of oscillations in two cells is assumedto occur via perturbation of the metabolite concentration nearone cell due to the metabolite diffusion flux from another cell.This direct channel of synchronization may be important ifthe distance between two cells is comparable with the cell diameter.The corresponding coupling coefficient is found to be proportionalto the metabolite diffusion coefficient and inversely proportionalto the cell radius and the distance between the cells.(ii) In the case of ensembles of adsorbed cells, synchronizationof oscillations is considered to be indirect, i.e., to occur viathe metabolite concentration formed outside the cells nearthe interface due to metabolite diffusion from the cells. We havederived a general integral equation relating the metaboliteconcentration near the interface with concentrations inside the cells.PACS: 82.37.-j, 82.40.Bj. PMID- 23345751 TI - Slow relaxation process in DNA. AB - A dynamic transition at temperatures ~200-230K is observed in manyhydrated bio polymers. It shows up as a sharp increase of the mean-squaredatomic displacements above this temperature range. We present neutronscattering data of DNA at different levels of hydration. The analysis showsthat the dynamic transition in DNA is related to a slow relaxation processin the MHz-GHz frequency range. This slow relaxation process iscompletely suppressed in the dry DNA sample where no dynamic transitionwas observed. The nature of the slow process is discussed. We ascribe it toa global relaxation of DNA molecule that involves cooperative motion ofmany base-pairs and backbone. PMID- 23345752 TI - DNA Replication and Cell Cycle Progression Regulatedby Long Range Interaction between Protein Complexes bound to DNA. AB - A nonstationary interaction that controlsDNA replication and the cell cycle isderived from many-body physics in achemically open T cell. The model predictsa long range force F'(xi) =- (kappa/2) xi(1 - xi)(2 - xi)between thepre-replication complexes (pre-RCs) boundby the origins in DNA, xi = phi/N being the relativedisplacement of pre-RCs, phi the number of pre-RCs, N the number of replicons to be replicated,and kappa the compressibilitymodulus in the lattice of pre-RCs whichbehaves dynamically like an elasticallybraced string. Initiation of DNAreplication is induced at the thresholdphi = N by a switch ofsign of F''(xi), fromattraction (-) and assembly in the G(1) phase (0 0.05 approves the existence of segmental motions(alpha-helices for myoglobin, alpha-helices and beta-sheets forlysozyme) as well as of individual motions. Further hydration increase themean-square displacements for both types of intraglobular motions for theseproteins, while the motions of the globule as a whole remain nearlythe same as for h = 0.05. Results of the study of the radial distributionfunction deduced by Fourier - transform from the diffuse x raymeasurements together with RSMR data allow to conclude that the waterduring hydration of proteins competes with the intramolecular hydrogenbonds, loosens the protein and increases the internal dynamics. At the sametime water arranges the ordering of macromolecule from 'glassy' state ath ~ 0.02 to the native state at h = 0.4-0.7. Differentarchitecture of proteins leads to the different structural dynamics as in thecase of lysozyme and myoglobin. PMID- 23345764 TI - Excited-state lifetimes of far-infrared collective modes in proteins. AB - Vibrational excitations of low frequency collective modes are essential for functionally important conformational transitions in proteins. Here we report the first direct measurement on the lifetime of vibrational excitations of the collective modes at 87 pm (115 cm(-1)) in bacteriorhodopsin, a transmembrane protein. The data show that these modes have extremely long lifetime of vibrational excitations, over 500 picoseconds, accommodating 1500vibrations. We suggest that there is a connection between this relativelyslow anharmonic relaxation rate of approximately 10 g sec(-1) and thesimilar observed rate of conformational transitions in proteins, which require require multi-level vibrational excitations and energy exchanges with othervibrational modes and collisional motions of solvent molecules. PMID- 23345765 TI - How the all-atom simulation and the ising-based theory reconcilewith each other on the helix-coil transition. AB - In this report, we addressed a somewhat basic question about how the twoextreme models, the all-atom model and the Ising-based model, can beconsistent with each other regarding the polypeptide helix-coil transition.Comparisons of several physical properties were made between the resultsof the all-atom simulations and those of the Ising-based theories. Fromthe equilibrium point of view, the two models were found to exhibit aqualitatively similar trend, which is significant considering the extremedifference in precision between the two models. On the other hand, fromthe kinetic viewpoint, there appeared a difference in relaxation behaviorbetween the two models; i.e., so-called stretched exponential relaxationwas observed in the all-atom simulation whereas the kinetic Ising modelshowed simple exponential relaxation. A plausible source of the observeddifference is briefly discussed. PMID- 23345766 TI - Infrared Study of Carbon Monoxide Migration among Internal Cavities of Myoglobin Mutant L29W. AB - Myoglobin, a small globular heme protein that binds gaseous ligands such asO(2), CO and NO reversibly at the heme iron, provides an excellent modelsystem for studying structural and dynamic aspects of protein reactions. Flashphotolysis experiments, performed over wide ranges in time and temperature, reveal a complex ligand binding reaction with multiple kinetic intermediates, resulting from protein relaxation and movements of the ligand within the protein. Our recent studies of carbonmonoxy-myoglobin (MbCO) mutant L29W, using time-resolved infrared spectroscopy in combination with x-ray crystallography, have correlated kinetic intermediates with photoproduct structures that are characterized by the CO residing in different internal protein cavities, so-called xenon holes. Here we have used Fourier transform infrared temperature derivative spectroscopy (FTIR TDS) to further examine the role of internal cavities in the dynamics. Different cavities can be accessed by the CO ligands at different temperatures, and characteristic infrared absorption spectra have been obtained for the different locations of the CO ligand within the protein, enabling us to monitor ligand migration through the protein as well as conformational changes of the protein. PMID- 23345767 TI - Water and protein movements in ligand-receptor interactions. AB - I have recently developed a novel method 'mutual repulsion' for simulating ligand unbindingfrom receptor. Combined with adiabatic switching,this method can evaluate the free energy change of unbinding. Mutualrepulsion has been applied to the bovine serum retinol-bindingprotein-retinol complex (1HBP). Large changes in amino acid configurationis observed in only three residues at the mouth of the binding site. Thechange in water structure around the ligand, from bulk-phase tohydrophobic hydration, as retinol unbinds, is also described. PMID- 23345768 TI - Prediction of MHC class I binding peptides by a query learning algorithm based on hidden markov models. AB - A query learning algorithm based on hidden Markov models (HMMs) isdeveloped to design experiments for string analysis and prediction of MHCclass I binding peptides. Query learning is introduced to aim at reducingthe number of peptide binding data for training of HMMs. A multiple numberof HMMs, which will collectively serve as a committee, are trained withbinding data and used for prediction in real-number values. The universeof peptides is randomly sampled and subjected to judgement by the HMMs.Peptides whose prediction is least consistent among committee HMMs aretested by experiment. By iterating the feedback cycle of computationalanalysis and experiment the most wanted information is effectivelyextracted. After 7 rounds of active learning with 181 peptides in all,predictive performance of the algorithm surpassed the so far bestperforming matrix based prediction. Moreover, by combining the bothmethods binder peptides (log Kd < -6) could be predicted with84% accuracy. Parameter distribution of the HMMs that can be inspectedvisually after training further offers a glimpse of dynamic specificity ofthe MHC molecules. PMID- 23345769 TI - Domains and rafts in membranes - hidden dimensions of selforganization. AB - Both biomembranes and biomimetic membranes such as lipid bilayers withseveral components contain intramembrane domains and rafts.Macromolecules, which are anchored to the membrane but have no tendeney tocluster, induce curved nanodomains. Clustering of membrane componentsleads to larger domains which can grow up to a certain maximal size andthen undergo a budding process. The maximal domain size depends on theinterplay of spontaneous curvature, bending rigidity, and line tension.It is argued that this interplay governs the formation of bothclathrin-coated buds and caveolae. Finally, membrane adhesion often leadsto domain formation within the contact zone. PMID- 23345770 TI - The lipid organisation of the skin barrier: liquid and crystalline domains coexist in lamellar phases. AB - The superficial layer of the skin, the stratum corneum, is the main barrier for diffusion of substances across the skin. The stratum corneum is composed of corneocytes embedded in lipid lamellae. In previous studies two lamellar phases have been identified with periodicities of 6.4 and 13.4 nm of which the 13.4 nm phase (long periodicity phase = LPP) is considered to be very important for the skin banier function. The main lipid classes in stratumcorneum are ceramides, free fatty acids and cholesterol. Until now 8 subclassesof ceramides are identified in human stratum corneum referred to as ceramide 1 to 8. Studies with mixtures prepared with isolated human ceramides revealed that cholesterol and ceramides are very important for the formation of the lamellar phases. After addition of free fatty acids the lipids are organised in an orthorhombic packing with a small proportion of lipids in a liquid phase. Our most recent results show that the presence of ceramide 1 and the formation of a liquid phase are crucial elements for the formation of the LPP. These observations and the broad narrowbroad sequence of lipid layers in the LPP led us to propose a molecular model for this phase. This consists of one narrow central lipid layer with fluid domains with on both sides a broad layer with a crystalline structure. This model is referred to as 'the sandwich model'. PMID- 23345771 TI - Morphological and topological transformation of membrane vesicles. AB - Liposomes are micro-compartments made of lipid bilayer membranes withcharacteristics quite similar to those of biological membranes. To formartificial cell-like structures, we generated liposomes that containedsubunit proteins of cytoskeletons: tubulin or actin. Spherical liposomeswere transformed into bipolar or cell-like shapes by mechanical forcesgenerated by the polymerization of encapsulated subunits of microtubules.Disk- or dumbbell-shaped liposomes were developed by the polymerizationof encapsulated actin. Dynamic processes of morphological transformationsof liposomes were visualized by high intensity dark-field lightmicroscopy.Topological changes, such as fusion and division of membrane vesicles,play an essential role in cellular activities. To investigate themechanism of these processes, we visualized in real time the liposomesundergoing topological transformation. A variety of novel topologicaltransformations were found, including the opening-up of liposomes and thedirect expulsion of inner vesicles. PMID- 23345772 TI - Estimation of Differently Bound Water Molecules for the Gel Phase of Dimyristoylphosphatidylethanolamine-Water System as Studied by DSC and (2)H-NMR Spectroscopy. AB - A measurement of (2)H spin-lattice relaxation time, T(1), forD(2)O was performed with a high resolution liquid NMR apparatus fortwo samples of dimyristoylphosphatidylethanolamine (DMPE)-D(2)Osystem in a full hydration at varying temperatures of -20, -10, and 5 ( degrees )C, and both components and compositions of differently boundfreezable water molecules were estimated from a best-fitted curve toexperimental inversion recovery data. A choice of the best fitted curve wasbased on a distribution of weighted residuals for the experimental data. Asingle component was found for a temperature of -20 ( degrees )C. At 5 ( degrees )C, where all the freezable water exists in the liquid state, threecomponents were observed to be characterized by T(1) values ofapproximately 20, 100, and 200 ms, respectively. By comparingcompositions of these individual components with those obtained in ourprevious DSC study, it was revealed that the first and secondarycomponents are members of freezable interlamellar water and the last oneis comparable to bulk water. PMID- 23345773 TI - Effect of electrostatic interactions on phase stability of cubic phases of biomembranes. AB - We investigated effect of electrostatic interactions due to surfacecharges on structures and stability of cubic phases of monoolein (MO)membrane using the small-angle X-ray scattering method. Firstly, wechanged the surface charge density of the membrane by usingdioleoylphosphatidic acid (DOPA). As increasing DOPA concentration in themembrane at 30 wt % lipid concentration, a Q(224) to Q(229) phasetransition occurred at 0.6 mol % DOPA, and at and above 25 mol %, DOPA/MOmembranes were in the L(alpha) phase. NaCl in the bulk phase reduced theeffect of DOPA. These results indicate that as the electrostaticinteractions increase, the most stable phase changes as follows: Q(224)=> Q(229) => L(alpha). The increase in DOPAconcentration reduced the absolute value of spontaneous curvature of themembrane, | H(0) |. Secondly, we changed the surface charge of themembrane by adding a de novo designed peptide, which has netpositive charges and a binding site on the electrically neutral membraneinterface. The peptide-1 (WLFLLKKK) induced a Q(224) to Q(229)phase transition in the MO membrane at low peptide concentration. As NaClconcentration increases, the MO/peptide-1 membrane changed from Q(229)to Q(224) phase. The increase in peptide-1 concentration reduced |H(0) |. Based on these results, the stability of the cubic phases and themechanism of phase transition between cubic phase and L(alpha) phase arediscussed. PMID- 23345774 TI - Linear free-energy relationships and the dynamics of gating in the acetylcholine receptor channel. AB - The muscle acetylcholine receptor channel (AChR) is a large (M(r) ?290K) transmembrane protein that mediates synaptic transmission. Theactivation of this ion channel can be understood in the framework of athermodynamic cycle with spontaneous gating (i.e., the closed ? open reaction) and ligand-binding events as the elementary steps. Becauseagonists bind more tightly to the open than to the closed state, gating ofliganded receptors is more favorable than that of unliganded receptors.Accordingly, channel opening must involve two major conformationalchanges: the ACh-binding sites switch from a low-affinity to a high affinityform, and the pore (located ~ 45 A away from the binding sites)switches from an ion-impermeable to an ion-permeable conformation. Togain insight into the reaction mechanism of fully-liganded gating, wecharacterized the corresponding transition state in the context of the 'linearfree-energy relationships' of physical organic chemistry (Phi-valueanalysis). Gating of fully-liganded AChRs was studied by recordingsingle-channel currents using the patch-clamp technique. Perturbations tothe wild-type receptor were either series of different mutations at individualpositions or series of different agonists. Based on the obtained 'snapshot'of the gating reaction at the transition state, and aware of the lack ofinformation about the rest of the energy profile, the most parsimoniousmechanism seems to be one where opening proceeds asynchronously, withthe low-to-high affinity change at the binding sites preceding the completeopening of the distant pore. PMID- 23345775 TI - A Stochastic Model of Conductance Transitions in Voltage-Gated IonChannels. AB - We present a statistical physics model to describe the stochastic behaviorof ion transport and channel transitions under an applied membrane voltage.To get pertinent ideas we apply our general theoretical scheme to ananalytically tractable model of the channel with a deep binding site whichinteracts with the permeant ions electrostatically. It is found that theinteraction is modulated by the average ionic occupancy in the bindingsite, which is enhanced by the membrane voltage increases. Above acritical voltage, the interaction gives rise to a emergence of a newconducting state along with shift of S4 charge residues in the channel.This exploratory study calls for further investigations to correlate thecomplex transition behaviors with a variety of ion channels, withparameters in the model, potential energy parameters, voltage, and ionicconcentration. PMID- 23345776 TI - Permeation models and structure-function relationships in ion channels. AB - Recent determination of the molecular structures of potassium andmechanosensitive channels from x-ray crystallography has led to arenewed interest in ion channels. The challenge for permeation modelsis to understand the functional properties of channels from the availablestructural information. Here we give a critical review of the three maincontenders, namely, continuum theories, Brownian dynamics and moleculardynamics. Continuum theories are shown to be invalid in a narrow channel environment because they ignore the self-energy of ions arising from theinduced charges on the dielectric boundary. Brownian and moleculardynamics are thus the only physically valid methods for studying thestructure-function relations in ion channels. Applications of thesemethods to potassium and calcium channels are presented, which illustratethe multi-ion nature of the permeation mechanism in selective biologicalchannels. PMID- 23345777 TI - Na,K-ATPase as A Brownian Motor: Electric Field-InducedConformational Fluctuation Leads to Uphill Pumping of Cation inthe Absence of ATP. AB - Na,K-ATPase uses chemical bond energy of ATP to pump K(+) into, andNa(+) out of a cell. Both are uphill transports. During the catalyticcycle the enzyme alternates between two conformational states, E(1) andE(2). This communication describes an experiment, which employs electricfield to drive oscillation or fluctuation of enzyme conformation betweenthe E(1) and the E(2) states. It is shown that the field-inducedconformational oscillation or fluctuation leads to uphill pumping of thecation by the enzyme without consumption of ATP. Biochemical specificityof the catalysis is preserved. Data indicate that Na,K-ATPase can harvestenergy from the applied electric field to perform chemical work, and aratchet mechanism is inherent in this energy transduction process. ATheory of Electroconformational Coupling (TEC) that embodies essentialfeatures of the Brownian Ratchet successfully simulates the field-frequencyand field-amplitude optima and other features of the ion pumping activity.A four-state TEC motor can achieve high efficiency of the energytransduction, asymptotically reaching 100% under the optimal condition.Pumping by ion rectification fails to reach high efficiency. The TECconcept is also mused to understand other biological motors and engines. PMID- 23345778 TI - Production of force and movement by polymerization of actin: mechanism and reconstitution in vitro. PMID- 23345779 TI - Mechanical Properties of a Single-Headed Processive Motor, Inner-Arm Dynein Subspecies-c of ChlamydomonasStudied at the Single Molecule Level. AB - Dynein from inner arms of Chlamydomonasflagella contains sevendistinct subspecies, a through g. Several lines of evidence suggest thesesubspecies play important roles in generating flagellar beating and thatthe different subspecies are functionally diverse. To evaluate theirroles and diversity, the mechanical properties of subspecies-c, which isa single-headed motor, were examined using optical trap nanometry. Apolystyrene bead coated with a small number of subspecies-c moleculeswas captured with the optical trap and brought into contact with amicrotubule fixed to a coverslip. Movements of the bead were measured bya quadrant photodiode sensor with sub-nanometer- and millisecond-resolution.Beads carrying a single active subspecies-c molecule moved processivelyalong the microtubules in 8-nm steps but slipped backwards under highloads. Force-velocity relationships of single subspecies-c molecules werealmost linear and the shapes of the normalized curves at 5 MUM and 100MUM ATP were similar. These results indicate that dynein subspecies-cfunctions in a very different way from conventional motor proteins, suchas myosin and kinesin, and has properties that could produceself-oscillation in vivo. PMID- 23345780 TI - Theoretical Characterization of the Long-range Attraction between G-actin Molecules through the Excluded Volume Effect. AB - One of the interactions between macromolecules is the attractive forcethrough the excluded volume effect. We studied the attraction betweenthe molecules of muscle protein, actin, in the two points by using theextended scaled particle theory (XSPT). I) we verified the basic assumptionused in the XSPT that topological elements which determine the analyticalexpression of the excluded volume are almost unchanged through the scalingdown of the solute molecule in the thought experiment. Results of thecomputational geometry method (alpha-shape method) showed that thisassumption is valid even in the case of the actin molecule. II) wecalculated the attraction between actin monomer molecules, G-actin.Calculated differences of the values of the attraction potential of twomacromolecules between at contact and at one macromolecule apart by theXSPT is almost the same as those by the Asakura-Oosawa theory. PMID- 23345781 TI - Longitudinal distortions and transversal fluctuations of an actin filament sliding on Myosin molecules. AB - An actin filament sliding on myosin moleculesdemonstrates both longitudinal distortions and transversal fluctuationswith the linear dimension far exceeding the diameter of an actinmonomer. Local swaying of a single actin filament was identified byreading speckled fluorescent markers attached on the filament. Theaccuracy of reading each speckled marker was about 10.4 nm (r.m.s.).Longitudinal distortions of an actin filament at a low ATP concentrationof 20 MUM were as much as 0.5 MUm for the average filament lengthof 5.4 MUm. The magnitude of transversal fluctuations was as much as60 nm, that was independent of the filament length. Both longitudinaldistortions and transversal fluctuations are suggested to play a pivotalrole for facilitating a smooth sliding movement of an actin filament. PMID- 23345782 TI - Unique mechanisms of excitation energy transfer, electron transfer and photoisomerization in biological systems. AB - We discuss unique mechanisms typical in the elementary processes ofbiological functions. We focus on three topics. Excitation energytransfer in the light harvesting antenna systems of photosyntheticbacteria is unique in its structure and the energy transfer mechanism. Inthe case of LH2 of Rhodopseudomonas acidophila, the B850 intra-ringenergy transfer and the inter-ring energy transfer between B800 and B850take place by the intermediate coupling mechanism of energy transfer. Theexcitonic coherent domain shows a wave-like movement along the ring, andthis property is expected to play a significant role in the inter-ringenergy transfer between LH2's. The electron transfer in biological systemsis mostly long range electron transfer that occurs by the electrontunneling through the protein media. There is a long-standing problem thatwhich part of protein media is used for the electron tunneling root. As aresult of our detailed analysis, we found that the global electron tunnelingroot is a little winded with a width of a few angstrom, reflecting theproperty of tertiary and secondary structures of the protein and it isaffected by the thermal fluctuation of protein structure. Photoisomerizationof rhodopsin is very unique: The cis-transphotoisomerization ofrhodopsin occurs only around the C11 = C12 bond in the counterclockwisedirection. Its molecular mechanism is resolved by our MD simulation studyusing the structure of rhodopsin which was recently obtained by the X-raycrystallographic analysis. PMID- 23345783 TI - Different scenarios for inter-protein electron tunneling: the effect of water mediated pathways. AB - Recent theoretical developments now allow for reliable calculation oftunneling matrix elements in unimolecular biological electron transferreactions that have been tested experimentally. Most biological ETprocesses, however, are bimolecular, or involve large-scale proteindomain motions. In this paper, initial advances in this direction bystudying the inter-protein electron transfer between cytochrome c(2)andthe photosynthetic reaction center. Utilizing an approach that integratesmolecular dynamics and the Pathways method, we have observed that theensemble dominant tunneling pathways in this reaction go though thetyrosine 162 or are water mediated. PMID- 23345784 TI - On the Configurational and Conformational Changes in Photoactive Yellow Protein that Leads to Signal Generation in Ectothiorhodospira halophila. AB - Photoactive Yellow Protein (PYP), a phototaxis photoreceptor from Ectothiorhodospira halophila, is a small water-soluble protein that iscrystallisable and excellently photo-stable. It can be activated with light(lambda(max)= 446 nm), to enter a series of transientintermediates that jointly form the photocycle of this photosensor protein.The most stable of these transient states is the signalling state forphototaxis, pB.The spatial structure of the ground state of PYP, pG and the spectralproperties of the photocycle intermediates have been very well resolved.Owing to its excellent chemical- and photochemical stability, also the spatialstructure of its photocycle intermediates has been characterised with X-raydiffraction and multinuclear NMR spectroscopy. Surprisingly, the resultsobtained showed that their structure is dependent on the molecular contextin which they are formed. Therefore, a large range of diffraction-,scattering- and spectroscopic techniques is now being employed to resolvein detail the dynamical changes of the structure of PYP while it progressesthrough its photocycle. This approach has led to considerable progress,although some techniques still result in mutually inconsistent conclusionsregarding aspects of the structure of particular intermediates.Recently, significant progress has also been made with simulations withmolecular dynamics analyses of the initial events that occur in PYP uponphoto activation. The great challenge in this field is to eventually obtainagreement between predicted dynamical alterations in PYP structure, asobtained with the MD approach and the actually measured dynamicalchanges in its structure as evolving during photocycle progression. PMID- 23345785 TI - Positions of Q(A)and Chl(Z)Relative to Tyrosine Y(Z)and Y(D)in Photosystem II Studied by Pulsed EPR. AB - PELDOR (Pulsed Electron eLectron DOuble Resonance) was applied to determinethe distance of between Y(Z)and Q(A) (-)inY(D)-less mutant of Chlamydomonas reinhardtiiin Tris-treatedand Zn-substituted preparation of photosystem II. The value of distance wasfound to be 34.5 +/- 1 A. A '2+1' electron spin echo method has beenapplied to measure the orientation of the radius-vector RfomY(D)to Chl(Z)in a membrane-oriented photosystem II. The anglebetween Rand the membrane normal nwas determined to be 50 +/-5( degrees ), using the distance 29.4 +/- 0.5 A determined in non-orientedPS II. PMID- 23345786 TI - Peptide free energy landscapes calibrated by molecular orbital calculations. AB - Free energy landscapes of peptide conformations werecalibrated by ab initiomolecular orbital calculations, after enhancedconformational sampling using the multicanonical molecular dynamicssimulations. Three different potentials of mean force for an isolateddipeptide were individually obtained using the conventional force fields,AMBER parm94, AMBER parm96, and CHARMm22. Each potential ofmean force was calibrated based on the umbrella sampling algorithm fromthe adiabatic energy map that was calculated separately by the abinitiomolecular orbital method. All the calibrated potentials of mean forcecoincided well. The calibration was applied to a peptide in explicit water,and the calibrated free energy landscapes did not depend on the force fieldused in conformational sampling, as far as the conformational space waswell sampled. PMID- 23345787 TI - Phylogeny Based on Whole Genome as inferred from Complete Information Set Analysis. AB - Previous molecular phylogeny algorithms mainly rely onmulti-sequence alignments of cautiously selected characteristic sequences,thus not directly appropriate for whole genome phylogeny where eventssuch as rearrangements make full-length alignments impossible. Weintroduce here the concept of Complete Information Set (CIS) and itsmeasurement implementation as evolution distance without reference tosizes. As method proof-test, the 16s rRNA sequences of 22 completelysequenced Bacteria and Archaea species are used to reconstruct aphylogenetic tree, which is generally consistent with the commonlyaccepted one. Based on whole genome, our further efforts yield a highlyrobust whole genome phylogenetic tree, supporting separate monophyleticcluster of species with similar phenotype as well as the early evolution ofthermophilic Bacteria and late diverging of Eukarya. The purpose of thiswork is not to contradict or confirm previous phylogeny standards butrather to bring a brand-new algorithm and tool to the phylogeny researchcommunity. The software to estimate the sequence distance and materialsused in this study are available upon request to corresponding author. PMID- 23345788 TI - System for automatically inferring a genetic netwerk from expression profiles. AB - A system is constructed to automatically infer a genetic network byapplication of graphical Gaussian modeling to the expression profiledata. Our system is composed of two parts: one part is automaticdetermination of cluster boundaries of profiles in hierarchicalclustering, and another part is inference of a genetic network byapplication of graphical Gaussian modeling to the clustered profiles.Since thousands of or tens of thousands of gene expression profiles aremeasured under only one hundred conditions, the profiles naturally showsome similar patterns. Therefore, a preprocessing for systematicallyclustering the profiles is prerequisite to infer the relationship betweenthe genes. For this purpose, a method for automatic determination ofcluster boundaries is newly developed without any biological knowledgeand any additional analyses. Then, the profiles for each cluster areanalyzed by graphical Gaussian modeling to infer the relationship betweenthe clusters. Thus, our system automatically provides a graph betweenclusters only by input the profile data. The performance of the presentsystem is validated by 2467 profiles from yeast genes. The clusters andthe genetic network obtained by our system are discussed in terms of thegene function and the known regulatory relationship between genes. PMID- 23345789 TI - Cell Simulation for Circadian Rhythm Based on Michaelis-MentenModel. AB - We report here the development of a cell biological simulation systembased on ordinary differential equations and the results on the simulationof the heat pulses' effects on the circadian rhythm in Drosophila.The simulator implements intra-cellular processes: transcription,translation, transport, modification (association, disassociation),degradation. It simulates the temporal behavior of concentrations ofproteins and mRNA involved in various biological phenomena. Moreover, thesystem is able to determine the exact type of reaction for a givenregulatory pathway. In order to prove the usefulness of the simulator weconstruct a model of the circadian rhythm in Drosophilaand wesimulate the effect of the heat pulses applied in early afternoon on thecircadian clock proteins PER and TIM. Our simulation results show therobustness of the genetic network as well as the important role playedby dClk mRNA in the mechanism of phase-shift responses. PMID- 23345790 TI - Molecular evolution in static and dynamical landscapes. AB - In an attempt to understand protein evolution, we address the issues ofhow much variety in the sequences is needed to prompt the evolution ofan enzyme from random polypeptides and how does cellular interactionaffect the dynamics of molecular evolution to allow genetic diversity inpopulation. The experimental evolution of phage-displayed randompolypeptides of about 140 amino acid residues panned with transition stateanalogue for an esterase reaction showed that even with a population sizeas small as ten, not only could significant varieties be found but also therandom polypeptides in each of the generation had great promise towardsdeveloping into functional proteins. Hence, it is evident that the enzymeevolution is prompted even within a small local area of the static landscapeof the sequence space. Considering that interaction among living cells is aninevitable event in natural evolution, its role was investigated through threeconsecutive rounds of random mutagenesis on the glutamine synthetasegene and chemostat culture of the transformed Escherichia colicellscontaining the mutated genes. The molecular phylogeny and populationdynamics show the coexistence of some mutants having different level ofglutamine synthetase at each generation. In addition, it was confirmed thatcellular interaction via the medium influences the stability of the coexistenceand bring forth fitness change to the coexisting members of the population,thereby, leading to a dynamical landscape. Based on experimental resultsreflecting the extent of interaction among members in population, here, Iproposed that protein evolution could change its mode from theoptimization on static landscape to diversification on dynamicallandscape. PMID- 23345791 TI - Correlation between the conformation space and the sequence space of Peptide chain. AB - Effects of point mutations are investigated in a computer model ofsequence selection. In the model, sequences are selected according totheir functional ability defined by the configuration at the active site.Through such functional selection on the local configuration, sequenceswhich fold globally into a unique conformation can be selected from randomsequences. The selected sequence accepts many point mutations as neutralmutations. More structurally fluctuating sites in the chain accept alarger variety of point mutations, which shows correlation between theconformational fluctuation and the sequence fluctuation. PMID- 23345792 TI - A DNA-based in vitroGenetic Program. AB - In PNA-mediated Whiplash PCR (PWPCR), autonomous molecular computation is implemented by the recursive polymerase extension of a mixture of DNA hairpins. Like other methods based on exhaustive search, however, application to problem instances of realistic size is prevented by the exponential scaling of thesolution space. The tendency of evolving populations to minimize the sampling of large, low fitness basins suggests that a DNA-based evolutionary approach might be an effective alternative to exhaustive search. In this work, PWPCR is modified to support the evolution of a population of finite state machines. A practical, in vitroalgorithm for applying this architecture to evolve approximate solutions to instances of the NP-complete problem, Hamiltonian Pathis described in detail. PMID- 23345793 TI - Correlated flexible molecular coding and molecular evolvability. AB - Evolvability of biopolymers is based on molecular coding. The molecular coding is represented by biopolymer function vs monomeric sequence relationship, that is, a proper fitness landscape on the sequence space. On the other hand, molecular coding is mostly realized by monomeric sequence vs biopolymer structure relationship. We suggest the evolution of evolvability based on flexible or multiplex coding originating from flexible or polymorphic conformation of evolving biopolymers. We report a finding supporting that the amino acid landscape of the standard genetic code for an amino acid property which is more important to the protein function gives higher value of an evolvability measure. We developed a promising molecular construct which realized genotype-phenotype linking in order to study the in vitroprotein evolution to clarify above mentioned protein evolvability. PMID- 23345794 TI - Echolocation of multiple targets in 3-d space from a single emission. AB - Using frequency-modulated echolocation sound, bat can capture a moving target in real three-dimensional (3-D) space. It is impossible to locate multiple targets in 3-D space by using only the delay time between an emission and the resultingechoes received at two points (i.e., two ears). To locate multiple targets in 3-D space requires directional information for each target. The spectrum of the echoes from nearly equidistant targets includes spectral components of both the interference between the echoes and the interference resulting from the physical process of reception at the external ear. The frequency of the spectral notch, which is the frequency corresponding to the minimum of the external ear's transfer function (EEDNF), provides a crucial cue for directional localization. In the model we present, a computational model todiscriminate multiple close targets in 3-D space utilizing echoes evoked by a single emission by distinguishing the interference of echoes from each object and the EEDNF corresponding to each target. PMID- 23345795 TI - Population-vector analysis by primate prefrontal neuron activities. AB - The population-vector analysis was applied to visualize neuronal processes of sensory-to-motor transformation in the prefrontal cortex while two monkeys performed two types of oculomotor delayed-response (ODR) tasks. In a standard ODR task, monkeys were required to make a quick eye movement to where thevisual cue had been presented 3 s before, whereas in R-ODR task, monkeys wererequired to make an eye movement 90( degrees )clockwise to the direction that the visual cue had been presented. In both tasks, directions of population vectors calculated from cue- and response-period activity were almost the same as cue directions and saccade directions, respectively, indicating that population vectors of cue- and response-period activity represent information of visual inputs and motor outputs, respectively. To visualize neuronal processes of information transformation, population vectors were calculated every 250 ms during a whole trial. In ODR task, population vectors weredirected the same direction as the cue direction during the delay period. However, in R-ODR task, population vector rotated gradually from the direction similar to the cue direction to the saccade direction during the delay period. These results indicate that visual-to-motor transformation occurs during the delay period and that this process can be visualized by the population-vectoranalysis. PMID- 23345796 TI - Hippocampal Damage Disrupts Eyeblink Conditioning in Mice Lacking Glutamate Receptor Subunit delta2. AB - Cerebellar long-term depression (LTD) at the parallel fiber-Purkinje cell synapses has been proposed to be a neural substrate for classical eyeblink conditioning. Mutant mice lacking the glutamate receptor subunit delta2 (GluRdelta2), in which the cerebellar LTD is disrupted, exhibited a severe impairment in the delay eyeblink conditioning with a temporal overlap of CS and US. However, they learned normally trace and delay conditioning without CS-US overlap, suggesting a learning mechanism which does not require the cerebellar LTD.In the present study, we tested possible involvement of the hippocampus in this cerebellar LTD-independent learning. We examined effects of scopolamine and hippocampal lesion on the delay conditioning without CS-US overlap. TheGluRdelta2 mutant mice that received scopolamine or aspiration of the dorsalhippocampus together with its overlying cortex exhibited a severe impairment in learning, while the control mutant mice that received saline or aspiration of the overlying cortex learned normally. In contrast, wild-type mice that received either treatment learned as normally as the control wild-type mice. These results suggest that the hippocampus is essential in the cerebellar LTD-independent learning in the GluRdelta2 mutant mice, indicating a newrole of hippocampus in the paradigm with a short trace interval. PMID- 23345797 TI - Photoresponse and learning behavior of ascidian larvae, a primitive chordate, to repeated stimuli of step-up and step-down of light. AB - Ascidians are lower chordates and their simple tadpole-like larvae share a basic body plan with vertebrates. Newly hatched larvae show no response to a stimulus of light. 4 h after hatching, the larvae were induced to swim upon a step-down of light and stop swimming upon a step-up of light. At weaker intensity of light, the larvae show the same response to a stimulus after presentation of repeated stimuli. When intensity of actinic light was increased, the larvae show sensitization and habituation of the swimming response to a stimulus after repeated stimuli of step-down and step-up of the light. Between 2 h 20 min and 3 h 40 min after hatching the larvae did not show any response to the first stimulus, but after several repeatedstimuli they show swimming response to a step down of light. A repeated series of stimulus cause sensitization. Between 4 h and 7 h after hatching, the larvae show photoresponse to the first stimulus, but after several repetition of the stimuli, the larvae could not stop swimming to a stimulus of a step-up of the actinic light. A repeated series of stimulus cause greaterhabituation. Both sensitization and habituation depend upon intensity ofactinic light. PMID- 23345798 TI - Nanotechnology and protein mechanics. AB - The atomic force microscope is currently used in our and many other laboratories to measure the mechanical response of polypeptide and proteins against tensile forces applied to well defined positions in their chemical structures. The resulting force vs. extension (F-E) curves are analyzed in relation to their known conformations under various conditions. The method can be extended to study the mechanical responses of other, often much larger biological structures, and extract the component proteins and DNAs from cell membranes and chromosomes. PMID- 23345799 TI - Single-molecule imaging and spectroscopy using fluorescence and surface-enhanced Raman scattering. AB - We extended single molecule fluorescence imaging and time-resolved fluorometry from the green to the violet-excitation regime to find feasibility of detecting and identifying fluorescent analogs of nucleic-acid bases at the single-molecule level. Using violet excitation, we observed fluorescent spotsfrom single complexes composed of a nucleotide analogue and the Klenow fragmentof DNA polymerase I. Also, we implemented Raman imaging and spectroscopy of adenine molecules adsorbed on Ag colloidal nanoparticles to find feasibility of identifying nucleic-acid bases at the single-molecule level. Surface enhanced Raman scattering (SERS) of adenine molecules showed an intermittent on-and-off behavior called blinking. The observation of blinking provides substantial evidence for detecting single adenine molecules. PMID- 23345800 TI - Manipulation of a Large DNA Molecule using the Phase Transition. AB - A conventional method of DNA sequencing can determine up to 1000 base pairs at one time. Therefore, long DNA should be cut into many short fragments that are suitable for DNA sequencing. Those fragments, however, lose their order information. If the fragments are prepared from the terminus of the long DNA, the reorganization process can be omitted. This process consists of following unit operations; manipulation of genomic DNA, fixation with a stretched form, cutting from the terminus, recovery and amplification. In these unit operations, manipulation and cutting of DNA are focused in this report. Globular transformation suppresses break down of long genome DNA and permits manipulation of large DNA. Because globular transition is reversible, the coiled DNA can be sequentially spun from the globular DNA like a spindle. Thespun DNA was successfully fixed on a glass surface in an arbitrary pattern. To prepare fragments from the stretched DNA molecule, a method to cut DNA moleculen was developed. Since most restriction enzyme requires magnesium ion for their activation, the restriction enzyme was successfully activated only when magnesium ion was electrochemically supplied. PMID- 23345801 TI - Controlling and measuring local composition and properties in lipid bilayer membranes. AB - Local composition, structure, morphology, and phase are interrelated in lipid bilayer membranes. This gives us the opportunity to control one or more of these properties by manipulating others. We investigate theserelationships with combinations of simultaneous two-color widefield fluorescence imaging, three dimensional rendering of vesicle domains, andmanipulation of the vesicle morphology via optical trapping and micropipetteaspiration. We describe methods to modulate, to measure, and to probe thelocal structure of model membranes through control of membrane curvature inliposomes. PMID- 23345802 TI - Single molecule probe scanning optical force imaging microscopefor viewing live cells. AB - We have developed an imaging system that combines the soft compliance of an optical trap with the sensitivity of single particle tracking to image forces on/in live cells using a single molecule probe. The probe used is a single (or few) molecule of interest that is conjugated with a single 40 nm colloidalgold probe. The colloidal gold/membrane protein complex, freely diffusing on a live cell, is held in a laser trap while the cell is scanned underneath. Computer control allows for synchronization of the cell scan and capture of the probe position. Resistance to the dragging of the probe images a fine structure of barriers in the membrane of live cells. PMID- 23345803 TI - A Novel Phase-contrast Transmission Electron Microscopy Producing High-contrast Topographic Images of Weak objects. AB - We report a novel class of transmission electron microscope (TEM), the difference contrast electron microscope (DTEM), which displays nanostructures of thin specimen objects in a topographical manner. Topography obtained by the difference contrast develops shadowgraphs in pseudo three-dimension, namely volume-like representation of projected objects as if things are illuminated by light from one direction. The specific optical device tomanipulate electron waves for DTEM is the hemicircular pi phase-plate, which appears to be quite distinguishable from the Zernike phase plate utilized in Zernike phase-contrast TEM, while both have to be placed onto the back-focal plane of the objective lens. The topographic images obtained with DTEM for ultrathin sections of kidney cells were compared with those obtained with conventional TEM. DTEM confirmed the experimental advantage of high contrast topography by visualizing ultrastructural details inside the cells. PMID- 23345804 TI - Deterministic versus stochastic models for circadian rhythms. AB - Circadian rhythms which occur with a period close to 24 h in nearly all living organisms originate from the negative autoregulation of gene expression.Deterministic models based on genetic regulatory processes account for theoccurrence of circadian rhythms in constant environmental conditions (e.g.constant darkness), for entrainment of these rhythms by light-dark cycles, and for their phase-shifting by light pulses. At low numbers of protein and mRNA molecules, it becomes necessary to resort to stochastic simulations to assess the influence of molecular noise on circadian oscillations. We address the effect of molecular noise by considering two stochastic versions of a core model for circadian rhythms. The deterministic version of this core modelwas previously proposed for circadian oscillations of the PER protein in Drosophila and of the FRQ protein in Neurospora. In the first, non-developed version of the stochastic model, we introduce molecular noise without decomposing the deterministic mechanism into detailed reaction steps while in the second, developed version we carry out such a detailed decomposition. Numerical simulations of the two stochastic versions of the model are performed by means of the Gillespie method. We compare the predictions of the deterministic approach with those of the two stochastic models, with respect both to sustained oscillations of the limit cycle type and to the influence of the proximity of a bifurcation point beyond which the system evolves to a stable steady state. The results indicate that robust circadian oscillations can occur even when the numbers of mRNA and nuclear protein involved in the oscillatory mechanism are reduced to a few tens orhundreds, respectively. The non-developed and developed versions of the stochastic model yield largely similar results and provide good agreement with the predictions of the deterministic model for circadian rhythms. PMID- 23345805 TI - Self-organization in living cells: networks of protein machines and nonequilibrium soft matter. AB - Microscopic self-organization phenomena inside a living cell should not represent merely a reduced copy of self-organization in macroscopic systems. A cell is populated by active protein machines that communicate via small molecules diffusing through the cytoplasm. Mutual synchronization of machine cycles can spontaneously develop in such networks - an effect which is similar to coherent laser generation. On the other hand, an interplay between reactions, diffusion and phase transitions in biological soft matter may lead to the formation of stationary or traveling nonequilibrium nanoscale structures. PMID- 23345806 TI - Long Range Force between Pre-Replication Complexes (Pre-RC) in DNA Controls Replication and Cell Cycle Progression. AB - A nonstationary interaction, that controls DNA replication and the cell cycle, is derived from a manybody physics model in a chemically open T cell. The model predicts a long range force F'(xi)=-(kappa/2) xi(1-xi)(2-xi) between the pre replication complexes (pre-RCs) bound by DNA, xi=phi/N being the relative displacement of preRCs, phi the number of pre-RCs, N the threshold for initiation, and kappa the compressibility modulus in thelattice of pre-RCs which behaves like an elastically braced string. Initiation of DNA replication is induced by a switch of sign of F'(xi), from attraction (-)and assembly in the G(1) phase (0 < phi < N), to repulsion (+) and partialdisassembly in the S phase (N < phi < 2N), with release of licensing factors from the pre-RCs, thus explaining prevention of re-replication. Replication is terminated by a switch of sign of F at phi = 2N, when all primed replicons are duplicated once, and F(0)=0 corresponds to a resting cell in absence of driving force at phi = 0. The switch of sign of force at phi = N also explains the dynamic instability in growing microtubules (MTs), as well as switch in the interleukin-2 (IL2) interaction with its receptor in late G(1), at the restriction point. Shape, slope and scale of the response curves derived agree well with experimental data from dividing T cells and polymerizing MTs, the variable length of which is due to anonlinear dependence of the growth amplitude on the initial concentrations of tubulin dimers and guanosine-tri-phosphate (GTP). PMID- 23345807 TI - Field Hypothesis on the Self-regulation of Gene Expression. AB - The mechanism of the self-regulation of gene expression in living cells is generally explained by considering complicated networks of key-lock relationships, and in fact there is a large body of evidence on a hugenumber of key-lock relationships. However, in the present article we stress that with the network hypothesis alone it is impossible to fully explain the mechanism of self regulation in life. Recently, it has been established that individual giant DNA molecules, larger than several tens of kilo base pairs, undergo a large discrete transition in their higher-order structure. It has become clear that nonspecific weak interactions with various chemicals, suchas polyamines, small salts, ATP and RNA, cause on/off switching in the higher-order structure of DNA. Thus, the field parameters of the cellular environment should play important roles in the mechanism of self-regulation, in addition to networks of key and locks. This conformational transition induced by field parameters may be related to rigid on/off regulation, whereas key-lock relationships may be involved in a more flexible control of gene expression. PMID- 23345808 TI - The sinus node as a nonlinear dynamic system. AB - The Sinus Node (SN) of the heart is the natural pacemaker driving electrical impulses into the atria, an ordinary excitable medium. In order to avoid wave interference, the SN operation must be of such a nature that no reflections from the atria should occur. It is shown that such a behavior is achieved when the SN operates in a nonlinear dynamical regime situated away from relaxation. PMID- 23345809 TI - Rhythmic Conformational Change in a SinglePolymer Chain Induced by Laser Irradiation. AB - We have investigated a rhythmic conformational change in a single polymer chain (T4DNA, 166 kbp, the contour length = 56 MUm) between a folded state and a elongated state under thermodynamically open conditions using a focused continuons wave (cw) Nd:YAG laser beam (wavelength lambda = 1064 nm), where the focused laser beam plays dual roles both of trapping of a polymer chain at the focus and making temperature gradient there. The oscillatory phenomenon is discuseed in terms of a limit-cycle oscillation with dissipation of photon energy. PMID- 23345810 TI - The use of liposomes for constructing cell models. AB - We illustrate here in a form of a short review some of the work developed in our and other groups aiming at performing inside liposomes enzymatic reactions relevant for the origin of life. The work on giant vesicles will not be considered here. The long-range goal of our work with SUVs or LUVs (small unilamellar vesicles or large unilamellar vesicles) is the construction of a model minimal cell. By this we mean a cell-like system containing the minimal and sufficient number of macromolecular components for expressingsome of the basic functions of a living cell- such as protein biosynthesis, growth and self reproduction, homeostasis based on a primitive metabolism. We begin describing a POPC liposomal system containing some of the enzymes of the salvage cycle for the synthesis of lecithin; then vesicles containing the nucleotide phosphorylase enzyme for the polymerisation of ADP into poly(A); an oleate self-reproducing vesicular system which hosts Qbeta replicase for the replication of a RNA template; a POPC systems (POPC = 1-palmitoyl-2-oleoyl-sn-phosphatidylcholine) hosting the elements for a polymerase chain reaction; and finally the attempts to organize inside liposomes the ribosomal system capable of the synthesis of poly(phenylalanine). This analysis of published work will be followed by the description of novel work aimed at expressing a protein (green fluorescent protein) inside liposomes. The possible development of this work and its limits will be discussed. PMID- 23345811 TI - A 21(st) Century View of Evolution. AB - Physicists question whether there are 'universals' in biology. One reason is that the prevailing theory of biological evolution postulates a random walk to each new adaptation. In the last 50 years, molecular genetics has revealed features of DNA sequence organization, protein structure and cellular processes of genetic change that suggest evolution by Natural Genetic Engineering. Genomes are hierarchically organized as systems assembled from DNA modules. Each genome is formatted and integrated by repetitive DNA sequence elements that do not code for proteins, much as a computer drive is formatted. These formatting elements constitute codons in multiple genetic codes for distinct functions such as transcription, replication, DNA compaction and genome distribution to daughter cells. Consequently, there is a computation-ready Genome System Architecture for each species. Whole-genome sequencing indicates that rearrangement of genetic modules plus duplication and reuse of existing genomic systems are fundamental events in evolution. Studies of genetic change show that cells possess mobile genetic elements and other natural genetic engineering activities to carry out the necessary DNA reorganizations. Natural genetic engineering functions are sensitive to biological inputs and their non-random operations help explain how novel genome system architectures can arise in evolution. PMID- 23345812 TI - Becoming Multicellular by Aggregation; The Morphogenesis of the Social Amoebae Dicyostelium discoideum. AB - The organisation and form of most organisms is generated during theirembryonic development and involves precise spatial and temporal controlof cell division, cell death, cell differentiation and cell movement.Differential cell movement is a particularly important mechanism in thegeneration of form. Arguably the best understood mechanism of directedmovement is chemotaxis. Chemotaxis plays a major role in the starvationinduced multicellular development of the social amoebae Dictyostelium.Upon starvation up to 10(5) individual amoebae aggregate to form afruiting body. In this paper we review the evidence that the movement ofthe cells during all stages of Dictyostelium development is controlled bypropagating waves of cAMP which control the chemotactic movement ofthe cells. We analyse the complex interactions between cell-cell signallingresulting in cAMP waves of various geometries and cell movement whichresults in a redistribution of the signalling sources and therefore changes thegeometry of the waves. We proceed to show how the morphogenesis,including aggregation stream and mound formation, slug formation andmigration, of this relatively simple organism is beginning to be understoodat the level of rules for cell behaviour, which can be tested experimentallyand theoretically by model calculations. PMID- 23345813 TI - Kinetic origin of heredity in a replicating system with a catalytic network. AB - The origin of heredity is studied as a recursive state in a replicatingprotocell consisting of many molecule species in mutually catalyzingreaction networks. Protocells divide when the number of molecules, increasing due to replication, exceeds a certain threshold. We study how the chemicals in a catalytic network can form recursive production states in the presence of errors in the replication process. Depending on the balance between the total number of molecules in a cell and the number of molecule species, we have found three phases; a phase without a recursive production state, a phase with itinerancy over a few recursive states, and a phase with fixedrecursive production states. Heredity is realized in the latter two phaseswhere molecule species that are population-wise in the minority are preserved and control the phenotype of the cell. It is shown that evolvability is realized in the itinerancy phase, where a change in the number of minority molecules controls a change of the chemical state. PMID- 23345814 TI - Unique Colony Housing the Coexisting Escherichia coli and Dictyostelium discoideum. AB - Two well-characterized and phylogenetically diverse species, Escherichiacoli and Dictyostelium discoideum, were used as the modelorganisms. When the two species were mixed and allowed to grow onminimal agar plates at 22 ( degrees )C, instead of the predator Dictyostelium exterminating E.coli, the two species remarkablyachieved a state of stable coexistence in about two weeks. In addition, theemerged colonies housing the coexisting species have a mucoidal naturethat is distinctive from its origin. The simplicity of the system and the shorttime span for the two species to develop the coexistence state, that isproven stable and reproducible on laboratory conditions, hence, providesa new model system for the study of symbiosis, particularly with referenceto the initial stages. PMID- 23345815 TI - Dynamical Systems Approach to Higher-level Heritability. AB - To explain higher-level heritability, we propose a dynamical systems approach, based on simulations of the high-dimensional replicator equation with mutation dynamics. We assume that all variants are generated from within the groups of variants through mutations. Simulating the equation with a random interaction matrix and possible variants, we report that this system tends to have many attractors, of fixed point, chaotic and quasiperiodic type. In a chaotic attractor, special gene-like variants appear to control the heritability ofthe system, in the sense that removal of the variants would easily enable the system to depart from the attractor. Those variants do not predominate in thepopulation size, but have the lowest net reproduction and mutation rates on average. Because their rate of growth is small, they are named neutral phenotypes. Additionally, combinatorial effects of these neutral variants to the entire system are reported. PMID- 23345816 TI - Reassessing models of hepatic extraction. AB - The aim of this investigation is to compare different mathematical models of the liver in the context of in vitro-in vivo correlation. We reanalyze drugs from the Houston reviews [1, 2], and compare the mathematical models. For the well-stirred model, a particular form of the distributed tubes model, and the dispersion model, fits are done to in vitro and in vivo intrinsic clearance data from microsomal and hepatocyte experiments. The distributed and dispersion models have decreased residuals as compared to the well-stirred model, but neither is to be clearly preferred over theother. It seems likely that drug-specific factors have a major impact on the quality of IVIVC correlations. While new experiments are needed to validate IVIVC models, our results indicate that improved correlation of in vitroand in vivo data is possible for high clearance drugs by using either a dispersion or distributed tube model rather than a well-stirred model. PMID- 23345817 TI - Comparison of Real Frequencies of Strings vs. the Expected Ones Reveals the Information Capacity of Macromoleculae. AB - The information capacity of nucleotide sequences is defined through the calculation of specific entropy of their frequency dictionary. The specificentropy of the frequency dictionary is calculated against the reconstructeddictionary; this latter bears the most probable continuations of the shorterstrings. This developed measure allows to distinguish the sequences both from the randons ones, and from those with high level of (rather simple) order. Some implications of the developed methodology in the fields of genetics,bioinformatics, and molecular biology are discussed. PMID- 23345818 TI - Random fields approach to the study of DNA chains. AB - We apply the random field theory tothe study of DNA chains which we assume tobe trajectories of a stochastic process. Weconstruct statistical potential betweennucleotides corresponding to theprobabilities of those trajectories thatcan be obtained from the DNA data basecontaining millions of sequences. It turnsout that this potential has aninterpretation in terms of quantitiesnaturally arrived at during the study ofevolution of species i.e. probabilities ofmutations of codons. Making use of recentlyperformed statistical investigations of DNAwe show that this potential has differentqualitative properties in coding andnoncoding parts of genes. We apply ourmodel to data for various organisms andobtain a good agreement with the resultsjust presented in the literature. We alsoargue that the coding/noncoding boundariescan corresponds to jumps of the potential. PMID- 23345819 TI - Kerr constant of vesicle-like droplets. AB - The Kerr effect on vesicle-likedroplets (vesicles, cells or emulsion droplets) is described. Wegive a derivation of the Kerr constant for a dielectric fluiddroplet immersed in another fluid, assuming that the droplet in aweak electric field becomes a prolate ellipsoid. The Kerr constantis evaluated also for a droplet covered by a membrane of nonzerothickness. Comparing the theory with the experiment on dropletmicroemulsions from the literature, the bending rigidity constantof the surface layer is estimated. PMID- 23345820 TI - The predictive power of r(0) in an epidemic probabilistic system. AB - An important issue in theoretical epidemiology is the epidemic thresholdphenomenon, which specify the conditions for an epidemic to grow or die out.In standard (mean-field-like) compartmental models the concept of the basic reproductive number, R(0), has been systematically employed as apredictor for epidemic spread and as an analytical tool to study thethreshold conditions. Despite the importance of this quantity, there are nogeneral formulation of R(0) when one considers the spread of a disease ina generic finite population, involving, for instance, arbitrary topology ofinter-individual interactions and heterogeneous mixing of susceptible andimmune individuals. The goal of this work is to study this concept in ageneralized stochastic system described in terms of global and localvariables. In particular, the dependence of R(0) on the space ofparameters that define the model is investigated; it is found that near ofthe 'classical' epidemic threshold transition the uncertainty about thestrength of the epidemic process still is significantly large. Theforecasting attributes of R(0) for a discrete finite system is discussedand generalized; in particular, it is shown that, for a discrete finitesystem, the pretentious predictive power of R(0) is significantlyreduced. PMID- 23345821 TI - Restrahlen to T-rays - 100 years of terahertz radiation. AB - Although a reliable source of subpicosecondterahertz (THz) pulses, or T-rays, wasdemonstrated in the late 1980s, it was notuntil 1995, when they were used forimaging, that their full potential wasrealized. However, much of the publicityat that time seemed to suggest that verylittle research had taken place in the THz(or far-infrared) region before then. Withthe - largely new - present day interest inbiological applications of THz radiation itis apposite to review the opening up ofthis spectral region over the past hundredyears. This paper attempts to show many ofthe significant developments in sources,detectors and spectroscopic systems for theTHz region and includes brief descriptionsof some of the more important applicationsand outcomes of the research.T-rays are only one of a number of verysignificant arrivals on the THz scene inrecent years. It does seem an ideal timeto pursue the exciting biologicalapplications of THz radiation which are tobe discussed at this Workshop. PMID- 23345822 TI - Trends and perspectives in molecular spectroscopy: an introduction. PMID- 23345823 TI - THz-Spectroscopy of Biological Molecules. AB - The terahertz frequency absorption spectraof DNA molecules reflect low frequencyinternal helical vibrations involvingrigidly bound subgroups that are connectedby the weakest bonds, including thehydrogen bonds of the DNA base pairs,and/or non-bonded interactions. Althoughnumerous difficulties make the directidentification of terahertz phonon modes inbiological materials very challenging, ourresearch has shown that such measurementsare both possible and fruitful. Spectra ofdifferent DNA samples reveal a large numberof modes and a reasonable level ofsequence-specific uniqueness. In an attemptto show that the long wavelength absorptionfeatures are intrinsic properties ofbiological materials determined by phononmodes, a normal mode analysis has been usedto predict the absorption spectra ofpolynucleotide RNA Poly[G]-Poly[C]. Directcomparison demonstrated a correlationbetween calculated and experimentallyobserved spectra of the RNA polymers, thusconfirming that the fundamental physicalnature of the observed resonance structureis caused by the internal vibration modesin the macromolecules.In this work we demonstrate results fromFourier-Transform Infrared (FTIR)spectroscopy of DNA macromolecules andrelated biological materials in theterahertz frequency range. Carefulattention was paid to the possibility ofinterference or etalon effects in thesamples, and phenomena were clearlydifferentiated from the actual phononmodes. In addition, we studied thedependence of transmission spectra ofaligned DNA and polynucleotide film sampleson molecule orientation relative to theelectromagnetic field, showing the expectedchange in mode strength as a function ofsample orientation. Further, the absorptioncharacteristics were extracted from thetransmission data using the interferencespectroscopy technique, and a stronganisotropy of terahertz characteristics wasdemonstrated. PMID- 23345824 TI - Experimental determination of the far-infrared optical properties of biological matter in aqueous solution. AB - Experimental details are given of how to reliably measure theoptical properties of aqueous solutions in the far-infraredspectral range using a Fourier transform spectrometer. We discussthe analysis of reflection and transmission data in order toobtain the refractive index and the absorption coefficient. Someresults on water and biological systems are presented. PMID- 23345825 TI - Terahertz pulse spectroscopy of biological materials: L-glutamic Acid. AB - We report the terahertzpulse spectra of L-glutamic acid. Thereare a number of well-resolved transitionsin the 1.75-2.5 THz (58-83 cm(-1))region. These are compared with publishedtheoretical data on intra andintermolecular transitions. We could notfind any correlation with the theoreticalvalues. However, it was noted that thetheoretical model did not include anycrystalline or hydrogen bonding effects. PMID- 23345826 TI - Terahertz time-domain spectroscopy of glucose and uric Acid. AB - We report the use ofterahertz time-domain spectroscopy for thestudy of two therapeutic bio-molecules:glucose and uric acid. Terahertztransmission spectra of crystalline samplesof both molecules were measured between 0.1-3.0 THz using an evacuated spectroscopysystem. We propose that the stereo-isomersof glucose show spectral featuresoriginating from intermolecular vibrationalmodes, as do uric acid and its derivativemolecule, allantoin. In addition, wepresent a full temperature dependence ofthe terahertz absorption of L-glucose. PMID- 23345827 TI - Catalogue of human tissue optical properties at terahertz frequencies. AB - Recently published studies suggest thatterahertz pulsed imaging will have applications inmedicine and biology, but there iscurrently very little information about the opticalproperties of human tissue at terahertzfrequencies. Such information would be useful forpredicting the feasibility of proposedapplications, optimising acquisition protocols,providing information about variability ofhealthy tissue and supplying data for studies of theinteraction mechanisms. Research ethicscommittee approval was obtained, andmeasurements made from samples of freshlyexcised human tissue, using a broadbandterahertz pulsed imaging system comprisingfrequencies approximately 0.5 to 2.5 THz.Refractive index and linear absorptioncoefficient were found. Reproducibility wasdetermined using blood from one volunteer,which was drawn and measured on consecutivedays. Skin, adipose tissue, striatedmuscle, vein and nerve were measured (to date, from oneindividual). Water had a higher refractiveindex (2.04 +/- 0.07) than any tissue.The linear absorption coefficient was higher formuscle than adipose tissue, as expectedfrom the higher hydration of muscle. As these samples camefrom a single subject, there is currentlyinsufficient statistical power to draw firmconclusions, but results suggest that in vivo clinical imaging will be feasible in certainapplications. PMID- 23345828 TI - Determination of Glucose Concentration in Whole Blood using Fourier-Transform Infrared Spectroscopy. AB - Fourier-transform infrared(FTIR) transmission spectroscopy has beenused for the determination of glucoseconcentrations in whole blood samples fromtwenty-eight patients. A four-vectorpartial least squares calibration model,using the spectral range 950-1200 cm(-1),yielded a standard error of prediction of0.59 mM for an independent test set. Forblood samples from a single patient, wefound that the glucose concentration wasproportional to the difference between thevalues of the second derivative spectrum at1082 cm(-1) and 1093 cm(-1), suggestingthat these two specific wavelengths can beused for determining glucose concentrationsin blood. PMID- 23345829 TI - Light-induced Difference Terahertz Spectroscopy. AB - Visible/near-infraredlaser-induced difference spectroscopy basedon a time-domain terahertz system has beendeveloped, and used to study copperpathancyonine. We find that the absorptionpeak of this molecule at 1.08 THz changessignificantly under 790 nm laserexcitation, suggesting that we haveobserved the first evidence of vibrationalmode changes in the THz range induced byvisible/near-infrared light. PMID- 23345830 TI - Two methods for modelling the propagation of terahertz radiation in a layered structure. AB - Modelling the interaction of terahertz(THz) radiation with biological tissueposes many interesting problems. THzradiation is neither obviously described byan electric field distribution or anensemble of photons and biological tissueis an inhomogeneous medium with anelectronic permittivity that is bothspatially and frequency dependent making ita complex system to model.A three-layer system of parallel-sidedslabs has been used as the system throughwhich the passage of THz radiation has beensimulated. Two modelling approaches havebeen developed a thin film matrix model anda Monte Carlo model. The source data foreach of these methods, taken at the sametime as the data recorded to experimentallyverify them, was a THz spectrum that hadpassed though air only.Experimental verification of these twomodels was carried out using athree-layered in vitro phantom. Simulatedtransmission spectrum data was compared toexperimental transmission spectrum datafirst to determine and then to compare theaccuracy of the two methods. Goodagreement was found, with typical resultshaving a correlation coefficient of 0.90for the thin film matrix model and 0.78 forthe Monte Carlo model over the full THzspectrum. Further work is underway toimprove the models above 1 THz. PMID- 23345831 TI - Photodissociation dynamics of DNA bases. AB - In order to access the damaging mechanismsof DNA and its bases on themolecular level by T Hz radiation, it isnecessary to create a database of assessingdamage at different spectral regions.Possible damage by T Hz radiation will beassessed by comparison. Furthermore, theexpose of the cytosine to radiation at157 nm, suggest that photochemical bondbreaking is the only damaging mechanism inthe vacuum ultraviolet region of thespectrum, (157-170) nm where one photonbreaks one chemical bond. PMID- 23345832 TI - Absorption and Diffusion Measurements of Biological Samples using a THz Free Electron Laser. AB - A compact THz Free Electron Laser (FEL) isbeing used to perform irradiation ofbiological samples to investigate possiblegenotoxic effects. In order to evaluate theexact radiation dose absorbed by the singlecomponents of the samples it is necessaryto study the optical properties of thesamples, separating the contributions tothe radiation attenuation coefficientcoming from absorption and from diffusion.Spectroscopic measurements have beenperformed on different biological samples, comparing the experimental results withtheoretical models. PMID- 23345833 TI - THz Exposure of Whole Blood for the Study of Biological Effects on Human Lymphocytes. AB - The aim of the present study is toinvestigate the genotoxic effect of THzradiation in human peripheral bloodlymphocytes following 20 minutes exposureto 1 mW average power Free Electron Laserradiation in the frequency range 120 140GHz. For this purpose 9 healthy donors wereemployed and cytokinesis block techniquewas applied to study micronucleusfrequency and cell proliferation. Theresults obtained indicate that all theelectromagnetic conditions adopted so far do not alter the investigated parameters,suggesting absence of direct chromosomaldamage and alteration of cell cyclekinetics (two tailed paired Student's test:p> 0.05 in all cases). PMID- 23345834 TI - Effects of THz Exposure on Human Primary Keratinocyte Differentiation and Viability. AB - Primary human keratinocytes can be driven,in vitro, to differentiate, viaactivation of transglutaminases, by raisingthe culture medium calcium concentrationabove 1 mM. This results intransglutaminase regulated cross linking ofspecific amino acids with resultantcornified envelope formation. Thedifferentiation was monitored via theincorporation of fluorescein cadaverineinto the cornified envelops. Thisdifferentiation assay was combined withassessment of reductive capacity ofresazurin, as a measure of cellactivity/viability.One primary aim is to assess the effects ofTHz radiation on human skin, since medicalimaging of the body through the skin isenvisaged.Human keratinocytes, at passage 2 fromisolation, were grown to confluence, andtransported in a buffered salt solution at22 ( degrees )C. The exposure to the THz sourcewas for 10, 20 or 30 minutes at roomtemperature.No donor specific inhibition or stimulationof cell activity, compared with non exposedcells, was noted following exposure in therange 1 to 3 THz, at up to 0.45J/cm(2).The differentiation also occurred in anormal way, for exposed and non exposedcells, with the FC incorporation increasingbetween day 3 and day 8, as previouslynoted. PMID- 23345835 TI - On-Chip THz Detection of Biomaterials: A Numerical Study. AB - The marker-free on-chip distinction betweenhybridised (double-stranded) DNA (HDNA) anddenatured (single-stranded) DNA (DDNA) hasrecently been demonstrated using ultrashortelectrical pulses. The electrical THzpulses propagate in integrated waveguidesincorporating resonant THz structures ontowhich the genetic material is deposited.For a possible future realisation of a highthroughput array, it is crucial to optimizethe experimental parameters and theresonant structure. In this paper weperform a first numerical study ofdifferent resonator geometries and examinethe influence of critical experimentalparameters on the transmissioncharacteristics of the resonant structures.Our simulations demonstrate that the ringresonator shows a comparable performance tothe parallel coupled resonator previouslyused in a first demonstration by Nagel andcoworkers. PMID- 23345836 TI - Status of THz-to-Visible Nanospectroscopy Development. AB - Quite unexpectedly, THz and infraredspectroscopy has now a real chance to solveproblems in the nanosciences. This rests ona new microscope technique that overcomesthe Abbe diffraction limit, by using thenear field of a metal antenna in closeproximity to a scanned sample surface. HereI briefly summarize present activities inthe microwave, mid-infrared and visiblespectral ranges. It seems straightforwardand highly desirable to fill the existinggap between about 20 GHz and 20 THz, andattain spatial resolution of 10 nm andbelow also in this important part of theelectromagnetic spectrum. PMID- 23345837 TI - Biological and biomedical applications of synchrotron infrared microspectroscopy. AB - The high brightness of synchrotron light,which is about three orders of magnitudegreater than a thermal source, has beenexploited in biological and biomedicalapplications of infrared microspectroscopy. The potential of this analytical tool isdocumented in this article in the study ofhuman tissue (hair and skin) and individualcells: biochemical and bio-structuralchanges based on corresponding functionalgroups have been identified and imaged withunprecedented spatial resolution. Thistechnique also provides a new tool foranalysis of biochemical kinetics of samplesduring disease and treatment. In the future, the combination ofinfrared microspectroscopy with othersynchrotron-based microscopic techniques,such as X-ray microscopy, at the samesample location is discussed. PMID- 23345838 TI - Synchrotron-based Biological Microspectroscopy: From the Mid-Infrared through the Far-Infrared Regimes. AB - Infrared radiation from synchrotron storagerings serves as a high-brightness source fordiffraction-limited microspectroscopy inboth the mid- and far-infrared spectralranges. Mid-infrared absorption, due to localvibrational modes within complex molecules,is shown to be sensitive to small chemicalchanges associated with certain diseases.Farinfrared modes are believed to result from thefolding or twisting of larger, morecomplex molecules. The ability for thesynchrotron source to perform microscopy ata frequency of 1 THz is demonstrated. PMID- 23345839 TI - A Near Field Microscope in the Tera-hertz Region. AB - This paper reports the study of aexperimental project for two near fieldmicroscopes to operate in the Tera-Hertz(THz) region of the electromagneticspectrum. The first design is suited moreproperly for the millimetre wave region,while the second is addressed to shorterwavelengths, typically below onemillimetre. PMID- 23345840 TI - Measurement of THz Spot Sizes with a lambda/200 Diameter in the Near-Field of a Metal Tip. AB - We report on a method to obtain asub-wavelength resolution in terahertz time domain imaging. In our method,a sharp copper tip is used to locallydistort and concentrate the THz electricfield. The distorted electric field, presentmainly in the near field of the tip, iselectro-optically measured in an (100)oriented GaP crystal. By raster scanning the tipalong the surface of the crystal we find asmallest THz spot size of 10 MUm forfrequencies from 0.1 to 2.5 THz. For ourpeak frequency of 0.15 THz this corresponds to aresolution of lambda/200. Our setup has thepotential to reach a resolution down to afew MUm, and is a promising candidate tostudy single, living cells in the THzfrequency range. PMID- 23345841 TI - T-ray Imaging and Tomography. AB - We demonstrate two algorithms used forreconstructing the target's structure basedon the diffracted pulses and additionallyshow that a three-dimensional target can bereconstructed using the broadband pulsesand a Fresnel lens by virtue of itsfrequency dependent focal length. Oneadvantage of T-ray imaging is the abilityto measure the far-infrared spectralresponse of the target. To highlight theimportance of this spectral information, wedemonstrate T-ray classification imagingwith different biological samples using asimple classification algorithm and twodimensional T-ray spectroscopic images. PMID- 23345842 TI - Terahertz pulsed imaging of skin cancer in the time and frequency domain. AB - Terahertz Pulsed Imaging(TPI) is a new medical imaging modality forthe detection of epithelial cancers. Overthe last two years this technique has beenapplied to the study of in vitrobasal cell carcinoma (BCC). Usingtime-domain analysis the contrast betweendiseased and normal tissue has been shownto be statistically significant, andregions of increased terahertz (THz)absorption correlated well with thelocation of the tumour sites in histology.Understanding the source of this contrastthrough frequency-domain analysis mayfacilitate the diagnosis of skin cancer andrelated skin conditions using TPI. Wepresent the first frequency domain analysisof basal cell carcinoma in vitro,with the raw power spectrum giving aninsight into the surface features of theskin. Further data manipulation is requiredto determine whether spectral informationcan be extrapolated at depth. These resultshighlight the complexity of working inreflection geometry. PMID- 23345843 TI - Risk perception and safety issues. PMID- 23345844 TI - Perception of risks from electromagnetic fields: lessons for the future. AB - Technologies based on extremely highfrequency electromagnetic fields, inparticular in the terahertz region, arequite recent and new to the public. While anumber of advantages have been shown,especially in the biomedical area,biological effects and possible healthimplications have not been fullyinvestigated. The experience gained withelectromagnetic fields of lowerfrequencies, from ELF to microwaves,suggests that innovating technologies maycreate concern, or even fear, among thepublic for hypothetical health risks.Social research has shown that worries arerelated to the perception of risks by thepublic more than to their actual existence.Risk perception depends on several factors,many of which are relevant forelectromagnetic fields. They include lackof familiarity with the agent, difficultyin understanding interaction mechanisms,and uncertainty in scientific knowledge.Lessons learnt from the past lead torecommend that specific research onbiological effects of terahertz radiationbe started from the very beginning of thedevelopment of technological applicationsand that a continuous and effectivedialogue be established between thescientific community and the public. PMID- 23345845 TI - Synchrotron-Based FTIR Spectromicroscopy: Cytotoxicity and Heating Considerations. AB - Synchrotron radiation-based Fouriertransform infrared (SR-FTIR)spectromicroscopy is a newly emergingbioanalytical and imaging tool. This uniquetechnique provides mid-infrared (IR)spectra, hence chemical information, withhigh signal-to-noise at spatial resolutionsas fine as 3 to 10 microns. Thus it enablesresearchers to locate, identify, and trackspecific chemical events within anindividual living mammalian cell. Mid-IRphotons are too low in energy (0.05-0.5eV) to either break bonds or to causeionization. In this review, we show thatthe synchrotron IR beam has no detectableeffects on the short- and long-termviability, reproductive integrity,cell-cycle progression, and mitochondrialmetabolism in living human cells, andproduces only minimal sample heating (<0.5 degrees C). These studies haveestablished an important foundation forSR-FTIR spectromicroscopy in biological andbiomedical research. PMID- 23345846 TI - Generation of Narrowband Tunable THz-Radiation via Optical Rectification in Periodically Poled Materials. AB - The generation of tunableTHz-radiation via optical rectification offs-pulses in periodically poled nonlinearmaterials is reported and its applicationfor biomedical sensing using THz-senorsbased on planar wave guides is discussed indetail. PMID- 23345847 TI - Performance characteristics of a smith-purcell tunable terahertz source. AB - A Tunable Terahertz Source (TTS) is beingdeveloped for commercial use by VermontPhotonics under exclusive license. The TTSis based on the Smith-Purcell free electronlaser first reported by the late ProfessorJohn E. Walsh and his co workers [1]. The TTS is continuouslytunable from less than 0.3 Thz to more than3 Thz (10-100 cm(-1)). It can beoperated CW or pulsed, with repetitionrates from DC to kHz. Detailed outputcharacteristics will be presented alongwith examples of use in spectroscopysystems using a grating monochromator, aFourier transform interferometer or ascanning Fabry Perot etalon. A comparisonwith other Thz sources will be given. PMID- 23345848 TI - Properties and Planned Use of the Intense THz Radiation from ELBE at Dresden Rossendorf. AB - The radiation source ELBE atDresden-Rossendorf is centered around asuperconducting ELectron accelerator ofhigh Brilliance and low Emittance (ELBE) which produces electronbeams up to 40 MeV. This new facility delivers secondary radiation of differentkinds. Special emphasis will be given tothe production of intense THz radiationfrom its Free-Electron Lasers (FEL). This radiation will be usedfor various research activities including the life sciences. Two additionalfemtosecond Ti:sapphire laser systems allowto exploit different methods of THzgeneration for such investigations. PMID- 23345849 TI - The Synchrotron Infrared Activities at BESSY. AB - The new multipurpose infrared (IR) beamlineat the electron storage ring BESSY IIprovides highly brilliant infrared radiation forstructural and time resolved studies in thebiological and material science. With this facility newresearch possibilities at BESSY are madeavailable to the scientific community. PMID- 23345850 TI - Terahertz Radiation at ANKA, the New Synchrotron Light Source in Karlsruhe. AB - ANKA is a new synchrotron light source atthe Karlsruhe Research Center in southwestGermany. The acronym stands for Angstrom Source Karlsruhe.The ANKA-IR beamline provides a highbrilliance infrared beam through the near,mid and far infrared range. Thefar-infrared range is of particularinterest, since at frequencies lower thanaround 200 cm(-1) (6 THz) synchrotronlight begins to outperform conventionalthermal sources in terms of total intensityas well as brilliance. The extraction ofthe entire flux is a challenge in the THzrange, since the natural verticaldivergence of synchrotron radiationincreases with wavelength and the openingangle for collection is limited by designconstraints. At ANKA-IR, this problem issolved by the collection of radiationemitted from a bending magnet edge source,which has a much smaller verticaldivergence than conventional synchrotronradiation emitted from the constantmagnetic field region within the dipolemagnet. Edge radiation at ANKA permits theextraction of the entire infrared flux downto around 100 cm(-1) (3 THz) while withconventional synchrotron radiation thiswould only be the case for frequencies downto 2500 cm( 1). ANKA-IR provides usableintensity down to 4 cm(-1) (120 GHz). PMID- 23345851 TI - Very High Power THz Radiation Sources. AB - We report the production of high power (20watts average, ~ 1 Megawatt peak) broadbandTHz light based on coherent emission fromrelativistic electrons. Such sources areideal for imaging, for high power damagestudies and for studies of non linearphenomena in this spectral range. Wedescribe the source, presenting theoreticalcalculations and their experimentalverification. For clarity we compare thissource with one based on ultrafast lasertechniques. PMID- 23345852 TI - Tunneling processes induced by terahertz electric fields. AB - Tunneling processes induced by terahertz frequency electric fields havebeen investigated.A drastic enhancement of the tunneling probabilityhas been observed by increasing the frequency omega atomegatau(e)? 1 wheretau(e) is the tunneling time.For a given constant tunneling rate an increase offrequency by a factor of seven leads to a drop of the requiredelectric field strengthby three orders of magnitude.It is shown that the enhancement of tunneling ionization at terahertz frequencies is due to the factthat electrons can absorb energy from the radiation field during tunnelingreducing the effective width of the tunneling barrier. PMID- 23345853 TI - Optical Constants of Two Typical Liquid Crystals 5CB and PCH5 in the THz Frequency Range. AB - The complex refractive indices of two benchmark nematic liquid crystal,4-4 '-n pentyl-cyanobiphenyl (5CB) and 4-(trans-4'pentylcyclohexyl)-benzonitrile (PCH5) have been determinedin the frequency range from 0.2 to 0.8 THz. The technique of coherent THztime-domain spectroscopy (THz-TDS) was used. We show that the birefringenceof 5CB is in the range of 0.15 to 0.21, while that of PCH is from 0.01 to0.08. Both liquid crystals exhibit relatively small absorption in thisfrequency range. The large birefringence of 5CB indicates possible applications of liquid-crystal-based devices for modulation and polarizationcontrol of electromagnetic radiation in the THz frequency range. PMID- 23345854 TI - Introduction to proceedings of the biophysics summer school - Australian national university, january 2001. PMID- 23345855 TI - Protein structure from x-ray diffraction. AB - Protein crystallography is the study of the three-dimensional structures of proteins at near atomic resolution. It has provided at remendous insight into the workings of numerous biological processes over the last few decades. The field has undergone a massive worldwide expansion over the last ten years, not only in academic laboratories, but also in the pharmaceutical industry. The main driving force for this expansion has been the promise of using three-dimensional atomic structures of proteins and other macromolecules to design lead drugs and to improve the action of existing drugs. PMID- 23345856 TI - The physics of cell membranes. AB - An overview is given of the fundamental physics underlying the self-assembly, molecular organisation and electrical properties of the membranes that envelop living cells. These ultra thin (~ 6 nm) membranes act as a diffusion barrier between the cell interior (cytoplasm) and the external medium. They consist basically of a bi-molecular film of lipid molecules in which are embedded functional proteins that perform a variety of functions, including energy transduction, signalling, transport of ions (and othermolecules), etc. Some examples are also presented of the fascinating and socially and commercially important applications of membrane biophysics. PMID- 23345858 TI - Physics of ion channels. AB - We review the basic physics involved in transport of ions across membrane channels in cells. Electrochemical forces that control the diffusion of ions are discussed both from microscopic and macroscopic perspectives. A case is made for use of Brownian dynamics as the minimal phenomenological model that provides a bridge between experiments and more fundamental theoretical approaches. Application of Brownian and molecular dynamics methods to channels with known molecular structures is discussed. PMID- 23345859 TI - Photosynthesis: from natural towards artificial. AB - Photosynthesis, the natural process that yields food, fuel and fibre, spans physical and biological sciences, spatially from atomic scales to the global and temporally from electronic transitions to the evolutionary time frame. Photosynthesis is highly efficient in its primary energy capture, but much less so in terms of conversion to crop yield. The natural photosynthetic system provides fertile ground for exploring and dissecting partial processes that may be mimicked inartificial systems for human needs, perhaps with improved efficiency. Future developments are limited only by the imagination. PMID- 23345857 TI - Models of the collective behavior of proteins in cells: tubulin, actin and motor proteins. AB - One of the most important issues of molecular biophysics is the complex and multifunctional behavior of the cell's cytoskeleton. Interiors of living cells are structurally organized by the cytoskeleton networks of filamentous protein polymers: microtubules, actin and intermediate filaments with motor proteins providing force and directionality needed for transport processes. Microtubules (MT's) take active part in material transport within the cell, constitute the most rigid elements of the cell and hence found many uses in cell motility (e.g. flagella andcilia). At present there is, however, no quantitatively predictable explanation of how these important phenomena are orchestrated at a molecular level. Moreover, microtubules have been demonstrated to self-organize leading to pattern formation. We discuss here several models which attempt to shed light on the assembly of microtubules and their interactions with motor proteins. Subsequently, an overview of actin filaments and their properties isgiven with particular emphasis on actin assembly processes. The lengths of actin filaments have been reported that were formed by spontaneous polymerization of highly purified actin monomers after labeling with rhodamine-phalloidin. The length distributions are exponential with a mean of about 7 MUm. This length is independent of the initial concentration of actin monomer, an observation inconsistent with a simple nucleation-elongation mechanism. However, with the addition of physically reasonable rates of filament annealing and fragmenting, a nucleation-elongation mechanism can reproduce the observed average length of filaments in two types of experiments: (1) filaments formed from a wide range of highly purified actin monomer concentrations, and (2) filaments formed from 24 mM actin over a range of CapZ concentrations. In the final part of the paper we briefly review the stochastic models used to describe the motion of motor proteins on protein filaments. The vast majority of these models are based on ratchet potentials with the presence of thermal noise and forcing due to ATP binding and a subsequent hydrolysis. Many outstanding questions remain to be quantitatively addressed on a molecular level in order to explain the structure to-function relationship for the key elements of the cytoskeleton discussed in this review. PMID- 23345860 TI - Computation of diffusion limited controlled actions for gene regulating repressor particles. AB - Temporal changes in association anddissociation kinetics of the repressor operator reaction were simulated by a computational approach using MATOLABO on the basis of strict mathematical description. The diffusion equation of a repressor particle has been combinedwith arrival probabilities of therepressor particle. Temporal behaviors of the repressor operator complex have been computed by inverting the Laplace transformed equations. The temporal kinetic data of association anddissociation obtained at differentionic strength and at different DNA length were successfully simulated. Those results could be achieved byregulating diffusion constants inmedium on the DNA, a reaction radius of the repressor and a reaction rate per one repressor on the reaction sphere surface, k value. The reported values of association rate constant ka obtained at different ionic strength were also successfully simulated. Amongthe regulated parameters to get these successful simulations, the reaction rate per one particle on the reaction sphere surface, k value has effectiveinfluences on the association anddissociation kinetics particularly those at varying ionic strength that were induced by high KCl condition. By an electro chemical consideration for thechange of k value in combinationwith the screening effects of counter ions around the repressor particle and the DNA molecule, the most effectivefactor seems to be the Coulombrepulsive forces and or Londondispersion forces. The sliding mechanism for facilitated translocation of a repressor protein ona DNA chain can be described by the present mathematical approach which describes the temporal changes in amounts of the species. To achieve such mechanism in varying ionic strength,the secondary changes in the diffusion constants, the reaction radius and the reaction rate per one particle on thereaction sphere surface k value (anelectro chemical factor) seemed to have important roles. PMID- 23345862 TI - Interactions of Cyclic AMP and Its Dibutyryl Analogue with a Lipid Layer in the Aqueous Mixtures of Monoolein Preparation and Dioleoyl Phosphatidylcholine as Probed by X-Ray Diffraction and Raman Spectroscopy. AB - Interactions of adenosine 3':5'-cyclicmonophosphate (cAMP) andN(6),2'-O dibutyryladenosine3':5'-cyclic monophosphate (dbcAMP) with alipid layer composed of monoolein-basedpreparation and dioleoylphosphatidylcholine (DOPC) wereinvestigated by small-angle X-raydiffraction (SAXD) and Raman spectroscopy.The reversed hexagonal (H(II))MO/DOPC/H(2)O phase of 65:15:20 wt.%composition was selected as a referencesystem. SAXD revealed that entrapment (atthe expense of water) of 3 wt.% cAMP intothe reference system did not change thepolymorphic form and structural parametersof the phase. The same content of dbcAMPinduced the transition from the H(II)phase to the reversed bicontinuous cubicphase of space group Ia3d. Thistransition is explained by the increase oflipid head-group area due to thepenetration of the acylated adenine groupof dbcAMP into the polar/apolar region oflipid layer. The conclusion is supported byRaman spectroscopy, showing thedisruption/weakening of hydrogen bonding inthe MO/DOPC-based matrix at the N1- andN3-sites of the dbcAMP adenine ring. Asdistinct from dbcAMP, cAMP remains mostlyin the water channels of the H(II)phase, although the phosphate residue ofnucleotide interacts with the quaternaryammonium group of DOPC. Both nucleotidesincrease the population of gaucheisomers in the DOPC choline group. PMID- 23345861 TI - Wavelet Analysis of DNA Bending Profiles reveals Structural Constraints on the Evolution of Genomic Sequences. AB - Analyses of genomic DNA sequences have shown in previous works that base pairs are correlated at large distances with scale-invariant statistical properties. We show in the present study that these correlations between nucleotides (letters) result in fact from long-range correlations (LRC) between sequence-dependent DNA structural elements (words) involved in the packaging of DNA in chromatin. Using the wavelet transform technique, we perform a comparative analysis of the DNA text and of the corresponding bending profiles generated with curvature tables based on nucleosome positioning data. This exploration through the optics of the so-called 'wavelet transform microscope' reveals a characteristic scale of 100 200 bp that separates two regimes of different LRC. We focus here on the existence of LRC in the small-scale regime (? 200 bp). Analysis of genomes in the three kingdoms reveals that this regime is specifically associated to the presence of nucleosomes. Indeed, small scale LRC are observed in eukaryotic genomes and to a less extent in archaeal genomes, in contrast with their absence in eubacterial genomes. Similarly, this regime is observed in eukaryotic but not in bacterial viral DNA genomes. There is one exception for genomes of Poxviruses, the only animal DNA viruses that do not replicate in the cell nucleus and do not present small scale LRC. Furthermore, no small scale LRC are detected in the genomes of all examined RNA viruses, with one exception in the case of retroviruses. Altogether, these results strongly suggest that small-scale LRC are a signature of the nucleosomal structure. Finally, we discuss possible interpretations of these small-scale LRC in terms of the mechanisms that govern the positioning, the stability and the dynamics of the nucleosomes along the DNA chain. This paper is maily devoted to a pedagogical presentation of the theoretical concepts and physical methods which are well suited to perform a statistical analysis of genomic sequences. We review the results obtained with the so-called wavelet-based multifractal analysis when investigating the DNA sequences of various organisms in the three kingdoms. Some of these results have been announced in B. Audit et al. [1, 2]. PMID- 23345863 TI - A model describing bending in flagella. AB - In Part I of this paper, we present a modelto account for the force generationproducing bending, and the formation of awaveform in sperm flagella. The model isbased on the observation that dimers, andhence microtubules, possess dipole moments.The electric field these dipoles produce isthe source for storing mechanical work indynein arms. The mechanical work is thenreleased and act on the doublets to producea distally directed force with the resultthat bending occurs. The model described isconsistent with experimental observationsreported in the literature. The flexuralrigidity of a dynein arm is alsocalculated. In Part II of this paper, theconsequences of the bending mechanism arediscussed. It is shown that the sum offorces from dynein arms acting distallyalong doublet microtubules in a flagellumis essentially zero when all dyneins areattached thus resulting in the rigor state.The waveform in a flagellum occurs if oneof the sets of bending moments is zero,that is, a row of dyneins are detached oversome distance along the flagellum. Thedirection of the bend in the waveform isdetermined by which set of dynein arms aredetached with respect to the verticalmedian plane of the flagellum. Thepropagation of a bending wave is the resultof a moving region in which alternate sidesfrom the vertical median plane haveinactive dynein arms. The processes bywhich this moving region occurs and therelationship of the above results to thepropulsion of the flagellum are notconsidered. PMID- 23345864 TI - Sequence dependent hole evolution in DNA. AB - The paper examines thedynamical behavior of a radical cation(G(+*)) generated in adouble stranded DNA for differentoligonucleotide sequences. The resonancehole tunneling through an oligonucleotidesequence is studied by the method ofnumerical integration of self-consistentquantum-mechanical equations. The holemotion is considered quantum mechanicallyand nucleotide base oscillations aretreated classically. The results obtaineddemonstrate a strong dependence of chargetransfer on the type of nucleotidesequence. The rates of the hole transferare calculated for different nucleotidesequences and compared with experimentaldata on the transfer from (G(+*))to a GGG unit. PMID- 23345865 TI - On a nonlinear master equation and the haken-kelso-bunz model. AB - A nonlinear master equation (NLME) is proposed basedon general information measures.Classical and cut-off solutions of the NLME are considered.In the former case, the NLME exhibits uniquely defined stationary distributions. In the latter case, there are multiple stationary distributions.In particular, for classical solutions, it is shown that transient solutions converge to stationary distributions that maximize information measures (H-theorem). Cut-off distributions arestudied numerically for the Haken-Kelso-Bunz model. The Haken Kelso-Bunz modelis known to describe multistable human motor control systems. It is shownthat a stochastic Haken-Kelso-Bunz model based on a NLME can exhibit multiplestationary cut-off distributions.In doing so, we illustrate that multistability in stochastic biological systems can beestablished by means of cut off distributions. PMID- 23345866 TI - AM1 Study of N-2-Acetylaminofluorene bonded to Deoxyguanosine at the Minor Adduct Site. AB - We have computed the total energy as a function of six important torsion angles of the carcinogen N-2-acetylaminofluorene (AAF) bonded to thenitrogen N2 of deoxyguanosine using the semiempirical quantum mechanical method AM1. One global minimum and one local minimum are found separated by a modest barrier. We have computed the normal-mode frequencies of the relevant torsional motions and have determined the rate of conversion betweenthe two minima. PMID- 23345868 TI - Hierarchy of motions and quasi-particles in a simplified model of potassium channel selectivity filter. AB - We develop a simplified model of themultiply occupied Kcsa-like selectivityfilter based on the best availablestructural data. The existence of hierarchyof motions in the selectivity filter isshown. Fast fluctuations of the ion-iondistances may be considered adiabaticallydecoupled from the slow diffusive motion ofthe ions' center of masses. The latter canbe considered as a quasi-particle, called aquasi ion, moving in an effectivepotential. In the Kcsa-like selectivityfilter occupied by three ions the effectivepotential allows free barrier-lessdiffusional motion of the quasi-ions. Theconcept of the quasi-ions performing iontranslocation through the channel may bevital in explaining barrier-less 'knock-on' conduction postulated for real channels. PMID- 23345867 TI - Toward correct protein folding potentials. AB - Empirical protein folding potentialfunctions should have a global minimum nearthe native conformationof globular proteins that fold stably, andthey should give the correct free energy offolding. We demonstrate that otherwise verysuccessful potentials fail to have even alocal minimumanywhere near the native conformation, anda seemingly well validated method ofestimatingthe thermodynamic stability of the nativestate is extremely sensitive to smallperturbations inatomic coordinates. These are bothindicative of fitting a great deal ofirrelevant detail. Here weshow how to devise a robust potentialfunction that succeeds very well at bothtasks, at least for alimited set of proteins, and this involvesdeveloping a novel representation of thedenatured state.Predicted free energies of unfolding for 25mutants of barnase are in close agreementwith theexperimental values, while for 17 mutantsthere are substantial discrepancies. PMID- 23345869 TI - A model of sequence-dependent protein diffusion along DNA. AB - We introduce a probabilistic model for protein sliding motion along DNA during the search of a target sequence. The model accounts for possible effects due to sequence-dependent interaction between the nonspecific DNA and the protein. Hydrogen bonds formed at the target site are used as the main sequence-dependent interaction between protein and DNA. The resulting dynamical properties and the possibility of an experimental verification are discussed in details. We show that, while at large times the process reaches a linear diffusion regime, it initially displays a sub-diffusive behavior. The sub-diffusive regime can last sufficiently long to be of biological interest. PMID- 23345870 TI - Charge Transport in Poly(dG)-Poly(dC) and Poly(dA)-Poly(dT) DNA Polymers. AB - We investigate the charge transport in synthetic DNA polymers built up from single type of base pairs. In the context of a polaronlike model, for which an electronic tight-binding system and bond vibrations of the double helix are coupled, we present estimates for the electron-vibration coupling strengths utilizing a quantum-chemical procedure. Subsequent studies concerning the mobility of polaron solutions, representing the state of a localized charge in unison with its associated helix deformation, show that the system for poly(dG) poly(dC) and poly(dA)-poly(dT) DNA polymers, respectively possess quantitatively distinct transport properties. While the former supports unidirectionally moving electron breathers attributed to highly efficient long-range conductivity, the breather mobility in the latter case is comparatively restrained, inhibiting charge transport. Our results are in agreement with recent experimental results demonstrating that poly(dG)-poly(dC) DNA molecules acts as a semiconducting nanowire and exhibit better conductance than poly(dA)-poly(dT) ones. PMID- 23345871 TI - Theoretical and computational multiple regression study of gastric electrical activity using dipole tracing from magnetic field measurements. AB - The biomagnetic inverse problem has captured the interest of both mathematicians and physicists due to its important applications in the medical field. As a result of our experience in analyzing the electrical activity of the gastric smooth muscle, we present here a theoretical model of the magnetic field in the stomach and a computational implementation whereby we demonstrate its realism and usefulness. The computational algorithm developed for this purpose consists of dividing the magnetic field signal input surface into centroid-based grids that allow recursive least-squares approximations to be applied, followed by comparison tests in which the locations of the best-fitting current dipoles are determined. In the second part of the article, we develop a multiple-regression analysis of experimental gastric magnetic data collected using Superconducting QUantum Interference Device (SQUID) magnetometers and successfully processed using our algorithm. As a result of our analysis, we conclude on statistical grounds that it is sufficient to model the electrical activity of the GI tract using only two electric current dipoles in order to account for the magnetic data recorded non-invasively with SQUID magnetometers above the human abdomen. PMID- 23345873 TI - Homogenization of Heterogeneously Coupled Bistable ODE's-Applied to Excitation Waves in Pancreatic Islets of Langerhans. AB - We consider a lattice of coupled identical differential equations. The coupling is between nearest neighbors and of resistance type, but the strength of coupling varies from site to site. Such a lattice can, for example, model an islet of Langerhans, where the sites in the lattice model individual but identical beta cells, and the coupling between cells is made of gap junctions.By using a homogenization technique we approximate the coupled discrete equations by a PDE, basically a nonlinear heat equation (a Fisher equation). For appropriate parameters this equation is known to have wave-solutions. Of importance is the fact, that the resulting diffusion coefficient does not only depend on the average of the coupling, but also on the variance of the strength. This means that the heterogeneity of the coupling strength influences the wave velocity-the greater the variance, the slower is the wave. This result is illustrated by simulations, both of a simple prototype equation, and for a full model of coupled beta-cells in both one and two dimensions, and implies that the natural heterogeneity in the islets of Langerhans should be taken into account. PMID- 23345872 TI - Neuromodulatory control of neocortical microcircuits with activity-dependent short-term synaptic depression. AB - A biophysical model of a neocortical microcircuit system is formulated and employed in studies of neuromodulatory control of dynamics and function. The model is based on recent observations of reciprocal connections between pyramidal cells and inhibitory interneurons and incorporates a new type of activity dependent short-term depression of synaptic couplings recently observed. The model neurons are of a low-dimensional type also accounting for neuronal adaptation, i.e. the coupling between neuronal activity and excitability, which can be regulated by various neuromodulators in the brain. The results obtained demonstrate a capacity for neuromodulatory control of dynamical mode linked to functional mode. The functional aspects considered refer to the observed resolution of multiple objects in working memory as well as the binding of different features for the perception of an object. The effects of neuromodulators displayed by the model are in accordance with many observations on neuromodulatory influence on cognitive functions and brain disorders. PMID- 23345874 TI - Autosomal similarity revealed by eukaryotic genomic comparison. AB - To describe eukaryotic autosomes quantitatively and determine differences between them in terms of amino acid sequences of genes, functional classification of proteins, and complete DNA sequences, we applied two theoretical methods, the Proteome-vector method and the function of degree of disagreement (FDOD) method, that are based on function and sequence similarity respectively, to autosomes from nine eukaryotes. No matter what aspect of the autosome is considered, the autosomal differences within each organism were less than that between species. Our results show that eukaryotic autosomes resemble each other within a species while those from different organisms differ. We propose a hypothesis (named intra species autosomal random shuffling) as an explanation for our results and suggest that lateral gene transfer (LGT) did not occur frequently during the evolution of eukarya. PMID- 23345875 TI - Dynamic light scattering application to study protein interactions in electrolyte solutions. AB - The concentration dependence of the diffusion coefficient of particles suspended in solution depends primarily on the occupied volume fraction and on repulsive and attractive forces. This dependency is expressed by the interaction parameter, which can be assessed experimentally by light scattering measurements and have been determined for the diffusion coefficient of BSA under different salt concentration conditions in the present work. The result shows that the diffusion coefficient of protein grows up with increasing protein concentration, and when the ionic strength turns up gradually the diffusion coefficient decreases with protein concentration's increasing. The concentration dependence of BSA diffusion coefficients is interpreted in the context of a two-body potential of mean force, which includes repulsive hard-sphere and Coulombic interactions and attractive dispersion. With the increase of ionic strength, Debye screening decreases, protein interaction changes from repulsion to attraction, and protein begins to aggregate. By means of the concentration dependence of BSA diffusion coefficients, one can obtain the parameters of protein interactions and can find that protein bears a net effective charge of -9.0 e and has a Hamaker constant of 2.8k(B)T. This work demonstrates that DLS is an effective technique of studying protein interactions. PMID- 23345877 TI - Cell movements and mechanical force distribution during the migration of dictyostelium slugs. AB - Migration of Dictyostelium discoideum slugs results from coordinated movement of their constituent cells. It is generally assumed that each cell contributes to the total motive force of the slug. However, the basic mechanisms by which mechanical forces (traction and resistive forces) are transmitted to the substrate, their magnitude and their location, are largely unknown. In this work, we performed detailed observations of cell movements by fluorescence microscopy using two-dimensional (2D) slugs. We show that 2D slugs share most of the properties of 3D ones. In particular, waves of movement propagate in long 2D slugs, and slug speed correlates with slug length as found in 3D slugs. We also present the first measurements of the distribution of forces exerted by 2D and 3D slugs using the elastic substrate method. Traction forces are mainly exerted in the central region of the slug. The large perpendicular forces around slug boundary and the existence of parallel resistive forces in the tip and/or the tail suggest an important role of the sheath in the transmission of forces to the substrate. PMID- 23345876 TI - Microtubule Dynamics may Embody a Stationary Bipolarity Forming Mechanism Related to the Prokaryotic Division Site Mechanism (Pole-to-Pole Oscillations). AB - Cell division mechanisms in eukaryotes and prokaryotes have until recently been seen as being widely different. However, pole-to-pole oscillations of proteins like MinE in prokaryotes are now known to determine the division plane. These protein waves arise through spontaneous pattern forming reaction-diffusion mechanisms, based on cooperative binding of the proteins to a quasistationary matrix (like the cell membrane or DNA). Rather than waves, stationary bipolar pattern formation may arise as well. Some of the involved proteins have eukaryotic homologs (e.g. FtsZ and tubulin), pointing to a possible ancient shared mechanism. Tubulin polymerizes to microtubules in the spindle. Mitotic microtubules are in a highly dynamical state, frequently undergoing rapid shortening (catastrophe), and fragments formed from the microtubule ends are inferred to enhance the destabilization. Here, we show that cooperative binding of such fragments to microtubules may set up a similar pattern forming mechanism as seen in prokaryotes. The result is a spontaneously formed, well controllable, bipolar state of microtubule dynamics in the cell, which may contribute to defining the bipolar spindle. PMID- 23345878 TI - Simulation of the effect of reorientation of hydrogen bonds in proteins on long range electron transfer. AB - We present Monte Carlo simulations illustrating the influence of reorientation of hydrogen bonds in proteins on long-range interprotein electron transfer. The lattice protein model employed mimics the electron donor (or acceptor) interacting with an antiparallel beta sheet. In addition, we take into account harmonic vibrations of the medium and also the dependence of the coupling matrix element on orientation of hydrogen bonds near the donor and/or acceptor. The results obtained show that the interaction between the tunneling electron and amino-acid residues, which are responsible for the formation of hydrogen bonds, may result in broadening the parabolic dependence of the electron-transfer rate constant on the reaction exothermicity and also in deviations from this dependence especially in the cases when the beta sheet is linked with the electron donor. PMID- 23345879 TI - Low pH Stabilizes the Inverted Hexagonal II Phase in Dipalmitoleoylphosphatidylethanolamine Membrane. AB - Dipalmitoleoylphosphatidylethanolamine (DPOPE) membrane is in the L(alpha) phase in neutral pH at 20 degrees C. The results of small-angle X-ray scattering (SAXS) indicate that an L(alpha) to H(II) phase transition in DPOPE membranes occurred at pH 1.9 in the absence of salt, and at pH 2.8 in the presence of 0.5 M KCl, at fully hydrated condition at 20 degrees C. The spontaneous curvature of DPOPE monolayer membrane did not change with a decrease in pH values. To elucidate the mechanism, we have investigated the effect of the cationic dioctadecyldimethylammonium (DODMA) on the structure and phase behavior of DPOPE membrane. The result shows that DODMA stabilizes the H(II) phase rather than the L(alpha) phase in DPOPE membrane at its low concentrations. Based on these results, the H(II) phase stability of DPOPE membrane due to low pH is discussed in terms of the spontaneous curvature of the monolayer membrane and the packing energy of acyl chains in the membrane. PMID- 23345880 TI - Editorial. PMID- 23345881 TI - A delay-diffusion model of marine plankton ecosystem exhibiting cyclic nature of blooms. AB - The cyclic nature of blooms is a very interesting characteristic of marine plankton ecosystem. Release of toxins by some phytoplanktons has an important role on planktonic interactions and hence on regulating the blooms. A mathematical model describing the phytoplankton-zooplankton interaction with these characteristics is studied. The time needed for liberation of toxins by phytoplanktons is considered. To account for the spatial heterogeneity of an aquatic environment, diffusivity of different plankton populations is also incorporated into the system. Stability and bifurcation behaviour of different steady states are analysed. PMID- 23345882 TI - The modulatory effect of calcium ions upon alamethicin monomers uptake on artificial phospholipid membranes. AB - In this paper, we examined the influence exerted by calcium ions upon physical properties of lipids constituting an artificial membrane. Our strategy was to study changes on alamethicin oligomer kinetic features embedded into such an artificial membrane. At neutral pH and in the presence of calcium ions, we observed an increase in the number of alamethicin monomers that oligomerize within the membrane, forming a multi-substate nanopore. We make the argument that calcium ions binding within the interface between the hydrophobic and the hydrophilic regions of the biomembrane causes a sizeable alteration of the physical properties of neutral lipid membranes. This in turn is seen to influence the translocation rates of alamethicin monomers from the solution adjacent to the biomembrane and leads to an augmentation in the subunit composition of the alamethicin oligomers, leaving the electrical conductance of the substates and their kinetics mainly unchanged. PMID- 23345883 TI - Dipole-dipole interactions in microtubules. AB - Dimers in microtubules possess a dipole moment with components along three axes. The interaction energy among all dipole components in a microtubule was calculated for an un-deformed and an elliptically deformed microtubule in a "dry" condition. The interaction energy was found to increase with deformation. The total interaction energy among all dipoles is positive, which implies that the un deformed cylindrical shape of a microtubule represents a condition of minimum energy. This suggests that the cylindrical shape of microtubules is a consequence of dipole-dipole interactions. There may be other causes as well but these are not discussed in this paper. From these results, the contributions of the dipole dipole interaction energy to the microtubule longitudinal and transverse flexural rigidities were calculated. It is shown that the longitudinal contribution to the elastic modulus is approximately 50-60% of the total measured value while the calculated transverse contribution is smaller than the longitudinal contribution by a factor of approximately 3. The ratio of the measured axial to the measured transverse flexural rigidity is approximately 125, in agreement with recent observations. However, these values are uncertain for reasons discussed in the text. PMID- 23345884 TI - The significance of pit shape for hydraulic isolation of embolized conduits of vascular plants during novel refilling. AB - During plant water transport, the water in the conducting tissue (xylem) is under tension. The system is then in a metastable state and prone to bubble development and subsequent embolism blocking further water transport. It has recently been demonstrated, that embolism can be repaired under tension (= novel refilling). A model (Pit Valve Mechanism = PVM) has also been suggested which is based on the development of a special meniscus in the pores (pits) between adjacent conduits. This meniscus is expected to be able to isolate embolized conduits from neighbouring conduits during embolism repair. In this contribution the stability of this isolating meniscus against perturbations is considered which inevitably occur in natural environments. It can be shown that pit shape affects the stability of PVM fundamentally in the case of perturbation. The results show that a concave pit shape significantly supports the stability of PVM. Concave pit shape should thus be of selective value for species practicing novel refilling. PMID- 23345885 TI - Orientation of red blood cells and rouleaux disaggregation in interference laser fields. AB - The effect of interference laser fields on red blood cells (RBCs) was investigated both theoretically and experimentally. The optical trapping and orientation of individual RBC in interference fringes were observed. It was found that RBC rouleaux undergo disaggregation under the action of interference laser fields. To describe the effect of RBC orientation in interference fringes, we used the equation for torque exerted on a discoid dielectric particle in a gradient light field. The experimental results are in agreement with the predictions of the developed theoretical model. PMID- 23345886 TI - Dynamics of Bio-Polymeric Brushes Growing from a Cellular Membrane: Tentative Modelling of the Actin Turnover within an Adhesion Unit; the Podosome. AB - Podosomes are involved in the adhesion process of various cells to a solid substrate. They have been proven to consist of a dense actin core surrounded by an actin cloud. The podosomes, which nucleate when the cell comes in the vicinity of a substrate, contribute to link the membrane to the solid surface, but rather than frozen links, collective dynamical behaviors are experimentally observed. Depending on the differentiation stage, podosomes assemble and form clusters, rings or belts. Considering the dynamics of a polymeric brush, we design a simple model aiming at the description of a single podosome, the basic unit of these complex adhesion-structures and compare our theoretical conclusions to recent experimental results. Particularly, we explain, by solving the diffusion problem around the podosome, why the structure is likely to have a finite life-span. PMID- 23345887 TI - Size effects on correlation measures. AB - The detection and quantification of long-range correlations in time series is a fundamental tool to characterize the properties of different dynamical systems, and is applied in many different fields, including physics, biology or engineering. Due to the diversity of applications, many techniques for measuring correlations have been designed. Here, we study systematically the influence of the length of a time series on the results obtained from several techniques commonly used to detect and quantify long-range correlations: the autocorrelation analysis, Hurst's analysis, and detrended fluctuation analysis (DFA). Using the Fourier filtering method, we generate artificial time series with known and controlled long-range correlations and with a broad range of lengths, and apply on them the different correlation measures we have studied. Our results indicate that while the DFA method is practically unaffected by the length of the time series, and almost always provides accurate results, the results from Hurst's analysis and the autocorrelation analysis strongly depend on the length of the time series. PMID- 23345888 TI - Equilibrium shape equation and geometrically permissible condition for two component lipid bilayer vesicles. AB - Equilibrium shapes of vesicles composed of a mixture of partially miscible amphiphiles are investigated. To take into account the influences of the composition, a simple phenomenological coupling between the co mposition and the curvatures, including the mean curvature and the Gauss curvature of the membrane surface, is suggested. By minimizing the potential functional, the general shape equation is obtained and solved analytically for vesicles with simple shapes. Besides, the geometrical constraint equation and geometrically permissible condition for the two-component lipid vesicles are put forward. The influences of physical parameters on the geometrically permissible phase diagrams are predicted. The close relations between the predictions and existing experimental phenomena published recently are shown. PMID- 23345889 TI - Dynamical theory of primary processes of charge separation in the photosynthetic reaction center. AB - A dynamical theory has been developed for primary separation of charges in the course of photosynthesis. The theory deals with both hopping and superexchange transfer mechanisms. Dynamics of electron transfer from dimeric bacteriochlorophyll to quinone has been calculated. The results obtained agree with experimental data and provide a unified explanation of both the hierarchy of the transfer time in the photosynthetic reaction center and the phenomenon of coherent oscillations accompanying the transfer process. PMID- 23345890 TI - Numerical Simulation of Physiological Blood Flow in 2-way Coronary Artery Bypass Grafts. AB - The Coronary Artery Bypass Graft (CABG) yields excellent results and remains the modern standard of care for treatment of occlusive disease in the cardiovascular system. However, the development of anastomotic Intimal Hyperplasia (IH) and restenosis can compromise the medium-and-long term effects of the CABG. This problem can be correlated with the geometric configuration and hemodynamics of the bypass graft. A novel geometric configuration was proposed for the CABG with two symmetrically implanted grafts for the purpose of improving the hemodynamics. Physiological blood flows in two models of bypass grafts were simulated using numerical methods. One model was for the conventional bypass configuration with a single graft (1-way model); the other model was for the proposed bypass configuration with two grafts (2-way model). The temporal and spatial distributions of hemodynamics, such as flow patterns and Wall Shear Stress (WSS) in the vicinity of the distal anastomoses, were analyzed and compared. Calculation results showed that the 2-way model possessed favorable hemodynamics with uniform longitudinal flow patterns and WSS distributions, which could decrease the probability of restenosis and improve the effect of the surgical treatment. Concerning the limitations of the 2-way bypass grafts, it is necessary to perform animal experiments to verify the viability of this novel idea for the CABG. PMID- 23345891 TI - A theory of plasma membrane calcium pump stimulation and activity. AB - The ATP-driven Plasma Membrane Calcium pump or Ca(2+)-ATPase (PMCA) is characterized by a high affinity for calcium and a low transport rate compared to other transmembrane calcium transport proteins. It plays a crucial role for calcium extrusion from cells. Calmodulin is an intracellular calcium buffering protein which is capable in its Ca(2+) liganded form of stimulating the PMCA by increasing both the affinity to calcium and the maximum calcium transport rate. We introduce a new model of this stimulation process and derive analytical expressions for experimental observables in order to determine the model parameters on the basis of specific experiments. We furthermore develop a model for the pumping activity. The pumping description resolves the seeming contradiction of the Ca(2+):ATP stoichiometry of 1:1 during a translocation step and the observation that the pump binds two calcium ions at the intracellular site. The combination of the calcium pumping and the stimulation model correctly describes PMCA function. We find that the processes of calmodulin-calcium complex attachment to the pump and of stimulation have to be separated. Other PMCA properties are discussed in the framework of the model. The presented model can serve as a tool for calcium dynamics simulations and provides the possibility to characterize different pump isoforms by different type-specific parameter sets. PMID- 23345892 TI - Neutron diffraction with an excess-water cell. AB - As part of a study of the molecular basis of membrane fusion by enveloped viruses, we have used neutron diffraction to study the lamellar (L(alpha)) to inverse hexagonal (H(II)) phase transition in the phospholipid N-methylated dioleoylphosphatidylethanolamine. This lipid was chosen because its phase transitions are particularly sensitive to the presence of agents that have been demonstrated to promote or inhibit membrane fusion. Two different geometries of neutron diffraction were used: small angle scattering (SANS) and a membrane diffractometer. The SANS measurements were carried out on the SWAN instrument at KEK, Japan, using dispersions of multilamellar vesicles (MLVs). The diffractometer measurements used the V1 instrument at BeNSC-HMI, Germany, with a specially-constructed cell that holds a stack of lipid bilayers in an excess water state. The two approaches are compared and discussed. Although the diffractometer takes considerably longer to collect the data, it records much higher resolution than the SANS instrument. The samples recorded in the excess water cell were shown to be well aligned, despite the lipids being fully hydrated, allowing for the production of high-resolution data. Trial measurements performed have demonstrated that sample alignment is preserved throughout the L(alpha) to H(II) phase transition, thereby opening up possibilities for obtaining high-resolution data from non-lamellar phases. PMID- 23345893 TI - Determination of some hydrodynamic parameters of ovine serum albumin solutions using viscometric measurements. AB - The influence of protein concentration and temperature on the viscosity of ovine serum albumin (OSA) solutions was studied. The Mooney equation and a modified Arrhenius formula were used to described the viscosity-concentration and viscosity-temperature dependence of the solutions, respectively. The effective specific volume, the activation energy and entropy of viscous flow for hydrated OSA were calculated. The axial ratio and the dimensions of the main semi-axes of hydrated OSA were established. At low concentration limit, the temperature dependence of the intrinsic viscosity and Huggins coefficient is presented. Comparison of some hydrodynamic parameters obtained for different proteins has been made. PMID- 23345894 TI - Completing our first decade of biological physics conferences. PMID- 23345895 TI - Extended abstract: plateaus and jumps in single-molecule DNA unzipping experiments. PMID- 23345896 TI - Single macromolecules: hierarchic thermodynamics, irreversibility and biological function. AB - Single homo-polymers show two different paths in the folding transition; a liquid like spherical globule is generated for flexible polymers, whereas a rich variety of ordered structures are formed for semi-flexible polymers. This unique characteristic is discussed in relation to its biological significance. PMID- 23345897 TI - Targeted Green-Red Photoconversion of EosFP, a Fluorescent Marker Protein. AB - EosFP is a novel fluorescent protein from the stony coral Lobophyllia hemprichii. Its gene was cloned in Escherichia coli to express the tetrameric wild-type protein. The protein emits strong green fluorescence (516 nm) that shifts toward red (581 nm) upon near-ultraviolet irradiation at ~390 nm due to a photo-induced modification that involves a break in the peptide backbone next to the chromophore. Using site-directed mutagenesis, dimeric (d1EosFP, d2EosFP) and monomeric (mEosFP) variants were produced with essentially unaltered spectroscopic properties. Here we present a spectroscopic characterization of EosFP and its variants, including room- and low-temperature spectra, fluorescence lifetime determinations, two-photon excitation and two-photon photoconversion. Furthermore, by transfection of a human cancer (HeLa) cell with a fusion construct of a mitochondrial targeting sequence and d2EosFP, we demonstrate how localized photoconversion of EosFP can be employed for resolving intracellular processes. PMID- 23345898 TI - Determining to divide: how do cells decide? AB - A cell's decision to divide must be regulated with the highest fidelity. Otherwise, abnormalities occurring in the replication of genetic material and cytokinesis would be incompatible with life. It has been known for almost a century that cells comprising a population undergo cellular division at extremely variable rates, even though genetically identical cell clones have been examined. Studies with T lymphocytes at the single cell level have revealed that the rate of cellular division is determined by the accumulation of a critical number of ligand-triggered interleukin-2 (IL2) receptors at the cell surface throughout the G(1) phase of the cell cycle. Thus, the cell "counts" the number of triggered IL2 receptors, and only decides to divide when the critical number has been attained. This information is then transferred to the cellular interior via intracellular sensors comprised of D-type cyclins, which ultimately determine when the cell surpasses the "Restriction Point" in late G(1), and which commits the cell irrevocably to initiate DNA replication. Beyond the R-point, the cell assembles a definite number of macromolecular pre-replication complexes (Pre-RCs) comprised of at least 6 distinct proteins at sites of the origin of replication on DNA. Complete assembly of the Pre-RCs is a prerequisite for their subsequent disassembly, which must occur before the initiation of DNA strand replication, and which occurs asynchronously throughout the S-phase of the cell cycle and only terminates when the entire DNA has been duplicated. Thus, the fidelity of the decision to divide is exquisitely regulated by macromolecular mechanisms initiated at the cell surface and transferred to the cellular interior so that the cell can make the decision in a quantal (all-or-none) fashion. The question before us is how this quantal decision is made at the molecular level. The available data indicate that the assembly and disassembly of a definite number of large multicomponent macromolecular complexes make the quantal decisions. Here, it is postulated that all fundamental cellular decisions, i.e. survival, death, proliferation and differentiation, are regulated in this fashion. It remains to be determined how the cell counts the signals it receives, and what the molecular forces are that dictate the behavior of macromolecular complexes. PMID- 23345899 TI - Can we model DNA at the mesoscale? AB - Modelling DNA is useful for understanding its properties better but it is also challenging because many of these properties involve hundreds of base pairs or more, or time scales which are much longer than the time scales accessible to molecular dynamics. It is therefore necessary to develop models at a mesoscale, which include enough details to describe the properties of interest, for instance the biological sequence, while staying sufficiently simple and realistic.We discuss here two examples: a dynamical model to study the mechanical denaturation of DNA, which probes the sequence on various scales, and a model for the self assembly of DNA which describes the formation of hairpins and allows us to study its kinetics. PMID- 23345900 TI - Model of DNA dynamics and replication. AB - Before DNA replication can be initiated a definite number of adenosine triphosphate (ATP) containing pre-replication protein complexes (pre-RCs) must be assembled and bound to DNA like in a super-critical mass. A chemically driven dynamics of the Ginzburg-Landau (GL) type is derived, using the non-equilibrium equation for binding of pre-RCs to DNA and a probabilistic conformational distribution of these protein complexes. This dynamics, in which the DNA-protein system behaves like a nonlinear elastically braced string (NEBS), can control the cell cycle via conformational transitions such that G(2) cells contain exactly twice as much DNA as G(1) cells. After adjustment of previously-made derivations, the model is compared with cell growth data from the T lymphocyte MLA-144. PMID- 23345901 TI - Modeling B-a transformations of the DNA double helix. AB - An approach to the description of DNA conformational transformations of B-A type is presented. Due to the consideration of joint motions of DNA structural elements the model for DNA transformation is constructed in the two-component form. One component is the degree of freedom of the elastic rod, and another component - the effective coordinate of the conformational transformation. In the model the internal and external components are interrelated, as it is characteristic for DNA B-A rearrangements. It is demonstrated that kinetic energy of the double helix transformations of heterogeneous DNA can be put in homogeneous form. In the frame of the developed approach the possible localized excitations in a static state are found to compare with the experiments on DNA B A deformability. The comparison shows good qualitative agreement between theory and experiment. The conclusion is made that the found excitations in the DNA structure may be classified as static conformational solitons, and that such localized excitations may play the key role in the mechanisms of DNA intrinsic bending. PMID- 23345902 TI - Dynamic approach to DNA breathing. AB - Even under physiological conditions, the DNA double-helix spontaneously denatures locally, opening up fluctuating, flexible, single-stranded zones called DNA bubbles. We present a dynamical description of this DNA-bubble breathing in terms of a Fokker-Planck equation for the bubble size, based on the Poland-Scheraga free energy for DNA denaturation. From this description, we can obtain basic quantities such as the lifetime, an important measure for the description of the interaction of a breathing DNA molecule and selectively single-stranded DNA binding proteins. Our approach is consistent with recent single molecule measurements of bubble fluctuation. We also introduce a master equation approach to model DNA breathing, and discuss its differences from the continuous Fokker Planck description. PMID- 23345903 TI - Dynamic simulation of active/inactive chromatin domains. AB - In the present study a model for the compactification of the 30 nm chromatin fibre into higher order structures is suggested. The idea is that basically every condensing agent (HMG/SAR, HP1, cohesin, condensin, DNA-DNA interaction ...) can be modeled as an effective attractive potential of specific chain segments. This way the formation of individual 1 Mbp sized rosettes from a linear chain could be observed. We analyse how the size of these rosettes depends on the number of attractive segments and on the segment length. It turns out that 8-20 attractive segments per 1 Mbp domain produces rosettes of 300-800 nm in diameter. Furthermore, our results show that the size of the rosettes is relatively insensitive to the segment length. PMID- 23345904 TI - Diffusion of DNA molecules in gel at high electric fields. AB - Problems related to the gel electrophoretic migration of polymers can be investigated by models based on a Brownian-type ratchet where a particle can undergo a net transport on a potential energy surface that is externally driven to fluctuate between several distinct states. Here we describe the method of polymer transport and separation by means of the cellular automata technique. Numerical simulations of the polymer reptation in the model system allow us to understand the band-broadening processes in the gel electrophoresis experiments. They indicate also possible ways of fine-tuning the parameters in designing desired resolution of the experiments. PMID- 23345905 TI - A nonadiabatic theory for ultrafast catalytic electron transfer: a model for the photosynthetic reaction center. AB - A non-adiabatic theory of Electron Transfer (ET), which improves the standard theory near the inversion point and becomes equivalent to it far from the inversion point, is presented. The complex amplitudes of the electronic wavefunctions at different sites are used as Kramers variables for describing the quantum tunneling of the electron in the deformable potential generated by its environment (nonadiabaticity) which is modeled as a harmonic classical thermal bath. After exact elimination of the bath, the effective electron dynamics is described by a discrete nonlinear Schrodinger equation with norm preserving dissipative terms and a Langevin random force, with a frequency cut-off, due to the thermalized phonons.This theory reveals the existence of a specially interesting marginal case when the linear and nonlinear coefficients of a two electronic states system are appropriately tuned for forming a Coherent Electron Phonon Oscillator (CEPO). An electron injected on one of the electronic states of a CEPO generates large amplitude charge oscillations (even at zero temperature) associated with coherent phonon oscillations and electronic level oscillations. This fluctuating electronic level may resonate with a third site which captures the electron so that Ultrafast Electron Transfer (UFET) becomes possible. Numerical results are shown where two weakly interacting sites, a donor and a catalyst, form a CEPO that triggers an UFET to an acceptor. Without a catalytic site, a very large energy barrier prevents any direct ET. This UFET is shown to have many qualitative features similar to those observed in the primary charge separation in photosynthetic reaction centers. We suggest that more generally, CEPO could be a paradigm for understanding many selective chemical reactions involving electron transfer in biosystems. PMID- 23345906 TI - Decomposition reaction of dioxetanone in firefly bioluminescence by computer experiment. AB - Firefly luciferin (Ln) reacts with molecular oxygen in the presence of the enzyme luciferase (E), the Mg(+2) ion and ATP to form a four-membered cyclic peroxide, so-called dioxetanone, which has not yet been observed by spectrophotometric techniques. Subsequently, dioxetanone decomposes into carbon dioxide (CO(2)) and electronically excited oxyluciferin (Oxyln(-*)), emitting yellow-green light. In order to clarify the characteristics of the elementary reaction path from dioxetanone to Oxyln(-*), the potential energy curve of the singlet ground-state (S(0)-PEC) along the reaction coordinate was obtained by the intrinsic reaction coordinate (IRC) calculations using the AM1 Hamiltonian. Furthermore, the potential energy curve of the singlet excited-state (S(1)-PEC) was calculated, because dioxetanone decomposes to Oxyln(-*) along the reaction coordinate. The S(1)-PEC relative to S(0)-PEC was estimated at each point of the reaction coordinate using the INDO/S, where only the singly-excited configuration interactions (CI) constructed from 20 occupied and 20 unoccupied molecular orbitals (MOs) were considered. As a result of these calculations, it was concluded that (1) firefly dioxetanone might not be an intermediate but rather be in an unstable transition state; (2) the S(0)-PEC has an activation barrier of 37.5 kcal/mol for dioxetanone formation and the reaction is exothermic along the S(0)-PEC; (3) the S(1)-PEC approaches the S(0)-PEC in a concave manner where dioxetanone decomposes to efficiently produce Oxyln(-*); and (4) rupturing of an O-O bond in dioxetanone can trigger the coming and going of electrons in a "cradle" motion mediated by S(0)- and S(1)-PECs in the chemiexcitation step toward Oxyln(-*). PMID- 23345907 TI - Energy landscape and dynamics of biomolecules extended abstract. AB - Proteins are not isolated homogeneous systems. Each protein can exist in a very large number of conformations (conformational substates) that are characterized by an energy landscape. The main conformational motions, similar to the alpha and beta fluctuations in glasses, are linked to fluctuations in the bulk solvent and the hydration shell. PMID- 23345908 TI - A spectroscopic study of structural heterogeneity and carbon monoxide binding in neuroglobin. AB - Neuroglobin (Ngb) is a small globular protein that binds diatomic ligands like oxygen, carbon monoxide (CO) and nitric oxide at a heme prosthetic group. We have performed FTIR spectroscopy in the infrared stretching bands of CO and flash photolysis with monitoring in the electronic heme absorption bands to investigate structural heterogeneity at the active site of Ngb and its effects on CO binding and migration at cryogenic temperatures. Four CO stretching bands were identified; they correspond to discrete conformations that differ in structural details and CO binding properties. Based on a comparison of bound-state and photoproduct IR spectra of the wild-type protein, Ngb distal pocket mutants and myoglobin, we have provided structural interpretations of the conformations associated with the different CO bands. We have also studied ligand migration to the primary docking site, B. Rebinding from this site is governed by very low enthalpy barriers (~1 kJ/mol), indicating an extremely reactive heme iron. Moreover, we have observed ligand migration to a secondary docking site, C, from which CO rebinding involves higher enthalpy barriers. PMID- 23345909 TI - Protein surface dynamics: interaction with water and small solutes. AB - Previous time resolved measurements had indicated that protons could propagate on the surface of a protein, or a membrane, by a special mechanism that enhances the shuttle of the proton towards a specific site [1]. It was proposed that a proper location of residues on the surface contributes to the proton shuttling function. In the present study, this notion was further investigated using molecular dynamics, with only the mobile charge replaced by Na(+) and Cl(-) ions. A molecular dynamics simulation of a small globular protein (the S6 of the bacterial ribosome) was carried out in the presence of explicit water molecules and four pairs of Na(+) and Cl(-) ions. A 10 ns simulation indicated that the ions and the protein's surface were in equilibrium, with rapid passage of the ions between the protein's surface and the bulk. Yet it was noted that, close to some domains, the ions extended their duration near the surface, suggesting that the local electrostatic potential prevented them from diffusing to the bulk. During the time frame in which the ions were detained next to the surface, they could rapidly shuttle between various attractor sites located under the electrostatic umbrella. Statistical analysis of molecular dynamics and electrostatic potential/entropy consideration indicated that the detainment state is an energetic compromise between attractive forces and entropy of dilution. The similarity between the motion of free ions next to a protein and the proton transfer on the protein's surface are discussed. PMID- 23345910 TI - Red blood cell shape and fluctuations: cytoskeleton confinement and ATP activity. AB - We review recent theoretical work that analyzes experimental measurements of the shape and fluctuations of red blood cells. Particular emphasis is placed on the role of the cytoskeleton and cell elasticity and we contrast the situation of elastic cells with that of fluid-filled vesicles. In red blood cells (RBCs), the cytoskeleton consists of a two-dimensional network of spectrin proteins. Our analysis of the wave vector and frequency dependence of the fluctuation spectrum of RBCs indicates that the spectrin network acts as a confining potential that reduces the fluctuations of the lipid bilayer membrane. However, since the cytoskeleton is only sparsely connected to the bilayer, one cannot regard the composite cytoskeleton membrane as a polymerized object with a shear modulus. The sensitivity of RBC fluctuations and shapes to ATP concentration may reflect the transient defects induced in the cytoskeleton network by ATP. PMID- 23345911 TI - Dielectric properties of yeast cells expressed with the motor protein prestin. AB - We report on the linear and nonlinear dielectric properties of budding yeast (S. cerevisiae) cells, one strain of which has been genetically modified to express prestin. This motor protein plays a crucial role in the large electromotility exhibited by the outer hair cells of mammalian inner ears. Live cell suspensions exhibit enormous dielectric responses, which can be used to probe metabolic activity, membrane potential, and other properties. The aims of this study are: (1) to compare the dielectric responses of organisms expressing prestin from those of control specimens, and (2) ultimately to further develop dielectric response as a tool to study live cells, proteins, and lipids. PMID- 23345912 TI - Gravitational symmetry breaking leads to a polar liquid crystal phase of microtubules in vitro. AB - Recent space-flight experiments performed by Tabony's team provided further evidence that a microgravity environment strongly affects the spatio-temporal organization of microtubule assemblies. Characteristic time and length scales were found that govern the organization of oriented bundles under Earth's gravitational field (GF). No such organization has been observed in a microgravity environment. This paper discusses physical mechanisms resulting in pattern formation under gravity and its disappearance in microgravity. The subtle interplay between chemical kinetics, diffusion, gravitational drift, thermal fluctuations, electrostatic interactions and liquid crystalline characteristics provides a plausible scenario. PMID- 23345913 TI - Nonlinear dynamics of microtubules: biophysical implications. AB - A recently developed model of nonlinear dynamics for microtubules is further expanded based on the biophysical arguments involving the secondary structure of the constitutive protein tubulin and on the ferroelectric properties of microtubules. It is demonstrated that kink excitations arise due to GTP hydrolysis that causes a dynamical transition in the structure of tubulin. The presence of an intrinsic electric field associated with the structure of a microtubule leads to unidirectional propagation of the kink excitation along the microtubule axis. This mechanism offers an explanation of the dynamic instability phenomenon in terms of the electric field effects. Moreover, a possible elucidation of the unidirectional transport of cargo via motor proteins such as kinesin and dynein is proposed within the model developed in this paper. PMID- 23345914 TI - Electromagnetic field of microtubules: effects on transfer of mass particles and electrons. AB - Biological polar molecules and polymer structures with energy supply (such as microtubules in the cytoskeleton) can get excited and generate an endogenous electromagnetic field with strong electrical component in their vicinity. The endogenous electrical fields through action on charges, on dipoles and multipoles, and through polarization (causing dielectrophoretic effect) exert forces and can drive charges and particles in the cell. The transport of mass particles and electrons is analyzed as a Wiener-Levy process with inclusion of deterministic force (validity of the Bloch theorem is assumed for transport of electrons in molecular chains too). We compare transport driven by deterministic forces (together with an inseparable thermal component) with that driven thermally and evaluate the probability to reach the target. Deterministic forces can transport particles and electrons with higher probability than forces of thermal origin only. The effect of deterministic forces on directed transport is dominant. PMID- 23345915 TI - Mathematical modelling of ca(2+) oscillations in airway smooth muscle cells. AB - The action of different agonists such as acetylcholine on the membrane of airway smooth muscle cells may induce cytosolic Ca(2+) oscillations which can be a part of the Ca(2+) signalling pathway, eventually leading to cell contraction. The aim of the present study is to present a mathematical model of the possible effect of the initial Ca(2+) distribution within the cell on the form and frequency of induced Ca(2+) oscillations. It takes into account intracellular Ca(2+) stores such as sarcoplasmic reticulum and cytosolic proteins as well as Ca(2+) exchange across the plasma membrane. We are able to demonstrate a closer agreement of model predictions with observed Ca(2+) traces for a significantly wider range of parameter values, as was previously reported. We show also that the total cellular Ca(2+) content is an important system parameter especially because of the content in sarcoplasmic reticulum. At a total Ca(2+) increase of about 20%, the oscillation frequency increases by 25%; also, damped oscillations become sustained. Cases are indicated in which such a situation could occur. PMID- 23345916 TI - Lyotropic ion channel current model compared with ising model. AB - Trans-membrane currents in ligand-gated ion channels are calculated in a non equilibrium, chemically open whole cell system. The model is lyotropic in the sense that dynamics and parameters such as ligand concentration for half-maximal response (scale of response), and threshold for firing in neurons, are nonlinear functions of the reactant concentrations. The derived total current fits recorded data significantly better than those derived from mass action, Ising, and other equilibrium type models, in which the derived response can be displaced from the assessed response by several orders in the ligand concentration. A comparison of the model obtained with an Ising-like model provides a methodology to obtain the non-equilibrium scaling dependence of Ising-like models on the reactant concentrations. PMID- 23345917 TI - The relation of different-scale membrane processes under nitric oxide influence. AB - Rhythmic activity, synaptic transmission and propagation of excitation depend on the processes that occur at different cellular levels. Modulation of neuron activity results from the changes of plasma membrane and organelles properties. We aimed to study the relationship between changes of the ion channels activity, membrane microviscosity and amount of bound Ca(2+) under the influence of nitric oxide (NO). We also investigated the effect of NO on the refractive index of neurons. We have shown that NO activates voltage-dependent K(K(V))-channels and leads to the decrease in the amount of membrane-bound and stored Ca(2+). NO causes a decrease in the microviscosity of the membrane of cytosomes and altered refractive index of neurones. The latter can result from the modification of plasma membrane physico-chemical properties and structural changes in the cytoplasm (vesicles movement, reorganisation of cytoskeleton, etc.). It is suggested that long-term modifications of the physico-chemical properties of membranes and reorganisation in the cytoplasm affect neuron activity and signal transmission. PMID- 23345918 TI - The sleep cycle modelled as a cortical phase transition. AB - We present a mean-field model of the cortex that attempts to describe the gross changes in brain electrical activity for the cycles of natural sleep. We incorporate within the model two major sleep modulatory effects: slow changes in both synaptic efficiency and in neuron resting voltage caused by the ~90-min cycling in acetylcholine, together with even slower changes in resting voltage caused by gradual elimination during sleep of somnogens (fatigue agents) such as adenosine. We argue that the change from slow-wave sleep (SWS) to rapid-eye movement (REM) sleep can be understood as a first-order phase transition from a low-firing, coherent state to a high-firing, desychronized cortical state. We show that the model predictions for changes in EEG power, spectral distribution, and correlation time at the SWS-to-REM transition are consistent not only with those observed in clinical recordings of a sleeping human subject, but also with the on-cortex EEG patterns recently reported by Destexhe et al. [J. Neurosci.19(11), (1999) 4595-4608] for the sleeping cat. PMID- 23345919 TI - A computer-glimpse of the origin of life. AB - Evolution is assumed to begin in a very particular compartmentalized location with periodic conditions. A highly diversified world is the driving force for the continuous increase in complexity by colonizing increasingly less favourable regions. Modeling the "origin-of-life" a Darwinian cyclic process is simulated (multiplication with sporadic errors followed by a construction and selection).Starting from a RNA-world (R-strands of R(1) and R(2) monomers building Hairpin-Assembler devices) and introducing another kind of monomers (A(1) and A(2) which interlink to the Hairpin-Assembler devices such that they become bound and form an A-oligomer) it is shown that a simple translation apparatus evolves producing enzymes (specific sequences of A(1) and A(2) monomers given by the sequences of R(1) and R(2) monomers on the assembler-strands). Later on D-strands are introduced, which are not capable of participating in the synthesis of A-oligomers. These D-strands become carriers of the genetic information and induce the formation of increasingly complex entities of functionally interplaying components. PMID- 23345920 TI - Survival chances of mutants starting with one individual. AB - A simple theoretical model of a Darwinian system (a periodic system with a multiplication phase and a selection phase) of entities (initial form of polymer strand, primary mutant and satellite mutants) is given. FIRST CASE: one mutant is considered. One individual of the mutant appears in the multiplication phase of the first generation. The probabilities to find N mutants W(n) (M)(N) after the multiplication phase M of the n-th generation (with probability delta of an error in the replication, where all possible errors are fatal errors) and W(n) (S)(N) after the following selection phase S (with probability beta that one individual survives) are given iteratively. The evolutionary tree is evaluated. Averages from the distributions and the probability of extinction W(infinity) (S)(0) are obtained.Second case: two mutants are considered (primary mutant and new form). One individual of the primary mutant appears in the multiplication phase of the first generation. The probabilities to find N(p) primary mutants and N(m) of the new form W(n) (M)(N(p), N(m)) after the multiplication phase M of the n-th generation (probability epsilon of an error in the replication of the primary mutant giving the new form) and W(n) (S)(N(p), N(m)) after the following selection phase S (probabilities beta(p) and beta(m) that one individual each of the primary mutant and of the new form survives) are given iteratively. Again the evolutionary tree is evaluated. Averages from the distributions are obtained. PMID- 23345921 TI - Homochirality in bio-organic systems and glyceraldehyde in the formose reaction. AB - The article explores the possibility that the ordering of bio-organic molecules into a homochiral assembly at the origin of life was performed not in aqueous solutions of amino acids or related materials but in racemic glyceraldehyde in the "formose" reaction at high concentration and temperature. Based on physical chemical evidence and computer simulations of condensed fluids, it is argued that the isomerization kinetics of glyceraldehyde is responszible of the symmetry break and the ordering of molecules into homochiral domains. PMID- 23345922 TI - The possibility of the formation of protocells and their structural components on the basis of the apatite matrix and cocrystallizing minerals. AB - This paper presents the author's theory on the possibility of simultaneous hard phase synthesis of various organic molecules from gas-phase elements on the basis of the apatite matrix and cocrystallizing minerals (carbonate-apatite, calcite, mica). These molecules and their ensembles gave rise to living systems and protocells of the pro- and eukaryotic types. Synthesis might have occurred through gradual substitution of the mineral matrix by crystal organic matter. The structure and size of the molecules synthesized were determined by the structure, physical parameters, and arrangement of organizing centers in the crystal lattice. Apatite phosphates were embedded in a synthesized nucleic helix and their size and purine-pyrimidine complementarity were determined. Apatite and cocrystallizing minerals were seen to be involved in the synthesis of four basic classes of cell components: apatite-DNA and nucleoproteide complexes; carbonate apatite-enzymes, other proteins involved in DNA replication, all RNA types and their complexes with the specific proteins and enzymes of transcription and translation; calcite-cytoskeletal proteins; and mica-membrane lipids and proteins. The evidence supporting this theory is presented. A possible mechanism to account for the transition from crystal through organo-mineral crystal to liquid crystal (protocell) and a model of the occurrence of the matrix mechanism of transcription and translation are proposed. Some principal problems in the biochemistry and molecular biology of the origin of life on the Earth are discussed. PMID- 23345923 TI - How nature modulates inherent fluctuations for biological self-organization - the case of membrane fusion. AB - Biological systems in nano-scale, due to the weak electrostatic interactions and structural connectivity therein, are flexible so that they undergo conformational transition subject to thermal fluctuations and external noises. In the presence of barriers, nature utilizes the fluctuations to give rise to self-organization, typically accompanied by conformational transitions. In two opposing membranes with like-charges, the cooperative coupling between the undulation and charge fluctuations give rise to a dynamic instability to spontaneous growth of the in phase membrane undulation, and thus a great reduction of the energy barrier to fusion. The multivalent counter-ions, the Ca(2+) for example, enhance the necessary charge density fluctuation leading to surface charge inversion and overcondensation. PMID- 23345924 TI - Ischemia/Reperfusion injury in liver surgery and transplantation. PMID- 23345925 TI - Acute phase pulmonary responses to a single intratracheal spray instillation of magnetite (fe(3)o(4)) nanoparticles in Fischer 344 rats. AB - Iron nanomaterials are of considerable interest for application to nanotechnology related fields including environmental catalysis, biomedical imaging, drug delivery and hyperthermia, because of their superparamagnetic characteristics and high catalytic abilities. However, information about potential risks of iron nanomaterials is limited. The present study assessed pulmonary responses to a single intratracheal spray instillation of triiron tetraoxide nanoparticles (magnetite) in rats. Ten-week-old male and female Fischer 344 rats (n=5/group) were exposed to a single intratracheal spray instillation of 0 (vehicle), 5.0, 15.0 or 45.0 mg/kg body weight (BW) of magnetite. After 14 days, the rats were sacrificed, and biological consequences were investigated. The lung weights of the 15.0 and 45.0 mg/kg BW male and female groups were significantly higher than those of the control groups. The lungs of treated rats showed enlargement and black patches originating from the color of magnetite. The typical histopathological changes in the lungs of the treated rats included infiltration of macrophages phagocytosing magnetite, inflammatory cell infiltration, granuloma formation and an increase of goblet cells in the bronchial epithelium. The results clearly show that instilled magnetite causes foreign body inflammatory and granulating lesions in the lung. These pulmonary responses occur in a dose dependent manner in association with the increase in lung weight. PMID- 23345926 TI - Involvements of Estrogen Receptor, Proliferating Cell Nuclear Antigen and p53 in Endometrial Adenocarcinoma Development in Donryu Rats. AB - Involvements of estrogen receptor (ER)alpha, proliferating cell nuclear antigen (PCNA) and p53 in the uterine carcinogenesis process in Donryu rats, a high yield strain of the uterine cancer were investigated immunohistochemically. ERalpha was expressed in atypical endometrial hyperplasia, accepted as a precancerous lesion of the uterine tumors, as well as well- and in moderately-differentiated endometrial adenocarcinomas, and the intensities of expression were similar to those in the luminal epithelial cells of the atrophic uterus at 15 months of age. The expression, however, was negative in the tumor cells of poorly differentiated type. Good growth of implanted grafts of the poorly-differentiated adenocarcinomas in both sexes with or without gonadectomy supported the estrogen independency of tumor progression to malignancy. PCNA labeling indices were increased with tumor development from atypical hyperplasia to adenocarcinoma. The tumor cells in poorly-differentiated adenocarcinomas were positive for p53 positive but negative for p21 expression, suggesting accumulation of mutated p53. These results indicate that the consistent ERalpha expression is involved in initiation and promotion steps of uterine carcinogenesis, but not progression. In addition, PCNA is related to tumor development and the expression of mutated p53 might be a late event during endometrial carcinogenesis. PMID- 23345927 TI - The Incidence of Lymphoplasmacytic Gastritis in the Fundus and Antrum of Cynomolgus Monkey ( Macaca fascicularis ) Stomachs. AB - Lymphoplasmacytic gastritis is a concern for toxicological pathologists reading preclinical, non-human primate toxicity studies because subtle gastric changes which could be treatment-related may be masked and gastritis lesions may be confused with treatment-related effects and thus a gastric finding may be incorrectly assigned as a treatment-related lesion. This paper discusses the incidence of lymphoplasmacytic gastritis in cynomolgus monkeys at a contract research organization. The incidence of lymphoplasmacytic gastritis in the fundus and antrum of control cynomolgus monkeys on 18 non-gastric compound studies, was scored. The average fundus score ranged from 0.3 to 1.5 and the average antral score ranged from 0.9 to 3.5 in the cynomolgus monkey stomachs examined. The number of affected control animals in a study ranged from 0 to 5 control animals. No correlation between the route of vehicle administration and the severity or incidence of the lesions was noted. The percentage incidence of affected animals ranged from 0 to 100%. An increased incidence lymphoplasmatic gastritis from 2000 to 2004 was noted. The implications of lymphoplasmacytic gastritis in cynomolgus monkeys used for acute toxicity studies are discussed. PMID- 23345928 TI - Toxicity of nicotine by repeated intratracheal instillation to f344 rats. AB - In vivo, nicotine in cigarette smoke induces various effects not only on the respiratory system but also the central and peripheral nerve systems, circulatory organs and digestive organs, and there is a possibility of promotion of lung tumorigenesis. The present experiment was conducted to examine histopathological changes caused by nicotine in the lung with repeated intratracheal instillation (i.t.). Six-week-old male F344 rats were administered nicotine by i.t. at doses of 0.05, 0.1 and 0.2 mg nicotine/rat every 3 weeks beginning at week 4, for up to a total of 9 times and were then sacrificed at week 30. The total number of administrations, total dose of nicotine and effective number of rats were 9 times, 0.45 mg and 5 rats and 4 times, 0.20 mg and 5 rats for the 0.05 mg nicotine/rat group; 3 times, 0.30 mg and 5 rats and 4 times, 0.40 mg and 3 rats for the 0.1 mg group; and 3 times, 0.60 mg and 3 rats for the 0.2 mg group, respectively. As a control group, 5 rats were administered 0.2 ml saline/rat 9 times. Some rats administered 0.1 and 0.2 mg nicotine suffered convulsions just after administration. Histopathologically, though proliferative changes were not observed, neutrophil infiltration, edema and fibrosis in the lung were induced by nicotine. In conclusion, repeated treatment of nicotine promoted neurologic symptoms in the acute phase, and strong inflammation in the lungs in the chronic phase, even at a low dose. Toxicity of nicotine is suggested to depend not on total dose of nicotine in the experiment but rather on repeated injury with consecutive administration. PMID- 23345929 TI - Spontaneous Adenosquamous Carcinoma with Rapid Growth and EMT-like Changes in the Mammary Gland of a Young Adult Female BALB/c Mouse. AB - This study histopathologically and immunohistochemically investigated a spontaneously occurring single mass subcutaneously located in the left lower abdomen of a female BALB/cAJcl-nu/+ mouse at 10 weeks of age. The mass was about 20 * 15 * 10 mm in size after formalin fixation; nevertheless, it was not detected by clinical observations at 9 weeks of age. H&E staining revealed the tumor origin was epithelial and probably arose from the mammary gland, and the tumor cells demonstrated a squamous, acinar or polyhedral/basal pattern. A cell kinetics analysis revealed that many of the tumor cells of the squamous, acinar or polyhedral/basal component were positive for PCNA and cyclin D1, although there were a few of TUNEL-positive tumor cells in all of the components. An epithelial/mesenchymal analysis demonstrated that most of the tumor cells of the squamous and acinar components contained keratin and E-cadherin; however, most of the tumor cells of the polyhedral/basal component were less or very weakly positive for these markers. The tumor cells of the squamous component were negative for vimentin and SMA; however, many of the tumor cells of the polyhedral/basal component exhibited vimentin. In addition, expression of SMA was confirmed in some tumor cells of the acinar and basal components. Based on the microscopic and immunohistochemical characterizations, the tumor was diagnosed to be adenosquamous carcinoma that originated from the mammary gland with rapid growth, and the tumor cells demonstrated epithelial-mesenchymal transition-like changes. PMID- 23345930 TI - Splenic hemangiosarcoma in a young sprague-dawley rat. AB - The present report describes a rare case of spontaneous hemangiosarcoma in a nine week-old male Sprague-Dawley rat. At necropsy, multiple white nodules of various sizes were observed on and within the enlarged spleen and liver and were histopathologically determined to be composed of spindle- to oval-shaped cells that showed invasive growth without encapsulation and were arranged solidly but partially in whorls or faint alveolar patterns with vascular-like spaces containing small clefts or erythrocytes in the tumor mass. Immunohistochemical analysis revealed that most of the tumor cells were strongly positive for vimentin, von Willebrand factor (vWF) and CD34 but negative for podoplanin. In addition, electron microscopic examination revealed the presence of Weibel-Palade bodies in the cytoplasm of the tumor cells. Based on these findings, this case was diagnosed as a hemangiosarcoma. The splenic masses were larger than the hepatic ones, with tumor cells mainly observed at periportal regions with tumor embolism in the liver, suggesting that primary hemangiosarcoma initially developed in the spleen before metastasizing. PMID- 23345931 TI - Spontaneous renal tumors suspected of being familial in sprague-dawley rats. AB - Spontaneous renal tubule tumors (RTTs), with a distinctive morphological phenotype, were present in three Sprague-Dawley rats, 1 male and 2 females, out a total of 120 animals of each sex from untreated and placebo control groups in a 2 year carcinogenicity study. One female had one carcinoma, adenoma and hyperplasia, and the other female had five adenomas and many hyperplastic lesions; the male case had one carcinoma. From these cases, a biological continuum of hyperplasia, adenoma and carcinoma could be recognized. The tumors were present in the renal cortex and appeared as solid lobulated growths with occasional central necrosis. The lobules were divided by a small amount of fibrovascular tissue. Occasionally the larger tumors contained a cystic area. Tumor cells appeared distinctive and exhibited variable amounts of eosinophilic/amphophilic and vacuolated cytoplasm. Nuclei were round to oval with a prominent nucleolus. Mitotic figures were uncommon, and no distant metastasis was noted. The tumors were seen as multiple and bilateral lesions in two animals and had no apparent relationship to chronic progressive nephropathy (CPN). Foci of tubule hyperplasia were also noted to contain the same type of cellular morphology. The morphological and biological features of these 3 cases resembled the amphophilic-vacuolar (AV) variant of RTT that has been posited to be of familial origin. This is a report of spontaneous familial renal tumors in Sprague Dawley rats from Japan. PMID- 23345932 TI - Stimulation of adrenal chromaffin cell proliferation by hypercalcemia induced by intravenous infusion of calcium gluconate in rats. AB - Increased incidence of adrenal pheochromocytoma is frequently encountered in rat carcinogenicity studies. In some of the studies, the finding is judged to be due to a rat-specific mechanism of carcinogenesis caused by a disturbance of calcium homeostasis. However, direct evidence that the proliferation of chromaffin cells in the adrenal medulla is induced solely by hypercalcemia is not available. In this study, calcium gluconate was intravenously infused for 7 days to rat chromaffin cells by a tail cuff method, and cumulative labeling with bromodeoxyuridine (BrdU) was carried out to evaluate the proliferative activity. The serum calcium concentration was dose-dependently increased, and a high calcium concentration was stably sustained from day 2 to 7. In the adrenal medulla, BrdU-positive chromaffin cells increased in the calcium gluconate treated animals, and the BrdU-labeling index increased in a dose-dependent manner. In addition, an increased BrdU-labeling index of chromaffin cells was shown to correlate with the serum calcium concentration. Our results demonstrate that hypercalcemia directly enhances the proliferative activity of chromaffin cells and that the proliferative activity is correlated with the serum calcium concentration. PMID- 23345933 TI - Age-related Histological Findings in the Pineal Gland of Crl:CD(SD) Rats. AB - To provide background data as the pathologic basis, the pineal glands of 190 male and 193 female Crl:CD(SD) rats at ages of 0-7, 51-58, 70-85 and 111 weeks were examined histologically in this study. Mineralization and fibrosis were common findings in the aged rats, whereas they were rarely found in the young ones; mineralization was present in 7, 44, 67 and 79% of males and in 0, 32, 67 and 79% in females, and fibrosis was present in 0, 29, 48 and 44% of males and 0, 18, 40 and 35% of females at ages of 0-7, 51-58, 70-85 and 111 weeks, respectively. Striated muscle fiber appeared regularly in the fibrosis region from 51-58 weeks of age when fibrosis increased, while the origin of this fiber remained unclear. Vacuolation of pineal cells also increased with age in both sexes, though the total incidence was low. There was a low incidence of lymphocytic infiltration in both sexes, but this was not related to age. PMID- 23345934 TI - The treg/th17 imbalance in patients with obstructive sleep apnoea syndrome. AB - Obstructive sleep apnoea syndrome (OSAS) is a chronic inflammatory disease regulated by T lymphocytes. Our purpose is to assess the pattern of Th17 cells and CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells in peripheral blood of patients with OSAS. Fourty-four OSAS men and 20 healthy volunteers were enrolled. Twenty-three patients were classified into mild to moderate group and 21 cases were classified into severe group according to the severity of OSAS. We detected the frequencies of Th17 and Treg and related serum cytokines secretion and expressions of key transcription factors. OSAS patients revealed significant increase in peripheral Th17 number, Th17-related cytokines (IL-17 and IL-6), and RORgammat mRNA levels. They also presented a significant decrease in Treg number, Treg-related cytokines (TGF-beta(1)), and Foxp3 mRNA levels as compared with normal persons. As a result, the Th17/Treg ratios were markedly more upregulated in OSAS patients than those in control group. Furthermore, the Th17/Treg ratio was positively related to the severity of OSAS and serum levels of C-reactive protein. The development of OSAS may be associated with peripheral Th17/Treg imbalance and characterized by a proinflammatory cytokine microenvironment. These results opened an alternative explanation for the substantial activation of immune cells in OSAS and the development of related complications. PMID- 23345935 TI - History, ethics, advantages and limitations of experimental models for hepatic ablation. AB - Numerous techniques developed in medicine require careful evaluation to determine their indications, limitations and potential side effects prior to their clinical use. At present this generally involves the use of animal models which is undesirable from an ethical standpoint, requires complex and time-consuming authorization, and is very expensive. This process is exemplified in the development of hepatic ablation techniques, starting experiments on explanted livers and progressing to safety and efficacy studies in living animals prior to clinical studies. The two main approaches used are ex vivo isolated non-perfused liver models and in vivo animal models. Ex vivo non perfused models are less expensive, easier to obtain but not suitable to study the heat sink effect or experiments requiring several hours. In vivo animal models closely resemble clinical subjects but often are expensive and have small sample sizes due to ethical guidelines. Isolated perfused ex vivo liver models have been used to study drug toxicity, liver failure, organ transplantation and hepatic ablation and combine advantages of both previous models. PMID- 23345936 TI - Bowel preparation prior to colonoscopy: a continual search for excellence. AB - Bowel preparation prior to colonoscopy is essential to maximize the benefits of colonoscopy. Numerous bowel preparations have been studied, ranging from 4 L polyethylene glycol (PEG) to split-dose regimens to 2 L PEG with an adjunct laxative (senna, bisacodyl, ascorbic acid). Due to the large volume of PEG required for adequate bowel preparation, many studies have focused on reducing this large volume to only 2 L PEG with the addition of an adjunct. Recently, a randomized controlled trial by Tajika et al showed that the addition of mosapride to only 1.5 L PEG was non-inferior to mosapride and 2 L PEG for bowel cleansing but did provide improvements in patient tolerance. This study offers yet another potential bowel preparation for patients undergoing colonoscopy and may trigger further studies with 1.5 L PEG with an adjunct. In this letter, we discuss the current state of bowel preparation prior to colonoscopy and offer information to guide clinicians on choosing the appropriate bowel preparation for their patients. PMID- 23345937 TI - Recurrent hepatitis C virus after transplant and the importance of plasma cells on biopsy. AB - Hepatitis C virus (HCV) is the leading indication for liver transplantation in the United States. It recurs universally after transplant but the rate of fibrosis and the development of graft failure is variable. Different donor and recipient features have been demonstrated to impact fibrosis. Plasma cell hepatitis, a histologic finding, is one feature associated with poor graft and patient outcomes. The pathogenic mechanism resulting in plasma cell hepatitis is poorly understood, with evidence suggesting a role for both the HCV and the immune system.A recent publication described plasma cell hepatitis in a larger context of immune medicated graft dysfunction in transplant recipients receiving interferon based therapy. This manuscript will highlight the topic of plasma cell hepatitis and provide commentary on the lack of recognition, the data regarding pathophysiologic mechanisms and the potential management options. PMID- 23345938 TI - Internal frontier: the pathophysiology of the small intestine. AB - Even though the small intestine occupies a major portion of the abdominal space and is essential for life, in most pathology textbooks any chapter on small intestinal diseases, especially in human beings, is typically shorter than those for other gastrointestinal organs. Clinical and experimental investigations of the small intestine in various clinical situations, such as nutrition management, obesity interventions, and emergency care, have elucidated several important biological problems associated with the small intestine, the last frontier of gastroenterology. In this issue, a review by Professor Basson and his team at Michigan State University sheds light on the changes in the human small intestine under various conditions based on their clinical and surgical experience. With the advent of recent innovations in enteroscopy, a form of endoscopy used to examine deep within the small intestine, the issue that they highlighted, i.e., mucosal adaptation and atrophy of the human small intestine, has emerged as a major and manageable challenge for gastroenterologists in general, including the readers of the World Journal of Gastroenterology. PMID- 23345939 TI - Endoscopic management of difficult common bile duct stones. AB - Endoscopy is widely accepted as the first treatment option in the management of bile duct stones. In this review we focus on the alternative endoscopic modalities for the management of difficult common bile duct stones. Most biliary stones can be removed with an extraction balloon, extraction basket or mechanical lithotripsy after endoscopic sphincterotomy. Endoscopic papillary balloon dilation with or without endoscopic sphincterotomy or mechanical lithotripsy has been shown to be effective for management of difficult to remove bile duct stones in selected patients. Ductal clearance can be safely achieved with peroral cholangioscopy guided laser or electrohydraulic lithotripsy in most cases where other endoscopic treatment modalities have failed. Biliary stenting may be an alternative treatment option for frail and elderly patients or those with serious co morbidities. PMID- 23345940 TI - Prognostic value of innate and adaptive immunity in colorectal cancer. AB - Colorectal cancer (CRC) remains one of the major public health problems throughout the world. Originally depicted as a multi-step dynamical disease, CRC develops slowly over several years and progresses through cytologically distinct benign and malignant states, from single crypt lesions through adenoma, to malignant carcinoma with the potential for invasion and metastasis. Moving from histological observations since a long time, it has been recognized that inflammation and immunity actively participate in the pathogenesis, surveillance and progression of CRC. The advent of immunohistochemical techniques and of animal models has improved our understanding of the immune dynamical system in CRC. It is well known that immune cells have variable behavior controlled by complex interactions in the tumor microenvironment. Advances in immunology and molecular biology have shown that CRC is immunogenic and that host immune responses influence survival. Several lines of evidence support the concept that tumor stromal cells, are not merely a scaffold, but rather they influence growth, survival, and invasiveness of cancer cells, dynamically contributing to the tumor microenvironment, together with immune cells. Different types of immune cells infiltrate CRC, comprising cells of both the innate and adaptive immune system. A relevant issue is to unravel the discrepancy between the inhibitory effects on cancer growth exerted by the local immune response and the promoting effects on cancer proliferation, invasion, and dissemination induced by some types of inflammatory cells. Here, we sought to discuss the role played by innate and adaptive immune system in the local progression and metastasis of CRC, and the prognostic information that we can currently understand and exploit. PMID- 23345943 TI - Intestinal injury can be reduced by intra-arterial postischemic perfusion with hypertonic saline. AB - AIM: To investigate the effect of local intestinal perfusion with hypertonic saline (HTS) on intestinal ischemia-reperfusion injury (IRI) in both ex vivo and in vivo rat models. METHODS: All experiments were performed on male Wistar rats anesthetized with pentobarbital sodium given intraperitoneally at a dose of 60 mg/kg. Ex vivo vascularly perfused rat intestine was subjected to 60-min ischemia and either 30-min reperfusion with isotonic buffer (controls), or 5 min with HTS of 365 or 415 mOsm/L osmolarity (HTS(365mOsm) or HTS(415mOsm), respectively) followed by 25-min reperfusion with isotonic buffer. The vascular intestinal perfusate flow (IPF) rate was determined by collection of the effluent from the portal vein in a calibrated tube. Spontaneous intestinal contraction rate was monitored throughout. Irreversible intestinal injury or area of necrosis (AN) was evaluated histochemically using 2.3.5-triphenyltetrazolium chloride staining. In vivo, 30-min ischemia was followed by either 30-min blood perfusion or 5-min reperfusion with HTS(365mOsm) through the superior mesenteric artery (SMA) followed by 25-min blood perfusion. Arterial blood pressure (BP) was measured in the common carotid artery using a miniature pressure transducer. Histological injury was evaluated in both preparations using the Chui score. RESULTS: Ex vivo, intestinal IRI resulted in a reduction in the IPF rate during reperfusion (P < 0.05 vs sham). The postischemic recovery of the IPF rate did not differ between the controls and the HTS(365mOsm) group. In the HTS(415mOsm) group, postischemic IPF rates were lower than in the controls and the HTS(365mOsm) group (P < 0.05). The intestinal contraction rate was similar at baseline in all groups. An increase in this parameter was observed during the first 10 min of reperfusion in the control group as compared to the sham-treated group, but no such increase was seen in the HTS(365mOsm) group. In controls, AN averaged 14.8% +/- 5.07% of the total tissue volume. Administration of HTS(365mOsm) for 5 min after 60-min ischemia resulted in decrease in AN (5.1% +/- 1.20% vs controls, P < 0.01). However, perfusion of the intestine with the HTS of greater osmolarity (HTS(415mOsm)) failed to protect the intestine from irreversible injury. The Chiu score was lower in the HTS(365mOsm) group in comparison with controls (2.4 +/- 0.54 vs 3.2 +/- 0.44, P = 0.042), while intestinal perfusion with HTS(415mOsm) failed to improve the Chiu score. Intestinal reperfusion with HTS(365mOsm) in the in vivo series secured rapid recovery of BP after its transient fall, whereas in the controls no recovery was seen. The Chiu score was lower in the HTS(365mOsm) group vs controls (3.1 +/- 0.26 and 3.8 +/- 0.22, P = 0.0079 respectively,), although the magnitude of the effect was lower than in the ex vivo series. CONCLUSION: Brief intestinal postischemic perfusion with HTS(365mOsm) through the SMA followed by blood flow restoration is a protective procedure that could be used for the prevention of intestinal IRI. PMID- 23345941 TI - Gastrointestinal radiation injury: symptoms, risk factors and mechanisms. AB - Ionising radiation therapy is a common treatment modality for different types of cancer and its use is expected to increase with advances in screening and early detection of cancer. Radiation injury to the gastrointestinal tract is important factor working against better utility of this important therapeutic modality. Cancer survivors can suffer a wide variety of acute and chronic symptoms following radiotherapy, which significantly reduces their quality of life as well as adding an extra burden to the cost of health care. The accurate diagnosis and treatment of intestinal radiation injury often represents a clinical challenge to practicing physicians in both gastroenterology and oncology. Despite the growing recognition of the problem and some advances in understanding the cellular and molecular mechanisms of radiation injury, relatively little is known about the pathophysiology of gastrointestinal radiation injury or any possible susceptibility factors that could aggravate its severity. The aims of this review are to examine the various clinical manifestations of post-radiation gastrointestinal symptoms, to discuss possible patient and treatment factors implicated in normal gastrointestinal tissue radiosensitivity and to outline different mechanisms of intestinal tissue injury. PMID- 23345942 TI - Gastrointestinal radiation injury: prevention and treatment. AB - With the recent advances in detection and treatment of cancer, there is an increasing emphasis on the efficacy and safety aspects of cancer therapy. Radiation therapy is a common treatment for a wide variety of cancers, either alone or in combination with other treatments. Ionising radiation injury to the gastrointestinal tract is a frequent side effect of radiation therapy and a considerable proportion of patients suffer acute or chronic gastrointestinal symptoms as a result. These side effects often cause morbidity and may in some cases lower the efficacy of radiotherapy treatment. Radiation injury to the gastrointestinal tract can be minimised by either of two strategies: technical strategies which aim to physically shift radiation dose away from the normal intestinal tissues, and biological strategies which aim to modulate the normal tissue response to ionising radiation or to increase its resistance to it. Although considerable improvement in the safety of radiotherapy treatment has been achieved through the use of modern optimised planning and delivery techniques, biological techniques may offer additional further promise. Different agents have been used to prevent or minimize the severity of gastrointestinal injury induced by ionising radiation exposure, including biological, chemical and pharmacological agents. In this review we aim to discuss various technical strategies to prevent gastrointestinal injury during cancer radiotherapy, examine the different therapeutic options for acute and chronic gastrointestinal radiation injury and outline some examples of research directions and considerations for prevention at a pre-clinical level. PMID- 23345944 TI - Characterization of focal liver masses using acoustic radiation force impulse elastography. AB - AIM: To investigate the diagnostic performance of acoustic radiation force impulse (ARFI) elastography for characterizing focal liver mass by quantifying their stiffness. METHODS: This prospective study included 62 patients with a focal liver mass that was well visualized on conventional ultrasonography performed in our institution from February 2011 to November 2011. Among them, 12 patients were excluded for ARFI measurement failure due to a lesion that was smaller than the region of the interest and at an inaccessible location (deeper than 8 cm) (n = 7) or poor compliance to hold their breath as required (n = 5). Finally, 50 patients with valid ARFI measurements were enrolled. If a patient had multiple liver masses, only one mass of interest was chosen. The masses were diagnosed by histological examination or clinical diagnostic criteria. During ultrasonographic evaluation, stiffness, expressed as velocity, was checked 10 times per focal liver mass and the surrounding liver parenchyma. RESULTS: After further excluding three masses that were non-diagnostic on biopsy, a total of 47 focal mass lesions were tested, including 39 (83.0%) malignant masses [24 hepatocellular carcinomas (HCC), seven cholangiocellular carcinomas (CCC), and eight liver metastases] and eight (17.0%) benign masses (five hemangiomas and three focal nodular hyperplasias, FNH). Thirty-seven (74.0%) masses were confirmed by histological examination. The mean velocity was 2.48 m/s in HCCs, 1.65 m/s in CCCs, 2.35 m/s in metastases, 1.83 m/s in hemangiomas, and 0.97 m/s in FNHs. Although considerable overlap was still noted between malignant and benign masses, significant differences in ARFI values were observed between malignant and benign masses (mean 2.31 m/s vs 1.51 m/s, P = 0.047), as well as between HCCs and benign masses (mean 2.48 m/s vs 1.51 m/s, P = 0.006). The areas under the receiver operating characteristics curves (AUROC) for discriminating the malignant masses from benign masses was 0.724 (95%CI, 0.566-0.883, P = 0.048), and the AUROC for discriminating HCCs from benign masses was 0.813 (95%CI, 0.649-0.976, P = 0.008). To maximize the sum of sensitivity and specificity, an ARFI value of 1.82 m/s was selected as the cutoff value to differentiate malignant from benign liver masses. Furthermore, the cutoff value for distinguishing HCCs from benign masses was also determined to be 1.82 m/s. The diagnostic performance of the sum of the ARFI values for focal liver masses and the surrounding liver parenchyma to differentiate liver masses improved (AUROC = 0.853; 95%CI, 0.745-0.960; P = 0.002 in malignant liver masses vs benign ones and AUROC = 0.948; 95%CI, 0.896-0.992, P < 0.001 in HCCs vs benign masses). CONCLUSION: ARFI elastography provides additional information for the differential diagnosis of liver masses. However, our results should be interpreted in clinical context, because considerable overlap in ARFI values existed among liver masses. PMID- 23345945 TI - Inositol-requiring enzyme 1alpha is required for gut development in Xenopus lavies embryos. AB - AIM: To investigate the role of inositol-requiring enzyme 1alpha (IRE1alpha) in gut development of Xenopus lavies embryos. METHODS: Xenopus embryos were obtained with in vitro fertilization and cultured in 0.1 * MBSH. One and half nanogram of IRE1alpha, 1 ng of IRE1alpha-GR mRNA, 1 ng of IRE1alphaDeltaC-GR mRNA, and 50 ng of IRE1alpha morpholino oligonucleotide (MO) or XBP1(C)MO were injected into four blastomeres at 4-cell stage for scoring the phenotype and marker gene analysis. To rescue the effect of IRE1alpha MO, 1 ng of IRE1alpha-GR mRNA was co-injected with 50 ng of MO. For the activation of the GR-fusion proteins, dexamethasone was prepared as 5 mmol/L stock solutions in 100% ethanol and applied to the mRNA injected embryos at desired stages in a concentration of 10 MUmol/L in 0.1 * MBSH. Embryos were kept in dexamethasone up to stage 41. Whole-mount in situ hybridization was used to determine specific gene expression, such as IRE1alpha, IRE1beta, Xbra and Xsox17alpha. IRE1alpha protein expression during Xenopus embryogenesis was detected by Western blotting. RESULTS: In the whole-mount in situ hybridization analysis, xenopus IRE1alpha and IRE1beta showed quite different expression pattern during tadpole stage. The relatively higher expression of IRE1alpha was observed in the pancreas, and significant transcription of IRE1beta was found in the liver. IRE1alpha protein could be detected at all developmental stages analyzed, from stage 1 to stage 42. Gain-of function assay showed that IRE1alpha mRNA injected embryos at tailbud stage were nearly normal and the expression of the pan-mesodermal marker gene Xbra and the endodermal gene Xsox17alpha at stage 10.5 was not significantly changed in embryos injected with IRE1alpha mRNA as compared to uninjected control embryos. And at tadpole stage, the embryos injected with IRE1alpha-GR mRNA did not display overt phenotype, such as gut-coiling defect. Loss-of-function assay demonstrated that the IRE1alpha MO injected embryos were morphologically normal before the tailbud stages. We did not observe a significant change of mesodermal and endodermal marker gene expression, while after stage 40, about 80% of the MO injected embryos exhibited dramatic gut defects in which the guts did not coil, but other structures outside the gastrointestinal tract were relatively normal. To test if the phenotypes were specifically caused by the knockdown of IRE1alpha, a rescue experiment was performed by co-injection of IRE1alpha-GR mRMA with IRE1alpha MO. The data obtained demonstrated that the gut coiling defect was rescued. The deletion mutant of IRE1alpha was constructed, consisting of the N terminal part without the C-terminal kinase and RNase domains named IRE1alphaDeltaC, to investigate the functional domain of IRE1alpha. Injection of IRE1alphaDeltaC-GR mRNA caused similar morphological alterations with gut malformation by interfering with the function of endogenous xIRE1alpha. In order to investigate if IRE1alpha/XBP1 pathway was involved in gut development, 50 ng of XBP1 MO was injected and the results showed that knockdown of XBP1 resulted in similar morphological alterations with gut-coiling defect at tadpole stage. CONCLUSION: IRE1alpha is not required for germ layer formation but for gut development in Xenopus lavies and it may function via XBP1-dependent pathway. PMID- 23345946 TI - Partially hydrolyzed guar gum in pediatric functional abdominal pain. AB - AIM: To assess the effects of partially hydrolyzed guar gum (PHGG) diet supplement in pediatric chronic abdominal pain (CAP) and irritable bowel syndrome (IBS). METHODS: A randomized, double-blind pilot study was performed in sixty children (8-16 years) with functional bowel disorders, such as CAP or IBS, diagnosed according to Rome III criteria. All patients underwent ultrasound, blood and stool examinations to rule out any organic disease. Patients were allocated to receive PHGG at dosage of 5 g/d (n = 30) or placebo (fruit-juice n = 30) for 4 wk. The evaluation of the efficacy of fiber supplement included IBS symptom severity score (Birmingham IBS Questionnaire), severity of abdominal pain (Wong-Baker Face Pain Rating Score) and bowel habit (Bristol Stool Scale). Symptom scores were completed at 2, 4, and 8 wk. The change from baseline in the symptom severity scale at the end of treatment and at 4 wk follow-up after treatment was the primary endpoint. The secondary endpoint was to evaluate compliance to supplementation with the PHGG in the pediatric population. Differences within groups during the treatment period and follow-up were evaluated by the Wilcoxon signed-rank test. RESULTS: The results of the study were assessed considering some variables, such as frequency and intensity of symptoms with modifications of the bowel habit. Both groups were balanced for baseline characteristics and all patients completed the study. Group A (PHGG group) presented a higher level of efficacy compared to group B (control group), (43% vs 5%, P = 0.025) in reducing clinical symptoms with modification of Birmingham IBS score (median 0 +/- 1 vs 4 +/- 1, P = 0.025), in intensity of CAP assessed with the Wong-Baker Face Pain Rating Score and in normalization of bowel habit evaluated with the Bristol Stool Scale (40% vs 13.3%, P = 0.025). In IBS subgroups, statistical analysis shown a tendency toward normalization of bowel movements, but there was no difference in the prevalence of improvement in two bowel habit subsets. PHGG was therefore better tolerated without any adverse effects. CONCLUSION: Although the cause of pediatric functional gastrointestinal disorders is not known, the results show that complementary therapy with PHGG may have beneficial effects on symptom control. PMID- 23345947 TI - Atorvastatin and rosuvastatin do not prevent thioacetamide induced liver cirrhosis in rats. AB - AIM: To examine whether the administration of atorvastatin and rosuvastatin would prevent experimentally-induced hepatic cirrhosis in rats. METHODS: Liver cirrhosis was induced by injections of thioacetamide (TAA). Rats were treated concurrently with TAA alone or TAA and either atorvastatin (1,10 and 20 mg/kg) or rosuvastatin (1, 2.5, 5, 10 and 20 mg/kg) given daily by nasogastric gavage. RESULTS: Liver fibrosis and hepatic hydroxyproline content, in the TAA-treated group was significantly higher than those of the controls [11.5 +/- 3.2 vs 2.6 +/ 0.6 mg/g protein (P = 0.02)]. There were no differences in serum aminotransferase levels in the TAA controls compared to all the groups treated concomitantly by statins. Both statins used in our study did not prevent liver fibrosis or reduce portal hypertension, and had no effect on hepatic oxidative stress. Accordingly, the hepatic level of malondialdehyde was not lower in those groups treated by TAA + statins compared to TAA only. In vitro studies, using the BrdU method have shown that atorvastatin had no effect of hepatic stellate cells proliferation. Nevertheless, statin treatment was not associated with worsening of liver damage, portal hypertension or survival rate. CONCLUSION: Atorvastatin or rosuvastatin did not inhibit TAA-induced liver cirrhosis or oxidative stress in rats. Whether statins may have therapeutic applications in hepatic fibrosis due to other etiologies deserve further investigation. PMID- 23345948 TI - Hyperglycemia is a significant prognostic factor of hepatocellular carcinoma after curative therapy. AB - AIM: To evaluate whether metabolic factors are related to distant recurrence of hepatocellular carcinoma (HCC) and survival after curative treatment. METHODS: This retrospective study included 344 patients whose HCC was treated curatively by radiofrequency ablation (RFA) therapy. The mean age was 67.6 years and the mean observation period was 4.04 years. The etiological background of liver disease was hepatitis B virus infection in 30, hepatitis C virus infection in 278, excessive alcohol drinking in 9, and other in 27 patients. The Child-Pugh classification grade was A (n = 307) or B (n = 37). The number of HCC nodules was one in 260, two in 61, and three in 23 patients. For surveillance of HCC recurrence after curative therapy with RFA, patients were radiologically evaluated every 3 mo. Factors associated with distant recurrence of HCC or survival were studied. RESULTS: Inadequate maintenance of blood glucose in diabetic patients was associated with higher incidence of distant recurrence. The 1-, 2-, and 3-year recurrence rates were significantly higher in diabetic patients with inadequate maintenance of blood glucose compared with the others: 50.6% vs 26.8%, 83.5% vs 54.4%, and 93.8% vs 73.0%, respectively (P = 0.0001). Inadequate maintenance of blood glucose was an independent predictor of distant recurrence [adjusted relative risk 1.97 (95%CI, 1.33-2.91), (P = 0.0007)] after adjustment for other risk factors, such as number of HCC nodules [2.03 (95%CI, 1.51-2.73), P < 0.0001] and initial level of serum alpha fetoprotein (AFP) [1.43 (95%CI, 1.04-1.97), P = 0.028]. Obesity was not an independent predictor of recurrence. The incidence of distant recurrence did not differ between diabetic patients with adequate maintenance of blood glucose and non-diabetic patients. Among 232 patients who had HCC recurrence, 138 had a second recurrence. The 1-, 2 , and 3-year rates of second recurrence were significantly higher in diabetic patients with inadequate maintenance of blood glucose than in the others: 9.0% vs 5.9%, 53.1% vs 24.3%, and 69.6% vs 42.3%, respectively (P = 0.0021). Inadequate maintenance of blood glucose in diabetic patients [1.99 (95%CI, 1.23-3.22), P = 0.0049] and presence of multiple HCC nodules [1.53 (95%CI, 1.06-2.22), P = 0.024] were again significantly associated with second HCC recurrence. Inadequate maintenance of blood glucose in diabetic patients was also a significant predictor of poor survival [2.77 (95%CI, 1.38-5.57), P = 0.0046] independent of excessive alcohol drinking [6.34 (95%CI, 1.35-29.7), P = 0.019], initial level of serum AFP [3.40 (95%CI, 1.88-6.18), P < 0.0001] and Child-Pugh classification grade B [2.24 (95%CI, 1.12-4.46), P = 0.022]. Comparing diabetic patients with inadequate maintenance of blood glucose vs the others, the 1-, 2-, and 3-year survival rates were significantly lower in diabetic patients with inadequate maintenance of blood glucose: 92% vs 99%, 85% vs 96%, and 70% vs 92%, respectively (P = 0.0003). CONCLUSION: Inadequate maintenance of blood glucose in diabetic patients is a significant risk factor for recurrence of HCC and for poor survival after curative RFA therapy. PMID- 23345949 TI - Gastrointestinal tuberculosis is not associated with proton pump inhibitors: a retrospective cohort study. AB - AIM: To evaluate the effect of proton pump inhibitors (PPIs) on the development of gastrointestinal tuberculosis. METHODS: All patients who were more than 20 years old and who had received a prescription for PPIs among those who visited Seoul National University Hospital from January 1, 2005 to December 31, 2009 were identified. Due to the low sensitivity of the microbiologic test and the nonspecific pathologic findings, the diagnosis of gastrointestinal tuberculosis was confirmed through the presence of active ulcerations and the responses to anti-tuberculosis medications. The patients were divided into two groups according to treatment duration (group 1: <= 3 mo; group 2: > 3 mo) and were followed up from the time they took the first prescription of PPIs until their last visit. Logistic regression analysis was used to calculate the relative risks (RR) and 95%CI, adjusting for covariates. RESULTS: Among the 61, 834 patients exposed to PPIs (50,534 in group 1; 11,300 in group 2), 21 patients were diagnosed with PPI-associated gastrointestinal tuberculosis during 124,274 person years of follow-up. Of 21 patients, the 12 who revealed only scar changes in the colonoscopy were excluded from the statistical analyses. Of those who remained, 2 were excluded because they underwent gastrointestinal endoscopy within 4 wk of the first prescription for PPIs. Longer exposure to PPI was associated with a higher mean age (55.0 +/- 14.5 in group 1 vs 58.2 +/- 13.3 in group 2, P < 0.001) and a higher Charlson co-morbidity index (0.50 +/- 0.93 in group 1 vs 0.77 +/- 1.14 in group 2, P < 0.001). The true incidence of active gastrointestinal tuberculosis was 0.65 per 1000 person-years in group 1 and 0.03 per 1 000 person years in group 2. Like the less-than-three-month PPI treatment period in group 1, the over-three-month PPI therapy period in group 2 was not associated with increased risk of acquiring gastrointestinal tuberculosis, after adjusting for age and co-morbidities, whereas the Charlson co-morbidity index was associated with increased risk of acquiring gastrointestinal tuberculosis based on the score [RR: (reference 1) in group 1 vs 1.518 in group 2; 95% CI: 1.040-2.216, P = 0.03]. CONCLUSION: Long-term PPI therapy does not seem to be associated with increased risk of acquiring gastrointestinal tuberculosis, but a higher Charlson co-morbidity index is associated with such. PMID- 23345950 TI - Clinical outcomes and predictive factors in oral corticosteroid-refractory active ulcerative colitis. AB - AIM: To evaluate the clinical outcomes and prognostic factors after intravenous corticosteroids following oral corticosteroid failure in active ulcerative colitis patients. METHODS: Consecutive patients with moderate to severe ulcerative colitis who had been treated with a course of intravenous corticosteroids after oral corticosteroid therapy failure between January 1996 and July 2010 were recruited at Severance Hospital, Seoul, South Korea. The disease activity was measured by the Mayo score, which consists of stool frequency, rectal bleeding, mucosal appearance at flexible sigmoidoscopy, and Physician Global Assessment. We retrospectively evaluated clinical outcomes at two weeks, one month, three months, and one year after the initiation of intravenous corticosteroid therapy. Two weeks outcomes were classified as responders or non-responders. One month, three month and one year outcomes were classified into prolonged response, steroid dependency, and refractoriness. RESULTS: Our study included a total of 67 eligible patients. At two weeks, 56 (83.6%) patients responded to intravenous corticosteroids. At one month, complete remission was documented in 18 (32.1%) patients and partial remission in 26 (46.4%). Eleven patients (19.7%) were refractory to the treatment. At three months and one year, we found 37 (67.3%) and 25 (46.3%) patients in prolonged response, ten (18.2%) and 23 (42.6%) patients in corticosteroid dependency, 8 (14.5%) and 6 (11.1%) patients with no response, respectively. Total 9 patients were underwent elective proctocolectomy within 1 year. The duration of oral corticosteroid therapy (> 14 d vs <= 14 d, P = 0.049) and lower hemoglobin level (<= 11.0 mg/dL vs >11.0 mg/dL, P = 0.02) were found to be poor prognostic factors for response at two weeks. For one year outcome, univariate analysis revealed that only a partial Mayo score (>= 6 vs <6, P = 0.057) was found to be associated with a poor response. CONCLUSION: The duration of oral corticosteroid therapy and lower hemoglobin level were strongly associated with poor outcome. PMID- 23345951 TI - Dual probiotic strains suppress high fructose-induced metabolic syndrome. AB - AIM: To investigate the effect of novel probiotics on the clinical characteristics of high-fructose induced metabolic syndrome. METHODS: Male Wistar rats aged 4 wk were fed a 70% w/w high-fructose diet (n = 27) or chow diet (n = 9) for 3 wk to induce metabolic syndrome, the rats were then randomized into groups and administered probiotic [Lactobacillus curvatus (L. curvatus) HY7601 and Lactobacillus plantarum (L. plantarum) KY1032] at 10(9) cfu/d or 10(10) cfu/d or placebo by oral gavage for 3 wk. Food intake and body weight were measured once a week. After 6 wk, the rats were fasted for 12 h, then anesthetized with diethyl ether and sacrificed. Blood samples were taken from the inferior vena cava for plasma analysis of glucose, insulin, C-peptide, total-cholesterol, triglycerides and thiobarbituric acid-reacting substances. Real-time polymerase chain reaction was performed using mouse-specific Taqman probe sets to assess genes related to fatty acid beta-oxidation, lipogenesis and cholesterol metabolism in the liver. Target gene expression was normalized to the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase. RESULTS: Rodents fed a high-fructose diet developed clinical characteristics of the metabolic syndrome including increased plasma glucose, insulin, triglycerides, total cholesterol and oxidative stress levels, as well as increased liver mass and liver lipids compared to chow fed controls. Probiotic treatment (L. curvatus HY7601 and L. plantarum KY1032) at high (10(10) cfu/d) or low dosage (10(9) cfu/d) lowered plasma glucose, insulin, triglycerides and oxidative stress levels. Only high dose probiotic treatment reduced liver mass and liver cholesterol. Probiotic treatment reduced lipogenesis via down-regulation of SREBP1, FAS and SCD1 mRNA levels and increased beta-oxidation via up-regulation of PPARalpha and CPT2 mRNA levels. CONCLUSION: Probiotic L. curvatus HY7601 and L. plantarum KY1032 combined suppressed the clinical characteristics of high-fructose-induced metabolic syndrome, therefore, may provide a natural alternative for the treatment of diet induced metabolic syndrome. PMID- 23345952 TI - Clinical significance and risk factors of postembolization fever in patients with hepatocellular carcinoma. AB - AIM: To investigate tumor response and survival in patients with postembolization fever (PEF) and to determine the risk factors for PEF. METHODS: Four hundred forty-three hepatocellular carcinoma (HCC) patients who underwent the first session of transcatheter arterial chemoembolization (TACE) between January 2005 and December 2009 were analyzed retrospectively. PEF was defined as a body temperature greater than 38.0 degrees C that developed within 3 d of TACE without evidence of infection. The tumor progression-free interval was defined as the interval from the first TACE to the second TACE based on mRECIST criteria. Clinical staging was based on the American Joint Committee on Cancer tumor, node, metastases (TNM) classification of malignant tumors. All patients were admitted before their 1(st) TACE treatment, and blood samples were obtained from all patients before and after treatment. Clinicoradiological variables and host related variables were compared between two groups: patients with PEF vs patients without PEF. Additionally, variables related to 20-mo mortality and tumor progression-free survival were analyzed. RESULTS: The study population comprised 370 (85.4%) men and 73 (14.6%) women with a mean age of 62.29 +/- 10.35 years. A total of 1836 TACE sessions were conducted in 443 patients, and each patient received between 1 and 27 (mean: 4.14 +/- 3.57) TACE sessions. The mean follow-up duration was 22.23 +/- 19.6 mo (range: 0-81 mo). PEF developed in 117 patients (26.41%) at the time of the first TACE session. PEF was not associated with 20-mo survival (P = 0.524) or computed tomography (CT) response (P = 0.413) in a univariate analysis. A univariate analysis further indicated that diffuse-type HCC (P = 0.021), large tumor size (>= 5 cm) (P = 0.046), lipiodol dose (>= 7 mL, P = 0.001), poor blood glucose control (P = 0.034), alanine aminotransferase (ALT) value after TACE (P = 0.004) and C-reactive protein (CRP) value after TACE (P = 0.036) served as possible risk factors correlated with PEF. The ALT value after TACE (P = 0.021) and lipiodol dose over 7 mL (P = 0.011) were independent risk factors for PEF in the multivariate analysis. For the 20-mo survival, poor blood sugar control (P < 0.001), portal vein thrombosis (P = 0.001), favorable CT response after TACE (P < 0.001), initial aspartate aminotransferase (P = 0.02), initial CRP (P = 0.042), tumor size (P < 0.001), TNM stage (P < 0.001) and lipiodol dose (P < 0.001) were possible risk factors in the univariate analysis. Tumor size (P = 0.03), poor blood sugar control (P = 0.043), and portal vein thrombosis (P = 0.031) were significant predictors of survival in the multivariate analysis. Furthermore, the tumor progression-free interval was closely associated with CRP > 1 mg/dL (P = 0.003), tumor size > 5 cm (P < 0.001), tumor type (poorly defined) (P < 0.001), and lipiodol dose (> 7 mL, P < 0.001). CONCLUSION: PEF has no impact on survival at 20 mo or radiologic response. However, the ALT level after TACE and the lipiodol dose represent significant risk factors for PEF. PMID- 23345953 TI - IL28B polymorphism and cytomegalovirus predict response to treatment in Egyptian HCV type 4 patients. AB - AIM: To test whether the status of positive cytomegalovirus (CMV) DNA detection adds to the predictive value of IL28B and to further categorize C/T allele carriers. METHODS: This study included 166 chronic hepatitis C (CHC) patients who received combined interferon and ribavirin therapy for 48 wk, 84 spontaneous hepatitis C virus (HCV) resolvers who were positive for IgG anti-HCV antibody and negative for HCV RNA, and 100 healthy subjects who were negative for both HCV antibodies and RNA as controls. Genomic DNA from peripheral blood was used for IL28B rs.12979860 single nucleotide polymorphism (SNP) and CMV DNA detection. A 139 bp fragment containing IL28B SNP was amplified in all subjects by polymerase chain reaction using a specifically designed primer. Then the IL28B rs.12979860 SNP was detected by restriction fragment length polymorphism (RFLP) genotyping. The presence of CMV DNA was tested by amplification of the gB1 gene using nested polymerase chain reaction. The role of CMV and IL28B rs.12979860 SNP genotypes in determining the response rate to combined interferon therapy and clinical status of patients were statistically analyzed. RESULTS: Current data showed that 67% of patients carrying the IL28B 12979860 C/C allele had a sustained viral response (SVR) while the genotypes C/T and TT were associated with lower SVR rates, 50% and 48%, respectively. SVR rates for the C/C allele were lower than other HCV genotypes and/or other populations. Genotype CC was associated with the response to interferon (P = 0.025). Genotype C/C was reduced from 48% in controls to 14% in CHC patients suggesting its protective role against progression to chronicity. The majority of spontaneously cleared subjects (86%) were C/C, confirming its protective role. The C/T allele was present in 71% of CHC patients compared with 38% of controls, so the use of IL28B SNP genotyping only in these patients may be of little value as a predictor of response. CMV reactivation occurred in 40% of CHC patients. Co-infection with CMV seriously diminished the response to interferon (IFN) therapy, with SVR rates in C/C genotypes 87.5% in CMV-negative patients and 12.5% in CMV-positive patients (P < 0.0001). SVR rates among C/T carriers were reduced to < 50% in patients with positive CMV DNA while the non response rate doubled. These data indicate that a supplemental assay for CMV viremia adds to the prognostic value of IL28B genotyping. CONCLUSION: The results suggest that both genetic (i.e., spontaneous) and therapeutic (IFN-based therapy) arms are complementary in the battle against HCV. CMV DNA testing may be of value to better predict the response to IFN, particularly in IL28B C/T carriers. PMID- 23345954 TI - Lubiprostone induced ischemic colitis. AB - Ischemic colitis accounts for 6%-18% of the causes of acute lower gastrointestinal bleeding. It is often multifactorial and more commonly encountered in the elderly. Several medications have been implicated in the development of colonic ischemia. We report a case of a 54-year old woman who presented with a two-hour history of nausea, vomiting, abdominal pain, and bloody stool. The patient had recently used lubiprostone with close temporal relationship between the increase in the dose and her symptoms of rectal bleeding. The radiologic, colonoscopic and histopathologic findings were all consistent with ischemic colitis. Her condition improved without any serious complications after the cessation of lubiprostone. This is the first reported case of ischemic colitis with a clear relationship with lubiprostone (Naranjo score of 10). Clinical vigilance for ischemic colitis is recommended for patients receiving lubiprostone who are presenting with abdominal pain and rectal bleeding. PMID- 23345955 TI - Lesson from an intriguing case of cryoglobulinemia. AB - Cryoglobulinemia is a pathological condition usually associated with hepatitis C virus (HCV) chronic liver disease and less commonly with autoimmune or lymphoproliferative disorders. The possible association of cryoglobulinemia with hepatitis B virus (HBV) infection is not widely accepted. In our patient, serum negativity for HCV markers initially led us to consider two other causes of cryoglobulinemia. Myelodysplastic disorders were excluded on the basis of hematological studies, while serum markers for active HBV infection were positive. Surprisingly, the detection of HCV RNA in the cryocrit, even in the absence of anti-HCV antibodies, suggested a pathogenetic role of HCV in this case of cryoglobulinemia. Negative "first level" tests for HCV in the serum do not completely exclude HCV involvement in the pathogenesis of cryoglobulinemia. Analysis of the cryoprecipitate is always essential for diagnosis. PMID- 23345956 TI - Recurrent cervical esophageal stenosis after colon conduit failure: use of myocutaneous flap. AB - A 53-year-old male developed cervical esophageal stenosis after esophageal bypass surgery using a right colon conduit. The esophageal bypass surgery was performed to treat multiple esophageal strictures resulting from corrosive ingestion three years prior to presentation. Although the patient underwent several endoscopic stricture dilatations after surgery, he continued to suffer from recurrent esophageal stenosis. We planned cervical patch esophagoplasty with a pedicled skin flap of sternocleidomastoid (SCM) muscle. Postoperative recovery was successful, and the patient could eat a solid meal without difficulty and has been well for 18 mo. SCM flap esophagoplasty is an easier and safer method of managing complicated and recurrent cervical esophageal strictures than other operations. PMID- 23345957 TI - A case of ascending colon variceal bleeding treated with venous coil embolization. AB - A 38-year-old female with a history of alcoholic liver cirrhosis visited our hospital with a massive hematochezia. An esophagogastroduodenoscopy did not demonstrate any bleeding source, and a colonoscopy showed a massive hemorrhage in the ascending colon but without an obvious focus. The source of the bleeding could not be found with a mesenteric artery angiography. We performed an enhanced abdominal computed tomography, which revealed a distal ascending colonic varix, and assumed that the varix was the source of the bleeding. We performed a venous coil embolization and histoacryl injection to obliterate the colon varix. The intervention appeared to be successful because the vital signs and hemoglobin laboratory data remained stable and because the hematochezia was no longer observed. We report here on a rare case of colonic variceal bleeding that was treated with venous coil embolization. PMID- 23345958 TI - Atypical presentation of pseudomembranous colitis localized in adenomatous polyps. AB - The most frequent cause of pseudomembranous colitis is Clostridium difficile (C. difficile) infection. This type of colitis is characterized by an endoscopic pattern of numerous small, yellowish or whitish plaques diffusely distributed, which typically compromises the rectum extending to proximal colon. Occasionally, the pseudomembranes compromise only the transverse or right colon, but their exclusive localization over polyps has not been reported. In this case report we have described a patient with symptoms compatible with C. difficile infection and positive for C. difficile toxigenic culture. Colonoscopy examination showed two small polyps with a whitish surface, and histopathological analysis confirmed them to be pseudomembranes over tubular adenomas. The rest of the colonic mucosa was normal and no other cause was demonstrated. We suggest that this particular distribution might be due to a higher affinity for dysplastic cells such as adenomatous polyps of colon by C. difficile and/or its toxins. PMID- 23345959 TI - Anesthetic management of the SRSTM Endoscopic Stapling System for gastro esophageal reflux disease. AB - The SRS(TM) Endoscopic Stapling System (Medigus, Tel Aviv, Israel) is a new tool capable of creating a totally endoscopic fundoplication, combined with an endoscope, endoscopic ultrasound and a surgical stapler. SRS(TM) endoscopic stapling for gastro-esophageal reflux disease is a minimally invasive, outpatient procedure, which requires general anesthesia with positive-pressure ventilation. Keeping the patient on positive end-expiratory pressure (PEEP) may minimize the pressure gradient between the esophagus and the mediastinum, as well as help to prevent air from leaking around the screws and causing pneumomediastinum. In addition, in patients with hiatal hernia, higher PEEP levels may be required to increase intra-thoracic pressure and to force the stomach to slide into the abdomen for ease of endoscopy. We advise smoother emergence from anesthesia, taking precautions for retching, postoperative nausea and vomiting (PONV), while coughing and gagging during extubation and PONV may affect the success of the procedure. Total intravenous anesthesia with propofol and remifentanil seems to be a good choice for these reasons. PMID- 23345960 TI - HIV and reproduction: fertility, contraception, and preconception issues and interventions. PMID- 23345961 TI - Movement of intraretinal fluid from distant branch retinal vein occlusion to the submacular space. AB - BACKGROUND: Extramacular branch retinal vein occlusion (BRVO) occasionally causes serous macular detachment. We studied the movement of extravasated fluid from BRVO lesions to the submacular space. METHODS: We examined nine eyes from nine patients with serous retinal detachment caused by extramacular BRVO. In addition to a comprehensive ophthalmic examination, optical coherence tomography was performed in all nine eyes. Six of the patients also underwent fluorescein angiography. RESULTS: Visual acuity ranged from 0.03 to 0.9 (median 0.5). All nine eyes showed localized macular detachment and retinal edema which extended from the extramacular BRVO to the macula. Fluorescein angiography revealed dye leakage in the extramacular area but no macular leakage in the six eyes examined. Optical coherence tomography revealed serous retinal detachment in the macula and intraretinal swelling, with low reflectivity in the outer retina extending from the distant BRVO toward the detached macula in all nine eyes. Six eyes were treated with laser photocoagulation, covering the entire area of BRVO, and the other three eyes were treated with intravitreal bevacizumab. Serous retinal detachment and retinal swelling resolved within 3 months of treatment in all nine eyes. CONCLUSION: Distant retinal vascular leakage appears to diffuse through the outer retina to the macula, then permeate into the subretinal space. PMID- 23345962 TI - Photoreceptor disruption in central serous chorioretinopathy treated by half-dose photodynamic therapy. AB - BACKGROUND: To evaluate photoreceptor disruption in patients with central serous chorioretinopathy (CSC) treated by half-dose photodynamic therapy (PDT). METHODS: A total of 29 patients with symptomatic CSC were recruited and underwent half dose verteporfin PDT covering the leakage sites as observed via fundus fluorescein angiography. The primary outcome was the percentage of patients with the presence of photoreceptor disruption, and the secondary outcome was the correlation between photoreceptor disruption and visual results at the 1-year follow-up. RESULTS: Photoreceptor disruption was identified in 13 eyes (44.8%) 12 months after treatment. Twenty-seven patients experienced best-corrected visual acuity (BCVA) improvement after PDT, while two patients showed stable BCVA. The mean BCVA in patients with photoreceptor disruption at the baseline and every follow-up visit was significantly lower than that of patients without photoreceptor disruption. However, there was no correlation between the presence or absence of photoreceptor disruption and the improvement of visual acuity because the BCVA gain at the last follow-up visit between the two groups was not significant (P = 0.69). No potential ocular complication was encountered in the study. CONCLUSION: Photoreceptor disruption was found in about 45% of CSC patients treated by PDT, which ultimately resulted in poor visual outcomes. However, a half-dose PDT might not affect or modify the photoreceptor function because it gave the same pattern of visual recovery in patients with and without photoreceptor cell loss. PMID- 23345963 TI - Increased preference of surface ablation over laser in situ keratomileusis between 2008-2011 is correlated to risk of ecatasia. AB - PURPOSE: To evaluate the trends in corneal refractive procedure selection for the correction of myopia, focusing on the relative proportions of laser in situ keratomileusis (LASIK) and surface ablation procedures. METHODS: Only eyes that underwent LASIK or surface ablation for the correction of myopia between 2008 2011 were included in this retrospective study. Additional recorded parameters included patient age, preoperative manifest refraction, corneal thickness, and calculated residual corneal bed thickness. A risk score was given to each eye, based on these parameters, according to the Ectasia Risk Factor Score System (ERFSS), without the preoperative corneal topography. RESULTS: This study included 16,163 eyes, of which 38.4% underwent LASIK and 61.6% underwent surface ablation. The risk score correlated with procedure selection, with LASIK being preferred in eyes with a score of 0 and surface ablation in eyes with a score of 2 or higher. When controlling for age, preoperative manifest refraction, corneal thickness, and all parameters, the relative proportion of surface ablation compared with LASIK was found to have grown significantly during the study period. CONCLUSIONS: Our results indicate that with time, surface ablation tended to be performed more often than LASIK for the correction of myopia in our cohort. Increased awareness of risk factors and preoperative risk assessment tools, such as the ERFSS, have shifted the current practice of refractive surgery from LASIK towards surface ablation despite the former's advantages, especially in cases in which the risk for ectasia is more than minimal (risk score 2 and higher). PMID- 23345964 TI - Diabetic and non-diabetic human cornea and tear gamma-glutamyl transpeptidase activity. AB - BACKGROUND: Diabetes-related eye disease is due in part to oxidative stress. Gamma-glutamyl transpeptidase (GGT) is a gamma-glutamyl cycle enzyme that protects against oxidative stress via glutathione recapture. This study investigates corneal and Schirmer tears GGT activity in diabetic and non-diabetic adults aged 50 to 83 years old. METHODS: GGT activity was determined by colorimetric assay on 50 corneas from 14 diabetic (without keratopathy) and 20 non-diabetic donors and on Schirmer type 1 test strips (no anesthesia) of 14 diabetic and 14 non-diabetic subjects. RESULTS: Type 1 (T1) diabetic cornea GGT activity was 40% lower than Type 2 (T2) diabetic cornea GGT activity (P = 0.04), but GGT activity was similar for corneas (without keratopathy) from diabetic and non-diabetic donors (P >= 0.44 for all). The number of endothelial cells/unit of GGT activity in diabetic corneas was 22% higher (P = 0.1) than in non-diabetic corneas. GGT activity per Schirmer strip and GGT activity per mm of tears were 36% and 50% higher (P <= 0.008 for all) for non-diabetic (tear volume dependent) than diabetic donors (tear volume independent), respectively. GGT activity per mm was 50% lower in T1 than T2 diabetics (P = 0.02). Higher tear GGT activity in non diabetic than diabetic females (P <= 0.05) was due to higher GGT activity in the African American females. CONCLUSION: GGT activity was less in T1 than T2 diabetics, but comparable to non-diabetic corneas. Schirmer tear GGT activity in diabetic eyes was tear volume independent, less in T1 than T2, lower than in tear volume dependent, non-diabetic female eyes. Low cornea and tear GGT activity suggests loss of antioxidant potential and supports ocular antioxidant therapy for diabetic patients. PMID- 23345965 TI - Association of systemic comorbidity in diabetic serous macular detachment and comparison of various combination therapies in its management. AB - BACKGROUND: The purpose of this research was to study the association between systemic comorbidity in diabetic serous macular detachment (DSMD) and the effect of different forms of combination therapies in its management. METHODS: In this prospective analysis, 34 eyes from 34 patients with DSMD were investigated for the presence of systemic comorbidity including anemia, dyslipidemia, nephropathy, and cardiac disease, and treated with combination therapy of either intravitreal bevacizumab + laser (group 1, n = 14) or intravitreal triamcinolone + laser (group 2, n = 20). Sequential macular laser was done 2 weeks after intravitreal pharmacotherapy in both groups. Outcome measures included visual acuity and central foveal thickness at 1 and 3 months. RESULTS: The mean age of the patients was 55.6 +/- 7.6 years. The commonest systemic association was nephropathy (82.3%). In group 1, mean visual acuity improved marginally from 6/17 at baseline to 6/16 at 1 month (P = 0.0001) and was maintained at 3 months (P = 0.008); and mean central foveal thickness decreased from 488.7 MUm to 318.7 MUm at 1 month (P = 0.0001) but increased to 414.4 MUm at 3 months (P = 0.049). In group 2, mean visual acuity improved from 6/22 at baseline to 6/19 at 1 month (P = 0.0001) and 6/12 at 3 months (P = 0.0001); and mean central foveal thickness decreased from 428.8 MUm to 323.8 MUm at 1 month (P = 0.0001) to 269.2 MUm at 3 months (P = 0.0001). CONCLUSION: Nephropathy should be ruled out in patients with DSMD. Although at 1 month both intravitreal triamcinolone and bevacizumab improved vision and decreased central foveal thickness in eyes with DSMD when administered along with focal laser treatment, the former had a more long-lasting effect in maintaining this gain at 3 months. PMID- 23345966 TI - Navigated macular laser decreases retreatment rate for diabetic macular edema: a comparison with conventional macular laser. AB - BACKGROUND: The purpose of this study was to evaluate and compare clinical outcomes and retreatment rates using navigated macular laser versus conventional laser for the treatment of diabetic macular edema (DME). METHODS: In this prospective, interventional pilot study, 46 eyes from 46 consecutive patients with DME were allocated to receive macular laser photocoagulation using navigated laser. Best corrected visual acuity and retreatment rate were evaluated for up to 12 months after treatment. The control group was drawn based on chart review of 119 patients treated by conventional laser at the same institutions during the same time period. Propensity score matching was performed with Stata, based on the nearest-neighbor method. RESULTS: Propensity score matching for age, gender, baseline visual acuity, and number of laser spots yielded 28 matched patients for the control group. Visual acuity after navigated macular laser improved from a mean 0.48 +/- 0.37 logMAR by a mean +2.9 letters after 3 months, while the control group showed a mean -4.0 letters (P = 0.03). After 6 months, navigated laser maintained a mean visual gain of +3.3 letters, and the conventional laser group showed a slower mean increase to +1.9 letters versus baseline. Using Kaplan Meier analysis, the laser retreatment rate showed separation of the survival curves after 2 months, with fewer retreatments in the navigated group than in the conventional laser group during the first 8 months (18% versus 31%, respectively, P = 0.02). CONCLUSION: The short-term results of this pilot study suggest that navigated macular photocoagulation is an effective technique and could be considered as a valid alternative to conventional slit-lamp laser for DME when focal laser photocoagulation is indicated. The observed lower retreatment rates with navigated retinal laser therapy in the first 8 months suggest a more durable treatment effect. PMID- 23345967 TI - Frontal suspension for congenital ptosis using an expanded polytetrafluoroethylene (Gore-Tex((r))) sheet: one-year follow-up. AB - BACKGROUND: The frontalis suspension technique is the surgical method of choice in patients with ptosis and a levator function of 4 mm or less. Several types of materials have been used, including Gore-Tex((r)), which has been used successfully as a frontalis sling material since 1986. Recently, a Gore-Tex sheet (wider than a sling or strip) suspension was reported. This paper reports the results of 27 eyes from 20 patients with congenital ptosis treated using the frontalis suspension technique with the newly developed Gore-Tex Most Versatile Patch (MVP) sheet. METHODS: All patients underwent surgery between April 2007 and September 2011 and were followed up for at least one year. The average follow-up duration was 18 months, with a range of 12-36 months. The average patient age was 45 (5-85) years, and the group included 11 males and nine females. Thirteen cases demonstrated ptosis in one eye, and seven cases involved both eyes. The patients were divided by age into a younger group and an older group. All ptosis procedures were performed using the Gore-Tex MVP sheet. The implant was normally 7 mm wide for adults and 5 mm wide for children. The implantation method was the same as that used for the sheet shape fascia. RESULTS: In all patients, satisfactory functional results were observed at the 6-month follow-up examination. Eyelid opening heights were also obtained. The average marginal reflex distance (MRD) was -0.5 mm preoperatively, which improved to +1.9 mm after surgery. After one year, average MRD was +1.6 mm. MRD attenuation was more frequent in the younger group. There were no cases requiring redo surgery and only one case of exposure. PMID- 23345968 TI - Anterior segment biometry using ultrasound biomicroscopy and the Artemis-2 very high frequency ultrasound scanner. AB - PURPOSE: To compare the precision of anterior chamber angle (ACA) and anterior chamber depth (ACD) measurements taken with ultrasound biomicroscopy (UBM) and the Artemis-2 Very High Frequency Ultrasound Scanner (VHFUS) in normal subjects. DESIGN: Prospective study. METHODS: We randomly selected one eye from each of 59 normal subjects in this study. Two subjects dropped out of the study; the associated data were excluded from analysis. ACA and ACD measurements were obtained using the VHFUS and the UBM. The results were compared statistically using repeated-measures analysis of variance for the intraobserver repeatability, unpaired t-test, and limits of agreement. RESULTS: The average ACA values for the UBM and the VHFUS (+/-standard deviation) were 41.83 degrees +/- 5.03 degrees and 33.36 degrees +/- 6.03 degrees , respectively. The average ACD values were 2.96 +/- 0.34 mm and 2.87 +/- 0.31 mm. The intraobserver repeatability analysis of variance P-values for ACA and ACD measurements using UBM were 0.10 and 0.68, respectively; for the Artemis-2 VHFUS, the respective values were 0.68 and 0.09. The difference in ACA measurements was statistically significant (t = 8.41; P < 0.0001), while the difference in ACD values was not (t = 1.51; P < 0.13). The mean ACA difference was 8.50 degrees +/- 2.50 degrees , and the limits of agreement were +13.30 degrees to -3.60 degrees . The mean ACD difference was 0.09 +/- 0.27 mm, and the limits of agreement ranged from 0.61 mm to -0.43 mm. The mean difference percentage of ACD was 3.1% for both instruments. CONCLUSION: In case of the ACD, both instruments can be used interchangeably; however, with the ACA instruments, they cannot be used interchangeably. PMID- 23345969 TI - Hippuric acid nanocomposite enhances doxorubicin and oxaliplatin-induced cytotoxicity in MDA-MB231, MCF-7 and Caco2 cell lines. AB - BACKGROUND: The aim of the current study is to design a new nanocomposite for inducing cytotoxicity of doxorubicin and oxaliplatin toward MDA-MB231, MCF-7, and Caco2 cell lines. A hippuric acid (HA) zinc layered hydroxide (ZLH) nanocomposite was synthesized under an aqueous environment using HA and zinc oxide (ZnO) as the precursors. METHODS: The hippuric acid nanocomposite (HAN) was prepared by the direct reaction of a HA solution with an aqueous suspension of ZnO. RESULTS: The basal spacing of the nanocomposite was 21.3 A, which is average of four harmonics at 2theta = 8.32 degrees , 12.50 degrees , 16.68 degrees , and 20.84 degrees . This result indicates that the hippurate anion was successfully intercalated into the interlayer space of ZLH. The combinations of HAN with chemotherapy (drugs) has inhibited the cell growth of the MDA-MB231, MCF-7, and Caco2 cancer cells when compared to drugs alone. An IC(50) value for the combination of HAN with doxorubicin toward MCF-7 is 0.19 +/- 0.15 MUg/mL and toward MDA-MB231 is 0.13 +/- 0.10 MUg/mL. Similarly, the IC(50) for the combination of HAN with oxaliplatin toward Caco2 is 0.24 +/- 0.11 MUg/mL. In the antiproliferative results, the equal combination of HAN (0.5 MUg/mL) with doxorubicin (0.5 MUg/mL) has reduced the cell proliferation in MCF-7 and MDA-MB-231 cells into 37.3% and 17.6%, respectively after 24 hours. Similarly, the antiproliferation percentage for equal combination HAN with oxaliplatin (5.00 MUg/mL) toward Caco2 is 72.7% after 24 hours. CONCLUSION: The resulting combination HAN with drugs has exhibited higher inhibition in cells growth in all cancer cell lines. PMID- 23345970 TI - Optimal treatment of actinic keratoses. AB - The most compelling reason and primary goal of treating actinic keratoses is to prevent malignant transformation into invasive squamous cell carcinoma, and although there are well established guidelines outlining treatment modalities and regimens for squamous cell carcinoma, the more commonly encountered precancerous actinic lesions have no such standard. Many options are available with variable success and patient compliance rates. Prevention of these lesions is key, with sun protection being a must in treating aging patients with sun damage as it is never too late to begin protecting the skin. PMID- 23345971 TI - The effect of laser repetition rate on the LASiS synthesis of biocompatible silver nanoparticles in aqueous starch solution. AB - Laser ablation-based nanoparticle synthesis in solution is rapidly becoming popular, particularly for potential biomedical and life science applications. This method promises one pot synthesis and concomitant bio-functionalization, is devoid of toxic chemicals, does not require complicated apparatus, can be combined with natural stabilizers, is directly biocompatible, and has high particle size uniformity. Size control and reduction is generally determined by the laser settings; that the size and size distribution scales with laser fluence is well described. Conversely, the effect of the laser repetition rate on the final nanoparticle product in laser ablation is less well-documented, especially in the presence of stabilizers. Here, the influence of the laser repetition rate during laser ablation synthesis of silver nanoparticles in the presence of starch as a stabilizer was investigated. The increment of the repetition rate does not negatively influence the ablation efficiency, but rather shows increased productivity, causes a red-shift in the plasmon resonance peak of the silver starch nanoparticles, an increase in mean particle size and size distribution, and a distinct lack of agglomerate formation. Optimal results were achieved at 10 Hz repetition rate, with a mean particle size of ~10 nm and a bandwidth of ~6 nm 'full width at half maximum' (FWHM). Stability measurements showed no significant changes in mean particle size or agglomeration or even flocculation. However, zeta potential measurements showed that optimal double layer charge is achieved at 30 Hz. Consequently, Ag-NP synthesis via the laser ablation synthesis in solution (LASiS) method in starch solution seems to be a trade-off between small size and narrow size distributions and inherent and long-term stability. PMID- 23345972 TI - Anti-alphavbeta3 antibody guided three-step pretargeting approach using magnetoliposomes for molecular magnetic resonance imaging of breast cancer angiogenesis. AB - PURPOSE: Pretargeting of biomarkers with nanoparticles in molecular imaging is promising to improve diagnostic specificity and realize signal amplification, but data regarding its targeting potential in magnetic resonance (MR) imaging are limited. The purpose of this study was to evaluate the tumor angiogenesis targeting efficacy of the anti-alphavbeta3 antibody guided three-step pretargeting approach with magnetoliposomes. METHODS: Polyethylene glycol modified and superparamagnetic iron oxide-encapsulated magnetoliposomes with and without biotin were synthesized and characterized. The cytotoxicity of both probes was evaluated using the methyl thiazdyl tetrazolium assay, and their cellular uptake by mouse macrophage was visualized using Prussian blue staining. Three-step pretargeting MR imaging was performed on MDA-MB-435S breast cancer bearing mice by intravenous administration of biotinylated anti-alphavbeta3 monoclonal antibodies (first step), followed by avidin and streptavidin (second step), and by biotinylated magnetoliposomes or magnetoliposomes in the targeted or nontargeted group, respectively (third step). The specificity of alphavbeta3 targeting was assessed by histologic examinations. RESULTS: The developed magnetoliposomes were superparamagnetic and biocompatible as confirmed by cell toxicity assay. The liposomal bilayer and polyethylene glycol modification protected Fe(3)O(4) cores from uptake by macrophage cells. MR imaging by three step pretargeting resulted in a greater signal enhancement along the tumor periphery, occupying 7.0% of the tumor area, compared with 2.0% enhancement of the nontargeted group (P < 0.05). Histologic analysis demonstrated the targeted magnetoliposomes colocalized with neovasculature, which was responsible for the MR signal decrease. CONCLUSION: These results indicate that our strategy for MR imaging of alphavbeta3-integrin is an effective means for sensitive detection of tumor angiogenesis, and may provide a targetable nanodelivery system for anticancer drugs. PMID- 23345973 TI - Effects of a hybrid micro/nanorod topography-modified titanium implant on adhesion and osteogenic differentiation in rat bone marrow mesenchymal stem cells. AB - BACKGROUND AND METHODS: Various methods have been used to modify titanium implant surfaces with the aim of achieving better osseointegration. In this study, we fabricated a clustered nanorod structure on an acid-etched, microstructured titanium plate surface using hydrogen peroxide. We also evaluated biofunctionalization of the hybrid micro/nanorod topography on rat bone marrow mesenchymal stem cells. Scanning electron microscopy and x-ray diffraction were used to investigate the surface topography and phase composition of the modified titanium plate. Rat bone marrow mesenchymal stem cells were cultured and seeded on the plate. The adhesion ability of the cells was then assayed by cell counting at one, 4, and 24 hours after cell seeding, and expression of adhesion-related protein integrin beta1 was detected by immunofluorescence. In addition, a polymerase chain reaction assay, alkaline phosphatase and Alizarin Red S staining assays, and osteopontin and osteocalcin immunofluorescence analyses were used to evaluate the osteogenic differentiation behavior of the cells. RESULTS: The hybrid micro/nanoscale texture formed on the titanium surface enhanced the initial adhesion activity of the rat bone marrow mesenchymal stem cells. Importantly, the hierarchical structure promoted osteogenic differentiation of these cells. CONCLUSION: This study suggests that a hybrid micro/nanorod topography on a titanium surface fabricated by treatment with hydrogen peroxide followed by acid etching might facilitate osseointegration of a titanium implant in vivo. PMID- 23345974 TI - Intracellular delivery of doxorubicin encapsulated in novel pH-responsive chitosan/heparin nanocapsules. AB - A novel polyelectrolyte nanocapsule system composed of biopolymers, chitosan and heparin has been fabricated by the layer-by-layer technique on silica nanoparticles followed by dissolution of the silica core. The nanocapsules were of the size range 200 +/- 20 nm and loaded with the positively charged anticancer drug doxorubicin with an efficiency of 89%. The loading of the drug into the capsule happens by virtue of the pH-responsive property of the capsule wall, which is determined by the pKa of the polyelectrolytes. As the pH is varied, about 64% of the drug is released in acidic pH while 77% is released in neutral pH. The biocompatibility, efficiency of drug loading, and enhanced bioavailability of the capsule system was confirmed by MTT assay and in vivo biodistribution studies. PMID- 23345976 TI - Preparation and characterization of an anti-inflammatory agent based on a zinc layered hydroxide-salicylate nanohybrid and its effect on viability of Vero-3 cells. AB - A new organic-inorganic nanohybrid based on zinc-layered hydroxide intercalated with an anti-inflammatory agent was synthesized through direct reaction of salicylic acid at various concentrations with commercially available zinc oxide. The basal spacing of the pure phase nanohybrid was 15.73 A, with the salicylate anions arranged in a monolayer form and an angle of 57 degrees between the zinc layered hydroxide interlayers. Fourier transform infrared study further confirmed intercalation of salicylate into the interlayers of zinc-layered hydroxide. The loading of salicylate in the nanohybrid was estimated to be around 29.66%, and the nanohybrid exhibited the properties of a mesoporous-type material, with greatly enhanced thermal stability of the salicylate compared with its free counterpart. In vitro cytotoxicity assay revealed that free salicylic acid, pure zinc oxide, and the nanohybrid have a mild effect on viability of African green monkey kidney (Vero-3) cells. PMID- 23345977 TI - Higher lung accumulation of intravenously injected organic nanotubes. AB - The size and shape of intravenously injected particles can affect their biodistribution and is of importance for the development of particulated drug carrier systems. In this study, organic nanotubes (ONTs) with a carboxyl group at the surface, a length of approximately 2 MUm and outer diameter of 70-90 nm, were injected intravenously into tumor-bearing mice. To use ONTs as drug carriers, the biodistribution in selected organs of ONTs postinjection was examined using irinotecan, as an entrapped water-soluble marker inside ONTs, and gadolinium chelated ONT, as an ONT marker, and compared with that of a 3 MUm fluorescently labeled spherical microparticle which was similar size to the length of ONTs. It was found that for irinotecan, its active metabolite and gadolinium-chelated ONTs were highly accumulated in the lung, but to a lower level in the liver and spleen. On the other hand, microparticles deposited less in the lung and more highly in the liver. Moreover, histologic examination showed ONTs distributed more in lung tissues in part, whereas microparticles were present in blood vessels postinjection. These preliminary results support the notion of using negatively charged ONTs as intravascular carriers to maximize accumulation in the lung whilst reducing sequestration by the liver and spleen. This finding suggested that ONTs are potential carriers for lung-targeting drug delivery. PMID- 23345978 TI - Evaluation of gold nanotracers to track adipose-derived stem cells in a PEGylated fibrin gel for dermal tissue engineering applications. AB - Evaluating the regenerative capacity of a tissue-engineered device in a noninvasive and synchronous manner is critical to determining the mechanisms for success in clinical applications. In particular, directly tracking implanted cells in a three-dimensional (3D) scaffold is desirable in that it enables the monitoring of cellular activity in a specific and localized manner. The authors' group has previously demonstrated that the PEGylation of fibrin results in a 3D scaffold that supports morphologic and phenotypic changes in mesenchymal stem cells that may be advantageous in wound healing applications. Recently, the authors have evaluated adipose-derived stem cells (ASCs) as a mesenchymal cell source to regenerate skin and blood vessels due to their potential for proliferation, differentiation, and production of growth factors. However, tracking and monitoring ASCs in a 3D scaffold, such as a PEGylated fibrin gel, have not yet been fully investigated. In the current paper, nanoscale gold spheres (20 nm) as cell tracers for ASCs cultured in a PEGylated fibrin gel were evaluated. An advanced dual-imaging modality combining ultrasound and photoacoustic imaging was utilized to monitor rat ASCs over time. The ASCs took up gold nanotracers and could be detected up to day 16 with high sensitivity using photoacoustic imaging. There were no detrimental effects on ASC morphology, network formation, proliferation, and protein expression/secretion (ie, smooth muscle alpha-actin, vascular endothelial growth factor, matrix metalloproteinase 2, and matrix metalloproteinase-9) associated with gold nanotracers. Therefore, utilization of gold nanotracers can be an effective strategy to monitor the regenerative process of a stem cell source in a 3D gel for vascular and dermal tissue engineering applications. PMID- 23345980 TI - Easy quantitative methodology to assess visual-motor skills. AB - INTRODUCTION: Visual-motor skills are the basis for a great number of daily activities. To define a correct rehabilitation program for neurological patients who have impairment in these skills, there is a need for simple and cost effective tools to determine which of the visual-motor system levels of organization are compromised by neurological lesions. In their 1995 book, The Visual Brain in Action (Oxford: Oxford University Press), AD Milner and MA Goodale proposed the existence of two pathways for the processing of visual information, the "ventral stream" and "dorsal stream," that interact in movement planning and programming. Beginning with this model, our study aimed to validate a method to quantify the role of the ventral and dorsal streams in perceptual and visual-motor skills. SUBJECTS AND METHODS: Nineteen right-handed healthy subjects (mean age 22.8 years +/- 3.18) with normal or corrected-to-normal vision were recruited. We proposed that a delayed pointing task, a distance reproduction task, and a delayed anti-pointing task could be used to assess the ventral stream, while the dorsal stream could be evaluated with a grasping task and an immediate pointing task. Performance was recorded and processed with the video analysis software Dartfish ProSuite. RESULTS: Results showed the expected pattern of predominance of attention for the superior left visual field, predominance of the flexor tone in proximal peri-personal space arm movements, tendency toward overestimation of short distances, and underestimation of long distances. CONCLUSION: We believe that our method is advantageous as it is simple and easily transported, but needs further testing in neurologically compromised patients. PMID- 23345979 TI - Techniques for fabrication and construction of three-dimensional scaffolds for tissue engineering. AB - Three-dimensional biomimetic scaffolds have widespread applications in biomedical tissue engineering because of their nanoscaled architecture, eg, nanofibers and nanopores, similar to the native extracellular matrix. In the conventional "top down" approach, cells are seeded onto a biocompatible and biodegradable scaffold, in which cells are expected to populate in the scaffold and create their own extracellular matrix. The top-down approach based on these scaffolds has successfully engineered thin tissues, including skin, bladder, and cartilage in vitro. However, it is still a challenge to fabricate complex and functional tissues (eg, liver and kidney) due to the lack of vascularization systems and limited diffusion properties of these large biomimetic scaffolds. The emerging "bottom-up" method may hold great potential to address these challenges, and focuses on fabricating microscale tissue building blocks with a specific microarchitecture and assembling these units to engineer larger tissue constructs from the bottom up. In this review, state-of-the-art methods for fabrication of three-dimensional biomimetic scaffolds are presented, and their advantages and drawbacks are discussed. The bottom-up methods used to assemble microscale building blocks (eg, microscale hydrogels) for tissue engineering are also reviewed. Finally, perspectives on future development of the bottom-up approach for tissue engineering are addressed. PMID- 23345981 TI - New and emerging treatments for estrogen receptor-positive breast cancer: focus on everolimus. AB - Management of patients with metastatic hormone receptor-positive breast cancer poses a challenge due to the inevitable development of endocrine resistance. Hormone resistance is associated with a complex interaction of the estrogen receptor with growth factors, transmembrane receptors, and intracellular growth cascades. The PI3K/Akt/mTOR pathway plays a major role in hormone resistance and proliferation of breast cancer. Preclinical and clinical data indicate that inhibitors of human epidermal growth factor receptor-2, epidermal growth factor receptor, insulin-like growth factor-1 receptor, and the mammalian target of rapamycin pathway may act synergistically with hormone therapy to circumvent endocrine resistance. Everolimus is currently approved for combination with exemestane in postmenopausal women with advanced hormone receptor-positive breast cancer. However, we still need to unfold the full potential of targeted agents in the hormone-refractory setting and to identify the subsets of patients who will benefit from combination hormonal therapy using targeted agents. PMID- 23345983 TI - Utility of adjunctive macrolide therapy in treatment of children with asthma: a systematic review and meta-analysis. AB - BACKGROUND: The purpose of this study was to investigate macrolides as an adjunct to an asthma controller regimen in children with asthma. METHODS: Prospective clinical trials of macrolide therapy in children with asthma using outcome measures of change in forced expiratory volume in one second (FEV(1)) and/or oral corticosteroid requirement were searched for in PubMed up to December 2009. The reference lists of studies were also included in the analysis, as well as those listed in published meta-analyses. RESULTS: The literature search yielded 116 studies, six of which were included in this meta-analysis. The change in FEV(1) from baseline with adjunctive use of macrolide therapy in all children was not significant (0.25% predicted; 95% confidence interval [CI] -0.37, 0.86 predicted, P = 0.43); however, the change in FEV(1) among children receiving daily oral corticosteroids was significant (3.89% predicted; 95% CI -0.01, 7.79, P = 0.05). Addition of macrolide therapy to the treatment of children with oral corticosteroid-dependent asthma resulted in a statistically significant decrease in daily corticosteroid dosage (-3.45 mg/day; 95% CI -5.79, -1.09 mg/day, P = 0.004). This reduction in daily corticosteroid dosage was directly proportional to the duration of macrolide therapy (-0.17 mg methylprednisolone per week of macrolide therapy; 95% CI -0.33, -0.021, P = 0.025). CONCLUSION: Addition of macrolides to the treatment regimen of children with oral corticosteroid dependent asthma improves FEV(1) and decreases the daily dosage of corticosteroids required for control in these children. The degree of dose reduction is directly related to the duration of macrolide therapy. Additional large, randomized, placebo-controlled trials of adjunctive macrolide use in children with oral corticosteroid-dependent asthma are required to verify this observation. PMID- 23345984 TI - Estimating the willingness to pay for a quality-adjusted life year in Thailand: does the context of health gain matter? AB - BACKGROUND: This study aims to elicit the value of the willingness to pay (WTP) for a quality-adjusted life year (QALY) and to examine the factors associated with the WTP for a QALY (WTP/QALY) value under the Thai health care setting. METHODS: A community-based survey was conducted among 1191 randomly selected respondents. Each respondent was interviewed face-to-face to elicit his/her health state preference in each of three pairs of health conditions: (1) unilateral and bilateral blindness, (2) paraplegia and quadriplegia, and (3) mild and moderate allergies. A visual analog scale (VAS) and time trade off (TTO) were used as the eliciting methods. Subsequently, the respondents were asked about their WTP for the treatment and prevention of each pair of health conditions by using a bidding-game technique. RESULTS: With regards to treatment, the mean WTP for a QALY value (WTP/QALY(treatment)) estimated by the TTO method ranged from 59,000 to 285,000 baht (16.49 baht = US$1 purchasing power parity [PPP]). In contrast, the mean WTP for a QALY value in terms of prevention (WTP/QALY(prevention)) was significantly lower, ranging from 26,000 to 137,000 baht. Gender, household income, and hypothetical scenarios were also significant factors associated with the WTP/QALY values. CONCLUSION: The WTP/QALY values elicited in this study were approximately 0.4 to 2 times Thailand's 2008 GDP per capita. These values were in line with previous studies conducted in several different settings. This study's findings clearly support the opinion that a single ceiling threshold should not be used for the resource allocation of all types of interventions. PMID- 23345982 TI - Atrial fibrillation and thromboprophylaxis in heart failure: the need for patient centered approaches to address adherence. AB - Atrial fibrillation is a common arrhythmia in heart failure and a risk factor for stroke. Risk assessment tools can assist clinicians with decision making in the allocation of thromboprophylaxis. This review provides an overview of current validated risk assessment tools for atrial fibrillation and emphasizes the importance of tailoring individual risk and the importance of weighing the benefits of treatment. Further, this review provides details of innovative and patient-centered methods for ensuring optimal adherence to prescribed therapy. Prior to initiating oral anticoagulant therapy, a comprehensive risk assessment should include evaluation of associated cardiogeriatric conditions, potential for adherence to prescribed therapy, frailty, and functional and cognitive ability. PMID- 23345985 TI - Thermal waters as cosmeceuticals: La Roche-Posay thermal spring water example. AB - The curative use of thermal spring water is well known, but further investigation of its biological properties and therapeutic benefits is necessary. This present article reports all available scientific data concerning La Roche-Posay Thermal Spring Water and provides a better understanding of the biological mechanism of action of this water in regard to its composition and physicochemical properties and its clinical benefits for patients. These data justify the use of this selenium-rich water as an active or "cosmeceutical" ingredient in topical formulations to increase quality of life and compliance in patients with chronic disease. PMID- 23345986 TI - Assessment of the types of catheter infectivity caused by Candida species and their biofilm formation. First study in an intensive care unit in Algeria. AB - Nosocomial candidiasis remains a potential risk in intensive care units (ICUs), wherein Candida albicans is most responsible for its occurrence. Equally, non-C. albicans species, especially C. glabrata, are also involved. These infections are frequently associated with biofilms that contaminate medical devices, such as catheters. These biofilms constitute a significant clinical problem, and cause therapeutic failures, because they can escape the immune response and considerably decrease sensitivity to antifungal therapy. The diagnosis of catheter-related candidiasis is difficult; however, the differentiation between an infection of the catheter (or other medical implant) and a simple contamination is essential to start an antifungal treatment. Among the methods used for this type of study is the Brun-Buisson method, but this method only examines the infectivity of catheters caused by bacteria. For this reason, we wanted to adapt this method to the yeast cells of Candida spp. To assess the various types of infectivity of catheters (contamination, colonization, or infection) and their corresponding rates, as well as the responsible yeast species, we conducted our study, between February 2011 and January 2012, in the ICU at the University Hospital Center of Sidi Bel Abbes, Algeria; during this study, we took photographic images of the tongue of one patient and of that patient's implanted orobronchial catheter. In addition, catheters contaminated by C. albicans biofilms were observed by scanning electron microscopy. PMID- 23345987 TI - Major stroke in a 19-year-old patient with a univentricular heart. AB - Patients with univentricular heart malformations are at increased risk of suffering from thromboembolic events. We present a case of a 19-year-old woman born with a univentricular heart who suffered a major stroke while being treated with only salicylic acid. At least 20% of patients with univentricular hearts have been reported to experience thromboembolic events, of which 25% are fatal. Despite the high incidence of thromboembolic events, no consensus has been reached regarding the role of long-term anti-thrombotic treatment in this group of patients. This lack of consensus warrants future studies that compare the different therapeutic strategies. PMID- 23345988 TI - Low dose aspirin therapy and renal function in elderly patients. AB - PURPOSE: To determine whether low dose aspirin has any deleterious effects on renal function in elderly patients. METHODS: We conducted a prospective pilot study of 30 Nigerians older than 60 years with various chronic ailments necessitating the use of low dose aspirin. Patients gave their consent, and institutional ethical clearance was obtained. Each patient's baseline samples at enrolment (before commencing aspirin use) served as a control, and subsequent weekly samples were compared. The weekly mean of each parameter was calculated, and the differences of means from baseline were determined, and values were compared for statistical differences with the Statistical Package for the Social Sciences, version 16. RESULTS: We found that a majority of patients (86.67%) had basal renal functions at chronic kidney disease stages 1 and 2. When compared with the corresponding baseline parameters, the mean weekly serum and urinary electrolytes, urea, creatinine, and uric acid parameters did not change, and the P-value did not show any statistical significance. However, there was positive statistical significance for the creatinine clearance (P = 0.025). Also, unlike in previous studies, anemia and hypoalbuminemia did not affect the renal function parameters. CONCLUSION: This study did not show any deleterious effects with short-term, low dose (75 mg daily) aspirin use on kidney functions in elderly patients. However, caution should be exercised when dealing with patients in renal stages 3-5 and the very elderly, aged >= 80 years. PMID- 23345989 TI - Physiologic approach for coronary intervention. AB - When invasively assessing coronary artery disease, the primary goal should be to determine whether the disease is causing a patient's symptoms and whether it is likely to cause future cardiac events. The presence of myocardial ischemia is our best gauge of whether a lesion is responsible for symptoms and likely to result in a future cardiac event. In the catheterization laboratory, fractional flow reserve (FFR) measured with a coronary pressure wire is the reference standard for identifying ischemia-producing lesions. Its spatial resolution is unsurpassed with it not only being vessel-specific, but also lesion-specific. There is now a wealth of data supporting the accuracy of measuring FFR to identify ischemia producing lesions. FFR-guided percutaneous coronary intervention of these lesions results in improved outcomes and saves resources. Non-hemodynamically significant lesions can be safely managed medically with a low rate of subsequent cardiac events. PMID- 23345990 TI - Endoscopic drainage in patients with inoperable hilar cholangiocarcinoma. AB - Hilar cholangiocarcinoma has an extremely poor prognosis and is usually diagnosed at an advanced stage. Palliative management plays an important role in the treatment of patients with inoperable hilar cholangiocarcinoma. Surgical, percutaneous, and endoscopic biliary drainage are three modalities available to resolve obstructive jaundice. Plastic stents were widely used in the past; however, self-expanding metal stents (SEMS) have become popular recently due to their long patency and reduced risk of side branch obstruction, and SEMS are now the accepted treatment of choice for hilar cholangiocarcinoma. Bilateral drainage provides more normal and physiological biliary flow through the biliary ductal system than that of unilateral drainage. Unilateral drainage was preferred until recently because of its technical simplicity. But, with advancements in technology, bilateral drainage now achieves a high success rate and is the preferred treatment modality in many centers. However, the choice of unilateral or bilateral drainage is still controversial, and more studies are needed. This review focuses on the endoscopic method and discusses stent materials and types of procedures for patients with a hilar cholangiocarcinoma. PMID- 23345991 TI - Gender and age differences in obesity among Korean adults. PMID- 23345992 TI - Diastolic dysfunction and chronic kidney disease. PMID- 23345993 TI - Anti-citrullinated protein antibodies in rheumatoid arthritis: a bridge between genetic predisposition and autoimmunity. PMID- 23345994 TI - Gender disparity in the secular trends for obesity prevalence in Korea: analyses based on the KNHANES 1998-2009. AB - BACKGROUND/AIMS: A similar gender-associated trend in obesity is observed worldwide. Nevertheless, systematic analyses of gender-specific characteristics in the general Korean population are rare. METHODS: We analyzed the prevalence of obesity in Korean adults aged >= 19 years based on data collected from the Korea Health and Nutrition Examination Surveys I to IV, and verified the obesity prevalence characteristics by gender. RESULTS: The prevalence of obesity in Korean males increased during the past 12 years from 25.1% to 35.7%, and the trend for an increase in obesity was significant in all age groups (p < 0.001). In contrast, no significant trend over the past 12 years was identified for females, but the prevalence of obesity in the 30- to 39-year, 40- to 49-year, and 50- to 59-year subgroups decreased significantly (p < 0.05). However, the obesity prevalence in the 60- to 69-year and > 70-year female subgroups increased significantly (p < 0.05). CONCLUSIONS: We observed a gradually widening gender disparity due to an increase in the prevalence of male obesity and a decrease in the obesity prevalence among young and middle-aged women. PMID- 23345995 TI - Tissue Doppler-derived E/e' ratio as a parameter for assessing diastolic heart failure and as a predictor of mortality in patients with chronic kidney disease. AB - BACKGROUND/AIMS: Diastolic dysfunction occurs frequently in patients with chronic kidney disease (CKD) and is associated with heart failure (HF) or mortality. We investigated whether the ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (E/e' ratio), estimated using tissue Doppler imaging, has prognostic value for cardiovascular morbidity and all-cause mortality in patients with CKD. METHODS: For 186 patients with CKD of stages III to V, we obtained echocardiograms with tissue Doppler imaging. A 5-year follow-up of 136 patients was performed based on hospital records and telephone interviews. The enrolled patients (79 males and 57 females) were categorized into the following CKD subgroups: stage III (n = 25); stage IV (n = 22); and stage V (n = 89). RESULTS: The average follow-up period was 30.45 months and the mean age of the patients was 61.13 years. The mortality rate after 5 years was 60.0%. The causes of death were: sepsis, 21.9%; HF, 16.2%; and sudden death, 15.2%. Age (p = 0.000), increased C-reactive protein level (p = 0.018), and increased E/e' ratio (p = 0.048) were found to correlate with mortality. Age (p = 0.000), decreased ejection fraction (p = 0.003), and increased E/e' ratio (p = 0.045) correlated with cardiovascular event. CONCLUSIONS: The E/e' ratio can predict mortality and cardiovascular events in patients with CKD who have diastolic dysfunction. PMID- 23345996 TI - Greater prevalence of seropositivity for anti-cyclic citrullinated peptide antibody in unaffected first-degree relatives in multicase rheumatoid arthritis affected families. AB - BACKGROUND/AIMS: This study determined the prevalence and determinants of seropositivity for rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibody, and anti-mutated citrullinated vimentin (anti-MCV) antibody in unaffected first-degree relatives (FDRs) of rheumatoid arthritis (RA) patients. METHODS: A total of 337 subjects (135 with RA and 202 FDRs) were enrolled in this case-control study. Serum RF, anti-CCP antibody, and anti-MCV antibody were assayed. Subjects in multicase families (>= 2 affected FDRs within the same family) were identified. Multivariate logistic regression analysis was used to identify risk factors associated with RA-related autoantibodies. RESULTS: Seropositivity for RF, anti-CCP antibody, or anti-MCV antibody was detected in 14.4%, 5.0%, or 13.4% of unaffected FDRs, respectively. Anti-CCP antibody seropositivity was more prevalent in FDRs in multicase families (17.8%) than in those not in multicase families (1.3%, p < 0.0001). Significant correlations between RA-associated autoantibodies were detected in the FDR group (between RF and anti-CCP antibody: r = 0.366, p < 0.0001; between RF and anti-MCV antibody: r = 0.343, p < 0.0001; and between anti-CCP antibody and anti-MCV antibody: r = 0.849, p < 0.0001). After adjustment for age and sex, anti-CCP antibody seropositivity in FDRs was significantly associated with being in a multicase family (odds ratio, 49.8; 95% confidence interval, 5.6 to 441.6). CONCLUSIONS: The association between anti-CCP antibody seropositivity in unaffected FDRs and being in a multicase family suggests that genetic and/or environmental factors may increase the risk for RA development in unaffected FDRs. PMID- 23345997 TI - Rectal hyposensitivity and functional anorectal outlet obstruction are common entities in patients with functional constipation but are not significantly associated. AB - BACKGROUND/AIMS: The causes of functional anorectal outlet obstruction (outlet obstruction) include functional defecation disorder (FDD), rectocele, and rectal intussusception (RI). It is unclear whether outlet obstruction is associated with rectal hyposensitivity (RH) in patients with functional constipation (FC). The aim of this study was to determine the association between RH and outlet obstruction in patients with FC. METHODS: This was a retrospective study using a prospectively collected constipation database, and the population comprised 107 patients with FC (100 females; median age, 49 years). We performed anorectal manometry, defecography, rectal barostat, and at least two tests (balloon expulsion test, electromyography, or colon transit time study). RH was defined as one or more sensory threshold pressures raised beyond the normal range on rectal barostat. We investigated the association between the presence of RH and an outlet obstruction such as large rectocele (> 2 cm in size), RI, or FDD. RESULTS: Forty patients (37.4%) had RH. No significant difference was observed in RH between patients with small and large rectoceles (22 [44.9%] vs. 18 [31%], respectively; p = 0.140). No significant difference was observed in RH between the non-RI and RI groups (36 [36.7%] vs. 4 [30.8%], respectively; p = 0.599). Furthermore, no significant difference in RH was observed between the non-FDD and FDD groups (19 [35.8%] vs. 21 [38.9%], respectively; p = 0.745). CONCLUSIONS: RH and outlet obstruction are common entities but appear not to be significantly associated. PMID- 23345998 TI - Neck circumference correlates with tumor size and lateral lymph node metastasis in men with small papillary thyroid carcinoma. AB - BACKGROUND/AIMS: Obesity is correlated with numerous diseases, including thyroid cancer, but the clinical significance of obesity with regard to the clinical characteristics of thyroid cancer remains unclear. Neck circumference is an index of upper-body adipose tissue distribution. METHODS: In total, 401 patients with papillary thyroid carcinoma (PTC) measuring <= 2 cm were included. Neck circumference was measured horizontally at the level just below the thyroid cartilage on preoperative neck computed tomographic images. RESULTS: Neck circumference correlated significantly with tumor size in men (p = 0.001) but not in women (p = 0.930). Body mass index (BMI) did not significantly correlate with tumor size in either sex. Neck circumference was significantly larger in men with lateral lymph node (LN) metastasis than in those without (p = 0.004). Neck circumference and BMI did not differ significantly in women according to other factors such as tumor size, multifocality, extrathyroid extension, and LN metastasis. Tumor size and the prevalence of lateral LN metastasis in men tended to increase in the middle/large neck circumference subgroup compared with those in the low neck circumference subgroup. Multivariate logistic regression analysis revealed that neck circumference (p = 0.009) was a predictor for the presence of lateral LN metastasis in men. BMI was not a predictive factor for lateral LN involvement in either sex. CONCLUSIONS: Neck circumference, an indicator of central or visceral obesity but not BMI, may be associated with some prognostic factors in men with small PTC. PMID- 23345999 TI - Clinical outcomes between different stent designs with the same polymer and drug: comparison between the Taxus Express and Taxus Liberte stents. AB - BACKGROUND/AIMS: The Taxus Liberte stent (Boston Scientific Co.) evolved from the Taxus Express stent, with enhanced stent deliverability and uniform drug delivery. This study was designed to compare angiographic and clinical outcomes in real-world practice between the Taxus Liberte and Taxus Express stents. METHODS: Between 2006 and 2008, 240 patients receiving the Taxus Liberte stent at three centers were registered and compared to historical control patients who had received the Taxus Express stent (n = 272). After propensity score matching, 173 patients treated with the Taxus Liberte stent and the same number of patients treated with the Taxus Express stent were selected. The primary outcome was a composite of major adverse cardiac events (MACE), including cardiac death, myocardial infarction (MI), ischemia driven target vessel revascularization (TVR), and stent thrombosis (ST) at 1 year. An additional angiographic assessment was conducted at 9 to 12 months. RESULTS: The study showed no significant difference between the Taxus Express and Taxus Liberte stents (death, 1.73% vs. 2.31%, p = 1.000; MI, 0% vs. 1.73%, p = 0.2478; TVR, 2.31% vs. 1.16%, p = 0.6848; and ST, 0% vs. 1.16%, p = 0.4986). The total MACE rate at 1 year did not differ between the groups (4.05% in Taxus Express vs. 4.05% in Taxus Liberte, p = 1.000). In addition, the binary restenosis rate did not differ (2.25% in Taxus Express vs. 1.80% in Taxus Liberte, p = 0.6848). CONCLUSIONS: In real-world experience with the two Taxus stent designs, both stents showed similarly good clinical and angiographic outcomes at 1 year. A long-term follow-up study is warranted. PMID- 23346000 TI - Analysis of 18F-fluorodeoxyglucose positron emission tomography findings in patients with pituitary lesions. AB - BACKGROUND/AIMS: Although magnetic resonance imaging (MRI) is a good visual modality for the evaluation of pituitary lesions, it has limited value in the diagnosis of mixed nodules and some cystic lesions. We evaluated the usefulness of (18)F-fluorodeoxyglucose positron emission tomography (FDG PET) for patients with pituitary lesions. METHODS: (18)F-FDG PET and MRI were performed simultaneously in 32 consecutive patients with pituitary lesions. The relationships between FDG uptake patterns in PET and MRI findings were analyzed. RESULTS: Of 24 patients with piuitary adenomas, 19 (79.2%) showed increased uptake of (18)F-FDG in the pituitary gland on PET scans. All patients with pituitary macroadenomas showed increased (18)F-FDG uptake on PET scans. Meanwhile, only five (50%) of the 10 patients with pituitary microadenomas showed positive PET scans. Interestingly, of two patients with no abnormal MRI findings, one showed increased (18)F-FDG uptake on PET. For positive (18)F-FDG uptake, maximum standardized uptake values (SUV(max)) > 2.4 had 94.7% sensitivity and 100% specificity. In addition, SUV(max) increased in proportion to the size of pituitary adenomas. Most cystic lesions did not show (18)F-FDG uptake on PET scans. CONCLUSIONS: About 80% of pituitary adenomas showed positivity on PET scans, and SUV(max) was related to the size of the adenomas. PET may be used as an ancillary tool for detection and differentiation of pituitary lesions. PMID- 23346001 TI - A case of papillary fibroelastoma in the left ventricle. AB - Cardiac papillary fibroelastoma (CPF) is a rare and benign primary cardiac neoplasm of unknown prevalence. The incidence of CPF in the left ventricle is lower than that in other parts of the heart. A 65-year-old female was referred to our cardiology department for evaluation of a cardiac mass of the left ventricle. Transthoracic echocardiography revealed a 1.8 * 1.7 cm highly mobile round mass attached by a stalk to the apical inferior wall of the left ventricle with an echolucent area. The mass was successfully removed without any postoperative complications and was identified as a CPF. PMID- 23346002 TI - Mycobacterium avium lung disease combined with a bronchogenic cyst in an immunocompetent young adult. AB - We report a very rare case of a bronchogenic cyst combined with nontuberculous mycobacterial pulmonary disease in an immunocompetent patient. A 21-year-old male was referred to our institution because of a cough, fever, and worsening of abnormalities on his chest radiograph, despite anti-tuberculosis treatment. Computed tomography of the chest showed a large multi-cystic mass over the right upper lobe. Pathological examination of the excised lobe showed a bronchogenic cyst combined with a destructive cavitary lesion with granulomatous inflammation. Microbiological culture of sputum and lung tissue yielded Mycobacterium avium. The patient was administered anti-mycobacterial treatment that included clarithromycin. PMID- 23346003 TI - Type B insulin-resistance syndrome presenting as autoimmune hypoglycemia, associated with systemic lupus erythematosus and interstitial lung disease. AB - We describe an unusual case of systemic lupus erythematosus with pulmonary manifestations presenting as hypoglycemia due to anti-insulin receptor antibodies. A 38-year-old female suffered an episode of unconsciousness and was admitted to hospital where her blood glucose was found to be 18 mg/dL. During the hypoglycemic episode, her serum insulin level was inappropriately high (2,207.1 pmol/L; normal range, 18 to 173) and C-peptide level was elevated (1.7 nmol/L; normal range, 0.37 to 1.47). Further blood tests revealed the presence of antinuclear antibodies, anti-double-stranded DNA antibodies, and anti-Ro/SSA, anti-La/SSB, anti-ribonucleoprotein, and anti-insulin receptor antibodies. A computed tomography scan of the abdomen, aimed at tumor localization, such as an insulinoma, instead revealed ground-glass opacities in both lower lungs, and no abnormal finding in the abdomen. For a definitive diagnosis of the lung lesion, video-associated thoracoscopic surgery was performed and histopathological findings showed a pattern of fibrotic non-specific interstitial pneumonia. PMID- 23346004 TI - Tuberculosis of the urachal cyst. AB - Urachal cysts are uncommon. Rarely, these cysts can become infected. Tuberculosis of the urachal cyst is exceedingly rare, with only one case reported previously in the English language literature. Here we report the case of a 23-year-old male who presented with an infra-umbilical mass that turned out to be tuberculosis of the urachal cyst. PMID- 23346005 TI - Ramosetron might be useful for treating diabetic diarrhea with a rapid small bowel transit time. PMID- 23346006 TI - Zotarolimus-eluting stent-induced hypersensitivity pneumonitis. PMID- 23346007 TI - Pulmonary thromboembolism due to severe hyperhomocysteinemia associated with a methyltetrahydrofolate reductase mutation. PMID- 23346008 TI - Migration of a sirolimus-eluting stent from the ostium of the left main coronary artery to the right deep femoral artery. PMID- 23346009 TI - Contact dermatitis caused by ambulatory blood pressure monitoring. PMID- 23346011 TI - Soft tissue sarcoma: new paradigms in care. PMID- 23346010 TI - Trismus in cephalic tetanus from a foot injury. PMID- 23346012 TI - Advances in bronchoscopy for lung cancer. AB - Bronchoscopic techniques have seen significant advances in the last decade. The development and refinement of different types of endobronchial ultrasound and navigation systems have led to improved diagnostic yield and lung cancer staging capabilities. The complication rate of these minimally invasive procedures is extremely low as compared to traditional transthoracic needle biopsy and surgical sampling. These advances augment the safe array of methods utilized in the work up and management algorithms of lung cancer. PMID- 23346013 TI - Hope for progress after 40 years of futility? Novel approaches in the treatment of advanced stage III and IV non-small-cell-lung cancer: Stereotactic body radiation therapy, mediastinal lymphadenectomy, and novel systemic therapy. AB - Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer mortality. The majority of patients present with advanced (stage III-IV) disease. Such patients are treated with a variety of therapies including surgery, radiation, and chemotherapy. Despite decades of work, however, overall survival in this group has been resistant to any substantial improvement. This review briefly details the evolution to the current standard of care for advanced NSCLC, advances in systemic therapy, and novel techniques (stereotactic body radiation therapy [SBRT], and transcervical extended mediastinal lymphadenectomy [TEMLA] or video-assisted mediastinal lymphadenectomy [VAMLA]) that have been used in localized NSCLC. The utility of these techniques in advanced stage therapy and potential methods of combining these novel techniques with systemic therapy to improve survival are discussed. PMID- 23346014 TI - Advances in lung cancer surgery. AB - The last few years have witnessed an explosion of the use of minimally invasive techniques for the detection, diagnosis, and treatment of all stages of lung Cancer. The use of these techniques has improved the risk-benefit ratio of surgery and has made it more acceptable to patients considering lung surgery. They have also facilitated the delivery of multi-modality therapy to patients with advanced lung cancer. This review article summarizes current surgical techniques that represent the "cutting edge" of thoracic surgery for lung cancer. PMID- 23346015 TI - Potentials and limitations of real-time elastography for prostate cancer detection: a whole-mount step section analysis. AB - OBJECTIVES: To evaluate prostate cancer (PCa) detection rates of real-time elastography (RTE) in dependence of tumor size, tumor volume, localization and histological type. MATERIALS AND METHODS: Thirdy-nine patients with biopsy proven PCa underwent RTE before radical prostatectomy (RPE) to assess prostate tissue elasticity, and hard lesions were considered suspicious for PCa. After RPE, the prostates were prepared as whole-mount step sections and were compared with imaging findings for analyzing PCa detection rates. RESULTS: RTE detected 6/62 cancer lesions with a maximum diameter of 0-5 mm (9.7%), 10/37 with a maximum diameter of 6-10 mm (27%), 24/34 with a maximum diameter of 11-20 20 mm (70.6%), 14/14 with a maximum diameter of >20 mm (100%) and 40/48 with a volume >=0.2 cm(3) (83.3%). Regarding cancer lesions with a volume >= 0.2 cm3 there was a significant difference in PCa detection rates between Gleason scores with predominant Gleason pattern 3 compared to those with predominant Gleason pattern 4 or 5 (75% versus 100%; P = 0.028). CONCLUSIONS: RTE is able to detect PCa of significant tumor volume and of predominant Gleason pattern 4 or 5 with high confidence, but is of limited value in the detection of small cancer lesions. PMID- 23346016 TI - Sorafenib inhibits tumor growth and improves survival in a transgenic mouse model of pancreatic islet cell tumors. AB - BACKGROUND: The purpose of the study was to evaluate Sorafenib (BAY 43-9006) derived receptor tyrosine kinase inhibition on tumor progression in murine islet cell tumors. Sorafenib is considered to be a potent inhibitor of tumor angiogenesis and neovascularization in various solid tumors. Rip1Tag2 mice were treated in two different groups according to the model of tumor progression: the early treatment group received vehicle or Sorafenib from 10 to 14 weeks of age and the late treatment group from week 12 until death. Tumor surface, tumor cell proliferation, and apoptosis were measured in both treatment groups to assess the in vivo effects of Sorafenib. Survival was recorded for the late treatment group. In the early treatment group Sorafenib led to a dramatic decrease in tumor volume compared to the control group. Apoptosis was significantly augmented and cell proliferation was inhibited. As a single therapy Sorafenib significantly improved survival in the late treatment group. Conclusion. Sorafenib may provide a new paradigm for the therapy of islet cell tumors. PMID- 23346017 TI - Actinobaculum suis detection using polymerase chain reaction. AB - Actinobaculum suis is an important agent related to urinary infection in swine females. Due to its fastidious growth characteristics, the isolation of this anaerobic bacterium is difficult, thus impairing the estimation of its prevalence. The purpose of this study was to develop and test a polymerase chain reaction (PCR) for the detection and identification of A. suis and then compare these results with traditional isolation methods. Bacterial isolation and PCR were performed on one hundred and ninety-two urine samples from sows and forty five preputial swabs from boars. The results indicate that this PCR was specific for A. suis, presenting a detection limit between 1.0 * 10(1) CFU/mL and 1.0 * 10(2) CFU/mL. A. suis frequencies, as measured by PCR, were 8.9% (17/192) in sow urine samples and 82.2% (37/45) in preputial swabs. Assessed using conventional culturing techniques, none of the urine samples were positive for A. suis; however, A. suis was detected in 31.1% (14/45) of the swabs. This PCR technique was shown to be an efficient method for the detection of A. suis in urine and preputial swabs. PMID- 23346018 TI - Influence of healthcare-associated factors on the efficacy of hepatitis C therapy. AB - Hepatitis C infection is a complex entity associated with sizable morbidity and mortality, with great social and economic consequences that put a heavy potential burden on healthcare systems allover the world. Despite the great improvement of hepatitis C virus (HCV) therapy and its high clinical efficacy, major influencing factors are still hindering and diminishing the effectiveness of hepatitis C treatment. This minimizes the quality of life of the infected patients and reduces the outcome of such therapy, particularly in certain groups of patients such as intravenous drug users and patients coinfected with human immune deficiency virus (HIV). A variety of factors were evolved either at patient individual level, healthcare providers, community surrounding levels, or healthcare setting systems. Analyzing and understanding these factors could help to improve HCV interventions and, thus, reduce the burden of such infection. The objectives of this paper were to highlight such factors and outline the holistic approaches that could be used to overcome such factors. PMID- 23346019 TI - HCHs and DDTs in soils around Guanting Reservoir in Beijing, China: spatial temporal variation and countermeasures. AB - The concentrations of hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethanes (DDTs) in the topsoil samples around the Guanting Reservoir in Beijing were measured, and their spatial distribution and environmental risks were analyzed by GIS. The results showed that in 2003, 2007, and 2009, the HCHs concentrations were 0.66, 0.85, and 0.73 ng/g, and the DDTs concentrations were 9.50, 7.80, and 6.46 ng/g in the studied area, respectively. In the topsoil, the HCHs concentrations did not change much while the DDTs concentrations declined steadily. Most of the current residues in soil come from the POPs used in the past years but some new input is also detected in certain regions. The level of HCHs and DDTs residues in the south reservoir is lower than that in the north reservoir. The middle region has the highest HCHs and DDTs concentrations, especially near the Beixinpu town. The high risk regions of pollution of HCHs and DDTs are mainly distributed in the vicinity of Beixinpu town as well. Based on the aforementioned results, a comprehensive countermeasure is proposed entailing decision making, local implementation, scientific support, and public participation with regard to the long-term control and management of POPs around the Guanting Reservoir. PMID- 23346020 TI - "Recovery came first": desistance versus recovery in the criminal careers of drug using offenders. AB - The aim of our paper is to gain insight in the desistance process of drug-using offenders. We explore the components of change in the desistance process of drug using offenders by using the cognitive transformation theory of Giordano et al. as a theoretical framework. The desistance process of drug-using offenders entails a two-fold process: desistance of criminal offending and recovery. The results however indicate that desistance is subordinate to recovery because of the fact that drug-using offenders especially see themselves as drug users and not as "criminals." Their first goal was to start recovery from drug use. They were convinced that recovery from drug use would lead them to a stop in their offending. In the discussion, we explore the implications of this result for further research. PMID- 23346021 TI - Chronic-alcohol-abuse-induced oxidative stress in the development of acute respiratory distress syndrome. AB - Chronic alcohol ingestion increases the risk of developing acute respiratory distress syndrome (ARDS), a severe form of acute lung injury, characterized by alveolar epithelial and endothelial barrier disruption and intense inflammation. Alcohol abuse is also associated with a higher incidence of sepsis or pneumonia resulting in a higher rate of admittance to intensive care, longer inpatient stays, higher healthcare costs, and a 2-4 times greater mortality rate. Chronic alcohol ingestion induced severe oxidative stress associated with increased ROS generation, depletion of the critical antioxidant glutathione (GSH), and oxidation of the thiol/disulfide redox potential in the alveolar epithelial lining fluid and exhaled breath condensate. Across intracellular and extracellular GSH pools in alveolar type II cells and alveolar macrophages, chronic alcohol ingestion consistently induced a 40-60 mV oxidation of GSH/GSSG suggesting that the redox potentials of different alveolar GSH pools are in equilibrium. Alcohol-induced GSH depletion or oxidation was associated with impaired functions of alveolar type II cells and alveolar macrophages but could be reversed by restoring GSH pools in the alveolar lining fluid. The aims of this paper are to address the mechanisms for alcohol-induced GSH depletion and oxidation and the subsequent effects in alveolar barrier integrity, modulation of the immune response, and apoptosis. PMID- 23346022 TI - VATS lobectomy: surgical evolution from conventional VATS to uniportal approach. AB - There is no standardized technique for the VATS lobectomy, though most centres use 2 ports and add a utility incision. However, the procedure can be performed by eliminating the two small ports and using only the utility incision with similar outcomes. Since 2010, when the uniportal approach was introduced for major pulmonary resection, the technique has been spreading worldwide. The single port technique provides a direct view to the target tissue. The conventional triple port triangulation creates a new optical plane with genesis of dihedral or torsional angle that is not favorable with standard two-dimension monitors. The parallel instrumentation achieved during single-port approach mimics inside the maneuvers performed during open surgery. Furthermore, it represents the less invasive approach possible, and avoiding the use of trocar, we minimize the compression of the intercostal nerve. Further development of new technologies like sealing devices for all vessels and fissure, robotic arms that open inside the thorax, and wireless cameras will facilitate the uniportal approach to become the standard surgical procedure for pulmonary resection in most thoracic departments. PMID- 23346023 TI - Informal and formal supports for former child soldiers in Northern Uganda. AB - This study aimed to evaluate the potential contribution of informal community initiatives and formal interventions in support of former child soldiers' resilience in the wake of armed conflict. Using a cross-sectional survey design, a stratified random sample of 330 formerly recruited and 677 nonrecruited young people was consulted about their perspective on desirable support for former child soldiers provided by close support figures, communities, humanitarian organizations, and governments. Data analysis occurred by conducting qualitative thematic analysis and statistical chi-square analysis to explore clusters, similarities, and variations in reported support across the different "agents," hereby comparing the perspectives of formerly recruited and non-recruited participants. The results indicated that formerly recruited and non-recruited participants had comparable perspectives that call for the contribution of various informal and formal support systems to former child soldiers' human capacities and the communal sociocultural fabric of war-affected societies. This highlights the importance of community-based, collective, and comprehensive support of formerly recruited young people and their surroundings in the aftermath of armed conflict. PMID- 23346024 TI - Fate and transport of polycyclic aromatic hydrocarbons in upland irish headwater lake catchments. AB - Polycyclic aromatic hydrocarbons (PAHs) are a concern due to their carcinogenicity and propensity for transboundary atmospheric transport. Ireland is located on the western periphery of Europe and assumed to receive clean Atlantic air. As such, it has been used as an atmospheric reference for comparison to other regions. Nonetheless, few studies have evaluated concentrations of PAHs within the Irish environment. In the current study, PAHs were measured at five upland (500-800 masl) headwater lake catchments in coastal regions around Ireland, remote from industrial point source emissions. Semipermeable membrane devices were deployed in lakes for a 6-month period in July 2009, and topsoils were sampled from each catchment during October 2010. The concentrations of PAHs were low at most study sites with respect to other temperate regions. Homologue groups partitioned between lake and soil compartments based on their molecular weight were: "lighter" substances, such as Phenanthrene and Fluorene, were found in higher proportions in lakes, whereas "heavier" compounds, such as Chrysene and Benz[a]anthracene, were more prominent in soils. Concentrations of PAHs were highest at the east coast sites, potentially due to contributions from historical transboundary and regional combustion sources. PMID- 23346025 TI - Predicting Outcomes and Tailoring Therapy in the Diagnosis and Treatment of IBD. AB - Standard laboratory indicators of inflammation such as erythrocyte sedimentation rate and C-reactive protein are of little value in the diagnosis of inflammatory bowel disease. Serologic markers for anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies have been available for some time but are not sufficiently specific or sensitive for use in first-line screening. The second- and third-generation serologic panels have increased sensitivity and specificity, and the addition of assays for anti-outer membrane porin protein C immunoglobulin A and anti-CBir1 have led to the identification of unique subsets of Crohn's disease patients at risk for more complicated and severe forms of disease. This may prove useful in determining whether early aggressive therapy is warranted. Tests are also available for genotyping patients before starting azathioprine and for monitoring clinical response once the patients are receiving the immunomodulator. For patients on anti-tumor necrosis factor-alfa therapy, a dual test measuring serum levels of infliximab and antibodies against infliximab can aid physicians in determining dose and infusion intervals, as well as alert them to the possibility of infusion reactions and/or a reduced duration of efficacy. PMID- 23346026 TI - Reflections on leadership. AB - Webster's dictionary offers numerous synonyms and related words for the word lead; the list includes words such as chief, commanding, first, foremost, high, preeminent, controlling, directing, reigning, sovereign, and superior. Some individuals (perhaps too many) in positions of authority rely very heavily on characteristics associated with these terms. Abusive leaders exploit their power and "lead" through intimidation and their ability to withhold rewards and distribute punishment. This article explores why some people are bad bosses and suggests six obligations of leaders who aspire to fulfilling the role of leadership done right. PMID- 23346027 TI - Leading by design. AB - Leaders have the responsibility to develop leadership in their departmental members. Leadership capacity is needed so that health information professionals will be able to successfully respond to the constant changes in the healthcare environment. This article demonstrates how leadership can be modeled and developed through the redesign of jobs in departments of health information services. PMID- 23346028 TI - Code of ethics: principles for ethical leadership. AB - The code of ethics for a professional association incorporates values, principles, and professional standards. A review and comparative analysis of a 1934 pledge and codes of ethics from 1957, 1977, 1988, 1998, 2004, and 2011 for a health information management association was conducted. Highlights of some changes in the healthcare delivery system are identified as a general context for the codes of ethics. The codes of ethics are examined in terms of professional values and changes in the language used to express the principles of the various codes. PMID- 23346029 TI - Breaking the glass ceiling: structural, cultural, and organizational barriers preventing women from achieving senior and executive positions. AB - The business case for gender diversity in senior and executive positions is compelling. Studies show that companies that have the best records for promoting women outstrip their competition on every measure of profitability. Yet women disproportionately are failing to attain high-level positions. Reviewing current data on women in the workplace, findings of studies on the relationship between gender diversity in senior management and company performance, and the literature on gender behavioral differences and the workplace, this article explores the possible reasons for the persistent wage and gender gap between women and men in senior leadership positions and discusses possible remedies. PMID- 23346030 TI - Leadership's role in support of online academic programs: implementing an administrative support matrix. AB - The proliferation of online education programs creates a myriad of challenges for those charged with implementation and delivery of these programs. Although creating and sustaining quality education is a shared responsibility of faculty, staff, and academic leaders, this article focuses on the pivotal role of leadership in securing the necessary resources, developing the organizational structures, and influencing organizational culture. The vital foundation for a successful outcome when implementing online education programs is the role of leadership in providing adequate and appropriate support. Abundant literature extols the roles of leadership in project management; however, there is a dearth of models or systematic methods for leaders to follow regarding how to implement and sustain online programs. Research conducted by the authors culminated in the development of an Administrative Support Matrix, thus addressing the current gap in the literature. PMID- 23346031 TI - Editor's Introduction to This Issue. PMID- 23346032 TI - Application of whole exome sequencing to identify disease-causing variants in inherited human diseases. AB - The recent advent of next-generation sequencing technologies has dramatically changed the nature of biomedical research. Human genetics is no exception-it has never been easier to interrogate human patient genomes at the nucleotide level to identify disease-associated variants. To further facilitate the efficiency of this approach, whole exome sequencing (WES) was first developed in 2009. Over the past three years, multiple groups have demonstrated the power of WES through robust disease-associated variant discoveries across a diverse spectrum of human diseases. Here, we review the application of WES to different types of inherited human diseases and discuss analytical challenges and possible solutions, with the aim of providing a practical guide for the effective use of this technology. PMID- 23346033 TI - A short history of the genome-wide association study: where we were and where we are going. AB - Recent rapid advances in genetic research are ushering us into the genome sequence era, where an individual's genome information is utilized for clinical practice. The most spectacular results of the human genome study have been provided by genome-wide association studies (GWASs). This is a review of the history of GWASs as related to my work. Further efforts are necessary to make full use of its potential power to medicine. PMID- 23346034 TI - Transposable Elements: No More 'Junk DNA'. AB - Since the advent of whole-genome sequencing, transposable elements (TEs), just thought to be 'junk' DNA, have been noticed because of their numerous copies in various eukaryotic genomes. Many studies about TEs have been conducted to discover their functions in their host genomes. Based on the results of those studies, it has been generally accepted that they have a function to cause genomic and genetic variations. However, their infinite functions are not fully elucidated. Through various mechanisms, including de novo TE insertions, TE insertion-mediated deletions, and recombination events, they manipulate their host genomes. In this review, we focus on Alu, L1, human endogenous retrovirus, and short interspersed element/variable number of tandem repeats/Alu (SVA) elements and discuss how they have affected primate genomes, especially the human and chimpanzee genomes, since their divergence. PMID- 23346035 TI - Understanding Disease Susceptibility through Population Genomics. AB - Genetic epidemiology studies have established that the natural variation of gene expression profiles is heritable and has genetic bases. A number of proximal and remote DNA variations, known as expression quantitative trait loci (eQTLs), that are associated with the expression phenotypes have been identified, first in Epstein-Barr virus-transformed lymphoblastoid cell lines and later expanded to other cell and tissue types. Integration of the eQTL information and the network analysis of transcription modules may lead to a better understanding of gene expression regulation. As these network modules have relevance to biological or disease pathways, these findings may be useful in predicting disease susceptibility. PMID- 23346036 TI - Finding genetic risk factors of gestational diabetes. AB - Gestational diabetes mellitus (GDM) is a complex metabolic disorder of pregnancy that is suspected to have a strong genetic predisposition. It is associated with poor perinatal outcome, and both GDM women and their offspring are at increased risk of future development of type 2 diabetes mellitus (T2DM). During the past several years, there has been progress in finding the genetic risk factors of GDM in relation to T2DM. Some of the genetic variants that were proven to be significantly associated with T2DM are also genetic risk factors of GDM. Recently, a genome-wide association study of GDM was performed and reported that genetic variants in CDKAL1 and MTNR1B were associated with GDM at a genome-wide significance level. Current investigations using next-generation sequencing will improve our insight into the pathophysiology of GDM. It would be important to know whether genetic information revealed from these studies could improve our prediction of GDM and the future development of T2DM. We hope further research on the genetics of GDM would ultimately lead us to personalized genomic medicine and improved patient care. PMID- 23346037 TI - Association analysis of reactive oxygen species-hypertension genes discovered by literature mining. AB - Oxidative stress, which results in an excessive product of reactive oxygen species (ROS), is one of the fundamental mechanisms of the development of hypertension. In the vascular system, ROS have physical and pathophysiological roles in vascular remodeling and endothelial dysfunction. In this study, ROS hypertension-related genes were collected by the biological literature-mining tools, such as SciMiner and gene2pubmed, in order to identify the genes that would cause hypertension through ROS. Further, single nucleotide polymorphisms (SNPs) located within these gene regions were examined statistically for their association with hypertension in 6,419 Korean individuals, and pathway enrichment analysis using the associated genes was performed. The 2,945 SNPs of 237 ROS hypertension genes were analyzed, and 68 genes were significantly associated with hypertension (p < 0.05). The most significant SNP was rs2889611 within MAPK8 (p = 2.70 * 10(-5); odds ratio, 0.82; confidence interval, 0.75 to 0.90). This study demonstrates that a text mining approach combined with association analysis may be useful to identify the candidate genes that cause hypertension through ROS or oxidative stress. PMID- 23346038 TI - A fosmid cloning strategy for detecting the widest possible spectrum of microbes from the international space station drinking water system. AB - In this study, fosmid cloning strategies were used to assess the microbial populations in water from the International Space Station (ISS) drinking water system (henceforth referred to as Prebiocide and Tank A water samples). The goals of this study were: to compare the sensitivity of the fosmid cloning strategy with that of traditional culture-based and 16S rRNA-based approaches and to detect the widest possible spectrum of microbial populations during the water purification process. Initially, microbes could not be cultivated, and conventional PCR failed to amplify 16S rDNA fragments from these low biomass samples. Therefore, randomly primed rolling-circle amplification was used to amplify any DNA that might be present in the samples, followed by size selection by using pulsed-field gel electrophoresis. The amplified high-molecular-weight DNA from both samples was cloned into fosmid vectors. Several hundred clones were randomly selected for sequencing, followed by Blastn/Blastx searches. Sequences encoding specific genes from Burkholderia, a species abundant in the soil and groundwater, were found in both samples. Bradyrhizobium and Mesorhizobium, which belong to rhizobia, a large community of nitrogen fixers often found in association with plant roots, were present in the Prebiocide samples. Ralstonia, which is prevalent in soils with a high heavy metal content, was detected in the Tank A samples. The detection of many unidentified sequences suggests the presence of potentially novel microbial fingerprints. The bacterial diversity detected in this pilot study using a fosmid vector approach was higher than that detected by conventional 16S rRNA gene sequencing. PMID- 23346039 TI - Network graph analysis of gene-gene interactions in genome-wide association study data. AB - Most common complex traits, such as obesity, hypertension, diabetes, and cancers, are known to be associated with multiple genes, environmental factors, and their epistasis. Recently, the development of advanced genotyping technologies has allowed us to perform genome-wide association studies (GWASs). For detecting the effects of multiple genes on complex traits, many approaches have been proposed for GWASs. Multifactor dimensionality reduction (MDR) is one of the powerful and efficient methods for detecting high-order gene-gene (GxG) interactions. However, the biological interpretation of GxG interactions identified by MDR analysis is not easy. In order to aid the interpretation of MDR results, we propose a network graph analysis to elucidate the meaning of identified GxG interactions. The proposed network graph analysis consists of three steps. The first step is for performing GxG interaction analysis using MDR analysis. The second step is to draw the network graph using the MDR result. The third step is to provide biological evidence of the identified GxG interaction using external biological databases. The proposed method was applied to Korean Association Resource (KARE) data, containing 8838 individuals with 327,632 single-nucleotide polymorphisms, in order to perform GxG interaction analysis of body mass index (BMI). Our network graph analysis successfully showed that many identified GxG interactions have known biological evidence related to BMI. We expect that our network graph analysis will be helpful to interpret the biological meaning of GxG interactions. PMID- 23346041 TI - Developing JSequitur to Study the Hierarchical Structure of Biological Sequences in a Grammatical Inference Framework of String Compression Algorithms. AB - Grammatical inference methods are expected to find grammatical structures hidden in biological sequences. One hopes that studies of grammar serve as an appropriate tool for theory formation. Thus, we have developed JSequitur for automatically generating the grammatical structure of biological sequences in an inference framework of string compression algorithms. Our original motivation was to find any grammatical traits of several cancer genes that can be detected by string compression algorithms. Through this research, we could not find any meaningful unique traits of the cancer genes yet, but we could observe some interesting traits in regards to the relationship among gene length, similarity of sequences, the patterns of the generated grammar, and compression rate. PMID- 23346040 TI - QCanvas: An Advanced Tool for Data Clustering and Visualization of Genomics Data. AB - We developed a user-friendly, interactive program to simultaneously cluster and visualize omics data, such as DNA and protein array profiles. This program provides diverse algorithms for the hierarchical clustering of two-dimensional data. The clustering results can be interactively visualized and optimized on a heatmap. The present tool does not require any prior knowledge of scripting languages to carry out the data clustering and visualization. Furthermore, the heatmaps allow the selective display of data points satisfying user-defined criteria. For example, a clustered heatmap of experimental values can be differentially visualized based on statistical values, such as p-values. Including diverse menu-based display options, QCanvas provides a convenient graphical user interface for pattern analysis and visualization with high-quality graphics. PMID- 23346042 TI - Preliminary Study of Bioinformatics Patents and Their Classifications Registered in the KIPRIS Database. AB - Whereas a vast amount of new information on bioinformatics is made available to the public through patents, only a small set of patents are cited in academic papers. A detailed analysis of registered bioinformatics patents, using the existing patent search system, can provide valuable information links between science and technology. However, it is extremely difficult to select keywords to capture bioinformatics patents, reflecting the convergence of several underlying technologies. No single word or even several words are sufficient to identify such patents. The analysis of patent subclasses can provide valuable information. In this paper, I did a preliminary study of the current status of bioinformatics patents and their International Patent Classification (IPC) groups registered in the Korea Intellectual Property Rights Information Service (KIPRIS) database. PMID- 23346043 TI - Aspects of vulnerable patients and informed consent in clinical trials. AB - SCOPE: To discuss the rationale behind informed consent in clinical trials focusing on vulnerable patients from a European and German viewpoint. METHODS: Scientific literature search via PubMed, Medline, Google. RESULTS: Voluntary informed consent is the cornerstone of policies regulating clinical trials. To enroll a patient into a clinical trial without having obtained written and signed consent is to be considered as a serious issue in the conduct of a clinical trial. Development of ethical guidance for physicians started before Christ Era with the Hippocratic Oath. Main function of consent, as articulated in all guidelines developed for clinical research, is to facilitate an individual's freedom of choice, respect autonomy, and thus to ensure welfare of the participants in clinical trials. Minors are unable to provide legally binding informed consent, this issue is addressed through a combination of parental permission and minor's assent. Illiteracy is a critical problem that affects all corners of our earth; it has no boundaries and exists among every race and ethnicity, age group, and economic class. New strategies to improve communication with patients including the use of videotapes or animated cartoon illustrations could be taught. Finally the time with the potential participant seems to be the best way to improve understanding. CONCLUSION: Discovery of life saving and life enhancing new treatments requires partnership that is based on good communication and trust between patients and researchers, sponsors, ethics committees, authorities, lawyers and politicians so that vulnerable patients can benefit from the results of well controlled clinical trials. PMID- 23346045 TI - Action of Neurotransmitter: A Key to Unlock the AgRP Neuron Feeding Circuit. AB - The current obesity epidemic and lack of efficient therapeutics demand a clear understanding of the mechanism underlying body weight regulation. Despite intensive research focus on obesity pathogenesis, an effective therapeutic strategy to treat and cure obesity is still lacking. Exciting studies in last decades have established the importance of hypothalamic agouti-related protein expressing neurons (AgRP neurons) in the regulation of body weight homeostasis. AgRP neurons are both required and sufficient for feeding regulation. The activity of AgRP neurons is intricately regulated by nutritional hormones as well as synaptic inputs from upstream neurons. Changes in AgRP neuron activity lead to alterations in the release of mediators, including neuropeptides Neuropeptide Y (NPY) and AgRP, and fast-acting neurotransmitter GABA. Recent studies based on mouse genetics, novel optogenetics, and designer receptor exclusively activated by designer drugs have identified a critical role for GABA release from AgRP neurons in the parabrachial nucleus and paraventricular hypothalamus in feeding control. This review will summarize recent findings about AgRP neuron-mediated control of feeding circuits with a focus on the role of neurotransmitters. Given the limited knowledge on feeding regulation, understanding the action of neurotransmitters may be a key to unlock neurocircuitry that governs feeding. PMID- 23346044 TI - Satiation and stress-induced hypophagia: examining the role of hindbrain neurons expressing prolactin-releasing Peptide or glucagon-like Peptide 1. AB - Neural circuits distributed within the brainstem, hypothalamus, and limbic forebrain interact to control food intake and energy balance under normal day-to day conditions, and in response to stressful conditions under which homeostasis is threatened. Experimental studies using rats and mice have generated a voluminous literature regarding the functional organization of circuits that inhibit food intake in response to satiety signals, and in response to stress. Although the central neural bases of satiation and stress-induced hypophagia often are studied and discussed as if they were distinct, we propose that both behavioral states are generated, at least in part, by recruitment of two separate but intermingled groups of caudal hindbrain neurons. One group comprises a subpopulation of noradrenergic (NA) neurons within the caudal nucleus of the solitary tract (cNST; A2 cell group) that is immunopositive for prolactin releasing peptide (PrRP). The second group comprises non-adrenergic neurons within the cNST and nearby reticular formation that synthesize glucagon-like peptide 1 (GLP-1). Axonal projections from PrRP and GLP-1 neurons target distributed brainstem and forebrain regions that shape behavioral, autonomic, and endocrine responses to actual or anticipated homeostatic challenge, including the challenge of food intake. Evidence reviewed in this article supports the view that hindbrain PrRP and GLP-1 neurons contribute importantly to satiation and stress-induced hypophagia by modulating the activity of caudal brainstem circuits that control food intake. Hindbrain PrRP and GLP-1 neurons also engage hypothalamic and limbic forebrain networks that drive parallel behavioral and endocrine functions related to food intake and homeostatic challenge, and modulate conditioned and motivational aspects of food intake. PMID- 23346047 TI - Closed-Loop, Multichannel Experimentation Using the Open-Source NeuroRighter Electrophysiology Platform. AB - Single neuron feedback control techniques, such as voltage clamp and dynamic clamp, have enabled numerous advances in our understanding of ion channels, electrochemical signaling, and neural dynamics. Although commercially available multichannel recording and stimulation systems are commonly used for studying neural processing at the network level, they provide little native support for real-time feedback. We developed the open-source NeuroRighter multichannel electrophysiology hardware and software platform for closed-loop multichannel control with a focus on accessibility and low cost. NeuroRighter allows 64 channels of stimulation and recording for around US $10,000, along with the ability to integrate with other software and hardware. Here, we present substantial enhancements to the NeuroRighter platform, including a redesigned desktop application, a new stimulation subsystem allowing arbitrary stimulation patterns, low-latency data servers for accessing data streams, and a new application programming interface (API) for creating closed-loop protocols that can be inserted into NeuroRighter as plugin programs. This greatly simplifies the design of sophisticated real-time experiments without sacrificing the power and speed of a compiled programming language. Here we present a detailed description of NeuroRighter as a stand-alone application, its plugin API, and an extensive set of case studies that highlight the system's abilities for conducting closed loop, multichannel interfacing experiments. PMID- 23346048 TI - A translational platform for prototyping closed-loop neuromodulation systems. AB - While modulating neural activity through stimulation is an effective treatment for neurological diseases such as Parkinson's disease and essential tremor, an opportunity for improving neuromodulation therapy remains in automatically adjusting therapy to continuously optimize patient outcomes. Practical issues associated with achieving this include the paucity of human data related to disease states, poorly validated estimators of patient state, and unknown dynamic mappings of optimal stimulation parameters based on estimated states. To overcome these challenges, we present an investigational platform including: an implanted sensing and stimulation device to collect data and run automated closed-loop algorithms; an external tool to prototype classifier and control-policy algorithms; and real-time telemetry to update the implanted device firmware and monitor its state. The prototyping system was demonstrated in a chronic large animal model studying hippocampal dynamics. We used the platform to find biomarkers of the observed states and transfer functions of different stimulation amplitudes. Data showed that moderate levels of stimulation suppress hippocampal beta activity, while high levels of stimulation produce seizure-like after discharge activity. The biomarker and transfer function observations were mapped into classifier and control-policy algorithms, which were downloaded to the implanted device to continuously titrate stimulation amplitude for the desired network effect. The platform is designed to be a flexible prototyping tool and could be used to develop improved mechanistic models and automated closed-loop systems for a variety of neurological disorders. PMID- 23346046 TI - Regulation of endogenous neural stem/progenitor cells for neural repair-factors that promote neurogenesis and gliogenesis in the normal and damaged brain. AB - Neural stem/precursor cells in the adult brain reside in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. These cells primarily generate neuroblasts that normally migrate to the olfactory bulb (OB) and the dentate granule cell layer respectively. Following brain damage, such as traumatic brain injury, ischemic stroke or in degenerative disease models, neural precursor cells from the SVZ in particular, can migrate from their normal route along the rostral migratory stream (RMS) to the site of neural damage. This neural precursor cell response to neural damage is mediated by release of endogenous factors, including cytokines and chemokines produced by the inflammatory response at the injury site, and by the production of growth and neurotrophic factors. Endogenous hippocampal neurogenesis is frequently also directly or indirectly affected by neural damage. Administration of a variety of factors that regulate different aspects of neural stem/precursor biology often leads to improved functional motor and/or behavioral outcomes. Such factors can target neural stem/precursor proliferation, survival, migration and differentiation into appropriate neuronal or glial lineages. Newborn cells also need to subsequently survive and functionally integrate into extant neural circuitry, which may be the major bottleneck to the current therapeutic potential of neural stem/precursor cells. This review will cover the effects of a range of intrinsic and extrinsic factors that regulate neural stem/precursor cell functions. In particular it focuses on factors that may be harnessed to enhance the endogenous neural stem/precursor cell response to neural damage, highlighting those that have already shown evidence of preclinical effectiveness and discussing others that warrant further preclinical investigation. PMID- 23346051 TI - Praxis and autism: the psychomotor regulation sensory processing dimension-a report from the field. PMID- 23346050 TI - Towards a circuit mechanism for movement tuning in motor cortex. AB - The firing rates of neurons in primate motor cortex have been related to multiple parameters of voluntary movement. This finding has been corroborated by stimulation-based studies that have mapped complex movements in rodent and primate motor cortex. However, it has been difficult to link the movement tuning of a neuron with its role within the cortical microcircuit. In sensory cortex, neuronal tuning is largely established by afferents delivering information from tuned receptors in the periphery. Motor cortex, which lacks the granular input layer, may be better understood by analyzing its efferent projections. As a primary source of cortical output, layer 5 neurons represent an ideal starting point for this line of experimentation. It is in these deep output layers that movements can most effectively be evoked by intracortical microstimulation and recordings can obtain the most useful signals for the control of motor prostheses. Studies focused on layer 5 output neurons have revealed that projection identity is a fundamental property related to the laminar position, receptive field and ion channel complement of these cells. Given the variety of brain areas targeted by layer 5 output neurons, knowledge of a neuron's downstream connectivity may provide insight into its movement tuning. Future experiments that relate motor behavior to the activity of neurons with a known projection identity will yield a more detailed understanding of the function of cortical microcircuits. PMID- 23346049 TI - The compartmental restriction of cerebellar interneurons. AB - The Purkinje cells (PC's) of the cerebellar cortex are subdivided into multiple different molecular phenotypes that form an elaborate array of parasagittal stripes. This array serves as a scaffold around which afferent topography is organized. The ways in which cerebellar interneurons may be restricted by this scaffolding are less well-understood. This review begins with a brief survey of cerebellar topography. Next, it reviews the development of stripes in the cerebellum with a particular emphasis on the embryological origins of cerebellar interneurons. These data serve as a foundation to discuss the hypothesis that cerebellar compartment boundaries also restrict cerebellar interneurons, both excitatory [granule cells, unipolar brush cells (UBCs)] and inhibitory (e.g., Golgi cells, basket cells). Finally, it is proposed that the same PC scaffold that restricts afferent terminal fields to stripes may also act to organize cerebellar interneurons. PMID- 23346052 TI - DBS in the basolateral amygdala improves symptoms of autism and related self injurious behavior: a case report and hypothesis on the pathogenesis of the disorder. AB - We treated a 13-year-old boy for life-threatening self-injurious behavior (SIB) and severe Kanner's autism with deep brain stimulation (DBS) in the amygdaloid complex as well as in the supra-amygdaloid projection system. Two DBS-electrodes were placed in both structures of each hemisphere. The stimulation contacts targeted the paralaminar, the basolateral (BL), the central amygdala as well as the supra-amygdaloid projection system. DBS was applied to each of these structures, but only stimulation of the BL part proved effective in improving SIB and core symptoms of the autism spectrum in the emotional, social, and even cognitive domains over a follow up of now 24 months. These results, which have been gained for the first time in a patient, support hypotheses, according to which the amygdala may be pivotal in the pathogeneses of autism and point to the special relevance of the BL part. PMID- 23346053 TI - Using a smart phone as a standalone platform for detection and monitoring of pathological tremors. AB - INTRODUCTION: Smart phones are becoming ubiquitous and their computing capabilities are ever increasing. Consequently, more attention is geared toward their potential use in research and medical settings. For instance, their built in hardware can provide quantitative data for different movements. Therefore, the goal of the current study was to evaluate the capabilities of a standalone smart phone platform to characterize tremor. RESULTS: Algorithms for tremor recording and online analysis can be implemented within a smart phone. The smart phone provides reliable time- and frequency-domain tremor characteristics. The smart phone can also provide medically relevant tremor assessments. DISCUSSION: Smart phones have the potential to provide researchers and clinicians with quantitative short- and long-term tremor assessments that are currently not easily available. METHODS: A smart phone application for tremor quantification and online analysis was developed. Then, smart phone results were compared to those obtained simultaneously with a laboratory accelerometer. Finally, results from the smart phone were compared to clinical tremor assessments. PMID- 23346054 TI - Lateralized interactive social content and valence processing within the human amygdala. AB - In the past, the amygdala has generally been conceptualized as a fear-processing module. Recently, however, it has been proposed to respond to all stimuli that are relevant with respect to the current needs, goals, and values of an individual. This raises the question of whether the human amygdala may differentiate between separate kinds of relevance. A distinction between emotional (vs. neutral) and social (vs. non-social) relevance is supported by previous studies showing that the human amygdala preferentially responds to both emotionally and socially significant information, and these factors might even display interactive encoding properties. However, no investigation has yet probed a full 2 (positive vs. negative valence) * 2 (social vs. non-social content) processing pattern, with neutral images as an additional baseline. Applying such an extended orthogonal factorial design, our fMRI study demonstrates that the human amygdala is (1) more strongly activated for neutral social vs. non-social information, (2) activated at a similar level when viewing social positive or negative images, but (3) displays a valence effect (negative vs. positive) for non-social images. In addition, this encoding pattern is not influenced by cognitive or behavioral emotion regulation mechanisms, and displays a hemispheric lateralization with more pronounced effects on the right side. Finally, the same valence * social content interaction was found in three additional cortical regions, namely the right fusiform gyrus, right anterior superior temporal gyrus, and medial orbitofrontal cortex. Overall, these findings suggest that valence and social content processing represent distinct kinds of relevance that interact within the human amygdala as well as in a more extensive cortical network, likely subserving a key role in relevance detection. PMID- 23346055 TI - An electrophysiological validation of stochastic DCM for fMRI. AB - In this note, we assess the predictive validity of stochastic dynamic causal modeling (sDCM) of functional magnetic resonance imaging (fMRI) data, in terms of its ability to explain changes in the frequency spectrum of concurrently acquired electroencephalography (EEG) signal. We first revisit the heuristic model proposed in Kilner et al. (2005), which suggests that fMRI activation is associated with a frequency modulation of the EEG signal (rather than an amplitude modulation within frequency bands). We propose a quantitative derivation of the underlying idea, based upon a neural field formulation of cortical activity. In brief, dense lateral connections induce a separation of time scales, whereby fast (and high spatial frequency) modes are enslaved by slow (low spatial frequency) modes. This slaving effect is such that the frequency spectrum of fast modes (which dominate EEG signals) is controlled by the amplitude of slow modes (which dominate fMRI signals). We then use conjoint empirical EEG-fMRI data-acquired in epilepsy patients-to demonstrate the electrophysiological underpinning of neural fluctuations inferred from sDCM for fMRI. PMID- 23346056 TI - A multi-scale modeling framework for individualized, spatiotemporal prediction of drug effects and toxicological risk. AB - In this study, we focus on a novel multi-scale modeling approach for spatiotemporal prediction of the distribution of substances and resulting hepatotoxicity by combining cellular models, a 2D liver model, and whole body model. As a case study, we focused on predicting human hepatotoxicity upon treatment with acetaminophen based on in vitro toxicity data and potential inter individual variability in gene expression and enzyme activities. By aggregating mechanistic, genome-based in silico cells to a novel 2D liver model and eventually to a whole body model, we predicted pharmacokinetic properties, metabolism, and the onset of hepatotoxicity in an in silico patient. Depending on the concentration of acetaminophen in the liver and the accumulation of toxic metabolites, cell integrity in the liver as a function of space and time as well as changes in the elimination rate of substances were estimated. We show that the variations in elimination rates also influence the distribution of acetaminophen and its metabolites in the whole body. Our results are in agreement with experimental results. What is more, the integrated model also predicted variations in drug toxicity depending on alterations of metabolic enzyme activities. Variations in enzyme activity, in turn, reflect genetic characteristics or diseases of individuals. In conclusion, this framework presents an important basis for efficiently integrating inter-individual variability data into models, paving the way for personalized or stratified predictions of drug toxicity and efficacy. PMID- 23346057 TI - Targeting the Intracellular Environment in Cystic Fibrosis: Restoring Autophagy as a Novel Strategy to Circumvent the CFTR Defect. AB - Cystic fibrosis (CF) patients harboring the most common deletion mutation of the CF transmembrane conductance regulator (CFTR), F508del, are poor responders to potentiators of CFTR channel activity which can be used to treat a small subset of CF patients who genetically carry plasma membrane (PM)-resident CFTR mutants. The misfolded F508del-CFTR protein is unstable in the PM even if rescued by pharmacological agents that prevent its intracellular retention and degradation. CF is a conformational disease in which defective CFTR induces an impressive derangement of general proteostasis resulting from disabled autophagy. In this review, we discuss how rescuing Beclin 1 (BECN1), a major player of autophagosome formation, either by means of direct gene transfer or indirectly by administration of proteostasis regulators, could stabilize F508del-CFTR at the PM. We focus on the relationship between the improvement of peripheral proteostasis and CFTR PM stability in F508del-CFTR homozygous bronchial epithelia or mouse lungs. Moreover, this article reviews recent pre-clinical evidence indicating that targeting the intracellular environment surrounding the misfolded mutant CFTR instead of protein itself could constitute an attractive therapeutic option to sensitize patients carrying the F508del-CFTR mutation to the beneficial action of CFTR potentiators on lung inflammation. PMID- 23346058 TI - Does sample rate introduce an artifact in spectral analysis of continuous processes? AB - Spectral analysis is a widely used method to estimate 1/f(alpha) noise in behavioral and physiological data series. The aim of this paper is to achieve a more solid appreciation for the effects of periodic sampling on the outcomes of spectral analysis. It is shown that spectral analysis is biased by the choice of sample rate because denser sampling comes with lower amplitude fluctuations at the highest frequencies. Here we introduce an analytical strategy that compensates for this effect by focusing on a fixed amount, rather than a fixed percentage of the lowest frequencies in a power spectrum. Using this strategy, estimates of the degree of 1/f(alpha) noise become robust against sample rate conversion and more sensitive overall. Altogether, the present contribution may shed new light on known discrepancies in the psychological literature on 1/f(alpha) noise, and may provide a means to achieve a more solid framework for 1/f(alpha) noise in continuous processes. PMID- 23346060 TI - Proof of concept trial of dronabinol in obstructive sleep apnea. AB - STUDY OBJECTIVE: Animal data suggest that Delta(9)-TetraHydroCannabinol (Delta(9)THC) stabilizes autonomic output during sleep, reduces spontaneous sleep disordered breathing, and blocks serotonin-induced exacerbation of sleep apnea. On this basis, we examined the safety, tolerability, and efficacy of dronabinol (Delta(9)THC), an exogenous Cannabinoid type 1 and type 2 (CB1 and CB2) receptor agonist in patients with Obstructive Sleep Apnea (OSA). DESIGN AND SETTING: Proof of concept; single-center dose-escalation study of dronabinol. PARTICIPANTS: Seventeen adults with a baseline Apnea Hypopnea Index (AHI) >=15/h. Baseline polysomnography (PSG) was performed after a 7-day washout of Continuous Positive Airway Pressure treatment. INTERVENTION: Dronabinol was administered after baseline PSG, starting at 2.5 mg once daily. The dose was increased weekly, as tolerated, to 5 mg and finally to 10 mg once daily. MEASUREMENTS AND RESULTS: Repeat PSG assessments were performed on nights 7, 14, and 21 of dronabinol treatment. Change in AHI (DeltaAHI, mean +/- SD) was significant from baseline to night 21 (-14.1 +/- 17.5; p = 0.007). No degradation of sleep architecture or serious adverse events was noted. CONCLUSION: Dronabinol treatment is safe and well-tolerated in OSA patients at doses of 2.5-10 mg daily and significantly reduces AHI in the short-term. These findings should be confirmed in a larger study in order to identify sub-populations with OSA that may benefit from cannabimimetic pharmacologic therapy. PMID- 23346059 TI - Environmental factors in autism. AB - Autism is a neurodevelopmental disorders characterized by impairments in communication and social behavior, and by repetitive behaviors. Although genetic factors might be largely responsible for the occurrence of autism they cannot fully account for all cases and it is likely that in addition to a certain combination of autism-related genes, specific environmental factors might act as risk factors triggering the development of autism. Thus, the role of environmental factors in autism is an important area of research and recent data will be discussed in this review. Interestingly, the results show that many environmental risk factors are interrelated and their identification and comparison might unveil a common scheme of alterations on a contextual as well as molecular level. For example, both, disruption in the immune system and in zinc homeostasis may affect synaptic transmission in autism. Thus, here, a model is proposed that interconnects the most important and scientifically recognized environmental factors. Moreover, similarities in how these risk factors impact synapse function are discussed and a possible influence on an already well described genetic pathway leading to the development of autism via zinc homeostasis is proposed. PMID- 23346062 TI - An external focus of attention enhances manual tracking of occluded and visible targets. AB - The present study investigated the enhancement effects of an external focus of attention (FOA) in the context of a manual tracking task, in which participants tracked both visible and occluded targets. Three conditions were compared, which manipulated the distance of the FOA from the participant as well as the external/internal dimension. As expected, an external FOA resulted in lower tracking errors than an internal FOA. In addition, analyses of participants' movement patterns revealed a systematic shift toward higher-frequency movements in the external FOA condition, consistent with the idea that an external FOA exploits the natural movement dynamics available during skilled action. Finally, target visibility did not influence the effect of focused attention on tracking performance, which provides evidence for the proposal that the mechanisms that underlie FOA do not depend directly on vision. PMID- 23346061 TI - A Cross-Modal Perspective on the Relationships between Imagery and Working Memory. AB - Mapping the distinctions and interrelationships between imagery and working memory (WM) remains challenging. Although each of these major cognitive constructs is defined and treated in various ways across studies, most accept that both imagery and WM involve a form of internal representation available to our awareness. In WM, there is a further emphasis on goal-oriented, active maintenance, and use of this conscious representation to guide voluntary action. Multicomponent WM models incorporate representational buffers, such as the visuo spatial sketchpad, plus central executive functions. If there is a visuo-spatial "sketchpad" for WM, does imagery involve the same representational buffer? Alternatively, does WM employ an imagery-specific representational mechanism to occupy our awareness? Or do both constructs utilize a more generic "projection screen" of an amodal nature? To address these issues, in a cross-modal fMRI study, I introduce a novel Drawing-Based Memory Paradigm, and conceptualize drawing as a complex behavior that is readily adaptable from the visual to non visual modalities (such as the tactile modality), which opens intriguing possibilities for investigating cross-modal learning and plasticity. Blindfolded participants were trained through our Cognitive-Kinesthetic Method (Likova, 2010a, 2012) to draw complex objects guided purely by the memory of felt tactile images. If this WM task had been mediated by transfer of the felt spatial configuration to the visual imagery mechanism, the response-profile in visual cortex would be predicted to have the "top-down" signature of propagation of the imagery signal downward through the visual hierarchy. Remarkably, the pattern of cross-modal occipital activation generated by the non-visual memory drawing was essentially the inverse of this typical imagery signature. The sole visual hierarchy activation was isolated to the primary visual area (V1), and accompanied by deactivation of the entire extrastriate cortex, thus 'cutting-off' any signal propagation from/to V1 through the visual hierarchy. The implications of these findings for the debate on the interrelationships between the core cognitive constructs of WM and imagery and the nature of internal representations are evaluated. PMID- 23346063 TI - To lead and to lag - forward and backward recalibration of perceived visuo-motor simultaneity. AB - Studies on human recalibration of perceived visuo-motor simultaneity so far have been limited to the study of recalibration to movement-lead temporal discrepancies (visual lags). We studied adaptation to both vision-lead and movement-lead discrepancies, to test for differences between these conditions, as a leading visual stimulus violates the underlying cause-effect structure. To this end, we manipulated the temporal relationship between a motor action (button press) and a visual event (flashed disk) in a training phase. Participants were tested in a temporal order judgment task and perceived simultaneity (PSS) was compared before and after recalibration. A PHANToM(c)force-feedback device that tracks the finger position in real time was used to display a virtual button. We predicted the timing of full compression of the button from early movement onset in order to time visual stimuli even before the movement event of the full button press. The results show that recalibration of perceived visuo-motor simultaneity is evident in both directions and does not differ in magnitude between the conditions. The strength of recalibration decreases with perceptual accuracy, suggesting the possibility that some participants recalibrate less because they detect the discrepancy. We conclude that the mechanisms of temporal recalibration work in both directions and that there is no evidence that they are asymmetrical around the point of actual simultaneity, despite the underlying asymmetry in the cause-effect relation. PMID- 23346064 TI - Using objective, real-time measures to investigate the effect of actual physical activity on affective States in everyday life differentiating the contexts of working and leisure time in a sample with students. AB - Multiple studies suggest that physical activity causes positive affective reactions and reduces depressive mood. However, studies and interventions focused mostly on structured activity programs, but rarely on actual physical activity (aPA) in daily life. Furthermore, they seldom account for the context in which the aPA occur (e.g., work, leisure). Using a prospective, real-time assessment design (ambulatory assessment), we investigated the effects of aPA on affective states (valence, energetic arousal, calmness) in real-time during everyday life while controlling for the context. Eighty-seven undergraduates students (Age: M = 24.6; SD = 3.2, females: 54%) participated in this study. aPA was assessed through accelerometers during 24-h. Palmtop devices prompted subjects approximately every 45 min during a 14-h daytime period to assess their affective states and the context. We analyzed within- and between-person effects with hierarchical modeling (HLM 6.0). Multilevel analyses revealed that both aPA and context influenced subsequent affective states. The interaction of aPA and context did predict energetic arousal only. State levels of affects did not differ between men and women. For both men and women, aPA in everyday life has an effect on individual's affective states. For valence and calmness, it seems to be independent of the context in which the aPA occur. For energetic arousal, men reported to have lower feelings of energy and women reported to have more feelings of energy during leisure time compared to working episodes. PMID- 23346065 TI - Computational Grounded Cognition: a new alliance between grounded cognition and computational modeling. AB - Grounded theories assume that there is no central module for cognition. According to this view, all cognitive phenomena, including those considered the province of amodal cognition such as reasoning, numeric, and language processing, are ultimately grounded in (and emerge from) a variety of bodily, affective, perceptual, and motor processes. The development and expression of cognition is constrained by the embodiment of cognitive agents and various contextual factors (physical and social) in which they are immersed. The grounded framework has received numerous empirical confirmations. Still, there are very few explicit computational models that implement grounding in sensory, motor and affective processes as intrinsic to cognition, and demonstrate that grounded theories can mechanistically implement higher cognitive abilities. We propose a new alliance between grounded cognition and computational modeling toward a novel multidisciplinary enterprise: Computational Grounded Cognition. We clarify the defining features of this novel approach and emphasize the importance of using the methodology of Cognitive Robotics, which permits simultaneous consideration of multiple aspects of grounding, embodiment, and situatedness, showing how they constrain the development and expression of cognition. PMID- 23346066 TI - Face context advantage explained by vernier and separation discrimination acuity. AB - Seeing facial features in the context of a full face is known to provide an advantage for perception. Using an interocular separation perception task we confirmed that seeing eyes within the context of a face improves discrimination in synthetic faces. We also show that this improvement of the face context can be explained using the presence of individual components of the face such as the nose mouth, or head-outline. We demonstrate that improvements due to the presence of the nose, and head-outline can be explained in terms of two-point separation measurements, obeying Weber's law as established in the literature. We also demonstrate that performance improvements due to the presence of the mouth can be explained in terms of Vernier acuity judgments between eye positions and the corners of the mouth. Overall, our study shows that the improvements in perception of facial features due to the face context effect can be traced to well understood basic visual measurements that may play a very general role in perceptual measurements of distance. Deficiencies in these measurements may also play a role in prosopagnosia. Additionally, we show interference of the eyebrows with the face-inversion effect for interocular discrimination. PMID- 23346067 TI - Temporal structure and complexity affect audio-visual correspondence detection. AB - Synchrony between events in different senses has long been considered the critical temporal cue for multisensory integration. Here, using rapid streams of auditory and visual events, we demonstrate how humans can use temporal structure (rather than mere temporal coincidence) to detect multisensory relatedness. We find psychophysically that participants can detect matching auditory and visual streams via shared temporal structure for crossmodal lags of up to 200 ms. Performance on this task reproduced features of past findings based on explicit timing judgments but did not show any special advantage for perfectly synchronous streams. Importantly, the complexity of temporal patterns influences sensitivity to correspondence. Stochastic, irregular streams - with richer temporal pattern information - led to higher audio-visual matching sensitivity than predictable, rhythmic streams. Our results reveal that temporal structure and its complexity are key determinants for human detection of audio-visual correspondence. The distinctive emphasis of our new paradigms on temporal patterning could be useful for studying special populations with suspected abnormalities in audio-visual temporal perception and multisensory integration. PMID- 23346069 TI - Repetition blindness for natural images of objects with viewpoint changes. AB - When stimuli are repeated in a rapid serial visual presentation (RSVP), observers sometimes fail to report the second occurrence of a target. This phenomenon is referred to as "repetition blindness" (RB). We report an RSVP experiment with photographs in which we manipulated object viewpoints between the first and second occurrences of a target (0 degrees , 45 degrees , or 90 degrees changes), and spatial frequency (SF) content. Natural images were spatially filtered to produce low, medium, or high SF stimuli. RB was observed for all filtering conditions. Surprisingly, for full-spectrum (FS) images, RB increased significantly as the viewpoint reached 90 degrees . For filtered images, a similar pattern of results was found for all conditions except for medium SF stimuli. These findings suggest that object recognition in RSVP are subtended by viewpoint-specific representations for all spatial frequencies except medium ones. PMID- 23346068 TI - Predictive feedback and conscious visual experience. AB - The human brain continuously generates predictions about the environment based on learned regularities in the world. These predictions actively and efficiently facilitate the interpretation of incoming sensory information. We review evidence that, as a result of this facilitation, predictions directly influence conscious experience. Specifically, we propose that predictions enable rapid generation of conscious percepts and bias the contents of awareness in situations of uncertainty. The possible neural mechanisms underlying this facilitation are discussed. PMID- 23346070 TI - Planning, prospective memory, and decision-making: three challenges for hierarchical predictive processing models. PMID- 23346071 TI - Neural dynamics of audiovisual synchrony and asynchrony perception in 6-month-old infants. AB - Young infants are sensitive to multisensory temporal synchrony relations, but the neural dynamics of temporal interactions between vision and audition in infancy are not well understood. We investigated audiovisual synchrony and asynchrony perception in 6-month-old infants using event-related brain potentials (ERP). In a prior behavioral experiment (n = 45), infants were habituated to an audiovisual synchronous stimulus and tested for recovery of interest by presenting an asynchronous test stimulus in which the visual stream was delayed with respect to the auditory stream by 400 ms. Infants who behaviorally discriminated the change in temporal alignment were included in further analyses. In the EEG experiment (final sample: n = 15), synchronous and asynchronous stimuli (visual delay of 400 ms) were presented in random order. Results show latency shifts in the auditory ERP components N1 and P2 as well as the infant ERP component Nc. Latencies in the asynchronous condition were significantly longer than in the synchronous condition. After video onset but preceding the auditory onset, amplitude modulations propagating from posterior to anterior sites and related to the Pb component of infants' ERP were observed. Results suggest temporal interactions between the two modalities. Specifically, they point to the significance of anticipatory visual motion for auditory processing, and indicate young infants' predictive capacities for audiovisual temporal synchrony relations. PMID- 23346072 TI - Pediatric obstructive sleep apnea and the critical role of oral-facial growth: evidences. AB - AIMS: Review of evidence in support of an oral-facial growth impairment in the development of pediatric sleep apnea in non-obese children. METHOD: Review of experimental data from infant monkeys with experimentally induced nasal resistance. Review of early historical data in the orthodontic literature indicating the abnormal oral-facial development associated with mouth breathing and nasal resistance. Review of the progressive demonstration of sleep-disordered breathing (SDB) in children who underwent incomplete treatment of OSA with adenotonsillectomy, and demonstration of abnormal oral-facial anatomy that must often be treated in order for the resolution of OSA. Review of data of long-term recurrence of OSA and indication of oral-facial myofunctional dysfunction in association with the recurrence of OSA. RESULTS: Presentation of prospective data on premature infants and SDB-treated children, supporting the concept of oral facial hypotonia. Presentation of evidence supporting hypotonia as a primary element in the development of oral-facial anatomic abnormalities leading to abnormal breathing during sleep. Continuous interaction between oral-facial muscle tone, maxillary-mandibular growth and development of SDB. Role of myofunctional reeducation with orthodontics and elimination of upper airway soft tissue in the treatment of non-obese SDB children. CONCLUSION: Pediatric OSA in non-obese children is a disorder of oral-facial growth. PMID- 23346073 TI - Biomarkers of brain injury in the premature infant. AB - The term "encephalopathy of prematurity" encompasses not only the acute brain injury [such as intraventricular hemorrhage (IVH)] but also complex disturbance on the infant's subsequent brain development. In premature infants, the most frequent recognized source of brain injury is IVH and periventricular leukomalacia (PVL). Furthermore 20-25% infants with birth weigh less than 1,500 g will have IVH and that proportion increases to 45% if the birth weight is less than 500-750 g. In addition, nearly 60% of very low birth weight newborns will have hypoxic-ischemic injury. Therefore permanent lifetime neurodevelopmental disabilities are frequent in premature infants. Innovative approach to prevent or decrease brain injury in preterm infants requires discovery of biomarkers able to discriminate infants at risk for injury, monitor the progression of the injury, and assess efficacy of neuroprotective clinical trials. In this article, we will review biomarkers studied in premature infants with IVH, Post-hemorrhagic ventricular dilation (PHVD), and PVL including: S100b, Activin A, erythropoietin, chemokine CCL 18, GFAP, and NFL will also be examined. Some of the most promising biomarkers for IVH are S100beta and Activin. The concentrations of TGF-beta1, MMP 9, and PAI-1 in cerebrospinal fluid could be used to discriminate patients that will require shunt after PHVD. Neonatal brain injury is frequent in premature infants admitted to the neonatal intensive care and we hope to contribute to the awareness and interest in clinical validation of established as well as novel neonatal brain injury biomarkers. PMID- 23346074 TI - Cerebrospinal fluid biomarker candidates for parkinsonian disorders. AB - The Parkinsonian disorders are a large group of neurodegenerative diseases including idiopathic Parkinson's disease (PD) and atypical Parkinsonian disorders (APD), such as multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies. The etiology of these disorders is not known although it is considered to be a combination of genetic and environmental factors. One of the greatest obstacles for developing efficacious disease-modifying treatment strategies is the lack of biomarkers. Reliable biomarkers are needed for early and accurate diagnosis, to measure disease progression, and response to therapy. In this review several of the most promising cerebrospinal biomarker candidates are discussed. Alpha-synuclein seems to be intimately involved in the pathogenesis of synucleinopathies and its levels can be measured in the cerebrospinal fluid and in plasma. In a similar way, tau protein accumulation seems to be involved in the pathogenesis of tauopathies. Urate, a potent antioxidant, seems to be associated to the risk of developing PD and with its progression. Neurofilament light chain levels are increased in APD compared with PD and healthy controls. The new "omics" techniques are potent tools offering new insights in the patho-etiology of these disorders. Some of the difficulties encountered in developing biomarkers are discussed together with future perspectives. PMID- 23346075 TI - Role of Biomarkers in the Clinical Management of Glioblastomas: What are the Barriers and How Can We Overcome Them? AB - Thousands of articles describing biomarkers predictive of treatment and prognostic of survival in cancer have been published, yet only a handful of biomarkers are currently used routinely in the clinic. Biomarkers need to be analytically standardized, validated, and clinically useful. This review will address the challenges and ways in which we can improve our discovery and translation of prospective biomarkers from the lab into validated diagnostic tests with a specific focus on patients diagnosed with glioblastoma and MGMT promoter methylation status. There has been long-held enthusiasm to use MGMT promoter methylation as a predictive biomarker for patients treated with the alkylating agent, temozolomide; however in the majority of centers around the world, this has not yet transpired. PMID- 23346076 TI - Association of intercellular adhesion molecule 1 (ICAM1) with diabetes and diabetic nephropathy. AB - Diabetes and diabetic nephropathy are complex diseases affected by genetic and environmental factors. Identification of the susceptibility genes and investigation of their roles may provide useful information for better understanding of the pathogenesis and for developing novel therapeutic approaches. Intercellular adhesion molecule 1 (ICAM1) is a cell surface glycoprotein expressed on endothelial cells and leukocytes in the immune system. The ICAM1 gene is located on chromosome 19p13 within the linkage region of diabetes. In the recent years, accumulating reports have implicated that genetic polymorphisms in the ICAM1 gene are associated with diabetes and diabetic nephropathy. Serum ICAM1 levels in diabetes patients and the icam1 gene expression in kidney tissues of diabetic animals are increased compared to the controls. Therefore, ICAM1 may play a role in the development of diabetes and diabetic nephropathy. In this review, we present genomic structure, variation, and regulation of the ICAM1 gene, summarized genetic and biological studies of this gene in diabetes and diabetic nephropathy and discussed about the potential application using ICAM1 as a biomarker and target for prediction and treatment of diabetes and diabetic nephropathy. PMID- 23346077 TI - Bone circulatory disturbances in the development of spontaneous bacterial chondronecrosis with osteomyelitis: a translational model for the pathogenesis of femoral head necrosis. AB - This review provides a comprehensive overview of the vascularization of the avian growth plate and its subsequent role in the pathogenesis of bacterial chondronecrosis with osteomyelitis (BCO, femoral head necrosis). BCO sporadically causes high incidences of lameness in rapidly growing broiler (meat-type) chickens. BCO is believed to be initiated by micro-trauma to poorly mineralized columns of cartilage cells in the proximal growth plates of the leg bones, followed by colonization by hematogenously distributed opportunistic bacteria. Inadequate blood flow to the growth plate, vascular occlusion, and structural limitations of the microvasculature all have been implicated in the pathogenesis of BCO. Treatment strategies have been difficult to investigate because under normal conditions the incidence of BCO typically is low and sporadic. Rearing broilers on wire flooring triggers the spontaneous development of high incidences of lameness attributable to pathognomonic BCO lesions. Wire flooring imposes persistent footing instability and is thought to accelerate the development of BCO by amplifying the torque and shear stress imposed on susceptible leg joints. Wire flooring per se also constitutes a significant chronic stressor that promotes bacterial proliferation attributed to stress-mediated immunosuppression. Indeed, dexamethasone-mediated immunosuppression causes broilers to develop lameness primarily associated with avascular necrosis and BCO. Prophylactic probiotic administration consistently reduces the incidence of lameness in broilers reared on wire flooring, presumably by reducing bacterial translocation from the gastrointestinal tract that likely contributes to hematogenous infection of the leg bones. The pathogenesis of BCO in broilers is directly relevant to osteomyelitis in growing children, as well as to avascular femoral head necrosis in adults. Our new model for reliably triggering spontaneous osteomyelitis in large numbers of animals represents an important opportunity to conduct translational research focused on developing effective prophylactic and therapeutic treatments. PMID- 23346078 TI - Analysis of composition and structure of coastal to mesopelagic bacterioplankton communities in the northern gulf of Mexico. AB - 16S rRNA gene amplicons were pyrosequenced to assess bacterioplankton community composition, diversity, and phylogenetic community structure for 17 stations in the northern Gulf of Mexico (nGoM) sampled in March 2010. Statistical analyses showed that samples from depths <=100 m differed distinctly from deeper samples. SAR 11 alpha-Proteobacteria and Bacteroidetes dominated communities at depths <=100 m, which were characterized by high alpha-Proteobacteria/gamma Proteobacteria ratios (alpha/gamma > 1.7). Thaumarchaeota, Firmicutes, and delta Proteobacteria were relatively abundant in deeper waters, and alpha/gamma ratios were low (<1). Canonical correlation analysis indicated that delta- and gamma Proteobacteria, Thaumarchaeota, and Firmicutes correlated positively with depth; alpha-Proteobacteria and Bacteroidetes correlated positively with temperature and dissolved oxygen; Actinobacteria, beta-Proteobacteria, and Verrucomicrobia correlated positively with a measure of suspended particles. Diversity indices did not vary with depth or other factors, which indicated that richness and evenness elements of bacterioplankton communities might develop independently of nGoM physical-chemical variables. Phylogenetic community structure as measured by the net relatedness (NRI) and nearest taxon (NTI) indices also did not vary with depth. NRI values indicated that most of the communities were comprised of OTUs more distantly related to each other in whole community comparisons than expected by chance. NTI values derived from phylogenetic distances of the closest neighbor for each OTU in a given community indicated that OTUs tended to occur in clusters to a greater extent than expected by chance. This indicates that "habitat filtering" might play an important role in nGoM bacterioplankton species assembly, and that such filtering occurs throughout the water column. PMID- 23346079 TI - Aspergillus fumigatus melanins: interference with the host endocytosis pathway and impact on virulence. AB - The opportunistic human pathogenic fungus Aspergillus fumigatus produces at least two types of melanin, namely pyomelanin and dihydroxynaphthalene (DHN) melanin. Pyomelanin is produced during tyrosine catabolism via accumulation of homogentisic acid. Although pyomelanin protects the fungus against reactive oxygen species (ROS) and acts as a defense compound in response to cell wall stress, mutants deficient for pyomelanin biosynthesis do not differ in virulence when tested in a murine infection model for invasive pulmonary aspergillosis. DHN melanin is responsible for the characteristic gray-greenish color of A. fumigatus conidia. Mutants lacking a functional polyketide synthase PksP, the enzyme responsible for the initial step in DHN-melanin formation, i.e., the synthesis of naphthopyrone, produce white spores and are attenuated in virulence. The activity of PksP was found to be essential not only for inhibition of apoptosis of phagocytes by interfering with the host PI3K/Akt signaling cascade but also for effective inhibition of acidification of conidia-containing phagolysosomes. These features allow A. fumigatus to survive in phagocytes and thereby to escape from human immune effector cells and to become a successful pathogen. PMID- 23346080 TI - Same, same but different: symbiotic bacterial associations in GBR sponges. AB - Symbioses in marine sponges involve diverse consortia of microorganisms that contribute to the health and ecology of their hosts. The microbial communities of 13 taxonomically diverse Great Barrier Reef (GBR) sponge species were assessed by DGGE and 16S rRNA gene sequencing to determine intra and inter species variation in bacterial symbiont composition. Microbial profiling revealed communities that were largely conserved within different individuals of each species with intra species similarity ranging from 65-100%. 16S rRNA gene sequencing revealed that the communities were dominated by Proteobacteria, Chloroflexi, Acidobacteria, Actinobacteria, Nitrospira, and Cyanobacteria. Sponge-associated microbes were also highly host-specific with no operational taxonomic units (OTUs) common to all species and the most ubiquitous OTU found in only 5 of the 13 sponge species. In total, 91% of the OTUs were restricted to a single sponge species. However, GBR sponge microbes were more closely related to other sponge-derived bacteria than they were to environmental communities with sequences falling within 50 of the 173 previously defined sponge-(or sponge-coral) specific sequence clusters (SC). These SC spanned the Acidobacteria, Actinobacteria, Proteobacteria, Bacteroidetes, Chloroflexi, Cyanobacteria, Gemmatimonadetes, Nitrospira, and the Planctomycetes-Verrucomicrobia-Chlamydiae superphylum. The number of sequences assigned to these sponge-specific clusters across all species ranged from 0 to 92%. No relationship between host phylogeny and symbiont communities were observed across the different sponge orders, although the highest level of similarity was detected in two closely related Xestospongia species. This study identifies the core microbial inhabitants in a range of GBR sponges thereby providing the basis for future studies on sponge symbiotic function and research aiming to predict how sponge holobionts will respond to environmental perturbation. PMID- 23346081 TI - Differential responses of ammonia-oxidizing archaea and bacteria to long-term fertilization in a New England salt marsh. AB - Since the discovery of ammonia-oxidizing archaea (AOA), new questions have arisen about population and community dynamics and potential interactions between AOA and ammonia-oxidizing bacteria (AOB). We investigated the effects of long-term fertilization on AOA and AOB in the Great Sippewissett Marsh, Falmouth, MA, USA to address some of these questions. Sediment samples were collected from low and high marsh habitats in July 2009 from replicate plots that received low (LF), high (HF), and extra high (XF) levels of a mixed NPK fertilizer biweekly during the growing season since 1974. Additional untreated plots were included as controls (C). Terminal restriction fragment length polymorphism analysis of the amoA genes revealed distinct shifts in AOB communities related to fertilization treatment, but the response patterns of AOA were less consistent. Four AOB operational taxonomic units (OTUs) predictably and significantly responded to fertilization, but only one AOA OTU showed a significant pattern. Betaproteobacterial amoA gene sequences within the Nitrosospira-like cluster dominated at C and LF sites, while sequences related to Nitrosomonas spp. dominated at HF and XF sites. We identified some clusters of AOA sequences recovered primarily from high fertilization regimes, but other clusters consisted of sequences recovered from all fertilization treatments, suggesting greater physiological diversity. Surprisingly, fertilization appeared to have little impact on abundance of AOA or AOB. In summary, our data reveal striking patterns for AOA and AOB in response to long-term fertilization, and also suggest a missing link between community composition and abundance and nitrogen processing in the marsh. PMID- 23346083 TI - Technological and probiotic potential of BGRA43 a natural isolate of Lactobacillus helveticus. AB - Lactobacillus helveticus BGRA43 is a human intestinal isolate showing antimicrobial activity, amongst others, against Yersinia enterocolitica, Shigella sonnei, Shigella flexneri, and Streptococcus pneumoniae. BGRA43 produces PrtH proteinase with proteolytic activity on both casein and beta-lactoglobulin (BLG). BGRA43 is able to reduce the allergenicity of BLG. Bioactive peptides released in BGRA43 fermented milk are potent modulators of innate immunity by modulating the production of proinflammatory cytokines IL-6 and TNF-alpha. BGRA43 is able to survive in simulated gastric and intestinal conditions. The growth of BGRA43 in milk results in a fast acidification lowering the milk pH to 4.53 generating mild, homogeneous, and viscous yogurt-like product. The strain BGRA43 grows suitably in pure cow or goat's milk as well as in milk containing inulin or nutrim even when they are used as the sole carbon source. It is suggested that strain BGRA43 could be used as a single-strain culture for the preparation of yogurt-like products from bovine or caprine milk. Overall, L. helveticus BGRA43 could be considered as a potential probiotic candidate with appropriate technological properties attractive for the dairy industry. PMID- 23346082 TI - Nucleic acid-based approaches to investigate microbial-related cheese quality defects. AB - The microbial profile of cheese is a primary determinant of cheese quality. Microorganisms can contribute to aroma and taste defects, form biogenic amines, cause gas and secondary fermentation defects, and can contribute to cheese pinking and mineral deposition issues. These defects may be as a result of seasonality and the variability in the composition of the milk supplied, variations in cheese processing parameters, as well as the nature and number of the non-starter microorganisms which come from the milk or other environmental sources. Such defects can be responsible for production and product recall costs and thus represent a significant economic burden for the dairy industry worldwide. Traditional non-molecular approaches are often considered biased and have inherently slow turnaround times. Molecular techniques can provide early and rapid detection of defects that result from the presence of specific spoilage microbes and, ultimately, assist in enhancing cheese quality and reducing costs. Here we review the DNA-based methods that are available to detect/quantify spoilage bacteria, and relevant metabolic pathways in cheeses and, in the process, highlight how these strategies can be employed to improve cheese quality and reduce the associated economic burden on cheese processors. PMID- 23346084 TI - Interactions between Co-Habitating fungi Elicit Synthesis of Taxol from an Endophytic Fungus in Host Taxus Plants. AB - Within a plant, there can exist an ecosystem of pathogens and endophytes, the latter described as bacterial and fungal inhabitants that thrive without causing disease to the host. Interactions between microbial inhabitants represent a novel area of study for natural products research. Here we analyzed the interactions between the fungal endophytes of Taxus (yew) trees. Fungal endophytes of Taxus have been proposed to produce the terpenoid secondary metabolite, Taxol, an anti cancer drug. It is widely reported that plant extracts stimulate endophytic fungal Taxol production, but the underlying mechanism is not understood. Here, Taxus bark extracts stimulated fungal Taxol production 30-fold compared to a 10 fold induction with wood extracts. However, candidate plant-derived defense compounds (i.e., salicylic acid, benzoic acid) were found to act only as modest elicitors of fungal Taxol production from the endophytic fungus Paraconiothyrium SSM001, consistent with previous studies. We hypothesized the Taxus plant extracts may contain elicitors derived from other microbes inhabiting these tissues. We investigated the effects of co-culturing SSM001 with other fungi observed to inhabit Taxus bark, but not wood. Surprisingly, co-culture of SSM001 with a bark fungus (Alternaria) caused a ~threefold increase in Taxol production. When SSM001 was pyramided with both the Alternaria endophyte along with another fungus (Phomopsis) observed to inhabit Taxus, there was an ~eightfold increase in fungal Taxol production from SSM001. These results suggest that resident fungi within a host plant interact with one another to stimulate Taxol biosynthesis, either directly or through their metabolites. More generally, our results suggest that endophyte secondary metabolism should be studied in the context of its native ecosystem. PMID- 23346085 TI - Protecting and rescuing the effectors: roles of differentiation and survival in the control of memory T cell development. AB - Vaccines, arguably the single most important intervention in improving human health, have exploited the phenomenon of immunological memory. The elicitation of memory T cells is often an essential part of successful long-lived protective immunity. Our understanding of T cell memory has been greatly aided by the development of TCR Tg mice and MHC tetrameric staining reagents that have allowed the precise tracking of antigen-specific T cell responses. Indeed, following acute infection or immunization, naive T cells undergo a massive expansion culminating in the generation of a robust effector T cell population. This peak effector response is relatively short-lived and, while most effector T cells die by apoptosis, some remain and develop into memory cells. Although the molecular mechanisms underlying this cell fate decision remain incompletely defined, substantial progress has been made, particularly with regards to CD8(+) T cells. For example, the effector CD8(+) T cells generated during a response are heterogeneous, consisting of cells with more or less potential to develop into full-fledged memory cells. Development of CD8(+) T cell memory is regulated by the transcriptional programs that control the differentiation and survival of effector T cells. While the type of antigenic stimulation and level of inflammation control effector CD8(+) T cell differentiation, availability of cytokines and their ability to control expression and function of Bcl-2 family members governs their survival. These distinct differentiation and survival programs may allow for finer therapeutic intervention to control both the quality and quantity of CD8(+) T cell memory. Effector to memory transition of CD4(+) T cells is less well characterized than CD8(+) T cells, emerging details will be discussed. This review will focus on the recent progress made in our understanding of the mechanisms underlying the development of T cell memory with an emphasis on factors controlling survival of effector T cells. PMID- 23346086 TI - Reactive oxidants and myeloperoxidase and their involvement in neutrophil extracellular traps. AB - Neutrophils release extracellular traps (NETs) in response to a variety of inflammatory stimuli. These structures are composed of a network of chromatin strands associated with a variety of neutrophil-derived proteins including the enzyme myeloperoxidase (MPO). Studies into the mechanisms leading to the formation of NETs indicate a complex process that differs according to the stimulus. With some stimuli an active nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is required. However, assigning specific reactive oxygen species involved downstream of the oxidase is a difficult task and definitive proof for any single oxidant is still lacking. Pharmacological inhibition of MPO and the use of MPO-deficient neutrophils indicate active MPO is required with phorbol myristate acetate as a stimulus but not necessarily with bacteria. Reactive oxidants and MPO may also play a role in NET-mediated microbial killing. MPO is present on NETs and maintains activity at this site. Therefore, MPO has the potential to generate reactive oxidants in close proximity to trapped microorganisms and thus effect microbial killing. This brief review discusses current evidence for the involvement of reactive oxidants and MPO in NET formation and their potential contribution to NET antimicrobial activity. PMID- 23346087 TI - Genetic dissection of NK cell responses. AB - The association of Natural Killer (NK) cell deficiencies with disease susceptibility has established a central role for NK cells in host defence. In this context, genetic approaches have been pivotal in elucidating and characterizing the molecular mechanisms underlying NK cell function. To this end, homozygosity mapping and linkage analysis in humans have identified mutations that impact NK cell function and cause life-threatening diseases. However, several critical restrictions accompany genetic studies in humans. Studying NK cell pathophysiology in a mouse model has therefore proven a useful tool. The relevance of the mouse model is underscored by the similarities that exist between cell-structure-sensing receptors and the downstream signaling that leads to NK cell activation. In this review, we provide an overview of how human and mouse quantitative trait locis (QTLs) have facilitated the identification of genes that modulate NK cell development, recognition, and killing of target cells. PMID- 23346089 TI - NK cell cytotoxicity mediated by 2B4 and NTB-A is dependent on SAP acting downstream of receptor phosphorylation. AB - 2B4 (CD244) and NK-T-B-antigen (NTB-A, CD352) are activating receptors on human natural killer (NK) cells and belong to the family of signaling lymphocyte activation molecule (SLAM)-related receptors (SRR). Engagement of these receptors leads to phosphorylation of their cytoplasmic tails and recruitment of the adapter proteins SLAM-associated protein (SAP) and Ewing's sarcoma-activated transcript-2 (EAT-2). X-linked lymphoproliferative syndrome (XLP) is a severe immunodeficiency that results from mutations in the SAP gene. 2B4 and NTB-A mediated cytotoxicity are abrogated in XLP NK cells. To elucidate the molecular basis for this defect we analyzed early signaling events in SAP knockdown cells. Similar to XLP NK cells, knockdown of SAP in primary human NK cells leads to a reduction of 2B4 and NTB-A-mediated cytotoxicity. We found that early signaling events such as raft recruitment and receptor phosphorylation are not affected by the absence of SAP, indicating the defect in the absence of SAP is downstream of these events. In addition, knockdown of EAT-2 does not impair 2B4 or NTB-A mediated cytotoxicity. Surprisingly, EAT-2 recruitment to both receptors is abrogated in the absence of SAP, revealing a novel cooperativity between these adapters. PMID- 23346090 TI - Subcellular compartmentation of sugar signaling: links among carbon cellular status, route of sucrolysis, sink-source allocation, and metabolic partitioning. AB - Recent findings suggest that both subcellular compartmentation and route of sucrolysis are important for plant development, growth, and yield. Signaling effects are dependent on the tissue, cell type, and stage of development. Downstream effects also depend on the amount and localization of hexoses and disaccharides. All enzymes of sucrose metabolism (e.g., invertase, hexokinase, fructokinase, sucrose synthase, and sucrose 6-phosphate synthase) are not produced from single genes, but from paralog families in plant genomes. Each paralog has unique expression across plant organs and developmental stages. Multiple isoforms can be targeted to different cellular compartments (e.g., plastids, mitochondria, nuclei, and cytosol). Many of the key enzymes are regulated by post-transcriptional modifications and associate in multimeric protein complexes. Some isoforms have regulatory functions, either in addition to or in replacement of their catalytic activity. This explains why some isozymes are not redundant, but also complicates elucidation of their specific involvement in sugar signaling. The subcellular compartmentation of sucrose metabolism forces refinement of some of the paradigms of sugar signaling during physiological processes. For example, the catalytic and signaling functions of diverse paralogs needs to be more carefully analyzed in the context of post-genomic biology. It is important to note that it is the differential localization of both the sugars themselves as well as the sugar-metabolizing enzymes that ultimately led to sugar signaling. We conclude that a combination of subcellular complexity and gene duplication/subfunctionalization gave rise to sugar signaling as a regulatory mechanism in plant cells. PMID- 23346088 TI - Professional antigen presenting cells in human herpesvirus 8 infection. AB - Professional antigen presenting cells (APC), i.e., dendritic cells (DC), monocytes/macrophages, and B lymphocytes, are critically important in the recognition of an invading pathogen and presentation of antigens to the T cell mediated arm of immunity. Human herpesvirus 8 (HHV-8) is one of the few human viruses that primarily targets these APC for infection, altering their cytokine profiles, manipulating their surface expression of MHC molecules, and altering their ability to activate HHV-8-specific T cells. This could be why T cell responses to HHV-8 antigens are not very robust. Of these APC, only B cells support complete, lytic HHV-8 infection. However, both complete and abortive virus replication cycles in APC could directly affect viral pathogenesis and progression to Kaposi's sarcoma (KS) and HHV-8-associated B cell cancers. In this review, we discuss the effects of HHV-8 infection on professional APC and their relationship to the development of KS and B cell lymphomas. PMID- 23346091 TI - Chloroplast Microsatellite Diversity in Phaseolus vulgaris. AB - Evolutionary studies that are aimed at defining the processes behind the present level and organization of crop genetic diversity represent the fundamental bases for biodiversity conservation and use. A Mesoamerican origin of the common bean Phaseolus vulgaris was recently suggested through analysis of nucleotide polymorphism at the nuclear level. Here, we have used chloroplast microsatellites to investigate the origin of the common bean, on the basis of the specific characteristics of these markers (no recombination, haploid genome, uniparental inheritance), to validate these recent findings. Indeed, comparisons of the results obtained through analysis of nuclear and cytoplasmic DNA should allow the resolution of some of the contrasting information available on the evolutionary processes. The main outcomes of the present study are: (i) confirmation at the chloroplast level of the results obtained through nuclear data, further supporting the Mesoamerican origin of P. vulgaris, with central Mexico representing the cradle of its diversity; (ii) identification of a putative ancestral plastidial genome, which is characteristic of a group of accessions distributed from central Mexico to Peru, but which have not been highlighted beforehand through analyses at the nuclear level. Finally, the present study suggests that when a single species is analyzed, there is the need to take into account the complexity of the relationships between P. vulgaris and its closely related and partially intercrossable species P. coccineus and P. dumosus. Thus, the present study stresses the importance for the investigation of the speciation processes of these taxa through comparisons of both plastidial and nuclear variability. This knowledge will be fundamental not only from an evolutionary point of view, but also to put P. coccineus and P. dumosus germplasm to better use as a source of useful diversity for P. vulgaris breeding. PMID- 23346092 TI - Rapid phosphatidic acid accumulation in response to low temperature stress in Arabidopsis is generated through diacylglycerol kinase. AB - Phosphatidic acid (PtdOH) is emerging as an important signaling lipid in abiotic stress responses in plants. The effect of cold stress was monitored using (32)P labeled seedlings and leaf discs of Arabidopsis thaliana. Low, non-freezing temperatures were found to trigger a very rapid (32)P-PtdOH increase, peaking within 2 and 5 min, respectively. In principle, PtdOH can be generated through three different pathways, i.e., (1) via de novo phospholipid biosynthesis (through acylation of lyso-PtdOH), (2) via phospholipase D hydrolysis of structural phospholipids, or (3) via phosphorylation of diacylglycerol (DAG) by DAG kinase (DGK). Using a differential (32)P-labeling protocol and a PLD transphosphatidylation assay, evidence is provided that the rapid (32)P-PtdOH response was primarily generated through DGK. A simultaneous decrease in the levels of (32)P-PtdInsP, correlating in time, temperature dependency, and magnitude with the increase in (32)P-PtdOH, suggested that a PtdInsP-hydrolyzing PLC generated the DAG in this reaction. Testing T-DNA insertion lines available for the seven DGK genes, revealed no clear changes in (32)P-PtdOH responses, suggesting functional redundancy. Similarly, known cold-stress mutants were analyzed to investigate whether the PtdOH response acted downstream of the respective gene products. The hos1, los1, and fry1 mutants were found to exhibit normal PtdOH responses. Slight changes were found for ice1, snow1, and the overexpression line Super-ICE1, however, this was not cold-specific and likely due to pleiotropic effects. A tentative model illustrating direct cold effects on phospholipid metabolism is presented. PMID- 23346093 TI - Subcellular protein overexpression to develop abiotic stress tolerant plants. AB - Environmental stresses are major factors limiting growth and development of crops. Plants respond to the stresses through a wide range of reactions from morphological changes to alterations in the patterns of protein expression. Understanding the mechanisms involved in the stress response is the first step to develop abiotic stress tolerant crops. Proteomics is a powerful tool in evaluating regulated proteins in the cell under stress and it is an efficient technique in studying stress tolerant plants. Because of the nature of abiotic stress, intracellular compartments play a main role in the stress response. Subcellular proteins such as ion and water transporters, reactive oxygen species (ROS) scavengers, and the proteins related to signaling and transcriptional regulation are frequently reported as being involved in stress tolerance. Overexpression of stress-responsive protein through generation of transgenic plants is one the main practical approaches in production of tolerant plants. In this article, recent studies on transgenic plants overexpressing subcellular proteins are reviewed and the role of organelles and over-expressed proteins is classified. PMID- 23346094 TI - MicroRNA dysregulation in multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory disease characterized by central nervous system (CNS) demyelination and axonal degeneration. Although the cause of MS is still unknown, it is widely accepted that novel drug targets need to focus on both decreasing inflammation and promoting CNS repair. In MS and experimental autoimmune encephalomyelitis, non-coding small microRNAs (miRNAs) are dysregulated in the immune system and CNS. Since individual miRNAs are able to down-regulate multiple targeted mRNA transcripts, even minor changes in miRNA expression may lead to significant alterations in gene expression. Herein, we review miRNA signatures reported in CNS tissue and immune cells of MS patients and consider how altered miRNA expression may influence MS pathology. PMID- 23346096 TI - Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer. AB - Breast cancer is the top cancer among women, and its incidence is increasing worldwide. Although the mortality tends to decrease due to early detection and treatment, there is great variability in the rates of clinical response and survival, which makes breast cancer one of the most appealing targets for pharmacogenomic studies. The recognition that functional CYP2D6 polymorphisms affect tamoxifen pharmacokinetics has motivated the attempts of using CYP2D6 genotyping for predicting breast cancer outcomes. In addition to tamoxifen, the chemotherapy of breast cancer includes combinations of cytotoxic drugs, which are substrates for various xenobiotic metabolizing enzymes. Because of these drugs' narrow therapeutic window, it has been postulated that impaired biotransformation could lead to increased toxicity. In the present review, we performed a systematic search of all published data exploring associations between polymorphisms in xenobiotic metabolizing enzymes and clinical outcomes of breast cancer. We retrieved 43 original articles involving either tamoxifen or other chemotherapeutic protocols, and compiled all information regarding response or toxicity. The data indicate that, although CYP2D6 polymorphisms can indeed modify tamoxifen pharmacokinetics, CYP2D6 genotyping alone is not enough for predicting breast cancer outcomes. The studies involving other chemotherapeutic protocols explored a great diversity of pharmacogenetic targets, but the number of studies for each functional polymorphism is still very limited, with usually no confirmation of positive associations. In conclusion, the application of pharmacogenetics to predict breast cancer outcomes and to select one individual's chemotherapeutic protocol is still far from clinical routine. Although some very interesting results have been produced, no clear practical recommendations are recognized yet. PMID- 23346095 TI - Dysregulated A to I RNA editing and non-coding RNAs in neurodegeneration. AB - RNA editing is an alteration in the primary nucleotide sequences resulting from a chemical change in the base. RNA editing is observed in eukaryotic mRNA, transfer RNA, ribosomal RNA, and non-coding RNAs (ncRNA). The most common RNA editing in the mammalian central nervous system is a base modification, where the adenosine residue is base-modified to inosine (A to I). Studies from ADAR (adenosine deaminase that act on RNA) mutants in Caenorhabditis elegans, Drosophila, and mice clearly show that the RNA editing process is an absolute requirement for nervous system homeostasis and normal physiology of the animal. Understanding the mechanisms of editing and findings of edited substrates has provided a better knowledge of the phenotype due to defective and hyperactive RNA editing. A to I RNA editing is catalyzed by a family of enzymes knows as ADARs. ADARs modify duplex RNAs and editing of duplex RNAs formed by ncRNAs can impact RNA functions, leading to an altered regulatory gene network. Such altered functions by A to I editing is observed in mRNAs, microRNAs (miRNA) but other editing of small and long ncRNAs (lncRNAs) has yet to be identified. Thus, ncRNA and RNA editing may provide key links between neural development, nervous system function, and neurological diseases. This review includes a summary of seminal findings regarding the impact of ncRNAs on biological and pathological processes, which may be further modified by RNA editing. NcRNAs are non-translated RNAs classified by size and function. Known ncRNAs like miRNAs, smallRNAs (smRNAs), PIWI interacting RNAs (piRNAs), and lncRNAs play important roles in splicing, DNA methylation, imprinting, and RNA interference. Of note, miRNAs are involved in development and function of the nervous system that is heavily dependent on both RNA editing and the intricate spatiotemporal expression of ncRNAs. This review focuses on the impact of dysregulated A to I editing and ncRNAs in neurodegeneration. PMID- 23346098 TI - How lifespan associated genes modulate aging changes: lessons from analysis of longitudinal data. AB - BACKGROUND AND OBJECTIVE: The influence of genes on human lifespan is mediated by biological processes that characterize body's functioning. The age trajectories of these processes contain important information about mechanisms linking aging, health, and lifespan. The objective of this paper is to investigate regularities of aging changes in different groups of individuals, including individuals with different genetic background, as well as their connections with health and lifespan. DATA AND METHOD: To reach this objective we used longitudinal data on four physiological variables, information about health and lifespan collected in the Framingham Heart Study (FHS), data on longevity alleles detected in earlier study, as well as methods of statistical modeling. RESULTS: We found that phenotypes of exceptional longevity and health are linked to distinct types of changes in physiological indices during aging. We also found that components of aging changes differ in groups of individuals with different genetic background. CONCLUSIONS: These results suggest that factors responsible for exceptional longevity and health are not necessary the same, and that postponing aging changes is associated with extreme longevity. The genetic factors which increase lifespan are associated with physiological changes typical of healthy and long living individuals, smaller mortality risks from cancer and CVD and better estimates of adaptive capacity in statistical modeling. This indicates that extreme longevity and health related traits are likely to be less heterogeneous phenotypes than lifespan, and studying these phenotypes separately from lifespan may provide additional information about mechanisms of human aging and its relation to chronic diseases and lifespan. PMID- 23346099 TI - Structural Features and Transcriptional Activity of Chicken PPARs (alpha, beta, and gamma). AB - While an understanding of lipid metabolism in chickens is critical for a further improvement of food production, there are few studies concerning differences in lipid metabolism mechanisms between chickens and other species at a molecular level. Chickens have three PPAR gene subtypes (alpha, beta, and gamma) that function differently from those present in humans and mice. The chicken PPAR gamma (cPPARgamma) gene is shorter than that in humans and lacks a gamma2 isoform. Moreover, in serum-free media, cPPARgamma shows high transcriptional activity without exogenous ligands. Luciferase reporter assays were used to examine the effect of sera on cPPAR transcriptional activities and showed that adult bovine serum and chicken serum highly activate cPPARalpha and beta functions. Moreover, we found that bezafibrate induces the transactivation function of cPPARbeta, but not human PPARdelta (human PPARbeta ortholog). This ligand selectivity relies on one amino acid residue (chicken: Val419, human: Met444). These results show the possibilities for unique functions of cPPARs on chicken-specific lipid glucose metabolism. As such, a better understanding of the molecular mechanisms of lipid metabolism in chickens could result in higher productivity for the poultry industry. PMID- 23346097 TI - Molecular Interactions between NAFLD and Xenobiotic Metabolism. AB - Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is a complex multifactorial disease characterized by metabolic deregulations that include accumulation of lipids in the liver, lipotoxicity, and insulin resistance. The progression of NAFLD to non-alcoholic steatohepatitis and cirrhosis, and ultimately to carcinomas, is governed by interplay of pro-inflammatory pathways, oxidative stress, as well as fibrogenic and apoptotic cues. As the liver is the major organ of biotransformation, deregulations in hepatic signaling pathways have effects on both, xenobiotic and endobiotic metabolism. Several major nuclear receptors involved in the transcription and regulation of phase I and II drug metabolizing enzymes and transporters also have endobiotic ligands including several lipids. Hence, hepatic lipid accumulation in steatosis and NAFLD, which leads to deregulated activation patterns of nuclear receptors, may result in altered drug metabolism capacity in NAFLD patients. On the other hand, genetic and association studies have indicated that a malfunction in drug metabolism can affect the prevalence and severity of NAFLD. This review focuses on the complex interplay between NAFLD pathogenesis and drug metabolism. A better understanding of these relationships is a prerequisite for developing improved drug dosing algorithms for the pharmacotherapy of patients with different stages of NAFLD. PMID- 23346102 TI - Autonomic nervous system, inflammation, and diabetes: mechanisms and possible interventions. PMID- 23346100 TI - Animal models of diabetes mellitus for islet transplantation. AB - Due to current improvements in techniques for islet isolation and transplantation and protocols for immunosuppressants, islet transplantation has become an effective treatment for severe diabetes patients. Many diabetic animal models have contributed to such improvements. In this paper, we focus on 3 types of models with different mechanisms for inducing diabetes mellitus (DM): models induced by drugs including streptozotocin (STZ), pancreatomized models, and spontaneous models due to autoimmunity. STZ-induced diabetes is one of the most commonly used experimental diabetic models and is employed using many specimens including rodents, pigs or monkeys. The management of STZ models is well established for islet studies. Pancreatomized models reveal different aspects compared to STZ-induced models in terms of loss of function in the increase and decrease of blood glucose and therefore are useful for evaluating the condition in total pancreatomized patients. Spontaneous models are useful for preclinical studies including the assessment of immunosuppressants because such models involve the same mechanisms as type 1 DM in the clinical setting. In conclusion, islet researchers should select suitable diabetic animal models according to the aim of the study. PMID- 23346101 TI - 5HT(2A) and 5HT(2B) receptors contribute to serotonin-induced vascular dysfunction in diabetes. AB - Although 5HT(2A) receptors mediate contractions of normal arteries to serotonin (5HT), in some cardiovascular diseases, other receptor subtypes contribute to the marked increase in serotonin contractions. We hypothesized that enhanced contractions of arteries from diabetics to 5HT are mediated by an increased contribution from multiple 5HT receptor subtypes. We compared responses to selective 5HT receptor agonists and expression of 5HT receptor isoforms (5HT(1B), 5HT(2A), and 5HT(2B)) in aorta from nondiabetic (ND) compared to type 2 diabetic mice (DB, BKS.Cg-Dock7(m)+/+Lepr(db)/J). 5HT, 5HT(2A) (TCB2 and BRL54443), and 5HT(2B) (norfenfluramine and BW723C86) receptor agonists produced concentration dependent contractions of ND arteries that were markedly increased in DB arteries. Neither ND nor DB arteries contracted to a 5HT(1B) receptor agonist. MDL11939, a 5HT(2A) receptor antagonist, and LY272015, a 5HT(2B) receptor antagonist, reduced contractions of arteries from DB to 5HT more than ND. Expression of 5HT(1B), 5HT(2A), and 5HT(2B) receptor subtypes was similar in ND and DB. Inhibition of rho kinase decreased contractions to 5HT and 5HT(2A) and 5HT(2B) receptor agonists in ND and DB. We conclude that in contrast to other cardiovascular diseases, enhanced contraction of arteries from diabetics to 5HT is not due to a change in expression of multiple 5HT receptor subtypes. PMID- 23346103 TI - Association between Genetic Instability and Helicobacter pylori Infection in Gastric Epithelial Dysplasia. AB - Background. In gastric carcinogenesis, changes of DNA methylation appear to be an early molecular event, and the genome-wide methylation state is closely correlated with the level of long interspersed nucleotide element-1 (LINE-1) methylation. In this study, we measured LINE-1 methylation level according to genetic instability and evaluated the effect of Helicobacter pylori infection on genetic instability in gastric epithelial dysplasia. Methods. Total 100 tissue samples of gastric epithelial dysplasia were analyzed. Seven loci that linked to tumor suppressor genes were used to identify significant structural chromosomal aberrations. Microsatellite status was investigated for two different microsatellite marker loci (BAT25 and BAT26). Also, we measured LINE-1 methylation level by combined bisulfite restriction analysis (COBRA-LINE-1) method. Results. There were no significant differences of LINE-1 methylation level according to chromosomal/microsatellite instability and H. pylori state. In the dysplastic lesions with H. pylori infection, LINE-1 methylation level of MSI lesion was significantly lower than that of microsatellite stable (MSS) lesion (40.23 +/- 4.47 versus 43.90 +/- 4.81%, P < 0.01). Conclusions. In gastric epithelial dysplasia with H. pylori infection, MSI is correlated with reduced LINE-1 methylation level. Coexistence of H. pylori infection and MSI might be a driving force of gastric carcinogenesis. PMID- 23346105 TI - Drug-eluting stents in multivessel coronary artery disease: cost effectiveness and clinical outcomes. AB - Multivessel coronary artery disease is more often treated either with coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) with stenting. The advent of drug-eluting stent (DES) has changed the revascularization strategy, and caused an increase in the use of DES in multivessel disease (MVD), with reduced rate of repeat revascularization compared to conventional bare metal stent. The comparative studies of DES-PCI over CABG have shown comparable safety; however, the rate of major adverse cerebrovascular and cardiac events and repeat revascularization was significantly higher with DES PCI at long term. In diabetic patients with MVD, concern of repeat revascularization with DES-PCI is persistent. More recent, one-year economic outcomes have reported that the CABG is favored among patients with high angiographic complexity. The higher rate of repeat revascularization with DES-PCI in MVD would lead to increased economic burden on patient at long term besides bearing high cost of DES. In diabetic MVD patients, CABG is associated with having better clinical outcomes and being more cost-effective approach when compared to DES-PCI at long term. PMID- 23346106 TI - Effect of coenzyme-q10 on Doxorubicin-induced nephrotoxicity in rats. AB - Nephrotoxicity is one of the limiting factors for using doxorubicin (Dox) as an anticancer chemotherapeutic. Here, we investigated possible protective effect of coenzyme-Q10 (CoQ10) on Dox-induced nephrotoxicity and the mechanisms involved. Two doses (10 and 100 mg/kg) of CoQ10 were administered orally to rats for 8 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of Dox (15 mg/kg) at day 4 of the experiment. Our results showed that the low dose of CoQ10 succeeded in reversing Dox-induced nephrotoxicity to control levels (e.g., levels of blood urea nitrogen and serum creatinine, concentrations of renal reduced glutathione (GSH) and malondialdehyde, catalase activity and caspase 3 expression, and renal histopathology). Alternatively, the high dose of CoQ10 showed no superior nephroprotection over the low dose, as there were no significant improvements in renal histopathology, catalase activity, or caspase 3 expression compared to the Dox-treated group. Interestingly, the high dose of CoQ10 alone significantly decreased renal GSH level as well as catalase activity and caused a mild induction of caspase 3 expression compared to control, probably due to a prooxidant effect at this dose of CoQ10. We conclude that CoQ10 protects from Dox induced nephrotoxicity with a precaution to dosage adjustment. PMID- 23346107 TI - Focal therapy for prostatic carcinoma. PMID- 23346104 TI - Melatonin levels in serum and ascitic fluid of patients with hepatic encephalopathy. AB - Cirrhotic patients exhibit disturbed melatonin homeostasis, which may lead to sleep disturbances, but an influence on the hepatic encephalopathy has not been elucidated. Aim. In the present study, the association of melatonin levels in serum and ascitic fluid and ammonia concentration related to the intensity of hepatic encephalopathy (HE) was investigated. Material and Methods. The study included 90 alcoholic patients with hepatic encephalopathy and 30 healthy volunteers (C). Patients were divided in three groups according to 0-4 West-Haven Score: HE(1) (n = 28), HE(2) (n = 30), and HE(3) (n = 32). Melatonin was measured by radioimmune assay. Results. In fasting patients with hepatic encephalopathy we noted higher melatonin serum levels [pg/mL] than in healthy subjects groups: C 11.3 +/- 3.9, HE(1) - 34.3 +/- 12.2 (P < 0.01), HE(2)-54.8 +/- 23.9, and HE(3) 119.8 +/- 96.4 (P < 0.001). No correlation between melatonin and ammonia levels was found. Melatonin was detected in ascetic fluid in 24 patients of group HE(2) and 27 patients of group HE(2) of hepatic encephalopathy. Conclusions. Our results suggest that high blood levels of melatonin in cirrhotic liver patients may account for some of the clinical manifestations of hepatic encephalopathy, for example, daytime sleepiness, fatigue. PMID- 23346108 TI - Mobility and Active Ageing in Suburban Environments: Findings from In-Depth Interviews and Person-Based GPS Tracking. AB - Background. Governments face a significant challenge to ensure that community environments meet the mobility needs of an ageing population. Therefore, it is critical to investigate the effect of suburban environments on the choice of transportation and its relation to participation and active ageing. Objective. This research explores if and how suburban environments impact older people's mobility and their use of different modes of transport. Methods. Data derived from GPS tracking, travel diaries, brief questionnaires, and semistructured interviews were gathered from thirteen people aged from 56 to 87 years, living in low-density suburban environments in Brisbane, Australia. Results. The suburban environment influenced the choice of transportation and out-of-home mobility. Both walkability and public transportation (access and usability) impact older people's transportation choices. Impracticality of active and public transportation within suburban environments creates car dependency in older age. Conclusion. Suburban environments often create barriers to mobility, which impedes older people's engagement in their wider community and ability to actively age in place. Further research is needed to develop approaches towards age-friendly suburban environments which will encourage older people to remain active and engaged in older age. PMID- 23346109 TI - Active Ageing in CIS Countries: Semantics, Challenges, and Responses. AB - Although the CIS countries are connected together by the legacy of breaking away from the Soviet Union, they have had a distinctive transition course and are rather diverse in terms of the population ageing challenges and policy responses in place. The commonality is that a comprehensive national strategy on ageing is lacking, and many of necessary reforms were put aside owing to political uncertainties, lack of societal consensus, and financial instability. The notion of active ageing is associated with the term "accelerated ageing," which is understood to be an individual living a life under harsh living conditions or a society experiencing rapid increases in the relative number of older persons, and therefore it carries a negative connotation. Yet, in the same spirit as the European Year for Active Ageing and Solidarity between Generations 2012, the CIS countries have initiated sectoral programmes towards enhancing employment of older workers, social participation of older people in the society in a wider sense and also measures promoting health and independent living of older persons. PMID- 23346110 TI - Endocrine function in aging. PMID- 23346111 TI - Head and neck pathology and radiology 2011. PMID- 23346112 TI - Management of oropharyngeal Dysphagia in laryngeal and hypopharyngeal cancer. AB - On considering a function-preserving treatment for laryngeal and hypopharyngeal cancer, swallowing is a capital issue. For most of the patients, achieving an effective and safe deglutition will mark the difference between a functional and a dysfunctional outcome. We present an overview of the management of dysphagia in head and neck cancer patients. A brief review on the normal physiology of swallowing is mandatory to analyze next the impact of head and neck cancer and its treatment on the anatomic and functional foundations of deglutition. The approach proposed underlines two leading principles: a transversal one, that is, the multidisciplinary approach, as clinical aspects to be managed in the oncologic patient with oropharyngeal dysphagia are diverse, and a longitudinal one; that is, the concern for preserving a functional swallow permeates the whole process of the diagnosis and treatment, with interventions required at multiple levels. We further discuss the clinical reports of two patients who underwent a supracricoid laryngectomy, a function-preserving surgical technique that particularly disturbs the laryngeal mechanics, and in which swallowing rehabilitation dramatically conditions the functional results. PMID- 23346113 TI - Radiotherapy can cause haemostasis in bleeding skin malignancies. AB - Radiotherapy (RT) can cause haemostasis in select cases of malignant bleeding. We present two cases where RT was used to prevent fatal exsanguination from bleeding skin malignancies. Treatment was with radical intent in one case and palliative intent in the other. The dose used in both cases was 20 Gray (Gy) in 5 fractions. To our knowledge, this is the first report of radiation-induced haemostasis in bleeding skin malignancies. PMID- 23346114 TI - Laser Therapy of Recurrent Aphthous Ulcer in Patient with HIV Infection. AB - The recurrent aphthous ulcer (RAU) is a pathological change found in the oral mucosa, characterized by painful single or multiple ulcers. The etiologic aspect of RAU is not well understood; however it is known that due to lower CD4 cell counts patients had higher prevalence of these oral lesions, and immunosuppressed patients with HIV are predisposed. Patient FC is African descent, 26 years old, male, HIV + CD4 67 cells/mm(3), with minor RAU in the upper and lower right side lip, measuring about 4 mm, and major RAU in tongue and the tonsillar pillar measuring 2 cm. The patient was treated with laser therapy with the objective to help reverse the damage and decrease the symptoms. After one week there was remission of the lesions. The laser showed to be an important alternative therapy that promoted analgesic, healing effects and improving the quality of life of patients. PMID- 23346116 TI - Fitness and physical activity in children and youth with disabilities. PMID- 23346117 TI - Identification and Characterization of a Novel Nontranslated Sequence Variant of the Human Intestinal Di-/Tripeptide Transporter, hPEPT1. AB - The human H(+)-coupled di-/tripeptide transporter (hPEPT1) mediates intestinal absorption of dietary di- and tripeptides, as well as several peptidomimetic drug compounds. The aim of the present study was to investigate the possible role of the hPEPT1 variant hPEPT1-RF in hPEPT1 regulation. However, the proposed hPEPT1 RF mRNA sequence could not be detected in Caco-2 cells or in human intestinal samples. Instead, a new sequence variant, hPEPT1-RFI, was found, which is almost identical to the proposed hPEPT1-RF, except for two nucleotide insertions and one deletion that resulted in a changed open reading frame as compared to hPEPT1-RF. In vitro translation analysis showed that hPEPT1-RFI was not translated. In conclusion, the existence of hPEPT1-RF could not be confirmed; furthermore, the identified sequence variant, hPEPT1-RFI, does not appear to be translated and is therefore unlikely to have a regulatory effect on hPEPT1 transport activity. PMID- 23346115 TI - Neurally Derived Tissues in Xenopus laevis Embryos Exhibit a Consistent Bioelectrical Left-Right Asymmetry. AB - Consistent left-right asymmetry in organ morphogenesis is a fascinating aspect of bilaterian development. Although embryonic patterning of asymmetric viscera, heart, and brain is beginning to be understood, less is known about possible subtle asymmetries present in anatomically identical paired structures. We investigated two important developmental events: physiological controls of eye development and specification of neural crest derivatives, in Xenopus laevis embryos. We found that the striking hyperpolarization of transmembrane potential (V(mem)) demarcating eye induction usually occurs in the right eye field first. This asymmetry is randomized by perturbing visceral left-right patterning, suggesting that eye asymmetry is linked to mechanisms establishing primary laterality. Bilateral misexpression of a depolarizing channel mRNA affects primarily the right eye, revealing an additional functional asymmetry in the control of eye patterning by V(mem). The ATP-sensitive K(+) channel subunit transcript, SUR1, is asymmetrically expressed in the eye primordia, thus being a good candidate for the observed physiological asymmetries. Such subtle asymmetries are not only seen in the eye: consistent asymmetry was also observed in the migration of differentiated melanocytes on the left and right sides. These data suggest that even anatomically symmetrical structures may possess subtle but consistent laterality and interact with other developmental left-right patterning pathways. PMID- 23346118 TI - "We are not being heard": Aboriginal perspectives on traditional foods access and food security. AB - Aboriginal peoples are among the most food insecure groups in Canada, yet their perspectives and knowledge are often sidelined in mainstream food security debates. In order to create food security for all, Aboriginal perspectives must be included in food security research and discourse. This project demonstrates a process in which Aboriginal and non-Aboriginal partners engaged in a culturally appropriate and respectful collaboration, assessing the challenges and barriers to traditional foods access in the urban environment of Vancouver, BC, Canada. The findings highlight local, national, and international actions required to increase access to traditional foods as a means of achieving food security for all people. The paper underscores the interconnectedness of local and global food security issues and highlights challenges as well as solutions with potential to improve food security of both Aboriginal and non-Aboriginal peoples alike. PMID- 23346119 TI - Changes in lower urinary tract symptoms after prostate brachytherapy. AB - PURPOSE: To further define the bothersome lower urinary tract symptoms that occur after prostate brachytherapy (PB) by evaluating patient's responses to the individual questions of the urinary portion of the Expanded Prostate Cancer Index Composite (EPIC) survey and the AUA symptoms score in men undergoing PB. MATERIAL AND METHODS: A longitudinal, prospective study of 170 patients who have undergone PB at a single institution was performed. All patients were asked to complete the EPIC survey pre-operatively and at 2 weeks, 4 weeks, 3 months, and 6 months post operatively. Starting with the 75(th) patient in the cohort, patients were also asked to complete the AUA symptom score. RESULTS: The pattern of changes for each question is similar for both the EPIC survey and the AUA symptom score, with a marked worsening of symptoms at 2 and 4 weeks and an improvement to baseline by 3 to 6 months. Hematuria questions had the quickest and dysuria questions had the longest return to baseline. The dysuria questions had the greatest change and the incontinence questions had the smallest change in magnitude. Obstructive symptoms had a greater magnitude of change when compared to irritative symptoms, but the irritative symptoms took longer to return to baseline. CONCLUSIONS: The present study adds to the fund of knowledge regarding the bothersome lower urinary tract symptoms which occur after PB by analyzing the individual questions of both the urinary portion of the EPIC survey and the AUA symptom score. PMID- 23346120 TI - The use of nomograms in LDR-HDR prostate brachytherapy. AB - PURPOSE: The common use of nomograms in Low Dose Rate (LDR) permanent prostate brachytherapy (BT) allows to estimate the number of seeds required for an implant. Independent dosimetry verification is recommended for each clinical dosimetry in BT. Also, nomograms can be useful for dose calculation quality assurance and they could be adapted to High Dose Rate (HDR). This work sets nomograms for LDR and HDR prostate-BT implants, which are applied to three different institutions that use different implant techniques. MATERIAL AND METHODS: Patients treated throughout 2010 till April 2011 were considered for this study. This example was chosen to be the representative of the latest implant techniques and to ensure consistency in the planning. A sufficient number of cases for both BT modalities, prescription dose and different work methodology (depending on the institution) were taken into account. The specific nomograms were built using the correlation between the prostate volume and some characteristic parameters of each BT modality, such as the source Air Kerma Strength, number of implanted seeds in LDR or total radiation time in HDR. RESULTS: For each institution and BT modality, nomograms normalized to the prescribed dose were obtained and fitted to a linear function. The parameters of the adjustment show a good agreement between data and the fitting. It should be noted that for each institution these linear function parameters are different, indicating that each centre should construct its own nomograms. CONCLUSIONS: Nomograms for LDR and HDR prostate brachytherapy are simple quality assurance tools, specific for each institution. Nevertheless, their use should be complementary to the necessary independent verification. PMID- 23346122 TI - A modified COMS plaque for iris melanoma. AB - Melanoma of the iris is a rare condition compared to posterior ocular tumors and in this case report we present a 51-year-old female patient with diffuse iris melanoma. Traditional COMS (Collaborative Ocular Melanoma Study) plaques are used at our institution for radiation therapy, so a novel modification of the traditional plaque was required to allow better conformance with placement on the cornea. The usual silastic insert was machined to dimensions in compliance with the cornea, placed without incident, and treatment delivered with excellent patient tolerance of the modified plaque. PMID- 23346121 TI - Evaluation of the effect of prostate volume change on tumor control probability in LDR brachytherapy. AB - PURPOSE: This study evaluates low dose-rate brachytherapy (LDR) prostate plans to determine the biological effect of dose degradation due to prostate volume changes. MATERIAL AND METHODS: In this study, 39 patients were evaluated. Pre implant prostate volume was determined using ultrasound. These images were used with the treatment planning system (Nucletron Spot Pro 3.1((r))) to create treatment plans using (103)Pd seeds. Following the implant, patients were imaged using CT for post-implant dosimetry. From the pre and post-implant DVHs, the biologically equivalent dose and the tumor control probability (TCP) were determined using the biologically effective uniform dose. The model used RBE = 1.75 and alpha/beta = 2 Gy. RESULTS: The prostate volume changed between pre and post implant image sets ranged from -8% to 110%. TCP and the mean dose were reduced up to 21% and 56%, respectively. TCP is observed to decrease as the mean dose decreases to the prostate. The post-implant tumor dose was generally observed to decrease, compared to the planned dose. A critical uniform dose of 130 Gy was established. Below this dose, TCP begins to fall-off. It was also determined that patients with a small prostates were more likely to suffer TCP decrease. CONCLUSIONS: The biological effect of post operative prostate growth due to operative trauma in LDR was evaluated using the concept. The post-implant dose was lower than the planned dose due to an increase of prostate volume post implant. A critical uniform dose of 130 Gy was determined, below which TCP begun to decline. PMID- 23346123 TI - Biological equivalence between LDR and PDR in cervical cancer: multifactor analysis using the linear-quadratic model. AB - PURPOSE: The purpose of this work was the biological comparison between Low Dose Rate (LDR) and Pulsed Dose Rate (PDR) in cervical cancer regarding the discontinuation of the afterloading system used for the LDR treatments at our Institution since December 2009. MATERIAL AND METHODS: In the first phase we studied the influence of the pulse dose and the pulse time in the biological equivalence between LDR and PDR treatments using the Linear Quadratic Model (LQM). In the second phase, the equivalent dose in 2 Gy/fraction (EQD(2)) for the tumor, rectum and bladder in treatments performed with both techniques was evaluated and statistically compared. All evaluated patients had stage IIB cervical cancer and were treated with External Beam Radiotherapy (EBRT) plus two Brachytherapy (BT) applications. Data were collected from 48 patients (26 patients treated with LDR and 22 patients with PDR). RESULTS: In the analyses of the influence of PDR parameters in the biological equivalence between LDR and PDR treatments (Phase 1), it was calculated that if the pulse dose in PDR was kept equal to the LDR dose rate, a small the-rapeutic loss was expected. If the pulse dose was decreased, the therapeutic window became larger, but a correction in the prescribed dose was necessary. In PDR schemes with 1 hour interval between pulses, the pulse time did not influence significantly the equivalent dose. In the comparison between the groups treated with LDR and PDR (Phase 2) we concluded that they were not equivalent, because in the PDR group the total EQD(2) for the tumor, rectum and bladder was smaller than in the LDR group; the LQM estimated that a correction in the prescribed dose of 6% to 10% was ne-cessary to avoid therapeutic loss. CONCLUSIONS: A correction in the prescribed dose was necessary; this correction should be achieved by calculating the PDR dose equivalent to the desired LDR total dose. PMID- 23346124 TI - Does help structures play a role in reducing the variation of dwell time in IPSA planning for gynaecological brachytherapy application? AB - PURPOSE: To report our experience of dosimetric comparison of IPSA and manual plans, with a focus on the use of help structures (HS) during optimization. MATERIAL AND METHODS: 33 patients who underwent MR image-based HDR intracavitary brachytherapy for cervix cancer based on GYN-ESTRO recommendations were selected for evaluation. Tandem/ovoid (T/O) and Vienna applicators were used. HS of diameter of 5 mm were drawn around the tandem/needles/ovoid and ring. Three plans were generated: manual optimized plan (MOPT), IPSA without help structures (IPSA_woHS) and IPSA with help structures (IPSA_wHS). Dose-volume parameters and the loading pattern were evaluated. RESULTS: For T/O, the use of HS did not make significant impact in the dose-volume parameters and in the loading of tandem and ovoids, however steep variation was found in the individual dwell time. In case of Vienna applicator, inclusion of HS in the optimization made a significant impact in loading of needles. The percentage ratio of total time of needles to the tandem (T(N/T%)) was found to be 14+/-2.5, 53+/-9, 22+/-6 for MOPT, IPSA_woHS and IPSA_wHS, respectively, which implies that in IPSA_woHS the dwell time in needles were half of the dwell time in the tandem, while in MOPT the needles were loaded only in 14%, and in IPSA_wHS it was 22% of the dwell time of tandem. Inclusion of HS in the optimization has reduced the contribution of dwell time of needle in IPSA_wHS. The individual variation of dwell time was also reduced in IPSA_wHS, however drawing of HS is a time consuming procedure and may not be practical for a routine practice. CONCLUSION: The role of HS was evaluated for IPSA for T/O and Vienna-applicator, the use of HS may be beneficial in case of combined intracavitary - interstitial approach. PMID- 23346125 TI - Assessment of dose homogeneity in conformal interstitial breast brachytherapy with special respect to ICRU recommendations. AB - PURPOSE: To present the results of dose homogeneity analysis for breast cancer patients treated with image-based conformal interstitial brachytherapy, and to investigate the usefulness of the ICRU recommendations. MATERIAL AND METHODS: Treatment plans of forty-nine patients who underwent partial breast irradiation with interstitial brachytherapy were analyzed. Quantitative parameters were used to characterize dose homogeneity. Dose non-uniformity ratio (DNR), dose homogeneity index (DHI), uniformity index (UI) and quality index (QI) were calculated. Furthermore, parameters recommended by the ICRU 58 such as minimum target dose (MTD), mean central dose (MCD), high dose volume, low dose volume and the spread between local minimum doses were determined. Correlations between the calculated homogeneity parameters and usefulness of the ICRU parameters in image based brachytherapy were investigated. RESULTS: Catheters with mean number of 15 (range: 6-25) were implanted in median 4 (range: 3-6) planes. The volume of the PTV ranged from 15.5 cm(3) to 176 cm(3). The mean DNR was 0.32, the DHI 0.66, the UI 1.49 and the QI 1.94. Related to the prescribed dose, the MTD was 69% and the MCD 135%. The mean high dose volume was 8.1 cm(3) (10%), while the low dose volume was 63.8 cm(3) (96%). The spread between minimum doses in central plane ranged from -14% to +20%. Good correlation was found between the DNR and the DHI (R(2)=0.7874), and the DNR correlated well with the UI (R(2)=0.7615) also. No correlation was found between the ICRU parameters and any other volumetric parameters. CONCLUSIONS: To characterize the dose uniformity in high-dose rate breast implants, DVH-related homogeneity parameters representing the full 3D dose distributions are mandatory to be used. In many respects the current recommendations of the ICRU Report 58 are already outdated, and it is well-timed to set up new recommendations, which are more feasible for image-guided conformal interstitial brachytherapy. PMID- 23346126 TI - Long-term tumor control after brachytherapy for base-of-prostate cancer. AB - PURPOSE: To evaluate the outcomes of patients presenting with cancer at the base of the prostate after brachytherapy as monotherapy. MATERIAL AND METHODS: We retrospectively reviewed the medical records of all patients who had undergone transperineal ultrasound-guided implantation with (125)I or (103)Pd seeds as monotherapy between March 1998 and December 2006, at our institution. A minimum follow-up interval of 2 years was required for inclusion in our analysis. Dosimetry was assessed using computed tomography 30 days after the implant. Treatment failure was defined as the appearance of biopsy-proved tumor after seed implantation, radiographic evidence of metastases, receipt of salvage therapy, or elevation of the prostate-specific antigen level beyond the nadir value plus 2 ng/mL. RESULTS: With a median follow-up interval of 89 months (range 25-128 months), all 52 of the identified patients had no evidence of disease progression or biochemical failure. The mean number of cores sampled at the prostate base was 2.84 (median 2); Gleason scores assigned at central review were 6-8 in all patients. Of the 30 patients (58%) for whom dosimetric data were available at day 30, the median V100 values of the right and left base were 92.0% and 93.5%, respectively, and the median D90 values of the right and left base were 148 Gy and 151 Gy, respectively. CONCLUSION: Permanent prostate brachytherapy as monotherapy results in a high probability of disease-free survival for men with cancer at the base of the prostate. PMID- 23346127 TI - Biological effective doses in the intracavitary high dose rate brachytherapy of cervical cancer. AB - PURPOSE: The aim of this study is to evaluate the decrease of biological equivalent dose and its correlation with local/loco-regional control of tumour in the treatment of cervical cancer when the strength of the Ir-192 high dose rate (HDR) brachytherapy (BT) source is reduced to single, double and triple half life in relation to original strength of 10 Ci (~ 4.081 cGy x m(2) x h(-1)). MATERIAL AND METHODS: A retrospective study was carried out on 52 cervical cancer patients with stage II and III treated with fractionated HDR-BT following external beam radiation therapy (EBRT). International Commission on Radiation Units and Measurement (ICRU) points were defined according to ICRU Report 38, using two orthogonal radiograph images taken by Simulator (Simulix HQ). Biologically effective dose (BED) was calculated at point A for different Ir-192 source strength and its possible correlation with local/loco-regional tumour control was discussed. RESULT: The increase of treatment time per fraction of dose due to the fall of dose rate especially in HDR-BT of cervical cancer results in reduction in BED of 2.59%, 7.02% and 13.68% with single, double and triple half life reduction of source strength, respectively. The probabilities of disease recurrence (local/loco-regional) within 26 months are expected as 0.12, 0.12, 0.16, 0.39 and 0.80 for source strength of 4.081, 2.041, 1.020, 0.510 and 0.347 cGy x m(2) x h( 1), respectively. The percentages of dose increase required to maintain the same BED with respect to initial BED were estimated as 1.71, 5.00, 11.00 and 15.86 for the dose rate of 24.7, 12.4, 6.2 and 4.2 Gy/hr at point A, respectively. CONCLUSIONS: This retrospective study of cervical cancer patients treated with HDR-BT at different Ir-192 source strength shows reduction in disease free survival according to the increase in treatment time duration per fraction. The probable result could be associated with the decrease of biological equivalent dose to point A. Clinical end point of this study is more significant from double half life reduction of original source strength. PMID- 23346128 TI - Comparison of apparent diffusion coefficient maps to T2-weighted images for target delineation in cervix cancer brachytherapy. AB - PURPOSE: T2-weighted (T2W) magnetic resonance imaging (MRI) has been used for target delineation in cervix cancer brachytherapy. The objective of this study was to examine the feasibility of using diffusion-weighted magnetic resonance imaging (DWI) for target delineation as compared against T2W imaging. MATERIAL AND METHODS: Fifteen cervix cancer patients, implanted with tandem and ovoid applicators, underwent T2W turbo-spin echo imaging and DWI with a maximum diffusion factor of 800 sec/mm(2) on a 1.5-T MR scanner. Apparent diffusion coefficient (ADC) maps were derived from the DWI. The gross tumor volume was manually delineated on the T2W and ADC datasets for each patient. The agreement between T2W- and ADC-delineated volumes was assessed using the Dice similarity coefficient (DSC). An algorithm was developed to compare the edge contrast of the delineated volumes on T2W images and ADC maps by calculating the percentage difference in the intensity values of selected regions of pixels inside versus outside the target contour. RESULTS: ADC-delineated volumes were generally smaller than T2W-delineated volumes, yielding a low DSC of 0.54 +/- 0.22. ADC maps were found to display superior definition of the target volume edge relative to T2W images, yielding a statistically significant difference between the mean edge contrast on ADC (12.7 +/- 7.7%) versus that on T2W images (4.6 +/- 3.2%; p = 0.0010). CONCLUSIONS: These results suggest that incorporating the use of DWI for cervix cancer brachytherapy may yield gross tumor volumes that are different from those based on T2W images alone. PMID- 23346129 TI - Comparison of (60)Co and (192)Ir sources in HDR brachytherapy. AB - This paper compares the isotopes (60)Co and (192)Ir as radiation sources for high dose-rate (HDR) afterloading brachytherapy. The smaller size of (192)Ir sources made it the preferred radionuclide for temporary brachytherapy treatments. Recently also (60)Co sources have been made available with identical geometrical dimensions. This paper compares the characteristics of both nuclides in different fields of brachytherapy based on scientific literature. In an additional part of this paper reports from medical physicists of several radiation therapy institutes are discussed. The purpose of this work is to investigate the advantages or disadvantages of both radionuclides for HDR brachytherapy due to their physical differences. The motivation is to provide useful information to support decision-making procedures in the selection of equipment for brachytherapy treatment rooms. The results of this work show that no advantages or disadvantages exist for (60)Co sources compared to (192)Ir sources with regard to clinical aspects. Nevertheless, there are potential logistical advantages of (60)Co sources due to its longer half-life (5.3 years vs. 74 days), making it an interesting alternative especially in developing countries. PMID- 23346130 TI - Effect of using different U/S probe Standoff materials in image geometry for interventional procedures: the example of prostate. AB - PURPOSE: This study investigates the distortion of geometry of catheters and anatomy in acquired U/S images, caused by utilizing various stand-off materials for covering a transrectal bi-planar ultrasound probe in HDR and LDR prostate brachytherapy, biopsy and other interventional procedures. Furthermore, an evaluation of currently established water-bath based quality assurance (QA) procedures is presented. MATERIAL AND METHODS: Image acquisitions of an ultrasound QA setup were carried out at 5 MHz and 7 MHz. The U/S probe was covered by EA 4015 Silicone Standoff kit, or UA0059 Endocavity balloon filled either with water or one of the following: 40 ml of Endosgel((r)), Instillagel((r)), Ultraschall gel or Space OARTM gel. The differences between images were recorded. Consequently, the dosimetric impact of the observed image distortion was investigated, using a tissue equivalent ultrasound prostate phantom - Model number 053 (CIRS Inc., Norfolk, VA, USA). RESULTS: By using the EA 4015 Silicone Standoff kit in normal water with sound speed of 1525 m/s, a 3 mm needle shift was observed. The expansion of objects appeared in radial direction. The shift deforms also the PTV (prostate in our case) and other organs at risk (OARs) in the same way leading to overestimation of volume and underestimation of the dose. On the other hand, Instillagel((r)) and Space OARTM "shrinks" objects in an ultrasound image for 0.65 mm and 0.40 mm, respectively. CONCLUSIONS: The use of EA 4015 Silicone Standoff kit for image acquisition, leads to erroneous contouring of PTV and OARs and reconstruction and placement of catheters, which results to incorrect dose calculation during prostate brachytherapy. Moreover, the reliability of QA procedures lies mostly in the right temperature of the water used for accurate simulation of real conditions of transrectal ultrasound imaging. PMID- 23346131 TI - Dose perturbation study in a multichannel breast brachytherapy device. AB - PURPOSE: A study was conducted to determine the dosimetric effects resulting from air pockets and high atomic number (Z) contrast medium within a multichannel breast brachytherapy device. MATERIAL AND METHODS: A 5-6 cm diameter Contura (SenoRx) brachytherapy device was inflated using 37 cm(3) of saline. Baseline dose falloff from an HDR Iridium-192 source was measured with the Iridium source centered in the central channel and an anterior off-center channel. Data were collected at distances from 1 to 50 mm. Comparison studies were conducted with identically inflated volume containing varied air pocket volumes (1-4 cm(3)) and concentrations of contrast solution (3%, 6%, and 9% by volume). Dose perturbation factors (DPF) were computed and evaluated. RESULTS: Dose perturbations due to air pockets and contrast solutions were observed. As the volume of air increased, the DPF increased by approximately 2.25%/cm(3). The effect was consistent for both channels. The contrast effects were more complex. The 3% contrast media had minimal dose perturbation. The 6% contrast solution caused dose reduction of 1.0% from the central channel but 1.5% dose increase from the anterior channel. The 9% contrast solution caused dose reductions by 4.0% (from central channel) and 3.0% (from anterior channel). The DPF from all contrast solutions moderated with increasing distance. CONCLUSIONS: Dose perturbations due to air pockets and high Z contrast solution can be significant. It is important to control these effects to avoid dose errors. PMID- 23346133 TI - Impact of point A asymmetry on local control and survival for low dose-rate (LDR) brachytherapy in cervical cancer. AB - PURPOSE: To evaluate whether Point A asymmetry in low dose-rate (LDR) brachytherapy is associated with local control (LC), disease-free survival (DFS) and/or overall survival (OS). MATERIAL AND METHODS: A retrospective analysis of disease control and survival outcomes was conducted for patients who underwent LDR brachytherapy for advanced cervical cancer. Institutional protocol entailed concurrent chemotherapy and whole pelvis radiotherapy (WPRT) over 5 weeks, followed by placement of Fletcher-Suit tandem and colpostat applicators at weeks 6 and 8. Objective Point A doses, 80-85 Gy, were accomplished by placement of Cesium-137 (Cs-137) sources. Cox proportional hazards regression models were used to assess associations between disease control and survival endpoints with variables of interest. RESULTS: The records of 50 patients with FIGO stage IB1 IVA cervical cancer undergoing LDR brachytherapy at our institution were identified. Thirty of these patients had asymmetry > 2.5%, and 11 patients had asymmetry > 5%. At a median survivor follow-up of 20.25 months, 15 patients had experienced disease failure (including 5 cervical/vaginal apex only failures and 2 failures encompassing the local site). Right/left dose asymmetry at Point A was associated with statistically significantly inferior LC (p = 0.035) and inferior DFS (p = 0.011) for patients with mean Point A dose of > 80 Gy. Insufficient evidence existed to conclude an association with OS. CONCLUSIONS: LDR brachytherapy may be associated with clinically significant dose asymmetry. The present study demonstrates that patients with Point A asymmetry have a higher risk of failure for DFS and LC. PMID- 23346132 TI - Penile cancer brachytherapy HDR mould technique used at the Holycross Cancer Center. AB - The aim of this pictorial essay is to present the mould based HDR brachytherapy technique used at the Holycross Cancer Center for penile cancer patients. We use images to describe this method step by step. PMID- 23346134 TI - Acute toxicity and early cosmetic outcome in patients treated with multilumen balloon brachytherapy with skin spacing <= 7.0 millimeters. AB - PURPOSE: To review institutional experience treating patients who underwent breast conserving surgery and adjuvant accelerated partial breast irradiation with multilumen balloon brachytherapy (MLB) with close skin spacing (<=7 mm). MATERIAL AND METHODS: Since July 2009, 26 patients with skin spacing <= 7.0 mm were treated with breast-conserving therapy and adjuvant MLB brachytherapy. Patients were treated with either the Contura or MammoSite ML catheter to a total dose of 34 Gy in 10 fractions. Patients were assessed for acute toxicity at the completion of treatment and 1-month post treatment. Cosmesis and late toxicity were assessed at three-month intervals thereafter. RESULTS: The median age of the patients was 56 years and median follow-up was 9 months. Sixteen patients had skin spacing of 5.0-7.0 mm, 10 with < 5.0 mm (median 5.8). The median percentage of the target (PTV_EVAL) receiving >= 95% of the prescription dose was 95.6%. The median volume of PTV_EVAL receiving >= 200% of the prescription dose was 6.1 cc. The maximum skin dose was 118.2% (median). The most commonly observed acute toxicity was grade 1-2 dermatitis (65.4%). The rate of post-treatment seroma and infection was 38.5% and 3.8%, respectively. Excellent/good cosmetic outcomes seen at the time of last follow-up was 92.3%. CONCLUSIONS: MLB brachytherapy is safe and feasible in patients with close skin spacing, with acute toxicity and early cosmesis similar to other published series. These devices may broaden the application of balloon brachytherapy in patients previously excluded from this treatment based on anatomy. PMID- 23346135 TI - Dose gradient impact on equivalent dose at 2 Gy for high dose rate interstitial brachytherapy. AB - PURPOSE: To evaluate a new calculation model estimating the equivalent dose at 2 Gy (EQD2) taking into account dose gradient in high dose rate interstitial brachytherapy (HDRIB). MATERIAL AND METHODS: Forty dose-volume histograms (DVHs) of breast (20 pts) and prostate (20 pts) cancer dose distributions were reviewed. Physical prescribed doses (PPD) were 34 Gy (10f/5d) and 18 Gy (6f/2d) for breast (partial irradiation protocol) and prostate (boost after external irradiation) treatment, respectively. For each DVH, clinical target volume (CTV), V100, V150, V200, D90 and D100 were determined. Based on DVH segmentation, elementary doses (d) delivered to elementary volumes were determined, then multiplied by C (% of CTV receiving d). According to the linear quadratic model, EQD2 was calculated for different alpha/beta ratios. RESULTS: For breast implant, median EQD2 (alpha/beta = 4) was 42 Gy and 76 Gy (66-85) without and with dose gradient consideration, respectively. For prostate implant, median EQD2 (alpha/beta = 1.5) was 39 Gy and 98 Gy (90-103) whether dose gradient was not or was taken into account, respectively. CONCLUSIONS: This study pointed out that for brachytherapy, EQD2 calculation must take into account the dose gradient. Because this model is a mathematical one, it has to be cautiously applied. Nevertheless, it appears as a useful tool for EQD2 comparison between the same PPD delivered through EBRT or brachytherapy regarding trial result interpretation. PMID- 23346136 TI - I-125 seed calibration using the SeedSelectron((r)) afterloader: a practical solution to fulfill AAPM-ESTRO recommendations. AB - PURPOSE: SeedSelectron((r)) v1.26b (Nucletron BV, The Netherlands) is an afterloader system used in prostate interstitial permanent brachytherapy with I 125 selectSeed seeds. It contains a diode array to assay all implanted seeds. Only one or two seeds can be extracted during the surgical procedure and assayed using a well chamber to check the manufacturer air-kerma strength (S(K)) and to calibrate the diode array. Therefore, it is not feasible to assay 5-10% seeds as required by the AAPM-ESTRO. In this study, we present a practical solution of the SeedSelectron((r)) users to fulfill the AAPM- ESTRO recommendations. MATERIAL AND METHODS: THE METHOD IS BASED ON: a) the SourceCheck((r)) well ionization chamber (PTW, Germany) provided with a PTW insert; b) n = 10 selectSeed from the same batch and class as the seeds for the implant; c) the Nucletron insert to accommodate the n = 10 seeds on the SourceCheck((r)) and to measure their averaged S(K). Results for 56 implants have been studied comparing the S(K) value from the manufacturer with the one obtained with the n = 10 seeds using the Nucletron insert prior to the implant and with the S(K) of just one seed measured with the PTW insert during the implant. RESULTS: We are faced with S(K) deviation for individual seeds up to 7.8%. However, in the majority of cases S(K) is in agreement with the manufacturer value. With the method proposed using the Nucletron insert, the large deviations of S(K) are reduced and for 56 implants studied no deviation outside the range of the class were found. CONCLUSIONS: The new Nucletron insert and the proposed procedure allow to evaluate the S(K) of the n = 10 seeds prior to the implant, fulfilling the AAPM-ESTRO recommendations. It has been adopted by Nucletron to be extended to seedSelectron((r)) users under request. PMID- 23346137 TI - On the feasibility of treating to a 1.5 cm PTV with a commercial single-entry hybrid applicator in APBI breast brachytherapy. AB - PURPOSE: To evaluate and determine whether 30 patients previously treated with the SAVITM device could have been treated to a PTV_EVAL created with a 1.5 cm expansion. This determination was based upon dosimetric parameters derived from current recommendations and dose-response data. MATERIAL AND METHODS: Thirty patients were retrospectively planned with PTV_EVALs generated with a 1.5 cm expansion (PTV_EVAL_1.5). Plans were evaluated based on PTV_EVAL_1.5 coverage (V90, V95, V100), skin and rib maximum doses (0.1 cc maximum dose as a percentage of prescription dose), as well as V150 and V200 for the PTV_EVAL_1.5. The treatment planning goal was to deliver >=90% of the prescribed dose to >=90% of the PTV_EVAL_1.5. Skin and rib maximum doses were to be <=125% of the prescription dose and preferably <=100% of the prescription dose. V150 and V200 were not allowed to exceed 52.5 cc and 21 cc, respectively. Plans not meeting the above criteria were recomputed with a 1.25 cm expanded PTV_EVAL and re-evaluated. RESULTS: Based on the above dose constraints, 30% (9/30) of the patients evaluated could have been treated with a 1.5 cm PTV_EVAL. The breakdown of cases successfully achieving the above dose constraints by applicator was: 0/4 (0%) 6 1, 6/15 (40%) 8-1, and 3/11 (27%) 10-1. For these PTV_EVAL_1.5 plans, median V90% was 90.3%, whereas the maximum skin and rib doses were all less than 115.2% and 117.6%, respectively. The median V150 and V200 volumes were 39.2 cc and 19.3, respectively. The treated PTV_EVAL_1.5 was greater in volume than the PTV_EVAL by 41.7 cc, and 60 cc for the 8-1, and 10-1 applicators, respectively. All remaining plans (17) successfully met the above dose constraints to be treated with a 1.25 cm PTV_EVAL (PTV_EVAL_1.25). For the PTV_EVAL_1.25 plans, V90% was 93.7%, and the maximum skin and rib doses were all less than 109.2% and 102.5%, respectively. The median V150 and V200 volumes were 41.2 cc and 19.3, respectively. The treated PTV_EVAL_1.25 was greater in volume than the PTV_EVAL by 16 cc, 24.9 cc, and 33.5 cc for the 6-1, 8-1 and 10-1 applicators, respectively. CONCLUSIONS: It is dosimetrically possible to treat beyond the currently advised 1.0 cm expanded PTV_EVAL. Most patients should be able to be treated with a 1.25 cm PTV_EVAL and a select group with a 1.5 cm PTV_EVAL. Applicator size appears to determine the ability to expand to a 1.5 cm PTV_EVAL, as smaller devices were not as propitious in this regard. Further studies may identify additional patient groups that would benefit from this approach. PMID- 23346138 TI - Monte Carlo dosimetric study of the Flexisource Co-60 high dose rate source. AB - PURPOSE: Recently, a new HDR (60)Co brachytherapy source, Flexisource Co-60, has been developed (Nucletron B.V. Veenendaal, The Netherlands). This study aims to obtain dosimetric data for this source for its use in clinical practice as required by AAPM and ESTRO. MATERIAL AND METHODS: TWO MONTE CARLO RADIATION TRANSPORT CODES WERE USED: Penelope2008 and GEANT4. The source was centrally positioned in a 100 cm radius water phantom. Absorbed dose and collisional kerma were obtained using 0.01 cm (close) and 0.1 cm (far) sized voxels to provide high resolution dosimetry near (far from) the source. Dose rate distributions obtained with the two Monte Carlo codes were compared. RESULTS AND DISCUSSION: Simulations performed with those two radiation transport codes showed an agreement typically within 0.2% for r > 0.8 cm and up to 2% closer to the source. Detailed results of dose distributions are being made available. CONCLUSIONS: Dosimetric data are provided for the new Flexisource Co-60 source. These data are meant to be used in treatment planning systems in clinical practice. PMID- 23346139 TI - Progressive transition from pre-planned to intraoperative optimizing seed implant: post implementation analysis. AB - PURPOSE: To perform a dosimetric comparison between a pre-planned technique and a pre-plan based intraoperative technique in prostate cancer patients treated with I-125 permanent seed implantation. MATERIAL AND METHODS: Thirty patients were treated with I-125 permanent seed implantation using TRUS guidance. The first 15 of these patients (Arm A) were treated with a pre-planned technique using ultrasound images acquired prior to seed implantation. To evaluate the reproducibility of the prostate volume, ultrasound images were also acquired during the procedure in the operating room (OR). A surface registration was applied to determine the 6D offset between different image sets in arm A. The remaining 15 patients (Arm B) were planned by putting the pre-plan on the intraoperative ultrasound image and then re-optimizing the seed locations with minimal changes to the pre-plan needle locations. Post implant dosimetric analyses included comparisons of V(100)(prostate), D(90)(prostate) and V(100)(rectum). RESULTS: In Arm A, the 6D offsets between the two image sets were theta(x)=-1.4+/-4.3; theta(y)=-1.7+/-2.6; theta(z)=-0.5+/-2.6; X=0.5+/-1.8 mm; Y= 1.3+/--3.5 mm; Z=-1.6+/-2.2 mm. These differences alone degraded V(100) by 6.4% and D(90) by 9.3% in the pre-plan, respectively. Comparing Arm A with Arm B, the pre-plan based intraoperative optimization of seed locations used in the plans for patients in Arm B improved the V(100) and D(90) in their post-implant studies by 4.0% and 5.7%, respectively. This was achieved without significantly increasing the rectal dose (V(100)(rectum)). CONCLUSIONS: We have progressively moved prostate seed implantation from a pre-planned technique to a pre-plan based intraoperative technique. In addition to reserving the advantage of cost effective seed ordering and efficient OR implantation, our intraoperative technique demonstrates increased accuracy and precision compared to the pre planned technique. PMID- 23346140 TI - Treatment planning study of the 3D dosimetric differences between Co-60 and Ir 192 sources in high dose rate (HDR) brachytherapy for cervix cancer. AB - PURPOSE: To evaluate whether Co-60 is equivalent to Ir-192 for HDR cervical brachytherapy, through 3D-DVH dose comparisons in standard and optimised plans. Previous studies have only considered 2D dosimetry, point dose comparisons or identical loading. Typical treatment times and economics are considered. MATERIAL AND METHODS: Plans were produced for eight cervix patients using Co-60 and Ir-192 sources, CT imaging and IU/two-channel-ring applicator (Eckert Ziegler BEBIG). The comparison was made under two conditions: (A) identical dwell positions and loading, prescribed to Point A and (B) optimised source dwells, prescribed to HR CTV. This provided a direct comparison of inherent differences and residual differences under typical clinical plan optimisation. The DVH (target and OAR), ICRU reference points and isodose distributions were compared. Typical treatment times and source replacement costs were compared. RESULTS: Small differences (p < 0.01) in 3D dosimetry exist when using Co-60 compared to Ir-192, prescribed to Point A with identical loading patterns, particularly 3.3% increase in rectum D2cc. No significant difference was observed in this parameter when prescribing to the HR-CTV using dwell-time optimisation. There was no statistically significant difference in D90 between the two isotopes. Co-60 plans delivered consistently higher V150% (mean +4.4%, p = 0.03) and V400% (mean +11.6%, p < 0.01) compared to Ir-192 in optimised plans. Differences in physical source properties were overwhelmed by geometric effects. CONCLUSIONS: Co-60 may be used as an effective alternative to Ir-192 for HDR cervix brachytherapy, producing similar plans of equivalent D90, but with logistical benefits. There is a small dose increase along the extension of the source axis when using Co-60 compared to Ir-192, leading to small rectal dose increases for identical loading patterns. This can be eliminated by planning optimisation techniques. Such optimisation may also be associated with increases in the overdose volume (V150-V400) with Co-60 compared to Ir-192. PMID- 23346141 TI - Non isocentric film-based intracavitary brachytherapy planning in cervical cancer: a retrospective dosimetric analysis with CT planning. AB - PURPOSE: To compare intracavitary brachytherapy dose estimation for organs at risk (bladder and rectum) based on semi-orthogonal reconstruction of radiographs on non-isocentric X-ray unit and Computed Tomography (CT) - based volumetric planning in cervical cancer. MATERIAL AND METHODS: Bladder and rectal points as per International Commission on Radiation Units and Measurements (ICRU) report 38, were retrospectively evaluated on 15 high dose rate intracavitary brachytherapy applications for cervical cancer cases. With the same source configuration as obtained during planning on radiographs performed on a non isocentric X-ray unit, the mean doses to 2cc of most irradiated part of bladder and rectum were computed by CT planning and these estimates were compared with the doses at ICRU bladder and rectal points. RESULTS: The mean ICRU point dose for bladder was 3.08 Gy (1.9-5.9 Gy) and mean dose to 2 cc (D2cc) bladder was 6.91 Gy (2.9-12.2 Gy). ICRU rectal dose was 3.8 Gy (2.4-4.45 Gy) and was comparable with D2cc rectum dose 4.2 Gy (2.8-5.9 Gy). Comparison of mean total dose (ICRU point vs. D2cc) for each patient was found to be significantly different for bladder (p = 0.000), but not for rectum (p = 0.08). CONCLUSIONS: On comparison of ICRU point based planning with volumetric planning on CT, it was found that bladder doses were underestimated by the film based method. However, the rectal doses were found to be similar to the D2cc doses. The results with non isocentric film based treatment planning were similar to the existing literature on orthogonal film based simulator planning. PMID- 23346142 TI - Dosimetry and toxicity outcomes in postoperative high-dose-rate intracavitary brachytherapy for endometrial carcinoma. AB - PURPOSE: The optimal dosimetric parameters and planning techniques for high-dose rate vaginal brachytherapy (HDR-VB) are unclear. Our aim was to evaluate the utility of bladder and rectal dosimetry for patients receiving HDR-VB for postoperative treatment of endometrial carcinoma. MATERIAL AND METHODS: Patients with endometrial cancer who underwent postoperative HDR-VB from January 1, 2004 through December 31, 2010 were included. All patients underwent primary surgery consisting of total hysterectomy and bilateral salpingo-oophrectomy (TH-BSO) with or without lymph node dissection and were treated with HDR-VB without pelvic external beam radiotherapy (EBRT) or chemotherapy. Demographic, pathologic, dosimetric and clinical data were collected. RESULTS: One hundred patients were identified with the majority of patients receiving HDR-VB in 700 cGy * 3 fractions (45%) or 550 cGy x 4 fractions (53%). No plan was altered based on bladder dosimetry at the time of planning. The rate of acute urinary reactions (< 90 days from beginning of RT) grades 1 and 2 were 14% and 2%, respectively. The rate of late urinary reactions (> 90 days after RT) grades 1 and 2 were 7% and 3%, respectively. Dose to the bladder point did not correlate with urinary toxicity. No rectal toxicity was reported by patients receiving HDR-VB. CONCLUSIONS: In the setting of HDR-VB without EBRT, the measured dose to the bladder point does not predict urinary toxicity and is very unlikely to indicate the need to change the treatment plan. The treatment of endometrial carcinoma utilizing HDR-VB alone is associated with very low rates of high-grade acute or late bladder toxicity. PMID- 23346143 TI - Benefits of a dual sagittal crystal transducer for ultrasound imaging during I 125 seed implantation for permanent prostate brachytherapy. AB - PURPOSE: To investigate whether a longer sagittal view and less movement using a dual sagittal crystal probe (DSCP) for trans rectal ultra sound (TRUS) allow for more accurate online-planning in I-125 permanent implant brachytherapy of the prostate, compared to a single sagittal crystal probe (SSCP). MATERIAL AND METHODS: Between March 2008 and March 2010, 50 patients with prostate cancer were consecutively included in the study. The first 25 of these patients had both their pre- and online-planning based on a single sagittal crystal probe (SSCP). The treatment-plans of the other 25 patients were based on a DSCP TRUS. Three weeks after implantation a post-planning was made based on CT. TRUS online and CT post-plan dose-volume histogram (DVH) parameters, D(90) and V(100), were compared for both groups. Also, the post-plan DVH parameters of SSCP were compared to DSCP. The possible factors that might influence the post-plan D(90) and V(100) were analysed using Analysis of Variance (ANOVA). RESULTS: SSCP and DSCP online mean D(90) and V(100) were significantly larger than post-plan mean D(90) and V(100) (P < 0.01). The post-plan mean D(90) and mean V(100) were both non significantly larger for SSCP based post-plans compared to DSCP based post plans (P = 0.76 and P = 0.68). ANOVA showed significant impact of prostate volume on the post-plan D(90) and V(100). CONCLUSIONS: The advantages of the dual sagittal crystal probe did not lead to more accurate online planning by investigating DVH parameters. The only factor found to have influence on the DVH-parameters was the prostate volume. PMID- 23346144 TI - A proposed protocol on HDR cylinder treatments: proof of avoidance of re-planning of CT based fractionated treatment, using a critical, statistical and graphical analysis of clinical data. AB - PURPOSE: An evaluation of CT plan data, using cylinder applicators, in fractionated HDR treatments of cervical cancers has been investigated in this clinical study. Critical and statistical analysis of the data, for each patient and fraction, for plan dose, doses for bladder and rectum have been enumerated and reported. Plans were done for each patient, following CT scans after insertion of the applicator in the respective cases. This process involved time for CT-scan and re-plan, in each fraction, adding cost of treatments for the poor patients. MATERIAL AND METHODS: This study on HDR brachytherapy for cervical cancer patients has applied the Co-60 BEBIG Multisource Unit. Cylinder applicators have been applied for treatments. A selection of twenty nine patients, out of a few hundred representative female patients, in the age group of 40-70 years, has been analyzed and presented in this paper. Radiation oncologists inserted the applicator and fixed it in more than 600 treatments. This study, therefore, aimed at their insertion technique, CT-planning by radiation oncology physicists and the delivery of the treatments. Details of set up and technique has been explained, where bladder and rectum doses has been assessed within the tolerance limit [1]. RESULTS: Statistical analysis of data from the treatment plans, substantiates the conclusion of the argument that there is no need to do CT-plans for each subsequently prescribed number of fractions as the doses in plan, bladder and rectum are restricted within the limits of tolerance. Data in Table 1 are analyzed in various graphs. This utilized the Empirical Null Distribution of Group Differences. A graphic study of dose distribution is reported to assure the expected variation of dose from the central tandem. This analysis proves to substantiate a protocol that no re-plan for fractionated delivery is essential following the approval of the first plan. CONCLUSIONS: The goal of this study was to critically evaluate the outcome of fractionated cylinder treatments of cervical cancers. This resulted in the set up technique for insertion of applicators and treatment plan, following a CT-scan and the assertion of the argument that re-plans are not necessary for multiple HDR cylinder treatments for the same patient [2, 3]. PMID- 23346146 TI - Keeping an eye on the ring: COMS plaque loading optimization for improved dose conformity and homogeneity. AB - PURPOSE: To improve tumor dose conformity and homogeneity for COMS plaque brachytherapy by investigating the dosimetric effects of varying component source ring radionuclides and source strengths. MATERIAL AND METHODS: The MCNP5 Monte Carlo (MC) radiation transport code was used to simulate plaque heterogeneity corrected dose distributions for individually-activated source rings of 14, 16 and 18 mm diameter COMS plaques, populated with (103)Pd, (125)I and (131)Cs sources. Ellipsoidal tumors were contoured for each plaque size and MATLAB programming was developed to generate tumor dose distributions for all possible ring weighting and radionuclide permutations for a given plaque size and source strength resolution, assuming a 75 Gy apical prescription dose. These dose distributions were analyzed for conformity and homogeneity and compared to reference dose distributions from uniformly-loaded (125)I plaques. The most conformal and homogeneous dose distributions were reproduced within a reference eye environment to assess organ-at-risk (OAR) doses in the Pinnacle(3) treatment planning system (TPS). The gamma-index analysis method was used to quantitatively compare MC and TPS-generated dose distributions. RESULTS: Concentrating > 97% of the total source strength in a single or pair of central (103)Pd seeds produced the most conformal dose distributions, with tumor basal doses a factor of 2-3 higher and OAR doses a factor of 2-3 lower than those of corresponding uniformly loaded (125)I plaques. Concentrating 82-86% of the total source strength in peripherally-loaded (131)Cs seeds produced the most homogeneous dose distributions, with tumor basal doses 17-25% lower and OAR doses typically 20% higher than those of corresponding uniformly-loaded (125)I plaques. Gamma-index analysis found > 99% agreement between MC and TPS dose distributions. CONCLUSIONS: A method was developed to select intra-plaque ring radionuclide compositions and source strengths to deliver more conformal and homogeneous tumor dose distributions than uniformly-loaded (125)I plaques. This method may support coordinated investigations of an appropriate clinical target for eye plaque brachytherapy. PMID- 23346145 TI - Brachytherapy in accelerated partial breast irradiation (APBI) - review of treatment methods. AB - Breast conserving surgery (BCS) with following radiotherapy (EBRT) of the conserved breast became widely accepted in the last decades as the treatment of early invasive breast cancer. In an early stage of breast cancer, research has shown that the area requiring radiation treatment to prevent cancer from local recurrence is the breast tissue that surrounds the area where the initial cancer was removed. Accelerated partial breast irradiation (APBI) is an approach that treats only the lumpectomy bed with 1-2 cm margin, rather than the whole breast and as a result allows accelerated delivery of the radiation dose in four to five days. Published results of APBI are very promising. It is evident that APBI will play a role in the management of a selected group of early breast cancer. We discuss current status, indications, technical aspects and recently published results of APBI using different brachytherapy techniques. PMID- 23346147 TI - Re-implantation of suboptimal prostate seed implantation: technique with intraoperative treatment planning. AB - PURPOSE: Post-implant dosimetry following prostate seed implantation (PSI) occasionally reveals suboptimal dosimetric coverage of the gland. Published reports of re-implantation techniques have focused on earlier-generation techniques, including preplanned approaches and stranded seeds. The purpose of this case report is to describe a customizable approach to perform corrective re implantation using loose seeds and intraoperative planning technique. MATERIAL AND METHODS: This case report describes a 63-year-old male with favorable risk prostate adenocarcinoma receiving PSI. Thirty day post-implant dosimetric evaluation revealed suboptimal coverage of the base of the gland. Using guidance from post-implant CT-images and real-time planning, the patient received a corrective re-implantation with intraoperative planning. RESULTS: Post-implant dosimetry after re-implantation procedure with intraoperative planning yielded improved target volume coverage that achieved standard dosimetric criteria. CONCLUSIONS: Re-implantation as a salvage treatment technique after sub-optimal PSI is a valid treatment option performed with intraoperative real-time planning. PMID- 23346148 TI - Investigation of DNA sequence in the Basal core promoter, precore, and core regions of hepatitis B virus from Tunisia shows a shift in genotype prevalence. AB - BACKGROUND: In this study, we evaluated the prevalence of the most common mutations occurring in Enhancer II (EnhII), Basal Core Promoter (BCP), Precore (PC), and Core (C) regions of hepatitis B virus (HBV) genome. OBJECTIVES: We also investigated the correlation between HBV variants, their genotypes, and patients' HBe antigen (HBeAg: soluble shape of the capsid antigen) status. PATIENTS AND METHODS: We retrieved viral DNA from 40 serum samples of Tunisian patients positive for hepatitis B surface antigen (HBsAg) and HBV DNA, amplified the above mentioned regions using specific primers, and sequenced the corresponding PCR (polymerase chain reaction) products. For further analysis purpose, the patients were divided into two groups: Group1 including 34 HBeAg-negative patients and Group2 with 6 HBeAg-positive patients. RESULTS: Twenty-one patients (52.5%) showed PC G1896A mutation and 11 (27.5%) carried A1762T/G1764A double mutations. These mutations were more frequent in HBeAg-negative patients than that in HBeAg positive ones. Indeed, 58.8% of patients bearing G1896A mutation were HBeAg negative while 16.7% were positive. In patients bearing T1762/A1764 double mutation, 29.4% were positive and 16.7% were negative. In addition, the A1896 mutation was restricted to HBV isolates that had wild-type T1858, while C1858 was rather linked to the occurrence of T1762/A1764 mutation. Interestingly, this study revealed a high frequency of genotype E. This frequency was important as compared to that of genotype D known to be predominant in the country as delineated in previous studies. CONCLUSIONS: Previous results supported and showed that HBV strains present in Tunisia belonging to genotype D and, to a lesser extent, to genotype E, were prone to mutations in BCP/ PC regions. This observation was more obvious in HBV isolates from asymptomatic chronic carriers (AsC). The high mutational rates observed in our study might result from a mechanism of viral escape that plays an important role in the loss of HBeAg. PMID- 23346149 TI - Non-invasive prediction of hepatic fibrosis in patients with chronic HCV based on the routine pre-treatment workup. AB - BACKGROUND: Hepatic fibrosis is an inclusion indicator for treatment and a major independent predictor of treatment response in patients with chronic hepatitis C. Liver biopsy, considered as the "gold standard" for evaluating liver fibrosis, has carried some drawbacks. Currently used noninvasive predictors of fibrosis are considered less accurate than liver biopsy. OBJECTIVES: Our aim was to assess noninvasive predictors of fibrosis in patients with chronic hepatitis C using the routine laboratory pre-treatment workup. PATIENTS AND METHODS: Cross sectional study including 4289 Egyptian patients with chronic hepatitis C were assessed for the need to interferon and ribavirin therapy. Routine pre-treatment workup and reference needle liver biopsy were performed. FIB-4 index, APRI and modified APRI scores were validated. Patients were divided into two groups, first with no or minimal fibrosis, and second with moderate and marked fibrosis using the Metavir score. RESULTS: Multivariate logistic regression analysis showed that age, body mass index, aspartate aminotransferase, alpha fetoprotein, platelets count, FIB-4 index, APRI and modified APRI score were significant independent predictors of fibrosis. Age > 43 years, aspartate aminotransferase > 47U/L, platelets < 205*103/mm(3), and alpha fetoprotein > 2.6 ng/ml had the highest cutoff points in receiver operator characteristic curves. Taking into account the four variables together; the presence of >= 2 variables is associated with moderate and advanced fibrosis with a sensitivity of 0.81, specificity of 0.5, positive predictive value of 0.53 and negative predictive value of 0.79. FIB-4 index represented the best performing receiver operator characteristic curve for diagnosing moderate and marked fibrosis among other independent factors with a sensitivity of 0.74, specificity of 0.6, positive predictive value of 0.56 and negative predictive value of 0.76. CONCLUSIONS: Chronic HCV pre-treatment routine work up and composite fibrosis scores are good noninvasive predictor of liver fibrosis and can be used as an alternative method to invasive liver biopsy without adding more financial expenses to the treatment. PMID- 23346150 TI - Predictive factors for ultrasonographic grading of nonalcoholic Fatty liver disease. AB - BACKGROUND: There are several studies in the literature investigating factors which can induce non-alcoholic fatty liver disease (NAFLD) in different populations. However, the existing literature lacks powerful studies addressing the factors which may predict the severity of NAFLD. OBJECTIVES: In the current study, we aimed to evaluate factors independently associated with liver echogenicity in an Iranian NAFLD patient population. PATIENTS AND METHODS: A total of 393 patients attending as outpatients at the Hepatology Clinic of Baqiyatallah University of Medical Sciences were entered into this analysis. Univariate and multivariable linear regression models were performed to evaluate the effects of the study variables on the NAFLD grade, defined by ultrasound hepatic echogenicity. RESULTS: Univariate linear analyses revealed a significant relationship between; the ultrasonographic grading of NAFLD and body weight (P < 0.001), abdominal girth (P = 0.007), pelvic girth (P = 0.032), fasting blood glucose (FBS) (P = 0.005), serum insulin (P = 0.035), hemoglobin A1c (HbA1c) (P = 0.012), triglycerides (P = 0.049), aspartate aminotransferase (AST) (P = 0.015), alanin aminotransferase (ALT) (P = 0.026), and homeostasis model assessment (HOMA) (P = 0.002). Multivariable linear regression models left only; HbA1C (P = 0.011, beta = 0.133), body weight (P = 0.001; beta = 0.176) and serum triglyceride (P = 0.034; beta = 0.112) as factors independently associated with liver echogenicity. CONCLUSIONS: Diabetic patients can reduce liver damage of NAFLD with control of their HbA1C through the lower ranges. Hypertriglyceridemia and body weight are the other implicated factors, which worsen hepatic echogenicity in the NAFLD patient population. We recommend future prospective studies and clinical trials to confirm our findings. PMID- 23346151 TI - High Serum Levels of TGF-beta in Iranians With Chronic HBV Infection. AB - BACKGROUND: The transforming growth factor-beta (TGF-beta) is an important cytokine with anti-inflammatory properties. OBJECTIVES: The main purpose of this study was to compare the serum levels of TGF-beta in a group of chronic HBV infected (CHB) patients as well as healthy individuals from South-East of Iran. PATIENTS AND METHODS: Sixty patients with CHB as well as sixty healthy individuals were enrolled in the study. ELISA technique was applied to measure the serum levels of TGF-beta in both groups. RESULTS: Our results revealed that the serum levels of TGF-beta were significantly increased in CHB patients in compare to healthy controls. CONCLUSIONS: According to this result, it may be concluded that high serum levels of TGF-beta may be a mechanism by which immune response against HBV is suppressed. PMID- 23346152 TI - First National Report on Aminotransaminases' Percentiles in Children of the Middle East and North Africa (MENA): the CASPIAN-III Study. AB - BACKGROUND: By the current global obesogenic environment, non-alcoholic fatty liver disease is becoming an important health problem in the pediatric age group. OBJECTIVES: This study aimed to determine the first age-and gender-specific percentiles and upper limit normal limit (ULN) of alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) among a nationally-representative sample of children and adolescents in the Middle East and North Africa (MENA). The second objective was to determine the linear association of obesity indexes and age with serum ALT and AST levels. PATIENTS AND METHODS: This nationwide study was conducted among a representative sample of 4078 students aged 10-18 years, who were selected by multistage random cluster sampling from 27 provinces of Iran. ALT and AST were measured on fresh sera. Body mass index (BMI) was calculated as an index of generalized obesity, and waist- to- height ratio (WHtR) as an index of abdominal obesity. The age- and gender-specific percentiles of ALT and AST were constructed, and the 95th percentile of each enzyme was considered as the ULN. Gender-specific linear regression analysis was employed to examine the association of BMI or WHtR with the levels of ALT and AST. RESULTS: Data of ALT and AST were available for 4078 (2038 girls) and 4150 (2061 girls),respectively. Participants had a mean (SD) age of 14.71 (2.41).The ULN of ALT for boys, girls,and the total individuals were 36.00; 38.00; and, 37.00 U/L, respectively. In both genders, ALT and AST had linear association with age. The association with BMI was significant for ALT in both genders and for AST only in boys, the association of ALT with WHtR was significant in both genders; the corresponding figures were not significant for AST. CONCLUSIONS: The findings of the current study confirmed the current ULN value of 40 U/L commonly used for the pediatric age group. The linear association of indexes for generalized and abdominal obesity with ALT underscores the importance of timely prevention and control of childhood obesity. PMID- 23346153 TI - Autonomic function tests: some clinical applications. AB - Modern autonomic function tests can non-invasively evaluate the severity and distribution of autonomic failure. They have sufficient sensitivity to detect even subclinical dysautonomia. Standard laboratory testing evaluates cardiovagal, sudomotor and adrenergic autonomic functions. Cardiovagal function is typically evaluated by testing heart rate response to deep breathing at a defined rate and to the Valsalva maneuver. Sudomotor function can be evaluated with the quantitative sudomotor axon reflex test and the thermoregulatory sweat test. Adrenergic function is evaluated by the blood pressure and heart rate responses to the Valsalva maneuver and to head-up tilt. Tests are useful in defining the presence of autonomic failure, their natural history, and response to treatment. They can also define patterns of dysautonomia that are useful in helping the clinician diagnose certain autonomic conditions. For example, the tests are useful in the diagnosis of the autonomic neuropathies and distal small fiber neuropathy. The autonomic neuropathies (such as those due to diabetes or amyloidosis) are characterized by severe generalized autonomic failure. Distal small fiber neuropathy is characterized by an absence of autonomic failure except for distal sudomotor failure. Selective autonomic failure (which only one system is affected) can be diagnosed by autonomic testing. An example is chronic idiopathic anhidrosis, where only sudomotor function is affected. Among the synucleinopathies, autonomic function tests can distinguish Parkinson's disease (PD) from multiple system atrophy (MSA). There is a gradation of autonomic failure. PD is characterized by mild autonomic failure and a length-dependent pattern of sudomotor involvement. MSA and pure autonomic failure have severe generalized autonomic failure while DLB is intermediate. PMID- 23346154 TI - Interaction between Sleep-Disordered Breathing and Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Sleep-disordered breathing (SDB) is suggested to be strongly associated with ischemic strokes. Risk factors, stroke subtypes, stroke lesion distribution, and the outcome of SDB in stroke patients remain unclear in Korea. METHODS: We prospectively studied 293 patients (159 men, 134 women; age 68.4+/-10.5) with acute ischemic stroke. Cardiovascular risk factors, stroke severity, sleep-related stroke onset, distribution of stroke lesions, and 3-month score on the modified Rankin Scale (mRS) were assessed. Stroke severity was assessed by the US National Institutes of Health Stroke Scale (NIHSS) and the mRS. The apnea-hypopnea index (AHI) was determined 6.3+/-2.2 days after stroke onset with the Apnea Link portable sleep apnea monitoring device. RESULTS: The prevalence of SDB (defined as an AHI of >=10) was 63.1% (111 men, 74 women). Those in the SDB group were older, had higher NIHSS and mRS scores, greater bulbar weakness, and a higher incidence of sleep-associated stroke onset. Among risk-factor profiles, alcohol consumption and atrial fibrillation were significantly related to SDB. The stroke outcome was worse in patients with SDB than in those without SDB. The lesion location and specific stroke syndrome were not correlated with SDB. CONCLUSIONS: SDB is very common in acute cerebral infarction. Different risk-factor profiles and sleep-related stroke onsets suggest SDB as a cause of ischemic stroke. The higher NIHSS score and greater bulbar involvement in the SDB group seem to show the influence of ischemic stroke on the increased SDB prevalence. PMID- 23346155 TI - Short-term and long-term stroke survival: the belgrade prognostic study. AB - BACKGROUND AND PURPOSE: The aims of this study were to determine the 28-day and 1 year survival rates after first-ever ischemic stroke and to identify their baseline predictors. METHODS: We prospectively and consecutively collected data on 300 patients with first-ever acute ischemic stroke admitted to 2 major neurological institutions for cerebrovascular diseases in Belgrade during March 2008. The Kaplan-Meier method was used to estimate the cumulative 28-day and 1 year survival rates, and the predictive values of different variables were assessed by Cox proportional-hazards regression model. RESULTS: The cumulative 28 day and 1-year survival rates of ischemic stroke patients in the cohort were 81.0% and 78.3%, respectively. The multivariate predictive model revealed that hypertension (p=0.017), National Institutes of Health Stroke Scale score (p=0.001), and in-hospital medical complications (p=0.029) were significant unfavorable independent outcome predictors, while early physical therapy (p=0.001) was a significant favorable prognostic factor for the 28-day mortality in our patients. Multivariate Cox regression analysis showed that age (p=0.001), National Institutes of Health Stroke Scale score (p=0.001), and in-hospital complications (p=0.008) remained significant predictors of 1-year mortality. CONCLUSIONS: The findings support the need for optimal control of vascular risk factors and treatment of atherosclerotic disease as well as appropriate prevention and management of in-hospital complications of stroke. PMID- 23346156 TI - Decreased Metabolism in the Cerebral Cortex in Early-Stage Huntington's Disease: A Possible Biomarker of Disease Progression? AB - BACKGROUND AND PURPOSE: Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder. Genetic analysis of abnormal CAG expansion in the IT15 gene allows disease confirmation even in the preclinical stage. However, because there is no treatment to cure or delay the progression of this disease, monitoring of biological markers that predict progression is warranted. METHODS: FDG-PET was applied to 13 patients with genetically confirmed HD in the early stage of the disease. We recorded the initial and follow-up statuses of patients using the Independence Scale (IS) of the Unified Huntington's Disease Rating Scale. The progression rate (PR) was calculated as the annual change in the IS. The patients were divided into two groups with faster and slower progression, using the median value of the PR as the cut-off. FDG-PET data were analyzed using regions of interest, and compared among the two patient groups and 11 age- and sex-matched controls. RESULTS: The mean CAG repeat size in patients was 44.7. The CAG repeat length was inversely correlated with the age at onset as reported previously, but was not correlated with the clinical PR. Compared with normal controls, hypometabolism was observed even at very early stages of the disease in the bilateral frontal, temporal, and parietal cortices on FDG-PET. The decreases in metabolism in the bilateral frontal, parietal, and right temporal cortices were much greater in the faster-progression group than in the slower progression group. CONCLUSIONS: A decrease in cortical glucose metabolism is suggested as a predictor for identifying a more rapid form of progression in patients with early-stage HD. PMID- 23346157 TI - Translation and validation of the korean version of the 39-item Parkinson's disease questionnaire. AB - BACKGROUND AND PURPOSE: The importance of health-related quality of life (HrQoL) has been increasingly emphasized when assessing and providing treatment to patients with chronic, progressive, degenerative disorders. The 39-item Parkinson's disease questionnaire (PDQ-39) is the most widely used patient reporting scale to assess HrQoL in Parkinson's disease (PD). This study evaluated the validity and reliability of the translated Korean version of the PDQ-39 (K PDQ-39). METHODS: One hundred and two participants with PD from 10 movement disorder clinics at university-affiliated hospitals in South Korea completed the K-PDQ-39. All of the participants were also tested using the Unified Parkinson's Disease Rating Scale (UPDRS), Korean version of the Mini-Mental State Examination (K-MMSE), Korean version of the Montgomery-Asberg Depression Scale (K-MADS), Epworth Sleepiness Scale (ESS) and non-motor symptoms scale (NMSS). Retests of the K-PDQ-39 were performed over time intervals from 10 to 14 days in order to assess test-retest reliability. RESULTS: Each K-PDQ-39 domain showed correlations with the summary index scores (rS=0.559-0.793, p<0.001). Six out of eight domains met the acceptable standard of reliability (Cronbach's alpha coefficient >=0.70). The Guttman split-half coefficient value of the K-PDQ-39 summary index, which is an indicator of test-retest reliability, was 0.919 (p<0.001). All of the clinical variables examined except for age, comprising disease duration, levodopa equivalent dose, modified Hoehn and Yahr stage (H&Y stage), UPDRS part I, II and III, mood status (K-MADS), cognition (K-MMSE), daytime sleepiness (ESS) and (NMSS) showed strong correlations with the K-PDQ-39 summary index (p<0.01). CONCLUSIONS: The K-PDQ-39 has been validated for use in the Korean-speaking PD population. The questionnaire is a valid and reliable assessment tool for assessing the HrQoL of Korean PD patients. PMID- 23346158 TI - Decremental responses to repetitive nerve stimulation in x-linked bulbospinal muscular atrophy. AB - BACKGROUND AND PURPOSE: X-linked bulbospinal muscular atrophy (X-BSMA) is characterized by bulbar and spinal muscular weakness and fasciculations. Although X-BSMA is a motor neuronopathy, there are several reports of myasthenic symptoms or decremental responses to repetitive nerve stimulation (RNS). We report the results of applying the RNS test to 15 patients among 41 with genetically confirmed X-BSMA; these 15 patients complained of fatigue, ease of becoming tired, or early muscular exhaustion. METHODS: The 3-Hz RNS test was performed on the trapezius, nasalis, orbicularis oculi, flexor carpi ulnaris, and abductor digiti quinti muscles. A decrement greater than 10% was considered abnormal. Additionally, a pharmacologic response to neostigmine was identified in three patients. RESULTS: A significant decrement was observed in 67% of patients, and was most common in the trapezius muscle (nine cases). The decrement of the trapezius muscle response ranged from 15.9% to 36.9%. The decrement was inversely correlated with the amplitude of compound muscle action potentials at rest. Neostigmine injection markedly improved the decrement in three patients, who showed noticeable decremental responses to 3-Hz RNS. CONCLUSIONS: This study shows that myasthenic symptoms and abnormal decremental responses to low-rate RNS are common in X-BSMA. PMID- 23346159 TI - Clinical efficacy of plasmapheresis in patients with neuromyelitis optica spectrum disorder and effects on circulating anti-aquaporin-4 antibody levels. AB - BACKGROUND AND PURPOSE: Although plasmapheresis is becoming standard practice as a rescue therapy for neuromyelitis optica (NMO), evidence for the therapeutic efficacy of plasmapheresis is limited, and the effect of plasmapheresis on anti aquaporin-4 (AQP4) levels in patients with NMO has not been reported. Here, our objective was to evaluate the clinical efficacy of therapeutic plasmapheresis and its effect on anti-AQP4 antibody levels in patients with NMO spectrum disorder (NMOSD). METHODS: We retrospectively reviewed the medical records of 15 patients with NMOSD who had 18 acute attacks and received plasmapheresis because they did not respond to high-dose intravenous methylprednisolone (IVMP) therapy. Anti-AQP4 antibodies were measured before and after plasmapheresis. The primary outcomes were functional improvements immediately and 6 months after plasmapheresis, and the secondary outcome was the change in anti-AQP4 antibody serum levels following plasmapheresis. RESULTS: Plasmapheresis following IVMP therapy led to significant improvement in 50% of the 18 attacks in 15 patients immediately after the procedure was completed, and in 78% (14 attacks) after 6 months. Plasmapheresis was generally well tolerated in all patients. Anti-AQP4 antibody serum levels declined significantly following plasmapheresis, to a mean of 15% of the preplasmapheresis levels. Lower scores on the visual outcome scale recorded before an attack were associated with significant immediate improvement upon the completion of plasmapheresis (p=0.03). CONCLUSIONS: Plasmapheresis following IVMP therapy effectively removed anti-AQP4 antibodies and was accompanied by a substantial improvement in the neurological disability of patients with NMOSD. Lower levels of pre-existing neurological damage may be associated with an improved acute response to plasmapheresis. PMID- 23346160 TI - Reduced Frontal P3a Amplitude in Migraine Patients during the Pain-Free Period. AB - BACKGROUND AND PURPOSE: Neuropsychological and neuroimaging studies both suggest that frontal lobe dysfunction is present in migraineurs. Since P3a abnormalities manifest in other diseases associated with attention problems, such as attention deficit hyperactivity disorder, we hypothesized that migraine patients have P3a abnormalities, particularly in the frontal region. METHODS: Event-related potentials were measured using a passive auditory oddball paradigm in 16 female migraineurs (aged 22.9+/-2.0 years, mean+/-SD) during the interictal period and in 16 age-matched healthy females (22.6+/-2.0 years). The amplitudes and latencies were analyzed independently using repeated-measures analysis of variance. Nonparametric statistical testing using a cluster-level randomization method was performed to localize the abnormalities. RESULTS: The mean P3a amplitude at frontal areas during the third trials was significantly lower in migraineurs (1.06 uV) than in controls (1.69 uV, p=0.026). P3a amplitudes were negatively correlated with the duration of the migraine history (r=-0.618, p=0.014). Cluster-based nonparametric statistical analysis showed that the amplitudes over left frontal areas were significantly lower in migraine patients than in controls. CONCLUSIONS: A reduced P3a amplitude of migraineurs reflects attentional deficits and frontal dysfunction. The negative correlation between P3a amplitude and the duration of the migraine history suggests that attentional deficits and frontal dysfunction are either the cause or the result of headache. PMID- 23346161 TI - The effect of ropinirole on the quality of life in patients with restless legs syndrome in Korea: an 8-week, multicenter, prospective study. AB - BACKGROUND AND PURPOSE: Dopamine agonists are first-line drugs for treating the symptoms of restless legs syndrome (RLS). However, few studies have investigated the effect of dopamine agonists on the quality of life (QoL) in RLS patients. We conducted a study to determine whether ropinirole exerts positive effects on the QoL in RLS patients and to analyze the underlying factors. METHODS: Primary RLS patients from eight medical centers were recruited in the study. They were evaluated in the baseline phase using various questionnaires including the Korean versions of the International Restless Legs Scale (K-IRLS), RLS QoL questionnaire (K-RLSQoL), and the Short Form 36 Health Survey (SF-36). After taking ropinirole for 8 weeks the same questionnaires were again completed as a re-evaluation. We analyzed the statistical difference using a paired t-test, a Pearson's correlation, and a stepwise multiple regression in order to identify the factors associated with the QoL change. RESULTS: A total of 107 subjects, including 65 (60.7%) females, completed this study. They were aged 51.68+/-14.80 years (mean+/ SD) and had a symptom duration of 8.8+/-9.0 months. After treatment with ropinirole, there were significant improvements on the K-RLSQoL, SF-36, and K IRLS. The Pearson's correlation analysis showed that the improvement of QoL in RLS patients was significantly correlated with the severity of RLS (r=0.236, p<0.014) at baseline. CONCLUSIONS: The results from this study suggest that treatment with ropinirole can improve the QoL in RLS patients. The improvement in the QoL is more related with the improvement of RLS symptoms. PMID- 23346162 TI - Two Cases of X-Linked Myotubular Myopathy with Novel MTM1 Mutations. AB - BACKGROUND: Myotubular myopathy (MTM) is a congenital myopathy characterized by centrally placed nuclei in muscle fibers. Mutations in the myotubularin 1 gene (MTM1) have been identified in the most of the patients with the X-linked recessive form. CASE REPORT: This report describes two male infants with X-linked MTM (XLMTM). Both patients presented with generalized hypotonia and respiratory difficulties since birth. We did not perform a muscle biopsy in either patient, but their conditions were diagnosed by genetic testing of MTM1. One splicing mutation, c.63+1G>C, and a frame-shift mutation, c.473delA (p. Lys158SerfxX28), were identified. Neither mutation has been reported previously. CONCLUSIONS: Genetic testing for MTM1 is helpful for the differential diagnosis of floppy male infants. We suggest that advanced molecular genetic testing may permit a correct diagnosis while avoiding invasive procedures. PMID- 23346163 TI - Acute myelitis in a patient with vogt-koyanagi-harada disease: case report and review of the literature. AB - BACKGROUND: Vogt-Koyanagi-Harada (VKH) disease is characterized by bilateral granulomatous uveitis with neurologic, auditory, and dermatologic manifestations. However, acute myelitis complicating VKH disease has rarely been reported. CASE REPORT: A 50-year-old Chinese Han woman presented with difficulty walking, numbness on the left side of the body, and difficulty with urination. The patient was diagnosed with incomplete VKH disease and received corticosteroid treatment prior to the neurological presentation. Acute myelitis was diagnosed based on both clinical and spinal-cord MRI findings. CONCLUSIONS: Clinicians should consider acute myelitis as a rare possible neurological manifestation in VKH disease patients, and early systemic administration of corticosteroids will suppress the acute inflammatory process and prevent recurrences. This report raises the possibility that VKH disease and acute myelitis share common pathogenic pathways. PMID- 23346165 TI - HER2 Status by Standardized Immunohistochemistry and Silver-Enhanced In Situ Hybridization in Korean Breast Cancer. AB - PURPOSE: Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in 18% to 20% of breast cancers, and it is recognized as a prognostic and predictive marker. We investigated the HER2 status in Korean breast cancer by immunohistochemistry (IHC) and silver-enhanced in situ hybridization (SISH), as the first step toward building a nationwide quality assurance program for HER2 testing. METHODS: A total of 1,198 breast carcinoma samples were collected from six institutions and IHC and SISH were performed using tissue microarrays in central laboratories. The results were compared to those of local laboratories. RESULTS: Available data were obtained from 959 samples. Central IHC results were negative, equivocal, and positive for 756 (78.8%; range among institutions, 76.8 81.8%), 37 (3.9%; 1.9-6.2%), and 166 (17.3%; 13.6-20%), respectively. SISH results were negative, equivocal, and positive for 756 (78.8%; 77.4-79.9%), 2 (0.2%; 0-0.7%), and 201 (21%; 20.1-22.2%), respectively. HER2 gene amplification was observed in 4.4%, 19%, and 73.9% of the negative, equivocal and positive groups stratified by local IHC results, respectively. When central SISH was considered to be the gold standard method for measuring HER2 status, the false negative and false-positive rates of local IHC were 14.4% (29/201) and 7.1% (54/756). The concordance rate between central IHC and SISH was 98.4%. CONCLUSION: Central IHC and SISH markedly decreased the interlaboratory variability of HER2 status and the results of the two were highly concordant. The quality control program for HER2 testing must be focused on decreasing both the false negativity and positivity of IHC in local laboratories. PMID- 23346164 TI - Seroma formation after breast cancer surgery: what we have learned in the last two decades. AB - Formation of a seroma most frequently occurs after mastectomy and axillary surgery. Prolonged drainage is troublesome as it increases the risk for infection and can significantly delay adjuvant therapy. Seroma has been defined as serous fluid collection under the skin flaps or in the axillary dead space following mastectomy and/or axillary dissection. Because the true etiology of a seroma is unknown, a multifactorial-causation hypothesis has been accepted. Surgical factors include technique, extent of dissection and the surgical devices used for dissection. Obliteration of dead space with various flap fixation techniques, use of sclerosants, fibrin glue and sealants, octreotide, and pressure garments have been attempted with conflicting results and none have been consistent. Early movement of the shoulder during the postoperative period may increase the formation of seroma, although delayed physiotherapy decreases the formation of seroma. A detailed analysis of the use of drains showed that use of single or multiple drains, early or late removal, and drains with or without suction are not significantly different for the incidence of seroma. Although there is evidence for reduced seroma formation after early drain removal, very early removal within 24 hours seems to increase formation of seroma. No patient or tumor factors seem to affect seroma formation except body mass index and body weight. Consensus is lacking among studies/trials with different groups producing conflicting evidence. Besides a few established factors such as body mass index, the use of electrocautery for dissection, early drain removal, low vacuum drains, obliteration of dead space, and delayed shoulder physiotherapy, most of the hypothesized causes have not been demonstrated consistently. Thus, seroma remains a threat to both the patient and surgeon. Recurrent transcutaneous aspiration remains the only successful management. PMID- 23346166 TI - Effect of bFGF on the MCF-7 Cell Cycle with CD44(+)/CD24(-): Promoting the G0/G1 >G2/S Transition. AB - PURPOSE: Few cells with stem cell characteristics possess capabilities of self renewal and differentiation, which leads to high tumorigenesis and resistance to standard chemotherapeutic agents. These cells are mostly quiescent, and arrest occurs at the mitotic G0/G1 phase in mitosis. We explored the effects of basic fibroblast growth factor (bFGF) on the MCF-7 cell cycle with CD44(+)/CD24(-). METHODS: Cancer-initiating cells were propagated as mammospheres. The CD44(+)/CD24(-) subpopulation was sorted by a fluorescence activating cell sorter Vantage flow cytometer. A cell cycle analysis was performed with different bFGF concentrations. RESULTS: Differences in the CD44(+)/CD24(-) cell proliferation under different bFGF concentrations were observed (p=0.001). When the bFGF concentration was increased, the proportion of CD44(+)/CD24(-) at G0/G1 decreased (p=0.023). CONCLUSION: We conclude that bFGF may sustain CD44(+)/CD24(-) cell proliferation and could promote cell progression through the G0/G1->G2/S phase transition. PMID- 23346167 TI - Changing patterns in the clinical characteristics of korean breast cancer from 1996-2010 using an online nationwide breast cancer database. AB - PURPOSE: Breast cancer is one of the most frequent malignancies in Korean women, and its incidence is increasing at a rapid rate. Since 1996, the Korean Breast Cancer Society has collected nationwide breast cancer data using an online registration program and analyzed the data biennial. The purpose of this study was to evaluate the characteristics of Korean breast cancer and to analyze changes in these characteristics over the period of time. METHODS: Data were collected from 41 medical schools (74 hospitals), 24 general hospitals, and 6 private clinics. Data on the total number, gender, and age of newly-diagnosed breast cancer patients were collected through a questionnaire. Additional data were collected and analyzed from the online database. RESULTS: In 2010, 16,398 patients in Korea were newly diagnosed with breast cancer. The crude incidence rate of female breast cancer was 67.2 cases per 100,000, and the median age at diagnosis was 49 years. The incidence of breast cancer was highest in patients aged between 40 and 49 years. Since 1996, there has been a significant increase in the proportion of early-stage cancers (detected in stage 1 or 2), the percentage of estrogen receptor-positive cancers, and in the proportion of patients receiving breast-conserving surgery. CONCLUSION: The incidence and clinical characteristics of Korean breast cancer are slowly changing to the patterns of Western countries. To understand changing patterns in the characteristics of Korean breast cancer, the nationwide data should be continuously analyzed. PMID- 23346168 TI - Analysis of the potent prognostic factors in luminal-type breast cancer. AB - PURPOSE: Luminal-type breast cancer has a good prognosis compared to other types, such as human epidermal growth factor receptor 2 and triple negative types. Luminal-type breast cancer is classified into luminal A and B, according to the proliferation index. We investigated the clinicopathological factors that affect the prognosis of the luminal-type subgroups. METHODS: We reviewed the medical records and the pathologic reports of 159 luminal-type breast cancer patients who were treated between February 2005 and November 2007. We divided luminal-type breast cancer into luminal A and B, according to Ki-67 (cutoff value, 14%) and analyzed the clinicopathologic factors, such as age at diagnosis, intensity score of estrogen receptor and progesterone receptor, histologic grade, and Bcl-2. Moreover, we compared the disease-free survival (DFS) of each group. RESULTS: In the univariate analysis, age (p=0.004), tumor size (p=0.010), lymph node metastasis (p=0.001), and Bcl-2 (p=0.002) were statistically significant factors in luminal-type breast cancer. In the multivariate analysis, lymph node (p=0.049) and Bcl-2 (p=0.034) were significant relevant factors in luminal-type breast cancer. In the subgroup analysis, the increased Bcl-2 (cutoff value, 33%) was related with a longer DFS in the luminal B group (p=0.004). CONCLUSION: In our study, luminal A breast cancer showed a longer DFS than luminal B breast cancer, further, Bcl-2 may be a potent prognostic factor in luminal-type breast cancer. PMID- 23346169 TI - Validation of a scoring system for predicting malignancy in patients diagnosed with atypical ductal hyperplasia using an ultrasound-guided core needle biopsy. AB - PURPOSE: The need for surgical excision in patients with ultrasound-guided core needle biopsy (CNB)-diagnosed atypical ductal hyperplasia (ADH) remains an issue of debate. The present study sought to validate a scoring system (the U score, for underestimation) that we have previously developed for predicting malignancy in CNB-diagnosed ADH. METHODS: The study prospectively enrolled 85 female patients with CNB-diagnosed ADH who underwent subsequent surgical excision. Underestimation was defined as a surgical specimen having malignant foci. RESULTS: The overall underestimation rate was 37% (31/85). Multivariate analysis showed that a clinically palpable mass, microcalcification on imaging, size >15 mm and a patient age of >=50 years were independently associated with underestimation. When applied to the scoring system, the validation score was significant (p<0.001; area under the curve, 0.852). No patient with a U score <3.5 had an underestimated lesion. CONCLUSION: The present study successfully validated the efficacy of our scoring system for predicting malignancy in CNB diagnosed ADH. A U score of <=3.5 indicates that surgical excision may not be necessary. PMID- 23346170 TI - Factors Associated with Re-excision after Breast-Conserving Surgery for Early Stage Breast Cancer. AB - PURPOSE: Re-excisions after breast-conserving surgery (BCS) for breast cancer cause delays in the adjuvant treatment, increased morbidity, and leads to poor aesthetic results. Thus, efforts to reduce the re-excision rate are essential. This study aimed to conclusively determine the re-excision rate and the factors associated with re-excision after BCS. METHODS: We retrospectively reviewed the medical records and pathological reports of 711 cases that underwent BCS for early-stage breast cancer. Univariate and multivariate analyses were performed. RESULTS: Of the 711 cases of BCS, 71 (10.0%) required re-excision. Patients in the re-excision group were younger than those in the no re-excision group. Non palpable lesions, the presence of non-mass-like enhancement at magnetic resonance imaging, multifocality, the presence of a ductal carcinoma in situ (DCIS) component, and an infiltrative tumor border were also significantly associated with re-excision. Multivariate analysis indicated that younger age, non-palpable lesions, multifocal lesions, and the presence of a DCIS component were factors which were independently associated with re-excision. Tumors located in the lower inner quadrant had a relatively high involved resection margin rate as well as a narrow resection margin width, especially at the superior and medial margins. Lateral margins showed a tendency toward a wider resection margin width. CONCLUSION: At our institution, the rate of re-excision was low despite the lack of an intraoperative frozen section. Patients with non-palpable or multifocal tumors, a DCIS component, or those who were younger than 50 years were more likely to require re-excision after BCS. These factors should be considered when planning surgical management of early-stage breast cancer. Positive resection margin rates and margin widths differed on a directional basis based on tumor location, and these differences were considerable. PMID- 23346171 TI - Multiple margin positivity of frozen section is an independent risk factor for local recurrence in breast-conserving surgery. AB - PURPOSE: Breast-conserving surgery (BCS) with radiotherapy has become a standard treatment for early stage breast cancer, since the installation of NSABP B-06. One of the serious problems in BCS is that of local recurrence. There are many risk factors for local recurrence, such as large tumor size, multiple tumors, axillary lymph node involvement, young age, high nuclear grade, and so on. The aim of this study is to identify patients with a higher risk of local recurrence of breast cancer. METHODS: Between January 2002 and December 2006, 447 patients with breast cancer, and who had undergone BCS with immediate breast reconstruction, were enrolled in the study. The follow-up period was 5 years from the time of operation and we analyzed local recurrence, disease-free survival (DFS), and overall survival (OS). The analysis included various clinicopathological factors such as age, chemotherapy, radiotherapy, hormone therapy, pathologic characteristics, and margin status. Statistical analysis was performed with log-rank test and Kaplan-Meier method. The p-value <0.05 was considered statistically significant. RESULTS: The mean follow-up period was 88 months and local recurrence of breast cancer occurred only in 16 cases (3.6%). The actual 5-year DFS, and OS rates were 90.6% and 93.3%, respectively. For the local recurrence of breast cancer, positive margin status, multiple margin positivity, conversed margin cases, T/N stages showed statistical significance in univariate analysis. However, only multiple margin positivity was identified as an independent risk factor for local recurrence in multivariate analysis. CONCLUSION: When the multiple margin positivity is diagnosed on intraoperative frozen biopsy, surgeons should consider a much wider excision of the breast and a more aggressive management. PMID- 23346172 TI - Body mass index is not associated with treatment outcomes of breast cancer patients receiving neoadjuvant chemotherapy: korean data. AB - PURPOSE: The effects of body mass index on pathologic complete response and survival have not been reported in Korean patients with breast cancer. The purpose of this study was to evaluate the predictive or prognostic value of obesity in breast cancer receiving neoadjuvant chemotherapy. METHODS: A total of 438 stage II or III breast cancer patients treated with neoadjuvant chemotherapy were enrolled and analyzed retrospectively. RESULTS: In the study, 319 patients (72.8%) were normal weight, 100 patients (22.8%) were overweight, and 19 patients (4.3%) were obese. Baseline clinicopathologic characteristics were not different among the groups, except for age. There were no differences in pathologic complete response rate between the groups (9.7% in normal weight, 10.0% in overweight, 5.3% in obese; p=0.804). Neither overweight nor obese patients showed a significant difference in relapse-free survival compared to normal weight patients (p=0.523 and p=0.931, respectively). Also, no significant difference in overall survival (p=0.520 and p=0.864, respectively) was observed. CONCLUSION: Obesity or higher body mass index was not significantly associated with pathologic complete response and survival in Korean patients with breast cancer who received neoadjuvant chemotherapy. Our results suggest that the prognostic impact of body mass index is different from that of Western patients. PMID- 23346173 TI - The Relationship between Surgery and Phase of the Menstrual Cycle Affects Survival in Breast Cancer. AB - PURPOSE: The impact of time of surgery based on the menstrual cycle is a controversial issue. Two decades after the first interest in this topic, a number of studies with conflicting results have not helped to resolve this problem. This study aimed to prospectively evaluate the impact of timing of surgery based on the menstrual cycle on survival rates of breast cancer patients, and various clinical and hormonal classifications of the menstrual cycle were compared in order to determine the phase of the menstrual cycle which showed the highest degree of surgical survival. METHODS: Premenopausal breast cancer patients treated with curative surgery between 1998 and 2002 were prospectively included in this study. Patients were divided into different groups according to the first day of their last menstrual cycle using three different classifications (clinical, Hrushesky, Badwe), and were also grouped according to their serum hormone levels. Serum levels of follicle stimulating hormone, luteinizing hormone, estrogen, and progesterone were measured on the day of surgery. RESULTS: Ninety patients were included in the study. Median follow-up time was 90 months. Nineteen patients (21.1%) had loco-regional recurrence and/or distant metastases while 12 patients (13.3%) died during follow-up. Five-year (78.6% vs. 90.6%) and 10-year (66.7% vs. 90.6%) disease-free survival (DFS) rates of patients in the clinically defined follicular phase were significantly decreased compared to luteal phase. On the other hand, hormonally determined phases of the menstrual cycle and grouping of patients according to clinical classifications did not show an impact on prognosis. CONCLUSION: In the current study performing surgery in the follicular phase of the menstrual cycle decreased DFS in premenopausal patients. According to these results, performing surgery during the luteal phase of the menstrual cycle might have a beneficial effect on survival. PMID- 23346174 TI - The Effects of Preoperative (18)F-FDG PET/CT in Breast Cancer Patients in Comparison to the Conventional Imaging Study. AB - PURPOSE: There have been recent studies of the (18)F-fluorodeoxyglucose positron emission tomography and computed tomography ((18)F-FDG PET/CT) in the staging, detection, and follow-up of the breast cancer occurrence and recurrence. There was controversy concerning the use of (18)F-FDG PET/CT for staging primary breast cancer. In this study, we investigated the potential effects of (18)F-FDG PET/CT in the initial assessment of patients with primary breast cancer. METHODS: From January 2008 to December 2009, 154 consecutive biopsy-proven invasive breast cancer patients were enrolled in this study. Patients underwent conventional imaging studies including mammography, breast ultrasonography (USG), and magnetic resonance imaging for local assessment, and plain chest X-ray, liver USG, and bone scan to rule out distant metastasis. All 154 patients underwent (18)F-FDG PET/CT in the initial assessment. RESULTS: (18)F-FDG PET/CT did not detect primary breast lesions in 16 patients with a sensitivity of 89.6% and detected only 5 multiple lesions (12.5%) out of 40 cases. Histologically confirmed axillary lymph node (LN) metastases were in 51 patients, and the sensitivity and specificity of (18)F-FDG PET/CT to detect metastatic axilla were 37.3% and 95.8%, respectively; whereas the corresponding estimates of USG were 41.2% and 93.7%, respectively. Eleven extra-axillary LN metastases were found in eight patients, and seven lesions were detected by (18)F-FDG PET/CT only. The sensitivity and specificity of (18)F-FDG PET/CT in detecting distant metastasis were 100% and 96.4%, respectively; whereas the sensitivity and specificity of the conventional imaging were 61.5% and 99.2%, respectively. CONCLUSION: (18)F-FDG PET/CT cannot be recommended as a primary diagnostic procedure in breast cancer, but it has the potential to be used as an additional imaging tool for the detection of axillary metastasis, distant metastasis, and extra-axillary LN metastasis. (18)F-FDG PET/CT cannot solely replace the conventional diagnostic procedure in primary breast cancer. The best approach may be the combination of different imaging modalities. PMID- 23346175 TI - Health-related quality of life in breast cancer patients with lymphedema who survived more than one year after surgery. AB - PURPOSE: To identify the influence of lymphedema on health-related quality of life (HRQOL) more than 1 year after breast cancer surgery. METHODS: Ninety-six breast cancer patients who survived more than 1 year after surgery and 104 members of the general population were recruited. Patients were divided into 2 groups according to the presence of lymphedema. HRQOL was evaluated with the Short-Form 36-Item Health Survey. RESULTS: THERE WERE NO STATISTICALLY SIGNIFICANT DIFFERENCES IN ANY SCALES BETWEEN GROUPS: groups of breast cancer survivors with and without lymphedema. Compared with the general population, breast cancer survivors had lower quality of life scores in all scales, although the vitality and mental health scales did not differ from chance variation at the 5% level. CONCLUSION: In this study, the presence of lymphedema in breast cancer patients who survived over 1 year after surgery might not affect the quality of life. However quality of life of breast cancer survivors is lower than in general population except for some mental health components. PMID- 23346176 TI - Unmet Needs and Their Relationship with Quality of Life among Women with Recurrent Breast Cancer. AB - PURPOSE: This study aimed to evaluate the prevalence and the effects of unmet needs on quality of life (QOL) among recurrent breast cancer survivors. METHODS: Completed questionnaires were collected from 52 women with recurrent breast cancer. Clinical and socio-demographic characteristics were reviewed, and the Supportive Care Needs Survey, Functional Assessment of Cancer Therapy-Breast Cancer Instrument, and Beck Depression Inventory (BDI) were administered. The frequency of unmet needs and the mean differences by patient characteristics and BDI scores were analyzed. The predictive value of unmet needs on QOL, controlling for socio-demographic variables and then for clinical variables, was analyzed in hierarchical regression models. RESULTS: The most common unmet needs belonged to the health system and information domain. The depressive group had greater unmet needs in the psychological domain (p<0.001), physical and daily living domain (p=0.001), and health and information domain (p=0.002). Patients with lower education attainment and those with lower performance status had greater unmet needs in the psychological needs (p=0.002) and in the physical and daily living needs domain (p=0.002), respectively. Unmet needs in the psychological domain (p=0.008), physical and daily living domain (p=0.022), and sexuality domain (p=0.040) strongly predicted QOL of women with recurrent breast cancer. CONCLUSION: Unmet needs were strong predictors for QOL among recurrent breast cancer patients. This suggests that QOL of women with recurrent breast cancer is possibly more affected by unmet needs than by patient's socio-demographic or clinical characteristics. Intervention strategies could be developed based on the identified needs of women with recurrent breast cancer in order to improve their QOL. Further longitudinal and prospective studies will be necessary to confirm the independent impact of unmet needs on QOL. PMID- 23346177 TI - Simultaneous chest wall reconstruction after sternectomy and modified radical mastectomy in locally advanced breast cancer with solitary sternal metastasis. AB - Bone is the most common metastatic organ in patients with breast cancer. The most significant clinical symptom of bone metastasis is pain which reduces quality of life in cancer patients. We report a case of chest wall reconstruction after partial sternal resection for solitary sternal metastasis and modified radical mastectomy in a patient with locally advanced breast cancer. The sternal defect was reconstructed with a 2 mm thick Gore-Tex patch. Postoperative pain was acceptable and the patient was discharged without any complications. The patient received the endocrine and bisphosphonate therapy combined with chemotherapy and radiotherapy. No recurrence or complications were observed during a follow-up period of 36 months. We describe our good surgical management results of sternal metastatic lesion in a patient with locally advanced breast cancer. We suggest that simultaneous sternectomy is a safe and curative surgical method for a solitary sternal metastasis when no evidence of systemic spread is noted. PMID- 23346178 TI - Oncoplastic technique combining an adipofascial flap with an extended glandular flap for the breast-conserving reconstruction of small dense breasts. AB - We introduce a method combining two oncoplastic techniques for breast-conserving reconstruction. The procedure is as follows: first, an extended glandular flap is made by undermining the breast from both the skin and the pectoralis fascia to the upper edge of the breast at the subclavicular area. After modeling the breast mound with the extended glandular flap, an inframammary adipofascial flap is made. The flap is reflected back to the breast area remodeled using the extended glandular flap. After reshaping the breast, the inframammary line is then re shaped. This method is indicated for patients with breast cancer in the outer portion of the breast, who have small dense breasts, and have undergone a large excision of about 40% of their breast volume. We treated four patients, all of whom had either excellent or good cosmetic results with no fat necrosis. PMID- 23346179 TI - A case of pseudo-meigs' syndrome associated with ovarian metastases from breast cancer. AB - A 54-year-old woman with long-lasting pleural effusion developed abdominal distention due to ascites from bilateral ovarian tumors. The patient had undergone breast-conserving surgery and axillary lymph node dissection for left breast cancer in October 2000, and had developed left pleural effusion in July 2006. Cytological examination of the pleural effusion found no malignant cells. Thoracic drainage with intrathoracic administration of OK-432 (Picibanil) had failed to control the pleural effusion. Positron emission tomography taken at the abdominal distention showed bilateral ovarian tumors. After failure to control the ascites with systemic and intra-abdominal chemotherapy, bilateral oophorectomy resulted in normalization of elevated serum tumor-marker levels and the disappearance of both the ascites and pleural effusions (i.e., pseudo-Meigs' syndrome). Pathological examination showed the tumors to be estrogen receptor positive metastatic ovarian tumors from her breast cancer. The patient remained well with no further recurrence for 40 months under aromatase inhibitor therapy. PMID- 23346180 TI - Differentiating lymphovascular invasion from retraction artifact on histological specimen of breast carcinoma and their implications on prognosis. AB - On a pathological specimen of breast cancer cells, retraction artifact during histological processing mimics true lymphovascular invasion (LVI). The accurate determination of the presence or absence of LVI is a factor in determining risk of having a positive sentinel node, or having additional positive axillary nodes after a positive sentinel node biopsy in women with early-stage breast cancer. The determination of nodal risk influences the decision of the treating physicians as to whether a sentinel node biopsy or completion axillary dissection is necessary. On slide preparation, ideal factors favoring true LVI include: a definite endothelial lining, with endothelial nuclei that seem to protrude into the lymphatic space; invasion in one lymphatic vessel (LV) lumen with nearby cancer glands that have minimal or no retraction; a tumor embolus in a LV clear lumen with outside nearby tumor bulk; a tumor embolus that is different in shape than its surrounding clear LV space; and a positive stain for fibrin, CD31, or CD34 on tumor embolus periphery. PMID- 23346181 TI - Emerging role of geminin as a prognostic marker in systemic malignancies. PMID- 23346183 TI - Dual functions of the C5a receptor as a connector for the K562 erythroblast-like cell-THP-1 macrophage-like cell island and as a sensor for the differentiation of the K562 erythroblast-like cell during haemin-induced erythropoiesis. AB - The transcriptional nuclear factor binding to the Y box of human leukocyte antigen genes (NF-Y) for the C5a receptor (C5aR) gene is active in erythroblasts. However, the roles of the C5aR in erythropoiesis are unclear. We have previously demonstrated that apoptotic cell-derived ribosomal protein S19 (RP S19) oligomers exhibit extraribosomal functions in promoting monocyte chemotaxis and proapoptosis via the C5aR without receptor internalisation. In contrast to the extraribosomal functions of the RP S19, a proapoptotic signal in pro-EBs, which is caused by mutations in the RP S19 gene, is associated with the inherited erythroblastopenia, Diamond-Blackfan anaemia. In this study, we detected C5aR expression and RP S19 oligomer generation in human erythroleukemia K562 cells during haemin-induced erythropoiesis. Under monocell culture conditions, the differentiation into K562 erythrocyte-like cells was enhanced following the overexpression of Wild-type RP S19. Conversely, the differentiation was repressed following the overexpression of mutant RP S19. An RP S19 oligomer inhibitor and a C5aR inhibitor blocked the association of the K562 basophilic EB-like cells and the THP-1 macrophage-like cells under coculture conditions. When bound to RP S19 oligomers, the C5aR may exhibit dual functions as a connector for the EB macrophage island and as a sensor for EB differentiation in the bone marrow. PMID- 23346184 TI - BPI-ANCA and long-term prognosis among 46 adult CF patients: a prospective 10 year follow-up study. AB - INTRODUCTION: Anti-neutrophil cytoplasmic antibodies specific for bactericidal/permeability-increasing protein (BPI-ANCA) are frequent in CF patients and mainly develop in response to infection with Pseudomonas aeruginosa. It is not known to what extent BPI-ANCA correlates to prognosis. OBJECTIVES: To evaluate the prognostic value of IgA-BPI-ANCA, measured at the beginning of the study, for transplantation-free survival. METHODS: A cohort of 46 adult, nontransplanted CF patients was generated, 1995-1998, and characterized using Leeds criteria, lung function, and IgA-BPI-ANCA levels measured by ELISA. The cohort was followed until December 2009, using the combined endpoint of death or lung transplantation. RESULTS: Lung function and IgA-BPI-ANCA, but not Leeds criteria, were significantly associated with adverse outcome. No patient with normal lung function at baseline reached endpoint. Within 10 years 8/11 with high BPI-ANCA reached an endpoint compared to 3/17 ANCA-negative patients. A similar result was seen within the Leeds I group where 7 out of 9 BPI-ANCA-positive patients reached endpoint, compared to none of the 5 patients without BPI-ANCA. CONCLUSIONS: IgA-BPI-ANCA is associated with adverse outcome among Pseudomonas aeruginosa infected CF patients, suggesting that BPI-ANCA is a biomarker of an unfavourable host-pathogen interaction. PMID- 23346185 TI - Complement activation and inhibition in wound healing. AB - Complement activation is needed to restore tissue injury; however, inappropriate activation of complement, as seen in chronic wounds can cause cell death and enhance inflammation, thus contributing to further injury and impaired wound healing. Therefore, attenuation of complement activation by specific inhibitors is considered as an innovative wound care strategy. Currently, the effects of several complement inhibitors, for example, the C3 inhibitor compstatin and several C1 and C5 inhibitors, are under investigation in patients with complement mediated diseases. Although (pre)clinical research into the effects of these complement inhibitors on wound healing is limited, available data indicate that reduction of complement activation can improve wound healing. Moreover, medicine may take advantage of safe and effective agents that are produced by various microorganisms, symbionts, for example, medicinal maggots, and plants to attenuate complement activation. To conclude, for the development of new wound care strategies, (pre)clinical studies into the roles of complement and the effects of application of complement inhibitors in wound healing are required. PMID- 23346187 TI - Immunotherapy for multiple myeloma. PMID- 23346186 TI - Variable EBV DNA load distributions and heterogeneous EBV mRNA expression patterns in the circulation of solid organ versus stem cell transplant recipients. AB - Epstein-Barr virus (EBV) driven post-transplant lymphoproliferative disease (PTLD) is a heterogeneous and potentially life-threatening condition. Early identification of aberrant EBV activity may prevent progression to B-cell lymphoma. We measured EBV DNA load and RNA profiles in plasma and cellular blood compartments of stem cell transplant (SCT; n = 5), solid organ transplant recipients (SOT; n = 15), and SOT having chronic elevated EBV-DNA load (n = 12). In SCT, EBV DNA was heterogeneously distributed, either in plasma or leukocytes or both. In SOT, EBV DNA load was always cell associated, predominantly in B cells, but occasionally in T cells (CD4 and CD8) or monocytes. All SCT with cell associated EBV DNA showed BARTs and EBNA1 expression, while LMP1 and LMP2 mRNA was found in 1 and 3 cases, respectively. In SOT, expression of BARTs was detected in all leukocyte samples. LMP2 and EBNA1 mRNA was found in 5/15 and 2/15, respectively, but LMP1 mRNA in only 1, coinciding with severe PTLD and high EBV DNA. CONCLUSION: EBV DNA is differently distributed between white cells and plasma in SOT versus SCT. EBV RNA profiling in blood is feasible and may have added value for understanding pathogenic virus activity in patients with elevated EBV-DNA. PMID- 23346188 TI - Analgesic and Anti-Inflammatory Activities of the Ethanolic Extract of Artemisia morrisonensis Hayata in Mice. AB - The aim of this study was to investigate the possible analgesic and anti inflammatory mechanisms of the ethanolic extract of A. morrisonensis Hayata (AM(EtOH)). Two models were employed for evaluation of the analgesic effects: acetic acid-induced writhing response and formalin-induced paw licking. The results demonstrated that AM(EtOH) decreased writhing response for both the acetic acid assay and the licking time in the formalin test. The anti inflammatory effect was evaluated by paw edema of mice induced by lambda carrageenan. AM(EtOH) significantly decreased induced paw edema three to four hours after lambda-carrageenan injection. Additionally, the results indicated that the anti-inflammatory mechanism of AM(EtOH) may be due to the declined levels of nitric oxide (NO) and malondialdehyde (MDA) in the edematous paw. Furthermore, AM(EtOH) decreased the tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels, leading to the reduction of prostaglandins and subsequently alleviated edema. Isolation and purification of the AM(EtOH) extract determined p-hydroxyacetophenone to be a major component at 130 mg/g of extract. No mortality was observed in the acute toxicity test given at the dose of 10 g/kg. This study demonstrated the possible mechanisms for the analgesic and anti inflammatory effects of AM(EtOH) for mice and provided evidence for the ethnobotanical uses of A. morrisonensis in treating inflammatory diseases. PMID- 23346190 TI - One-year effectiveness of a 3-week balneotherapy program for the treatment of overweight or obesity. AB - Objective. To assess the one-year effectiveness on weight loss of a 3-week balneotherapy program (BT). Method. A Zelen double consent randomised controlled trial to compare one-year BMI loss between a 3-week BT program versus usual care (UC) for overweight or obese patients (BMI: 27-35 kg/m(2)), associated or not with a dietary motivational interview (DMI) during the follow-up, using a 2 * 2 factorial design. Main analysis was a per protocol analysis comparing patients attending BT to patients managed by UC, matched on sex, overweight or obese status, DMI randomisation and a propensity score to attend BT or to be managed by UC. Results. From the 257 patients who completed the follow-up, 70 patients of each group could be matched. Mean BMI loss was 1.91 kg/m(2) [95%CI: 1.46; 2.35] for the BT patients and 0.20 kg/m(2) [-0.24; 0.64] for the UC patients (P < 0.001), corresponding to a significant BT benefit of 1.71 kg/m(2) [1.08; 2.33]. There was no significant effect of DMI and no interaction with BT or UC. No adverse reaction was observed for patients attending BT. Conclusion. A 3-week BT program provided a significant one-year benefit over the usual GP dietary advice for overweight and obese patients. PMID- 23346189 TI - Traditional chinese medicine-based network pharmacology could lead to new multicompound drug discovery. AB - Current strategies for drug discovery have reached a bottleneck where the paradigm is generally "one gene, one drug, one disease." However, using holistic and systemic views, network pharmacology may be the next paradigm in drug discovery. Based on network pharmacology, a combinational drug with two or more compounds could offer beneficial synergistic effects for complex diseases. Interestingly, traditional chinese medicine (TCM) has been practicing holistic views for over 3,000 years, and its distinguished feature is using herbal formulas to treat diseases based on the unique pattern classification. Though TCM herbal formulas are acknowledged as a great source for drug discovery, no drug discovery strategies compatible with the multidimensional complexities of TCM herbal formulas have been developed. In this paper, we highlighted some novel paradigms in TCM-based network pharmacology and new drug discovery. A multiple compound drug can be discovered by merging herbal formula-based pharmacological networks with TCM pattern-based disease molecular networks. Herbal formulas would be a source for multiple compound drug candidates, and the TCM pattern in the disease would be an indication for a new drug. PMID- 23346191 TI - Research on nonlinear feature of electrical resistance of acupuncture points. AB - A highly sensitive volt-ampere characteristics detecting system was applied to measure the volt-ampere curves of nine acupuncture points, LU9, HT7, LI4, PC6, ST36, SP6, KI3, LR3, and SP3, and corresponding nonacupuncture points bilaterally from 42 healthy volunteers. Electric currents intensity was increased from 0 MUA to 20 MUA and then returned to 0 MUA again. The results showed that the volt ampere curves of acupuncture points had nonlinear property and magnetic hysteresis-like feature. On all acupuncture point spots, the volt-ampere areas of the increasing phase were significantly larger than that of the decreasing phase (P < 0.01). The volt-ampere areas of ten acupuncture point spots were significantly smaller than those of the corresponding nonacupuncture point spots when intensity was increase (P < 0.05 ~ P < 0.001). And when intensity was decrease, eleven acupuncture point spots showed the same property as above (P < 0.05 ~ P < 0.001), while two acupuncture point spots showed opposite phenomenon in which the areas of two acupuncture point spots were larger than those of the corresponding nonacupuncture point spots (P < 0.05 ~ P < 0.01). These results show that the phenomenon of low skin resistance does not exist to all acupuncture points. PMID- 23346192 TI - Predictors of complementary and alternative medicine use in cancer care: results of a nationwide multicenter survey in Korea. AB - Background. Although studies have shown that the use of complementary and alternative medicine (CAM) is common in cancer patients, few surveys have assessed CAM use and associated factors in various cancers in Korea. Objectives. We explored factors predicting CAM use among a nationally representative sample of cancer patients. Methods. In total, 2,661 cancer patients were administered questionnaires about their CAM use and factors that might predict CAM use including sociodemographics, clinical and quality-of-life factors, time since diagnosis, trust in physicians, trust in hospitals, satisfaction, and informational needs. Data were analyzed using Pearson's chi(2) tests and multivariate logistic regression analysis. Results. Overall, 25.5% reported that they had used or were using CAM. Higher income, presence of metastasis, longer time since diagnosis, less trust in hospitals, lower overall satisfaction, and higher degree of informational need were significantly associated with CAM use. Conclusions. The use of CAM in patients with cancer can be interpreted as an attempt to explore all possible options, expression of an active coping style, or expression of unmet needs in the cancer care continuum. Physicians need to openly discuss the use of CAM with their patients and identify whether they have other unmet supportive needs. PMID- 23346193 TI - Treatment of common cold patients with the shi-cha capsule: a multicenter, double blind, randomized, placebo-controlled, dose-escalation trial. AB - This study was designed to determine the therapeutic efficacy and safety of the Shi-cha capsule, a Chinese herbal formula, in the treatment of patients with wind cold type common cold. In our multi-center, prospective, double-blind, randomized, placebo-controlled, dose-escalation trial, patients with wind-cold type common cold received 0.6 g of Shi-cha capsule plus 0.6 g placebo (group A), 1.2 g of Shi-cha capsule (group B), or 1.2 g placebo (group C), three times daily for 3 days and followed up to 10 days. The primary end point was all symptom duration. The secondary end points were main symptom duration, minor symptom duration, the changes in cumulative symptom score, main symptom score, and minor symptom score 4 days after the treatment, as well as adverse events. A total of 377 patients were recruited and 360 met the inclusive criteria; 120 patients constituted each treatment group. Compared with patients in group C, patients in groups A and B had significant improvement in the all symptom duration, main symptom duration, minor symptom duration, as well as change from baseline of cumulative symptom score, main symptom score, and minor symptom score at day 4. The symptom durations and scores showed slight superiority of group B over group A, although these differences were not statistically significant. There were no differences in adverse events. The Shi-cha capsule is efficacious and safe for the treatment of patients with wind-cold type common cold. Larger trials are required to fully assess the benefits and safety of this treatment for common cold. PMID- 23346194 TI - Dose-Dependent Effects of the Cimicifuga racemosa Extract Ze 450 in the Treatment of Climacteric Complaints: A Randomized, Placebo-Controlled Study. AB - Extracts from Cimicifuga racemosa (CR, synonym Actaea racemosa) have shown efficacy in trials in women with menopausal symptoms. Yet, dose dependency remains unclear. Therefore, 180 female outpatients with climacteric complaints were treated for 12 weeks in a randomized, double-blind, placebo-controlled, 3 armed trial (CR extract Ze 450 in 6.5 mg or 13.0 mg, or placebo). Primary outcome was the difference in menopausal symptoms (vasomotor, psychological, and somatic), assessed by the Kupperman Menopausal Index between baseline and week 12. Secondary efficacy variables were patients' self-assessments of general quality of life (QoL), responder rates, and safety. Compared to placebo, patients receiving Ze 450 showed a significant reduction in the severity of menopausal symptoms in a dose-dependent manner from baseline to endpoint (mean absolute differences 17.0 (95% CI 14.65-19.35) score points, P < 0.0001 for 13.0 mg; mean absolute differences 8.47 (95% CI 5.55-11.39) score points, P = 0.0003 for 6.5 mg). QoL and responder rates corresponded with the main endpoint. Changes in menopausal symptoms and QoL were inversely correlated. Reported adverse events and clinical laboratory testing did not raise safety concerns. The CR extract Ze 450 is an effective and well-tolerated nonhormonal alternative to hormone treatment for symptom relief in menopausal women. PMID- 23346195 TI - Effects of Tai Chi versus Proprioception Exercise Program on Neuromuscular Function of the Ankle in Elderly People: A Randomized Controlled Trial. AB - Background. Tai Chi is a traditional Chinese medicine exercise used for improving neuromuscular function. This study aimed to investigate the effects of Tai Chi versus proprioception exercise program on neuromuscular function of the ankle in elderly people. Methods. Sixty elderly subjects were randomly allocated into three groups of 20 subjects per group. For 16 consecutive weeks, subjects participated in Tai Chi, proprioception exercise, or no structured exercise. Primary outcome measures included joint position sense and muscle strength of ankle. Subjects completed a satisfaction questionnaire upon study completion in Tai Chi and proprioception groups. Results. (1) Both Tai Chi group and proprioception exercise group were significantly better than control group in joint position sense of ankle, and there were no significant differences in joint position sense of ankle between TC group and PE group. (2) There were no significant differences in muscle strength of ankle among groups. (3) Subjects expressed more satisfaction with Tai Chi than with proprioception exercise program. Conclusions. None of the outcome measures on neuromuscular function at the ankle showed significant change posttraining in the two structured exercise groups. However, the subjects expressed more interest in and satisfaction with Tai Chi than proprioception exercise. PMID- 23346196 TI - Beneficial effect of shikonin on experimental colitis induced by dextran sulfate sodium in BALB/c mice. AB - The naphthoquinone shikonin, a major component of the root of Lithospermum erythrorhizon, now is studied as an anti-inflammatory agent in the treatment of ulcerative colitis (UC). Acute UC was induced in Balb/C mice by oral administration of 5% dextran sodium sulfate (DSS). The disease activity index was evaluated, and a histologic study was carried out. Orally administered shikonin reduces induced UC in a dose-dependent manner, preventing the shortening of the colorectum and decreasing weight loss by 5% while improving the appearance of feces and preventing bloody stools. The disease activity index score was much lower in shikonin-treated mice than in the colitic group, as well as the myeloperoxidase activity. The expression of cyclooxygenase-2 was reduced by 75%, activation of NF-kappaB was reduced by 44%, and that of pSTAT-3 by 47%, as well as TNF-alpha, IL-1beta, and IL-6 production. Similar results were obtained in primary macrophages culture. This is the first report of shikonin's ability to attenuate acute UC induced by DSS. Shikonin acts by blocking the activation of two major targets: NF-kappaB and STAT-3, and thus constitutes a promising potential therapeutic agent for the management of the inflammatory bowel disease. PMID- 23346197 TI - Herbal Medicine in Primary Healthcare in Germany: The Patient's Perspective. AB - Herbal medicine (HM) is one of the most widely used Complementary and Alternative Medicine (CAM) therapies throughout the world. The WHO has recognized HM as an essential component of primary healthcare. The aim of this study was to explore patients' attitudes towards using HM, their sources of information and the role of costs. Within a qualitative research approach, semi-standardized interviews with 18 patients using HM were conducted and analyzed according to Mayring's content analysis. Patients highlighted their active role and perceived autonomy choosing HM. Most interviewees experienced HM as better, with more sustainable effects and fewer side effects compared to conventional medicine. All media, family, friends, and healthcare professionals were reported as sources of information. Some patients complained that doctors and pharmacists have insufficient knowledge of HM. Most patients expressed their regret that HM is not reimbursed by statutory health insurances but also their general willingness to pay extra for HM. The main challenge for German primary care, besides the reintroduction of reimbursement, is the promotion of knowledge and skill development in HM. This is to ensure patient safety and work in partnership with patients. Appropriate strategies for education must be tailored to the specific needs of health professional groups. PMID- 23346198 TI - Dry needling at myofascial trigger spots of rabbit skeletal muscles modulates the biochemicals associated with pain, inflammation, and hypoxia. AB - Background and Purpose. Dry needling is an effective therapy for the treatment of pain associated with myofascial trigger point (MTrP). However, the biochemical effects of dry needling that are associated with pain, inflammation, and hypoxia are unclear. This study investigated the activities of beta-endorphin, substance P, TNF-alpha, COX-2, HIF-1alpha, iNOS, and VEGF after different dosages of dry needling at the myofascial trigger spots (MTrSs) of a skeletal muscle in rabbit. Materials and Methods. Dry needling was performed either with one dosage (1D) or five dosages (5D) into the biceps femoris with MTrSs in New Zealand rabbits. Biceps femoris, serum, and dorsal root ganglion (DRG) were sampled immediately and 5 d after dry needling for beta-endorphin, substance P, TNF-alpha, COX-2, HIF 1alpha, iNOS, and VEGF immunoassays. Results. The 1D treatment enhanced the beta endorphin levels in the biceps femoris and serum and reduced substance P in the biceps femoris and DRG. The 5D treatment reversed these effects and was accompanied by increase of TNF-alpha, COX-2, HIF-1alpha, iNOS, and VEGF production in the biceps femoris. Moreover, the higher levels of these biochemicals were still maintained 5 d after treatment. Conclusion. Dry needling at the MTrSs modulates various biochemicals associated with pain, inflammation, and hypoxia in a dose-dependent manner. PMID- 23346199 TI - Triptolide Transcriptionally Represses HER2 in Ovarian Cancer Cells by Targeting NF-kappaB. AB - Triptolide (TPL) inhibits the proliferation of a variety of cancer cells and has been proposed as an effective anticancer agent. In this study, we demonstrate that TPL downregulates HER2 protein expression in oral, ovarian, and breast cancer cells. It suppresses HER2 protein expression in a dose- and time-dependent manner. Transrepression of HER2 promoter activity by TPL is also observed. The interacting site of TPL on the HER2 promoter region is located between -207 and 103 bps, which includes a putative binding site for the transcription factor NF kappaB. Previous reports demonstrated that TPL suppresses NF-kappaB expression. We demonstrate that overexpression of NF-kappaB rescues TPL-mediated suppression of HER2 promoter activity and protein expression in NIH3T3 cells and ovarian cancer cells, respectively. In addition, TPL downregulates the activated (phosphorylated) forms of HER2, phosphoinositide-3 kinase (PI3K), and serine/threonine-specific protein kinase (Akt). TPL also inhibits tumor growth in a mouse model. Furthermore, TPL suppresses HER2 and Ki-67 expression in xenografted tumors based on an immunohistochemistry (IHC) assay. These findings suggest that TPL transrepresses HER2 and suppresses the downstream PI3K/Akt signaling pathway. Our study reveals that TPL can inhibit tumor growth and thereby may serve as a potential chemotherapeutic agent. PMID- 23346200 TI - Remote subcutaneous needling to suppress the irritability of myofascial trigger spots: an experimental study in rabbits. AB - Objective. To obtain electrophysiological effects of Fu's subcutaneous needling (FSN) on needling distance by assessment of endplate noise (EPN) recorded from the myofascial trigger spots (MTrSs) in rabbit skeletal muscle. Method. Eighteen New Zealand rabbits weighing 2.5-3.0 kg were randomly divided into two groups as follows: proximal needling (PN) group and distal needling (DN) group. The needling procedure followed the instructions described by the inventor of FSN, including needling insertion and swaying movement. The amplitudes of EPN on the MTrS region of BF muscle were recorded as an index of MTrS irritability. Random sampling of EPN tracings were taken for further analyses before, during, and after FSN treatment. Results. In PN and DN groups, the trends of EPN amplitude alterations were similar at conditions before, during, and after FSN treatment. The degree of reduction in the EPN amplitude in PN group was significantly higher than that in DN group. There were no significant changes in EPN amplitudes in the MTrS of contralateral BF without FSN intervention either in DN or PN group. Conclusion. The irritability of proximal MTrSs could be modulated after ipsilateral FSNs. The placement of FSN may affect the effectiveness of suppression of irritability of MTrSs. PMID- 23346201 TI - Effects of Fructus mume Extract on MAPK and NF-kappaB Signaling and the Resultant Improvement in the Cognitive Deficits Induced by Chronic Cerebral Hypoperfusion. AB - Fructus mume (F. mume) has been used as a medicinal food in Japan and has been reported to have anti-inflammatory effects in inflammatory bowel disease and macrophage-mediated inflammation. We investigated the effects of F. mume extracts on cognitive dysfunction in rats with chronic cerebral hypoperfusion and the molecular mechanisms underlying these effects. Chronic cerebral hypoperfusion was induced in male Wister rats by bilateral common artery occlusion (BCCAo). Daily administration of F. mume extracts was started on day 20 after post-BCCAo and continued for 40 days. The status of hippocampus-dependent memory was evaluated in control rats, rats with chronic cerebral hypoperfusion, and rats with chronic cerebral hypoperfusion that were administered F. mume. The levels of microglial activation were measured in the hippocampus and the fimbria of hippocampus, and expression levels of hippocampal mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) were examined. Rats that received chronic cerebral hypoperfusion showed spatial memory impairments relative to the control rats; these impairments were reduced by daily administration of F. mume. Administration of F. mume mitigated the microglial activation and alterations of hippocampal MAPK and NF-kappaB signaling in the rats with chronic cerebral hypoperfusion. These results indicate that F. mume may possess therapeutic potential for the prevention of vascular dementia via inhibition of inflammatory processes. PMID- 23346202 TI - The ent-15alpha-Acetoxykaur-16-en-19-oic Acid Relaxes Rat Artery Mesenteric Superior via Endothelium-Dependent and Endothelium-Independent Mechanisms. AB - The objective of the study was to investigate the mechanism of the relaxant activity of the ent-15alpha-acetoxykaur-16-en-19-oic acid (KA-acetoxy). In rat mesenteric artery rings, KA-acetoxy induced a concentration-dependent relaxation in vessels precontracted with phenylephrine. In the absence of endothelium, the vasorelaxation was significantly shifted to the right without reduction of the maximum effect. Endothelium-dependent relaxation was significantly attenuated by pretreatment with L-NAME, an inhibitor of the NO-synthase (NOS), indomethacin, an inhibitor of the cyclooxygenase, L-NAME + indomethacin, atropine, a nonselective antagonist of the muscarinic receptors, ODQ, selective inhibitor of the guanylyl cyclase enzyme, or hydroxocobalamin, a nitric oxide scavenger. The relaxation was completely reversed in the presence of L-NAME + 1 mM L-arginine or L-arginine, an NO precursor. Diterpene-induced relaxation was not affected by TEA, a nonselective inhibitor of K+ channels. The KA-acetoxy antagonized CaCl(2)-induced contractions in a concentration-dependent manner and also inhibited an 80 mM KCl induced contraction. The KA-acetoxy did not interfere with Ca(2+) release from intracellular stores. The vasorelaxant induced by KA-acetoxy seems to involve the inhibition of the Ca(2+) influx and also, at least in part, by endothelial muscarinic receptors activation, NO and PGI(2) release. PMID- 23346203 TI - Effect of the Velvet Antler of Formosan Sambar Deer (Cervus unicolor swinhoei) on the Prevention of an Allergic Airway Response in Mice. AB - Two mouse models were used to assay the antiallergic effects of the velvet antler (VA) of Formosan sambar deer (Cervus unicolor swinhoei) in this study. The results using the ovalbumin- (OVA-) sensitized mouse model showed that the levels of total IgE and OVA-specific IgE were reduced after VA powder was administrated for 4 weeks. In addition, the ex vivo results indicated that the secretion of T helper cell 1 (Th1), regulatory T (Treg), and Th17 cytokines by splenocytes was significantly increased (P < 0.05) when VA powder was administered to the mice. Furthermore, OVA-allergic asthma mice that have been orally administrated with VA powder showed a strong inhibition of Th2 cytokine and proinflammatory cytokine production in bronchoalveolar fluid compared to control mice. An increase in the regulatory T-cell population of splenocytes in the allergic asthma mice after oral administration of VA was also observed. All the features of the asthmatic phenotype, including airway inflammation and the development of airway hyperresponsiveness, were reduced by treatment with VA. These findings support the hypothesis that oral feeding of VA may be an effective way of alleviating asthmatic symptoms in humans. PMID- 23346204 TI - Epicatechin used in the treatment of intestinal inflammatory disease: an analysis by experimental models. AB - Background. This study was pathway of (-)-epicatechin (EC) in the prevention and treatment of intestine inflammation in acute and chronic rat models. Methods. Intestine inflammation was induced in rats using TNBS. The morphological, inflammatory, immunohistochemical, and immunoblotting characteristics of colon samples were examined. The effects of EC were evaluated in an acute model at doses of 5, 10, 25, and 50 mg/kg by gavage for 5 days. The chronic colitis model was induced 1st day, and treated for 21 days. For the colitis relapse model, the induction was repeated on 14th. Results. EC10 and EC50 effectively reduced the lesion size, as assessed macroscopically; and confirmed by microscopy for EC10. The glutathione levels were higher in EC10 group but decreased COX-2 expression and increased cell proliferation (PC) were observed, indicating an anti inflammatory activity and a proliferation-stimulating effect. In the chronic colitis model, EC10 showed lower macroscopic and microscopic lesion scores and increase in glutathione levels. As in the acute model, a decrease in COX-2 expression and an increase in PC in EC10, the chronic model this increase maybe by the pathway EGF expression. Conclusion. These results confirm the activity of EC as an antioxidant that reduces of the lesion and that has the potential to stimulate tissue healing, indicating useful for preventing and treating intestine inflammation. PMID- 23346205 TI - Traditional Oriental Herbal Medicine for Children and Adolescents with ADHD: A Systematic Review. AB - Objective. To evaluate the efficacy of traditional Oriental herbal medicines (TOHM) for children and adolescents with ADHD. Methods. Randomized clinical trials published from January 1, 1990, to December 31, 2010, in English, Chinese, Japanese, or Korean language which evaluated the use of TOHM on ADHD subjects of 18 years old or below, diagnosed based on DSM-IV, were searched from MEDLINE, EMBASE, PsyINFO, Cochrane Library, and 10 other databases. Results. Twelve studies involving 1189 subjects met the inclusion criteria. In general, the included studies claimed that TOHM has similar efficacy to methylphenidate and at the same time has fewer side effects compared to methylphenidate. Some studies also suggested that the effect of TOHM sustained better than methylphenidate. However, solid conclusions could not be drawn because the included studies were not of high quality. Risk of bias issues such as randomization, allocation, concealment and blinding were not addressed in most of the studies, and the risk of publication bias could not be ruled out. Conclusion. Currently, there is not strong evidence to say that TOHM is effective in treating the core symptoms of ADHD. PMID- 23346206 TI - Building a strategic framework for comparative effectiveness research in complementary and integrative medicine. AB - The increasing burden of chronic diseases presents not only challenges to the knowledge and expertise of the professional medical community, but also highlights the need to improve the quality and relevance of clinical research in this domain. Many patients now turn to complementary and integrative medicine (CIM) to treat their chronic illnesses; however, there is very little evidence to guide their decision-making in usual care. The following research recommendations were derived from a CIM Stakeholder Symposium on Comparative Effectiveness Research (CER): (1) CER studies should be made a priority in this field; (2) stakeholders should be engaged at every stage of the research; (3) CER study designs should highlight effectiveness over efficacy; (4) research questions should be well defined to enable the selection of an appropriate CER study design; (5) the CIM community should cultivate widely shared understandings, discourse, tools, and technologies to support the use and validity of CER methods; (6) Effectiveness Guidance Documents on methodological standards should be developed to shape future CER studies. CER is an emerging field and its development and impact must be reflected in future research strategies within CIM. This stakeholder symposium was a first step in providing systematic guidance for future CER in this field. PMID- 23346207 TI - Tuina-focused integrative chinese medical therapies for inpatients with low back pain: a systematic review and meta-analysis. AB - Objective. To evaluate the effectiveness of Tuina-focused integrative Chinese medical therapies (TICMT) on inpatients with low back pain (LBP). Methods. 6 English and Chinese databases were searched for randomized controlled trials (RCTs) of TICMT for in-patients with LBP. The methodological quality of the included RCTs was assessed based on PEDro scale. And the meta-analyses of TICMT for LBP on pain and functional status were conducted. Results. 20 RCTs were included. The methodological quality of the included RCTs was poor. The meta analyses' results showed that TICMT had statistically significant effects on pain and functional status, especially Tuina plus Chinese herbal medicine (standardised mean difference, SMD: 1.17; 95% CI 0.75 to 1.60 on pain; SMD: 1.31; 95% CI 0.49 to 2.14 on functional status) and Tuina plus acupuncture (SMD: 0.94; 95% CI 0.38 to 1.50 on pain; SMD: 0.53; 95% CI 0.21 to 0.85 on functional status). But Tuina plus moxibustion or hot pack did not show significant improvements on pain. And the long-term evidence of TICMT was far from sufficient. Conclusions. The preliminary evidence from current studies suggests that TICMT might be effective complementary and alternative treatments for in patients with LBP. However, the poor methodological quality of the included RCTs means that high-quality RCTs with long follow-up are warranted. PMID- 23346208 TI - Transcutaneous auricular vagus nerve stimulation protects endotoxemic rat from lipopolysaccharide-induced inflammation. AB - Background. Transcutaneous auricular vagus nerve stimulation (ta-VNS) could evoke parasympathetic activities via activating the brainstem autonomic nuclei, similar to the effects that are produced after vagus nerve stimulation (VNS). VNS modulates immune function through activating the cholinergic anti-inflammatory pathway. Methods. VNS, ta-VNS, or transcutaneous electrical acupoint stimulation (TEAS) on ST36 was performed to modulate the inflammatory response. The concentration of serum proinflammatory cytokines and tissue NF-kappa B p65 (NF kappaB p65) were detected in endotoxaemia affected anesthetized rats. Results. Similar to the effect of VNS, ta-VNS suppressed the serum proinflammatory cytokines levels, such as tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and interleukin-6 (IL-6) as well as NF-kappa B p65 expressions of lung tissues. ST36 stimulation also decreases LPS-induced high TNF-alpha level and NF-kappaB signal, but it did not restrain proinflammatory cytokine IL-1beta and IL-6. Neither ta-VNS nor ST36 stimulation could suppress LPS-induced TNF alpha and NF-kappaB after vagotomy or with alpha7nAChR antagonist injection. Conclusions. The present paper demonstrated that ta-VNS could be utilized to suppress LPS-induced inflammatory responses via alpha7nAChR-mediated cholinergic anti-inflammatory pathway. PMID- 23346209 TI - The flexner report of 1910 and its impact on complementary and alternative medicine and psychiatry in north america in the 20th century. AB - America experienced a genuinely vast development of biomedical science in the early decades of the twentieth century, which in turn impacted the community of academic psychiatry and changed the way in which clinical and basic research approaches in psychiatry were conceptualized. This development was largely based on the restructuring of research universities in both of the USA and Canada following the influential report of Johns Hopkins-trained science administrator and politician Abraham Flexner (1866-1959). Flexner's report written in commission for the Carnegie Foundation for the Advancement of Teaching in Washington, DC, also had a major influence on complementary and alternative medicine (CAM) in psychiatry throughout the 20th century. This paper explores the lasting impact of Flexner's research published on modern medicine and particularly on what he interpreted as the various forms of health care and psychiatric treatment that appeared to compete with the paradigm of biomedicine. We will particularly draw attention to the serious effects of the closing of so many CAM-oriented hospitals, colleges, and medical teaching programs following to the publication of the Flexner Report in 1910. PMID- 23346210 TI - Outcome measures of chinese herbal medicine for hypertension: an overview of systematic reviews. AB - Objective. The aim of this overview was to summarize the outcome measures of Chinese herbal medicine (CHM) for the treatment of hypertension based on available systematic reviews (SRs), so as to evaluate the potential benefits and advantages of CHM on hypertension. Methods. Literature searches were conducted in the Cochrane Database of Systematic Reviews, MEDLINE, and 4 databases in Chinese. SRs of CHM for hypertension were included. Two independent reviewers (J. Wang and X. J. Xiong) extracted the data. Results. 10 SRs were included. 2 SRs had primary endpoints, while others focused on secondary endpoints to evaluate CHM for hypertension such as blood pressure (BP) and Traditional Chinese Medicine (TCM) syndrome. 6 SRs have reported the adverse effects, whereas the other 4 SRs have not mentioned it at all. Many CHM appeared to have significant effect on improving BP, TCM syndrome, and so on. However, most SRs failed to make a definite conclusion for the effectiveness of CHM for hypertension due to poor evidence. Conclusion. Primary endpoints have not been widely used currently. The benefits of CHM for hypertension need to be confirmed in the future with randomized controlled trials (RCTs) of more persuasive primary endpoints and high quality SRs. PMID- 23346211 TI - Probable mechanisms of needling therapies for myofascial pain control. AB - Myofascial pain syndrome (MPS) has been defined as a regional pain syndrome characterized by muscle pain caused by myofascial trigger points (MTrPs) clinically. MTrP is defined as the hyperirritable spot in a palpable taut band of skeletal muscle fibers. Appropriate treatment to MTrPs can effectively relieve the clinical pain of MPS. Needling therapies, such as MTrP injection, dry needling, or acupuncture (AcP) can effectively eliminate pain immediately. AcP is probably the first reported technique in treating MPS patients with dry needling based on the Traditional Chinese Medicine (TCM) theory. The possible mechanism of AcP analgesia were studied and published in recent decades. The analgesic effect of AcP is hypothesized to be related to immune, hormonal, and nervous systems. Compared to slow-acting hormonal system, nervous system acts in a faster manner. Given these complexities, AcP analgesia cannot be explained by any single mechanism. There are several principles for selection of acupoints based on the TCM principles: "Ah-Shi" point, proximal or remote acupoints on the meridian, and extra-meridian acupoints. Correlations between acupoints and MTrPs are discussed. Some clinical and animal studies of remote AcP for MTrPs and the possible mechanisms of remote effectiveness are reviewed and discussed. PMID- 23346212 TI - Explore the Molecular Mechanism of Apoptosis Induced by Tanshinone IIA on Activated Rat Hepatic Stellate Cells. AB - Since the activated hepatic stellate cell (HSC) is the predominant event in the progression of liver fibrosis, selective clearance of HSC should be a potential strategy in therapy. Salvia miltiorrhiza roots ethanol extract (SMEE) remarkably ameliorates liver fibrogenesis in DMN-administrated rat model. Next, tanshinone IIA (Tan IIA), the major compound of SMEE, significantly inhibited rat HSC viability and led to cell apoptosis. Proteome tools elucidated that increased prohibitin is involved in cell cycle arrest under Tan IIA is the treatment while knockdown of prohibitin could attenuate Tan IIA-induced apoptosis. In addition, Tan IIA mediated translocation of C-Raf which interacted with prohibitin activating MAPK and inhibiting AKT signaling in HSC. MAPK antagonist suppressed ERK phosphorylation which was necessary for Tan IIA-induced expression of Bax and cytochrome c. PD98059 also abolished Tan IIA-modulated cleavage of PARP. Our findings suggested that Tan IIA could contribute to apoptosis of HSC by promoting ERK-Bax-caspase pathways through C-Raf/prohibitin complex. PMID- 23346213 TI - The neural pathway of reflex regulation of electroacupuncture at orofacial acupoints on gastric functions in rats. AB - Acupuncture has a reflex regulation in gastrointestinal functions, which is characterized with segment. In the present study, the neural pathway of electroacupuncture (EA) at orofacial acupoints (ST2) on gastric myoelectric activity (GMA) in rats was investigated. The results indicated that EA at ST2 facilitated spike bursts of GMA, which is similar to EA at limbs and opposite to EA at abdomen. The excitatory effect was abolished by the transaction of infraorbital nerves, dorsal vagal complex lesion, and vagotomy, respectively. In addition, microinjection of L-glutamate into the nucleus of the solitary tract (NTS) attenuated the excitatory effect. All these data suggest that the dorsal vagal complex is involved in the reflex regulation of EA at orofacial acupoints on gastric functions and NTS-dorsal motor nucleus of the vagus (DMV) inhibitory connections may be essential for it. PMID- 23346214 TI - Biophysical characteristics of meridians and acupoints: a systematic review. AB - As an integral part of traditional Chinese medicine (TCM), acupuncture is a convenient and effective therapy with fewer adverse effects. Recently, researches on meridian essence have become core issues of modern TCM. Numerous experiments have demonstrated the objective existence of meridians by different technologies since 1950s, such as biophysics, biochemistry, and molecular biology. In this paper, we review biophysical studies on electric, acoustic, thermal, optical, magnetic, isotopic, and myoelectric aspects of meridians and acupoints. These studies suggest that meridians/acupoints have biophysical characteristics which are different from nonacupuncture points. Owing to the limitations of previous studies, future research using high-throughput technologies such as omics and multicenter randomized controlled trials should be performed to explore the acupuncture's mechanisms of action and demonstration of efficacy. PMID- 23346215 TI - Natural products for liver diseases: basic, clinical, and translational research. PMID- 23346216 TI - In vivo anti-influenza virus activity of Japanese herbal (kampo) medicine, "shahakusan," and its possible mode of action. AB - Background. A Kampo medicine, Shahakusan (SHS), has been prescribed in late phase of infection that causes inflammations in the lung. But effect of SHS on viral infection in respiratory tract has never been reported. Objectives. To evaluate anti-influenza virus activity of SHS and its mode of actions through immune systems. Methods. SHS (0.3 g/kg/day) was orally administered to BALB/c miceforupper (URI) or lower respiratory tract infection (LRI) of influenza virus A/PR/8/34. The virus titer of nasal lavage fluid (NLF) at 5 or 2 day postinfection (p.i.) and cytokine mRNA expressions in mandibular lymph node or lung at 5 or 4 day p.i. were evaluated for URI or LRI, respectively. The histopathological examinations of lung tissue and NK cell activity in the splenocytes were also evaluated at 4 day p.i. on LRI. Results. When SHS was administered from 7 days before to 4 days p.i. for URI, the virus titer was significantly decreased in comparison with water-treated control, and IL-4, IL 1beta, and IL-10 mRNA expression was decreased, but IL-12A mRNA expression was increased. Administration of SHS from one day before to one day p.i. for LRI significantly decreased the virus titer. SHS also decreased infiltration of inflammatory cells in the bronchoalveolar spaces and damage of desquamated mucosal epithelia of bronchiole, decreased IP-10 mRNA expression, and increased NK cell activity. Conclusion. SHS has no direct effect on influenza virus infection but exerts antiviral effect in mice by its immunomodulating activity through action of NK cells and anti-inflammatory activity in the lung. PMID- 23346217 TI - Identification of Major Active Ingredients Responsible for Burn Wound Healing of Centella asiatica Herbs. AB - Centella asiatica herbs have been prescribed as a traditional medicine for wound healing in China and Southeast Asia for a long time. They contain many kinds of triterpenoid compounds, mainly including glycosides (asiaticoside and madecassoside) and corresponding aglycones (asiatic acid and madecassic acid). To identify which is the major active constituent, a comprehensive and comparative study of these compounds was performed. In vitro, primary human skin fibroblasts, originating from healthy human foreskin samples, were treated with various concentrations of asiaticoside, madecassoside, asiatic acid, and madecassic acid, respectively. Cell proliferation, collagen synthesis, MMP-1/TIMP-1 balance, and TGF-beta/Smad signaling pathway were investigated. In vivo, mice were orally administered with the four compounds mentioned above for two weeks after burn injury. The speed and quality of wound healing, as well as TGF-beta(1) levels in skin tissues, were examined. Interestingly, in contrast to prevalent postulations, asiaticoside and madecassoside themselves, rather than their corresponding metabolites asiatic acid and madecassic acid, are recognized as the main active constituents of C. asiatica herbs responsible for burn wound healing. Furthermore, madecassoside is more effective than asiaticoside (P = 0.0446 for procollagen type III synthesis in vitro, P = 0.0057 for wound healing speed, and P = 0.0491 for wound healing pattern in vivo, correspondingly). PMID- 23346218 TI - Integrative approaches in computational biomedical imaging. PMID- 23346219 TI - Functional dynamics of proteins. PMID- 23346220 TI - Immune system modeling and related pathologies. PMID- 23346221 TI - Identification and functional annotation of genome-wide ER-regulated genes in breast cancer based on ChIP-Seq data. AB - Estrogen receptor (ER) is a crucial molecule symbol of breast cancer. Molecular interactions between ER complexes and DNA regulate the expression of genes responsible for cancer cell phenotypes. However, the positions and mechanisms of the ER binding with downstream gene targets are far from being fully understood. ChIP-Seq is an important assay for the genome-wide study of protein-DNA interactions. In this paper, we explored the genome-wide chromatin localization of ER-DNA binding regions by analyzing ChIP-Seq data from MCF-7 breast cancer cell line. By integrating three peak detection algorithms and two datasets, we localized 933 ER binding sites, 92% among which were located far away from promoters, suggesting long-range control by ER. Moreover, 489 genes in the vicinity of ER binding sites were identified as estrogen response elements by comparison with expression data. In addition, 836 single nucleotide polymorphisms (SNPs) in or near 157 ER-regulated genes were found in the vicinity of ER binding sites. Furthermore, we annotated the function of the nearest-neighbor genes of these binding sites using Gene Ontology (GO), KEGG, and GeneGo pathway databases. The results revealed novel ER-regulated genes pathways for further experimental validation. ER was found to affect every developed stage of breast cancer by regulating genes related to the development, progression, and metastasis. This study provides a deeper understanding of the regulatory mechanisms of ER and its associated genes. PMID- 23346223 TI - Highlights in applied evolutionary biology. PMID- 23346222 TI - Cardiovascular system modeling. PMID- 23346224 TI - On-farm dynamic management of genetic diversity: the impact of seed diffusions and seed saving practices on a population-variety of bread wheat. AB - Since the domestication of crop species, humans have derived specific varieties for particular uses and shaped the genetic diversity of these varieties. Here, using an interdisciplinary approach combining ethnobotany and population genetics, we document the within-variety genetic structure of a population variety of bread wheat (Triticum aestivum L.) in relation to farmers' practices to decipher their contribution to crop species evolution. Using 19 microsatellites markers, we conducted two complementary graph theory-based methods to analyze population structure and gene flow among 19 sub-populations of a single population-variety [Rouge de Bordeaux (RDB)]. The ethnobotany approach allowed us to determine the RDB history including diffusion and reproduction events. We found that the complex genetic structure among the RDB sub-populations is highly consistent with the structure of the seed diffusion and reproduction network drawn based on the ethnobotanical study. This structure highlighted the key role of the farmer-led seed diffusion through founder effects, selection and genetic drift because of human practices. An important result is that the genetic diversity conserved on farm is complementary to that found in the genebank indicating that both systems are required for a more efficient crop diversity conservation. PMID- 23346225 TI - Natural selection in utero induced by mass layoffs: the hCG evidence. AB - Evolutionary theory, when coupled with research from epidemiology, demography, and population endocrinology, suggests that contracting economies affect the fitness and health of human populations via natural selection in utero. We know, for example, that fetal death increases more among males than females when the economy unexpectedly contracts; that unexpected economic contraction predicts low secondary sex ratios; and that males from low sex ratio birth cohorts live, on average, longer than those from high sex ratio cohorts. We also know that low levels of human chorionic gonadotropin (i.e., hCG) measured in the serum of pregnant women predict fetal death. We do not, however, know whether male survivors of conception cohorts subjected to contracting economies exhibit, as theory predicts, higher hCG than those from other cohorts. We show, in 71 monthly conception cohorts including nearly two million California births, that they do. We thereby add to the literature suggesting that the economy, a phenomenon over which we collectively exercise at least some control, affects population health. Our findings imply that the effect arises via natural selection - a mechanism we largely ignore when attempting to explain, or alter, how collective choice affects our biology. PMID- 23346226 TI - Conservation genetics and evolution in an endangered species: research in Sonoran topminnows. AB - Conservation genetics of endangered species has primarily focused on using neutral markers to determine units of conservation and estimating evolutionary parameters. Because the endangered Sonoran topminnow can be bred in the laboratory and has a relatively short generation length, experiments to examine both detrimental and adaptive variations are also possible. Here, we discuss over two decades of empirical and experimental observations in the Sonoran topminnow. Results from this research have been used to determine species and evolutionary significant units using neutral markers, document inbreeding and outbreeding depression and genetic load using experimental crosses, and measure adaptive differences in fitness-related traits and variation in pathogen resistance among populations and major histocompatibility complex genotypes. In addition, both premating and postmating reproductive isolation between Gila and Yaqui topminnows have been experimentally determined, and the predicted and observed ancestry of these two species in experimental crosses has been examined over time. Although some have suggested that endangered species are unsuitable for experimentation because of both practical and ethical considerations, these results demonstrate that in this case an endangered species can be employed to examine fundamental questions in conservation and evolution. PMID- 23346227 TI - Incorporating deep and shallow components of genetic structure into the management of Alaskan red king crab. AB - Observed patterns of genetic variability among marine populations are shaped not only by contemporary levels of gene flow, but also by divergences during historical isolations. We examined variability at 15 SNP loci and in mtDNA sequences (COI, 665 bp) in red king crab from 17 localities in the North Pacific. These markers define three geographically distinct evolutionary lineages (SNPs, F(CT) = 0.054; mtDNA Phi(CT) = 0.222): (i) Okhotsk Sea-Norton Sound-Aleutian Islands, (ii) southeastern Bering Sea-western Gulf of Alaska, and (iii) Southeast Alaska. Populations in the Bering Sea and in Southeast Alaska are genetically heterogeneous, but populations in the center of the range are homogeneous. Mitochondrial DNA diversity drops from h = 0.91 in the northwestern Pacific to h = 0.24 in the Southeast Alaska. Bayesian skyline plots (BSPs) indicate postglacial population expansions, presumably from ice-age refugia. BSPs of sequences simulated under a demographic model defined by late Pleistocene temperatures failed to detect demographic variability before the last glacial maximum. These results sound a note of caution for the interpretation of BSPs. Population fragmentation in the Bering Sea and in Southeast Alaskan waters requires population management on a small geographic scale, and deep evolutionary partitions between the three geographic groups mandate regional conservation measures. PMID- 23346228 TI - Mutualism effectiveness and vertical transmission of symbiotic fungal endophytes in response to host genetic background. AB - Certain species of the Pooideae subfamily develop stress tolerance and herbivory resistance through symbiosis with vertically transmitted, asexual fungi. This symbiosis is specific, and genetic factors modulate the compatibility between partners. Although gene flow is clearly a fitness trait in allogamous grasses, because it injects hybrid vigor and raw material for evolution, it could reduce compatibility and thus mutualism effectiveness. To explore the importance of host genetic background in modulating the performance of symbiosis, Lolium multiflorum plants, infected and noninfected with Neotyphodium occultans, were crossed with genetically distant plants of isolines (susceptible and resistant to diclofop methyl herbicide) bred from two cultivars and exposed to stress. The endophyte improved seedling survival in genotypes susceptible to herbicide, while it had a negative effect on one of the genetically resistant crosses. Mutualism provided resistance to herbivory independently of the host genotype, but this effect vanished under stress. While no endophyte effect was observed on host reproductive success, it was increased by interpopulation plant crosses. Neither gene flow nor herbicide had an important impact on endophyte transmission. Host fitness improvements attributable to gene flow do not appear to result in direct conflict with mutualism while this seems to be an important mechanism for the ecological and contemporary evolution of the symbiotum. PMID- 23346229 TI - Evolution of root plasticity responses to variation in soil nutrient distribution and concentration. AB - Root plasticity, a trait that can respond to selective pressure, may help plants forage for nutrients in heterogeneous soils. Agricultural breeding programs have artificially selected for increased yield under comparatively homogeneous soil conditions, potentially decreasing the capacity for plasticity in crop plants like barley (Hordeum vulgare). However, the effects of domestication on the evolution of root plasticity are essentially unknown. Using a split container approach, we examined the differences in root plasticity among three domestication levels of barley germplasm (wild, landrace, and cultivar) grown under different concentrations and distribution patterns of soil nutrients. Domestication level, nutrient concentration, and nutrient distribution interactively affected average root diameter; differential root allocation (within-plant plasticity) was greatest in wild barley (Hordeum spontaneum), especially under low nutrient levels. Correlations of within-plant root plasticity and plant size were most pronounced in modern cultivars under low nutrient conditions. Barley plants invested more resources to root systems when grown in low-nutrient soils and allocated more roots to higher-nutrient locations. Root plasticity in barley is scale dependent and varies with domestication level. Although wild barley harbors a greater capacity for within plant root plasticity than domesticated barley, cultivars exhibited the greatest capacity to translate within-plant plasticity into increased plant size. PMID- 23346230 TI - Post-introduction evolution in the biological control agent Longitarsus jacobaeae (Coleoptera: Chrysomelidae). AB - Rapid evolution has rarely been assessed in biological control systems despite the similarity with biological invasions, which are widely used as model systems. We assessed post-introduction climatic adaptation in a population of Longitarsus jacobaeae, a biological control agent of Jacobaea vulgaris, which originated from a low-elevation site in Italy and was introduced in the USA to a high-elevation site (Mt. Hood, Oregon) in the early 1980s. Life-history characteristics of beetle populations from Mt. Hood, from two low-elevation sites in Oregon (Italian origin) and from a high-elevation site from Switzerland were compared in common gardens. The performance of low- and high-elevation populations at a low- and a high-elevation site was evaluated using reciprocal transplants. The results revealed significant changes in aestival diapause and shifts in phenology in the Mt. Hood population, compared with the low-elevation populations. We found increased performance of the Mt. Hood population in its home environment compared with the low-elevation populations that it originated from. The results indicate that the beetles at Mt. Hood have adapted to the cooler conditions by life history changes that conform to predictions based on theory and the phenology of the cold-adapted Swiss beetles. PMID- 23346231 TI - Evolutionary tools for phytosanitary risk analysis: phylogenetic signal as a predictor of host range of plant pests and pathogens. AB - Assessing risk from a novel pest or pathogen requires knowing which local plant species are susceptible. Empirical data on the local host range of novel pests are usually lacking, but we know that some pests are more likely to attack closely related plant species than species separated by greater evolutionary distance. We use the Global Pest and Disease Database, an internal database maintained by the United States Department of Agriculture Animal and Plant Health Inspection Service - Plant Protection and Quarantine Division (USDA APHIS-PPQ), to evaluate the strength of the phylogenetic signal in host range for nine major groups of plant pests and pathogens. Eight of nine groups showed significant phylogenetic signal in host range. Additionally, pests and pathogens with more known hosts attacked a phylogenetically broader range of hosts. This suggests that easily obtained data - the number of known hosts and the phylogenetic distance between known hosts and other species of interest - can be used to predict which plant species are likely to be susceptible to a particular pest. This can facilitate rapid assessment of risk from novel pests and pathogens when empirical host range data are not yet available and guide efficient collection of empirical data for risk evaluation. PMID- 23346232 TI - Characterizing the physical and genetic structure of the lodgepole pine * jack pine hybrid zone: mosaic structure and differential introgression. AB - Understanding the physical and genetic structure of hybrid zones can illuminate factors affecting their formation and stability. In north-central Alberta, lodgepole pine (Pinus contorta Dougl. ex Loud. var. latifolia) and jack pine (Pinus banksiana Lamb) form a complex and poorly defined hybrid zone. Better knowledge of this zone is relevant, given the recent host expansion of mountain pine beetle into jack pine. We characterized the zone by genotyping 1998 lodgepole, jack pine, and hybrids from British Columbia, Alberta, Saskatchewan, Ontario, and Minnesota at 11 microsatellites. Using Bayesian algorithms, we calculated genetic ancestry and used this to model the relationship between species occurrence and environment. In addition, we analyzed the ancestry of hybrids to calculate the genetic contribution of lodgepole and jack pine. Finally, we measured the amount of gene flow between the pure species. We found the distribution of the pine classes is explained by environmental variables, and these distributions differ from classic distribution maps. Hybrid ancestry was biased toward lodgepole pine; however, gene flow between the two species was equal. The results of this study suggest that the hybrid zone is complex and influenced by environmental constraints. As a result of this analysis, range limits should be redefined. PMID- 23346233 TI - Hybridization, cryptic diversity, and invasiveness in introduced variable-leaf watermilfoil. AB - Hybridization may be important in the evolution of invasiveness, but few empirical studies compare introduced hybrid and parental lineages. Invasive 'variable-leaf watermilfoil' (Myriophyllum heterophyllum) in the northeastern United States consists of at least three distinct lineages: an interspecific hybrid (M. heterophyllum * Myriophyllum laxum) and two historically allopatric lineages of pure M. heterophyllum. Previous observations suggested that hybrid populations of variable-leaf watermilfoil may be comparatively more 'invasive' than pure lineages. However, no quantitative data comparing hybrid and parental lineages have been collected, nor has invasiveness been compared between parental lineages. Here, we demonstrate that these distinct lineages are also ecologically distinct. We find some support for the hypothesis that hybridization has played a role in the evolution of invasiveness: hybrids exhibited higher biomass, individual plant size, and greater branching than at least one parental lineage of M. heterophyllum. However, parental lineages did not differ from the hybrid for some traits, demonstrating that pure parental lineages can also be invasive. In addition, we found no evidence for a role of intraspecific hybridization in the evolution of invasiveness in these lineages of variable-leaf watermilfoil, even where they co-occurred locally. Our study suggests that distinguishing among cryptic lineages will help prioritize rapid response control efforts. PMID- 23346234 TI - Exposure to an environmental estrogen breaks down sexual isolation between native and invasive species. AB - Environmental change can increase the likelihood of interspecific hybridization by altering properties of mate recognition and discrimination between sympatric congeners. We examined how exposure to an environmentally widespread endocrine disrupting chemical (EDC), bisphenol A (BPA), affected visual communication signals and behavioral isolation between an introduced freshwater fish and a native congener (genus: Cyprinella). Exposure to BPA induced changes in the expression of male secondary traits as well as male and female mate choice, leading to an overall reduction in prezygotic isolation between congeners. Changes in female mate discrimination were not tightly linked to changes in male phenotypic traits, suggesting that EDC exposure may alter female choice thresholds independently of the effects of exposure on males. These findings indicate that environmental exposure to EDCs can lead to population declines via the erosion of species boundaries and by promoting the establishment and spread of non-native species via hybridization. PMID- 23346235 TI - Predicting local adaptation in fragmented plant populations: implications for restoration genetics. AB - Understanding patterns and correlates of local adaptation in heterogeneous landscapes can provide important information in the selection of appropriate seed sources for restoration. We assessed the extent of local adaptation of fitness components in 12 population pairs of the perennial herb Rutidosis leptorrhynchoides (Asteraceae) and examined whether spatial scale (0.7-600 km), environmental distance, quantitative (Q(ST)) and neutral (F(ST)) genetic differentiation, and size of the local and foreign populations could predict patterns of adaptive differentiation. Local adaptation varied among populations and fitness components. Including all population pairs, local adaptation was observed for seedling survival, but not for biomass, while foreign genotype advantage was observed for reproduction (number of inflorescences). Among population pairs, local adaptation increased with Q(ST) and local population size for biomass. Q(ST) was associated with environmental distance, suggesting ecological selection for phenotypic divergence. However, low F(ST) and variation in population structure in small populations demonstrates the interaction of gene flow and drift in constraining local adaptation in R. leptorrhynchoides. Our study indicates that for species in heterogeneous landscapes, collecting seed from large populations from similar environments to candidate sites is likely to provide the most appropriate seed sources for restoration. PMID- 23346238 TI - Quality of life in Parkinson's disease. AB - In this review report, current possibilities of evaluation of quality of life in Parkinson's disease have been critically presented. Health Related Quality of Life (-HRQoL) comprises a wide spectrum of consequences of the disease. Measurement of quality of life has become increasingly relevant as an outcome parameter, especially in long-term trials. Most of the available QoL instruments depend on patient self-reports. The data can be collected by written questionnaires. There are universal questionnaires of QoL--for many diseases and the specific ones--specially created for one disease. Among universal questionnaires, the Sickness Impact Profile (SIP) and the Short-Form Health Status Survey (SF-36) are the most popular in Parkinson's disease. As for specific questionnaires: the Parkinson's Disease Questionnaire (PDQ-39) and the Parkinson's Disease Quality of Life Questionnaire (PDQL) have been described. PMID- 23346240 TI - Psychoemotional features in irritable bowel syndrome. AB - OBJECTIVE: To delineate the psychological profile of individuals with irritable bowel syndrome (IBS). METHOD: A triple questionnaire of 614 items (including psychological and medical ones) was given to 10192 respondents and the results were analyzed by means of Cronbach alpha and Chi square test, together with an ad hoc designed method that implied ranking and outliers detecting. RESULTS AND CONCLUSIONS: Anxiety and depression are general psychological tendencies unspecifcally linked with IBS. Among the features with a relatively more specific correlation with IBS, tension has the strongest association, followed by the inclination to endure unacceptable situations, preoccupation for health, and susceptibility, and then by fear of failure and sense of demanding profession. IBS individuals readily accept a subordinate position, which may be connected to their history of tyrannical parents, and also to their preoccupation for authority factors. The sense of being treated unfairly by the authority persons during the school years nuances this last feature. Some features that bring some nuances to this psychological portrait are: contemplative nature and analyzing tendency, preoccupation with health issues, a reserved, unsociable, and precautious nature, clinging to known circumstances. PMID- 23346239 TI - Gingival crevicular fluid as a periodontal diagnostic indicator--I: Host derived enzymes and tissue breakdown products. AB - Researchers involved in the delivery of periodontal therapy are currently investigating the possible use of oral fluids in the diagnosis of oral diseases and drug development. Substantial improvements have been made in the understanding of the mediators implicated on the initiation, pathogenesis, and progression of periodontitis. This review will analyze the mechanisms involved in the breakdown of periodontal supporting tissues during chronic periodontitis and highlights the potential array of biomarkers present in gingival crevicular fluid (GCF), which may relate to existing or predicted tissue regions undergoing metabolic change. PMID- 23346241 TI - Functional implications of radical neck dissection and the impact on the quality of life for patients with head and neck neoplasia. AB - Radical neck dissection is a concept that was presented in 1906 by GW Crile and suffered constant improvement ever since. The surgical oncology procedure included the resection of the internal jugular vein, the sternocleidomastoid muscle, and the submandibular gland and the spinal accessory nerve. Deformities and impairment in the functionality of different regions of the neck and scapular regions have great implications on the quality of life of the patients who undergo such a procedure. Modifications to the radical neck dissection were made in the attempt to maintain the efficacy of the surgical oncology therapy. The authors try to assess the functional implications of radical neck dissection and the impact on the quality of life for patients with head and neck neoplasia. PMID- 23346242 TI - Nutrition and depression at the forefront of progress. AB - Depression is a debilitating disorder estimated to become the second cause of morbidity worldwide by the year 2020. The limited efficacy of antidepressant therapy, as well as the major negative consequences of this disorder, has stimulated additional research in order to determine possible adjunctive treatments. There is mounting evidence linking dietary patterns to major depression development. This article presents some of the most significant findings concerning the role of nutrition in major depressive disorder. Although more focused and clear results are needed, the correlation between nutrition and mental health is gaining attention. Now, there is evidence supporting the importance of nutrition in maintaining good mental health. We emphasize multiple findings that support adherence to healthy dietary patterns, taking into account that the production of neurotransmitters need, among others, right amounts of nutrients, a lot of which can only be supplied through diet. Not only certain nutrients are needed for proper brain functioning, but also others can be harmful, promoting depression. The Mediterranean diet has been linked to a low prevalence of depression while fast-food consumption has been found to increase the risk of developing and aggravating this disorder, hence the need for nutritional interventions. From the perspective of discovering modifiable risk factors, the role of nutrition in psychiatry could be more important than it was initially considered. PMID- 23346243 TI - Albuminuria--marker of progressive renal disease. AB - The presence of albuminuria has long been recognized as an adverse prognostic feature in patients with renal disease: the patients with appreciable albuminuria are much more likely to develop tubulointerstitial scarring and fibrosis and progress to end-stage renal failure. For many years, it was thought that excess albuminuria was simply a marker of a more severe renal disease, which was more likely to progress as a result of this severity rather than as a result of the albuminuria itself. This conviction was strengthened by the general assumption that albumin was a benign or inert molecule serving primarily to exert oncotic pressure and act as a carrier within the circulation. More recently, this view has been challenged with the accumulation of evidence suggesting that albumin is able to influence the function of cells with which it makes contact in the manner of a signalling molecule. PMID- 23346244 TI - Magnetic resonance spectroscopy--a non-invasive method in evaluating focal and diffuse central nervous system disease. AB - Magnetic Resonance Spectroscopy is a non-invasive method, which can be performed following a routine Magnetic Resonance investigation within the same examination, and can provide very useful molecular information related to the metabolism and function of the normal and pathological structures of the brain. Its role is increasing in the establishment of a clear diagnosis, in both focal and diffuse central nervous system diseases, and the tendency is to replace the histopathology test, in certain cases, with similar or sometimes better diagnostic accuracy. This paper summarizes the principle, method, and main clinical applications, standing as a guide to procedure performing and results interpretation. PMID- 23346245 TI - Neuromarketing techniques in pharmaceutical drugs advertising. A discussion and agenda for future research. AB - Recent years have seen an "explosion" in the abilities of scientists to use neuroscience in new domains. Unfortunately, it is little known and reported on how advertising companies make more effective pharmaceutical drugs commercials. The purpose of this paper is to analyze how neuromarketing techniques may impact the consumer response to pharmaceutical advertising campaigns. The result shows that using neuromarketing methods a pharmaceutical company can better understand the conscious and unconscious consumer's thoughts and tailor specific marketing messages. PMID- 23346246 TI - Medium term outcome of bipolar plasma vaporization in prostate cancer patients--a palliative modality of preserving spontaneous voiding. AB - OBJECTIVES: This retrospective analysis evaluated the efficiency, safety, and medium term postoperative results of bipolar plasma vaporization (BPV) in prostate cancer (PCa) cases associating complete urinary retention. MATERIALS AND METHODS: A series of 40 patients diagnosed with locally advanced or metastatic PCa and complete urinary retention requiring a Foley catheter indwelling underwent BPV aiming to restore spontaneous voiding. A total of 35 patients completed the one year evaluation protocol consisting of International Prostate Symptom Score (IPSS), quality of life score (QoL), maximum flow rate (Q(max)) and post-voiding residual urinary volume (PVR), measured at 1, 3, 6 and 12 months after surgery. RESULTS: BPV was successfully performed in all cases with satisfactory efficiency, as confirmed by the mean operation time (42.8 minutes) and hemoglobin drop (0.7 g/dl). A fast and safe postoperative recovery period was described in this series (hematuria rate--7.5%; mean catheterization period--36 hours; mean hospital stay--2.5 days; early-irritative symptoms' rate--15%). At 1, 3, 6 and 12 months, satisfactory values were determined in terms of IPSS, Qmax, QoL and PVR. These parameters emphasized a stable evolution throughout the entire follow-up, as 88.6% of the patients maintained spontaneous voiding. CONCLUSIONS: The present trial confirmed the plasma-button vaporization as a promising therapeutic approach in PCa cases associating complete urinary retention. The technique displayed good efficacy, low perioperative morbidity, short convalescence, and satisfactory urodynamics and symptom score parameters during the one-year follow-up period. PMID- 23346247 TI - Clinical particularities and response to the anti-inflammatory effect of antiviral treatment in patients with chronic hepatitis C and rheumatoid syndrome. AB - Hepatitis C virus (HCV) is an important cause for the development of serious hepatic disease such as chronic hepatitis and liver cirrhosis. Though the pathological mechanisms are poorly understood, it is well established that CHC plays an important role in several immune mediated conditions, including rheumatoid arthritis. We focused on the clinical particularities of patients with CHC and associated RS and we specifically investigated the anti-inflammatory role of IFN-alpha concerning the rheumatic symptoms. PMID- 23346248 TI - Anastomotic dehiscence (AD) in colorectal cancer surgery: mechanical anastomosis versus manual anastomosis. AB - INTRODUCTION: Anastomotic dehiscence (AD) is the "Achilles heel" for resectional colorectal pathology and is the most common cause of postoperative morbidity and mortality. AD incidence is 3-8%; mortality rate due to AD two decades ago was around 60% and at present is 10%. This paper analyzes the incidence of AD after colorectal resection performed both in emergency and elective situations, depending on the way it is done: manually or mechanically. METHODS: Retrospective, single-center, observational study of patients operated in the period from 1st of January 2009 to 31th of December 2011 for malignant colorectal pathology in the Emergency Clinical Hospital of Bucharest. We evaluated the incidence of digestive fistulas according to the segment of digestive tract and time from hospital admission, to the way the anastomosis was achieved (mechanical vs. Manual), to the complexity of intervention, to the transfusion requirements pre/intra or postoperative, to the past medical history of patients (presence of colorectal inflammatory diseases: ulcerative colitis and Crohn's disease), to the average length of hospital stay and time of postoperative resumption of bowel transit. RESULTS: We included 714 patients who had surgery between 1st of January 2009 and 31th of December 2011. 15.26% (109/714) of the cases were operated in emergency conditions. Of the 112 cases of medium and lower rectum, 76 have "benefited" from preoperative radiotherapy with a fistula rate of 22.36% (17/76). The incidence of anastomotic dehiscence in the group with preoperative radiotherapy and mechanical anastomosis was 64.7% (11/17) versus 35.3% (6/17) incidence recorded in the group with manual anastomosis. Colorectal inflammatory diseases have been found as a history of pathology in 41 patients--incidence of fistulas in this group was of 12.2% (5/41), compared to only 6.83% (46/673) incidence seen in patients without a history of such disease. For the group with bowel inflammatory disease, anastomotic dehiscence incidence was of 13.8% (4/29) when using mechanical suture and 8.3% (1/12) when using manual suturing. The period required for postoperative resumption of intestinal transit was of 3.12 days for mechanical suturing and 3.93 days in case of manual suture. The mean time (MT) to perform the ileocolic and colocolic mechanical anastomosis is 9 +/- 2 minutes. If anastomosis is "cured" with surjet wire or separate threads, MT is 11 +/- 5 minutes. MT to perform the ileocolic and colocolic manual anastomosis is 9 +/- 3 minutes for surjet wire and 18 +/- 5 minutes for separate threads. MT to perform the colorectal mechanical anastomosis is 15 +/- 4 minutes. MT to perform the colorectal manual anastomosis is 30 +/- 7 minutes (using separate threads). Detailing the nature of the surgical reinterventions, we have found: 7 reinterventions for AD post mechanical anastomoses (1 case of suture defect, 2 cases of resection and re-anastomoses, 4 cases with external branching stoma); 5 reinterventions for AD post manual anastomoses (0 cases of suture defect, 1 case of resection with re-anastomosis, 4 cases of external shunt stoma). In the analyzed group, we recorded a total of 57 deaths from a total of 714 cases resulting in a mortality rate of 7.98%. CONCLUSIONS: Mechanical suture technique is not ideal for making digestive sutures. With the exception of low colorectal anastomoses where mechanical sutures are preferable, we cannot claim the superiority of mechanical anastomoses over those manually made, for colorectal neoplasia. PMID- 23346249 TI - Tympanometry as a predictor factor in the evolution of otitis media with effusion. AB - BACKGROUND: Otitis media with effusion (OME) is one of the most frequently met pathologies in small children. Long-term persistence of the liquid in the middle ear cavity correlates with the impairment in speech acquisition and poor results in school. AIM: To evaluate the predictive value of impedancemetry in recovery of the normal middle ear status. METHODS: 30 children (age 4 month-9 years) with OME were periodically monitored by means of tympanometry. The children were treated with the same treatment protocol for 7 days minimum and tympanometry was repeated after seven and fourteen days. After follow-up tympanometry at 7 days, children with abnormal middle ear condition were randomly allocated into two groups: one, which continued the same treatment for another 7 days and one group with no treatment for the next 7 days. RESULTS: After 7 days, 64% of the patients had an improvement in tympanometry (type C tympanogram) and 10% had a complete resolution of the middle ear effusion (type A tympanogram). After 14 days, tympanometry was normal in 74% of the patients (53.9% rate of success in the no treatment group). CONCLUSION: Complete resolution of the middle ear effusion is obtained in various periods of time, depending on numerous factors, with an appropriate treatment. Tympanometry proved to be a good tool in predicting the length of the treatment. PMID- 23346250 TI - Immunological aspects predicting metastatic sentinel lymph node in early breast cancer patients. AB - Tumour antigens are poorly expressed, heterogeneous and they modulate rapidly. As a result, their recognition and elimination by the immune system is very difficult. There are several mechanisms, by means of which, the host can neutralize oncogenesis and prevent it from occurring. The sentinel lymph node concept has brought about a revolution in the surgical treatment of the regional lymphatic basin while preserving the prognostic value of the regional lymph node status in breast cancer. This prospective study included 93 women with early breast cancer with initial indication for surgery in whom the sentinel lymph node technique was employed. Cell immune response was assessed prior to surgery by means of in vitro mononuclear cells blastic transformation assay (BLT), of immunoglobulin (Ig) and interleukin 2 (IL-2) measurements. The results were correlated with tumour size, presence of positive sentinel lymph node, tumour proliferation and growth markers (Ki-67, c-erbB2, bcl-2). Even in its less advanced stages, breast cancer is more aggressive and associates with an increased rate of sentinel lymph node metastases in patients below 50 years old, the tumour size exceeds 20 mm, with the presence of peritumoral lymphocytic infiltrate, positive Ki-67 and bcl-2, an alteration of T helper (Th) lymphocytes function, increased immune suppression through IL-2 decrease, signalled by blastic transformation indexes modifications and a drop in IL-2 production (p<0.01). PMID- 23346251 TI - Anti-Mullerian hormone--a prognostic marker for metformin therapy efficiency in the treatment of women with infertility and polycystic ovary syndrome. AB - BACKGROUND: The anti-Mullerian hormone (AMH) is secreted in women exclusively by the granulosa cells of the ovarian follicles. The serum level of AMH is a precise marker of follicle pool size. In recent clinical studies of polycystic ovary syndrome (PCOS), the serum levels of AMH were elevated about two to threefold. The use of metformin in women with infertility and PCOS has proved to be efficient: restoring ovulation and reducing metabolic dysfunctions. The aim of our study is to assess AMH as a prognostic marker for metformin therapy efficiency in the treatment of women with infertility and polycystic ovary syndrome (PCOS). METHODS: Eleven patients with infertility and PCOS were enrolled; PCOS was diagnosed according to the criteria of Androgen Excess and Polycystic Ovarian Syndrome Society 2006 (AE/PCOS). All patients have received metformin therapy. Serum AMH was recorded before and after 2 months of treatment; the normal laboratory values were 2.0-6.8 ng/ml. RESULTS: The primary serum AMH level of all women in study was very high: 8.99+/-0.99 ng/ml. After 2 months of treatment with metformin ovulation was restored in all the patients and the serum AMH levels were significantly decreased. CONCLUSIONS: In clinical practice, serum AMH levels of women with infertility and PCOS receiving metformin are a useful predictive marker for the treatment efficiency. PMID- 23346252 TI - Semen parameters of non-infertile smoker and non-smoker men. AB - INTRODUCTION: According to the world Health organization, approximately one third of the world' population older than 15 years are smokers. Evidences indicate that both in men and in women, cigarette smoking affects reproductive health more than the consumption of caffeine or alcohol in comparable doses. The mechanisms according to which tobacco affects spermatozoa are poorly understood. Some of the studies focused on the relation between cigarette smoking and the principal semen analysis, variable such as concentration, Morphology and Motility. In this study, we compared the sperm parameters between smokers and non-smokers. MATERIAL AND METHODS: This case control study was done on men from infertile couples who were referred to Yazd research and clinical center for infertility but the cause of infertility was not the male factor. The semen analysis was compared between the smokers and non-smokers. RESULTS: 151 infertile men were enrolled in the present study. 98 non-smokers and 53 smokers the mean age of patients was not significantly different between groups. There were no significant differences among groups according to sperm concentration (P-Value 0.108), Morphology (P Value 0.138) and Motility (P-Value 0.082). Also there were no significant relationship between sperm parameters and the amount of cigarettes people had used (based on Pack/year scale). CONCLUSION: Semen parameters (Morphology, Motility and concentration) were lower in smokers but there were no significant differences between groups. PMID- 23346253 TI - The modern treatment of the simple bone cysts. AB - This study was performed between 2007-2012 and encompasses 94 patients. The patients were divided in two groups. The first group included the patients who have benefited from surgical treatment (42 cases) and the second one included patients who benefited from conservative treatment. Out of the total number of cases, 63 cases showed an intact simple bone cyst that was most of the time an accidental discovery. 31 patients presented with fracture sustained on a simple bone cyst. There were 63 boys and 31 girls. Their mean age was 9.9 +/- 2.34 years. Single injection was performed for 49 patients; the rest had double or triple injections. The mean follow-up was 34.5 +/- 6.6 months. The procedure succeeded in obtaining healing in 77 cysts (82%). Cyst index of more than five and cortical index of less than 1 mm were significantly prone to pathological fractures and had significant poor results after treatment. Our results suggested that an autogenous bone marrow injection is a safe and effective treatment method for simple bone cysts, when compared with the surgical management, but sometimes repeated injections are necessary. Cyst index and cortical width are good indicators for treatment outcome. PMID- 23346254 TI - Endoprosthetic reconstructive surgery with medical grade long term implantable silicone in facial asymmetry. AB - The authors present their experience over a period of 13 years (1998-2011) regarding a cohort of 54 patients. In an extensive loss of tissues resulted from congenital malformations (maxillary and mandibular malformations, micro stoma), collagenosis (scleroderma, Romberg Syndrome), traffic and work accidents, post surgical (cancer and facial nerve paralyze), when usual surgical procedures fail to establish the normal look of the patient medical grade long-term implantable silicone endoprosthetic reconstruction (rehabilitation) intervenes. Using a specific technique and materials like long-term implantable silicone grade, the resulted endoprostheses replace and create the aesthetic and a normal anatomy of the specified region, very well tolerated, elastic and non-allergic and with a perfect acceptation from the body all the life. PMID- 23346255 TI - Evidence of nNOS and ChAT positive phenotypes in nervous ganglia of the retrostyloid space. AB - The cholinergic and nitrergic phenotypes in human fetal ganglia (inferior) of the glossopharyngeal and vagus nerves were overlooked in basic research. Lack of a positive neuronal NO synthase (nNOS) phenotype in the inferior vagal fetal ganglion was recently suggested to be an individually variable phenotype. Choline acetyltransferase (ChAT) was not evaluated previously in ontogenesis. We aimed to evaluate these phenotypes in human midterm fetuses. Samples from five specimens with gestational ages varying from 4 to 6 months were used. Immunohistochemistry for nNOS, ChAT, neurofilaments, and S100 protein was performed. Neuronal somata were positively stained for nNOS, ChAT and neurofilaments in the inferior glossopharyngeal and vagal ganglia. S100 protein distinctively labelled the satellite glial cells ensheating the respective neurons. In human midterm fetuses vagal and glossopharyngeal inferior ganglia are nitrergic and cholinergic. To evaluate a functional role of these phenotypes in ontogenesis, the specific anatomic circuits should be further checked. Differences in immune labelling should be evaluated by use of similar antibodies from different manufacturers. PMID- 23346256 TI - Surgical management of extensive burns treatment using allografts. AB - Patients with extensive burns (TBSA over 45%) can benefit from treatment with split thickness skin allotransplants (skin bank or honorific donors). In this study, we present our protocols for the surgical treatment by using allografts. We emphasize the criteria for the staging of the procedures, the prioritisation of the areas that need to be grafted and the postoperative management. The treatment includes a serial excision grafting with simple grafts or the sandwich method, which implies the covering of the wound with a widely meshed autograft (6:1). This layer is covered by a 1,5:1 or 3:1 expanded mesh allograft. PMID- 23346257 TI - Uterine artery embolization for leioyomas, ultrasonography and angiography aspects. AB - OBJECTIVE AND RATIONALE: The purpose of this study is to evaluate the degree of fibroid shrinkage which well correlates with symptom regression, and thus to assess the effectiveness of the procedure. METHOD: 31 patients were included in the trial after selection. All the patients were thoroughly evaluated before embolization, the following day and at a month after but also at 3 months for 10 of them. A certain protocol was followed passing through well established steps. The purpose was to discover and rule out any associated possible disease and to assess and grade the symptoms, ultrasound and angiographic aspects. RESULTS: Regarding the uterus, its volume evolution registered a descending trend, the mean decrease at 30 days being of 25% (-81,6 cm3) and at 90 days of 52%(-173,15 cm3). The fibroids also decreased statistically, the mean global variation at 30 days registering a decrease of -17,66 cm3(27%) and 61% at day 90. The mean global reduction at 30 days was of 44% (-33,18 cm3) and of 62% (-60,85 cm3) at 90 days. Absence of uterine anastomoses lead to proper fibroid decrease whereas their presence diminished the chances. CONCLUSIONS: The uterine and fibroid volumes registered a statistical volume decrease at 30 and 90 days in comparison with the volumes before embolization. Absence of uterine anastomoses led to proper fibroid decrease. Longer evaluation time is needed for an accurate evaluation of volume reduction degree. PMID- 23346259 TI - Two Valid Measures of Self-rated Physical Activity and Capacity. AB - OBJECTIVES: Questionnaires on physical activity (PA) and physical capacity (PC) are valuable tools, as they are cost beneficial, and have high response rates. The validity of short versions of such questionnaires has not been examined satisfactorily. Therefore, we aimed at examining the validity of a set of questions coding for PA and PC. DESIGN: The questions were administered to 217 men and women attending a cardiac rehabilitation program. Participants also gave blood samples, measuring HDL cholesterol, triglycerides (TG), insulin, glucose, and microCRP. The relations between PA and PC and biological markers were examined by linear regression analyses. RESULTS: Measures for PC and for PA were identified by factor analysis, which proved internally consistent. TG, homeostatic model assessment (HOMA) score, and mCRP were all significantly associated with the measures of PC and PA. CONCLUSIONS: The measures of PA and PC are valid compared with biological markers, allowing cost-beneficial and time efficient evaluation of important measures for cardiovascular health. PMID- 23346258 TI - The role of psychobiological and neuroendocrine mechanisms in appetite regulation and obesity. AB - Obesity is a multifactorial disease. Among its causes are physical inactivity and overeating. In addition, other factors may play an important role in the development of overweight/obesity. For example, certain hormones including leptin, insulin and ghrelin, may influence appetite and consequently body weight. Obesity frequently co-exists with metabolic disorders including dyslipidemia, hypertension and insulin resistance, thus constituting the metabolic syndrome which is characterized by increased cardiovascular risk. Lack of comprehensive knowledge on obesity-related issues makes both prevention and treatment difficult. This review considers the psychobiological and neuroendocrine mechanisms of appetite and food intake. Whether these factors, in terms of obesity prevention and treatment, will prove to be relevant in clinical practice (including reducing the cardiovas-cular risk associated with obesity) remains to be established. PMID- 23346261 TI - Influence of psychosocial factors and habitual behavior in temporomandibular disorder-related symptoms in a working population in Japan. AB - BACKGROUND: The symptoms of temporomandibular disorders (TMD) are directly influenced by numerous factors, and it is thought that additional factors exert indirect influences. However, the relationships between TMD-related symptoms (TRS) and these contributing factors are largely unknown. Thus, the goal of the present study was to investigate influences on TRS in a working population by determining the prevalence of TRS, analyzing contributing factors, and determining their relative influences on TRS. MATERIALS AND METHODS: The study subjects were 2203 adults who worked for a single company. Subjects completed a questionnaire assessing TRS, psychosocial factors (stress, anxiety, depressed mood, and chronic fatigue), tooth-contacting habit, and sleep bruxism-related morning symptoms, using a 5-point numeric rating scale. Our analysis proceeded in 2 phases. First, all variables of the descriptor were divided into parts by using an exploratory factor analysis. Second, this factorial structure was verified by using a confirmatory factor analysis with structural equation modeling. RESULTS: Of 2203 employees, 362 reported experiencing TRS (16.4%). Structural equation modeling generated a final model with a goodness of fit index of 0.991, an adjusted goodness of fit index of 0.984, and a root mean square error of approximately 0.021. These indices indicate a strong structural model. The standardized path coefficients for "habitual behavioral factors and TRS," "psychosocial factors and habitual behavioral factors," "psychosocial factors and TRS," and "gender and habitual behavior factors" were 0.48, 0.38, 0.14, and 0.18, respectively. CONCLUSIONS: Habitual behavioral factors exert a stronger effect on TRS than do psychosocial factors. PMID- 23346260 TI - Chronic or late lyme neuroborreliosis: analysis of evidence compared to chronic or late neurosyphilis. AB - Whether spirochetes persist in affected host tissues and cause the late/chronic manifestations of neurosyphilis was the subject of long-lasting debate. Detection of Treponema pallidum in the brains of patients with general paresis established a direct link between persisting infection and tertiary manifestations of neurosyphilis. Today, the same question is in the center of debate with respect to Lyme disease. The goal of this review was to compare the established pathological features of neurosyphilis with those available for Lyme neuroborreliosis. If the main tertiary forms of neurosyphilis also occur in Lyme neuroborreliosis and Borrelia burgdorferi can be detected in brain lesions would indicate that the spirochete is responsible for the neuropsychiatric manifestations of late/chronic Lyme neuroborreliosis. The substantial amounts of data available in the literature show that the major forms of late/chronic Lyme neuroborreliosis (meningovascular and meningoencephalitis) are clinically and pathologically confirmed. Borrelia burgdorferi was detected in association with tertiary brain lesions and cultivated from the affected brain or cerebrospinal fluid. The accumulated data also indicate that Borrelia burgdorferi is able to evade from destruction by the host immune reactions, persist in host tissues and sustain chronic infection and inflammation. These observations represent evidences that Borrelia burgdorferi in an analogous way to Treponema pallidum is responsible for the chronic/late manifestations of Lyme neuroborreliosis.Late Lyme neuroborreliosis is accepted by all existing guidelines in Europe, US and Canada. The terms chronic and late are synonymous and both define tertiary neurosyphilis or tertiary Lyme neuroborreliosis. The use of chronic and late Lyme neuroborreliosis as different entities is inaccurate and can be confusing. Further pathological investigations and the detection of spirochetes in infected tissues and body fluids are strongly needed. PMID- 23346262 TI - Congenitally missing maxillary lateral incisors: functional and periodontal aspects in patients treated with implants or space closure and tooth re contouring. AB - To evaluate functional and periodontal aspects in patients with unilateral or bilateral congenitally missing maxillary lateral incisors, treated with either implants or space closure and tooth re-contouring. The sample consisted of 68 volunteers, divided into 3 groups: SCR - space closure and tooth re-contouring with composite resin (n = 26); SOI - implants placed in the area of agenesis (n = 20); and CG - control group (n = 22). A modified Helkimo questionnaire and the Research Diagnostic Criteria for Temporomandibular Disorders were used by a single, previously calibrated evaluator to assess signs and symptoms of temporomandibular joint disorder. The periodontal assessment involved the following aspects: plaque index, bleeding upon probing, pocket depth greater than 3 mm, gingival recession, abfraction, periodontal biotype and papilla index. The data were analyzed using Fisher's exact test and the nonparametric Mann-Whitney and Kruskal-Wallis tests (alpha=.05). No differences in periodontal status were found between treatments. None of the groups were associated with signs and symptoms of temporomandibular joint disorder. Both treatment alternatives for patients with congenitally missing maxillary lateral incisors were satisfactory and achieved functional and periodontal results similar to those of the control group. PMID- 23346263 TI - Biomarkers of fibroproliferative healing in fibrosing idiopathic interstitial pneumonias. AB - AIMS: The main feature of fibrosing idiopathic interstitial pneumonias (fIIPs) is the fibroproliferative potential of underlying pathogenetic process. We hypothesize that the concentration of potential markers of fibroproliferative healing, PAR-2, TGF-beta1, TNF-alpha and IL-4Ralpha in bronchoalveolar lavage fluid (BALF) differ in patients with fIIPs compared to controls (C). PATIENTS AND METHODS: 10 patients with fIIPs and 9 controls (C) were included to the study. Concentrations of CD124 (IL4Ralpha), PAR-2, TGF-beta1 and TNF-alpha in BALF were determined using the ELISA method. RESULTS: We observed higher concentrations of IL4Ralpha (fIIPS 1499.4 pg/ml vs C 255.5 pg/ml; p < 0.05), PAR-2 (fIIPS 1807.9 pg/ml vs C 421.0 pg/ml; p < 0.05) and TGF-beta1(fIIPS 283.0 pg/ml vs C 197.1 pg/ml; p < 0.01) in BALF in fIIPs versus C. The values of TNF-a in BALF did not differ significantly in fIIPs compared to controls. The ratios also showed differences in fIIPS and C: IL4Ralpha/TGF-beta1 (fIIPS 6.19 vs C 0.68; p = 0.0143); TNF-alpha/IL4Ralpha (fIIPS 0.84 vs C 7.93; p = 0.043); TGF-beta1/TNF alpha (fIIPS 0.21 vs C 0.16; p = 0.0179) and protein/PAR-2 (fIIPS 0.06 vs C 0.28; p = 0.0033). CONCLUSIONS: We found that PAR-2, TGF-beta1 and IL-4Ralpha are significantly up-regulated in the BALF of fIIPs compared to controls, therefore we suppose they could become biomarkers of fibroproliferative healing. PMID- 23346264 TI - ONCOGENIC HUMAN PAPILLOMAVIRUSES: High-Risk Human Papillomaviruses: Towards a Better Understanding of the Mechanisms of Viral Transformation, Latency and Immune-Escape. PMID- 23346265 TI - Initial evidence of religious practice and belief in depressed african american cancer patients. AB - OBJECTIVE: This study examined spiritual coping (beliefs and practices) of depressed African American cancer patients through a comparison with depressed White cancer patients and non-depressed African American cancer patients. METHODS: Using mixed methods, 74 breast (n=41) and prostate (n=33) cancer survivors including 34 depressed and 23 nondepressed African Americans and 17 depressed Whites were interviewed. The interviews were audiotaped and transcribed. Qualitative data analysis identified themes that were coded. The codes were entered into SPSS software. The Fisher's exact test was performed to examine group differences in self-reported spiritual coping. RESULTS: Significantly more depressed African Americans questioned God when learning of a cancer diagnosis than the non-depressed African Americans (p=.03), but they did not differ from the depressed Whites in this regard (p=.70). Significantly more depressed African Americans reported having faith in God (p=.04), reading the bible (p=.02), and conversing with God (p=.01) than did the depressed Whites. They also reported praying alone (p=.01) more frequently than the depressed Whites who, on the other hand, reported praying with others (non-family members) together for one's own health more frequently (p=.04). CONCLUSIONS: Depression is associated with a deepening need for spirituality and it affects religious beliefs and practices more in African American than White cancer patients. Given its important role in the lives of African American cancer patients, spirituality may be utilized as a reasonable, culturally-based approach to better assess and treat depression in these patients. PMID- 23346266 TI - Informal caregivers of people with dementia: problems, needs and support in the initial stage and in subsequent stages of dementia: a questionnaire survey. AB - OBJECTIVE: The ageing of the population is expected to lead to an increase in the prevalence of dementia. Providing support to informal caregivers is essential to promote their wellbeing and prevent serious caregiver burden. The aim of the study is to investigate whether differences occur between the initial and later stages of dementia in terms of (1) problems experienced by informal caregivers in the provision of care, (2) use of professional support by persons with dementia, (3) informal caregivers' needs for additional professional support. METHODS: The data were collected within the framework of the Dutch National Dementia Program, which was instigated in 2005 by the Dutch Ministry of Health, Welfare and Sport to improve integrated care for people with dementia and their informal caregivers. This paper is based on data of a questionnaire survey among 1494 informal caregivers, collected between September 2007 and December 2008. RESULTS: Most informal caregivers (98-99%) experienced problems in caring for a person with dementia, irrespective of the stage of the illness process. In later stages, informal caregivers more often experienced problems in their social networks. Most dementia patients (87-94%) received ambulatory professional support. CONCLUSIONS: Since informal caregivers indicate a need for additional professional support in all stages of dementia, professional support should be provided during the entire illness process. Informal caregivers need advice on how to cope with symptoms of dementia, how to deal with behavior problems and receive more information about (early and advanced stages of) dementia and the supply of support. PMID- 23346267 TI - Comparative Evaluation of HIV-1 Neutralization in External Secretions and Sera of HIV-1-Infected Women. AB - OBJECTIVES: Although human immunodeficiency virus type 1 (HIV-1)-specific antibodies are detectable in external secretions by ELISA and western blot (WB), the presence of HIV-1 neutralizing antibodies is difficult to evaluate due to the low levels of immunoglobulins (Ig) and the presence of humoral factors of innate immunity. The objective of this study was to determine virus neutralization activity and the relative contribution of HIV-1-specific antibodies of various isotypes to virus neutralization in serum/plasma samples, cervicovaginal lavages (CVL), and rectal lavages (RL). DESIGN: Serum/plasma, CVL, and RL samples were examined by ELISA, WB and HIV-1 neutralization assays. Selected samples were Ig depleted and analyzed for virus neutralization. RESULTS: IgG specific for three HIV-1 ENV antigens was detected in all serum/plasma samples, while IgA to at least one ENV glycoprotein was found at the low levels in 95% samples. Serum/plasma samples had the ability to neutralize at least one of three clade B and two clade C viruses. The neutralizing titers were reduced significantly or became undetectable after IgG removal. In corresponding CVL and RL, HIV-1 ENV specific IgG antibodies were readily detected compared to IgA. Furthermore, IgG in CVL had greater ability than IgA to reduce virus infectivity. The difference in HIV-1 neutralization before and after Ig depletion was not observed in RL, implying that innate humoral factors were involved in anti-HIV-1 activity. CONCLUSIONS: Results demonstrate that HIV-1-specific neutralizing antibodies are almost exclusively of the IgG isotype in serum/plasma and CVL samples. HIV-1 specific binding antibodies detected in RL are not responsible for neutralization activity, suggesting that the antibody-mediated virus neutralization in external secretions should be verified by means of a selective depletion of Ig. PMID- 23346268 TI - High-Throughput Multiplexed Quantitation of Protein Aggregation and Cytotoxicity in a Huntington's Disease Model. AB - A hallmark of Huntington's disease is the presence of a large polyglutamine expansion in the first exon of the Huntingtin protein and the propensity of protein aggregation by the mutant proteins. Aberrant protein aggregation also occurs in other polyglutamine expansion disorders, as well as in other neurodegenerative diseases including Parkinson's, Alzheimer's, and prion diseases. However, the pathophysiological role of these aggregates in the cell death that characterizes the diseases remains unclear. Identification of small molecule probes that modulate protein aggregation and cytotoxicity caused by aggregated proteins may greatly facilitate the studies on pathogenesis of these diseases and potentially lead to development of new therapies. Based on a detergent insoluble property of the Huntingtin protein aggregates, we have developed a homogenous assay to rapidly quantitate the levels of protein aggregates in a cellular model of Huntington's disease. The protein aggregation assay has also been multiplexed with a protease release assay for the measurement of cytotoxicity resulting from aggregated proteins in the same cells. Through a testing screen of a compound library, we have demonstrated that this multiplexed cytotoxicity and protein aggregation assay has ability to identify active compounds that prevent cell death and/or modulate protein aggregation in cells of the Huntington's disease model. Therefore, this multiplexed screening approach is also useful for development of high-throughput screening assays for other neurodegenerative diseases involving protein aggregation. PMID- 23346269 TI - A comparison of the performance and application differences between manual and automated patch-clamp techniques. AB - The patch clamp technique is commonly used in electrophysiological experiments and offers direct insight into ion channel properties through the characterization of ion channel activity. This technique can be used to elucidate the interaction between a drug and a specific ion channel at different conformational states to understand the ion channel modulators' mechanisms. The patch clamp technique is regarded as a gold standard for ion channel research; however, it suffers from low throughput and high personnel costs. In the last decade, the development of several automated electrophysiology platforms has greatly increased the screen throughput of whole cell electrophysiological recordings. New advancements in the automated patch clamp systems have aimed to provide high data quality, high content, and high throughput. However, due to the limitations noted above, automated patch clamp systems are not capable of replacing manual patch clamp systems in ion channel research. While automated patch clamp systems are useful for screening large amounts of compounds in cell lines that stably express high levels of ion channels, the manual patch clamp technique is still necessary for studying ion channel properties in some research areas and for specific cell types, including primary cells that have mixed cell types and differentiated cells that derive from induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs). Therefore, further improvements in flexibility with regard to cell types and data quality will broaden the applications of the automated patch clamp systems in both academia and industry. PMID- 23346270 TI - [Management of a uterus didelphys associated with a blind hemivagina]. PMID- 23346271 TI - Cerebral venous thrombosis in a child with nephrotic syndrome: case report. AB - Cerebral venous thrombosis (CVT), a rare and life threatening complication of nephrotic syndrome, has a variable and non-specific presentation, posing diagnostic challenges. We describe a case of CVT in a Sierra Leonean child with nephrotic syndrome who was successfully treated for the condition despite the resource limitations of the hospital. This case highlights the importance of considering cerebral venous thrombosis as a complication of idiopathic nephrotic syndrome in children presenting with neurological symptoms. PMID- 23346272 TI - Thromboembolic complication in essential thrombocythemia. PMID- 23346273 TI - Unusual gastric band migration outcome: distal small bowel obstruction and coming out per-rectum. AB - We describe a case of unusual gastric band migration outcome. A 54 years old female was submitted to laparoscopic adjustable gastric band in September 2001. In September 2009 she developed access-port infection which needed drainage and access-port removal. Three months later in December 2009 the patient was investigated due to abdominal pain and abdominal distention. X-rays and Abdomen CT revealed migrated gastric band which is completely intraluminal with its connecting tube, causing transient distal small bowel obstruction and subsequently comes out per-rectum. Band erosion and intragastric migration is a late complication that frequently needs surgical removal. There are few reported cases in the literature of migrated gastric band removal by endoscopy. However according to my knowledge, this is the first reported case of migrated gastric band coming out per rectum without need for surgical or enoscoipic removal. PMID- 23346274 TI - Recurrent desmoid tumor of the abdominal wall. AB - Desmoid tumors most often occur in abdominal wall. Their tendency to recur lead to repeated operations which can make the abdominal wall reconstruction difficult. We report a 28-year-old female history. The patient was referred to our hospital for a recurrent desmoid tumor of the abdominal wall. The tumor was totally removed. The reconstruction was successful and the patient recovery was uneventful. Radical surgery still the mainstay of the desmoid tumors treatement. In abdominal wall location, the reconstruction can be a real challenge. Many procedures are discussed in literature. We used a double layer mesh covered by a fascial bepedicled flap. Taking into account their unpredictable behaviour and treatment complications, recurrent abdominal desmoid tumors can be managed simply and efficiently. PMID- 23346276 TI - [Sporadic thoracic ectopia cordis: clinical description of a case]. PMID- 23346275 TI - [Colon trauma: experience of the CHU Hassan II of Fez]. PMID- 23346277 TI - [Apple peel syndrome with intestinal necrosis]. PMID- 23346278 TI - [Huge cerebral hydatid cyst revealed by a coma]. PMID- 23346279 TI - Sociodemographic factors in Arab children with Autism Spectrum Disorders. AB - INTRODUCTION: There is a critical gap in Autistic Spectrum Disorders (ASD) research with respect to manifestations of the condition in developing countries This study examined the influence of sociodemographic variables on the severity of autistic symptoms and behavioral profile in Arab children. METHODS: The total study sample comprised of 60 Arab children (38 boys and 22 girls) from three Arab countries (22 Jordanians, 19 Saudis and 19 Egyptians). The diagnosis of Autism Spectrum Disorders (ASD) was based on DSM-IV criteria supplemented by direct observation according to the Indian Scale for Assessment of Autism (ISAA) and assessment of Intelligent Quotient (IQ). Finally, parents rated their child on the Achenbach Child Behavior Checklist (CBCL). RESULTS: It was found that the housewives and Saudi parents described more autistic symptoms and externalizing behavior problems. A significant negative correlation was found between IQ and each of ISAA, CBCL Internalizing and Externalizing problems scores. CONCLUSION: The study concluded that the clinical presentation of ASD may be shaped by cultural factors that are likely to help to formulate specific diagnosis and intervention techniques in Arab children with ASD. PMID- 23346280 TI - Epidemiology and clinical characteristics of the Measles outbreak in the Nylon Health District, Douala Cameroon: a retrospective descriptive cross sectional study. AB - INTRODUCTION: Measles is a public health problem especially in South Asia and Africa. Nylon Health District has experienced two measles outbreaks over a period of three years. We hereby describe the epidemiology and clinical characteristics of the outbreak of February 2011. METHODS: A retrospective descriptive cross sectional study was conducted in November 2011. All suspected measles cases according to the World Health Organization case definition line listed in the district service were included. Data was analyzed using Epi Info version 3.5.3 for Windows and Microsoft Office Excel 2010. An epidemic curve was drawn and proportions per variable category were estimated and presented in frequency tables. RESULTS: The outbreak started from the 4(th) to the 25(th) epidemiological week of 2011 with a peak on the 10(th) week after onset. The attack and case fatality rates were 34/100000 inhabitants and zero respectively. Females and infants aged 9-59 months represented 97(63.4%) and 75(49%) of cases respectively. Bonadiwoto health area alone had 81(52.9%) of cases. Of the 153 cases, only 34(22.2%) had a card-confirmed measles vaccination status. Active community surveillance permitted the identification of 42(27.5%) cases. CONCLUSION: Low measles vaccine coverage rate over the past years in the Nylon health district led to the accumulation of susceptible individuals which coupled with poor environmental conditions favoured inter-human spread of measles. Developing novel strategies to vaccinate every child, especially the Hard-to Reach in the slums of the district will help to prevent future outbreaks. PMID- 23346281 TI - [Early neonatal mortality and its determinants in a Level 1 maternity in Yaounde, Cameroon]. PMID- 23346282 TI - Oxidative stress in cardiovascular pathologies: genetics, cellular, and molecular mechanisms and future antioxidant therapies. PMID- 23346285 TI - Is dynamic left ventricular dyssynchrony a novel surrogate marker in the patient with hypertension? PMID- 23346284 TI - Surgical timing of degenerative mitral regurgitation: what to consider. AB - Severe primary mitral regurgitation (MR) is a progressive condition which engenders significant mortality and morbidity if left untreated. The optimal timing of surgery in patients with MR of degenerative origin continues to be debated, especially for those who are asymptomatic. Apart from symptoms, current authoritative guidelines recommend intervention when there is incipient left ventricular dysfunction, pulmonary hypertension or new onset atrial fibrillation. This review focuses on the asymptomatic subject with severe MR, and examines contemporary clinical decision-making and management strategies, including the 2012 European guidelines on valvular heart disease. We discuss the rationale for risk stratifying the asymptomatic individual, and highlight current and novel diagnostic tools that may have a useful role, with an emphasis on echocardiographic imaging. PMID- 23346283 TI - Oxidative stress and immunosenescence: therapeutic effects of melatonin. AB - Age-associated deterioration in the immune system, which is referred to as immunosenescence, contributes to an increased susceptibility to infectious diseases, autoimmunity, and cancer in the elderly. A summary of major changes associated with aging in immune system is described in this paper. In general, immunosenescence is characterized by reduced levels of peripheral naive T cells derived from thymus and the loss of immature B lineage cells in the bone marrow. As for macrophages and granulocytes, they show functional decline with advancing age as evidenced by their diminished phagocytic activity and impairment of superoxide generation. The indole melatonin is mainly secreted in the pineal gland although it has been also detected in many other tissues. As circulating melatonin decreases with age coinciding with the age-related decline of the immune system, much interest has been focused on melatonin's immunomodulatory effect in recent years. Here, we underlie the antioxidant and immunoenhancing actions displayed by melatonin, thereby providing evidence for the potential application of this indoleamine as a "replacement therapy" to limit or reverse some of the effects of the changes that occur during immunosenescence. PMID- 23346286 TI - The Association of Left Ventricular Hypertrophy with Intraventricular Dyssynchrony at Rest and during Exercise in Hypertensive Patients. AB - BACKGROUND: Impaired exercise tolerance with dyspnea is common in hypertensive patients and this may be due to the exaggeration of nonuniform ventricular activation during exercise. So we want to evaluate the effect of left ventricular hypertrophy (LVH) on systolic intraventricular dyssynchrony during exercise. METHODS: A total of 85 patients with hypertension who having exertional dyspnea and 30 control individuals were enrolled. Exercise stress echocardiography was performed using a symptom limited, multistage supine bicycle test. To evaluate the dyssynchrony of left ventricular (LV), we calculated the standard deviation (SD) of the averaged time-to-peak systolic velocity (TPs-SD, ms) of 12 middle and basal LV segments obtained from the three standard apical views at rest and peak exercise. RESULTS: There was no significant difference in systolic blood pressure (BP) and heart rate between the two groups. TPs-SD was significantly higher in patients with LVH at rest (31.5 +/- 12.1 vs. 22.0 +/- 12.6 ms, p = 0.002) with exaggeration of the degree at peak exercise (39.0 +/- 11.9 vs. 24.6 +/- 13.3 ms, p < 0.001). Multiple regression analysis showed LV mass index was independently associated with LV dyssynchrony at peak exercise (beta = 0.515, p = 0.001) when controlled for age, sex, and systolic BP at peak exercise. CONCLUSION: Intraventricular systolic dyssynchrony during exercise is significantly associated with the degree of LVH in hypertensive patients. PMID- 23346287 TI - Evaluation of right ventricular systolic function by the analysis of tricuspid annular motion in patients with acute pulmonary embolism. AB - BACKGROUND: Measurement of right ventricular (RV) systolic function is important for patients with acute pulmonary embolism (PE). However, assessment of RV function is a challenge due to its complex anatomy. We measured RV systolic function with analysis of tricuspid annular motion in acute PE patients. METHODS: From August 2007 to May 2011, all consecutive PE patients were prospectively included. Tricuspid annular motion was analyzed with tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular systolic velocity (TASV). RESULTS: We analyzed total 50 patients (38 females, 68 +/- 14 years). Mean RV fractional area change (RVFAC) was 26.2 +/- 10.8%; RV Tei index 0.78 +/- 0.35; TR Vmax 3.8 +/- 0.5 m/sec; pulmonary vascular resistance (PVR) 3.5 +/- 1.2 WU. TAPSE was 16 +/- 4 mm and TASV was 11.7 +/- 4.0 cm/sec. TAPSE showed significant correlations with RVFAC (r = 0.841, p < 0.001), RV Tei index (r = -0.347, p = 0.018), Log B-type natriuretic peptide (BNP) (r = -0.634, p < 0.001) and PVR (r = -0.635, p < 0.001). TASV also revealed significant correlations with RVFAC (r = 0.605, p < 0.001), RV Tei index (r = -0.380, p = 0.009), LogBNP (r = -0.477, p = 0.001) and PVR (r = -0.483, p = 0.001). The best cutoff of TAPSE for detection of RV systolic dysfunction (defined as RVFAC < 35%) was 1.75 cm [Areas under the curve (AUC) = 0.96, p < 0.001] with a sensitivity of 87% and specificity 91%. The best cutoff for TASV was 13.8 cm/sec (AUC = 0.90, p < 0.001), sensitivity 86% and specificity 78%. However, there was no statistical significance in the detection of RV dysfunction (difference = 0.07, 95% CI = -0.21-0.17, p = 0.130) between TAPSE and TASV. CONCLUSION: TAPSE and TASV showed significant correlations with conventional echocardiographic parameters of RV function and LogBNP value. These values can be used to detect RV systolic dysfunction more easily in patients with acute PE. PMID- 23346288 TI - Total Occlusion of Right Main Pulmonary Artery in a Patient with Takayasu's Arteritis and Severe Pulmonary Hypertension. AB - Takayasu's arteritis is a chronic inflammatory disorder that mainly involves medium to large sized arteries. Although pulmonary artery involvement is reported with a prevalence of about 10% to 50%, its clinical significance is underestimated. We report here one case of Takayasu's arteritis complicated by severe pulmonary hypertension due to right main pulmonary artery total occlusion. PMID- 23346289 TI - Porcelain heart: rapid progression of cardiac calcification in a patient with hemodialysis. AB - Cardiac calcification usually occurs in patients with end-stage renal disease. However, rapid progression of cardiac calcification is rarely associated with secondary hyperparathyroidism of end-stage renal disease. We report a patient with end-stage renal disease who showed moderate left ventricular hypertrophy at the first echocardiography, and showed severe myocardial calcification and severe mitral valve stenosis 4 years later. We suspected a rapid progression 'porcelain heart' cardiomyopathy secondary to hyperparathyroidism of end-stage renal disease. The patient underwent parathyroidectomy, and considered mitral valve replacement. PMID- 23346290 TI - Anomalous origin of the left coronary artery from the pulmonary artery initially visualized by echocardiography and multidetector computed tomography coronary angiography. AB - Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly associated with very high mortality during infancy. We report a 35-year-old female patient with ALCAPA initially visualized by echocardiography. She visited outpatient department presenting with intermittent chest discomfort for 3 weeks. Transthoracic echocardiography showed left coronary artery arising from main pulmonary artery and abundant septal color flow Doppler signals. Transesophageal echocardiography clearly revealed markedly dilated and tortuous right coronary artery showing windsock appearance. Multidetector computed tomography and coronary angiography enabled visualization of anomalous left coronary artery originating from left side of main pulmonary trunk. After treadmill exercise test which showed ST-segment depression presenting inducible myocardial ischemia, patient underwent direct re-implantation of the anomalous coronary artery into the aorta without any complication. PMID- 23346291 TI - Subacute, silent embolization of amplatzer atrial septal defect closure device to the pulmonary artery. AB - Embolization of the closure device is a rare but potentially fatal complication of percutaneous atrial septal defect (ASD) closure. We report a case of 45-year old woman who underwent ASD device closure with 32 mm Amplatzer device, which was embolized to the pulmonary artery without symptom one day after successful device implantation. PMID- 23346292 TI - A case of carbon monoxide poisoning with thrombus in right atrium. AB - Carbon monoxide is a nonirritant, odorless, colorless gas. Its effects are prominent in organs most sensitive to oxygen deprivation, such as the heart, brain, and kidney. Although less frequently, an association between thromboembolic events and carbon monoxide poisoning has been shown in the literatures. In this case, we report a case of atrial thrombus associated with carbon monoxide poisoning. PMID- 23346293 TI - Familial Transthyretin Amyloidosis with Variant Asp38Ala Presenting with Orthostatic Hypotension and Chronic Diarrhea. AB - A 53-year-old man complained of orthostatic, non-rotating dizziness, and chronic watery diarrhea of several years duration. His nerve-conduction velocity test revealed peripheral sensory-motor polyneuropathy and he showed an autonomic function abnormality. Echocardiographic examination showed ventricular and atrial wall thickening with a granular "sparkling" appearance. Left ventricular systolic function was preserved but pseudonormal diastolic dysfunction was present. Coronary angiography showed normal coronary arteries and an endomyocardial biopsy revealed lesions consistent with cardiac amyloidosis. Colonoscopic biopsy also revealed the deposition of amyloid fibrils. Gene analysis found the transthyretin variant Asp38Ala. His son had same mutation, but three daughters did not. In conclusion, we report a case of familial transthyretin amyloidosis with Asp38Ala. PMID- 23346294 TI - Papillary fibroelastoma mimicking vegetation of the mitral valve. AB - Although cardiac papillary fibroelastoma is rare, it is the most common primary tumor of cardiac valves. The clinical presentation of these tumors varies from asymptomatic to embolic complications. We report an asymptomatic case of papillary fibroelastoma of mitral valve which was diagnosed by transthoracic echocardiography. The tumor was successfully resected by surgery. PMID- 23346295 TI - Infective endocarditis with dissection of sinus of valsalva mimicking type a aortic dissection. PMID- 23346296 TI - A case of esophageal achalasia compressing left atrium diagnosed by echocardiography in patient with acute chest pain. PMID- 23346298 TI - Antioxidant activities of licorice-derived prenylflavonoids. AB - Glycyrrhiza uralensis (or licorice) is a widely used Oriental herbal medicine from which the phenylflavonoids dehydroglyasperin C (DGC), dehydroglyasperin D (DGD), and isoangustone A (IsoA) are derived. The purpose of the present study was to evaluate the antioxidant properties of DGC, DGD, and IsoA. The three compounds showed strong ferric reducing activities and effectively scavenged DPPH, ABTS(+), and singlet oxygen radicals. Among the three compounds tested, DGC showed the highest free radical scavenging capacity in human hepatoma HepG2 cells as assessed by oxidant-sensitive fluorescent dyes dichlorofluorescein diacetate and dihydroethidium bromide. In addition, all three compounds effectively suppressed lipid peroxidation in rat tissues as well as H(2)O(2)-induced ROS production in hepatoma cells. This study demonstrates that among the three phenylflavonoids isolated from licorice, DGC possesses the most potent antioxidant activity, suggesting it has protective effects against chronic diseases caused by reactive oxygen species as well as potential as an antioxidant food additive. PMID- 23346297 TI - Carotenoids and total phenolic contents in plant foods commonly consumed in Korea. AB - Phytochemicals are reported to provide various biological functions leading to the promotion of health as well as the reduced risk of chronic diseases. Fat soluble plant pigments, carotenoids, are extensively studied micronutrient phytochemicals for their potential health benefits. It is noteworthy that specific carotenoids may be responsible for different protective effects against certain diseases. In addition, each carotenoid can be obtained from different types of plant foods. Considering the fact that the phytochemical content in foods can vary according to, but not limited to, the varieties and culture conditions, it is important to establish a database of phytochemicals in locally produced plant foods. Currently, information on individual carotenoid content in plant foods commonly consumed in Korea is lacking. As the first step to support the production and consumption of sustainable local plant foods, carotenoids and total phenolic contents of plant foods commonly consumed in Korea are presented and their potential biological functions are discussed in this review. PMID- 23346299 TI - Resveratrol inhibits the protein expression of transcription factors related adipocyte differentiation and the activity of matrix metalloproteinase in mouse fibroblast 3T3-L1 preadipocytes. AB - This study attempted to investigate the effects of resveratrol on the differentiation of adipocytes. After cells were treated with various concentrations of resveratrol (0, 10, 20, and 40 umol/L), adipocyte proliferation, the protein expression of transcription factors, and MMPs' activities were determined. Cell proliferation was inhibited more within 4 days of incubation (P < 0.05), and lipid accumulation in adipocyte was significantly inhibited by 93.8%, 92.4% and 91.5%, respectively, after two days of 10, 20, and 40 umol/L resveratrol treatment (P < 0.05). Six days of incubation with the three resveratrol concentrations caused a significantly decreases of 63%, 59.9%, and 25.1% GPDH activity as a dose-dependent response. The triglyceride concentration also decreased significantly with the increase of resveratrol concentration (P < 0.05). The protein expression of CCAAT/enhancer-binding protein (C/EBPbeta) was decreased significantly by 56% and 30% while PPARgamma was significantly reduced by 57% and 15% with resveratrol treatments of 20 and 40 umol/L, respectively (P < 0.05). The protein expression of C/EBPalpha was decreased by 83%, 74%, and 38% to increased dosage levels, with significance determined for this decrease from 20 umol/L of resveratrol. The protein expression of fatty acid binding protein (FABP4) was decreased significantly by 88%, 72%, and 46% with the increase of resveratrol concentration. The activity of MMP-2 was decreased significantly by 84%, 70%, and 63% while MMP-9 activity was decreased significantly by 74%, 62%, and 39% with the increased resveratrol concentrations of 10, 20, and 40 umol/L, respectively (P < 0.05). PMID- 23346300 TI - Improvement of andropause symptoms by dandelion and rooibos extract complex CRS 10 in aging male. AB - Many aging male suffer various andropause symptoms including loss of physical and mental activities. This study evaluated the putative alleviative effects of CRS 10 dandelion and rooibos extract complex (CRS-10) on the symptoms of andropause. The survival rate of TM3 Leydig cells (TM3 cells) treated with CRS-10 was measured based on typical physiological stress. After daily intake of CRS-10 for 4 weeks, the level of testosterone, physical activity and both the number and activity of sperm in older rats (18 weeks) were measured. Furthermore, thirty males were surveyed with AMS (Aging Males' Symptoms) questionnaire after intake of 400 mg of CRS-10. Overall, CRS-10 protected TM3 cells from serum restriction and oxidative stress via activation of ERK and Akt pathways. The level of testosterone and activation of spermatogenesis in rats were significantly enhanced. In addition, physical locomotion was markedly improved. Daily intake of 400 mg of CRS-10 improved the quality of life among agingmale respondents, according to a clinical survey using the AMS. The results indicate the potential of CRS-10 as a safe and efficacious natural substance for reducing or alleviating andropause symptoms. PMID- 23346301 TI - Aged garlic extract enhances exercise-mediated improvement of metabolic parameters in high fat diet-induced obese rats. AB - Aged garlic extract (AGE) is known to have a protective effect against immune system, endothelial function, oxidative stress and inflammation. We examined the effects of exercise with and without aged garlic extract administration on body weight, lipid profiles, inflammatory cytokines, and oxidative stress marker in high-fat diet (HFD)-induced obese rats. Forty-five Sprague-Dawley rats were fed either a HFD (HFD, n = 40) or a normal diet (ND, n = 5) for 6 weeks and thereafter randomized into ND (n = 5), HFD (n = 10), HFD with AGE (n = 10), HFD with Exercise (n = 10), or HFD with Exercise+AGE (n = 10) for 4 weeks. AGE groups were administered at a dose of 2.86 g/kg.body weight, orally. Exercise consisted of running 15-60 min 5 days/week with gradually increasing intensity. AGE (P < 0.01), Exercise, and Exercise+AGE (P < 0.001) attenuated body weight gain and food efficiency ratio compared to HFD. Visceral fat and liver weight gain were attenuated (P < 0.05) with all three interventions with a greater effect on visceral fat in the Exercise+AGE than AGE (P < 0.001). In reducing visceral fat (P < 0.001), epididymal fat (P < 0.01) and liver weight (P < 0.001), Exercise+AGE was effective, but exercise showed a stronger suppressive effect than AGE. Exercise+AGE showed further additive effects on reducing visceral fat and liver weight (P < 0.001). AGE significantly attenuated the increase in total cholesterol and low-density lipoprotein-cholesterol compared with HFD (P < 0.05). Exercise+AGE attenuated the increase in triglycerides compared with HFD (P < 0.05). Exercise group significantly decrease in C-reactive protein (P < 0.001). These results suggest that AGE supplementation and exercise alone have anti obesity, cholesterol lowering, and anti-inflammatory effects, but the combined intervention is more effective in reducing weight gain and triglycerides levels than either intervention alone. PMID- 23346302 TI - Visceral fat and body weight are reduced in overweight adults by the supplementation of Doenjang, a fermented soybean paste. AB - Various forms of fermented soybean products are well documented for their health benefits. The efficacy of anti-obesogenic effect of Doenjang, one of the most commonly used seasonings in Korean cuisine, has been reported only in animal models; thus, an evaluation of Doenjang needs to be conducted in human studies. We aimed to test the hypothesis that Doenjang supplementation reduces body weight and changes body composition in overweight adults. A total of 51 overweight adults participated in this study. A group of males with BMI >= 23 kg/m(2) and waist to hip ratio (WHR) >= 0.90, and a group of females with BMI >= 23 kg/m(2) and WHR >= 0.85 were randomly assigned to either a Doenjang supplement (9.9 g dry/day) group or a placebo group for a 12-week randomized, double-blind and placebo-controlled study. Anthropometric parameters, abdominal fat distribution by computerized tomography (CT) and blood components were measured before and after the intervention period. After the 12-week study, the Doenjang supplementation group had significant reductions in body weight (kg), body fat mass (kg) and body fat (%) compared to the placebo group, the supplementation of Doenjang resulted in a significant reduction in visceral fat (cm(2)), although no changes were observed in total and subcutaneous fat are as (cm(2)), serum lipid profiles and dietary intakes. The present study demonstrated that daily supplementation of 9.9 g dry/day of Doenjang for 12 weeks reduces body weight and visceral fat in overweight adults. PMID- 23346303 TI - Low dietary calcium is associated with self-rated depression in middle-aged Korean women. AB - It is thought that calcium (Ca) and magnesium (Mg) may be related to mental disorders such as depression; however, there have been few studies investigating the association between Ca and Mg nutrition status with depression in middle-aged female adults. Study subjects in this study included 105 women between the ages of 41 and 57 years. The subjects were divided into three groups according to the Zung Self-rating Depression Scale (SDS) score: Group I (SDS score < 33 percentile; n = 32), Group II (33 percentile <= SDS score < 67 percentile; n = 37), and Group III (67 percentile <= SDS score; n = 36). Anthropometric measurements, dietary intake survey using 3-day dietary records, SDS questionnaire and measurement of serum Ca and Mg were obtained and analyzed. No differences were observed in Ca, plant Ca, and Mg intake among the three groups. However, animal Ca intake by Group III was 141.3 mg, which was significantly lower than 207.6 mg by Group I and 198.3 mg by Group II (P = 0.0345). There were no significant differences in serum levels of Ca, and Mg among the three groups. Correlation analysis indicated that the SDS score had negative correlations with Ca intake (r = -0.2927, P < 0.01) and animal Ca (r = -0.3411, P < 0.001) after adjusting for age, menopause and energy intake. In conclusion, dietary Ca and animal Ca had negative associations with SDS score among middle-aged Korean female adults. Additional analysis of factors related to the association of calcium and magnesium nutritional status and depression is necessary. PMID- 23346304 TI - Comparison of salty taste acuity and salty taste preference with sodium intake and blood pressure based on zinc nutritional status in two rural populations in Korea. AB - This study examined salty taste acuity and salty taste preference and sodium intake in relation to zinc nutritional status in 2 rural populations in Korea. And we also examined the main food contributors of their sodium intakes. We enrolled 218 adults (66 men and 152 women) from the Kangneung and Samcheok regions in Korea's Kangwon province in our study conducted from December 2011 to February 2012. Participants from each region were divided into 3 groups based on their serum zinc level (T1: lowest, T2: intermediate, T3: highest). We compared the salty taste acuity and preference, Na index (Dish Frequency Questionnaire for estimation of habitual sodium intake), blood pressure, and intakes of nutrients including sodium by 3 groups of serum zinc level. The results were as follows: a higher serum zinc level indicated a lower sodium intake and Na index (P < 0.05). The salty taste acuity was considerably higher for participants from the Kangneung region than those from the Samcheok region (P < 0.05). And the serum zinc level was significantly higher in participants from the Kangneung region than those from the Samcheok region (P < 0.05). We further divided the participants into 2 groups: those who consumed more zinc than the recommended intake (RI) and the others. We compared salty taste acuity and salty taste preference in the 2 groups. The salty taste threshold and palatable salty taste concentrations were lower for the group with a zinc intake above RI than for the group with zinc intake below the RI. However, the difference was not significant. This study confirms that taste function differs depending on zinc nutritional status. In future, it is required to a large-scale, long-term, prospective study on the correlation between zinc intake, serum zinc levels, and taste perception function and blood pressure. PMID- 23346306 TI - Applying the Health Belief Model to college students' health behavior. AB - The purpose of this research was to investigate how university students' nutrition beliefs influence their health behavioral intention. This study used an online survey engine (Qulatrics.com) to collect data from college students. Out of 253 questionnaires collected, 251 questionnaires (99.2%) were used for the statistical analysis. Confirmatory Factor Analysis (CFA) revealed that six dimensions, "Nutrition Confidence," "Susceptibility," "Severity," "Barrier," "Benefit," "Behavioral Intention to Eat Healthy Food," and "Behavioral Intention to do Physical Activity," had construct validity; Cronbach's alpha coefficient and composite reliabilities were tested for item reliability. The results validate that objective nutrition knowledge was a good predictor of college students' nutrition confidence. The results also clearly showed that two direct measures were significant predictors of behavioral intentions as hypothesized. Perceived benefit of eating healthy food and perceived barrier for eat healthy food to had significant effects on Behavioral Intentions and was a valid measurement to use to determine Behavioral Intentions. These findings can enhance the extant literature on the universal applicability of the model and serve as useful references for further investigations of the validity of the model within other health care or foodservice settings and for other health behavioral categories. PMID- 23346305 TI - Production and evaluation of children's dietary life safety index data on metropolitan cities and provinces in Korea. AB - This pilot study was performed to produce data of the Children's Dietary Life Safety (CDLS) Index which is required by the Special Act on Safety Management of Children's Dietary Life and to evaluate the CDLS Index for 7 metropolitan cities and 9 provinces in Korea. To calculate the CDLS Index score, data regarding the evaluation indicators in the children's food safety domain and children's nutrition safety domain were collected from the local governments in 2009. For data regarding the indicators in the children's perception & practice domain, a survey was conducted on 2,400 5th grade children selected by stratified sampling in 16 local areas. Relative scores of indicators in each domain were calculated using the data provided by local governments and the survey, the weights are applied on relative scores, and then the CDLS Index scores of local governments were produced by adding scores of the 3 domains. The national average scores of the food safety domain, the nutrition safety domain and the perception and practice domain were 23.74 (14.67-26.50 on a 40-point scale), 16.65 (12.25-19.60 on a 40-point scale), and 14.88 (14.16-15.30 on a 20-point scale), respectively. The national average score of the CDLS Index which was produced by adding the scores of the three domains was 55.27 ranging 46.44-58.94 among local governments. The CDLS Index scores produced in this study may provide the motivation for comparing relative accomplishment and for actively achieving the goals through establishment of the target value by local governments. Also, it can be used as useful data for the establishment and improvement of children's dietary life safety policy at the national level. PMID- 23346307 TI - Coexisting carcinoma in endometrial hyperplasia: does more risk factor mean better discrimination? PMID- 23346309 TI - Risk factor analysis of coexisting endometrial carcinoma in patients with endometrial hyperplasia: a retrospective observational study of Taiwanese Gynecologic Oncology Group. AB - OBJECTIVE: To evaluate the clinical outcome and parameters related to coexisting endometrial carcinoma in women with tissue-diagnosed endometrial hyperplasia. METHODS: Between January 1991 and December 2009, three hundred and eighty-six patients with the presumptive diagnosis of endometrial hyperplasia were retrieved. Among these, one hundred and twenty-five patients were identified as having coexisting endometrial carcinoma in hysterectomy specimens. The three hundred and eighty-six patients were divided into two groups: the hyperplasia benign group (261 cases) and the hyperplasia-malignant group (125 cases). Several clinical parameters including age, menopausal status, history of abnormal uterine bleeding, obstetrical history, medical history of diabetes and hypertension, BMI, and preoperative pathologic results were investigated. RESULTS: Age >=53 (odds ratio [OR], 2.40; 95% confidence interval [CI], 1.26 to 4.57), menopausal status (OR, 2.07; 95% CI, 1.14 to 3.76), diabetes history (OR, 7.33; 95% CI, 2.79 to 19.26), abnormal uterine bleeding (OR, 3.99; 95% CI, 1.22 to 13.02), atypical endometrial hyperplasia (OR, 7.38; 95% CI, 4.03 to 13.49), and body mass index >=27 (OR, 3.24; 95% CI, 1.76 to 5.97) were independent risk factors for prediction of endometrial hyperplasia coexisting with endometrial carcinoma. The diagnostic efficacy of atypical endometrial hyperplasia to predict the endometrial hyperplasia coexisting with endometrial carcinoma was better than or similar to those of other independent factors and combinations of these factors. CONCLUSION: Coexisting malignancy should be considered when examining endometrial hyperplasia patients with the related risk factors, especially atypical endometrial hyperplasia. PMID- 23346308 TI - Knowledge about HPV, relation between HPV and cervix cancer and acceptance of HPV vaccine in women in eastern region of Turkey. AB - OBJECTIVE: The aim of this study is to determine the knowledge of the women living in the eastern region of Turkey about human papillomavirus (HPV) and cervix cancer and their approaches to HPV vaccine. METHODS: The questionnaire forms were distributed to 1,052 patients who applied to the Gynecology Department of Elazig Training and Research Hospital. The subjects were recruited from the general gynecology outpatient clinic of the hospital. The patients from sexually transmitted disease and oncology outpatient clinics were not included in the study. The information about 945 women who completely filled in the questionnaire form was included into the study. The questions set forth in the questionnaire form consisting of 20 questions were prepared by taking the studies previously performed as model. RESULTS: Ninety-five percent of the women were married and 83.5% were housewives (unemployed). Thirteen percent of the women were illiterate, only 12% were graduated from university. Seventy-four percent of the women did not hear about HPV, 78.4% did not know about HPV vaccine, 63% did not know about the fact that some viruses cause cancer, and 83% did not know about the relation between HPV and cervix cancer. According to the multivariate analysis, free-of-charge vaccination, vaccinated relatives or friends, graduation from university and being under the age of 25 predict to accept the vaccine for themselves. CONCLUSION: The young population and the women who graduated from university seem to be more well-informed about HPV and more sensitive about being vaccinated. In addition, free vaccination will ensure the expansion of the vaccine. PMID- 23346310 TI - Integration of robotics into two established programs of minimally invasive surgery for endometrial cancer appears to decrease surgical complications. AB - OBJECTIVE: To compare peri- and postoperative outcomes and complications of laparoscopic vs. robotic-assisted surgical staging for women with endometrial cancer at two established academic institutions. METHODS: Retrospective chart review of all women that underwent total hysterectomy with pelvic and para-aortic lymphadenectomy by robotic-assisted or laparoscopic approach over a four-year period by three surgeons at two academic institutions. Intraoperative and postoperative complications were measured. Secondary outcomes included operative time, blood loss, transfusion rate, number of lymph nodes retrieved, length of hospital stay and need for re-operation or re-admission. RESULTS: Four hundred and thirty-two cases were identified: 187 patients with robotic-assisted and 245 with laparoscopic staging. Both groups were statistically comparable in baseline characteristics. The overall rate of intraoperative complications was similar in both groups (1.6% vs. 2.9%, p=0.525) but the rate of urinary tract injuries was statistically higher in the laparoscopic group (2.9% vs. 0%, p=0.020). Patients in the robotic group had shorter hospital stay (1.96 days vs. 2.45 days, p=0.016) but an average 57 minutes longer surgery than the laparoscopic group (218 vs. 161 minutes, p=0.0001). There was less conversion rate (0.5% vs. 4.1%; relative risk, 0.21; 95% confidence interval, 0.03 to 1.34; p=0.027) and estimated blood loss in the robotic than in the laparoscopic group (187 mL vs. 110 mL, p=0.0001). There were no significant differences in blood transfusion rate, number of lymph nodes retrieved, re-operation or re-admission between the two groups. CONCLUSION: Robotic-assisted surgery is an acceptable alternative to laparoscopy for staging of endometrial cancer and, in selected patients, it appears to have lower risk of urinary tract injury. PMID- 23346311 TI - Analysis of para-aortic lymphadenectomy up to the level of the renal vessels in apparent early-stage ovarian cancer. AB - OBJECTIVE: The aim of this study was to evaluate the impact of para-aortic lymphadenectomy up to the renal vessels on the accurate staging in ovarian cancer patients presumed preoperatively to be confined to the ovary. METHODS: We retrospectively analyzed data on 124 patients with primary epithelial ovarian cancer who were preoperatively thought to have tumor confined to the ovary and underwent primary staging surgery. The distribution of lymph node metastasis and various risk factors for nodal involvement were investigated. RESULTS: SURGICAL STAGING YIELDED: 87 (70.2%) patients had International Federation of Gynecology and Obstetrics (FIGO) stage I disease and 37 (29.8%) patients had stage II-III disease: 4 IIA, 6 IIB, 9 IIC, 1 IIIA, and 17 IIIC. Eighty-six patients had pelvic lymphadenectomy only and 69 had pelvic and para-aortic lymphadenectomy. Lymph node metastases were found in 17 (24.6%) of 69 patients; 5 (7.2%) patients had lymph node metastasis in the pelvic lymph nodes only, 8 (11.6%) in the para aortic lymph nodes only, and 4 (5.8%) in both pelvic and para-aortic lymph nodes. Six (8.7%) patients had lymph node metastasis in the para-aortic lymph node above the level of the inferior mesenteric artery. On multivariate analysis, grade 3 tumor (p=0.01) and positive cytology (p=0.03) were independent predictors for lymph node metastasis. CONCLUSION: A substantial number of patients with apparently early ovarian cancer had upstaged disease. Of patients who underwent lymphadenectomy, some patients had lymph node metastasis above the level of the inferior mesenteric artery. Para-aortic lymphadenectomy up to the renal vessels may detect occult metastasis and be of help in tailoring appropriate adjuvant treatment as well as giving useful information about the prognosis. PMID- 23346312 TI - Clear cell histology as a poor prognostic factor for advanced epithelial ovarian cancer: a single institutional case series through central pathologic review. AB - OBJECTIVE: Compared with serous adenocarcinoma (SAC), clear cell carcinoma (CCC) often shows chemo-resistance, which would potentially lead to a poor prognosis. On the other hand, there have been arguments over prognoses of CCC and SAC disease. In the present study, multivariate analysis to compare prognosis of CCC patients with that of SAC was aimed for the patients selected from central pathologic review. METHODS: Between 1984 and 2009, a total of 500 ovarian cancer patients were treated at our university hospital. Among them, 111 patients with CCC and 199 patients with SAC were identified through central pathological review. Overall survival and progression-free survival were compared using Kaplan Meier method, and prognostic factors were investigated by multiple regression analyses. RESULTS: Median age was 52 years for CCC and 55 years for SAC (p=0.03). The ratio of stage I patients were significantly higher in CCC compared with SAC (55% vs. 13%, p<0.01). Among evaluable cases, response rate was significantly lower in CCC than that in SAC (32% vs. 78%, p<0.01). No significant differences of progression-free survival and overall survival were observed in stage I patients; however, prognoses of CCC were significantly poorer than those of SAC in advanced-stage disease. In stage II-IV patients, not only residual tumors and clinical stages, but also clear cell histology were identified as predictors for poor prognosis. CONCLUSION: Clear cell histology was identified as a prognostic factor for advanced-stage ovarian cancers. Histologic subtypes should be considered in further clinical studies, especially for advanced epithelial ovarian cancers. PMID- 23346313 TI - Histologic distribution of borderline ovarian tumors worldwide: a systematic review. AB - OBJECTIVE: The histologic types of borderline ovarian tumors (BOTs) exhibit striking differences in clinical behavior and prognosis. Yet, there is no information available on the histologic distribution of BOTs according to geographic region. The purpose of this study was to systematically review this issue worldwide. METHODS: A comprehensive search of the literature was conducted using electronic databases. Studies were eligible if BOTs were investigated and the histologic distribution of the data was shown. The studies were grouped by geographic region and totaled by country. RESULTS: Of 487 potentially relevant studies, 51 met our inclusion criteria, as follows: 8 studies from North America (2 countries); 26 studies from Europe (14 countries); 7 studies from the Middle East (3 countries); and 10 studies from East Asia (5 countries). The histologic distribution of BOTs was considerably different in different parts of the world, but follows specific patterns. In general, serous-type BOTs were the predominantly identified histology in North America, the Middle East, and Europe, while mucinous-type BOTs predominated in East Asia. CONCLUSION: Significant geographic variation is evident among BOT histology in different parts of the world. More research is needed to understand this phenomenon. PMID- 23346314 TI - Effect of ovarian tumor characteristics on venous thromboembolic risk. AB - OBJECTIVE: Deep venous thrombosis and pulmonary embolism are common in patients with epithelial ovarian cancer, resulting in high costs associated with diagnosis and treatment. I aimed to identify subtypes of epithelial ovarian cancer that pose greater and lesser venous thromboembolism (VTE) risk. METHODS: I assessed the outcomes of 641 patients with epithelial ovarian, fallopian tube, and primary peritoneal cancer over a ten-year period. All inpatient, outpatient, and pathology records were reviewed. The rates at which people were evaluated for and diagnosed with venous thromboembolism were assessed. RESULTS: Of the 641 cases, 30.0% underwent an imaging test to evaluate for deep venous thrombosis (DVT) and 21.7% underwent testing for pulmonary embolism (PE). A 10.8% of all subjects were diagnosed with DVT and 7.2% were diagnosed with PE. Borderline tumors and mucinous showed a strikingly low rate of both DVT and PE. Clear cell and high grade undifferentiated adenocarcinomas were the most likely to result in VTE. In a multivariate model, pathologic subtype was not only a significant predictor of VTE, but was the single best predictor of VTE. CONCLUSION: Clear cell and undifferentiated pathology in epithelial ovarian carcinomas is associated with a higher VTE risk. The underlying reason for this may related to differences in tumor biology. By identifying low and high risk groups, I may both better conserve medical resources and design more effective thromboprophylaxis for my patients. PMID- 23346315 TI - Establishment of a Korea HPV cohort study. AB - We have designed a five-year multicentre prospective cohort study in women who are both human papillomavirus (HPV)-positive with either atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) of cervix. This study aimed to analyze the risk of developing a high-grade squamous intraepithelial lesion (HSIL) from either ASCUS or LSIL in HPV-positive women, so called 'progression' rate, to investigate differences in the progression rates according to HPV type-specific infection, and to evaluate the various factors associated with the persistence or clearance of HPV infection in the Korean population. At present, the study protocol composed of cervical cytology, HPV DNA testing, and questionnaire have been conducted actively since the first participant was enrolled in 2010. This study is the first nationwide Korea HPV cohort study. Our data will provide valuable information about not only the ambiguous cytology results of ASCUS and LSIL but also the effect of the specific HPV type and other various factors on the progression to HSIL. Finally, the results of our study will be helpful and applicable to determine the primary cervical cancer prevention strategies. PMID- 23346316 TI - Major clinical research advances in gynecologic cancer in 2012. AB - Ten topics were chosen among major clinical research achievements in gynecologic oncology in 2012. For ovarian cancer, comprehensive review of the history of bevacizumab studies was followed by poly adenosine diphosphate [ADP]-ribose polymerase (PARP) inhibitors and other molecular targeted agents such as epidermal growth factor receptor tyrosine kinase inhibitor and AMG 386. For the development of genomic study in gynecologic cancers, BRCA and DICER1 mutations were covered in epithelial and nonepithelial ovarian cancer, respectively. For endometrial cancer, targeted agents including mammalian target of rapamycin (mTOR) inhibitors and bevacizumab were discussed. Radiation therapy "sandwiched" between combination chemotherapy schedules for the treatment of uterine papillary serous carcinoma was also reviewed. Preoperative prediction of lymph node metastasis, definition of low-risk group, and recurrence and survival outcomes of laparoscopic approaches were addressed. For cervical cancer, we reviewed long term benefit of human papillomavirus test and efficacy of paclitaxel/carboplatin versus paclitaxel/cisplatin in stage IVB, persistent or recurrent disease. In addition, the effect of three dimensional image-based high-dose rate brachytherapy was also reviewed. For vulvar cancer, the diagnostic value of sentinel lymph node biopsy was discussed. For breast cancer, positive results of three outstanding phase III randomized clinical trials, CLEOPATRA, EMILIA, and BOLERO-2 were introduced. Lastly, updates of major practice guidelines were summarized. PMID- 23346318 TI - Minimal deviation adenocarcinoma of the cervix and tumorlets of sex-cord stromal tumor with annular tubules of the ovary in Peutz-Jeghers syndrome. AB - We report 2 cases of minimal deviation adenocarcinoma of the cervix and tumorlets of sex cord tumor with annular tubules (SCTATs) of the ovaries, accompanied by Peutz-Jeghers syndrome. Case 1 is a 36-year-old woman and case 2 is a 35-year-old woman. Grossly, the cervix of both cases showed markedly barrel shaped enlargement with an infiltrating tumor. Microscopically, well-differentiated atypical glands were infiltrating into the entire thickness of the cervix. The ovarian masses in case 1 were diagnosed as metastatic carcinoma in mucinous cystadenoma with tumorlets of SCTATs of the ovaries. Multiple scattered tumorlets of SCTATs were also found in the ovary of case 2. By direct DNA sequencing analysis, a frame shift mutation of the STK11/LKB1 gene was identified in case 1. Case 1 represented the more aggressive clinical course, and although the patient received additional combined chemo-radiation therapy, she expired 1 year later. In general, mutation of the STK11/LKB1 gene is associated with poor clinical outcome in malignant tumors accompanied by Peutz-Jeghers syndrome. PMID- 23346317 TI - Advanced ovarian cancer: what should be the standard of care? AB - The standard treatment of advanced ovarian cancer is rapidly changing. As we begin to understand that epithelial ovarian cancer is a heterogeneous disease, our treatment strategies are evolving to include novel biologic drugs that specifically exploit altered pathways. Surgery remains an essential component in the treatment of ovarian cancer; however, the importance of surgical specialization and defining "optimal cytoreduction" as no visible residual disease has been further validated. Ongoing studies are defining the role of neoadjuvant chemotherapy in the upfront treatment of advanced ovarian cancer. In addition, clinical trials are evaluating intraperitoneal, dose dense, antiangiogenic drugs as well as targeted maintenance therapies which will establish new standards of care in the near future. PMID- 23346319 TI - Pharmacokinetics and cytotoxic effect of selenium compounds in rodent cancer xenograft model for therapy experiment. PMID- 23346320 TI - Neuroprotective effects of sacral epidural neuromodulation following spinal cord injury : an experimental study in rats. AB - OBJECTIVE: The purpose of this study is to evaluate neuroprotective effect of sacral neuromodulation in rat spinal cord injury (SCI) model in the histological and functional aspects. METHODS: Twenty-one female Sprague Dawley rats were randomly divided into 3 groups : the normal control group (CTL, n=7), the SCI with sham stimulation group (SCI, n=7), and the SCI with electrical stimulation (SCI+ES, n=7). Spinal cord was injured by dropping an impactor from 25 mm height. Sacral nerve electrical stimulation was performed by the following protocol : pulse duration, 0.1 ms; frequency, 20 Hz; stimulation time, 30 minutes; and stimulation duration, 4 weeks. Both locomotor function and histological examination were evaluated as scheduled. RESULTS: The number of anterior horn cell was 12.3+/-5.7 cells/high power field (HPF) in the CTL group, 7.8+/-4.9 cells/HPF in the SCI group, and 6.9+/-5.5 cells/HPF in the SCI+ES group, respectively. Both the SCI and the SCI+ES groups showed severe loss of anterior horn cells and myelin fibers compared with the CTL group. Cavitation and demyelinization of the nerve fibers has no significant difference between the SCI group and the SCI+ES group. Cavitation of dorsal column was more evident in only two rats of SCI group than the SCI+ES group. The locomotor function of all rats improved over time but there was no significant difference at any point in time between the SCI and the SCI+ES group. CONCLUSION: In a rat thoracic spinal cord contusion model, we observed that sacral neuromodulation did not prevent SCI induced myelin loss and apoptosis. PMID- 23346321 TI - Medial loop of v2 segment of vertebral artery causing compression of proximal cervical root. AB - OBJECTIVE: It is rare that the medial loop in the V2 segment of the vertebral artery (VA) causes compression of the proximal cervical root of the spinal cord without leading to bony erosion and an enlarged foramen. We evaluated the clinical significance and incidence of the medial loop in the V2 segment of the VA. METHODS: We reviewed the records from 1000 consecutive patients who had undergone magnetic resonance imaging evaluation of the cervical spine between January 2005 and January 2008. The inclusion criteria were that over a third of the axial aspect of the VA located in the intervertebral foramen was inside the line between the most ventral points of the bilateral lateral mass, and that the ipsilateral proximal root deviated dorsally because of the medial loop of the VA. We excluded cases of bone erosion, a widened foramen at the medial loop of the VA, any bony abnormalities, tumors displacing VA, or vertebral fractures. The medical records were reviewed retrospectively to search for factors of clinical significance. RESULTS: In six patients (0.6%), the VA formed a medial loop that caused compression of the proximal cervical root. One of these patients had the cervical radiculopathy that developed after minor trauma but the others did not present with cervical radiculopathy related to the medial loop of the VA. CONCLUSION: The medial loop of the VA might have a direct effect on cervical radiculopathy. Therefore, this feature should be of critical consideration in preoperative planning and during surgery. PMID- 23346322 TI - Long-term follow-up result of hydroxyurea chemotherapy for recurrent meningiomas. AB - OBJECTIVE: Meningiomas represent 18-20% of all intracranial tumors and have a 20 50% 10-year recurrence rate, despite aggressive surgery and irradiation. Hydroxyurea, an inhibitor of ribonucleotide reductase, is known to inhibit meningioma cells by induction of apoptosis. We report the long-term follow-up result of hydroxyurea therapy in the patients with recurrent meningiomas. METHODS: Thirteen patients with recurrent WHO grade I or II meningioma were treated with hydroxyurea (1000 mg/m(2)/day orally divided twice per day) from June 1998 to February 2012. Nine female and 4 male, ranging in age from 32 to 83 years (median age 61.7 years), were included. Follow-up assessment included physical examination, computed tomography, and magnetic resonance imaging (MRI). Standard neuro-oncological response criteria (Macdonald criteria) were used to evaluate the follow-up MRI scans. The treatment was continued until there was objective disease progression or onset of unmanageable toxicity. RESULTS: Ten of the 13 patients (76.9%) showed stable disease after treatment, with time to progression ranging from 8 to 128 months (median 72.4 months; 6 patients still accruing time). However, there was no complete response or partial response in any patients. Three patients had progressive disease after 88, 89, 36 months, respectively. There was no severe (Grade III-IV) blood systemic disorders and no episodes of non-hematological side effects. CONCLUSION: This study showed that hydroxyurea is a modestly active agent against recurrent meningiomas and can induce long-term stabilization of disease in some patients. We think that hydroxyurea treatment is well tolerated and convenient, and could be considered as an alternative treatment option in patients with recurrent meningiomas prior to reoperation or radiotherapy. PMID- 23346324 TI - Clinical comparison of the predictive value of the simple skull x-ray and 3 dimensional computed tomography for skull fractures of children. AB - OBJECTIVE: In the pediatric population the skull has not yet undergone ossification and it is assumed that the diagnostic rate of skull fractures by simple X-rays are lower than that of adults. It has been recently proposed that the diagnostic rates of skull fractures by 3-dimensional computer tomography (3D CT) are higher than simple X-rays. The authors therefore attempted to compare the diagnostic rates of pediatric skull fractures by simple X-rays and 3D-CTs with respect to the type of fracture. METHODS: One-hundred patients aged less than 12 years who visited the Emergency Center for cranial injury were subject to simple X-rays and 3D-CTs. The type and location of the fractures were compared and Kappa statistical analysis and the t-test were conducted. RESULTS: Among the 100 pediatric patients, 65 were male and 35 were female. The mean age was 50+/-45 months. 63 patients had simple skull fractures and 22 had complex fractures, and the types of fractures were linear fractures in 74, diastatic fractures 15, depressed fractures in 10, penetrating fracture in 1, and greenstick fractures in 3 patients. Statistical difference was observed for the predictive value of simple skull fractures' diagnostic rate depending on the method for diagnosis. A significant difference of the Kappa value was noted in the diagnosis of depressed skull fractures and diastatic skull fractures. CONCLUSION: In the majority of pediatric skull fractures, 3D-CT showed superior diagnosis rates compared to simple skull X-rays and therefore 3D-CT is recommended whenever skull fractures are suspected. This is especially true for depressed skull fractures and diastatic skull fractures. PMID- 23346323 TI - Clinical Outcomes of Spontaneous Spinal Epidural Hematoma : A Comparative Study between Conservative and Surgical Treatment. AB - OBJECTIVE: The incidence of spontaneous spinal epidural hematoma (SSEH) is rare. Patients with SSEH, however, present disabling neurologic deficits. Clinical outcomes are variable among patients. To evaluate the adequate treatment method according to initial patients' neurological status and clinical outcome with comparison of variables affecting the clinical outcome. METHODS: We included 15 patients suffered from SSEH. Patients were divided into two groups by treatment method. Initial neurological status and clinical outcomes were assessed by the American Spinal Injury Association (ASIA) impairment scale. Also sagittal hematoma location and length of involved segment was analyzed with magnetic resonance images. Other factors such as age, sex, premorbid medication and duration of hospital stay were reviewed with medical records. Nonparametric statistical analysis and subgroup analysis were performed to overcome small sample size. RESULTS: Among fifteen patients, ten patients underwent decompressive surgery, and remaining five were treated with conservative therapy. Patients showed no different initial neurologic status between treatment groups. Initial neurologic status was strongly associated with neurological recovery (p=0.030). Factors that did not seem to affect clinical outcomes included : age, sex, length of the involved spinal segment, sagittal location of hematoma, premorbid medication of antiplatelets or anticoagulants, and treatment methods. CONCLUSION: For the management of SSEH, early decompressive surgery is usually recommended. However, conservative management can also be feasible in selective patients who present neurologic status as ASIA scale E or in whom early recovery of function has initiated with ASIA scale C or D. PMID- 23346325 TI - Radiosurgical techniques and clinical outcomes of gamma knife radiosurgery for brainstem arteriovenous malformations. AB - OBJECTIVE: Brainstem arteriovenous malformation (AVM) is rare and radiosurgical management is complicated by the sensitivity of the adjacent neurological structures. Complete obliteration of the nidus is not always possible. We describe over 20 years of radiosurgical procedures for brainstem AVMs, focusing on clinical outcomes and radiosurgical techniques. METHODS: Between 1992 and 2011, the authors performed gamma knife radiosurgery (GKRS) in 464 cerebral AVMs. Twenty-nine of the 464 patients (6.3%) reviewed had brainstem AVMs. This series included sixteen males and thirteen females with a mean age of 30.7 years (range : 5-71 years). The symptoms that led to diagnoses were as follows : an altered mentality (5 patients, 17.3%), motor weakness (10 patients, 34.5%), cranial nerve symptoms (3 patients, 10.3%), headache (6 patients, 20.7%), dizziness (3 patients, 10.3%), and seizures (2 patients, 6.9%). Two patients had undergone a previous nidus resection, and three patients had undergone a previous embolization. Twenty-four patients underwent only GKRS. With respect to the nidus type and blood flow, the ratio of compact type to diffuse type and high flow to low flow were 17 : 12 and 16 : 13, respectively. In this series, 24 patients (82.8%) had a prior hemorrhage. The mean target volume was 1.7 cm(3) (range 0.1 11.3 cm(3)). The mean maximal and marginal radiation doses were 38.5 Gy (range 28.6-43.6 Gy) and 23.4 Gy (range 18-27 Gy), and the mean isodose profile was 61.3% (range 50-70%). RESULTS: Twenty-four patients had brainstem AVMs and were followed for more than 3 years. Obliteration of the AVMs was eventually documented in 17 patients (70.8%) over a mean follow-up period of 77.5 months (range 36-216 months). With respect to nidus type and blood flow, the obliteration rate of compact types (75%) was higher than that of diffuse types (66.7%), and the obliteration rate of low flow AVMs (76.9%) was higher than that of high flow AVMs (63.6%) (p<0.05). Two patients (6.9%) with three hemorrhagic events suffered a hemorrhage during the follow-up period. The annual bleeding rate of AVM after GKRS was 1.95% per year. No adverse radiation effects or delayed cystic formations were found. CONCLUSION: GKRS has an important clinical role in treatment of brainstem AVMs, which carry excessive surgical risks. Angiographic features and radiosurgical techniques using a lower maximal dose with higher isodose profiles are important for lesion obliteration and the avoidance of complications. PMID- 23346326 TI - Customized cranioplasty implants using three-dimensional printers and polymethyl methacrylate casting. AB - OBJECTIVE: The prefabrication of customized cranioplastic implants has been introduced to overcome the difficulties of intra-operative implant molding. The authors present a new technique, which consists of the prefabrication of implant molds using three-dimensional (3D) printers and polymethyl-methacrylate (PMMA) casting. METHODS: A total of 16 patients with large skull defects (>100 cm(2)) underwent cranioplasty between November 2009 and April 2011. For unilateral cranial defects, 3D images of the skull were obtained from preoperative axial 1 mm spiral computed tomography (CT) scans. The image of the implant was generated by a digital subtraction mirror-imaging process using the normal side of the cranium as a model. For bilateral cranial defects, precraniectomy routine spiral CT scan data were merged with postcraniectomy 3D CT images following a smoothing process. Prefabrication of the mold was performed by the 3D printer. Intraoperatively, the PMMA implant was created with the prefabricated mold, and fit into the cranial defect. RESULTS: The median operation time was 184.36+/ 26.07 minutes. Postoperative CT scans showed excellent restoration of the symmetrical contours and curvature of the cranium in all cases. The median follow up period was 23 months (range, 14-28 months). Postoperative infection was developed in one case (6.2%) who had an open wound defect previously. CONCLUSION: Customized cranioplasty PMMA implants using 3D printer may be a useful technique for the reconstruction of various cranial defects. PMID- 23346327 TI - Successful treatment of tracheoinnominate artery fistula following tracheostomy in a patient with cerebrovascular disease. AB - Tracheoinnominate artery fistula is a critical complication of tracheostomy. The most important factors influencing patient outcome are prompt diagnosis, immediate control of bleeding with a patent airway, and emergency operation with or without interruption of the innominate artery. Here, we report a case of tracheoinnominate artery fistula in a 40-year-old woman with cerebrovascular accident who was successfully managed with an aorta-axillary artery bypass. PMID- 23346328 TI - Superficial temporal artery-middle cerebral artery anastomosis for internal carotid artery occlusion by subacute in-stent thrombosis after carotid artery stenting. AB - Alternative to carotid endarterectomy, carotid artery stenting (CAS) can be performed for symptomatic severe stenosis of internal carotid artery, especially for high-risk patients. Among several complications after CAS, subacute in-stent thrombosis is rare but important, because patient's condition can deteriorate rapidly. Subacute in-stent thrombosis with carotid artery occlusion can be managed by superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis. We report two cases of STA-MCA anastomosis for internal carotid artery occlusion by subacute in-stent thrombosis after CAS. PMID- 23346329 TI - Endoscope-Assisted Trans-Sphenoidal Approach for Treatment of Sternberg's Canal. AB - We report an uncommon case of a 45-year-old woman who presented with spontaneous rhinorrhea. A computed tomography (CT) scan of the head revealed an abnormally large sphenoid sinus associated with a parasellar bony defect (Sternberg's canal) through which magnetic resonance imaging could detect an encephalocele of the right temporal lobe. An endoscope-assisted trans-sphenoidal approach was performed and, with the aid of image guided surgery, reduction of the encephalocele was obtained and followed by surgical repair of the dural and bony defects. The postoperative course was uneventful and the cerebrospinal fluid fistula was closed as confirmed by the postoperative CT scan and by the absence of rhinorrhea. After three years of monitoring the patient remained asymptomatic. PMID- 23346330 TI - Experience with 5-aminolevulinic Acid in fluorescence-guided resection of a deep sylvian meningioma. AB - The 5-aminolevulinic acid (5-ALA)-induced tumor fluorescence is a useful intraoperative marker for the diagnosis and the detection of various malignancies, but its use in meningioma is only reported infrequently. In meningioma, a complete resection of the tumor mass is crucial for the prevention of recurrence and postoperative morbidities. Deep sylvian meningioma is a rare type of meningioma where complete tumor removal is complicated by its deep anatomical location and close involvement with the middle cerebral artery. From our experience, 5-ALA-mediated fluorescence facilitated a safe excision whilst preserving critical neurovascular structures. To our best knowledge, this is first report from use of 5-ALA in a deep sylvian meningioma. PMID- 23346331 TI - Desmoplastic fibroma of the cranium in a young man. AB - Desmoplastic fibroma, which develops predominantly in long bones and the mandible, is a rare and benign but locally aggressive tumor. Desmoplastic fibroma of the cranium is extremely rare. We report a case of desmoplastic fibroma of the frontal bone in a young man. Because of its locally aggressive behavior, complete surgical excision with a safety margin is essential. PMID- 23346332 TI - Solitary lymphoblastic lymphoma of the thoracic spine. AB - Non-Hodgkin's lymphoma rarely originates from bone, and even more infrequently from a vertebral body. Lymphoblastic lymphoma is a rare type of non-Hodgkin's lymphoma, and results from an abnormality in adaptive immune cells. A 27-year-old man presented with a two-month history of night sweats, weight loss, and severe back pain. Radiological studies demonstrated an osteolytic lesion compressing the subarachnoid space at the T11 level. Posterolateral fusion with decompression was performed and a pathologic examination confirmed lymphoblastic lymphoma of the B cell precursor type. To our knowledge, this is the first report of solitary lymphoblastic lymphoma from B-cell precursors in of the thoracic spine. Herein, we discuss the presenting symptoms and the management of this rare case of lymphoblastic lymphoma. PMID- 23346333 TI - Hemorrhagic lumbar synovial cyst. AB - Synovial cysts of the lumbar spine are an uncommon cause of back and radicular pain. These cysts most frequently present as back pain, followed by chronic progressive radiculopathy or gradual onset of symptoms secondary to spinal canal compromise. Although less common, they can also present with acute spinal cord or root compression symptoms. We report of a case in which hemorrhaging into a right L2-3 facet synovial cyst caused an acute onset of back pain and radiculopathy, requiring surgical excision. PMID- 23346334 TI - Multiple cervical spinous process fractures in a novice golf player. AB - Avulsion of spinous process, also called Clay-shoveler's fracture, is most prevalent among those engaged in hard physical labor. To the best of the author's knowledge, only one case of multiple spinous process fractures of the upper thoracic spine in a novice golfer has been reported. A 45-year-old female presented with intractable posterior neck pain. The patient experienced a sharp, sudden pain on the neck while swinging a golf club, immediately after the club head struck the ground. Dynamic cervical radiographic findings were C6 and C7 spinous process fractures. Magnetic resonance imaging revealed C6 and C7 spinous process fractures without spinal cord pathology. The patient was treated with pain medications and cervical bracing. The patient's pain gradually improved. The injury mechanism was speculated to be similar to Clay-shoveler's fracture. Lower cervical spinous process fractures can be associated with a golf swing. If the patient complains of long lasting neck pain and has a history of golf activity, further study should be conducted to rule out lower cervical spinous fracture. PMID- 23346335 TI - Pain control following impacted third molar surgery with bupivacaine irrigation of tooth socket: a prospective study. AB - BACKGROUND AND AIMS: The surgical removal of the lower third molars is a procedure generally followed by side effects such as postoperative pain. The aim of this study was to evaluate the efficacy of socket irrigation with an anesthetic solution in relieving pain following impacted third molar surgery. MATERIALS AND METHODS: Thirty-four patients (17 males and 17 females), aged 18-24 years, with bilateral impacted lower third molars were selected. Both third molars were extracted in one surgical session. Tooth sockets in each patient were rinsed randomly either with 4 mL of 0.5% bupivacaine hydrochloride plain (without vasoconstrictor) anesthetic solu-tion or 4 mL of normal saline, used as control. The patients were instructed not to use analgesics as long as possible, and if not, they were instructed to use an analgesic, and record the time. Pain severity was assessed using a visual analogue pain scale (VAPS) at 1-, 6-, 12-, and 24 hour intervals post-operatively. Data were analyzed using Pearson's chi-square test and P <0.05 was considered statistically significant. RESULTS: Post operative pain difference between the two groups was statistically significant at 1-, 6-, 12- and 24-hour post-operative intervals (P <0.05). Post-operative pain increased in both groups to a maximum 12 hours after surgery with signif-icant improvements after that. CONCLUSION: Based on the results, the irrigation of surgery site with bupivacaine after third molar surgery significantly reduces post-operative pain. PMID- 23346336 TI - Effect of Long-term Smoking on Whole-mouth Salivary Flow Rate and Oral Health. AB - BACKGROUND AND AIMS: Change in the resting whole-mouth salivary flow rate (SFR) plays a significant role in patho-genesis of various oral conditions. Factors such as smoking may affect SFR as well as the oral and dental health. The primary purpose of this study was to determine the effect of smoking on SFR, and oral and dental health. MATERIALS AND METHODS: One-hundred smokers and 100 non-tobacco users were selected as case and control groups, respectively. A questionnaire was used to collect the demographic data and smoking habits. A previously used questionnaire about dry mouth was also employed. Then, after a careful oral examination, subjects' whole saliva was collected in the resting condition. Data was analyzed by chi-square test using SPSS 15. RESULTS: The mean (+/-SD) salivary flow rate were 0.38 (+/- 0.13) ml/min in smokers and 0.56 (+/- 0.16) ml/min in non-smokers. The difference was statistically significant (P=0.00001). Also, 39% of smokers and 12% of non-smokers reported experiencing at least one xerostomia symptom, with statistically significant difference between groups (p=0.0001). Oral lesions including cervical caries, gingivitis, tooth mobility, calculus and halitosis were significantly higher in smokers. CONCLUSION: Our findings indicated that long-term smoking would significantly reduce SFR and increase oral and dental disorders associated with dry mouth, especially cervical caries, gingivitis, tooth mobility, calculus, and halitosis. PMID- 23346337 TI - Oral Manifestations Related To CD4 Lymphocyte Count in HIV-Positive Patients. AB - BACKGROUND AND AIMS: The onset of opportunistic infections in HIV-positive patients is generally associated with a low CD4 count. Oral manifestations can be the first clinical sign of the infection and also determine the progression of disease. The purpose of this study was to determine the prevalence of oral soft tissue manifestations and their relationship with the degree of immunosuppression observed in HIV-positive patients. MATERIALS AND METHODS: 100 HIV-positive patients were examined. Oral lesions were evaluated according to EEC clearing house criteria. The degree of immunosuppression was based on the CD4 count closest to the oral examination. Data were analyzed using Student's t-test and chi-square test. RESULTS: The most common oral lesions were rampant caries (54%), periodontal disease (44%), and hyperpigmentation (42%). Salivary glands enlargements and leukoplakia were associated with more severe immunosuppression. CONCLUSION: According to the results, it seems that occurrence of only some of oral lesions are related to the degree of immunosuppression and such lesions can be considered as indicators of the progression of the HIV infection. PMID- 23346338 TI - Epithelial salivary gland tumors in ahvaz, southwest of iran. AB - BACKGROUND AND AIMS: Salivary gland tumors are rare and specific lesions. There are differences in the incidence and frequency of salivary tumors in both minor and major salivary glands in different countries. This study was carried out to determine the prevalence of major and minor salivary gland tumors in Ahvaz in the south of Iran. MATERIALS AND METHODS: All the cases, recorded in Imam Khomeyni Hospital and Shafa Hospital, Ahvaz, Iran from 1997 to 2008 were assessed. Age, gender, anatomical location, and histology of all the specimens were evaluated. RESULTS: Of 112 cases, 84 cases were benign and 28 cases were malignant. Female predominance was observed in these cases. Most lesions appeared in the third to fifth decades of life (60.71%). The incidence of malignant salivary gland tumors increased with age and male predominance was found in malignant tumors. The majority of the tumors occurred in parotid gland. Pleomorphic adenoma was the most common histological type (65.17%). Mucoepidermoid carcinoma and adenoid cystic carcinoma were the most common malignant tumors. CONCLUSION: It was shown that the peak incidence age of all salivary gland tumors was the third to fifth decades, and malignant tumors mostly occurred in the sixth to eighth decades. Female predominance for all the tumors and slight male predominance in malignant tumors were observed. Pleomorphic adenoma was the most common benign tumor. The most common malignant tumors were mucoepidermoid carcinoma and adenoid cystic carcinoma. PMID- 23346339 TI - The effect of disinfection by spray atomization on dimensional accuracy of condensation silicone impressions. AB - BACKGROUND AND AIMS: The condensation silicone impression materials are available, but there is little knowledge of their accuracy after disinfection. The objective of this study was to evaluate the effect of the disinfection by spray atomization on dimensional accuracy of condensation silicone impressions. MATERIALS AND METHODS: Impressions were made on a stainless steel master model containing a simulated two complete crown preparation with an edentulous space interposed using Spidex(r) and Rapid(r) impression materials. 44 impressions were made with each material, of which 16 were disinfected with 5.25% sodium hypochlorite, 16 were disinfected with 10% iodophor and 12 were not disinfected. Three dimensional measurements of working casts, including interpreparation distance, height, and diameter, were calculated using a measuring microscope graduated at 0.001 mm. Dimensional changes (mm) between the disinfected and non disinfected working casts were compared. One-way analysis of variance (ANOVA) was employed to analyze the data (alpha=0.05). RESULTS: Disinfection of each condensation silicone material by spraying atomization with two different disinfectant material resulted in significant change in interpreparation distance (p<0.05). Changes in height and diameter were only significant in Spidex(r) impressions (p<0.05). CONCLUSION: Significant changes in the mean dimensions were seen as a result of disinfection by spraying; however, the dimensional changes do not seem great enough to cause critical positional distortion of teeth when fixed partial denture restorations are made. PMID- 23346340 TI - In vitro evaluation of dimensional stability of alginate impressions after disinfection by spray and immersion methods. AB - BACKGROUND AND AIMS: The most common method for alginate impression disinfection is spraying it with disinfecting agents, but some studies have shown that these impressions can be immersed, too. The aim of this study was to evaluate the dimensional stability of alginate impressions following disinfecting by spray and immersion methods. MATERIALS AND METHODS: Four common disinfecting agents (Sodium Hypochlorite, Micro 10, Glutaraldehyde and De-conex) were selected and the impressions (n=108) were divided into four groups (n=24) and eight subgroups (n=12) for disinfecting by any of the four above-mentioned agents by spray or immersion methods. The control group (n=12) was not disinfected. Then the impressions were poured by type III Dental Stone Plaster in a standard method. The results were ana-lyzed by descriptive methods (mean and standard deviation), t-test, two-way analysis of variance (ANOVA) and Duncan test, using SPSS 14.0 software for windows. RESULTS: The mean changes of length and height were significant between the various groups and disinfecting methods. Regarding the length, the greatest and the least amounts were related to Deconex and Micro 10 in the immersion method, respectively. Regarding height, the greatest and the least amounts were related to Glutaraldehyde and Deconex in the im-mersion method, respectively. CONCLUSION: Disinfecting alginate impressions by Sodium Hypochlorite, Deconex and Glutaraldehyde by immersion method is not recommended and it is better to disinfect alginate impressions by spraying of Micro 10, Sodium Hypochlorite, Glutaraldehyde and immersion in Micro 10. PMID- 23346341 TI - Oromandibular-limb Hypogenesis Syndrome Type II C: A Rare Case. AB - The oromandibular-limb hypogenesis syndrome comprises a group of anomalies which simultaneously affect the mandible, tongue, and maxilla with or without reductive limb anomalies. It is characterized by failure of development of the intraoral region and distal extremities. Multiple and variable deformities of the mandible, maxilla and tongue may occur in combination with a variety of limb defects. The wide range of presentation and combination of anomalies make classification difficult. They usually feature primarily in sporadic case reports because of their low incidence. The genetic origin of this syndrome is uncertain. It is congenital and there seems to be no sex predilection. The key radiographic features are retruded mandible, impacted teeth and malformed phalanges. When compared to available literature, frequently reported features like hypodontia, hypoglossia, microstomia, protruded maxilla and limb anomalies were present in our case. The case presented here is one of the rarest subtypes of this rare syndrome. PMID- 23346342 TI - Bilateral mandibular supernumerary canines: a case report. AB - Supernumerary teeth are defined as the teeth developed in excess of the number found in a normal dentition. Supernumerary canine is an extremely rare finding particularly in the mandible. This case report presents a 25-year-old female patient with the unique feature of bilateral mandibular supplemental supernumerary canines. The patient was non-syndromic without any other supernumerary teeth. PMID- 23346343 TI - Comparative morphology, biology and histology of reproductive development in three lines of Manihot esculenta Crantz (Euphorbiaceae: Crotonoideae). AB - BACKGROUND AND AIMS: Cassava (Manihot esculenta), a major food staple in the tropics and subtropics, thrives even in environments undergoing threatening climate change. To satisfy the increasing demand for crop improvement and overcome the limitations of conventional breeding, the introduction of inbreeding techniques such as the production of doubled haploid lines via androgenesis or gynogenesis offers advantages. However, comprehensive studies on cassava flower bud biology or structural development are lacking and precise structural and biological information is a prerequisite to enhance the efficiency of these techniques. METHODOLOGY: The floral biology of three selected cassava lines was studied, focusing on morphology, phenology and pollen biology (quantity, viability and dimorphism). Histological studies were also conducted on microsporogenesis/microgametogenesis and megasporogenesis/megagameto-genesis to generate precise developmental data for these lines. PRINCIPAL RESULTS: Male and female cyathia have distinct developmental phases. Pollen viability was high during immature stages of plant development; however, pollen mortality was common at later stages. Pollen trimorphism in male gametophytes towards the larger or smaller pollen size, as compared with normal size, was observed. Ten characteristic events were identified in male gametogenesis and six in female gametogenesis that were correlated with flower bud diameter. Male gametophyte diameter at different developmental stages was also determined. CONCLUSIONS: Results indicate that the three lines did not differ significantly, except regarding a few morphological aspects such as plant height, flower colour and number of male cyathia. Pollen grains were initially viable, but viability decreased drastically at later stages of growth. Abnormal meiosis or mitosis triggered pollen trimorphism. The demonstrated sequential events of reproductive development generated valuable information at the cellular level, which will help close the current information gap for cassava improvement via breeding programmes and doubled haploid plant production. PMID- 23346344 TI - SEPALLATA1/2-suppressed mature apples have low ethylene, high auxin and reduced transcription of ripening-related genes. AB - BACKGROUND AND AIMS: Fruit ripening is an important developmental trait in fleshy fruits, making the fruit palatable for seed dispersers. In some fruit species, there is a strong association between auxin concentrations and fruit ripening. We investigated the relationship between auxin concentrations and the onset of ethylene-related ripening in Malus * domestica (apples) at both the hormone and transcriptome levels. METHODOLOGY: Transgenic apples suppressed for the SEPALLATA1/2 (SEP1/2) class of gene (MADS8/9) that showed severely reduced ripening were compared with untransformed control apples. In each apple type, free indole-3-acetic acid (IAA) concentrations were measured during early ripening. The changes observed in auxin were assessed in light of global changes in gene expression. PRINCIPAL RESULTS: It was found that mature MADS8/9 suppressed apples had a higher concentration of free IAA. This was associated with increased expression of the auxin biosynthetic genes in the indole-3 acetamide pathway. Additionally, in the MADS8/9-suppressed apples, there was less expression of the GH3 auxin-conjugating enzymes. A number of genes involved in the auxin-regulated transcription (AUX/IAA and ARF classes of genes) were also observed to change in expression, suggesting a mechanism for signal transduction at the start of ripening. CONCLUSIONS: The delay in ripening observed in MADS8/9 suppressed apples may be partly due to high auxin concentrations. We propose that, to achieve low auxin associated with fruit maturation, the auxin homeostasis is controlled in a two-pronged manner: (i) by the reduction in biosynthesis and (ii) by an increase in auxin conjugation. This is associated with the change in expression of auxin-signalling genes and the up-regulation of ripening-related genes. PMID- 23346347 TI - Peptide-conjugation induced conformational changes in human IgG1 observed by optimized negative-staining and individual-particle electron tomography. AB - Peptides show much promise as potent and selective drug candidates. Fusing peptides to a scaffold monoclonal antibody produces a conjugated antibody which has the advantages of peptide activity yet also has the pharmacokinetics determined by the scaffold antibody. However, the conjugated antibody often has poor binding affinity to antigens that may be related to unknown structural changes. The study of the conformational change is difficult by conventional techniques because structural fluctuation under equilibrium results in multiple structures co-existing. Here, we employed our two recently developed electron microscopy (EM) techniques: optimized negative-staining (OpNS) EM and individual particle electron tomography (IPET). Two-dimensional (2D) image analyses and three-dimensional (3D) maps have shown that the domains of antibodies present an elongated peptide-conjugated conformational change, suggesting that our EM techniques may be novel tools to monitor the structural conformation changes in heterogeneous and dynamic macromolecules, such as drug delivery vehicles after pharmacological synthesis and development. PMID- 23346348 TI - hDbr1 is a nucleocytoplasmic shuttling protein with a protein phosphatase-like motif essential for debranching activity. AB - In higher eukaryotes most genes contain multiple introns. Introns are excised from pre-mRNAs by splicing and eventually degraded in the nucleus. It is likely that rapid intron turnover in the nucleus is important in higher eukaryotes, but this pathway is poorly understood. In order to gain insights into this pathway, we analyzed the human lariat RNA debranching enzyme1 (hDbr1) protein that catalyzes debranching of lariat-intron RNAs. Transfection experiments demonstrate that hDbr1 is localized in a nucleoplasm of HeLa cells through a bipartite type nuclear localization signal near carboxyl-terminus. The conserved GNHE motif, originally identified in protein phosphatase protein family, is critical for hDbr1 to dissolve lariat structure in vitro. Furthermore, heterokaryon experiments show that hDbr1 is a nucleocytoplasmic shuttling protein, suggesting novel role(s) of hDbr1 in the cytoplasm. PMID- 23346349 TI - Sedimentation of macroscopic rigid knots and its relation to gel electrophoretic mobility of DNA knots. AB - We address the general question of the extent to which the hydrodynamic behaviour of microscopic freely fluctuating objects can be reproduced by macrosopic rigid objects. In particular, we compare the sedimentation speeds of knotted DNA molecules undergoing gel electrophoresis to the sedimentation speeds of rigid stereolithographic models of ideal knots in both water and silicon oil. We find that the sedimentation speeds grow roughly linearly with the average crossing number of the ideal knot configurations, and that the correlation is stronger within classes of knots. This is consistent with previous observations with DNA knots in gel electrophoresis. PMID- 23346350 TI - Tracking actomyosin at fluorescence check points. AB - Emerging concepts for on-chip biotechnologies aim to replace microfluidic flow by active, molecular-motor driven transport of cytoskeletal filaments, including applications in bio-simulation, biocomputation, diagnostics, and drug screening. Many of these applications require reliable detection, with minimal data acquisition, of filaments at many, local checkpoints in a device consisting of a potentially complex network of channels that guide filament motion. Here we develop such a detection system using actomyosin motility. Detection points consist of pairs of gold lines running perpendicular to nanochannels that guide motion of fluorescent actin filaments. Fluorescence interference contrast (FLIC) is used to locally enhance the signal at the gold lines. A cross-correlation method is used to suppress errors, allowing reliable detection of single or multiple filaments. Optimal device design parameters are discussed. The results open for automatic read-out of filament count and velocity in high-throughput motility assays, helping establish the viability of active, motor-driven on-chip applications. PMID- 23346354 TI - APG: an Active Protein-Gene network model to quantify regulatory signals in complex biological systems. AB - Synergistic interactions among transcription factors (TFs) and their cofactors collectively determine gene expression in complex biological systems. In this work, we develop a novel graphical model, called Active Protein-Gene (APG) network model, to quantify regulatory signals of transcription in complex biomolecular networks through integrating both TF upstream-regulation and downstream-regulation high-throughput data. Firstly, we theoretically and computationally demonstrate the effectiveness of APG by comparing with the traditional strategy based only on TF downstream-regulation information. We then apply this model to study spontaneous type 2 diabetic Goto-Kakizaki (GK) and Wistar control rats. Our biological experiments validate the theoretical results. In particular, SP1 is found to be a hidden TF with changed regulatory activity, and the loss of SP1 activity contributes to the increased glucose production during diabetes development. APG model provides theoretical basis to quantitatively elucidate transcriptional regulation by modelling TF combinatorial interactions and exploiting multilevel high-throughput information. PMID- 23346356 TI - An exhaustive epistatic SNP association analysis on expanded Wellcome Trust data. AB - We present an approach for genome-wide association analysis with improved power on the Wellcome Trust data consisting of seven common phenotypes and shared controls. We achieved improved power by expanding the control set to include other disease cohorts, multiple races, and closely related individuals. Within this setting, we conducted exhaustive univariate and epistatic interaction association analyses. Use of the expanded control set identified more known associations with Crohn's disease and potential new biology, including several plausible epistatic interactions in several diseases. Our work suggests that carefully combining data from large repositories could reveal many new biological insights through increased power. As a community resource, all results have been made available through an interactive web server. PMID- 23346358 TI - Radial arrangement of Janus-like setae permits friction control in spiders. AB - Dynamic attachment is the key to move on steep surfaces, with mechanisms being still not well understood. The hunting spider Cupiennius salei (Arachnida, Ctenidae) possesses hairy attachment pads (claw tufts) at its distal legs, consisting of directional branched setae. The morphological investigation revealed that adhesive setae are arranged in a radial manner within the distal tarsus. Friction of claw tufts on smooth glass was measured to reveal the functional effect of seta arrangement within the pad. Measurements revealed frictional anisotropy in both longitudinal and transversal directions. Contact behaviour of adhesive setae was investigated in a reflection interference contrast microscope (RICM). Observations on living spiders showed, that only a small part of the hairy pads is in contact at the same time. Thus the direction of frictional forces is depending on leg placement and rotation. This may aid controlling the attachment to the substrate. PMID- 23346359 TI - Statistically invalid classification of high throughput gene expression data. AB - Classification analysis based on high throughput data is a common feature in neuroscience and other fields of science, with a rapidly increasing impact on both basic biology and disease-related studies. The outcome of such classifications often serves to delineate novel biochemical mechanisms in health and disease states, identify new targets for therapeutic interference, and develop innovative diagnostic approaches. Given the importance of this type of studies, we screened 111 recently-published high-impact manuscripts involving classification analysis of gene expression, and found that 58 of them (53%) based their conclusions on a statistically invalid method which can lead to bias in a statistical sense (lower true classification accuracy then the reported classification accuracy). In this report we characterize the potential methodological error and its scope, investigate how it is influenced by different experimental parameters, and describe statistically valid methods for avoiding such classification mistakes. PMID- 23346360 TI - Feedback mechanism in depolarization-induced sustained activation of extracellular signal-regulated kinase in the hippocampus. AB - Phosphorylation plays important roles in several processes including synaptic plasticity and memory. The critical role of extracellular signal-regulated kinase (ERK) in these processes is well established. ERK is activated in a sustained manner by different stimuli. However, the mechanisms of sustained ERK activation are not completely understood. Here we show that KCl depolarization-induced sustained ERK activation in the hippocampal slices is critically dependent on protein synthesis and transcription. In addition, the sustained ERK activation requires receptor tyrosine kinase(s) activity. In support of a role for a growth factor in sustained ERK activation, KCl depolarization enhances the level of brain-derived neurotrophic factor (BDNF). Furthermore, BDNF antibody blocks KCl induced sustained ERK activation. These results suggest a positive feed-back loop in which depolarization-induced BDNF maintains ERK activation in the sustained phase. PMID- 23346361 TI - Potential use of folate-appended methyl-beta-cyclodextrin as an anticancer agent. AB - To obtain a tumor cell-selectivity of methyl-beta-cyclodextrin (M-beta-CyD), we newly synthesized folate-appended M-beta-CyD (FA-M-beta-CyD), and evaluated the potential of FA-M-beta-CyD as a novel anticancer agent in vitro and in vivo. Potent antitumor activity and cellular association of FA-M-beta-CyD were higher than those of M-beta-CyD in KB cells, folate receptor (FR)-positive cells. FA-M beta-CyD drastically inhibited the tumor growth after intratumoral or intravenous injection to FR-positive Colon-26 cells-bearing mice. The antitumor activity of FA-M-beta-CyD was comparable and superior to that of doxorubicin after both intratumoral and intravenous administrations, respectively, at the same dose, in the tumor-bearing mice. All of the tumor-bearing mice after an intravenous injection of FA-M-beta-CyD survived for at least more than 140 days. Importantly, an intravenous administration of FA-M-beta-CyD to tumor-bearing mice did not show any significant change in blood chemistry values. These results strongly suggest that FA-M-beta-CyD has the potential as a novel anticancer agent. PMID- 23346363 TI - A cell-based screening system for influenza A viral RNA transcription/replication inhibitors. AB - Although two classes of antivirals, NA inhibitors and M2 ion channel blockers, are licensed for influenza treatment, dual resistant mutants, including highly pathogenic H5N1 viruses, have appeared. Alternative treatment options are, therefore, needed. Influenza A viral RNA (vRNA) transcription/replication is a promising target for antiviral development, since it is essential for virus replication. Accordingly, an efficient and reliable method to identify vRNA transcription/replication inhibitors is desirable. Here, we developed a cell based screening system by establishing a cell line that stably expresses influenza viral ribonucleoprotein complex (vRNP). Compound library screening using this cell line allowed us to identify a compound that inhibits vRNA transcription/replication by using reporter protein expression from virus-like RNA as a readout and virus replication in vitro. vRNP-expressing cells have potential as a simple and convenient high-throughput screening (HTS) system, and, thus, are promising to identify vRNA transcription/replication inhibitors for various RNA viruses, especially for primary screens. PMID- 23346364 TI - Heterologous viral expression systems in fosmid vectors increase the functional analysis potential of metagenomic libraries. AB - The extraordinary potential of metagenomic functional analyses to identify activities of interest present in uncultured microorganisms has been limited by reduced gene expression in surrogate hosts. We have developed vectors and specialized E. coli strains as improved metagenomic DNA heterologous expression systems, taking advantage of viral components that prevent transcription termination at metagenomic terminators. One of the systems uses the phage T7 RNA polymerase to drive metagenomic gene expression, while the other approach uses the lambda phage transcription anti-termination protein N to limit transcription termination. A metagenomic library was constructed and functionally screened to identify genes conferring carbenicillin resistance to E. coli. The use of these enhanced expression systems resulted in a 6-fold increase in the frequency of carbenicillin resistant clones. Subcloning and sequence analysis showed that, besides beta-lactamases, efflux pumps are not only able contribute to carbenicillin resistance but may in fact be sufficient by themselves to convey carbenicillin resistance. PMID- 23346366 TI - Mammalian cell entry genes in Streptomyces may provide clues to the evolution of bacterial virulence. AB - Understanding the evolution of virulence is key to appreciating the role specific loci play in pathogenicity. Streptomyces species are generally non-pathogenic soil saprophytes, yet within their genome we can find homologues of virulence loci. One example of this is the mammalian cell entry (mce) locus, which has been characterised in Mycobacterium tuberculosis. To investigate the role in Streptomyces we deleted the mce locus and studied its impact on cell survival, morphology and interaction with other soil organisms. Disruption of the mce cluster resulted in virulence towards amoebae (Acanthamoeba polyphaga) and reduced colonization of plant (Arabidopsis) models, indicating these genes may play an important role in Streptomyces survival in the environment. Our data suggest that loss of mce in Streptomyces spp. may have profound effects on survival in a competitive soil environment, and provides insight in to the evolution and selection of these genes as virulence factors in related pathogenic organisms. PMID- 23346368 TI - Molecular recognition using receptor-free nanomechanical infrared spectroscopy based on a quantum cascade laser. AB - Speciation of complex mixtures of trace explosives presents a formidable challenge for sensors that rely on chemoselective interfaces due to the unspecific nature of weak intermolecular interactions. Nanomechanical infrared (IR) spectroscopy provides higher selectivity in molecular detection without using chemoselective interfaces by measuring the photothermal effect of adsorbed molecules on a thermally sensitive microcantilever. In addition, unlike conventional IR spectroscopy, the detection sensitivity is drastically enhanced by increasing the IR laser power, since the photothermal signal comes from the absorption of IR photons and nonradiative decay processes. By using a broadly tunable quantum cascade laser for the resonant excitation of molecules, we increased the detection sensitivity by one order of magnitude compared to the use of a conventional IR monochromator. Here, we demonstrate the successful speciation and quantification of picogram levels of ternary mixtures of similar explosives (trinitrotoluene (TNT), cyclotrimethylene trinitramine (RDX), and pentaerythritol tetranitrate (PETN)) using nanomechanical IR spectroscopy. PMID- 23346367 TI - Microbiotas from UC patients display altered metabolism and reduced ability of LAB to colonize mucus. AB - We compared fecal microbial communities derived either from Ulcerative Colitis (UC) patients in remission (n = 4) or in relapse (n = 4), or from healthy subjects (n = 4). These communities were used for inoculation of a dynamic in vitro gut model, which contained integrated mucin-covered microcosms. We found that the microbiota of the 'mucus' largely differed from that of the 'lumen'. This was partly due to decreased mucus-associated populations of lactic acid producing bacterial populations (LAB), as LAB originating from UC patients had a significantly decreased capacity to colonize the mucin-covered microcosms as compared to those originating from healthy subjects. We found significant differences between the metabolomes of UC patients in relapse and remission, respectively, while the metabolome of patients in remission resembled that of healthy subjects. These novel findings constitute an important contribution to the understanding of the complex etiology of UC. PMID- 23346370 TI - 4-D photoacoustic tomography. AB - Photoacoustic tomography (PAT) offers three-dimensional (3D) structural and functional imaging of living biological tissue with label-free, optical absorption contrast. These attributes lend PAT imaging to a wide variety of applications in clinical medicine and preclinical research. Despite advances in live animal imaging with PAT, there is still a need for 3D imaging at centimeter depths in real-time. We report the development of four dimensional (4D) PAT, which integrates time resolutions with 3D spatial resolution, obtained using spherical arrays of ultrasonic detectors. The 4D PAT technique generates motion pictures of imaged tissue, enabling real time tracking of dynamic physiological and pathological processes at hundred micrometer-millisecond resolutions. The 4D PAT technique is used here to image needle-based drug delivery and pharmacokinetics. We also use this technique to monitor 1) fast hemodynamic changes during inter-ictal epileptic seizures and 2) temperature variations during tumor thermal therapy. PMID- 23346371 TI - S100+ cells: a new neuro-immune cross-talkers in lymph organs. AB - Up to now, the 'hardwired' neural pathway of the neuro-immune regulation is not fully understood. Here we reported a new neural pathway which links sympathetic nerves with immune cells of the lymphoid tissues. Our results demonstrated that nerve fibers derived from superior cervical ganglion directly targeted only S100(+) cells in the cervical lymph nodes. Moreover, we found co-expression of neurotransmitters such as norepinephrine, vasoactive intestinal polypeptide and neuropeptide Y in the postganglionic sympathetic nerve endings that innervate S100(+) cells. Our findings suggested that S100(+) cells serve as a neuro-immune cross-talker in lymph organs that may play a significant role in transmitting signals of nervous cells to targeted immune cells. The new findings provide better understanding of the cross-talk mechanism between the nervous system and the immune system. PMID- 23346373 TI - DMD-based LED-illumination super-resolution and optical sectioning microscopy. AB - Super-resolution three-dimensional (3D) optical microscopy has incomparable advantages over other high-resolution microscopic technologies, such as electron microscopy and atomic force microscopy, in the study of biological molecules, pathways and events in live cells and tissues. We present a novel approach of structured illumination microscopy (SIM) by using a digital micromirror device (DMD) for fringe projection and a low-coherence LED light for illumination. The lateral resolution of 90 nm and the optical sectioning depth of 120 MUm were achieved. The maximum acquisition speed for 3D imaging in the optical sectioning mode was 1.6*10(7) pixels/second, which was mainly limited by the sensitivity and speed of the CCD camera. In contrast to other SIM techniques, the DMD-based LED illumination SIM is cost-effective, ease of multi-wavelength switchable and speckle-noise-free. The 2D super-resolution and 3D optical sectioning modalities can be easily switched and applied to either fluorescent or non-fluorescent specimens. PMID- 23346375 TI - Selection of nanobodies that target human neonatal Fc receptor. AB - FcRn is a key player in several immunological and non-immunological processes, as it mediates maternal-fetal transfer of IgG, regulates the serum persistence of IgG and albumin, and transports both ligands between different cellular compartments. In addition, FcRn enhances antigen presentation. Thus, there is an intense interest in studies of how FcRn binds and transports its cargo within and across several types of cells, and FcRn detection reagents are in high demand. Here we report on phage display-selected Nanobodies that target human FcRn. The Nanobodies were obtained from a variable-domain repertoire library isolated from a llama immunized with recombinant human FcRn. One candidate, Nb218-H4, was shown to bind FcRn with high affinity at both acidic and neutral pH, without competing ligand binding and interfering with FcRn functions, such as transcytosis of IgG. Thus, Nb218-H4 can be used as a detection probe and as a tracker for visualization of FcRn-mediated cellular transport. PMID- 23346377 TI - Recombinant influenza vaccines. AB - This review covers the problems encountered in the construction and production of new recombinant influenza vaccines. New approaches to the development of influenza vaccines are investigated; they include reverse genetics methods, production of virus-like particles, and DNA- and viral vector-based vaccines. Such approaches as the delivery of foreign genes by DNA- and viral vector-based vaccines can preserve the native structure of antigens. Adenoviral vectors are a promising gene-delivery platform for a variety of genetic vaccines. Adenoviruses can efficiently penetrate the human organism through mucosal epithelium, thus providing long-term antigen persistence and induction of the innate immune response. This review provides an overview of the practicability of the production of new recombinant influenza cross-protective vaccines on the basis of adenoviral vectors expressing hemagglutinin genes of different influenza strains. PMID- 23346379 TI - Effect of 3D Cultivation Conditions on the Differentiation of Endodermal Cells. AB - Cellular therapy of endodermal organs is one of the most important issues in modern cellular biology and biotechnology. One of the most promising directions in this field is the study of the transdifferentiation abilities of cells within the same germ layer. A method for anin vitroinvestigation of the cell differentiation potential (the cell culture in a three-dimensional matrix) is described in this article. Cell cultures of postnatal salivary gland cells and postnatal liver progenitor cells were obtained; their comparative analysis under 2D and 3D cultivation conditions was carried out. Both cell types have high proliferative abilities and can be cultivated for more than 20 passages. Under 2D cultivation conditions, the cells remain in an undifferentiated state. Under 3D conditions, they undergo differentiation, which was confirmed by a lower cell proliferation and by an increase in the differentiation marker expression. Salivary gland cells can undergo hepatic and pancreatic differentiation under 3D cultivation conditions. Liver progenitor cells also acquire a pancreatic differentiation capability under conditions of 3D cultivation. Thus, postnatal salivary gland cells exhibit a considerable differentiation potential within the endodermal germ layer and can be used as a promising source of endodermal cells for the cellular therapy of liver pathologies. Cultivation of cells under 3D conditions is a useful model for thein vitroanalysis of the cell differentiation potential. PMID- 23346380 TI - N-terminal fusion tags for effective production of g-protein-coupled receptors in bacterial cell-free systems. AB - G-protein-coupled receptors (GPCR) constitute one of the biggest families of membrane proteins. In spite of the fact that they are highly relevant to pharmacy, they have remained poorly explored. One of the main bottlenecks encountered in structural-functional studies of GPCRs is the difficulty to produce sufficient amounts of the proteins. Cell-free systems based on bacterial extracts fromE. colicells attract much attention as an effective tool for recombinant production of membrane proteins. GPCR production in bacterial cell free expression systems is often inefficient because of the problems associated with the low efficiency of the translation initiation process. This problem could be resolved if GPCRs were expressed in the form of hybrid proteins with N terminal polypeptide fusion tags. In the present work, three new N-terminal fusion tags are proposed for cell-free production of the human beta2-adrenergic receptor, human M1 muscarinic acetylcholine receptor, and human somatostatin receptor type 5. It is demonstrated that the application of an N-terminal fragment (6 a.a.) of bacteriorhodopsin fromExiguobacterium sibiricum(ESR-tag), N terminal fragment (16 a.o.) of RNAse A (S-tag), and Mistic protein fromB. subtilisallows to increase the CF synthesis of the target GPCRs by 5-38 times, resulting in yields of 0.6-3.8 mg from 1 ml of the reaction mixture, which is sufficient for structural-functional studies. PMID- 23346381 TI - Identification of Novel RNA-Protein Contact in Complex of Ribosomal Protein S7 and 3'-Terminal Fragment of 16S rRNA in E. coli. AB - For prokaryotes in vitro, 16S rRNA and 20 ribosomal proteins are capable of hierarchical self- assembly yielding a 30S ribosomal subunit. The self-assembly is initiated by interactions between 16S rRNA and three key ribosomal proteins: S4, S8, and S7. These proteins also have a regulatory function in the translation of their polycistronic operons recognizing a specific region of mRNA. Therefore, studying the RNA-protein interactions within binary complexes is obligatory for understanding ribosome biogenesis. The non-conventional RNA-protein contact within the binary complex of recombinant ribosomal protein S7 and its 16S rRNA binding site (236 nucleotides) was identified. UV-induced RNA-protein cross-links revealed that S7 cross-links to nucleotide U1321 of 16S rRNA. The careful consideration of the published RNA- protein cross-links for protein S7 within the 30S subunit and their correlation with the X-ray data for the 30S subunit have been performed. The RNA - protein cross-link within the binary complex identified in this study is not the same as the previously found cross-links for a subunit both in a solution, and in acrystal. The structure of the binary RNA-protein complex formed at the initial steps of self-assembly of the small subunit appears to be rearranged during the formation of the final structure of the subunit. PMID- 23346378 TI - Epigenetics of pluripotent cells. AB - Pluripotency is maintained by a complex system that includes the genetic and epigenetic levels. Recent studies have shown that the genetic level (transcription factors, signal pathways, and microRNAs) closely interacts with the enzymes and other specific proteins that participate in the formation of the chromatin structure. The interaction between the two systems results in the unique chromatin state observed in pluripotent cells. In this review, the epigenetic features of embryonic stem cells and induced pluripotent stem cells are considered. Special attention is paid to the interplay of the transcription factors OCT4, SOX2, and NANOG with the Polycomb group proteins and other molecules involved in the regulation of the chromatin structure. The participation of the transcription factors of the pluripotency system in the inactivation of the X chromosome is discussed. In addition, the epigenetic events taking place during reprogramming of somatic cells to the pluripotent state and the problem of "epigenetic memory" are considered. PMID- 23346382 TI - Carbocyclic analogues of inosine-5'-monophosphate: synthesis and biological activity. AB - 9-(4'-Phosphonomethoxy-2'-cyclopenten-1'-yl)hypoxanthine and 9-(4' phosphonomethoxy-2',3'-dihydroxycyclopenten-1'-yl)hypoxanthine were synthesized as isosteric carbocyclic analogues of inosine-5'-monophosphate. The synthesized compounds were shown to be capable of inhibiting the activity of human type II inosine-5'-monophosphate dehydrogenase (IMPDH II) (IC(50 )= 500 uM) and to have no significant effects on the growth ofMycobacterium tuberculosis. PMID- 23346383 TI - Gold nanoparticle clusters in quasinematic layers of liquid-crystalline dispersion particles of double-stranded nucleic acids. AB - The interaction between gold nanoparticles and particles of cholesteric liquid crystalline dispersions formed by double-stranded DNA and poly(I)*poly(C) molecules is considered. It is shown that small-sized (~ 2 nm) gold nanoparticles induce two different structural processes. First, they facilitate the reorganization of the spatial cholesteric structure of the particles into a nematic one. This process is accompanied by a fast decrease in the amplitude of an abnormal band in the CD spectrum. Second, they induce cluster formation in a "free space" between neighboring nucleic acid molecules fixed in the structure of the quasinematic layers of liquid-crystalline particles. This process is accompanied by slow development of the surface plasmon resonance band in the visible region of the absorption spectrum. Various factors influencing these processes are outlined. Some assumptions concerning the possible mechanism(s) of fixation of gold nanoparticles between the neighboring double-stranded nucleic acid molecules in quasinematic layers are formulated. PMID- 23346384 TI - Methanogenic Community Dynamics during Anaerobic Utilization of Agricultural Wastes. AB - This work is devoted to the investigation of the methanogenic archaea involved in anaerobic digestion of cattle manure and maize straw on the basis of terminal restriction fragment length polymorphism (T-RFLP) analysis of archaeal 16S rRNA genes. The biological diversity and dynamics of methanogenic communities leading to anaerobic degradation of agricultural organic wastes with biogas production were evaluated in laboratory-scale digesters. T-RFLP analysis, along with the establishment of archaeal 16S rRNA gene clone libraries, showed that the methanogenic consortium consisted mainly of members of the generaMethanosarcinaandMethanoculleus,with a predominance ofMethanosarcinaspp. throughout the experiment. PMID- 23346385 TI - RAS in Pregnancy and Preeclampsia and Eclampsia. AB - Preeclampsia is a common disease of pregnancy characterized by the presence of hypertension and commitment of many organs, including the brain, secondary to generalized endothelial dysfunction. Its etiology is not known precisely, but it involved several factors, highlighting the renin angiotensin system (RAS), which would have an important role in the origin of multisystem involvement. This paper reviews the evidence supporting the involvement of RAS in triggering the disease, in addition to the components of this system that would be involved and how it eventually produces brain engagement. PMID- 23346387 TI - Anti-integrin therapy for multiple sclerosis. AB - Integrins are the foremost family of cell adhesion molecules that regulate immune cell trafficking in health and diseases. Integrin alpha4 mediates organ-specific migration of immune cells to the inflamed brain, thereby playing the critical role in the pathogenesis of multiple sclerosis. Anti-alpha4 integrin therapy aiming to block infiltration of autoreactive lymphocytes to the inflamed brain has been validated in several clinical trials for the treatment of multiple sclerosis. This paper provides readers with an overview of the molecular and structural bases of integrin activation as well as rationale for using anti alpha4 integrin therapy for multiple sclerosis and then chronicles the rise and fall of this treatment strategy using natalizumab, a humanized anti-alpha4 integrin. PMID- 23346386 TI - Theranostic implications of nanotechnology in multiple sclerosis: a future perspective. AB - Multiple Sclerosis is a multifactorial disease with several pathogenic mechanisms and pathways. Successful MS management and medical care requires early accurate diagnosis along with specific treatment protocols based upon multifunctional nanotechnology approach. This paper highlights advances in nanotechnology that have enabled the clinician to target the brain and CNS in patient with multiple sclerosis with nanoparticles having therapeutic and imaging components. The multipartite theranostic (thera(py) + (diag)nostics) approach puts forth strong implications for medical care and cure in MS. The current nanotheranostics utilize tamed drug vehicles and contain cargo, targeting ligands, and imaging labels for delivery to specific tissues, cells, or subcellular components. A brief overview of nonsurgical nanorepair advances as future perspective is also described. Considering the potential inflammatory triggers in MS pathogenesis, a multifunctional nanotechnology approach will be needed for the prognosis. PMID- 23346388 TI - Inflammatory demyelinating central nervous system diseases in childhood: clinical and paraclinical profiles in 133 patients. AB - In a retrospective review of patients with acquired demyelinating disorders of the central nervous system, 133 patients (5.6%) whose diseases started in childhood, were selected from 2369 patients, who had medical records in the Neurology Department of Dokuz Eylul University. Out of 133, 98 had relapsing remitting multiple sclerosis, 21 had secondary progressive multiple sclerosis, 8 had clinically isolated syndrome, 3 had neuromyelitis optica, 2 had Marburg disease, and 1 had radiologically isolated syndrome. In 55 patients (41.3%), disease onset was before age 16. Polysymptomatic presentation (22.6%) was the most common initial feature. The EDSS scores ranged from 0 to 9 with a median of 2.0 (2.22 +/- 1.88) for 126 patients. MRI records of 111 patients were obtained. 97 patients had clinically definite multiple sclerosis. 11 MS patients (11.3%) did not initially present the diagnostic MRI features. All of the remaining multiple sclerosis patients fulfilled Barkhof-Tintore criteria (100%) and 88.7% fulfilled KIDMUS criteria. Cranial MRI of NMO patients was normal. Our findings demonstrate some important clinical and paraclinical features that can help the literature on acquired demyelinating disorders of childhood by utilizing data from Western Turkey. PMID- 23346389 TI - The Female Sex Work Industry in a District of India in the Context of HIV Prevention. AB - HIV prevalence in India remains high among female sex workers. This paper presents the main findings of a qualitative study of the modes of operation of female sex work in Belgaum district, Karnataka, India, incorporating fifty interviews with sex workers. Thirteen sex work settings (distinguished by sex workers' main places of solicitation and sex) are identified. In addition to previously documented brothel, lodge, street, dhaba (highway restaurant), and highway-based sex workers, under-researched or newly emerging sex worker categories are identified, including phone-based sex workers, parlour girls, and agricultural workers. Women working in brothels, lodges, dhabas, and on highways describe factors that put them at high HIV risk. Of these, dhaba and highway based sex workers are poorly covered by existing interventions. The paper examines the HIV-related vulnerability factors specific to each sex work setting. The modes of operation and HIV-vulnerabilities of sex work settings identified in this paper have important implications for the local programme. PMID- 23346390 TI - The Intersection between Sex Work and Reproductive Health in Northern Karnataka, India: Identifying Gaps and Opportunities in the Context of HIV Prevention. AB - Objective. To examine the reproductive health practices of female sex workers (FSWs) in the context of an HIV prevention program in Karnataka, India. Methods. Data obtained from a survey of 1,011 FSWs registered with an HIV prevention program. We examined reproductive health indicators, and performed multivariate logistic regression among primiparous FSWs to assess sex work during pregnancy and antenatal HIV testing. Results. Among primiparous FSWs (N = 251), 92.0% continued sex work during pregnancy, and 55.4% received antenatal HIV testing. A longer duration in sex work (AOR 2.7, 95% CI: 1.0-7.5), rural residence (AOR 3.3, 95% CI: 1.2-8.9), and antenatal HIV testing (AOR 6.3, 95% CI: 2.0-20.1) were associated with continued sex work during pregnancy. Older FSWs (age >25 years, AOR 0.12, 95% CI: 0.05-0.33), who delivered at home (AOR 0.14, 95% CI: 0.09 0.34), were least likely to receive antenatal HIV testing. Antenatal HIV testing was associated with awareness of methods to prevent vertical HIV transmission (AOR 3.9, 95% CI: 1.9-14.1). Conclusions. Antenatal HIV testing remains low in the context of ongoing sex work during pregnancy. Existing HIV prevention programs are well positioned to immediately integrate reproductive health care with HIV interventions targeted to FSWs. PMID- 23346391 TI - High Frequency Jet Ventilation during Initial Management, Stabilization, and Transport of Newborn Infants with Congenital Diaphragmatic Hernia: A Case Series. AB - Objective. To review experience of the transport and stabilization of infants with CDH who were treated with high frequency jet ventilation (HFJV). Study Design. Retrospective chart review was performed of infants with antenatal diagnosis of CDH born between 2004 and 2009, at Mount Sinai Hospital Toronto, Ontario, Canada. Detailed information was abstracted from the charts of all infants who received HFJV. Results. Of the 55 infants, 25 were managed with HFJV at some point during resuscitation and stabilization prior to transport. HFJV was the initial ventilation mode in six cases and nineteen infants were placed on HFJV as rescue therapy. Blood gases procured from the umbilical artery before and/or after the initiation of HFJV. There was a significant difference detected for both PaCO(2) (P = 0.0002) and pH (P < 0.0001). The pre- and posttransport vital signs remained stable and no transport related deaths or significant complications occurred. Conclusion. HFJV appears to be safe and effective providing high frequency rescue therapy for infants with CDH failing conventional mechanical ventilation. This paper supports the decision to utilize HFJV as it likely contributed to safe transport of many infants that would not otherwise have tolerated transport to a surgical centre. PMID- 23346392 TI - Epileptic encephalopathy. PMID- 23346393 TI - Comparing Deaths from Influenza H1N1 and Seasonal Influenza A: Main Sociodemographic and Clinical Differences between the Most Prevalent 2009 Viruses. AB - Background. During the 2009 spring epidemic outbreak in Mexico, an important research and policy question faced was related to the differences in clinical profile and population characteristics of those affected by the new H1N1 virus compared with the seasonal virus. Methods and Findings. Data from clinical files from all influenza A deaths in Mexico between April 10 and July 13, 2009 were analyzed to describe differences in clinical and socioeconomic profile between H1N1 and non-H1N1 cases. A total of 324 influenza A mortality cases were studied of which 239 presented rt-PCR confirmation for H1N1 virus and 85 for seasonal influenza A. From the differences of means and multivariate logistic regression, it was found that H1N1 deaths occurred in younger and less educated people, and among those who engage in activities where there is increased contact with other unknown persons (OR 4.52, 95% CI 1.56-13.14). Clinical symptoms were similar except for dyspnea, headache, and chest pain that were less frequently found among H1N1 cases. Conclusions. Findings suggest that age, education, and occupation are factors that may be useful to identify risk for H1N1 among influenza cases, and also that patients with early dyspnea, headache, and chest pain are more likely to be non-H1N1 cases. PMID- 23346394 TI - Skin-sparing mastectomy with immediate breast and nipple reconstruction: a new technique of nipple reconstruction. AB - Background. Most women with breast cancer today can be managed with breast conservation; however, some women still require mastectomy for treatment of their disease. Skin-sparing mastectomy (SSM) with immediate reconstruction has emerged as a favorable option for many of these patients. The authors combined the SSM technique with the preservation of a small part of the areola with immediate nipple together with with breast reconstruction. Methods. In an 8-year-period 155 female patients (age: 20-52 years old; mean age: 37.5 years) with extensive ductal intraepithelial neoplasia (DIN) or invasive breast cancer were treated with areola skin sparing mastectomy with immediate nipple and breast reconstruction. Patients were followed up prospectively by the breast surgeon, the plastic surgeon, and the oncologist for complications and recurrence. Results. After treatment, only 2 cases (1.29%) had a local recurrence. 8 out of 155 (5.5%) patients developed early complications (infections, seroma, haematoma), and 5 out of 155 patients (3.22%) developed delayed complications (implant rotation, aestethic deterioration) in the post operative time period. The final aesthetic outcome was judged as positive in 150 out of 155 patients (96.78%). Conclusion. In our experience, immediate nipple reconstruction after skin-sparing mastectomy is a technically feasible procedure which can give excellent cosmetic results. PMID- 23346395 TI - Signals regulating adhesion dynamics. PMID- 23346396 TI - Patient's Knowledge and Attitude towards Tuberculosis in an Urban Setting. AB - Tuberculosis is a public health problem in Bangladesh. This cross-sectional study was conducted to assess knowledge of TB patients about symptoms, ways of transmission and treatment of tuberculosis, and their perception of the illness. Between March and August 2008, 762 adult TB patients were interviewed at selected DOTS centre of Dhaka city. Male and female distribution was 55.6% and 44.4%, respectively. One quarter of them were illiterate, and more than half had extended family and live in a congested situation. Night fever was the most common symptom known (89.9%), and 56% were aware that it could spread through sneezing/coughing. Television was mentioned as a source of information about TB. The majority expressed a helping attitude towards other TB patients. Although most of them were positive about getting family support, 46.6% mentioned discrimination of separate utensils for food or drink. About 50.5% expressed increased sadness, 39.8% had fear of loss of job/wedges, and 21.4% felt socially neglected. Along with drug treatment the psychosocial reactions of TB patients should be addressed at DOTS centers for better control of the disease. PMID- 23346397 TI - A multivariable index for grading exercise gas exchange severity in patients with pulmonary arterial hypertension and heart failure. AB - Patients with pulmonary arterial hypertension (PAH) and heart failure (HF) display many abnormalities in respiratory gas exchange. These abnormalities are accentuated with exercise and track with disease severity. However, use of gas exchange measures in day-to-day clinical practice is limited by several issues, including the large number of variables available and difficulty in data interpretation. Moreover, maximal exercise testing has limitations in clinical populations due to their complexity, patient anxiety and variability in protocols and cost. Therefore, a multivariable gas exchange index (MVI) that integrates key gas exchange variables obtained during submaximal exercise into a severity score that ranges from normal to severe-very-severe is proposed. To demonstrate the usefulness of this index, we applied this to 2 groups (PAH, n = 42 and HF, n = 47) as well as to age matched healthy controls (n = 25). We demonstrate that this score tracks WHO classification and right ventricular systolic pressure in PAH (r = 0.53 and 0.73, P <= 0.01) and NYHA and cardiac index in HF (r = 0.49 and 0.74, P <= 0.01). This index demonstrates a stronger relationship than any single gas exchange variable alone. In conclusion, MVI obtained from light, submaximal exercise gas exchange is a useful approach to simplify data interpretation in PAH and HF populations. PMID- 23346398 TI - Mammographic breast density patterns in asymptomatic mexican women. AB - Breast density (BD) is a risk factor for breast cancer. Aims. To describe BD patterns in asymptomatic Mexican women and the pathological mammographic findings. Methods and Material. Prospective, descriptive, and comparative study. Women answered a questionnaire and their mammograms were analyzed according to BI RADS. Univariate (chi(2)) and conditional logistic regression analyses were performed. Results. In 300 women studied the BD patterns were fat 56.7% (170), fibroglandular 29% (87), heterogeneously dense 5.7% (17), and dense pattern 8.6% (26). Prevalence of fat pattern was significantly different in women under 50 years (37.6%, 44/117) and older than 50 (68.8%, 126/183). Patterns of high breast density (BD) (dense + heterogeneously dense) were observed in 25.6% (30/117) of women <=50 years and 7.1% (13/183) of women >50. Asymmetry in BD was observed in 22% (66/300). Compression cone ruled out underlying disease in 56 cases. In the remaining 10, biopsy revealed one fibroadenoma, one complex cyst, and 6 invasive and 2 intraductal carcinomas. 2.6% (8/300) of patients had non-palpable carcinomas. Benign lesions were observed in 63.3% (190/300) of cases, vascular calcification in 150 cases (78.9%), and fat necrosis in 38 cases (20%). Conclusions. Mexican women have a low percentage of high-density patterns. PMID- 23346400 TI - Expression of Angiotensin II Receptor-1 in Human Articular Chondrocytes. AB - Background. Besides its involvement in the cardiovascular system, the renin angiotensin-aldosterone (RAS) system has also been suggested to play an important role in inflammation. To explore the role of this system in cartilage damage in arthritis, we investigated the expression of angiotensin II receptors in chondrocytes. Methods. Articular cartilage was obtained from patients with osteoarthritis, rheumatoid arthritis, and traumatic fractures who were undergoing arthroplasty. Chondrocytes were isolated and cultured in vitro with or without interleukin (IL-1). The expression of angiotensin II receptor types 1 (AT1R) and 2 (AT2R) mRNA by the chondrocytes was analyzed using reverse transcription polymerase chain reaction (RT-PCR). AT1R expression in cartilage tissue was analyzed using immunohistochemistry. The effect of IL-1 on AT1R/AT2R expression in the chondrocytes was analyzed by quantitative PCR and flow cytometry. Results. Chondrocytes from all patient types expressed AT1R/AT2R mRNA, though considerable variation was found between samples. Immunohistochemical analysis confirmed AT1R expression at the protein level. Stimulation with IL-1 enhanced the expression of AT1R/AT2R mRNA in OA and RA chondrocytes. Conclusions. Human articular chondrocytes, at least partially, express angiotensin II receptors, and IL-1 stimulation induced AT1R/AT2R mRNA expression significantly. PMID- 23346399 TI - Prescribing optimal nutrition and physical activity as "first-line" interventions for best practice management of chronic low-grade inflammation associated with osteoarthritis: evidence synthesis. AB - Low-grade inflammation and oxidative stress underlie chronic osteoarthritis. Although best-practice guidelines for osteoarthritis emphasize self-management including weight control and exercise, the role of lifestyle behavior change to address chronic low-grade inflammation has not been a focus of first-line management. This paper synthesizes the literature that supports the idea in which the Western diet and inactivity are proinflammatory, whereas a plant-based diet and activity are anti-inflammatory, and that low-grade inflammation and oxidative stress underlying osteoarthritis often coexist with lifestyle-related risk factors and conditions. We provide evidence-informed recommendations on how lifestyle behavior change can be integrated into "first-line" osteoarthritis management through teamwork and targeted evidence-based interventions. Healthy living can be exploited to reduce inflammation, oxidative stress, and related pain and disability and improve patients' overall health. This approach aligns with evidence-based best practice and holds the promise of eliminating or reducing chronic low-grade inflammation, attenuating disease progression, reducing weight, maximizing health by minimizing a patient's risk or manifestations of other lifestyle-related conditions hallmarked by chronic low grade inflammation, and reducing the need for medications and surgery. This approach provides an informed cost effective basis for prevention, potential reversal, and management of signs and symptoms of chronic osteoarthritis and has implications for research paradigms in osteoarthritis. PMID- 23346401 TI - Kidney disease in disadvantaged populations. PMID- 23346402 TI - Proteomics sample preparation, preservation, and fractionation. PMID- 23346404 TI - Active Targeting to Osteosarcoma Cells and Apoptotic Cell Death Induction by the Novel Lectin Eucheuma serra Agglutinin Isolated from a Marine Red Alga. AB - Previously, we demonstrated that the novel lectin Eucheuma serra agglutinin from a marine red alga (ESA) induces apoptotic cell death in carcinoma. We now find that ESA induces apoptosis also in the case of sarcoma cells. First, propidium iodide assays with OST cells and LM8 cells showed a decrease in cell viability after addition of ESA. With 50 MUg/ml ESA, the viabilities after 24 hours decreased to 54.7 +/- 11.4% in the case of OST cells and to 41.7 +/- 12.3% for LM8 cells. Second, using fluorescently labeled ESA and flow cytometric and fluorescence microscopic measurements, it could be shown that ESA does not bind to cells that were treated with glycosidases, indicating importance of the carbohydrate chains on the surface of the cells for efficient ESA-cell interactions. Third, Span 80 vesicles with surface-bound ESA as active targeting ligand were shown to display sarcoma cell binding activity, leading to apoptosis and complete OST cell death after 48 hours at 2 MUg/ml ESA. The findings indicate that Span 80 vesicles with surface-bound ESA are a potentially useful drug delivery system not only for the treatment of carcinoma but also for the treatment of osteosarcoma. PMID- 23346403 TI - Use of medicines with unknown fetal risk among parturient women from the 2004 Pelotas Birth Cohort (Brazil). AB - BACKGROUND: To estimate the exposure to medicines with unknown fetal risk during pregnancy and to analyze the maternal characteristics associated with it. METHODS: A questionnaire was administered to 4,189 mothers of children belonging to the 2004 Pelotas (Brazil) birth cohort study about use of any medicine during gestation. We evaluated the associations between use of medicines with unknown fetal risk and the independent variables through logistic regression models. Unknown fetal risk was defined as medicines in which studies in animals have revealed adverse effects on the fetus, and no controlled studies in women, or studies in women and animals, are available. RESULTS: Out of the 4,189 women, 52.5% used at least one medicine from unknown fetal risk. Use of these medicines was associated with white skin color, high schooling, high income, six or more antenatal care consultations, hospital admission during pregnancy, and morbidity during gestation. CONCLUSION: The use of unknown fetal risk medicines is high, suggesting that their use must be addressed with caution with the aim of restricting their use to cases in which the benefits are greater than the potential risks. PMID- 23346405 TI - The role of targeted focal therapy in the management of low-risk prostate cancer: update on current challenges. AB - Prostate cancer is one of the most prevalent cancers among men in the United States, second only to nonmelanomatous skin cancer. Since prostate-specific antigen (PSA) testing came into widespread use in the late 1980s, there has been a sharp increase in annual prostate cancer incidence. Cancer-specific mortality, though, is relatively low. The majority of these cancers will not progress to mortal disease, yet most men who are diagnosed opt for treatment as opposed to observation or active surveillance (AS). These men are thus burdened with the morbidities associated with aggressive treatments, commonly incontinence and erectile dysfunction, without receiving a mortality benefit. It is therefore necessary to both continue investigating outcomes associated with AS and to develop less invasive techniques for those who desire treatment but without the significant potential for quality-of-life side effects seen with aggressive modalities. The goals of this paper are to discuss the problems of overdiagnosis and overtreatment since the advent of PSA screening as well as the potential for targeted focal therapy (TFT) to bridge the gap between AS and definitive therapies. Furthermore, patient selection criteria for TFT, costs, side effects, and brachytherapy template-guided three-dimensional mapping biopsies (3DMB) for tumor localization will also be explored. PMID- 23346406 TI - Effect of Berry Extracts and Bioactive Compounds on Fulvestrant (ICI 182,780) Sensitive and Resistant Cell Lines. AB - Fulvestrant (ICI 182,780; ICI) is approved for the treatment of advanced metastatic breast cancer that is unresponsive to other endocrine therapies. Berries are frequently consumed for their antioxidant, anti-inflammatory, and anticancer potential. In this study, we tested the efficacy of two berry extracts (Jamun-EJAE and red raspberry-RRE) and their bioactive compounds (Delphinidin-Del and Ellagic acid-EA) to inhibit cell proliferation with or without a sublethal dose of ICI in various breast cancer cell lines. ICI-sensitive (LCC1, ZR75-1, and BT474) and -resistant (LCC9, ZR75-1R) cells were subjected to treatment with berry extracts alone (0.1-100 MUg/mL) or with a sub-lethal dose of ICI ( 1). EA, in doses tested, did not have any significant effects on any of the cell lines. Finally, we found that the extracts were more effective at lower, physiologically relevant concentrations than at higher experimental doses. PMID- 23346407 TI - A comparison of cholesterol uptake and storage in inflammatory and noninflammatory breast cancer cells. AB - Although there are many subtypes of breast cancer, inflammatory breast cancer (IBC) is arguably the deadliest. Research over the past decade has demonstrated that IBC is a distinct entity from other forms of breast cancer. Important risk factors that have been associated with the development of aggressive breast cancers, such as IBC, include obesity and diet, which are evident in the United States, where the overconsumption of high-fat foods continues to contribute to obesity in the nation. Here we investigate differences in cholesterol uptake and storage between IBC, non-IBC, and mammary epithelial cell lines. Our results demonstrate that compared with human mammary epithelial cells (HMECs), both IBC and non-IBC cells have increased cholesterol content. IBC cells retain intracellular cholesterol esters, free cholesterol, and triglycerides in lipid deficient environments. In contrast, we observe in cell-type-of-origin-matched non-IBC a significant decrease in lipid content under the same lipid-deficient conditions. These data suggest that cholesterol storage may be affected by the cholesterol content of the environment where the tumor cell was isolated. Here, we suggest that breast cancer cells may migrate when they are unable to obtain cholesterol from their extracellular environments. PMID- 23346408 TI - Preclinical evaluation of oncolytic deltagamma(1)34.5 herpes simplex virus expressing interleukin-12 for therapy of breast cancer brain metastases. AB - The metastasis of breast cancer to the brain and central nervous system (CNS) is a problem of increasing importance. As improving treatments continue to extend patient survival, the incidence of CNS metastases from breast cancer is on the rise. New treatments are needed, as current treatments are limited by deleterious side effects and are generally palliative. We have previously described an oncolytic herpes simplex virus (HSV), designated M002, which lacks both copies of the gamma(1)34.5 neurovirulence gene and carries a murine interleukin 12 (IL-12) expression cassette, and have validated its antitumor efficacy in a variety of preclinical models of primary brain tumors. However, M002 has not been yet evaluated for use against metastatic brain tumors. Here, we demonstrate the following: both human breast cancer and murine mammary carcinoma cells support viral replication and IL-12 expression from M002; M002 replicates in and destroys breast cancer cells from a variety of histological subtypes, including "triple negative" and HER2 overexpressing; M002 improves survival in an immunocompetent model more effectively than does a non-cytokine control virus. Thus, we conclude from this proof-of-principle study that a gamma(1)34.5-deleted IL-12 expressing oncolytic HSV may be a potential new therapy for breast cancer brain metastases. PMID- 23346409 TI - The Relationship between Life Stress and Breastfeeding Outcomes among Low-Income Mothers. AB - Stressful life events during pregnancy negatively affect maternal and infant outcomes including breastfeeding initiation. Their impact on breastfeeding duration is uncertain. Given breastfeeding's important health benefits we analyzed stressful life event types and cessation of any and exclusive breastfeeding by 4 and 13 weeks. Methods. We collected self-administered survey data at 5-7 months postpartum from over 700 primarily urban low-income US mothers. Data covered prepregnancy, prenatal, and postpartum periods including 14 stressful life events (categorized into financial, emotional, partner-associated, traumatic). Analyses included only mothers initiating breastfeeding (n = 341). Logistic regressions controlled for maternal characteristics including a breastfeeding plan. Results. All four stress categories were associated with shorter duration of any and exclusive breastfeeding. In the adjusted models, statistically significant relationships remained for financial stress (4 weeks cessation of any breastfeeding duration) and traumatic stress (13 weeks exclusive breastfeeding cessation). Controlling for stress, a longer breastfeeding plan was significantly associated with a shorter breastfeeding duration (all models) as was depression during pregnancy and current smoking (several models). Conclusions. Among low-income women, impact of stressful life events on cessation of breastfeeding may differ by stress type and interfere with achievement of breastfeeding goal. Among these stressed mothers, breastfeeding may serve as a coping mechanism. PMID- 23346410 TI - An Overview of HIV Prevention Interventions for People Who Inject Drugs in Tanzania. AB - In the past decade, Tanzania has seen a rapid rise in the number of people who inject drugs (PWID), specifically heroin. While the overall HIV prevalence in Tanzania has declined recently to 5.6%, in 2009, the HIV prevalence among PWID remains alarmingly high at 35%. In this paper, we describe how the Tanzania AIDS Prevention Program (TAPP), Medecins du Monde France (MdM-F), and other organisations have been at the forefront of addressing this public health issue in Africa, implementing a wide array of harm reduction interventions including medication-assisted treatment (MAT), needle and syringe programs (NSP), and "sober houses" for residential treatment in the capital, Dar es Salaam, and in Zanzibar. Looking toward the future, we discuss the need to (1) extend existing services and programs to reach more PWID and others at risk for HIV, (2) develop additional programs to strengthen existing programs, and (3) expand activities to include structural interventions to address vulnerabilities that increase HIV risk for all Tanzanians. PMID- 23346411 TI - Long-term outcome after resection rectopexy for internal rectal intussusception. AB - Background and Aims. The optimal treatment of patients with internal rectal intussusception (IRI) is unresolved. The aim was to study the short- and long term outcome of resection rectopexy in these patients. Methods. An observational and mainly prospective study of 48 patients (44 women) with IRI who had ligament preserving suture rectopexy by laparoscopic (n = 25) or open (n = 23) technique. Outcome measures were morbidity, scores for constipation and anal incontinence, patients' report, and health-related quality of life (HRQoL). Results. From preoperatively to a median of 6 months and 76 months postoperatively, constipation scores were reduced from a mean of (95% CI) 13.20 (11.41 to 15.00) to 6.91 (5.29 to 8.54) and 6.35 (4.94 to 7.76) (P < 0.0001). The number of constipated patients was reduced from 35 to eleven and eight, respectively, and none became constipated. Nine of ten symptoms of constipation improved. Corresponding scores for anal incontinence were 4.7 (2.4-7.0), 4.0 (2.4-5.7), and 4.1 (2.3-5.8), respectively. HRQoL at long-term followup compared to the general Norwegian population was reduced in four out of eight dimensions concerning physical factors. The patient-reported outcome at short- and long-term followup was improved by 85.4% and 75.0%, respectively. Conclusions. Resection rectopexy for IRI improved the outcome. HRQoL was reduced compared with the general population. PMID- 23346412 TI - Biochip technology for the serological diagnosis of bullous pemphigoid. AB - Bullous pemphigoid is an autoimmune blistering skin disease characterized by the presence of circulating autoantibodies which recognize specific proteins of the epidermis and dermoepidermal junction. Diagnosis is based on clinical criteria and laboratory investigations, notably histology, direct and indirect immunofluorescence, and ELISA. This study describes a new immunofluorescence assay for parallel determination of anti-BP180 and anti-BP230 based on recombinant antigenic substrates. The aim of the study was to detect BP180 and BP230 autoantibodies by BIOCHIP technology using both a specially designed recombinant BP180-NC16A protein and cells expressing the BP230-gc antigen fragment. 18 patients with bullous pemphigoid were included in the study. Autoantibodies to BP180 were detected by the BIOCHIP technique in 83.33% of patients with clinical, serological, and immunohistological confirmed bullous pemphigoid while autoantibodies against BP230-gC were detected only in 39% of patients. The detection of anti-BP180-NC16A and anti-BP230-gC by a new biochip based immunoassay is a suitable alternative to indirect immunofluorescence and ELISA. This method has the advantage of easily discriminating the different autoantibody specificities. The BIOCHIP method is faster, cheaper, and easy to use when compared with the ELISA approach. For this reason, the new method could be used as an initial screening test to identify patients with bullous pemphigoid, and doubtful results could then be confirmed by ELISA. PMID- 23346413 TI - Long-term health-related quality of life of surgically treated pituitary adenoma patients: a descriptive study. AB - Context. The literature concerning the health-related quality of life (HRQoL) of patients with surgically treated PA is controversial. Objective. To describe the long-term HRQoL of surgically treated patients in all PA classes. Design and subjects. The 15D, a generic HRQoL instrument producing a 15-dimensional profile and a single 15D index score (a difference >=0.03 on a 0-1 scale is considered clinically important), was used to assess the HRQoL of a 13-year surgical cohort of PA patients in Northern Finland. Results and Conclusion. Nighty-eight eligible consecutive patients with surgically treated PA were studied at an average of 6.3 years after their latest pituitary operation. The average postoperative 15D profiles in patients with non-functioning PA and in acromegalics without GH suppressive medical treatment were similar to those of the age-standardized general population. However, after this rather long followup, the mean 15D score and the number of statistically significant 15D dimension impairments, compared with those of their reference population, were 0.11 and 9/15, 0.10 and 3/15, and 0.08 and 7/15 for Cushing's disease, acromegalics needing somatostatin analog, and prolactinoma patients, respectively. Hypopituitarism with replacement medication was not associated with impaired HRQoL. The somatostatin-analog associated HRQoL finding warrants further clinical research. PMID- 23346414 TI - Pathobiology of obstructive sleep apnea-related dyslipidemia: focus on the liver. AB - Obstructive sleep apnea and dyslipidemia are common medical disorders that independently increase vascular morbidity and mortality. Current animal and human data show that, indeed, obstructive sleep apnea may mediate pathological alterations in cholesterol and triglyceride metabolism. The mechanisms involved are increased lipolysis, decreased lipoprotein clearance, and enhanced lipid output from the liver. Human evidence shows that the treatment of obstructive sleep apnea with continuous positive airway pressure leads to an improvement of postprandial hyperlipidemia. However, more studies are needed, to clarify the pathophysiology of the interrelationship between obstructive sleep apnea and dyslipidemia and whether treatment of obstructive sleep apnea will lead to an improvement in the lipid profile and, more importantly, reduce hyperlipidemia related vascular outcomes. PMID- 23346415 TI - A multisource approach to improving epidemiologic estimates: application to global B-cell malignancies. AB - The compilation of comprehensive, worldwide epidemiologic data can inform hypotheses on cancer etiology and guide future drug development. These statistics are reported by a multitude of sources using varying methods; thus, compiling a complete database of these statistics is a challenge. To this end, this paper examined the usefulness of a novel, multisource approach-extracting data from the peer-reviewed literature, online reports, and query systems from cancer registries and health agencies and directly contacting cancer registry personnel for building a comprehensive, multinational epidemiologic cancer database. The major B-cell malignancies were chosen as the cancer subtype to test this approach largely because their epidemiology has not been well characterized in the peer reviewed literature. We found that a multisource approach yields a more comprehensive epidemiologic database than what would have been possible with the use of literature searches alone. In addition, our paper revealed that cancer registries vary considerably in their methodology, comprehensiveness, and ability to gather information on specific B-cell malignancy subtypes. Collectively, this paper demonstrates the feasibility and value of a multisource approach to gathering epidemiologic data. PMID- 23346416 TI - External Beam Therapy in a Four-Field Box Technique with Paclitaxel versus a Two Field Technique with Cisplatin in Locally Advanced Carcinoma Cervix: A Phase II Monocentric Trial. AB - Introduction. External beam pelvic radiotherapy with cisplatin and brachytherapy is the standard of care for patients with advanced cervical malignancy. This study was aimed at evaluating the toxicity of a two-field radiotherapy with cisplatin and brachytherapy compared to a four-field box technique with paclitaxel and brachytherapy for stages IIB/IIIB cervical cancer. The differences in response to the overall treatment were also examined. Methods. 35 patients were enrolled in this phase II prospective randomized trial conducted from February 2006 to February 2007. In arm I, up to 40 Gy in 20 fractions followed by 10 Gy in 5 fractions in split field with cisplatin 40 mg/M(2) and, in arm II, 50 Gy in 25 fractions with paclitaxel 50 mg/M(2) were given. Results. Toxicity in genitourinary, lower gastrointestinal, and hematological tissues was significantly higher in arm I. The duration of concurrent chemoradiotherapy in either arm was similar. The overall treatment time was less in arm II. No statistically significant difference in the objective response was observed between arms. Conclusion. Two-field radiotherapy with cisplatin is a tolerable regime but more toxic than four-field box radiotherapy with paclitaxel. The major setbacks are that a radiotherapy technique as well as chemotherapy is different; hence, toxicity and outcome of treatment should be viewed as a collective response of the whole treatment regimen and the small sample size. PMID- 23346417 TI - The biology of ewing sarcoma. AB - Objective. The goal of this study was to review the current literature on the biology of Ewing's sarcoma, including current treatments and the means by which an understanding of biological mechanisms could impact future treatments. Methods. A search of PubMed and The Cochrane Collaboration was performed. Both preclinical and clinical evidence was considered, but specific case reports were not. Primary research articles and reviews were analyzed with an emphasis on recent publications. Results. Ewing sarcoma is associated with specific chromosomal translocations and the resulting transcripts/proteins. Knowledge of the biology of Ewing sarcoma has been growing but has yet to significantly impact or produce new treatments. Localized cases have seen improvements in survival rates, but the same cannot be said of metastatic and recurrent cases. Standard surgical, radiation, and chemotherapy treatments are reaching their efficacy limits. Conclusion. Improving prognosis likely lies in advancing biomarkers and early diagnosis, determining a cell(s) of origin, and developing effective molecular therapeutics and antiangiogenic agents. Preclinical evidence suggests the utility of molecular therapies for Ewing sarcoma. Early clinical results also reveal potential for novel treatments but require further development and evaluation before widespread use can be advocated. PMID- 23346420 TI - Oculomotor Nerve Palsy due to an Odontogenic Abscess Originating from the Mandibular Third Molar. AB - We report a case of oculomotor nerve palsy (ONP) as a result of odontogenic infection originating from the third molar, which is considered rare. PMID- 23346421 TI - Heterotopic ossification: an unusual presentation. AB - Heterotopic ossification (HO) is usually seen after-trauma, following traumatic injuries, surgeries involving major joints, neurogenic injury, and burns; however, atraumatic cases have also been reported. HO tends to cause pain, swelling, and limitation of joint movements. HO has been reported in adults as well as in pediatric cases, however, our search in the English literature has not revealed a single case in the infratemporal region, especially in children of developing age, where HO tends to affect the development and growth of adjacent bones. We are reporting a case of HO in close proximity to TMJ affecting the development of mandible and maxilla. PMID- 23346419 TI - Functional role of adult hippocampal neurogenesis as a therapeutic strategy for mental disorders. AB - Adult neurogenesis, the process of generating new neurons from neural stem cells, plays significant roles in synaptic plasticity, memory, and mood regulation. In the mammalian brain, it continues to occur well into adulthood in discrete regions, namely, the hippocampus and olfactory bulb. During the past decade, significant progress has been made in understanding the mechanisms regulating adult hippocampal neurogenesis and its role in the etiology of mental disorders. In addition, adult hippocampal neurogenesis is highly correlated with the remission of the antidepressant effect. In this paper, we discuss three major psychiatric disorders, depression, schizophrenia, and drug addiction, in light of preclinical evidence used in establishing the neurobiological significance of adult neurogenesis. We interpret the significance of these results and pose questions that remain unanswered. Potential treatments which include electroconvulsive therapy, deep brain stimulation, chemical antidepressants, and exercise therapy are discussed. While consensus lacks on specific mechanisms, we highlight evidence which indicates that these treatments may function via an increase in neural progenitor proliferation and changes to the hippocampal circuitry. Establishing a significant role of adult neurogenesis in the pathogenicity of psychiatric disorders may hold the key to potential strategies toward effective treatment. PMID- 23346422 TI - Autotransplantation of mandibular third molar: a case report. AB - Autogenous transplantation is a feasible, fast, and economical option for the treatment of nonsalvageable teeth when a suitable donor tooth is available. This paper presents successful autotransplantation of a mature mandibular left third molar (38) without anatomical variances is used to replace a mandibular left second molar (37). The mandibular second molar was nonrestorable due to extensive root caries and resorption of distal root. After extraction of mandibular second and third molars, root canal therapy was done for the third molar extraorally, and the tooth was reimplanted into the extracted socket of second molar site. After one year, clinical and radiographic examination revealed satisfactory outcome with no signs or symptoms suggestive of pathology. In selected cases, autogenous tooth transplantation, even after complete root formation of the donor tooth, may be considered as a practical treatment alternative to conventional prosthetic rehabilitation or implant treatment. PMID- 23346424 TI - Triple teeth: report of an unusual case. AB - Fusion or synodontia is a union of two or more than two developing teeth. Commonly fusion occurs between teeth of the same dentition, mixed dentition, or between normal and supernumerary teeth. Fused primary teeth present with several clinical problems like caries, periodontal problem, arch asymmetry, delayed eruption, ectopic eruption of succedaneous teeth, aesthetic, and other complications. This paper presents a rare and unusual case of triple teeth in mandibular primary dentition. PMID- 23346423 TI - Fused double supernumerary premolars of the mandible: a rare case. AB - The incidence of nonsyndromic supernumerary premolars is rare. Supernumerary premolars are likely to undergo pathological changes. The most commonly encountered complications with these teeth are dentigerous cyst and root resorption of the adjacent tooth. This paper is about impacted double fused supernumerary premolars in the right mandiblular body associated with an impacted first premolar in a 17-year-old male. Under local anesthesia, the supernumerary premolars and the impacted permanent first premolar were surgically removed. Early diagnosis followed by an appropriate treatment at the right time will result in favorable prognosis in such cases. PMID- 23346425 TI - An unusual erupted complex composite odontoma: a rare case. AB - Odontomas are malformations of the dental tissues and may interfere with the eruption of the associated tooth. Complex composite odontoma (CO) was described as a distinct entity for the first time by Broca in 1866. This lesion takes place due to the developmental disturbances where the dental components are laid down in a disorganized manner, due to failure of normal morphodifferentiation. Very few cases of erupted complex composite odontomas have been reported in the literature. The case reported here is of an odontoma found in the left mandibular body, associated with an impacted second molar of a 17-year-old Saudi male. Under local anesthesia the odontoma was surgically removed. Histopathological examination confirmed the diagnosis of CO. The impacted second molar which was left in the mandibular body erupted clinically after 6 months. Erupted CO is rarely seen in the mandibular left body. The early diagnosis, followed by a proper treatment at the right time, will result in a favorable prognosis. PMID- 23346426 TI - Tumor-induced osteomalacia caused by primary fibroblast growth factor 23 secreting neoplasm in axial skeleton: a case report. AB - We report the case of a 66-year-old woman with tumor-induced osteomalacia (TIO) caused by fibroblast growth factor 23 (FGF-23) secreting mesenchymal tumor localized in a lumbar vertebra and review other cases localized to the axial skeleton. She presented with nontraumatic low back pain and spontaneous bilateral femur fractures. Laboratory testing was remarkable for low serum phosphorus, phosphaturia, and significantly elevated serum FGF-23 level. Magnetic resonance imaging (MRI) of the lumbar spine showed a focal lesion in the L-4 vertebra which was hypermetabolic on positron emission tomography (PET) scan. A computed tomography (CT) guided needle biopsy showed a low grade spindle cell neoplasm with positive FGF-23 mRNA expression by reverse transcriptase polymerase chain reaction (RT-PCR), confirming the diagnosis of a phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT). The patient elected to have surgery involving anterior resection of L-4 vertebra with subsequent normalization of serum phosphorus. Including the present case, we identified 12 cases of neoplasms localized to spine causing TIO. To our knowledge, this paper represents the first documented case of lumbar vertebra PMT causing TIO. TIO is a rare metabolic bone disorder that carries a favorable prognosis. When a lesion is identifiable, surgical intervention is typically curative. PMID- 23346427 TI - Eosinophilic gastrointestinal disorder in coeliac disease: a case report and review. AB - Eosinophilic gastrointestinal disorder is a rare disorder characterised by eosinophilic infiltration of the gastrointestinal tract. There are various gastrointestinal manifestations with eosinophilic ascites being the most unusual and rare presentation. Diagnosis requires high index of suspicion and exclusion of various disorders associated with peripheral eosinophilia. There are no previous case reports to suggest an association between eosinophilic gastrointestinal disorder and coeliac disease in adults. We report a case of eosinophilic ascites and gastroenteritis in a 30-year-old woman with a known history of coeliac disease who responded dramatically to a course of steroids. PMID- 23346428 TI - Pancolitis with ischemic injury as a complication of immunosuppressive treatment in a patient with autoimmune hepatitis: a case report. AB - Ischemic colitis is a serious drug-induced adverse event. There are only few cases of immunosuppression-associated ischemic colitis described in the literature, but none with a pancolitis-like manifestation. We report the case of a 72-year-old female patient who developed a pancolitis with ischemic injury on immunosuppressive treatment with steroids and azathioprine for autoimmune hepatitis. The patient presented with massive rectal bleeding. Colonoscopy confirmed the diagnosis of pancolitis. The results of histological examination indicated drug-induced ischemic colitis involving the entire colon. This is the first case of ischemic pancolitis mimicking an inflammatory bowel disease (IBD) in a patient with immunosuppressive therapy. PMID- 23346429 TI - Sickle retinopathy in a person with hemoglobin s/new york disease. AB - A patient who presented with sickle retinopathy and hemoglobin electrophoresis results compatible with sickle cell trait was found, on further investigation, to be a compound heterozygote with hemoglobin S and hemoglobin New York disease. This recently reported form of sickle cell disease was not previously known to cause retinopathy and surprisingly was observed in a non-Asian individual. The ophthalmological findings, the laboratory diagnosis, and possible pathophysiology of this disorder are discussed. Persons diagnosed with sickle cell trait who present with symptoms of sickle cell disease may benefit from specific screening for this variant. PMID- 23346430 TI - Deep Vein Thrombosis, Raynaud's Phenomenon, and Prinzmetal Angina in a Patient with Glanzmann Thrombasthenia. AB - Patients with Glanzmann thrombasthenia fail to form large platelet thrombi due to mutations that affect the biosynthesis and/or function of the alphaIIbbeta3 integrin. The result is a moderate to severe bleeding syndrome. We now report unusual vascular behaviour in a 55-year-old woman with classic type I disease (with no platelet alphaIIbbeta3 expression) and a homozygous ITGA2B missense mutation (E324K) affecting the terminal beta-propeller domain of alphaIIb. While exhibiting classic bleeding symptoms as a child, in later life this woman first developed deep vein thrombosis after a long air flight then showed vascular problems characteristic of Raynaud's phenomenon, and finally this year she presented with chest pains suggestive of coronary heart disease. Yet while coronary angiography first showed a stenosis, this was not seen on a second examination when she was diagnosed with coronary spastic angina and Prinzmetal phenomenon. It is significant that the absence of platelet aggregation with physiologic agonists had not prevented any of the above cardiovascular or vascular diseases. PMID- 23346432 TI - Disseminated Infection Caused by Eggerthella lenta in a Previously Healthy Young Man: A Case Report. AB - Anaerobic bacteria are the predominant normal flora of the mucous membranes which may cause life-threatening disseminated infections and are often difficult to culture from infected sites. Eggerthella (previously known as Eubacteria species) is an anaerobic, nonsporulating, nonmotile, Gram-positive rod that is found in the human colon and feces and has been isolated from various other clinical specimens. We report a case of complicated disseminated anaerobic bacterial infection with Eggerthella lenta in a healthy immunocompetent man causing multiple brain abscesses, liver abscesses, necrotizing pneumonia, and osteomyelitis of the left radial bone. He was successfully treated with empiric penicillin G and metronidazole. PMID- 23346431 TI - t(17;19) in Children with Acute Lymphocytic Leukemia: A Report of 3 Cases and a Review of the Literature. AB - Several cytogenetic abnormalities identified in patients with childhood acute lymphocytic leukemia (ALL) have been associated with a poor prognosis. There are several case reports in the literature describing t(17;19) in children with ALL. This translocation has been associated with hypercalcemia, coagulopathy, and poor outcome. We present three cases of ALL with t(17;19) treated at our institution and review the outcome of children reported in the medical literature. PMID- 23346433 TI - Perianal tuberculosis: a case report and a review of the literature. AB - Extra pulmonary tuberculosis accounts for less than 15% of all cases of tuberculosis whereas the Intestinal one constitutes less than 1% of the extrapulmonary forms of the disease. The lesions of abdominal organs are more common while they rarely occur in the anoperineal area for the spread of the disease to the anus is extremely rare. We report a case of a 37-year-old male patient with large bilateral infected perianal tubercular ulcerations as well as pulmonary and peritoneal tuberculosis. The treatment was both surgical and medical and the therapy lasted for seven months. After six months from the beginning of the treatment, the lesion had totally disappeared and there is still no recurrence after one year of followup. Tuberculosis should generally be taken into consideration in the differential diagnosis of the ulcerative lesions of the anal and perianal regions for these lesions do occur in the said areas despite their rarity. The treatment is usually both surgical and medical so as to get excellent results. PMID- 23346434 TI - Extrapontine myelinolysis-induced parkinsonism in a patient with adrenal crisis. AB - Background. Extrapontine myelinolysis (EPM) has been well described in the presence of rapid correction of hyponatremia. It is seldom reported with adrenal insufficiency. We report a unique case where a patient developed EPM as a result of adrenal insufficiency where the brain MRI revealed symmetrical lesion in the basal ganglia with pallidal sparing. Case Report. A 30-year-old gentleman with panhypopituitarism developed adrenal crisis, hyponatremia, and hyponatremic encephalopathy. Seven days after the rapid correction of hyponatremia, he developed parkinsonism and neuropsychiatric symptoms. MRI showed extrapontine myelinolysis without central pontine myelinolysis. Conclusion. Extrapontine myelinolysis without central pontine myelinolysis is rare and should raise a concern of associated adrenal insufficiency in the right clinical setting. Rapid correction of hyponatremia particularly in steroid-deficient states should be avoided as it can predispose to extrapontine myelinolysis. Magnetic resonance imaging is very helpful in supporting the diagnosis of EPM. PMID- 23346418 TI - Skull base inverted papilloma: a comprehensive review. AB - Skull base inverted papilloma (IP) is an unusual entity for many neurosurgeons. IP is renowned for its high rate of recurrence, its ability to cause local destruction, and its association with malignancy. This paper is a comprehensive review of the reports, studies, and reviews published in the current biomedical literature from 1947 to September 2010 and synthesize this information to focus on its potential invasion to the base of the skull and possible intradural extension. The objective is to familiarize the clinician with the different aspects of this unusual disease. The role of modern diagnostic tools in medical imaging in order to assess clearly the limits of the tumors and to enhance the efficiency and the safety in the choice of a surgical approach is pointed out. The treatment guidelines for IP have undergone a complex evolution that continues today. Radical excision of the tumour is technically difficult and often incomplete. Successful management of IP requires resection of the affected mucosa which could be achieved with open surgery, endoscopic, or combined approach. Radio and chemotherapy were used for certain indications. More optimally research would be a multicenter randomized trials with large size cohorts. PMID- 23346435 TI - Spontaneous rupture of an adrenal artery in pregnancy: a case report. AB - A spontaneous rupture of an adrenal artery is a rare cause of abdominal pain in pregnancy. We present a case of a pregnant woman who needed to be operated on because of a rupture of the right adrenal artery associated with a fetal bradycardia. An immediate caesarean section was performed. The intra-abdominal palpation identified an extensive retroperitoneal mass near the right kidney and a postoperative computer tomography confirmed an active bleeding near the kidney. For this reason our interventional radiology team, using a right femoral artery approach, performed a flush aortogram and identified the source of bleeding in the right adrenal artery. After two attempts, a coiling of the artery stopped the haemorrhage. The pathogenesis of arterial haemorrhage is still poorly understood although a possible cause could be the excess of hormones during pregnancy, which can lead to a significant arterial wall degeneration. In case of a retroperitoneal bleeding and if the patient is still haemodynamically stable, a transcatheter embolization using microcoils must be considered. This technique is nowadays safe and effective and can be performed within a short time with a lower risk of complications. PMID- 23346436 TI - Abdominal Wall Desmoid during Pregnancy: Diagnostic Challenges. AB - Background. Desmoids are benign tumors, with local invasive features and no metastatic potential, which have rarely been described to be pregnancy associated. Case. We described the rapid growth of an anterior abdominal wall mass in a 40-year-old pregnant woman. Due to its close proximity to the enlarged uterus, it was misdiagnosed to be a uterine leiomyoma by ultrasound examination. Final tissue diagnosis and radical resection were done at the time of abdominal delivery. Conclusion. Due to the diagnostic limitations of imaging techniques, desmoids should always be considered when the following manifestations are observed in combination: progressive growth of a solitary abdominal wall mass during pregnancy and well-delineated smooth tumor margins demonstrated by imaging techniques. This case emphasizes the importance of entertaining uncommon medical conditions in the differential diagnosis of seemingly common clinical manifestations. PMID- 23346437 TI - Hypertrophic Cardiomyopathy due to Mitochondrial Disease: Prenatal Diagnosis, Management, and Outcome. AB - A case of prenatally diagnosed fetal hypertrophic cardiomyopathy is reported. The mother was referred to our department at 37 weeks' gestation because of suspected congenital heart disease. Prenatal echocardiography showed biventricular hypertrophy and pericardial effusion, without additional abnormalities. Postnatal echocardiography confirmed prenatal diagnosis. Neonatal EKG showed biventricular hypertrophy and Wolff-Parkinson-White syndrome. Skeletal muscle biopsy was consistent with mitochondrial oxidative phosphorylation defect involving a combined defect of respiratory complexes I and IV. Echocardiographic followup during the first year of life showed progressive regression of hypertrophy and evolution to left ventricular myocardial noncompaction. PMID- 23346438 TI - Small cell carcinoma of the ovary of hypercalcemic type: a case report. AB - Introduction. The small cell carcinoma of hypercalcemic type of ovary is a very aggressive tumor. It is associated with two-thirds of cases with hypercalcemia most often asymptomatic. It occurs mostly for young women. The treatment combines surgery, chemotherapy, and radiotherapy. Case Presentation. We report a case of small cell carcinoma of the ovary hypercalcemic type in a young Tunisian woman aged 25 years after a severe abdominal pain syndrome and a large ovarian mass discovered in scanner; a laparotomy was performed by radical surgery. The pathological examination of the specimen confirmed the diagnosis. The radiological assessment performed after surgery showed a continuing evolution. Palliative chemotherapy was established, and the patient had died two months after diagnosis. Conclusion. The hypercalcemic small cell carcinoma of the ovary is a rare disease of poor prognosis. PMID- 23346439 TI - An Unusual Case of Madelung's Disease with Multiple Atypical Fractures. AB - Madelung's disease is a rare acquired disorder of fat metabolism characterized by multiple symmetric lipomas with typical distribution mainly around the upper trunk, neck, and shoulders. The condition is strongly associated with chronic alcohol use and has various systemic manifestations like polyneuropathy, muscle weakness, and small bone fractures. Herein, we report a 56-year-old male patient with Madelung's disease and multiple fractures and discuss possible underlying factors leading to multiple fractures. PMID- 23346440 TI - Neurocysticercosis, meningioma, and silent corticotroph pituitary adenoma in a 61 year-old woman. AB - We report here the case of a 61-year-old woman who presented with hydrocephalus and cystic and solid lesions in sella turcica, suprasellar areas, and third ventricle. After ventriculoperitoneal shunt she developed cognitive changes and the cystic lesions enlarged. Magnetic resonance imaging (MRI) demonstrated multiple cysts and a solid lesion in the sella and around the anterior clinoid process. With diagnosis of neurocysticercosis she underwent craniotomy. Pathologic examination documented two different lesions: viable and dead cysticerci with inflaming infiltration and a left anterior clinoidal meningioma. At the second surgery, six weeks later via transnasal transsphenoidal approach a silent corticotroph pituitary adenoma was removed which was studied by histology, immunohistochemistry, and electron microscopy. To our knowledge, the occurrence of these three different lesions in the sellar area was not described before. PMID- 23346441 TI - The role of ultrasound and computed tomography in the evaluation of subcutaneous esophageal bypass in a dysphagic patient. AB - Several conditions require subcutaneous colon bypass surgery in the esophageal diseases treatment. Esophageal reconstructions are high risk procedures because of their morbidity and mortality rate. Cervical anastomotic strictures, colon transplant redundancy, recurrent dysphagia, intestinal obstruction, regurgitation, and aspiration are the most frequent late complications. The patient assessment should be performed with noninvasive methods in order to prevent long-term complications. We report the use of ultrasound (US) and computed tomography (CT) for evaluating a dysphagic patient, after subcutaneous esophageal bypass. A thorax and upper abdomen contrast media CT study with volume rendering reconstruction was performed in order to evaluate late post operative complications. In addition a US examination, performed after CT scan, was used for the assessment of the colonic wall and its vascularization. The subcutaneous esophageal bypass allowed for an effective ultrasound evaluation with no additional discomfort for the patient. ultrasonography has been shown effective in the esophageal bypass follow up, when subcutaneous colon bypass surgery was performed. The ultrasonography evaluation, also thanks to a Doppler flowmetry, allowed completing the patient assessment without additional invasive procedures or contrast. Thus it may be performed as a first level evaluation or in the follow up of subcutaneous esophageal bypass patients. PMID- 23346442 TI - The efficacy of exposure and response prevention for geriatric obsessive compulsive disorder: a clinical case illustration. AB - Obsessive compulsive disorder (OCD) is one of the most frequently occurring psychiatric conditions in older adults. While exposure and response prevention (ERP) is considered the most effective psychological treatment for children and adults with OCD, research investigating its effectiveness for older adults is scarce. This clinical case study investigates the effectiveness of ERP in an 80 year-old man with a 65-year history of OCD. The client received 14 individual, 50 minute ERP treatment sessions. Clinician-based Y-BOCS scores reduced by 65% from 20 (moderate) at pretreatment to 7 (subclinical) at 7-month posttreatment followup. OCI-R total scores reduced by 45% from 38 at baseline to 21 at 7-month follow-up. Despite his long history of the disorder, ERP was effective and well tolerated. The application of ERP for older adults with OCD, including age specific modifications that may be required for this treatment approach, is discussed. PMID- 23346443 TI - Diagnostic and therapeutic challenges of a large pleural inflammatory myofibroblastic tumor. AB - We report a 48-year-old woman with a pleural pseudoneoplasm requiring different diagnostic and therapeutic strategies. After initial presentation with increasing dyspnoea, temperature, dry cough, and interscapular pain diagnostic processing showed a large mediastinal mass with marked pleural effusion and high metabolic activity in the 18F-FDG-PET/CT. Extensive CT-guided biopsy of the tumor reaching from the visceral pleura into the right upper lobe revealed no malignancy, but a marked inflammatory tissue reaction containing foam cells. Initial empiric antibiotic therapy was temporarily successful. However, in the further course the mass relapsed and was resistant to antibiotics and a corticosteroid trial. With the working hypothesis of an inflammatory myofibroblastic tumor the patient underwent surgical tumor resection, finally confirming the suspected diagnosis. Due to residual disease intravenous immunoglobulins were administered leading to sustained response. This case with a pleural localisation of a large inflammatory pseudotumor with responsiveness to immunomodulation after incomplete resection extends the reported spectrum of thoracopulmonary manifestations of this rare entity. PMID- 23346444 TI - A Rare Presentation of Xanthogranulomatous Cholecystitis as Bouveret's Syndrome. AB - The purpose of this paper is to present sonographic and CT imaging findings of xanthogranulomatous cholecystitis (XGC) presented as Bouveret's syndrome, a very rare cause of gastric obstruction. While the patient's physical examination, upper GI endoscopy, and radiological findings all pointed to Bouveret's syndrome, CT differential diagnosis suggested either XGC or gallbladder carcinoma, and the final diagnosis was done histopathologically. Our paper aims to increase awareness in radiologically diagnosing XGC cases by introducing the possibility of existence of Bouveret's syndrome. PMID- 23346445 TI - Bouveret's Syndrome: 64-Slice CT Diagnosis and Surgical Management-A Case Report. AB - Gastric outlet obstruction caused by duodenal impaction of a large gallstone migrated through a cholecystoduodenal fistula has been referred to as Bouveret's syndrome. We present a case of gallstone-induced duodenal obstruction in an elderly female patient, diagnosed on a 64-slice MDCT scanner. One-stage surgery, that is, stone removal and cholecystectomy, was performed resulting in relief of obstruction and complete cure. Clinical features, multidetector computed tomography (MDCT) findings, and surgical management are discussed. PMID- 23346446 TI - A Rare Case of Kikuchi Fujimoto's Disease with Subsequent Development of Systemic Lupus Erythematosus. AB - Kikuchi Fujimoto's disease (KFD) is a rare, immune-mediated, self-limiting disorder with unique histopathological features. KFD is usually seen in young Asian females; however, cases have been reported throughout the world and in all ethnicities. It has been recognized that there is a rare association between Systemic Lupus Erythematosus (SLE) and KFD via sporadic case reports. The exact pathophysiological relationship between these two diseases is still unclear. We report a case of a young Asian female who presented with persistent fever and lymphadenopathy and was diagnosed with Kikuchi Fujimoto's disease based on lymph node biopsy; although an SLE workup was done, she did not meet the American Rheumatology Association (ARA) diagnostic criteria for lupus, and the lymph node biopsy did not show features of SLE. She improved clinically with a short course of steroid therapy. Two months later, the patient presented with central facial rash and arthralgia. SLE workup was repeated, a skin biopsy was done, and the results at this time supported a diagnosis of SLE. PMID- 23346447 TI - Cocaine induced vasculitis: have we found a culprit? AB - Cocaine abuse is relatively common in our society. To enhance profitability and acceptability of the product, it is not uncommon for illicit drugs to undergo several processes. The Drug Enforcement Agency (DEA) has reported that seventy percent (70%) of cocaine seized at USA borders has been adulterated with levamisole, previously used as chemotherapeutic and immunomodulator for several conditions. Among the side effects of levamisole-adulterated cocaine, necrotizing vasculitis is the more dramatic. We report three cases of necrotizing vasculitis associated with antineutrophils cytoplasmic antibodies (ANCAs) positivity, linked to the use of cocaine. To our knowledge, these are the first cases of cocaine induced vasculitis reported in the Caribbean. PMID- 23346448 TI - Free Intra-Abdominal Air without Peritoneal Perforation after TEM: A Report of Two Cases. AB - Transanal endoscopic microsurgery (TEM) is a minimally invasive treatment modality for a variety of rectal lesions. Due to its minimally invasive nature, TEM has emerged as a safe method. Among most threatening complications are hemorrhage and peritoneal perforation. We report on two patients who demonstrated intra-abdominal free air on an erect chest X-ray after TEM procedure without other findings of a pneumoperitoneum. We hypothesize that due to the combination of elevated pressures in the retroperitoneal cavity and decreased integrity of the retroperitoneal barrier, insufflated CO(2) gas can diffuse into the intraperitoneal cavity. Conservative treatment should be considered in patients with free intra-abdominal air postoperatively. However, there should be no suspicion of peritoneal entry during the procedure and the patient should be in generally good condition without severe abdominal symptoms. PMID- 23346449 TI - Aortocaval fistula: a rare cause of venous hypertension and acute renal failure. AB - Spontaneous rupture of abdominal aortic aneurysm into the inferior vena cava is rare and is associated with high mortality and morbidity. The clinical presentation can be variable and thus the diagnosis can be difficult. It can present with symptoms and signs of an abdominal emergency, venous hypertension, or systemic hypoperfusion. The traditional method of repair has been open surgery which is associated with high rate of complications. We report a case of aortocaval fistula (ACF) presenting with acute renal failure and heart failure, which was treated successfully with a novel, endovascular approach. PMID- 23346450 TI - Adult ileo-ileo-caecal intussusception: case report and literature review. AB - Adult intussusception is a rare entity accounting for only 5% of all intussusceptions and causes approximately 1% of all adult intestinal obstructions. Unlike paediatric intussusceptions which are usually idiopathic, there is usually a lead point pathology which might be malignant in up to 50% cases. We present an unusual case of adult intussusception which was not diagnosed on any investigation including computerized tomographic (CT) scan and magnetic resonance imaging (MRI). It was a case of ileo-ileo-cecal intussusception caused by a large lipoma 38 mm * 43 mm * 61 mm. It was treated by emergency laparotomy for acute intestinal obstruction. A conservative resection with ileostomy was performed with good postoperative recovery. PMID- 23346451 TI - Small Bowel Intussusception due to Metastasized Sarcomatoid Carcinoma of the Lung: A Rare Cause of Intestinal Obstruction in Adults. AB - Although small bowel intussusception is one of the most common abdominal emergencies in childhood, it is rare in adults and usually occurs as a result of an underlying pathology. Sarcomatoid carcinoma, a very rare subtype of lung cancer, rarely metastasizes to small bowel and causes complications. In this paper, we aim to describe a patient with small bowel intussusception caused by an isolated small bowel metastasis of the sarcomatoid carcinoma of the lung by reviewing the literature. PMID- 23346452 TI - Agenesis of isthmus of the thyroid gland in a patient with graves-basedow disease and a solitary nodule. AB - The thyroid is a vascular endocrine gland with two lateral lobes connected by a narrow, median isthmus. Although a wide range of congenital anomalies of the thyroid gland has been reported in the literature, agenesis of the thyroid isthmus is a very rare congenital anomaly. Thyroid isthmus agenesis does not manifest clinical symptoms, and it can be confused with other thyroid pathologies. We describe a patient with no isthmus of the thyroid, associated with Graves-Basedow disease. Thyroid isthmus agenesis should be kept in mind in order for surgical procedures involving thyroid pathologies to be carried out safely. PMID- 23346453 TI - Treatment of locally advanced prostate cancer: a case report and narrative review. AB - Introduction. Treatment of locally advanced prostate cancer is under discussion. Differences between clinical and pathological staging and risk factors such as positive surgical margins and seminal vesicle involvement challenge the individual treatment decisions. Case Presentation. Clinical tumor stage before treatment was assessed to be T2. After radical prostatectomy, pathological examination revealed the stage pT3b N0 M0 including positive surgical margin and seminal vesicle involvement. Early adjuvant androgen deprivation therapy and late adjuvant radiation therapy were added in response to the pathological risk factors. No evidence of disease was observed for 15 years after the treatment. The unexpected pathological findings were not explained by the physicians in charge. Discussion. A narrative review of the recent literature showed that multiple treatment modalities including adjuvant radiotherapy following radical prostatectomy are consistent with current recommendations. The multimodal approach has possibly cured a high-risk patient and may also work successfully in other patients. An alternative treatment option with better preservation of health-related quality of life might have also achieved a similar good overall survival. PMID- 23346454 TI - Bilateral vascular variations at the renal hilum: a case report. AB - Imaging technology with its advancement in the field of urology is the boon for the patients who require minimally invasive approaches for various kidney disorders. These approaches require a precise knowledge of the normal and variant anatomy of vascular structures at the hilum of the kidney in terms of their pattern of arrangement and division. The present paper describes a bilateral anomalous arrangement of the structures at the renal hilum as well as their peculiar branching pattern which is of clinical and surgical relevance. Multiple branching of the renal vessels was observed in both kidneys due to which the hila were congested. The right renal artery immediately after its origin divided into 2 branches. The upper branch represented an aberrant artery whereas the lower branch gave 5 divisions. The left renal artery also divided into 2 branches much before the hilum as anterior and posterior divisions. The anterior branch took an arched course and gave 6 branches. The posterior branch gave 3 terminal branches before entering the renal substance. In addition to anomalous hilar structures, normal architecture of both kidneys was altered and the hilum of the left kidney was found on its anterior surface. PMID- 23346455 TI - Omega-3 Status and the Relationship between Plasma Asymmetric Dimethylarginine and Risk of Myocardial Infarction in Patients with Suspected Coronary Artery Disease. AB - Background. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. A previous rat study revealed an ADMA lowering effect following treatment with omega-3 polyunsaturated fatty acids (n-3 PUFAs). We sought to examine if an association between plasma ADMA and risk of acute myocardial infarction (AMI) was modified by serum n-3 PUFA status. Methods. The cohort included 1364 patients who underwent coronary angiography for suspected coronary artery disease in 2000-2001. Fatal and nonfatal AMI events were registered until December 31, 2006. Risk associations with AMI were estimated across ADMA quartiles (linear trend) and the upper decile. Results. No association between concentration of any n-3 PUFA and ADMA was observed. Only ADMA levels in upper decile were significantly associated with AMI with a multivariate adjusted hazard ratio (HR) (95% confidence interval) versus the rest of the population of 2.11 (1.34, 3.32). The association was strengthened among patients with below median levels of alpha-linolenic acid (ALA) (HR 3.12 (1.64, 5.93)), but was only influenced by longer chain n-3 PUFA after additional adjustments for HbA1c, estimated glomerular filtration rate, and hypercholesterolemia. Conclusions. The association of ADMA with risk of AMI is influenced by serum n-3 PUFA and particularly ALA. PMID- 23346456 TI - Impact of peripheral arterial disease on functional limitation in congestive heart failure: results from the national health and nutrition examination survey (1999-2004). AB - Background. Peripheral arterial disease (PAD) often coexists with congestive heart failure (CHF) and can be masked by symptoms of CHF such as functional limitation (FL), a common manifestation for both. Therefore, we sought to estimate the prevalence of PAD and its independent association with FL in CHF. Methods. We conducted a cross-sectional study on National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004 to quantify weighted prevalence of CHF and PAD. Study cohort consisted of 7513, with ankle brachial index (ABI) measurements at baseline. Independent association of PAD (ABI <= 0.9) with FL in CHF was determined with multivariate logistic regression (MVLR). Results. Overall weighted PAD prevalence was 5.2%. CHF was present in 305 participants, and the weighted prevalence of PAD in this subgroup was 19.2%. When compared, participants with CHF and PAD were more likely to be older (P < 0.001), hypertensive (P = 0.005) and hypercholesterolemic (P = 0.013) than participants with CHF alone. MVLR showed that PAD (adjusted OR = 5.15; 95% CI: 2.2, 12.05: P < 0.05) and arthritis (adjusted OR = 2.36; 95% CI: 1.10, 5.06: P < 0.05) were independently associated with FL in CHF. Conclusion. Independent association of PAD with FL suggests the need for reinforced screening for PAD in individuals with CHF. PMID- 23346457 TI - Omega-3 Fatty acids and vitamin d in cardiology. AB - Dietary modification and supplementation play an increasingly important role in the conservative treatment of cardiovascular disease. Current interest has focused on n-3 polyunsaturated fatty acids (PUFA) and vitamin D. Clinical trial results on this subject are contradictory in many aspects. Several studies indicate that n-3 PUFA consumption improves vascular and cardiac hemodynamics, triglycerides, and possibly endothelial function, autonomic control, inflammation, thrombosis, and arrhythmia. Experimental studies show effects on membrane structure and associated functions, ion channel properties, genetic regulation, and production of anti-inflammatory mediators. Clinical trials evaluating a possible reduction in cardiovascular disease by n-3 PUFA have shown different results. Supplementation of vitamin D is common regarding prevention and treatment of osteoporosis. But vitamin D also seems to have several effects on the cardiovascular system. Vitamin D deficiency appears to be related to an increase in parathyroid hormone levels and can predispose to essential hypertension and left ventricular hypertrophy, increased insulin resistance, and eventually to atherosclerosis and adverse cardiovascular events. Randomized prospective clinical trials are needed to determine whether vitamin D and omega-3 FA supplementation therapy should be recommended as a routine therapy for primary or secondary prevention of cardiovascular disease. PMID- 23346458 TI - gamma-Secretase-Dependent Proteolysis of Transmembrane Domain of Amyloid Precursor Protein: Successive Tri- and Tetrapeptide Release in Amyloid beta Protein Production. AB - gamma-Secretase cleaves the carboxyl-terminal fragment (betaCTF) of APP not only in the middle of the transmembrane domain (gamma-cleavage), but also at sites close to the membrane/cytoplasm boundary (epsilon-cleavage), to produce the amyloid beta protein (Abeta) and the APP intracellular domain (AICD), respectively. The AICD49-99 and AICD50-99 species were identified as counterparts of the long Abeta species Abeta48 and Abeta49, respectively. We found that Abeta40 and AICD50-99 were the predominant species in cells expressing wild-type APP and presenilin, whereas the production of Abeta42 and AICD49-99 was enhanced in cells expressing familial Alzheimer's disease mutants of APP and presenilin. These long Abeta species were identified in cell lysates and mouse brain extracts, which suggests that epsilon-cleavage is the first cleavage of betaCTF to produce Abeta by gamma-secretase. Here, we review the progress of research on the mechanism underlying the proteolysis of the APP transmembrane domain based on tri- and tetrapeptide release. PMID- 23346459 TI - Acute and chronic pancreatic inflammation. PMID- 23346460 TI - Vitamin d receptor, retinoid x receptor, ki-67, survivin, and ezrin expression in canine osteosarcoma. AB - Canine osteosarcoma (OS) is an aggressive malignant bone tumor. Prognosis is primarily determined by clinical parameters. Vitamin D has been postulated as a novel therapeutic option for many malignancies. Upon activation, vitamin D receptors (VDRs) combine with retinoid receptor (RXR) forming a heterodimer initiating a cascade of events. Vitamin D's antineoplastic activity and its mechanism of action in OS remain to be clearly established. Expression of VDR, RXR, Ki-67, survivin, and ezrin was studied in 33 archived, canine OS specimens. VDR, RXR, survivin, and ezrin were expressed in the majority of cases. There was no statistically significant difference in VDR expression in relationship with tumor grade, type, or locations or animal breed, age, and/or sex. No significant association (p = 0.316) between tumor grade and Ki-67 expression was found; in particular, no difference in Ki-67 expression between grades 2 and 3 OSs was found, while a negative correlation was noted between Ki-67 and VDR expression (rho = -0.466), a positive correlation between survivin and RXR expression was found (p = 0.374). A significant relationship exists between VDR and RXR expression in OSs and proliferative/apoptosis markers. These results establish a foundation for elucidating mechanisms by which vitamin D induces antineoplastic activity in OS. PMID- 23346462 TI - Subepithelial connective tissue graft with and without the use of plasma rich in growth factors for treating root exposure. AB - PURPOSE: The aim of this study was to evaluate the clinical efficiency of the subepithelial connective tissue graft (SCTG) with and without plasma rich in growth factor (PRGF) in the treatment of gingival recessions. METHODS: Twenty bilateral buccal gingival Miller's Class I and II recessions were selected. Ten of the recessions were treated with SCTG and PRGF (test group). The rest ten of the recessions were treated with SCTG (control group). The clinical parameters including recession depth (RD), percentage of root coverage (RC), mucogingival junction (MGJ) position, clinical attachment level (CAL), and probing depth (PD) were measured at the baseline, and 1 and 3 months later. The data were analyzed using the Wilcoxon signed rank and Mann-Whitney U tests. RESULTS: After 3 months, both groups showed a significant improvement in all of the mentioned criteria except PD. Although the amount of improvement was better in the SCTG+PRGF group than the SCTG only group, this difference was not statistically significant. The mean RC was 70.85+/-12.57 in the test group and 75.83+/-24.68 in the control group. CONCLUSIONS: Both SCTG+PRGF and SCTG only result in favorable clinical outcomes, but the added benefit of PRGF is not evident. PMID- 23346461 TI - Anti-inflammatory effect of (-)-epigallocatechin-3-gallate on Porphyromonas gingivalis lipopolysaccharide-stimulated fibroblasts and stem cells derived from human periodontal ligament. AB - PURPOSE: (-)-epigallocatechin-3-gallate (EGCG) has been reported to exert anti inflammatory and antibacterial effects in periodontitis. However, its exact mechanism of action has yet to be determined. The present in vitro study evaluated the anti-inflammatory effects of EGCG on human periodontal ligament fibroblasts (hPDLFs) and human periodontal ligament stem cells (hPDLSCs) affected by bacterial lipopolysaccharide (LPS) extracted from Porphyromonas gingivalis. METHODS: hPDLFs and hPDLSCs were extracted from healthy young adults and were treated with EGCG and/or P. gingivalis LPS. After 1, 3, 5, and 7 days from treatment, cytotoxic and proliferative effects were evaluated using a 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and bromodeoxyuridine assay, respectively. And then, the gene expressions of hPDLFs and hPDLSCs were observed for interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-B ligand (RANKL), and RANKL/OPG using real-time polymerase chain reaction (PCR) at 0, 6, 24, and 48 hours after treatment. The experiments were performed with the following groups for hPDLFs and hPDLSCs; 1) No treat, 2) EGCG alone, 3) P. gingivalis LPS alone, 4) EGCG+P. gingivalis LPS. RESULTS: The 20 uM of EGCG and 20 ug/mL of P. gingivalis LPS had the lowest cytotoxic effects, so those concentrations were used for further experiments. The proliferations of hPDLFs and hPDLSCs increased in all groups, though the 'EGCG alone' showed less increase. In real-time PCR, the hPDLFs and hPDLSCs of 'EGCG alone' showed similar gene expressions to those cells of 'no treat'. The gene expressions of 'P. gingivalis LPS alone' in both hPDLFs and hPDLSCs were highly increased at 6 hours for IL-1beta, IL-6, TNF-alpha, RANKL, and RANKL/OPG, except the RANKL/OPG in hPDLSCs. However, those increased gene expressions were down-regulated in 'EGCG+P. gingivalis LPS' by the additional treatment of EGCG. CONCLUSIONS: Our results demonstrate that EGCG could exert an anti-inflammatory effect in hPDLFs and hPDLSCs against a major pathogen of periodontitis, P. gingivalis LPS. PMID- 23346463 TI - Rabbit maxillary sinus augmentation model with simultaneous implant placement: differential responses to the graft materials. AB - PURPOSE: This study was performed to establish an experimental rabbit model for single-stage maxillary sinus augmentation with simultaneous implant placement. METHODS: Twelve mature New Zealand white rabbits were used for the experiments. The rabbit maxillary sinuses were divided into 3 groups according to sinus augmentation materials: blood clot (BC), autogenous bone (AB), and bovine-derived hydroxyapatite (BHA). Small titanium implants were simultaneously placed in the animals during the sinus augmentation procedure. The rabbits were sacrificed 4 and 8 weeks after surgery and were observed histologically. Histomorphometric analyses using image analysis software were also performed to evaluate the parameters related to bone regeneration and implant-bone integration. RESULTS: The BC group showed an evident collapse of the sinus membrane and limited new bone formation around the original sinus floor at 4 and 8 weeks. In the AB group, the sinus membrane was well retained above the implant apex, and new bone formation was significant at both examination periods. The BHA group also showed retention of the elevated sinus membrane above the screw apex and evident new bone formation at both points in time. The total area of the mineral component (TMA) in the area of interest and the bone-to-implant contact did not show any significant differences among all the groups. In the AB group, the TMA had significantly decreased from 4 to 8 weeks. CONCLUSIONS: Within the limits of this study, the rabbit sinus model showed satisfactory results in the comparison of different grafting conditions in single-stage sinus floor elevation with simultaneous implant placement. We found that the rabbit model was useful for maxillary sinus augmentation with simultaneous implant placement. PMID- 23346464 TI - Relationship between maternal periodontal disease and Apgar score of newborns. AB - PURPOSE: The aim of this study was to evaluate the relationship between maternal periodontal disease and the health status of newborns using Apgar scores. METHODS: One hundred pregnant women with periodontal disease were included in the case series and 100 pregnant women without periodontal disease were placed in the control group, respectively. The periodontal parameters of bleeding on probing (BOP), clinical attachment loss (CAL), probing depth (PD), birth weight, and Apgar scores were recorded in both groups. T-tests and Pearson's correlation coefficient were used to determine the birth weight odds ratio to analyze the relationship between the periodontal parameters of BOP, CAL, and PD on the one hand and an Apgar score of less than 7. An unpaired Student's t-test was used to analyze differences in means between the case and control groups using SPSS ver. 13. RESULTS: The means of the ages, periodontal pocket depths, attachment loss, areas with BOP, Apgar score in the first 5 minutes and infant birth weight exhibited statistically significant differences between the case and control groups. The ratio of an Apgar score of <7 to periodontal disease was 3.14; the ratio of low birth weight risk in mothers with periodontal disease to that in mothers without periodontal disease was 2.74. Pearson's correlation coefficient revealed a significant correlation between the infant birth weight and BOP, CAL, and PD of the mother. In addition, there was a significant correlation between the Apgar score and BOP, CAL, and PD and also between the Apgar score and infant birth weight. CONCLUSIONS: The results of this study showed a significant relationship between periodontal disease and infant birth weight; in addition, there was a significant relationship between the periodontal indexes of BOP, CAL, and PD on the one hand and the Apgar score on the other. PMID- 23346465 TI - Bacterial adhesion and colonization differences between zirconia and titanium implant abutments: an in vivo human study. AB - PURPOSE: Several parameters have been described for determining the success or failure of dental implants. The surface properties of transgingival implant components have had a great impact on the long-term success of dental implants. The purpose of this study was to compare the tendency of two periodontal pathogens to adhere to and colonize zirconia abutments and titanium alloys both in hard surfaces and soft tissues. METHODS: Twelve patients participated in this study. Three months after implant placement, the abutments were connected. Five weeks following the abutment connections, the abutments were removed, probing depth measurements were recorded, and gingival biopsies were performed. The abutments and gingival biopsies taken from the buccal gingiva were analyzed using real-time polymerase chain reaction to compare the DNA copy numbers of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and total bacteria. The surface free energy of the abutments was calculated using the sessile water drop method before replacement. Data analyses used the Mann Whitney U-test, and P-values below 0.05 find statistical significance. RESULTS: The present study showed no statistically significant differences between the DNA copy numbers of A. actinomycetemcomitans, P. gingivalis, and total bacteria for both the titanium and zirconia abutments and the biopsies taken from their buccal gingiva. The differences between the free surface energy of the abutments had no influence on the microbiological findings. CONCLUSIONS: Zirconia surfaces have comparable properties to titanium alloy surfaces and may be suitable and safe materials for the long-term success of dental implants. PMID- 23346466 TI - In vitro assay for osteoinductive activity of different demineralized freeze dried bone allograft. AB - PURPOSE: Various bone graft materials have been used for periodontal tissue regeneration. Demineralized freeze-dried bone allograft (DFDBA) is a widely used bone substitute. The current widespread use of DFDBA is based on its potential osteoinductive ability. Due to the lack of verifiable data, the purpose of this study was to assess the osteoinductive activity of different DFDBAs in vitro. METHODS: Sarcoma osteogenic (SaOS-2) cells (human osteoblast-like cells) were exposed to 8 mg/mL and 16 mg/mL concentrations of three commercial types of DFDBA: Osseo+, AlloOss, and Cenobone. The effect of these materials on cell proliferation was determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide assay. The osteoinductive ability was evaluated using alizarin red staining, and the results were confirmed by evaluating osteogenic gene expression using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: In the SaOS-2 cells, an 8 mg/mL concentration of Osseo+ and Cenobone significantly increased cell proliferation in 48 hours after exposure (P<0.001); however, in these two bone materials, the proliferation of cells was significantly decreased after 48 hours of exposure with a 16 mg/mL concentration (P<0.001). The alizarin red staining results demonstrated that the 16 mg/mL concentration of all three tested DFDBA induced complete morphologic differentiation and mineralized nodule production of the SaOS-2 cells. The RT-PCR results revealed osteopontin gene expression at a 16 mg/mL concentration of all three test groups, but not at an 8 mg/mL concentration. CONCLUSIONS: These commercial types of DFDBA are capable of decreasing proliferation and increasing osteogenic differentiation of the SaOS-2 cell line and have osteoinductive activity in vitro. PMID- 23346467 TI - Influence of crown-to-implant ratio on periimplant marginal bone loss in the posterior region: a five-year retrospective study. AB - PURPOSE: The aim of this study was to evaluate the influence of the crown-to implant (C/I) ratio on the change in marginal bone level around the implant and to determine the site-related factors influencing the relationship between the C/I ratio and periimplant marginal bone loss. METHODS: A total of 259 implants from 175 patients were evaluated at a mean follow-up of five years. Implants were divided into two groups according to their C/I ratios: <=1, and >1. Site-related factors having an influence on the relationship between C/I ratio and periimplant marginal bone loss were analyzed according to the implant location, implant diameter, implant manufacturer, prosthesis type, and guided bone regeneration (GBR) procedure. RESULTS: It was found that 1) implants with a C/I ratio below 1 exhibited greater periimplant marginal bone loss than implants with a C/I ratio more than 1, 2) site-related factors had an effect on periimplant marginal bone loss, except for the implant system used, 3) the C/I ratio was the factor having more dominant influence on periimplant marginal bone loss, compared with implant diameter, prosthesis type, implant location, and GBR procedure, 4) implants with a C/I ratio below 1 showed greater periimplant marginal bone loss than implants with a C/I ratio greater than 1 in the maxilla, but not in the mandible, 5) and periimplant marginal bone loss was more affected by the implant system than the C/I ratio. CONCLUSIONS: Within the limitations of this study, implants with a higher C/I ratio exhibited less marginal bone loss than implants with a lower C/I ratio in the posterior regions. The C/I ratio was a more dominant factor affecting periimplant marginal bone loss in the maxilla than the mandible. Meanwhile, the implant system was a more dominant factor influencing periimplant marginal bone loss than the C/I ratio. PMID- 23346468 TI - Evaluation of calcium sulphate barrier to collagen membrane in intrabony defects. AB - PURPOSE: The aim of this study was to clinically and radiographically evaluate and compare treatment of intrabony defects with the use of decalcified freeze dried bone allograft in combination with a calcium sulphate barrier to collagen membrane. METHODS: Twelve patients having chronic periodontal disease aged 20 to 50 years and with a probing depth >6 mm were selected. Classification of patient defects into experimental and control groups was made randomly. In the test group, a calcium sulphate barrier membrane, and in control group, a collagen membrane, was used in conjunction with decalcified freeze-dried bone graft in both sides. Ancillary parameters as well as soft tissue parameters along with radiographs were taken at baseline and after 6 months of surgery. Parameters assessed were plaque index, modified gingival index, probing depth, relative attachment level, and location of the gingival margin. A Student's t-test was done for intragroup and a paired t-test for intergroup analysis. RESULTS: Intragroup analysis revealed statistically significant improvement in all the ancillary parameters and soft tissue parameters with no statistically significant difference in intergroup analysis. CONCLUSIONS: The study concluded that a calcium sulphate barrier was comparable to collagen membrane in achieving clinical benefits and hence it can be used as an economical alternative to collagen membrane. PMID- 23346469 TI - A comparison of magnetostrictive and piezoelectric ultrasonic scaling devices: an in vitro study. AB - PURPOSE: The effects of magnetostrictive and piezoelectric devices on tooth surfaces seem to differ with regard to the root surface roughness they produce. This study aimed to compare the results of scaling using magnetostrictive and piezoelectric devices on extracted teeth. METHODS: Forty-four human extracted teeth were assigned to four study groups (n=11). In two groups (C100 and C200), the teeth were scaled using a magnetostrictive device and two different lateral forces: 100 g and 200 g, respectively. In the other two groups (P100 and P200), the teeth were scaled with a piezoelectric device with 100 g and 200 g of lateral force, respectively. he teeth were scaled and the data on the duration of scaling and the amount of surface were collected and analyzed using the t-test. RESULTS: The mean time needed for instrumentation for the piezoelectric and magnetostrictive devices was 50:54 and 41:10, respectively, but their difference was not statistically significant (P=0.171). For root surface roughness, we only found a statistically significantly poorer result for the C200 group in comparison to the P200 group (P=0.033). CONCLUSIONS: This study revealed that applying a piezoelectric scaler with 200 g of lateral force leaves smoother surfaces than a magnetostrictive device with the same lateral force. PMID- 23346470 TI - Surface characteristics and osteoblastic cell response of alkali-and heat-treated titanium-8tantalum-3niobium alloy. AB - PURPOSE: The aim of the present study was to evaluate the biological response of alkali- and heat-treated titanium-8tantalum-3niobium surfaces by cell proliferation and alkaline phosphatase (ALP) activity analysis. METHODS: Commercial pure titanium (group cp-Ti) and alkali- and heat-treated titanium 8tantalum-3niobium (group AHT) disks were prepared. The surface properties were evaluated using scanning electron microscopy, energy dispersed spectroscopy and X ray photoelectron spectroscopy (XPS). The surface roughness was evaluated by atomic force microscopy and a profilometer. The contact angle and surface energy were also analyzed. The biological response of fetal rat calvarial cells on group AHT was assessed by cell proliferation and ALP activity. RESULTS: Group AHT showed a flake-like morphology microprofile and dense structure. XPS analysis of group AHT showed an increased amount of oxygen in the basic hydroxyl residue of titanium hydroxide groups compared with group cp-Ti. The surface roughness (Ra) measured by a profilometer showed no significant difference (P>0.05). Group AHT showed a lower contact angle and higher surface energy than group cp-Ti. Cell proliferation on group AHT surfaces was significantly higher than on group cp-Ti surfaces (P<0.05). In comparison to group cp-Ti, group AHT enhanced ALP activity (P<0.05). CONCLUSIONS: These results suggest that group AHT stimulates osteoblast differentiation. PMID- 23346472 TI - Looking back, looking forward. PMID- 23346471 TI - Differential diagnosis and treatment of periodontitis-mimicking actinomycosis. AB - PURPOSE: Actinomycosis is an uncommon chronic granulomatous disease that presents as a slowly progressive, indolent, indurated infiltration with multiple abscesses, fistulas, and sinuses. The purpose of this article is to report on a case of actinomycosis with clinical findings similar to periodontitis. METHODS: A 46-year-old female presented with recurrent throbbing pain on the right first and second molar of the mandible three weeks after root planing. Exploratory flap surgery was performed, and the bluish-gray tissue fragment found in the interproximal area between the two molars was sent for histopathology. RESULTS: The diagnosis from the biopsy was actinomycosis. The clinical and radiographic manifestations of this case were clinically indistinguishable from periodontitis. The patient did not report any symptoms, and she is scheduled for a follow-up visit. CONCLUSIONS: The present study has identified periodontitis-mimicking actinomycosis. Actinomycosis should be included in the differential diagnosis in cases with periodontal pain and inflammation that do not respond to nonsurgical treatment for periodontitis. More routine submissions of tissue removed from the oral cavity for biopsies may be beneficial for differential diagnosis. PMID- 23346473 TI - Human Factors Engineering in HI: So What? Who Cares? and What's in It for You? AB - OBJECTIVES: Human factors engineering is a discipline that deals with computer and human systems and processes and provides a methodology for designing and evaluating systems as they interact with human beings. This review article reviews important current and past efforts in human factors engineering in health informatics in the context of the current trends in health informatics. METHODS: The methodology of human factors engineering and usability testing in particular were reviewed in this article. RESULTS: This methodology arises from the field of human factors engineering, which uses principles from cognitive science and applies them to implementations such as a computer-human interface and user centered design. CONCLUSIONS: Patient safety and best practice of medicine requires a partnership between patients, clinicians and computer systems that serve to improve the quality and safety of patient care. People approach work and problems with their own knowledge base and set of past experiences and their ability to use systems properly and with low error rates are directly related to the usability as well as the utility of computer systems. Unusable systems have been responsible for medical error and patient harm and have even led to the death of patients and increased mortality rates. Electronic Health Record and Computerized Physician Order Entry systems like any medical device should come with a known safety profile that minimizes medical error and harm. This review article reviews important current and past efforts in human factors engineering in health informatics in the context of the current trends in health informatics. PMID- 23346474 TI - Ubiquitous health in Korea: progress, barriers, and prospects. AB - OBJECTIVES: Korea has one of the most advanced information technology (IT) infrastructures in the world, and the application of IT in health systems is rapidly progressing from computerization to information systems, ubiquitous systems, and smart systems. This study aims to analyze Korean environments in regards to the development of their u-Health industry and propose directions for u-Healthcare services based on this analysis. METHODS: This paper reviews the background, progress history, and current status of u-Health in Korea, and suggests strategies for the u-Health industry based on an analysis of its barriers and obstacles. RESULTS: When u-Health was introduced to Koreans, their policies and approaches focused mainly on environmental factors, yet these efforts have not progressed further to impact the u-Healthcare service industry itself. To develop the u-Healthcare industry, four points need to be considered: the development and support of the practical service model, institutional support, support of core technology and industry, and the institutionalization of health management service. CONCLUSIONS: Korea is at a strategic point to start building u-Healthcare service delivery models. u-Healthcare is a healthcare service that provides added value through u-Health environments. By identifying critical success factors in u-Healthcare, we can strengthen the u-Health industry and implement policies to coordinate our efforts in the process of value chains to which we belong. PMID- 23346475 TI - Expert System Shells for Rapid Clinical Decision Support Module Development: An ESTA Demonstration of a Simple Rule-Based System for the Diagnosis of Vaginal Discharge. AB - OBJECTIVES: This study demonstrates the feasibility of using expert system shells for rapid clinical decision support module development. METHODS: A readily available expert system shell was used to build a simple rule-based system for the crude diagnosis of vaginal discharge. Pictures and 'canned text explanations' are extensively used throughout the program to enhance its intuitiveness and educational dimension. All the steps involved in developing the system are documented. RESULTS: The system runs under Microsoft Windows and is available as a free download at http://healthcybermap.org/vagdisch.zip (the distribution archive includes both the program's executable and the commented knowledge base source as a text document). The limitations of the demonstration system, such as the lack of provisions for assessing uncertainty or various degrees of severity of a sign or symptom, are discussed in detail. Ways of improving the system, such as porting it to the Web and packaging it as an app for smartphones and tablets, are also presented. CONCLUSIONS: An easy-to-use expert system shell enables clinicians to rapidly become their own 'knowledge engineers' and develop concise evidence-based decision support modules of simple to moderate complexity, targeting clinical practitioners, medical and nursing students, as well as patients, their lay carers and the general public (where appropriate). In the spirit of the social Web, it is hoped that an online repository can be created to peer review, share and re-use knowledge base modules covering various clinical problems and algorithms, as a service to the clinical community. PMID- 23346476 TI - Implementation Issues of Virtual Desktop Infrastructure and Its Case Study for a Physician's Round at Seoul National University Bundang Hospital. AB - OBJECTIVES: The cloud computing-based virtual desktop infrastructure (VDI) allows access to computing environments with no limitations in terms of time or place such that it can permit the rapid establishment of a mobile hospital environment. The objective of this study was to investigate the empirical issues to be considered when establishing a virtual mobile environment using VDI technology in a hospital setting and to examine the utility of the technology with an Apple iPad during a physician's rounds as a case study. METHODS: Empirical implementation issues were derived from a 910-bed tertiary national university hospital that recently launched a VDI system. During the physicians' rounds, we surveyed patient satisfaction levels with the VDI-based mobile consultation service with the iPad and the relationship between these levels of satisfaction and hospital revisits, hospital recommendations, and the hospital brand image. Thirty-five inpatients (including their next-of-kin) and seven physicians participated in the survey. RESULTS: Implementation issues pertaining to the VDI system arose with regard to the highly availability system architecture, wireless network infrastructure, and screen resolution of the system. Other issues were related to privacy and security, mobile device management, and user education. When the system was used in rounds, patients and their next-of-kin expressed high satisfaction levels, and a positive relationship was noted as regards patients' decisions to revisit the hospital and whether the use of the VDI system improved the brand image of the hospital. CONCLUSIONS: Mobile hospital environments have the potential to benefit both physicians and patients. The issues related to the implementation of VDI system discussed here should be examined in advance for its successful adoption and implementation. PMID- 23346477 TI - Monitor preference for electronic medical record in outpatient clinic. AB - OBJECTIVES: The objective of this paper is to assess which wide type monitor configurations are preferred when physicians use an Electronic Medical Record (EMR) system in an outpatient clinic setting. METHODS: We selected three kinds of monitor configurations available for adoption at outpatient clinics with reference to monitor market trends. Fifteen attending physicians of the Seoul National University Bundang Hospital used each monitor configuration in their outpatient clinics. After completing the outpatient sessions, they selected the best monitor configuration for criteria described in five questionnaire items. We counted the number of votes and reviewed opinions of participants. RESULTS: The Wide Quad High Definition (WQHD) 27-inch single monitor configuration was most preferred for all questionnaire items. All participants answered that the WQHD 27 inch single monitor configuration was the best for desk space utilization. Eleven out of fifteen participants chose the WQHD 27-inch single monitor configuration as the most suitable monitor for outpatient practice. CONCLUSIONS: This study found that physicians preferred the WQHD 27-inch single monitor configuration in outpatient clinic settings. Healthcare organizations need to consider this finding when they purchase wide type monitors for EMR systems instead of the standard type monitor. PMID- 23346478 TI - Development of korean rare disease knowledge base. AB - OBJECTIVES: Rare disease research requires a broad range of disease-related information for the discovery of causes of genetic disorders that are maladies caused by abnormalities in genes or chromosomes. A rarity in cases makes it difficult for researchers to elucidate definite inception. This knowledge base will be a major resource not only for clinicians, but also for the general public, who are unable to find consistent information on rare diseases in a single location. METHODS: We design a compact database schema for faster querying; its structure is optimized to store heterogeneous data sources. Then, clinicians at Seoul National University Hospital (SNUH) review and revise those resources. Additionally, we integrated other sources to capture genomic resources and clinical trials in detail on the Korean Rare Disease Knowledge base (KRDK). RESULTS: As a result, we have developed a Web-based knowledge base, KRDK, suitable for study of Mendelian diseases that commonly occur among Koreans. This knowledge base is comprised of disease summary and review, causal gene list, laboratory and clinic directory, patient registry, and so on. Furthermore, database for analyzing and giving access to human biological information and the clinical trial management system are integrated on KRDK. CONCLUSIONS: We expect that KRDK, the first rare disease knowledge base in Korea, may contribute to collaborative research and be a reliable reference for application to clinical trials. Additionally, this knowledge base is ready for querying of drug information so that visitors can search a list of rare diseases that is relative to specific drugs. Visitors can have access to KRDK via http://www.snubi.org/software/raredisease/. PMID- 23346479 TI - Barriers to the operation of patient safety incident reporting systems in korean general hospitals. AB - OBJECTIVES: This study aimed to explore the barriers to and factors facilitating the operation of patient safety incident reporting systems. METHODS: A qualitative study that used a methodological triangulation method was conducted. Participants were those who were involved in or responsible for managing incident reporting at hospitals, and they were recruited via a snowballing sampling method. Data were collected via interviews or emails from 42 nurses at 42 general hospitals. A qualitative content analysis was performed to derive the major themes related to barriers to and factors facilitating incident reporting. RESULTS: Participants suggested 96 barriers to incident reporting in their hospitals at the organizational and individual levels. Low reporting rates, especially for near misses, were the most commonly reported issue, followed by poorly designed incident reporting systems and a lack of adequate patient safety leadership by mid-level managers. To resolve and overcome these barriers, 104 recommendations were suggested. The high-priority recommendations included introducing reward systems; improving incident reporting systems, by for instance implementing a variety of reporting channels and ensuring reporter anonymity; and creating a strong safety culture. CONCLUSIONS: The barriers to and factors facilitating incident reporting include various organizational and individual factors. As an important way to address these challenging issues and to improve the incident reporting systems in hospitals, we suggest several feasible methods of doing so. PMID- 23346481 TI - 'Omics' approaches to understanding interstitial cystitis/painful bladder syndrome/bladder pain syndrome. AB - Recent efforts in the generation of large genomics, transcriptomics, proteomics, metabolomics and other types of 'omics' data sets have provided an unprecedentedly detailed view of certain diseases, however to date most of this literature has been focused on malignancy and other lethal pathological conditions. Very little intensive work on global profiles has been performed to understand the molecular mechanism of interstitial cystitis/painful bladder syndrome/bladder pain syndrome (IC/PBS/BPS), a chronic lower urinary tract disorder characterized by pelvic pain, urinary urgency and frequency, which can lead to long lasting adverse effects on quality of life. A lack of understanding of molecular mechanism has been a challenge and dilemma for diagnosis and treatment, and has also led to a delay in basic and translational research focused on biomarker and drug discovery, clinical therapy, and preventive strategies against IC/PBS/BPS. This review describes the current state of 'omics' studies and available data sets relevant to IC/PBS/BPS, and presents opportunities for new research directed at understanding the pathogenesis of this complex condition. PMID- 23346482 TI - Expression of caveolin-1 in rat urinary bladder with cyclophosphamide-induced cystitis. AB - PURPOSE: The purposes of this study were to investigate the effect of cyclophosphamide (CYP)-induced inflammatory cystitis on caveolin 1 in rat urinary bladder and to determine the role of these molecules in the bladder dysfunction that occurs in inflammatory change in rat urinary bladder. METHODS: Female Sprague-Dawley rats were divided into control (n=30) and experimental (n=30) groups. Cystitis in experimental group was induced by intraperitoneal injection of CYP (200 mg/kg). The control group underwent an intraperitoneal saline injection. After 3 days, urodynamic studies were done to measure the contraction interval and contraction pressure. The expression and cellular localization of caveolin 1 were determined by Western blot and immunofluorescent study in rat urinary bladder. RESULTS: In cystometrograms, the contraction interval (minute) was significantly increased in the CYP-induced cystitis rats (15.8+/-1.5) than in the control group (6.3+/-0.5) (P<0.05). Conversely, the average contraction pressure (mmHg) was significantly higher in the CYP-induced cystitis rats (15.6+/ 1.7) than in the control group (11.3+/-0.5) (P<0.05). Caveolin 1 was expressed in the capillaries, arteriols and venules. The protein expression of caveolin 1 was significantly decreased in the CYP-induced cystitis rats (P<0.05). CONCLUSIONS: Inflammatory change of urinary bladder maybe causes a significant change in the expression of caveolin 1. These findings suggest that caveolin 1 might have a functional role in the bladder dysfunction related with cystitis in rat urinary bladder. PMID- 23346483 TI - Effects of a Short Course of Oral Prednisolone in Patients with Bladder Pain Syndrome with Fluctuating, Worsening Pain despite Low-Dose Triple Therapy. AB - PURPOSE: Triple therapy with gabapentin, amitriptyline, and nonsteroidal antiinflammatory drugs is efficacious for chronic bladder pain syndrome/interstitial cystitis (BPS/IC). However, transient, fluctuating, worsening pain or flare-up symptoms may develop during treatment for a variety of reasons. Here, we assessed the validity of our observational experience regarding a short course of oral prednisolone therapy, which might be of value in the management of flare-up symptoms of BPS/IC. METHODS: Between May 2007 and May 2012, 7 women (mean age, 61.5 years; range, 44.8 to 75.4 years) with BPS/IC presenting with transient, fluctuating, worsening pain as a flare-up symptom despite low-dose triple therapy received a 1- to 3-month course of oral prednisolone 10 mg. The outcome measures used were the IC symptom scale (ICSS, O'Leary-Sant Interstitial Cystitis Symptom Index) and a visual analogue scale (VAS), which were completed at baseline and after treatment. RESULTS: There were statistically significant differences in the ICSS and VAS score before and after prednisolone treatment (P<0.05 by Wilcoxon singed-rank test). The pretreatment IC symptom index (ICSI), IC problem index (ICPI), and VAS score were 16.7+/- 2.2, 13.7+/-2.3, and 8.3+/-1.5 (mean+/-standard deviation [SD]), and the posttreatment scores were 4.9+/-2.3, 4.3+/-1.1, and 2.5+/-0.9 (mean+/-SD), respectively. The ICSI, ICPI, and VAS scores were improved after prednisolone treatment by 70.7%, 68.6%, and 69.9%, respectively. Low-dose triple therapy with prednisolone caused no significant adverse effects. CONCLUSIONS: In patients with BPS/IC who show transient, fluctuating, worsening pain as flare-up symptoms despite undergoing low-dose triple therapy, a short course of oral prednisolone therapy was sufficiently effective. However, large-scale studies should be performed to verify our findings. PMID- 23346484 TI - Association of insulin resistance with overactive bladder in female patients. AB - PURPOSE: Metabolic syndrome and obesity have been advocated to be risk factors for the development of overactive bladder (OAB). Additionally, insulin resistance is the underlying mechanism of metabolic syndrome. We aimed to investigate the association of insulin resistance with overactive bladder in female patients. METHODS: We prospectively conducted the study in our urology department. Female patients aged between 30 and 76 years old applied to our policlinics with or without OAB symptoms were enrolled. One hundred and twenty-two patients with OAB and 62 age-matched controls without OAB were included into the study. Fasting serum insulin, glucose, high-density lipoprotein (HDL-c), and triglycerides levels were measured. Insulin resistance value was obtained via the homeostasis model assessment of insulin resistance (HOMA-IR) calculator. The chi-square and Mann-Whitney U tests were used to compare differences in variables. RESULTS: Serum insulin level was found higher in female patients with OAB (11.5+/-6.2 uU/mL) relative to controls (6.4+/-2.1 uU/mL), statistically significant (P=0.036). In addition, HOMA-IR was significantly found higher in the OAB group, 2.86 (0.76 to 17.04) in comparison to controls, 1.32 (0.67 to 224), P=0.018. High density lipoprotein cholesterol levels (HDL-c) were significantly found lower in females with OAB. CONCLUSIONS: Insulin resistance can be associated to overactive bladder and may play significant role in pathogenesis. PMID- 23346485 TI - Impact of intravesical protrusion of the prostate in the treatment of lower urinary tract symptoms/benign prostatic hyperplasia of moderate size by alpha receptor antagonist. AB - PURPOSE: To evaluate whether intravesical protrusion of the prostate (IPP) is related to the treatment effect of alpha-1 receptor antagonist in patients with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) with a prostate size of less than 40 g. METHODS: A total of 77 BPH patients over 50 years of age treated with alfuzosin (alpha blocker) were enrolled prospectively. The study included only patients with BPH of 40 g or less. The patients were classified into two groups depending on the presence of IPP at baseline: the IPP group (41 patients) and the non-IPP group (36 patients). Prostate volume, prostate-specific antigen (PSA), International Prostate Symptom Score and quality of life (IPSS/QoL), maximum flow rate (Qmax), and postvoid residual (PVR) volume were compared between the groups. The clinical significance of IPP was evaluated after the patients had been taking alfuzosin for 8 weeks. RESULTS: PSA and IPSS (total and voiding subscore) showed significant correlations with IPP (P<0.05). Comparison of parameters before and after 8 weeks showed that alfuzosin improved the total IPSS and all subscores (P<0.001), QoL (P<0.001), Qmax (P<0.001), and PVR (P=0.030) in the non-IPP group. CONCLUSIONS: Alfuzosin may be less effective in improving symptom scores, PVR, and Qmax in the treatment of LUTS/BPH in the presence of IPP. PMID- 23346486 TI - Chinese urologists' views of practice patterns in the diagnosis and treatment of benign prostatic hyperplasia: a nationwide survey. AB - PURPOSE: To assess the compliance of Chinese urologists with China's benign prostatic hyperplasia (BPH) clinical practice guideline and to explore the diagnosis and therapy modalities for geriatric patients with BPH. METHODS: A cross-sectional survey study was carried out in 33 medical centers in 11 different cities in China. A total of 190 urologists participated in a survey to record their preferences for diagnostic tests and treatment options for BPH outpatients. Diagnostic test results as well as health care demands were collected by surveying 2,027 outpatients aged 60 years and older. RESULTS: The survey response rate was 97.4%. The respondents generally used the diagnostic tests recommended in China's BPH clinical practice guideline at varying rates. The used rates for medical history, ultrasonography, and urinalysis were above 90.0%; that for uroflowmetry was 31.2%. In addition, the rate of use of recommended tests was higher among doctors in the north than among those in the south. Combination therapy with alpha-adrenoceptor antagonists and 5alpha reductase inhibitors was the preferred treatment option for BPH, and was increasingly used with worsening lower urinary tract symptoms. Finasteride was the most prescribed medication (48.0%), followed by tamsulosin (22.7%). CONCLUSIONS: This study assessed the preferences of urologists in the diagnosis and treatment of BPH, which will serve as an important reference for updating and improving China's current BPH clinical practice guideline. PMID- 23346487 TI - Long-term outcome of primary endoscopic realignment for bulbous urethral injuries: risk factors of urethral stricture. AB - PURPOSE: Although endoscopic realignment has been accepted as a standard treatment for urethral injuries, the long-term follow-up data on this procedure are not sufficient. We report the long-term outcome of primary endoscopic realignment in bulbous urethral injuries. METHODS: Patients with bulbous urethral injuries were treated by primary endoscopic realignment between 1991 and 2005. The operative procedure included suprapubic cystostomy and transurethral catheterization using a guide wire, within 72 hours of injury. The study population included 51 patients with a minimum follow-up duration of 5 years. RESULTS: The most common causes of the injuries were straddle injury from falling down (74.5%), and pelvic bone fracture (7.8%). Gross hematuria was the most common complaint (92.2%). Twenty-three patients (45.1%) had complete urethral injuries. The mean time to operation after the injury was 38.8+/-43.2 hours. The mean operation time and mean indwelling time of a urethral Foley catheter were 55.5+/-37.6 minutes and 22.0+/-11.9 days, respectively. Twenty out of 51 patients (39.2%) were diagnosed with urethral stricture in 89.1+/-36.6 months after surgery. A multivariate analysis revealed that young age and operation time were independent risk factors for strictures as a complication of urethral realignment (hazard ratio [HR], 6.554, P=0.032; HR, 6.206, P=0.035). CONCLUSIONS: Urethral stricture commonly developed as a postoperative complication of primary endoscopic urethral realignment for bulbous urethral injury, especially in young age and long operation time. PMID- 23346488 TI - Neurogenic bladder in lyme disease. AB - Lyme disease is a multi-systemic, tick-borne infectious disease caused by a spirochete, Borrelia burgdorferi. Various urologic symptoms are associated with Lyme disease, which can be primary or late manifestations of the disease. Although voiding dysfunction is a rarely reported symptom in patients with Lyme disease, it is one of the most disabling complications of Lyme disease. Korea is not an endemic area of Lyme disease, thus, fewer cases have been reported. Herein, we report a case of a 32-year-old man with rapidly progressive bilateral ptosis, dysphagia, spastic paraparesis, and voiding difficulty in whom Lyme disease was diagnosed through serologic tests for antibodies and Western blot testing. A urodynamic study demonstrated detrusor areflexia and bulbocavernosus reflex tests showed delayed latency, indicating demyelination at S2-S4 levels. He received a 4-week course of intravenous ceftriaxone (2 g/day). The patient has recovered from the bilateral ptosis and spastic paraparesis but still suffers from neurogenic bladder. PMID- 23346489 TI - Atypical epidermoid cyst in renal pelvis and histogenetic implications. AB - Since the renal epidermoid cyst is too rare, the mechanisms of squamous morphogenesis have not well characterized. A 73-year-old female was referred with an incidentally detected renal pelvis mass. Abdominopelvic computed tomography scan revealed a noncalcified soft tissue mass in the renal pelvis. Total nephroureterectomy was performed under the impression of a renal pelvis malignancy. The patient was discharged without postoperative complication. The outer surface of mass lesion was lined with urothelia and squamous epithelia, containing keratinous materials. The urothelia were positively stained against uroplakin II and cytokeratin 7, whereas almost of the squamous epithelia were negative with uroplakin II. The two different epithelia were generally sharply demarcated. Interestingly, some part of squamous epithelia contained uroplakin positive and many more cytokeratin 7-positive cells. The atypical clinical features in our case can reconsider the diagnostic clues of renal epidermoid cysts that have been reported before, and the unique immunohistochemical results may understand the histogenetic implications of the lesion. PMID- 23346490 TI - Bladder failure? PMID- 23346491 TI - Postoperative adjuvant radiotherapy for patients with gastric adenocarcinoma. AB - In gastric adenocarcinoma, high rates of loco-regional recurrences have been reported even after complete resection, and various studies have been tried to find the role of postoperative adjuvant therapy. Among them, Intergroup 0116 trial was a landmark trial, and demonstrated the definite survival benefit in adjuvant chemoradiotherapy, compared with surgery alone. However, the INT 0116 trial had major limitation for global acceptance of the INT 0116 regimen as an adjuvant treatment modality because of the limited lymph node dissection. Lately, several randomized studies that were performed to patients with D2-dissected gastric cancer were published. This review summarizes the data about patterns of failure after surgical resection and the earlier prospective studies, including INT 0116 study. Author will introduce the latest studies, including ARTIST trial and discuss whether external beam radiotherapy should be applied to patients receiving extended lymph node dissection and adjuvant chemotherapy. PMID- 23346492 TI - Prognostic factors on overall survival in lymph node negative gastric cancer patients who underwent curative resection. AB - PURPOSE: To assess independent prognostic factors for lymph node-negative metastatic gastric cancer patients following curative resection is valuable for more effective follow-up strategies. MATERIALS AND METHODS: Among 1,874 gastric cancer patients who received curative resection, 967 patients were lymph node negative. Independent prognostic factors for overall survival in lymph node negative gastric cancer patients grouped by tumor invasion depth (early gastric cancer versus advanced gastric cancer) were explored with univariate and multivariate analyses. RESULTS: There was a significant difference in the distribution of recurrence pattern between lymph node-negative and lymph node positive group. In the lymph node-negative group, the recurrence pattern differed by the depth of tumor invasion. In univariate analysis for overall survival of the early gastric cancer group, age, macroscopic appearance, histologic type, venous invasion, lymphatic invasion, and carcinoembryonic antigen level were significant prognostic factors. Multivariate analysis for these factors showed that venous invasion (hazard ratio, 6.695), age (>=59, hazard ratio, 2.882), and carcinoembryonic antigen level (>=5 ng/dl, hazard ratio, 3.938) were significant prognostic factors. Multivariate analysis of advanced gastric cancer group showed that depth of tumor invasion (T2 versus T3, hazard ratio, 2.809), and age (hazard ratio, 2.319) were prognostic factors on overall survival. CONCLUSIONS: Based on our results, independent prognostic factors such as venous permeation, carcinoembryonic antigen level, and age, depth of tumor invasion on overall survival were different between early gastric cancer and advanced gastric cancer group in lymph node-negative gastric cancer patients. Therefore, we are confident that our results will contribute to planning follow-up strategies. PMID- 23346493 TI - Clinical Correlation between Gastric Cancer Type and Serum Selenium and Zinc Levels. AB - PURPOSE: We conducted this study to study the clinical correlation between the characteristics of gastric cancer and serum selenium and zinc levels. MATERIALS AND METHODS: The following data were measured in the baseline serum selenium and zinc levels of 74 patients with curative gastrectomy subsequent to confirmed gastric cancer, from March 2005 to August 2012. RESULTS: Among the 74 gastric cancer patients, 53 patients were male. Mean serum selenium and zinc levels were 118.7+/-33.1 ug/L and 72.2+/-24.3 ug/dl, respectively. Seven patients (9.5%) showed lower selenium level, and 33 patients (44.6%) showed lower zinc level. Serum Selenium level was 99.1+/-31.8 ug/L in cardia cancer group (10 cases) and 121.8+/-32.4 ug/L in non-cardia cancer group (64 cases)(P=0.044). According to tumor gross type, zinc level was 78.7+/-29.6 ug/dl in early gastric cancer (33) and 66.9+/-17.8 ug/dl in advanced gastric cancer (41) (P=0.064). CONCLUSIONS: The serum selenium level was highly correlated with the location of gastric cancer. The serum zinc level was lower in advanced gastric cancer. PMID- 23346494 TI - Diagnostic value of clinical T staging assessed by endoscopy and stomach protocol computed tomography in gastric cancer: the experience of a low-volume institute. AB - PURPOSE: Clinical staging of gastric cancer appears to be important more and more for tailored therapy. This study aimed to verify the accuracy of clinical T staging in a low-volume institute. MATERIALS AND METHODS: We retrospectively reviewed prospectively collected data of gastric cancer patients who underwent resection. A total of 268 patients of gastric cancer were enrolled from March 2004 to June 2012. These demographics, tumor characteristics, and clinical stages were analyzed for identification of diagnostic value of clinical T staging. RESULTS: The predictive values for pT1 of endoscopy and computed tomography were 90.0% and 89.4%, respectively. In detail, the predictive values of endoscopy for pT1a, pT1b, and pT2 or more were 87%, 58.5%, and 90.6%, respectively. The predictive values of computed tomography for pT1a, pT1b, and pT2 or more were 68.8%, 73.9%, and 84.4%, respectively. The factors leading to underestimation of pT2 or more lesions by gastroscopy were the middle third location, the size greater than 2 cm, and younger age. Those for overestimation of pT1 lesion by computed tomography were male, age more than 70 years, elevated type, and size greater than 3 cm. CONCLUSIONS: Diagnostic accuracy of early gastric cancer was 90%, which is comparable to those of high volume center. In patients with early gastric cancer, limited gastrectomy or minimal invasive surgery can be safely introduced at a low volume center also. However, the surgeon of low-volume institute should consider the accuracy of clinical staging before extending the indication of limited treatment. PMID- 23346495 TI - Laparoscopy-assisted distal gastrectomy for early gastric cancer in the elderly. AB - PURPOSE: With an increase in life expectancy, more elderly patients are presenting with gastric cancer. As a result it is yet be resolved whether laparoscopy assisted distal gastrectomy is a suitable treatment for elderly patients with early gastric cancer. This study retrospectively compared surgical outcomes of laparoscopy assisted distal gastrectomy between elderly and nonelderly patients with gastric cancer. MATERIALS AND METHODS: The study group was comprised of 316 patients who underwent laparoscopy assisted distal gastrectomy between April 2005 and December 2010. Of these patients, 93 patients whose ages were 65 years or more were compared with 223 patients who were younger. RESULTS: There were no differences in the short term outcome or minor complication rate between the elderly patients and the nonelderly patients. The hospital stay was significantly longer and the major complication rate was significantly higher for the elderly patients compared with nonelderly patients. CONCLUSIONS: Laparoscopy assisted distal gastrectomy for early gastric cancer in the elderly patients had comparable operation time and blood loss with the nonelderly group. However, the safety and advantage of laparoscopy assisted distal gastrectomy in the elderly patients need to be further studied in higher volume trials. PMID- 23346496 TI - Laparoscopic primary repair with omentopexy for duodenal ulcer perforation: a single institution experience of 21 cases. AB - PURPOSE: Despite the great advances in laparoscopic techniques, most active general surgeons do not apply laparoscopic surgery in the treatment of duodenal ulcer perforation when facing a real-life emergency. Therefore, our study was designed to evaluate the feasibility of laparoscopic surgery in duodenal ulcer perforation, and provide a step-by-step protocol with tips and recommendations for less experienced surgeons. MATERIALS AND METHODS: Between March, 2011 and May, 2012, 21 patients presenting with duodenal ulcer perforation underwent laparoscopic primary repair with omentopexy. There were no contraindications to perform laparoscopic surgery, and the choice of primary repair was decided according to the size of the perforation. The procedure for laparoscopic primary repair with omentopexy consisted of peritoneal lavage, primary suture, and omentopexy using a knot pusher. RESULTS: During the operation, no conversion to open surgery or intra-operative events occurred. The median operation time was 45.0 minutes (20~80 minutes). Median day of commencement of a soft diet was day 6 (4~17 days). After surgery, the median hospital stay was 8.0 days (5~27 days). Postoperative complications occurred in one patient, which included a minor leakage. This complication was resolved by conservative management. CONCLUSIONS: Although our study was carried out on a small number of patients at a single institution, we conclude that laparoscopic primary repair can be an effective surgical method in the treatment of duodenal ulcer perforation. We believe that the detailed explanation of our procedure will help beginners to perform laparoscopic primary repair more easily. PMID- 23346497 TI - Treatment Results of Small Intestinal Gastrointestinal Stromal Tumors Less than 10 cm in Diameter: A Comparison between Laparoscopy and Open Surgery. AB - PURPOSE: To evaluate the technical feasibility and oncologic safety, we assessed the short-term and long-term outcomes of laparoscopic resection of the small bowel gastrointestinal stromal tumors smaller than 5 cm by comparing those of open surgery by subgroup analysis based on tumor size. MATERIALS AND METHODS: From November 1993 to January 2011, 41 laparoscopic resections were performed among the 95 patients who underwent resection of small intestine <=10 cm in diameter. The clinicopathologic features, perioperative outcomes, recurrences and survival of these patients were reviewed. RESULTS: The postoperative morbidity rates were comparable between the 2 groups. Laparoscopic surgery group showed significantly shorter operative time (P=0.004) and duration of postoperative hospital stay (P<0.001) than open surgery group and it was more apparent in the smaller tumor size group. There were no difference in 5-year survival for the laparoscopic surgery versus open surgery groups (P=0.163), and in 5-year recurrence-free survival (P=0.262). The subgroup analysis by 5 cm in tumor size also shows no remarkable differences in 5-year survival and recurrence-free survival. CONCLUSIONS: Laparoscopic resection for small bowel gastrointestinal stromal tumors of size less than 10 cm has favorable short-term postoperative outcomes, while achieving comparable oncologic results compared with open surgery. Thus, laparoscopic approach can be recommended as a treatment modality for patients with small bowel gastrointestinal stromal tumors less than 10 cm in diameter. PMID- 23346498 TI - Two Cases of Laparoscopic Adhesiolysis for Chronic Abdominal Pain without Intestinal Obstruction after Total Gastrectomy. AB - Chronic abdominal pain remains a challenge to all known diagnostic and treatment methods with patients undergoing numerous diagnostic work-ups including surgery. However, the surgical treatment of patients with chronic intractable abdominal pain is controversial. There has been no discussion of the indications for adhesiolysis in cases of obstruction or strangulation of the bowel, and adhesiolysis by laparotomy has never gained acceptance as a treatment modality for chronic abdominal pain. One of the reasons for this lack of acceptance is the high complication rate during and after adhesiolysis. Laparoscopic surgery has been accepted as a technique for diagnostic and therapeutic procedures in general surgery. Laparoscopy allows surgeons to see and treat many abdominal changes that could not otherwise be diagnosed. Here we report two cases of successful symptomatic improvement through laparoscopic adhesiolysis for chronic abdominal pain without intestinal obstruction after total gastrectomy. PMID- 23346499 TI - Gastric cancer and concomitant gastric tuberculosis: a case report. AB - Gastric tuberculosis is rare even in the endemic areas of tuberculosis, and can mimic neoplasm by causing elevation of the mucosa with or without ulceration. Here, we report a case in which a 54-year-old female patient admitted for resection of early gastric cancer was found to have coexisting histopathologically and bacteriologically confirmed gastric cancer and tuberculosis. PMID- 23346500 TI - Ewing's Sarcoma of the Stomach; Rare Case of Ewing's Sarcoma and Suggestion of New Treatment Strategy. AB - Ewing's sarcoma is a neoplasm of the undifferenciated small round cells, which generally affects the bone and deep soft tissues of children and adolescents. We present a case of gastric Ewing's sarcoma; a 35-year-old female who had no symptoms. While she was at a routine medical checkup, a protruding mass in her gastric antrum was incidentally found on esophagogastroduodenoscopy. Endoscopic ultrasonogram showed a submucosal mass on the same lesion and a laparosopic wedge resection was done. Pathologic gross findings showed a granular grape appearance tissue and histoloigc examination revealed a small round cell tumor with CD 99 immunoexpression positive. In general, a combined modality therapy for Ewing's sarcoma such as surgical resection with chemotherapy, is accepted as an effective method. However, this patient had no adjuvant chemotherapy after surgery and she has no recurrence for eleven months. PMID- 23346502 TI - Condyloma acuminate and increase in the number of human immunodeficiency virus positive patients. PMID- 23346503 TI - Risk factors for incisional hernia and parastomal hernia after colorectal surgery. PMID- 23346504 TI - Single-incision laparoscopic appendectomy. PMID- 23346505 TI - Finding a new prognostic biomarker for metastatic colorectal cancer. PMID- 23346506 TI - Pelvic exenteration: surgical approaches. AB - Although the incidence of local recurrence after curative resection of rectal cancer has decreased due to the understanding of the anatomy of pelvic structures and the adoption of total mesorectal excision, local recurrence in the pelvis still remains a significant and troublesome complication. While surgery for recurrent rectal cancer may offer a chance for a cure, conservative management, including radiation and chemotherapy, remain widely accepted courses of treatment. Recent improvement in imaging modalities, perioperative care, and surgical techniques, including bone resection and wound coverage, have allowed for reductions in operative mortality, though postoperative morbidity still remains high. In this review, the techniques, including surgical approaches, employed for management of locally recurrent rectal cancer are highlighted. PMID- 23346507 TI - Association of immune status with recurrent anal condylomata in human immunodeficiency virus-positive patients. AB - PURPOSE: An anal condyloma is a proliferative disease of the genital epithelium caused by the human papillomavirus. This condition is most commonly seen in male homosexuals and is frequently recurrent. Some reports have suggested that immunosuppression is a risk factor for recurrence of a condyloma. Thus, we investigated the risk factors for a recurrent anal condyloma in human immunodeficiency virus (HIV)-positive patients. METHODS: We retrospectively analyzed 85 consecutive patients who were diagnosed with and underwent surgery for an anal condyloma from January 2007 to December 2011. Outcomes were analyzed based clinical and immunologic data. RESULTS: Recurrent anal condylomata were found in 25 patients (29.4%). Ten cases (40.0%) were within postoperative 3 months. At postoperative 6 months, the CD4 lymphocyte count in the recurrent group was lower than it was in the nonrecurrent group (P = 0.023). CONCLUSION: CD4-mediated immunosuppression is a risk factor for recurrent anal condylomata in HIV-positive patients. PMID- 23346508 TI - Analysis of risk factors for the development of incisional and parastomal hernias in patients after colorectal surgery. AB - PURPOSE: The purpose of this study was to evaluate the overall rate and risk factors for the development of an incisional hernia and a parastomal hernia after colorectal surgery. METHODS: The study cohort consisted of 795 consecutive patients who underwent open colorectal surgery between 2005 and 2007 by a single surgeon. A retrospective analysis of prospectively collected data was performed. RESULTS: The overall incidence of incisional hernias was 2% (14/690). This study revealed that the cumulative incidences of incisional hernia were 1% at 12 months and 3% after 36 months. Eighty-six percent of all incisional hernias developed within 3 years after a colectomy. The overall rate of parastomal hernias in patients with a stoma was 6.7% (7/105). The incidence of parastomal hernias was significantly higher in the colostomy group than in the ileostomy group (11.9% vs. 0%; P = 0.007). Obesity, abdominal aortic aneurysm, American Society of Anesthesiologists score, serum albumin level, emergency surgery and postoperative ileus did not influence the incidence of incisional or parastomal hernias. However, the multivariate analysis revealed that female gender and wound infection were significant risk factors for the development of incisional hernias female: P = 0.009, wound infection: P = 0.041). There were no significant factors related to the development of parastomal hernias. CONCLUSION: Our results indicate that most incisional hernias develop within 3 years after a colectomy. Female gender and wound infection were risk factors for the development of an incisional hernia after colorectal surgery. In contrast, no significant factors were found to be associated with the development of a parastomal hernia. PMID- 23346509 TI - Comparative study of a single-incision laparoscopic and a conventional laparoscopic appendectomy for the treatment of acute appendicitis. AB - PURPOSE: For the treatment of acute appendicitis, a conventional laparoscopic appendectomy (LA) has been widely performed. Recently, the use of single incision laparoscopic surgery (SILS) is increasing because it is believed to have advantages over conventional laparoscopic surgery. In this study, we compared SILS and a conventional LA. METHODS: We analyzed the 217 patients who received laparoscopy-assisted appendectomies between August 2010 and April 2012 at Inje University Sanggye Paik Hospital. One hundred-twelve patients underwent SILS, and 105 patients underwent LA. For the two groups, we compared the operation times, postoperative laboratory results, postoperative pain, hospital stay, and postoperative complications. RESULTS: The patients' demographics, including body mass index, were not significantly different between the two groups. There were 6 perforated appendicitis cases in the SILS group and 5 cases in the LA group. The mean operative time in the SILS group was 65.88 +/- 22.74 minutes whereas that in the LA group was 61.70 +/- 22.27 minutes (P = 0.276). There were no significant differences in the mean hospital stays, use of nonsteroidal antiinflammatory drugs, and wound infections between the two groups. CONCLUSION: Postoperative pain, complications and hospital stay showed no statistically significant differences between the SILS and the LA groups. However, our SILS method uses a single trocar and two latex tubes, so cost savings and reduced interference during surgery are expected. PMID- 23346510 TI - The use of a staged drainage seton for the treatment of anal fistulae or fistulous abscesses. AB - PURPOSE: The aim of this retrospective study was to evaluate the rate of recurrence and incontinence after the treatment of fistulae or fistulous abscesses by using the staged drainage seton method. METHODS: According to the condition, a drainage seton alone or a drainage seton combined with internal opening (IO) closure and relocation of the seton was used. After a period of time, the seton was changed with 3-0 nylon; then, after another period of time, the authors terminated the treatment by removing the 3-0 nylon. Telephone interviews were used for follow-up. The following were evaluated: the relationship between the type of fistula and recurrence; the relationship between the type of fistula and the period of treatment; the relationship between the recurrence and presence of abscess; the relationship between IO closure and recurrence; the relationship between the period of seton change and recurrence; reported continence for flatus, liquid stool, and solid stool. RESULTS: The recurrence rate of fistulae or suppuration was 6.5%, but for cases of horseshoe extension, the recurrence rate was 57.1%. The rate of recurrence was related to the type of fistula (P = 0.001). Incontinence developed in 3.8% of the cases. No statistically significant relationship was found between the rate of recurrence and the presence of an abscess or between the closure of the IO and the period of seton change or removal. CONCLUSION: In the treatment of anal fistulae or fistulous abscesses, the use of a staged drainage seton can reduce the rate of recurrence and incontinence. PMID- 23346511 TI - Expression of placenta growth factor in colorectal carcinomas. AB - PURPOSE: Placenta growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family. PlGF is implicated in several pathologic processes, including the growth and spread of cancer and tumor angiogenesis. The aim of this study was to evaluate the expression and the clinical implications of PlGF in colorectal cancer. METHODS: In order to ascertain the clinical significance of PlGF expression in colorectal cancer, the researcher analyzed the expression pattern of PlGF by using an immunohistochemical method and attempted to establish if a relationship existed between PlGF expression and microvessel density (MVD), and subsequently between PlGF expression and the predicted prognosis. A total of 83 patients with colorectal cancer were included for immunohistochemical staining. Clinicopathological characteristics were defined according to the tumor node-metastasis (TNM) criteria of the Union for International Cancer Control. Clinicopathologic factors, such as age, sex, histological types of tumors, tumor cell grade, TNM stage, lymphovascular invasion, and lymph-node metastasis, were reviewed. RESULTS: In this study, the PlGF protein expression level was significantly correlated with MVD, patient survival, and clinicopathological factors such as lymph-node metastasis, TNM staging, lymphatic invasion and vascular invasion. CONCLUSION: PlGF may be an important angiogenic factor in human colorectal cancer, and in this study, PlGF expression level was significantly correlated with positive lymph-node metastases, tumor stage, and patient survival. These findings suggest that PlGF expression correlates with disease progression and may be used as a prognostic marker for colorectal cancer. PMID- 23346512 TI - Colouterine fistula caused by diverticulitis of the sigmoid colon. AB - Colouterine fistula is an extremely rare condition because the uterus is a thick, muscular organ. Here, we present a case of a colouterine fistula secondary to colonic diverticulitis. An 81-year-old woman was referred to the emergency department with abdominal pain and vaginal discharge. Computed tomography showed a myometrial abscess cavity in the uterus adherent to the thick sigmoid wall. Upon contrast injection via the cervical os for fistulography, we observed spillage of the contrast into the sigmoid colon via the uterine fundus. Inflammatory adhesion of the distal sigmoid colon to the posterior wall of the uterus was found during surgery. The colon was dissected off the uterus. Resection of the sigmoid colon, primary anastomosis, and repair of the fistula tract of the uterus were performed. The postoperative course was uneventful. This case represents an unusual type of diverticulitis complication and illustrates diagnostic procedures and surgical management for a colouterine fistula. PMID- 23346513 TI - Necrotizing fasciitis of the thigh secondary to radiation colitis in a rectal cancer patient. AB - Necrotizing fasciitis usually occurs after dermal injury or through hematogenous spread. To date, few cases have been reported as necrotizing fasciitis of the thigh secondary to rectal perforation in rectal cancer patients. A 66-year-old male complained of pelvic and thigh pain and subsequently developed necrotizing fasciitis in his right thigh. Four years earlier, he had undergone a low anterior resection and radiotherapy due to of rectal cancer. An ulcerative lesion had been observed around the anastomosis site during the colonoscopy that had been performed two months earlier. Pelvic computed tomography and sigmoidoscopy showed rectal perforation and presacral abscess extending to buttock and the right posterior thigh fascia. Thus, the necrotizing fasciitis was believed to have occurred because of ulcer perforation, one of the complications of chronic radiation colitis, at the anastomosis site. When a rectal-cancer patient complains of pelvic and thigh pain, the possibility of a rectal perforation should be considered. PMID- 23346514 TI - Deep brain stimulation: a novel strategy for treating Alzheimer's disease. AB - Recent studies have identified an association between memory deficits and defects of the integrated neuronal cortical areas known collectively as the default mode network. It is conceivable that the amyloid deposition or other molecular abnormalities seen in patients with Alzheimer's disease may interfere with this network and disrupt neuronal circuits beyond the localized brain areas. Therefore, Alzheimer's disease may be both a degenerative disease and a broader system-level disorder affecting integrated neuronal pathways involved in memory. In this paper, we describe the rationale and provide some evidence to support the study of deep brain stimulation of the hippocampal fornix as a novel treatment to improve neuronal circuitry within these integrated networks and thereby sustain memory function in early Alzheimer's disease. PMID- 23346515 TI - Hematologic impact of antibiotic administration on patients taking clozapine. AB - OBJECTIVE: The purpose of this study was to determine if the drop in white blood cell/absolute neutrophil count for clozapine patients on antibiotics is a normal response to the resolution of infection or if the concurrent administration resulted in an abnormal drop in blood counts and further reduction of white blood cell/absolute neutrophil below baseline prior to infection. DESIGN: This was a retrospective record review of all patients who received clozapine and antibiotics concurrently between June 30, 2010, and June 30, 2011. SETTING: Subjects included inpatients on clozapine therapy at a state psychiatric facility. PARTICIPANTS: This protocol was approved by the Institutional Review Board of record. A total of 42 patients prescribed 93 antibiotic regimens were found to meet all of the above requirements. MEASUREMENTS AND METHODS: Medications were placed into distinct groups based on approved use and mechanism of action. Pearson Correlation Coefficients were utilized and were found to be 0.409 (p<0.01), indicating that a statistically significant relationship existed between the use of systemic antibiotics and alterations in hematologic parameters. RESULTS: Each regimen was classified by specific agent as well as whether the final white blood cell/absolute neutrophil was above or below the baseline established for each patient. CONCLUSION: Antibiotics have been identified as one category of medications that may cause decreased white blood cell/absolute neutrophil counts when combined with clozapine. Our study supports the use of either ciprofloxacin or moxifloxacin as agents that may have less risk of reductions in white blood cell/absolute neutrophil counts than are seen with penicillins, cephalosporins, and other antibiotics that may ultimately require interruption or discontinuation of clozapine therapy. PMID- 23346516 TI - A case of treatment refractory hyperemesis gravidarum in a patient with comorbid anxiety, treated successfully with adjunctive gabapentin: a review and the potential role of neurogastroentereology in understanding its pathogenesis and treatment. AB - Hyperemesis gravidarum occurs in 0.3 to 10 percent of pregnant women, with a 0.8 percent hospital admission rate. While older theories supported the psychosocial model as a cause for hyperemesis gravidarum, more recent studies have shown significant data to support a biological etiology. Hyperemesis gravidarum has serious complications including include increased risk for miscarriage, low birth weight infants, dehydration, Wernicke's encephalopathy, secondary depression, and negative attitudes toward a consecutive pregnancy. Because of these life threatening complications and complexity of the disease, it is important to treat both somatic and psychosocial causes of hyperemesis gravidarum to provide the best care for the patient. This paper presents a case of a woman with anxiety symptoms who was experiencing severe nausea and vomiting since Week 2 of pregnancy, with minimal reduction of these symptoms on standard medications utilized in hyperemesis gravidarum. The patient had marked reduction of nausea and vomiting with adjunctive gabapentin. After a brief review of relevant neurogastroenterology, we discuss a possible mechanism for the added gabapentin. PMID- 23346517 TI - Successful use of rasagiline in combination with two antidepressants: a case report. AB - Parkinson's disease is the second most common neurodegenerative disorder, affecting 1 to 2 percent of people older than 60 years. Recent reviews show that depression is a common and potentially debilitating aspect of Parkinson's disease, affecting 40 to 50 percent of patients. Depression in Parkinson's disease is demonstrably different from ordinary major depression in terms of gender ratio, age, symptom profile, comorbidity, and chronicity. Pharmacotherapy for depression in Parkinson's disease entails special concerns related to side effects and drug-drug interactions. Rasagiline is a novel, potent, and irreversible monoamine oxidase type B (MAO-B) inhibitor that has recently been approved by the Food and Drug Administration for treatment of Parkinson's disease. Current rasagiline labeling advises the avoidance of coadministration of rasagiline and antidepressants, which is a challenge in itself for patients with co-morbid depression. We present a case of a 58-year-old woman who failed most of the pharmacologic treatments for Parkinson's disease, including deep brain stimulation, and was recently prescribed rasagiline with good response. She also met the Diagnostic and Statistical Manual, Fourth Edition, Text Revision criteria of major depressive disorder, which was treated with venlafaxine and bupropion. To our knowledge, this is first clinical case report of successful use of a combination of antidepressants and rasagiline in a patient with Parkinson's disease. PMID- 23346518 TI - Doctor shopping: a phenomenon of many themes. AB - Doctor shopping is defined as seeing multiple treatment providers, either during a single illness episode or to procure prescription medications illicitly. According to the available literature, prevalence rates of doctor shopping vary widely, from 6.3 to 56 percent. However, this variability is partially attributable to research methodology, including the study definition of doctor shopping as well as the patient sample. The reasons for doctor shopping are varied. Some patient explanations for this phenomenon relate to clinician factors, such as inconvenient office hours or locations, long waiting times, personal characteristics or qualities of the provider, and/or insufficient communication time between the patient and clinician. Some patient explanations relate to personal factors and include both illness factors (e.g., symptom persistence, lack of understanding or nonacceptance of the diagnosis or treatment) as well as psychological factors (e.g., somatization, prescription drug-seeking). Importantly, not all doctor shopping is driven by suspect motivations. Being aware of these various patient justifications for doctor shopping is important in understanding and managing these challenging patients in the clinical setting, whether they emerge in psychiatric or primary care environments. PMID- 23346519 TI - Technology, society, and mental illness: challenges and opportunities for assessment and treatment. AB - Technology is rapidly changing society, and many activities now require the ability to use technology. This situation has the potential to lead to problems for several populations, including the elderly, the disadvantaged, and people with severe mental illness. In this column, we review the state of technology as it affects daily activities. We then review previous efforts to use technology positively for both the assessment and treatment of psychiatric conditions, including posttraumatic stress disorder and severe mental illness. We conclude that technology-based interventions and assessment strategies have the potential to deliver benefit to a wide array of older people and those with severe mental illness, including reaching people who would not have had access otherwise. PMID- 23346520 TI - Hipaa-should I be worried? PMID- 23346521 TI - Transcription factors in the maintenance and survival of primordial follicles. AB - Primordial follicles are formed prenatally in mammalian ovaries, and at birth they are fated to be activated to primary follicles, to be dormant, or to die. During the early stage of folliclulogenesis, the oocyte undergoes dynamic alterations in expression of numerous genes, which are regulated by transcription factors. Several germ-cell specific transcriptional regulators are critical for formation and maintenance of follicles. These transcriptional regulators include: Figla, Lhx8, Nobox, Sohlh1, and Sohlh2. A subset of these transcriptional regulators is mutated in women with ovarian insufficiency and infertility. Establishment of this oocyte pool is essential for fertility. This review focuses on these transcriptional regulators of female primordial follicles. PMID- 23346522 TI - Empty follicle syndrome. AB - Empty follicle syndrome (EFS) is a condition in which no oocytes are retrieved after an apparently adequate ovarian response to stimulation and meticulous follicular aspiration. EFS can be classified into 'genuine' and 'false' types according to hCG levels. It is a rare condition of obscure etiology. The existence of genuine EFS has been questioned and is still controversial. The limitation around EFS is that the definition of EFS is obscure. Management of patients with EFS is a challenge to physicians. No single treatment is known to be universally effective. However, patients should be adequately informed regarding the importance of correct hCG administration because improper hCG administration is a common and preventable cause of EFS. EFS is a syndrome that deserves additional study because such investigation could lead to a further understanding of ovarian biology and infertility. PMID- 23346523 TI - Current issues on a standard for surrogate pregnancy procedures. AB - While Korea does not have any legal statement on surrogacy, treatments are carried out in practice. As a result, every Institutional Review Board (IRB) of each fertility clinic faces an ethical predicament in reviewing each case. There is a need to arrange the institutions' own standards of surrogate pregnancy procedures before the establishment of national or professional regulation. This article examines the legal, social, and medical issues of surrogacy to help IRBs to judge their cases. PMID- 23346524 TI - Maternal caffeine consumption has irreversible effects on reproductive parameters and fertility in male offspring rats. AB - OBJECTIVE: Concerns are growing about the decrease in male reproductive health. Caffeine is one of the popular nutrients that has been implicated as a risk factor for infertility. In the present study, we examined whether in utero and lactational exposure to caffeine affects the reproductive function of the offspring of rats. METHODS: Pregnant rats received caffeine via drinking water during gestation (26 and 45 mg/kg) and lactation (25 and 35 mg/kg). Body and reproductive organ weight, seminiferous tubule diameter, germinal epithelium height, sperm parameters, fertility rate, number of implantations, and testosterone level of the offspring were assessed from birth to adulthood. RESULTS: Significant dose-related decreases were observed in the body and reproductive organ weight, seminiferous tubule diameter, and germinal epithelium height of the offspring. Sperm density had declined significantly in offspring of the low-dose and high-dose groups, by 8.81% and 19.97%, respectively, by postnatal day 150. The number of viable fetuses had decreased significantly in females mated with male offspring of the high-dose group at postnatal days 60, 90, 120, and 150. There were also significant reductions in testosterone levels of high-dose group offspring from birth to postnatal day 150. CONCLUSION: It is concluded that maternal caffeine consumption impairs gonadal development and has long-term adverse effects on the reproductive efficiency of male offspring rats. PMID- 23346525 TI - Vitrification of mouse embryos using the thin plastic strip method. AB - OBJECTIVE: The aim of this study was to compare vitrification optimization of mouse embryos using electron microscopy (EM) grid, cryotop, and thin plastic strip (TPS) containers by evaluating developmental competence and apoptosis rates. METHODS: Mouse embryos were obtained from superovulated mice. Mouse cleavage-stage, expanded, hatching-stage, and hatched-stage embryos were cryopreserved in EM grid, cryotop, and TPS containers by vitrification in 15% ethylene glycol, 15% dimethylsulfoxide, 10 ug/mL Ficoll, and 0.65 M sucrose, and 20% serum substitute supplement (SSS) with basal medium, respectively. For the three groups in which the embryos were thawed in the EM grid, cryotop, and TPS containers, the thawing solution consisted of 0.25 M sucrose, 0.125 M sucrose, and 20% SSS with basal medium, respectively. Rates of survival, re-expansion, reaching the hatched stage, and apoptosis after thawing were compared among the three groups. RESULTS: Developmental competence after thawing of vitrified expanded and hatching-stage blastocysts using cryotop and TPS methods were significantly higher than survival using the EM grid (p<0.05). Also, apoptosis positive nuclei rates after thawing of vitrified expanded blastocysts using cryotop and TPS were significantly lower than when using the EM grid (p<0.05). CONCLUSION: The TPS vitrification method has the advantages of achieving a high developmental ability and effective preservation. PMID- 23346526 TI - Hysterosalpingo-contrast sonography: is possible to quantify the therapeutic effect of a diagnostic test? AB - OBJECTIVE: To evaluate the effect of hysterosalpingo-contrast sonography (HyCoSy) on natural conception in the infertile patient. METHODS: We conducted a prospective observational study recruiting 180 patients admitted to Infertility Center of Ferrara University from January 2010 to February 2012. The essential inclusion criteria was the couple's desire to perform only diagnostic evaluation on infertility causes and to wait for natural conception before proceeding with further management. Couples were investigated with hormonal profile, semen analysis and HyCoSy. Expected time for spontaneous pregnancy was 180 days from HyCoSy. First datation sonography of pregnancy was used calculating time elapsed from HyCoSy at conception. RESULTS: Forty patients (22.2%) obtained spontaneous pregnancy within 6 months after HyCoSy. The mean of "conception time" was 75 days. The pregnancy rate was significantly higher in the first 30 days (45%) compared to other the months of observation (p<0.0005). Multiple linear regression analysis showed that maternal age and sterility duration proved independent variables in detecting the "conception time" after HyCoSy (t=3.742, p=0.001, t=2.371, p=0.02, respectively). CONCLUSION: A possible beneficial effect of HyCoSy is feasible especially in the days following its execution. This temporal correlation supports its therapeutic use. PMID- 23346527 TI - Comparison of assisted reproductive technology outcomes in infertile women with polycystic ovary syndrome: In vitro maturation, GnRH agonist, and GnRH antagonist cycles. AB - OBJECTIVE: We compared the assisted reproductive technology (ART) outcomes among infertile women with polycystic ovary syndrome (PCOS) treated with IVM, conventional IVF, GnRH agonist, and GnRH antagonist cycles. METHODS: The prospective study included a total of 67 cycles in 61 infertile women with PCOS. The women with PCOS were randomized into three IVF protocols: IVM/IVF with FSH and hCG priming with immature oocyte retrieval 38 hours later (group A, 14 cycles), GnRH agonist long protocol (group B, 14 cycles), and GnRH antagonist multi-dose flexible protocol (group C, 39 cycles). IVF outcomes, such as clinical pregnancy rate (CPR), implantation rate (IR), miscarriage rate (MR), and live birth rate (LBR), were compared among the three groups. RESULTS: Age, BMI, and basal FSH and LH levels did not differ among the three groups. The number of retrieved oocytes and 2 pronucleus embryos was significantly lower in group A compared with groups B and C. The CPR, IR, MR, and LBR per embryo transfer showed no differences among the three groups. There was no incidence of ovarian hyperstimulation syndrome in group A. CONCLUSION: The IR, MR, and LBR in the IVM cycles were comparable to those of the GnRH agonist and GnRH antagonist cycles. The IVM protocol, FSH and hCG priming with oocyte retrieval 38 hours later, is an effective ART option that is comparable with conventional IVF for infertile women with PCOS. PMID- 23346528 TI - Causes and classification of male infertility in Korea. AB - OBJECTIVE: The aim of this study is to investigate the various causes of male infertility using multiple approaches. METHODS: Nine-hundred-twenty infertile male patients were analyzed at their first visit with one physician between January 1 and December 31, 2009. All patients were subjected to physical examination, semen analysis and azoospermic patients underwent hormonal testing, chromosomal tests, and testicular biopsy. Semen analysis was based on the definition of the World Health Organization. RESULTS: Among the 920 patients, 555 patients (60.3%) had semen results within the normal range, 269 patients (29.2%) within the abnormal range, and 96 (10.5%) were diagnosed with azoospermia. Varicoceles were diagnosed in 84 of the 555 normal-range patients (15.1%) and in 113 of the 269 abnormal-range patients (42.0%). Of the 96 patients with azoospermia, 24 patients (25%) were diagnosed with obstructive azoospermia, 68 patients (71%) with non-obstructive azoospermia, and 4 patients (4%) with retrograde ejaculation. CONCLUSION: Various causes of male infertility have been reported and diverse treatment methods can be adopted for each cause. In this regard, research must be conducted on a larger number of patients to accurately assess the various causes of infertility in Korean patients and to investigate various infertility treatment methods. PMID- 23346529 TI - Clinical application of anti-Mullerian hormone as a predictor of controlled ovarian hyperstimulation outcome. AB - OBJECTIVE: In 2009 anti-Mullerian hormone (AMH) assay was approved for clinical use in Korea. This study was performed to determine the reference values of AMH for predicting ovarian response to controlled ovarian hyperstimulation (COH) using the clinical assay data. METHODS: One hundred sixty-two women who underwent COH cycles were included in this study. We collected data on age, basal AMH and FSH levels, total dose of gonadotropins, stimulation duration, and numbers of oocytes retrieved and fertilized. Blood samples were obtained on cycle day 3 before gonadotropin administration started. Serum AMH levels were measured at a centralized clinical laboratory center. The correlation between the AMH level and COH outcomes and cut-off values for poor and high response after COH was analyzed. RESULTS: Concentration of AMH was significantly correlated with the number of oocytes retrieved (OPU; r=0.700, p<0.001). The mean+/-SE serum AMH levels for poor (OPU<=3), normal (4<=OPU<=19), and high (OPU>=20) response were 0.94+/-0.15 ng/mL, 2.79+/-0.21 ng/mL, and 6.94+/-0.90 ng/mL, respectively. The cut-off level, sensitivity and specificity for poor and high response were 1.08 ng/mL, 85.8%, and 78.6%; and 3.57 ng/mL, 94.4%, and 83.3%, respectively. CONCLUSION: Our data present clinical reference values of the serum AMH level for ovarian response in Korean women. The serum AMH level could be a clinically useful predictor of ovarian response to COH. PMID- 23346530 TI - Comparison of IVF-ET outcomes in patients with hydrosalpinx pretreated with either sclerotherapy or laparoscopic salpingectomy. AB - OBJECTIVE: Many studies have demonstrated that hydrosalpinx has a detrimental effect on the outcome of IVF. Treating hydrosalpinges prior to the IVF procedure in women with hydrosalpinges is thought to improve the likelihood of successful IVF outcome. Vaginal ultrasound-guided aspiration of hydrosalpinx fluid (HSF) with injection of the sclerosing agent in situ might be simpler than invasive procedures like salpingectomy. Therefore, we carried out a retrospective study on the effects of ultrasound-guided HSF aspiration and injection of the sclerosing agent of ultrasonically diagnosed hydrosalpinx on IVF outcome. METHODS: In our retrospective study, 97 tubal factor infertile female patients that underwent IVF treatment between January 2005 and December 2012 at the Reproductive Medicine Center of CHA Hospital were divided into two study groups. Fifty-six patients underwent interventional ultrasound sclerotherapy (group 1), and the remaining 41 patients received laparoscopic salpingectomy (group 2) before IVF. We compared the IVF outcomes of the two groups. RESULTS: The results showed that ultrasound guided HSF aspiration and sclerotherapy have IVF outcomes comparable to laparoscopic salpingectomy. CONCLUSION: Interventional ultrasound guided sclerotherapy before IVF is an effective and less invasive prophylactic intervention alternative to salpingectomy with hydrosalpinx. PMID- 23346531 TI - What is the best treatment of heterotopic cervical pregnancies for a successful pregnancy outcome? AB - Heterotopic pregnancy is rare event and the risk is increased with assisted reproductive technology procedures. Heterotopic cervical pregnancy is even more unusual. We report a rare case of heterotopic cervical pregnancy that was managed successfully. A 36-year-old women who conceived by IVF-ICSI was diagnosed with heterotopic cervical pregnancy. She visited the emergency room with vaginal bleeding at 5 weeks of gestation and underwent careful intracervical gestational sac reduction with forceps under abdominal guidance the next day. The postoperative course was uneventful and with regular check-ups, the intrauterine pregnancy (IUP) progressed unremarkably through 41 weeks with delivery of a healthy newborn. We reviewed a total of 37 cases of heterotopic pregnancy that have been reported in the English language literature. There have been many attempts to eliminate the cervical embryo while preserving the IUP, and complete cervical evacuation is important in order to avoid infection, bleeding, and premature birth. PMID- 23346533 TI - Role of radiotherapy in local control of non-AIDS associated Kaposi's sarcoma patients in Korea: a single institution experience. AB - PURPOSE: There has been no definite consensus on standard treatment, either local or systemic, for the Kaposi's sarcoma (KS). Radiotherapy (RT) can be a good local therapeutic choice especially in non-AIDS associated KS (NAKS) for its indolent behavior. MATERIALS AND METHODS: Medical records of 17 KS patients treated with RT at the Seoul National University Hospital from February 1998 to January 2012 were retrospectively reviewed. One human immunodeficiency virus (HIV)+ patient with 3 lesions was excluded. The total number of the lesion was 23 among the 16 patients. The median follow-up period was 27.9 months. Correlation between response and variables was analyzed using the logistic regression model. Median age of the patients was 75 years. All the 23 lesions were located at the extremities. Fourteen (61%) of those had pain or local swelling as the initial presentation. Ten patients had possible causes of immunodeficiency and were regarded as iatrogenic, and other 6 were classic KS. Median dose of RT was 36 Gy. RESULTS: No KS-related death was observed. Excluding 2 with short-term follow-up only, complete response and partial response were obtained in 2 (9%) and 19 (73%) lesions, respectively. Of those, 3 lesions underwent local progression. Six had out-of-field recurrence after RT. Symptom improvement was achieved in 13 (93%) of 14 patients. Grade 2 skin toxicities were found in 9 lesions but all got improvement after treatment. When divided into responsive and progressive group, free from progression was not related to any of the possible variables. CONCLUSION: RT is effective in local control of NAKS resulting great response rate. PMID- 23346534 TI - Postoperative radiotherapy for ependymoma. AB - PURPOSE: To evaluated the patterns of failure, survival rate, treatment-related toxicity and prognostic factors in postoperative radiotherapy of patients with ependymoma. MATERIALS AND METHODS: Thirty patients who underwent surgery and postoperative radiotherapy for ependymoma between the period of June 1994 and June 2008 were reviewed retrospectively. The age of patients ranged from 21 months to 66 years (median, 19 years). Seventeen patients had grade II ependymoma, and 13 had grade III anaplastic ependymoma according to the World Health Organization grading system. The postoperative irradiation was performed with 4 or 6 MV photon beam with median dose of 52.8 Gy (range, 45 to 63 Gy), and radiation field including 2 cm beyond the preoperative tumor volume. Median follow-up period was 51 months (range, 12 to 172 months). RESULTS: Fourteen out of 30 (46.7%) patients experienced recurrence, and 12 of those died. Among those 14 patients who experienced recurrence, 11 were in-field and 3 were out-of-field recurrence. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 66.7% and 56.1%, respectively. On univariate analysis, tumor grade was a statistically significant prognostic factor for OS and PFS. There were two complications after surgery and postoperative radiotherapy, including short stature and facial palsy on the left side. CONCLUSION: We observed good survival rates, and histologic grade was a prognostic factor affecting the OS and PFS. Almost all recurrence occurred in primary tumor site, thus we suggest further evaluation on intensity-modulated radiotherapy or stereotatic radiosurgery for high-risk patients such as who have anaplastic ependymoma. PMID- 23346535 TI - Total lymphoid irradiation based conditioning for hematopoietic stem cell transplantation in severe aplastic anemia. AB - PURPOSE: To retrospectively evaluate the outcome and toxicity of total lymphoid irradiation (TLI) based conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) patients who experienced an engraftment failure from prior HSCT or were heavily transfused. MATERIALS AND METHODS: Between 1995 and 2006, 20 SAA patients received TLI for conditioning of HSCT. All patients were multi-transfused or had long duration of disease. Fifteen (75%) patients had graft failure from prior HSCT. In 18 (90%) patients, the donors were human leukocyte antigen identical siblings. The stem cell source was the peripheral blood stem cell in 15 (75%) patients. The conditioning regimen was composed of antithymocyte globulin plus TLI with a median dose of 750 cGy in 1 fraction. The graft-versus-host disease (GVHD) prophylaxis used cyclosporine with methotrexate. RESULTS: With a median follow-up of 10.8 years, graft failures developed in 6 patients. Among them, 3 patients received their third HSCT to be engrafted finally. The Kaplan-Meier overall survival rate was 85.0% and 83.1% at 5 and 10 years, respectively. The incidence of acute and chronic GVHD was 20% and 20%, respectively. None of the patients have developed a malignancy after HSCT. CONCLUSION: In our study, TLI based conditioning in allogeneic HSCT was feasible with acceptable rates of GVHD in SAA patients who experienced graft failure from prior HSCT or was at a high risk of graft rejection. We achieved relatively better results of engraftment and survival with a long term follow-up. PMID- 23346536 TI - Prognostic value of (18)F-fluorodeoxyglucose positron emission tomography, computed tomography and magnetic resonance imaging in oral cavity squamous cell carcinoma with pathologically positive neck lymph node. AB - PURPOSE: To evaluate the prognostic value of preoperative neck lymph node (LN) assessment with (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET), computed tomography (CT), and magnetic resonance imaging (MRI) in oral cavity squamous cell carcinoma (OSCC) patients with pathologically positive LN. MATERIALS AND METHODS: In total, 47 OSCC patients with pathologically positive LN were retrospectively reviewed with preoperative (18)F-FDG PET and CT/MRI. All patients underwent surgical resection, neck dissection and postoperative adjuvant radiotherapy and/or chemotherapy between March 2002 and October 2010. Histologic correlation was performed for findings of (18)F-FDG PET and CT/MRI. RESULTS: Thirty-six (76.6%) of 47 cases were correctly diagnosed with neck LN metastasis by (18)F-FDG PET and 32 (68.1%) of 47 cases were correctly diagnosed by CT/MRI. Follow-up ranged from 20 to 114 months (median, 56 months). Clinically negative nodal status evaluated by (18)F-FDG PET or CT/MRI revealed a trend toward better clinical outcomes in terms of overall survival, disease-free survival, local recurrence-free survival, regional nodal recurrence-free survival, and distant metastasis-free survival rates even though the trends were not statistically significant. However, there was no impact of neck node standardized uptake value (SUV(max)) on clinical outcomes. Notably, SUV(max) showed significant correlation with tumor size in LN (p < 0.01, R(2) = 0.62). PET and CT/MRI status of LN also had significant correlation with the size of intranodal tumor deposit (p < 0.05, R(2) = 0.37 and p < 0.01, R(2) = 0.48, respectively). CONCLUSION: (18)F-FDG PET and CT/MRI at the neck LNs might improve risk stratification in OSCC patients with pathologically positive neck LN in this study, even without significant prognostic value of SUV(max). PMID- 23346537 TI - Re-irradiation of recurrent esophageal cancer after primary definitive radiotherapy. AB - PURPOSE: For recurrent esophageal cancer after primary definitive radiotherapy, no general treatment guidelines are available. We evaluated the toxicities and clinical outcomes of re-irradiation (re-RT) for recurrent esophageal cancer. MATERIALS AND METHODS: We analyzed 10 patients with recurrent esophageal cancer treated with re-RT after primary definitive radiotherapy. The median time interval between primary radiotherapy and re-RT was 15.6 months (range, 4.8 to 36.4 months). The total dose of primary radiotherapy was a median of 50.4 Gy (range, 50.4 to 63.0 Gy). The total dose of re-RT was a median of 46.5 Gy (range, 44.0 to 50.4 Gy). RESULTS: The median follow-up period was 4.9 months (range, 2.6 to 11.4 months). The tumor response at 3 months after the end of re-RT was complete response (n = 2), partial response (n = 1), stable disease (n = 2), and progressive disease (n = 5). Grade 5 tracheoesophageal fistula developed in three patients. The time interval between primary radiotherapy and re-RT was less than 12 months in two of these three patients. Late toxicities included grade 1 dysphagia (n = 1). CONCLUSION: Re-RT of recurrent esophageal cancer after primary radiotherapy can cause severe toxicity. PMID- 23346538 TI - Changes of the liver volume and the Child-Pugh score after high dose hypofractionated radiotherapy in patients with small hepatocellular carcinoma. AB - PURPOSE: To investigate the safety of high dose hypofractionated radiotherapy (RT) in patients with small hepatocellular carcinoma (HCC) in terms of liver volumetric changes and clinical liver function. MATERIALS AND METHODS: We retrospectively reviewed 16 patients with small HCC who were treated with high dose hypofractionated RT between 2006 and 2009. The serial changes of the liver volumetric parameter were analyzed from pre-RT and follow-up (FU) computed tomography (CT) scans. We estimated linear time trends of whole liver volume using a linear mixed model. The serial changes of the Child-Pugh (CP) scores were also analyzed in relation to the volumetric changes. RESULTS: Mean pre-RT volume of entire liver was 1,192.2 mL (range, 502.6 to 1,310.2 mL) and mean clinical target volume was 14.7 mL (range, 1.56 to 70.07 mL). Fourteen (87.5%) patients had 4 FU CT sets and 2 (12.5%) patients had 3 FU CT sets. Mean interval between FU CT acquisition was 2.5 months. After considering age, gender and the irradiated liver volume as a fixed effects, the mixed model analysis confirmed that the change in liver volume is not significant throughout the time course of FU periods. Majority of patients had a CP score change less than 2 except in 1 patient who had CP score change more than 3. CONCLUSION: The high dose hypofractionated RT for small HCC is relatively safe and feasible in terms of liver volumetric changes and clinical liver function. PMID- 23346539 TI - Molecular biomarkers in extrahepatic bile duct cancer patients undergoing chemoradiotherapy for gross residual disease after surgery. AB - PURPOSE: To analyze the outcomes of chemoradiotherapy for extrahepatic bile duct (EHBD) cancer patients who underwent R2 resection or bypass surgery and to identify prognostic factors affecting clinical outcomes, especially in terms of molecular biomarkers. MATERIALS AND METHODS: Medical records of 21 patients with EHBD cancer who underwent R2 resection or bypass surgery followed by chemoradiotherapy from May 2001 to June 2010 were retrospectively reviewed. All surgical specimens were re-evaluated by immunohistochemical staining using phosphorylated protein kinase B (pAKT), CD24, matrix metalloproteinase 9 (MMP9), survivin, and beta-catenin antibodies. The relationship between clinical outcomes and immunohistochemical results was investigated. RESULTS: At a median follow-up of 20 months, the actuarial 2-year locoregional progression-free, distant metastasis-free and overall survival were 37%, 56%, and 54%, respectively. On univariate analysis using clinicopathologic factors, there was no significant prognostic factor. In the immunohistochemical staining, cytoplasmic staining, and nuclear staining of pAKT was positive in 10 and 6 patients, respectively. There were positive CD24 in 7 patients, MMP9 in 16 patients, survivin in 8 patients, and beta-catenin in 3 patients. On univariate analysis, there was no significant value of immunohistochemical results for clinical outcomes. CONCLUSION: There was no significant association between clinical outcomes of patients with EHBD cancer who received chemoradiotherapy after R2 resection or bypass surgery and pAKT, CD24, MMP9, survivin, and beta-catenin. Future research is needed on a larger data set or with other molecular biomarkers. PMID- 23346540 TI - The role of postoperative pelvic radiation in stage IV rectal cancer after resection of primary tumor. AB - PURPOSE: To evaluate the effect of pelvic radiotherapy (RT) in patients with stage IV rectal cancer treated with resection of primary tumor with or without metastasectomy. MATERIALS AND METHODS: Medical records of 112 patients with stage IV rectal cancer treated with resection of primary tumor between 1990 and 2011 were retrospectively reviewed. Fifty-nine patients received synchronous or staged metastasectomy whereas fifty-three patients did not. Twenty-six patients received pelvic radiotherapy. RESULTS: Median overall survival (OS), locoregional recurrence-free survival (LRFS), and progression-free survival (PFS) of all patients was 27, 70, and 11 months, respectively. Pathologic T (pT), N (pN) classification and complete metastasectomy were statistically significant factors in OS (p = 0.040, 0.020, and 0.002, respectively). RT did not improve OS or LRFS. There were no significant factors in LRFS. pT and pN classification were also significant prognostic factors in PFS (p = 0.010 and p = 0.033, respectively). In the subgroup analysis, RT improved LRFS in patients with pT4 disease (p = 0.026). The locoregional failure rate of the RT group and the non-RT group were 23.1% and 33.7%, showing no difference in the failure pattern of both groups (p = 0.260). CONCLUSION: Postoperative pelvic RT did not improve LRFS of all metastatic rectal cancer patients; however, it can be recommended to patients with pT4 disease. A complete resection of metastatic masses should be performed if possible. PMID- 23346541 TI - Postoperative chemoradiotherapy in high risk locally advanced gastric cancer. AB - PURPOSE: To evaluate treatment outcome of patients with high risk locally advanced gastric cancer after postoperative chemoradiotherapy. MATERIALS AND METHODS: Between May 2003 and May 2012, thirteen patients who underwent postoperative chemoradiotherapy for gastric cancer with resection margin involvement or adjacent structure invasion were retrospectively analyzed. Concurrent chemotherapy was administered in 10 patients. Median dose of radiation was 50.4 Gy (range, 45 to 55.8 Gy). RESULTS: The median follow-up duration for surviving patients was 48 months (range, 5 to 108 months). The 5-year overall survival rate was 42% and the 5-year disease-free survival rate was 28%. Major pattern of failure was peritoneal seeding with 46%. Locoregional recurrence was reported in only one patient. Grade 2 or higher gastrointestinal toxicity occurred in 54% of the patients. However, there was only one patient with higher than grade 3 toxicity. CONCLUSION: Despite reported suggested role of adjuvant radiotherapy with combination chemotherapy in gastric cancer, only very small portion of the patients underwent the treatment. Results from this study show that postoperative chemoradiotherapy provided excellent locoregional control with acceptable and manageable treatment related toxicity in patients with high risk locally advanced gastric cancer. Thus, postoperative chemoradiotherapy may improve treatment result in terms of locoregional control in these high risk patients. However, as these findings are based on small series, validation with larger cohort is suggested. PMID- 23346543 TI - Troglitazone and tumor inhibition: an evolving concept in the management of systemic malignancies. PMID- 23346542 TI - Prognostic implications of tumor volume response and COX-2 expression change during radiotherapy in cervical cancer patients. AB - PURPOSE: The relationship between treatment outcomes, alteration of the expression of biological markers, and tumor volume response during radiotherapy (RT) in patients with uterine cervical cancer was analyzed. MATERIALS AND METHODS: Twenty patients with cervical squamous cell carcinoma received definitive RT with (n = 17) or without (n = 3) concurrent chemotherapy. Tumor volumes were measured by three serial magnetic resonance imaging scans at pre-, mid-, and post-RT. Two serial punch biopsies were performed at pre- and mid-RT, and immunohistochemical staining for cyclooxygenase (COX)-2 and epidermal growth factor receptor was performed. The median follow-up duration was 60 months. RESULTS: The median tumor volume response at mid-RT (V2R) was 0.396 (range, 0.136 to 0.983). At mid-RT, an interval increase in the distribution of immunoreactivity for COX-2 was observed in 8 patients, and 6 of them showed poor mid-RT tumor volume response (V2R >= 0.4). Four (20%) patients experienced disease progression after 10 to 12 months (median, 11 months). All 4 patients had poor mid-RT tumor volume response (p = 0.0867) and 3 of them had an interval increase in COX-2 expression. Overall survival (OS) and progression-free survival (PFS) decreased in patients with V2R >= 0.4 (p = 0.0291 for both). An interval increase in COX-2 expression at mid-RT was also associated with a decreased survival (p = 0.1878 and 0.1845 for OS and PFS, respectively). CONCLUSION: Poor tumor volume response and an interval increase in COX-2 expression at mid-RT decreased survival outcomes in patients with uterine cervical cancer. PMID- 23346544 TI - Surgical treatment of unruptured intracranial middle cerebral artery aneurysms: angiographic and clinical outcomes in 143 aneurysms. AB - OBJECTIVE: The purpose of this study was to determine the outcomes of surgical clipping in patients with unruptured middle cerebral artery (MCA) aneurysms. METHODS: A retrospective single-center database of 125 consecutive patients with 143 small MCA aneurysms (< 10 mm) who underwent surgical clipping was reviewed from January 2007 to December 2010. Clinical outcomes were assessed based on surgery-related complications and follow-up (mean: 17 months) using the modified Rankin scale (mRS). Angiographic outcomes were evaluated by conventional angiography (N = 96) or computed tomography angiography (N = 29) at postoperative weeks 1 and 6. RESULTS: There were no cases of mortality. There were three surgery-related complications (intracranial hemorrhage, meningitis and wound infection, respectively). The hemorrhagic event caused transient neurological deficits. All patients showed good clinical outcomes during follow-up (mRS 0-1). There was angiographic evidence of complete occlusion in 137 aneurysms (95.8%), a small residual neck in three aneurysms (2.2%) and partial for three aneurysms. In the three cases with partial clipping, the decision was made preoperatively to leave the residual sac to maintain distal flow, and muscular wrapping was performed. CONCLUSION: Our study demonstrates that surgical clipping of unruptured small MCA aneurysms yields favorable clinical and angiographic outcomes. Aneurysmal clipping can be safely recommended for patients with small unruptured MCA aneurysms. PMID- 23346545 TI - Supraclinoid internal carotid artery fenestration harboring an unruptured aneurysm and another remote ruptured aneurysm: case report and review of the literature. AB - A fenestration of the supraclinoid internal carotid artery (ICA) is a rare congenital condition. We report an aneurysm arising from the proximal end of an ICA fenestration that was treated by endovascular coiling. Three-dimensional rotational angiography of preoperative cerebral angiography provided an understanding of the complex anatomy of the aneurysms associated with the fenestration and may facilitate the clinical decision regarding the treatment option. Endovascular coiling appears to be safe and effective for treating an aneurysm originating from a fenestration on the supraclinoid ICA, which is a difficult lesion to treat using a conventional surgical approach. PMID- 23346546 TI - Intracranial aneurysm following cranial radiation therapy. AB - We report herein a case of a radiation-induced aneurysm. A 69-year-old woman presented with subarachnoid hemorrhage. Eight years previously, she had undergone cranial radiation therapy (total dose of 59.4 Gy) as adjuvant therapy after surgical resection for a chondrosarcoma that was destroying her sphenoid sinus. The patient underwent catheter angiography, which revealed an aneurysm of the anterior communicating artery and luminal narrowing and irregularity in the petrous and lacerum segments of the right internal carotid artery. We attempted surgical clipping of the aneurysm, but there was repeated bleeding. Finally the aneurysm was treated with endovascular trapping. Potentially fatal bleeding also occurred from her internal carotid artery, which had also been irradiated during the previous cranial radiation therapy. We stopped the bleeding with endovascular coil embolization. Because of diffuse vascular changes of the cerebral vessels within irradiated fields, special attention must be paid to their treatment. PMID- 23346547 TI - Intracranial pial arteriovenous fistula presenting with hemorrhage: a case report. AB - Intracranial pial arteriovenous fistula (AVF) is a rare cerebrovascular malformation, which has a single or multiple arterial connections to a single venous channel without intervening nidus, and is different from arteriovenous malformation (AVM). We report on a case of a surgically treated pial AVF. A 15 year-old girl with an altered mental state was brought to our hospital. Computed tomography (CT) showed a subcortical hematoma of approximately 24 ml in her right temporal lobe. Cerebral angiography showed an AVF supplied by the right middle cerebral artery with early drainage into the Sylvian vein and the vein of Labbe. She underwent surgical treatment with feeding artery obliteration using a clip and hematoma removal. The patient was discharged without neurologic deficits. Despite the rarity of pial AVF, for correct diagnosis and treatment, neurosurgeons should recognize this condition. Pial AVF can be managed simply by disconnection of the shunt by surgery or endovascular treatment, and a good result can be achieved. PMID- 23346548 TI - Spontaneous complete occlusion of middle cerebral artery aneurysm: case report. AB - There are few observation papers regarding the natural history of an aneurysm. We report on a case of a completely occluded middle cerebral artery (MCA) aneurysm. A 47-year-old female patient presented with a headache and was diagnosed with rupture of a right MCA aneurysm. Due to a high risk of direct neck clipping, she received conservative treatment after craniotomy and wrapping of her aneurysm. The patient's condition showed improvement, with complete occlusion of the aneurysm and considerable reduction of the aneurysm in size after approximately three years. This is a rare case of an aneurysm of MCA that showed spontaneous resolution. Finally, on the angiogram, characteristics of an aneurysm to occlude spontaneously will be presumed based on literature reviews. PMID- 23346549 TI - Warburg effect and translocation-induced genomic instability: two yeast models for cancer cells. AB - Yeast has been established as an efficient model system to study biological principles underpinning human health. In this review we focus on yeast models covering two aspects of cancer formation and progression (i) the activity of pyruvate kinase (PK), which recapitulates metabolic features of cancer cells, including the Warburg effect, and (ii) chromosome bridge-induced translocation (BIT) mimiking genome instability in cancer. Saccharomyces cerevisiae is an excellent model to study cancer cell metabolism, as exponentially growing yeast cells exhibit many metabolic similarities with rapidly proliferating cancer cells. The metabolic reconfiguration includes an increase in glucose uptake and fermentation, at the expense of respiration and oxidative phosphorylation (the Warburg effect), and involves a broad reconfiguration of nucleotide and amino acid metabolism. Both in yeast and humans, the regulation of this process seems to have a central player, PK, which is up-regulated in cancer, and to occur mostly on a post-transcriptional and post-translational basis. Furthermore, BIT allows to generate selectable translocation-derived recombinants ("translocants"), between any two desired chromosomal locations, in wild-type yeast strains transformed with a linear DNA cassette carrying a selectable marker flanked by two DNA sequences homologous to different chromosomes. Using the BIT system, targeted non-reciprocal translocations in mitosis are easily inducible. An extensive collection of different yeast translocants exhibiting genome instability and aberrant phenotypes similar to cancer cells has been produced and subjected to analysis. In this review, we hence provide an overview upon two yeast cancer models, and extrapolate general principles for mimicking human disease mechanisms in yeast. PMID- 23346551 TI - Stereotactic body radiation therapy in the treatment of oligometastatic prostate cancer. AB - PURPOSE/OBJECTIVE(S): To report outcomes and toxicity for patients with oligometastatic (<=5 lesions) prostate cancer (PCa) treated with stereotactic body radiation therapy (SBRT). MATERIALS/METHODS: Seventeen men with 21 PCa lesions were treated with SBRT between February 2009 and November 2011. All patients had a detectable prostate-specific antigen (PSA) at the time of SBRT, and 11 patients (65%) had hormone-refractory (HR) disease. Treatment sites included bone (n = 19), lymph nodes (n = 1), and liver (n = 1). For patients with bone lesions, the median dose was 20 Gy (range, 8-24 Gy) in a single fraction (range, 1-3). All but two patients received some form of anti-androgen therapy after completing SBRT. RESULTS: Local control (LC) was 100%, and the PSA nadir was undetectable in nine patients (53%). The first post-SBRT PSA was lower than pre-treatment levels in 15 patients (88%), and continued to decline or remain undetectable in 12 patients (71%) at a median follow-up of 6 months (range, 2-24 months). Median PSA measurements before SBRT and at last follow-up were 2.1 ng/dl (range, 0.13-36.4) and 0.17 ng/dl (range, <0.1-140), respectively. Six (55%) of the 11 patients with HR PCa achieved either undetectable or declining PSA at a median follow-up of 4.8 months (range, 2.2-6.0 months). Reported toxicities included one case each of grade 2 dyspnea and back pain, there were no cases of grade >=3 toxicity following treatment. CONCLUSION: We report excellent LC with SBRT in oligometastatic PCa. More importantly, over half the patients achieved an undetectable PSA after SBRT. Further follow-up is necessary to assess the long term impact of SBRT on LC, toxicity, PSA response, and clinical outcomes. PMID- 23346550 TI - Chromatin modifications and the DNA damage response to ionizing radiation. AB - In order to survive, cells have evolved highly effective repair mechanisms to deal with the potentially lethal DNA damage produced by exposure to endogenous as well as exogenous agents. Ionizing radiation exposure induces highly lethal DNA damage, especially DNA double-strand breaks (DSBs), that is sensed by the cellular machinery and then subsequently repaired by either of two different DSB repair mechanisms: (1) non-homologous end joining, which re-ligates the broken ends of the DNA and (2) homologous recombination, that employs an undamaged identical DNA sequence as a template, to maintain the fidelity of DNA repair. Repair of DSBs must occur within the natural context of the cellular DNA which, along with specific proteins, is organized to form chromatin, the overall structure of which can impede DNA damage site access by repair proteins. The chromatin complex is a dynamic structure and is known to change as required for ongoing cellular processes such as gene transcription or DNA replication. Similarly, during the process of DNA damage sensing and repair, chromatin needs to undergo several changes in order to facilitate accessibility of the repair machinery. Cells utilize several factors to modify the chromatin in order to locally open up the structure to reveal the underlying DNA sequence but post translational modification of the histone components is one of the primary mechanisms. In this review, we will summarize chromatin modifications by the respective chromatin modifying factors that occur during the DNA damage response. PMID- 23346553 TI - The chromatin remodeling protein BRG1 modulates BRCA1 response to UV irradiation by regulating ATR/ATM activation. AB - The SWI/SNF chromatin remodeling complex plays a role in the repair of UV-induced DNA damage. It was proposed that chromatin remodeling activities are utilized to increase the accessibility of nucleotide excision repair (NER) machinery and checkpoint factors to the damaged DNA. It was shown recently that BRCA1 contributes to UV damage response by promoting photoproduct excision, triggering post-UV checkpoint activation and post-replicative repair. In this study, we show that BRCA1 rapidly binds to UV damage sites when cells are undergoing DNA synthesis. In contrast, two phosphorylated forms of BRCA1 do not accumulate at sites of UV damage. Depletion of BRG1, a core subunit of the human SWI/SNF-BAF complex, impairs the recruitment of BRCA1 to the damage sites and attenuates DNA damage induced BRCA1 phosphorylation. At UV lesions-stalled replication forks, BRG1 promotes RPA phosphorylation in response to UV irradiation, since UV-induced phosphorylation of chromatin bound RPA drops significantly when BRG1 is depleted in human cells. Importantly, activation of the ATM/ATR kinases is attenuated when BRG1 is depleted. We propose that BRG1 modulates BRCA1 response to UV irradiation by regulating ATM/ATR activation. PMID- 23346552 TI - Histopathology of gastrointestinal neuroendocrine neoplasms. AB - Gastrointestinal neuroendocrine neoplasms (GI-NENs) arise from neuroendocrine cells distributed mainly in the mucosa and submucosa of the gastrointestinal tract. In 2010, the World Health Organization (WHO) classification of NENs of the digestive system was changed, categorizing these tumors as grade 1 neuroendocrine tumor (NET), grade-2NET, neuroendocrine carcinoma (large- or small-cell type), or mixed adenoneuroendocrine carcinoma (MANEC). Such a classification is based on the Ki-67 index and mitotic count in histological material. For the accurate pathological diagnosis and grading of NENs, it is important to clearly recognize the characteristic histological features of GI-NENs and to understand the correct method of counting Ki-67 and mitoses. In this review, we focus on the histopathological features of GI-NENs, particularly regarding biopsy and cytological diagnoses, neuroendocrine markers, genetic and molecular features, and the evaluation of the Ki-67 index and mitotic count. In addition, we will address the histological features of GI-NEN in specific organs. PMID- 23346554 TI - Shiga toxin-producing Escherichia coli in beef retail markets from Argentina. AB - Shiga toxin-producing Escherichia coli (STEC) are foodborne pathogens that cause mild or serious diseases and can lead to people death. This study reports the prevalence and characteristics of STEC O157 and non-O157 in commercial ground beef and environmental samples, including meat table, knife, meat mincing machine, and manipulator hands (n = 450) obtained from 90 retail markets over a nine-month period. The STEC isolates were serotyped and virulence genes as stx (Shiga toxin), rfb(O157)] (O157 lipopolysaccharide), fliC(H7) (H7 flagellin), eae (intimin), ehxA (enterohemolysin) and saa (STEC autoagglutinating adhesin), were determined. STEC O157 were identified in 23 (25.5%) beef samples and 16 (4.4%) environmental samples, while STEC non-O157 were present in 47 (52.2%) and 182 (50.5%), respectively. Among 54 strains isolated, 17 were STEC O157:H7 and 37 were STEC non-O157. The prevalent genotype for O157 was stx(2)/eae/ehxA/fliC(H7) (83.4%), and for STEC non-O157 the most frequent ones were stx(1)/stx(2)/saa/ehxA (29.7%); stx(2) (29.7%); and stx(2)/saa/ehxA (27%). None of the STEC non-O157 strains were eae-positive. Besides O157:H7, other 20 different serotypes were identified, being O8:H19, O178:H19, and O174:H28 the prevalent. Strains belonging to the same serotype could be isolated from different sources of the same retail market. Also, the same serotype could be detected in different stores. In conclusion, screening techniques are increasingly sensitive, but the isolation of STEC non-O157 is still a challenge. Moreover, with the results obtained from the present work, although more studies are needed, cross-contamination between meat and the environment could be suspected. PMID- 23346555 TI - Suicidal expressions in young Swedish Sami, a cross-sectional study. AB - OBJECTIVES: To investigate the experience of suicidal expressions (death wishes, life weariness, ideation, plans and attempts) in young Swedish Sami, their attitudes toward suicide (ATTS), and experience of suicidal expressions and completed suicide in significant others and to compare with Swedes in general. METHODS: A cross-sectional study comprising 516 Swedish Sami, 18-28 years of age together with an age and geographically matched reference group (n=218). Parts of the ATTS questionnaire have been used to cover different aspects of the suicidal complex. Data were analysed with regard to gender, occupation, counties and experience of negative societal treatment due to Sami background. RESULTS: Both young Sami and young Swedes reported suicidal ideation, life weariness, and death wishes in a high degree (30-50%), but it was more common among the Sami. Having had plans to commit suicide showed a significant gender difference only in the Sami. The prevalence of suicide attempts did not differ significantly between Sami and Swedes. Subgroups of the Sami reported a higher degree of suicidal behaviour, Sami women and reindeer herders reported a 3, 5-fold higher odds of suicide attempts and a 2-fold higher odds having had plans committing suicide. Sami living in Vasterbotten/Jamtland/Vasternorrland and Sami with experience of ethnicity related bad treatment 2-fold higher odds of suicidal plans compared to those living in other counties. CONCLUSION: An increased occurrence of suicidal ideation/death wishes/life weariness in young Sami compared to young majority Swedes was found, but not an increased prevalence of suicide attempts and positive attitudes together with an increased awareness to handle suicide problems could be a contributing factor. Severe circumstances and experience of ethnicity-related bad treatment seems to contribute to increased levels of suicidal plans and attempts in subgroups of Sami. PMID- 23346556 TI - Loading of the knee joint during ergometer cycling: telemetric in vivo data. AB - STUDY DESIGN: Within-subject, repeated-measures design. OBJECTIVES: To measure tibiofemoral contact forces during cycling in vivo and to quantify the influences of power, pedaling cadence, and seat height on tibiofemoral contact forces. BACKGROUND: Cycling is usually classified as a low-demand activity for the knee joint and is therefore recommended for persons with osteoarthritis and rehabilitation programs following knee surgery. However, there are limited data regarding actual joint loading. METHODS: Instrumented knee implants with telemetric data transmission were used to measure the tibiofemoral contact forces. Data were obtained in 9 subjects, during ergometer cycling and walking, 15 +/- 7 months after total knee arthroplasty. Tibiofemoral forces during cycling at power levels between 25 and 120 W, cadences of 40 and 60 rpm, and 2 seat heights were investigated. RESULTS: Within the examined power range, tibiofemoral forces during cycling were smaller than those during walking. At the moderate condition of 60 W and 40 rpm, peak resultant forces of 119% of body weight were measured during the pedal downstroke. Shear forces ranged from 5% to 7% of body weight. Forces increased linearly with cycling power. Higher cadences led to smaller forces. A lower seat height did not increase the resultant force but caused higher posterior shear forces. CONCLUSION: Due to the relatively small tibiofemoral forces, cycling with moderate power levels is suited for individuals with osteoarthritis and rehabilitation programs following knee surgery, such as cartilage repair or total knee replacement. The lowest forces can be expected while cycling at a low power level, a high cadence, and a high seat height. PMID- 23346557 TI - Concluding remarks. PMID- 23346558 TI - European Medicines Agency guidelines to increase the pace of biosimilar development. PMID- 23346559 TI - Quotient Bioresearch complete L1.5 million expansion of bioanalytical research facilities. PMID- 23346560 TI - Saladex Biomedical and Bristol-Myers Squibb have entered into a further collaboration. PMID- 23346561 TI - Retraction notice to: "Antibacterial activity and in vitro cytotoxicity of extracts and fractions of Parkia biglobosa (Jacq.) Benth. stem bark and Ageratum conyzoides Linn. leaves" [Environ. Toxicol. Pharmacol. 34 (2012) 478-483]. PMID- 23346562 TI - Scripps researchers develop technology for biomarker identification in ulcerative colitis. PMID- 23346563 TI - Cardiovascular bioassay to be distributed across Europe. PMID- 23346564 TI - The health of mine(r)s. PMID- 23346565 TI - Stem cells on South African shores: proposed guidelines for comprehensive informed consent. PMID- 23346566 TI - Poor maternal outcomes. PMID- 23346567 TI - Can a new paediatric sub-specialty improve child health in South Africa. PMID- 23346568 TI - When will we escape from the medical funding industry's 'spin'? PMID- 23346569 TI - Multilayered nanoparticles for siRNA delivery. PMID- 23346570 TI - Rationally designed vaccines. PMID- 23346571 TI - Nanozymes for antiviral therapy. PMID- 23346572 TI - Key developments in stem cell therapy in cardiology. AB - A novel therapeutic strategy to prevent or reverse ventricular remodeling, the substrate for heart failure and arrhythmias following a myocardial infarction, is the use of cell-based therapy. Successful cell-based tissue regeneration involves a complex orchestration of cellular and molecular events that include stem cell engraftment and differentiation, secretion of anti-inflammatory and angiogenic mediators, and proliferation of endogenous cardiac stem cells. Recent therapeutic approaches involve bone marrow-derived mononuclear cells and mesenchymal stem cells, adipose tissue-derived stem cells, cardiac-derived stem cells and cell combinations. Clinical trials employing mesenchymal stem cells and cardiac- derived stem cells have demonstrated efficacy in infarct size reduction and regional wall contractility improvement. Regarding delivery methods, the safety of catheter-based, transendocardial stem cell injection has been established. These proof-of-concept studies have paved the way for ongoing pivotal trials. Future studies will focus on determining the most efficacious cell type(s) and/or cell combinations and the mechanisms underlying their therapeutic effects. PMID- 23346574 TI - [Recent marketing authorization applications in France]. PMID- 23346573 TI - [The future of vaccination in France]. PMID- 23346575 TI - The evolution of writing. PMID- 23346576 TI - Vincent Laudet. PMID- 23346577 TI - MGMA advocacy priorities. PMID- 23346578 TI - Work some magic to change minds. PMID- 23346579 TI - Opposition to physician assistants continues. PMID- 23346580 TI - Dealing with a norovirus outbreak. PMID- 23346581 TI - Managing scabies in residential aged-cared facilities. PMID- 23346582 TI - Summaries for patients. Hepatitis C Virus testing of persons born during 1945 1965: recommendations from the Centers for Disease Control and Prevention. PMID- 23346583 TI - Symposium on Myeloid Neoplasms on June 9, 2012 in honor of Dr. John M. Bennett. PMID- 23346584 TI - Proceedings of the 3rd International Symposium on Non-Neuronal Acetylcholine, August 24-26, 2011, Groningen, the Netherlands. PMID- 23346585 TI - Symposium on congenital and acquired bleeding disorders in children in honor of the lifetime accomplishments of Dr. Victor S. Blanchette in pediatric hematology. PMID- 23346587 TI - Special issue in honor of Professor Milton Lee on the occasion of his 65th birthday. PMID- 23346588 TI - Public health failings behind Pakistan's measles surge. PMID- 23346589 TI - India unveils plans to improve stroke research and care. PMID- 23346590 TI - Proceedings of the The 2011 International Conference on Intelligent Computing (ICIC 2011), August 11-14, 2011, Zhengzhou, China. PMID- 23346591 TI - Sierra Leone's free health-care initiative: work in progress. PMID- 23346592 TI - A London inquest jury inspects a corpse. PMID- 23346593 TI - Proceedings of the 13th Servier-IGIS Symposium, March 15-18, 2012, St Jean Cap Ferrat, France. PMID- 23346595 TI - Proceedings of the 2nd MS Food Day Conference, October 19-21, 2011, Trieste, Italy. PMID- 23346594 TI - Special issue in honor of Professor Rudolf Geyer on the occasion of the 65th birthday. PMID- 23346596 TI - Festschrift in Honour A Safe Community - a tribute to Leif Svanstrom. PMID- 23346597 TI - Proceedings of the 9th International Veterinary Immunology Symposium, August 16 20, 2010, Tokyo, Japan. PMID- 23346598 TI - Special Issue in Commemoration of the 70th Birthday of Dr. David R. Bickers. PMID- 23346599 TI - Proceedings of the 5th International Conference on Polyphenols and Health, October 17-20, 2011, Sitges, Spain. PMID- 23346600 TI - Proceedings of the 3rd Congress of Psychiatrists of Bosnia-Herzegovina with International Participation, October 12-14, 2012, Tuzla, Bosnia-Herzegovina. PMID- 23346601 TI - The role of mandatory lifelong annual surveillance following thoracic endovascular repair. PMID- 23346602 TI - Mission critical. Linking supply chain to organizational objectives and patient outcomes once seemed a distant goal. Not any more. PMID- 23346612 TI - Ask the doctor. I have frequent migraine headaches. Does this increase my risk of memory loss or dementia? PMID- 23346613 TI - Can aspirin help fight cancer? Doctors have discovered a new use for this centuries-old pain reliever. PMID- 23346614 TI - Stopping repeated urinary tract infections. What to do when these common infections keep returning. PMID- 23346615 TI - Treating many conditions--with just one pill. The polypill could make your medicines much easier to take. PMID- 23346616 TI - Making smart screening decisions. Part 4: commercial screening tests. Does screening for serious health conditions at your local gym or mall make sense? PMID- 23346618 TI - Fall prevention: what works? PMID- 23346617 TI - Pain-relieving creams ease arthritis aches. PMID- 23346619 TI - No evidence black cohosh helps with hot flashes. PMID- 23346620 TI - Better sleep means better health . . . but are sleep aids and prescription drugs hurting or helping? PMID- 23346621 TI - Ask the doctor. What do doctors think of alternative medicine? PMID- 23346622 TI - Ask the doctor. I[ve heard bariatric surgery can reduce type 2 diabetes. How about type 1? PMID- 23346623 TI - Missing out on aspirin therapy? Research finds most people skip the proven measure. PMID- 23346625 TI - Making peace with holiday buffets. Tactical strategies to get you through the season of eating. PMID- 23346624 TI - High blood sugar linked to brain shrinkage. What this means for preventing cognitive decline. PMID- 23346626 TI - In search of vitamin D. The right dose for bone health depends on key factors. PMID- 23346627 TI - Do-it-yourself skin cancer checks. How to spot potential problems and get peace of mind. PMID- 23346628 TI - Losing your sense of smell? How to know when it signals a bigger health issue. PMID- 23346629 TI - Pelvic organ prolapse. How does controversy affect your treatment? PMID- 23346631 TI - Education, psychological support vital for ICD users. PMID- 23346630 TI - What you should know about: aspirin during a heart attack. PMID- 23346632 TI - Understand your heightened risk of blood clots if you have rheumatoid arthritis. PMID- 23346633 TI - Total knee replacements on the rise, despite high costs. PMID- 23346634 TI - The secrets of longevity. PMID- 23346635 TI - [Not Available]. PMID- 23346636 TI - [Not Available]. PMID- 23346637 TI - [CORECT registry]. PMID- 23346638 TI - [Surviving resistance to hormone therapy in hormone-dependent metastatic breast carcinoma]. PMID- 23346640 TI - Abstracts of the 3rd Winter Workshop of the Society for Biology of Reproduction. January 30-February 1, 2013. Zakopane, Poland. PMID- 23346639 TI - [Aprepitant and pruritus--comment]. PMID- 23346641 TI - The influence of Dr. Hsiang-Tung Chang on neuroscience in Union of Soviet Socialist Republics. AB - As one of the founders of Chinese neuroscience, Dr. Hsiang-Tung Chang's return to China has a profound impact on neuroscience in China. As many people expected, this action also may have influenced the development of neuroscience in other Eastern countries. Therefore, Dr. Chang's move may have changed the history of neuroscience in a greater area than China. PMID- 23346642 TI - Hsiang-Tung Chang's scientific contributions: a legend and a legacy. PMID- 23346643 TI - [Analysis on 424 cases of sudden deaths in Emergency Room]. PMID- 23346644 TI - [Surveillance on effect of casual sexual behavior to HIV infection among unmarried adolescents and young people from rural areas in Liangshan prefecture]. PMID- 23346645 TI - [Analysis on genomic characteristics of coxsackie virus A6 strains isolated from Henan province]. PMID- 23346646 TI - [A survey on mental health among traffic policemen in Tianjin]. PMID- 23346647 TI - [A nested case-control study on the influencing factors of Streptococcus pneumoniae meningitis among patients with acute encephalitis and meningitis]. PMID- 23346648 TI - [Threshold survey on HIV-1 drug resistance in Dehong of Yunnan province in 2011]. PMID- 23346649 TI - [Epidemiological and clinical characteristics on death cases of 635 hand-foot mouth disease]. PMID- 23346650 TI - [Incidence and influencing factors of anxiety in patients with epilepsy]. PMID- 23346651 TI - [Genetic characterization of coxsackievirus A16 isolated in Nanjing city in 2010]. PMID- 23346652 TI - President's report on process and progress at the MDA. PMID- 23346653 TI - First things first. PMID- 23346654 TI - Come Friday: thoughts on the ADA annual session. PMID- 23346655 TI - Common medical conditions in elderly dental patients. Part two: Diabetes, stroke, and breathing problems. PMID- 23346656 TI - As far as you can: a tribute to Lynda Young. PMID- 23346657 TI - The effect of occlusal forces on restorations. AB - This review will focus on the effect occlusal forces, both normal masticatory force and paranormal bruxing and clenching force, have on various restorative materials and their interaction with the teeth through a variety of bonding mechanisms. Salient physical properties of each of the materials will be reviewed, as well as the effect occlusal force has on restoration durability. PMID- 23346658 TI - Jack of all trades. PMID- 23346659 TI - Female pattern hair loss. PMID- 23346660 TI - Striae distensae: the fibrillin/transforming growth factor beta signaling puzzle. PMID- 23346661 TI - Hair care practices in diverse populations: what makes the difference? AB - This study examines whether sociodemographic factors and/or hair attributes are better predictors of hair wash frequency. A total of 96 patients were recruited from the general dermatology outpatient clinic to complete an 18-item questionnaire by self-report. Three linear regression models were constructed and compared to determine whether sociodemographic factors, hair wash frequency, or a combination of the two would best predict wash frequency. Results showed that sociodemographic factors, specifically race, sex, and age group, are all better predictors of hair wash frequency than hair attributes such as hair type, texture, length, and scalp type (adjusted R2 = 0.59 vs 0.27, respectively). PMID- 23346662 TI - Topical acne treatment with acetylcysteine: clinical and experimental effects. AB - Among the large variety of effects of acetylcysteine, several of them relate to cutaneous function in general and to sebaceous activity in particular. Due to the latter, a study was undertaken to investigate a possible effect of this substance in grade I acne. An analysis of the data from 99 patients in a double-blind study demonstrated that 5% acetylcysteine topical gel is significantly superior to placebo (P = .04) in reducing comedo counts. Comparable results were obtained in both sexes. This study indicates that acetylcysteine is an effective therapeutic option for the treatment of mild to moderate acne. PMID- 23346663 TI - Green tea in dermatology. AB - The purpose of this brief review is to summarize all in vitro, in vivo, and controlled clinical trials on green tea preparations and their uses in dermatology. An extensive literature search was carried out to identify in vivo and in vitro studies as well as clinical trials. Twenty studies were assessed and the results suggest that oral administration of green tea can be effective in the scavenging of free radicals, cancer prevention, hair loss, and skin aging plus protection against the adverse effects associated with psoralen-UV-A therapy. Topical application of green tea extract should be potentially effective for atopic dermatitis, acne vulgaris, rosacea, androgenetic alopecia, hirsutism, keloids, genital warts, cutaneous leishmaniasis, and candidiosis. There are promising results with the use of green tea for several dermatologic conditions; however, the efficacy of oral and topical green tea has not always been confirmed. PMID- 23346664 TI - Topical vitamin D analogs available to treat psoriasis. AB - Psoriasis is a chronic and currently incurable inflammatory skin disease, affecting 2% to 3% of the US population. The cost of care in the United States for hospitalizations, outpatient physician visits, phototherapy, prescription therapies, and over-the-counter medications is estimated to be more than $650 million per year. Guidelines developed by the American Academy of Dermatology in 2009 state that approximately 80% of these patients with psoriasis have mild to moderate disease that can be managed with topical agents, including corticosteroids and vitamin D analogs. Topical vitamin D analogs provide "steroid sparing" effects and a favorable safety profile. Many experts, including a recent consensus conference, classify topical vitamin D agents as first-line therapy for psoriasis either as monotherapy or in combination with topical steroids due to a synergistic, complementary effectiveness. Vitamin D analogs are an indispensable component of the current physician's armamentarium for psoriasis treatment. This review, therefore, is oriented to give a comprehensive understanding of this group of drugs and display the available clinical data for each formulation. PMID- 23346665 TI - The safety, efficacy, and tolerability of a novel silicone gel dressing following dermatological surgery. AB - Silicone gel has for many years had a primary role in the treatment and prevention of abnormal scars, in the form of hypertrophic scars and keloids after epithelialization. The authors report preliminary findings on the use of a new, medical-grade, film-forming silicone gel dressing approved for use on open wounds and injured skin as monotherapy and in combination with other treatments prior to re-epithelialization. An observational study involving 105 patients examined the silicone gel's effectiveness in promoting accelerated epithelialization, reducing the inflammatory response and in the prevention of scarring. The study was conducted on a range of dermatological surgical interventions. The authors' observations confirmed silicone's role in promoting accelerated wound healing, scar prevention, and the utility of this new film-forming silicone dressing when used in combination with various other treatment modalities. PMID- 23346666 TI - Pathophysiology of adverse cutaneous drug reactions--applied perceptions: Part II. AB - Adverse cutaneous drug reactions are a group with common morphology. Much research has been performed on such reactions, but their pathophysiology is largely unknown. The authors provide a critical appraisal of the various aspects of their diagnosis and treatment. Some of the common reaction patterns are included with the prime objective of highlighting their pathophysiology. PMID- 23346667 TI - On bossing: taking charge without the facts. PMID- 23346668 TI - Mosquito wars: malaria and bioterrorism in Italy, 1943-1945. PMID- 23346669 TI - Radiation port erythema multiforme: erythema multiforme localized to the radiation port in a patient with non-small cell lung cancer. AB - A 75-year-old man was treated with stereotactic radiation to 50 gray units in 4 fractions for stage IB non-small cell lung cancer. Radiotherapy was directed at the right lower lobe segment of the lung and lasted 4 days. He developed radiodermatitis, which completely resolved within a few weeks after radiotherapy was finished. Three months after completing radiation therapy, he developed a pruritic red lesion within his radiation port on his right mid back with the formation of blisters a week later. Two weeks after the onset of the patient's blisters, cutaneous examination showed individual and convergent erythematous papules and plaques with superficial scaling at sites of resolving vesicles located within the radiated area (Figures 1 and 2). The patient had neither symptoms of mycoplasma pneumoniae, nor lesions or history of present or past herpetic infection. Also, he had not recently been placed on any new medications, and he did not have any other erythema multiforme-associated risk factors. A biopsy from the erythematous lesions showed a band-like infiltrate of lymphocytes in the dermis. The overlying epidermis contained necrotic keratinocytes and there was alteration of the basal layer. Correlation of the clinical presentation and pathologic changes established a diagnosis of erythema multiforme localized to the radiation port. The patient was treated with topical triamcinolone acetonide 0.1% cream twice daily for 10 days and once daily for 4 days. His lesions resolved and there was mild hyperpigmentation of the affected area. PMID- 23346670 TI - Cladosporium scalp infection. AB - An 11-year-old healthy red-haired girl presented with a 3-year history of hair loss and mild pruritus of her scalp. She had previously been diagnosed with trichotillomania. Cutaneous examination showed scant hair loss with neither crusting nor scaly lesions. The scalp hair was diffusely thin, dry, and brittle on the frontal, mid-parietal, and anterior occipital scalp (Figure 1A). A pull test was negative, and a significant number of hair shafts were not detached on repeated traction. Closer examination using a dermatoscope showed follicles with broken hair shafts. The dermatoscopic evaluation also showed frequent pinpoint black dots scattered among the terminal hair shafts at their bases. No scale, scar, or inflammatory changes were seen in the involved areas (Figure 1B). A 20% potassium hydroxide (KOH) preparation of material obtained after gentle scrapping of the black dots on the scalp provided fragments of hair fibers containing aggregates of pigmented yeast forms (Figure 2A) and brown septate hyphae (Figure 2B). Two samples were sent for fungal culture and both showed dark brown colonies on the surface and black coloration when viewed from the reverse side (Figure 3A). Lactophenol cotton blue preparation of the fungal colonies revealed long and septate hyphae with laterally branching conidiophores ending in round-shaped conidia (Figure 3B). The microorganism was identified by the reference laboratory as Cladosporium species. The conidia were usually noted to be single-celled with a distinct dark hilum. They also exhibited prominent attachment scars that caused the cells to appear "shield-shaped." These features were considered to be diagnostic for Cladosporium; however, the reference laboratory could not identify the organism to the species level. The girl's Cladosporium scalp infection was treated with itraconazole at an oral daily dose of 200 mg for 2 months. Upon re evaluation, she showed significant improvement with not only discontinuation of her alopecia and new hair growth (Figure 4A), but also an absence of broken hair shafts and the dark pigmentation found initially at their base when her scalp was examined using a dermatoscope (Figure 4B). In addition, a new KOH preparation did not reveal the presence of conidia. PMID- 23346671 TI - Metastatic melanoma from an unknown primary site presenting as skin-colored nodules and multiple visceral involvement. AB - A 55-year-old man presented with multiple gradually progressing asymptomatic swellings on his body for the preceding 6 months. He had no personal or family history of any skin disease. There was no systemic symptom apart from occasional constipation. Examination revealed multiple discrete, firm, nontender, skin colored nodules of varying sizes, fixed to the skin but free from the underlying structures on his chest, abdomen, and back. The overlying skin of the nodules was erythematous at places (Figure 1). A solitary depigmented, nonanesthetic patch (measuring 3 cm x 3 cm) was noted around a central gray macule (4 mm x 4 mm) on his left shin (Figure 2). The surface of this lesion was otherwise normal. Wood's lamp examination of this area showed attenuation of pigmentation in the central area and total depigmentation surrounding it. No dyspigmented area was noted on Wood's lamp examination of the other areas. There was no abnormality of the orogenital mucosae. General examination revealed mild pallor and multiple discrete, nontender, firm lymph nodes, measuring 3 cm x 3 cm, attached to the skin in the left inguinal region. The overlying skin was normal. Ocular examination (including direct and indirect ophthalmoscopy) and otolaryngologic evaluation were normal. Proctoscopic examination revealed a reddish-black indurated mass at the right lateral wall of the lower third of the rectum. Examination of the other system was noncontributory. Complete hemogram showed mild anemia (hemoglobin % = 10 gm%) and raised ESR, (80 mm in the first hour; Westergren's method). Biochemistry panel was normal apart from raised levels of aspertate transaminase (78 U/L), alanine transaminase (68 U/L), alkaline phosphatase (386 U/L), and lactate dehydrogenase (692 U/L). Chest x-ray showed a rounded opacity in the left apical area suggestive of cannon-ball metastasis (Figure 3). Ultrasonography and computed tomography of the abdomen revealed multiple liver nodules suggestive of hepatic metastasis. Findings from omputed tomography of the brain and upper gastrointestinal endoscopy were normal. Colonoscopic examination did not reveal any colonic lesion. Fine needle aspiration cytology of the enlarged inguinal lymph node was suggestive of malignant melanoma (MM). Histopathologic examination of the excision biopsy specimen of a skin nodule showed a tumor mass in the dermis composed of nests of oval to polygonal cells with vesicular nuclei and large prominent nucleoli (Figure 4). Extensive areas of necrosis were also seen. The tumor cells contained brownish pigment that stained positively with Masson Fontana stain. Pearl's stain was negative. Excision biopsy of the depigmented patch on the left shin showed mild hyperkeratosis, proliferation of capillary-sized blood vessels in the dermis, and thick-walled blood vessels in the subcutaneous tissue (Figure 5). No cellular atypia or any other evidence of malignancy was noted in this specimen. Biopsy from the rectal growth was suggestive of MM. Tumor cells were positive for S100 and human melanin black 45. Based on the clinical presentation, histopathology, and laboratory investigations, a diagnosis of metastatic MM (stage IV: T(x)N(3)M(1c)) with unknown primary site was made. Treatment was started with injection dacarbazine 250 mg/m2 intravenous infusion daily for 5 days intended to be given every 3 weeks for palliation. The patient died 2 week after the first treatment with chemotherapy. PMID- 23346672 TI - [Sepsis and acute respiratory distress syndrome, two major challenges for intensive care]. PMID- 23346673 TI - [Non-invasive ventilation: indication for acute respiratory failure]. AB - Mask or Non-invasive ventilation (NIV) is used for critically ill patients with acute respiratory failure (ARF): acute exacerbation of chronic obstructive bronchopulmonary disease and severe cardiogenic pulmonary edema are considered as the best indications for NIV since it improves the outcome of these patients. This technique is also proposed for hypoxemic respiratory failure, with more various results. To be effective here, NIV must be established early enough and should not delay intubation if required. NIV is also proposed after invasive ventilation or in patients in whom endotracheal intubation is not desirable. Its use has increased and its effectiveness seems to have improved, due to a better understanding of the technique but also thanks to technological progress. PMID- 23346674 TI - [Left ventricular assist devices in cardiogenic shock and chronic refractory heart failure]. AB - Decompensated heart failure, either acute (cardiogenic shock) or chronic (terminal heart failure) may become refractory to conventional therapy, then requiring mechanical assistance of the failing heart to improve hemodynamics. In the acute setting, aortic balloon counterpulsation is used as first line therapy. In case of failure, other techniques include the extracorporal membrane oxygenator or a percutaneous left ventricular assist device, such as the TandemHeart or the Impella. In chronic heart failure, long-term left ventricular assist devices can be surgically implanted. The continuous flow devices give here the best results. The aim of the present review article is to present with some details the various methods of mechanical left ventricle assistance to which the intensivist may be confronted in his daily practice. PMID- 23346675 TI - [Exertional heatstroke]. AB - Exertional heatstroke is defined by an increase of core body temperature above 40 degrees C and neurological symptoms in association with exercise. It is related to excessive heat production, which overwhelms the endogenous mechanisms of thermoregulation. It is observed during intense physical activity in a hot and humid environment, most commonly in untrained subjects poorly adapted to such conditions. Clinical manifestations of exertional heatstroke are related to the induction of a systemic inflammatory response and a disseminated intravascular coagulation triggered by heat stress, which may lead to multiorgan dysfunction and death. Early management through rapid cooling is mandatory to prevent the devastating consequences of exertional heatstroke. PMID- 23346676 TI - [Burnout in intensive care units]. AB - Intensive care units are highly stressful for the patients but for the caregivers as well, including nurse-assistants, nurses and physicians. The psychological syndrome of work exhaustion more commonly named burnout threatens these caregivers. The aims of the present paper are to describe: a) the incidence of burnout in intensive care units; b) the factors favoring burnout and c) the impacts of burnout at the individual, at the unit and institutional level. We suggest some possible ways to decrease the incidence of burnout. Finally, since the problematic of burnout is not specific to intensive care, we sought to underline some possible consequences of the burnout of caregivers on health systems. PMID- 23346677 TI - [A train can hide another]. PMID- 23346678 TI - [Cross-eyed view on a moment of madness]. PMID- 23346679 TI - [Ponce Pilate]. PMID- 23346680 TI - [End of Life medical care: France is not an island in the sea]. PMID- 23346681 TI - [2012: less and less AIDS-related deaths in developed countries]. PMID- 23346682 TI - [From drunkenness and from social contract]. PMID- 23346683 TI - [The Supra case, a thick fog and jamming]. PMID- 23346684 TI - More about transitions. PMID- 23346685 TI - Can my family remove gold crowns after death? PMID- 23346686 TI - Are we willing to change? PMID- 23346687 TI - National Practitioner Data Bank reporting requirements. PMID- 23346688 TI - 'I'm not as busy as I once was'--part II. PMID- 23346689 TI - Waiver of co-pay and overbilling. PMID- 23346690 TI - All payer claims databases and what they mean to you. PMID- 23346691 TI - Collaboration and empowerment: a pathway to greater freedom. PMID- 23346692 TI - Working for you...your MDA staff. PMID- 23346693 TI - The relationship between your practice and personal budget. PMID- 23346694 TI - Gummy smile: could it be genetic? Hereditary gingival fibromatosis. AB - Gingival enlargement is common among patients and can be caused by a variety of etiological factors. The most common reason is poor oral hygiene and high bacterial load that leads to gingival inflammation and enlargement. Other implicated factors include systemic drugs, such as Phenytoin (Dilantin) taken by epileptic patients, Calcium Channel Blockers such as Nifedipine (Procardia) and Verapamil (Calan) for the treatment of hypertension, arrhythmia and angina. Another class of medication associated with gingival enlargement is immunosuppressive agents given to organ-transplant patients to prevent rejection of the new element, such as Cyclosporine. Some enlargements could be associated with other conditions such as puberty, pregnancy or diabetes or be a symptom of a systemic disease (leukemia, Wegener's granulomatosis or sarcoidosis). In rare cases the cause for the enlargement is genetic and termed Hereditary Gingival Fibromatosis (HGF). HGF is a genetic disorder characterized by a progressive enlargement of the gingiva. Histologically, the gingiva is characterized by an accumulation of dense fibrous connective tissue. This is believed to be due to an imbalance between synthesis and degradation of extracellular matrix composed mainly of collagen molecules or due to an alteration in fibroblast proliferation. Different pathogenic mechanisms have been proposed and examined over the years but no precise process has been identified. The main objective of this paper is to discuss this genetic anomaly and support it with clinical cases of a mother and her two children. It will focus on the clinical and histologic characteristics of HGF as well as known biologic and genetic features and treatment modalities. PMID- 23346695 TI - Resources are crucial to curing any care malaise. PMID- 23346696 TI - 'Cartel' ploughs on with regional pay despite government U-turn. PMID- 23346697 TI - Broadcasters warned about hoax the day before nurse's tragic death. PMID- 23346698 TI - England's CNO unveils strategy to promote compassionate care. PMID- 23346699 TI - Audit exposes a lack of progress in addressing problems at NMC. PMID- 23346700 TI - Nursing in 2012: an Olympic fight for employment rights. PMID- 23346701 TI - Resources are the bottom line for healthcare quality. PMID- 23346702 TI - Stay on the right path. AB - Public criticism of the Liverpool Care Pathway has left many patients and relatives suspicious of the framework, which was developed in the 1990s to improve care in the final hours or days of life. Here nurses explain the benefits of the approach and warn against turning back the clock. PMID- 23346703 TI - Freeing minds. AB - Nursing Standard's nurse of the year Johanne Tomlinson won the award for her innovative anxiety management programme at Stafford prison. Here, a group of serving prisoners explain how it helped them to cope with traumatic experiences, rebuild their confidence and look to the future. PMID- 23346704 TI - The nurses' champion. PMID- 23346705 TI - The lymphatic system. AB - This article, which forms part of the life sciences series, examines the lymphatic system, focusing on the anatomy and physiology of lymphatic vessels, lymph nodes and lymph fluid. The flow of lymph through the body is described and the regulatory mechanisms involved are identified and discussed. In addition, there is a brief examination of common disorders of the lymphatic system, including lymphoma, lymphoedema and tonsillitis. PMID- 23346706 TI - Cognitive impairment in patients with diabetes. AB - Type land type 2 diabetes are associated with major complications that shorten life expectancy. Fluctuations in the amount of glucose reaching the brain cause a wide range of alterations to cerebral function, from mild impairment through to dementia-like states and even death. The responsibility is on the patient with diabetes to control his or her blood glucose levels to reduce any mental decline. However, nursing staff should be aware that patients with diabetes experiencing a loss of mental function may have difficulty in understanding information and instructions. This article examines the current literature on loss of mental function as a chronic complication of diabetes. PMID- 23346707 TI - Understanding quantitative research: part 1. AB - This article, which is the first in a two-part series, provides an introduction to understanding quantitative research, basic statistics and terminology used in research articles. Critical appraisal of research articles is essential to ensure that nurses remain up to date with evidence-based practice to provide consistent and high-quality nursing care. This article focuses on developing critical appraisal skills and understanding the use and implications of different quantitative approaches to research. Part two of this article will focus on explaining common statistical terms and the presentation of statistical data in quantitative research. PMID- 23346708 TI - Pre-operative assessment. PMID- 23346709 TI - The gold standard. PMID- 23346710 TI - The partnership that works. PMID- 23346711 TI - Flagging up differences. PMID- 23346712 TI - An imprecise science. PMID- 23346713 TI - Rewriting our food future. PMID- 23346714 TI - Promoting the healthy life. PMID- 23346715 TI - Best hospital food. PMID- 23346716 TI - Dietitian or nutritionist? PMID- 23346717 TI - Food for thought. PMID- 23346718 TI - Gluten and the gut. PMID- 23346719 TI - Death by poverty. PMID- 23346720 TI - Harbinger or squeaky wheels? PMID- 23346721 TI - The obesity challenge. PMID- 23346722 TI - Fitness not dieting is the prescription for obesity. PMID- 23346723 TI - Our unhealthy food system. PMID- 23346724 TI - Nutritional assessment in vegetarians and vegans: questions clinicians should ask. AB - Not all who adhere to vegetarian, vegan or other special diets have nutritionally sound eating habits. The clinical consequences of an insufficiently mindful vegetarian or vegan diet include many common symptoms such as anxiety, brain fog, depression, fatigue, insomnia, neuropathies and other neurologic dysfunction. Patients with such symptoms who report having a vegetarian or vegan diet, or a diet that severely restricts meat consumption, require a slightly expanded differential diagnosis. The challenge is to identify which patients require closer attention. This article lists questions to use to quickly assess for potential dietary drivers of clinical symptoms. In many cases, simple nutritional interventions, through diet and/or supplementation, can resolve or minimize problematic symptoms. PMID- 23346725 TI - Elevated homocysteine? Consider testing for folate metabolism gene variants. AB - Folate metabolism is fundamental to health, as it closely regulates homocysteine level. Recent research suggests there is a genomic basis for individual variation in folate metabolism related to single nucleotide polymorphisms (SNPs). This article describes how two SNPs, both of which are methylenetetrahydrofolate reductase (MTHFR) variants, can affect the way an individual metabolizes folate, resulting in elevated homocysteine level, and why testing for these SNPs may be important. PMID- 23346726 TI - The elimination/challenge diet. AB - Elimination diets can be both a diagnostic tool and a therapeutic intervention for people with a suspected food sensitivity or allergy. They are clinically relevant not only for patients with functional gastrointestinal disorders but also for those with conditions where symptoms are refractory and a diagnosis is elusive. Elimination diets can help a physician make a diagnosis or identify an underlying cause of symptoms. The physician and team treating the patient can then use that information to recommend appropriate dietary and lifestyle changes as well as judicious drug therapy. This article describes the elimination/challenge diet approach and explains the rationale for undertaking it. PMID- 23346728 TI - Using the right information to make staffing decisions. PMID- 23346727 TI - Introduction to traditional Asian therapeutic diets: two enduring perspectives. AB - In some ancient systems of medicine, health was understood as a state of balance, and diet was considered essential to achieving and maintaining that balance. Traditional Chinese medicine and Ayurveda are based on this premise. Here we present an overview of these two traditional systems' views on diet and eating. This article aims to explain the reasoning behind some of the recommendations that practitioners of these forms of medicine may be making. PMID- 23346729 TI - The future of research in staffing: an interview with Sean Clarke. Interview by Kathy S. Douglas and Karlene M. Kerfoot. PMID- 23346730 TI - Are nurses ready for health care reform? A decade of survey research. AB - As health care delivery organizations react to the changes brought about by public and private sector reform initiatives, RNs can anticipate that, in addition to intended outcomes, there will be unpredictable pressures and unintended consequences arising from reform. Biennial national surveys of RNs conducted over the past decade have explored various changes in the nursing workforce, quality of the workplace environment, staffing and payment policies, and RNs' views of health policy, including their expectations of health reform. The latest survey results offer a picture of RNs' capacity to practice successfully in a care delivery environment that, over the current decade, is expected to emphasize teams, care coordination, and become driven increasingly by payment incentives that reward quality, safety, and efficiency. If RNs are provided with strong clinical leadership, participate in developing an achievable vision of the future, and if supported to take risks and innovate to improve the quality and efficiency of care delivery, then the profession is likely to thrive rather than struggle during the health reform years that lie ahead. Increasing the education and preparation of nursing leaders, and particularly unit-level managers, will be increasingly vital for nursing to prosper in the future. PMID- 23346731 TI - Strengthening the workforce through meaningful recognition. AB - Meaningfully recognizing the extraordinary contributions of nurses is a key element in creating and sustaining healthy work environments. Publically honoring the work of nursing reinforces those actions and behaviors that patients, families, and colleagues truly value. A multi-site research study provided a 360 degree perspective of the impact this type of acknowledgment had on strengthening the nursing workforce at 20 health care organizations who use The DAISY Award to recognize extraordinary nurses. Data analysis of 2,195 DAISY Award nominations from patients, families, and colleagues at 20 hospitals identified 22 behavioral themes associated with extraordinary nursing. PMID- 23346732 TI - Are staffing changes in California's hospitals sensitive to individual hospital characteristics? AB - Although differences in nurse staffing have been associated with individual hospital characteristics in the literature, there have been no studies on how these factors may influence nurse staffing changes made after the mandated nurse to-patient ratios in acute care hospitals in California. The aim of this study was to determine if changes in medical-surgical nurse staffing (registered nurses and registry nurses) were associated with particular hospital characteristics. Researchers found the baseline level of nurse staffing was the variable most associated with change in mean productive hours per patient day from FY 2000 to FY 2006. Those hospitals with nurse staffing below 4.0 mean productive medical surgical RN and registry hours per patient day in FY 2000 had a significantly larger, positive change in mean productive hours than did hospitals with average mean productive hours (approximately 5 hours) in FY 2000. Hospitals staffing above 6.0 mean productive hours per patient day in FY 2000 changed their staffing less than did hospitals with average mean productive hours. PMID- 23346733 TI - Nurse staff allocation by nurse patient ratio vs. a computerized nurse dependency management system: a comparative cost analysis of Australian and New Zealand hospitals. AB - Coding, costing, and accounting for nursing care requirements in Australian public and private hospitals lacks systematic research. Nurse costing for two nurse staffing allocation methods--nurse patient ratios and a computerized nurse dependency management system--were compared. Retrospective nursing workload management data were obtained from hospital information systems in 21 acute care public and private hospitals in Australia and New Zealand. Descriptive statistics, cost analysis, and cost modeling were conducted for 103,269 shifts of nursing care. The comparison of costs for nursing staff by nurse-patient ratios and by a computerized nurse dependency management system demonstrated differences. The provision of nursing care using the computerized nurse dependency management system was, overall, lower in cost than for nurse-patient ratios. PMID- 23346734 TI - Changing tides: increasing evidence to embrace a patient classification system. AB - The effective use of a patient classification system (PCS) in a way that provides value to all health care organizations has yet to be realized given the challenging developmental pathway of these systems. As the science and technology of workforce management emerges along with evidence to support the relationships between nurse work and patient care needs, it is no longer appropriate to rely on systems that provide aggregated and minimal data to address the need for safer patient care and retention of nurses. Specificity about patient care needs in a valid and reliable PCS is essential on our pathway to improved resource utilization, improved decision making, integration of nurse cognitive and knowledge work, and management of variances from planned resource use. Advancements with technology, the ability to create and monitor equitable nurse patient assignments, conceptual clarity, evidence, regulatory requirements, and professional role development point to a new receptiveness for PCSs. PMID- 23346735 TI - AARP: national champions of nursing for consumers. AB - The focus of AARP's Future of Nursing Campaign for Action is on fundamental transformation of the health care delivery system in America for consumers. AARP strongly supports full utilization of the education and training of all health professionals and workers. AARP supports educational progression and lifelong learning, a more diversified workforce, and a culture of true partnership and engagement with patients and their families to achieve better health. It is essential for nurses to build synergistic alliances with powerful groups who share the goal of health system transformation. AARP will continue to enhance effective methods to build coalitions, communicate in messages targeted to different stakeholder audiences, develop "asks," and sustain reciprocal relationships. PMID- 23346736 TI - Diagnosis and treatment of lumbar spinal disorders--a multidisciplinary approach: introduction. PMID- 23346737 TI - Approach to the patient with low back pain. PMID- 23346738 TI - Interventional approach to low back pain. PMID- 23346739 TI - Surgery in the treatment of lower back pain I. PMID- 23346740 TI - Surgery in the treatment of lower back pain II--lumbar stenosis and disc herniations. PMID- 23346741 TI - Failed back syndrome. PMID- 23346742 TI - The impact of the 2007-2009 US recession on the health of children with asthma: evidence from the national Child Asthma Call-Back Survey. PMID- 23346743 TI - Left atrial myxoma presenting with cerebral embolism. PMID- 23346744 TI - [Hyperspecialization in orthopedics: a real benefit for the patient and for our health care system?]. PMID- 23346745 TI - [Scapular dyskinesis]. AB - The scapula plays a crucial role for proper shoulder function, serving as a stable base for rotator cuff activation and as a link in the kinetic chain. Joint, ligament or muscular problems near the scapula can lead to malpositions or to an altered movement pattern. This abnormal situation is called "scapular dyskinesis", which appears to be a non-specific response to a painful condition of the shoulder. The clinical examination of the scapula is crucial for every patient presenting a painful shoulder. Systematic observation and testing enable the practitioner to detect subtle static and dynamic abnormalities. Visual evaluation, objective measurements and corrective manoeuvres can evaluate the role of the "scapular dyskinesis" in the shoulder painful condition. The scapular rehabilitation will address muscular retractions and imbalances and restore a good dynamic stability, starting with analytical work, and evolving into more functional and specific exercises. PMID- 23346746 TI - [Total hip arthroplasty through anterior "minimal invasive" approach]. AB - Total hip replacement has seen a tremendous development and has become one of the most successful surgical interventions in orthopaedics. While during the first decades of development of total hip arthroplasty the fixation of the implant into the bone was the main concern, the focus has shifted towards surgical technique and soft tissue handling. In order to avoid permanent soft tissue damage, muscular dysfunction and concerns in regards to cosmetics, minimal invasive and anatomic approaches have been developed. We here provide a short overview on various methods of total hip replacements and we describe our technique through a minimal invasive direct anterior approach. While muscle and nerve damage is minimal, this technique allows for a rapid rehabilitation and is associated with an excellent functional outcome and a minimal risk for dislocation. PMID- 23346747 TI - [Treatment and outcome of fractures around the knee in the older patients]. AB - From the age of 50 the risk of fracture during the remaining years of life is estimated to be 40% in women and 20% men. The management of a fracture in the elderly is complex for several reasons, including decreased bone strength, a frequent association with previous joint replacement surgery or another orthopaedic implant, a high risk for anesthesia, difficulty in following postoperative recommendations, and an increased postoperative mortality. This article offers a review of fractures around the knee: distal femur, proximal tibia, patella and periprosthetic fractures. The vast majority of these fractures are treated surgically. When surgery is indicated, treatment should be initiated as soon as possible according to the patient's general condition in order to minimize the risk of complications and deconditioning. PMID- 23346748 TI - [The 12 keypoints for rehabilitation after total knee arthroplasty]. AB - The rehabilitation process after total knee arthroplasty (TKA) relies more and more on the family doctor. Many factors contribute to this development: the constantly increasing number of TKA performed, the reduced length of stay at the hospital and the rehabilitation process after TKA requiring care for 3 to 4 months. After this time, it is also of major importance to encourage patients to take up physical activities in order to limit the negative effects of sedentarity. The goal of this paper is to give family doctors an overview of the current knowledge in the area of rehabilitation after TKA for physicians. PMID- 23346749 TI - [Orthopaedic management of long bones metastasis]. AB - The recent progress in oncologic management of patients with metastatic disease has permitted a significant improvement of their life expectancy. Many of these patients will suffer from complications related to bone metastasis. Unfortunately an orthopaedic treatment is seldom offered to them, mainly because of the misconception that this would not bring them any benefice. However these patients are often good candidates for an orthopaedic management, which objectives are to relieve pain and to re-establish their quality of life. The available surgical techniques are well described and the management protocols are clearly defined, as are the expectable complications and the errors that must not be done. PMID- 23346750 TI - [Ten errors to avoid while dealing with infected total joint arthroplasties]. AB - Infections after total joint arthroplasty are rare but come with severe consequences. Timely, adequate and standardized treatment beginning at the onset of symptoms will have a major impact on the handling of this dreaded complication. In absences of clear guidelines, errors are often committed, with occasionally severe consequences for the patient. In this article, the 10 most frequent errors starting with diagnostics till antibiotic and surgical treatment will be discussed. PMID- 23346751 TI - [To dare trying a diuretic in autism treatment]. PMID- 23346752 TI - [The flavor of everyday Life]. PMID- 23346753 TI - [Conditioning, spermatozoa and mobile phones]. PMID- 23346754 TI - [How the Devil got into a school in Brittany]. PMID- 23346755 TI - [Certainty crisis]. PMID- 23346757 TI - Leonurus japonicus, Leonurus cardiaca, Leonotis leonurus: a novel HPLC study on the occurrence and content of the pharmacologically active guanidino derivative leonurine. AB - Leonurine is a prominent pharmacologically active guanidine alkaloid (4 {[amino(imino)methyl]amino} butyl-4-hydroxy-3,5-dimethoxybenzoate), mainly exerting cardiovascular, hypotensive, uterotonic, and neuroprotective effects. It is commonly regarded as the predominant active principle of Leonurus and Leonotis drugs (subfamily Lamioideae), though its presence has only been unambiguously proven for the aerial parts of Leonurus japonicus Houtt. (yimucao/Chin.Ph.,DAB), used in TCM/Kampo for the treatment of various gynaecological and cardiovascular disorders. Although a series of claims concerning the occurrence of leonurine in European Leonurus cardiaca L. (Ph.Eur.) can be found describing it as an important active principle, this has never been conclusively demonstrated. The same holds true for the officinal Leonurus japonicus fruits (chongweizi/Chin.Ph.) and the closely related South African herb Leonotis leonurus (L.) R.Br. Since no reliable HPLC determination and quantification method for leonurine has been published up to now, in the present study, a highly reproducible RP-HPLC method was newly developed using a special octadecyl-bonded stationary phase and an acetonitrile/water gradient (adjusted to pH 2.5 by phosphoric acid) as mobile phase (DAD/277nm). In particular, this use of reversed phase packing with hydrophilic endcapping clearly contributes to an improved peak shape for leonurine, to our knowledge the first application of this technique on a natural zwitterionic analyte, and clearly enhances the selectivity of separation compared to classical RP-phases. The method was shown to be precise with respect to concentration, exhibiting a linear response in the range of 2.5-12.5 microg/ml leonurine, detection limit well below 0.5 microg/ml, and correlation coefficients constantly higher than 0.99 (5 levels, n = 3) over numerous inter day repetitions, demonstrating the robustness of the newly developed HPLC protocol. Thus, nine samples of L. japonicus aerial parts, two of L. japonicus fruits, four of L. cardiaca aerial parts, as well as one sample each of L. cardiaca fruits, and Leonotis leonurus aerial parts were examined. No leonurine could be detected in any sample of L. cardiaca in contrast to newly published official drug assessments, which consequently have to be revised. Leonotis leonurus and surprisingly, seeds of L. japonicus did not contain leonurine, either. However, in aerial parts of L. japonicus drug samples, obtained from China and Japan, leonurine contents between 0.001 and 0.049% were determined, while L. japonicus from domestic cultivation displayed significantly higher amounts of at least 0.1%. Thus, the HPLC method described above could be used for quality control of leonurine contained in TCM/Kampo medicines and in pharmacopeial analytics for the differentiation of L. japonicus and L. cardiaca samples. PMID- 23346756 TI - Telaprevir for genotype 1 chronic hepatitis C: a systematic review and meta analysis. AB - OBJECTIVES: To assess the beneficial and harmful effects of telaprevir for patients with genotype 1 chronic hepatitis C. METHODS: We searched Cochrane Central Register of Controlled Trials (Issue 4, 2012), MEDLINE, EMBASE, Chinese Biomedical Database (CBM), CNKI database and Chinese WanFang Database between 1980 and May 2012. Randomized clinical trials assessing telaprevir in combination with peginterferon alfa and ribavirin versus no intervention or placebo in combination with peginterferon alfa and ribavirin in patients with genotype 1 chronic hepatitis C were included. The primary outcome measure was viral response, including sustained virologic response and virologic response at the end of treatment. The secondary outcome measures were relapse rate, severe adverse events, treatment discontinuation and commonly reported adverse events. RESULTS: Six trials with 2,775 participants were included. Telaprevir in combination with peginterferon alfa and ribavirin seemed to show a significant effect on sustained virologic response, virologic response at the end of treatment and relapse rate in naive patients and previously unsuccessfully treated patients, except T12PR12 which seemed without beneficial effect on sustained virologic response (Odds Ratio (OR) 1.41; 95% CI 0.83 to 2.40) and relapse rate (Odds Ratio (OR) 1.55; 95% CI 0.71 to 3.36) in naive patients. It also was associated with a significantly higher incidence of severe adverse events (Odds Ratio (OR) 2.15, 95% CI 1.29 to 3.58) and treatment discontinuation (Odds Ratio (OR) 4.79, 95% CI 1.72 to 13.37) because of adverse events in previously unsuccessfully treated patients, but not in naive patients. CONCLUSIONS: Telaprevir in combination with peginterferon alfa and ribavirin has been recommended as option for the treatment of genotype 1 chronic hepatitis C. It has been considered as effective to improve viral response and reduce relapse rate in patient who suffer genotype 1 chronic hepatitis C. However, the treatment should be monitored carefully as it may cause some severe adverse events. For further confirmation of its treatment effect and clarify its possible adverse events, more randomized clinical trials need to be carried out. PMID- 23346758 TI - Evaluation of a short stability-indicating HPLC method for diclofenac sodium gels. AB - A fast and reproducible high performance liquid chromatography method has been developed for the determination of diclofenac sodium and its degradation products in commercial and in in-house produced ointments. The method employs a RP LiChrospher select B (C8) column with a mobile phase containing methanol/water (63:37, v/v) and detection at 220 nm. This rapid and simple HPLC assay was used for QA/QC of large scale in-house produced diclofenac gel. The validation protocol was designed following international guidelines, e. g. ICH Q2(R1). Selectivity tests also included the separation of synthesis related by-products like 1-(2,6-dichlorphenyl)indoline-2-one (impurity A) and indoline-2-one (impurity E), and in addition selectivity with regard to several photodegradation products produced by both UV and simulated sunlight irradiation has been shown. PMID- 23346759 TI - A novel reversed-phase LC method for quantitative detection of azithromycin in bulk drug and tablet formulations in various aqueous media. AB - A novel reversed-phase HPLC method with UV-detection for separation, identification and quantification of azithromycin (AZH) was developed. The method was validated for the purpose of quantifying AZH in stability, dissolution and solubility studies. The method was validated at two optimum wavelengths where linear regression at both 205 and 210 nm, resulted in correlation coefficients of r2 = 0.9999. This HPLC method proved to be superior to other published methods due to the specificity, resulting in less peak interference and tailing. The pH of the mobile phase, as well as the ratio of buffer to organic component included in the mobile phase, proved to be critical factors in the improved detection of AZH. PMID- 23346760 TI - Differential pulse polarographic investigation of the antifungal drugs itraconazole, ketoconazole, fluconazole and voriconazole using a dropping mercury electrode. AB - The electrochemical reactions of the antifungal drugs itraconazole, ketoconazole, fluconazole and voriconazole have been investigated by differential pulse polarography (DPP) using a dropping mercury electrode (DME). All investigations were carried out in Britton-Robinson buffer solutions and methanol with varying pH values. Ketoconazole and itraconazole both showed a reduction peak with a potential between -1.5V and -1.6 V. Stable and reproducible conditions for the determination of itraconazole (c = 1 x 10(-7) M) were found within the pH range of 6.0 to 8.0 and for the determination of ketoconazole (c = 5 x 10(-8) M) within pH 6.0 to 7.0. Voriconazole showed a reduction peak with a peak potential of -1.7 V (c = 1 x 10(-5) M) within the pH range of 8.0 to 10.0. In the case of fluconazole no electrochemical activity was found. PMID- 23346761 TI - Isoquercitrin provides better bioavailability than quercetin: comparison of quercetin metabolites in body tissue and brain sections after six days administration of isoquercitrin and quercetin. AB - In the present study, over a period of 8 days 12 mg/kg/d quercetin aglycone and 18 mg/kg/d isoquercitrin were orally given to rats, respectively. Four hours after administration, plasma samples were taken as well as tissue samples of liver, lung, heart, kidney and the brain sections hippocampus, cerebellum, striatum, cortex and the remaining brain. A HPLC-FD method with in-line post column complexation was employed to quantify the quercetin metabolites (QM) in plasma and tissues. Compared to the quercetin gavage the isoquercitrin gavage consistently produced higher levels of QM in tissues (double to five-fold) as well as in plasma (double to three-fold). In body tissues, the highest amounts of QM were observed in the lung. In brain tissue, the highest levels of QM were found in the cerebellum, while the striatum contained the lowest levels of QM. In conclusion, this study clearly demonstrates that orally given isoquercitrin leads to higher levels in plasma and in all investigated tissue than quercetin aglycone. PMID- 23346762 TI - Pharmacokinetics of paeoniflorin microemulsion after repeated dosing in rats with adjuvant arthritis. AB - An investigation was designed and conducted to detect pharmacokinetic differences between paeoniflorin (Pae) microemulsion and Pae saline. Pae microemulsion (25, 50,100 mg x kg(-1)) was administered to three groups of rats with adjuvant arthritis (AA) while Pae (25, 50,100 mg x kg(-1)) was given to another three groups of rats both for ten days. A HPLC assay was developed to determine the plasma concentrations of Pae. The plasma concentrations of Pae groups (25, 50 mg x kg(-1)) were undetectable. Furthermore, compared with pharmacokinetic parameters of Pae group (100 mg x kg(-1)), maximum concentration (C(max)), the area under the plasma concentration-time curve (AUC(0-t)), and mean retention time MRT(0-infinity))(h) of Pae microemulsion (100 mg x kg(-1)) increased apparently, while volume of distribution (Vd) and clearance rate (CL/F) decreased. These results indicate that a microemulsion significantly improves the absorption of Pae in AA rats. PMID- 23346763 TI - Identification of CYP isoforms involved in the metabolism of thymol and carvacrol in human liver microsomes (HLMs). AB - Carvacrol and thymol are phenolic compounds with similar structures isolated from many aromatic plants, and have been demonstrated to exert multiple pharmacological effects. The metabolic and pharmacokinetic behaviour of thymol and carvacrol has received much attention. Carvacrol and thymol have been demonstrated to undergo phase I metabolism such as hydroxylation reaction. However, drug-metabolizing enzymes involved in this process remain unclear. Given that cytochrome P450s (CYPs) are involved in most phase I metabolism, the aim of the present study was to investigate the role of CYPs in the metabolism of thymol and carvacrol. After incubation with human liver microsomes (HLMs) in the presence of NADPH, a new metabolite and two metabolites were detected for thymol and carvacrol, respectively. A combination of chemical inhibition studies and assays with recombinant CYP isoforms demonstrated that CYP2A6 was the predominant drug-metabolizing enzyme involved in the metabolism of thymol and carvacrol. All these results remind the researchers that special attention should be paid on pharmacokinetic and clinical outcomes when thymol or carvacrol was co administrated with other compounds mainly undergoing CYP2A6-mediated metabolism. PMID- 23346764 TI - Effects of an aqueous-ethanolic extract of ginger on cytochrome P450 enzyme mediated drug metabolism. AB - Ginger has been extensively used as a herbal medicine for thousands of years in Asia; it has also been used as a seasoning agent in several foods and beverages worldwide. In this study, the effect of an aqueous-ethanolic extract of ginger on CYP450-mediated drug metabolism was investigated in vitro to elucidate the herb drug interactions. A CYP450-specific substrates mixture was incubated with an aqueous-ethanolic extract of ginger in human liver microsomes fortified with an NADPH-generating system, and the metabolites generated from each of the CYP450 specific metabolic reactions were measured by liquid chromatography-tandem mass spectrometry. The ginger extracts were tested at concentrations of 0.05-5 microg/mL. The resulting data showed that the ginger extract inhibited CYP2C19 mediated drug metabolism in a concentration-dependent manner with an IC50 value of 3.8 microg/mL. When the ginger extract was pre-incubated and assessed, the inhibition pattern did not change, indicating that the inhibition of CYP2C19 was competitive rather than mechanism-based. The effects on other CYP isozyme activity were negligible at the concentrations tested. In conclusion, this inhibitory effect of ginger extract could affect the pharmacokinetics and lead to interactions with drugs that are metabolized by CYP2C19. PMID- 23346765 TI - Reduction in tumour cell invasion by pigment epithelium-derived factor is mediated by membrane type-1 matrix metalloproteinase downregulation. AB - Prostate cancer and breast cancer are major killers among males and females respectively. In this study, pigment epithelium-derived factor (PEDF) was examined for its effect on commonly used human prostate cancer and human breast cancer cell lines. PEDF increased adhesion of cells to collagen-I, with decreased expression of phosphorylated focal adhesion kinase (p-Fak) consistent between the two cell types. Invasion of both tumour cell types through collagen-I was also reduced by PEDF, with decreased expression of membrane type-1 matrix metalloproteinase (MT1-MMP). These results were confirmed with specific antibodies to MT-MMP1. This study provides some vital clues as to which molecular players are perturbed by PEDF treatment of human prostate and breast cancer cells, raising hope that PEDF can in future be trialled against these major cancers in attempts to procure safer yet effective therapies for cancer. PMID- 23346767 TI - Examination of factors that delay the elution of acetaminophen from over-the counter drugs. AB - The information on the stability of medications is important to secure their quality. There is, however, little information about the stability of medications which assume to be kept by patients and customers. We previously showed that a delay in drug release occurs in some over-the-counter (OTC) drugs following storage in a high temperature, high humidity environment. In this study we prepared model tablet formulations containing an active ingredient and excipients to investigate the cause of this delayed release. The results reveal that delayed release occurs in preparations compounded with acetaminophen (AA) as the active ingredient and erythritol (ET) and crospovidone (CP) as excipients. In addition, ET deliquesces in a high humidity environment, then incorporates other particles during room temperature storage to form an aggregate. SEM observations and micropore distribution measurements conducted on OTC tablets that exhibit delayed release revealed that the number of intraparticle pores decreased after storage under high temperature, high humidity conditions. Thus, the delayed release by these pharmaceutical product formulations may be due to a change in the micropore structure both on the surface and within the particles, thereby decreasing the solvent infiltration pathways leading to the interior of the preparation. PMID- 23346766 TI - The effect of dilution and prolonged injection time on dexamethasone-induced perineal pruritus. AB - Dexamethasone has been widely used before general anesthesia induction. However, previous studies have found that a pre-induction bolus dose of dexamethasone sometimes causes perineal pruritus. We hypothesized that an appropriate prolongation of the injection time might suppress dexamethasone-induced perineal pruritus. Four hundred patients requiring general anaesthesia were randomly allocated into four groups: group I receiving 2 ml dexamethasone (5 mg/ml); group II receiving 4 ml dexamethasone (2.5mg/ml); group III receiving 10 ml dexamethasone (1 mg/ml); and group IV receiving 20 ml dexamethasone (0.5 mg/ml). Dexamethasone was diluted with 0.9% sodium chloride. The injection time of dexamethasone was 5s in groups I, II and III; while the injection time of dexamethasone was 30s in group IV. Occurrence of perineal pruritus was significantly reduced in Group IV (0% vs 38%, 32% and 12% in Groups I, II and III, respectively, p < 0.05). The incidence was higher in females than in males (p < 0.05). The duration of perineal pruritus was longer in females than in males in groups I, II and III (p < 0.05). We conclude that the dilution of dexamethasone to 0.5 mg/ml with 0.9% sodium chloride combined with prolonged injection time to 30 s eliminates dexamethasone-induced perineal pruritus. PMID- 23346768 TI - Paraoxonase-1 Q192R polymorphism is not associated with clopidogrel response in Chinese stroke patients. AB - It is well known that CYP2C19*2/*2 is associated with attenuated response to clopidogrel, but recent findings indicated that in white patients, paraoxonase-1 (PON1) 192Q/Q was a major determinant of clopidogrel efficacy. The objective of this research was to assess the impact of PON1 Q192R polymorphism on the maximum platelet aggregation (MPA) and the anti-platelet effect of clopidogrel in clopidogrel-treated Chinese stroke patients. The study recruited 183 eligible Chinese stroke patients treated with a loading dose of 300-mg clopidogrel and a 75-mg daily maintenance dose. CYP2C19*2 and PON1 Q192R were genotyped, a subcohort of 13 patients with CYP2C19 *2/*2 genotype was excluded. Finally 170 patients with CYP2C19*1/*1 (wild-type homozygotes, n = 87) or CYP2C19*1/*2 (mutant heterozygotes, n = 83) were enrolled in the study population. These patients were divided into three groups according to their PON1 Q192R genotype: wild-type homozygotes, PON1 192QQ, n = 17; mutant heterozygotes, PON1 192QR, n = 81; mutant homozygotes, PON1 192RR, n = 72. MPA was measured by light transmittance aggregometry (LTA) to assess platelet function after seven 75-mg maintenance doses of clopidogrel before discharge. In those patients who were carriers of 1 mutant allele (PON1 Q/R192), ADP-induced MPA were not significantly different compared with wild-type homozygous patients [30.5% (IQR, 17.5 to 49.1%) versus 25.0% (IQR, 10.0 to 52.5%), respectively; P = 0.910]. In addition, in the patients who were carriers of the 2 mutant allele (PON1 R/R192), MPA were also not significantly different from wild-type homozygous patients [29.2% (IQR, 15.0 to 43.4%) versus 25.0% (IQR, 10.0 to 52.5%), respectively; P = 0.717]. Results of a multivariable linear regression model demonstrated that PON1 192R allele carriage was not independently associated with ADP-induced MPA measurements (P = 0.408). PON1 Q192R polymorphism does not seem to exhibit any impact on MPA and clopidogrel response at all. PMID- 23346770 TI - Let's tap the patient potential. PMID- 23346771 TI - Public involvement in research. PMID- 23346769 TI - Clinical efficacy of two forms of intravenous iron--saccharated ferric oxide and cideferron--for iron deficiency anemia. AB - Over 90% of iron deficiency anemia cases are due to iron deficiency associated with depletion of stored iron or inadequate intake. Parenteral iron supplementation is an important part of the management of anemia, and some kinds of intravenous iron are used. However, few studies have evaluated the clinical efficacy of these drugs. The purpose of this study was to compare and assess the clinical efficacy of two types of intravenous iron injection, saccharated ferric oxide (SFO) and cideferron (CF). Medical records were obtained for 91 unrelated Japanese anemia patients treated with SFO (n = 37) or CF (n = 54) from May 2005 to May 2010 at Gunma University Hospital. Patients treated with blood transfusion, erythropoietin or oral iron were excluded. Hemoglobin (Hb) values measured on day 0, 7 and 14 were used to assess the efficacy of intravenous irons. A significant increase was observed in the mean Hb value by day 14 of administration in both the CF group and SFO group, and the mean Hb increase due to administration of CF for 7 days was comparable to that of SFO for 14 days. Age and sex did not affect improvement of Hb value. CF is fast acting and highly effective compared with SFO for the treatment of iron deficiency anemia. The use of CF may shorten a therapeutic period for iron deficiency anemia, and CF may be feasible for reducing the hospitalization period. PMID- 23346772 TI - How to develop a patient and carer advisory group in stroke care research. AB - AIM: The aim of this paper is to inform and advise researchers on the practical issues associated with involving stroke patients and their carers in research. BACKGROUND: The involvement of patients and carers in research is increasingly recognised as important, yet researchers are often unclear on how to do this in practice. This is particularly evident in the field of stroke care, where there is limited information available about how to involve stroke patients and their carers in research effectively, or about the difficulties associated with this. DATA SOURCE: Experience of developing a patient and carer advisory group. REVIEW METHODS: This paper reflects on the process the authors undertook when developing a stroke patient and darer advisory group as part of a research study exploring the effect of interprofessional team working on the experiences and outcomes after stroke of patients and carers. DISCUSSION: This paper discusses the challenges and the benefits of deveong a stroke patient and carer and advisory group, and offers advice to other researchers undertaking a similar process. It aims to provide some practical suggestions that may aid researchers wishing to involve stroke patients and carers in their research. CONCLUSION: Stroke patients are likely to be older and have long-term physical disabilities or communication problems that may make their involvement in research more challenging to implement. However, with planning and consideration and the allocation of sufficient time and resources, stroke patients and their carers can be effectively involved, resulting in benefits to the research process and output, and to researchers, patients and carers. IMPLICATIONS FOR PRACTICE/RESEARCH: Pay attention to planning and the practical details of involving stroke patients and their carers in research, ensuring that meetings are arranged in an accessible venue. Use straightforward language in all forms of communication. Listen carefully to their views and perspectives and be prepared to make changes to the study and revise methods if appropriate. PMID- 23346773 TI - To what extent can people with communication difficulties contribute to health research? AB - AIM: To present an approach to involving people with communication disorders in research. BACKGROUND: Patient and public involvement (PPI) is promoted at all stages of research, with everyone having a right to be involved. However, the high level of communication skills often required precludes the involvement of people with communication disorders. As people from several healthcare groups have communication difficulties, it is important to establish approaches that can help to involve them. DATA SOURCE: A study involving people with communication difficulties using computerised aphasia treatment. REVIEW METHODS: The paper describes techniques used to help an advisory group comprising people with aphasia and their carers to collaborate. Reflections on participating in a research group were elicited through videoed interviews. A thematic analysis of the video transcripts identified issues important to the group's members. DISCUSSION: The approach to patient and public involvement in research enabled collaboration with people with aphasia at all stages of research, including contributing to recruitment, refinement of protocols, new research methods and dissemination of project outcomes. Allowing time for careful preparation of group meetings, facilitation techniques and activities is crucial to achieve this level of involvement. CONCLUSION: The group experienced increased confidence in communicating, stimulation and feelings of empowerment and being able to influence the future treatment of people with aphasia. IMPLICATIONS FOR PRACTICE/RESEARCH: People with communication difficulties need not be excluded from PPI activities designed to inform clinical practice or health research. Inclusion of this group can be made possible by using creative methods of exchanging ideas, reducing reliance on rapid, complex spoken interaction. PMID- 23346774 TI - From Darwin to constructivism: the evolution of grounded theory. AB - AIM: To explore the evolution of grounded theory and equip the reader with a greater understanding of the diverse conceptual positioning that is evident in the methodology. BACKGROUND: Grounded theory was developed during the modernist phase of research to develop theories that are derived from data and explain human interaction. Its philosophical foundations derive from symbolic interactionism and were influenced by a range of scholars including Charles Darwin and George Mead. DISCUSSION: Rather than a rigid set of rules and procedures, grounded theory is a way of conceptualising data. Researchers demonstrate a range of perspectives and there is significant variation in the way the methodology is interpreted and executed. Some grounded theorists continue to align closely with the original post-positivist view, while others take a more constructivist approach. Although the diverse interpretations accommodate flexibility, they may also result in confusion. CONCLUSION: The grounded theory approach enables researchers to align to their own particular world view and use methods that are flexible and practical. IMPLICATIONS FOR PRACTICE/RESEARCH: With an appreciation of the diverse philosophical approaches to grounded theory, researchers are enabled to use and appraise the methodology more effectively. PMID- 23346775 TI - Using grounded theory to create a substantive theory of promoting schoolchildren's mental health. AB - AIM: To discuss the creation of a substantive theory using grounded theory. This article provides an example of generating theory from a study of mental health promotion at a high school in Finland. BACKGROUND: Grounded theory is a method for creating explanatory theory. It is a valuable tool for health professionals when studying phenomena that affect patients' health, offering a deeper understanding of nursing methods and knowledge. DATA SOURCES: Interviews with school employees, students and parents, and verbal responses to the 'school wellbeing profile survey', as well as working group memos related to the development activities. Participating children were aged between 12 and 15. REVIEW METHODS: The analysis was conducted by applying the grounded theory method and involved open coding of the material, constant comparison, axial coding and selective coding after identifying the core category. DISCUSSION AND CONCLUSIONS: The analysis produced concepts about mental health promotion in school and assumptions about relationships. Grounded theory proved to be an effective means of eliciting people's viewpoints on mental health promotion. The personal views of different parties make it easier to identify an action applicable to practice. PMID- 23346776 TI - An introduction to Q methodology. AB - AIM: To explain Q methodology, an untraditional approach to nursing research, by exploring the various stages involved in it and using two studies. BACKGROUND: Q has some of the advantages of qualitative and quantitative, methodologies. A defining principle of Q is its assumption that subjective viewpoints are amenable to systematic analysis. Q aims to identify shared views across a population. The orientation of the uncovered perspectives differs significantly from qualitative research and there is no researcher bias. DATA SOURCES: Studies on living with chronic pain and the therapeutic relationship in mental health nursing. REVIEW METHODS: A review of the advantages and disadvantages of Q. DISCUSSION: In areas where there are many contradictions and contrasting views, for example nursing practice, such a methodology could bring clarity in identifying subjective views of different groups. This article will first present the methodology followed by two examples of studies that have been carried out. CONCLUSION: This article demonstrates that Q has much to offer nurse researchers, because the identification of patients' viewpoints in a reliable way has the potential to help nurses to deliver evidence-based practice in response to patients' needs. IMPLICATIONS FOR RESEARCH/PRACTICE: Q methodology has much to offer nursing research because the identification of patients' viewpoints has the potential to enhance nurses' abilities to deliver responsive evidence-based practice. PMID- 23346777 TI - Conducting research into hidden or hard-to-reach populations. AB - AIM: To explore the problems involved in conducting research with populations that are hidden or hard to reach, and to suggest strategies to recruit participants. BACKGROUND: Conducting research with populations that are hidden or hard to reach can pose problems. Recruitment is, by definition, difficult and it is impossible to determine if participants are representative of these populations. Nevertheless, it is important to extend research strategies to include such groups, particularly when developing targeted services. DATA SOURCES: This methodological paper draws on a research study undertaken as part of the author's doctoral studies, in which seven men aged 16-20 years old took part in semi-structured interviews. DISCUSSION: Several factors make research with populations that are hidden and hard to reach difficult, yet information from such populations is essential in identifying strategies that address the needs of the population as a whole. Researchers should adopt methods that allow them to engage with, rather than exclude, these populations, but this requires a critical acknowledgement and evaluation of the potential limitations of the chosen strategies. CONCLUSION: Problems with sampling must be examined and discussed. Well-evaluated but limited research data are preferable to no information from groups that are hidden and hard to reach. IMPLICATIONS FOR RESEARCH OR PRACTICE: Engaging these populations in research can further professionals' understanding of service provision. PMID- 23346778 TI - Use of reflexivity in a mixed-methods study. AB - AIM: To present a novice researcher's use of a reflective research diary in the quantitive measure of a mixed methods study and to recommend resulting changes to practice. BACKGROUND: Reflexivity is often regarded as a useful tool for ensuring the standard of qualitative research. Reflexivity provides transparent information about the positionality and personal values of the researcher that could affect data collection and analysis; this research process is deemed to be best practice. A reflective research diary also allows researchers to record observations about the research process. However, such diaries are rarely used in quantitative research and are even contraindicated. DATA SOURCES: A reflective research diary maintained while conducting a retrospective audit of 150 hospice casenotes. REVIEW METHODS: A reflective research diary was written at the end of every research session to keep a detailed history of the research process and to critically reflect on the researcher's thoughts, feelings and observations on the day's work. DISCUSSION: This paper raises questions about whether reflexivity is appropriate in quantitative research, whether it has the capacity to add something of value or whether it endangers the robustness of the method. The authors consider the place of grounded theory's commitment to reflexivity in this mixed-methods study and discuss whether reflexivity offers any benefits to researcher development. CONCLUSION: Use of reflexivity had a positive impact on the progress of the quantitative measure of this study: it enabled work to be reviewed efficiently and served to inform future research practice. Reflexivity stimulated the acquisition of researcher skills and contributed positively to the development of confidence in the novice researcher. IMPLICATIONS FOR RESEARCH/PRACTICE: Reflexivity in quantitative research practice can be an effective, ongoing means of critically reviewing work, process and researcher development. Reflexivity is recommended to other quantitative researchers. PMID- 23346779 TI - Supervision provides a sense of professional satisfaction. PMID- 23346780 TI - Research in nursing education: a vision for the future. PMID- 23346781 TI - The case for certification and certification research. PMID- 23346782 TI - Cultural safety and nursing education in divided societies. AB - AIM: This research explores the experiences of cultural safety among nursing students from majority and minority groups in a divided society with implications for academic satisfaction and success. BACKGROUND: The study takes place in an academic nursing program in Israel, where Arab and Jewish students study together. METHODS: A researcher-developed questionnaire was used with 17 statements concerning social relations between students, faculty support, and the effects of social relations on academic satisfaction and outcomes. RESULTS: Significant differences were found in the ways Arab and Jewish students perceived the cultural safety of the environment. Arab students perceived social relations and faculty attitude as less positive than Jewish students and perceived cultural safety as having greater influence on academic satisfaction and success. CONCLUSION: The findings indicate that students from different groups will perceive the same shared reality in significantly different ways. Nurse faculty and administrators need to make efforts to bring perceptions into closer alignment and to minimize the negative impact of external conflicts on feelings of cultural safety. PMID- 23346783 TI - Development and psychometric testing of the Nursing Student Satisfaction Scale. AB - AIM: The purpose of this study was to develop an instrument with rigorous psychometric properties to comprehensively measure nursing student satisfaction and to identify areas for nursing program enhancement. BACKGROUND: Measures of program quality are frequently designed to demonstrate to professional groups that the educational program will prepare graduates for success in a rapidly changing world. METHOD: This was a longitudinal methodological study.The Nursing Student Satisfaction Scale (NSSS) was used to gather students' perceptions of satisfaction with a nursing program at a university. RESULTS: In total, 303 nursing students enrolled in the final semester of the associate degree in nursing program participated in the study. Psychometric evaluation of the NSSS included content validity, item analysis for internal consistency reliability, and construct validity. CONCLUSION: The NSSS demonstrated sound psychometric properties through the pilot test and the three-year longitudinal study. It provides a theory-based approach to the measurement of nursing student satisfaction. PMID- 23346784 TI - Program outcomes following implementation of a hybrid curriculum at the certificate level. AB - AIM: This study examined satisfaction levels and learning outcomes before and after implementation of a hybrid curriculum. BACKGROUND: Increased competition for clinical sites pressured a practical nursing program to explore alternative placement solutions. A hybrid curriculum, defined as offering 50 percent of second-semester theory course content online, was implemented in order to free students from place-bound instruction and thereby open new clinical opportunities. METHODS: A summative evaluation was conducted to compare NCLEX-PN pass rates, grade outcomes, student satisfaction, and attrition rates between a prehybrid group of 119 practical nursing students and a hybrid group of 106 practical nursing students. RESULTS: Findings indicate no significant differences in NCLEX pass rates and grade outcomes between the groups and an improvement in satisfaction and attrition rates. CONCLUSION: It was concluded that use of a hybrid curriculum can open new clinical opportunities while maintaining the learning outcomes of NCLEX-PN pass rates and course grades. PMID- 23346785 TI - The use of position statements in teaching best practices in nursing. AB - The use of nursing position statements to guide nursing students' discovery of nursing practice was found to be an effective teaching strategy in preparing future clinicians. Nurse educators, seeking to develop strategies for applying research to practice, can use nursing specialty organizations' position statements to promote nursing knowledge dissemination and provide an avenue for sharing evidence-based practice. This article reports on the development of position statements, obstacles to their dissemination, and offers recommendations for nurse educators. PMID- 23346786 TI - Cultural competence of practicing nurses entering an RN-BSN program. AB - AIM: The aim of this exploratory research was to examine the cultural competence of practicing nurses entering an RN to BSN program. BACKGROUND: As nonwhite populations increase in the United States, the cultural competence of nurses increases in importance. With 38 percent of baccalaureate nursing students in RN BSN programs, it is important to examine the cultural competence of this population. METHOD: Fifty-three RN-BSN students completed the Inventory for Assessing the Process of Cultural Competency Among Healthcare Professionals Revised (IAPCC-R) upon program entry; 50.9 percent were culturally competent as determined by the tool. RESULTS: A strong correlation existed between IAPCC-R scores and student age, with students 20 to 30 years old scoring significantly higher than those in the age range of 41 to 50. CONCLUSION: The findings suggest and invite more extensive research on the success of the systematic nursing education initiatives of current associate degree programs and adherence to NLNAC standards for cultural competence, particularly in the cultural skill construct. PMID- 23346787 TI - Asynchronous discussion: a comparison of larger and smaller discussion group size. AB - AIM: To explore the effect of size and strategy on asynchronous discussions (AD) in a small baccalaureate nursing program. BACKGROUND: As the prevalence of e learning increases in nursing education, the use of AD as a learning strategy will increase. Because the AD can be engaging, group size should be considered to enhance learning. METHOD: Descriptive, correlational, and quasi-experimental methodologies were used to gather and analyze data from 23 junior baccalaureate nursing students. Variables included differences in group size (12 versus 23) and strategy (Virtual Clinical Excursions versus faculty-developed questions). RESULTS: There was no statistically significant difference in student outcomes for group size or strategy. The data suggested that smaller group size would help students "dig deeper" into the content being explored. CONCLUSIONS: Student perception responses indicate that Virtual Clinical Excursions was more likely to prepare them for nursing and clinical practice. Future research should include larger sample sizes and more variety in the sample demographics. PMID- 23346788 TI - PDA-assisted simulated clinical experiences in undergraduate nursing education: a pilot study. AB - BACKGROUND: Descriptive literature on use of personal digital assistants (PDAs) in nursing education exists; but, quantitative outcome-driven studies of efficacy are lacking. Few studies have explored the integration of technologies like simulated clinical experiences (SCEs) with informatics competencies. AIM: The purpose of this pilot study was to determine if nursing students' knowledge and attitude scores following a PDA-assisted SCE would be equivalent to textbook assisted scores. METHOD: Using a convenience sample of first-semester baccalaureate students and an equivalence design, multiple lessons were learned about the use of PDAs in the context of SCE. RESULTS/CONCLUSION: Learning was supported through use of PDAs in place of traditional text references; students viewed PDAs as beneficial resources in the provision of care; PDA use prompted reflection and triggered important need-learning connections; orientation to the use of PDAs promoted positive student attitudes; and use of PDAs helped meet nursing informatics curricular requirements. PMID- 23346789 TI - Change and administrative barriers: nurse educators' perceptions concerning the use of simulators. AB - AIM: The purpose of this descriptive correlational research study was twofold: to examine the adoption of simulators in the nursing classroom and the relationship between adoption and nurse educators' perceptions of established change strategies as followed by program administrators. BACKGROUND: The use of simulators in education is important and requires many nurse educators to change their current teaching strategies. METHOD: Data were collected from a purposive population using a demographic questionnaire, the nursing practice questionnaire (NPQ), and the change process survey. RESULTS: The overall diffusion score, as measured by the NPQ, was 2.6. A statistically significant correlation was noted between level of use and the perception of established change strategies being followed (r = .340, p < .01). CONCLUSION: Findings indicate that nurse educators adopt simulators sometimes when appropriate. Administrators of nursing programs can enhance this change by using established change strategies. PMID- 23346790 TI - Barriers and strategies toward the implementation of a full-time faculty-at-a distance nurse educator role. AB - AIM: The purpose of this two-phase exploratory, descriptive study was to uncover and describe barriers and potential strategies toward implementation of a full time faculty-at-a-distance nurse educator (FDNE) role, with all responsibilities of instruction, governance, research, and student service, as perceived by hirers and potential hires. BACKGROUND: The faculty deficit has reached critical proportions that directly affect the nation's nursing workforce. There is a growing need to use nontraditional methods to reinforce, energize, and expand faculty capacity. METHOD: The two-phase study was conducted using online questionnaires with two samples: decision makers with regard to faculty hiring and current, experienced nurse faculty. Respondents were asked to rate how National League for Nursing Nurse Educator Core Competencies could be achieved by a FDNE. RESULTS: The ability to facilitate student learning development and socialization was ranked most difficult, while engagement in scholarship and use of assessment and evaluation strategies were ranked least difficult. Both groups of respondents identified "tradition" and "perceived faculty role change" as the highest ranked barriers. Technological and administrative support and support of colleagues were seen as strategies for the implementation of the role. CONCLUSION: Perceived barriers to the FDNE were attitudinal and infrastructural. The findings of this study may pave the way toward development of a prefatory faculty-at-a-distance model. PMID- 23346791 TI - A quantitative approach to evaluating caring in nursing simulation. AB - AIM: This study was designed to test a quantitative method of measuring caring in the simulated environment. BACKGROUND: Since competency in caring is central to nursing practice, ways of including caring concepts in designing scenarios and in evaluation of performance need to be developed. Coates' Caring Efficacy scales were adapted for simulation and named the Caring Efficacy Scale-Simulation Student Version (CES-SSV) and Caring Efficacy Scale-Simulation Faculty Version (CES-SFV). METHOD: A correlational study was designed to compare student self ratings with faculty ratings on caring efficacy during an adult acute simulation experience with traditional and accelerated baccalaureate students in a nursing program grounded in caring theory. RESULTS: Student self-ratings were significantly correlated with objective ratings (r = 0.345, 0.356). CONCLUSIONS: Both the CES-SSV and the CES-SFV were found to have excellent internal consistency and significantly correlated interrater reliability. They were useful in measuring caring in the simulated learning environment. PMID- 23346792 TI - Teaching strategies that promote a culturally sensitive nursing education. PMID- 23346793 TI - Building an educational model that promotes competence through innovation. PMID- 23346794 TI - Disruption in higher education: massively open online courses (MOOCs). PMID- 23346795 TI - Nursing judgment: educating nurses to make decisions in practice. PMID- 23346796 TI - One's location of residence as an important factor related to the occurrence of multiple primary cancer among patients with uveal melanoma. AB - PURPOSE: This study has attempted to analyze the impact of where one lives related to the incidence of multiple primary cancer among patients with uveal melanoma. MATERIAL AND METHODS: The group that was studied consisted of 240 patients. They were separated from other patients who had been diagnosed and treated with uveal melanoma at the Department of Ophthalmology and Ocular Oncology at Jagiellonian University Medical College in the period between January 1998 to December 2007. Ninety seven patients, diagnosed with another primary cancer, was defined as a test group. The remaining 143 patients constituted the control group. RESULTS: In the test group individuals were mostly residents of large cities, most often with population of more than 500 thousand inhabitants. The control group represented residents of small towns, each having less than 10000 persons population. CONCLUSIONS: The findings of this study are pointing to the dependence of the detectability of multiple primary cancer among patients with uveal melanoma on the availability of modern diagnostic methods. uveal melanoma, multiple primary cancer. PMID- 23346797 TI - Assessment of the influence of one's education on early diagnosis of multiple primary cancer in patients with uveal melanoma. AB - PURPOSE: This study will show a comparison of two groups of patients with uveal melanoma; one group with multiple primary cancer, and a second group with no identifiable second cancer, in terms of education and occupation. MATERIAL AND METHODS: Study concerns 240 patients, who were isolated from patients being treated with uveal melanoma at the Department of Ophthalmology and Ocular Oncology Jagiellonian University Medical College in the period from 1998 to 2007. On the basis of medical history and medical records 97 patients were diagnosed with the one or more independent primary cancers. These patients were subjected to comparative analysis with a group of 143 patients with uveal melanoma as a control group. RESULTS: Analyzing the impact of education on the recognition of multiple primary cancer, there were significantly more frequent diagnoses of second primary cancers among patients with secondary and higher education than among those who had primary and vocational education. Among the obtained data on patients in the study group, the largest occupational group (according to the ISCO-88 (COM)) constituted "professionals". In the control group prevailed "craft and related trades workers". CONCLUSIONS: The results suggest the great importance of knowledge about risk factors for the development of cancer among patients with uveal melanoma and the ensuing more scrupulous search for succesive primary neoplasm and indicate the neccesity of organizing broad prophylactic actions. uveal melanoma, multiple primary cancer. PMID- 23346799 TI - [Orbital lymphoblastic lymphoma in 7 years old child]. AB - The aim of the study is to present a case of unilateral orbital tumor (lymphoma) in a 7 years old boy. The edema of the temporal area of the right orbit with considerable narrowing of the palpebral fissure increased quickly during about 3 weeks. The skin redness without increased skin warmness and hardening by palpation above the lesion were observed. The orbit ultrasound and nuclear magnetic resonance were performed and the biopsy for histopathologic evaluation and immunohistochemical staining was taken. The last examination reveled a very rare kind type of the lymphoma in this age and location--lymphoblastic lymphoma beginning from B cells. In case of lymphoma the biopsy for histopathologic and immunohistochemical evaluation is essential, allowing for diagnosis and appropriate chemotherapy, as far as there is different outline for the treatment of different lymphomas. PMID- 23346798 TI - PEDF and VEGF plasma level alterations in patients with dry form of age-related degeneration--a possible link to the development of the disease. AB - PURPOSE: The aim of the study is to explore the interaction between stimulators and inhibitors of angiogenesis by measuring pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) plasma levels in patients with the wet and dry forms of age-related macular degeneration (AMD). MATERIAL AND METHODS: Forty-six subjects with the wet form, 31 with the dry form of AMD as well as 47 non-AMD healthy controls were enrolled in the study. Plasma concentrations of VEGF and PEDF were measured using ELISA test. RESULTS: A significant decrease in the PEDF plasma level in patients with the dry form of AMD was found. Multivariate analyses of patients and controls adjusted for age, sex, smoking, and concomitant vascular diseases as independent variables revealed that the dry form of AMD was the only independent factor associated with lower plasma PEDF levels (beta = -0.34; p = 0.026). On the contrary, in the wet AMD group, a strong positive correlation between VEGF and PEDF concentrations was observed (Rs = +0.63; p = 0.002), and significantly higher PEDF and VEGF plasma levels in patients with bilateral manifestations of the disease were also found. CONCLUSIONS: These findings suggest that different manifestations of AMD, i.e. the dry and wet forms, may be associated with various altered concentrations of counterbalancing stimulators and inhibitors of the angiogenesis process. PMID- 23346800 TI - [Orbital tumor--hemangiopericytoma--in a neonate]. AB - PURPOSE: To present a case of Haemangiopericytoma (HPC), a rare neopalsm which originates from the vascular pericytes. HPC occurs most commonly in adults. Only 5-10% of cases occur in children. Congenital orbital HPC is generally unknown in the field of ophthalmology. MATERIAL AND METHODS: A case of congenital, large exophthalmus is reported in a 1 day old male neonate. Imaging studies demonstrated a vascular, orbital mass involving skull base and cranial fossa. RESULTS: The diagnosis of HPC was established after histological exmination. Lesion did not qualify to surgical resection. The child was treated with chemotherapy for 10 months and a great regression of tumor was noted. There was no tumor recurrence during 4 years of a follow up. CONCLUSIONS: Chemotherapy may have a significant role in the treatment of infants with nonoperative malignant hemangiopericytoma. PMID- 23346801 TI - [The role of SOCT in monitoring the course of disease and modification of treatment in Birdshot chorioretinopathy--two years of clinical observation]. AB - The aim of the article is to present the role of SOCT in monitoring the treatment of Birdshot chorioretinopathy based on a clinical case. A 78 years old woman with Birdshot retinopathy was referred to the Department of Ophthalmology for visual deterioration since 2 months. The patient complained about blurred vision and floaters. Eye examination revealed changes on the fundus typical for birdshot chorioretinopathy. Two years of regular checking and SOCT scans allowed for better monitoring and modification of treatment both with steroids and with non steroid immunosuppressive agents. Finally, based on the changes at the vitreo retinal interface revealed in SOCT examination, the patient was treated with PPV with satisfactory functional and anatomic results. PMID- 23346802 TI - [The regulating mechanisms of retinal and choroidal circulation]. AB - The purpose of this article was to describe the phenomena related to the mechanisms regulating alterations of vascular blood flow in ophthalmic and retrobulbar circulation. In this review, various indirect and direct methods of evaluating retinal blood flow have been discussed. Laser, contrast and ultrasonographic techniques, including color Doppler ultrasonography, electroretinography, electroencephalography, calorimetric investigations, with the radiographic entities and registering changes in tunica vasculosa circulation were described. Additionally, radiographic investigations, isometric measurements and studies with the use of pharmacological agents, evaluation of partial pressure of oxygen or carbon dioxide in both inhaled and exhaled air, and in daylight as well as in darkness were presented. Although there are many control methods of regulating mechanisms of bulbar circulation, none of those techniques used presently and in the past is ideal, hence the only investigations widely applied for this purpose have been both Doppler ultrasonography and laser methods. In the review influence of myogenic and neurogenic mechanisms on blood flow in eyeball was described. Moreover, the part of vessels coarcting and dilating substances in these hemodynamic phenomena has been included. CONCLUSIONS: In the course of various ophthalmic disease entities of vascular origin, different substances take part in general and local regulation of ocular and retrobulbar circulation, whose action mechanism might be the cause of hemodynamic disorders. Color Doppler ultrasonography remains one of the more frequently used methods which could indirectly register alterations of vascular blood flow in retrobulbar arteries. PMID- 23346803 TI - Influence of rheological factors on the development of primary open angle glaucoma. AB - The aim of this study was to compare our non published investigation on the effect of rheological factors on the development of primary open angle glaucoma (POAG)--to literature data. POAG is a chronic eye disease characterised by a slowly progressive neuropathy of the optic nerve with typical anatomical and functional lesions and is associated with specific visual field defects. PMID- 23346804 TI - The photopic negative response as a promising diagnostic tool in glaucoma. A review. AB - PURPOSE: Based on the available literature, the clinical usefulness of Photopic Negative Response (PhNR) of flash Electroretinogram (ERG) in detecting glaucoma has been described. MATERIALS AND METHODS: Data published in the literature available at the Pub Med library between 1999-2011. Different techniques of eliciting, assessing and measuring PhNR have been analyzed. Relations between results of static automated perimetry (SAP), Gdx, optical coherence tomography (OCT), pattern electroretinogram (PERG) and PhNR in glaucomatous patients have been described. RESULTS: 1. The most frequent method of PhNR recording has been brief (< 6 ms), red stimulus against the blue background with thread active DTL electrodes. 2. There has been a significant decrease of PhNR amplitude and PhNR/b wave ratio in patients with different stages of glaucoma field defect. 3. Curvilinear and linear correlation between retinal sensitivity (SAP), retinal nerve fibre layer thickness (RNFLT), PhNR amplitude and PhNR/b-wave ratio has been found. 4. A significant correlation occurred between PhNR and PERG amplitudes. 5. Focal PhNR seems to be a more specific and sensitive tool in comparison to full field PhNR. CONCLUSIONS: PhNR is a promising tool in glaucoma neuropathy assessment. Up to date the value of PhNR has not been definitely proved. More research is necessary to con rm the usefulness of PhNR in diagnosing glaucoma. PMID- 23346805 TI - [Qualification and methods of laser capsulotomy in pseudophakic eye]. AB - Posterior capsule opacification (PCO) called secondary cataract is one of the most common late complication after the cataract surgery. This drawback might happened in 25 to 50 per cent in adult group and 51 to 100 per cent in children and adolescent group during 2 to 5 years after surgery. Currently Nd: YAG capsulotomy is the best method of secondary cataract treatment. Decision making about PCO should be based on thorough analysis of potential risk factors and advantages which follows that procedure. Advantages are: improvement of visual acuity, improvement of contrast sensivity, reducing glare and better appearance of eye fundus. However after capsulotomy some complications may happen: cystoid macular edema (CME), retinal detachment (RD), intraocular pressure increase (IOP), intraocular lens (IOL) dislocation. Nowadays it is growing awareness of prevention PCO. Counteracting arise PCO include treatment before, during and after surgery and it is strictly connected with reduction of inflammatory reaction, proper of surgical technique. In our publication we would like to stress some important issue about qualification process and techniques of Nd: YAG capsulotomy. PMID- 23346806 TI - [Meibomian gland dysfunction--review]. AB - Meibomian gland dysfunction is a common ocular disorder affecting from 39 to 50% of population. Despite that, so far a pathophysiology path of the disease remains unknown, moreover there is no distinct border between physiology and the disease. There has been no clear diagnostic criteria. The purpose of this review was to combine a current knowledge of Meibomian gland anatomy, Meibomian gland dysfunction epidemiology, as well as presenting current definition, nomenclature, classification and diagnostic criteria. The importance of diagnosis associated with conditions such as aqueous tear deficiency, seborrheic dermatitis, and rosacea is emphasized. The available treatment methods are discussed. Meibomian gland dysfunction, blepharitis, dry eye syndrome. PMID- 23346807 TI - [Idiopathic intracranial hypertension and organ of vision]. AB - Idiopathic intracranial hypertension (IIH) is defined as a syndrome of increased intracranial pressure without causative lesions on magnetic resonance imaging. The symptoms of IIH patients are headache, transient visual obscurations, photopsia, retrobulbar pain, diplopia, visual loss and papilledema. Management of intracranial hypertension is initially medical, using a combination of managed weight body reduction and diuretic, non-steroid and steroid therapy. Surgical therapy may be required to stabilize vision. PMID- 23346808 TI - [Does cardiovascular comorbidities are important as far as ophthalmology treatment is concerned?]. AB - Majority of patients with glaucoma, age-related maculopathy or diabetic macular edema is old. Therefore arterial hypertension, coronary arterial disease, diabetes and dyslipidemia are common finding in patients with sick eye. In this article some situations needing cooperation of cardiologist and ophthalmologist have been pointed. The influence of treatment of hypertension on glaucoma outcomes and the influence of intraocular injections of biological drugs on cardiovascular risk seems to be the most important issues. PMID- 23346809 TI - [Survey on the actual condition of psychiatrists and psychiatric services in Japan. (Part 1): Basic data on number and distribution of psychiatrists]. AB - BACKGROUND: To ensure that psychiatric services adequately meet the needs of the Japanese people, planning a prospective design based on a needs analysis is required. Presently, the distribution of medical resources in Japan is skewed and the priorities of psychiatric services are unclear. OBJECTIVE: To determine the current status of psychiatric services. METHOD: The definition of a psychiatrist was determined by qualified specialists of the Japanese Society for Psychiatry and Neurology (JSPN). Of the 11,169 candidates who applied for the specialist psychiatry examination, 246 were excluded due to a lack of personal information and 4 due to refusal. The remaining 10,919 agreed to allow the verification of their personal data. This study was conducted with the approval of the JSPN. The total number of psychiatrists, their demographic backgrounds, the number of psychiatrists by prefecture, and the number of psychiatrists in each secondary medical care block in Japan were calculated. RESULTS: Of the 10,919 psychiatrists included in this analysis, 2,124 were female and 8,790 were male. Approximately 90% were < 65 years old, and 42% were < 45 years old. Their primary work places were as follows: psychiatric hospitals (n = 5,233, 47.9%); university departments of psychiatry (n=1,353, 12.4%); general hospitals (n = 1,064, 9.7%); psychiatric clinics (n = 2,456, 22.5%); nonpsychiatric clinics (n = 687, 6.3%); and nonclinical work places such as basic science departments (n = 124, 1.1%). The number of psychiatrists per 100,000 inhabitants in each prefecture was determined. The highest numbers of psychiatrists were from Kochi (13.20), Tokyo (12.76), and Tokushima (12.24), and the lowest numbers were from Ibaraki (5.34), Aomori (5.36), and Saitama (5.67). The number of psychiatrists per 100,000 inhabitants in Kochi was 1.48 per area (100 km square), and Tokyo showed the highest at 75.99 psychiatrists per area, followed by Osaka and Kanagawa. The five Tohoku prefectures and Hokkaido had the fewest psychiatrists per area. CONCLUSION: For planning the future management of psychiatric services, continuous investigation of the actual number of psychiatrists and the status of psychiatric services in Japan is required with the constant cooperation of the JSPN. PMID- 23346810 TI - [Survey on the actual condition of psychiatrists and psychiatric services in Japan. (Part 2): Change in geographical working area and setting of each psychiatrist]. AB - BACKGROUND: The shortage of psychiatrists has recently become a public concern; however, the reason for this shortage has not been clearly discussed or explained on the basis of real data. We assumed that it is not only due to the lack of the absolute number of psychiatrists, but also due to an imbalance in their distribution in geographical working areas and settings. OBJECTIVE: To evaluate the change in distribution of Japanese psychiatrists. METHOD: We analyzed the change in the geographical working area and setting of each psychiatrist from September 2006 to March 2009 using data obtained from psychiatrists who applied for the Board Certification Examination of the Japanese Psychiatric Association. Our data included 6,881 psychiatrists. RESULTS: With regard to the geographical working area, the number of psychiatrists in ordinance-designated cities (urban areas) increased by 2.2%, whereas that in other areas decreased by 3.0%. On examination of work settings, we noted a 16.0% decrease in the number of psychiatric departments in general hospitals and a 20.0% increase in the number of psychiatric clinics. Surprisingly, more than 10% of middle-aged psychiatrists (10.3% of 36 45-year-olds and 12.2% of 46-55-year olds) who worked in general hospitals moved to clinics. CONCLUSION: The present study revealed that, although psychiatrists did not tend to move from rural to urban areas, they showed a tendency to move from general hospitals to psychiatric clinics. PMID- 23346811 TI - [Research on the method of stress assessment--from the research findings of 2010]. AB - The Japanese Society for Occupational Mental Health has conducted research on assessment of the psychological load (i.e., stress) among workers. Investigations were conducted three times, and those were contract research projects assigned by the Ministry of Health, Labour and Welfare. In this project, the author was the primary researcher. In the latest research, a survey utilizing the Live Event Method was performed extensively nationwide; the survey covered 10,494 subjects (including 1,977 females) from all types of industry and occupation. The objective of this research was to reevaluate the Psychological Load Assessment Sheet used as an evaluation basis for the "Certification of workers' compensation related to mental disorders from psychological load." Two previous research investigations, conducted in 2002 and 2006, had suggested the need for such reevaluation. The outcomes revealed that, the longer the monthly overtime working hours, the higher the stress scores (in the range of 0 to 10), and the lower the appearance rate of stress. Subjects who performed 140 hours or more of overtime work per month, which fell under the category of "Extremely Excessive Overtime Work," showed 6.3 points, which was markedly high, and ranked fourth in the survey with 63 assessment items. The category, "Extremely Excessive Overtime Work," includes two working hour ranges, 120 hours or more and 160 hours or more; those working hour ranges were defined in the revision based on the latest research. Monthly overtime work of 120 hours or more, but less than 140 hours, was ranked ninth and scored 6.3 points. Monthly overtime work of 80 hours or more, but less than 100 hours, scored 5.3 points with a frequency of 14.2%. Based on the above results, new assessment items were added to the Psychological Load Assessment Sheet. This paper addresses and studies the issues explained above. PMID- 23346812 TI - [Problems stemming from recently revised government standard for job-induced mental disorders in the future]. AB - On December 26, 2011 the Ministry of Health, Labour and Welfare issued a new standard in the Workers' Compensation Law for Job-Induced Mental Disorders. The standard provides new guidelines for determining the degree to which conditions in the workplace bring on stress that results in mental disorders in workers. One case study will be discussed. An employee developed a mood disorder resulting in prolonged sick leave because of overly severe scaldings and warnings from the boss. The employee applied for workers' compensation 7 years after the incident and after the implementation of the new Workers' Compensation Law. I will discuss how the new law allows workers to claim compensation for work-induced mental disorders that happened before the law came into effect. PMID- 23346813 TI - [Necessity of a diagnosis guidelines for non-changing medical conditionins work related mental disorders in Japan]. AB - The expert committee's report about a new standard of employment injuries authorization of mental disorders for the use of the Industrial Accident Compensation Insurance Act was shown on the website of the Ministry of Health, Labour and Welfare, Japan on November 8th, 2011. Unfortunately, a significant number of patients with mental disorders do not achieve a fully symptom-free recovery, and display residual symptoms and lower levels of social and psychological functioning. Definitions of recovery from mental disorders can vary, and it is difficult to decide on the boundary between reversible and irreversible medical conditions. Psychiatrists should prepare diagnosis guidelines for when the medical condition is viewed as non-changing (symptom fixation) for work-related mental disorders after treatments are given for a period deemed long enough for a return (or not) to premorbid psychosocial functioning. PMID- 23346814 TI - [New guidelines for the assessment of mental disorders--from a standpoint of lawyer]. AB - In the field of Workers' Compensation Law, new guidelines were issued by the Ministry of Health, Labour and Welfare (Circular 26 Dec. 2011). This article briefly explains its content and function. Compared with medical insurance, a worker's compensation solely covers the diseases arising "out of employment", and the guidelines prescribe the criteria in order to decide on a causal relationship (nessocausale) between work and a mental disorder. By doing so, the guidelines aim to secure the fair and appropriate administration of compensation. The guidelines set the "Table" by which the events at the workplace are evaluated. When the event is "strong", the compensation is to be given. There are several other events which are, by themselves, "strong" (ex., work-related death). In parallel with the events, the working time (especially overtime) is also measured as a factor showing the heaviness of the work. PMID- 23346815 TI - [Evaluation of suicide risk factors based on a survey of suicides and suicidal attempts at psychiatric hospitals in Aichi Prefecture]. AB - This investigation examined cases of suicide, suicidal attempts, and risk factors in 41 psychiatric hospitals of Aichi Prefecture. As a result, some characteristics of psychiatric wards considered to be effective in suicide prevention were shown. In addition, as for measures to resolve risk factors and the state of the patients, there were many which were effective in the prevention of suicide attempts. Regarding measures to reduce risk factors for symptoms and treat patients, there were many techniques which were effective in the prevention of suicidal attempts, but, for cases which did not respond to treatment, suicide was frequent. In addition, a "suicide preventive manual in a psychiatric hospital" produced based on these results was distributed. PMID- 23346816 TI - [State of suicide and effective efforts in suicide prevention in psychiatric hospitals and clinics]. AB - Although factors related to suicide are complicated, mental health disorders are an important risk factor. It is anticipated that suicide prevention measures will be implemented from the perspective of improved psychiatric medicine. No national scale study has been carried out in Japan on the state of psychiatric medicine and its influence on suicide since 2000. Moreover, many efforts not intended for suicide prevention have been shown to be effective for this purpose. Here, we conducted surveys to obtain basic data on suicide prevention and improvements in mental health care among 1,728 psychiatric hospitals and clinics in Japan in 2010. The incidence of suicide in psychiatric hospitals and clinics from January to December 2009 was estimated to be 100.5 for outpatients and 154.5 for inpatients per 100,000 patients. Regarding the duration from consultation to suicide, 87% of outpatients committed suicide less than one month following their last consultation. Moreover, approximately two-thirds of patients had undergone consultations for more than one year. A number of suicides in psychiatric hospitals and clinics occurred while patients were continuously undergoing treatment. Efforts shown to be effective in suicide prevention included risk assessment with multiple medical staff (i.e., doctors and nurses), a 24-hour crisis line, and a follow-up system for discontinued outpatients. We expect that the results of this survey will aid in the implementation of effective suicide prevention in psychiatric medicine. PMID- 23346817 TI - [Recommendation for revision of the General Principles of Suicide Prevention Policy]. AB - Since the promulgation of the Basic Act for Suicide Prevention, suicide prevention in Japan has developed rapidly. In order to further reinforce such activities, it is necessary to balance universal, selective, and indicated prevention. For the revision of the General Principles of Suicide Prevention Policy, the Center for Suicide Prevention announced this recommendation with 29 societies. We hope that it will promote suicide prevention in Japan and lead to expansion of the suicide prevention network by academic organizations, NGOs, as well as local and central government. PMID- 23346818 TI - [Approaches for suicide prevention in Osaka Psychiatric Medical Center: the importance of multi-disciplinary cooperation and partnerships with other organizations]. AB - Suicide is a very common problem in psychiatric practice today. Therefore, almost all staff of psychiatric hospitals have encountered the suicide of one or more of their patients. Our hospital, Osaka Psychiatric Medical Center, is a public psychiatric hospital in Japan. We provide treatment and support for patients from the acute to chronic phases of psychiatric disorders, and patients range from children to the elderly. Because we accept many patients with severe mental illness from other hospitals, many of our staff are routinely confronted with patients' violence or suicidal attempts. If a patient commits suicide, the relevant staff immediately have a conference to implement measures for preventing a recurrence. At the same time, information about the incident is conveyed to the medical safety management office and made known to all staff in our hospital. This office was established in 2007. Currently, all information about incidents and accidents in our hospital (e.g., suicide, problems between patients, problems with hospital facilities) is aggregated in the office and distributed to all staff members through the hospital intranet. This system makes it possible for staff to consider countermeasures against similar incidents and accidents, even if not involved in the incident. Additionally, we make an effort to develop cooperative relationships with organizations including the police, public health centers, and the fire department. The social welfare council in Hirakata City, where our hospital is located, provides some services to prevent suicide (e.g., telephone counseling, meetings with bereaved family members). Our hospital cooperates with these services by providing lecturers. The partnerships with these organizations help regarding the mental crises of patients in our hospital and fulfill a role to prevent suicide. Multi-disciplinary cooperation and partnerships with community organizations are not special approaches to suicide prevention, but ordinary approaches in everyday clinical practice. The most important factor is the relationship between staff and organizations relevant to preventing suicide. PMID- 23346819 TI - [Integrated care in community psychiatric medicine]. AB - A common factor underlying the current issues in psychiatric medicine is the lack of visualization of the process of medical practice. An approach to visualization of this process facilitates solving the problems faced in this field. Psychiatric care often comes into effect based on the cooperation of a number of institutions and professions, rather than being completed within a single institution. To visualize the process of psychiatric care, it is important to establish face-to face relationships between patients and psychiatrists, introduce the care system in which two doctors share the responsibility of managing a single patient, and formulate an integrated care pathway in the community. Although many consider the clinical pathway concept to be unsuitable for psychiatric practice, it is possible to introduce a community cooperation care pathway into psychiatric practice if consideration is first given to several significant issues. Community cooperation activities in the field of psychiatric care including the integrated care pathway help to harmonize the efforts of supporters, patients, and families, and increase the overall sense of security. It is also expected that such activities will allow us to obtain useful indices for assessing the quality of care. PMID- 23346820 TI - [Postvention: how a psychiatrist should face a patient's suicide]. AB - Suicide by a patient in therapy, which is not a rare encounter for most psychiatrists, may be a traumatic experience for the treating psychiatrist. The psychiatrist should sincerely face the patient's suicide, which can be a part of crisis management in psychiatric care. If a patient commits suicide, appropriate care should be offered to: 1) the patient's family members, 2) other vulnerable patients, 3) medical and nursing staff, and 4) the treating psychiatrist and nurse in charge of the deceased patient. The patient's family members should be informed of patient factors before the suicide and the care required by the family members. Information on what actually happened before the suicide should be given to other patients, and individuals who are severely influenced by the suicide should be offered appropriate care. The medical and nursing staff should examine the case from the viewpoint of what they can learn from the death. With the help of the supervisor, the treating psychiatrist and nurse in charge of the deceased patient should look into the case, and his/her negative countertransference and attitude toward death and suicide. This can help the psychiatrist acquire better therapeutic skills for treating suicidal patients in the future. PMID- 23346821 TI - [This month's image: Gleno Labral Articular Disruption (GLAD) and glenoid cartilage's "bare spot"]. PMID- 23346822 TI - [An unexpected finding in a 14-year-old girl]. AB - A 14-year-old girl was admitted to the Emergency department for abdominal pain. An abdominal mass of 7-8 cm was detected and surgically resected. At anatomopathology a solid pseudopapillary neoplasm of the pancreas was observed. This tumour is rare and is included in the pancreatic cystic neoplasms. It frequently concerns 20-30-year-old girls. In all cases, the treatment consists of surgical resection, even in the rare cases with metastases. Prognosis is usually good, but careful follow-up is mandatory. PMID- 23346823 TI - [Herpes hepatic failure during the third quarter of pregnancy]. AB - Acute liver diseases of pregnancy are common and usually transient and reversible. Given the number of different possible diagnoses, performing a large biological screening and a proper iconographic documentation is key. It makes sure no etiology fatal to the mother and her fetus is missed. PMID- 23346824 TI - [2011 ESC guidelines on the diagnosis and treatment of peripheral artery diseases]. AB - In this article, we present the 2011 guidelines on the diagnosis and treatment of peripheral artery diseases. The document covers the diagnostic modalities and therapeutic strategies for the atherosclerotic disease of the extra-cranial carotid, mesenteric, renal, upper and lower extremity arteries indicating the class and level of evidence of the recommendations. PMID- 23346825 TI - [Clinical and therapeutical approach of depression in old age]. AB - Despite recent clinical and scientific developments in the psychogeriatric field, depression in old age remains an underdiagnosed and undertreated disorder. However, depressive symptoms are frequent in older people and the impact on patients, their family and the society is very important. Depression is also frequently associated with somatic illnesses, with alcoholism, anxiety and a significant risk of suicide. In this context, a systematic screening of depression and an adequate treatment are a priority. PMID- 23346826 TI - [Climatic impact on venous ulcers of the leg]. AB - Venous leg ulcers have a multifactorial origin. The environmental temperature appears to distinctly modulate the initiation and the subsequent evolution of the leg ulcer. The chronobiology of both episodes is quite distinct. A cold climate favors the initiation while a warmer climate tends to aggravate the ulcer. The seasonal fluctuations of the ulcer process are likely correlated with vasomotor phenomena taking place in the skin following variation in ambient temperature. PMID- 23346827 TI - [Should asymptomatic small popliteal artery aneurysms be operated on?]. AB - The authors recently observed two patients who suffered acute lower limb ischemia secondary to thrombosis of a small (diameter of less than 2 cm) popliteal artery aneurysm. A literature search lead to the conclusion that small popliteal aneurysms, covered with mural thrombus and presenting a distorted neck due to elongation, are prone to thrombosis. Another risk factor is a restrained outflow bed as a result of previous micro-embolisations into the tibial arteries. The authors conclude that small popliteal artery aneurysms are not so innocent as is often presumed. PMID- 23346828 TI - [Peritoneal carcinomatosis of unknown origin]. AB - Peritoneal carcinomatosis is defined as a secondary neoplastic invasion of the peritoneum. This entity may represent a significant challenge in terms of its diagnosis, its exploration and research of its origin and its treatment. This clinical history illustrates the difficulties generated by a case of peritoneal carcinomatosis and describes the importance of a multidisciplinary approach. When the primary origin is unknown before the initiation of treatment, the peritoneal carcinomatosis is a form of carcinoma of unknown primary (CUP). When this condition affects a woman, it becomes a particular entity with a better outcome, for which a specific first-line treatment should be initiated. PMID- 23346829 TI - [Pregnancy and systemic lupus erythematosus: compatible?]. AB - Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease that predominantly occurs in women of childbearing age. The risk of obstetric complications in lupus parturients is significant. In addition, pregnancy may be associated with flares of the disease requiring immunosuppressive therapy. For these reasons, SLE pregnancies are considered high risk and involve careful collaboration of the obstetrician and rheumatologist. Through the latter and medical advances including a better and better understanding of the binomial mother-child, most pregnancies end in a success. PMID- 23346830 TI - [Blood conservation strategy: a current issue]. AB - In view of the demographic evolution, the progress of quality requirements and the shortage of donors, a deficiency of blood components is to be feared in the coming years. This implies the development of a blood conservation strategy, the revision of transfusion practices and the implementation of preventive measures to limit transfusion requirements. Each service caring for patients at high transfusion risk should assess and rationalize its transfusion practices in a structured multidisciplinary way. PMID- 23346831 TI - [How I explore ... a risk difference in the occurrence of an event in clinical trials]. AB - Evidence-based medicine often requires the comparison of two therapeutic interventions in controlled clinical trials with the demonstration of a superiority (versus a placebo or an active comparator) or at least a non inferiority (versus an active reference) concerning a primary endpoint that has been defined a priori (occurrence of a major clinical event, for instance). The difference in the occurrence of such an event between two treatments may be statistically analyzed by absolute risk reduction, relative risk reduction, hazard ratio or odds ratio. The present article discusses the nuances, sometimes of importance, concerning the significance of these various indices and analyses the cautions to be taken and the pitfalls to be avoided in their interpretation and use in practice. The clinician is, indeed, increasingly confronted to results of clinical trials, but is generally poorly informed regarding the nuances of these various statistical analyses. PMID- 23346832 TI - [Not Available]. PMID- 23346833 TI - [Comments on inclusive schooling]. PMID- 23346834 TI - [Treatment with "natural medicine" in North Mozambique]. PMID- 23346835 TI - [Sport mentors for persons with Down Syndrome sought]. PMID- 23346836 TI - [My dear Ulla]. PMID- 23346837 TI - ["Grandmother, why do you have such large ears". The ear grows also in old age and is larger in men than in women]. PMID- 23346838 TI - [Family, health and pediatric nursing in a practice test: nursing health consultation in the family center]. PMID- 23346839 TI - [Solid food instead of mush: less overweight in babies. Proper weaning method promotes healthy dietary habits in early childhood]. PMID- 23346840 TI - [Prevalence of infections on the intensive care unit. The EPIC-2 Study illustrates a change in the pathogen spectrum]. PMID- 23346841 TI - [Self determined living. On the visit to the "RehaCare 2012" in Dusseldorf]. PMID- 23346842 TI - [Continuous decline in child mortality. Worldwide 51 fatalities, in Germany only 4 per 1,000 children]. PMID- 23346843 TI - [Working together - learning from each other]. PMID- 23346844 TI - [Competent and fair nutrition counseling. Nationwide over 280 counseling offers - independent without advertising and product sale]. PMID- 23346845 TI - [Routine nursing on a bone marrow and stem cell transplantation department]. PMID- 23346846 TI - [A matter of honor! Pediatric and adolescent Balthasar Hospice was presented with the Springer Medicine Charity Award for its engagement with terminally ill children]. PMID- 23346847 TI - ["Do you believe in a God in heaven"?]. PMID- 23346848 TI - [On the trail of the spiral staircase. One day of gene research with children]. PMID- 23346849 TI - [Social pediatric treatment of early childhood feeding and eating disorders - nursing aspects]. PMID- 23346850 TI - [Eating disorder in adolescence: not dismiss as a "phase". Early onset anorexia or bulimia worsens prognoses]. PMID- 23346851 TI - [Mary Eliza Mahoney - first Afro American nurse]. PMID- 23346852 TI - Is it time for an 'Occupy QIP' movement? PMID- 23346853 TI - The KDIGO anemia guideline: can reason triumph over regulation? PMID- 23346854 TI - Dietary management of the nocturnal home hemodialysis patient. PMID- 23346855 TI - Identification of viral pathogen diversity in sewage sludge by metagenome analysis. AB - The large diversity of viruses that exist in human populations are potentially excreted into sewage collection systems and concentrated in sewage sludge. In the U.S., the primary fate of processed sewage sludge (class B biosolids) is application to agricultural land as a soil amendment. To characterize and understand infectious risks associated with land application, and to describe the diversity of viruses in human populations, shotgun viral metagenomics was applied to 10 sewage sludge samples from 5 wastewater treatment plants throughout the continental U.S, each serving between 100,000 and 1,000,000 people. Nearly 330 million DNA sequences were produced and assembled, and annotation resulted in identifying 43 (26 DNA, 17 RNA) different types of human viruses in sewage sludge. Novel insights include the high abundance of newly emerging viruses (e.g., Coronavirus HKU1, Klassevirus, and Cosavirus) the strong representation of respiratory viruses, and the relatively minor abundance and occurrence of Enteroviruses. Viral metagenome sequence annotations were reproducible and independent PCR-based identification of selected viruses suggests that viral metagenomes were a conservative estimate of the true viral occurrence and diversity. These results represent the most complete description of human virus diversity in any wastewater sample to date, provide engineers and environmental scientists with critical information on important viral agents and routes of infection from exposure to wastewater and sewage sludge, and represent a significant leap forward in understanding the pathogen content of class B biosolids. PMID- 23346856 TI - Controlled synthesis of amino acid-based pH-responsive chiral polymers and self assembly of their block copolymers. AB - Leucine/isoleucine side chain polymers are of interest due to their hydrophobicity and reported role in the formation of alpha-helical structures. The synthesis and reversible addition-fragmentation chain transfer (RAFT) polymerization of amino acid-based chiral monomers, namely Boc-L-leucine methacryloyloxyethyl ester (Boc-L-Leu-HEMA, 1a), Boc-L-leucine acryloyloxyethyl ester (Boc-L-Leu-HEA, 1b), Boc-L-isoleucine methacryloyloxyethyl ester (Boc-L-Ile HEMA, 1c), and Boc-L-isoleucine acryloyloxyethyl ester (Boc-L-Ile-HEA, 1d), are reported. The controlled nature of the polymerization of the said chiral monomers in N, N-dimethylformamide (DMF) at 70 degrees C is evident from the formation of narrow polydisperse polymers, the molecular weight controlled by the monomer/chain transfer agent (CTA) molar ratio and the linear relationship between molecular weight and monomer conversion. The resulting well-defined polymers were used as macro-CTAs to prepare corresponding diblock copolymers by RAFT polymerization of methyl (meth)acrylate monomers. Deprotection of Boc groups in the homopolymers and block copolymers under acidic conditions produced cationic, pH-responsive polymers with primary amine moieties at the side chains. The optical activity of the homopolymers and block copolymers were studied using circular dichroism (CD) spectroscopy and specific rotation measurements. The self assembling nature of the block copolymers to produce highly ordered structures was illustrated through dynamic light scattering (DLS) and atomic force microscopy (AFM) studies. The side chain amine functionality instills pH responsive behavior, which makes these cationic polymers attractive candidates for drug delivery applications, as well as for conjugation of biomolecules. PMID- 23346857 TI - Recent trends in resistance to cell envelope-active antibacterial agents among key bacterial pathogens. AB - Cell envelope-active agents, particularly beta-lactams, play a pivotal role in the treatment of bacterial infections and the extent to which their activity is affected by the emergence of multidrug-resistant organisms is of concern. We analyzed the Surveillance Network (TSN) database to evaluate resistant trends for key cell envelope-active drugs among ESKAPE pathogens. Analysis demonstrated that the activity of these drugs has been notably influenced by the emergence of multidrug resistance; this was especially evident for the beta-lactam drugs. For example, Acinetobacter baumannii resistance to imipenem increased from 23.9% to 34.3%, and resistance to piperacillin-tazobactam increased from 37.0% to 49.7% between 2007 and 2011. During the same time period Klebsiella pneumoniae resistance to imipenem increased from 0.8% to 3.8%. As beta-lactams are a cornerstone of anti-infective therapy, it is important to closely monitor the activity of the agents being used today and to aggressively pursue new strategies that can augment current drugs and thwart ever-emerging beta-lactam resistance mechanisms that are continuously encountered. PMID- 23346858 TI - beta-Lactam antimicrobials: what have you done for me lately? AB - The "perpetual challenge of infectious diseases" is no better exemplified than by the phenomena of rapid emergence and spread of bacterial resistance. Although beta-lactam antimicrobials have thus far been a mainstay of the therapeutic armamentarium for treatment of severe infections, their preeminent position has been challenged by an onslaught of resistance mechanisms in major nosocomial and community-acquired pathogens, including modification of penicillin-binding proteins, production of beta-lactamases, overexpression of efflux pumps, and loss of porins. Given this formidable array of resistance mechanisms facing patients and their physicians, one can reasonably ask if there is hope for the future of beta-lactams. PMID- 23346859 TI - Proliferation and significance of clinically relevant beta-lactamases. AB - Inactivation of beta-lactam antibiotics by beta-lactamases in bacterial infections is associated with some of the most serious infectious disease issues that are currently encountered. The evolution of unique beta-lactamases has resulted in more than 1,300 distinct enzymes that have been identified in natural clinical isolates. Of these enzymes, the most deleterious beta-lactamases are the extended-spectrum beta-lactamases, or ESBLs, that hydrolyze most penicillins and cephalosporins, and the carbapenemases that may inactivate all beta-lactam classes of drugs. The most prominent ESBLs worldwide are the CTX-M-14 and CTX-M 15 enzymes. Among enzyme families, the TEM and OXA beta-lactamases exhibit the greatest number of variants. The broad groups of carbapenemases are particularly treacherous, especially the KPC serine carbapenemases and the NDM family of metallo-beta-lactamases, both of which appear in multidrug-resistant Gram negative pathogens that are often resistant to most classes of antibiotics. Although new beta-lactamase inhibitor combinations are being investigated as a means of controlling infections caused by these organisms, additional approaches are sorely needed. PMID- 23346860 TI - New beta-lactam-beta-lactamase inhibitor combinations in clinical development. AB - Tazobactam was the most recent beta-lactamase inhibitor to be approved in 1993. Since the approval of piperacillin-tazobactam, the complexity of beta-lactamase mediated resistance among Gram-negative bacilli has increased enormously. After more than 20 years since the first such combination, amoxicillin-clavulanic acid, was approved, several new beta-lactam-beta-lactamase inhibitor combinations have reached late-stage (phase II and beyond) clinical trials. These include ceftolozane-tazobactam (2:1, ratios of beta-lactam to beta-lactamase inhibitor in parentheses), ceftazidime-avibactam (4:1), ceftaroline-avibactam (1:1), and imipenem-cilastatin-MK-7655 (2:2:1 and 4:4:1). Avibactam and MK-7655 are diazabicyclooctane (DABCO) inhibitors and thus not beta-lactams themselves; they include class A carbapenemases and class C enzymes within their spectra of activity. Ceftolozane is an antipseudomonal cephalosporin, and tazobactam is used to protect it against extended spectrum beta-lactamases to which it is labile. Additional novel combinations are in preclinical development. This review will focus on the biochemistry, antimicrobial activity, pharmacodynamics, and clinical development of these novel combinations. PMID- 23346861 TI - Siderophore conjugates. AB - There has been considerable effort expended in the investigation of the potential of siderophore conjugates of antibiotics to circumvent the permeability barrier imposed by the outer membrane of Gram-negative bacteria. There is also a small group of natural conjugates, the sideromycins. Among the synthetic analogues that have been investigated are conjugates of nucleosides, glycopeptides, macrolides, fluroquinolones, and, above all, beta-lactams. Despite this effort, few compounds have progressed beyond experimental studies. One compound, the siderophore monosulfactam BAL30072, is in early clinical studies. PMID- 23346862 TI - Introduction to Antimicrobial Therapeutics Reviews: the bacterial cell wall as an antimicrobial target. PMID- 23346863 TI - Thermal conductivity and phonon transport in suspended few-layer hexagonal boron nitride. AB - The thermal conductivity of suspended few-layer hexagonal boron nitride (h-BN) was measured using a microbridge device with built-in resistance thermometers. Based on the measured thermal resistance values of 11-12 atomic layer h-BN samples with suspended lengths ranging between 3 and 7.5 MUm, the room temperature thermal conductivity of a 11-layer sample was found to be about 360 W m(-1) K(-1), approaching the basal plane value reported for bulk h-BN. The presence of a polymer residue layer on the sample surface was found to decrease the thermal conductivity of a 5-layer h-BN sample to be about 250 W m(-1) K(-1) at 300 K. Thermal conductivities for both the 5-layer and the 11-layer samples are suppressed at low temperatures, suggesting increasing scattering of low frequency phonons in thin h-BN samples by polymer residue. PMID- 23346864 TI - Excimer of 9-aminoacridine hydrochloride hydrate in confined medium: an integrated experimental and theoretical study. AB - We aim to find out the extent of stability of the excimer of 9-aminoacridine hydrochloride hydrate (9AA), a prospective PDT drug, in different confined media with varying cavity size. When confined in cetyltrimethyl ammonium bromide micelles, although at low concentration of 9AA, only a single distinct peak (lambda(max) at 460 nm) with a shoulder at 485 nm is observed in steady-state fluorescence spectrum, yet with increase in concentration the peak and the shoulder merge with simultaneous emergence of another peak at 535 nm, which is assigned to excimer. Similar behavior is also observed in Triton-X, crown ether, alpha-cyclodextrin, beta-cyclodextrin, and homogeneous aqueous medium. The formation of excimer, which reflects the extent of confinement of 9AA, is maximum in beta-cyclodextrin followed by others. Steady-state and time-resolved fluorescence studies along with TRES and TRANES analyses coupled with anisotropy data and transient absorption studies reveal the presence of monomer-dimer equilibrium of 9AA in the excited state. Molecular modeling indicates that the structure of excimer is stabilized by locking of the two monomeric species via four hydrogen bonds formed between the amino-H and imino-N of 9AA monomers, whereas the dimer in the ground state has only two such hydrogen bonds. PMID- 23346865 TI - Noninvasive coronary flow reserve evaluation of coronary stenosis detected by multislice computed tomography: a value added proposition? PMID- 23346866 TI - Synthesis of antioxidants for prevention of age-related macular degeneration. AB - Photooxidation of A2E may be involved in diseases of the macula, and antioxidants could serve as therapeutic agents for these diseases. Inhibitors of A2E photooxidation were prepared by Mannich reaction of the antioxidant quercetin. These compounds contain water-solubilizing amine groups, and several were more potent inhibitors of A2E photooxidation than quercetin. PMID- 23346867 TI - The impact of child sexual abuse on the course of bipolar disorder: a systematic review. AB - OBJECTIVES: The aim of this review was to elucidate the impact of child sexual abuse on all clinical phenomena that occur after the onset of bipolar disorder, including associated clinical features that are not part of the diagnostic criteria for the disorder. METHODS: Five databases were searched and supplemented with a hand search of reference lists from retrieved papers. Study quality was assessed using a validated quality assessment tool. Blind assessments of study eligibility and quality were conducted by two independent researchers to reduce bias, minimize errors, and enhance the reliability of findings. Disagreements were resolved by consensus. RESULTS: Eighteen studies that included a total of 2996 adults and youths with bipolar disorder and met the minimum quality criteria necessary to ensure objectivity and not invalidate results were analyzed. Across studies, child sexual abuse was strongly (and perhaps directly) associated with posttraumatic stress disorder; whereas it was less strongly (and perhaps indirectly) related to suicide attempts, alcohol and/or drug abuse or dependence, psychotic symptoms, and an early age of illness onset. In regard to the association between child sexual abuse and other clinical variables concerning the course of bipolar disorder, evidence was scant or conflicting. CONCLUSIONS: Child sexual abuse is associated (either directly or indirectly) with some clinical phenomena that represent a more severe form of bipolar disorder. Although such a traumatic experience may directly affect the development of posttraumatic stress disorder, the effects of early sexual abuse on later suicidal behavior, substance abuse, and psychotic symptoms may operate through the mediating influences of certain psychopathological or neurobiological variables. PMID- 23346868 TI - Bench-top validation testing of selected immunological and molecular Renibacterium salmoninarum diagnostic assays by comparison with quantitative bacteriological culture. AB - No gold standard assay exhibiting error-free classification of results has been identified for detection of Renibacterium salmoninarum, the causative agent of salmonid bacterial kidney disease. Validation of diagnostic assays for R. salmoninarum has been hindered by its unique characteristics and biology, and difficulties in locating suitable populations of reference test animals. Infection status of fish in test populations is often unknown, and it is commonly assumed that the assay yielding the most positive results has the highest diagnostic accuracy, without consideration of misclassification of results. In this research, quantification of R. salmoninarum in samples by bacteriological culture provided a standardized measure of viable bacteria to evaluate analytical performance characteristics (sensitivity, specificity and repeatability) of non culture assays in three matrices (phosphate-buffered saline, ovarian fluid and kidney tissue). Non-culture assays included polyclonal enzyme-linked immunosorbent assay (ELISA), direct smear fluorescent antibody technique (FAT), membrane-filtration FAT, nested polymerase chain reaction (nested PCR) and three real-time quantitative PCR assays. Injection challenge of specific pathogen-free Chinook salmon, Oncorhynchus tshawytscha (Walbaum), with R. salmoninarum was used to estimate diagnostic sensitivity and specificity. Results did not identify a single assay demonstrating the highest analytical and diagnostic performance characteristics, but revealed strengths and weaknesses of each test. PMID- 23346869 TI - Unconventional doctoring: a medical student's reflections on total suffering. PMID- 23346870 TI - Palliative medicine physician education in the United States: a historical review. AB - In this review we discuss the history of Hospice and Palliative Medicine (HPM) physician education in the United States over the last 20 years, as there has been dramatic growth in our specialty during this time. A Medline literature search was completed and we surveyed leaders in the field of HPM education regarding their experiences in promoting palliative medicine education. Educators were selected based on their peer reviewed publications on key educational initiatives since 1990. A survey tool was designed and emailed to 18 educators across the country and follow-up phone interviews were done to further explore specific questions. The survey and interviews sought information about major palliative care education milestones, instrumental projects, and barriers to further development of palliative medicine education. PMID- 23346871 TI - Graft incorporation and implant osseointegration following the use of autologous and fresh-frozen allogeneic block bone grafts for lateral ridge augmentation. AB - OBJECTIVES: To compare autogenous bone (AT) and fresh-frozen allogeneic bone (AL) in terms of histomorphometrical graft incorporation and implant osseointegration after grafting for lateral ridge augmentation in humans. MATERIALS AND METHODS: Thirty-four patients were treated with either AL (20 patients) or AT (14 patients) onlay grafts. During implant installation surgery 6 months after grafting, cylindrical biopsies were harvested perpendicularly to the lateral aspect of the augmented alveolar ridge. Additionally, titanium mini-implants were installed in the grafted regions, also perpendicularly to the ridge; these were biopsied during second-stage surgery. Histological/histomorphometric analysis was performed using decalcified and non-decalcified sections. RESULTS: Histological analysis revealed areas of necrotic bone (NcB) occasionally in contact with or completely engulfed by newly formed vital bone (VB) in both AT and AL groups (55.9 +/- 27.6 vs. 43.1 +/- 20.3, respectively; P = 0.19). Statistically significant larger amounts of VB (27.6 +/- 17.5 vs. 8.4 +/- 4.9, respectively; P = 0.0002) and less soft connective tissue (ST) (16.4 +/- 15.6 vs. 48.4 +/- 18.1, respectively; P <= 0.0001) were seen for AT compared with AL. No significant differences were observed between the groups regarding both bone-to-implant contact (BIC) and the bone area between implant threads (BA) on the mini-implant biopsies. CONCLUSION: Allogeneic bone block grafts may be an option in cases where a limited amount of augmentation is needed, and the future implant can be expected confined within the inner aspect of the bone block. However, the clinical impact of the relatively poor graft incorporation on the long-term performance of oral implants placed in AL grafts remains obscure. PMID- 23346872 TI - Morphology of Bromeliophrya quadristicha n. spec., an inhabitant of tank bromeliads (Bromeliaceae), and phylogeny of the Bromeliophryidae (Ciliophora, Tetrahymenida). AB - Using morphological, morphometric, and molecular methods, we describe Bromeliophrya quadristicha n. spec. from tank bromeliads of Jamaica and the Dominican Republic. The new species differs from the single congener, B. brasiliensis, mainly in having four (vs. 2) left lateral kinetofragments, 23 (vs. 32) ciliary rows, and a short (vs. long and C-shaped) adoral membranelle 3. Both the morphological and molecular phylogenies show Bromeliophrya and Glaucomides as sister group of the Glaucomidae. Thus, they should have the same (family) rank. PMID- 23346873 TI - Does occiput posterior position in the second stage of labour increase the operative delivery rate? AB - OBJECTIVES: To assess the impact of occipito-posterior position in the second stage of labour on operative delivery. METHODS: Double-blinded prospective cohort study of ultrasound determined occiput-posterior position during the second stage of labour compared with occiput-anterior position. The primary outcome was operative (caesarean section, forceps or vacuum) delivery. RESULTS: A total of 68% (13/19) women in the occiput-posterior group, and 27% (39/141) in the occiput anterior group had an operative delivery (unadjusted: P < 0.001). Caesarean section was performed in 37% and 5%, respectively (P < 0.001). The occiput posterior group had a longer second stage (mean 2 h 59 minutes vs 1 h 54 minutes; P = 0.001) and larger infants (mean 3723 g vs 3480 g, P = 0.024). In the logistic regression, occiput-posterior position, nulliparity, abnormal second stage cardiotocograph and epidural analgesia were independent predictors for operative delivery. CONCLUSIONS: Occiput-posterior position early in the second stage of labour is strongly associated with operative delivery. There is potential to explore interventions such as manual rotation. PMID- 23346874 TI - Iridium-catalyzed intermolecular asymmetric hydroheteroarylation of bicycloalkenes. AB - Catalytic hydroarylation of alkenes is a desirable process because it can occur under neutral conditions with regioselectivity complementary to that of acid catalyzed reactions and stereoselectivity derived from the catalyst. We report an intermolecular asymmetric addition of the C-H bonds of indoles, thiophenes, pyrroles, and furans to bicycloalkenes in high yield with high enantiomeric excess. These heteroarene alkylations occur ortho to the heteroatom. This selectivity is observed even with unprotected indoles, which typically undergo alkylation at the C3 position. Initial mechanistic studies revealed that oxidative addition of a heteroarene C-H bond to a neutral Ir(I) species occurs within minutes at room temperature and occurs in the catalytic cycle prior to the turnover-limiting step. Products from syn addition of the C-H bond across the olefin were observed. PMID- 23346875 TI - A ubiquitin carboxyl extension protein secreted from a plant-parasitic nematode Globodera rostochiensis is cleaved in planta to promote plant parasitism. AB - Nematode effector proteins originating from esophageal gland cells play central roles in suppressing plant defenses and in formation of the plant feeding cells that are required for growth and development of cyst nematodes. A gene (GrUBCEP12) encoding a unique ubiquitin carboxyl extension protein (UBCEP) that consists of a signal peptide for secretion, a mono-ubiquitin domain, and a 12 amino acid carboxyl extension protein (CEP12) domain was cloned from the potato cyst nematode Globodera rostochiensis. This GrUBCEP12 gene was expressed exclusively within the nematode's dorsal esophageal gland cell, and was up regulated in the parasitic second-stage juvenile, correlating with the time when feeding cell formation is initiated. We showed that specific GrUBCEP12 knockdown via RNA interference reduced nematode parasitic success, and that over-expression of the secreted Gr(Delta) (SP) UBCEP12 protein in potato resulted in increased nematode susceptibility, providing direct evidence that this secreted effector is involved in plant parasitism. Using transient expression assays in Nicotiana benthamiana, we found that Gr(Delta) (SP) UBCEP12 is processed into free ubiquitin and a CEP12 peptide (GrCEP12) in planta, and that GrCEP12 suppresses resistance gene-mediated cell death. A target search showed that expression of RPN2a, a gene encoding a subunit of the 26S proteasome, was dramatically suppressed in Gr(Delta) (SP) UBCEP12 but not GrCEP12 over-expression plants when compared with control plants. Together, these results suggest that, when delivered into host plant cells, Gr(Delta) (SP) UBCEP12 becomes two functional units, one acting to suppress plant immunity and the other potentially affecting the host 26S proteasome, to promote feeding cell formation. PMID- 23346877 TI - Pretransplant model for end stage liver disease score predicts posttransplant incidence of fungal infections after liver transplantation. AB - Liver transplant recipients are at a significant risk for invasive fungal infections (IFI). This retrospective study evaluated the impact of the pretransplant model for end stage liver disease (MELD) on the incidence of posttransplant IFI in a single centre. From 2004 to 2008, 385 liver transplantations were included, from which 210 transplantations were conducted allocated by Child Turcotte Pugh and 175 were allocated by MELD score. Both groups differed regarding the age of transplant recipients (50.1 +/- 10.7 vs. 52.5 +/- 9.9, P = 0.036), pretransplant MELD score (16.43 +/- 8.33 vs. 18.29 +/- 9.05), rate of re-transplantations, duration of surgery, demand in blood transfusions and rates of renal impairments. In the MELD era, higher incidences of IFI (pre-MELD 11.9%, MELD 24.0%, P < 0.05) and Candida infections (9% vs. 18.9%, P < 0.05) were observed. There was no difference in the incidence of probable or possible aspergillosis. Mortality, length of stay in intensive care or hospital, and duration of mechanical ventilation did not differ between the pre-MELD and MELD era. Regardless the date of transplantation, patients with fungi-positive samples showed higher mortality rates than patients without. MELD score was analysed as independent predictors for posttransplant IFI. Higher MELD scores predispose to a more problematic postoperative course and are associated with an increase in fungal infections. PMID- 23346876 TI - Dispersion and domestication shaped the genome of bread wheat. AB - Despite the international significance of wheat, its large and complex genome hinders genome sequencing efforts. To assess the impact of selection on this genome, we have assembled genomic regions representing genes for chromosomes 7A, 7B and 7D. We demonstrate that the dispersion of wheat to new environments has shaped the modern wheat genome. Most genes are conserved between the three homoeologous chromosomes. We found differential gene loss that supports current theories on the evolution of wheat, with greater loss observed in the A and B genomes compared with the D. Analysis of intervarietal polymorphisms identified fewer polymorphisms in the D genome, supporting the hypothesis of early gene flow between the tetraploid and hexaploid. The enrichment for genes on the D genome that confer environmental adaptation may be associated with dispersion following wheat domestication. Our results demonstrate the value of applying next generation sequencing technologies to assemble gene-rich regions of complex genomes and investigate polyploid genome evolution. We anticipate the genome-wide application of this reduced-complexity syntenic assembly approach will accelerate crop improvement efforts not only in wheat, but also in other polyploid crops of significance. PMID- 23346878 TI - Assembly of phosphide nanocrystals into porous networks: formation of InP gels and aerogels. AB - The applicability of sol-gel nanoparticle assembly routes, previously employed for metal chalcogenides, to phosphides is reported for the case of InP. Two different sizes (3.5 and 6.0 nm) of InP nanoparticles were synthesized by solution-phase arrested precipitation, capped with thiolate ligands, and oxidized with H2O2 or O2/light to induce gel formation. The gels were aged, solvent exchanged, and then supercritically dried to obtain aerogels with both meso- (2 50 nm) and macropores (>50 nm) and accessible surface areas of ~200 m2/g. Aerogels showed higher band gap values relative to precursor nanoparticles, suggesting that during the process of assembling nanoparticles into 3D architectures, particle size reduction may have taken place. In contrast to metal chalcogenide gelation, InP gels did not form using tetranitromethane, a non oxygen-transferring oxidant. The requirement of an oxygen-transferring oxidant, combined with X-ray photoelectron spectroscopy data showing oxidized phosphorus, suggests gelation is occurring due to condensation of phosphorus oxoanionic moieties generated at the interfaces. The ability to link discrete InP nanoparticles into a 3D porous network while maintaining quantum confinement is expected to facilitate exploitation of nanostructured InP in solid-state devices. PMID- 23346879 TI - Histone deacetylase induces accelerated maturation in Xenopus laevis oocytes. AB - In oocyte maturation in Xenopus laevis, nuclear material induces rapid maturation and is required for entry into meiosis II. Nuclear material contains a large number of RNAs and proteins, including histone deacetylase (HDAC); however, it is not known which materials induce accelerated maturation. The HDAC activity modifies transcription rate and is required for normal meiosis; however, its function in oocyte maturation is still unclear. We investigated the function of HDAC activity, which is localized in the nuclear material, in the regulation of the speed of oocyte maturation. Inhibition of HDAC activity with trichostatin A (TSA) induced hyperacetylation of histone H3 and prolonged oocyte maturation. In contrast, increase in HDAC activity with an injection of FLAG-tagged maternal histone deacetylase (HDACm-FLAG) mRNA induced deacetylation of histone H3 and reduced the duration of oocyte maturation. Cdc2 kinase, Cdc25C or mitogen activated protein kinase (MAPK), which are key regulators of the meiosis, were activated coincidently with maturation progression. In oocytes, the mRNA level of Cdc25C, an activator of Cdc2, was increased by HDACm-FLAG mRNA-injection; in contrast, the mRNA level of Cdc2 inhibitor Wee1 was increased by TSA treatment. These results suggest that HDAC activity is involved in the control of maturation speed through the regulation of mRNA levels of cell cycle regulators. Thus, HDACm is a candidate for the nuclear material component that induces rapid maturation in Xenopus oocytes. PMID- 23346880 TI - Prevalence of activating thyrotropin receptor and Gsalpha gene mutations in paediatric thyroid toxic adenomas: a multicentric Italian study. PMID- 23346881 TI - Infection-related hospital admissions after transrectal biopsy of the prostate. AB - BACKGROUND: Urosepsis is the most common complication requiring hospital admission after transrectal biopsy of the prostate. This study aims to assess the local incidence and causative organisms of hospital admissions with urosepsis after transrectal ultrasound-guided prostate (TRUS) biopsy. As morbidity is high, treatment must be commenced empirically prior to cultures. A review of bacterial antibiotic susceptibilities was undertaken to guide optimal treatment of post biopsy urosepsis. METHODS: A total of 1421 patients underwent TRUS biopsy in a single city over a 2-year period. All patients received prophylactic antibiotics prior to the procedure. A retrospective review of a prospectively collated database was performed in all patients admitted to Christchurch Hospital, the only acute admitting hospital in Christchurch, with infection within 30 days after biopsy. Hospital admission records were reviewed, including urine and blood culture results. RESULTS: Forty patients (2.8%) were admitted with infection after the biopsy, the majority occurring within the first week after procedure and four required intensive care unit (ICU) admission (10%). The most common organism isolated on urine and blood cultures was Escherichia coli. Significant E. coli resistance was seen to fluoroquinolones, amoxicillin and trimethoprim. CONCLUSION: Rates of infection after TRUS biopsy and antibiotic resistance are increasing internationally. Treatment for urosepsis should be aggressive as 10% of those patients admitted required ICU admission. TRUS biopsy with ciprofloxacin prophylaxis led to infectious complications comparable with other international reports and appears to remain an appropriate prophylactic antibiotic of choice. Infections requiring hospital admission were all susceptible to a combination of ceftriaxone and gentamicin, and would be an effective initial antibiotic of choice. PMID- 23346882 TI - Menatetrenone for the treatment of osteoporosis. AB - INTRODUCTION: The effect of the anti-osteoporosis medicine, menatetrenone (vitamin K(2); menaquinone-4) on the skeleton remains a matter of controversy. The objective of the present review study was to evaluate the effect of menatetrenone on the skeleton of postmenopausal women, men and glucocorticoid treated patients. METHODS: PubMed was used to search the literature for randomized controlled trials (RCTs), meta-analyses and systematic reviews. Thirteen RCTs, one meta-analysis and one systematic review were available for analysis. RESULTS: Except for one large Japanese RCT (Phase IV trial: Osteoporotic Fracture (OF) study, n = 4378), RCTs with small sample size showed non-significant or modest effect on bone mineral density (BMD) in postmenopausal women and patients treated with glucocorticoid, positive effect on hip geometry in postmenopausal women and efficacy against fractures (mainly vertebral fractures) in postmenopausal women with osteoporosis. A post hoc analysis of the OF study showed that the incidence of vertebral fractures decreased in postmenopausal women with at least five vertebral fractures. A meta-analysis study, but not a systematic review study, showed efficacy against vertebral and non-vertebral fractures mainly in postmenopausal women with osteoporosis. There was no available evidence for men with osteoporosis. CONCLUSION: The present review of the literature revealed some evidence of a positive effect of menatetrenone on the skeleton of postmenopausal women and in patients treated with glucocorticoid. EXPERT OPINION: Menatetrenone is considered to be a second line medicine for postmenopausal osteoporotic women with an increased risk for vertebral fractures. PMID- 23346883 TI - Are we ready for a new definition? PMID- 23346884 TI - The inhibitory receptor CD300a is up-regulated by hypoxia and GM-CSF in human peripheral blood eosinophils. AB - BACKGROUND: Eosinophils are involved in several inflammatory processes including allergic inflammation. It has been shown that eosinophil functions may be regulated by activating or inhibitory receptors. Hypoxia is a feature of inflamed tissues and has recently been shown to regulate eosinophil viability and pro angiogenic potential. In this study, the effect of hypoxia and GM-CSF on the inhibitory receptor CD300a in human peripheral blood eosinophils was investigated. METHODS: CD300a expression on eosinophils was analyzed by flow cytometry and evaluated by immuno-fluorescence; mRNA levels were evaluated by RT PCR. RESULTS: An increase in the expression of CD300a was observed in hypoxic eosinophils compared to the normoxic ones. GM-CSF strongly induced CD300a increase also after 3 h in culture. In addition, hypoxia augmented mRNA levels of CD300a. Inhibition of hypoxia-inducible factor (HIF)-1 abolished the hypoxia-/GM CSF-induced CD300a increase. CONCLUSION: CD300a expression is up-regulated by hypoxia, and GM-CSF where HIF-1 might play an important role. These results are important for the understanding of eosinophils behavior in inflamed tissue and suggest a new effect on their function in allergic inflammation. Taken together our data point out CD300a as a novel target for the treatment of allergy. PMID- 23346885 TI - Nanometres-resolution Kikuchi patterns from materials science specimens with transmission electron forward scatter diffraction in the scanning electron microscope. AB - A charge-coupled device camera of an electron backscattered diffraction system in a scanning electron microscope was positioned below a thin specimen and transmission Kikuchi patterns were collected. Contrary to electron backscattered diffraction, transmission electron forward scatter diffraction provides phase identification and orientation mapping at the nanoscale. The minimum Pd particle size for which a Kikuchi diffraction pattern was detected and indexed reliably was 5.6 nm. An orientation mapping resolution of 5 nm was measured at 30 kV. The resolution obtained with transmission electron forward scatter diffraction was of the same order of magnitude than that reported in electron nanodiffraction in the transmission electron microscope. An energy dispersive spectrometer X-ray map and a transmission electron forward scatter diffraction orientation map were acquired simultaneously. The high-resolution chemical, phase and orientation maps provided at once information on the chemical form, orientation and coherency of precipitates in an aluminium-lithium 2099 alloy. PMID- 23346886 TI - Effect of Hofmeister and alkylcarboxylate anionic counterions on the Krafft temperature and melting temperature of cationic gemini surfactants. AB - The effect of counterions was investigated to probe the principal ionic effects on the solubility in water and melting behavior of cationic gemini surfactants. We focused on two types of counterions: (1) small inorganic counterions that are typically taken from the Hofmeister series were studied to focus on the effect of ion type and (2) n-alkylcarboxylate counterions were studied to focus on the effect of the hydrophobicity of counterions. The Krafft temperature (Tk) and melting temperature (Tm) were obtained by conductivity measurements, calorimetric measurements, and optical microscopy observation. The results clearly indicate that Tk, which represents the solubility of surfactants, is not determined by a single parameter of ions such as the hydration free energy, as is too often assumed, but rather by the combined effects between the hydrophobicity of anions associated with other effects such as the polarizability, dehydrated ion size, and ionic morphology. In parallel, our observation demonstrated that all of the surfactants showed a transition from a crystalline phase to a thermotropic liquid crystalline phase at around ca. 70 degrees C, which transformed to an isotropic liquid phase at around ca. 150 degrees C, and that the transition temperatures depended strongly on the counterion type. The counterion effects on the solubilization and melting behaviors were then compared with micellization properties that have been reported previously. These results provide new insight into understanding the effect of ions on the delicate balance of forces controlling the solution properties and aggregate morphology of charged amphiphilic molecules. Specifically, the solubilization properties of these cationic surfactants with various counterions were determined mainly by the subtle interplay between the hydration of counterions and the dissociation energies (stability of crystallinity) of the ion pair. PMID- 23346887 TI - Ezetimibe-Simvastatin, a pharmacodynamic interaction? PMID- 23346888 TI - Rapid formation of N-Glycopeptides via Cu(II)-promoted glycosylative ligation. AB - Herein is described the chemoselective Cu(II)-HOBt promoted chemical ligation of glycosylamines and peptide thioacids to give N-glycosylated peptides. The method is distinguished from other chemical approaches to peptide N-glycosylation in that (1) it can be employed in the presence of unprotected N-terminal and Lys side chain amines; (2) it is remarkably fast, going to completion in under 30 min; and (3) it produces glycopeptides without attendant aspartimide formation. PMID- 23346889 TI - An update on the prevalence of cerebral palsy: a systematic review and meta analysis. AB - AIMS: The aim of this study was to provide a comprehensive update on (1) the overall prevalence of cerebral palsy (CP); (2) the prevalence of CP in relation to birthweight; and (3) the prevalence of CP in relation to gestational age. METHOD: A systematic review and meta-analysis was conducted and reported, based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta analyses) statement. Population-based studies on the prevalence of CP in children born in 1985 or after were selected. Statistical analysis was carried out using computer package R, version 2.14. RESULTS: A total of 49 studies were selected for this review. The pooled overall prevalence of CP was 2.11 per 1000 live births (95% confidence interval [CI] 1.98-2.25). The prevalence of CP stratified by gestational age group showed the highest pooled prevalence to be in children weighing 1000 to 1499g at birth (59.18 per 1000 live births; 95% CI 53.06-66.01), although there was no significant difference on pairwise meta-regression with children weighing less than 1000g. The prevalence of CP expressed by gestational age was highest in children born before 28 weeks' gestation (111.80 per 1000 live births; 95% CI 69.53-179.78; p<0.0327). INTERPRETATION: The overall prevalence of CP has remained constant in recent years despite increased survival of at-risk preterm infants. PMID- 23346890 TI - OsORC3 is required for lateral root development in rice. AB - The origin recognition complex (ORC) is a pivotal element in DNA replication, heterochromatin assembly, checkpoint regulation and chromosome assembly. Although the functions of the ORC have been determined in yeast and model animals, they remain largely unknown in the plant kingdom. In this study, Oryza sativa Origin Recognition Complex subunit 3 (OsORC3) was cloned using map-based cloning procedures, and functionally characterized using a rice (Oryza sativa) orc3 mutant. The mutant showed a temperature-dependent defect in lateral root (LR) development. Map-based cloning showed that a G->A mutation in the 9th exon of OsORC3 was responsible for the mutant phenotype. OsORC3 was strongly expressed in regions of active cell proliferation, including the primary root tip, stem base, lateral root primordium, emerged lateral root primordium, lateral root tip, young shoot, anther and ovary. OsORC3 knockdown plants lacked lateral roots and had a dwarf phenotype. The root meristematic zone of ORC3 knockdown plants exhibited increased cell death and reduced vital activity compared to the wild-type. CYCB1;1::GUS activity and methylene blue staining showed that lateral root primordia initiated normally in the orc3 mutant, but stopped growing before formation of the stele and ground tissue. Our results indicate that OsORC3 plays a crucial role in the emergence of lateral root primordia. PMID- 23346891 TI - A survey of prescribing for the management of nausea and vomiting in pregnancy in Australasia. AB - BACKGROUND: There is an impression of poor management of pregnancy sickness in Australia, specifically an apparent total reliance on metoclopramide, as a first line choice. AIMS: To determine what management options are commonly used in by distributing a survey to Fellows and Diplomates of RANZCOG. METHODS: A web-based survey questionnaire distributed using an email list obtained from RANZCOG. RESULTS: A total of 495 responses were received (23%). For morning sickness, 89% of those replying give dietary advice frequently or always, and 70% prescribe metoclopramide frequently or always, whereas 59% advise pyridoxine and 10% prescribe doxylamine. For hyperemesis gravidarum, 86% prescribe metoclopramide and 75% ondansetron. CONCLUSIONS: Despite guidelines suggesting the use of antihistamines and dopamine agonists (phenothiazines), very few practitioners in this region make use of these in any numbers. PMID- 23346892 TI - Multimodality imaging of a right atrial thrombus obliterating inferior vena cava. PMID- 23346893 TI - Dermatophytes isolated from superficial fungal infections in Krakow, Poland, between 1995 and 2010. AB - Superficial fungal infections due to dermatophytes are common over the world and their frequency is constantly increasing. The aim of our study was to discuss fungal infections with frequency of occurrence, clinical stages and aetiology in patients admitted to dermatological ward and microbiological laboratory of the specialist hospital in Krakow. Investigations performed between 1995 and 2010 included the group of 5333 individuals. Dermatophyte infections, confirmed by culture, were revealed in 1007 subjects (18.9%), i.e. in 553 males and 454 females. The most frequent clinical forms of infections were tinea unguium and tinea pedis, caused mainly by Trichophyton rubrum and by Trichophyton mentagrophytes. Tinea corporis, tinea manuum, tinea capitis and tinea cruris constituted a small percentage of infections and the main aetiological factors of these dermatomycoses were also T. rubrum and T. mentagrophytes. Between 1995 and 2000 there were stated small differences in the number of isolated strains of dermatophytes in comparison with the number of examined patients. Since 2006 there has been observed a decrease in number of patients in our hospital with suspected fungal infections, but per cent of positive cultures has remained unchanged in comparison with earlier period. PMID- 23346894 TI - Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine. AB - OBJECTIVE: We previously showed that maternal under-nutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. Also, we found increased neonatal adiposity among the grandchildren of women who had been undernourished during pregnancy. In the present study we investigated whether these transgenerational effects have led to altered body composition and poorer health in adulthood in the grandchildren. DESIGN: Historical cohort study. SETTING: Web-based questionnaire. POPULATION: The adult offspring (F2) of a cohort of men and women (F1) born around the time of the 1944-45 Dutch famine. METHODS: We approached the F2 adults through their parents. Participating F2 adults (n = 360, mean age 37 years) completed an online questionnaire. MAIN OUTCOME MEASURES: Weight, body mass index (BMI), and health in F2 adults, according to F1 prenatal famine exposure. RESULTS: Adult offspring (F2) of prenatally exposed F1 fathers had higher weights and BMIs than offspring of prenatally unexposed F1 fathers (+4.9 kg, P = 0.03; +1.6 kg/m(2), P = 0.006). No such effect was found for the F2 offspring of prenatally exposed F1 mothers. We observed no differences in adult health between the F2 generation groups. CONCLUSIONS: Offspring of prenatally undernourished fathers, but not mothers, were heavier and more obese than offspring of fathers and mothers who had not been undernourished prenatally. We found no evidence of transgenerational effects of grandmaternal under-nutrition during gestation on the health of this relatively young group, but the increased adiposity in the offspring of prenatally undernourished fathers may lead to increased chronic disease rates in the future. PMID- 23346895 TI - Ridge dimensional changes following single-tooth extraction in the aesthetic zone. AB - OBJECTIVES: The aims of this study were to investigate the magnitude of the dimensional changes following extraction of a single tooth in the aesthetic zone over a 6- to 8-week healing period and to examine the degree and pattern of resorption of the buccal bone plate during this time frame. MATERIALS AND METHODS: Twenty subjects who were to have a single tooth in the aesthetic zone extracted and replaced by an implant after a 6-8 week healing period were selected for this study. Hard and soft tissue measurements of the extraction site were obtained pre-extraction and were repeated 6-8 weeks post-extraction at defined points using a key. RESULTS: After a 6- to 8-week healing period, the total ridge thickness in the crestal midline reduced by 15% of the original value. The buccal plate resorbed in an "inverted V shape". Forty-two percentage of subjects had lost 4 mm or more of buccal bone in the midpoint of the extraction socket. DISCUSSION: After a 6- to 8-week healing period post extraction, there were significant reductions in the hard and soft tissue dimensions of the ridge, most notably on the most coronal mid-buccal aspect. All implants placed required simultaneous augmentation as a result. PMID- 23346896 TI - A new tetrahymena (ciliophora, oligohymenophorea) from groundwater of cape town, South Africa. AB - The identification of species within the genus Tetrahymena is known to be difficult due to their essentially identical morphology, the occurrence of cryptic and sibling species and the phenotypic plasticity associated with the polymorphic life cycle of some species. We have combined morphology and molecular biology to describe Tetrahymena aquasubterranea n. sp. from groundwater of Cape Town, Republic of South Africa. The phylogenetic analysis compares the cox1 gene sequence of T. aquasubterranea with the cox1 gene sequences of other Tetrahymena species and uses the interior-branch test to improve the resolution of the evolutionary relationships. This showed a considerable genetic divergence of T. aquasubterranea to its next relative, T. farlyi, of 9.2% (the average cox1 divergence among bona fide species of Tetrahymena is ~ 10%). Moreover, the analysis also suggested a sister relationship between T. aquasubterranea and a big clade comprising T. farleyi, T. tropicalis, T. furgasoni and T. mobilis. The morphological data available for these species show that they share with T. aquasubterranea a pyriformis-like life style and at least two of them, T. farleyi and T. mobilis, a similar type II silverline pattern consisting of primary and secondary meridians. Tetrahymena aquasubterranea exhibits a biphasic life cycle with trophonts and theronts, is amicronucleate, and feeds on bacteria. PMID- 23346897 TI - Quantification of the interaction forces between metals and graphene by quantum chemical calculations and dynamic force measurements under ambient conditions. AB - The two-dimensional material graphene has numerous potential applications in nano(opto)electronics, which inevitably involve metal graphene interfaces.Theoretical approaches have been employed to examine metal graphene interfaces, but experimental evidence is currently lacking. Here, we combine atomic force microscopy (AFM) based dynamic force measurements and density functional theory calculations to quantify the interaction between metal-coated AFM tips and graphene under ambient conditions. The results show that copper has the strongest affinity to graphene among the studied metals (Cu, Ag, Au, Pt, Si), which has important implications for the construction of a new generation of electronic devices. Observed differences in the nature of the metal-graphene bonding are well reproduced by the calculations, which included nonlocal Hartree Fock exchange and van der Waals effects. PMID- 23346898 TI - Giant Ising-type magnetic anisotropy in trigonal bipyramidal Ni(II) complexes: experiment and theory. AB - This paper reports the experimental and theoretical investigations of two trigonal bipyramidal Ni(II) complexes, [Ni(Me(6)tren)Cl](ClO(4)) (1) and [Ni(Me(6)tren)Br](Br) (2). High-field, high-frequency electron paramagnetic resonance spectroscopy performed on a single crystal of 1 shows a giant uniaxial magnetic anisotropy with an experimental D(expt) value (energy difference between the M(s) = +/- 1 and M(s) = 0 components of the ground spin state S = 1) estimated to be between -120 and -180 cm(-1). The theoretical study shows that, for an ideally trigonal Ni(II) complex, the orbital degeneracy leads to a first order spin-orbit coupling that results in a splitting of the M(s) = +/- 1 and M(s) = 0 components of approximately -600 cm(-1). Despite the Jahn-Teller distortion that removes the ground term degeneracy and reduces the effects of the first-order spin-orbit interaction, the D value remains very large. A good agreement between theoretical and experimental results (theoretical D(theor) between -100 and -200 cm(-1)) is obtained. PMID- 23346899 TI - Age-related differences in cognitive function for interlimb coordination during split-belt walking: a pilot study. AB - While walking is considered a task demanding cognitive functions rather than an automatic motor task, it is still unclear whether cognitive tasks influence interlimb coordination during walking. The present study revealed that the elderly require cognitive function to control temporal interlimb coordination under difficult walking conditions. Risk of falls is thus likely to be increased in the elderly when performing attention-demanding tasks while walking. PMID- 23346900 TI - Elevation of temperature and crowding trigger acute viral nervous necrosis in zebra fish, Brachydanio rerio (Hamilton-Buchanan), subclinically infected with betanodavirus. PMID- 23346901 TI - Exploring the active site structure of a photoreceptor protein by Raman optical activity. AB - We have developed a near-infrared excited Raman optical activity (ROA) spectrometer and report the first measurement of near-infrared ROA spectra of a light-driven proton pump, bacteriorhodopsin. Our results demonstrate that a near infrared excitation enables us to measure the ROA spectra of the chromophore within a protein environment. Furthermore, the ROA spectra of the all-trans, 15 anti and 13-cis, 15-syn isomers differ significantly, indicating a high structural sensitivity of the ROA spectra. We therefore expect that future applications of the near-infrared ROA will allow the experimental elucidation of the active site structures in other proteins as well as reaction intermediates. PMID- 23346902 TI - Screening for X-linked adrenoleukodystrophy among adult men with Addison's disease. AB - OBJECTIVES: X-linked adrenoleukodystrophy is an important cause of Addison's disease in boys, but less is known about its contribution to Addison's disease in adult men. After surveying all known cases of X-linked adrenoleukodystrophy in Norway in a separate study, we aimed to look for any missed cases among the population of adult men with nonautoimmune Addison's disease. STUDY DESIGN: Among 153 adult men identified in a National Registry for Addison's Disease (75% of identified male cases of Addison's disease in Norway), those with negative indices for 21-hydroxylase autoantibodies were selected. Additionally, cases with low autoantibody indices (48-200) were selected. Sera from subjects included were analysed for levels of very long-chain fatty acids, which are diagnostic for X linked adrenoleukodystrophy in men. RESULTS: Eighteen subjects had negative indices and 17 had low indices for 21-hydroxylase autoantibodies. None of those with low indices and only one of those with negative indices were found to have X linked adrenoleukodystrophy; this subject had already been diagnosed because of the neurological symptoms. Cases of Addison's disease proved to be caused by X linked adrenoleukodystrophy constitute 1.5% of all adult male cases in Norway; the proportion among nonautoimmune cases was 15%. CONCLUSIONS: We found X-linked adrenoleukodystrophy to be an uncommon cause of Addison's disease in adult men. However, this aetiological diagnosis has far-reaching consequences both for the patient and for his extended family. We therefore recommend that all adult men with nonautoimmune Addison's disease be analysed for levels of very long-chain fatty acids. PMID- 23346903 TI - Can lower aldehyde dehydrogenase activity in saliva be a risk factor for oral cavity cancer? AB - OBJECTIVES: Salivary ALDH3A1 protects the oral cavity from aromatic and medium chain aliphatic aldehydes originating from food and air pollution and generated during oxidative stress. Due to their reactivity, aldehydes may exhibit an irritating effect as well as cytotoxic, genotoxic, mutagenic and even carcinogenic effects. The aim of this study was to verify whether lower ALDH3A1 activity is a risk factor for oral cavity cancer. SUBJECTS AND METHODS: Fasting saliva samples were collected one day before and about one week after surgery from patients with oral cancer (OCC) (n = 59), other tumours (cysts, neoplasms) (n = 108), gnathic defects and fractures (controls after the surgery) (n = 63), and from healthy volunteers (n = 116). Enzyme activity was measured using a fluorometric method. RESULTS: Total ALDH3A1 activity [U g(-1) ] in patients with OCC was statistically lower than in patients with keratocystic odontogenic tumour (KCOT) (P = 0.00697), odontogenic cysts (OC) (P < 0.00001), neoplasms (P = 0.03343) and the healthy volunteers up to and over 40 years old (P < 0.00001; P = 0.00019). The activity in the saliva of OCC after surgery was lower than in the healthy volunteers (P < 0.00001) and in the groups with fractures (P = 0.00303) and gnathic defects (P = 0.00538). CONCLUSION: Low salivary ALDH activity may be a risk factor for oral cancer development. PMID- 23346904 TI - Proof-of-concept study of an aerobic vapor migration barrier beneath a building at a petroleum hydrocarbon-impacted site. AB - A proof-of-concept study was conducted to evaluate an alternative to traditional extraction-based subslab vapor mitigation systems at sites with petroleum hydrocarbon and/or methane vapor impact concerns. The system utilizes the slow delivery of air beneath a foundation to attenuate vapor migration to the building via aerobic biodegradation. The study was conducted at a site having elevated hydrocarbon plus methane and depleted O(2) vapor concentrations (160 mg/L and <1% v/v, respectively) beneath a building having a 195 m(2) footprint and a basement extending 1.5 m below ground surface (BGS). Nonaqueous phase liquid (NAPL) impacted soils, first encountered at about 7.6 to 9.1 m BGS, were the source of hydrocarbon and methane vapors, with the latter being generated by anaerobic methanagenesis of the former. O(2) concentrations beneath and around the building were monitored prior to and during air injection through a horizontal well installed about 1.5 m beneath the foundation. The air injection rate was increased from 1 to 5 to 10 L/min, with each held steady until the O(2) distribution stabilized (46-60 d). The 10 L/min flow rate achieved >5% v/v soil gas O(2) concentrations beneath the foundation and spanning a 1.5 m vertical interval. It was within 3* of the pretest stoichiometric requirement estimate of 3.8 L/min. This resulted in reductions in subslab hydrocarbon plus methane concentrations from 80 to <0.01 mg/L and benzene, toluene, ethylbenzene, and xylenes (BTEX) reductions to below detection limits (0.5-0.74 ppb(v)). This air injection rate is <1% of flows for typical extraction-based mitigation systems. PMID- 23346905 TI - Swimming behavior of the monotrichous bacterium Pseudomonas fluorescens SBW25. AB - Motility is an important trait for some bacteria living in nature and the analyses of it can provide important information on bacterial ecology. While the swimming behavior of peritrichous bacteria such as Escherichia coli has been extensively studied, the monotrichous bacteria such as the soil inhabiting and plant growth promoting bacterium Pseudmonas fluorescens is not very well characterized. Unlike E. coli that is propelled by a left-handed flagella bundle, P. fluorescens SBW25 swims several times faster by rotating a right-handed flagellum. Its swimming pattern is the most sophisticated known so far: it swims forward (run) and backward (backup); it can swiftly 'turn' the run directions or 'reorient' at run-backup transitions; it can 'flip' the cell body continuously or 'hover' in the milieu without translocation. The bacteria swam in circles near flat surfaces with reduced velocity and increased turn frequency. The viscous drag load due to wall effect potentially accounts for the circular motion and velocity change, but not the turn frequency. The flagellation and swimming behavior of P. fluorescens SBW25 show some similarity to Caulobacter, a fresh water inhabitant, while the complex swimming pattern might be an adaptation to the geometrically restricted rhizo- and phyllospheres. PMID- 23346906 TI - Applicability of the new ILAE classification for epilepsies (2010) in persons with epilepsy at a tertiary care center in India. AB - PURPOSE: To test the applicability of the new International League Against Epilepsy (ILAE) 2010 classification for epilepsies and to compare it with the ILAE 1989 classification and the ILAE 2001 diagnostic scheme in developing countries with limited resources such as India. METHODS: Prospective data of 500 consecutive patients with epilepsy, presenting in neurology department of All India Institute of Medical Sciences, was collected from January 2011 to June 2012 and analyzed according to the three systems proposed by ILAE in 1989, 2001, and 2010. KEY FINDINGS: All 500 patients could be classified in the ILAE 1989 classification system, but only 413 in the ILAE 2001 diagnostic scheme (in axes 3 and 4) and 420 in the ILAE 2010 classification system. Leading categories were localization-related epilepsies, symptomatic focal epilepsies, perinatal insult, and epilepsies attributed to structural and metabolic cause in ILAE 1989, 2001 axis 3, 2001 axis 4, and 2010 systems, respectively. The ILAE 1989 classification system could categorize significantly greater numbers of patients compared to the 2001 and 2010 systems, whereas the latter two remained similar. SIGNIFICANCE: A large group of patients remained unclassified in the new classification system despite our tremendous gain in knowledge through improved imaging, genomics, and molecular biology, and so on, which could be attributed to lack of availability of facilities in developing countries. Dichotomy of localization-related and generalized epilepsy still makes for a fundamental and pragmatic working diagnosis and guides the physician about the extent of investigations and treatment especially in "epilepsies of unknown cause." PMID- 23346907 TI - Indirect pulp treatment vs antibiotic sterilization of deep caries in mandibular primary molars. AB - BACKGROUND: Calcium hydroxide indirect pulp treatment (CH-IPT) and antibiotic sterilization using a mixture of three antibiotics (3Mix-MP) of deep caries are similar non-invasive vital pulp treatments. No studies have compared their clinical and radiographic success rates in primary molars. AIM: To compare the clinical and radiographic success rates of CH-IPT and 3Mix-MP in carious lesions approaching the pulp of mandibular primary molars. DESIGN: Eighty-two mandibular primary molars from 50 children, aged 3-8 years, with carious lesions approaching the pulp, and meeting the inclusion criteria, were randomly assigned for either treatment. After treatment, blinded clinical/radiographic evaluation was performed at 6-11 and 12-29 month recalls. RESULTS: At 6-11 months, the overall success rates of CH-IPT and 3Mix-MP were 82% and 81% (P = 0.91), respectively. At 12-29 months, the success rates were 94% and 78% (P = 0.08), respectively. The most frequently observed failure at the 12-29 month recall was internal resorption (one CH-IPT tooth and three 3Mix-MP teeth). CONCLUSION: There was no statistically significant difference in overall success rates between CH-IPT and 3Mix-MP in treating deep caries approaching the pulp in mandibular primary molars at either 6-11 month or 12-29 month follow-up. PMID- 23346908 TI - Cigarette smoking is associated with high prevalence of chronic rhinitis and low prevalence of allergic rhinitis in men. AB - BACKGROUND: The harmful effects of tobacco smoke on human health, including respiratory health, are extensive and well documented. Previous data on the effect of smoking on rhinitis and allergic sensitization are inconsistent. We sought to investigate how smoking correlates with prevalence of allergic and chronic rhinitis among adults in Sweden. METHODS: The study population comprised 27 879 subjects derived from three large randomly selected cross-sectional population surveys conducted in Sweden between 2006 and 2008. The same postal questionnaire on respiratory health was used in the three surveys, containing questions about obstructive respiratory diseases, rhinitis, respiratory symptoms and possible determinants of disease, including smoking habits. A random sample from one of the cohorts underwent a clinical examination including skin prick testing. RESULTS: Smoking was associated with a high prevalence of chronic rhinitis in both men and women and a low prevalence of allergic rhinitis in men. These associations were dose dependent and remained when adjusted for a number of possible confounders in multiple logistic regression analysis. Prevalence of chronic rhinitis was lowest in nonsmokers and highest in very heavy smokers (18.5% vs 34.5%, P < 0.001). Prevalence of sensitization to common airborne allergens was lower in current smokers (25.9%, P = 0.008) and ex-smokers (28.2%, P = 0.022) than in nonsmokers (38.5%). CONCLUSION: We found that smoking was associated with a high prevalence of chronic rhinitis in both sexes and a low prevalence of allergic rhinitis in men. The associations were dose dependent and remained when adjusting for several possible confounders. PMID- 23346909 TI - Enantioselective total synthesis of (-)-Delta8-THC and (-)-Delta9-THC via catalytic asymmetric hydrogenation and S(N)Ar cyclization. AB - The highly efficient asymmetric total syntheses of (-)-Delta(8) tetrahydrocannabinol ((-)-Delta(8)-THC) (13 steps, 35%) and (-)-Delta(9) tetrahydrocannabinol ((-)-Delta(9)-THC) (14 steps, 30%) have been developed by using ruthenium-catalyzed asymmetric hydrogenation of racemic alpha-aryl cyclic ketones via dynamic kinetic resolution and intramolecular S(N)Ar cyclization. PMID- 23346910 TI - Multiple in silico tools predict phenotypic manifestations in congenital thrombotic thrombocytopenic purpura. AB - Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare, recessively inherited genetic disorder with varying clinical presentation that is caused by ADAMTS13 mutations. Several studies have found limited associations between ADAMTS13 mutations and cTTP phenotype. The use of in silico tools that examine multiple mutation characteristics may better predict phenotype. We analysed 118 ADAMTS13 mutations found in 144 cTTP patients reported in the literature and examined associations of several mutation characteristics, including N-terminal proximity, the evolutionary conservation of the affected amino acid position, as well as amino acid charge/phosphorylation and genetic codon usage to disease phenotype. Structure-altering mutations were examined for their impact on ADAMTS13 function based on existing ADAMTS13 crystallographic data (AA 77-685). Our in silico data indicate that: (i) The position of the mutation in the N- or C terminus, (ii) evolutionary conservation and (iii) codon usage of the affected mutation position are associated with disease parameters, such as age of onset, organ damage and fresh frozen plasma prophylaxis. In conclusion, the usage of multiple in silico tools presents a promising strategy in refining predictions for the diverse presentation of cTTP. Enhancing our utilization of in silico tools to find genotype-phenotype associations will create better-tailored approaches for individual patient treatment. PMID- 23346912 TI - Improved transplantation outcome through delivery of DNA encoding secretion signal peptide-linked glucagon-like peptide-1 into mouse islets. AB - Glucagon-like peptide-1 (GLP-1) stimulates cell proliferation and has anti apoptotic effects on pancreatic islet beta cells. In our previous study, the transduction of mouse islets with a recombinant adenovirus containing GLP-1 cDNA enhanced islet graft survival. In this study, we sought to deliver the GLP-1 gene using a nonviral vector, which raises fewer safety issues in clinical application. We constructed a plasmid, pbeta-SP-GLP-1, in which a secretion signal peptide (SP) was inserted to increase GLP-1 secretion, and transfected mouse islets using the nonviral carrier Effectene. Transfection of pbeta-SP-GLP-1 induced a significant increase in bioactive GLP-1 levels in islet cultures. Islets transfected with pbeta-SP-GLP-1 were protected from H2 O2 -induced cell damage in vitro. In addition, glucose-stimulated insulin secretion was significantly increased in pbeta-SP-GLP-1-transfected islets. Diabetic syngeneic mice transplanted under the kidney capsule with a marginal mass of pbeta-SP-GLP-1 transfected islets rapidly became normoglycemic, with 88% of recipients being normoglycemic at 30 days post-transplantation compared with 52% of mice that received pbeta-transfected islet grafts (P < 0.05). Islet grafts retrieved 7 days after transplantation revealed that the pbeta-SP-GLP-1-transfected group had significantly more Ki67-positive cells as compared with the pbeta-transfected group. In conclusion, delivery of a plasmid containing a secretion SP and GLP-1 cDNA using a nonviral carrier leads to efficient secretion of GLP-1 in mouse islet cells, enhances islet cell survival during the early post-transplant period, and improves islet transplantation outcome. PMID- 23346913 TI - Quantum-dot-sensitized solar cells: understanding linker molecules through theory and experiment. AB - We have investigated the role of linker molecules in quantum-dot-sensitized solar cells (QDSSCs) using density-functional theory (DFT) and experiments. Linkers not only govern the number of attached QDs but also influence charge separation, recombination, and transport. Understanding their behavior is therefore not straightforward. DFT calculations show that mercaptopropionic acid (MPA) and cysteine (Cys) exhibit characteristic binding configurations on TiO(2) surfaces. This information is used to optimize the cell assembly process, yielding Cys based cells that significantly outperform MPA cells, and reach power conversion efficiencies (PCE) as high as 2.7% under AM 1.5 illumination. Importantly, the structural information from theory also helps understand the cause for this improved performance. PMID- 23346911 TI - Regional registration of [6-(14)C]glucose metabolism during brain activation of alpha-syntrophin knockout mice. AB - alpha-Syntrophin is a component of the dystrophin scaffold-protein complex that serves as an adaptor for recruitment of key proteins to the cytoplasmic side of plasma membranes. alpha-Syntrophin knockout (KO) causes loss of the polarized localization of aquaporin4 (AQP4) at astrocytic endfeet and interferes with water and K(+) homeostasis. During brain activation, release of ions and metabolites from endfeet is anticipated to increase perivascular fluid osmolarity, AQP4 mediated osmotic water flow from endfeet, and metabolite washout from brain. This study tests the hypothesis that reduced levels of endfoot AQP4 increase retention of [(14)C]metabolites during sensory stimulation. Conscious KO and wild-type mice were pulse-labeled with [6-(14)C] glucose during unilateral acoustic stimulation or bilateral acoustic plus whisker stimulation, and label retention was assayed by computer-assisted brain imaging or analysis of [(14)C]metabolites in extracts, respectively. High-resolution autoradiographic assays detected a 17% side-to-side difference (p < 0.05) in inferior colliculus of KO mice, not wild-type mice. However, there were no labeling differences between KO and wild-type mice for five major HPLC fractions from four dissected regions, presumably because of insufficient anatomical resolution. The results suggest a role for AQP4-mediated water flow in support of washout of metabolites, and underscore the need for greater understanding of astrocytic water and metabolite fluxes. PMID- 23346914 TI - Steric and electronic effects influencing beta-aryl elimination in the Pd catalyzed carbon-carbon single bond activation of triarylmethanols. AB - An analysis of the palladium-catalyzed activation of carbon-carbon single bonds within triarylmethanols has led to a greater understanding of factors influencing the beta-aryl elimination process responsible for C-C bond cleavage. A series of competition reactions were utilized to determine that beta-aryl elimination of aryl substituents containing ortho-substitution proceeds with significant preference to unsubstituted phenyl rings. Further experiments indicate that substrates containing either strongly donating or withdrawing substituents are cleaved from triarylmethanols more readily than relatively neutral species. PMID- 23346915 TI - Coronary artery wall thickness of the left anterior descending artery using high resolution transthoracic echocardiography--normal range of values. AB - Recently it has been demonstrated that high resolution transthoracic echocardiography (HRTTE) is able to detect differences in the wall thickness of the left anterior descending coronary artery (LAD) between patients with coronary artery disease (CAD) and normal volunteers. We sought to validate this technique, develop a normal range of values and demonstrate the test-retest variability of each measurement. Two hundred forty-two volunteer participants had a HRTTE study to measure their LAD wall thickness, luminal, and external diameters. Thirty of these subjects had these measurements taken on 3 separate occasions by 2 different echosonographers. All subjects were free of clinical CAD, hypertension, hyperlipidemia, and diabetes mellitus. The average anterior wall thickness was 1.1 +/- 0.2 mm; posterior wall thickness was 1.1 +/- 0.2 mm, luminal diameter 2.2 +/- 0.6 mm, and external elastic membrane (EEM) diameter 4.5 +/- 0.9 mm. The bias of the measurements within the same operator for LAD wall thickness, luminal diameter, and EEM was 0.042, -0.06, and -0.077 mm, respectively. The bias of the measurements between 2 different operators for LAD wall thickness, luminal diameter, and EEM was 0.082, -0.077, and -0.027 mm, respectively. In conclusion, HRTTE measurement of the LAD vessel is reproducible within and between operators in normal volunteers. This technique therefore warrants further study as a potential screening modality for subclinical coronary atherosclerosis. PMID- 23346916 TI - Continuation of pregnancy after first-trimester exposure to mifepristone: an observational prospective study. AB - OBJECTIVE: To report the follow-up of continuing pregnancies after first trimester exposure to mifepristone. DESIGN: Observational prospective study. SETTING: France. SAMPLE: Patients exposed to mifepristone during the first 12 weeks of pregnancy. METHODS: Women were included in the study when they or their doctors asked a French pharmacovigilance centre or the Paris Teratogen Information Service about the risk of mifepristone exposure in early pregnancy. Exclusion criteria were requests received after 22 weeks of gestation or subsequent elective termination of pregnancy without a pathological examination of the fetus. Data on maternal history and drug exposure were collected on first contact, and pregnancy outcomes were documented at follow-up. MAIN OUTCOME MEASURES: Rate of major congenital malformations. RESULTS: A total of 105 pregnancies were included, with 46 exposed to mifepristone alone, and 59 exposed to both mifepristone and misoprostol. There were 94 live births (90.4%) and 10 (9.6%) miscarriages (including one with major malformation). Elective termination of pregnancy was performed after the subsequent diagnosis of trisomy 21 in one case. The overall rate of major congenital malformations was 4.2% (95% CI 1.2 10.4%), with two cases among 38 patients exposed to mifepristone alone, and two cases among 57 patients exposed to both mifepristone and misoprostol. CONCLUSIONS: This first prospective study found that the rate of major malformations after first-trimester exposure to mifepristone is only slightly higher than the expected 2-3% rate in the general population. Such findings provide reassuring data for risk evaluation for continuation of pregnancy after mifepristone exposure. PMID- 23346917 TI - Primary Sjogren syndrome: an update on current pharmacotherapy options and future directions. AB - INTRODUCTION: Primary Sjogren syndrome (SS) is a chronic systemic autoimmune disease characterized by sicca features and systemic manifestations, and requires a multidisciplinary therapeutic approach. AREAS COVERED: Treatment of sicca manifestations is symptomatic and is based on the administration of topical therapies (saliva substitutes and preservative-free artificial tears). In severe cases of keratoconjunctivitis sicca, topical cyclosporine A may be used. For patients with residual salivary gland function, stimulation of salivary flow with a sialogogue (pilocarpine or cevimeline) is the treatment of choice. The management of extraglandular features must be tailored to the specific organ(s) involved. Hydroxychloroquine may be appropriate for patients with fatigue, arthralgia and myalgia, while glucocorticoids and immunosuppressive agents should be reserved for severe systemic involvement (although no controlled trials in primary SS guide their use). RCTs have demonstrated the lack of efficacy of antitumor necrosis factor agents and promising results for B-cell depleting agents. EXPERT OPINION: The overall low level of evidence in therapeutic studies in primary SS suggests that much larger trials of the most promising therapies are necessary. The use of drugs targeting molecules and receptors involved in the etiopathogenesis of primary SS may open up a new era in the therapeutic management of the disease, but the potential risks and benefits of these agents must be weighed carefully. PMID- 23346918 TI - Phylogenetic investigations on ten genera of tintinnid ciliates (Ciliophora: Spirotrichea: Tintinnida), based on small subunit ribosomal RNA gene sequences. AB - Tintinnida is a diverse taxon that accommodates over 1,500 morphospecies, which is an important component of marine planktonic food webs. However, evolutionary relationships of tintinnids are poorly known because molecular data of most groups within this order are lacking. In our study, the small subunit (SSU) rRNA genes representing 10 genera, 5 families of Tintinnida were sequenced, including the first SSU rRNA gene sequences for Coxliella, Dadayiella, Epiplocyloides, and Protorhabdonella, and phylogenetic trees were constructed to assess their intergeneric relationships. Phylogenies inferred from different methods showed that (1) Three newly sequenced Eutintinnus species fell into Eutintinnus clade forming a sister group to the clade containing Amphorides, Steenstrupiella, Amphorellopsis, and Salpingella; (2) Surprisingly, the genetic distances between Amphorides amphora and Amphorellopsis acuta population 1 was even smaller than that between the two populations of Amphorellopsis acuta, casting doubt on the validity of Amphorides and Amphorellopsis as presently defined; (3) The SSU rRNA sequences of Dadayiella ganymedes and Parundella aculeata were almost identical. Therefore, Parundella ganymedes novel combination is proposed; (4) Coxliella, which is currently assigned within Metacylididae, branched instead with some Tintinnopsis species. Furthermore, the validation of Coxliella, which was considered to be a "questionable" genus, was confirmed based on evidences from morphology, ecology, and molecular data; (5) Protorhabdonella and Rhabdonella showed rather low intergeneric distance and grouped together with strong support suggesting that Rhabdonellidae is a well-defined taxon; and (6) Epiplocyloides branched with species in Cyttarocylididae indicating their close relationship. PMID- 23346919 TI - Alpine cushion plants inhibit the loss of phylogenetic diversity in severe environments. AB - Biotic interactions can shape phylogenetic community structure (PCS). However, we do not know how the asymmetric effects of foundation species on communities extend to effects on PCS. We assessed PCS of alpine plant communities around the world, both within cushion plant foundation species and adjacent open ground, and compared the effects of foundation species and climate on alpha (within microsite), beta (between open and cushion) and gamma (open and cushion combined) PCS. In the open, alpha PCS shifted from highly related to distantly related with increasing potential productivity. However, we found no relationship between gamma PCS and climate, due to divergence in phylogenetic composition between cushion and open sub-communities in severe environments, as demonstrated by increasing phylo-beta diversity. Thus, foundation species functioned as micro refugia by facilitating less stress-tolerant lineages in severe environments, erasing a global productivity - phylogenetic diversity relationship that would go undetected without accounting for this important biotic interaction. PMID- 23346920 TI - Differences between aerobic and anaerobic degradation of microphytobenthic biofilm-derived organic matter within intertidal sediments. AB - Within intertidal sediments, much of the dissolved organic carbon (DOC) consists of carbohydrate-rich extracellular polymeric substances (EPS) produced by microphytobenthic biofilms. EPS are an important source of carbon and energy for aerobic and anaerobic microorganisms owing to burial of microphytobenthos and downward transport of their exudates. We established slurries of estuarine biofilms to determine the fate of organic carbon and EPS fractions, differing in size and complexity, under oxic and anoxic conditions. DOC and hot-water extracted organic matter (predominately diatom chrysolaminarin) were utilised rapidly at similar rates in both conditions. Concentrations of insoluble, high molecular-weight EPS were unchanged in oxic microcosms, but were significantly degraded under anoxic conditions (39% degradation by day 25). Methanogenesis and sulphate reduction were major anaerobic processes in the anoxic slurries, and 16S rRNA gene pyrosequencing revealed that Desulfobacteraceae (relative sequence abundance increased from 1.9% to 12.2%) and Desulfobulbaceae (increased from 1.5% to 4.3%) were the main sulphate reducers, whilst Clostridia and Bacteroidetes were likely responsible for anaerobic hydrolysis and fermentation of EPS. We conclude that a diverse consortium of anaerobic microorganisms (including coexisting sulphate reducers and methanogens) degrade both labile and refractory microphytobenthic-derived carbon and that anaerobic degradation may be the primary fate of more structurally complex components of microphytobenthic EPS. PMID- 23346921 TI - Redox control and hydrogen bonding networks: proton-coupled electron transfer reactions and tyrosine Z in the photosynthetic oxygen-evolving complex. AB - In photosynthetic oxygen evolution, redox active tyrosine Z (YZ) plays an essential role in proton-coupled electron transfer (PCET) reactions. Four sequential photooxidation reactions are necessary to produce oxygen at a Mn(4)CaO(5) cluster. The sequentially oxidized states of this oxygen-evolving cluster (OEC) are called the S(n) states, where n refers to the number of oxidizing equivalents stored. The neutral radical, YZ*, is generated and then acts as an electron transfer intermediate during each S state transition. In the X-ray structure, YZ, Tyr161 of the D1 subunit, is involved in an extensive hydrogen bonding network, which includes calcium-bound water. In electron paramagnetic resonance experiments, we measured the YZ* recombination rate, in the presence of an intact Mn(4)CaO(5) cluster. We compared the S(0) and S(2) states, which differ in Mn oxidation state, and found a significant difference in the YZ* decay rate (t(1/2) = 3.3 +/- 0.3 s in S(0); t(1/2) = 2.1 +/- 0.3 s in S(2)) and in the solvent isotope effect (SIE) on the reaction (1.3 +/- 0.3 in S(0); 2.1 +/- 0.3 in S(2)). Although the YZ site is known to be solvent accessible, the recombination rate and SIE were pH independent in both S states. To define the origin of these effects, we measured the YZ* recombination rate in the presence of ammonia, which inhibits oxygen evolution and disrupts the hydrogen bond network. We report that ammonia dramatically slowed the YZ* recombination rate in the S(2) state but had a smaller effect in the S(0) state. In contrast, ammonia had no significant effect on YD*, the stable tyrosyl radical. Therefore, the alterations in YZ* decay, observed with S state advancement, are attributed to alterations in OEC hydrogen bonding and consequent differences in the YZ midpoint potential/pK(a). These changes may be caused by activation of metal-bound water molecules, which hydrogen bond to YZ. These observations document the importance of redox control in proton-coupled electron transfer reactions. PMID- 23346922 TI - Patients' and neurologists' perception of epilepsy and psychogenic nonepileptic seizures. AB - PURPOSE: Although differences in illness perceptions between neurologists and patients with epilepsy or psychogenic nonepileptic seizures (PNES) are likely to be clinically relevant, this is the first study to attempt a direct comparison. In addition, this study compares the illness perceptions of patients with epilepsy with those of patients with PNES. METHODS: Thirty-four patients with epilepsy, 40 patients with PNES, and 45 neurologists were recruited. All patient participants completed versions of the illness perception questionnaire revised (IPQ-R) adapted for epileptic or nonepileptic seizure disorders, single-item symptom attribution question (SAQ), Hospital Anxiety and Depression Scale (HADS), Quality of Life in Epilepsy-31 (QOLIE-31), and Liverpool Seizure Severity Scale (LSSS). Participating neurologists completed two versions of the IPQ-R and two SAQs for epileptic and nonepileptic seizure disorders. KEY FINDINGS: Differences in illness perceptions between patients with epilepsy and patients with PNES were minor compared to those between patients with either seizure disorder and neurologists. Neurologists considered both seizure disorders more treatable and more amenable to personal control than did the patients themselves. Neurologists had much more polarized views of the etiology of both conditions; whereas patients mostly considered the causes of their seizure disorders as partially "physical" and partially "psychological," neurologists perceived epilepsy as an essentially "physical" and PNES as a clearly "psychological" problem. SIGNIFICANCE: There are considerable differences between the illness perceptions of patients with seizure disorders and their doctors, which could represent barriers to successful clinical management. In particular, a discrepancy between neurologists' and patients' beliefs about the personal control that patients may be able to exert over PNES could contribute to the confusion or anger some patients report after the diagnosis has been explained to them. Furthermore, patients' endorsement of "physical" causes for PNES may reflect an unrealistic faith in the effectiveness of "physical" treatments and could be a cause of tension in patients' relationship with their doctor, for instance when the neurologist attempts to withdraw antiepileptic drug treatment or refers patients for psychological interventions. PMID- 23346923 TI - Controlled release behaviour of protein-loaded microparticles prepared via coaxial or emulsion electrospray. AB - Biodegradable poly (lactic-co-glycolic acid) (PLGA) microparticles are an effective way to achieve sustained drug release. In this study, we investigated a sustained release model of PLGA microparticles with incorporated protein via either emulsion or coaxial electrospray techniques. PLGA (75:25) was used as the carrier, and bovine serum albumin as a model protein. Coaxial electrospray resulted in a type of core-shell structure with mean diameters of 2.41 +/- 0.60 um and a centralised protein distribution within the core. Emulsion electrospray formed bigger microparticles with mean diameters of 22.75 +/- 8.05 um and a heterogeneous protein distribution throughout the microparticles. The coaxial electrospray microparticles presented a much slighter burst release than the emulsion electrospray microparticles. Loading efficiency was significantly higher (p < 0.05) in the coaxial group than emulsion group. This indicated that both emulsion and coaxial electrospray could produce protein-loaded microparticles with sustained release behaviour, but the former revealed a superior approach for drug delivery. PMID- 23346924 TI - Characteristics of condom and lubricant use among a nationally representative probability sample of adults ages 18-59 in the United States. AB - INTRODUCTION: Although most Americans have used condoms and/or lubricant during sex, little is known about the context of sexual events that involve the use of such products outside of experimentally manipulated studies. AIMS: To assess, in a nationally representative study of men and women in the United States ages 18 59, the characteristics of condom and lubricant use during participants' most recent sexual event and the relationship of their condom and lubricant use to event-level ratings of sexual quality. METHODS: Data are from the National Survey of Sexual Health and Behavior, which involved the administration of an online questionnaire to a nationally representative probability sample of the U.S. adults. MAIN OUTCOME MEASURES: Sociodemographic items: event-level items related to sexual behavior, condom use, lubricant use, and participants' perceptions of their arousal, pleasure, ease of erection or lubrication, and pain associated with sex. RESULTS: During their most recent sexual experience, 27.5% of men (N = 237) and 22.3% of women (N = 175) reported using a condom. More than twice as many women as men were unsure whether the condom was lubricated (26.6% vs. 11.4%) and the material it was made of (23.6% vs. 8.9%). Participants consistently rated sex to be arousing and pleasurable whether or not they used condoms or lubricant. No significant differences were found in regard to men's ratings of the ease of their erections based on condom and lubricant use. CONCLUSIONS: Although some have concerns about how condoms or lubricants may impact their enjoyment of sex, in a nationally representative sample of men and women ages 18-59, ratings of sex were largely quite high, with few differences based on condom and lubricant use. Women, more often than men, reported being unsure about the type of condom and lubricant used, which has implications for patient education. PMID- 23346925 TI - A case of antibacterial-responsive mucocutaneous disease in a seven-year-old dwarf lop rabbit (Oryctolagus cuniculus) resembling mucocutaneous pyoderma of dogs. AB - A seven-year-old, ovariohysterectomised female dwarf lop rabbit (Oryctolagus cuniculus) was referred with severe swelling and erythema of the mucocutaneous junctions of the lips, nares and vulva. Bilateral, severe periocular dermatitis was also present. Heavy pure growths of a member of the Staphylococcus intermedius group were cultured from nasal and aural swabs and skin biopsies. Other possible differential diagnoses were eliminated by standard tests. The clinical features and histopathological characteristics of the biopsies were most consistent with mucocutaneous pyoderma, a dermatosis previously reported in dogs but not in rabbits. Treatment of the bacterial infection with oral marbofloxacin and topical ofloxacin eye drops together with supportive therapy resulted in resolution of the lesions. To the authors' knowledge, this is the first report of mucocutaneous bacterial pyoderma, similar to mucocutaneous pyoderma of dogs, in a rabbit. PMID- 23346926 TI - In vivo comparison between laser-treated and grit blasted/acid etched titanium. AB - OBJECTIVE: Laser profiling of titanium has been of considerable interest in the field of oral implantology. However, very few pre-clinical and clinical studies have been performed with laser-treated implants, especially focusing on isotropic roughness topography. The aim of the study was to compare the cortical bone response of Ti-implants discs treated with pico-sec pulsed laser (LAS) and conventional grit-blasted/acid-etched (GAE) method. MATERIALS AND METHODS: Prior to the in vivo experiment, in vitro cell viability testing of the LAS surface treatment was preformed. Then, 5 mm diameter Titanium (Ti) discs treated with LAS and GAE method were implanted in a pre-validated rabbit tibia cortical bone model and assessed with histology and histomorphometric measurements. In total, eight New Zealand White adult female rabbits were used. RESULTS: The in vitro cell viability testing with osteoblast-like cells confirmed cytocompatibility of the LAS surface treatment. Further, the rabbit experiment demonstrated a bone-to implant contact of 68% (+/-17) for the laser-treated discs and 49% (+/-21) for the GAE discs 8 weeks after the implantation, which was statistically not different. CONCLUSION: Laser surface treatment gives the same results to the grit blasting/acid-etched method and thus is a valid alternative to conventional roughening for dental implant materials. PMID- 23346927 TI - Self-assembling semiconducting polymers--rods and gels from electronic materials. AB - In an effort to favor the formation of straight polymer chains without crystalline grain boundaries, we have synthesized an amphiphilic conjugated polyelectrolyte, poly(fluorene-alt-thiophene) (PFT), which self-assembles in aqueous solutions to form cylindrical micelles. In contrast to many diblock copolymer assemblies, the semiconducting backbone runs parallel, not perpendicular, to the long axis of the cylindrical micelle. Solution-phase micelle formation is observed by X-ray and visible light scattering. The micelles can be cast as thin films, and the cylindrical morphology is preserved in the solid state. The effects of self-assembly are also observed through spectral shifts in optical absorption and photoluminescence. Solutions of higher-molecular weight PFT micelles form gel networks at sufficiently high aqueous concentrations. Rheological characterization of the PFT gels reveals solid-like behavior and strain hardening below the yield point, properties similar to those found in entangled gels formed from surfactant-based micelles. Finally, electrical measurements on diode test structures indicate that, despite a complete lack of crystallinity in these self-assembled polymers, they effectively conduct electricity. PMID- 23346928 TI - Use of a cane for recovery from backward balance loss during treadmill walking. AB - PURPOSE: To study whether a cane improved balance recovery after perturbation during walking. METHOD: This study was a crossover comparison comparing the effect of walking with and without a cane for balance recovery after perturbation during treadmill walking. Five normal young volunteers participated. The velocity and acceleration of a marker sited on the seventh cerebral vertebra (C7) and vertical hand motion were measured by a motion analysis system. RESULT: When using a cane, C7 backward velocity increased by approximately 15% (413 SD 95 mm/s with cane vs. 358 SD 88 mm/s without). In addition, C7 backward acceleration increased by approximately 23% (3.2 SD 0.7 m/s(2) with cane vs. 2.6 SD 0.8 m/s(2) without) and the vertical motion of the right hand decreased (187 SD 98 mm with cane vs. 372 SD 260 mm without). Additionally, no subject was able to use a cane to broaden their base of support. CONCLUSIONS: The ability to limit trunk extension is crucial for preventing falls. Therefore, using a cane jeopardizes recovery from backward balance loss. The results encourage further research on the risk of a cane on balance recovery for the elderly population and habitual cane users. PMID- 23346929 TI - Twisted tethered tolanes: unanticipated long-lived phosphorescence at 77 K. AB - Influencing the communication within a conjugated system as diphenylacetylene is a challenging subject in molecular electronics. Some examples of twisted tolanes are known, where high twists have been achieved in the solid state by steric encumbrance. The insertion of a spacer system is an alternative way to tailor rotation. Only a few examples of such tethered tolanes exist, and they all suffer from small twist angles (<35 degrees ). We report on tolanophanes containing a malonyl tether, where twist angles of almost 80 degrees were reached. Long-lived phosphorescence (4 s at 77 K) was recorded, and quantum-chemical calculations were performed to confirm the experimental results. PMID- 23346930 TI - RalA GTPase tethers insulin granules to L- and R-type calcium channels through binding alpha2 delta-1 subunit. AB - RalA GTPase has been implicated in the regulated delivery of exocytotic vesicles to the plasma membrane (PM) in mammalian cells. We had reported that RalA regulates biphasic insulin secretion, which we have now determined to be contributed by RalA direct interaction with voltage-gated calcium (Cav ) channels. RalA knockdown (KD) in INS-1 cells and primary rat beta-cells resulted in a reduction in Ca(2+) currents arising specifically from L-(Cav 1.2 and Cav 1.3) and R-type (Cav 2.3) Ca(2+) channels. Restoration of RalA expression in RalA KD cells rescued these defects in Ca(2+) currents. RalA co-immunoprecipitated with the Cav alpha2 delta-1 auxiliary subunit known to bind the three Cav s. Moreover, the functional molecular interactions between Cav alpha2 delta-1 and RalA on the PM shown by total internal reflection fluorescent microscopy/FRET analysis could be induced by glucose stimulation. KD of RalA inhibited trafficking of alpha2 delta-1 to insulin granules without affecting the localization of the other Cav subunits. Furthermore, we confirmed that RalA and alpha2 delta-1 functionally interact since RalA KD-induced inhibition of Cav currents could not be recovered by RalA when alpha2 delta-1 was simultaneously knocked down. These data provide a mechanism for RalA function in insulin secretion, whereby RalA binds alpha2 delta-1 on insulin granules to tether these granules to PM Ca(2+) channels. This acts as a chaperoning step prior to and in preparation for sequential assembly of exocyst and excitosome complexes that mediate biphasic insulin secretion. PMID- 23346932 TI - Bioaffinity sensor based on nanoarchitectonic films: control of the specific adsorption of proteins through the dual role of an ethylene oxide spacer. AB - The identification and quantification of biomarkers or proteins is a real challenge in allowing the early detection of diseases. The functionalization of the biosensor surface has to be properly designed to prevent nonspecific interactions and to detect the biomolecule of interest specifically. A multilayered nanoarchitecture, based on polyelectrolyte multilayers (PEM) and the sequential immobilization of streptavidin and a biotinylated antibody, was elaborated as a promising platform for the label-free sensing of targeted proteins. We choose ovalbumin as an example. Thanks to the versatility of PEM films, the platform was built on two types of sensor surface and was evaluated using both optical- and viscoelastic-based techniques, namely, optical waveguide lightmode spectroscopy and the quartz crystal microbalance, respectively. A library of biotinylated poly(acrylic acids) (PAAs) was synthesized by grafting biotin moieties at different grafting ratios (GR). The biotin moieties were linked to the PAA chains through ethylene oxide (EO) spacers of different lengths. The adsorption of the PAA-EOn-biotin (GR) layer on a PEM precursor film allows tuning the surface density in biotin and thus the streptavidin adsorption mainly through the grafting ratio. The nonspecific adsorption of serum was reduced and even suppressed depending on the length of the EO arms. We showed that to obtain an antifouling polyelectrolyte the grafting of EO9 or EO19 chains at 25% in GR is sufficient. Thus, the spacer has a dual role: ensuring the antifouling property and allowing the accessibility of biotin moieties. Finally, an optimized platform based on the PAA-EO9-biotin (25%)/streptavidin/biotinylated antibody architecture was built and demonstrated promising performance as interface architecture for bioaffinity sensing of a targeted protein, in our case, ovalbumin. PMID- 23346931 TI - Relative stability of human centrins and its relationship to calcium binding. AB - Centrins are calcium binding proteins that belong to the EF-hand superfamily with diverse biological functions. Herein we present the first systematic study that establishes the relative stability of related centrins via complementary biophysical techniques. Our results define the stepwise molecular behavior of human centrins by two-dimensional infrared (2D IR) correlation spectroscopy, the change in heat capacity and enthalpy of denaturation by differential scanning calorimetry, and the relative stability of the helical regions of centrins by circular dichroism. More importantly, 2D IR correlation spectroscopy provides unique information about the similarities and differences in dynamics between these related proteins. The thermally induced molecular behavior of human centrins can be used to predict biological target interactions that have a relative dependence on calcium affinity. This information is essential for understanding why certain isoforms may be used to rescue a phenotype and therefore also for explaining the different functions these proteins may have in vivo. Furthermore, this comparative approach can be applied to the study of recombinant therapeutic protein candidates for the treatment of disease states. PMID- 23346933 TI - Career development: graduate nurse views. AB - AIMS AND OBJECTIVES: To explore recent Singapore nursing graduates' experience of and views about their career development and progress. BACKGROUND: The recruitment and retention of an adequate number of registered nurses is a continuing workforce issue in Singapore and other major cities. DESIGN: Survey of recent nursing graduates. METHODS: Recent nursing graduates from the Bachelor programme (n = 147) were sent an individual survey; a response rate of 54% was achieved. RESULTS: Findings show that nurses rated their self-concept in a positive manner and were most satisfied (moderately to very) with helping patients and providing effective care, and the level of patient involvement. They were least satisfied (moderately to only a little) with prestige among the general medical community and the general public, hours of work, lifestyle factors and research opportunities. The following four factors were identified as significant impediments to career development; lack of support in the work place; perceived insufficient clinical career development opportunities; excessive work hours; and limited access to merit-based places in further education. CONCLUSIONS: Suggestions made to overcome perceived career development barriers are as follows: broad multifactorial healthcare system changes; decreased and more flexible working hours; and fairer access to further clinical and higher education. RELEVANCE TO CLINICAL PRACTICE: Results highlight the value clinical nurses place on having access to career development opportunities, merit-based further education and work place supports. These factors also have the potential to influence patient care and impact on the retention of nurses in their present job and satisfaction with their nursing career. PMID- 23346934 TI - Farm exposure and time trends in early childhood may influence DNA methylation in genes related to asthma and allergy. AB - BACKGROUND: Genetic susceptibility and environmental influences are important contributors to the development of asthma and atopic diseases. Epigenetic mechanisms may facilitate gene by environment interactions in these diseases. METHODS: We studied the rural birth cohort PASTURE (Protection against allergy: study in rural environments) to investigate (a) whether epigenetic patterns in asthma candidate genes are influenced by farm exposure in general, (b) change over the first years of life, and (c) whether these changes may contribute to the development of asthma. DNA was extracted from cord blood and whole blood collected at the age of 4.5 years in 46 samples per time point. DNA methylation in 23 regions in ten candidate genes (ORMDL1, ORMDL2, ORMDL3, CHI3L1, RAD50, IL13, IL4, STAT6, FOXP3, and RUNX3) was assessed by pyrosequencing, and differences between strata were analyzed by nonparametric Wilcoxon-Mann-Whitney tests. RESULTS: In cord blood, regions in ORMDL1 and STAT6 were hypomethylated in DNA from farmers' as compared to nonfarmers' children, while regions in RAD50 and IL13 were hypermethylated (lowest P-value (STAT6) = 0.001). Changes in methylation over time occurred in 15 gene regions (lowest P-value (IL13) = 1.57*10(-8)). Interestingly, these differences clustered in the genes highly associated with asthma (ORMDL family) and IgE regulation (RAD50, IL13, and IL4), but not in the T-regulatory genes (FOXP3, RUNX3). CONCLUSIONS: In this first pilot study, DNA methylation patterns change significantly in early childhood in specific asthma- and allergy-related genes in peripheral blood cells, and early exposure to farm environment seems to influence methylation patterns in distinct genes. PMID- 23346935 TI - Animal models for bisphosphonate-related osteonecrosis of the jaws--an appraisal. AB - The prolonged use of bisphosphonates has been shown to cause a condition termed 'bisphosphonate related osteonecrosis of the jaws' (BRONJ). BRONJ is a disease entity which has only been described relatively recently, and its multi-factorial aetiology is yet to be fully elucidated. Therefore, the treatment of BRONJ lesions remains a challenge, and animal models are necessary to assist researchers in better understanding the disease. This has led to the recent publication of a number of studies utilising a variety of animal models of BRONJ. This review outlines the factors to be considered when selecting an animal model for BRONJ and discusses the current literature in this rapidly progressing field of research. It is important to consider the applicability of a given model to the clinical condition presenting in humans, and to this end, thorough characterisation of the clinical, histological, radiographic and systemic features is necessary. The development of a clinical lesion is an important consideration in terms of choosing a relevant model, and it appears clear that surgical manipulation, generally involving tooth extraction, is necessary for successful induction of the classic 'clinical' lesion of BRONJ. PMID- 23346936 TI - A novel synthesis of (-)-huperzine A via tandem intramolecular aza-Prins cyclization-cyclobutane fragmentation. AB - The acetylcholinesterase inhibitor (-)-huperzine A was synthesized from (S)-4 hydroxycyclohex-2-enone in 17 steps by a route that involved two cyclobutane fragmentations. The first of these employed a retro-aldol cleavage to generate the alpha-pyridone ring of huperzine A, and the second invoked a novel intramolecular aza-Prins reaction in tandem with stereocontrolled scission of a cyclobutylcarbinyl cation to create the aminobicyclo[3.3.1]nonene framework of the natural alkaloid. PMID- 23346937 TI - Transport and retention of selected engineered nanoparticles by porous media in the presence of a biofilm. AB - Column experiments were conducted to investigate the transport of aqueous C60 (aqu-nC60), fullerol, silver nanoparticles (NPs) coated with polyvinylpyrrolidone (Ag-PVP) and stabilized by citrate (Ag-CIT) in biofilm-laden porous media. Gram negative Pseudomonas aeruginosa (PA) and Gram-positive Bacillus cereus (BC) biofilm-laden glass beads were selected to represent the bacterial interfaces NPs might encounter in the natural aquatic environment. The biomass distribution, extracellular polymeric substances (EPS) components, electrokinetic property, and hydrophobicity of these interfaces were characterized, and the hydrophobicity was found to correlate with the quantity of proteins in EPS. The retention of NPs on glass beads coated with bovine serum albumin (BSA) and alginate were also studied. Except for Ag-PVP, the affinity of NPs for porous medium, indicated by attachment efficiency alpha, increased in the presence of biofilms, BSA and alginate. For hydrophobic aqu-nC60, the larger the proteins/polysaccharides ratio, the larger the alpha, suggesting the hydrophobic interaction determines the attachment of aqu-nC60 to the collector surface. Uncharged PVP stabilized Ag PVP by steric repulsion, and the attachment to glass beads was not enhanced by biofilm. The presence of divalent ion Ca(2+) significantly hydrophobized biofilm, BSA, and alginate-coated glass beads and further retarded the mobility of aqu nC60, fullerol, and Ag-CIT; while Ag-PVP was again sterically stabilized. PMID- 23346938 TI - Oxidative stress during pregnancy in the sheep. AB - During physiological pregnancy, all tissues and, mostly, placenta and foetus require high amounts of oxygen. Reactive oxygen species (ROS), generated both by mother and foetus, are implicated in foetal growth because they promote replication, differentiation and maturation of cells and organs. Nevertheless, ROS excess, if not properly counterbalanced, may lead to an alteration in cell constituents, with harmful effects both on mother and foetus.ROS exert a biphasic effect because adequate ROS concentration is essential for embryo development, implant, foetal defence against uterine infections, steroidogenesis, pregnancy maintainance and partum. On the other hand, an uncontrolled ROS generation, beyond physiological antioxidant defences, may lead to embryo resorption, placental degeneration with subsequent alteration in maternal-foetal exchanges, delay in foetal growth, pregnancy interruption, stillbirths. This review investigates the mechanisms underlying ROS generation and effects, throughout physiological and pathological pregnancy in sheep, with a look to antioxidants and their importance in such a critical phase of the reproductive cycle of the sheep. PMID- 23346939 TI - Precision medicines for B-cell leukaemias and lymphomas; progress and potential pitfalls. AB - There is now a plethora of new precision medicines for B-cell malignancy including 'classical' kinase inhibitors, rationally designed inhibitors of anti apoptotic proteins and antibody or antibody drug/toxin conjugates with functional properties. Some are showing spectacular single agent activity in early phase clinical studies and may reduce or, in combination, even obviate the need for chemotherapy. Nevertheless, significant problems remain if these medicines are to be introduced into routine clinical practice in a rational and affordable manner. Firstly, precision medicines must be carefully matched in a mechanistic fashion with specific subtypes of disease. Whilst sensitivity may be predicted by the detection of key mutations or by expression of target molecules, for therapies that depend on intact intracellular signalling pathways, functional assessment on viable primary malignant cells will be necessary using assays that faithfully mimic in vivo conditions. A second, but no less important challenge is to define mechanism-based synergistic combinations associated with minimal toxicities rather than simply adding new precision medicines to existing chemotherapeutic regimens. Finally, a closer, open, two-way interaction between academic medicine and the pharmaceutical industry will be necessary to achieve these aims. Implementing such changes would change radically how and where patients with B cell malignancies are managed. PMID- 23346940 TI - Novel simple approach for detection of regional perturbations of cardiac function in mouse models of cardiovascular disease. AB - AIMS: Transthoracic murine echocardiography is a cornerstone of small animal research, but conventional methods cannot detect regional perturbations in cardiac function. Reliable assessment of regional cardiac function would be of value in transgenic models of myocardial disease. Until now automatized algorithms for achieving this suffers from a number of drawbacks. We developed a simple algorithm for rapidly assessing the relative myocardial radial thickening that occurs between end-diastole and end-systole, that is, regional radial transmural end-systolic strain (RTESS). METHODS AND RESULTS: Echocardiographic assessment was performed in mice at baseline (n = 8), 2 hours postintraperitoneal isoprenaline (ISO) injection (n = 8), and 10 days postmyocardial infarction (post MI) (n = 6). A >1000 frames/sec cine loop was acquired by the ECG-gated Kilohertz visualization technique in the parasternal short-axis projection at 3 mm below the mitral annulus. Endo- and epicardial borders were traced at end-diastole and end-systole and RTESS was calculated for each of n segments by the algorithm. The intra- and inter-observer coefficients of variation for segmental RTESS assessment were 5.11 and 7.32, respectively. At baseline, average segmental RTESS was 56.75% and RTESS was similar in all cardiac segments regardless of how many segments the heart was divided into. In the akinetic myocardium of MI and ISO mice, 47.36% and 26.22% length of the endocardium, respectively, RTESS was near zero and significantly different from the remaining myocardium. CONCLUSION: We describe a simple and straightforward approach to quantify regional myocardial deformation in mouse models of cardiovascular disease. PMID- 23346941 TI - Health care utilisation in patients with non-cardiac chest pain: a longitudinal analysis of chest pain, anxiety and interoceptive fear. AB - Chest pain can be a frightening experience that leads many to seek medical evaluation. The symptom results in costly health care utilisation. Over half of patients referred for cardiac evaluations of chest pain do not obtain definitive medical explanations for their symptoms; these cases are described as non-cardiac chest pain (NCCP). Some patients with NCCP are not reassured after being informed their chest pain is non-cardiac in origin and seek repeated medical evaluation. Co-morbid anxiety and mood disorders often coexist with NCCP and are associated with health care utilisation. The current study examined chest pain, general anxiety, interoceptive fear and health care utilisation in a sample of 196 chest pain patients near the time of cardiac evaluation (Time 1), and 70 of these patients one year later (Time 2). Results indicate that anxiety and interoceptive fear were significantly associated with health care utilisation at Time 1, and only interoceptive fear (at Time 1) predicted health care utilisation at Time 2. This study develops research in this area by examining the relation of anxiety and health care utilisation longitudinally in patients with NCCP. PMID- 23346942 TI - Sources of organic nitrogen at the serpentinite-hosted Lost City hydrothermal field. AB - The reaction of ultramafic rocks with water during serpentinization at moderate temperatures results in alkaline fluids with high concentrations of reduced chemical compounds such as hydrogen and methane. Such environments provide unique habitats for microbial communities capable of utilizing these reduced compounds in present-day and, possibly, early Earth environments. However, these systems present challenges to microbial communities as well, particularly due to high fluid pH and possibly the availability of essential nutrients such as nitrogen. Here we investigate the source and cycling of organic nitrogen at an oceanic serpentinizing environment, the Lost City hydrothermal field (30 degrees N, Mid Atlantic Ridge). Total hydrolizable amino acid (THAA) concentrations in the fluids range from 736 to 2300 nm and constitute a large fraction of the dissolved organic carbon (2.5-15.1%). The amino acid distributions, and the relative concentrations of these compounds across the hydrothermal field, indicate they most likely derived from chemolithoautotrophic production. Previous studies have identified the presence of numerous nitrogen fixation genes in the fluids and the chimneys. Organic nitrogen in actively venting chimneys has delta(15) N values as low as 0.10/00 which is compatible with biological nitrogen fixation. Total hydrolizable amino acids in the chimneys are enriched in (13) C by 2-70/00 compared to bulk organic matter. The distribution and absolute delta(13) C(THAA) values are compatible with a chemolithoautotrophic source, an attribution also supported by molar organic C/N ratios in most active chimneys (4.1-5.5) which are similar to those expected for microbial communities. In total, these data indicate nitrogen is readily available to microbial communities at Lost City. PMID- 23346943 TI - Fluorescence in situ hybridisation analysis of sex chromosome in non-obstructive azoospermic men. AB - The aim of this study was to compare results of karyotypes and fluorescence in situ hybridisation (FISH) technique among non-obstructive azoospermic men and to evaluate feasibility of using FISH to assess the types of major sex chromosome abnormalities. We compared results of karyotypes and FISH technique in those patients, and the association between genetic abnormality and clinical and hormonal parameters was evaluated. We studied 68 non-obstructive azoospermic men using conventional cytogenetics and FISH. Karyotyping revealed chromosomal abnormalities in 28 males (41%); the most common was Klinefelter syndrome (82%). FISH proved very effective in verifying low level of mosaisim in two cases with Klinefelter syndrome and complex chromosomal rearrangements in four cases with structural sex chromosome abnormalities. Our results indicate that genetic testing and screening is important in men with hypergonadotrophic azoospermia prior to the employment of assisted reproduction techniques. FISH analysis is recommended before discussing the risk of chromosomal aberrations in the offspring of infertile couples. PMID- 23346944 TI - Regulation of soil organic C mineralisation at the pore scale. AB - Little is known about the factors that regulate C mineralisation at the soil pore scale or how these factors vary throughout the pore network. This study sought to understand how the decomposition of organic carbon varies within the soil pore network and to determine the relative importance of local environmental properties relative to biological properties as controlling factors. This was achieved by sterilising samples of soil and reinoculating them with axenic bacterial suspensions using the matric potential to target different locations in the pore network. Carbon mineralisation curves were described with two compartment first-order models to distinguish CO2 derived from the labile organic carbon released during sterilisation from CO2 derived from organic C unaffected by sterilisation. The data indicated that the size of the labile pool of organic C, possibly of microbial origin, varied as a function of location in the pore network but that the organic carbon unaffected by sterilisation did not. The mineralisation rate of the labile C varied with the bacterial type inoculated, but the mineralisation rate of the organic C unaffected by sterilisation was insensitive to bacterial type. Taken together, the results suggest that microbial metabolism is a less significant regulator of soil organic carbon decomposition than are microbial habitat properties. PMID- 23346945 TI - Killing the dead: chemotherapeutic strategies against free-living cyst-forming protists (Acanthamoeba sp. and Balamuthia mandrillaris). AB - The opportunist free-living protists such as Acanthamoeba spp. and Balamuthia mandrillaris have become a serious threat to human life. As most available drugs target functional aspects of pathogens, the ability of free-living protists to transform into metabolically inactive cyst forms presents a challenge in treatment. It is hoped, that the development of broad spectrum antiprotist agents acting against multiple cyst-forming protists to provide target-directed inhibition will offer a viable drug strategy in the treatment of these rare infections. Here, we present a comprehensive report on upcoming drug targets, with emphasis on cyst wall biosynthesis along with the related biochemistry of encystment pathways, as we strive to bring ourselves a step closer to being able to combat these deadly diseases. PMID- 23346946 TI - The impact of profitability of hospital admissions on mortality. AB - BACKGROUND: Fiscal constraints faced by Medicare are leading to policies designed to reduce expenditures. Evidence of the effect of reduced reimbursement on the mortality of Medicare patients discharged from all major hospital service lines is limited. METHODS: We modeled risk-adjusted 30-day mortality of patients discharged from 21 hospital service lines as a function of service line profitability, service line time trends, and hospital service line and year-fixed effects. We simulated the effect of alternative revenue-neutral reimbursement policies on mortality. Our sample included all Medicare discharges from PPS eligible hospitals (1997, 2001, and 2005). RESULTS: The results reveal a statistically significant inverse relationship between changes in profitability and mortality. A $0.19 average reduction in profit per $1.00 of costs led to a 0.010-0.020 percentage-point increase in mortality rates (p < .001). Mortality in newly unprofitable service lines is significantly more sensitive to reduced payment generosity than in service lines that remain profitable. Policy simulations that target service line inequities in payment generosity result in lower mortality rates, roughly 700-13,000 fewer deaths nationally. CONCLUSIONS: The policy simulations raise questions about the trade-offs implicit in universal reductions in reimbursement. The effect of reduced payment generosity on mortality could be mitigated by targeting highly profitable services only for lower reimbursement. PMID- 23346947 TI - Biodiversity and ecosystem stability: a synthesis of underlying mechanisms. AB - There is mounting evidence that biodiversity increases the stability of ecosystem processes in changing environments, but the mechanisms that underlie this effect are still controversial and poorly understood. Here, we extend mechanistic theory of ecosystem stability in competitive communities to clarify the mechanisms underlying diversity-stability relationships. We first explain why, contrary to a widely held belief, interspecific competition should generally play a destabilising role. We then explore the stabilising effect of differences in species' intrinsic rates of natural increase and provide a synthesis of various potentially stabilising mechanisms. Three main mechanisms are likely to operate in the stabilising effects of biodiversity on ecosystem properties: (1) asynchrony of species' intrinsic responses to environmental fluctuations, (2) differences in the speed at which species respond to perturbations, (3) reduction in the strength of competition. The first two mechanisms involve temporal complementarity between species, while the third results from functional complementarity. Additional potential mechanisms include selection effects, behavioural changes resulting from species interactions and mechanisms arising from trophic or non-trophic interactions and spatial heterogeneity. We conclude that mechanistic trait-based approaches are key to predicting the effects of diversity on ecosystem stability and to bringing the old diversity-stability debate to a final resolution. PMID- 23346948 TI - Phosphodiesterase type 5 inhibitor treatment for erectile dysfunction in patients with end-stage renal disease receiving dialysis or after renal transplantation. AB - INTRODUCTION: The phosphodiesterase type 5 (PDE5) inhibitors are generally well tolerated and effective for treating erectile dysfunction (ED), including in patients with significant comorbidity. Because of this benign safety profile, investigators have used PDE5 inhibitors to treat patients with ED and severe renal disease or those who have received renal transplants. AIM: To assess safety and efficacy of PDE5 inhibitors in patients receiving dialysis or renal transplants. MAIN OUTCOME MEASURES: Erectile function as assessed by the International Index of Erectile Function (IIEF) and Global Assessment Questions; adverse events (AEs). METHODS: We reviewed published studies of PDE5 inhibitors in patients receiving dialysis or renal transplants. RESULTS: In double-blind, placebo-controlled studies in patients receiving dialysis or renal transplants, sildenafil significantly improved erectile function as assessed by the IIEF, and 75-85% of patients reported improved erectile function on Global Assessment Questions; efficacy was more variable in less well-controlled studies. In >260 patients undergoing dialysis who received sildenafil in clinical studies, there were only six reported discontinuations because of AEs (headache [N=3], headache and nausea [N=1], gastrointestinal [N=1], and symptomatic blood pressure decrease [N=1]). In approximately 400 patients with renal transplants who received sildenafil, only three patients discontinued because of AEs. Vardenafil improved IIEF scores of up to 82% of renal transplant recipients in randomized, controlled studies (N=59, total), with no reported discontinuations because of AEs. Limited data also suggest benefit with tadalafil. CONCLUSIONS: ED is common in patients undergoing renal dialysis or postrenal transplant and substantially affects patient quality of life. Sildenafil and vardenafil appear to be efficacious and well tolerated in patients receiving renal dialysis or transplant. PMID- 23346949 TI - Controlling the orientation, edge geometry, and thickness of chemical vapor deposition graphene. AB - We report that the shape, orientation, edge geometry, and thickness of chemical vapor deposition graphene domains can be controlled by the crystallographic orientations of Cu substrates. Under low-pressure conditions, single-layer graphene domains align with zigzag edges parallel to a single <101> direction on Cu(111) and Cu(101), while bilayer domains align to two directions on Cu(001). Under atmospheric pressure conditions, hexagonal domains also preferentially align. This discovery can be exploited to generate high-quality, tailored graphene with controlled domain thickness, orientations, edge geometries, and grain boundaries. PMID- 23346950 TI - Sensitivity of plants to changing atmospheric CO2 concentration: from the geological past to the next century. AB - The rate of CO(2) assimilation by plants is directly influenced by the concentration of CO(2) in the atmosphere, c(a). As an environmental variable, c(a) also has a unique global and historic significance. Although relatively stable and uniform in the short term, global c(a) has varied substantially on the timescale of thousands to millions of years, and currently is increasing at seemingly an unprecedented rate. This may exert profound impacts on both climate and plant function. Here we utilise extensive datasets and models to develop an integrated, multi-scale assessment of the impact of changing c(a) on plant carbon dioxide uptake and water use. We find that, overall, the sensitivity of plants to rising or falling c(a) is qualitatively similar across all scales considered. It is characterised by an adaptive feedback response that tends to maintain 1 - c(i)/c(a), the relative gradient for CO(2) diffusion into the leaf, relatively constant. This is achieved through predictable adjustments to stomatal anatomy and chloroplast biochemistry. Importantly, the long-term response to changing c(a) can be described by simple equations rooted in the formulation of more commonly studied short-term responses. PMID- 23346951 TI - The relation of serum nesfatin-1 level with metabolic and clinical parameters in obese and healthy children. AB - BACKGROUND: Nesfatin-1, a recently discovered anorexigenic neuropeptide, is expressed in several tissues including pancreatic islet cells and central nervous system. This peptide seems to play an important role in hypothalamic pathways regulating food intake and energy homeostasis. OBJECTIVE: We aimed to investigate the relation of serum nesfatin-1 level with metabolic and anthropometric parameters in obese children. METHODS: The study included obese children with a body mass index (BMI) above the 95th percentile and healthy children with a BMI below the 85th percentile. The healthy and obese subjects had similar age and gender distribution. Fasting serum glucose, insulin, lipid profile, and nesfatin 1 levels were measured to evaluate metabolic parameters. RESULTS: Obese group (n = 37) had significantly higher BMI, BMI-SDS (standard deviation score of BMI), triglyceride, insulin, and insulin resistance index by the homeostasis model assessment, systolic and diastolic blood pressure values compared with the control group (n = 31) (p < 0.05). Serum nesfatin-1 level of the obese subjects was significantly lower than that of the control subjects (p = 0.001). No statistically significant difference was found when nesfatin-1 levels were compared among obese patients regarding the presence of insulin resistance (p = 0.202). In the obese group, nesfatin-1 level was negatively correlated with BMI SDS, but not with insulin resistance index (p = 0.02 and p = 0.361, respectively). CONCLUSIONS: This is the first study to evaluate nesfatin-1 levels in relation with anthropometric and metabolic parameters in obese patients who had significantly lower nesfatin-1 levels. Our results underline that nesfatin-1 may play an important role in regulation of food intake in obese individuals. PMID- 23346952 TI - Engineering cellular fibers for musculoskeletal soft tissues using directed self assembly. AB - Engineering strategies guided by developmental biology may enhance and accelerate in vitro tissue formation for tissue engineering and regenerative medicine applications. In this study, we looked toward embryonic tendon development as a model system to guide our soft tissue engineering approach. To direct cellular self-assembly, we utilized laser micromachined, differentially adherent growth channels lined with fibronectin. The micromachined growth channels directed human dermal fibroblast cells to form single cellular fibers, without the need for a provisional three-dimensional extracellular matrix or scaffold to establish a fiber structure. Therefore, the resulting tissue structure and mechanical characteristics were determined solely by the cells. Due to the self-assembly nature of this approach, the growing fibers exhibit some key aspects of embryonic tendon development, such as high cellularity, the rapid formation (within 24 h) of a highly organized and aligned cellular structure, and the expression of cadherin-11 (indicating direct cell-to-cell adhesions). To provide a dynamic mechanical environment, we have also developed and characterized a method to apply precise cyclic tensile strain to the cellular fibers as they develop. After an initial period of cellular fiber formation (24 h postseeding), cyclic strain was applied for 48 h, in 8-h intervals, with tensile strain increasing from 0.7% to 1.0%, and at a frequency of 0.5 Hz. Dynamic loading dramatically increased cellular fiber mechanical properties with a nearly twofold increase in both the linear region stiffness and maximum load at failure, thereby demonstrating a mechanism for enhancing cellular fiber formation and mechanical properties. Tissue engineering strategies, designed to capture key aspects of embryonic development, may provide unique insight into accelerated maturation of engineered replacement tissue, and offer significant advances for regenerative medicine applications in tendon, ligament, and other fibrous soft tissues. PMID- 23346953 TI - Diaryl hydrazones as multifunctional inhibitors of amyloid self-assembly. AB - The design and application of an effective, new class of multifunctional small molecule inhibitors of amyloid self-assembly are described. Several compounds based on the diaryl hydrazone scaffold were designed. Forty-four substituted derivatives of this core structure were synthesized using a variety of benzaldehydes and phenylhydrazines and characterized. The inhibitor candidates were evaluated in multiple assays, including the inhibition of amyloid beta (Abeta) fibrillogenesis and oligomer formation and the reverse processes, the disassembly of preformed fibrils and oligomers. Because the structure of the hydrazone-based inhibitors mimics the redox features of the antioxidant resveratrol, the radical scavenging effect of the compounds was evaluated by colorimetric assays against 2,2-diphenyl-1-picrylhydrazyl and superoxide radicals. The hydrazone scaffold was active in all of the different assays. The structure-activity relationship revealed that the substituents on the aromatic rings had a considerable effect on the overall activity of the compounds. The inhibitors showed strong activity in fibrillogenesis inhibition and disassembly, and even greater potency in the inhibition of oligomer formation and oligomer disassembly. Supporting the quantitative fluorometric and colorimetric assays, size exclusion chromatographic studies indicated that the best compounds practically eliminated or substantially inhibited the formation of soluble, aggregated Abeta species, as well. Atomic force microscopy was also applied to monitor the morphology of Abeta deposits. The compounds also possessed the predicted antioxidant properties; approximately 30% of the synthesized compounds showed a radical scavenging effect equal to or better than that of resveratrol or ascorbic acid. PMID- 23346954 TI - Metabolic acclimation to excess light intensity in Chlamydomonas reinhardtii. AB - There are several well-described acclimation responses to excess light in green algae but the effect on metabolism has not been thoroughly investigated. This study examines the metabolic changes during photoacclimation to high-light (HL) stress in Chlamydomonas reinhardtii using nuclear magnetic resonance and mass spectrometry. Using principal component analysis, a clear metabolic response to HL intensity was observed on global metabolite pools, with major changes in the levels of amino acids and related nitrogen metabolites. Amino acid pools increased during short-term photoacclimation, but were especially prominent in HL acclimated cultures. Unexpectedly, we observed an increase in mitochondrial metabolism through downstream photorespiratory pathways. The expression of two genes encoding key enzymes in the photorespiratory pathway, glycolate dehydrogenase and malate synthase, were highly responsive to the HL stress. We propose that this pathway contributes to metabolite pools involved in nitrogen assimilation and may play a direct role in photoacclimation. Our results suggest that primary and secondary metabolism is highly pliable and plays a critical role in coping with the energetic imbalance during HL exposure and a necessary adjustment to support an increased growth rate that is an effective energy sink for the excess reducing power generated during HL stress. PMID- 23346955 TI - Crestal bone reactions to immediate implants placed at different levels in relation to crestal bone. A pilot study in Foxhound dogs. AB - OBJECTIVES: The aim of the present study was to evaluate bone-to-implant contact (BIC) and bone remodeling dynamics after immediate implant placement at different levels in relation to the crestal bone. MATERIALS AND METHODS: The mandibular second, third, and fourth premolars of six Foxhound dogs were extracted bilaterally. Randomly, three implants were immediately placed in the hemi-arches of each dog, crestally or 2 mm subcrestally. Three dogs were allowed an 8-week submerged healing period, and the other three at 12-week submerged healing period. The animals were sacrificed at 12 weeks and samples were obtained. Biopsies were processed for ground sectioning. Histomorphometric analysis was carried out to compare BIC, bone neoformation, and bone remodeling. RESULTS: All implants osseointegrated clinically and histologically. Healing patterns examined microscopically at eight and twelve weeks for both groups (crestal and subcrestal) yielded similar qualitative bone findings. The Total BIC mean value for the crestal group 44.52% at 8 weeks and 39.50% at 12 weeks, and for the subcrestal group was 47.33% at 8 weeks and 53.85% at 12 weeks%. There was less bone resorption in the subcrestal group (test) than in crestal group (control). CONCLUSIONS: Within the limitations of this study, our findings suggest that apical positioning of the top of the implant does not jeopardize bone crest and peri-implant tissue remodeling. However, less resorption of the lingual crest may be expected when implants are placed 2 mm subcrestally. Moreover, higher BIC values were found in implants placed subcrestally. PMID- 23346956 TI - A generic approach for the synthesis of dimer nanoclusters and asymmetric nanoassemblies. AB - Controlled assembly of nanoparticles into asymmetric configurations is of great interest due to their novel properties and promising applications. In this Article, we report a generic strategy for the synthesis of dimer nanoclusters and asymmetric nanoassemblies by using magnetic colloidal substrates, on which tailored surface modification and controlled physical confinement are applied. The modularity of our approach facilitates the fabrication of asymmetric nanostructures with varying sizes, shapes, compositions, surface chemistry, and surface hydrophobicity. Success in the syntheses sheds a light on the versatility of our strategy in rationally designing and synthesizing asymmetric nanostructures with tailored properties and functionalities. PMID- 23346957 TI - Distant lymph nodes serve as pools of Th1 cells induced by neonatal BCG vaccination for the prevention of asthma in mice. AB - BACKGROUND: Neonatal Bacillus Calmette-Guerin (BCG) vaccination induces vigorous T-helper type 1 (Th1) responses and inhibits allergy-related airway dysfunction, but the exact mechanisms remain unclear. The objective of this study was to address where the Th1 cells induced by neonatal BCG vaccination are generated and stored, and how they are recruited into the inflamed airway for the prevention of allergen-induced airway inflammation. METHODS: We vaccinated neonatal C57BL/6 mice with BCG in a mouse model of asthma and analyzed the expression and function of Th1 cells in vivo and in vitro. RESULTS: BCG vaccination-induced Th1 cells in the local inguinal lymph nodes (ILN) migrated into the lungs upon inhaled ovalbumin (OVA) challenge in OVA-sensitized mice. These CD4(+) T cells in the ILN exhibited potentials of activation, proliferation and cytokine secretion and expressed high levels of CXCR3. Adoptive transfer of CD4(+) T cells from BCG treated ILN significantly decreased allergic airway responses. In addition, the protective effect of BCG vaccination against allergic airway inflammation was lost upon the excision of the ILN. CONCLUSIONS: These data demonstrate that ILN serves as a 'weapon' pool of Th1 cells following BCG vaccination, and these cells are ready for the migration into the inflamed lungs upon the allergen challenge, thereby inhibiting allergen-induced airway disorder. PMID- 23346958 TI - Adsorption of carbon dioxide, methane, and their mixtures in porous carbons: effect of surface chemistry, water content, and pore disorder. AB - The adsorption of carbon dioxide, methane, and their mixtures in nanoporous carbons in the presence of water is studied using experiments and molecular simulations. Both the experimental and numerical samples contain polar groups that account for their partially hydrophilicity. For small amounts of adsorbed water, although the shape of the adsorption isotherms remain similar, both the molecular simulations and experiments show a slight decrease in the CO2 and CH4 adsorption amounts. For large amounts of adsorbed water, the experimental data suggest the formation of methane or carbon dioxide clathrates in agreement with previous work. In contrast, the molecular simulations do not account for the formation of such clathrates. Another important difference between the simulated and experimental data concerns the number of water molecules that desorb upon increasing the pressure of carbon dioxide and methane. Although the experimental data indicate that water remains adsorbed upon carbon dioxide and methane adsorption, the molecular simulations suggest that 40 to 75% of the initial amount of adsorbed water desorbs with carbon dioxide or methane pressure. Such discrepancies show that differences between the simulated and experimental samples are crucial to account for the rich phase behavior of confined water-gas systems. Our simulations for carbon dioxide-methane coadsorption in the presence of water suggest that the pore filling is not affected by the presence of water and that adsorbed solution theory can be applied for pressures as high as 15 MPa. PMID- 23346959 TI - Identification of polymorphisms in the osteopontin gene and their associations with certain semen production traits of water buffaloes in the Brazilian Amazon. AB - The osteopontin gene may influence the fertility of water buffaloes because it is a protein present in sperm. The aim of this work was to identify polymorphisms in this gene and associate them with fertility parameters of animals kept under extensive grazing. A total of 306 male buffaloes older than 18 months, from two farms, one in the state of Amapa and the other in the state of Para, Brazil were used in the study. Seven SNPs were identified in the regions studied. The polymorphisms were in gene positions 1478, 1513 and 1611 in the region 5'upstrem and positions 6690, 6737, 6925 and 6952 in the region amplified in intron 5. The SNPs were associated with the traits, namely scrotal circumference, scrotal volume, sperm motility, sperm concentration and sperm pathology. There were significant SNPs (p < 0.05) for all the traits. The SNP 6690 was significant for scrotal circumference, sperm concentration, sperm motility and sperm pathology and the SNP 6737 for scrotal volume. The genotype AA of SNP 6690 presented the highest averages for scrotal circumference, sperm concentration and motility and the lowest total number of sperm pathologies. For the scrotal volume trait, the animals with the largest volume were correlated with the presence of the genotype GG of SNP 6737. These results indicate a significance of the osteopontin gene as it seems to exert a substantial influence on the semen production traits of male buffaloes. PMID- 23346960 TI - Altered methylation levels in elderly acute myeloid leukaemia patients compared to elderly well individuals. PMID- 23346961 TI - Telomere length behaves as biomarker of somatic redundancy rather than biological age. AB - Biomarkers of aging are essential to predict mortality and aging-related diseases. Paradoxically, age itself imposes a limitation on the use of known biomarkers of aging because their associations with mortality generally diminish with age. How this pattern arises is, however, not understood. With meta-analysis we show that human leucocyte telomere length (TL) predicts mortality, and that this mortality association diminishes with age, as found for other biomarkers of aging. Subsequently, we demonstrate with simulation models that this observation cannot be reconciled with the popular hypothesis that TL is proportional to biological age. Using the reliability theory of aging, we instead propose that TL is a biomarker of somatic redundancy, the body's capacity to absorb damage, which fits the observed pattern well. We discuss to what extent diminishing redundancy with age may also explain the observed diminishing mortality modulation with age of other biomarkers of aging. Considering diminishing somatic redundancy as the causal agent of aging may critically advance our understanding of the aging process, and improve predictions of life expectancy and vulnerability to aging related diseases. PMID- 23346962 TI - Enantioselective synthesis of 3,4-disubstituted cis- and trans-1,2,5 thiadiazolidine-1,1-dioxides as precursors for chiral 1,2-diamines. AB - Both, cis- and trans-3,4-disubstituted thiadiazolidines 5 and 6 can enantioselectively be obtained from thiadiazoles 2 which, in turn, are efficiently prepared from the respective 1,2-diketone by an improved protocol. An asymmetric ruthenium-catalyzed transfer hydrogenation followed by a diastereoselective hydride addition furnishes exclusively the cis-isomers 5 which, under acidic conditions, undergo a novel isomerization into the trans isomers 6. These cyclic sulfamides can be transformed into 1,2-diamines as well as 2,3-diamino acids. PMID- 23346963 TI - Nurse practitioner prescribing practices: the most frequently prescribed medications. AB - AIMS AND OBJECTIVES: To explore which medications Australian nurse practitioners most frequently prescribe. BACKGROUND: Although nurse practitioners in Australia have prescriptive authority, little is known about which specific medications nurse practitioners are prescribing and how frequently they do so. DESIGN: Descriptive electronic survey. METHODS: A total of 209 nurse practitioners reported current prescribing practices. Medications reported were categorised according to the Australian Medicines Handbook major drug classifications and frequencies presented. RESULTS: Seventy-eight per cent of respondents reported prescribing medications as part of their Nurse Practitioner practice. In total, participants reported prescribing 234 separate medications from most Australian Medicines Handbook major drug classifications. Medications from the classification anti-infective drugs were most frequently prescribed followed by medications from analgesic, psychotropic, cardiovascular, musculoskeletal, genitourinary and gastrointestinal classifications. CONCLUSION: The majority of nurse practitioners in Australia prescribe medications in their clinical practice, although the proportion of nurse practitioners prescribing has not changed significantly in the past four years. The medications prescribed are comparable with those most frequently prescribed by all prescribers in Australia and highlight the diversity in scope of practice among nurse practitioners. RELEVANCE TO CLINICAL PRACTICE: Findings highlight the importance of Nurse Practitioner's a capacity to prescribe wide variety of medications, especially in practice areas such acute, primary and emergency care. The unique role nurse practitioners in relation to management of patients with infective processes and patients requiring pain relief is highlighted. Insight into current Nurse Practitioner prescribing trends informs future Nurse Practitioner curricular and future continuing education programmes. Findings give unique insight for future service planning, especially service providers considering introducing nurse practitioners to their service. The finding that nurse practitioners prescribing patterns are similar to other non-nurse practitioner prescribers in Australia highlights the potential for service providers to introduce new models of care that are Nurse Practitioner lead. PMID- 23346964 TI - Does sex moderate the relationship between anxiety and pain? AB - OBJECTIVES: Sex differences exist in the relationship between anxiety and pain, although findings are mixed. One reason could be because a number of anxiety measures have been used. Therefore, this study aimed to identify the core components within commonly used pain anxiety measures, and see whether these components are differentially related to sensation and pain thresholds in men and women. DESIGN, MAIN OUTCOME MEASURES: One hundred and eighty-nine healthy adults (119 female) completed the Fear of Pain Questionnaire, Pain Catastrophising Scale, Pain Anxiety Symptoms Scale, Anxiety Sensitivity Index-3 and the Depression Anxiety Stress Scale. Thermal sensation and pain thresholds, mechanical sensation and pressure pain thresholds were also collected. RESULTS: A Principal Components Analysis of anxiety measures revealed three constructs: general distress, cognitive intrusion and fear of pain from injury/insult. Sex did not moderate the relationship between these anxiety constructs and sensation/pain thresholds. However, a significant main effect of sex was found to predict thermal pain thresholds. CONCLUSION: Preliminary indications suggest that pain anxiety dimensions can be reduced to three core constructs, and used to examine pain sensation. However, sex did not moderate this relationship. Further research is required to establish the extent and strength of sex differences in the relationship between anxiety and pain. PMID- 23346965 TI - Bayesian network meta-analysis of root coverage procedures: ranking efficacy and identification of best treatment. AB - AIMS: The aim of this work was to conduct a Bayesian network meta-analysis (NM) of randomized controlled trials (RCTs) to establish a ranking in efficacy and the best technique for coronally advanced flap (CAF)-based root coverage procedures. MATERIAL AND METHODS: A literature search on PubMed, Cochrane libraries, EMBASE, and hand-searched journals until June 2012 was conducted to identify RCTs on treatments of Miller Class I and II gingival recessions with at least 6 months of follow-up. The treatment outcomes were recession reduction (RecRed), clinical attachment gain (CALgain), keratinized tissue gain (KTgain), and complete root coverage (CRC). RESULTS: Twenty-nine studies met the inclusion criteria, 20 of which were classified as at high risk of bias. The CAF+connective tissue graft (CTG) combination ranked highest in effectiveness for RecRed (Probability of being the best = 40%) and CALgain (Pr = 33%); CAF+enamel matrix derivative (EMD) was slightly better for CRC; CAF+Collagen Matrix (CM) appeared effective for KTgain (Pr = 69%). Network inconsistency was low for all outcomes excluding CALgain. CONCLUSION: CAF+CTG might be considered the gold standard in root coverage procedures. The low amount of inconsistency gives support to the reliability of the present findings. PMID- 23346967 TI - Deposition and survival of Escherichia coli O157:H7 on clay minerals in a parallel plate flow system. AB - Understanding bacterial pathogens deposition and survival processes in the soil groundwater system is crucial to protect public health from soilborne and waterborne diseases. However, mechanisms of bacterial pathogen-clay interactions are not well studied, particularly in dynamic systems. Also, little is known about the viability of bacterial pathogens when attached to clays. In this study, a parallel plate flow system was used to determine the deposition kinetics and survival of Escherichia coli O157:H7 on montmorillonite, kaolinite, and goethite over a wide range of ionic strengths (IS) (0.1-100 mM KCl). E. coli O157:H7 deposition on the positively charged goethite is greater than that on the negatively charged kaolinite and montmorillonite. Although the zeta potential of kaolinite was more negative than that of montmorillonite, kaolinite showed a greater deposition for E. coli O157:H7 than montmorillonite, which is attributed to the chemical heterogeneity of clay minerals. Overall, increasing IS resulted in an increase of E. coli O157:H7 deposition on montmorillonite and kaolinite, and a decrease on goethite. Interaction energy calculations suggest that E. coli O157:H7 deposition on clays was largely governed by DLVO (Derjaguin-Landau-Verwey Overbeek) forces. The loss of bacterial membrane integrity was investigated as a function of time using the Live/Dead BacLight viability assay. During the examined period of 6 h, E. coli O157:H7 retained its viability in suspension and when attached to montmorillonite and kaolinite; however, interaction with the goethite was detrimental. The information obtained in this study is of fundamental significance for the understanding of the fate of bacterial pathogens in soil environments. PMID- 23346966 TI - Opioid system in the medial prefrontal cortex mediates binge-like eating. AB - Binge eating disorder is an addiction-like disorder characterized by excessive food consumption within discrete periods of time. This study was aimed at understanding the role of the opioid system within the medial prefrontal cortex (mPFC) in the consummatory and motivational aspects of binge-like eating. For this purpose, we trained male rats to obtain either a sugary, highly palatable diet (Palatable rats) or a chow diet (Chow rats) for 1 hour/day. We then evaluated the effects of the opioid receptor antagonist, naltrexone, given either systemically or site-specifically into the nucleus accumbens (NAcc) or the mPFC on a fixed ratio 1 (FR1) and a progressive ratio schedule of reinforcement for food. Finally, we assessed the expression of the genes proopiomelanocortin (POMC), pro-dynorphin (PDyn) and pro-enkephalin (PEnk), coding for the opioids peptides in the NAcc and the mPFC in both groups. Palatable rats rapidly escalated their intake by four times. Naltrexone, when administered systemically and into the NAcc, reduced FR1 responding for food and motivation to eat under a progressive ratio in both Chow and Palatable rats; conversely, when administered into the mPFC, the effects were highly selective for binge eating rats. Furthermore, we found a twofold increase in POMC and a ~50% reduction in PDyn gene expression in the mPFC of Palatable rats, when compared to control rats; however, no changes were observed in the NAcc. Our data suggest that neuroadaptations of the opioid system in the mPFC occur following intermittent access to highly palatable food, which may be responsible for the development of binge-like eating. PMID- 23346975 TI - Anatomic and neuromuscular characterisation of the equine cricothyroid muscle. AB - REASONS FOR PERFORMING STUDY: As part of investigation into laryngeal stability and reanimation using functional electrical stimulation, the cricothyroid muscle might be utilised to increase laryngeal cross-sectional area in horses with recurrent laryngeal neuropathy. For optimal electrode placement and muscle recruitment, the neuroanatomy and excitability of the equine cricothyroid muscle needs to be defined. OBJECTIVES: To describe the anatomy, innervation and function of the equine cricothyroid muscle and its contribution to laryngeal diameter. METHODS: Seventeen equine larynges were collected at necropsy and 12 were grossly dissected. Seven larynges (five grade 1, two grade 4) were prepared for immunohistochemistry following gross dissection and 5 larynges were prepared for special staining: acetylcholinesterase staining of motor endplates (n = 3) and Sihler's staining (n = 2). Three larynges were stimulated following in situ cadaver dissection and 2 larynges were removed and stimulated ex vivo. RESULTS: Three neuromuscular compartments, each innervated by a primary nerve branch of the external branch of the cranial laryngeal nerve, were identified in all larynges. Stimulation of each neuromuscular compartment resulted in ventral displacement of the thyroid cartilage with respect to the cricoid cartilage, thereby increasing dorsoventral height of the rima glottis. CONCLUSIONS: The equine cricothyroid muscle has 3 distinct neuromuscular compartments with discrete innervation, fibre type distribution and muscle fibre sizes. All neuromuscular compartments tense the vocal cords by increasing dorsoventral height of the rima glottis through ventral displacement of the thyroid cartilage with respect to the cricoid cartilage. POTENTIAL RELEVANCE: Simultaneous functional electrical stimulation of the cricothyroid and dorsal cricoarytenoid muscles may enhance laryngeal cross-sectional area in horses with recurrent laryngeal neuropathy. PMID- 23346976 TI - Modeling employer self-insurance decisions after the Affordable Care Act. AB - OBJECTIVE: To present a microsimulation model that addresses the methodological challenge of estimating the firm decision to self-insure. METHODOLOGY: The model considers the risk that the firm bears when self-insuring and the opportunity to mitigate that risk by purchasing stop-loss insurance. The model makes use of a structural, utility maximization framework to account for numerous aspects of the firm decision, and a multinomial probit to reproduce the elasticity of the firm's demand for health insurance. FINDINGS AND CONCLUSIONS: Our simulations provide three important conclusions. First, they project significant increases in self insurance rates among small firms--presumably induced by the desire to avoid ACA's rate-banding and risk adjustment regulations-only if generous stop-loss policies become widely available. Second, they show that this increase would be due to this hypothetical adoption of widespread, generous reinsurance by the market and not by passage of the ACA. Third, even with a substantial increase of self-insurance rates among small firms, they project negligible adverse selection in the exchanges, as indicated by our finding that the increase in exchange premium is less than 0.5% when assuming very generous stop-loss policies after implementation of the ACA. PMID- 23346977 TI - Designing a Bernal spiral from patchy colloids. AB - A model potential for colloidal building blocks is defined with two different types of attractive surface sites, described as complementary patches and antipatches. A Bernal spiral is identified as the global minimum for clusters with appropriate arrangements of three patch-antipatch pairs. We further derive a minimalist design rule with only one patch and antipatch, which also produces a Bernal spiral. Monte Carlo simulations of these patchy colloidal building blocks in the bulk are generally found to corroborate the global optimization results. PMID- 23346978 TI - Oscillation of a polymer gel entrained with a periodic force. AB - The oscillation of a polymer gel induced by the Belousov-Zhabotinsky (BZ) reaction was investigated under an external force composed of a square wave. The oscillation of the BZ reaction entrained to the periodic force and the features of this entrainment changed depending on the period and duty cycle of the square wave. The experimental results suggest that the change in the volume of the gel also gave feedback to the BZ reaction. The mechanism of entrainment is discussed in relation to the compression of the gel and the reaction-diffusion system in the BZ reaction. PMID- 23346979 TI - The relative contribution of methanotrophs to microbial communities and carbon cycling in soil overlying a coal-bed methane seep. AB - Seepage of coal-bed methane (CBM) through soils is a potential source of atmospheric CH4 and also a likely source of ancient (i.e. (14) C-dead) carbon to soil microbial communities. Natural abundance (13) C and (14) C compositions of bacterial membrane phospholipid fatty acids (PLFAs) and soil gas CO2 and CH4 were used to assess the incorporation of CBM-derived carbon into methanotrophs and other members of the soil microbial community. Concentrations of type I and type II methanotroph PLFA biomarkers (16:1omega8c and 18:1omega8c, respectively) were elevated in CBM-impacted soils compared with a control site. Comparison of PLFA and 16s rDNA data suggested type I and II methanotroph populations were well estimated and overestimated by their PLFA biomarkers, respectively. The delta(13) C values of PLFAs common in type I and II methanotrophs were as negative as 670/00 and consistent with the assimilation of CBM. PLFAs more indicative of nonmethanotrophic bacteria had delta(13) C values that were intermediate indicating assimilation of both plant- and CBM-derived carbon. Delta(14) C values of select PLFAs (-351 to -9360/00) indicated similar patterns of CBM assimilation by methanotrophs and nonmethanotrophs and were used to estimate that 35-91% of carbon assimilated by nonmethanotrophs was derived from CBM depending on time of sampling and soil depth. PMID- 23346980 TI - Oxidatively damaged DNA in animals exposed to particles. AB - Exposure to combustion-derived particles, quartz and asbestos is associated with increased levels of oxidized and mutagenic DNA lesions. The aim of this survey was to critically assess the measurements of oxidatively damaged DNA as marker of particle-induced genotoxicity in animal tissues. Publications based on non optimal assays of 8-oxo-7,8-dihydroguanine by antibodies and/or unrealistically high levels of 8-oxo-7,8-dihydroguanine (suggesting experimental problems due to spurious oxidation of DNA) reported more induction of DNA damage after exposure to particles than did the publications based on optimal methods. The majority of studies have used single intracavitary administration or inhalation with dose rates exceeding the pulmonary overload threshold, resulting in cytotoxicity and inflammation. It is unclear whether this is relevant for the much lower human exposure levels. Still, there was linear dose-response relationship for 8-oxo-7,8 dihydroguanine in lung tissue without obvious signs of a threshold. The dose response function was also dependent on chemical composition and other characteristics of the administered particles, whereas dependence on species and strain could not be equivocally determined. Roles of cytotoxicity or inflammation for oxidatively induced DNA damage could not be documented or refuted. Studies on exposure to particles in the gastrointestinal tract showed consistently increased levels of 8-oxo-7,8-dihydroguanine in the liver. Collectively, there is evidence from animal experimental models that both pulmonary and gastrointestinal tract exposure to particles are associated with elevated levels of oxidatively damaged DNA in the lung and internal organs. However, there is a paucity of studies on pulmonary exposure to low doses of particles that are relevant for hazard/risk assessment. PMID- 23346984 TI - Molecular evolution and expression divergence of the Populus polygalacturonase supergene family shed light on the evolution of increasingly complex organs in plants. AB - Plant polygalacturonases (PGs) are involved in cell separation processes during many stages of plant development. Investigation into the diversification of this large gene family in land plants could shed light on the evolution of structural development. We conducted whole-genome annotation, molecular evolution and gene expression analyses of PG genes in five species of land plant: Populus, Arabidopsis, rice, Selaginella and Physcomitrella. We identified 75, 44, 16 and 11 PG genes from Populus, rice, Selaginella and Physcomitrella genomes, respectively, which were divided into three classes. We inferred rapid expansion of class I PG genes in Populus, Arabidopsis and rice, while copy numbers of classes II and III PG genes were relatively conserved in all five species. Populus, Arabidopsis and rice class I PG genes were under more relaxed selection constraints than class II PG genes, while this selective pressure divergence was not observed in Selaginella and Physcomitrella PG families. In addition, class I PG genes underwent marked expression divergence in Populus, rice and Selaginella. Our results suggest that PG gene expansion occurred after the divergence of the lycophytes and euphyllophytes, and this expansion was likely paralleled by the evolution of increasingly complex organs in land plants. PMID- 23346985 TI - Convergence of potential net ecosystem production among contrasting C3 grasslands. AB - Metabolic theory and body size constraints on biomass production and decomposition suggest that differences in the intrinsic potential net ecosystem production (NEPPOT ) should be small among contrasting C3 grasslands and therefore unable to explain the wide range in the annual apparent net ecosystem production (NEPAPP ) reported by previous studies. We estimated NEPPOT for nine C3 grasslands under contrasting climate and management regimes using multiyear eddy covariance data. NEPPOT converged within a narrow range, suggesting little difference in the net carbon dioxide uptake capacity among C3 grasslands. Our results indicate a unique feature of C3 grasslands compared with other terrestrial ecosystems and suggest a state of stability in NEPPOT due to tightly coupled production and respiration processes. Consequently, the annual NEPAPP of C3 grasslands is primarily a function of seasonal and short-term environmental and management constraints, and therefore especially susceptible to changes in future climate patterns and associated adaptation of management practices. PMID- 23346982 TI - Health risk of chrysotile revisited. AB - This review provides a basis for substantiating both kinetically and pathologically the differences between chrysotile and amphibole asbestos. Chrysotile, which is rapidly attacked by the acid environment of the macrophage, falls apart in the lung into short fibers and particles, while the amphibole asbestos persist creating a response to the fibrous structure of this mineral. Inhalation toxicity studies of chrysotile at non-lung overload conditions demonstrate that the long (>20 um) fibers are rapidly cleared from the lung, are not translocated to the pleural cavity and do not initiate fibrogenic response. In contrast, long amphibole asbestos fibers persist, are quickly (within 7 d) translocated to the pleural cavity and result in interstitial fibrosis and pleural inflammation. Quantitative reviews of epidemiological studies of mineral fibers have determined the potency of chrysotile and amphibole asbestos for causing lung cancer and mesothelioma in relation to fiber type and have also differentiated between these two minerals. These studies have been reviewed in light of the frequent use of amphibole asbestos. As with other respirable particulates, there is evidence that heavy and prolonged exposure to chrysotile can produce lung cancer. The importance of the present and other similar reviews is that the studies they report show that low exposures to chrysotile do not present a detectable risk to health. Since total dose over time decides the likelihood of disease occurrence and progression, they also suggest that the risk of an adverse outcome may be low with even high exposures experienced over a short duration. PMID- 23346986 TI - Postoperative normalization of left ventricular noncompaction and new echocardiographic signs in aorta to left ventricular tunnel. AB - We report postoperative normalization of left ventricular noncompaction in a neonate undergoing successful neonatal surgery for type II aorta to left ventricular tunnel (ALVT) associated with a large patent ductus arteriosus, floppy and extremely redundant anterior mitral leaflet, right coronary artery arising directly from the tunnel, and severe left ventricular noncompaction. We also described 2 novel echocardiographic findings in ALVT including "triple wavy line sign" on M-mode echocardiography which disappeared 1 month after operation and "abnormally increased left ventricular posterior wall motion" on M-mode of standard parasternal long-axis view on color tissue Doppler imaging (TDI) that also normalized postoperatively. We showed that proper definition of endocardial border is extremely important in strain and strain rate imaging in the context of left ventricular noncompaction. Preoperative longitudinal strain and strain rate were significantly decreased in comparison to radial strain and strain rate. Circumferential strain and strain rate were normal. PMID- 23346981 TI - The use of biomonitoring data in exposure and human health risk assessment: benzene case study. AB - Abstract A framework of "Common Criteria" (i.e. a series of questions) has been developed to inform the use and evaluation of biomonitoring data in the context of human exposure and risk assessment. The data-rich chemical benzene was selected for use in a case study to assess whether refinement of the Common Criteria framework was necessary, and to gain additional perspective on approaches for integrating biomonitoring data into a risk-based context. The available data for benzene satisfied most of the Common Criteria and allowed for a risk-based evaluation of the benzene biomonitoring data. In general, biomarker (blood benzene, urinary benzene and urinary S-phenylmercapturic acid) central tendency (i.e. mean, median and geometric mean) concentrations for non-smokers are at or below the predicted blood or urine concentrations that would correspond to exposure at the US Environmental Protection Agency reference concentration (30 ug/m(3)), but greater than blood or urine concentrations relating to the air concentration at the 1 * 10(-5) excess cancer risk (2.9 ug/m(3)). Smokers clearly have higher levels of benzene exposure, and biomarker levels of benzene for non smokers are generally consistent with ambient air monitoring results. While some biomarkers of benzene are specific indicators of exposure, the interpretation of benzene biomonitoring levels in a health-risk context are complicated by issues associated with short half-lives and gaps in knowledge regarding the relationship between the biomarkers and subsequent toxic effects. PMID- 23346988 TI - A predicted structure for the PixD-PixE complex determined by homology modeling, docking simulations, and a mutagenesis study. AB - PixD is a blue light-using flavin (BLUF) photoreceptor that controls phototaxis in the cyanobacterium Synechocystis sp. PCC6803. PixD interacts with the response regulator-like protein PixE in a light-dependent manner, and this interaction is critical for light signal transduction in vivo. However, the structure of the PixD-PixE complex has not been determined. To improve our understanding of how PixD transmits its captured light signal to PixE, we used blue-native polyacrylamide gel electrophoresis to characterize the molecular mass of a recombinant PixD-PixE complex purified from Escherichia coli and found it to be 342 kDa, suggesting that the complex contains 10 PixD and 4 PixE monomers. The stoichiometry of the complex was confirmed by Western blotting. Specifically, three intermediate states, PixD(10)-PixE(1), PixD(10)-PixE(2), and PixD(10) PixE(3), were detected. The apparent dissociation constant for PixE and PixD is ~5 MUM. A docking simulation was performed using a modeled PixE structure and the PixD(10) crystal structure. The docking simulation showed how the molecules in the PixD(10)-PixE(4) structure interact. To verify the accuracy of the docked model, a site-directed mutagenesis study was performed in which Arg80 of PixE, which appears to be capable of interacting electrostatically with Asp135 of PixD in the predicted structure, was shown to be critical for complex formation as mutation of PixE Arg80 to Asp or Ala prevented PixD-PixE complex formation. This study provides a structural basis for future investigations of the light signal transduction mechanism involving PixD and PixE. PMID- 23346989 TI - Music reduces patient anxiety during Mohs surgery: an open-label randomized controlled trial. AB - BACKGROUND: Many patients undergoing Mohs micrographic surgery (MMS) experience anxiety and stress. Although music has been proven to reduce anxiety and promote relaxation in other fields of medicine, scant research investigates the effect of music on anxiety during MMS. OBJECTIVES: To determine whether music can reduce anxiety in patients undergoing MMS. METHODS AND MATERIALS: An open-labeled randomized controlled trial was conducted to assess anxiety before and after listening to music. Subjects undergoing MMS were randomly allocated to listen to self-selected music (n = 50) or to have surgery without music (n = 50). Anxiety was measured using the State-Trait Anxiety Inventory (STAI) and on a visual analog scale (VAS). RESULTS: Subjects in the music group experienced statistically significantly lower STAI and VAS scores than those in the control group. STAI and VAS scores were significantly lower in subjects who underwent MMS for the first time. Anxiety measures did not correlate with sex or type of skin cancer. CONCLUSION: Listening to self-selected music reduces anxiety in patients undergoing MMS, especially those who undergo MMS for the first time. Presenting patients the opportunity to listen to music is a simple strategy to minimize anxiety during MMS. PMID- 23346987 TI - Early knee changes in dancers identified by ultra-high-field 7 T MRI. AB - We aimed to determine whether a unique, ultra-high-field 7 T magnetic resonance imaging (MRI) scanner could detect occult cartilage and meniscal injuries in asymptomatic female dancers. This study had Institutional Review Board approval. We recruited eight pre-professional female dancers and nine non-athletic, female controls. We scanned the dominant knee on a 7 T MRI scanner using a three dimensional fast low-angle shot sequence and a proton density, fast spin-echo sequence to evaluate cartilage and menisci, respectively. Two radiologists scored cartilage (International Cartilage Repair Society classification) and meniscal (Stoller classification) lesions. We applied two-tailed z- and t-tests to determine statistical significance. There were no cartilage lesions in dancers or controls. For the medial meniscus, the dancers demonstrated higher mean MRI score (2.38 +/- 0.61 vs 1.0 +/- 0.97, P < 0.0001) and higher frequency of mean grade 2 lesions (88% vs 11%, P < 0.01) compared with the controls. For the lateral meniscus, there was no difference in score (0.5 +/- 0.81 vs 0.5 +/- 0.78, P = 0.78) in dancers compared with the control groups. Asymptomatic dancers demonstrate occult medial meniscal lesions. Because this has been described in early osteoarthritis, close surveillance of dancers' knee symptoms and function with appropriate activity modification may help maintain their long-term knee health. PMID- 23346990 TI - Tadalafil once daily improves ejaculatory function, erectile function, and sexual satisfaction in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia and erectile dysfunction: results from a randomized, placebo- and tamsulosin-controlled, 12-week double-blind study. AB - INTRODUCTION: Tadalafil, a long-acting phosphodiesterase type 5 inhibitor, is approved for treating signs and symptoms of benign prostatic hyperplasia (BPH) and erectile dysfunction (ED); tamsulosin, an alpha-blocker, is approved for treating signs and symptoms of BPH. AIM: To determine the effects of tadalafil or tamsulosin on sexual function, including ejaculation and orgasm, satisfaction, and erectile function, in sexually active men with ED and lower urinary tract symptoms suggestive of BPH (LUTS/BPH). METHODS: A randomized, double-blind, placebo-controlled study of tadalafil 5 mg once daily for 12 weeks in men with LUTS/BPH; tamsulosin 0.4 mg once daily was an active control. MAIN OUTCOME MEASURES: The International Index of Erectile Function (IIEF) questionnaire was administered at baseline and 4, 8, and 12 weeks. Analysis of orgasm and ejaculation was post hoc based on the IIEF-Orgasmic Function (OF) domain (IIEF-Q9 [ejaculatory frequency] and Q10 [orgasmic frequency]). Other measures included IIEF-Intercourse Satisfaction (IS), Overall Satisfaction (OS), and Erectile Function (EF) domains. Changes from baseline to 12 weeks (or last observation) vs. placebo were analyzed using analysis of covariance. Higher IIEF scores indicate better functioning. RESULTS: Of 511 study participants, 310 (60.7%) had ED and were sexually active. The IIEF-OF increased significantly through 12 weeks with tadalafil vs. placebo (P = 0.048), as did IIEF-Q9 (P = 0.045) but not IIEF Q10 (P = 0.100). Compared with placebo, IIEF-OF, Q9, and Q10 decreased significantly with tamsulosin (all P < 0.05). The IIEF-IS and OS increased significantly at end point with tadalafil (both P < 0.001); for tamsulosin, change was not significant for IS, while OS decreased significantly (P = 0.009). The IIEF-EF domain increased significantly vs. placebo with tadalafil (P < 0.001) but not tamsulosin (P = 0.699). CONCLUSIONS: Tadalafil 5 mg once daily significantly improved ejaculation and orgasm, intercourse and overall satisfaction, and erectile function. Men receiving tamsulosin 0.4 mg once daily experienced a decrease in both ejaculatory/orgasmic frequency and overall satisfaction vs. placebo, with no significant effect on erectile function. PMID- 23346991 TI - A retrospective, dual-isotope approach reveals individual predispositions to winter-drought induced tree dieback in the southernmost distribution limit of Scots pine. AB - Winter-drought induced forest diebacks in the low-latitude margins of species' distribution ranges can provide new insights into the mechanisms (carbon starvation, hydraulic failure) underlying contrasting tree reactions. We analysed a winter-drought induced dieback at the Scots pine's southern edge through a dual isotope approach (Delta(13) C and delta(18) O in tree-ring cellulose). We hypothesized that a differential long-term performance, mediated by the interaction between CO(2) and climate, determined the fates of individuals during dieback. Declining trees showed a stronger coupling between climate, growth and intrinsic water-use efficiency (WUEi) than non-declining individuals that was noticeable for 25 years prior to dieback. The rising stomatal control of water losses with time in declining trees, indicated by negative Delta(13) C-delta(18) O relationships, was likely associated with their native aptitude to grow more and take up more water (suggested by larger tracheid lumen widths) than non declining trees and, therefore, to exhibit a greater cavitation risk. Freeze-thaw episodes occurring in winter 2001 unveiled such physiological differences by triggering dieback in those trees more vulnerable to hydraulic failure. Thus, WUEi tightly modulated growth responses to long-term warming in declining trees, indicating that co-occurring individuals were differentially predisposed to winter-drought mortality. These different performances were unconnected to the depletion of stored carbohydrates. PMID- 23346992 TI - Allergic rhinitis and risk of erectile dysfunction--a nationwide population-based study. AB - BACKGROUND: A growing body of evidence has disclosed that allergic rhinitis (AR) is a systemic inflammatory disease. Inflammatory mediators and cells involved in AR have also been reported to be implicated in the process of atherosclerosis, which is relevant to the occurrence of erectile dysfunction (ED). Our objective was to explore the relationship between AR and future ED events. METHODS: From 1 January 2000 to 31 December 2008, we identified male patients, who were aged 18 55 years and newly diagnosed with AR from the Taiwan National Health Insurance Research Database. A control cohort without AR, which was matched for age, comorbidities and medications, was selected for comparison. The two cohorts were followed up until 31 December 2009 and observed for occurrence of ED by registry of ED diagnosis in the database. RESULTS: Of the 128,118 sampled male patients (64,059 AR patients vs 64,059 matched controls), 1455 (1.16%) experienced ED during a mean follow-up period of 5.82 years, including 844 (1.32% of the AR patients) from the AR cohort and 611 (0.95%) from the controls. Kaplan-Meier analysis revealed a tendency of AR patients to develop ED (log-rank test, P < 0.001). After adjusting confounder variables by Cox regression, subjects with AR experienced a 1.37-fold (95% CI, 1.24-1.52; P < 0.001) increase in incident ED. The risk of ED was higher in cases with more frequent clinical visits for AR and in cases needing medication more than 4 weeks. CONCLUSIONS: Patients with AR appeared to be at higher risk of future ED, possibly in a severity-dependent manner. PMID- 23346993 TI - Free fructose is conformationally locked. AB - Fructose has been examined under isolation conditions using a combination of UV ultrafast laser vaporization and Fourier-transform microwave (FT-MW) spectroscopy. The rotational spectra for the parent, all (six) monosubstituted (13)C species, and two single D species reveal unambiguously that the free hexoketose is conformationally locked in a single dominant beta-pyranose structure. This six-membered-chair skeleton adopts a (2)C(5) configuration (equivalent to (1)C(4) in aldoses). The free-molecule structure sharply contrasts with the furanose form observed in biochemically relevant polysaccharides, like sucrose. The structure of free fructose has been determined experimentally using substitution and effective structures. The enhanced stability of the observed conformation is primarily attributed to a cooperative network of five intramolecular O-H...O hydrogen bonds and stabilization of both endo and exo anomeric effects. Breaking a single intramolecular hydrogen bond destabilizes the free molecule by more than 10 kJ mol(-1). The structural results are compared to ribose, recently examined with rotational resolution, where six different conformations coexist with similar conformational energies. In addition, several DFT and ab initio methods and basis sets are benchmarked with the experimental data. PMID- 23346994 TI - Stepwise colonization of the Andes by ruddy ducks and the evolution of novel beta globin variants. AB - Andean uplift played a key role in Neotropical bird diversification, yet past dispersal and genetic adaptation to high-altitude environments remain little understood. Here we use multilocus population genetics to study population history and historical demographic processes in the ruddy duck (Oxyura jamaicensis), a stiff-tailed diving duck comprising three subspecies distributed from Canada to Tierra del Fuego and inhabiting wetlands from sea level to 4500 m in the Andes. We sequenced the mitochondrial DNA, four autosomal introns and three haemoglobin genes (alpha(A), alpha(D), beta(A)) and used isolation-with migration (IM) models to study gene flow between North America and South America, and between the tropical and southern Andes. Our analyses indicated that ruddy ducks dispersed first from North America to the tropical Andes, then from the tropical Andes to the southern Andes. While no nonsynonymous substitutions were found in either alpha globin gene, three amino acid substitutions were observed in the beta(A) globin. Based on phylogenetic reconstruction and power analysis, the first beta(A) substitution, found in all Andean individuals, was acquired when ruddy ducks dispersed from low altitude in North America to high altitude in the tropical Andes, whereas the two additional substitutions occurred more recently, when ruddy ducks dispersed from high altitude in the tropical Andes to low altitude in the southern Andes. This stepwise colonization pattern accompanied by polarized beta(A) globin amino acid replacements suggest that ruddy ducks first acclimatized or adapted to the Andean highlands and then again to the lowlands. In addition, ruddy ducks colonized the Andean highlands via a less common route as compared to other waterbird species that colonized the Andes northwards from the southern cone of South America. PMID- 23346995 TI - von Economo neurones are selectively targeted in frontotemporal dementia. AB - BACKGROUND: von Economo neurones (VEN) are bipolar neurones located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI), areas affected early in behavioural variant frontotemporal dementia (bvFTD), in which VEN may constitute a selectively vulnerable cellular population. AIM: A previous study has shown a selective loss of VEN in FTD above other neurones in the ACC of FTD. The aim of this study was to confirm this finding in a larger cohort, using a different methodology, and to examine VEN loss in relation to neuropathological severity and molecular pathology. METHODS: VEN and neighbouring neurones (NN) were quantified in layers Va and Vb of the right dorsal ACC in 21 cases of bvFTD, 10 cases of Alzheimer's disease (AD) and 10 non-demented controls (NDC). RESULTS: A marked VEN reduction was seen in all FTD cases. In the neuropathologically early cases of FTD (n = 13), VEN/10,000 NN was significantly reduced by 53% compared with NDC (P < 0.001) and 41% compared with AD (P = 0.019), whereas AD patients showed a non-significant 30% reduction of VEN/10,000 NN compared with NDC. VEN reduction was present in all protein pathology subgroups. DISCUSSION: In conclusion, this study confirms selective sensitivity of VEN in FTD and suggests that VEN loss is an early event in the neurodegenerative process. PMID- 23346996 TI - Do developmental orthopaedic disorders influence future jumping performances in Warmblood stallions? AB - REASONS FOR PERFORMING THE STUDY: Few reports are available on the relationship between developmental orthopaedic diseases (DOD) and future performances in Warmblood horses. OBJECTIVES: To investigate the relationship between performance and the presence of DOD lesions. METHODS: Records of Warmblood stallions for which radiographic and performance data were available were collected. Showjumping performances were expressed as scores derived from the final ranking of horses in each competition. These scores are available in an established performance database. The relationship between radiographic findings and both performance scores and number of performances was analysed using a linear regression model. RESULTS: Two hundred and fifteen horses met the inclusion criteria. There was no difference in either the number of performances or performance score between horses categorised as affected with DOD lesions (independent of joint location) compared with controls. Significantly lower numbers of performances were recorded for horses with osteochondral fragments (OCD) located at the dorsal aspect of the sagittal ridge of the metacarpo/metatarsophalangeal bone. No significant difference was found between horses affected with DOD lesions of the tarsocrural joint and controls. Horses with osteochondrosis of the lateral trochlear ridge of the femur had both significantly lower performance scores and numbers of performances compared with controls. CONCLUSION: This study demonstrated that specific DOD location and site within the joint have an influence on performance. Osteochondral fragments in the femoropatellar and at the dorsal aspect of the sagittal ridge of the metacarpo/metatarsophalangeal joint resulted in lowered performance. Fragmentation in the tarsocrural joint had no influence on performance. POTENTIAL RELEVANCE: The future athletic performance of Warmblood jumping horses may be limited as a result of OCD in the femoropatellar joint and to a certain extent the metacarpo/metatarsophalangeal joint. PMID- 23346997 TI - Two-step evolution of the hepatitis B drug-resistant mutations in a patient who developed primary entecavir resistance. AB - AIM: Few cases of primary entecavir resistance in chronic hepatitis B patients have been reported to date. The serial profiling of the HBV polymerase gene mutations from a treatment-naive patient who developed drug resistance after 32 months of entecavir therapy is presented here. DESIGN: Serum samples were collected at multiple time points from before the start of therapy to virological and biochemical breakthrough. The evolution of the hepatitis B virus polymerase gene mutations was analysed with commercial line probe assay and pyrosequencing. RESULTS: Drug resistance mutation analysis by pyrosequencing revealed a two-step process in the selection of drug resistance. The patient had a good initial response to entecavir 0.5 mg/day. A partially resistant HBV strain first emerged as the predominant species from as early as 2 weeks. After a period of non compliance to therapy, there was virological breakthrough, which resolved on restarting entecavir. Shortly after, there was secondary failure of entecavir therapy, caused by a new resistant strain carrying all three mutations required. CONCLUSION: In this patient, pre-existence of minor population of partially resistant viral strains and treatment non-compliance probably contributed to his development of primary entecavir resistance. PMID- 23346998 TI - Hydrophobic Fe-zeolites for removal of MTBE from water by combination of adsorption and oxidation. AB - Several zeolites were evaluated as adsorbents for the removal of MTBE from water in a screening process. It was observed that the SiO2/Al2O3 molar ratio is a decisive factor for the adsorption properties, at least in the case of ZSM5 zeolites. ZSM5 zeolites with SiO2/Al2O3 ratios >200 were found to provide the best sorption properties for MTBE. To design a combined sorption/reaction method, regeneration of the loaded zeolites by selected advanced oxidation processes (AOP) was studied: (1) Fenton treatment using H2O2 with dissolved iron salts and (2) heterogeneous Fenton-like oxidation with Fe immobilized on the zeolites. The first was ineffective in regenerating loaded zeolites. However, heterogeneous catalysis using Fe species immobilized on the zeolite by liquid ion exchange was markedly more effective. Although these hydrophobic zeolites have a low ion exchange capacity, resulting in iron loadings of <= 0.09 wt %, it was possible to obtain sufficiently active catalysts. Hydrophobic Fe-zeolites can therefore be regarded as promising materials for the removal of MTBE from water, since they allow the combination of efficient adsorption and oxidative degradation of MTBE by H2O2. In contrast to the homogeneous catalysis by dissolved iron ions, these heterogeneous catalysts work at near-neutral pH and can be easily reused. Fe zeolites as adsorbents/catalysts showed a good stability in both batch and column experiments. PMID- 23346999 TI - Assessment of everyday beliefs about health: the lay concepts of health inventory, college student version. AB - This research investigated lay conceptualisations about health using a progressive mixed-method approach, culminating in a new self-report measure of lay concepts of health. In Study 1, 223 community and college-aged adults provided everyday descriptors of healthy people. These open-ended qualitative responses were narrowed to 259 distinct descriptors, and subsequently rated on their importance to health by a second lay sample (Study 2). The health descriptors rated as most important were then subjected to exploratory factor analysis in Study 3, resulting in five distinguishable factors. Proposed scale items were then administered again (to college students, in Study 4), and a confirmatory factor analysis (CFA) was performed. The CFA supported a four-factor model, comprised of Social-Emotional Health, Positive Health Practices, Absence of Stress and Anxiety, and Adequate Rest, presented as the college student version of the Lay Concepts of Health Inventory. The measure, as well as limitations and recommendations for future research, are presented. PMID- 23347000 TI - Hot electron injection from graphene quantum dots to TiO2. AB - The Shockley-Queisser limit is the maximum power conversion efficiency of a conventional solar cell based on a single semiconductor junction. One approach to exceed this limit is to harvest hot electrons/holes that have achieved quasi equilibrium in the light absorbing material with electronic temperatures higher than the phonon temperature. We argue that graphene based materials are viable candidates for hot carrier chromophores. Here we probe hot electron injection and charge recombination dynamics for graphene quantum dots (QDs, each containing 48 fused benzene rings) anchored to the TiO2(110) surface via carboxyl linkers. We find ultrafast electron injection from photoexcited graphene QDs to the TiO2 conduction band with time constant tau(i) < 15 fs and charge recombination dynamics characterized by a fast channel (tau(r1) = 80-130 fs) and a slow one (tau(r2) = 0.5-2 ps). The fast decay channel is attributed to the prompt recombination of the bound electron-hole pair across the interface. The slow channel depends strongly on excitation photon energy or sample temperature and can be explained by a "boomerang" mechanism, in which hot electrons are injected into bulk TiO2, cooled down due to electron-phonon scattering, drifted back to the interface under the transient electric field, and recombine with the hole on graphene QDs. We discuss feasibilities of implementing the hot carrier solar cell using graphene nanomaterials. PMID- 23347001 TI - Biotransformation and pharmacokinetics of inositol hexanicotinate in rats. AB - Inositol hexanicotinate (IHN) is an ester of the anti-hyperlipidemic drug nicotinic acid (NA). This study assessed the hydrolysis rate of IHN in human and rat plasma, and pharmacokinetics of the drug using a rat animal model. IHN (10 or 50 ug/mL) was incubated in plasma at 37 degrees C for 72 h. Kinetic parameters were determined based on the disappearance of IHN and the appearance of NA. The mean IHN disappearance and NA appearance half-lives were 1.07 and 3.93 h in human plasma, and 0.152 and 2.68 h in rat plasma. Increasing the initial plasma concentration to 50 ug/mL increased the NA appearance half-life in human and rat plasma to 4.66 and 6.47 h, respectively. After single 50 or 100 mg/kg intravenous dose of IHN to Sprague-Dawley rats, the drug showed statistically significant dose-dependent alterations in systemic clearance, suggesting a non-linear saturable elimination of IHN. Dose-normalized mean plasma levels of NA increased by 30% with increasing IHN dose (p < 0.02). The mean metabolic ratio (i.e. NA/IHN AUC ratio) significantly increased with increasing IHN dose (p < 0.05). The results provide first indication of saturable elimination and rapid disappearance of IHN, while niacin was slowly formed. PMID- 23347002 TI - Resource use trajectories for aged medicare beneficiaries with complex coronary conditions. AB - OBJECTIVE: To use coronary revascularization choice to illustrate the application of a method simulating a treatment's effect on subsequent resource use. DATA SOURCES: Medicare inpatient and outpatient claims from 2002 to 2008 for patients receiving multivessel revascularization for symptomatic coronary disease in 2003 2004. STUDY DESIGN: This retrospective cohort study of 102,877 beneficiaries assessed survival, days in institutional settings, and Medicare payments for up to 6 years following receipt of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). METHODS: A three-part estimator designed to provide robust estimates of a treatment's effect in the setting of mortality and censored follow-up was used. The estimator decomposes the treatment effect into effects attributable to survival differences versus treatment-related intensity of resource use. PRINCIPAL FINDINGS: After adjustment, on average CABG recipients survived 23 days longer, spent an 11 additional days in institutional settings, and had cumulative Medicare payments that were $12,834 higher than PCI recipients. The majority of the differences in institutional days and payments were due to intensity rather than survival effects. CONCLUSIONS: In this example, the survival benefit from CABG was modest and the resource implications were substantial, although further adjustments for treatment selection are needed. PMID- 23347003 TI - Analysis of nursing education in Ghana: Priorities for scaling-up the nursing workforce. AB - In this cross-sectional study, the strengths, challenges and current status of baccalaureate nursing education in Ghana were described using a descriptive design. The World Health Organization Global Standards for the Initial Education of Nurses and Midwives were used as the organizing framework, with baseline data on the status of nursing education from two state-funded universities in Ghana presented. A serious shortage of qualified faculty was identified, along with the need for significant upgrading to the existing infrastructure. Additionally, the number of qualified applicants far exceeds the available training slots. Faculty and infrastructure shortages are common issues in nursing education and workforce expansion; however, in low-resource countries, such as Ghana, these issues are compounded by high rates of preventable disease and injury. An understanding of the strengths and challenges of nursing education in Ghana can inform the development of strategies for nursing workforce expansion for other low-resource countries. PMID- 23347004 TI - The use of fluorescent reporter protein tagging to study the interaction between Root-Knot Nematodes and Soft Rot Enterobacteriaceae. AB - The study of plant parasitic nematodes such as Meloidogyne spp. and their interactions with phytopathogenic bacteria remains underexplored. One of the challenges towards establishing such interactions is the dependence on symptom development as a measure of interaction. In this study, mCherry was employed as a reporter protein to investigate the interaction between the soft rot Enterobacteriaceae (SRE) Pectobacterium carotovorum subsp. brasiliensis (Pcb) and root-knot nematode (M. incognita). Pectobacterium carotovorum subsp. brasiliensis was transformed with pMP7604 generating Pcb_mCherry strain. This strain was shown to attach to the surface coat of M.incognita J2 at the optimum temperature of 28 degrees C. This suggests that RKN juveniles may play a role in disseminating Pcb in soils that are heavily infested with Pcb. The presence of RKN juveniles was shown to play a role in introducing Pcb_mCherry into potato tubers potentially acting as a source of latent tuber infections. PMID- 23347005 TI - Sensitized photooxidation of s-methylglutathione in aqueous solution: intramolecular (S?O) and (S?N) bonded species. AB - Nanosecond laser flash photolysis was used to generate sulfur radical cations of the thioether, S-methylglutathione (S-Me-Glu), via the one-electron oxidation of this thioether by triplet 4-carboxybenzophenone. The purpose of this investigation was to follow the neighboring group effects resulting from the interactions between the sulfur radical cationic sites and nearby lone-pair electrons on heteroatoms within the radical cation, especially the electron lone pairs on heteroatoms in the peptide bonds. The tripeptide, S-Me-Glu, offers several possible competing neighboring group effects that are characterized in this work. Quantum yields of the various radicals and three-electron bonded (both intramolecular and intermolecular) species were determined. The pH dependence of photoinduced decarboxylation yields was used as evidence for the identification of a nine-membered ring, sulfur-nitrogen, three-electron bonded species. The mechanisms of the secondary reactions of the radicals and radical cations were characterized by resolving their overlapping transient-absorption spectra and following their kinetic behavior. In particular, sulfur-oxygen and sulfur nitrogen three-electron bonded species were identified where the oxygen and nitrogen atoms were in the peptide bonds. PMID- 23347006 TI - Hydrogen peroxide-regulated genes in the Medicago truncatula-Sinorhizobium meliloti symbiosis. AB - Reactive oxygen species (ROS), particularly hydrogen peroxide (H(2)O(2)), play an important role in signalling in various cellular processes. The involvement of H(2)O(2) in the Medicago truncatula-Sinorhizobium meliloti symbiotic interaction raises questions about its effect on gene expression. A transcriptome analysis was performed on inoculated roots of M. truncatula in which ROS production was inhibited with diphenylene iodonium (DPI). In total, 301 genes potentially regulated by ROS content were identified 2 d after inoculation. These genes included MtSpk1, which encodes a putative protein kinase and is induced by exogenous H(2)O(2) treatment. MtSpk1 gene expression was also induced by nodulation factor treatment. MtSpk1 transcription was observed in infected root hair cells, nodule primordia and the infection zone of mature nodules. Analysis with a fluorescent protein probe specific for H(2)O(2) showed that MtSpk1 expression and H(2)O(2) were similarly distributed in the nodule infection zone. Finally, the establishment of symbiosis was impaired by MtSpk1 downregulation with an artificial micro-RNA. Several genes regulated by H(2)O(2) during the establishment of rhizobial symbiosis were identified. The involvement of MtSpk1 in the establishment of the symbiosis is proposed. PMID- 23347007 TI - Blood eosinophil counts rarely reflect airway eosinophilia in children with severe asthma. AB - BACKGROUND: The inflammatory phenotypes of severe asthma in adults may be reflected in peripheral blood. If this were true in children with severe therapy resistant asthma (STRA), invasive tests could be avoided. At the moment there is no conclusive evidence in children. METHODS: All patients underwent blood tests, exhaled nitric oxide (FeNO), sputum induction, bronchoalveolar lavage (BAL) and endobronchial biopsy (EB). RESULTS: Sixty-three (71.6%) patients had a normal blood profile and only 1/88 had a combined blood eosinophilia and neutrophilia. 76/88 (86%) had normal blood eosinophils, but of these, 84% had airway eosinophilia in either BAL (n = 43;66%) or EB (n = 41;79%). In children with STRA blood eosinophilia was associated with airway eosinophilia. However, normal blood eosinophil levels did not exclude airway eosinophilic inflammation. CONCLUSIONS: Peripheral blood counts are not reliable in characterising airway inflammation in severe asthmatic children exposed to high dose steroid therapy, therefore bronchoscopy with BAL should be considered. PMID- 23347008 TI - Relationship between changes in pulmonary VO2 kinetics and autonomic regulation of blood flow. AB - Various regulatory mechanisms of pulmonary oxygen uptake (VO2) kinetics have been postulated. The purpose of this study was to investigate the relationship between vagal withdrawal, measured using RMSSDRR, the root mean square of successive differences in cardiac interval (RR) kinetics, a mediator of oxygen delivery, and VO2 kinetics. Forty-nine healthy adults (23 +/- 3 years; 72 +/- 13 kg; 1.80 +/- 0.08 m) performed multiple repeat transitions to moderate- and heavy-intensity exercise. Electrocardiography, impedance cardiography, and pulmonary gas exchange parameters were measured throughout; time domain measures of heart rate variability were subsequently derived. The parameters describing the dynamic response of VO2, cardiac output (Q) and RMSSDRR were determined using a mono exponential model. During heavy-intensity exercise, the phase II tau of VO2 was significantly correlated with the tau of RR (r = 0.36, P < 0.05), Q (r = 0.67, P < 0.05), and RMSSDRR (r = 0.38, P < 0.05). The tau describing the rise in Q explained 47% of the variation in VO2 tau, with 30% of the rate of this rise in Q explained by the tau of RR and RMSSDRR. No relationship was evident between VO2 kinetics and those of Q, RR, or RMSSDRR during moderate exercise. Vagal withdrawal kinetics support the concept of a centrally mediated oxygen delivery limitation partly regulating VO2 kinetics during heavy-, but not moderate-, intensity exercise. PMID- 23347009 TI - Multiple infections and the evolution of virulence. AB - Infections that consist of multiple parasite strains or species are common in the wild and are a major public health concern. Theory suggests that these infections have a key influence on the evolution of infectious diseases and, more specifically, on virulence evolution. However, we still lack an overall vision of the empirical support for these predictions. We argue that within-host interactions between parasites largely determine how virulence evolves and that experimental data support model predictions. Then, we explore the main limitation of the experimental study of such 'mixed infections', which is that it draws conclusions on evolutionary outcomes from studies conducted at the individual level. We also discuss differences between coinfections caused by different strains of the same species or by different species. Overall, we argue that it is possible to make sense out of the complexity inherent to multiple infections and that experimental evolution settings may provide the best opportunity to further our understanding of virulence evolution. PMID- 23347010 TI - A comparison of anthropometric and training characteristics between recreational female marathoners and recreational female Ironman triathletes. AB - A personal best marathon time has been reported as a strong predictor variable for an Ironman race time in recreational female Ironman triathletes. This raises the question whether recreational female Ironman triathletes are similar to recreational female marathoners. We investigated similarities and differences in anthropometry and training between 53 recreational female Ironman triathletes and 46 recreational female marathoners. The association of anthropometric variables and training characteristics with race time was investigated using bi- and multi variate analysis. The Ironman triathletes were younger (P < 0.01), had a lower skin-fold thickness at pectoral (P < 0.001), axillar (P < 0.01), and subscapular (P < 0.05) site, but a thicker skin-fold thickness at the calf site (P < 0.01) compared to the marathoners. Overall weekly training hours were higher in the Ironman triathletes (P < 0.001). The triathletes were running faster during training than the marathoners (P < 0.05). For the triathletes, neither an anthropometric nor a training variable showed an association with overall Ironman race time after bi-variate analysis. In the multi-variate analysis, running speed during training was related to marathon split time for the Ironman triathletes (P = 0.01) and to marathon race time for the marathoners (P = 0.01). To conclude, although personal best marathon time is a strong predictor variable for performance in recreational female Ironman triathletes, there are differences in both anthropometry and training between recreational female Ironman triathletes and recreational female marathoners and different predictor variables for race performance in these two groups of athletes. These findings suggest that recreational female Ironman triathletes are not comparable to recreational female marathoners regarding the association between anthropometric and training characteristics with race time. PMID- 23347011 TI - Differential inhibitory effects of 2-azafluorenones on PI-PLC activation but not on PC-PLC- or PC-PLD-activation induced by histamine, PAF, PMA or A23187 in C6 glioma cells. AB - In this study, C6 glioma cells were used to test the effects of 2-azafluorenone and its related compounds on membrane phosphatidylinositol (PI) and phosphatidylcholine (PC) turnover. An increase of [3H]-labeled inositol phosphate (IP1) formation by histamine (100 MUM) or A23187 (100 nM) via the activation of phosphatidylinositol-specific phospholipase C (PI-PLC) to breakdown labeled substrate was observed, and this effect could be partially blocked by about half at 100 MUM of 2-azafluorenones. Histamine induced the increase of IP1 formation, but failed to cause an increase in extracellularly releasing of [3H]choline metabolites, or intracellular accumulation of [3H]phosphscholine. However, platelet activation factor (PAF) from 0.2 to 1 MUM, and phorbol 12 myristate-13-acetate (PMA) at 1 MUM caused an increase in extracellularly releasing of [3H]choline metabolites, and intracellular accumulation of [3H]phosphocholine via the activation on phosphatidylcholine (PC)-PLC. These responses of PAF and PMA were not affected by 2-azafluorenone or 4-methyl-2 azafluorenone even at high concentration (10-4 M). A23187 induced an increase of intracellular [3H]choline release via the activation of PCphospholipase D (PLD). This increasing effect of 100 nM A23187 was not affected by 2-azafluorenone or 4 methyl-2-azafluorenone even at a high concentration of 10-4 M. In summary, the inhibitory effect of 2-azafluorenone and its related compound 4-methyl-2 azafluorenone was observed selectively on PIPLC, but not on PC-PLC or PC-PLD based on changes of products after the activation of these enzymes. PMID- 23347012 TI - Reducing body fat with altitude hypoxia training in swimmers: role of blood perfusion to skeletal muscles. AB - Swimmers tend to have greater body fat than athletes from other sports. The purpose of the study was to examine changes in body composition after altitude hypoxia exposure and the role of blood distribution to the skeletal muscle in swimmers. With a constant training volume of 12.3 km/day, young male swimmers (N = 10, 14.8 +/- 0.5 years) moved from sea-level to a higher altitude of 2,300 meters. Body composition was measured before and after translocation to altitude using dual-energy X-ray absorptiometry (DXA) along with 8 control male subjects who resided at sea level for the same period of time. To determine the effects of hypoxia on muscle blood perfusion, total hemoglobin concentration (THC) was traced by near-infrared spectroscopy (NIRS) in the triceps and quadriceps muscles under glucose-ingested and insulin-secreted conditions during hypoxia exposure (16% O2) after training. While no change in body composition was found in the control group, subjects who trained at altitude had unequivocally decreased fat mass (-1.7 +/- 0.3 kg, -11.4%) with increased lean mass (+0.8 +/- 0.2 kg, +1.5%). Arterial oxygen saturation significantly decreased with increased plasma lactate during hypoxia recovery mimicking 2,300 meters at altitude (~93% versus ~97%). Intriguingly, hypoxia resulted in elevated muscle THC, and sympathetic nervous activities occurred in parallel with greater-percent oxygen saturation in both muscle groups. In conclusion, the present study provides evidence that increased blood distribution to the skeletal muscle under postprandial condition may contribute to the reciprocally increased muscle mass and decreased body mass after a 3-week altitude exposure in swimmers. PMID- 23347013 TI - M-3M3FBS-induced Ca2 + movement and apoptosis in HA59T human hepatoma cells. AB - The effect of 2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl) benzenesulfonamide (m-3M3FBS), a presumed phospholipase C activator, on cytosolic free Ca2 + concentrations ([Ca2 + ]i ) in HA59T human hepatoma cells is unclear. This study explored whether m-3M3FBS elevated basal [Ca2 + ]i levels in suspended cells by using fura-2 as a Ca2 + -sensitive fluorescent dye. M-3M3FBS at concentrations of 10- 50 MUM increased [Ca2 + ]i in a concentration-dependent fashion. The Ca2 + signal was reduced partly by removing extracellular Ca2 + . M-3M3FBS-induced Ca2 + influx was inhibited by nifedipine, econazole, SK&F96365, aristolochic acid, and GF109203X. In Ca2 + -free medium, 50 MUM m-3M3FBS pretreatment inhibited the [Ca2 + ]i rise induced by the endoplasmic reticulum Ca2 + pump inhibitor thapsigargin. Conversely, pretreatment with thapsigargin partly reduced m-3M3FBS-induced [Ca2 + ]i rise. Inhibition of inositol 1,4,5 trisphosphate formation with U73122 did not alter m-3M3FBS-induced [Ca2 + ]i rise. At concentrations between 10 and 40 MUM m-3M3FBS killed cells in a concentration-dependent manner. The cytotoxic effect of m-3M3FBS was not reversed by prechelating cytosolic Ca2 + with 1,2-bis(2- aminophenoxy)ethane-N,N,N',N' tetraacetic acid (BAPTA). Annexin V/propidium iodide staining data suggest that m-3M3FBS induced apoptosis in a concentration-dependent manner. M-3M3FBS also increased levels of reactive oxygen species. Together, in human hepatoma cells, m-3M3FBS induced a [Ca2 + ]i rise by inducing phospholipase C-independent Ca2 + release from the endoplasmic reticulum and Ca2 + entry via protein kinase C sensitive store-operated Ca2 + channels. M-3M3FBS induced cell death that might involve apoptosis via mitochondrial pathways. PMID- 23347014 TI - Social isolation during peri-adolescence or adulthood: effects on sexual motivation, testosterone and corticosterone response under conditions of sexual arousal in male rats. AB - Reproductive functions in adult organism are known to be affected by different factors. Effects of social environment at the postnatal ontogenesis attract particular attention since it has deep impact on the development of physiological and emotional state of an individual. Effects of chronic social isolation at different ages on male sexual motivation, testosterone and corticosterone response under conditions of sexual arousal were studied in Wistar rats. After weaning at the 21st [corrected] day of age, rats of one group were isolated for six weeks and after that they were housed in groups of five per cage for ten weeks (Iso3-9). Rats of the second group were housed in groups of five animals per cage till 13 weeks of age, and then they were isolated for six weeks (Iso13 19). Rats of the control group were housed in groups during the experiment. Adult 19 week- old male rats were tested under conditions of sexual arousal. The expression of sexual motivation was estimated as the behavioral activity of a male at the transparent perforated partition separating a receptive female. Isolation of adult male rats reduced the number of approaches to the partition, while the period of time a male spent at the partition was not changed and testosterone response was enhanced as compared to control rats. Chronic social isolation during peri-adolescence reduced sexual motivation and prevented arousal induced elevation of testosterone. Plasma corticosterone increases at sexual arousal in the two groups of isolated rats did not differ from that in controls. Our results are evidence that social isolation during the post-maturity stage (Iso13-19) did not diminish the manifestation of sexual motivation and hormonal response to a receptive female, while isolation during peri-adolescence attenuated behavioral and hormonal expression of sexual arousal in adult males. PMID- 23347015 TI - Impairment of an electroconvulsive stimulus on reconsolidation of memories established by conditioning. AB - The deduced memory consolidation and reconsolidation phases are sensitive to similar amnesic and memory-enhancing treatment. Electroconvulsive stimulus has been well known to impair memory consolidation. Therefore, we hypothesized that electroconvulsive stimulus might disrupt reconsolidation for conditioning established memories. Delivery of a 200-msec electroconvulsive stimulus (500 V, 25 mA) between mouse pinnas immediately after recall of the cocaine-induced conditioned place preference (CPP) impaired the reconsolidation and subsequent expression of this memory. In contrast, the electroconvulsive stimulus (500 V, 25 mA, lasting for 200 ms) did not affect subsequent cocaine-induced CPP performance when the recall procedure was omitted. Systemic pentobarbital injection immediately after the CPP test did not affect subsequent cocaine induced CPP. Interestingly, several regimens of electroconvulsive stimulus given immediately after the recall of cocaine-induced CPP did not affect subsequent CPP performance when mice were anesthetized by pentobarbital throughout the ECS regimens. Finally, delivery of the ECS (500 V, 25 mA, lasting for 200 ms) immediately after the reactivation of passive avoidance (PA) and food-induced CPP impaired subsequent performance of these memories in the retest. Taken together, we conclude that a short-lasting electroconvulsive stimulus can deteriorate the reconsolidation of various forms of memory established by conditioning. PMID- 23347016 TI - Determination of glottic opening fluctuation by a new method based on nasopharyngoscopy. AB - Understanding the opening fluctuation of glottis is meaningful in diagnosing vocal cord dysfunction. Nasopharyngoscopy can offer a direct method for visualizing the opening and closing of the glottis. However, the large amount of image data presents a significant challenge for quantitative analysis of the video recordings. Thus, automatic image processing method allowing for batch analysis of glottic images becomes clinically important. Here, we present an image processing method using Gaussian smoothing filter and threshold segmentation, followed by differentiation and Canny image edge detection for tracking changes in glottis dimensions (the opening area). A quantitative assessment of true glottic size was also developed for calibration in our study. This method was used to analyze different video data acquired from clinical nasopharyngoscopy of 8 healthy subjects during either normal breathing, breathing with cough or with 'Hee' sound. The results indicated that the computed glottic area change waveform was consistent with the observed glottic fluctuation in the video from nasopharyngoscopy. Thus, our proposed method may provide an accurate and efficient detection of glottic aperture and quick assessment of glottic fluctuations to assist clinical diagnosis of vocal cord dysfunction and other airway pathologies. PMID- 23347017 TI - Erectile dysfunction precedes and is associated with severity of coronary artery disease among Asian Indians. AB - INTRODUCTION: Erectile dysfunction (ED) and coronary artery disease (CAD) often share common risk factors, and there is growing evidence that ED might serve as a clinical marker for cardiovascular disease. Despite rising trends of CAD in Asian Indians, limited data are available on the prevalence of ED and its correlation with CAD severity in such patients. AIM: To study the prevalence of ED in Asian Indian patients undergoing coronary angiography and to assess if the severity of ED correlates with angiographic severity of CAD. METHODS: In all patients undergoing coronary angiography, ED was assessed using the International Index of Erectile Function-5 questionnaire. MAIN OUTCOME MEASURES AND RESULTS: Among 175 male patients, ED was present in 70%; patients with ED had a higher incidence of multivessel CAD (80% vs. 36%, P 0.001), diffuse CAD (81% vs. 34%, P 0.001), and higher number of mean coronary vessels involved compared with those without ED. Those with severe ED had higher prevalence of multivessel CAD and higher number of mean coronary vessels involved compared with those with milder grades of ED. Onset of symptoms of ED preceded symptoms of CAD by a mean of 24.6 months in 84% of patients. The presence of severe ED was associated with a 21-fold higher risk of having triple-vessel disease (odds ratio [OR] 21.94, 95% confidence interval [CI] 3.41-141.09, P = 0.001) and an 18-fold higher risk of having diffuse angiographic CAD (OR 17.91, 95% CI 3.11-111.09, P = 0.001). CONCLUSION: Asian Indians with angiographic CAD frequently have ED; symptoms of ED precede that of CAD in most patients. Incidence of multivessel and diffuse CAD is significantly more common in patients with ED. It is important for physicians to be aware of the close relationship between the two conditions so that patients with ED can have optimal risk stratification for concomitant CAD whenever required. PMID- 23347018 TI - Hydrogen sulfide: environmental factor or signalling molecule? AB - Hydrogen sulfide (H2S) has traditionally been thought of as a phytotoxin, having deleterious effects on the plant growth and survival. It is now recognized that plants have enzymes which generate H2S, cysteine desulfhydrase, and remove it, O acetylserine lyase. Therefore, it has been suggested that H2S is considered as a signalling molecule, alongside small reactive compounds such as hydrogen peroxide (H2O2) and nitric oxide (NO). Exposure of plants to low of H2S, for example from H2S donors, is revealing that many physiological effects are seen. H2S seems to have effects on stomatal apertures. Intracellular effects include increases in glutathione levels, alterations of enzyme activities and influences on NO and H2O2 metabolism. Work in animals has shown that H2S may have direct effects on thiol modifications of cysteine groups, work that will no doubt inform future studies in plants. It appears therefore, that instead of thinking of H2S as a phytotoxin, it needs to be considered as a signalling molecule that interacts with reactive oxygen species and NO metabolism, as well as having direct effects on the activity of proteins. The future may see H2S being used to modulate plant physiology in the field or to protect crops from postharvest spoilage. PMID- 23347020 TI - Fungal host specificity is not a bottleneck for the germination of Pyroleae species (Ericaceae) in a Bavarian forest. AB - Plants that produce dust seeds can recruit fungi to meet their earliest requirements for carbon and other nutrients. This germination strategy, termed initial mycoheterotrophy, has been well investigated among the orchid family, but there are numerous other plant lineages that have independently evolved mycoheterotrophic germination strategies. One of these lineages is the tribe Pyroleae (Ericaceae). While the fungi associated with mature plants in Pyroleae have been fairly well documented, their mycobionts at the germination and seedling stages are largely unknown. Here, we use an in situ seed baiting experiment along with molecular fingerprinting techniques and phylogenetic tests to identify the fungi associated with seedlings of two Pyroleae species, Pyrola chlorantha and Orthilia secunda. Our results indicate that similar to adult plants, Pyroleae seedlings can associate with a suite of ectomycorrhizal fungi. Some seedlings harboured single mycobionts, while others may have been inhabited by multiple fungi. The dominant seedling mycobiont of both Pyroleae species was a fungus of unknown trophic status in the order Sebacinales. This taxon was also the only one shared among seedlings of both investigated Pyroleae species. We discuss these results juxtaposed to orchids and one additional Pyrola species in the context of ontogenetic shifts in fungal host specificity for mycoheterotrophic nutrition. PMID- 23347021 TI - A reappraisal on lidocaine-sensitive repetitive, uniform atrial tachycardia. AB - BACKGROUND: Lidocaine sensitive, repetitive atrial tachycardia is an unusual arrhythmia whose electrophysiologic substrate remains undefined. We aimed to analyze the electropharmacologic characteristics of this arrhythmia with emphasis on its cellular substrate and response to drug challenges. METHODS: We retrospectively analyzed a series of 18 patients from an electrocardiographic and electrophysiologic perspective and the response to pharmacological challenge. RESULTS: There was no evidence of structural heart disease in 12 patients, 4 patients presented with systemic hypertension; one patient had a prior myocardial infarction and one a mitral valve prolapse. The arrhythmia depicted a consistent pattern in nine patients. The first initiating ectopic beat showed a long coupling interval, the cycle length of the second atrial ectopic beat presented the shortest cycle length and a further prolongation was apparent towards the end of the atrial salvos. Conversely, in the other nine cases, the atrial tachycardia cycle length was erratic. The arrhythmia was suppressed by asynchronous atrial pacing at cycle lengths longer than those of the atrial tachycardia. Intravenous lidocaine eliminated the arrhythmia in all patients, but intravenous verapamil suppressed the atrial tachycardia in only two patients while adenosine caused a transient disappearance in 2/8 patients. Only one patient responded to all the three agents. Radiofrequency ablation was successfully performed in 10 patients. CONCLUSIONS: Repetitive uniform atrial tachycardia can be sensitive to lidocaine. In few cases, this rare focal arrhythmia may be also suppressed by adenosine and/or verapamil, which suggests a diversity of electrophysiologic substrates that deserve to be accurately identified. PMID- 23347023 TI - Diagnosis of left ventricular hypertrophy in the presence of left anterior fascicular block: a reexamination of the 2009 AHA/ACCF/HRS guidelines. AB - BACKGROUND: The 2009 "AHA/ACCF/HRS Recommendations for Standardization and Interpretation of the Electrocardiogram" state that left ventricular hypertrophy (LVH) criteria that include R-wave amplitude in leads I and aVL are not likely reliable in the presence of left anterior fascicular block (LAFB). This statement was referenced to three relatively small studies. The present study reexamines the utility of selected electrocardiographic (ECG) criteria for LVH in the presence of LAFB. METHODS: We identified 185 ECG tracings with LAFB from patients in whom echocardiogram had been performed within 30 days of the ECG. These ECGs were evaluated for the presence of selected LVH criteria: (1) Sokolow index (R wave-aVL > 11 mm); (2) Cornell criteria (R-wave-aVL + S-wave-V3 > 28 mm in men (>20 mm in women); (3) Gertsch criterion (S-wave-III + (R + S) maximal precordial >30 mm); and (4) Bozzi criterion (SV1 or SV2 + (RV6 + SV6) > 25 mm). The "gold standard" for LVH was left ventricular mass index on echocardiogram. RESULTS: Although the aVL-based LVH criteria demonstrated lower sensitivity (45-68%) and a trend toward higher specificity (67-81%) compared to non-aVL-based criteria, the four studied criteria demonstrated similar diagnostic accuracy. CONCLUSIONS: In the presence of LAFB, the aVL-based Sokolow index and Cornell criteria, which were excluded from 2009 multisociety ECG guidelines, identify LVH with similar diagnostic accuracy as the non-aVL-based criteria that were included. Moreover, they are easier to calculate and are included in some of the computer-assisted ECG interpretation software presently in use. Their exclusion from the 2009 guidelines was unnecessary. PMID- 23347022 TI - Omega-3 PUFAs and atrial fibrillation: have we made up our mind yet? AB - Atrial fibrillation (AF) is the most common type of arrhythmia in adults, accounting for about one third of total arrhythmia-related hospitalizations. AF impact on daily clinical practice is steadily rising, together with population aging and increased survival from underlying conditions closely associated with AF such as coronary heart disease and heart failure. Although antiarrhythmic therapy, oral anticoagulation, implanted device therapy, and ablation techniques are now all common and promptly available strategies in AF management, some of them are burdened by a low efficacy rate, while others are associated with increased proarrhythmic or hemorrhagic risk. Consequently, useful alternatives are being sought. Between those, polyunsaturated fatty acids (n-3 PUFAs) have risen from mere alternative to statins in dyslipidemia management to powerful and well-tolerated antiinflammatory, antithrombotic, and antiarrhythmogenic drugs. From the evidence collected through basic science studies, whether on in vivo myocytes, animal models, or surrogate end points in human, n-3 PUFAs seem to offer innumerable advantages. On the other hand, epidemiological and clinical trials failed to demonstrate a clear efficacy of n-3 PUFAs as antiarrhythmic drugs, although covered by an optimal safety profile. The aim of the present review is to summarize the most important evidences currently available on the role of n-3 PUFA in AF management and therapy. PMID- 23347025 TI - Association between atrial fibrillatory rate and heart rate variability in patients with atrial fibrillation and congestive heart failure. AB - BACKGROUND: Even if atrial fibrillatory rate (AFR) has been related to clinical outcome in patients with atrial fibrillation (AF), its relation with ventricular response has not been deeply studied. The aim of this study was to investigate the relation between AFR and RR series variability in patients with AF. METHODS: Twenty-minute electrocardiograms in orthogonal leads were processed to extract AFR, using spatiotemporal QRST cancellation and time frequency analysis, and RR series in 127 patients (age 69 +/- 11 years) with congestive heart failure (NYHA II-III) enrolled in the MUSIC study (MUerte Subita en Insufficiencia Cardiaca). Heart rate variability and irregularity were assessed by time domain parameters and entropy-based indices, respectively and their correlation with AFR investigated. RESULTS: Variability measures seem not to be related to AFR, while irregularity measures do. A significant correlation between AFR and variability parameters of heart rate variability during AF was found only in patients not treated with antiarrhythmics drugs (correlation = 0.56 P < 0.05 for pNN50), while this correlation was lost in patients taking rate- or rhythm-control drugs. A significant positive correlation between AFR and indices of RR irregularity was found, showing that a higher AFR is related to a less organized RR series (correlation = 0.33 P < 0.05 for regularity index for all patients, correlation increased in subgroups of patients treated with the same drug). CONCLUSIONS: These results suggest that a higher AFR is associated with a higher degree of irregularity of ventricular response that is observed regardless of the use of rate-controlling drugs. PMID- 23347024 TI - Associations between NOS1AP single nucleotide polymorphisms (SNPs) and QT interval duration in four racial/ethnic groups in the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUNDS: QT is a risk factor for sudden cardiac death (SCD). A genome-wide association study identified NOS1AP variants associated with QT, which have been replicated in predominantly Caucasian (CAU) populations. We used the Multi-Ethnic Study of Atherosclerosis to examine association of QT with NOS1AP variants in an ethnically diverse cohort. METHODS: Twenty-eight tagging SNPs spanning NOS1AP were genotyped in 2847 MESA participants (approximately equal numbers of CAU, African Americans (AFA), Hispanics (HIS), and Chinese (CHN)), age 45-84 years, without cardiovascular disease. QT was measured using 12-lead ECG. Associations between QT and NOS1AP variants were evaluated using linear regression, adjusted for heart rate, age, gender, and field center stratified by ancestry, using an additive inheritance model. Ancestry informative markers (AIMs) and principal components using AIMs were used as additional covariates. RESULTS: More NOS1AP SNPs were associated with QT in CAU than the other races. In CAU, each copy of rs1932933 risk allele was associated with an increase in QT (4.9 msec, P = 7.20 * 10-7). Significant associations in CAU and HIS were located at the 5' end, while associations in CHN were located at the 3' end. CONCLUSIONS: NOS1AP variants were associated with QT in CAU, with weaker evidence for selected variants in HIS and CHN. Location of significant SNPs varied across ancestry. We identified possible novel associations at the 3' end of NOS1AP, where we observed significant association with QT in CHN only. Genotyping within these regions may determine functional variants affecting QT and SCD risk. In addition, investigations are needed across ethnically diverse population cohorts. PMID- 23347026 TI - Prognostic significance of T-wave amplitude in lead aVR on the admission electrocardiography in patients with anterior wall ST-elevation myocardial infarction treated by primary percutaneous intervention. AB - BACKGROUND: T-wave positivity in aVR lead patients with heart failure and anterior wall old ST-segment elevation myocardial infarction (STEMI) are shown to have a higher frequency of cardiovascular mortality, although the effects on patients with STEMI treated with primary percutaneous coronary intervention (PCI) has not been investigated. In this study, we sought to determine the prognostic value of T wave in lead aVR on admission electrocardiography (ECG) for in hospital mortality in patients with anterior wall STEMI treated with primary PCI. METHODS: After exclusion, 169 consecutive patients with anterior wall STEMI (mean age: 55 +/- 12.9 years; 145 men) undergoing primary PCI were prospectively enrolled in this study. Patients were classified as a T-wave positive (n = 53, group 1) or T-wave negative (n = 116, group 2) in aVR based upon the admission ECG. All patients were evaluated with respect to clinical features, primary PCI findings, and in-hospital clinical results. RESULTS: T-wave positive patients who received primary PCI were older, multivessel disease was significantly more frequent and the duration of the patient's hospital stay was longer than T-wave negative patients. In-hospital mortality tended to be higher in the group 1 when compared with group 2 (7.5% vs 1.7% respectively, P = 0.05). After adjusting the baseline characteristics, positive T wave remained an independent predictor of in hospital mortality (odds ratio: 4.41; 95% confidence interval 1.2-22.1, P = 0.05). CONCLUSIONS: T-wave positivity in lead aVR among patients with an anterior wall STEMI treated with primary PCI is associated with an increase in hospital cardiovascular mortality. PMID- 23347027 TI - Prevention of post-coronary artery bypass grafting (CABG) atrial fibrillation: efficacy of prophylactic beta-blockers in the modern era: a meta-analysis of latest randomized controlled trials. AB - BACKGROUND: Atrial fibrillation/flutter (AF) is a common complication of open heart surgery and ACC/AHA guidelines strongly recommend the use of prophylactic beta-blockers (BB) for its prevention. Several recent studies, however, have failed to show the desired protective effects of BB against post-coronary artery bypass grafting (CABG) AF. As the protocols of CABG, medical management of CAD (coronary artery disease) and demographic features of the patients undergoing open heart surgery have evolved significantly over the last two decades, we decided to perform a review of evidence from latest randomized controlled trials (RCTs) to confirm the efficacy of prophylactic BB. METHODS: We searched for RCTs comparing the efficacy of prophylactic BB versus placebo/control against post CABG AF. We limited our search to 1995 till present to reflect ongoing advancements in the protocols of CABG and the medical management of CAD. Initially, 34 trials were selected; however after certain exclusions only 10 RCTs were included in the final analysis. RESULTS: Prophylactic BB decreased the incidence of post-CABG AF from 32.8% in the control group to 20% in the prophylactic group with risk ratio (RR) of 0.50 with 95% CI of 0.36-0.69, P value < 0.001. In a subgroup analysis, carvedilol appears to be superior to metoprolol for the prevention of postoperative AF. CONCLUSIONS: Despite several limitations, this analysis confirms the efficacy of prophylactic BB against post-CABG AF in this era. We recommend continuing perioperative BB in the open heart surgery patients in the absence of contraindications. PMID- 23347028 TI - Association of fragmented QRS complex with myocardial reperfusion in acute ST elevated myocardial infarction. AB - In this study, we aimed to evaluate the relationship between TIMI myocardial perfusion (TMP) grade, as an indicator of myocardial reperfusion, and fragmented QRS (fQRS) in standard 12-lead electrocardiogram. Also, we evaluate fQRS is an additional indicator of myocardial reperfusion. One hundred patients admitted with first STEMI to Coronary Intensive Care Unit and who were used thrombolytic therapy was included in this retrospective study. Standard 12-lead electrocardiogram records of patients simultaneous with coronary angiography (second day) were assessed and analysed for the presence of fQRS. Also, coronary angiography images were analyzed to identify the infarct related artery, TIMI grade of infarct related artery and TMP grade of infarct related artery. The patients with fQRS demonstrated a significantly lower TMP grade, TIMI grade and ejection fraction compared with the non-fQRS patients (P = 0.004, P = 0.003, P = 0.02 respectively). The patients with inadequate myocardial reperfusion demonstrated a significantly higher fQRS compared with the adequate myocardial reperfusion patients. (56.9% versus 23.5%, P = 0.002 respectively). On correlation analysis, there was a significant negative correlation between fQRS and left ventricular ejection fraction (r = -232, P = 0.02) TMP grade and adequate myocardial reperfusion (TMP 3) showed significant negative correlation with fQRS (r = -0.370, P = 0.000; r = -0.318, P = 0.001 respectively). Presence of fragmented QRS in STEMI patients was associated with inadequate myocardial reperfusion and it can be used as a simple, noninvasive parameter to evaluate myocardial reperfusion. PMID- 23347029 TI - An adolescent with possible arrhythmogenic right ventricular dysplasia and long QT syndrome: evaluation and management. AB - We describe a unique presentation of arrhythmogenic right ventricular dysplasia (ARVD) in a 14-year-old Caucasian male who was additionally diagnosed with long QT syndrome (LQTS). Genetic testing eventually confirmed the diagnosis of both ARVD and LQTS, which combined, to our knowledge, has not been reported in the literature. PMID- 23347030 TI - Cardiac rhythm device contact dermatitis. AB - We present a series of three cases of patch testing confirmed cardiac rhythm device induced contact dermatitis. In the first two cases, there was complete resolution with device extraction and reimplantation with another device with either an absence of the offending agent or a coating with another resin or metal. These cases illustrate the difficulties in diagnosing pain, tenderness, and dermatological manifestations in patients with cardiac rhythm devices (pacemakers and implantable cardioverter defibrillators). PMID- 23347031 TI - Undersensing by an ICD due to alternans of the ventricular electrogram. AB - Alternans of the ventricular electrogram (VEGM) during ventricular tachycardia (VT) is a rare cause of ventricular undersensing by an implantable cardioverter defibrillator (ICD). This report describes a patient with a St. Jude ICD who exhibited sustained monomorphic VT associated with surface QRS alternans, alternating cycle lengths, alternans of the VEGM causing intermittent undersensing of the smaller component, and intermittent 2:1 counting of ventricular intervals during 1:1 sensing in response to the ICD detection algorithm. VEGM undersensing was corrected noninvasively simply by programming the threshold start from 62.5% to 50% which increased the sensitivity based on the amplitude of the VEGM. This maneuver did not affect the satisfactory and stable defibrillation threshold. PMID- 23347032 TI - Ventricular extrasystoles with interpolation or postponed compensatory pause during atrial fibrillation: fact or fiction? AB - A Holter recording obtained from a patient with atrial fibrillation showed ventricular extrasystoles often in bigeminal rhythm. Most extrasystoles were followed by a long return cycle, and only in a few instances the postextrasystolic interval was short. The latter phenomenon was interpreted as a manifestation of poor retrograde concealed penetration of the ventricular impulse into the atrioventricular (A-V) junction: accordingly, an ensuing relatively early fibrillation impulse reached the ventricular chamber, since it did not find the A-V node refractory. These events are similar to what happens in interpolated ventricular extrasystoles occurring during sinus rhythm, the absent or minimal concealed retrograde penetration of the ectopic impulse into the A-V node being necessary to permit anterograde conduction of the ensuing sinus impulse. Analysis of the recording also revealed that a very long (>2 second) interval between two consecutive narrow beats only occurred after an "interpolated" extrasystole. This was interpreted with the same mechanism underlying the "postponed compensatory pause" observed at times after interpolated ventricular extrasystoles during sinus rhythm: the minimal or nil penetration of the ventricular ectopic impulse into the A-V junction, followed by conduction of an ensuing early atrial impulse, "shifts to the right" the A-V nodal refractory period, preventing conduction of several further supraventricular impulses and generating a pause. Both interpolated ventricular extrasystoles and the phenomenon of "postponed compensatory pause" are, thus, conceivable during atrial fibrillation, although no definite demonstration is possible. PMID- 23347033 TI - Hyperkalemia-induced Brugada pattern with electrical alternans. AB - The Brugada syndrome is a genetic disease (mutation of the SCN5A gene) that predisposes to syncope and life-threatening sudden cardiac death. The case highlights the importance of recognizing hyperkalemia, as potential triggers of the acquired Brugada sign with electrical alternans. PMID- 23347034 TI - T-wave alternans by a 16-lead electrocardiogram system. PMID- 23347035 TI - Response to Dr. Madias' comments on "T-wave alternans by a 16-lead electrocardiogram system". PMID- 23347036 TI - Statement on matching language to the type of evidence used in describing outcomes data. PMID- 23347038 TI - The mannose 6-phosphate-binding sites of M6P/IGF2R determine its capacity to suppress matrix invasion by squamous cell carcinoma cells. AB - The M6P (mannose 6-phosphate)/IGF2R (insulin-like growth factor II receptor) interacts with a variety of factors that impinge on tumour invasion and metastasis. It has been shown that expression of wild-type M6P/IGF2R reduces the tumorigenic and invasive properties of receptor-deficient SCC-VII squamous cell carcinoma cells. We have now used mutant forms of M6P/IGF2R to assess the relevance of the different ligand-binding sites of the receptor for its biological activities in this cellular system. The results of the present study demonstrate that M6P/IGF2R does not require a functional binding site for insulin like growth factor II for inhibition of anchorage-independent growth and matrix invasion by SCC-VII cells. In contrast, the simultaneous mutation of both M6P binding sites is sufficient to impair all cellular functions of the receptor tested. These findings highlight that the interaction between M6P/IGF2R and M6P modified ligands is not only important for intracellular accumulation of lysosomal enzymes and formation of dense lysosomes, but is also crucial for the ability of the receptor to suppress SCC-VII growth and invasion. The present study also shows that some of the biological activities of M6P/IGF2R in SCC-VII cells strongly depend on a functional M6P-binding site within domain 3, thus providing further evidence for the non-redundant cellular functions of the individual carbohydrate-binding domains of the receptor. PMID- 23347039 TI - A comparison of the pharmacological profiles of prasugrel and ticagrelor assessed by platelet aggregation, thrombus formation and haemostasis in rats. AB - BACKGROUND AND PURPOSE: Prasugrel is a third-generation thienopyridine prodrug and ticagrelor is a non-competitive P2Y12 receptor antagonist. In their phase 3 studies, both agents reduced rates of ischemic events relative to treatment with clopidogrel. EXPERIMENTAL APPROACH: The pharmacodynamic profile of anti-platelet effects of prasugrel was compared with that of ticagrelor in rats. KEY RESULTS: The active metabolite of prasugrel was less potent than ticagrelor and its active metabolite on platelet aggregation in vitro. In contrast, prasugrel was a more potent antiplatelet agent than ticagrelor on ex vivo platelet aggregation: their ED50 values at peak for ADP 20 MUmol.L(-1) were 1.9 and 8.0 mg.kg(-1) , respectively. Prasugrel's inhibition of platelet aggregation was maintained for up to 24 h after administration, but ticagrelor's duration of action was substantially shorter. Prasugrel and ticagrelor significantly inhibited thrombus formation with ED50 values of 1.8 and 7.7 mg.kg(-1) , respectively. Both agents also prolonged bleeding times (ED200 values of 3.0 and 13 mg.kg(-1) respectively) suggesting that at equivalent levels of inhibition of platelet aggregation, the agents would show comparable antithrombotic activity with similar bleeding risk. Platelet transfusion significantly increased blood platelet numbers similarly in prasugrel- and ticagrelor-treated rats. In the prasugrel-treated group, platelet transfusion caused significant shortening of bleeding time, while in the ticagrelor-treated group, platelet transfusion showed no influence on bleeding time under the experimental conditions employed. CONCLUSIONS AND IMPLICATIONS: Prasugrel and ticagrelor showed several differences in their pharmacological profiles and these disparities may reflect their differing reversibility and/or pharmacokinetic profiles. PMID- 23347040 TI - Serum coenzyme Q10 levels and coronary flow reserve in hemodialysis patients. PMID- 23347041 TI - Opportunities and challenges in supply-side simulation: physician-based models. AB - OBJECTIVE: To provide a conceptual framework and to assess the availability of empirical data for supply-side microsimulation modeling in the context of health care. DATA SOURCES: Multiple secondary data sources, including the American Community Survey, Health Tracking Physician Survey, and SK&A physician database. STUDY DESIGN: We apply our conceptual framework to one entity in the health care market-physicians-and identify, assess, and compare data available for physician based simulation models. PRINCIPAL FINDINGS: Our conceptual framework describes three broad types of data required for supply-side microsimulation modeling. Our assessment of available data for modeling physician behavior suggests broad comparability across various sources on several dimensions and highlights the need for significant integration of data across multiple sources to provide a platform adequate for modeling. A growing literature provides potential estimates for use as behavioral parameters that could serve as the models' engines. Sources of data for simulation modeling that account for the complex organizational and financial relationships among physicians and other supply-side entities are limited. CONCLUSIONS: A key challenge for supply-side microsimulation modeling is optimally combining available data to harness their collective power. Several possibilities also exist for novel data collection. These have the potential to serve as catalysts for the next generation of supply-side-focused simulation models to inform health policy. PMID- 23347043 TI - Structural and mechanical heterogeneity of the erythrocyte membrane reveals hallmarks of membrane stability. AB - The erythrocyte membrane, a metabolically regulated active structure that comprises lipid molecules, junctional complexes, and the spectrin network, enables the cell to undergo large passive deformations when passing through the microvascular system. Here we use atomic force microscopy (AFM) imaging and quantitative mechanical mapping at nanometer resolution to correlate structure and mechanics of key components of the erythrocyte membrane, crucial for cell integrity and function. Our data reveal structural and mechanical heterogeneity modulated by the metabolic state at unprecedented nanometer resolution. ATP depletion, reducing skeletal junction phosphorylation in RBC cells, leads to membrane stiffening. Analysis of ghosts and shear-force opened erythrocytes show that, in the absence of cytosolic kinases, spectrin phosphorylation results in membrane stiffening at the extracellular face and a reduced junction remodeling in response to loading forces. Topography and mechanical mapping of single components at the cytoplasmic face reveal that, surprisingly, spectrin phosphorylation by ATP softens individual filaments. Our findings suggest that, besides the mechanical signature of each component, the RBC membrane mechanics is regulated by the metabolic state and the assembly of its structural elements. PMID- 23347044 TI - Potential impact of soil microbiomes on the leaf metabolome and on herbivore feeding behavior. AB - It is known that environmental factors can affect the biosynthesis of leaf metabolites. Similarly, specific pairwise plant-microbe interactions modulate the plant's metabolome by stimulating production of phytoalexins and other defense related compounds. However, there is no information about how different soil microbiomes could affect the plant growth and the leaf metabolome. We analyzed experimentally how diverse soil microbiomes applied to the roots of Arabidopsis thaliana were able to modulate plant growth and the leaf metabolome, as assessed by GC-MS analyses. Further, we determined the effects of soil microbiome-driven changes in leaf metabolomics on the feeding behavior of Trichopulsia ni larvae. Soil microbiomes differentially impacted plant growth patterns as well as leaf metabolome composition. Similarly, most microbiome-treated plants showed inhibition to larvae feeding, compared with unamended control plants. Pyrosequencing analysis was conducted to determine the soil microbial composition and diversity of the soils used in this study. Correlation analyses were performed to determine relationships between various factors (soil microbial taxa, leaf chemical components, plant growth patterns and insect feeding behavior) and revealed that leaf amino acid content was positively correlated with both microbiome composition and insect feeding behavior. PMID- 23347042 TI - Malaria parasites tolerate a broad range of ionic environments and do not require host cation remodelling. AB - Malaria parasites grow within erythrocytes, but are also free in host plasma between cycles of asexual replication. As a result, the parasite is exposed to fluctuating levels of Na(+) and K(+) , ions assumed to serve important roles for the human pathogen, Plasmodium falciparum. We examined these assumptions and the parasite's ionic requirements by establishing continuous culture in novel sucrose based media. With sucrose as the primary osmoticant and K(+) and Cl(-) as the main extracellular ions, we obtained parasite growth and propagation at rates indistinguishable from those in physiological media. These conditions abolish long-known increases in intracellular Na(+) via parasite-induced channels, excluding a requirement for erythrocyte cation remodelling. We also dissected Na(+) , K(+) and Cl(-) requirements and found that unexpectedly low concentrations of each ion meet the parasite's demands. Surprisingly, growth was not adversely affected by up to 148 mM K(+) , suggesting that low extracellular K(+) is not an essential trigger for erythrocyte invasion. At the same time, merozoite egress and invasion required a threshold ionic strength, suggesting critical electrostatic interactions between macromolecules at these stages. These findings provide insights into transmembrane signalling in malaria and reveal fundamental differences between host and parasite ionic requirements. PMID- 23347045 TI - Recombinant Luteinizing Hormone supplementation in poor responders undergoing IVF: a systematic review and meta-analysis. AB - The results of several studies about the effectiveness of recombinant luteinizing hormone (rLH) supplementation in poor responder in vitro fertilization (IVF) patients were conflicting. To evaluate the current available data regarding the efficacy of rLH supplementation in poor responders, a meta-analysis was performed. A systemic search was performed without language limitation but restricted to randomized controlled trial (RCT). We mainly explored MEDLINE, EMBASE, CNKI and Cochrane Library for the relevant studies. Three studies were considered eligible for inclusion. The meta-analysis indicated that rLH supplementation did not increase the ongoing pregnancy rate in poor responders (OR 1.30, 95% CI: 0.80, 2.11). Furthermore, there was no significant difference in the number of oocytes retrieved, total dose of rFSH used, total duration of stimulation, number of retrieved metaphase II oocytes and cycle cancellation rate between the study and control groups. In conclusions, the available evidence does not support the addition of rLH in poor responders treated with rFSH and GnRHa for IVF. It was inconclusive. Future research should be based on strict criteria to define poor responders, and large, well-designed RCTs are necessary to definitively answer the important question of whether there was need to use rLH in poor responders undergoing IVF. PMID- 23347046 TI - Glycinergic transmission and postsynaptic activation of CaMKII are required for glycine receptor clustering in vivo. AB - Synaptic transmission-dependent regulation of neurotransmitter receptor accumulation at postsynaptic sites underlies the formation, maintenance and maturation of synaptic function. Previous in vitro studies showed that glycine receptor (GlyR) clustering requires synaptic inputs. However, in vivo GlyR regulation by synaptic transmission is not fully understood. Here, we established a model system using developing zebrafish, in which GlyRs are expressed in Mauthner cells (M-cells), a pair of giant, reticulospinal, hindbrain neurons, thereby enabling analysis of GlyR clusters over time in identifiable cells. Bath application of a glycinergic blocker, strychnine, to developing zebrafish prevented postsynaptic GlyR cluster formation in the M-cells. After strychnine removal, the GlyR clusters appeared in the M-cells. At a later stage, glycinergic transmission blockade impaired maintenance of GlyR clusters. We also found that pharmacological blockade of either L-type Ca(2+) channels or calcium-/calmodulin dependent protein kinase II (CaMKII) disturbed GlyR clustering. In addition, the M-cell-specific CaMKII inactivation using the Gal4-UAS system significantly impaired GlyR clustering in the M-cells. Thus, the formation and maintenance of GlyR clusters in the M-cells in the developing animals are regulated in a synaptic transmission-dependent manner, and CaMKII activation at the postsynapse is essential for GlyR clustering. This is the first demonstration of synaptic transmission-dependent modulation of synaptic GlyRs in vivo. PMID- 23347047 TI - Optical measures of thermally induced chain ordering and oxidative damage in polythiophene films. AB - Thermally induced chain ordering (aggregation) and oxidative damage in neat poly(3-hexylthiophene) (P3HT) films were assessed using multiple optical metrics (low-temperature photoluminescence (LT-PL), Raman, absorbance, and IR spectroscopies) and NMR through quantitative analysis of exciton/chromophore bandwidths, emission, vibronic line shapes, and changes in film chemistry. Polymer morphology is discussed in light of how absorbance and PL provide complementary information about physically and chemically related changes in conjugation due to chain alignment (kinking and torsion), pi-stacking, crystallite domain growth, and photo-oxidation. LT-PL is shown to be sensitive to oxidation phenomena, while absorbance and Raman are not; in contrast, aggregation can be most easily evaluated via absorbance using a Franck-Condon-like model of vibronic excitation. IR and NMR reveal how hexyl side chains and thiophene units are attacked during annealing in O(2). We also demonstrate that competition exists between the "disordering" effect of photodegradation and the physical "ordering" effect of aggregation, each of which dominates under different processing conditions. Ultimately, it is shown that various optical metrics of film disorder must be considered collectively to understand how processing affects film morphology. PMID- 23347048 TI - Bis[(E)-2,6-bis(1H-pyrazol-1-yl)-4-styrylpyridine]iron(II) complex: relationship between thermal spin crossover and crystal solvent. AB - The crystal structures and thermal spin-crossover (SCO) behavior of [Fe(E dpsp)(2)](BF(4))(2).X [E-dpsp = (E)-2,6-bis(1H-pyrazol-1-yl)-4-styrylpyridine; X = crystal solvent] are investigated. The titled iron(II) complex features polymorphology induced by crystal solvents, which is identified by means of single-crystal X-ray diffraction analysis: For [Fe(E-dpsp)(2)](BF(4))(2).acetone and [Fe(E-dpsp)(2)](BF(4))(2).4MeNO(2), detailed analyses at various temperatures are conducted. The magnetic properties of bulk microcrystalline samples of [Fe(E dpsp)(2)](BF(4))(2).X are assessed using a SQUID magnetometer. Among the series, only [Fe(E-dpsp)(2)](BF(4))(2).acetone undergoes peculiar thermal SCO, such as a precipitous and hysteretic spin-state change (T(1/2?) = 179 K, T(1/2?) = 164 K, and DeltaT(1/2) = 15 K) and frozen-in effect. All single crystals of [Fe(E dpsp)(2)](BF(4))(2).X are free from intermolecular interaction except for [Fe(E dpsp)(2)](BF(4))(2).acetone: One of the phenyl rings in [Fe(E dpsp)(2)](BF(4))(2).acetone is twisted appreciably and features an intermolecular H-H short contact with one of the neighboring complexes to form a one-dimensional network. The twisted phenyl group also participates in pi-pi stacking with one of the pyrazolyl rings of another neighboring molecule, constructing a dimeric couple. These intermolecular interactions would induce cooperative effects, which leads to the good thermal SCO phenomenon of [Fe(E-dpsp)(2)](BF(4))(2).acetone. PMID- 23347049 TI - Catalytic DNAs that harness violet light to repair thymine dimers in a DNA substrate. AB - UV1C is an in vitro selected catalytic DNA that shows efficient photolyase activity, using light of <310 nm wavelength to photo-reactivate CPD thymine dimers within a substrate DNA. We show here that a minimal mutational strategy of substituting a guanine analogue, 6MI, for single guanine residues within UV1C extends the DNAzyme's activity into the violet region of the spectrum. These 6MI point mutant DNAzymes fall into three distinct functional classes, which photo reactivate the thymine dimer along different pathways. Cumulatively, they reveal the modus operandi of the original UV1C DNAzyme to be a surprisingly versatile one. The interchangeable properties of no less than six of the G->6MI point mutants highlight UV1C's built-in functional flexibility, which may serve as a starting point for the creation of efficient, visible light-harnessing, photolyase DNAzymes for either the prophylaxis or therapy of UV damage to human skin. PMID- 23347050 TI - Impact of antenatal glucocorticosteroids on whole-genome expression in preterm babies. AB - AIM: To study the impact that using antenatal steroid to treat threatened preterm delivery has on whole-genome expression. METHODS: A prospective whole-genome expression study was carried out on 50 newborn infants, delivered before 32 weeks gestation, who had been exposed to antenatal steroids, including 40 who had received a full antenatal steroid course. Seventy infants not exposed to antenatal steroids formed the control group. Microarray analyses were performed five and 28 days after delivery, and the results were validated by real-time PCR. The study was conducted between September 2008 and November 2010. RESULTS: Twenty thousand six hundred and ninety-three genes were studied in the infants' leucocytes. Thirteen were differentially expressed 5 days after delivery, but there were no differences at day 28. Four genes related to cancer or inflammation were up-regulated. Nine genes were down-regulated: six were Y-linked and associated with malignancies, graft-versus-host disease, male infertility and cell differentiation and three were associated with pre-eclampsia, oxidative stress and chloride/bicarbonate exchange. Seven gene pathways were up-regulated at day five and only one at day 28. These were associated with cell growth, cell cycle regulation, metabolism and apoptosis. CONCLUSION: Antenatal steroid therapy affects a limited number of genes and gene pathways in leucocytes in preterm babies at day five of life. The effect is short-lived, but long-term effects cannot be ruled out. PMID- 23347051 TI - Real-time PCR-based rapid and culture-independent detection of Salmonella in dairy milk--addressing some core issues. AB - In this study, methodologies were developed for cost-effective, rapid and user friendly culture-independent detection of Salmonella in milk by real-time PCR. The SYBR Green-based real-time PCR assay was standardized with primers targeting the Salmonella enterotoxin gene (stn) that have been earlier used for its detection by conventional PCR. Inclusivity tests generated the specific amplifications with a Tm corresponding to 81 +/- 0.5 degrees C. The specificity of the reaction was evaluated with a panel of 36 non-Salmonella strains. Standard curves generated, with different number of cells of this organism in milk, depicted the detection of five cells with a CT value of 37.17 (SD 0.43). To make the assays user-friendly and suitable for field applications, protocols were also established for the immobilization of the SYBR Green reaction mixes in the reaction tubes. The immobilized master mixes were stable at 25 degrees C for 4 months and at 8 degrees C for over 6 months. Total DNA was prepared from 150 samples of full-fat dairy milk and subjected to real-time PCR detection wherein 31 samples tested positive for Salmonella. The time of analysis was <5 h. PMID- 23347052 TI - Self-healing mussel-inspired multi-pH-responsive hydrogels. AB - Self-healing hydrogels can be made using either reversible covalent cross-links or coordination chemistry bonds. Here we present a multi-pH-responsive system inspired by the chemistry of blue mussel adhesive proteins. By attaching DOPA to an amine-functionalized polymer, a multiresponsive system is formed upon reaction with iron. The degree of polymer cross-linking is pH controlled through the pH dependent DOPA/iron coordination chemistry. This leads to the formation of rapidly self-healing high-strength hydrogels when pH is raised from acidic toward basic values. Close to the pK(a) value, or more precisely the pI value, of the polymer, the gel collapses due to reduced repulsion between polymer chains. Thereby a bistable gel-system is obtained. The present polymer system more closely resembles mussel adhesive proteins than those previously reported and thus also serves as a model system for mussel adhesive chemistry. PMID- 23347054 TI - Effect of training cessation on muscular performance: a meta-analysis. AB - The purpose of this study was to assess the effect of resistance training cessation on strength performance through a meta-analysis. Seven databases were searched from which 103 of 284 potential studies met inclusion criteria. Training status, sex, age, and the duration of training cessation were used as moderators. Standardized mean difference (SMD) in muscular performance was calculated and weighted by the inverse of variance to calculate an overall effect and its 95% confidence interval (CI). Results indicated a detrimental effect of resistance training cessation on all components of muscular performance: [submaximal strength; SMD (95% CI) = -0.62 (-0.80 to -0.45), P < 0.01], [maximal force; SMD (95% CI) = -0.46 (-0.54 to -0.37), P < 0.01], [maximal power; SMD (95% CI) = 0.20 (-0.28 to -0.13), P < 0.01]. A dose-response relationship between the amplitude of SMD and the duration of training cessation was identified. The effect of resistance training cessation was found to be larger in older people (> 65 years old). The effect was also larger in inactive people for maximal force and maximal power when compared with recreational athletes. Resistance training cessation decreases all components of muscular strength. The magnitude of the effect differs according to training status, age or the duration of training cessation. PMID- 23347053 TI - The adjuvant-like activity of staphylococcal enterotoxin B in a murine asthma model is independent of IL-1R signaling. AB - BACKGROUND: Staphylococcal enterotoxin B (SEB) is a superantigen known to be a modulator of chronic airway inflammation in mice and humans, yet little is known about the mechanisms that regulate its interaction with the innate immune system. We investigated this mechanism in a murine model of allergic airway inflammation induced by OVA (ovalbumin) in the presence of SEB. METHODS: Superantigen-induced allergic inflammation was studied in IL-1R knockout (KO) mice exposed to OVA+SEB. Multicolor flow cytometry was used to analyze the inflammatory cell profile in airways and lymph nodes. Production of IL-4, IL-5, IL-10, and IL-13 in lymph nodes was assessed by Luminex technology. RESULTS: In wild-type mice, endonasal instillation of OVA+SEB induced a pulmonary inflammation, characterized by an increase in the number of eosinophils, T cells, and dendritic cells and in the production of Th2 cytokines and OVA-specific IgE. In IL-1R KO mice exposed to OVA+SEB, attraction of CD4+ cells and production of Th2 cytokines were reduced. However, knocking out IL-1R did not affect any of the features of allergic airway inflammation, such as bronchial eosinophilia, OVA-specific IgE production and goblet cell metaplasia. CONCLUSION: We provide new insights into the mechanisms of airways allergy development in the presence of bacterial superantigen. The asthma features induced by OVA+SEB, such as bronchial eosinophilia, goblet cell proliferation, production of OVA-specific IgE and increase in inflammatory dendritic cells, are IL-1R independent. Yet, IL-1R signaling is crucial for CD4 cell accumulation and Th2 cytokine production. PMID- 23347055 TI - Artificial Cells, Nanomedcine & Biotechnology. PMID- 23347057 TI - High incidence of DNA ploidy abnormalities and increased Mcm2 expression may predict malignant change in oral proliferative verrucous leukoplakia. AB - AIMS: To assess the DNA content of cases of oral proliferative verrucous leukoplakia (PVL) and correlate the DNA ploidy findings with the expression of Mcm2, geminin, and Ki67, and with clinicopathological data. METHODS AND RESULTS: DNA quantification was performed by image cytometry using the ACIS III Automated Cellular Imaging System. Expression of Ki67, Mcm2 and geminin was determined by immunohistochemistry. There were 21 cases of PVL, the female/male ratio was 6:1, and the average age was 65.5 years. Seventeen patients (81.0%) did not report tobacco and alcohol consumption. Nine patients (42.9%) developed verrucous or squamous cell carcinoma. Levels of Mcm2 expression showed a positive correlation with increasingly severe epithelial changes (P = 0.03). Twenty patients had their DNA examined by ACIS III, and 19 (95%) showed aneuploidy. The frequency and severity of aneuploidy (P < 0.0001), the mean values of the DNA heterogeneity index (P < 0.0001) and the 5n-exceeding fractions (P = 0.0007) increased according to epithelial alterations. Abnormal DNA content was observed even in the more indolent lesions. CONCLUSIONS: Mcm2 expression and DNA ploidy analysis could be used to predict areas of malignant transformation. The clinicopathological findings associated with the immunohistochemical and DNA ploidy results support the distinct and aggressive profile of this entity. PMID- 23347058 TI - Social support within a mother and child group: An ethnographic study situated in the UK. AB - Social support has been associated with positive outcomes regarding the mothering experience, and professional interventions have therefore been developed in formal settings to promote this. An ethnographic approach was used to consider the subjective experiences of mothers attending a professionally-facilitated group for parents and children aged 0-4 years, focusing on relationships within the group and their importance within existing social networks. Qualitative data were collected from seven participants using interviews and participant observation. These were analyzed by the constant comparison method into codes, categories, and themes. Three themes emerged: past history, being a mother, and function of the group. To ensure mothers and children benefit from such groups, nurses who participate in developing and leading community interventions for mothers and their children need to be aware of the importance of maternal identity and the factors that can impact the relationships between mothers within group settings. PMID- 23347056 TI - Lowering of elevated tissue PCO2 in a hemorrhagic shock rat model after reinfusion of a novel nanobiotechnological polyhemoglobin-superoxide dismutase catalase-carbonic anhydrase that is an oxygen and a carbon dioxide carrier with enhanced antioxidant properties. AB - Even though erythrocytes transport both oxygen and carbon dioxide, research on blood substitutes has concentrated on the transport of oxygen and its vasoactivity and oxidative effects. Recent study in a hemorrhagic shock animal model shows that the degree of tissue PCO(2) elevation is directly related to mortality rates. We therefore prepared a novel nanobiotechnological carrier for both O(2) and CO(2) with enhanced antioxidant properties. This is based on the use of glutaraldehyde to crosslink stroma free hemoglobin (SFHb), superoxide dismutase (SOD), catalase (CAT) and carbonic anhydrase (CA) to form a soluble PolySFHb-SOD-CAT-CA. It was compared to blood and different resuscitation fluids on the ability to lower elevated tissue PCO(2) in a 2/3 blood volume loss rat hemorrhagic shock model. Sixty minutes of sustained hemorrhagic shock at 30 mm Hg resulted in the increase of tissue PCO(2) to 95 mm +/- 3 mmHg from the control level of 55 mm Hg. Reinfusion of whole blood (Hb 15 g/dL with its RBC enzymes) lowered the tissue PCO2 to 72 +/- 4.5 mmHg 60 minutes after reinfusion. PolySFHb SOD-CAT-CA (SFHb 10 g/dL plus additional enzymes) was more effective than whole blood in lowering PCO(2) lowering this to 66.2 +/- 3.5 mmHg. Ringer's Lactated solution or polyhemoglobin lowered the elevated PCO2 only slightly to 87 +/- 4.5 mmHg and 84.8 +/- 1.5 mmHg, respectively. Moreover, ST-elevation for whole blood (Hb 15 g/dL) and PolySFHb-SOD-CAT-CA (Hb 10 g/dL) was respectively 12.8% +/- 4% and 13.0% +/- 2% of the control 60 minutes after reinfusion. Both are significantly better than those in the Ringer's lactated group and the PolyHb group. In conclusion, this novel approach for blood substitute design has resulted in a novel nanobiotechnological carrier for both O(2) and CO(2) with enhanced antioxidant properties. PMID- 23347059 TI - Micellar liquid chromatographic determination of arbutin and hydroquinone in medicinal plant extracts and commercial cosmetic products. AB - A simple micellar liquid chromatographic (MLC) procedure for simultaneous determination of arbutin and hydroquinone in medicinal plant extracts and commercial cosmetic products was proposed. This method was developed and validated. The chromatographic conditions were also optimized. All analyses were performed at room temperature in an isocratic mode, using a mixture of 1% (v/v) acetonitrile and 0.006 mol L-1 Brij 35 (pH 6.0) as a mobile phase. The flow rate was set at 1.0 mL min-1. The analytical column was a 150 * 3.9 mm Nova-Pak C-18 column. The effluent from the analytical column was monitored by UV detection at 280 nm. Under the optimum conditions, arbutin and hydroquinone could be determined within a concentration range of 2-50 MUg mL-1 of arbutin, and hydroquinone was obtained with the regression equations; y = 0.045x + 0.042 (r2 = 0.9923) and y = 0.091x + 0.050 (r2 = 0.9930) respectively. The limits of detection were found to be 0.51 MUg mL-1 and 0.37 MUg mL-1 for arbutin and hydroquinone respectively. The proposed MLC method was applied for the determination of arbutin and hydroquinone contents in medicinal plant extracts and commercial cosmetic products. This proposed MLC method is thus suitable for routine analysis of arbutin and hydroquinone in the pharmaceutical formulations, cosmetic products and raw medicinal plant extracts. PMID- 23347060 TI - Life-history constraints in grassland plant species: a growth-defence trade-off is the norm. AB - Plant growth can be limited by resource acquisition and defence against consumers, leading to contrasting trade-off possibilities. The competition defence hypothesis posits a trade-off between competitive ability and defence against enemies (e.g. herbivores and pathogens). The growth-defence hypothesis suggests that strong competitors for nutrients are also defended against enemies, at a cost to growth rate. We tested these hypotheses using observations of 706 plant populations of over 500 species before and following identical fertilisation and fencing treatments at 39 grassland sites worldwide. Strong positive covariance in species responses to both treatments provided support for a growth-defence trade-off: populations that increased with the removal of nutrient limitation (poor competitors) also increased following removal of consumers. This result held globally across 4 years within plant life-history groups and within the majority of individual sites. Thus, a growth-defence trade off appears to be the norm, and mechanisms maintaining grassland biodiversity may operate within this constraint. PMID- 23347061 TI - Psychometric properties of the Iranian version of the Sexual Quality of Life Scale among women. AB - INTRODUCTION.: Female sexual dysfunction has a known impact on the quality of life. AIM.: The purpose of this study was the translation and validation of an Iranian version of the Sexual Quality of Life questionnaire-Female (SQOL-F) in Iranian women. METHODS.: A population sample of N = 2,675 women aged 17-67 years from Qazvin City of Iran and two clinical population samples (women with sexual dysfunctions N = 295 and women with type 2 diabetes N = 449) participated in the study. A self-constructed demographic questionnaire, the SQOL-F, the Short Form Health Survey (SF-36), and the Female Sexual Function Index (FSFI) were used for data collection. MAIN OUTCOME MEASURES.: Internal consistency and test-retest reliability were examined. Correlations between the SQOL-F, SF-36, and FSFI were assessed with convergent validity. Furthermore, known-groups comparison analysis was conducted to compare differences in SQOL-F scores between healthy women and those with sexual problems and diabetes. Confirmatory factor analysis assessed the factor structure of the SQOL-F. RESULTS.: Cronbach's alpha ranged from 0.84 to 0.98. Significant correlations between the SQOL-F, SF-36, and FSFI scores were found (ranging from r = 0.4 to r = 0.72). The SQOL-F scores were significantly different between women with and without a clinical condition (P < 0.05). A unifactorial model provided the best fit to the data. CONCLUSION.: The questionnaire represents a suitable measure to assess sexuality-related quality of life to sexual function in healthy women, as well as in women suffering from a chronic medical condition. Application of the scale to other clinical samples needs to be further explored. PMID- 23347062 TI - Diversity and evolutionary patterns of bacterial gut associates of corbiculate bees. AB - The animal gut is a habitat for diverse communities of microorganisms (microbiota). Honeybees and bumblebees have recently been shown to harbour a distinct and species poor microbiota, which may confer protection against parasites. Here, we investigate diversity, host specificity and transmission mode of two of the most common, yet poorly known, gut bacteria of honeybees and bumblebees: Snodgrassella alvi (Betaproteobacteria) and Gilliamella apicola (Gammaproteobacteria). We analysed 16S rRNA gene sequences of these bacteria from diverse bee host species across most of the honeybee and bumblebee phylogenetic diversity from North America, Europe and Asia. These focal bacteria were present in 92% of bumblebee species and all honeybee species but were found to be absent in the two related corbiculate bee tribes, the stingless bees (Meliponini) and orchid bees (Euglossini). Both Snodgrassella alvi and Gilliamella apicola phylogenies show significant topological congruence with the phylogeny of their bee hosts, albeit with a considerable degree of putative host switches. Furthermore, we found that phylogenetic distances between Gilliamella apicola samples correlated with the geographical distance between sampling locations. This tentatively suggests that the environmental transmission rate, as set by geographical distance, affects the distribution of G. apicola infections. We show experimentally that both bacterial taxa can be vertically transmitted from the mother colony to daughter queens, and social contact with nest mates after emergence from the pupa greatly facilitates this transmission. Therefore, sociality may play an important role in vertical transmission and opens up the potential for co-evolution or at least a close association of gut bacteria with their hosts. PMID- 23347063 TI - Case report: atenolol overdose successfully treated with hemodialysis. AB - Owing to the drug's favorable hydrophilic and pharmacokinetic characteristics, a number of case reports have demonstrated effective treatment of atenolol overdose with hemodialysis. However, the efficiency of atenolol clearance throughout hemodialysis treatments has not previously been examined. In this report, a patient with impaired renal function was successfully treated with two 5-hour intermittent high-flux high-efficiency hemodialysis therapies after atenolol overdose. Serial atenolol levels were measured during his hemodialysis treatments. We observed an over 50% plasma atenolol concentration reduction after each 5-hour hemodialysis therapy. Hemodialysis therapy is an effective treatment for atenolol overdose, especially in patients with impaired renal function. PMID- 23347065 TI - An interesting case where water behaves as a unique solvent. 4-Aminophthalimide emission profile to monitor aqueous environment. AB - The behavior of 4-aminophthalimide (4-AP), a common molecular probe utilized in solvation dynamics experiments, was revisited in polar aprotic and protic solvents using absorption, steady-state, and time-resolved fluorescence (TRES) techniques. Also, the deuterium isotope effect was investigated using D(2)O as solvent. The absorption spectra of 4-AP consist of two absorption bands with maxima around 300 nm (B2 band) and 370 nm (B1 band) depending on the environment, while the emission feature consists of a single band. In all the solvents investigated (excluding water), the 4-AP photophysics is similar and the emission spectra are independent of the excitation wavelength used. In water the behavior is unique and the emission spectra maximum is different depending on the excitation wavelength used. The emission maximum is 561.7 nm using the excitation wavelength that correspond to the B2 absorption band maximum (lambda(excB2) = 303.4 nm) but is 545.7 nm when the excitation wavelength that correspond to the B1 absorption maximum (lambda(excB1) = 370.0 nm) is used. Moreover, while the fluorescence decays of 4-AP in water exhibit no emission wavelength dependence at lambda(excB2), the situation is quite different when lambda(excB1) is used. In this case, we found a time-dependent emission spectrum that shifts to the blue with time. Our results show that the solvent-mediated proton transfer process displays a fundamental role in the 4-AP emission profile and for the first time a mechanism was proposed that fully explains the 4-AP behavior in every solvent including water. The deuterium isotope effect confirms the assumption because the proton-transfer process is dramatically retarded in this solvent. Consequently, we were able to elucidate not only why in water the emission spectra depend on the excitation wavelength but also why the time-dependent emission spectra shift to the blue with time. Thus, our work reveals the importance that the medium has on the behavior of a widespread dye used as chromophore. This is significant since the use of chromophores without understanding its chemistry can induce artifacts into the interpretation of solvation dynamics in heterogeneous environments, in particular, those provided by aqueous biological systems. PMID- 23347066 TI - Low root reserve accumulation during drought may lead to winter mortality in poplar seedlings. AB - Climate models suggest that more frequent drought events of greater severity and length, associated with climate change, can be expected in the coming decades. Although drought-induced tree mortality has been recognized as an important factor modulating forest demography at the global scale, the mechanisms underlying drought-induced tree mortality remain contentious. Above- and below ground growth, gas exchange, water relations and carbon reserve accumulation dynamics at the organ and whole-plant scale were quantified in Populus tremuloides and P. balsamifera seedlings in response to severe drought. Seedlings were maintained in drought conditions over one growing and one dormant winter season. Our experiment presents a detailed description of the effect of severe drought on growth and physiological variables, leading to seedling mortality after an extended period of drought and dormancy. After re-watering following the dormant period, drought-exposed seedlings did not re-flush, showing that the root system had died off. The results of this study suggest a complex series of physiological feedbacks between the measured variables in both Populus species. Further, they reveal that reduced reserve accumulation in the root system during drought decreases the conversion of starch to soluble sugars in roots, which may contribute to the root death of drought-exposed seedlings during the dormant season by compromising the frost tolerance of the root system. PMID- 23347067 TI - Cancer and fertility preservation: Barcelona consensus meeting. AB - Improvements in early diagnosis and treatment strategies in cancer patients have enabled younger women with cancer to survive. In addition to the stressful event of the diagnosis, patients with malignant diseases face the potential loss of the opportunity to have children. Preservation of fertility has become a challenging issue and it is still surrounded by controversies. On the basis of available evidence, a group of experts reached a consensus regarding the options for trying to preserve fertility in women with cancer: among established methods, in postpubertal women, oocyte cryopreservation is the preferred option, whereas ovarian tissue cryopreservation is the only possibility for prepubertal girls. Combining several strategies on an individual basis may improve the chances of success. Realistic information should be provided before any intervention is initiated. Counseling should offer support for patients and provide better care by understanding emotional needs, psychological predictors of distress and methods of coping. Early referral to the fertility specialist is essential as fertility preservation (FP) may improve quality of life in these patients. The information summarized here is intended to help specialists involved in the treatment of cancer and reproductive medicine to improve their understanding of procedures available for FP in young cancer patients. PMID- 23347064 TI - Pharmacological potential of biogenic amine-polyamine interactions beyond neurotransmission. AB - Histamine, serotonin and dopamine are biogenic amines involved in intercellular communication with multiple effects on human pathophysiology. They are products of two highly homologous enzymes, histidine decarboxylase and l-aromatic amino acid decarboxylase, and transmit their signals through different receptors and signal transduction mechanisms. Polyamines derived from ornithine (putrescine, spermidine and spermine) are mainly involved in intracellular effects related to cell proliferation and death mechanisms. This review summarizes structural and functional evidence for interactions between components of all these amine metabolic and signalling networks (decarboxylases, transporters, oxidases, receptors etc.) at cellular and tissue levels, distinct from nervous and neuroendocrine systems, where the crosstalk among these amine-related components can also have important pathophysiological consequences. The discussion highlights aspects that could help to predict and discuss the effects of intervention strategies. PMID- 23347068 TI - HLA-G 2012 conference: the 15-year milestone update. AB - The non-classical human leukocyte antigen (HLA) Class I molecule HLA-G is best known for its tolerogenic function at the maternal-fetal interface, where it protects the fetus from destruction by the immune system of its mother. Yet, HLA G has been the topic of intense investigations and its functions reach much further than originally believed. International conferences on HLA-G have taken place every 3 years since 1998, and the Sixth International Conference on HLA-G, that took place in Paris in July 2012. It counted 180 attendees from 28 countries, 35 speakers in plenary sessions, and 63 presentations of research in symposia and poster sessions, bringing new insight in HLA-G research. Here we summarize the major advances on the function and nature of HLA-G molecule that were reported, with particular interest on the findings in new mechanisms of action through regulatory cells, its relevance in cancer as well as in the molecular structure and functions of HLA-G, which are key for its clinical application. PMID- 23347069 TI - Detection of microdoses of rhEPO with the MAIIA test. AB - The detection of recombinant human erythropoietin (rhEPO) is difficult and becomes more challenging when only microdoses are administered intravenously. Twenty-three subjects were divided into two groups: EPO group (n = 7) and CONTROL group (n = 16). Seven urine and blood samples per subject were collected at least 5 days apart to determine within- and between-subject standard deviations in the percentage of migrating isoforms by the MAIIA test. Six injections of 50 IU/kg bw (boosting dosage) of epoetin beta (Neorecormon, Roche Diagnostics, Hvidovre, Denmark) were performed intravenously during a 3-week period, followed by two microinjections of only 10 IU/kg bw. Blood and urine samples were collected 2, 6, 12, and 72 h after the microinjection, as well as 72 h after the last boosting dose. Sensitivities and specificities of the MAIIA test were examined by absolute and passport thresholds. Sensitivity was 100% for at least 12 h after the microinjection, with ~30% of plasma samples still exceeding the 99.9% passport threshold 72 h after a microinjection. The specificity was higher for the passport approach compared to the absolute approach, but there were no differences in sensitivities between approaches or between specimens (urine and plasma). We conclude that the MAIIA test shows potential for detecting very small doses of rhEPO. PMID- 23347070 TI - Spontaneous resolution of vitreomacular traction: a case series. AB - Three patients had unilateral vitreomacular traction (VMT) syndrome and the diagnosis was confirmed by spectral domain-type optical coherence tomography (OCT). All patients were female aged 51, 55 and 62 years. All denied surgical intervention. In one patient, rapid spontaneous resolution of the vitreomacular traction with a complete posterior vitreous detachment (PVD) and a normal foveal contour was achieved within 15 days. In the remaining two cases a complete PVD could be detected as late as seven months after the initial presentation. In one, though the vitreomacular adhesion released spontaneously, there was a minimal residual epiretinal membrane. In all three eyes, visual acuity was considerably improved. Spontaneous, uneventful resolution has been rarely reported in the natural course of VMT but several recent studies with the aid of OCT have shown that spontaneous resolution might be more common than previously known. In light of our cases, we believe that there is still room to search for OCT clues in eyes with VMT to predict eyes with higher likelihood of spontaneous resolution, thereby avoiding unnecessary pharmacologic and/or surgical intervention. PMID- 23347071 TI - Supramolecular hydrogels from in situ host-guest inclusion between chemically modified cellulose nanocrystals and cyclodextrin. AB - When grafted beta-cyclodextrin is used as targeting sites, Pluronic polymers have been introduced on the surface of cellulose nanocrystals by means of inclusion interaction between beta-cyclodextrin and hydrophobic segment of the polymer. Because of the steric stabilization effect, surface poly(ethylene glycol) chains facilitate the dispersion and compatibility of nanocrystals, which also enhance the loading levels of nanocrystals in the hydrogel system. Meanwhile, uncovered poly(ethylene glycol) segments render the participating inclusion of alpha cyclodextrin for the architecture of in situ hydrogels. Surface grafting and inclusion reactions were proved by solid (13)C NMR and FTIR. Grafting efficiency of beta-cyclodextrin and inclusion efficiency of Pluronic on the surface of nanocrystals were confirmed by UV spectroscopy and elemental analysis. A significant enhancement of the structural and thermal stability of in situ hydrogels with high loading levels of modified nanocrystals (>5.77 wt %) was observed by rheological analysis. Further study reveals the performance and behavior of hydrogels under a different pH environment. Finally, in situ hydrogels were used as drug carrier for in vitro release of doxorubicin and exhibit the behavior of prolonged drug release with special release kinetics. PMID- 23347073 TI - Development of the Thai healthy aging model: A grounded theory study. AB - To develop a model of healthy aging from the perspective of Thais, a grounded theory approach, including in-depth interviews and focus groups, was used. A purposive sample of 39 community-dwelling adults aged 40-85 years old was interviewed. The Thai healthy aging model composed of three themes: normality, nature, and dharma. In Thai, they are called tham-ma-da, tham-ma-chat, and tham ma, or "Thai 3Ts". The theme of normality encompasses subthemes of staying physically active by being involved in plenty of physical activities, and being mentally active with creative and thoughtful hobbies and work. The theme of nature encompasses subthemes of living simply and being careful with money. The theme of dharma encompasses subthemes of enjoyment through helping family and participating in community activities, staying away from stress and worries by talking openly and honestly with someone, making merit, and helping other people without expecting anything in return. A greater understanding of healthy aging is a benefit for older adults and healthcare providers in an intervention-design process. Research can contribute valuable information to shape policy for healthy aging as well. PMID- 23347074 TI - Three different adhesive systems; three different bond strength test methods. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of the microtensile, microshear and shear bond strength test methods to assess the bond strength of two self-etch adhesives and one etch&rinse adhesive on dentin. MATERIALS AND METHODS: Seventy-five extracted human molars were ground to expose their flat dentin surfaces and randomly assigned to one of three groups according to the type of test method (15 for microtensile, 15 for microshear, 45 for shear). Each of these groups was then assigned to three sub-groups according to the bonding systems (Clearfil SE Bond, Kuraray; G Bond, GC; Prime&Bond NT, Dentsply) used. Then, 15 specimens were prepared for each sub-group according to the test method employed (n = 15). After being stored in distilled water at 37 degrees C for 24 h, the specimens were placed in a universal testing machine for three test methods and stressed at a crosshead speed of 0.5 mm/min. Mean bond strengths were analyzed using Kruskall-Wallis and Mann-Whitney U-tests at a significance level of p < 0.05. RESULTS: The microtensile test had the highest bond strength (p = 0.046). Clearfil SE Bond and Prime&Bond NT produced significantly higher values than the G Bond in the microtensile bond test (p < 0.05), whereas no significant differences were found among the adhesives in the microshear bond test (p > 0.05). For the shear test, Clearfil SE Bond showed higher bond strength than Prime&Bond NT and G Bond (p < 0.05). CONCLUSION: Bond strength to dentin depends on the material and the test method used. PMID- 23347072 TI - Eosinophil-derived cytokines in health and disease: unraveling novel mechanisms of selective secretion. AB - Over the past two decades, our understanding of eosinophils has evolved from that of categorically destructive effector cells to include active participation in immune modulation, tissue repair processes, and normal organ development, in both health and disease. At the core of their newly appreciated functions is the capacity of eosinophils to synthesize, store within intracellular granules, and very rapidly secrete a highly diverse repertoire of cytokines. Mechanisms governing the selective secretion of preformed cytokines from eosinophils are attractive therapeutic targets and may well be more broadly applicable to other immune cells. Here, we discuss recent advances in deciphering pathways of cytokine secretion, both from intact eosinophils and from tissue-deposited cell free eosinophil granules, extruded from eosinophils undergoing a lytic cell death. PMID- 23347075 TI - Oral health patterns of independently living dentate older people: a cross sectional survey of dental attendees in south-east London. AB - BACKGROUND: The oral health needs of older adults present increasing challenges to dental services. OBJECTIVES: To examine the clinical oral health status of dentate older people living in the community and attending dental services. METHODS: One hundred and eighty-six dentate adults, aged >=60 years, underwent clinical examination (DMFS, Plaque and Gingival Indexes), salivary analysis and completed a questionnaire. RESULTS: Participants had an average of 21.4 (+/-6.2) teeth present and 1.2 (+/-3.0) decayed, 51.0 (+/-28.8) missing and 32.6 (+/-20.5) restored surfaces. Individuals living in the most deprived areas had significantly lower numbers of teeth than those in the least deprived areas (19.1 +/- 7.5 cf 23.8 +/- 4.1; p < 0.001). Whilst there were no significant differences in DMFS score, residents in the most deprived areas had significantly more missing and fewer filled surfaces than those in the least deprived areas (p = 0.001 and p < 0.001, respectively). Participants with >=21 teeth (64%) had lower plaque scores, fewer decayed root surfaces, higher stimulated saliva flow rates and lower salivary lactobacilli and yeast counts than those with <21 teeth (p < 0.05 for all). CONCLUSIONS: The findings highlight differences in clinical oral health by age and deprivation status and underline the importance of saliva and retaining a functional dentition. PMID- 23347076 TI - An alternative sigma factor governs the principal sigma factor in Streptomyces griseus. AB - In bacteria, the RNA polymerase holoenzyme comprises a five-subunit core enzyme and a dissociable subunit, sigma factor, which is responsible for transcriptional initiation. The filamentous bacterium Streptomyces griseus has 52 sigma factors, including one essential 'principal' sigma factor (sigma(HrdB) ) that is responsible for the transcription of housekeeping genes. Here we characterized an alternative sigma factor (sigma(ShbA) ), which is highly conserved within the genus Streptomyces. A sigma(ShbA) -deficient mutant showed a severe growth defect and transcriptome analysis indicated that many housekeeping genes were downregulated in response to insufficient sigma(ShbA) production. Biochemical and genetic analyses proved that sigma(ShbA) is a major determinant of transcription of the sigma(HrdB) gene. This observation of a principal sigma factor being governed by another sigma factor throughout growth is unprecedented. We found that increasing sigma(ShbA) production with mycelial growth maintained a high sigma(HrdB) level late in growth. Furthermore, a hrdB-autoregulatable sigma(ShbA) -deficient mutant, in which the principal sigma factor gene can be transcribed by RNA polymerase containing sigma(HrdB) itself, showed several defects: rapid mycelial lysis in stationary phase in liquid culture and delayed morphological development and impaired streptomycin production in solid culture. From these observations, we discuss the biological significance of control of sigma(HrdB) by sigma(ShbA) in S. griseus. PMID- 23347077 TI - Mechanisms and transition states of 1,3-dipolar cycloadditions of phenyl azide with enamines: a computational analysis. AB - The transition structures for the 1,3-dipolar cycloadditions of phenyl azide to enamines derived from acetophenone or phenylacetaldehyde and piperidine, morpholine, or pyrrolidine were located using quantum mechanical methods. These cycloadditions were studied experimentally in 1975 by Meilahn, Cox, and Munk (J. Org. Chem. 1975, 40, 819-823). Calculations were carried out with M06-2X/6 311+G(d,p), SCS-MP2/6-311+G(d,p)//M06-2X/6-311+G(d,p), and B97D/6-311+G(d,p) methods with the IEF-PCM solvation model for chloroform and ethanol. The distortion/interaction model was utilized to understand mechanisms, reactivities, and selectivities. PMID- 23347078 TI - Risk factors associated with primary and secondary reduced libido in male patients with sexual dysfunction. AB - INTRODUCTION: Hypoactive sexual desire is defined as a persistent or recurrent deficient or absent sexual fantasies or desire for sexual activity that should not be comorbid with other medical conditions or with the use of psychoactive medications. Reduced libido is a symptom referring more to a reduction in sexual drive for sexual activity. AIM: To investigate the risk factors of primary reduced libido (i.e., not associated with conditions causing loss of libido such as hypogonadism, hyperprolactinemia, psychopathology, and/or psychoactive medications) or secondary reduced libido (i.e., with aforementioned conditions) in male patients with sexual dysfunction. METHOD: A consecutive series of 3,714 men (mean age 53.2 +/- 12.5 years) was retrospectively studied. MAIN OUTCOME MEASURES: Patient's reduced libido was evaluated using question #14 of structured interview for erectile dysfunction (SIEDY) ("Did you have more or less desire to make love in the last 3 months?"). RESULTS: Reduced libido was comorbid with erectile dysfunction, premature ejaculation, and delayed ejaculation in 38%, 28.2%, and 50%, respectively, whereas it was isolated in 5.1%. Reduced libido prevalence was substantially increased by hypogonadism, almost doubled by psychopathology and universally present in subjects with hyperprolactinemia (secondary reduced libido). Subjects with primary reduced libido are characterized by higher postschool qualification, more disturbances in domestic and dyadic relationships, and an overall healthy body (lower glycemia and triglyceride levels). Accordingly, in patients with primary reduced libido, the risk of major cardiovascular events as calculated with the Progetto Cuore algorithm was lower than in the rest of the sample. Features of hypogonadism- or psychopathology-associated reduced libido essentially reflect their underlying conditions. Comorbidity with other sexual dysfunctions did not affect the main characteristics of primary or secondary reduced libido. CONCLUSIONS: Primary and secondary reduced libido have different risk factors and clinical characteristics. Recognizing primary or secondary reduced libido will help clinicians to identify comorbidities and to tailor appropriate treatments. PMID- 23347079 TI - Simulating the impact of long-term care policy on family eldercare hours. AB - OBJECTIVE: To understand the effect of current and future long-term care (LTC) policies on family eldercare hours for older adults (60 years of age and older) in Singapore. DATA SOURCES: The Social Isolation Health and Lifestyles Survey, the Survey on Informal Caregiving, and the Singapore Government's Ministry of Health and Department of Statistics. STUDY DESIGN: An LTC Model was created using system dynamics methodology and parameterized using available reports and data as well as informal consultation with LTC experts. PRINCIPAL FINDINGS: In the absence of policy change, among the elderly living at home with limitations in their activities of daily living (ADLs), the proportion of those with greater ADL limitations will increase. In addition, by 2030, average family eldercare hours per week are projected to increase by 41 percent from 29 to 41 hours. All policy levers considered would moderate or significantly reduce family eldercare hours. CONCLUSION: System dynamics modeling was useful in providing policy makers with an overview of the levers available to them and in demonstrating the interdependence of policies and system components. PMID- 23347080 TI - Singlet molecular oxygen quenching by the antioxidant dimethylmethoxy chromanol in solution and in ex vivo porcine skin. AB - Singlet-oxygen is a non-radical reactive oxygen species believed to play a major role in many photooxidation processes in connection with diverse photo-biological processes such as skin ageing or photocarcinogenesis. Dimethylmethoxy chromanol (3,4-dihydro-6-hydroxy-2,2-dimethyl-7-methoxy-1(2H)-benzopyran) is a potent antioxidant used in cosmetic and pharmaceutical formulations. We have assessed the singlet oxygen quenching ability of dimethylmethoxy chromanol, by monitoring the near-IR phosphorescence of singlet-oxygen in solution and in ex vivo porcine skin samples. Dimethylmethoxy chromanol quenches singlet oxygen with a rate constant of (1.3 +/- 0.1) * 108 M-1 s-1 in solution. Consistent with this, a clear reduction in the singlet oxygen lifetime and emission intensity was observed when ex vivo porcine skin samples were treated with dimethylmethoxy chromanol. PMID- 23347082 TI - From formamide to purine: an energetically viable mechanistic reaction pathway. AB - A step-by-step mechanistic pathway following the transformation of formamide to purine through a five-membered ring intermediate has been explored by density functional theory computations. The highlight of the mechanistic route detailed here is that the proposed pathway represents the simplest reaction pathway. All necessary reactants are generated from a single starting compound, formamide, through energetically viable reactions. Several important reaction steps are involved in this mechanistic route: formylation-dehydration, Leuckart reduction, five- and six-membered ring-closure, and deamination. On the basis of the study of noncatalytic pathways, catalytic water has been found to provide energetically viable step-by-step mechanistic pathways. Among these reaction steps, five-member ring-closure is the rate-determining step. The energy barrier (ca. 42 kcal/mol) of this rate-control step is somewhat lower than the rate-determining step (ca. 44 kcal/mol) for a pyrimidine-based pathway reported previously. The mechanistic pathway reported herein is less energetically demanding than for previously proposed routes to adenine. PMID- 23347081 TI - IL-33/ST2 signalling contributes to carrageenin-induced innate inflammation and inflammatory pain: role of cytokines, endothelin-1 and prostaglandin E2. AB - BACKGROUND AND PURPOSE: IL-33 signals through ST2 receptors and induces adaptive and innate inflammation. IL-33/ST2 is involved in adaptive inflammation-induced pain. Here, we have investigated the contribution of IL-33/ST2-triggered mechanisms to carrageenin-induced innate inflammation. EXPERIMENTAL APPROACH: Carrageenin- and IL-33-induced inflammatory responses were assessed in BALB/c- (WT) and ST2-deficient ((-/-) ) mice as follows: oedema (plethysmometer), myeloperoxidase activity (colorimetric assay), mechanical hyperalgesia (electronic version of von Frey filaments), cytokine levels (ELISA), PGE2 (RIA), mRNA expression (quantitative PCR), drug treatments targeting leukocyte recruitment (fucoidin), TNF-alpha (infliximab), CXCL1 (antibody to CXCL1), IL-1 (IL-1ra), endothelin ETA (clazosentan) and ETB (BQ788) receptors and COX (indomethacin). KEY RESULTS: Carrageenin injection increased ST2 and IL-33 mRNA expression and IL-33 production in paw skin samples. Carrageenin-induced paw oedema, hyperalgesia and myeloperoxidase activity were reduced in ST2(-/-) compared with WT mice, effects mimicked by IL-33 injection in the paw. Furthermore, IL-33-induced hyperalgesia was reduced by fucoidin suggesting a role for recruited leukocytes in its hyperalgesic effect. IL-33-induced hyperalgesia in naive mice was reduced by treatments targeting TNF, CXCL1, IL-1, endothelin receptors and COX while carrageenin-induced ST2-dependent TNF-alpha, CXCL1, IL 1beta, IL-10 and PGE2 production and preproET-1 mRNA expression. Combining IL-33 and carrageenin at doses that were ineffective as single treatment induced significant hyperalgesia, oedema, myeloperoxidase activity and cytokine production in a ST2-dependent manner. CONCLUSIONS AND IMPLICATIONS: IL-33/ST2 signalling triggers the production of inflammatory mediators contributing to carrageenin-induced inflammation. These data reinforces the importance of IL 33/ST2 signalling as a target in innate inflammation and inflammatory pain. PMID- 23347083 TI - Reactions of acids with naphthyridine-functionalized ferrocenes: protonation and metal extrusion. AB - Reaction of 1,8-naphthyrid-2-yl-ferrocene (FcNP) with a variety of acids affords protonated salts at first, whereas longer reaction time leads to partial demetalation of FcNP resulting in a series of Fe complexes. The corresponding salts [FcNP.H][X] (X = BF(4) or CF(3)SO(3) (1)) are isolated for HBF(4) and CF(3)SO(3)H. Reaction of FcNP with equimolar amount of CF(3)CO(2)H for 12 h affords a neutral complex [Fe(FcNP)(2)(O(2)CCF(3))(2)(OH(2))(2)] (2). Use of excess acid gave a trinuclear Fe(II) complex [Fe(3)(H(2)O)(2)(O(2)CCF(3))(8)(FcNP.H)(2)] (3). Three linear iron atoms are held together by four bridging trifluoroacetates and two aqua ligands in a symmetric fashion. Reaction with ethereal solution of HCl afforded [(FcNP.H)(3)(Cl)][FeCl(4)](2) (4) irrespective of the amount of the acid used. Even the picric acid (HPic) led to metal extrusion giving rise to [Fe(2)(Cl)(2)(FcNP)(2)(Pic)(2)] (5) when crystallized from dichloromethane. Metal extrusion was also observed for CF(3)SO(3)H, but an analytically pure compound could not be isolated. The demetalation reaction proceeds with an initial proton attack to the distal nitrogen of the NP unit. Subsequently, coordination of the conjugate base to the electrophilic Fe facilitates the release of Cp rings from metal. The conjugate base plays an important role in the demetalation process and favors the isolation of the Fe complex as well. The 1,1'-bis(1,8-naphthyrid-2 yl)ferrocene (FcNP(2)) does not undergo demetalation under identical conditions. Two NP units share one positive charge causing the Fe-Cp bonds weakened to an extent that is not sufficient for demetalation. X-ray structure of the monoprotonated FcNP(2) reveals a discrete dimer [(FcNP(2).H)](2)[OTf](2) (6) supported by two N-H...N hydrogen bonds. Crystal packing and dispersive forces associated with intra- and intermolecular pi-pi stacking interactions (NP...NP and Cp...NP) allow the formation of the dimer in the solid-state. The protonation and demetalation reactions of FcNP and FcNP(2) with a variety of acids are reported. PMID- 23347084 TI - Adipophilin/perilipin-2 as a lipid droplet-specific marker for metabolically active cells and diseases associated with metabolic dysregulation. AB - AIMS: Lipid droplets (LDs) are dynamic storage compartments for energy-rich fats that are nearly ubiquitously present in eukaryotic cells, exerting tissue specific functions in metabolically active cell types, and are increased in conditions following cellular damage or lipid overload. The LD-cytoplasm interface is stabilized by amphiphilic proteins of the PAT/perilipin family (perilipin/perilipin-1, adipophilin/perilipin-2, and TIP47/perilipin-3). We evaluated the value of adipophilin immunohistochemistry for the diagnosis of diseases associated with LD accumulation. METHODS AND RESULTS: In human tissues, adipophilin-positive LDs were especially prominent in steroidogenic cells of the adrenal gland, testis, and ovary, in hepatocytes and hepatic stellate cells, in cardiac, striated and smooth myocytes, in lactating mammary gland epithelial cells, and in plurivacuolar adipocytes. Variable amounts of adipophilin-positive LDs were also detected almost ubiquitously in epithelial cells of the gastrointestinal tract and skin. In diseases associated with lipid storage, adipophilin was strongly expressed in lipid-laden macrophages in atherosclerosis, in cardiomyopathies, kidney diseases, hepatocyte steatosis, colon ischaemia, and at the border of organ infarcts. CONCLUSIONS: Adipophilin immunohistochemistry visualizes small LDs in tissues under physiological and disease conditions that are not visible by conventional light microscopy. Immunohistology for adipophilin may facilitate histomorphological diagnosis of diseases and definition of the extent of metabolic dysregulation, such as in organ infarcts, cardiomyopathies, kidney diseases, and microvesicular steatosis. PMID- 23347086 TI - Ontogenic changes rather than difference in temperature cause understory trees to leaf out earlier. AB - In a temperate climate, understory trees leaf out earlier than canopy trees, but the cause of this discrepancy remains unclear. This study aims to investigate whether this discrepancy results from ontogenic changes or from microclimatic differences. Seedlings of five deciduous tree species were grown in spring 2012 in the understory and at canopy height using a 45-m-high construction crane built into a mature mixed forest in the foothills of the Swiss Jura Mountains. The leaf development of these seedlings, as well as conspecific adults, was compared, taking into account the corresponding microclimate. The date of leaf unfolding occurred 10-40 d earlier in seedlings grown at canopy level than in conspecific adults. Seedlings grown in the understory flushed c. 6 d later than those grown at canopy height, which can be attributed to the warmer temperatures recorded at canopy height (c. 1 degrees C warmer). This study demonstrates that later leaf emergence of canopy trees compared with understory trees results from ontogenic changes and not from the vertical thermal profile that exists within forests. This study warns against the assumption that phenological data obtained in warming and photoperiod experiments on juvenile trees can be used for the prediction of forest response to climate warming. PMID- 23347085 TI - Treatment of sirolimus-eluting stent restenosis: additional stent, balloon angioplasty, and coronary artery bypass graft. AB - OBJECTIVE: Sirolimus-eluting stent (SES) has shown a significant efficacy in reducing restenosis after percutaneous coronary interventions. However, an increase in total number of SES use along with targeting more complex lesions generated a large number of SES restenosis. This study aimed to investigate the clinical and angiographic outcomes of different revascularization strategies for SES restenosis. METHODS AND RESULTS: A total of 176 lesions in 149 patients were included in the study. Fifteen patients underwent coronary artery bypass graft surgery (CABG group) and the remaining patients were treated with percutaneous coronary intervention (PCI). Stent reimplantation was performed in 88 patients (Stent group), whereas 46 patients received balloon therapy (Balloon group). Among 176 lesions, major cardiac adverse event (MACE) occurred in 41 lesions (23.3%) during a median follow-up of 310 days (interquartile range: 146-517 days). The Kaplan-Meier method with a log-rank test revealed no significant difference in MACE rates between the three groups (6%, 25%, 26%, p = 0.13; CABG group, Stent group, Balloon group, respectively). However, when the Balloon group and Stent group were combined together as a PCI group, PCI group had a significantly higher rate of MACE compared with the CABG group (p = 0.04). In addition, angiographic restenosis was significantly less prevalent in the CABG group when compared with the other two groups (8%, 57%, 46%, p = 0.006; CABG group, Stent group, Balloon group, respectively). CONCLUSIONS: CABG surgery for patients with SES restenosis is associated with the better clinical outcomes as well as better angiographic outcomes when compared with that of PCI. PMID- 23347087 TI - Hospitalization for vitamin-K-antagonist-related bleeding: treatment patterns and outcome. AB - BACKGROUND: Bleeding complications are common side effects of vitamin-K antagonist (VKA) therapy. Data on the in-hospital management and outcomes of these bleeding events are scarce and information is mostly derived from trial cohorts. OBJECTIVES: The objective was to collect data on the management and clinical outcome of hospitalizations owing to VKA-related bleeding in real-world practice. PATIENTS AND METHODS: We performed a multicenter observational cohort study involving 21 secondary and tertiary care hospitals in the administrative district Dresden, Saxony, Germany throughout the year 2005. All consenting patients presenting with VKA-related bleeding complications were included. No exclusion criteria applied. Data were collected at admission, at discharge and at 90 days to evaluate resource consumption, length of hospital stay and risk factors for in-hospital- and 3-month mortality. RESULTS: Two hundred and ninety patients were included (median age 74 years; 50.7% male). The main indications for VKA therapy were atrial fibrillation (63.4%), prior thromboembolism (18.6%) and mechanical heart valves (11.4%), and most common bleeding localizations were large hematoma (23.1%), upper gastrointestinal (GI) tract (17.9%) and intracranial bleeding (14.1%). On hospital admission, the median International Normalized Ratio (INR) was 3.0 (range 0.9-12.5, interquartile range [IQR] 2.1 3.9). In-hospital mortality was 7.6% with impaired renal function as the most relevant risk factor. At 90 days mortality was 14.1% and 15.3% of survivors were help-dependent. CONCLUSIONS: VKA-related bleeding leading to hospitalization is associated with long hospitalization, relevant resource utilization, high mortality or persistent sequlae. Patient-related factors such as impaired renal function, chronic cardiac or pulmonary disease and dementia are predictive of in hospital and 3-month mortality. PMID- 23347088 TI - Association of a missense nucleotide polymorphism in the MT-ND2 gene with mitochondrial reactive oxygen species production in the Tibet chicken embryo incubated in normoxia or simulated hypoxia. AB - NADH dehydrogenase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone with pumping protons across the mitochondrial inner membrane and produces reactive oxygen species as a major source in mitochondria. A missense mutation in the mitochondrially encoded NADH dehydrogenase 2 (MT-ND2) gene, which could produce a change in the protein's secondary structure, has been found in the Tibet chicken breed. In this study, breeding eggs of the Tibet chicken breed with the two genotypes were divided into two groups. One group was incubated in normoxia (20.9% oxygen concentration) and the other in simulated hypoxia (14.5% oxygen concentration). On the 16th day of incubation, complex I activity and mitochondrial reactive oxygen species production in the Tibet chicken embryonic liver with different genotypes in each group were measured. Results showed that: (1) hypoxia reduced complex I activity standardized and mitochondrial reactive oxygen species production significantly compared with normoxia and (2) the missense mutation in the MT-ND2 gene was significantly associated with the production of reactive oxygen species in mitochondria while not associated with the standardized or unstandardized activity of complex I. PMID- 23347089 TI - The influence of endocrine disruptors in a selected population of infertile women. AB - Several studies report that endocrine disrupting chemicals (EDC) able to interfere with endocrine homeostasis may affect women's reproductive health. We analyzed EDC serum levels and nuclear receptors (NRs) expression in order to have an indication of the internal dose of biologically active compounds and a measurement of indicators of their effects, as a result of the repeated uptake from environmental source. The percentage of patients with detectable bisphenol A (BPA) concentrations was significantly higher in the infertile patients compared with fertile subjects. No significant difference was found between the groups with regard to perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), mono-ethylhexyl phthalate (MEHP) and di-(2-ethylhexyl) phthalate (DEHP) concentrations. Among infertile women, the mean expression of estrogen receptor alpha (ERalpha) and beta (Erbeta), androgen receptor (AR) and pregnane X receptor (PXR) was significantly higher than fertile patients. The mean expression of aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor gamma (PPARgamma) did not show significant differences between two groups. Patients with endometriosis had higher levels of PPARgamma than all women with other causes of infertility. This study led further support to EDC exposure as a risk factor for women's fertility. PMID- 23347090 TI - Two new HLA alleles, HLA-A*23:20 and HLA-A*02:127 identified in Chinese individuals. AB - Two new HLA-A alleles, A*23:20 and A*02:127, differ from their closely related alleles by nucleotide mutations. PMID- 23347091 TI - Competition for inorganic carbon between oxygenic and anoxygenic phototrophs in a hypersaline microbial mat, Guerrero Negro, Mexico. AB - While most oxygenic phototrophs harvest light only in the visible range (400-700 nm, VIS), anoxygenic phototrophs can harvest near infrared light (> 700 nm, NIR). To study interactions between the photosynthetic guilds we used microsensors to measure oxygen and gross oxygenic photosynthesis (gOP) in a hypersaline microbial mat under full (VIS + NIR) and VIS illumination. Under normal dissolved inorganic carbon (DIC) concentrations (2 mM), volumetric rates of gOP were reduced up to 65% and areal rates by 16-31% at full compared with VIS illumination. This effect was enhanced (reduction up to 100% in volumetric, 50% in areal rates of gOP) when DIC was lowered to 1 mM, but diminished at 10 mM DIC or lowered pH. In conclusion, under full-light illumination anoxygenic phototrophs are able to reduce the activity of oxygenic phototrophs by efficiently competing for inorganic carbon within the highly oxygenated layer. Anoxygenic photosynthesis, calculated from the difference in gOP under full and VIS illumination, represented between 10% and 40% of the C-fixation. The DIC depletion in the euphotic zone as well as the significant C-fixation by anoxygenic phototrophs in the oxic layer influences the carbon isotopic composition of the mat, which needs to be taken into account when interpreting isotopic biosignals in geological records. PMID- 23347092 TI - Global alcohol exposure estimates by country, territory and region for 2005--a contribution to the Comparative Risk Assessment for the 2010 Global Burden of Disease Study. AB - AIMS: This study aimed to estimate the prevalence of life-time abstainers, former drinkers and current drinkers, adult per-capita consumption of alcohol and pattern of drinking scores, by country and Global Burden of Disease region for 2005, and to forecast these indicators for 2010. DESIGN: Statistical modelling based on survey data and routine statistics. SETTING AND PARTICIPANTS: A total of 241 countries and territories. MEASUREMENTS: Per-capita consumption data were obtained with the help of the World Health Organization's Global Information System on Alcohol and Health. Drinking status data were obtained from Gender, Alcohol and Culture: An International Study, the STEPwise approach to Surveillance study, the World Health Survey/Multi-Country Study and other surveys. Consumption and drinking status data were triangulated to estimate alcohol consumption across multiple categories. FINDINGS: In 2005 adult per capita annual consumption of alcohol was 6.1 litres, with 1.7 litres stemming from unrecorded consumption; 17.1 litres of alcohol were consumed per drinker, 45.8% of all adults were life-time abstainers, 13.6% were former drinkers and 40.6% were current drinkers. Life-time abstention was most prevalent in North Africa/Middle East and South Asia. Eastern Europe and Southern sub-Saharan Africa had the most detrimental pattern of drinking scores, while drinkers in Europe (Eastern and Central) and sub-Saharan Africa (Southern and West) consumed the most alcohol. CONCLUSIONS: Just over 40% of the world's adult population consumes alcohol and the average consumption per drinker is 17.1 litres per year. However, the prevalence of abstention, level of alcohol consumption and patterns of drinking vary widely across regions of the world. PMID- 23347093 TI - 'A giant mess'--making sense of complexity in the accounts of people with fibromyalgia. AB - OBJECTIVES: The diagnosis of fibromyalgia is based on self-report and indirect measures and thus is unavoidably influenced by patients' own understanding of their symptoms. In order to provide appropriate support for people with fibromyalgia, it is important to understand variation in patients' interpretations of their own symptoms. METHODS: Twenty people with fibromyalgia participated in email interviews exploring their experiences, history and diagnosis. Respondents answered a series of questions in their own time. Rich accounts were elicited. A hermeneutic phenomenological approach linked two stages of analysis. In the first instance, an in-depth, inductive analysis was developed around a subset of eight transcripts, using interpretative phenomenological analysis. The outcomes of this work were then used to inform a template analysis, which was applied to the remaining 12 transcripts, in order to extend and check the credibility of the in-depth analysis. RESULTS: Participants described enduring the course of a 'giant mess' of unpleasant symptoms, some of which were understood to be symptoms of fibromyalgia and some the interactive or parallel effects of comorbid illness. The respondents also demonstrated their considerable efforts at imposing order and sense on complexity and multiplicity, in terms of the instability of their symptoms. They expressed ambivalence towards diagnosis, doctors and medication, and we noted that each of the above areas appeared to come together to create a context of relational uncertainty, which undermined the security of connections to family, friends, colleagues and the workplace. CONCLUSIONS: Three key issues were discussed. First, there was not one overall symptom (e.g., pain) driving the unpleasantness of fibromyalgia; second, participants spent excessive time and energy trying to manage forces outside their control; third, because there is no definitive 'fibromyalgia experience', each diagnosis is unique, and our participants often appeared to be struggling to understand the course of their illness. Issues of stigma and legitimacy need to be considered carefully by health professionals in the context of the complex and uncertain experience of patients. PMID- 23347094 TI - Real-time feedback on knee abduction moment does not improve frontal-plane knee mechanics during jump landings. AB - Excessive knee abduction loading is a contributing factor to anterior cruciate ligament (ACL) injury risk. The purpose of this study was to determine whether a double-leg landing training program with real-time visual feedback improves frontal-plane mechanics during double- and single-leg landings. Knee abduction angles and moments and vertical ground reaction forces (GRF) of 21 recreationally active women were quantified for double- and single-leg landings before and after the training program. This program consisted of two sessions of double-leg jump landings with real-time visual feedback on knee abduction moments for the experimental group and without real-time feedback for the control group. No significant differences were found between training groups. In comparison with pre-training data, peak knee abduction moments decreased 12% post-training for both double- and single-leg landings; whereas peak vertical GRF decreased 8% post training for double-leg landings only, irrespective of training group. Real-time feedback on knee abduction moments, therefore, did not significantly improve frontal-plane knee mechanics during landings. The effect of the training program on knee abduction moments, however, transferred from the double-leg landings (simple task) to single-leg landings (more complex task). Consequently, ACL injury prevention efforts may not need to focus on complex tasks during which injury occurs. PMID- 23347095 TI - Investigating the impact of a community-based geriatric dentistry rotation on oral health literacy and oral hygiene of older adults. AB - OBJECTIVE: This study investigated the impact of a community-based geriatric dentistry rotation on older adults' oral health literacy and oral hygiene. MATERIALS AND METHODS: A pre-post study design was used to assess the impact of the educational intervention. The study sample consisted of 67 older adults, who resided in independent or assisted living apartments (age: M = 84, SD = 7.3). Over the course of the programme, participants received patient education pertaining to oral health and oral hygiene. Oral health literacy was assessed using the Rapid Estimation of Adult Literacy in Dentistry (REALD-30) test at baseline and on the final visit. Oral hygiene was measured on four visits using the O'Leary, Drake and Naylor Plaque Control Record (PI). RESULTS: REALD-30 scores significantly increased, and PI scores significantly decreased for all subjects following participation in the programme (p < 0.001, and p < 0.01, respectively). Hierarchical multiple regression demonstrated that neither study subjects' individual characteristics nor their health literacy significantly predicted the change in oral hygiene. CONCLUSION: This study demonstrated that a community-based geriatric dentistry rotation involving multiple interactions with dental students can in the short term significantly and positively impact older adults' oral health literacy and oral hygiene status. PMID- 23347096 TI - Air pollution interacts with past episodes of bronchiolitis in the development of asthma. AB - BACKGROUND: Exposure to ambient air pollution and bronchiolitis are risk factors for asthma. The aim of this study was to investigate the effect of air pollution on the development of asthma in children with past episodes of bronchiolitis. METHODS: A prospective 2-year follow-up survey consisting of parental responses to the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, and allergy evaluations were conducted in 1743 children with a mean age of 6.8 years. Recent 5-year exposure to air pollution was estimated using a geographic information system. RESULTS: Higher exposure to ozone was associated with airway hyper-responsiveness (PC20 <= 16 mg/ml) at enrollment (odds ratio [OR] = 1.60, 95% CI [confidence interval] = 1.13-2.27) and with new episodes of wheezing during the 2-year period (OR = 1.92, 95% CI = 0.96-3.83). Past episodes of bronchiolitis were associated with both current wheezing and physician-diagnosed asthma. When the two factors were combined, the prevalence of bronchial hyper-reactivity (OR = 2.96, 95% CI = 1.41-6.24) and new wheezing (OR = 4.17, 95% CI = 0.89-19.66) as well as current wheezing and physician-diagnosed asthma was even greater (P for trend <0.05 for all). In children with both risk factors, lung function was significantly decreased, with atopic children being particularly vulnerable. CONCLUSION: In children, the interaction between air pollution and past episodes of bronchiolitis resulted in a greater prevalence of asthma and pointed to an association with bronchial hyper-reactivity and decreased lung function. These results suggest mechanisms underlying the development of asthma. PMID- 23347097 TI - Health status and preventative behaviors of immigrants by gender and origin: a Portuguese cross-sectional study. AB - Migration has been associated with a greater vulnerability in health. Migrants, especially women, go through several experiences during the migration process and in the host countries that ultimately put their health at risk. This study examines self-reported health status and preventive behaviors among female and male immigrants in Portugal, and identifies sociodemographic and behavioral factors underlying gender differences. A sample of 1375 immigrants (51.1% women) was studied. Data were analyzed through logistic regression. Good health status was reported by 66.7% of men and by 56.6% of women (P < 0.001). Gender differences were also found across preventative behaviors. Among women and men, reported good health was associated with younger age, African and Brazilian origin (compared to Eastern European), secondary/higher education, no chronic disease, and concern about eating habits. Among women, good health was also associated with perceived sufficient income, no experience of mental illness, and regular physical exercise. When developing health programs to improve immigrants' health, special attention must be given to existing gender inequalities, and socioeconomic and cultural context, in accordance with their experience of living in the host country over time. PMID- 23347098 TI - Introduction to nuclear chemistry. PMID- 23347099 TI - The MYSTerious MOZ, a histone acetyltransferase with a key role in haematopoiesis. AB - The MOnocytic leukaemia Zing finger (MOZ; MYST3 or KAT6A(1)) gene is frequently found translocated in acute myeloid leukaemia. MOZ encodes a large multidomain protein that contains, besides others, a histone acetyl transferase catalytic domain. Several studies have now established the critical function of MOZ in haematopoiesis. In this review we summarize the recent findings that underscore the relevance of the different biological activities of MOZ in the regulation of haematopoiesis. PMID- 23347100 TI - Prospective, multidimensional evaluation of sexual disorders in men after laser photovaporization of the prostate. AB - INTRODUCTION: A few studies have investigated the impact of photovaporization of the prostate (PVP) on sexual function and were mainly focused on erectile function. AIMS: To comprehensively evaluate the impact of PVP on sexual function. METHODS: A prospective evaluation involved sexually active patients needing surgical relief of bladder outlet obstruction due to benign prostatic enlargement in a single center between August 2007 and November 2011. All patients underwent PVP using the GreenLight HPSTM 120W system (AmericanMedicalSystems, Minnetonka, MN, USA). MAIN OUTCOME MEASURES: Patients were evaluated preoperatively and postoperatively by International Prostate Symptom Score (I-PSS), I-PSS question 8, uroflowmetry parameters (maximum urinary flow rate [Qmax ] and postvoid residual [PVR] volume), Danish Prostate Symptom Score Sexual items (DAN-PSSsex), and overall sexual satisfaction using a seven-grade Likert scale. Operative parameters and postoperative complications were also assessed. Preoperative and postoperative values were compared using the Pearson chi-square test and the Wilcoxon paired test. A multivariable model was used to investigate the determinants of variation of global sexual satisfaction. RESULTS: One hundred and two consecutive patients with 12-month follow-up data were included in the analysis. Urinary parameters (I-PSS, Qmax , and PVR) were significantly improved compared with preoperative values. Compared with baseline, postoperative erection symptom score was not significantly different, whereas ejaculation symptom score was significantly worse. Global DAN-PSSsex score was unchanged, but DAN-PSSsex symptom score was worse (P = 0.04) and DAN-PSSsex bother score was significantly improved (P < 0.0001). Global sexual satisfaction was significantly improved compared with baseline (P = 0.02) and was significantly associated with I-PSS but not with erection and ejaculation score in a multivariable model. CONCLUSION: Ejaculation is the main sexual function impacted by PVP. Despite this, sexual satisfaction and bother due to sexual symptoms were significantly improved, probably due to the positive impact of urinary symptom relief. PMID- 23347101 TI - Phylogenetic group-associated differences in regulation of the common colonization factor Mat fimbria in Escherichia coli. AB - Heterogeneity of cell population is a key component behind the evolutionary success of Escherichia coli. The heterogeneity supports species adaptation and mainly results from lateral gene transfer. Adaptation may also involve genomic alterations that affect regulation of conserved genes. Here we analysed regulation of the mat (or ecp) genes that encode a conserved fimbrial adhesin of E. coli. We found that the differential and temperature-sensitive expression control of the mat operon is dependent on mat promoter polymorphism and closely linked to phylogenetic grouping of E. coli. In the mat promoter lineage favouring fimbriae expression, the mat operon-encoded regulator MatA forms a positive feedback loop that overcomes the repression by H-NS and stabilizes the fimbrillin mRNA under low growth temperature, acidic pH or elevated levels of acetate. The study exemplifies phylogenetic group-associated expression of a highly common surface organelle in E. coli. PMID- 23347102 TI - Alcohol and sleep I: effects on normal sleep. AB - This review provides a qualitative assessment of all known scientific studies on the impact of alcohol ingestion on nocturnal sleep in healthy volunteers. At all dosages, alcohol causes a reduction in sleep onset latency, a more consolidated first half sleep and an increase in sleep disruption in the second half of sleep. The effects on rapid eye movement (REM) sleep in the first half of sleep appear to be dose related with low and moderate doses showing no clear trend on REM sleep in the first half of the night whereas at high doses, REM sleep reduction in the first part of sleep is significant. Total night REM sleep percentage is decreased in the majority of studies at moderate and high doses with no clear trend apparent at low doses. The onset of the first REM sleep period is significantly delayed at all doses and appears to be the most recognizable effect of alcohol on REM sleep followed by the reduction in total night REM sleep. The majority of studies, across dose, age and gender, confirm an increase in slow wave sleep (SWS) in the first half of the night relative to baseline values. The impact of alcohol on SWS in the first half of night appears to be more robust than the effect on REM sleep and does not appear to be an epiphenomenon REM sleep reduction. Total night SWS is increased at high alcohol doses across gender and age groups. PMID- 23347103 TI - Prevalence of MED12 mutations in uterine and extrauterine smooth muscle tumours. AB - AIMS: To determine the prevalence of MED12 mutations in smooth muscle tumours of different organs. METHODS AND RESULTS: A total of 142 smooth muscle tumours of the uterus, gastrointestinal tract, retroperitoneum and soft tissue were analysed for MED12 mutations using Sanger sequencing. Among the uterine tumours that were examined, MED12 mutations were identified in 36 of 45 conventional leiomyomas (80%), two of six cellular leiomyomas (33%), one of four bizarre leiomyomas (25%), none of four lipoleiomyomas (0%), and two of 12 leiomyosarcomas (17%). The two MED12-mutated leiomyosarcomas were associated with benign leiomyomatous components that also harboured MED12 mutations identical to those in the respective leiomyosarcomatous components. None of the extrauterine smooth muscle tumours, including the leiomyomas, leiomyosarcomas, and angioleiomyomas, had MED12 mutations. CONCLUSIONS: Among uterine smooth muscle tumours, MED12 mutations are frequently present in conventional leiomyomas, but are significantly less common in histological variants of leiomyoma and leiomyosarcoma. In contrast to uterine lesions, none of the extrauterine smooth muscle tumours had MED12 mutations. PMID- 23347104 TI - Hydrophilic and hydrophobic hydration of sodium propanoate and sodium butanoate in aqueous solution. AB - Aqueous solutions of sodium propanoate (NaOPr) and n-butanoate (NaOBu) have been studied at concentrations of c ~/< 3 M by broadband dielectric relaxation spectroscopy over the frequency range 0.2 <= nu/GHz <= 89 at 25 degrees C. Three relaxation modes were resolved, centered at (approximately) 1, 8, and 18 GHz, for both sets of solutions. The two faster modes were assigned to the cooperative relaxation of "slow" and bulk water molecules. Detailed analysis of the spectra indicated that both OPr(-) and OBu(-) were strongly hydrated, with ~23 and ~33 slow water molecules per anion, respectively, at infinite dilution. These effective hydration numbers include ~6 water molecules hydrophilically bound to the carboxylate moiety, with the remainder arising from the hydrophobic hydration of the nonpolar alkyl chains. The latter shows a characteristic rapid decrease with increasing solute concentration, which facilitated the separation of the hydrophobic and hydrophilic contributions. The lowest frequency mode was a composite with contributions from ion-cloud, ion-pair, and anion relaxations. Although this low intensity mode provided specific evidence of weak ion pairing between Na(+)(aq) and the carboxylate anions, reliable estimates of the association constant could not be made because of its composite nature. PMID- 23347105 TI - Use of the canonical discriminant analysis to select SNP markers for bovine breed assignment and traceability purposes. AB - Several market research studies have shown that consumers are primarily concerned with the provenance of the food they eat. Among the available identification methods, only DNA-based techniques appear able to completely prevent frauds. In this study, a new method to discriminate among different bovine breeds and assign new individuals to groups was developed. Bulls of three cattle breeds farmed in Italy - Holstein, Brown, and Simmental - were genotyped using the 50K SNP Illumina BeadChip. Multivariate canonical discriminant analysis was used to discriminate among breeds, and discriminant analysis (DA) was used to assign new observations. This method was able to completely identify the three groups at chromosome level. Moreover, a genome-wide analysis developed using 340 linearly independent SNPs yielded a significant separation among groups. Using the reduced set of markers, the DA was able to assign 30 independent individuals to the proper breed. Finally, a set of 48 high discriminant SNPs was selected and used to develop a new run of the analysis. Again, the procedure was able to significantly identify the three breeds and to correctly assign new observations. These results suggest that an assay with the selected 48 SNP could be used to routinely track monobreed products. PMID- 23347106 TI - Effect of inhaled corticosteroids on the microbiology of the respiratory tract. PMID- 23347109 TI - Valvular heart disease in patients with osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) or "brittle bone disease" is a rare connective tissue hereditary disorder. The most common clinical presentation of OI is bone fractures. OI also involves extraskeletal structures; however, cardiovascular manifestations are rare. In this report, we describe the cardiovascular anomalies of patients with OI who underwent valve surgery and review the literature on this subject. PMID- 23347110 TI - Routine bacterial screening of apheresis platelets on Day 4 using a rapid test: a 4-year single-center experience. AB - BACKGROUND: The platelet (PLT) Pan Genera Detection test (PGD) is a rapid bacterial detection system used to screen PLTs for bacterial contamination. We report a single center 46-month experience with secondary screening of apheresis PLTs by PGD testing. STUDY DESIGN AND METHODS: Existing testing records of apheresis PLTs screened by PGD from July 2008 to April 2012 were reviewed. All PLT units were initially screened by routine postcollection culture methods. Secondary screening using PGD was performed for indated PLTs on PLT storage Day 4 and for outdated PLTs on Day 8. RESULTS: A total of 8535 apheresis PLTs were available in inventory during the study period. Of these, 5030 (58.9%) were dispensed and transfused before PGD testing and 3505 (41.1%) underwent PGD testing on Day 4. Twenty-five units tested on Day 4 were PGD initial reactive (0.71%). All were confirmed to be false positive by repeat PGD testing in triplicate (n=20) or by confirmatory culture (n=5). An additional 364 units that were PGD nonreactive on Day 4 were approved for transfusion on Day 6 or Day 7 due to urgent clinical need. A total of 371 outdated units underwent repeat PGD testing before discard on Day 8; all were nonreactive. CONCLUSION: Secondary PGD testing of culture-screened apheresis PLTs results in low yield in a medium-sized transfusion service. Use of PGD testing on Day 4 may allow for extension of the apheresis PLT shelf life to Day 7 for hospitals that face supply constraints. PMID- 23347113 TI - Who sleeps best? Longitudinal patterns and covariates of change in sleep quantity, quality, and timing across four university years. AB - This study tracked change over time in sleep quantity, disturbance, and timing, and sleep's covariations with living situation, stress, social support, alcohol use, and grade point average (GPA) across four years of university in 186 Canadian students. Women slept longer as they moved through university, and men slept less; rise times were later each year. Students reported sleeping fewer hours, more sleep disturbances, and later rise times during years with higher stress. In years when students lived away from home, they reported more sleep disturbances, later bedtimes, and later rise times. Living on campus was associated with later bedtimes and rise times. Alcohol use was higher and GPA was lower when bedtimes were later. The implications of these observed patterns for understanding the correlates and consequences of university students' sleep are discussed. PMID- 23347114 TI - Patient-reported outcomes in insomnia: development of a conceptual framework and endpoint model. AB - This article describes qualitative research conducted with patients with clinical diagnoses of insomnia and focuses on the development of a conceptual framework and endpoint model that identifies a hierarchy and interrelationships of potential outcomes in insomnia research. Focus groups were convened to discuss how patients experience insomnia and to generate items for patient-reported questionnaires on insomnia and associated daytime consequences. Results for the focus group produced two conceptual frameworks: one for sleep and one for daytime impairment. Each conceptual framework consists of hypothesized domains and items in each domain based on patient language taken from the focus group. These item pools may ultimately serve as a basis to develop new questionnaires to assess insomnia. PMID- 23347115 TI - The oft-forgotten side of our behavioral sleep medicine work. PMID- 23347116 TI - Understanding patient responses to insomnia. AB - To better gain insight into patient responses to insomnia, we take a medical anthropologically informed approach to patient beliefs and behaviors, particularly those related to self-diagnosis, management, help-seeking, and self treatment of insomnia. We conducted 24 in-depth qualitative interviews in which participants were asked their beliefs about the origin of their insomnia, its anticipated course, their evaluation of symptoms, their responses, and their expectations surrounding treatment. Important and novel data were generated about patient beliefs and behaviors related to problem sleeping. Patients identified barriers to treatment, particularly those contextualized within a general social stigma and personal isolation, in which their problems sleeping were not taken seriously. The interview format was particularly conducive to making patients comfortable discussing the personal changes they made to their medically prescribed treatment plans, or supplanting their medical therapy with some kind of complimentary and alternative medicine (CAM) therapy. These are important issues in the long term management of chronic insomnia. We underscore concern about the need to evaluate the efficacy of therapies that so many people with insomnia are driven to try. PMID- 23347117 TI - Information processing varies between insomnia types: measures of N1 and P2 during the night. AB - This study compared cortical arousal mechanisms during the night using event related potentials (N1 and P2), and compared sleep misperception in 30 adults with psychophysiological insomnia (Psy-I), 28 adults with paradoxical insomnia (Para-I), and 30 good sleepers (GS). Participants (age range = 25-55 years) spent 4 consecutive nights in the laboratory, and Night-4 data were used for analysis. N1 amplitude was generally larger in both insomnia groups compared to GS, and P2 amplitude was larger in Para-I than in the 2 other groups, especially in REM sleep. Results suggest that, although hyperarousal appears to persist during sleep in adults with insomnia, inhibition deficits are more likely to be present in Para-I compared to Psy-I. PMID- 23347119 TI - A chemosensor built with rhodamine derivatives appended to an aromatic platform via 1,2,3-triazoles: dual detection of aluminum(III) and fluoride/acetate ions. AB - A triazole-ring-appended rhodamine dye (L) has been synthesized that serves as a chromogenic and fluorogenic sensor for dual sensing of aluminum(III) and fluoride or acetate ions specifically. PMID- 23347120 TI - Measuring Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: A recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. AB - Oral direct inhibitors (ODIs) of thrombin and factor Xa are now approved as anticoagulant drugs. The first two drugs to complete phase III clinical trials for thromboprophylaxis in orthopaedic surgery and treatment of patients with atrial fibrillation or venous thromboembolism were dabigatran and rivaroxaban. These small molecules are given at fixed dose with no requirement for monitoring as pharmacokinetic and pharmacodynamic responses are reliably predicted in patients with adequate renal function who are not taking other interacting drugs. However, there will be clinical circumstances in specific patients when measurement of the anticoagulant effect of an ODI will be required. (c) 2013 International Society on Thrombosis and Haemostasis. PMID- 23347118 TI - Inhibition of fatty acid amide hydrolase activates Nrf2 signalling and induces heme oxygenase 1 transcription in breast cancer cells. AB - BACKGROUND AND PURPOSE: Endocannabinoids such as anandamide (AEA) are important lipid ligands regulating cell proliferation, differentiation and apoptosis. Their levels are regulated by hydrolase enzymes, the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Here, we investigated whether FAAH or AEA are involved in NF (erythroid-derived 2)-like 2 (Nrf2)/antioxidant responsive element (ARE) pathway. EXPERIMENTAL APPROACH: The aim of this study was to analyse the effects of AEA or FAAH inhibition by the URB597 inhibitor or FAAH/siRNA on the activation of Nrf2-ARE signalling pathway and heme oxygenase-1 (HO-1) induction and transcription. KEY RESULTS: Endogenous AEA was detected in the immortalized human mammary epithelial MCF-10A cells (0.034 ng per 10(6) cells) but not in MCF 7 or MDA-MB-231 breast cancer cells. Because breast tumour cells express FAAH abundantly, we examined the effects of FAAH on Nrf2/antioxidant pathway. We found that inhibition of FAAH by the URB597 inhibitor induced antioxidant HO-1 in breast cancer cells and MCF-10A cells. RNAi-mediated knockdown of FAAH or treatment with AEA-activated ARE-containing reporter induced HO-1 mRNA and protein expression, independent of the cannabinoid receptors, CB1, CB2 or TRPV1. Furthermore, URB597, AEA and siRNA-FAAH treatments induced the nuclear translocation of Nrf2, while siRNA-Nrf2 treatment and Keap1 expression blocked AEA, URB597 and si-FAAH from activation of ARE reporter and HO-1 induction. siRNA HO-1 treatment decreased the viability of breast cancer cells and MCF-10A cells. CONCLUSIONS AND IMPLICATIONS: These data uncovered a novel mechanism by which inhibition of FAAH or exposure to AEA induced HO-1 transcripts and implicating AEA and FAAH as direct modifiers in signalling mediated activation of Nrf2-HO-1 pathway, independent of cannabinoid receptors. PMID- 23347122 TI - Many apples a day keep the blues away--daily experiences of negative and positive affect and food consumption in young adults. AB - OBJECTIVES: Prior research has focused on the association between negative affect and eating behaviour, often utilizing laboratory or cross-sectional study designs. These studies have inherent limitations, and the association between positive affect and eating behaviour remains relatively unexplored. Therefore, the objective of this study was to investigate the bidirectional relationships between daily negative and positive affective experiences and food consumption in a naturalistic setting among healthy young adults. DESIGN: Daily diary study across 21 days (microlongitudinal, correlational design). METHODS: A total of 281 young adults with a mean age of 19.9 (+/- 1.2) years completed an Internet-based daily diary for 21 consecutive days. Each day they reported their negative and positive affect, and their consumption of five specific foods. Hierarchical linear modelling was used to test same-day associations between daily affect and food consumption, and next-day (lagged) associations to determine directionality. Moderating effects of BMI and gender were also examined in exploratory analyses. RESULTS: Analyses of same-day within-person associations revealed that on days when young adults experienced greater positive affect, they reported eating more servings of fruit (p = .002) and vegetables (p < .001). Results of lagged analysis showed that fruits and vegetables predicted improvements in positive affect the next day, suggesting that healthy foods were driving affective experiences and not vice versa. Meaningful changes in positive affect were observed with the daily consumption of approximately 7-8 servings of fruit or vegetables. CONCLUSIONS: Eating fruit and vegetables may promote emotional well being among healthy young adults. PMID- 23347121 TI - Paediatric oral peanut challenges: a comparison of practice in London and western Switzerland. AB - BACKGROUND: There are guidelines on how to develop a food challenge protocol, but at present there is no gold standard guidance on method, and separate units produce differing protocols. METHODS: We performed a retrospective analysis of 200 patients' data from the paediatric allergy units in Lausanne and Geneva, Western Switzerland, and St Thomas' Hospital (STH), UK. RESULTS: St Thomas' Hospital has a younger cohort with a lower overall mean spIgE (2.36 kU/l vs. 8.00 kU/l, P = 0.004). The target peanut protein volumes differed: Switzerland 4.4 g vs. STH 8.4 g. Despite this, the dose actually achieved in positive challenges was not significantly different (2.33 g vs. 1.49 g, P = 0.16). 26% of challenges reacted at 4 g or more of peanut protein. CONCLUSIONS: The differences in results highlight how the variation in reasoning behind food challenge alters the outcome. Standardization of food challenges would allow easy comparison between hospitals and geographical areas for research purposes. PMID- 23347123 TI - The new HLA-C variant HLA-C*05:26 is likely to be structurally identical to the C*05:01P alleles. AB - The novel allele HLA-C*05:26 differs from HLA-C*05:01 by the non-synonymous amino acid exchange Gly16Ser. PMID- 23347124 TI - Decline in incidence of HIV and hepatitis C virus infection among injecting drug users in Amsterdam; evidence for harm reduction? AB - AIMS: In Amsterdam, HIV prevalence has nearly halved among injecting drug users (IDU) since 1990. Hepatitis C virus (HCV) prevalence also declined; HIV and HCV incidence dropped to nearly zero. We examined possible explanations for these time trends, among which the implementation of harm reduction measures aimed at reducing the risk behaviour of IDU. DESIGN: We used individual-based modelling of the spread of HIV and HCV. Information about demographic parameters was obtained from the Amsterdam Cohort Study (ACS) among drug users. The model included changes in inflow of new IDU and death rates over time, the latter dependent on age and time since HIV seroconversion. We considered different scenarios of risk behaviour. SETTING: IDU in Amsterdam. MEASUREMENTS: Simulated HIV and HCV incidence and prevalence were compared with ACS data. FINDINGS: Assuming that harm reduction measures had led to a strong decrease in risk behaviour over time improved the model fit (squared residuals decreased by 30%). However, substantial incidence and HIV prevalence decline were already reproduced by incorporating demographic changes into the model. In particular, lowered disease spread might be a result of depletion of high-risk IDU among those at risk for disease, and a decrease in the number of high-risk individuals in the population due to HIV related mortality. CONCLUSIONS: Marked decreases in HIV and HCV in Amsterdam since 1990 could be due partly to harm reduction measures; however, they may also be attributable largely to changes in the IDU population. Future research aimed at quantifying the benefits of interventions should not neglect the impact of natural epidemic progression and demographic changes. PMID- 23347125 TI - Two different solicitation methods for obtaining information on adverse events associated with methylphenidate in adolescents: a 12-week multicenter, open-label study. AB - OBJECTIVE: We explored two different methods of determining adverse events (AEs) among methylphenidate (MPH)-treated adolescents with attention deficit/hyperactivity disorder (ADHD). METHODS: We performed a 12-week open label study of osmotic-release oral system (OROS) MPH in adolescents with ADHD who were recruited from four child and adolescent psychiatric outpatient clinics. The AEs were evaluated via a two-step procedure at weeks 1, 3, 6, and 12. The first step was to ask a general question to subjects and their parents regarding AEs. The second step included an AE evaluation process by the investigators, which was performed using a drug-specific checklist. One-way repeated measures ANOVA were used to compare the number of AEs reported by patients and their parents compared with the number reported by clinicians. This statistical technique was also used to compare the number of AEs reported by various sources (i.e., patients, parents, and clinicians) at weeks 1, 3, 6, and 12. RESULTS: Of the 55 participants (43 males, 12 females) between the ages of 12 and 18 enrolled in this study, 47 participants completed the trial. When the number of AEs reported by patients, parents and clinicians were compared, there were no statistically significant differences. When the numbers of AEs obtained from the three different information sources at each study visit were compared, we noted differences. At week 6, the number of AEs evaluated by clinical investigators was higher than those reported by patients and their parents (p=0.003). Although the results did not reach statistical significance, the number of AEs reported by clinical investigators appeared to be greater than those obtained from patients or parents at weeks 3 and 12. The number of AEs reported by patients and their parents were similar at every visit. There were some differences in the pattern of AEs reported between patients and their parents. CONCLUSIONS: Clinicians should supplement the subjective report on AEs from patients or their parents with a more drug-specific checklist to obtain drug side effects more effectively. As there are some differences in the pattern of AEs reported by patients and their parents, it is generally recommended that clinicians obtain information from both parties when possible. PMID- 23347126 TI - Clozapine in severe conduct disorder. AB - METHOD: An open, naturalistic observational study design was used, in which a sample of seven boys between 10 and 14 years of age was assessed over 26 weeks. RESULTS: The subjects were all diagnosed with conduct disorder (CD) and exhibited high levels of aggression that were refractory to psychosocial approaches (parent counseling, school counseling, and psychotherapy) and to more than three pharmacological treatments. Levels of aggression, side effects, and hematological parameters were evaluated weekly. Clinical response was evaluated using the standardized instruments Clinical Global Impressions (CGI) and Child Behavior Check List (CBCL) 6-18 before starting medication and after 26 weeks. CONCLUSION: We observed good tolerability of clozapine in doses from 100 to 600 mg/day with no significant side effects or hematological changes. The CGI and CBCL 6-18 scales indicated that clozapine led to a marked control of symptoms. PMID- 23347127 TI - Informed decision making regarding antenatal screening for fetal abnormality in the United Kingdom: a qualitative study of parents and professionals. AB - The aim of this study was to explore the views of parents and health professionals regarding informed decision making for antenatal screening for Down syndrome. This qualitative study was based on thematic analysis and conducted in England, where screening for Down syndrome is universally offered to all pregnant women. Four focus groups were held with pregnant women and/or their partners (n = 22), and another four groups were held with health professionals who offer antenatal screening (n = 22). Data were analyzed through coding of the transcribed focus group discussions and extraction of main themes. Extracted themes were: information overload, gaps in information, challenges in providing information and involvement of both parents in the decision. Parents and professionals believed that burdening parents with untimely information on a wide range of topics in the first trimester detracted from decision making about screening. Many parents also reported they were not sufficiently informed and wanted individualized discussion with a health professional. To ensure parents make informed decisions, information on screening should be provided at the appropriate time, with opportunity for personal discussion with a knowledgeable health professional. PMID- 23347128 TI - Microcystin production revisited: conjugate formation makes a major contribution. AB - The impact of environmental stimuli on the production of the widespread cyanobacterial hepatotoxin microcystin (MC) is under debate. Whereas transcriptional studies of the biosynthetic genes suggest a clear influence of light conditions on toxin production the data for the metabolite itself are inconsistent and highly strain-specific. Here, we have reassessed the MC content by using two immunological detection techniques that allow a parallel quantification of MC in the methanolic extracts and the residual pellet fraction that contains high molecular weight proteins. Our results show a significant proportion of MC in the protein bound fraction in strains of Microcystis and Planktothrix and of the related toxin nodularin (NOD) in Nodularia. Moreover, we could show a very strong increase of MC after high light illumination in the protein fraction contributing to a significant overall increase in MC production under these conditions that is not seen in extracts analysed by LC-MS and ELISA. The fact that a considerable portion of MC is neglected with current analysis techniques was also confirmed for selected field samples. Immunofluorescence studies suggest strain-specific differences in the amount of MC conjugate formation. PMID- 23347129 TI - Assessment of subendocardial contractile function in aortic stenosis: a study using speckle tracking echocardiography. AB - BACKGROUND: Angina and an electrocardiographic strain pattern are potential manifestations of subendocardial ischemia in aortic stenosis (AS). Left ventricular (LV) twist is known to increase proportionally to the severity of AS, which may be a result of loss of the inhibiting effect of the subendocardial fibers due to subendocardial dysfunction. It has also been shown that the ratio of LV twist to circumferential shortening of the endocardium (twist-to-shortening ratio [TSR]) is a reliable parameter of subendocardial dysfunction. The aim of this study was to investigate whether these markers are increased in AS patients with angina and/or electrocardiographic strain. METHODS: The study comprised 60 AS patients with an aortic valve area <2.0 cm(2) and LV ejection fraction >50%, and 30 healthy-for age and gender matched-control subjects. LV rotation parameters were determined by speckle tracking echocardiography. RESULTS: Comparison of patients without angina and strain (n = 22), with either angina or strain (n = 28), and with both angina and strain (n = 8), showed highest peak systolic LV apical rotation, peak systolic LV twist, and TSR, in patients with more signs of subendocardial ischemia. In a multivariate linear regression model, only severity of AS and the presence of angina and/or strain could be identified as independent predictors of peak systolic LV twist and TSR. CONCLUSIONS: Peak systolic LV twist and TSR are increased in AS patients and related to the severity of AS and symptoms (angina) or electrocardiographic signs (strain) compatible with subendocardial ischemia. PMID- 23347130 TI - Characterization and quantification of porcine circulating endothelial cells. AB - BACKGROUND: Endothelial damage is a critical step in the development of (xeno) transplantation-related and cardiovascular pathology. In humans, the amount of circulating endothelial cells (CEC) correlates to disease intensity and functions as a valuable damage marker. While (xeno) transplantation and cardiovascular research is regularly performed in porcine models, the paucity of antibodies against porcine endothelium epitopes hinders the use of CEC as damage marker. OBJECTIVE: This study aimed to develop a method for porcine CEC detection using anti-human antibodies against porcine endothelium epitopes. METHODS: Human umbilical vein endothelial cells (HUVEC, control) and their swine equivalent (SUVEC) were used to assess the cross-species immunoreactivity of fluorescently labeled anti-human CD31/CD51/CD54/CD62E/CD105/CD106/CD144/CD146/PAL-E/lectin 1/vWF antibodies by isotype-controlled fluorescence-activated cell sorting (FACS) and confocal microscopy. Next, reactivity was ascertained with mature porcine kidney-derived endothelial cells (PKEC), and a FACS-based whole blood CEC quantification method was employed using osmotic erythrolysis and CD105 and CD146 double staining after CD45 exclusion. RESULTS: Of the 21 assayed antibodies, the MEM-229 clone of CD105 and P1H12 clone of CD146 showed immunoreactivity with SUVEC and PKEC. Double staining showed baseline porcine CEC count of 673.1 +/- 551.4 CEC/ml, while the first 7.5 ml of drawn blood (representative of vascular damage) contained 1118 +/- 661.4 CEC/ml (n = 14, P = 0.04). A second experiment (n = 5) including CD45 exclusion identified only 14.5 +/- 10.8% double-positive CD105-146 events per ml blood. CONCLUSION: Porcine endothelium can be specifically labeled using anti-human CD146 and CD105 antibodies. These antibodies can therefore be used for the identification and quantification of CEC in porcine whole blood by FACS after osmotic erythrolysis. PMID- 23347131 TI - Body mass index, Stunkard Figure Rating Scale, and sexuality in young Italian women: a pilot study. AB - INTRODUCTION: Increased body mass index is associated with a higher prevalence of metabolic diseases, depression, and sexual dysfunction. In obese patients, the perception of an altered body image may influence health and psychologically related behaviors. Furthermore, there is a significant positive relationship between sexual function, sexual satisfaction, and all body image variables. AIM: To evaluate the relationship between body weight, perceived body image, and sexual behavior. METHODS: Ninety women underwent ultrasonographic clitoral volume measurement and color Doppler evaluation of the clitoral and ophthalmic arteries. The subjects filled the McCoy Female Sexuality Questionnaire (MFSQ), the Stunkard Figure Rating Scale (FRS), and the Beck's Depression Inventory (BDI) questionnaire. MAIN OUTCOME MEASURES: Clitoral volume, clitoral and ophthalmic artery pulsatility index (PI), MFSQ, FRS, and BDI. RESULTS: The women were distributed into three groups: lean (N = 47); overweight (N = 22); and obese (N = 21). The ophthalmic artery showed lower PI in lean (1.72 +/- 0.39) than in overweight (1.99 +/- 0.30) and obese women (2.08 +/- 0.19). The obese subjects presented the worst clitoral vascularization. The MFSQ for sexuality was higher in lean (45.8 +/- 11.8) than in overweight (36.4 +/- 15.0) and obese (36.1 +/- 10.8) women. The frequency of intercourse per week was higher in lean (2.2 +/- 1.4) than in overweight (1.3 +/- 0.7) and obese (1.2 +/- 0.4) women. The percentage of anorgasmic women was higher in obese (23%) than in lean subjects (6%). The FRS evidenced that the lean subjects represented themselves with a mean value (3.5 +/- 1.0) lower than overweight (4.8 +/- 0.7) and obese women (5.9 +/- 0.6). The silhouette that represented their own ideal was significantly higher in obese (4.0 +/- 0.4) than in overweight (3.3 +/- 0.5) and lean (2.9 +/- 0.7) subjects. The mean BDI was significantly higher in obese (15.8 +/- 5.4) than in lean (8.4 +/- 6.8) women. CONCLUSIONS: Lifestyle modifications such as weight loss may be mandatory in obese subjects because obesity might impair the quality of sexual life by inducing genital and general vascular stiffness and body image distortion. PMID- 23347133 TI - The burden of lung disease: the need for stem cell therapy--a review series prologue. PMID- 23347132 TI - Protease-activated receptor-2 signalling by tissue factor on dendritic cells suppresses antigen-specific CD4+ T-cell priming. AB - The precise function of tissue factor (TF) expressed by dendritic cells (DC) is uncertain. As well as initiating thrombin generation it can signal through protease-activated receptor 2 (PAR-2) when complexed with factor VIIa. We investigated the expression and function of TF on mouse bone marrow (BM) -derived DC; 20% of BM-derived DC expressed TF, which did not vary after incubation with lipopolysaccharide (LPS) or dexamethasone (DEX). However, the pro-coagulant activity of DEX-treated DC in recalcified plasma was 30-fold less than LPS treated DC. In antigen-specific and allogeneic T-cell culture experiments, the TF on DEX-treated DC provided a signal through PAR-2, which contributed to the reduced ability of these cells to stimulate CD4(+) T-cell proliferation and cytokine production. In vivo, an inhibitory anti-TF antibody and a PAR-2 antagonist enhanced antigen-specific priming in two models where antigen was given without adjuvant, with an effect approximately 50% that seen with LPS, suggesting that a similar mechanism was operational physiologically. These data suggest a novel TF and PAR-2-dependent mechanism on DEX-DC in vitro and unprimed DC in vivo that contributes to the low immunogenicity of these cells. Targeting this pathway has the potential to influence antigen-specific CD4(+) T-cell activation. PMID- 23347135 TI - Controlling the morphology and performance of bulk heterojunctions in solar cells. Lessons learned from the benchmark poly(3-hexylthiophene):[6,6]-phenyl-C61 butyric acid methyl ester system. PMID- 23347134 TI - Direct evidence for the adaptive role of copy number variation on antifolate susceptibility in Plasmodium falciparum. AB - Resistance to antimalarials targeting the folate pathway is widespread. GTP cyclohydrolase (gch1), the first enzyme in this pathway, exhibits extensive copy number variation (CN) in parasite isolates from areas with a history of longstanding antifolate use. Increased CN of gch1 is associated with a greater number of point mutations in enzymes targeted by the antifolates, pyrimethamine and sulphadoxine. While these observations suggest that increases in gch1 CN are an adaptation to drug pressure, changes in CN have not been experimentally demonstrated to directly alter drug susceptibility. To determine if changes in gch1 expression alone modify pyrimethamine sensitivity, we manipulated gch1 CN in several parasite lines to test the effect on drug sensitivity. We report that increases in gch1 CN alter pyrimethamine resistance in most parasites lines. However we find evidence of a detrimental effect of very high levels of gch1 overexpression in parasite lines with high endogenous levels of gch1 expression, revealing the importance of maintaining balance in the folate pathway and implicating changes in gch1 expression in preserving proper metabolic flux. This work expands our understanding of parasite adaptation to drug pressure and provides a possible mechanism for how specific mutations become fixed within parasite populations. PMID- 23347136 TI - Anti-tumour efficacy on glioma models of PHA-848125, a multi-kinase inhibitor able to cross the blood-brain barrier. AB - BACKGROUND AND PURPOSE: Malignant gliomas, the most common primary brain tumours, are highly invasive and neurologically destructive neoplasms with a very bad prognosis due to the difficulty in removing the mass completely by surgery and the limited activity of current therapeutic agents. PHA-848125 is a multi-kinase inhibitor with broad anti-tumour activity in pre-clinical studies and good tolerability in phase 1 studies, which could affect two main pathways involved in glioma pathogenesis, the G1-S phase progression control pathway through the inhibition of cyclin-dependent kinases and the signalling pathways mediated by tyrosine kinase growth factor receptors, such as tropomyosin receptors. For this reason, we tested PHA-848125 in glioma models. EXPERIMENTAL APPROACH: PHA-848125 was tested on a panel of glioma cell lines in vitro to evaluate inhibition of proliferation and mechanism of action. In vivo efficacy was evaluated on two glioma models both as single agent and in combination with standard therapy. KEY RESULTS: When tested on a subset of representative glioma cell lines, PHA-848125 blocked cell proliferation, DNA synthesis and inhibited both cell cycle and signal transduction markers. Relevantly, PHA-848125 was also able to induce cell death through autophagy in all cell lines. Good anti-tumour efficacy was observed by oral route in different glioma models both with s.c. and intracranial implantation. Indeed, we demonstrate that the drug is able to cross the blood brain barrier. Moreover, the combination of PHA-848125 with temozolomide resulted in a synergistic effect, and a clear therapeutic gain was also observed with a triple treatment adding PHA-848125 to radiotherapy and temozolomide. CONCLUSIONS AND IMPLICATIONS: All the pre-clinical data obtained so far suggest that PHA 848125 may become a useful agent in chemotherapy regimens for glioma patients and support its evaluation in phase 2 trials for this indication. PMID- 23347137 TI - Binge ethanol and liver: new molecular developments. AB - Binge consumption of alcohol is an alarming global health problem. Binge (acute) ethanol (EtOH) is implicated in the pathophysiology of alcoholic liver disease (ALD). New studies from experimental animals and from humans indicate that binge EtOH has profound effects on immunological, signaling, and epigenetic parameters of the liver. This is in addition to the known metabolic effects of acute EtOH. Binge EtOH alters the levels of several cellular components and dramatically amplifies liver injury in chronically EtOH exposed liver. These studies highlight the importance of molecular investigations into binge effects of EtOH for a better understanding of ALD and also to develop therapeutic strategies to control it. This review summarizes these recent developments. PMID- 23347138 TI - Influence of cardiac output on the pseudo-steady state remifentanil and propofol concentrations in swine. AB - BACKGROUND: The propofol concentration during constant infusion is affected by a change in cardiac output, but the effect of this change on remifentanil, which is frequently used in combination with propofol, is unclear. METHODS: Ten swine were anaesthetised through inhalation of isoflurane and maintained with 1.5% isoflurane. After infusion of remifentanil (0.5 MUg/kg/min) and propofol (6 mg/kg/h after 2 mg/kg bolus infusion) for 60 min (baseline 1), cardiac output was increased by continuous infusion of dobutamine and termination of isoflurane (high cardiac output state). Dobutamine infusion was then stopped, 1.5% isoflurane was restarted, and cardiac output was allowed to return to baseline (baseline 2). Finally, cardiac output was decreased by administration of 3% isoflurane (low cardiac output state). Blood samples were collected from the femoral artery at 10, 30, and 60 min after the change to each haemodynamic state. RESULTS: An inverse relationship was found between cardiac output and the plasma remifentanil and propofol concentrations. The plasma drug concentrations were given by the following equations: [remifentanil] (ng/ml) = 17.5/cardiac output (l/min) + 4.52; and [propofol] (MUg/ml) = 3.34/cardiac output + 1.17. The influence of changes in cardiac output on remifentanil were similar to those for coadministered propofol and the influence on the concentration of each drug was greater with decreasing cardiac output. CONCLUSIONS: The plasma remifentanil concentration is influenced by cardiac output in a similar manner to that of propofol during remifentanil and propofol anaesthesia, although the metabolic sites are different. PMID- 23347139 TI - Motorsports involvement among adolescents and young adults with childhood ADHD. AB - Although children with attention-deficit/hyperactivity disorder (ADHD) are at risk for impulsive, health-endangering behavior, few studies have examined nonsubstance, use-related risk-taking behaviors. This study examined whether adolescents and young adults with ADHD histories were more likely than those without ADHD histories to report frequent engagement in motorsports, a collection of risky driving-related activities associated with elevated rates of physical injury. Path analyses tested whether persistent impulsivity, comorbid conduct disorder or antisocial personality disorder (CD/ASP), and heavy alcohol use mediated this association. Analyses also explored whether frequent motorsporting was associated with unsafe and alcohol-influenced driving. Two hundred twenty-one adolescent and young adult males (16-25 years old) diagnosed with ADHD in childhood and 139 demographically similar males without ADHD histories reported their motorsports involvement. Persistent impulsivity, CD/ASP, heavy drinking, and hazardous driving were also measured in adolescence/young adulthood. Adolescents and young adults with ADHD histories were more likely to report frequent motorsports involvement than those without childhood ADHD. Impulsivity, CD/ASP, and heavy drinking partially mediated this association, such that individuals with ADHD histories, who had persistent impulsivity or CD/ASP diagnoses, were more likely to engage in heavy drinking, which was positively associated with frequent motorsporting. Motorsports involvement was associated with more unsafe and alcohol-influenced driving, and this association was more often found among those with, than without, ADHD histories. Adolescents and young adults with ADHD histories, especially those with persisting impulsivity, comorbid CD/ASP and heavy drinking tendencies, are more likely to engage in motorsports, which may heighten risk of injury. PMID- 23347140 TI - Clot resolution after 3 weeks of anticoagulant treatment for pulmonary embolism: comparison of computed tomography and perfusion scintigraphy. AB - INTRODUCTION: Little is known about the natural history of clot resolution in the initial weeks of anticoagulant therapy in patients with acute pulmonary embolism (PE). Clot resolution of acute PE was assessed with either computed tomography pulmonary angiography scan (CT-scan) or perfusion scintigraphy scan (Q-scan) after 3 weeks of treatment. METHODS: This was a predefined safety analysis of the Einstein PE study, including PE patients, randomized to either enoxaparin with vitamin K antagonist (VKA) or rivaroxaban. A similar scan as at baseline was repeated after 3 weeks. The percentage of vascular obstruction (PVO) was calculated on the basis of a weighted semiquantitative estimation of obstruction. Clot resolution was assessed blindly by calculating the relative change after 3 weeks. RESULTS: PE was diagnosed in 264 patients with CT-scan and in 83 with Q scan. Baseline characteristics were similar. At baseline, the mean PVO assessed with CT-scan (PVO-CT) and the mean PVO assessed with Q-scan (PVO-Q) were both 21% (standard deviation [SD] 13%) (P = 0.9). The mean relative decrease in PVO was 71% (SD 33%) for PVO-CT, and 62% (SD 36%) for PVO-Q (P = 0.02); complete resolution was observed in 44% (116/264; 95% confidence interval [CI] 38-50%) and 31% (26/83; 95% CI 22-42%) with CT-scan and Q-scan, respectively (P = 0.04). No difference in clot resolution between enoxaparin/VKA and rivaroxaban was found. CONCLUSION: In patients with acute PE, only 3 weeks of anticoagulant treatment leads to complete clot resolution in a considerable proportion of patients, and normalization is more often observed with CT-scan than with Q-scan. PMID- 23347141 TI - Bifunctional mesoporous zirconium phosphonates for delivery of nucleic acids. AB - The bifunctional mesoporous zirconium phosphonates (ZrBFs) were synthesized through surfactant-assisted co-condensation of ZrCl(4) with two different phosphonic acids, both 1-phosphomethylproline (H(3)PMP) and 1,4 bis(phosphomethyl)piperazine (BPMP), in a one-pot procedure. The L-proline group of H(3)PMP and piperazine group of BPMP in the frameworks endow ZrBFs with pH controllable release function and high cell penetration capability, which was derived from the reversible protonation-deprotonation of L-proline groups and piperazine groups on the mesoporous walls under different pH values (pH sensitivity) as well as further functionalization with biological modifiers via the carboxyls in L-proline groups on the outer surface (functionalizability), respectively. ZrBFs, possessing cationic frameworks once formed, exhibit high payload for salmon sperm DNA as model nucleic acid owing to strong electrostatic attraction between them. On the basis of pH-sensitive ZrBFs carriers and assisted by lag-time films coating, the time- and pH-controlled oral colon-targeted nucleic acid delivery systems have been developed, which can carry most of the loaded salmon sperm DNA to the colon under dual control, time control and pH value control. Furthermore, salmon sperm DNA can remain intact during delivery, as evidenced by the fact that the released salmon sperm DNA in the pH transition release experiment still retain its structural integrity and native conformation. Also, fluorescence spectra demonstrate that ZrBFs can be further functionalized with a cell-penetrating peptide of octaarginine (R8) via the carboxyls in L proline groups of H(3)PMP on the outer surface using a coupling agent, which will enhance the penetration capability of ZrBFs through biomembranes. ZrBFs have a potential application as a new kind of carrier in oral delivery of nucleic acids targeting the colon for gene therapy of colon-related diseases due to their unique bifunctionality. PMID- 23347142 TI - After the doctorate: a qualitative study investigating nursing research career development in Jordan. AB - There is a dearth of research exploring the development of postdoctoral nursing research careers in non-Western contexts. This paper reports on a qualitative study of Jordanian graduates of UK PhD programs. Interviews were held with 16 graduates who worked in the nursing faculty of seven different universities in Jordan. Participants reported that their doctoral degree had equipped them with confidence and enthusiasm for developing a research career. Mentorship, leadership, and peer support were identified as essential to supporting ongoing research activity. Access to these sources of support was variable and participants also described a range of institutional and organizational structures that directly or indirectly discouraged them from developing research productivity. This research suggests that support for postdoctoral novice researchers is an important area for further attention - for Jordanian universities, for UK PhD supervisors (and their associated academic departments), and for the wider nursing community. PMID- 23347143 TI - Ovarian cellular fibroma harbouring an isocitrate dehydrogenase 1 (1DH1) mutation in a patient with Ollier disease: evidence for a causal relationship. PMID- 23347144 TI - PAS-G supports platelet reconstitution after cryopreservation in the absence of plasma. AB - BACKGROUND: Platelet (PLT) concentrates frozen in dimethyl sulfoxide (DMSO) can be stored for extended periods at -80 degrees C. PLTs are frozen in a hyperconcentrated state to avoid postthaw washing and minimize residual DMSO. Consequently, PLTs require reconstitution upon thawing. Although plasma, saline, and PLT additive solutions (PASs) have been used to reconstitute frozen PLTs, a comparison to define an optimal solution for PLT recovery has not been performed. STUDY DESIGN AND METHODS: DMSO (5% final concentration) was added to buffy coat derived PLTs, followed by centrifugation to concentrate and freezing at -80 degrees C. Cryopreserved PLTs (n=12 per group) were thawed at 37 degrees C, reconstituted in a unit of thawed frozen plasma, SSP+, or PAS-G. In vitro PLT quality was examined before freezing, immediately after thawing, and 6 and 24 hours after thawing. RESULTS: After thawing and reconstitution, PLTs in plasma and PAS-G displayed similar recovery (69 and 73%, respectively), while PLT recovery in SSP+ was lower (62%). All PLTs maintained an acceptable pH and metabolic activity during postthaw storage. Frozen PLTs were activated, although the extent differed depending on the reconstitution solution, with PLTs in PAS-G retaining better aggregation responses than PLTs in plasma or SSP+. CONCLUSION: Thawing cryopreserved PLTs in PAS-G, without plasma supplementation, resulted in PLTs with similar recovery and in vitro quality indicators as those suspended in plasma. Importantly, using PAS-G enables the PLTs to be ready for use significantly faster than when having to thaw frozen plasma, which may be beneficial in trauma situations. PMID- 23347145 TI - Paternal origins of Chinese cattle. AB - To determine the genetic diversity and paternal origin of Chinese cattle, 302 males from 16 Chinese native cattle breeds as well as 30 Holstein males and four Burma males as controls were analysed using four Y-SNPs and two Y-STRs. In Chinese bulls, the taurine Y1 and Y2 haplogroups and indicine Y3 haplogroup were detected in seven, 172 and 123 individuals respectively, and these frequencies varied among the Chinese cattle breeds examined. Y2 dominates in northern China (91.4%), and Y3 dominates in southern China (90.8%). Central China is an admixture zone, although Y2 predominates overall (72.0%). The geographical distributions of the Y2 and Y3 haplogroup frequencies revealed a pattern of male indicine introgression from south to north China. The three Y haplogroups were further classified into one Y1 haplotype, five Y2 haplotypes and one Y3 haplotype in Chinese native bulls. Due to the interplay between taurine and indicine types, Chinese cattle represent an extensive reservoir of genetic diversity. The Y haplotype distribution of Chinese cattle exhibited a clear geographical structure, which is consistent with mtDNA, historical and geographical information. PMID- 23347147 TI - Diagnosis of bicuspid aortic valve: role of three-dimensional transesophageal echocardiography and multiplane review analysis. PMID- 23347146 TI - T-cell memory differentiation: insights from transcriptional signatures and epigenetics. AB - A critical component of vaccine design is to generate and maintain antigen specific memory lymphocytes of sufficient quantity and quality to give the host life-long protection against re-infection. Therefore, it is important to understand how memory T cells acquire the ability for self-renewal while retaining a potential for heightened recall of effector functions. During acute viral infection or following vaccination, antigen-specific T cells undergo extensive phenotypic and functional changes during differentiation to the effector and memory phases of the immune response. The changes in cell phenotype that accompany memory T-cell differentiation are predominantly mediated through acquired transcriptional regulatory mechanisms, in part achieved through epigenetic modifications of DNA and histones. Here we review our current understanding of epigenetic mechanisms regulating the off-on-off expression of CD8 and CD4 T-cell effector molecules at naive, effector and memory stages of differentiation, respectively, and how covalent modifications to the genome may serve as a mechanism to preserve 'poised' transcriptional states in homeostatically dividing memory cells. We discuss the potential of such mechanisms to control genes that undergo on-off-on patterns of expression including homing and pro-survival genes, and the implications on the development of effector-memory and central-memory T-cell differentiation. Lastly, we review recent studies demonstrating epigenetic modifications as a mechanism for the progressive loss of transcriptional adaptation in antigen-specific T cells that undergo sustained high levels of T-cell receptor signalling. PMID- 23347148 TI - Mycotic pseudoaneurysm of the proximal saphenous vein graft. PMID- 23347149 TI - Statistical optimization of culture conditions for biomass production of probiotic gut-borne Saccharomyces cerevisiae strain able to reduce fumonisin B1. AB - AIM: To evaluate the ability of probiotic Saccharomyces cerevisiae RC016 strain to reduce fumonisin B(1) (FB(1)) in vitro and to optimize the culture conditions for the growth of the yeast employing surface response methodology. METHODS AND RESULTS: Using Plackett-Burman screening designs (PBSD) and central composite designs (CCD), an optimized culture medium containing (g l(-1)) fermentable sugars provided by sugar cane molasses (CMs), yeast extract (YE) and (NH(4))(2) HPO(4) (DAP) was formulated. The S. cerevisiae RC016 strain showed the greatest binding at all assayed FB1 concentration. The CMs, YE, DAP concentrations and incubation time influenced significantly the biomass of S. cerevisiae RC016. CONCLUSION: A combination of CMs 17%; YE 4.61 g l(-1) and incubation time 60 h was optimum for maximum biomass of S. cerevisiae RC016. SIGNIFICANCE AND IMPACT OF THE STUDY: The importance of this work lies in the search for live strains with both probiotic and fumonisin B1 decontamination properties that could be sustainably produced in a medium just containing cheap carbon, nitrogen and phosphorus sources and would be included in a novel product to animal feed. PMID- 23347150 TI - The resurgence of the vacuum erection device (VED) for treatment of erectile dysfunction. AB - INTRODUCTION: Vacuum erection devices (VEDs) have been approved in the United States since 1982 and offer a viable alternative to oral phosphodiesterase type 5 inhibitors (PDE5i), injections and transurethral suppositories. Studies have demonstrated efficacy in erectile dysfunction (ED) associated with a variety of conditions. More recently, this modality has been evaluated in initial phosphodiesterase inhibitor nonresponders as well as for post-prostatectomy penile rehabilitation. AIM: This article provides a detailed overview of the history of VEDs, a review of the literature, and a concise description of their new applications in modern urological practice. METHODS: A retrospective review of publications relevant to the field of VEDs. MAIN OUTCOME MEASURES: Review of the historical milestones, evolution, and modern utilization of VEDs in modern urological protocols. RESULTS: Studies have demonstrated efficacy in ED associated with a variety of conditions. Early penile rehabilitation after surgery for prostate cancer with the VED appears to improve erectile function and penile length. Adverse events are transient and not serious. CONCLUSIONS: The VED has continued to show efficacy for treatment of ED due to various etiologies and should be considered an attractive second-line therapy. In select cases such post prostatectomy penile rehabilitation, as well as in men who cannot use a PDE5i, the vacuum device should be considered first-line treatment. PMID- 23347151 TI - Effects of hydrogen bonding on internal conversion of GFP-like chromophores. I. The para-amino systems. AB - To understand the effects of solvent-solute hydrogen bonding (SSHB) on the excited-state dynamics of two GFP-like chromophores, p-ABDI and p-CFABDI, we have determined the quantum yields for fluorescence (Phif) and the isomerization Z -> E (PhiZE) and the femtosecond fluorescence and transient infrared absorption in selected solvents. The behavior that PhiZE ? 0.50 in aprotic solvents, such as CH3CN, indicates that the E-Z photoisomerization adopts a one-bond-flip mechanism through the torsion of the exocyclic C?C bond (the tau torsion) to form a perpendicular species (tau ~90 degrees ) in the singlet excited state followed by internal conversion (IC) to the ground state and partition to form the E and Z isomers with equal probabilities. The observed PhiZE decreased from 0.50 to 0.15 0.28 when CH3CN was replaced with the protic solvents CH3OH and CF3CH2OH. In conjunction with the solvent-independent rapid (<1 ps) kinetics for the fluorescence decay and the solvent-dependent slow (7-20 ps) kinetics for the ground-state recovery, we conclude that the SSHB modifies the potential energy surface for the tau torsion in a way that the IC occurs also for the twisted intermediates with a tau-torsion angle smaller than 90 degrees , which favors the formation of the Z isomers. The possibility of IC induced by torsion of the exocyclic C-C bond (the phi torsion) is also considered but excluded. PMID- 23347152 TI - Clinical implications of periostin in the liver metastasis of colorectal cancer. AB - AIM: To investigate the expression status of periostin in colorectal cancer (CRC) to lay a foundation for managing this disease. METHODS: Periostin expression status was detected by immunohistochemistry staining in 720 CRC specimens. The relationship between the periostin protein and clinicopathological factors and prognosis was subsequently determined. RESULT: The periostin protein was expressed significantly higher in CD133+ tumor cells compared to CD133- tumor cells. Positively expressed periostin was observed in 218 (30.28%) of the 720 cases. Spearman correlation analysis showed that periostin expression has a linear correlation to the tumor size, histological type, lymph node metastasis, TNM stage, and postoperative liver metastasis (p=0.02, 0.035, 0.001, 0.001, and 0.001, respectively). Multivariate analysis showed that histological type, lymph node metastasis, TNM stage, and periostin were found to be related to liver metastasis (p=0.01, 0.035, 0.01, and 0.001, respectively). In the Cox regression test, the histological grade, Lymph node metastasis, TNM stage, and periostin were detected as independent prognostic factors (p=0.01, 0.001, 0.001, and 0.001, respectively). CONCLUSION: Periostin was found to be related to the liver metastasis of CRC and may be a potential target for CRC. PMID- 23347153 TI - Acid suppression does not reduce symptoms from vocal cord dysfunction, where gastro-laryngeal reflux is a known trigger. AB - Vocal cord dysfunction (VCD) is characterized by paradoxical inspiratory abduction of the vocal cords. Gastro-oesophageal reflux disease (GORD) is a known trigger. We studied 77 patients referred to a tertiary VCD clinic. VCD was diagnosed in 62, of which 83.9% had proven GORD. Following 8 weeks of acid suppression, 24.2% reported improvement in the severity and frequency of VCD attacks. This study suggests that empirical treatment of GORD in VCD marginally improves symptom control. PMID- 23347154 TI - Klebsiella pneumoniae targets an EGF receptor-dependent pathway to subvert inflammation. AB - The NF-kappaB transcriptional factor plays a key role governing the activation of immune responses. Klebsiella pneumoniae is an important cause of community acquired and nosocomial pneumonia. Evidence indicates that K. pneumoniae infections are characterized by lacking an early inflammatory response. Recently, we have demonstrated that Klebsiella antagonizes the activation of NF-kappaB via the deubiquitinase CYLD. In this work, by applying a high-throughput siRNA gain of-function screen interrogating the human kinome, we identified 17 kinases that when targeted by siRNA restored IL-1beta-dependent NF-kappaB translocation in infected cells. Further characterization revealed that K. pneumoniae activates an EGF receptor (EGFR)-phosphatidylinositol 3-OH kinase (PI3K)-AKT-PAK4-ERK-GSK3beta signalling pathway to attenuate the cytokine-dependent nuclear translocation of NF-kappaB. Our data also revealed that CYLD is a downstream effector of K. pneumoniae-induced EGFR-PI3K-AKT-PAK4-ERK-GSK3beta signalling pathway. Our efforts to identify the bacterial factor(s)responsible for EGFR activation demonstrate that a capsule (CPS) mutant did not activate EGFR hence suggesting that CPS could mediate the activation of EGFR. Supporting this notion, purified CPS did activate EGFR as well as the EGFR-dependent PI3K-AKT-PAK4-ERK-GSK3beta signalling pathway. CPS-mediated EGFR activation was dependent on a TLR4-MyD88-c SRC-dependent pathway. Several promising drugs have been developed to antagonize this cascade. We propose that agents targeting this signalling pathway might provide selective alternatives for the management of K. pneumoniae pneumonias. PMID- 23347155 TI - Structural and computational studies of the maleate isomerase from Pseudomonas putida S16 reveal a breathing motion wrapping the substrate inside. AB - Nicotine is an environmental toxicant in tobacco waste, imposing a serious hazard for human health. Some bacteria including Pseudomonas spp. strains are able to metabolize nicotine to non-toxic compounds. The pyrrolidine pathway of nicotine degradation in Pseudomonas putida S16 has recently been revealed. The maleate isomerase (Pp-Iso) catalyses the last step in nicotine degradation of P. putida S16, the cis-trans isomerization of maleate to fumarate. In this study, we determined the crystal structures of both wild type isomerase by itself and its C200A point mutant in complex with its substrate maleate, to resolutions of 2.95 A and 2.10 A respectively. Our structures reveal that Asn17 and Asn169 play critical roles in recognizing the maleate by site-directed mutants' analysis. Surprisingly, our structure shows that the maleate is completely wrapped inside the isomerase. Examination of the structure prompted us to hypothesize that the beta2-alpha2 loop and the beta6-alpha7 loop have a breathing motion that regulates substrate/solvent entry and product departure. Our results of molecular dynamics simulation and enzymatic activity assay are fully consistent with this hypothesis. The isomerase probably uses this breathing motion to prevent the solvent from entering the active site and prohibit unproductive side reactions from happening. PMID- 23347156 TI - Arylglyoxals in synthesis of heterocyclic compounds. PMID- 23347158 TI - Determination of absolute configuration and conformation of a cyclic dipeptide by NMR and chiral spectroscopic methods. AB - Increasing precision of contemporary computational methods makes spectroscopies such as vibrational (VCD) and electronic (ECD) circular dichroism attractive for determination of absolute configurations (AC) of organic compounds. This is, however, difficult for polar, flexible molecules with multiple chiral centers. Typically, a combination of several methods provides the best picture of molecular behavior. As a test case, all possible stereoisomers with known AC (RS, SR, SS, and RR) of the cyclic dipeptide cyclo(Arg-Trp) (CAT) were synthesized, and the performances of the ECD, infrared (IR), VCD, Raman, Raman optical activity (ROA), and nuclear magnetic resonance (NMR) techniques for AC determination were investigated. The spectra were interpreted with the aid of density functional theory (DFT) calculations. Folded geometries stabilized by van der Waals and electrostatic interactions between the diketopiperazine (DKP) ring and the indole group are predicted to be preferred for CAT, with more pronounced folding due to Arg-Trp stacking in the case of SS/RR-CAT. The RS/SR isomers prefer a twist-boat puckering of the DKP ring, which is relatively independent of the orientation of the side chains. Calculated conformer-averaged VCD and ECD spectra explain most of the experimentally observed bands and allow for AC determination of the tryptophan side-chain, whereas the stereochemical configuration of the arginine side-chain is visible only in VCD. NMR studies provide characteristic long-range (2)J(C,H) and (3)J(C,H) coupling constants, and nuclear Overhauser effect (NOE) correlations, which in combination with either ECD or VCD also allow for complete AC determination of CAT. PMID- 23347157 TI - Genetic and environmental predictors of latent trajectories of alcohol use from adolescence to adulthood: a male twin study. AB - BACKGROUND: Adolescence is characterized by higher levels of novelty-seeking and risk-taking behavior, including initiation of alcohol use. Also, there is considerable heterogeneity in the change and continuity of alcohol use over time, which emphasizes the need to examine factors predicting alcohol use and the patterns of use over time. METHODS: Retrospective data on average monthly alcohol use and risk and protective factors were obtained through interviews and questionnaires in 1,560 adult male twins. Latent class growth analysis in Mplus was performed on data of alcohol use over ages 15 to 36. Second, logistic regression analyses were used to associate risk and protective characteristics with membership in distinct latent trajectories of alcohol use. RESULTS: Six trajectories of alcohol use were identified, varying in the level of alcohol use, the rate of change in use in early adolescence and the persistence of use into adulthood. Genetic risk of externalizing disorder and peer deviance showed the greatest risks for unfavorable alcohol trajectories with higher levels of use and higher rates of early increase in use. Parental monitoring and involvement in social activities showed protective effects. Involvement in religious activities was strongly associated with reduced persistence of high-level drinking in univariate but not multivariate regression analyses. CONCLUSIONS: Risk and protective factors impacted differentially on level of alcohol use, rate of increase in use during adolescence, and persistence of heavy alcohol use over time. Insight into the different ways in which predictors impact on alcohol use is relevant for the development of new intervention strategies. For this purpose, causality of the associations should be further examined. PMID- 23347160 TI - Evidence of exotoxin secretion of Piscirickettsia salmonis, the causative agent of piscirickettsiosis. AB - Piscirickettsia salmonis is the aetiological agent of piscirickettsiosis, a disease which affects a variety of teleost species and that is particularly severe in salmonid fish. Bacterial-free supernatants, obtained from cultures of three isolates of Piscirickettsia salmonis, were inoculated in Atlantic salmon, Salmo salar L., and in three continuous cell lines in an effort to determine the presence of secretion of extracellular products (ECPs) by this microorganism. Although steatosis was found in some liver samples, no mortalities or clinical signs occurred in the inoculated fish. Clear cytotoxicity was observed after inoculation in the cell lines CHSE-214 and ASK, derived from salmonid tissues, but not in MDBK, which is of mammalian origin. The degree of cytotoxicity of the ECPs was different among the P. salmonis isolates tested. The isolate that evidenced the highest cytotoxicity in its ECPs exhibited only an intermediate virulence level after challenging fish with bacterial suspensions of the three P. salmonis isolates. Almost complete inhibition of the cytotoxic activity of ECPs was seen after proteinase K treatment, indicating their peptidic nature, and a total preclusion of the cytotoxicity was shown after their incubation at 50 degrees C for 30 min. Results show that P. salmonis can produce ECPs and at least some of them are thermolabile exotoxins that probably play a role in the pathogenesis of piscirickettsiosis. PMID- 23347163 TI - Paranuclear dot-like immunostaining of CD99 in rhabdomyosarcoma. PMID- 23347164 TI - Quantum chemical topology study of the water-platinum(II) interaction. AB - The "inverse hydration" of neutral complexes of Pt(II) by an axial water molecule, whose one OH-bond is oriented toward Pt, has been the subject of recent works, theoretical as well as experimental. To study the influence of the ligands on this non-conventional H-bond, we extend here our previous energy calculations, using the second-order Moeller-Plesset perturbation theory (MP2) method together with the Dolg-Pelissier pseudopotential for platinum, to various neutral complexes including the well-known chemotherapeutic agent "cisplatin". The stabilization energy, depending on the nature and the configuration of platinum ligands, is dominated by the same important dispersive component, for all the investigated complexes. For a further characterization of this particular H-bond, we used the atoms in molecules theory (AIM) and the topological analysis of the electron localization function (ELF). The charge transfer occurring from the complex to the water molecule and the Laplacian of the density at the bond critical point between water and Pt are identified as interesting AIM descriptors of this non-conventional H-bond. Beyond this AIM analysis, we show that the polarization of the ELF bonding O-H basin involved in the non-conventional H-bond is enhanced during the approach of the water molecule to the Pt complexes. When the water medium, treated in an implicit solvation model, is taken into account, the interaction energies become independent on the nature and configuration of platinum ligands. However, the topological descriptors remain qualitatively unchanged. PMID- 23347159 TI - Design and pharmacological characterization of VUF14480, a covalent partial agonist that interacts with cysteine 98(3.36) of the human histamine H4 receptor. AB - BACKGROUND AND PURPOSE: The recently proposed binding mode of 2-aminopyrimidines to the human (h) histamine H4 receptor suggests that the 2-amino group of these ligands interacts with glutamic acid residue E182(5.46) in the transmembrane (TM) helix 5 of this receptor. Interestingly, substituents at the 2-position of this pyrimidine are also in close proximity to the cysteine residue C98(3.36) in TM3. We hypothesized that an ethenyl group at this position will form a covalent bond with C98(3.36) by functioning as a Michael acceptor. A covalent pyrimidine analogue will not only prove this proposed binding mode, but will also provide a valuable tool for H4 receptor research. EXPERIMENTAL APPROACH: We designed and synthesized VUF14480, and pharmacologically characterized this compound in hH4 receptor radioligand binding, G protein activation and beta-arrestin2 recruitment experiments. The ability of VUF14480 to act as a covalent binder was assessed both chemically and pharmacologically. KEY RESULTS: VUF14480 was shown to be a partial agonist of hH4 receptor-mediated G protein signalling and beta-arrestin2 recruitment. VUF14480 bound covalently to the hH4 receptor with submicromolar affinity. Serine substitution of C98(3.36) prevented this covalent interaction. CONCLUSION AND IMPLICATIONS: VUF14480 is thought to bind covalently to the hH4 receptor-C98(3.36) residue and partially induce hH4 receptor-mediated G protein activation and beta-arrestin2 recruitment. Moreover, these observations confirm our previously proposed binding mode of 2-aminopyrimidines. VUF14480 will be a useful tool to stabilize the receptor into an active confirmation and further investigate the structure of the active hH4 receptor. PMID- 23347165 TI - Integration of solid-state nanopores in microfluidic networks via transfer printing of suspended membranes. AB - Solid-state nanopores have emerged as versatile single-molecule sensors for applications including DNA sequencing, protein unfolding, micro-RNA detection, label-free detection of single nucleotide polymorphisms, and mapping of DNA binding proteins involved in homologous recombination. While machining nanopores in dielectric membranes provides nanometer-scale precision, the rigid silicon support for the membrane contributes capacitive noise and limits integration with microfluidic networks for sample preprocessing. Herein, we demonstrate a technique to directly transfer solid-state nanopores machined in dielectric membranes from a silicon support into a microfluidic network. The resulting microfluidic-addressable nanopores can sense single DNA molecules at high bandwidths and with low noise, owing to significant reductions in membrane capacitance. This strategy will enable large-scale integration of solid-state nanopores with microfluidic upstream and downstream processing and permit new functions with nanopores such as complex manipulations for multidimensional analysis and parallel sensing in two and three-dimensional architectures. PMID- 23347166 TI - Distinct effects of Re- and S-forms of LPS on modulating platelet activation. PMID- 23347167 TI - Outpatient parenteral antimicrobial therapy is safe and effective for the treatment of infective endocarditis: a retrospective cohort study. AB - BACKGROUND: Outpatient parenteral antibiotic therapy has been shown to be efficacious, safe and cost-effective for a variety of infections. The data from managing infective endocarditis (IE) with hospital in the home (HITH) are limited. We evaluated the safety and outcomes of patients with IE treated with HITH at our centre. AIMS: To evaluate the safety, efficacy and 1-year outcomes of patients with IE treated under HITH at our centre over 9 years. METHOD: A retrospective analysis of the clinical outcomes of all cases of IE treated with HITH at a tertiary referral centre was undertaken for patients treated between June 2002 and July 2011 (9 years). Outcome measures included clinical cure, readmission rate, relapses and 1-year mortality. RESULTS: Sixty-eight cases of IE were treated with HITH over the study period, including 29 native valve infections, 24 prosthetic valve infections, 12 pacemaker lead infections, 1 defibrillator lead infection, 1 myocardial wall infection and 1 aortic graft infection. Thirteen cases had valve replacement surgery and 12 cases had removal of infected pacemaker leads. Staphylococcus aureus (18 cases), Coagulase-negative staphylococcus (10 cases) and viridians-group streptococcus (18 cases) were the most common pathogens. Median duration of antimicrobial therapy with HITH was 24 days (range 4 to 42 days). There were three readmissions during antimicrobial therapy with HITH. Two patients relapsed. There were two deaths and one patient was lost to follow up. One-year survival was 96% (65/68). CONCLUSION: Outpatient antimicrobial therapy with HITH is safe and effective in carefully selected cases of IE. PMID- 23347168 TI - Safety and efficacy of ureteroscopy after obstructive pyelonephritis treatment. AB - OBJECTIVES: An obstructed, infected kidney combined with ureteral stones can be lethal, and requires urgent drainage and complete stone removal. However, the optimal method of stone removal, and its safety and efficacy have yet to be conclusively established. The aim of this study was to determine the safety and efficacy of carrying out ureteroscopy after kidney drainage for septic patients with obstructing stones. METHODS: From January 2004 to September 2011, 88 patients underwent stone removal by either ureteroscopy (n = 48) or extracorporeal shock wave lithotripsy (n = 40) after drainage of obstructive pyelonephritis. Patients' characteristics were analyzed, and treatment outcomes between the ureteroscopy and extracorporeal shock wave lithotripsy groups were compared. The outcomes of ureteroscopy carried out during the same period between patients with preoperative obstructive pyelonephritis and those without were also compared. RESULTS: Obstructed, infected kidneys were decompressed with retrograde ureteral stenting, except for two and three cases treated with nephrostomy in the ureteroscopy and extracorporeal shock wave lithotripsy groups, respectively. The severity of preoperative pyelonephritis was similar in both groups. Importantly, the success rate was 67.5% for extracorporeal shock wave lithotripsy and 98% for ureteroscopy (P < 0.001). Likewise, the retreatment and auxiliary procedure rates were significantly greater in the extracorporeal shock wave lithotripsy group than in the ureteroscopy group (90% vs 0% and 32.5% vs 2%, respectively). Furthermore, patients treated by ureteroscopy with or without preoperative pyelonephritis had similar stone-free and ureteroscopy complication rates (97% vs 93%, and 10% vs 12%). CONCLUSIONS: Ureteroscopy after drainage of an obstructed infected kidney can be a safe and effective option, as it seems to not be associated with an increased risk of complications. PMID- 23347169 TI - Variability in the melanocortin 1 receptor (MC1R) gene in wild boars and local pig breeds in Poland. PMID- 23347170 TI - Establishment of an unrelated umbilical cord blood bank qualification program: ensuring quality while meeting Food and Drug Administration vendor qualification requirements. AB - BACKGROUND: Qualification of a cord blood bank (CBB) is a complex process that includes evaluation of multiple aspects of donor screening and testing, processing, accreditation and approval by professional cell therapy groups, and results of received cord blood units. The University of Minnesota Medical Center Cell Therapy Laboratory has established a CBB vendor qualification process to ensure the CBB meets established regulatory and quality requirements. STUDY DESIGN AND METHODS: The deployed qualification of CBBs is based on retrospective and prospective review of the CBB. RESULTS: Forty-one CBBs were evaluated retrospectively: seven CBBs were disqualified based on failed quality control (QC) results. Eight CBBs did not meet the criteria for retrospective qualification because fewer than 3 cord blood units were received and the CBB was not accredited. As of March 2012, three US and one non-US CBBs have been qualified prospectively. One CBB withdrew from the qualification process after successful completion of the comprehensive survey and subsequent failure of the provided QC unit to pass the minimum criteria. One CBB failed the prospective qualification process based on processing methods that were revealed during the paper portion of the evaluation. CONCLUSIONS: A CBB qualification process is necessary for a transplant center to manage the qualification of the large number of CBBs needed to support a umbilical cord blood transplantation program. A transplant center that has utilized cord blood for a number of years before implementation of a qualification process should use a retrospective qualification process along with a prospective process. PMID- 23347171 TI - Three-dimensional echocardiography in the evaluation of global and regional function in patients with recent myocardial infarction: a comparison with magnetic resonance imaging. AB - We aimed to compare three-dimensional (3D) and two-dimensional (2D) echocardiography in the evaluation of patients with recent myocardial infarction (MI), using late-enhancement magnetic resonance imaging (LE-MRI) as a reference method. Echocardiography and LE-MRI were performed approximately 1 month after first-time MI in 58 patients. Echocardiography was also performed on 35 healthy controls. Left ventricular (LV) ejection fraction by 3D echocardiography (3D LVEF), 3D wall-motion score (WMS), 2D-WMS, 3D speckle tracking-based longitudinal, circumferential, transmural and area strain, and 2D speckle tracking-based longitudinal strain (LS) were measured. The global correlations to infarct size by LE-MRI were significantly higher (P < 0.03) for 3D-WMS and 2D-WMS compared with 3D-LVEF and the 4 different measurements of 3D strain, and 2D global longitudinal strain (GLS) was more closely correlated to LE-MRI than 3D GLS (P < 0.03). The segmental correlations to infarct size by LE-MRI were also significantly higher (P < 0.04) for 3D-WMS, 2D-WMS, and 2D LS compared with the other indices. Three-dimensional WMS showed a sensitivity of 76% and a specificity of 72% for identification of LV infarct size >12%, and a sensitivity of 73% and a specificity of 95% for identification of segments with transmural infarct extension. Three-dimensional WMS and 2D gray-scale echocardiography showed the strongest correlations to LE-MRI. The tested 3D strain method suffers from low temporal and spatial resolution in 3D acquisitions and added diagnostic value could not be proven. PMID- 23347172 TI - Intrathoracic implantation of a dual-chamber pacemaker in a preterm infant with congenital AV block. AB - Congenital complete atrioventricular block can be concomitant with congenital heart diseases or maternal connective tissue disorders like systemic lupus erythematosus and Sjogren's syndrome. Such patients may require implantation of a permanent pacemaker due to ventricular dysfunction. While many methods of pacemaker implantation have been tested, one that is optimal for low birth weight infants remains to be determined. We present a preterm infant with maternal Sjogren's syndrome with congenital heart block and describe the technique for implantation of an intrathoracic dual-chamber pacemaker. PMID- 23347173 TI - S. aureus haemolysin A-induced IL-8 and IL-6 release from human airway epithelial cells is mediated by activation of p38- and Erk-MAP kinases and additional, cell type-specific signalling mechanisms. AB - Soluble virulence-associated factors of Staphylococcus aureus like haemolysin A (Hla) induce secretion of chemo/cytokines from airway epithelial cells. To elucidate the potential roles of specific signalling pathways in this response, we treated 16HBE14o-, S9 or A549 cells with recombinant Hla (rHla). In a dose dependent manner, rHla induced secretion of IL-8 in all three cell types, but IL 6 release only in 16HBE14o- and S9 cells. rHla-mediated secretion of IL-8 and IL 6 was suppressed by pre-incubation of cells with inhibitors of Erk type or p38 MAP kinases, indicating that activation of these signalling pathways is essential for IL-8 release in all three cell types and for IL-6 release in 16HBE14o- and S9 cells. The rHla-mediated phosphorylation and activation of p38 MAP kinase seem to depend on elevations in [Ca(2+)]i, an early response in rHla-treated cells. Inhibitors of calmodulin or calcium/calmodulin-dependent kinase II attenuated rHla-mediated release of IL-8 in 16HBE14o- and A549 cells and of IL-6 in 16HBE14o cells. This indicates that rHla may mediate simultaneous activation of calmodulin-dependent processes as additional prerequisites for chemo/cytokine secretion.However, the inhibitors of calmodulin-dependent signalling did not affect rHla-induced p38 MAP kinase phosphorylation, indicating that this pathway works in parallel with p38 MAP kinase. PMID- 23347174 TI - Encephalitis with infiltration by CD8+ lymphocytes in HIV patients receiving combination antiretroviral treatment. AB - We report the neuropathological findings in 10 HIV-infected patients treated by combination antiretroviral therapy who developed subacute encephalopathy of rapidly progressive onset. Brain biopsy showed encephalitic lesions variably associated with myelin loss and slight axonal damage. There was inconstant, weak expression of HIV protein p24; tests for other pathogens were negative. The most striking feature was diffuse, perivascular and intraparenchymal infiltration by CD8+ T-lymphocytes. Six patients improved after the treatment. Four had an unfavorable outcome and died within a year. Post-mortem in one case confirmed HIV leukoencephalitis with p24-positive multinucleated giant cells, associated with acute demyelinating encephalomyelitis (ADEM) in the cerebellum. There was diffuse infiltration by CD8+ lymphocytes; CD4+ cells were virtually absent. These cases may represent a specific clinicopathological entity, of which a few comparable cases have been already described. They can be included in the wide framework of immune reconstitution disease. Such syndromes have been described with opportunistic infections, but only seldom with HIV infection of the central nervous system (CNS). Our findings support the hypothesis that CD8+ cytotoxic lymphocytes can be harmful in immune reconstitution disease, particularly in the absence of CD4+ lymphocytes. CD8 cytotoxicity produces an acutization of a smoldering infection and/or an immunopathological reaction similar to ADEM. PMID- 23347176 TI - Assessment of the efficacy of combination therapy with folic acid and tadalafil for the management of erectile dysfunction in men with type 2 diabetes mellitus. AB - INTRODUCTION.: Phosphodiesterase type 5 inhibitors PDE5Is are less effective in diabetic men with erectile dysfunction (ED); however, the effect of combination therapy with folic acid and PDE5Is in these patients has not been investigated. AIM.: To evaluate the efficacy and safety of combination therapy with folic acid and tadalafil for the management of ED in men with type 2 diabetes mellitus. METHODS.: Eighty-three patients with type 2 diabetes mellitus and ED were included in this randomized double-blind clinical trial. They were randomly divided into two groups. Group A was treated with tadalafil 10 mg every other day plus folic acid 5 mg daily and group B received tadalafil 10 mg every other day plus placebo daily for 3 months. The mean International Index of Erectile Function (IIEF) scores before and after treatment in each groups were recorded. Men with diagnosis of psychological ED, spinal cord injury, or who used folic acid in the past 3 months and patients with any contradiction for use of PDE5Is were excluded. MAIN OUTCOMES MEASURES.: The cross tabulation and independent t test were used to evaluate the difference between baseline characteristic of the patients in the two groups. Wilcoxon signed-ranks test and Mann-Whitney U-test were used to evaluate the IIEF score and also its changes before and after treatment in the two groups. RESULTS.: The mean IIEF scores before and after treatment were 11.65 +/- 2.67 and 16.80 +/- 4.03 in group A (P < 0.001) and 12.70 +/- 2.31 and 14.37 +/- 2.17 in group B (P < 0.001), respectively. The difference of mean IIEF score after treatment between the two groups was significant (16.80 +/- 4.03 vs. 14.37 +/- 2.17 in groups A and B, respectively) (P = 0.002). Also, the mean IIEF score was significantly increased in group A as compared with group B (5.14 +/- 3.84 vs. 1.68 +/- 0.99 in groups A and B, respectively) (P < 0.001). Both folic acid and tadalafil were well tolerated by all the patients. CONCLUSION.: Sexual function in diabetic patients with ED treated with the combination of tadalafil and folic acid improved significantly as compared with the placebo group. The use of folic acid and tadalafil is safe. PMID- 23347175 TI - SMAD regulatory networks construct a balanced immune system. AB - A balanced immune response requires combating infectious assaults while striving to maintain quiescence towards the self. One of the central players in this process is the pleiotropic cytokine transforming growth factor-beta (TGF-beta), whose deficiency results in spontaneous systemic autoimmunity in mice. The dominant function of TGF-beta is to regulate the peripheral immune homeostasis, particularly in the microbe-rich and antigen-rich environment of the gut. To maintain intestinal integrity, the epithelial cells, myeloid cells and lymphocytes that inhabit the gut secrete TGF-beta, which acts in both paracrine and autocrine fashions to activate its signal transducers, the SMAD transcription factors. The SMAD pathway regulates the production of IgA by B cells, maintains the protective mucosal barrier and promotes the balanced differentiation of CD4(+) T cells into inflammatory T helper type 17 cells and suppressive FOXP3(+) T regulatory cells. While encounters with pathogenic microbes activate SMAD proteins to evoke a protective inflammatory immune response, SMAD activation and synergism with immunoregulatory factors such as the vitamin A metabolite retinoic acid enforce immunosuppression toward commensal microbes and innocuous food antigens. Such complementary context-dependent functions of TGF-beta are achieved by the co-operation of SMAD proteins with distinct dominant transcription activators and accessory chromatin modifiers. This review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-beta in the gut that are dictacted by fluid orchestrations of SMADs and their myriad partners. PMID- 23347177 TI - The persistent effects of minimum legal drinking age laws on drinking patterns later in life. AB - BACKGROUND: Exposure to permissive minimum legal drinking age (MLDA) laws not only affects young adults in the short term, but also later in life; for example, individuals who could legally purchase alcohol before the age of 21 are more likely to suffer from drinking problems as older adults, long after the laws had been changed. However, it is not known how permissive MLDA exposure affects specific drinking behavior. This present study uses changes in MLDA laws during the 1970s and 1980s as a natural experiment to investigate the potential impact of permissive MLDA exposure on average alcohol consumption, frequency of drinking, and patterns of binging and more moderate, nonheavy drinking. METHODS: Policy exposure data were paired with alcohol use data from the 1991 to 1992 National Longitudinal Alcohol Epidemiologic Survey and the 2001 to 2002 National Epidemiologic Survey on Alcohol and Related Conditions. Past-year drinkers born between 1949 and 1972 (n = 24,088) were included. Average daily intake, overall drinking frequency, and frequency of both binge episodes (5+ drinks) and days without a binge episode (nonheavy drinking) for the previous year at the time of interview were tracked for each respondent. RESULTS: Exposure to permissive MLDAs was associated with higher odds to report frequent binging and lower odds to report any moderate drinking; these associations were largely driven by men and those who did not attend college. Overall drinking frequency and average alcohol consumption were not affected by MLDA exposure. CONCLUSIONS: The ability to legally purchase alcohol before the age of 21 does not seem to increase overall drinking frequency, but our findings suggest that it is associated with certain types of problematic drinking behaviors that persist into later adulthood: more frequent binge episodes and less frequent nonheavy drinking. We also propose that policymakers and critics should not focus on college drinking when evaluating the effectiveness of MLDAs. PMID- 23347178 TI - Further evidence that E-cadherin is not a tumour suppressor gene in invasive ductal carcinoma of the breast: an immunohistochemical study. AB - AIMS: E-cadherin is a cell adhesion molecule expressed in normal breast tissue; it is used generally as a phenotypical marker in breast cancer, with the absence of its expression observed frequently in lobular tumours. We have reported E cadherin expression previously in 1516 ductal breast carcinoma using tissue microarray (TMA), where 7% of cases showed a complete absence of membrane staining. In this study, we investigated further the existence of E-cadherin negative ductal carcinoma and evaluated the status of the E-cadherin-catenin complex in this subgroup. MATERIAL AND METHODS: Full-face sections from excision specimens of 72 ductal breast carcinomas reported previously as E-cadherin negative were assessed morphologically using haematoxylin and eosin staining, and immunohistochemically using two E-cadherin antibodies (HECD-1 and CDH1/4A2C7) and antibodies recognizing beta-catenin and p120 proteins. Only membrane expression was considered. RESULTS: Forty-seven ductal carcinomas were assessed after the exclusion of inappropriate cases; 34 of these showed positive E-cadherin (HECD-1) membrane expression which was focal and weak and seen mainly in invasion fronts. Ten cases showed E-cadherin (4A2C7) staining. Staining for p120 and beta-catenin showed membrane staining in all cases for both antibodies, which was variable in both intensity and the proportion of positive cells. CONCLUSION: These results demonstrate that E-cadherin-negative ductal carcinoma is rare, and in these cases p120 and beta-catenin maintained their membranous localization, suggesting a functional E-cadherin-membrane complex. PMID- 23347179 TI - Food label usage and reported difficulty with following a gluten-free diet among individuals in the USA with coeliac disease and those with noncoeliac gluten sensitivity. AB - BACKGROUND: Individuals with coeliac disease (CD) and those with noncoeliac gluten sensitivity (GS) have reported difficulty following a gluten-free diet (GFD); however, few studies have explored the link between the food label, gluten free (GF) claims and the difficulty associated with following a GFD. METHODS: The present study surveyed adults with CD (n = 1,583) and adults with GS (n = 797) about their reported difficulty following a GFD, including assessing the role of food labels and GF claims, as well as other factors known to contribute to this difficulty. A two-sample t-test and chi-squared tests for equality of means or proportions were used for the descriptive data and ordinal logistic regression (OLR) was used to model associations. RESULTS: On average, individuals with GS reported slightly more difficulty following the GFD than did participants with CD. According to the OLR results, reading the food label often was significantly associated with less reported difficulty following a GFD, whereas consuming packaged processed foods and looking for GF claims more often were significantly associated with more reported difficulty for both respondent groups. CONCLUSIONS: Individuals with GS may rely more heavily on the GF claim for information about a product's gluten content. Individuals with CD, on the other hand, may be more experienced food label readers and may rely more on the ingredient list for finding GF foods. More studies are needed aiming to understand the role of the food label in facilitating consumers' ability to follow a GFD. PMID- 23347180 TI - Direct electrodeposition of crystalline silicon at low temperatures. AB - An electrochemical liquid-liquid-solid (ec-LLS) process that yields crystalline silicon at low temperature (80 degrees C) without any physical or chemical templating agent has been demonstrated. Electroreduction of dissolved SiCl(4) in propylene carbonate using a liquid gallium [Ga(l)] pool as the working electrode consistently yielded crystalline Si. X-ray diffraction and electron diffraction data separately indicated that the as-deposited materials were crystalline with the expected patterns for a diamond cubic crystal structure. Scanning and transmission electron microscopies further revealed the as-deposited materials (i.e., with no annealing) to be faceted nanocrystals with diameters in excess of 500 nm. Energy-dispersive X-ray spectra further showed no evidence of any other species within the electrodeposited crystalline Si. Raman spectra separately showed that the electrodeposited films on the Ga(l) electrodes were not composed of amorphous carbon from solvent decomposition. The cumulative data support two primary contentions. First, a liquid-metal electrode can serve simultaneously as both a source of electrons for the heterogeneous reduction of dissolved Si precursor in the electrolyte (i.e., a conventional electrode) and a separate phase (i.e., a solvent) that promotes Si crystal growth. Second, ec-LLS is a process that can be exploited for direct production of crystalline Si at much lower temperatures than ever reported previously. The further prospect of ec-LLS as an electrochemical and non-energy-intensive route for preparing crystalline Si is discussed. PMID- 23347181 TI - Charging free energy calculations using the Generalized Solvent Boundary Potential (GSBP) and periodic boundary condition: a comparative analysis using ion solvation and oxidation free energy in proteins. AB - Free energy simulations using a finite sphere boundary condition rather than a periodic boundary condition (PBC) are attractive in the study of very large biomolecular systems. To understand the quantitative impact of various approximations in such simulations, we compare charging free energies in both solution and protein systems calculated in a linear response framework with the Generalized Solvent Boundary Potential (GSBP) and PBC simulations. For simple ions in solution, we find good agreements between GSBP and PBC charging free energies, once the relevant correction terms are taken into consideration. For PBC simulations with the particle-mesh-Ewald for long-range electrostatics, the contribution (DeltaG(P-M)) due to the use of a particle rather than molecule based summation scheme in real space is found to be significant, as pointed out by Hunenberger and co-workers. For GSBP, when the inner region is close to be charge neutral, the key correction is the overpolarization of water molecules at the inner/outer dielectric boundary; the magnitude of the correction (DeltaG(s pol)), however, is relatively small. For charging (oxidation) free energy in proteins, the situation is more complex, although good agreement between GSBP and PBC can still be obtained when care is exercised. The smooth dielectric boundary approximation inherent to GSBP tends to make significant errors when the inner region is featured with a high net charge. However, the error can be corrected with Poisson-Boltzmann calculations using snapshots from GSBP simulations in a straightforward and robust manner. Because of the more complex charge and solvent distributions, the magnitudes of DeltaG(P-M) and DeltaG(s-pol) in protein simulations appear to be different from those derived for solution simulations, leading to uncertainty in directly comparing absolute charging free energies from PBC and GSBP simulations for protein systems. The relative charging/oxidation free energies, however, are robust. With the linear response approximation, for the specific protein system (CueR) studied, the effect of freezing the protein structure in the outer region is found to be small, unless a very small (8 A) inner region is used; even in the latter case, the result is substantially improved when the nearby metal binding loop is allowed to respond to metal oxidation. The implications of these results to the applicability of GSBP to complex biomolecules and in ab initio QM/MM simulations are discussed. PMID- 23347182 TI - Characterization of bacteriocin bificin C6165: a novel bacteriocin. AB - AIMS: To purify and primarily characterize an anti-Alicyclobacillus bacteriocin produced by Bifidobacterium animalis subsp. animalis CICC 6165, suggested to be named bificin C6165. METHODS AND RESULTS: During purification of the bificin C6165, optimal recovery was achieved with ammonium sulfate precipitation followed by two chromatographic steps. Mass spectrometry analyses revealed a distinctive peak corresponding to a molecular mass of 3395.1 Da. This bacteriocin was heat stable, effective after refrigerated storage and freeze-thaw cycles. The primary mode of action of bificin C6165 is most probably due to pore formation, as indicated by the efflux of K(+) from metabolically active cells of Alicyclobacillus acidoterrestris. In the presence of 10 mmol l(-1) gadolinium, bificin C6165 did not affect cells of Alicyclobacillus acidoterrestris. This suggests that the mode of action of bificin C6165 relies on a net negatively charged cell surface. CONCLUSIONS: Bificin C6165 is indeed a novel bacteriocin and it exhibited remarkable potency for Alicyclobacillus control. SIGNIFICANCE AND IMPACT OF THE STUDY: Application of bacteriocins in preservation of fruit juices has seldom been studied. Bificin C6165 may be an alternative method to control juice spoilage by this Alicyclobacillus acidoterrestris and meet increasing consumer demand for nature and artificial chemical additive-free food products. PMID- 23347183 TI - Placenta accreta: incidence and risk factors in an area with a particularly high rate of cesarean section. AB - Placenta accreta is a rare and potentially life-threatening complication of pregnancy characterized by abnormal adherence of the placenta to the uterine wall. A previously scarred uterus or an abnormal site of placentation in the lower segment is a major risk factor. The aim of this study was to investigate the change in the incidence of placenta accreta and associated risk factors along four decades, from the 1970s to 2000s, in a tertiary south Italian center. We analyzed all cases of placenta accreta in a sample triennium for each decade. The incidence increased from 0.12% during the 1970s, to 0.31% during the 2000s. During the same period, cesarean section rates increased from 17 to 64%. Prior cesarean section was the only risk factor showing a significant concomitant rise. Our results reinforce cesarean section as the most significant predisposing condition for placenta accreta. PMID- 23347185 TI - Direct inhibition of factor VIIa by TFPI and TFPI constructs. AB - BACKGROUND: Tissue factor pathway inhibitor (TFPI) is a multi-Kunitz domain protease inhibitor that down-regulates the extrinsic coagulation pathway by inhibiting FXa and FVIIa. OBJECTIVES: To investigate the role of the three Kunitz domains (KDs) of TFPI in FVIIa inhibition using full-length TFPI (TFPIfl ) and truncated TFPI constructs. METHODS: Inhibition of FVIIa with/without relipidated tissue factor (TF) or soluble TF (sTF) by TFPIfl /TFPI constructs was quantified with a FVIIa-specific chromogenic substrate. RESULTS AND CONCLUSIONS: TFPIfl inhibited TF-FVIIa via a monophasic reaction, which is rather slow at low TFPIfl concentrations (t1/2 ~ 5 min at 2 nm TFPI) and has a Ki of 4.6 nm. In the presence of sTF and without TF, TFPIfl was a poor FVIIa inhibitor, with Ki values of 122 nm and 1118 nm, respectively. This indicates that phospholipids and TF significantly contribute to FVIIa inhibition by TFPIfl . TFPI constructs without the KD3-c-terminus (TFPI1-150 and KD1-KD2) were 7-10-fold less effective than TFPIfl in inhibiting TF-FVIIa and sTF-FVIIa, indicating that the KD3-C-terminus significantly contributes to direct inhibition of FVIIa by TFPI. Compared with KD1-KD2, KD1 was a poor TF-FVIIa inhibitor (Ki =434 nm), which shows that the KD2 domain of TFPI also contributes to FVIIa inhibition. Protein S stimulated TF FVIIa inhibition by TFPIfl (Ki =0.7 nm). In the presence of FXa, a tight quaternary TF-FVIIa-TFPI-FXa complex is formed with TFPIfl , TFPI1-150 and KD1 KD2, with Ki values of < 0.15 nm, 0.5 nm and 0.8 nm, respectively, indicating the KD3-C-terminus is not a prerequisite for quaternary complex formation. Phospholipids and the Gla-domain of FXa are required for quaternary complex formation. PMID- 23347184 TI - The beta-catenin pathway contributes to the effects of leptin on SREBP-1c expression in rat hepatic stellate cells and liver fibrosis. AB - BACKGROUND AND PURPOSE: Liver fibrosis is commonly associated with obesity and most obese patients develop hyperleptinaemia. The adipocytokine leptin has a unique role in the development of liver fibrosis. Activation of hepatic stellate cells (HSCs) is a key step in hepatic fibrogenesis and sterol regulatory element binding protein-1c (SREBP-1c) can inhibit HSC activation. We have shown that leptin strongly inhibits SREBP-1c expression in rat HSCs. Hence, we aimed to clarify whether the beta-catenin pathway, the crucial negative regulator of adipocyte differentiation, mediates the effects of leptin on SREBP-1c expression in HSCs and in mouse liver fibrosis. EXPERIMENTAL APPROACH: HSCs were prepared from rats and mice. Gene expressions were analysed by real-time PCR, Western blot analysis, immunostaining and transient transfection assays. KEY RESULTS: Leptin increased beta-catenin protein but not mRNA levels in cultured HSCs. Leptin induced phosphorylation of glycogen synthase kinase-3beta at Ser(9) and subsequent stabilization of beta-catenin protein was mediated, at least in part, by ERK and p38 MAPK pathways. The leptin-induced beta-catenin pathway reduced SREBP-1c expression and activity but did not affect protein levels of key regulators controlling SREBP-1c activity, and was not involved in leptin inhibition of liver X receptor alpha. In a mouse model of liver injury, the beta catenin pathway was shown to be involved in leptin-induced liver fibrosis. CONCLUSIONS AND IMPLICATIONS: The beta-catenin pathway contributes to leptin regulation of SREBP-1c expression in HSCs and leptin-induced liver fibrosis in mice. These results have potential implications for clarifying the mechanisms of liver fibrogenesis associated with elevated leptin levels. PMID- 23347186 TI - Kinetics of heterogeneous reaction of ozone with linoleic acid and its dependence on temperature, physical state, RH, and ozone concentration. AB - Heterogeneous reaction between ozone and linoleic acid (LA) thin film was investigated by a flow reactor coupled to attenuated total reflection infrared spectroscopy (FR-ATR-IR) over wide ranges of temperature, relative humidity (RH), and ozone concentration under atmospheric pressure condition. Pseudo-first-order rate constants kapp and overall reactive uptake coefficients gamma were acquired on the basis of changes in absorbance from peaks located near 1743, 1710, 1172, and 1110 cm(-1), which can be assigned to C?O in ester, C?O in acid, and C-C and C-O stretching modes, respectively. Results showed that the kapp and gamma increased nearly by a factor of 6 with increasing temperatures from 258 to 314 K. It was noted the temperature effect on the reaction kinetics was much more pronounced at lower temperatures. Such behavior can be explained by a change in the physical state of LA at lower temperatures. In addition, kapp and gamma were enhanced by 2-fold as the RH increased from 0 to 80%. Moreover, the effect of ozone concentration on the reaction kinetics was reported for the first time. kapp was found to display a Langmuir-Hinshelwood dependence on ozone concentration with KO3 = (1.146 +/- 0.017) * 10(-15) molecules cm(-3) and k[S] = 0.0522 +/- 0.0004 s(-1), where KO3 is a parameter that describes the partitioning of ozone to the thin film surface, and k[S] is the maximum pseudo-first-order coefficient at high ozone concentration. Furthermore, yields and hygroscopic properties of reaction products were also investigated by FTIR spectroscopy. The intensity ratio of two C?O stretching bands, A1743/A1710, which was utilized as an indicator of the product yields, increased sharply with increasing temperatures in the lower temperature region (258-284 K), and then remained nearly constant in the higher temperature region (284-314 K). The product yields showed no significant variation with RH, for the intensity ratio of A1743/A1710 barely changed in the wide RH range 0-80%. Water uptake studies showed that the LA thin film absorbed water with an increasing RH, and the hygroscopicity of the thin film was enhanced after ozone exposure. PMID- 23347187 TI - Simultaneous determination of 13 fluoroquinolone and 22 sulfonamide residues in milk by a dual-colorimetric enzyme-linked immunosorbent assay. AB - Enzyme-linked immunosorbent assays (ELISAs) usually focus on the detection of a single analyte or a single group of analytes, e.g., fluoroquinolones or sulfonamides. However, it is often necessary to simultaneously monitor two classes of antimicrobial residues in different food matrixes. In this paper, we describe a dual-colorimetric ELISA for the simultaneous detection of 13 fluoroquinolone and 22 sulfonamide residues. The limit of detection for fluoroquinolones and sulfonamides was 2.4 and 5.8 ng/mL, respectively. The developed immunoassay is suitable for high-throughput screening of these low molecular weight contaminants. This is the first report where two different enzymes (alkaline phosphatase and horseradish peroxidase) were used in one immunoassay and together in a single well for simultaneous detection of multiple low-molecular weight chemical residues. PMID- 23347188 TI - Detection of emamectin benzoate tolerance emergence in different life stages of sea lice, Lepeophtheirus salmonis, on farmed Atlantic salmon, Salmo salar L. AB - Emamectin benzoate has been used to treat sea lice, Lepeophtheirus salmonis, infestations on farmed Atlantic salmon, Salmo salar. Recent evidence suggests a reduction in effectiveness in some locations. A major challenge in the detection of tolerance emergence can be the typically low proportion of resistant individuals in a population during the early phases. The objectives of this study were to develop a method for determining differences in temporal development of tolerance between sea lice life stages and to explore how these differences might be used to improve the monitoring of treatment effectiveness in a clinical setting. This study examined two data sets based on records of sea lice abundance following emamectin benzoate treatments from the west coast of Scotland (2002 2006) and from New Brunswick, Canada (2004-2008). Life stages were categorized into two groups (adult females and the remaining mobile stages) to examine the trends in mean abundance and treatment effectiveness. Differences in emamectin benzoate effectiveness were found between the two groups by year and location, suggesting that an important part of monitoring drug resistance development in aquatic ectoparasites may be the need to focus on key life stages. PMID- 23347189 TI - Validation of the prognostic grouping of the seventh edition of the tumor-nodes metastasis classification using a large-scale prospective cohort study database of prostate cancer treated with primary androgen deprivation therapy. AB - OBJECTIVE: In the TNM seventh edition, a prognostic grouping for prostate cancer incorporating prostate-specific antigen and Gleason score was advocated. The present study was carried out to evaluate and validate prognostic grouping in prostate cancer patients. METHODS: The 15 259 study patients treated with primary androgen deprivation therapy were enrolled in the Japan Study Group of Prostate Cancer. Overall survival was stratified by tumor-nodes-metastasis, Gleason score and prostate-specific antigen, and extensively analyzed. The accuracy of grouping systems was evaluated by the concordance index. RESULTS: The 5-year overall survival in prognostic grouping-I, IIA, IIB, III and IV was 90.0%, 88.3%, 84.8%, 80.6% and 57.1%, respectively. When considering subgroup stratification, the 5 year overall survival of subgroups prognostic grouping-IIA, IIB, III and IV was 80.9~90.5%, 75.4~91.8%, 75.7~89.0% and 46.9~86.2%, respectively. When prognostic grouping-IIB was subclassified into IIB1 (except IIB2) and IIB2 (T1-2b, prostate specific antigen >20, Gleason score >=8, and T2c, Gleason score >=8), the 5-year overall survival of IIB2 was significantly lower than that of IIB1 (79.4% and 87.3%, P < 0.0001). Also, when prognostic grouping-IV was subclassified into IV1 (except IV2) and IV2 (M1, prostate-specific antigen >100 or Gleason score >=8), the 5-year overall survival of prognostic grouping-IV1 was superior to that of IV2 (72.9% and 49.5%, P < 0.0001). Prognostic groupings were reclassified into modified prognostic groupings, divided into modified prognostic grouping-A (prognostic grouping-I, IIA, and IIB1), modified prognostic grouping-B (prognostic grouping-IIB2 and III), modified prognostic grouping-C (prognostic grouping-IV1) and modified prognostic grouping-D (prognostic grouping-IV2). The concordance index of prognostic grouping and modified prognostic grouping for overall survival was 0.670 and 0.685, respectively. CONCLUSION: Prognostic grouping could stratify the prognosis of prostate cancer patients. However, there is considerable variation among the prognostic grouping subgroups. Thus, the use of a modified prognostic grouping for patients treated with primary androgen deprivation therapy is advisable. PMID- 23347190 TI - Physical activity and cardiovascular risk factors at menopause: the Nord Trondelag health study. AB - BACKGROUND: Lowered physical activity levels may partially explain changes in metabolic risk factors in women after menopause. OBJECTIVES: To evaluate the association between physical activity and metabolic risk factors at baseline and after 11 years, as well as the change in that association over time in women who were premenopausal and >= 40 years at baseline. METHODS: Subjects in a Norwegian population-based health survey answered questionnaires and had body and serum measurements during 1995-1997 (HUNT 2) and in a follow-up study during 2006-2008 (HUNT 3). Repeated-measures analyses were used to estimate the association between physical activity and metabolic factors, adjusting for age, smoking status, education, alcohol intake, and parity. Adjustment for hormonal treatment and medication was made, as appropriate. RESULTS: In women remaining premenopausal, a higher physical activity score in HUNT 3 was associated with lower weight (p < 0.01) and waist-hip ratio (p < 0.01) and higher high density lipoprotein (HDL) cholesterol in HUNT 3 (p < 0.01). In women that were postmenopausal by the time of follow-up, a higher physical activity score in HUNT 3 was associated with lower weight (p < 0.01), waist-hip ratio (p < 0.01), triglycerides (p < 0.01), and higher total cholesterol (p < 0.05), HDL cholesterol (p < 0.01), and diastolic blood pressure (p < 0.05) in HUNT 3. The association of total physical activity score with weight and waist-hip ratio was stronger in HUNT 3 than in HUNT 2 (p < 0.01). CONCLUSION: Increased physical activity may reduce the risk of adverse outcomes and use of pharmacological management in women of menopausal age. PMID- 23347192 TI - Treatment of Raynaud phenomenon in systemic sclerosis. AB - Systemic sclerosis is a connective tissue disease characterised by microvascular injury and excessive fibrosis of the skin and internal organs. Most patients with this condition experience Raynaud phenomenon, usually as the earliest manifestation of disease. In addition to pain and functional impairment, Raynaud phenomenon can produce tissue ischaemia resulting in digital ulceration and gangrene. Current treatments have been only moderately successful in reducing the frequency and severity of Raynaud phenomenon in patients with systemic sclerosis. This review will address treatments available for Raynaud phenomenon in systemic sclerosis. PMID- 23347191 TI - Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease. AB - BACKGROUND: Current approaches to the detection of colorectal neoplasia associated with inflammatory bowel disease (IBD-CRN) are suboptimal. AIM: To test the feasibility of using stool assay of exfoliated DNA markers to detect IBD-CRN. METHODS: This investigation comprised tissue and stool studies. In the tissue study, gene sequencing and methylation assays were performed on candidate genes using tissue DNA from 25 IBD-CRNs and from 25 IBD mucosae without CRN. Mutations on p53, APC, KRAS, BRAF or PIK3CA genes were insufficiently informative, but several aberrantly methylated genes were highly discriminant. In the stool study, we evaluated candidate methylated genes (vimentin, EYA4, BMP3, NDRG4) in a prospective blinded study on buffered stools from 19 cases with known IBD-CRN and 35 age- and sex-matched IBD controls without CRN. From stool-extracted DNA, target genes were assayed using quantitative allele-specific real-time target and signal amplification method. RESULTS: IBD-CRN cases included 17 with ulcerative colitis (UC) and two with Crohn's disease (CD); nine had cancer and 10 had dysplasia. Controls included 25 with UC and 10 with CD. Individually, BMP3, vimentin, EYA4 and NDRG4 markers showed high discrimination in stools with respective areas under the ROC curve of 0.91, 0.91, 0.85 and 0.84 for total IBD CRN and of 0.97, 0.97, 0.95 and 0.85 for cancer. At 89% specificity, the combination of BMP3 and mNDRG4 detected 9/9 (100%) of CRC and 80% of dysplasia, 4/4 (100%) of high grade and 4/6 (67%) of low grade. CONCLUSION: These findings demonstrate the feasibility of stool DNA testing for non-invasive detection of colorectal neoplasia associated with inflammatory bowel disease. PMID- 23347193 TI - Endoscopic transnasal septotomy for contralateral orbital apex venous angioma resection and decompression. AB - Tumors of the orbital apex region are traditionally difficult to approach surgically due to key anatomic structures found in this highly crowded region. We present a case of progressively enlarging orbital apex venous angioma treated with a novel endoscopic transnasal septotomy technique. We highlight the key steps to this approach, as well as specific landmarks necessary to achieve a safe and successful outcome. PMID- 23347194 TI - HNA-1d: a new human neutrophil antigen located on Fcgamma receptor IIIb associated with neonatal immune neutropenia. AB - BACKGROUND: Neonatal immune neutropenia (NIN) is a rare, but potentially life threatening, disorder caused by maternal alloantibodies recognizing paternal neutrophil antigens on fetal cells. Alloantibodies directed against the human neutrophil alloantigen system (HNA)-1 located on Fcgamma receptor IIIb (FcgammaRIIIb) are most frequently implicated in NIN. In this report, we describe two cases of NIN with alloantibodies against FcgammaRIIIb, which did not match one of the known HNA-1a, -1b, or -1c specificities, but define a new antigen, HNA 1d. STUDY DESIGN AND METHODS: Neutrophil-reactive antibodies were detected by agglutination, microscopic immunofluorescence, and monoclonal antibody (MoAb) specific immobilization of neutrophil antigens (MAIGA) assay. For epitope mapping of FcgammaRIIIb-reactive antibodies, recombinant chimeric variants of FcgammaRIIIb were used in the MAIGA assay. Genotyping of FCGR3B was performed by allele-specific polymerase chain reaction. RESULTS: Both mothers were typed FCGR3B*01+, *02-, *03+. Antibody screening revealed the presence of alloantibodies reactive with FcgammaRIIIb encoded by FCGR3B*02, but not with FcgammaRIIIb encoded by FCGR3B*03. MAIGA with recombinant, partly chimeric FcgammaRIIIb variants demonstrated that the antigen recognized by maternal antibodies is characterized by two amino acids, Ala78 and Asp82. Among the FCGR3B alleles, the sequence Ala78---Asn82 is exclusively encoded by FCGR3B *02. CONCLUSION: A previously unrecognized second antigen, HNA-1d, is present on FcgammaRIIIb encoded by FCGR3B*02. This antigen is characterized by the sequence Ala78---Asn82. It appears that only individuals carrying the HNA-1c phenotype can form anti-HNA-1d alloantibodies. The HNA-1 system now consists of four antigens encoded by three alleles. PMID- 23347195 TI - Coronary interventions in congenital heart diseases: from preterm to young adult patients. AB - BACKGROUND: The small vessel size of infants and children makes interventional treatment of impaired coronary perfusion, such as stenoses, complete occlusions, and fistulae, demanding. Materials and techniques appropriate for this young age group have to demonstrate their ability to effectively treat these lesions. METHODS AND RESULTS: Between 2004 and 2011, 14 patients with an age of 9 days to 25 years (median 4.6 years) and a bodyweight of 1.7-65 kg (median 14 kg) underwent coronary intervention. In 3 cases, emergency revascularization of the left coronary artery (CA) was performed successfully, followed by stent implantation in 1 patient. Embolization of coronary arterial fistulae with coils and vascular plugs was effective in 10 patients. An antegrade, retrograde or combined approach to achieve the most distal device placement preserved all side branches. One infant with pulmonary atresia and an intact ventricular septum was prepared for biventricular repair by step-by-step closure of the right ventricular to the CA connections. No procedure-related deaths occurred. CONCLUSION: Congenital and post-procedural coronary obstructive lesions can be considered for effective treatment with balloon dilation at any age as a salvage procedure. In coronaries impaired by external compression, stent implantation can restore perfusion, but long-term results are missing. Interventional closure of coronary fistulae has shown improvement of coronary arterial perfusion. The latter techniques can be used to close right ventricular to CA connections in patients with pulmonary atresia to prepare for biventricular repair, but bail-out strategies should be planned in all coronary interventions. PMID- 23347198 TI - Comparison of alternating pressure mattresses and overlays for prevention of pressure ulcers in ventilated intensive care patients: a quasi-experimental study. AB - AIM: To compare the effectiveness of alternating pressure air mattresses vs. overlays to prevent pressure ulcers in mechanically ventilated patients in intensive care units. BACKGROUND: Pressure ulcers prevention is an important issue in the nursing of critically ill patients. It is not clear whether alternating pressure air mattresses are more effective than overlays to prevent pressure ulcers. DESIGN: Prospective quasi-experimental study. METHODS: A prospective quasi-experimental study was conducted among patients in the medical surgery intensive care unit of a university hospital on mechanical ventilation >=24 hours during two time periods (2001 and 2006). Overlays were used in 2001 and mattresses in 2006. Primary outcome was the incidence of pressure ulcers grade >=II (according to the European Pressure Ulcer Advisory Panel) during intensive care unit stay. RESULTS: The study included 221 patients (116 in 2001 and 105 in 2006). Baseline characteristics were similar between groups except for a higher Acute Physiology and Chronic Health Evaluation III score, total and first-day respiratory Sequential Organ Failure Assessment Score on day 1 in overlay group. There was significantly lower incidence density in the mattress vs. overlay group (12.41 cases/1000 days vs. 18.67 cases/1000 days of stay). The multivariate analyses showed the use of the mattress to be a protective factor against pressure ulcer onset. CONCLUSION: This quasi-experiment study that alternative pressure air mattresses were more effective than alternating pressure air overlays in preventing pressure ulcers in mechanically ventilated critical care patients. PMID- 23347196 TI - Assessment of a modified DSM-5 diagnosis of alcohol use disorder in a genetically informative population. AB - BACKGROUND: Proposed changes to the upcoming DSM-5 include the following: (i) combining criteria for DSM-IV alcohol abuse (AA) and alcohol dependence (AD) into 1 diagnostic category (alcohol use disorder [AUD]); (ii) exclusion of the "legal problems" (LP) criterion; and (iii) addition of a "craving" criterion. Few published studies empirically assess the potential consequences of the proposed changes. METHODS: Using a population-based sample of twins assessed for lifetime AA/AD diagnoses, we explored phenotypic differences across DSM-IV and a modified DSM-5 diagnoses without craving because of its unavailability in the data set. We used factor analysis and item response theory (IRT) to evaluate the potential consequences of excluding the LP criterion from AUD and used twin modeling to examine genetic differences between DSM-IV and the modified DSM-5 diagnoses. RESULTS: The prevalence of AUD was slightly higher than that of DSM-IV diagnoses. Individuals meeting DSM-IV or DSM-5 criteria, but not both, exhibit fewer comorbid diagnoses than those meeting both sets of criteria. Individuals meeting only DSM-5 criteria were slightly less severely affected than those meeting only DSM-IV criteria. Factor analysis indicated that the LP criterion loading is the lowest of all symptoms; IRT analysis suggested that this criterion has low discriminatory power. The genetic correlation between DSM-IV and DSM-5 diagnoses was slightly but significantly lower than unity. CONCLUSIONS: The proposed DSM-5 AUD criteria are unlikely to result in significant changes in prevalence of diagnosed alcohol problems. However, it is unclear whether the new criteria represent a more valid diagnosis: new cases are no more severely affected than DSM-IV-only cases. Given the psychometric properties of LP, its exclusion should not negatively impact diagnostic validity. Similarly, the stable heritability across DSM-IV and DSM-5 diagnoses suggests that the proposed changes will not have substantial negative consequences in terms of familial influences, a key validator. These results provide equivocal empirical support for the proposed DSM 5 changes for AUDs. PMID- 23347199 TI - High prevalence of rheumatic heart disease in schoolchildren detected by echocardiography screening in New Caledonia. AB - AIM: Despite the well-documented burden of rheumatic heart disease (RHD) in several Pacific countries, the disease is poorly understood in New Caledonia. The aim of this study was to assess the prevalence of RHD detected by echocardiographic screening in school children. METHODS: An annual RHD screening programme is conducted by the Health and Social Agency of New Caledonia for school-aged children in their fourth year of primary school. For the purpose of this study, we used data collected during this echocardiographic screening between 2008 and 2010. RESULTS: Of 12,728 children screened, 50.2% were male and the mean age was 9.6 +/- 0.6 years. Between 2008 and 2010, 114 children had RHD, corresponding to a prevalence of 8.9 cases per 1000 (95% confidence interval (CI) (7.3-10.6)). Prevalence of RHD was higher on the main island outside Greater Noumea (13.7 per 1000; 95% CI (9.8-17.5)) and in the outlying island groups (14.6 per 1000; 95% CI (8.4-20.9)) than in Greater Noumea (5.8 per 1000; 95% CI (4.1 7.5)). RHD was more prevalent in Melanesian children (13.5 per 1000; 95% CI (10.9 16.1)) than in European (1.8 per 1000; 95% CI (0.4-3.1)). CONCLUSION: This study documented a high prevalence of RHD in New Caledonia, particularly in districts located outside Noumea and in children of Melanesian heritage. These results uncover a hitherto unknown burden of disease in New Caledonia and underline the importance of delivering secondary prophylaxis to reduce the prevalence of RHD. PMID- 23347200 TI - Effect of an increase in left ventricular pressure overload on left atrial-left ventricular coupling in patients with hypertension: a two-dimensional speckle tracking echocardiographic study. AB - BACKGROUND: Two-dimensional speckle tracking echocardiography (2DSTE) has recently been applied to evaluate left atrial (LA) function in addition to left ventricular (LV) function. However, whether 2DSTE can provide insight into LA-LV interaction related to an increase in LV pressure overload remains unknown. METHODS: One hundred five asymptomatic patients with hypertension were studied by conventional, pulsed and tissue Doppler, and 2DSTE. Hypertensive patients were classified into 2 groups according to the ratio of early diastolic to atrial systolic velocity (E/A) of transmitral flow: E/A >= 1 (n = 37) and E/A < 1 (n = 68). We used (E/peak early diastolic mitral annular motion velocity [e'])/peak systolic LA strain (S-LAs) and E/e', as parameters of LA stiffness during ventricular systole and LV diastolic stiffness, respectively. RESULTS: The peak early diastolic LV longitudinal strain rate, and peak early diastolic LA strain and strain rate were lower in the E/A < 1 group than in the E/A >= 1 group. The E/e'/S-LAs and E/e' were greater in the E/A < 1 group. In the E/A < 1 group, systolic blood pressure (SBP) correlated with LV wall thickness parameters, A, e', E/e', peak early diastolic LV longitudinal strain rate, and E/e'/S-LAs. Multivariate regression analysis indicated that A, E/e', and E/e'/S-LAs were defined as strong predictors related to SBP. CONCLUSION: In patients with hypertension, an elevation in SBP leads to increased LA stiffness during ventricular systole and LV diastolic stiffness, in association with continued and further advanced LV diastolic dysfunction. 2DSTE is considered a sensitive tool for detecting abnormal LA-LV coupling related to an increased LV pressure overload. PMID- 23347201 TI - Patterns of functional decline in hospice: what can individuals and their families expect? AB - OBJECTIVES: To describe the trajectory of functional decline after an individual is referred to hospice. DESIGN: Electronic health record-based retrospective cohort study. SETTING: Three hospice programs in the U.S. southeast, northeast, and midwest. PARTICIPANTS: Individuals in hospice. MAIN OUTCOME MEASURES: Palliative Performance Scale (PPS) scores measured at intervals between hospice enrollment and death, on a scale from 10 to 100. RESULTS: In 8,669 decedents, there was an average 13.8-point decline in PPS score. After adjusting for baseline PPS score and length of stay in hospice, three distinct trajectories were identified, each of which consisted of two diagnoses whose rates of decline had 95% confidence intervals (CIs) that overlapped. The most rapid decline was observed for individuals with cancer (adjusted decline 8.44 points/wk; 95% CI = 8.03-8.82) and stroke (adjusted decline 7.67 points/wk, 95% CI = 7.08-8.29). A significantly slower decline was observed in individuals with pulmonary disease (adjusted decline 5.02 points/wk, 95% CI = 4.24-5.75) and cardiac disease (adjusted decline 4.53 points/wk, 95% CI = 4.05-5.05). Individuals with debility (adjusted decline 1.86 points/wk, 95% CI = 0.95-2.78) and dementia (adjusted decline 1.98 points/wk, 95% CI = 1.01-2.89) had the slowest decline. In an inverse probability-weighted sample of individuals who had a PPS score recorded in the last day of life (n = 1,959, 22.6%), 35.9% had a PPS score of at least 40, indicating some oral intake, variable mental status, limited self-care, and an ability to get out of bed for at least part of the day. CONCLUSION: Although functional status generally declines in individuals in hospice, this decline is heterogeneous. Some individuals retain some physical and cognitive function until the last day of life. PMID- 23347202 TI - Genital abnormalities in early childhood in sexual homicide perpetrators. AB - INTRODUCTION.: The present study investigates the relevance of genital abnormalities (GA) like cryptorchidism, hypospadias, and phimosis usually diagnosed in early childhood for the development of psychosexual problems and deficits in a sample of N = 163 convicted sexual homicide perpetrators. AIMS.: The first aim was to investigate the prevalence of early childhood GA in a sample of sexual homicide perpetrators. The second was to explore differences in the psychosexual development of participants with GA in early childhood compared with those without GA. It was expected that offenders with GA show specific problems in their psychosexual development compared with offenders without GA. METHODS.: The data for the present study were obtained by reanalyzing an existing database derived from a large-scale research project about sexual homicide. Using a predominantly exploratory design we, therefore, divided the total sample into two subgroups (with vs. without indicators of GA). MAIN OUTCOME MEASURES.: Main outcome measures were the number of sexual homicide perpetrators showing GA in early childhood and the differences of subjects with and without GA with regard to their psychosexual development (i.e., according to sexual deviant interests or sexual dysfunctions). RESULTS.: The prevalence of GA is substantially higher in this sample than epidemiological studies indicated in the normal population. This result provided first support for the importance of GA in the population of sexual homicide perpetrators. Further analyses indicate significant differences between both subgroups: Offenders with GA in early childhood showed indicators for more sexual dysfunctions (e.g., erectile dysfunction) in adulthood and a distinct tendency of more masochistic sexual interests. CONCLUSION.: Even if the exploratory design of the present investigation allows no causal conclusions between GA and sexual homicide offenses, the result provided support for the relevance of early childhood sexual diseases in the assessment (and treatment) of offenders who have committed severe sexual violence. PMID- 23347203 TI - Efficacy of the treatments used for the control of Caligus rogercresseyi infecting Atlantic salmon, Salmo salar L., in a new fish-farming location in Region XI, Chile. AB - Caligus rogercresseyi is the most important parasite affecting Atlantic salmon and rainbow trout farming in sea water in Chile. After the outbreaks of the infectious salmon anaemia recorded in Region X from 2007, the salmon industry has expanded southwards to Region XI, where 60% of Atlantic salmon in Chile is now produced. In parallel with the relocation of salmon production, sea lice infestation has also spread to Region XI, and today C. rogercresseyi is the most serious threat to the salmon-farming industry in this region. The results obtained through a year of monitoring between September 2007 and August 2008 on a farm located in the 'Las Guaitecas Archipelago' in Region XI (44 degrees S; 74 degrees W) showed that treatments with emamectin benzoate and deltamethrin did not give the expected control of Caligus. Failures of the treatments were associated with the loss of sensitivity recorded for C. rogercresseyi to emamectin benzoate in Region X. In addition, a major influence was the lack of delousing coordination measures with the neighbouring farms sharing the same area in that period. PMID- 23347204 TI - Treating Cryptosporidium parvum infection in calves. AB - The present study evaluated the therapeutic efficacy of azithromycin, co trimoxazole and kalvangi (Nigella sativa, also known as Black Cumin) against Cryptosporidium parvum infection in calves under field conditions. The experimental calves were treated with azithromycin (group A) at 1500 mg/calf/day, co-trimoxazole (group B) at 30 mg Kg-1 and kalvangi seeds powder (group C) at 750 mg Kg-1 BW orally for 7 days. Calves in the group D were naturally infected with C. parvum , untreated animals (positive control) while the calves in the group E were uninfected negative control animals. A significant decrease (p < 0.05) in oocyst counts for calves in groups A, B and C was observed compared to group D. When the oocyst counts amongst the treatment groups A, B and C were compared, a significant decrease (p < 0.05) was observed in group A. On day 21 post treatment, the efficacy of azithromycin, co-trimoxazole and kalvangi in calves was 88.2% (95% C.I. +/- 15.4), 45% (95% C.I. +/- 21.8) and 27.8% (95% C.I. +/- 20.7), respectively. This study confirmed previous reports of azithromycin efficacy against C. parvum infection, but found co-trimoxazole and kalvangi to be ineffective for this infection under these treatment regimens. PMID- 23347205 TI - Role of mammalian target of rapamycin inhibitor in the treatment of metastatic epithelioid angiomyolipoma: a case report. AB - Epithelioid angiomyolipoma has malignant potential; however, no effective therapy has been established for advanced cases. A 50-year-old woman with a history of right nephrectomy for epithelioid angiomyolipoma was referred to our institution. Computed tomography and magnetic resonance imaging showed multiple tumors in her lung, liver and pelvic cavity. The liver and pelvic tumor specimens obtained by needle biopsy confirmed the diagnosis of epithelioid angiomyolipoma recurrence. The patient was treated with everolimus (10 mg/day). Three months later, pulmonary lesions disappeared; liver and pelvic tumors significantly shrank in size, but the pelvic tumor gradually enlarged again. We carried out surgical resection of the residual liver and pelvic cavity tumors. Although the mammalian target of rapamycin inhibitor seems to be effective for treating epithelioid angiomyolipoma, its long-term effects remain unknown. Thus, aggressive administration of a multidisciplinary treatment including molecular target therapy and surgical resection is required to improve the prognosis of epithelioid angiomyolipoma. PMID- 23347206 TI - Masked mycotoxins are efficiently hydrolyzed by human colonic microbiota releasing their aglycones. AB - Fusarium mycotoxins are secondary metabolites produced by Fusarium spp. in cereals. Among them, deoxynivalenol (DON) and zearalenone (ZEN) are widespread worldwide contaminants of cereal commodities and are ranked as the most important chronic dietary risk factors. Their conjugates, known as masked mycotoxins, have been described but are still not accounted for in risk assessment studies. This study demonstrates for the first time that DON and ZEN are effectively deconjugated by the human colonic microbiota, releasing their toxic aglycones and generating yet unidentified catabolites. For this reason, masked mycotoxins should be considered when evaluating population exposure. PMID- 23347207 TI - A new generation of B(n)N(n) rings as a supplement to boron nitride tubes and cages. AB - In B(n)N(n) cages or tubes, when the quasi-borazine rings are attached to each other through a pair of common atoms of B and N, the bonding structure is named class A. On the other hand, there are some B(n)N(n) rings including a covalent bond between two atoms of B and N, which are named class B. In all previous studies, both reports of synthesis and theoretical calculation of boron nitride tubes and cages, the quasi-borazine units are attached together like class A. There are no theoretical or experimental reports from class B compounds except for a brief study in our previous works (Struct. Chem. 2012, 23, 551-580; J. Phys. Chem. C 2010, 114, 15315.). In this study, we have used two kinds of boron nitride rings from a twisted BN sheet in the same chirality created by different mechanisms. For (4, 4) chirality, the molecules B(16)N(16) and B(15)N(15) are found to respectively represent class A and B, and for (5, 5) chirality the molecules B(20)N(20) and B(18)N(18) are respectively again of class A and B. The structure of class A rings is similar to boron nitride tubes, but we have shown that it is impossible to produce a macromolecule of class B form as tubes or cages, because there is much more instability and intermolecular tension in macro forms of class B. This is the main reason that the class B molecules are rare and, because of their small size, have not yet been synthesized, although we have some suggestions for the synthesis of these kinds of molecules. The stability and electromagnetic properties with hybrid density functional theory using the EPR III and EPR-II basis sets for explanation of hyperfine parameters and spin densities, electrical potential, and isotropic Fermi coupling constant of these rings have been studied by the nonbonded interaction models. Normal mode analyses including aromaticity have been investigated by using the nucleus independent chemical shift values at the ring center. Interaction energy and gain in energy aid in describing the stability that is promoted upon gradual binding with molecular hydrogen, and a linear relationship occurred between them. PMID- 23347208 TI - Interaction of monocytes/macrophages with ovarian cancer cells promotes angiogenesis in vitro. AB - It has been established that macrophages and endothelial cells infiltrate peritoneum in the vicinity of tumor implants of epithelial ovarian cancer (EOC). This study investigates whether the interaction of ovarian cancer cells and tumor associated macrophages could promote the involvement of endothelial cells in angiogenesis. Macrophage phenotypes were detected by fluorescence-activated cell sorting, and cytokine/chemokine secretion was measured by enzyme linked immunosorbent assay. The effect of co-culture of ovarian cancer cells and tumor associated macrophage (TAM) cells on endothelial cell migration and tube formation was investigated. Signaling pathway mediators were also evaluated for their potential roles in endothelial cell activation by ovarian cancer cells co cultured with TAM cells. Our results showed that higher expression of interleukin 8 (IL-8) expression associated with 54.26 +/- 34.46% of TAM infiltration of peritoneum was significantly higher than 16.58 +/- 17.74% of CD3(+) T-cell by immunofluorescence co-staining and confocal microscopy. THP-1 cells exhibited M2 polarized phenotype markers with high proportion of CD68(+) , CD206(+) and CD204(+) markers after phorbol 12-myristate 13-acetate (PMA) treatment, After co culturing with TAM cells in a transwell chamber system, EOC cells (SKOV3) increased their IL-8 expression at the level of mRNA and protein. After exposure to the conditioned medium obtained by co-culturing TAM and SKOV3 cells, the migration and tube formation of endothelial cells were enhanced significantly. Furthermore, the upregulation of IL-8 expression in ovarian cancer cells induced by macrophages could be inhibited by pyrollidine dithiocarbamate, an inhibitor of nuclear factor (NF)- kappaB signal pathway. We suggest that the interaction of ovarian cancer cells and tumor-associated macrophages enhances the ability of endothelial cells to promote the progression of ovarian cancer. PMID- 23347209 TI - Behavior and evaluation of tetraalkylammonium bromides as instrument test materials in thermal desorption ion mobility spectrometers. AB - Ion mobility spectrometers have found widespread use for the screening of explosives, chemical warfare agents, and illicit drugs. These instruments often rely on drift-time calibrants to perform qualitative identification. Such calibrants are suitable to determine the reduced mobility of compounds, but may not necessarily provide information on instrument performance. These calibrants are often internal and behave in a fashion similar to that of analytes in terms of sensitivity to a variety of instrumental and environmental variations. Ideally, test materials used to evaluate instrument performance would be insensitive to these changes. Current calibrants are sometimes not designed to satisfy these requirements, and although several instrument test materials are also in use, a consensus has not been reached on best practices. A homologous series of tetraalkylammonium salts has been proposed as one alternative instrumental test material set and has been successfully used for electrospray ion mobility spectrometry (IMS)-MS experiments. This study extends these analyses to thermal desorption IMS instruments. The reduced mobility (K0) values for these compounds, measured on a thermal desorption IMS instrument, are reported and are similar to those reported for electrospray IMS. The variability of daily instrument response to these compounds is small, further supporting their use as test materials. The ionization behavior and thermal profile of the compounds in the thermal desorption process are discussed. PMID- 23347210 TI - Overview: cytomegalovirus and the herpesviruses in transplantation. AB - Herpesviruses infect most animal species. Infections due to the eight human herpesviruses (HHV) are exacerbated by immunosuppression in organ transplantation. The special features of the herpesvirus life cycle include the ability to establish latent, nonproductive infection and the life-long capacity for reactivation to productive, lytic infection. Interactions between latent virus and the immune system determine the frequency and severity of symptomatic infections. The immunologic and cellular effects of herpesvirus infections contribute to risk for opportunistic infections and graft rejection. Among the most important advances in transplantation are laboratory assays for the diagnosis and monitoring of herpesvirus infections and antiviral agents with improved efficacy in prophylaxis and therapy. For herpes simplex virus, varicella zoster virus and cytomegalovirus, these advances have significantly reduced the morbidity of infection. The syndromes of EBV-associated posttransplant lymphoproliferative disorders (PTLD) and Kaposi's sarcoma remain important complications of immunosuppression. The epidemiology and essential biology of human herpesvirus is reviewed. PMID- 23347211 TI - Immune regulation of human herpesviruses and its implications for human transplantation. AB - Human herpesviruses including cytomegalovirus, Epstein-Barr virus, HHV6, HHV7, HHV8, Herpes simplex virus (HSV)-1 and HSV-2 and varicella zoster virus (VZV) have developed an intricate relationship with the human immune system. This is characterized by the interplay between viral immune evasion mechanisms that promote the establishment of a lifelong persistent infection and the induction of a broad humoral and cellular immune response, which prevents the establishment of viral disease. Understanding the immune parameters that control herpesvirus infection, and the strategies the viruses use to evade immune recognition, has been critical in understanding why immunological dysfunction in transplant patients can lead to disease, and in the development of immunological strategies to prevent and control herpesvirus associated diseases. PMID- 23347212 TI - CMV: Prevention, Diagnosis and Therapy. AB - Cytomegalovirus (CMV) is the most common infection after organ transplantation and has a major impact on morbidity, mortality and graft survival. Optimal prevention, diagnosis and treatment of active CMV infection enhance transplant outcomes, and are the focus of this section. Methods to prevent CMV include universal prophylaxis and preemptive therapy; each has its merits, and will be compared and contrasted. Diagnostics have improved substantially in recent years, both in type and quality, allowing for more accurate and savvy treatment; advances in diagnostics include the development of an international standard, which should allow comparison of results across different methodologies, and assays for cellular immune function against CMV. Therapy primarily involves ganciclovir, now rendered more versatile by data suggesting oral therapy with valganciclovir is not inferior to intravenous therapy with ganciclovir. Treatment of resistant virus remains problematic, but is enhanced by the availability of multiple novel therapeutic agents. PMID- 23347213 TI - Epstein-Barr virus infection and posttransplant lymphoproliferative disorder. AB - Epstein-Barr virus (EBV) is an important pathogen in recipients of solid organ transplants (SOT). Infection with EBV manifests as a spectrum of diseases/malignancies ranging from asymptomatic viremia through infectious mononucleosis to posttransplant lymphoproliferative disorder (PTLD). EBV disease and its associated PTLD is more frequently seen when primary EBV infection occurs after transplant, a common scenario in pediatric SOT recipients. Intensity of immunosuppressive therapies also influences the risk for PTLD. The use of EBV viral load monitoring facilitates the diagnosis and management of EBV/PTLD as well as being used to inform preemptive therapy with reduction of immunosuppression, the most effective intervention for prevention of and treatment for PTLD. Other therapies, including the rituximab (anti-CD20 monoclonal antibody) and traditional chemotherapy, are also useful in the treatment of established PTLD. The future development of standards for management based on EBV viral load and routine monitoring of EBV-specific CTL responses promise further improvement in outcomes with EBV and PTLD. PMID- 23347214 TI - Varicella zoster virus (VZV) and herpes simplex virus (HSV) in solid organ transplant patients. AB - Varicella zoster virus (VZV) and the two herpes simplex viruses (HSV) are human alpha-herpesviruses that establish life-long latency in neural ganglia after initial primary infection. In the solid organ transplant (SOT) population, manifestations of VZV or HSV may be seen in up to 70% of recipients if no prophylaxis is used, some of them life and organ threatening. While there are effective vaccines to prevent VZV primary infection and reactivation in immunocompetent adults, these vaccines are contraindicated after SOT because they are live-virus vaccines. For HSV, prevention has focused primarily on antiviral strategies because the immunologic correlates of protection and control are different from VZV, making vaccine development more challenging. Current antiviral therapy remains effective for the majority of clinical VZV and HSV infections. PMID- 23347215 TI - Human herpesviruses 6, 7 and 8 in solid organ transplant recipients. AB - Human herpesviruses (HHV) 6 and 7 are ubiquitous infections that reactivate commonly in transplant recipients. However, clinical diseases due to these viruses are reported only in 1% of solid organ transplant recipients. Fever, rash and bone marrow suppression are the most common manifestations, but symptoms of tissue invasive disease may be observed. Treatment of HHV-6 and HHV-7 disease includes antiviral therapy and cautious reduction in immunosuppression. HHV-8 is an oncogenic gamma-herpesvirus that causes Kaposi's sarcoma, Castleman's disease and primary effusion lymphomas in transplant recipients. Nonmalignant diseases such as bone marrow suppression and multiorgan failure have also been associated with HHV-8. Reduction in immunosuppression is the first line treatment of HHV-8 infection. Other alternatives for treatment, especially for HHV-8 diseases not responsive to immuno-minimization strategies, are surgery and chemotherapy. Sirolimus has been shown to be a beneficial component for the treatment of Kaposi's sarcoma and the role of antivirals for HHV-8 infection is being investigated. PMID- 23347216 TI - Human herpesvirus vaccines and future directions. AB - Over the last few years there has been an impressive increase in the virological and immunological tools available to detect both human herpesvirus (HHV) and immune control of replication post-solid organ transplantation. This has allowed a greater appreciation of pathogenesis, studies to be designed to evaluate potential vaccines, new approaches adopted for antiviral deployment and the success of interventions to be judged. This chapter aims to summarize the state of-the-art in vaccine development and look forward to the role that vaccines, immune monitoring, viral kinetics and new antiherpesvirus agents may play in the future management of HHV infections after transplantation. PMID- 23347217 TI - Continuing medical education program in American Journal of Transplantation. PMID- 23347218 TI - Long-term clinical outcomes after Streptococcus bovis isolation in asymptomatic blood donors in Hong Kong. AB - BACKGROUND: Risk of transfusion-transmitted bacterial sepsis has been substantially reduced by a bacterial surveillance program (BST). However, new problems emerge as asymptomatic bacteremia is detected in blood donors. Streptococcus bovis bacteremia, which is known to associate with infective endocarditis and colonic carcinoma, is an example. STUDY DESIGN AND METHODS: A retrospective study was conducted to examine the demographic and clinical outcome of this group of donors. All confirmed culture-positive cases under the BST were retrieved and those donors with S. bovis bacteremia were contacted for follow-up. Viable culture samples were sent for detailed microbiologic analysis. RESULTS: From 1998 to 2012, a total of 16 donors were found to have S. bovis bacteremia, giving an estimated prevalence of 1 in 110,800 donations. They consisted of nine men and seven women with median age of 43.5 years. Eight donors had undergone colonoscopy with colonic carcinoma detected in two and benign adenoma in four. Five of the 16 isolates could be retrieved for 16S DNA sequencing. Four were identified as S. gallolyticus ssp. pasteurianus and one as S. gallolyticus ssp. gallolyticus. The two patients with colonic carcinoma had one each of subspecies pasteurianus and gallolyticus. CONCLUSION: The findings highlight a close association of S. bovis and colonic carcinoma. We recommend prompt donor follow up if S. bovis bacteremia is detected. Besides, all confirmed S. bovis should be fully characterized by molecular technique. PMID- 23347219 TI - Significance of elevated transplant renal artery velocities in the postoperative renal transplant patient. AB - INTRODUCTION: Non-invasive imaging studies can provide visualization of allograft perfusion in the postoperative evaluation of newly transplanted renal allografts. AIM: The purpose of our study was to evaluate the significance of elevated renal artery velocities in the immediate postoperative period. METHODS: Peak systolic velocities (PSVs) were obtained in the transplanted renal artery of 128 patients immediately after transplantation. Repeat allograft Doppler ultrasonography was performed on patients with elevated values. RESULTS: Of the 128 patients, 57 (44.5%) had severely elevated Doppler velocities >400 cm/s on the initial studies. Three patients within this category had persistently elevated values of >400 cm/s, warranting angiographic visualization of the renal vessels. Stent placement within the transplanted renal artery was required in two of these patients. There was normalization of the PSV in the remaining patients. CONCLUSIONS: Routine allograft Doppler ultrasonography in the immediate postoperative period allows for visualization of allograft perfusion. Elevated renal artery velocities in the immediate postoperative period do not necessarily represent stenosis requiring intervention. Failure of the PSV to normalize may require further intervention, and angiography continues to be the gold standard. PMID- 23347221 TI - Effectiveness of simulator-based echocardiography training of noncardiologists in congenital heart diseases. AB - BACKGROUND: Congenital heart diseases (CHD) are responsible for substantial morbidity and mortality in neonates. The preliminary diagnosis often is made by noncardiologists. For this reason, there is a huge demand of training in echocardiography of CHD. This is difficult to achieve due to limited resources of specialized centers. OBJECTIVE: The goal of this study was to investigate the training effect of the echocardiography simulator EchoCom on trainee's ability to diagnose CHD. DESIGN/METHODS: We enrolled 10 residents for simulator-based training in echocardiography of CHD. All participants were instructed on the simulator's basic handling and had one hour to scan the first 9 datasets information (ventricular septal defect, atrial septal defect, atrioventricular septal defect, Tetralogy of Fallot, transposition of great arteries, congenital corrected transposition of great arteries, common arterial trunk, hypoplastic left heart syndrome, normal anatomy) and establish a diagnosis. No help was given except for support regarding simulator related issues. Afterward, 2 rounds of structured simulator based echocardiography training focused on echocardiographic anatomy, spatial orientation, standard views, and echocardiographic anatomy of different CHD followed. All participants completed a standardized questionnaire containing 10 multiple-choice (MC) questions focusing on basic theoretical knowledge in echocardiographic anatomy and common CHD. RESULTS: Almost all of the residents invited from the affiliated children's hospital had little (20%) or no experience (80%) in echocardiography of CHD. Their Pretest and Posttest scores showed significant improvement for both, MC test and performance test, respectively. CONCLUSIONS: Our study showed that simulator-based training in echocardiography in CHD could be very effective and may assist with training outside the scope of CHD. PMID- 23347220 TI - Determining the threshold for alcohol-induced brain damage: new evidence with gliosis markers. AB - BACKGROUND: Chronic intake of ethanol (EtOH) has been linked to serious health consequences such as cardiac and liver problems, cognitive impairments, and brain damage. Alcohol's detrimental effects depend upon the dose, duration, and pattern of exposure with binge drinking as one of the most common, but most damaging, patterns of intake. Little is known about the threshold of the damaging effects of alcohol. Therefore, these experiments sought to determine a threshold for brain damage using various markers of neurodegeneration. METHODS: Adult male Sprague-Dawley rats were administered nutritionally complete liquid diet containing either EtOH (25% w/v) or isocaloric dextrose every 8 hours for either 1 (mean dose, 13.4 +/- 0.3 g/kg/d; mean blood EtOH concentration (BEC), 336.2 +/- 18.8 mg/dl) or 2 days (mean dose, 10.9 +/- 0.3 g/kg/d; mean BEC, 369.8 +/- 18.1 mg/dl). On the basis of a known time course of various neurodegeneration associated events, rats were perfused transcardially immediately following, 2 days after, or 7 days post EtOH exposure. To label actively dividing cells, some animals were injected with BromodeoxyUridine (BrdU) 2 hours prior to perfusion. Tissue was then analyzed for the presence of BrdU (cell proliferation), FluoroJade B (degenerative neurons), and vimentin (reactive astrogliosis) immunoreactivity. RESULTS: One or 2 days of EtOH exposure failed to alter cell proliferation at any of the time points analyzed. However, significant 2- to 9 fold increases in neuronal degeneration in limbic cortex and clear evidence of reactive gliosis as indicated by a 2- to 8-fold upregulation in vimentin immunoreactivity in the hippocampus were observed following as little as 1 day of binge EtOH exposure. CONCLUSIONS: These results indicate that as little as 1 day (24 hours) of high BEC, binge-like EtOH exposure is enough to elicit signs of alcohol-induced brain damage in adult rats. Further, reactive gliosis may be a more sensitive marker of alcohol-induced damage in the hippocampus. PMID- 23347222 TI - Burden of paediatric pyoderma and scabies in North West Queensland. AB - AIM: The study aims to assess the health burden of children admitted with 'scabies' to Mt Isa Hospital, the referral centre for North West Queensland, from 2006 to 2010. METHODS: This is a retrospective chart audit of admissions of children with 'scabies' including age, sex, date, residence, Indigenous status, result of skin swabs and length of stay, and the number of admissions with acute rheumatic fever (ARF) and acute post-streptococcal glomerulo-nephritis (APSGN) in that period. Financial burden was estimated from daily bed costs and transportation. RESULTS: There were 113 admissions with mean age of 23/12: 11% were <2/12 and mean stay was 4.5 days. 19 were admitted twice, 5 thrice and 2 four times. 7 individuals accounted for 25% of admissions. 'Scabies' accounted for 10.1% of medical admissions <5 years of age. Admissions increased from 10 in 2005 to 39 in 2010. The minimum cost per admission was $9584.07. Seventy-one per cent of swabs grew Group A streptococcus, all sensitive to penicillin. Sixty three per cent of these were accompanied by Staphylococcus aureus, which was the sole organism in 18%. Sixty-four per cent of S. aureus were methicillin resistant. There were 29 admissions for ARF and 23 with APSGN. All children with 'scabies' and ARF and all but three with APSGN were Indigenous. CONCLUSION: Pyoderma and scabies are major health burdens in North West Queensland, requiring organised community-based prevention. The number of repeat admissions emphasises the futility of individual treatment. PMID- 23347225 TI - PLP1 gene analysis in 88 patients with leukodystrophy. AB - Pelizaeus-Merzbacher disease (PMD) is caused in most cases by either duplications or point mutations in the PLP1 gene. This disease, a dysmyelinating disorder affecting mainly the central nervous system, has a wide clinical spectrum and its causing mutations act through different molecular mechanisms. Eighty-eight male patients with leukodystrophy were studied. PLP1 gene analysis was performed by the Multiplex Ligation-dependent Probe Amplification technique and DNA sequencing, and, in duplicated cases of PLP1, gene dosage was completed by using array-CGH. We have identified 21 patients with mutations in the PLP1 gene, including duplications, short and large deletions and several point mutations in our cohort. A customized array-CGH at the Xq22.2 area identified several complex rearrangements within the PLP1 gene region. Mutations found in the PLP1 gene are the cause of PMD in around 20% of the patients in this series. PMID- 23347224 TI - Self-advocacy and cancer: a concept analysis. AB - AIM: To report an analysis of the concept of self-advocacy among individuals with cancer to clarify its meaning, to differentiate this meaning with related concepts, and to unify understanding of the concept in cancer research and practice. BACKGROUND: Cancer survivors are increasingly required to assume an active role in their health care. A thorough analysis of how survivors advocate for themselves is a crucial aspect in supporting survivors' ability to engage and manage their care throughout all stages of cancer survivorship. DESIGN: Walker and Avant's eight-step process of conducting a concept analysis was used. DATA SOURCES: PubMed, PsycINFO, and CINAHL databases were searched for articles, reviews, editorials, and grey literature directly addressing self-advocacy. REVIEW METHODS: A broad inquiry into the literature from 1960 to 2012 that produces a definition of self-advocacy. Model and contrary cases of self-advocacy demonstrate the concept's application and intricacies. RESULTS: Antecedents to self-advocacy include particular personal characteristics, learned skills, and attainable support. The essential element of self-advocacy and what differentiates it from related concepts, is the internalization of these antecedent resources into self-advocacy thoughts and actions while incorporating personal values and priorities in a way that upholds the survivors' goals and beliefs. A full realization of self-advocacy facilitates a cancer survivor attaining a strong self-concept, sense of control, and adaptation to a life with cancer. CONCLUSIONS: Self-advocacy is a process of internalizing skills and resources to act in a way that supports survivors' needs and goals. PMID- 23347226 TI - Impaired masturbation-induced erections: a new cardiovascular risk factor for male subjects with sexual dysfunction. AB - INTRODUCTION: Erectile dysfunction (ED) is considered an early surrogate marker of silent, or even overt, cardiovascular diseases (CVD). However, epidemiological studies take into account only sexual intercourse-related erections. Although autoeroticism is a very common practice, data on masturbation-induced erections as a possible predictor of major adverse cardiovascular events (MACE) are lacking. AIM: To evaluate the clinical correlates of impaired masturbation induced erections and to verify the importance of this sexual aspect in predicting MACE. METHODS: A consecutive series of 4,031 male patients attending the Outpatient Clinic for sexual dysfunction for the first time was retrospectively studied. Among these subjects, 64% reported autoeroticism during the last 3 months, and only this subset was considered in the following analyses. In the longitudinal study, 862 subjects reporting autoeroticism were enrolled. MAIN OUTCOME MEASURES: Several clinical, biochemical, and instrumental (Prostaglandin E1 [PGE1 ] test and penile color Doppler ultrasound) parameters were studied. RESULTS: Subjects with an impaired erection during masturbation (46% of those reporting autoeroticism) had more often a positive personal or family history of CVD, a higher risk of reduced intercourse- and sleep-related erections, hypoactive sexual desire and perceived reduced ejaculate volume, and impaired PGE1 test response. Prolactin levels were lower in those having impaired erection during masturbation. In the longitudinal study, unadjusted incidence of MACE was significantly associated with impaired masturbation-induced erections. When dividing the population according to the median age and diagnosis of diabetes, the association between impaired masturbation-induced erections and incidence of MACE was maintained only in the youngest (<55 years old) and in nondiabetic subjects, even after adjusting for confounders (hazard ratio [HR] = 3.348 [1.085-10.335], P = 0.032 and HR = 2.108 [1.002-4.433], P = 0.049; respectively). CONCLUSION: This study indicates that, in subjects with male sexual dysfunction, evaluating an often neglected sexual parameter, such as masturbation-induced erections, can provide further insights on forthcoming MACE in particular in "low risk" subjects. PMID- 23347227 TI - Testicular tumour in northern pike, Esox lucius L. PMID- 23347228 TI - Two new Eimeria species parasitic in corncrakes (Crex crex) (Gruiformes: Rallidae) in the United Kingdom. AB - In this study we describe 2 new species of coccidia (Apicomplexa: Eimeriidae) parasites isolated from the feces of corncrake (Crex crex) (Gruiformes: Rallidae), bred in captivity in the U.K. Oocysts of Eimeria crecis n. sp. were approximately spherical and measured 15.3 MUm (13-18) * 14.3 (12-16), providing an oocyst shape index of 1.1. A micropyle and oocyst residuum were absent, but a polar granule was present. Oocysts of Eimeria nenei n. sp. were ellipsoidal and measured 23.6 (21-26) * 18.1 (17-20), providing an oocyst shape index of 1.3. A micropyle and polar granule were present. Surveying free-living, wild adult corncrakes in Scotland (U.K.) demonstrated both parasite species to be widespread. These are the first species described to infect the corncrake, and they are distinct from those previously found to infect members of the closely related crane family (Gruiformes: Gruidae). Partial amplification and sequencing of the 18S rRNA gene and internal transcribed spacer 2 indicated a close relationship between the 2 proposed new species as a group distinct from the Eimeria species known to infect cranes. These newly identified parasite species have been associated with enteric disease in corncrakes being prepared for reproduction in captivity and reintroduction into England (U.K.). PMID- 23347229 TI - The relative impact of psoriasis and obesity on socioeconomic and medical outcomes in psoriasis patients. AB - BACKGROUND: Psoriasis is a chronic, inflammatory skin disorder that is associated with obesity. Independently, both psoriasis and obesity likely impose impressive physical and psychosocial burdens on affected patients. OBJECTIVE: The purpose of this study was to evaluate the relative impact of body mass index (BMI) on the socioeconomic status, medical co-morbidities, and current and chronic quality of life of psoriasis patients. METHODS: Overall, 114 subjects were examined and asked to complete a self-administered questionnaire regarding disabilities, relationships, education, as well as medical and economic outcomes. Participants also answered the ten questions used in the Dermatology Life Quality Index modified to ask 'over the last week', 'over the last year' and 'over your lifetime with psoriasis'. Survey responses were compared amongst the three patient groups based on BMI (normal, overweight, obese). RESULTS: Patients with elevated BMI were more likely to rate their general health lower (P < 0.001), believe that psoriasis caused their weight gain (P = 0.014), experience sleep problems over their lifetime (P = 0.016), hide their psoriasis over their lifetime (P = 0.010), have their self-confidence affected by their psoriasis over their lifetime (P = 0.011) and avoid common activities over their lifetime (P = 0.012). CONCLUSION: There are long-term negative effects of elevated BMI that impose additional burdens on psoriasis patients, including impairments in sleep quality and increased social anxiety. PMID- 23347230 TI - Pain measures and cut-offs - 'no worse than mild pain' as a simple, universal outcome. PMID- 23347232 TI - Tautomerism and possible polymorphism in solid hydroxypyridines and pyridones studied by 14N NQR. AB - (14)N nuclear quadrupole resonance frequencies have been measured in solid 2 pyridone, 3-hydroxypyridine, and 4-pyridone by (1)H-(14)N nuclear quadrupole double resonance. Two slightly nonequivalent nitrogen positions are observed in solid 3-hydroxypyridine, whereas only one nitrogen position has been observed in 2-pyridone and 4-pyridone within the experimental resolution. Rather low (14)N quadrupole coupling constants in pyridones are the consequence of the delocalization of the nitrogen lone pair electrons in the aromatic rings. Two different compounds have been obtained by crystallization of 4-pyridone from ethanol in a normal and in a dry atmosphere. The compound obtained in the dry atmosphere is identical to the commercial sample. The compound obtained in the normal atmosphere cannot be converted to the commercial polymorph by melting. It is thus not a polymorph of anhydrous 4-pyridone. The temperature coefficient of the (14)N quadrupole coupling constant is negative in 3-hydroxypyridine and positive in 2- and 4-pyridone. Therefore, in 3-hydroxypyridine, molecular librations dominate the temperature variation of the quadrupole coupling constant, whereas in 2- and 4-pyridone, the changes in the hydrogen bonding interactions with temperature seem to give the dominant effect. PMID- 23347231 TI - Development of a method to quantitate nematode pheromone for study of small molecule metabolism in Caenorhabditis elegans. AB - Pheromones produced by Caenorhabditis elegans are considered key regulators of development, mating, and social behaviors in this organism. Here, we present a rapid mass spectrometry-based method (PheroQu) for absolute quantitation of nematode pheromones (e.g., daumone 1, 2, and 3) both in C. elegans worm bodies (as few as 20 worms) and in liquid culture medium. Pheromones were separated by ultra performance liquid chromatography and monitored by a positive electrospray ionization detector in the multiple-reaction monitoring mode. The daf-22 mutant worms were used as surrogate matrix for calibration, and stable deuterated isotope-containing pheromone was used as internal standard for measuring changes in pheromones in N2 wild-type and other strains under different growth conditions. The worm-body pheromones were extracted by acidified acetonitrile solvent, and the secreted pheromones were extracted from culture medium with solid-phase extraction cartridges. The run time was achieved in less than 2 min. The method was validated for specificity, linearity, accuracy, precision, recovery, and stability. The assay was linear over an amount range of 2-250 fmol, and the limit of quantitation was 2 fmol amounts for daumone 1, 2, and 3 in both worm bodies and culture medium. With the PheroQu method, we were able to identify the location of pheromone biosynthesis and determine the changes in different pheromone types synthesized, according to developmental stages and aging process. This method, which is simple, rapid, sensitive, and specific, will be useful for the study of small-molecule metabolism during developmental stages of C. elegans. PMID- 23347233 TI - Microparticle formation in apheresis platelets is not affected by three leukoreduction filters. AB - BACKGROUND: Microparticles in blood components might contribute to transfusion related immunomodulation or other side effects. To elucidate the role of leukofiltration, we compared three commercially available filters for their effect on platelet (PLT)-derived (PDMP), leukocyte-derived (LDMP), and red blood cell-derived (RDMP) microparticle formation in apheresis PLTs. STUDY DESIGN AND METHODS: Apheresis PLTs from pairs of ABO-identical male donors were pooled and divided into four volumes. One volume was stored without filtration, whereas the other three were filtered with different devices. PDMPs, LDMPs, and RDMPs were measured by flow cytometry during 2 weeks of controlled-temperature (22 degrees C) agitated storage. RESULTS: On average, PDMPs doubled over 5 days of storage, followed by a much steeper increase by which PDMPs on Day 14 were nearly 20 times higher than on Day 0. LDMP and RDMP counts were relatively stable over 14 days. Significant differences among filtered and nonfiltered products did not emerge. CONCLUSION: Although the conditions of this study showed no favorable or unfavorable effects of three different filters on microparticle formation, surveillance and investigation of unanticipated outcomes in other experimental and clinical circumstances should continue. PMID- 23347234 TI - Comparison of systemic atracurium, retrobulbar lidocaine, and sub-Tenon's lidocaine injections in akinesia and mydriasis in dogs. AB - OBJECTIVE: To compare the effect of sub-Tenon's lidocaine injections (ST) on akinesia and mydriasis to those of systemic atracurium (AT) and retrobulbar lidocaine injections in dogs. ANIMAL STUDIED: Ten healthy beagle dogs without apparent ocular disease. PROCEDURES: Three treatments were performed on 10 beagle dogs with a minimum 7-day washout period: intravenous injection of AT (0.2 mg/kg, AT group); retrobulbar (RB) injection of 2% lidocaine (2.0 mL, RB group) in one eye; and sub-Tenon's injection of 2% lidocaine (2.0 mL, ST group) in the opposite eye. When the akinesia was not obtained within 10 min, an additional 1 mL of lidocaine was administered in the RB and the ST groups. RESULTS: Onset of akinesia in the AT (1.5 +/- 0.9 min) and the ST (3.8 +/- 5.8 min) groups was significantly shorter than that in the RB group (9.0 +/- 6.5 min). Duration of akinesia in the ST group (116.2 +/- 32.8 min) was longer compared to the AT (60.6 +/- 23.6 min) and the RB (89.0 +/- 52.8 min) groups, even though there was only a significant difference between the AT and the ST groups. Mydriasis was achieved in five eyes in the RB group and nine eyes in the ST group. There was no significant difference in onset (3.6 +/- 3.1 and 2.9 +/- 2.3 min, respectively) or duration (91.4 +/- 31.9 and 102.1 +/- 35.8 min, respectively) of mydriasis between the groups. CONCLUSIONS: Sub-Tenon's lidocaine injections provide excellent akinesia and mydriasis compared to systemic AT and retrobulbar lidocaine injections. Therefore, sub-Tenon's anesthesia could be an alternative to the systemic administration of neuromuscular blockers and retrobulbar anesthesia for ophthalmic surgery in dogs. PMID- 23347235 TI - MDM2 is a useful prognostic biomarker for resectable gastric cancer. AB - Expression of MDM2 protein appears to be increased in malignancy and correlated to prognosis of tumors, but its role in gastric cancer remains controversial. Our recent investigations indicated that JWA was a novel candidate biomarker for gastric cancer. To evaluate the impact of MDM2 protein expression alone, and in combination with JWA, on the prognostic and predictive of patients with resectable gastric cancer, expression of MDM2 and JWA were examined by immunohistochemistry in three large cohorts (total n = 1131) of patient with gastric cancer. We found that MDM2 protein levels were significantly upregulated in gastric cancer (70.4%, 57 of 81) compared with adjacent non-cancerous tissues. High tumoral MDM2 expression significantly correlated with clinicopathologic characteristics, as well as with shorter overall survival (OS; P < 0.001 for all cohorts) in patients without adjuvant treatment. The effect of adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) in improving OS compared with surgery alone was evident only in the high MDM2 group (hazard ratio = 0.57; 95% confidence interval, 0.37-0.89; P = 0.013). Furthermore, knockdown of MDM2 and overexpression of JWA had a synergistic effect on suppression of gastric cancer cell proliferation and migration. Patients with low MDM2 and high JWA expression had a better outcome of survival compared with the other groups (P < 0.001 for all cohorts). For the first time, our data suggest that MDM2 is a potent prognostic and predictive factor for benefit from adjuvant fluorouracil leucovorin-oxaliplatin chemotherapy in resectable gastric cancer. The combination of MDM2 expression and JWA could serve as a more effective candidate prognostic biomarker for gastric cancer. PMID- 23347236 TI - Early subjective response and acquired tolerance as predictors of alcohol use and related problems in a clinical sample. AB - BACKGROUND: Previous studies have demonstrated that a low subjective response (SR) to alcohol is a risk factor for alcohol use disorders (AUDs), and a recent study suggests that acquired tolerance can be differentiated from initial SR and is also significantly associated with drinking problems. Because the prior study of SR and tolerance focused on a sample of moderate drinkers, the goal of the current study was to examine relations between early SR, acquired tolerance, alcohol use, and alcohol-related problems in a sample of young adults with clinically significant alcohol problems. METHODS: The current study examined associations between early SR and acquired tolerance and both drinking behavior and alcohol-related problems within a sample of 113 heavy drinking young adults (66.1% male) volunteering for a clinical trial of naltrexone in combination with brief motivational counseling. RESULTS: Consistent with the 1 prior study examining simultaneous effects of early SR and tolerance, both early SR and acquired tolerance were positively associated with typical drinking behavior, although tolerance was a much stronger predictor within this clinical sample. In contrast to the prior study, early SR was inversely associated with risk for alcohol-related problems, and tolerance was not a significant predictor of problems. CONCLUSIONS: The results suggested that, controlling for weekly drinking, a low early SR protected against acute negative consequences within a sample of heavy drinkers who had acquired significant tolerance to alcohol effects. It is possible that this protective effect may eventually shift to a risk factor by allowing individuals with a low SR to persist in a pattern of hazardous drinking. PMID- 23347237 TI - Candidaemia detected on direct blood smears. PMID- 23347238 TI - Role analysis of the nurse/midwives in the health services in Sub-Saharan Africa. AB - AIM: To describe the tasks and the roles of nurses and midwives in Sub-Saharan African health services. BACKGROUND: The current roles of nurses and midwives in the African region of the World Health Organization have not been empirically established, with only studies from two countries found (South Africa and Mozambique). This makes it difficult to establish whether current nursing/midwifery education programmes and regulations adequately address the needs in the health services. DESIGN: A descriptive quantitative study. METHODS: A survey questionnaire was administered to ambulatory and hospital services. Data were collected between June-December 2010, with completed responses from 734 nurses from nine African countries (five Anglophone and four Francophone). RESULTS: The highest reported role functioning in both settings was for 'General Care and Treatment'. The lowest role functioning reported in both settings was in the role 'Maternal and Child Health' and in 'The Provision of Mental Health Care'. The reported role performance in Anglophone countries was significantly greater than in Francophone countries. CONCLUSION: The development of competency in nursing/midwifery roles other than medical surgical roles (general assessment and care) should receive more attention in curricula. Special attention needs to be given to Francophone countries, where the professions of nursing and midwifery are poorly developed. PMID- 23347239 TI - Viral transduction of the neonatal brain delivers controllable genetic mosaicism for visualising and manipulating neuronal circuits in vivo. AB - The neonatal intraventricular injection of adeno-associated virus has been shown to transduce neurons widely throughout the brain, but its full potential for experimental neuroscience has not been adequately explored. We report a detailed analysis of the method's versatility with an emphasis on experimental applications where tools for genetic manipulation are currently lacking. Viral injection into the neonatal mouse brain is fast, easy, and accesses regions of the brain including the cerebellum and brainstem that have been difficult to target with other techniques such as electroporation. We show that viral transduction produces an inherently mosaic expression pattern that can be exploited by varying the titer to transduce isolated neurons or densely-packed populations. We demonstrate that the expression of virally-encoded proteins is active much sooner than previously believed, allowing genetic perturbation during critical periods of neuronal plasticity, but is also long-lasting and stable, allowing chronic studies of aging. We harness these features to visualise and manipulate neurons in the hindbrain that have been recalcitrant to approaches commonly applied in the cortex. We show that viral labeling aids the analysis of postnatal dendritic maturation in cerebellar Purkinje neurons by allowing individual cells to be readily distinguished, and then demonstrate that the same sparse labeling allows live in vivo imaging of mature Purkinje neurons at a resolution sufficient for complete analytical reconstruction. Given the rising availability of viral constructs, packaging services, and genetically modified animals, these techniques should facilitate a wide range of experiments into brain development, function, and degeneration. PMID- 23347240 TI - Chromosomal microarray impacts clinical management. AB - Chromosomal microarray analysis (CMA) is standard of care, first-tier clinical testing for detection of genomic copy number variation among patients with developmental disabilities. Although diagnostic yield is higher than traditional cytogenetic testing, management impact has not been well studied. We surveyed genetic services providers regarding CMA ordering practices and perceptions about reimbursement. Lack of insurance coverage because of perceived lack of clinical utility was cited among the most frequent reasons why CMA was not ordered when warranted. We compiled a list of genomic regions where haploinsufficiency or triplosensitivity cause genetic conditions with documented management recommendations, estimating that at least 146 conditions potentially diagnosable by CMA testing have published literature supporting specific clinical management implications. Comparison with an existing clinical CMA database to determine the proportion of cases involving these regions showed that CMA diagnoses associated with such recommendations are found in approximately 7% of all cases (n = 28,526). We conclude that CMA impacts clinical management at a rate similar to other genetic tests for which insurance coverage is more readily approved. The information presented here can be used to address barriers that continue to contribute to inequities in patient access and care in regard to CMA testing. PMID- 23347241 TI - What goes up must come down! A primary care approach to preventing injuries amongst highflying cheerleaders. AB - PURPOSE: This article provides information regarding the most common nonlife threatening and catastrophic injuries that occur during cheerleading, and describes the role of the nurse practitioner (NP) in managing patients who participate in cheerleading. DATA SOURCES: Literature review of evidence-based research articles, epidemiological reports, and current guidelines. CONCLUSIONS: Cheerleading is one of the most popular sports among adolescent females, and participation has increased rapidly in recent years. Rates of injury have also increased as the difficulty of this activity reaches new heights. Several factors such as body changes during puberty, societal pressures affecting nutrition, and lack of safety regulations place cheerleaders at risk for injury. Sprains/strains are the most common injury, and concussions are the most common traumatic injury. Injuries occur as a result of tumbling, stunting, falling, spotting, and unsafe practice surfaces. IMPLICATIONS FOR PRACTICE: The role of the NP in injury prevention is to identify risk factors during preparticipation physicals, initiate conditioning and strength training routines, and implement safety measures during practices and competitions. The NP should also provide education and guidance to cheerleaders, parents, and coaches. PMID- 23347242 TI - Putting medications where they belong: practical advice for managing type 2 diabetes in clinical practice. AB - PURPOSE: Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder that affects almost 24 million Americans. Healthcare providers often do not initiate and/or intensify therapy appropriately during patient visits, which may be due, in part, to a lack of understanding of the new diabetes medications. This review focuses on means by which primary care nurse practitioners (NPs) might evaluate the utility of pharmacologic agents based upon their relation to the pathogenesis of T2DM. DATA SOURCES: The evidence used in developing this review included evidence-based reviews, clinical trials, cohort studies, position statements, and guidelines. The authors obtained relevant reports through a computerized search of the literature using PubMed, MEDLINE, and other search engines and scanning syllabi from national and international meetings on the subject of type 2 diabetes. CONCLUSIONS: Medications used to manage T2DM utilize different pharmacologic approaches. These include stimulating insulin production, reducing hepatic gluconeogenesis, slowing polysaccharide digestion, and increasing insulin sensitivity in muscle, liver, and fat to achieve euglycemia. IMPLICATIONS FOR PRACTICE: Patients with T2DM should be treated to their lowest targeted glycemic goals as soon as they are diagnosed as safely and as rationally as possible. NPs in primary care practice can facilitate more effective diabetes management. PMID- 23347243 TI - My military: a navy nurse practitioner's perspective on military culture and joining forces for veteran health. AB - PURPOSE: This article responds to the need for improved integration of veteran health considerations across the broader community. A focus of the Joining Forces initiative is to foster partnerships between veterans and their communities through enhanced education, knowledge, and commitment of resources and support. DATA RESOURCES: Data and resources on known threats to veteran health are widely available in the literature. Personal perspectives on military culture and experience expand the body of knowledge and lead to improved outcomes in both established and evolving care delivery models and best practices for veteran health. CONCLUSIONS: The need for veteran health care outside of military and Veterans Affairs facilities is vast and expanding. Enhancing resources for health care of veterans is of critical importance. An understanding of military culture offers a basic reference for nonmilitary care providers to consider when providing and facilitating care across the continuum of veterans' health. IMPLICATIONS FOR PRACTICE: Nurse practitioners (NPs) are ideal providers of care for veteran and military family healthcare needs. NP practice incorporates cultural sensitivity, prevention strategies, and wellness-focused care while delivering and facilitating optimal patient, family, and community outcomes. The NP will be of critical community value in joining forces for veteran health. PMID- 23347244 TI - Depression in rural women: implications for nurse practitioners in primary care settings. AB - PURPOSE: The purpose of this study was threefold: (a) to determine what percent of rural women self-report as currently depressed when asked; (b) to explore the congruence between self-report of depression and Center for Epidemiologic Studies Depression Scale (CES-D) score; and (c) to identify factors associated with congruence between self-report of depression and CES-D score. DATA SOURCE: Self report data were collected from 140 women who lived in a rural community in the Midwest. The convenience sample was recruited at a Federally Qualified Health Center. CONCLUSIONS: The percent of rural women who self-reported as currently depressed was 36.4%. Congruence between self-report of depression and CES-D score was 76.8%, indicating the majority of women were able to identify if they were depressed or not. Women in the incongruent group were significantly more likely to be diagnosed with diabetes, reported more headaches, and received treatment for depression in the past. IMPLICATIONS FOR PRACTICE: Dependence on primary care providers to identify and treat depression is the current standard of care for the vast majority of rural women. As more advanced practice registered nurses work in rural areas, they need to be cognizant of the high rates of depression in women and the most effective strategies for identifying and treating. PMID- 23347245 TI - The communicative power of nurse practitioners in multidisciplinary primary healthcare teams. AB - PURPOSE: The purpose of the study is to explore the role of the nurse practitioner (NP) in facilitating knowledge exchange within multidisciplinary primary healthcare teams. The rationale for the study is that most knowledge transfer and exchange literature is from a single profession perspective; yet, an increasing number of healthcare practitioners work in the context of multidisciplinary teams. There is little research examining the mechanisms by which knowledge crosses professional and disciplinary boundaries. DATA SOURCE: The study's data source is a survey administered to NPs in urban, rural, and remote primary healthcare teams in Saskatchewan. The mapping techniques of social network analysis are applied to the survey data. CONCLUSIONS: The study's conclusions concern the structure of the intrateam knowledge-exchange behaviors and, in particular, the role of the NP as knowledge boundary spanner. IMPLICATIONS FOR PRACTICE: The study hypothesizes that the hallmark of well functioning multidisciplinary teams is the effective intrateam knowledge exchange and that Saskatchewan's new NPs bring a "boundary-spanning" capacity to the knowledge exchange of the province's multidisciplinary primary healthcare teams. The study fills this gap in the conceptual and empirical research within the evolving context of the reorganization of primary health care. PMID- 23347247 TI - Right ventricular outflow tract systolic excursion: a distinguishing echocardiographic finding in acute pulmonary embolism. AB - BACKGROUND: Even though chronic pulmonary hypertension (cPH) and acute pulmonary embolism (aPE) increase pulmonary vascular resistance and result in right ventricular (RV) dilatation and systolic dysfunction; both conditions operate through drastically different mechanisms. Unfortunately, simple echocardiographic examination might be insufficient to distinguish both entities. This study attempted to determine which objective measures would be useful in differentiating aPE from cPH. METHODS: Standard measures of main RV as well as RV outflow tract (RVOT) size and systolic performance calculations were retrospectively measured from 15 patients with confirmed aPE by chest computed tomography and compared with similar data collected from the same number of age matched patients with moderate (mcPH), severe (scPH), and patients without PH. RESULTS: Although a positive McConnell sign was seen in 60% of aPE patients and in 17% of the cPH patients, all aPE had a profound reduction in RVOT systolic excursion when compared with cPH patients. Furthermore, maximal tricuspid annular plane systolic excursion, velocity time integral of the RVOT ejection signal, end systolic or end-diastolic RV to left ventricle (LV) dimension ratio were not useful to distinguish aPE from any of the 2 forms of cPH. CONCLUSION: This study demonstrated that measurement of RVOT systolic excursion not only is feasible but also extremely useful in identifying aPE and it is particularly helpful in differentiating it from patients with either mcPH or scPH. This variable might be useful to estimate the global impairment in RV contractility and acute hemodynamic derangement seen in aPE. PMID- 23347246 TI - Comparison of demographic, psychosocial, and clinical characteristics among younger and older persons with acute coronary syndrome. AB - PURPOSE: The aim of this study was to examine the differences in demographic, psychosocial (depression), and clinical profiles among younger (males <= 50 years of age and females <= 55 years of age) and older (males > 50 years of age and females > 55 years of age) patients with acute coronary syndrome (ACS). DATA SOURCES: This study is a preliminary analysis of data collected from 1140 patients with ACS enrolled in an ongoing longitudinal investigation. CONCLUSIONS: As compared to their older counterparts, younger ACS patients were significantly more likely to be obese (p < .001), to smoke (p < .001), to have a higher BDI-II depression score (p < .001), and to feel depressed in the last year (p < .001). In contrast, younger ACS patients were significantly less likely to be dyslipidemic (p < .001), diabetic (p = 0.025), or hypertensive (p < .001) than their older counterparts. IMPLICATIONS FOR PRACTICE: Clinicians need to be persistent in promoting the importance of weight loss and smoking cessation. Screening and treating depression in younger persons is a prudent approach. The significance of regular screening and aggressive treatment of other risk factors (i.e., diabetes, hypertension, and dyslipidemia) should not be overlooked. PMID- 23347248 TI - X-ray photoelectron spectroscopy of fast-frozen hematite colloids in aqueous solutions. 5. Halide ion (F-, Cl-, Br-, I-) adsorption. AB - Halide anion (F(-), Cl(-), Br(-), and I(-)) adsorption and its impact on sodium adsorption at the hematite/water interface were studied by cryogenic X-ray photoelectron spectroscopy (XPS). Measurements were carried out on frozen, centrifuged wet hematite pastes that were previously equilibrated in 50 mM electrolytic solutions in the pH 2-11 range. XPS-derived halide ion surface loadings decreased in the order F(-) > I(-) ~ Cl(-) > Br(-), whereas sodium loadings were in the order Na(F) > Na(I) > Na(Br) > Na(Cl). The greater sodium loadings in NaF and in NaI resulted from larger anion loadings in these systems. Bromide ion had the lowest loading among all halide ions despite having a charge to-size ratio that is intermediate between those of Cl(-) and I(-). This unexpected result may have arisen from specific properties of the hematite/water interface, such as water structure and electric double layer thickness. Fluoride ion adsorption proceeded via the formation of hydrogen bonds with the surface hydroxo groups (e.g., =Fe-OH(2)...F(-) or =Fe-OH...F(-)). Surface-bound fluoride ions exert a greater charge-screening effect than the other halide anions, as demonstrated by considerably small zeta potential values. Fe-F bond formation was excluded as a possible interfacial process as the F 1s peak binding energy (684.2 eV) was more comparable to that of NaF (684.6 eV) than FeF(3) (685.4 eV). Overall, these findings motivate further refinements of existing thermodynamic adsorption models for predicting the ionic composition of hematite particle surfaces contacted with sodium halide aqueous solutions. PMID- 23347249 TI - Association of chromosome 9p21 genetic variants with risk of coronary heart disease in the East Asian population: a meta-analysis. AB - Our aim was to evaluate the effect of SNPs in the 9p21 locus on genetic susceptibility of coronary heart disease in the East Asian population. We searched PubMed, EMBASE and CNKI for publications relating to the association between SNPs within the 9p21 locus and coronary heart disease in the East Asian population. This meta-analysis was assessed by STATA 9.2. Twenty-one studies from 15 eligible papers composing 25,945 cases and 31,777 control subjects were included in the meta-analysis. The odds ratio (OR) and 95% confidence interval (CI) for the risk allele was 1.30 (1.25-1.35) with moderate heterogeneity. No publication bias was observed in this study. Sensitivity analysis further strengthened the validity of this association. In conclusion, SNPs within the 9p21 locus were strongly associated with the risk of coronary heart disease in the East Asian population with a similar risk OR to the Caucasian population. PMID- 23347250 TI - Transmission of Streptococcus agalactiae from a hatchery into a newly established red hybrid tilapia, Oreochromis niloticus (L.) * Oreochromis mossambicus (Peters), farm. PMID- 23347251 TI - Role of dG/dw and dV/dw in AIM analysis: an approach to the nature of weak to strong interactions. AB - Role of dG(b)(r(c))/dw and dV(b)(r(c))/dw is revealed as the basic atoms-in molecules (AIM) functions to evaluate, classify, and understand the nature of interactions, as well as G(b)(r(c)) and V(b)(r(c)). The border area between van der Waals (vdW) adducts and hydrogen-bonded (HB) adducts is shown to appear at around dG(b)(r(c))/dw = -dV(b)(r(c))/dw and that between molecular complexes (MC) and trigonal bipyramidal adducts (TBP) of chalcogenide dihalides appears at around 2dG(b)(r(c))/dw = -dV(b)(r(c))/dw. H(b)(r(c)) are plotted versus H(b)(r(c)) - V(b)(r(c))/2 at bond critical points (BCPs) in the AIM dual functional analysis. The plots incorporate the classification of interactions by the signs of ?(2)rho(b)(r(c)) and H(b)(r(c)). R [= (x(2) + y(2))(1/2)] corresponds to the energy for the interaction in question at BCPs, where (x, y) = (H(b)(r(c)), H(b)(r(c)) - V(b)(r(c))/2) and (x, y) = (0, 0) at the origin. The segment of lines for the plots (S) should correspond to energy, if the segment is substantially linear. The first derivative of S (dS) is demonstrated to be proportional to R. Relations between AIM functions, such as dV(b)(r(c))/dw, dG(b)(r(c))/dw, dH(b)(r(c))/d[H(b)(r(c)) - V(b)(r(c))/2], d(2)V(b)(r(c))/dw(2), d(2)G(b)(r(c))/dw(2), and d(2)H(b)(r(c))/d[H(b)(r(c)) - V(b)(r(c))/2](2), are also discussed. The results help us to understand the nature of interactions. PMID- 23347252 TI - A highly efficient and visualized method for glycan enrichment by self-assembling pyrene derivative functionalized free graphene oxide. AB - Protein glycosylation plays key roles in many biological processes, such as cell growth, differentiation, and cell-cell recognition. Therefore, global structure profiling of glycans is very important for investigating the biological significance and roles of glycans in disease occurrence and development. Mass spectrometry (MS) is currently the most powerful technique for structure analysis of oligosaccharides, but the limited availability of glycan/glycoproteins from natural sources restricts the wide adoption of this technique in large-scale glycan profiling. Though various enrichment methods have been developed, most methods relay on the weak physical affinity between glycans and adsorbents that yields insufficient enrichment efficiency. Furthermore, the lack of monitoring the extent/completeness of enrichment may lead to incomplete enrichment unless repeated sample loading and prolonged incubation are adopted, which limits sample handling throughput. Here, we report a rapid, highly efficient, and visualized approach for glycan enrichment using 1-pyrenebutyryl chloride functionalized free graphene oxide (PCGO). In this approach, glycan capturing is achieved by reversible covalent bond formation between the hydroxyl groups of glycans and the acyl chloride groups on graphene oxide (GO) introduced by pi-pi stacking of 1 pyrenebutyryl chloride on the GO surface. The multiple hydroxyl groups of glycans lead to cross-linking and self-assembly of free PCGO sheets into visible aggregation within 30 s, therefore achieving simple visual monitoring of the enrichment process. Improved enrichment efficiency is achieved by the large specific surface area of free PCGO and heavy functionalization of highly active 1 pyrenebutyryl chloride. Application of this method in enrichment of standard oligosaccharides or N-glycans released from glycoproteins results in remarkably increased MS signal intensity (approximately 50 times), S/N, and number of glycoform identified. PMID- 23347253 TI - The efficacy in melasma treatment using a 1410 nm fractional photothermolysis laser. AB - BACKGROUND: Melasma treatment modalities including topical and procedural therapy have been employed with variable results and high recurrence rate. OBJECTIVE: To quantitatively assess improvement in melasma and side effects after 1410 nm fractional photothermolysis laser treatments and to determine efficacy at 1-, 2- and 3-month follow-up after treatment. METHODS: Thirty volunteers with melasma were treated with 1410 nm fractional photothermolysis for four passes on full face and additional four passes on melasma area. They were randomly treated on one side of their face with 20 mJ at 5% coverage and the other side of their face with 20 mJ at 20% coverage. All subjects were treated monthly for five times. Melanin index, Visual analogue scale and Melasma Area and Severity Index score were measured at baseline and 1-, 2- and 3-month follow-up after complete treatment protocol. RESULTS: There was statistically significant improvement of Melanin index at 2- and 3-month follow-up visits, but not at 1-month follow-up visit. Visual analogue scale and Melasma Area and Severity Index score improved significantly on both sides at 1-, 2- and 3-month follow-ups. The overall patients' satisfaction was significantly higher on the side treated with 20 mJ, 5% coverage. Adverse reactions included erythema, dryness and post-inflammatory hyperpigmentation on melasma area. Those side effects were significantly more intense on the side treated with 20 mJ, 20% coverage. CONCLUSIONS: 1410 nm fractional photothermolysis laser treatment is a safe and temporary effective procedure for melasma; however, long-term follow-up is still needed. Only 5% coverage should be used to minimize risks of adverse effects. PMID- 23347254 TI - Intravascular immune hemolysis caused by the contrast medium iomeprol. AB - BACKGROUND: Immune-mediated hemolysis is not included in the list of adverse reactions related to contrast medium (CM). Here, we report on a patient who developed immune hemolytic anemia (IHA) related to iomeprol, a nonionic CM. STUDY DESIGN AND METHODS: A 34-year-old female patient developed massive hemolysis during infusion of 50 mL of iomeprol. Serologic studies were performed using standard techniques. RESULTS: Before hemolysis, the patient's serum was weakly positive with e+ red blood cells (RBCs; autoanti-e) and the direct antiglobulin test (DAT) was negative. After hemolysis, the patient's serum samples became significantly reactive with e- RBCs in the presence of iomeprol but not in the presence of two other similar CM. The DAT became strongly positive only with anti C3d. CONCLUSION: Initially, an allergic reaction was suggested, and as the hemolysis became obvious, a toxic hemolysis was suspected. However, serologic reexamination revealed an iomeprol-dependent antibody. IHA related to CM has yet only been described in one patient in 1991. The hemolysis in that patient was related to Isopaque, an older ionic CM. Here, we describe an additional patient and recommend that CM should be considered as a rare risk in the development of IHA. PMID- 23347255 TI - Silencing brassinosteroid receptor BRI1 impairs herbivory-elicited accumulation of jasmonic acid-isoleucine and diterpene glycosides, but not jasmonic acid and trypsin proteinase inhibitors in Nicotiana attenuata. AB - The brassinosteroid (BR) receptor, BR insensitive 1 (BRI1), plays a critical role in plant development, but whether BRI1-mediated BR signaling is involved in plant defense responses to herbivores was largely unknown. Here, we examined the function of BRI1 in the resistance of Nicotiana attenuata (Solanaceae) to its specialist insect herbivore Manduca sexta. Jasmonic acid (JA) and JA-isoleucine conjugate (JA-Ile) are important hormones that mediate resistance to herbivores and we found that after wounding or simulated herbivory NaBRI1 had little effect on JA levels, but was important for the induction of JA-Ile. Further experiments revealed that decreased JAR (the enzyme for JA-Ile production) activity and availability of Ile in NaBRI1-silenced plants were likely responsible for the low JA-Ile levels. Consistently, M. sexta larvae gained more weight on NaBRI1 silenced plants than on the control plants. Quantification of insect feeding induced secondary metabolites revealed that silencing NaBRI1 resulted in decreased levels of carbon-rich defensive secondary metabolites (hydroxygeranyllinalool diterpene glycosides, chlorogenic acid, and rutin), but had little effect on the nitrogen-rich ones (nicotine and trypsin proteinase inhibitors). Thus, NaBRI1-mediated BR signaling is likely involved in plant defense responses to M. sexta, including maintaining JA-Ile levels and the accumulation of several carbon-rich defensive secondary metabolites. PMID- 23347256 TI - Functional roles of tumor necrosis factor-related apoptosis-inducing ligand-DR5 interaction in B16F10 cells by activating the nuclear factor-kappaB pathway to induce metastatic potential. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been recognized as a promising target for cancer therapy because it can induce apoptotic cell death in tumor cells but not normal cells. Although TRAIL shows specific tumoricidal activity, resistance to TRAIL-induced apoptosis in some tumor cells has been considered a clinical obstacle of its application. It has been shown that TRAIL provides inflammatory signals that may contribute to the TRAIL-resistance of cancer cells; however, it is not known whether TRAIL itself is involved in malignant cancer cell behavior. In the present study, we examined the functional role of TRAIL in B16F10 mouse melanoma cells, which are totally insensitive to TRAIL-induced apoptosis. By establishing B16F10 cells stably expressing the nuclear factor-kappaB (NFkappaB)-luciferase reporter gene, we found that TRAIL can activate NFkappaB through its death receptor DR5 in B16F10 cells. Furthermore, TRAIL-DR5 interaction not only promoted malignant behaviors of B16F10 cells, such as cell proliferation and MMP-9 production, but also induced lung metastasis of B16F10 cells in vivo. These findings may imply a contrary role for the TRAIL-DR5 pathway in the inflammatory tumor microenvironment, in its ability to induce the metastatic potential of B16F10 melanoma cells instead of inducing apoptosis. PMID- 23347257 TI - Theoretical investigation on antioxidant activity of bromophenols from the marine red alga Rhodomela confervoides: H-atom vs electron transfer mechanism. AB - Bromophenols are known as antioxidant radical scavengers for some biomolecules such as those in marine red alga. Full understanding of the role played by bromophenols requires detailed knowledge of the radical scavenging activities in probable pathways, a focus of ongoing research. To gain detailed insight into two suggested pathways, H-atom transfer and electron transfer, theoretical studies employing first principle quantum mechanical calculations have been carried out on selected bromophenols. Detailed investigation of the aforementioned routes revealed that upon H-atom abstraction or the electron transfer process, bromophenols cause an increase in radical species in which the unpaired electron appears to be delocalized as much as possible over the whole aromatic ring, especially in the bromine substituent. The O-H bond dissociation energies (BDEs) and ionization potential energies (IPs) are reported at the B3LYP level of theory, providing the first complete series of BDEs and IPs for bromophenols. The observations are compared to those of other antioxidants for which BDEs and IPs have been previously obtained. PMID- 23347258 TI - Health-related quality of life as an independent predictor of long-term disability for patients with relapsing-remitting multiple sclerosis. AB - BACKGROUND AND PURPOSE: Predictive factors of long-term disability in patients with relapsing-remitting multiple sclerosis (RR-MS) are well known, but the weight of these factors does not explain the entire change of disability. Few studies have examined the predictive value of quality of life (QoL). OBJECTIVES: To determine the value of the initial level of QoL to predict changes in the disability status of patients with MS and to determine if specific-MS questionnaires predict more accuracy in these changes than generic questionnaires. METHODS: DESIGN: multicenter, multi-regional, and longitudinal study. Main inclusion criteria: patients with RR-MS subtype and an Expanded Disability Status Scale (EDSS) score lower than 7.0. Sociodemographic and clinical data were recorded at baseline. Every 6 months up to month 24, QoL (MusiQoL and SF-36) was recorded. At 24 months, individuals were defined into two 'disability change' groups: the worsened and not worsened patients. RESULTS: Five hundred and twenty-six patients were enrolled: 386 (83.7%) not worsened and 75 (16.3%) worsened patients at 24 months. The activity of daily living and the relationship with healthcare workers dimensions of MusiQoL questionnaire were independent predictors of change in the EDSS score after 24 months. The physical functioning dimension of the SF-36 questionnaire predicted independently disability change after 24 months. CONCLUSIONS: Patient-reported baseline QoL levels provide additional prognostic information on MS disability beyond traditional clinical or sociodemographic factors. These findings reinforce the importance of incorporating a patient's evaluation of their own QoL level during patient monitoring and the assessment of treatment effects. PMID- 23347259 TI - Briefly trained medical students can effectively identify rheumatic mitral valve injury using a hand-carried ultrasound. AB - BACKGROUND: Rheumatic heart disease (RHD) is common and remains a major cause of morbidity, particularly in developing countries. Its diagnosis relies on expertise-dependent echocardiographic studies. We evaluated the accuracy of briefly trained examiners in identifying RHD utilizing a hand-carried cardiac ultrasound (HCU) device. METHODS: Three medical students received 8 hours of training in cardiac ultrasound, focused on assessment of rheumatic valve injury and its complications, using a prototype of HCU device, OptiGo. The students, blinded to the patients' medical condition, performed an auscultation-based physical examination and a focused HCU study on volunteers and patients with known RHD. A standard echocardiography study was used to validate the results. RESULTS: Each student performed a physical examination followed by an HCU study on 45 subjects (mean age 57 +/- 14 years, 52% men), 14 of whom (31%) had rheumatic mitral valve injury. The students' averaged sensitivity for diagnosing RHD by HCU examination was 81%, while specificity was 95%. The interrater agreement (kappa) of the 3 students' HCU study and the standard echocardiography examination were between 0.55 and 0.88 (P < 0.01), and among the students themselves between 0.57 and 0.74 (P < 0.01), as students 1 and 2 had better results than student 3. Auscultation-based physical examination rendered low sensitivity (16%) for diagnosing rheumatic valve complications, namely mitral regurgitation and stenosis; however, it improved by 26% when students based their diagnosis on an HCU study. CONCLUSIONS: The ability to detect rheumatic valve injury using a portable ultrasound device by operators who only received brief echocardiographic training is remarkably high. However, the diagnosis of RHD complications is only modest. This result highlights the utility of portable cardiac ultrasound devices operated by basically trained personnel as a valuable diagnostic tool for RHD. PMID- 23347260 TI - Differential effects of site-specific knockdown of estrogen receptor alpha in the medial amygdala, medial pre-optic area, and ventromedial nucleus of the hypothalamus on sexual and aggressive behavior of male mice. AB - Testosterone is known to play an important role in the regulation of male-type sexual and aggressive behavior. As an aromatised metabolite of testosterone, estradiol-induced activation of estrogen receptor alpha (ERalpha) may be crucial for the induction of these behaviors in male mice. However, the importance of ERalpha expressed in different nuclei for this facilitatory action of testosterone has not been determined. To investigate this issue, we generated an adeno-associated virus vector expressing a small hairpin RNA targeting ERalpha to site-specifically knockdown ERalpha expression. We stereotaxically injected either a control or ERalpha targeting vector into the medial amygdala, medial pre optic area (MPOA), or ventromedial nucleus of the hypothalamus (VMN) in gonadally intact male mice. Two weeks after injection, all mice were tested biweekly for sexual and aggressive behavior, alternating between behavior tests each week. We found that suppressing ERalpha in the MPOA reduced sexual but not aggressive behavior, whereas in the VMN it reduced both behaviors. Knockdown of ERalpha in the medial amygdala did not alter either behavior. Additionally, it was found that ERalpha knockdown in the MPOA caused a parallel reduction in the number of neuronal nitric oxide synthase-expressing cells. Taken together, these results indicate that the testosterone facilitatory action on male sexual behavior requires the expression of ERalpha in both the MPOA and VMN, whereas the testosterone facilitatory action on aggression requires the expression of ERalpha in only the VMN. PMID- 23347261 TI - Distinguishing ecological from evolutionary approaches to transposable elements. AB - Considerable variation exists not only in the kinds of transposable elements (TEs) occurring within the genomes of different species, but also in their abundance and distribution. Noting a similarity to the assortment of organisms among ecosystems, some researchers have called for an ecological approach to the study of transposon dynamics. However, there are several ways to adopt such an approach, and it is sometimes unclear what an ecological perspective will add to the existing co-evolutionary framework for explaining transposon-host interactions. This review aims to clarify the conceptual foundations of transposon ecology in order to evaluate its explanatory prospects. We begin by identifying three unanswered questions regarding the abundance and distribution of TEs that potentially call for an ecological explanation. We then offer an operational distinction between evolutionary and ecological approaches to these questions. By determining the amount of variance in transposon abundance and distribution that is explained by ecological and evolutionary factors, respectively, it is possible empirically to assess the prospects for each of these explanatory frameworks. To illustrate how this methodology applies to a concrete example, we analyzed whole-genome data for one set of distantly related mammals and another more closely related group of arthropods. Our expectation was that ecological factors are most informative for explaining differences among individual TE lineages, rather than TE families, and for explaining their distribution among closely related as opposed to distantly related host genomes. We found that, in these data sets, ecological factors do in fact explain most of the variation in TE abundance and distribution among TE lineages across less distantly related host organisms. Evolutionary factors were not significant at these levels. However, the explanatory roles of evolution and ecology become inverted at the level of TE families or among more distantly related genomes. Not only does this example demonstrate the utility of our distinction between ecological and evolutionary perspectives, it further suggests an appropriate explanatory domain for the burgeoning discipline of transposon ecology. The fact that ecological processes appear to be impacting TE lineages over relatively short time scales further raises the possibility that transposons might serve as useful model systems for testing more general hypotheses in ecology. PMID- 23347262 TI - TREM2: a new risk factor for Alzheimer's disease. PMID- 23347263 TI - Magnetic moment assisted layer-by-layer film formation of a Prussian Blue analog. AB - We formed magnetic moment assisted layer-by-layer (LbL) films of a Prussian Blue analogue (PB). We applied an external magnetic field to each monolayer of PB to orient the magnetic moment of the compound perpendicular to the substrate. Aligned moments or orientation of the magnetic compounds themselves were immobilized in each monolayer, so that the moments could augment formation of the subsequent monolayers of LbL adsorption process. We hence could form multilayered LbL films of PB molecules with their magnetic moments oriented perpendicular to the substrate. We also formed LbL films of the compound with their moments oriented parallel to the substrate and facing one particular direction. We have measured conductivity and dielectric constant of the two types of films and compared the parameters with that of conventional LbL films deposited without orienting magnetic moments of the molecules. PMID- 23347266 TI - Accurate study on the quantum dynamics of the He + HeH(+) (X1Sigma+) reaction on a new ab initio potential energy surface for the lowest 1(1)A' electronic singlet state. AB - A time-dependent quantum wave packet method is used to investigate the dynamics of the He + HeH(+)(X(1)Sigma(+)) reaction based on a new potential energy surface [Liang et al., J. Chem. Phys.2012, 136, 094307]. The coupled channel (CC) and centrifugal-sudden (CS) reaction probabilities as well as the total integral cross sections are calculated. A comparison of the results with and without Coriolis coupling revealed that the number of K states N(K) (K is the projection of the total angular momentum J on the body-fixed z axis) significantly influences the reaction threshold. The effective potential energy profiles of each N(K) for the He + HeH(+) reaction in a collinear geometry indicate that the barrier height gradually decreased with increased N(K). The calculated time evolution of CC and CS probability density distribution over the collision energy of 0.27-0.36 eV at total angular momentum J = 50 clearly suggests a lower reaction threshold of CC probabilities. The CC cross sections are larger than the CS results within the entire energy range, demonstrating that the Coriolis coupling effect can effectively promote the He + HeH(+) reaction. PMID- 23347264 TI - Replication of established common genetic variants for adult BMI and childhood obesity in Greek adolescents: the TEENAGE study. AB - Multiple genetic loci have been associated with body mass index (BMI) and obesity. The aim of this study was to investigate the effects of established adult BMI and childhood obesity loci in a Greek adolescent cohort. For this purpose, 34 variants were selected for investigation in 707 (55.9% females) adolescents of Greek origin aged 13.42 +/- 0.88 years. Cumulative effects of variants were assessed by calculating a genetic risk score (GRS-34) for each subject. Variants at the FTO, TMEM18, FAIM2, RBJ, ZNF608 and QPCTL loci yielded nominal evidence for association with BMI and/or overweight risk (p < 0.05). Variants at TFAP2B and NEGR1 loci showed nominal association (p < 0.05) with BMI and/or overweight risk in males and females respectively. Even though we did not detect any genome-wide significant associations, 27 out of 34 variants yielded directionally consistent effects with those reported by large-scale meta-analyses (binomial sign p = 0.0008). The GRS-34 was associated with both BMI (beta = 0.17 kg/m(2) /allele; p < 0.001) and overweight risk (OR = 1.09/allele; 95% CI: 1.04 1.16; p = 0.001). In conclusion, we replicate associations of established BMI and childhood obesity variants in a Greek adolescent cohort and confirm directionally consistent effects for most of them. PMID- 23347267 TI - Effects of asthma on nicotine dependence development and smoking cessation attempts in adolescence. AB - OBJECTIVE: The aim of this study was to investigate whether asthma predicts the development of nicotine dependence and unsuccessful smoking cessation attempts in adolescent smokers. In addition, whether nicotine dependence could explain the relation between asthma and unsuccessful cessation attempts was also investigated. METHODS: A longitudinal survey study was conducted among 286 adolescents (aged 12-15 at T1) who had never used tobacco at baseline and were current smokers at follow-up 22 months later. Regression analyses were applied to test the effects of four asthma indicators (current wheeze, indication of asthma, symptom severity, and current diagnosed asthma) on nicotine dependence and smoking cessation attempts. RESULTS: Both adolescents who had an indication of asthma as well as adolescents with higher symptom severity developed higher levels of nicotine dependence over time and made a greater number of unsuccessful smoking cessation attempts in the past 12 months compared to those without asthma or less severe symptoms. Nicotine dependence partly mediated the effects of asthma symptoms on unsuccessful cessation attempts. Current wheezing and current diagnosed asthma did not predict nicotine dependence or unsuccessful quit attempts. CONCLUSIONS: Nicotine dependence develops more quickly in youth with symptoms of asthma, and this partly explains the increased number of unsuccessful cessation attempts of adolescents with asthma. Smoking prevention and smoking cessation programs are encouraged to provide additional support for youth with asthma, focusing on both the physiological and psychological aspects of dependence. PMID- 23347268 TI - Co-infection patterns of infectious salmon anaemia and sea lice in farmed Atlantic salmon, Salmo salar L., in southern Chile (2007-2009). AB - Infectious salmon anaemia virus (ISAV) caused a large epidemic in farmed Atlantic salmon in Chile in 2007-2009. Here, we assessed co-infection patterns of ISAV and sea lice (SL) based on surveillance data collected by the fish health authority. ISAV status and SL counts in all Atlantic salmon farms located in the 10th region of Chile were registered monthly from July 2007 through December 2009. Each farm was categorized monthly according to its ISAV and SL status. A multinomial time space scan test using a circular window was applied to identify disease clusters, and a multivariate regression model was fitted to quantify the association between disease-clustering and farm-management factors. Most of the identified clusters (9/13) were associated with high SL burdens. There were significant associations (P < 0.05) between management factors and ISAV/SL status. Areas in which good management practices were associated with a reduced disease risk were identified. The findings of this study suggest that certain management practices can effectively reduce the risk of SL and ISAV in the face of an epidemic and will be helpful towards creating an effective disease control programme in Chile. PMID- 23347269 TI - Dose overactive bladder (OAB) type affect the strength of the association between OAB and erectile dysfunction? PMID- 23347270 TI - Reticulocyte count in red-blood-cell units stored in AS-1. AB - BACKGROUND AND OBJECTIVES: Previous data that showed maintenance of reticulocyte percentage in whole blood stored in CPDA-1 have led to the assumption that reticulocyte maturation becomes arrested during refrigerated storage. However, reticulocyte behaviour in red-blood-cell units stored in additive solutions has not yet been studied. This study was thus aimed at determining reticulocyte count and reticulocyte subtypes in red-blood-cells units stored in AS-1. MATERIALS AND METHODS: Reticulocyte percentage and subtypes were determined by flow cytometry with thiazole orange in six red-blood-cells units stored in AS-1. RESULTS: Reticulocyte count was 26.8 +/- 4.6 * 10(9) /l at week 0.5 and 8.2 +/- 2.9 * 10(9) /l at week 6. Total haemolysis during storage was 0.19 +/- 0.08%. High fluorescence reticulocytes were 2.0 +/- 3.2 * 10(9) /l at week 0.5 and decreased by weeks 2, 4 and 6. Low-fluorescence reticulocytes were 22.1 +/- 3.1 * 10(9) /l at week 0.5 and decreased by weeks 4 and 6. CONCLUSION: A significant decrease in reticulocytes occurred during red-blood-cells units' storage in AS-1. Even if it were assumed that all of haemolysed cells during storage were reticulocytes, there are a number of them whose disappearance cannot be explained by this mechanism. Changes observed in reticulocyte subtypes suggest that they mature during storage. PMID- 23347271 TI - Prevalence and risk factors of actinic keratoses in Germany--analysis of multisource data. AB - BACKGROUND: In Europe, only few and inconsistent data on the prevalence and treatment of actinic keratoses (AK) are available. OBJECTIVES: To determine the prevalence of AK in Germany, to identify potential predictors and to estimate the number of AK cases treated in dermatological practices. METHODS: In a multiple source approach, prevalence was assessed from whole-body examinations in a cohort of 90 800 employees and from nationwide statutory health insurance (SHI) data of 2008. The number of cases documented in dermatological offices was estimated from statistics of a SHI Physicians Association. RESULTS: Standardized prevalence of AK from dermatological examinations was 2.7%; the rate increased with age (11.5% in the group 60-70 years) and was higher for men (3.9%) than for women (1.5%). Significant associations were also identified for skin phototype I, sunburns in childhood and solar lentigines. Vitiligo and a history of melanoma were also, but not significantly, associated with AK. In the SHI data analysis, standardized AK prevalence was 1.8%. Age-specific rates were below 1.5% up to 60 years and rose to 8.2% (13.2% in men) in the group 80-89 years. The prevalence from these large data sets--which is at the lower limit of studies from other countries--suggests about 1.7 million estimated AK cases in Germany. In 2011, AK accounted for 8.3% of the hundred most frequently treated dermatological outpatient diagnoses. The proportion of AK cases has risen almost continuously over the last 10 years, compared to other dermatological conditions. Estimated annual number of AK cases documented by dermatologists in Germany is about 1.7 million. CONCLUSIONS: Actinic keratosis is a frequent condition in higher age groups and more prevalent in men; a relevant need for health care is evident. Predictors and risk factors for AK are easy to identify in the population, which could also help to detect groups with special need for preventive measures. PMID- 23347272 TI - Mixed miniature postsynaptic currents resulting from co-release of glycine and GABA recorded from glycinergic neurons in the neonatal respiratory network. AB - Inhibitory neurons are involved in the generation and patterning of the respiratory rhythm in the adult animal. However, the role of glycinergic neurons in the respiratory rhythm in the developing network is still not understood. Although the complete loss of glycinergic transmission in vivo is lethal, the blockade of glycinergic transmission in slices of the medulla has little effect on pre-Botzinger complex network activity. As 50% of the respiratory rhythmic neurons in this slice preparation are glycinergic, they have to be considered as integrated parts of the network. We aimed to investigate whether glycinergic neurons receive mixed miniature inhibitory postsynaptic currents (mIPSCs) that result from co-release of GABA and glycine. Quantification of mixed mIPSCs by the use of different objective detection methods resulted in a wide range of results. Therefore, we generated traces of mIPSCs with a known distribution of mixed mIPSCs and mono-transmitter-induced mIPSCs, and tested the detection methods on the simulated data. We found that analysis paradigms, which are based on fitting the sum of two mIPSC templates, to be most acceptable. On the basis of these protocols, 20-40% of all mIPSCs recorded from respiratory glycinergic neurons are mixed mIPSCs that result from co-release of GABA and glycine. Furthermore, single cell reverse transcriptase polymerase chain reaction revealed that 46% of glycinergic neurons co-express mRNA of glycine transporter 2 together with at least one marker protein of GABAergic neurons. Our data suggest that significant co-transmission occurs in the pre-Botzinger complex that might be involved in the shaping of synaptic inhibition of respiratory glycinergic neurons. PMID- 23347265 TI - Evidence for a role for the adaptive immune response in human term parturition. AB - PROBLEM: Spontaneous labor at term involves leukocyte recruitment and infiltration into the choriodecidua; yet, characterization of these leukocytes and their immunological mediators is incomplete. The purpose of this study was to characterize the immunophenotype of choriodecidual leukocytes as well as the expression of inflammatory mediators in human spontaneous parturition at term. METHOD OF STUDY: Choriodecidual leukocytes were analyzed by FACS, immunohistochemistry, and RT-PCR in three different groups: (i) preterm gestation delivered for medical indications without labor; (ii) term pregnancy without labor; and (iii) term pregnancy after spontaneous labor. RESULTS: Two T-cell subsets of memory-like T cells (CD3(+) CD4(+) CD45RO(+) and CD3(+) CD4(-) CD8(-) CD45RO(+) cells) were identified in the choriodecidua of women who had spontaneous labor. Evidence for an extensive immune signaling network composed of chemokines (CXCL8 and CXCL10), chemokine receptors (CXCR1-3), cytokines (IL-1beta and TNF-alpha), cell adhesion molecules, and MMP-9 was identified in these cells during spontaneous labor at term. CONCLUSIONS: The influx of memory-like T cells in the choriodecidua and the evidence that they are active by producing chemokines and cytokines, and expressing chemokine receptors, cell adhesion molecules, and a matrix-degrading enzyme provides support for the participation of the adaptive immune system in the mechanisms of spontaneous parturition at term. PMID- 23347273 TI - Early development and regression in Rett syndrome. AB - This study utilized developmental profiling to examine symptoms in 14 girls with genetically confirmed Rett syndrome and whose families were participating in the Australian Rett syndrome or InterRett database. Regression was mostly characterized by loss of hand and/or communication skills (13/14) except one girl demonstrated slowing of skill development. Social withdrawal and inconsolable crying often developed simultaneously (9/14), with social withdrawal for shorter duration than inconsolable crying. Previously acquired gross motor skills declined in just over half of the sample (8/14), mostly observed as a loss of balance. Early abnormalities such as vomiting and strabismus were also seen. Our findings provide additional insight into the early clinical profile of Rett syndrome. PMID- 23347274 TI - Functions, diversity, and evolution of traumatic mating. AB - Copulation can involve the wounding of the mating partner by specialised devices. This type of mating, which we term traumatic mating, has been regarded as exceptional. Its prevalence, however, has not been compared across taxa, nor have its functions and putative evolutionary pathways. A categorisation has been lacking to date. We here show that traumatic mating is a widespread and diverse phenomenon that likely evolved via several pathways. Its putative functions include: (i) anchorage during mating; (ii) stimulation of short-term female reproductive investment; (iii) male paternity advantages; and (iv) enhanced fertilisation efficiency in transitions to internal fertilisation. Both natural and sexual selection have likely contributed to the parallel evolution of traumatic intromittent organs in phylogenetically distant taxa. These organs are sometimes remarkably similar in shape and often, but not always, inject sperm. The target sites of trauma infliction and the nature of secretions delivered alongside sperm are thus far poorly studied, but data on both are needed to elucidate the function of traumatic mating. The few existing studies that explicitly quantify fitness impacts of traumatic mating indicate that this strategy may often be costly to the party being wounded. However, a comprehensive approach to assess overall investments and returns for both sexes is a major target for future work. Finally, for the first time, we corroborate quantitatively the hypothesis that traumatic mating evolved relatively more often among hermaphroditic than among gonochoric taxa. PMID- 23347275 TI - Structure of polyelectrolyte brushes subject to normal electric fields. AB - Molecular dynamic simulations of salt-free polyelectrolyte brushes subject to external fields applied normal to the grafting substrate reveal the three dimensional monomer and counterion distributions. It is found that below a critical electric field, local electroneutrality holds for densely grafted brushes and the brush height remains independent of field intensity. Above this critical field (which scales as 1/3 with grafting density) brush height increases smoothly, and the fraction of condensed counterions decreases. The brush bifurcates into two subpopulations of stretched and collapsed chains when the grafting density is not low. At intermediate grafting densities, the majority of chains are stretched and the minority are nonstretched. At high grafting densities bifurcation and brush height growth occur consecutively. The majority of the chains are nonstretched at high grafting densities. Although not observed prior to overstretching of the chain model, it is predicted that the two subpopulations will re-merge to a single highly stretched phase when field intensity reaches a third critical value. The ability to control subpopulations of chains suggests that utilizing electric fields normal to polyelectrolyte brushes holds potential as controllable gates in microfluidic devices. PMID- 23347277 TI - Polymorphisms within the COL5A1 3'-UTR that alters mRNA structure and the MIR608 gene are associated with Achilles tendinopathy. AB - COL5A1 encodes for the alpha1 chain of type V collagen, an important regulator of fibril assembly in tendons, ligaments and other connective tissues. A polymorphism (rs12722) within the functional COL5A1 3'-untranslated region (UTR) has been shown to associate with chronic Achilles tendinopathy and other exercise related phenotypes. The COL5A1 3'-UTR contains several putative cis-acting elements including a functional Hsa-miR-608 binding site. The aim of this study was to determine whether previously uncharacterized polymorphisms within a functional region of the COL5A1 3'-UTR or the MIR608 gene are associated with chronic Achilles tendinopathy. The effect of these COL5A1 3'-UTR polymorphisms on the 3'-UTR predicted mRNA secondary structure was also investigated. One hundred and sixty Caucasian chronic Achilles tendinopathic and 342 control participants were genotyped for the COL5A1 3'-UTR markers rs71746744, rs16399 and rs1134170, as well as marker rs4919510 within MIR608. All four genetic markers were independently associated with chronic Achilles tendinopathy. The COL5A1 polymorphisms appear to alter the predicted secondary structure of the 3'-UTR. We propose that the secondary structure plays a role in the regulation of the COL5A1 mRNA stability and by implication type V collagen production. PMID- 23347276 TI - Antibody screening identifies 78 putative host proteins involved in Cyprinid herpesvirus 3 infection or propagation in common carp, Cyprinus carpio L. AB - Cyprinid herpesvirus 3 (CyHV-3) is the aetiological agent of a serious and notifiable disease afflicting common and koi carp, Cyprinus carpio L., termed koi herpesvirus disease (KHVD). Significant progress has been achieved in the last 15 years, since the initial reports surfaced from Germany, USA and Israel of the CyHV-3 virus, in terms of pathology and detection. However, relatively few studies have been carried out in understanding viral replication and propagation. Antibody-based affinity has been used for detection of CyHV-3 in enzyme-linked immunosorbent assay and PCR-based techniques, and immunohistological assays have been used to describe a CyHV-3 membrane protein, termed ORF81. In this study, monoclonal antibodies linked to N-hydroxysuccinimide (NHS)-activated spin columns were used to purify CyHV-3 and host proteins from tissue samples originating in either CyHV-3 symptomatic or asymptomatic fish. The samples were next analysed either by polyacrylamide gel electrophoresis (PAGE) and subsequently by electrospray ionization coupled to mass spectrometry (ESI-MS) or by ESI-MS analysis directly after purification. A total of 78 host proteins and five CyHV-3 proteins were identified in the two analyses. These data can be used to develop novel control methods for CyHV-3, based on pathways or proteins identified in this study. PMID- 23347278 TI - Decreasing central-line-associated bloodstream infections in Connecticut intensive care units. AB - Central-line-associated bloodstream infections (CLABSIs) are a significant cause of preventable harm. A collaborative project involving a multifaceted intervention was used in the Michigan Keystone Project and associated with significant reductions in these infections. This intervention included the Comprehensive Unit-based Safety Program, a multifaceted approach to CLABSI prevention, and the monitoring and reporting of infections. The purpose of this study was to determine whether the multifaceted intervention from the Michigan Keystone program could be implemented in Connecticut and to evaluate the impact on CLABSI rates in intensive care units (ICUs). The primary outcome was the NHSN defined rate of CLABSI. Seventeen ICUs, representing 14 hospitals and 104,695 catheter days were analyzed. The study period included up to four quarters (12 months) of baseline data and seven quarters (21 months) of postintervention data. The overall mean (median) CLABSI rate decreased from 1.8 (1.8) infections per 1,000 catheter days at baseline to 1.1 (0) at seven quarters postimplementation of the intervention. This study demonstrated that the multifaceted intervention used in the Keystone program could be successfully implemented in another state and was associated with a reduction in CLABSI rates in Connecticut. Moreover, even though the statewide baseline CLABSI rate in Connecticut was low, rates were reduced even further and well below national benchmarks. PMID- 23347280 TI - Dynamic behavior of hydrogen bonds from pure closed shell to shared shell interaction regions elucidated by AIM dual functional analysis. AB - The dynamic behavior of hydrogen bonds (HBs) was clarified for the wide range of interactions applying AIM dual functional analysis. Plots of H(b)(r(c)) versus H(b)(r(c)) - V(b)(r(c))/2 are analyzed in the polar (R, theta) representation, where H(b)(r(c)) and V(b)(r(c)) are total electron and potential energy densities at bond critical points, respectively, for the fully optimized structures. Data of the fully optimized structure and four perturbed ones around it are plotted for each interaction, which give a specific curve. The curve is analyzed by (theta(p), kappa(p)): theta(p) corresponds to the tangent line from the y direction and kappa(p) is the curvature. Whereas (R, theta) correspond to the static nature, (theta(p), kappa(p)) represent the dynamic nature of interactions. Indeed, HBs can be classified only by one parameter of theta, but theta(p) supplies more information necessary for better understanding of HBs. Although H(2)Se-*-HSeH and H(3)N-*-HNH(2) show the nature of pure CS (closed shell) of the vdW-type, H(2)S-*-HSH and H(2)O-*-HOH contain the nature of pure CS other than the vdW-type (HB-typical). The regular CS nature is observed for B-*-HF (B = HF, H(2)Se, H(2)S, H(2)O, and H(2)C?O). The HF-*-HF interaction is described as HB typical, whereas others are by CT(MC)-type. The nature of H(3)N-*-HX (X = F, Cl, Br) is regular CS of the CT(TBP)-type. HBs in charged species, such as [HOH-* OH](-) and [H(2)O-*-H-*-OH(2)], show the weak covalent nature of SS (shard shell). The dynamic behavior of HBs helps us to understand HBs in more detail, in addition to the static behavior. PMID- 23347281 TI - Suicide risk by military occupation in the DoD active component population. AB - Suicide risk based on occupational cohorts within the U.S. military was investigated. Rates of suicide based on military occupational categories were computed for the Department of Defense (DoD) active component population between 2001 and 2010. The combined infantry, gun crews, and seamanship specialist group was at increased risk of suicide compared to the overall military population even when adjusted for gender, age, and deployment history. The results provide useful information that can help inform the DoD's suicide prevention mission. Data limitations and recommended areas for future research are discussed. PMID- 23347279 TI - Strategy for dual-analyte luciferin imaging: in vivo bioluminescence detection of hydrogen peroxide and caspase activity in a murine model of acute inflammation. AB - In vivo molecular imaging holds promise for understanding the underlying mechanisms of health, injury, aging, and disease, as it can detect distinct biochemical processes such as enzymatic activity, reactive small-molecule fluxes, or post-translational modifications. Current imaging techniques often detect only a single biochemical process, but, within whole organisms, multiple types of biochemical events contribute to physiological and pathological phenotypes. In this report, we present a general strategy for dual-analyte detection in living animals that employs in situ formation of firefly luciferin from two complementary caged precursors that can be unmasked by different biochemical processes. To establish this approach, we have developed Peroxy Caged Luciferin-2 (PCL-2), a H(2)O(2)-responsive boronic acid probe that releases 6-hydroxy-2 cyanobenzothiazole (HCBT) upon reacting with this reactive oxygen species, as well as a peptide-based probe, z-Ile-Glu-ThrAsp-D-Cys (IETDC), which releases D cysteine in the presence of active caspase 8. Once released, HCBT and D-cysteine form firefly luciferin in situ, giving rise to a bioluminescent signal if and only if both chemical triggers proceed. This system thus constitutes an AND-type molecular logic gate that reports on the simultaneous presence of H(2)O(2) and caspase 8 activity. Using these probes, chemoselective imaging of either H(2)O(2) or caspase 8 activity was performed in vitro and in vivo. Moreover, concomitant use of PCL-2 and IETDC in vivo establishes a concurrent increase in both H(2)O(2) and caspase 8 activity during acute inflammation in living mice. Taken together, this method offers a potentially powerful new chemical tool for studying simultaneous oxidative stress and inflammation processes in living animals during injury, aging, and disease, as well as a versatile approach for concurrent monitoring of multiple analytes using luciferin-based bioluminescence imaging technologies. PMID- 23347282 TI - Safety assessment and caloric value of partially hydrolyzed guar gum. AB - Guar gum and partially hydrolyzed guar gum (PHGG) are food ingredients that have been available for many years. PHGG is the partially hydrolyzed product from guar gum obtained from the Indian cluster bean (Cyanopsis tetragonolopus). The gum (CAS Registry No. 9000-30-0) is composed of galactomannan, a gel-forming polysaccharide with a molecular weight ranging from 200 to 300 kDa. The intact and partially hydrolyzed forms have multiple food applications. The intact material can be used to control the viscosity, stability, and texture of foods. PHGG is highly soluble and has little physical impact on foods. Both forms are indigestible but are excellent sources of fermentable dietary fiber. The caloric value of intact guar gum is accepted as 2.0, whereas the caloric value of PHGG has not been firmly established. It is the goal of this paper to review the chemistry, safety, in vivo effects, and caloric value of PHGG. PMID- 23347283 TI - Influence of dimehylsulfoxide on protein-ligand binding affinities. AB - Because of its favorable physicochemical properties, DMSO is the standard solvent for sample storage and handling of compounds in drug discovery. To date, little attention was given to how DMSO influences protein-ligand binding strengths. In this study we investigated the effects of DMSO on different noncovalent protein ligand complexes, in particular in terms of the binding affinities, which we determined using nanoESI-MS. For the investigation, three different protein ligand complexes were chosen: trypsin-Pefabloc, lysozyme-tri-N-acetylchitotriose (NAG3), and carbonic anhydrase-chlorothiazide. The DMSO content in the nanoESI buffer was increased systematically from 0.5 to 8%. For all three model systems, it was shown that the binding affinity decreases upon addition of DMSO. Even 0.5 1% DMSO alters the KD values, in particular for the tight binding system carbonic anhydrase-chlorothiazide. The determined dissociation constant (KD) is up to 10 times higher than for a DMSO-free sample in the case of carbonic anhydrase chlorothiazide binding. For the trypsin-Pefabloc and lysozyme-NAG3 complexes, the dissociation constants are 7 and 3 times larger, respectively, in the presence of DMSO. This work emphasizes the importance of effects of DMSO as a co-solvent for quantification of protein-ligand binding strengths in the early stages of drug discovery. PMID- 23347284 TI - Surgical solutions for the complications of the Vaseline self-injection of the penis. AB - INTRODUCTION: Penile girth enhancement by the injection of Vaseline is an existing practice. Many cases develop severe complications that need surgery. AIM: To report on the reconstructive surgical solutions of the complications of Vaseline self-injection and the outcomes. To develop a modification of a one-step reconstruction method involving the use of pedicled scrotal flaps. MAIN OUTCOME MEASURES: The complications and their surgical solutions were classified as regards severity and difficulty. The outcomes were observed and a newly introduced one-step surgical method was investigated. METHODS: Seventy-eight consecutive patients (87.2% of them with a history of imprisonment) were divided into three groups. In group A, aesthetic penile defects or phimosis caused by the Vaseline necessitated circumcision or local excision. In group B, the whole penile skin was involved, and total skin removal and two- or (a newly modified) one-step reconstructive surgery were performed. In group C, both the whole penile skin and the scrotum were involved: complete skin removal and skin grafting or skin pedicled flap transplantation were carried out. RESULTS: In five cases in group B, postoperative skin necrosis made a second operation necessary. There was one intraoperative urethral injury, where a urethral fistula developed and a second urethral reconstruction was performed. There was no major complication with the newly developed one-stage pedicled flap procedure. At the end of the therapy, all the cases were healed. All of the patients reported successful sexual intercourse after the operations and 91% were satisfied with the result. CONCLUSIONS: The complications depend mainly on the amount of Vaseline injected, the hygienic circumstances, and the personal tolerability. In the worst cases, only radical skin removal and skin transplantation can solve the problem. The newly developed one-step arterial branch-preserving scrotal skin flap reconstruction appears to be a suitable and cost-effective solution for these patients. PMID- 23347285 TI - Assessment of left atrial function after percutaneous closure of patent foramen ovale. AB - BACKGROUND: The influence of atrial septal occluders in left atrial (LA) function after percutaneous closure of patent foramen ovale (PFO) has not been thoroughly studied. METHODS: Twenty-five patients (mean age 40.7 +/- 12 years) undergoing percutaneous PFO closure were enrolled in this study. Transthoracic echocardiogram (TTE) was performed 3 and 6 months before the procedure. Volumetric indices (active emptying fraction: LA AEF, expansion index: LA EI, and passive emptying fraction: LA PEF), strain and strain rate (SR), were calculated during the contractile, reservoir, and conduit LA phases for the lateral, anterior, and inferior LA walls with TTE. RESULTS: After 3 months, a decrease in the SR of the LA anterior wall was observed (from 2.12 +/- 0.22 to 1.66 +/- 0.26, P < 0.045), while the LA lateral wall strain was found to be increased (from 0.708 +/- 0.15 to 0.783 +/- 0.159, P < 0.001). Moreover, simultaneously LA AEF was greater compared with baseline (from 31.0 +/- 1.6 to 34.0 +/- 1.6, P < 0.004). However, all these alterations reversed at 6 months. CONCLUSIONS: Segmental LA function is altered transiently after percutaneous PFO closure with a septal occlude. The LA anterior wall SR decreases, while the lateral wall strain increases. The impact of these alterations needs further clarification. PMID- 23347286 TI - Impact of glucose and acetate on the characteristics of the platelet storage lesion in platelets suspended in additive solutions with minimal plasma. AB - BACKGROUND AND OBJECTIVES: Glucose and acetate have been proposed to be required elements in platelet storage media. This study investigated the role of these compounds on the varied elements that comprise the platelet storage lesion. MATERIALS AND METHODS: For each replicate, four pooled and split ABO group specific buffy coat-derived platelet concentrates were suspended in an in-house additive solution with minimal plasma and varying final concentrations of acetate or glucose. Units were sampled on days 2, 3, 6, 8 and 10 and tested for markers of platelet morphology, activation, function, metabolism and indicators of cell death. RESULTS: The absence of glucose was associated with a decrease in ATP, falling to a mean of 1.1 +/- 0.1 MUmol/10(11) plts in units with no added glucose compared with 4.2 +/- 0.6 MUmol/10(11) plts (P < 0.001) in units with 30 mm glucose. As glucose became depleted, the decrease in ATP to levels below 3 MUmol/10(11) plts was associated with an increase in both annexin V binding and intracellular free calcium. In units lacking exogenous acetate, ATP levels on day 10 were 5.2 +/- 1.5 MUmol/10(11) plts compared with 2.7 +/- 0.9 MUmol/10(11) plts in units with 56 mm acetate (P = 0.006). Higher concentrations of exogenous acetate were associated with a lower hypotonic shock response and higher surface expression of CD62P suggestive of a dose dependency. CONCLUSION: Under current physical storage conditions, glucose appears necessary for the maintenance of platelets stored as concentrates in minimal volumes of plasma. The addition of acetate was associated with increased platelet activation and reduced ATP levels. PMID- 23347287 TI - Nurses' views of interprofessional education and collaboration: a comparative study of recent graduates from three universities. AB - Today interprofessional education (IPE) is spread throughout the world. In Sweden only one of the existing nursing programs has an IPE curriculum on several levels during the training. The aim of this study was to examine how nurses who recently graduated from universities with IPE or non-IPE curricula perceive the importance of different educational goals and whether they found themselves prepared for their profession, and especially for collaboration with other professions. Three universities with different commitments to IPE were studied. We used a survey with eight different targets: communication skills, cooperation with other professions, problem-solving capability, self-directed learning skills, whether their education has prepared them to work professionally, to perform research, to take care of acutely ill patients, to work preventively and working as a nurse. The participants were asked whether their undergraduate education had prepared them for these targets and whether they perceived that the targets were important goals for their education. A main result in this study was that nurses who had recently graduated from the IPE university perceived to a greater extent that their undergraduate training had prepared them to work together with other professions in comparison with nursing students from non-IPE universities. PMID- 23347288 TI - Immune responses of different species of tilapia infected with Streptococcus agalactiae. PMID- 23347289 TI - Preparation of films of a highly aligned lipid cubic phase. AB - We demonstrate a method by which we can produce an oriented film of an inverse bicontinuous cubic phase (Q(II)(D)) formed by the lipid monoolein (MO). By starting with the lipid as a disordered precursor (the L(3) phase) in the presence of butanediol, we can obtain a film of the Q(II)(D) phase showing a high degree of in-plane orientation by controlled dilution of the sample under shear within a linear flow cell. We demonstrate that the direction of orientation of the film is different from that found in the oriented bulk material that we have reported previously; therefore, we can now reproducibly form Q(II)(D) samples oriented with either the [110] or the [100] axis aligned in the flow direction depending on the method of preparation. The deposition of MO as a film, via a moving fluid-air interface that leaves a coating of MO in the L(3) phase on the capillary wall, leads to a sample in the [110] orientation. This contrasts with the bulk material that we have previously demonstrated to be oriented in the [100] direction, arising from flow producing an oriented bulk slug of material within the capillary tube. The bulk sample contains significant amounts of residual butanediol, which can be estimated from the lattice parameter of the Q(II)(D) phase obtained. The sample orientation and lattice parameters are determined from synchrotron small-angle X-ray scattering patterns and confirmed by simulations. This has potential applications in the production of template materials and the growth of protein crystals for crystallography as well as deepening our understanding of the mechanisms underlying the behavior of lyotropic liquid-crystal phases. PMID- 23347290 TI - The evolutionary ecology of alternative migratory tactics in salmonid fishes. AB - Extensive individual variation in spatial behaviour is a common feature among species that exhibit migratory life cycles. Nowhere is this more evident than in salmonid fishes; individual fish may complete their entire life cycle in freshwater streams, others may migrate variable distances at sea and yet others limit their migrations to larger rivers or lakes before returning to freshwater streams to spawn. This review presents evidence that individual variation in migratory behaviour and physiology in salmonid fishes is controlled by developmental thresholds and that part of the variation in proximal traits activating the development of alternative migratory tactics is genetically based. We summarize evidence that alternative migratory tactics co-exist within populations and that all individuals may potentially adopt any of the alternative phenotypes. Even though intra-specific genetic divergence of migratory tactics is uncommon, it may occur if female competition for oviposition sites results in spawning segregation of alternative phenotypes. Because of their polygenic nature, alternative migratory tactics are considered as threshold traits. Threshold traits have two characteristics: an underlying 'liability' trait that varies in a continuous fashion, and a threshold value which is responsible for the discreetness observed in phenotypic distribution. We review evidence demonstrating that body size is an adequate proxy for the liability trait controlling the decision to migrate, but that the same phenotypic outcome (anadromy or residency) may be reached by different developmental pathways. The evidence suggesting a significant heritable component in the development of alternative migratory tactics is subsequently reviewed, leading us to conclude that alternative migratory tactics have considerable potential to respond to selection and evolve. We review what is known about the proximal physiological mechanisms mediating the translation of the continuous value of the liability trait into a discontinuous migratory tactic. We conclude by identifying several avenues for future research, including testing the frequency-dependent selection hypothesis, establishing the relative importance of adaptive phenotypic plasticity in explaining some geographic gradients in migratory behaviour and identifying the physiological and genetic basis of the switching mechanisms responsible for alternative migratory tactics. PMID- 23347291 TI - Focus on echocardiographic and Doppler analysis of coronary artery abnormal origin from the pulmonary trunk with mild myocardial dysfunction. AB - BACKGROUND: Late presentation of abnormal origin of coronary artery from the pulmonary artery (ACAPA) is uncommon compared with early presentation, which usually induces extended myocardial necrosis and severe heart failure. The late presentation is characterized by abundant development of intercoronary collaterals resulting in mild and rare symptoms, but nevertheless can cause sudden cardiac death. Our objective was to describe presentation, cardiovascular imaging methods for diagnosis and outcomes of patients with late presentation of ACAP. METHODS: The study is a retrospective review of a single-center database to identify all patients diagnosed with ACAPA beyond the first year of life. RESULTS: From 1976 to 2011, 10 patients were identified with ACAPA at the age of 1.1-64 years: 6 with left coronary artery from the pulmonary artery (ALCAPA) and 4 with right coronary artery from the pulmonary artery (ARCAPA). Echocardiography and Doppler imaging evidenced: (1) direct signs: the abnormal coronary ostium arising from the pulmonary trunk with retrograde coronary artery flow and (2) indirect signs: abundant intercoronary septal collaterals with anterograde flow (ARCAPA) or retrograde flow (ALCAPA) and dilatation of the controlateral normally originated coronary artery. Nine patients underwent surgical implantation of the ACAPA into the ascending aorta. After 7.9 years mean follow-up, all were asymptomatic except one who required a second surgery. CONCLUSIONS: Noninvasive cardiovascular imaging, namely transthoracic echocardiography and Doppler specific parameters, can reach diagnosis of late presentation of ACAPA. Direct aortic implantation is a reliable and effective to establish dual coronary artery circulation and prevent risks due to myocardial ischemia. PMID- 23347292 TI - Making it legal: abortion providers' knowledge and use of abortion law in New South Wales and Queensland. AB - OBJECTIVES: To explore the knowledge of state abortion law of doctors providing abortion in New South Wales and Queensland, their attitudes towards this law, and their application of both knowledge and attitudes to their day-to-day practice of abortion. DESIGN AND PARTICIPANTS: Qualitative study using interviews of twenty two medical practitioners agreeing to participate and identified as providing surgical and/or medical abortions in NSW or Queensland. Specific questions about practice as well as responses to ten common clinical scenarios formed the basis of each interview. MAIN OUTCOME MEASURES: Familiarity of participants with abortion law of their state, documentation of views on legality and probable availability of abortion in each scenario provided. RESULTS: All participants were aware that abortion in their state is covered by criminal legislation, which they believe is out-of-date with current medical practice, in particular with regard to the diagnosis of serious fetal abnormality, and that there is limited case law to assist doctors in a defence to a charge of abortion. All were concerned about requirements to conform to state law when agreeing to provide abortion services to women, and about the possible constraints of these requirements on women's accessibility to abortion services. CONCLUSIONS: Review and reform of abortion laws in Queensland and NSW, as has occurred in other states and territories, has the potential to bring the law into conformity with current medical practice and to clarify the legal position of doctors providing abortion services, thereby providing an opportunity to improve women's accessibility to these services. PMID- 23347293 TI - Fournier's gangrene associated with intradermal injection of cocaine. AB - INTRODUCTION: Cocaine abuse is associated with a number of medical complications, most notably arrhythmias, myocardial infarction, and cerebral hemorrhages. The injection of cocaine in the penis has been predominantly recorded into the corpus cavernosae and is associated with priapism. AIM: Here we describe the injection of subcutaneous cocaine within the penile shaft skin producing ischemic necrosis and Fournier's gangrene. MAIN OUTCOME MEASURES: We sought to highlight the effects of cocaine use within the penis and emphasize the different effects that may ensue. METHODS: We reviewed a recent clinical case and conducted a literature review on the use of cocaine within the penis. RESULTS: The use of cocaine has been reported previously within the literature and is mainly limited to case reports. Cocaine use within the corpora and the subcutaneous tissues produces significantly different consequences ranging from priapism to Fournier's gangrene. CONCLUSIONS: The case illustrates the growing use of cocaine and other illicit drugs and emphasizes the importance of this issue to all clinicians. PMID- 23347294 TI - Histology-driven data mining of lipid signatures from multiple imaging mass spectrometry analyses: application to human colorectal cancer liver metastasis biopsies. AB - Imaging mass spectrometry (IMS) represents an innovative tool in the cancer research pipeline, which is increasingly being used in clinical and pharmaceutical applications. The unique properties of the technique, especially the amount of data generated, make the handling of data from multiple IMS acquisitions challenging. This work presents a histology-driven IMS approach aiming to identify discriminant lipid signatures from the simultaneous mining of IMS data sets from multiple samples. The feasibility of the developed workflow is evaluated on a set of three human colorectal cancer liver metastasis (CRCLM) tissue sections. Lipid IMS on tissue sections was performed using MALDI-TOF/TOF MS in both negative and positive ionization modes after 1,5-diaminonaphthalene matrix deposition by sublimation. The combination of both positive and negative acquisition results was performed during data mining to simplify the process and interrogate a larger lipidome into a single analysis. To reduce the complexity of the IMS data sets, a sub data set was generated by randomly selecting a fixed number of spectra from a histologically defined region of interest, resulting in a 10-fold data reduction. Principal component analysis confirmed that the molecular selectivity of the regions of interest is maintained after data reduction. Partial least-squares and heat map analyses demonstrated a selective signature of the CRCLM, revealing lipids that are significantly up- and down regulated in the tumor region. This comprehensive approach is thus of interest for defining disease signatures directly from IMS data sets by the use of combinatory data mining, opening novel routes of investigation for addressing the demands of the clinical setting. PMID- 23347295 TI - Elevated levels of thrombin-generating microparticles in stored red blood cells. AB - BACKGROUND: During storage, red blood cells (RBCs) lose their membrane stability, leading to haemolysis and microparticle (MP) formation. The use of RBCs stored for more than 28 days has been associated with an increased incidence of deep vein thrombosis. However, the exact mechanism by which coagulation activation is enhanced in stored RBCs is still unknown. OBJECTIVES: To investigate the relevant potential procoagulant activities of MPs and study the relative procoagulant factors for initiating the coagulation on MPs in stored RBCs. STUDY DESIGN AND METHODS: MPs were isolated from the plasma of RBC units stored in citrate phosphate-dextrose-adenine. At seven storage time-points (d0, d7, d14, d21, d28, d35 and d42), MPs were morphologically observed, quantified and analysed for tissue factor, factor XI (FXI) and their thrombin-generating potential. RESULTS: MPs were observed using electron microscopy. The size of the MPs ranged from 0.272 MUm to 0.973 MUm in diameter. During the storage of RBCs in plastic bags, the MP concentration increased from 3389 +/- 218/MUl at day 0 to 61 586 +/- 2237/MUl at d42. Thrombin generation was dependent on the total number of MPs (r = 0.987). Anti-human FXI antibody inhibited thrombin concentrations by 50.3% compared with control plasma, whereas antitissue factor and antitissue factor pathway inhibitor failed to reduce thrombin concentrations. CONCLUSIONS: Our study provides evidence that MP formation due to RBC storage might propagate coagulation not only by exposing phosphatidylserine, but also by initiating thrombin generation independently of tissue factor in a FXI -dependent manner. PMID- 23347296 TI - Quantum-chemical studies on the favored and rare tautomers of neutral and redox adenine. AB - All possible twenty-three prototropic tautomers of neutral and redox adenine (nine amine and fourteen imine forms, including geometric isomerism of the exo ?NH group) were examined in vacuo {DFT(B3LYP)/6-311+G(d,p)}. The NH -> NH conversions as well as those usually omitted, NH -> CH and CH -> CH, were considered. An interesting change of the tautomeric preference occurs when proceeding from neutral to reduced adenine. One-electron reduction favors the nonaromatic amine C8H-N10H tautomer. This tautomeric preference is similar to that (C2H) for reduced imidazole. Water molecules (PCM model) seem to not change this trend. They influence solely the relative energies. The DFT vertical detachment energy in the gas phase is positive for each tautomer, e.g., 0.03 eV for N9H-N10H and 1.84 eV for C8H-N10H. The DFT adiabatic electron affinity for the favored process, neutral N9H-N10H -> reduced C8H-N10H (ground states), is equal to 0.18 eV at 0 K (ZPE included). One-electron oxidation does not change the tautomeric preference in the gas phase. The aromatic amine N9H-N10H tautomer is favored for the oxidized molecule similarly as for the neutral one. The DFT adiabatic ionization potential for the favored process, neutral N9H-N10H -> oxidized N9H-N10H (ground states), is equal to 8.12 eV at 0 K (ZPE included). Water molecules (PCM model) seem to influence solely the composition of the tautomeric mixture and the relative energies. They change the energies of the oxidation and reduction processes by ca. 2 eV. PMID- 23347298 TI - A firm, bluish, hemorrhagic nodule on the left heel. PMID- 23347297 TI - A novel standardized bone model for thermal evaluation of bone osteotomies with various irrigation methods. AB - OBJECTIVES: Based on a novel standardized bovine specimen, the aim of this study was to investigate thermal effects of different irrigation methods during intermittent and graduated drilling. MATERIAL AND METHODS: Temperature changes during implant osteotomies (n = 320) of 10 and 16 mm drilling depths with various irrigation methods were investigated on manufactured uniform bone samples providing homogenous cortical and cancellous areas and analogous thermal conductivity comparable to human bone. Automated sequences were performed with surgical twist drills of 2 mm ? and conical drills of 3.5, 4.3 and 5 mm ?. Real time recording of temperature increase was done using two custom-built multichannel thermoprobes with 14 temperature sensors at a predefined distance of 1 and 2 mm to the final osteotomy. The effects of drilling depth, drilling diameter and irrigation methods on temperature changes were investigated by a linear mixed model. RESULTS: Using this uniform bone specimen, the greatest temperature rise was observed without any coolant supply with 29.87 degrees C, followed by external with 28.47 degrees C and then internal with 25.86 degrees C and combined irrigation with 25.68 degrees C. Significant differences (P <= 0.0156) between drill depths of 10 vs. 16 mm could be observed with all irrigation methods evaluated. With each of the irrigation methods, significantly higher temperature changes (P < 0.0001) during osteotomies could be observed between twist drills of 2 mm ? and conical drills of 3.5, 4.3 and 5 mm ?. During 10 and 16 mm drilling osteotomies, external irrigation showed significantly higher temperatures (P < 0.05) for all conical drills compared with internal or combined irrigation, respectively. Significantly lower temperatures (P < 0.05) could be detected with internal or combined irrigation for the use of conical drills with various diameters and drilling depths. CONCLUSIONS: This fully standardized bone model provides optimized comparability for the evaluation of bone osteotomies and resulting temperature changes. As regards the efficiency of the various irrigation methods, it could be demonstrated that internal and combined irrigation appears to be more beneficial than external irrigation. PMID- 23347299 TI - Bilateral thick crusts on the legs. PMID- 23347300 TI - Aquatic dermatology: encounters with the denizens of the deep (and not so deep) a review. Part I: the invertebrates. AB - Aquatic dermatoses encompass a broad spectrum of cutaneous injuries. These injuries may present through contact with invertebrate organisms such as jellyfish, sea urchins, corals, and molluscs. Each organism is equipped with a unique method of causing harm to man, therefore a myriad of presenting signs and symptoms should be recognized in order to initiate treatment. Aquatic injuries are not limited to areas of the world where these species originate. With the advent of rapid world travel and the hobby of home aquariums, dermatologists play a key role in the early diagnosis and treatment of such injuries. The method of injury, including a discussion of organism identification will be presented. Additionally, treatment of injuries caused by aquatic life will follow. PMID- 23347301 TI - Cardiovascular aspects of psoriasis: an updated review. AB - Psoriasis, a systemic inflammatory disease, is associated with enhanced atherosclerosis and risk of cardiovascular (CV) disease, which may account for higher morbidity and mortality rates in psoriatic patients. It especially applies to younger psoriatic patients with more severe disease, reducing their life expectancy. The aim of the study was to review the literature on CV disease in psoriasis as well as the pathogenic mechanisms shared between psoriasis and atherosclerosis. Moreover, case-control and cohort studies published between 2006 and 2011 were selected for meta-analysis. The meta-analysis indicates elevated risk of cardiovascular events in psoriatic patients in relation to non-psoriatic controls (OR 1.28; 95% CI 1.18-1.38). It is suggested that the treatment of the inflammatory processes involved in the pathogenesis of both psoriasis and atherosclerosis may be beneficial in reducing the CV risk in psoriatic patients. Further in-depth investigations, including prospective studies, are needed to enable more effective management of psoriatic patients in the future. PMID- 23347302 TI - Mood changes, depression and suicide risk during isotretinoin treatment: a prospective study. AB - BACKGROUND: Depression and mood changes appear as potentional side effects of isotretinoin in the Summary of Product Characteristics. There have been many studies treating this topic but in most cases not identifying any significant depression or suicide risk. To further investigate this issue, we conducted a prospective, uncontrolled study to evaluate mood changes and suicidal ideations in patients receiving isotretinoin therapy. METHODS: One-hundred patients were included in our single center, no-blind, and no controlled prospective study. All patients completed the Beck's Depression Inventory, Version II (BDI-II) before the treatment, following the first month of the treatment and then every third month until finishing the isotretinoin therapy. All questionnaires were checked by a psychiatrist. Suicidal ideations were monitored. Statistical analysis of BDI II scores was performed. RESULTS: All patients completed the study. Before the treatment, six percent of the patients had suffered from depressive symptoms. During the isotretinoin treatment, we did not find any deterioration of depression problems in any of these patients. On the contrary, in most patients the depressive symptoms disappeared. Symptoms of depression occurred in two patients, in which case coexisting situational factors were found to be the cause. No occurrence of suicidal ideations was found. CONCLUSIONS: We did not find any depressive symptoms or suicide risk caused by isotretinoin. On the contrary, a statistically significant improvement of BDI-II scores was found. In our opinion, patients have to be informed about the risk of depression but emphasizing the fact that it is very rare. PMID- 23347303 TI - Head lice: the feelings people have. AB - BACKGROUND: Head lice are a source of amusement for outsiders and an embarrassing nuisance to those who have to deal with them. Our study collected the emotions experienced by people dealing with head lice. An area with extremely sparse literature, our purpose is to inform the development of more effective programs to control head lice. METHODS: We asked "what were your feelings upon discovery of head lice?" as part of a study exploring the experience of those treating head lice. A short questionnaire was available via the authors' head lice information internet site. A total of 294 eligible responses were collected over several months and analyzed, supported by QSR N6. RESULTS: The predominantly female (90 . 9%) respondents were residents of Australia (56 . 1%), USA (20 . 4%), Canada (7 . 2%), or UK (4 . 4%), and working full-time (43.0%) or part-time (34 . 2%). Reactions and feelings fell into three categories: strong (n = 320; 79% of all stated emotions), mediocre (n = 56; 20%), and neutral (n = 29; 9 . 8%). There were no positive emotions. COMMENT: The significant negative reaction was expected. The range of feeling expressed demonstrates the stigma held for these ectoparasites within western market economies. This contrasts with conceptions of head lice in traditional societies. The negative social effects of this perception create more problematic issues than the infection itself; these include quarantine, overtreatment, and a potentially negative psychological impact. Head lice control strategies and programs that address these negative emotional reactions may prove more effective than current biomedical focus. PMID- 23347304 TI - Rabson-Mendenhall syndrome with recurrent cerebral infarcts caused by a novel INSR mutation. AB - Rabson-Mendenhall syndrome (RMS) is an autosomal recessive disorder characterized by extreme insulin resistance and certain characteristic phenotypic features. The primary defect lies in the insulin receptor and involves biallelic mutations that lead to a loss of function through various postulated defects. We present a 9 year-old female patient with RMS complicated by multiple cerebral infarcts, in whom genetic analysis revealed a novel insulin receptor mutation. PMID- 23347305 TI - Netherton's syndrome and lepromatous leprosy: a mere coincidence? AB - OBJECTIVES: Netherton's syndrome (NS) is a rare autosomal recessive condition, first described in 1958, which involves a complex immunological dysfunction, ichthyosiform dermatitis, and erythroderma, characteristic defects of the hair shaft and atopy. Recurrent bacterial infection in the skin of patients with NS is frequent. METHODS: This paper represents the first case report of leprosy and concurrent NS. DISCUSSION: This case merits discussion among doctors in endemic and non-endemic areas to evaluate the chronic use of systemic corticosteroids as a risk factor for leprosy. The present patient came from an endemic area of leprosy and was treated chronically with systemic corticosteroids for erythroderma. This treatment, along with the immunodeficiency related to the syndrome and caused by a genetic mutation in SPINK5, may be a facilitating factor for the infection. PMID- 23347306 TI - Quality of life of patients with vitiligo attending the Regional Dermatology Training Center in Northern Tanzania. AB - BACKGROUND: Vitiligo is an acquired, predominantly asymptomatic, depigmenting disorder with profound psychological effects. METHODS: This was a cross-sectional study conducted at the Regional Dermatology Training Center in Moshi, Tanzania. All 88 patients with vitiligo older than 15 years of age who attended the skin clinic from October 2009 to April 2010 were recruited. Data were collected using a structured questionnaire, Dermatology Life Quality Index questionnaire (DLQI), and Vitiligo European Task Force form. RESULTS: Vitiligo moderately affects patient's quality of life, as indicated by a DLQI mean score of 7.2 +/- 4.8. The mean age was 41 years with a male/female ratio of 1:1.7. The mean age of disease onset was 33.5 years (range 16-83 years); vitiligo vulgaris was the most common disease form seen (n = 49). None of the factors considered were found to be significantly associated with impaired quality of life on multivariate analysis. The majority of patients (73.8%) perceived that their disease was moderate to severe in contrast to the clinical grading in which only 49.2% patients were classified as having mild disease. This difference in classification of disease severity was statistically significant (Fishers exact test = 0.001). CONCLUSION: Patients with vitiligo of African descent have a moderate impairment of quality of life. PMID- 23347307 TI - Multiple lymphatic-type, atypical vascular lesions of the breast following radiation therapy. PMID- 23347308 TI - Ulcerated hidradenoma papilliferum. PMID- 23347309 TI - Guidelines on the role of skin care in the management of mobile populations. AB - The Task Force for Skin Care for All: Community Dermatology, when seeking to collate evidence for capacity to benefit, wanted to know how best to manage mobile populations. The task force met where there is most experience at a time of maximum migration to the Mediterranean islands and to Italy from Somalia, Sudan, Cote d'Ivoire, Tunisia, and Libya. Members attended the workshop hosted by Aldo Morrone at the San Gallicano Hospital, Rome, Italy. Issues discussed were the size of the problem, ethics and legality, potential value of the migrant, dermatologist as carer, challenges met by interpretation, good listening, and transcultural mediation. The experiences of the National Institute for Health Migration and Poverty at the San Gallicano Hospital in Rome, Ethiopia, Malta, and Lampedusa were key to the development of guidelines on cultural competence. PMID- 23347310 TI - Multiple nodules on scalp in a middle-aged female. PMID- 23347311 TI - A 10-year analysis of primary cutaneous malignant melanoma with sentinel lymph node biopsy and long-term follow-up. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) is an important tool for accurate staging of patients with melanoma. There is an ongoing debate whether the procedure provides therapeutic benefits or not. OBJECTIVE: We wanted to analyze 10-year data from an academic teaching hospital. PATIENTS AND METHODS: During 1999-2009, 977 patients with early cutaneous melanoma have been treated. Of these, 419 patients had tumors >= 1 mm thickness. Patients with head and neck tumors were excluded, leaving 364 patients (202 men and 162 women). SLNB was not performed in 163 patients but was performed in 201 patients. For correction of bias, tumors >4 mm thickness were excluded from further statistical analysis. RESULTS: The detection rate of SLN was 94.4%. False negative SLN were observed in 8.9%. Adverse effects occurred in 5.5%. The rate of positive SLNB was 16.4% and lymph node involvement 20%. Patients undergoing SLNB had a lower relapse rate (10.6% vs. 33.3%; P < 0.001). The most important finding is an almost 50% lower total death rate and melanoma-related death rate in the SLNB subgroup (P < 0.001 for both). CONCLUSIONS: Sentinel lymph node biopsy is an accurate instrument for melanoma staging to detect occult regional lymph node involvement. Data suggest a positive effect on relapse-free survival. The observation of improved long-term survival needs validation in prospective multicenter trials. The limitations of this study were that it was a single center retrospective analysis. PMID- 23347312 TI - Molecular analysis of Malassezia species isolated from Israeli patients with pityriasis versicolor. AB - BACKGROUND: Pityriasis versicolor (PV) is a common superficial fungal infection of the skin caused by Malassezia species. The clinical significance of each of these species is not fully understood. M. furfur has long been identified as the causative agent of PV. Several recent studies suggest that M. globosa is most frequently associated with PV. OBJECTIVES: The aim of this study was to examine the prevalence of Malassezia species in affected and unaffected skin in Israeli patients with PV using a polymerase chain reaction (PCR)-based culture independent method. METHODS: Samples were taken from affected skin of 75 patients with PV (35 females and 40 males, age range 18-65 years) who visited our outpatient clinic and from unaffected skin in 26 patients for direct microscopy and detection of Malassezia species using a PCR-based method. RESULTS: The major Malassezia species in PV was M. globosa, found in 97.3% (73 of 75) of samples from affected skin and 80.8% (21 of 26) samples of unaffected skin. M. restricta was associated with M. globosa in 1.3% (one of 75) of patients. No cases of M. furfur were detected in this study. There was no difference in the distribution of Malassezia species between affected and unaffected skin. CONCLUSION: Based on the PCR test, we have shown that M. globosa is probably most frequently associated with PV. PMID- 23347313 TI - The Factory as a metaphor. PMID- 23347314 TI - Negative direct immunofluorescence and nonspecific histology do not exclude the diagnosis of dermatitis herpetiformis Duhring. PMID- 23347315 TI - Familial multiple pilomatricomas showing clinical features of a giant mass without associated diseases. PMID- 23347316 TI - Recall phenomena: another facet of the immunocompromised district. PMID- 23347317 TI - International Vitiligo Symposium, Shenyang, China, November 16-18, 2012. PMID- 23347319 TI - Lycopene partially reverses symptoms of diabetes in rats with streptozotocin induced diabetes. AB - In the present study, we describe the effects of lycopene on the symptoms of streptozotocin (STZ)-induced diabetes in rats. Lycopene at the dose of 2.5 mg/kg body weight (bw) per day was orally administered to STZ-induced diabetic rats for a period of 7 days after onset of diabetes. At the same time, food-water intake and body weight change were recorded daily. Upon sacrifice, biochemical parameters, such as the serum glucose, insulin, total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), were measured in all experimental groups. Administration of lycopene at the dose of 2.5 mg/kg bw per day significantly reduced serum glucose, TC, TG, ALT, and AST levels, and increased serum insulin levels, but there were no improvements in food-water intake and body weight change parameters in lycopene treated diabetic rats. The results suggest that orally administrated lycopene exhibits a potent hypoglycemic effect in STZ-induced diabetic rats and that lycopene may be useful for the management of diabetes mellitus. PMID- 23347320 TI - Discovery of a diverse clade of gregarine apicomplexans (Apicomplexa: Eugregarinorida) from Pacific eunicid and onuphid polychaetes, including descriptions of Paralecudina n. gen., Trichotokara japonica n. sp., and T. eunicae n. sp. AB - Marine gregarines are poorly understood apicomplexan parasites with large trophozoites that inhabit the body cavities of marine invertebrates. Two novel species of gregarines were discovered in polychaete hosts collected in Canada and Japan. The trophozoites of Trichotokara japonica n. sp. were oval to rhomboidal shaped, and covered with longitudinal epicytic folds with a density of six to eight folds/micron. The nucleus was situated in the middle of the cell, and the mucron was elongated and covered with hair-like projections; antler-like projections also extended from the anterior tip of the mucron. The distinctively large trophozoites of Trichotokara eunicae n. sp. lacked an elongated mucron and had a tadpole-like cell shape consisting of a bulbous anterior region and a tapered tail-like posterior region. The cell surface was covered with longitudinal epicytic folds with a density of three to five folds/micron. Small subunit (SSU) rDNA sequences of both species were very divergent and formed a strongly supported clade with the recently described species Trichotokara nothriae and an environmental sequence (AB275074). This phylogenetic context combined with the morphological features of T. eunicae n. sp. required us to amend the description for Trichotokara. The sister clade to the Trichotokara clade consisted of environmental sequences and Lecudina polymorpha, which also possesses densely packed epicyctic folds (3-5 folds/micron) and a prominently elongated mucron. This improved morphological and molecular phylogenetic context justified the establishment of Paralecudina (ex. Lecudina) polymorpha n. gen. et comb. PMID- 23347321 TI - Effects of pre-partum milking of dairy cows on calcium metabolism at start of milking and at calving. AB - This experiment studied the effect of pre-partal milk removal on calcium metabolism at start of milking and at calving. Nine cows of the Swedish Red breed were milked for 1-7 days pre-partum. The average milk yield at the first milking was 4.8 l, and the average yield the last day prior to calving was 13.4 l. Five cows were used as control cows and were only milked post-partum. Samples of plasma and urine were taken to determine the effect of pre-partum milking and calving on levels of calcium, magnesium, parathyroid hormone and plasma C terminal crosslinked telopeptide of type 1-collagen (CTx), used as a marker of bone resorption. Pre-partum milking resulted in a decrease in plasma calcium that was evident 2 days after the first milking. Parathyroid hormone increased at the same time, and CTx started to increase from 24 h after the first milking. There were no effects on plasma magnesium or urinary output of calcium or magnesium. The first week after calving, there were no differences between pre-partum milked cows and control cows in plasma or urine variables, or in milk yield. In conclusion, pre-partum milking activated the calcium-restoring mechanisms but did not improve calcium status at calving. PMID- 23347322 TI - Pemphigus vulgaris in a Welsh pony stallion: case report and demonstration of antidesmoglein autoantibodies. AB - HYPOTHESIS/OBJECTIVES: To describe the clinical, histological and immunological findings of an equine case of pemphigus vulgaris, including the demonstration of antidesmoglein (anti-Dsg) autoantibodies. CASE REPORT: The diagnosis of pemphigus vulgaris was confirmed in a 9-year-old Welsh pony stallion with both direct and indirect immunofluorescence and immunoprecipitation studies, the latter identifying circulating anti-Dsg3 IgG. Treatment with immunosuppressive medications was initiated. Lesions were seen in the perineal area, sheath, mane, tail, eyelids, coronary bands and mucosa of the mouth and oesophagus. Initial corticosteroid treatment improved the clinical signs, but the onset of laminitis necessitated a reduction in dosage, which was associated with a recurrence of lesions and development of oral ulcers. A corneal ulcer developed after 60 days of treatment. Despite treatment with azathioprine, gold salts and dapsone, the disease progressed and the pony was euthanized. Postmortem examination showed additional lesions of the cardia of the stomach. CONCLUSIONS AND CLINICAL IMPORTANCE: Pemphigus vulgaris is rarely diagnosed in equids. We describe a case that was substantiated by the demonstration of anti-Dsg3 IgG. Response to treatment was poor, with the best response to high doses of prednisolone. Equine pemphigus vulgaris is likely to carry a poor prognosis and if there is no response to treatment, humane euthanasia is warranted. PMID- 23347323 TI - Do predators influence the behaviour of bats? AB - Many aspects of animal behaviour are affected by real-time changes in the risk of predation. This conclusion holds for virtually all taxa and ecological systems studied, but does it hold for bats? Bats are poorly represented in the literature on anti-predator behaviour, which may reflect a lack of nocturnal predators specialized on bats. If bats actually experience a world with minimal anti predator concerns, then they will provide a unique contrast within the realm of vertebrate ecology. Alternatively, such predator-driven behaviour in bats may not yet be fully understood, given the difficulties in working with these highly mobile and nocturnal animals. We provide a wide-ranging exploration of these issues in bat behaviour. We first cover the basic predator-prey information available on bats, both on potential predators and the ways in which bats might perceive predators and respond to attacks. We then cover work relevant to key aspects of bat behaviour, such as choice of daytime roosts, the nature of sleep and torpor, evening roost departures, moonlight avoidance, landscape-related movement patterns, and habitat selection. Overall, the evidence in favour of a strong influence of predators on bat behaviour is equivocal, with the picture clouded by contradictory results and a lack of information on potential predators and the perception of risk by bats. It seems clear that day-active bats run a considerable risk of being killed by diurnal raptors, which are able to capture bats with relative ease. Thus, bats taking advantage of a pulse of insects just prior to sunset are likely taking risks to gain much-needed energy. Further, the choice of daytime roosts by bats is probably strongly influenced by roost safety. Few studies, however, have directly addressed either of these topics. As a group, insectivorous temperate-zone bats show no clear tendency to avoid apparently risky situations, such as activity on moonlit nights. However, some observations are consistent with the idea that predation risk affects choice of movement paths and feeding areas by temperate-zone bats, as well as the timing of roost departures. The behaviour of tropical bats, on the other hand, seems more generally influenced by predators; this is especially true for tropical nectarivores and frugivores, but also for insectivorous bats. Presumably there are more serious predators on bats in the tropics (e.g. specialized raptors or carnivorous bats), but the identity of these predators is unclear. More information is needed to assess fully the influence of predators on bat behaviour. There is much need for work on the ways in which bats perceive predators via auditory, visual, and olfactory cues, and whether bats have some knowledge of the risks posed by different predators. Also needed is information on how predators attack bats and how bats react to attacking predators. Difficult to obtain, but of critical value, will be information on the nature of the predation risk experienced by bats while away from roosts and during the full darkness of night. PMID- 23347324 TI - Nonlinear scaling of surface water diffusion with bulk water viscosity of crowded solutions. AB - The translational hydration dynamics within 0.5-1.5 nm of the surface of a DPPC liposome, a model biomacromolecular surface, is analyzed by the recently developed Overhauser dynamic nuclear polarization (ODNP) technique. We find that dramatic changes to the bulk solvent cause only weak changes in the surface hydration dynamics. Specifically, both a >10-fold increase in bulk viscosity and the restriction of diffusion by confinement on a multiple nm length-scale change the local translational diffusion coefficient of the surface water surrounding the lipid bilayer by <2.5-fold. By contrast, previous ODNP studies have shown that changes to the biomacromolecular surface induced by folding, binding, or aggregation can cause local hydration dynamics to vary by factors of up to 30. We suggest that the surface topology and chemistry at the <=1.5 nm scale, rather than the characteristics of the solvent, nearly exclusively determine the macromolecule's surface hydration dynamics. PMID- 23347325 TI - Inhibition of phosphodiesterase 4 enhances clitoral and vaginal blood flow responses to dorsal clitoral nerve stimulation or PGE1 in anesthetized female rats. AB - INTRODUCTION.: Cyclic adenosine 3'5' monophosphate (cAMP) is produced by adenylate cyclase after activation by, e.g., vasoactive intestinal polypeptide or prostaglandin E1 (PGE1). The cAMP-degrading phosphodiesterase 4 (PDE4) is expressed in the vagina and clitoris, but no information is available on the functional role for PDE4-related signals in the female neurovascular genital response. AIM.: The aim of this study is to study the effect of inhibition of PDE4 with rolipram on nerve- and PGE1-induced vaginal and clitoral blood flow responses of rat. METHODS.: Measure of clitoral and vaginal blood flow and blood pressure in anesthetized rats during activation of the dorsal clitoral nerve (DCN) before and after intraperitoneal administration of rolipram or sildenafil (phosphodiesterase type 5 inhibitors [PDE5]) and nitro-L-arginine (L-NNA) (nitric oxide synthase inhibitor). Effect by topical administration of PGE1 on genital blood flow was also evaluated. MAIN OUTCOME MEASURE.: Blood flow was recorded as tissue perfusion units (TPU) by a Laser Doppler Flowmeter. Mean arterial blood pressure (MAP) was recorded (cmH2 O) in the carotid artery. Blood flow responses are expressed as TPU/MAP. Unpaired t-test and an analysis of variance were used. RESULTS.: Compared with control stimulations, rolipram (0.3 mg/kg) caused a twofold increase in peak blood flow (P < 0.05) and fourfold increase of the rate of clitoral blood flow during activation of the DCN (P < 0.05). Simultaneously, a twofold increase in peak blood flow and threefold increase in rate of blood flow were noted in the vagina (P < 0.05). Similar effects were noted for sildenafil (0.2 mg/kg) (P < 0.05). Inhibitory effects by L-NNA (60 mg/kg) on blood flow responses to DCN activation were significantly lower for rats treated with rolipram than with sildenafil (P < 0.05). PGE1-induced (10 MUg) blood flow responses were significantly higher (P < 0.05) in rats treated with rolipram than with sildenafil. CONCLUSIONS.: These findings suggest that the cAMP/PDE4 system may be of similar functional importance as the nitric oxide/cyclic guanosine monophosphate/PDE5 pathway for neurovascular genital responses of the female rat. PMID- 23347326 TI - Ethnicity and risk of caesarean section in a term, nulliparous New Zealand obstetric cohort. AB - BACKGROUND: One in four New Zealand (NZ) women undergo caesarean section (CS); however, little is understood about how ethnicity influences CS rates. Previous NZ studies do not include many of NZ's ethnic groups and have been unable to account comprehensively for clinical risk factors. AIM: To investigate ethnicity as an independent risk factor for elective and emergency CS in nulliparous women at term. We hypothesised that compared with European, Maori and Pacific women would have a lower risk of elective CS, but there would be no ethnic differences in emergency CS. METHODS: This was a retrospective cohort analysis of prospectively recorded maternity data at National Women's Health, Auckland, NZ from 2006 to 2009. The study population was 11 848 singleton, nulliparous, term births. Multivariable logistic regression analysis was performed for elective and emergency CS, accounting for comprehensive confounding factors. RESULTS: The overall CS rate was 31.2% (elective 7.8%, n = 923 and emergency 23.4%, n = 2770). Compared with European ethnicity, Pacific and Chinese women had a reduced odds of elective CS (adjusted odds ratios, aOR 0.42, [95% CI 0.24-0.73] and 0.68, [0.49 0.94], respectively), while Indian women had an increased odds of emergency CS (aOR 1.54, [1.26-1.88]). Rates of elective or emergency CS for other ethnicities were similar to European. CONCLUSIONS: After adjustment for confounding, we report ethnic differences in elective and emergency CS rates, which may be related to patient and/or care provider factors. Further prospective research is recommended to examine reasons for these ethnic differences in CS rates. PMID- 23347327 TI - Nanocomposites derived from montmorillonite and metallosupramolecular polyelectrolytes: modular compounds for electrorheological fluids. AB - Nanocomposites made from Na-montmorillonite and metallo-supramolecular polyelectrolytes (MEPE) based on nickel and ditopic bis-terpyridine ligands are prepared by an aqueous synthesis. Intercalation is confirmed by IR-spectroscopy, thermogravimetric analysis, and X-ray powder diffraction. The rheological response in the presence of an electric field of the dispersed nanocomposites in silicone oil is measured with a rheometer. The nanocomposites show a distinct electrorheological effect depending on the concentration and the kind of intercalated species. The effect occurs with a low content of active material while only very small currents are observed. PMID- 23347328 TI - Preparation of covalently linked complexes between DNA and O(6)-alkylguanine-DNA alkyltransferase using interstrand cross-linked DNA. AB - O(6)-alkylguanine-DNA alkyltransferases (AGT) are responsible for the removal of alkylation at both the O(6) atom of guanine and O(4) atom of thymine. AGT homologues show vast substrate differences with respect to the size of the adduct and which alkylated atoms they can restore. The human AGT (hAGT) has poor capabilities for removal of methylation at the O(4) atom of thymidine, which is not the case in most homologues. No structural data are available to explain this poor hAGT repair. We prepared and characterized O(6)G-butylene-O(4)T (XLGT4) and O(6)G-heptylene-O(4)T (XLGT7) interstrand cross-linked (ICL) DNA as probes for hAGT and the Escherichia coli homologues, OGT and Ada-C, for the formation of DNA-AGT covalent complexes. XLGT7 reacted only with hAGT and did so with a cross linking efficiency of 25%, while XLGT4 was inert to all AGT tested. The hAGT mediated repair of XLGT7 occurred slowly, on the order of hours as opposed to the repair of O(6)-methyl-2'-deoxyguanosine which requires seconds. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the repair reaction revealed the formation of a covalent complex with an observed migration in accordance with a DNA-AGT complex. The identity of this covalent complex, as determined by mass spectrometry, was composed of a heptamethylene bridge between the O(4) atom of thymidine (in an 11-mer DNA strand) to residue Cys145 of hAGT. This procedure can be applied to produce well-defined covalent complexes between AGT with DNA. PMID- 23347329 TI - Losing a job on purpose: relationships with borderline personality symptomatology. AB - AIM: The purpose of the present study was to examine one facet of employment viability, losing a job on purpose, among individuals with borderline personality symptomatology (BPS). METHODS: Using a cross-sectional self-report survey methodology in a combined sample of four prior studies from the same study site (n = 1493), we examined the relationship between losing a job on purpose and two self-report measures for BPS. RESULTS: There were 7.6% of participants that endorsed losing a job on purpose, with no statistically significant difference between the proportions of males and females. Point-biserial correlation coefficients revealed that those who endorsed losing a job on purpose scored statistically significantly higher on both measures of BPS and were more likely to exceed the clinical cut-off scores on both measures of BPS. Multiple regression analyses indicated that findings were independent of gender or age. CONCLUSION: One factor in poor employment viability among individuals with BPS appears to be the behaviour of losing a job on purpose. PMID- 23347330 TI - High-density dependence but low impact on selected reproduction parameters of Brucella suis biovar 2 in wild boar hunting estates from South-Western Spain. AB - Porcine brucellosis is a disease caused by Brucella suis, which is characterized by reproductive disorders in pigs. The number of cases of swine brucellosis has risen in many European countries, likely because of the presence of a wild reservoir of B. suis in wild boar. This study aimed at evaluating factors that may influence the probability of infection with Brucella spp. in wild boar and at assessing the impact of a previous contact with Brucella spp. on reproductive parameters of wild boar. Two hundred and four wild boar living in Extremadura (south-western Spain) were studied. The presence of anti-Brucella antibodies was determined using an indirect ELISA, while the presence of living bacteria in genital organs was evaluated through microbiological cultures. Sex, age, density of wild boar in summer and presence of outdoor pigs were selected as possible risk factors for being seropositive for Brucella spp. in wild boar. In addition, reproductive parameters such as breeding status or potential fertility in females and testis weight in males were estimated and related to the presence of anti Brucella antibodies. A total of 121 animals were seropositive, resulting in a prevalence of 59.3% (95% CI). In addition, seven isolates of B. suis biovar 2 were obtained. Wild boar density in summer, as well as age and sex, was proposed as factors to explain the probability of Brucella seroconversion, although wild boar density in summer was the key factor. Current measures of reproductive parameters were not influenced by a previous contact with Brucella spp. Isolation of B. suis confirms that wild boar could represent a risk to domestic pig health in the study area. Wild boar density seems to have a great influence in the probability of infections with B. suis and suggests that density management could be useful to control Brucella infection in wild boar. PMID- 23347331 TI - A new reconstructive technique for posterior vaginal wall defects, a case report. AB - INTRODUCTION: Post-partum vaginal laxity is a problem encountered by many women. More uncommon is a resulting vaginal defect. In most cases of laxity, a period of extensive physiotherapy can strengthen the pelvic muscles enough for symptoms to be minimized. However, this is not the case once there is a tissue defect. AIM: To present a new reconstructive method for patients with posterior vaginal wall defects. METHODS: We present a case of a 38-year-old female who, 12 years prior to presentation, had a vaginal delivery. Due to complications during the delivery, she sustained pelvic trauma and developed a posterior vaginal wall defect. She had a sizable soft tissue defect, causing sexual, urinary, and confidence problems. Fat was harvested from the patient's abdomen and injected into the defect after more conservative treatment options were exhausted. RESULTS: The defect was corrected successfully using the minimally invasive Coleman fat grafting technique. DISCUSSION/CONCLUSION: This is to our knowledge the first case in the literature where a posterior vaginal defect has been corrected using Coleman fat grafting, and we believe that this treatment method may be of benefit to more patients. PMID- 23347332 TI - A novel echocardiographic method for the detection of subclinical atherosclerosis in newly diagnosed, untreated type 2 diabetes. AB - BACKGROUND: Diabetes accelerates the natural process of atherosclerosis and is a predictor for progression of atherosclerotic lesions. To improve clinical outcomes, noninvasive imaging modalities have been proposed to measure and monitor atherosclerosis. Recently, it has been shown that the color M-mode derived propagation velocity of the descending thoracic aorta (aortic velocity propagation [AVP]) was associated with coronary and carotid atherosclerosis. METHODS: Carotid intima-media thickness (CIMT) and AVP were measured in 72 patients with newly diagnosed type 2 diabetes and 44 healthy people. Individuals who had previously used oral hypoglycemic agents or insulin treatment or had a history of hyperlipidemia, cigarette smoking, hypertension, and cardiovascular disease were excluded from this study. RESULTS: Compared with control group, patients with type 2 diabetes had significantly lower AVP (39.9 +/- 6.5 vs. 58.4 +/- 6.7 cm/sec, P < 0.001) and higher CIMT (1.1 +/- 0.1 vs. 0.95 +/- 0.12 mm, P < 0.001) measurements. There were significant correlations between AVP and CIMT (r = -0.835, P < 0.001), AVP and fasting plasma glucose (r = -0.796, P < 0.001)), AVP and HbA1 c (r = -0918 P < 0.001). CONCLUSIONS: Diabetes mellitus may be associated with subclinical atherosclerosis assessed by measurement of AVP and CIMT. These simple methods might improve patient selection for primary prevention atherosclerotic progression. PMID- 23347333 TI - Influence of humic acid on titanium dioxide nanoparticle toxicity to developing zebrafish. AB - Titanium dioxide nanoparticle (TiO2NP) suspension stability can be altered by adsorption of dissolved organic matter (DOM). This is expected to impact their environmental fate and bioavailability. To date, the influence of DOM on the toxicity of TiO2NPs to aquatic vertebrates has not been reported. We examined the impact of Suwannee River humic acid (HA) on the toxicity of TiO2NPs to developing zebrafish (Danio rerio) in the dark and under simulated sunlight illumination. Adsorption of HA increased suspension stability and decreased TiO2NP exposure. TiO2NPs were more toxic in the presence of HA. In the absence of simulated sunlight, a small but significant increase in lethality was observed in fish exposed to TiO2NPs in the presence of HA. Under simulated sunlight illumination, photocatalytic degradation of HA reduced suspension stability. Despite the lower concentrations of Ti associated with fish in the treatments containing HA, under simulated sunlight illumination, median lethal concentrations were lower and oxidative DNA damage was elevated relative to fish exposed to TiO2NPs in the absence of HA. This study demonstrates the importance of considering environmental factors (i.e., exposure to sunlight, adsorption of DOM) when assessing the potential risks posed by engineered nanomaterials in the environment. PMID- 23347334 TI - A prospective single-centre evaluation of the intra-individual variability of faecal calprotectin in quiescent Crohn's disease. AB - BACKGROUND: As a non-invasive marker of gastrointestinal inflammation, faecal calprotectin (FC) is being increasingly used to guide the management of Crohn's disease. It is therefore a concern that studies have shown variability in day to day levels. AIM: To determine the degree of this intrapersonal variability in the context of quiescent Crohn's disease. METHODS: A single-centre prospective study was undertaken in 143 Crohn's disease patients in clinical remission. Three faecal calprotectin levels were analysed from stool samples on consecutive days. Consistency of faecal calprotectin levels was determined by measuring the intraclass correlation (ICC). Due to higher variability at higher faecal calprotectin levels, the ICC was calculated for the log-transformed values. The reliability of detecting a 'case' of active inflammation as defined for specific concentrations of faecal calprotectin was measured by the kappa statistic. RESULTS: Ninety-eight complete sets of results were obtained. The ICC was 0.84 (95% CI: 0.79-0.89), which represents low variability across samples. The kappa statistic for the reliability of detecting a case as defined by an FC level of >50 MUg/g was substantial at 0.648 (0.511-0.769). CONCLUSIONS: Day to day variability of faecal calprotectin is low in our cohort of quiescent Crohn's disease patients and the reliability of defining a 'case' is moderately good. These data provide reassurance to clinicians using a single calprotectin sample to inform therapeutic strategies in this cohort. PMID- 23347335 TI - Cigarette smoke increases BLT2 receptor functions in bronchial epithelial cells: in vitro and ex vivo evidence. AB - Leukotriene B(4) (LTB(4)) is a neutrophil chemotactic molecule with important involvement in the inflammatory responses of chronic obstructive pulmonary disease (COPD). Airway epithelium is emerging as a regulator of innate immune responses to a variety of insults including cigarette smoke, the major risk factor for COPD. In this study we have explored whether cigarette smoke extracts (CSE) or soluble mediators present in distal lung fluid samples (mini bronchoalveolar lavages) from smokers alter the expression of the LTB(4) receptor 2 (BLT2) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in bronchial epithelial cells. We also evaluated the effects of CSE on the expression of intercellular adhesion molecule 1 (ICAM-1) and on the binding of signal transducer and activator of transcription 1 (STAT-1) to ICAM-1 promoter as well as the adhesiveness of neutrophils to bronchial epithelial cells. CSE and mini-bronchoalveolar lavages from smokers increased BLT2 and ICAM-1 expression as well as the adhesiveness of neutrophils to bronchial epithelial cells and decreased PPAR-alpha expression. CSE induced the activation of STAT-1 and its binding to ICAM-1 promoter. These findings suggest that, in bronchial epithelial cells, CSE promote a prevalent induction of pro-inflammatory BLT2 receptors and activate mechanisms leading to increased neutrophil adhesion, a mechanism that contributes to airway neutrophilia and to tissue damage. PMID- 23347336 TI - Effect of systemic antibiotics on clinical and patient-reported outcomes of implant therapy - a multicenter randomized controlled clinical trial. AB - OBJECTIVES: To determine the effect of various systemic antibiotic prophylaxis regimes on patient-reported outcomes and postsurgical complications in patients undergoing conventional implant installation. MATERIAL AND METHODS: Three hundred and twenty-nine healthy adults in need of conventional implant installation were randomly assigned to one of four groups: (i) preoperatively 2 g of amoxycillin 1 h before surgery (positive control, PC), (ii) postoperatively 2 g of amoxycillin immediately following surgery (test 1, T1), (iii) preoperatively 2 g of amoxycillin 1 h before and 500 mg thrice daily on days 2 and 3 after surgery (test 2, T2), (iv) preoperatively 2 g of placebo 1 h before surgery (negative control, NC). Subjects were examined clinically by blinded examiners over 8 weeks after implant installation. In addition, Visual Analogue Scales (VAS) for pain, swelling, bruising and bleeding were obtained over 14 days. ANOVA was performed for the VAS. Chi-square tests were applied for postsurgical complications. RESULTS: All VAS scores were low for all groups and decreased over time (P < 0.001). There were no significant differences for the VAS scores between the various groups at any time point (P > 0.05). There was only a significant difference in flap closure at week 4, where NC had 5% of the subjects not achieving complete wound closure compared to 0% for the three other groups (P = 0.01), with no other significant differences for any postsurgical complications (P > 0.05). CONCLUSION: For standard single implant placement, prophylactic systemic antibiotics either before or after, or before and after the surgical procedure do not improve patient-reported outcomes or prevalence of postsurgical complications. PMID- 23347337 TI - Is intensive chemotherapy safe for rural cancer patients? AB - BACKGROUND: To provide equality of cancer care to rural patients, Townsville Cancer Centre administers intensive chemotherapy regimens to rural patients with node-positive breast and metastatic colorectal cancers at the same doses as urban patients. Side-effects were usually managed by rural general practitioners locally. AIM: The aim is to determine the safety of this practice by comparing the profile of serious adverse events and dose intensities between urban and rural patients at the Townsville Cancer Centre. METHOD: A retrospective audit was conducted in patients with metastatic colorectal and node-positive breast cancers during a 24-month period. Fisher's exact test was used for analysis. Rurality was determined as per rural, remote and metropolitan classification. RESULTS: Of the 121 patients included, 70 and 51 patients had breast and colon cancers respectively. The urban versus rural patient split among all patients, breast and colorectal cancer subgroups was 68 versus 53, 43 versus 27 and 25 versus 26 respectively. A total of 421 cycles was given with dose intensity of >95% for breast cancer in both groups (P > 0.05). Rate of febrile neutropenia was 9.3% versus 7.4% (P = 0.56). For XELOX, rate of diarrhoea was 20% versus 19% (P = 0.66) and rate of vomiting was 20% versus 11% (P = 0.11). Only two patients were transferred to Townsville for admission. No toxic death occurred in either group. CONCLUSION: It appears safe to administer intensive chemotherapy regimens at standard doses to rural patients without increased morbidity or mortality. Support for general practitioners through phone or videoconferencing may reduce the safety concerns. PMID- 23347338 TI - Identification of rice Allene Oxide Cyclase mutants and the function of jasmonate for defence against Magnaporthe oryzae. AB - Two photomorphogenic mutants of rice, coleoptile photomorphogenesis 2 (cpm2) and hebiba, were found to be defective in the gene encoding allene oxide cyclase (OsAOC) by map-based cloning and complementation assays. Examination of the enzymatic activity of recombinant GST-OsAOC indicated that OsAOC is a functional enzyme that is involved in the biosynthesis of jasmonic acid and related compounds. The level of jasmonate was extremely low in both mutants, in agreement with the fact that rice has only one gene encoding allene oxide cyclase. Several flower-related mutant phenotypes were observed, including morphological abnormalities of the flower and early flowering. We used these mutants to investigate the function of jasmonate in the defence response to the blast fungus Magnaporthe oryzae. Inoculation assays with fungal spores revealed that both mutants are more susceptible than wild-type to an incompatible strain of M. oryzae, in such a way that hyphal growth was enhanced in mutant tissues. The level of jasmonate isoleucine, a bioactive form of jasmonate, increased in response to blast infection. Furthermore, blast-induced accumulation of phytoalexins, especially that of the flavonoid sakuranetin, was found to be severely impaired in cpm2 and hebiba. Together, the present study demonstrates that, in rice, jasmonate mediates the defence response against blast fungus. PMID- 23347340 TI - The effect of age and menopausal status on musculoskeletal symptoms in Chinese women aged 35-64 years. AB - OBJECTIVE: To assess the prevalence of musculoskeletal symptoms at four different anatomical sites and the impact of menopause, age, and other factors on musculoskeletal symptoms. METHODS: Generally healthy women aged 35-64 years were recruited from a general community in Beijing, People's Republic of China. Data were collected with a questionnaire including the basic conditions, menopausal status, and frequency of musculoskeletal symptoms (rarely, occasionally or frequently) during the previous 2 weeks at the neck, lower back, knee and other sites. The prevalences of frequent symptoms were calculated for each site. RESULTS: A total of 743 women were enrolled in the study; 33.4% complained of frequent lower back pain, 31.0% of frequent knee pain, 29.7% of frequent neck pain, 25.6% of joint pain at other sites, 23.6% of joint stiffness and 21.1% of hand joint swelling. Postmenopausal women experienced a significantly higher prevalence of musculoskeletal symptoms compared with premenopausal women. There was a peak in prevalence of musculoskeletal symptoms at early postmenopause. The prevalences of neck pain and lower back pain were not associated with age, but did increase during the perimenopausal stage. The prevalences of knee pain, joint stiffness and hand joint swelling increased significantly with age. Higher body mass index (BMI) was related to increased prevalences of knee pain, joint stiffness and hand joint swelling. Logistic regression analysis showed odds ratios for knee pain, joint stiffness and hand joint swelling of 2.256, 1.865 and 1.955, respectively, in the obese women (BMI >= 28 kg/m(2)), compared with women with normal BMI (< 24 kg/m(2)). CONCLUSION: Menopause is known to be a time of increased musculoskeletal symptoms, but the association of musculoskeletal symptoms with age and BMI also should be considered. PMID- 23347339 TI - Antimicrobial susceptibility and genetic characteristics of Neisseria gonorrhoeae isolates from India, Pakistan and Bhutan in 2007-2011. AB - BACKGROUND: Knowledge on antimicrobial drug resistance and genetic characteristics of Neisseria gonorrhoeae isolates circulating in India, Pakistan, and Bhutan is sorely lacking. In this paper, we describe the prevalence of antimicrobial resistance and molecular characteristics of N. gonorrhoeae isolates from India, Pakistan, and Bhutan in 2007-2011. METHODS: Antimicrobial susceptibility and beta-lactamase production were tested for 65 N. gonorrhoeae isolates from India (n=40), Pakistan (n=18) and Bhutan (n=7) using Etest methodology (eight antimicrobials) and nitrocefin solution, respectively. Resistance determinants, i.e. penA, mtrR, porB1b, gyrA, and parC, were sequenced. N. gonorrhoeae multiantigen sequence typing (NG-MAST) was performed for molecular epidemiology. RESULTS: The highest resistance level was observed for ciprofloxacin (94%), followed by penicillin G (68%), erythromycin (62%), tetracycline (55%), and azithromycin (7.7%). All the isolates were susceptible to ceftriaxone, cefixime, and spectinomycin. Thirty-four (52%) of the isolates were producing beta-lactamase. No penA mosaic alleles or A501-altered alleles of penicillin-binding protein 2 were identified. Forty-nine NG-MAST STs were identified, of which 42 STs have not been previously described worldwide. CONCLUSIONS: Based on this study, ceftriaxone, cefixime, and spectinomycin can be used as an empirical first-line therapy for gonorrhoea in India, Pakistan, and Bhutan, whereas ciprofloxacin, penicillin G, tetracycline, erythromycin, and azithromycin should not be. It is imperative to strengthen the laboratory infrastructure in this region, as well as to expand the phenotypic and genetic surveillance of antimicrobial resistance, emergence of new resistance, particularly, to extended-spectrum cephalosporins, and molecular epidemiology. PMID- 23347341 TI - Testosterone replacement with 1% testosterone gel and priapism: no definite risk relationship. AB - INTRODUCTION: Although testosterone replacement therapy (TRT) is the preferred treatment for hypogonadism, information for patients using testosterone includes too frequent or prolonged erections as a potential side effect. AIM: To assess the frequency and risk of priapism or related adverse events (AEs) in hypogonadal men treated with a 1% testosterone gel. METHODS: Safety and tolerability data for AndroGel 1% were assessed, including three randomized, controlled clinical trials in varying populations of hypogonadal or near hypogonadal men. Study 1 was a Phase 3 trial of AndroGel 1% 5 g, 7.5 g, or 10 g once daily for 6 months (N = 227). Study 2 was a Phase 2 trial of AndroGel 1% 7.5 g once daily titrated as needed vs. placebo for 26 weeks in men with type 2 diabetes (N = 180). Study 3 was a Phase 4 trial of AndroGel 1% 5 g once daily vs. placebo for 12 weeks in men previously unresponsive to sildenafil 100 mg monotherapy and receiving concomitant sildenafil 100 mg (N = 75). Postmarketing AndroGel pharmacovigilance reporting data from 2001 to 2011 was searched for events coded as priapism. MAIN OUTCOME MEASURES: The incidence of priapism and/or related symptoms reported as urogenital or reproductive system AEs. RESULTS: In the 283 men exposed to AndroGel 1% over the three trials, mean exposure ranged from 84 days to 149 days. No AEs described as priapism or related symptoms were reported in the three trials. In the postmarketing data, representing 40 million units sold, eight cases described as priapism were reported. Of the six cases with accompanying data, all were judged as possibly related to AndroGel. CONCLUSIONS: Safety data from the clinical trials for AndroGel 1% did not report any cases of priapism, and its incidence in the postmarketing pharmacovigilance data is extremely low, indicating a minimal risk of inducing priapism. PMID- 23347342 TI - Description of Glaucomides bromelicola n. gen., n. sp. (Ciliophora, Tetrahymenida), a macrostome forming inhabitant of bromeliads (Bromeliaceae), including redescriptions of Glaucoma scintillans and G. reniformis. AB - Glaucomides bromelicola n. gen., n. sp. is a tetrahymenid ciliate common in tank bromeliads of Central and South America. The new genus is characterized by having a kinety fragment along the left mouth margin, an unciliated dorsolateral area, a tetrahymenid silverline pattern, and the ability to produce macrostomes when bacterial food is depleted. I provide a detailed description of the microstome and the macrostome morph, using several morphological methods. This showed that G. bromelicola does not belong to the Glaucomidae, but to the Bromeliophryidae. However, various morphological traits are highly similar to those of Glaucoma reniformis and G. scintillans, which are thus redescribed and compared with G. bromelicola. Most differences are inconspicuous, showing that new tetrahymenids must be described very carefully. The morphological and molecular data suggest a common ancestor for Glaucoma and Glaucomides, both performing their own radiation, the former in ordinary limnetic habitats, the latter in tank bromeliads. PMID- 23347343 TI - Optimizing patient derived mesenchymal stem cells as virus carriers for a phase I clinical trial in ovarian cancer. AB - BACKGROUND: Mesenchymal stem cells (MSC) can serve as carriers to deliver oncolytic measles virus (MV) to ovarian tumors. In preparation for a clinical trial to use MSC as MV carriers, we obtained cells from ovarian cancer patients and evaluated feasibility and safety of this approach. METHODS: MSC from adipose tissues of healthy donors (hMSC) and nine ovarian cancer patients (ovMSC) were characterized for susceptibility to virus infection and tumor homing abilities. RESULTS: Adipose tissue (range 0.16-3.96 grams) from newly diagnosed and recurrent ovarian cancer patients yielded about 7.41*106 cells at passage 1 (range 4-9 days). Phenotype and doubling times of MSC were similar between ovarian patients and healthy controls. The time to harvest of 3.0*108 cells (clinical dose) could be achieved by day 14 (range, 9-17 days). Two of nine samples tested had an abnormal karyotype represented by trisomy 20. Despite receiving up to 1.6*109 MSC/kg, no tumors were seen in SCID beige mice and MSC did not promote the growth of SKOV3 human ovarian cancer cells in mice. The ovMSC migrated towards primary ovarian cancer samples in chemotaxis assays and to ovarian tumors in athymic mice. Using non-invasive SPECT-CT imaging, we saw rapid co-localization, within 5-8 minutes of intraperitoneal administration of MV infected MSC to the ovarian tumors. Importantly, MSC can be pre-infected with MV, stored in liquid nitrogen and thawed on the day of infusion into mice without loss of activity. MV infected MSC, but not virus alone, significantly prolonged the survival of measles immune ovarian cancer bearing animals. CONCLUSIONS: These studies confirmed the feasibility of using patient derived MSC as carriers for oncolytic MV therapy. We propose an approach where MSC from ovarian cancer patients will be expanded, frozen and validated to ensure compliance with the release criteria. On the treatment day, the cells will be thawed, washed, mixed with virus, briefly centrifuged and incubated for 2 hours with virus prior to infusion of the virus/MSC cocktail into patients. PMID- 23347344 TI - Medical undergraduates' use of behaviour change talk: the example of facilitating weight management. AB - BACKGROUND: Obesity, an increasing problem worldwide, is a leading cause of morbidity and mortality. Management principally requires lifestyle (i.e. behavioural) changes. An evidence-base exists of behaviour change techniques for weight loss; however, in routine practice doctors are often unsure about effective treatments and commonly use theoretically-unfounded communication strategies (e.g. information-giving). It is not known if communication skills teaching during undergraduate training adequately prepares future doctors to engage in effective behaviour change talk with patients. The aim of the study was to examine which behaviour change techniques medical undergraduates use to facilitate lifestyle adjustments in obese patients. METHODS: Forty-eight medical trainees in their clinical years of a UK medical school conducted two simulated consultations each. Both consultations involved an obese patient scenario where weight loss was indicated. Use of simulated patients (SPs) ensured standardisation of key variables (e.g. barriers to behaviour change). Presentation of scenario order was counterbalanced. Following each consultation, students assessed the techniques they perceived themselves to have used. SPs rated the extent to which they intended to make behavioural changes and why. Anonymised transcripts of the audiotaped consultations were coded by independent assessors, blind to student and SP ratings, using a validated behaviour change taxonomy. RESULTS: Students reported using a wide range of evidence-based techniques. In contrast, codings of observed communication behaviours were limited. SPs behavioural intention varied and a range of helpful elements of student's communication were revealed. CONCLUSIONS: Current skills-based communication programmes do not adequately prepare future doctors for the growing task of facilitating weight management. Students are able to generalise some communication skills to these encounters, but are over confident and have limited ability to use evidence-based theoretically informed techniques. They recognise this as a learning need. Educators will need to tackle the challenges of integrating theoretically informed and evidence based behaviour change talk within medical training. PMID- 23347345 TI - Analysis of occlusal stresses transmitted to the inferior alveolar nerve by multiple threaded implants. AB - BACKGROUND: Potential nerve injury or loss of sensation can occur after mandibular implant placement or loading. To avoid this type of damage, it is critical to determine the proper distance from implants to the mandibular nerve. Hence, the purpose of this study is to use biomechanical analyses to determine the safe distance from multiple implants to the inferior alveolar nerve. METHODS: Using the boundary element method, a numerical mandibular model was designed to simulate a mandibular segment containing multiple threaded fixtures. This model allows assessment of the pressure, as induced by occlusal loads, on the trigeminal nerve. Such pressure distribution was evaluated against different distances from the fixtures to the mandibular canal, against the possible lack of the central fixture in a three-abutment configuration, and against different levels of implant osseointegration. All the simulations considered a canal that is orthogonal to the implant axis. RESULTS: Nerve pressure increased quickly when the implant-canal distance decreased in the range studied. Lack of the central implant to support the central abutment caused major increases in nerve pressure. CONCLUSIONS: This study suggests a minimal implant-canal distance of 1 mm to prevent inferior alveolar nerve damage caused by three connected implants. For clinical safety, an additional 0.5 mm is recommended as a cushion, so a 1.5-mm minimal distance should be planned to avoid potential nerve injury. PMID- 23347346 TI - Long-term stability of contour augmentation with early implant placement following single tooth extraction in the esthetic zone: a prospective, cross sectional study in 41 patients with a 5- to 9-year follow-up. AB - BACKGROUND: Early implant placement with simultaneous contour augmentation is documented with short- and medium-term studies. The long-term stability of contour augmentation is uncertain. METHODS: In this prospective, cross-sectional study, 41 patients with an implant-borne single crown were examined twice, in 2006 and 2010. Clinical, radiologic, and esthetic parameters were assessed at both examinations. In addition, a cone beam computed tomographic (CBCT) image was obtained during the second examination to assess the dimensions of the facial bone wall. RESULTS: All 41 implants demonstrated ankylotic stability without signs of peri-implant infection at both examinations. The clinical parameters remained stable over time. Satisfactory esthetic outcomes were noted, as assessed by the pink and white esthetic score (PES/WES) indices. Overall, the PES scores were slightly higher than the WES scores. None of the implants developed mucosal recession over time, as confirmed by values of the distance between implant shoulder and mucosal margin and cast measurements. The periapical radiographs yielded stable peri-implant bone levels, with a mean distance between implant shoulder and first visible bone-implant contact value of 2.18 mm. The CBCT analysis demonstrated a mean thickness of the facial bone wall ~2.2 mm. In two implants (4.9%) no facial bone wall was detectable radiographically. CONCLUSIONS: This prospective cross-sectional study demonstrates stable peri-implant hard and soft tissues for all 41 implants examined and satisfactory esthetic outcomes overall. The follow-up of 5 to 9 years confirmed again that the risk for mucosal recession is low with early implant placement. In addition, contour augmentation with guided bone regeneration was able to establish and maintain a facial bone wall in 95% of patients. PMID- 23347347 TI - In vitro evaluation of demineralized freeze-dried bone allograft in combination with enamel matrix derivative. AB - BACKGROUND: Preclinical and clinical studies suggest that a combination of enamel matrix derivative (EMD) with demineralized freeze-dried bone allograft (DFDBA) may improve periodontal wound healing and regeneration. To date, no single study has characterized the effects of this combination on in vitro cell behavior. The aim of this study is to test the ability of EMD to adsorb to the surface of DFDBA particles and determine the effect of EMD coating on downstream cellular pathways such as adhesion, proliferation, and differentiation of primary human osteoblasts and periodontal ligament (PDL) cells. METHODS: DFDBA particles were precoated with EMD or human blood and analyzed for protein adsorption patterns via scanning electron microscopy. Cell attachment and proliferation were quantified using a commercial assay. Cell differentiation was analyzed using real-time polymerase chain reaction for genes encoding Runx2, alkaline phosphatase, osteocalcin, and collagen 1alpha1, and mineralization was assessed using alizarinred staining. RESULTS: Analysis of cell attachment revealed no significant differences among control, blood-coated, and EMD-coated DFDBA particles. EMD significantly increased cell proliferation at 3 and 5 days after seeding for both osteoblasts and PDL cells compared to control and blood-coated samples. Moreover, there were significantly higher messenger ribonucleic acid levels of osteogenic differentiation markers, including collagen 1alpha1, alkaline phosphatase, and osteocalcin, in osteoblasts and PDL cells cultured on EMD-coated DFDBA particles at 3, 7, and 14 days. CONCLUSION: The results suggest that the addition of EMD to DFDBA particles may influence periodontal regeneration by stimulating PDL cell and osteoblast proliferation and differentiation. PMID- 23347348 TI - Effect of flapless surgery on single-tooth implants in the esthetic zone: a randomized clinical trial. AB - BACKGROUND: Implant therapy is a highly predictable treatment option; however, insufficient data exist to show whether flapless implant surgery provides better esthetic outcomes and less bone loss than implant surgery with a flap approach. METHODS: In this randomized, controlled study comparing the flapless and traditional flap protocol for implant placement, 24 patients received a single implant in the anterior maxillary region. A cone beam computed tomography-aided surgical guide was used for implant placement surgery for both groups. Implants were restored using a one-piece, screw-retained ceramic crown at 3 months. Radiographic and clinical measurements were assessed at baseline (implant placement) and at 3 (crown placement), 6, 9, and 15 months. Clinical parameters evaluated were plaque index, gingival index, papillary index (PPI) (0 = no papilla, 1 = less than half, 2 = more than half but not complete, 3 = complete fill, and 4 = overfill), marginal tissue levels, biotype, width of keratinized tissue, and soft tissue thickness. RESULTS: Implant success rate was 92% in both groups. Mean PPI values for the flap control group and flapless test group were 2.38 +/- 0.51 versus 2.31 +/- 0.48 at crown placement (P = 0.68) and 2.52 +/- 0.52 versus 2.64 +/- 0.54 at 15 months (P = 0.42), respectively. PPI increased over time in both groups, although the flapless group had a significantly larger change in PPI from crown placement to 6 and 9 months (P <0.01). Crestal bone levels in the flap group were more apical in relation to the implant platform than those in the flapless group for the duration of the study. No differences among groups were noted for all other measurements. CONCLUSIONS: Both flapless and flap implant placement protocols resulted in high success rates. A flapless protocol may provide a better short-term esthetic result, although there appears to be no long-term advantage. PMID- 23347349 TI - Salivary cotinine concentrations and prevalence of periodontal disease in young Japanese women: the Kyushu Okinawa maternal and child health study. AB - BACKGROUND: The authors investigated the relationship between objectively assessed tobacco smoke exposure and periodontal disease. METHODS: This cross sectional study included 1,103 women with a mean age of 31.5 years. Information on potential confounding factors was obtained through a self-administered questionnaire. Periodontal disease was defined as positive if a woman had at least one tooth with a probing depth of >= 3.5 mm. Exposure to tobacco smoke was determined based on salivary cotinine concentration. Adjustment was made for age, region of residence, household income, education, toothbrushing frequency, and use of an interdental brush. RESULTS: The prevalence of periodontal disease was 11.3%. Salivary cotinine concentration was independently positively associated with the prevalence of periodontal disease: the adjusted odds ratio for every 1 unit (ng/mL) increase in salivary cotinine was 1.004 (95% confidence interval: 1.000 to 1.007). CONCLUSION: Salivary cotinine concentrations were positively associated with the prevalence of periodontal disease among young women. PMID- 23347350 TI - Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. AB - Clinical, in vitro, and experimental animal observations indicate that antineutrophil cytoplasmic autoantibodies (ANCA) are pathogenic. The genesis of the ANCA autoimmune response is a multifactorial process that includes genetic predisposition, environmental adjuvant factors, an initiating antigen, and failure of T cell regulation. ANCA activate primed neutrophils (and monocytes) by binding to certain antigens expressed on the surface of neutrophils in specific inflammatory microenvironments. ANCA-activated neutrophils activate the alternative complement pathway, establishing an inflammatory amplification loop. The acute injury elicits an innate inflammatory response that recruits monocytes and T lymphocytes, which replace the neutrophils that have undergone karyorrhexis during acute inflammation. Extravascular granulomatous inflammation may be initiated by ANCA-induced activation of extravascular neutrophils, causing tissue necrosis and fibrin formation, which would elicit an influx of monocytes that transform into macrophages and multinucleated giant cells. Over time, the neutrophil-rich acute necrotizing lesions cause the accumulation of more lymphocytes, monocytes, and macrophages and produce typical granulomatous inflammation. PMID- 23347352 TI - The immunobiology and pathophysiology of primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by clinical homogeneity among patients, an overwhelming female predominance, production of a multilineage immune response to mitochondrial autoantigens, inflammation of small bile ducts, and in some patients the development of fibrosis and cirrhosis. The targets in this disease are small bile ducts, and the prototypic serologic response includes antimitochondrial antibodies (AMAs). Several key observations have greatly advanced our understanding of PBC. First, the multilineage immune response, including AMAs, is directed at the E2 component of the 2-oxo-dehydrogenase pathway, particularly PDC-E2. Second, such autoantibodies may be identified years before the clinical diagnosis of disease. Third, the autoreactive T cell precursor frequency for both CD4 and CD8 cells is significantly higher in liver and regional lymph node than in blood, so the multilineage antimitochondrial response may be required for the development of this disease. Fourth, the apotope of biliary cells contains intact PDC-E2; this apotope, in a setting that includes granulocyte macrophage colony-stimulating factor-stimulated macrophages and AMAs, produces an intense proinflammatory response. Fifth, several mouse models of PBC highlight the importance of loss of tolerance to PDC-E2 as well as a critical role for the interleukin (IL)-12 signaling pathway. Finally, genome-wide association studies suggest an important role for the IL-12 pathway in disease susceptibility. Taken together, these findings have resulted in a better understanding of the mechanism for selective biliary cell destruction and have also suggested unique pathways for therapeutic intervention. PMID- 23347353 TI - Acting on impulse: dissecting the dynamics of the NFAT transcriptional response. AB - Examining NFAT transcription factor dynamics in single cells during signal propagation from cell membrane to the nucleus reveals unique modes of operation for protein isoforms. PMID- 23347351 TI - Molecular basis of asbestos-induced lung disease. AB - Asbestos causes asbestosis and malignancies by molecular mechanisms that are not fully understood. The modes of action underlying asbestosis, lung cancer, and mesothelioma appear to differ depending on the fiber type, lung clearance, and genetics. After reviewing the key pathologic changes following asbestos exposure, we examine recently identified pathogenic pathways, with a focus on oxidative stress. Alveolar epithelial cell apoptosis, which is an important early event in asbestosis, is mediated by mitochondria- and p53-regulated death pathways and may be modulated by the endoplasmic reticulum. We review mitochondrial DNA (mtDNA) damage and -repair mechanisms, focusing on 8-oxoguanine DNA glycosylase, as well as cross talk between reactive oxygen species production, mtDNA damage, p53, OGG1, and mitochondrial aconitase. These new insights into the molecular basis of asbestos-induced lung diseases may foster the development of novel therapeutic targets for managing degenerative diseases (e.g., asbestosis and idiopathic pulmonary fibrosis), tumors, and aging, for which effective management is lacking. PMID- 23347354 TI - Warming effect on miriplatin-lipiodol suspension for potential use as a chemotherapeutic agent for transarterial chemoembolization of hepatocellular carcinoma: In vitro study. AB - AIM: To elucidate whether warming may reduce the viscosity of miriplatin-lipiodol suspension (MPT/LPD) and also the injection pressure through microcatheters, for potential use as a chemotherapeutic agent of transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). METHODS: Viscosity of MPT/LPD prepared at on-label dose was measured in vitro at 25 degrees C, 30 degrees C, 40 degrees C, 50 degrees C and 60 degrees C using capillary tube method. Reproducibility of viscosity change was also tested. Injection pressure through two different commercially available microcatheters was measured using a rheometer. Data sampling was performed at least twice for each measurement. RESULTS: Viscosity of MPT/LPD was significantly reduced as the temperature was elevated (R(2) = 0.9586, P < 0.0001, Pearson's correlation); at 40 degrees C, it was almost half of that at room temperature (25 degrees C). Repeated warming and cooling down of MPT/LPD revealed good reproducibility of viscosity change. Injection pressure through either microcatheter showed significant reduction when MPT/LPD was warmed (P < 0.05, Spearman's rank correlation coefficient). CONCLUSION: The viscosity and injection pressure through microcatheters of MPT/LPD was confirmed to reduce significantly as the temperature is elevated. MPT/LPD warmed to 40 degrees C has half viscosity as that at room temperature and is considered suitable for clinical use. Warming MPT/LPD may have potential to facilitate the procedure of TACE for HCC. PMID- 23347355 TI - Electrically modulated microtransfer molding for fabrication of micropillar arrays with spatially varying heights. AB - The ability to generate a large area micropillar array with spatially varying heights allows for exploring numerous new interesting applications in biotechnology, surface engineering, microfluidics, and so forth. This Letter presents a clever and straightforward method, called electrically modulated microtransfer molding (EM3), for generating such unique microstructures from a silicon mold arrayed with microholes. The key to the process is an application of electrically tunable wettability caused by a spatially modulated voltage, which electrohydrodynamically drives a photocurable and dielectric prepolymer to fill the microholes to a depth depending on the voltage amplitude. Using EM3, micropillar arrays with stepwise or continuously varying heights are successfully fabricated, with the diameter scalable to 1.5 MUm and with the maximum height being equal to the depth of the high-aspect-ratio (more than 10:1) microholes. PMID- 23347356 TI - Assessment of brain metabolites change during visual sexual stimulation in healthy women using functional MR spectroscopy. AB - INTRODUCTION: Numerous functional magnetic resonance imaging (fMRI) studies demonstrated the key brain areas associated with visual sexual arousal. However, the changes in brain metabolites involved in sexual stimuli have not been reported. AIM: This study utilized functional MR spectroscopy (fMRS) to evaluate the changes in brain metabolites associated with sexual arousal induced by stimulation with erotic video clips in healthy women. METHODS: Twenty-three healthy, right-handed women (38.4 +/- 10.0 years) participated in (1) H-fMRS and fMRI studies. T1 and T2 MR images were used for voxel localization of the anterior cingulate gyrus, which is one of the most important key centers associated with sexual arousal. MAIN OUTCOME MEASURES: The changes of brain metabolites were measured using (1) H-fMRS during time-course activation: "before," "during," and "after" visual sexual stimulation. The time-course variation of the brain metabolites was analyzed by the repeated-measures analysis of variance. RESULTS: The CVmean of all the metabolites had <30% (range, 9-29%). The ICCs of alpha-glutamine-glutamate (Glx), choline (Cho), beta.gamma-Glx, N acetylaspartate (NAA) and lactate (Lac) all exceeded 0.6. However, myo-inositol (mI) and lipid (Lip) were <0.6. The concentration of brain metabolites including alpha-Glx, beta.gamma-Glx, Cho, and Lac comparatively increased significantly during visual sexual stimulation. CONCLUSIONS: (1) H-fMRS, for the first time, was applied to assess the brain metabolic changes during visually-evoked sexual arousal. The fMRS outcomes in relation to functional MRI data will be useful to understand the neural mechanism associated with sexual arousal. PMID- 23347357 TI - WhatisKT wiki: a case study of a platform for knowledge translation terms and definitions--descriptive analysis. AB - BACKGROUND: More than a hundred terms, often with unclear definitions and varying emphases, are used by health research and practice communities across the world who are interested in getting the best possible evidence applied (e.g., knowledge translation, implementation science, diffusion of innovations, and technology transfer). This makes finding published evidence difficult and can result in reduced, misinterpreted, or challenging interactions among professionals. Open dialogue and interaction among various professionals is needed to achieve consolidation of vocabulary. We use case report methods to describe how we sought to build an online tool to present the range of terms and facilitate the dialogue process across groups and disciplines interested in harnessing research evidence for healthcare. METHODS: We used a wiki platform from Wikispaces to present the problem of terminology and make a case and opportunity for collaboration on usage. Wikis are web sites where communities of users can collaborate online to build content and discuss progress. We gathered terms related to getting research into practice, sought published definitions, and posted these on the wiki (WhatisKT http://whatiskt.wikispaces.com/). We built the wiki in mid-2008 and promoted it through various groups and publications. This report describes the content of the site, our promotion efforts, use of the site, and how the site was used for collaboration up to the end of 2011. RESULTS: The WhatisKT wiki site now includes more than 120 pages. Traffic to the site has increased substantially from an average of 200 monthly visits in 2008 to 1700 in 2011. Visitors from 143 countries viewed the wiki in 2011, compared with 12 countries in 2008. However, most use has been limited to short term accesses of about 40 seconds per visit, and discussion of consolidation and solidifying terminology is conspicuously absent. CONCLUSIONS: Although considerable interest exists in the terms and definitions related to getting research into practice based on increasing numbers of accesses, use of the WhatisKT wiki site for anything beyond quick lookups was minimal. Additional efforts must be directed towards increasing the level of interaction among the members of the site to encourage collaboration on term use. PMID- 23347358 TI - Cooperative supramolecular polymerization driven by metallophilic Pd...Pd interactions. AB - A new oligophenyleneethynylene (OPE)-based Pd(II) pyridyl complex has been synthesized, and its self-assembly has been investigated in solution, in the bulk state, and on surfaces. Detailed analysis of concentration- and temperature dependent UV-vis studies in methylcyclohexane supported by DFT calculations demonstrate for the first time that cooperative supramolecular polymerization processes can be driven by metallophilic interactions. PMID- 23347359 TI - Allopurinol safely and effectively optimises thiopurine metabolites in patients with autoimmune hepatitis. AB - BACKGROUND: Ten percent of patients with autoimmune hepatitis (AIH) are nonresponsive or intolerant to thiopurine therapy. A skewed metabolism, leading to the preferential generation of (hepato)toxic thiopurine metabolites (6-MMPs) instead of the metabolic active 6-tioguanine (thioguanine) nucleotides (6-TGNs), may explain this unfavourable outcome. Co-administration of allopurinol to low dose thiopurine therapy may effectively revert this deviant metabolism, as has been shown in inflammatory bowel disease. AIM: To describe the effect of adding allopurinol to low-dose thiopurine therapy in patients with AIH with intolerance or nonresponse to normal thiopurine dosages due to a skewed metabolism. METHODS: We describe the clinical efficacy and tolerability of allopurinol-thiopurine combination therapy with allopurinol 100 mg and low-dose thiopurine (25-33% of the original dosage) in eight AIH patients with a skewed thiopurine metabolism. Patients were switched because of dose-limiting intolerance (n = 3), nonresponse (n = 3) or loss of response (n = 2) to conventional thiopurine treatment. RESULTS: All eight patients showed biochemical improvement with a reduction in median alanine aminotransferase (ALT) levels of 62 U/L at start to 35 U/L at 1 month (P = 0.03). This clinical benefit was sustained in seven patients. Allopurinol-thiopurine combination therapy effectively bypassed thiopurine side effects in four of five patients. Median 6-tioguanine nucleotides levels increased from 100 to 200 pmol/8 * 10(8) red blood cells (RBC) at 3 months (P = 0.04). Median 6-MMP levels decreased in all patients from 6090 to 175 pmol/8 * 10(8) RBC (P = 0.01). CONCLUSION: Allopurinol safely and effectively optimises thiopurine therapy in patients with autoimmune hepatitis with intolerance and/or nonresponse due to an unfavourable thiopurine metabolism. PMID- 23347360 TI - Rhodotorula minuta fungemia in a ewe lamb. AB - An 8-month-old crossbred ewe, normal upon physical examination, was humanely euthanized for tissue collection. After approximately 3 weeks in tissue culture, fungi began budding out of cells obtained from the choroid plexus. After an additional 3 weeks, budding was observed in kidney cell cultures and eventually in monocyte cultures as well. Serum from the lamb was submitted to the Veterinary Diagnostic Laboratory at Colorado State University for fungal diagnosis and was found negative for Aspergillus, Blastomyces, Coccidioidomycosis and Histoplasmosis. DNA was isolated from fungi collected from tissue culture supernatants and used in a set of pan-fungal PCR assays with DNA from Candida acting as a positive control. PCR products were sequenced and BLAST analysis performed. The unknown fungal sequence aligned with 100% identity to Rhodotorula minuta an emerging opportunistic pathogen. Samples were submitted to The Fungal Testing Laboratory at The University of Texas Health Science Center at San Antonio for additional validation. We believe this to be the first report of Rhodotorula fungemia in a sheep in the United States. PMID- 23347361 TI - Help seeking by Aboriginal men who are mentally unwell: a pilot study. AB - AIMS: Mental illness is widespread among Aboriginal men in Australia. However, they do not access mental health services in proportion to their need. Although several reports implicate cultural differences of mental health services as the cause of underutilization, very little is known about help seeking by Aboriginal men who are mentally unwell. This study explores the help-seeking behaviour of Aboriginal men who are mentally unwell in a rural Victorian community. METHODS: The study was carried out using a combination of culturally appropriate research methodologies. Within a Qualitative Description design, semi-structured interviews were conducted with a range of Aboriginal people including men, carers and those involved in service delivery. A total of 17 Aboriginal people were interviewed, of whom 15 were men. Data were analysed thematically. RESULTS: Four themes emerged from the data collected. They included 'Difficulty in recognizing mental health problems', 'Barriers to disclosing one's problems', 'Reluctance to contact services' and 'Alternate coping strategies'. CONCLUSIONS: These findings suggest that there is a need for programmes that aim to improve mental health literacy and promote help seeking among Aboriginal men who are mentally unwell. Such programmes need to be developed jointly by mental health services as well as Aboriginal stakeholders, and implemented in a culturally sensitive and acceptable way. PMID- 23347363 TI - Comparison of three different methods to prevent heat loss in healthy dogs undergoing 90 minutes of general anesthesia. AB - OBJECTIVE: To compare a towel under, a warm water pad under or a forced warm air blanket over dogs as techniques to reduce heat loss during a standardized anesthetic. STUDY DESIGN: Prospective, randomized, crossover study. ANIMALS: Eight, healthy, mixed breed dogs weighing 16.3-19.6 kg. METHODS: Dogs were anesthetized four times for 90 minutes. Dogs were placed on a steel table (treatment TA), with a cotton towel (treatment TO) or a circulating warm water pad (treatment WP) between the dog and the table, or with, a towel under the dog and covered with a forced warm air blanket (treatment WAB). Rectal temperature (RT) was recorded at 5 minute intervals. Changes in temperature (DeltaRT) were calculated as the RT at a given point subtracted from the RT before anesthesia (baseline) and compared over time. RESULTS: After 90 minutes of anesthesia, the DeltaRT was 3.42 degrees C +/- 0.29 for TA, 2.78 degrees C +/- 0.43 for TO, 1.98 degrees C +/- 0.29 for WP, and 0.91 degrees C +/- 0.27 for WAB. Significant differences in DeltaRT occurred between TA and WAB at 20 minutes (0.94 degrees C +/- 0.42, p = 0.0206), between TO and WAB at 30 minutes (1.16 degrees C +/- 0.62, p = 0.0063), between WP and WAB at 50 minutes (0.96 degrees C +/- 0.98, p = 0.0249), between TA and WP at 35 minutes (1.19 degrees C +/- 0.54, p = 0.0091), between TO and WP at 70 minutes (1.12 degrees C +/- 0.56, p = 0.0248), and between TA and TO at 75 minutes (0.96 degrees C +/- 0.62, p = 0.0313). These differences in DeltaRT between each treatment persisted from the times indicated until the end of the anesthesia. CONCLUSION AND CLINICAL RELEVANCE: During anesthesia, forced warm air blankets were superior to other methods tested for limiting heat loss. An efficient heat loss technique should be used for anesthesia longer than 20 minutes duration in medium sized dogs. PMID- 23347362 TI - Toll-like receptor-mediated eosinophil-basophil differentiation: autocrine signalling by granulocyte-macrophage colony-stimulating factor in cord blood haematopoietic progenitors. AB - Eosinophils are multi-functional leucocytes that play a role in inflammatory processes including allergy and infection. Although bone marrow (BM) inflammatory cells are the main source of eosinophil-basophil (Eo/B) differentiation-inducing cytokines, a recent role has been demonstrated for cytokine induction through Toll-like receptor (TLR)-mediated signalling in BM progenitors. Having previously demonstrated that cord blood (CB) progenitors induce Eo/B colony-forming units (CFU) after lipopolysaccharide (LPS) stimulation, we sought to investigate the intracellular mechanisms by which LPS induces Eo/B differentiation. Freshly isolated CD34-enriched human CB cells were stimulated with LPS (and/or pharmacological inhibitors) and assessed for alterations in haematopoietic cytokine receptor expression and signalling pathways by flow cytometry, Eo/B CFU in methylcellulose cultures, and cytokine secretion using Luminex assays. The LPS stimulation resulted in a significant increase in granulocyte-macrophage colony stimulating factor (GM-CSF)-responsive, as opposed to interleukin-5-responsive, Eo/B CFU, which also correlated with significant increases in CD34(+) cell GM CSFRalpha expression. Functionally, CB CD34(+) cells secrete abundant amounts of GM-CSF following LPS stimulation, via a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism; this secretion was responsible for Eo/B CFU formation ex vivo, as shown by antibody blockade. We show for the first time that LPS stimulation of CB progenitor cells results in autocrine activation of p38 MAPK dependent GM-CSF secretion facilitating Eo/B differentiation ex vivo. This work provides evidence that early life exposure to products of bacterial agents can modulate Eo/B differentiation, representing a novel mechanism by which progenitor cells can respond to microbial stimuli and so affect immune and inflammatory responses. PMID- 23347365 TI - Corneal collagen cross-linking: new and expanding applications. PMID- 23347364 TI - Review of medical discharge summaries and medical documentation in a metropolitan hospital: impact on diagnostic-related groups and Weighted Inlier Equivalent Separation. AB - BACKGROUND: Accurate and comprehensive clinical documentation is crucial for effective ongoing patient care, follow up and to optimise case mix-based funding. Each Diagnostic Related Group (DRG) is assigned a 'weight', leading to Weighted Inlier Equivalent Separation (WIES), a system many public and private hospitals in Australia subscribe to. AIMS: To identify the top DRG in a general medical inpatient service, the completeness of medical discharge documentation, commonly missed comorbidities and system-related issues and subsequent impact on DRG and WIES allocation. METHODS: One hundred and fifty completed discharge summaries were randomly selected from the top 10 medical DRG in our health service. From a detailed review of the clinical documentation, principal diagnoses, associated comorbidities and complications, where appropriate, the DRG and WIES were modified. RESULTS: Seventy-two (48%) of the 150 reviewed admissions resulted in a revision of DRG and WIES equivalent to an increase of AUD 142,000. Respiratory based DRG generated the largest revision of DRG and WIES, while 'Cellulitis' DRG had the largest relative change. Twenty-seven per cent of summaries reviewed necessitated a change in coding with no subsequent change in DRG allocation or WIES. Acute renal failure, anaemia and electrolyte disturbances were the most commonly underrepresented entities in clinical discharge documentation. Seven patients had their WIES downgraded. CONCLUSION: Comprehensive documentation of principal diagnosis/diagnoses, comorbidities and their complications is imperative to optimal DRG and WIES allocation. Regular meetings between clinical and coding staff improve the quality and timeliness of medical documentation, ensure adequate communication with general practitioners and lead to appropriate funding. PMID- 23347366 TI - Evaluation of haze formation after thin-flap microkeratome LASIK for myopia. PMID- 23347367 TI - Progression of keratoconus and efficacy of pediatric [corrected] corneal collagen cross-linking in children and adolescents. AB - PURPOSE: To study the progression rate of keratoconus and assess the clinical outcome of corneal collagen cross-linking (CXL) with riboflavin and ultraviolet A light in children and adolescent patients up to 3 years after treatment. METHODS: Fifty-nine eyes from 42 children and adolescents (aged 9 to 19 years) with confirmed keratoconus were included in this retrospective interventional cohort study. Refraction, slit-lamp examination, Placido-based corneal topography, and Scheimpflug imaging were performed bilaterally in all patients preoperatively and at 6 and 12 months postoperatively. Maximal keratometry readings (Kmax), corrected distance visual acuity (CDVA), corneal thickness, and the keratoconus index (KI) were analyzed. Follow-up was up to 36 months (mean follow-up: 26.3 months [range: 12 to 36 months]). RESULTS: Fifty-two of the 59 eyes enrolled in this study showed progression, corresponding to a progression rate of 88%. Forty six eyes were treated by CXL. Maximal keratometry, CDVA, and KI showed significant changes over the follow-up period. However, significant Kmax reduction observed up to 24 months after CXL lost significance at 36 months. CONCLUSIONS: Cross-linking seems to be safe in children and adolescents. Progression of keratoconus occurred in 88%. We propose that awaiting documentation of progression is not mandatory and CXL in children and adolescents should be performed as soon as the diagnosis has been made. However, the effect of arrest of disease progression might not be as long-lasting as in adults and longer follow-up is needed to verify this trend. PMID- 23347368 TI - Results of corneal collagen cross-linking in pediatric patients. AB - PURPOSE: To evaluate the safety and efficacy of corneal collagen cross-linking (CXL) in the treatment of keratoconus in pediatric patients. METHODS: Epithelium off CXL using the standard protocol was performed in 15 eyes from 15 patients (age range: 10 to 15 years) with moderate keratoconus in 1 eye and advanced disease in the fellow eye. Principal outcomes included uncorrected and corrected distance visual acuity (CDVA), refraction, and topography-derived outcomes of maximum and average keratometry (K). RESULTS: Mean uncorrected distance visual acuity improved significantly from 1.00 +/- 0.30 (20/200) to 0.72 +/- 0.29 (20/100) logMAR (P=.035) and mean CDVA from 0.56 +/- 0.21 (20/70) to 0.30 +/- 0.15 (20/40) logMAR (P=.003) at the end of 12 months. Mean change in apical K (1.01 +/- 2.40 diopters) was also significant (P=.004). No significant complications were noted. CONCLUSIONS: Corneal collagen CXL was found to be safe and effective in the first 12 months for keratoconus in children with similar initial efficacy as in adults in terms of improvement in visual and topographic outcomes. PMID- 23347369 TI - Transepithelial corneal cross-linking in pediatric patients: early results. AB - PURPOSE: To report 18-month follow-up after transepithelial cross-linking (CXL) in young patients. METHODS: Thirteen eyes with keratoconus were evaluated (mean patient age: 14.4 +/- 3.7 years [range: 8 to 18 years]). Corrected distance visual acuity (CDVA); spherical equivalent refraction; keratometry (K); coma, spherical aberration, and higher order aberrations (HOAs) for a 5.0-mm pupil; and thinnest point were measured preoperatively and 1, 3, 6, 9, 12, and 18 months postoperatively by Scheimplflug camera. Endothelial cell density and anterior segment optical coherence tomography were also evaluated. Paired Student t test was used to compare preoperative and 12- and 18-month postoperative data. P<.05 was considered significant. RESULTS: Eighteen months after treatment, CDVA improved significantly, whereas K readings and HOAs showed statistically significant worsening (P<.05). Spherical equivalent refraction, sphere and cylinder, coma, spherical aberration, thinnest point, and endothelial cell density did not show statistically significant changes (P>.05). The mean demarcation line depth was 105 MUm. No side effects were observed. CONCLUSIONS: Transepithelial CXL appears to be a safe treatment in children. Although improved CDVA was noted 18 months after treatment, this technique does not effectively halt keratoconus progression in children compared to standard CXL. PMID- 23347370 TI - Corneal confocal microscopy following conventional, transepithelial, and accelerated corneal collagen cross-linking procedures for keratoconus. AB - PURPOSE: To compare early corneal healing following conventional, transepithelial, and accelerated corneal collagen cross-linking (CXL) protocols. METHODS: Twenty-four patients with progressive keratoconus were divided into three groups to receive conventional, transepithelial, or accelerated CXL. In vivo corneal confocal microscopy was performed on each patient preoperatively and at 1, 3, and 6 months postoperatively. RESULTS: Closure of the epithelial wound was complete 3 days following conventional and accelerated CXL. The subbasal nerve plexus was essentially obliterated immediately following conventional and accelerated CXL, and virtually no nerve fibers had regenerated by 6 months. The anterior stroma showed significant changes 1 month following conventional CXL; these changes were similar but more pronounced following accelerated CXL. Observed stromal changes included complete obliteration of keratocytes, increased tissue reflectivity, a honeycomb-like appearance, and circular lacunae. Some recovery of keratocyte density was noted after 6 months. These changes were less pronounced in the mid-stroma, and there were no apparent changes to the posterior stroma or endothelium. The cornea appeared to be unaltered following transepithelial CXL. CONCLUSIONS: In vivo corneal confocal microscopy analysis of the postoperative impact of CXL on the cornea revealed clear differences among conventional, accelerated, and transepithelial CXL protocols. Accelerated CXL had a greater impact than conventional CXL on the anterior cornea, whereas transepithelial CXL did not appear to alter corneal morphology. PMID- 23347371 TI - In vivo imaging of riboflavin penetration during collagen cross-linking with hand held spectral domain optical coherence tomography. AB - PURPOSE: To compare the effect of complete versus grid-like epithelial removal on riboflavin penetration during collagen cross-linking (CXL) in vivo using hand held spectral domain optical coherence tomography (OCT, Bioptigen Inc). METHODS: In this prospective, observational, comparative case series, patients with progressive keratoconus undergoing CXL with riboflavin and ultraviolet A (UVA) light were enrolled. Twenty eyes (20 patients) undergoing CXL using 0.1% riboflavin and UVA light (365 nm) were imaged intraoperatively at 30 and 60 minutes after starting the procedure, using hand-held spectral domain OCT. In 10 eyes, the epithelium was removed completely in the central 7-mm zone (complete removal group) whereas in the remaining 10 eyes, the epithelium was removed in a grid pattern, leaving behind intact islands of epithelium (grid-like removal group). The depth of hyperreflective band (representing penetration of riboflavin) in the anterior corneal stroma was measured. RESULTS: In the complete removal group, the hyper-reflective band was homogenous, extending to a mean depth of 54.2+/-5.2 MUm and 72.4+/-7.1 MUm at 30 and 60 minutes, respectively (P<.001). In the grid-like removal group, the mean depth of the hyperreflective band was uneven, being significantly more in the "epithelium off" areas (56.90+/ 4.66 MUm and 74.2+/-6.7 MUm at 30 and 60 minutes, respectively) (P<.001) compared to the "epithelium on" areas (18.9+/-2.3 MUm and 24.7+/-2.3 MUm at 30 and 60 minutes, respectively) (P<.001). CONCLUSIONS: Epithelial removal appears to be an essential step prior to performing CXL, as an intact epithelium appears to block penetration of riboflavin in the anterior corneal stroma. PMID- 23347372 TI - Corneal transparency after cross-linking for keratoconus: 1-year follow-up. AB - PURPOSE: To evaluate the changes in corneal transparency and thickness measured objectively using Pentacam Scheimpflug (Oculus Optikgerate GmbH) corneal tomography (densitometry) after corneal cross-linking (CXL). METHODS: Twenty-two eyes from 15 patients with keratoconus underwent CXL. Corneal thickness and curvature as well as lens and corneal densitometry were measured at baseline and 1, 3, 6, and 12 months after CXL with Pentacam. RESULTS: Immediately after CXL, central corneal thickness significantly decreased (-40 MUm) and corneal densitometry increased significantly. At 6-month follow-up, densitometry values were reduced and seemed to stabilize at a higher value than baseline. No statistically significant differences were noted (mean difference at 12 months: +30%). Changes in corneal densitometry were detected with the Pentacam even when clinical haze did not increase beyond grade 1 during follow-up. CONCLUSIONS: Corneal CXL is associated with a transient reduction in central corneal thickness, which recovered to baseline after 12 months. During the same time period, corneal densitometry experienced a transient increase that recovered to baseline values after 3 months. Changes in compactness of the corneal tissue after CXL may have an impact in corneal power not due to curvature changes, but to refractive index changes as a result of hydration changes. Pentacam is a useful objective method to monitor corneal transparency after CXL. PMID- 23347373 TI - Outcomes of a new microwave procedure followed by accelerated cross-linking for the treatment of keratoconus: a pilot study. AB - PURPOSE: To analyze the initial data obtained in a group of patients treated with microwave keratoplasty followed by accelerated corneal collagen cross-linking (CXL) for the correction of keratoconus. METHODS: Prospective, nonrandomized clinical study including six eyes from four patients treated with microwave thermal keratoplasty followed by accelerated CXL. Refractive, topographic, anterior aberrometry, and corneal biomechanics outcomes were analyzed during 6 month follow-up. RESULTS: Immediately after the procedure, a significant reduction of >7.00 diopters (D) was observed in mean keratometry (P=.02). Uncorrected distance visual acuity increased from 0.92+/-0.52 logMAR (Snellen 20/160) preoperatively to 0.47+/-0.19 logMAR (Snellen 20/60) postoperatively (P=.05). No statistically significant change was found in corrected distance visual acuity (P=.28). Corneal higher order aberration decreased from 1.89+/-0.90 to 1.51+/-0.65 MUm and corneal primary coma aberration decreased from 1.45+/-0.68 MUm preoperatively to 0.84+/-0.23 MUm postoperatively (P>.10). No statistically significant changes were found in the biomechanics variables (P=.40). A significant regression of the effect was assessed in keratometry at the end of follow-up (P=.03). CONCLUSIONS: The Keraflex procedure may have the ability to improve refractive status in patients who suffer from keratoconus, as well as induce corneal remodeling to a more anterior regular surface. However, the current treatment regimen is not sufficient to maintain the flattening effect achieved and significant regression occurs. PMID- 23347374 TI - Corneal collagen cross-linking for progressive keratoconus in pediatric patients: a feasibility study. AB - PURPOSE: To evaluate the outcomes of corneal collagen cross-linking (CXL) in pediatric patients with bilateral progressive keratoconus. METHODS: This retrospective case series included four pediatric patients (eight eyes) with progressive keratoconus aged 14.0+/-2.2 years (range: 11 to 16 years). All eyes underwent CXL in accordance with the standard Dresden protocol. Pre- and 1-, 12-, 24-, and 36-month postoperative examinations included corneal thickness at the thinnest point (using a topographic system), corneal topographic evaluation (flat and steep meridian keratometry [K1 and K2]), refraction, and visual acuity. RESULTS: All patients completed 36-month follow-up. No intra- or postoperative complications were observed. Stabilization of K1 and K2 was demonstrated in all cases throughout follow-up (from the first postoperative interval), while visual acuity improved in six eyes and remained stable in the remaining two eyes. Manifest refraction remained stable, and corneal thickness decreased at the first postoperative month with gradual return to preoperative values during follow-up. CONCLUSIONS: Preliminary data of four pediatric patients with moderate keratoconus show feasibility of treatment by CXL in these select patients with no intra- or postoperative complications over 3-year follow-up. PMID- 23347375 TI - Corneal collagen cross-linking for nonectatic disorders: a systematic review. AB - PURPOSE: To provide a background regarding the biochemical rationale for corneal collagen cross-linking (CXL) and outline its current use, critically evaluate the current literature for the use of CXL in nonectatic disorders, highlight limitations and areas for further research, and address additional novel applications of CXL. METHODS: A literature search was performed using the EMBASE and MEDLINE database from 1970 to November 2011. Keywords included "corneal collagen cross linking," "crosslinking," "cross-linking," "ultraviolet," "riboflavin," "corneal edema," and "keratitis" in various combinations. A search through the references of retrieved articles was also performed. RESULTS: Cross linking for corneal edema showed a temporary improvement in objective measures of central corneal thickness, corrected distance visual acuity, and corneal clarity along with subjective measures such as pain and irritation. Cross-linking was also tolerated as an adjunctive therapy for infectious keratitis without complications. In all studies, the progression of corneal melting was halted after treatment, avoiding the need for emergency keratoplasty. CONCLUSIONS: Cross linking with riboflavin and ultraviolet A light is a promising, minimally invasive treatment for corneal ectasia. A growing number of studies suggest additional application in corneal edema and infectious keratitis may be beneficial. However, further studies are needed to address long-term outcomes and safety concerns. PMID- 23347376 TI - A RING-type E3 ligase controls anther dehiscence by activating the jasmonate biosynthetic pathway gene DEFECTIVE IN ANTHER DEHISCENCE1 in Arabidopsis. AB - Suppression of expression of DAF [DEFECTIVE IN ANTHER DEHISCENCE1 (DAD1) Activating Factor], a gene that encodes a putative RING-finger E3 ligase protein, causes non-dehiscence of the anthers, alters pollen development and causes sterility in 35S:DAF RNAi/antisense Arabidopsis plants. This mutant phenotype correlates with the suppression of DAF but not with expression of the two most closely related genes, DAFL1/2. The expression of DAD1 was significantly reduced in 35S:DAF RNAi/antisense plants, and complementation with 35S:DAF did not rescue the dad1 mutant, indicating that DAF acts upstream of DAD1 in jasmonic acid biosynthesis. This assumption is supported by the finding that 35S:DAF RNAi/antisense plants showed a similar cellular basis for anther dehiscence to that found in dad1 mutants, and that external application of jasmonic acid rescued the anther non-dehiscence and pollen defects in 35S:DAF antisense flowers. We further demonstrate that DAF is an E3 ubiquitin ligase and that its activity is abolished by C132S and H137Y mutations in its RING motif. Furthermore, ectopic expression of the dominant-negative C132S or H137Y mutations causes similar indehiscence of anthers and reduction in DAD1 expression in transgenic Arabidopsis. This result not only confirms that DAF controls anther dehiscence by positively regulating the expression of DAD1 in the jasmonic acid biosynthesis pathway, but also supports the notion that DAF functions as an E3 ubiquitin ligase, and that the conserved RING-finger region is required for its activity. PMID- 23347377 TI - A preliminary report on the usage of an intracorporal antibiotic cast with synthetic high purity CaSO4 for the treatment of infected penile implant. AB - INTRODUCTION: Currently, the surgical treatment of infected penile prostheses is complete removal and either immediate salvage procedure, which carries a significant infection risk, or delayed implantation. With delayed implantation the risk of infection is lower, but the patient loses penile length and width due to corporal fibrosis. AIM: We present our experience with the use of a novel temporary synthetic high purity calcium sulfate (SHPCaSO4) component that acts as a "spacer" at the time of removal of an infected prosthesis while providing constant delivery of local antibiotic elution to the infected area. MAIN OUTCOME MEASURES: Demonstrate that the use of a novel material, SHPCaSO4, can be an innovative way to bridge the gap between removal of an infected penile implant and delayed reimplantation. METHODS: Two patients (Patient A and B) presented with pain and erythema and were found to have infected malleable penile prosthesis. Both underwent removal of all infected components, and sent for tissue culture. The SHPCaSO4 was mixed with vancomycin and tobramycin, allowed to set up for 5 minutes, and then injected into the corporal space followed by closure with 2-0 Vicryl sutures. The injected SHPCaSO4 was palpable in the penile shaft both proximally and distally, as an "intracorporal casts." RESULTS: Patients denied pain postoperatively. Delayed implantation occurred at 6 weeks for patient A. This went uneventful and a new three-piece inflatable implant was inserted. Patient B underwent salvage placement of right malleable implant at 15 weeks, and here significant corporal fibrosis was encountered. Patients have had no infection since their delayed implantation (mean follow-up 4 months). CONCLUSIONS: Data in reference to SHPCaSO4 shows that this product dissolves in approximately 4-6 weeks. This may account for the difference in the ease of delayed implantation between the two patients. Further investigation is warranted. PMID- 23347378 TI - Introduction to optical methods for characterizing liquid crystals at interfaces. AB - This Instructional Review describes methods and underlying principles that can be used to characterize both the orientations assumed spontaneously by liquid crystals (LCs) at interfaces and the strength with which the LCs are held in those orientations (so-called anchoring energies). The application of these methods to several different classes of LC interfaces is described, including solid and aqueous interfaces as well as planar and nonplanar interfaces (such as those that define a LC-in-water emulsion droplet). These methods, which enable fundamental studies of the ordering of LCs at polymeric, chemically functionalized, and biomolecular interfaces, are described in this Instructional Review on a level that can be easily understood by a nonexpert reader such as an undergraduate or graduate student. We focus on optical methods because they are based on instrumentation that is found widely in research and teaching laboratories. PMID- 23347379 TI - Contrast sensitivity in the 'good eye' of adult patients with severe impairment in the other eye. AB - PURPOSE: It is widely accepted that monocular deprivation results in improved visual performance in the non-pathological eye. The current study investigates the effect of deprivation due to severe impairment in one eye during late childhood or adulthood, on the spatial performance of the fellow 'good' eye. METHODS: Twenty patients (age: 29 +/- 9 years) with severe visual impairment in one eye (visual acuity equal or worse than count fingers at 1 m), for a period longer than 2 years, participated in the study. Only patients with an age less than 50 years and monocular deprivation onset greater than 9 years were included. On the basis of the time of deprivation the patients were categorised into two subgroups: (i) long-past deprivation (N = 8, age 28 +/- 8 years, 9-20 years of deprivation) and recent deprivation (N = 12, age 30 +/- 11 years, 2-4 years of deprivation). Eighteen more participants (age: 28 +/- 5 years) with normal binocular vision served as the control group. Best-corrected contrast sensitivity was evaluated using reversing (2 Hz) vertical sinusoidal gratings. Seven spatial frequencies (1, 2, 4, 8, 12, 16 and 24 c/deg) were tested. Performance of the control group was tested both monocularly (dominant eye) and binocularly. RESULTS: In normal subjects, binocular viewing improved contrast sensitivity on average by 4.2 dB (corresponding to a 70% improvement in contrast threshold) compared to monocular recordings. Average contrast sensitivity in subjects with impaired vision in one eye was found to be higher by 5.0 dB (corresponding to an 83% improvement in contrast threshold) compared with the dominant eye of the control group. The increase in sensitivity was independent of spatial frequency. No differences were observed between the two subgroups with recent and long-past deprivation. CONCLUSIONS: Notable improvement in contrast sensitivity was found in the non-pathological eye of patients with severe impairment in the other eye at an age after the "critical" period of visual development. These findings are consistent with growing evidence supporting functional changes as a result of altered experience or injury in the adult vision system. PMID- 23347380 TI - Effects of soy isoflavones and mechanical vibration on rat bone tissue. AB - OBJECTIVE: To investigate the effects of soy isoflavones (Iso) and mechanical vibration treatments alone or combined on bone extracellular matrix constituents of ovariectomized rats. METHODS: Forty female Wistar rats at the age of 6 months were ovariectomized (Ovx) and ten were sham-operated (sham). After 3 months, the animals were divided into five groups: GI (sham); GII (Ovx); GIII, ovariectomized and orally treated with isoflavones (200 mg/kg) for 90 consecutive days; GIV, ovariectomized and submitted to vibration for 90 days (5 days/week); GV, ovariectomized and treated with isoflavones plus vibration. After treatments, the rats were euthanized, and their femurs were removed for histological routine and biochemical study. Histological sections were stained with hematoxylin-eosin, picrosirius red and alcian blue. Shaft of femurs were submitted to biochemical assay and tibias were subjected to biophysical and biomechanical tests. RESULTS: Treatments did not have significant effects on the trabecular bone volume, but the combined treatments showed trophic effects on the cortical bone width and area. Bone density and the content of organic material of the tibias were higher in the GIV and GV groups. The GV group showed the highest presence of mature collagen fibers and content of total glycosaminoglycans, while the highest contents of chondroitin sulfate and other sulfated glycosaminoglycans were seen in the GIV group. CONCLUSION: The mechanical vibration treatment is more efficient than soy isoflavones in improving bone quality by increasing the bone density, the content of sulfated glycosaminoglycans and the presence of mature collagen fibers. In addition, the combined interventions have partial trophic and synergistic effects that are bone site-specific in ovariectomized rats. PMID- 23347381 TI - Characteristics of Porphyromonas gingivalis lipopolysaccharide in co-culture with Fusobacterium nucleatum. AB - Porphyromonas gingivalis is associated with chronic periodontitis and forms multi species biofilms. They can communicate within species as well as with other species found in the subgingiva, which may induce changes in the growth ratio and virulence of periodontopathogens. The lipopolysaccharide (LPS) of P. gingivalis shows different virulence by growth condition. The purpose of this study was to investigate the characteristics of P. gingivalis LPS when co-cultured with Fusobacterium nucleatum. After culture of P. gingivalis in the presence or absence of F. nucleatum, P. gingivalis LPS was extracted. THP-1 cells were treated with the LPS and induction of cytokine expression was investigated using real-time reverse transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). For the analysis of P. gingivalis LPS, LPS biosynthesis-related genes such as lpxA and lpxD were evaluated with real-time RT PCR. Finally, molecular mass of lipid A was measured by mass spectrometry after hydrolysis of the LPS. Co-cultured P. gingivalis LPS exhibited higher induction of expression of interleukin 1beta, 6, and 8 than single-cultured P. gingivalis LPS. These symptoms may be caused by an increase in m/z 1689 lipid A through the upregulation of lpxA and lpxD expression by communication between P. gingivalis and F. nucleatum. PMID- 23347382 TI - Preparation of sustained-release dosage form of Venlafaxine HCl using liquisolid technique. AB - CONTEXT: The aim of this study is to control the dissolution rate of Venlafaxine HCl. OBJECTIVE: To prepare sustained release tablets of Venlafaxine HCl. MATERIAL AND METHODS: Different liquisolid formulations, liquid vehicles, drug concentration in the liquid medication and different ratios of carrier to coating material (R) were prepared. The prepared powders were characterized for possible interactions between drug and excipients using differential scanning calorimetry, X-ray, Fourier transform infrared analysis and scanning electron microscopy. Powder flowability was also evaluated, then they are compressed at different compression forces, and the compressed tablets were evaluated for their mechanical properties and dissolution profile. RESULTS: Release results show that sustained release behavior can be obtained from liquisolid formulation containing Tween 80 as liquid vehicle. DISCUSSION: Many factors affect the retardation effect of Venlafaxine HCl such as the type of liquid vehicle, drug concentration in the liquid medication and R. The mechanism of the in vitro release profiles was found to be mainly controlled by diffusion and polymer relaxation. CONCLUSION: Sustained release formulation of Venlafaxine HCl was attained using the liquisolid technique. PMID- 23347383 TI - The effects of a stimulating intron on the expression of heterologous genes in Arabidopsis thaliana. AB - Introns are often added to transgenes to increase expression, although the mechanism through which introns stimulate gene expression in plants and other eukaryotes remains mysterious. While introns vary in their effect on expression, it is unknown whether different genes respond similarly to the same stimulatory intron. Furthermore, the degree to which gene regulation is preserved when expression is increased by an intron has not been thoroughly investigated. To test the effects of the same intron on the expression of a range of genes, GUS translational fusions were constructed using the promoters of eight Arabidopsis genes whose expression was reported to be constitutive (GAE1, CNGC2 and ROP10), tissue specific (ADL1A, YAB3 and AtAMT2) or regulated by light (ULI3 and MSBP1). For each gene, a fusion containing the first intron from the UBQ10 gene was compared to fusions containing the gene's endogenous first intron (if the gene has one) or no intron. In every case, the UBQ10 intron increased expression relative to the intronless control, although the magnitude of the change and the level of expression varied. The UBQ10 intron also changed the expression patterns of the CNGC2 and YAB3 fusions to include strong activity in roots, indicating that tissue specificity was disrupted by this intron. In contrast, the regulation of the ULI3 and MSBP1 genes by light was preserved when their expression was stimulated by the intron. These findings have important implications for biotechnology applications in which a high level of transgene expression in only certain tissues is desired. PMID- 23347385 TI - Differences in latency to first pharmacological treatment (duration of untreated illness) in anxiety disorders: a study on patients with panic disorder, generalized anxiety disorder and obsessive-compulsive disorder. AB - AIM: The latency to first pharmacological treatment (duration of untreated illness or 'DUI') is supposed to play a major role in terms of outcome in psychotic conditions. Interest in the field of affective disorders and, in particular, of duration of untreated anxiety, has been recently registered as well. However, a preliminary epidemiologic investigation of the phenomenon is necessary. The present study was aimed to investigate and compare age at onset, age at first pharmacological treatment and DUI in a sample of patients affected by different anxiety disorders. DUI was defined as the interval between the onset of the specific anxiety disorder and the administration of the first adequate pharmacological treatment in compliant subjects. METHODS: Study sample included 350 patients, of both sexes, with a DSM-IV-TR diagnosis of panic disorder (n = 138), generalized anxiety disorder (n = 127) and obsessive-compulsive disorder (n = 85). RESULTS: Panic disorder was associated with the shortest DUI (39.5 months), whereas obsessive-compulsive disorder was associated with the longest latency to treatment (94.5 months) (F = 13.333; P < 0.0001). Patients with generalized anxiety disorder showed a mean DUI of 81.6 months. CONCLUSION: Present results indicate that patients with different anxiety disorders may wait for years (from 3 up to 8) before receiving a first adequate pharmacological treatment. Differences in terms of age at onset, age at the first pharmacological treatment and, ultimately, in DUI in specific anxiety disorders may depend on multiple clinical and environmental factors. Latency to non-pharmacological interventions (e.g. psychoeducation and different forms of psychotherapy) needs to be addressed and correlated with DUI in future studies. PMID- 23347384 TI - Temperature sculpting in yoctoliter volumes. AB - The ability to perturb large ensembles of molecules from equilibrium led to major advances in understanding reaction mechanisms in chemistry and biology. Here, we demonstrate the ability to control, measure, and make use of rapid temperature changes in fluid volumes that are commensurate with the size of single molecules. The method is based on attaching gold nanoparticles to a single nanometer-scale pore formed by a protein ion channel. Visible laser light incident on the nanoparticles causes a rapid and large increase of the adjacent solution temperature, which is estimated from the change in the nanopore ionic conductance. The temperature shift also affects the ability of individual molecules to enter into and interact with the nanopore. This technique could significantly improve sensor systems and force measurements based on single nanopores, thereby enabling a method for single molecule thermodynamics and kinetics. PMID- 23347387 TI - Recent topics on alpha-fetoprotein. AB - Zinc-fingers and homeoboxes 2 (ZHX2) and zinc-finger and BTB domain containing 20 (ZBTB20) repress the postnatal expression of alpha-fetoprotein (AFP) by interacting with the AFP gene promoter regions. ZHX2 inhibits the expression of AFP and cyclins A and E. ZBTB20 is negatively regulated by CUX1, which promotes cell-cycle progression, suggesting that AFP reactivation is closely linked to hepatocyte proliferation. A slight elevation in the serum AFP level often occurs in patients with chronic hepatitis C in the absence of hepatocellular carcinoma (HCC) and is an independent risk factor for HCC development to complement the fibrosis stage. In addition, the sustained elevation of AFP after interferon therapy is a risk factor of HCC development. AFP levels are clinically useful in predicting the outcomes of liver transplantation and sorafenib therapy for HCC patients. A low preoperative AFP level is a predictor of long-term survival and is associated with a low recurrence rate of HCC after liver transplantation. AFP response (>=20% decrease in AFP during 6-8 weeks of treatment) rather than radiological outcomes is a significant prognostic factor for survival in sorafenib-treated HCC patients. Highly sensitive Lens culinaris agglutinin reactive AFP (AFP-L3) is 5-10 times more sensitive than conventional AFP-L3, and useful for early detection of HCC in patients with total AFP below 20 ng/mL. PMID- 23347386 TI - Curcumin alleviates immune-complex-mediated glomerulonephritis in factor-H deficient mice. AB - Complement factor H (Cfh) is a key regulator of the complement cascade and protects C57BL/6 mice from immune complex-mediated complement-dependent glomerulonephritis. In chronic serum sickness (CSS) there are increased deposits of immune complexes in the glomeruli with inflammation and a scarring phenotype. As cucurmin is an effective anti-inflammatory agent and reduces complement activation, we hypothesized that it should alleviate renal disease in this setting. To determine the effectiveness of curcumin, an apoferritin-induced CSS model in Cfh-deficient (Cfh(-/-)) mice was used. Curcumin treatment (30 mg/kg) given every day in parallel with apoferritin reduced glomerulonephritis and enhanced kidney function (blood urea nitrogen, 45.4 +/- 7.5 versus 35.6 +/- 5.1; albuminuria, 50.1 +/- 7.1 versus 15.7 +/- 7.1; glomerulonephritis, 2.62 + 0.25 versus 2 + 0.3, P < 0.05). In line with reduced IgG deposits in mice with CSS given curcumin, C9 deposits were reduced indicating reduced complement activation. Mice treated with curcumin had a significant reduction in the number of splenic CD19(+) B cells and the ratio of CD19 : CD3 cells (P < 0.05) with no change in the T-cell population. Myeloperoxidase assay showed reduced macrophages in the kidney. However, a significant reduction in the M2 subset of splenic macrophages by apoferritin was prevented by curcumin, suggesting a protective function. Curcumin treatment reduced mRNA expression of inflammatory proteins monocyte chemoattractant protein-1 and transforming growth factor-beta and matrix proteins, fibronectin, laminin and collagen. Our results clearly illustrate that curcumin reduces glomerulosclerosis, improves kidney function and could serve as a therapeutic agent during serum sickness. PMID- 23347388 TI - Addressing physical inactivity in Omani adults: perceptions of public health managers. AB - OBJECTIVE: To explore barriers and solutions to addressing physical inactivity and prolonged sitting in the adult population of Oman. DESIGN: Qualitative study involving semi-structured interviews that took place from October 2011 to January 2012. Participants were recruited through purposive sampling. Data collection and analysis was an iterative process; later interviews explored emerging themes. Interviews were audio-recorded and transcribed and continued until data saturation; this occurred by the tenth interviewee. Thematic content analysis was carried out, guided by an ecological model of health behaviour. SETTING: Muscat, Oman. SUBJECTS: Ten mid-level public health managers. RESULTS: Barriers for physical inactivity were grouped around four themes: (i) intrapersonal (lack of motivation, awareness and time); (ii) social (norms restricting women's participation in outdoor activity, low value of physical activity); (iii) environment (lack of places to be active, weather); and (iv) policy (ineffective health communication, limited resources). Solutions focused on culturally sensitive interventions at the environment (building sidewalks and exercise facilities) and policy levels (strengthening existing interventions and coordinating actions with relevant sectors). Participants' responses regarding sitting time were similar to, but much more limited than those related to physical inactivity, except for community participation and voluntarism, which were given greater emphasis as possible solutions to reduce sitting time. CONCLUSIONS: Given the increasing prevalence of chronic disease in Oman and the Arabian Gulf, urgent action is required to implement gender-relevant public health policies and programmes to address physical inactivity, a key modifiable risk factor. Additionally, research on the determinants of physical inactivity and prolonged sitting time is required to guide policy makers. PMID- 23347389 TI - Gender identity disorder and eating disorders: similarities and differences in terms of body uneasiness. AB - INTRODUCTION: Subjects with gender identity disorder (GID) have been reported to be highly dissatisfied with their body, and it has been suggested that the body is their primary source of suffering. AIMS.: To evaluate quality and intensity of body uneasiness in GID subjects, comparing them with a sample of eating disorder patients and a control group. To detect similarities and differences between subgroups of GID subjects, on the basis of genotypic sex and transitional stage. METHODS: Fifty male-to-female (MtF) GID (25 without and 25 with genital reassignment surgery performed), 50 female-to-male (FtM) GID (28 without and 22 with genital reassignment surgery performed), 88 eating disorder subjects (26 anorexia nervosa, 26 bulimia nervosa, and 36 binge eating disorder), and 107 healthy subjects were evaluated. MAIN OUTCOME MEASURES: Subjects were studied by means of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, the Symptom Checklist (SCL-90), and the Body Uneasiness Test (BUT). RESULTS: GID and controls reported lower psychiatric comorbidity and lower SCL-90 General Severity Index (GSI) scores than eating disorder subjects. GID MtF without genital reassignment surgery showed the highest BUT values, whereas GID FtM without genital reassignment surgery and eating disorder subjects showed higher values compared with both GID MtF and FtM who underwent genital reassignment surgery and controls. Considering BUT subscales, a different pattern of body uneasiness was observed in GID and eating disorder subjects. GID MtF and FtM without genital reassignment surgery showed the highest BUT GSI/SCL-90 GSI ratio compared with all the eating disorder groups. CONCLUSIONS: GID and eating disorders are characterized by a severe body uneasiness, which represents the core of distress in both conditions. Different dimensions of body uneasiness seem to be involved in GID subsamples, depending on reassignment stage and genotypic sex. In eating disorder subjects body uneasiness is primarily linked to general psychopathology, whereas in GID such a relationship is lacking. PMID- 23347390 TI - Campylobacter infection in poultry-processing workers, Virginia, USA, 2008-2011. AB - During a health hazard evaluation, we investigated 29 cases of laboratory diagnosed Campylobacter infection among workers at a poultry-processing plant. Most infected employees worked at the plant <1 month, worked as live hangers, and lived at a state-operated center. To lessen the infection risk, we recommended improvements to engineering and administrative controls at the plant. PMID- 23347391 TI - Post-prandial carbohydrate ingestion during 1-h of moderate-intensity, intermittent cycling does not improve mood, perceived exertion, or subsequent power output in recreationally-active exercisers. AB - BACKGROUND: This study compared the effects of ingesting water (W), a flavored carbohydrate-electrolyte (CE) or a flavored non-caloric electrolyte (NCE) beverage on mood, ratings of perceived exertion (RPE), and sprint power during cycling in recreational exercisers. METHODS: Men (n = 23) and women (n = 13) consumed a 24-h standardized diet and reported 2-4 h post-prandial for all test sessions. After a familiarization session, participants completed 50 min of stationary cycling in a warm environment (wet bulb globe temperature = 25.0 degrees C) at ~ 60-65% of heart rate reserve (146 +/- 4 bpm) interspersed with 5 rest periods of 2 min each. During exercise, participants consumed W, CE, or NCE, served in a counterbalanced cross-over design. Beverage volume was served in 3 aliquots equaling each individual's sweat losses (mean 847 +/- 368 mL) during the familiarization session. Profiles of Mood States questionnaires (POMS) were administered and blood glucose levels were determined pre- and post- sub-maximal cycling. Following sub-maximal exercise, participants completed 3 30-s Wingate anaerobic tests (WAnT) with 2.5 min rest between tests to assess performance. RESULTS: Blood glucose was higher (p < 0.05) after 50 min of submaximal cycling just prior to the WAnT for CE (6.1 +/- 1.7 mmol/L) compared to W (4.9 +/- 1.5 mmol/L) and NCE (4.6 +/- 1.2 mmol/L). Nonetheless, there were no differences among treatments in peak (642 +/- 153, 635 +/- 143, 650 +/- 141 watts for W, NCE, and CE, respectively; p = 0.44) or mean (455 +/- 100, 458 +/- 95, 454 +/- 95 watts for W, NCE, and CE, respectively; p = 0.62) power for the first WAnT or mean (414 +/- 92, 425 +/- 85, 423 +/- 82 watts, respectively; p = 0.13) power output averaged across all 3 WAnT. Likewise, RPE during submaximal exercise, session RPE, and fatigue and vigor assessed by POMS did not differ among beverage treatments (p > 0.05). CONCLUSIONS: Carbohydrate ingestion consumed by recreational exercisers during a 1-h, moderate-intensity aerobic workout did not alter mood or perceived exertion, nor did it affect subsequent anaerobic performance under the conditions of this study. Drinking caloric sport beverages does not benefit recreational exercisers in a non-fasted state. PMID- 23347392 TI - Power of the policy: how the announcement of high-stakes clinical examination altered OSCE implementation at institutional level. AB - BACKGROUND: The Objective Structured Clinical Examination (OSCE) has been widely applied as a high-stakes examination for assessing physicians' clinical competency. In 1992, OSCE was first introduced in Taiwan, and the authorities announced that passing the OSCE would be a prerequisite for step-2 medical licensure examination in 2013. This study aimed to investigate the impacts of the announced national OSCE policy on implementation of OSCE at the institutional level. Further, the readiness and the recognition of barriers toward a high stakes examination were explored. METHODS: In 2007 and 2010, the year before and after the announcement of high-stakes OSCE policy in 2008, respectively, questionnaires on the status of OSCE implementation were distributed to all hospitals with active OSCE programs in Taiwan. Information on OSCE facilities, equipment, station length, number of administrations per year, and the recognition of barriers to the success of implementing an OSCE were collected. The missing data were completed by telephone interviews. The OSCE format, administration, and facilities before and after the announcement of the nationwide OSCE policy were compared. RESULTS: The data were collected from 17 hospitals in 2007 and 21 in 2010. Comparing the OSCE formats between 2007 and 2010, the number of stations increased and the station length decreased. The designated space and the equipment for OSCE were also found to have been improved. As for the awareness of OSCE implementation barriers, the hospital representatives concerned mostly about the availability and quality of standardized patients in 2007, as well as space and facilities in 2010. CONCLUSIONS: The results of this study underscored an overall increase in the number of OSCE hospitals and changes in facilities and formats. While recruitment and training of standardized patients were the major concerns before the official disclosure of the policy, space and facilities became the focus of attention after the announcement. The study results highlighted the influence of government policy on different aspects of OSCE implementation in Taiwanese training institutes that showed high level of support as reflected in the improved hardware and the change in OSCE format to serve the summative purpose. PMID- 23347393 TI - Rapid screening for Chlamydia trachomatis infection by detecting alpha mannosidase activity in urogenital tract specimens. AB - BACKGROUND: Chlamydia trachomatis may cause multiple different urogenital tract disorders, but current non-culture assays for rapid screening of C. trachomatis typically use immunochromatography-based methods. We established another new rapid non-culture method for detection of C. trachomatis based on the measurement of alpha-mannosidase enzymatic activity in urogenital tract specimens. METHOD: To evaluate the performance of this method, alpha-mannosidase activities of C. trachomatis serotype D strain , and 29 standard strains related to clinical urogenital pathogens were investigated. Furthermore, 553 urogenital tract specimens were used for clinical assays via cell culture method and ligase chain reaction method (LCR), adopting an expanded gold standard. RESULTS: Only C. trachomatis was positive for alpha-mannosidase activity among different types of microbes tested in the research. When prostate fluid specimens, which have some interfering activity, were excluded, the sensitivity and specificity of the enzymatic method were 91.8% (78/85) and 98.3% (409/416), respectively. There were no significant differences (P > 0.05). CONCLUSIONS: These results showed that alpha-mannosidase activity could be utilised as a screening marker of C. trachomatis infection. PMID- 23347394 TI - Protective effect of transparent film dressing on proton therapy induced skin reactions. AB - OBJECTIVE: Proton therapy can result in clinically significant radiation dermatitis. In some clinical scenarios, such as lung or breast cancer, the risk of severe radiation dermatitis may limit beam arrangement and prescription doses. Patients undergoing proton therapy for prostate cancer commonly develop mild radiation dermatitis. Herein, we report the outcomes of two prostate cancer patients whose radiation dermatitis appears to have been substantially diminished by transparent film dressings (Beekley stickers). METHODS: This is a descriptive report of the skin toxicity observed in two patients undergoing proton therapy for prostate cancer at a single institution in 2011. A phantom dosimetric study was performed to evaluate the impact of a transparent film dressing on a beam's spread out Bragg peak (SOBP). RESULTS: Two patients with low risk prostate cancer were treated with proton therapy to a total dose of 79.2Gy (RBE) in 1.8 Gy (RBE) fractions using two opposed lateral beams daily. Both patients had small circular (2.5 cm diameter) transparent adhesive markers placed on their skin to assist with daily alignment. Patient 1 had markers in place bilaterally for the entirety of treatment. Patient 2 had a marker in place for three weeks on one side and six weeks on the other. Over the course of therapy, both men developed typical Grade 1 radiation dermatitis (asymptomatic erythema) on their hips; however, in both patients, the erythema was substantially decreased beneath the markers. Patient 2 demonstrated less attenuation and thus greater erythema in the skin covered for three weeks compared to the skin covered for six weeks. The difference in skin changes between the covered and uncovered skin persisted for at least 1 month. A phantom study of double scattered beam SOBP with and without the marker in the beam path showed no gross dosimetric effect. CONCLUSIONS: Transparent adhesive markers appear to have attenuated radiation dermatitis in these two patients without affecting the SOBP. One patient may have exhibited a dose-response effect. The reproducibility and underlying mechanisms are unclear. However, the potential to leverage this effect to improve proton-related radiation dermatitis in other clinical scenarios is intriguing. Exploratory animal studies are underway. PMID- 23347396 TI - Adsorption and dilational rheology of mixed beta-casein/DoTAB layers formed by sequential and simultaneous adsorption at the water/hexane interface. AB - The interfacial behavior of beta-casein (betaCS) has been investigated in presence of the cationic surfactant dodecyl trimethyl ammonium bromide (DoTAB) at the water/hexane interface and compared to that obtained for the water/air interface. The used experimental technique is a drop profile analysis tensiometer specially equipped with a coaxial double capillary, which allows investigation of sequential adsorption of individual components besides the traditional simultaneous adsorption of two species. This method also provides the dilational rheological measurements based on low frequency harmonic drop oscillations. The tensiometric results show that the equilibrium states of the mixed betaCS/DoTAB layers built up on the two different routes do not differ significantly, that is, the general compositions of the mixed layers are similar. However, the results of dilational rheology for the two adsorption strategies are remarkably different indicating different dynamic characteristics of the adsorbed layers. These findings suggest that the respective mixed layers are more proteinlike if they are formed via sequential adsorption and more surfactant-like after simultaneous adsorption. In contrast to the W/A interface, at the W/H interface proteins remain at the interface once adsorbed and cannot be displaced just by competitive adsorption of surfactants. PMID- 23347395 TI - Inflammation-associated enterotypes, host genotype, cage and inter-individual effects drive gut microbiota variation in common laboratory mice. AB - BACKGROUND: Murine models are a crucial component of gut microbiome research. Unfortunately, a multitude of genetic backgrounds and experimental setups, together with inter-individual variation, complicates cross-study comparisons and a global understanding of the mouse microbiota landscape. Here, we investigate the variability of the healthy mouse microbiota of five common lab mouse strains using 16S rDNA pyrosequencing. RESULTS: We find initial evidence for richness driven, strain-independent murine enterotypes that show a striking resemblance to those in human, and which associate with calprotectin levels, a marker for intestinal inflammation. After enterotype stratification, we find that genetic, caging and inter-individual variation contribute on average 19%, 31.7% and 45.5%, respectively, to the variance in the murine gut microbiota composition. Genetic distance correlates positively to microbiota distance, so that genetically similar strains have more similar microbiota than genetically distant ones. Specific mouse strains are enriched for specific operational taxonomic units and taxonomic groups, while the 'cage effect' can occur across mouse strain boundaries and is mainly driven by Helicobacter infections. CONCLUSIONS: The detection of enterotypes suggests a common ecological cause, possibly low-grade inflammation that might drive differences among gut microbiota composition in mammals. Furthermore, the observed environmental and genetic effects have important consequences for experimental design in mouse microbiome research. PMID- 23347397 TI - Time course of the effects of orthokeratology on peripheral refraction and corneal topography. AB - PURPOSE: To describe the time course of changes in both peripheral refraction and corneal topography in myopic adults wearing myopic orthokeratology (OK) lenses. METHODS: Nineteen adult myopes were fitted with OK lenses in both eyes for overnight wear. Central and peripheral refraction and corneal topography were measured along the horizontal meridian at baseline and after 1, 4, 7 and 14 nights of lens wear. RESULTS: At baseline, refraction was myopic at all positions along the horizontal meridian. Two weeks of OK lens wear caused a significant change in refraction where the general trend was a hyperopic shift in spherical equivalent (M) except at 35 degrees in the nasal visual field where there was instead a myopic shift in M. The most significant change in M occurred between baseline and after 1 night of OK lens wear and the effect became less dramatic across subsequent days of OK treatment. Similarly, OK caused significant change in corneal refractive power at all positions along the horizontal corneal chord. There was a reduction in corneal power or flattening of the cornea at all positions except at 2.4 mm and 2.8 mm on the nasal cornea where there was an increase in corneal refractive power or steepening of the cornea. This change was most apparent after 1 night of OK lens wear and, similar to changes in peripheral refraction, changes in corneal refractive power on subsequent days of OK treatment became less marked. CONCLUSIONS: Orthokeratology caused significant changes in both peripheral refraction and corneal topography. The greatest change in refraction and corneal refractive power across the horizontal corneal meridian occurred during the first night of OK lens wear. Subsequent changes in both peripheral refraction and corneal topography were less dramatic, in the same manner as reported changes in apical radius and central refraction after OK. This study confirms that with OK treatment, the peripheral retina experiences myopic defocus, which is conjectured to underlie the observed slowing of myopia progression. PMID- 23347399 TI - Manganese-induced parkinsonism in methcathinone abusers: bio-markers of exposure and follow-up. AB - BACKGROUND AND PURPOSE: Methcathinone abuse is a new cause of manganism. The psychostimulant is prepared from pseudoephedrine using potassium permanganate as an oxidant. We describe the clinical, biological, neuroimaging characteristics and follow-up results in a large Estonian cohort of intravenous methcathinone users. METHODS: During 2006-2012 we studied 38 methcathinone abusers with a mean age of 33 years. Subjects were rated by the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (HY), and Schwab and England (SE) rating scales. Twenty-four cases were reassessed 9-70 (20 +/- 15) months after the initial evaluation. Manganese (Mn) in plasma and hair was analysed by inductively coupled plasma-atom emission spectrometry. Magnetic resonance imaging (MRI) was performed in 11, and single-photon emission computed tomography (SPECT) with iodobenzamide (IBZM) in eight subjects. RESULTS: The average total UPDRS score was 43 +/- 21. The most severely affected domains in UPDRS Part III were speech and postural stability, the least affected domain was resting tremor. At follow-up there was worsening of HY and SE rating scales. Subjects had a higher mean level of Mn in hair (2.9 +/- 3.8 ppm) than controls (0.82 +/- 1.02 ppm), P = 0.02. Plasma Mn concentrations were higher (11.5 +/- 6.2 ppb) in active than in former users (5.6 +/- 1.8 ppb), P = 0.006. Active methcathinone users had increased MRI T1-signal intensity in the globus pallidus, substantia nigra and periaquaductal gray matter. IBZM-SPECT showed normal symmetric tracer uptake in striatum. CONCLUSION: Methcathinone abusers develop a distinctive hypokinetic syndrome. Though the biomarkers of Mn exposure are characteristic only of recent abuse, the syndrome is not reversible. PMID- 23347398 TI - Innate immune markers that distinguish red deer (Cervus elaphus) selected for resistant or susceptible genotypes for Johne's disease. AB - While many factors contribute to resistance and susceptibility to infectious disease, a major component is the genotype of the host and the way in which it is expressed. Johne's disease is a chronic inflammatory bowel disease affecting ruminants and is caused by infection with Mycobacterium avium subspecies paratuberculosis (MAP). We have previously identified red deer breeds (Cervus elaphus) that are resistant; have a low rate of MAP infection and do not progress to develop Johne's disease. In contrast, susceptible breeds have a high rate of MAP infection as seen by seroconversion and progress to develop clinical Johne's disease. The aim of this study was to determine if immunological differences exist between animals of resistant or susceptible breeds. Macrophage cultures were derived from the monocytes of deer genotypically defined as resistant or susceptible to the development of Johne's disease. Following in vitro infection of the cells with MAP, the expression of candidate genes was assessed by quantitative PCR as well as infection rate and cell death rate. The results indicate that macrophages from susceptible animals show a significantly higher upregulation of inflammatory genes (iNOS, IL-1alpha, TNF-alpha and IL-23p19) than the macrophages from resistant animals. Cells from resistant animals had a higher rate of apoptosis at 24 hours post infection (hpi) compared to macrophages from susceptible animals. The excessive expression of inflammatory mRNA transcripts in susceptible animals could cause inefficient clearing of the mycobacterial organism and the establishment of disease. Controlled upregulation of inflammatory pathways coupled with programmed cell death in the macrophages of resistant animals may predispose the host to a protective immune response against this mycobacterial pathogen. PMID- 23347400 TI - Ultra-low-dose estriol and lactobacilli in the local treatment of postmenopausal vaginal atrophy. AB - OBJECTIVE: The aim of this study was to demonstrate the efficacy of an ultra-low dose vaginal estriol 0.03 mg in combination with viable Lactobacillus acidophilus KS400 (Gynoflor((r)) vaginal tablets) in the short-term therapy and to investigate the long-term maintenance dose in the treatment of vaginal atrophy. METHODS: This was a double-blind, randomized, placebo-controlled study (Controlled phase--initial therapy) followed by an open-label follow-up (Open phase--test medication initial and maintenance therapy). Included were postmenopausal women with vaginal atrophy symptoms and Vaginal Maturation Index (VMI) of <= 40%. The method of treatment was initial therapy with test medication (or placebo in first phase), one vaginal tablet daily for 12 days, followed by maintenance therapy, one tablet on two consecutive days weekly for 12 weeks. RESULTS: A total of 87 women completed the study. The Controlled phase results for a change in VMI demonstrated superiority of the 0.03 mg estriol-lactobacilli combination to placebo (p < 0.001). In the test group, the positive change in VMI was 35.2%, compared to 9.9% in the placebo group. In the Open phase after the initial therapy, the VMI was increased to 55.4% and, during maintenance therapy, it stayed at a comparable level (52.8-49.4%). The maturation of epithelium was followed by improvement of clinical symptoms and normalization of the vaginal ecosystem. CONCLUSIONS: The ultra-low-dose, vaginal 0.03 mg estriol-lactobacilli combination (Gynoflor((r))) was superior to placebo with respect to changes in VMI after the 12-day initial therapy, and the maintenance therapy of two tablets weekly was sufficient to prevent the relapse of vaginal atrophy. PMID- 23347401 TI - Resumption of work or studies after first-episode psychosis: the impact of vocational case management. AB - BACKGROUND: Psychosis compromises the educational and professional projects of young patients. Vocational case management (VCM) offers comprehensive support for reintegration into work or studies within an early psychosis intervention programme. AIMS: To evaluate the effectiveness of VCM in resumption of work or school and to identify the predictive factors of occupational outcome. METHODS: This descriptive study focused on occupational status of an early psychosis cohort during the first 5 years of VCM. RESULTS: 56.6% of 97 study subjects had a diagnosis of schizophrenia, 32% had type I bipolar disorder with psychotic features. 68% held a productive occupation the year prior to admission, and 47.4% at admission. The occupational rate rose from 57.1% at 12 months to over 70% after 48 months. 65.6% maintained or improved their occupational status. Most subjects held competitive employment, and the employment rate was similar to that of the general population. Prior employment and affective psychosis were associated with better outcome. [Correction added on 2 April 2013, after first online publication: 'Non-affective psychosis' has been changed to 'affective psychosis' in the Results section.] CONCLUSION: The majority of individuals suffering from early psychosis resume productive activity rapidly when offered VCM within an early intervention programme during a follow-up period of up to 5 years. PMID- 23347402 TI - Comparison between two types of local resection in the treatment of ampullary cancer. AB - BACKGROUND: This study aims to compare the effects of two different local resection procedures on the prognosis of ampullary cancer. METHODS: We carried out a retrospective study using clinical and pathological data from patients with ampullary cancer who underwent local resection between February 1996 and February 2009 in the PLA General Hospital. In these participants, we carried out a comparative analysis between the transduodenal (the transduodenal group) and the extraduodenal (extraduodenal group) surgical approaches. RESULTS: No significant differences in gender, age, preoperative bilirubin levels, CA19-9 values, biopsy results, tumour size, differentiation status, degree of invasion, surgical margins, recurrence, metastasis and complication rates, and intraoperative blood loss were found. As compared to the transduodenal group, the extraduodenal group showed a longer duration of surgery and higher survival rates. CONCLUSIONS: Even though the operation time for the extraduodenal resection of ampullary cancer was longer, the survival rate was higher than in patients who underwent transduodenal resection. For certain patients, the extraduodenal approach may be more appropriate when technical conditions allow it. PMID- 23347403 TI - Insights from the Forum 12 Business Networking Roundtable. PMID- 23347404 TI - Better sleep means better health. PMID- 23347405 TI - Unambiguous phosphosite localization using electron-transfer/higher-energy collision dissociation (EThcD). AB - We recently introduced a novel scheme combining electron-transfer and higher energy collision dissociation (termed EThcD), for improved peptide ion fragmentation and identification. We reasoned that phosphosite localization, one of the major hurdles in high-throughput phosphoproteomics, could also highly benefit from the generation of such EThcD spectra. Here, we systematically assessed the impact on phosphosite localization utilizing EThcD in comparison to methods employing either ETD or HCD, respectively, using a defined synthetic phosphopeptide mixture and also using a larger data set of Ti(4+)-IMAC enriched phosphopeptides from a tryptic human cell line digest. In combination with a modified version of phosphoRS, we observed that in the majority of cases EThcD generated richer and more confidently identified spectra, resulting in superior phosphosite localization scores. Our data demonstrates the distinctive potential of EThcD for PTM localization, also beyond protein phosphorylation. PMID- 23347406 TI - Superoxide anion production by NADPH oxidase plays a major role in erectile dysfunction in middle-aged rats: prevention by antioxidant therapy. AB - INTRODUCTION.: Prevalence of erectile dysfunction (ED) increases progressively with aging, but the ED pathophysiology at its early stages is still poorly investigated. AIM.: This study aimed to evaluate the functional and molecular alterations of erectile function at middle age, focusing on the contribution of oxidative stress in erectile tissue for the ED. METHODS.: Young (3.5-month) and middle-aged (10-month) male Wistar rats were used. Rat corpus cavernosum (RCC) was dissected free and mounted in 10-mL organ baths containing Krebs solution. Intracavernosal pressure (ICP) in anesthetized rats was evaluated. MAIN OUTCOME MEASURES.: Concentration-response curves to endothelium-dependent and endothelium independent agents, as well as to electrical field stimulation (EFS), were obtained in RCC strips. Measurement of cyclic guanosine monophosphate (cGMP) and expressions of neuronal nitric oxide synthase (nNOS) and endothelial NOS (eNOS), gp91(phox) and superoxide dismutase-1 (SOD-1) expressions in RCC were evaluated. RESULTS.: ICP was significantly reduced in middle-aged compared with young rats. RCC relaxations to acetylcholine (10(-8) to 10(-2) M), sodium nitroprusside (10( 8) to 10(-2) M), sildenafil (10(-9) to 10(-5) M), BAY 41-2272 (10(-9) to 10(-5) M), and EFS (4-32 Hz) were decreased in middle-aged group, which were nearly normalized by apocynin (NADPH oxidase inhibitor; 10(-4) M) or SOD (75 U/mL). Prolonged treatment with apocynin (85 mg/rat/day, 4 weeks) also restored the impaired relaxations in middle-aged rats. Relaxations to 8-bromoguanosine 3',5' cyclic monophosphate sodium salt (8-Br-cGMP; 10(-8) to 3 * 10(-4) M) remained unchanged between groups. Basal and stimulated cGMP production were lower in middle-aged group, an effect fully restored by apocynin and SOD. Protein expression of nNOS and phosphorylated eNOS (p-eNOS) (Ser-1177) reduced, whereas gp(91phox) mRNA expression increased in RCC from middle-aged rats. CONCLUSIONS.: ED in middle-aged rats is associated with decreased NO bioavailability in erectile tissue due to upregulation of NADPH oxidase subunit gp91(phox) and downregulation of nNOS/p-eNOS. Antioxidant therapies may be a good pharmacological approach to prevent ED at its early stages. PMID- 23347407 TI - Tissue-specific direct targets of Caenorhabditis elegans Rb/E2F dictate distinct somatic and germline programs. AB - BACKGROUND: The tumor suppressor Rb/E2F regulates gene expression to control differentiation in multiple tissues during development, although how it directs tissue-specific gene regulation in vivo is poorly understood. RESULTS: We determined the genome-wide binding profiles for Caenorhabditis elegans Rb/E2F like components in the germline, in the intestine and broadly throughout the soma, and uncovered highly tissue-specific binding patterns and target genes. Chromatin association by LIN-35, the C. elegans ortholog of Rb, is impaired in the germline but robust in the soma, a characteristic that might govern differential effects on gene expression in the two cell types. In the intestine, LIN-35 and the heterochromatin protein HPL-2, the ortholog of Hp1, coordinately bind at many sites lacking E2F. Finally, selected direct target genes contribute to the soma-to-germline transformation of lin-35 mutants, including mes-4, a soma specific target that promotes H3K36 methylation, and csr-1, a germline-specific target that functions in a 22G small RNA pathway. CONCLUSIONS: In sum, identification of tissue-specific binding profiles and effector target genes reveals important insights into the mechanisms by which Rb/E2F controls distinct cell fates in vivo. PMID- 23347409 TI - Excellent electrical conductivity of the exfoliated and fluorinated hexagonal boron nitride nanosheets. AB - The insulator characteristic of hexagonal boron nitride limits its applications in microelectronics. In this paper, the fluorinated hexagonal boron nitride nanosheets were prepared by doping fluorine into the boron nitride nanosheets exfoliated from the bulk boron nitride in isopropanol via a facile chemical solution method with fluoboric acid; interestingly, these boron nitride nanosheets demonstrate a typical semiconductor characteristic which were studied on a new scanning tunneling microscope-transmission electron microscope holder. Since this property changes from an insulator to a semiconductor of the boron nitride, these nanosheets will be able to extend their applications in designing and fabricating electronic nanodevices. PMID- 23347411 TI - Ecological and demographic correlates of helping behaviour in a cooperatively breeding bird. AB - The evolution of cooperation is a persistent problem for evolutionary biologists. In particular, understanding of the factors that promote the expression of helping behaviour in cooperatively breeding species remains weak, presumably because of the diverse nature of ecological and demographic drivers that promote sociality. In this study, we use data from a long-term study of a facultative cooperative breeder, the long-tailed tit Aegithalos caudatus, to investigate the factors influencing annual variation in helping behaviour. Long-tailed tits exhibit redirected helping in which failed breeders may become helpers, usually at a relative's nest; thus, helping is hypothesised to be associated with causes of nest failure and opportunities to renest or help. We tested predictions regarding the relationship between annual measures of cooperative behaviour and four explanatory variables: nest predation rate, length of the breeding season, population-level relatedness and population density. We found that the degree of helping was determined principally by two factors that constrain successful independent reproduction. First, as predicted, cooperative behaviour peaked at intermediate levels of nest predation, when there are both failed breeders (i.e. potential helpers) and active nests (i.e. potential recipients) available. Second, there were more helpers in shorter breeding seasons when opportunities for renesting by failed breeders are more limited. These are novel drivers of helping behaviour in avian cooperative breeding systems, and this study illustrates the difficulty of identifying common ecological or demographic factors underlying the evolution of such systems. PMID- 23347410 TI - Intensity modulated radiotherapy (IMRT) combined with concurrent but not adjuvant chemotherapy in primary nasopharyngeal cancer - a retrospective single center analysis. AB - BACKGROUND: We report our experience in 49 consecutive patients with nasopharyngeal carcinoma who were treated by Intensity-modulated radiation therapy (IMRT) combined with simultaneous but not adjuvant chemotherapy (CHT). METHODS: The medical records of 49 patients with histologically proven primary nasopharygeal carcinoma treated with IMRT and concurrent platin-based CHT (predominantly cisplatin weekly) were retrospectively reviewed. The majority of patients showed advanced clinical stages (stage III/IV:72%) with undifferentiated histology (82%). IMRT was performed in step-and-shoot technique using an integrated boost concept in 84%. In this concept, the boost volume covered the primary tumor and involved nodes with doses of 66-70.4 Gy (single dose 2.2 Gy). Uninvolved regional nodal areas were covered with doses of 54-59.4 Gy (median single dose 1.8 Gy). At least one parotid gland was spared. None of the patients received adjuvant CHT. RESULTS: The median follow-up for the entire cohort was 48 months. Radiation therapy was completed without interruption in all patients and 76% of the patients received at least 80% of the scheduled CHT. Four local recurrences have been observed, transferring into 1-, 3-, and 5-year Local Control (LC) rates of 98%, 90% and 90%. One patient developed an isolated regional nodal recurrence, resulting in 1-, 3-, and 5-year Regional Control (RC) rates of 98%. All locoregional failures were located inside the radiation fields. Distant metastases were found in six patients, transferring into 1-, 3, and 5 year Distant Control (DC) rates of 92%, 86% and 86%. Progression free survival (PFS) rates after 1, 3 and 5 years were 86%, 70% and 69% and 1-, 3- and 5-year Overall Survival (OS) rates were 96%, 82% and 79%. Acute toxicity >= grade III mainly consisted of dysphagia (32%), leukopenia (24%), stomatitis (16%), infection (8%) and nausea (8%). Severe late toxicity (grade III) was documented in 18% of the patients, mainly as xerostomia (10%). CONCLUSION: Concurrent chemoradiation without the addition of adjuvant chemotherapy cycles using IMRT with an integrated boost concept yielded good disease control and overall survival in patients suffering from primary nasopharyngeal cancer with acceptable acute side effects and limited rates of late toxicity. PMID- 23347412 TI - Medical Humanities: a question of style. AB - The Medical Humanities go beyond bioethics, cross over multiple disciplines and represent a new way of perceiving, seeing and thinking about illness. They represent a different view that gives value to the human side of treatment, that recognizes in self-narration an authentic and living foundation. Today, the technical aspects of medicine need more than ever to be accompanied by content derived from the arts and social or human sciences that focus on other, but not less important, aspects of being sick or in health. Everyday clinical practice in a "Medical Humanities style" can change the encounter with patients and their families, as well as the relationship with one's self and with colleagues. Adopting this wider perspective allows us to go further than contemporary biomedicine and continue to explore a unique understanding of mankind. PMID- 23347408 TI - Persistent digestive disorders in the tropics: causative infectious pathogens and reference diagnostic tests. AB - BACKGROUND: Persistent digestive disorders account for considerable disease burden in the tropics. Despite advances in understanding acute gastrointestinal infections, important issues concerning epidemiology, diagnosis, treatment and control of most persistent digestive symptomatologies remain to be elucidated. Helminths and intestinal protozoa are considered to play major roles, but the full extent of the aetiologic spectrum is still unclear. We provide an overview of pathogens causing digestive disorders in the tropics and evaluate available reference tests. METHODS: We searched the literature to identify pathogens that might give rise to persistent diarrhoea, chronic abdominal pain and/or blood in the stool. We reviewed existing laboratory diagnostic methods for each pathogen and stratified them by (i) microscopy; (ii) culture techniques; (iii) immunological tests; and (iv) molecular methods. Pathogen-specific reference tests providing highest diagnostic accuracy are described in greater detail. RESULTS: Over 30 pathogens may cause persistent digestive disorders. Bacteria, viruses and parasites are important aetiologic agents of acute and long-lasting symptomatologies. An integrated approach, consisting of stool culture, microscopy and/or specific immunological techniques for toxin, antigen and antibody detection, is required for accurate diagnosis of bacteria and parasites. Molecular techniques are essential for sensitive diagnosis of many viruses, bacteria and intestinal protozoa, and are increasingly utilised as adjuncts for helminth identification. CONCLUSIONS: Diagnosis of the broad spectrum of intestinal pathogens is often cumbersome. There is a need for rapid diagnostic tests that are simple and affordable for resource-constrained settings, so that the management of patients suffering from persistent digestive disorders can be improved. PMID- 23347413 TI - Narrative in cancer research and policy: voice, knowledge and context. AB - The potential applications of narrative within medical practice are attracting increased interest. In particular, personal narratives afford rich insights into how encounters with cancer and the associated provision of care are experienced, understood and represented. Such first-person accounts are practically useful in indicating improvements to cancer care and politically significant in providing a means to enable the patient voice and legitimising experiential knowledge alongside a biomedical paradigm. However, personal narratives are necessarily and always constructed in particular social and political contexts and through existing 'meta-narratives' relating to cancer, health, illness and a flourishing life. The present paper first examines work on personal cancer narratives to critically review the opportunities for narrative within cancer care. We then reflect on the crucial role of meta-narratives of cancer as framings within which personal narratives can be both enabled and constrained. PMID- 23347414 TI - An alternative view on the task of prognosis. AB - Prognosis is central to clinical medical practice. In oncology, an accurate prognosis is a key requirement for making the right therapeutical decisions. Prognosis is even more important when medicine extends its predictive capacities using genetic data. Based on statistics and probability, indices, survival curves and prognostic scores are established. Intending to be an objective and neutral description of reality, this kind of prognosis and the corresponding practices of medical care however carry and imply a particular conception of human life and destiny. Medical Humanities can help to develop reflexivity regarding prognostic practices. This paper intends to clarify which particular assumptions are implied in the current way of doing prognosis in medicine, and highlights its advantages and limitations. Prognosis not only describes but also affects present and future patient experience. An alternative view on the task of prognosis is then developed with a broader understanding of the prognostic act. Based on a phenomenology of time, distinguishing between a quantitative chronological understanding of time (chronos) and an experienced qualitative time (kairos), the article contrasts a conception of the prognosis as forecast ('probabilistic prognosis') with a conception of prognosis as perspective ('hermeneutic prognosis'). In probabilistic prognosis, the future is seen as something that can be read from presently accessible signs, as something that we can anticipate within ranges of uncertainty. The patient's lifetime, which has been open toward the future, becomes closed through this kind of prognosis. In a hermeneutic conception of prognosis as a perspective on the future, which is thought of as an open space of possibilities, the future as not-yet is what can be envisioned without being known. A hermeneutic approach emphasizes the meanings of the experience of illness for the patient, helps to improve the practice of prognosis today, and offers caregivers and patients an opportunity for living better. PMID- 23347415 TI - The place of the unknown in the Medical Humanities. AB - In the birth and development of the Medical Humanities, literature has played a crucial role, both as an educational resource and as an analytical device. This article proposes an appraisal of this approach by focussing on a model literary situation. Taking the move from Alberto Barrera Tyszka's novel La enfermedad [The illness], the authors identify and explore some of the "places of ignorance" that can emerge in the doctor-patient relationship, as potentially in any form of intersubjective encounter. The analysis aims at highlighting the constructive potential of such spaces of not knowing as a positive element to deal with, rather than a mere limitation of our power of intervention. PMID- 23347416 TI - Constructing the Medical Humanities gaze. AB - In the last few decades genomics has completely reshaped the way in which patients and physicians experience and make sense of illness. In this paper we build upon a real case - namely that of breast cancer genetic testing - in order to point to the shortcomings of the paradigm currently driving healthcare delivery. In particular, we put forward a viable analytical model for the construction of a proper decisional process broadening the scope of medical gaze onto human experience of illness. This model revolves around four main conceptual axes: (i) communicating information; (ii) informing decisions; (iii) respecting narratives; (iv) empowering decision-making. These four kernels, we argue, map precisely onto the main pitfalls of the model presently dealing with genetic testing provision. Medical Humanities, we conclude, ought to play a pivotal role in constructing the environment for competent decision-making, autonomous self determination and respectful narritivization of one's own life. PMID- 23347417 TI - Protocol for development of the guideline for reporting evidence based practice educational interventions and teaching (GREET) statement. AB - BACKGROUND: There are an increasing number of studies reporting the efficacy of educational strategies to facilitate the development of knowledge and skills underpinning evidence based practice (EBP). To date there is no standardised guideline for describing the teaching, evaluation, context or content of EBP educational strategies. The heterogeneity in the reporting of EBP educational interventions makes comparisons between studies difficult. The aim of this program of research is to develop the Guideline for Reporting EBP Educational interventions and Teaching (GREET) statement and an accompanying explanation and elaboration (E&E) paper. METHODS/DESIGN: Three stages are planned for the development process. Stage one will comprise a systematic review to identify features commonly reported in descriptions of EBP educational interventions. In stage two, corresponding authors of articles included in the systematic review and the editors of the journals in which these studies were published will be invited to participate in a Delphi process to reach consensus on items to be considered when reporting EBP educational interventions. The final stage of the project will include the development and pilot testing of the GREET statement and E&E paper. OUTCOME: The final outcome will be the creation of a Guideline for Reporting EBP Educational interventions and Teaching (GREET) statement and E&E paper. DISCUSSION: The reporting of health research including EBP educational research interventions, have been criticised for a lack of transparency and completeness. The development of the GREET statement will enable the standardised reporting of EBP educational research. This will provide a guide for researchers, reviewers and publishers for reporting EBP educational interventions. PMID- 23347419 TI - Electron microscopy characterization of Ni-Cr-B-Si-C laser deposited coatings. AB - During laser deposition of Ni-Cr-B-Si-C alloys with high amounts of Cr and B, various microstructures and phases can be generated from the same chemical composition that results in heterogeneous properties in the clad layer. In this study, the microstructure and phase constitution of a high-alloy Ni-Cr-B-Si-C coating deposited by laser cladding were analyzed by a combination of several microscopy characterization techniques including scanning electron microscopy in secondary and backscatter imaging modes, energy dispersive spectroscopy (EDS), electron backscatter diffraction (EBSD), and transmission electron microscopy (TEM). The combination of EDS and EBSD allowed unequivocal identification of micron-sized precipitates as polycrystalline orthorhombic CrB, single crystal tetragonal Cr5B3, and single crystal hexagonal Cr7C3. In addition, TEM characterization showed various equilibrium and metastable Ni-B, Ni-Si, and Ni-Si B eutectic products in the alloy matrix. The findings of this study can be used to explain the phase formation reactions and to tune the microstructure of Ni-Cr B-Si-C coatings to obtain the desired properties. PMID- 23347418 TI - Transmission and maintenance cycle of Bartonella quintana among rhesus macaques, China. AB - We detected Bartonella quintana in 48.6% of captive rhesus macaques from an animal facility in Beijing, China. Prevalence of infection increased over the period of observation. Our findings suggest that macaques may serve as reservoir hosts for B. quintana and that Pedicinus obtusus lice might act as efficient vectors. PMID- 23347420 TI - Evaluation of the effect of sorafenib using serum NX-des-gamma-carboxyprothrombin in patients with hepatocellular carcinoma. AB - AIM: Des-gamma-carboxyprothrombin (DCP) is known to be increased by the use of sorafenib for the treatment of hepatocellular carcinoma (HCC), despite its therapeutic efficacy. In addition to the tumor progression, hypoxia that impairs vitamin K uptake is known to induce DCP and this mechanism may explain DCP elevation by sorafenib. In this study, we tried to evaluate the effect of sorafenib treatment using a new marker, NX-DCP, which is specific to vitamin K absence. METHODS: Serum DCP and NX-DCP were measured in 50 consecutive HCC patients before and 1 week after starting sorafenib, and compared with the treatment effect using the modified Response Evaluation Criteria in Solid Tumors guidelines. RESULTS: DCP and NX-DCP increased 1.58- (median, range 0.21-28.7) and 1.20-fold (median, range 0.41-14.2) after the administration of sorafenib, respectively. The increases of both markers were less than twofold in approximately half of the patients (low-elevation group). However, 12 patients showed over twofold increase of both DCP and NX-DCP (double-elevation group), and eight patients showed over twofold increase of DCP alone (DCP-elevation group). The disease control rate (DCR) of the DCP-elevation group (12.5%) was significantly lower than those of the double-elevation group (75.0%, P = 0.020) and the low-elevation group (60.0%, P = 0.042). Progression-free survival (PFS) was significantly shorter in the DCP-elevation group than in the double-elevation group (P = 0.006) and the low-elevation group (P = 0.001). CONCLUSION: NX-DCP in combination with DCP could be a useful biomarker of sorafenib treatment for advanced HCC. PMID- 23347421 TI - Does senescence affect lymph node number and morphology? A systematic review. AB - BACKGROUND: Immunosenescence may contribute to an observed increase in infections and specific cancers in the elderly. Lymph nodes play a key role in the body's immune system. A systematic review was undertaken to investigate the effects of senescence on lymph node number and morphology. METHODS: Electronic databases Ovid MEDLINE, Embase and Google Scholar were searched for relevant articles examining normal lymph node number and morphology with senescence. Data on lymph node number, gross anatomy and histo-architecture were collated and analysed. RESULTS: A total of 20 articles (15 human and 5 animal studies) were eligible for inclusion; many were limited by poorly standardized methods and relatively small sample sizes. However, there is evidence to suggest both a decrease in lymph node number and histological lymph node degeneration with senescence, at least in some lymph node basins. Degenerative changes include loss of lymphoid tissue from both the cortex and the medulla of lymph nodes, a reduction in the number and size of germinal centres, and changes such as hyalinization, fibrosis, fat deposition, a decrease in high endothelial venules and 'transparency'. CONCLUSION: In this first systematic review to examine changes in lymph nodes with senescence, evidence was accrued to suggest a decline in lymph node number and morphological degeneration in older age groups. These changes might adversely affect immune function and the prognosis of infections and selected cancers in the elderly. Further research is required to confirm these morphological changes and to explore their potential immunological and functional effects. PMID- 23347422 TI - Surface functionalization of a polymeric lipid bilayer for coupling a model biological membrane with molecules, cells, and microstructures. AB - We describe a stable and functional model biological membrane based on a polymerized lipid bilayer with a chemically modified surface. A polymerized lipid bilayer was formed from a mixture of two diacetylene-containing phospholipids, 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DiynePC) and 1,2 bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphoethanolamine (DiynePE). DiynePC formed a stable bilayer structure, whereas the ethanolamine headgroup of DiynePE enabled functional molecules to be grafted onto the membrane surface. Copolymerization of DiynePC and DiynePE resulted in a robust bilayer. Functionalization of the polymeric bilayer provided a route to a robust and biomimetic surface that can be linked with biomolecules, cells, and three dimensional (3D) microstructures. Biotin and peptides were grafted onto the polymeric bilayer for attaching streptavidin and cultured mammalian cells by molecular recognition, respectively. Nonspecific adsorption of proteins and cells on polymeric bilayers was minimum. DiynePE was also used to attach a microstructure made of an elastomer (polydimethylsiloxan: PDMS) onto the membrane, forming a confined aqueous solution between the two surfaces. The microcompartment enabled us to assay the activity of a membrane-bound enzyme (cyochrome P450). Natural (fluid) lipid bilayers were incorporated together with membrane-bound proteins by lithographically polymerizing DiynePC/DiynePE bilayers. The hybrid membrane of functionalized polymeric bilayers and fluid bilayers offers a novel platform for a wide range of biomedical applications including biosensor, bioassay, cell culture, and cell-based assay. PMID- 23347423 TI - Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses. AB - BACKGROUND: Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice. METHODS: BALB/c mice were sensitized and challenged (primary) with ovalbumin (OVA). Six weeks later, a single OVA aerosol (secondary challenge) was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge. RESULTS: Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN) T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL 4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-beta1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice. CONCLUSION: These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the neutrophil elastase inhibitor reduced AHR to inhaled methacholine indicating the potential for its use as a modulator of the immune/inflammatory response in both the neutrophil- and eosinophil-dominant phases of the response to secondary allergen challenge. PMID- 23347424 TI - Outcomes of cluster profiles within stages of change for sun protection behavior. AB - OBJECTIVE: Predictive and external validity was studied among cluster profiles for sun protection behavior within stages from Transtheoretical Model of behavior change using follow-up data. METHODS: Data from participants in a home-based expert system were analyzed. Longitudinal patterns of clusters on the precontemplation, contemplation, and preparation stages of change were assessed. Differences between clusters on membership in action/maintenance stages and scores on the Sun Protection Behavior Scale (SPBS) were measured at 12 and 24 months after intervention. RESULTS: Differences between clusters on stage progression and on scores from the SPBS were found at 12 and 24 months after intervention at all stages. DISCUSSION: Predictive and external validity of sun protection subtypes was established using sun protection variables after a stage matched intervention. Results provide information to improve interventions for sun protection. PMID- 23347425 TI - Validation of the Arabic version of the Comprehensive Assessment of At Risk Mental States (CAARMS) in Tunisian adolescents and young adults. AB - AIM: The study aimed to examine whether the Arabic version of the Comprehensive Assessment of At Risk Mental States (CAARMS) has good construct validity, concurrent validity and reliability. METHODS: Validity was established on a sample of 58 Tunisian adolescents and young adults aged between 16 and 30 years. These subjects were divided into three groups according to the CAARMS scores: ultra-high risk positive subjects (UHR (+) ) (n = 22), ultra-high risk negative subjects (UHR (-) ) (n = 25) and subjects meeting the criteria of a first-episode psychosis (FEP) (n = 11). For construct validity, we used the convergent validity. We used the Positive and Negative Syndrome Scale (PANSS) concomitantly with the CAARMS. For concurrent validity, we studied the correlation between symptoms of the CAARMS and their equivalents in the PANSS. The CAARMS reliability was conducted by the study of interrater reliability. RESULTS: The UHR (+) group was shown with intermediate scores of PANSS between the two groups UHR (-) and FEP. That confirms a good construct validity of the Arabic version of the CAARMS. We noted a correlation between the scores in positive and negative sections measured by the CAARMS and their corresponding level of the PANSS. These results show that the CAARMS has a good concurrent validity with the PANSS. For the reliability study, we noted a good correlation between the two raters with a Pearson coefficient ranging from 0.55 to 0.90. CONCLUSION: Analysis of the results of construct validity, concurrent validity and reliability of the CAARMS indicates that this version translated into Arabic is valid and reliable. PMID- 23347426 TI - Exposure to anaesthetic agents does not affect multiple sclerosis risk. AB - BACKGROUND AND PURPOSE: It has been hypothesized that exposure to anaesthetic agents, some of which are chemically related to organic solvents, may affect the risk of developing multiple sclerosis (MS). The aim of this study was to estimate the influence of occupational exposure to anaesthetic agents on the risk for MS. We further aimed to investigate the impact of general anaesthesia and usage of nitrous oxide. METHODS: This report is based on two population-based, case control studies, one with incident cases (1798 cases, 3907 controls) and one with prevalent cases (5216 cases, 4701 controls). Using logistic regression, the occurrence of MS among subjects who have been exposed to anaesthetic agents was compared with that of those who have never been exposed by calculating the odds ratio with a 95% confidence interval. RESULTS: No association was found between occupational exposure to anaesthetic agents and risk of developing MS, also general anaesthesia or usage of nitrous oxide had no impact on MS risk. CONCLUSIONS: Neither occupational exposure to anaesthetic agents, nor general anaesthesia or usage of nitrous oxide has any impact on MS risk and is safe also for people with a genetic susceptibility to the disease. However, further studies would be valuable in order to clarify whether other forms of organic solvents contribute to the triggering of MS. PMID- 23347427 TI - Effects of endopeptidase inhibition on the contraction-relaxation response of isolated human vaginal tissue. AB - INTRODUCTION.: Vasoactive peptides, such as bradykinin, C-type natriuretic peptide (CNP), vasoactive intestinal polypeptide (VIP), and endothelin 1 (ET-1), are assumed to be involved in the control of female genital vascular and nonvascular smooth muscle. Tissue levels of said peptides are controlled by the activity of endopeptidase enzymes. Theoretically, in female genital tissues, inhibiting the degradation of bradykinin, CNP, and VIP, or the conversion of Big ET-1 into ET-1 should result in an enhancement in smooth muscle relaxation and, thus, an improvement in sexual response. AIM.: Elucidate the effects of the endopeptidase inhibitor KC 12615 on the contraction/relaxation response of isolated human vaginal smooth muscle to Big ET-1, bradykinin, CNP, or VIP. METHODS.: Tissue bath experiments were carried out to ascertain the responses of human vaginal tissue challenged by ET-1 (0.1 MUM) to increasing concentrations of bradykinin, CNP, and VIP (0.01 MUM, 0.1 MUM, and 1 MUM, respectively). The effects were also evaluated following preexposure to KC 12615 (10 MUM, for 20 minutes). MAIN OUTCOME MEASURES.: Measure the effects of KC 12615 on the relaxation of isolated human vaginal smooth muscle brought about by bradykinin, CNP, or VIP and the contraction mediated by Big ET-1. RESULTS.: The tension induced by ET-1 was reversed by bradykinin, CNP, or VIP (-25 +/- 6.6%, -13.3 +/- 2.2%, and -17.6 +/- 10%, respectively). Big ET-1 induced contraction of the vaginal tissue. Preexposure of the tissue to KC 12615 increased the relaxation exerted by bradykinin, CNP, or VIP (to -39.2 +/- 5.8%, -40.7 +/- 7.3%, and -44.6 +/- 19%, respectively). The contraction induced by Big ET-1 was attenuated in the presence of KC 12615 (to approximately 25% of the initial response). CONCLUSION.: Inhibition of endopeptidase activity can antagonize the contraction of human vaginal tissue induced by Big ET-1 and increase the relaxation induced by vasoactive endogenous peptides. PMID- 23347428 TI - Pancreatitis and myocarditis followed by pulmonary hemorrhage, a rare presentation of leptospirosis- a case report and literature survey. AB - BACKGROUND: Leptospirosis is a potentially fatal disease which can cause multi organ dysfunction. It can rarely present as acute pancreatitis. This is the first ever report of leptospirosis presenting with acute pancreatitis and myocarditis followed by diffuse pulmonary hemorrhages to the best of our knowledge. CASE PRESENTATION: A 15-year-old South Asian boy presented with high grade fever, epigastric discomfort and was anicteric on admission. He developed tachycardia, transient hypotension, changes of electro-cardiogram and positive troponin I suggestive of myocarditis. Acute pancreatitis was diagnosed with 12 fold high serum amylase and with the evidence of computerized tomography. Then he developed diffuse pulmonary hemorrhages and later acute renal failure. Leptospirosis was confirmed by positive leptospira IgM, negative IgG and strongly positive Microscopic Agglutination Test. Other possible infective and autoimmune causes were excluded. Patient recovered completely with antibiotics and the supportive care. CONCLUSION: This case illustrates diagnostic difficulties especially in resource poor settings where leptospirosis is common. Additionally it highlights the fact that leptospirosis should be considered in patients presenting with pancreatitis which can be complicated with myocarditis and diffuse pulmonary hemorrhages. We hypothesize that Toll like receptors may play a role in such systemic involvement. PMID- 23347429 TI - Memristive properties of hexagonal WO3 nanowires induced by oxygen vacancy migration. AB - Tungsten trioxide (WO3) is always oxygen-deficient or non-stoichiometric under atmospheric conditions. Positively charged oxygen vacancies prefer to drift as well as electrons when the electric field is strong enough, which will alter the distribution of oxygen vacancies and then endow WO3 with memristive properties. In Au/WO3 nanowire/Au sandwich structures with two ohmic contacts, the axial distribution of oxygen vacancies and then the electrical transport properties can be more easily modulated by bias voltage. The threshold electric field for oxygen vacancy drifting in single-crystal hexagonal WO3 nanowire is about 106 V/m, one order of magnitude less than that in its granular film. At elevated temperatures, the oxygen vacancy drifts and then the memristive effect can be enhanced remarkably. When the two metallic contacts are asymmetric, the WO3 nanowire devices even demonstrate good rectifying characteristic at elevated temperatures. Based on the drift of oxygen vacancies, nanoelectronic devices such as memristor, rectifier, and two-terminal resistive random access memory can be fabricated on individual WO3 nanowires. PMID- 23347431 TI - No need for disease: testing extinction hypotheses for the thylacine using multi species metamodels. AB - Population viability analysis (PVA) is widely used to assess the extinction risk of threatened species and to evaluate different management strategies. However, conventional PVA neglects important biotic interactions and therefore can fail to identify important threatening processes. We designed a new PVA approach that includes species interactions explicitly by networking species models within a single 'metamodel'. We demonstrate the utility of PVA metamodels by employing them to reinterpret the extinction of the carnivorous, marsupial thylacine Thylacinus cynocephalus in Tasmania. In particular, we test the claim that well documented impacts of European settlement cannot account for this extinction and that an unknown disease must have been an additional and necessary cause. We first constructed a classical, single-species PVA model for thylacines, which was then extended by incorporation within a dynamic predator-herbivore-vegetation metamodel that accounted for the influence of Europeans on the thylacine's prey base. Given obvious parameter uncertainties, we explored both modelling approaches with rigorous sensitivity analyses. Single-species PVA models were unable to recreate the thylacine's extinction unless a high human harvest, small starting population size or low maximum population growth rate was assumed, even if disease effects were included from 1906 to 1909. In contrast, we readily recreated the thylacine's demise using disease-free multi-species metamodels that simulated declines in native prey populations (particularly due to competition with introduced sheep). Dynamic, multi-species metamodels provide a simple, flexible framework for studying current species declines and historical extinctions caused by complex, interacting factors. PMID- 23347430 TI - Genome-wide mapping of FOXM1 binding reveals co-binding with estrogen receptor alpha in breast cancer cells. AB - BACKGROUND: The forkhead transcription factor FOXM1 is a key regulator of the cell cycle. It is frequently over-expressed in cancer and is emerging as an important therapeutic target. In breast cancer FOXM1 expression is linked with estrogen receptor (ERalpha) activity and resistance to endocrine therapies, with high levels correlated with poor prognosis. However, the precise role of FOXM1 in ER positive breast cancer is not yet fully understood. RESULTS: The study utilizes chromatin immunoprecipitation followed by high-throughput sequencing to map FOXM1 binding in both ERalpha-positive and -negative breast cancer cell lines. The comparison between binding site distributions in the two cell lines uncovered a previously undescribed relationship between binding of FOXM1 and ERalpha. Further molecular analyses demonstrated that these two factors can bind simultaneously at genomic sites and furthermore that FOXM1 regulates the transcriptional activity of ERalpha via interaction with the coactivator CARM1. Inhibition of FOXM1 activity using the natural product thiostrepton revealed down regulation of a set of FOXM1-regulated genes that are correlated with patient outcome in clinical breast cancer samples. CONCLUSIONS: These findings reveal a novel role for FOXM1 in ERalpha transcriptional activity in breast cancer and uncover a FOXM1-regulated gene signature associated with ER-positive breast cancer patient prognosis. PMID- 23347432 TI - Postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting or cardiac valve surgery: intraoperative use of landiolol. AB - BACKGROUND: Landiolol hydrochloride is a new beta-adrenergic blocker with a pharmacological profile that suggests it can be administered safely to patients who have sinus tachycardia or tachyarrhythmia and who require heart rate reduction. This study aimed to investigate whether intraoperative administration of landiolol could reduce the incidence of atrial fibrillation (AF) after cardiac surgery. METHODS: Of the 200 consecutive patients whose records could be retrieved between October 2006 and September 2007, we retrospectively reviewed a total of 105 patients who met the inclusion criteria: no previous permanent/persistent AF, no permanent pacemaker, no renal insufficiency requiring dialysis, and no reactive airway disease, etc. Landiolol infusion was started after surgery had commenced, at an infusion rate of 1 MUg/kg/min, titrated upward in 3-5 MUg/kg/min increments. The patients were divided into 2 groups: those who received intraoperative beta-blocker therapy with landiolol (landiolol group) and those who did not receive any beta-blockers during surgery (control group). An unpaired t test and Fisher's exact test were used to compare between-group differences in mean values and categorical data, respectively. RESULTS: Seventeen of the 105 patients (16.2%) developed postoperative atrial fibrillation: 5/57 (8.8%) in the landiolol group and 12/48 (25%) in the control group. There was a significant difference between the two groups (P=0.03). The incidence of AF after valve surgery and off-pump coronary artery bypass grafting was lower in the landiolol group, although the difference between the groups was not statistically significant. CONCLUSIONS: Our retrospective review demonstrated a marked reduction of postoperative AF in those who received landiolol intraoperatively. A prospective study of intraoperative landiolol for preventing postoperative atrial fibrillation is warranted. PMID- 23347433 TI - Information technology systems in public sector health facilities in developing countries: the case of South Africa. AB - BACKGROUND: The public healthcare sector in developing countries faces many challenges including weak healthcare systems and under-resourced facilities that deliver poor outcomes relative to total healthcare expenditure. Global references demonstrate that information technology has the ability to assist in this regard through the automation of processes, thus reducing the inefficiencies of manually driven processes and lowering transaction costs. This study examines the impact of hospital information systems implementation on service delivery, user adoption and organisational culture within two hospital settings in South Africa. METHODS: Ninety-four interviews with doctors, nurses and hospital administrators were conducted in two public sector tertiary healthcare facilities (in two provinces) to record end-user perceptions. Structured questionnaires were used to conduct the interviews with both qualitative and quantitative information. RESULTS: Noteworthy differences were observed among the three sample groups of doctors, nurses and administrators as well as between our two hospital groups. The impact of automation in terms of cost and strategic value in public sector hospitals is shown to have yielded positive outcomes with regard to patient experience, hospital staff workflow enhancements, and overall morale in the workplace. CONCLUSION: The research provides insight into the reasons for investing in system automation, the associated outcomes, and organisational factors that impact the successful adoption of IT systems. In addition, it finds that sustainable success in these initiatives is as much a function of the technology as it is of the change management function that must accompany the system implementation. PMID- 23347434 TI - Automated podosome identification and characterization in fluorescence microscopy images. AB - Podosomes are cellular adhesion structures involved in matrix degradation and invasion that comprise an actin core and a ring of cytoskeletal adaptor proteins. They are most often identified by staining with phalloidin, which binds F-actin and therefore visualizes the core. However, not only podosomes, but also many other cytoskeletal structures contain actin, which makes podosome segmentation by automated image processing difficult. Here, we have developed a quantitative image analysis algorithm that is optimized to identify podosome cores within a typical sample stained with phalloidin. By sequential local and global thresholding, our analysis identifies up to 76% of podosome cores excluding other F-actin-based structures. Based on the overlap in podosome identifications and quantification of podosome numbers, our algorithm performs equally well compared to three experts. Using our algorithm we show effects of actin polymerization and myosin II inhibition on the actin intensity in both podosome core and associated actin network. Furthermore, by expanding the core segmentations, we reveal a previously unappreciated differential distribution of cytoskeletal adaptor proteins within the podosome ring. These applications illustrate that our algorithm is a valuable tool for rapid and accurate large-scale analysis of podosomes to increase our understanding of these characteristic adhesion structures. PMID- 23347435 TI - A comparison between intensive and conventional cabergoline treatment of newly diagnosed patients with macroprolactinoma. AB - CONTEXT: Intensive treatment with cabergoline may lead to earlier reduction in prolactin and tumour volume in comparison to conventional schedule. OBJECTIVE: To compare the efficacy and safety of two different dosing schedules of cabergoline in patients with macroprolactinoma. DESIGN: Prospective, randomized trial in drug naive patients assigned to conventional (4 weekly escalation by 0.5 mg per week, group A) or intensive (weekly increase by 1 mg per week followed by 4 weekly escalation, group B) treatment with cabergoline. OUTCOME MEASURE: The duration required to achieve normoprolactinemia and tumour shrinkage of >50% as a composite end-point. RESULTS: 38 patients (19 in each group) completed the study with a mean follow-up of 64.3 +/- 24.9 weeks. More subjects (22%) achieved the composite end-point in group B (18/19) as compared to the group A (14/19) (P = 0.18). The duration of cabergoline treatment required to achieve the composite end-point was 13.1 +/- 9.5 weeks vs 19.3 +/- 15.7 weeks (P = 0.34) in the group A and B, respectively. A reduction in prolactin of >=90% by the fourth week of cabergoline therapy predicted subsequent normalization of prolactin (AUC 0.78; P = 0.04). A further increase in cabergoline dosage after normalization of prolactin in patients with tumour reduction of <50%, led to further tumour shrinkage by 31.2% in an additional 26.3% of patients. CONCLUSIONS: Intensive treatment with cabergoline is not superior to the conventional recommended dosage schedule in respect to the time necessary to achieve normoprolactinemia and >=50% tumour shrinkage. CLINICAL TRIAL REGISTRY: NCT 01143584. PMID- 23347436 TI - Borrelia crocidurae meningoencephalitis, West Africa. AB - Borrelia crocidurae-associated relapsing fever is endemic to West Africa and is considered benign. We report 4 patients with B. crocidurae-associated neurologic symptoms; 2 of their cases had been misdiagnosed. Frequency and severity of this disease could be underestimated; molecular methods and serodiagnostic tests for Lyme disease might be helpful in its detection. PMID- 23347437 TI - Survey of non-B, non-C liver cirrhosis in Japan. AB - AIM: The aim of this survey was to reveal clinical features for each etiology of non-B, non-C liver cirrhosis (NBNC LC) in Japan. METHODS: In a nationwide survey of NBNC LC in Japan at the 15th General Meeting of the Japan Society of Hepatology, 6999 NBNC LC patients were registered at 48 medical institutions. Epidemiological and clinical factors were investigated. RESULTS: The percentage of NBNC LC among LC patients was 26%. NBNC LC patients were categorized into 11 types according to etiological agents: non-alcoholic steatohepatitis (NASH), 14.5%; alcoholic liver disease (ALD), 55.1%; fatty liver disease (FLD), except NASH, ALD, and other known etiology, 2.5%; primary biliary cirrhosis, 8.0%; other biliary cirrhosis, 0.8%; autoimmune hepatitis, 6.8%; metabolic disease, 0.6%; congestive disease, 0.8%; parasitic disease, 0.2%; other known etiology, 0.2%; and unknown etiology, 10.5%. Compared with previous surveys, the percentage of ALD remained unchanged, whereas that of NASH increased. The mean age and percentage of females were significantly higher in NASH patients than in ALD and FLD patients. Prevalence of diabetes mellitus was significantly higher in NASH and FLD patients than in ALD ones. Prevalence of hepatocellular carcinoma (HCC) in NBNC LC patients was 35.9%. Among NASH, ALD and FLD patients, 50.9%, 34.3% and 54.5% had HCC, respectively. Positivity of hepatitis B core antibody was significantly higher in HCC patients than in those without HCC (41.1% vs 24.8%). CONCLUSION: This survey determined the etiology of NBNC LC in Japan. These results should contribute new ideas toward understanding NBNC LC and NBNC HCC. PMID- 23347438 TI - A bi-national perspective on the management of young patients with colorectal cancer. AB - BACKGROUND: Young patients with colorectal cancer pose diagnostic and management challenges. The study aim was to assess colorectal surgical practice in Australia and New Zealand with respect to management of young patients with colorectal cancer and the impact of family history. METHODS: An electronic survey was sent to members of the Colorectal Surgical Society of Australia and New Zealand (CSSANZ). The survey assessed the clinical practice of the respondent and utilized scenario-based questions to investigate their clinical approach to patients under 50 years who develop colorectal cancer with respect to management and surveillance. Colorectal society trainees, members and fellows were also questioned on a scenario of polyposis and no vertical transmission, and which operation they would perform. RESULTS: Of the 189 surveys sent out, 114 respondents completed the survey (60.3%) with 99 (86.8%) respondents practicing colorectal surgeons and 13.2% (15) CSSANZ trainees. Ninety-five percent of respondents had a practice with greater than 70% colorectal work. Of the surgeons and trainees, 92.1% (105) would perform a limited resection in a young patient with a right-sided cancer. Six percent altered the approach if there was a first degree relative with colorectal cancer, and 68% altered the approach if the family history fulfilled criteria for hereditary non-polyposis colorectal cancer. Only 22.8% of respondents could recognize potential MutYH-associated polyposis with moderate polyposis and absence of vertical transmission. DISCUSSION: Colorectal surgeons in Australia will modify their management of patients under 50 years with colorectal cancer based on a family history and risk of inherited colorectal cancer syndromes. Further education could improve management. PMID- 23347439 TI - Readmissions for COPD: propensity case-matched comparison between pulmonary and non-pulmonary departments. AB - INTRODUCTION: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common cause of hospitalisation, and the readmission rate is high. We aimed to determine whether patients discharged from a pulmonary department (PD) after an AECOPD episode had a lower COPD-related readmission rate during the next 12 months than comparable patients discharged from other internal medicine departments (ODs). METHODS: The medical records of 566 patients discharged after an episode of AECOPD between March 2006 and December 2008 at Oslo University Hospital, Aker, were reviewed retrospectively. Demographic and medical data, together with number of readmissions because of AECOPD during 12 months following the index admission were extracted. We matched patients discharged from the PD and the ODs using a propensity score and used the paired t-test to compare COPD related readmission rates between the matched patients. RESULTS: In total, 481 patients were included in the analysis, 247 patients discharged from the PD and 234 from ODs. The propensity score matching process resulted in 155 well-matched pairs. The mean (standard deviation) number of readmissions within 1 year was 0.8 (1.3) for the PD versus 1.1 (1.9) for ODs (P = 0.09). After adjusting for exposure time, the corresponding readmission rates were 1.1 (2.3) and 1.6 (4.0) per year, respectively (P = 0.17). CONCLUSION: There was little difference in COPD-related readmission rates between comparable patients discharged from the PD and the ODs after an AECOPD during 1 year following the index admission. PMID- 23347440 TI - [Surgeons, financial crisis and burnout]. PMID- 23347442 TI - Concerns about the future of the scientific workforce. PMID- 23347441 TI - Systematic review of the incidence and prevalence of genital warts. AB - BACKGROUND: Anogenital warts (AGWs) are a common, highly infectious disease caused by the human papillomavirus (HPV), whose high recurrence rates contribute to direct medical costs, productivity loss and increased psychosocial impact. Because of the lack of a systematic review of the epidemiology of AGWs in the literature, this study reviewed the published medical literature on the incidence and prevalence of AGWs. METHODS: A comprehensive literature search was performed on the worldwide incidence and prevalence of AGWs between 2001 and 2012 using the PubMed and EMBASE databases. An additional screening of abstracts from relevant sexual health and infectious disease conferences from 2009 to 2011 was also conducted. Only original studies with general adult populations (i.e., at least including ages 20 through 40 years) were included. RESULTS: The overall (females and males combined) reported annual incidence of any AGWs (including new and recurrent) ranged from 160 to 289 per 100,000, with a median of 194.5 per 100,000. New AGW incidence rates among males ranged from 103 to 168 per 100,000, with a median of 137 per 100,000 and among females from 76 to 191 per 100,000, with a median of 120.5 per 100,000 per annum. The reported incidence of recurrent AGWs was as high as 110 per 100,000 among females and 163 per 100,000 among males. Incidence peaked before 24 years of age in females and between 25 and 29 years of age among males. The overall prevalence of AGWs based on retrospective administrative databases or medical chart reviews or prospectively collected physician reports ranged from 0.13% to 0.56%, whereas it ranged from 0.2% to 5.1% based on genital examinations. CONCLUSIONS: The literature suggests that AGWs are widespread and the prevalence depends on study methodology as suggested by higher rates reported from routine genital examinations versus those from treatment records. However, there remains a need for more population-based studies from certain regions including Africa, Latin America and Southern Asia to further elucidate the global epidemiology of this disease. PMID- 23347444 TI - Crocin triggers the apoptosis through increasing the Bax/Bcl-2 ratio and caspase activation in human gastric adenocarcinoma, AGS, cells. AB - We previously showed the anticancer property of crocin, a carotenoid isolated and purified from saffron against chemical-induced gastric and breast cancer in rats. In this study, the mechanism of crocin action was investigated in the gastric adenocarcinoma (AGS) cells in comparison with human normal fibroblast skin cells (HFSF-PI3). Crocin revealed a dose- and time-dependent cytotoxic effect against an AGS cell line, as determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Crocin-induced apoptosis was evidenced by flow cytometry and measuring caspase activity. The increased sub-G1 population and activated caspases in the treated AGS cells confirmed its anticancer effect. Expression of both Bax and Bcl-2 was determined using a semiquantitative reverse transcriptase-polymerase chain reaction and Western blot in these cells before and after treatment with crocin. Apoptosis was significantly stimulated as indicated by increasing the Bax/Bcl-2 ratio after crocin treatment. All of the above-mentioned parameters remained normal in HFSF-PI3 treated with crocin. These data are providing insight into the molecular mechanisms underlying the crocin induced apoptosis in the AGS cells, rendering it as the potential anticancer agent. PMID- 23347443 TI - Signaling molecules involved in lipid-induced pancreatic beta-cell dysfunction. AB - The increasing incidence of type 2 diabetes mellitus is partially due to the rising obesity rates and the elevated levels of free fatty acids (FFAs). It is known that FFAs are putative mediators of beta-cell dysfunction, which is characterized with impaired glucose-stimulated insulin secretion and increased apoptosis, being defined as lipotoxicity. To date, many factors and their related signal pathways have been reported to be involved in FFA-induced beta-cell dysfunction. However, the entire blueprint is still not obtained. Some essential and newfound effectors, including the sterol regulatory element-binding protein (SREBP)-1c, farnesoid X receptor (FXR), forkhead box-containing protein O (FoxO) 1, ubiquitin C-terminal hydrolase L (UCHL) 1, N-myc downstream-regulated gene (NDRG) 2, perilipin family proteins, silent information regulator 2 protein 1 (Sirt1), pituitary adenylate cyclase-activating polypeptide (PACAP), and ghrelin are described in this review, which may help to further understand the molecular network for lipotoxicity. PMID- 23347445 TI - Effects of the adverse life events and Disrupted in Schizophrenia-1 (DISC1) gene polymorphisms on acute symptoms of schizophrenia. AB - The aim of this study was to evaluate the effects of traumatic childhood events and recent adverse life events, as well as the Disrupted in Schizophrenia-1 (DISC1) gene polymorphisms on types of last acute symptoms of patients with schizophrenia. Hundred patients with schizophrenia were given the Childhood Trauma Questionnaire, the Social Readjustment Rating Scale, Scale for Assessment of Positive Symptoms (SAPS), Scale for Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), and Calgary Depression Scale for Schizophrenia (CDSS). The patients' and healthy controls' DISC1 gene was evaluated for the -274G>C, c.791G>A, and c.2110A>T polymorphisms. There was no statistically significant difference with regard to the DISC1 gene polymorphisms between patient and healthy control groups. No significant relationship was found between the -274G>C, c.791G>A, and c.2110A>T haplotypes and development of different acute symptoms of schizophrenia. Having a recent stressful life event significantly affected SAPS (95% confidence interval [CI]=-67.547, -21.473; p=0.00) and BPRS-1 scores (95% CI=-51.405, -6.885; p=0.01), whereas emotional abuse at childhood significantly affected SANS scores (95% CI=-37.300, -10.401; p=0.00). This study shows that features of acute symptoms in schizophrenia are not influenced by the polymorphisms on the DISC1 gene, but are influenced by recent adverse life events and emotional abuse at childhood. PMID- 23347447 TI - Dual origin of melanocytes defined by Sox1 expression and their region-specific distribution in mammalian skin. AB - Melanocytes are pigment-producing cells generated from neural crest cells (NCCs) that delaminate from the dorsal neural tube. The widely accepted premise that NCCs migrating along the dorsolateral pathway are the main source of melanocytes in the skin was recently challenged by the finding that Schwann cell precursors are the major cellular source of melanocytes in the skin. Still, in a wide variety of vertebrate embryos, melanocytes are exclusively derived from NCCs. In this study, we show that a NCC population that is not derived from Sox1(+) dorsal neuroepithelial cells but are derived from Sox1(-) cells differentiate into a significant population of melanocytes in the skin of mice. Later, these Sox1(-) cells clearly segregate from cells that originated from Sox1(+) dorsal neuroepithelial cell-derived NCCs. The possible derivation of Sox1(-) cells from epidermal cells also strengthens their non-neuroepithelial origin. PMID- 23347448 TI - A hybrid zone between Bathymodiolus mussel lineages from eastern Pacific hydrothermal vents. AB - BACKGROUND: The inhabitants of deep-sea hydrothermal vents occupy ephemeral island-like habitats distributed sporadically along tectonic spreading-centers, back-arc basins, and volcanically active seamounts. The majority of vent taxa undergo a pelagic larval phase, and thus varying degrees of geographical subdivision, ranging from no impedance of dispersal to complete isolation, often exist among taxa that span common geomorphological boundaries. Two lineages of Bathymodiolus mussels segregate on either side of the Easter Microplate, a boundary that separates the East Pacific Rise from spreading centers connected to the Pacific-Antarctic Ridge. RESULTS: A recent sample from the northwest flank of the Easter Microplate contained an admixture of northern and southern mitochondrial haplotypes and corresponding alleles at five nuclear gene loci. Genotypic frequencies in this sample did not fit random mating expectation. Significant heterozygote deficiencies at nuclear loci and gametic disequilibria between loci suggested that this transitional region might be a 'Tension Zone' maintained by immigration of parental types and possibly hybrid unfitness. An analysis of recombination history in the nuclear genes suggests a prolonged history of parapatric contact between the two mussel lineages. We hereby elevate the southern lineage to species status as Bathymodiolus antarcticus n. sp. and restrict the use of Bathymodiolus thermophilus to the northern lineage. CONCLUSIONS: Because B. thermophilus s.s. exhibits no evidence for subdivision or isolation-by-distance across its 4000 km range along the EPR axis and Galapagos Rift, partial isolation of B. antarcticus n. sp. requires explanation. The time needed to produce the observed degree of mitochondrial differentiation is consistent with the age of the Easter Microplate (2.5 to 5.3 million years). The complex geomorphology of the Easter Microplate region forces strong cross-axis currents that might disrupt self-recruitment of mussels by removing planktotrophic larvae from the ridge axis. Furthermore, frequent local extinction events in this tectonically dynamic region might produce a demographic sink rather than a source for dispersing mussel larvae. Historical changes in tectonic rates and current patterns appear to permit intermittent contact and introgression between the two species. PMID- 23347449 TI - Trade-offs in cavefish sensory capacity. AB - In caves one repeatedly finds strikingly convergent patterns of evolution in diverse sets of organisms involving 'regressive' traits such as the loss of eyes and pigmentation. Ongoing debate centers around whether these regressive traits arise as the result of neutral evolutionary processes, or rather by natural selection of 'constructive' traits that arise at the expense of eyes and pigmentation. Recent research on cavefish points to the latter, suggesting that the 'constructive' trait vibrational attractive behavior and the reduction of eye size may share a common genetic basis.See research article http://www.biomedcentral.com/1741-7007/10/108. PMID- 23347450 TI - Plastic larval development in a butterfly has complex environmental and genetic causes and consequences for population dynamics. AB - 1. In insects, the length of larval development time typically influences adult body size and individual fitness, and hence development time can be expected to respond in an adaptive manner to variation in environmental conditions. In the wild, larval growth may be influenced by individual condition, which can be affected by population-level parameters such as population density and abundance and quality of resources. 2. We sampled larvae of the Glanville fritillary butterfly (Melitaea cinxia) from 514 local populations across a large metapopulation before the winter diapause and reared the larvae in common garden conditions after diapause. Here, we report that small post-diapause larvae prolonged their development via an extra larval instar, apparently to compensate for their 'bad start' after diapause. The number of instars was additionally a plastic response to environmental conditions, as the frequency of the extra instar increased under cooler thermal conditions. 3. The benefit of the extra instar is clear, as it allows individuals to develop into larger adults, but the cost is delayed adult eclosion, which is likely to select against the extra instar especially in males, in which early eclosion is critical for mating success. In support of this, the frequency of the extra instar was significantly lower in males (7%) than in females (42%). 4. Polymorphisms in three genes, serpin-1, vitellin-degrading protease precursor and phosphoglucose isomerase, which are known to influence development in insects, were associated with the occurrence of the extra instar. 5. At the level of local populations, the frequency of the extra instar was higher in newly established populations than that in old local ones, possibly reflecting maternal effects, as new populations are often established by females with heavy investment in dispersal. The frequency of the extra instar in turn correlated with the change in population size over 1 year and the risk of local extinction in the natural metapopulation of the Glanville fritillary. 6. Our results highlight the importance of the physiological condition of individuals in shaping subsequent life-history events and even population dynamics. PMID- 23347451 TI - Influenza A(H5N1) virus surveillance at live poultry markets, Cambodia, 2011. AB - In Cambodia, influenza A(H5N1) virus surveillance at live poultry markets (LPMs) relies on virus isolation from poultry specimens; however, virus is rarely detected by this method. We tested 502 environmental LPM samples: 90 were positive by PCR, 10 by virus isolation. Virus circulation could be better monitored by environmental sampling of LPMs. PMID- 23347452 TI - Selective accumulation of platinum and formation of platinum-DNA adducts in hepatocellular carcinoma after transarterial chemoembolization with miriplatin. AB - AIM: Miriplatin, a lipophilic platinum complex, is a novel intra-arterial chemotherapeutic agent for hepatocellular carcinoma (HCC). Little is known about platinum-DNA adduct levels in human HCC after administration of platinum-based drugs. We investigated whether miriplatin selectively accumulates and forms platinum-DNA adducts in human HCC tumors. METHODS: Using inductively coupled plasma mass spectrometry, we determined the platinum concentrations and platinum DNA adduct levels in paired HCC tumors and non-tumor liver tissues of four patients who received transcatheter arterial chemoembolization with miriplatin and subsequently underwent hepatic resection. RESULTS: The mean (+/- standard deviation) platinum concentrations were 730 +/- 350 MUg/g (range, 400-1100) in HCC tumors and 16 +/- 9.2 MUg/g (range, 9.2-29) in non-tumor liver tissues. The concentrations were approximately 50-fold higher in HCC tumors than in non-tumor liver tissues. The mean platinum-DNA adduct levels were 54 +/- 16 pg Pt/MUg DNA (range, 37-69) in HCC tumors and 13 +/- 13 pg Pt/MUg DNA (range, 4.8-33) in non tumor liver tissues. The adduct levels were roughly 7.6-fold higher in HCC tumors than in non-tumor liver tissues. There were no significant correlations between platinum concentrations and platinum-DNA adduct levels in HCC tumors. CONCLUSION: Our results quantitatively demonstrate that there is a selective accumulation of platinum and formation of platinum-DNA adducts in human HCC tumors after transarterial chemoembolization with miriplatin. No correlation was observed between platinum concentrations and platinum-DNA adduct levels. PMID- 23347454 TI - Female sexual dysfunction and diabetes: a systematic review and meta-analysis. AB - INTRODUCTION: Sexual dysfunction is reported in diabetic women (female sexual dysfunction [FSD]). AIM: To examine the frequency of FSD in diabetic women, and its clinical or metabolic correlates, through meta-analysis of available studies. METHODS: We searched in MEDLINE, EMBASE, Cochrane Library, and in reference lists of articles and systematic reviews; we considered human clinical studies published as full articles reporting on FSD in diabetic and control women. In total, we considered 26 studies, including 3,168 diabetic and 2,823 control women. MAIN OUTCOME MEASURES: Frequency of FSD and score of Female Sexual Function Index (FSFI) as a function of study size, patient details (age, body mass index [BMI], duration of diabetes, metabolic control [HbA1c], chronic complications, Beck Depression Inventory [BDI] score). RESULTS: Frequency of FSD was higher in type 1 (OR [95%CI] 2.27 [1.23, 4.16]), in type 2 diabetes (2.49 [1.55, 3.99]), and in "any diabetes" (type 1 and 2) women (2.02 [1.49, 2.72]) than in controls for any duration of diabetes. FSFI was lower in type 1 (-0.27 [ 0.41, -0.12]), in type 2 diabetes (-0.65 [-0.75, -0.54]), and in "any diabetes" women (-0.80 [-0.88, -0.71]) than in controls. Depression was significantly more frequent in diabetic than in control women. At meta-regression only BMI was significantly associated with effect size (P = 0.005). At weighed regression, the only significant association was found between age and FSFI (P = 0.059). The limitations were as follows: only studies of observational nature were available, and heterogeneity was seen among studies. CONCLUSIONS: FSD is more frequent in diabetic than in control women, but it is still poorly understood; low FSFI is associated with high BMI. Further studies are necessary to better understand risk factors for FSD in diabetic women. PMID- 23347453 TI - Does googling for preconception care result in information consistent with international guidelines: a comparison of information found by Italian women of childbearing age and health professionals. AB - BACKGROUND: Preconception counseling is effective in reducing the risk of adverse pregnancy outcomes. The Internet is commonly used by women and health professionals to search for health information. We compared the consistency of preconception information found on the Internet with the recommendations published by American Journal of Obstetrics and Gynecology (AJOG) simulating a web search by women of childbearing age and health professionals. METHODS: We reviewed websites resulting from a Google search performed using search strings selected by Italian women of childbearing age and health professionals. We investigated if retrieved information was consistent with AJOG recommendations for preconception care. Logistic regression was used to compare presence of consistent recommendations between women and health professionals. RESULTS: The highest frequency of correct recommendations was found for folic acid supplementation (39.4% of websites). Consistency of preconception information did not significantly differ between search strategies except for folic acid supplementation. "Communities and blogs" website category provided less frequently correct recommendations compared with "Medical/Public Agency" category (i.e. folic acid supplementation (aOR 0.254; CI 0.098-0.664; p = <0.01). Commercial links, found in 60% of websites, were associated with presence of correct recommendations excepting few items (i.e. physical exercise (aOR 1.127; CI 0.331-3.840; p = 0.848). CONCLUSIONS: Preconception information found is poor and inaccurate regardless of the search is performed by women or health professionals. It is unlikely that information found on the web have any positive impact among women and health professionals in our setting. Strategies to improve preconception information on the web and education of health professionals for web searching of health information should be considered. PMID- 23347455 TI - The Refugee Health Screener-15 (RHS-15): development and validation of an instrument for anxiety, depression, and PTSD in refugees. AB - OBJECTIVE: Screening for emotional distress in newly arrived refugees is not a standard practice due to multiple barriers, one being the absence of a valid screening instrument for multiple refugee populations. The Refugee Health Screener-15 (RHS-15) was empirically developed to be a valid, efficient and effective screener for common mental disorders in refugees. METHOD: Development followed published methods. Two hundred fifty-one refugees from three countries were screened at their public health visit with a pilot instrument, and 190 were administered diagnostic proxy instruments (DPs). Data analyses using multiple methods selected the best items for classification on DPs. Follow-up clinical service data were obtained. RESULTS: Post hoc analyses of the developed RHS-15 showed good sensitivity(range .81 to .95) and specificity (range .86 to .89) to DP's in two of three ethnic groups. Seventy-four percent of positive cases accepted treatment services. Of those, 79% engaged in treatment, and 92% continued treatment more than 3 months. CONCLUSIONS: The RHS-15 is a screener for common mental disorders in newly-arrived refugees in public health. The RHS 15appears to be effective, but further prospective research in a broad range of refugee groups is required to establish generalizability. Strengths, limitations, methods to apply the RHS-15 for optimal performance, and future directions for research and implementation are discussed. PMID- 23347456 TI - Musical hallucinations of an unidentified melody. PMID- 23347457 TI - Three-dimensional semiconductor device investigation using focused ion beam and scanning electron microscopy imaging (FIB/SEM tomography). AB - Three-dimensional focused ion beam/scanning electron microscopy (FIB/SEM tomography) is currently an important technique to characterize in 3D a complex semiconductor device or a specific failure. However, the industrial context demands low turnaround time making the technique less useful. To make it more attractive, the following study focuses on a specific methodology going from sample preparation to the final volume reconstruction to reduce the global time analysis while keeping reliable results. The FIB/SEM parameters available will be first analyzed to acquire a relevant dataset in a reasonable time (few hours). Then, a new alignment strategy based on specific alignment marks [using tetraethoxylisane (TEOS) and Pt deposition] is proposed to improve the volume reconstruction speed. These points combined represent a considerable improvement regarding the reliability of the results and the time consumption (gain of factor 3). This method is then applied to various case studies illustrating the benefits of the FIB/SEM tomography technique such as the precise identification of the origin of 3D defects, or the capability to perform a virtual top-down deprocessing on soft material not possible by any mechanical solution. PMID- 23347459 TI - Antifungal coatings based on Ca(OH)2 mixed with ZnO/TiO2 nanomaterials for protection of limestone monuments. AB - The presence and deteriorating action of microbial biofilms on historic stone buildings have received considerable attention in the past few years. Among microorganisms, fungi are one of the most damaging groups. In the present work, antimicrobial surfaces were prepared using suspensions of Ca(OH)2 particles, mixed with ZnO or TiO2 nanoparticles. The antimicrobial surfaces were evaluated for their antifungal activity both in the dark and under simulated natural photoperiod cycles, using Penicillium oxalicum and Aspergillus niger as model organisms, and two limestone lithotypes commonly used in construction and as materials for the restoration of historic buildings. Both Ca(OH)2-ZnO and Ca(OH)2 TiO2 materials displayed antifungal activity: ZnO-based systems had the best antifungal properties, being effective both in the dark and under illumination. In contrast, TiO2-based coatings showed antifungal activity only under photoperiod conditions. Controls with coatings consisting of only Ca(OH)2 were readily colonized by both fungi. The antifungal activity was monitored by direct observation with microscope, X-ray diffraction (XRD), and scanning electron microscopy (SEM), and was found to be different for the two lithotypes, suggesting that the mineral grain distribution and porosity played a role in the activity. XRD was used to investigate the formation of biominerals as indicator of the fungal attack of the limestone materials, while SEM illustrated the influence of porosity of both the limestone material and the coatings on the fungal penetration into the limestone. The coated nanosystems based on Ca(OH)2 50%ZnO and pure zincite nanoparticulate films have promising performance on low porosity limestone, showing good antifungal properties against P. oxalicum and A. niger under simulated photoperiod conditions. PMID- 23347458 TI - Comparison of serum cystatin C, serum creatinine, measured GFR, and estimated GFR to assess the risk of kidney failure in American Indians with diabetic nephropathy. AB - BACKGROUND: We compared values of baseline serum cystatin C (SCysC), serum creatinine (SCr), and measured glomerular filtration rate (mGFR) for predicting end-stage renal disease (ESRD) in patients with type 2 diabetes and elevated albuminuria. STUDY DESIGN: Observational longitudinal study. SETTING & PARTICIPANTS: Pima Indians with type 2 diabetes and elevated albumin-creatinine ratio (ACR >=30 mg/g). PREDICTORS: Baseline SCysC, SCr, and mGFR. OUTCOMES & MEASUREMENTS: Individuals were followed up from their first examination with diabetes and ACR >=30 mg/g until December 2010, onset of ESRD, or death, whichever came first. Incidence rates adjusted for age and sex were computed by Mantel-Haenszel stratification. The abilities of SCysC, SCr, and mGFR values to predict ESRD were compared with receiver operating characteristic curves. RESULTS: Of 234 Pima Indians with a mean age of 42.8 years who were followed up for a median of 10.7 (range, 0.6-21.3) years, 68 (29%) developed ESRD. The incidence of ESRD was significantly higher in patients in the lowest versus highest tertile of 1/SCysC (incidence rate ratio, 2.43; 95% CI, 1.31-4.50). By contrast, mGFR and 1/SCr had J-shaped associations with ESRD. In unadjusted analyses, 1/SCysC had the highest area under the receiver operating characteristic curve (AUROC; 0.719 +/- 0.035) and mGFR had the lowest (0.585 +/- 0.042; P < 0.001); the AUROC for 1/SCr was intermediate (0.672 +/- 0.040; P = 0.1 and P = 0.03 vs 1/SCysC and mGFR, respectively). In analyses adjusted for age, sex, diabetes duration, height, weight, hemoglobin A1c level, and ACR, 1/SCysC had the highest AUROC (0.845 +/- 0.026). Models with mGFR or 1/SCr alone had similar AUROCs (P = 0.9) and both were lower than the model with 1/SCysC alone (P = 0.02 and P = 0.03, respectively). LIMITATIONS: The predictive values of the filtration markers are limited to the extent that their precision is based on a single measurement. CONCLUSIONS: SCysC level was a better predictor of ESRD than mGFR or SCr level in Pima Indians with type 2 diabetes and elevated albuminuria. PMID- 23347460 TI - The silence of MUC2 mRNA induced by promoter hypermethylation associated with HBV in Hepatocellular Carcinoma. AB - BACKGROUND: To evaluate the promoter methylation status of MUC2 gene and mRNA expression in patients with hepatocellular carcinoma. METHODS: We analyzed MUC2 methylation by MSP, and MUC2 mRNA by real-time PCR in 74 HCC. RESULTS: MUC2 mRNA were lower in HCC tissues (Mean -DeltaCt = -4.70) than that in Non-HCC tissues (Mean -DeltaCt = -2.98). Expression of MUC2 was elevated in only 23 (31.08%) of the 74 HCC patients. MUC2 promoter was hypermethylated in 62.2% (46/74) of HCCs, and in only 18.9% (14/74) of non-tumor samples. MUC2 mRNA were lower in HCC patients with hypermethylation (Mean -DeltaDeltaCt = -2.25) than those with demethylation (Mean -DeltaDeltaCt = -0.22), and there is a decreased tendency for MUC2 mRNA in HCC patients with promoter hypermethylation (p = 0.011). There was a significantly correlation found between MUC2 mRNA and HBV and AFP in HCC. The loss of MUC2 mRNA and hypermethylation could be poor prognostic factors. After treated by 5-Aza-CdR and TSA, we found that MUC2 mRNA induced significantly in 7721, Huh7 and HepG2 cells. CONCLUSION: The results suggested that MUC2 mRNA silenced by promoter hypermethylation is associated with high levels HBV in HCC. PMID- 23347461 TI - Exercise barriers and preferences among women and men with multiple sclerosis. AB - PURPOSE: The primary objective of this study was to estimate the extent to which women and men with MS present different exercise barriers. The secondary objective was to estimate the extent to which women and men with MS present different perceived-health, depressive symptoms, and current exercise routines or preferences. METHODS: This was a cross sectional survey. RESULTS: 417 people with MS completed a survey of exercise barriers and current exercise routines, perceived-health and depressive symptoms. The top three exercise barriers were: too tired; impairment; and lack of time, regardless of their gender. Regardless of their gender, three times/week and 60 min/session was identified as the most common current exercise structure among physically active participants. The top three currently preferred exercise by men included walking, strengthening/weights and flexibility/stretch exercise. Women reported the same three exercises but flexibility/stretch exercise were slightly more popular than other exercise. Similarities in perceived health status and depressive symptoms were seen between women and men; expect more men were diagnosed with progressive MS (20% higher) than women, leading to a higher rate of men reporting problems with mobility. CONCLUSION: Women and men with MS differed very little on exercise barriers and current exercise routines, perceived health and depressive symptoms. Even though MS is generally considered a woman's disease, this study did not find a strong need to develop gender specific exercise or physical activity interventions for this population. PMID- 23347462 TI - Identification of medium-sized genomic deletions with low coverage, mate-paired restricted tags. AB - BACKGROUND: Genomic deletions are known to be widespread in many species. Variant sequencing-based approaches for identifying deletions have been developed, but their powers to detect those deletions that affect medium-sized regions are limited when the sequencing coverage is low. RESULTS: We present a cost-effective method for identifying medium-sized deletions in genomic regions with low genomic coverage. Two mate-paired libraries were separately constructed from human cancerous tissue to generate paired short reads (ditags) from restriction fragments digested with a 4-base restriction enzyme. A total of 3 Gb of paired reads (1.0* genome size) was collected, and 175 deletions were inferred by identifying the ditags with disorder alignments to the reference genome sequence. Sanger sequencing results confirmed an overall detection accuracy of 95%. Good reproducibility was verified by the deletions that were detected by both libraries. CONCLUSIONS: We provide an approach to accurately identify medium sized deletions in large genomes with low sequence coverage. It can be applied in studies of comparative genomics and in the identification of germline and somatic variants. PMID- 23347463 TI - Integrating genetic and imaging investigations into the clinical management of congenital hyperinsulinism. AB - Congenital Hyperinsulinism (CHI) is a rare but important cause of hypoglycaemia in infancy. CHI is a heterogeneous disease, but has a strong genetic basis; a number of genetic causes have been identified with CHI in about a third of individuals, chiefly in the genes that code for the ATP sensitive K(+) channels (KATP ) in the pancreatic beta-cells. Rapid KATP channel gene testing is a critical early step in the diagnostic algorithm of CHI, with paternal heterozygosity correlating with the occurrence of focal lesions. Imaging investigations to diagnose and localize solitary pancreatic foci have evolved over the last decade with (18)F-DOPA PET-CT scanning as the current diagnostic tool of choice. Although clinical management of CHI has improved significantly with the application of genetic screening and imaging investigations, much remains to be uncovered. This includes a better understanding of the molecular mechanisms for dysregulated insulin release in those patients without known genetic mutations, and the development of biomarkers that could characterize CHI, including long-term prognosis and targeted treatment planning, i.e. 'personalised medicine'. From the perspective of pancreatic imaging, it would be important to achieve greater specificity of diagnosis not only for focal lesions but also for diffuse and atypical forms of the disease. PMID- 23347464 TI - Mitochondrial genome primers for Lake Malawi cichlids. AB - Resolving the evolutionary history of rapidly diversifying lineages like the Lake Malawi Cichlid Flock demands powerful phylogenetic tools. Although this clade of over 500 species of fish likely diversified in less than two million years, the availability of extensive sequence data sets, such as complete mitochondrial genomes, could help resolve evolutionary patterns in this group. Using a large number of newly developed primers, we generated whole mitochondrial genome sequences for 14 Lake Malawi cichlids. We compared sequence divergence across protein-coding regions of the mitochondrial genome and also compared divergence in the mitochondrial loci to divergence at two nuclear protein-coding loci, Mitfb and Dlx2. Despite the widespread sharing of haplotypes of identical sequences at individual loci, the combined use of all protein-coding mitochondrial loci provided a bifurcating phylogenetic hypothesis for the exemplars of major lineages within the Lake Malawi cichlid radiation. The primers presented here could have substantial utility for evolutionary analyses of mitochondrial evolution and hybridization within this diverse clade. PMID- 23347465 TI - pH induced reversible assembly of DNA wrapped carbon nanotubes. AB - BACKGROUND: Reversible assembly and disassembly of nanostructures has important function in controllable construction of nanodevices. There are several methods to achieve reversible assembly/disassembly, such as pH, temperature, DNA hybridization and so on. Among these methods, pH driven reversible assembly presents superiority due to its ease-of-use and no waste produced. Herein we report a novel design that use two single-stranded (ss) DNAs wrapped single walled carbon nanotubes (SWCNTs) for the pH controlled assembly of SWCNTs without generation of waste. RESULTS: Both of the two DNAs with a same wrapping sequence of d(GT)20 and different free terminals showed a very high tendency to wrap around carbon nanotubes. The assembly was driven by the hybridization between the two free terminals of wrapped DNAs on the neighboring SWCNTs: i-motif (four stranded C-quadruplex) and its complemental stranded G-quadruplex which would form tight tetraplexes and break the hybridization under slightly acidic conditions. Thus the assembly and disassembly are reversibly controlled by pH. And this assembly/disassembly process can be easily distinguished by naked eyes. Gel electrophoresis and Atomic Force Microscope are used to demonstrate the assembly and disassembly of SWCNTs at different pH. CONCLUSIONS: A novel pH induced reversible assembly and disassembly of SWCNTs was realized which may have potential applications in the area of controlled assembly of nanostructures. PMID- 23347466 TI - Current options for management of biliary atresia. AB - It is encouraging that we are improving the technical aspects of treatment modalities for biliary atresia. However, it is clear that more needs to be done to best develop new treatment plans while applying the modalities we have (porto enterostomy or liver transplantation or both) in a way that will afford the best survival and quality-of-life. This review article will discuss a number of points that are vital to improving care and illustrates the need to further scrutinize treatment decisions. PMID- 23347468 TI - Commentary on: Comparison of chest digital tomosynthesis and chest radiography for detection of asbestos-related pleuropulmonary disease. PMID- 23347467 TI - Actigraphy assessments of circadian sleep-wake cycles in the Vegetative and Minimally Conscious States. AB - BACKGROUND: The Vegetative and Minimally Conscious States (VS; MCS) are characterized by absent or highly disordered signs of awareness alongside preserved sleep-wake cycles. According to international diagnostic guidelines, sleep-wake cycles are assessed by means of observations of variable periods of eye-opening and eye-closure. However, there is little empirical evidence for true circadian sleep-wake cycling in these patients, and there have been no large scale investigations of the validity of this diagnostic criterion. METHODS: We measured the circadian sleep-wake rhythms of 55 VS and MCS patients by means of wrist actigraphy, an indirect method that is highly correlated with polysomnographic estimates of sleeping/waking. RESULTS: Contrary to the diagnostic guidelines, a significant proportion of patients did not exhibit statistically reliable sleep-wake cycles. The circadian rhythms of VS patients were significantly more impaired than those of MCS patients, as were the circadian rhythms of patients with non-traumatic injuries relative to those with traumatic injuries. The reliability of the circadian rhythms were significantly predicted by the patients' levels of visual and motor functioning, consistent with the putative biological generators of these rhythms. CONCLUSIONS: The high variability across diagnoses and etiologies highlights the need for improved guidelines for the assessment of sleep-wake cycles in VS and MCS, and advocates the use of actigraphy as an inexpensive and non-invasive alternative. PMID- 23347469 TI - Clinical applications of preoperative perforator planning using CT angiography in the anterolateral thigh perforator flap transplantation. AB - AIM: To evaluate the reliability and utility of preoperative perforator planning using computed tomography angiography (CTA) in anterolateral thigh perforator flap (ALTPF) transplantation. MATERIALS AND METHODS: Thirty-two consecutive patients who underwent extremity reconstruction using the ALTPF were retrospectively reviewed from 2008 to 2012. These patients were divided into two groups. In group I (n = 16), suitable perforators were designed based on four criteria using CTA. These were used for the operation and compared with the intraoperative findings. In group II (n = 16), all patients underwent operation using conventional methods without preoperative perforator planning. The surgical results of all patients were evaluated for flap complications, alteration of the donor site, donor site morbidity, and the incidence of reoperation. RESULTS: In group I, there were no statistically significant differences between the parameters, including the calibre and location of the origin (perpendicular and horizontal distance from the origin of the perforator to both the superior lateral border of the patella and the lateral region of the thigh) of all planning perforators and the operative measurement results (p-values were 0.3, 0.422, and 0.129, respectively). The types were consistent with the operative findings; the rate of the septocutaneous type was 31.25% (5/16), and the rate of the musculocutaneous type was 68.75% (11/16). The use of preoperative perforator planning in group I was associated with a significant reduction in flap complications (p = 0.009) compared with group II. There was no difference between the two groups in alteration of the donor site, donor site morbidity, or the incidence of reoperation (p-values were 0.225, 0.225, and 0.33, respectively). CONCLUSION: Preoperative perforator planning using CTA in ALTPF transplantation is a reliable and useful method resulting in safer operation with optimal outcome. PMID- 23347470 TI - The identification of prediabetes condition with ARIC algorithm predicts long term CV events in patients with erectile dysfunction. AB - INTRODUCTION: The Atherosclerosis Risk in Communities (ARIC) algorithm is one of the most efficient instruments for the prediction of incident type 2 diabetes. Recently, it has been shown to predict another relevant cardiovascular (CV) risk factor, such as chronic kidney disease. AIM: To verify whether, in patients with erectile dysfunction (ED), the use of ARIC diabetes risk score might improve the efficacy in predicting major CV events of other CV risk algorithms specifically developed for the assessment of CV risk. METHODS: A consecutive series of 2,437 men (mean age 52.5 +/- 12.9 years) attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of this sample (N = 1,687) was enrolled in a longitudinal study (mean follow-up of 4.3 +/- 2.6 years). MAIN OUTCOME MEASURES: The assessment of metabolic risk was evaluated with the ARIC algorithm. The assessment of CV risk was evaluated using the Progetto Cuore risk engine. RESULTS: In the cross-sectional study, ARIC score was inversely related with testosterone levels, sexual functioning, and penile blood flow. When longitudinal sample was analyzed, higher baseline ARIC score significantly predicted major adverse cardiovascular event (MACE) even when subjects with diabetes mellitus at baseline were excluded from the analysis (hazard ratio = 1.522 [1.086-2.135]; P = 0.015 for trend). In addition, among subjects classified as "low risk" (CV risk <20% at 10 years corresponding to <9% at 4.3 years) by Progetto Cuore, a receiving operating curve (ROC) analysis for ARIC (vs. MACE) allowed the identification of a threshold of 0.22, which had a positive predictive value for 4.3-year MACE of 9%. Applying the ARIC score (with a threshold of 0.22) to Progetto Cuore "low-risk" subjects, we could classify as "at high risk" 89.8% of subjects with incident MACE vs. 79.6% with Progetto Cuore only. CONCLUSIONS: In patients with ED, identifying prediabetes, even with algorithms, predicts long-term CV events. PMID- 23347472 TI - Subjective sleep quality in relation to inhibition and heart rate variability in patients with panic disorder. AB - BACKGROUND: Patients with panic disorder (PD) are known to report impaired sleep quality and symptoms of insomnia. PD is an anxiety disorder characterised by deficient physiological regulation as measured by heart rate variability (HRV), and reduced HRV, PD and insomnia have all been related to impaired inhibitory ability. The present study aimed to investigate the interrelationships between subjectively reported sleep impairment, cognitive inhibition and vagally mediated HRV in a sample characterised by variability on measures of all these constructs. METHODS: Thirty-six patients with PD with or without agoraphobia were included. Cognitive inhibition was assessed with the Color-Word Interference Test from the Delis-Kaplan Executive Function System (D-KEFS), HRV was measured using high frequency (HF) power (ms(2)), and subjectively reported sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI). RESULTS: Cognitive inhibition was related to both Sleep latency and Sleep disturbances, whereas HRV was only related to Sleep disturbances. These relationships were significant also after controlling for depression. LIMITATIONS: Correlational design. CONCLUSION: Cognitive inhibition is related to key insomnia symptoms: sleep initiation and sleep maintenance. The data supports the psychobiological inhibition model of insomnia, and extends previous findings. Possible clinical implications of these findings are discussed. PMID- 23347471 TI - Psychiatric outcomes at age seven for very preterm children: rates and predictors. AB - BACKGROUND: Uncertainty remains about the rate of specific psychiatric disorders and associated predictive factors for very preterm (VPT) children. The aims of this study were to document rates of psychiatric disorders in VPT children aged 7 years compared with term born children, and to examine potential predictive factors for psychiatric diagnoses in VPT children. METHODS: Participants were 177 VPT and 65 term born children. Perinatal medical data were collected, which included brain abnormalities detected using magnetic resonance imaging. The Infant-Toddler Social-Emotional Assessment (ITSEA) and Strengths and Difficulties Questionnaire (SDQ) were administered at 2 and 5 years respectively. At 7 years of age, the Developmental and Well-being Assessment (DAWBA) was used to indicate psychiatric diagnoses. RESULTS: Compared with term born children, VPT children had three times the odds of meeting criteria for any psychiatric diagnosis at age 7 years (odds ratio 3.03; 95% confidence interval 1.23, 7.47, p = .02). The most common diagnoses were anxiety disorders (11% VPT, 8% term), attention-deficit/hyperactivity disorder (10% VPT, 3% term) and autism spectrum disorder (4.5% VPT, 0% term). For VPT children, those with severe global brain abnormalities (p = .02), those who displayed social-emotional problems at age 5 (p = .000) and those with higher social risk at age 7 (p = .001) were more likely to meet criteria for a psychiatric illness at age 7. CONCLUSIONS: Compared with term born children, VPT children have higher rates of psychiatric diagnoses at early school age, predicted by neonatal brain abnormalities, prior social emotional problems and social factors. PMID- 23347474 TI - Changing work values in the United States, 1973-2006. AB - This article examines changes in workers' work values for the period 1973-2006 using General Social Survey data. We assess the relative importance that workers assign to high income, as opposed to security, advancement, short hours and "importance and sense of accomplishment." The latter ranked highest throughout this period, but the relative priority placed on income and job security generally increased. We suggest that the rising relative rankings of earnings and job security reflect growing job, employability, and economic insecurity that workers generally experienced during this period, making these job characteristics generally more difficult to attain. Groups most vulnerable to job, employability, and economic insecurity-such as less educated workers and blacks-were most apt to place high importance on income and security. Differences in rankings between men and women, blacks and nonblacks, and college and high school graduates remained fairly stable over this period. PMID- 23347475 TI - Job-related resources and the pressures of working life. AB - Data from a 2011 representative sample of Canadian workers are used to test the resource versus the stress of higher status hypotheses. Drawing on the Job Demands-Resources model (JD-R), the resource hypothesis predicts that job-related resources reduce job pressure. The stress of higher status hypothesis predicts that job-related resources increase job pressure. Findings tend to favor the resource hypothesis for job autonomy and schedule control, while supporting the stress of higher status for job authority and challenging work. These findings help elaborate on the "resource" concept in the JD-R model and identify unique ways that such resources might contribute to the pressures of working life. PMID- 23347473 TI - Strengthening health workforce capacity through work-based training. AB - BACKGROUND: Although much attention has been given to increasing the number of health workers, less focus has been directed at developing models of training that address real-life workplace needs. Makerere University School of Public Health (MakSPH) with funding support from the Centers for Disease Control and Prevention (CDC) developed an eight-month modular, in-service work-based training program aimed at strengthening the capacity for monitoring and evaluation (M&E) and continuous quality improvement (CQI) in health service delivery. METHODS: This capacity building program, initiated in 2008, is offered to in-service health professionals working in Uganda. The purpose of the training is to strengthen the capacity to provide quality health services through hands-on training that allows for skills building with minimum work disruptions while encouraging greater involvement of other institutional staff to enhance continuity and sustainability. The hands-on training uses practical gaps and challenges at the workplace through a highly participatory process. Trainees work with other staff to design and implement 'projects' meant to address work-related priority problems, working closely with mentors. Trainees' knowledge and skills are enhanced through short courses offered at specific intervals throughout the course. RESULTS: Overall, 143 trainees were admitted between 2008 and 2011. Of these, 120 (84%) from 66 institutions completed the training successfully. Of the trainees, 37% were Social Scientists, 34% were Medical/Nursing/Clinical Officers, 5.8% were Statisticians, while 23% belonged to other professions. Majority of the trainees (80%) were employed by Non-Government Organizations while 20% worked with the public health sector. Trainees implemented 66 projects which addressed issues such as improving access to health care services; reducing waiting time for patients; strengthening M&E systems; and improving data collection and reporting. The projects implemented aimed to improve trainees' skills and competencies in M&E and CQI and the design of the projects was such that they could share these skills with other staff, with minimal interruptions of their work. CONCLUSIONS: The modular, work-based training model strengthens the capacity of the health workforce through hands-on, real-life experiences in the work-setting and improves institutional capacity, thereby providing a practical example of health systems strengthening through health workforce capacity building. PMID- 23347476 TI - Across the continuum of satisfaction with work-family balance: Work hours, flexibility-fit, and work-family culture. AB - This study investigated the association between hours worked per week and satisfaction with work-family balance, using data from a 2007-2008 survey of employees nested within organizations. We tested hypotheses informed by the resource drain and resources-and-demands perspectives using quantile regression. We found that the negative association between hours worked per week and satisfaction with work-family balance was significantly stronger at the 25th percentile, as compared to at the 75th percentile, of satisfaction with work family balance. Further, there was some evidence that perceived flexibility-fit (i.e., the fit between worker needs and flexible work options available) and supportive work-family culture attenuated the relationship between hours worked and satisfaction with work-family balance. The results suggest that analyses focusing on the average relationship between long work hours (such as those using ordinary least squares regression) and satisfaction with work-family balance may underestimate the importance of long work hours for workers with lower satisfaction levels. PMID- 23347477 TI - The causal effects of Vietnam-era military service on post-war family dynamics. AB - Past work has suggested a lasting impact of military service on the lives of veterans. By intervening at a critical stage in the lives of young men, service may open up opportunities for disadvantaged youth. In contrast, the negative consequences of exposure to combat may offset these presumed advantages. Induction into the military is also a nonrandom process that makes identifying the effects of service exceedingly difficult. In this study we use an instrumental variable (IV) approach to model the causal impact of Vietnam-era military service on two outcomes, marital stability and co-residence with adult offspring. We find limited evidence to suggest that military service may have a lasting effect on family life. In particular, we find that service reduces the probability of marital dissolution for white men. Service also significantly increases the probability of filial co-residence for men of other races. PMID- 23347479 TI - Variety in cultural choice and the activation of social ties. AB - This paper builds on the general connection between culture consumption and sociability which has been the focus of recent research in the sociology of culture. I propose that cultural variety, as given by the number of cultural activities that the person engages in, is tied not only to static properties of social networks (such as range), but also to the likelihood of having benefited from this connectivity (social capital). Taking the classic example of finding a job via a network contact as the main outcome, I show that persons who have a propensity to engage in a wide variety of cultural activities have a higher likelihood of having found out about their current job via a weak tie and that different types of weak tie activation are selectively correlated with distinct cultural taste profiles. PMID- 23347480 TI - Religion, networks, and neighborliness: The impact of religious social networks on civic engagement. AB - A substantial literature has found that religiosity is positively related to individuals' civic engagement and informal helping behavior. Concurrently, social networks as sources of information and encouragement have been suggested as the mechanism underlying phenomena including successful job searches, improved health and greater subjective well-being. In this paper we use data from the Portraits of American Life Study (PALS) to examine whether religiously based social networks explain the well-established relationship between religion and civic engagement. We test potential mechanisms including beliefs, affiliation, and social networks, and we find that having a strong network of religious friends explains the effect of church attendance for several civic and neighborly outcomes. We suggest this phenomenon may exist in other, non-religious, spheres that also produce strong friendship networks. PMID- 23347478 TI - Does a cancer diagnosis influence religiosity? Integrating a life course perspective. AB - Based on a life course framework we propose that a cancer diagnosis is associated with increased religiosity and that this relationship is contingent upon three social clocks: cohort (1920-1945, 1946-1964, 1964+), age-at-diagnosis, and years since-diagnosis. Using prospective data from the National Survey of Midlife Development (N=3443), taken in 1994-1995 and 2004-2006, we test these arguments. Results showed that a cancer diagnosis was associated with increased religiosity. Moreover, we found: (a) no evidence that the influence of cancer varied by cohort; (b) strong evidence that people diagnosed with cancer at earlier ages experienced the largest increases in religiosity; and (c) no evidence that changes in religiosity are influenced by years-since-diagnosis. Our study emphasizes how personal reactions to cancer partly reflect macro-level processes, represented by age-at-diagnosis, and shows that the religion-health connection can operate such that health influences religiosity. The study also highlights the sociological and psychological interplay that shapes people's religiosity. PMID- 23347481 TI - Does inequality erode social trust? Results from multilevel models of US states and counties. AB - Previous research has argued that income inequality reduces people's trust in other people, and that declining social trust in the United States in recent decades has been due to rising levels of income inequality. Using multilevel models fitted to data from the General Social Survey, this paper substantially qualifies these arguments. We show that while people are less trusting in US states with higher income inequality, this association holds only cross sectionally, not longitudinally; since the 1970s, states experiencing larger increases in inequality have not suffered systematically larger declines in trust. For counties, there is no statistically significant relationship either cross-sectionally or longitudinally. There is therefore only limited empirical support for the argument that inequality influences generalized social trust; and the declining trust of recent decades certainly cannot be attributed to rising inequality. PMID- 23347482 TI - Interpersonal trust: An age-period-cohort analysis revisited. AB - Building on the previous work of Robinson and Jackson(1), this study addresses the extent to which interpersonal trust in America is changing due to age, period, or cohort effects (APC). The importance of APC in explaining variations in trust stems from the understanding that the specific source of change can have important - albeit different and possibly, negative - consequences on society. Moreover, 3years after the previous study concluded, the country experienced the largest concerted terrorist attacks on US soil. Little is known about how the attacks affected the dynamics of interpersonal trust relative to the processes of birth, aging, and historical change - such an investigation has important implications for our understanding of the sources and consequences of interpersonal trust. Two analysis techniques for disentangling APC effects are used: constrained generalized linear models and intrinsic estimator models. The results show that while period effects are an important contributor to declining trust, the attacks exert little influence over one's decision to trust others. Also, the investigation provides further confirmation that trust in others has fallen dramatically in the US with the scarcity being led by individuals coming of age in the late 1940s, after which, trust falls with each successive cohort. If this trend continues, through the process of cohort replacement, we will become a society of "distrusters". PMID- 23347483 TI - Class voting and Left-Right party positions: A comparative study of 15 Western democracies, 1960-2005. AB - Studies that explain the class voting have often focused on "bottom-up" social factors, but paid little attention to 'top-down' political factors. We argue that party positions on left-right ideology have an effect on the strength of class voting. This argument is tested by estimating the impact of the Left-Right party positions on the class-vote association through a Two-Step Hierarchical analysis of integrated data from 15 countries in Western-Europe, the United States and Australia (1960-2005) supplemented with data from the Comparative Manifesto Project. Although there is a general trend for class voting to decline over time, partially accounted for by the impact of education, we find that most variation in class voting does not take the form of a linear decline. The ideological positions of left-wing parties alone do not have any effect, but the polarization of parties along the left-right dimension is associated with substantially higher levels of class voting. PMID- 23347484 TI - Explaining the trade-growth link: Assessing diffusion-based and structure-based models of exchange. AB - International development scholars advance contrasting theoretical explanations for the hypothesized link between trade and growth. Diffusion-based models suggest that trade with integrated partners provides states with greater access to technical knowledge. Structure-based models propose that trading with isolated partners produces a bargaining advantage. In this study, we adjudicate between these competing visions by applying Bonacich's (1987) measure of power centrality to the international trade network. We manipulate the procedure's "attenuation factor" (beta) such that a state's trade centrality can be enhanced when a state is connected to either central or isolated partners. Drawing from a sample of 101 states during the 1980-2000 period, we use difference-of-logs models to assess the impact of trade centrality on economic growth net of controls. We find that the positive relationship between trade centrality and growth peaks when states trade with isolated partners in the periphery. PMID- 23347485 TI - Individual environmental concern in the world polity: A multilevel analysis. AB - The authors assess the extent to which national-level integration in the world polity influences individual-level concern for the environment. While theoretically-derived propositions about such relationships have a deep history in comparative sociology, they-with few exceptions-remain untested. Consistent with past research, employed national-level measures of world polity integration include the relative presence of environmental international nongovernmental organizations (EINGOs) and the existence of environmental ministries. Results of multilevel analyses of individual-level environmental concern in 37 nations indicate that both forms of world polity integration increase the likelihood of individual-level environmental concern, net of other national-level factors and individual-level characteristics; although we find stronger support for the influence of EINGOs as a key variable indicating world polity connection. The findings provide unique support for world polity theory, suggesting that future research should consider how elements of world polity integration influence other forms of individual attitudes and behaviors. The results also highlight the importance in considering global and transnational factors when assessing the determinants of individual attitudes about the environment. PMID- 23347486 TI - Educational standardization and gender differences in mathematics achievement: A comparative study. AB - We argue that between-country variations in the gender gap in mathematics are related to the level of educational system standardization. In countries with standardized educational systems both genders are exposed to similar knowledge and are motivated to invest in studying mathematics, which leads to similar achievements. We hypothesize that national examinations and between-teacher uniformity in covering major mathematics topics are associated with a smaller gender gap in a country. Based on Trends of International Mathematical and Science Study (TIMSS) 2003, we use multilevel regression models to compare the link of these two factors to the gender gap in 32 countries, controlling for various country characteristics. The use of national examinations and less between-teacher instructional variation prove major factors in reducing the advantage of boys over girls in mathematics scores and in the odds of excelling. Factors representing gender stratification, often analyzed in comparative gender gap research in mathematics, are at most marginal in respect of the gap. PMID- 23347487 TI - The family, neuroscience, and academic skills: An interdisciplinary account of social class gaps in children's test scores. AB - Current explanations of social class gaps in children's early academic skills tend to focus on non-cognitive skills that more advantaged children acquire in the family. Accordingly, social class matters because the cultural resources more abundant in advantaged families cultivate children's repertories and tool kits, which allow them to more easily navigate social institutions, such as schools. Within these accounts, parenting practices matter for children's academic success, but for seemingly arbitrary reasons. Alternatively, findings from current neuroscience research indicate that family context matters for children because it cultivates neural networks that assist in learning and the development of academic skills. That is, children's exposure to particular parenting practices and stimulating home environments contribute to the growth in neurocognitive skills that affect later academic performance. We synthesize sociological and neuroscience accounts of developmental inequality by focusing on one such skill-fine motor skills-to illustrate how family context alters children's early academic performance. Our findings support an interdisciplinary account of academic inequality, and extend current accounts of the family's role in the transmission of social inequality. PMID- 23347489 TI - Permutation tests for goodness-of-fit testing of mathematical models to experimental data. AB - This paper presents statistical procedures for improving the goodness-of-fit testing of theoretical models to data obtained from laboratory experiments. We use an experimental study in the expectation states research tradition which has been carried out in the "standardized experimental situation" associated with the program to illustrate the application of our procedures. We briefly review the expectation states research program and the fundamentals of resampling statistics as we develop our procedures in the resampling context. The first procedure we develop is a modification of the chi-square test which has been the primary statistical tool for assessing goodness of fit in the EST research program, but has problems associated with its use. We discuss these problems and suggest a procedure to overcome them. The second procedure we present, the "Average Absolute Deviation" test, is a new test and is proposed as an alternative to the chi square test, as being simpler and more informative. The third and fourth procedures are permutation versions of Jonckheere's test for ordered alternatives, and Kendall's tau(b), a rank order correlation coefficient. The fifth procedure is a new rank order goodness-of-fit test, which we call the "Deviation from Ideal Ranking" index, which we believe may be more useful than other rank order tests for assessing goodness-of-fit of models to experimental data. The application of these procedures to the sample data is illustrated in detail. We then present another laboratory study from an experimental paradigm different from the expectation states paradigm - the "network exchange" paradigm, and describe how our procedures may be applied to this data set. PMID- 23347488 TI - Educational differentials in US adult mortality: An examination of mediating factors. AB - We use human capital theory to develop hypotheses regarding the extent to which the association between educational attainment and US adult mortality is mediated by such economic and social resources as family income and social support; such health behaviors as inactivity, smoking, and excessive drinking; and such physiological measures as obesity, inflammation, and cardiovascular risk factors. We employ the NHANES Linked Mortality File, a large nationally representative prospective data set that includes an extensive number of factors thought to be important in mediating the education-mortality association. We find that educational differences in mortality for the total population and for specific causes of death are most prominently explained by family income and health behaviors. However, there are age-related differences in the effects of the mediating factors. Higher education enables individuals to effectively coalesce and leverage their diverse and substantial resources to reduce their mortality and increase their longevity. PMID- 23347490 TI - Yes, magnitudes of difference on status characteristics do matter for small group inequalities. PMID- 23347491 TI - Are proxy interviews associated with biased earnings reports? Marital status and gender effects of proxy. AB - Social science findings routinely rely on proxy-reported economic data in household surveys. A typical assumption is that this information is not biased compared to self-reports, but empirical findings on the issue are mixed. Using a dataset that links workers in the 2004 Survey of Income and Program Participation to their W-2 tax records, we estimate the effects of reporting status (proxy vs. self) on the magnitude and direction of measurement bias in earnings data and explore whether these effects are heterogeneous across gender and marital status. A slight downward bias in proxy-reported earnings is observed; however, these effects are associated with demographic variables. For married workers, proxies do not contribute substantial bias in earnings measurement regardless of the target respondent's gender. However, for single female workers, proxy interviews are a significant source of downward bias in earnings estimates. The implications of these findings are discussed. PMID- 23347492 TI - Murder, political resources, and women's political success. AB - This analysis tests overlooked sociological hypotheses about women's presence in the state legislatures and the House of Representatives. Stereotypes about women suggest that shifts in social conditions affect these political outcomes by making such stereotypes more or less salient. Findings indicate that beliefs about female competencies-such as women's purported unwillingness to endorse violent solutions-should reduce support for female candidates when increases in violent crime create demands for increasingly severe punishments. Since women also are typecast as being more protective of vulnerable populations than males, states with larger minority populations should have additional women in both legislatures. Pooled time-series models based on 1127 state-years show that fewer women were present in the state legislatures or in state delegations to the House after increases in the murder rates. States with larger minority populations, however, had more women in these two legislative bodies. Our results support claims that under researched social conditions produce political climates that either benefit or harm women who seek these offices. PMID- 23347493 TI - Foreign-born out-migration from new destinations: Onward or back to the enclave? AB - Immigrants have a markedly higher likelihood of internal mignation if they live in new destinations. This paper looks at why that pattern occurs and at how immigrants' out-migration to new versus traditional destinations responds to their labor market economic and industrial structure, nativity origins and concentration, geographic region, and labor market type. Confidential data from the 2000 and 1990 decennial censuses are used for the analysis. Metropolitan and non-metropolitan areas are categorized into 741 local labor markets and classified as new or traditional based on the nativity concentrations of immigrants from the 24 largest Asian, Caribbean and Latin American origins. The analysis shows that immigrants are less likely to migrate to new destinations if they live in areas of higher nativity concentration, foreign-born population growth, and wages but more likely to make that move if they are professionals, agricultural or blue collar workers, highly educated, fluent in English, and live in new destinations. While immigrants are more likely to migrate to new rather than traditional destinations that outcome differs sharply for immigrants from different origins and for some immigrants, particularly those from the Caribbean, the dispersal process to new destinations has barely started. PMID- 23347494 TI - Is race a 'salient...' or 'dominant identity' in the early 21st century: The evidence of UK survey data on respondents' sense of who they are. AB - The term 'master status', coined by Everett Hughes in 1945 with special reference to race, was conceptualised as one which, in most social situations, will dominate all others. Since then race and other collective social identities have become key features of people's lives, shaping their 'life scripts'. But is race still a 'master' or 'dominant identity' and, if not, what has replaced it? Analyses of recent social surveys show that race has lost its position to family, religion (in the South Asian and Black groups) and (amongst young mixed race people) also age/life-stage and study/work. However, many of these different identity attributes are consistently selected, suggesting the possibility - confirmed in in-depth interviews - that they may work through each other via intersectionality. In Britain race appears to have been undermined by the rise of 'Muslim' identity, the increasing importance of 'mixed race', and the fragmentation of identity now increasingly interwoven with other attributes like religion. PMID- 23347495 TI - A normative explanation of antisocial punishment. AB - While much research shows that people punish free-riders, recent studies find evidence that people also engage in antisocial punishment. That is, they sometimes punish those who contribute generously to collective actions. Such sanctioning is puzzling because generous individuals increase the welfare of all group members. When and why are such individuals punished? In this paper, we propose that descriptive norms are part of the explanation. People may sanction those whose behavior is atypical - even when that behavior benefits the group. We test our theory with a laboratory experiment. We examine the effect of descriptive norms on sanctioning of generous and stingy deviants and find that descriptive norms encourage antisocial punishment, but not punishment of free riders. PMID- 23347496 TI - The fiscal impact of informal caregiving to home care recipients in Canada: how the intensity of care influences costs and benefits to government. AB - The objective of this study was to estimate the annual costs and consequences of unpaid caregiving by Canadians from a government perspective. We estimated these costs both at the individual and population levels for caregivers aged 45 and older. We conducted a cost-benefit analysis where we considered the costs of unpaid caregiving to be potential losses in income tax revenues and changes in social assistance payments and the potential benefit of reduced paid care expenditures. Our costing methods were based on multivariate analyses using the 2007 General Social Survey, a cross-sectional survey of 23,404 individuals. We determined the differential probability of employment, wages, and hours worked by caregivers of varying intensity versus non-caregivers. We also used multivariate analysis to determine how receiving different intensities of unpaid care impacted both the probability of receiving paid care and the weekly hours of paid care received. At the lowest intensities of caregiving, there was a net benefit to government from caregiving, at both the individual and population levels. At the population level, the net benefit to government was estimated to be $4.4 billion for caregivers providing less than five hours of weekly care. At the highest intensity of caregiving, there was a net cost to government of $641 million. Our overall findings were robust to a number of changes applied in our sensitivity analysis. We found that the factor with the greatest impact on cost was the probability of labour force participation. As the biggest cost driver appears to be the higher likelihood of intense caregivers dropping out of the labour force, government policies that enable intense caregivers to balance caregiving with employment may help to mitigate these losses. PMID- 23347497 TI - A commentary on "A randomized controlled trial to improve health among women receiving welfare in the US: the relationship between employment outcomes and the economic recession". PMID- 23347498 TI - Ma-PbFRET: multiple acceptors FRET measurement based on partial acceptor photobleaching. AB - Fluorescence resonance energy transfer (FRET) measurement based on partial acceptor photobleaching (PbFRET) is easy to implement without external references. However, the current PbFRET methods are inapplicable to the construct with multiple acceptors, which largely increase the Forster distance. Here, we proposed a linear theory for the dependence of the acceptor photobleaching probability of construct with multiple acceptors on the photobleaching degree (x) and developed a multiple acceptors PbFRET method (Ma-PbFRET) to measure the FRET efficiency of construct with multiple acceptors (n) by measuring the fluorescence intensities of both donor and acceptor channels before and after acceptor photobleaching. The Ma-PbFRET method was validated by measuring the FRET efficiency of construct with two or three acceptors under different x in living cells. Our experimental results demonstrate that the Ma-PbFRET method is capable of exactly quantifying the FRET efficiency of construct with multiple acceptors, providing a simple and powerful tool to investigate the assembly/disassembly of biomolecular complexes with larger distance in living cells. PMID- 23347499 TI - Birth order progressively affects childhood height. AB - BACKGROUND: There is evidence suggesting that first-born children and adults are anthropometrically different to later-borns. Thus, we aimed to assess whether birth order was associated with changes in growth and metabolism in childhood. METHODS: We studied 312 healthy prepubertal children: 157 first-borns and 155 later-borns. Children were aged 3-10 years, born 37-41 weeks gestation, and of birth weight appropriate-for-gestational-age. Clinical assessments included measurement of children's height, weight, fasting lipid and hormonal profiles and DEXA-derived body composition. RESULTS: First-borns were taller than later-borns (P < 0.0001), even when adjusted for parents' heights (0.31 vs 0.03 SDS; P = 0.001). There was an incremental height decrease with increasing birth order, so that first-borns were taller than second-borns (P < 0.001), who were in turn taller than third-borns (P = 0.007). Further, among sibling pairs both height SDS (P = 0.009) and adjusted height SDS (P < 0.0001) were lower in second- vs first born children. Consistent with differences in stature, first- (P = 0.043) and second-borns (P = 0.003) had higher IGF-I concentrations than third-borns. Both first- (P < 0.001) and second-borns (P = 0.004) also had reduced abdominal adiposity (lower android fat to gynoid fat ratio) when compared with third-borns. Other parameters of adiposity and blood lipids were unaffected by birth order. CONCLUSIONS: First-borns were taller than later-born children, with an incremental height reduction from first to third birth order. These differences were present after correction for genetic height, and associated to some extent with alterations in plasma IGF-I. Our findings strengthen the evidence that birth order is associated with phenotypic changes in childhood. PMID- 23347500 TI - Risk Factors for influenza A(H1N1)pdm09 among students, Beijing, China. AB - To identify risk factors associated with influenza A(H1N1)pdm09 among students in Beijing, China, we conducted a case-control study. Participants (304 case patients and 608 controls, age range 6-19 years) were interviewed by using a standardized questionnaire. We found that in addition to vaccination, nonpharmaceutical interventions appeared to be protective. PMID- 23347501 TI - Photocurrent enhancement for Ti-doped Fe2O3 thin film photoanodes by an in situ solid-state reaction method. AB - In this work, a higher concentration of Ti ions are incorporated into hydrothermally grown Ti-doped (2.2% by atomic ratio) micro-nanostructured hematite films by an in situ solid-state reaction method. The doping concentration is improved from 2.2% to 19.7% after the in situ solid-state reaction. X-ray absorption analysis indicates the substitution of Fe ions by Ti ions, without the generation of Fe2+ defects. Photoelectrochemical impedance spectroscopy reveals the dramatic improvement of the electrical conductivity of the hematite film after the in situ solid-state reaction. As a consequence, the photocurrent density increases 8-fold (from 0.15 mA/cm2 to 1.2 mA/cm2), and it further increases up to ~1.5 mA/cm2 with the adsorption of Co ions. Our findings demonstrate that the in situ solid-state reaction is an effective method to increase the doping level of Ti ions in hematite films with the retention of the micro-nanostructure of the films and enhance the photocurrent. PMID- 23347502 TI - [Translation and cross-cultural adaptation of the Quick Environmental Exposure and Sensitivity Inventory for use in the Spanish population]. AB - OBJECTIVE: To perform the translation and cross-cultural adaptation of the Quick Environmental Exposure and Sensitivity Inventory (QEESI) for the Spanish population. PATIENTS AND METHODS: Seventy-seven patients diagnosed with multiple chemical sensitivity (MCS) and 154 subjects without the syndrome, matched by sex and age, were included in this cross-sectional study. A translation, back translation and a cross-cultural adaptation of the original questionnaire were performed. Subsequently, the Mann-Whitney test was used to compare the median score by scale between the subjects previously diagnosed and undiagnosed. Internal consistency by scale was analyzed (Cronbach's alpha). RESULTS: Significant higher median score was found in subjects previously diagnosed on 4 out of 5 scales (P<.001). Good internal consistency was found in these 4 scales. Previously diagnosed subjects presented lower median scores on the Masking Index scale (P<.001). CONCLUSIONS: Except for the Masking Index, the scales present strong potential for detecting cases of MCS among symptomatic subjects. PMID- 23347503 TI - Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients (INSPiRE-TMS): a protocol for a randomised controlled trial. AB - BACKGROUND: Patients with recent stroke or TIA are at high risk for new vascular events. Several evidence based strategies in secondary prevention of stroke are available but frequently underused. Support programs with multifactorial risk factor modifications after stroke or TIA have not been investigated in large scale prospective controlled trials so far. INSPiRE-TMS is a prospective, multi center, randomized open intervention trial for intensified secondary prevention after minor stroke and TIA. METHODS/DESIGN: Patients with acute TIA or minor stroke admitted to the participating stroke centers are screened and recruited during in-hospital stay. Patients are randomised in a 1:1 ratio to intervention (support program) and control (usual care) arms. Inclusion of 2.082 patients is planned. The support program includes cardiovascular risk factor measurement and feedback, monitoring of medication adherence, coaching in lifestyle modifications, and active involvement of relatives. Standardized motivational interviewing is used to assess and enhance patients' motivation. Primary objective is a reduction of new major vascular events defined as nonfatal stroke and myocardial infarction or vascular death. Recruitment time is planned for 3.5 years, follow up time is at least 2 years for every patient resulting in a total study time of 5 years (first patient in to last patient out). DISCUSSION: Given the high risk for vascular re-events in acute stroke and the available effective strategies in secondary prevention, the INSPIRE-TMS support program has the potential to lead to a relevant reduction of recurrent events and a prolongation of the event-free survival time. The trial will provide the basis for the decision whether an intensified secondary prevention program after stroke should be implemented into regular care. A cost-effectiveness evaluation will be performed. TRIAL REGISTRATION: clinicaltrials.gov: 01586702. PMID- 23347504 TI - Liver transplantation for urea cycle disorders in pediatric patients: a single center experience. AB - LT has emerged as a surgical treatment for UCDs. We hypothesize that LT can be safely and broadly utilized in the pediatric population to effectively prevent hyperammonemic crises and potentially improve neurocognitive outcomes. To determine the long-term outcomes of LT for UCDs, charts of children with UCD who underwent LT were retrospectively reviewed at an academic institution between July 2001 and May 2012. A total of 23 patients with UCD underwent LT at a mean age of 3.4 yr. Fifteen (65%) patients received a whole-liver graft, seven patients (30%) received a reduced-size graft, and one patient received a living donor graft. Mean five-yr patient survival was 100%, and allograft survival was 96%. Mean peak blood ammonia (NH(3) ) at presentation was 772 MUmol/L (median 500, range 178-2969, normal <30-50). After transplantation, there were no episodes of hyperammonemia. Eleven patients were diagnosed with some degree of developmental delay before transplantation, which remained stable or improved after transplantation. Patients without developmental delay before transplantation maintained their cognitive abilities at long-term follow-up. LT was associated with the eradication of hyperammonemia, removal of dietary restrictions, and potentially improved neurocognitive development. Long-term follow-up is underway to evaluate whether LT at an early age (<1 yr) will attain improved neurodevelopmental outcomes. PMID- 23347505 TI - Inflammation, NK cells and implantation: friend and foe (the good, the bad and the ugly?): replacing placental viviparity in an evolutionary perspective. AB - This review summarises an invited talk presented at the 2012 ESRI/ASRI meeting in Hamburg, concerning current views of inflammation in pregnancy, which is timely given that the effects of a local injury in the uterus acts to favour implantation. Recalling that inflammation can be good (it is useful and necessary for implantation), bad (in implantation failure, RSA) and ugly (at the extreme, endometriosis is associated with pain and infertility) leads to consideration of its status in pregnancy. Its role in implantation and the fact that pregnancy maintains some aspects of inflammation throughout, leads to revision of not only concepts of immunosuppression and the Th1/Th2 paradigm, but also the feto maternal relationship as seen since Medawar's hypotheses were advanced. This is examined from an evolutionary perspective, which should lead to further review of our perception of uterine NK cells, and the emergence of Treg cells to control some aspects of adaptive immunity, which appeared long after placentation. PMID- 23347506 TI - Skull destruction from intracranial metastasis arising from pulmonary squamous cell carcinoma: a case report. AB - INTRODUCTION: Squamous cell carcinoma of the lung represents 30% of all non small cell lung carcinomas. It arises from dysplasia of squamous epithelium of the bronchi and is strongly associated with cigarette smoking. Squamous cell carcinoma of the lung is known to produce metastases in the brain parenchyma. CASE PRESENTATION: We present the case of an 80-year-old indigenous Australian man with an unusual presentation of metastatic carcinoma of the lung. The case demonstrated a squamous cell carcinoma of the lung with an intracranial metastatic lesion destroying the parietal bone and extending into the extracranial soft tissue. A visible deformity as a result of the metastasis was evident on physical examination and computed tomography demonstrated extensive bone destruction. CONCLUSION: The authors were unable to find a case of this occurring from a squamous cell carcinoma of the lung anywhere in the world literature. The case report demonstrates an unusual disease presentation with a rare intracranial metastasis invading through the skull. PMID- 23347507 TI - An improved high yield method to obtain microsatellite genotypes from red deer antlers up to 200 years old. AB - Analysis of DNA from older samples, such as museum specimen, is a promising approach to studying genetics of populations and ecological processes across several generations. Here, we present a method for extracting high quality nuclear DNA for microsatellite analysis from antlers of red deer (Cervus elaphus). The genotyping of individuals was based on nine microsatellite loci. Because the amount of DNA found in antlers was high, we could reduce the amount of sample and chemicals used and shorten the decalcification time in comparison to other methods. Using these methods, we obtained genotypes from antlers up to 200 years old. PMID- 23347509 TI - An improvement of independent component analysis with projection method applied to multi-task fMRI data. AB - Independent Component Analysis with projection (ICAp) method proposed by Long et al. Hum. Brain Mapp. 30 (2009) 417-431, can solve the interaction among task related components of multi-task functional magnetic resonance imaging (fMRI) data. However, the departure of the ideal homodynamic response function (HRF) for projection from the true HRF may worse the ICAp results. In order to improve the performance of ICAp, the deconvolved ICAp (DICAp) method is proposed. Both the simulated and real fMRI experiments demonstrate that DICAp can separate more accurate time course corresponding to each task-related components and is more powerful to detect regions activated by each task only than ICAp. PMID- 23347508 TI - Hydrogels for lentiviral gene delivery. AB - INTRODUCTION: Gene delivery from hydrogel biomaterials provides a fundamental tool for a variety of clinical applications including regenerative medicine, gene therapy for inherited disorders and drug delivery. The high water content and mild gelation conditions of hydrogels support their use for gene delivery by preserving activity of lentiviral vectors and acting to shield vectors from any host immune response. AREAS COVERED: Strategies to control lentiviral entrapment within and retention/release from hydrogels are reviewed. The authors discuss the ability of hydrogel design parameters to control the transgene expression profile and the capacity of hydrogels to protect vectors from (and even modulate) the host immune response. EXPERT OPINION: Delivery of genetic vectors from scaffolds provides a unique opportunity to capitalize on the potential synergy between the biomaterial design for cell processes and gene delivery. Hydrogel properties can be tuned to directly control the events that determine the tissue response to controlled gene delivery, which include the extent of cell infiltration, preservation of vector activity and vector retention. While some design parameters have been identified, numerous opportunities for investigation are available in order to develop a complete model relating the biomaterial properties and host response to gene delivery. PMID- 23347510 TI - HIV diagnosis and testing: what every healthcare professional can do (and why they should). AB - Over the last thirty years, the human immunodeficiency virus (HIV) epidemic has matured. In the United States, HIV has changed from an explosive outbreak to an endemic disease; currently, an estimated 1.1 million people are infected with HIV, including a substantial number who are unaware of their status. With recent findings demonstrating the high transmissibility of HIV early in infection, and the potential benefit of early initiation of treatment, it is essential to identify as many infected individuals as possible. The Centers for Disease Control and Prevention (CDC) has expanded HIV testing to include any healthcare setting, including dental offices. Testing advances, including oral testing, have reduced the window period of HIV infection. Dental care represents a key, reliable, independent, and confidential link between the healthcare system and the general population that has been under-utilized in the effort to control the HIV epidemic. HIV testing is straightforward, and knowledge of the types of testing will afford dentists an important opportunity to help advance and preserve the health of their patients and to promote the public health of their community. Here, we review the basics of HIV testing and discuss new changes in the approach to HIV diagnostics. PMID- 23347511 TI - Sleeping well. AB - In a study by Cruse et al. published in BMC Medicine, patients with severe brain damage who were in the Vegetative or Minimally Conscious States (VS or MCS, respectively) from traumatic and nontraumatic etiologies had assessments of circadian rhythms using an actigraph, a device worn on a limb to evaluate circadian rhythmicity, in this population. This is a novel approach and is being used as a surrogate for polysomnography and other reference standards. Cruse et al. showed more disruption in circadian rhythms in the VS when compared to the MCS. This suggests that more brain injury occurs in the areas that control circadian rhythmicity in VS than in MCS patients. The study provides opportunities for improved prognostication and rehabilitation strategies in this patient population. PMID- 23347512 TI - Evidence for heritability of adult men's sexual interest in youth under age 16 from a population-based extended twin design. AB - INTRODUCTION: Sexual interest in children resembles sexual gender orientation in terms of early onset and stability across the life span. Although a genetic component to sexual interest in children seems possible, no research has addressed this question to date. Prior research showing familial transmission of pedophilia remains inconclusive about shared environmental or genetic factors. Studies from the domains of sexual orientation and sexually problematic behavior among children pointed toward genetic components. Adult men's sexual interest in youthfulness-related cues may be genetically influenced. AIM: The aim of the present study was to test whether male sexual interest in children and youth under age 16 involves a heritable component. MAIN OUTCOME MEASURES: The main outcome measure was responses in a confidential survey concerning sexual interest, fantasies, or activity pertaining to children under the age of 16 years during the previous 12 months. METHODS: The present study used an extended family design within behavioral genetic modeling to estimate the contributions of genetic and environmental factors in the occurrence of adult men's sexual interest in children and youth under age 16. Participants were male twins and their male siblings from a population-based Finnish cohort sample aged 21-43 years (N = 3,967). RESULTS: The incidence of sexual interest in children under age was 3%. Twin correlations were higher for monozygotic than for dizygotic twins. Behavioral genetic model fitting indicated that a model including genetic effects as well as nonshared environmental influences (including measurement error), but not common environmental influences, fits the data best. The amount of variance attributable to nonadditive genetic influences (heritability) was estimated at 14.6%. CONCLUSIONS: The present study provides the first indication that genetic influences may play a role in shaping sexual interest toward children and adolescents among adult men. Compared with the variance attributable to nonshared environmental effects (plus measurement error), the contribution of any genetic factors seems comparatively weak. Future research should address the possible interplay of genetic with environmental risk factors, such as own sexual victimization in childhood. PMID- 23347513 TI - Transcriptome of the dead: characterisation of immune genes and marker development from necropsy samples in a free-ranging marine mammal. AB - BACKGROUND: Transcriptomes are powerful resources, providing a window on the expressed portion of the genome that can be generated rapidly and at low cost for virtually any organism. However, because many genes have tissue-specific expression patterns, developing a complete transcriptome usually requires a 'discovery pool' of individuals to be sacrificed in order to harvest mRNA from as many different types of tissue as possible. This hinders transcriptome development in large, charismatic and endangered species, many of which stand the most to gain from such approaches. To circumvent this problem in a model pinniped species, we 454 sequenced cDNA from testis, heart, spleen, intestine, kidney and lung tissues obtained from nine adult male Antarctic fur seals (Arctocephalus gazella) that died of natural causes at Bird Island, South Georgia. RESULTS: After applying stringent quality control criteria based on length and annotation, we obtained 12,397 contigs which, in combination with 454 data previously obtained from skin, gave a total of 23,096 unique contigs. Homology was found to 77.0% of dog (Canis lupus familiaris) transcripts, suggesting that the combined assembly represents a substantial proportion of this species' transcriptome. Moreover, only 0.5% of transcripts revealed sequence similarity to bacteria, implying minimal contamination, and the percentage of transcripts involved in cell death was low at 2.6%. Transcripts with immune-related annotations were almost five-fold enriched relative to skin and represented 13.2% of all spleen specific contigs. By reference to the dog, we also identified transcripts revealing homology to five class I, ten class II and three class III genes of the Major Histocompatibility Complex and derived the putative genomic distribution of 17,121 contigs, 2,119 in silico mined microsatellites and 9,382 single nucleotide polymorphisms. CONCLUSIONS: Our findings suggest that transcriptome development based on samples collected post mortem may greatly facilitate genomic studies, not only of marine mammals but also more generally of species that are of conservation concern. PMID- 23347515 TI - What goes up must come down: transcription factors have their say in making ecdysone pulses. AB - Insect metamorphosis is one of the most fascinating biological processes in the animal kingdom. The dramatic transition from an immature juvenile to a reproductive adult is under the control of the steroid hormone ecdysone, also known as the insect molting hormone. During Drosophila development, periodic pulses of ecdysone are released from the prothoracic glands, upon which the hormone is rapidly converted in peripheral tissues to its biologically active form, 20-hydroxyecdysone. Each hormone pulse has a unique profile and causes different developmental events, but we only have a rudimentary understanding of how the timing, amplitude, and duration of a given pulse are controlled. A key component involved in the timing of ecdysone pulses is PTTH, a brain-derived neuropeptide. PTTH stimulates ecdysone production through a Ras/Raf/ERK signaling cascade; however, comparatively little is known about the downstream targets of this pathway. In recent years, it has become apparent that transcriptional regulation plays a critical role in regulating the synthesis of ecdysone, but only one transcription factor has a well-defined link to PTTH. Interestingly, many of the ecdysteroidogenic transcription factors were originally characterized as primary response genes in the ecdysone signaling cascade that elicits the biological responses to the hormone in target tissues. To review these developments, we will first provide an overview of the transcription factors that act in the Drosophila ecdysone regulatory hierarchy. We will then discuss the roles of these transcriptional regulators in controlling ecdysone synthesis. In the last section, we will briefly outline transcription factors that likely have roles in regulating ecdysone synthesis but have not been formally identified as downstream effectors of ecdysone. PMID- 23347516 TI - Hormonal regulation of insect metamorphosis with special reference to juvenile hormone biosynthesis. AB - Ecdysteroids and juvenile hormones (JHs) are key hormones that are responsible for insect molting and metamorphosis. JH maintains the larval state and the decline of its level in the hemolymph is crucial to elicit transformation to the pupal stage; therefore, the precise control of JH biosynthesis is necessary for normal development and the initiation of metamorphosis. This chapter summarizes mechanisms of the regulation of JH biosynthesis by the corpora allata and shows that several factors such as ecdysteroids, neurotransmitters, and peptides act together in the stage-specific manner to guarantee the accurate production of JH in each stage, in particular, in the last larval stage when metamorphosis is initiated with the transformation of the larva to the pupa. In addition, recent progress in understanding the JH signaling pathway is briefly discussed, including the identification of a long elusive JH receptor. PMID- 23347514 TI - Developmental checkpoints and feedback circuits time insect maturation. AB - The transition from juvenile to adult is a fundamental process that allows animals to allocate resource toward reproduction after completing a certain amount of growth. In insects, growth to a species-specific target size induces pulses of the steroid hormone ecdysone that triggers metamorphosis and reproductive maturation. The past few years have seen significant progress in understanding the interplay of mechanisms that coordinate timing of ecdysone production and release. These studies show that the neuroendocrine system monitors complex size-related and nutritional signals, as well as external cues, to time production and release of ecdysone. Based on results discussed here, we suggest that developmental progression to adulthood is controlled by checkpoints that regulate the genetic timing program enabling it to adapt to different environmental conditions. These checkpoints utilize a number of signaling pathways to modulate ecdysone production in the prothoracic gland. Release of ecdysone activates an autonomous cascade of both feedforward and feedback signals that determine the duration of the ecdysone pulse at each developmental transitions. Conservation of the genetic mechanisms that coordinate the juvenile adult transition suggests that insights from the fruit fly Drosophila will provide a framework for future investigation of developmental timing in metazoans. PMID- 23347519 TI - Flatfish: an asymmetric perspective on metamorphosis. AB - The most asymmetrically shaped and behaviorally lateralized of all the vertebrates, the flatfishes are an endless source of fascination to all fortunate enough to study them. Although all vertebrates undergo left-right asymmetric internal organ placement during embryogenesis, flatfish are unusual in that they experience an additional period of postembryonic asymmetric remodeling during metamorphosis, and thus deviate from a bilaterally symmetrical body plan more than other vertebrates. As with amphibian metamorphosis, all the developmental programs of flatfish metamorphosis are ultimately under the control of thyroid hormone. At least one gene pathway involved in embryonic organ lateralization (nodal-lefty-pitx2) is re-expressed in the larval stage during flatfish metamorphosis. Aspects of modern flatfish ontogeny, such as the gradual translocation of one eye to the opposite side of the head and the appearance of key neurocranial elements during metamorphosis, seem to elegantly recapitulate flatfish phylogeny. This chapter highlights the current state of knowledge of the developmental biology of flatfish metamorphosis with emphases on the genetic, morphological, behavioral, and evolutionary origins of flatfish asymmetry. PMID- 23347517 TI - The role of autophagy in Drosophila metamorphosis. AB - Macroautophagy (autophagy) is a conserved catabolic process that targets cytoplasmic components to lysosomes for degradation. Autophagy is required for cellular homeostasis and cell survival in response to starvation and stress, and paradoxically, it also plays a role in programmed cell death during development. The mechanisms that regulate the relationship between autophagy, cell survival, and cell death are poorly understood. Here we review research in Drosophila that has provided insights into the regulation of autophagy by steroid hormones and nutrient restriction and discuss how autophagy influences cell growth, nutrient utilization, cell survival, and cell death. PMID- 23347520 TI - Neuroendocrinology of amphibian metamorphosis. AB - The timing of metamorphosis is a central amphibian life history trait and is controlled by the interplay of developmental progression, body size and condition, and environmental signals. These different processes and signals are integrated by the neuroendocrine system to regulate production of hormones by the thyroid gland. Thyroid hormone (TH) is the primary morphogen controlling metamorphosis, while corticosteroids (CSs) produced by the interrenal glands synergize with TH to promote metamorphic changes. The actions of TH are modulated by monodeiodinase enzymes expressed in TH target tissues. CSs act by sensitizing tissues to the actions of TH via the upregulation of TH receptors and monodeiodinases. The increase in thyroid gland activity during metamorphosis is controlled by the hypothalamus and pituitary gland. The hypothalamo-pituitary thyroid and hypothalamo-pituitary-interrenal axes are regulated at multiple levels. Hypothalamic corticotropin-releasing factor (CRF) functions as a common, central regulator of pituitary thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) secretion in tadpoles. CRF neurons transduce the signals of environmental change (e.g., pond drying, resource availability, etc.) on metamorphic timing by regulating TSH and ACTH secretion, and consequently the production of TH and CS. PMID- 23347518 TI - Metamorphosis in teleosts. AB - Teleosts are the largest and most diverse group of vertebrates, and many species undergo morphological, physiological, and behavioral transitions, "metamorphoses," as they progress between morphologically divergent life stages. The larval metamorphosis that generally occurs as teleosts mature from larva to juvenile involves the loss of embryo-specific features, the development of new adult features, major remodeling of different organ systems, and changes in physical proportions and overall phenotype. Yet, in contrast to anuran amphibians, for example, teleost metamorphosis can entail morphological change that is either sudden and profound, or relatively gradual and subtle. Here, we review the definition of metamorphosis in teleosts, the diversity of teleost metamorphic strategies and the transitions they involve, and what is known of their underlying endocrine and genetic bases. We suggest that teleost metamorphosis offers an outstanding opportunity for integrating our understanding of endocrine mechanisms, cellular processes of morphogenesis and differentiation, and the evolution of diverse morphologies and life histories. PMID- 23347521 TI - Salamander paedomorphosis: linking thyroid hormone to life history and life cycle evolution. AB - Many salamanders have biphasic life cycles with aquatic larval and terrestrial adult phases. In these species, the transition between phases-metamorphosis requires thyroid hormone (TH) activation of transcriptional programs that cause regression of larval traits and development of adult traits. During salamander evolution, TH signaling pathways have been altered in biphasic species to yield paedomorphic salamanders that retain larval traits and attain sexual maturity in larval aquatic habitats. We review literature concerning the ecology, evolution, and hormonal regulation of metamorphic, paedomorphic, and facultative salamander life histories. We then discuss recent microarray results that detail gene expression signatures of metamorphosis and paedomorphosis, and genetic results that establish TH responsiveness as a continuous trait with a quantitative trait locus (QTL) basis. TH-responsive QTL from ambystomatid salamanders explain variation in metamorphic timing, expression of metamorphosis versus paedomorphosis, and adult fitness traits. We propose a model for salamander life history evolution that links adaptation to aquatic habitats with TH-responsive loci that pleiotropically alter metamorphic timing and adult body size. Future studies that adopt genetic and genomic approaches will further establish salamanders as ideal models for investigating TH signaling mechanisms that regulate postembryonic development and the expression of alternate life histories. PMID- 23347522 TI - Metamorphosis in a frog that does not have a tadpole. AB - The evolutionary removal of the tadpole from the frog life history is a very successful strategy, particularly in the tropics. These direct developers form limbs and a frog-like head early in embryogenesis, and they have reduced or lost tadpole-specific structures, like gills, a long, coiled intestine, and tadpole teeth and jaws. Despite the apparently continuous development to the frog morphology, the direct developer, Eleutherodactylus coqui, undergoes a cryptic metamorphosis requiring thyroid hormone. As in Xenopus laevis, there is a stimulation by corticotrophin-releasing factor (CRF) and an upregulation of thyroid hormone receptor beta (thrb). In addition to changes in skin and muscle, thyroid hormone stimulates yolk utilization for froglet growth from a novel tissue, the nutritional endoderm. The activities of CRF and corticosterone (CORT) in metamorphosis may provide the basis for the multiple evolutionary origins of direct development in anuran amphibians. Potential roles for maternally supplied thyroid hormone and its receptor and for deiodinases in regulating tissue sensitivity to thyroid hormone should be the subjects of future investigations. PMID- 23347523 TI - High-throughput sequencing will metamorphose the analysis of thyroid hormone receptor function during amphibian development. AB - Amphibian metamorphosis is marked by dramatic thyroid hormone (T(3))-induced changes including de novo morphogenesis, tissue remodeling, and organ resorption through programmed cell death. These changes involve cascades of gene regulation initiated by thyroid hormone (TH). TH functions by regulating gene expression through TH receptors (TR). TR are DNA-binding transcription factors that belong to the steroid hormone receptor superfamily. In the absence of ligand, TR can repress gene expression by recruiting a corepressor complex, whereas liganded TR recruits a coactivator complex for gene activation. Earlier studies have led us to propose a dual function model for TR during development. In premetamorphic tadpoles, unliganded TR represses transcription involving corepressors. During metamorphosis, endogenous T(3) allows TR to activate gene expression. To fully understand the diversity of T(3) effects during metamorphosis, whole genome analysis of transcriptome and mechanism of TR action should be carried out. To this end, the new sequencing technologies have dramatically changed how fundamental questions in biology are being addressed and is now making the transition from technology development to being a standard for genomic and functional genomic analysis. This review focuses on the applications of high throughput technologies to the field of amphibian metamorphosis. PMID- 23347524 TI - Establishment of intestinal stem cell niche during amphibian metamorphosis. AB - In the amphibian intestine during metamorphosis, most of the larval epithelial cells undergo apoptosis, whereas a small number of them survive. These cells dedifferentiate into stem cells through interactions with the microenvironment referred to as "stem cell niche" and generate the adult epithelium analogous to the mammalian counterpart. Since all processes of the larval-to-adult intestinal remodeling can be experimentally induced by thyroid hormone (TH) both in vivo and in vitro, the amphibian intestine provides us a valuable opportunity to study how adult stem cells and their niche are formed during postembryonic development. To address this issue, a number of expression and functional analyses of TH response genes have been intensely performed in the Xenopus laevis over the past two decades, by using organ culture and transgenic techniques. We here review recent progress in this field, focusing on key signaling pathways involved in establishment of the stem cell niche and discuss their evolutionarily conserved roles in the vertebrate intestine. PMID- 23347525 TI - Developmental programs and endocrine disruption in frog metamorphosis: the perspective from microarray analysis. AB - A major goal for understanding the role of thyroid hormone (TH) in development has been to identify genes regulated by TH in different tissues during frog metamorphosis. The exquisite dependence of metamorphosis on TH also provides a model to study TH endocrine disruption. To identify such TH-regulated genes and select biomarkers for TH endocrine disruption, global gene expression analyses in tadpoles using microarrays have been done in 21 studies, involving five frog species, seven organs, and four endocrine disrupting chemicals. As expected, each organ has a unique set of genes associated with its tissue-specific metamorphic outcome, and functions ascribed to many of these genes correspond to histological changes induced by TH. Also, the large number of transcription factors identified in microarrays is consistent with the molecular mechanisms of TH action. On the other hand, microarray analysis has also revealed interesting findings not predicted from previous morphological or molecular studies. Furthermore, endocrine disruption studies identified candidate biomarkers for TH disruption, and the mechanisms of action of several endocrine disrupting chemicals have been examined. The microarray studies described here have produced a wealth of data on gene expression that requires further functional studies to elucidate the roles of these genes in development and endocrine disruption. PMID- 23347526 TI - Is thyroid hormone signaling relevant for vertebrate embryogenesis? AB - Classically, thyroid hormones (THs) have been primarily associated with postembryonic development (Tata, 1968), notably metamorphosis in anuran amphibians and flat fish. This period is parallel to the perinatal period in man and many marked developmental transitions in other species. As amply described in other chapters, metamorphosis is characterized by a peak of thyroxine (T(4)) and triiodothyronine (T(3)) that is synchronous with the metamorphic climax. In contrast, the developmental period that characterizes embryonic development prior to the significant production of TH by the endogenous thyroid gland has received little attention. Furthermore, the prevailing concepts of TH physiology during this period have been framed by two observations in amphibians and mammals: first, TRs are expressed, while circulating TH levels are much lower than those during metamorphosis and, second, extrapolating from the knowledge largely obtained from in vitro models, in the absence of TH, the aporeceptor represses target gene transcription during premetamorphic development. We propose to revisit both concepts in the light of accumulating data, first, on TH availability both in eggs and in embryos and, second, on the increasing knowledge of the complexity of TR and TH control of transcription. PMID- 23347527 TI - Thyroid hormones and postembryonic development in amniotes. AB - In chordates, metamorphosis is a developmental event well described in amphibians in which thyroid hormone triggers this event. Interestingly, among amphibians, several variations upon the eggs/tadpole/frog developmental sequence are observed such as direct development or neoteny. The fact that TH-regulated metamorphosis is conserved in invertebrate chordates such as amphioxus implies that this event is an ancient feature of all vertebrates. This allows us to propose that TH may play an important role in coordinating the postembryonic development of apparently nonmetamorphosing vertebrates such as mammals or sauropsids. Indeed, the observations of thyroid hormone levels in mammals and sauropsids draw interesting parallels with what is observed during amphibian metamorphosis. At the physiological level, the increase of thyroid hormone signaling is required for the normal development particularly for the intestine and the brain. At the behavioral level, a peak of TH often precedes the autonomy of the young from parental care. At the ecological level, offspring with a TH peak close to birth/hatching tends to be precocial young whereas offspring with a TH peak long after birth/hatching tends to be altricial young. Taken together, these observations in amniotes, which are not considered as undergoing metamorphosis during their development, are consistent with the idea of a late developmental step controlled by TH and allowing the accession to the adult ecological niche. Thus, according to this view, at the molecular level all vertebrates undergo a period of remodeling controlled by TH that is reminiscent of metamorphosis. PMID- 23347528 TI - Current Topics in Developmental Biology. Animal metamorphosis. Preface. PMID- 23347529 TI - High seroprevalence for typhus group rickettsiae, southwestern Tanzania. AB - Rickettsioses caused by typhus group rickettsiae have been reported in various African regions. We conducted a cross-sectional survey of 1,227 participants from 9 different sites in the Mbeya region, Tanzania; overall seroprevalence of typhus group rickettsiae was 9.3%. Risk factors identified in multivariable analysis included low vegetation density and highway proximity. PMID- 23347530 TI - Dyspnea and emotional states in health and disease. AB - Anxiety and depression can increase the intensity of dyspnea out of proportion to the impairment in cardiorespiratory function and may contribute to the degree of disability associated with dyspnea. The effect of anxiety/depression on the sensory and affective components of reported dyspnea in patients with respiratory disorders might be of particular importance in improving the accuracy of the diagnostic process. However, the exact cause-relationship between dyspnea and anxiety/depression are unclear. A multidimensional model of dyspnea subsuming sensory components (i.e. intensity and quality) and affective components has recently been proposed. Affective responses drive patients to seek treatment which can cause them to alter their lifestyle to avoid dyspnea. Brain imaging techniques help identify distinct cortical structures involved in processing the discrete components of dyspnea. PMID- 23347531 TI - A case of neonatal human parechovirus encephalitis with a favourable outcome. AB - Human parechoviruses (HPeVs) are a new family of neurotropic viruses that cause central nervous system (CNS) infections similar to enterovirus (EVs) meningoencephalitis in the neonatal period, resulting in white matter lesions that can be visualized with cranial ultrasonography and magnetic resonance imaging, and correlated to a large spectrum of neurological outcomes. HPeV should be suspected in neonates with signs and symptoms of sepsis-like illness or CNS disease. We report a case of neonatal HPeV encephalitis, diagnosed on the basis of clinical and radiological findings and HPeV RT-PCR, with a good neurological outcome. PMID- 23347532 TI - Mental healthcare efforts for the public after the Great East Japan Earthquake: "Guide to Good Mental Health for Those Affected by Natural Disasters" published by the Cabinet Office. PMID- 23347534 TI - Pathogenesis of listeriosis during pregnancy. AB - Listeria monocytogenes causes several clinical manifestations in humans and domestic animals. This bacterium is a saprophyte in soil and ensiled feeds, which are sources of infection for food producing animals (i.e. ruminants). The most common route of infection for people is via ingestion of contaminated ready-to eat food products such as produce, soft cheeses and deli meats. In the United States, L. monocytogenes causes relatively few cases of clinical disease compared to other food-borne pathogens. However, clinical listeriosis is associated with high mortality, especially in immunocompromised patients, pregnant women, neonates, and the elderly. Listeria is an intracellular pathogen, which has been widely used in basic research to elucidate mechanisms of molecular pathogenesis and protective cell-mediated immunity. Despite the sizeable knowledge on L. monocytogenes pathogenesis, key points regarding listeriosis during pregnancy and the perinatal period remain unknown. This review summarizes listeriosis in humans and domestic animals during pregnancy, and animal models used to study the pathogenesis and immune response to L. monocytogenes infection during these periods. PMID- 23347533 TI - Cardiovascular risk escalation with caloric excess: a prospective demonstration of the mechanics in healthy adults. AB - CONTEXT: The link between weight gain and cardiovascular risk characterized with circadian blood pressure variability [CBPV] and endothelial function [EF] is unexplored. OBJECTIVE: To prospectively demonstrate weight gain in healthy adults, increases body fat [BF], enlarges waist circumference [WC], expands visceral adipose tissue [VAT], exacerbates systemic inflammation [sIF], worsens insulin resistance [IR] and enhances functional cardiovascular disease [CVD] risk. DESIGN, SETTING AND PARTICIPANTS: Healthy men [n=11] and women [n=3] provided initial and eight-week post-caloric excess anthropometric and fasting laboratory measures. Functional CVD risk assessments: CBPV and resting EF were also obtained with 7-day automatic ambulatory BP monitoring and increased test finger peripheral arterial tone [PAT] relative to control [reported as relative hyperemia index (RHI)], respectively. INTERVENTION: After determining individualized mean energy requirements for weight maintenance over 7-days, each participant received a personalized over feeding prescription (1.4 times; 41% carbohydrate, 44% fat, and 15% protein) for 8-weeks. RESULTS: mean (SEM). Participants increased body weight [BW; +7.4(0.1) kg]*, body mass index [BMI; +2.5(0.2) kg/m2]*, BF [+2.0(0.01)%]*, WC [+8.2(1.0) cm]*, and VAT [+0.2(0.03) L]* and intrahepatic lipid [IHL + 0.0004(0.002) L] :*all p < 0.01. Increased subcutaneous adipose cell size [+0.3(0.01) rhoL; p = 0.02] accompanied significant sIF [hs-CRP + 0.4(0.09) mg/dL; p = 0.04; leptin 6.63 ng/ml; p = 0.0008] and IR [fasting plasma glucose; [FPG] +7.0(0.6) mg/dL;p = 0.01, fasting insulin; [FI] +5.7(1.4) uIU/ml; p = 0.001, HOMA-IR +1.6(0.5); p = 0.02]. Abn CBPV {systolic [+5.4(0.8); p = 0.002, diastolic [+1.7(0.1); p = 0.07 and pulse pressure [PP] [+3.5(0.4); p = 0.003 mm Hg} or elevated heart rate [HR] [+4.9(0.5) bpm; p = 0.003] ensued. Resting RHI declined by 0.47(0.004) from initial 2.24(0.09) to 1.77(0.1); p = 0.001, indicating endothelial dysfunction [ED]. CONCLUSIONS: Controlled caloric excess in healthy human adults over only 8-weeks significantly increased BF, VAT, sIF [hs-CRP], IR [FPG, FI, HOMA-IR] and functional CVD risk [measured as abnormal circadian blood pressure variability and impaired resting endothelial function]. PMID- 23347536 TI - Parental refusal of vaccination and transplantation listing decisions: a nationwide survey. AB - Many professional societies and research studies recommend complete vaccination before pediatric solid organ transplantation. Nevertheless, incompletely vaccinated children often receive transplants. As the number of parents refusing to vaccinate children for nonmedical reasons increases, pediatric transplantation programs face difficult listing decisions. Given the importance of psychosocial criteria in listing decisions, this study explores how parental refusal of vaccination affects those listing decisions. Surveys were emailed to individuals at 195 pediatric solid organ transplantation programs in the United States, with a 71% response rate. Forty-four respondents (39%) reported that their programs have had cases involving parental refusal of vaccination. In response to hypothetical scenarios, 93 respondents (82%) would list a child not vaccinated for medical reasons, whereas only 54 respondents (47%) would list a child whose parents refused vaccination. Only five respondents (4%) reported that their programs had written policies regarding parental refusal of vaccination. These data reveal inconsistencies across pediatric transplantation programs regarding how parental refusal of vaccination affects listing decisions and raise the issue of whether and how the reason for incomplete vaccination should be factored into listing decisions. We recommend further discussion and the development of written guidelines to unify programs' assessments of incompletely vaccinated pediatric transplantation candidates. PMID- 23347535 TI - Flaxseed oil does not affect inflammatory markers and lipid profile compared to olive oil, in young, healthy, normal weight adults. AB - OBJECTIVE: Olive oil (OO) is a rich source of monounsaturated fat and bioactive components that exert strong anti-oxidant and anti-inflammatory properties. Flaxseed oil (FO) is rich in alpha-linolenic n-3 fatty acid (ALA), which also exhibits anti-inflammatory effects. This randomized, cross-over study aimed at exploring whether diet's enrichment with FO could beneficially alter inflammatory markers and lipid profile, compared to OO, in a sample of normal weight, apparently healthy young adults. MATERIALS AND METHODS: Participants were supplied with 15 mL/day of either FO or OO. Each intervention and the wash-out period lasted 6 weeks. Dietary, anthropometric and physical activity variables were recorded at the beginning and the end of each intervention. Serum biochemical and inflammatory markers were measured. Compliance to the intervention was evaluated by fatty acid analysis in erythrocytes. Repeated Measures ANOVA was used to assess the effect of the treatment. RESULTS: Thirty seven participants completed the study. No difference between the two interventions was observed in adiponectin, TNF-alpha, high sensitivity-CRP or glucose levels and lipid profile. At the end of the FO period, participants exhibited significant reductions in total (-5.0%) and LDL-cholesterol (-6.7%) levels (all P<0.01). During the FO and the OO period serum adiponectin changes were significantly correlated with changes in erythrocyte %ALA (rs=0.34, P=0.007) and in erythrocyte %EPA (r(s)=0.47, P=0.01), respectively. CONCLUSIONS: Daily consumption of FO did not confer any benefit in inflammatory or biochemical markers in normal weight young adults, who traditionally use olive oil as the main edible oil. PMID- 23347537 TI - Clinical hematology in reptilian species. AB - The presence of nucleated erythrocytes and thrombocytes in reptile blood limits the use of electronic cell-counting devices for leukocytes so that manual counting techniques and evaluation of blood smears are necessary, resulting in time-consuming procedures requiring good training and experience. The evaluation of most hematologic values is complicated by the many physiologic adaptations occurring in reptiles, making references values very difficult to interpret. This article brings together most of the bibliography about hemochrome evaluation in reptiles, with schematic instruction about sample collection, handling, and evaluation. Information about evaluation of both qualitative and quantitative aspects of reptile hematology are also given. PMID- 23347538 TI - Clinical and laboratory practice for canaries and true finches. AB - The canary (Serinus canaria) is a highly popular bird with families as a companion animal and among breeders for competitive purposes. The mortality rate in these animals is very high at the onset of an epidemic, and the technical times of a laboratory often necessitate starting treatment before having completed the diagnostic procedure. This article describes a practical approach that deals with the first things to do in the clinic as soon as the animal arrives or the breeder asks for advice and explains the procedure in a specialist laboratory for processing samples and completing the diagnosis. PMID- 23347539 TI - Acid-base status in the avian patient using a portable point-of-care analyzer. AB - The i-STAT PCA can be used as a blood analyzer in critical avian patients, although single values must be interpreted carefully. The study of the acid-base status in companion birds is still in its infancy. Further research is needed to establish normal reference values in arterial blood gases, compare them with venous blood gas, and to determine if the formulas that deviate from small animal medicine are or are not applicable. PMID- 23347540 TI - Overview of psittacine blood analysis and comparative retrospective study of clinical diagnosis, hematology and blood chemistry in selected psittacine species. AB - Part 1 presents a comprehensive overview of the differences between mammals on sampling methods, processing, testing, and interpretation of data, with special attention to the meaning of pathologic and normal, and the differences among species and diseases. Part 2 critically analyzes 150 different hematologic and biochemical profiles obtained over 5 years from 150 psittacine birds belonging to 29 different species, brought to our clinic and/or examined in other locations, with confirmed or strongly suspected diseases. The results are grouped according to the various pathologies observed with respect to species and the degree of variation from the reference range of each species. PMID- 23347541 TI - Diagnosis of liver disease in domestic ferrets (Mustela putorius). AB - Liver disease in ferrets is often subclinical and underdiagnosed. Clinical pathology and diagnostic imaging are needed to guide clinicians but definite diagnosis is based on histopathologic lesions. Inflammatory digestive conditions can lead to ascending tract infection and hepatobiliary inflammation. Ferrets have a specific sensitivity to hepatic lipidosis. Incidence of hepatic neoplasia is high in ferrets. After a summary of anatomy and physiology of the ferret liver, hepatic diseases known in ferret species are reviewed with their subsequent diagnostic procedures. PMID- 23347542 TI - Diagnosis of renal disease in rabbits. AB - There are differences in renal anatomy and physiology between rabbits and other domestic species. Neurogenic renal ischemia occurs readily. Reversible prerenal azotemia may be seen in conjunction with gut stasis. Potentially fatal acute renal failure may be due to structural kidney damage or post-renal disease. Chronic renal failure is often associated with encephalitozoonosis. Affected rabbits cannot vomit and often eat well. Weight loss, lethargy, and cachexia are common clinical signs. Polydypsia/polyuria may be present. Derangements in calcium and phosphorus metabolism are features of renal disease. Radiography is always indicated. Urolithiasis, osteosclerosis, aortic and renal calcification are easily seen on radiographs. PMID- 23347543 TI - Point-of-care blood gas and electrolyte analysis in rabbits. AB - This article outlines a practical approach for the use of blood-gas analysis in pet rabbits using the I-STAT analyzer. Sampling techniques and a theoretic approach to diagnosis are described. The following 95% RI were obtained from venous samples of 45 healthy rabbits: pH (7.245-7.533), PCO(2) (28.9-52.9 mm Hg), HCO(3) (17.0-32.5 mmol/L), total CO(2) (18-34 mmol/L), BE(ecf) (-10-8 mmol/L), AnGap (11-26 mmol/L), Na (136-147 mmol/L), K (3.4-5.7 mmol/L), Cl (93-113 mmol/L), Glu (93-245 mg/dL), BUN (9-33 mg/dL). Results from 20 arterial samples were pH (7.358-7.502), PCO(2) (29.1-36.8 mm Hg), HCO(3) (17.5-27.6 mmol/L), BE(ecf) (-7-5 mmol/L), PO(2) (75-101 mm Hg), iCa (1.67-1.85). The article also includes some conclusions obtained comparing results from healthy and ill rabbits over an 18-month period. PMID- 23347544 TI - Sexual hormone fluctuation in chinchillas. AB - The data about chinchilla (Chinchilla laniger) reproduction are limited and in some cases discordant. The aim of this study was to monitor the sexual hormone fluctuation by fecal progesterone level and colpocytology analysis by vaginal smears in order to evaluate the different phases of the oestrus cycle. Twenty four non pregnant chinchillas aged from 1 to 4 years old and subdivided in three groups were monitored. In contrast with findings reported in other study, the high values of progesterone recorded in autumn suggested the presence of a ciclicity also in this period. The data indicate that chinchilla presents a continuous cycle. PMID- 23347545 TI - Applications of serum protein electrophoresis in exotic pet medicine. AB - Serum Protein Electrophoresis (SPE) is a useful diagnostic and prognostic tool in human and companion animals medicine: several experiences show that it can be useful in exotic practice as well. The fundamentals of SPE interpretation as well as some normal and pathological patterns for the species most commonly seen in practice are provided. PMID- 23347546 TI - Clinical and diagnostic pathology. PMID- 23347547 TI - Quercetin-loaded microcapsules ameliorate experimental colitis in mice by anti inflammatory and antioxidant mechanisms. AB - Quercetin (1) is an anti-inflammatory and antioxidant flavonoid. However, the oral administration of 1 did not lead to beneficial effects in experimental animal colitis models, which involve cytokines and oxidative stress. A possible explanation is that the absorption profile of 1 prevents its activity. Therefore, it was reasoned that the controlled release of 1 would improve its therapeutic effect. Thus, the therapeutic effect and mechanisms of 1-loaded microcapsules in acetic acid-induced colitis in mice were evaluated. Microcapsules were prepared using pectin/casein polymer and 1. The oral administration of 1-loaded microcapsules decreased neutrophil recruitment, attenuated histological alterations, and reduced macroscopical damage, edema, and IL-1beta and IL-33 production in the colon samples. Microcapsules loaded with 1 also prevented the reduction of anti-inflammatory cytokine IL-10 and the antioxidant capacity of the colon. These preclinical data indicate that pectin/casein polymer microcapsules loaded with 1 improved the anti-inflammatory and antioxidant effects of 1 compared to the nonencapsulated drug. Therefore, quercetin seems to be a promising active molecule in inflammatory bowel disease if provided with adequate controlled release. PMID- 23347548 TI - Study protocol for promoting respectful maternity care initiative to assess, measure and design interventions to reduce disrespect and abuse during childbirth in Kenya. AB - BACKGROUND: Increases in the proportion of facility-based deliveries have been marginal in many low-income countries in the African region. Preliminary clinical and anthropological evidence suggests that one major factor inhibiting pregnant women from delivering at facility is disrespectful and abusive treatment by health care providers in maternity units. Despite acknowledgement of this behavior by policy makers, program staff, civil society groups and community members, the problem appears to be widespread but prevalence is not well documented. Formative research will be undertaken to test the reliability and validity of a disrespect and abuse (D&A) construct and to then measure the prevalence of disrespect and abuse suffered by clinic clients and the general population. METHODS/DESIGN: A quasi-experimental design will be followed with surveys at twelve health facilities in four districts and one large maternity hospital in Nairobi and areas before and after the introduction of disrespect and abuse (D&A) interventions. The design is aimed to control for potential time dependent confounding on observed factors. DISCUSSION: This study seeks to conduct implementation research aimed at designing, testing, and evaluating an approach to significantly reduce disrespectful and abusive (D&A) care of women during labor and delivery in facilities. Specifically the proposed study aims to: (i) determine the manifestations, types and prevalence of D&A in childbirth (ii) develop and validate tools for assessing D&A (iii) identify and explore the potential drivers of D&A (iv) design, implement, monitor and evaluate the impact of one or more interventions to reduce D&A and (v) document and assess the dynamics of implementing interventions to reduce D&A and generate lessons for replication at scale. PMID- 23347549 TI - Modern non-invasive mechanical ventilation turns 25. AB - The history of non-invasive mechanical ventilation goes back more than 100 years, but it was not until 1987 when what we could call "modern" non-invasive mechanical ventilation was developed. The description of Delaubier and Rideau of a patient with Duchenne's disease who had been effectively ventilated through a nasal mask marked the start of a new era in the history of non-invasive mechanical ventilation. Over these last 25years, we have witnessed exponential growth in its use, field of activity and technological advances on an exciting fast-paced track. We believe that it is time to review the main milestones that have marked the development of non-invasive mechanical ventilation to date, while paying homage to this therapeutic method that has contributed so much to the advancement of respiratory medicine in the last 25years. PMID- 23347550 TI - Management of tracheobronchial amyloidosis with therapeutic bronchoscopic techniques. AB - Amyloidosis is a systemic disease caused by abnormal deposition of amyloid material that is detected with Congo red staining and is difficult to diagnose. Involvement of the tracheobronchial tree is rare and is a challenge for pulmonologists because of the wide differential diagnosis of this disease. We present two cases where tracheobronchial affectation has been observed: in one of them as a primary disease, and in another as secondary affectation. The use of bronchoscopic techniques is essential for the diagnosis of tracheobronchial involvement. In the absence of an effective drug therapy, local management of this disease with endoscopic techniques for bronchial repermeabilization is able to provide clinical improvement and expand the treatment options and prognosis in this disease. PMID- 23347551 TI - Steep temporal reward discounting in ADHD-Combined type: acting upon feelings. AB - Difficulty waiting plays a primary role in symptoms of attention deficit/hyperactivity disorder (ADHD), in particular, impulsivity. Current theories suggest that relatively strong preferences for small immediate rewards as observed in ADHD-Combined type are the result of delay-related negative feelings. However, the measurement of difficulty waiting is typically limited to objective choices between small immediate and large delayed rewards. This study aimed at extending the measurement of difficulty waiting in ADHD-Combined type with ratings about subjective feelings. Children and adolescents (ages 6-17) with ADHD-Combined type (n=25), ADHD-Inattentive type (n=20) and matched typically developing participants (n=37) performed temporal reward discounting tasks, and completed a Visual Analogue Scale of subjectively experienced ease/difficulty waiting. Although those with ADHD-Combined type demonstrated relatively steep temporal reward discounting, as reported elsewhere (Scheres et al., 2010), there were no group differences for subjectively experienced ease/difficulty waiting. Additionally, correlations between subjective and objective measures of difficulty waiting were significantly higher in the ADHD-Combined type group than in the control group. These findings suggest that (a) those with ADHD-Combined type do not choose impulsively because they have more negative feelings about waiting than controls; (b) choices in the ADHD-Combined type group are more in accordance with/driven by their feelings than choices made by participants in the control group. PMID- 23347552 TI - Polyviologen hydrogel with high-rate capability for anodes toward an aqueous electrolyte-type and organic-based rechargeable device. AB - A highly cross-linked polyviologen hydrogel, poly(tripyridiniomesitylene) (PTPM), has been designed as an anode-active material. It displays a reversible two electron redox capability at -0.4 and -0.8 V vs Ag/AgCl in an aqueous electrolyte. The PTPM layer coated on a current collector by electropolymerization via a 4-cyanopyridinium electro-coupling reaction demonstrates a rapid charging-discharging reaction with a redox capacity comparable to that obtainable using the formula weight-based theoretical density, because of the combination of the redox-active viologen moieties built into the hydrogel. A test cell that has been fabricated using the developed PTPM anode, a poly(2,2,6,6-tetramethylpiperidinyloxy-4-yl acrylamide) (PTAm)-based cathode, and an aqueous electrolyte exhibits a discharging voltage of 1.1 and 1.5 V, and has proven its ability to be recharged more than 2000 times. PMID- 23347553 TI - Response to Prof Kapoor. PMID- 23347554 TI - Vascular tissue engineering: biodegradable scaffold platforms to promote angiogenesis. AB - The ability to understand and regulate human vasculature development and differentiation has the potential to benefit patients suffering from a variety of ailments, including cardiovascular disease, peripheral vascular disease, ischemia, and burn wounds. Current clinical treatments for vascular-related diseases commonly use the grafting from patients of autologous vessels, which are limited and often damaged due to disease. Considerable progress is being made through a tissue engineering strategy in the vascular field. Tissue engineering takes a multidisciplinary approach seeking to repair, improve, or replace biological tissue function in a controlled and predictable manner. To address the clinical need to perfuse and repair damaged, ischemic tissue, one approach of vascular engineering aims to understand and promote the growth and differentiation of vascular networks. Vascular tissue engineered constructs enable the close study of vascular network assembly and vessel interactions with the surrounding microenvironment. Scaffold platforms provide a method to control network development through the biophysical regulation of different scaffold properties, such as composition, mechanics, dimensionality, and so forth. Following a short description of vascular physiology and blood vessel biomechanics, the key principles in vascular tissue engineering are discussed. This review focuses on various biodegradable scaffold platforms and demonstrates how they are being used to regulate, promote, and understand angiogenesis and vascular network formation. PMID- 23347555 TI - A systematic review assessing the economic impact of sildenafil citrate (Viagra) in the treatment of erectile dysfunction. AB - INTRODUCTION: Sildenafil was the first oral phosphodiesterase type 5 (PDE5) inhibitor introduced as primary therapy for erectile dysfunction (ED). In the 7 years following its market launch, sildenafil was prescribed by more than 750,000 physicians to more than 23 million men worldwide. To date, few studies have evaluated the economic impact of sildenafil in treating ED. AIM: To evaluate the cost-effectiveness and impact of sildenafil on health care costs for patients with ED in multiple countries. MAIN OUTCOMES MEASURES: Economic outcomes including cost, cost-effectiveness, cost of illness, cost consequence, resource use, productivity, work loss, and willingness to pay (WTP) were investigated. METHODS: Using keywords related to economic outcomes and sildenafil, we systematically searched literature published between July 2001 and July 2011 using MEDLINE and EMBASE. Included articles pertained to costs, WTP, and economic evaluations. RESULTS: In the last 10 years, 12 studies assessed economic outcomes associated with sildenafil for ED. Most studies were conducted in the United States and the United Kingdom, with one study identified in Canada and one from Mexico. Six studies evaluated cost of illness, cost consequence, or cost of care, and four studies evaluated WTP or drug pricing by country in the United States and the United Kingdom. In the United States and the United Kingdom, costs to health care systems have increased with demand for treatment. Cost analyses suggested that sildenafil would lower direct costs compared with other PDE5 inhibitors. U.S. and U.K. studies found that patients exhibited WTP for sildenafil. The two cost-effectiveness models we identified examined ED sub groups, those with spinal cord injury and those with diabetes or hypertension. These models indicated favorable cost-effectiveness profiles for sildenafil compared with other active-treatment options in both Mexico and Canada. CONCLUSIONS: The relative value of sildenafil vs. surgically implanted prosthetic devices and other PDE5 inhibitors, is underscored by patients' WTP, and cost effectiveness in ED patients with comorbidities. PMID- 23347556 TI - Registered reports: a new publishing initiative at Cortex. PMID- 23347557 TI - Abnormal visual field maps in human cortex: a mini-review and a case report. AB - Human visual cortex contains maps of the visual field. Much research has been dedicated to answering whether and when these visual field maps change if critical components of the visual circuitry are damaged. Here, we first provide a focused mini-review of the functional magnetic resonance imaging (fMRI) studies that have evaluated the human cortical visual field maps in the face of retinal lesions, brain injury, and atypical retinocortical projections. We find that there is a fair body of research that has found abnormal fMRI activity, but also that this abnormal activity does not necessarily stem from cortical remapping. The abnormal fMRI activity can often be explained in terms of task effects and/or the uncovering of normally hidden system dynamics. We then present the case of a 16-year-old patient who lost the entire left cerebral hemisphere at age three for treatment of chronic focal encephalitis (Rasmussen syndrome) and intractable epilepsy. Using an fMRI retinotopic mapping procedure and population receptive field (pRF) modeling, we found that (1) despite the long period since the hemispherectomy, the retinotopic organization of early visual cortex remained unaffected by the removal of an entire cerebral hemisphere, and (2) the intact lateral occipital cortex contained an exceptionally large representation of the center of the visual field. The same method also indicates that the neuronal receptive fields in these lateral occipital brain regions are extraordinarily small. These features are clearly abnormal, but again they do not necessarily stem from cortical remapping. For example, the abnormal features can also be explained by the notion that the hemispherectomy took place during a critical period in the development of the lateral occipital cortex and therefore arrested its normal development. Thus, caution should be exercised when interpreting abnormal fMRI activity as a marker of cortical remapping; there are often other explanations. PMID- 23347559 TI - Layer-specific diffusion weighted imaging in human primary visual cortex in vitro. AB - One of the most prominent characteristics of the human neocortex is its laminated structure. The first person to observe this was Francesco Gennari in the second half the 18th century: in the middle of the depth of primary visual cortex, myelinated fibres are so abundant that he could observe them with bare eyes as a white line. Because of its saliency, the stria of Gennari has a rich history in cyto- and myeloarchitectural research as well as in magnetic resonance (MR) microscopy. In the present paper we show for the first time the layered structure of the human neocortex with ex vivo diffusion weighted imaging (DWI). To achieve the necessary spatial and angular resolution, primary visual cortex samples were scanned on an 11.7 T small-animal MR system to characterize the diffusion properties of the cortical laminae and the stria of Gennari in particular. The results demonstrated that fractional anisotropy varied over cortical depth, showing reduced anisotropy in the stria of Gennari, the inner band of Baillarger and the deepest layer of the cortex. Orientation density functions showed multiple components in the stria of Gennari and deeper layers of the cortex. Potential applications of layer-specific diffusion imaging include characterization of clinical abnormalities, cortical mapping and (intra)cortical tractography. We conclude that future high-resolution in vivo cortical DWI investigations should take into account the layer-specificity of the diffusion properties. PMID- 23347558 TI - A new method for automated high-dimensional lesion segmentation evaluated in vascular injury and applied to the human occipital lobe. AB - Making robust inferences about the functional neuroanatomy of the brain is critically dependent on experimental techniques that examine the consequences of focal loss of brain function. Unfortunately, the use of the most comprehensive such technique-lesion-function mapping-is complicated by the need for time consuming and subjective manual delineation of the lesions, greatly limiting the practicability of the approach. Here we exploit a recently-described general measure of statistical anomaly, zeta, to devise a fully-automated, high dimensional algorithm for identifying the parameters of lesions within a brain image given a reference set of normal brain images. We proceed to evaluate such an algorithm in the context of diffusion-weighted imaging of the commonest type of lesion used in neuroanatomical research: ischaemic damage. Summary performance metrics exceed those previously published for diffusion-weighted imaging and approach the current gold standard-manual segmentation-sufficiently closely for fully-automated lesion-mapping studies to become a possibility. We apply the new method to 435 unselected images of patients with ischaemic stroke to derive a probabilistic map of the pattern of damage in lesions involving the occipital lobe, demonstrating the variation of anatomical resolvability of occipital areas so as to guide future lesion-function studies of the region. PMID- 23347560 TI - Long lasting clinical response to chemotherapy for advanced uterine leiomyosarcoma: a case report. AB - INTRODUCTION: Uterine leiomyosarcoma is one of the most frequent uterine sarcomas. In the metastatic setting it is sensitive to doxorubicin, ifosfamide, gemcitabine, docetaxel and a few other drugs, but time to progression is generally short. For this reason prognosis is often poor and there are few reports in the literature of long responders. CASE PRESENTATION: We report a case of a 40-year-old Caucasian woman with metastatic uterine leiomyosarcoma who began treatment six years before the presentation of this case report and for the following six years underwent ten lines of chemotherapy, achieving excellent results and a good quality of life. Among the treatments administered we observed a long response to temolozomide, an unconventional drug for this kind of disease. CONCLUSION: Although there are few chemotherapeutic options for the management of metastatic uterine leiomyosarcoma, a small number of patients have an unexpected long lasting response to treatment. For this reason further research is needed to identify new therapeutic agents and the predictive factors for the achievement of response. PMID- 23347561 TI - Targeting histone modifications--epigenetics in cancer. AB - Cancer is one of the most common human diseases. It is long known that mutations in key regulator genes are hallmarks of all cancer types. Apart from these classical genetic pathways there is more and more evidence that also epigenetic alterations are crucially involved in tumourigenesis. In this review we discuss and summarise recent findings of mechanisms responsible for cancer formation apart from the classic genetic mutations. Furthermore, we show how epigenetic and genetic mechanisms could depend on each other and contribute together to cancer formation. We focus mainly on post-translational histone modifications since they are one of the major epigenetic mechanisms regulating gene expression and when they are imbalanced this can result in cancer. PMID- 23347562 TI - Wnt signaling in stem and cancer stem cells. AB - The functional versatility of Wnt/beta-catenin signaling can be seen by its ability to act in stem cells of the embryo and of the adult as well as in cancer stem cells. During embryogenesis, stem cells demonstrate a requirement for beta catenin in mediating the response to Wnt signaling for their maintenance and transition from a pluripotent state. In adult stem cells, Wnt signaling functions at various hierarchical levels to contribute to specification of different tissues. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signaling in stem and progenitor cells is subverted in cancer cells to allow malignant progression. Intensive work is currently being performed to resolve how intrinsic and extrinsic factors that regulate Wnt/beta-catenin signaling coordinate the stem and cancer stem cell states. PMID- 23347563 TI - Small RNA pyrosequencing in the protozoan parasite Entamoeba histolytica reveals strain-specific small RNAs that target virulence genes. AB - BACKGROUND: Small RNA mediated gene silencing is a well-conserved regulatory pathway. In the parasite Entamoeba histolytica an endogenous RNAi pathway exists, however, the depth and diversity of the small RNA population remains unknown. RESULTS: To characterize the small RNA population that associates with E. histolytica Argonaute-2 (EhAGO2-2), we immunoprecipitated small RNAs that associate with it and performed one full pyrosequencing run. Data analysis revealed new features of the 27nt small RNAs including the 5'-G predominance, distinct small RNA distribution patterns on protein coding genes, small RNAs mapping to both introns and exon-exon junctions, and small RNA targeted genes that are clustered particularly in sections of genome duplication. Characterization of genomic loci to which both sense and antisense small RNAs mapped showed that both sets of small RNAs have 5'-polyphosphate termini; strand specific RT-PCR detected transcripts in both directions at these loci suggesting that both transcripts may serve as template for small RNA generation. In order to determine whether small RNA abundance patterns account for strain-specific gene expression profiles of E. histolytica virulent and non-virulent strains, we sequenced small RNAs from a non-virulent strain and found that small RNAs mapped to genes in a manner consistent with their regulation of strain-specific virulence genes. CONCLUSIONS: We provided a full spectrum analysis for E. histolytica AGO2-2 associated 27nt small RNAs. Additionally, comparative analysis of small RNA populations from virulent and non-virulent amebic strains indicates that small RNA populations may regulate virulence genes. PMID- 23347565 TI - A method for estimating population sex ratio for sage-grouse using noninvasive genetic samples. AB - Population sex ratio is an important metric for wildlife management and conservation, but estimates can be difficult to obtain, particularly for sexually monomorphic species or for species that differ in detection probability between the sexes. Noninvasive genetic sampling (NGS) using polymerase chain reaction (PCR) has become a common method for identifying sex from sources such as hair, feathers or faeces, and is a potential source for estimating sex ratio. If, however, PCR success is sex-biased, naively using NGS could lead to a biased sex ratio estimator. We measured PCR success rates and error rates for amplifying the W and Z chromosomes from greater sage-grouse (Centrocercus urophasianus) faecal samples, examined how success and error rates for sex identification changed in response to faecal sample exposure time, and used simulation models to evaluate precision and bias of three sex assignment criteria for estimating population sex ratio with variable sample sizes and levels of PCR replication. We found PCR success rates were higher for females than males and that choice of sex assignment criteria influenced the bias and precision of corresponding sex ratio estimates. Our simulations demonstrate the importance of considering the interplay between the sex bias of PCR success, number of genotyping replicates, sample size, true population sex ratio and accuracy of assignment rules for designing future studies. Our results suggest that using faecal DNA for estimating the sex ratio of sage-grouse populations has great potential and, with minor adaptations and similar marker evaluations, should be applicable to numerous species. PMID- 23347564 TI - Differential expression of major histocompatibility complex class I in developmental glioneuronal lesions. AB - PURPOSE: The expression of the major histocompatibility complex class I (MHC-I) in the brain has received considerable interest not only because of its fundamental role in the immune system, but also for its non-immune functions in the context of activity-dependent brain development and plasticity. METHODS: In the present study we evaluated the expression and cellular pattern of MHC-I in focal glioneuronal lesions associated with intractable epilepsy. MHC-I expression was studied in epilepsy surgery cases with focal cortical dysplasia (FCD I, n = 6; FCD IIa, n = 6 and FCD IIb, n = 15), tuberous sclerosis complex (TSC, cortical tubers; n = 6) or ganglioglioma (GG; n = 15) using immunocytochemistry. Evaluation of T lymphocytes with granzyme-B+ granules and albumin immunoreactivity was also performed. RESULTS: All lesions were characterized by MHC-I expression in blood vessels. Expression in both endothelial and microglial cells as well as in neurons (dysmorphic/dysplastic neurons) was observed in FCD II, TSC and GG cases. We observed perivascular and parenchymal T lymphocytes (CD8+, T-cytotoxic) with granzyme-B+ granules in FCD IIb and TSC specimens. Albumin extravasation, with uptake in astrocytes, was observed in FCD IIb and GG cases. CONCLUSIONS: Our findings indicate a prominent upregulation of MHC-I as part of the immune response occurring in epileptogenic glioneuronal lesions. In particular, the induction of MHC-I in neuronal cells appears to be a feature of type II FCD, TSC and GG and may represent an important accompanying event of the immune response, associated with blood-brain barrier dysfunction, in these developmental lesions. PMID- 23347566 TI - Employer-provided health insurance and hospital mergers. AB - This paper explores the impact of employer-provided health insurance on hospital competition and hospital mergers. Under employer-provided health insurance, employer executives act as agents for their employees in selecting health insurance options for their firm. The paper investigates whether a merger of hospitals favored by executives will result in a larger price increase than a merger of competing hospitals elsewhere. This is found to be the case even when the executive has the same opportunity cost of travel as her employees and even when the executive is the sole owner of the firm, retaining all profits. This is consistent with the Federal Trade Commission's findings in its challenge of Evanston Northwestern Healthcare's acquisition of Highland Park Hospital. Implications of the model are further tested with executive location data and hospital data from Florida and Texas. PMID- 23347567 TI - [Does aspirin still play a role in secondary prevention of venous thromboembolism?]. PMID- 23347569 TI - An adolescent presenting with malignant fibrous histiocytoma of the testis: a case report. AB - INTRODUCTION: Malignant fibrous histiocytoma is a very common subtype of soft tissue sarcoma in middle and late adulthood. However, malignant fibrous histiocytoma of the testis is very rare in adolescents. CASE PRESENTATION: We report here the case of a 14-year-old Han Chinese boy, who presented with left scrotal mass lasting for 20 days along with distending pain for 5 days. A physical examination revealed a chicken egg-sized, firm, well-defined mass and unclear epididymis. A B-scan ultrasonography of the left scrotum displayed a 9.0*5.2*4.5cm medium- or low-echoic lobulated mass, which suggested a left testicular neoplasm. A fine needle aspiration cytology examination revealed that the cells obtained from the patient's testicular neoplasm were composed of myxoid spindle, and ovoid cells with nuclear atypia and mitotic activity, and arranged in a whirlpool or storiform pattern. Under histological examination, the tumor cells were arranged in a storiform pattern, which displayed mucoid matrix degeneration, and grew invasively. Consequently, a histopathological diagnosis suggested myxofibrosarcoma (or myxoid malignant fibrous histiocytoma). CONCLUSIONS: An ultrasonic examination combined with fine needle aspiration cytology should be helpful for the initial differential diagnosis of testicular malignant fibrous histiocytoma. However, the final confirmation relies on histopathological examination. To the best of our knowledge, this is the first reported case of malignant fibrous histiocytoma of the testis in an adolescent. PMID- 23347568 TI - Induction without methanol: novel regulated promoters enable high-level expression in Pichia pastoris. AB - BACKGROUND: Inducible high-level expression is favoured for recombinant protein production in Pichia pastoris. Therefore, novel regulated promoters are desired, ideally repressing heterologous gene expression during initial growth and enabling it in the production phase. In a typical large scale fed-batch culture repression is desired during the batch phase where cells grow on a surplus of e.g. glycerol, while heterologous gene expression should be active in the feed phase under carbon (e.g. glucose) limitation. RESULTS: DNA microarray analysis of P. pastoris wild type cells growing in glycerol-based batch and glucose-based fed batch was used for the identification of genes with both, strong repression on glycerol and high-level expression in the feed phase. Six novel glucose-limit inducible promoters were successfully applied to express the intracellular reporter eGFP. The highest expression levels together with strong repression in pre-culture were achieved with the novel promoters P(G1) and P(G6). Human serum albumin (HSA) was used to characterize the promoters with an industrially relevant secreted protein. A P(G1) clone with two gene copies reached about 230% of the biomass specific HSA titer in glucose-based fed batch fermentation compared to a P(GAP) clone with identical gene copy number, while P(G6) only achieved 39%. Two clones each carrying eleven gene copies, expressing HSA under control of P(G1) and P(G6) respectively were generated by post-transformational vector amplification. They produced about 1.0 and 0.7 g L(-1) HSA respectively in equal fed batch processes. The suitability in production processes was also verified with HyHEL antibody Fab fragment for P(G1) and with porcine carboxypeptidase B for P(G6). Moreover, the molecular function of the gene under the control of P(G1) was determined to encode a high-affinity glucose transporter and named GTH1. CONCLUSIONS: A set of novel regulated promoters, enabling induction without methanol, was successfully identified by using DNA microarrays and shown to be suitable for high level expression of recombinant proteins in glucose-based protein production processes. PMID- 23347570 TI - Global Contact Lens Care Summit--introduction. PMID- 23347571 TI - 3. Ocular surface health with contact lens wear. AB - Eye care practitioners (ECPs) would tend to agree that wearing contact lenses increases the risk for infection, but millions of patients are still fitted with lenses every year because ECPs feel that the risk is manageable and that their patients' eye health can be protected. The Fusarium and Acanthamoeba keratitis outbreaks of years past were a wake-up call to manufacturers, ECPs, and regulatory agencies that risk cannot be managed without diligence, and that the complex relationship between contact lens materials, contact lens solutions, and compliance needs to be better understood in order to optimize the efficacy of contact lens care and improve care guidelines. PMID- 23347572 TI - 4. Contemporary research in contact lens care. AB - As our understanding of the eye and how it works evolves, we must re-evaluate previous findings, beliefs, and methods of diagnosis and treatment. The eye has proven to be naturally adept at protecting itself from pathogenic intruders, but contact lens wear and lens cleaning products can adversely impact this innate ability. Keeping up to date on the latest information is challenging, and becomes more complex when trying to incorporate the new scientific data into clinical practice. Several factors prevent drawing a straight line from study findings to real-world results, such as patient compliance and potentially flawed diagnostic tools. In this section, we review the latest research findings and opinions related to contact lens care and further explore compliance and its effect on ocular health. PMID- 23347573 TI - 5. What do we do now? Implications for the clinical practice. AB - The primary objective of this supplement is to provide eye care practitioners (ECPs) with the latest research and experience on topics related to contact lens use and patient eye health. This section examines a variety of topics, including the challenges of keeping abreast of the scientific literature, recognizing data that are borne from well-designed studies, and keys to their implementation in clinical practice. Insights are also provided on how eye care is practiced in Asia, where regulations and patient perceptions result in care that is delivered much differently than in North America and Europe. The role of silicone hydrogel (SiHy) lenses in the clinical practice and how advances with this lens material may shape future lens prescribing are then reviewed. The final part examines the current thinking regarding corneal infiltrates, microbial keratitis (MK), and multipurpose solution (MPS)-related corneal staining, and how ECPs should approach these issues. PMID- 23347575 TI - 2. Contact lens care and ocular surface homeostasis. AB - The early focus of contact lens wear and ocular health was on oxygen delivery. However, as we learn more about how the eye works, and investigate how the contact lens interacts with the cornea, the role of the tear film has risen in prominence. A healthy tear film is critical for normal ocular homeostasis, and abnormalities of the tear film are the primary cause of dry eye. In order to improve patient eye health and comfort during lens wear, we need to further elucidate the relationship among contact lenses, contact lens solutions, the tear film, and the corneal epithelium, and find ways to maintain homeostasis of the ocular surface. In this section, we review the latest data and opinions on this complex relationship between contact lenses and lens care solutions. PMID- 23347574 TI - 1. History, evolution, and evolving standards of contact lens care. AB - Contact lenses and lens care regimens are an important part of eyecare practices and vital to lens-wearing patients. New contact lens materials and cleaning options continue to come to market and affect how patients wear and care for their lenses. In this section we look at how the contact lens and lens solution revolution started, how it has evolved over the last 40 years, and how standards have evolved and impacted these new offerings. PMID- 23347576 TI - Echinococcus infections in Chinese dogs: a comparison of coproantigen kits. AB - Coproantigen test kits for Echinococcus spp. worms in dogs, designed for commercial use, were obtained from three different Chinese producers, and were compared with a laboratory kit using reagents from New Zealand. None of the three producers would provide details of their test validation. From a known set of dog faeces obtained at necropsy from infected and uninfected dogs, and from faeces collected from dogs necropsied in the field, results differed between the kits. For field material, the Tiankang kit showed the best specificity but lacked sensitivity. The Combined kit showed best sensitivity but lacked specificity. Results for the Haitai kit were intermediate. With samples from experimentally infected dogs, both the Haitai and Combined kits lacked sensitivity. Kits will need to be validated by the user before they can be relied on to predict progress in Echinococcus spp. control in China or in other countries. PMID- 23347577 TI - Weight loss by multidisciplinary intervention improves endothelial and sexual function in obese fertile women. AB - INTRODUCTION: Weight loss in sexually active women improves their quality of life. At present, no studies have investigated whether weight loss may affect female sexual function in severe obese women. AIM: The aim of this study was to investigate the effects of different programs of weight loss on female sexual dysfunction complaints and on endothelial function in premenopausal obese females. METHODS: Forty-four out of overall 80 obese fertile women (age 18-49 years; mean 36 years) were enrolled because of sexual complaints at Female Sexual Function Index-6 (FSFI-6 score <=19). Patients were then allocated to different treatments of 8 weeks duration each: an intensive residential program with hypocaloric diet plus controlled physical exercise along with lifestyle modifications at a specialized clinic (Group A, N = 23) and a non-intensive outpatient clinic program consisting of hypocaloric diet and physical exercise at home (Group B, N = 21). Afterward, overall patients were allocated to an extended 8-week follow-up period consisting of outpatient clinic controlled diet plus physical exercise at home. MAIN OUTCOME MEASURES: Primary end points were modifications of FSFI-6 scores and endothelial function as measured by reactive hyperemia (RHI) with EndoPat-2000. Secondary end points were modifications in body composition as measured by dual-energy X-ray absorptiometry (DEXA). RESULTS: After 16 weeks, FSFI-6 score and the frequency of sexual activity were significantly higher in Group A compared with Group B (P < 0.01), and significant improvements in arousal, lubrication, and satisfaction sub-domain scores were also found (P < 0.01). Group A showed improvements in RHI (P < 0.01) and marked improvement in homeostasis model assessment of insulin resistance (P < 0.001), anthropometric parameters as weight (P < 0.01), body mass index (P < 0.01), fat mass (P < 0.0001), and percentage of fat mass (P < 0.005) compared with Group B. A relationship between peak insulin (P < 0.0001) and RHI (P < 0.001) vs. FSFI-6 scores was found, respectively. CONCLUSIONS: A multidisciplinary approach to female obesity appears to be superior to conventional outpatient clinic to produce weight loss and to improve several aspects of sexual dysfunction in obese women. Such changes might be related to persistent improvements in endothelial function and in insulin resistance. PMID- 23347578 TI - Imported hepatitis e virus, central african republic, 2011. PMID- 23347579 TI - Cerebral inflammation and mobilization of the peripheral immune system following global hypoxia-ischemia in preterm sheep. AB - BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of brain injury in preterm infants. Preterm HIE is predominantly caused by global hypoxia-ischemia (HI). In contrast, focal ischemia is most common in the adult brain and known to result in cerebral inflammation and activation of the peripheral immune system. These inflammatory responses are considered to play an important role in the adverse outcomes following brain ischemia. In this study, we hypothesize that cerebral and peripheral immune activation is also involved in preterm brain injury after global HI. METHODS: Preterm instrumented fetal sheep were exposed to 25 minutes of umbilical cord occlusion (UCO) (n = 8) at 0.7 gestation. Sham-treated animals (n = 8) were used as a control group. Brain sections were stained for ionized calcium binding adaptor molecule 1 (IBA-1) to investigate microglial proliferation and activation. The peripheral immune system was studied by assessment of circulating white blood cell counts, cellular changes of the spleen and influx of peripheral immune cells (MPO-positive neutrophils) into the brain. Pre-oligodendrocytes (preOLs) and myelin basic protein (MBP) were detected to determine white matter injury. Electro encephalography (EEG) was recorded to assess functional impairment by interburst interval (IBI) length analysis. RESULTS: Global HI resulted in profound activation and proliferation of microglia in the hippocampus, periventricular and subcortical white matter. In addition, non-preferential mobilization of white blood cells into the circulation was observed within 1 day after global HI and a significant influx of neutrophils into the brain was detected 7 days after the global HI insult. Furthermore, global HI resulted in marked involution of the spleen, which could not be explained by increased splenic apoptosis. In concordance with cerebral inflammation, global HI induced severe brain atrophy, region-specific preOL vulnerability, hypomyelination and persistent suppressed brain function. CONCLUSIONS: Our data provided evidence that global HI in preterm ovine fetuses resulted in profound cerebral inflammation and mobilization of the peripheral innate immune system. These inflammatory responses were paralleled by marked injury and functional loss of the preterm brain. Further understanding of the interplay between preterm brain inflammation and activation of the peripheral immune system following global HI will contribute to the development of future therapeutic interventions in preterm HIE. PMID- 23347581 TI - Networks of recyclable material waste-picker's cooperatives: an alternative for the solid waste management in the city of Rio de Janeiro. AB - The objective of this study is to discuss the role of networks formed of waste picker cooperatives in ameliorating problems of final disposal of solid waste in the city of Rio de Janeiro, since the city's main landfill will soon have to close because of exhausted capacity. However, it is estimated that in the city of Rio de Janeiro there are around five thousand waste-pickers working in poor conditions, with lack of physical infrastructure and training, but contributing significantly by diverting solid waste from landfills. According to the Sustainable Development Indicators (IBGE, 2010a,b) in Brazil, recycling rates hover between 45% and 55%. In the municipality of Rio de Janeiro, only 1% of the waste produced is collected selectively by the government (COMLURB, 2010), demonstrating that recycling is mainly performed by waste-pickers. Furthermore, since the recycling market is an oligopsony that requires economies of scale to negotiate directly with industries, the idea of working in networks of cooperatives meets the demands for joint marketing of recyclable materials. Thus, this work presents a method for creating and structuring a network of recycling cooperatives, with prior training for working in networks, so that the expected synergies and joint efforts can lead to concrete results. We intend to demonstrate that it is first essential to strengthen the waste-pickers' cooperatives in terms of infrastructure, governance and training so that solid waste management can be environmentally, socially and economically sustainable in the city of Rio de Janeiro. PMID- 23347580 TI - Risk adapted transmission prophylaxis to prevent vertical HIV-1 transmission: effectiveness and safety of an abbreviated regimen of postnatal oral zidovudine. AB - BACKGROUND: Antiretroviral drugs including zidovudine (ZDV) are effective in reducing HIV mother to child transmission (MTCT), however safety concern remains. The optimal duration of postnatal ZDV has not been established in clinical studies and there is a lack of consensus regarding optimal management. The objective of this study was to investigate the effectiveness and safety of a risk adapted two week course of oral postnatal ZDV as part of a combined intervention to reduce MTCT. METHODS: 118 mother infant pairs were treated according to the German-Austrian recommendations for HIV therapy in pregnancy and in HIV exposed newborns between 2000-2010. In the absence of factors associated with an increased HIV-1 transmission risk, children were assigned to the low risk group and treated with an abbreviated postnatal regimen with oral ZDV for 2 weeks. In the presence of risk factors, postnatal ZDV was escalated accordingly. RESULTS: Of 118 mother-infant pairs 79 were stratified to the low risk group, 27 to the high risk group and 11 to the very high risk group for HIV-1 MTCT. 4 children were lost to follow up. Overall Transmission risk in the group regardless of risk factors and completion of prophylaxis was 1.8% (95% confidence interval (CI) 0.09 6.6). If transmission prophylaxis was complete, transmission risk was 0.9% (95% CI 0.01-5.7). In the low risk group receiving two week oral ZDV transmission risk was 1.4% (95% CI 0.01-8.4) CONCLUSION: These data demonstrate the effectiveness of a short neonatal ZDV regimen in infants of women on stable ART and effective HIV-1 suppression. Further evaluation is needed in larger studies. PMID- 23347582 TI - Repressible promoters - a novel tool to generate conditional mutants in Pichia pastoris. AB - BACKGROUND: Repressible promoters are a useful tool for down-regulating the expression of genes, especially those that affect cell viability, in order to study cell physiology. They are also popular in biotechnological processes, like heterologous protein production. RESULTS: Here we present five novel repressible Pichia pastoris promoters of different strength: PSER1, PMET3, PTHR1, PPIS1 and PTHI11. eGFP was expressed under the control of each of these promoters and its fluorescence could be successfully decreased in liquid culture by adding different supplements. We also expressed the essential genes with different native promoter strength, ERO1 and PDI1, under the control of two of the novel promoters. In our experiments, a clear down-regulation of both repressible promoters on transcriptional level could be achieved. Compared to the transcript levels of these two genes when expressed under the control of their native promoters, only ERO1 was significantly down-regulated. CONCLUSION: Our results show that all of the novel promoters can be used for repression of genes in liquid culture. We also came to the conclusion that the choice of the repressible promoter is of particular importance. For a successful repression experiment it is crucial that the native promoter of a gene and the repressible promoter in its non-repressed state are of similar strength. PMID- 23347584 TI - Anti-inflammatory diterpenoids from Croton tonkinensis. AB - Phytochemical investigation of the methanolic extract of Croton tonkinensis afforded two known kauranes (1, 2), eight new ent-kauranes (3-10), and 16 known ent-kaurane-type diterpenoids (12-27). In addition, 30 known compounds were identified by comparison of their physical and spectroscopic data with reported data. Among the isolated compounds, ent-18-acetoxykaur-16-en-15-one (20) displayed the most significant inhibition of superoxide anion generation and elastase release. PMID- 23347583 TI - Effects of HIV-1-induced CD1c and CD1d modulation and endogenous lipid presentation on CD1c-restricted T-cell activation. AB - BACKGROUND: It has been shown that human immunodeficiency virus (HIV)-1 infection induces the production of endogenous lipids required for effective viral production, and the cluster of differentiation (CD)1 molecule CD1d is downregulated by HIV-1 infection. However, the role of endogenous lipid presentation and the implications of CD1 downregulation by HIV-1 infection have not yet been characterized. RESULTS: In this study, we observed downregulation of both CD1c and CD1d expression through a Vpu-dependent and Nef-independent mechanism, and the concomitant HIV-1-induced production of host cholesterol decreased the extent of CD1c and CD1d modulation. While the modest downregulation of CD1c by HIV-1 infection decreased the ability of CD1c-restricted T cells to respond and secrete interferon-gamma, the cholesterol upregulation in the same cells by HIV-1 infection appears to limit the downregulation of CD1c. CONCLUSIONS: The two conflicting HIV-1-mediated changes in CD1c expression appear to minimize the modulation of CD1c expression, thus leading the host to maintain a CD1c-restricted T-cell response against HIV-1. PMID- 23347585 TI - Electrically conductive polyaniline/polyimide nanofiber membranes prepared via a combination of electrospinning and subsequent in situ polymerization growth. AB - Highly aligned polyimide (PI) nanofiber membranes have been prepared by electrospinning equipped with a high speed rotating collector. As the electrospun polyimide nanofiber membranes possess large surface area, they can be used as the template for in situ growth of polyaniline (PANi) by using FeCl3 as the oxidant. It is found that PANi nanoparticles can be uniformly distributed on the surface of highly aligned PI nanofibers due to the low oxidization/reduction potential of FeCl3 and the active nucleation sites of the functionalized PI nanofibers. The as prepared PANi/PI composite membranes not only possess excellent thermal and mechanical properties but also show good electrical conductivity, pH sensitivity and significantly improved electromagnetic impedance properties. This is a facile method for fabricating high-performance and multifunctional composites that can find potential applications in electrical and aerospace fields. PMID- 23347586 TI - A sensitive and specific multiplex PCR approach for sex identification of ursine and tremarctine bears suitable for non-invasive samples. AB - We report a new approach for molecular sex identification of extant Ursinae and Tremarctinae bears. Two Y-specific fragments (SMCY and 318.2) and one X-specific fragment (ZFX) are amplified in a multiplex PCR, yielding a double test for male specific amplification and an internal positive control. The primers were designed and tested to be bear-specific, thereby minimizing the risk of cross amplification in other species including humans. The high sensitivity and small amplicon sizes (100, 124, 160 base pairs) facilitate analysis of non-invasively obtained DNA material. DNA from tissue and blood as well as from 30 non invasively collected hair and faeces yielded clear and easily interpretable results. The fragments were detected both by standard gel electrophoresis and automated capillary electrophoresis. PMID- 23347588 TI - Biology and hemodynamics of aneurismal vasculopathies. AB - Aneurysm vasculopathies represents a group of vascular disorders that share a common morphological diagnosis: a vascular dilation, the aneurysm. They can have a same etiology and a different clinical presentation or morphology, or have different etiology and very similar anatomical geometry. The biology of the aneurysm formation is a complex process that will be a result of an endogenous predisposition and epigenetic factors later on including the intracranial hemodynamics. We describe the biology of saccular aneurysms, its growth and rupture, as well as, current concepts of hemodynamics derived from application of computational flow dynamics on patient specific vascular models. Furthermore, we describe different aneurysm phenotypes and its extremely variability on morphological and etiological presentation. PMID- 23347587 TI - Differences in resting corticolimbic functional connectivity in bipolar I euthymia. AB - OBJECTIVE: We examined resting state functional connectivity in the brain between key emotion regulation regions in bipolar I disorder to delineate differences in coupling from healthy subjects. METHODS: Euthymic subjects with bipolar I disorder (n = 20) and matched healthy subjects (n = 20) participated in a resting state functional magnetic resonance imaging scan. Low-frequency fluctuations in blood oxygen level-dependent (BOLD) signal were correlated in the six connections between four anatomically defined nodes: left and right amygdala and left and right ventrolateral prefrontal cortex (vlPFC). Seed-to-voxel connectivity results were probed for commonly coupled regions. Following this, an identified region was included in a mediation analysis to determine the potential of mediation. RESULTS: The bipolar I disorder group exhibited significant hyperconnectivity between right amygdala and right vlPFC relative to healthy subjects. The connectivity between these regions in the bipolar I disorder group was partially mediated by activity in the anterior cingulate cortex (ACC). CONCLUSIONS: Greater coupling between right amygdala and right vlPFC and their partial mediation by the ACC were found in bipolar I disorder subjects in remission and in the absence of a psychological task. These findings have implications for a trait-related and clinically important imaging biomarker. PMID- 23347589 TI - The effect of flexor tenotomy on healing and prevention of neuropathic diabetic foot ulcers on the distal end of the toe. AB - BACKGROUND: Flexor tenotomy is a minimally invasive surgical alternative for the treatment of neuropathic diabetic foot ulcers on the distal end of the toe. The influence of infection on healing and time to heal after flexor tenotomy is unknown. Flexor tenotomy can also be used as a prophylactic treatment. The effectiveness as a prophylactic treatment has not been described before. METHODS: A retrospective study was performed with the inclusion of all consecutive flexor tenotomies from one hospital between January 2005 and December 2011. RESULTS: From 38 ulcers, 35 healed (92%), with a mean time to heal of 22 +/- 26 days. The longest duration for healing was found for infected ulcers that were penetrating to bone (35 days; p = .042). Cases of prophylactic flexor tenotomies (n=9) did not result in any ulcer or other complications during follow-up. CONCLUSIONS: The results of this study suggest that flexor tenotomy may be beneficial for neuropathic diabetic foot ulcers on the distal end of the toe, with a high healing percentage and a short mean time to heal. Infected ulcers that penetrated to bone took a significantly longer time to heal. Prospective research, to confirm the results of this retrospective study, should be performed. PMID- 23347590 TI - Molecular identification of Taenia spp. in the Eurasian lynx (Lynx lynx) from Finland. AB - Cestodes of the genus Taenia are parasites of mammals, with mainly carnivores as definitive and herbivores as intermediate hosts. Various medium-sized cats, Lynx spp., are involved in the life cycles of several species of Taenia. The aim of the present study was to identify Taenia tapeworms in the Eurasian lynx (Lynx lynx) from Finland. In total, 135 tapeworms from 72 lynx were subjected to molecular identification based on sequences of 2 mtDNA regions, the cytochrome c oxidase subunit 1 and the NADH dehydrogenase subunit 1 genes. Available morphological characters of the rostellar hooks and strobila were compared. Two species of Taenia were found: T. laticollis (127 samples) and an unknown Taenia sp. (5 samples). The latter could not be identified to species based on mtDNA, and the rostellar hooks were short relative to those described among other Taenia spp. recorded in felids from the Holarctic region. In the phylogenetic analyses of mtDNA sequences, T. laticollis was placed as a sister species of T. macrocystis, and the unknown Taenia sp. was closely related to T. hydatigena and T. regis. Our analyses suggest that these distinct taeniid tapeworms represent a putative new species of Taenia. The only currently recognized definitive host is L. lynx and the intermediate host is unknown. PMID- 23347591 TI - The role of co-crystals in pharmaceutical design. AB - Pharmaceutical co-crystal formation represents a straightforward way to dramatically influence the solid-state properties of a drug substance, particularly its solubility and hence bioavailability. This short review summarises this highly topical field, covering why the topic is of interest in pharmaceutical formulation, the definitions and practical scope of co-crystals, co-crystal preparation and characterisation, and implications for regulatory control and intellectual property (IP) protection. Concepts are illustrated with highly selected examples of pharmaceutical co-crystal systems within the wider context of crystal engineering and research in molecular solids. PMID- 23347592 TI - Pelvic floor dysfunction: women's sexual concerns unraveled. AB - INTRODUCTION: Sexual function of women suffering from pelvic organ prolapse (POP) and/or urinary incontinence (UI) is adversely affected. However, our current understanding of the exact relationship between female sexual dysfunction and POP and/or UI is incomplete. A qualitative study can improve our understanding by describing what women themselves perceive as the real problem. AIM: To gain a more in-depth understanding of the impact of POP and/or UI on the different categories of female sexual dysfunction by way of a qualitative study. METHODS: Qualitative semistructured interviews were conducted in 37 women scheduled for pelvic floor surgery, and one was excluded from analysis due to incomplete recordings. MAIN OUTCOME MEASURES: The impact of POP and/or UI on female sexual function. RESULTS: Only 17% of women were completely positive about their sex life. Both POP and UI had a negative effect on body image. Women with POP had a negative image of their vagina, which caused them to be insecure about their partner's sexual experience, while women with UI were embarrassed about their incontinence and pad use, and feared smelling of urine. Worries about the presence of POP during sexual activity, discomfort from POP, and reduced genital sensations were the most important reasons for decreased desire, arousal, and difficulty reaching an orgasm in women with POP. Fear of incontinence during intercourse affected desire, arousal, and orgasm and could be a cause for dyspareunia in women with UI. Desire was divided into two main elements: "drive" and "motivation." Although "drive," i.e., spontaneous sexual interest, was not commonly affected by POP and/or UI, a decrease in "motivation" or the willingness to engage in sexual activity was the most common sexual dysfunction mentioned. CONCLUSIONS: Body image plays a key role in the sexual functioning of women with POP and/or UI with the biggest impact on women's "motivation." PMID- 23347594 TI - Tropheryma whipplei genotypes 1 and 3, Central Europe. PMID- 23347593 TI - On the implementation of an automated acoustic output optimization algorithm for subharmonic aided pressure estimation. AB - Incident acoustic output (IAO) dependent subharmonic signal amplitudes from ultrasound contrast agents can be categorized into occurrence, growth or saturation stages. Subharmonic aided pressure estimation (SHAPE) is a technique that utilizes growth stage subharmonic signal amplitudes for hydrostatic pressure estimation. In this study, we developed an automated IAO optimization algorithm to identify the IAO level eliciting growth stage subharmonic signals and also studied the effect of pulse length on SHAPE. This approach may help eliminate the problems of acquiring and analyzing the data offline at all IAO levels as was done in previous studies and thus, pave the way for real-time clinical pressure monitoring applications. The IAO optimization algorithm was implemented on a Logiq 9 (GE Healthcare, Milwaukee, WI) scanner interfaced with a computer. The optimization algorithm stepped the ultrasound scanner from 0% to 100% IAO. A logistic equation fitting function was applied with the criterion of minimum least squared error between the fitted subharmonic amplitudes and the measured subharmonic amplitudes as a function of the IAO levels and the optimum IAO level was chosen corresponding to the inflection point calculated from the fitted data. The efficacy of the optimum IAO level was investigated for in vivo SHAPE to monitor portal vein (PV) pressures in 5 canines and was compared with the performance of IAO levels, below and above the optimum IAO level, for 4, 8 and 16 transmit cycles. The canines received a continuous infusion of Sonazoid microbubbles (1.5 MUl/kg/min; GE Healthcare, Oslo, Norway). PV pressures were obtained using a surgically introduced pressure catheter (Millar Instruments, Inc., Houston, TX) and were recorded before and after increasing PV pressures. The experiments showed that optimum IAO levels for SHAPE in the canines ranged from 6% to 40%. The best correlation between changes in PV pressures and in subharmonic amplitudes (r=-0.76; p=0.24), and between the absolute PV pressures and the subharmonic amplitudes (r=-0.89; p<0.01) were obtained for the optimized IAO and 4 transmit cycles. Only for the optimized IAO and 4 transmit cycles did the subharmonic amplitudes differ significantly (p<0.01) before and after increasing PV pressures. A new algorithm to identify optimum IAO levels for SHAPE has been developed and validated with the best results being obtained for 4 transmit cycles. The work presented in this study may pave the way for real-time clinical applications of estimating pressures using the subharmonic signals from ultrasound contrast agents. PMID- 23347595 TI - Boosted protease inhibitor monotherapy in HIV-infected adults: outputs from a pan European expert panel meeting. AB - While the introduction of combination highly active antiretroviral therapy (HAART) regimens represents an important advance in the management of human immunodeficiency virus (HIV)-infected patients, tolerability can be an issue and the use of several different agents may produce problems. The switch of combination HAART to ritonavir-boosted protease inhibitor (PI) monotherapy may offer the opportunity to maintain antiviral efficacy while reducing treatment complexity and the risks of toxicity. Current European AIDS Clinical Society (EACS) guidelines recognise ritonavir-boosted PI monotherapy with twice-daily lopinavir/ritonavir or once-daily darunavir/ritonavir as a possible option in patients who have intolerance to nucleoside reverse transcriptase inhibitors, or for treatment simplification. Clinical trials data for PI boosted monotherapy are encouraging, showing substantial efficacy in the majority of patients; however, further data are required before this approach can be recommended as a routine treatment. Available data indicate that the most suitable candidates for the use of boosted PI monotherapy are long-term virologically suppressed patients who have demonstrated good adherence to antiretroviral therapy, who do not have chronic hepatitis B, have no history of treatment failure on PIs and are able to tolerate low-dose ritonavir. PMID- 23347596 TI - Chromatin dynamics at the replication fork: there's more to life than histones. AB - Before each division, eukaryotic cells face the daunting task of completely and accurately replicating a heterogeneous, chromatinized genome and repackaging both resulting daughters. Because replication requires strand separation, interactions between the DNA and its many associated proteins--including histones--must be transiently broken to allow the passage of the replication fork. Here, we will discuss the disruption and re-establishment of chromatin structure during replication, and the consequences of these processes for epigenetic inheritance. PMID- 23347597 TI - A mixed exercise training programme is feasible and safe and may improve quality of life and muscle strength in multiple myeloma survivors. AB - BACKGROUND: Exercise programmes are beneficial for cancer patients however evidence is limited in patients with multiple myeloma (MM), a cancer that is characterised by osteolytic bone disease, giving rise to high levels of bone morbidity including fractures and bone pain. METHODS: We conducted a single arm phase 2 study of an exercise programme (EP) as rehabilitation for treated MM patients, to evaluate feasibility, effects on QOL and physiological parameters. Patients were given individualised programmes, comprising stretching, aerobic and resistance exercises, carried out under supervision for 3 months then at home for a further 3 months. RESULTS: Study uptake was high, 60 of 75 (80%) patients approached consented to the study. Screen failures (11, due to fracture risk and disease relapse) and patient withdrawals (12) resulted in a final 37 patients enrolling on the programme. These 37 patients demonstrated high attendance rates in the supervised classes (87%), and high levels of adherence in home exercising (73%). Patients reported better QOL following the EP, with improvement in FACT-G and Fatigue scores over time from baseline (p<0.01 for both, one-way repeated measures ANOVA) to 6 months. Upper and lower limb strength also improved on the EP, from baseline to 6 months (p<0.01 for both). There were no adverse reactions. CONCLUSIONS: An EP in MM patients is feasible and safe, with high attendance and adherence. Benefits in QOL, fatigue and muscle strength await confirmation in randomized studies, prompting urgent evaluation of the benefits of EP in the rehabilitation of MM patients. PMID- 23347598 TI - Efficient synthesis of L-lactic acid from glycerol by metabolically engineered Escherichia coli. AB - BACKGROUND: Due to its abundance and low-price, glycerol has become an attractive carbon source for the industrial production of value-added fuels and chemicals. This work reports the engineering of E. coli for the efficient conversion of glycerol into L-lactic acid (L-lactate). RESULTS: Escherichia coli strains have previously been metabolically engineered for the microaerobic production of D lactic acid from glycerol in defined media by disrupting genes that minimize the synthesis of succinate, acetate, and ethanol, and also overexpressing the respiratory route of glycerol dissimilation (GlpK/GlpD). Here, further rounds of rationale design were performed on these strains for the homofermentative production of L-lactate, not normally produced in E. coli. Specifically, L lactate production was enabled by: 1), replacing the native D-lactate specific dehydrogenase with Streptococcus bovis L-lactate dehydrogenase (L-LDH), 2) blocking the methylglyoxal bypass pathways to avoid the synthesis of a racemic mixture of D- and L-lactate and prevent the accumulation of toxic intermediate, methylglyoxal, and 3) the native aerobic L-lactate dehydrogenase was blocked to prevent the undesired utilization of L-lactate. The engineered strain produced 50 g/L of L-lactate from 56 g/L of crude glycerol at a yield 93% of the theoretical maximum and with high optical (99.9%) and chemical (97%) purity. CONCLUSIONS: This study demonstrates the efficient conversion of glycerol to L-lactate, a microbial process that had not been reported in the literature prior to our work. The engineered biocatalysts produced L-lactate from crude glycerol in defined minimal salts medium at high chemical and optical purity. PMID- 23347599 TI - Fluorescence amplified fragment length polymorphism compared to pulsed field gel electrophoresis for Listeria monocytogenes subtyping. AB - BACKGROUND: Listeriosis is a severe infection which mainly affects pregnant women, neonates and immuno-compromised adults. ANSES's Laboratory for Food safety has been the European Union Reference Laboratory (EURL) for L. monocytogenes in the food chain since 2006. Pulsed Field Gel Electrophoresis (PFGE) is routinely used in the EURL for the surveillance of L. monocytogenes isolated from foods, animals and the environment. One of the main EURL activities is to evaluate alternative molecular subtyping methods to PFGE, and integrate their use within the National Reference Laboratories (NRL) network. Since 2008, the United Kingdom (UK)-NRL for L. monocytogenes at the Health Protection Agency (HPA), London, has used fluorescent Amplified Fragment Length Polymorphism (fAFLP) for the routine surveillance of L. monocytogenes isolated from human clinical cases, food and food processing environments in the UK. This study compares fAFLP with PFGE for subtyping L. monocytogenes. RESULTS: A panel of 109 L. monocytogenes isolates from either human cases of listeriosis, foods, food processing environments and animals were used for the comparative evaluation. Among these, 2 strains were tested from duplicate culture by both methods. The panel also included field isolates, isolates associated with outbreaks or sporadic cases and reference strains. The two strains tested in duplicate displayed the same fAFLP and PFGE types. Strains known to be epidemiologically associated with one another were found to have unique PFGE and fAFLP types. FAFLP and PFGE divided the strains into 76 and 82 distinct profiles, or types, respectively. The discriminatory index calculated was 0.993 and 0.996 for fAFLP and PFGE, respectively. CONCLUSIONS: The discriminatory ability of fAFLP was similar to that of PFGE for the subtyping of L. monocytogenes isolates. As a less labour intensive technique fAFLP may be a better method to use than PFGE in investigating outbreaks of human listeriosis and tracking the source of contamination in food processing facilities in real time. PMID- 23347600 TI - Highly efficient wettability control via three-dimensional (3D) suspension of titania nanoparticles in polystyrene nanofibers. AB - Electrospinning is a simple and highly versatile method for the large-scale fabrication of polymeric nanofibers. Additives or fillers can also be used to functionalize the nanofibers for use in specific applications. Herein, we demonstrate a novel and efficient way to fabricate superhydrophobic to hydrophilic tunable mats with the combined use of electrospinning and electrospraying that may be suitable for mass production on the merits of rapid deposition. The tunable nanocomposite mats were comprised of hydrophobic polystyrene nanofibers and hydrophilic titania nanoparticles. When the electrical conductivity of the electrospinning solution was increased, the surface morphology of the mats changed noticeably from a bead-on-string structure to an almost bead-free structure. Polystyrene (PS)-titania nanocomposite mats initially yielded a static water contact angle as high as 140 degrees +/- 3 degrees . Subsequently exposing these mats with relatively weak ultraviolet irradiation (lambda = 365 nm, I = 0.6 mW/cm2) for 2 h, the unique 3D suspension of the photoactive titania nanoparticles maximized the hydrophilic performance of the mats, reducing the static water contact angle to as low as 26 degrees +/- 2 degrees . The tunable mats were characterized by scanning electron microscopy (SEM), static water contact angle (WCA) measurements, and energy-dispersive X-ray spectroscopy (EDX). Our findings confirmed that the tunable mats fabricated by the simultaneous implementation of electrospraying and electrospinning had the most efficient ultraviolet (UV)-driven wettability control in terms of cost effectiveness. Well-controlled tunable hydrophobic and hydrophilic mats find potential applications in functional textiles, environmental membranes, biological sensors, scaffolds, and transport media. PMID- 23347602 TI - Correlations between microstructural alterations and severity of cognitive deficiency in Alzheimer's disease and mild cognitive impairment: a diffusional kurtosis imaging study. AB - OBJECT: Diffusional kurtosis imaging (DKI), a natural extension of diffusion tensor imaging (DTI), can characterize non-Gaussian diffusion in the brain. We investigated the capability of DKI parameters for detecting microstructural changes in both gray matter (GM) and white matter (WM) in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) and sought to determine whether these DKI parameters could serve as imaging biomarkers to indicate the severity of cognitive deficiency. MATERIALS AND METHODS: DKI was performed on 18AD patients and 12 MCI patients. Fractional anisotropy, kurtosis and diffusivity parameters in the temporal, parietal, frontal and occipital lobes were compared between the two groups using Mann-Whitney U test. The correlations between regional DKI parameters and mini-mental state examination (MMSE) score were tested using Pearson's correlation. RESULTS: In ADs, significantly increased diffusivity and decreased kurtosis parameters were observed in both the GM and WM of the parietal and occipital lobes as compared to MCIs. Significantly decreased fractional anisotropy was also observed in the WM of these lobes in ADs. With the exception of fractional anisotropy and radial kurtosis, all the five other DKI parameters exhibited significant correlations with MMSE score in both GM and WM. CONCLUSION: Bearing additional information, the DKI model can provide sensitive imaging biomarkers for assessing the severity of cognitive deficiency in reference to MMSE score and potentially improve early detection and progression monitoring of AD based on characterizing microstructures in both the WM and especially the GM. PMID- 23347601 TI - Visualizing iron in multiple sclerosis. AB - Magnetic resonance imaging (MRI) protocols that are designed to be sensitive to iron typically take advantage of (1) iron effects on the relaxation of water protons and/or (2) iron-induced local magnetic field susceptibility changes. Increasing evidence sustains the notion that imaging iron in brain of patients with multiple sclerosis (MS) may add some specificity toward the identification of the disease pathology. The present review summarizes currently reported in vivo and post mortem MRI evidence of (1) iron detection in white matter and gray matter of MS brains, (2) pathological and physiological correlates of iron as disclosed by imaging and (3) relations between iron accumulation and disease progression as measured by clinical metrics. PMID- 23347603 TI - Expression of DJ-1 proteins in placentas from women with severe preeclampsia. AB - OBJECTIVE: Lately, DJ-1 has been identified as a novel mediator of hypoxia induced cellular responses. The aim of this study was to determine the difference of DJ-1 expression in the placentas of women with normal and preeclamptic pregnancies. STUDY DESIGN: DJ-1 mRNA expression was quantified by quantitative reverse transcription polymerase chain reaction (RT-PCR). Also, immunoperoxidase and immunofluorescent staining for DJ-1 was performed on 11 normal and 12 preeclamptic placental tissues. RESULTS: The expression of mRNA of DJ-1 was significantly higher in the study group than in the control group. The immunoreactivity was especially higher in the syncytiotrophoblast of preeclamptic placentas compared to the control group. CONCLUSION: Overexpression of the DJ-1 protein in the placentas of severe PE patients is thought to be a causative or compensatory mechanism in response to hypoxia, and this finding might contribute to a better understanding of the pathophysiology of preeclampsia. PMID- 23347604 TI - Quality of life and predictive factors in patients undergoing assisted reproduction techniques. AB - OBJECTIVES: To evaluate the quality of life (QOL) of a cohort of women undergoing assisted reproduction techniques (ART), to compare two QOL questionnaires [Short Form 36 (SF36) and FertiQoL], and to identify the predictive factors related to QOL. STUDY DESIGN: Women who received infertility medication from a hospital pharmacist during a one-year period were included in this study. Two standardized validated questionnaires - FertiQoL and SF36 - were used. Multivariate analyses were used to assess predictive factors for QOL. RESULTS: Sixty-one women participated in this study. Median QOL scores ranged from 58 to 100. Comparisons between the two questionnaires revealed lower QOL scores when using FertiQoL. Most correlations between the questionnaires were positive, and significant for the majority of SF36 mental dimensions. The major predictors of QOL were: accompanied to the pharmacist's visit by partner, nationality, ART (in vitro fertilization or artificial insemination), employment status (employed or unemployed), tobacco consumption, age, number of cycles, infertility factor and treatment results (pregnancy, no pregnancy or treatment cancellation). CONCLUSIONS: FertiQoL examines dimensions such as partner and social relationships. As such, it is recommended that FertiQoL should be used together with a short version of SF36 to investigate QOL among patients undergoing ART. PMID- 23347605 TI - Role of phyto-oestrogens in ovulation induction in women with polycystic ovarian syndrome. AB - OBJECTIVE: To study the role of a phyto-oestrogen, Cimicifuga racimosa extract (Klimadynon((r)), Bionorica, Neumarkt i.d.OBf., Germany), in ovulation induction in women with polycystic ovarian syndrome (PCOS). STUDY DESIGN: Prospective randomized controlled trial in Minia University Hospital, Minia, Egypt. One hundred women with PCOS were allocated into one of two groups: one group (n=50) received clomiphene citrate 100mg daily for 5 days, and the other group (n=50) received C. racimosa 20mg daily for 10 days. Both groups received medication starting from the second day of the cycle for three consecutive cycles, during which changes in follicle-stimulating hormone (FSH), luteinizing hormone (LH), FSH/LH ratio, progesterone, endometrial thickness and pregnancy rate were measured. RESULTS: The groups were similar in terms of age, clinical presentation and hormonal levels before treatment. Following treatment, significant favourable changes in LH level and FSH/LH ratio (p=0.007 and 0.06, respectively) were seen in the Klimadynon group. In this group the progesterone level was higher from the first treatment cycle, indicating better ovulation (p=0.0001), and endometrial thickness was greater (p=0.0004). The pregnancy rate was higher in the Klimadynon group but the difference between the groups was not significant (p=0.1). CONCLUSION: Phyto-oestrogen can be used as an alternative to clomiphene citrate for ovulation induction in women with polycystic ovarian syndrome. PMID- 23347606 TI - Does the method of dissecting in anterior colporraphy lead to a difference in thickness of removed vaginal tissue? AB - OBJECTIVE: To evaluate the difference in thickness of the anterior vaginal wall removed after different surgical dissecting techniques of anterior colporrhaphy. STUDY DESIGN: In patients undergoing primary anterior colporrhaphy, trimmed vaginal tissue was taken following different surgical techniques of vaginal wall dissection. Tissues were preserved in formalin and stained with hematoxylin-eosin and elastica-van Giesen stains. The examiner was an experienced pathologist blinded to the surgical technique. The specimens were examined for the epithelial thickness (ET), lamina propria thickness (LPT), muscular layer thickness (MT) and total thickness (TT). RESULTS: Tissue was analysed in 93 women who underwent anterior compartment pelvic organ prolapse surgery. There was no difference between the different surgical techniques in thickness measured in the three histological layers and for the total thickness. The use of hydrodissection was the only independent factor leading to thicker removed vaginal tissue. CONCLUSIONS: Dissecting the vaginal wall as thin as possible does not result in a thinner vaginal layer than dissecting in the most optimal surgical plane. The use of hydrodissection provides a thicker trimmed tissue. PMID- 23347607 TI - Difficult embryo transfers or blood on catheter and assisted reproductive outcomes: a systematic review and meta-analysis. AB - We performed a systematic review and meta-analysis to examine whether a difficult embryo transfer or the presence of blood on the transfer catheter affects assisted reproduction outcomes. We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Literatura Latino-Americana e do Caribe em Ciencias da Saude (LILACS). We aimed to determine the risk ratio (RR) associated with difficult embryo transfer or the presence of blood on the transfer catheter for the following outcomes: live birth, clinical pregnancy, and miscarriage. We identified 3066 papers, of which 194 were reviewed and nine were included. The outcome of live birth was not reported in any of the included studies and the effect on miscarriage was too imprecise for any conclusions. Pooled analysis of five studies demonstrated lower clinical pregnancy rates following a non-easy embryo transfer (RR=0.75; 95% CI=0.66-0.86). This included three studies showing subjectively difficult transfers reducing clinical pregnancies (RR=0.67; 95% CI=0.51-0.87) and two studies in which the need for additional manoeuvers reduced clinical pregnancies (RR=0.78; 95% CI=0.67-0.91). The presence of blood on the transfer catheter did not affect clinical pregnancy rates (RR=0.96; 95% CI=0.82 1.14) in five studies. We concluded that low quality evidence suggests that a difficult embryo transfer but not a bloody catheter reduces the chance of achieving a clinical pregnancy. More good quality studies are needed to evaluate the effect of difficult embryo transfer and the presence of blood on the catheter on the main outcomes of assisted reproduction. PMID- 23347608 TI - Feasibility of laparoscopically assisted extracorporeal cystectomy via single suprapubic incision using an adjustable-view laparoscope to treat large benign ovarian cysts: comparison with conventional procedure. AB - OBJECTIVE: To demonstrate the feasibility of minimally invasive surgery using a novel optical device to treat large benign ovarian cysts and to compare the safety of the procedure with that of conventional laparoscopically assisted multiport extracorporeal cystectomy. STUDY DESIGN: Twenty-one patients with large benign ovarian cysts underwent laparoscopically assisted extracorporeal ovarian cystectomy via a single suprapubic incision using a novel 10-mm rigid laparoscope with an adjustable direction of view and a multiport device, between October 2010 and July 2012. The surgical outcomes were retrospectively compared between these patients (Group A) and 32 patients who underwent the conventional 3-port laparoscopically assisted extracorporeal procedure between January 2009 and September 2010 (Group B). Data were statistically analyzed using the Mann-Whitney U-test or Fisher's exact test. RESULTS: None of Group A required conversion to conventional multiport laparoscopy. The total duration of surgery, elapsed time between skin incision and the start of pneumoperitoneum, and time required for intra- and extra-corporeal manipulations did not significantly differ between the groups. The time required for skin closure, however, was significantly decreased in Group A compared with Group B (13.0 +/- 3.5 vs. 20.2 +/- 4.8 min, P=0.005). The volume of blood loss and postoperative blood findings were similar to those associated with the conventional procedure. Postoperative visual analog pain scales at 3h were significantly lower in Group A than in Group B (3.7 +/- 2.6 vs. 4.8 +/- 2.0, P=0.04). Postoperative complications did not arise after either procedure. CONCLUSION: Laparoscopically assisted extracorporeal cystectomy via a single suprapubic incision is a feasible and safe alternative to conventional multiport cystectomy for treating large benign ovarian cysts. PMID- 23347609 TI - Bovine tuberculosis and badgers in Britain: relevance of the past. AB - The European badger (Meles meles) has been identified as a wildlife reservoir of bovine tuberculosis and a source of transmission to cattle in Britain and Ireland. Both behavioural ecology and statistical ecological modelling have indicated the long-term persistence of the disease in some badger communities, and this is postulated to account for the high incidence of bovine tuberculosis in cattle across large tracts of England and Wales. This paper questions this consensus by using historical cartographic evidence to show that tuberculosis in cattle had a very different spatial distribution before 1960 to the present day. Since few of the badgers collected in road traffic accidents between 1972 and 1990 had tuberculosis in counties such as Cheshire, where the disease had until shortly before that been rife in the cattle population, the role of badgers as reservoirs in spreading disease in similar counties outside the south-west of England has to be questioned. PMID- 23347610 TI - A phase 2a multicenter, double-blind, placebo-controlled, crossover trial to investigate the efficacy, safety, and toleration of CP-866,087 (a high-affinity mu-opioid receptor antagonist) in premenopausal women diagnosed with female sexual arousal disorder (FSAD). AB - INTRODUCTION: Female sexual arousal disorder (FSAD) is a condition that can affect women of all ages and have a significant negative impact on emotional well being. AIMS: The aim of this study is to prospectively evaluate the effects of CP 866,087, a selective mu-opioid receptor antagonist, in premenopausal women with FSAD. METHODS: The study included 51 women (20-45 years of age) with FSAD. All women received placebo and two of three planned doses of CP-866,087 (1, 3, and 10 mg) for 6 weeks in each of three double-blind treatment periods. Efficacy was determined through a series of measures to assess sexual functioning, sexual activity, sexual distress, and perceived meaningful benefit as a result of treatment. In addition, a semi-structured exit interview was conducted at the end of the fourth treatment period or withdrawal to provide a more in-depth, qualitative description of the participants' symptoms, response to treatment, and treatment satisfaction to augment the quantitative assessments. MAIN OUTCOME MEASURES: The within-subject differences from placebo in the change from baseline were compared across a range of measures of sexual function. Summary statistics and 90% confidence intervals were calculated. A qualitative analysis of the exit interview was conducted based on grounded theory methods. RESULTS: Although improvements were seen with CP-866,087 in the key efficacy end points, there was no clinical treatment benefit over placebo. The exit interview analysis suggested that being part of the study and taking positive action to search for a solution to the women's sexual disorder may have been a significant factor in the behavioral changes that were seen, as opposed to the drug treatment itself. CONCLUSIONS: Discerning the potential benefit of pharmacotherapy in a heterogeneous condition such as FSAD is challenging. Participation in a clinical trial combined with a commitment to actively engage in sexual activity may in itself create an environment that is conducive to symptom improvement. PMID- 23347611 TI - 320-row computed tomography coronary angiography vs. conventional coronary angiography in patients with suspected coronary artery disease: a systematic review and meta-analysis. PMID- 23347612 TI - Circulating miR-133a and miR-423-5p fail as biomarkers for left ventricular remodeling after myocardial infarction. AB - BACKGROUND: Recent studies have suggested that the microRNAs miR-133a and miR-423 5p may serve as useful biomarkers in patients with left ventricular (LV) heart failure or with LV remodeling after myocardial infarction (MI). These results were however obtained in small series of patients and control subjects were used as reference groups. Whether these microRNAs may be indicators of the degree of LV remodeling after MI is unknown. METHODS: 246 patients with a first anterior Q wave MI were included. Serial echocardiographic studies were performed at hospital discharge, 3 months, and 1 year after MI and analyzed at a core laboratory. We investigated the temporal profile (baseline, 1, 3 and 12 months) of circulating miR-133a and miR-423-5p and their relations with cardiac biomarkers (B-type natriuretic peptide, C-reactive protein, and cardiac troponin I) and LV remodeling during the 1 year follow-up. RESULTS: There were time dependent changes in the levels of circulating miR-133a and miR-423-5p with significant increase of miR-133a at 12 months compared to 3 months and significant increase of miR-423-5p at 1, 3, and 12 months compared to baseline. However, miR-133a and miR-423-5p were not associated with indices of LV function and LV remodeling serially assessed during a 1 year period after an acute anterior MI, nor with B-type natriuretic peptide. CONCLUSIONS: Circulating levels of miR-133a and miR-423-5p are not useful biomarkers of LV remodeling after MI. PMID- 23347613 TI - The impact of triple anti-platelet therapy for endothelialization and inflammatory response at overlapping bioabsorbable polymer coated drug-eluting stents in a porcine coronary model. AB - BACKGROUND: This study was conducted to evaluate the endothelialization and the inflammatory responses depending on the administration duration of triple anti platelet therapy at overlapping bioabsorbable polymer coated biolimus-eluting stents (BESs) in a porcine coronary model. METHODS: We successfully deployed 36 overlapping BESs for the left anterior descending coronary and left circumflex artery or right coronary artery in 18 non-injured pigs. Total pigs were divided into 3 groups (12 overlapping stents of 6 pigs in each group) as follows: group I received aspirin 100mg and clopidogrel 75 mg daily for 8 weeks, group II received aspirin 100mg and clopidogrel 75 mg daily for 8 weeks and cilostazol 200mg daily for initial 4 weeks, and group III received aspirin 100mg, clopidogrel 75 mg, and cilostazol 200mg daily for 8 weeks. Follow-up coronary angiograms and histomorphometric and histopahtologic analyses at overlapping and non-overlapping segments were performed respectively. RESULTS: Inflammation score was similar between overlapping and non-overlapping segments in all pigs (1.2 +/- 0.33 vs. 1.1 +/- 0.17, p=0.117). The neointima area (NA) and percent area stenosis (%AS) at overlapping segments were not significantly different among the 3 groups. However, at non-overlapping segments, NA and %AS in group III were significantly smaller than those in group I (2.3 +/- 0.50mm(2) vs. 1.8 +/- 0.43 mm(2), p=0.037; 48.9 +/- 12.85% vs. 37.7 +/- 9.08%, p=0.031). CONCLUSIONS: Our study shows that BES appears to be reliable on the inflammatory response at overlapping segments as well as non-overlapping segments. Long-term administration of cilostazol is more effective in reducing neointimal formation at non-overlapping segments of BESs in a porcine coronary model. PMID- 23347614 TI - Subtotal nephrectomy accelerates pathological cardiac remodeling post-myocardial infarction: implications for cardiorenal syndrome. AB - BACKGROUND: To further understand the pathophysiology of concomitant cardiac and renal dysfunction, we investigated molecular, structural and functional changes in heart and kidney that occur when a kidney insult (5/6 nephrectomy-STNx) follows myocardial infarction (MI). METHODS: Male Sprague Dawley rats (n=43) were randomized into four groups: Sham-operated MI+Sham-operated STNx (Sham+Sham), MI+Sham-operated STNx (MI+Sham), Sham-operated MI+STNx (Sham+STNx) and MI+STNx. MI/Sham surgery was followed by STNx/Sham surgery 4 weeks later. Cardiac and renal function was assessed prior to STNx/Sham surgery and again 10 weeks later. Hemodynamic parameters were measured prior to sacrifice. RESULTS: Compared to the MI+Sham group, STNx further accelerated the reduction in left ventricular (LV) ejection fraction by 21% (p<0.01), and increased tau logistic by 38% (p<0.01) in MI+STNx animals. Heart weight/body weight (BW) and lung weight/BW ratios were 39% (p<0.001) and 16% (p<0.01) greater in MI+STNx compared to MI+Sham animals. Similarly, myocyte cross-sectional area (p<0.001), cardiac interstitial fibrosis (p<0.01) and collagen I (p<0.01) were increased in the LV non-infarct zone of the myocardium in the MI+STNx group. These changes were associated with significant increases in atrial natriuretic peptide (p<0.001), transforming growth factor beta1 (p<0.05) and collagen I (p<0.05) gene expression in MI+STNx animals. In comparison with the Sham+STNx group, renal tubulointerstitial fibrosis was increased by 64% in MI+STNx animals (p<0.001), with no further deterioration in renal function. CONCLUSIONS: STNx accelerated cardiac changes post-MI whilst MI accelerated STNx-induced renal fibrosis, supporting bidirectional interactions in cardiorenal syndrome (CRS). This animal model may be of use in assessing the impact of therapies to treat CRS. PMID- 23347616 TI - 5' C-rich telomeric overhangs are an outcome of rapid telomere truncation events. AB - A subset of human tumors ensures indefinite telomere length maintenance by activating a telomerase-independent mechanism known as Alternative Lengthening of Telomeres (ALT). Most tumor cells of ALT origin share a constellation of unique characteristics, which include large stores of extra-chromosomal telomeric material, chronic telomere dysfunction and a peculiar enrichment in chromosome ends with 5' C-rich overhangs. Here we demonstrate that acute telomere de protection and the subsequent DNA damage signal are not sufficient to facilitate formation of 5' C-overhangs at the chromosome end. Rather chromosome ends bearing 5' C-overhangs are a by-product of rapid cleavage events, processing of which occurs independently of the DNA damage response and is partly mediated through the XRCC3 endonuclease. PMID- 23347618 TI - Metal extraction from the artificially contaminated soil using supercritical CO2 with mixed ligands. AB - Supercritical fluids have good penetrating power with a high capacity to dissolve certain solutes in the fluid itself, making it applicable for soil cleaning. Supercritical CO2 along with mixed ligands has been used for cleaning artificially contaminated soil. The extraction of metal from the soil was successful, and the molar ratio of ligands to the extracted metal was as low as 3. Complicated structures with a large surface area of the real soil seemed to cause the lower efficiency. Reduced efficiency was also observed over time after the sample preparation, indicating the possibility of chemisorption of the metal ion onto the soil. The use of supercritical CO2 with dissolved mixed ligands was sufficient to extract metal from the soil. PMID- 23347615 TI - Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. AB - BACKGROUND: The mitochondrial genome (mtDNA) is particularly susceptible to damage mediated by reactive oxygen species (ROS). Although elevated ROS production and elevated biomarkers of oxidative stress have been found in tissues from children with autism spectrum disorders, evidence for damage to mtDNA is lacking. FINDINGS: mtDNA deletions were evaluated in peripheral blood monocytic cells (PBMC) isolated from 2-5 year old children with full autism (AU; n = 67), and typically developing children (TD; n = 46) and their parents enrolled in the CHildhood Autism Risk from Genes and Environment study (CHARGE) at University of California Davis. Sequence variants were evaluated in mtDNA segments from AU and TD children (n = 10; each) and their mothers representing 31.2% coverage of the entire human mitochondrial genome. Increased mtDNA damage in AU children was evidenced by (i) higher frequency of mtDNA deletions (2-fold), (ii) higher number of GC->AT transitions (2.4-fold), being GC preferred sites for oxidative damage, and (iii) higher frequency of G,C,T->A transitions (1.6-fold) suggesting a higher incidence of polymerase gamma incorporating mainly A at bypassed apurinic/apyrimidinic sites, probably originated from oxidative stress. The last two outcomes were identical to their mothers suggesting the inheritance of a template consistent with increased oxidative damage, whereas the frequency of mtDNA deletions in AU children was similar to that of their fathers. CONCLUSIONS: These results suggest that a combination of genetic and epigenetic factors, taking place during perinatal periods, results in a mtDNA template in children with autism similar to that expected for older individuals. PMID- 23347619 TI - Pilot-scale washing of Pb, Zn and Cd contaminated soil using EDTA and process water recycling. AB - Pb, Zn and Cd contaminated garden soil (5249, 3348 and 20.6 mg kg(-1), respectively) rich with fines and organic matter was washed with a solution of 120 mmol EDTA kg(-1) of soil in a pilot-scale remediation plant operating in a batch (60 kg of soil) mode. After soil washing, the solid phase and used washing solution were separated in a chamber filter press. A base/acid pair Ca(OH)(2)/H(2)SO(4) was used to impose a pH gradient for EDTA recycling from used washing solution and, coupled with an electrochemical advanced oxidation process using a graphite anode, for cleansing and recycling the process water, which was used for rinsing the soil solid phase in the press. On average (5 batches), 75%, 26% and 66% of Pb, Zn and Cd, respectively, was removed from the soil, 71% of EDTA was recycled and no waste water was generated. The variable costs of the novel remediation process (materials, energy but not labour) amounted to 66 ? t( 1) of remediated soil. The results of the pilot-scale testing indicate that scaling-up the process to a commercial level is technically and economically feasible. PMID- 23347621 TI - The inexorable progress of norovirus. PMID- 23347620 TI - Verification of enzymes deterioration due to Cu(II) presence in an enhanced biological phosphorus removal system. AB - This study experimentally demonstrated that polyphosphate accumulating organisms (PAOs) losing the abilities of anaerobically synthesizing polyhydroxyalkanoates and aerobically taking up phosphate under Cu(II) presence was due to the inhibition of enzyme activities of acetyl-CoA synthases (ACS) and polyphosphate kinase (PPK), respectively. ACS activity tests showed the apparent maximum specific activity (Vmax) of ACS decreased with increasing Cu(II) concentration, revealing Cu(II) is a mixed inhibitor for ACS. Inhibition coefficients showed Cu(II) has a higher affinity for free ACS than for ACS-coenzyme A complex. PPK activity tests showed the Vmax substantially decreased with increasing Cu(II) concentration, revealing Cu(II) is also a mixed inhibitor for PPK. Inhibition coefficients showed Cu(II) more easily bound to free PPK than to PPK-Adenosine triphosphate complex. Experimental data also showed the aerobic mechanism of PAOs taking up phosphate was completely interrupted when 3mgL(-1) of Cu(II) was added. PMID- 23347622 TI - An epidemiological view of microbial genomic data. PMID- 23347623 TI - The Chennai declaration on antimicrobial resistance in India. PMID- 23347624 TI - Drotrecogin alfa (activated) in severe sepsis. PMID- 23347625 TI - Drotrecogin alfa (activated) in severe sepsis. PMID- 23347626 TI - Drotrecogin alfa (activated) in severe sepsis. PMID- 23347627 TI - Drotrecogin alfa (activated) in severe sepsis. PMID- 23347628 TI - Drotrecogin alfa (activated) in severe sepsis--authors' reply. PMID- 23347629 TI - Synergies in integrated malaria control--authors' reply. PMID- 23347630 TI - Synergies in integrated malaria control. PMID- 23347631 TI - Slow parasite clearance rates in response to artemether in patients with severe malaria. PMID- 23347632 TI - Artemisinin resistance or artemisinin-based combination therapy resistance? PMID- 23347634 TI - Rapidly growing mycobacterial bloodstream infections. AB - About 20 species of rapidly growing mycobacteria species that are capable of infecting human beings and causing bloodstream infections have been identified. Many more of these species are being discovered worldwide, especially in resource poor settings. These microorganisms have been known to cause outbreaks and pseudo outbreaks. Although rapidly growing mycobacteria are not highly virulent or life threatening, they have a high predisposition to create biofilms and to colonise and infect intravascular catheters. Early detection and identification of specific species can help to estimate predictable antimicrobial susceptibility patterns. However, because susceptibility data originate from developed countries, studies in resource-poor settings urgently need to be done. The best outcome of cure without recurrence depends on a combination of at least 4 weeks of treatment with two or more active antimicrobial agents, plus removal of the intravascular catheter. We review and discuss the epidemiology, pathogenesis, diagnosis, management, and outcomes of rapidly growing mycobacterial bloodstream infections. PMID- 23347633 TI - The role of the natural environment in the emergence of antibiotic resistance in gram-negative bacteria. AB - During the past 10 years, multidrug-resistant Gram-negative Enterobacteriaceae have become a substantial challenge to infection control. It has been suggested by clinicians that the effectiveness of antibiotics is in such rapid decline that, depending on the pathogen concerned, their future utility can be measured in decades or even years. Unless the rise in antibiotic resistance can be reversed, we can expect to see a substantial rise in incurable infection and fatality in both developed and developing regions. Antibiotic resistance develops through complex interactions, with resistance arising by de-novo mutation under clinical antibiotic selection or frequently by acquisition of mobile genes that have evolved over time in bacteria in the environment. The reservoir of resistance genes in the environment is due to a mix of naturally occurring resistance and those present in animal and human waste and the selective effects of pollutants, which can co-select for mobile genetic elements carrying multiple resistant genes. Less attention has been given to how anthropogenic activity might be causing evolution of antibiotic resistance in the environment. Although the economics of the pharmaceutical industry continue to restrict investment in novel biomedical responses, action must be taken to avoid the conjunction of factors that promote evolution and spread of antibiotic resistance. PMID- 23347635 TI - Mucormycosis cerebral arteritis mimicking a flare in ANCA-associated vasculitis. PMID- 23347636 TI - Yersinia pestis plasminogen activator gene homolog in rat tissues. PMID- 23347637 TI - Antimicrobial activity, antibiotic susceptibility and virulence factors of Lactic Acid Bacteria of aquatic origin intended for use as probiotics in aquaculture. AB - BACKGROUND: The microorganisms intended for use as probiotics in aquaculture should exert antimicrobial activity and be regarded as safe not only for the aquatic hosts but also for their surrounding environments and humans. The objective of this work was to investigate the antimicrobial/bacteriocin activity against fish pathogens, the antibiotic susceptibility, and the prevalence of virulence factors and detrimental enzymatic activities in 99 Lactic Acid Bacteria (LAB) (59 enterococci and 40 non-enterococci) isolated from aquatic animals regarded as human food. RESULTS: These LAB displayed a broad antimicrobial/bacteriocin activity against the main Gram-positive and Gram negative fish pathogens. However, particular safety concerns based on antibiotic resistance and virulence factors were identified in the genus Enterococcus (86%) (Enterococcus faecalis, 100%; E. faecium, 79%). Antibiotic resistance was also found in the genera Weissella (60%), Pediococcus (44%), Lactobacillus (33%), but not in leuconostocs and lactococci. Antibiotic resistance genes were found in 7.5% of the non-enterococci, including the genera Pediococcus (12.5%) and Weissella (6.7%). One strain of both Pediococcus pentosaceus and Weissella cibaria carried the erythromycin resistance gene mef(A/E), and another two P. pentosaceus strains harboured lnu(A) conferring resistance to lincosamides. Gelatinase activity was found in E. faecalis and E. faecium (71 and 11%, respectively), while a low number of E. faecalis (5%) and none E. faecium exerted hemolytic activity. None enterococci and non-enterococci showed bile deconjugation and mucin degradation abilities, or other detrimental enzymatic activities. CONCLUSIONS: To our knowledge, this is the first description of mef(A/E) in the genera Pediococcus and Weissella, and lnu(A) in the genus Pediococcus. The in vitro subtractive screening presented in this work constitutes a valuable strategy for the large-scale preliminary selection of putatively safe LAB intended for use as probiotics in aquaculture. PMID- 23347638 TI - Preclinical evaluation of sunitinib as a single agent in the prophylactic setting in a mouse model of bone metastases. AB - BACKGROUND: A substantial number of breast cancer patients are identified as being at high risk of developing metastatic disease. With increasing number of targeted therapeutics entering clinical trials, chronic administration of these agents may be a feasible approach for the prevention of metastases within this subgroup of patients. In this preclinical study we examined whether sunitinib, a multi-tyrosine kinase inhibitor which has anti-angiogenic and anti-resorptive activity, is effective in the prevention of bone metastases. METHOD: Sunitinib was administered daily with the first dose commencing prior to tumor cell inoculation. Intracardiac injection was performed with MDA-MB23 bone-seeking cells, which were stably transfected with DsRed2. In vivo plain radiography and fluorescent imaging (Berthold NightOwl) was used in the analysis of bone metastases. Histomorphometry was used for the quantification of TRAP+ cells from bone sections and immunohistochemistry was performed using an antibody reactive to CD34 for quantification of microvessel density. RESULTS: Preventive dosing administration of sunitinib does not inhibit colonization of tumor cells to bone or reduce the size of osteolytic lesions. There was a decrease in the number of TRAP+ cells with sunitinib treatment but this did not reach significance. Sunitinib inhibited tumor growth as determined by imaging of fluorescent tumor area. Immunohistochemical analyses of microvessel density revealed a concomitant decrease in the number of tumor blood vessels. CONCLUSIONS: The findings suggest that sunitinib can be used as a therapeutic agent for the treatment of bone metastases but as a single agent it is not effective in terms of prevention. Therefore a combination approach with other cytostatic drugs should be pursued. PMID- 23347639 TI - High frequency of the erythroid silent Duffy antigen genotype and lack of Plasmodium vivax infections in Haiti. AB - BACKGROUND: Malaria is a significant public health concern in Haiti where approximately 30,000 cases are reported annually with CDC estimates as high as 200,000. Malaria infections in Haiti are caused almost exclusively by Plasmodium falciparum, while a small number of Plasmodium malariae and an even smaller number of putative Plasmodium vivax infections have been reported. The lack of confirmed P. vivax infections in Haiti could be due to the genetic background of native Haitians. Having descended from West African populations, many Haitians could be Duffy negative due to a single nucleotide polymorphism from thymine to cytosine in the GATA box of the promoter region of the Duffy antigen receptor for chemokines (DARC) gene. This mutation, encoded by the FYES allele, eliminates the expression of the Duffy antigen on erythrocytes, which reduces invasion by P. vivax. This study investigated the frequency of the FYES allele and P. vivax infections in malaria patients with the goal of uncovering factors for the lack of P. vivax infections reported in Haiti. METHODS: DNA was extracted from dried blood spots collected from malaria patients at four clinic locations in Haiti. The samples were analysed by polymerase chain reaction (PCR) for the presence of the P. vivax small subunit ribosomal RNA gene. PCR, sequencing, and restriction enzyme digestion were used to detect the presence of the FYES allele. Matched samples were examined for both presence of P. vivax and the FYES allele. RESULTS: No cases of P. vivax were detected in any of the samples (0/136). Of all samples tested for the FYES allele, 99.4% had the FYES allele (163/164). Of the matched samples, 99% had the FYES allele (98/99). CONCLUSIONS: In this preliminary study, no cases of P. vivax were confirmed by PCR and 99% of the malaria patients tested carried the FYES allele. The high frequency of the FYES allele that silences erythroid expression of the Duffy antigen offers a biologically plausible explanation for the lack of P. vivax infections observed. These results provide insights on the host susceptibility for P. vivax infections that has never before been investigated in Haiti. PMID- 23347640 TI - A cross-sectional study on biosecurity practices and communication networks of poultry exhibition in Australia. AB - Poultry exhibitors are perceived to pose a biosecurity risk due to the high frequency of movements of birds and the close contact between birds at poultry shows. This cross-sectional study assessed the risks posed by poultry exhibitors in Australia using face-to-face interviews (n=46) at eight poultry shows and a postal survey. Univariable and multivariable logistic regression analyses were used to investigate associations between age, sex, location, number of birds, number of shows attended per year and distance travelled to a show, with biosecurity and communication practices. A total of 357 (29.1%) exhibitors responded to the postal survey. Among all participants (n=403), most had owned poultry for more than 15 years (71.9%), kept less than 200 birds (83.4%), mainly chicken (96.7%) and waterfowl (17.8%), and reported not having any commercial poultry operation within 5 km of their property (85.4%). Despite most exhibitors (90.8%) having at least some knowledge of biosecurity principles; some of their practices could pose a risk for disease introduction and spread. Most exhibitors kept their birds with outdoor access (87.0%) and 67.0% of exhibitors reported contact of wild birds with domestic birds being possible. Only 60% and 40.6% of exhibitors cleaned transport cages after each use and isolated birds for over two weeks, respectively, with men and exhibitors keeping more birds less likely (P=0.003) to conduct this practice. Most exhibitors (75.0%) attended more than 5 shows per year, travelling long distances (up to 1000 km) to attend a show. Although most exhibitors would source and sell their birds from and to other exhibitors and at poultry shows, some reported sourcing (15.2%) and selling (25.3%) their birds at live bird markets. In addition, contact with veterinarians was low (23.1%), with younger exhibitors and women more likely to contact a veterinarian than older exhibitors (P=0.006) and men (P=0.017). Other poultry exhibitors were reported as the most useful source of information, followed by the poultry club, the veterinarian and Internet. Less than a quarter of exhibitors perceived the government agencies as a useful source of information. Newspapers, newsletters, emails and websites were the preferred methods of information delivery. However, information seeking behaviour was found to differ significantly (P<0.05) among gender and different age groups. Differing biosecurity, health and communication practices among poultry exhibitors found in this study need to be considered for the development of successful biosecurity extension and communication programmes. PMID- 23347641 TI - Pore formation in a p-type silicon wafer using a platinum needle electrode with application of square-wave potential pulses in HF solution. AB - By bringing an anodically biased needle electrode into contact with n-type Si at its tip in a solution containing hydrofluoric acid, Si is etched at the interface with the needle electrode and a pore is formed. However, in the case of p-type Si, although pores can be formed, Si is likely to be corroded and covered with a microporous Si layer. This is due to injection of holes from the needle electrode into the bulk of p-type Si, which shifts its potential to a level more positive than the potential needed for corrosion and formation of a microporous Si layer. However, by applying square-wave potential pulses to a Pt needle electrode, these undesirable changes are prevented because holes injected into the bulk of Si during the period of anodic potential are annihilated with electrons injected into Si during the period of cathodic potential. Even under such conditions, holes supplied to the place near the Si/metal interface are used for etching p type Si, leading to formation of a pore at the place where the Pt needle electrode was in contact. PMID- 23347642 TI - In vivo application of short-lag spatial coherence imaging in human liver. AB - We present the results of a patient study conducted to assess the performance of two novel imaging methods, namely short-lag spatial coherence (SLSC) and harmonic spatial coherence imaging (HSCI), in an in vivo liver environment. Similar in appearance to the B-mode images, SLSC and HSCI images are based solely on the spatial coherence of fundamental and harmonic echo data, respectively, and do not depend on the echo magnitude. SLSC and HSCI suppress incoherent echo signals and thus tend to reduce clutter. The SLSC and HSCI images of 17 patients demonstrated sharper delineation of blood vessel walls, suppressed clutter inside the vessel lumen, and showed reduced speckle in surrounding tissue compared to matched B modes. Target contrast and contrast-to-noise ratio (CNR) show statistically significant improvements between fundamental B-mode and SLSC imaging and between harmonic B-mode and HSCI imaging (in all cases p < 0.001). The magnitude of improvement in contrast and CNR increases as the overall quality of B-mode images decreases. Poor-quality fundamental B-mode images (where image quality classification is based on both contrast and CNR) exhibit the highest improvements in both contrast and CNR (288% improvement in contrast and 533% improvement in CNR). PMID- 23347643 TI - Secondary bjerknes forces deform targeted microbubbles. AB - In this study, we investigated the effect of secondary Bjerknes forces on targeted microbubbles using high-speed optical imaging. We observed that targeted microbubbles attached to an underlying surface and subject to secondary Bjerknes forces deform in the direction of their neighboring bubble, thereby tending toward a prolate shape. The deformation induces an elastic restoring force, causing the bubbles to recoil back to their equilibrium position; typically within 100 MUs after low-intensity ultrasound application. The temporal dynamics of the recoil was modeled as a simple mass-spring system, from which a value for the effective spring constant k of the order 10(-3) Nm(-1) was obtained. Moreover, the translational dynamics of interacting targeted microbubbles was predicted by a hydrodynamic point particle model, including a value of the spring stiffness k of the very same order as derived experimentally from the recoiling curves. For higher acoustic pressures, secondary Bjerknes forces rupture the molecular adhesion of the bubbles to the surface. We used this mutual attraction to quantify the binding force between a single biotinylated microbubble and an avidin-coated surface, which was found to be between 0.9 and 2 nanonewtons (nN). The observation of patches of lipids left at the initial binding site suggests that lipid anchors are pulled out of the microbubble shell, rather than biotin molecules unbinding from avidin. Understanding the effect of ultrasound application on targeted microbubbles is crucial for further advances in the realm of molecular imaging. PMID- 23347644 TI - Social judgments from faces. AB - People make rapid and consequential social judgments from minimal (non-emotional) facial cues. There has been rapid progress in identifying the perceptual basis of these judgments using data-driven, computational models. In contrast, our understanding of the neural underpinnings of these judgments is rather limited. Meta-analyses of neuroimaging studies find a wide range of seemingly inconsistent responses in the amygdala that co-vary with social judgments from faces. Guided by computational models of social judgments, these responses can be accounted by positing that the amygdala (and posterior face selective regions) tracks face typicality. Atypical faces, whether positively or negatively evaluated, elicit stronger responses in the amygdala. We conclude with the promise of data-driven methods for modeling neural responses to social judgments from faces. PMID- 23347645 TI - Control-related systems in the human brain. AB - A fundamental question in cognitive neuroscience is how the human brain self organizes to perform tasks. Multiple accounts of this self-organization are currently influential and in this article we survey one of these accounts. We begin by introducing a psychological model of task control and several neuroimaging signals it predicts. We then discuss where such signals are found across tasks with emphasis on brain regions where multiple control signals are present. We then present results derived from spontaneous task-free functional connectivity between control-related regions that dovetail with distinctions made by control signals present in these regions, leading to a proposal that there are at least two task control systems in the brain. This prompts consideration of whether and how such control systems distinguish themselves from other brain regions in a whole-brain context. We present evidence from whole-brain networks that such distinctions do occur and that control systems comprise some of the basic system-level organizational elements of the human brain. We close with observations from the whole-brain networks that may suggest parsimony between multiple accounts of cognitive control. PMID- 23347646 TI - Translational research in Huntington's disease: opening up for disease modifying treatment. AB - Research on the molecular mechanisms involved in Huntington's disease, a monogenic disorder with a complex phenotype including motor, behaviour, and cognitive impairments, is advancing at a rapid path. Knowledge on several of the multimodal pathways has now lead to the establishment of rational strategies to prepare trials of several compounds in affected people. Furthermore, improved understanding of the phenotype and on ways of assessing it, as well as the process of developing biomarkers, allows setting the frame for such studies. In this brief review, the present status of some of these aspects is examined. PMID- 23347647 TI - Virological failure of staggered and simultaneous treatment interruption in HIV patients who began Efavirenz-based regimens after allergic reactions to nevirapine. AB - OBJECTIVE: The objective of this work was to study the virological outcomes associated with two different types of treatment interruption strategies in patients with allergic reactions to nevirapine (NVP). We compared the virological outcomes of (1) HIV-1-infected patients who discontinued an initial NVP-based regimen because of cutaneous allergic reactions to NVP; different types of interruption strategies were used, and second-line regimen was based on efavirenz (EFV); and (2) HIV-1-infected patients who began an EFV-based regimen as a first line therapy (controls). METHODS: This retrospective cohort included patients who began an EFV-based regimen, between January 2002 and December 2008, as either an initial regimen or as a subsequent regimen after resolving a cutaneous allergic reaction against an initial NVP-based regimen. The study ended in March 2010. The primary outcome was virological failure, which was defined as either (a) two consecutive plasma HIV-1 RNA levels >400 copies/mL or (b) a plasma HIV-1 RNA level >1,000 copies/mL plus any genotypic resistance mutation. RESULTS: A total of 559 patients were stratified into three groups: (a) Simultaneous Interruption, in which the subjects simultaneously discontinued all the drugs in an NVP-based regimen following an allergic reaction (n=161); (b) Staggered Interruption, in which the subjects discontinued NVP treatment while continuing nucleoside reverse transcriptase inhibitor (NRTI) backbone therapy for a median of 7 days (n=82); and (c) Control, in which the subjects were naive to antiretroviral therapy (n=316). The overall median follow-up time was 43 months. Incidence of virological failure in Simultaneous Interruption was 12.9 cases per 1,000 person years, which trended toward being higher than the incidences in Staggered Interruption (5.4) and Control (6.6). However, differences were not statistically significant. CONCLUSIONS: Among the patients who had an acute allergic reaction to first-line NVP-based therapy and later began an EFV-based regimen, virological outcomes resulting from a staggered interruption of treatment (with a continuation of NRTI backbone therapy for 7 days after discontinuing NVP) did not differ from those of the patients who began an EFV-based regimen as their initial therapy (Control). However, the virological failure of Simultaneous Interruption was possibly higher than those of Control and Staggered Interruption. PMID- 23347648 TI - Prevalence and epidemiological traits of HIV infections in populations with high risk behaviours as revealed by genetic analysis of HBV. AB - The prevalence and epidemiological traits of human immunodeficiency virus (HIV)/hepatitis B virus (HBV) infections in high-risk populations (HRPs) remained unclarified in Japan. We determined the prevalence of HIV, HBV and Treponema pallidum (TP) and the viral genotypes in HRPs who attended primary sexually transmitted infection (STI) clinics in Osaka province during 2006-2011. Of 7898 specimens, 133 (1.7%) were HIV positive, which was significantly higher than the figures reported by Japanese Red Cross (0.0019%) and public health centres (0.27%) in Japan. The frequency of HIV-1 subtype B was 88.7%, followed by CRF01_AE (2.3%) and C (0.8%), which were almost identical to the national trend. HBV seroprevalence was surprisingly high in the HIV-positive group (63.2%), which was significantly higher than that in the HIV-negative group (25.6%). By contrast, there was no statistical correlation between HIV and TP infection. Interestingly, the distinct HBV genotypes Ae and G were prevalent in the HIV positive population (60.0% and 20.0%, respectively), although both were rarely detected during nationwide surveillance. The transmission of HIV and HBV appeared to occur largely within a closed community early in life. Of note, about one quarter of HIV-positive cases would have remained untested if health professionals had not motivated individuals to undergo HIV testing. This is the first evidence-based assessment of HIV positivity and HIV/HBV co-infection in HRPs at primary STIs in Japan and the effect of the involvement of health professionals in the diagnosis of HIV infections in asymptomatic carriers. The genotyping of HBV provided valuable information for understanding HIV epidemical traits. PMID- 23347649 TI - High-throughput NIR-chemometric methods for determination of drug content and pharmaceutical properties of indapamide tablets. AB - This paper describes the development, validation and application of NIR chemometric methods for API content and pharmaceutical characterization (disintegration time and crushing strength) of indapamide intact tablets. Development of the method for chemical characterization was performed on samples corresponding to 80, 90, 100, 110 and 120% of indapamide content and for pharmaceutical characterization on samples prepared at nine different compression forces (covering the interval 7-45 kN). NIR spectra of prepared tablets were recorded in transmission mode, and partial least-squares followed by leave-one out cross-validation were used to develop models for the prediction of the drug content and the pharmaceutical properties of tablets. All developed models were validated in terms of trueness, precision and accuracy. No statistical differences were found between results predicted by NIR-chemometric methods and the ones determined by reference methods. Therefore, the developed NIR chemometric methods meet the requirements of a high-throughput method for the determination of drug content, pharmaceutical properties of indapamide tablets. PMID- 23347650 TI - Needle washing increases the diagnostic yield of fine needle aspiration biopsy of the thyroid gland. AB - BACKGROUND AND OBJECTIVE: Nodular thyroid disease is a common condition in our clinical practice, and fine needle aspiration biopsy (FNAB) is the diagnostic procedure of choice. Its main limitation is the number of non-diagnostic samples. Since the Bethesda criteria were implemented in 2007 (a consensus document on the morphologic criteria and diagnostic terminology for interpretation of thyroid cytological samples), a higher prevalence of non-diagnostic FNAB was shown. In addition to the standard technique, we decided to collect and centrifuge the material remaining in puncture needles by washing them in a ThinPrep((r)) solution, and to assess the increase in the diagnostic yield of FNAB after this change. PATIENTS AND METHODS: Systematic sampling of 168 patients who underwent FNAB at the Nutrition and Endocrinology Department of the Xeral-Cies Hospital (Vigo, Spain) from January 2010 to November 2011. Patients were classified into 2 groups: 75 patients in whom the residual material in the needle was not collected (non-washing group) and 93 patients in whom the material was collected (washing group). All FNABs were performed by the same endocrinologist. Data are shown as percentage (+/- standard error) for ordinal variables or as mean (+/- standard deviation) for quantitative variables. A Chi-square test was used for statistical analysis of comparisons between percentages, and a Student's t test for comparisons between quantitative variables. A value of p<0.05 was considered statistically significant. RESULTS: No significant differences were found between the groups in age, sex, plasma TSH levels or nodule size. The rate of non diagnostic FNABs was 44% (+/- 0.06) in the non-washing group and 17.2% (+/- 0.04%) in the washing group, with a significant difference (p < 0.01). DISCUSSION: Collection and subsequent processing of the residual material in the needle after FNAB significantly decreased the prevalence of non-diagnostic punctures in our patients. Collection of the residual material in the needle in this way is strongly recommended. PMID- 23347651 TI - Immunohistochemical expression of SALL4 in hepatocellular carcinoma, a potential pitfall in the differential diagnosis of yolk sac tumors. AB - SALL4 is a transcription factor that serves as a marker of yolk sac tumor. Yolk sac tumor and hepatocellular carcinoma share histologic, serologic, and immunohistochemical features. Previous studies have shown lack of SALL4 expression in hepatocellular carcinoma, suggesting utility in this differential diagnosis. Sixty-nine samples of hepatocellular carcinoma were retrieved from surgical pathology archives and used to construct 9 tissue microarrays. A germ cell tumor tissue microarray containing 10 yolk sac tumors was used for comparison. Extent, intensity, and pattern of nuclear SALL4 expression were assessed in each spot. Mean percentage of expression was calculated for each tumor and used during analysis. Optimal discriminatory extent of expression cutoff was determined by receiver operating characteristic curve analysis. Other potential discriminatory markers including Hep Par1 were also evaluated. Forty six percent (32/69) of hepatocellular carcinoma and all yolk sac tumors revealed at least focal expression of SALL4. A unique punctuate/clumped pattern of nuclear staining was present in 94% (30/32) of hepatocellular carcinoma, whereas all yolk sac tumors displayed a diffuse finely granular nuclear staining pattern. A 25% extent of SALL4 expression cutoff was found to be optimal for the distinction of yolk sac tumor from hepatocellular carcinoma yielding a sensitivity of 100%, specificity of 92.8%, and a positive predictive value of 66.6% for yolk sac tumor diagnosis. The addition of Hep Par1 increased the specificity (99%) and positive predictive value (90%). This is the first report of SALL4 expression in hepatocellular carcinoma. Our finding should be taken into consideration in the differential diagnosis of hepatocellular carcinoma and yolk sac tumor. The unique punctuate/clumped pattern seen in hepatocellular carcinoma cases could be of further discriminatory value. PMID- 23347652 TI - PDGFB rearrangement in dermatofibrosarcoma protuberans: correlation with clinicopathologic characteristics and clinical implications. AB - Dermatofibrosarcoma protuberans (DFSP) is characterized genetically by the translocation t(17;22)(q22;q13), which creates a COL1A1/PDGFB fusion gene. The implications of this gene for the clinicopathologic features of the disease are not fully understood. Fifty-one cases of DFSP from 46 patients were reclassified as DFSP (n=29) and DFSP-fibrosarcomatous variant (DFSP-FS; n=22). Fluorescence in situ hybridization was performed using a dual-color break-apart probe to detect rearrangements involving PDGFB, and CD34 immunohistochemistry staining was done. The DFSP-FS was found in older patients, and the tumors were larger, with a smaller mean area of staining for CD34. PDGFB rearrangement was found in 45 cases (95.7%). The mean gene copy number was 3.82 (range 2.2-6.45) and was higher in DFSP-FS than in classic DFSP (4.54 vs. 3.47; P < .001). The PDGFB copy number showed a moderate positive correlation with the number of mitotic figures and tumor size. Patients undergoing wide excision or having no involvement of the resection margin had no relapses. These results suggest a role for COL1A1/PDGFB in sarcomatous change in DFSP over time. Detection of COL1A1/PDGFB rearrangement by fluorescence in situ hybridization is useful for confirmation of the diagnosis. Patients who present with metastatic DFSP-FS show less typical histologic findings and loss of CD34 staining, leaving PDGFB rearrangement as the preferred adjunctive method for diagnosis from small biopsies and for prediction of the value of imatinib therapy. PMID- 23347653 TI - Rift Valley fever and a new paradigm of research and development for zoonotic disease control. AB - Although Rift Valley fever is a disease that, through its wider societal effects, disproportionately affects vulnerable communities with poor resilience to economic and environmental challenge, Rift Valley fever virus has since its discovery in 1931 been neglected by major global donors and disease control programs. We describe recent outbreaks affecting humans and animals and discuss the serious socioeconomic effects on the communities affected and the slow pace of development of new vaccines. We also discuss the mixed global response, which has largely been fueled by the classification of the virus as a potential bioterrorism agent and its potential to migrate beyond its traditional eastern African boundaries. We argue for a refocus of strategy with increased global collaboration and a greater sense of urgency and investment that focuses on an equity-based approach in which funding and research are prioritized by need, inspired by principles of equity and social justice. PMID- 23347654 TI - Accessible and diverse educational strategies. PMID- 23347655 TI - Perinatal exposure to nicotine and implications for subsequent obstructive lung disease. AB - Many diseases are due to gene-environment or epigenetic-environment interactions resulting in a change in the program that controls tissue structure and function. Changes in the in utero and external environment during perinatal development due to parental smoking, or nicotine exposure, may reduce the capacity of the offspring to protect themselves against environmental stressors. Nicotine is genotoxic and also induces reactive oxygen species [ROS] production. It also reduces the antioxidant capacity of the lung. The lungs of the offspring are therefore developing in an environment of an oxidant-antioxidant imbalance with the concomitant adverse effects of the oxidants and nicotine on cell integrity. Consequently, they are more prone to develop respiratory diseases such as asthma and emphysema later in life. The use of NRT by pregnant or lactating females is therefore not an appropriate strategy to quit smoking. PMID- 23347656 TI - Acetaminophen and asthma. AB - Acetaminophen is a widely used medication for the treatment of pain and fever in children and pregnant women. There is substantial epidemiological evidence in adults and children that acetaminophen use is associated with asthma symptoms. There is also a considerable body of evidence that supports a modest but consistent association of acetaminophen use in pregnancy and early infancy with asthma in later childhood. This relationship is robust to adjustment for a large range of potential confounding factors and, in some studies, shows clear evidence of a dose-dependent association but the possibility of confounding by indication has remained a concern. However, the epidemiological evidence is now compelling and there is a clear need to establish causation so that appropriate advice and interventions can be developed for children at risk of asthma. This requires randomised trials of analgesics and antipyretics, including acetaminophen, in a variety of clinical settings. PMID- 23347658 TI - Respiratory distress of the term newborn infant. AB - Respiratory distress is recognised as any signs of breathing difficulties in neonates. In the early neonatal period respiratory distress is common, occurring in up to 7% of newborn infants, resulting in significant numbers of term-born infants being admitted to neonatal units. Many risk factors are involved; the increasing number of term infants delivered by elective caesarean section has also increased the incidence. Additionally the risk decreases with each advancing week of gestation. At 37 weeks, the chances are three times greater than at 39-40 weeks gestation. Multiple conditions can present with features of respiratory distress. Common causes in term newborn infants include transient tachypnoea of the newborn, respiratory distress syndrome, pneumonia, meconium aspiration syndrome, persistent pulmonary hypertension of the neonate and pneumothorax. Early recognition of respiratory distress and initiation of appropriate treatment is important to ensure optimal outcomes. This review will discuss these common causes of respiratory distress in term-born infants. PMID- 23347657 TI - Perinatal exposure to alcohol: implications for lung development and disease. AB - In utero alcohol exposure dramatically increases the risk of premature delivery. However, the majority of premature and term newborns exposed to alcohol remain undetected by medical caregivers. There is a desperate need for reliable and accurate biomarkers of alcohol exposure for the term and premature newborn population. The inability to identify the exposed newborn severely limits our understanding of alcohol's pathophysiological effects on developing organs such as the lung. This chapter will review potential advancements in future biomarkers of alcohol exposure for the newborn population. We will discuss alcohol's effects on redox homeostasis and cellular development of the neonatal lung. Finally, we will present the evidence describing in utero alcohol's derangement of innate and adaptive immunity and risk for infectious complications in the lung. Continued investigations into the identification and understanding of the mechanisms of alcohol-induced alterations in the premature lung will advance the care of this vulnerable patient population. PMID- 23347659 TI - New molecular virus detection methods and their clinical value in lower respiratory tract infections in children. AB - During the past decade, several new respiratory viruses and their subgroups have been discovered. All these new viruses, as well as previously known respiratory viruses, can be detected by sensitive PCR methods, which have become popular in the diagnostic workup of respiratory viral infections. Currently, respiratory viruses can be detected in up to 95% of children with lower respiratory tract illness. On the other hand, virus detection rates in asymptomatic children are also high (up to 68%), as are coinfection rates in symptomatic children (up to 43%) and justified concerns of causality have been raised. Imposing progress has been made in developing multiplex quantitative PCR assays; here, several primer sets are run within a single PCR mixture. These PCR assays give a better understanding of the dominant viral infection, of viral infections that may be incipient and of any waning infections than does a single-target PCR. Multiplex PCR assays are also gaining popularity due to their cost-effectiveness and short throughput time compared to multiple single-target PCRs. Our understanding of the indications of virus PCRs and our ability to interpret the results from a clinical point of view have improved. This paper reviews the progress in PCR assays and discusses their role in the diagnosis of lower respiratory tract infections in children. PMID- 23347660 TI - Predicting persistence of asthma in preschool wheezers: crystal balls or muddy waters? AB - Since preschool wheezing is the common expression of several heterogeneous disorders, identification of children at risk for persistent asthma is particularly challenging. To date, efforts to predict the outcome of preschool wheeze have mainly relied on predictive rules consisting of simple clinical and laboratory parameters. Among these tools, the asthma predictive index (API) has been introduced in international guidelines and position papers and is recommended for use in clinical practice. This article reviews the currently available asthma predictive models focusing on their validity and performance characteristics. Although these tools are generally simple and easy to apply, they suffer important intrinsic and practical limitations and they have been insufficiently validated to allow for widespread use in clinical settings. We also present evidence that their ability to predict the long-term outcome of preschool wheeze is limited in general populations, and even poorer in high-risk children in which prediction of asthma persistence might have important clinical and prognostic implications. Due to the complex and multifactorial nature of asthma, prediction of asthma persistence based on simple clinical models is practically impossible. PMID- 23347661 TI - Recurrent lower respiratory tract infections in children: a practical approach to diagnosis. AB - Many children are affected by recurrent lower respiratory tract infections (LRTIs), but the majority of them do not suffer from serious lung or extrapulmonary disease. The challenge for clinicians is to distinguish the recurrent RTIs with self-limiting or minor problems from those with underlying disease. The aim of this review is to describe a practical approach to children with recurrent LRTIs that limits unnecessary, expensive and time-consuming investigations. The children can be divided into three groups on the basis of their personal and family history and clinical findings: 1) otherwise healthy children who do not need further investigations; 2) those with risk factors for respiratory infections for whom a wait-and-see approach can be recommended; and 3) those in whom further investigations are mandatory. However, regardless of the origin of the recurrent LRTIs, it is important to remember that prevention by means of vaccines against respiratory pathogens (i.e. type b Haemophilus influenzae, pertussis, pneumococcal and influenza vaccines) can play a key role. PMID- 23347664 TI - Challenges of glaucoma care -- high volume, high quality, low cost. PMID- 23347662 TI - Involvement of the mitogen activated protein kinase Hog1p in the response of Candida albicans to iron availability. AB - BACKGROUND: Iron is an essential nutrient for almost all organisms, and generating iron limiting conditions for pathogens is one of the host defense strategies against microbial infections. Excess of iron can be toxic; therefore, iron uptake is tightly controlled. The high affinity iron uptake system of the opportunistic pathogenic yeast Candida albicans has been shown to be essential for virulence. Several transcription factors and regulators of iron uptake genes were identified, but the knowledge of signaling pathways is still limited. Gene expression profiling of the Deltahog1 deletion mutant indicated an involvement of the mitogen activated protein (MAP) kinase Hog1p. However, the function of Hog1p in the response of C. albicans to iron availability was not studied in detail. Thus, we analyzed phenotypic and molecular responses of C. albicans to different iron concentrations particularly with respect to the activity of the Hog1p MAP kinase module. RESULTS: We observed flocculation of yeast cells, when the iron ion concentration was equal to or higher than 5 MUM. This phenotype was dependent on the MAP kinase Hog1p and the corresponding MAP kinase kinase Pbs2p. Moreover, high extracellular iron ion concentrations led to hyper-phosphorylation of Hog1p. We determined lower amounts of multicopper ferroxidase (MCFO) proteins and lower ferric reductase activity, when the iron ion concentration in the medium was increased. This effect was also observed for the Deltahog1 mutant. However, the amounts of MCFO proteins and the cell surface ferric reductase activity were increased in the Deltahog1 in comparison to wild type cells. This effect was independent of iron availability in growth media. CONCLUSIONS: In C. albicans, the MAP kinase Hog1p is part of the network regulating the response of the organism to iron availability. Hog1p was transiently phosphorylated under high iron concentrations and was essential for a flocculent phenotype. Furthermore, deletion of HOG1 led to increased levels of components of the reductive iron uptake system in comparison to the wild-type, independent of iron concentrations in the media. However, the additional induction of this system by low iron concentrations was independent of HOG1. PMID- 23347666 TI - [Confirmation of the dimensions of the French version of the self-assessment scale of the Center for Epidemiological Studies-Depression (CES-D)]. PMID- 23347665 TI - Multicenter Spanish study of spectral-domain optical coherence tomography in normal children. AB - PURPOSE: To compile a multicenter normative database of retinal nerve fibre layer (RNFL) and macular thicknesses and macular volume values in healthy Caucasian children 4-17 years using spectral-domain optical coherence tomography (SD-OCT). To analyse variations in the OCT measurements as a function of age, sex, refraction, and axial length (AL). METHODS: An observational, multicenter and cross-sectional study among 301 healthy Caucasian children recruited at three Spanish centres was performed. To compile the database, each child underwent a dilated eye examination and a cycloplegic refraction, five AL measurements (IOL Master; Carl Zeiss Meditec, Dublin, CA, USA), five OCT scans with Cirrus OCT: three peripapillary RNFL scans (Optic Disc Cube 200X200 protocol) and two macular scans (Macular Cube 512X128 protocol). One eye of each subject was selected randomly for analysis. RESULTS: Two hundred eighty-three children (117 boys, 41.34%; 166 girls, 58.66%) were included in this study. The mean age of the children was 9.58 +/- 3.12 years (range, 4-17). The mean SE was +0.63 +/- 1.65 D; (range, -4.88 to +5.25). The mean AL was 22.94 +/- 1.10 mm (range, 20.10-26.27). The mean global RNFL thickness was 97.40 +/- 9.0 MUm (range, 77-121.7 MUm). Multivariate analysis showed a positive correlation between the RNFL and spherical equivalent (SE) (p = 0.014). The mean central macular thickness was 253.85 +/- 19.76 MUm, the average thickness 283.62 +/- 14.08 MUm, and the mean macular volume 10.22 +/- 0.49 MUm(3) . Multivariate analysis showed a positive correlation between central macular thickness and age (p < 0.001). Boys had a significantly thicker central macula than girls (p < 0.001). CONCLUSIONS: Normative paediatric SD-OCT data might facilitate use of SD-OCT for assessing childhood ophthalmic diseases. This study provides a multicenter paediatric normative database of SD-OCT peripapillary RNFL and macular data. PMID- 23347667 TI - Epizootic hemorrhagic disease in brocket deer, Brazil. PMID- 23347668 TI - Further studies are necessary in order to conclude a causal association between the consumption of monosodium L-glutamate (MSG) and the prevalence of metabolic syndrome in the rural Thai population. AB - : Please see related articles and author responses: http://www.nutritionandmetabolism.com/content/9/1/50http://www.nutritionandmetabo ism.com/content/10/1/10http://www.nutritionandmetabolism.com/content/10/1/13 ABSTRACT: The article entitled "Monosodium glutamate (MSG) intake is associated with the prevalence of metabolic syndrome in a rural Thai population", concluded that higher amounts of individual's MSG consumption are associated with the risk of having the metabolic syndrome and being overweight independent of other major determinants. However, this epidemiological study is the only study indicating such a relationship between MSG intake and the prevalence of metabolic syndrome and there is no direct supporting evidence for a causal relationship between MSG intake and prevalence of metabolic syndrome. This study does not indicate that MSG causes metabolic syndrome. Furthermore, there are several questionable points concerning study methods. Further carefully designed studies taking into account all glutamate sources are necessary to demonstrate the relationship between overweight, metabolic syndrome, MSG intake and umami sensitivity. PMID- 23347669 TI - Gametocyte carriage in Plasmodium falciparum-infected travellers. AB - BACKGROUND: Gametocytes are the sexual stage of Plasmodium parasites. The determinants of gametocyte carriage have been studied extensively in endemic areas, but have rarely been explored in travellers with malaria. The incidence of gametocytaemia, and factors associated with gametocyte emergence in adult travellers with Plasmodium falciparum malaria was investigated at the Hospital for Tropical Diseases in London. METHODS: Clinical, parasitological and demographic data for all patients presenting with P. falciparum malaria between January 2001 and December 2011 were extracted from a prospective database. These data were supplemented by manual searches of laboratory records and patient case notes. RESULTS: Seven hundred and seventy three adult patients with laboratory confirmed P. falciparum malaria were identified. Four hundred and sixty five (60%) were born in a country where malaria is endemic. Patients presented to hospital a median of four days into their illness. The median maximum parasite count was 0.4%. One hundred and ninety six patients (25%) had gametocytes; 94 (12%) on admission, and 102 (13%) developing during treatment. Gametocytaemia on admission was associated with anaemia and a lower maximum parasitaemia. Patients with gametocytes at presentation were less likely to have thrombocytopenia or severe malaria. Patients who developed gametocytes during treatment were more likely to have had parasitaemia of long duration, a high maximum parasitaemia and to have had severe malaria. There was no apparent association between the appearance of gametocytes and treatment regimen. CONCLUSIONS: The development of gametocytaemia in travellers with P. falciparum is associated with factors similar to those reported among populations in endemic areas. These data suggest that acquired immunity to malaria is not the only determinant of patterns of gametocyte carriage among patients with the disease. PMID- 23347670 TI - Unusual case of severe arrhythmia developed after acute intoxication with tosylchloramide. AB - BACKGROUND: Drugs not commonly considered to be cardioactive agents may cause prolongation of the QT interval with resultant torsades de pointes and ventricular fibrillation. This form of drug toxicity often causes cardiac arrest or sudden death. CASE PRESENTATION: After accidental ingestion of tosylchloramide a caucasian 77-year-old woman, with a family history of cardiovascular disease and hypertension, was admitted to the intensive care unit following episodes of torsades de pointes with a prolonged QT/QTc interval (640/542 ms). The patient received an implantable cardioverter-defibrillator, was discharged from the hospital with normal QT/QTc interval and did not experience additional ventricular arrhythmias during one year of follow-up. CONCLUSION: This is the first report concerning an unusual case of torsades de pointes after accidental intoxication by ingestion of tosylchloramide. The pronounced impact of the oxidyzing agent tosylchloramide on the activity of some of the ion channels regulating the QT interval was identified as a probable cause of the arrhythmia. PMID- 23347671 TI - Bariatric surgery in the era of personalized medicine. PMID- 23347672 TI - Update in print and digital media reviews: not your father's book review section. PMID- 23347673 TI - Familial colorectal cancer screening: so close, so far. PMID- 23347674 TI - Personal perspectives on mentoring. PMID- 23347675 TI - Two paths diverge in the brain: melanin-concentrating hormone controls hepatic and adipose metabolism. PMID- 23347676 TI - National cardiac meetings-what's wrong? PMID- 23347677 TI - A modified Delphi study of screening for fetal alcohol spectrum disorders in Australia. AB - BACKGROUND: There is little reliable information on the prevalence of fetal alcohol spectrum disorders (FASD) in Australia and no coordinated national approach to facilitate case detection. The aim of this study was to identify health professionals' perceptions about screening for FASD in Australia. METHOD: A modified Delphi process was used to assess perceptions of the need for, and the process of, screening for FASD in Australia. We recruited a panel of 130 Australian health professionals with experience or expertise in FASD screening or diagnosis. A systematic review of the literature was used to develop Likert statements on screening coverage, components and assessment methods which were administered using an online survey over two survey rounds. RESULTS: Of the panel members surveyed, 95 (73%) responded to the questions on screening in the first survey round and, of these, 81 (85%) responded to the second round. Following two rounds there was consensus agreement on the need for targeted screening at birth (76%) and in childhood (84%). Participants did not reach consensus agreement on the need for universal screening at birth (55%) or in childhood (40%). Support for targeted screening was linked to perceived constraints on service provision and the need to examine the performance, costs and benefits of screening.For targeted screening of high risk groups, we found highest agreement for siblings of known cases of FASD (96%) and children of mothers attending alcohol treatment services (93%). Participants agreed that screening for FASD primarily requires assessment of prenatal alcohol exposure at birth (86%) and in childhood (88%), and that a checklist is needed to identify the components of screening and criteria for referral at birth (84%) and in childhood (90%). CONCLUSIONS: There is an agreed need for targeted but not universal screening for FASD in Australia, and sufficient consensus among health professionals to warrant development and evaluation of standardised methods for targeted screening and referral in the Australian context. Participants emphasised the need for locally-appropriate, evidence-based approaches to facilitate case detection, and the importance of ensuring that screening and referral programs are supported by adequate diagnostic and management capacity. PMID- 23347678 TI - Nipah virus infection outbreak with nosocomial and corpse-to-human transmission, Bangladesh. AB - Active Nipah virus encephalitis surveillance identified an encephalitis cluster and sporadic cases in Faridpur, Bangladesh, in January 2010. We identified 16 case-patients; 14 of these patients died. For 1 case-patient, the only known exposure was hugging a deceased patient with a probable case, while another case patient's exposure involved preparing the same corpse for burial by removing oral secretions and anogenital excreta with a cloth and bare hands. Among 7 persons with confirmed sporadic cases, 6 died, including a physician who had physically examined encephalitis patients without gloves or a mask. Nipah virus-infected patients were more likely than community-based controls to report drinking raw date palm sap and to have had physical contact with an encephalitis patient (29% vs. 4%, matched odds ratio undefined). Efforts to prevent transmission should focus on reducing caregivers' exposure to infected patients' bodily secretions during care and traditional burial practices. PMID- 23347679 TI - Drosophila MOF controls Checkpoint protein2 and regulates genomic stability during early embryogenesis. AB - BACKGROUND: In Drosophila embryos, checkpoints maintain genome stability by delaying cell cycle progression that allows time for damage repair or to complete DNA synthesis. Drosophila MOF, a member of MYST histone acetyl transferase is an essential component of male X hyperactivation process. Until recently its involvement in G2/M cell cycle arrest and defects in ionizing radiation induced DNA damage pathways was not well established. RESULTS: Drosophila MOF is highly expressed during early embryogenesis. In the present study we show that haplo insufficiency of maternal MOF leads to spontaneous mitotic defects like mitotic asynchrony, mitotic catastrophe and chromatid bridges in the syncytial embryos. Such abnormal nuclei are eliminated and digested in the yolk tissues by nuclear fall out mechanism. MOF negatively regulates Drosophila checkpoint kinase 2 tumor suppressor homologue. In response to DNA damage the checkpoint gene Chk2 (Drosophila mnk) is activated in the mof mutants, there by causing centrosomal inactivation suggesting its role in response to genotoxic stress. A drastic decrease in the fall out nuclei in the syncytial embryos derived from mof1/+; mnkp6/+ females further confirms the role of DNA damage response gene Chk2 to ensure the removal of abnormal nuclei from the embryonic precursor pool and maintain genome stability. The fact that mof mutants undergo DNA damage has been further elucidated by the increased number of single and double stranded DNA breaks. CONCLUSION: mof mutants exhibited genomic instability as evidenced by the occurance of frequent mitotic bridges in anaphase, asynchronous nuclear divisions, disruption of cytoskeleton, inactivation of centrosomes finally leading to DNA damage. Our findings are consistent to what has been reported earlier in mammals that; reduced levels of MOF resulted in increased genomic instability while total loss resulted in lethality. The study can be further extended using Drosophila as model system and carry out the interaction of MOF with the known components of the DNA damage pathway. PMID- 23347681 TI - Atheroprotective effect of dietary walnut intake in ApoE-deficient mice: involvement of lipids and coagulation factors. AB - INTRODUCTION: Consumption of n-3 polyunsaturated fatty acids (PUFA) and antioxidant polyphenols is considered to decline the risk of cardiovascular disease. MATERIALS AND METHODS: To provide an explanation for this cardioprotective effect, we performed an intervention study with proatherogenic Apoe(-/-) mice which were fed during eight weeks with a high fat diet supplemented with either walnuts (rich in n-3 PUFA and antioxidant compounds), walnut oil (with n-3 PUFA only) or sunflower oil as a control (12 mice per group). RESULTS: Feeding walnuts, but not walnut oil, caused a 55% reduction in atherosclerotic plaque development in the aortic arch in comparison to the control diet. This was associated with reduced staining of plaques for CD36, a scavenger receptor expressed by macrophages. Feeding mice with walnuts also lowered plasma levels of triglycerides, cholesterol and prothrombin with 36%, 23% and 21 %, respectively, compared to control diet. In addition, accumulation of lipids in the liver was decreased, while plasma antioxidant capacity was increased. On the other hand, feeding mice with walnut oil did not provoke significant changes in these parameters in comparison to the control diet. Platelet activation and thrombus formation under flow remained unchanged with either diet. CONCLUSIONS: In Apoe(-/-) mice on high fat diet, intake of dietary walnut (but not walnut oil) beneficially influences lipid metabolism and atherosclerotic plaque development, with no more than limited effects on platelet and coagulation function. PMID- 23347682 TI - Impact of changes in haematocrit level and platelet count on thromboelastometry parameters. AB - INTRODUCTION: To what extent haematocrit levels (Hct) and platelet counts (PLT) influence the measurement of parameters of thromboelastometry when assessed with the ROTEM(r) device is unclear. We investigated to what extent thromboelastometry measurements depend on Hct and PLT. MATERIALS AND METHODS: Whole blood samples were taken for in-vitro preparations of mixtures with three different levels of PLT and a varying Hct. Maximum clot firmness (MCF), clotting time (CT), clot formation time (CFT) and alpha angle (alpha) for INTEM, EXTEM, FIBTEM and APTEM was recorded. RESULTS: Measurements depended substantially on Hct and PLT. MCF readings were systematically lower with increasing Hct (0.2 vs. 0.4: -7.8 (-8.3 to -7.2); p<0.001, 0.2 vs. 0.55: -14.5 (-17.3 to -14.3); p<0.001) but higher with increasing PLT (50 vs. 125*10(9)/l: 8.2 (4.2 to 12.3); p=0.005, 50 vs. 250*10(9)/l: 12.0 (7.2 to 16.8); p=0.002). CT readings were systematically higher with increasing Hct (0.2 vs. 0.4: 9.2 (6.2 to 12.1); p=0.001, 0.2 vs. 0.55: 38.2 (21.5 to 54.9); p=0.003) while increasing PLT had no influence. CFT readings were also systematically higher with increasing Hct (0.2 vs. 0.4: 83.8 (40.2 to 127.6); p=0.006, 0.2 vs. 0.55: 226.2 (110.7 to 341.7); p=0.006) but systematically lower with increasing PLT (50 vs. 125*10(9)/l: -144.0 (-272.3 to 15.6); p=0.036, 50 vs. 250*10(9)/l: -189.2 (-330.4 to -48.0); p=0.02); readings of the alpha angle showed a similar pattern. CONCLUSIONS: Our results suggest that readings of thromboelastometry parameters need to be adjusted by Hct and PLT to avoid potential confounding and miss-interpretations in clinical practice. PMID- 23347683 TI - A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: synthesis and structure activity relationships. AB - A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior. PMID- 23347684 TI - Synthesis of 2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes via LiAlH4 induced reductive cyclization of 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines and evaluation of their antimalarial activity. AB - 2-(4-Chloro-2-cyano-2-phenylbutyl)aziridines were employed for the one-step stereoselective construction of both endo- and exo-2-aminomethyl-4-phenyl-1 azabicyclo[2.2.1]heptanes as new azaheterobicyclic scaffolds via a double LiAlH(4)-induced reductive cyclization protocol. Antiplasmodial assessment of these 1-azabicyclo[2.2.1]heptanes revealed moderate to good activities in the micromolar range, with the exo-isomers being the most promising structures. Furthermore, the proposed mode of action was supported by ligand docking studies, pointing to a strong binding interaction with the enzyme plasmepsin II. PMID- 23347685 TI - Synthesis and in vitro cytotoxic activity evaluation of novel heterocycle bridged carbothioamide type isosteviol derivatives as antitumor agents. AB - Two series of novel carbothioamide-substituted pyrazole and isoxazolidine derivatives were facilely prepared by functional interconversions in ring D of the tetracyclic diterpene isosteviol. The in vitro cytotoxic activities against four human tumor cell lines were evaluated. Our results indicated that carbothioamide-substituted pyrazole derivatives exhibited noteworthy cytotoxic activities. Specifically, compound 12p (IC(50)=6.51 MUM) had the most potent cytotoxicity against Raji cell, which may be exploitable as a lead compound for the development of potent antitumor agents. PMID- 23347686 TI - Discovery of olmesartan hexetil: a new potential prodrug of olmesartan. AB - Synthesis of a new ester prodrug of olmesartan, olmesartan hexetil (1), is described. It is in vitro stabilities and in vivo pharmacokinetics (PK) were evaluated. It showed high stability in simulated gastric juice, and was rapidly hydrolyzed to olmesartan in rat liver microsomes and rat plasma in vitro. C(max) and AUC(last) for olmesartan were significantly increased in case of hexetil prodrug, compared with olmesartan medoxomil. Olmesartan hexetil is proposed to be an efficient prodrug of olmesartan with markedly increased oral bioavailability. PMID- 23347687 TI - Image guidance to improve reliability and data integrity of transcranial Doppler sonography. AB - BACKGROUND: Principles and accuracy of image-guided transcranial Doppler (IG TCD) sonography have been published recently. However, it remains open whether combination of image guidance and TCD offers an additional clinical advantage. This study scores the accuracy of conventional TCD examinations and investigates the potential improvement of TCD data integrity and reliability regarding the additional use of IG. METHODS: Conventional TCD was performed by a group of experienced investigators, who were blinded to images of a navigation system tracking the Doppler probe, whereas an independent observer documented the TCD findings, acquired by the investigators, due to saving spatial data of the TCD sample volume using IG for subsequent analysis. In a second set of experiments, image guidance was available to investigators without any previous TCD experience. RESULTS: The analysis of 3D data of vessels (n=173) labeled by experienced investigators in conventional TCD, revealed a rate of 37% misinterpreted Doppler signals regarding the target vessel. Correctness of labeling was comparable between the different vascular segments. The rate of correct labeling was higher for right- (69%) than for left-sided vessels (57%). In comparison, by using IG, TCD investigators without any previous TCD experience achieved a significantly lower rate of 10% (n=39) mislabeled vessels. CONCLUSIONS: Our data suggest, that misinterpretation of the vascular source of the Doppler signal is a common source of errors in conventional TCD. Visualization of the vascular anatomy by image guidance offers improved accuracy and reliability of TCD results and may positively influence the learning curve for inexperienced investigators. PMID- 23347688 TI - An evaluation of SaTScan for the prospective detection of space-time Campylobacter clusters in the North East of England. AB - Campylobacteriosis is the commonest cause of bacterial enteritis in England yet the epidemiology of apparently sporadic cases is not well understood. Here we evaluated the feasibility of applying a space-time cluster detection method to routine laboratory surveillance data in the North East of England by simulating prospective weekly space-time cluster detection using SaTScan as if it had been performed for 2008-2011. From the 209 simulated weekly runs using a circular window, 20 distinct clusters were found which contained a median of 30 cases (interquartile range 15-66) from a median population of ~134,000 persons. This corresponds to detection of a new cluster every 10 weeks. We found significant differences in age, sex and deprivation score distributions between areas within clusters compared to those without. The results of this study suggest that space time detection of Campylobacter clusters could be used to find groups of cases amenable to epidemiological investigation. PMID- 23347689 TI - Continuous C-peptide loss in patients with type 1 diabetes and multiethnic background. AB - C peptide (CP) was evaluated in 88 individuals with type 1 diabetes, variable disease duration and multiethnic background. Initially, 28 patients had detectable CP, which persisted in 46.2% after 17.4+/-4 months. CP decline was associated with ethnicity, HbA1c and baseline CP, but not with GADA, PTPN22 or insulin gene polymorphisms. PMID- 23347691 TI - Magnetic resonance T2*-weighted study of U87 MG glioma tumors and its relationship between tumor hypoxia and VEGF expression. PMID- 23347690 TI - Analysis of antibody induction upon immunization with distinct NTS-DBL1alpha domains of PfEMP1 from rosetting Plasmodium falciparum parasites. AB - BACKGROUND: Rosette-formation of Plasmodium falciparum parasitized erythrocytes is of importance in the development of severe malaria. The parasite-derived molecule PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1), central to rosetting, is suggested to be included in a multimeric vaccine targeting severe disease. METHODS: Three recombinant NTS-DBL1alpha-domains of PfEMP1 were generated in Escherichia coli, purified and used for immunization of rats and goats. Antibody titres were determined in ELISA assays and responses were compared in-between different individual animals and species. Reactivity with the parasites was tested in live pRBC using FACS. B-cell epitopes prediction was carried out in silico and compared to the results obtained by peptide microarray. Screening for serological cross-reactivity with heterologous NTS-DBL1alpha variants was carried out by ELISA, peptide array and FACS on pRBC of different laboratory strains and patient isolates. RESULTS: All three NTS-DBL1alpha-domains induced high titres of antibodies that were biologically active with no apparent difference between constructs covering slightly different parts of the DBL1alpha sequence. The different animal species showed comparable titres of antibodies, while variations within individuals of the species could be observed.Mapping of the recognized epitopes revealed that most parts of the molecule were able to induce an antibody response with a tendency for the N and C terminal parts of the molecule for slightly higher recognition. Important differences to the epitopes predicted were found as some of the most conserved parts of the DBL1alpha-domain contained the main epitopes for antibody reactivity. ELISA assays and peptide microarray demonstrated substantial cross-reactivity to heterologous variants, while binding to native PfEMP1 was observed only in few combinations on the pRBC surface, underlining that mainly internal, conserved and not surface exposed parts of the DBL1alpha-domain are responsible for this observation. CONCLUSION: Biologically active antibodies can be induced consistently, with high titres, in different animal species and the antibodies elicited by different constructs react with similar epitopes. Induced antibodies recognize epitopes localized in all subdomains of the DBL1alpha-sequence. Cross-reactivity between NTS-DBL1alpha variants is common in ELISA, but rare with live pRBC emphasizing that also internal, conserved areas of PfEMP1 carry important highly immunogenic epitopes of the molecule. PMID- 23347693 TI - Predictors and impact of non-adherence in adults with attention deficit/hyperactivity disorder receiving OROS methylphenidate: results from a randomized, placebo-controlled trial. AB - BACKGROUND: Medication non-adherence has an important impact on treatment efficacy and healthcare burden across a range of conditions and therapeutic areas. The aim of this analysis was to determine predictors of non-adherence and impact of non-adherence on treatment response in adults with attention deficit/hyperactivity disorder (ADHD). METHODS: Post-hoc analysis of a 13-week randomized, double-blind placebo-controlled study of OROS methylphenidate (MPH) 54 and 72 mg/day. Primary efficacy variable was the Conners' Adult ADHD Rating Scale - Screening Version (CAARS:O-SV). Daily adherence was calculated as average daily adherence (100 * capsules taken/2), with overall adherence calculated as the average daily adherence. Predictors of adherence were assessed using mixed effects logistic regression. Descriptive statistics were generated for change in CAARS:O-SV score for adherent (> 95% adherence) and non-adherent subjects. Predictors of change were analyzed using a mixed model. RESULTS: Subjects were allocated to OROS MPH (54 mg, n = 87; 72 mg, n = 92) or placebo (n = 97). Mean adherence was 92.6% and 93.3% (OROS MPH 54 and 72 mg/day, respectively), versus 97.5% (placebo). Adherence was higher and less variable in completers. Factors significantly associated with non-adherence included female sex, shorter time since ADHD diagnosis, higher education level (completion of university) and score on the Drug Use Screening Inventory psychiatric disorders subscale. Improvements from baseline in CAARS:O-SV score were numerically greater in subjects defined as adherent than in those who were non-adherent. Significant predictors of CAARS:O SV change in patients who completed the study included percentage adherence up to the point of assessment (p < 0.0001), baseline score (p < 0.0001) and family history of ADHD (p = 0.0003). CONCLUSION: The results of this analysis suggest that newly diagnosed patients, those with a high score on the DUSI-R psychiatric disorder scale, women, and subjects with high educational degrees may be at increased risk of non-adherence. Clinicians and policymakers should therefore pay special attention to these individuals, as non-adherence is a significant predictor of reduced response to treatment. TRIAL REGISTRATION: EudraCT #: 2007 002111-82. PMID- 23347695 TI - Laboratory-based surveillance for hepatitis E virus infection, United States, 2005-2012. AB - To investigate characteristics of hepatitis E cases in the United States, we tested samples from persons seronegative for acute hepatitis A and B whose clinical specimens were referred to the Centers for Disease Control and Prevention during June 2005-March 2012 for hepatitis E virus (HEV) testing. We found that 26 (17%) of 154 persons tested had hepatitis E. Of these, 15 had not recently traveled abroad (nontravelers), and 11 had (travelers). Compared with travelers, nontravelers were older (median 61 vs. 32 years of age) and more likely to be anicteric (53% vs. 8%); the nontraveler group also had fewer persons of South Asian ethnicity (7% vs. 73%) and more solid-organ transplant recipients (47% vs. 0). HEV genotype 3 was characterized from 8 nontravelers and genotypes 1 or 4 from 4 travelers. Clinicians should consider HEV infection in the differential diagnosis of hepatitis, regardless of patient travel history. PMID- 23347696 TI - Chronic activation of vasopressin V2 receptor signalling lowers renal medullary oxygen levels in rats. AB - AIM: In the present study, we aimed to elucidate the effects of chronic vasopressin administration on renal medullary oxygen levels. METHODS: Adult Sprague Dawley or vasopressin-deficient Brattleboro rats were treated with the vasopressin V2 receptor agonist, desmopressin (5 ng/h; 3d), or its vehicle via osmotic minipumps. Immunostaining for pimonidazole and the transcription factor HIF-1alpha (hypoxia-inducible factor-1alpha) were used to identify hypoxic areas. Activation of HIF-target gene expression following desmopressin treatment was studied by microarray analysis. RESULTS: Pimonidazole staining was detected in the outer and inner medulla of desmopressin-treated rats, whereas staining in control animals was weak or absent. HIF-1alpha immunostaining demonstrated nuclear accumulation in the papilla of desmopressin-treated animals, whereas no staining was observed in the controls. Gene expression analysis revealed significant enrichment of HIF-target genes in the group of desmopressin-regulated gene products (P = 2.6*10(-21) ). Regulated products included insulin-like growth factor binding proteins 1 and 3, angiopoietin 2, fibronectin, cathepsin D, hexokinase 2 and cyclooxygenase 2. CONCLUSION: Our results demonstrate that an activation of the renal urine concentrating mechanism by desmopressin causes renal medullary hypoxia and an upregulation of hypoxia-inducible gene expression. PMID- 23347694 TI - Evidence review and clinical guidance for the use of ziprasidone in Canada. AB - While indicated for schizophrenia and acute mania, ziprasidone's evidence base and use in clinical practice extends beyond these regulatory approvals. We, an invited panel of experts led by a working group of 3, critically examined the evidence and our collective experience regarding the effectiveness, tolerability and safety of ziprasidone across its clinical uses. There was no opportunity for manufacturer input into the content of the review. As anticipated, ziprasidone was found to be effective for its indicated uses, although its utility in mania and mixed states lacked comparative data. Beyond these uses, the available data were either unimpressive or were lacking. An attractive characteristic is its neutral effect on weight thereby providing patients with a non-obesogenic long term treatment option. Key challenges in practice include the need for dosing on a full stomach and managing its early onset adverse effect of restlessness. Addressing these issues are critical to its long-term success. PMID- 23347697 TI - Clinical and laboratory characteristics of adolescents with platelet function disorders and heavy menstrual bleeding. AB - BACKGROUND: Platelet function disorders (PFDs) have emerged as an important etiology of heavy menstrual bleeding (HMB) in adolescents. However, neither clinical nor laboratory data have been methodically analyzed in this population subset. The objective of this study was to evaluate these parameters in order to distinguish characteristics of the disorder that in turn will lead to earlier diagnosis and therapy initiation. METHODS: Retrospective review of medical records from postmenarcheal adolescents with documented PFDs referred to a hemophilia treatment center and university faculty practices for bleeding diatheses with their clinical and laboratory data evaluated. RESULTS: Of 63 teens with documented PFDs, HMB was the most common clinical manifestation of PFD (43; 68.3%). Of these, 37 (86%) were diagnosed with PFD either at or after menarche with the diagnosis based on HMB symptoms alone. Only 6 (14%) were diagnosed with a PFD prior to menarche, based on associated bleeding, i.e., epistaxis, ecchymosis, and all developed HMB after menstruation onset. Interestingly, 20 girls were diagnosed with a PFD prior to menarche and of these, only 6 (30%) went on to develop HMB after pubertal transition, while the majority (14; 70%) did not. The average age-at-PFD diagnosis was 14.5yrs, significantly differing from the 10.9yrs average age-at-PFD diagnosis in their counterparts that, after menarche, did not develop HMB (P<.01) Blood type O occurred significantly more frequently (76%) than national norms (P <.037). Incidence of delta-Storage Pool deficiency (delta-SPD) was significantly higher (74%) than their non-HMB cohorts (45%) (P <.007). Coagulation and von Willebrand factor studies were all normal. Abnormal closure times and aggregation studies were observed in 42% and 60%, respectively, of tested girls. In 25.6% for whom standard platelet studies were normal, electron microscopy detected reduced platelet delta-granules numbers (delta-SPD). CONCLUSIONS: Adolescents with PFDs and HMB appear to be clinically distinct from their non-HMB counterparts. This group of girls is characterized by HMB the major bleeding symptom, significantly high incidences of blood group O and the delta-SPD with a PFD diagnosed well after menarche. High false negative standard platelet function study results indicate additional diagnostic strategies, particularly for delta-SPD, should be considered. PMID- 23347698 TI - Health-related quality-of-life instruments for Alzheimer's disease and mixed dementia. AB - BACKGROUND: Over the last 20 years, a number of instruments developed for the assessment of health-related quality of life (HRQL) in dementia have been introduced. The aim of this review is to synthesize evidence from published reviews on HRQL measures in dementia and any new literature in order to identify dementia specific HRQL instruments, the domains they measure, and their operationalization. METHODS: An electronic search of PsycINFO and PubMed was conducted, from inception to December 2011 using a combination of key words that included quality of life and dementia. RESULTS: Fifteen dementia-specific HRQL instruments were identified. Instruments varied depending on their country of development/validation, dementia severity, data collection method, operationalization of HRQL in dementia, psychometric properties, and the scoring. The most common domains assessed include mood, self-esteem, social interaction, and enjoyment of activities. CONCLUSIONS: A number of HRQL instruments for dementia are available. The suitability of the scales for different contexts is discussed. Many studies do not specifically set out to measure dementia-specific HRQL but do include related items. Determining how best to operationalize the many HRQL domains will be helpful for mapping measures of HRQL in such studies maximizing the value of existing resources. PMID- 23347700 TI - Elevated expression of forkhead box protein O1 (FoxO1) in alcohol-induced intestinal barrier dysfunction. AB - Alcohol-induced intestinal barrier dysfunction is a major contributor to alcoholic liver disease (ALD). Forkhead box protein O1 (FoxO1) is a member of the mammalian forkhead box O class (FoxO) subfamily that regulates a wide array of cellular processes. In the present study, we used both an alcohol-fed mouse model and an alcohol-treated Caco-2 intestinal epithelial cell monolayer in vitro model to investigate whether FoxO1 is involved in alcohol-induced intestinal barrier dysfunction. We found that chronic alcohol exposure to mice significantly increased both mRNA and protein levels of FoxO1 in all the examined intestinal segments with the most remarkable changes in the ileum. Alcohol treatment increased mRNA and protein levels of FoxO1 and promoted nuclear translocation of FoxO1 in Caco-2 cells. Furthermore, alcohol treatment with Caco-2 cells resulted in a significant decrease in the epithelial transepithelial electrical resistance (TEER) value, which was attenuated by knockdown of FoxO1 expression. In conclusion, our data suggest that activation of FoxO1 is likely to be a novel mechanism contributing to the deleterious effects of alcohol on intestinal barrier function. PMID- 23347699 TI - Rearing in enriched environment increases parvalbumin-positive small neurons in the amygdala and decreases anxiety-like behavior of male rats. AB - BACKGROUND: Early life experiences including physical exercise, sensory stimulation, and social interaction can modulate development of the inhibitory neuronal network and modify various behaviors. In particular, alteration of parvalbumin-expressing neurons, a gamma-aminobutyric acid (GABA)ergic neuronal subpopulation, has been suggested to be associated with psychiatric disorders. Here we investigated whether rearing in enriched environment could modify the expression of parvalbumin-positive neurons in the basolateral amygdala and anxiety-like behavior. RESULTS: Three-week-old male rats were divided into two groups: those reared in an enriched environment (EE rats) and those reared in standard cages (SE rats). After 5 weeks of rearing, the EE rats showed decreased anxiety-like behavior in an open field than the SE rats. Under another anxiogenic situation, in a beam walking test, the EE rats more quickly traversed an elevated narrow beam. Anxiety-like behavior in the open field was significantly and negatively correlated with walking time in the beam-walking test. Immunohistochemical tests revealed that the number of parvalbumin-positive neurons significantly increased in the basolateral amygdala of the EE rats than that of the SE rats, while the number of calbindin-D28k-positive neurons did not change. These parvalbumin-positive neurons had small, rounded soma and co expressed the glutamate decarboxylase (GAD67). Furthermore, the number of parvalbumin-positive small cells in the basolateral amygdala tended to positively correlate with emergence in the center arena of the open field and negatively correlated with walking time in the beam walking test. CONCLUSION: Rearing in the enriched environment augmented the number of parvalbumin-containing specific inhibitory neuron in the basolateral amygdala, but not that of calbindin containing neuronal phenotype. Furthermore, the number of parvalbumin-positive small neurons in the basolateral amygdala was negatively correlated with walking time in the beam walking test and tended to be positively correlated with activity in the center arena in the open field test. The results suggest that rearing in the enriched environment augmented parvalbumin-positive specific neurons in the basolateral amygdala, which induced behavioral plasticity that was reflected by a decrease in anxiety-like behavior in anxiogenic situations. PMID- 23347701 TI - BMI and psychological distress in 68,000 Swedish adults: a weak association when controlling for an age-gender combination. AB - BACKGROUND: Study results concerning associations between body mass index (BMI) and psychological distress are conflicting. The purpose of this study was to describe the shape of the association between BMI and psychological distress in a large sample of Swedish adults. METHODS: Data was measured with the General Health Questionnaire-12 (GHQ-12), in 68,311 adults aged 18-74. Self-reported data was derived from a merger of the 2000, 2004 and 2008 Life and Health (Liv och Halsa) questionnaires focusing general perceived distress as well as living conditions. Logistic regression analysis was used to describe the association between BMI and psychological distress when controlled for age and gender in combination. RESULTS: Women reported an overall higher psychological distress than men. A significant pattern of decreasing psychological distress with increasing age emerged among women in all BMI categories. Trends of this same pattern showed for men. Small or no differences were seen in psychological distress between those in normal weight, overweight, and obesity I categories (among women: 20.4%, 18.4%, 20.5%; among men: 12.8%, 11.2%, 12.9%). For both genders, any notable increase in psychological distress appeared first in the obesity II category (among women: 27.2%. Among men: 17.8%). CONCLUSIONS: Psychological distress decreases with increasing age regardless of BMI; a pattern more obvious for women. Being categorized with obesity II leads to a markedly higher psychological distress than being categorized with normal weight, overweight or obesity I. From this, we suggest that future obesity research focusing on psychological distress could investigate the role of stigma and norm susceptibility in relationships where people are evaluated through the eyes of the other. PMID- 23347702 TI - Severe lower respiratory tract infection in early infancy and pneumonia hospitalizations among children, Kenya. AB - Severe lower respiratory tract infection (LRTI) in infants caused by respiratory syncytial virus (RSV) has been associated with later pneumonia hospitalization among children. To determine risk for pneumonia after RSV hospitalization in infancy, we conducted a retrospective cohort analysis of 2,813 infants admitted to a hospital in Kenya and identified readmissions for pneumonia among this group during early childhood (<60 months of age). Incidence of readmission for pneumonia was higher for children whose first admission as infants was for LRTI and who were <3 months of age than for children who were first admitted as infants for non-LRTI, irrespective of RSV status. Incidence of readmission for pneumonia with wheeze was higher for children whose first admission involved RSV compared with those who had non-RSV LRTI. Excess pneumonia risk persisted for 2 years after the initial hospitalization. Close postdischarge follow-up of infants with LRTI, with or without RSV, could help prevent severe pneumonia later in childhood. PMID- 23347703 TI - Travel history and malaria infection risk in a low-transmission setting in Ethiopia: a case control study. AB - BACKGROUND: Malaria remains the leading communicable disease in Ethiopia, with around one million clinical cases of malaria reported annually. The country currently has plans for elimination for specific geographic areas of the country. Human movement may lead to the maintenance of reservoirs of infection, complicating attempts to eliminate malaria. METHODS: An unmatched case-control study was conducted with 560 adult patients at a Health Centre in central Ethiopia. Patients who received a malaria test were interviewed regarding their recent travel histories. Bivariate and multivariate analyses were conducted to determine if reported travel outside of the home village within the last month was related to malaria infection status. RESULTS: After adjusting for several known confounding factors, travel away from the home village in the last 30 days was a statistically significant risk factor for infection with Plasmodium falciparum (AOR 1.76; p=0.03) but not for infection with Plasmodium vivax (AOR 1.17; p=0.62). Male sex was strongly associated with any malaria infection (AOR 2.00; p=0.001). CONCLUSIONS: Given the importance of identifying reservoir infections, consideration of human movement patterns should factor into decisions regarding elimination and disease prevention, especially when targeted areas are limited to regions within a country. PMID- 23347704 TI - State-based and demographic variation in parent-reported medication rates for attention-deficit/hyperactivity disorder, 2007-2008. AB - Medication is the most effective treatment of attention-deficit/hyperactivity disorder (ADHD), a common neurobehavioral disorder of childhood. We used data from the 2007-2008 National Survey of Children's Health to calculate weighted estimates of parent-reported ADHD and medication treatment among US children aged 4 to 17 years, by state and sex-stratified age. State-based rates of ADHD medication treatment ranged from 33% in Nevada to 79% in Mississippi; rates of medicated ADHD were higher among boys than girls at every age. State-based investigations of ADHD medication treatment factors are needed, and our findings may inform these public health efforts. PMID- 23347706 TI - Thoracoscopic resection of congenital cystic adenomatoid malformation in an adolescent. AB - Congenital cystic adenomatoid malformation (CCAM) in adolescents or adults is extremely rare. In this case study, a 17-year-old boy was admitted to our clinic for the treatment of a giant bulla in the lower lobe of the right lung. Preoperative imaging studies led to the diagnosis of cystic lung disease. The patient underwent wedge resection of the right lower lobe with VATS, and histological examination confirmed the presentation of type 1 CCAM. A thoracoscopic lobectomy was performed after the second surgery because of postoperative air leakage.Herein, we report a case of CCAM in an adolescent. VATS was a suitable procedure for the operation. Between the parenchyma-saving resection and lobectomy for CCAM, we believe that the lobectomy is the better treatment option when the extent of the disease cannot be determined clearly or it is extremely large. Therefore, strategies for deciding between parenchyma saving resection and lobectomy for the treatment of CCAM should be developed. PMID- 23347707 TI - Transumbilical single-incision laparoscopic ileocecal resection for Crohn's disease in a child. AB - We report the pediatric case of ileal Crohn's disease in which the patient underwent transumbilical single-incision laparoscopic ileocecal resection. A 14 year-old boy with severe growth disturbance presented with intestinal obstruction. Transanal double-balloon enteroscopy and contrast study during endoscopy revealed a cobble stone appearance and a severe stricture 15 cm in length located slightly proximal to the ileocecal valve. There was no evidence of fistula or abscess formation. Ileocecal resection was performed via an umbilical incision with conventional laparoscopic instruments, and the postoperative course was uneventful. Single-incision laparoscopic ileocecal resection is a good procedure for uncomplicated Crohn's disease patients in childhood. PMID- 23347708 TI - Single-incision laparoscopic cholecystectomy for porcelain gallbladder: a case report. AB - Single-incision laparoscopic cholecystectomy (SILC) has been performed in patients with gallbladder stones without inflammation. Porcelain gallbladder is a rare finding of chronic cholecystitis that is characterized by extensive calcification of the gallbladder wall. Herein we describe our experience with SILC for porcelain gallbladder with a successful outcome. A 67-old-year woman was diagnosed with porcelain gallbladder. We performed SILC using a SILS Port and a 5 mm forceps through the umbilical incision. Because a small amount of the omentum around the gallbladder was left to facilitate grasping the fundus, a view of both the cystic artery and the cystic duct was easily obtained. The operative time and the intraoperative blood loss were 66 min and less than 1 mL, respectively. The patient was discharged 3 days after surgery and was satisfied with the cosmetic results. Our procedure may represent an alternative to conventional laparoscopic cholecystectomy in patients with porcelain gallbladder. PMID- 23347709 TI - Complex Mullerian malformation without any present classification: unilateral ovarian and tubal absence with an arcuate uterus. AB - Mullerian duct anomalies are known to cause infertility and reproductive problems. The true incidence of such abnormalities is not well defined. The most widely accepted method of classification for a Mullerian duct anomaly is the American Society of Reproductive Medicine classification (1988). However, there are some rare anomalies inconsistent with the current classification. Herein, we report a rare case of Mullerian duct anomaly, unilateral ovarian and tubal absence with an arcuate uterus. The failure of the Mullerian ducts to canalize can also lead to the development of a unicornuate uterus and adnexal agenesis. An arcuate uterus indicates incomplete septal absorption after normal fusion of the Mullerian ducts. Therefore, its coexistence with adnexal absence and an arcuate uterus is considered to be extremely unlikely. PMID- 23347705 TI - Provider compliance with guidelines for management of cardiovascular risk in HIV infected patients. AB - INTRODUCTION: Compliance with National Cholesterol Education Program Adult Treatment Panel III (NCEP) guidelines has been shown to significantly reduce incident cardiovascular events. We investigated physicians' compliance with NCEP guidelines to reduce cardiovascular disease (CVD) risk in a population infected with HIV. METHODS: We analyzed HIV Outpatient Study (HOPS) data, following eligible patients from January 1, 2002, or first HOPS visit thereafter to calculate 10-year cardiovascular risk (10yCVR), until September 30, 2009, death, or last office visit. We categorized participants into four 10yCVR strata, according to guidelines determined by NCEP, the Infectious Disease Society of America, and the Adult AIDS Clinical Trials Group. We calculated percentages of patients treated for dyslipidemia and hypertension, calculated percentages of patients who achieved recommended goals, and categorized them by 10yCVR stratum. RESULTS: Of 2,005 patients analyzed, 33.7% had fewer than 2 CVD risk factors. For patients who had 2 or more risk factors, 10yCVR was less than 10% for 28.2%, 10% to 20% for 18.2%, and higher than 20% for 20.0% of patients. Of patients eligible for treatment, 81% to 87% were treated for elevated low-density lipoprotein cholesterol/non-high-density lipoprotein cholesterol (LDL-C/non-HDL-C), 2% to 11% were treated for low HDL-C, 56% to 91% were treated for high triglycerides, and 46% to 69% were treated for hypertension. Patients in higher 10yCVR categories were less likely to meet treatment goals than patients in lower 10yCVR categories. CONCLUSION: At least one-fifth of contemporary HOPS patients have a 10yCVR higher than 20%, yet a large percentage of at-risk patients who were eligible for pharmacologic treatment did not receive recommended interventions and did not reach recommended treatment goals. Opportunities exist for CVD prevention in the HIV-infected population. PMID- 23347710 TI - Perspectives of the community-based dementia care workforce: "occupational communion" a key finding from the Work 4 Dementia Project. AB - BACKGROUND: Community care workers' experience of delivering support to people with dementia is less researched than that of residential workers. The purpose of the study is to explore community-based dementia care workers' perspectives about their roles and the contextual variables that impact upon their work experiences. METHOD: A qualitative design was employed. Twenty-five community dementia care workers (average age 53 years, majority female and employed casually) participated in standardized semi-structured interviews about their job roles, training, employer agenda, organizational support, and intention to stay. A deductive approach to Interpretive Phenomenological Analysis was adopted to identify key themes. RESULTS: Three themes highlighted workers' experiences. Occupational communion described strong attachment to clients and a desire for greater connection with colleagues. Job demands described the challenges of work, which varied with intensity. Job resources ranged from positive (strong organizational commitment) to negative (poor pay and conditions). Occupational communion was identified as a concept that exists at the interface between social and organization psychology that was perceived to be essential for adaptive coping. Identifying themes informed a conceptual model for designing intervention components aimed at improving workers' skills, capabilities, and employer supportive functions. CONCLUSION: Occupational communion may be particularly relevant for women's caring careers and future research is needed to explore the relevance of this concept for men. To determine reliable change associated with interventions that target occupational communion, further investigation is required in relation to measurement approaches. PMID- 23347712 TI - Association between takotsubo syndrome and thrombocytopenia. PMID- 23347711 TI - Use of the 'patient journey' model in the internet-based pre-fitting counseling of a person with hearing disability: study protocol for a randomized controlled trial. AB - BACKGROUND: Hearing impairment is one of the most frequent chronic conditions. Persons with a hearing impairment (PHI) have various experiences during their 'journey' through hearing loss. In our previous studies we have developed a 'patient journey' model of PHI and their communication partners (CPs). We suggest this model could be useful in internet-based pre-fitting counseling of a person with hearing disability (PHD). METHODS/DESIGN: A randomized controlled trial (RCT) with waiting list control (WLC) design will be used in this study. One hundred and fifty eight participants with self-reported hearing disability (that is, score > 20 in the Hearing Handicap Questionnaire (HHQ)) will be recruited to participate in this study. They will be assigned to one of two groups (79 participants in each group): (1) Information and counseling provision using the 'patient journey' model; and (2) WLC. They will participate in a 30 day (4 weeks) internet-based counseling program based on the 'patient journey' model. Various outcome measures which focuses on hearing disability, depression and anxiety, readiness to change and acceptance of hearing disability will be administered pre (one week before) and post (one week and six months after) intervention to evaluate the effectiveness of counseling. DISCUSSION: Internet-based counseling is being introduced as a viable option for audiological rehabilitation. We predict that the 'patient journey' model will have several advantages during counseling of a PHD. Such a program, if proven effective, could yield cost and time-efficient ways of managing hearing disability. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System NCT01611129. PMID- 23347713 TI - Systematic combined noncontrast CT-CT angiography in the management of unexplained nontraumatic coma. AB - BACKGROUND: Nontraumatic impaired consciousness is a common issue in emergency departments with a serious but widely variable prognosis. STUDY OBJECTIVES: The aim of this prospective study was to evaluate the ability of systematic combined noncontrast computed tomography (NCCT)/computed tomography angiography (CTA) imaging, firstly to provide a neurologic prognosis and secondly to ensure early detection of basilar artery occlusion (BAO), in unexplained nontraumatic impaired consciousness management. METHODS: Combined NCCT/CTA imaging was performed on 65 patients with impaired consciousness and no history of trauma prospectively over 14 months in a single center. Images were assessed based on visual and quantitative criteria. Clinical outcome was assessed using the modified Rankin Scale at 3 months. Statistical analysis aimed to identify the prognostic value of combined NCCT/CTA imaging and its ability for early BAO detection. RESULTS: This study shows that combined NCCT/CTA imaging was a significant predictor of poor neurological outcome, with a positive predictive value of 94.6%. The combination was also crucial for early detection of BAO, given that 42.8% of cases were misdiagnosed with NCCT alone. Basilar artery occlusion represented 10.8% of all unexplained nontraumatic impaired consciousness. CONCLUSIONS: Systematic combined NCCT/CTA imaging is an efficient tool for predicting poor neurologic prognosis in cases of unexplained nontraumatic impaired consciousness and is also essential for detecting BAO. PMID- 23347714 TI - Evaluation of the effectiveness of peer pressure to change disposition decisions and patient throughput by emergency physician. AB - OBJECTIVES: The aim of this study was to develop a strategy for imposing peer pressure on emergency physicians to discharge patients and to evaluate patient throughput before and after intervention. METHODS: A before-and-after study was conducted in a medical center with more than 120 000 annual emergency department (ED) visits. All nontraumatic adult patients who presented to the ED between 7:30 and 11:30 am Wednesday to Sunday were reviewed. We created a "team norm" imposed peer-pressure effect by announcing the patient discharge rate of each emergency physician through monthly e-mail reminders. Emergency department length of stay (LOS) and 8-hour (the end of shift) and final disposition of patients before (June 1, 2011-September 30, 2011) and after (October 1, 2011-January 30, 2012) intervention were compared. RESULTS: Patients enrolled before and after intervention totaled 3305 and 2945. No differences existed for age, sex, or average number of patient visits per shift. The 8-hour discharge rate increased significantly for all patients (53.5% vs 48.2%, P < .001), particularly for triage level III patients (odds ratio, 1.3; 95% confidence interval, 1.09-1.38) after intervention and without corresponding differences in the final disposition (P = .165) or admission rate (33.7% vs 31.6%, P = .079). Patients with a final discharge disposition had a shorter LOS (median, 140.4 min vs 158.3 min; P < .001) after intervention. CONCLUSIONS: The intervention strategy used peer pressure to enhance patient flow and throughput. More patients were discharged at the end of shifts, particularly triage level III patients. The ED LOS for patients whose final disposition was discharge decreased significantly. PMID- 23347715 TI - Potential barriers associated with increased prevalence of perforated appendicitis in Colorado's pediatric Medicaid population. AB - OBJECTIVE: We sought to identify barriers and delays in care associated with the increased prevalence of perforated appendicitis among Colorado's pediatric Medicaid population. METHODS: We conducted a retrospective cohort study of all cases of pediatric appendicitis, which had Colorado Medicaid from 2007 to 2008 using descriptive statistics, bivariate analysis, and multivariable logistic regression. RESULTS: Of the 479 appendicitis cases, 42.6% were perforated. In both the bivariate and multivariate analysis, perforated cases did not significantly differ from nonperforated cases with respect to sex, rurality of residence, or race with the exception of black race in the multivariate model. Perforated cases were more likely to be younger, have been enrolled in Medicaid for less than 6 months, have seen a provider within 5 days of their diagnosis, and have been transferred to another hospital for treatment. CONCLUSIONS: The high prevalence of perforated appendicitis in Colorado children with Medicaid coverage is not associated with race or physical proximity to care but may be associated with the duration of Medicaid coverage, which highlights the importance of establishing medical homes to direct patients on where and how to seek care. PMID- 23347716 TI - Work-related stressors and occurrence of adverse events in an ED. AB - OBJECTIVE: The purpose of this study was to investigate the relationship between 12 work-related stressors and the occurrence of adverse events in an emergency department (ED). METHODS: Nurses and physicians, working in an ED at a Danish regional hospital, filled out a questionnaire on occurrence and emotional impact of 12 work-related stressors after each shift during a 4-week period. The questionnaire also instructed the participants to describe any adverse events that they were involved in during the shift. RESULTS: Two hundred fourteen adverse events were reported during the 979 studied shifts. During the same period, only 27 adverse events were reported to the mandatory national reporting system, and only 10 of these were duplicates. A high variability of stressors and emotional impact among the different groups of participants was found. Linear regression analysis showed an association between involvement in adverse events and the occurrence and emotional impact of stressors across groups, whereas no significant association was found for age, seniority, shift type, or length. CONCLUSION: The study showed an association between the occurrence and impact of 12 work-related stressors and involvement in adverse events across the groups of participants. Furthermore, the study showed that most adverse events were not reported to the mandatory national reporting system. PMID- 23347717 TI - Emergency ultrasound in the diagnosis of traumatic extrathoracic lung herniation. PMID- 23347718 TI - Emergency ultrasonography for the early diagnosis of necrotizing fasciitis: a case series from the ED. PMID- 23347719 TI - Decreasing door-to-balloon times via a streamlined referral protocol for patients requiring transport. AB - PURPOSES: The objective of this study was to evaluate the effectiveness of a streamlined interfacility referral protocol in reducing door-to-balloon (D2B) times for patients experiencing acute ST-segment elevation myocardial infarction (STEMI). BASIC PROCEDURES: In a retrospective database review, we compared D2B times for patients requiring interfacility transfer after the implementation of a streamlined referral protocol. All patients undergoing interfacility transport with a referring diagnosis of STEMI were eligible for inclusion. Quality management databases were reviewed by trained abstractors using standardized data entry forms for D2B times from July 2009 through June 2010. Median D2B times with interquartile ranges are reported. MAIN FINDINGS: A total of 133 patients exhibited complete data and were included in the analysis, 54 of which were transferred via the streamlined referral protocol. Streamlined referral patients exhibited a median D2B time of 101 minutes (interquartile range, 88-128) vs a median D2B time of 122 minutes (interquartile range, 99-157) for the traditional referral group (P = .001). Door-to-balloon times of 90 minutes or less were achieved in 13% of the traditional referral patients and in 30% of the streamlined protocol group (odds ratio, 2.9; 95% confidence interval, 1.2-7). PRINCIPAL CONCLUSION: The implementation of a streamlined referral protocol has significantly reduced D2B times for patients diagnosed with STEMI that required interfacility transport for intervention. PMID- 23347720 TI - Anaphylaxis and delayed hymenoptera in a child with fire ant envenomation. PMID- 23347721 TI - Use and efficacy of nebulized naloxone in patients with suspected opioid intoxication. AB - OBJECTIVE: To describe the use and efficacy of nebulized naloxone in patients with suspected opioid intoxication. METHODS: This was an observational study conducted at an inner city emergency department. Patients were eligible if they had self-reported or suspected opioid intoxication and a spontaneous respiratory rate >=6 breaths/minute. Nebulized naloxone (2 mg in 3 mL normal saline) was administered through a standard face mask at the discretion of the treating physician. Structured data collection included demographics, vital signs pre and post naloxone administration and adverse events. The primary outcome was level of consciousness, which was recorded pre and 15 minutes postnaloxone administration using the Glasgow Coma Scale (GCS) and the Richmond Agitation Sedation Scale (RASS). RESULTS: Of the 73 patients who presented with suspected opioid intoxication and were given naloxone over the study period, 26 were initially treated with nebulized naloxone. After nebulized naloxone administration, median GCS improved from 11 [interquartile range (IQR) 3.5] to 13 (IQR, 2.5), P = .001. Median RASS improved from -3.0 (IQR, -1.0) to -2.0 (IQR, -1.5), P < .0001. Need for supplemental oxygen decreased from 81% to 50%, P = .03. Vital signs did not differ pre/post therapy. There were few adverse effects from nebulized naloxone administration: 12% experienced moderate-severe agitation, 8% were diaphoretic and none vomited. Eleven required subsequent administrations of naloxone, nine of whom self-reported using either heroin, methadone or both. Of these, 5 underwent urine drug screening and all 5 tested positive for either opiates or methadone. CONCLUSIONS: Nebulized naloxone was well-tolerated and led to a reduction in the need for supplemental oxygen as well as improved median GCS and RASS scores in patients with suspected opioid intoxication. PMID- 23347722 TI - Evaluation of the Storz CMAC(r), Glidescope(r) GVL, AirTraq(r), King LTS-DTM, and direct laryngoscopy in a simulated difficult airway. AB - OBJECTIVE: The aim of this study was to compare first-attempt and overall success rates and success rates in relation to placement time among 5 different airway management devices: Storz CMAC, Glidescope GVL, AirTraq, King LTS-D, and direct laryngoscopy (DL). METHODS: Emergency medical technician basic (EMT-B), EMT paramedics (EMT-P), and emergency medicine residents and staff physicians placed each of the 5 devices in a random order into an AirSim (TruCorp, Belfast, UK) part-task training manikin. The difficult airway scenario was created by fixing the manikin head to a stationary object and introducing simulated emesis into the hypopharynx. First-attempt and overall success and success in relation to placement time were compared. Provider feedback about device performance was also evaluated. RESULTS: Ninety-four providers (16 EMT-basics, 54 EMT-paramedics, and 24 emergency department doctors of medicine) consented to participation. First attempt and overall success rates for DL, King LTS-D, GVL, and CMAC were not statistically different. Compared with DL, the AirTraq was 96% less likely to be placed successfully (odds ratio, 0.04; 95% confidence interval [CI], 0.01-0.14). When time was factored into the model, the odds of successful placement of the King LTS-D were higher compared with DL (hazard ratio [HR], 1.80; 95% CI, 1.34 2.42) and lower for GVL (HR, 0.59; 95% CI, 0.44-0.80) and AirTraq (HR, 0.228; 95% CI, 0.16-0.325). Providers ranked the CMAC first in terms of performance and preference for use in their practice setting. CONCLUSION: Overall success rates for DL, King-LTS-D, and both video laryngoscope systems were not different. When time was factored into the model, the King LTS-D was more likely to be placed successfully. PMID- 23347723 TI - Phase-amplitude descriptions of neural oscillator models. AB - Phase oscillators are a common starting point for the reduced description of many single neuron models that exhibit a strongly attracting limit cycle. The framework for analysing such models in response to weak perturbations is now particularly well advanced, and has allowed for the development of a theory of weakly connected neural networks. However, the strong-attraction assumption may well not be the natural one for many neural oscillator models. For example, the popular conductance based Morris-Lecar model is known to respond to periodic pulsatile stimulation in a chaotic fashion that cannot be adequately described with a phase reduction. In this paper, we generalise the phase description that allows one to track the evolution of distance from the cycle as well as phase on cycle. We use a classical technique from the theory of ordinary differential equations that makes use of a moving coordinate system to analyse periodic orbits. The subsequent phase-amplitude description is shown to be very well suited to understanding the response of the oscillator to external stimuli (which are not necessarily weak). We consider a number of examples of neural oscillator models, ranging from planar through to high dimensional models, to illustrate the effectiveness of this approach in providing an improvement over the standard phase-reduction technique. As an explicit application of this phase-amplitude framework, we consider in some detail the response of a generic planar model where the strong-attraction assumption does not hold, and examine the response of the system to periodic pulsatile forcing. In addition, we explore how the presence of dynamical shear can lead to a chaotic response. PMID- 23347724 TI - Toxicity of organoclays to microbial processes and earthworm survival in soils. AB - Organoclays have wide spread application in environmental remediation and nanocomposites synthesis. Some of the quaternary ammonium compounds (QACs) commonly used to prepare organoclays are toxic to biota. However, information on the toxicity of organoclays is rarely available in the literature. This study assessed the toxicity of three laboratory prepared bentonite organoclays on the soil microbially mediated processes (such as dehydrogenase activity and potential nitrification) and soil inhabiting animals, such as earthworms. Toxicity to both microbial processes and earthworm followed the order: hexadecyltrimethyl ammonium modified bentonite>octadecyltrimethyl ammonium modified bentonite>arquad modified bentonite>unmodified bentonite. The organoclays were able to cause slight improvement (up to 25%) in the potential nitrification in some soils when they were added at low application rates up to 5%, but caused reduction (3-86%) in the dehydrogenase activity in all the soils irrespective of loading rates. The organoclays were extremely toxic to the survival and vigour of the earthworms. The average body weight loss of the worms reached as high as 62% in hexadecyltrimethyl ammonium modified bentonite treated soil even at 1% loading. This study holds utmost importance in assessing the toxicity of organoclays to soil microbially mediated processes and earthworms. PMID- 23347725 TI - Transcriptome analysis of bitter acid biosynthesis and precursor pathways in hop (Humulus lupulus). AB - BACKGROUND: Bitter acids (e.g. humulone) are prenylated polyketides synthesized in lupulin glands of the hop plant (Humulus lupulus) which are important contributors to the bitter flavour and stability of beer. Bitter acids are formed from acyl-CoA precursors derived from branched-chain amino acid (BCAA) degradation and C5 prenyl diphosphates from the methyl-D-erythritol 4-phosphate (MEP) pathway. We used RNA sequencing (RNA-seq) to obtain the transcriptomes of isolated lupulin glands, cones with glands removed and leaves from high alpha acid hop cultivars, and analyzed these datasets for genes involved in bitter acid biosynthesis including the supply of major precursors. We also measured the levels of BCAAs, acyl-CoA intermediates, and bitter acids in glands, cones and leaves. RESULTS: Transcripts encoding all the enzymes of BCAA metabolism were significantly more abundant in lupulin glands, indicating that BCAA biosynthesis and subsequent degradation occurs in these specialized cells. Branched-chain acyl CoAs and bitter acids were present at higher levels in glands compared with leaves and cones. RNA-seq analysis showed the gland-specific expression of the MEP pathway, enzymes of sucrose degradation and several transcription factors that may regulate bitter acid biosynthesis in glands. Two branched-chain aminotransferase (BCAT) enzymes, HlBCAT1 and HlBCAT2, were abundant, with gene expression quantification by RNA-seq and qRT-PCR indicating that HlBCAT1 was specific to glands while HlBCAT2 was present in glands, cones and leaves. Recombinant HlBCAT1 and HlBCAT2 catalyzed forward (biosynthetic) and reverse (catabolic) reactions with similar kinetic parameters. HlBCAT1 is targeted to mitochondria where it likely plays a role in BCAA catabolism. HlBCAT2 is a plastidial enzyme likely involved in BCAA biosynthesis. Phylogenetic analysis of the hop BCATs and those from other plants showed that they group into distinct biosynthetic (plastidial) and catabolic (mitochondrial) clades. CONCLUSIONS: Our analysis of the hop transcriptome significantly expands the genomic resources available for this agriculturally-important crop. This study provides evidence for the lupulin gland-specific biosynthesis of BCAAs and prenyl diphosphates to provide precursors for the production of bitter acids. The biosynthetic pathway leading to BCAAs in lupulin glands involves the plastidial enzyme, HlBCAT2. The mitochondrial enzyme HlBCAT1 degrades BCAAs as the first step in the catabolic pathway leading to branched chain-acyl-CoAs. PMID- 23347726 TI - Illness experience of adults with cervical spinal cord injury in Japan: a qualitative investigation. AB - BACKGROUND: There is growing recognition that healthcare policy should be guided by the illness experience from a layperson's or insider's perspective. One such area for exploration would include patient-centered research on traumatic Spinal Cord Injury (SCI), a condition associated with permanent physical disability requiring long-term and often complex health care. The chronicity of SCI can, in turn, affect individuals' sense of self. Although previous research in Western countries suggests that people with SCI find a way to cope with their disability through social participation and family bonds, the process of adjustment among people with cervical SCI (CSCI) living in Japan may be different because of the restrained conditions of their social participation and the excessive burden on family caregivers. The purpose of this study was to examine the impact of injury and the process of accommodation in people with CSCI in Japan. METHODS: Semi structured home interviews were conducted with 29 participants who were recruited from a home-visit nursing care provider and three self-help groups. Interviews were recorded, transcribed and analyzed based on the grounded theory approach. RESULTS: Five core categories emerged from the interview data: being at a loss, discrediting self by self and others, taking time in performance, restoring competency, and transcending limitations of disability. Overall, the process by which participants adjusted to and found positive meaning in their lives involved a continuous search for comfortable relationships between self, disability and society. CONCLUSIONS: The results of this study suggest that persons with CSCI do not merely have disrupted lives, but find positive meaning through meaningful interactions. Family members added to the discredit of self by making the injured person entirely dependent on them. Gaining independence from family members was the key to restoring competency in people with CSCI. At the same time, social participation was pursued for transcending the limitations of disability. The results also imply that social issues affect how people interpret their disability. These findings suggest that public health policy makers should recognize the need to enhance independence in people with disability as well as change the social assumptions about their care. PMID- 23347728 TI - Familiarity, knowledge, and preferences of family physicians regarding mild cognitive impairment. AB - BACKGROUND: Mild cognitive impairment (MCI) is a common condition among elderly persons. Its early identification is important because MCI can be a precursor of dementia. Since physicians' knowledge and preferences regarding MCI can be critical in its identification, this study assessed family physicians' familiarity, knowledge, and preferences regarding help-seeking, diagnosis, and treatment options for MCI. METHOD: A convenience sample of 197 family physicians working in one of the largest Health Maintenance Organizations (HMOs) in Israel completed a structured questionnaire. Familiarity, knowledge, and preferences regarding diagnosis, help-seeking, and treatment of MCI were assessed. RESULTS: The majority of the participants had heard about MCI but a third of those familiar with the term reported knowing almost nothing about it. Participants' objective knowledge was good regarding several causes of MCI, but 70% reported it to be caused by normal aging. Help-seeking and treatment preferences corresponded with the literature on MCI. CONCLUSION: Our findings stress the need to broaden the understanding of primary care physicians' knowledge and preferences regarding MCI. This research can guide in developing continuous education programs to strengthen areas and groups of physicians reporting low knowledge. PMID- 23347727 TI - Pfhrp2 and pfhrp3 polymorphisms in Plasmodium falciparum isolates from Dakar, Senegal: impact on rapid malaria diagnostic tests. AB - BACKGROUND: An accurate diagnosis is essential for the rapid and appropriate treatment of malaria. The accuracy of the histidine-rich protein 2 (PfHRP2)-based rapid diagnostic test (RDT) Palutop+4(r) was assessed here. One possible factor contributing to the failure to detect malaria by this test is the diversity of the parasite PfHRP2 antigens. METHODS: PfHRP2 detection with the Palutop+4(r) RDT was carried out. The pfhrp2 and pfhrp3 genes were amplified and sequenced from 136 isolates of Plasmodium falciparum that were collected in Dakar, Senegal from 2009 to 2011. The DNA sequences were determined and statistical analyses of the variation observed between these two genes were conducted. The potential impact of PfHRP2 and PfHRP3 sequence variation on malaria diagnosis was examined. RESULTS: Seven P. falciparum isolates (5.9% of the total isolates, regardless of the parasitaemia; 10.7% of the isolates with parasitaemia <=0.005% or <=250 parasites/MUl) were undetected by the PfHRP2 Palutop+4(r) RDT. Low parasite density is not sufficient to explain the PfHRP2 detection failure. Three of these seven samples showed pfhrp2 deletion (2.4%). The pfhrp3 gene was deleted in 12.8%. Of the 122 PfHRP2 sequences, 120 unique sequences were identified. Of the 109 PfHRP3 sequences, 64 unique sequences were identified. Using the Baker's regression model, at least 7.4% of the P. falciparum isolates in Dakar were likely to be undetected by PfHRP2 at a parasite density of <=250 parasites/MUl (slightly lower than the evaluated prevalence of 10.7%). This predictive prevalence increased significantly between 2009 and 2011 (P = 0.0046). CONCLUSION: In the present work, 10.7% of the isolates with a parasitaemia <=0.005% (<=250 parasites/MUl) were undetected by the PfHRP2 Palutop+4(r) RDT (7.4% by the predictive Baker'model). In addition, all of the parasites with pfhrp2 deletion (2.4% of the total samples) and 2.1% of the parasites with parasitaemia >0.005% and presence of pfhrp2 were not detected by PfHRP2 RDT. PfHRP2 is highly polymorphic in Senegal. Efforts should be made to more accurately determine the prevalence of non-sensitive parasites to pfHRP2. PMID- 23347729 TI - [To go in-depth in the knowledge of the device to control fecal elimination in the critical patient]. AB - OBJECTIVE: To describe the general characteristics of the patient and device use. To know retention balloon pressure (RBP) and related factors. To identify rate of leakage incidence, relocation and perineal damage due to the device (PSD) and related risk factors. MATERIAL AND METHODS: An analytical observational, cross sectional study conducted in a polyvalent ICU from June-December 2010 was performed. The sample included Flexi-Seal((r)) carriers. Variables evaluated were patient and device use characteristics, RBP, leakage and quantity, relocation and reason, PSD, sedoanalgesia infusion, neuromuscular block, patient position, Flexi Seal type catheter, ventilatory mode (VM), intra-abdominal pressure (IAP), mean intrathoracic pressure (MITP), PEEP, Glasgow, color-aspect, fecal consistency and volume. Significance P<.05. RESULTS: Twenty-one patients were included, 52% male, aged 54+/-17 with 30 insertion episodes, Flexi-Seal-Signal((r)) 33%, 10+/-8 days permanency, main indication 33% "diarrhea and injured skin"," 30% device removal "intolerance and/or spontaneous expulsion". Median (Me) PGR =40; RI (61-19) cmH2O. Factors associated to higher PGR: SCI absence, prone-decubitus position, leakage, relocation, conventional Flexi-Seal((r)), MV, lower PEEP and IMP, Color aspect, higher MITP. Leakage, relocation and PSD incidence density 43, 30 and 2 cases/100 days of catheter, respectively. Leakage and relocation risk factors: higher PGR, Glasgow and fecal volume, lower MITP, MV, assisted-spontaneous mode OR 2.5 CI (1.6-3.8) and OR 1.7(1.1-2.7), absence SCI OR 3.3 (2.2-5.1) and OR 2.4(1.5-3.8), absence neuromuscular block OR 2.4 (1.4-3.9) and OR 1.8 (1.1-3.1), Flexi-Seal((r)) conventional OR 2.7(1.7-4.1) and OR 2 (1.2-3.3), respectively. Leakage risk factors: color-aspect, supine position, lower IMP and PEEP. CONCLUSIONS: Monitoring RBP may alert us about leakage presence and relocation need. Knowing associated risk factors to RBP, leakage and relocation would help to develop strategies to reduce their high incidence rate such as decreasing RBP by reducing inflated volume. PMID- 23347730 TI - Additional prognostic value of the 70-gene signature (MammaPrint((r))) among breast cancer patients with 4-9 positive lymph nodes. AB - BACKGROUND: The 70 gene-signature (MammaPrint((r))) is a prognostic profile of distant recurrence and survival of primary breast cancer (BC). BC patients with 4 9 positive nodes (LN 4-9) are considered clinically at high-risk. Herein we examined MammaPrint((r)) added prognostic value in this group. PATIENTS AND METHODS: MammaPrint((r)) profiles were generated from frozen tumours of patients operated from primary BC. Samples were classified as genomic Low Risk (GLR) or genomic High Risk (GHR). RESULTS: Among the 173 samples, 70 (40%) were classified as GLR and 103 (60%) as GHR. Tumours in the GHR group were significantly more often ductal carcinomas (93%), grade 3 (60%), oestrogen and progesterone negative, Her2 positive (25%). In the GLR category, the 5-year overall survival was 97% vs. 76% for in the GHR group (p < 0.01); Distant Metastasis Free Survival (DMFS) at 5 years was 87% for GLR patients and 63% for GHR patients (p < 0.01). In the Luminal A subgroup, the genomic profile was the only independent risk factor for DM and BC specific death. CONCLUSION: In the Luminal A subgroup, MammaPrint((r)) is an independent prognostic marker in BC patients with LN 4-9 and may be integrated in a selection strategy of patients candidate for more aggressive therapeutic approaches. PMID- 23347731 TI - The effectiveness of transplant legislation, procedures and management: cross country evidence. AB - This article investigates the impact of legal determinants of cadaveric and living donor organ transplantation rates using panel data on legislative, procedural and managerial aspects of organ transplantation and procurement, government health expenditures, enrollment rates, religious beliefs, legal systems and civil rights and liberties for 62 countries over a 2-year period. Under living donor organ transplantation, we found that guaranteeing traceability of organs by law or performing psychiatric evaluation to living donors has a sizeable, negative impact on living transplant rates once the remaining determinants of living transplantation have been controlled for. Under cadaveric transplantation, our findings do not suggest an unequivocal and positive association between presumed consent, donor registries and cadaveric transplant rates. However, legally requiring family consent or maintaining written procurement standards for deceased donors has a sizeable, negative impact on cadaveric transplant rates. The latter finding suggests that informing families rather than asking for consent may be an effective strategy to raise procurement rates while respecting patient autonomy. Finally, we confirm that predominantly non-Christian countries have significantly higher living but lower cadaveric transplant rates. PMID- 23347732 TI - [Good Danish logistics on patients with acute coronary syndrome]. PMID- 23347733 TI - [When time flies]. PMID- 23347734 TI - [Primary percutaneous coronary intervention as a national Danish reperfusion strategy of ST-elevation myocardial infarction]. AB - The use of primary percutaneous coronary intervention (PCI) as the preferred reperfusion strategy in ST-elevation myocardial infarction (STEMI) requires optimal systems-of-care and logistics in order to enable rapid treatment of all patients. In Denmark, this has been achieved through prehospital electrocardiogram diagnosis, field triage and dedicated PCI centres 24/7. Today, primary PCI is an option for all Danish patients with STEMI, regardless of the distance to a PCI centre. This has led to a decline in both mortality and morbidity. PMID- 23347735 TI - [Prehospital point of care testing of biomarkers has diagnostic value in relation to acute myocardial infarction]. AB - Prehospital point of care testing (POCT) of biomarkers may be a valuable tool for optimizing prehospital diagnosis. We report the status of prehospital POCT in relation to acute myocardial infarction (AMI). No randomized studies have been performed. Eight observational studies collectively show added diagnostic value of prehospital POCT in relation to AMI. The revised European NSTEMI guidelines focus on early risk assessment in relevant timing of reperfusion strategy. We anticipate that prehospital POCT will be central in NSTEMI care in the near future. PMID- 23347736 TI - [Time gain by helicopter transportation of ST-elevation myocardial infarction patients]. AB - Helicopter transportation of ST-elevation myocardial infarction patients have verified a reduction in the overall system delay, and should be considered in case of long transportation. The most suitable location of the helicopter base is in remote areas, close to the patients to be transferred. Helipads should be adjoining the percutaneous coronary intervention centre in order to allow direct transfer without the ambulance transfer. Helicopters that can operate both day and night and in poor visibility are recommended. Specially trained physicians, able to provide the required, advanced, in-flight treatment, should staff the helicopters. PMID- 23347737 TI - [Identification of patients admitted acutely on suspicion of cardiac disease]. AB - Overall, the future emergency departments in Denmark serve as a single portal of entry for all acute patients. At the same time an expansion of prehospital diagnosing and triage will take place. In patients suspected of life-threatening cardiac conditions with specialized treatment requirements where the time factor is important, the prehospital triage will be important to identify patients who should be transferred directly to a cardiac care unit to reduce prehospital and in-hospital delays of treatment. PMID- 23347738 TI - [Early invasive examination of coronary arteries are indicated by non-ST elevation myocardial infarction]. AB - Today there is solid evidence that high-risk patients with acute myocardial infarction without ST-elevation should undergo routine invasive treatment, preferably with a very short delay. Evidence suggests that acute coronary occlusions are present in many of these patients. Nevertheless, so far no studies have been powered to evaluate the impact of primary percutaneous coronary intervention on outcome in this patient population. With the advanced, prehospital, diagnostic possibilities available today it would be possible to investigate this issue further. PMID- 23347739 TI - [Acute coronary angiography should be considered in patients with ST segment elevation after out-of-hospital cardiac arrest]. AB - Guidelines suggest that acute coronary angiography (CAG) is considered in patients resuscitated from out-of-hospital cardiac arrest with presumed cardiac aetiology. Since specialized post-resuscitation care, including therapeutic hypothermia, has proved beneficial in randomized studies, CAG should be offered to patients with a high likelihood of thrombotic coronary lesions, i.e. patients with ST-segment elevation in electrocardiogram (ECG) following resuscitation. This article suggests a triage and referral based on electronic transmission of ECG and teleconference with specialized centres in all patients. PMID- 23347740 TI - [Treatment of cardiogenic shock with percutanous mechanical circulatory support]. AB - Despite rapid revascularisation with circulatory support using inotropes and intra-aortic balloon counterpulsation, the mortality of cardiogenic shock complicating acute myocardial infarction still exceeds 50%. An alternative treatment strategy is restoration of cardiac output by using a ventricular assist device which can be inserted in the acute setting using the Impella device, a catheter-based flow pump. DanShock is a Danish multicentre study that will assess whether circulatory support using the Impella device will improve the outcome of cardiogenic shock compared to conventional management. PMID- 23347741 TI - [Successful prehospital diagnosis secures fast and correct treatment of acute aorta dissection]. AB - Time from symptom onset to final treatment is crucial for survival. We present a case where prehospital diagnosis by the emergency physician in the ambulance was followed by a telemedicine conference and data transfer to the hospital. This was combined with bypassing of the emergency room and direct transfer to the thoracic surgical theatre, and time to treatment was reduced considerably. Obtaining a prehospital diagnosis in time-dependent life-threatening disease as basement for supportive treatment and transfer directly to treatment is very important. PMID- 23347742 TI - The UK national evaluation of the development and impact of Early Intervention Services (the National EDEN studies): study rationale, design and baseline characteristics. AB - AIMS: National EDEN aims to evaluate the implementation and impact on key outcomes of somewhat differently configured Early Intervention Services (EIS) across sites in England and to develop a model of variance in patient outcomes that includes key variables of duration of untreated psychosis (DUP), fidelity to the EIS model and service engagement. The cohort is being followed up for two further years as patients are discharged, to observe the stability of change and the impact of the discharge settings. METHODS: A longitudinal cohort study of patients with a first episode of a psychosis, managed by EIS in six services across England. Patients are followed up 12 months after inception, then up to 2 years following discharge. Measures of DUP, psychosis, social functioning and relapse were taken. User and carer experience of EIS were monitored over time; as was the fidelity of each EIS to national guidelines. Service use is costed for a health economic evaluation. RESULTS: 1027 people consented to the study of which 75% were successfully followed up at 12 months, with almost 100% data on treatment, relapse and recovery and service use. CONCLUSIONS: National EDEN is the largest cohort study of young people with psychosis receiving care under EIS. It will be able definitively to indicate whether this major investment in the United Kingdom in EI is achieving meaningful change for its users in practice and provide indications concerning who does well under this approach and who does not, and the long-term stability of any improvements. PMID- 23347743 TI - Plague outbreak in Libya, 2009, unrelated to plague in Algeria. AB - After 25 years of no cases of plague, this disease recurred near Tobruk, Libya, in 2009. An epidemiologic investigation identified 5 confirmed cases. We determined ribotypes, Not1 restriction profiles, and IS100 and IS1541 hybridization patterns of strains isolated during this outbreak. We also analyzed strains isolated during the 2003 plague epidemic in Algeria to determine whether there were epidemiologic links between the 2 events. Our results demonstrate unambiguously that neighboring but independent plague foci coexist in Algeria and Libya. They also indicate that these outbreaks were most likely caused by reactivation of organisms in local or regional foci believed to be dormant (Libya) or extinct (Algeria) for decades, rather than by recent importation of Yersinia pestis from distant foci. Environmental factors favorable for plague reemergence might exist in this area and lead to reactivation of organisms in other ancient foci. PMID- 23347744 TI - Determinants of transition across the spectrum of alcohol use and misuse in Nigeria. AB - Many studies have examined the risk factors associated with alcohol use disorders. No information is available from developing countries about the factors that may determine the transitions across different levels of use and misuse. Alcohol use and its misuse were assessed in a cohort of 2143 Nigerians using Version 3.0 of the World Health Organization Composite International Diagnostic Interview (WHO-CIDI). This generated six levels of alcohol use and related disorders. Using age of onset variables created for the purpose, analysis was done to determine rates of and risk factor for transition between the levels. Lifetime prevalence estimates were 57.8% for alcohol use, 27.6% for regular use, 2.9% for abuse, and 0.3% for dependence. Whereas 47.8% transited to regular use from lifetime ever use, only 10.5% transited to abuse from regular use and 9.5% from abuse to dependence. Male sex, age 18-49 years and being never married predicted onset of alcohol use. Transition to regular use was predicted only by male sex while transition to abuse was predicted by male sex and age 35-49 years. Factors associated with recovery from abuse were female sex and a student status. Higher rates of transition occurred in the stages preceding the onset of alcohol use disorders. Sex and age were the main determinants of transition, with male gender and middle age being risk factors for transition to problematic use of alcohol. PMID- 23347745 TI - Improvement of porcine cloning efficiency by trichostain A through early-stage induction of embryo apoptosis. AB - Trichostain A (TSA), an inhibitor of histone deacetylases, improved developmental competence of SCNT embryos in many species, apparently by improved epigenetic reprogramming. The objective of the present study was to determine the effects of TSA-induced apoptosis in cloned porcine embryos. At various developmental stages, a comet assay and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining were used to detect apoptosis, and real time polymerase chain reaction was used to assess expression of genes related to apoptosis and pluripotency. In this study, TSA significantly induced apoptosis (in a dose-dependent manner) at the one-, two-, and four-cell stages. However, in blastocyst stage embryos, TSA decreased the apoptotic index (P < 0.05). Expression levels of Caspase 3 were higher in TSA-treated versus control embryos at the two-cell stage (not statistically significant). The expression ratio of antiapoptotic Bcl-xl gene to proapoptotic Bax gene, an indicator of antiapoptotic potential, was higher in TSA-treated groups at the one-, two-, and four-cell and blastocyst stages. Furthermore, expression levels of pluripotency-related genes, namely, Oct4 and Nanog, were elevated at the morula stage (P < 0.05) in TSA treatment groups. We concluded that inducing apoptosis might be a mechanism by which TSA promotes development of reconstructed embryos. At the initial stage of apoptosis induction, abnormal cells were removed, thereby enhancing proliferation of healthy cells and improving embryo quality. PMID- 23347746 TI - Estradiol has a major role in antrum formation of porcine preantral follicles cultured in vitro. AB - Antrum formation and estradiol (E2) secretion occur during early folliculogenesis. The objective was to determine the role of E2 in antrum formation of oocyte-granulosa cell complexes (OGCs) derived from porcine preantral follicles (PAFs). Supplementation of the culture medium with E2 (1 MUg/mL) improved antrum formation of OGCs during 14 days of in vitro culture. Furthermore, adding 0.1 MUg/mL androstenedione (a precursor of E2) to the medium also improved antrum formation. Concentration of E2 was higher in the medium of developmentally competent OGCs versus incompetent OGCs (8.5 vs. 3.5 ng/mL, P < 0.05). Fulvestrant (1 MUg/mL), a competitive inhibitor of E2, completely inhibited antrum formation of OGCs that were cultured in medium containing either E2 (0.1 MUg/mL) or androstenedione (0.1 MUg/mL); however, increasing E2 to 1 MUg/mL ameliorated the inhibitory effect. Conversely, in the case of early antral follicles, OGCs formed antrums without E2 supplementation. After E2 pretreatment, OGCs derived from PAFs formed antrums even when the OGCs were subsequently cultured in medium without E2. Furthermore, when OGCs derived from PAFs were cultured without E2 followed by an additional in vitro culture with E2, antrums were formed, albeit with the same period delay by the same pretreatment periods. In conclusion, E2 in the culture medium was indispensable for in vitro antrum formation of OGCs derived from PAFs; therefore, one of the roles of E2 is in the initiation of antrum formation. PMID- 23347747 TI - Alcohol-related dementia: an update of the evidence. AB - The characteristics of dementia relating to excessive alcohol use have received increased research interest in recent times. In this paper, the neuropathology, nosology, epidemiology, clinical features, and neuropsychology of alcohol-related dementia (ARD) and alcohol-induced persisting amnestic syndrome (Wernicke Korsakoff syndrome, or WKS) are reviewed. Neuropathological and imaging studies suggest that excessive and prolonged use of alcohol may lead to structural and functional damage that is permanent in nature; however, there is debate about the relative contributions of the direct toxic effect of alcohol (neurotoxicity hypothesis), and the impact of thiamine deficiency, to lasting damage. Investigation of alcohol-related cognitive impairment has been further complicated by differing definitions of patterns of alcohol use and associated lifestyle factors related to the abuse of alcohol. Present diagnostic systems identify two main syndromes of alcohol-related cognitive impairment: ARD and WKS. However, 'alcohol-related brain damage' is increasingly used as an umbrella term to encompass the heterogeneity of these disorders. It is unclear what level of drinking may pose a risk for the development of brain damage or, in fact, whether lower levels of alcohol may protect against other forms of dementia. Epidemiological studies suggest that individuals with ARD typically have a younger age of onset than those with other forms of dementia, are more likely to be male, and often are socially isolated. The cognitive profile of ARD appears to involve both cortical and subcortical pathology, and deficits are most frequently observed on tasks of visuospatial function as well as memory and higher-order (executive) tasks. The WKS appears more heterogeneous in nature than originally documented, and deficits on executive tasks commonly are reported in conjunction with characteristic memory deficits. Individuals with alcohol-related disorders have the potential to at least partially recover - both structurally and functionally - if abstinence is maintained. In this review, considerations in a clinical setting and recommendations for diagnosis and management are discussed. PMID- 23347748 TI - Management of patients with chronic cough using a clinical protocol: a prospective observational study. AB - BACKGROUND AND AIMS: Chronic cough is a common symptom the aetiology of which can be challenging to diagnose. Diagnostic protocols for chronic cough have required the use of specialist investigations which are not always easily available. We wanted to determine whether patients with chronic cough can be successfully managed using a clinical algorithm. METHODS: 112 consecutive patients with chronic cough were prospectively recruited into this study. They were assessed by history, physical examination, chest radiograph, spirometry and reversibility to nebulised salbutamol. A clinical diagnosis was made and the patient had an 8-week trial of appropriate therapy. Further therapeutic trials were carried out depending on response to treatment and the possible differential diagnoses. Investigations were carried out in cases of failed clinical trials and to exclude specific pathology. The "clinical arm" comprised patients managed on the basis of clinical assessment and without any investigations. The "investigative arm" comprised those who needed further investigations. RESULTS: 81 (72%) were managed in the clinical arm. Of these 74 (66%) were discharged following response to therapy. 31 (28%) patients were converted to the investigative arm after failure of diagnosis in the clinical protocol. The commonest causes of cough were gastroesophageal reflux, asthma and chronic rhinitis. 51 (45.5%) patients responded to therapy based on diagnosis at initial assessment while a further 23 (20.5%) patients responded to sequential clinical trials for the commonest causes of cough. Cough severity score improved by a mean of 3.6 points on a numeric response score (from 0-10, p < 0.0001). CONCLUSION: It is possible to manage a majority of chronic cough patients successfully using a protocol based on presenting symptoms and therapeutic trials for the common causes of cough. PMID- 23347751 TI - Intrapapillary mucinous tumor of the pancreas (with video). PMID- 23347749 TI - Characterization of the basal angiosperm Aristolochia fimbriata: a potential experimental system for genetic studies. AB - BACKGROUND: Previous studies in basal angiosperms have provided insight into the diversity within the angiosperm lineage and helped to polarize analyses of flowering plant evolution. However, there is still not an experimental system for genetic studies among basal angiosperms to facilitate comparative studies and functional investigation. It would be desirable to identify a basal angiosperm experimental system that possesses many of the features found in existing plant model systems (e.g., Arabidopsis and Oryza). RESULTS: We have considered all basal angiosperm families for general characteristics important for experimental systems, including availability to the scientific community, growth habit, and membership in a large basal angiosperm group that displays a wide spectrum of phenotypic diversity. Most basal angiosperms are woody or aquatic, thus are not well-suited for large scale cultivation, and were excluded. We further investigated members of Aristolochiaceae for ease of culture, life cycle, genome size, and chromosome number. We demonstrated self-compatibility for Aristolochia elegans and A. fimbriata, and transformation with a GFP reporter construct for Saruma henryi and A. fimbriata. Furthermore, A. fimbriata was easily cultivated with a life cycle of just three months, could be regenerated in a tissue culture system, and had one of the smallest genomes among basal angiosperms. An extensive multi-tissue EST dataset was produced for A. fimbriata that includes over 3.8 million 454 sequence reads. CONCLUSIONS: Aristolochia fimbriata has numerous features that facilitate genetic studies and is suggested as a potential model system for use with a wide variety of technologies. Emerging genetic and genomic tools for A. fimbriata and closely related species can aid the investigation of floral biology, developmental genetics, biochemical pathways important in plant insect interactions as well as human health, and various other features present in early angiosperms. PMID- 23347750 TI - Factors influencing attendance in a structured physical activity program for Aboriginal and Torres Strait Islander women in an urban setting: a mixed methods process evaluation. AB - BACKGROUND: Aboriginal and Torres Strait Islander women experience higher rates of obesity, chronic disease, and are less active than non-Indigenous Australian women. Lifestyle programs designed to increase physical activity and encourage healthy eating are needed to ameliorate this disparity. The aim of this study was to identify participants' perceived barriers and enablers to attend group exercise classes as part of a 12-week fitness program. METHODS: To understand the factors that influence attendance, a mixed method process evaluation was undertaken in which a quantitative measure of attendance in the group exercise classes was used to identify cases for further qualitative investigation. Aboriginal and/or Torres Strait Islander women aged 18 to 64 years were recruited to a research trial of a fitness program. The 12-week program included two 60 minute group exercise classes per week, and four nutrition education workshops. Semi-structured interviews were conducted at program completion. Participants were stratified by attendance, and interviews from the highest and lowest 25 percentiles analysed. Rigour was strengthened through use of multiple data analysts, member checking and prolonged engagement in the field. RESULTS: Analyses of the post-program interviews revealed that participants enrolled in the program primarily for the perceived health benefits and all (with one exception) found the program met their needs and expectations. The atmosphere of classes was positive and comfortable and they reported developing good relationships with their fellow participants and program staff. Low attendees described more barriers to attendance, such as illness and competing work and family obligations, and were more likely to report logistical issues, such as inconvenient venue or class times. CONCLUSIONS: Attendance to the 'Aboriginal and Torres Strait Islander Women's Fitness Program' was primarily influenced by the participant's personal health, logistics and competing obligations. Low attendees reported more barriers during the 12-week period and identified fewer enabling factors than high attendees. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000224022. PMID- 23347752 TI - Randomized controlled trial of mibampator for behavioral and psychological symptoms of dementia: comments on the trial and thoughts for future studies. PMID- 23347753 TI - Upper limb cumulative trauma disorders for the orthopaedic surgeon. AB - Work-related musculoskeletal disorders (WRMSDs) of the upper limb have become a serious concern in many countries and have been steadily progressing for several decades. The cause of WRMSDs is assumed to be the direct consequence of repetitiveness, extreme postures, and intensive efforts in a problematic psychosocial environment. Therapy should therefore associate the occupational physician and the regulatory bodies. It may be necessary to modify the individual workstation and to reorganize the company. Such upper limb pathologies may be surgically treated but the results are often delayed and poorer when compared to the general population. PMID- 23347754 TI - Idiopathic congenital clubfoot: Initial treatment. AB - Clubfoot (talipes equinovarus) is a three-dimensional deformity of unknown etiology. Treatment aims at correction to obtain a functional, plantigrade pain free foot. The "French" functional method involves specialized physiotherapists. Daily manipulation is associated to immobilization by adhesive bandages and pads. There are basically three approaches: the Saint-Vincent-de-Paul, the Robert-Debre and the Montpellier method. In the Ponseti method, on the other hand, the reduction phase using weekly casts usually ends with percutaneous tenotomy of the Achilles tendon to correct the equinus. Twenty-four hour then nighttime splinting in abduction is then maintained for a period of 3 to 4 years. Recurrence, mainly due to non-compliance with splinting, is usually managed by cast and/or anterior tibialis transfer. The good long-term results, with tolerance of some anatomical imperfections, in contrast with the poor results of extensive surgical release, have led to a change in clubfoot management, in favor of such minimally invasive attitudes. The functional and the Ponseti methods reported similar medium term results, but on scores that were not strictly comparable. A comparative clinical and 3D gait analysis with short follow-up found no real benefit with the increasingly frequent association of Achilles lengthening to the functional method (95% to 100% initial correction). Some authors actually suggest combining the functional and Ponseti techniques. The Ponseti method seems to have a slight advantage in severe clubfoot; if it is not properly performed, however, the risk of failure or recurrence may be greater. "Health economics" may prove decisive in the choice of therapy after cost-benefit study of each of these treatments. PMID- 23347755 TI - Arthroscopic management of tibial plateau fractures: surgical technique. AB - Tibial plateau fractures are serious articular fractures that are challenging to treat. Arthroscopy-assisted percutaneous fixation is the treatment of choice in Schatzker types 1, 2, 3, and 4 fractures, as it ensures optimal reduction and stable fixation consistent with early mobilisation. The most reliable fixation method seems to be percutaneous cannulated screw fixation, which is less invasive than open plate fixation. In complex proximal tibial fractures, arthroscopy may allow an evaluation of articular fracture reduction, thereby obviating the need for extensive arthrotomy. Complementary stable fixation is crucial and should allow early mobilisation to reap the benefits of the arthroscopic assistance. This article aims to review the technical points that are useful to the successful video-assisted management of tibial plateau fractures. PMID- 23347756 TI - Representations of influenza and influenza-like illness in the community--a qualitative study. AB - BACKGROUND: There is little information regarding lay-people's representations of influenza and influenza-like illness in their day-to-day lives. An insight into these views may aid our understanding of community attitudes regarding official recommendations for its prevention. METHODS: This was a qualitative research. Semi-structured face-to-face interviews were conducted with 40 French participants from the community, and from five different locations. Questions elicited the participants' representations of onset of flu and influenza-like illness, as well as their views on what can/should be done to deal with symptoms and their personal experience with flu and flu-like symptoms. RESULTS: Thematic content analyses allowed us to identify five main themes: the presence of a clear continuum between influenza-like illness and flu; a description of flu as a very contagious disease; flu as being benign, except in "frail people", which the respondents never considered themselves to be; interruption of daily activities, which could be considered pathognomonic for influenza for most subjects; self medication as the main current practice, and requests for healthcare mainly to confirm an auto-diagnosis. CONCLUSIONS: There was a large homogeneity in the representation of flu. There was also a gap between people's representations (i.e., a continuum from having a "cold" to having "influenza") and scientific knowledge (i.e., a distinction between "true" influenza and influenza-like illnesses based on the existence of a confirmatory virological diagnosis). This gap raises issues for current campaigns for flu prevention, as these may not be congruent with the representation of flu being responsible for interrupting daily activities while also being seen as a non-severe disease, as well as the perception that flu is only a risk to "frail people" though no participants considered themselves to be "frail". PMID- 23347757 TI - Does the local food environment around schools affect diet? Longitudinal associations in adolescents attending secondary schools in East London. AB - BACKGROUND: The local retail food environment around schools may act as a potential risk factor for adolescent diet. However, international research utilising cross-sectional designs to investigate associations between retail food outlet proximity to schools and diet provides equivocal support for an effect. In this study we employ longitudinal perspectives in order to answer the following two questions. First, how has the local retail food environment around secondary schools changed over time and second, is this change associated with change in diet of students at these schools? METHODS: The locations of retail food outlets and schools in 2001 and 2005 were geo-coded in three London boroughs. Network analysis in a Geographic Information System (GIS) ascertained the number, minimum and median distances to food outlets within 400 m and 800 m of the school location. Outcome measures were 'healthy' and 'unhealthy' diet scores derived from adolescent self-reported data in the Research with East London Adolescents: Community Health Survey (RELACHS). Adjusted associations between distance from school to food retail outlets, counts of outlets near schools and diet scores were assessed using longitudinal (2001-2005 n=757) approaches. RESULTS: Between 2001 and 2005 the number of takeaways and grocers/convenience stores within 400 m of schools increased, with many more grocers reported within 800 m of schools in 2005 (p< 0.001). Longitudinal analyses showed a decrease of the mean healthy ( 1.12, se 0.12) and unhealthy (-0.48, se 0.16) diet scores. There were significant positive relationships between the distances travelled to grocers and healthy diet scores though effects were very small (0.003, 95%CI 0.001 - 0.006). Significant negative relationships between proximity to takeaways and unhealthy diet scores also resulted in small parameter estimates. CONCLUSIONS: The results provide some evidence that the local food environment around secondary schools may influence adolescent diet, though effects were small. Further research on adolescents' food purchasing habits with larger samples in varied geographic regions is required to identify robust relationships between proximity and diet, as small numbers, because of confounding, may dilute effect food environment effects. Data on individual foods purchased in all shop formats may clarify the frequent, overly simple classification of grocers as 'healthy'. PMID- 23347758 TI - Effect of aqueous extracts of Baccharis trimera on development and hatching of Rhipicephalus microplus (Acaridae) eggs. AB - This study evaluated the effects of aqueous extracts of Baccharis trimera (Less.) DC (Asteraceae), colloquially known as carqueja, on egg production, and hatching rate of larvae of Rhipicephalus microplus. Plant samples were collected in Montes Claros, north of Minas Gerais, Brazil. Adult female ticks were distributed into 24 homogeneous groups of 10. The in vitro test was performed by immersing each group in 10 ml solutions of aqueous extracts at 50, 100, 150, or 200mg of fresh leaves ml(-1). These concentrations were compared with distilled water as negative control and a commercial product as positive control and the tests were repeated four times. The carqueja extract at concentrations of 150 and 200mg of fresh leaves ml(-1) showed 100% efficacy in inhibiting egg hatching and therefore could have potential as an acaricide. PMID- 23347759 TI - Effect of new ethyl and methyl carbamates on biological parameters and reproduction of the cattle tick Rhipicephalus microplus. AB - The effect of carbamates on engorged female Rhipicephalus microplus ticks and larvae was evaluated using the adult immersion test (AIT) and the larval packet test (LPT), respectively. Seventeen synthetic carbamates different from current commercial acaricides were synthesised at the National Autonomous University of Mexico. None of the carbamates had an effect on the percentage of females laying eggs. Six of the compounds inhibited egg laying up to 65.4% and inhibited egg hatching by up to 100% (p<0.05). Compared to untreated females, eggs produced by treated females had a dark, dry, opaque appearance and were less adherent. Carbamates LQM 934 and LQM 938 had an effect on larval mortality (p<0.05). Carbamate LQM 934 showed lethal concentrations (LC) of LC90=0.76% and LC99=0.87%, while LQM 938 showed concentrations of LC90=0.267% and LC99=0.305%. The compounds were distributed into three classes of acaricidal activity using the AIT or the LPT. These three classes were as follows: (1) compounds having no apparent effect; (2) compounds that inhibit egg laying and embryo development or (3) compounds that exhibit acaricidal activity to larval ticks. PMID- 23347760 TI - Campanulotes compar (Burmeister, 1838) (Phthiraptera: Ischnocera) in chickens (Gallus gallus domesticus) from Rio Grande do Norte State, Brazil. The reemergence of an ectoparasite? AB - The importance of ectoparasites in the transmission of pathogens, as well as the variability of species from one region to another, motivated this notification of the ectoparasite lice Campanulotes compar in range chickens (Gallus gallus domesticus L.) reared in an extensive system in the city of Apodi, Rio Grande do Norte state, in the Northeast region of Brazil. The examined birds were infested with ten males and six females of C. compar. Thus, C. compar is recorded as parasitizing chickens in the state of Rio Grande do Norte after 77 years from its unique citation in the Southeast region of Brazil. We further discuss the possible risks of this finding. PMID- 23347761 TI - Improving recovery-Learning from patients' experiences after injury: a qualitative study. AB - OBJECTIVES: To explore experiences of patients after injury and identify implications for clinical care and support within the hospital setting and primary care. DESIGN: Semi-structured telephone administered qualitative interviews with purposive sampling and thematic qualitative analysis. PARTICIPANTS: Patients who have experienced an unintentional injury and attended hospital. SETTING: Bristol, Surrey and Swansea. RESULTS: Key issues that emerged were: most patients reported mixed experiences of hospital care but some described the delivery of care as depersonalising; the need for clinicians to provide adequate, timely and realistic information to patients about their injury and treatment to inform their expectations of recovery; the impact of pain at the time of the injury and for an extended period afterwards; the experience of injury on patients' emotional state with possible implications for longer term mental health issues; the pivotal role of physiotherapy care in providing practical and individualised strategies for recovery; and the importance of social support for recovery. CONCLUSIONS: Trauma patients' recovery needs to be supported by information protocols. The social circumstances of patients need to be considered at the point of discharge and during recovery. There is a need to identify people who may be experiencing mental health issues for timely referral to assessment services and appropriate care. Signposting to support groups may also be helpful for those with life changing injuries. Improved pain management would help alleviate discomfort and stress. Physiotherapy has a key role to play in supporting patients in recovery. PMID- 23347762 TI - Predicting work-related disability and medical cost outcomes: a comparison of injury severity scoring methods. AB - INTRODUCTION: Acute work-related trauma is a leading cause of death and disability among U.S. workers. Occupational health services researchers have described the pressing need to identify valid injury severity measures for purposes such as case-mix adjustment and the construction of appropriate comparison groups in programme evaluation, intervention, quality improvement, and outcome studies. The objective of this study was to compare the performance of several injury severity scores and scoring methods in the context of predicting work-related disability and medical cost outcomes. METHODS: Washington State Trauma Registry (WTR) records for injuries treated from 1998 to 2008 were linked with workers' compensation claims. Several Abbreviated Injury Scale (AIS)-based injury severity measures (ISS, New ISS, maximum AIS) were estimated directly from ICD-9-CM codes using two software packages: (1) ICDMAP-90, and (2) Stata's user written ICDPIC programme (ICDPIC). ICDMAP-90 and ICDPIC scores were compared with existing WTR scores using the Akaike Information Criterion, amount of variance explained, and estimated effects on outcomes. Competing risks survival analysis was used to evaluate work disability outcomes. Adjusted total medical costs were modelled using linear regression. RESULTS: The linked sample contained 6052 work related injury events. There was substantial agreement between WTR scores and those estimated by ICDMAP-90 (kappa=0.73), and between WTR scores and those estimated by ICDPIC (kappa=0.68). Work disability and medical costs increased monotonically with injury severity, and injury severity was a significant predictor of work disability and medical cost outcomes in all models. WTR and ICDMAP-90 scores performed better with regard to predicting outcomes than did ICDPIC scores, but effect estimates were similar. Of the three severity measures, maxAIS was usually weakest, except when predicting total permanent disability. CONCLUSIONS: Injury severity was significantly associated with work disability and medical cost outcomes for work-related injuries. Injury severity can be estimated using either ICDMAP-90 or ICDPIC when ICD-9-CM codes are available. We observed little practical difference between severity measures or scoring methods. This study demonstrated that using existing software to estimate injury severity may be useful to enhance occupational injury surveillance and research. PMID- 23347763 TI - Ilizarov treatment of scaphoid nonunion. AB - INTRODUCTION: This is single centre retrospective review of a consecutive series of patients with scaphoid nonunion (SNU) treated using the Ilizarov technique without bone graft. Fifteen of the original 18 patients were available for clinical and radiological examination at a minimum follow-up of 5 years (range 5 10 years). An evaluation was made of the late functional results, satisfaction scores, residual symptoms, grip strength and the presence of radiocarpal and scaphoid degenerative changes. METHODS: The series consisted of 15 patients; 14 males; 1 female, with a mean SNU duration of 15.7 months, and a mean age of 23.6 years. Patients with carpal instability, humpback deformity, carpal collapse, avascular necrosis or marked degenerative change, were excluded from this treatment method. Following frame application the treatment consisted of three stages: distraction, compression and immobilisation. The technique is detailed herein. RESULTS: Radiographic (CT) and clinical bony union was achieved in all 15 patients after a mean of 88 days (70-130 days). Mean modified Mayo wrist scores initially improved from 21 preoperatively to 86 at previous review, and were 96 at a mean follow-up of 81 months (62-120 months), with excellent results in 10, and good results seen in 5 patients. At latest review the mean grip strengths had returned to 96% of the uninjured hand, and 7 patients had regained full strength; mean wrist flexion/extension arc of motion had also continued to improve to 136 degrees from 131 degrees . All patients returned to their pre-injury occupations and levels of activity at a mean of 117 days. Three patients suffered superficial K-wire infections, which resolved with oral antibiotics. One patient continues to suffer intermittent mild aching in the wrist. No patient suffered loss of scaphoid height, humpback deformity, DISI instability or collapse of the regenerate bone. CONCLUSION: In these selected patients this technique safely achieved bony union without the need to open the SNU site and without the need for bone graft. These patients also had the capacity to continually improve their wrist function beyond 3 years following their treatment. PMID- 23347764 TI - An innovative technique of rear entry creation for retrograde humeral nailing: how to avoid iatrogenic comminution. AB - BACKGROUND: Antegrade and retrograde nails are widely used for intramedullary fixation of humeral shaft fractures. Creating the rear entry is the crucial step for retrograde nailing. The common manual technique is associated with considerable risks of additional iatrogenic comminution of the distal humerus. DESCRIPTION OF THE TECHNIQUE: A specific device for the creation of a rear entry hole has been developed as part of the instruments for humeral shaft nailing (Targon H) and made commercially available (BBraun Aesculap, Germany). After standard triceps-splitting approach, a guide instrument is firmly applied to the distal humerus with one screw. The screw hole is later used for distal interlocking. The oval rear entry hole is then performed by frontal cutter along the guide. PATIENTS AND METHODS: We have been performing a retrospective evaluation of all unreamed humeral nailings (Targon H) since 2000. Operation time, use of the guide instrument and intra-operative problems were analysed. X rays were checked for iatrogenic humeral comminution directly after the operation and after physiotherapy. Cases of infection and nonunion were noted. RESULTS: We identified 87 cases of intramedullary fracture fixation with an interlocking nail (46 antegrade, 41 retrograde). In all retrograde cases a guide instrument and an access reamer were used for the creation of an entry hole. No iatrogenic comminutions were observed during the operation or on postoperative X-rays. Active postoperative exercises were generally allowed in every patient. Mean operative time was shorter for retrograde than for antegrade nailing (90 min vs. 108 min; p = 0.012). We saw two nonunions (2%) and no infections. CONCLUSIONS: Use of access reamer and guide instrument is a safe and reproducible way of creating a rear entry hole for retrograde humeral nailing. The risk of additional comminution seems to be eliminated. PMID- 23347765 TI - Rehabilitation of flexor and extensor tendon injuries in the hand: current updates. AB - In recent years, a significant amount of research in the field of tendon injury in the hand has contributed to advances in both surgical and rehabilitation techniques. The introduction of early motion has improved tendon healing, reduced complications, and enhanced final outcomes. There is overwhelming evidence to show that carefully devised rehabilitation programs are critical to achieving favourable outcomes. Whatever the type, or level, of flexor or extensor injury, the ultimate goal of both the surgeon and therapist is to protect the repair, modify peritendinous adhesions, promote optimal tendon excursion and preserve joint motion. Early tendon motion regimens are initiated at surgery or within 5 days post repair. Intra-operative information from the surgeon to the therapist is vital to the choice of splint protected position to reduce repair rupture/gap forces, and to commencement of active, or splint controlled, motion for tendon excursion. Decisions should align with the phases of healing, the clinician's observations, frequent range of motion measurements and patient input. Clinical concepts pertinent to early motion rehabilitation decisions are presented by zone of injury for both flexor and extensor tendons during the early phases of healing. PMID- 23347766 TI - Tracheostomy in craniectomised survivors after traumatic brain injury: a cross sectional analytical study. AB - BACKGROUND: Decompressive craniectomy (DC) is a life-saving measure for traumatic brain injury (TBI). However, survivors may remain in a vegetative or minimally conscious state and require tracheostomy to facilitate airway management. In this cross-sectional analytical study, we investigated the predictors for tracheostomy requirement and influence of tracheostomy timing on outcomes in craniectomised survivors after TBI. METHODS: We enrolled 160 patients undergoing DC and surviving >7 days after TBI in this 3-year retrospective study. The patients were subdivided into 2 groups based on whether tracheostomy was (N=38) or was not (N=122) performed. We identified intergroup differences in early clinical parameters. Multivariable logistic regression was used to adjust for independent predictors of the need for tracheostomy. Early tracheostomy was defined as the performance of the procedure within the first 10 days after DC. Intensive care unit (ICU) stay, hospital stay, mortality, and Glasgow outcome scale (GOS) were analysed according to the timing of the tracheostomy procedure. RESULTS: After TBI, 24% of craniectomised survivors required tracheostomy. In the multivariate logistic regression mode, the significant factors related to the need for tracheostomy were age (odds ratio=1.041; p=0.002), the Glasgow coma score (GCS) at admission (odds ratio=0.733; p=0.005), and normal status of basal cisterns (odds ratio=0.000; p=0.008). The ICU stay was shorter for patients with early tracheostomy than for those undergoing late tracheostomy (p=0.004). The timing of tracheostomy had no influence on the hospital stay, mortality, or GOS. CONCLUSION: Age and admission GCS were independent predictors of the need for tracheostomy in craniectomised survivors after TBI. If tracheostomy is necessary, an earlier procedure may assist in patient care. PMID- 23347767 TI - Secondary repair of flexor tendon injuries. AB - Tendon adhesions or even secondary ruptures causing severe hand functional impairment still represent a frequent complication after repair of flexor tendon injuries. Secondary treatment of these problems includes tenolysis, one or two stages flexor tendons reconstruction by grafts or even the use of tendon prosthesis. The mechanism and severity of injury, the status of the surrounding tissues and injured finger, the presence of associated lesions, the age of the patient, post-operative management, patient motivation and the surgeon's skill, may all have implications in the final outcome of the tendon reconstruction. A correct evaluation of the problem by means of classifications such as the one described by Boyes, may help the surgeon in choosing the appropriate technique. PMID- 23347768 TI - Influence of visual feedback sampling on obstacle crossing behavior in people with Parkinson's disease. AB - The purpose of the current study was to investigate the role of visual information on gait control in people with Parkinson's disease as they crossed over obstacles. Twelve healthy individuals, and 12 patients with mild to moderate Parkinson's disease, walked at their preferred speeds along a walkway and stepped over obstacles of varying heights (ankle height or half-knee height), under three visual sampling conditions: dynamic (normal lighting), static (static visual samples, similar to stroboscopic lighting), and voluntary visual sampling. Subjects wore liquid crystal glasses for visual manipulation. In the static visual sampling condition only, the patients with Parkinson's disease made contact with the obstacle more often than did the control subjects. In the successful trials, the patients increased their crossing step width in the static visual sampling condition as compared to the dynamic and voluntary visual sampling conditions; the control group maintained the same step width for all visual sampling conditions. The patients showed lower horizontal mean velocity values during obstacle crossing than did the controls. The patients with Parkinson's disease were more dependent on optic flow information for successful task and postural stability than were the control subjects. Bradykinesia influenced obstacle crossing in the patients with Parkinson's disease. PMID- 23347769 TI - Is basic self-disturbance in ultra-high risk for psychosis ('prodromal') patients associated with borderline personality pathology? AB - AIM: Research in the phenomenological tradition suggests that the schizophrenia spectrum is characterized by disturbance of the 'basic' self, whereas borderline personality disorder involves disturbance of the 'narrative' self. The current study investigated this proposal in an ultra-high risk for psychosis sample. METHODS: The sample consisted of 42 ultra-high-risk participants with a mean age of 19.22 years. Basic self-disturbance was measured using the Examination of Anomalous Self-Experience. Borderline personality pathology was measured using the borderline personality disorder items from the structured clinical interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) Axis II Personality Questionnaire. RESULTS: No correlation was found between the measures of basic self-disturbance and borderline personality pathology. CONCLUSIONS: The finding is consistent with the proposal that different (although not mutually exclusive) types of self-disturbance characterize the schizophrenia spectrum and borderline personality disorder. Further research should further examine the question of basic self-disturbance in patients with established borderline personality disorder. PMID- 23347770 TI - Phylogenetic and ecologic perspectives of a monkeypox outbreak, southern Sudan, 2005. AB - Identification of human monkeypox cases during 2005 in southern Sudan (now South Sudan) raised several questions about the natural history of monkeypox virus (MPXV) in Africa. The outbreak area, characterized by seasonally dry riverine grasslands, is not identified as environmentally suitable for MPXV transmission. We examined possible origins of this outbreak by performing phylogenetic analysis of genome sequences of MPXV isolates from the outbreak in Sudan and from differing localities. We also compared the environmental suitability of study localities for monkeypox transmission. Phylogenetically, the viruses isolated from Sudan outbreak specimens belong to a clade identified in the Congo Basin. This finding, added to the political instability of the area during the time of the outbreak, supports the hypothesis of importation by infected animals or humans entering Sudan from the Congo Basin, and person-to-person transmission of virus, rather than transmission of indigenous virus from infected animals to humans. PMID- 23347771 TI - Initial staging of squamous cell carcinoma of the oral cavity, larynx and pharynx (excluding nasopharynx). Part I: Locoregional extension assessment: 2012 SFORL guidelines. AB - OBJECTIVES: To set out good practice guidelines for locoregional extension assessment of squamous cell carcinoma of the head and neck (excluding nasopharynx, nasal cavities and sinuses). MATERIALS AND METHODS: A critical multidisciplinary review of the literature on locoregional extension assessment of squamous cell carcinoma of the head and neck was conducted, applying levels of evidence in line with the French health authority's (HAS) literature analysis guide of January 2000. CONCLUSION: Based on the levels of evidence of the selected articles and on work-group consensus, graded guidelines are set out for clinical, endoscopic and imaging locoregional extension assessment of head and neck cancer. PMID- 23347772 TI - Translation and validation of Berlin questionnaire in primary health care in Greece. AB - BACKGROUND: The aim of our study was to validate a Greek translation of the Berlin Questionnaire (BQ) for obstructive sleep apnoea syndrome (OSAS) and to explore whether this screening questionnaire could be used to help identify primary care patients at greater risk of having OSAS. METHODS: We recruited 189 patients visiting a primary health care setting on the island of Crete, Greece. They all completed the Greek Version of the BQ. Patients were then referred to a Sleep Disorders Unit for evaluation of suspected sleep-disordered breathing. RESULTS: A PSG study was performed in 129 of the 189 subjects (68.3%). BQ identified 74.4% (n = 96) of the patients as high-risk for OSAS and the remaining 25.6% (n = 33) as low-risk. The sensitivity and specificity of BQ for OSAS diagnosis were 76% and 40%, respectively, for an apnoea-hypopnoea index (AHI) >=5 per hour but <15 per hour, 84% and 61% for an AHI >=15 per hour but <=30 per hour, and 79% and 39% for an AHI >30 per hour. CONCLUSIONS: In conclusion, the Greek Version of the BQ is a useful instrument for identifying patients at risk for OSAS in primary health care in Greece. The findings of our study confirm that such screening tools should be used by primary care clinicians for OSAS prediction. PMID- 23347773 TI - In vivo 3D kinematics of the cervical spine segments during pre-manipulative positioning at the C4/C5 level. AB - Segmental range of motion (ROM) during high-velocity manipulative spinal treatment is generally considered an important factor for the risk of adverse side effects, especially in the cervical spine region. Among the many techniques reported, the so-called multiple-component technique (MCT) is increasingly recommended. Such a technique is assumed to induce a relatively low three dimensional (3D) segmental ROM compared with other techniques. The aims of our study are to quantify the 3D segmental ROM and to determine the pattern of motion between cervical vertebrae during the pre-manipulative position at the C4-C5 level. Ten healthy volunteers participated in this study. Two CT scans were conducted: one in a neutral position and the other in the pre-manipulative positioning. The manipulation using MCT was carried out by a skilled practitioner. During positioning, the head was rotated to the left and bent laterally to the right, and the upper cervical spine was rotated to the left and bent laterally to the right. In contrast, the lower cervical spine underwent right rotation and was bent laterally to the right. Segmental ROM was lower than the values obtained during active physiological rotation (P < 0.05). This study provides new insight into the 3D kinematics of the cervical spine during manipulation. An unexpected mechanism of counter-rotation was identified at the lower cervical levels and could represent a valuable and convenient way for precisely focussing on the level for manipulation. PMID- 23347774 TI - Inhaled corticosteroid use is associated with increased circulating T regulatory cells in children with asthma. AB - BACKGROUND: T regulatory (Treg) cells are important in balancing immune responses and dysregulation of Treg cells has been implicated in the pathogenesis of multiple disease states including asthma. In this study, our primary aim was to determine Treg cell frequency in the peripheral blood of children with and without asthma. The secondary aim was to explore the association between Treg cell frequency with allergen sensitization, disease severity and medication use. METHODS: Peripheral blood mononuclear cells from healthy control subjects (N = 93) and asthmatic children of varying disease severity (N = 66) were characterized by multi-parameter flow cytometry. RESULTS: Our findings demonstrate that children with asthma had a significantly increased frequency of Treg cells compared to children without asthma. Using a multivariate model, increased Treg cell frequency in children with asthma was most directly associated with inhaled corticosteroid use, and not asthma severity, allergic sensitization, or atopic status of the asthma. CONCLUSION: We conclude that low dose, local airway administration of corticosteroids is sufficient to impact the frequency of Treg cells in the peripheral blood. These data highlight the importance of considering medication exposure when studying Treg cells and suggest inhaled corticosteroid use in asthmatics may improve disease control through increased Treg cell frequency. PMID- 23347775 TI - Atypical florid vascular proliferation in appendix: a diagnostic dilemma. AB - Vascular abnormality of the intestine is rare, except angiodysplasia. We report on an unusual case of atypical florid vascular proliferations of the appendix. A 41-year old male presented with melena. Adhesioned blood clots in the appendiceal orifice were observed by colonoscopy. He underwent laparoscopic appendectomy. Microscopically, a tiny exophytic polypoid mass was observed. The mass showed pyogenic granuloma-like features in the superficial portion and infiltrative florid vascular proliferations in the deeper portion. Endothelial cells showed minimal nuclear atypia, and mitotic figures were observed infrequently and showed positivity for CD31 and CD34 and negativity for HHV-8. Differential diagnoses include from benign vascular tumor to angiosarcoma or Kaposi's sarcoma, but this lesion does not fit the description of any defined vascular entity. We diagnosed atypical florid vascular proliferations and the patient has been well during the five-month postoperative follow-up. VIRTUAL SLIDE: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1386921325843104. PMID- 23347776 TI - Cardiac tamponade as an initial manifestation of systemic lupus erythematosus in a child. AB - Cardiac involvement is a rare initial presentation of systemic lupus erythematosus. An 11-year-old girl was described to have massive haemorrhagic pericardial effusion and cardiac tamponade, which was later diagnosed as systemic lupus erythematosus. Therefore, in children presenting with cardiac tamponade, systemic lupus erythematosus should be considered as one of the differential diagnoses, as morbidity and mortality associated with cardiac tamponade can be dramatically reduced with early diagnosis and use of steroids. PMID- 23347777 TI - Contemporary management of perianal conditions in febrile neutropenic patients. AB - INTRODUCTION: The aim of this study was to examine the type and frequency of perianal conditions in a contemporary series of febrile neutropenic patients and to examine the risk factors, management options and outcome of septic perianal conditions. METHODS: Medical records of all adult febrile neutropenic patients (933 patients) who were admitted during the period from January, 2009 to December 2011 were retrospectively review. All patients with perianal complaints or conditions were included. The clinical features, management and outcome of septic conditions were recorded. RESULTS: Of all the reviewed charts, 101 (10.8%) had perianal complaints or conditions. Most of them were non septic (74.3%), like piles and fissures, and were treated conservatively. In 26 patients the diagnosis was a septic condition: abscess (12 patients), fistula (4), inflammation (9) and necrotizing fasciitis (1). Septic conditions were more commonly found in males younger than 40 years. Surgery was done in 13 patients to drain a collection and in 2 patients to debride necrotic tissue. Most patients who had no collection had conservative management. There was 1 fatality only (3.8%) in those 26 patients. CONCLUSION: Most of the perianal conditions in febrile neutropenic patients are non septic and are managed conservatively. Septic perianal conditions are not associated with a poor prognosis as in the past. Surgical drainage should be reserved to conditions where there is a collection; otherwise patients should be managed conservatively but with close monitoring. PMID- 23347778 TI - Oncological outcome of patients with deeply located soft tissue sarcoma of the pelvis: a follow up study at minimum 5 years after diagnosis. AB - AIMS: The treatment of pelvic soft tissue sarcomas (STS) presents one of the most challenging problems in musculoskeletal oncology because of the complex anatomy of the pelvis, late diagnosis and large tumor size. Our study was designed to determine the outcome and prognostic factors for survival and local recurrence in patients with pelvic STS located deep to the fascia and deemed suitable for curative surgical treatment. PATIENTS AND METHODS: Ninety consecutive pelvic STS patients with at least 5-year possible follow-up from diagnosis were studied. Mean age at diagnosis was 54 years. Mean follow-up and tumor size were 69 months and 13 cm, respectively. Histological grades were grade 3 in 51, grade 2 in 22 and grade 1 in 17 patients. Tumor locations were extra-pelvic or outside pelvic brim (n=67), intra-pelvic or within pelvic brim (n=10), and combined or involving both outside and within pelvic brim (n=13). RESULT: Surgical treatment was excision in 84 patients and hindquarter amputation in 6 patients. In 84 patients who underwent excision, surgical margin was wide in 21 patients, marginal in 33, and intralesional in 30. Radiotherapy was used for all high grade tumors. Disease specific survival was 53.3% at 5 years. Local recurrence occurred in 23%. Development of local recurrence was related to surgical margin (p=0.03). Local recurrence, tumor histological grade and metastasis at diagnosis independently influenced disease-specific survival (p=0.0008, p<0.0001, p=0.02, respectively). CONCLUSION: The patients with high grade tumors and positive surgical margins represent a particular group with high risk of local recurrence even with radiotherapy. PMID- 23347779 TI - Lots of autoantibodies equal lupus? AB - Autoantibodies may be found years before an autoimmune disease becomes clinically apparent. For systemic lupus erythematosus (SLE), those to RNA-binding proteins, to phospholipids, and to double-stranded DNA, in particular, have been found in sera of SLE patients years before the diagnosis was made. New data now show in an unbiased way that, in patients with early SLE, no single antibody class or specificity is associated with progression to SLE. Rather, an increasing number of autoantibody specificities, such as to thyroid antigens, was observed in patients progressing. This points to more generalized B cell autoreactivity during progression to SLE, underlying lupus disease manifestations. PMID- 23347780 TI - Development of a new, fast, user friendly, ray tracing program "CSIM" for the simulation of parallelhole collimators. AB - We have developed a fast, user friendly, ray-tracing program, "CSIM" for low energy gamma rays (up to ~200keV) to simulate the performance characteristics of parallelhole collimators. We have used a ray-tracing approach to find the sensitivity and resolution of the parallelhole collimator by including the penetration of photons through the collimator due to the finite attenuation of the collimator material. "CSIM" can calculate the sensitivity of the collimator, the geometric and penetrating photon ratios, and the 1D and 2D point source response functions (PSF) with the statistical uncertainty for different hole shapes (e.g. square, hexagonal, and cylindrical). We have used "CSIM" to simulate the collimator of the YAP-(S)PETII small animal scanner. We present the analysis of the YAP-(S)PETII scanner round-hole parallel collimator designed for nuclear medicine imaging at 140keV. For this aim, different designs have been considered for a variety of source-collimator distances (b=5, 10, 15, 20cm). Resolution and sensitivity characteristics have been plotted as a function of the collimator thickness and the diameter of the hole. For each value of the source-collimator distance, and for each collimator thickness investigated, the trade-off between sensitivity and spatial resolution has been given as a series of characteristic curves. Then, we compare our simulated resolution and sensitivity results to the analytically calculated ones and found that the analytically calculated results for the YAP-(S)PETII scanner collimator are not far away the results predicted by CSIM and also with the experimentally measured resolution values. PMID- 23347781 TI - Clinical features and phylogenetic analysis of Coxsackievirus A9 in Northern Taiwan in 2011. AB - BACKGROUND: Coxsackievirus A9 (CA9) was one of the most prevalent serotype of enteroviral infections in Taiwan in 2011. After several patient series were reported in the 1960s and 1970s, few studies have focused on the clinical manifestations of CA9 infections. Our study explores and deepens the current understanding of CA9. METHODS: We analyzed the clinical presentations of 100 culture-proven CA9-infected patients in 2011 by reviewing their medical records and depicted the CA9 phylogenetic tree. RESULTS: Of the 100 patients with culture proven CA9 infections, the mean (SD) age was 4.6 (3.4) years and the male to female ratio was 1.9. For clinical manifestations, 96 patients (96%) had fever and the mean (SD) duration of fever was 5.9 (3.4) days. Sixty one patients (61%) developed a skin rash, and the predominant pattern was a generalized non-itchy maculopapular rash without vesicular changes. While most patients showed injected throat, oral ulcers were found in only 19 cases (19%), among whom, 6 were diagnosed as herpangina. Complicated cases included: aseptic meningitis (n=8), bronchopneumonia (n=6), acute cerebellitis (n=1), and polio-like syndrome (n=1). Phylogenetic analysis for current CA9 strains is closest to the CA9 isolate 27-YN 2008 from the border area of mainland China and Myanmar. CONCLUSIONS: The most common feature of CA9 during the 2011 epidemic in Taiwan is generalized febrile exanthema rather than herpangina or hand, foot, and mouth disease. Given that prolonged fever and some complications are possible, caution should be advised in assessing patients as well as in predicting the clinical course. PMID- 23347782 TI - Giant congenital left atrial appendage aneurysm. PMID- 23347783 TI - Methodologic problems in the assessment of bleed scores. PMID- 23347784 TI - The analysis of bleeding risk-prediction scores should include all major bleeds. PMID- 23347785 TI - Reply: To PMID 22858389. PMID- 23347786 TI - Straining with the ventricular assist device and right ventricular function. PMID- 23347787 TI - Reply: To PMID 22858287. PMID- 23347788 TI - Hepatocellular carcinoma metastatic to the right ventricle. PMID- 23347789 TI - The durability of phosphoric acid promoted bioglass-dentin interaction layer. AB - OBJECTIVES: Phosphoric acid-Bioglass 45S5 paste can create an interaction layer formed of calcium-phosphate crystals on the dentin surface. In this study, the efficiency of decreasing the dentin permeability exerted by the interaction layer formed between bioglass and dentin was compared to a resin-containing oxalate desensitizing agent (MS Coat One) and a resin-free oxalate desensitizing agent (Super Seal). METHODS: Dentin permeability was measured before/after a brushing abrasion challenge, followed by examining the top and the fractured dentin surfaces with a field emission scanning electron microscope. Moreover, the chemical nature of the compounds formed on top of the dentin surface was examined using the field emission scanning electron microscope (FE-SEM) equipped with an energy-dispersive X-ray spectroscope (EDS), and the crystalline structures of the dentinal surfaces were examined by X-ray diffraction (XRD). RESULTS: The results showed that application of 45S5 bioglass paste to dentin was able to occlude patent dentinal tubule orifices with a layer of calcium-phosphate crystals, while the oxalate containing agents were able to form small crystals which were found in dentinal tubule orifices and scattered along the superficial parts of the dentinal tubule lumen. The brushing-abrasion challenge significantly increased the permeability of dentin treated by Super Seal and MS Coat One, while these challenges had no significant effect on the dentin permeability of specimens treated with 45S5 bioglass paste. SIGNIFICANCE: The new technique provided better durability than two products available on the market. Moreover, our previous research showed the biocompatibility of using this technique on dental pulp cells, suggesting that this technique can aid in treating dentin hypersensitivity cases. PMID- 23347790 TI - Rift Valley fever, Sudan, 2007 and 2010. AB - To elucidate whether Rift Valley fever virus (RVFV) diversity in Sudan resulted from multiple introductions or from acquired changes over time from 1 introduction event, we generated complete genome sequences from RVFV strains detected during the 2007 and 2010 outbreaks. Phylogenetic analyses of small, medium, and large RNA segment sequences indicated several genetic RVFV variants were circulating in Sudan, which all grouped into Kenya-1 or Kenya-2 sublineages from the 2006-2008 eastern Africa epizootic. Bayesian analysis of sequence differences estimated that diversity among the 2007 and 2010 Sudan RVFV variants shared a most recent common ancestor circa 1996. The data suggest multiple introductions of RVFV into Sudan as part of sweeping epizootics from eastern Africa. The sequences indicate recent movement of RVFV and support the need for surveillance to recognize when and where RVFV circulates between epidemics, which can make data from prediction tools easier to interpret and preventive measures easier to direct toward high-risk areas. PMID- 23347791 TI - Patient specific cutting guides versus an imageless, computer-assisted surgery system in total knee arthroplasty. AB - BACKGROUND: Patient specific cutting guides (PSC) in total knee arthroplasty (TKA) have recently been introduced, in which preoperative 3-dimensional imaging is used to manufacture disposable cutting blocks specific to a patient's anatomy. The purpose of this study was to compare the alignment accuracy of PSC to an imageless CAS system in TKA. METHODS: Thirty-seven patients (41 knees), received a TKA using an imageless CAS system. Subsequently, 38 patients (41 knees), received a TKA using a MRI-based, PSC system. Postoperatively, standing AP hip-to ankle radiographs were obtained, from which the lower extremity mechanical axis, tibial component varus/valgus, and femoral component varus/valgus mechanical alignment were digitally measured. Each measurement was performed by two blinded, independent observers, and interclass correlations were calculated. A student's two-tailed t test was used to compare the two cohorts (p-value<0.05=significant). RESULTS: In the PSC cohort, 70.7% of patients had an overall alignment within 3 degrees of a neutral mechanical axis (vs. 92.7% with CAS, p=0.02), 87.8% had a tibial component alignment within 2 degrees of perpendicular to the tibial mechanical axis (vs. 100% with CAS, p=0.04), and 90.2% had a femoral component alignment within 2 degrees of perpendicular to the femoral mechanical axis (vs. 100% with CAS, p=0.2). Interclass correlation coefficients were good to excellent for all radiographic measurements. CONCLUSION: While PSC techniques appear sound in principle, this study did not demonstrate patient specific cutting guides to obtain the same degree of overall mechanical and tibial component alignment accuracy as a CAS technique. LEVEL OF EVIDENCE: III: Retrospective cohort study. PMID- 23347792 TI - The antioxidant response of the liver of male Swiss mice raised on a AIN 93 or commercial diet. AB - BACKGROUND: Reactive oxygen species (ROS) are formed under natural physiological conditions and are thought to play an important role in many human diseases. A wide range of antioxidants are involved in cellular defense mechanisms against ROS, which can be generated in excess during stressful conditions, these include enzymes and non-enzymatic antioxidants. The aim of this study was to evaluate the antioxidant responses of mice to two diets control, commercial and the purified AIN 93 diet, commonly used in experiments with rodents. RESULTS: Malondialdehyde (MDA) and hydrogen peroxide (H2O2) concentrations and superoxide dismutase (SOD) and glutathione reductase (GR) activities determined in the liver were lower in the group of mice fed with the AIN 93 diet, while catalase (CAT) activity was higher in the same group, when compared to the group fed on the commercial diet. Liver glutathione peroxidase (GSH-Px) activity was similar in the groups fed on either AIN 93 or the commercial diets. Two SOD isoforms, Mn-SODII and a Cu/Zn SODV, were specifically reduced in the liver of the AIN 93 diet fed animals. CONCLUSIONS: The clear differences in antioxidant responses observed in the livers of mice fed on the two diets suggest that the macro- and micro-nutrient components with antioxidant properties, including vitamin E, can promote changes in the activity of enzymes involved in the removal of the ROS generated by cell metabolism. PMID- 23347794 TI - Current barrier membranes: titanium mesh and other membranes for guided bone regeneration in dental applications. AB - Research on guided bone regeneration (GBR) is still ongoing, with evidence mainly from preclinical studies. Various current barrier membranes should fulfill the main design criteria for GBR, such as biocompatibility, occlusivity, spaciousness, clinical manageability and the appropriate integration with the surrounding tissue. These GBR characteristics are required to provide the maximum membrane function and mechanical support to the tissue during bone formation. In this review, various commercially available, resorbable and non-resorbable membranes with different characteristics are discussed and summarized for their usefulness in preclinical studies. Membranes offer promising solutions in animal models; however, an ideal membrane has not been established yet for clinical applications. Every membrane type presents both advantages and disadvantages. Titanium mesh membranes offer superb mechanical properties for GBR treatment and its current efficacy in trials will be a focus in this review. A thorough understanding of the benefits and limitations inherent to various materials in specific clinical applications will be of great value and aid in the selection of an optimal membrane for GBR. PMID- 23347793 TI - Psychometric validation of the Visual Function Questionnaire-25 in patients with diabetic macular edema. AB - BACKGROUND: Diabetic Macular Edema (DME) is a common cause of impaired vision and blindness amongst diabetics. If not detected and treated early, the resulting vision loss can lead to considerable health costs and decreased health-related quality of life (HRQoL). The aim of this study was to provide evidence of the psychometric properties of the National Eye Institute - Visual Functioning Questionnaire (VFQ-25) for use in a cohort of DME patients who participated in a clinical efficacy and safety trial of pegaptinib sodium (Macugen). METHODS: A phase 2/3 randomised, double masked trial evaluated pegaptanib injection versus sham injection in patients with DME. The analysis was conducted using baseline HRQoL data of the VFQ-25 and the EQ-5D, on a modified intent-to-treat sample of 235 patients. These measures were administered by a trained interviewer by telephone in all but one of the study countries, where face-to-face interviews were conducted in the clinic. The measures were completed in the week prior to baseline, and after 54 weeks of treatment. Distance visual acuity, measured according to the Early Treatment Diabetic Retinopathy Study (ETDRS), was assessed at all time points. Psychometric properties of the VFQ-25 assessed included domain structure, reliability, concurrent and construct validity, responsiveness. RESULTS: The VFQ-25 was found to consist of 11 domains slightly different than those proposed. Nevertheless, none of the eight established multi-item scales met the criterion for further splitting and the VFQ-25 was scored as in the developers' instructions. Internal consistency reliability was demonstrated for six out of the eight original multi-item scales, with Cronbach's alpha ranging from 0.58 (Distance Activities) to 0.85 (Vision Specific: Dependency). The VFQ-25 domains generally showed a low to moderate correlation with EQ-5D visual analogue scale (range 0.16-0.43) and with the visual acuity score (range 0.10-0.41). Construct validity was upheld with higher VFQ-25 scores for patients who saw more letters according to the ETDRS. Almost all scales were shown to be responsive with Guyatt's statistic ranging from 0.10 to 0.56 at 54 weeks. CONCLUSIONS: The VFQ-25 has evidence to support its validity and reliability for measuring HRQoL in DME. However, some operating characteristics of the instrument need further consideration and discussion in the case of DME patients. Further research is therefore warranted in this indication. PMID- 23347795 TI - Laboratory capacity for diagnosis of foot-and-mouth disease in Eastern Africa: implications for the progressive control pathway. AB - BACKGROUND: Accurate diagnosis is pertinent to any disease control programme. If Eastern Africa is to work towards control of foot-and-mouth disease (FMD) using the Progressive Control Pathway for FMD (PCP-FMD) as a tool, then the capacity of national reference laboratories (NRLs) mandated to diagnose FMD should match this task. This study assessed the laboratory capacity of 14 NRLs of the Eastern Africa Region Laboratory Network member countries using a semi-structured questionnaire and retrospective data from the World Reference Laboratory for FMD annual reports and Genbank(r) through National Centre for Biotechnology Information for the period 2006-2010. RESULTS: The questionnaire response rate was 13/14 (93%). Twelve out of the 13 countries/regions had experienced at least one outbreak in the relevant five year period. Only two countries (Ethiopia and Kenya) had laboratories at biosecurity level 3 and only three (Ethiopia, Kenya and Sudan) had identified FMD virus serotypes for all reported outbreaks. Based on their own country/region assessment, 12/13 of these countries /regions were below stage 3 of the PCP-FMD. Quarantine (77%) and vaccination (54%) were the major FMD control strategies employed. The majority (12/13) of the NRLs used serological techniques to diagnose FMD, seven used antigen ELISA and three of these (25%) also used molecular techniques which were the tests most frequently requested from collaborating laboratories by the majority (69%) of the NRLs. Only 4/13 (31%) participated in proficiency testing for FMD. Four (31%) laboratories had no quality management systems (QMS) in place and where QMS existed it was still deficient, thus, none of the laboratories had achieved accreditation for FMD diagnosis. CONCLUSIONS: This study indicates that FMD diagnostic capacity in Eastern Africa is still inadequate and largely depends on antigen and antibody ELISAs techniques undertaken by the NRLs. Hence, for the region to progress on the PCP-FMD, there is need to: implement regional control measures, improve the serological diagnostic test performance and laboratory capacity of the NRLs (including training of personnel as well as upgrading of equipment and methods, especially strengthening the molecular diagnostic capacity), and to establish a regional reference laboratory to enforce QMS and characterization of FMD virus containing samples. PMID- 23347796 TI - Interactive programme to enhance protective factors for eating disorders in girls with type 1 diabetes. AB - AIMS: This study evaluated the effectiveness of a pilot programme in enhancing protective factors for eating disorders in young girls with type 1 diabetes (T1D). METHODS: Twenty girls with T1D (M age = 11.06 years) attended two 4-h group sessions. A 4-week baseline control period was compared against changes at post-programme and at 1-month follow-up on measures of eating disorder risk factors and indicators of glycaemic control. RESULTS: At post-intervention, significant improvements were found for self-efficacy related to diabetes management, self-esteem, body-esteem,thin-ideal internalization and perfectionism. These gains were maintained at 1-month follow-up. Participants were also rated by their parents as assuming more responsibility for specific diabetes-related tasks at follow-up. CONCLUSIONS: A brief interactive programme can favourably impact protective factors for disordered eating. The development of effective disordered eating prevention strategies for girls with T1D is an urgent priority and the current study is a first step in this direction. PMID- 23347797 TI - Feasibility of conductance catheter-derived pressure-volume loops to investigate ventricular mechanics in shunted single ventricles. AB - We present pressure-volume loops obtained from two patients with single-ventricle physiology, one with a modified Blalock-Taussig shunt and one with a right ventricle-to-pulmonary artery shunt. The dissimilarities in pressure-volume loop contour and related indices highlight potentially important differences in ventricular mechanics between the shunt types. PMID- 23347798 TI - [Scarf pin: an intrabronchial foreign body who is not unusual]. AB - OBJECTIVE: Inhalation of foreign bodies is rare in adults. Inhalation of scarf pin is a phenomenon more frequent in the female population in Morocco. The aim of our study was to describe the characteristics of this particular foreign body and illustrate the circumstances and consequences of its inhalation. PATIENTS AND METHODS: Twenty-six young patients, all veiled, were hospitalized in the service of Respiratory Diseases University Hospital Ibn Rushd of Casablanca between January 2005 and July 2011 for inhaled scarf pin. RESULTS: The mean age was 16 years. Inhalation was accidental in all cases, whereas patients initiated to wear the veil. The penetration syndrome was found in all cases. Clinical examination was normal in all patients. The chest X-ray showed the foreign body as a linear opacity, located right in 18 cases and left in eight cases. Flexible bronchoscopy was able to extract the pin in 21 cases. The pin was released spontaneously in three cases and two patients were operated on. CONCLUSION: The scarf pin is a foreign body especially more common in women who wear the Islamic veil. Flexible bronchoscopy is an essential means of therapy, but the best preventive treatment is avoiding to put in the mouth sharp objects. PMID- 23347799 TI - Extravascular lung water and the pulmonary vascular permeability index may improve the definition of ARDS. AB - The recent Berlin definition has made some improvements in the older definition of acute respiratory distress syndrome (ARDS), although the concepts and components of the definition remained largely unchanged. In an effort to improve both predictive and face validity, the Berlin panel has examined a number of additional measures that may reflect increased pulmonary vascular permeability, including extravascular lung water. The panel concluded that although extravascular lung water has improved face validity and higher values are associated with mortality, it is infeasible to mandate on the basis of availability and the fact that it does not distinguish between hydrostatic and inflammatory pulmonary edema. However, the results of a multi-institutional study that appeared in the previous issue of Critical Care show that this latter reservation may not necessarily be true. By using extravascular lung water and the pulmonary vascular permeability index, both of which are derived from transpulmonary thermodilution, the authors could successfully differentiate between patients with ARDS and other patients in respiratory failure due to either cardiogenic edema or pleural effusion with atelectasis. This commentary discusses the merits and limitations of this study in view of the potential improvement that transpulmonary thermodilution may bring to the definition of ARDS. PMID- 23347800 TI - Evaluation of maxillary anterior teeth and their relation to the golden proportion in Malaysian population. AB - BACKGROUND: The maxillary anterior teeth are important in achieving pleasing dental aesthetics. Various methods are used to measure the size and form of them, including the golden proportion between their perceived widths, and the width-to height ratio, referred to as the golden standard. The purpose of this study was conducted to evaluate whether consistent relationships exist between tooth width and height of the clinical crown dimensions; and to investigate the occurrence of the golden proportion of the maxillary anterior teeth. METHODS: Dental casts of the maxillary arches were made in this cross-sectional study from MAHSA University College students who met the inclusion criteria. The 49 participants represented the Malaysian population main ethnics. The dimensions of the anterior teeth and the perceived width of anterior teeth viewed from front were measured using a digital caliper. RESULTS: Comparison of the perceived width ratio of lateral to central incisor and canine to lateral incisor with the golden proportion of 0.618 revealed there were a significant statistical difference (p < 0.05). The statistical difference was significant for the width-to-height ratio of central incisors to the golden standard of 80%. There was no significant difference in the comparison among ethnic groups for the golden proportion and the golden standard. CONCLUSIONS: The golden proportion was not found to exist between the perceived widths of maxillary anterior teeth. No golden standard were detected for the width-to-height proportions of maxillary incisors. Specific population characteristics and perception of beauty must be considered. However, ethnicity has no association with the proportions of maxillary anterior teeth. PMID- 23347801 TI - Crimean-Congo hemorrhagic fever virus in ticks from migratory birds, Morocco. AB - Crimean-Congo hemorrhagic fever virus was detected in ticks removed from migratory birds in Morocco. This finding demonstrates the circulation of this virus in northwestern Africa and supports the hypothesis that the virus can be introduced into Europe by infected ticks transported from Africa by migratory birds. PMID- 23347802 TI - Choosing adolescent smokers as friends: the role of parenting and parental smoking. AB - The present study examined whether parenting and parental smoking can prevent children from selecting smoking friends during adolescence. 254 Adolescents of one Belgian secondary school participated. Self-administered questionnaires were distributed among 2nd-4th graders (mean ages = 14.2-16.2 years) during spring 2006. Follow-up was conducted 12 months later. Data was analyzed conducting longitudinal social network analyses. Results showed adolescents perceiving high parental psychological control had a significant higher tendency to select smoking friends. Perceived behavioral control and perceived parental support did not affect the selection of smoking friends. Furthermore, maternal smoking behavior affected the selection of smoking friends, although no effect of paternal smoking behavior on the selection of smoking friends was found. Adolescent smoking prevention efforts should focus on the influence of parents through their smoking behavior and their psychological control to decrease adolescents' tendency to select smoking friends resulting in fewer opportunities for negative peer influences to occur. PMID- 23347803 TI - Naphthalenyl derivatives for hitting P-gp/MRP1/BCRP transporters. AB - Substituted naphthalenyl derivatives bearing oxazole, or thiazole or furyl heteronuclei have been carried out as bioisosters of aryl-oxazoles and -thiazoles derivatives previously reported in order to investigate the role of the hindrance on the activity towards P-gp/BCRP/and MRP1 transporters. In addition, the role of naphthalenyl group to modulate P-gp intrinsic activity of these compounds was ascertained. The results demonstrated that all naphthalenyl derivatives displayed comparable P-gp activity with respect to lead compounds previously characterized in our SAR studies but were less active towards BCRP and MRP1 pumps. In terms of intrinsic activity, the replacement of aryl with naphthalenyl moiety led to P-gp inhibitors, unambiguous or ambiguous substrates on the base of the heteronucleus and the substituent on the naphthalenyl fragment. Indeed, oxazole derivatives were: inhibitors (R=H, F, OH), unambiguous substrates (R=OCH(3)), or ambiguous substrate (R=Br); thiazole derivatives were: unambiguous substrates (R=OCH(3), Br), or ambiguous substrates (R=H, F). Finally furyl derivatives were ambiguous substrates. PMID- 23347804 TI - Synthesis of a 2,4,6-trisubstituted 5-cyano-pyrimidine library and evaluation of its immunosuppressive activity in a Mixed Lymphocyte Reaction assay. AB - A series of novel pyrimidine analogues were synthesized and evaluated for immunosuppressive activity in the Mixed Lymphocyte Reaction assay, which is well known as the in vitro model for in vivo rejection after organ transplantation. Systematic variation of the substituents at positions 2, 4 and 6 of the pyrimidine scaffold led to the discovery of 2-benzylthio-5-cyano-6-(4 methoxyphenyl)-4-morpholinopyrimidine with an IC(50) value of 1.6 MUM in the MLR assay. PMID- 23347805 TI - An empirical mucosal toxicity measuring tool would elucidate the pattern of mucosal ulceration in cytotoxic therapy. PMID- 23347806 TI - Glucose abnormalities in hepatitis C virus infection. AB - Hepatitis C virus (HCV) infection is one of the most important causes of cirrhosis and hepatocellular carcinoma and has a tremendous impact on public health worldwide. HCV is both hepatotropic and lymphotropic. Replication of HCV in diseased extrahepatic organs and tissues may either trigger latent autoimmunity or induce autoimmune disorders. In addition to established liver injury, type 2 diabetes mellitus (T2DM) is an important feature of extrahepatic metabolic disorders which is attributed to HCV infection. It also has some impact on the disease activity, disease course, clinical outcomes, and treatment efficacy of antiviral therapy. Previous experimental and clinical findings have highly suggested that HCV per se is diabetogenic. The cause-effect interaction between a common endocrine disorder and an infectious disease is an important issue to elucidate. Although the precise mechanisms whereby HCV infection leads to insulin resistance (IR) and glucose abnormalities are not entirely clear, it differs from the usual pathogenesis of T2DM in those with non-HCV liver diseases. This review initially highlights epidemiological and pathophysiological studies addressing the mutual link between chronic HCV infection (CHC) and T2DM. The characteristics of glucose abnormalities in this special population are depicted from the current evidence. The mutual roles of IR and CHC with respect to the prediction of treatment efficacy, how treatment response affects IR, and the role of pancreatic beta cell function in the entire suite are discussed. With the rapid progression of antiviral therapy for CHC in the past decade, we have also listed some points of future perspective in this issue. PMID- 23347807 TI - Effect of ghrelin on inflammatory response in lung contusion. AB - The purpose of this study was to investigate the effects of ghrelin on inflammatory response and tissue damage following trauma-induced acute lung injury. Thirty male wistar albino rats (300-400 g) were randomly assigned into three groups: control group (n = 6), lung contusion plus saline (saline-treated, n = 12), and lung contusion plus ghrelin (ghrelin-treated, n = 12). Saline- or ghrelin-treated traumatic rats were sacrificed at two time points (24 and 72 hours) after lung contusion. Blood was collected for the analysis of serum adenosine deaminase (ADA). Tissue transforming growth factor-beta 1 (TGF-beta1) and matrix metalloproteinase-2 (MMP-2) levels were measured by enzyme-linked immunosorbent assay and histopathological examination was performed on the lung tissue samples. Our results indicated that ghrelin significantly reduced morphologic damages. Serum ADA activities were significantly decreased after lung contusion and this decline started early with ghrelin treatment. TGF-beta1 and MMP-2 levels in lung tissue were elevated at 72 hours after lung contusion and treatment with ghrelin significantly increased TGF-beta1 level and reduced MMP-2 level. In conclusion, our study demonstrates that acute lung injury initiated proinflammatory responses and ghrelin administration showed an anti-inflammatory effect in lung contusion. PMID- 23347809 TI - Risk factors of accelerated progression of peripheral artery disease in hemodialysis. AB - Ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) are markers for peripheral artery occlusive disease (PAOD) and arterial stiffness, respectively. The aims of this study were to assess whether PAOD and arterial stiffness progressed and to determine the risk factors for ABI and baPWV progression in patients on hemodialysis. This study enrolled 173 routine patients on hemodialysis. Both ABI and baPWV were measured by an ABI-form device at baseline and at 1 year of follow-up. Progression in ABI was defined as reduction in ABI exceeding 0.3, while baPWV measured at 1 year of follow-up exceeding that at baseline indicated baPWV progression. Comparison with baseline data showed increase in both prevalence of ABI < 0.9 (p = 0.045) and baPWV (p = 0.028) at 1 year of follow-up. Multiple linear regression analyses identified high fasting glucose and old age as independent factors of annual change in ABI and baPWV, respectively. Good control of blood sugar may contribute to delay the progression of peripheral artery disease in patients on hemodialysis. PMID- 23347808 TI - Dexmedetomidine did not reduce the effects of tourniquet-induced ischemia reperfusion injury during general anesthesia. AB - Ischemia reperfusion injury causes the release of free oxygen radicals. Free oxygen radicals initiate the production of toxic metabolites, such as malondialdehyde (MDA), through the lipid peroxidation of cellular membranes. Following lipid peroxidation, the antioxidant enzyme system is activated against reactive oxygen species (ROS) and attempts to protect cells from oxidative damage. There is a balance between the scavenging capacity of antioxidant enzymes and ROS. Because of this balance, the total antioxidant capacity (TAC) measurement is a sensitive indicator of the overall protective effects of the antioxidants. Alpha(2) receptor agonists are effective in preventing hemodynamic reactions during extremity surgeries by preventing the release of catecholamines secondary to tourniquet application. They have also been shown to possess preventive effects in various ischemia-reperfusion injury models. In our study, we examined the effects of dexmedetomidine on tourniquet-induced ischemia reperfusion injury in lower extremity surgeries performed under general anesthesia. The effects of dexmedetomidine were measured with serum MDA and TAC levels. We studied 60 adult American Society of Anesthesiologists (ASA) physical status I or II patients undergoing one-sided lower extremity surgery with tourniquet. The patients were randomly divided into two groups. Group D was administered a dexmedetomidine infusion at a rate of 0.1MUg/kg/minute(-1) for 10 minutes prior to induction and then at 0.7MUg/kg/hour(-1) until 10 minutes before the end of the operation. The control group (Group C) received a saline infusion of the same amount and for the same period of time. General anesthesia was induced with thiopental, fentanyl, and rocuronium and maintained with nitrous oxide and sevoflurane in both groups. Venous blood samples were obtained before the administration of the study drugs (basal) at 1 minute before tourniquet release and at 5 and 20 minutes after tourniquet release (ATR). In both groups, MDA levels decreased at 5 and 20 minutes ATR when compared with the basal values (p<0.05). TAC levels decreased at 1 and 5 minutes ATR and then returned to basal values at 20 minutes ATR (p<0.05). In reference to the prevention of lipid peroxidation in tourniquet-induced ischemia-reperfusion injury, the results from the two groups in our study showed that dexmedetomidine did not have an additional protective role during routine general anesthesia. PMID- 23347810 TI - Effects of dietary interventions on 24-hour urine parameters in patients with idiopathic recurrent calcium oxalate stones. AB - The aim of this study is to investigate the effects of dietary factors on 24-hour urine parameters in patients with idiopathic recurrent calcium oxalate stones. A total of 108 of idiopathic recurrent calcium oxalate stones were included in the study. A 24-hour urinalysis was performed and metabolic abnormalities were measured for all of the patients. All of the patients were given specialized diets for their 24-hour urine abnormalities. At the end of first month, the same parameters were examined in another 24-hour urinalysis. Hyperoxaluria, hypernatruria, and hypercalciuria were found in 84 (77%), 43 (39.8%), and 38 (35.5%) of the patients, respectively. The differences between the oxalate, sodium, volume, uric acid, and citrate parameters before and after the dietary intervention were significant (p < 0.05). The calcium parameters were not significantly different before and after the intervention. We found that oxalate, sodium, volume, uric acid, and citrate-but not calcium-abnormalities in patients with recurrent calcium oxalate stones can be corrected by diet. The metabolic profiles of idiopathic calcium oxalate stone patients should be evaluated and the appropriate dietary interventions should be implemented to decrease stone recurrence. PMID- 23347811 TI - Comparison of three data mining models for predicting diabetes or prediabetes by risk factors. AB - The purpose of this study was to compare the performance of logistic regression, artificial neural networks (ANNs) and decision tree models for predicting diabetes or prediabetes using common risk factors. Participants came from two communities in Guangzhou, China; 735 patients confirmed to have diabetes or prediabetes and 752 normal controls were recruited. A standard questionnaire was administered to obtain information on demographic characteristics, family diabetes history, anthropometric measurements and lifestyle risk factors. Then we developed three predictive models using 12 input variables and one output variable from the questionnaire information; we evaluated the three models in terms of their accuracy, sensitivity and specificity. The logistic regression model achieved a classification accuracy of 76.13% with a sensitivity of 79.59% and a specificity of 72.74%. The ANN model reached a classification accuracy of 73.23% with a sensitivity of 82.18% and a specificity of 64.49%; and the decision tree (C5.0) achieved a classification accuracy of 77.87% with a sensitivity of 80.68% and specificity of 75.13%. The decision tree model (C5.0) had the best classification accuracy, followed by the logistic regression model, and the ANN gave the lowest accuracy. PMID- 23347812 TI - Factors associated with premenstrual syndrome - a survey of new female university students. AB - Premenstrual syndrome (PMS) can impact an individual's interpersonal relationships, social interactions, productivity, lifestyle, school performance and emotional well-being. This study was designed to explore the factors associated with PMS in new female university students in Taiwan. The test battery included a self-administered structured questionnaire, the five-item brief symptoms rating scale, the Pittsburgh Sleep Quality Index and the Chinese Premenstrual Symptom Questionnaire. Additionally, details of the participants' lifestyles and family and personal histories of physical illness were recorded. Serum lipids were also measured. Of all the participants (N = 1699), 39.85% were defined as having PMS. Using logistical regression analysis, we found a positive relationship between PMS and consuming more foods containing egg yolk, greater alcohol intake, poorer sleep quality, higher likelihood of psychiatric morbidity, family history of dyslipidemia, and a higher serum cholesterol level. The results show that PMS is prevalent among new female university students and that lifestyle and nutritional/metabolic factors may play a role in this disorder. PMID- 23347813 TI - A case of alpha-fetoprotein-producing esophageal adenocarcinoma. AB - Alpha-fetoprotein is a well-known tumor marker in the screening and follow-up of hepatocellular carcinoma. In Taiwanese society, a high prevalence of hepatitis and hepatoma and elevation of alpha-fetoprotein associated with liver function impairment usually suggested clinics undertake further examination for liver or genital tumor. We report the case of 45-year-old man who was found to have an alpha-fetoprotein-producing esophageal adenocarcinoma with an initial presentation of liver function impairment and rapid elevation of alpha fetoprotein. Esophageal cancer was diagnosed via endoscope and a biopsy proved the presence of adenocarcinoma. A small endoscopic biopsy specimen failed to identify the alpha-fetoprotein positive tumor cell. Esophagectomy was performed and histopathological study of surgical specimen revealed grade II adenocarcinoma with regional metastatic lymphadenopathy. Immunohistochemical study was focal positive for alpha-fetoprotein. Serum alpha-fetoprotein declined transiently after esophagectomy and fluctuation of alpha-fetoprotein level was noted during the treatment with adjuvant chemotherapy. Finally, 19 months after the operation, the patient died due to multiple organ metastases with multiple organ failure. Thus, a small specimen for upper endoscopy may not be sufficient in the presence of alpha-fetoprotein-producing adenocarcinoma. Monitoring of serum alpha fetoprotein may be useful in the evaluation and follow-up of esophageal alpha fetoprotein-producing adenocarcinoma. PMID- 23347814 TI - A case of cutaneous malignant fibrous histiocytoma with multiple organ metastases. AB - Malignant fibrous histiocytoma is a soft tissue sarcoma that most commonly occurs in the extremities and rarely metastasizes cutaneously. A 79-year-old male patient consulted a dermatologist 11 months after recognizing an intractable ulcer on the right mandible. Punch biopsy revealed eosinophilic tumor cells in the dermal area and proliferation of rich spindle cells. Malignant fibrous histiocytoma or atypical fibroxanthoma was suspected and he was referred to our hospital. Red plaque tumors on the right mandible and right temple were 30 mm and 15 mm in size, respectively. The right mandible lesion was ulcerated. Immunohistochemically, the lesions were positive for CD10, CD74 and alpha-smooth muscle actin. Radiological analysis revealed multiple organ metastases, including bone, liver, lung and skin on the right temple. The patient was diagnosed with malignant fibrous histiocytoma, stage IV and died 8 weeks after the first visit due to respiratory failure. Cutaneous malignant fibrous histiocytoma has a poor prognosis resulting in death. PMID- 23347815 TI - Meningitis and hydrocephalus secondary to panfacial fracture repair in a traumatic brain injury patient. PMID- 23347816 TI - Multimodality imaging of an adult with Shone complex. AB - Shone complex is a rare combination of valvular or supravalvular aortic stenosis, supra-valvular mitral membrane, parachute mitral valve, and coarctation of the aorta. This article presents an unusual case of a 40-year-old woman who presented with a history of progressive dyspnea. We describe the main imaging features and protocol used for visualizing this syndrome using various imaging modalities. PMID- 23347817 TI - Effects of manual lymphatic drainage on breast cancer-related lymphedema: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Lymphedema is a common complication of axillary dissection for breast cancer. We investigated whether manual lymphatic drainage (MLD) could prevent or manage limb edema in women after breast-cancer surgery. METHODS: We performed a systematic review and meta-analysis of published randomized controlled trials (RCTs) to evaluate the effectiveness of MLD in the prevention and treatment of breast-cancer-related lymphedema. The PubMed, EMBASE, CINAHL, Physiotherapy Evidence Database (PEDro), SCOPUS, and Cochrane Central Register of Controlled Trials electronic databases were searched for articles on MLD published before December 2012, with no language restrictions. The primary outcome for prevention was the incidence of postoperative lymphedema. The outcome for management of lymphedema was a reduction in edema volume. RESULTS: In total, 10 RCTs with 566 patients were identified. Two studies evaluating the preventive outcome of MLD found no significant difference in the incidence of lymphedema between the MLD and standard treatment groups, with a risk ratio of 0.63 and a 95% confidence interval (CI) of 0.14 to 2.82. Seven studies assessed the reduction in arm volume, and found no significant difference between the MLD and standard treatment groups, with a weighted mean difference of 75.12 (95% CI, -9.34 to 159.58). CONCLUSIONS: The current evidence from RCTs does not support the use of MLD in preventing or treating lymphedema. However, clinical and statistical inconsistencies between the various studies confounded our evaluation of the effect of MLD on breast-cancer-related lymphedema. PMID- 23347818 TI - Dormancy removal of apple seeds by cold stratification is associated with fluctuation in H2O2, NO production and protein carbonylation level. AB - Reactive oxygen (ROS) and nitrogen (RNS) species play a signaling role in seed dormancy alleviation and germination. Their action may be described by the oxidative/nitrosative "window/door". ROS accumulation in embryos could lead to oxidative modification of protein through carbonylation. Mature apple (Malus domestica Borkh.) seeds are dormant and do not germinate. Their dormancy may be overcome by 70-90 days long cold stratification. The aim of this work was to analyze the relationship between germinability of embryos isolated from cold (5 degrees C) or warm (25 degrees C) stratified apple seeds and ROS or nitric oxide (NO) production and accumulation of protein carbonyl groups. A biphasic pattern of variation in H2O2 concentration in the embryos during cold stratification was detected. H2O2 content increased markedly after 7 days of seeds imbibition at 5 degrees C. After an additional two months of cold stratification, the H2O2 concentration in embryos reached the maximum. NO production by the embryos was low during entire period of stratification, but increased significantly in germination sensu stricto (i.e. phase II of the germination process). The highest content of protein carbonyl groups was detected after 6 weeks of cold stratification treatment. Fluctuation of H2O2 and protein carbonylation seems to play a pivotal role in seed dormancy alleviation by cold stratification, while NO appears to be necessary for seed germination. PMID- 23347819 TI - Epidemiological analysis, serological prevalence and genotypic analysis of foot and-mouth disease in Nigeria 2008-2009. AB - The epidemiological situation of foot-and-mouth disease virus (FMDV) is uncertain in Nigeria, where the disease is endemic, and the majority of outbreaks are unreported. Control measures for FMD in Nigeria are not being implemented due to the absence of locally produced vaccines and an official ban on vaccine importation. This study summarizes the findings of a 3-year study aimed at quantifying the seroprevalence of FMD, its distribution in susceptible species and the genetic diversity of FMDV isolated from the Plateau State of Nigeria. A 29% FMD prevalence was estimated using 3ABC enzyme-linked immunosorbent assay (3ABC ELISA). Farms with suspected FMD nearby, with contact with wildlife, that used drugs or FMD vaccines or with >100 animals, and animals of large ruminant species and in pastures other than nomadic grazing were significantly (P < 0.05) associated with FMD. Antibodies against five FMDV serotypes, (A, O, SAT1, SAT2 and SAT3) were detected by the virus neutralization test (VNT) at various titres (<100->800) from all tested sera from most parts of the region. This is probably the first report of the presence of FMDV SAT3 in Nigeria. Further studies to investigate the potential probable presence and prevalence of SAT 3 virus in Nigeria are required. Tissue samples collected from clinical animals were positive for FMDV. Virus isolates were sequenced and confirmed as serotype A. All of the isolates showed marked genetic homogeneity with >99% genetic identity in the VP1 region and were most closely related to a previously described virus collected from Cameroon in 2000. This study provides knowledge on the epidemiological situation of FMD in Plateau State, Nigeria, and will probably help to develop effective control and preventive strategies for the disease in Nigeria and other countries in the West African subregion. PMID- 23347820 TI - Ischaemic stroke with intact atrial septum--exclude arteriovenous malformations. AB - A 44-year-old woman was referred to our centre for interventional cardiac catheterisation. The diagnostic work-up after a preceding ischaemic stroke led to the assumption of a patent foramen ovale due to a positive bubble study. Before the planned percutaneous closure of the patent foramen ovale, we performed a second bubble study, which showed an intact atrial septum. However, after two to three heart cycles bubbles could be detected in the left atrium, assuming a right to-left shunt of an extracardiac origin most likely in the lung. We therefore performed cardiac catheterisation, yielding a pulmonary arteriovenous malformation in the lower lobe of the right lung. This was successfully closed interventionally by placing a Cook coil, as well as several plugs into the malformation and feeding vessels. PMID- 23347821 TI - The influenza A (H1N1) pandemic in Reunion Island: knowledge, perceived risk and precautionary behaviour. AB - BACKGROUND: The effectiveness of preventive measures depends on prevailing attitudes and mindsets within a population. Perceived risk is central to a shift in mindset and behaviour. The present study aims to investigate the perceived severity, vulnerability and precautionary behaviour adopted in response to the influenza A (H1N1) epidemic that broke out in 2009 on Reunion Island (Indian Ocean). As no H1N1 vaccination was available at the time, non-medical interventions appeared of crucial importance to the control of the epidemic. METHODS: A cross sectional survey was conducted in Reunion Island between November 2009 and April 2010 within 2 months of the passage of the influenza A (H1N1) epidemic wave. Individual contacts representing 725 households (one contact per household) were interviewed by telephone using validated questionnaires on perceived risks. Mean scores were calculated for perceived severity, vulnerability, efficacy of preventive measures and precautionary behaviour. Univariate analysis was applied to identify preventive measures and attitudes and multivariate analysis was used to study the determinants of precautionary behaviour. RESULTS: More than 95% of contacted persons accepted to participate to the survey. Eighty seven percent of respondents believed that prevention was possible. On average, three out of six preventive measures were deemed effective. Spontaneously, 57% of the respondents reported that they took one or more preventive measures. This percentage increased to 87% after the interviewer detailed possible precautions one by one. The main precautions taken were frequent hand washing (59%) and avoidance of crowded places (34%). In multivariate logistic regression analysis the following factors were significantly associated with taking one or more preventive measures: young age, previous vaccination against seasonal influenza, having had seasonal influenza in the last five years, effectiveness of the preventive measures taken and low standards of education. CONCLUSION: Inhabitants of Reunion Island have expressed a preventive approach adapted to the realities of the H1N1 pandemic, a feature that likely reflects some preparedness gained after the large and severe chikungunya epidemic that hit the island in 2006. The degree of severity was well assessed despite the initial alarmist messages disseminated by national and international media. Precautions that were undertaken matched the degree of severity of the epidemic and the recommendations issued by health authorities. Further qualitative studies are needed to help adapting public messages to the social and cultural realities of diverse communities and to prevent misconceptions. PMID- 23347823 TI - [Usefulness of cardiac computed tomography in planning and evaluating alcohol septal ablation]. PMID- 23347822 TI - Do parent-child acculturation gaps affect early adolescent Latino alcohol use? A study of the probability and extent of use. AB - The literature has been mixed regarding how parent-child relationships are affected by the acculturation process and how this process relates to alcohol use among Latino youth. The mixed results may be due to, at least, two factors: First, staggered migration in which one or both parents arrive to the new country and then send for the children may lead to faster acculturation in parents than in children for some families. Second, acculturation may have different effects depending on which aspects of alcohol use are being examined. This study addresses the first factor by testing for a curvilinear trend in the acculturation-alcohol use relationship and the second by modeling past year alcohol use as a zero inflated negative binomial distribution. Additionally, this study examined the unique and mediation effects of parent-child acculturation discrepancies (gap), mother involvement in children's schooling, father involvement in children's schooling, and effective parenting on youth alcohol use during the last 12 months, measured as the probability of using and the extent of use. Direct paths from parent-child acculturation discrepancy to alcohol use, and mediated paths through mother involvement, father involvement, and effective parenting were also tested. Only father involvement fully mediated the path from parent-child acculturation discrepancies to the probability of alcohol use. None of the variables examined mediated the path from parent-child acculturation discrepancies to the extent of alcohol use. Effective parenting was unrelated to acculturation discrepancies; however, it maintained a significant direct effect on the probability of youth alcohol use and the extent of use after controlling for mother and father involvement. Implications for prevention strategies are discussed. PMID- 23347824 TI - [Infective endocarditis as a form of late presentation of congenital heart disease]. AB - A diagnosis of congenital heart disease is usually established at an early age, so infective endocarditis is a rare form of presentation. The authors describe the case of a male adolescent with a week-long history of intermittent fever and unquantified weight loss. Physical examination detected pansystolic and diastolic murmurs, and an associated precordial thrill. Laboratory tests showed evidence of an active infection. Etiological investigation revealed a perimembranous ventricular septal defect, aortic regurgitation, and aortic and mitral valve vegetations. A diagnosis of mitral-aortic infective endocarditis was made and he was started on intravenous antibiotics and anticongestive therapy. After initial clinical improvement, he developed symptoms and signs of congestive heart failure. Repeat echocardiography showed an extensive mitral-aortic paravalvular abscess. The antibiotics were changed and anticongestive therapy was intensified, and he subsequently underwent surgery. The outcome has been generally favorable, and at present he is asymptomatic under anticongestive therapy. PMID- 23347826 TI - Geometric variations of acetabular component design and its effect on radiographic osseointegration. AB - The Reflection uncemented acetabular component (Smith & Nephew, Memphis, Tenn) for total hip arthroplasty is available in 2 geometric variants. The first has a completely hemispherical design; the second has a peripheral rim expansion designed to increase initial press fit and aid osseointegration. The clinical and radiologic outcomes of 527 consecutive primary total hip arthroplasties were reviewed to investigate the differences in component design. Of the components, 95.6% survived at 96 months with revision for aseptic loosening as the end point, with no significant difference between the 2 component designs. Eighty percent of hemispherical and 57% of peripherally expanded components were considered completely osseointegrated at final radiologic review. The midterm radiologic outcome of peripherally expanded acetabular components is inferior to that of a completely hemispherical design. PMID- 23347825 TI - Fluid balance and urine volume are independent predictors of mortality in acute kidney injury. AB - INTRODUCTION: In ICUs, both fluid overload and oliguria are common complications associated with increased mortality among critically ill patients, particularly in acute kidney injury (AKI). Although fluid overload is an expected complication of oliguria, it remains unclear whether their effects on mortality are independent of each other. The aim of this study is to evaluate the impact of both fluid balance and urine volume on outcomes and determine whether they behave as independent predictors of mortality in adult ICU patients with AKI. METHODS: We performed a secondary analysis of data from a multicenter, prospective cohort study in 10 Italian ICUs. AKI was defined by renal sequential organ failure assessment (SOFA) score (creatinine >3.5 mg/dL or urine output (UO) <500 mL/d). Oliguria was defined as a UO <500 mL/d. Mean fluid balance (MFB) and mean urine volume (MUV) were calculated as the arithmetic mean of all daily values. Use of diuretics was noted daily. To assess the impact of MFB and MUV on mortality of AKI patients, multivariate analysis was performed by Cox regression. RESULTS: Of the 601 included patients, 132 had AKI during their ICU stay and the mortality in this group was 50%. Non-surviving AKI patients had higher MFB (1.31 +/- 1.24 versus 0.17 +/- 0.72 L/day; P <0.001) and lower MUV (1.28 +/- 0.90 versus 2.35 +/ 0.98 L/day; P <0.001) as compared to survivors. In the multivariate analysis, MFB (adjusted hazard ratio (HR) 1.67 per L/day, 95%CI 1.33 to 2.09; <0.001) and MUV (adjusted HR 0.47 per L/day, 95%CI 0.33 to 0.67; <0.001) remained independent risk factors for 28-day mortality after adjustment for age, gender, diabetes, hypertension, diuretic use, non-renal SOFA and sepsis. Diuretic use was associated with better survival in this population (adjusted HR 0.25, 95%CI 0.12 to 0.52; <0.001). CONCLUSIONS: In this multicenter ICU study, a higher fluid balance and a lower urine volume were both important factors associated with 28 day mortality of AKI patients. PMID- 23347827 TI - Use of the EZ-Blocker for lung separation. PMID- 23347828 TI - Hepatitis E virus in pork liver sausage, France. AB - We investigated viability of hepatitis E virus (HEV) identified in contaminated pork liver sausages obtained from France. HEV replication was demonstrated in 1 of 4 samples by using a 3-dimensional cell culture system. The risk for human infection with HEV by consumption of these sausages should be considered to be high. PMID- 23347829 TI - Radiosynthesis and initial evaluation of (18)F labeled nanocarrier composed of poly(L-lactic acid)-block-poly(sarcosine) amphiphilic polydepsipeptide. AB - INTRODUCTION: With the aim of developing radiotracers for in vivo positron emission tomography (PET) imaging of solid tumors based on the enhanced permeability and retention effect of nanocarriers, we have developed a polymer micelle named "Lactosome", which is composed of the amphiphilic polydepsipeptide, poly(L-lactic acid)-block-poly(sarcosine). This paper describes and evaluates the initial evaluation of the (18)F-labeled Lactosome as a novel contrast agent for the tumor PET imaging technique carried out. METHODS: (18)F-labeled Lactosomes were prepared by a film hydration method under sonication in water at 50 degrees C from a mixture of 4-[(18)F]fluoro-benzoyl poly-L-lactic acid ((18)F-BzPLLA30) and the amphiphilic polydepsipeptide. For biodistribution studies, BALB/cA Jcl nu/nu mice bearing HeLa cells in the femur region were used. We took both PET and near-infrared fluorescence (NIRF) images of tumor bearing mice after co-injection of (18)F-labeled Lactosome and NIRF-labeled Lactosome. RESULTS: (18)F-labeled Lactosomes were prepared at good yields (222-420MBq) and more than 99% of (18)F BzPLLA30 was incorporated into (18)F-labeled Lactosome. The radioactivity of (18)F-labeled Lactosome was found to be stable and maintained at high level for up to 6h after injection into the blood stream. Tumor uptake increased gradually after the injection. The uptake ratio of tumor/muscle was 2.7 at 6h from the time of injection. Tumor PET imaging with (18)F-labeled Lactosome was as capable as tumor NIRF imaging with NIRF-labeled Lactosome. CONCLUSION: Tumor PET imaging using Lactosome as a nanocarrier may be therefore a potential candidate for a facile and general solid tumor imaging technique. PMID- 23347830 TI - Antifungal, anti-inflammatory and cytotoxicity activities of three varieties of labisia pumila benth: from microwave obtained extracts. AB - BACKGROUND: Labisia pumila, locally known as Kacip Fatimah, is a forest-floor plant that has tremendous potential in the herbal industry. It is one of the five herbal plants identified by the government as one of the national key economic areas to be developed for commercial purposes. There are three varieties of L. pumila namely, L. pumila var. pumila, L. pumila var. alata and L. pumila var. lanceolata and each has its own use. METHODS: The leaves and roots of the three varieties of L. pumila Benth. were extracted using microwave assisted extraction (MAE). Antifungal activity of all plant extracts were characterized against Fusarium sp., Candida sp. and Mucor using the agar diffusion disc. Anti inflammatory assays were performed using NO production by macrophage RAW 264.7 cell lines induced by LPS/IFN-g and cytotoxic activity was determined using several cancer cell lines and one normal cell line. RESULTS: The overall result demonstrated that leaf and root extracts of all three varieties of L. pumila exhibited moderate to appreciable antifungal activity against Fusarium sp., Candida sp. and Mucor compared to streptomycin used as positive control. Leaf and root extracts of all varieties significantly decreased NO release. However, the root extracts showed higher activity compared to the leaf extracts. Cytotoxic activity against MCF-7, MDA-MB-231 and Chang cell lines were observed with all extracts. CONCLUSIONS: These findings suggest the potential use of L. pumila Benth. as a natural medicine and indicated the possible application of this medicinal plant such anti inflammatory activity and cytotoxic agents. PMID- 23347831 TI - Effect of amino acid distribution of amphipathic helical peptide derived from human apolipoprotein A-I on membrane curvature sensing. AB - Amphipathic helix, which senses membrane curvature, is of growing interest. Here we explore the effect of amino acid distribution of amphipathic helical peptide derived from the C-terminal region (residues 220-241) of human apolipoprotein (apo) A-I on membrane curvature sensing. This peptide preferred a curved membrane in a manner similar to full-length apoA-I, although its model peptide did not sense membrane curvature. Substitution of several residues both on the polar and non-polar faces of the amphipathic helix had no significant effect on sensing, suggestive of the elaborate molecular architecture in the C-terminal helical region of apoA-I to exert lipid efflux function. PMID- 23347832 TI - Full-length Mst1 exhibits growth promoting function in human hepatocellular carcinoma cells. AB - The putative tumor suppressor Mst1, when cleaved to its 36kDa cleaved form, amplifies apoptotic signals. We found that Mst1 was predominantly expressed in its full-length form in 76% (17/25 cases) of hepatocellular carcinoma (HCC) tumors. Mst1 cleavage was basically absent in HCC cells. Ectopic full-length Mst1 expression increased the growth of HCC cells by 55-80% within 3days after transfection. Expression of exogenous NORE1B, a tumor suppressor commonly lost in HCC tumors (~56% of our cohort), was sufficient to suppress the growth promotion of full-length Mst1. Hence, Mst1 exhibits a growth promoting activity in HCC cells upon NORE1B downregulation. PMID- 23347833 TI - Terminator still moving forward: expanding roles for Rho factor. AB - Rho factor is a molecular motor that translocates along nascent RNA and acts on the transcription elongation complex to promote termination. Besides contributing to transcriptional punctuation of the bacterial genome, Rho can act intragenically under conditions that perturb coupling of translation and transcription. Recent advances have shed new light onto several aspects of Rho function, including the translocation mechanism, the avoidance of potential conflicts between DNA replication and transcription, suppression of pervasive antisense transcription and recruitment in riboswitch and small RNA-dependent regulation. Altogether, these findings further highlight the relevance of Rho factor, both as a multi-task housekeeper and gene regulator. PMID- 23347834 TI - Decellularized musculofascial extracellular matrix for tissue engineering. AB - Ideal scaffolds that represent native extracellular matrix (ECM) properties of musculofascial tissues have great importance in musculofascial tissue engineering. However, detailed characterization of musculofascial tissues' ECM (particularly, of fascia) from large animals is still lacking. In this study, we developed a decellularization protocol for processing pig composite musculofascial tissues. Decellularized muscle (D-muscle) and decellularized fascia (D-fascia), which are two important components of decellularized musculofascial extracellular matrix (DMM), were comprehensively characterized. D muscle and D-fascia retained intact three-dimensional architecture, strong mechanical properties, and bioactivity of compositions such as collagen, laminin, glycosaminoglycan, and vascular endothelial growth factor. D-muscle and D-fascia provided a compatible niche for human adipose-derived stem cell integration and proliferation. Heterotopic and orthotopic implantation of D-muscle and D-fascia in a rodent model further proved their biocompatibility and myogenic properties during the remodeling process. The differing characteristics of D-muscle from D fascia (e.g. D-muscle's strong pro-angiogenic and pro-myogenic properties vs. D fascia's strong mechanical properties) indicate different clinical application opportunities of D-muscle vs. D-fascia scaffolds. DMM comprising muscle and fascia ECM as a whole unit can thus provide not only a clinically translatable platform for musculofascial tissue repair and regeneration but also a useful standard for scaffold design in musculofascial tissue engineering. PMID- 23347835 TI - Microencapsulation of cells, including islets, within stable ultra-thin membranes of maleimide-conjugated PEG-lipid with multifunctional crosslinkers. AB - The encapsulation of islets of Langerhans (islets) and insulin-secreting cells within a semi-permeable membrane has been suggested as a safe and simple technique for islet transplantation to attenuate early graft loss and avoid immunosuppressive therapy. The total volume of these implants tends, however, to increase upon encapsulation of the islets and cells within the polymer membrane, limiting transport between encapsulated cells and the surrounding tissue. Ultra thin membranes could potentially overcome these diffusion limitations to provide for clinically applicable implants. Here we propose a method to encapsulate islets and cells within a stable ultra-thin polymer membrane using poly(ethylene glycol)-conjugated phospholipid bearing a maleimide group (Mal-PEG-lipids) and multiple interactive polymers (e.g., 4-arm PEG-Mal and 8-arm PEG-SH). When Mal PEG-lipids were added to islet and cell suspensions, spontaneous incorporation into a cell surface occurred from the micelles at an equilibrium state. The addition of 4-arm PEG-Mal and 8-arm PEG-SH to the mixture induced a substantial increase in the membrane thickness because a number of Mal-PEG-lipid micelles were involved in the membrane formation at the micrometer level. No appreciable increase in islet volume was observed after microencapsulation by this method. Microencapsulation of islets with the polymer membranes, which showed semi permeability, did not impair insulin release in response to glucose stimulation, even after 7 days. The polymer membrane structure surrounding the islets and cells was well maintained for at least 30 days. In addition, the membrane formed showed much lower thrombogenicity and inhibited complement activation upon exposure to human whole blood and serum. PMID- 23347836 TI - Non-invasive characterization of polyurethane-based tissue constructs in a rat abdominal repair model using high frequency ultrasound elasticity imaging. AB - The evaluation of candidate materials and designs for soft tissue scaffolds would benefit from the ability to monitor the mechanical remodeling of the implant site without the need for periodic animal sacrifice and explant analysis. Toward this end, the ability of non-invasive ultrasound elasticity imaging (UEI) to assess temporal mechanical property changes in three different types of porous, biodegradable polyurethane scaffolds was evaluated in a rat abdominal wall repair model. The polymers utilized were salt-leached scaffolds of poly(carbonate urethane) urea, poly(ester urethane) urea and poly(ether ester urethane) urea at 85% porosity. A total of 60 scaffolds (20 each type) were implanted in a full thickness muscle wall replacement in the abdomens of 30 rats. The constructs were ultrasonically scanned every 2 weeks and harvested at weeks 4, 8 and 12 for compression testing or histological analysis. UEI demonstrated different temporal stiffness trends among the different scaffold types, while the stiffness of the surrounding native tissue remained unchanged. The changes in average normalized strains developed in the constructs from UEI compared well with the changes of mean compliance from compression tests and histology. The average normalized strains and the compliance for the same sample exhibited a strong linear relationship. The ability of UEI to identify herniation and to characterize the distribution of local tissue in-growth with high resolution was also investigated. In summary, the reported data indicate that UEI may allow tissue engineers to sequentially evaluate the progress of tissue construct mechanical behavior in vivo and in some cases may reduce the need for interim time point animal sacrifice. PMID- 23347837 TI - Particle-induced osteolysis mediated by endoplasmic reticulum stress in prosthesis loosening. AB - We hypothesized that endoplasmic reticulum (ER) stress in macrophages induced by wear particles was one of the reasons for particle-induced osteolysis (PIO) in total hip arthroplasty (THA) failure. In the present study, the expression of ER stress markers was examined by Western blot in macrophages treated with particles from materials used in prosthetics, specimens from PIO animal models and patients suffering from aseptic loosening. To address whether ER stress triggers these inflammatory responses, the effect of an ER stress blocker on the expression of inflammatory cytokines in particle-treated macrophages and PIO animal models was tested. The results demonstrated that ER stress markers were significantly upregulated in particle-treated macrophages, periosteum tissues from PIO animal models and clinical specimens of prosthesis loosening. Blocking ER stress with a specific inhibitor dramatically reduced the particle-induced expression of inflammatory cytokines in vitro and in vivo. Furthermore, in PIO animal models, this ER stress blocker dramatically suppressed the differentiation of osteoclasts and reduced the severity of osteolysis. Thus, the results of the present study suggest that ER stress plays a key role in particle-induced osteolysis and that targeting the ER stress pathway may lead to novel therapeutic approaches for the treatment of aseptic prosthesis loosening. PMID- 23347838 TI - Multifunctional polymeric nanoparticles for oral delivery of TNF-alpha siRNA to macrophages. AB - Oral delivery of therapeutic siRNA is an appealing strategy for the treatment of many diseases, however poses numerous challenges to escort siRNA from the site of administration to the cytoplasm of the target cells. Mannose-modified trimethyl chitosan-cysteine (MTC) conjugate nanoparticles (NPs) were developed via ionic gelation and performed as highly effective polymeric vehicles for oral delivery of TNF-alpha siRNA. The chitosan backbone as well as trimethyl, thiol, and mannose groups of MTC NPs could be activated at proper time and location to overcome the extracellular and intracellular barriers to oral siRNA delivery, thereby promoting gene silencing efficiency. MTC NPs effectively improved siRNA integrity in physiological environment, enhanced siRNA permeation across the intestinal epithelium, facilitated siRNA uptake by macrophages through clathrin independent endocytosis, and promoted cytoplasmic siRNA release. At equivalent TNF-alpha siRNA dose, MTC NPs notably outperformed Lipofectamine2000 in terms of in vitro knockdown of TNF-alpha production in macrophages. Orally delivered MTC NPs containing low amount of TNF-alpha siRNA (3.75 nm/kg) inhibited TNF-alpha production in macrophages in vivo, which protected mice with acute hepatic injury from inflammation-induced liver damage and lethality. This study could provide broad insights into the rational design of oral siRNA vehicles for the treatment of inflammatory diseases. PMID- 23347839 TI - Chasing notifiable avian influenza in domestic poultry: a case report of low pathogenic avian influenza h5 viruses in two Belgian holdings. AB - In December 2008, bird species in two geographically distant holdings were found positive for H5 viruses following the annual Avian influenza serological screening in Belgium. The virological tests performed identified in one holding a low-pathogenic avian influenza (LPAI) virus subtype H5N2, and a H5 LPAI virus was identified by real-time PCR and direct sequencing at the second holding. The first farm was an outdoor mixed holding housing ornamental birds and poultry (n = 6000) and the second a free-range geese breeding farm (n = 1500). No clinical signs or mortalities were reported. Control measures defined by Council Directive 2005/94/EC were followed, including notification to the European Commission via the Animal Disease Notification System and to the World Organization for Animal Health, and poultry were killed, while ornamental bird species were quarantined. Partial sequencing of the H5N2 virus haemagglutinin and neuraminidase N2 gene sequences revealed a close homology to some recent LPAI isolates identified from wild birds in Germany and Italy and from wild birds in Eurasia and Africa, respectively. It is noteworthy that, these two holdings were already H5 positive based on HI test results carried out during the previous serological screening; however, no virus was detected at that time. To have a better understanding of the potential 'silent' circulation of the H5N2 isolate in the field, experimental infections of chickens and turkeys were performed. The low excretion detected might in part explain viral persistence not associated with spread between gallinaceous birds in the same holding, indicating that the H5N2 LPAI isolate was not fully adapted to these two poultry species. Our results highlighted limitations to only using serological screening for the early detection of LPAI in an 'at-risk farm', suggesting that virological and serological monitoring tests be applied simultaneously as a means of testing animals in 'at-risk farms'. PMID- 23347840 TI - Non-alcoholic steatohepatitis in morbidly obese patients. AB - The hepatic complications of morbid obesity range from steatosis to steatohepatitis (Non-alcoholic steatohepatitis [NASH]), fibrosis, cirrhosis and finally hepatocellular carcinoma. The pathophysiological mechanisms of the progression of a normal liver to a liver showing steatosis and then steatohepatitis are complex, including, per se, insulin-resistance, iron accumulation, oxidative stress and hepatocyte death. An imbalance in anti- and pro-inflammatory factors may be the trigger. These factors can originate from intra- or extrahepatic sites, particularly the adipose tissue and the gut. This review will provide insight into the current diagnosis and understanding of hepatic inflammation including non-invasive markers of NASH (markers of hepatocyte death), intrahepatic mechanisms (regulation of the immune and inflammatory response, hepatocellular iron deposition, hepatocyte death) and extrahepatic factors (from adipose tissue and gut) in morbidly obese patients. PMID- 23347842 TI - Chronic sympathectomy of the caudal artery delays cutaneous heat loss during passive heating. AB - The present study aimed to investigate the chronic effects of caudal artery sympathectomy on thermoregulatory adjustments induced by passive heating. Male Wistar rats were subjected to two surgical procedures: caudal artery denervation (CAD) or sham surgery (Sham-CAD) and intraperitoneal implantation of a temperature sensor. On the day of the experiments, the animals were exposed to an ambient temperature of 36 degrees C for 60min or allowed to rest under thermoneutral conditions (26 degrees C). During the experiments, the tail skin temperature (T(skin)) and the core body temperature (T(core)) were measured. Under thermoneutral conditions, although sympathetic denervation did not change the average values of T(core) and T(skin), CAD rats exhibited decreased T(skin) variability compared with Sham-CAD rats (0.020+/-0.005 degrees C vs. 0.031+/ 0.005 degrees C; P=0.024). During heat exposure, no differences were observed in the T(core) between the groups. In contrast, although peak T(skin) values were not affected by chronic sympathectomy of the caudal artery, CAD animals showed a delayed increase in T(skin); the time until the stabilization of T(skin) was three-fold longer in CAD rats than in Sham-CAD rats (15.3+/-2.5min vs. 4.9+/ 0.6min; P=0.001). In conclusion, chronic sympathectomy of the caudal artery delays cutaneous heat loss during passive heating and decreases T(skin) variability under thermoneutral conditions. Taken together, our results indicate that the sympathetic innervation of cutaneous vessels is essential for the precise regulation of tail heat loss. PMID- 23347841 TI - 25-Hydroxycholesterol regulates cholesterol homeostasis in the murine CATH.a neuronal cell line. AB - Aberrant oxysterol biosynthesis is implicated in the pathogenesis of neurodegenerative diseases. During the present study we have investigated the effects of exogenously added 25-hydroxycholesterol (25-HC) on transcription of cholesterol biosynthetic genes, sterol-regulatory element binding protein (SREBP) processing and cholesterol biosynthesis in the murine CATH.a neuronal cell line. A single i.p. injection of lipopolysaccharide resulted in robust induction of cholesterol 25-hydroxylase mRNA and protein levels in brains of treated mice. In vitro, 25-HC upregulated the transcription of ATP-binding cassette transporter A1 (ABCA1) and (to a lesser extent) apolipoprotein E (apoE) in CATH.a neurons. Cholesterol biosynthetic gene expression (squalene synthase, HMG-CoA synthase, HMG-CoA reductase, and SREBP2) was downregulated by 25-HC. 25-HC also significantly attenuated proteolytic processing of SREBP2. Finally, 25-HC downregulated cholesterol biosynthesis in CATH.a neurons. Our results demonstrate that 25-HC is a potent effector oxysterol of neuronal cholesterol homeostasis. PMID- 23347843 TI - Development and review of vignettes representing older people with cognitive impairment. AB - This paper describes a process undertaken to develop and review five clinical vignettes to be used in geriatric nursing educational research. The purpose of this process was to provide valid depictions of delirium and its subtypes and distinguish delirium from dementia. Five vignettes depicting hospital bedside interactions between nursing staff, family, and an older patient who displayed signs of one of the following conditions: delirium (hyper and hypoactive types respectively), dementia, or delirium (both types) superimposed on dementia were constructed. Vignette accuracy and reliability were established using a multistage process that culminated in formal review by a group of ten international nursing and medical delirium experts. The final five vignettes accurately depicted the given scenario as agreed by the experts and were at an appropriate level of simplicity and clarity. Given the increased interest in vignettes for both nursing research and educational purposes, the described method of vignette development and review has the ability to assist other vignette developers in creating reliable representations of their desired clinical scenarios. PMID- 23347844 TI - Usutu virus, Italy, 1996. AB - Retrospective analysis of archived tissue samples from bird deaths in the Tuscany region of Italy in 1996 identified Usutu virus. Partial sequencing confirmed identity with the 2001 Vienna strain and provided evidence for a much earlier introduction of this virus into Europe than previously assumed. PMID- 23347846 TI - Anti-inflammatory and apoptotic effects of the polyphenol curcumin on human fibroblast-like synoviocytes. AB - BACKGROUND: It has recently been reported that the polyphenol curcumin has pronounced anti-carcinogenic, anti-inflammatory and pro-apoptotic properties. This study investigated possible anti-inflammatory and apoptotic effects of curcumin on the human synovial fibroblast cell line MH7A, and on fibroblast-like synoviocytes (FLS) derived from patients with rheumatoid arthritis (RA). METHODS: MH7A cells and RA-FLS were stimulated either with interleukin (IL)-1beta or phorbol 12-myristate 13 acetate (PMA), and treated simultaneously or sequentially with increasing concentrations of curcumin. Release of interleukin (IL)-6 and vascular endothelial growth factor (VEGF)-A was quantified by enzyme-linked immunosorbent assays (ELISAs). In MH7A cells, modulation of the transcription factor nuclear factor kappa-B (NF-kappaB) and mitogen-activated protein kinases (MAPKs) such as p38 and extracellular-signal regulated kinase (ERK1/2) were analysed by a reporter gene assay and Western blot, respectively. Pro-apoptotic events were monitored by Annexin-V/7-AAD based assay. Cleavage of pro-caspase-3 and -7 was checked with specific antibodies. RESULTS: Curcumin effectively blocked IL-1beta and PMA-induced IL-6 expression both in MH7A cells and RA-FLS. VEGF-A expression could only be detected in RA-FLS and was induced by PMA, but not by IL-1beta. Furthermore, curcumin inhibited activation of NF-kappaB and induced dephosphorylation of ERK1/2. Treatment of FLS with high concentrations of curcumin was associated with a decrease in cell viability and induction of apoptosis. CONCLUSION: The natural compound curcumin represents strong anti inflammatory properties and induces apoptosis in FLS. This study provides an insight into possible molecular mechanisms of this substance and suggests it as a natural remedy for the treatment of chronic inflammatory diseases like RA. PMID- 23347847 TI - Are we doing enough to ensure quality of trials? PMID- 23347845 TI - Increase of cyclooxygenase-2 inhibition with celecoxib combined with 5-FU enhances tumor cell apoptosis and antitumor efficacy in a subcutaneous implantation tumor model of human colon cancer. AB - BACKGROUND: The purpose of this study was to investigate the anti-tumor effect and explore the mechanisms of celecoxib (a selective cyclooxygenase-2 inhibitor) combined with 5-fluorouracil (5-FU) on the treatment of human colorectal cancer in a BALB/C nude mouse subcutaneous xenograft model. METHODS: Effects of celecoxib combined with 5-FU on the proliferation of xenograft carcinoma induced by HT-29 were investigated. The apoptotic cells were detected by electron microscope and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay. Immunohistochemistry and Western blot were used to estimate the expression of cytochrome C, caspase-3 and caspase-9. RESULTS: Compared with the control group, treatment groups showed significant inhibition of tumor growth. More apoptotic cells existed after treatment with celecoxib combined with 5-FU. Cytochrome C, caspase-3 and caspase-9 were increased in treated groups, and more obviously in the drug combination group. Cyclooxygenase-2 (COX-2) were decreased after treatment with celecoxib only or combined with 5-FU. And the combined group showed a greater decrease. CONCLUSIONS: Celecoxib combined with 5-FU could inhibit the growth of tumors in vivo by inducing apoptosis and activation of the cytochrome C dependency apoptosis signal pathway. A decrease of COX-2 and an increase of cytochrome C, caspase-3 and caspase-9 may be involved in this process. PMID- 23347848 TI - Response to M. Boers' concerns about spydergrams. PMID- 23347849 TI - Some improvements are apparent in identifying adverse effects in systematic reviews from 1994 to 2011. AB - OBJECTIVE: An increasing amount of research and guidelines has been published on search methodology and the reporting of search strategies in systematic reviews. This research assessed whether this has lead to any improvements in the reporting and quality of searching in systematic reviews of adverse effects. STUDY DESIGN AND SETTING: All records within Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects were scanned for systematic reviews of adverse effects. Data were then extracted on the methods used for information retrieval in these reviews and a descriptive analysis conducted by publication year. RESULTS: A total of 849 reviews published from 1994 to 2011 met the inclusion criteria. There has been a significant increase (P<0.001) in the number of adverse effects reviews per year from 1994 (n=5) to 2010 (n=104). Some improvements were apparent, such as an increase in the number of databases searched and fewer date and language restrictions applied. However, there has been an increase in reviews limited to data from randomized controlled trials, whereas the reporting of search strategies could still be improved further, with only 9% (74/849) of the reviews reporting reproducible searches. CONCLUSION: Some improvements in searching systematic reviews of adverse effects are apparent; however, poor reporting of search strategies remains a great obstacle to readers. PMID- 23347850 TI - Meta-analysis identifies Back Pain Questionnaire reliability influenced more by instrument than study design or population. AB - OBJECTIVE: To assess if predefined variables in study design, instrument type, and patient characteristics account for variance in reported retest reliability for the Oswestry Disability Index (ODI) and Roland-Morris Questionnaire (RMQ). A second aim was a more precise estimate of instrument reliability. STUDY DESIGN AND SETTING: A systematic literature search of MEDLINE, EMBASE, AMED, PsycINFO, and CINAHL was performed from inception to January 2011. Hand search, gray literature, and reference retrieval completed the search. Two blinded reviewers extracted the data. Original authors were contacted for the missing data. A meta analysis was performed with the intraclass correlation coefficient as the outcome measure. RESULTS: Fifty studies on 31 ODI and 28 RMQ cohorts were retrieved that met the inclusion criteria. Meta-analysis found the ODI more reliable than the RMQ (coefficient, -0.2840; P = 0.009) and lower reliability on increased days to retest (coefficient, -0.0089; P = 0.005) and in low back pain (LBP) with leg pain than LBP only cohorts (coefficient, -0.2194; P = 0.046). The use of a transition item to identify stable patients and percentage of cohort not included at retest were significant only on single variable analysis. CONCLUSION: Study design and population influence the reliability of a given instrument, however, a greater difference in reliability exists between instruments. PMID- 23347851 TI - The validity of administrative data to identify hip fractures is high--a systematic review. AB - OBJECTIVE: To determine the validity of the diagnostic algorithms for osteoporosis and fractures in administrative data. STUDY DESIGN AND SETTING: A systematic search was conducted to identify studies that reported the validity of a diagnostic algorithm for osteoporosis and/or fractures using administrative data. RESULTS: Twelve studies were reviewed. The validity of the diagnosis of osteoporosis in administrative data was fair when at least 3 years of data from hospital and physician visit claims were used (area under the receiver operating characteristic [ROC] curve [AUC]=0.70) or when pharmacy data were used (with or without the use of hospital and physician visit claims data, AUC>0.70). Nonetheless, the positive predictive values (PPVs) were low (<0.60). There was good evidence to support the use of hospital data to identify hip fractures (sensitivity: 69-97%; PPV: 63-96%) and the addition of physician claims diagnostic and procedural codes to hospitalization diagnostic codes improved these characteristics (sensitivity: 83-97%; PPV: 86-98%). Vertebral fractures were difficult to identify using administrative data. There was some evidence to support the use of administrative data to define other fractures that do not require hospitalization. CONCLUSIONS: Administrative data can be used to identify hip fractures. Existing diagnostic algorithms to identify osteoporosis and vertebral fractures in administrative data are suboptimal. PMID- 23347852 TI - Randomized trials published in higher vs. lower impact journals differ in design, conduct, and analysis. AB - OBJECTIVE: To compare methodological characteristics of randomized controlled trials (RCTs) published in higher vs. lower impact Core Clinical Journals. STUDY DESIGN AND SETTING: We searched MEDLINE for RCTs published in 2007 in Core Clinical Journals. We randomly sampled 1,140 study reports in a 1:1 ratio in higher (five general medicine journals with the highest total citations in 2007) and lower impact journals. RESULTS: Four hundred sixty-nine RCTs proved eligible: 219 in higher and 250 in lower impact journals. RCTs in higher vs. lower impact journals had larger sample sizes (median, 285 vs. 39), were more likely to receive industry funding (53% vs. 28%), declare concealment of allocation (66% vs. 36%), declare blinding of health care providers (53% vs. 41%) and outcome adjudicators (72% vs. 54%), report a patient-important primary outcome (69% vs. 50%), report subgroup analyses (64% vs. 26%), prespecify subgroup hypotheses (42% vs. 20%), and report a test for interaction (54% vs. 27%); P < 0.05 for all differences. CONCLUSION: RCTs published in higher impact journals were more likely to report methodological safeguards against bias and patient-important outcomes than those published in lower impact journals. However, sufficient limitations remain such that publication in a higher impact journal does not ensure low risk of bias. PMID- 23347853 TI - Citation bias favoring statistically significant studies was present in medical research. AB - OBJECTIVE: Statistically significant studies may be cited more than negative studies on the same topic. We aimed to assess here whether such citation bias is present across the medical literature. STUDY DESIGN AND SETTING: We conducted a cohort study of the association between statistical significance and citations. We selected all therapeutic intervention studies included in meta-analyses published between January and March 2010 in the Cochrane database, and retrieved citation counts of all individual studies using ISI Web of Knowledge. The association between the statistical significance of each study and the number of citations it received between 2008 and 2010 was assessed in mixed Poisson models. RESULTS: We identified 89 research questions addressed in 458 eligible articles. Significant studies were cited twice as often as nonsignificant studies (multiplicative effect of significance: 2.14, 95% confidence interval: 1.38 3.33). This association was partly because of the higher impact factor of journals where significant studies are published (adjusted multiplicative effect of significance: 1.14, 95% confidence interval: 0.87-1.51). CONCLUSION: A citation bias favoring significant results occurs in medical research. As a consequence, treatments may seem more effective to the readers of medical literature than they really are. PMID- 23347854 TI - Insufficient evidence to determine the impact of patient preferences on clinical outcomes in acupuncture trials: a systematic review. AB - OBJECTIVE: To review reporting of preferences in acupuncture studies and their effect on clinical outcomes. STUDY DESIGN AND SETTING: Systematic review of published randomized and quasi-randomized controlled trials of acupuncture reporting participant preferences for randomization or treatment or using a preference design. RESULTS: Of the 31 included trials, 5 reported on randomization preference, 18 on treatment preference, and 1 reported on both. Seven used a preference design. Four out of seven trials noted that the group with preferences had different baseline characteristics (less education, worse baseline measure score, and greater or fewer years with pain). There was a tendency for greater attrition in nonpreference arms at 6 months but not earlier. Around three-quarters of participants turned down randomization in favor of nontrial treatment, and preference for acupuncture was around 20% when offered multiple treatments. Questions used to elicit preferences varied across trials and were poorly reported. Ten trials reported the effects of preferences on outcomes; only one detected a statistically (but not clinically) significant difference. CONCLUSION: There is little evidence that preferences cause detectable effects on outcomes in acupuncture trials; however, trials use inconsistent methods and poorly report these data. Monitoring the level and effect of preferences in trials is recommended. PMID- 23347855 TI - The EORTC computer-adaptive tests measuring physical functioning and fatigue exhibited high levels of measurement precision and efficiency. AB - OBJECTIVES: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group is developing a computer-adaptive test (CAT) version of the EORTC Quality of Life Questionnaire (QLQ-C30). We evaluated the measurement properties of the CAT versions of physical functioning (PF) and fatigue (FA) and compared these with the corresponding QLQ-C30 scales. STUDY DESIGN AND SETTING: Based on international samples of more than 1,000 cancer patients, we simulated CAT administration of varying numbers of items and compared the resulting scores with those based on all items in the respective item pools. Furthermore, the relative validity (RV) of CATs was compared with that of the QLQ-C30 scales using known groups validity. RESULTS: For both dimensions, CATs of all lengths resulted in unbiased score estimates. CATs consisting of five or more items had reliability>0.90, correlated >= 0.97 with the full scale, and had root mean square error <0.25. The average RVs for these CATs ranged 1.02-1.33, indicating possible savings in sample size requirements of 3-42% using CAT. CONCLUSION: The CAT versions of PF and FA exhibited high levels of measurement precision and efficiency. The potential savings in sample size requirements using CATs compared with those using the original QLQ-C30 scales were typically 20% or more. PMID- 23347856 TI - A prenotification letter increased initial response, whereas sender did not affect response rates. AB - OBJECTIVE: To find ways to improve response rates of medical and health surveys. We investigated whether a prenotification letter instead of a second reminder and varying senders of the questionnaires would affect response rates. STUDY DESIGN AND SETTING: We present the results of two studies. In the first study, four groups were compared that either received a prenotification letter (group 1 and 2) or a second reminder letter (group 3 and 4); received the questionnaire from either a research institute (group 1 and 3) or a health insurance company (HIC; group 2 and 4). In the second study, we compared two groups that received the questionnaire sent by either a HIC or a hospital. Response rates, response speed, respondent characteristics, item nonresponse, and mean scores on quality aspects and global ratings were compared. RESULTS: Response rates did not differ significantly between groups. Prenotification groups returned their questionnaires faster. No other significant differences were found for response speed, respondent characteristics, item nonresponse, or mean scores. CONCLUSION: A prenotification letter does only increase initial response speed and does not increase total response rates. A prenotification letter should be considered when quick response is desirable. Varying senders had no effect on response rates. PMID- 23347857 TI - "Precision" or "relevance"? Reporting considerations for articles focusing on evaluation of search strategies. PMID- 23347858 TI - Comparison of bare-metal stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery: 10-year follow-up of a randomized trial. AB - OBJECTIVES: The aim of this prospective, randomized trial was to assess the 10 year long-term safety and effectiveness of percutaneous coronary intervention (PCI) and minimally invasive direct coronary artery bypass surgery (MIDCAB) for the treatment of proximal left anterior descending (LAD) lesions. BACKGROUND: Long-term follow-up data comparing PCI and MIDCAB surgery for isolated proximal LAD lesions are sparse. METHODS: Patients with significant isolated proximal LAD stenoses were randomized either to PCI with bare-metal stents (n = 110) or MIDCAB (n = 110). At 10 years, data were obtained with respect to the primary endpoint (death, myocardial infarction, target vessel revascularization). Angina was assessed by the Canadian Cardiovascular Society classification. RESULTS: Follow up was conducted for 212 patients at a median time of 10.3 years. There were no significant differences in the binary primary composite endpoint (47% vs. 36%; p = 0.12) and hard endpoints (death and infarction) between PCI and MIDCAB. However, a higher target vessel revascularization rate in the PCI group (34% vs. 11%; p < 0.01) was observed. Clinical symptoms improved significantly from baseline and were similar between both treatment groups. CONCLUSIONS: At 10-year follow-up, PCI and MIDCAB in isolated proximal LAD lesions yielded similar long term outcomes regarding the primary composite clinical endpoint. Target vessel revascularization was more frequent in the PCI group. PMID- 23347859 TI - Minimally invasive bypass surgery for stenosis of the left anterior descending artery: 10-year results from a randomized controlled trial. PMID- 23347860 TI - Left main coronary atherosclerosis progression, constrictive remodeling, and clinical events. AB - OBJECTIVES: The aim of this study was to evaluate the progression of atherosclerosis within the left main coronary artery (LMCA) in association with risk factor modifying therapies. BACKGROUND: Despite studies demonstrating slowing of disease progression within epicardial coronaries with risk factor modification, little is known about the natural history and clinical sequelae of atherosclerosis progression within the LMCA. METHODS: In 340 patients with angiographic coronary artery disease who underwent serial intravascular ultrasound imaging to evaluate the effects of anti atherosclerotic therapies across 7 clinical trials, LMCA and epicardial disease progression was characterized. Relationships between changes in plaque burden with remodeling parameters and the incidence of major adverse cardiovascular events (MACE) (death, myocardial infarction, hospital stay for unstable angina, and coronary revascularization) were investigated. RESULTS: Plaque regression was observed in the LMCA segment, and progression was observed in adjacent epicardial segments (percent atheroma volume [PAV] -0.39 +/- 0.1% vs. +0.37 +/- 0.1%, p < 0.001). Changes in LMCA lumen volume correlated strongly with changes in external elastic membrane (beta coefficient 0.91, p < 0.001) and negatively with the change in PAV (beta coefficient -0.55, p < 0.001). Patients who experienced a MACE had smaller baseline LMCA minimum lumen area (11.6 vs. 12.2 mm(2), p = 0.05) and greater progression of PAV in the LMCA (+0.51 +/- 0.3% vs. -0.35 +/- 0.2%, p = 0.02) compared with those who were MACE-free. Significant reductions from baseline in both external elastic membrane (-4.7 +/- 1.7 mm(3), p < 0.01) and lumen volumes ( 4.0 +/- 1 mm(3), p < 0.01) were also observed in those having an event. CONCLUSIONS: Left main coronary atherosclerosis responds to systemic risk factor modification. Patients experiencing a MACE were more likely to demonstrate progressive disease and constrictive arterial remodeling within the LMCA segment. PMID- 23347861 TI - Calculation of the index of microcirculatory resistance without coronary wedge pressure measurement in the presence of epicardial stenosis. AB - OBJECTIVES: This study sought to investigate a novel method to calculate the index of microcirculatory resistance (IMR) in the presence of significant epicardial stenosis without the need for balloon dilation to measure the coronary wedge pressure (P(w)). BACKGROUND: The IMR provides a quantitative measure of coronary microvasculature status. However, in the presence of significant epicardial stenosis, IMR calculation requires incorporation of the coronary fractional flow reserve (FFR(cor)), which requires balloon dilation within the coronary artery for P(w) measurement. METHODS: A method to calculate IMR by estimating FFR(cor) from myocardial FFR (FFR(myo)), which does not require P(w) measurement, was developed from a derivation cohort of 50 patients from a single institution. This method to calculate IMR was then validated in a cohort of 72 patients from 2 other different institutions. Physiology measurements were obtained with a pressure-temperature sensor wire before coronary intervention in both cohorts. RESULTS: From the derivation cohort, a strong linear relationship was found between FFR(cor) and FFR(myo) (FFR(cor) = 1.34 * FFR(myo) - 0.32, r(2) = 0.87, p < 0.001) by regression analysis. With this equation to estimate FFR(cor) in the validation cohort, there was no significant difference between IMR calculated from estimated FFR(cor) and measured FFR(cor) (21.2 +/- 12.9 U vs. 20.4 +/- 13.6 U, p = 0.161). There was good correlation (r = 0.93, p < 0.001) and agreement by Bland-Altman analysis between calculated and measured IMR. CONCLUSIONS: The FFR(cor), and, by extension, microcirculatory resistance can be derived without the need for P(w). This method enables assessment of coronary microcirculatory status before or without balloon inflation, in the presence of epicardial stenosis. PMID- 23347862 TI - Carotid artery stenting of a contralateral occlusion and in-hospital outcomes: results from the CARE (Carotid Artery Revascularization and Endarterectomy) registry. AB - OBJECTIVES: The authors sought to study the characteristics and outcomes of patients with contralateral carotid artery occlusions (CCOs) undergoing elective carotid artery stenting (CAS). BACKGROUND: CCOs are associated with adverse neurological events following carotid endarterectomy. METHODS: In-hospital outcomes were examined in patients with and without CCO undergoing elective CAS in the Carotid Artery Revascularization and Endarterectomy (CARE) registry. A CCO was defined as a 100% occlusion of the contralateral internal carotid artery. To minimize differences in measured comorbidities, a 3:1 propensity matching analysis was performed comparing 42 clinical and demographic variables between CCO and non-CCO patients from the CARE registry. The primary endpoint was a composite of in-hospital death, nonfatal myocardial infarction, and nonfatal stroke. RESULTS: Between April 2005 and January 2012, 13,993 eligible patients underwent elective CAS, of whom 1,450 (10%) had CCO. There were 5,500 CAS procedures (1,375 CCO and 4,125 non-CCO) identified in the propensity analysis. The primary composite endpoint occurred in 29 (2.1%) and 107 (2.6%) patients with and without CCO, respectively (adjusted odds ratio: 0.81, 95% confidence interval: 0.53 to 1.23, p = 0.316). CONCLUSIONS: In the CARE registry, there was no evidence that the presence of a CCO was associated with an increased risk of in-hospital death, nonfatal myocardial infarction, or nonfatal stroke in patients undergoing elective CAS. These findings may have implications on the selection of carotid revascularization procedures for such patients. PMID- 23347863 TI - Treatment of complex atherosclerotic popliteal artery disease with a new self expanding interwoven nitinol stent: 12-month results of the Leipzig SUPERA popliteal artery stent registry. AB - OBJECTIVES: We examined the efficacy and durability of a new interwoven self expanding nitinol stent system in the treatment of complex popliteal artery lesions in unselected patients. BACKGROUND: The optimal endovascular treatment strategy for atherosclerotic popliteal artery disease is not known. METHODS: We retrospectively analyzed the data gathered in 101 consecutive patients presenting with atherosclerotic, popliteal arterial disease, who underwent implantation of 125 stents. The patients were followed for 12 months by Doppler ultrasound examinations, stent roentgenograms, and estimation of Rutherford-Becker class (RBC) and ankle-brachial index (ABI). RESULTS: The mean age of the patients was 73.1 years, and 52.5% were men. Total occlusions were present in 48 patients (47.5%). The mean stent length was 84.3 +/- 45.1 mm (range 40 to 240 mm). A <30% residual stenosis was achieved in 98.0% of procedures. The 6- and 12-month primary patency rates were 94.6 +/- 2.3% and 87.7 +/- 3.7%, respectively, and the secondary patency rates 97.9 +/- 1.5% and 96.5 +/- 2.0%, respectively. Between baseline and 12 months of follow-up, mean ABI increased from 0.58 +/- 0.15 to 0.97 +/- 0.18, and mean RBC decreased from 3.1 +/- 0.9 to 1.4 +/- 0.8 (p < 0.001 for both comparisons). Radiographs performed on 51 patients, at a mean of 15.2 months, confirmed the absence of stent fractures in 100% of examinations. CONCLUSIONS: Over a 12-month observation period, the patency rate and durability of SUPERA stents implanted for severe popliteal artery disease were high. PMID- 23347864 TI - Aortic root dimensions among patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. AB - OBJECTIVES: The aim of this study was to characterize aortic root dimensions of patients with aortic valve stenosis undergoing transcatheter aortic valve replacement (TAVR) and to evaluate sex differences. BACKGROUND: The advent of TAVR makes a precise delineation of the aortic root anatomy mandatory and requires a profound anatomic understanding. METHODS: Patients planned to undergo TAVR underwent screening imaging with use of a 64-slice or dual-source electrocardiogram-gated contrast-enhanced computed tomography. Anatomic dimensions were assessed at the level of the left ventricular outflow tract (LVOT), annulus, sinus of Valsalva, and ascending aorta. RESULTS: The study population comprised 80 men and 97 women (age: 82 +/- 6 years) with symptomatic severe aortic valve stenosis. Multislice computed tomography aortic root assessment revealed larger annular and LVOT dimensions in men than women (area annulus: 483.1 +/- 75.6 mm(2) vs. 386.9 +/- 58.5 mm(2), p = 0.0002; area LVOT: 478.2 +/- 131.0 mm(2) vs. 374.0 +/- 94.2 mm(2), p = 0.0024), whereas dimensions of the ascending aorta were comparable. Both LVOT and annulus were predominantly oval without sex differences, with a higher mean ellipticity index for the LVOT compared with the annulus (1.49 +/- 0.2 vs. 1.29 +/- 0.1); the ascending aorta was primarily circular (1.07 +/- 0.1). Although similar in mean surface area, an area mismatch of annulus and LVOT of more than 10%, 20%, and 40% was detected in 42, 9, and 2 patients, respectively. The mean distance from annulus to the left coronary ostium was smaller than the mean distance of the right coronary ostium (14.4 +/- 3.6 mm vs. 16.7 +/- 3.6 mm), and distances were lower among women than men. CONCLUSIONS: The aortic root has specific anatomic characteristics, which affect device design, selection, and clinical outcome in patients undergoing TAVR. Female sex is associated with smaller annular and LVOT but not aortic dimensions. The degree of ellipticity as well as a significant mismatch between annular and LVOT dimensions in selected patients deserve careful evaluation. PMID- 23347865 TI - Percutaneous transcatheter aortic valve closure successfully treats left ventricular assist device-associated aortic insufficiency and improves cardiac hemodynamics. AB - OBJECTIVES: This study sought to assess the effectiveness of a novel percutaneous method to treat left ventricular assist device (LVAD)-associated severe aortic insufficiency (AI) in a series of patients determined to be poor reoperative candidates. BACKGROUND: The increased use of continuous-flow LVAD in advanced heart failure has led to marked changes in the management of patients with this condition. However, secondary AI can become a significant complication. METHODS: Five patients with continuous-flow LVAD and severe post-LVAD AI underwent percutaneous transcatheter aortic valve closure from September to October 2011 at a single quaternary care academic medical center. All patients had LVAD implanted as destination therapy. LVAD parameters, hemodynamics, and echocardiographic measurements were obtained before and after aortic valve closure. RESULTS: All patients underwent successful closure with the Amplatzer cribriform device (AGA Medical, Plymouth, Minnesota) via a percutaneous transcatheter femoral approach with a significant reduction of AI from severe to trivial. Cardiac hemodynamics improved, and the pulmonary capillary wedge pressure was reduced in all patients. There was no change in mitral or tricuspid regurgitation, LVAD power, or pulsatility index. CONCLUSIONS: Percutaneous transcatheter closure of the aortic valve effectively treats LVAD-associated AI and reduces pulmonary capillary wedge pressure. This procedure should be considered to treat LVAD-associated AI in patients who are poor candidates for repeat operation. Further data are needed to assess long-term results. PMID- 23347866 TI - Successful management of annulus rupture in transcatheter aortic valve implantation. PMID- 23347867 TI - Intracardiac visualization of transcatheter aortic valve and valve-in-valve implantation in an in vitro passive beating heart. PMID- 23347868 TI - Concomitant transcatheter aortic and mitral valve-in-valve replacements using transfemoral devices via the transapical approach: first case in United States. PMID- 23347869 TI - Is coronary arteriography a diagnostic test? PMID- 23347870 TI - Catheter closure of a right aortico-atrial tunnel in a patient 4 years of age. PMID- 23347871 TI - Left main coronary artery compression by an enlarged pulmonary artery. PMID- 23347873 TI - Genetic damage in soybean workers exposed to pesticides: evaluation with the comet and buccal micronucleus cytome assays. AB - Soybean cultivation is widespread in the State of Rio Grande do Sul (RS, Brazil), especially in the city of Espumoso. Soybean workers in this region are increasingly exposed to a wide combination of chemical agents present in formulations of fungicides, herbicides, and insecticides. In the present study, the comet assay in peripheral leukocytes and the buccal micronucleus (MN) cytome assay (BMCyt) in exfoliated buccal cells were used to assess the effects of exposures to pesticides in soybean farm workers from Espumoso. A total of 127 individuals, 81 exposed and 46 non-exposed controls, were evaluated. Comet assay and BMCyt (micronuclei and nuclear buds) data revealed DNA damage in soybean workers. Cell death was also observed (condensed chromatin, karyorhectic, and karyolitic cells). Inhibition of non-specific choline esterase (BchE) was not observed in the workers. The trace element contents of buccal samples were analyzed by Particle-Induced X-ray Emission (PIXE). Higher concentrations of Mg, Al, Si, P, S, and Cl were observed in cells from workers. No associations with use of personal protective equipment, gender, or mode of application of pesticides were observed. Our findings indicate the advisability of monitoring genetic toxicity in soybean farm workers exposed to pesticides. PMID- 23347872 TI - Moderate and prolonged hypercapnic acidosis may protect against ventilator induced diaphragmatic dysfunction in healthy piglet: an in vivo study. AB - INTRODUCTION: Protective ventilation by using limited airway pressures and ventilation may result in moderate and prolonged hypercapnic acidosis, as often observed in critically ill patients. Because allowing moderate and prolonged hypercapnia may be considered protective measure for the lungs, we hypothesized that moderate and prolonged hypercapnic acidosis may protect the diaphragm against ventilator-induced diaphragmatic dysfunction (VIDD). The aim of our study was to evaluate the effects of moderate and prolonged (72 hours of mechanical ventilation) hypercapnic acidosis on in vivo diaphragmatic function. METHODS: Two groups of anesthetized piglets were ventilated during a 72-hour period. Piglets were assigned to the Normocapnia group (n = 6), ventilated in normocapnia, or to the Hypercapnia group (n = 6), ventilated with moderate hypercapnic acidosis (PaCO2 from 55 to 70 mm Hg) during the 72-hour period of the study. Every 12 hours, we measured transdiaphragmatic pressure (Pdi) after bilateral, supramaximal transjugular stimulation of the two phrenic nerves to assess in vivo diaphragmatic contractile force. Pressure/frequency curves were drawn after stimulation from 20 to 120 Hz of the phrenic nerves. The protocol was approved by our institutional animal-care committee. RESULTS: Moderate and prolonged hypercapnic acidosis was well tolerated during the study period. The baseline pressure/frequency curves of the two groups were not significantly different (Pdi at 20 Hz, 32.7 +/- 8.7 cm H2O, versus 34.4 +/- 8.4 cm H2O; and at 120 Hz, 56.8 +/ 8.7 cm H2O versus 60.8 +/- 5.7 cm H2O, for Normocapnia and Hypercapnia groups, respectively). After 72 hours of ventilation, Pdi decreased by 25% of its baseline value in the Normocapnia group, whereas Pdi did not decrease in the Hypercapnia group. CONCLUSIONS: Moderate and prolonged hypercapnic acidosis limited the occurrence of VIDD during controlled mechanical ventilation in a healthy piglet model. Consequences of moderate and prolonged hypercapnic acidosis should be better explored with further studies before being tested on patients. PMID- 23347874 TI - Implementing training and support, financial reimbursement, and referral to an internet-based brief advice program to improve the early identification of hazardous and harmful alcohol consumption in primary care (ODHIN): study protocol for a cluster randomized factorial trial. AB - BACKGROUND: The European level of alcohol consumption, and the subsequent burden of disease, is high compared to the rest of the world. While screening and brief interventions in primary healthcare are cost-effective, in most countries they have hardly been implemented in routine primary healthcare. In this study, we aim to examine the effectiveness and efficiency of three implementation interventions that have been chosen to address key barriers for improvement: training and support to address lack of knowledge and motivation in healthcare providers; financial reimbursement to compensate the time investment; and internet-based counselling to reduce workload for primary care providers. METHODS/DESIGN: In a cluster randomized factorial trial, data from Catalan, English, Netherlands, Polish, and Swedish primary healthcare units will be collected on screening and brief advice rates for hazardous and harmful alcohol consumption. The three implementation strategies will be provided separately and in combination in a total of seven intervention groups and compared with a treatment as usual control group. Screening and brief intervention activities will be measured at baseline, during 12 weeks and after six months. Process measures include health professionals' role security and therapeutic commitment of the participating providers (SAAPPQ questionnaire). A total of 120 primary healthcare units will be included, equally distributed over the five countries. Both intention to treat and per protocol analyses are planned to determine intervention effectiveness, using random coefficient regression modelling. DISCUSSION: Effective interventions to implement screening and brief interventions for hazardous alcohol use are urgently required. This international multi-centre trial will provide evidence to guide decision makers. PMID- 23347876 TI - Cyclosporine A-induced apoptosis in renal tubular cells is related to oxidative damage and mitochondrial fission. AB - Cyclosporine A (CsA) nephrotoxicity has been linked to reactive oxygen species (ROS) production in renal cells. We have demonstrated that the antioxidant Vitamin E (Vit E) abolished renal toxicity in vivo and in vitro models. As one of the main sources of intracellular ROS are mitochondria, we studied the effects of CsA on several mitochondrial functions in LLC-PK1 cells. CsA induced ROS synthesis and decreased reduced glutathione (GSH). The drug decreased mitochondrial membrane potential (DeltaPsim) and induced physiological modifications in both the inner (IMM) and the outer mitochondrial membranes (OMM). In the IMM, CsA provoked mitochondrial permeability transition pores (MPTP) and cytochrome c was liberated into the intermembrane space. CsA also induced pore formation in the OMM, allowing that intermembrane space contents can reach cytosol. Furthermore, CsA altered the mitochondrial dynamics, inducing an increase in mitochondrial fission; CsA increased the expression of dynamin related protein 1 (Drp1) that contributes to mitochondrial fission, and decreased the expression of mitofusin 2 (Mfn2) and optic atrophy protein 1 (Opa1), proteins involved in the fusion process. All these phenomena were related to apoptosis. These effects were inhibited when cells were treated with the antioxidant Vit E suggesting that they were mediated by the synthesis of ROS. PMID- 23347877 TI - 5-Iodo-2-aminoindan (5-IAI): chemistry, pharmacology, and toxicology of a research chemical producing MDMA-like effects. AB - In 2010, an internet snapshot of EMCDDA anticipated the presence of 5-iodo-2 aminoindan (5-IAI) within the recreational drug market. In 2011, this compound, a psychoactive derivative of 2-aminoindane, was identified in recreational products sold in the United Kingdom. 5-IAI is a rigid analogue of p-iodoamphetamine producing MDMA-like effects. The aim of this paper is to summarize the clinical, pharmacological, and toxicological information about this new potential drug of abuse. PMID- 23347875 TI - Acute effects of hexabromocyclododecane on Leydig cell cyclic nucleotide signaling and steroidogenesis in vitro. AB - Hexabromocyclododecane (HBCDD), an additive brominated flame retardant routinely added to various consumer products, was reported to have toxic effects upon biota, including endocrine disruption. In this study, the potential toxicity of HBCDD was tested in peripubertal rat Leydig cells in vitro during 6h exposure. HBCDD inhibited human chorionic gonadotropin- and forskolin-supported cAMP accumulation and steroidogenesis. It also inhibited basal cAMP production, but elevated basal steroidogenesis. The expression of several cAMP-dependent genes, including steroidogenic acute regulatory protein, cholesterol side chain cleavage enzyme, and 3beta-hydroxysteroid dehydrogenase, was also inhibited by HBCDD treatment. Nevertheless, this was not accompanied by a decrease in steroidogenic acute regulatory protein expression, as documented by western blot analysis, and activity of steroidogenic enzymes, as documented by unaffected steroidogenesis in the presence of permeable 22(R)-hydroxycholesterol. However, HBCDD caused significant decrease in mitochondrial membrane potential in untreated and human chorionic gonadotropin-treated cells. This indicates that HBCDD acute toxicity in Leydig cells reflects changes in mitochondrial membrane potential-dependent cAMP production and basal and cAMP-regulated cholesterol transport. This in turn facilitates basal but inhibits cAMP-dependent steroidogenesis. Acute effects of HBCDD treatment on transcription are also indicative of its sustained effects on Leydig cell function. PMID- 23347878 TI - Macrolide- and rifampin-resistant Rhodococcus equi on a horse breeding farm, Kentucky, USA. AB - Macrolide and rifampin resistance developed on a horse breeding farm after widespread use was instituted for treatment of subclinical pulmonary lesions in foals. Resistance occurred in 6 (24%) of 25 pretreatment and 8 (62%) of 13 (62%) posttreatment isolates from affected foals. Drug-resistant isolates formed 2 distinct genotypic clusters. PMID- 23347879 TI - Effect of alveolar bone support on zygomatic implants: a finite element analysis study. AB - The objective of this study was to investigate the influence of maxillary alveolar bone on the stress distribution of zygomatic implants. A three dimensional finite element model was created of half of a skull. Two zygomatic implants were modelled, placed in the skull supported by the zygomatic bone and the maxillary alveolar bone and connected by a fixed bridge. This model was duplicated, and the area of the maxillary alveolar bone supporting the implants was removed. Occlusal and lateral forces were applied to both models and the maximum von Mises stresses were recorded. Higher maximum stresses were noted in the model with no alveolar support. Occlusal stresses were higher than lateral stresses in the model with no alveolar support. Low stresses were noted in the zygomatic bone in both models. In conclusion, maxillary alveolar bone support is beneficial in the distribution of forces for zygomatic implants. PMID- 23347880 TI - Extensive bowenoid papulosis of the vulva treated by carbon dioxide laser in a patient with AIDS. PMID- 23347881 TI - MRI atlas of ectopic endometriosis. AB - Ectopic endometriosis is a common condition which is often underdiagnosed, where MRI can help make a diagnosis simply, non-invasively and without irradiation. However, imagery signs of it are enormously polymorphic with a wide range of possible locations. In this paper, we have tried to illustrate comprehensively all its MRI appearances depending on the different locations where it occurs. PMID- 23347882 TI - The U.S. training institute for dissemination and implementation research in health. AB - BACKGROUND: The science of dissemination and implementation (D&I) is advancing the knowledge base for how best to integrate evidence-based interventions within clinical and community settings and how to recast the nature or conduct of the research itself to make it more relevant and actionable in those settings. While the field is growing, there are only a few training programs for D&I research; this is an important avenue to help build the field's capacity. To improve the United States' capacity for D&I research, the National Institutes of Health and Veterans Health Administration collaborated to develop a five-day training institute for postdoctoral level applicants aspiring to advance this science. METHODS: We describe the background, goals, structure, curriculum, application process, trainee evaluation, and future plans for the Training in Dissemination and Implementation Research in Health (TIDIRH). RESULTS: The TIDIRH used a five day residential immersion to maximize opportunities for trainees and faculty to interact. The train-the-trainer-like approach was intended to equip participants with materials that they could readily take back to their home institutions to increase interest and further investment in D&I. The TIDIRH curriculum included a balance of structured large group discussions and interactive small group sessions.Thirty-five of 266 applicants for the first annual training institute were accepted from a variety of disciplines, including psychology (12 trainees); medicine (6 trainees); epidemiology (5 trainees); health behavior/health education (4 trainees); and 1 trainee each from education & human development, health policy and management, health services research, public health studies, public policy and social work, with a maximum of two individuals from any one institution. The institute was rated as very helpful by attendees, and by six months after the institute, a follow-up survey (97% return rate) revealed that 72% had initiated a new grant proposal in D&I research; 28% had received funding, and 77% had used skills from TIDIRH to influence their peers from different disciplines about D&I research through building local research networks, organizing formal presentations and symposia, teaching and by leading interdisciplinary teams to conduct D&I research. CONCLUSIONS: The initial TIDIRH training was judged successful by trainee evaluation at the conclusion of the week's training and six-month follow-up, and plans are to continue and possibly expand the TIDIRH in coming years. Strengths are seen as the residential format, quality of the faculty and their flexibility in adjusting content to meet trainee needs, and the highlighting of concrete D&I examples by the local host institution, which rotates annually. Lessons learned and plans for future TIDIRH trainings are summarized. PMID- 23347883 TI - Metabolic syndrome in survivors from the 2009 earthquake in Italy. PMID- 23347884 TI - Three-dimensional vector analysis of mandibular structural asymmetry. AB - OBJECTIVES: The three-dimensional (3D) asymmetric structure of the mandible makes it necessary to analyze both its size and angle. Currently the developing 3D analysis techniques are not able to perform the simultaneous linear and angular measurements. Our aim was to evaluate mandibular asymmetry using a vector-based system by constructing 3D vectors for the mandibular functional units. MATERIAL AND METHODS: We analyzed the 3D computed tomography images of normal control (N = 27) and asymmetric mandibles (N = 40). We created 3D vectors for the condylar, coronoid, body, gonial, and symphyseal functional units and compared the corresponding pairs of 3D vectors by calculating vector operations. RESULTS: The vector difference and other vector components represented the individual 3D architectural pattern and severity of the asymmetric mandible. The body unit contributed most to mandibular asymmetry followed by the condylar unit. CONCLUSIONS: The results indicate that 3D vector analysis can improve our understanding of the 3D architecture of asymmetric mandibles. This type of 3D vector analysis can be a useful tool for the comprehensive evaluation of its asymmetric mandibular structure. PMID- 23347885 TI - Assessment of skeletal stability of intraoral vertical ramus osteotomy with one day maxillary-mandibular fixation followed by early jaw exercise. AB - PURPOSE: Intraoral vertical ramus osteotomy (IVRO) is an effective surgical technique for cases of mandibular setback, is simpler and has a lower incidence of mental paraesthesia when compared to sagittal split ramus osteotomy (SSRO). However, IVRO has a disadvantage in the prolonged duration of postoperative maxillary-mandibular fixation (MMF) required due to the absence of rigid bone fixation. To avoid an extended MMF period, we developed a postoperative management protocol for our IVRO patients, using jaw exercises with elastic bands starting on the second day after surgery. METHODS: We evaluated the cephalometric skeletal and dental stabilities of 16 IVRO patients as they followed our protocol. RESULTS: The stabilities were confirmed and were similar to those of previous reports. CONCLUSION: One-day MMF and early initiation of jaw exercise after IVRO did not affect the jaw position stability. Moreover, our findings suggest that starting jaw exercise earlier after IVRO surgery is beneficial, as it allows patients to avoid a long period of rigid MMF so that they can resume their normal daily activities sooner. PMID- 23347886 TI - Acquisition and evaluation of verb subcategorization resources for biomedicine. AB - BACKGROUND: Biomedical natural language processing (NLP) applications that have access to detailed resources about the linguistic characteristics of biomedical language demonstrate improved performance on tasks such as relation extraction and syntactic or semantic parsing. Such applications are important for transforming the growing unstructured information buried in the biomedical literature into structured, actionable information. In this paper, we address the creation of linguistic resources that capture how individual biomedical verbs behave. We specifically consider verb subcategorization, or the tendency of verbs to "select" co-occurrence with particular phrase types, which influences the interpretation of verbs and identification of verbal arguments in context. There are currently a limited number of biomedical resources containing information about subcategorization frames (SCFs), and these are the result of either labor intensive manual collation, or automatic methods that use tools adapted to a single biomedical subdomain. Either method may result in resources that lack coverage. Moreover, the quality of existing verb SCF resources for biomedicine is unknown, due to a lack of available gold standards for evaluation. RESULTS: This paper presents three new resources related to verb subcategorization frames in biomedicine, and four experiments making use of the new resources. We present the first biomedical SCF gold standards, capturing two different but widely-used definitions of subcategorization, and a new SCF lexicon, BioCat, covering a large number of biomedical sub-domains. We evaluate the SCF acquisition methodologies for BioCat with respect to the gold standards, and compare the results with the accuracy of the only previously existing automatically-acquired SCF lexicon for biomedicine, the BioLexicon. Our results show that the BioLexicon has greater precision while BioCat has better coverage of SCFs. Finally, we explore the definition of subcategorization using these resources and its implications for biomedical NLP. All resources are made publicly available. CONCLUSION: The SCF resources we have evaluated still show considerably lower accuracy than that reported with general English lexicons, demonstrating the need for domain- and subdomain-specific SCF acquisition tools for biomedicine. Our new gold standards reveal major differences when annotators use the different definitions. Moreover, evaluation of BioCat yields major differences in accuracy depending on the gold standard, demonstrating that the definition of subcategorization adopted will have a direct impact on perceived system accuracy for specific tasks. PMID- 23347887 TI - Immunoregulatory cytokines in mouse placental extracts inhibit in vitro osteoclast differentiation of murine macrophages. AB - INTRODUCTION: Previous studies showed that placental extracts (PE) alleviates arthritic symptoms in animal models of arthritis. METHODS: To evaluate whether murine PEs obtained at embryonic days 7.5 (PE7) and 17.5 (PE18) regulate RANKL induced osteoclast differentiation, RAW 264.7 cells were cultured with RANKL and MCSF in presence or not of PEs. Tartrate-resistant acid phosphatase (TRAP) was stained and multinucleated TRAP positive cells were visualized under a light microscope. Cathepsin K and metalloprotease expression was assessed by RT-PCR and gelatin zymography respectively. NFATc1 expression was determined by immunoblot. To analyze NFAT-dependent transcription, macrophages were transfected with a luciferase reporter plasmid. Cytokines were determined in PEs by ELISA and immunoblot. Transforming growth factor (TGF)- beta and Interleukin (IL)-10 receptor were inhibited in cell cultures with specific antibodies. RESULTS: PE7 and PE18 inhibited RANKL-induced multinucleated TRAP positive cells, Cathepsin K expression and metalloprotease activity, as well as NFATc1 expression and activity, thereby inhibiting osteoclast differentiation of RAW cells. Inflammatory/Regulatory cytokine ratio was higher in PE7 than in PE18. Blocking TGF-beta abolished the effect of both, PE7 and PE18, on multinucleated TRAP positive cells and metalloprotease expression, whereas blocking IL-10 receptor reverted the effect of PE18 but not of PE7. DISCUSSION: Inhibition of osteoclast differentiation by PEs was not unexpected, since cytokines detected in extracts were previously found to regulate osteoclast differentiation. CONCLUSIONS: PEs inhibited osteoclast differentiation of macrophages in vitro. Downregulation of NFATc1 might be involved in this effect. Regulatory/Th2 cytokines play a role in the effect of PEs on osteoclast differentiation. PMID- 23347888 TI - Thick and thin fingers point out Turing waves. AB - Mouse genetics and computer simulations demonstrate that digit number and width are controlled by a Turing-type mechanism in which distal Hox genes modulate periodicity. PMID- 23347889 TI - The development and preliminary validation of the Taiwanese Manual Ability Measure for Burns. AB - OBJECTIVE: To develop and validate the Taiwanese Manual Ability Measure for Burns (T-MAM for Burns), a task-oriented functional evaluation tool to assess self reported manual ability in burn patients. DESIGN: A longitudinal study. PARTICIPANTS: A sample of 45 burn patients from burn rehabilitation centers with varying degrees of hand involvement. METHODS: The preliminary testing version was formed by adding burn specific items to the Taiwanese version of the Manual Ability Measure. A field test was then conducted for item reduction and psychometric properties testing. RESULTS: Out of 55 initial items, 20 were selected into the final version of the T-MAM for Burns. Psychometric analyses indicated that it was reliable (test-retest ICC=.99), with adequate concurrent validity with various other hand function tests (r=-.79 with the short form Disabilities of the Arm, Shoulder, and Hand, or, the QuickDASH) and discriminative validity (significant difference (t=2.99, P=.005) between groups with unilateral vs. bilateral hand burns), and responsive (ES=.24 and .44 at one- and 3-month evaluations). CONCLUSION: This study shows that the T-MAM for Burns has great potential to be a functional outcome measure for burn rehabilitation. Additional research with a larger sample should be conducted to further confirm its validity and reliability. PMID- 23347890 TI - How much do parents know about first aid for burns? AB - BACKGROUND: Prompt first aid reduces burn morbidity. With an estimated 19,000 children attending emergency departments (ED) with a burn or scald every year in the UK, a parent's knowledge of first aid is particularly important. This study evaluates the extent and source of this knowledge. METHODS: Parents attending the emergency and antenatal departments of a University Hospital answered a structured questionnaire detailing demographics, knowledge of burns first aid and its source. Knowledge was stratified into 4 categories: contraindicated, poor, inadequate and adequate. Individual chi-squared tests and ordered logistic regressions were performed to relate knowledge to demographic features. RESULTS: The 106 respondents (44% men) reflected a wide range of socio-economic (SE) grouping and educational level. Overall 32% had an adequate knowledge of burns first aid while 43% had poor or no knowledge. There was no significant correlation between gender, educational status or age and knowledge; however those from higher SE groups (p<0.05) and those who had undergone first aid training (p<0.01) had greater knowledge. Among 40% of parents who had undergone first aid training, 74% had adequate knowledge. The logistic regression accounting for all significant variables showed that previous first aid training was the most influential factor in knowledge of first aid (p<0.001). Interestingly, although 2/3 of parents wanted further training, 75% of those who did not had poor or no first-aid knowledge. CONCLUSIONS: Overall, the knowledge of burns first aid among parents is inadequate and correlates with lower SE groups. There was a significant association between knowledge and previous first aid training. Results suggest that targeting burns first aid training to all new parents, particularly those in low income households, would be of value. PMID- 23347891 TI - Characteristics of sequential targeting of brain glioma for transferrin-modified cisplatin liposome. AB - Methods on how to improve the sequential targeting of glioma subsequent to passing of drug through the blood-brain barrier (BBB) have been occasionally reported. However, the characteristics involved are poorly understood. In the present study, cisplatin (Cis) liposome (lipo) was modified with transferrin (Tf) to investigate the characteristics of potential sequential targeting to glioma. In bEnd3/C6 co-culture BBB models, higher transport efficiency across the BBB and cytotoxicity in basal C6 cells induced by Cis-lipo(Tf) than Cis-lipo and Cis solution, suggest its sequential targeting effect. Interestingly, similar liposomal morphology as that of donor compartment was first demonstrated in the receptor solution of BBB models. Meanwhile, a greater acquisition in the lysosome of bEnd3, distributed sequentially into the nucleus of C6 cells were found for the Cis-lipo(Tf). Pre-incubation of chlorpromazine and Tf inhibited this process, indicating that a clathrin-dependent endocytosis is involved in the transport of Cis-lipo(Tf) across the BBB. PMID- 23347892 TI - Poly(N-isopropylacrylamide)-coated microwell arrays for construction and recovery of multicellular spheroids. AB - Microwell arrays that have many micro-sized cavities on the device have been employed to form multicellular spheroids. However, methods to efficiently harvest the constructed spheroids from the microwell arrays have not been thoroughly investigated. We evaluated the effects of poly(N-isopropylacrylamide) (PNIPAAm) for constructing and harvesting spheroids from microwell arrays. Microwell arrays were coated with ethanol containing 1%, 2.5%, 5%, or 10% PNIPAAm by a solvent casting method and then dried. Spheroids formed using the coated microwell arrays were harvested. Highly efficient and rapid recovery of NIH3T3 mouse fibroblast spheroids were achieved for the 5% and 10% coated wells (93.2% +/- 1.6% and 93.6% +/- 1.1% at 60 s, respectively), whereas recovery was not efficient for 0%, 1%, and 2.5% coated wells (0.2% +/- 0.2%, 1.1% +/- 0.6%, and 7.8% +/- 4.0% at 60 s, respectively). Because PNIPAAm is a thermoresponsive polymer that exhibits a lower critical solution temperature (LCST) of 32 degrees C, we examined the effects of temperature on the recovery rate. The recovery rates at 4 degrees C (below LCST) were equivalent to or higher than those at 37 degrees C (above LCST) for all four cell types examined. Functional assessment suggests that the PNIPAAm microwell arrays are not toxic to the formed spheroids. The PNIPAAm microwell array developed in the present study will be useful for constructing and harvesting spheroids. PMID- 23347893 TI - A flexible hydrophilic-modified graphene microprobe for neural and cardiac recording. AB - A graphene-based flexible microprobe developed by microelectromechanical system technology shows high resolution for the detection of electrophysiological signals from various bio-objects. The hydrophilization post-treatment using steam plasma was performed on the graphene surface to decrease the interfacial impedance between graphene and electrolyte, and thus improve the signal-to-noise ratio during neural and cardiac recording. The signal-to-noise ratio of the action potentials from axons of a crayfish measured by hydrophilic-modified graphene microprobe (27.8+/-4.0dB) is higher than that of untreated device (20.3+/-3.3dB). Also, the form of the QRS complex and T wave in the electrocardiogram of the zebrafish heart can be clearly distinguished using the modified device. The total measured noise levels of the overall stability of the system were 4.2MUVrms (hydrophilic graphene) and 7.64MUVrms (hydrophobic graphene). The graphene-based implant can be further used for in vivo, long-term recording and retina prosthesis. FROM THE CLINICAL EDITOR: In this study a graphene-based flexible microprobe developed using microelectromechanical system technology was demonstrated to enable high resolution detection of electrophysiological signals, including EKG in zebrafish models. Both hydrophilic and hydrophobic graphene were studied, paving the way to potential future clinical applications of this new technology. PMID- 23347894 TI - Alginate-coated chitosan nanogel capacity to modulate the effect of TLR ligands on blood dendritic cells. AB - Biodegradable nanoparticles have been employed for vaccine delivery, frequently admixed with adjuvants. Surprisingly, there is little information on their modulation of immune responses, speculated to be negligible. We analyzed the immunomodulatory capacity of alginate-coated chitosan nanogels (Ng), on porcine and human blood dendritic cells (DCs), when applied with defined adjuvants targeting different DC subpopulations. DC maturation, cytokine production and cell migration were assessed. Ng differentially influenced the immunomodulatory characteristics of individual Toll-like receptor (TLR) ligands: Pam3Cys-SK4 induced IL-1beta was enhanced; CpG-oligodeoxynucleotides (CpG-ODN)-induced IFN alpha, IL-6 and TNFalpha were impaired; CpG-ODN-induced CD86 and CCR7, and cell migration, were diminished-plasmacytoid DCs (pDCs) were particularly sensitive. Therein, the Ng influence on DC endocytosis of the TLR ligands was apparently a major contributory element. This demonstrates the importance of predefining the interplay between delivery vehicles and admixed immunostimulatory moieties, for ensuring appropriate immune activation and efficacious combinations. FROM THE CLINICAL EDITOR: Biodegradable nanoparticles have been utilized in vaccine delivery; however, there is little information available on their immunomodulatory properties, which are thought to be negligible. This study clearly demonstrates that nanogels do influence the developing immune response, which needs to be taken into consideration when utilizing these otherwise very efficacious vaccine delivery approaches. PMID- 23347895 TI - Pharmaceutically versatile sulfated polysaccharide based bionano platforms. AB - Sulfated polysaccharides are complex polysaccharide molecules with excellent physico-chemical properties and bioactivities. On the basis of origin, they are classified as plant, animal, microbial and chemically synthesized sulfated polysaccharides. They have been widely applied in the fields of material and biological sciences. Biocompatibility and biodegradability of these molecules facilitate their increased use in the nanoparticle synthesis and tissue engineering applications. This review focuses on the structure, function and applications of important types of natural and chemically derived sulfated polysaccharides in the fields of nanotechnology and biomedical sciences. In the first part, we discuss the classification and role of sulfated polysaccharides in various fields. Later, we elaborate the specific bionano applications of commercially important sulfated polysaccharides in ionic gelation, stabilizing, cross-linking, capping and encapsulation of drugs. Finally, we conclude with the future scope and advanced applications of sulfated polysaccharides in various fields of interdisciplinary science. FROM THE CLINICAL EDITOR: This comprehensive review focuses on the structure, function, and applications of natural and chemically derived sulfated polysaccharides in the fields of nanotechnology and biomedical sciences. PMID- 23347896 TI - SNEDDS curcumin formulation leads to enhanced protection from pain and functional deficits associated with diabetic neuropathy: an insight into its mechanism for neuroprotection. AB - Curcumin has shown to be effective against various diabetes related complications. However major limitation with curcumin is its low bioavailability. In this study we formulated and characterized self nano emulsifying drug delivery system (SNEDDS) curcumin formulation to enhance its bioavailability and then evaluated its efficacy in experimental diabetic neuropathy. Bioavailability studies were performed in male Sprague Dawley rats. Further to evaluate the efficacy of formulation in diabetic neuropathy various parameters like nerve function and sensorimotor perception were assessed along with study of inflammatory proteins (NF-kappaB, IKK-beta, COX-2, iNOS, TNF-alpha and IL-6). Nanotechnology based formulation resulted in prolonged plasma exposure and bioavailability. SNEDDS curcumin provided better results against functional, behavioural and biochemical deficits in experimental diabetic neuropathy, when compared with naive curcumin. Further western blot analysis confirmed the greater neuroprotective action of SNEDDS curcumin. SNEDDS curcumin formulation due to higher bioavailability was found to afford enhanced protection in diabetic neuropathy. FROM THE CLINICAL EDITOR: In this study the authors formulated and characterized a self-emulsifying drug delivery system for formulation to enhance curcumin bioavailability in experimental diabetic neuropathy. Enhanced efficacy was demonstrated in a rat model. PMID- 23347898 TI - The synthesis and evaluation of polymer prodrug/collagen hybrid gels for delivery into metastatic cancer cells. AB - Metastatic cancer cells degrade extracellular matrix containing collagen. In this study, a variety of different polymer prodrugs have been synthesized and embedded in collagen gels for application in a metastasis-associated drug delivery system (DDS). Dendrimer-doxorubicin (Dox) prodrugs were prepared with different surfaces, including collagen peptides and polyethylene glycol. Furthermore, Dox was conjugated to linear poly(glutamic acid) (poly-Glu) instead of the dendrimer. The cytotoxicities of each of these polymer prodrug systems against the poorly invasive MCF-7 and highly invasive MDA-MB-231 cells were similar. The highly invasive MDA-MB-231 cells, however, were more sensitive than the MCF-7 cells to the polymer prodrugs-embedded collagen gels, suggesting that these polymer prodrugs/collagen hybrid gels would be useful for the development of metastasis associated DDSs. The cytotoxicities of the polymer prodrugs were dependent on their chemical compositions. The collagen peptide-conjugated dendrimer prodrug/collagen hybrid gel demonstrated in vivo anticancer effects in an orthotopic metastatic mouse model. FROM THE CLINICAL EDITOR: In this study, a variety of polymer prodrugs have been synthesized and embedded in collagen gels to be used in a metastasis-associated drug delivery system, demonstrating in vivo anticancer effects in an orthotopic metastatic mouse model. PMID- 23347899 TI - Three stars of the constellation of color intravascular ultrasound in the space of tissue characterization of coronary plaque. PMID- 23347897 TI - A novel peptide nanomedicine for treatment of pancreatogenic diabetes. AB - Pancreatogenic diabetes (PD) is a potentially fatal disease that occurs secondary to pancreatic disorders. The current anti-diabetic therapy for PD is fraught with adverse effects that can increase morbidity. Here we investigated the efficacy of novel peptide nanomedicine: pancreatic polypeptide (PP) in sterically stabilized micelles (SSM) for management of PD. PP exhibits significant anti-diabetic efficacy but its short plasma half-life curtails its therapeutic application. To prolong and improve activity of PP in vivo, we evaluated the delivery of PP in SSM. PP-SSM administered to rats with PD, significantly improved glucose tolerance, insulin sensitivity and hepatic glycogen content compared to peptide in buffer. The studies established the importance of micellar nanocarriers in protecting enzyme-labile peptides in vivo and delivering them to target site, thereby enhancing their therapeutic efficacy. In summary, this study demonstrated that PP-SSM is a promising novel anti-diabetic nanomedicine and therefore should be further developed for management of PD. FROM THE CLINICAL EDITOR: Pancreatic peptide was earlier demonstrated to address pancreatogenic diabetes, but its short half-life represented major difficulties in further development for therapeutic use. PP-SSM (pancreatic polypeptide in sterically stabilized micelles) is a promising novel anti-diabetic nanomedicine that enables prolonged half-life and increased bioactivity of PP, as shown in this novel study, paving the way toward clinical studies in the near future. PMID- 23347900 TI - On the effect of a therapy able to modify both the growth rates in a Gompertz stochastic model. AB - A Gompertz-type diffusion process characterized by the presence of exogenous factors in the drift term is considered. Such a process is able to describe the dynamics of populations in which both the intrinsic rates are modified by means of time-dependent terms. In order to quantify the effect of such terms the evaluation of the relative entropy is made. The first passage time problem through suitable boundaries is studied. Moreover, some simulation results are shown in order to capture the dependence of the involved functions on the parameters. Finally, an application to tumor growth is presented and simulation results are shown. PMID- 23347901 TI - Clinical characteristics and outcome of isolated extramedullary relapse in acute leukemia after allogeneic stem cell transplantation: a single-center analysis. AB - Isolated extramedullary relapse (EMR) of acute leukemia (AL) is a rare occurrence. However, it appears to be more common after allogeneic stem cell transplantation (allo-SCT). To characterize what has been observed in isolated EMR, we investigated 287 consecutive AL patients (144 acute myeloid leukemia; 138 acute lymphocytic leukemia; 5 acute mixed-lineage leukemia) who underwent allo SCT. Twelve cases experienced relapse at extramedullary sites without concomitant involvement of the bone marrow (BM). The onset to relapse after allo-SCT was longer in extramedullary sites than in the BM (median, 10 months versus 5.5 months). EMR sites varied widely and included the central nervous system, skin, bone, pelvis and breasts. Univariate analysis demonstrated that cytogenetic abnormalities were correlated significantly with the onset of isolated EMR (P=0.001). The prognosis for patients who develop EMR remained poor but was relatively better than that after BM relapse (overall survival, 10 versus 18 months). Compared with local or single therapy, patients treated with systemic treatment in combination with local treatment could yield a favorable prognosis. In conclusion, we observed a significant number of isolated cases of EMR in AL patients after allo-SCT, cytogenetic abnormalities were correlated significantly with the onset of isolated EMR. We found that intensive approaches combining local and systemic therapy could produce favorable responses which may cure a proportion of these patients. PMID- 23347902 TI - Myelodysplastic syndromes should been renamed as myelodysplastic neoplasms. PMID- 23347904 TI - Is immune escape via human leukocyte antigen expression clinically relevant in chronic lymphocytic leukemia? Focus on the controversies. AB - Changes in classical and non-classical human leukocyte antigen expression by tumor cells can play a critical role in the generation of tumor antigen-specific immune responses and can modulate the interactions of natural killer cells and T cell subpopulations with target cells. Recently, several studies have investigated the relations between HLA molecules and prognosis in B-CLL, suggesting a potential clinical relevance of tumor escape mechanisms. In this paper, we will summarize conflicting information about the role of HLA-related prognostic factors in B-CLL, such as downregulation of HLA class I antigen expression, interactions between natural killer cell receptor and certain ligands and the role of HLA-G expression. PMID- 23347903 TI - Distinguishing hairy cell leukemia variant from hairy cell leukemia: development and validation of diagnostic criteria. AB - Hairy cell leukemia (HCL) and hairy cell leukemia-variant (HCL-v) are rare diseases with overlapping clinico-pathological features. We performed flow cytometry analysis (FCM) of 213 cases (169 HCL, 35 HCL-v, 9 splenic marginal zone lymphoma (SMZL)), correlating results with available corresponding clinical and morphological data. FCM distinguished HCL-v from HCL and SMZL based solely upon expression of four antigens (CD11c, CD25, CD103, CD123) combined with B-cell markers (CD19, CD20, CD22). HCL-v expressed bright CD20, bright CD22, CD11c(100%), CD103(100%), dim(40%) or negative(60%) CD123, and uniformly lacked CD25(100%). HCL expressed bright CD20, bright CD22, bright CD11c, bright CD25, CD103, and bright homogeneous CD123(100%). Aberrant expression of CD5(2%/3%), CD10(12%/3%), CD23(21%/11%), CD38(14%/0%), CD2(2%/9%), CD4(0.5%/0%) and CD13(0.5%/3%), was observed in HCL/HCL-v, respectively. SMZL cases were CD103(-) and CD123(-) except for one case with dim CD123. HCL showed significantly greater marrow infiltration over HCL-v. Prominent nucleoli were observed in most HCL-v but rarely in HCL. A third of HCL and HCL-v marrows were hypocellular or aplastic appearing. Detection of BRAFV600E mutation and annexin A1 were examined in a subset of cases to further validate FCM diagnostic criteria. HCL-v was negative for both annexin A1 (100%) and BRAFV600E mutation (100%), in contrast to HCL (74% positive for annexin A1; 76% positive for BRAFV600E mutation). HCL-v is resistant to traditional HCL therapy, making accurate diagnosis imperative. We have defined FCM criteria for differentiation of HCL-v from HCL and SMZL. PMID- 23347905 TI - SO2-catalyzed steam pretreatment enhances the strength and stability of softwood pellets. AB - Densification can partially resolve the logistical challenges encountered when large volumes of biomass are required for bioconversion processes to benefit from economies-of-scale. Despite the higher bulk density of pellets, their lower mechanical strength and sensitivity to moisture are still recurring issues hindering long term transportation and storage. In this study, we have evaluated the potential benefits of SO(2)-catalyzed steam treatment to achieve both the needed size reduction prior to pelletization while improving the stability of the produced pellets. This pretreatment substantially reduced the particle size of the woodchips eliminating any further grinding. The treated pellets had a higher density and exhibited a two-time higher mechanical strength compared to untreated pellets. Despite a higher moisture adsorption capacity, treated pellets remained intact even under highly humid conditions. The high heating values, low ash content and good overall carbohydrate recovery of treated pellets indicated their potential suitability for both biochemical and thermochemical applications. PMID- 23347906 TI - [Percutaneous tracheostomy in the ventilated patient]. AB - The medical indications of tracheostomy comprise the alleviation of upper airway obstruction; the prevention of laryngeal and upper airway damage due to prolonged translaryngeal intubation in patients subjected to prolonged mechanical ventilation; and the facilitation of airway access for the removal of secretions. Since 1985, percutaneous tracheostomy (PT) has gained widespread acceptance as a method for creating a surgical airway in patients requiring long-term mechanical ventilation. Since then, several comparative trials of PT and surgical tracheostomy have been conducted, and new techniques for PT have been developed. The use of percutaneous dilatation techniques under bronchoscopic control are now increasingly popular throughout the world. Tracheostomy should be performed as soon as the need for prolonged intubation is identified. However a validated model for the prediction of prolonged mechanical ventilation is not available, and the timing of tracheostomy should be individualized. The present review analyzes the state of the art of PT in mechanically ventilated patients--this being regarded by many as the technique of choice in performing tracheostomy in critically ill patients. PMID- 23347907 TI - Joint motion pattern classification by cluster analysis of kinematic, demographic, and subjective variables. AB - The purpose of this study is to identify joint motion patterns by classifying the full range of motion (ROM) into several sections. Forty participants were stratified by age and gender and they performed 18 full-swing motions at a self selected speed. Joint angle, angular velocity, angular acceleration, and subjective discomfort rating were collected for each motion. K-means cluster analyses were used to classify joint motion patterns and ROM sections. The results showed that two or three clusters were mainly determined by the kinematic variables of angular velocity and acceleration. The motions of three clusters showed that the ROM sections of low and moderate velocity with moderate and high accelerations occurred in the initial (negative) and terminal (positive) phases, respectively, whereas those of high velocity with low acceleration were shown in the mid (neutral) phase. The motions of two clusters revealed that while the patterns of high velocity and high acceleration were found on the positive side of the ROM, those of low velocity and low acceleration were on the negative and neutral sides. The ROM sections close to both ends of the ROM may have a larger physical load than the others. This study provides information that could be useful for developing postural analysis tools for dynamic work. PMID- 23347908 TI - The Glasgow Sleep Impact Index (GSII): a novel patient-centred measure for assessing sleep-related quality of life impairment in Insomnia Disorder. AB - OBJECTIVES: Daytime dysfunction and quality of life impairment are important and salient consequences of poor sleep in those with insomnia. Existing measurement approaches to functional impact tend to rely on non-specific generic tools, non validated scales, or ad hoc single scale items. Here we report the development and validation of the Glasgow Sleep Impact Index (GSII), a novel self-report measure which asks patients to generate, and assess, three domains of impairment unique to their own individual context. These three patient-generated areas of impairment are ranked in order of concern (1-3; i.e. 1=the most concerning impairment), and then rated on a visual analogue scale with respect to impact in the past two weeks. Patients re-rate these specified areas of impairment, post intervention, permitting both individual and group-level analyses. METHODS: One hundred and eight patients (71% female; Mean age=45 yrs) meeting Research Diagnostic Criteria for Insomnia Disorder completed the GSII, resulting in the generation of 324 areas (ranks) of sleep-related daytime and quality of life impairment. Fifty-five patients also completed the GSII pre- and post-sleep restriction therapy. The following psychometric properties were assessed: content validity of generated domains; relationship between ranks of impairment; and sensitivity to change post-behavioural intervention. RESULTS: Content analysis of generated domains support recent DSM-5 proposals for specification of daytime consequences of insomnia; with the most commonly cited areas reflecting impairments in energy/motivation, work performance, cognitive functioning, emotional regulation, health/well-being, social functioning and relationship/family functioning. Preliminary results with 108 patients indicate the GSII to have excellent face and construct validity. The GSII was found to be sensitive to change, post-behavioural treatment (p<0.001; Cohen's d>=0.85 for all three ranks of impairment), and improvements were associated with reductions in insomnia severity in both correlational (range of r=0.28-0.56) and responder versus non-responder analyses (all p<0.05). CONCLUSIONS: The development of the GSII represents a novel attempt to capture and measure sleep-related quality of life impairment in a valid and meaningful way. Further psychometric and clinical evaluation is suggested. PMID- 23347909 TI - Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. AB - OBJECTIVE: To provide a 16-year update from the authors' 1996 report documenting a 38% conversion from idiopathic rapid eye movement sleep behavior disorder (iRBD) to a parkinsonian disorder at a mean interval of nearly 13 years after the onset of iRBD in a series of 29 males > or =50 years old. METHODS: The methods of evaluation, diagnosis and follow-up were previously described in the 1996 report. All patients had video-polysomnography (vPSG) confirmed RBD. RESULTS: 80.8% (21/26) of patients who were initially diagnosed with iRBD eventually developed parkinsonism/dementia (three of the original 29 patients were lost to follow-up). The distribution of diagnoses was as follows: n=13, Parkinson's disease (PD); n=3, dementia with Lewy bodies (DLB); n=1, dementia (unspecified; profound); n=2, multiple system atrophy (MSA); n=2, clinically diagnosed Alzheimer's Disease (AD) with autopsy-confirmed combined AD plus Lewy body disease pathology. Among the 21 iRBD "converters," the mean age (+/-SD) of iRBD onset was 57.7+/-7.7 years; mean age (+/-SD) of parkinsonism/dementia onset was 71.9+/-6.6 years; and mean interval (+/-SD) from iRBD onset to parkinsonism/dementia onset was 14.2+/-6.2 years (range: 5-29 years). CONCLUSION: The vast majority of men > or =50 years old initially diagnosed with iRBD in this study eventually developed a parkinsonian disorder/dementia, often after a prolonged interval from onset of iRBD, with the mean interval being 14 years while the range extended to 29 years. Also, the specificity of iRBD converting to parkinsonism/dementia is striking. These findings carry important clinical and research implications in the convergent fields of sleep medicine, neurology, and neuroscience, and identify an optimal clinical group for conducting prospective research studies utilizing putative neuroprotective agents to delay the emergence of, or halt the progression to, parkinsonism and/or cognitive impairment as manifestations of either PD, DLB or MSA. PMID- 23347910 TI - Rapid eye movement sleep behavior disorder in adults younger than 50 years of age. AB - Rapid eye movement (REM) sleep behavior disorder (RBD) occurring prior to age 50 is termed early-onset RBD. Early-onset RBD comprises a substantial minority of cases, and demonstrates the differences in demographics, comorbidities, and clinical considerations from previously described typical RBD with onset >50years. The world literature on RBD is reviewed with specific focus on features that distinguish early-onset RBD, including more gender parity, increased proportion of idiopathic cases, increased proportion of cases associated with narcolepsy, parasomnia overlap disorder, antidepressants, and possibly autoimmune disorders, and clinical presentation. PMID- 23347911 TI - Gender specific association of child abuse and adult cardiovascular disease in a sample of patients with basal cell carcinoma. AB - OBJECTIVE: The aim of this study is to examine whether child abuse or neglect is more strongly associated with adult cardiovascular disease, and whether these associations differ by gender. METHODS: A total of 116 participants (mean age 57.75 years) reported their experience of childhood maltreatment using the well validated Childhood Experience of Care and Abuse Questionnaire. Cardiovascular disease was assessed using the Older Adults Resources Survey Multidimensional Functional Assessment Questionnaire. RESULTS: Child abuse but not neglect was significantly associated with adult cardiovascular disease. The significant relationship between child abuse and cardiovascular disease was specific to women. CONCLUSION: The results of this study indicate that being abused as a child is significantly associated with cardiovascular disease in adulthood, particularly among women. PMID- 23347912 TI - [Reliability of a questionnaire used in the long-term follow up of the opinion and perceptions of family medicine by medical students of the University of Zaragoza (Spain)]. AB - AIM: Family medicine deals with certain aspects and perspectives that are often left behind in the training of other levels of care, thus the need for medical students to make contact with Primary Care is of increasing importance. The aim of this study is to evaluate the reliability of the questionnaire of the UNIMEDIFAM group (FIS PI070975) for the long-term outcome of expectations and knowledge about family medicine. DESIGN: Reliability of a questionnaire. SETTING: University of Zaragoza. PARTICIPANTS: 371 students from the 1st, 3rd, 5th, and 6th years. METHOD: The internal consistency of the questionnaire was determined using Cronbach's alpha coefficient, and the stability using the test-retest. RESULTS: On scale A of the questionnaire we found that three of 19 items were unstable, in 8 of 26 on scale B, and 3 of 38 items on scale C. The Cronbach's alpha value of scale A was 0.722, 0.861 on scale B, and 0,663 on scale C. CONCLUSIONS: The 3 scales are within the appropriate values, except scale C, which is very close. The findings of this validation process can serve as a reference that may be extrapolated to the UNIMEDIFAM national questionnaire. PMID- 23347913 TI - [Gender violence in nursing students during their dating relationships]. AB - AIM: To determine the prevalence of gender violence (GV) suffered by student nurses and to identify its relationship with some sociodemographic and personal variables (social support and self-esteem) and their perception about their role as primary care providers. DESIGN: Cross-sectional study. LOCATION: Faculty of Medicine and Health Sciences (University of Oviedo). PARTICIPANTS: Nursing students. MAIN MEASUREMENTS: The CUVINO questionnaire was used. It measures 42 behavioral indicators and 8 GV factors and allows to identify technical and perceived violence during courtship and other related situations. The level of social self-esteem, support and variables related with the nursing role were also measured. RESULTS: Using the standard of "zero tolerance", 85.8% suffered technical violence, mainly by "detachment" and "coercion" (73.3%), while almost 1 in 5 also suffered "physical" violence (18.3%). A lower percentage (9.0%) reported having been really ill-treated, perception related to the global proportion of students who felt trapped (31.7%, P <.001), felt fear (13.8%, P <.001) and a further delay in breaking the relationship (13.2 months vs. 3.6; P <.05). Suffering technical violence was associated with less social support (P <.05) and less social self-esteem (P <.01). Academic training in GV improves recognition. CONCLUSIONS: The prevalence of GV situations between student nurses is very high and recognition is poor. Academic training could improve the perception of the problem, thus it would be desirable to strengthen its inclusion in the university curriculum, together with specific skills training. PMID- 23347914 TI - Gastric undifferentiated carcinoma with diffuse c-kit overexpression and focal neuroendocrine differentiation. AB - A case of gastric undifferentiated carcinoma with diffuse c-kit overexpression and focal neuroendocrine differentiation is described. A 76-year-old man presented appetite loss for 1 month. Gastric endoscopy showed an exophytic huge nodular mass with central ulceration at the gastric prepylorus. Distal gastrectomy was performed with lymph node dissection. Histology indicated anaplastic medium- to large-sized round tumor cells in discohesive sheets. Adenocarcinomatous areas forming tubular glands or with intracytoplasmic mucin on PAS and Alcian-blue staining were not found in any sections. Immunohistochemistry showed that the tumor cells were diffusely positive for cytokeratin, vimentin, c kit and focally positive for chromogranin A and synaptophysin. We hypothesized that c-kit overexpression of this tumor was attributed to neuroendocrine differentiation. PMID- 23347915 TI - Eustachian tube pressure equilibration. Temporal analysis of pressure changes based on direct physiological recordings with an intact tympanic membrane. AB - Eustachian tube function is important in pressure regulation of the middle ear. The efficacy or magnitude of pressure equilibration by tube openings should be determined by the gradient between middle ear and ambient pressure, but in theory also the duration of the tube opening may play a role. This study employed direct measurements of middle ear pressure in patients, who after parotidectomy had a catheter inserted into the mastoid with a pressure transducer connected. Thus, monitoring of the middle ear pressure in response to experimentally induced pressure changes could be performed under physiological conditions with an intact tympanic membrane. A set of six experiments was performed in four healthy subjects with different pressure deviations, where the counter-regulation was recorded over 10 min's time frames; a total of 75 events of tube openings were recorded. The transducer had a high accuracy of +/-0.1 daPa, and data were sampled at 10 Hz, so that detailed parameters for each tube opening event could be obtained: the pressure change, the pressure gradient, and the duration of the opening were determined. The pressure changes in response to Eustachian tube openings showed significant positive correlation to the pressure gradient and ambient pressure (p < 0.001). However, the duration of the opening time was not related to the pressure gradient (p = 0.16), as well as the pressure change was also not related to the duration of the opening time (p = 0.34). This meant that the magnitude of a pressure equilibration during tube openings was only determined by the pressure gradient and not variations in the duration of the opening time. Additional correlations were investigated including the pressure change rate. In conclusion, under physiological conditions the opening of the Eustachian tube behaves similarly to a reflex mechanism with relative constant duration. Therefore, in order to equilibrate higher pressure gradients, series of Eustachian tube openings are needed, rather than the tube will open during a longer period of time. This article is part of a special issue entitled "MEMRO 2012". PMID- 23347916 TI - Rapid measurement of auditory filter shape in mice using the auditory brainstem response and notched noise. AB - The notched noise method is an effective procedure for measuring frequency resolution and auditory filter shapes in both human and animal models of hearing. Briefly, auditory filter shape and bandwidth estimates are derived from masked thresholds for tones presented in noise containing widening spectral notches. As the spectral notch widens, increasingly less of the noise falls within the auditory filter and the tone becomes more detectible until the notch width exceeds the filter bandwidth. Behavioral procedures have been used for the derivation of notched noise auditory filter shapes in mice; however, the time and effort needed to train and test animals on these tasks renders a constraint on the widespread application of this testing method. As an alternative procedure, we combined relatively non-invasive auditory brainstem response (ABR) measurements and the notched noise method to estimate auditory filters in normal hearing mice at center frequencies of 8, 11.2, and 16 kHz. A complete set of simultaneous masked thresholds for a particular tone frequency were obtained in about an hour. ABR-derived filter bandwidths broadened with increasing frequency, consistent with previous studies. The ABR notched noise procedure provides a fast alternative to estimating frequency selectivity in mice that is well-suited to high through-put or time-sensitive screening. PMID- 23347919 TI - Experimental investigation on gaseous emissions from the combustion of date palm residues in laboratory scale furnace. AB - Emissions characteristics from the combustion of five date palm residues, DPR, (Date Palm Leaflets, Date Palm Rachis, Date Palm Trunk, Date Stones and fruitstalk prunings) in a laboratory scale furnace were investigated. Release of gaseous products such as CO2, CO, VOC, NOx and SO2 were measured at 600-800 degrees C. The main goal was to analyze thermal behaviors and gaseous emissions in order to select the most convenient biofuel for an application in domestic boiler installations. Regards to biofuel characteristics, date stone have the highest energy density (11.4GJ/m(3)) and the lowest ash content (close to 1.2%). Combustion tests show that among the tested date palm residues, date stone may be the promising biofuel for the design of combustion processing system. However, a special attention to the design of the secondary air supply should be given to prevent high emissions of CO and volatile matters. PMID- 23347918 TI - Tissue and cell-specific transcriptional activity of the human cytomegalovirus immediate early gene promoter (UL123) in zebrafish. AB - The human cytomegalovirus (CMV) is a member of the herpesvirus superfamily and causes different diseases including encephalitis, gastrointestinal diseases, pneumonitis, hepatitis, and retinitis. The immediate early (IE) gene of the human cytomegalovirus is essential to the viral replication. The proximal promoter region of this gene behaves as a strong enhancer and was commonly used to overexpress genes in vitro and in vivo in numerous cell types and species. However, there was no detailed report on the spatial and temporal transcriptional activity of the human CMV-IE gene promoter in zebrafish. In the present study, we generated stable transgenic zebrafish lines carrying the eGFP reporter gene under the control of the human CMV-IE gene promoter (-602/-14). We demonstrated that the hCMV-IE:eGFP transgene was expressed in numerous tissues but transgene expression was either regionalized or restricted to specific cell types as embryo and larval development progressed. In adult, the global expression pattern was similar but not identical to that described for the simian CMV-IE gene promoter in stable zebrafish with high transgene expression in the spinal cord, olfactory organs, central nervous system, neuromasts, retina, and skeletal muscles. However, we describe additional major expression sites in the hepatocytes, the epithelial cells of the intestine, the epithelial cells of the renal tubules, and the oocytes. Interestingly, our study shows that the tissue and cell specific expression pattern of the human CMV-IE gene promoter is rather well conserved in stable transgenic zebrafish compared to that observed in mouse. The major expression sites described in zebrafish are in agreement with the targeted cells and symptoms resulting from CMV infections in human. Finally, the hCMV:eGFP transgenic lines described in the present study will be valuable tools to trace specific cell lineages in adult zebrafish. PMID- 23347920 TI - High pressure thermal hydrolysis as pre-treatment to increase the methane yield during anaerobic digestion of microalgae. AB - Anaerobic digestion of algal biomass will be an essential component of algal biofuel production systems, yet the methane yield from digestion of algae is typically much lower than the theoretical potential. In this work, high pressure thermal hydrolysis (HPTH) is shown to enhance methane yield during algae digestion. HPTH pre-treatment was applied to both raw algae and algal residue resulting from lipid extraction. HPTH and even the lipid extraction process itself increased methane yield, by 81% and 33% respectively; in combination they increased yield by 110% over that of the raw algae (18L CH4 gVS(-1) substrate). HPTH had little effect on the rate of anaerobic digestion, however lipid extraction enhanced it by 33% over that for raw algae (0.21day(-1)). Digestion resulted in solubilisation of nitrogen (and phosphorous to a lesser degree) in all cases, showing that there is potential for nutrient recycling for algal growth. PMID- 23347921 TI - Sequential generation of hydrogen and methane from glutamic acid through combined photo-fermentation and methanogenesis. AB - Glutamic acid can hardly produce hydrogen via dark- or photo-fermentation without pretreatment. In this study, a novel process of acidogenic pretreatment with bacteria and zeolite treatment for NH4(+) removal was proposed to use glutamic acid as feedstock in photo-fermentation for efficient hydrogen production. Glutamic acid pretreated with acidogenic bacteria produces soluble metabolite products. After zeolite treatment, the acidulated solution, which mainly contains acetate, butyrate, and NH4(+), shows a decrease in NH4(+) concentration from 36.7mM to 3.2mM (NH4(+) removal efficiency of 91.1%). After NH4(+) removal, the treated solution is incubated with photosynthetic bacteria, exhibiting a maximum hydrogen yield of 292.9mL/g(-glutamic acid) during photo-fermentation. The residual solution from photo-fermentation is reused by methanogenic bacteria to produce a maximum methane yield of 102.7mL/g. The heating value conversion efficiency from glutamic acid to gas fuel significantly increases from 18.9% during photo-fermentation to 40.9% in the combined photo-fermentation and methanogenesis process. PMID- 23347917 TI - Lead roles for supporting actors: critical functions of inner ear supporting cells. AB - Many studies that aim to investigate the underlying mechanisms of hearing loss or balance disorders focus on the hair cells and spiral ganglion neurons of the inner ear. Fewer studies have examined the supporting cells that contact both of these cell types in the cochlea and vestibular end organs. While the roles of supporting cells are still being elucidated, emerging evidence indicates that they serve many functions vital to maintaining healthy populations of hair cells and spiral ganglion neurons. Here we review recent studies that highlight the critical roles supporting cells play in the development, function, survival, death, phagocytosis, and regeneration of other cell types within the inner ear. Many of these roles have also been described for glial cells in other parts of the nervous system, and lessons from these other systems continue to inform our understanding of supporting cell functions. This article is part of a Special Issue entitled "Annual Reviews 2013". PMID- 23347922 TI - Changes of heavy metal speciation during high-solid anaerobic digestion of sewage sludge. AB - The sequential extraction procedure developed by Tessier et al. was used in sludge anaerobic digestion to determine the heavy metal speciation. Sludge samples were taken every three days to investigate humic substances, VS/TS, pH, VFA, alkalinity, ammonia, the total content of Zn, Pb, Cu, Ni, and Cr, and also their distribution into EXCH, CARB, FeMnOx, OMB and RESI fractions. Results showed that, (1) Heavy metals were concentrated during the anaerobic digestion process. The concentration of all five kinds of heavy metals increased by about 50%. (2) The distribution of these heavy metals differed. (3) High-solid anaerobic digestion much or less increased the bioavailability of Cu, Zn, Ni and Cr while decreased the bioavailability of Pb. (4) There were significant degrees of correlation between heavy metal fractions and changes of some selected parameters (for example, pH, VS/TS, and VFA content). Except for Pb, the contents of total mobile fractions for Cu, Zn, Ni, Cr could be predictable from its total content. PMID- 23347923 TI - Fluorescence detection to determine proteins and humic-like substances fingerprints of exopolymeric substances (EPS) from biological sludges performed by size exclusion chromatography (SEC). AB - Fingerprints of extracellular polymeric substances (EPS) from activated and anaerobic granular sludges were obtained by size exclusion chromatography coupled to UV (210 and 280 nm) and fluorescence (221/350 nm (protein-like molecules) and 345/443 nm (humic-like substances)) detection. The total area below the peaks obtained with fluorescence detection is linked to the protein or humic-like substances EPS content. The EPS protein fingerprints, usually recorded with UV 280 nm, change dramatically, mainly in the relative size of peaks when they were measured by a florescence detection method. It means that the apparent molecular weight (aMW) distribution of EPS chomatophores and fluorophores is different. Protein-like and humic-like substances were found to be specific fingerprints of the EPS, affected by the type and origin of the bacterial aggregate and improve EPS sample differentiation. The protein-like fraction of EPS displays a wide range of aMW (>600 kDa-<10 kDa) whereas the humic-like substances fraction is composed of molecules of low aMW (6-<1.2 kDa). PMID- 23347924 TI - Life cycle assessment of biochar cofiring with coal. AB - This study used life cycle assessment software SimaPro 7.2 and impact assessment model IMPACT 2002+ to evaluate the environmental impact and benefits of a biochar cofiring supply chain used for electricity generation. The biochar was assumed to be produced by rice straw torrefaction and the case study was located in Taoyuan County, Taiwan. This supply chain may provide impact reduction benefits in five categories (aquatic ecotoxicity, terrestrial ecotoxicity, land occupation, global warming, and non-renewable energy) but cause higher impacts than coal firing systems in other categories. Damage assessment of cofiring systems indicated that damage to human health was higher while the damage categories of ecosystem quality, climate change, and resources were lower. Carbon reduction could be 4.32 and 4.68metric tons CO2eq/ha/yr at 10% and 20% cofiring ratios, respectively. The improvement of electricity generation efficiency of cofiring systems may be the most important factor for reducing its environmental impact. PMID- 23347925 TI - Enhanced catalysis of Yarrowia lipolytica lipase LIP2 immobilized on macroporous resin and its application in enrichment of polyunsaturated fatty acids. AB - An immobilization strategy was employed to improve activity and operational stability of Yarrowia lipolytica lipase LIP2 (YlLIP2) by using macroporous resins as carrier. D152H, a cation-exchange resin, was the best support. Under the optimized conditions, the immobilization efficiency was 89.81% and the specific activity was 809,751 U/g, being 2.1-fold higher than that of the free lipase. Bioimprinting and interfacial activation were used to further boost the catalytic activity of YlLIP2, respectively enhanced 21.5-fold, 231.2% and 107.2% compared to the free, non-bioimprinted and non-interfacial-activated lipases. The immobilized lipase exhibited much better thermal and pH stability and broader substrate specificity; when used to enrich docosahexaenoic acid (DHA) from Chlorella protothecoides oil, it could increase 1.66-fold of DHA content and show good operational stability. These indicate that the immobilized YlLIP2 offers a promising approach for the enrichment of DHA. PMID- 23347926 TI - Understanding precision nitrogen stress to optimize the growth and lipid content tradeoff in oleaginous green microalgae. AB - Nitrogen deficiency promotes lipid formation in many microalgae, but also limits growth and lipid productivity. In spite of numerous studies, there is poor understanding of the interactions of growth and lipid content, the time course of lipid accumulation and the magnitude of nitrogen deficiency required to stimulate lipid formation. These relationships were investigated in six species of oleaginous green algae, comparing high and low levels of deficiency. Nitrogen stress typically had disproportionate effects on growth and lipid content, with profound differences among species. Optimally balancing the tradeoffs required a wide range in nitrogen supply rate among species. Some species grew first and then accumulated lipids, while other species grew and accumulated lipids concurrently which resulted in increased lipid productivity. Accumulation of high lipid content generally resulted from a response to minimal stress. The data highlight the tremendous biodiversity that may be exploited to optimally produce lipids with precision nitrogen stress. PMID- 23347927 TI - Microalgae-associated bacteria play a key role in the flocculation of Chlorella vulgaris. AB - Flocculation is most preferred method for harvesting microalgae, however, the role of bacteria in microalgal flocculation process is still unknown. This study proves that bacteria play a profound role in flocculating by increasing the floc size resulting in sedimentation of microalgae. A flocculating activity of 94% was achieved with xenic Chlorella vulgaris culture as compared to 2% achieved with axenic culture. Denaturing gradient gel electrophoresis (DGGE) analysis of 16S rRNA gene of xenic C. vulgaris culture revealed the presence of Flavobacterium sp., Terrimonas sp., Sphingobacterium sp., Rhizobium sp. and Hyphomonas sp. as microalgae-associated bacteria. However when Flavobacterium, Terrimonas, Sphingobacterium were eliminated by fluorescence activated cell sorter (FACS), flocculating activity reduced to 3%. Further studies with cell free extracts also suggest that bacterial extracellular substances might also have a role in enhancing flocculation. We conclude that the collective presence of certain bacteria is the determining factor in flocculation of C. vulgaris. PMID- 23347928 TI - Characterisation of spruce, salix, miscanthus and wheat straw for pyrolysis applications. AB - This research details the characterisation of four Irish-grown lignocellulosic biomasses for pyrolysis by biomass composition analysis, TGA, and Py-GC/MS-FID. Ash content (mf) increased in the order spruce (0.26 wt.%) < salix (1.16 wt.%) < miscanthus (3.43 wt.%) < wheat straw (3.76 wt.%). Analysis of hydrolysis-derived sugar monomers showed that xylose concentrations (4.69-26.76 wt.%) ranged significantly compared to glucose concentrations (40.98-49.82 wt.%). Higher hemicellulose and ash contents probably increased non-volatile matter, and decreased the temperature of maximum degradation by TGA as well as yields of GC detectable compounds by Py-GC/MS-FID. Differences in composition and degradation were reflected in the pyrolysate composition by lower quantities of sugars (principally levoglucosan), pyrans, and furans for salix, miscanthus, and wheat straw compared to spruce, and increased concentrations of cyclopentenones and acids. PMID- 23347929 TI - Dry anaerobic digestion of food waste under mesophilic conditions: performance and methanogenic community analysis. AB - The performance of dry anaerobic digestion (AD) of food waste was investigated under mesophilic conditions and the methanogenic community was investigated using 454 pyrosequencing. Stable dry AD was achieved by hydraulic retention time (HRT) control without the addition of alkali agents. The average CH4 production rate, CH4 content, and volatile solid reduction rate were 2.51+/-0.17m(3)/m(3)/d, 66+/ 2.1%, and 65.8+/-1.22%, respectively, at an HRT of 40d. The methanogenic community of the seed sludge experienced a significant reduction in genus diversity from 18 to 4 and a dominant methanogenic shift from hydrogenotrophic to acetoclastic groups after the acclimation under dry condition. Almost all sequences of the dry anaerobic digester were closely related with those of Methanosarcina thermophila with similarity of 96.4-99.1%. The experimental results would serve as useful information to understand the dry AD system. PMID- 23347930 TI - Sugar recoveries from wheat straw following treatments with the fungus Irpex lacteus. AB - Irpex lacteus is a white-rot fungus capable of increasing sugar recovery from wheat straw; however, in order to incorporate biopretreatment in bioethanol production, some process specifications need to be optimized. With this objective, I. lacteus was grown on different liquid culture media for use as inoculums. Additionally, the effect of wheat straw particle size, moisture content, organic and inorganic supplementations, and mild alkali washing during solid-state fermentation (SSF) on sugar yield were investigated. Wheat thin stillage was the best medium for producing inoculums. Supplementation of wheat straw with 0.3mM Mn(II) during SSF resulted in glucose yields of 68% as compared to yields of 62% and 33% for cultures grown without supplementation or on untreated raw material, respectively after 21 days. Lignin loss, wheat straw digestibility, peroxidase activity, and fungal biomass were also correlated with sugar yields in the search for biopretreatment efficiency indicators. PMID- 23347931 TI - Characterization of cell wall components of wheat straw following hydrothermal pretreatment and fractionation. AB - Thermophysical pretreatment enhances the enzymatic hydrolysis of lignocellulose. However, its impact on cell wall chemistry is still poorly understood. This paper reports the effects of hydrothermal pretreatment on the degradation and alkali extractability of wheat straw cell wall polymers. Pretreatment resulted in loss and/or solubilization of arabinoxylans (by 53%), ferulic and diferulic acids which are important cross-linking agents accompanied by concomitant increases in cellulose (up to 43%) and lignin (29%). The remaining water-insoluble hemicelluloses were more readily extractable in alkali and were reduced in molecular weight indicating substantial thermochemical depolymerization. They were also associated with smaller but significant amounts of (cellulose-derived) glucose. The alkali-insoluble residues consisted predominantly of cellulosic glucose and lignin and contained p-coumaric acid. The depolymerization of hemicelluloses, reduction in cinnamic acids and partial degradation of cellulose is likely to contribute significantly to the accessibility of cellulases during subsequent enzymolysis. PMID- 23347932 TI - Evaluation of two statistical methods for optimizing the feeding composition in anaerobic co-digestion: mixture design and central composite design. AB - To investigate the feasibility of statistical methods in optimizing the feeding composition in anaerobic co-digestion, a simplex-centroid mixture design (SCMD) and central composite design (CCD) were evaluated with methane potential as the response variable. Dairy manure, chicken manure, swine manure and rice straw (RS) were selected as raw materials and two kinds of manures and RS were mixed in each blend. Each component served as an independent variable in the SCMD and CCD and involved two factors, the manure and C/N ratios. Co-digestion of three-component substrates resulted in higher methane potentials than single and two-component substrates. In response surface plots, SCMD showed the interactions among each component in the co-substrates and CCD presented the interaction between the ratio of manures and the C/N ratio. SCMD and CCD are both suitable methods for optimizing the feeding composition during anaerobic co-digestion. PMID- 23347933 TI - The importance of autopsy after failed delivery room resuscitation. PMID- 23347934 TI - Aquaporins. PMID- 23347935 TI - In vivo male fertility is affected by naturally occurring mitochondrial haplotypes. PMID- 23347936 TI - Embodiment of an alien hand interferes with intact-hand movements. PMID- 23347937 TI - Olfactory evolution: mice rethink stink. AB - Animals use a vast array of chemicals to communicate with others. How such signals originate is poorly known. Now a study traces the emergence of a signal from a metabolic product and the evolution of its behavioural significance. PMID- 23347938 TI - Visual attention: a cell that focuses on one object at a time. AB - A new study has identified a remarkable neuron in the dragonfly brain that chooses and faithfully follows one and only one prey-like visual target, completely ignoring another, thereby demonstrating a form of competitive selection required for visual attention. PMID- 23347939 TI - Brain size evolution: how fish pay for being smart. AB - An artificial selection experiment demonstrates that large-brained guppies learn better, but produce less offspring and have smaller guts. A close link between brain size and fertility suggests that energetic trade-offs play an important role in brain size evolution. PMID- 23347940 TI - Development: new wrinkles on genetic control of the MBT. AB - Three recent studies revise the prevailing view of regulation of the mid-blastula transition in Drosophila, indicating particular requirements for the Cdc25 phosphatase Twine and for zygotic transcription of a specific set of genes. PMID- 23347941 TI - Animal cognition: an end to insight? AB - Once hailed as insightful, the string-pulling behaviour of birds may actually rely on immediate visual feedback rather than mental simulation or planning. But is this an end to the study of animal insight or a call for a new approach? PMID- 23347942 TI - Visual attention: bringing the unseen past into view. AB - Attention facilitates perception and can bring stimuli too faint to see into consciousness. A new study shows that attention can reach into the past, acting on the memory trace of a stimulus that has disappeared before being attended. PMID- 23347943 TI - Adaptive radiation: convergence and non-equilibrium. AB - The spectacular adaptive radiation of cichlid fish in Lake Tanganyika encompasses extensive morphological convergence and co-occurrence of ecologically similar species, forcing a reevaluation of non-equilibrium dynamics in community assembly. PMID- 23347944 TI - Quality control: putting protein aggregates in a bind. AB - Asymmetric inheritance of protein aggregates in budding yeast is a fascinating yet controversial area of aging research. A recent study demonstrates that unfolded protein aggregates are confined to the mother by tethering to organelles rather than retrograde transport. PMID- 23347945 TI - Immune priming: mothering males modulate immunity. AB - The transfer of immunity from mother to offspring is widespread in animals. The father's contribution to this is usually negligible. However, in a sex-role reversed pipefish where fathers do the mothering, fathers make an important immune priming contribution, too. PMID- 23347947 TI - Comparative evaluation of antimicrobials for textile applications. AB - Many antimicrobial technologies are available for textiles. They may be used in many different textile applications to prevent the growth of microorganisms. Due to the biological activity of the antimicrobial compounds, the assessment of the safety of these substances is an ongoing subject of research and regulatory scrutiny. This review aims to give an overview on the main compounds used today for antimicrobial textile functionalization. Based on an evaluation of scientific publications, market data as well as regulatory documents, the potential effects of antimicrobials on the environment and on human health were considered and also life cycle perspectives were taken into account. The characteristics of each compound were summarized according to technical, environmental and human health criteria. Triclosan, silane quaternary ammonium compounds, zinc pyrithione and silver-based compounds are the main antimicrobials used in textiles. The synthetic organic compounds dominate the antimicrobials market on a weight basis. On the technical side the application rates of the antimicrobials used to functionalize a textile product are an important parameter with treatments requiring lower dosage rates offering clear benefits in terms of less active substance required to achieve the functionality. The durability of the antimicrobial treatment has a strong influence on the potential for release and subsequent environmental effects. In terms of environmental criteria, all compounds were rated similarly in effective removal in wastewater treatment processes. The extent of published information about environmental behavior for each compound varies, limiting the possibility for an in-depth comparison of all textile-relevant parameters across the antimicrobials. Nevertheless the comparative evaluation showed that each antimicrobial technology has specific risks and benefits that should be taken into account in evaluating the suitability of different antimicrobial products. The results also indicated that nanoscale silver and silver salts that achieve functionality with very low application rates offer clear potential benefits for textile use. The regular care of textiles consumes lots of resources (e.g. water, energy, chemicals) and antimicrobial treatments can play a role in reducing the frequency and/or intensity of laundering which can give potential for significant resource savings and associated impact on the environment. PMID- 23347946 TI - The biology of fear. AB - Each of us has felt afraid, and we can all recognize fear in many animal species. Yet there is no consensus in the scientific study of fear. Some argue that 'fear' is a psychological construct rather than something discoverable through scientific investigation. Others argue that the term 'fear' cannot properly be applied to animals because we cannot know whether they feel afraid. Studies in rodents show that there are highly specific brain circuits for fear, whereas findings from human neuroimaging seem to make the opposite claim. Here, I review the field and urge three approaches that could reconcile the debates. For one, we need a broadly comparative approach that would identify core components of fear conserved across phylogeny. This also pushes us towards the second point of emphasis: an ecological theory of fear that is essentially functional. Finally, we should aim even to incorporate the conscious experience of being afraid, reinvigorating the study of feelings across species. PMID- 23347948 TI - Climate change driven plant-metal-microbe interactions. AB - Various biotic and abiotic stress factors affect the growth and productivity of crop plants. Particularly, the climatic and/or heavy metal stress influence various processes including growth, physiology, biochemistry, and yield of crops. Climatic changes particularly the elevated atmospheric CO2 enhance the biomass production and metal accumulation in plants and help plants to support greater microbial populations and/or protect the microorganisms against the impacts of heavy metals. Besides, the indirect effects of climatic change (e.g., changes in the function and structure of plant roots and diversity and activity of rhizosphere microbes) would lead to altered metal bioavailability in soils and concomitantly affect plant growth. However, the effects of warming, drought or combined climatic stress on plant growth and metal accumulation vary substantially across physico-chemico-biological properties of the environment (e.g., soil pH, heavy metal type and its bio-available concentrations, microbial diversity, and interactive effects of climatic factors) and plant used. Overall, direct and/or indirect effects of climate change on heavy metal mobility in soils may further hinder the ability of plants to adapt and make them more susceptible to stress. Here, we review and discuss how the climatic parameters including atmospheric CO2, temperature and drought influence the plant-metal interaction in polluted soils. Other aspects including the effects of climate change and heavy metals on plant-microbe interaction, heavy metal phytoremediation and safety of food and feed are also discussed. This review shows that predicting how plant metal interaction responds to altering climatic change is critical to select suitable crop plants that would be able to produce more yields and tolerate multi stress conditions without accumulating toxic heavy metals for future food security. PMID- 23347949 TI - Theory of mind impairments in first-episode psychosis, individuals at ultra-high risk for psychosis and in first-degree relatives of schizophrenia: systematic review and meta-analysis. AB - Theory of mind (ToM) deficit is a well-established feature of schizophrenia and has been suggested as a vulnerability marker of this disorder. However, as most of this evidence is based on studies in chronic patients, it is less clear whether ToM is impaired prior to or following the onset of a first-episode and whether it is evident in unaffected relatives of patients. In this meta-analysis, ToM performance of 3005 individuals with first-episode psychosis (FEP), individuals at ultra-high risk for psychosis (UHR) and unaffected relatives were compared with 1351 healthy controls. ToM was substantially impaired in first episode psychosis (Cohen d=1.0) and this deficit was comparable to findings in chronic patients. ToM was also impaired in unaffected relatives (d=0.37) and UHR subjects (d=0.45) and performances of these groups were intermediate between FES and healthy controls. Severity of ToM deficits in unaffected relatives and UHR subjects was similar to other cognitive deficits observed in these groups. Longitudinal studies of clinical and genetic high-risk subjects are necessary to investigate the trajectory of development of ToM deficits in schizophrenia. PMID- 23347950 TI - Cocaine facilitates glutamatergic transmission and activates lateral habenular neurons. AB - Cocaine administration can be both rewarding and aversive. While much effort has gone to investigating the rewarding effect, the mechanisms underlying cocaine induced aversion remain murky. There is increasing evidence that the lateral habenula (LHb), a small epithalamic structure, plays a critical role in the aversive responses of many addictive drugs including cocaine. However, the effects of cocaine on LHb neurons are not well explored. Here we show that, in acute brain slices from rats, cocaine depolarized LHb neurons and accelerated their spontaneous firing. The AMPA and NMDA glutamate receptor antagonists, 6, 7 dinitroquinoxaline-2, 3-dione, DL-2-amino-5-phosphono-valeric acid, attenuated cocaine-induced acceleration. In addition, cocaine concentration-dependently enhanced glutamatergic excitation: enhanced the amplitude but reduced the paired pulse ratio of EPSCs elicited by electrical stimulations, and increased the frequency of spontaneous EPSCs in the absence and presence of tetrodotoxin. Dopamine and the agonists of dopamine D1 (SKF 38393) and D2 (quinpirole) receptors, as well as the dopamine transporter blocker (GBR12935), mimicked the effects of cocaine. Conversely, both D1 (SKF83566) and D2 (raclopride) antagonists substantially attenuated cocaine's effects on EPSCs and firing. Together, our results provide evidence that cocaine may act primarily via an increase in dopamine levels in the LHb that activates both D1 and D2 receptors. This leads to an increase in presynaptic glutamate release probability and LHb neuron activity. This may contribute to the aversive effect of cocaine observed in vivo. PMID- 23347952 TI - Morphine withdrawal produces ERK-dependent and ERK-independent epigenetic marks in neurons of the nucleus accumbens and lateral septum. AB - Epigenetic changes such as covalent modifications of histone proteins represent complex molecular signatures that provide a cellular memory of previously experienced stimuli without irreversible changes of the genetic code. In this study we show that new gene expression induced in vivo by morphine withdrawal occurs with concomitant epigenetic modifications in brain regions critically involved in drug-dependent behaviors. We found that naloxone-precipitated withdrawal, but not chronic morphine administration, caused a strong induction of phospho-histone H3 immunoreactivity in the nucleus accumbens (NAc) shell/core and in the lateral septum (LS), a change that was accompanied by augmented H3 acetylation (lys14) in neurons of the NAc shell. Morphine withdrawal induced the phosphorylation of the epigenetic factor methyl-CpG-binding protein 2 (MeCP2) in Ser421 both in the LS and the NAc shell. These epigenetic changes were accompanied by the activation of members of the ERK pathway as well as increased expression of the immediate early genes (IEG) c-fos and activity-regulated cytoskeleton-associated protein (Arc/Arg3.1). Using a pharmacological approach, we found that H3 phosphorylation and IEG expression were partially dependent on ERK activation, while MeCP2 phosphorylation was fully ERK-independent. These findings provide new important information on the role of the ERK pathway in the regulation of epigenetic marks and gene expression that may concur to regulate in vivo the cellular changes underlying the onset of the opioid withdrawal syndrome. PMID- 23347951 TI - Hippocampal Galphaq/11 but not Galphao-coupled receptors are altered in aging. AB - Normal aging may limit the signaling efficacy of certain GPCRs by disturbing the function of specific Galpha-subunits and leading to deficient modulation of intracellular functions that subserve synaptic plasticity, learning and memory. Evidence suggests that Galphaq/11 is more sensitive to the effects of aging relative to other Galpha-subunits, including Galphao. To test this hypothesis, the functionality of Galphaq/11 and Galphao were compared in the hippocampus of young (6 months) and aged (24 months) F344 * BNF1 hybrid rats assessed for spatial learning ability. Basal GTPgammaS-binding to Galphaq/11 was significantly elevated in aged rats relative to young and but not reliably associated with spatial learning. mAChR stimulation of Galphaq/11 with oxotremorine-M produced equivocal GTPgammaS-binding between age groups although values tended to be lower in the aged hippocampus and were inversely related to basal activity. Downstream Galphaq/11 function was measured in hippocampal subregion CA1 by determining changes in [Ca(2+)]i after mAChR and mGluR (DHPG) stimulation. mAChR-stimulated peak change in [Ca(2+)]i was lower in aged CA1 relative to young while mGluR mediated integrated [Ca(2+)]i responses tended to be larger in aged. GPCR modulation of [Ca(2+)]i was observed to depend on intracellular stores to a greater degree in aged than young. In contrast, measures of Galphao-mediated GTPgammaS-binding were stable across age, including basal, mAChR-, GABABR (baclofen)-stimulated levels. Overall, the data indicate that aging selectively modulates the activity of Galphaq/11 within the hippocampus leading to deficient modulation of [Ca(2+)]i following stimulation of mAChRs but these changes are not related to spatial learning. PMID- 23347953 TI - Motivational properties of D2 and D3 dopamine receptors agonists and cocaine, but not with D1 dopamine receptors agonist and L-dopa, in bilateral 6-OHDA-lesioned rat. AB - Dopamine dysregulation syndrome in Parkinson's disease (PD) has been attributed to dopamine replacement therapy (DRT). We hypothesize that DRT can induce a potential rewarding effect in an animal model of PD. Using the conditioned place preference (CPP) paradigm, we investigated the motivational effects of L-dopa, dopamine receptor agonists (DRAs), and cocaine in rat with a bilateral 6-OHDA lesion of the nigrostriatal dopaminergic pathway. In 6-OHDA animals, D1 receptors agonist (SKF81297) revealed significantly a conditioned place aversion (CPA) at 3 mg/kg and 9 mg/kg doses. D2 receptors agonist (bromocriptine) induced both CPP and CPA at 1 mg/kg and 10 mg/kg doses respectively. D3 receptors agonist (PD128907) induced a CPP only at 1 mg/kg, comparable to that of cocaine. Sham animals revealed biphasic CPP curves, with significant dose effect, for the intermediate dose of the 3 DRAs. However, L-dopa induced no significant effect while cocaine induced CPP in both lesioned and sham animals. In conclusion, this study confirms the predominant roles of D2R class, and most specifically D3R subtypes, in rewarding properties of DRT. PMID- 23347954 TI - H1152 promotes the degradation of polyglutamine-expanded ataxin-3 or ataxin-7 independently of its ROCK-inhibiting effect and ameliorates mutant ataxin-3 induced neurodegeneration in the SCA3 transgenic mouse. AB - Spinocerebellar ataxia type 3 (SCA3) caused by polyglutamine-expanded ataxin-3 is the most prevalent subtype of spinocerebellar ataxias. A compound, which decreases protein level of mutant ataxin-3 in SCA3 affected CNS regions, should be a promising therapeutic agent for SCA3. SCA3 and Huntington's disease (HD) belong to a family of polyglutamine neurodegenerative diseases. Rho-kinase (ROCK) inhibitor Y27632 reduced brain level of polyglutamine-expanded huntingtin in HD transgenic mouse. Therefore, we tested the possibility that ROCK inhibitors, Y27632, H1152 and GSK429286, downregulate protein expression of polyglutamine expanded ataxin-3-Q79. Y27632 or H1152 reduced protein level of HA-tagged ataxin 3-Q79 (ATX-3-Q79HA) expressed in HEK 293 cells. Compared to Y27632, H1152 decreased ATX-3-Q79HA protein level with a significantly more potency and efficacy. H1152 also reduced protein level of HA-tagged polyglutamine-expanded ataxin-7-Q52 (ATX-7-Q52HA), which causes spinocerebellar ataxia type 7 (SCA7). H1152 decreased ATX-3-Q79HA or ATX-7-Q52HA protein level in vitro by augmenting proteasome activity and promoting ATX-3-Q79HA or ATX-7-Q52HA degradation. GSK429286, which is structurally different from H1152 but equally inhibits ROCK, failed to affect protein level of ATX-3-Q79HA or ATX-7-Q52HA. Furthermore, shRNA mediated suppression of ROCK1 or ROCK2 expression in 293 cells did not affect protein level of ATX-3-Q79HA or ATX-7-Q52HA and H1152 reduction of ATX-3-Q79HA. Daily intraperitoneal administration of H1152 significantly decreased protein level of ATX-3-Q79HA in the cerebellum, pontine nuclei and spinal cord of SCA3 transgenic mice. H1152 also ameliorated pontine neuronal death and neurological phenotype of SCA3 transgenic mice. Our results suggest that H1152 might be an effective therapeutic agent for SCA3 or SCA7. PMID- 23347955 TI - Expression and characterization of SUMO-conjugated metal-responsive transcription factor 1: SIM-dependent cross-interaction and distinct DNA binding activity. AB - Metal-responsive transcription factor 1 (MTF-1) regulates a variety of genes involving in metal homeostasis and oxidative stress. We have shown that MTF-1 can be conjugated by small ubiquitin-like modifier (SUMO) and forms complexes with cellular factor(s) in a SUMO-interacting motif (SIM)-dependent manner. To investigate whether the interaction of MTF-1 and its SUMO conjugate occurs, we expressed and isolated MTF-1 and sumoylated MTF-1 (S-MTF-1) for functional studies. Various conditions were examined to optimize the expressions of MTF-1 and S-MTF-1. Results from affinity column chromatography demonstrated that the unmodified MTF-1 consistently co-eluted with the S-MTF-1. Mutations at the SIM did not reduce the level of MTF-1 sumoylation but the sumoylated product can then be purified to homogeneity. The presence of MTF-1 cross-interaction was further supported by in vitro pull-down assays. The ability of the purified proteins in binding metal-responsive element (MRE) was assessed with electrophoretic mobility shift assay. Noticeably, MTF-1 required the presence of cell extracts to render the binding activity. However, S-MTF-1 binds MRE in void of other cellular factors. The same characteristic was found for MTF-1 with SUMO fusion at the carboxyl terminus. These results indicate that the presence of SUMO moiety allows the protein to interact directly with MRE. PMID- 23347956 TI - Detection of Actinobacillus pleuropneumoniae in drinking water from pig farms. AB - Actinobacillus pleuropneumoniae is the aetiological agent of porcine pleuropneumonia and is normally transmitted by aerosols and direct contact between animals. A. pleuropneumoniae has traditionally been considered an obligate pathogen of pigs and its presence in the environment has yet to be investigated. Here, the presence of A. pleuropneumoniae was detected in drinking water of pig farms in Mexico using a PCR specific for the RTX toxin gene, apxIV. The presence of A. pleuropneumoniae in farm drinking water was confirmed by indirect immunofluorescence using an A. pleuropneumoniae-specific polyclonal antibody and by fluorescent in situ hybridization. Viable bacteria from the farm drinking water were detected using the Live/Dead BacLight stain. Additionally, viable A. pleuropneumoniae was selected and isolated using the cAMP test and the identity of the isolated bacteria were confirmed by Gram staining, a specific polyclonal antibody and an A. pleuropneumoniae-specific PCR. Furthermore, biofilms were observed by scanning electron microscopy in A. pleuropneumoniae positive samples. In conclusion, our data suggest that viable A. pleuropneumoniae is present in the drinking water of swine farms and may use biofilm as a strategy to survive in the environment. PMID- 23347957 TI - The regulatory mechanism of 2,4,6-trichlorophenol catabolic operon expression by HadR in Ralstonia pickettii DTP0602. AB - Ralstonia pickettii DTP0602 utilizes 2,4,6-trichlorophenol (2,4,6-TCP) as its sole source of carbon. The expression of catabolic pathway genes (hadA, hadB and hadC) for 2,4,6-TCP has been reported to be regulated by the LysR-type transcriptional regulator (LTTR) HadR. Generally, coinducers are recognized as being important for the function of LTTRs, and alteration of the LTTR-protection sequence and the degree of DNA bending are characteristic of LTTRs with or without a recognized coinducer. In this study, we describe the mechanism by which HadR regulates the expression of 2,4,6-TCP catabolic genes. The 2,4,6-TCP catabolic pathway genes in DTP0602 consist of two transcriptional units: hadX hadA-hadB-hadC and monocistronic hadR. Purified HadR binds to the hadX promoter and HadR-DNA complex formation was induced in the presence of 16 types of substituted phenols, including chloro- and nitro-phenols and tribromo-phenol. In contrast with observations of other well-characterized LTTRs, the tested phenols showed no diversity of the bending angle of the HadR binding fragment. The expression of 2,4,6-TCP catabolic pathway genes, which are regulated by HadR, was not influenced by the DNA bending angle of HadR. Moreover, the transcription of hadX, hadA and hadB was induced in the presence of seven types of substituted phenols, whereas the other substituted phenols, which induced formation of the HadR-DNA complex, did not induce the transcription of hadX, hadA or hadB in vivo. PMID- 23347958 TI - Bioinformatics and systems biology analysis of genes network involved in OLP (Oral Lichen Planus) pathogenesis. AB - BACKGROUND: Genes involved in different biological processes form complex interaction networks. However, only few of them have a high number of interactions with the other genes in the network and therefore they may play a major role. In previous bioinformatics and experimental studies, these genes were identified and termed as "leader genes". In the current ab initio theoretical study, genes involved in human OLP (Oral Lichen Planus) pathogenesis are identified and ranked according to their number of interactions, in order to obtain a broader view of its molecular mechanisms and to plan targeted experimentations. METHODS: Genes involved or potentially involved in OLP were identified by systematically querying several databases until the identification of a final set of genes. Interactions among these genes were mapped and given a significance score using STRING database. For each gene, significance scores were summed to obtain a weighted number of links (WNL) and subsequently genes were clustered according to this parameter. The genes in the highest cluster were termed as leader genes; the other ones were ranked as class B genes, class C genes, and so on. This study was complemented by a topological analysis of the network, carried out using Cytoscape, BinGO and FANMOD software. RESULTS: The interactions in the obtained network showed power law behaviour, in agreement with the scale-free topology theory of the biological graphs. 132 genes were identified and five of them (namely, JUN, EGFR, FOS, IL2, ITGB4) were classified as leaders. Interestingly, all of them but EGFR were up-regulated and were widely distributed in the network (in term of topological parameters such as stress, eccentricity and radiality) and showed higher topological coefficients than the other genes. CONCLUSIONS: Even with the limitations of any ab initio analysis, this study can suggest targeted experimentation, focused on the leader genes and therefore simpler to be analysed than mass scale molecular genomics. Moreover, it may suggest new potential risk factors and therapeutic targets. PMID- 23347959 TI - Differences in absolute risk of cardiovascular events using risk-refinement tests: a systematic analysis of four cardiovascular risk equations. AB - BACKGROUND: Current cardiovascular risk assessment guidelines incorporate judicious use of C-reactive protein (CRP), carotid intima-media thickness (CIMT), and coronary artery calcium (CAC) in selected populations and describe threshold levels for higher and lower cardiovascular risk for each of the three risk refinement tests. However, the effect of these suggested thresholds of relative risk on absolute global risk remains uncertain. METHODS: Systematic permutation of risk factors provided 10-year risk estimates using the Framingham risk score, equations derived from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Atherosclerosis Risk in Communities (ARIC) study, and the Reynolds risk score. Low-, high-, and very-high-risk values of CAC, CIMT, and hsCRP were defined as: 0, 100, 400 Agatston units; 25th percentile without plaque, 75th percentile without plaque, 75th percentile with plaque; and 1.0, 3.0, 7.0 mg/L. RESULTS: Incorporation of low-, high-, and very-high-risk CAC values using the MESA risk score resulted in greater changes in absolute risk from the Framingham risk score than the addition of either CIMT or hsCRP values using the ARIC or Reynolds risk scores. CONCLUSIONS: Although certain values of CAC, CIMT, and hsCRP have been similarly designated as low, high, or very-high risk, incorporation of these thresholds into validated risk equations yielded substantially different levels of absolute cardiovascular risk. Use of available risk equations may be advisable to calculate absolute risk rather than relying on risk-marker thresholds derived from relative risk estimates. PMID- 23347960 TI - Simultaneously evaluate the toxic levels of fluoride and arsenic species in underground water of Tharparkar and possible contaminant sources: a multivariate study. AB - The present study investigated total arsenic (tAs), inorganic arsenic (iAs) species and fluoride ion (F(-)) contamination in underground water of Mithi and Nangarparkar subdistricts of Tharparkar, Pakistan. Statistical parameters, principal component analysis, cluster analysis, sodium absorption ratio and saturation indices (SI) were used to detect interrelation and sources of concentration of tAs, iAs species (As(3+) and As(5+)), F(-) and others physicochemical parameters. The concentration of As(3+) was measured by cloud point extraction using ammonium pyrrolidinedithiocarbamate (APDC) as complexing reagent, while inorganic arsenic (iAs) was determined by solid phase extraction, using titanium dioxide. The positive correlation was observed between F(-) contents with As species and other major ions, found in the underground water of the study area. The resulted data indicated that underground water samples of two areas of Tharparkar were severely contaminated with arsenic (0.100-3.83 mg/L) and fluoride ion (13.8-49.3mg/L), which were exceeded the World Health Organization provisional guideline values, 0.01 mg/L and 1.5mg/L, respectively. The SI of fluorite and calcite in the underground water samples showed that most of the samples were oversaturated with respect to calcite and fluorite. PMID- 23347961 TI - Da-Bu-Yin-Wan and Qian-Zheng-San, two traditional Chinese herbal formulas, up regulate the expression of mitochondrial subunit NADH dehydrogenase 1 synergistically in the mice model of Parkinson's disease. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Da-Bu-Yin-Wan (DBYW) and Qian-Zheng-San (QZS), two traditional Chinese herbal formulas, were clinically employed to treat Parkinson's disease (PD) for decades. AIM OF THE STUDY: Our previous studies demonstrated neuroprotective effects of DBYW and QZS on mitochondrial function in mice model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In present research, we aimed to investigate the possible neuroprotective mechanisms of DBYW and QZS. MATERIALS AND METHODS: The effects of DBYW and QZS on the behavioral changes (pole test), expression of tyrosine hydroxylase (TH) of substantia nigra by immunohistochemistry, monoaminergic contents and activity of striatum by high performance liquid chromatography, neuronal ultrastructure changes by transmission electron microscopy, mitochondrial DNA (mtDNA) damage by long-extension polymerase chain reaction (PCR), and mRNA expression of mitochondrial subunit NADH dehydrogenase 1(ND1) by qualitative real-time PCR were investigated. RESULTS: Present study demonstrated that DBYW and QZS not only ameliorated the behavior induced by the administration of MPTP and synergistically prevented the decreasing of TH expression, but also increased monoaminergic contents and activity, improved the ultrastructural changes, decreased the mtDNA damage, and synergistically up-regulated the expression of ND1 in mRNA level. CONCLUSIONS: These results suggest that DBYW and QZS possess anti-parkinsonism and neuroprotective properties. PMID- 23347962 TI - Reply--Malnutrition and its impact on cost of hospitalization, length of stay, readmission and 3-year mortality. PMID- 23347964 TI - On the relationship between learning strategy and feedback processing in the weather prediction task--Evidence from event-related potentials. AB - Previous work has shown that both declarative and non-declarative strategies can be engaged in probabilistic classification learning. With respect to the neural correlates of these strategies, earlier studies have focused on the classification process itself. In the present experiment, we asked whether the feedback for classification performance is processed differently by declarative and non-declarative learners. We recorded event-related potentials (ERPs) while participants performed a modified version of the weather prediction task, a well known probabilistic classification learning task. ERP analysis focused on two ERP components typically associated with feedback processing, the feedback-related negativity (FRN) and the P300. FRN amplitude was not affected by learning strategy. The P300, however, was more pronounced in declarative learners, particularly at frontal electrode site Fz. In addition, P300 topography was different in declarative learners, with amplitude differences between negative and positive feedback being more pronounced over the frontal than the parietal cortex. Differences in feedback processing between groups were still seen after declarative learners had switched to a non-declarative strategy in later phases of the task. Our findings provide evidence for different neural mechanisms of feedback processing in declarative and non-declarative learning. This difference emerges at later stages of feedback processing, after the typical time window of the FRN. PMID- 23347963 TI - Intelligence and executive functions in frontotemporal dementia. AB - Recently (Roca et al. (2010), we used the relationship with general intelligence (Spearman's g) to define two sets of frontal lobe or "executive" tests. For one group, including Wisconsin card sorting and verbal fluency, reduction in g entirely explained the deficits found in frontal patients. For another group, including tests of social cognition and multitasking, frontal deficits remained even after correction for g. Preliminary evidence suggested a link of the latter tasks to more anterior frontal regions. Here we develop this distinction in the context of behavioural-variant frontotemporal dementia (bvFTD), a disorder which progressively affects frontal lobe cortices. In bvFTD, some executive tests, including tests of social cognition and multitasking, decline from the early stage of the disease, while others, including classical executive tests such as Wisconsin card sorting, verbal fluency or Trail Making Test part B, show deficits only later on. Here we show that, while deficits in the classical executive tests are entirely explained by g, deficits in the social cognition and multitasking tests are not. The results suggest a relatively selective cognitive deficit at mild stages of the disease, followed by more widespread cognitive decline well predicted by g. PMID- 23347965 TI - Near-infrared fluorescing IR820-chitosan conjugate for multifunctional cancer theranostic applications. AB - This study reports the preparation and characterization of IR820-chitosan conjugates that have potential multifunctional imaging-hyperthermia applications in cancer. The conjugates were formulated by covalentcouplingofchitosan to a carboxyl derivatized IR820, and studied for optical imaging and hyperthermia applications. IR820-chitosan conjugates were able to generate heat upon exposure to 808nm laser and produce hyperthermic cell growth inhibition in cancer cell lines MES-SA, SKOV-3 and Dx5. The level of cell growth inhibition caused by hyperthermia was significantly higher for IR820-chitosan compared to IR820 in MES SA and Dx5 cells. Fluorescent microscope images of these cancer cell lines after 3-h exposure to 5MUM IR820-chitosan showed that the conjugates can be used for in vitro near-infrared imaging. In an in vivo rat model, the conjugates accumulated in the liver after i.v. injection and were excreted through the gastrointestinal tract, demonstrating a different biodistribution when compared to the free dye. The accumulation of these conjugates in bile with subsequent gastrointestinal excretion allows for potential applications as gastrointestinal contrast agents and delivery vehicles. This formulation can potentially be used in multifunctional cancer theranostics. PMID- 23347966 TI - Blue light induced free radicals from riboflavin on E. coli DNA damage. AB - The micronutrients in many cellular processes, riboflavin (vitamin B(2)), FMN, and FAD are photo-sensitive to UV and visible light to generate reactive oxygen species (ROS). The riboflavin photochemical treatment with UV light has been applied for the inactivation of microorganisms to serve as an effective and safe technology. Ultra-violet or high-intensity radiation is, however, considered as a highly risky practice. This study was working on the application of visible LED lights to riboflavin photochemical reactions to development an effective antimicrobial treatment. The photosensitization of bacterial genome with riboflavin was investigated in vitro and in vivo by light quality and irradiation dosage. The riboflavin photochemical treatment with blue LED light was proved to be able to inactivate E. coli by damaging nucleic acids with ROS generated. Riboflavin is capable of intercalating between the bases of bacterial DNA or RNA and absorbs lights in the visible regions. LED light illumination could be a more accessible and safe practice for riboflavin photochemical treatments to achieve hygienic requirements in vitro. PMID- 23347967 TI - Household fuels, low birth weight, and neonatal death in India: the separate impacts of biomass, kerosene, and coal. AB - We examined the impact of maternal use of different household cooking fuels in India on low birth weight (LBW<2500g), and neonatal mortality (death within 28 days of birth). Using cross-sectional data from India's National Family Health Survey (NFHS-3), we separately analyzed the prevalence of these two outcomes in households utilizing three types of high-pollution fuels for cooking - biomass, coal, and kerosene - using low-pollution fuels (gas and biogas) as the comparison "control" group. Taking socioeconomic and child-specific factors into account, we employed logistic regression to examine the impact of fuel use on fetal and infant health. The results indicate that household use of high-pollution fuels is significantly associated with increased odds of LBW and neonatal death. Compared to households using cleaner fuels (in which the mean birth weight is 2901g), the primary use of coal, kerosene, and biomass fuels is associated with significant decreases in mean birth weight (of -110g for coal, -107g for kerosene, and -78g for biomass). Kerosene and biomass fuel use are also associated with increased risk of LBW (p<0.05). Results suggest that increased risk of neonatal death is strongly associated with household use of coal (OR 18.54; 95% CI: 6.31-54.45), and perhaps with kerosene (OR 2.30; 95% CI: 0.95-5.55). Biomass is associated with increased risk of neonatal death among infants born to women with no more than primary education (OR 7.56; 95% CI: 2.40-23.80). These results are consistent with a growing literature showing health impacts of household air pollution from these fuels. PMID- 23347968 TI - Coxiella burnetii in sewage water at sewage water treatment plants in a Q fever epidemic area. AB - During 2007-2010, over 4000 persons in The Netherlands contracted Q-fever, a zoonosis caused by the bacterium Coxiella burnetii. Goats and sheep are the main reservoir of C. burnetti and infected animals shed the bacterium with their urine, faeces and birth products. Human infections may occur through direct contact with infected animals, or through inhalation of contaminated dust particles or aerosols. Discharge of waste water from Q fever contaminated goat farms may result in the presence of C. burnetii in sewage water and aerosols at sewage water treatment plants (SWTPs) which may pose a health risk for workers or neighbouring residents. The objectives of this study were to determine the presence of C. burnetii at SWTPs and to optimize available detection methods. In March-July 2011, sewage influent and aeration tank samples from four SWTPs receiving discharge from Q fever positive goat farms were examined by using a multiplex real-time PCR detecting C. burnetii DNA by targeting IS1111 and com1 genes. Influent (44%; n=16/36) and active sludge (36%; n=13/36) samples were positive with low C. burnetii DNA content. Percentage positive samples per SWTP were 28-61%. Positive samples were most frequent in March 2011 and least frequent in May 2011. The presence of C. burnetii DNA in sewage water samples suggests that SWTPs receiving waste water from Q fever contaminated goat farms may contribute to the spread of C. burnetii to the environment. The low levels of C. burnetii DNA in sewage water during the decline of the Q fever outbreak in The Netherlands in 2011 indicate a low health risk for SWTP workers and residents. PMID- 23347969 TI - Whole genomic analyses of asymptomatic human G1P[6], G2P[6] and G3P[6] rotavirus strains reveal intergenogroup reassortment events and genome segments of artiodactyl origin. AB - Although P[6] group A rotaviruses (RVA) cause diarrhoea in humans, they have been also associated with endemics of predominantly asymptomatic neonatal infections. Interestingly, strains representing the endemic and asymptomatic P[6] RVAs were found to possess one of the four common human VP7 serotypes (G1-G4), and exhibited little antigenic/genetic differences with the VP4 proteins/VP4 encoding genome segments of P[6] RVAs recovered from diarrhoeic children, raising interest on their complete genetic constellations. In the present study, we report the overall genetic makeup and possible origin of three such asymptomatic human P[6] RVA strains, RVA/Human-tc/VEN/M37/1982/G1P2A[6], RVA/Human tc/SWE/1076/1983/G2P2A[6] and RVA/Human-tc/AUS/McN13/1980/G3P2A[6]. G1P[6] strain M37 exhibited an unusual genotype constellation (G1-P[6]-R1-C1-M1-A1-N1-T2-E1 H1), not reported previously, and was found to originate from possible intergenogroup reassortment events involving acquisition of a DS-1-like NSP3 encoding genome segment by a human Wa-like RVA strain. On the other hand, G2P[6] strain 1076 exhibited a DS-1-like genotype constellation, and was found to possess several genome segments (those encoding VP1, VP3, VP6 and NSP4) of possible artiodactyl (ruminants) origin on a human RVA genetic backbone. The whole genome of G3P[6] strain McN13 was closely related to that of asymptomatic human Wa-like G3P[6] strain RV3, and both strains shared unique amino acid changes, which might have contributed to their attenuation. Taken together, the present study provided insights into the origin and complex genetic diversity of P[6] RVAs possessing the common human VP7 genotypes. This is the first report on the whole genomic analysis of a G1P[6] RVA strain. PMID- 23347970 TI - A nationwide study of social-emotional problems in young children in Turkey. AB - We aimed to assess the prevalence of social-emotional problems of Turkish children in early childhood and to understand their association with various bio psycho-social risk factors, in order to establish guidelines in planning training programs for parents and professionals. Data from a representative sample of 1507 boys (54.3%) and 1268 girls (45.7%) aged 10-48 months were collected. The primary caregivers (mothers=91.4%) completed the Brief Infant-Toddler Social and Emotional Assessment (BITSEA), the Brief Symptom Inventory (BSI) and a form designed to gather information about various bio-psycho-social risk factors. Based on the caregiver terms, a total of 1626 children (60.1%) were reported to experience social-emotional problems. However, based on the BITSEA-problem clinical (1.5 SD) cut-off scores, 9.3% (9.1% of boys; 9.5% of girls) of all children were found to experience social-emotional problems. The variables, that showed a significant association with BITSEA-problem scores in pairwise comparisons, were entered in logistic regression analysis to determine the variables that predict the group with scores of above clinical cut-point. Higher total score of BSI of the primary caregiver, being separated from the mother for more than a month, and lower income of the family were found to be significant predictors of social-emotional problems. Caregiver reports highlight that maternal variables of mothers' psychological well-being, education and access to sources of support are closely related to the social-emotional wellbeing of their off-spring. The findings obtained from this study may be used for detection of prioritized domains in terms of management of preventive mental health services. PMID- 23347971 TI - Limited utility of number needed to treat and the polarity index for bipolar disorder to characterize treatment response. AB - The medical community increasingly supports the use of simplifying constructs or ratios to facilitate incorporation of evidence-based medicine into clinical practice such as number needed to treat (NNT) and polarity index (PI). Clinicians and teachers find them to be an appealing, easy-to remember integer that can be readily translated into clinical practice. However, serious questions have been raised with respect to the validity, reliability and value of these descriptors of response. This commentary identifies some of the specific limitations of the NNT and PI constructs when applied to treatments of bipolar disorder. PMID- 23347972 TI - How a phosphorus-acquisition strategy based on carboxylate exudation powers the success and agronomic potential of lupines (Lupinus, Fabaceae). AB - Lupines (Lupinus species; Fabaceae) are an ancient crop with great potential to be developed further for high-protein feed and food, cover crops, and phytoremediation. Being legumes, they are capable of symbiotically fixing atmospheric nitrogen. However, Lupinus species appear to be nonmycorrhizal or weakly mycorrhizal at most; instead some produce cluster roots, which release vast amounts of phosphate-mobilizing carboxylates (inorganic anions). Other lupines produce cluster-like roots, which function in a similar manner, and some release large amounts of carboxylates without specialized roots. These traits associated with nutrient acquisition make lupines ideally suited for either impoverished soils or soils with large amounts of phosphorus that is poorly available for most plants, e.g., acidic or alkaline soils. Here we explore how common the nonmycorrhizal phosphorus-acquisition strategy based on exudation of carboxylates is in the genus Lupinus, concluding it is very likely more widespread than generally acknowledged. This trait may partly account for the role of lupines as pioneers or invasive species, but also makes them suitable crop plants while we reach "peak phosphorus". PMID- 23347973 TI - Palm stem anatomy and computer-aided identification: the Coryphoideae (Arecaceae). AB - PREMISE OF THE STUDY: Through a comparative study of the anatomy of palm stems and the development of an interactive web-based tool, the present paper aims to provide a method of identifying palm stems. The stem determination will allow specialists in archaeology and paleontology to better exploit palm fossils for paleoenvironmental interpretations. The precise anatomical description also provides new systematic data tested in phylogenetic analyses (new anatomical characters, stratigraphic calibrations). METHODS: Stem samples were collected, including representatives from each tribe of the five palm subfamilies, and 25 descriptors (with 78 states) were defined within 37 taxa and registered in Xper(2), a management tool for taxonomic description that allows editing of standardized descriptions. Some descriptors were used for the first time in this work; others were compiled from the existing literature. While all the palm subfamilies were included in the present study, the focus here is on the Coryphoideae. KEY RESULTS: Descriptors were mainly based on the general organization of the transverse section and the structure of the fibrovascular bundles as well as ground parenchyma. Coryphoideae have 1, 2, or more metaxylem elements, whereas the other subfamilies systematically present only 1 or 1 and 2 metaxylem elements. The centrifugal differentiation of the sheath of phloem fibers is described in other subfamilies but is not found in the Coryphoideae (except in Caryoteae). CONCLUSION: Some tribes are easy to identify (Borasseae, Cryosophileae, Phoeniceae, Caryoteae); others are rather heterogeneous and more difficult to define (Chuniophoeniceae, Trachycarpeae). Caryoteae presents some unique states of the Arecoideae. PMID- 23347974 TI - Do ray cells provide a pathway for radial water movement in the stems of conifer trees? AB - PREMISE OF THE STUDY: The pathway of radial water movement in tree stems presents an unknown with respect to whole-tree hydraulics. Radial profiles have shown substantial axial sap flow in deeper layers of sapwood (that may lack direct connection to transpiring leaves), which suggests the existence of a radial pathway for water movement. Rays in tree stems include ray tracheids and/or ray parenchyma cells and may offer such a pathway for radial water transport. This study investigated relationships between radial hydraulic conductivity (k(s-rad)) and ray anatomical and stem morphological characteristics in the stems of three conifer species whose distributions span a natural aridity gradient across the Cascade Mountain range in Oregon, United States. METHODS: The k(s-rad) was measured with a high-pressure flow meter. Ray tracheid and ray parenchyma characteristics and water transport properties were visualized using autofluorescence or confocal microscopy. KEY RESULTS: The k(s-rad) did not vary predictably with sapwood depth among species and populations. Dye tracer did not infiltrate ray tracheids, and infiltration into ray parenchyma was limited. Regression analyses revealed inconsistent relationships between k(s-rad) and selected anatomical or growth characteristics when ecotypes were analyzed individually and weak relationships between k(s-rad) and these characteristics when data were pooled by tree species. CONCLUSIONS: The lack of significant relationships between k(s-rad) and the ray and stem morphologies we studied, combined with the absence of dye tracer in ray tracheid and limited movement of dye into ray parenchyma suggests that rays may not facilitate radial water transport in the three conifer species studied. PMID- 23347975 TI - Temporal and spatial regulation of glucomannan deposition and mobilization in corms of Amorphophallus konjac (Araceae). AB - PREMISE OF THE STUDY: Konjac glucomannan (KGM), the main biologically active constituent of konjac flour extracted from corms of Amorphophallus konjac (konjac), has potential to be used as a nutraceutical (satiety agent) to combat obesity. Here we present the results of an immunocytochemical investigation of the developmental regulation of the deposition and mobilization of glucomannan in corm tissues of konjac, using an antiheteromannan (mannan/glucomannan) antiserum. METHODS: The intensity of antibody binding to glucomannan idioblasts at six developmental stages (i.e., dormancy, leaf bud emergence, leaf bud elongation, leaflet emergence, leaf expansion, and shoot senescence) was compared. KEY RESULTS: A temporally regulated pattern of glucomannan deposition and mobilization within the glucomannan idioblasts was observed. A source-sink transition in the corm was shown to occur after leaflet emergence, prior to complete expansion of the leaves. Our data also suggest that the mobilization of KGM initiates at the periphery of the corm and proceeds inward toward the center of the corm. CONCLUSIONS: This study represents a significant milestone in our understanding of the mechanisms involved in the physiological and biochemical control of KGM biosynthesis, partitioning, storage, and remobilization. Moreover, this information and the methodology presented provide valuable data for future improvement of the yield and productivity of this important crop. PMID- 23347976 TI - Assigning atropisomer elution orders using atropisomerically enriched polychlorinated biphenyl fractions generated by microsomal metabolism. AB - Changes in the enantiomeric fraction of chiral polychlorinated biphenyls (PCBs) are a powerful tool to investigate the movement of PCBs in the environment, for example as part of source apportionment and ecological studies. Environmental studies typically employ a series of cyclodextrin-based gas chromatography columns to separate all environmentally relevant PCB congeners. The elution order of most PCB atropisomers has not been established on different enantioselective columns due to the unavailability of analytical standards. To overcome this limitation, the current study generated atropisomerically enriched fractions of chiral PCBs with rat liver microsomes. Subsequently, the enrichment profile of the enriched PCB fractions was used to determine the elution order of PCB atropisomers on selected enantioselective gas chromatography columns. While the elution order of PCB 95, 131, 132, 136, 149 and 176 atropisomers was identical on all enantioselective columns investigated, an inversion of the elution order was observed for PCB 45, 84, 91 and 174 atropisomers on a few columns. These results demonstrate that atropisomerically enriched fractions obtained from microsomal metabolism can be used to unambiguously establish the relative elution order of the atropisomers of PCBs and potentially other environmental pollutant, especially if pure enantiomers are not available. PMID- 23347977 TI - Untargeted and targeted comprehensive two-dimensional GC analysis using a novel unified high-speed triple quadrupole mass spectrometer. AB - The present manuscript is focused on the evaluation of a novel high-speed triple quadrupole mass spectrometer (QqQ MS), carried out under extreme GC conditions, namely those generated by a flow-modulated (FM) comprehensive two-dimensional GC (GC*GC) system. The novel QqQ MS system is capable of operation under high speed conditions, in both full-scan (maximum scan speed: 20,000 amu/s) and multiple reaction monitoring (MRM) modes. Moreover, the QqQ MS instrument can generate simultaneous full scan/MRM data, also in a very rapid manner. An FM GC * GC-MSMS method was developed for the simultaneous full-scan qualitative analysis of untargeted essential oil compounds, and MRM quali/quantitative analysis of targeted ones, namely three preservatives [o-phenylphenol (OPP), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA)]. The QqQMS system generated a sufficient number of data points per peak, for both qualitative and quantitative purposes. The degree of sensitivity, reached through the MRM analysis, widely exceeded current-day regulations. Method validation, related to the MRM analysis, was performed considering retention time, peak area and ion ratio repeatability, limits of detection and quantification, and accuracy. Additionally, a spearmint essential oil was spiked with 5 phytosanitary compounds at the 1 ppb level, and analysed through an MRM-only GC * GC-MSMS application. Emphasis was devoted not only on sensitivity (satisfactory for all the contaminants), but also on the importance of precursor ion selection, and of the GC * GC separation process. Finally, sensitivity was compared between the MRM and SIM modes, in scan/MRM, MRM, scan/SIM and SIM analyses, performed on a mixture of 22 phytosanitary products, at a concentration level in the 50-150 ppb range. PMID- 23347978 TI - Structure and protein adsorption mechanisms of clean and fouled tentacle-type anion exchangers used in a monoclonal antibody polishing step. AB - The properties of Fractogel((r)) EMD TMAE HiCap (M), a tentacle-type anion exchange resin used for a polishing step in a monoclonal antibody (mAb) purification process, were investigated for both virgin and used samples to determine the influence of process related fouling. Inverse size exclusion chromatography indicated a bimodal distribution of pore sizes consisting mostly of small pores, 4-5 nm in radius and likely associated with the grafted tentacles. Similar results were obtained for resin samples fouled by process use, indicating that the core structure of these particles is unchanged. Transmission electron micrographs showed that the resin backbone matrix has a microgranular structure. However, a dense skin layer, 0.2-0.5 MUm thick, was also seen at the exterior surface of the fouled particles. The binding capacity attained for BSA after 90 min of contact was 165 +/- 4 mg/mL for both virgin and fouled samples, close to the equilibrium capacity of 178 +/- 2 mg/mL attained after 24h. On the other hand, the capacities attained at 90 min for the much larger thyroglobulin were only 90 +/- 4 and 25 +/- 2 mg/mL, respectively, for virgin and fouled samples. The BSA adsorption kinetics was also slower for the fouled resin, but much larger kinetic differences between virgin and fouled resin were seen for thyroglobulin. Based on the shape of intraparticle protein concentration profiles determined by confocal laser scanning microscopy (CLSM), the protein transport mechanism is consistent with solid diffusion for both virgin and fouled resin samples and proteins. However, transport is hindered by the foulant layer to a much greater extent for thyroglobulin as a result of its larger size. Additional measurements indicated that the foulant layer is consistent with mAb aggregates irreversibly bound at the particle exterior surface. PMID- 23347979 TI - Rapid analysis of multiclass antibiotic residues and some of their metabolites in hospital, urban wastewater and river water by ultra-high-performance liquid chromatography coupled to quadrupole-linear ion trap tandem mass spectrometry. AB - The present work describes the development of a fast and robust analytical method for the determination of 53 antibiotic residues, covering various chemical groups and some of their metabolites, in environmental matrices that are considered important sources of antibiotic pollution, namely hospital and urban wastewaters, as well as in river waters. The method is based on automated off-line solid phase extraction (SPE) followed by ultra-high-performance liquid chromatography coupled to quadrupole linear ion trap tandem mass spectrometry (UHPLC-QqLIT). For unequivocal identification and confirmation, and in order to fulfill EU guidelines, two selected reaction monitoring (SRM) transitions per compound are monitored (the most intense one is used for quantification and the second one for confirmation). Quantification of target antibiotics is performed by the internal standard approach, using one isotopically labeled compound for each chemical group, in order to correct matrix effects. The main advantages of the method are automation and speed-up of sample preparation, by the reduction of extraction volumes for all matrices, the fast separation of a wide spectrum of antibiotics by using ultra-high-performance liquid chromatography, its sensitivity (limits of detection in the low ng/L range) and selectivity (due to the use of tandem mass spectrometry) The inclusion of beta-lactam antibiotics (penicillins and cephalosporins), which are compounds difficult to analyze in multi-residue methods due to their instability in water matrices, and some antibiotics metabolites are other important benefits of the method developed. As part of the validation procedure, the method developed was applied to the analysis of antibiotics residues in hospital, urban influent and effluent wastewaters as well as in river water samples. PMID- 23347980 TI - Inhibition of DNA topoisomerase I activity and induction of apoptosis by thiazacridine derivatives. AB - Thiazacridine derivatives (ATZD) are a novel class of cytotoxic agents that combine an acridine and thiazolidine nucleus. In this study, the cytotoxic action of four ATZD were tested in human colon carcinoma HCT-8 cells: (5Z)-5-acridin-9 ylmethylene-3-(4-methylbenzyl)-thiazolidine-2,4-dione - AC-4; (5ZE)-5-acridin-9 ylmethylene-3-(4-bromo-benzyl)-thiazolidine-2,4-dione - AC-7; (5Z)-5-(acridin-9 ylmethylene)-3-(4-chloro-benzyl)-1,3-thiazolidine-2,4-dione - AC-10; and (5ZE)-5 (acridin-9-ylmethylene)-3-(4-fluoro-benzyl)-1,3-thiazolidine-2,4-dione - AC-23. All of the ATZD tested reduced the proliferation of HCT-8 cells in a concentration- and time-dependent manner. There were significant increases in internucleosomal DNA fragmentation without affecting membrane integrity. For morphological analyses, hematoxylin-eosin and acridine orange/ethidium bromide were used to stain HCT-8 cells treated with ATZD, which presented the typical hallmarks of apoptosis. ATZD also induced mitochondrial depolarisation and phosphatidylserine exposure and increased the activation of caspases 3/7 in HCT-8 cells, suggesting that this apoptotic cell death was caspase-dependent. In an assay using Saccharomyces cerevisiae mutants with defects in DNA topoisomerases 1 and 3, the ATZD showed enhanced activity, suggesting an interaction between ATZD and DNA topoisomerase enzyme activity. In addition, ATZD inhibited DNA topoisomerase I action in a cell-free system. Interestingly, these ATZD did not cause genotoxicity or inhibit the telomerase activity in human lymphocyte cultures at the experimental levels tested. In conclusion, the ATZD inhibited the DNA topoisomerase I activity and induced tumour cell death through apoptotic pathways. PMID- 23347981 TI - Lectin functionalized nanocarriers for gene delivery. AB - Gene therapy has emerged as one of the most promising therapeutic methods to treat various diseases. However, inadequate gene transfection efficacy during gene therapy demands further development of more efficient gene delivery strategies. Targeting genetic material to specific sites of action endows numerous advantages over non-targeted delivery. An ample variety of non-viral gene delivery vectors have been developed in recent years owing to the safety issues raised by viral vectors. Non-viral gene delivery vectors containing specific targeting ligands on their surfaces have been reported to enhance the gene transfection efficiency via receptor-mediated endocytosis for gene delivery. Among various targeting moieties investigated, carbohydrates and lectins (carbohydrate-binding proteins) played an essential role in gene delivery via either direct or reverse lectin targeting strategies. Lectins have a specific carbohydrate binding domain that can bind specifically to the carbohydrates. This review sheds light on various gene delivery nanovectors conjugated with either lectins or carbohydrates for enhanced gene transfection. PMID- 23347982 TI - Visualization of blebs using anterior-segment optical coherence tomography after glaucoma drainage implant surgery. AB - OBJECTIVE: The current study investigated the internal structure of blebs using anterior-segment optical coherence tomography (AS-OCT) in patients who had undergone Ahmed glaucoma valve (AGV) (New World Medical Inc, Rancho Cucamonga, CA) implantation and compared the differences between successful and failed surgeries. DESIGN: Cross-sectional, observational study. PARTICIPANTS: A total of 76 patients who had undergone AGV implantation. METHODS: The blebs after AGV implantation were examined using AS-OCT. The relationship between intraocular pressure (IOP) or the number of glaucoma medications and intrableb parameters was evaluated. Success was defined as IOP <= 21 mmHg with a maximum of 2 glaucoma medications, and the remaining cases were assigned to the "failed surgery group." Logistic regression was used to determine the predictive value of various bleb parameters measured by AS-OCT for bleb success. MAIN OUTCOME MEASURES: The bleb wall thickness (minimum and maximum) and the reflectivity of the bleb wall (mean, modal value, minimum, and maximum). RESULTS: Blebs from 46 successful (60.5%) and 30 failed (39.5%) AGV implantation surgeries were analyzed. The AS-OCT imaging of the intrableb configuration revealed a relatively regular surface and a homogeneous and hyperreflective bleb wall. The maximum and minimum bleb wall thicknesses were significantly different between the 2 groups (P<0.001, P<0.005). No significant differences were observed between the 2 groups in mean, modal, maximum, or minimum reflectivity of the bleb wall. The maximum and minimum bleb wall thicknesses were significantly correlated with the postoperative maximum IOP (r = 0.402, P<0.001; r = 0.280, P = 0.014). The maximum and minimum bleb wall thicknesses showed a significant correlation with the number of postoperative glaucoma eye drops (r = 0.452, P<0.001; r = 0.327, P = 0.004). Maximum bleb wall thickness was significantly associated with the success of AGV surgery by multivariate analysis (P<0.001). CONCLUSIONS: Anterior-segment OCT can be used for bleb imaging after glaucoma valve implantation. The AS-OCT results revealed that the maximum bleb wall was significantly thinner in successful AGV implant surgeries compared with unsuccessful AGV implant surgeries. This technique may facilitate the investigation of surgical outcomes and pathogenesis in patients receiving glaucoma valve implants. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23347983 TI - Scleral necrosis after plaque radiotherapy of uveal melanoma: a case-control study. AB - PURPOSE: To identify risk factors and outcome of scleral necrosis after plaque radiotherapy of uveal melanoma. DESIGN: Case-control study. PARTICIPANTS: A total of 73 cases with scleral necrosis and 73 controls without necrosis after plaque radiotherapy. Controls were matched for anteroposterior tumor epicenter and follow-up duration. INTERVENTION: Plaque radiotherapy with iodine-125, cobalt-60, iridium-192, or ruthenium-106. MAIN OUTCOME MEASURES: Scleral necrosis. RESULTS: Of 5057 patients treated with plaque radiotherapy for uveal melanoma, 73 (1%) developed radiotherapy-induced scleral necrosis. Scleral necrosis occurred in <1% of patients (3/1140) when plaque radiotherapy was used for tumors <3 mm in thickness, 1% of patients (33/3155) with 3- to 8-mm tumor thickness, and 5% of patients (37/762) with >8-mm-thick tumors. On the basis of tumor location, scleral necrosis was detected after plaque radiotherapy of iris melanoma in 0% of patients (0/91), ciliary body melanoma in 29% of patients (67/235), and choroid melanoma in <1% of patients (6/4731). The mean time interval between plaque radiotherapy and scleral necrosis was 32 months (median, 23 months; range, 4-126 months). The mean basal dimension of scleral necrosis was 4 mm (median, 3 mm; range, 1-15 mm), equivalent to 29% of mean tumor base (median, 24%; range, 6% 100%) and 22% of mean plaque size (median, 19%; range, 5%-75%). Multivariate analysis of factors that predicted clinically evident scleral necrosis included ciliary body (P = 0.0001) and pars plana to ora serrata (P < 0.0001) locations of anterior tumor margin, tumor thickness >= 6 mm (P = 0.0001), and radiation dose >= 400 Gy to the outer sclera (P = 0.0455). Scleral necrosis remained stable in 48% of patients (35/73), increased in size/severity in 48% of patients (35/73), or progressed to scleral perforation in 4% of patients (3/73) over a mean follow up of 79 months (median, 54 months; range, 5-351 months). Treatment of scleral necrosis included observation in 81% of patients (59/73), scleral patch graft in 14% of patients (10/73), and enucleation in 5% of patients (4/73). CONCLUSIONS: Scleral necrosis after plaque radiotherapy of uveal melanoma was detected in 1% of cases. Factors predictive of scleral necrosis included increasing tumor thickness, ciliary body and peripheral choroidal location, and higher radiation dose to sclera. Most patients (81%) did not require treatment, and 4% evolved to full-thickness perforation. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23347984 TI - Diagnosis of ocular surface lesions using ultra-high-resolution optical coherence tomography. AB - PURPOSE: To assess the use of ultra-high-resolution (UHR) optical coherence tomography (OCT) in the diagnosis of ocular surface lesions. DESIGN: Prospective, noncomparative, interventional case series. PARTICIPANTS: Fifty-four eyes of 53 consecutive patients with biopsy-proven ocular surface lesions: 8 primary acquired melanosis lesions, 5 amelanotic melanoma lesions, 2 nevi, 19 ocular surface squamous neoplasia lesions, 1 histiocytosis lesion, 6 conjunctival lymphoma lesions, 2 conjunctival amyloidosis lesions, and 11 pterygia lesions. INTERVENTION: Ultra-high-resolution OCT imaging of the ocular surface lesions. MAIN OUTCOME MEASURES: Clinical course and photographs, UHR OCT image, and histopathologic findings. RESULTS: Ultra-high-resolution OCT images of all examined ocular surface lesions showed close correlation with the obtained histopathologic specimens. When clinical differential diagnosis of ocular surface lesions was broad, UHR OCT images provided optical signs indicating a more specific diagnosis and management. In cases of amelanotic melanoma, conjunctival amyloidosis, and primary histiocytosis and in 1 case of ocular surface squamous neoplasia, UHR OCT was instrumental in guiding the diagnosis. In those cases, UHR OCT suggested that the presumed clinical diagnosis was incorrect and favored a diagnosis that later was confirmed by histopathologic examination. CONCLUSIONS: Correlations between UHR OCT and histopathologic findings confirm that UHR OCT is an adjunctive diagnostic method that can provide a noninvasive means to help guide diagnosis and management of ocular surface lesions. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23347985 TI - Regulation of mitochondrial biogenesis and PGC-1alpha under cellular stress. AB - Cell function relies on the constant supply of ATP and it is crucial that mitochondrial ATP production adapts to environmental and cellular challenges to maintain cellular function. Key molecules in sensing cellular stress situations seem to be the PGC-family of transcriptional co-activators, which are key regulators of mitochondrial biogenesis. Recent work has identified several stress regulated pathways that affect mitochondrial biogenesis through modulation of the activity of PGC-1alpha. This review focuses on caloric restriction, hypoxia as well as the role of reactive oxygen species in regulating mitochondrial biogenesis and how this process is linked to other cellular stress responses. PMID- 23347986 TI - Optional copayments on anti-cancer drugs. PMID- 23347987 TI - Indian court upholds government order to include bar codes on drugs and devices. PMID- 23347988 TI - Mental health approach works better than information at preventing problem drinking in teenagers. PMID- 23347989 TI - Alcohol alliance responds to government's minimum price strategy. PMID- 23347990 TI - Chief medical officer speaks out on antimicrobial resistance, drugs, and homeopathy. PMID- 23347991 TI - Scottish GPs prescribe more now but spend less. PMID- 23347992 TI - Hospital care or home care after allogeneic hematopoietic stem cell transplantation--patients' experiences of care and support. AB - PURPOSE: Treatment at home during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation (HSCT) has been an option for patients at our center since 1998. Earlier studies have shown that home care is safe and has medical advantages. In this study, we present patients' experiences of care and support while being treated in hospital or at home during the acute post transplantation phase. METHOD: Patients (n = 41, 22 in hospital care and 19 in home care) answered the SAUC questionnaire at discharge (when home, or from hospital). Both statistical analysis and deductive content analysis were used. RESULTS: The patients were highly satisfied with the care and support during the acute post-transplantation phase. Patients in home care were found to be more satisfied with care in general than patients in hospital care. The importance of safety, empathy, and encouragement from healthcare staff were expressed regardless of where care was given. Patients also felt that receipt of continuous, updated information during treatment was important and they had a strong belief in HSCT but were uncertain of the future regarding recovery. CONCLUSIONS: The main findings of this study were that in comparison to hospital care, home care does not appear to have a significant negative effect on patients' experiences of care and support during the acute post-transplantation phase. In addition patients in home care felt safe, seen as a person and encouragement seem to empower the patients at home. Thus, this study may encourage other transplantation centers to provide home care if the patients want it. PMID- 23347993 TI - The use of a beveled excision for skin cancers of the scalp to aid reconstruction with a split thickness skin graft. PMID- 23347994 TI - Cycling attributes that enhance running performance after the cycle section in triathlon. AB - PURPOSE: To determine how cycling with a variable (triathlon-specific) power distribution affects subsequent running performance and quantify relationships between an individual cycling power profile and running ability after cycling. METHODS: Twelve well-trained male triathletes (VO2peak 4.9 +/- 0.5 L/min; mass 73.5 +/- 7.7 kg; mean +/- SD) undertook a cycle VO2peak and maximal aerobic power (MAP) test and a power profile involving 6 maximal efforts (6 s to 10 min). Each subject then performed 2 experimental 1-h cycle trials, both at a mean power of 65% MAP, at either variable power (VAR) ranging from 40% to 140% MAP or constant power (CON) followed by an outdoor 9.3-km time-trial run. Subjects also completed a control 9.3-km run with no preceding exercise. RESULTS: The 9.3-km run time was 42 +/- 37 s slower (mean +/- 90% confidence limits [CL]) after VAR (35:32 +/- 3:18 min:s, mean +/- SD) compared with CON cycling (34:50 +/- 2:49 min:s). This decrement after VAR appeared primarily in the first half of the run (35 +/- 20 s; mean +/- 90% CL). Higher blood lactate and rating of perceived exertion after 1 h VAR cycling were moderately correlated (r = .51-.55; +/- ~.40) with a larger decrement in run performance. There were no clear associations between the power profile test and decrement in run time after VAR compared with CON. CONCLUSIONS: A highly variable power distribution in cycling is likely to impair 10-km triathlon run performance. Training to lower physiological and perceptual responses during cycling should limit the negative effects on triathlon running. PMID- 23347995 TI - Sonochemical deposition of platinum nanoparticles on polymer beads and their transfer on the pore surface of a silica matrix. AB - This study reported the sonochemical deposition of platinum on the surface of polystyrene beads (PSBs) and the transfer of obtained Pt nanoparticles into a porous silica matrix using the PSB as a sacrificial template. Platinum nanoparticle deposition was ensured by the sonochemical reduction of Pt(IV) at room temperature in latex solutions containing polystyrene beads in the presence of formic acid under Ar or under Ar/CO atmosphere without any additives. After ultrasonic treatments for few hours, well dispersed Pt nanoparticles within the range of 3-5 nm deposited on PSB were obtained in both studied conditions. Samples were then mixed with TEOS, dried, and heated at 450 degrees C to ensure the PSB removal from the silica matrix. TEM and SEM results clearly show that final silica pore size is within the same order of magnitude than initial PSB. Finally, platinum decorated silica matrix with chosen pore sizes was successfully prepared. PMID- 23347996 TI - Size and charge characterisation of a submicrometre oil-in-water emulsion using resistive pulse sensing with tunable pores. AB - Resistive pulse sensing (RPS) with tunable pores (TPs) has been used to investigate an oil-in-water emulsion stabilised with beta-lactoglobulin (BLG). The mode of the droplet size distribution steadily increased over four months, from less than 150 nm to more than 200 nm. Results suggest that the dominant growth mechanism was migration of oil to relatively large droplets, as in Ostwald ripening. In contrast, the growth dynamics for salt-induced aggregation suggest flocculation and coalescence of droplets coming into contact. The charge measurement method recently developed by Vogel et al. was also applied to the emulsion. The two data analysis methods used yielded average droplet zeta potentials of -18.9 mV and -21.8 mV, compared with -27.6 mV obtained using light scattering. Methods for measuring emulsion droplet deformation and the charge on individual droplets are under development. Tunable pores are a useful tool for improved characterisation of submicrometre emulsions, as well as other synthetic and biological particles, as they provide better precision than light scattering for particle number distributions. PMID- 23347997 TI - Self-assembly of polyoxometalate-thionine multilayer films on magnetic microspheres as photocatalyst for methyl orange degradation under visible light irradiation. AB - (PW(12)-TH)(n) multilayer films (PW(12)=PW(12)O(40)(3-), TH=thionine) were deposited successfully on core-shell structured Fe(3)O(4)@SiO(2) magnetic microspheres through layer-by-layer (LbL) self-assembly method. The physical and photocatalytic properties of such magnetic microspheres coated with (PW(12) TH)(n) films have been characterized by SEM, FTIR, and UV-vis spectra. The microspheres exhibit better photocatalytic activity toward the degradation of methyl orange (MO) under visible light irradiation than the quartz slides support. In addition, the use of magnetic support guarantees facile, clean, fast, and efficient separation of the photocatalyst after the degradation of MO. Such catalysts can be reused several times and display good reproducibility by magnetic separation. PMID- 23347998 TI - Embedding DNA in surfactant mesophases: the phase diagram of the ternary system dodecyltrimethylammonium-DNA/monoolein/water in comparison to the DNA-free analogue. AB - The self-assembly of a true ternary mixture comprising an electroneutral complex of DNA anions and surfactant cations (dodecyltrimethylammonium cations, DTA), water, and nonionic surfactant (monoolein, MO) has been studied. The phase diagrams of two systems, DTA-DNA/MO/water and, for comparison, dodecyltrimethylammonium bromide (DTAB)/MO/water, were obtained by visual inspection, microscopic examination under polarized light, small-angle X-ray scattering (SAXS) and deuterium NMR ((2)H NMR) at 298 K and normal pressure. The isothermal phase diagram of the DTA-DNA/MO/water system contains four liquid crystalline (LC) phase regions (reversed hexagonal, Pn3m, Ia3d, lamellar). The supramolecular assemblies evolve from a bicontinuous cubic structure of the reversed type to the two-dimensional hexagonal phase as the content of DTA-DNA is increased. While DTA-DNA tends to form a reversed hexagonal phase, DTAB is incorporated into the existing lamellar phase formed by MO and water giving rise to swelling and to significant extension of the lamellar phase region. There is only a small tendency of the cubic phases existing in the binary system MO/water to accommodate DTAB or DTA-DNA. PMID- 23347999 TI - Surface kinetics for cooperative fungal cellulase digestion of cellulose from quartz crystal microgravimetry. AB - The kinetic behavior of aqueous cellulase on insoluble cellulose is best quantified through surface-based assays on a well-defined cellulose substrate of known area. We use a quartz crystal microbalance (QCM) to measure the activity of binary mixtures of Trichoderma longibrachiatum cellobiohydrolase I (Cel7A) and endoglucanase I (Cel7B) on spin-coated cellulose films. By extending a previous surface kinetic model for cellulase activity, we obtain rate constants for competitive adsorption of Cel7A and Cel7B, their irreversible binding, their complexation with the cellulose surface, and their cooperative cellulolytic activity. The activity of the two cellulases is linked through the formation of cellulose chain ends by Cel7B that provide complexation sites from which Cel7A effects cellulose chain scission. Although the rate-limiting step in Cel7A activity is complexation, Cel7B activity is limited by adsorption to the cellulose surface. A 2:1 bulk mass ratio of aqueous Cel7A:Cel7B, corresponding to a 4:1 surface mass ratio, effects the greatest rate of cellulose degradation across a range of cellulase concentrations at 25 degrees C. We find that surface chain-end concentration is a major predictor of Cel7A activity. Disruption of the hydrogen-bonding structure of cellulose by Cel7B enhances the activity of Cel7A on the cellulose surface. PMID- 23348000 TI - Modeling and simulation of dielectrophoretic particle-particle interactions and assembly. AB - Electric field induced particle-particle interactions and assembly are of great interest due to their useful applications in micro devices. The behavior of particles becomes more complex if multiple particles interact with each other at the same time. In this paper, we present a numerical study of two dimensional DC dielectrophoresis based particle-particle interactions and assembly for multiple particles using a hybrid immersed interface-immersed boundary method. The immersed interface method is employed to capture the physics of electrostatics in a fluid media with suspended particles. Particle interaction based dielectrophoretic forces are obtained using Maxwell's stress tensor without any boundary or volume integration. This electrostatic force distribution mimics the actual physics of the immersed particles in a fluid media. The corresponding particle response and hydrodynamic interactions are captured through the immersed boundary method by solving the transient Navier-Stokes equations. The interaction and assembly of multiple electrically similar and dissimilar particles are studied for various initial positions and orientations. Numerical results show that in a fluid media, similar particles form a chain parallel to the applied electric field, whereas dissimilar particles form a chain perpendicular to the applied electric field. Irrespective of initial position and orientation, particles first align themselves parallel or perpendicular to the electric field depending on the similarity or dissimilarity of particles. The acceleration and deceleration of particles are also observed and analyzed at different phases of the assembly process. This comprehensive study can be used to explain the multiple particle interaction and assembly phenomena observed in experiments. PMID- 23348001 TI - Quantum dot-assembled nanoparticles with polydiacetylene supramolecule toward label-free, multiplexed optical detection. AB - Quantum dot (QD)-assembled silica nanoparticles bearing a polydiacetylene (PDA) supramolecule on their surface (SiO(2)@QDs@PDA NPs) were developed for label-free and multiplexed detection of biological molecules. Two types of QD-assembled silica NPs (SiO(2)@QDs NPs) were prepared and coated with the PDA supramolecule via photo-induced polymerization of 10,12-pentacosadiynoic acid. One of the SiO(2)@QDs NPs was embedded with blue-QDs, and the other was embedded with green QDs for encoding. The resulting SiO(2)@QDs@PDA NPs showed discrete QD photoluminescence for encoding as well as PDA fluorescence for sensing a target without interference or overlap. Under heating stress of the SiO(2)@QDs@PDA NPs, the color of the PDA changed from blue to red, which allowed us to observe the fluorescence emitted from red PDA. The mixture of two different SiO(2)@QDs@PDA NPs, SiO(2)@QDs@blue-PDA NPs not emitting the fluorescence of PDA and SiO(2)@QDs@red-PDA NPs where stress was brought onto turn on the PDA fluorescence, was effectively imaged and readily distinguished via fluorescence microscopy, indicating their potential for label-free and multiplexed detection of target molecules. PMID- 23348002 TI - Overestimation of the effects of the BDNF val66met polymorphism on episodic memory-related hippocampal function: a critique of a recent meta-analysis. PMID- 23348003 TI - Genesis and regulatory wiring of retroelement-derived domesticated genes: a phylogenomic perspective. AB - Molecular domestications of transposable elements have occurred repeatedly during the evolution of eukaryotes. Vertebrates, especially mammals, possess numerous single copy domesticated genes (DGs) that have originated from the intronless multicopy transposable elements. However, the origin and evolution of the retroelement-derived DGs (RDDGs) that originated from Metaviridae has been only partially elucidated, due to absence of genome data or to limited analysis of a single family of DGs. We traced the genesis and regulatory wiring of the Metaviridae-derived DGs through phylogenomic analysis, using whole-genome information from more than 90 chordate genomes. Phylogenomic analysis of these DGs in chordate genomes provided direct evidence that major diversification has occurred in the ancestor of placental mammals. Mammalian RDDGs have been shown to originate in several steps by independent domestication events and to diversify later by gene duplications. Analysis of syntenic loci has shown that diverse RDDGs and their chromosomal positions were fully established in the ancestor of placental mammals. By analysis of active Metaviridae lineages in amniotes, we have demonstrated that RDDGs originated from retroelement remains. The chromosomal gene movements of RDDGs were highly dynamic only in the ancestor of placental mammals. During the domestication process, de novo acquisition of regulatory regions is shown to be a prerequisite for the survival of the DGs. The origin and evolution of de novo acquired promoters and untranslated regions in diverse mammalian RDDGs have been explained by comparative analysis of orthologous gene loci. The origin of placental mammal-specific innovations and adaptations, such as placenta and newly evolved brain functions, was most probably connected to the regulatory wiring of DGs and their rapid fixation in the ancestor of placental mammals. PMID- 23348004 TI - Sleep in America: role of racial/ethnic differences. AB - Sleep duration in America has gradually declined over the last four decades and appears to have reached a plateau for the last six years, with recent studies reporting that the population's current average sleep duration is approximately 6 h. In this paper, we examine epidemiologic and community-based data on sleep complaints reported by American adults, specifically addressing the role of race/ethnicity in the subjective report of sleep problems. Subjective and objective findings indicate that black (throughout the text, we use the term black in lieu of African American for there are instances where we refer to individuals with self-ascribed race/ethnicity as black, African American, African, or Caribbean American; the term white is used to denote individuals of European descent). Americans have higher rates of long (>=9 h) and short (<=5 h) sleep than their white counterparts, and this may mediate a higher risk of cardiovascular disease, obesity and diabetes among blacks. In addition, studies show mixed results on sleep complaints among blacks compared to those among other ethnicities. This paper explores factors that may contribute to racial/ethnic differences in sleep including intra-ethnic variation, cultural biases, genetics and psychosocial factors. PMID- 23348005 TI - Quercetin ameliorate insulin resistance and up-regulates cellular antioxidants during oleic acid induced hepatic steatosis in HepG2 cells. AB - Hepatic lipid accumulation and oxidative stress contribute to non-alcoholic fatty liver disease (NAFLD). Thus, we hypothesized that the hypolipidemic and antioxidant activity of quercetin would attenuate events leading to NAFLD. Addition of 2.0mM oleic acid (OA) into the culture media induced fatty liver condition in HepG2 cells by 24h. It was marked by significant accumulation of lipid droplets as determined by Oil-Red-O (ORO) based colorimetric assay, increased triacylglycerol (TAG) and increased lipid peroxidation. The inflammatory cytokines TNF-alpha and IL-8 levels were significantly increased with decreased antioxidant molecules. OA induced insulin resistance which was evident by inhibition of glucose uptake and cell proliferation. Quercetin (10 MUM) increased cell proliferation by 3.05 folds with decreased TAG content (45%) and was effective in increasing insulin mediated glucose uptake by 2.65 folds. The intracellular glutathione content was increased by 2.0 folds without substantial increase in GSSG content. Quercetin (10 MUM) decreased TNF-alpha and IL-8 by 59.74% and 41.11% respectively and inhibited generation of lipid peroxides by 50.5%. In addition, RT-PCR results confirmed quercetin (10 MUM) inhibited TNF-alpha gene expression. Further, superoxide dismutase, catalase and glutathione peroxidase activities were increased by 1.68, 2.19 and 1.71 folds respectively. Albumin and urea content was increased while the alanine aminotransferase (ALAT) activity was significantly decreased by quercetin. Hence, quercetin effectively reversed NAFLD symptoms by decreased triacyl glycerol accumulation, insulin resistance, inflammatory cytokine secretion and increased cellular antioxidants in OA induced hepatic steatosis in HepG2 cells. PMID- 23348007 TI - Re: "hemochromatosis gene (HFE) polymorphisms and risk of type 2 diabetes mellitus: a meta-analysis". PMID- 23348006 TI - Behavioral and molecular tracing of risky sexual contacts in a sample of Chinese HIV-infected men who have sex with men. AB - Contact tracing, coupled with molecular epidemiologic investigation, is especially useful for identifying an infection with few cases in the population, such as human immunodeficiency virus (HIV) infection in China. No such research is available on Chinese men who have sex with men (MSM). From 2008 to 2010 in Taizhou Prefecture in China, every newly diagnosed HIV-infected MSM was invited to participate as an "index case" in a contact tracing survey by providing contact information for up to 8 sexual contacts, who themselves were approached to receive voluntary HIV counseling and testing. Those who tested HIV-positive were then subjected to another contact tracing survey. This process was repeated until no more sexual contacts were reported or tested positive. A total of 100 HIV-infected MSM served as "index cases," including the initial 49 cases identified through routine surveillance programs and 51 cases from the present survey. Traced MSM exhibited little willingness to receive voluntary counseling and testing. CRF01_AE (HIV type 1) was the dominant subtype. Seven of 49 independent sexual networks were deemed HIV transmission clusters. Fear of stigma or discrimination may deter Chinese MSM from receiving voluntary counseling and testing. Nonetheless, the integration of behavioral network analysis and HIV phylogenetic analysis provides enhanced evidence for developing tailored prevention strategies for HIV-infected MSM. PMID- 23348008 TI - How Do Older Adults Respond to Active Australia Physical Activity Questions? Lessons from Cognitive Interviews. AB - The aim of this study was to examine older adults' understanding and interpretation of a validated questionnaire for physical activity surveillance, the Active Australia Survey (AAS). To address this aim, cognitive interviewing techniques were used during face-to-face semi-structured interviews with 44 adults aged 65-89 years. Qualitative data analysis revealed that participants were confused with questionnaire phrasing, misunderstood the scope of activities to include in answers, and misunderstood the time frame of activities to report. They also struggled to accurately estimate the frequency and duration of their activities. Our findings suggest that AAS questions may be interpreted differently by older adults than intended by survey developers. Findings also suggest that older adults use a range of methods for calculating PA frequency and duration. The issues revealed in this study may be useful for adapting AAS for use in older community-dwelling adults. PMID- 23348009 TI - Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits. AB - BACKGROUND: The neurosteroid allopregnanolone is a potent allosteric modulator of the gamma-aminobutyric acid type A receptor with anxiolytic properties. Exogenous administration of allopregnanolone reduces anxiety, and allopregnanolone blockade impairs social and affective functioning. However, the neural mechanism whereby allopregnanolone improves mood and reduces anxiety is unknown. In particular, brain imaging has not been used to link neurosteroid effects to emotion regulation neurocircuitry. METHODS: To investigate the brain basis of allopregnanolone's impact on emotion regulation, participants were administered 400 mg of pregnenolone (n=16) or placebo (n=15) and underwent 3T functional magnetic resonance imaging while performing the shifted-attention emotion appraisal task, which probes emotional processing and regulation. RESULTS: Compared with placebo, allopregnanolone was associated with reduced activity in the amygdala and insula across all conditions. During the appraisal condition, allopregnanolone increased activity in the dorsal medial prefrontal cortex and enhanced connectivity between the amygdala and dorsal medial prefrontal cortex, an effect that was associated with reduced self-reported anxiety. CONCLUSIONS: These results demonstrate that in response to emotional stimuli, allopregnanolone reduces activity in regions associated with generation of negative emotion. Furthermore, allopregnanolone may enhance activity in regions linked to regulatory processes. Aberrant activity in these regions has been linked to anxiety psychopathology. These results thus provide initial neuroimaging evidence that allopregnanolone may be a target for pharmacologic intervention in the treatment of anxiety disorders and suggest potential future directions for research into neurosteroid effects on emotion regulation neurocircuitry. PMID- 23348011 TI - Field fertility of frozen boar semen: a retrospective report comprising over 2600 AI services spanning a four year period. AB - Worldwide, greater than 90% of sows are inseminated with fresh semen. Less than 1% is inseminated using frozen semen. Albeit, frozen semen is an effective technology for the transfer of genes between breeding pyramids and also to reliably provide semen for planned matings. Little information exists on the long term use of frozen boar semen in commercial pork production operations. The objective in the present study was to assess application of frozen semen throughout a 4 year period comprising more than 2600 AI services. The frozen semen sourced from a boar stud in Manitoba, Canada. All artificial insemination (AI) occurred on a single 1800 sow farm in Indiana, USA. The sperm-rich fraction was collected and only those collections having >=80% motility and <=15% abnormalities were further processed. Semen was prepared for cryopreservation using Androhep((r)) CryoGuardTM, packaged in 0.5mL French straws (average 500 million total sperm per straw) and frozen using a programmable freezer (IceCubeTM). For each frozen ejaculate, a post-thaw quality check was performed. Ninety eight percent of the ejaculates that were frozen showed at least a 50% post-thaw motility and were approved for shipment. For AI, eight straws were thawed (to achieve at least 2.0*10(9)motile sperm) and diluted with 60mL of extender pre-warmed to 26 degrees C. Within 2-5min of thawing, the sows or gilts were inseminated via intra-cervical deposition using a standard AI pipette. Sows and gilts were inseminated three times PM/AM/PM and AM/PM/AM, respectively. Of 2696 recorded services, 2122 (78.7%) of the females farrowed. The mean (+/-SD) total number piglets born were 12.5 (+/-3.9). A progressive improvement of fertility over time was observed mainly due to adaptive procedures associated with an introduced technology. In summary, acceptable fertility is possible with frozen semen and has merit for application as a reproductive management tool. PMID- 23348010 TI - Social isolation exacerbates schizophrenia-like phenotypes via oxidative stress in cortical interneurons. AB - BACKGROUND: Our previous studies indicated that N-methyl-D-aspartate receptor (NMDAR) deletion from a subset of corticolimbic interneurons in the mouse brain during early postnatal development is sufficient to trigger several behavioral and pathophysiological features resembling the symptoms of human schizophrenia. Interestingly, many of these behavioral phenotypes are exacerbated by social isolation stress. However, the mechanisms underlying the exacerbating effects of social isolation are unclear. METHODS: With gamma-aminobutyric acid-ergic interneuron-specific NMDAR hypofunction mouse model (Ppp1r2-Cre/fGluN1 knockout [KO] mice), we investigated whether oxidative stress is implicated in the social isolation-induced exacerbation of schizophrenia-like phenotypes and further explored the underlying mechanism of elevated oxidative stress in KO mice. RESULTS: The reactive oxygen species (ROS) level in the cortex of group-housed KO mice was normal at 8 weeks although increased at 16 weeks old. Postweaning social isolation (PWSI) augmented the ROS levels in KO mice at both ages, which was accompanied by the onset of behavioral phenotype. Chronic treatment with apocynin, an ROS scavenger, abolished markers of oxidative stress and partially alleviated schizophrenia-like behavioral phenotypes in KO mice. Markers of oxidative stress after PWSI were especially prominent in cortical parvalbumin (PV)-positive interneurons. The vulnerability of PV interneurons to oxidative stress was associated with downregulation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), a master regulator of mitochondrial energy metabolism and antioxidation. CONCLUSIONS: These results suggest that a PWSI-mediated impairment in antioxidant defense mechanisms, presumably mediated by PGC-1alpha downregulation in the NMDAR-deleted PV-positive interneurons, results in oxidative stress, which, in turn, might contribute to exacerbation of schizophrenia-like behavioral phenotypes. PMID- 23348012 TI - Predictors of fielding performance in professional baseball players. AB - The ultimate zone-rating extrapolation (UZR/150) rates fielding performance by runs saved or cost within a zone of responsibility in comparison with the league average (150 games) for a position. Spring-training anthropometric and performance measures have been previously related to hitting performance; however, their relationships with fielding performance measures are unknown. PURPOSE: To examine the relationship between anthropometric and performance measurements on fielding performance in professional baseball players. METHODS: Body mass, lean body mass (LBM), grip strength, 10-yd sprint, proagility, and vertical-jump mean (VJMP) and peak power (VJPP) were collected during spring training over the course of 5 seasons (2007-2011) for professional corner infielders (CI; n = 17, fielding opportunities = 420.7 +/- 307.1), middle infielders (MI; n = 14, fielding opportunities = 497.3 +/- 259.1), and outfielders (OF; n = 16, fielding opportunities = 227.9 +/- 70.9). The relationships between these data and regular-season (100-opportunity minimum) fielding statistics were examined using Pearson correlation coefficients, while stepwise regression identified the single best predictor of UZR/150. RESULTS: Significant correlations (P < .05) were observed between UZR/150 and body mass (r = .364), LBM (r = .396), VJPP (r = .397), and VJMP (r = .405). Of these variables, stepwise regression indicated VJMP (R = .405, SEE = 14.441, P = .005) as the single best predictor for all players, although the addition of proagility performance strengthened (R = .496, SEE = 13.865, P = .002) predictive ability by 8.3%. The best predictor for UZR/150 was body mass for CI (R = .519, SEE = 15.364, P = .033) and MI (R = .672, SEE = 12.331, P = .009), while proagility time was the best predictor for OF (R = .514, SEE = 8.850, P = .042). CONCLUSIONS: Spring-training measurements of VJMP and proagility time may predict the defensive run value of a player over the course of a professional baseball season. PMID- 23348013 TI - GDNF, NGF and BDNF as therapeutic options for neurodegeneration. AB - Glial cell-derived neurotrophic factor (GDNF), and the neurotrophin nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the survival, maintenance and regeneration of specific neuronal populations in the adult brain. Depletion of these neurotrophic factors has been linked with disease pathology and symptoms, and replacement strategies are considered as potential therapeutics for neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's diseases. GDNF administration has recently been shown to be an effective treatment for Parkinson's disease, with clinical trials currently in progress. Trials with NGF for Alzheimer's disease are ongoing, with some degree of success. Preclinical results using BDNF also show much promise, although there are accompanying difficulties. Ultimately, the administration of a therapy involving proteins in the brain has inherent problems. Because of the blood-brain barrier, the protein must be infused directly, produced by viral constructs, secreted from implanted protein-secreting cells or actively transported across the brain. An alternative to this is the use of a small molecule agonist, a modulator or enhancer targeting the associated receptors. We evaluate these neurotrophic factors as potential short or long-term treatments, weighing up preclinical and clinical results with the possible effects on the underlying neurodegenerative process. PMID- 23348014 TI - Biological rhythms and melatonin in mood disorders and their treatments. AB - Affective disorders such as major depression, bipolar disorders and seasonal affective disorders have been described as alterations of various neuronal systems. In addition to the classical monoaminergic hypotheses that have been long proposed to explain the pathophysiology of these disorders, a strong association between circadian rhythms and mood regulation has been suggested in the light of several clinical and preclinical findings. In this review, we summarize the different hypotheses on pathophysiology mechanisms underlying depressive disorders and put a special emphasis on the alterations of melatonin secretion and associated changes in biological rhythms that characterize mood disorders. Causal relationships between alterations in circadian rhythms and mood disorders are strongly supported by the antidepressant efficacy of innovative pharmacological treatments aimed at resynchronizing endogenous rhythms in depressed patients. Genetic, epigenetic and environmental factors generating desynchronization between endogenous biological rhythms and exogenous rhythms driven by environmental and societal constraints are very probably involved in the vulnerability to mood disorders. Further investigations of the molecular/cellular bases of the relationships between stress axis dysfunctions, endogenous biological rhythm dysregulations and associated functional and anatomical brain alterations should allow important progress in the knowledge of pathophysiological mechanisms of affective disorders and the downstream development of innovative, more effective and better tolerated, therapies. PMID- 23348015 TI - The dental pathology of southern sea otters (Enhydra lutris nereis). AB - Skulls (n = 1,205) of southern sea otters were examined macroscopically according to defined criteria. The museum specimens, acquired from strandings, varied in age from juvenile to adult, with an equal sex distribution. The results from all young adult and adult specimens were pooled according to tooth type. Ninety-two percent of teeth were available for examination, with 6.5% artifactually absent, 0.6% deemed absent due to acquired tooth loss and 0.03% deemed congenitally absent. All teeth were normal in morphology, except for three pairs of fused teeth, including two instances of fused maxillary first incisor teeth. Supernumerary teeth were associated with 97 normal teeth (most commonly maxillary canine teeth) in 68 specimens. At least one persistent deciduous tooth was present in six skulls, two of which were from adults. The majority (94.6%) of alveoli, either with or without teeth, were not associated with bony changes consistent with periodontitis; however, the majority (74.4%) of specimens did have at least one tooth associated with mild periodontitis. The mesial root of the mandibular third premolar tooth was the most common location at which periodontal hard tissue lesions were observed (56.6%). Ten sea otters had lesions consistent with focal enamel hypoplasia. Approximately half of the teeth (52.0%) were abraded; almost all adult specimens (98.1%) contained at least one abraded tooth, while fewer young adults were affected (76.4%). Tooth fractures were uncommon, affecting 1,343 teeth (4.5%). Periapical lesions were associated with 409 teeth (1.3%) in a total of 176 specimens, and these would likely have caused considerable morbidity while the animals were alive. PMID- 23348016 TI - Vaginal canine transmissible venereal tumour associated with intra-tumoural Leishmania spp. amastigotes in an asymptomatic female dog. AB - A 2-year-old female boxer dog was presented with a vaginal serosanguineous discharge not associated with oestrus. There was a friable mass occupying the upper caudal part of the vagina. Cytological and histological examination revealed a monomorphic population of neoplastic round cells consistent with canine transmissible venereal tumour (TVT). In addition, Leishmania spp. amastigotes were found within the neoplastic tissue. In order to characterize whether the amastigotes were present inside macrophages and/or neoplastic cells, a co-localization study using cell- and pathogen-specific markers was performed. To detect Leishmania spp. a 5.8S ribosomal RNA (rRNA) parasite-specific sequence was used for in-situ hybridization and Mac387 was used as a macrophage marker for immunohistochemistry. Leishmania spp. rRNA was detected inside Mac387(+) macrophages and within the cytoplasm of some neoplastic cells. DNA isolation and polymerase chain reaction using specific primers and sequencing analysis identified the organism as Leishmania infantum (syn. Leishmania chagasi). This is the first report describing infection of tumour cells by L. infantum in a genital TVT from an asymptomatic bitch. Transplantation of Leishmania-laden neoplastic cells could represent an alternative route of venereal transmission of leishmaniasis among dogs. PMID- 23348017 TI - Correlation of inflammation with adrenocortical atrophy in canine adrenalitis. AB - Hypoadrenocorticism or Addison's disease (AD) is a functional disorder in which insufficient mineralocorticoid and glucocorticoid hormones are produced by the adrenal cortex. Human AD is usually attributed to lymphoplasmacytic adrenalitis with autoimmune destruction of the adrenal cortex. Lymphoplasmacytic adrenalitis is also reported in some descriptions of canine AD; however, the histological aspects of adrenalitis or adrenocortical atrophy have not been well characterized because microscopical examination is not required for diagnosis of AD. In this study, sections of adrenal glands from 33 dogs with adrenalitis were compared with those of 37 dogs without adrenal lesions. The affected dogs were classified clinically as having AD (n = 3), being suspected of having AD (n = 17), not having AD (n = 11) or were unclassified (n = 2). The adrenal inflammation was lymphoplasmacytic in 17 dogs, lymphocytic in four, lymphohistiocytic in one, granulomatous in three and neutrophilic in eight cases. Adrenal glands from control dogs lacked leucocyte infiltration and had a cortical to medullary area ratio of 1.1-7.2. All three dogs with AD, 8/17 dogs with suspected AD and 1/11 dogs without AD had a cortical to medullary area ratio <1.1. Because the area ratio was correlated (r = 0.94) with a linear cortical to medullary thickness ratio, a thickness ratio <1.1 could also indicate severe adrenocortical atrophy. Severe adrenocortical atrophy was associated typically with lymphoplasmacytic infiltration and nearly complete loss of cortical cells; however, the zona glomerulosa was partially spared in three dogs with lymphoplasmacytic adrenalitis and severe cortical atrophy. In contrast, non-lymphoid inflammation was generally part of systemic disease, multifocal and was unaccompanied by severe adrenocortical atrophy. PMID- 23348018 TI - Immunohistochemical evaluation of heat shock protein expression in normal canine nerve and peripheral nerve sheath tumours. AB - Abnormal expression of heat shock proteins (HSPs) has been observed in many human neoplasms and such expression has prognostic, predictive and therapeutic implications. The aim of this study was to evaluate immunohistochemically the expression of HSP 27, HSP 32 and HSP 90 in normal canine peripheral nerves and in four benign and 15 malignant canine peripheral nerve sheath tumours (PNSTs). In normal nerve, all of the HSPs were detected in axons, epineurial fibroblasts and scattered Schwann cell bodies. Cytoplasmic expression of HSP 27 was more widespread and intense in benign PNSTs compared with malignant PNSTs (P <0.05). Widespread and intense nuclear expression of HSP 32 was also associated with benign tumours (P <0.01), while high HSP 90 immunoreactivity was detected in all tumours, suggesting that HSP 90 might represent a new therapeutic target. PMID- 23348019 TI - The emerging role of hOGG1 Ser326Cys polymorphisms in gastrointestinal carcinogenesis. PMID- 23348020 TI - Compensated heart failure does not always alleviate overestimation of liver stiffness by transient elastography. PMID- 23348021 TI - gamma-Glutamyl transferase and its role as a biomarker of systemic malignancies other than hepatocellular carcinomas. PMID- 23348024 TI - Laryngeal reflex apnea in neonates: effects of CO2 and the complex influence of hypoxia. AB - We have examined influence of hypocapnia, mild hypercapnia and hypoxia on the durations of fictive apnea and respiratory disruption elicited by injection of 0.1ml of water into the laryngeal lumen-the laryngeal chemoreflex (LCR)-in 20 unanesthetized, decerebrate, vagotomized piglets aged 4-10 days that were paralyzed and ventilated with a constant frequency and tidal volume. The LCR was enhanced by hypocapnia and attenuated by hypercapnia as reported by others. The responses to laryngeal stimulation during hypoxia were varied and complex: some animals showed abbreviated responses during the tachypnea of early hypoxia, followed after 10-15min by more prolonged apnea and respiratory disruption accompanying the reduction in ventilatory activity that commonly occurs during sustained hypoxia in neonates. We speculate that this later hypoxic enhancement of the LCR may be due to accumulation of adenosine in the brain stem. PMID- 23348025 TI - Effects of unsupported arm training on arm exercise-related perception in COPD patients. AB - We hypothesized that arm training might affect unsupported arm exercise-related perception by decreasing motor output to arm/torso muscles in patients with chronic obstructive pulmonary disease (COPD). Eleven patients were studied at 80% of peak incremental arm exercise, before and after unsupported arm training. Training increased endurance time, decreased respiratory effort and much more arm effort (by Borg scale) without affecting chest wall dynamic hyperinflation or configuration. Ventilatory response to carbon dioxide output was the same before and after training so that at isotime the reduction in ventilation correlated strongly with a simultaneous reduction in metabolic output. These changes reflect a reduced ventilatory drive. We conclude that: (i) a reduced level of ventilation, relative to a decrease in central motor output, is the contribution of arm training to symptom alleviation during unsupported arm exercise in COPD patients, and (ii) arm training improved patients' exercise-related perception without affecting chest wall operational volumes or configuration. PMID- 23348027 TI - Sex differences in the effects of adolescent stress on adult brain inflammatory markers in rats. AB - Both basic and clinical research indicates that females are more susceptible to stress-related affective disorders than males. One of the mechanisms by which stress induces depression is via inflammatory signaling in the brain. Stress during adolescence, in particular, can also disrupt the activation and continued development of both the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes, both of which modulate inflammatory pathways and brain regions involved in affective behavior. Therefore, we tested the hypothesis that adolescent stress differentially alters brain inflammatory mechanisms associated with affective like behavior into adulthood based on sex. Male and female Wistar rats underwent mixed-modality stress during adolescence (PND 37-48) and were challenged with lipopolysaccharide (LPS; 250MUg/kg, i.p.) or saline 4.5weeks later (in adulthood). Hippocampal inflammatory marker gene expression and circulating HPA and HPG axes hormone concentrations were then determined. Despite previous studies indicating that adolescent stress induces affective-like behaviors in female rats only, this study demonstrated that adolescent stress increased hippocampal inflammatory responses to LPS in males only, suggesting that differences in neuroinflammatory signaling do not drive the divergent affective like behaviors. The sex differences in inflammatory markers were not associated with differences in corticosterone. In females that experienced adolescent stress, LPS increased circulating estradiol. Estradiol positively correlated with hippocampal microglial gene expression in control female rats, whereas adolescent stress negated this relationship. Thus, estradiol in females may potentially protect against stress-induced increases in neuroinflammation. PMID- 23348029 TI - Complete low-cost implementation of a teleoperated control system for a humanoid robot. AB - Humanoid robotics is a field of a great research interest nowadays. This work implements a low-cost teleoperated system to control a humanoid robot, as a first step for further development and study of human motion and walking. A human suit is built, consisting of 8 sensors, 6 resistive linear potentiometers on the lower extremities and 2 digital accelerometers for the arms. The goal is to replicate the suit movements in a small humanoid robot. The data from the sensors is wirelessly transmitted via two ZigBee RF configurable modules installed on each device: the robot and the suit. Replicating the suit movements requires a robot stability control module to prevent falling down while executing different actions involving knees flexion. This is carried out via a feedback control system with an accelerometer placed on the robot's back. The measurement from this sensor is filtered using Kalman. In addition, a two input fuzzy algorithm controlling five servo motors regulates the robot balance. The humanoid robot is controlled by a medium capacity processor and a low computational cost is achieved for executing the different algorithms. Both hardware and software of the system are based on open platforms. The successful experiments carried out validate the implementation of the proposed teleoperated system. PMID- 23348026 TI - Mechanistic basis of immunotherapies for type 1 diabetes mellitus. AB - Type 1 diabetes (T1D) is an autoimmune disease for which there is no cure. The pancreatic beta cells are the source of insulin that keeps blood glucose normal. When susceptible individuals develop T1D, their beta cells are destroyed by autoimmune T lymphocytes and no longer produce insulin. T1D patients therefore depend on daily insulin injections for survival. Gene therapy in T1D aims at the induction of new islets to replace those that have been destroyed by autoimmunity. A major goal of T1D research is to restore functional beta cell mass while eliminating diabetogenic T cells in the hope of achieving insulin independence. Multiple therapeutic strategies for the generation of new beta cells have been under intense investigations. However, newly formed beta cells would be immediately destroyed by diabetogenic T cells. Therefore, successful islet induction therapy must be supported by potent immunotherapy that will protect the newly formed beta cells. Herein, we will summarize the current information on immunotherapies that aim at modifying T cell response to beta cells. We will first outline the immune mechanisms that underlie T1D development and progression and review the scientific background and rationale for specific modes of immunotherapy. Numerous clinical trials using antigen-specific strategies and immune-modifying drugs have been published, though most have proved too toxic or have failed to provide long-term beta cell protection. To develop an effective immunotherapy, there must be a continued effort on defining the molecular basis that underlies T cell response to pancreatic islet antigens in T1D. PMID- 23348028 TI - Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain. AB - We have previously observed that the non-opioid morphine metabolite, morphine-3 glucuronide, enhances pain via a toll-like receptor 4 (TLR4) dependent mechanism. The present studies were undertaken to determine whether TLR4-dependent pain enhancement generalizes to other classes of glucuronide metabolites. In silico modeling predicted that glucuronic acid alone and ethyl glucuronide, a minor but long-lasting ethanol metabolite, would dock to the same MD-2 portion of the TLR4 receptor complex previously characterized as the docking site for morphine-3 glucuronide. Glucuronic acid, ethyl glucuronide and ethanol all caused an increase in TLR4-dependent reporter protein expression in a cell line transfected with TLR4 and associated co-signaling molecules. Glucuronic acid-, ethyl glucuronide-, and ethanol-induced increases in TLR4 signaling were blocked by the TLR4 antagonists LPS-RS and (+)-naloxone. Glucuronic acid and ethyl glucuronide both caused allodynia following intrathecal injection in rats, which was blocked by intrathecal co-administration of the TLR4 antagonist LPS-RS. The finding that ethyl glucuronide can cause TLR4-dependent pain could have implications for human conditions such as hangover headache and alcohol withdrawal hyperalgesia, as well as suggesting that other classes of glucuronide metabolites could have similar effects. PMID- 23348030 TI - Human behavior cognition using smartphone sensors. AB - This research focuses on sensing context, modeling human behavior and developing a new architecture for a cognitive phone platform. We combine the latest positioning technologies and phone sensors to capture human movements in natural environments and use the movements to study human behavior. Contexts in this research are abstracted as a Context Pyramid which includes six levels: Raw Sensor Data, Physical Parameter, Features/Patterns, Simple Contextual Descriptors, Activity-Level Descriptors, and Rich Context. To achieve implementation of the Context Pyramid on a cognitive phone, three key technologies are utilized: ubiquitous positioning, motion recognition, and human behavior modeling. Preliminary tests indicate that we have successfully achieved the Activity-Level Descriptors level with our LoMoCo (Location-Motion-Context) model. Location accuracy of the proposed solution is up to 1.9 meters in corridor environments and 3.5 meters in open spaces. Test results also indicate that the motion states are recognized with an accuracy rate up to 92.9% using a Least Square-Support Vector Machine (LS-SVM) classifier. PMID- 23348031 TI - Fiber optic pH sensor with self-assembled polymer multilayer nanocoatings. AB - A fiber-optic pH sensor based on a tilted fiber Bragg grating (TFBG) with electrostatic self-assembly multilayer sensing film is presented. The pH sensitive polymeric film, poly(diallyldimethylammonium chloride) (PDDA) and poly(acrylic acid) (PAA) was deposited on the circumference of the TFBG with the layer-by-layer (LbL) electrostatic self-assembly technique. The PDDA/PAA film exhibits a reduction in refractive index by swelling in different pH solutions. This effect results in wavelength shifts and transmission changes in the spectrum of the TFBG. The peak amplitude of the dominant spectral fringes over a certain window of the transmission spectrum, obtained by FFT analysis, has a near-linear pH sensitivity of 117 arbitrary unit (a.u.)/pH unit and an accuracy of +/-1 a.u. (in the range of pH 4.66 to pH 6.02). The thickness and surface morphology of the sensing multilayer film were characterized to investigate their effects on the sensor's performance. The dynamic response of the sensor also has been studied (10 s rise time and 18 s fall time for a sensor with six bilayers of PDDA/PAA). PMID- 23348033 TI - Virtual induction loops based on cooperative vehicular communications. AB - Induction loop detectors have become the most utilized sensors in traffic management systems. The gathered traffic data is used to improve traffic efficiency (i.e., warning users about congested areas or planning new infrastructures). Despite their usefulness, their deployment and maintenance costs are expensive. Vehicular networks are an emerging technology that can support novel strategies for ubiquitous and more cost-effective traffic data gathering. In this article, we propose and evaluate VIL (Virtual Induction Loop), a simple and lightweight traffic monitoring system based on cooperative vehicular communications. The proposed solution has been experimentally evaluated through simulation using real vehicular traces. PMID- 23348032 TI - Synthetic and bio-artificial tactile sensing: a review. AB - This paper reviews the state of the art of artificial tactile sensing, with a particular focus on bio-hybrid and fully-biological approaches. To this aim, the study of physiology of the human sense of touch and of the coding mechanisms of tactile information is a significant starting point, which is briefly explored in this review. Then, the progress towards the development of an artificial sense of touch are investigated. Artificial tactile sensing is analysed with respect to the possible approaches to fabricate the outer interface layer: synthetic skin versus bio-artificial skin. With particular respect to the synthetic skin approach, a brief overview is provided on various technologies and transduction principles that can be integrated beneath the skin layer. Then, the main focus moves to approaches characterized by the use of bio-artificial skin as an outer layer of the artificial sensory system. Within this design solution for the skin, bio-hybrid and fully-biological tactile sensing systems are thoroughly presented: while significant results have been reported for the development of tissue engineered skins, the development of mechanotransduction units and their integration is a recent trend that is still lagging behind, therefore requiring research efforts and investments. In the last part of the paper, application domains and perspectives of the reviewed tactile sensing technologies are discussed. PMID- 23348034 TI - Nanobiosensors based on chemically modified AFM probes: a useful tool for metsulfuron-methyl detection. AB - The use of agrochemicals has increased considerably in recent years, and consequently, there has been increased exposure of ecosystems and human populations to these highly toxic compounds. The study and development of methodologies to detect these substances with greater sensitivity has become extremely relevant. This article describes, for the first time, the use of atomic force spectroscopy (AFS) in the detection of enzyme-inhibiting herbicides. A nanobiosensor based on an atomic force microscopy (AFM) tip functionalised with the acetolactate synthase (ALS) enzyme was developed and characterised. The herbicide metsulfuron-methyl, an ALS inhibitor, was successfully detected through the acquisition of force curves using this biosensor. The adhesion force values were considerably higher when the biosensor was used. An increase of ~250% was achieved relative to the adhesion force using an unfunctionalised AFM tip. This considerable increase was the result of a specific interaction between the enzyme and the herbicide, which was primarily responsible for the efficiency of the nanobiosensor. These results indicate that this methodology is promising for the detection of herbicides, pesticides, and other environmental contaminants. PMID- 23348035 TI - Scour monitoring system for subsea pipeline based on active thermometry: numerical and experimental studies. AB - A scour monitoring system for subsea pipeline based on active thermometry is proposed in this paper. The temperature reading of the proposed system is based on a distributed Brillouin optical fiber sensing technique. A thermal cable acts as the main component of the system, which consists of a heating belt, armored optical fibers and heat-shrinkable tubes which run parallel to the pipeline. The scour-induced free span can be monitored through different heat transfer behaviors of in-water and in-sediment scenarios during heating and cooling processes. Two sets of experiments, including exposing different lengths of the upper surface of the pipeline to water and creating free spans of various lengths, were carried out in laboratory. In both cases, the scour condition was immediately detected by the proposed monitoring system, which confirmed the system is robust and very sensitive. Numerical study of the method was also investigated by using the finite element method (FEM) with ANSYS, resulting in reasonable agreement with the test data. This brand new system provides a promising, low cost, highly precise and flexible approach for scour monitoring of subsea pipelines. PMID- 23348036 TI - Low-Cost MEMS sensors and vision system for motion and position estimation of a scooter. AB - The possibility to identify with significant accuracy the position of a vehicle in a mapping reference frame for driving directions and best-route analysis is a topic which is attracting a lot of interest from the research and development sector. To reach the objective of accurate vehicle positioning and integrate response events, it is necessary to estimate position, orientation and velocity of the system with high measurement rates. In this work we test a system which uses low-cost sensors, based on Micro Electro-Mechanical Systems (MEMS) technology, coupled with information derived from a video camera placed on a two wheel motor vehicle (scooter). In comparison to a four-wheel vehicle; the dynamics of a two-wheel vehicle feature a higher level of complexity given that more degrees of freedom must be taken into account. For example a motorcycle can twist sideways; thus generating a roll angle. A slight pitch angle has to be considered as well; since wheel suspensions have a higher degree of motion compared to four-wheel motor vehicles. In this paper we present a method for the accurate reconstruction of the trajectory of a "Vespa" scooter; which can be used as alternative to the "classical" approach based on GPS/INS sensor integration. Position and orientation of the scooter are obtained by integrating MEMS-based orientation sensor data with digital images through a cascade of a Kalman filter and a Bayesian particle filter. PMID- 23348037 TI - Strategy for the development of a smart NDVI camera system for outdoor plant detection and agricultural embedded systems. AB - The application of (smart) cameras for process control, mapping, and advanced imaging in agriculture has become an element of precision farming that facilitates the conservation of fertilizer, pesticides, and machine time. This technique additionally reduces the amount of energy required in terms of fuel. Although research activities have increased in this field, high camera prices reflect low adaptation to applications in all fields of agriculture. Smart, low cost cameras adapted for agricultural applications can overcome this drawback. The normalized difference vegetation index (NDVI) for each image pixel is an applicable algorithm to discriminate plant information from the soil background enabled by a large difference in the reflectance between the near infrared (NIR) and the red channel optical frequency band. Two aligned charge coupled device (CCD) chips for the red and NIR channel are typically used, but they are expensive because of the precise optical alignment required. Therefore, much attention has been given to the development of alternative camera designs. In this study, the advantage of a smart one-chip camera design with NDVI image performance is demonstrated in terms of low cost and simplified design. The required assembly and pixel modifications are described, and new algorithms for establishing an enhanced NDVI image quality for data processing are discussed. PMID- 23348038 TI - Motion mode recognition and step detection algorithms for mobile phone users. AB - Microelectromechanical Systems (MEMS) technology is playing a key role in the design of the new generation of smartphones. Thanks to their reduced size, reduced power consumption, MEMS sensors can be embedded in above mobile devices for increasing their functionalities. However, MEMS cannot allow accurate autonomous location without external updates, e.g., from GPS signals, since their signals are degraded by various errors. When these sensors are fixed on the user's foot, the stance phases of the foot can easily be determined and periodic Zero velocity UPdaTes (ZUPTs) are performed to bound the position error. When the sensor is in the hand, the situation becomes much more complex. First of all, the hand motion can be decoupled from the general motion of the user. Second, the characteristics of the inertial signals can differ depending on the carrying modes. Therefore, algorithms for characterizing the gait cycle of a pedestrian using a handheld device have been developed. A classifier able to detect motion modes typical for mobile phone users has been designed and implemented. According to the detected motion mode, adaptive step detection algorithms are applied. Success of the step detection process is found to be higher than 97% in all motion modes. PMID- 23348039 TI - Contrasted evolution of the vomeronasal receptor repertoires in mammals and squamate reptiles. AB - The vomeronasal organ (VNO) is an olfactory structure that detects pheromones and environmental cues. It consists of sensory neurons that express evolutionary unrelated groups of transmembrane chemoreceptors. The predominant V1R and V2R receptor repertoires are believed to detect airborne and water-soluble molecules, respectively. It has been suggested that the shift in habitat of early tetrapods from water to land is reflected by an increase in the ratio of V1R/V2R genes. Snakes, which have a very large VNO associated with a sophisticated tongue delivery system, are missing from this analysis. Here, we use RNA-seq and RNA in situ hybridization to study the diversity, evolution, and expression pattern of the corn snake vomeronasal receptor repertoires. Our analyses indicate that snakes and lizards retain an extremely limited number of V1R genes but exhibit a large number of V2R genes, including multiple lineages of reptile-specific and snake-specific expansions. We finally show that the peculiar bigenic pattern of V2R vomeronasal receptor gene transcription observed in mammals is conserved in squamate reptiles, hinting at an important but unknown functional role played by this expression strategy. Our results do not support the hypothesis that the shift to a vomeronasal receptor repertoire dominated by V1Rs in mammals reflects the evolutionary transition of early tetrapods from water to land. This study sheds light on the evolutionary dynamics of the vomeronasal receptor families in vertebrates and reveals how mammals and squamates differentially adapted the same ancestral vomeronasal repertoire to succeed in a terrestrial environment. PMID- 23348040 TI - Mechanisms and dynamics of orphan gene emergence in insect genomes. AB - Orphan genes are defined as genes that lack detectable similarity to genes in other species and therefore no clear signals of common descent (i.e., homology) can be inferred. Orphans are an enigmatic portion of the genome because their origin and function are mostly unknown and they typically make up 10% to 30% of all genes in a genome. Several case studies demonstrated that orphans can contribute to lineage-specific adaptation. Here, we study orphan genes by comparing 30 arthropod genomes, focusing in particular on seven recently sequenced ant genomes. This setup allows analyzing a major metazoan taxon and a comparison between social Hymenoptera (ants and bees) and nonsocial Diptera (flies and mosquitoes). First, we find that recently split lineages undergo accelerated genomic reorganization, including the rapid gain of many orphan genes. Second, between the two insect orders Hymenoptera and Diptera, orphan genes are more abundant and emerge more rapidly in Hymenoptera, in particular, in leaf-cutter ants. With respect to intragenomic localization, we find that ant orphan genes show little clustering, which suggests that orphan genes in ants are scattered uniformly over the genome and between nonorphan genes. Finally, our results indicate that the genetic mechanisms creating orphan genes-such as gene duplication, frame-shift fixation, creation of overlapping genes, horizontal gene transfer, and exaptation of transposable elements-act at different rates in insects, primates, and plants. In Formicidae, the majority of orphan genes has their origin in intergenic regions, pointing to a high rate of de novo gene formation or generalized gene loss, and support a recently proposed dynamic model of frequent gene birth and death. PMID- 23348041 TI - Discovery of MicroRNA169 gene copies in genomes of flowering plants through positional information. AB - Expansion and contraction of microRNA (miRNA) families can be studied in sequenced plant genomes through sequence alignments. Here, we focused on miR169 in sorghum because of its implications in drought tolerance and stem-sugar content. We were able to discover many miR169 copies that have escaped standard genome annotation methods. A new miR169 cluster was found on sorghum chromosome 1. This cluster is composed of the previously annotated sbi-MIR169o together with two newly found MIR169 copies, named sbi-MIR169t and sbi-MIR169u. We also found that a miR169 cluster on sorghum chr7 consisting of sbi-MIR169l, sbi-MIR169m, and sbi-MIR169n is contained within a chromosomal inversion of at least 500 kb that occurred in sorghum relative to Brachypodium, rice, foxtail millet, and maize. Surprisingly, synteny of chromosomal segments containing MIR169 copies with linked bHLH and CONSTANS-LIKE genes extended from Brachypodium to dictotyledonous species such as grapevine, soybean, and cassava, indicating a strong conservation of linkages of certain flowering and/or plant height genes and microRNAs, which may explain linkage drag of drought and flowering traits and would have consequences for breeding new varieties. Furthermore, alignment of rice and sorghum orthologous regions revealed the presence of two additional miR169 gene copies (miR169r and miR169s) on sorghum chr7 that formed an antisense miRNA gene pair. Both copies are expressed and target different set of genes. Synteny-based analysis of microRNAs among different plant species should lead to the discovery of new microRNAs in general and contribute to our understanding of their evolution. PMID- 23348043 TI - Core muscle strengthening's improvement of balance performance in community dwelling older adults: a pilot study. AB - To determine the effect of core muscle strengthening on balance in community dwelling older adults, 24 healthy men and women between 65 and 85 years old were randomized to either exercise (EX; n = 12) or control (CON; n = 12) groups. The exercise group performed a core strengthening home exercise program thrice weekly for 6 wk. Core muscle (curl-up test), functional reach (FR) and Star Excursion Balance Test (SEBT) were assessed at baseline and follow-up. There were no group differences at baseline. At follow-up, EX exhibited significantly greater improvements in curl-up (Cohen's d = 4.4), FR (1.3), and SEBT (>1.9 for all directions) than CON. The change in curl-up was significantly correlated with the change in FR (r = .44, p = .03) and SEBT (r > .61, p <= .002). These results suggest that core strengthening should be part of a comprehensive balance training program for older adults. PMID- 23348044 TI - A HaloTag(r) method for assessing the retrograde axonal transport of the p75 neurotrophin receptor and other proteins in compartmented cultures of rat sympathetic neurons. AB - We have adapted HaloTag(r) (HT) technology for use in compartmented cultures of rat sympathetic neurons in order to provide a technique that can be broadly applied to studies of the retrograde transport of molecules that play roles in neurotrophin signaling. Transfected neurons expressing HT protein alone, HT protein fused to the p75 neurotrophin receptor (p75NTR) or HT protein fused to tubulin alpha-1B were maintained in compartmented cultures in which cell bodies and proximal axons of rat sympathetic neurons reside in proximal compartments and their distal axons extend into distal compartments. HT ligand containing a fluorescent tetramethylrhodamine (TMR) label was applied either in the distal compartments or the proximal compartments, and the transport of labeled proteins was assayed by gel fluorescence imaging and TMR immunoblot. HT protein expressed alone displayed little or no retrograde transport. HT protein fused to either the intracellular C-terminus or the extracellular N-terminus of p75NTR was retrogradely transported. The retrograde transport of p75NTR was augmented when the distal axons were provided with nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) or antibodies to BDNF. The anterograde transport of HT protein fused to the N-terminus of tubulin alpha-1B was also demonstrated. We conclude that retrograde transport of HT fusion proteins provides a powerful and novel approach in studies of axonal transport. PMID- 23348045 TI - A reliable in vitro model for studying peripheral nerve myelination in mouse. AB - The rat dorsal root ganglia (DRG) model is a long-standing in vitro model for analysis of myelination in the peripheral nervous system. For performing systematic, high throughput analysis with transgenic animals, a simplified BL6 mouse protocol is indispensable. Here we present a stable and reliable protocol for myelinating co-cultures producing a high myelin ratio using cells from C57BL/6 mice. As an easy accessible and operable method, Sudan staining proved to be efficient in myelin detection for fixed cultures. Green fatty acid stain turned out to be highly reliable for analysis of the dynamic biological processes of myelination in vital cultures. Once myelinated we were able to induce demyelination by the addition of forskolin into the model system. In addition, we provide an optimised rat DRG protocol with significantly improved myelin ratio and a comparison of the protocols presented. Our results strengthen the value of ex vivo myelination models in neurobiology. PMID- 23348042 TI - Estrogen synthesis and signaling pathways during aging: from periphery to brain. AB - Estrogens are the primary female sex hormones and play important roles in both reproductive and non-reproductive systems. Estrogens can be synthesized in non reproductive tissues such as liver, heart, muscle, bone and brain, and tissue specific estrogen synthesis is consistent with a diversity of estrogen actions. In this article we review tissue and cell-specific estrogen synthesis and estrogen receptor signaling in three parts: (i) synthesis and metabolism, (ii) the distribution of estrogen receptors and signaling, and (iii) estrogen functions and related disorders, including cardiovascular diseases, osteoporosis, Alzheimer's disease (AD), and Parkinson disease (PD). This comprehensive review provides new insights into estrogens by giving a better understanding of the tissue-specific estrogen effects and their roles in various diseases. PMID- 23348046 TI - Multi-slice parallel transmission three-dimensional tailored RF (PTX 3DTRF) pulse design for signal recovery in ultra high field functional MRI. AB - T(2)(*) weighted fMRI at high and ultra high field (UHF) is often hampered by susceptibility-induced, through-plane, signal loss. Three-dimensional tailored RF (3DTRF) pulses have been shown to be an effective approach for mitigating through plane signal loss at UHF. However, the required RF pulse lengths are too long for practical applications. Recently, parallel transmission (PTX) has emerged as a very effective means for shortening the RF pulse duration for 3DTRF without sacrificing the excitation performance. In this article, we demonstrate a RF pulse design strategy for 3DTRF based on the use of multi-slice PTX 3DTRF to simultaneously and precisely recover signal with whole-brain coverage. Phantom and human experiments are used to demonstrate the effectiveness and robustness of the proposed method on three subjects using an eight-channel whole body parallel transmission system. PMID- 23348047 TI - Use of molecular biomarkers to quantify the spatial distribution of effects of anticancer drugs in solid tumors. AB - Poor distribution of anticancer drugs within solid tumors may limit their effectiveness. Here, we characterize the distribution within solid tumors of biomarkers of drug effect. gamma-H2AX, cleaved-caspase-3 or -6, and Ki67 were quantified in tumor sections in relation to blood vessels (recognized by CD31) using monoclonal antibodies and immunohistochemistry. To validate their use, we compared their time-dependent distribution with that of (i) fluorescent doxorubicin and (ii) a monoclonal antibody that detects melphalan-induced DNA adducts. The biomarkers were then used to quantify the distribution of docetaxel in relation to tumor blood vessels. Activation of gamma-H2AX was evaluated following in vitro exposure of tumor cells to multiple drugs. Distributions of doxorubicin in MDA-MB-231 and MCF-7 xenografts and of melphalan-induced DNA adducts in MCF-7 and EMT-6 tumors decreased with distance from blood vessels, similar to the distributions of (i) gamma-H2AX at 10 minutes, (ii) cleaved caspase-3 or -6, and (iii) change in Ki67 at 24 hours following treatment. The distribution of these biomarkers following treatment with docetaxel also decreased with increasing distance from tumor blood vessels. Activation of gamma H2AX occurred within 1 hour after exposure to several drugs in culture. Multiple anticancer drugs show a decrease in activity with increasing distance from tumor blood vessels; poor drug distribution is an important cause of drug resistance. The above biomarkers may be used in designing strategies to overcome therapeutic resistance by modifying or complementing the limited spatial distribution of drug activity in solid tumors. PMID- 23348049 TI - Training and competition workloads and fatigue responses of elite junior cricket players. AB - PURPOSE: This study investigated key fatigue and workload variables of cricket fast bowlers and nonfast bowlers during a 7-wk physical-preparation period and 10 d intensified competition period. METHODS: Twenty-six elite junior cricketers (mean +/- SD age 17.7 +/- 1.1 y) were classified as fast bowlers (n = 9) or nonfast bowlers (n = 17). Individual workloads were measured via global positioning system technology, and neuromuscular function (countermovement jump [relative power and flight time]), endocrine (salivary testosterone and cortisol concentrations), and perceptual well-being (soreness, mood, stress, sleep quality, and fatigue) markers were recorded. RESULTS: Fast bowlers performed greater competition total distance (median [interquartile range] 7049 [3962] m vs 5062 [3694] m), including greater distances at low and high speeds, and more accelerations (40 [32] vs 19 [21]) and had a higher player load (912 [481] arbitrary units vs 697 [424] arbitrary units) than nonfast bowlers. Cortisol concentrations were higher in the physical-preparation (mean +/- 90% confidence intervals, % likelihood; d = -0.88 +/- 0.39, 100%) and competition phases (d = 0.39 +/- 0.30, 85%), and testosterone concentrations, lower (d = 0.56 +/- 0.29, 98%), in the competition phase in fast bowlers. Perceptual well-being was poorer in nonfast bowlers during competition only (d = 0.36 +/- 0.22, 88%). Differences in neuromuscular function between groups were unclear during physical preparation and competition. CONCLUSIONS: These findings demonstrate differences in the physical demands of cricket fast bowlers and nonfast bowlers and suggest that these external workloads differentially affect the neuromuscular, endocrine, and perceptual fatigue responses of these players. PMID- 23348048 TI - Targeting IGF-IR with ganitumab inhibits tumorigenesis and increases durability of response to androgen-deprivation therapy in VCaP prostate cancer xenografts. AB - Prostate cancer is the most commonly diagnosed malignancy in men. While tumors initially respond to androgen-deprivation therapy, the standard care for advanced or metastatic disease, tumors eventually recur as castration-resistant prostate cancer (CRPC). Upregulation of the insulin-like growth factor receptor type I (IGF-IR) signaling axis drives growth and progression of prostate cancer by promoting proliferation, survival, and angiogenesis. Ganitumab (formerly AMG 479) is a fully human antibody that inhibits binding of IGF-I and IGF-II to IGF-IR. We evaluated the therapeutic value of ganitumab in several preclinical settings including androgen-dependent prostate cancer, CRPC, and in combination with androgen-deprivation therapy. Ganitumab inhibited IGF-I-induced phosphorylation of the downstream effector AKT and reduced proliferation of multiple androgen dependent and castration-resistant human prostate cancer cell lines in vitro. Ganitumab inhibited androgen-dependent VCaP xenograft growth and increased tumor doubling time from 2.3 +/- 0.4 weeks to 6.4 +/- 0.4 weeks. Ganitumab blocked growth of castration-resistant VCaP xenografts for over 11.5 weeks of treatment. In contrast, ganitumab did not have appreciable effects on the castration resistant CWR-22Rv1 xenograft model. Ganitumab was most potent against VCaP xenografts when combined with complete androgen-deprivation therapy (castration). Tumor volume was reduced by 72% after 4 weeks of treatment and growth suppression was maintained over 16 weeks of treatment. These data suggest that judicious use of ganitumab particularly in conjunction with androgen-deprivation therapy may be beneficial in the treatment of prostate cancer. PMID- 23348050 TI - Late embryos and bony skull development in Bothropoides jararaca (Serpentes, Viperidae). AB - In recent years, developmental anatomy received increasing interest as a potential new source for phylogenetic research. For skeletal development, studies mainly rely on the first appearance of ossification centers. However, informative events occur during the whole course of skeletogenesis; interactions between external and internal development occur and morphometric changes take place - all of which present potential sources for phylogenetic analyses. Therefore, the Standard Event System (SES) was used to traceably describe the external development of the snake species Bothropoides jararaca and external measurements were analyzed. We then applied micro-computed tomography (MUCT), clearing and double-staining, and 2D and 3D morphometric methods to describe, illustrate, and analyze the development of the head in great detail. We found a 3D flattening of the skull during ontogeny, a pattern that is not reflected in external development. This may be explained by a different relationship of skeletogenesis and external characters to the developing jaw musculature or simply by the different type of data. Clearing and double-staining and MUCT-scanning revealed a broadly similar sequence in the onset of ossification. Minute differences may be due to the treatment of embryos. Bones of the dermatocranium are among the first to ossify and the development of the calcified endolymph may reflect its function as a calcium source during development. The value of phylogenetic observations using the sequence of first ossifications is critically discussed. The related heterochronic changes are interpreted to contribute at least to the very first phase of divagating skull formation among taxa. PMID- 23348051 TI - Does the U.S. health care sector suffer from Baumol's cost disease? Evidence from the 50 states. AB - This study examines if health care costs in the United States are affected by Baumol's cost disease. It relies on an empirical test proposed by Hartwig (2008) and extended by Colombier (2010) and uses a panel data set of 50 states over the 1980-2009 period. The results suggest that health care costs grow more rapidly when economy-wide wage increases exceed productivity gains. The findings are fairly robust with respect to time- and state-fixed effects, individual state time trends, and two-stage least square estimation. Consequently, this study suggests that the U.S. health care sector suffers from Baumol's cost disease. PMID- 23348053 TI - Interactions of PLA2-s from Vipera lebetina, Vipera berus berus and Naja naja oxiana venom with platelets, bacterial and cancer cells. AB - Secretory phospholipasesA(2) (sPLA(2)s) form a large family of structurally related enzymes widespread in nature. Herein, we studied the inhibitory effects of sPLA(2)s from Vipera lebetina (VLPLA(2)), Vipera berus berus (VBBPLA(2)), and Naja naja oxiana (NNOPLA(2)) venoms on (i) human platelets, (ii) four different bacterial strains (gram-negative Escherichia coli and Vibrio fischeri; gram positive Staphylococcus aureus and Bacillus subtilis) and (iii) five types of cancer cells (PC-3, LNCaP, MCF-7, K-562 and B16-F10) in vitro. sPLA(2)s inhibited collagen-induced platelet aggregation: VBBPLA(2) IC(50) = 0.054, VLPLA(2) IC(50) = 0.072, NNOPLA(2) IC(50) = 0.814 MUM. p-Bromophenacylbromide inhibited sPLA(2) had no inhibitory action on platelets. 36.17 MUM VBBPLA(2 )completely inhibited the growth of gram-positive Bacillus subtilis whereas no growth inhibition was observed towards gram-negative Escherichia coli. The inhibitory action of sPLA(2)s (~0.7 MUM and ~7 MUM) towards cancer cells depended on both venom and cell type. VBBPLA(2 )(7.2 MUM) inhibited significantly the viability of K-562 cells and the cell death appeared apoptotic. The sPLA(2)s exhibited no inhibitory effect towards LNCaP cells and some effect (8%-20%) towards other cells. Thus, already sub-MUM concentrations of sPLA(2)s inhibited collagen-induced platelet aggregation and from the current suite of studied svPLA(2)s and test cells, VBBPLA(2) was the most growth inhibitory towards Bacillus subtilis and K-562 cells. PMID- 23348054 TI - Ambra1 knockdown in zebrafish leads to incomplete development due to severe defects in organogenesis. AB - AMBRA1 is a positive regulator of the BECN1-dependent program of autophagy recently identified in mouse. In this study, we cloned the full-length cDNAs of ambra1a and ambra1b zebrafish paralogous genes. As in mouse, both Ambra1 proteins contain the characteristic WD40 repeat region. The transcripts of both genes are present as maternal RNAs in the eggs and display a gradual decline until 8 hpf, being replaced by zygotic mRNAs from 12 hpf onwards. After 24 hpf, the transcripts are mainly localized in the head, suggesting a possible role in brain development. To check their developmental roles, we adopted morpholino knockdown to block either translation (ATGMOs) or splicing (SPLICMOs). Treatment with ATGMOs causes severe embryonic malformations, as prelarvae could survive for only 3 and 4 days in ambra1a and b morphants, respectively. Treatment with SPLICMOs led to developmental defects only at a late stage, indicating the importance of maternally supplied ambra1 transcripts. Analysis of the levels of Lc3-II, an autophagosome-specific marker, in the presence of lysosome inhibitors evidenced a reduction in the rate of autophagosome formation in both MOs-injected embryos at 48 hpf, more pronounced in the case of ambra1a gene. Although some defects, such as body growth delay, curved shape and hemorrhagic pericardial cavity were present in both morphants, the occurrence of specific phenotypes, such as major abnormalities of brain development in ambra1a morphants, suggests the possible acquisition of specific functions by the two paralogous genes that are both required during development and do not compensate each other following knockdown. PMID- 23348055 TI - The male mammary gland: a target for the xenoestrogen bisphenol A. AB - Males of some strains of mice retain their mammary epithelium even in the absence of nipples. Here, we have characterized the mammary gland in male CD-1 mice both in whole mounts and histological sections. We also examined the effects of bisphenol A (BPA), an estrogen mimic that alters development of the female mouse mammary gland. BPA was administered at a range of environmentally relevant doses (0.25-250MUg/kg/day) to pregnant and lactating mice and then the mammary glands of male offspring were examined at several periods in adulthood. We observed age- and dose-specific effects on mammary gland morphology, indicating that perinatal BPA exposures alter the male mammary gland in adulthood. These results may provide insight into gynecomastia, the most common male breast disease in humans, where proliferation of the mammary epithelium leads to breast enlargement. PMID- 23348056 TI - Improving the content and face validity of OSCE assessment marking criteria on an undergraduate midwifery programme: a quality initiative. AB - Objective Structured Clinical Examinations (OSCE's) have been adopted as a means of assessing midwifery students' clinical skills. The purpose of the OSCE is to provide a standardised method for the evaluation of clinical skill performance in a simulated environment. This paper describes how a quality improvement initiative using both internal and external expert review was utilised to improve OSCE assessment marking criteria. The purpose of the quality initiative was to review the content and face validity of the marking criteria for assessing performance. The design and choice of tools used to score students' performance is central to reliability and validity. 20 videos of students from year one of a midwifery preregistration programme undertaking an OSCE assessment on abdominal examination and 18 videos of students response to obstetric emergencies e.g. PPH, and shoulder dystocia were available for review. The quality initiative aimed to strengthen the reliability and validity of the OSCE in assessing student performance. CONCLUSION: the use of global rating scales allows for the capturing of elements of professional competency that do not appear on specific criteria for skills performance checklists. PMID- 23348057 TI - Analysis of changing paradigms of management in 179 patients with spinal tuberculosis over a 12-year period and proposal of a new management algorithm. AB - OBJECTIVE: To describe management and outcome in a large cohort of patients with spinal tuberculosis (TB). METHODS: Of 212 patients with spinal TB treated between January 1999 and June 2011, 179 patients were included in the study (>=6 months follow-up; mean age, 34.8 years; age range, 10-75 years). The cohort was divided into two groups (n = 89 and n = 90); group I was treated from 1999-2003, and group II was treated from 2004-2011. RESULTS: The study cohort comprised 93 male patients. Mean age was 34.8 years +/- 7.2 (range, 10-75 years). Mean duration of symptoms was 2.4 months. Sensorimotor deficits were present in 167 patients (93.5%; 74 patients were paraplegic), pain was present in 156 patients (87%), bladder involvement was present in 127 patients (71.7%), and extraspinal TB was present in 36 patients (22.3%). Of patients, 92% were receiving prior chemotherapy; one fifth of these patients were on second-line chemotherapy. Thoracic spine involvement was most common (n = 86; 57%), followed by cervical spine (n = 50; 29%), craniovertebral junction (n = 22; 15%), and lumbosacral spine (n = 20; 10.5%). Surgery was performed in 146 patients (68% instrumented fusions and 16% circumferential fusions). Mean follow-up was 20.2 months (range, 6-60 months). Sensorimotor deficits improved in 89% of patients, pain improved in 71%, bladder symptoms improved in 88%, and paraplegia improved in 77%. Patients in group II had a higher incidence of cord compression (P < 0.01), severe vertebral body collapse (P < 0.001), and paraplegia (P < 0.001). Group II patients underwent more instrumented surgeries (P < 0.01), especially circumferential fusions (P < 0.001). The improvement in paraplegia was better after 2004 (group II). Bladder symptoms correlated with the timing of surgery (P < 0.1). CONCLUSIONS: Medical treatment of spinal TB is the mainstay; however, radical, instrumented surgeries should be offered when indicated. The presence of paraplegia should not preclude surgery. A practical management paradigm is also suggested. PMID- 23348059 TI - Ferromagnetic interactions through double hydrogen bonding bridges in manganese(II) coordination polymers. AB - Three isostructural Mn(II) compounds with a zwitterionic dicarboxylate ligand and different pseudohalides were synthesized, and then structurally and magnetically characterized. They are formulated as [Mn(L)(X)(2)(H(2)O)(2)](n) [X = N(3)(-) (1), NCO(-) (2), NCS(-) (3), L = 1,4-bis(4-carboxylato-1-pyridinium)butane]. In these compounds, adjacent Mn(II) ions are connected into coordination chains by long zwitterionic linkers and into hydrogen-bonded chains by short double O-H...N bridges involving coordinated water and pseudohalide ligands. Magnetic studies revealed for the first time that the double hydrogen bridges induce ferromagnetic coupling between the Mn(II) ions. PMID- 23348058 TI - Quantitation of HIV DNA integration: effects of differential integration site distributions on Alu-PCR assays. AB - In many studies of HIV replication, it is useful to quantify the number of HIV proviruses in cells against a background of unintegrated forms of the HIV DNA. A popular method for doing so involves quantitative PCR using one primer complementary to the HIV long terminal repeat (LTR), and a second primer complementary to a cellular Alu repeat, so that PCR product only forms from templates where a provirus is integrated in the human genome near an Alu repeat. However, several recent studies have identified conditions that alter distributions of HIV integration sites relative to genes. Because Alu repeats are enriched in gene rich regions, this raises the question of whether altered integration site distributions might confound provirus abundance measurements using the Alu-PCR method. Here modified versions of the HIV tethering protein LEDGF/p75 were used to retarget HIV integration outside of transcription units, and show that this has a negligible effect on Alu-PCR quantitation of proviral abundance. Thus altered integration targeting, at least to the degree achieved here, is not a major concern when using the Alu-PCR assay. PMID- 23348061 TI - A 1-year follow-up of effects of exercise programs on well-being in older adults. AB - PURPOSE: The purpose of this study was to investigate the long-term effects of three types of training on wellbeing and frequency of physical activity and to determine whether preintervention motivation moderates the effects. METHODS: Sixty-two older adults (M = 75 years old, SD = 5; 61% women) completed 4-mo programs of endurance, functional or strength training, with reassessment of well being (life satisfaction, positive affect, negative affect, vitality) and physical activity 12 mo later. RESULTS: All groups showed small improvements in most measures of well-being at 4 mo. At follow-up, endurance training still had small beneficial effects, while changes with functional and strength training were generally trivial or harmful. Analysis for moderators indicated that autonomously motivated individuals better maintained gains in well-being and had higher frequencies of physical activity at follow-up compared with controlled individuals. CONCLUSION: Endurance training is recommended for older adults, but the long-term outcomes depend on the individual's motivational regulation at commencement. PMID- 23348062 TI - Comparative study on CdSe QDs synthesized from water and ethanol: Hydrogen bond induced particle agglomeration and enhancement on photoluminescence. AB - In this paper a comparative study is carried out on the CdSe QDs synthesized from water and ethanol. Our purpose is to present an insight understanding on how hydrogen bonds affect particle agglomeration and consequently photoluminescence (PL) behavior of the QDs. In comparison with those from water, the CdSe QDs from ethanol show super PL with high brightness. Detailed characterization gives the only difference of large agglomerates presented in the QDs from ethanol. The TEM and HRTEM observations reveal a tri-level microstructure for the QDs from ethanol while in the case of those from water it is bi-level. With these direct evidences weak hydrogen bond of TGA with ethanol is proposed to be responsible for these large agglomerates and consequently super PL behavior. Additional investigations on some other alcohols of methanol, n-propanol, and i-butanol yield positive results and confirm the truth of our proposal. PMID- 23348060 TI - Is there a role for cyclophilin inhibitors in the management of primary biliary cirrhosis? AB - Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are poorly understood autoimmune liver diseases. Immunosuppression is used to treat AIH and ursodeoxycholic acid is used to slow the progression of PBC. Nevertheless, a proportion of patients with both disorders progress to liver failure. Following liver transplantation, up to a third of patients with PBC experience recurrent disease. Moreover a syndrome referred to as "de novo AIH" occurs in a proportion of patients regardless of maintenance immunosuppression, who have been transplanted for disorders unrelated to AIH. Of note, the use of cyclosporine A appears to protect against the development of recurrent PBC and de novo AIH even though it is a less potent immunosuppressive compared to tacrolimus. The reason why cyclosporine A is protective has not been determined. However, a virus resembling mouse mammary tumor virus (MMTV) has been characterized in patients with PBC and AIH. Accordingly, we hypothesized that the protective effect of cyclosporine A in liver transplant recipients may be mediated by the antiviral activity of this cyclophilin inhibitor. Treatment of the MMTV producing MM5MT cells with different antivirals and immunosuppressive agents showed that both cyclosporine A and the analogue NIM811 inhibited MMTV production from the producer cells. Herein, we discuss the evidence supporting the role of MMTV-like human betaretrovirus in the development of PBC and de novo AIH and speculate on the possibility that the agent may be associated with disease following transplantation. We also review the mechanisms of how both cyclosporine A and NIM811 may inhibit betaretrovirus production in vitro. PMID- 23348063 TI - Hypothalamic kappa-opioid receptor modulates the orexigenic effect of ghrelin. AB - The opioid system is well recognized as an important regulator of appetite and energy balance. We now hypothesized that the hypothalamic opioid system might modulate the orexigenic effect of ghrelin. Using pharmacological and gene silencing approaches, we demonstrate that ghrelin utilizes a hypothalamic kappa opioid receptor (KOR) pathway to increase food intake in rats. Pharmacological blockade of KOR decreases the acute orexigenic effect of ghrelin. Inhibition of KOR expression in the hypothalamic arcuate nucleus is sufficient to blunt ghrelin induced food intake. By contrast, the specific inhibition of KOR expression in the ventral tegmental area does not affect central ghrelin-induced feeding. This new pathway is independent of ghrelin-induced AMP-activated protein kinase activation, but modulates the levels of the transcription factors and orexigenic neuropeptides triggered by ghrelin to finally stimulate feeding. Our novel data implicate hypothalamic KOR signaling in the orexigenic action of ghrelin. PMID- 23348065 TI - Sensitivity analysis for nonignorable missingness and outcome misclassification from proxy reports. AB - Researchers often recruit proxy respondents, such as relatives or caregivers, for epidemiologic studies of older adults when study participants are unable to provide self-reports (eg, because of illness or cognitive impairment). In most studies involving proxy-reported outcomes, proxies are recruited only to report on behalf of participants who have missing self-reported outcomes; thus, either a proxy report or participant self-report, but not both, is available for each participant. When outcomes are binary and investigators conceptualize participant self-reports as gold standard measures, substituting proxy reports in place of missing participant self-reports in statistical analysis can introduce misclassification error and lead to biased parameter estimates. However, excluding observations from participants with missing self-reported outcomes may also lead to bias. We propose a pattern-mixture model that uses error-prone proxy reports to reduce selection bias from missing outcomes, and we describe a sensitivity analysis to address bias from differential outcome misclassification. We perform model estimation with high-dimensional (eg, continuous) covariates using propensity-score stratification and multiple imputation. We apply the methods to the Second Cohort of the Baltimore Hip Studies, a study of elderly hip fracture patients, to assess the relation between type of surgical treatment and perceived physical recovery. Simulation studies show that the proposed methods perform well. We provide SAS programs in the eAppendix (http://links.lww.com/EDE/A646) to enhance the methods' accessibility. PMID- 23348064 TI - Metabotropic glutamate receptor I (mGluR1) antagonism impairs cocaine-induced conditioned place preference via inhibition of protein synthesis. AB - Antagonism of group I metabotropic glutamate receptors (mGluR1 and mGluR5) reduces behavioral effects of drugs of abuse, including cocaine. However, the underlying mechanisms remain poorly understood. Activation of mGluR5 increases protein synthesis at synapses. Although mGluR5-induced excessive protein synthesis has been implicated in the pathology of fragile X syndrome, it remains unknown whether group I mGluR-mediated protein synthesis is involved in any behavioral effects of drugs of abuse. We report that group I mGluR agonist DHPG induced more pronounced initial depression of inhibitory postsynaptic currents (IPSCs) followed by modest long-term depression (I-LTD) in dopamine neurons of rat ventral tegmental area (VTA) through the activation of mGluR1. The early component of DHPG-induced depression of IPSCs was mediated by the cannabinoid CB1 receptors, while DHPG-induced I-LTD was dependent on protein synthesis. Western blotting analysis indicates that mGluR1 was coupled to extracellular signal regulated kinase (ERK) and mammalian target of rapamycin (mTOR) signaling pathways to increase translation. We also show that cocaine conditioning activated translation machinery in the VTA via an mGluR1-dependent mechanism. Furthermore, intra-VTA microinjections of mGluR1 antagonist JNJ16259685 and protein synthesis inhibitor cycloheximide significantly attenuated or blocked the acquisition of cocaine-induced conditioned place preference (CPP) and activation of translation elongation factors. Taken together, these results suggest that mGluR1 antagonism inhibits de novo protein synthesis; this effect may block the formation of cocaine-cue associations and thus provide a mechanism for the reduction in CPP to cocaine. PMID- 23348066 TI - Mother's and offspring's use of antibiotics and infant allergy to cow's milk. AB - BACKGROUND: Evidence on the association between antibiotics and the risk of food allergies is limited. We explored the associations between mother's and offspring's use of antibiotics and the risk of cow's milk allergy in infancy. METHODS: We used a national registry to identify all children who were born in 1996-2004 in Finland and diagnosed with cow's milk allergy after 1 month of age by November 2005 (n = 15,672). For each case, we selected one control matched for birth date, sex, and hospital district. Information on antibiotic purchases and putative confounders was obtained from registries. The associations were analyzed using conditional logistic regression. RESULTS: Maternal use of antibiotics before and during pregnancy was associated with an increased risk of cow's milk allergy in the offspring (odds ratio = 1.26 [95% confidence interval = 1.20-1.33] and 1.21 [1.14-1.28], respectively, adjusting for putative confounders). The risk of cow's milk allergy increased with increasing number of child's antibiotics used from birth to diagnosis (test for trend P < 0.001). CONCLUSIONS: Both maternal and child's use of antibiotics were associated with an increased risk of cow's milk allergy. Future studies are needed to confirm these novel findings and to explore the potential biologic mechanisms behind the association. PMID- 23348067 TI - Organochlorine pesticides, polychlorinated biphenyls, seafood consumption, and time-to-pregnancy. AB - BACKGROUND: People in developed countries are widely exposed to low levels of organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). Seafood is a major contributor to PCB exposure. Toxicity of those various pollutants to reproductive and endocrine functions raises questions about possible effects on fertility. We explored whether serum levels of these pollutants and seafood consumption were associated with the fertility of couples enrolled in a French birth cohort (PELAGIE). METHODS: Time-to-pregnancy was investigated in 3,421 pregnant women by asking how many months they had taken to conceive. Levels of 14 organochlorine pesticides, 12 PCBs, and 10 PBDE compounds were measured in cord blood serum from a random subcohort (n = 394). Mercury concentrations measured in maternal hair were considered as a potential coexposure. Fecundability odds ratios (ORs) were estimated from multivariate discrete-time Cox proportional hazard models. RESULTS: Shellfish consumption was associated with longer time-to-pregnancy (fecundability OR >=twice/week vs. 0.410 ug/L vs. <0.266 ug/L, fecundability OR = 0.46 [0.32-0.66]). In multiple sensitivity analyses, reduced fecundability was most consistently associated with shellfish consumption, p,p'-DDE, total PCBs, PCB153, and PCB187. Models that simultaneously included multiple coexposure factors led to similar conclusions. CONCLUSIONS: Our findings were robust in sensitivity analyses, including analysis restricted to primiparous women. These results suggest that PCBs, p,p'-DDE, and other shellfish contaminants may impair human fertility. PMID- 23348068 TI - Risk of injury due to alcohol: evaluating potential bias using the case-crossover usual-frequency method. AB - BACKGROUND: The usual-frequency case-crossover method, comparing exposure before an event with typical exposure of the same person, is widely used to estimate the risk of injury related to acute alcohol use. Prior results suggest that risk estimates might be biased upward compared with other methods. METHODS: Using data from 15 emergency room studies in seven countries, we compared the usual frequency case-crossover method with case-control analysis, using noninjury patients as controls. Control-crossover analysis was performed to examine potential bias and to adjust risk estimates. RESULTS: The cross-study pooled odds ratio (OR) of injury related to drinking was 4.7 (95% confidence interval = 2.6 8.5) in case-crossover analysis and 2.1 (1.6-2.7) in case-control analysis. A control-crossover analysis found an indication of bias (OR = 2.2 [1.8-2.8]), which was larger among less-frequent drinkers. CONCLUSION: Findings suggest that the potential overestimation of injury risk based on the usual-frequency case crossover method might be best explained by recall bias in usual-frequency estimates. PMID- 23348071 TI - Fruit intake and incident diabetic retinopathy with type 2 diabetes. AB - BACKGROUND: Antioxidants and dietary fiber are postulated to have preventive effects on diabetic retinopathy, but evidence is lacking. We investigated this association in a cohort with type 2 diabetes 40-70 years of age with hemoglobin (Hb)A1C >=6.5%, originally part of the Japan Diabetes Complications Study. METHODS: After excluding people who did not respond to a dietary survey and patients with diabetic retinopathy or a major ocular disease at baseline, we analyzed 978 patients. Baseline dietary intake was assessed by a food frequency questionnaire based on food groups and 24-hour dietary records. Primary outcome was incident diabetic retinopathy determined using international severity scales. RESULTS: Mean fruit intake in quartiles ranged from 23 to 253 g/day, with increasing trends across quartiles of fruit intake for vitamin C, vitamin E, carotene, retinol equivalent, dietary fiber, potassium, and sodium. Mean energy intake ranged from 1644 to 1863 kcal/day, and fat intake was approximately 25%. HbA1C, body mass index, triglycerides, and systolic blood pressure were well controlled. During the 8-year follow-up, the numbers of incident cases of diabetic retinopathy from the first through the fourth quartiles of fruit intake were 83, 74, 69, and 59. Multivariate-adjusted hazard ratios for the second, third, and fourth quartiles of fruit intake compared with the first quartile were 0.66 (95% confidence interval = 0.46-0.92), 0.59 (0.41-0.85), and 0.48 (0.32 0.71) (test for trend, P < 0.01). There was no substantial effect modification by age, sex, HbA1C, diabetes duration, overweight, smoking, and hypertension. Risk for diabetic retinopathy declined with increased intake of fruits and vegetables, vitamin C, and carotene. CONCLUSION: Increased fruit intake in ranges commonly consumed was associated with reduced incident diabetic retinopathy among patients adhering to a low-fat energy-restricted diet. PMID- 23348072 TI - Preoperative administration of erythropoietin stimulates tumor recurrence after surgical excision of colon cancer in mice by a vascular endothelial growth factor independent mechanism. AB - BACKGROUND: It has been suggested that preoperative administration of erythropoietin (Epo) in patients with gastrointestinal cancer reduces transfusional needs and is also associated with lower morbidity. On the other hand, experimental and clinical studies show that Epo might enhance tumor growth and angiogenesis. Our aim was to ascertain whether preoperative administration of Epo has any effect on tumor recurrence after curative surgery using an experimental model of colon cancer. MATERIALS AND METHODS: We induced tumors by injecting B51LiM colon cancer cells into the cecal wall of Balb/c mice. We randomized the animals into three groups of treatment with (1) recombinant human Epo, (2) recombinant mouse Epo, or (3) vehicle alone, for 12 d until cecectomy. On postoperative day 12, we killed mice and analyzed tumor recurrence. We measured serum levels of vascular endothelial growth factor and determined vascular endothelial growth factor expression and tumor microvessel density by immunohistochemistry. We also investigated the in vitro effect of Epo on B51LiM cell line proliferation. RESULTS: All three groups displayed tumor recurrence, but the final tumor load score and total tumoral weight were higher in the two groups that included Epo. The differences were statistically significant when we compared the recombinant mouse Epo group with the control group. We found no evidence of increased angiogenesis or enhanced cell proliferation as possible mechanisms of Epo-induced recurrence. CONCLUSIONS: Preoperative administration of Epo stimulates tumor recurrence in an animal model of colon cancer. Our results point to the need for further research on the mechanisms of tumor growth enhancement by Epo, to better understand the benefits or disadvantages of Epo treatment. PMID- 23348073 TI - Cell-mediated killing of Listeria monocytogenes by leucocin C producing Escherichia coli. AB - Listeria monocytogenes is a foodborne pathogen causing listeriosis. Listeria in foods can be inhibited with bacteriocins or bacteriocin producing cultures. The aim of this study was to enhance the killing of L. monocytogenes by binding bacteriocin producing Escherichia coli cells to Listeria cells. Antilisterial E. coli was obtained by transferring leucocin C production from Leuconostoc carnosum 4010. For binding of E. coli cells to Listeria cells, the Listeria phage endolysin PlyP35 cell wall binding domain (CBD) was displayed on E. coli cell surface as FliC::CBD chimeric protein in flagella. CBD insertion in flagella was confirmed by Western analysis and enterokinase cleavage. By mixing isolated flagella with L. monocytogenes WSLC 1019 cells, the FliC::CBD flagella was shown to bind to Listeria cells. However, the wild type flagella also attached to Listeria cells masking putative additional binding mediated by the CBD. Yet, the cell-mediated leucocin C killing resulted in two-log reduction of Listeria, whereas the corresponding amount of leucocin C in spent culture medium could only inhibit growth without bacteriocidal effect. Cells binding Listeria and secreting antilisterial peptides may have applications in protection against listeriosis as they kill Listeria better than free antilisterial peptides. PMID- 23348069 TI - Prenatal and infant exposures and age at menarche. AB - BACKGROUND: Early menarche is related to increased risk of breast cancer. The number of established factors that contribute to early menarche is limited. We studied prenatal and infant exposures in relation to age at menarche in a nationwide cohort of women who have a family history of breast cancer. METHODS: The study comprised 33,501 women in the Sister Study who were 35-59 years of age at baseline (2003-2009). We used polytomous logistic regression to estimate separate relative risk ratios (rRRs) and 95% confidence intervals (CIs) for associations of self-reported exposures with menarche at <=10, 11, 14, and >=15 years relative to menarche at 12-13 years. RESULTS: Early menarche (<=10 or 11 years) was associated with having low birth weight, having had a teenage mother, being firstborn, and specific prenatal exposures: mother's smoking, diethylstilbestrol (DES), prepregnancy diabetes, and pregnancy-related hypertensive disorder. Prenatal exposures most strongly associated with very early menarche (<=10 years) were DES (rRR = 1.56 [95% CI = 1.24-1.96]), maternal prepregnancy diabetes (2.24 [1.37-3.68]), and pregnancy-related hypertensive disorder (1.45 [1.18-1.79]). Soy formula was associated with both very early menarche (1.21 [0.94-1.54]) and late menarche (14 years: 1.17 [0.98-1.40] or >=15 years: 1.28 [1.06-1.56]). CONCLUSIONS: Although menarche is only one marker of pubertal development, it is a commonly used surrogate. The observed associations of prenatal DES and soy formula exposure with age at menarche are consistent with animal data on exogenous estrogens and pubertal timing. Early-life exposures may confound associations between age at menarche and hormonally dependent outcomes in adults. PMID- 23348074 TI - No association between ACTN3 R577X polymorphism and elite judo athletic status. AB - The authors compared ACTN3 R577X genotype and allele frequencies in the majority of all-time-best Spanish judo male athletes (n = 108) and 343 ethnically matched nonathletic men. No between-groups differences were found in allele (P = .077) or genotype distributions (P = .178). Thus, the R577X polymorphism was not significantly associated with the status of being an elite judo athlete, at least in the Spanish population. The contribution of genetics to sports-related phenotype traits is undeniable with some genotypes, of which ACTN3 R577X is currently the leading candidate, partly distinguishing individuals predisposed to either endurance or power sports. However, few athletic events can be categorized as purely power or endurance based. Although genetic testing (ie, for ACTN3 R577X) is already being marketed to predict sports talent and potential of young children, its usefulness is still questionable, at least in competitive judo. PMID- 23348075 TI - Arthroscopic bone marrow stimulation techniques for osteochondral lesions of the talus: prognostic factors for small lesions. AB - BACKGROUND: The defect size of an osteochondral lesion of the talus is one of the most important prognostic factors for deciding clinical outcomes. However, the prognostic factors for small osteochondral lesions of the talus are unknown. PURPOSE: To investigate the significant prognostic factors for small osteochondral lesions of the talus using arthroscopic bone marrow stimulation techniques. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Fifty ankles in 50 patients treated with arthroscopic bone marrow stimulation techniques for an osteochondral lesion of the talus (<150 mm(2)) were evaluated for prognostic factors. The patients were 22 men and 28 women (mean age, 35.0 years). Outcomes were measured using the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale, Berndt and Harty scale, and Saxena criteria. RESULTS: The mean lesion size was 62 mm(2) (range, 7-119 mm(2)). The mean AOFAS score improved from 74 (range, 18-90) preoperatively to 90 (range, 67 100) postoperatively. The Saxena criteria results were excellent, good, fair, and poor in 36 (72%), 8 (16%), 5 (10%), and 1 (2%) patients, respectively. The Berndt and Harty scale results were good in 34 (68%), fair in 6 (12%), and poor in 10 (20%) patients. Linear regression analyses showed prognostic significance for lesion depth and outcome. Medial lesions had a significantly higher incidence of poor outcomes than lateral lesions (P < .05). Among the medial lesions, lesions uncovered with the medial malleolus had inferior outcomes compared with covered lesions (P < .0001). There was no association between clinical outcome and lesion size or body mass index. In older patients (>=40 years), there was a significant trend toward inferior clinical outcomes (P < .05). CONCLUSION: Arthroscopic bone marrow stimulation techniques provided satisfactory clinical outcomes. However, older patients, deep lesions, and medial lesions uncovered with the medial malleolus were associated with inferior clinical outcomes. PMID- 23348076 TI - In Situ, noninvasive, T2*-weighted MRI-derived parameters predict ex vivo structural properties of an anterior cruciate ligament reconstruction or bioenhanced primary repair in a porcine model. AB - BACKGROUND: Magnetic resonance imaging (MRI) is a noninvasive technology that can quantitatively assess anterior cruciate ligament (ACL) graft size and signal intensity. However, how those properties relate to reconstructed or repaired ligament strength during the healing process is yet unknown. HYPOTHESIS: Magnetic resonance imaging-derived measures of graft volume and signal intensity are significant predictors of the structural properties of an ACL or ACL graft after 15 weeks and 52 weeks of healing. STUDY DESIGN: Controlled laboratory study. METHODS: The current data were gathered from 2 experiments evaluating ACL reconstruction and repair techniques. In the first experiment, pigs underwent unilateral ACL transection and received (1) ACL reconstruction, (2) ACL reconstruction with collagen-platelet composite (CPC), or (3) no treatment. The surgical legs were harvested after 15 weeks of healing. In the second experiment, pigs underwent ACL transection and received (1) ACL reconstruction, (2) ACL reconstruction with CPC, (3) bioenhanced ACL primary repair with CPC, or (4) no treatment. The surgical legs were harvested after 52 weeks. The harvested knees were imaged using a T2*-weighted 3-dimensional constructive interference in steady state (CISS) sequence. Each ligament was segmented from the scans, and the intra-articular volume and the median grayscale values were determined. Mechanical testing was performed to establish the ligament structural properties. RESULTS: Volume significantly predicted the structural properties (maximum load, yield load, and linear stiffness) of the ligaments and grafts (R (2) = 0.56, 0.56, and 0.49, respectively; P <= .001). Likewise, the median grayscale values (ie, signal intensity) significantly predicted the structural properties of the ligaments and grafts (R (2) = 0.42, 0.37, and 0.40, respectively; P < .001). The combination of these 2 parameters in a multiple regression model improved the predictions (R (2) = 0.73, 0.72, and 0.68, respectively; P <= .001). CONCLUSION: Volume and grayscale values from high-resolution T2*-weighted MRI scans are predictive of structural properties of the healing ligament or graft in a porcine model. CLINICAL RELEVANCE: This study provides a critical step in the development of a noninvasive method to predict the structural properties of the healing ACL graft or repair. This technique may prove beneficial as a surrogate outcome measure in preclinical animal and clinical studies. PMID- 23348077 TI - The "bony Bankart bridge" technique for restoration of anterior shoulder stability. AB - BACKGROUND: Bony deficiency of the anteroinferior glenoid rim can cause recurrent glenohumeral instability. To address this problem, bony reconstruction is recommended in patients with glenoid bone loss more than 20% to 25%. Recent advances in shoulder surgery techniques allow for the arthroscopic reconstruction of glenoid bone defects to restore stability. HYPOTHESIS: The all-arthroscopic "bony Bankart bridge" (BBB) technique for bony anterior glenohumeral instability can restore shoulder stability and provide good shoulder function as well as improve patient satisfaction for these difficult-to-treat cases. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A consecutive series of 15 patients with bony anterior shoulder instability were treated using the arthroscopic BBB technique. All patients were assessed with the Disabilities of the Arm, Shoulder and Hand-short version (QuickDASH), American Shoulder and Elbow Surgeons (ASES) score, and Short Form-12 (SF-12) preoperatively and at final evaluation. In addition, a specific questionnaire evaluated patient satisfaction and possible complications. RESULTS: Two women and 13 men were included in the study, with an average age of 44 years (range, 24-70 years). The average glenoid bone loss was 29% (range, 17%-49%). The mean duration of follow-up was 2.7 years (range, 2.0 4.4 years). At that time, the mean ASES score had improved from 81 (range, 50-98) to 98 (range, 88-100) (P = .133). Although this change was not statistically significant because of low patient numbers, the amount of improvement was almost 3 times the minimal clinically important difference of 6.4 points as reported in previous studies. The mean SF-12 (physical component) improved from 46.8 to 56.2 at final follow-up (P = .015). The mean QuickDASH score at final follow-up was 2.8 (range, 0-15.9), and the mean Single Assessment Numeric Evaluation score was 99 (range, 95-100). There were 14 (93%) stable shoulders and 1 (7%) failure with redislocation from a fall. Median patient satisfaction at final follow-up was 10 (range, 7-10) out of 10. CONCLUSION: The arthroscopic BBB technique for anterior instability with glenoid rim fracture successfully restores shoulder stability with a high median patient satisfaction (10/10) and a very low complication rate. PMID- 23348079 TI - Developing a unified list of physicians' reasoning tasks during clinical encounters. AB - PURPOSE: The clinical reasoning literature focuses on how physicians reason while making decisions, rather than on what they reason about while performing their clinical tasks. In an attempt to provide a common language for discussing, teaching, and researching clinical reasoning, the authors undertook the task of developing a unified list of physicians' reasoning tasks, or what they reason about, during clinical encounters. METHOD: The authors compiled an initial list of 20 reasoning tasks based on the literature from four content areas--clinical reasoning, communications, medical errors, and clinical guidelines. In the summer and fall of 2010, they surveyed a purposive sample of 46 international experts in clinical reasoning and communications. From the results of the first survey, the authors refined their list of reasoning tasks, then resurveyed 22 of the original participants. From the results of the second survey, they further refined their list and validated the inclusion of the reasoning tasks. RESULTS: Twenty-four of 46 (52%) and 15 of 22 (65%) participants completed the first- and second-round surveys, respectively. Following the second-round survey, the authors' list included 24 reasoning tasks, and a clinical example corresponding to each, that fell into four broad categories: framing the encounter (3), diagnosis (8), management (11), and self-reflection (2). CONCLUSIONS: The development of this unified list represents a first step in offering a vocabulary for discussing, reflecting on, teaching, and studying physicians' reasoning tasks during clinical encounters. PMID- 23348078 TI - New strategy for selective and sensitive assay of cathepsin B using a dityrosine based material. AB - The increasing number of reports for disease-related proteases has necessitated materials for the fast, sensitive, and specific assessment of protease activities. The purpose of this study was to synthesize and test a dityrosine based substrate for the selective assay of a specific cysteine cathepsin. DBDY Gly-INH)2 was synthesized from the conjugation of N,N'-diBoc-dityrosine (DBDY) with two molecules of glycine and isoniazid (INH) for this purpose. The fluorescence of DBDY (lambdaex=284-320nm, lambdaem=400-420nm) disappeared due to the quenching effect of INH. However, the protease-catalyzed hydrolysis resulted in the release of INH and recovered the fluorescence of DBDY. When reacted with 13 proteases, DBDY-Gly-INH)2 was hydrolyzed by the cysteine proteases only. Meeting the growing need to discriminate cysteine cathepsins (e.g., cathepsins B, L, and S found at high levels in various cancers), DBDY-Gly-INH)2 was tested as a substrate for cathepsins B, L, and S. Only cathepsin B catalyzed the hydrolysis reaction among the three cathepsins. The reaction rate followed the Michaelis Menten kinetics, and the KM and kcat/KM values were 2.88MUM and 3.87*10(3)M(-1)s( 1), respectively, which were comparable to those for the materials reported for the selective assay of cathepsin B. Considering the simple preparation of DBDY (Gly-INH)2, DBDY-(Gly-INH)2 is believed to be valuable for the sensitive and selective assay of cathepsin B activity. PMID- 23348080 TI - Medical students' experiences with authorship in biomedical research: a national survey. AB - PURPOSE: To explore authorship issues related to medical students' primary research projects, assess medical students' knowledge about authorship issues in biomedical research, and determine their interest in learning about authorship guidelines. METHOD: In 2011, the authors developed and conducted an electronic survey of 243 U.S. medical students who attended an educational event at the National Institutes of Health as part of their funded, yearlong research fellowship programs. The authors then analyzed the results using descriptive statistics. RESULTS: Of 243 students, 152 (63%) responded. Most (120/151; 79%) had completed or were in the process of writing a manuscript based on their projects. Of these, most (95/119; 80%) wrote the entire manuscript independently or with guidance. Whereas almost two-thirds (99/152; 65%) indicated that expectations and criteria for authorship were clarified for them, 26% (40/152) indicated that they were not. Most students (108/118; 92%) were in the authorship position they expected and had no concerns about who the other authors were (91/119; 77%). Of those with concerns, 52% (11/21) did not raise the issue for fear of challenging their mentor. Two-thirds (95/145; 66%) never received formal training in authorship guidelines, and 41% (42/103) believed such training would be valuable. CONCLUSIONS: Although a majority of students had conversations about authorship and were clear about the guidelines for ethical authorship, additional work is needed. The authors recommend that academic institutions develop a menu of options for teaching students about this important area in research ethics. PMID- 23348081 TI - A multi-institutional medical educational collaborative: advocacy training in California pediatric residency programs. AB - Educational collaboratives offer a promising approach to disseminate educational resources and provide faculty development to advance residents' training, especially in areas of novel curricular content; however, their impact has not been clearly described. Advocacy training is a recently mandated requirement of the Accreditation Council for Graduate Medical Education that many programs struggle to meet.The authors describe the formation (in 2007) and impact (from 2008 to 2010) of 13 California pediatric residency programs working in an educational collaboration ("the Collaborative") to improve advocacy training. The Collaborative defined an overarching mission, assessed the needs of the programs, and mapped their strengths. The infrastructure required to build the collaboration among programs included a social networking site, frequent conference calls, and face-to-face semiannual meetings. An evaluation of the Collaborative's activities showed that programs demonstrated increased uptake of curricular components and an increase in advocacy activities. The themes extracted from semistructured interviews of lead faculty at each program revealed that the Collaborative (1) reduced faculty isolation, increased motivation, and strengthened faculty academic development, (2) enhanced identification of curricular areas of weakness and provided curricular development from new resources, (3) helped to address barriers of limited resident time and program resources, and (4) sustained the Collaborative's impact even after formal funding of the program had ceased through curricular enhancement, the need for further resources, and a shared desire to expand the collaborative network. PMID- 23348082 TI - Balancing personalized medicine and personalized care. AB - The current description of personalized medicine by the National Institutes of Health is "the science of individualized prevention and therapy." Although physicians are beginning to see the promise of genetic medicine coming to fruition, the rapid pace of sequencing technology, informatics, and computer science predict a revolution in the ability to care for patients in the near future. The enthusiasm expressed by researchers is well founded, but the expectations voiced by the public do not center on advancing technology. Rather, patients are asking for personalized care: a holistic approach that considers physical, mental, and spiritual well-being. This perspective considers psychological, religious, and ethical challenges that may arise as the precision of preventive medicine improves. Psychological studies already highlight the barriers to single gene testing and suggest significant barriers to the predictive testing envisioned by personalized medicine. Certain religious groups will likely mount opposition if they believe personalized medicine encourages embryo selection. If the technology prompts cost-containment discussions, those concerned about the sanctity of life may raise ethical objections. Consequently, the availability of new scientific developments does not guarantee advances in treatment because patients may prove unwilling to receive and act on personalized genetic information. This perspective highlights current efforts to incorporate personalized medicine and personalized care into the medical curriculum, genetic counseling, and other aspects of clinical practice. Because these efforts are generally independent, the authors offer recommendations for physicians and educators so that personalized medicine can be implemented in a manner that meets patient expectations for personalized care. PMID- 23348083 TI - Estimating learning outcomes from pre- and posttest student self-assessments: a longitudinal study. AB - PURPOSE: Learning outcome is an important measure for overall teaching quality and should be addressed by comprehensive evaluation tools. The authors evaluated the validity of a novel evaluation tool based on student self-assessments, which may help identify specific strengths and weaknesses of a particular course. METHOD: In 2011, the authors asked 145 fourth-year students at Gottingen Medical School to self-assess their knowledge on 33 specific learning objectives in a pretest and posttest as part of a cardiorespiratory module. The authors compared performance gain calculated from self-assessments with performance gain derived from formative examinations that were closely matched to these 33 learning objectives. RESULTS: Eighty-three students (57.2%) completed the assessment. There was good agreement between performance gain derived from subjective data and performance gain derived from objective examinations (Pearson r=0.78; P<.0001) on the group level. The association between the two measures was much weaker when data were analyzed on the individual level. Further analysis determined a quality cutoff for performance gain derived from aggregated student self-assessments. When using this cutoff, the evaluation tool was highly sensitive in identifying specific learning objectives with favorable or suboptimal objective performance gains. CONCLUSIONS: The tool is easy to implement, takes initial performance levels into account, and does not require extensive pre-post testing. By providing valid estimates of actual performance gain obtained during a teaching module, it may assist medical teachers in identifying strengths and weaknesses of a particular course on the level of specific learning objectives. PMID- 23348084 TI - The construct and criterion validity of the mini-CEX: a meta-analysis of the published research. AB - PURPOSE: To conduct a meta-analysis of published studies to determine the construct and criterion validity of the mini-clinical evaluation exercise (mini CEX) to measure clinical performance. METHOD: The authors included all peer reviewed studies published from 1995 to 2012 that reported the relationship between participants' performance on the mini-CEX and on other standardized academic and clinical performance measures. Moderator variables and performance and standardized exam measures were extracted and reviewed independently using a standardized coding protocol. RESULTS: Performance measures from 11 studies were identified. A random-effects model of weighted mean effect size differences (d) resulted in: (1) construct validity coefficients for the mini-CEX on the trainees' performance across different residency year levels ranging from d=0.25 (95% confidence intervals [CI]: 0.04-0.46) to d=0.50 (95% CI: 0.31-0.70), and (2) concurrent validity coefficients for the mini-CEX based on personnel ratings ranging from d=0.23 (95% CI: 0.04-0.50) to d=0.50 (95% CI: 0.34-0.65). Also, a random-effects model of weighted correlation effect size differences (r) resulted in predictive validity coefficients for the mini-CEX on trainees' performance across different standardized measures ranging from r=0.26 (95% CI: 0.16-0.35) to r=0.85 (95% CI: 0.47-0.96). CONCLUSIONS: The construct and criterion validity of the mini-CEX was supported by small to large effect size differences based on measures between trainees' achievement and clinical skills performance, indicating that it is an important instrument for the direct observation of trainees' clinical performance. PMID- 23348085 TI - Creating "innovator's DNA" in health care education. AB - Serious deficits in health care education have been identified recently, yet proposed solutions call for faculty skill sets not typically developed in health professional schools or in continuing professional development (CPD) programs. The authors propose that addressing the oft-cited problems in health care education (e.g., it is not learner-centered and does not take advantage of insights gained from the learning sciences) requires faculty to develop "innovator's skills" including the ability to facilitate organizational change. Given increased social responsibilities and decreased financial resources, it is imperative that more health care educators and health care delivery system leaders not only become innovators themselves but also develop systems that support the next generation of innovators. Dyer et al conducted a comprehensive study of successful innovators and found five behavioral and cognitive "discovery" skill sets that constitute the "innovator's DNA": associating, questioning, observing, networking, and experimenting. This article uses the prism of innovator's DNA to examine a CPD program for health care educators, the Harvard Macy Institute (HMI), whose overarching purpose is to develop innovation skills in participants so that they can build their own educational models customized for implementing changes in their home institutions. A retrospective review of HMI alumni from 1995 to 2010 suggests that innovator skills can be taught and applied. The conceptual framework of the innovator's DNA provides a useful model for other CPD program leaders seeking to enable health care educators to develop the capacity for successfully examining problems and then customizing and implementing organizational change to solve them. PMID- 23348086 TI - Can incorporating inpatient overnight work hours into a pediatric clerkship improve the clerkship experience for students? AB - PURPOSE: After incorporating medical students into pediatric resident night-float teams, the authors studied the effects of the new schedule on (1) cognitive performance, (2) number of new admissions, (3) clerkship satisfaction, and (4) amount and quality of resident teaching. METHOD: Part 1 was a retrospective historical controls study. The intervention was a schedule change that eliminated inpatient call. The historical control group had a four-week inpatient schedule of daytime hours plus five calls (DT+C). The comparison group had a schedule of three weeks of daytime hours plus five consecutive overnight shifts (DT+OS). National Board of Medical Examiners (NBME) Pediatrics Subject Exam scores, number of admission history and physicals (HPEs), and clerkship satisfaction data from both groups were compared. Part 2 was a two-item survey with open-ended comments that measured perceptions of resident teaching time and quality of resident teaching (QRT) from students on the DT+OS schedule. RESULTS: DT+OS students had a significantly increased number of HPEs (t=2.17; P=.03) compared with the DT+C group (mean=7.49, standard deviation [SD]=3.34 in DT+OS versus mean=6.11, SD=2.95 in DT+C). The paired samples t test showed that students rated QRT significantly higher when on overnights than when they were on daytime hours (t=2.47; P=.02). There were no differences in satisfaction or NBME scores. CONCLUSION: Overnight work hours for medical students increased clerkship capacity while maintaining student satisfaction and cognitive performance. Added benefits included increased clinical experience and improved QRT. PMID- 23348087 TI - The community leaders institute: an innovative program to train community leaders in health research. AB - An emerging best practice of addressing health and improving health disparities in communities is ensuring that academic health centers (AHCs) are engaged with area schools, primary care practices, and community advocates as equal partners in research, services, and programs. The literature documents the importance of ensuring that academic-community collaboration is based on equity, trust, and respect and that there is capacity (time and resources) and a shared culture (language, skills, and applied knowledge) for accomplishing mutual goals in academic-community research partnerships. It is also essential that an academic community collaboration result in tangible and measurable goals and outcomes for both the target community and the AHC. Currently, the models for implementing best practices in community health partnerships, especially training programs, are limited.This article summarizes the goals and outcomes for the Community Leaders Institute (CLI), a six-week innovative leadership development training program designed to enhance academic-community research, integrate the interests of community leaders and AHC researchers, and build research capacity and competencies within the community. On the basis of two years of outcome data, the CLI is achieving its intended goals of engaging faculty as trainer-scholars while promoting academic-community partnerships that align with community and AHC priorities. The training and collaborative research paradigm used by the CLI has served to accelerate AHC-community engagement and integration efforts, as CLI graduates are now serving on AHC steering, bioethics, and other committees. PMID- 23348088 TI - MiPLAN: a learner-centered model for bedside teaching in today's academic medical centers. AB - Clinician educators and medical trainees face intense pressure to complete numerous patient care and teaching activities in a limited amount of time. To address the need for effective and efficient teaching methods for use in the inpatient setting, the authors used constructivist learning theory, the principles of adult learning, and their expertise as clinician educators to develop the MiPLAN model for bedside teaching. This three-part model is designed to enable clinical teachers to simultaneously provide care to patients while assessing learners, determining high-yield teaching topics, and providing feedback to learners.The "M" refers to a preparatory meeting between teacher and learners before engaging in patient care or educational activities. During this meeting, team members should become acquainted and the teacher should set goals and clarify expectations. The "i" refers to five behaviors for the teacher to adopt during learners' bedside presentations: introduction, in the moment, inspection, interruptions, and independent thought. "PLAN" is an algorithm to establish priorities for teaching subsequent to a learner's presentation: patient care, learners' questions, attending's agenda, and next steps.The authors suggest that the MiPLAN model can help clinical teachers gain more confidence in their ability to teach at the bedside and increase the frequency and quality of bedside teaching. They propose further research to assess the generalizability of this model to other institutions, settings, and specialties and to evaluate educational and patient outcomes. PMID- 23348089 TI - How do social networks and faculty development courses affect clinical supervisors' adoption of a medical education innovation? An exploratory study. AB - PURPOSE: To examine the impact of social networks and a two-day faculty development course on clinical supervisors' adoption of an educational innovation. METHOD: During 2007-2010, 571 residents and 613 clinical supervisors in four specialties in the Netherlands were invited to complete a Web-based questionnaire. Residents rated their clinical supervisors' adoption of an educational innovation, the use of structured and constructive (S&C) feedback. Clinical supervisors self-assessed their adoption of this innovation and rated their communication intensity with other clinical supervisors in their department. For each supervisor, a centrality score was calculated, representing the extent to which the supervisor was connected to departmental colleagues. The authors analyzed the effects of supervisor centrality and participation in a two day Teach-the-Teacher course on the degree of innovation adoption using hierarchical linear modeling, adjusting for age, gender, and attitude toward the S&C feedback innovation. RESULTS: Respondents included 370 (60%) supervisors and 357 (63%) residents. Although Teach-the-Teacher course participation (n=172; 46.5%) was significantly related to supervisors' self-assessments of adoption (P=.001), it had no effect on residents' assessments of supervisors' adoption (P=.371). Supervisor centrality was significantly related to innovation adoption in both residents' assessments (P=.023) and supervisors' self-assessments (P=.024). CONCLUSIONS: A clinical supervisor's social network may be as important as faculty development course participation in determining whether the supervisor adopts an educational innovation. Faculty development initiatives should use faculty members' social networks to improve the adoption of educational innovations and help build and maintain communities of practice. PMID- 23348091 TI - Creating a longitudinal environment of awareness: teaching professionalism outside the anatomy laboratory. AB - Anatomy educators have long understood the role that professionalism education plays in the dissection laboratory. The process of dissecting human material forces students to address such issues as human mortality, their responsibility to the vulnerability of the deceased, their privileged position in society, and their commitment to scientific ideals. Educators have offered a wealth of opinions and curricula dedicated to teaching professionalism in first-year anatomy courses. That they have risen to this challenge is laudable. However, professionalism education is a longitudinal process of acculturation. What happens, then, to students after they leave the anatomy classroom? As it is not taught in other basic science courses, professionalism education effectively becomes a null curriculum, teaching students to compartmentalize professionalism questions so that they can be addressed in anatomy courses or during dedicated professionalism course work. In their training, medical students spend 4 to 12 years navigating this shifting environment of hidden, null, or explicit curricula, which have a significant impact on their attitudes and character.In this perspective, the author highlights, from his experience as a medical student, specific professionalism challenges in anatomy--such as encountering mortality, enacting contracts with society and those who are most vulnerable, and upholding scientific excellence--and discusses how these challenges are addressed by anatomy educators. He then provides analogous examples of opportunities to teach professionalism in other basic science courses, such as pathology, microbiology, and pharmacology. He concludes by describing the goal of incorporating professionalism into all basic science courses--a longitudinal, cohesive environment of awareness. PMID- 23348090 TI - "URM candidates are encouraged to apply": a national study to identify effective strategies to enhance racial and ethnic faculty diversity in academic departments of medicine. AB - PURPOSE: There is little evidence regarding which factors and strategies are associated with high proportions of underrepresented minority (URM) faculty in academic medicine. The authors conducted a national study of U.S. academic medicine departments to better understand the challenges, successful strategies, and predictive factors for enhancing racial and ethnic diversity among faculty (i.e., physicians with an academic position or rank). METHOD: This was a mixed methods study using quantitative and qualitative methods. The authors conducted a cross-sectional study of eligible departments of medicine in 125 accredited U.S. medical schools, dichotomized into low-URM (bottom 50%) versus high-URM rank (top 50%). They used t tests and chi-squared tests to compare departments by geographic region, academic school rank, city type, and composite measures of "diversity best practices." The authors also conducted semistructured in-depth interviews with a subsample from the highest- and lowest-quartile medical schools in terms of URM rank. RESULTS: Eighty-two medical schools responded (66%). Geographic region and academic rank were statistically associated with URM rank, but not city type or composite measures of diversity best practices. Key themes emerged from interviews regarding successful strategies for URM faculty recruitment and retention, including institutional leadership, the use of human capital and social relationships, and strategic deployment of institutional resources. CONCLUSIONS: Departments of medicine with high proportions of URM faculty employ a number of successful strategies and programs for recruitment and retention. More research is warranted to identify new successful strategies and to determine the impact of specific strategies on establishing and maintaining workforce diversity. PMID- 23348092 TI - Training in Urban Medicine and Public Health: TRIUMPH. AB - PURPOSE: The number of U.S. medical school graduates who choose to practice in health professional shortage areas (HPSAs) has not kept pace with the needs of society. The University of Wisconsin School of Medicine and Public Health has created a new program that prepares medical students to reduce health disparities for urban medically underserved populations in Milwaukee. The authors describe the Training in Urban Medicine and Public Health (TRIUMPH) program and provide early, short-term outcomes. METHOD: TRIUMPH integrates urban clinical training, community and public health curricula, longitudinal community and public health projects, mentoring, and peer support for select third- and fourth-year medical students. The authors tracked and held focus groups with program participants to assess their knowledge, skills, satisfaction, confidence, and residency matches. The authors surveyed community partners to assess their satisfaction with students and the program. RESULTS: From 2009 to 2012, 53 students enrolled in the program, and 45 have conducted projects with community organizations. Participants increased their knowledge, skills, confidence, and commitment to work with urban medically underserved populations. Compared with local peers, TRIUMPH graduates were more likely to select primary care specialties and residency programs serving urban underserved populations. Community leaders have reported high levels of satisfaction and benefits; their interest in hosting students exceeds program capacity. CONCLUSIONS: Early, short-term outcomes confirm that TRIUMPH is achieving its desired goals: attracting and preparing medical students to work with urban underserved communities. The program serves as a model to prepare physicians to meet the needs of urban HPSAs. PMID- 23348093 TI - If every fifth physician is affected by burnout, what about the other four? Resilience strategies of experienced physicians. AB - PURPOSE: To identify health-promoting strategies employed by experienced physicians in order to define prototypical resilience processes and key aspects of resilience-fostering preventive actions. METHOD: From January 2010 to March 2011, the authors conducted 200 semistructured interviews with physicians of different ages, disciplines, and hierarchical status from across Germany. The interview transcripts were analyzed according to the Content Analysis method. RESULTS: Analysis revealed 30 subcodes in three dimensions: (1) job-related gratifications derived from treatment interactions, (2) practices, such as leisure-time activities, self-demarcation, limitation of working hours, and continuous professional development, and (3) attitudes, such as acceptance of professional and personal boundaries, a focus on positive aspects of work, and personal reflexivity. CONCLUSIONS: The reported strategies and attitudes helped to develop mental, physical, and social resource pools that fostered effective decision making. Successful coping, in turn, encouraged the maintenance of resilience-promoting abilities. In relation to Conservation of Resources Theory, physician resilience emerged as the ability to invest personal resources in a way that initiates positive resource spirals in spite of stressful working conditions. Enriching traditional stress management approaches with the dynamic of positive as well as negative resource spirals would thus appear to be a promising approach. PMID- 23348094 TI - Employee health benefit redesign at the academic health center: a case study. AB - The rapidly escalating cost of health care, including the cost of providing health care benefits, is a significant concern for many employers. In this article, the authors examine a case study of an academic health center that undertook a complete redesign of its health benefit structure to control rising costs, encourage use of its own provider network, and support employee wellness. With the implementation in 2006 of a high-deductible health plan combined with health reimbursement arrangements and wellness incentives, the Penn State Hershey Medical Center (PSHMC) was able to realize significant cost savings and increase use of its own network while maintaining a high level of employee satisfaction. By contracting with a single third-party administrator for its self-insured plan, PSHMC reduced its administrative costs and simplified benefit choices for employees. In addition, indexing employee costs to salary ensured that this change was equitable for all employees, and the shift to a consumer-driven health plan led to greater employee awareness of health care costs. The new health benefit plan's strong focus on employee wellness and preventive health has led to significant increases in the use of preventive health services, including health risk assessments, cancer screenings, and flu shots. PSHMC's experience demonstrates the importance of clear and ongoing communication with employees throughout--before, during, and even after--the process of health benefit redesign. PMID- 23348095 TI - A bibliometric analysis of evaluative medical education studies: characteristics and indexing accuracy. AB - PURPOSE: To determine the characteristics of medical education studies published in general and internal medicine (GIM) and medical education journals, and to analyze the accuracy of their indexing. METHOD: The authors identified the five GIM and five medical education journals that published the most articles indexed in MEDLINE as medical education during January 2001 to January 2010. They searched Ovid MEDLINE for evaluative medical education studies published in these journals during this period and classified them as quantitative or qualitative studies according to MEDLINE indexing. They also examined themes and learner levels targeted. Using a random sample of records, they assessed the accuracy of study-type indexing. RESULTS: Of 4,418 records retrieved, 3,853 (87.2%) were from medical education journals and 565 (12.3%) were from GIM journals. Qualitative studies and program evaluations were more prevalent within medical education journals, whereas GIM journals published a higher proportion of clinical trials and systematic reviews (chi=74.28, df=3, P<.001). Medical education journals had a concentration of studies targeting medical students, whereas GIM journals had a concentration targeting residents; themes were similar. The authors confirmed that 170 (56.7%) of the 300 sampled articles were correctly classified in MEDLINE as evaluative studies. CONCLUSIONS: The majority of the identified evaluative studies were published in medical education journals, confirming the integrity of medical education as a specialty. Findings concerning the study types published in medical education versus GIM journals are important for medical education researchers who seek to publish outside the field's specialty journals. PMID- 23348096 TI - Mixed phosphine/N-heterocyclic carbene palladium complexes: synthesis, characterization and catalytic use in aqueous Suzuki-Miyaura reactions. AB - A series of N-heterocyclic carbene (NHC)/PR3 palladium(II) and palladium(0) complexes has been synthesized and fully characterized. X-ray crystallographic data have allowed comparison of ligand steric properties. The NHC ligand was found to vary its steric properties as a function of the phosphine co-ligand. These complexes display interesting catalytic properties in the Suzuki-Miyaura reaction performed in aqueous media. The pre-catalyst [PdCl2(IPr)(XPhos)] (IPr = N,N'-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene; XPhos = 2 dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) was found to be the most efficient system, promoting the coupling of a wide range of aryl chlorides with boronic acids in aqueous media with a typical catalyst loading of 0.03 mol%. PMID- 23348097 TI - XLID CUL4B mutants are defective in promoting TSC2 degradation and positively regulating mTOR signaling in neocortical neurons. AB - Truncating or missense mutation of cullin 4B (CUL4B) is one of the most prevalent causes underlying X-linked intellectual disability (XLID). CUL4B-RING E3 ubiquitin ligase promotes ubiquitination and degradation of various proteins. Consistent with previous studies, overexpression of wild-type CUL4B in 293 cells enhanced ubiquitylation and degradation of TSC2 or cyclin E. The present study shows that XLID mutant (R388X), (R572C) or (V745A) CULB failed to promote ubiquitination and degradation of TSC2 or cyclin E. Adenoviruses-mediated expression of wild-type CUL4B decreased protein level of TSC2 or cyclin E in cultured neocortical neurons of frontal lobe. Furthermore, shRNA-mediated CUL4B knockdown caused an upregulation of TSC2 or cyclin E. XLID mutant (R388X), (R572C) or (V745A) CUL4B did not downregulate protein expression of TSC2 or cyclin E in neocortical neurons. By promoting TSC2 degradation, CUL4B could positively regulate mTOR activity in neocortical neurons of frontal cortex. Consistent with this hypothesis, CUL4B knockdown-induced upregulation of TSC2 in neocortical neurons resulted in a decreased protein level of active phospho mTOR(Ser2448) and a reduced expression of active phospho-p70S6K(Thr389) and phospho-4E-BP1(Thr37/46), two main substrates of mTOR-mediated phosphorylation. Wild-type CUL4B also increased protein level of active phospho-mTOR(Ser2448), phospho-p70S6K(Thr389) or phospho-4E-BP1(Thr37/46). XLID CUL4B mutants did not affect protein level of active phospho-mTOR(Ser2448), phospho-p70S6K(Thr389) or phospho-4E-BP1(Thr37/46). Our results suggest that XLID CUL4B mutants are defective in promoting TSC2 degradation and positively regulating mTOR signaling in neocortical neurons. PMID- 23348098 TI - Molecular mechanisms beyond glucose transport in diabetes-related male infertility. AB - Diabetes mellitus (DM) is one of the greatest public health threats in modern societies. Although during a few years it was suggested that DM had no significant effect in male reproductive function, this view has been challenged in recent years. The increasing incidence of DM worldwide will inevitably result in a higher prevalence of this pathology in men of reproductive age and subfertility or infertility associated with DM is expected to dramatically rise in upcoming years. From a clinical perspective, the evaluation of semen parameters, as well as spermatozoa deoxyribonucleic acid (DNA) integrity, are often studied due to their direct implications in natural and assisted conception. Nevertheless, recent studies based on the molecular mechanisms beyond glucose transport in testicular cells provide new insights in DM-induced alterations in male reproductive health. Testicular cells have their own glucose sensing machinery that react to hormonal fluctuations and have several mechanisms to counteract hyper- and hypoglycemic events. Moreover, the metabolic cooperation between testicular cells is crucial for normal spermatogenesis. Sertoli cells (SCs), which are the main components of blood-testis barrier, are not only responsible for the physical support of germ cells but also for lactate production that is then metabolized by the developing germ cells. Any alteration in this tied metabolic cooperation may have a dramatic consequence in male fertility potential. Therefore, we present an overview of the clinical significance of DM in the male reproductive health with emphasis on the molecular mechanisms beyond glucose fluctuation and transport in testicular cells. PMID- 23348100 TI - Self-efficacy of first aid for home accidents among parents with 0- to 4-year-old children at a metropolitan community health center in Taiwan. AB - Although accidental injury is the main factor involved in the death of young children in many countries, few studies have focused on parents' competence with regard to self-efficacy of first aid for their children following injuries occurring at home. The purpose of this cross-sectional study was to investigate parental self-sufficiency of first aid for home accidents in children aged 0-4 years. The study is a cross-sectional designed. Data from 445 parents recruited were collected by purposive sampling at eight metropolitan community health centers in central Taiwan. Measurements were taken from a self-developed questionnaire that included 37 questions. Logistic regression analysis was applied to explore the associations between factors and parents' self-efficacy of first aid at home accident. Our findings show that parents' overall rate of knowledge of first aid was 72%. The mean score for 100% certainty in parents' self-efficacy of first aid was 26.6%. The lowest scores for self-efficacy were with regard to choking and cardiopulmonary resuscitation (CPR). There was a significantly positive correlation between parents' knowledge and self-efficacy of first aid (p<0.01), and thus knowledge of first aid is a predictor of parents' self-efficacy. Knowledge of first aid is also a partly mediator between participants' attending first aid program, participants' first aid information obtained from health personnel and self-efficacy of first aid. Our findings suggest that medical services should provide first aid resources to help manage accidental injuries involving children, particularly information on how to deal with choking and CPR. With an appropriate program provided by health professionals, parents' self-efficacy of first aid for home accidents will be positively enhanced. PMID- 23348101 TI - The effects of sunshields on red light running behavior of cyclists and electric bike riders. AB - Bicycles held an important position in transportation of China and other developing countries. As accidents rate involving electronic and regular bicycles is increasing, the severity of the bicycle safety problem should be paid more attention to. The current research explored the effect of sunshields (a kind of affordable traffic facility built on stop line of non-motor vehicle lanes (According to National Standard in China, e-bikes share the non-motor vehicle lane with regular bikes.) which was undertaken to avoid riders suffering from sunlight and high temperature) on diminishing red light running behavior of cyclists and e-bike riders. An observational study of 2477 riders was conducted to record and analyze their crossing behaviors at two sites across the city of Hangzhou, China. Results from logistic regression and analysis of variance indicated a significant effect of sunshield on reducing red light infringement rate both on sunny and cloudy days, while this effect of sunshield was larger on sunny days than on cloudy days based on further analysis. The effect of intersection type in logistic regression showed that riders were 1.376 times more likely to run through a red light upon approaching the intersection without sunshields compared to with sunshields in general. The results of MANCOVA further confirmed that rates of running behaviors against red lights were significantly lower at the intersections with a sunshield than at intersections without sunshields when other factors including traffic flow were statistically controlled. To sum up, it is concluded that sunshields installed at intersections can reduce the likelihood of red light infringement of cyclists and e-bike riders on both sunny and cloudy days. For those areas or countries with a torrid climate, sunshield might be a recommended facility which offers an affordable way to improve the safety of cyclists and e-bike riders at intersections. Limitations of the current sunshield design and current study are also discussed. PMID- 23348102 TI - The effect of prophylactic ankle support during simulated soccer activity. AB - OBJECTIVE: Ankle injuries are common in soccer and may result in ongoing functional deficiency. Ankle-joint prophylactic support is hypothesized to reduce the risk of injury. Analysis of the effects of prophylactic support has so far lacked application to soccer. Therefore, the purpose of this study was to illustrate the effects of tape and brace on selected proprioceptive components and range of motion (ROM) before, after, and during a soccer-match-simulation protocol. DESIGN AND SETTING: A crossover study design was used to investigate plantarflexion (PF) ROM, inversion (INV) ROM, and joint-position sense (weight bearing and non-weight-bearing [NWBJPS]; +/- error) in tape, brace, and control conditions. Measures were gathered from the dominant leg in a biomechanics laboratory at 0, 15, 30, and 45 min of a soccer-specific aerobic field test 90 min (SAFT90) protocol. PARTICIPANTS: Eight healthy male subjects (age 20.5 +/- 0.5 y) experienced the 3 conditions in random order with 7 d between conditions. INTERVENTION: The tape condition used an open basket-weave technique; the brace was an AirCast AirSport brace. For the control condition no prophylactic support was applied. RESULTS: Application of prophylactic support significantly decreased active ROM in PF and INV (P < .05), with tape performing better than the brace (0 min). Tape lost its restrictive benefits by 15 min (P < .001) and was no different than control, while the brace maintained some effect until 45 min. Application of prophylactic support increased NWBJPS performance (P < .01; 0 min); by 15 min the tape had lost its proprioceptive benefit (P < .01) compared with the brace. CONCLUSIONS: Our findings suggest that the clinical usefulness of ankle-joint prophylactic support is limited if the aim is to restrict ROM and improve proprioceptive capability under soccer-specific conditions. The relative benefits of each type of support need to be considered in the context of the time specific nature of the activity. PMID- 23348103 TI - Quantitative structure-activity relationship of organophosphate compounds based on molecular interaction fields descriptors. AB - By using multi-block partial least-squares (MBPLS) method, quantitative structure activity relationship (QSAR) between 35 organophosphate compounds (OP) and their 24h acute toxicities towards the housefly (Musca nebulo L.) was built on the molecular interaction fields (MIF) descriptors, which were obtained with O, N and DRY as probes, and then normalised with block unscaled weights (BUW) technique. The best QSAR model had 8 principal components, with the coefficient of determination R(2)=0.995 and that of leave-one-out cross-validation Q(2)=0.865, and the corresponding standard deviation of error 0.076 and 0.361, respectively. Block importance in the prediction (BIP) for O, N and DRY probe were 1.030, 0.962 and 1.007, respectively. Contour map of variable coefficients showed that hydrogen bonding between the O atom in PO and the NH groups in acetylcholinesterase (AChE) played an important role in the interaction between OP and AChE. Meanwhile, the hydrophobicity of OP also had significant contribution. QSAR based on the MIF descriptors could be a potential means to interpret the mechanisms of ligand-receptor interaction when the receptor was well known. PMID- 23348104 TI - Differential chemokine induction by 1-nitropyrene and 1-aminopyrene in bronchial epithelial cells: importance of the TACE/TGF-alpha/EGFR-pathway. AB - 1-nitropyrene (1-NP), a common PAH in diesel exhaust, and its amine metabolite 1 aminopyrene (1-AP) induce distinctly different chemokine-responses in bronchial epithelial cells (BEAS-2B) characterized by increases in CXCL8 and CCL5, respectively. Tumor necrosis factor-alpha converting enzyme (TACE), which cleaves membrane-bound transforming growth factor (TGF)-alpha, activating the epidermal growth factor receptor (EGFR), may regulate pro-inflammatory responses induced by a variety of endogenous and exogenous agents. The present results suggest that CXCL8, but not CCL5 responses in 1-NP- or 1-AP-exposed cells required TACE/TGF alpha/EGFR-signaling. The findings strengthen the notion that TACE/TGF-alpha/EGFR signaling is central in epithelial CXCL8-regulation upon exposure to multiple airborne pollutants. PMID- 23348105 TI - RNA pathogen detection with one-step reverse transcription PCR and strand displacement based signal amplification. AB - A novel detection method for RNA pathogens based on one-step reverse transcription PCR is introduced here. This method utilized the reverse transcriptase activity and the 5'-nuclease activity of TaqM1 DNA polymerase to transform target RNA into cDNA. The following PCR process released a fragment from the 5' end as a specific probe. Afterwards this fragment triggered a strand displacement based signal amplification to release large amounts of G-quadruplex DNAzymes. All the probes applied in our method were unmodified DNA oligonucleotides. The detection results could be reported without sophisticated instruments either in the colorimetric way through oxidizing ABTS or in the fluorometric way by using tyramine as substrate. This approach could successfully detect HIV-1 in a blood sample and it has a linear concentration range of 6 fM to 60 pM. PMID- 23348106 TI - Resolution of giant left atrial appendage thrombus with rivaroxaban. PMID- 23348107 TI - The action of kisspeptin-13 on passive avoidance learning in mice. Involvement of transmitters. AB - Kisspeptins are G protein-coupled receptor ligands originally identified as human metastasis suppressor gene products that have the ability to suppress melanoma and breast cancer metastasis and recently found to play an important role in initiating the secretion of gonadotropin-releasing hormone at puberty. Kisspeptin 13 is an endogenous isoform that consists of 13 amino acids. The action of kisspeptin in the regulation of gonadal function has been widely studied, but little is known as concerns its function in limbic brain structures. In the brain, the gene is transcribed within the hippocampal dentate gyrus. This paper reports on a study the effects of kisspeptin-13 on passive avoidance learning and the involvement of the adrenergic, serotonergic, cholinergic, dopaminergic and GABA-A-ergic, opiate receptors and nitric oxide in its action in mice. Mice were pretreated with a nonselective alpha-adrenergic receptor antagonist, phenoxybenzamine, an alpha2-adrenergic receptor antagonist, yohimbine, a beta adrenergic receptor antagonist, propranolol, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a nonselective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a nonselective muscarinic acetylcholine receptor antagonist, atropine, D2, D3, D4 dopamine receptor antagonist, haloperidol, a gamma-aminobutyric acid subunit A (GABAA) receptor antagonist, bicuculline, naloxone, a nonselective opioid receptor antagonist and nitro-l-arginine, a nitric oxide synthase inhibitor. Kisspeptin-13 facilitated learning and memory consolidation in a passive avoidance paradigm. Phenoxybenzamine, yohimbine, propranolol, methysergide, cyproheptadine, atropine, bicuculline and nitro-l arginine prevented the action of kisspeptin-13 on passive avoidance learning, but haloperidol and naloxone did not block the effects of kisspeptin-13. The results demonstrated that the action of kisspeptin-13 on the facilitation of passive avoidance learning and memory consolidation is mediated, at least in part, through interactions of the alpha2-adrenergic, beta-adrenergic, 5-HT2 serotonergic, muscarinic cholinergic and GABA-A-ergic receptor systems and nitric oxide. PMID- 23348108 TI - An analysis of the dentate gyrus function. AB - In this review article the emphasis will be on the role of the DG (dorsal and ventral) in supporting memory based on the operation of specific processes. Based on the development of computational models of dorsal dentate gyrus (dDG) and behavioral evidence based on dysfunction of dDG, this review will show that the dDG mediates mnemonic processing of spatial information. The processes subserved by dDG include (a) the operation of conjunctive encoding of multiple sensory inputs, implying an integration of sensory inputs to determine a spatial representation, and (b) pattern separation of spatial (especially metric) information, involving the reduction of interference between similar spatial locations (c) pattern separation of context (d) importance of context in object recognition, and (e) temporal integration and remote memory and spatial pattern separation based in part on neurogenesis. In addition the ventral dentate gyrus (vDG) mediates mnemonic processing of odor information as indicated by odor pattern separation. PMID- 23348109 TI - Doppler ultrasound--a valid and reliable tool to assess spondyloarthritis. AB - Enthesitis is the hallmark of spondyloarthritis and is observed in all subtypes. Namely, a wide information on spondyloarthritis abnormalities, including synovitis, bursitis, tendinitis, enthesitis and cortical bone abnormalities (erosions and enthesophytes), can be efficiently perceived by ultrasound power Doppler. Furthermore, several studies on imaging of enthesis showed that imaging techniques are better than clinical examination to detect pathology at asymptomatic enthesis. Vascularized enthesitis detected by ultrasound power Doppler appears to be a valuable diagnostic tool to confirm spondyloarthritis diagnosis. This article focuses on the validity and reliability of ultrasound enthesitis assessment in the management of spondyloarthritis patients. PMID- 23348110 TI - [Livedo reticular: classification, causes and differential diagnoses]. AB - Livedo reticularis (LR) is a common finding and results from a physiological vasospastic response to cold or systemic disease, characterized by a pattern of cyanotic discoloration, or erythematous-cyanotic aspect. LR can be congenital or acquired. Among the acquired LR stand out from the physiological or cutis marmorata, the idiopathic, the induced vasospastic, those due to intravascular diseases or even in the wall of the vessels. This article reviews several clinical features, differential diagnosis and various causes of livedo. PMID- 23348111 TI - [Epidemiological assessment of the socioeconomic status as a factor associated with the occurrence of musculoskeletal disorders]. AB - Musculoskeletal diseases are included as priorities among Public Health topics, particularly in Worker's Health, because of the high incidence and multiple factors that are associated with their occurrence. The purpose of this study is to assess the association between social and economic status of occupations, consolidated in the form of the socio-economic index of occupational status (ISEI) and the occurrence of musculoskeletal diseases. METHODS: The population studied included 157,676 workers of both genders, with ages ranging from 18 to 65, included in the Brazilian National Household Survey (PNAD--"Pesquisa Nacional de Amostra de Domicilios") carried out in 2003. The types of occupations were classified using the Socio-Economic Index (ISEI), as proposed by Ganzeboom and Treiman (1996). Prevalence rates for self-referred pathologies such as tendinitis/tenosynovitis and back pain (low back pain) in large occupational groups and in speci fic occupations were calculated. Study variables were applied to a linear regression model with 95% confidence intervals calculated in conformity with the ISEI quintiles. RESULTS: The highest socio-economic status presented the higher odds ratio for tendinitis or tenosynovitis (OR 2.93; 2.66 3.22), while the lowest status presented the highest odds ratio for spine or back problems (OR 1.31; 1.26-1.37), even when corrected by confounding variables, such as age, gender and educational status. CONCLUSION: This result suggests that this indicator is an important factor for the occurrence of Musculoskeletal Diseases. PMID- 23348112 TI - Autonomic functions and their relations with disease activity in ankylosing spondylitis. AB - OBJECTIVES: To evaluate the autonomic functions in patients with ankylosing spondylitis (AS) by means of clinical and electrophysiological tests, to compare the data with those of healthy individuals and to investigate the relationship with the disease activity. PATIENTS AND METHODS: 32 asymptomatic AS patients and 30 healthy controls were included in the study. Parasympathetic functions were evaluated clinically with heart rate variability (HRV) and electrophysiologically with R-R interval variation (RRIV). Sympathetic functions were evaluated clinically with diastolic blood pressure response to isometric exercise (DBP) and electrophysiologically with sympathetic skin response (SSR). Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score -C (ASDAS-C) were used to estimate the disease activity. RESULTS: HRV and RRIV was significantly lower in patients with AS when compared to controls, and in patients with BASDAI greater or equal to 4 when compared to the patients with BASDAI less than 4. There was no difference between the AS and the control groups and between the groups with BASDAI greater or equal to 4 and BASDAI less than 4 for DBP. Although there was no difference for SSR between AS and the control groups, SSR latency was significantly longer and SSR amplitude was significantly smaller in the group with BASDAI greater or equal to 4 when compared to the group with BASDAI less than 4. CONCLUSIONS: Our results indicate a parasympathetic dysfunction in AS patients, however the sympathetic system seems to be affected when the disease activity is increased. Patients with AS even they are asymptomatic must be investigated for autonomic dysfunction. PMID- 23348113 TI - Multidisciplinary and biodanza intervention for the management of fibromyalgia. AB - OBJECTIVE: To evaluate and compare the effectiveness of a 16-week multidisciplinary (exercise plus psychological therapy) and biodanza intervention in women with fibromyalgia. PATIENTS AND METHODS: Thirty-eight women with fibromyalgia were distributed to a 16-week multidisciplinary (3-times/week) intervention (n=21) or Biodanza (1-time/week) intervention (n=17). We assessed tender point, body composition, physical fitness and psychological outcomes (Fibromyalgia Impact Questionnaire, the Short-Form Health Survey 36 questionnaire (SF-36), the Hospital Anxiety and Depression Scale, Vanderbilt Pain Management Inventory (VPMI), Rosenberg Self-Esteem Scale and General Self-Efficacy Scale). RESULTS: We observed a significant group*time interaction effect for the scales of SF-36 physical role (P=0.038) and social functioning (P=0.030) and for the passive coping scale in VPMI (P=0.043). Post hoc analysis revealed a significant improvement on social functioning (P=0.030) in the multidisciplinary group whereas it did not change in the Biodanza group. Post hoc analysis revealed a reduction in the use of passive coping (positive) (P less than 0.001) in the multidisciplinary group. There was no significant interaction or time effect in body composition and physical fitness. CONCLUSIONS: 16 weeks of multidisciplinary intervention induced greater benefits than a Biodanza intervention for social functioning and the use of passive coping strategies in women with fibromyalgia. PMID- 23348114 TI - Position paper on tuberculosis screening in patients with immune mediated inflammatory diseases candidates for biological therapy. AB - Chronic immunosuppression is a known risk factor for tuberculosis. Our aim was to reach a consensus on screening and prevention of tuberculosis in patients with immune mediated inflammatory diseases candidates to biologic therapy. METHODS: Critical appraisal of the literature and expert opinion on immunosuppressive therapies and risk of tuberculosis. RESULTS AND CONCLUSION: The currently recommended method for screening is the tuberculin skin test and the interferon gamma assay, after exclusion of active tuberculosis. Positively screened patients should be treated for latent tuberculosis infection. Patients may start biological therapy after 1 to 2 months, as long as they are strictly adhering to and tolerating their preventive regimen. PMID- 23348115 TI - Klebsiella pneumoniae Spinal Epidural Abscess treated conservatively: case report and review. AB - Spinal infections are rare but potentially life-threatening disorders. A high level of clinical suspicion is necessary for rapid diagnosis and treatment initiation. The treatment combines both antibiotics and surgical intervention in the vast majority of cases. The authors report the case of a 84-year old female patient with a three week history of persistent lumbar back pain radiating to both thighs following a lower respiratory tract infection. She had lumbar spine tenderness but no neurological compromise. Her inflammatory markers were elevated and lumbar spine magnetic resonance imaging revealed L4-L5 spondylodiscitis with spinal epidural abscess. Blood cultures isolated Klebsiella pneumoniae and, since she was neurologically stable, conservative treatment with two-week intravenous gentamicin and eight-week intravenous ceftriaxone was initiated with positive inpatient and outpatient evolution. PMID- 23348116 TI - [Autoimmune hepatitis and dermatomyositis: a rare association]. AB - The association between autoimmune hepatitis and idiopathic inflammatory myopathies has been rarely described in literature. To our knowledge, there are only five reports of autoimmune hepatitis, all coursing with polymyositis. In the present work, we describe a female patient at the age of 58 with cutaneous lesions (heliotrope), progressive proximal muscle weakness of four limbs and constitutional symptoms for 12 months, and worsened two months ago. She had also been episodes of jaundice for five months. During hospitalization, after intense clinical investigation, the diagnosis of dermatomyositis and autoimmune hepatitis were defined, and the patient had a good clinical and laboratory response to corticosteroids and immunosuppressive. PMID- 23348117 TI - [Right axillary artery occlusion associated with stroke as manifestation of Takayasu's arteritis--case report and literature review]. AB - Takayasu's arteritis (TA) is an inflammatory chronic disease which damages large and medium caliber arteries, particularly aorta and its branches, and is more frequent in young women, usually starting in those who are less than 40 years old. The uncommon case reported herein concerns a 39-year-old female patient with damage of the right axillary artery only and stroke, emphasizing the need of arterial investigation in regions not usually affected by the disease. PMID- 23348118 TI - Primary antiphospholipid syndrome and panhypopituitarism: a unique presentation. AB - Lymphocytic hypophysitis (LH) has been described previously in systemic lupus erythematosus (1.3%), Sjogren's syndrome (0.8%). Lymphocytic hypophysitis (LH) is rarely associated with rheumatic diseases, although three cases of pituitary disease associated with antiphospholipid syndrome (APS) have been described. Here, we report a possible association between APS and LH for the first time. A 34-yr-old woman with primary APS presented with polyuria, polydipsia, hypernatremia and impaired vision. Her hormone profile was compatible with panhypopituitarism, and sellar magnetic resonance imaging (MRI) depicted a normal pituitary gland with a thickened and displaced stalk and infundibulum portion. Hormone replacement was started, and the patient experienced a good clinical evolution. PMID- 23348119 TI - Disseminated histoplasmosis in a juvenile lupus erythematosus patient. AB - INTRODUCTION: Histoplasmosis is an infection caused by dimorphic fungus, Histoplasma capsulatum, and it has not been reported in juvenile systemic lupus erythematosus (JSLE) patients, particularly progressive disseminated histoplasmosis (PDH) subtype. CASE REPORT: We reported herein a 14-year old girl who was diagnosed with JSLE. Six months later, she had abdominal distension and received prednisone, hydroxychloroquine and azathioprine. Computer tomography evidenced hepatosplenomegaly and multiple mesenteric, mediastinal and retroperitoneal enlarged lymph nodes, forming large conglomerates at the mesentery, suggestive of lymphoproliferative disorder. After 10 days, she had acute surgical abdominal, and underwent a laparotomy and intestinal perforation and conglomerates of lymph nodes were observed. The jejunum biopsy showed perforated acute enteritis with hemorrhage and necrosis, and Grocott staining identified Histoplasma sp. and the culture showed a heavy growth of Histoplasma capsulatum. At that moment liposomal amphotericin B (1.0 mg/Kg/day) was introduced. Despite this treatment she died due to septic shock eight days later. Diffuse Histoplasma capsulatum was evidenced at autopsy. CONCLUSION: We reported a severe opportunistic infection in JSLE patient with adenopathy and multiple intestinal perforations. This study reinforces the importance of early diagnosis and antifungal therapy, especially in patients with these uncommon clinical manifestations. PMID- 23348120 TI - Genetic susceptibility in IBD: overlap between ulcerative colitis and Crohn's disease. AB - BACKGROUND: The etiology of ulcerative colitis (UC) and Crohn's disease (CD) involves both genetic and environmental components. Multiple UC and CD susceptibility genes have been identified through genome-wide association studies and subsequent meta-analyses. These studies have also highlighted the presence of genes common to both diseases, and shared with several other autoimmune disorders. The aim of this study was to identify single nucleotide polymorphisms (SNPs) recently identified by the International IBD Genetics Consortium (IIBDGC) demonstrating that highly significant associations with CD could also confer genetic susceptibility to UC. METHODS: Statistical modeling was performed on 29 CD-associated SNPs. The study comprised of 1652 UC cases from the Australia and New Zealand IBD Consortium and 2363 Australian population-based controls. RESULTS: After adjustment for multiple comparisons, only one SNP, rs3024505, was significantly associated with UC (P = 0.001). Independent chi-square analyses identified odds ratios of 2.22 (1.48-3.37) for the rare homozygous genotype, and 1.20 (1.06-1.35) for the minor allele. Five other SNPs demonstrated moderate to weak associations with UC. CONCLUSIONS: Of the 29 SNPs conferring high genetic susceptibility to CD, 28 were not associated with UC, thus indicating that for this SNP set there is a low level of overlap between the two major forms of IBD. Only one SNP, rs3024505 (Chr 1q32.1, upstream of IL10), was associated with susceptibility to UC. The identification of this SNP replicates a finding from Franke et al (2008), where the rs3024505 SNP was strongly associated with UC across multiple European populations. PMID- 23348121 TI - Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia. AB - BACKGROUND: The expression and distribution of farnesoid X receptor (FXR) in colitis and colitis-associated neoplasia (CAN) is unknown. We investigated FXR expression in neoplastic and nonneoplastic tissue from ulcerative colitis (UC) patients, with or without primary sclerosing cholangitis (PSC), as well as the role of DNA methylation in FXR expression in colorectal cancer (CRC) cell lines. METHODS: Samples from the right (RC) and left (LC) colon of patients with UC, with and without PSC, and with or without CAN, were stained by immunohistochemistry and scored semiquantitatively for nuclear FXR expression. FXR expression was analyzed by western blot and polymerase chain reaction (PCR) in nine different CRC cell lines before and after demethylation with 5 azacytidine. RESULTS: In nondysplastic samples, FXR expression demonstrated a diminishing expression from proximal to distal colon (strong FXR expression: 39% RC samples vs. 14% LC samples; P = 0.007). With moderate-to-severe inflammation, FXR expression was almost always absent or weak in both UC and PSC-UC, regardless of location. With quiescent/mild inflammation, 56% of UC samples in the RC retained strong FXR expression versus 24% of PSC-UC samples (P= 0.017). FXR was absent in 72% of the neoplastic samples, with an inverse association with the grade of dysplasia. FXR expression was absent in all CRC cell lines, in some cases due to DNA methylation. CONCLUSIONS: FXR expression is inversely correlated with neoplastic progression and severity of inflammation in UC. Patients with PSC UC have diminished FXR expression in the proximal colon compared to UC patients. This finding could contribute to the higher risk of proximal neoplasia in PSC patients. PMID- 23348122 TI - An electrochemical impedance study of the oxygen evolution reaction at hydrous iron oxide in base. AB - The oxygen evolution reaction at multi-cycled iron oxy-hydroxide films in aqueous alkaline solution is discussed. Steady-state Tafel plot analysis and electrochemical impedance spectroscopy have been used to elucidate the kinetics and mechanism of oxygen evolution. Tafel slopes of ca. 60 mV dec(-1) and 40 mV dec(-1) are found at low overpotentials depending on the oxide growth conditions, with an apparent Tafel slope of ca. 120 mV dec(-1) at high overpotentials. Reaction orders of ca. 0.5 and 1.0 are observed at low and high overpotentials, again depending on the oxide growth conditions. A mechanistic scheme involving the active participation of octahedrally coordinated anionic iron oxyhydroxide surfaquo complexes, which form the porous hydrous layer, is proposed. The latter structure contains considerable quantities of water molecules which facilitate hydroxide ion discharge at the metal site during active oxygen evolution. This work brings together current research in heterogeneous electrocatalysis and homogeneous molecular catalysis for water oxidation. PMID- 23348123 TI - [Intracranial microhemorrhage following Morphine poisoning identical to "High Altitude Cerebral Edema"]. PMID- 23348124 TI - [Improved magnetic resonance myelography using image fusion]. AB - PURPOSE: To demonstrate that the disadvantage of missing anatomical information in heavily T2-weighted MR myelography images can be eliminated by image fusion and phase encoding in the coronal direction of the source images, resulting in MR myelography images comparable to the gold standard, i. e., post-myelography CT. MATERIALS AND METHODS: This study included 110 patients suffering from extradural pathologies of the cervical and lumbar spine. All patients were investigated using 3D MR myelography and post-myelography CT. The MRI data were post-processed using image fusion and reconstruction algorithms and were compared to the corresponding images of post-myelography CT. RESULTS: Our approach for visualization (3D MR myelography) was able to depict intradural structures in high spatial resolution and without artifacts. The results of our visualization approach were comparable to the gold standard - post-myelography CT. Anatomical correlation was reached by image fusion of different MR data sets. The required post-processing steps were performed quickly and were available on a commercial workstation. CONCLUSION: Image fusion of different MR data sets allows for visualization of 3D data sets with enhanced quality. The results for the visualization of MR myelography in particular are comparable to conventional myelography and post-myelography CT. The missing anatomical information in heavily T2-weighted MR myelography images can be compensated by image fusion with conventional MRI. PMID- 23348125 TI - Participation after multidisciplinary rehabilitation for moderate to severe traumatic brain injury in adults: a systematic review. AB - OBJECTIVE: To determine the effectiveness and comparative effectiveness of multidisciplinary rehabilitation programs for moderate to severe traumatic brain injury (TBI) in improving participation-related outcomes in adults. This article presents results of select key questions from a recent Agency for Healthcare Quality and Research comparative effectiveness review. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, and PsycINFO; hand searches of previous relevant reviews. STUDY SELECTION: We included prospective controlled studies that evaluated the effectiveness or comparative effectiveness of multidisciplinary rehabilitation programs delivered to adults with moderate to severe TBI on their participation in life and community. DATA EXTRACTION: We extracted data, assessed risk of bias, and evaluated strength of evidence. Participation was selected as our primary outcome and included measures of productivity (eg, return to employment or military service) and select scales measuring community integration. Only data from studies with a low or moderate risk of bias were synthesized. DATA SYNTHESIS: Twelve studies met our inclusion criteria; of these, 8 were of low or moderate risk of bias (4 randomized controlled trials of 680 patients and 4 cohort studies of 190 patients, sample size 36-366). Heterogeneous populations, interventions, and outcomes precluded pooled analysis. Evidence was insufficient to draw conclusions about effectiveness. Evidence on comparative effectiveness often demonstrated that improvements were not different between groups; however, this evidence was low strength and may have limited generalizability. CONCLUSIONS: Our review used a rigorous systematic review methodology and focused on participation after multidisciplinary rehabilitation programs for impairments from moderate to severe TBI. The available evidence did not demonstrate the superiority of one approach over another. This conclusion is consistent with previous reviews that examined other patient-centered outcomes. While these findings will have little clinical impact, they do point out the limited evidence available to assess effectiveness and comparative effectiveness while highlighting important issues to consider in future comparative effectiveness research on this topic. PMID- 23348128 TI - Acute effects of passive stretching on the electromechanical delay and evoked twitch properties: a gender comparison. AB - This study examined the acute effects of passive stretching on electromechanical delay (EMD), peak twitch force (PTF), rate of force development (RFD), and peak to-peak M-wave (PPM) for the soleus muscle during evoked isometric plantar flexion muscle actions. Fourteen men (mean age +/- SD = 21.2 +/- 2.4 years; body mass = 80.0 +/- 14.9 kg; height = 176.9 +/- 7.2 cm) and 20 women (20.9 +/- 2.5 years; 61.3 +/- 8.9 kg; 165.3 +/- 7.5 cm) volunteered for the study. Five single square, supramaximal transcutaneous electrical stimuli (each separated by 5 s) were delivered to the tibial nerve before and after passive stretching. A time * gender interaction was observed for EMD, and the post hoc dependent-samples t tests indicated that EMD increased 4% for the women (p = .023), but not for the men (p = .191). There were no other stretching-related changes for PTF, RFD, or p p M-wave for either the men or women (p > .05). These findings tentatively suggested that mechanical factors related to the stiffness of the muscle-tendon unit may contribute to the explanation for why stretching caused an acute increase in the EMD during evoked twitches in the women, but not in the men. PMID- 23348130 TI - Normalization of ground reaction forces, joint moments, and free moments in human locomotion. AB - Authors who report ground reaction force (GRF), free moment (FM), and resultant joint moments usually normalize these variables by division normalization. Normalization parameters include body weight (BW), body weight x height (BWH), and body weight x leg length (BWL). The purpose of this study was to explore the appropriateness of division normalization, power curve normalization, and offset normalization on peak GRF, FM, and resultant joint moments. Kinematic and kinetic data were collected on 98 subjects who walked at 1.2 and 1.8 m/s and ran at 3.4 and 4.0 m/s. Linear curves were best fit to the data, and regression analyses performed to test the significance of the correlations. It was found that the relationship between peak force and BW, as well as joint moments and BW, BWH, and BWL, were not always linear. After division normalization, significant correlations were still found. Power curve and offset normalization, however, were effective at normalizing all variables; therefore, when attempting to normalize GRF and joint moments, perhaps nonlinear or offset methods should be implemented. PMID- 23348132 TI - Lower extremity kinematics and kinetics when landing from unloaded and loaded jumps. AB - Countermovement jumps loaded with a weighted vest are often used for the training of lower body power to improve jump performance. However, it is currently unknown how this added load affects the lower extremity kinematics and kinetics, in particular whether this results in an increased injury risk. Therefore, the purpose of this investigation was to determine how lower extremity kinematics and kinetics during landing are affected by loaded jumps as demonstrated in a volleyball block jump landing. Ten elite male volleyball players performed block jump landings in an unloaded and loaded (9.89 kg) condition. Kinematic and kinetic landing data from the three highest jumps were collected and assessed. Paired samples t test was used to establish whether load condition had a significant effect on lower extremity kinematics and kinetics. Hip flexion was significantly greater in the unloaded condition compared with the loaded condition (p = .004). There was no significant difference in any other kinematic or kinetic variables measures between the unloaded and loaded conditions. These results suggest that landing from loaded volleyball block jumps does not increase injury risk compared with unloaded jumps in elite male volleyball players. PMID- 23348134 TI - Estimated force and moment of shoulder external rotation muscles: differences between transverse and sagittal planes. AB - The aim of this study was to compare shoulder muscle force and moment production during external rotation performed in the transverse and sagittal planes. An optimization model was used for estimating shoulder muscle force production of infraspinatus, teres minor, supraspinatus, anterior deltoid, middle deltoid and posterior deltoid muscles. The model uses as input data the external rotation moment, muscle moment arm magnitude, muscle physiologic cross-sectional area and muscle specific tension. The external rotation moment data were gathered from eight subjects in transverse and six subjects in sagittal plane using an isokinetic dynamometer. In the sagittal plane, all studied muscles presented larger estimated force in comparison with the transverse plane. The infraspinatus, teres minor, supraspinatus and posterior deltoid muscles presented larger moment in sagittal when compared with transverse plane. When prescribing shoulder rehabilitation exercises, therapists should bear in mind the described changes in muscle force production. PMID- 23348140 TI - An isovelocity dynamometer method to determine monoarticular and biarticular muscle parameters. AB - This study aimed to determine whether subject-specific individual muscle models for the ankle plantar flexors could be obtained from single joint isometric and isovelocity maximum torque measurements in combination with a model of plantar flexion. Maximum plantar flexion torque measurements were taken on one subject at six knee angles spanning full flexion to full extension. A planar three-segment (foot, shank and thigh), two-muscle (soleus and gastrocnemius) model of plantar flexion was developed. Seven parameters per muscle were determined by minimizing a weighted root mean square difference (wRMSD) between the model output and the experimental torque data. Valid individual muscle models were obtained using experimental data from only two knee angles giving a wRMSD score of 16 N m, with values ranging from 11 to 17 N m for each of the six knee angles. The robustness of the methodology was confirmed through repeating the optimization with perturbed experimental torques (+/- 20%) and segment lengths (+/- 10%) resulting in wRMSD scores of between 13 and 20 N m. Hence, good representations of maximum torque can be achieved from subject-specific individual muscle models determined from single joint maximum torque measurements. The proposed methodology could be applied to muscle-driven models of human movement with the potential to improve their validity. PMID- 23348141 TI - Vulvar vascular tumors: a clinicopathologic study of 85 patients. AB - The subepidermal hormonally sensitive tissue of the vulva is anatomically unique and may give rise to a wide variety of vascular tumors. As a consequence, classifying vulvar vascular lesions has been challenging due both to the wide variety of lesions that may be encountered and the heterogeneity in reporting across several disciplines. The purpose of this study is to present an institutional experience of vulvar vascular lesions. Overall, 85 patients were identified over a 26-year period. Vascular lesions belonging to the following classes included (n, %total) benign vascular tumors (32, 38%), dilatations of preexisting vessels (31, 36%), hyperplasia/reactive (7, 8%), tumors with significant vascular component (11, 13%), malformations (3, 4%), and malignant vascular tumors (1, 1%). Two reaction patterns based on vulvar lymphatic pathology were identified: one is a stromal dominant pattern and the other is a vascular dominant pattern. Vulvar vascular malformations and true vascular malignancies, although rare, may have associated high morbidity. To accurately classify vulvar lymphatic lesions, the pathologist must carefully consider the patient's clinical history taking into account features such as preexisting lymphedema. PMID- 23348142 TI - The grenz zone. AB - The grenz zone is a narrow area of the papillary dermis uninvolved by underlying pathology. Historically believed to be a feature unique to granuloma faciale, this feature has also been observed in other cutaneous inflammatory conditions, infectious entities, and neoplastic benign and malignant tumors. This review attempts to enumerate cutaneous entities commonly displaying a grenz zone with an emphasis on histopathological features that help in their differentiation. It also attempts to answer the obvious question of why select entities have this histopathologic feature by ascertaining the defining structure of a grenz zone. PMID- 23348143 TI - Does altered basement membrane of melasma lesion affect treatment outcome in Asian skin? PMID- 23348144 TI - Mitotically active proliferative nodule arising in a giant congenital melanocytic nevus: a diagnostic pitfall. AB - Proliferative (cellular) nodules (PN) which mimic malignant melanoma clinically and histologically are described in congenital melanocytic nevi (CMN) and may pose significant diagnostic challenges. We report the case of a 10-day-old male with a giant congenital nevus involving the neck, upper chest, back, and left shoulder containing several nodular lesions, some crusted. Biopsy of a nodule revealed densely packed nevus cells with hyperchromatic round to oval and occasionally irregularly shaped nuclei. There was no necrosis or pushing border, and the nodule blended with the adjacent nevus; however, the lesion demonstrated a significant number of mitoses (27 per mm2) and a 60% labeling index with Ki-67. Further analysis by fluorescence in situ hybridization (FISH) with a 4-color probe set targeting 6p25, 6q23, 11q13, and centromere 6 revealed increased chromosomal copy numbers of all 4 probes, which was interpreted as evidence of polyploidy. In addition, analysis of DNA copy number changes using a single nucleotide polymorphism microarray (Affymetrix, Santa Clara, CA) showed no chromosomal aberrations. The diagnosis of PN in a giant congenital nevus was eventually rendered. At 13-month follow-up, the nodules showed no evidence of growth. Our case illustrates that PNs in the neonatal period might demonstrate extreme mitotic activity. This feature is worrisome when encountered in melanocytic lesions; however, it should not trigger by itself a diagnosis of melanoma in the absence of other histologic criteria of malignancy. In addition, we document polyploidy by FISH in PN, which can potentially be misinterpreted as a FISH-positive result. PMID- 23348145 TI - Novel oral anticoagulants and gastrointestinal bleeding: a case for cardiogastroenterology. PMID- 23348146 TI - High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. AB - BACKGROUND: The mucolytic and antioxidant effects of N-acetylcysteine (NAC) may have great value in COPD treatment. However, beneficial effects have not been confirmed in clinical studies, possibly due to insufficient NAC doses and/or inadequate outcome parameters used. The objective of this study was to investigate high-dose NAC plus usual therapy in Chinese patients with stable COPD. METHODS: The 1-year HIACE (The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of Chronic Obstructive Pulmonary Disease-a Double blinded, Randomized, Placebo-controlled Trial) double-blind trial conducted in Kwong Wah Hospital, Hong Kong, randomized eligible patients aged 50 to 80 years with stable COPD to NAC 600 mg bid or placebo after 4-week run-in. Lung function parameters, symptoms, modified Medical Research Council (mMRC) dyspnea and St. George's Respiratory Questionnaire (SGRQ) scores, 6-min walking distance (6MWD), and exacerbation and admission rates were measured at baseline and every 16 weeks for 1 year. RESULTS: Of 133 patients screened, 120 were eligible (93.2% men; mean age, 70.8+/-0.74 years; %FEV1 53.9+/-2.0%). Baseline characteristics were similar in the two groups. At 1 year, there was a significant improvement in forced expiratory flow 25% to 75% (P=.037) and forced oscillation technique, a significant reduction in exacerbation frequency (0.96 times/y vs 1.71 times/y, P=.019), and a tendency toward reduction in admission rate (0.5 times/y vs 0.8 times/y, P=.196) with NAC vs placebo. There were no significant between-group differences in mMRC dypsnea score, SGRQ score, and 6MWD. No major adverse effects were reported. CONCLUSION: In this study, 1-year treatment with high-dose NAC resulted in significantly improved small airways function and decreased exacerbation frequency in patients with stable COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01136239; URL: www.clinicaltrials.gov. PMID- 23348147 TI - Thrombosis in association with a novel substitution (gamma346Gly->Val) at an absolutely conserved site in the fibrinogen gamma chain. PMID- 23348148 TI - Pediatric urolithiasis: experience from a tertiary referral center. AB - OBJECTIVE: Pediatric urolithiasis can cause significant morbidity and damage to the kidney, or even renal failure. We review our experience of the management of urolithiasis in pediatric patients at a tertiary referral center. PATIENTS AND METHODS: We reviewed medical records of all children with urolithiasis who were diagnosed and managed at our center from August 2003 to October 2011. Management was planned according to stone burden and location. We noted and statistically analysed data about age, sex, stone burden, clinical features, management, metabolic abnormalities and recurrence. RESULTS: There were 325 children with 378 stone sites. Age range was 3-17 (mean 8) years. The male to female ratio was 3:1. Most common presentation was abdominal pain in 257 children (79%), and the most common stone site was kidney in 215 (57%). Twenty-four (7%) children (stone burden <=3 mm) were managed conservatively, while the rest received some form of intervention. Metabolic workup could be done in 154 (47%) children. A metabolic abnormality was seen in 67 (43%) children, normocalcemic hypercalciuria being the most common. Recurrence of urolithiasis was seen in 78 (24%) children after a mean follow-up of 3.2 (1-6) years, and was more common in those who had a metabolic abnormality or in whom small residual fragments were left in situ. CONCLUSIONS: Availability of smaller instruments has led to safer use of percutaneous endoscopy and ureteroscopy in children, with results comparable to those in adults and an acceptable complication rate. The presence of a metabolic abnormality is quite common and is a cause of recurrence. PMID- 23348149 TI - Interaction between lung cancer cell and myofibroblast influenced by cyclic tensile strain. AB - Using a cell culture chip with a deformable substrate driven by a hydraulic force, we investigated the motility of cancer cells affected by myofibroblasts undergoing cyclic tensile strain (CTS). CTS reduced both the expression of alpha smooth muscle actin in the myofibroblast and the ability of the myofibroblast to accelerate cancer cell migration. However, with the treatment of a pro inflammatory factor interleukin-1beta on the myofibroblasts, the effects of CTS on the myofibroblast were diminished. This result suggests an antagonism between mechanical and chemical stimulations on mediating cancer metastasis by the stromal myofibroblast. PMID- 23348150 TI - The future of cognitive behavioral therapy for insomnia: what important research remains to be done? AB - The efficacy of cognitive-behavioral therapy for insomnia (CBT-I) to improve both short- and long-term outcomes in both uncomplicated and comorbid insomnia patients has been repeatedly and conclusively demonstrated. Further demonstrations of efficacy, per se, in additional comorbid insomnia populations are likely not the best use of limited energy and resources. Rather, we propose that future CBT-I research would be better focused on three key areas: (a) increasing treatment efficacy, particularly for more clinically relevant outcomes; (b) increasing treatment effectiveness and potential for translation into the community, with a particular focus on variants of CBT-I and alternative delivery modalities within primary healthcare systems; and (c) increasing CBT-I practitioner training and dissemination. PMID- 23348151 TI - New insight into the discharge mechanism of silicon-air batteries using electrochemical impedance spectroscopy. AB - The mechanism of discharge termination in silicon-air batteries, employing a silicon wafer anode, a room-temperature fluorohydrogenate ionic liquid electrolyte and an air cathode membrane, is investigated using a wide range of tools. EIS studies indicate that the interfacial impedance between the electrolyte and the silicon wafer increases upon continuous discharge. In addition, it is shown that the impedance of the air cathode-electrolyte interface is several orders of magnitude lower than that of the anode. Equivalent circuit fitting parameters indicate the difference in the anode-electrolyte interface characteristics for different types of silicon wafers. Evolution of porous silicon surfaces at the anode and their properties, by means of estimated circuit parameters, is also presented. Moreover, it is found that the silicon anode potential has the highest negative impact on the battery discharge voltage, while the air cathode potential is actually stable and invariable along the whole discharge period. The discharge capacity of the battery can be increased significantly by mechanically replacing the silicon anode. PMID- 23348152 TI - Disubstituted diaryl diselenides as potential atheroprotective compounds: Involvement of TrxR and GPx-like systems. AB - Oxidative modifications of low-density lipoproteins (LDLs) have a determinant role in atherogenesis and the study of agents that can modulate LDL oxidation is of pharmacological and therapeutic significance. Therefore, the aim of this study was to evaluate the antioxidant effect of the disubstituted diaryl diselenides, p methoxyl-diphenyl diselenide (p-CH(3)O-C(6)H(4)Se)(2) (DM) and p-chloro-diphenyl diselenide (p-Cl-C(6)H(4)Se)(2) (DC), on Cu(2+)-induced LDL oxidation. Both compounds caused a dose-dependent inhibition of human serum and isolated LDL oxidation evidenced by the increasing of the lag phase of lipid peroxidation and decreased the lipid oxidation rate (V(max)). The protein moieties from isolated LDL were also protected from Cu(2+)-induced oxidation. Moreover, the disubstituted diaryl diselenides efficiently decreased the oxidized LDL (ox-LDL) induced foam cell formation in J774A.1 macrophage cells. Mechanistically, we have demonstrated that the antioxidant and antiatherogenic effects of DM and DC are related to formation of their selenol intermediates (RSeH) either by a direct reaction with endogenous thiols (GPx-like activity) or via their reduction by TrxR (using NADPH as electron donor). Considering the powerful effect of DM and DC against LDL-induced toxicity, they could be considered for developing of new therapeutic approaches to preventing and treating atherosclerosis and cardiovascular diseases. PMID- 23348153 TI - The use of inorganic salts to improve the dissolution characteristics of tablets containing Soluplus(r)-based solid dispersions. AB - The dissolution enhancement advantages inherent to amorphous solid dispersions systems are often not fully realized once they are formulated into a solid dosage form. The objective of this study was to investigate the ability of inorganic salts to improve the dissolution rate of carbamazepine (CBZ) from tablets containing a high loading of a Soluplus(r)-based solid dispersion. Cloud point and viscometric studies were conducted on Soluplus(r) solutions to understand the effect of temperature, salt type and salt concentration on the aqueous solubility and gelling tendencies of Soluplus(r), properties that can significantly impact dissolution performance. Studies indicated that Soluplus(r) exhibited a cloud point that was strongly dependent on the salt type and salt concentration present in the dissolving medium. The presence of kosmotropic salts dehydrated the polymer, effectively lowering the cloud point and facilitating formation of a thermoreversible hydrogel. The ability of ions to impact the cloud point and gel strength generally followed the rank order of the Hofmeister series. Solid dispersions of CBZ and Soluplus(r) were prepared by KinetiSol(r) Dispersing, characterized to confirm an amorphous composition was formed and incorporated into tablets at very high levels (70% w/w). Dissolution studies demonstrated the utility of including salts in tablets to improve dissolution properties. Tablets that did not contain a salt or those that included a chaotropic salt hydrated at the tablet surface and did not allow for sufficient moisture ingress into the tablet. Conversely, the inclusion of kosmotropic salts allowed for rapid hydration of the entire tablet and the formation of a gel structure with strength dependent on the type of salt utilized. Studies also showed that, in addition to allowing tablet hydration, potassium bicarbonate and potassium carbonate provided effervescence which effectively destroyed the gel network and allowed for rapid dissolution of CBZ. Subsequent dissolution studies in 0.1 N HCl showed that potassium bicarbonate was an effective tablet disintegrant at levels as low as 1% and provided for tablets that rapidly disintegrated over a wide range of applied compression forces, presumably due to synergy between the ability to form a weak hydrogel structure and carbon dioxide liberation. Similar dissolution performance was measured in pH 4.5 acetate buffer, despite reduced polymer solubility caused by kosmotropic salts in solution, demonstrating robustness. With the use of inorganic salts such as potassium bicarbonate, it may be possible to substantially improve disintegration and dissolution characteristics of tablets containing Soluplus(r). PMID- 23348154 TI - Campylobacter infections in Zenica-Doboj Canton, Bosnia and Herzegovina - a story. AB - During the 2002-2006 periods two bilateral government scientific projects between R Slovenia and R/F Bosna and Herzegovina related to Campylobacter epidemiology and antimicrobial resistance took place, resulting in significant results. In this review key findings relating to Campylobacter epidemiology in Zenica-Doboj Canton, Bosnia and Herzegovina, were presented. PMID- 23348155 TI - Influence of physical activity to bone metabolism. AB - Bone remodeling is a lifetime process. Peak bone mass is achieved in the twenties, and that value is very important for skeleton health in older years of life. Modern life style with its diet poor in nutrients, and very low intensity of physical activity negatively influences health in general, and bone health as well. Bones are adapting to changes in load, so applying mechanical strain to bones results in greater bone mass and hardness. That makes physical activity important in maintaining skeleton health. Numerous studies confirm good influence of regular exercising to bone health, and connection of physical activity in youth to better bone density in older age. To activate bone remodeling mechanisms, it is necessary to apply mechanical strain to bones by exercise. Considering global problem of bone loss and osteoporosis new ways of activating young people to practice sports and active stile of life are necessary to maintain skeleton health and health in general. This paper aims to review physiological mechanisms of bone remodeling that are influenced by physical exercise. PMID- 23348156 TI - Non-invasive liver fibrosis markers: use of serum levels of cytokines IL 1alpha and TGF beta1 in management of chronic liver diseases. AB - AIM: To analyze the usefulness of specified immunological parameters, proinflammatory IL-1alpha and profibrogenic, antiinflammatory TGF-beta1, along with routinely used laboratory tests, in the differential - diagnostic procedure of chronic hepatitis of infectious and noninfectious etiology. METHODS: A total of 150 subjects were divided into two groups, depending on the infectious or noninfectious etiology of liver damage, and the control group. Apart from standard laboratory tests, the analysis included serum levels of cytokines: IL 1alpha and TGF-beta1. RESULTS: A high degree of correlation of serum level of IL 1alpha with viral hepatitis has been found, especially with active replication of genetic material ( HBV-DNA or HCV-RNA-PCR positive), p less 0.01. The highest mean concentration of TGF-beta1 was noted in the group of malignant and toxic hepatitis, p less 0.0001. A negative correlation between the concentration of IL 1alpha and TGF-beta1 has been found (-0.18). For IL-1 alpha significant predictive parameters included a previous infection of hepatitis B, lower serum level of TGFbeta, age, use of alcohol, lower MELD and Chilld-Pugh scores. For TGF beta1 significant predictive parameters were age, lower MELD and Child-Pugh scores, history of receiving transfusions, lower serum level of IL-1alpha, higher serum level of fibrinogen. A predictive model has been delivered MELD = (TGF beta1) x 0,001- (IL-1 alpha) x 0,085 + CTP x 1,771-2,052; ( +/- 2.04, R2=0,61; p less 0,001). CONCLUSION: Inflammatory and immune parameters, analyzed together could significantly contribute to the understanding of chronic liver damage and thus differential diagnostic procedure. IL-1alpha and TGF-beta1 are important parameters of inflammatory activity and fibrosis evaluation in chronic liver damage. PMID- 23348157 TI - Urinary tract infections in preschool children. AB - AIM: To determine the prevalence and etiological agents of significant bakteriuria in children younger than six, as well as the incidence of anatomical abnormalities of the urinary system in children with established significant bakteriuria. METHODS: Data were collected from hospital records of children treated at the Department for Preschool and School Health Care, the Primary Health Care Center Zenica and from discharge letters for children hospitalized at the Department of Pediatrics, Cantonal Hospital Zenica, Bosnia and Herzegovina in the period 2007-2009. RESULTS: A total of 5379 children were included in the study. Significant bacteriuria was present in 352 (6.5%) children, among those 114 (32.4%) were boys and 238(67.6%) girls. Recidivism of significant bakteriuria was found in 92 children (26.1%), and abnormal ultrasound findings in 58 (16.4%) children. The most common isolated pathogens were E. coli, in 170 (48.3%), K. pneumoniae, in 61 (17.3%), P. mirabilis in 53 (15%), and P. vulgaris, in 12 (34.1%) cases. CONCLUSION: As UTIs in children are often symptomless and unrecognizable, and an untreated UTI can lead to subsequent impairment of renal function, it is very important to detect bakteriuria in children. PMID- 23348159 TI - Mechanical and infectious complications developing due to central venous catheterizations in the Emergency Department. AB - AIM: To investigate the rate of catheter-related bloodstream infections (CRBSI) and mechanical complications due to central venous catheter (CVC) insertion in the emergency department (ED) and the contributing factors. METHODS: A total of 236 patients who were admitted to our ED and underwent CVC insertion between July 2008 and July 2009 were included in this prospective study. The CVC indications, the urgency of the insertion (emergency or elective), catheter complications (mechanical or CRBSI) and the compliance of the emergency physician placing the catheter with infection control and prevention measures were investigated. RESULTS: The CVC had been inserted urgently in 103 (44%) of the cases and mechanical complication rates in these patients were higher than those receiving it electively (p less 0.05). Our total mechanical complication rate was 27 (11.4%) with the highest rate for femoral catheter (FC). The CRBSI rate was 5/1000 catheter days. None of the physicians inserting a catheter ensured hand hygiene before the procedure. CONCLUSION: The FC is used as the most common access route for a CVC in our ED but CRBSI rate and mechanical complication rate were lower than in the literature. We believe that increasing compliance with infection control and prevention measures, especially hand hygiene, can further decrease the CRBSI rate in the ED. PMID- 23348158 TI - Could thrombocyte parameters be an inflammatory marker in the brucellosis? AB - AIM: To investigate links between platelet parameters mean platelet volume (MPV), platelet count (PC), platelet distribution width (PDW), platelet mass (PM) and brucella tube agglutination titers (BSTAT) in patients with brucellosis. Initially, PC, MPV, PM and PDW calculations were compared between periods before and after treatment. The correlation between inflammation markers (erythrocyte sedimentation rate, ESR, white blood cell count, WBC, and C reactive protein, CRP) and platelet parameters was subsequently investigated. METHODS: This self controlled study included 40 patients who had positive BSTAT at least at a titer of 1/160. Platelet parameters and inflammation values (CRP, ESR) at the time of positive BSTAT at least at a titer of 1/160 (pre-treatment) were compared with control of the same parameters at the time when BSTAT became negative or when the titers reduced 4 folds (post-treatment). RESULTS: Mean platelet volume values (7.90+1.96) were significantly elevated in post treatment period when compared to pre treatment (7.58+1.96), (p= 0.023). Post treatment CRP, ESR and PC were significantly reduced when compared to pretreatment values (p=0.000, p=0.000 and p=0.025, respectively). In the pretreatment period, a direct correlation between ESR and PC values (r=0.036, p=0.025), and inverse correlations between ESR with MPV (r=-0.337, p=0.038) was found. A dependent predictive factor in multivariate logistic regression analysis for BSTAT was not found. CONCLUSION: We suggest that PC and MPV may be inflammatory markers in brucellosis. PMID- 23348160 TI - Postoperative epidural analgesia in obese patients undergoing liver resection surgery. AB - AIM: To investigate the relation of body mass index (BMI) with postoperative pain scores and volume of local anaesthetic (LA) administered epidurally in patients undergoing liver resection surgery. METHODS: Retrospective data from 167 patients who had epidural analgesia (EA) for liver resection surgery were analysed: 123 with BMI < 30kgm-2 and 44 with BMI > 30kgm-2. RESULTS: Total volume of intraoperative bolus of epidural analgesia (EA) was not different between the BMI more than 30 kgm-2 and BMI less than 30 kgm-2 groups (p less 0.05). Mean rate of infusion (8.2+/-2.7 ml/h vs. 7.9+/-1.9 ml/h, p=0.0018), pain scores immediately after extubation of the trachea (0.91+/-0.9 vs. 0.55+/-0.7, p=0.017) and that before removal of epidural catheter (0.7+/-0.55 vs. 0.7+/-0.95, p=0.015) were higher in the BMI > 30kgm-2 group when compared with the BMI <= 30kgm-2 group. However, there was no significant difference between the numbers of segments blocked. CONCLUSION: The patients with BMI more than 30 kgm-2 undergoing liver resection experienced more postoperative pain on the day of surgery and before epidural catheter removal than patients with BMI less than 30 kgm-2, despite a higher rate of epidural infusion. Further studies are necessary to confirm these findings in order to determine adequate local anaesthetic dosing for thoracic epidural analgesia in obese patients. PMID- 23348161 TI - The relationship between CYP2C9 gene polymorphisms and upper gastrointestinal bleeding in patients who used warfarin. AB - AIM: Oral anticoagulants are the most common used substance for treatment and prophylaxis of warfarin venous and arterial thromboembolic disorders in the world. Therapeutic index of warfarin is narrow. CYP2C9 is a hepatic microsomal enzyme and has a primary role in metabolism of warfarin and genetic variations of CYP2C9 may cause a serious effect on the response to warfarin in patients. The aim of this study was to determine the efficiency of CYP2C9 gene polymorphisms on drug metabolism in patients who had upper gastrointestinal system bleeding while using warfarin. METHODS: There was a total of 67 patients in this study, 37 of whom had upper gastrointestinal system bleeding when INR was above 3 while using warfarin (group 1), 30 of whom had no bleeding and INR was stable under 3 (group 2). RESULTS: There was no difference in terms of warfarin dose used among the groups (p>0.05). Mutant genotype, INR and aspirin usage were found significantly different in the group with bleeding (p less 0.05). When analyzed in terms of drug interaction, there was no difference between the two groups (p>0.05). Logistic regression analysis was made in order to determine the risk factors that may cause bleeding. Aspirin usage (p= 0.016) and genetic polymorphism (p= 0.024) were related to the increased risk of bleeding. CONCLUSION: CYP2C9*2 and CYP2C9*3 polymorphisms were related to the increase of excessive anticoagulation and bleeding risk in the patients who used warfarin. PMID- 23348163 TI - The significance of mean platelet volume on diagnosis and management of adenomyosis. AB - AIM: The present study was designed to assess the significance of mean platelet volume on the pathogenesis and management of adenomyosis. METHODS: A total of 26 patients out of 123 with pathologically confirmed adenomyosis in hysterectomy specimens without concomitant gynecological pathology were selected for the study. Control group was consisted of 24 symptom-free subjects out of 35, with normal smear test and without infection. Groups were compared in terms of mean platelet volumes and platelet counts. RESULTS: The mean platelet volume values of patients with pathologically confirmed adenomyosis were found to be significantly higher than the values in the control group (9.3+/-0.8 fL versus 7.3+/-0.8 fL; p less 0.05). Platelet count comparison between the two groups showed no statistical significance (p>0.05). CONCLUSION: This study confirms the previous studies indicating endometriosis and adenomyosis as inflammatory processes. As a result, mean platelet volume has shown to be a significant clinical marker for chronic inflammatory process of adenomyosis and endometriosis. This basic finding should be supported by new studies concerning the correlation of mean platelet volume levels with severity and duration of the disease, as well as response of mean platelet volume levels to therapies targeting chronic inflammatory process in adenomyosis and endometriosis pathogenesis. PMID- 23348162 TI - Determination of underlying causes in asymptomatic, early-stage renal diseases by dipstick test. AB - AIM: To prevent possible chronic kidney diseases in healthy school- age children by screening for hematuria and proteinuria using a urine strip. METHODS: The incidence of hematuria and proteinuria was determined in 1848 healthy school-age children aged 7 to 14 years by urine screening in the eastern region of Turkey in 2008. Cases with persistent hematuria and/or proteinuria were referred to a pediatric nephrologist, and further examinations were carried out. RESULTS: Isolated hematuria, isolated proteinuria, and combined hematuria-proteinuria were found in 92 (4.9%), 16 (0.8%) and 10 (0.5%) patients, respectively. In addition, 11.9% (11/92) of cases of isolated hematuria and 40% (4/10) of cases of combined hematuria- proteinuria were observed to have persisted. Persistent hematuria and persistent hematuria-proteinuria were found in 11 (0.5%) and 4 (0.2%) patients, respectively. In these cases, underlying causes were found: renal stone disease, hypercalciuria, urinary tract infection, vesicoureteral reflux, atrophic kidney, and IgA nephropathy. CONCLUSION: According to this study, cases with persistent hematuria should be examined especially in terms of renal stones, hypercalciuria, and urinary tract infection. PMID- 23348164 TI - Evaluation of myocardial ischemia in coronary artery disease with cardiac MR perfusion method: comparison with the results of catheter or CT angiography. AB - AIM: To evaluate the efficacy of the Cardiac Magnetic Resonance Perfusion (CMRP) method in detection of Coronary Artery Disease (CAD) by comparing CMRP findings with the results of Coronary Computed Tomography Angiography (CCTA) or Catheter Coronary Angiography (CCA). METHODS: Thirty one patients in whom CMRP was performed along with CCTA or CCA within a month after CMRP between December 2009 and November 2010 were selected for the study. In CMRP, after adenosine administration as a stress agent Balanced TFE sequences were used to gather dynamic images that include the myocardial first pass of contrast media. Image analysis was performed visually. CMRP findings were compared to CCTA or CCA results for each coronary artery territories and for all territories. RESULTS: Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CMRP test in the identification of patients with significant (>=70%) coronary artery stenosis were 94.7%, 83%, 90.3%, 90%, and 90.9% for all coronary arteries, respectively; 94.4%, 84.6%, 90.3%, 89.4%, and 91.6% for left anterior descending artery, respectively; and 100%, 100%, 100%, 100%, and 100% for circumflex and right coronary artery, respectively. There was no statistically significant difference between angiography methods (CCTA/CCA) and CMRP (p>0.05). Methods had good to perfect consistency (K = 0.79-1.00). CONCLUSION: CMRP test seems to be a reasonable alternative for catheter angiography, which is considered the gold standard for evaluation of CAD and exclusion of significant coronary artery obstruction. PMID- 23348165 TI - Maternal and neonatal outcome of controlled gestational diabetes mellitus versus high risk group without gestational diabetes mellitus: a comparative study. AB - AIM: To analyze maternal and neonatal short term outcomes in pregnancies with controlled gestational diabetes mellitus (GDM) versus high risk group without GDM. METHODS: The data about all singleton pregnancies with diagnosis of GDM was retrospectively retrieved from patients' files from 1st June 2008 to 30th November 2008 by the Department of Endocrinology, Alnoor Specialist Hospital, Makkah, Saudi Arabia. The diagnosis of GDM was made according to O'Sullivan and National Diabetes Data Group (NDDG) criteria. Subjects were divided into Controlled GDM group (A) and high risk group without GDM (B). Odd ratio (OR) and 95% confidence interval (CI) was measured for GDM. group. RESULTS: Incidence of GDM was found 5.9%. The risk of cesarean section (CS), pregnancy induced hypertension (PIH) and pre-term delivery was significantly high in the group A than B, i.e., OR 2.5, 95% CI 1.1-5.8, p=0.04; OR 2.6, 95% CI 1.1-6.2, p=0.03; OR 3.2, 95% CI 1.1-9.5, p=0.04; respectively. On the other hand, risks for gestational age (LGA) newborns, neonatal hypoglycemia, respiratory distress and neonatal intensive care unit (NICU) admissions were also significantly higher in the group A than B neonates, i.e., OR 3.6, 95% CI 1.1-11.9, p=0.04; OR 4.7, 95% CI 1.7-12.6, p=0.002; OR 4.2, 95% CI 1.4-12.2, p=0.009; OR 3.2, 95% CI 1.1- 9.4, p=0.04, respectively. CONCLUSION: Pregnancy outcome was found unfavorable even with controlled GDM in comparison with high risk subjects. PMID- 23348166 TI - Gender differences in patients with metabolic syndrome in coronary artery interventions. AB - AIM: We tried to understand whether or not there was a gender difference in coronary artery interventions in coronary heart disease (CHD) cases in the present study. METHODS: The study was performed in two phases. The first phase was performed at the Internal Medicine Polyclinic of the Dumlupinar University between August 2005 and March 2007. CHD was diagnosed either angiographically or with history of coronary artery stenting (CAS) and/or coronary artery bypass graft (CABG) surgery. The second phase was performed at the Internal Medicine Polyclinic of the Mustafa Kemal University between March 2007 and April 2012. During the second phase, the CHD patients with CAS and/or CABG surgery were detected and divided into two groups according to the gender. RESULTS: Mean age and prevalence of CHD were similar in both genders (p>0.05 for both) in the first phase. Smoking was higher in males with CHD, in 30 cases (54.5%) of males versus six (9.6%) cases of females (p < 0.001), as well as chronic obstructive pulmonary disease (COPD), in ten (18.1%) cases of males versus four (6.4%) cases of females (p < 0.05). Although the body mass index (BMI) and white coat hypertension (WCH) were insignificantly higher (p>0.05 for both), low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) were significantly higher in females with CHD (p= 0.008 and p= 0.002, respectively). Hypertension (HT) and diabetes mellitus (DM) were higher in females with CHD, too (p < 0.001 and p < 0.05, respectively). On the other hand, CAS and/or CABG surgery were significantly higher in male CHD cases (21.8% versus 1.6%, p less 0.001). Parallel to the first phase cases, majority of CAS and/or CABG surgery cases were males in the second phase cases too (90.2% versus 9.7%, p less 0.001). CONCLUSION: As some components of the metabolic syndrome, smoking and COPD were higher in males whereas BMI, WCH, LDL-C, TG, HT and DM were higher in females. Despite similar prevalences of CHD in both sexes, CAS and/or CABG surgery were significantly higher in males probably due to fear of loss of power required for their dominant roles in life and sexuality. PMID- 23348167 TI - Comparison of partial matrixectomy and combination treatment (partial matrixectomy + phenol) in ingrown toenail. AB - To compare only partial matrixectomy and combination techniques (partial matrixectomy + phenol application) in the treatment of patients with an ingrown toenail in terms of recurrence, residual pain level and time of return to daily activities. METHODS: The study included 118 patients with moderately ingrown toenails who were unresponsive to conservative treatment together with severely ingrown toenail patients. Of these patients, 76 cases were treated with a partial matrixectomy technique and 42 patients received combination treatment. Patients having nail infection received preoperative oral antibiotics. RESULTS: Of 118 patients, 87 were males and 31 were females. The disease relapsed in seven (9.2%) of the patients treated with the partial matrixectomy technique, and in two (4.8%) patients from the combination treatment group (p=0.5). No statistically significant difference was found between the groups in terms of return time to daily activities (p=0.5) nor in terms of residual pain (p=0.7). CONCLUSIONS: Treatment costs and operation times of patients who underwent phenol application in addition to partial matrixectomy were found to be higher compared to only partial matrixectomy, however combined therapy was not found to be superior to only partial matrixectomy in terms of recurrence, post-op pain and return to daily activities. PMID- 23348168 TI - The analysis of factors associated with improved glycemic control in patients with insulin-requiring type 2 diabetes mellitus after treatment. AB - AIM: To observe the effect of standardized ten-day diabetes prevention and control program on glycemic control, and to analyze factors contributing significantly to improvement of glycemic control after the program/intervention. METHODS: A cross-sectional nested case-control study on 91 adult patients with insulin-requiring type 2 diabetes mellitus who underwent a standardized ten-day diabetes program in the Specialized Hospital "Merkur" in Vrnjacka Banja, Serbia, from June the 1st to August 1st 2010 was performed. All necessary data were obtained from patients' medical files archived in this institution. Cases (n=32) and controls (n=32) were matched for age and sex. RESULTS: Diabetes program led to a significant decrease in mean daily blood glucose (p=0.039), achieved at the expense of the reduction of postprandial hyperglycemia (p=0.013). Male patients, patients with mean daily glycemia above the acceptable range before the intervention, and patients who were receiving combined therapy (insulin plus oral antidiabetics) before the intervention, were significantly more likely to achieve such positive outcome (ORadjusted = 344.48, 12.83, and 25.44 respectively, with 95%CIs that not included 1). CONCLUSION: Standardized ten-day diabetes educational and rehabilitation program in the Specialized Hospital "Merkur" could be efficient in improving glycemic control, especially for male patients whose glucoregulation was poor despite the combined therapy with insulin and oral antidiabetic agents. Further investigation on determinants of efficiency of this program are necessary to understand better how to facilitate and support improvements in diabetes control at the population level. PMID- 23348169 TI - The investigation of effects of fluorosis on thyroid volume in school-age children. AB - AIM: To compare the urine iodine, fluoride, and to measure thyroid volumes in 10 15-year-old children using ultrasonography, a gold standard in evaluating thyroid volume. METHODS: A total of 261 children were enrolled into the study group from the 4-8th grades of 3 different primary schools, which were in the zone with high fluoride levels. The control group was formed by enrolling 298 children from the 4-8th grades of only one primary school. Age, gender, height, and weight values were recorded for the children. The urine iodine, fluoride, and thyroid volumes were measured with ultrasonography in 10-15-year-old children with fluorosis and controls and compared between two groups. RESULTS: The mean urine fluoride level was 0.48+/-0.24 mg/L in the study group and 0.22+/-0.17 mg/L in the control group (p < 0.001). The mean urine iodine level did not differ between two groups. The mean total thyroid volume was 8.60+/-3.11 mL and 8.73+/- 2.75 mL in the study and control group, respectively. The groups were also compared according to the echobody index, and the score was 6.94+/-2.14 ml/m2 in the study group and 6.48+/ 1.53 ml/m2 in the control group (p=0.003). Mean thyroid volumes did not differ between two groups. However, the echobody index in the study group was higher than in the control group. CONCLUSION: A relation between fluoride concentration and thyroid gland with ultrasonographic examination was firstly evaluated, and it was concluded that fluoride affected thyroid gland although it was weakly significant. After puberty, echobody index in subjects with fluorosis was markedly high. Based on our results, we thought that fluorosis increases thyroid volume in children with fluorosis after puberty. PMID- 23348170 TI - Spatial tuning function of pattern visual evoked potentials in multiple sclerosis patients without optic neuritis history. AB - AIM: To explore amplitude and latency-check size function in multiple sclerosis (MS) patients without optic neuritis history. METHODS: Thirty-six MS patients and 21 control subjects were included. Pattern visual evoked responses to ive check sizes (2 degrees , 1 degrees , 30', 15', and 7') were recorded. RESULTS: P100 amplitudes were significantly reduced in 2 degrees , 1 degrees and 7' checks and, P100 latencies were significantly delayed in all checks in MS patients (p < 0.05). Inter-ocular amplitude/ latency differences were significantly higher in MS patients than control group (p < 0.05). The P100 amplitudes for 2 degrees check was somewhat higher than amplitudes for 1 degrees check in MS and control groups. However, MS patients had latter amplitude-check size function curve in large checks. In small checks, the slope of the amplitude-check size curves were similar for MS and control groups. The flattening of amplitude-check size function curve in large checks increased in MS patients with reduced P100 amplitudes. The P100 amplitudes for 2 degrees check was lower than P100 amplitudes for 1 degrees check in MS patients with reduced P100 amplitudes in contrast to normal subjects and MS patients with normal P100 amplitudes. Both groups had almost parallel P100 latency-check size curves in all checks. With respect to 95% confidence limit in control subjects in each check sizes, the number of eyes with delayed latency and reduced amplitude in MS patients were higher in large checks. CONCLUSION: This study showed that P100 amplitudes are reduced in MS patients without optic neuritis history, and responses to large checks are affected more than small checks. PMID- 23348171 TI - Effects of treatment adherence on clinical and economic outcomes in patients with psoriasis. AB - AIM: To compare clinical and cost outcomes of psoriasis in non-biological treatment of adherent and non-adherent patients in a developing Balkans country going through socio-economic transition. METHODS: The study was designed as a retrospective cohort study involving patients with psoriasis adherent and non adherent to the prescribed treatment regimen. The patients were followed for a period of one year, through four visits with intervals of three months. The adherence to the prescribed regimen was measured at the end of the follow-up period by the medication possession ratio. Clinical outcomes of the treatment were estimated by the Psoriasis Area Severity Index (PASI) at each visit and the treatment costs were collected from patients' files at each visit. RESULTS: The study enrolled 108 patients, 61 (56.5%) were adherent to the prescribed treatment, and 47 (43.5%) were non-adherent. A signiicant decrease of PASI score was noted in the patients adherent to prescribed therapy (p < 0.001). The costs also decreased significantly in the group of adherent patients (p=0.001), and the drop of costs was the highest from the visit 3. The decrease in PASI score and costs were less rapid in non-adherent patients. CONCLUSION: Better treatment adherence leads to faster clinical improvement and a more rapid decrease in costs of treatment, which diminish overall expenditure of the health system and society, leaving room for treatment of other diseases more efficiently. Therefore, health systems of developing countries should support additional research of causes of treatment non-adherence in patients with psoriasis, in order to minimize this fenomenon more efficiently, and make significant savings. PMID- 23348172 TI - Quality of life in patients with multiple sclerosis in Republic of Srpska. AB - AIM: To estimate health-related quality of life (HRQoL) in patients with multiple sclerosis (MS), and to investigate relationship between HRQoL and selected demographic and clinical parameters. METHODS: In this cross-sectional study HRQoL was measured using the MS-specific MSQoL-54 questionnaire. Neurological impairment was assessed using the Expanded Disability Status Scale (EDSS), and presence of depression and anxiety using the Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS). Statistical analysis included descriptive statistics and correlation analysis. RESULTS: The results confirmed that physical disability had a significant impact on HRQoL. Correlations were the strongest for the domains of physical health (PH) (r= 0.718), overall quality of life (QL) (r=-0.528), satisfaction with sexual function (r=-0.493) and role limitations due to emotional problems (r=-0.493) of MSQoL- 54 scales. It was found that there were statistically significant correlations between composite score of PH of MSQoL-54 scale and duration of MS ( r=-0.381), employment status (r=-0.624), educational level (r=0.384), occupation (r= 0.552), and age at disease onset (r=-0.434). There were statistically significant correlations between anxiety and depression and low scores on a majority of MSQoL-54 subscales. Correlations were the strongest for the subscales of QL (r=-0.674), energy (r=-0.629), sexual function (r=-0.579) and PH (r=-0.573) for HARS and QL (r=-0.751), PH (r=-0.629) and satisfaction with sexual function (r=-0.612) for HDRS. CONCLUSION: Our results indicate that HRQoL is influenced not only by disability itself, but rather by interactions of a range of physical, psychological and social factors. PMID- 23348173 TI - Disturbed family functioning in patients suffering from posttraumatic stress disorder. AB - AIM: To investigate whether the presence of posttraumatic stress disorder (PTSD) symptomatology is related to specific family problems. METHODS: The study included 94 subjects who were divided into three groups: a group with posttraumatic stress disorder (based on PCL for DSM-IV National Center for PTSD) (N=31), a group with problems in postwar functioning but without posttraumatic stress disorder (N=33), a group of subjects who were mobilized but with no combat exposure experience (N=30). The first and the second group had the experience of combat exposure. The first group was experimental, being diagnosed with PTSD. The second and the third group were control groups (the first and the second control group). The groups were compared by intensity and quality of family dysfunction, in relation to parameters, determined by specific instruments used in this research. RESULTS: The subjects with the experience of combat exposure had the problems in family functioning independently of the existence of PTSD diagnosis. Many of these problems were caused by the damage of combat experience. We also found a high level of secondary traumatization among other family members. CONCLUSION: The combat experience causes problems in postwar family functioning of combatants independently of PTSD diagnosis being confirmed. It is, therefore, necessary to help all of the combatants and their families reintegrate, regardless of their PTSD diagnosis. PMID- 23348174 TI - Denture relining as an indicator of residual ridge resorption. AB - AIM: Residual ridges change in shape and reduce in size due to alveolar bone resorption. Therefore, the purpose was to investigate changes in denture base thickness (DBT) and interocclusal rest space (IRS) with regard to the denture relining procedure. METHODS: The IRS and DBT were measured (before and after denture relining) in the case of 74 patients and their removable dental prostheses by using a precise sliding gauge. The DBT measuring was performed in 6 points for maxillary and in 3 points for mandibular removable dental prosthesis. The IRS values were measured as the distance (in mm) between the incisal edges of the maxillary and mandibular central incisors with patient's mandible in a physiological "rest position" with head and neck in the upright posture. RESULTS: In a group of patients wearing maxillary and mandibular removable dental prosthesis mean values of DBT after denture relining were statistically significantly higher (p <0.05) in almost all measuring points. The IRS mean values after relining were statistically significantly lower (p <0.05). Statistically significant differences (p <0.05) of DBT were also observed in groups of "day-night time" and "day time" denture wearers, and in a group of patients for whom a period shorter than one year had passed since the last tooth extraction and the time when a functional impression for removable dental prostheses was taken. CONCLUSION: The DBT and IRS values change after the denture relining procedure due to the alveolar bone resorption. Therefore, these measures could be used as resorption indicators in dental practice. PMID- 23348175 TI - Types of HLA in the bladder transitional cell carcinoma (TCC). AB - HLA plays a complementary role in the interaction between tumor and body immunology. The aim of this study was to determine the existence of the association between the HLA system and transitional cell carcinoma (TCC). Using standard micro-lymphocytotoxic method of Terasaki, HLA-A, B, DR and DQ antigen types of 30 patients with TCC of the bladder were compared with the control group (30 healthy people). In the TCC patient group, HLA -DQ6(1) and HLA -DQ7(3) antigens were detected with a significantly higher frequency than in the control group (p=0.018 and p=0.038, respectively), whereas HLA-A10, B4, DR53 and DQ1 antigens were detected with significantly higher frequency in the control group (p less 0.05 in all). It suggests that patients who had the antigens detected were at higher risk of TCC, and the ones who had the antigens displaying protective features as were detected in the control group, were at lesser risk. PMID- 23348176 TI - Impact of hypertension on angiographic findings in patients with coronary artery disease. AB - The aim of this study was to assess the impact of hypertension on angiographic results in Iraqi patients with coronary artery disease. Six hundred and fifty seven patients with coronary artery disease (CAD) were submitted to routine coronary angiography in the period from January 2008 to December 2010. A comparison and evaluation have been divided into 2 stages. There was no significant association between patients with CAD who had a history of hypertension only with the number and distribution of coronary artery vessels involvement, as well as with morphological severity of coronary lesions. But, there was a statistically significant association between hypertension associated with other cardiac risk factors with multiple coronary lesions. Hypertension was significantly associated with multiple coronary artery lesions when combined with other cardiac risk factors. PMID- 23348177 TI - Influence of surgical complications on graft and patients' survival after a kidney transplantation according to donors' age. AB - The aim of this study was to determine a frequency and a type of early and late surgical complications in kidney transplantation, their impact on renal graft survival among 80 patients, 54 (67.5%) males and 26 (32.5%) females who had undergone a living and cadaveric kidney transplant at the Surgery Center in Tuzla in the period from 15.09.1999 until 31.12.2008. The subjects were divided into two groups according to donor age, younger and older than 55. A significantly higher incidence of early rather than late surgical complications was observed in an experimental group (p=0.001, and p=0.77, respectively). There was a statistically significant difference in the length of graft survival (p=0.004) and the number of deaths (p=0.038). Older age of kidney graft donor had an impact on the occurrence of early surgical complications and no influence on the occurrence of late surgical complications. Fatal outcome after kidney transplantation was significantly higher in patients who received grafts of elderly people. PMID- 23348178 TI - Emergency upper gastrointestinal endoscopy at the Emergency Department of Izzet Baysal Hospital: analysis of 263 patients. AB - To evaluate the epidemiological characteristics, etiology, and therapeutic outcome of gastrointestinal disorders in 269 patients who underwent emergency upper gastrointestinal (EUGI) endoscopy at the Emergency Department. Abdominal pain was the most common clinical indication, in 90 (33.5%) patients. The clinical reasons for emergency admission were significantly related to endoscopic diagnostic yield. Non-erosive gastritis was the most common diagnosis, in 76 (28.3%) of EUGIE patients. Erosive duodenitis and gastric ulcer were found to be the other most common clinical indications, in 69 (25.7%) and 31 (11.5%) of EUGIE patients, respectively. The majority of patients who presented with abdominal pain and loss of appetite were between the age of 41 and 60 years, while a significant number of patients presenting with the same symptoms did so during the winter season. Emergency endoscopy is a procedure of choice for the investigation of upper gastrointestinal complaints. Emergency endoscopy is not only a diagnostic tool but also a therapeutic modality. PMID- 23348179 TI - Surgical site infections in orthopedic patients; prospective cohort study in a university hospital in Serbia. AB - The aim of this study was to investigate a potential association of certain risk factors in orthopedic patients with surgical site infection (SSI) occurrence. The study population consisted of all patients who underwent surgery at the Orthopedic and Traumatology Clinic of the University Hospital in Kragujevac (n = 801) over a 12- month period. Surgical site infections were found in 104 patients (13.0%). Results of multivariate regression analysis indicated that SSIs were significantly more frequent in patients who had a contaminated or dirty wound (RR = 27.68, 95% CI = 11.54 to 66.40; p = 0.0000), with drainage (RR = 4.62, 95% CI = 2.33 to 9.15; p = 0.0000), and who were at the Intensive Care Unit (RR = 3.25, 95% CI = 1.38 to 7.69; p = 0.0072). PMID- 23348180 TI - Comparison of contamination in simultaneous blood cultures with clinical findings. AB - Blood culture, the basic method used in the diagnosis of bacteremia or sepsis, is decisive for patient's treatment. It is emerging whether the isolated microorganism is a causative agent of the infection or a contaminant. The aim of this study was to determine whether Gram-positive microorganisms, which were isolated from blood cultures simultaneously collected from two distinct veins both revealed the same species and same susceptibility profiles as they were causative agents of the bloodstream infection. Among the strains isolated from a total of 67 cultures, which revealed the same species, 52.2% (35/67) were considered to be clinical causative agents and 47.8% (32/67) were considered as skin contaminants. Inoculation of the simultaneous blood cultures collected from two distinct veins should be performed. PMID- 23348181 TI - Clinical manifestation and neuroimaging methods in diagnosing basal ganglia calcifications. AB - The aim of this case study was to evaluate the clinical symptoms in patients with basal ganglia calcifications and compare the neuroimaging methods used in confirming this state. The clinical status and performed transcranial sonography of basal ganglia structures in patients with brain calcifications found by computed brain tomography was examined. In one of these patients DaTSCAN was performed. A large spectrum of different symptoms was found. Transcranial sonography of basal ganglia showed the hyperechogenicity of nucleus lenticularis in eight out of 10 patients. DaTSCAN, which was performed to one patient with parkinsonian signs and the hyperechogenicity of substantia nigra found by transcranial sonography, was normal. Transcranial sonography is a newly neuroimaging method which can contribute to diagnosing basal ganglia calcifications in patients with different neurological signs. Computed tomography of brain remains the most adequate technique in visualising calcifications. PMID- 23348182 TI - Intracranial meningeoma--ten-year evaluation. AB - The aim of the study was to analyze the prevalence, occurrence by gender, age, place of residence, location and pathohistological type, focusing on peculiarities of the surgically removed meningiomas in the first post-war decade in Bosnia and Herzegovina. The study was conducted in the region comprising more than 600.000 inhabitants. During the post-war decade 162 patients were surgically treated. Females accounted for 65.4%, convexity meningioma accounted for 43.8%. WHO grade I meningiomas occurred in majority of patients, 60.5%, grade II in 23.5%, and grade III in 16.0% patients. The prevalence of malignant menigeomas was significantly higher in males, 26.8%. Meningiomas were more common during the sixth (33.9%) and seventh (35.2%) decade of life. The somewhat higher prevalence of atypical and malignant meningiomas especially in males requires further analysis that would clarify this phenomenon. PMID- 23348183 TI - The analysis of limbs acute ischemia during seasons on the territory of South Serbia. AB - The aim of this study was to examine the seasons variations in incidence of limbs acute ischemia (LAI) as well as the connection between seasons with location of LAI, old age and gender. During the three year period between January 2009 and December 2011, at the Clinic for Vascular Surgery, Clinical Center of Nis, Serbia, 167 patients were hospitalized diagnosed with limbs acute ischemia. There was no statistically significant difference in patients distribution with LAI compared with seasons (p=0.726) and months of the year (p=0.0741). There was no statistically significant difference in patients age (p=0.066), sex (p=0.923) and LAI localization (p=0.219 ) in different seasons. The absence of seasonal and monthly patterns for the AIE creation as well as its localization is followed by the absence of a connection between the age and the sex.. PMID- 23348184 TI - Clinical management and outcomes of papillary, follicular and medullary thyroid cancer surgery. AB - The clinical characteristics, pathological subtypes and patients' survival in 40 patients with thyroid carcinoma between March 2007 and March 2012 were evaluated. This study included 33 (82.5 %) females and seven (17.5%) males (female to male ratio of 4.7:1). The median age of patients was 47.5 (range; 24-64). Papillary carcinoma was the commonest pathological subtype (23 patients, 57.5%), followed by follicular carcinoma (14 patients, 35%) and medullary carcinoma (3 cases, 7.5%). Total thryoidectomy was performed in 30 (75%), lobectomy in six (15%), subtotal and multifocal thryoidectomy in two (5%) patients. The median time of follow up was 3 years with range of 1-5 years. After ive years 34 (85%) patients were alive and six (15%) were dead. The overall 5-year actuarial survival was 85%, for papillary carcinoma 91.3%, for follicular carcinoma 85.7% and for medullary carcinoma it was 33.3%. The results suggest that total thryoidectomy had better outcome in comparison with other surgeries. PMID- 23348185 TI - Preoperative evaluation in the era of laparoscopic surgery. AB - To confirm the importance of preoperative evaluation of a patient's health state, to reduce perioperative morbidity and mortality after laparoscopic surgery. A total number of 1,070 patients were selected into groups based on a type of intervention, gender, ASA and NYHA classification. The most common laparoscopic procedure that was performed was cholecystectomy in 920 (86%) patients. Cardiovascular disease had been presented in 952 (89%) patients, 1006 (94 %) of patients were ASA class I- III, while 1049 (98%) patients were NYHA class I and II. Frequency of lethal outcome was 0.1% due to postoperative thromboembolic complications. A lower mortality rate is a result of prescribed protocol and adequate preoperative examination. PMID- 23348186 TI - MRSA joint infection in a psoriatic patient with a coexisting respiratory infection. AB - In September 2011, a 52-year old patient suffering from psoriatic arthritis and being treated for an upper respiratory tract infection, presented to the emergency department of Argos General Hospital with fever and a painful, swollen right knee. He underwent clinical, laboratory and imaging examinations. Initially blood and synovial fluid cultures were negative. After an arthroscopic collection of pus, the culture showed a methicillin resistant Staphylococcus aureus which was sensitive only to daptomycin. PMID- 23348187 TI - Pericardial effusion complicating swine origin influenzae A (H1N1) infection in a 50-year-old woman. AB - Acute pericarditis is a well-recognized but rare complication of numerous viral infections. We report a case of a 50-year-old woman with novel influenza A (H1N1) infection complicated by pericardial effusion. Resolution of both symptoms and pericardial effusion occurred after a treatment with oseltamivirin and ibuprofen. There were no signs of acute left or right ventricle dysfunction. Pericarditis and pericardial effusion are occasionally associated with influenza A infections. To our knowledge, this is a rare case of pericardial effusion associated with influenza A (H1N1) reported during the current novel influenza A (H1N1) pandemic that responded well to conservative management. PMID- 23348188 TI - Blunt trauma of the thoracic aortic isthmus. AB - Blunt trauma of the thoracic aorta is the second leading cause of death in traffic accidents, after head injuries. A polytraumatized patient, aged 40, was admitted, with trauma of the thoracic aortic isthmus, after a traffic accident. Adequate resuscitation and intensive therapy, angiographic and MSCT diagnostics enabled the urgent surgical treatment. On the sixty-seventh day of surgery, the patient was successfully transferred to a regional health center in good general condition. Blunt aortic injury occurs in 1% of casualties in traffic and causes 16% mortality. More than 80% of patients die before arrival to hospital. In conclusion, we point out with satisfaction the successful surgical treatment and survival of injured patients admitted to our hospital. PMID- 23348189 TI - Enhanced therapeutic response with addition of loratadine in subserosal eosinophilic gastroenteritis. AB - A case of a 45-year-old Caucasian male initially reported with symptoms of acute intestinal obstruction was presented. Diagnostic tests revealed presence of eosinophilic ascites with marked peripheral eosinophilia, a significant thickening of stomach and intestinal wall and infiltration of gastric and duodenal mucosa with eosinophiles. Findings were conclusive with subserosal type of eosinophilic gastroenteritis and the patient's treatment started with a combination of parenteral methylprednisolone and oral loratadine. A prompt clinical response was encountered after 5 days of treatment with complete resolution. PMID- 23348190 TI - Pseudo-subarachnoid hemorrhage and death after a bee sting. AB - We report a case of a 33-year-old woman who developed severe brain edema and pseudo-subarachnoid hemorrhage (SAH) at 36-hour follow-up after successful cardiopulmonary resuscitation for anaphylactic shock as a result of a bee sting. The patient died on the sixth day of the follow-up due to multiple organ failure and brain herniation. Our case suggests that the SAH-like findings on computed tomography scanning were not a new complication ("real" SAH) arising from the bee sting; rather, it was a pseudo-SAH related to prolonged cardiopulmonary resuscitation). PMID- 23348191 TI - Antrochoanal polyp of unusual size. AB - This paper presents antrochoanal polyp of unusually large size (8x5 cm), which we removed in a 34-year old patient by the antral portion by the Caldwell-Luc approach and the portion form the epipharynx through the oral cavity with skew pliers for the pharynx biopsy. PMID- 23348192 TI - Phacoemulsification of irradiation cataract after brachytherapy. AB - A 24-year old man presented to the Policlinic with severe visual impairment in his left eye. The patient had been treated earlier with Iodine-125 brachytherapy due to iris melanoma. Clinical examination revealed low visual acuity, filtration device, iris atrophy, posterior synachiae and completely white cataract. Ultrasonography revealed scleral thinning with no signs of retinal detachment. The patient underwent synechiolysis, trypan blue capsule staining, phacoemulsification and implantation of 23D intraocular lens Alcon AcrySof (MA60BM). Phacoemulsification went uneventful and early postoperative recovery was successful. Visual acuity improved to 0,2 and fundus examination revealed radiation retinopathy with diffuse retinal scaring. PMID- 23348193 TI - Acute posterior multifocal placoid pigment epitheliopathy-retinal "white dot syndrome". AB - Acute posterior multifocal placoid pigment epitheliopathy- APMPPE is an acquired idiopathic inflammatory disease of the chorioretina. This case report presents a typical clinical manifestation of a very rare condition: a twenty ive-year old female complained of a sudden bilateral decrease of vision. She reported lu-like symptoms and taking antibiotics therapy. Fundus examination revealed numerous discrete yellow-white lesions at posterior pole involving the macula. After a period of 7 days oral prednisone treatment she was completely recovered. Usage of steroids is recommended for treating APMPPE in cases where macula is involved and in recurrent cases. PMID- 23348194 TI - Risk factors and diabetic retinopathy. PMID- 23348195 TI - The cellular protein TIP47 restricts Respirovirus multiplication leading to decreased virus particle production. AB - The cellular tail-interacting 47-kDa protein (TIP47) acts positively on HIV-1 and vaccinia virus production. We show here that TIP47, in contrast, acts as a restriction factor for Sendai virus production. This conclusion is supported by the occurrence of increased or decreased virus production upon its suppression or overexpression, respectively. Pulse-chase metabolic labeling of viral proteins under conditions of TIP47 suppression reveals an increased rate of viral protein synthesis followed by increased incorporation of viral proteins into virus particles. TIP47 is here described for the first time as a viral restriction factor that acts by limiting viral protein synthesis. PMID- 23348196 TI - Scanning electrochemical microscopy at variable temperatures. AB - All chemical reactions are influenced by temperature, however, temperature is usually not considered an important parameter which has to be varied or at least controlled in SECM measurements. A precise temperature-control unit was designed and integrated into a SECM setup which allows setting the temperature of the sample and the adjacent electrolyte in a range between 0 and 100 degrees C without causing convection. Data acquisition was synchronized with the current pulses through the Peltier element to decrease the noise and keep the tip-to sample distance constant during imaging. SECM images in the feedback mode, generator collector mode and the redox competition mode for model samples such as an enzyme entrapped within a polymer spot or oxygen reduction catalysts demonstrate the importance of controlling temperature as well as performing SECM experiments at predefined and constant increased temperature. PMID- 23348197 TI - Analysis of UV and vibrational spectra (FT-IR and FT-Raman) of hexachlorocyclotriphosphazene based on normal coordinate analysis, MP2 and DFT calculations. AB - The Raman (1400-100 cm(-1)) and infrared (4000-400 cm(-1)) of solid hexachlorocyclotriphosphazene, P(3)N(3)Cl(6) (HCCTP) were recorded. The conformational energies were calculated using MP2 and DFT (B3LYP and B3PW91) methods utilizing a variety of basis sets up to 6-311+G(d). On the basis of D(3h) symmetry, the simulated vibrational spectra of P(3)N(3)Cl(6) from MP2 and DFT methods were in excellent agreement with those obtained experimentally. Additionally, Frontier Molecular Orbitals and electronic transitions were predicted using steady state and time dependent DFT(B3LYP)/PCM calculations respectively, each employing the 6-311+G(d,p) optimized structural parameters. The predicted wavelengths were in excellent agreement with experimental values when CH(2)Cl(2) was used as solvent. The (14)N and (31)P chemical shifts were predicted with B3LYP/6-311+G(2d,p) calculations using the GIAO technique with solvent effect modeled using the PCM method. The computed structural parameters of the planar P(3)N(3)Cl(6) (D(3h)) agree well with experimental values from both X-ray and electron diffraction data with slight distortions observed due to lattice defects in the solid phase. The experimental/computational results favor a slightly distorted D(3h) symmetry for the title compound in the gas and solid phases and in solution (tauPNPN and tauNPNP ranged from 0.018 degrees to 0.90 degrees ). Aided by normal coordinate analysis, and the simulated vibrational spectra utilizing MP2, B3LYP and B3PW91 methods at 6-31G(d) basis set, revised and complete vibrational assignments for all fundamentals are provided herein. PMID- 23348198 TI - Theoretical study of the electronic and spectroscopic properties of some Ru(II) anticancer complexes. AB - DFT method has been applied to study the thermodynamic and spectroscopic properties of three Ru-based complexes. Possible reasons for the reported experimental stability of complexes 1 and 2 with bidentate chelating ligands over complex 3 have been explained using computed properties. The results show that the trend in their thermodynamic, hyperpolarizabilities, magnetizabilities and the NMR isotropic shielding agree well with many of their experimental properties which give further detail explanation to the reported differences in their stability, hydrolysis and anticancer activities. We also found out that these complexes which were originally designed as anticancer agents have high hyperpolarizabilities which suggest that they can also act as good non-linear optical (NLO) materials. PMID- 23348199 TI - Trans/cis isomerization of [RuCl2(diphosphine)(diamine)] complexes: synthesis, X ray structure and catalytic activity in hydrogenation. AB - The diamine (N-N) co-ligand 2,2-dimethyl-1,3-propanediamine and 2,3 diaminophathalene react individually with [RuCl(2)(dppb)(2)(MU-dppb)] to afford complexes with kinetically stable trans-[Cl(2)Ru(dppb)(N-N)] as the favoured isomer. The thermodynamically stable cis-[Cl(2)Ru(dppb)(N-N)] isomer of complex 1 was formed from the trans-1 isomer. The trans to cis isomerization reaction was conducted in CHCl(3) at RT and monitored by (31)P{(1)H} NMR. The structures of the desired complexes were characterized via elemental analyses, IR and, UV visible spectroscopy, FAB-MS and NMR. The structure of the cis-1 isomer was determined by single crystal X-ray measurements. Both the trans-1 and cis-1 isomers were shown to have a significant catalytic role in selective hydrogenation reactions under mild conditions using cinnamic aldehyde as typical model reaction. PMID- 23348200 TI - The emission spectroscopy of the (2)Phi(5/2)-1(2)Delta(3/2) system of VO molecule. AB - VO and other vanadium oxides are important in catalysts, semiconductors and optical devices. Studying its interior microstructure is necessary for fully understanding its intrinsic nature and better applications. The P and R-branch emission spectraof the (0, 0) band in the (2)Phi(5/2)-1(2)Delta(3/2) system of VO molecule are studied using the analytical formulae derived by Sun group in their previous work. The calculated result reproduced all known experimental spectral lines accurately, and the correct values of the unknown spectral lines up to J=80.5 were predicted in this work that were not given experimentally. PMID- 23348201 TI - First fixations in face processing: the more diagnostic they are the smaller the face-inversion effect. AB - Hills, Ross, and Lewis (2011) introduced the concept that the face-inversion effect may, in part, be carried by the first feature attended to, since the first feature fixated upon is different for upright and inverted faces. An eye-tracking study that directly assesses this hypothesis by using fixation crosses to guide attention to the eye or mouth region of the to-be-presented upright and inverted faces was devised. Recognition was better when the fixation cross appeared at the eye region than at the mouth region. The face-inversion effect was smaller when the eyes were cued than when the mouth was cued or when there was no cueing. The eye-tracking measures confirmed that the fixation crosses attracted the first fixation but did not affect other measures of eye-movements. Furthermore, the location of the first fixation predicted recognition accuracy: when the first fixation was to the eyes, recognition accuracy was higher than when the first fixation was to the mouth, irrespective of facial orientation. The results suggest that the first facial feature attended to is more predictive of recognition accuracy than the face orientation in which they are presented. PMID- 23348202 TI - Comparison of arterial pressure and plethysmographic waveform-based dynamic preload variables in assessing fluid responsiveness and dynamic arterial tone in patients undergoing major hepatic resection. AB - BACKGROUND: Dynamic preload variables to predict fluid responsiveness are based either on the arterial pressure waveform (APW) or on the plethysmographic waveform (PW). We compared the ability of APW-based variations in stroke volume (SVV) and pulse pressure (PPV) and of PW-based plethysmographic variability index (PVI) to predict fluid responsiveness and to track fluid changes in patients undergoing major hepatic resection. Furthermore, we assessed whether the PPV/SVV ratio, as a measure of dynamic arterial elastance (Eadyn), could predict a reduction in norepinephrine requirement after fluid administration. METHODS: Thirty patients received i.v. fluid (15 ml kg(-1) in 30 min) after hepatic resection and were considered responders when stroke volume index (SVI) increased >=20% after fluid administration. SVV and SVI were measured by the FloTrac Vigileo((r)) device, and PVI was measured by the Masimo Radical 7 pulse co oximeter((r)). RESULTS: The areas under a receiver operating characteristic curve for SVV, PPV, and PVI were 0.81, 0.77, and 0.78, respectively. In responders, all dynamic variables, except PVI, decreased after fluid administration. Eadyn predicted a reduced norepinephrine requirement (AUC = 0.81). CONCLUSIONS: In patients undergoing major hepatic resection, both APW- and PW-based dynamic preload variables predict fluid responsiveness (preload) to a similar extent. Most variables (except PVI) also tracked fluid changes. Eadyn, as a measure of arterial elastance (afterload), might be helpful to distinguish the origin of hypotension. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01060683. PMID- 23348203 TI - Comparison of subgluteal sciatic nerve block duration in type 2 diabetic and non diabetic patients. AB - BACKGROUND: Although animal studies demonstrated delayed recovery after nerve block in laboratory models of diabetes, the duration of the action of sciatic nerve blocks clinically in patients with diabetes remains to be determined. We studied the duration of a sciatic nerve block in type 2 diabetic patients compared with non-diabetic patients. METHODS: We prospectively included consecutive patients aged 50-80 yr, with type 2 diabetes with minor nerve injury (confirmed with 5.07 at 10 g monofilament test, n=23) and non-diabetic patients (n=49) scheduled for distal lower limb surgery. Before surgery, a subgluteal sciatic nerve block (20 ml of ropivacaine 4.75 mg ml(-1)) was performed with an ultrasound approach coupled with nerve stimulation. The primary endpoint was the sensory block duration. RESULTS: There was no significant difference between groups for age, but haemoglobin A1c and creatinine values were significantly higher in the diabetic group. There was no difference in 5.07 (10 g) monofilament testing, but the diabetic group had lower scores for the 0.4 and 0.07 g tests (P<0.01). There was no significant difference in the median onset time for the sensory block (25 vs 25 min, NS), but the median duration of the sensory block (21 vs 17 h, P<0.01) and the motor block (16 vs 12 h, P<0.01) were higher in the diabetic group. No complication occurred in either group. CONCLUSIONS: These findings demonstrate that diabetic patients with pre-existing incipient neuropathy exhibit delayed recovery from the block with ropivacaine, confirming animal studies. Clinical trial registration ClinicalTrials.gov, NCT01704612. PMID- 23348204 TI - Dedifferentiation in gastrointestinal stromal tumor to an anaplastic KIT-negative phenotype: a diagnostic pitfall: morphologic and molecular characterization of 8 cases occurring either de novo or after imatinib therapy. AB - Most gastrointestinal stromal tumors (GISTs) can be recognized by their monotonous cytologic features and overexpression of KIT oncoprotein. Altered morphology and loss of CD117 reactivity has been described previously after chronic imatinib treatment; however, this phenomenon has not been reported in imatinib-naive tumors. Eight patients with abrupt transition from a classic CD117 positive spindle cell GIST to an anaplastic CD117-negative tumor were investigated for underlying molecular mechanisms of tumor progression. Pathologic and molecular analysis was performed on each of the 2 components. Genomic DNA polymerase chain reaction for KIT, PDGFRA, BRAF, and KRAS hot spot mutations and fluorescence in situ hybridization for detecting KIT gene copy number alterations were performed. TP53 mutational analysis was performed in 5 cases. There were 7 men and 1 woman, with an age range of 23 to 65 years. Five of the primary tumors were located in the stomach, and 1 case each originated in the small bowel, colon, and rectum. In 3 patients, the dedifferentiated component occurred in the setting of imatinib resistance, whereas the remaining 5 occurred de novo. The dedifferentiated component had an anaplastic appearance, including 1 angiosarcomatous phenotype, with high mitotic activity and necrosis, and showed complete loss of CD117 (8/8) and CD34 (5/8) expression and de novo expression of either cytokeratin (4/8) or desmin (1/8). There was no difference in the KIT genotype between the 2 components. However, 2 imatinib-resistant tumors showed coexistence of KIT exon 11 and exon 13 mutations. Fluorescence in situ hybridization showed loss of 1 KIT gene in 3 cases and low-level amplification of KIT in 2 other cases in the CD117-negative component, compared with the CD117 positive area. TP53 mutation was identified in 1/5 cases tested, being present in both components. In summary, dedifferentiation in GIST may occur either de novo or after chronic imatinib exposure and can represent a diagnostic pitfall. This phenomenon is not related to additional KIT mutations, but might be secondary to genetic instability, either represented by loss of heterozygosity or low level of KIT amplification. PMID- 23348205 TI - Double-hit B-cell lymphomas with BCL6 and MYC translocations are aggressive, frequently extranodal lymphomas distinct from BCL2 double-hit B-cell lymphomas. AB - Double-hit (DH) lymphomas with MYC and either BCL2 (DH-BCL2/MYC) or BCL6 (DH BCL6/MYC) rearrangements are considered very aggressive, many of which are now included in the category B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) (DLBCL/BL). However, data describing the DH cases are largely based on DH BCL2/MYC cases. To better characterize DH-BCL6/MYC cases, the clinical, morphologic, phenotypic, and cytogenetic features of 6 cases from University of Pittsburgh Medical Center and 17 cases from the Mitelman database were reviewed. In the University of Pittsburgh Medical Center cases, the median age was 83 years (range, 51 to 89 y) with 5/6 DLBCL/BL cases and 1 large B-cell lymphoma, not otherwise specified. Five of 6 had a germinal center phenotype, 1/6 was BCL2(+), and the median Ki-67 score was 98% (35% to 100%). The Mitelman DH-BCL6/MYC cases included 13 aggressive B-cell lymphomas (diagnosed as DLBCL-5, BL-5, BL-like lymphomas-2, and primary effusion lymphoma-1) and 4 other lymphoid/plasmacytic neoplasms. The median cytogenetic complexity score was 2.5 (range, 0 to 14) in 14 evaluable mature aggressive lymphomas with an immunoglobulin gene partner for MYC in 9/14 and for BCL6 in 7/14 cases. Ten of 13 cases involved extranodal extramedullary sites at presentation, and the median survival for the 10 patients with large cell neoplasms or BL and with available follow-up data was 9 months. Thus, DH-BCL6/MYC lymphomas are aggressive, frequently involve extranodal sites, and are often DLBCL/BL with a germinal center phenotype. Unlike DH-BCL2/MYC lymphomas, however, they are more likely to be CD10(-) but IRF4/MUM-1(+) (P=0.03) and, more like BL, only infrequently express BCL2 (P<0.001), and are cytogenetically less complex (P<0.04). PMID- 23348206 TI - Reproducibility of the villous component and high-grade dysplasia in colorectal adenomas <1 cm: implications for endoscopic surveillance. AB - The presence of high-grade dysplasia (HGD) or villous component (VC) defines an advanced adenoma (AA) in patients with 1 or 2 adenomas <1 cm in size. Current consensus guidelines recommend that patients with AA undergo more intense postpolypectomy surveillance. In these clinical situations, the interobserver reliability in determining VC and HGD would play a major role in the credibility of these consensus guidelines. Therefore, the purpose of this study was to evaluate interobserver variability of VC and HGD in polyps <1 cm before and after the development of consensus criteria among gastrointestinal (GI) pathologists. Five GI pathologists independently evaluated 107 colorectal adenomas <1 cm, and classified them into tubular adenomas or adenomas with a VC (A-VC) and into low grade dysplasia or HGD. Then a consensus conference was held and consensus criteria for VC and HGD were developed by group review. The same set of 107 slides were rereviewed independently by the same 5 GI pathologists. Interobserver variability using kappa statistical analysis before and after the application of consensus criteria was assessed. A 1-sided z-test was used to determine whether kappa scores increased after the consensus conference. Interobserver agreement before and after the consensus conference was poor for assessment of A-VC, HGD, and AA. These data calls into question the validity of basing clinical decisions on this distinction. PMID- 23348207 TI - Embryonal rhabdomyosarcoma (botryoid type) of the uterine corpus and cervix in adult women: report of a case series and review of the literature. AB - In its classical form, embryonal rhabdomyosarcoma (ERMS, botryoid type) is a vaginal neoplasm occurring in infants and young girls and is often not considered in the differential diagnosis of uterine corpus and cervical spindle cell tumors in adult women. Clinicopathologic and immunohistochemical features of 25 cases of ERMS in women 20 years of age or older were analyzed. Patient age ranged from 20 to 89 years (mean, 44.4 y; median, 46 y), with 8 patients aged 20 to 39 years, 14 patients aged 40 to 59 years, and 3 patients older than 60 years of age. Tumors originated in the cervix in 20 cases and in the uterine corpus in 5. They were characterized by an edematous hypocellular spindle cell proliferation, typically with cellular condensation beneath epithelial surfaces (cambium layer), in which tightly packed hypercellular foci were scattered. Neoplastic cells had hyperchromatic nuclei and minimal cytoplasm, usually with delicate cytoplasmic processes. Occasionally, elongated or globular cells with eosinophilic cytoplasm (rhabdomyoblasts) were evident, but cytoplasmic cross-striations were only rarely identified. Apoptotic bodies and mitotic figures were usually identified in the hypercellular foci. Hemorrhage was common, often making recognition of the hypercellular foci difficult. Desmin and myogenin were coexpressed in 22 of 23 (95.6%) tumors evaluated. Proliferative activity, as assessed by Ki-67 expression, was notably elevated in all tumors evaluated, typically concentrated in the hypercellular foci. Estrogen and progesterone receptors were expressed focally in only 3 of 12 (25%) and 1 of 8 (12.5%) tumors evaluated, respectively. Follow-up was available in 7 cases. Five patients were alive without evidence of disease with follow-up of 3 to 8 years, and 1 patient was alive with disease at 5 months. One patient died at 5 months with pulmonary nodules, but it was not determined whether this was due to metastatic ERMS or the patient's known ductal breast carcinoma. ERMS has a broader clinical profile than classically expected and should be considered in the differential diagnosis of a uterine corpus or cervical spindle cell tumor, regardless of patient age. Recognition can be rendered difficult by the hypocellular background, which can suggest a benign polyp or low-grade tumor, and hemorrhage, which can obscure the characteristic hypercellular foci. Identification of hypercellular foci in which mitotic activity and apoptotic bodies are found, desmin and myogenin are coexpressed, proliferative activity is notably elevated, and hormone receptor expression is usually absent is very useful for establishing the diagnosis. PMID- 23348208 TI - Islet-1 is a sensitive but not entirely specific marker for pancreatic neuroendocrine neoplasms and their metastases. AB - Islet-1 (Isl1) is a transcription factor involved in the embryogenesis of islets of Langerhans. Immunohistochemically, Isl1 is a sensitive lineage-specific marker for pancreatic neuroendocrine neoplasms (NENs) and their metastases. Its specificity has not been documented, nor have large numbers of NENs from other parts of the gut or other organs been studied. We examined Isl1 expression in 203 primary NENs (gastroenteropancreatic, lung, breast, and ovarian neoplasms) and 40 hepatic NEN metastases (enteropancreatic and lung neoplasms) from known primaries. The correlation between Isl1 and CDX2 expression was studied using a tissue microarray containing 46 pancreatic NENs. Immunostaining for Isl1 and CDX2 was also performed in selected NENs from other sites. Isl1 was positive in 90% of pancreatic, 89% of duodenal, 100% of rectal, 38% of colonic, 14% of appendiceal, and 6% of ileal primaries. Isl1 was negative in all other NENs. Among metastatic neoplasms, 76% of pancreatic and 2 of 2 rectal NEN metastases were Isl1 positive, whereas all other tested metastases were negative. The overall sensitivity and specificity of Isl1 in identifying primary pancreatic NENs was 88% and 80%, respectively. Thirty-six of 46 pancreatic NENs in the tissue microarray were Isl1 positive; 4 were Isl1 negative but CDX2 positive. Our findings confirm that Isl1 is a sensitive marker of pancreatic origin in cases of metastatic NEN. However, Isl1 does not distinguish pancreatic NEN from duodenal and colorectal NEN, even when used in association with CDX2. PMID- 23348209 TI - A novel grading system for clear cell renal cell carcinoma incorporating tumor necrosis. AB - Grading of renal cell carcinoma (RCC) has prognostic significance, and there is recent consensus by the International Society of Urological Pathology (ISUP) that for clear cell and papillary RCC, grading should primarily be based on nucleolar prominence. Microscopic tumor necrosis also predicts outcome independent of tumor grading. This study was undertaken to assess whether the incorporation of microscopic tumor necrosis into the ISUP grading system provides survival information superior to ISUP grading alone. Data on 3017 patients treated surgically for clear cell RCC, 556 for papillary RCC, and 180 for chromophobe RCC were retrieved from the Mayo Clinic Registry. Median follow-up periods were 8.9, 9.7, and 8.5 years, respectively. Four proposed grades were defined: grade 1: ISUP grade 1+ISUP grade 2 without necrosis; grade 2: ISUP grade 2 with necrosis+ISUP grade 3 without necrosis; grade 3: ISUP grade 3 with necrosis+ISUP grade 4 without necrosis; grade 4: ISUP grade 4 with necrosis or sarcomatoid/rhabdoid tumors. There was a significant difference in survival between each of the grades for clear cell RCC, and the concordance index was superior to that of ISUP grading. The proposed grading system also outperformed the ISUP grading system when cases were stratified according to the TNM stage. Similar results were not obtained for papillary RCC or chromophobe RCC. We conclude that grading for clear cell RCC should be based on nucleolar prominence and necrosis, that ISUP grading should be used for papillary RCC, and that chromophobe RCC should not be graded. PMID- 23348210 TI - Biopsy-site changes in lung adenocarcinoma with prior core needle biopsy: a potential pitfall in the assessment of stromal invasion. AB - Although biopsy-site changes are known to cause diagnostic difficulties in thyroid and breast specimens, especially when assessing invasion, such changes have not been described in the lung. Assessment of invasion is important in lung cancers to distinguish bronchioloalveolar carcinoma [adenocarcinoma in situ (AIS)] from invasive adenocarcinoma. The aim of this study was to determine whether biopsy-site changes occur in the lung and whether they may impact this differential diagnosis. Lobectomy specimens were examined from patients whose previous core needle biopsies showed well-differentiated adenocarcinoma with a lepidic pattern. There were 26 adenocarcinomas, including 14 minimally invasive adenocarcinomas, 2 invasive well-differentiated adenocarcinomas, and 10 AISs. Biopsy-site changes were identified in 9 of 26 (35%), including 4 minimally invasive adenocarcinomas, 3 AISs, and 2 well-differentiated adenocarcinomas. The interval between biopsy and resection ranged from 12 to 45 days (mean, 26.1 d). The biopsy sites consisted of a linear scar composed of collagen and plump fibroblasts, ranging from 2.0 to 13.1 mm in length and 0.5 to 1.6 mm in width. Scattered lymphocytes and plasma cells were present in 8 cases, pigment-laden macrophages in 4, and foreign body giant cells in 3. Benign entrapped lung epithelium was present within the scar in all 9 and entrapped malignant epithelium in 4. Biopsy-site changes can be identified in a significant proportion of lung tumors after core needle biopsy. They need to be distinguished from tumor-related stromal reactions that are considered an indication of invasion and are important in the differentiation of AIS and invasive adenocarcinoma. PMID- 23348211 TI - TCR-gamma expression in primary cutaneous T-cell lymphomas. AB - Primary cutaneous gammadelta T-cell lymphomas (PCGD-TCLs) are considered a subgroup of aggressive cytotoxic T-cell lymphomas (CTCLs). We have taken advantage of a new, commercially available antibody that recognizes the T-cell receptor-gamma (TCR-gamma) subunit of the TCR in paraffin-embedded tissue. We have analyzed a series of 146 primary cutaneous T-cell lymphomas received for consultation or a second opinion in the CNIO Pathology Department. Cases were classified according to the World Health Organization 2008 classification as mycosis fungoides (MF; n=96), PCGD-TCLs (n=5), pagetoid reticulosis (n=6), CD30(+) primary cutaneous anaplastic large cell lymphomas (n=5), primary cutaneous CD8 aggressive epidermotropic CTCLs (n=3), primary cutaneous CTCL, not otherwise specified (n=4), and extranodal nasal-type NK/T-cell lymphomas primarily affecting the skin or subcutaneous tissue (n=11). Sixteen cases of the newly named lymphomatoid papulosis type D (LyP-D; n=16) were also included. In those cases positive for TCR-gamma, a further panel of 13 antibodies was used for analysis, including TIA-1, granzyme B, and perforin. Clinical and follow-up data were recorded in all cases. Twelve cases (8.2%) were positive for TCR-gamma, including 5 PCGD-TCLs, 2 MFs, and 5 LyP-Ds. All 5 PCGD-TCL patients and 1 MF patient died of the disease, whereas the other MF patient and all those with LyP D were alive. All cases expressed cytotoxic markers, were frequently CD3(+)/CD8(+), and tended to lose CD5 and CD7 expressions. Eight of 12 and 5 of 11 cases were CD30(+) and CD56(+), respectively. Interestingly, 5/12 TCR-gamma positive cases also expressed TCR-BF1. All cases analyzed were negative for Epstein-Barr virus-encoded RNA. In conclusion, TCR-gamma expression seems to be rare and is confined to cytotoxic primary cutaneous TCLs. Nevertheless, its expression is not exclusive to PCGD-TCLs, as TCR-gamma protein can be found in other CTCLs. Moreover, its expression does not seem to be associated with bad prognosis by itself, as it can be found in cases with good and bad outcomes. PMID- 23348212 TI - Renal medullary carcinoma: molecular, immunohistochemistry, and morphologic correlation. AB - Renal medullary carcinoma, a highly aggressive tumor mainly occurring in patients with sickle cell hemoglobinopathy, is characterized by advanced stage at the time of presentation and poor response to treatment. Currently, the pathogenesis of this tumor is not well understood. In this study, the clinicopathologic features and molecular changes of 15 renal medullary carcinoma cases were evaluated. These cases demonstrated male predominance (M:F=2:1) with a median age of 26 years. The tumors occurred predominantly in the right kidney with an average size of 5.9 cm. Immunohistochemistry analysis showed that the neoplastic cells were positive for CEA (7/8), AE1/3 (8/8), CAM5.2 (7/7), CK7 (5/5), CK20 (4/6), and vimentin (6/6). Absence of SMARCB1 protein expression in tumor cells was demonstrated in all of the 7 cases analyzed. By polymerase chain reaction-based microsatellite analysis, loss of heterozygosity of SMARCB1 was identified in 9 of 10 cases. These data suggest that inactivation of SMARCB1 may play a role in the pathogenesis of renal medullary carcinoma. PMID- 23348213 TI - Yolk sac tumor with a prominent polyvesicular vitelline pattern: a report of three cases. AB - We report 3 cases of the rare polyvesicular vitelline variant of ovarian yolk sac tumor (YST). The patients were 23, 29, and 43 years old, and all presented with large unilateral adnexal masses confined to the ovary. One tumor was predominantly cystic, and the other 2 had prominent cystic components; all 3 also had solid components. Microscopic examination of the cystic regions showed dilated cysts that largely effaced the stroma resulting in a honeycomb-like appearance. The solid foci were characterized predominantly by small tubules in a fibrous stroma; the tubules exhibited variably conspicuous cystic dilatation to merge with the microcystic appearance. The tumor cells varied from large and primitive-appearing to flattened and deceptively innocuous when lining large cysts. They were immunoreactive for alpha-fetoprotein and glypican-3. Non polyvesicular vitelline components of YST were present focally in 2 cases (hepatoid in one, reticular and endometrioid like in the second). Two patients are disease free after 20 and 26 years, respectively; disease-free follow-up is of short duration in the third case (2 years). The good long-term outcome in 2 cases supports prior evidence that suggests that the natural history of this form of YST may be more indolent than conventional forms of the tumor. PMID- 23348214 TI - Basic values for heart and respiratory rates during different sleep stages in healthy infants. AB - The aim of this study was to systematically register data for respiratory and heart rates (RR and HR, respectively) during different sleep stages [active (AS, i.e., rapid eye movement) and quiet (QS, i.e., non-rapid eye movement) sleep] and age in a large number of healthy infants (277) during the first year of life to simplify polysomnography. The reference values in this age group differ significantly between the number of patients and age at time of investigation. According to strict inclusion and exclusion criteria, the measurement of polysomnography included HR (beats per minute, or bpm), RR (breaths per minute, or breaths/min), brain waves, SO2, sound, and video. Data recording and evaluation occurred via Alice 3(r)/3.5(r)(Respironics(r)), classification into AS and QS sleep according to maturity. For RR, the 5th-95th percentiles during AS decreased from 25.8-47.7 breaths/min (1st month) to 17.8-27.7 breaths/min (>9 months). During QS, RR ranged from 27.4-51.5 breaths/min (1st month) to 17.8-29.2 breaths/min (>9 months). HR decreased during AS from 118.3-150.6 bpm (1st month) to 100.9-126.4 bpm (>9 months). During QS, HR decreased from 116.0-149.9 bpm (1st month) to 93.7-119.8 bpm (>9 months). The mean HR and RR significantly decreased with age in both sleep stages (p<0.05). The mean HR is significantly lower during QS compared with AS (p<0.05). Our data may serve as basic values for HR and RR in different sleep stages during the first year of life. PMID- 23348215 TI - Novel electrode configuration for highly linear impedance pneumography. AB - Impedance pneumography (IP) is a non-invasive respiration measurement technique. Emerging applications of IP in respiratory medicine use the measured signal to monitor pulmonary flow and volume parameters related to airway obstruction during tidal breathing (TB). This requires a high impedance change (DeltaZ)-to-lung volume change (DeltaV) linearity. Four potential electrode configurations were tested on 10 healthy subjects. Only the novel configuration where the electrodes were placed in both the thorax and the arms yielded a highly linear DeltaZ/DeltaV in all subjects. The presented electrode configuration may expand the clinical use of IP from the conventional tidal volume estimation to flow measurement. PMID- 23348216 TI - Brainstem dysgenesis during the neonatal period: diagnosis and management. AB - AIMS: To report our neonatal management experience in patients who received a diagnosis of brainstem dysgenesis (BSD). PATIENTS AND METHODS: This study retrospectively reviewed the medical records of 15 neonates with BSD diagnosed between 1984 and 2011. Data on the perinatal period, physical examination, laboratory findings, and management by systems were systematically analyzed. RESULTS: All cases were sporadic. Cocaine abuse and misoprostol use were recorded in two pregnancies. The reason for admission was prematurity (2 of 15), respiratory distress (8 of 15), gastroschisis (1 of 15), and abnormal neurological examination (4 of 15). Clinically, the most commonly affected cranial nerves were the 7th (13 of 15), 9th (11 of 15), 10th (8 of 15), 5th (7 of 15), 12th (7 of 15), 6th (3 of 15), 4th (1 of 15), and 3rd (1 of 15). Five patients required positive pressure ventilation during delivery room resuscitation, three had difficult airways, and two needed tracheostomy during admission. Most patients required nasogastric tube feeding shortly after birth, and four patients had a gastrostomy on discharge. Two patients died of respiratory and cardiac failure. Electromyography and nerve conduction velocity were used to exclude generalized neuromuscular disorders, and in conjunction with other neurophysiological and gastrointestinal tract studies, helped uncover the extent of brainstem involvement in most cases. Cranial magnetic resonance imaging supported the diagnosis in more than half of the patients. CONCLUSIONS: Early diagnosis of BSD is mainly clinical, difficult to establish unless suspected, and crucial to prevent complications. Neonatal care of patients with BSD requires a comprehensive approach that must take into consideration the etiological, anatomical, and pathogenic aspects contributing to the clinical manifestations of this disorder. Care should be provided by multidisciplinary teams, in which neonatologists, pediatric neurologists, nutritionists, physical therapists, and other professionals participate, depending on the associated morbidity in order to improve its management and prognosis. PMID- 23348217 TI - Parathyroid adenoma presented with multiple brown tumors and nephrocalcinosis. PMID- 23348218 TI - Bupropion can close KATP channel and induce insulin secretion. AB - Recently, a case of newborn infant with transient hyperinsulinism has been reported. This infant was reported to be free from typical perinatal risk factors of hyperinsulinism except for the fact that the mother of the baby was receiving the antidepressant bupropion during her pregnancy. However, the mother did not experience hyperinsulinism and, so far, there are no reports about the pharmacological mechanism of bupropion causing hyperinsulinemia. In this study, bupropion was shown to inhibit KATP channel activity in pancreatic beta-cell membranes and induce insulin secretion in relatively high concentration. This study shows, for the first time, that bupropion has a direct electrophysiological action on pancreatic beta-cells and can cause insulin secretion and also highlights the risk of using bupropion during pregnancy. PMID- 23348219 TI - alpha2-HS glycoprotein is an essential component of cryoglobulin associated with chronic hepatitis C. PMID- 23348220 TI - Attribution of risk for coronary heart disease in a vulnerable immigrant population: a survey study. AB - BACKGROUND: Coronary heart disease (CHD) is a common and costly condition and is increasing at a higher rate among Asian Indians than among other ethnic groups. An understanding of how Asian Indians perceive their risk is important for health providers to develop culturally appropriate programs to raise awareness of the risk of CHD. OBJECTIVE: The aim of this survey was to investigate the attribution of risk factors for CHD among the Asian Indian community in Australia. METHODS: Asian Indian community leaders were recruited to provide their views of how their community perceived the risk of CHD. An online survey collected demographic data and information from the Illness Perception Questionnaire-Revised, which measures 6 domains of illness perception: timeline acute/chronic, consequences, emotional impact, personal control, treatment efficacy, and illness comprehension. RESULTS: An 84% response rate (n = 49) was achieved from Asian Indian community leaders. Heart disease and cancer were considered to be the illnesses of major concern. Participants indicated that people in their community perceived hereditary factors (90%), hypertension, stress or worry (84%), and aging (86%) as the major cause of their illnesses. Smoking, high blood pressure, and cholesterol were identified as being major risk factors for CHD. CONCLUSIONS: These data suggest that as well as strategies to address risk factors such as diet and exercise, stress management is an important issue to consider in developing community-based programs. PMID- 23348221 TI - Measuring self-care in patients with hypertension: a systematic review of literature. AB - BACKGROUND: High blood pressure (HBP) self-care is critical for the control of HBP. Adequate measurement of HBP self-care is a necessary first step toward ameliorating the global pandemic of HBP. OBJECTIVE: The aims of this study were to identify, describe, and critique existing HBP self-care instruments. The degree of adequacy of these instruments was evaluated against well-established behavioral guidelines for HBP care. METHODS: This review was limited to articles published in English before October 2012. In addition, the following criteria were used: (1) the study described the validity and/or the reliability of a self care/self-management instrument and (2) the study targeted patients with hypertension. Electronic database searches identified 1701 potentially relevant articles. Two authors reviewed the titles and the abstracts of all the retrieved articles independently. On the basis of the inclusion and the exclusion criteria, as well as cross-referencing, 29 articles were included in this review. RESULTS: From the 29 articles, 19 unique HBP self-care instruments were identified (some were modified or translated versions of an original measure). Medication taking, a key domain of HBP self-care, was the main focus of 12 of the 19 instruments. Other key domains of HBP self-care were often missing or omitted. Seven instruments measured multiple dimensions of self-care; however, these either failed to capture all the main HBP self-care domains or had poor psychometric profiles. Nineteen of the 29 articles reported both validity and reliability, with varying degrees of rigor. CONCLUSIONS: The current assessment tools do not capture all the critical elements of HBP self-care. The few instruments that attempted to measure the multiple behavioral dimensions of HBP self-care failed to report adequate levels of psychometric properties of those domains because of their incompleteness. Challenges remain in translating the HBP self-care guidelines into effective intervention and relevant assessment tools. Developing a valid and reliable instrument that captures the multidimensional nature of HBP self-care is urgently needed. PMID- 23348222 TI - The impact of technology dependency on device acceptance and quality of life in persons with implantable cardioverter defibrillators. AB - BACKGROUND: The impact of implantable cardioverter defibrillator (ICD) technology on the quality of life (QOL) experienced by recipients has been a major focus of recent research. Numerous studies have found psychological distress to be important in determining QOL in persons receiving ICDs, yet the source of psychological distress is not well understood. OBJECTIVE: The aim of this study was to determine the impact of technology dependency on psychological outcomes in ICD recipients. METHODS: With the use of a cross-sectional design, 161 ICD recipients from 1 device clinic were mailed self-administered questionnaires, including the Dependency on Technology Scale, Brief Illness Perception Questionnaire, Florida Shock Anxiety Scale, Florida Patient Acceptance Survey, and Short Form-12 (SF-12). Hierarchical multiple regressions and analyses of variance were performed. RESULTS: The final sample size was 101 participants. Mean (SD) age was 68 (13) years; 72% of the participants were men, 99% were white, and 30% reported receiving a shock(s). A total of 80% reported positive attitudes toward technology dependency; 14%, neutral; and 6%, negative (Dependency on Technology Scale). Illness perceptions were positive (Brief Illness Perception Questionnaire; mean[SD], 34.5 [12.6]), shock anxiety was elevated (Florida Shock Anxiety Scale; mean [SD], 16.5 [6.7]), and device acceptance was good (Florida Patient Acceptance Survey; mean [SD], 74.9 [17.0]). Physical health QOL was low (SF-12; mean [SD], 38.6 [11.3]) and mental health QOL was moderate (SF-12; mean [SD], 50.6 [10.0]). Attitudes toward technology dependency significantly accounted for the variance seen in device acceptance and mental health QOL beyond age, gender, number of shocks, illness perceptions, and shock anxiety by 5.7% (P = .001) and 3.3% (P = .04), respectively. Significant differences were seen in device acceptance between those with negative and neutral attitudes (P = .001) and those with negative and positive attitudes (P < .001) and in shock anxiety and mental health QOL between those with negative and those with positive attitudes (P < .001). CONCLUSIONS: Attitudes toward technology dependency is significantly associated with psychological outcomes and may explain the psychological distress in some ICD recipients. Degree of positivity toward technology dependency influences these outcomes. Research evaluating attitudes toward technology dependency and testing of interventions focusing on these attitudes is warranted. PMID- 23348223 TI - Transitional care programs improve outcomes for heart failure patients: an integrative review. AB - BACKGROUND: Individuals with heart failure are frequently rehospitalized owing to a lack of knowledge concerning how to perform their self-care and when to inform their healthcare provider of worsening symptoms. Because there are an overwhelming number of hospital readmissions for individuals with heart failure, efforts are underway to discover how they can be supported and educated during their hospitalization and subsequently followed by a nurse after discharge for continued education and support. PURPOSE: The purpose of this integrative review was to critically examine the interventions, quality of life, and readmission rates of individuals with heart failure who are enrolled in a transitional care program. The second aim was to examine the cost-effectiveness of nurse-led transitional care programs. CONCLUSIONS: The results of this integrative review (n = 20) showed that transitional care programs for individuals with heart failure can increase a patient's quality of life and decrease the number of readmissions and the overall cost of care. The types of interventions that were most successful in decreasing readmissions used home visits alone or in combination with telephone calls. There is a need for nurse researchers to address gaps in transitional care for heart failure patients by performing studies with larger randomized clinical trials and measuring outcomes such as readmissions at regular intervals over the study period. CLINICAL IMPLICATIONS: The Patient Protection and Affordable Care Act will change reimbursement for heart failure readmissions and presents opportunities for healthcare teams to build transitional care programs for patients with conditions such as heart failure. This integrative review can be used to determine effective intervention strategies for transitional care programs and highlights the gaps in research. Healthcare teams that use these programs within their practice may increase continuity of care and quality of life and decrease readmissions and healthcare costs for individuals with heart failure. PMID- 23348224 TI - The endothelial protein C receptor and activated protein C play a limited role in host defense during experimental tuberculosis. AB - The protein C (PC) system is an important regulator of both coagulation and inflammation. Activated PC (APC), together with its receptor the endothelial protein C receptor (EPCR), has anticoagulant and anti-inflammatory properties. During tuberculosis (TB), a devastating chronic pulmonary disease caused by Mycobacterium (M.) tuberculosis, both a local inflammatory reaction characterised by the recruitment of mainly mononuclear cells and the formation of pulmonary granulomas as well as activation of coagulation occurs as part of the host immune response. We investigated the role of EPCR and APC in a mouse model of TBusing mice overexpressing EPCR (Tie2-EPCR), mice deficient for EPCR (EPCR-/-), mice treated with APC-inhibiting antibodies and mice overexpressing APC (APChigh) and compared them with wild-type (WT) mice. Blood and organs were harvested to quantify bacterial loads, cellular influxes, cytokines, histopathology and coagulation parameters. Additionally observation studies were performed. Lung EPCR expression was upregulated during experimental TB. No significant differences in bacterial growth were seen between WT and Tie2-EPCR mice. However, Tie2-EPCR mice had decreased pulmonary coagulation activation, displayed an increased influx of macrophages 2 and 6 weeks after infection, but no increase in other proinflammatory markers. On the other hand, in EPCR-/--mice coagulation activation was decreased 6 weeks post-infection, with little impact on other inflammation markers. APC-overexpression or treatment with anti-(A)PC antibodies displayed minimal effects during experimental TB. In conclusion, EPCR and APC play a limited role in the host response during experimental pulmonary TB. PMID- 23348225 TI - The Gly-Ala repeat modulates the interaction of Epstein-Barr virus nuclear antigen-1 with cellular chromatin. AB - The Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA1) plays a pivotal role in EBV infection by anchoring the viral episome to cellular DNA, which regulates replication and partitioning in dividing cells. Here, we have used fluorescence recovery after photobleaching (FRAP) and fluorescence loss in photobleaching (FLIP) techniques to study the interaction of EBNA1 with cellular chromatin in interphase and mitosis. This analysis revealed that while EBNA1 is highly mobile in both conditions, mobility is significantly reduced in mitosis when an immobile fraction is also detected. The N-terminal chromatin-targeting module of EBNA1 includes two Gly-Arg rich domains (GR1 and GR2) separated by a Gly-Ala repeat (GAr) of variable length. Using a set of deletion mutants and GFP-fusion reporters, we found that the GR domains cooperatively determine the mobility of EBNA1, whereas mobility is increased by the interposed GAr in a length-dependent manner. These findings highlight a previously unrecognized property of the interaction of EBNA1 with cellular chromatin that may fine-tune its function in the maintenance of viral latency. PMID- 23348226 TI - 2,3,6-Trisubstituted quinoxaline derivative, a small molecule inhibitor of the Wnt/beta-catenin signaling pathway, suppresses cell proliferation and enhances radiosensitivity in A549/Wnt2 cells. AB - GDK-100017, a 2,3,6-trisubstituted quinoxaline derivative, reduced beta-catenin-T cell factor/lymphoid enhancer factor (TCF/LEF)-dependent transcriptional activity and inhibited cell proliferation in a dose-dependent manner with an IC50 value of about 10 MUM in A549/Wnt2 cells. GDK-100017 down-regulated the expression of Wnt/beta-catenin pathway target genes such as cyclin D1 and Dkk1 but not c-myc or survivin. GDK-100017 inhibited cell proliferation by arresting the cell cycle in the G1 phase not only in A549/wnt2 cells but also in SW480 colon cancer cells. In addition to its wnt signaling inhibitory properties, GDK-100017 also enhanced the radiosensitivity of the A549 human NSCLC line. These results suggest that GDK 100017 possesses potential anti-cancer activity by inhibiting the Wnt/beta catenin signal pathway, blocking the beta-catenin-TCF/LEF interaction, and enhancing radiosensitivity. PMID- 23348227 TI - Lancemaside A inhibits microglial activation via modulation of JNK signaling pathway. AB - Microglial activation plays an important role in neurodegenerative diseases. Thus, controlling microglial activation is considered to be a promising therapeutic target for neurodegenerative diseases. In the present study, we found that lancemaside A, a triterpenoid saponin isolated from Codonopsislanceolata, inhibited iNOS and proinflammatory cytokines in LPS-stimulated BV2 microglial cells. By analyzing molecular mechanisms underlying the anti-inflammatory effects of lancemaside A, we found that lancemaside A selectively inhibited LPS-induced JNK phosphorylation among the three types of MAP kinases. A JNK-specific inhibitor, SP600125, like lancemaside A, significantly inhibited not only NO, TNF alpha, and IL-6 productions, but also NF-kappaB and AP-1 activities, suggesting that JNK inhibition is largely involved in the anti-inflammatory mechanism of lancemaside A. Interestingly, both the lancemaside A and SP600125 inhibited ROS production by suppressing the expression and/or phosphorylation of NADPH oxidase subunit proteins, such as p47(phox), p67(phox), and gp91(phox). The antioxidant effects of lancemaside A and SP600125 appear to be related with an increase of hemeoxygenase-1 expression by both agents. Finally, we demonstrated the neuroprotective effects of lancemaside A and SP600125 in microglia-neuron coculture systems. Collectively, our data suggest that JNK pathway plays a key role mediating anti-inflammatory effects of lancemaside A in LPS-stimulated microglia. PMID- 23348228 TI - Fucoidan inhibits activation and receptor binding of transforming growth factor beta1. AB - Fucoidan, a sulfated, fucose-rich polysaccharide isolated from marine brown algae, has antifibrotic effects. We investigated the biologic effects of interactions of fucoidan with transforming growth factor-beta1 (TGF-beta1) and latent TGF-beta1 (LTGF-beta1). TGF-beta1 bound to fucoidan was unable to interact with its receptor. In agreement with this, fucoidan attenuated the cellular effect of TGF-beta1 as measured by phosphorylation of Smad2. Binding of fucoidan rendered LTGF-beta1 resistant to activation as follows. Fucoidan inhibited furin like proprotein convertase-mediated activation of platelet LTGF-beta1 without suppression of the enzyme. In addition, acid- or heat-activation of small recombinant LTGF-beta1 and acid-activation of large LTGF-beta1 in cultured cell supernatant were also inhibited by fucoidan. Fucoidan is a mixture of polysaccharides of different sizes. As molecular weight of fucoidan increases, it had more inhibitory effects on TGF-beta1 and LTGF-beta1. In conclusion, inhibitions of LTGF-beta1 activation and TGF-beta1 receptor binding by fucoidan may in part account for its antifibrotic effects. PMID- 23348229 TI - Outcomes of total hip arthroplasty in the octogenarian population. AB - BACKGROUND: The outcomes of total hip arthroplasty (THA) in the elderly population are uncertain. With the rapid expansion of this population group, this study aims to determine whether increasing age affects the outcomes of THA by utilising the largest patient cohort and follow-up period within the literature. PATIENTS AND METHODS: All patients of 80 years and over who underwent primary THA between 1994 and 2004 at the authors' institution were compared to a cohort aged under 80 with the same diagnoses and during the same time period. Mean follow-up time was 5.9 years with a select group being reviewed at year 10. RESULTS: Pain scores were comparable at year five, whilst mean Harris hip scores were significantly lower in the octogenarians. Median hospital stay was three days longer in the elderly group. Complication rates were also higher (38.1% cf 28.7%) however fewer cases of revision were noted (1.4% cf 3.8%). Patient satisfaction was comparable between groups. CONCLUSION: This study suggests pain improvement, low revision rates and high satisfaction are sufficient to justify THA in the elderly population. PMID- 23348230 TI - [The Joint Annual Congress of "DGVS"/"DGAV" 2011 - Selected Topics Outlined by Organiser & Participant, Gastroenterologist & Abdominal Surgeon]. PMID- 23348231 TI - [Anatomy of the oesophagogastric junction]. AB - The oesophagogastric junction is increasingly gaining importance due to the difficulty of allocating adenocarcinomas that develop in this region to the stomach or the oesophagus. The present article gives an overview of important anatomic structures in this area, which are responsible for the closure of the distal oesophagus and the entry of the stomach. Moreover, the structures of the mucosa in healthy and under pathological conditions (e.g., oesophagogastric reflux disease and infection with Helicobacter pylori) are discussed in this article. PMID- 23348233 TI - Drugs for epilepsy. PMID- 23348232 TI - Toll-like receptor 3 stimulation causes corticosteroid-refractory airway neutrophilia and hyperresponsiveness in mice. AB - BACKGROUND: RNA virus infections, such as rhinovirus and respiratory syncytial virus, induce exacerbations in patients with COPD and asthma, and the inflammation is corticosteroid refractory. The main aim of this study is to establish a murine model induced by a Toll-like receptor 3 (TLR3) agonist, an RNA virus mimic, and investigate the response to corticosteroid. METHODS: A/J mice were given polyinosinic-polycytidylic acid (poly[I:C]), a TLR3 agonist, intranasally, in the presence or absence of cigarette smoke exposure. Inflammatory cell accumulation and C-X-C motif chemokine (CXCL) 1, interferon (IFN), and CXCL10 production in BAL fluid (BALF) were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively, and airway hyperresponsiveness (AHR) to histamine/methacholine was determined by a two chambered, double-flow plethysmography system. BALB/c and C57BL/6J mice were also used for comparisons. RESULTS: Intranasal treatment of poly(I:C) significantly induced airway neutrophilia; production of CXCL1, IFN-beta, and CXCL10; and necrotic cell accumulation in BALF. It also increased airway responsiveness to histamine or methacholine inhalation. This poly(I:C)-dependent airway inflammation and AHR was not inhibited by the corticosteroid fluticasone propionate (FP) (up to 0.5 mg/mL intranasal), although FP strongly inhibited lipopolysaccharide (TLR4 agonist)-induced airway neutrophilia. Furthermore, cigarette smoke exposure significantly increased TLR3 expression in murine lung tissue and exacerbated poly(I:C)-induced neutrophilia and AHR. CONCLUSIONS: These results suggest that TLR3 stimulation is involved in corticosteroid-refractory airway inflammation in lung, which is enhanced by cigarette smoking, and this may provide a model for understanding virus-induced exacerbations in COPD and their therapy. PMID- 23348234 TI - Understanding the effect of side groups in ionic liquids on carbon-capture properties: a combined experimental and theoretical effort. AB - Ionic liquids are an emerging class of materials with applications in a variety of fields. Steady progress has been made in the creation of ionic liquids tailored to specific applications. However, the understanding of the underlying structure-property relationships has been slower to develop. As a step in the effort to alleviate this deficiency, the influence of side groups on ionic liquid properties has been studied through an integrated approach utilizing synthesis, experimental determination of properties, and simulation techniques. To achieve this goal, a classical force field in the framework of OPLS/Amber force fields has been developed to predict ionic liquid properties accurately. Cu(I)-catalyzed click chemistry was employed to synthesize triazolium-based ionic liquids with diverse side groups. Values of densities were predicted within 3% of experimental values, whereas self-diffusion coefficients were underestimated by about an order of magnitude though the trends were in excellent agreement, the activation energy calculated in simulation correlates well with experimental values. The predicted Henry coefficient for CO(2) solubility reproduced the experimentally observed trends. This study highlights the importance of integrating experimental and computational approaches in property prediction and materials development, which is not only useful in the development of ionic liquids for CO(2) capture but has application in many technological fields. PMID- 23348235 TI - A novel coating concept for ileo-colonic drug targeting: proof of concept in humans using scintigraphy. AB - The in vivo proof of concept of a novel double-coating system, based on enteric polymers, which accelerated drug release in the ileo-colonic region, was investigated in humans. Prednisolone tablets were coated with a double-coating formulation by applying an inner layer composed of EUDRAGIT S neutralised to pH 8.0 and a buffer salt (10% KH2PO4), which was overcoated with layer of standard EUDRAGIT S organic solution. For comparison, a single coating system was produced by applying the same amount of EUDRAGIT S organic solution on the tablet cores. Dissolution tests on the tablets were carried out using USP II apparatus in 0.1N HCl for 2 h and subsequently in pH 7.4 Krebs bicarbonate buffer. For comparison, tablets were also tested under the USP method established for modified release mesalamine formulations. Ten fasted volunteers received the double-coated and single-coated tablets in a two-way crossover study. The formulations were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. There was no drug release from the single-coated or double-coated tablets in 0.1N HCl for 2h. The single-coated tablets showed slow release in subsequent Krebs bicarbonate buffer with a lag time of 120 min, while in contrast drug release from the double-coated tablets was initiated at 60 min. In contrast, using the USP dissolution method, normally employed for modified release mesalamine products, no discrimination was attained. The in vivo disintegration of the single-coated EUDRAGIT S tablets in the large intestine was erratic. Furthermore, in 2 volunteers, the single-coated tablet was voided intact. Double-coated tablets disintegrated in a more consistent way, mainly in the ileo-caecal junction or terminal ileum. The accelerated in vivo disintegration of the double-coating EUDRAGIT S system can overcome the limitations of conventional enteric coatings targeting the colon and avoid the pass-through of intact tablets. Moreover, Krebs bicarbonate buffer has the ability to discriminate between formulations designed to target the ileo-colonic region. PMID- 23348236 TI - Hemorrhagic ascites. Clinical presentation and outcomes in patients with cirrhosis. AB - BACKGROUND & AIMS: Hemorrhagic ascites can pose diagnostic and therapeutic dilemmas in patients with cirrhosis. We aimed at exploring the characteristics and outcomes of patients with cirrhosis and hemorrhagic ascites. METHODS: The records of all patients with cirrhosis and ascites, who underwent paracentesis between 2003 and 2010 at Parkland Memorial Hospital, were retrospectively reviewed. Hemorrhagic ascites was defined as an ascitic fluid red blood cell (RBC) count >= 10,000/MUl. We compared each patient with 3 age- and gender matched controls (cirrhotic patients with ascites and an ascitic RBC count <10,000/MUl). Survival curves were generated using Kaplan-Meier plots and compared using the log rank test. RESULTS: 1113 cirrhotic patients underwent paracentesis; 214 (19%) had hemorrhagic ascites. Patients with hemorrhagic ascites had higher rates of spontaneous bacterial peritonitis (p <0.001), acute kidney injury (AKI, p <0.001), and were more likely to require intensive care unit (ICU)-level care (p=0.01) compared to patients without hemorrhagic ascites. Patients with hemorrhagic ascites had a higher mortality than controls at one month (87% vs. 72%), 1 year (72% vs. 50%) and 3 years (61% vs. 41%). Using multivariate regression analysis, hemorrhagic ascites was also an independent predictor of mortality (HR 1.34, 95% CI 1.07-1.68) after adjusting for the model for end-stage liver disease score (HR 1.04, 1.03-1.05), ICU-level care (HR 2.02, 1.63-2.51) and presence of hepatocellular carcinoma (HR 2.27, 1.61-3.19). CONCLUSIONS: Patients with hemorrhagic ascites had a significantly higher rate of ICU care, AKI, and mortality than patients with portal hypertension and ascites but without hemorrhagic ascites. We conclude that hemorrhagic ascites is a marker of advanced liver disease and poor outcome. PMID- 23348237 TI - HBV core promoter mutations promote cellular proliferation through E2F1-mediated upregulation of S-phase kinase-associated protein 2 transcription. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV) core promoter (CP) mutations have been associated with an increased risk of hepatocellular carcinoma (HCC) in clinical studies. We previously reported that a combination of CP mutations seen in HCC patients, expressed in HBx gene, increased SKP2 (S-phase kinase-associated protein 2) expression, thereby promoting cellular proliferation. Here, we investigate the possible mechanisms by which CP mutations upregulate SKP2. METHODS: We used immunoblotting and ATPlite assay to validate the effect of CP mutations in full-length HBV genome on cell cycle regulator levels and cell proliferation. Activation of SKP2 mRNA was assessed by quantitative real-time PCR in primary human hepatocytes (PHH) and HCC cell lines. Effect of CP mutations on SKP2 promoter activity was determined by luciferase assay. Target regulation of E2F1 on SKP2 was analyzed by siRNAs. RESULTS: CP mutations in full-length HBV genome upregulated SKP2 expression, thereby downregulating cell cycle inhibitors and accelerating cellular proliferation. CP mutations enhanced SKP2 promoter activity but had no effect on SKP2 protein stability. Mapping of the SKP2 promoter identified a region necessary for activation by CP mutations that contains an E2F1 response element. Knocking down E2F1 reduced the effects of CP mutations on SKP2 and cellular proliferation. The effect of CP mutations on E2F1 might be mediated through hyperphosphorylation of RB. CONCLUSIONS: HBV CP mutations enhance SKP2 transcription by activating the E2F1 transcription factor and in turn downregulate cell cycle inhibitors, thus providing a potential mechanism for an association between CP mutations and HCC. PMID- 23348238 TI - Molecular and metabolic changes in human liver clear cell foci resemble the alterations occurring in rat hepatocarcinogenesis. AB - BACKGROUND & AIMS: Activation of the AKT/mTOR and Ras/MAPK pathways and the lipogenic phenotype occurs in both a rat model of insulin-induced hepatocarcinogenesis and in human hepatocellular carcinoma (HCC). In the rat model, activation of these pathways is evident within the earliest morphologic detectable alterations, i.e., clear cell foci (CCF) of altered hepatocytes. CCF have also been described in the human liver, but molecular and metabolic alterations within these foci remain to be determined. METHODS: A collection of human liver specimens was examined using electron microscopy, histology, enzyme- and immunohistochemistry, and molecular analysis. Human data were compared to rat preneoplastic CCF and HCC induced by N-nitrosomorpholine administration. RESULTS: CCF occurred in ~33% of extrafocal tissues of human non-cirrhotic livers. Electron microscopy showed massive glycogen storage within CCF, largely due to the reduced activity of the glycogenolytic enzyme glucose-6-phosphatase. Hepatocytes in CCF overexpressed the insulin receptor and glucose transporter proteins. AKT/mTOR and Ras/MAPK pathways as well as enzymes of glycolysis, de novo lipogenesis, beta-oxidation, and cholesterol synthesis were upregulated, both in human CCF, and in CCF and HCC of N-nitrosomorpholine-treated rats. The Ki 67 proliferation index was 2-fold higher in human CCF than in extrafocal tissue. CONCLUSIONS: The high degree of similarity between human CCF and pre-neoplastic lesions from experimental models of hepatocarcinogenesis in terms of morphologic, molecular and metabolic features suggests a low-grade dysplastic nature of these lesions in human non-cirrhotic livers. PMID- 23348239 TI - Reply to: "New onset diabetes after transplantation: a type 1.5 diabetes or latent autoimmune diabetes of adults?". PMID- 23348240 TI - Template-free synthesis of 3D Nb(3)O(7)F hierarchical nanostructures and enhanced photocatalytic activities. AB - Single-crystalline niobium oxide fluoride (Nb(3)O(7)F) hierarchical nanostructures are firstly prepared via a facile hydrothermal method without using any template or surfactant. The results of scanning electron microscopy and transmission electron microscopy showed that the hierarchical morphology of Nb(3)O(7)F could be effectively controlled by adjusting the reaction time. Ultraviolet-visible spectra showed that such nanostructures have a narrow absorption peak at around 400 nm compared to Nb(2)O(5). Based on the first principles plane-wave ultrasoft pseudo potential (USPP) method, the crystal structures of Nb(3)O(7)F was optimally calculated for the total density of states (TDOS) and the partial density of states (PDOS) of Nb, O and F atoms. According to the observations of architectures formation, a possible growth mechanism was proposed to explain the transformation of nanoparticles to hierarchical nanostructures via an Ostwald ripening mechanism followed by self-assembly. In particular, the excellent photocatalytic activity of the Nb(3)O(7)F hierarchical nanostructures was confirmed by photodegradation of methylene blue, methyl orange and rhodamine B molecules. PMID- 23348241 TI - Structure of the O-polysaccharide of Edwardsiella tarda PCM 1150 containing an amide of D-glucuronic acid with L-alanine. AB - Mild acid degradation of the lipopolysaccharide of Edwardsiella tarda PCM 1150 afforded an O-polysaccharide, which was isolated by GPC on Sephadex G-50 and studied by sugar and methylation analyses along with 1D and 2D 1H and 13C NMR spectroscopies, including experiments performed in a 9:1 H2O/D2O mixture to detect NH protons and their correlations with CH protons. The O-polysaccharide was found to contain an amide of d-glucuronic acid with l-alanine (d-GlcA6Ala) and the following structure of the branched hexasaccharide repeating unit was established: -->4)-beta-D-GlepA6Ala-(1-->4)-alpha-L-Fucp-(1-->4)-alpha-D-Glcp-(1- >4)-alpha-D-Quip-(1-->3)-beta-D-GlcpNAc-(1-->3<--1alpha-D-GalpNAc. PMID- 23348242 TI - Catalytic dehydration of fructose to 5-hydroxymethylfurfural over Nb2O5 catalyst in organic solvent. AB - The catalytic dehydration of fructose to 5-hydroxymethylfurfural (HMF) in DMSO was performed over Nb2O5 derived from calcination of niobic acid at various temperatures (300-700 degrees C). The catalysts were characterized by powder X ray diffraction, N2 physical adsorption, temperature-programed desorption of NH3, n-butylamine titration using Hammett indicators, infrared spectroscopy of adsorbed pyridine, and X-ray photoelectron spectroscopy. It was found that both catalytic activity and surface acid sites decrease with increasing calcination temperatures. The Nb2O5 derived from calcination of niobic acid at 400 degrees C reveals the maximum yield of HMF among all the catalysts, although the amount of acid sites on the catalyst is lower than that on the sample calcined at 300 degrees C. The results suggest that the presence of larger amounts of strong acid sites on the surface of the Nb2O5 calcined at 300 degrees C may promote side reactions. The Nb2O5 prepared at 400 degrees C shows 100% fructose conversion with 86.2% HMF yield in DMSO at 120 degrees C after 2 h. The activity of the catalyst decreases gradually during recycle because of coke deposition; however, it can be fully recovered by calcination at 400 degrees C for 2 h, suggesting that this catalyst is of significance for practical applications. PMID- 23348243 TI - Family history of VTE: an easy tool to score the individual risk. PMID- 23348244 TI - Comparable proportions of classes of experiences and intracerebral consequences for surgical stimulation and external application of weak magnetic field patterns: implications for converging effects in complex partial seizures. AB - The similarity of the proportions of different types of experiences reported during surgical electrical stimulation of epileptic temporal lobes published in the scientific literature and those reported following exposures to weak, applied magnetic fields was supported by direct comparisons in a retrospective analysis. Of the 20 types of specific experiences, the surgical stimulation groups reported proportionally more fear experiences, while the groups exposed to temporally patterned magnetic fields applied across the temporoparietal regions reported more somesthetic and vestibular experiences. There were no group differences for the other 17 types of experiences. Calculations indicated that the spread of charge displacement from neuronal membranes by the currents employed in the surgical studies and the magnetic field energy associated with the applied fields could affect similar numbers of cortical neurons. The similar subjective experiences of the two techniques indicate that the less invasive procedures might be employed to systematically study complex partial seizures. PMID- 23348245 TI - Long-term response in high-grade optic glioma treated with medically induced hypothyroidism and carboplatin: a case report and review of the literature. AB - Glioblastoma multiforme (GBM) is the most malignant and frequent brain tumor, with an aggressive growth pattern and poor prognosis despite best treatment modalities. Long-term survival of patients with GBM is rare. Optic glioma represents 0.6-1.2% of all brain tumors. Unlike low-grade optic gliomas in children, optic gliomas in adults are highly aggressive and death usually occurs in less than a year. Prolonged progression-free survival and survival rates have been reported in association with induced hypothyroidism in two clinical trials for recurrent GBM. We present the clinical, radiological, and pathological findings in a patient with inoperable GBM of the optic chiasm. Following failure of initial, standard radiation and temozolomide therapy, chemical hypothyroidism was induced using the antithyroid thioamide, propylthiouracil, followed by carboplatin chemotherapy. Initial thyroid stimulating hormone, free T4, and free T3 analysis was carried out and then monthly. This patient responded rapidly to treatment (clinically and with tumor regression within 4 weeks) on two separate occasions with an extended remission period (2.5 years) and prolonged overall survival (4.5 years). We report the successful long-term tumor response to medically induced chemical hypothyroidism in conjunction with carboplatinum chemotherapy of an adult patient with grade IV GBM of the optic chiasm. These clinical observations find mechanistic support from the recent identification of potent mitogenic actions of the thyroid hormone, L-thyroxine, in malignant glioma through binding to a cognate thyroid hormone receptor on the alphavbeta3 integrin. Approaches to block its activity are now explored in preclinical studies. PMID- 23348246 TI - Ipilimumab in cancer patients: the issue of early metabolic response. PMID- 23348247 TI - Identification and detection of the isolated sinus venosus from the Asian toad. AB - The pacemaker activity of mammalian sinoatrial node (SAN) of the heart plays a fundamental role in the integration of vital functions. Studying factors such as drugs that influence pacemaker activity of SAN has its significance. In this study, we isolated sinus venosus, SAN from toads (Bufo gargarizans), and analysed its electronic signal, histological characteristics and the influence of acetylcholine (ACh) and ivabradine on its pacemaker activity using PowerLab(r) and Chart(r) 5.0 software. We found that when isolated sinus venosus was treated with ACh, its histological distribution was disorganized and inter-beat (RR) interval was also broadened. The high frequency normalized unit (HFnu) and Poincare plot of heart rate variability (HRV) of the isolated sinus venosus was also altered upon ACh treatment in a time-dependent and dose-dependent manner. When treated with ivabradine, these parameters of HRV such as square root of the mean of the squared differences between adjacent NN intervals (RMSSD) and HFnu were in the upward tendency, but low frequency normalized unit and low frequency/high frequency were in the opposite tendency. Taken together, we have developed a new model for studying the influences of drugs on autorhythmicity using isolated sinus venosus of the toad. With this model, we showed that ACh and ivabradine may affect the pacemaker activity by stimulating muscarinic receptor or inhibiting If current, respectively. PMID- 23348248 TI - Pathway Pattern-based prediction of active drug components and gene targets from H1N1 influenza's treatment with maxingshigan-yinqiaosan formula. AB - Traditional Chinese Medicine (TCM) remedies are composed of different chemical compounds. To understand the underlying pharmacological basis, we need to explore the active components, which function systematically against multiple gene targets to exert efficacy. Predicting active component-gene target interactions could help us decipher the mechanism of action of TCM. Here, we introduce a Pathway Pattern-based method to prioritize the 153 candidate compounds and 7895 associated genes using the extracted Pathway Pattern, which is made up of groups of pathways. The gene prioritization result is compared to previous literature findings to demonstrate the top ranked genes' roles in the pathogenesis of H1N1 influenza. Further, molecular docking is utilized to validate compounds' effects through docking compounds into drug targets of oseltamivir. After setting thresholds, 16 active components, 29 gene targets and 162 active component-gene target interactions are finally identified to elucidate the pharmacology of maxingshigan-yinqiaosan formula. This novel strategy is expected to serve as a springboard for the efforts to standardize and modernize TCM. PMID- 23348249 TI - Advanced glycation end-products diminish tendon collagen fiber sliding. AB - Connective tissue aging and diabetes related comorbidity are associated with compromised tissue function, increased susceptibility to injury, and reduced healing capacity. This has been partly attributed to collagen cross-linking by advanced glycation end-products (AGEs) that accumulate with both age and disease. While such cross-links are believed to alter the physical properties of collagen structures and tissue behavior, existing data relating AGEs to tendon mechanics is contradictory. In this study, we utilized a rat tail tendon model to quantify the micro-mechanical repercussion of AGEs at the collagen fiber-level. Individual tendon fascicles were incubated with methylglyoxal (MGO), a naturally occurring metabolite known to form AGEs. After incubation in MGO solution or buffer only, tendons were stretched on the stage of a multiphoton confocal microscope and individual collagen fiber stretch and relative fiber sliding were quantified. Treatment by MGO yielded increased fluorescence and elevated denaturation temperatures as found in normally aged tissue, confirming formation of AGEs and related cross-links. No apparent ultrastructural changes were noted in transmission electron micrographs of cross-linked fibrils. MGO treatment strongly reduced tissue stress relaxation (p<0.01), with concomitantly increased tissue yield stress (p<0.01) and ultimate failure stress (p=0.036). MGO did not affect tangential modulus in the linear part of the stress-strain curve (p=0.46). Microscopic analysis of collagen fiber kinematics yielded striking results, with MGO treatment drastically reducing fiber-sliding (p<0.01) with a compensatory increase in fiber-stretch (p<0.01). We thus conclude that the main mechanical effect of AGEs is a loss of tissue viscoelasticity driven by matrix-level loss of fiber-fiber sliding. This has potentially important implications to tissue damage accumulation, mechanically regulated cell signaling, and matrix remodeling. It further highlights the importance of assessing viscoelasticity - not only elastic response - when considering age-related changes in the tendon matrix and connective tissue in general. PMID- 23348250 TI - Saxifragifolin D induces the interplay between apoptosis and autophagy in breast cancer cells through ROS-dependent endoplasmic reticulum stress. AB - Breast cancer is the leading cause of cancer death among females, and novel chemotherapeutic drugs for treating breast cancer are needed urgently. Saxifragifolin D (SD) was isolated by our group from Androsace umbellata which is commonly used to treat solid tumor. In this study, we evaluated its growth inhibitory effect on breast cancer cells and explored the underlying molecular mechanisms. Our results showed that SD inhibited the growth of both MCF-7 and MDA MB-231 cells significantly. Mechanistic studies demonstrated that SD induced apoptosis through mitochondrial apoptotic pathway. Evidence of SD-induced autophagy included the occurrence of autophagic vacuoles, up-regulation of LC3 II, Beclin1 and Vps34. Inhibition of autophagy by bafilomycin A1 or Beclin1 siRNA pretreatment decreased the ratio of apoptosis, indicating that autophagy induction contributes to apoptosis and is required for the latter. SD was also found to induce endoplasmic reticulum stress, accompanied by ROS production, increase of intracellular calcium and up-regulation of Bip, IRE1alpha and XBP-1s. Inhibition of endoplasmic reticulum stress by N-acetyl-l-cysteine, tauroursodeoxycholic acid or IRE1alpha siRNA pretreatment could suppress both apoptosis and autophagy. Besides, increases in CHOP, calnexin, calpain, p-JNK and p-Bcl-2 were followed by subsequent dissociation of Beclin1 from Bcl-2, further suggesting endoplasmic reticulum stress to be the common signaling pathway shared by SD-induced apoptosis and autophagy. In conclusion, SD inhibits breast cancer cell growth and induces interplay between apoptosis and autophagy through ROS mediated endoplasmic reticulum stress. It will provide molecular bases for developing SD into a drug candidate for the treatment of breast cancer. PMID- 23348251 TI - The master of plastic surgery as clinician, educator, and researcher. PMID- 23348253 TI - Secondary effects of botulinum toxin injections into salivary glands for the management of pediatric drooling. AB - This study aimed to assess the secondary benefits and adverse effects of botulinum toxin A injections into the parotid and submandibular glands in children with developmental disability and to determine whether these effects are related to reduction in drooling. Twenty-six children were injected (14 boys and 12 girls; mean age, 11 years 3 months). The Drooling Impact Scale and a secondary effects questionnaire covering aspects of eating, speech, saliva management, and sleep, were administered to the main carer at specific times before and after injection. Group mean preinjection and postinjection item and domain scores were compared using paired t tests. Change scores were calculated; individually categorized as improvement, no change, or deterioration; and related to change in drooling scores using linear regression analysis. Over 4 weeks, evidence of improvement was seen for the entire group with respect to drooling (P < 0.001), eating (P = 0.05), speech (P = 0.04), and sleep (P = 0.01), but not saliva management. Conversely, a minority of families reported worsening of eating skills after the injections that was directly related to lack of improvement in drooling. Because a minority of children unpredictably experience temporary adverse effects after botulinum toxin A injections into the salivary glands, swallowing function and nutritional status should be taken into account before proceeding with treatment. PMID- 23348254 TI - Delayed repair of lateral orbital wall and orbital floor fracture. AB - Timing of surgical management of facial fractures may differ from the current standard when an associated severe ophthalmologic injury exists; this may necessitate a delay in repair to protect the patient's vision. We set out to demonstrate that good functional and aesthetic outcomes can be achieved in cases where zygoma bone fracture repair had to be delayed for more than 21 days after injury with a specific surgical plan.Using the electronic database from Montreal General Hospital, a level I trauma center, a retrospective review of all facial fractures occurring from 1994 to 2009 was performed. Our review returned a total of 22,727 trauma patients admitted to Montreal General Hospital. Of these, 2672 sustained 1 or more facial fractures. Among the facial trauma patients, 945 patients' injuries included a zygoma fracture, 324 (35.3%) of which were managed operatively. Seven cases had their surgery delayed for more than 21 days after injury, 2 of which were managed using simple osteotomies and plate fixations, without the need for bone grafts. Both patients demonstrated a satisfactory outcome with improvement relative to their preoperative status. We provide a detailed description of our most recent case of a 73-year-old woman in whom the surgical repair of the lateral orbital rim and orbital floor was delayed for 10 weeks to allow healing of her associated traumatic retinal detachment.For patients with associated ocular injuries who cannot undergo orbital fracture repair within 21 days of the trauma, delayed surgery may still result in an acceptable aesthetic result. PMID- 23348255 TI - Incidence of oronasal fistula formation after nasoalveolar molding and primary cleft repair. AB - The incidence of postoperative complications in cleft care is low. In this 19 year retrospective analysis of cleft lip and palate patients treated with preoperative nasoalveolar molding, we examine the incidence of postoperative oronasal fistulae. The charts of 178 patients who underwent preoperative nasoalveolar molding by the same orthodontist/prosthodontist team and primary cleft lip/palate repair by the same surgeon over a 19-year period were reviewed. Millard, Mohler, Cutting, or Mulliken-type techniques were used for cleft lip repairs. Oxford-, Bardach-, or von Langenbeck-type techniques were used for cleft palate repairs. One nasolabial fistula occurred after primary cleft lip repair (0.56% incidence) and was repaired surgically. Four palatal fistulae (3 at the junction between soft and hard palate and 1 at the right anterior palate near the incisive foramen) occurred, but 3 healed spontaneously. Only 1 palatal fistula (0.71%) required surgical repair. All 5 fistulae occurred within the first 8 years of the study period, with 4 (80%) of 5 occurring within the first 3 years. Although fistula rate may be related to surgeon experience and the evolution of presurgical techniques, nasoalveolar molding in conjunction with nasal floor closure contributes to a low incidence of oronasal fistulae. PMID- 23348256 TI - Complex scalp, skull, and dural defect reconstruction using a turnover "tournedos" myocutaneous free flap. AB - BACKGROUND: The latissimus dorsi flap is one of the most commonly used flaps for calvarial defect reconstruction. In the setting of radiation and/or chronic infection and when skeletal reconstruction of the cranium is not recommended, standard calvarial reconstruction needs to be refined. The standard use of the latissimus dorsi only was associated with potential dead space over the dura, limited skin paddle size, and potential external contour irregularities. METHODS: In this study, we present our approach to complex calvarial reconstruction with free tissue transfer without bone grafting while avoiding contour deformities in 1 efficient surgical procedure. We propose the "tournedos" turnover de epithelialized latissimus dorsi flap, which provides stable dermal and subdermal tissue that will not undergo atrophy over time over the dura. To reach an adequate aesthetic result, we used a uniform, unmeshed, thick split-thickness skin graft over the muscular portion of the tournedos flap. Patients who underwent this procedure, from March 1992 to March 2012, at McGill University Health Center and the Montreal Neurological Institute were included. RESULTS: Thirty-three complex microsurgical procedures for oncologic calvarial defect reconstructions were performed from March 1992 to March 2012. Among them, 6 patients benefited from the tournedos procedure. The average age was 74 years. Scalp defects sizes ranged from 4 * 10 to 16 * 18 cm (40-288 cm). All latissimus dorsi flap donor sites were closed primarily. Patients kept their donor-site drains for approximately 18 days (+/-5 days). One patient developed a seroma at the donor site after drain removal that was treated conservatively. All patients were satisfied with their reconstructions, and no secondary procedures were necessary. We present our most recent case with good photographic documentation. CONCLUSIONS: Our approach using the tournedos turnover de-epithelialized free flap provides durable and stable coverage for irradiated and/or previously infected calvarial defects. It is a safe procedure in those challenging complex cases and offers many advantages. PMID- 23348257 TI - Factors associated with converting scientific abstracts to published manuscripts. AB - PURPOSE: The objective of this study was to identify factors associated with the conversion of scientific abstracts to publications in peer-reviewed journals. METHODS: This was a retrospective study of abstracts presented by members of the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery between 2000 and 2010. Predictor variables were categorized as abstract- or author-specific. The outcome variable was conversion of an abstract presented at a meeting to a published manuscript. Descriptive, bivariate, and multiple regression statistics were computed. P < 0.05 was significant. RESULTS: The sample was composed of 122 abstracts presented at meetings. Ninety abstracts (73.8%) were published in a peer-reviewed literature within 5 years of presentation. The mean time between presentation to publication was 21.9 +/- 17.3 months (median, 19.0 months; range, 0-99 months). In bivariate analyses, study design, number of prior publications by the presenting author, and number of prior publications by the senior author were associated with time to publication (P < 0.06). In a multiple Cox proportional hazards model, higher levels of evidence (hazard ratio, 1.2; 95% confidence interval, 1.04-1.3; P = 0.006) and volume of prior publications by the senior author (hazard ratio, 1.007; 95% confidence interval, 1.003-1.011; P < 0.001) were associated with shorter publication times. CONCLUSIONS: Time to publication of scientific abstracts is associated with study quality, prior research experience by the presenting author, and senior author identity and experience. PMID- 23348258 TI - Sagittal split osteotomy of the fibula for modeling the new mandibular angle. AB - Fibula modeling techniques for mandible reconstruction carry a high risk of bone perfusion impairment and low predictability of osteotomy angles. To restore the parabolic shape of the mandible, the number of osteotomies should be as small as possible to preserve both periosteal and endosteal perfusion. We report our approach with sagittal split osteotomy (SSO) technique for mandibular angle reconstruction.Obwegeser-Dal Pont SSO of fibula flaps was performed on 10 patients who underwent mandibular angle reconstruction. Bone segments were tilted according to stereolithographic template and fixed with 3 bicortical screws in triangular fashion. Fibula-gonial angle at 15 days and 6 months from surgery was compared with the contralateral-mandibular-gonial angle using Kruskal-Wallis test with a P < 0.05 considered significant.Mean bone length and skin paddle size were 15.6 cm (range, 13-18 cm) and 22.5 cm (range, 3 * 4 cm to 11 * 5 cm). Bone unions occurred at 12 months (mean follow-up, 39 months). No differences (P > 0.05) between fibula-gonial angle at 15 days (mean, 122.88 +/- 0.55 degrees; range, 122.49-123.27 degrees) and 6 months (mean, 123.36 +/- 0.88 degrees; range, 122.73 123.99 degrees) and contralateral-mandibular-gonial angle (mean, 123.20 +/- 0.80 degrees; range, 122.62-123.77 degrees) were observed.Fibula SSO allows for new mandible angle shaping, reducing risk of pedicle and endosteal vascular impairment. Triangular bone fixation thereby emerges as a reliable technique, enhancing functional and aesthetic long-term outcomes. PMID- 23348259 TI - Extended Abbe flap for secondary correction of the bilateral cleft lip. AB - Nearly 60 years ago, Joseph Murray described several advancements to Bradford Cannon's Abbe flap reconstruction of secondary bilateral cleft lips in order to simplify the technique and improve results. Unlike their predecessors, Drs. Cannon and Murray modified the Abbe flap by splitting its apex in order to obtain a symmetrical correction of the upper lip and allow the 2 suture lines to extend vertically and laterally past the base of the columella and disappear within the floor of the nose. Eighteen years later, Dr. Murray reviewed the evolution of his own secondary cleft lip reconstruction experience to include a new approach to advance the maxilla rather than set back the mandible. In this Signature Issue, we reflect on contemporary innovations in secondary bilateral cleft lip Abbe flap reconstruction. Today, we approach the secondary reconstruction of the bilateral cleft lip in 3 stages. First, we establish normal anatomic positioning of the midface. Second, we perform secondary cleft nasal surgery as necessary. Finally, only after the midfacial skeleton and nose have been treated do we proceed with Abbe flap reconstruction of the upper lip. We inset the Abbe flap a quarter of the way out on the columella and wrap the Abbe darts around the sides of the columella. We find that designing the Abbe flap this way avoids the saber cut like notching at the lip-columella junction, redundant vermilion, and excess flap length, and it also reduces or eliminates the need for upper or lower lip scar revision. PMID- 23348260 TI - Two-stage distraction lengthening of the forearm. AB - Single-stage lengthening of the forearm using callus distraction is well described; however, forearm lengthening using a 2-stage technique of distraction followed by bone grafting has received less attention. A 2-staged technique can be a better alternative in cases where the surgeon desires extensive lengthening. A retrospective review was undertaken of eleven 2-stage forearm lengthening procedures performed by 1 surgeon over a 15-year period. Indications were radial longitudinal deficiency (8 patients), neonatal ischemic contractures (2 patients), and septic growth arrest (1 patient). Average follow-up was 2.8 years. Distraction was performed on patients an average of 82 mm over an average duration of 24 weeks. Average time to union from the time of distractor removal and grafting was 87 days. Average healing index was 32.1 d/cm. Distraction problems were common and related to the length of time that the distractor was in place; they included pain, pin-related infections, and multiple mechanical device difficulties. Three patients had nonunion, and another had delayed union; however, additional procedures resulted in ultimate bony union in all patients. Demineralized bone matrix and autologous corticocancellous bone grafts yielded predictable healing and good functional results in short-distance distractions. For longer distractions, free vascularized fibula transfer produced the best outcomes. Intercalary cortical allografts did not heal well. Patients with neonatal Volkmann contractures had the most difficulty with distraction and healing, ultimately obtaining little to no lengthening and poor functional outcomes. PMID- 23348261 TI - Cleft palate midface is both hypoplastic and displaced. AB - Despite significant advances in cleft lip and palate treatment, anatomical controversies remain. Some have proposed that the width of the cleft is due to alveolar segmental displacement. Others suggest that the width is due to palatoalveolar hypoplasia. Improving our understanding of cleft anatomy may have implications for presurgical orthopedics and tissue engineering therapies. Palatoalveolar impressions of 17 noncleft children and 11 children with complete (alveolar, primary, and secondary) unilateral cleft palates were taken. Maxillary tuberosity positions and maxillary volumes were compared. Tuberosity position was determined by facebow transfer of palatoalveolar casts into geodetic datum boxes, and identification of the Cartesian coordinates (x, y, z) of the tuberosities relative to the box surfaces and Frankfurt horizontal. Maxillary volume was determined by immersing the palatoalveolar casts and measuring sand displacement. A significant difference was noted in the average tuberosity to contralateral tuberosity distance between cleft and noncleft cohorts. On average, cleft palate tuberosities were laterally displaced 8.7 mm compared with noncleft palates (P < 0.05). There was neither statistically significant alveolar segment elevation nor retroversion. A significant difference was noted in the average palatoalveolar volumes. The cleft palatoalveolar volume was 5.7 cm, and the noncleft palatoalveolar volume was 7.2 cm (P < 0.05). A palatal cleft is due to both alveolar tissue displacement and deficiency. Therefore, ideal cleft palate care should involve the correction of a displaced and deficient alveolus. PMID- 23348262 TI - Creativity in plastic surgery as a major contribution to medicine, surgery, and patient care. AB - All human beings are provided by nature with the ability not only to survive but also to improve the quality of life. A sort of brain plasticity allows us to adapt to new information and circumstances. This also accounts for what is called creativity. Due to its etymological roots in Latin, the word suggests that by means of imagination either a new idea of significant value may be ''created'' or an already existing and valid one may be improved, transformed, and applied so as to serve more purposes. As the German poet Goethe aptly observed, the ''birth'' of something new often requires the ''death,'' or the letting go, of old ideas. In the course of history, creativity has brought about changes, innovations and advances in all aspects of human life. Creativity, accompanied by talent, motivation and interest, patience and perseverance, self-confidence and courage, as well as the determination to overcome obstacles, is highly significant also in the field of medicine, in surgery, and, of course, in Plastic Surgery. Specific techniques and methods, invented by creative individuals and/or the research community, have contributed to a history of great innovations in Plastic Surgery and have also proved useful in other surgical institutions. Cooperation beyond the scope of 1 discipline has always been highly important, as it is the patient who is meant to profit from the products of creative minds in these fields. Two examples from my own experience shall serve to illustrate the vast scope of possibilities in the field of Plastic Surgery: cross-face nerve grafting and total reconstruction of a trachea. PMID- 23348263 TI - Age at initial consultation for craniosynostosis: comparison across different patient characteristics. AB - BACKGROUND: The severity and dysmorphology that results from the premature fusion of one or more cranial sutures is not uniform. Less striking phenotypes may be more easily missed on routine screening, possibly leading to delayed diagnosis and treatment. The purpose of this study was to compare the age at initial presentation for the different forms of craniosynostosis. METHODS: The authors reviewed the records of all patients who underwent open craniofacial repair of craniosynostosis at a single institution from 1996 to 2009. Relationships between type of suture fusion and age at initial consultation were compared. RESULTS: Two hundred eleven patients (136 males, 75 females) were identified. Indications included sagittal (n = 96), metopic (n = 39), unicoronal (n = 33), bicoronal (n = 24), multisutural (n = 15), bilambdoidal (n = 3), and unilambdoidal (n = 1) synostoses. Seventeen patients (8.1%) had a craniosynostosis syndrome and 5 (2.4%) had a syndrome or disorder not typically associated with craniosynostosis [X-linked hypophosphatemic rickets (n = 3), achondroplasia (n = 1), and Beckwith Wiedemann (n = 1)]. Median age at initial consultation was 4.1 months; there was no gender difference. Patients with X-linked hypophosphatemic rickets presented at a significantly older age than nonsyndromic patients or those with a known craniosynostosis syndrome. Those with multisutural synostosis presented at a significantly older age than patients with sagittal or bicoronal synostosis. CONCLUSIONS: Patients with multisutural involvement or X-linked hypophosphatemic rickets had a significant delay in presentation for craniosynostosis. The latter group of patients may especially benefit from routine surveillance for craniosynostosis given their advanced age at diagnosis. PMID- 23348264 TI - Evolution and limitations of conventional autologous reconstruction of the head and neck. AB - Conventional reconstruction in the head and neck has undergone a revolution as microsurgery has evolved and expanded our ability to reconstruct the most difficult defects. Vascularized composite allotransplantation (VCA) has provided a new paradigm of options to restore in 1 stage what in the past has been performed in multiple stages with multiple combinations of free flaps and local flap options. This review demonstrates an evolving perspective of head and neck reconstructive surgery incorporating the indications and advantages gained over a career that has developed in parallel with microsurgery, prefabrication, prelamination, and face transplant. All current conventional reconstructions for the most severe defects often involve multistage procedures, using every rung of the reconstructive ladder, and the end results can still be lacking despite our best efforts. Despite all the tailoring and planning of these multiple flap and multiple-stage reconstructions, in our experience, these interventions never quite exactly recapitulate the face and fall short of full restoration. The early experience with VCA has been very promising and yields results that are superior to those achieved using conventional methods of reconstruction. However, it will be synergistic efforts in both VCA and conventional reconstruction to take us to the next level of full face restoration. PMID- 23348265 TI - Gustav Simon's band and the evolution of labial adhesion. AB - "Simonart's band" is an eponymic misnomer. In the mid-19th century, Pierre-Joseph Simonart described congenital bands in the limb, not in the lip. Shortly thereafter, Gustav Simon reported preliminary closure of bilateral cleft lip and thus deserves credit for labial adhesion (Simon's band). Labial adhesion was rediscovered 100 years later; however, with increasing use of infant-dentofacial orthopedics, its popularity has declined in many centers. The authors continue to use this procedure before formal repair of unilateral complete cleft lip/palate, unilateral complete cleft lip and alveolus, severe unilateral incomplete cleft lip, and bilateral asymmetrical cleft lip (on the complete side). Bilateral labial adhesion may also have a preparatory role in double cleft lip whenever dentofacial orthopedic manipulation is unavailable or unsuccessful. PMID- 23348266 TI - Does conventional posterior vault remodeling alter endocranial morphology in patients with true lambdoid synostosis? AB - BACKGROUND: True lambdoid synostosis (TLS) produces a consistent morphology that includes occipital flattening, an ipsilateral occipitomastoid prominence, and a mild contralateral hemifacial deficiency that minimally improves with surgery. Prior studies have demonstrated that dysmorphic middle and posterior cranial fossae contribute to the craniofacial scoliosis characteristic of TLS. We hypothesize that these endocranial features remain after surgery, causing the persistent hemifacial deficiency seen in these patients. METHODS: Three dimensional anthropometric measurements were made on preoperative and postoperative CT scans of patients with TLS (n = 5). Quantitative analysis was performed on the middle cranial fossa area (MCF), anterior cranial fossa area (ACF), posterior fossa deflection angle (PFA), petrous ridge angle (PRA), temperomandibular joint (TMJ) angle, and external auditory meatus angle. The results were analyzed using a 2-tailed t test. RESULTS: Preoperative CT scans were obtained at a mean age of 1.05 years. Patients underwent posterior vault remodeling at a mean age of 1.33 years. Postoperative CT scans were obtained a mean age of 3.14 years. Following surgery, patients with TLS demonstrated an unchanged PFA (P = 0.76) with deviation toward the affected suture. The ACF remained symmetrical (P = 0.212), and the contralateral MCF remained enlarged relative to the ipsilateral side (P = 0.003). The contralateral middle fossa became more retrodisplaced (P = 0.021). The ipsilateral PRA remained unchanged (P = 0.95). Ear position also remained asymmetrical (P = 0.037). The position of the TMJ was not statistically different between sides before (P = 0.24) or after surgery (P = 0.07). CONCLUSIONS: Traditional cranioplasty effectively restores calvarial shape, but does not significantly alter the dysmorphic features seen in the endocranium of patients with TLS. PMID- 23348267 TI - Management of severe craniofacial vascular malformation operated under bypass: evolution from a "no-flow" to a "low-flow". AB - BACKGROUND: Cardiopulmonary bypass (CBP) and circulatory arrest as an assist in the surgical excision of a severe facial vascular malformation were first described by Mulliken et al in 1979. Later on, its use had expanded for resection of intracranial vascular malformations. However, to date, there have not been any published series of these procedures being used in the resection of craniofacial vascular malformations. We sought to review the first 10 surgical procedures performed at McGill University Health Centre for large vascular malformations resection using hypothermic CBP with or without circulatory arrest. METHODS: All consecutive patients at the McGill University Health Centre who had a craniofacial vascular malformation resected with the aid of CBP were reviewed. A comparison of the classic midline sternotomy with cardiac arrest to percutaneous femoral bypass with hypothermic "low flow" was performed. Charts were reviewed for the operative intervention including bypass parameters and short- and long term complications of the procedure. RESULTS: Cardiopulmonary bypass was used in 9 patients for 10 surgical procedures for the resection of a variety of craniofacial vascular malformations from 1987 to 2001. All lesions had sclerotherapy and embolization of the feeding vessels 72 to 96 hours preoperatively. The average age of our patients was 21 +/- 13.4 years (2-37 years). Procedures were conducted via either an open bypass or a closed femoral approach. There were no mortalities. There were 2 major cardiac intraoperative complications and 1 major postoperative complication, which were managed with no sequelae. The average length of postoperative hospital stay was 10 days. All patients went on to full recovery. The blood transfusions varied from 10 U to 0 U for our last patient. CONCLUSIONS: The assistance and adjunct of CBP are a useful procedure in the resection of very large vascular malformations, in selected cases. There were no major long-term complications in this series. With the evolution of our approach, the use of complete circulatory arrest was not required in the majority of cases, and an adequate resection was usually possible with the low-flow state alone as we developed this technique with more experience through the process. PMID- 23348268 TI - RUNX2 quadruplication: additional evidence toward a new form of syndromic craniosynostosis. AB - The RUNX2 transcription factor regulates osteoblast differentiation. Its absence, as with cleidocranial dysplasia, results in deficient bone formation. However, its excess seems to follow a dose response of over ossification. RUNX2 duplications (3 copies) are exceedingly rare but have been reported to cause craniosynostosis. There are no existing reports of quadruplications (4 copies). We present a case study of a boy with an atypical skull deformity with pan craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. Further characterization of this osteogenic pathway may aid in our understanding of the pathogenesis and subsequent prevention and treatment of syndromic craniosynostosis. PMID- 23348269 TI - Biology of RUNX2 and Cleidocranial Dysplasia. AB - Three features of cleidocranial dysplasia that are not always appreciated are hypoplastic iliac wings, short stature, and brachydactyly. Because of the pelvic abnormality, pregnant women may require a cesarean delivery. Short stature and brachydactyly indicate more generalized skeletal abnormalities. These are derived from endochondral and intramembranous ossification, but the distinction between these 2 processes is oversimplified because both processes are involved in long bone and clavicular development. Two sections follow: the biology of RUNX2 and the nature of haploinsufficiency in RUNX2 mutations for cleidocranial dysplasia. PMID- 23348270 TI - Oversized design of the anterolateral thigh flap for head and neck reconstruction. AB - Most surgical protocols for head and neck cancer extirpation require concurrent neck lymph node dissection. Hence, the defect involves not only the cancerous anatomical structures but also the neck. The tissue deficiency in the latter region imposes potential problems such as carotid and jugular vein exposure risking blowout, infections and orocutaneous fistulae in the neck, and a cosmetically untoward sunken appearance. The free anterolateral thigh flap (ALT) provides abundant tissue and is often the flap of choice in head and neck reconstruction. To replace the proper amount of postoperative soft tissue deficit in the neck area, we use an oversized ALT flap design. This allows reconstruction of the specific anatomical defects, protection of the important neck structures, and prevention of a sunken appearance. An oversized flap may also provide additional coverage for fixation hardware to prevent its exposure, especially after radiotherapy. In the event of partial flap loss, some viable parts of the oversized flap may be possible to advance or rotate to replace the nonviable part to avoid a repeated free flap procedure or other more complicated reconstructive procedures. PMID- 23348271 TI - An international survey of craniofacial surgeons: current trends in practice. AB - BACKGROUND: Craniofacial surgery is a diverse subspecialty of plastic surgery that focuses on a wide range of head and neck pathology in children and adults. The purpose of this study was to define the characteristics of this group of surgeons and to compare subgroups within the specialty. METHODS: A 36-question, anonymous, electronic survey was sent to 403 craniofacial surgeons; the response rate was 30% (121). Distribution was to members of the International Society of Craniofacial Surgeons and to graduates of fellowships recognized by the American Society of Craniofacial Surgeons. Data were collected and analyzed for surgeon demographics, geography, practice setting (academic vs private), case mix and volume, and career satisfaction. Comparisons were made between US and international surgeons, males and females, and surgeons of different ages. RESULTS: The craniofacial surgeons in this study ranged in age from 29 to 75 years (mean, 53 years); 92% were male, and 8% were female. They are largely academic (69%), high in academic rank (54% full professors), predominantly male (92%), and actively practicing craniofacial surgery. There are significant differences between international and domestic surgeons in terms of training background (64% vs 36% plastic surgery residency, P = 0.003) and volume of craniofacial surgery (56% vs 26% performing more than 5 complex craniofacial procedures per year, P = 0.002). CONCLUSIONS: Craniofacial surgeons are a highly successful academic group with high career satisfaction. There are significant differences between US and international craniofacial surgeons in terms of demographics and practice, with more US surgeons performing fewer major craniofacial osteotomies. There is a significant gender disparity, which warrants further study. PMID- 23348272 TI - Spontaneous malignant transformation in craniomaxillofacial fibrous dysplasia. AB - Spontaneous malignant transformation in craniomaxillofacial fibrous dysplasia (FD) is extremely rare and its clinicopathological characteristics remain largely unknown. Here, we aimed to characterize the epidemiology and clinicopathological features of malignancies arising from preexisting FD by presenting data from a Chinese tertiary referral hospital and review of English and Chinese literatures. The craniomaxillofacial disease registry of Shanghai Ninth People's Hospital was searched and reviewed to collect relevant information for patients diagnosed as malignant transformation in craniomaxillofacial FD between January 1993 and December 2010. An English and Chinese literature review was conducted to retrieve pertinent cases published in the past 2 decades with preset inclusion criteria. All included cases were further analyzed with regard to associated clinical and pathological variables. Three cases with osteosarcoma arising from previous craniomaxillofacial FD were found at our institution and 35 other cases were identified by literature review. These uncommon entities usually occurred in adults with a mean age of 39.8 years and equal gender preponderance. Maxilla remained the most common sites for malignancies followed by mandible and zygoma. Most malignancies were diagnosed as osteosarcoma followed by fibrosarcoma, chondrosarcoma, and malignant fibrous histiocytoma. Radical resection alone or with postoperative radiotherapy/chemotherapy remains the main treatment strategy with unfavorable prognosis due to local recurrence and distant metastasis. Taken together, our findings might for the first time provide the comprehensive information regarding the epidemiology, clinicopathological features, treatment, and prognosis of malignancies in craniomaxillofacial FD. Further investigations are warranted to improve early diagnosis and proper treatment for these uncommon entities. PMID- 23348273 TI - Postoperative cranial vault growth in premature sagittal craniosynostosis. AB - Various techniques for the correction of sagittal craniosynostosis have been described in the literature. Nevertheless, there is a lack of consensus regarding surgical procedure and timing, although a long-term anthropometric analysis may shed light on this controversy. The aim of the current study was to collect serial anthropometric data of children before and after total cranial vault remodeling and to evaluate cranial vault growth pattern. Twenty-nine Swiss children with a surgical age between 8 and 10 months were included in this 5-year follow-up. Anthropologic data of sex- and age-matched healthy Swiss children served as a control. A standardized time protocol (before, after, 6 wk after surgery, 6 mo after surgery, and then annually until the age of six) for anthropometric skull measurements (head circumference, cranial length, breadth, and cephalic index) was used. Data were converted into the z score for standardized intercenter comparison. Postoperatively, all patients showed a marked benefit in cranial vault shape. Significant differences in long-term cranial growth pattern could be seen and a relapse into a dolichocephal skull growth. Both observations were rated as clinically irrelevant. PMID- 23348274 TI - FGFR1 and FGFR2 mutations in Pfeiffer syndrome. AB - Pfeiffer syndrome (PS) (MIM 101600) is one of the most common syndromic forms of craniosynostosis. It is characterized by craniosysnostosis, midface hypoplasia, broad and medially deviated thumbs, and great toes with partial syndactyly of the digits. Here, we described clinical and genetic features of 12 unrelated Thai individuals with PS. All 12 patients were sporadic, and advanced paternal age was found in 50% of the cases. Polymerase chain reaction sequencing of FGFR1 exon 5 and FGFR2 exons 8, 10, 15, 16, and 17 was performed in all PS patients and revealed 9 recurrent mutations in all patients. Most of the mutations clustered in exons 8 and 10 (9/12) accounting for 75% of PS cases. The most frequently detected mutation, p.S351C, was associated with the severe form of PS in the Thai population. Less frequent mutations in exons 16 (p.K641R) and 17 (p.G663E) were also identified. In addition, the p.P252R mutation in FGFR1 was detected in 1 PS patient with unilateral coronal craniosynostosis expanding the phenotypic spectrum of PS with this particular mutation. Knowing the mutation spectrum of the responsible genes could lead to the most effective strategy in identifying mutations causing Pfeiffer syndrome in the Thai population. PMID- 23348275 TI - Maxillofacial fractures in children. AB - Maxillofacial fractures in Japanese children were retrospectively analyzed. The subjects were 287 patients aged 15 years and younger seeking treatment for maxillofacial fractures in the Department of Oral and Maxillofacial Surgery, Nara Medical University. The patients were 186 males and 101 females. Injuries most frequently occurred as a result of traffic accidents in 125 patients, 92 of which were bicycle-related accidents. Injuries by falling from one level to another were found in 49, primarily in younger children. One hundred seventy-nine fractures occurred in the mandible, 100 in the midface, and 8 in both. In the mandible, fractures most frequently occurred in condyle followed by symphysis. In the midface, alveolus was mostly involved. The facial injury severity scale ranged from 1 to 9 with an average of 1.83 and was higher in traffic accidents. Injury to other sites of the body was found in 33 patients, 28 of which occurred in traffic accidents. Observation was most frequently chosen in 84 patients. Intramaxillary fixation was chosen in 79, primarily for alveolar fractures and in younger children. Maxillomandibular fixation was chosen in 62 for mandibular fractures in older children. Open reduction and internal fixation was performed in 40, primarily in older children. The facial injury severity scale was higher in patients treated by open reduction and internal fixation and maxillomandibular fixation. Maxillofacial fractures in Japanese children showed characteristic features primarily depending on their age in terms of etiology, patterns, and treatment modalities. PMID- 23348276 TI - Novel application of human morphomics to quantify temporal soft tissues in Pierre Robin and Treacher Collins. AB - INTRODUCTION: Pierre Robin sequence (PR) and Treacher Collins syndrome (TC) are congenital disorders associated with multiple craniofacial abnormalities. The mandibular malformations linked with these maladies are closely associated with the form and function of the temporalis muscle. Despite these associations, a paucity of research has been directed at quantifying how these malformations affect the tissues of the temporal region. In this paper, we seek to quantify differences in the temporalis muscle and the temporal fat pad using a novel CT derived analytic program to examine craniofacial morphomic indices within these patient groups in comparison to normal age-matched controls. We posit that the temporalis muscle and temporal fat pad, like other derivatives of the first branchial arch, are hypoplastic in patients with TC and PR compared to age matched controls. METHODS: High-throughput image analysis was used to reconstruct the 3-dimensional (3D) anatomy and quantify morphomic measures of the temporalis muscle and temporal fat pad in children with PR, TC, and age-matched controls. These steps were completed in a semi-automated method using algorithms programmed in MATLAB v13.0. The 3D reconstructions were analyzed in 3 children with PR (6 temporal regions), 3 children with TC (6 temporal regions), and a control group of 19 children (38 temporal regions). We also quantified the same measurements in a localized "core" sample in the area of greatest thickness, providing a more consistent sample of the tissue position. Relationships between the temporal muscle and fat pad values and craniofacial abnormality type were assessed using Wilcoxon nonparametric test using exact distribution, with a P value of less than 0.05 being deemed significant. RESULTS: The mean age of our patients was 6.0 years in PR and 4.5 years in TC cohorts. We were able to establish an automated methodology to quantify the temporalis muscle and temporal fat pad based on CT characteristics. Localized temporalis volume and localized temporalis area were significantly smaller in children with PR than in the control group. Total temporalis fat volume and localized temporalis area were significantly less in children with TC than in the control group. When compared to each other, the PR group had small morphomic values compared to TC group. CONCLUSIONS: There are significant morphomic differences in the temporalis muscle and the temporal fat pad in children with either PR or TC when compared to age-matched control group which can be measured from pre-existing CT scans. Specifically, both of these test groups show decreases in the morphomic measures of the temporalis region. The quantification of these changes corroborates and objectifies the clinical findings associated with these congenital deformities while simultaneously allowing for preoperative planning. Furthermore, this finding confirms that the hypoplasia seen in these patient populations is not only hypoplasia of the mandible but also of the surrounding functional matrix, which includes the temporalis muscle and temporal fat pad. PMID- 23348277 TI - Hardware removal rates for mandibular angle fractures: comparing the 8-hole strut and champy plates. AB - OBJECTIVE: To compare the removal rates of 8-hole angle strut plate and Champy line plate in repairing mandibular angle fractures. METHODS: Retrospective chart review at a tertiary care academic center of adults who were at least 18 years old with at least 1 mandibular angle fracture of a traumatic origin who underwent open reduction and internal fixation by using single monocortical miniplate fixation in Champy line or by using 8-hole angle strut plate via transbuccal approach. The outcome measures were hardware removal rates and the reason for removal of the hardware. RESULTS: One hundred four patients with a total of 106 angle fractures met the inclusion criteria for this study. Seventy-three angle fractures were treated with the 8-hole strut, and 33 angle fractures were treated with the Champy line plates. There were 6 plates removed in both groups. This resulted in 8.2% of plates removed in the 8-hole strut plate group and 18.2% in the Champy line group (P = 0.133). Loose hardware was determined to be the cause of plate removal in 2 (2.7%) of the 8-hole strut plate group compared with all 6 (18.2%) of the Champy group (P = 0.005). CONCLUSIONS: Overall, removal rates between Champy line and 8-hole strut plates are not different in treating mandibular angle fractures, although the 8-hole strut plate has a lower rate of loose hardware-related plate removal compared with the Champy line plate. PMID- 23348278 TI - A novel quantitative image-based method for evaluating cranial symmetry and its usefulness in patients undergoing surgery for unicoronal synostosis. AB - BACKGROUND: Unicoronal synostosis presents with cranial asymmetry. Fixed points are difficult to identify; surgical results are therefore difficult to evaluate. The aim of this study was to develop a computer-based method for evaluation of forehead symmetry to enable evaluation of surgical results in unicoronal synostosis. METHODS: The MATLAB tool was programmed to segment computed tomographic images, leaving the outermost contour. Cephalometric images were segmented manually due to lower contrast. A center-point (O) and an end-point were manually defined in the midline of the forehead and at the nonfused coronal suture, respectively. The program then found a point (p) on the fused side, at the same distance from the O as the end-point. The contours of the left and right side of the forehead were thereafter superimposed, and the position of minimal area mismatch of the sides was identified. To correct for growth between preoperative images and follow-up, the number of mismatching pixels was related to the area outlined by the contour of the forehead, the end-point and p. Two quantities, the relative symmetry change and the absolute symmetry change, were defined and evaluated by repeated measurements on spherical and elliptical phantoms and 15 patients. RESULTS: Measurements with the MATLAB program were reliable with an SD of 0.26% to 5.39% for the expected range of differences. The SD was lower for measurements on computed tomographic images than for measurements on cephalometric images. The SD was also lower in patients with large surgical improvement than in patients with little improvement. The results support the use of relative symmetry change to evaluate surgical results. CONCLUSIONS: Our new computer-based method is capable of measuring forehead symmetry with good precision. This method can be used for systematic evaluation of surgical outcome for unicoronal synostosis and other asymmetric skull deformities. PMID- 23348279 TI - Endoscope-assisted versus open repair of craniosynostosis: a comparison of perioperative cost and risk. AB - BACKGROUND: Craniosynostosis, the premature closure of calvarial sutures, results in characteristic skull deformations. Correction of craniosynostosis has traditionally involved an open cranial vault remodeling procedure. A technique recently developed uses an endoscope to perform a strip craniectomy in conjunction with a postoperative molding helmet to guide cranial growth. Few studies compare these 2 approaches to the treatment of the various forms of craniosynostosis. In this study, we present a single institution's experience with open cranial vault remodeling and endoscope-assisted strip craniectomy. METHODS: This study is a retrospective review of 57 patients that underwent craniosynostosis repair by either the endoscope-assisted or open techniques, and compared operating room times, blood loss, volume of transfused blood, length of hospital stay, and overall costs. RESULTS: The endoscopic technique is performed on younger children (4.7 months vs 10.6 months, P = 0.001), has shorter operating room times (2 hours 13 minutes vs 5 hours 42 minutes, P = 0.001), lower estimated blood loss (74.4 mL vs 280.2 mL, P = 0.001), less transfused blood (90.6 mL vs 226.9 mL), shorter hospital stays (1.2 days vs 4.9 days, P = 0.001), and decreased cost ($24,404 vs $42,744, P = 0.008) relative to the traditional open approach. CONCLUSIONS: Issues with the endoscope-assisted procedure primarily concerned the postoperative helmet regimen, specifically patient compliance (17.1% noncompliance rate) and minor skin breakdown (5.7%). The endoscope assisted repair with postoperative helmet molding therapy is a cost-effective procedure with less operative risk and minimal postoperative morbidity. This is a valuable treatment option in younger patients with compliant caregivers. PMID- 23348280 TI - Preoperative planning for the separation of omphalopagus conjoined twins-the role of a multicomponent medical model. AB - Abdominal wall reconstruction after the separation of omphalopagus conjoined twins poses a challenge for the reconstructive surgeon as separation often results in large defects involving both the skin and the abdominal wall. We describe the fabrication of a multicomponent medical model devised to simulate the various soft tissue elements and enhance presurgical planning capabilities.A life-size model was cast of omphalopagus conjoined twins including a circumferential rendition of the lower thorax and abdomen. The model consisted of a foam core simulating the density of the soft tissue with a silicone rubber skin. Tissue expanders at different stages of enlargement were sculpted onto the model to determine the amount of additional skin required. The reconstructive design elaborated on the model was used during the 20-hour operation that resulted in the twins' successful separation.We believe the creation of a customized multicomponent medical model enhances presurgical planning capabilities for complex reconstructive endeavors. PMID- 23348281 TI - Making the diagnosis: metopic ridge versus metopic craniosynostosis. AB - INTRODUCTION: The metopic suture is the only calvarial suture which normally closes during infancy. Upon closure, a palpable and visible ridge often forms which can be confused with metopic craniosynostosis. Metopic ridging (MR) is treated nonsurgically while metopic craniosynostosis (MCS) is treated surgically. Differentiating between the two is paramount; however, consensus is lacking about where a clear diagnostic threshold lies. The goal of this study is to describe the physical examination and CT scan characteristics which may help to differentiate between physiological closure of the metopic suture with ridging (MR) and MCS. METHODS: A retrospective chart review of all patients seen at Seattle Children's Hospital between 2004 and 2009 with the diagnosis of either MCS or MR (n = 282) was performed. Physical examination characteristics described by diagnosing practitioners were analyzed. Clinical photos were assessed by 3 expert raters to determine the importance of these characteristics. CT scan findings were abstracted and compared between the two diagnoses. RESULTS: The "classic" triad of narrow forehead, biparietal widening, and hypotelorism was present in only 14% of patients with MCS. Ninety-eight percent of patients in both groups had a palpable metopic ridge. The photographic finding of narrow forehead and pterional constriction was present in all patients with MCS, but only in 11.2% and 2.8% of patients with MR. On CT scan, the presence of 3 or more MCS findings was diagnostic of MCS in 96% of patients. Patients with MCS were more likely to present before 6 months of age (66% vs. 32%). CONCLUSIONS: Patients with MCS tend to present earlier than those with MR. Upon physical examination, the relationship between the lateral frontal bone and the lateral orbit is important in distinguishing between the two diagnoses. A CT scan can be helpful in making the diagnosis not to confirm a closed suture but to identify 3 or more MCS characteristics. PMID- 23348282 TI - Presurgical nasoalveolar molding and primary gingivoperiosteoplasty reduce the need for bone grafting in patients with bilateral clefts. AB - Preoperative nasoalveolar molding (NAM) in combination with primary gingivoperiosteoplasty (GPP) reduces the need for secondary alveolar bone grafting by 60% in patients with unilateral cleft lip and palate (CL/P). Herein, we investigate the efficacy of NAM and primary GPP in patients with bilateral CL/P. All patients (n = 38) with bilateral CL/P who underwent NAM and primary GPP from 1988 to 1998 with at least 14 years of follow-up were included in this study. Panoramic and periapical radiographs were used to assess dentoalveolar bone formation. A total of 38 patients were identified with median follow-up of 18 years (range 14-26 years). Of the 27 patients who underwent bilateral GPP, 14 (51%) patients had successful dentoalveolar bone formation bilaterally and 13 (49%) had unilateral bone formation. No patient had a bilateral failure. Of the 11 patients who underwent unilateral GPP, 7 (63%) patients had successful dentoalveolar bone formation. Bilateral successful dentoalveolar bone formation following primary bilateral GPP has a dependent probability of 52% and a conditional probability of 82%. PMID- 23348283 TI - Preoperative and postoperative orbital volume in patients with Crouzon and Apert syndrome. AB - Crouzon and Apert syndromes are frequently complicated by ocular abnormalities and patients with these syndromes often present with abnormal ocular morphology. The present study assesses orbital volume and ocular complications in patients associated with Crouzon and Apert syndromes.During an 8-year period starting in 2002, fronto-orbital advancement was used for cranial expansion on 23 cases of syndromic craniosynostosis. Of those, it was possible to evaluate 5 Crouzon and eight Apert syndrome cases. Orbital volume was measured using multislice CT scans. Both preoperative and postoperative orbital volumes were compared with normal orbital volume.Preoperative orbital volume was 5.8 to 10.0 cm (mean, 7.1 cm) in patients with Crouzon syndrome and 7.2 to 10.8 cm (mean, 9.1 cm) in patients with Apert syndrome. Postoperative intraorbital volume was 9.4 to 11.2 cm (mean, 10.4 cm) in patients with Crouzon syndrome and 11.6 to 13.2 cm (mean, 12.4 cm) in patients with Apert syndrome. The mean of orbital volume relative to the normal volume was 58% preoperatively and 74% postoperatively in patients with Crouzon syndrome and 69% (56-81%) preoperatively and 88% (81-95%) postoperatively in patients with Apert syndrome.In conclusion, orbital volume was smaller in the Crouzon syndrome group than in the Apert syndrome group, and symptoms, such as exophthalmos and exotropia, were noted in the Crouzon syndrome group. Orbit expansion did not fully restore normal orbital volume, but in most cases, it was useful for alleviation of preoperative symptoms (exophthalmos/eyeball prolapse, corneal erosion, conjunctivitis). PMID- 23348284 TI - Inner table corticectomy of the fronto-orbital bar in correction of metopic and coronal craniosynostoses. AB - Fronto-orbital advancement is an established method for correction of metopic and coronal craniosynostoses. Many techniques involve creation of a single fronto orbital bar that is then shaped with osteotomies with or without bone grafting. We present a technique that minimizes osteotomy of the frontal bar and gives superior lateral brow aesthetics.Standard fronto-orbital bar bone cuts are made without a midline osteotomy. Selective inner table corticectomy of the fronto orbital bar allows the bone to become malleable without greensticking. The need for osteotomy of the fronto-orbital bar is obviated. An additional bandeau is created from the temporoparietal calvaria. The malleable fronto-orbital bar is then fixed to this bandeau. The frontal bar and bandeau complex is then advanced in a conventional manner. The remaining frontal calvaria is then rotated creating a more vertical forehead.This technique has been used in Leeds for more than 10 years with good cosmetic results. It has become our standard method for management of the fronto-orbital bar in correction of nonsyndromic metopic and coronal craniosynostoses. PMID- 23348285 TI - Linear measurements of healthy adults' coronal section of hippocampus on brain magnetic resonance imaging. AB - To figure out hippocampal anatomy features, which can be used as reference in determination of hippocampus-related disease, we rebuilt 3-dimensional brain models with magnetic resonance imaging; then, we chose 1 coronal section of the hippocampus and took 22 linear measurements of each section in 74 healthy adults. In each section, we took paired sample T test for the left and right measurements comparison, independent sample T test for sex difference comparison, and correlation analysis for relationships between age and other measurements. For the left and right comparison, 9 measurements have no significant difference (P > 0.05). For sex difference, 8 measurements have significant differences (P < 0.05). In age linear regression analysis, 5 measurements have significance in statistical analysis. All results above demonstrate that measurements of this section have little significance in L/R difference, but for different sexes, these measurements show significant results, which means male and female were different. As for age linear regression analysis, brain shape and distances were age related. This study provides reference for diagnosis of hippocampal atrophy, and it is an easy approach instead of areal and volumetric measurements in clinical practice. PMID- 23348286 TI - Modified nasomaxillary and hard palatine osteotomy combined nasal implantation to correct Binder syndrome. AB - Maxillonasal dysplasia, or Binder syndrome, is a congenital condition consisting of midfacial hypoplasia with a characteristic of flat nasal deformity. Overall goal of treatment is to advance skeletal dysplasia of the midface and correct the deformities of the flat nose. Surgical approach is mainly varied with the degree of deformity from simple nasal implant to complicated naso-maxillary osteotomy. In our study, we reported 8 patients with maxillonasal dysplasia using modified naso-maxillary complex and hard palatine "box" osteotomy, combined with chondrocostal bone grafts or nasal implant to correct the retruded nasal deformity. The technique has been used in all patients with ages and degree of deformity. All patients were satisfied with outcome of operation, no severe complication was found. Six-month follow-up evaluation showed good correction of the midface profile and nasal projection, the advancement of midface was found stable, chondrocostal bone graft was fixed perfectly, and no obvious absorption and remodeling was found in short time. The lateral cephalometric analysis and superimposition results showed after the operation, sella-nasion distance had been increased approximately 5 mm, and SNA angle had been increased about 10 degrees. Soft tissue measurement showed the facial convexity angle has increased 8 degrees; the nasolabial angle had increased about 10 degrees after surgery. The tip of the nose had moved 10.0 mm anteriorly and 3.0 mm coronally, respectively. As the result showed modified nasomaxillary complex and hard palatine "box" osteotomy can be a good alternative for advancement of midfacial hypoplasia instead of traditional Le Fort I, II osteotomy, chondrocostal bone graft is a perfect option to correct nasal deformity of Binder syndrome, and both can satisfy requirement of patients. PMID- 23348287 TI - Pfeiffer syndrome: analysis of a clinical series and development of a classification system. AB - Among the craniosynostosis syndromes, Pfeiffer syndrome is notable because of high mortality and the need for multiple surgical interventions. However, it is variable in severity. We propose a new classification of Pfeiffer Syndrome to define pathology and function. A retrospective review was conducted of 42 patients with Pfeiffer syndrome treated from 1975 to 2010, the largest series reported to date. The classification was based on a functional assessment of patients in terms of respiratory, ocular, otological, and neurological status. This classification was tested by scoring and stratifying patients as follows: type A (mild problems), B (moderate problems), or C (severe problems). Patients were scored both at the time of presentation and after all surgical interventions to assess change in functional outcome. The functional classification system was compared to another previously reported. Type A patients did not have any change in postoperative functional outcomes (mean preoperative score 1.6, mean postoperative score 1.6); type B patients showed functional improvement (mean preoperative score 4.1, mean postoperative score 3.4) but type C patients (mean preoperative score 7.7, mean postoperative score 4.8) demonstrated the greatest improvement in functional scores after surgical intervention. Suture pathology did not indicate the clinical severity of phenotype, a variance from a previously published classification. The proposed classification is useful to assess severity of phenotype: respiratory, ocular, otologic, and neurologic problems are key indicators of the need for treatment. The classification can provide a helpful guide in multidisciplinary treatment planning, in reporting outcomes, and in the sharing of data among craniofacial anomalies centers. PMID- 23348288 TI - Treatment of complex facial fractures: clinical experience of different timing and order. AB - Given the variability of the timing and order of surgeries, it is difficult to choose the best treatment for patients with complex facial fractures. Based on the clinical experiences, the authors have reviewed their experience with the timing and order of operations depending on the sites of complex facial fractures and their concurrent injuries. The current study was based on a total of 105 patients with complex facial fractures from the year 2002 to 2011. After assessing the patients' clinical records, radiological data, and clinical photographs, the following data were analyzed: patients' age and sex, causes of injury, concurrent injuries, sites of fractures, the interval between trauma and the operations, the presence of additional surgeries, and the aesthetic and functional outcomes.For most of the patients, early operation was performed (within 2 weeks in 95.2%). Additional surgeries within 1 month after injuries were performed in 22 patients. Usually, a top-to-bottom direction repair was applied when head injuries were involved, and bottom-to-top direction repair was applied when occlusal problems were involved. Of 105 patients whom we were able to follow up, 49 patients showed complications or were dissatisfied with the outcomes. However, except them, most of the patients were satisfied with the outcomes of surgical treatments. There were 14 cases of cheek asymmetry, 9 enophthalmos, 30 paresthesia, 4 malocclusion, and a single case of persistent trismus.In the current study, satisfactory results could be achievable under the following principles: a repair should be done in the early stage after the onset of the injury; supportive surgeries should be done, if necessary, within 2 weeks (no later than 4 weeks); and the order of surgical treatment should be determined by the severity of bone fracture and the systemic status. PMID- 23348289 TI - Real-time navigation-assisted orthognathic surgery. AB - BACKGROUND: One limitation of orthognathic surgery is the narrow surgical field, which makes it difficult to view the operative site directly. Thus, many perioperative complications can occur. In this study, we evaluated the usefulness of computer-aided navigation techniques in orthognathic surgery. METHODS: We enrolled 10 patients (3 men and 7 women) with facial deformities who were treated between July 2010 and February 2011. A Le Fort I osteotomy, sagittal split ramus osteotomy, and reduction malarplasty were performed with guided navigation. RESULTS: All 10 patients were treated successfully using the computer-assisted navigation surgery. Using the navigation system, instruments were visualized on a monitor in real time and all maneuvers were performed safely. CONCLUSIONS: Orthognathic surgery, such as a Le Fort 1 osteotomy, sagittal split ramus osteotomy, and reduction malarplasty, can be performed safely under the guidance of a surgical navigation system. Navigation systems enable surgeons to carry out preoperative plans accurately without injuring important anatomic structures because the positions of the instruments can be visualized on site in real time. PMID- 23348290 TI - Regression modeling to inform cell incorporation into therapies for craniosynostosis. AB - Designing an appropriate tissue engineering solution for craniosynostosis (CS) necessitates determination of whether CS-derived cells differ from normal (wild type, WT) cells and what assays are appropriate to test for differences. Traditional methodologies to statistically compare cellular behavior may not accurately reflect biologically relevant differences because they poorly address variation. Here, logistic regression was used to determine which assays could identify a biological difference between WT and CS progenitor cells. Quantitative alkaline phosphatase and MTS proliferation assays were performed on adipose, muscle, and bone marrow-derived cells from WT and CS rabbits. Data were stratified by assay, cell type, and days in culture. Coefficients of variation were calculated and assay results coded as predictive variables. Phenotype (WT or CS) was coded as the dependent variable. Sensitivity-specificity curves, classification tables, and receiver operating characteristic curves were plotted for discriminating models. Two data sets were utilized for subsequent analyses; one was used to develop the logistic regression models for prediction, and the other independent data set was used to determine the ability to predict group membership based on the predictive equation. The resulting coefficients of variation were high for all differentiation measures. Upon model implementation, bone marrow assays were observed to result in 72%-100% predictability for phenotype. We found predictive differences in our muscle-derived and bone marrow derived cells suggesting biologically relevant differences. This data analysis methodology could help identify homogenous cells that do not differ between pathologic and normal individuals or cells that differ in their osteogenic potential, depending on the type of cell-based therapy being developed. PMID- 23348291 TI - Effect of gene transfecting at different times on mandibular distraction osteogenesis. AB - BACKGROUND: Recently, numerous research of gene therapy for mandibular distraction has been published. Based on previous study, the authors used New Zealand rabbits bilateral mandibular distraction model and used electroporation mediate gene therapy at different time, to explore the optimal time for gene therapy and obtain a better effect. METHODS: Forty-eight New-Zealand rabbits were used; after accomplished osteotomy and implant distraction devices on mandible bilaterly, the rabbits were randomly divided into 4 groups: groups A, B, and C were transfected recombinant plasmids pIRES-hBMP2-hVEGF165 via electroporation mediated approach at latency period, distraction period, and consolidation period, respectively. Group D is a control group, only distracted without gene transfection. After 3 days of latency period, the device was activated at the rate of 1 mm per day for 10 days. Three rabbits of each group were sacrificed at 1, 2, 4, and 8 weeks of consolidation, respectively. The mandibles were harvested; the left was subject to radiograph examination for bone healing, and quantitative computed tomography detect for the bone mineral density (BMD) of newly formed bone in the distraction gap. The biomechanical properties of the new generation bone at the fourth and eighth weeks of consolidation of each group were detected using 3-point bending test. RESULTS: The BMD and the stiffness of newly formed bone increased with the pass of the consolidation time in each group. After 1 week of consolidation, there is no significant difference of BMD among groups A, B, and C. However, the BMD of groups A, B, and C is higher than that of group D. After 2, 4, and 8 weeks of consolidation, the BMD of group B is significantly higher than those of groups A, C, and D. The biomechanical parameters are also higher in group B than those of groups A, C, and D after 4 and 8 weeks of consolidation. CONCLUSIONS: It is better to transfect gene at distraction period than at other stages of DO; in this way, we can obtain more remarkable effect on new bone formation. It suggests that the distraction stage is the optimal time for gene therapy. PMID- 23348292 TI - Variable and invariable proportions in the ontogenesis of the human face. AB - The human face shows individual features and features that are characteristic for sex and age (the loss of childlike characteristics during maturation). The analysis of facial dimensions is essential for identifying individual features also for forensic issues.The analysis of facial proportions was performed on photogrammetric data from front views of 125 children. The data were pooled from 2 different studies. The children's data were obtained from a longitudinal study and reduced by random generator to ensure the data of adults from a separate cross-sectional study.We applied principal component analysis on photogrammetric facial proportions of 169 individuals: 125 children (63 boys and 62 girls) aged 2 7 years and 44 adults (18 men and 26 women) aged 18-65 years.Facial proportions depend on age and sex. Three components described age: (1) proportions of facial height to head height, (2) proportions that involve endocanthal breadth, and (3) bigonial to bizygonial proportions. Proportions that associate with sex are connected with nasal distances and nasal to bizygonial distances.Twenty-three percent of the variance, particularly variance that are connected with proportions of lower and middle face heights to head height, do neither depend on sex nor on age and thus appear useful for screening purposes, eg, for dysmorphic genetic syndromes. PMID- 23348293 TI - Monobloc and bipartition in craniofacial surgery. AB - BACKGROUND: The frontofacial monobloc advancement with osteogenic distraction is increasingly used as a surgical treatment for children with complex craniosynostosis-associated syndromes. However, the subfrontal osteotomy cuts to free the facial skeleton from the skull base require extradural retraction of the frontal lobes. The purpose of this study was to determine the frequency and degree of radiologically identifiable frontal lobe changes and whether any such changes affected the patients' outcome. METHODS: The clinical records and preoperative and postoperative computed tomography imaging of all patients undergoing monobloc frontofacial distraction advancement (with or without bipartition) were reviewed. A retrospective medical notes review was undertaken to assess any patient or surgically related factors that might predispose to frontal lobe changes and evaluate outcome from surgery. Where available, magnetic resonance imaging scans were reviewed to compare outcome with that on computed tomography. RESULTS: Fifty cases were identified as suitable for the study. Eighteen patients (36%) had no frontal lobe changes. Thirty-two cases (64%) did have changes that appeared related to the position of maximum retraction during subfrontal osteotomy cuts. There were no changes in the incidence/extent of these changes over time or of any link to the patients' diagnosis, age at surgery, phenotype severity, surgery type, or any surgical or postoperative adverse events. We found no evidence that these changes were responsible for neurologic problems (eg, epilepsy) or reduced cognitive function. CONCLUSIONS: This study reveals a high incidence of frontal lobe changes demonstrable on neuroimaging following the frontofacial monobloc procedure reflecting the retraction points during surgery. Although no postoperative disability was reported, it is clearly important to consider more detailed neuropsychologic testing and review current surgical techniques to ensure that such changes are kept to a minimum. PMID- 23348295 TI - Novel temporalis muscle and fat pad morphomic analyses aids preoperative risk evaluation and outcome assessment in nonsyndromic craniosynostosis. AB - INTRODUCTION: Analytical morphomics is the term we created to describe an innovative, highly automated, anatomically indexed processing of 3D medical imaging data captured during the course of a patients' preoperative CT scan. Our specific aim is to determine the efficacy of craniofacial morphomic indices (CMI) such as temporalis muscle and temporal fat pad morphometric values to predict blood transfusion requirement and hospital stay in a cohort of children with nonsyndromic craniosynostosis (NSC). METHODS: High-throughput, semi-automated image analysis was used to reconstruct the 3-dimensional anatomy of the temporalis muscle and temporal fat pad and to quantify CMIs. The prognostic effect of CMI on clinical outcomes were evaluated among all NSC patients and compared across various craniosynostosis subtypes using Wilcoxon nonparametric tests and Kendall's tau to determine significance. RESULTS: Using preoperative CT images, we evaluated 117 children with NSC from the University of Michigan Health System. Results demonstrate that increased temporal fat pad volume and local temporalis muscle volume are associated with better clinical outcomes in craniosynostosis patients. More specifically, temporal fat pad volume was shown to be a significant predictor of perioperative blood transfusion requirements (P = 0.0033) and increased temporal muscle volume correlated with decreased hospital stay (P = 0.016) when controlling for other covariates including age, sex, weight, and preoperative hematocrit. In addition, the same significant predictors were found when examining individual subtypes of craniosynostosis. CONCLUSION: Our findings demonstrate that maxillofacial CT scans provide a useful quantitative index reflecting general patient health, risk stratification, and probabilities of intervention in addition to their previously established ability to determine the specific pathology of the patient. We demonstrate that temporal morphomics predict the incidence of blood transfusion, hospital stay, and serve as a proxy for fitness in patients undergoing craniosynostosis surgery. PMID- 23348294 TI - Cranial reconstruction with titanium clamps in frontal comminuted depressed skull fractures. AB - OBJECTIVE: Frontal comminuted depressed skull fractures need special attention due to complications and aesthetics. The optimal method of reconstruction and fixation of frontal bone fragments remains a matter of discussion. We explored the advantages of reconstruction of frontal bone with titanium clamps. PATIENTS AND METHODS: From May 2007 to September 2011, we performed 18 craniotomies with titanium clamps to fix the cranial fragments. On the beginning of craniotomy, single-window craniotomy (n = 11) and 2-window craniotomy (n = 9) were designed. After dural closure and frontobasal reconstruction, these fragments were fixed with titanium clamps. A helical CT scan was obtained after operation and a 3 dimensional technique was performed to evaluate the postoperative results. RESULTS: The CranioFix titanium clamp system was applied in 18 patients. No intraoperative and postoperative complications related to clamps were observed. The number of bone fragments ranged from 2 to 5 (average 3.3 pieces) while the number of clamps ranged from 3 to 8 (average 5.8). The time of refixation ranged from 5 to 17 minutes with an average of 9.4 minutes. Obvious statistical significance (P = 0.015) was found in postoperative CT scan results between single-window group and 2-window group, although it is not statistically different in intraoperative subjective valuation (P > 0.05). In all 18 cases, the alignment of fragments was precise, the fixation rigid, and the aesthetic result satisfying. CONCLUSIONS: Reconstruction of the forehead by refixation of bone fragments with titanium clamps in frontal depressed skull fractures is safe and suitable. This technique promises to be a good alternative in the repair of frontal comminuted depressed skull fractures. The simplicity, reliable fixation, and fast handling are its prominent features. PMID- 23348296 TI - Vascularized composite allotransplantation and tissue engineering. AB - For many living with the devastating aftermath of disfiguring facial injuries, extremity amputations, and other composite tissues defects, conventional reconstruction offers limited relief. Full restoration of the face or extremities with anatomic equivalents recently became possible with decades of advancements in transplantation and regenerative medicine. Vascularized composite allotransplantation (VCA) is the transfer of anatomic equivalents from immunologically and aesthetically compatible donors to recipients with severe defects. The transplanted tissues are "composite" because they include multiple types essential for function, for example, skin, muscle, nerves, and blood vessels. More than 100 patients worldwide have benefited from VCA, the majority receiving hand or face transplants. Despite its demonstrated results, the clinical practice of VCA is limited by center experience, public awareness, donor shortage, and the risks of lifelong immune suppression. Tissue engineering (TE) is the generation of customized tissues in the laboratory using cells, biomaterials and bioreactors. Tissue engineering may eventually supersede VCA in the clinic, because it bypasses donor shortage and immune suppression challenges. Billions of dollars have been invested in TE research and development, which are expected to result in a myriad of clinical products within the mid- to long-term. First, tissue engineers must address challenges such as vascularization of engineered tissues and maintenance of phenotype in culture. If these hurdles can be overcome, it is to be hoped that the lessons learned through decades of research in both VCA and TE will act synergistically to generate off-the-shelf composite tissues that can thrive after implantation and in the absence of immune suppression. PMID- 23348297 TI - Anatomical background for the development of preformed cranioplasty implants. AB - Preformed cranioplasty implants form a new concept of implants to repair relatively large-sized calvarial defects. They could offer an alternative treatment to manually molded cranioplasty, and to flat or patient specific implants, while still achieving a satisfactory clinical result.We report on 3D statistical modeling and analysis performed in 80 clinical CT data of adult European Whites with unaffected calvarial bones to establish an anatomical background for the development of preformed alloplastic cranioplasty implants.Most size and shape (=form) variation was observed bilateral symmetrically in the central temporal region, showing up to 26.8 mm variation and 9.4 mm standard deviation from the mean form. Large deviation was also observed in the central lower forehead, in the central occipital region at the protuberantia occipitalis externa and laterally to it. An intermediate variation was detected at the transition area from the temporal to other regions, as well as in the frontal and occipital area. The cranial roof, the temporal fossa, and the nuchal region exhibited the lowest variability with a standard deviation of about 4 mm. Principal components analysis revealed no relevant shape but a significant size difference between genders. Size contributed to 24.4% of the overall form variability. The mean surface area difference between genders was 67 cm.The size and number of implant forms required have to be referred to the relatively large anatomical variation experienced, and also to considerations related to implant location, design, and material. A rigid material is considered to significantly increase the number of implants forms, especially when repairing relatively large-sized defects. PMID- 23348298 TI - Soft tissue management of orbitotemporal neurofibromatosis. AB - PURPOSE: The aim of this study was to provide an overview of a single institution, 30-year surgical experience with the soft tissue management of orbitotemporal neurofibromatosis. Lessons learned are highlighted in case presentations. METHODS: From 1981 to 2011, all patients who presented to the Chang Gung Memorial Hospital Craniofacial Center with craniofacial neurofibromatosis and orbitotemporal involvement were retrospectively reviewed. The medical records of those patients who underwent surgical correction were reviewed for age, extent of involvement, procedures performed, histologic confirmation, and acute complications. All patients were grouped according to the Jackson Classification. The electronic photobank was queried to evaluate results. RESULTS: Thirty-five patients presented to our center with orbitotemporal neurofibromatosis during the study period. Thirty-one patients underwent surgical management of their disease. The average age was 25 years (range 4 to 57 years). Over half of our patients (n = 18) presented with concomitant disease of the cheek. The 2 most common procedures performed were lateral canthopexy (n = 24) and upper eyelid excision (n = 24). The only acute complication recorded was a postoperative hematoma on the fourth postoperative day following simultaneous lateral canthopexy and upper eyelid excision which required operative evacuation. CONCLUSIONS: In orbitotemporal neurofibromatosis, tissue hyperextensibility and tumor weight adversely affect outcomes. Treatment of concomitant disease of the cheek should be prioritized in order to provide periorbital support prior to addressing the delicate structures of the eyelids. Preservation of the lateral canthal unit and levator muscle, despite neurofibroma infiltration, is critical to maximize outcomes following debulking procedures of the eyelid and orbit. PMID- 23348299 TI - Extended composite temporoparietal fascial flap: clinical implications for tissue engineering in mandibular reconstruction. AB - BACKGROUND: The authors have expanded upon a well-described and widely used flap in the head and neck region. The purpose of the cadaver study was to determine the feasibility, angiosome, and the potential application of this pedicled flap in bone tissue engineering of the mandible. METHODS: A total of 6 fresh human cadaver heads were dissected for a total of 12 flaps. The extended composite temporoparietal fascial flap, based on the superficial temporal artery (STA) and including cranial periosteum, was dissected and the dimensions were measured. Through a combined submandibular and preauricular incision, the mandible was exposed and the dimensions were measured from the sigmoid notch to the gonion angle and from the gonion angle to the symphysis. CT angiography and silicone injections were performed to identify the vascular anatomy of the flap. RESULTS: The combined distance from the sigmoid notch to the gonion and the gonion to the symphysis, plotted versus the cranial apex to tragus length, demonstrated adequate flap dimensions in all specimens for hemi-mandibular reconstruction. The average flap length was 16.5 +/- 1.40 cm and the average flap width was 11.4 +/- 0.98 cm, resulting in an average flap surface area of 94.5 +/- 13.08 cm. Radiographic images and silicone injections confirmed STA perfusion of the cranial periosteum. CONCLUSIONS: The extended composite temporoparietal fascial flap with periosteum can be a viable option for providing vascularized periosteum in tissue-engineered craniofacial reconstruction. PMID- 23348300 TI - Comparison of perivascular and intramuscular applied botulinum toxin a pretreatment on muscle flap ischemia-reperfusion injury and chemical delay. AB - BACKGROUND AND PURPOSE: Muscle flaps are known to be prone to local ischemia more than other flaps. The local and systemic injury that ensues after reperfusion of ischemic skeletal muscle is an important clinical problem in flap surgery. Flap delay may be applied chemically or sympathetically. Early use of botulinum toxin A (Btx-A) in muscle flap surgery relied on chemical denervation; however, in our study, we tried to emphasize a possible chemical delay mechanism of Btx-A, through the release of substance P and calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF). METHODS: Pretreatment with perivascular or intramuscular Btx-A was applied 1 week before the flap elevation, 3.5 units in 2 experimental groups each containing 8 Sprague-Dawley rats. The control groups (2 groups, each containing 8 rats) received 0.07 mL saline perivascularly and intramuscularly. The right gastrocnemius muscle flap was used as the experimental model. Ischemia-reperfusion cycle was applied to all groups. On the seventh day, the gastrocnemius flap was elevated, and perivascular tissues were observed macroscopically. Comparisons between perivascular Btx-A and intramuscular Btx-A groups were made, and the animals were killed. Muscle biopsies were taken. Damaged myocytes were counted using McCormack technique, and chemical delay was shown as angiogenesis, lymphocyte counts, and edema formation with VEGF3-R, CGRP, and substance P markers as immunohistochemical staining. RESULTS: The amount of muscle necrosis was the highest in intramuscular Btx-A admitted groups. The intramuscular and perivascular Btx-A groups showed significant angiogenesis scored blindly by the senior pathologist. CONCLUSIONS: Potential role of Btx-A in ischemic preconditioning of muscle flaps achieved through the release of substance P, CGRP, and VEGF was investigated. Chemical delay was shown objectively by Btx-applied groups. PMID- 23348301 TI - Optic canal location by computed tomography. AB - The aim of this study was to provide anatomic data for optic canal decompression. One hundred twenty people (55 males and 65 females) were involved in this study anonymously. Twelve parameters are measured in computed tomography: P1 is the nasal bone tip; P2 is the middle point of tuberculum sellae; P3 is the root of columella nasi; P4 is the cranium end of the optic canal; P5 is the orbit end of the optic canal; P1' is P1's projection on L2; L1 is the line that links P1 and P2; L2 goes through P3 and parallel to L1; L3 is the bisector of right and left and goes through P1. The distance between LI and L2 was 30.47 +/- 3.71 mm. The distance between P3 and P1' was 11.66 +/- 2.82 mm. The medial canal wall length was 10.64 +/- 1.10 mm on the right and 10.51 +/- 1.07 mm on the left (P = 0.001). The distance between P1 and P4 was 66.74 +/- 5.97 mm. The distance between P1 and P5 was 73.04 +/- 6.33 mm on the right and 72.82 +/- 6.33 mm on the left (P = 0.004). The distance between P5 and L3 was 6.62 +/- 1.33 mm. The distance between P4 and L3 was 12.26 +/- 1.63 mm. The distance between P3 and P4 was 75.82 +/- 4.63 mm. The distance between P3 and P5 was 82.87 +/- 4.60 mm on the right and 82.25 +/- 4.86 mm on the left (P = 0.003). The angle between P1P4 and L3 was 12.26 +/- 1.63 degrees. The angle between P1P5 and L3 was 5.28 +/- 1.13 degrees. The angle between P3P5 and P3P4 was 5.80 +/- 0.97 degrees. These results provide a precise location of the optic canal. PMID- 23348302 TI - Treatment strategy of a huge ameloblastic carcinoma. AB - Ameloblastic carcinoma is a very rare malignant odontogenic tumor. We report a case of secondary-type ameloblastic carcinoma that extended transversally over almost half of the side of the face. Malignant transformation and identification of the malignant region in the large tumor were achieved using L-3-[F]fluoro alpha-methyltyrosine (FAMT)-positron emission tomography (PET); FAMT is transported into cancer cells by L-type amino acid transporter 1 and shows high specificity for malignant tumors. The malignant region determined by microscopic evaluation of resected samples was similar to the region showing high FAMT uptake in PET. Using preoperative FAMT-PET and magnetic resonance imaging, we were able to achieve total resection of the very large tumor, while avoiding excessive resection that could cause severe functional loss or a poor aesthetic facial appearance. We used a modified Weber-Fergusson incision along the nasolabial fold to the labiajugal fold and reconstruction with a pectoralis major muscle flap, and this gave a good aesthetic outcome. Safe surgical resection was possible because preoperative three-dimensional computed tomography angiography was used to identify the position of the main trunk of the external carotid artery, which was closely aligned with the tumor in a posterior direction in the infratemporal fossa region. PMID- 23348303 TI - Management of isolated fractures of the medial orbital wall. AB - The purpose of the present study was to retrospectively review the management and outcome of patients treated by the Australian Craniofacial Unit (ACFU) for isolated fractures of the medial orbital wall. A retrospective medical record review of patients treated between 2008 and 2012 was performed. Ethical approval was granted by the ethics committee of the Women's and Children's Hospital. Patient demographics, causes of injury, physical examination findings, management (conservative or surgical), and findings at follow-up were recorded. Computed tomographic scans were reviewed, and values for fracture area and volume of displaced tissue were calculated. Twenty-four patients with this injury were treated by the ACFU between 2008 and 2012. Eighteen were male, and 6 were female. Assault was the most common cause (15/24 patients). Fifteen patients were managed conservatively, and 9 were treated surgically. In those patients managed conservatively, the mean fracture area was 1.44 cm (0.47-2.47 cm), and the mean volume of displaced tissue was 0.48 mL (0.03-1.15 mL). In patients treated surgically, the mean fracture surface area was 2.32 cm (0.07-3.43 cm), and mean volume of displaced tissue was 0.94 mL (0.00-1.47 mL). No patients were found to have clinically significant enophthalmos at follow-up examination. The current practice of managing isolated fractures of the medial orbital wall at the ACFU has been successful in preventing significant enophthalmos. The thresholds for fracture area and, in particular, volume of displaced tissue, proposed by Jin et al (J Oral Maxillofac Surg 2000;58:617-620), show merit as a tool for determining patient management. PMID- 23348304 TI - Treatment protocol of traumatic pseudoaneurysm of the superficial temporal artery. AB - Pseudoaneurysm of the superficial temporal artery is an unusual complication. Diagnosis is based on clinical findings and radiologic study. The standard treatment is surgical ligation and resection, and other treatment options include radiologic intervention, thrombin injection, and conservative treatment. In this article, the authors report several cases of pseudoaneurysm and suggest a treatment protocol to manage pseudoaneurysm of the superficial temporal artery.We conducted a retrospective review of 11 patients who underwent treatment of superficial temporal artery pseudoaneurysm between April 2002 and July 2011. According to the duration of the aneurysm, we divided the superficial temporal artery pseudoaneurysms into 3 stages: "Acute" stage is less than 3 weeks, "Subacute" stage is from 3 weeks to 3 months, and "Chronic" stage is more than 3 months.Among the 11 patients who were diagnosed with superficial temporal artery pseudoaneurysms, 7 cases were treated by surgical resection, 2 cases by conservative treatment, 2 cases by thrombin injection, and 1 case by radiologic intervention. There was no recurrence during the follow-up periods.The most successful standard treatment is surgical resection. More recently, many nonsurgical treatments have been used, such as conservative treatment, thrombin injection, endovascular embolization, or coiling. Every method has its advantages and disadvantages and should be chosen according to the chronicity and size of the pseudoaneurysm, patient's clinical status, including hemodynamic stability, patient's aesthetic preferences, and compliance. The authors suggest a systematic treatment protocol depending on the stage of the pseudoaneurysm, patients' status, and preferences. PMID- 23348305 TI - Tranexamic Acid reducing blood transfusion in children undergoing craniosynostosis surgery. AB - BACKGROUND: Surgical correction of craniosynostosis in children is associated with substantial intraoperative bleeding. Intraoperatively administered tranexamic acid (TXA) can lessen blood loss during orthopedic and cardiovascular surgery, but its efficacy in craniosynostosis surgery is uncertain. Therefore, a meta-analysis performed with published comparative studies was to determine whether TXA could reduce packed red blood cells (or erythrocytes) (PRBCs) transfused and blood loss during pediatric craniosynostosis surgery. METHODS: Two PubMed and EMBASE electronic databases were searched until June 2012. Eligible studies were restricted in comparative controlled trials. RESULTS: Four studies in 3 articles with 138 patients were included. The results showed that intraoperative administration of TXA can significantly reduce transfusion of PRBCs (weighed mean difference [WMD] = -10.81, 95% confidence interval [CI] = 16.84 to -4.78, P < 0.00001). In the level of blood loss, the meta-analysis on 4 studies showed that the difference was statistically significant (WMD = -20.53, 95% CI = -32.26 to -8.80, P = 0.0006) between the TXA groups and the control groups. However, the subgroup analysis on randomized controlled trials showed that TXA did not significantly reduce blood loss during surgery compared with the placebo group (WMD = -30.79, 95% CIs = -71.72 to 10.14, P = 0.14). CONCLUSIONS: Tranexamic acid can significantly reduce the transfusion of PRBCs in children undergoing craniosynostosis surgery. However, there is a controversy on the efficacy of TXA in reducing blood loss. Therefore, new randomized controlled trials to assess the effects of TXA in children with craniosynostosis surgery should be conducted. PMID- 23348306 TI - Analysis of cosmetic results of metopic synostosis: concordance and interobserver variability. AB - Trigonocephaly is caused by premature fusion of the metopic suture of the calvarium. The resultant facial and skull deformities place a newborn at a higher risk of cerebral impairment. Frontal orbital advancement and remodeling is the accepted surgical management. An analysis was undertaken to assess the cosmetic results for nonsyndromic metopic synostosis following frontal orbital advancement and remodeling and to determine whether the observer technique used had validity.The photographs of 20 consecutive patients with metopic synostosis were assessed preoperatively, postoperatively, and at 3 and 5 years of age. Each photograph was analyzed by 2 pairs of trained rotating observers. The findings were compared and reviewed by the fifth member, who acted as a "referee." Where there were disagreements between the findings, the referee came to a final decision. The presence and severity of trigonocephaly, temporal hollowing, hypotelorism, orbital asymmetry, epicanthic folds, and scarring were assessed. kappa Analysis was used to determine the validity of observer concordance when using photographic material.There was a significant overall trend in craniofacial aesthetic improvement with time. However, 12% had some persistence of trigonocephaly. Temporal hollowing was usually persistent. kappa Statistics varied among attributes and time period assessed. The greatest concordance was for improvement of epicanthic folds and trigonocephaly, with observers agreeing 84.1% and 82.6% of the time, respectively. There was least concordance for severity of hypotelorism and scarring.This study suggests that observer analysis of photographic records is a valid outcome measure for cosmesis, although it yields variable interobserver concordance according to the feature assessed. Surgery corrected most but not all the features of trigonocephaly. The prognostic indicators for good cosmetic outcome are presented. PMID- 23348307 TI - Face transplant: is it feasible in developing countries? AB - This article is based on the case of a 28-year-old woman who was involved in a car accident, with diagnosis of polytrauma, loss of left eye, and second- and third-degree burns over the left midface, rendering an exposed area of 8 cm wide and 19 cm length, ranging from glabella to mandible, with skull exposure and loss of left eye.A latissimus dorsi musculocutaneous free flap was transferred into the defect; left eye and nose prosthetics were necessary to restore normal appearance. Excellent results were obtained; reinsertion to patient's normal life and reinstatement of facial appearance were achieved with minimal costs and no postsurgical complications.Analysis of the current situation in developing countries demonstrates that technique and infrastructure do not represent a real challenge to carry on face transplants. However, socioeconomic reality in these societies makes it difficult to establish face transplant as a feasible therapeutic opportunity for the overwhelming majority of patients who are victims of severe facial damage.Therefore, strategies such as latissimus dorsi free flap remains as an excellent therapy to face off our complex facial reconstructive challenges in developing countries such as Mexico. PMID- 23348308 TI - Three-dimensional assessment of facial development in children with unilateral cleft lip with and without alveolar cleft. AB - Children with cleft lip or cleft lip and alveolus represent a minor group in the cleft population. The aim of this study was to analyze the faces of these children. In a prospective, cross-sectional study, 344 healthy children and 30 children with cleft lip or cleft lip and alveolus were scanned three dimensionally at the age of 0 to 6 years. Twenty-one standard anthropometric landmarks were identified, and the images were superimposed. Growth curves for normal facial development were calculated. The facial morphology of cleft children was compared with that of unaffected children.Facial morphology and growth in the transverse direction of the examined patients appeared broadened in all levels. Especially the nasal landmarks indicated a widening of the nose. The landmarks ac l, sbal l, sbal r, c l, sn l, and ls l differed significantly from unaffected children. In the sagittal and vertical dimensions, there was no significant difference compared with unaffected children.Our study demonstrates that surgical and orthodontic treatment can restore the vertical and sagittal dimensions of the face in children with cleft lip with and without alveolar clefts; however, the transverse dimension-especially the nose-remains too broad. PMID- 23348309 TI - Identification of normal cranial sutures in infants on routine magnetic resonance imaging. AB - There are increasing concerns relating to the ionizing effects of computed tomography imaging in infants with benign conditions. Magnetic resonance imaging (MRI) is a potential alternative to ionizing radiation when determining patency of the cranial sutures; however, there is no documentation in the literature on the appearance of normal cranial sutures in infants on MRI. This study reviews the appearance of the cranial sutures, their widths, and accuracy of identification in the first year of life on MRI.The coronal, sagittal, and lambdoid sutures were evaluated by 5 assessors on 100 anonymized MRI scans in infants aged 1 to 361 days. The sutures were scored on a 3-point scale. The MRI sequences investigated were axial T1, axial T2, coronal fluid attenuated inversion recovery, axial short tau inversion recovery, and sagittal T1. The suture widths were measured in those cases where they were clearly identifiable, and agreement was obtained in the first aspect of the study (n = 38).A kappa score of 0.6 was obtained for interrater agreement. An increasing total score for all sutures with advancing age was found (P < 0.05). The mean suture widths for the coronal, sagittal, and lambdoid sutures were 1.2 (SD, 0.4), 1.4 (SD, 0.4), and 1.3 (SD, 0.3) mm, respectively. There was no significant difference in suture width with age.The appearance of cranial sutures on MRI is as an area of signal void, which may be difficult to clearly define, thus making it unreliable as a standard investigation in the diagnosis of craniosynostosis. PMID- 23348310 TI - Frontal sinus mucocele development in an adult patient with Apert syndrome. AB - Frontal sinus mucoceles may present many years after traumatic injuries or surgical procedures involving the frontal bone, but have been rarely reported after fronto-orbital advancement. We describe a case of frontal sinus mucocele development in a 43-year-old patient with Apert syndrome who underwent fronto orbital advancement as a child. This was treated with resection and free fibula osteomuscular flap reconstruction. Computer-aided design and manufacturing techniques were used to virtually plan the procedure and guide the osteotomies intraoperatively. Follow-up at 1 year postoperatively revealed no evidence of recurrence. PMID- 23348311 TI - Reflections on a curious career-from solid organ to vascular composite tissue allotransplantation. PMID- 23348312 TI - My craniofacial adventure. PMID- 23348313 TI - Joseph Murray. PMID- 23348316 TI - Titanium miniplates: a new risk factor for the development of the bisphosphonate related osteonecrosis of the jaw. AB - Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but potentially severe condition, and the etiopathology and risk factors are poorly defined. The American Association of Oral and Maxillofacial Surgeons position paper on BRONJ update 2009 remarks all the risk factors of developing BRONJ. Local anatomy such as lingual tori, mylohyoid ridge or palatal tori, and areas with thin mucosa overlying bony prominences represent some of these local factors. We have recently treated a patient presenting a mandibular osteonecrosis involving a rigid miniplate which had been placed 18 years ago during a surgical excision of a radicular cyst. The patient, a 70-year-old female, did not show any other risk factors which could expose her to BRONJ, such as cortisone therapy, head and neck radiotherapy, chemotherapy, periodontal disease, or other. PMID- 23348317 TI - Adenomatoid odontogenic tumor with fibro-osseous reaction in the surrounding tissue. AB - Adenomatoid odontogenic tumor (AOT) is a relatively rare odontogenic tumor that is exclusively odontogenic epithelium in origin. We present a rare case of an AOT in a patient with fibro-osseous reaction in the surrounding tissue. A 22-year-old woman complained of gradual swelling of the right maxillary for 1 month. Radiography showed a well-defined radiolucent lesion with root resorption of the involved teeth. The biopsy revealed a primarily cystic lesion surrounded by a solid portion. Microscopically, the cystic part mainly consisted of epithelial cells organized in solid nodules, whorls, and rosettes, typically characteristic of AOT. But the surrounding solid portion showed cellular fibroconnective tissue stroma with prominent calcified spherules corresponding to ossicles and cementicles, characteristic of ossifying fibroma. The presence of a prominent fibro-osseous reaction in our case is unique. To our knowledge, these findings have not been observed in the previous reports of AOT. It could well represent a cellular cystic wall with metaplastic ossification, rather than a benign fibro osseous neoplasm such as ossifying fibroma. The tumor had no recurrence after local resection at 5-year follow-up. PMID- 23348318 TI - Results of endoscopic endonasal dacryocystorhinostomy. AB - Nasolacrimal ductus obstruction cause Epifora. Two widely accepted treatment modalities are external and endoscopic dacryocystorhinostomy. Currently available rigid nasal endoscopes are safe for intranasal manipulation of structures of the nasal cavity, including the region of the lacrimal sac. Twenty-eight patients with complete stenosis of the nasolacrimal duct were treated with endoscopically controlled endonasal dacryocystorhinoslomy. Approximately 97% of the patients were symptom free, and 3% of these felt improved postoperatively. This procedure appears to be safe and effective, which should be considered as an alternative to external dacryocystorhinostomy for the surgical treatment of the nasolacrimal duct obstruction. PMID- 23348319 TI - Intra-auricular sinus: first description of a variant of the pre-auricular cyst. AB - OBJECTIVE: The aim of this study was to describe a rare intra-auricular sinus. An otherwise healthy 15-year-old girl presented with recurrent infections in her right pinna from early infancy. Physical examination revealed a draining sinus which opened to the descending helical limb, while its cystic component was entrapped within the cartilaginous antitragus. Comprehensive surgical excision was performed after the tract and the more distal cyst was delineated. Surgical pathology revealed a true sinus, measuring 2 cm. Follow-up was unremarkable. DISCUSSION: In addition to the two previously described variants of pre-auricular cyst: the classic variant (the pit is anterior to the external auditory canal) and the postauricular variant (the pit is behind the ascending limb of the helix), we suggest a third variant which opens to the descending helical rim. PMID- 23348320 TI - Supernumerary nostril. AB - Supernumerary nostril is a rare congenital anomaly that is classified under duplication of nose. Only 32 cases have been reported so far in the English literature. We attended to an adult female having supernumerary nostril. Surgical correction with minimum intervention was planned, keeping an option of open tip rhinoplasty as backup in case the patient needs it later. She was satisfied with the outcome in spite of having little asymmetry of her nostrils. This case is being reported here as an addition to the published list and the literature reviewed in this context. PMID- 23348321 TI - Induction of periimplantitis in dental implants. AB - Development, progression, and therapy of periimplantitis are nonresolved emerging problems. The aim of this pilot study was to establish a model for periimplantitis in mice to have a base for tests with immune-deficient knockout organisms to improve the knowledge about development and progression of periimplantitis and to develop further therapeutic options.In 8 mice, titanium implants were inserted in the median of the palate. Four of these implants had ligatures (periimplantitis group). After 2 weeks, the animals received a special diet enriched with sugar and flavor. After 9 weeks, micro-computed tomography (micro-CT) examinations to evaluate the periimplant tissue and histologies were performed.Dental implant insertions within the oral cavity are possible in living mice. Implants with ligatures showed significantly larger periimplant bone defects than controls. The radiologic findings were confirmed by histology. At the end of the observation period, the portion of implants lost was higher in the ligature group.This is the first publication to describe the insertion of dental implants in living mice. In addition, it is the first time that periimplant infection could be induced in that species. This model will pave the way to study knockout mice with reduced or even enhanced resistance to periimplantitis. PMID- 23348322 TI - Seasonal variation in birth months of patients with oral-facial clefts. AB - BACKGROUND: Seasonality of the incidence of congenital anomalies has provided useful clues in etiological research. However, seasonality of oral-facial clefts is inconsistent in many countries, including native China. The aim of this study was to determine whether births of patients with oral-facial clefts follow a seasonal pattern in a native Chinese population. METHODS: Patients with oral facial clefts treated at the Plastic Surgery Hospital between January 2002 and December 2011 were retrospectively investigated. The controls comprised all living births from the obstetric department of the Third Affiliated Hospital of Peking University from January 2002 to December 2011. Seasonal variations in birth months were analyzed using the chi test. RESULTS: A total of 6193 patients with oral-facial clefts and 13,254 healthy living newborns were included in this study. Birth time peaks of the patients occurred in autumn and winter, especially in October and January, compared with the nadir in the summer (P < 0.05). The birth time peaks of male patients occurred in autumn and winter, especially in October, February, and January. The birth time peaks of female patients occurred in autumn and winter, especially in January, October, and November. There was a statistical difference in birth distribution among the different months (P < 0.05) and 4 seasons (P < 0.05) in female patients. No statistical difference was found in male patients (P > 0.05). CONCLUSIONS: There is a possible seasonality in birth months and a difference between sexes of patients with oral-facial clefts in this native Chinese population. This approach could be useful to study the etiology and pathogenesis of oral-facial clefts. PMID- 23348323 TI - Bear maul craniocerebral trauma in Kashmir Valley. AB - Craniocerebral injuries constitute the bulk of the trauma patients in all the tertiary-care hospitals. Bear attacks as a cause of trauma to the brain and its protective covering are rare. This was a hospital-based retrospective (January 1990 to July 2005) and prospective study (August 2005 to December 2010). Craniocerebral trauma was seen in 49 patients of bear maul injuries. Loss of scalp tissue was seen in 17 patients, 13 of whom had exposed pericranium and needed split-thickness skin grafting, while 4 patients with exposed skull bones required scalp transposition flaps as an initial procedure. Skull bone fractures without associated brain injury were observed in 24 cases. Frontal bone was the site of fracture in the majority of cases (95%). Surgical intervention was needed in 18 patients for significantly depressed fractures. Three of these patients had depressed frontal bone fractures with underlying contusions and needed brain debridement and duraplasty. Injury to the brain was observed in 8 patients. Trauma to the brain and its protective coverings as a result of bear attacks is rarely known. Brain injury occurs less commonly as compared to soft tissue and bony injury. Craniocerebral trauma as a result of bear assaults has been a hitherto neglected area of trauma as the past reported incidence has been very low. Of late, the incidence and severity of such attacks has assumed grave proportions in areas adjacent to known bear habitats. An innocuous-looking surface wound might be the only presentation of an underlying severe brain trauma. Public awareness has to be generated to protect the people living in hilly areas. PMID- 23348324 TI - Anesthetic risks associated with Antley-Bixler syndrome. AB - Antley-Bixler syndrome is an autosomal recessive disorder characterized by multiple bone and cartilaginous abnormalities. The main features of this syndrome include brachycephaly, midface hypoplasia, dysplasia of ears and nose, radiohumeral synostosis, choanal stenosis, or atresia. Distinctive features are based on craniofacial deformity and humeroradial synostosis. In this report, we describe the anesthesia management of a 20-year-old Antley-Bixler syndrome patient who underwent maxillary advancement via Le Fort I osteotomy. During surgical management of craniofacial syndrome patients, particularly Antley-Bixler syndrome, the whole surgical team should be aware of possible deformities involving the airway, which may be underestimated or nondetected prior to surgery. These deformities including choanal atresia/stenosis may lead to failure of nasotracheal intubation and mask ventilation, therefore jeopardizing the surgical procedure and/or patient safety. Accurate preoperative preparation and being aware of the components of this syndrome is vital to eliminate respiratory complications and enable uneventful anesthetic and surgical management. PMID- 23348325 TI - Evaluation of maxillary sinus volume in cleft alveolus patients using 3 dimensional computed tomography. AB - OBJECTIVE: The aim of the study was to evaluate the volume of the maxillary sinus in patients with cleft alveolus. STUDY DESIGN: This is a retrospective, descriptive study. PATIENTS AND METHODS: The 3-dimensional computed tomographic data of 218 maxillary sinuses of 109 patients with cleft alveolus were compared with those of 100 sinuses of 50 healthy individuals. RESULTS: No significant difference in the maxillary sinus volume was found between the patients with cleft alveolus and the noncleft individuals. In the patients with cleft palate and alveolus, the maxillary sinus volume was significantly larger on the right side, but no significant difference was found between the cleft and noncleft sides. CONCLUSIONS: The volume of the maxillary sinus in the patients with cleft alveolus is not different from that of the noncleft individuals. The information about the maxillary sinus is clinically important in executing such operations as endoscopic sinus surgery. PMID- 23348326 TI - Dermatofibroma located on the tarsal plate after upper blepharoplasty? AB - Dermatofibroma is a firm, skin-colored or reddish-brown sessile papule or nodule. It arises spontaneously without a known cause or after a minor trauma, such as an insect bite. A 39-year-old Asian woman complained of a palpable mass and tenderness in the right upper eyelid. On physical examination, a firm palpable subcutaneous mass was detected in the upper eyelid. Surgical exploration under local anesthesia showed a fibrotic and firmly attached mass to the tarsal plate. In histopathologic examination, the mass was characterized by a fibroblast proliferation in the dermis with an overlying hyperplastic epidermis with frequent basal hyperpigmentation. As far as we know, there have been no previous reports of dermatofibroma located on the tarsal plate. This article is a good example for intratarsal location of dermatofibroma. PMID- 23348327 TI - Scalp erosion in ankyloblepharon-ectodermal defect-cleft lip and/or palate (AEC syndrome): treatment with acellular dermal matrix. AB - Ankyloblepharon-ectodermal defect-cleft lip and/or palate (AEC syndrome, also known as Hay-Wells syndrome) is an autosomal dominant disease caused by mutation in the p63 gene that is primarily characterized by facial clefting, presence of ankyloblepharon, ectodermal dysplasia, and scalp erosion. Scalp erosion is perhaps the most debilitating manifestation of AEC due to its problematic treatment that is fraught with failure given the underlying pathology of the p63 mutation causing dysfunctional wound healing. Management is often targeted in a stepwise fashion, beginning with daily baths, light debridement, and emollients and progressing to extensive skin excision. Skin grafting has limited success and, inevitably, infections requiring aggressive debridement and antibiotic therapy result from dysfunctional healing. The use of acellular dermal matrix for treatment of scalp erosion is a novel approach attempted in a patient with severe scalp disease. Here we report her case and the failure of treatment, along with possible explanations and suggestions for future therapy. PMID- 23348328 TI - Suspension sutures in facial reconstruction: surgical techniques and medium-term outcomes. AB - The purpose of this study was to assess the medium-term results of using thread lift sutures as a means to support soft tissues in facial reconstructive surgery. The rationale for the introduction of this method was to provide support for tissues used in the reconstruction in cases where this would otherwise have been difficult to achieve, or would have demanded major additional surgery in patients already undergoing major surgical procedures. The outcome of the procedure was assessed 12 and 24 months after surgery. Patients were satisfied with the results. Judging from the findings of this study, Silhouette sutures are a valuable asset in facial reconstruction surgery when associated with a scrupulous technique and used for the right indications. PMID- 23348329 TI - Complication following reconstruction of orbital floor with temporalis-coronoid flap after subtotal maxillectomy. AB - A 33-year-old lady was referred to the Department of Oral and Maxillofacial Surgery of Taleghani hospital in 2008. She complained of firm swelling on the left side of her face with toothache, lacrimation, and nasal stiffness. There was a large mass in the left maxillary sinus with extension to the orbital floor, nasal bone, ethmoid sinus, and infratemporal fossa. The incisional biopsy revealed a neurofibroma of the maxilla. She underwent hemimaxillectomy and simultaneous reconstruction with temporalis-coronoid flap for orbital floor reconstruction. After 2 months' follow-up with no complication, she complained of left globe upward movement during gum chewing. The orbital and visual examinations were otherwise normal. This unusual complication has continued for 4 years with no resolution, although the patient does not worry about it any more. PMID- 23348330 TI - Nasal fractures: is closed reduction satisfying? AB - OBJECTIVE: This study aims to evaluate the efficacy of closed reduction and the effects of timing and fracture types on patient satisfaction. METHODS: Only patients with isolated nasal fractures were included in the study. Patients with additional maxillofacial fractures and patients whose application time to our clinic was more than 10 days after the trauma were excluded. Patients were classified into 5 types according to their fracture. All patients underwent closed reduction and external fixation under local anesthesia. Patients were asked about their satisfaction in a survey at 28th day and sixth month after the surgery. Patients were divided into groups according to fracture type and intervention time, and the results of the survey were evaluated. RESULTS: Of the 43 patients included in the study, 38 were male, 5 were female, and the average age was 24.9. The average intervention time of the patients was 5.44 days. Twenty eight (65%) of 43 patients were satisfied with the result, whereas 15 (35%) patients were not happy with their operation. In a comparison of patient satisfaction rates according to fracture type, the mild fracture group had a higher satisfaction rate compared to the severe fracture group. CONCLUSION: Closed reduction is an easy and sufficient treatment for nasal fractures, especially for mild nasal fractures. Early intervention raises the patient satisfaction rate. PMID- 23348331 TI - Syringocystadenocarcinoma papilliferum with squamous cell carcinoma differentiation and with locoregional metastasis. AB - Syringocystadenocarcinoma papilliferum is the rare malignant counterpart of a more common, benign adnexal neoplasm known as syringocystadenoma papilliferum. Review of the literature identified 21 cases of syringocystadenocarcinoma papilliferum. Most reported SCACP seem to represent examples of in situ adenocarcinoma or invasive adenocarcinomas, whereas to our knowledge, only 3 cases were described as SCACP with squamous cell carcinoma. In the present series of 2 cases, we report of SCACP with squamous differentiation and 1 case of SCACP with regional lymph node metastasis. The risk of regional lymph node metastasis is low with SCACP, but it should be kept in mind for the risk of regional metastasis of its morphological type of invasive squamous cell carcinoma. PMID- 23348332 TI - Prevalence and characteristics of HPV infection in oropharyngeal cancer. AB - BACKGROUND: The purpose of this prospective study was to analyze the human papillomavirus (HPV) infection status and its impact on the outcome in a consecutive series of patients affected by oropharyngeal cancer. METHODS: The specimens of consecutive subjects surgically treated for oropharyngeal squamous cell carcinoma were obtained. Samples were collected by broom-type cell sampling devices and they underwent the Roche Linear Array HPV Genotyping Test to identify the presence of HPV types. RESULTS: In all, 52 patients were enrolled. The presence of HPV was detected in 13 samples, with HPV type 16 as the most frequently encountered type. Statistically significant associations were found between HPV-positive patients and a higher tumor grading (P < 0.05), and between HPV-positive patients and a higher number of negative prognostic factors (P < 0.05). CONCLUSIONS: A subset of oropharyngeal squamous cell carcinomas with a higher tumor grading is strongly linked to HPV16 infection. PMID- 23348333 TI - Reactive post-radiotherapy bone formation in the maxilla. AB - OBJECTIVE: High-dose radiation therapy affects bone metabolism, and therefore post-radiotherapy bone formation is an uncommon finding. This case describes an unusual ossification in the maxillary region identified after head and neck radiotherapy. RESULTS: A 45-year-old female patient was submitted to maxillary surgical resection and orbital exenteration due to squamous cell carcinoma. Radiotherapy post-surgery was performed because of compromised surgical margins. After 4 months of the conclusion of radiotherapy, the patient presented a bone exposition at surgical site. Surprisingly, the oral examination and computed tomography revealed a new formation of the right palatine vault and bone formation filling the nasal and orbital cavity. The incisional biopsy discarded residual disease or osteoradionecrosis and showed normal tissue. CONCLUSIONS: To the best of the authors' knowledge, this is the first case of wide bone formation as an early effect of head and neck radiotherapy. PMID- 23348334 TI - Primary bone xanthoma of the inferior orbital rim. AB - Primary bone xanthoma is an extremely rare benign bone tumor histologically characterized by mononuclear macrophage-like cells, abundant foam cells, and multinucleated giant cells. Xanthomas of the bone usually appear as a benign secondary manifestation of some diseases. Therefore, they are denominated primary xanthomas when the other diseases are discarded.We report a peculiar case of primary bone xanthoma of the inferior orbital rim in the absence of hyperlipidemic conditions. Surgical intervention was performed under local anesthesia via a subtarsal 1-cm incision. Histopathological examination confirmed the diagnosis of bone xanthoma. Primary bone xanthomas are extremely rare. Diagnosis of such lesions is challenging and requires both radiographic and histopathological features assessment. A careful work-up and a full lipid profile should be performed to rule out underlying diseases. PMID- 23348335 TI - Endoscopic removal of an ectopic tooth in maxillary sinus. AB - Ectopic teeth erupted in the maxillary sinus are rarely reported. Although the causes of eruption of a tooth into the maxillary sinus are unclear, some clinical conditions are suspected to be responsible, such as developmental disturbances (cleft palate), displacement of teeth by trauma, interventions or cyst, infection, genetic factors, crowding, and dense bone. Most cases of ectopic teeth in the maxillary sinus are asymptomatic and are occasionally diagnosed thanks to routine radiographic investigations.The aim of this article is to present and discuss the surgical management of an ectopic third molar in the roof of the maxillary sinus. PMID- 23348336 TI - New type of sauna-related burn: conductive contact burn. AB - A 70-year-old woman visited a Korean-style hot dry sauna room. The patient had a medical history of hypertension and hyperlipidemia. During the sauna, the patient slept for 30 minutes. During the sleep, the right medial thigh was covered with a fully wet towel. The patient sustained a second-degree burn on the right medial thigh area with multiple bullas. On physical examination, erythema, heating sensation, and swelling around the bullas were noted. The patient was admitted and received intravenous antibiotics for 7 days. A dressing with Silmazine 1% cream (sulfadiazine) was applied twice a day for prevention of local infection. The patient was discharged on day 14 without complication. In this case, the mechanism of the burn was different. Hot air has much thermal energy but is not conducted to the skin directly. A wet towel will have a relatively higher thermal capacity or heat capacity than a dry or damp towel, and the sodden water might be a medium for the conduction of thermal energy. Owing to the global popularity of sauna bathing, it is important to recognize all sources of sauna-related burns. PMID- 23348337 TI - Vascular pericranial graft: a viable resource for frontal sinus obliteration. AB - Inappropriate treatments of frontal sinus fractures may lead to serious complications, such as mucopyocele, meningitis, and brain abscess. Assessment of nasofrontal duct injury is crucial, and nasofrontal duct injury requires sinus obliteration, which is often accomplished by autologous grafts such as fat, muscle, or bone. These avascular grafts have an increased risk of resorption and infection, as well as donor site morbidity. For these reasons, pericranial flap, which is vascular, should be used for frontal sinus obliteration. The pericranial flap presented with less morbidity procedure and has decreased infection rates, which justifies its use in frontal sinus obliteration. This paper aims to report a case of a comminuted frontal sinus fracture in a 29-year-old man who was successfully treated by frontal sinus obliteration, using pericranial local flap. The patient was followed up postoperatively for 16 months without infection. PMID- 23348338 TI - Clinical evaluation of distraction osteogenesis in the treatment of mandibular hypoplasia. AB - BACKGROUND: Mandibular hypoplasia is one of the most frequently encountered craniofacial anomalies with a variety of etiologies, including congenital, developmental, and acquired. It can lead to significant functional issues at birth by creating an obstruction of the hypopharynx with the retropositioning of the base of the tongue, which lead to respiratory and feeding difficulties at birth. Later in life, mandibular hypoplasia may have a severe impact on the quality of life of the patient, affecting mastication, speech, and appearance. Distraction osteogenesis (DO) of the craniofacial skeleton emerged as an alternative to orthognathic surgery. It is a topic of great interest; the technique is gaining enthusiasm for the treatment of a wide range of deformities and achieved wide acceptance in orthopedics. AIM: The objective of the study was to determine the changes in overbite, overjet, and midline shift following mandibular DO in Iraqi patients. METHODS: Nine patients (3 males and 6 females) underwent extraoral multidirectional mandibular DO after proper clinical evaluation. After performing the corticotomy and a mean of 5-day latency period, the distraction was performed at a rate of 0.5 mm twice a day. Subsequent consolidation period mean was 2 months. RESULTS: The mandible was successfully elongated in 9 patients with significant decrease in overbite, overjet, and midline shift, and the actual horizontal movement needed in the correction of overjet is more than the horizontal distractor lengthening. PMID- 23348339 TI - Lower eyelid and cheek reconstruction by a temporally extended V-Y cheek flap. AB - Reconstruction of medium and large cheek defects involving the whole length of the lower eyelid and suborbital region is a challenging procedure. Several cervicofacial flaps are well described in the literature; most of them require extensive undermining and retroauricular and cervical incisions. A case is presented of an 84-year-old woman, a smoker, with a recurrent squamous cell carcinoma on the left suborbital region. Excision resulted in a 5.5 * 3.5-cm defect of the suborbital region and the whole length of the lower eyelid. Considering that the patient was an elderly smoker, a simple technique was sought. Reconstruction was achieved by a wide temporally extended V-Y cheek flap. The extension was used to reconstruct the eyelid and the main flap to cover the cheek defect. The procedure necessitated minimal undermining and was done under local anesthesia with an excellent functional and cosmetic result. PMID- 23348340 TI - Autoclaved autologous bone graft for orbital reconstruction for recurrent temporal bone orbital osteosarcoma. AB - Post-tumor excision and reconstruction of the craniofacial region is a complex and technically demanding process due to its proximity to numerous vital structures and irregularly shaped bony tissue. As such, novel methods are needed when reconstruction of irregularly shaped structures is necessary. Autoclaving of autologous bone grafts is an established practice in orthopedic and neurosurgical practice, but has only been described twice previously for orbital reconstruction. We performed grafting of an autoclaved autologous bone segment as part of surgery on a 30-year-old man to treat his recurrent temporal osteosarcoma with orbital involvement, which is rare. In addition, we went on to highlight key differences between bone autoclaving and pasteurization, an alternative heat treatment technique, for orbital reconstruction post-tumor excision. Although he suffered a second recurrence 8 months later, there was no evidence of recurrence in the autoclaved bone. To treat his second recurrence, he subsequently underwent a modified eyelid-conjunctiva sparing orbital exenteration, also an uncommonly performed procedure. Also, we subsequently examined the novel technique of a lid sparing and conjunctiva-sparing orbital exenteration and its benefits. He continues to remain under follow-up. PMID- 23348341 TI - Oral hyaline ring granuloma. AB - Hyaline ring granuloma is a rare oral lesion with an unclear and controversial etiology, characterized by the presence of rings of palely eosinophilic structureless material (the so-called hyaline rings) with multinucleated giant cells around and within the very same rings.Various theories have been proposed about the pathogenesis of hyaline ring granulomas. Many authors consider a vegetable origin, suggesting that it may represent a reaction to foreign material such as food (and in particular pulses). Instead, other authors deny this possibility, proposing that the hyaline rings might represent degenerated blood vessels, degenerated collagen, or fibrosed extravasated serum proteins.The aim of this article is to present a case of hyaline ring granuloma and to briefly review the literature. PMID- 23348342 TI - Metastasis to paranasal sinuses and orbita of breast cancer with a rare metachronous tumor of the uterine cervix. AB - Breast cancer metastases are rarely seen in paranasal sinuses or orbit with a poor prognosis, and these cases were published as case reports. Moreover, metachronous tumors following breast cancer diagnosis are somewhat common, but uterine cervix is infrequent in them. In the present case, we report a 61-year old female patient who had a biopsy-proven metastatic breast cancer to paranasal sinuses and orbita. She also had a cervical uterine cancer which is also unusually diagnosed following breast cancer. Palliative radiotherapy to paranasal sinuses (30 Gy) achieved a good response. However, she died due to leptomeningeal progression. PMID- 23348343 TI - Bone transport and bone graft using auto-tooth bone for alveolar cleft repair. AB - We herein report the application of a combination of maxillary bone transport and auto-tooth bone grafting for alveolar cleft repair using autogenous extracted teeth developed in Korea.A 9-year-old female patient suffering from unilateral cleft lip and palate was treated with this method. After sagittal interdental right-sided maxillary osteotomy was performed completely between #11 and #12 to the nasal floor, alveolar maxillary bone (#11, 21) was transported in the planned direction and the alveolar cleft was closed. At the end of the transporter activation period, soft tissue in the cleft was removed during so-called "docking surgery" using an electric knife for close bone contact at the docking site. We performed bone transporter removal and simultaneous auto-tooth bone grafting of the patient's supernumerary teeth to the docking site.Maxillary bone transport allowed for simultaneous correction of the nasal septal deviation, maxillary arch deformities, and malocclusion since the dental arch was expanded without donor sacrifice or soft tissue expansion. Auto-tooth bone grafting to the docking site allowed for repair of the bone defects of the nasal floor and alveolar cleft and resulted in a superior bone connection.A combination of maxillary bone transport and auto-tooth bone grafting to the docking site appears to be an effective approach for alveolar cleft repair. PMID- 23348344 TI - Healing of extraction sockets and augmented alveolar defects following 1-year treatment with bisphosphonate. AB - To assess the effect of bisphosphonates on healing of extraction sockets and augmented alveolar defects, 12 adult female mongrel dogs were assigned to 2 experimental groups and a control group. The experimental groups received oral alendronate (ALN, 3.5 mg/kg/wk) or IV pamidronate (PAM, 1 mg/kg/wk) for 12 months. Animals were randomly tested for serum C-terminal telopeptide of collagen I (CTx). The right first and second premolars were extracted. After 8 weeks, extraction sites were evaluated for healing. Subsequently, 3-wall defects were created in ridges and filled with human mineralized cortical particulate bone. Two months post-augmentation, animals were sacrificed and mandibles were collected for cone-beam computed tomography (CBCT) and histomorphometric appraisal. The obtained data were compared using 1-way ANOVA test. CTx test results in both experimental groups were comparable (<10 pg/mL) but lower than that of the control group (minimum 159.2 pg/mL). Two months post-extraction, bone sequestra were noticed in extraction sites in BP-treated groups, involving the entire alveolar bone in the PAM group and the upper rim of the alveoli in the ALN group. Histologically, bone sequestra from the PAM group demonstrated empty osteocyte lacunae, while in the ALN group areas of necrotic bone along with evidence of active bone remodeling was distinguished. Eight weeks post augmentation, the experimental groups showed no evidence of bone formation in the augmented area, while bone formation ratio was measured to be 18.32% in the control group. The mean amount of pixel intensity calculated from the CBCT images of the ALN, PAM, and control group was 113.69 +/- 11.04, 124.94 +/- 4.72, and 113.69 +/- 6.63, respectively. Pixel intensity in PAM-treated group was significantly higher than both other groups. This study demonstrated that 1-year treatment with ALN/PAM was associated with impairment of post-extraction and post augmentation bone healing in dogs. PMID- 23348345 TI - Laryngeal foreign body mimicking croup. AB - Foreign body aspiration can be a fatal problem in all groups of ages. However, it is a leading cause of accidental deaths in children. Especially in the pediatric age group, diagnosis can be delayed because of various challenges. Children younger than 3 years carry the highest risk, as they are inclined to explore objects with their mouths. In most cases of inhaled foreign body, a positive history of aspiration is obtained. We are reporting a case of laryngeal foreign body that is mistreated for 1 week as a croup syndrome. PMID- 23348346 TI - Subacute massive edema of the submandibular region after frenuloplasty. AB - An unusual complication, subacute massive edema of the submandibular region, encountered after a conventional frenuloplasty procedure in a 3-year-old boy is presented. PMID- 23348347 TI - Expression of OPG, RANK, and RANKL proteins in tooth repair processes after immediate and delayed tooth. AB - This study evaluated the immunohistochemical expression of OPG, RANK, and RANKL proteins in the repair after immediate and delayed replantation of rat teeth. Fifty-six Wistar rats (Rattus norvegicus albinus) had their maxillary right lateral incisor extracted and then replanted, according to the following conditions: group I (control; n = 8), teeth were not extracted; group II (n = 16), immediate replantation; group III (n = 16), delayed replantation without treatment; and group IV (n = 16), delayed replantation after root surface treatment (periodontal ligament removal and immersion in 2% acidulated-phosphate sodium fluoride) and calcium hydroxide intracanal dressing. Rats in group I were euthanized on the first day of the experiment, while the animals in the other groups were euthanized 10 and 60 days after replantation (n = 8/period). Hematoxylin and eosin-stained sections were obtained for histological analysis. The immunohistochemical analysis revealed expression of OPG and RANKL proteins in all groups and both postreplantation times, except for group II at 60 days. In the experimental groups, RANK expression was observed only at 10 days. In conclusion, there was strong immunostaining for the OPG-RANK-RANKL system at the earlier postreplantation time, suggesting a more effective participation of these proteins at the start of the healing process, as their expression decreased at 60 days. PMID- 23348348 TI - Soft-tissue profile changes associated with anterior maxillary osteotomy for severe maxillary protrusion. AB - OBJECTIVES: The aim of this study was to evaluate the soft-tissue profile changes after correction of severe maxillary protrusion with anterior maxillary osteotomy via a cephalometric analysis. PATIENTS AND METHODS: Using Wunderer technique, anterior maxillary osteotomies were performed in 14 patients (12 females and 2 males) having severe maxillary protrusion. Standardized lateral digital cephalograms, true size, were taken before the treatment and 12 months after removal of the fixation means. The soft-tissue profile changes resulting from anterior maxillary osteotomy were evaluated by comparing the preoperative and postoperative cephalometric analyses. A statistical analysis was performed using paired t test. The differences were considered significant at P < 0.05. RESULTS: The labial prominence showed reductions of 31% and 20% for the upper and lower lips, respectively. An increase in the nasolabial angle (16%) was noted subsequent to anterior maxillary osteotomies. Also, the facial convexity angle was increased (7%) postoperatively. The interlabial gap and the upper-lip curvature obviously decreased (56% and 60%, respectively) after surgery. The curvature of the lower lip, labiomental fold, showed a decrease of 17% after surgery, causing flatness to the lower face. The postoperative changes in the soft-tissue cephalometric measurements were statistically significant except for the lower-lip curvature and prominence as well as the lower-face height. CONCLUSIONS: Anterior maxillary osteotomy is a highly recommended treatment modality for patients with severe maxillary protrusion. The technique is simple with minimal postoperative complications, and the soft-tissue profile changes after surgery are predictable. PMID- 23348349 TI - Heterotopic ossification in orbital roof, frontal sinus, and ethmoidal cells leading to hypoglobus and upward-gaze deficit. AB - Heterotopic ossification (HO) of facial sinuses is very rare. In this article, we present an extensive HO case covering the right frontal sinus, superior ethmoidal cells, and upper orbital rim and roof. This mass was leading to a hypoglobus and upward-gaze deficit due to mass effect. With an upper eyelid incision, mass over the upper orbital rim and roof was excised by an osteotome. Histopathologic examination was compatible with HO. On the postoperative 18-month follow-up, hypoglobus and upward-gaze deficit have significantly regressed. There were no relapses or enlargement over the operative field or the primary mass seen on computed tomography scans. PMID- 23348350 TI - Extramedullary plasmacytoma of maxillary sinus. AB - Solitary extramedullary plasmacytomas are rare tumors that often affect the head and neck region. Diagnosis of solitary extramedullary plasmocytoma can be confirmed only when the presence of systemic disease is excluded by performing clinical, biological, and radiological investigations. Radiotherapy is considered the treatment of choice, surgery being limited to biopsy and to excision of residual disease. We report herein the case of a 62-year-old man with an extramedullary plasmacytoma arising in the left maxillary sinus who was referred for chemoradiotherapy. PMID- 23348351 TI - Three-stage mandible reconstruction after firearm injury. AB - Firearm injuries in the lower jaw may cause significant loss of hard and soft facial tissues, resulting in aesthetic and functional deformity. In this article, we present a case of a patient who suffered avulsion of the soft and hard tissues of the left mandible body and symphysis. After the emergency treatment, the patient was referred to our service, and the treatment was performed in 3 stages: surgical reconstruction with vascularized fibula flap, distraction osteogenesis, and dental implant rehabilitation. During 5 years of follow-up period, the aesthetic and functional condition of the patient improved considerably. PMID- 23348352 TI - Benign paroxysmal positional vertigo following septorhinoplasty. AB - We present 2 cases of benign paroxysmal positional vertigo (BPPV) following septorhinoplasty. Benign paroxysmal positional vertigo following septorhinoplasty is an unusual entity. Two young women who had difficulty in breathing and nasal deformity underwent septorhinoplasty. On the second and the third postoperative days, the patients experienced vertigo that was induced by position changes. Both patients had neither preexisting ear disease nor vertigo before the surgery. All the examinations were normal. With Dix-Hallpike maneuver, which is the criterion standard test, the characteristic nystagmus was observed. Right posterior canal BPPV was diagnosed, and they were both treated with Epley canalith repositioning maneuver. Publications related to postsurgical vertigo are available in literature, but it is still an underdiagnosed disorder. We would like to mention about this rare entity and inform the surgeons that they must keep in mind that a patient who is complaining about vertigo or dizziness after the surgery should be observed and investigated for BPPV. PMID- 23348353 TI - Surgical approaches for tongue base schwannoma. AB - Schwannomas (neurilemmomas) are benign nerve sheath tumor originating from Schwann cells. They are well circumscribed and rarely infiltrate and metastasize. Schwannomas of the head and neck commonly occur in the tongue followed by the palate, floor of mouth, buccal mucosa, and mandible. Tongue base schwannomas could extend to the pharyngeal cavity or the floor of the mouse, and it is difficult to differentiate between tumors of the lingual, hypoglossal, and glossopharyngeal nerves.Surgical treatment of tongue base schwannomas is difficult because of limited operative exposure. Although mandibulotomy with lip splitting could obtain good exposure, surgeons might strike a balance between exposure obtaining and morbidity following because there are intricate neurovascular anatomical relationships in this region, and mandibulotomy with lip splitting would cause significant morbidity. Surgical approach options are important for tongue base schwannoma removal. From March 2008 to March 2010, 8 patients were clinically and pathologically diagnosed with tongue base schwannomas in our department, and all underwent surgical treatment. In our experience, transoral approach was used for tongue base schwannomas extending to the floor of the mouse and suprahyroid pharyngotomy approach for those extending to the pharyngeal cavity. Follow-up was made until now. One patient who experienced transoral excision still experienced numbness in the region of the lateral tongue tip, and the other 7 patients had no postoperative long-term complications. PMID- 23348354 TI - Spontaneous lateral temporal encephalocele. AB - A spontaneous encephalocele is one that develops either because of embryological maldevelopment or from a poorly understood postnatal process that permits brain herniation to occur. We here report a rare case of lateral temporal encephalocele extending to the infratemporal fossa under the zygomatic arch. At birth, the infant was noted to have a large cystic mass in the right side of the face. After being operated on initially in another center in the newborn period, the patient was referred to our clinic with a diagnosis of temporal encephalocele. He was 6 months old at the time of admission. Computerized tomography scan and magnetic resonance imaging studies revealed a 8 * 9 cm fluid-filled, multiloculated cystic mass at the right infratemporal fossa. No intracranial pathology or connection is seen. The patient was operated on to reduce the distortion effect of the growing mass. The histopathological examination of the sac revealed well-differentiated mature glial tissue stained with glial fibrillary acid protein. This rare clinical presentation of encephaloceles should be taken into consideration during the evaluation of the lateral facial masses in the infancy period, and possible intracranial connection should be ruled out before surgery to avoid complications. PMID- 23348355 TI - Double-skin paddled superficial temporofascial flap for the reconstruction of full-thickness cheek defect. AB - The most common causes of cheek defects include trauma, burn, and tumor resections. In the reconstruction of the defects in this region, it is essential to use similar or adjacent tissue considering the aesthetic and functional properties. For this purpose, numerous local, regional, or distant free flaps were described. The local flaps harvested from the head and neck region are the most frequent methods because of the similar skin color, texture, and compatibility with cheek.In this study, the reconstruction in a 29-year-old male patient who had a full-thickness cheek defect due to tumor resection on the left side was performed, wherein a hairless skin island was carried through the frontal branch of superficial temporal artery for oral mucosa, and a hairy skin island through the parietal branch of the same pedicle was carried for the bearded skin defect. No complication occurred postoperatively and both aesthetic and functional satisfactory results were obtained, providing the oral mucosal and natural beard integrity. Donor-site scarring and temporal alopecia were recorded as the disadvantages of this method.This technique is a useful method for the reconstruction of full-thickness cheek defects because of its advantages including compatibility of color and texture, reliable blood supply, requiring single-session procedure, and being able to carry 2 different skin islands on the same pedicle. PMID- 23348356 TI - Aggressive condylar resorption. AB - This article describes the clinical and radiographic findings in a patient with unilateral aggressive condylar resorption that was diagnosed as osteoarthritis. We present a comprehensive documentation of the clinical manifestations, the appearance on conventional and advanced imaging, and the histopathologic findings. We discuss the systematic approach to develop a differential diagnosis, with specific emphasis on osteoarthritis and idiopathic condylar resorption. Finally, we also discuss the factors that play a role in management of this condition. PMID- 23348357 TI - Giant epignathus teratoma involving the palate, tongue, and floor of the mouth. AB - A teratoma is a true neoplasm composed of multiple tissues foreign to the sites from which they originate. The estimated incidence of mature congenital teratomas at all sites is 1 in 4000 live births, of which at least 2% are oropharyngeal. An epignathus tumor is a congenital malformation classified as a mature teratoma. The incidence of epignathus is much rarer, estimated from 1:35,000 to 1:200,000 live births and has a female predominance. Teratomas, by definition, are neoplasms that consist of all 3 germ cell layers, and in the case of epignathus teratomas, the germ cell layers are mature differentiated tissue. A 1-day-old infant presented to us with giant epignathus that arose from the palate and extended to the lateral oropharynx and to the tongue. The tumor did not cause immediate respiratory obstruction, but there was difficulty with feeding. At the fifth day of the baby's life, the tumor was excised completely under general anesthesia through an endotracheal intubation. PMID- 23348358 TI - FDA requires lower dosing of zolpidem. PMID- 23348359 TI - Colonoscopy preperations. PMID- 23348360 TI - Identity dimensions and related processes in emerging adulthood: helpful or harmful? AB - OBJECTIVES: The current study evaluated the mediational role of well-being in the relationship between identity development and psychosocial functioning. METHOD: A sample of 7,649 undergraduate students (73% female; mean age = 19.95, standard deviation = 1.98; 62% Caucasian) completed measures of personal identity, well being, internalizing symptoms, externalizing problems, and health-risk behaviors. RESULTS: Results revealed that (a) identity exploration and commitment were negatively associated with internalizing symptoms, health-risk behaviors, and externalizing problems through well-being, (b) ruminative exploration was negatively associated with well-being and positively associated with externalizing problems, and (c) increased levels of ruminative exploration appear more detrimental for men than for women. CONCLUSION: The study shed light on the mechanisms through which identity processes are related to internalizing symptoms, externalizing problems, and health-risk behaviors. The role of well being in these associations, and the potentially deleterious "side effects" of exploration and commitment appear to suggest new and important directions for identity research. PMID- 23348361 TI - A history of the identification of the characteristic eating disturbances of Bulimia Nervosa, Binge Eating Disorder and Anorexia Nervosa. AB - During the last 25 years, the careful examination of the eating behavior of individuals with eating disorders has provided critical insights into the nature of these disorders. Crucially, studies investigating components of different eating behaviors have documented that Anorexia Nervosa (AN), Bulimia Nervosa (BN), and Binge Eating Disorder (BED) are characterized by objective disturbances in eating patterns that are significantly different than behaviors exhibited by individuals who do not have these eating disorders. The detailed description of the disturbances in eating behavior has helped to identify diagnostic criteria associated with each disorder, and has led to important hypotheses about the underlying pathophysiology. These advances in understanding have provided, and continue to provide, a foundation for translational research and for the development of novel treatment interventions. This review is based on a presentation given by B. Timothy Walsh, M.D. at the 40th anniversary symposium of the Columbia University Appetite talks outlining the evolution of the discovery of the characteristic eating disturbances seen with each disorder. PMID- 23348362 TI - Quantifying spatial organization in point-localization superresolution images using pair correlation analysis. AB - The distinctive distributions of proteins within subcellular compartments both at steady state and during signaling events have essential roles in cell function. Here we describe a method for delineating the complex arrangement of proteins within subcellular structures visualized using point-localization superresolution (PL-SR) imaging. The approach, called pair correlation photoactivated localization microscopy (PC-PALM), uses a pair-correlation algorithm to precisely identify single molecules in PL-SR imaging data sets, and it is used to decipher quantitative features of protein organization within subcellular compartments, including the existence of protein clusters and the size, density and number of proteins in these clusters. We provide a step-by-step protocol for PC-PALM, illustrating its analysis capability for four plasma membrane proteins tagged with photoactivatable GFP (PAGFP). The experimental steps for PC-PALM can be carried out in 3 d and the analysis can be done in ~6-8 h. Researchers need to have substantial experience in single-molecule imaging and statistical analysis to conduct the experiments and carry out this analysis. PMID- 23348363 TI - In situ detection of individual mRNA molecules and protein complexes or post translational modifications using padlock probes combined with the in situ proximity ligation assay. AB - Analysis at the single-cell level is essential for the understanding of cellular responses in heterogeneous cell populations, but it has been difficult to perform because of the strict requirements put on detection methods with regard to selectivity and sensitivity (i.e., owing to the cross-reactivity of probes and limited signal amplification). Here we describe a 1.5-d protocol for enumerating and genotyping mRNA molecules in situ while simultaneously obtaining information on protein interactions or post-translational modifications; this is achieved by combining padlock probes with in situ proximity ligation assays (in situ PLA). In addition, we provide an example of how to design padlock probes and how to optimize staining conditions for fixed cells and tissue sections. Both padlock probes and in situ PLA provide the ability to directly visualize single molecules by standard microscopy in fixed cells or tissue sections, and these methods may thus be valuable for both research and diagnostic purposes. PMID- 23348365 TI - Bio-inspired aquatic robotics by untethered piezohydroelastic actuation. AB - This paper investigates fish-like aquatic robotics using flexible bimorphs made of macro-fiber composite (MFC) piezoelectric laminates for carangiform locomotion. In addition to noiseless and efficient actuation over a range of frequencies, geometric scalability, and simple design, bimorph propulsors made of MFCs offer a balance between the actuation force and velocity response for performance enhancement in bio-inspired swimming. The experimental component of the presented work focuses on the characterization of an elastically constrained MFC bimorph propulsor for thrust generation in quiescent water as well as the development of a robotic fish prototype combining a microcontroller and a printed circuit-board amplifier to generate high actuation voltage for untethered locomotion. From the theoretical standpoint, a distributed-parameter electroelastic model including the hydrodynamic effects and actuator dynamics is coupled with the elongated-body theory for predicting the mean thrust in quiescent water. In-air and underwater experiments are performed to verify the incorporation of hydrodynamic effects in the linear actuation regime. For electroelastically nonlinear actuation levels, experimentally obtained underwater vibration response is coupled with the elongated-body theory to predict the thrust output. The measured mean thrust levels in quiescent water (on the order of ~10 mN) compare favorably with thrust levels of biological fish. An untethered robotic fish prototype that employs a single bimorph fin (caudal fin) for straight swimming and turning motions is developed and tested in free locomotion. A swimming speed of 0.3 body-length/second (7.5 cm s-1 swimming speed for 24.3 cm body length) is achieved at 5 Hz for a non-optimized main body-propulsor bimorph combination under a moderate actuation voltage level. PMID- 23348364 TI - Incorporation of a viral DNA-packaging motor channel in lipid bilayers for real time, single-molecule sensing of chemicals and double-stranded DNA. AB - Over the past decade, nanopores have rapidly emerged as stochastic biosensors. This protocol describes the cloning, expression and purification of the channel of the bacteriophage phi29 DNA-packaging nanomotor and its subsequent incorporation into lipid membranes for single-pore sensing of double-stranded DNA (dsDNA) and chemicals. The membrane-embedded phi29 nanochannel remains functional and structurally intact under a range of conditions. When ions and macromolecules translocate through this nanochannel, reliable fingerprint changes in conductance are observed. Compared with other well-studied biological pores, the phi29 nanochannel has a larger cross-sectional area, which enables the translocation of dsDNA. Furthermore, specific amino acids can be introduced by site-directed mutagenesis within the large cavity of the channel to conjugate receptors that are able to bind specific ligands or analytes for desired applications. The lipid membrane-embedded nanochannel system has immense potential nanotechnological and biomedical applications in bioreactors, environmental sensing, drug monitoring, controlled drug delivery, early disease diagnosis and high-throughput DNA sequencing. The total time required for completing one round of this protocol is around 1 month. PMID- 23348366 TI - Anatomic predictors of unsatisfactory outcomes in surgical rejuvenation of the midface. AB - OBJECTIVE: To aid the aesthetic surgeon in midface analysis and selection of treatment plans offering the greatest likelihood of success in midface rejuvenation. METHODS: We performed a retrospective review of all patients who underwent surgical midface rejuvenation by a single surgeon. We recorded demographics, history, procedures, outcomes, and complications. Results of physical examination and photography were used to classify patients by volume loss, midface ptosis, skin elasticity, and skeletal anatomy. Outcome was determined by patient satisfaction at the 12-month follow-up; unsatisfactory results were further analyzed by a blinded independent expert with more than 15 years' experience. RESULTS: We included 150 patients. Mean patient age was 51 years; 93.3% were women, and 20.7% had undergone previous procedures, including malar implants, autologous fat grafting, rhytidectomy, midface-lift, and extended lower blepharoplasty. Multimodality treatment was used in 34.0%. Patient dissatisfaction was encountered in 14.0% of cases; the expert concurred in each case. Autologous fat grafting alone demonstrated the greatest propensity for dissatisfaction (4 of 12 cases [33%]). Rate of dissatisfaction was significantly higher with malar hypoplasia (41% vs 7%; P < .001) or loss of elasticity (16% vs 3%; P = .01) but was not highly correlated with age (r = 0.15). CONCLUSIONS: Successful midface rejuvenation requires accurate diagnosis and avoidance of anatomic pitfalls. Many patients require multimodality therapy, including lifting and volumizing techniques. Unsatisfactory results are most common when midfacial aging is accompanied by skeletal insufficiency or loss of elasticity. Respective consideration of these defects should be given to placement of malar implants and rhytidectomy approaches targeting the midface. PMID- 23348367 TI - BiVO(4)/CuWO(4) heterojunction photoanodes for efficient solar driven water oxidation. AB - BiVO(4)/CuWO(4) heterojunction electrodes were prepared using spray deposition of a highly porous bismuth vanadate film onto the surface of an electrodeposited three dimensional network connected copper tungstate. Bilayer BiVO(4)/CuWO(4)/fluorine doped tin oxide glass (FTO) electrodes demonstrated higher photocurrent magnitudes than either with BiVO(4)/FTO or CuWO(4)/FTO electrodes in 1.0 M Na(2)SO(4) electrolyte buffered at pH 7. The photocurrent is enhanced by the formation of the heterojunction that aids charge carrier collection brought about by the band edge offsets. When the pH 7 buffered electrolytes contained 1.0 M bicarbonate is employed instead of 1.0 M sulfate, the charge transfer resistance was decreased. This led to nearly 1.8 times the photocurrent density at 1.0 V vs. Ag/AgCl. The photocurrent was stable over 24 hours in bicarbonate electrolyte. PMID- 23348368 TI - Quantification of intact carboplatin in human plasma ultrafitrates using hydrophilic interaction liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. AB - Carboplatin is a platinum agent that is used for treatment of non-small-cell lung cancer and ovarian cancer. A sensitive and selective analytical method for the quantification of carboplatin in human plasma ultrafiltrates using liquid chromatography-tandem mass spectrometry was developed. Human plasma ultrafiltrates were precipitated by acetonitrile containing carboplatin-d4 as an internal standard and were further diluted with acetonitrile. Chromatographic separation was performed on a Accucore HILIC (50mm*2.1mm i.d., 2.6MUm) column using mobile phase (acetonitrile-water-acetic acid=90:10:0.1, v/v/v) at the flow rate of 0.2mL/min. Detection was performed on electrospray ionization triple quadrupole tandem mass spectrometer using low-energy collision induced dissociation (CID-MS/MS) analysis operating in the selected reaction monitoring (SRM) scan mode. The lower limit of quantification for carboplatin was 0.025MUg/mL. This method covered a linearity range of 0.025-50MUg/mL. The intra day precision and inter-day precision (R.S.D.) ranged from 1.5 to 4.3%, and the accuracy (R.E.) was within +/-2.9%. The present method was applied to a clinical pharmacokinetic study of carboplatin in a cancer patient. PMID- 23348369 TI - Modelling carbon membranes for gas and isotope separation. AB - Molecular modelling has become a useful and widely applied tool to investigate separation and diffusion behavior of gas molecules through nano-porous low dimensional carbon materials, including quasi-1D carbon nanotubes and 2D graphene like carbon allotropes. These simulations provide detailed, molecular level information about the carbon framework structure as well as dynamics and mechanistic insights, i.e. size sieving, quantum sieving, and chemical affinity sieving. In this perspective, we revisit recent advances in this field and summarize separation mechanisms for multicomponent systems from kinetic and equilibrium molecular simulations, elucidating also anomalous diffusion effects induced by the confining pore structure and outlining perspectives for future directions in this field. PMID- 23348370 TI - Sexually dimorphic effects of unpredictable early life adversity on visceral pain behavior in a rodent model. AB - Visceral pain is the hallmark feature of irritable bowel syndrome (IBS), a gastrointestinal disorder, which is more commonly diagnosed in women. Female IBS patients frequently report a history of early life adversity (ELA); however, sex differences in ELA-induced visceral pain and the role of ovarian hormones have yet to be investigated. Therefore, we tested the hypothesis that ELA induces visceral hypersensitivity through a sexually dimorphic mechanism mediated via estradiol. As a model of ELA, neonatal rats were exposed to different pairings of an odor and shock to control for trauma predictability. In adulthood, visceral sensitivity was assessed via a visceromotor response to colorectal distension. Following ovariectomy and estradiol replacement in a separate group of rats, the visceral sensitivity was quantified. We found that females that received unpredictable odor-shock developed visceral hypersensitivity in adulthood. In contrast, visceral sensitivity was not significantly different following ELA in adult males. Ovariectomy reversed visceral hypersensitivity following unpredictable ELA, whereas estradiol replacement reestablished visceral hypersensitivity in the unpredictable group. This study is the first to show sex related differences in visceral sensitivity following unpredictable ELA. Our data highlight the activational effect of estradiol as a pivotal mechanism in maintaining visceral hypersensitivity. PERSPECTIVE: This article directly implicates a critical role for ovarian hormones in maintaining visceral hypersensitivity following ELA, specifically identifying the activational effect of estradiol as a key modulator of visceral sensitivity. These data suggest that ELA induces persistent functional abdominal pain in female IBS patients through an estrogen-dependent mechanism. PMID- 23348371 TI - Accessibility of low-molecular-mass molecules to the median eminence and arcuate hypothalamic nucleus of adult mouse. AB - Blood-derived molecules are able to access to the median eminence (ME) and arcuate hypothalamic nucleus (Arc) due to the lack of the blood-brain barrier. In the present study, we examined the accessibility of low-molecular-mass (LMM) molecules into parenchyma in the ME and Arc of adult mice by administration of Dextran 3000 (Dex3k), Dex10k, Evans blue (EB) and fluorescein isothiocyanate (FITC). In the external zone of the ME, the fluorescence of Dex3k, EB and FITC tracers generated an intensity gradient from fenestrated capillary, but that of Dex10k was detected only between the inner and outer basement membrane of pericapillary space. The fluorescence of FITC in the external zone of the ME was closely associated with axonal terminals and surrounded by cellular processes of tanycytes-like cells and astrocytes. In the ependymal/internal zone of the ME and Arc, the fluorescence of all LMM tracers was seen at tanycytes-like cells and neurons. The fluorescence of EB and FITC in these regions was not detected when brains were fixed during or before the administration of tracers. The inhomogeneity of accessibility for fluorescent tracers depended on routes for tracer administration. Thus, the present study indicates that the accessibility of LMM blood-derived molecules to parenchyma depends on fenestration of the capillary in the external zone of the ME and active transport of ependymal cells in the ependymal/internal zone of the ME and Arc. PMID- 23348372 TI - Investigations of protein-protein interactions using time-resolved fluorescence and phasors. AB - Protein interactions are critical for biological specificity and techniques able to characterize these interactions are of fundamental importance in biochemistry and cell biology. Fluorescence methodologies have been extremely useful for studying many biological systems including protein-ligand and protein-protein interactions. In this review we focus on the application of time-resolved fluorescence approaches to macromolecular systems. We also include a detailed discussion of a relatively new time-resolved technique, the phasor method, for studying protein interactions both in vitro and in live cells. PMID- 23348376 TI - The influence of directed attention at encoding on source memory retrieval in the young and old: an ERP study. AB - Neuroimaging evidence suggests that older adults exhibit deficits in frontally mediated strategic retrieval processes, such as post-retrieval monitoring. Behavioral research suggests that explicitly directing attention toward source features during encoding may improve source memory for both young and older adults and alleviate age-related source memory impairments, in part, by reducing demands on post-retrieval monitoring. We investigated this hypothesis in the present event-related potential (ERP) study. Young and older adults attended to either objects and their presented color (source) or to the object alone during study and made color source memory decisions at test. We attempted to match performance between groups by halving the memory load for older adults. Behavioral results showed that, while direction of attention to object and color improved source memory for both groups, older adults benefited less than the young. ERPs revealed that demands on late right frontal effects, indicative of post-retrieval monitoring, were similarly reduced by directed attention at encoding for both groups. However, older adults showed reduced ERP correlates of recollection (parietal old-new effect), as well as a sustained widespread negativity, potentially indicative of memory searches for perceptual details in the face of impaired recollection. These results suggest that older adults, like the young, can engage in post-retrieval monitoring when source details are difficult to recover. However, impaired recollection may underlie persistent age related source memory deficits, even when encoding is supported via directed attention. PMID- 23348377 TI - Effects of acute microinjections of thyroid hormone to the preoptic region of euthyroid adult male rats on sleep and motor activity. AB - In adult brain tissue, thyroid hormones are known to have multiple effects which are not mediated by chronic influences of the hormones on heterodimeric thyroid hormone nuclear receptors. Previous work has shown that acute microinjections of l-triiodothyronine (T3) to the preoptic region significantly influence EEG defined sleep in hypothyroid rats. The current study examined the effects of similar microinjections in euthyroid rats. In 7 rats with histologically confirmed microinjection sites bilaterally placed in the preoptic region, slow wave sleep time was significantly decreased, but REM and waking were increased as compared to vehicle-injected controls. The EEG-defined parameters were significantly influenced by the microinjections in a biphasic dose-response relationship; the lowest (0.3MUg) and highest (10MUg) doses tested were without significant effect while intermediate doses (1 and 3MUg) induced significant differences from controls. There were significant diurnal variations in the measures, yet no significant interactions between the effect of hormone and time of day were demonstrated. Core body temperature was not significantly altered in the current study. The demonstration of effects of T3 within hours instead of days is consistent with a rapid mechanism of action such as a direct influence on neurotransmission. Since the T3-mediated effects were robust in the current work, euthyroid rats retain thyroid hormone sensitivity which would be needed if sleep regulatory mechanisms in the preoptic region are continuously modulated by the hormones. This article is part of a Special Issue entitled LInked: BRES-D-12 01552 & BRES-D-12-01363R2. PMID- 23348378 TI - A glutamatergic projection from the lateral hypothalamus targets VTA-projecting neurons in the lateral habenula of the rat. AB - Homeostasis describes the fundamental biological ability of individuals to maintain stable internal conditions in a changing environment. Homeostatic reactions include internal adjustments as well as behavioral responses. In vertebrates, behavioral responses are induced by the reward system. This system originates in the ventral tegmental area (VTA) and leads to increased dopamine levels in the forebrain whenever activated. A major inhibitor of VTA activity is the lateral habenula (LHb). This epithalamic structure is able to almost completely suppress dopamine release, either directly or via the rostromedial tegmental nucleus (RMTg), when rewarding expectations are not met. A major input to the LHb arises from the lateral hypothalamic area (LHA), an important regulator of the homeostatic system. Currently, little is known about the effects of the strong hypothalamic projection on the activity of LHb neurons. In the present study, we analyze neurotransmitters and cellular targets of the LHA-LHb projection in the rat. Therefore, anterograde tracing from the LHA was combined with the visualization of neurotransmitters in the LHb. These experiments revealed a mainly glutamatergic projection, probably exerting excitatory effects on the targeted LHb cells. These cellular targets were analyzed in a second step. Anterograde tracing from the LHA in combination with retrograde tracing from the VTA/RMTg region revealed that LHb neurons projecting to the VTA/RMTg region are densely targeted by the LHA projection. Visualization of synaptophysin at these contact sites indicates that the contact sites indeed are synapses. Taken together, the present study describes a strong mainly glutamatergic projection from the LHA that targets VTA/RMTg-projecting neurons in the LHb. These findings emphasize the potential role of the LHb as direct link between homeostatic areas and reward circuitries, which may be important for the control of homeostatic behaviors. PMID- 23348379 TI - Gremlin is a novel VTA derived neuroprotective factor for dopamine neurons. AB - Parkinson's disease and its characteristic symptoms are thought to arise from the progressive degeneration of specific midbrain dopamine (DA) neurons. In humans, DA neurons of the substantia nigra (SN) and their projections to the striatum show selective vulnerability, while neighboring DA neurons of the ventral tegmental area (VTA) are relatively spared from degeneration. Recent studies from our laboratory have shown that the VTA exhibits a unique transcriptional response when exposed to MPTP (Phani et al., 2010), a neurotoxin able to mimic the selective cell loss observed in PD (Schneider et al., 1987). In this study, we focus on gremlin, a peptide that is transcriptionally increased in the VTA in response to MPTP. We describe a novel role for gremlin as a neuroprotective agent both in vitro and in vivo and show that gremlin is capable of protecting SN DA neurons and several DA cell lines against MPP+/MPTP. We propose that this protection is mediated by VEGFR2, and by the MAP kinase signaling pathway downstream of the receptor. Our data indicate that gremlin may be a key factor in protecting the VTA against MPTP-induced cell death, and that exogenous application of gremlin is capable of protecting SN DA neurons, and therefore may provide an opportunity for the development of novel PD therapeutic compounds. PMID- 23348380 TI - Effects of fluoxetine on cloned Kv4.3 potassium channels. AB - Fluoxetine is widely used for the treatment of depression. We examined the action of fluoxetine on cloned Kv4.3 stably expressed in CHO cells using the whole-cell patch-clamp technique. Fluoxetine did not significantly produce a reduction in the peak amplitude of Kv4.3, but increased the rate of current inactivation in a concentration-dependent manner. Thus, the effect of fluoxetine on Kv4.3 was measured from the integral of the current during the depolarizing pulse. The integral of Kv4.3 was reduced by fluoxetine in a concentration-dependent manner with an IC50 of 11.8MUM. Using first-order kinetics analysis, the apparent association and dissociation rate constants were 1.5MUM(-1)s(-1) and 22.2s(-1), respectively, with a K(D) of 14.2MUM, similar to the IC50 value calculated from the concentration-response curve. Under control conditions, the inactivation of Kv4.3 was best fit by a biexponential function. The fast and slow time constants were significantly decreased in the presence of fluoxetine. Time-to-peak and activation kinetics were significantly accelerated by fluoxetine. The block of Kv4.3 by fluoxetine became more prominent as the membrane potential became more depolarized, displaying a shallow voltage dependence (delta=0.29) in the full activation voltage range. Fluoxetine did not affect the steady-state inactivation curves, but significantly accelerated the closed-state inactivation of Kv4.3. The block of Kv4.3 by fluoxetine was use-dependent during repetitive stimulation, which explained the slowing of the recovery from inactivation of Kv4.3. Our results indicate that fluoxetine blocks Kv4.3 by preferentially interacting with the open and accelerating closed-state inactivation of the channel. PMID- 23348382 TI - Role of podoplanin expression in squamous cell carcinoma of upper aerodigestive tract. AB - Podoplanin, a type-1 transmembrane glycoprotein, was originally named due to its expression in renal podocytes of rats. It was subsequently detected in a variety of normal human tissues, including lymphatic endothelium. Although podoplanin has been identified as the endogenous ligand of C-type lectin-like receptor 2 (CLEC 2) on platelets, its physiological functions and pathways remain largely unknown. A role in lymphangiogenesis has been suggested, since podoplanin-deficient mice were found to die at birth with a phenotype of dilated, malfunctioning lymphatic vessels and lymphedema. Podoplanin is invariably expressed in some tumors, such as lymphangioma, seminoma and follicular dendritic cell tumor, but tumor cell expression of podoplanin is highly variable in squamous cell carcinoma (SCC). It has been found that high podoplanin expression is associated with lymph node metastasis and poor prognosis in SCC of the upper aerodigestive tract. Now there is growing evidence that podoplanin is also involved in carcinogenesis, cell motility, tumor invasiveness, platelet aggregation and hematogenous metastasis. Additionally, animal studies confirmed some in vivo effects of podoplanin overexpressing tumors, including formation of more tumor lymphatic vessels, larger lymph node metastases, more platelet aggregation, and more pulmonary metastases. Several recently developed anti-podoplanin antibodies, such as NZ-1, P2-0 and hP2-0, have been shown to attenuate podoplanin-induced platelet aggregation and prevent experimental hematogenous metastasis in nude mice. These antibodies may be applied in preclinical and clinical studies to evaluate the possibility of podoplanin-targeted therapy. PMID- 23348383 TI - Neurobiological toxicity of radiation in hippocampal cells. AB - Worldwide radiation exposure is increasing due to recent nuclear accidents, space travel, atomic weapons testing and use, and medical treatments. In adult animals, ionizing radiation can significantly impact hippocampal neurogenesis and negatively affect hippocampal functions such as cognition. However, there is considerable uncertainty regarding the mechanisms underlying these effects. This article reviews in vivo and in vitro studies on the effects of irradiation on hippocampal neurogenesis and function in order to gain new mechanistic insights. This information will provide complementary views of our understanding of the normal brain's tolerance to radiation exposure, the potentially serious implications of radiation exposure to cognition, and lead to a discussion of potential strategies for pharmacotherapy and behavioral intervention. PMID- 23348381 TI - Metastasis suppressor genes. AB - Metastasis is a major cause of cancer mortality. Metastasis is a complex process that requires the regulation of both metastasis-promoting and metastasis suppressor genes. The discovery of metastasis suppressor genes contributes significantly to our understanding of metastasis mechanisms and provides prognostic markers and therapeutic targets in clinical cancer management. In this review, we summarize the methods that have been used to identify metastasis suppressors and the potential clinical impact of these genes. PMID- 23348384 TI - Chromosome 16q loss--a genetic key to the understanding of breast carcinogenesis. AB - In the last decade the concepts of breast cancer dedifferentiation and progression have undergone a significant and substantial change. In the past it was widely believed that the detailed associations between genetic and morphological changes defined in the Vogelstein model of colorectal cancer pathogenesis could be transferred to breast carcinogenesis. A multitude of studies seemed to verify this a priori hypothesis. However, with the introduction of global screening techniques, predominantly at the DNA level, it became obvious that this linear model might be oversimplified for breast cancer. It is now widely accepted that losses of chromosomal 16q characterize in-situ and invasive breast cancer tumours with predominantly low tumour grade and estrogen receptor (ER) positivity (luminal breast cancers). In contrast, high grade breast cancers of the HER2, the basal or the non expressor phenotype with 16q-losses are rarely seen and in consequence a concept of multiple, parallel pathways with defined precursor lesions emerged. As a consequence, it became obvious that the hunt for oncogenes/tumour suppressor genes in invasive breast cancer is pathway specific. Whereas high grade breast cancers have been relatively well characterized by several recurrent changes in oncogenes/tumour suppressor genes located on various chromosomal regions (e.g. egfr, p53, HER2), the characterization of a 16q-specific tumour suppressor gene in ER-positive breast cancer is still a tremendous challenge. This review will focus on the role of 16q in breast cancer and aims to give insights into actual research efforts, e.g. alternative explanations in order to unravel the central role of 16q in breast cancer. PMID- 23348385 TI - Clear cell papillary cystadenocarcinoma of the epididymis: a case report and immunohistochemistry of markers for renal cell carcinoma. AB - Neoplasms of the epididymis are uncommon, and malignant tumors are extremely rare. We report a case of clear cell papillary cystadenocarcinoma of the epididymis presenting with a long history of painless scrotal mass on the left side. Immunohistochemical markers for clear cell renal cell carcinoma (RCC) were examined to distinguish between clear cell papillary cystadenocarcinoma of the epididymis and metastatic clear cell renal cell carcinoma. The present case was positive for cytokeratin-7, PAX2, vinculin, vimentin and carbonic anhydrase IX. Expression of CD10 was focally observed. In contrast, no immunoreactivities for alpha-methylacyl-CoA racemase, RCC marker, glutathione S-transferase alpha or C KIT were detected. The immunophenotypic profile of clear cell papillary cystadenocarcinoma of the epididymis closely resembles that of clear cell papillary RCC, although the immunohistochemical markers tested in this study are useful to make a differential diagnosis between clear cell papillary cystadenocarcinoma of the epididymis and metastatic clear cell RCC. PMID- 23348386 TI - Histological examination on osteoblastic activities in the alveolar bone of transgenic mice with induced ablation of osteocytes. AB - The purpose of this study was to examine histological alterations on osteoblasts from the alveolar bone of transgenic mice with targeted ablation of osteoctyes. Eighteen weeks-old transgenic mice based on the diphtheria toxin (DT) receptor mediated cell knockout (TRECK) system were used in these experiments. Mice were injected intraperitoneally with 50 ug/kg of DT in PBS, or only PBS as control. Two weeks after injections, mice were subjected to transcardiac perfusion with 4% paraformaldehyde in 0.1M phosphate buffer (pH 7.4), and the available alveolar bone was removed for histochemical analyses. Approximately 75% of osteocytes from alveolar bones became apoptotic after DT administration, and most osteocytic lacunae became empty. Osteoblastic numbers and alkaline phosphatase (ALP) activity were markedly reduced at the endosteum of alveolar bone after DT administration compared with the control. Osteoblastic ALP activity in the periodontal ligament region, on the other hand, hardly showed any differences between the two groups even though numbers were reduced in the experiment group. Silver impregnation showed a difference in the distribution of bone canaliculi between the portions near the endosteum and the periodontal ligament: the former appeared regularly arranged in contrast to the latter's irregular distribution. Under transmission electron microscopy (TEM), the osteoblasts in the periodontal ligament showed direct contact with the Sharpey's fibers. Thus, osteoblastic activity was affected by osteocyte ablation in general, but osteoblasts in contact with the periodontal ligament were less affected than endosteal osteoblasts. PMID- 23348387 TI - Malignant transformation of nasal chondromesenchymal hamartoma in adult: a case report and review of the literature. AB - Nasal chondromesenchymal hamartoma (NCMH) is an extremely rare benign tumor arising in the sinonasal tract, predominantly involving infants and children. To date, only 27 cases are reported in the international literature and there have been no reported cases of malignant transformation. We present a 40-year-old female patient with nasal obstruction and bloody rhinorrhea. Computed tomography (CT) of the nose and paranasal sinuses confirmed a heterogeneous polypoid soft tissue mass filling the nasal cavity and extending into the maxillary and ethmoid sinus. The patient underwent a complete radical resection. Histological and immunohistochemical analyses showed a portion of the mass was consistent with typical NCMH. However, some areas of mass exhibited cytological atypia, marked mitotic activity and foci of necrosis. The atypical mesenchymal spindle cells were immunoreactive for vimentin, CD99 and smooth muscle actin (SMA) diffusely. The cartilaginous cells were immunopositive for S-100 protein. Ki-67 index was high in atypical areas, accounting for 50%. A rapid mass recurrence was observed at the original site only 3 months after surgery. The final diagnosis of NCMH with malignant transformation was made. To our knowledge, this is the first report of malignant transformation occurring in an adult with NCMH. Although NCMH commonly develops in the neonate or young infants and exhibits benign histological appearance and favorable prognosis, there is a possibility of malignant transformation in adult patients. Thoroughly histological inspections are suggested to be necessary to accurately diagnose this tumor when it is encountered in adults. PMID- 23348388 TI - Immunohistochemical study of enteric nervous system in hirschsprung's disease and intestinal neuronal dysplasia. AB - BACKGROUND: Hirschsprung's disease (HD) is one of the most common motility disorders in pediatric age groups and it is very important that it be differentiated from other types of motility disorders, especially intestinal neuronal dysplasia B (IND B). Although many studies regarding the differences between the two disorders by immunohistochemical studies exist, there is as yet no consistent result. The purpose of this research was to study the immunohistochemical findings of enteric nervous system in these two motility disorders in comparison with colectomies without motility disorder. METHODS: Full wall thickness specimens of three groups of patients (HD, IND B and non motility disorders) were included in the study to be evaluated by immunohistochemistry (IHC). Markers were specific for neuronal cells and pace maker cells composed of PGP 9.5, c-kit, synaptophysin, S100 and CD56. The number of cells was evaluated in the muscularis properia, and myenteric plexus. RESULTS: The number of all the IHC markers i.e. PGP9.5, c-kit, synaptophysin, S100 and CD56 was completely different in HD from the two other groups, while IND B was quite similar to control group. CONCLUSION: Our finding suggests that there is a marked and significant difference between HD and IND B by IHC markers, which can be used as an additional test for the diagnosis of HD with more accuracy. Further multicenter studies with a greater number of cases would be necessary to find a cut-off point for every IHC marker to differentiate HD and IND B. PMID- 23348389 TI - Levels of acyl-coenzyme A synthetase 5 in urothelial cells and corresponding neoplasias reflect cellular differentiation. AB - Metabolic components like fatty acids and acyl-Coenzyme A (acyl-CoA) thioesters have been implicated in the pathogenesis of various tumours. The activation of fatty acids to acyl-CoAs is catalysed by long chain acyl-CoA synthetases (ACSLs), and impairment of ACSL expression levels has been associated with tumourigenesis and progression. Since ACSLs have never been investigated in bladder tissues, the study aims to characterize ACSL expression and acyl-CoA synthesis in normal and neoplastic bladder tissues, as well as cell lines. ACSL isoforms 1, 3, 4 and 5 and synthesis of acyl-CoAs were analysed using qRT-PCR, western blot analysis, immunohistochemistry and lipid mass spectrometry. In normal urothelium, expression of ACSL1, 3, 4 and 5, with highest levels of ACSL isoform 5 was found. However, ACSL5 expression was reduced in corresponding neoplastic tissues and urothelial cell lines depending on the grade of cellular differentiation. Anti ACSL5 immunostainings showed expression in normal urothelium and a gradual loss of ACSL5 protein via pre-invasive lesions to invasive carcinomas. High expression of ACSL5 correlated with increased alpha-galactosidase activity and positive Uroplakin III staining in tumours. In contrast, synthesis of acyl-CoAs was enhanced in neoplastic bladder tissues compared to normal urothelium, and reflected an increase with respect to cellular differentiation. These results confirm an expression of ACSLs, especially isoform 5, in human urothelium, prove enzymatic/lipidomic changes in bladder cancer tissues, and suggest an involvement of ACSL5 in cellular maturation and/or senescence with possible effects onto induction of tumour formation or progression. Further work may identify responsible pathway alterations, and attempting to re-balance the metabolic equilibrium of the urothelium may offer a further opportunity for tumour treatment and prevention. PMID- 23348390 TI - DKC1 gene mutations in human sporadic cancer. AB - INTRODUCTION: Germline mutations in the tumour suppressor gene dyskeratosis congenit 1 (DKC1) cause the cancer prone syndrome called X-linked dyskeratosis congenita. The present study aims to determine whether mutations of the DKC1 gene may also be present in frequent human sporadic cancers (breast, colon and lung cancers), thus potentially contributing to the neoplastic phenotype. MATERIALS AND METHODS: mutation analysis of the DKC1 gene was performed on DNA from 110 primary human lung, 54 breast, and 35 colon cancers, focusing on gene regions where pathogenic germline mutations have been described previously (promoter and exons 1, 3, 9, 10, 11, and 14). RESULTS: Out of a total of 199 primary tumours of different origins, only 5 turned out to have sequence variations in the DKC1 gene. These variations were of two kinds, C8120T and C13554T, which are both classified as synonymous mutations and do not affect DKC1 mRNA splicing. CONCLUSION: direct DKC1 gene mutations are not a frequent event in tumourigenesis, at least in the tumour types investigated and for the DKC1 gene portions considered in this study. PMID- 23348391 TI - Different influence of ovine estrus synchronization treatments on caruncular early angiogenesis. AB - The present study compares two protocols for ovine estrus synchronization by assessing the caruncular angiogenic response to the establishment of pregnancy. The analysis consisted of the immunohistochemical evaluation of Vascular Endothelial Growth Factor (VEGF), Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1, CD31) and Von Willebrand Factor (vWF) in ovine caruncular stroma. A flock of thirty-eight adult ewes was divided in two groups and synchronized with either progestagens (Group P) or prostaglandin analogues (Group PG). Immunohistochemistry was performed in uterine samples obtained from pregnant ewes (P, n=15; PG, n=13) on days 15 post coitus (pc), 17pc and 21pc (day 0 =day of estrus). Each factor was assessed by total vascular density (TVD, total positive blood vessels/mm2), capillary vascular density (CVD, positive blood capillaries/mm2) and arteriolar vascular density (AVD, positive arterioles/mm2). Group P demonstrated higher VEGF-CVD (P=0.045) when compared to prostaglandin treated animals. Vascular CD31-expression decreased on days 15pc and 21pc (TVD, P=0.007 and CVD, P=0.014) in both groups. vWF analysis did not show significant differences between groups or days of study. These results demonstrate a different influence of progestagen-based and prostaglandin analogues-based synchronization treatments over VEGF vascular expression during caruncular development taking place in response to pregnancy establishment. In addition, observations pointed out in this study support the involvement of CD31 in the angiogenic stimulus that occurs during early maternal placentation in the ewe. PMID- 23348392 TI - Postnatal neurogenesis in the cow pineal gland: an immunohistochemical study. AB - In the pineal gland of cows and rats structures designated rosettes have been described both during embryonic development and in adult animals. In order to investigate the possible nature of the cells comprising such structures, in the present work we studied the pineal glands from 10 cows of one- or four-years-old using conventional immunocytochemical and confocal microscopy techniques. As markers of glial cells, we used anti-vimentin (Vim) and glial fibrillary acidic protein (GFAP) and anti-S-100 sera, and the pinealocytes were labelled with beta III tubulin. As a marker of stem cells, we used an antinestin serum, while an anti-PCNA serum was employed to label proliferating cells. To explore the neuronal nature of some cells of the rosettes, we used an anti-SRIF serum. The rosettes were seen to be present throughout the glandular parenchyma and displayed a central cavity surrounded by cells, most of which expressed all or just some of the above glial labels and nestin, although there were also some rosettes with cells that expressed beta-III tubulin and other cells that expressed SRIF. Likewise, in the cells of the rosettes the cell nucleus showed strong expression of PCNA. Confocal microscopy revealed that the walls of the rosettes contained cells that coexpressed Vim/S-100, Vim/GFAP and Vim/nestin. The number of rosettes was significantly greater in the animals of one year of age with respect to the four-year-old cows. The present findings allow us to suggest that rosettes are evolving structures and that most of the cells present in their walls should be considered stem cells, and hence responsible for the postnatal neurogenesis occurring in the pineal gland of cows. PMID- 23348393 TI - Analysis of animal and plant selenometabolites in roots of a selenium accumulator, Brassica rapa var. peruviridis, by speciation. AB - Many studies have examined the metabolic pathway of selenium (Se) compounds in Se accumulating plants (hereafter "Se accumulators") when the plants are exposed to inorganic Se, such as selenite and selenate. However, if we were to consider Se circulation in the biosphere, the metabolism of organic Se, in particular, selenometabolites of animals and plants, in plants should be elucidated. In this study, Brassica rapa var. peruviridis, a known Se accumulator, was hydroponically cultivated and then exposed to selenometabolites of animals and plants, such as methyl-2-acetamido-2-deoxy-1-seleno-beta-d-galactopyranoside (selenosugar, SeSug), trimethylselenonium (TMSe), selenomethionine (SeMet), and Se methylselenocysteine (MeSeCys). Then, the metabolic pathway of the organic Se compounds/selenometabolites in B. rapa var. peruviridis was investigated by speciation analysis. Two selenometabolites were detected in the roots when the plant was exposed to SeMet, MeSeCys, and SeSug. They were assigned to S (methylseleno)-glutathione and MeSeCys using electrospray tandem mass spectrometry (ESI-MS-MS) and HPLC-inductively coupled plasma mass spectrometry (ICP-MS). Contrary to SeMet, MeSeCys, and SeSug, TMSe was not metabolized even if it was more efficiently incorporated into the roots than the other Se compounds. The identified metabolites enabled us to propose a metabolic pathway for the organic Se metabolites except TMSe in the plant roots: a monomethylseleno moiety (CH3Se-) commonly existing in SeMet, MeSeCys, and SeSug was cleaved off and conjugated with GSH, and then the CH3Se group was transferred to O-acetylserine to form MeSeCys. PMID- 23348394 TI - Changes in the blood flow of the femoral artery by botulinum toxin A in rats. AB - We examined the changes in blood flow in the femoral artery caused by botulinum toxin A in rats. Blood flow was measured using laser Doppler flowmetry. We used male Sprague-Dawley-derived rats weighing between 350 and 400 g. The study was performed on 6 groups; each of them consisted of 30 rats (control and botulinum toxin A 0.5, 1, 2, 4, and 8 units). The laser Doppler flowmetry revealed that blood flow in the femoral artery increased by the third day in the groups injected with 1 or more units of botulinum toxin A. In the groups injected with 8 units of botulinum toxin A, we recognized an increase of blood flow from the second day. Our results suggest that botulinum toxin A is concerned in improving blood flow. PMID- 23348395 TI - Increased mortality in patients with differentiated thyroid cancer associated with Graves' disease. AB - CONTEXT: We previously reported that differentiated thyroid cancer (DTC) has higher aggressiveness and poorer prognosis in patients with Graves' disease (GD) than DTC in euthyroid control patients. Subsequent studies on this issue reached controversial conclusions. Genetic and environmental factors, as well as the lack of appropriate control subjects and/or inadequate patient follow-up, may account for these discrepancies. OBJECTIVE: The aim of this study was to investigate the long-term disease-specific mortality of nonoccult DTCs occurring in patients with GD compared with DTCs in matched euthyroid control patients. PATIENTS AND DESIGN: The previously described cohorts of nonoccult DTCs occurring in either patients with GD (DTC-GD, n = 21) or matched euthyroid DTC control patients (n = 70) were compared again after a longer follow-up (50-363.6 months; median, 165.6 months) to compare the major clinical endpoints of persistent/recurrent disease and overall survival. Both cohorts were recruited in 1982-1994 at a single institution. All patients had undergone total thyroidectomy and were followed up according to a standardized protocol. RESULTS: Persistent/recurrent disease was more frequent in DTC-GD patients than in control patients (P = .0119). Disease specific mortality was also significantly higher in DTC-GD patients (6 of 21, 28.6%) than in euthyroid control patients (2 of 70, 2.9%) (P = .0001). At the last visit, the percentage of disease-free patients was 57.1% (12 of 21) in the DTC-GD group vs 87.1% (61 of 70) in the control group (P = .0025). CONCLUSIONS: Nonoccult DTCs occurring in patients with GD cause increased disease-specific mortality compared with DTCs in matched euthyroid control patients. These findings emphasize the need for early diagnosis and aggressive treatment of nonoccult DTCs in patients with GD. PMID- 23348397 TI - Computed tomography of the anterior skull base in Kallmann syndrome reveals specific ethmoid bone abnormalities associated with olfactory bulb defects. AB - CONTEXT: Kallmann syndrome (KS) is characterized by congenital hypogonadotropic hypogonadism (CHH) and an impaired sense of smell related to defective development of the olfactory system. OBJECTIVE: The aim of the study was to use high-resolution computed tomography (CT) to detect specific abnormalities in the ethmoid bone region surrounding the olfactory bulbs in patients with KS. PATIENTS: Thirty-seven KS patients were compared to normosmic CHH (nCHH) patients (n = 15) and controls (n = 30) of similar age. DESIGN AND METHODS: We conducted a prospective study in a single referral center. Subjects underwent CT in bone windows with axial, coronal, and sagittal reconstructions centered on the olfactory fossa (OF) and cribriform plate (CP). We characterized the OF structure by measuring OF height, width, and surface area and a series of angles. The CP foramina were counted bilaterally. Olfactory bulb magnetic resonance imaging, performed in parallel, was compared with CT findings. RESULTS: OF height, width, and surface area were all significantly lower in KS patients than in nCHH patients and controls (P < .0001). KS patients also had wider angles than nCHH patients and controls (P < .0001). KS subjects with olfactory bulb agenesis on magnetic resonance imaging or who harbored KAL1 mutations had the most marked changes in OF measurements and angles. Coronal OF height distinguished KS patients from controls with the best sensitivity and specificity. The mean number of CP foramina was similar in KS, nCHH, and control subjects. CONCLUSIONS: KS is associated with specific ethmoid bone abnormalities. The preserved number of CP foramina in KS patients suggests that the integrity of olfactory structures is not mandatory for their formation during fetal development or their maintenance in adult life. PMID- 23348396 TI - The role of IL-6 trans-signaling in vascular leakage: implications for ovarian hyperstimulation syndrome in a murine model. AB - CONTEXT: The inflammatory cytokine IL-6 is related to ovarian hyperstimulation syndrome (OHSS), although the functional role of IL-6 in OHSS remains largely unknown. OBJECTIVE: A key feature of the IL-6 response is that its regulation is dependent on IL-6 trans-signaling via soluble IL-6 receptor-alpha (sIL-6Ralpha). The objective of the study was to elucidate the mechanistic role of IL-6 trans signaling in the vascular leakage that underlies the pathophysiology of OHSS. DESIGN: Ovarian endothelial cells (ECs) and granulosa-lutein cells were obtained from women undergoing in vitro fertilization. OHSS was induced in mice by administering gonadotropins for 2 days followed by human chorionic gonadotropin. The functional role of IL-6 trans-signaling in OHSS was verified using the designer cytokines Hyper IL-6 and sgp130-Fc. RESULTS: The follicular fluid levels of sIL-6Ralpha were elevated in women at high risk for OHSS. In the murine OHSS model, stimulation with gonadotropins significantly induces ovarian IL-6 and sIL 6Ralpha expression. In vitro, FSH induces de novo sIL-6Ralpha synthesis in granulosa-lutein cells through a protein kinase C-dependent pathway. In addition, sIL-6Ralpha was released by leukocytes in the presence of conditioned medium from human chorionic gonadotropin-treated granulosa-lutein cells. Ovarian ECs responded to the IL-6Ralpha-IL-6 complex (Hyper IL-6) but not to IL-6 alone. With activation of signal transducer and activator of transcription 3 (STAT3) and ERK, Hyper IL-6 increased vascular endothelial growth factor expression and the vascular permeability of ECs. Selective blockade of IL-6 trans-signaling by sgp130-Fc significantly inhibited vascular endothelial growth factor expression and prevented OHSS in mice. CONCLUSIONS: IL-6 trans-signaling is activated during the ovarian stimulation process. Our findings provide insight into the biologic effects of IL-6 trans-signaling in OHSS and highlight that IL-6 trans-signaling can induce vascular leakage in this disease. PMID- 23348399 TI - A nontargeted proteomic study of the influence of androgen excess on human visceral and subcutaneous adipose tissue proteomes. AB - CONTEXT: Sex hormones, particularly androgens, may influence not only adipose tissue distribution but also its functions. OBJECTIVE: We aimed to evaluate if sexual dimorphism in body composition is accompanied by differences in the protein abundance of adipose tissue by applying a nontargeted proteomic approach. DESIGN: This was a case-control study. SETTINGS: The setting was an academic hospital. PATIENTS: Twenty-one morbidly obese patients, including 7 men, 7 women showing no evidence of androgen excess, and 7 hyperandrogenic women with polycystic ovary syndrome. INTERVENTIONS: We obtained subcutaneous (SAT) and visceral (VAT) adipose tissue samples during bariatric surgery. MAIN OUTCOME MEASURES: Protein abundance in VAT and SAT was analyzed by 2-dimensional differential gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight/time-of-flight coupled to mass spectrometry. Results were validated by RT-PCR. RESULTS: The abundance of 2 spots of peroxiredoxin 6, creatine kinase B-type, 2 spots of selenium-binding protein 1, ruvB-like 2, 4 trimethylaminobutyraldehyde dehydrogenase, and albumin were higher in VAT compared with SAT in women with polycystic ovary syndrome. Men showed a similar pattern, whereas no difference between adipose tissue depots was observed in control women. Other proteins showed differences between VAT and SAT, confirming previous studies, or between the groups of subjects, without interaction between both effects. Several findings were confirmed by RT-PCR. CONCLUSIONS: Sexual dimorphism influences the abundance of several proteins in VAT and SAT. The patterns of abundance in adipose tissue depots of several proteins involved in metabolic processes were similar in women with androgen excess and in men, suggesting that androgens influence adipose tissue function. PMID- 23348398 TI - Androgen synthesis in the gonadotropin-suppressed human testes can be markedly suppressed by ketoconazole. AB - CONTEXT: The concentration of intratesticular testosterone (IT-T) required for human spermatogenesis is unknown because spermatogenesis can persist despite the markedly reduced IT-T concentrations observed with LH suppression. Methods to lower IT-T further are needed to determine the relationship between IT-T and spermatogenesis. OBJECTIVE: The objective of the study was to determine the effect of inhibiting the synthesis and metabolism of testosterone (T) on IT-T in gonadotropin-suppressed human testes. DESIGN/SETTING/PATIENTS: Forty normal men participated in a blinded, placebo-controlled, randomized trial at an academic center. INTERVENTION/OUTCOME MEASURES: All men were first administered the GnRH antagonist acyline to suppress LH. Forty-eight hours after acyline administration, subjects were randomly assigned to placebo, ketoconazole (to inhibit T synthesis) at 400 or 800 mg, dutasteride (to inhibit T metabolism) 2.5 mg, or anastrazole (to inhibit T metabolism) 1 mg, daily for 7 days (n = 8/group). Intratesticular steroid concentrations were measured 48 hours after acyline administration alone and again after 7 days of combination treatment. RESULTS: After 7 days of combination treatment, the median IT-T (25th, 75th percentile) in the placebo group was 14 (8.0, 21.2) ng/mL. IT-T was reduced to 3.7 (2.5, 7.1) ng/mL in the ketoconazole 400 mg group and 1.7 (0.8, 4.0) ng/mL in the ketoconazole 800 mg group (P < .001 vs placebo for both comparisons). IT-T concentrations in the dutasteride and anastrazole groups were similar to placebo. CONCLUSION: Combining inhibition of steroidogenesis with gonadotropin suppression lowers IT-T more than gonadotropin suppression alone. This combination might be useful to determine the minimum IT-T concentration necessary for human spermatogenesis, information essential for developing male hormonal contraceptives. PMID- 23348400 TI - Impact of early nutrient restriction during critical illness on the nonthyroidal illness syndrome and its relation with outcome: a randomized, controlled clinical study. AB - CONTEXT: Both critical illness and fasting induce low circulating thyroid hormone levels in the absence of a rise in TSH, a constellation-labeled nonthyroidal illness syndrome (NTI). The contribution of restricted nutrition during critical illness in the pathophysiology of NTI remains unclear. OBJECTIVE: The objective of the study was to investigate the impact of nutrient restriction early during critical illness on the NTI, in relation to outcome. DESIGN AND PATIENTS: A preplanned subanalysis in a group of intensive care unit (ICU) patients admitted after complicated surgery and for whom enteral nutrition was contraindicated (n = 280) of a randomized controlled trial, which compared tolerating pronounced nutritional deficit for 1 week in the ICU [late parenteral nutrition (PN)] with early initiation of parenteral nutrition (early PN). MEASUREMENTS: Circulating TSH, total T4, T3, rT3, and leptin levels were quantified upon admission and on ICU day 3 or the last day when patients were discharged earlier. After correction for baseline risk factors, the role of these changes from baseline in explaining the outcome benefit of late PN was assessed with the multivariable Cox proportional hazard analysis. RESULTS: Late PN reduced complications and accelerated recovery. Circulating levels of TSH, total T4, T3, the T3 to rT3 ratio, and leptin levels were all further reduced by late PN. The further lowering of T4 appeared to reduce the outcome benefit of late PN, whereas the further reduction of T3 to rT3 ratio appeared to statistically explain part of the outcome benefit. CONCLUSIONS: Tolerating nutrient restriction early during critical illness, shown to accelerate recovery, further aggravated the NTI. The statistical analyses suggested that the more pronounced peripheral inactivation of the thyroid hormone with nutrient restriction during critical illness could be a beneficial adaptation, whereas the lowering of T4 could be deleterious. PMID- 23348402 TI - Outcome of treatment of complex, perilunate fracture-dislocation of the wrist: a case report. AB - Complex, perilunate fracture-dislocations of the wrist comprise severe and challenging injuries, characterised by a total loss of contact between the lunate bone and the head of the capitate as well as fracture of one, or more bones surrounding lunate bone. The principle of treatment of such injuries involves stable fixation of fractures, anatomical reduction of the displaced carpal bones with temporary arthrodesis wit K-wires to maintain their position. We present a patient who sustained a complex, perilunate fracture-dislocation of the wrist with fractures of the scaphoid, hamate and base of the IV metacarpal bone, as a result of a blast. Assessment at one year after the surgery showed satisfactory result: mean range of motion in the wrist was 50-60% of the healthy side, grip strength was 55%, DASH score of 36 and Mayo score of 65. PMID- 23348401 TI - Ultrasound is superior to computed tomography for assessment of medullary nephrocalcinosis in hypoparathyroidism. AB - CONTEXT: Nephrocalcinosis is a complication of hypoparathyroidism and other metabolic disorders. Imaging modalities include ultrasonography (US) and computed tomography (CT). Few studies have compared these modalities, and standard clinical practice is not defined. OBJECTIVE: The objective of the study was to determine the preferred method for assessing nephrocalcinosis. DESIGN: The design of the study was a retrospective, blinded analysis. SETTING: The study was conducted at a clinical research center. PATIENTS: Twenty-two hypoparathyroid subjects and 7 controls participated in the study. INTERVENTIONS: Contemporaneous renal US and CT images were reviewed in triplicate by 4 blinded radiologists. Nephrocalcinosis was classified using a 0-3 scale with 0 meaning no nephrocalcinosis and 3 meaning severe nephrocalcinosis. MAIN OUTCOME MEASURES: Intraobserver, interobserver, and interdevice agreements were measured. RESULTS: Intraobserver agreement was high, with an overall weighted kappa of 0.83 for CT and 0.89 for US. Interobserver agreement was similar between modalities, with kappas of 0.74 for US and 0.70 for CT. Only moderate agreement was found between US and CT scores, with an intermodality kappa of 0.47 and 60% concordance. Of discordant pairs, 81% had higher US scores and only 19% had higher CT scores. Of nephrocalcinosis seen on US and not CT, 45%, 46%, and 9% were grades 1, 2, and 3, respectively. Overall, US scores were higher than CT with a cumulative odds ratio (95% confidence interval) of 5.97 (2.60, 13.75) (P < .01). In controls, 100% of US ratings were 0, and 95% of CT ratings were 0. CONCLUSIONS: US is superior to CT for assessment of mild to moderate nephrocalcinosis in patients with hypoparathyroidism. This finding, in combination with its low cost, lack of radiation, and portability, defines US as the preferred modality for assessment of nephrocalcinosis. PMID- 23348403 TI - Priming of courageous behavior: contrast effects in spider fearful women. AB - OBJECTIVE: Recently, researchers have called for therapeutic applications of behavioral primes (Shalev & Bargh, 2011). We evaluated whether courageous approach behavior might be facilitated through priming in a sample of spider fearful women. METHOD: Undergraduate student women reporting elevated spider fear (N = 33, Age mean = 18.88) were recruited for this study. Participants completed self-report measures of spider fear and dispositional courage. They then completed either a courage or neutral word search prime, which was followed by a behavioral approach task involving a tarantula. RESULTS: Consistent with predictions, among those reporting lower dispositional courage, the courage prime led to reduced approach behavior relative to the neutral prime. However, no group differences were found among those high in dispositional courage. CONCLUSIONS: These findings point to the importance of self-perceptions in moderating the effects of behavioral primes and suggest limitations to the use of such interventions with individuals with psychological dysfunction. PMID- 23348404 TI - Self-reported head injury among refugee survivors of torture. AB - OBJECTIVE: To examine the prevalence of self-reported head injury among treatment seeking refugee survivors of torture, a population at high risk for such injuries. PARTICIPANTS: A total of 488 survivors of torture accepted at a torture treatment clinic between January 1, 2008, and December 31, 2011. MAIN MEASURES: Harvard Trauma Questionnaire, incidence of head injury and resulting loss of consciousness (LOC), chief physical complaints, general health scale, indicators of torture severity (length of detention, sexual assault, and number of different persecution types). RESULTS: Of the 488 cases reviewed, 335 (69%) patients reported sustaining a blow to the head. Of the 335 with head injury, 185 (55%) reported LOC following the injury. Those who reported sustaining a head injury were significantly more likely to be men, to have a greater number of types of torture experiences, and report sleep disturbances and headaches as their primary medical complaints. CONCLUSIONS: The high rates of head injury and head injury followed by LOC among treatment-seeking survivors of torture indicates the need for torture treatment centers to assess for possible brain injury. Our findings suggest that patients with possible traumatic brain injury (TBI) may be at a higher risk of negative physical outcomes than those without possible TBI. PMID- 23348405 TI - Cardiovascular fitness is unrelated to mobility limitations in ambulant people with traumatic brain injury. AB - OBJECTIVE: The aim of this study was to evaluate the relationship between mobility, activity levels, and cardiovascular fitness in patients with traumatic brain injury (TBI) currently undergoing rehabilitation, and to determine whether mobility and cardiovascular fitness differs between people with TBI and matched healthy controls (HCs). DESIGN: Cross-sectional cohort study. PARTICIPANTS: Twenty-eight people with TBI and 28 matched HCs. OUTCOME MEASURES: The primary outcome measure for mobility was the high-level mobility assessment tool. Steps per day was the outcome measure for activity level, and the physical work capacity at 130 (PWC130) submaximal VO2 Monark bike test was the primary outcome measure for cardiovascular fitness. RESULTS: Results revealed no relationship (P > .05) between mobility, activity levels, and cardiovascular fitness in the TBI cohort. Participants with TBI had significantly reduced capacity for mobility (P < .001) and performed less physical activity (P = .002) than matched HCs; however, there was no significant difference in cardiovascular fitness (P = .094) between groups. CONCLUSIONS: Despite reduced physical activity and a wide range in capacity to mobilize, no relationship was identified between mobility and cardiovascular fitness following TBI. PMID- 23348406 TI - The effect of apricots on the experimental cataract model formed by sodium selenite. AB - This study was designed in order to investigate whether sun dried apricots have a preventive effect on the experimental cataract model formed by sodium selenite in rats. Fifty-nine Spraque-Dawley rat pups were divided into three groups. Group 1 (control group) consisted of twenty rat pups, born from the rats nourished ad libitum. Group 2 consisted of 18 newborn rats, born from the rats nourished ad libitum with 10% sun dried natural apricots. Group 3 consisted of 21 newborn rats, born from the rats nourished ad libitum. Subcutaneous (30nmol/gr) sodium selenite injection was applied to all the newborn rats except the control group (Group 1) on postpartum day 10. Cataract development was graded by slit-lamp examination and photography. Encapsulated lenses were analyzed for reduced glutathione (GSH) and malondialdehyde (MDA), a marker of lipid per oxidation. Lenses were also analyzed for total nitrite (TN). The presence of oxidative stress in selenite cataract development and its prevention by sun dried apricots. PMID- 23348407 TI - Dietary relevant mixtures of phytoestrogens inhibit adipocyte differentiation in vitro. AB - Phytoestrogens (PEs) are naturally occurring plant components, with the ability to induce biological responses in vertebrates by mimicking or modulating the action of endogenous hormones. Single isoflavones have been shown to affect adipocyte differentiation, but knowledge on the effect of dietary relevant mixtures of PEs, including for instance lignans, is lacking. In the current study dietary relevant mixtures of isoflavones and their metabolites, lignans and their metabolites, coumestrol, and a mixture containing all of them, were examined for effects on adipogenesis in 3T3-L1 adipocytes, as well as tested for their PPARgamma activating abilities. The results showed that mixtures of isoflavonoid parent compounds and metabolites, respectively, a mixture of lignan metabolites, as well as coumestrol concentration-dependently inhibited adipocyte differentiation. Furthermore, a mixture of isoflavonoid parent compounds, and a mixture of isoflavonoid metabolites were found to have PPARgamma activating abilities. These results suggest that PEs can affect pathways known to play a role in obesity development, and indicate that the inhibitory effect on adipocyte differentiation does not appear to be strictly associated with PPARgamma activation/inhibition. The current study support the hypothesis that compounds with endocrine activity can affect pathways playing a role in the development obesity and obesity related diseases. PMID- 23348408 TI - Anti-inflammatory activity of patchouli alcohol in RAW264.7 and HT-29 cells. AB - Patchouli alcohol (PA) is a chemical compound extracted from patchouli which belongs to the genus Pogostemon, herb of mint family. Recently, it has been reported that PA inhibits the production of inflammatory mediators. However, the biological mechanisms of PA for anti-inflammatory activities have not been studied. In this study, we investigated whether PA decreases the production of inflammatory mediators through downregulation of the NF-kappaB and ERK pathway. Our data indicated that PA inhibits the over-expression of iNOS and IL-6 in protein and mRNA levels in LPS-stimulated RAW264.7 and TNF-alpha stimulated HT-29 cells. PA inhibited IkappaB-alpha degradation and p65 nuclear translocation, and subsequently suppressed transcriptional activity of NF-kappaB in LPS-stimulated RAW264.7 and TNF-alpha-stimulated HT-29 cells. In addition, PA inhibited LPS- or TNF-alpha-stimulated ERK1/2 activation by decreasing phosphorylation of ERK1/2. These findings suggest that PA shows anti-inflammatory activities through suppressing ERK-mediated NF-kappaB pathway in mouse macrophage and human colorectal cancer cells. PMID- 23348409 TI - Genotoxicity of dried Hoodia parviflora aerial parts. AB - Hoodia parviflora is being developed commercially for use in weight loss food and dietary supplement products. Its effects are ascribed to a number of glycosides that have been shown to be present in plant extracts from several Hoodia species, the best known of which is H. gordonii. H. parviflora has been identified as an alternative to H. gordonii, and, as part of the process to develop H. parviflora, in vitro genotoxicity tests, as recommended by recent European Food Safety Authority guidance, were conducted on a dried powder preparation of H. parviflora aerial parts. The preparation was tested for reverse mutation at doses up to 5,000MUg/plate in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, and in Escherichia coli WP2 uvrA TA, both in the presence and in the absence of an exogenous source of metabolic activation (rat liver S9). In addition, the dried powder was evaluated in an in vitro cytotoxicity chromosome aberration assay using human lymphocytes. Test conditions included both a 4 (up to 2500MUg/mg) and 44-h exposure period (up to 1000MUg/mg) and the incorporation of an exogenous source of metabolic activation (4-h exposure only). H. parviflora dried powder was non-genotoxic in both in vitro assays. PMID- 23348410 TI - Innate-like lymphocytes: Will the real ILC1 please stand up? PMID- 23348411 TI - Neuroimmunology: ChATty B cells. PMID- 23348415 TI - Six-of-the-best: unique contributions of gammadelta T cells to immunology. AB - gammadelta T cells are a unique and conserved population of lymphocytes that have been the subject of a recent explosion of interest owing to their essential contributions to many types of immune response and immunopathology. But what does the integration of recent and long-established studies really tell us about these cells and their place in immunology? The time is ripe to consider the evidence for their unique and crucial functions. We conclude that whereas B cells and alphabeta T cells are commonly thought to contribute primarily to the antigen specific effector and memory phases of immunity, gammadelta T cells are distinct in that they combine conventional adaptive features (inherent in their T cell receptors and pleiotropic effector functions) with rapid, innate-like responses that can place them in the initiation phase of immune reactions. This underpins a revised perspective on lymphocyte biology and the regulation of immunogenicity. PMID- 23348418 TI - Adsorption, intrusion and freezing in porous silica: the view from the nanoscale. AB - This review presents the state of the art of molecular simulation and theory of adsorption, intrusion and freezing in porous silica. Both silica pores of a simple geometry and disordered porous silicas which exhibit morphological and topological disorders are considered. We provide a brief description of the numerical models of porous silicas available in the literature and present the most common molecular simulation and theoretical methods. Adsorption in regular and irregular pores is discussed in the light of classical theories of adsorption and capillary condensation in pores. We also present the different evaporation mechanisms for disordered systems: pore blocking and cavitation. The criticality of fluids confined in pores, which is still the matter of debate, is then discussed. We review theoretical results for intrusion/extrusion and freezing in silica pores and discuss the validity of classical approaches such as the Washburn-Laplace equation and Gibbs-Thomson equation to describe the thermodynamics of intrusion and in-pore freezing. The validity of the most widely used characterization techniques is then discussed. We report some concluding remarks and suggest directions for future work. PMID- 23348417 TI - Innate lymphoid cells--a proposal for uniform nomenclature. AB - Innate lymphoid cells (ILCs) are a family of developmentally related cells that are involved in immunity and in tissue development and remodelling. Recent research has identified several distinct members of this family. Confusingly, many different names have been used to characterize these newly identified ILC subsets. Here, we propose that ILCs should be categorized into three groups based on the cytokines that they can produce and the transcription factors that regulate their development and function. PMID- 23348419 TI - The effects of temperature priming on cooperation in the iterated prisoner's dilemma. AB - Based on initial research findings by Williams and Bargh (2008) and Kang, Williams, Clark, Gray and Bargh (2011) on the interaction between interpersonal and physical warmth, theoretical models such as cognitive scaffolding and the importance of evaluations of interpersonal warmth in trust-based decisions, this experiment investigated the effect of temperature priming on 30 pairs of British university students with hot and cold objects on frequency of cooperation in a game of iterated Prisoner's Dilemma. Participants were found to cooperate significantly more frequently when primed with hot objects than with cold objects, supporting the assertion that physical warmth sensation positively affects interpersonal trust evaluation. No support was found for the prediction that male-male pairs would cooperate less than female-female pairs. The implications of these findings to evolutionary and developmental theories of interpersonal warmth are discussed. PMID- 23348416 TI - Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. AB - Protective responses to microorganisms involve the nonspecific but rapid defence mechanisms of the innate immune system, followed by the specific but slow defence mechanisms of the adaptive immune system. Located as sentinels at the interface between the circulation and lymphoid tissue, splenic marginal zone B cells rapidly respond to blood-borne antigens by adopting 'crossover' defensive strategies that blur the conventional boundaries of innate and adaptive immunity. This Review discusses how marginal zone B cells function as innate-like lymphocytes that mount rapid antibody responses to both T cell-dependent and T cell-independent antigens. These responses require the integration of activation signals from germline-encoded and somatically recombined receptors for microorganisms with helper signals from effector cells of the innate and adaptive immune systems. PMID- 23348420 TI - Selective laser trabeculoplasty for the management of open-angle glaucoma in St. Lucia. AB - OBJECTIVE: To evaluate the efficacy of selective laser trabeculoplasty (SLT) for the treatment of primary open-angle glaucoma in an African-derived population in the developing world. METHODS: Sixty-one subjects from St. Lucia with medically treated primary open-angle glaucoma underwent a 30-day washout, followed by bilateral 360 degrees SLT. Intraocular pressure (IOP) was measured 1 hour; 1 week; and 1, 3, 6, 9, and 12 months after SLT. RESULTS: Mean (SD) IOP with medical therapy was 17.3 (5.0) mm Hg and 17.5 (4.0) mm Hg in the right and left eyes, respectively, and increased to 21.4 (3.6) mm Hg and 21.1 (3.5) mm Hg, respectively, after washout. Both eyes demonstrated a prompt and sustained IOP response to SLT therapy. Intraocular pressure dropped significantly by the first week and remained in the range of 13 to 14 mm Hg without medical therapy through 12 months in patients deemed successful. The mean IOP reductions from baseline ranged from 7.3 to 8.3 mm Hg (34.1%-38.8%) in right eyes and from 7.6 to 8.2 mm Hg (36.0%-38.9%) in left eyes through 12 months. The 12-month Kaplan-Meier survival rate (>=10% IOP reduction from postwashout baseline) was 77.7%, and 93% of successful subjects experienced IOP levels less than with-medication values. Most subjects reported moderate photophobia for 2 to 3 days after SLT; only 1 received anti-inflammatory therapy. Five eyes of 3 subjects had IOP spikes between 5 and 10 mm Hg that resolved without treatment. CONCLUSIONS: The magnitude and duration of IOP reduction are clinically relevant in individuals from St. Lucia of African descent. If repeatable, SLT could be a powerful tool for reducing glaucoma-related blindness in this population. PMID- 23348421 TI - Phase I trial of recombinant modified vaccinia ankara encoding Epstein-Barr viral tumor antigens in nasopharyngeal carcinoma patients. AB - Epstein-Barr virus (EBV) is associated with several malignancies including nasopharyngeal carcinoma, a high incidence tumor in Chinese populations, in which tumor cells express the two EBV antigens EB nuclear antigen 1 (EBNA1) and latent membrane protein 2 (LMP2). Here, we report the phase I trial of a recombinant vaccinia virus, MVA-EL, which encodes an EBNA1/LMP2 fusion protein designed to boost T-cell immunity to these antigens. The vaccine was delivered to Hong Kong patients with nasopharyngeal carcinoma to determine a safe and immunogenic dose. The patients, all in remission more than 12 weeks after primary therapy, received three intradermal MVA-EL vaccinations at three weekly intervals, using five escalating dose levels between 5 * 10(7) and 5 * 10(8) plaque-forming unit (pfu). Blood samples were taken during prescreening, immediately before vaccination, one week afterward and at intervals up to one year later. Immunogenicity was tested by IFN-gamma ELIspot assays using complete EBNA1 and LMP2 15-mer peptide mixes and known epitope peptides relevant to patient MHC type. Eighteen patients were treated, three per dose level one to four and six at the highest dose, without dose-limiting toxicity. T-cell responses to one or both vaccine antigens were increased in 15 of 18 patients and, in many cases, were mapped to known CD4 and CD8 epitopes in EBNA1 and/or LMP2. The range of these responses suggested a direct relationship with vaccine dose, with all six patients at the highest dose level giving strong EBNA1/LMP2 responses. We concluded that MVA-EL is both safe and immunogenic, allowing the highest dose to be forwarded to phase II studies examining clinical benefit. PMID- 23348422 TI - Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells. AB - Pancreatic stellate cells (PSC), which are implicated in desmoplasia in pancreatic cancer, enhance the malignancy of cancer cells and confer resistance to established treatments. We investigated whether the antifibrotic agent pirfenidone can suppress desmoplasia and exert antitumor effects against pancreatic cancer. Primary PSCs were established from pancreatic cancer tissue obtained during surgery. In vitro, pirfenidone inhibited the proliferation, invasiveness, and migration of PSCs in a dose-dependent manner. Although supernatants of untreated PSCs increased the proliferation, invasiveness, and migration of pancreatic cancer cells (PCC), supernatants of pirfenidone-treated PSCs decreased these effects. Exposure to PCC supernatant increased the production of platelet-derived growth factor-A, hepatic growth factor, collagen type I, fibronectin, and periostin in PSCs, which was significantly reduced by pirfenidone. Mice were subcutaneously implanted with PCCs (SUIT-2 cells) and PSCs into the right flank and PCCs alone into the left flank. Oral administration of pirfenidone to these mice significantly reduced tumor growth of co-implanted PCCs and PSCs, but not of PCCs alone. Pirfenidone also decreased the proliferation of PSCs and the deposition of collagen type I and periostin in tumors. In mice with orthotopic tumors consisting of PCCs co-implanted with PSCs, pirfenidone suppressed tumor growth, reduced the number of peritoneal disseminated nodules, and reduced the incidence of liver metastasis. Pirfenidone in combination with gemcitabine more effectively suppressed orthotopic tumor growth compared with pirfenidone or gemcitabine alone. In conclusion, our findings indicate that pirfenidone is a promising antitumor agent for pancreatic cancer, owing to its suppression of desmoplasia through regulating PSCs. PMID- 23348423 TI - The insulin receptor negatively regulates the action of Pseudomonas toxin-based immunotoxins and native Pseudomonas toxin. AB - SS1P is a recombinant immunotoxin composed of an antimesothelin Fv fragment fused to a truncated portion of Pseudomonas exotoxin A. SS1P targets and kills mesothelin-expressing tumors, which include mesothlioma as well as ovarian, lung, and pancreatic cancers. SS1P is currently in clinical trials in mesothelioma. Because insulin acting through the insulin receptor is a survival factor for many cancer cell lines, we explored how lowering insulin receptor level would affect the cytotoxic action of SS1P. We show here that siRNA knockdown of the insulin receptor enhanced the cytotoxic action of native Pseudomonas exotoxin and enhanced SS1P toxicity on several human cell lines, but did not affect the response to other cytotoxic agents such as TRAIL, etoposide, and cycloheximide. To determine how insulin receptor knockdown enhances SS1P action, we analyzed various steps involved in cell killing. We found that insulin receptor knockdown increases the cleavage of SS1P by furin, which allows more toxin to reach the cytosol and inactivate elongation factor 2. These findings indicate that the insulin receptor negatively regulates immunotoxin action. PMID- 23348425 TI - Comparison and evaluation of indicator dilution models for bolus of ultrasound contrast agents. AB - Dynamic contrast-enhanced ultrasound (DCE-US) imaging is a promising diagnostic method, which enables the evaluation of tissue perfusion via different parameters. The mean transit time and time-to-peak parameters are the main time parameters and their values depend on the model used for the approximation of the noisy perfusion curves. In this paper, we described a new comparison of different perfusion models using a tissue mimicking phantom. The following models were compared: log-normal, lagged, Erlang, Gamma and the local density random walk model. We discovered that the mean-square error is not the best criterion for model evaluation. More important is the comparison between the estimated time perfusion parameters and the physical parameters of the developed tissue mimicking phantom. Based on the statistical analysis, we can suggest that for the DCE-US perfusion analysis more models should be used, excluding the log-normal model, which gives the highest error of mean transit time value. PMID- 23348424 TI - Surface oxidation of gold nanoparticles supported on a glassy carbon electrode in sulphuric acid medium: contrasts with the behaviour of 'macro' gold. AB - Consecutive electro-oxidation and reduction cycling of gold macroelectrodes in sulphuric acid medium is a widely-used cleaning and calibration procedure. In this paper this method is applied to electrodeposited nanoparticles revealing significant differences in the electro-oxidation process and the cleaning effectiveness. This suggests a higher density of surface defects on the nanoparticles. PMID- 23348426 TI - In vitro metabolism study of Strychnos alkaloids using high-performance liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry. AB - In this report, the in vitro metabolism of Strychnos alkaloids was investigated using liquid chromatography/high-resolution mass spectrometry for the first time. Strychnine and brucine were selected as model compounds to determine the universal biotransformations of the Strychnos alkaloids in rat liver microsomes. The incubation mixtures were separated by a bidentate-C18 column, and then analyzed by on-line ion trap/time-of-flight mass spectrometry. With the assistance of mass defect filtering technique, full-scan accurate mass datasets were processed for the discovery of the related metabolites. The structural elucidations of these metabolites were achieved by comparing the changes in accurate molecular masses, calculating chemical component using Formula Predictor software and defining sites of biotransformation based upon accurate MS(n) spectral information. As a result, 31 metabolites were identified, of which 26 metabolites were reported for the first time. These biotransformations included hydroxylation, N-oxidation, epoxidation, methylation, dehydrogenation, de methoxylation, O-demethylation, as well as hydrolysis reactions. PMID- 23348427 TI - Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy. AB - Metachromatic leukodystrophy (MLD) is an inherited demyelinating disease that causes progressive neurologic deterioration, leading to severe motor disability, developmental regression, seizures, blindness, deafness, and death. The disease presents as a late-infantile, juvenile, or adult form. Hematopoietic stem cell transplantation has been shown to slow disease progression. The purpose of this longitudinal study was to evaluate long-term treatment outcomes after unrelated donor umbilical cord blood (UCB) transplantation in pediatric patients according to disease burden and age at onset (ie, late-infantile versus juvenile). Engraftment, survival, treatment-related toxicity, graft-versus-host disease, neurophysiologic measures, and neurodevelopmental function were assessed. To evaluate whether signal intensity abnormalities on magnetic resonance imaging (ie, modified Loes scores) predict post-transplant cognitive and gross motor development, a general linear mixed model was fit to the data. Twenty-seven patients underwent transplantation after myeloablative chemotherapy; 24 patients engrafted after the initial transplantation. Seven patients died of infection, regimen-related toxicity, or disease progression. Twenty patients (6 with late infantile onset and 14 with juvenile onset) were followed for a median of 5.1 years (range, 2.4 to 14.7). We found that patients with motor function symptoms at the time of transplant did not improve after transplantation. Brainstem auditory evoked responses, visual evoked potentials, electroencephalogram, and/or peripheral nerve conduction velocities stabilized or improved in juvenile patients but continued to worsen in most patients with the late-infantile presentation. Pretransplant modified Loes scores were highly correlated with developmental outcomes and predictive of cognitive and motor function. Children who were asymptomatic at the time of transplantation benefited most from the procedure. Children with juvenile onset and minimal symptoms showed stabilization or deterioration of motor skills but maintained cognitive skills. Overall, children with juvenile onset had better outcomes than those with late-infantile onset. As in other leukodystrophies, early intervention correlated with optimal outcomes. We conclude that UCB transplantation benefits children with presymptomatic late-infantile MLD or minimally symptomatic juvenile MLD. PMID- 23348428 TI - Differential profiles of thrombin inhibitors (heparin, hirudin, bivalirudin, and dabigatran) in the thrombin generation assay and thromboelastography in vitro. AB - Thrombin is a central enzyme in hemostasis and thrombosis, and a proven target for anticoagulant therapies. We compared four marketed and representative thrombin inhibitors, heparin, hirudin, bivalirudin, and dabigatran, in in-vitro spike-in assays that covered their therapeutic ranges. The assays employed were low tissue factor (1 pmol/l)-triggered thrombin generation assay (TGA) with plasma and 1:8000 Recombiplastin-triggered thromboelastography (TEG) with whole blood, with or without tissue plasminogen activator (tPA)-induced fibrinolysis. The three direct thrombin inhibitors (DTIs) prolonged TGA lag time and TEG clotting time (R) with a potency stack-ranking of hirudin>dabigatran approximately equal to bivalirudin. Heparin had the most steep concentration response curve for both parameters. In TGA, 1-2 MUmol/l dabigatran or hirudin resulted in complete inhibition on peak, slope, and endogenous thrombin potential, whereas bivalirudin had no effect on these parameters up to 10 MUmol/l. All three DTIs, but not heparin, displayed a paradoxical increase in peak and slope in the low concentration range. In TEG, whereas all four agents reduced clot strength (maximal amplitude) in synergy with tPA, hirudin was the only DTI that reduced maximal amplitude appreciably without tPA. Dabigatran had the strongest potentiating effect on tPA-induced fibrinolytic activity (Ly30). With regard to the effects on coagulation and clot strength (lag time, R, and maximal amplitude) in the respective therapeutic range, dabigatran elicited the most modest changes. In summary, our observations highlight the distinct features of each agent in thrombin generation, coagulation, and fibrinolysis. The contrasts between the agents are consistent with their known properties and are informative on efforts to define the optimal profiles of new anticoagulants. PMID- 23348429 TI - The effects of Gilbert's syndrome on the mean platelet volume and other hematological parameters. AB - The protective effect of increased levels of indirect bilirubin on atherosclerotic heart disease in patients of Gilbert's syndrome is well known. The aim of the study was to investigate the effects of increased levels of bilirubin on the mean platelet volume (MPV) and other hematological parameters. Thirty-two men and 36 women (a total of 68 Gilbert's syndrome patients) and a similar age group of 68 healthy individuals (32 men and 36 women) were included in the study. Hematologic tests, C-reactive protein (CRP) and biochemical values of the two groups were checked. MPV level of Gilbert's syndrome group was 7.8+/ 1.0fl and CRP 0.2+/-0.27mg/dl. In the control group MPV was 8.6+/-1.0fl and CRP 0.3+/-0.38mg/dl. MPV of patients group (P<0.001) and CRP (P=0.037) were significantly lower than the control group. When dividing Gilbert's syndrome and control groups according to sex into subgroups the level of indirect bilirubin in men with Gilbert's syndrome (1.8+/-0.8mg/dl) was found to be higher than other groups. Healthy men had higher levels of MPV (8.8+/-0.9fl) whereas Gilbert's syndrome male patients had lower levels (7.7+/-1.1fl), (P<0.001). The elevated levels of bilirubin and decreasing levels of MPV and CRP in Gilbert's syndrome patients may have an effect on the slowing down of the atherosclerotic process. PMID- 23348430 TI - Characterization of inhalable, thoracic, and respirable fractions and ultrafine particle exposure during grinding, brazing, and welding activities in a mechanical engineering factory. AB - OBJECTIVE: To investigate the emission sources of fine and ultrafine particles (UFPs) during brazing, welding, and grinding in a mechanical engineering factory and to characterize UFP exposure by measuring size distributions, number, and surface area concentrations. METHODS: Samplings lasted 4 hours and were conducted during 5 days using the Grimm 1.109 portable aerosol spectrometer, the Grimm portable NanoCheckTM 1.320, the electrical low pressure impactor, and the nanoparticle aerosol monitor AeroTrakTM 9000. RESULTS: Higher concentrations of fine particles were observed in welding and grinding activities. The highest values of UFP number and alveolar surface area concentrations were detected in the welding booth. CONCLUSIONS: Potential emission sources of fine particles and UFPs can be identified by the multifaceted approach outlined in this study. This sampling strategy provides important data on key UFP metrics. PMID- 23348431 TI - The in-betweeners. PMID- 23348432 TI - Helping families access care. PMID- 23348433 TI - Bountiful data. PMID- 23348434 TI - New twist to an old story. PMID- 23348435 TI - Two small puncture wounds. PMID- 23348436 TI - Implants and dementia. PMID- 23348437 TI - Increasing integration. PMID- 23348438 TI - Questionable value. PMID- 23348439 TI - Acclimatising child patients. PMID- 23348440 TI - Fat faces and swellings. PMID- 23348443 TI - The early bird gets the hard exoskeletons. PMID- 23348448 TI - What ethical difference does an apostrophe make? Balancing the interests of patients and dental professionals. AB - Dental professionals are obliged to put the interests of patients first. This is certainly laudable but it is unclear how far this duty extends. A further concern is whether it relates to the interests of a practitioner's own patients or to patients in general. The particular placement of an apostrophe in the General Dental Council's guidance is ambiguous. Dental professionals also have their own interests and might well ask if those interests should always be superseded. Every dental professional has a responsibility to put patient interests first as part of their professional registration; understanding this duty is therefore vital. PMID- 23348449 TI - Minimal intervention dentistry: part 6. Caries inhibition by resin infiltration. AB - Resin infiltration has made possible an innovative way of treating initial carious lesions that fits perfectly with the concept of minimal intervention dentistry. Infiltration of carious lesions represents a new approach to the treatment of non-cavitated lesions of proximal and smooth surfaces of deciduous and permanent teeth. The major advantage of this method is that it is a non invasive treatment, preserving tooth structure and that it can be achieved in a single visit. While this therapy can rightly be categorised as minimum intervention dentistry, clinical experience is limited and further controlled clinical trials are required to assess its long-term results. The inhibition of caries progression by resin infiltration should now be considered an alternative to invasive restorations, but involves early detection of lesions and does not allow for appropriate monitoring of the caries risk. PMID- 23348450 TI - Clinical case reports using a novel calcium-based cement. AB - A novel calcium-based cement was launched in 2009 claiming to be a revolutionary material capable of offering a bioactive and biocompatible replacement for dentine. The calcium-based cement has been reported to encourage the repair and regeneration of lost dental tissue, preserve pulp vitality, promote pulp healing and provide a bioactive substitute for natural dentine. This article looks at two clinical cases using this new material for endodontic purposes. PMID- 23348455 TI - Summary of: Developing professional status: an investigation into the working patterns, working relationships and vision for the future of UK clinical dental technicians. AB - AIMS: To investigate the working patterns and patient base of registered clinical dental technicians (CDTs); their relationships with dentists and other professionals in the dental team; their willingness to work within the NHS and their expectations for the future as a new professional group.Methods Face-to face qualitative interviews of registered CDTs, selected because of their geographic representation and mode of working, informed the development of a postal questionnaire survey of all early registrants with the General Dental Council (GDC). Results The majority of CDTs reported working part-time, often combining clinical practice with their role as a dental technician. They reported both positive and negative working relationships with dentists and dental technicians, demonstrating collaboration and/or competition depending on whether the scope of CDTs was respected and patient care was shared or lost. CDTs role in the NHS was limited because they did not have the status of becoming a recognised provider of dental care. There was a desire to expand their scope of practice in future. Conclusion CDTs are embracing their new status as an occupational group within dentistry. Core features of becoming a professional group were exhibited including the importance of social and financial status and the need to negotiate their current and future roles in the healthcare system [corrected]. PMID- 23348456 TI - Summary of: the admissions process in a graduate-entry dental school: can we predict academic performance? PMID- 23348457 TI - Adult Dental Health Survey 2009: implications of findings for clinical practice and oral health policy. AB - This is the final paper in a series reporting on the results of the 2009 Adult Dental Health Survey. Since 1968 national adult surveys have been repeated every decade with broadly similar methods providing a unique overview of trends in oral health over a 40-year period. This paper aims to explore the implications for dentists and oral health policy of the key results from the Adult Dental Health Survey 2009. Although repeat, cross-sectional, epidemiological surveys provide very valuable data on trends in disease patterns, they do not provide answers to test causal relationships and therefore cannot identify the causes for the significant improvements in oral health over the last 40 years. Evidence would indicate, however, that broad societal shifts in population norms and behaviours, combined with changes in clinical diagnostic criteria, treatment planning and clinical procedures are the main reasons for the changes that have taken place. Key implications of the survey results include the need to monitor, support and maintain the good state of oral health of the increasing proportion of younger adults with relatively simple treatment needs. A smaller number of young and middle aged adults but a significant proportion of older adults will have far more complex treatment needs requiring advanced restorative and periodontal care. Future oral health policy will need to address oral health inequalities, encourage skill mix and promote and facilitate the dental profession to deliver appropriate and high quality care relevant to the needs of their local population. PMID- 23348474 TI - Short-term cosmetic orthodontics for general dental practitioners. AB - The demand for cosmetic dental treatments in the UK has grown dramatically in the last decade possibly due to increased public awareness of new techniques coupled with greater media attention for celebrities following smile enhancement treatments. In view of this, the aim of this article and the associated presentation at the 2013 British Dental Conference and Exhibition is to provide an overview of short-term cosmetic orthodontics for general dental practitioners. The presentation will cover the differences between short-term cosmetic orthodontics and comprehensive orthodontic treatment, and explain how using short term orthodontics can be an effective tool to deliver minimally invasive cosmetic dentistry. PMID- 23348475 TI - Kathryn Harley: 'often when we see paediatric patients it's already too late'. Interview by Ruth Doherty. AB - Kathryn Harley, Dean of the Faculty of Dental Surgery of the RCS, talks to the British Dental Journal about working with the press to spread oral health messages, the importance of prevention and the joy of treating children. PMID- 23348480 TI - Developing professional status: an investigation into the working patterns, working relationships and vision for the future of UK clinical dental technicians. AB - AIMS: To investigate the working patterns and patient base of registered clinical dental technicians (CDTs); their relationships with dentists and other professionals in the dental team; their willingness to work within the NHS and their expectations for the future as a new professional group. METHODS: Face-to face qualitative interviews of registered CDTs, selected because of their geographic representation and mode of working, informed the development of a postal questionnaire survey of all early registrants with the General Dental Council (GDC). RESULTS: The majority of CDTs reported working part-time, often combining clinical practice with their role as a dental technician. They reported both positive and negative working relationships with dentists and dental technicians, demonstrating collaboration and/or competition depending on whether the scope of CDTs was respected and patient care was shared or lost. CDTs role in the NHS was limited because they did not have the status of becoming a recognised provider of dental care. There was a desire to expand their scope of practice in future. CONCLUSION: CDTs are embracing their new status as an occupational group within dentistry. Core features of becoming a professional group were exhibited including the importance of social and financial status and the need to negotiate their current and future roles in the healthcare system. PMID- 23348481 TI - The admissions process in a graduate-entry dental school: can we predict academic performance? AB - AIM: To assess the association between the admissions performance and subsequent academic achievement within a graduate-entry dental school. METHODS: The study was conducted at the University of Aberdeen Dental School. UCAS forms for course applicants were reviewed and assigned a pre-admission score (PAS) and a tariff given for the UCAS personal statement (UCAS). Individuals ranked highest were invited to attend multiple mini-interviews (MMI), which were scored. Data was correlated with academic performance reported as the University Common Assessment Scale (0-20). Comparisons were also made between the first degree and subsequent educational achievement. STATISTICS: Data were analysed by multiple linear regression, Pearson correlation and unstacked ANOVA (IBM SPSS Statistics 19). RESULTS: Data were obtained for 75 students (F: 50; M: 25). A correlation between performance at MMI and CAS scores was identified (r = 0.180, p = 0.001, df = 538). A correlation was also noted between each student's first degree and the CAS scores (F = 4.08, p = 0.001, df = 9). CONCLUSIONS: This study suggests that candidate performance at MMI might be a stronger predictor of academic and clinical performance of graduate-entry dental students compared to other pre interview selection criteria. The first degree for such a programme also appears to be significant. PMID- 23348482 TI - A biocompatible and bioactive replacement for dentine: is this a reality? The properties and uses of a novel calcium-based cement. AB - As part of the continuing evolution towards conservative dentistry there has been a drive to push further and investigate the possibility of inducing the repair and regeneration of lost dental hard tissue. Until recently, the prospect of repair and regeneration had been confined to laboratory studies and hypothesised scientific models. In 2009, a new product was launched claiming to be a revolutionary material capable of offering a bioactive and biocompatible replacement for dentine. The calcium-based cement is reported to preserve pulp vitality, promote pulp healing and provide a natural substitute for dentine through bioactive stimulation of the dentino-pulpal complex. Its clinical indications are extensive, described as a restorative material suitable for use wherever dentine replacement is required. In this article the physical, mechanical, chemical and biological properties of this novel material are presented, together with the results of experimental laboratory-based investigations and on-going clinical in vivo investigations. PMID- 23348483 TI - Mortality after surgery in Europe: a 7 day cohort study - the story of one study. PMID- 23348484 TI - Guidelines of the Polish Society of Anaesthesiology and Intensive Therapy determining principles, conditions and organisational aspects of anaesthesiology and intensive therapy services. PMID- 23348485 TI - Assessment of three minimally invasive continuous cardiac output measurement methods in critically ill patients and a review of the literature. AB - BACKGROUND: In this study we compared the accuracy of three continuous cardiac output (CCO) measurement methods, with intermittent transcardiopulmonary thermodilution (TPTD-CO) as the gold standard. The three studied CCO measurement methods were: uncalibrated peripheral pulse contour measurement (FCCO), calibrated central pulse contour measurement (PCCO), and CCO obtained by indirect Fick principle (NCCO). METHODS: We performed an observational study in 23 critically ill patients. Statistical analysis was done using Pearson's correlation and Bland-Altman analysis. A review of the relevant medical literature was performed. RESULTS: Only PCCO showed good correlation (R = 0.9) and agreement with a bias of 0.0 +/- 0.8 L min-1 and percentage error of 24.5% when compared to TPTD-CO. In patients with normal systemic vascular resistance index (SVRI > 1,700 dyne sec cm-5 m-2), NCCO (R = 0.8 and bias 0.4 +/- 1.3 L min 1) and FCCO (R = 0.8 and bias 0.1 +/- 1 L min-1) also produced reliable results. CONCLUSIONS: These results indicate that in our patient population, CCO can be most reliably monitored by calibrated central pulse contour measurements. All other methods appeared less accurate, especially in situations of low SVRI. PMID- 23348486 TI - Risk management in intensive therapy units - the method of determination of black spots. AB - BACKGROUND: Patients hospitalised in intensive care units are more likely to suffer an adverse event than those treated in other hospital wards. The aim of this study was to assess the usefulness of identifying the events (the so-called 'black spots') that constitute a significant threat to life and health of patients and/or financing of the hospital. METHODS: We retrospectively analysed 30 medical records and other documents relating to the stay of patients hospitalised in the Department of Anaesthesiology and Intensive Care at the Regional Hospital in Swidnica in 2010. To determine the 'black spots', the authors used their own methods. RESULTS: We identified 31 adverse events (12 types of events) that occurred during the provision of healthcare in the intensive care unit. Six black spots were determined based on the model adopted in the study. CONCLUSIONS: Identifying black spots can help to substantially reduce morbidity and mortality in hospitalised patients. It also allows optimisation of therapeutic entities, particularly in intensive care units. PMID- 23348487 TI - Weekend admissions to paediatric/neonatal intensive care units are associated with longer hospitalisation time but not with greater mortality. AB - BACKGROUND: To evaluate the impact on mortality and duration of stay of weekend admission of paediatric patients to the Paediatric/Neonatal Intensive Care Unit (PNICU). METHODS: Retrospective, nine-year cohort study. The study was performed in a tertiary level PNICU between 1 January 1999 and 31 December 2007. Data about the day of admission, diagnosis, outcome, and duration of stay was collected using a computerised database. RESULTS: 2,223 out of 2,240 patients treated in the PNICU during the analysed period were enrolled to the analysis. 61.9% of the group were newborns. Overall mortality equalled 10.9% and did not differ depending on weekend or weekday admission (10.95% vs. 10.86% respectively, P = 0.96). A negative trend of mortality in both groups was observed (P < 0.001). The frequency of deaths occurring during the initial 48 hours of treatment also did not differ between weekend and weekday admissions (4.1% vs. 3.3%, P = 0.52). Overall duration of PNICU stay was significantly longer for weekend admissions (median 10 vs. 8 days, P = 0.01). The difference was absent in the neonatal group (12 vs. 11 days; P = 0.9) but was evident in children (median 6 vs. 5 days P = 0.002) regardless of primary diagnosis. The difference was the greatest in children with sepsis and/or haematological malignancy (five days in both subgroups, P = 0.01 and 0.002 respectively). CONCLUSIONS: No day-of-admission dependent differences of mortality were detected in the analysed group. Weekend admissions were associated with longer duration of PNICU stay in children. PMID- 23348488 TI - Usefulness of ultrasound guidance for central venous catheterisation in patients with end-stage renal disease. AB - BACKGROUND: Renal replacement therapy often requires the insertion of a central venous catheter. The procedure is invasive and can lead to a number of complications. To minimise the risk of such complications, ultrasonography is used. The aim of the present study was to assess the usefulness of ultrasound assisted vs. traditional method of location of anatomical orientation points for the placement of central venous catheters. METHODS: . The prospective and randomised study was carried out, which included 135 patients requiring central venous catheterisation. Patients were allocated into two groups: group I (without ultrasound) - 70 patients and group II (ultrasound guidance) - 65 patients. In the latter, the procedure was performed in 38 cases due to technical problems. The following parameters were compared: age, patient's condition, results of blood clotting tests, and selected renal function parameters. Moreover, the mode of procedure (emergent, scheduled), factors directly affecting the efficacy of catheter insertion and complications (use of anticoagulants, anatomical variants, sites of access, number of cannulation attempts) were analysed. RESULTS. Ultrasound was significantly more commonly used during emergent cannulation procedures (P = 0.002), in the elderly (P = 0.001) and unconscious patients (P = 0.001). Moreover, it was more frequently applied in patients undergoing anticoagulation (P = 0.01) and during the insertion of access through the subclavian and femoral vein (P = 0.013). The percentage of successful first attempt cannulation was higher in ultrasound-guided cases (P = 0.013). There were no significant intergroup differences in the incidence of early complications (P = 0.269). CONCLUSIONS: The study findings did not demonstrate significant differences in the incidence of early complications during cannulation with and without ultrasound guidance. The first attempt success rate was found to be significantly higher in cases of ultrasound-assisted central venous catheterisation. PMID- 23348489 TI - Advanced therapeutic methods for the treatment of meningococcal septic shock - case report. AB - BACKGROUND: Meningitis caused by Neisseria meningitidis is primarily a disease of children and young adults. If septic shock complicates the course of meningitis, it must be treated in the intensive care unit. CASE REPORT: An 18 year-old man with symptoms of meningococcal meningitis and clinical features of septic shock was admitted to the ICU. Tachycardia (heart rate 140 min-1) required vasopressor to maintain blood pressure (noradrenalin 1 MUg kg-1 min-1) on admission. Respiratory failure developed (respiratory rate of 40 min-1, SaO2 79%, PaO2/FiO2 ratio = 55) and mechanical ventilatory support was used. The presence of Neisseria meningitidis was confirmed by a rapid latex agglutination test. Cefotaxime with vancomycin was administered on day one, and vancomycin was replaced by meropenem on day two. Additionally to the standard treatment of septic shock and multiorgan failure, haemoperfusion with LPS adsorber was performed to eliminate endotoxins from the bloodstream, and drotrecogin alfa was administered. Haemoperfusion was performed twice for sessions of two hours, and blood endotoxin activity decreased from 0.75 EAU to 0.4 EAU after 48 hours. The patient was admitted with signs of acute kidney injury and required continuous renal replacement therapy (Ca-Ca CVVHD, CVVHDF). CONCLUSIONS: Rapid pathogen identification, adequate antimicrobial therapy and endotoxin elimination from the bloodstream improved the haemodynamic and respiratory parameters of the patient. The application of routine plus non-standard methods of treatment of septic shock prevented the progression of the biological cascade in sepsis, and improved the patient's clinical condition. PMID- 23348490 TI - Perioperative management of cardiac surgery patients with factor XII deficiency - two case reports. AB - This paper presents two patients with factor XII deficiency, a rare coagulation disorder, who successfully underwent surgery with cardiopulmonary bypass (CPB) in Cardiac Surgery Clinic of the 4th Military Clinical Hospital in Wroclaw. Diagnosis, intra- and postoperative course as well as proposed management strategy are described. PMID- 23348491 TI - Molecular basics of sepsis developement. AB - Bacterial infections and sepsis remain major causes of morbidity and mortality in intensive care units. The normal host response to infection is a complex process that serves to localise and control the invasion of microbes and to repair injured tissue. Local inflammatory processes are regulated through the production of cytokines by macrophages. In some cases, mediator release exceeds the boundaries of the local environment and results in the development of sepsis. It is well known that the innate immune system plays a crucial role in preventing microbial invasion. The human innate immune system consists of genetically programmed defence mechanisms that are directed against molecular components found only in microorganisms. Understanding the complexity of early response to infection with respect to innate immune response is required for the future development of drugs that will effectively control infectious diseases. PMID- 23348492 TI - Modern methods of assessment of lung aeration during mechanical ventilation. AB - Despite the fact that several modes of ventilation are being used, it is not always possible to maintain adequate parameters of gas exchange. In order to provide proper ventilation, it is necessary to assess the lung function. The aim of this article is presentation of different methods of assesment of lung aerations including its advantages, disadvantages and possibilities for implementation in clinical practice. Computed tomography provides information regarding morphology and aeration of lung tissue, but has several limitations: necessity of patients transportation, it cannot be performed in a continuous manner, a quantitative assessment of picture seems to be rather complicated. Ultrasonography is widely used in intensive care and is a noninvasive and bedside method. It gives the opportunity to assess an investigated organ in real time. Its clinical utility in patients with ARDS was proved by Lichtenstein et al. Another technology which has been implemented for the purpose of lungs visualization is electrobioimpedancy (EIT). This new method consists of continuous monitoring of chest electrobioimpedancy changes due to its air content. Unlike to techniques mentioned above, lung images generated with EIT do not provide any information about morphology of affected tissue. The method which indirectly describes the sum of lung interactions is the assessment of quasi-static P/V curve. This method provides information allowing to draw conclusions regarding the usefulness of recruitment maneuvers, but does not provide information regarding the nature of morphologic changes and their location. In the search for the ideal method of lung aeration assessment, it is necessary to define its characteristics, such as noninvasiveness, availability and visualization of tissue morphologic changes in real time. PMID- 23348494 TI - Usefulness of the Finnish system of intensive care data collection. PMID- 23348493 TI - Current management of congenital diaphragmatic hernia. AB - The treatment of congenital diaphragmatic hernia (CDH) still represents a challenge, even for the specialised multidisciplinary teams in centres that provide treatment for CDH. Despite significant progress in the fields of pathophysiology, prenatal diagnosis, surgical techniques and intensive care, CDH is a disease still burdened with a high mortality. Due to the paucity of randomised studies, there are no standard guidelines for treatment. The present review looks at existing diagnostic and therapeutic principles based on the available literature. PMID- 23348495 TI - A conceptual framework and ethics analysis for prevention trials of Alzheimer Disease. AB - As our understanding of the neurobiology of Alzheimer Disease deepens, it has become evident that early intervention is critical to achieving successful therapeutic impact. The availability of diagnostic criteria for preclinical Alzheimer Disease adds momentum to research directed at this goal and even to prevention. The landscape of therapeutic research is thus poised to undergo a dramatic shift in the next 5-10 years, with clinical trials involving subjects at risk for Alzheimer Disease who have few or no symptoms. These trials will also likely rely heavily on genetics, biomarkers, and or risk factor stratification to identify individuals at risk for Alzheimer Disease. Here, we propose a conceptual framework to guide this next generation of pharmacological and non pharmacological clinical pursuit, and discuss some of the foreseeable ethical considerations that may accompany them. PMID- 23348496 TI - Enzymatic glycosylation of multivalent scaffolds. AB - The design of glycoclusters, glycodendrimers, glycopolymers and other complex glycostructures that mimic the multivalent carbohydrate display on the cell surface is of immense interest for diagnosis and therapy. This review presents a detailed insight into the exciting possibilities of multiple glycosylation using enzymes, particularly glycosyltransferases (EC 2.4). A representative choice of available scaffolds for the enzyme action is practically infinite and comprises synthetic polymers, carbosilane dendrimers, multiantennary glycans or hyperbranched conjugates. The introduced glyco-patterns range from common sialyl Lewis(x) and sialyl lacto-chains to chemically functionalized carbohydrate units for detection purposes. The possibilities of in vitro enzymatic production of N- and O-glycans and other natural polymers are also discussed. In harmony with their natural tasks, glycosyltransferases may in vitro complete the imperfect glycosylation pattern of proteins, recombinantly produced in pro- and eukaryotic hosts. What is more, the required enzymatic battery may be directly co-expressed with the protein, in order to elegantly accomplish the production of eukaryotic glycans. Ingenious metabolic labeling enables facile imaging of glycostructures. The boom of glycoarray technology opens vast possibilities in high-throughput screening for novel enzymes and substrate specificities as well as in the synthesis. Though there is still a long way until the Nature's ideal of multivalent glycans is achievable in the laboratory, the sketched pathways to multivalent glycostructures open tremendous possibilities for the future glycobiological research. PMID- 23348498 TI - Ionotropic glutamate receptors: regulation by G-protein-coupled receptors. AB - The function of many ion channels is under dynamic control by coincident activation of G-protein-coupled receptors (GPCRs), particularly those coupled to the Galphas and Galphaq family members. Such regulation is typically dependent on the subunit composition of the ionotropic receptor or channel as well as the GPCR subtype and the cell-specific panoply of signaling pathways available. Because GPCRs and ion channels are so highly represented among targets of U.S. Food and Drug Administration-approved drugs, functional cross-talk between these drug target classes is likely to underlie many therapeutic and adverse effects of marketed drugs. GPCRs engage a myriad of signaling pathways that involve protein kinases A and C (PKC) and, through PKC and interaction with beta-arrestin, Src kinase, and hence the mitogen-activated-protein-kinase cascades. We focus here on the control of ionotropic glutamate receptor function by GPCR signaling because this form of regulation can influence the strength of synaptic plasticity. The amino acid residues phosphorylated by specific kinases have been securely identified in many ionotropic glutamate (iGlu) receptor subunits, but which of these sites are GPCR targets is less well known even when the kinase has been identified. N-methyl-d-aspartate, alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid, and heteromeric kainate receptors are all downstream targets of GPCR signaling pathways. The details of GPCR-iGlu receptor cross-talk should inform a better understanding of how synaptic transmission is regulated and lead to new therapeutic strategies for neuropsychiatric disorders. PMID- 23348497 TI - ALDH16A1 is a novel non-catalytic enzyme that may be involved in the etiology of gout via protein-protein interactions with HPRT1. AB - Gout, a common form of inflammatory arthritis, is strongly associated with elevated uric acid concentrations in the blood (hyperuricemia). A recent study in Icelanders identified a rare missense single nucleotide polymorphism (SNP) in the ALDH16A1 gene, ALDH16A1*2, to be associated with gout and serum uric acid levels. ALDH16A1 is a novel and rather unique member of the ALDH superfamily in relation to its gene and protein structures. ALDH16 genes are present in fish, amphibians, protista, bacteria but absent from archaea, fungi and plants. In most mammalian species, two ALDH16A1 spliced variants (ALDH16A1, long form and ALDH16A1_v2, short form) have been identified and both are expressed in HepG-2, HK-2 and HK 293 human cell lines. The ALDH16 proteins contain two ALDH domains (as opposed to one in the other members of the superfamily), four transmembrane and one coiled coil domains. The active site of ALDH16 proteins from bacterial, frog and lower animals contain the catalytically important cysteine residue (Cys-302); this residue is absent from the mammalian and fish orthologs. Molecular modeling predicts that both the short and long forms of human ALDH16A1 protein would lack catalytic activity but may interact with the hypoxanthine-guanine phosphoribosyltransferase (HPRT1) protein, a key enzyme involved in uric acid metabolism and gout. Interestingly, such protein-protein interactions with HPRT1 are predicted to be impaired for the long or short forms of ALDH16A1*2. These results lead to the intriguing possibility that association between ALDH16A1 and HPRT1 may be required for optimal HPRT activity with disruption of this interaction possibly contributing to the hyperuricemia seen in ALDH16A1*2 carriers. PMID- 23348499 TI - Differential activation and modulation of the glucagon-like peptide-1 receptor by small molecule ligands. AB - The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target for the treatment of type 2 diabetes due to its role in glucose homeostasis. Despite the availability of peptide-based GLP-1R drugs for treatment of this disease, there is great interest in developing small molecules that can be administered orally. The GLP-1R system is complex, with multiple endogenous and clinically used peptide ligands that exhibit different signaling biases at this receptor. This study revealed that small molecule ligands acting at this receptor are differentially biased to peptide ligands and also from each other with respect to the signaling pathways that they activate. Furthermore, allosteric small molecule ligands were also able to induce bias in signaling mediated by orthosteric ligands. This was dependent on both the orthosteric and allosteric ligand as no two allosteric-orthosteric ligand pairs could induce the same signaling profile. We highlight the need to profile compounds across multiple signaling pathways and in combination with multiple orthosteric ligands in systems such as the GLP-1R where more than one endogenous ligand exists. In the context of pleiotropical coupling of receptors and the interplay of multiple pathways leading to physiologic responses, profiling of small molecules in this manner may lead to a better understanding of the physiologic consequences of biased signaling at this receptor. This could enable the design and development of improved therapeutics that have the ability to fine-tune receptor signaling, leading to beneficial therapeutic outcomes while reducing side effect profiles. PMID- 23348500 TI - A novel metabotropic glutamate receptor 5 positive allosteric modulator acts at a unique site and confers stimulus bias to mGlu5 signaling. AB - Metabotropic glutamate receptor 5 (mGlu5) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease. Furthermore, mGlu5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term potentiation (LTP), which is thought to be involved in cognition. Multiple mGlu5-positive allosteric modulators (PAMs) have been developed from a variety of different scaffolds. Previous work has extensively characterized a common allosteric site on mGlu5, termed the MPEP (2-Methyl-6 (phenylethynyl)pyridine) binding site. However, one mGlu5 PAM, CPPHA (N-(4-chloro 2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide), interacts with a separate allosteric site on mGlu5. Using cell-based assays and brain slice preparations, we characterized the interaction of a potent and efficacious mGlu5 PAM from the CPPHA series termed NCFP (N-(4-chloro-2-((4-fluoro 1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide). NCFP binds to the CPPHA site on mGlu5 and potentiates mGlu5-mediated responses in both recombinant and native systems. However, NCFP provides greater mGlu5 subtype selectivity than does CPPHA, making it more suitable for studies of effects on mGlu5 in CNS preparations. Of interest, NCFP does not potentiate responses involved in hippocampal synaptic plasticity (LTD/LTP), setting it apart from other previously characterized MPEP site PAMs. This suggests that although mGlu5 PAMs may have similar responses in some systems, they can induce differential effects on mGlu5 mediated physiologic responses in the CNS. Such stimulus bias by mGlu5 PAMs may complicate drug discovery efforts but would also allow for specifically tailored therapies, if pharmacological biases can be attributed to different therapeutic outcomes. PMID- 23348501 TI - Formation, reactivity, and antiplatelet activity of mixed disulfide conjugates of clopidogrel. AB - In this work, we investigated the formation, reactivity, and antiplatelet activity of various mixed disulfide conjugates of clopidogrel. Our results showed that the production of the active metabolite (AM) from 2-oxoclopidogrel by human liver microsomes (HLMs) is greatly affected by the thiol reductants used. Among the 10 thiol compounds tested, glutathione (GSH) is most efficient in producing the AM at a rate of 167 pmoles AM/min/mg HLM. Interestingly, no AM but only the mixed disulfide conjugates were formed in the presence of 6-chloropyridazine-3 thiol (CPT), 2,5-dimethylfuran-3-thiol, and 3-nitropyridine-2-thiol (NPT). The mass spectrometry (MS) and MS(2) spectra of the conjugates of these thiol compounds confirmed the presence of a mixed disulfide bond linkage between the AM and the thiol reductants. Kinetic studies revealed that the mixed disulfide conjugates were capable of exchanging thiols with GSH to release the AM with second order rate constants ranging from 1.2 to 28 M(-1)s(-1). The mixed disulfide conjugates of CPT and NPT showed potent inhibition of platelet aggregation after pretreatment with 1 mM GSH, confirming that the AM is responsible for the antiplatelet activity of clopidogrel. Collectively, our results provide strong support for a cytochrome P450 (P450)-mediated bioactivation mechanism involving the initial formation of a glutathionyl conjugate, followed by thiol-disulfide exchange with another GSH molecule to release the AM. Furthermore, the stable mixed disulfide conjugates identified in this study provide a platform to quantitatively generate the therapeutic AM without the need for P450-mediated bioactivation. This property can be further explored to overcome the interindividual variability in clopidogrel therapy. PMID- 23348502 TI - Template-free and filamentary growth of silver nanowires: application to anisotropic conductive transparent flexible electrodes. AB - Silver nanowires (NWs) are currently fabricated via template-free or template assisted methods. The former is based on a medium-mediated anisotropic synthesis, which enables precursor atoms to be selectively adsorbed onto specific crystallographic planes, and the latter is performed via directional growth guided by preformed templates. These methods are costly and complicated. We outline a facile and low-cost approach for the electrochemical synthesis of silver NWs in a manner that is template- and surfactant-free and that provides control over the NW diameter in the range of 80 to 800 nm by the repetition of nucleation and dissolution. The nanowires vertically grow with the help of the interface anisotropy driven by a field enhancement at the tips of the islands nucleated on the substrate in ultra-dilute electrolytes (ca. 10(-5) M), which is similar to a lightning-rod effect. The silver nanowires of vertical configuration are utilized for fabrication of anisotropic conducting, transparent, and flexible films. PMID- 23348503 TI - TERT promoter mutations in familial and sporadic melanoma. AB - Cutaneous melanoma occurs in both familial and sporadic forms. We investigated a melanoma-prone family through linkage analysis and high-throughput sequencing and identified a disease-segregating germline mutation in the promoter of the telomerase reverse transcriptase (TERT) gene, which encodes the catalytic subunit of telomerase. The mutation creates a new binding motif for Ets transcription factors and ternary complex factors (TCFs) near the transcription start and, in reporter gene assays, caused up to twofold increase in transcription. We then screened the TERT promoter in sporadic melanoma and observed recurrent ultraviolet signature somatic mutations in 125 of 168 (74%) of human cell lines derived from metastatic melanomas, 45 of 53 corresponding metastatic tumor tissues (85%), and 25 of 77 (33%) primary melanomas. The majority of those mutations occurred at two positions in the TERT promoter and also generated binding motifs for Ets/TCF transcription factors. PMID- 23348504 TI - Coherence and indistinguishability of single electrons emitted by independent sources. AB - The on-demand emission of coherent and indistinguishable electrons by independent synchronized sources is a challenging task of quantum electronics, in particular regarding its application for quantum information processing. Using two independent on-demand electron sources, we triggered the emission of two single electron wave packets at different inputs of an electronic beam splitter. Whereas classical particles would be randomly partitioned by the splitter, we observed two-particle interference resulting from quantum exchange. Both electrons, emitted in indistinguishable wave packets with synchronized arrival time on the splitter, exited in different outputs as recorded by the low-frequency current noise. The demonstration of two-electron interference provides the possibility of manipulating coherent and indistinguishable single-electron wave packets in quantum conductors. PMID- 23348505 TI - Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. AB - We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics. PMID- 23348506 TI - Highly recurrent TERT promoter mutations in human melanoma. AB - Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes but rarely in gene regulatory regions. Here, we describe two independent mutations within the core promoter of telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) melanomas examined. These mutations generate de novo consensus binding motifs for E-twenty six (ETS) transcription factors, and in reporter assays, the mutations increased transcriptional activity from the TERT promoter by two- to fourfold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. Thus, somatic mutations in regulatory regions of the genome may represent an important tumorigenic mechanism. PMID- 23348508 TI - Crystalline inorganic frameworks with 56-ring, 64-ring, and 72-ring channels. AB - The development of zeolite-like structures with extra-large pores (>12-membered rings, 12R) has been sporadic and is currently at 30R. In general, templating via molecules leads to crystalline frameworks, whereas the use of organized assemblies that permit much larger pores produces noncrystalline frameworks. Synthetic methods that generate crystallinity from both discrete templates and organized assemblies represent a viable design strategy for developing crystalline porous inorganic frameworks spanning the micro and meso regimes. We show that by integrating templating mechanisms for both zeolites and mesoporous silica in a single system, the channel size for gallium zincophosphites can be systematically tuned from 24R and 28R to 40R, 48R, 56R, 64R, and 72R. Although the materials have low thermal stability and retain their templating agents, single-activator doping of Mn(2+) can create white-light photoluminescence. PMID- 23348507 TI - Caspase-11 protects against bacteria that escape the vacuole. AB - Caspases are either apoptotic or inflammatory. Among inflammatory caspases, caspase-1 and -11 trigger pyroptosis, a form of programmed cell death. Whereas both can be detrimental in inflammatory disease, only caspase-1 has an established protective role during infection. Here, we report that caspase-11 is required for innate immunity to cytosolic, but not vacuolar, bacteria. Although Salmonella typhimurium and Legionella pneumophila normally reside in the vacuole, specific mutants (sifA and sdhA, respectively) aberrantly enter the cytosol. These mutants triggered caspase-11, which enhanced clearance of S. typhimurium sifA in vivo. This response did not require NLRP3, NLRC4, or ASC inflammasome pathways. Burkholderia species that naturally invade the cytosol also triggered caspase-11, which protected mice from lethal challenge with B. thailandensis and B. pseudomallei. Thus, caspase-11 is critical for surviving exposure to ubiquitous environmental pathogens. PMID- 23348509 TI - Fitness and frailty: opposite ends of a challenging continuum! Will the end of age discrimination make frailty assessments an imperative? PMID- 23348510 TI - It's the destination and it's the journey: using multilevel modeling to assess patterns of change in psychotherapy. AB - BACKGROUND: The pairing of analysis of variance (ANOVA)-based analyses with designs lacking multiple measurement of client change may lead to conclusions that are inconsistent with theoretical expectations about how change will occur. Multilevel modeling (MLM), when used with multiple assessments of client outcomes, provides a flexible set of tools to analyze trajectories of client change. PURPOSE: The authors present an overview of MLM and growth curve analysis as applied to psychotherapy outcome. Results from a simulated data set illustrate how MLM-specifically, growth curve analysis-can be used to test hypotheses from randomized clinical trials. RESULTS: Growth curve analyses were applied to simulated data from an experimental design (treatment versus control group) with multiple assessments of client distress and a client individual difference variable. Results of growth curve analyses confirmed what was found with a pretreatment/posttreatment repeated-measures ANOVA but provided additional information not available from the ANOVA framework. CONCLUSIONS: Given its flexibility, MLM is the recommended method to assess patterns of change in studies of psychotherapy outcome. PMID- 23348511 TI - Ten year research update (2001-2010): evaluations for competence to stand trial (adjudicative competence). AB - This article reviews and evaluates publications during 2001-2010 with relevance for assessments of competence to stand trial, referred to in this article as adjudicative competence. The review focuses specifically on articles that provide new concepts or data supported by research or case analyses. The studies are reviewed under the following headings: (i) systemic issues, (ii) conceptual guidelines for AC evaluations, (iii) AC assessment methods, (iv) empirical correlates of AC judgments and psycholegal abilities, (v) quality of AC evaluations and reports, (vi) interpretive issues, (vii) special populations (defendants who are elderly, defendants with intellectual disabilities), (viii) AC evaluations of juveniles, and (ix) treatment of incompetent defendants. Suggestions are offered for further research to advance the quality of clinical evaluations of adjudicative competence. PMID- 23348512 TI - C-N coupling in the gas-phase reactions of ammonia and [M(CH)]+ (M = Ni, Pd, Pt): a combined experimental/computational exercise. AB - Electrospray ionization (ESI) of methanolic solutions of monomeric nickel(II) acetate, [Ni(CH(3)COO)(2)], and tetrameric platinum(II) acetate, [Pt(4)(CH(3)COO)(8)], leads to the formation of the corresponding methylidyne complexes [M(CH)](+) (M = Ni, Pt), which react with ammonia under C-N coupling. While the product couples M/[CH(4)N](+) and [M(CH(2)N)](+)/H(2) are observed for both metals, hydrogen-atom expulsion to generate [M(CHNH(2))](+)/H is only observed in the case of the nickel-containing system, and the proton transfer leading to M/[NH(4)](+) is limited to platinum. Attempts to conduct related experiments with [Pd(CH)](+)/NH(3) failed. The mechanisms that explain the experimentally observed reaction channels have been investigated computationally using the B3LYP functional for all metals of the nickel group (M = Ni, Pd, Pt). In line with labeling experiments using the reaction pairs [M(CD)](+)/NH(3) and [M(CH)](+)/ND(3) (M = Ni, Pt), two different mechanistic scenarios of the dehydrogenation process are operative for the Ni and Pt systems, respectively. PMID- 23348513 TI - In vivo regulation of the MU opioid receptor: role of the endogenous opioid agents. AB - It is well known that genotypic differences can account for the subject-specific responses to opiate administration. In this regard, the basal activity of the endogenous system (either at the receptor or ligand level) can modulate the effects of exogenous agonists as morphine and vice versa. The MU opioid receptor from zebrafish, dre-oprm1, binds endogenous peptides and morphine with similar affinities. Morphine administration during development altered the expression of the endogenous opioid propeptides proenkephalins and proopiomelanocortin. Treatment with opioid peptides (Met-enkephalin [Met-ENK], Met-enkephalin-Gly-Tyr [MEGY] and beta-endorphin [beta-END]) modulated dre-oprm1 expression during development. Knocking down the dre-oprm1 gene significantly modified the mRNA expression of the penk and pomc genes, thus indicating that oprm1 is involved in shaping penk and pomc expression. In addition, the absence of a functional oprm1 clearly disrupted the embryonic development, since proliferation was disorganized in the central nervous system of oprm1-morphant embryos: mitotic cells were found widespread through the optic tectum and were not restricted to the proliferative areas of the mid- and hindbrain. Transferase-mediated dUTP nick-end labeling (TUNEL) staining revealed that the number of apoptotic cells in the central nervous system (CNS) of morphants was clearly increased at 24-h postfertilization. These findings clarify the role of the endogenous opioid system in CNS development. Our results will also help unravel the complex feedback loops that modulate opioid activity and that may be involved in establishing a coordinated expression of both receptors and endogenous ligands. Further knowledge of the complex interactions between the opioid system and analgesic drugs will provide insights that may be relevant for analgesic therapy. PMID- 23348514 TI - Effects of metformin on burn-induced hepatic endoplasmic reticulum stress in male rats. AB - Severe burn injury causes hepatic dysfunction that results in major metabolic derangements including insulin resistance and hyperglycemia and is associated with hepatic endoplasmic reticulum (ER) stress. We have recently shown that insulin reduces ER stress and improves liver function and morphology; however, it is not clear whether these changes are directly insulin mediated or are due to glucose alterations. Metformin is an antidiabetic agent that decreases hyperglycemia by different pathways than insulin; therefore, we asked whether metformin affects postburn ER stress and hepatic metabolism. The aim of the present study is to determine the effects of metformin on postburn hepatic ER stress and metabolic markers. Male rats were randomized to sham, burn injury and burn injury plus metformin and were sacrificed at various time points. Outcomes measured were hepatic damage, function, metabolism and ER stress. Burn-induced decrease in albumin mRNA and increase in alanine transaminase (p < 0.01 versus sham) were not normalized by metformin treatment. In addition, ER stress markers were similarly increased in burn injury with or without metformin compared with sham (p < 0.05). We also found that gluconeogenesis and fatty acid metabolism gene expressions were upregulated with or without metformin compared with sham (p < 0.05). Our results indicate that, whereas thermal injury results in hepatic ER stress, metformin does not ameliorate postburn stress responses by correcting hepatic ER stress. PMID- 23348515 TI - Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria. AB - X-linked protoporphyria (XLP) (MIM 300752) is a recently recognized erythropoietic porphyria due to gain-of-function mutations in the erythroid specific aminolevulinate synthase gene (ALAS2). Previously, two exon 11 small deletions, c.1699_1670DeltaAT (DeltaAT) and c.1706_1709DeltaAGTG (DeltaAGTG), that prematurely truncated or elongated the ALAS2 polypeptide, were reported to increase enzymatic activity 20- to 40-fold, causing the erythroid accumulation of protoporphyrins, cutaneous photosensitivity and liver disease. The mutant DeltaAT and DeltaAGTG ALAS2 enzymes, two novel mutations, c.1734DeltaG (DeltaG) and c.1642C>T (p.Q548X), and an engineered deletion c.1670-1671TC>GA p.F557X were expressed, and their purified enzymes were characterized. Wild-type and DeltaAGTG enzymes exhibited similar amounts of 54- and 52-kDa polypeptides on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), whereas the DeltaAT and p.F557X had only 52-kDa polypeptides. Compared to the purified wild type enzyme, DeltaAT, DeltaAGTG and Q548X enzymes had increased specific activities that were only 1.8-, 3.1- and 1.6-fold, respectively. Interestingly, binding studies demonstrated that the increased activity Q548X enzyme did not bind to succinyl-CoA synthetase. The elongated DeltaG enzyme had wild-type specific activity, kinetics and thermostability; twice the wild-type purification yield (56 versus 25%); and was primarily a 54-kDa form, suggesting greater stability in vivo. On the basis of studies of mutant enzymes, the maximal gain-of function region spanned 57 amino acids between 533 and 580. Thus, these ALAS2 gain-of-function mutations increased the specific activity (DeltaAT, DeltaAGTG and p.Q548X) or stability (DeltaG) of the enzyme, thereby leading to the increased erythroid protoporphyrin accumulation causing XLP. PMID- 23348516 TI - Innate immune functions of immature neutrophils in patients with sepsis and severe systemic inflammatory response syndrome. AB - OBJECTIVE: A hallmark of sepsis and severe systemic inflammatory response syndrome (SIRS) is the massive recruitment of immature neutrophils from the bone marrow into the circulation (left shift, band forms). Their capacity to participate in innate defense against bacteria is ill defined. We aimed at comparing various innate immune functions of mature vs. immature neutrophils circulating during sepsis and SIRS. DESIGN: Prospective, observational cohort study. SETTING: Tertiary level ICU and associated research laboratory. PATIENTS: : Thirty-three ICU patients with sepsis; 12 ICUs with SIRS; 32 healthy volunteers. INTERVENTIONS: Twenty milliliters of whole heparinized blood was used for in vitro studies including neutrophil viability and apoptosis, surface expression of CD16, Toll-like receptors () 4 and TLR2, CD14, MD-2, HLA-DP,-DQ and -DR, and CXCR2, chemotaxis, phagocytosis, bacterial killing, and tumor necrosis factor-alpha/interleukin-10 baseline intracellular cytokine levels. MEASUREMENTS AND MAIN RESULTS: Immature neutrophils were capable of mediating important innate immune functions such as bacterial phagocytosis and killing via the production of reactive oxygen species, although less efficiently than mature neutrophils. Immature neutrophils had a longer life span and resistance to spontaneous apoptosis, and could mature ex vivo. They expressed lower levels of receptors for bacterial molecules such as CD14 and MD-2 and migrated less efficiently than mature granulocytes. Immature neutrophils had higher basal intracellular tumor necrosis factor-alpha/interleukin-10 ratio than that of mature neutrophils, suggesting a proinflammatory phenotype. No significant differences were observed between immature neutrophils isolated from patients with sepsis and those from patients with severe SIRS. CONCLUSIONS: Despite their "immaturity", band forms are capable of mediating crucial innate immune functions during severe infections and sepsis. Their fate and capacity to mature in vivo remain to be determined. PMID- 23348517 TI - Esotropia greater at distance: children vs adults. AB - IMPORTANCE: Esotropia greater at distance than at near can be related to abducens palsy or to divergence insufficiency. Mild abduction weakness can be difficult to detect, blurring the distinction between these 2 conditions. OBJECTIVES: To examine the clinical and eye movement findings that distinguish abducens palsy from divergence insufficiency and to account for these findings based on current knowledge of vergence neurophysiology and saccadic adaptation. DESIGN: Retrospective medical record review. SETTING: A pediatric referral center. PARTICIPANTS: The medical records of 32 patients with esotropia greater at distance seen during a 17-year period from August 1989 to July 2006 were reviewed. MAIN OUTCOME MEASURES: Details regarding age, medical history, oculomotor and neurological examinations, and result of any neuroimaging studies were recorded. Eye movements were recorded in 2 subjects using binocular video oculography. RESULTS: Fifteen children and 17 adults were identified; 93.3% of the children had an underlying central nervous system disorder that coincided with the onset of their esodeviation, and 23.5% of the adult patients had an underlying central nervous system disorder. Eye movement recordings in 2 pediatric patients revealed lateral incomitance suggestive of abducens palsy not detected by clinical examination. CONCLUSIONS AND RELEVANCE: The acute onset of an esodeviation greater at distance in a child is frequently associated with an underlying central nervous system disorder. Several features suggest that the children, unlike the adults, likely had a subtle abducens paresis rather than divergence insufficiency. This was confirmed by formal eye movement studies in 2 children in whom lateral incomitance was not detected clinically. The same pattern of strabismus in an otherwise healthy adult is more likely due to age related reduction in accommodation, increased ratio of accommodative vergence to accommodation, and relative divergence insufficiency. PMID- 23348518 TI - Interaction of dependent and non-dependent regions of the acutely injured lung during a stepwise recruitment manoeuvre. AB - The benefit of treating acute lung injury with recruitment manoeuvres is controversial. An impediment to settling this debate is the difficulty in visualizing how distinct lung regions respond to the manoeuvre. Here, regional lung mechanics were studied by electrical impedance tomography (EIT) during a stepwise recruitment manoeuvre in a porcine model with acute lung injury. The following interaction between dependent and non-dependent regions consistently occurred: atelectasis in the most dependent region was reversed only after the non-dependent region became overdistended. EIT estimates of overdistension and atelectasis were validated by histological examination of lung tissue, confirming that the dependent region was primarily atelectatic and the non-dependent region was primarily overdistended. The pulmonary pressure-volume equation, originally designed for modelling measurements at the airway opening, was adapted for EIT based regional estimates of overdistension and atelectasis. The adaptation accurately modelled the regional EIT data from dependent and non-dependent regions (R(2) > 0.93, P < 0.0001) and predicted their interaction during recruitment. In conclusion, EIT imaging of regional lung mechanics reveals that overdistension in the non-dependent region precedes atelectasis reversal in the dependent region during a stepwise recruitment manoeuvre. PMID- 23348519 TI - The etiology of uterine sarcomas: a pooled analysis of the epidemiology of endometrial cancer consortium. AB - BACKGROUND: Uterine sarcomas are characterised by early age at diagnosis, poor prognosis, and higher incidence among Black compared with White women, but their aetiology is poorly understood. Therefore, we performed a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We also examined risk factor associations for malignant mixed mullerian tumours (MMMTs) and endometrioid endometrial carcinomas (EECs) for comparison purposes. METHODS: We pooled data on 229 uterine sarcomas, 244 MMMTs, 7623 EEC cases, and 28,829 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with uterine sarcoma, MMMT, and EEC were estimated with polytomous logistic regression. We also examined associations between epidemiological factors and histological subtypes of uterine sarcoma. RESULTS: Significant risk factors for uterine sarcoma included obesity (body mass index (BMI)>=30 vs BMI<25 kg m(-2) (OR: 1.73, 95% CI: 1.22-2.46), P-trend=0.008) and history of diabetes (OR: 2.33, 95% CI: 1.41-3.83). Older age at menarche was inversely associated with uterine sarcoma risk (>=15 years vs <11 years (OR: 0.70, 95% CI: 0.34-1.44), P-trend: 0.04). BMI was significantly, but less strongly related to uterine sarcomas compared with EECs (OR: 3.03, 95% CI: 2.82-3.26) or MMMTs (OR: 2.25, 95% CI: 1.60-3.15, P-heterogeneity=0.01). CONCLUSION: In the largest aetiological study of uterine sarcomas, associations between menstrual, hormonal, and anthropometric risk factors and uterine sarcoma were similar to those identified for EEC. Further exploration of factors that might explain patterns of age- and race-specific incidence rates for uterine sarcoma are needed. PMID- 23348521 TI - Environmental factors and quality improvement in county and local health departments. AB - OBJECTIVE: On the basis of resource dependency theory and the uncertainty principle, this study examines the relationship between the local public health market environment and the use of quality improvement (QI) strategies in local health departments. DESIGN: This cross-sectional study uses secondary data from the 2008 National Association of County & City Health Officials profile study, the Health Resources and Services Administration's Area Resource File, and the County Health Rankings 2010 data set. SETTING AND PARTICIPANTS: US local health departments. MAIN OUTCOME MEASURES: Seven binary dependent variables that represented the use of QI processes or QI training within local health departments were used. Eight independent variables were identified and operationalized to measure the constructs of munificence, dynamism, and complexity for the local public health market environment. Bivariate and multivariate regression analyses were used. RESULTS: Two of the 3 munificence variables were positively associated with QI, as predicted. These included percentage of zip codes with healthy food outlets (beta = +.016, P < .05) and the number of primary care physicians per capita (beta = +1.327, P < .05). Two of the 3 measures of complexity were, as predicted, negatively associated with indicators of QI. These included smoking prevalence (beta = -.118, P < .05) and obesity rates (beta = -.081, P < .10). With respect to dynamism, 1 variable (change in population size over a 5-year period) was unexpectedly, positively related to QI (beta = +.118, P < .10 and beta = +0.235, P < .05). CONCLUSIONS: Overall findings provide moderate support for the use of resource dependency theory and the uncertainty perspective to understand the influence of the external environment on QI within the local public health setting. Future research should examine other ways of operationalizing these environmental constructs to examine the relationship between the environment and other elements of public health practice. PMID- 23348520 TI - HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients. AB - BACKGROUND: In metastatic colorectal cancer (mCRC), KRAS is the only validated biomarker used to select patients for administration of epidermal growth factor receptor (EGFR)-targeted therapies. To identify additional predictive markers, we investigated the importance of HER2, the primary EGFR dimerisation partner, in this particular disease. METHODS: We evaluated the HER2 gene status by fluorescence in situ hybridisation (FISH) in 170 KRAS wild-type mCRC patients treated with cetuximab or panitumumab. RESULTS: Depending on HER2 gene copy number status, patients showed three distinct cytogenetic profiles: 4% of patients had HER2 gene amplification (R:HER2/CEP17 >= 2) in all neoplastic cells (HER2-all-A), 61% of patients had HER2 gain due to polysomy or to gene amplification in minor clones (HER2-FISH+*), and 35% of patients had no or slight HER2 gain (HER2-FISH-). These subgroups were significantly correlated with different clinical behaviours, in terms of response rate (RR; P=0.0006), progression-free survival (PFS; P<0.0001) and overall survival (OS; P<0.0001). Patients with HER2-all-A profile experienced the worst outcome, patients with HER2-FISH- profile showed an intermediate behaviour and patients with HER2-FISH+* profile were related to the highest survival probability (median PFS in months: 2.5 vs 3.9 vs 7.6, respectively; median OS in months: 4.2 vs 9.7 vs 13, respectively). CONCLUSION: HER2 gene copy number status may influence the clinical response to anti-EGFR-targeted therapy in mCRC patients. PMID- 23348522 TI - Critical systems for public health management of floods, North Dakota. AB - Availability of emergency preparedness funding between 2002 and 2009 allowed the North Dakota Department of Health to build public health response capabilities. Five of the 15 public health preparedness capability areas identified by the Centers for Disease Control and Prevention in 2011 have been thoroughly tested by responses to flooding in North Dakota in 2009, 2010, and 2011; those capability areas are information sharing, emergency operations coordination, medical surge, material management and distribution, and volunteer management. Increasing response effectiveness has depended on planning, implementation of new information technology, changes to command and control procedures, containerized response materials, and rapid contract procedures. Continued improvement in response and maintenance of response capabilities is dependent on ongoing funding. PMID- 23348523 TI - Peptide regulators of peripheral taste function. AB - The peripheral sensory organ of the gustatory system, the taste bud, contains a heterogeneous collection of sensory cells. These taste cells can differ in the stimuli to which they respond and the receptors and other signaling molecules they employ to transduce and encode those stimuli. This molecular diversity extends to the expression of a varied repertoire of bioactive peptides that appear to play important functional roles in signaling taste information between the taste cells and afferent sensory nerves and/or in processing sensory signals within the taste bud itself. Here, we review studies that examine the expression of bioactive peptides in the taste bud and the impact of those peptides on taste functions. Many of these peptides produced in taste buds are known to affect appetite, satiety or metabolism through their actions in the brain, pancreas and other organs, suggesting a functional link between the gustatory system and the neural and endocrine systems that regulate feeding and nutrient utilization. PMID- 23348525 TI - Fundamental formulations and recent achievements in piezoelectric nano structures: a review. AB - Piezoelectric nano-structures have been regarded as the next-generation piezoelectric material due to their inherent nano-sized piezoelectricity. This review summarizes the recent theoretical and experimental findings in piezoelectric nano-structures, including piezoelectric nanowires, nanoplates, nanobeams, nanofilms, nanoparticles, and piezoelectric heterogeneous materials containing piezoelectric nano-inhomogeneities. To begin, the types of piezoelectric nano-structured materials and the wide application of piezoelectric nano-structures in recent years are delineated. Next, the theoretical foundations including the definition of surface stress and electric displacement, the surface constitutive relations, the surface equilibrium equations, and nonlocal piezoelectricity, and their applications, are illustrated. Then, the effective mechanical and piezoelectric properties are depicted. Furthermore, the experimental investigations are classified, and some important observations are discussed. Finally, the perspectives and challenges for the future development of piezoelectric nano-structures are pointed out. PMID- 23348526 TI - [Editor's words]. PMID- 23348527 TI - RAAS inhibition and mortality in hypertension: from pharmacology to clinical evidence. PMID- 23348528 TI - Percutaneous closure of the left atrial appendage using the Amplatzer Cardiac Plug in patients with atrial fibrillation: evaluation of safety and feasibility. AB - BACKGROUND: Ischaemic stroke is a common complication of atrial fibrillation (AF). Cardiology societies recommend assessing the risk of ischaemic stroke and using adequate prevention in patients with AF. Currently, oral anticoagulants and antiplatelet drugs are the most commonly used methods of stroke prevention. Left atrial appendage (LAA) is thought to be the main source of thrombi in patients with AF. LAA closure procedures that have been recently introduced into the clinical practice are an alternative method of stroke prevention in patients with contraindications to oral anticoagulants or with a high risk of bleeding. Two systems of percutaneous LAA closure are currently available, the Watchman plug and the Amplatzer Cardiac Plug, but experience with these procedures is still very limited. AIM: To provide early results regarding safety and feasibility of percutaneous LAA closure with the Amplatzer Cardiac Plug in patients with AF and multiple comorbidities resulting in a high risk of stroke and bleeding complications. METHODS: Twenty one patients with AF, at least 2 points in the CHADS2/CHA2DS2VASc score and a high risk of bleeding as assessed by the HAS-BLED score (at least 3 points) underwent percutaneous Amplatzer Cardiac Plug implantation. Patients with less than 3 points in the HAS-BLED score were also included in the study if they had contraindications to oral anticoagulants (e.g. previous haemorrhage, recurrent bleeding, epidermolysis) or suffered from recurrent ischaemic stroke despite anticoagulant treatment. The Amplatzer Cardiac Plug was implanted using the standard technique under fluoroscopic and echocardiographic guidance. RESULTS: Percutaneous LAA closure with the Amplatzer Cardiac Plug was performed in a group of patients with many comorbidities who had a high risk of ischaemic stroke (CHA2DS2VASc score 4.43 +/- 1.4 points) as well as a high risk of bleeding (HAS-BLED score 3.0 +/- 0.7 points). LAA occlusion was successfully performed in 20 (95.2%) patients. A serious periprocedural complication (cardiac tamponade requiring pericardiocentesis) occurred in 1 (4.76%) patient. CONCLUSIONS: Successful LAA occlusion is feasible in a vast majority of patients undergoing this procedure. The rate of serious periprocedural complications is relatively low. LAA occlusion is justified in a group of patients with a high risk of ischaemic stroke and a high risk of bleeding or contraindications to oral anticoagulants. PMID- 23348529 TI - Catheter ablation of atrial fibrillation in patients with hypertrophic cardiomyopathy: atrial fibrillation type determines the success rate. AB - BACKGROUND: Atrial fibrillation (AF) in patients with hypertrophic cardiomyopathy (HCM) is generally associated with deterioration of the clinical status, functional capacity, and quality of life. It is also an independent risk factor for stroke and death. Studies evaluating the effectiveness of AF ablation in this cohort are relatively scant, have included relatively few patients, and their results are somewhat conflicting. Thus, the aim of this study was to assess the safety and efficacy of catheter ablation of AF in patients with HCM. METHODS: Thirty patients (10 females; mean age 48.7 +/- 11 years) with drug-refractory paroxysmal (n = 14), persistent (n = 7), or long-persistent (> 1 year; n = 9) AF were prospectively recruited into the study. Eleven patients were in New York Heart Association (NYHA) class I, 13 patients were in NYHA class II, and 6 patients were in NYHA class III. Mean atrial volume was 180 +/- 47 mL, interventricular septum thickness was 20.5 +/- 6.3 mm, and left atrial area was 29.8 +/- 6.2 cm2. Ablation protocol was adjusted to the clinical and electrophysiological status of the patients. Pulmonary vein isolation and bidirectional cavo-tricuspid isthmus block were performed in all patients. In addition, left atrial linear lesions were created and complex fragmented atrial potentials were ablated in patients with persistent and long-persistent AF, as well as during repeated procedures. RESULTS: At 12 months, stable sinus rhythm (SR) was present in 16 (53%) patients, significantly more frequently in patients with paroxysmal AF (71% in SR) compared to those with persistent (57.1% in SR) or long-persistent (22% in SR) AF. A significant reduction of AF burden was observed in 85.7% of patients with paroxysmal AF, 71.4% of patients with persistent AF, and 55.5% of patients with long-persistent AF. Single procedure success rate was 33% (10 patients), and repeat ablation procedures were performed in 13 patients. No periprocedural complications occurred. Thromboembolic events were noted in 2 patients with arrhythmia recurrence during the follow-up, including stroke in 1 patient and peripheral embolism in the other patient. In both these patients, heart failure worsening was observed during these events, and anticoagulation was inadequate in one of them. Five of 16 patients in whom stable SR was observed during the follow-up were off antiarrhythmic drug therapy at final evaluation. In the other 6 patients, antiarrhythmic drug therapy was continued due to ventricular arrhythmias. Successfully treated patients more often had paroxysmal AF (successful ablation: paroxysmal AF in 10 of 16 patients; unsuccessful ablation: paroxysmal AF in 4 of 14 patients; p = 0.009) and were younger (45 +/- 11.5 years vs. 52.6 +/- 9.2 years; p = 0.046). In addition, a trend toward a reduced need for cardioversion at the end of the procedure was also observed in these patients (3 patients in the successful ablation group vs. 8 patients in the unsuccessful ablation group; p = 0.056). In multivariate regression analysis, paroxysmal AF was the only independent predictor of a successful outcome. CONCLUSIONS: Catheter ablation of AF in patients with HCM is an effective and safe therapeutic option, particularly in patients with paroxysmal AF. Effectiveness of ablation is significantly smaller in patients with persistent AF and even more so in those with long-persistent AF. Repeated procedures were often necessary. Continued antiarrhythmic drug therapy is often required due to a significant degree of atrial remodelling. PMID- 23348524 TI - The biosynthesis of nitrogen-, sulfur-, and high-carbon chain-containing sugars. AB - Carbohydrates serve many structural and functional roles in biology. While the majority of monosaccharides are characterized by the chemical composition (CH2O)n, modifications including deoxygenation, C-alkylation, amination, O- and N methylation, which are characteristic of many sugar appendages of secondary metabolites, are not uncommon. Interestingly, some sugar molecules are formed via modifications including amine oxidation, sulfur incorporation, and "high-carbon" chain attachment. Most of these unusual sugars have been identified over the past several decades as components of microbially produced natural products, although a few high-carbon sugars are also found in the lipooligosaccharides of the outer cell walls of Gram-negative bacteria. Despite their broad distribution in nature, these sugars are considered "rare" due to their relative scarcity. The biosynthetic steps that underlie their formation continue to perplex researchers to this day and many questions regarding key transformations remain unanswered. This review will focus on our current understanding of the biosynthesis of unusual sugars bearing oxidized amine substituents, thio-functional groups, and high-carbon chains. PMID- 23348530 TI - Comparison of drug-eluting stents to bare-metal stents in ST-elevation myocardial infarction in long-term follow-up. AB - BACKGROUND: Recent data from "real world" registries and some randomised trials concerning the safety and efficacy of drug-eluting stents (DES) in patients with acute ST-elevation myocardial infarction (STEMI) are equivocal. AIM: We sought to compare DES with bare-metal stents (BMS) in STEMI patients treated with primary percutaneous coronary intervention in terms of safety and efficacy parameters in long-term follow-up. METHODS: 895 consecutive STEMI patients admitted between 2003 and 2006 were included in this observational study. The clinical and procedural characteristic as well as long-term outcome of 327 patients treated with DES were compared with 568 patients treated with BMS. Combined primary endpoint consisted of: death, myocardial infarction (MI) and target vessel revascularisation (TVR). RESULTS: Age, sex, risk factors, presence of 3-vessel disease, left ventricular ejection fraction and the use of IIb/IIIa antagonist were comparable in both groups. During a mean follow-up of 570 +/- 490 days, the mortality rate was 8.9% in the DES group vs. 15.5% in the BMS group (p = 0.005). In the DES group, lower incidences of both death and MI (9.5% vs. 16%, p = 0.006) as well as the combined endpoint of death, MI and TVR (19.3% vs. 31.3%, p < 0.001) were recorded. Target lesion revascularisation was more frequently performed in the BMS group (13.4% vs. 8.6%, p = 0.03). However, patients who received BMS more frequently had history of MI and coronary interventions, Killip class > 1 on admission, lower level of haemoglobin and HDL-cholesterol and higher level of troponin than those who received DES. After adjustment, the use of BMS was no longer significantly associated with worse clinical outcome with a trend in favour of DES. The only independent factor associated with increased risk of the combined endpoint was the Killip class > 1 (p = 0.003). CONCLUSIONS: In STEMI patients, DES are not inferior in comparison to BMS in terms of safety and efficacy parameters and seem to be associated with a lower rate of target lesion revascularisations. Additionally, Killip classification remains a simple and important classification used to stratify risk in patients with acute MI. PMID- 23348531 TI - Early and long term coronary artery bypass grafting outcomes in patients under 45 years of age. AB - BACKGROUND: In Poland, mortality and morbidity rates due to ischaemic heart disease (IHD) remain high and concern the whole population. An interesting issue is rapid development of IHD in some younger subjects and uncertain treatment outcomes in this patient subset. Premature cessation of professional activity, along with worsening of quality of life due to IHD in the population under 45 years of age is a huge medical, economic, and social problem. Only few studies evaluated early and long-term outcomes of coronary artery bypass grafting (CABG) used for the treatment of IHD in young patients, especially in premenopausal women. AIM: The purpose of the study was to analyse early and long-term outcomes of CABG in patients under 45 years of age. METHODS: We studied 125 patients under 45 years of age who underwent a CABG procedure. The study group included 65 women aged 27-45 (mean 41.5 +/- 3.5) years operated upon in 1990-1999, and 60 men aged 33-45 (mean 41 +/- 3.2) years operated upon in 1993. We evaluated early postoperative outcomes. The two genders were compared in regard to survival free from death, recurrent angina, and repeated myocardial during long-term follow-up. We also evaluated other variables such as education level, professional activity, and exposure to IHD risk factors before and after the operation. RESULTS: Seven women and two men died in hospital after CABG (p = 0.2). Analysis of major postoperative outcomes like myocardial infarction, low cardiac output syndrome requiring support with intra-aortic balloon pump (IABP), a lower limb amputation following the use of IABP, ischaemic stroke, and respiratory failure showed that these complications were significantly more frequent in women than in men (p < 0.01). Differences between the two groups regarding other adverse outcomes including atrial fibrillation, sternal instability, haemothorax, and pneumothorax were not significant. Analysis of long-term survival curves did not show any significant differences between men and women in regard to rates of death, recurrent angina, and the need for repeated myocardial revascularisation (p = 0.64, p = 0.93, and p = 0.13, respectively). CONCLUSIONS: Young women who underwent CABG were burdened with higher early postoperative morbidity and mortality than young men. However, long-term outcomes (mortality, recurrent angina, and repeated myocardial revascularisation rates) did not differ significantly between the two groups. Regardless of gender, repeated myocardial revascularisation rate was significantly higher among those patients who continued to smoke after the surgery (p < 0.01). PMID- 23348532 TI - The utility of NT-proBNP and various echocardiographic methods in the determination of doxorubicin induced subclinical late cardiotoxicity. AB - BACKGROUND AND AIM: Our aims were to investigate the utility of plasma N terminal pro B-type natriuretic peptide (NT-proBNP) level and find the most beneficial echocardiographic parameters to detect subclinical cardiotoxicity in childhood- cancer survivors treated with doxorubicin. METHODS: The study included 23 patients with a mean age of 17.1 years, who had received doxorubicin therapy with a mean cumulative dose of 241.1 mg/m2 with a median time period of 10.5 years since the last dose of doxorubicin. The control group consisted of 19 healthy volunteers matched for age, sex, and weight. RESULTS: The serum NT-proBNP levels of the patient group were higher than the control group. The measurements of myocardial performance index (MPI), tissue Doppler mitral septal annulus systolic (S's) and early diastolic (E's) velocities, ratio of early mitral flow velocity (E) to E's (E/E's), left ventricular diastolic volume (LVDV), tricuspid early diastolic velocity (TE) and percentage of left ventricular posterior wall thickness (%LVPWt) were found to be significantly different from the control group. MPI values were significantly correlated with NT-proBNP levels and cumulative doxorubicin doses. CONCLUSIONS: Elevated MPI values, associated with high NT-pro BNP levels and high cumulative doxorubicin doses, could be a useful indicator of subclinical cardiotoxicity. NT-proBNP could be an effective marker in the long-term follow up of subclinical cardiotoxicity. PMID- 23348533 TI - Heart rate and double product in relation to insulin resistance in patients with hypertension and coronary artery disease. AB - BACKGROUND: Elevated values of heart rate (HR) and insulin resistance (IR) reflect enhanced sympathetic nervous system activity and may be connected to the development of coronary artery disease (CAD) and diabetes. AIM: To evaluate the relationship between HR, blood pressure (BP), double product and IR in nondiabetic hypertensive patients with stable CAD. METHODS: There were 73 patients included in the study. Ambulatory BP monitoring was recorded in all patients by a Spacelabs 90207 device. Homeostasis model assessment (HOMA-IR) was used to estimate IR. Double product was calculated by multiplying systolic BP and HR. RESULTS: In the study population (mean age 67.1 +/- 8.4 years, 52% males) there was a positive correlation between HOMAIR and 24-h double product (r = 0.35, p < 0.01) and body mass index (BMI) (r = 0.45, p < 0.001). The receiver operating characteristic analysis of 24-h double product and BMI as predictive markers of IR did not reveal statistical differences between AUC (0.72 +/- 0.09 vs. 0.72 +/- 0.08, 24-h double product and BMI, respectively, p = NS). The best cut-off points in predicting IR were 8,978 mm Hg/min for 24-h double product and 33.02 kg/m2 for BMI. There were differences between the non obese (n = 44, mean age 67.9 +/- 9.2 years) and obese (n = 29, mean age 65.8 +/- 6.9 years) groups in: serum insulin level (7.3 +/- 2.3 uU/mL vs. 12.0 +/- 7.3 uU/mL, p < 0.01), HOMA-IR (1.8 +/- 0.7 uU/mL * mmol/L vs. 3.0 +/- 2.0 uU/mL * mmol/L, p < 0.01), and day systolic BP (128.0 +/- 10.8 mm Hg vs. 134.1 +/- 10.1 mm Hg, p < 0.02). CONCLUSIONS: 24-h double product and BMI may be complementary parameters in the prediction of IR in hypertensive nondiabetics with CAD confirmed by percutaneous coronary interventions in history and/or at least one coronary artery stenosis ? 70% in elective coronary angiography. PMID- 23348534 TI - [Not Available]. PMID- 23348535 TI - The effect of physical activity on serum levels of selected biomarkers of atherosclerosis. AB - BACKGROUND: Physical activity is associated with a lower risk of cardiovascular disease but the mechanism underlying this association is unclear. These benefits of physical activity might result from its effects on inflammation and endothelial function. AIM: We investigated whether cardiorespiratory fitness and the level of physical activity are associated with biomarkers of atherosclerosis in athletes and nonathletes. METHODS: Forty six athletes and 46 age- and sex matched subjects who did not exercise regularly were studied. All subjects underwent anthropometric measurements and maximal treadmill cardiopulmonary exercise tests. Physical activity level was assessed using the International Physical Activity Questionnaire-Short Form (IPAQ-SF). Blood samples were taken before and immediately after exercise. Serum interleukin (IL)-6, soluble CD40 ligand (sCD40L) and soluble intercellular adhesion molecule- 1 (sICAM-1) levels were determined using the ELISA method. RESULTS: In all participants, IL-6 level was significantly increased after exercise as compared to baseline (1.35 +/- 2.6 vs. 1.46 +/- +/- 2.1 pg/mL, p = 0.01). Resting IL-6 and sCD40L levels were lower in athletes as compared to nonathletes (0.7 +/- 0.92 vs. 1.8 +/- 3.52 pg/mL, p = 0.003, and 888.8 +/- 892.9 vs. 2367.7 +/- 8743.4 pg/mL, p = 0.005, respectively), while sICAM-1 levels did not differ between the two groups. IL-6 level correlated negatively with peak oxygen consumption (r = -0.25, p = 0.035) and the IPAQ-SF score (r = -0.26, p = 0.02), and sCD40L level correlated negatively with the IPAQ SF score (r = -0.4, p = 0.004). CONCLUSIONS: Intensive exercise training and high exercise capacity are associated with lower serum IL-6 and sCD40L levels. This may constitute an important factor limiting progression of atherosclerosis. PMID- 23348536 TI - [Acute cardiorenal syndrome: recovery of renal function after renal replacement therapy]. AB - Utilisation of invasive treatment in the form of elective dialysis end extracorporeal ultrafiltration as a method of complementary to pharmacotherapy was presented by the example of the patient with acute decompensated heart failure with diagnosed cardiorenal syndrome type 1. Such procedure reduced symptoms of overhydration, restored sensitivity to oral diuretics and allow to obtain a partial return of renal function, improved prognosis and quality of life of the patient. PMID- 23348537 TI - [Mid-aortic syndrome in 18 year-old woman with arterial hypertension and bilateral renal artery stenosis]. AB - Mid-aortic syndrome (MAS) is characterised by narrowing of the abdominal aorta, often with involvement of the renal and splanchnic arterial branches. Although uncommon, MAS is an important cause of renovascular hypertension in children and adolescents and should be considered in the differential diagnosis of hypertension . Hypertension is typically severe and often difficult to manage. The management of MAS should always be individualised and may include percutaneous transluminal renal angioplasty, stent implantation or surgical revascularisation. We present a 18 year-old woman with hypertension and MAS coexisting with bilateral renal artery stenosis who underwent left renal artery angioplasty and than was followed-up for one year. PMID- 23348538 TI - [High-risk pulmonary embolism in early post-operative period]. AB - High risk pulmonary embolism remains a major diagnostic and therapeutic challenge. One of the most difficult clinical situation is pulmonary embolism in patients in early postoperative period as most of them has contraindication to fibrinolysis. In this paper we present the case of patient with thrombophilia and pulmonary embolism diagnosed on the third day after cancer-related laparoscopic prostatectomy. Patient was successfully treated by means of percutaneous catheter thrombus defragmentation and intraarterial infusion of the reduced dose of alteplase. PMID- 23348539 TI - [Peritoneal dialysis as an alternative in the treatment of patient with heart failure refractory to conventional therapy]. AB - Peritoneal ultrafiltration and dialysis is a feasible therapy in selected patients with heart failure (HF). This method is effective in slow and continuous plasma volume reduction, maintenance of normonatraemia, the removal of cytokines and humoral factors involved in the development and progression of HF and middle molecule clearance. We present a 26-year-old woman with HF refractory to conventional treatment. Peritoneal dialysis improved both the clinical status and the quality of life. Peritoneal dialysis is an invasive method of treatment therefore more studies are necessary to identify patients who would benefit from this form of therapy. PMID- 23348540 TI - [Hypertension caused by renal artery stenosis: new view on a difficult clinical problem]. PMID- 23348541 TI - [2D and 3D speckle tracking echocardiography: clinical application]. PMID- 23348542 TI - [Chronic pulmonary heart disease. Does it require cardiologist's attention?]. PMID- 23348543 TI - Osborn waves during therapeutic hypothermia in a young ST-ACS patient after out of-hospital cardiac arrest. AB - A 37 year-old male patient was admitted to the intensive care unit after an out of-hospital cardiac arrest due to ventricular fibrillation in a course of ST segment elevation acute coronary syndrome. On admission, the patient was unconscious with a Glasgow Coma Scale (GCS) score of 5. A percutaneous coronary intervention and mild therapeutic hypothermia (HT), defined as maintaining body temperature between 32 degrees C and 34 degrees C, were performed. During HT on ECG, we observed Osborn waves, which resolved spontaneously after re-warming. After five days of recovery, the patient scored 15 on GCS and did not show any neurological deficits. PMID- 23348544 TI - [Commentary]. PMID- 23348545 TI - [Contemporary imaging of pericardial diseases. Part 2. Expert consensus statement of the Polish Clinical Forum for Cardiovascular Imaging]. PMID- 23348546 TI - Patient with atrial fibrillation and myocardial infarction due to coronary artery embolism treated with thrombus aspiration. AB - We present the case of a 77 year-old male patient diagnosed with ST-segment elevation myocardial infarction of anterior wall due to coronary embolism secondary to paroxysmal atrial fibrillation. The patient was qualified for emergent coronary angiography and aspiration thrombectomy. Due to lack of atherosclerotic lesions and probable embolic origin of the occlusion of the infarct-related artery, the patient underwent a successful thrombus aspiration procedure without stent implantation, followed by oral anticoagulant therapy. PMID- 23348547 TI - [Unusual picture of pacemaker leads in patient after Senning procedure]. AB - We present a case of a 21-year-old man after Senning operation admitted to our hospital for transvenous implantation of a dual chamber pacemaker. The presence of persistent left superior vena cava enabled us to implant the desired dual chamber pacemaker. It is an extremely unusual situation when two pacemaker leads utilise two different routes to the heart: superior caval vein - atrial baffle - ventricle and persistent left superior caval vein - atrium. PMID- 23348548 TI - Multimodality imaging of a congenital Gerbode defect. PMID- 23348549 TI - [Endovascular management of superior vena cava syndrome prior to arterio-venous fistula creation in patient treated by repeated haemodialysis]. PMID- 23348550 TI - [Forty-three-years proper functioning of the Starr-Edwards tricuspid valve prosthesis in the patient with Ebstein's anomaly]. PMID- 23348551 TI - [Management of familial heterozygous hypercholesterolaemia. Position paper of the Polish Lipid Expert Forum]. PMID- 23348554 TI - Mastery: a comparison of wife and daughter caregivers of a person with dementia. AB - PURPOSE: The purpose was to obtain a better understanding of the role of mastery (global and caregiving) in wives' versus daughters' experience of caring for a person with dementia. METHOD: A total of 67 caregivers participated in a cross sectional study. Variables measured were global mastery, caregiving mastery, stress, and depressive symptoms. Analysis included t tests, correlations, and multiple regressions. FINDINGS: Wives and daughters reported similar levels of stress and depressive symptoms. The correlations between stressors, caregiver stress, and depressive symptoms were significant for wives but not daughters. The relationships between global mastery and stress, and global mastery and depressive symptoms were significant for both wives and daughters, but the magnitude was less for daughters in the relationship of global mastery and depressive symptoms. Caregiver mastery was strongly related to stress and depressive symptoms for wives but not for daughters. CONCLUSIONS: Consideration must be given to the differences in the experience of mastery so that evaluations and interventions can be tailored to the unique experiences of wives and daughters. PMID- 23348553 TI - Assessing smectic liquid-crystal continuum models for elastic bilayer deformations. AB - For four decades, since W. Helfrich's pioneering study of smectic A liquid crystals in 1973, continuum elastic models (CEMs) have been employed as tools to understand the energetics of protein-induced lipid bilayer deformations. Among the assumptions underlying this use is that all relevant protein-lipid interactions can be included in the continuum representation of the protein bilayer interactions through the physical parameters determined for protein-free bilayers and the choice of boundary conditions at the protein/bilayer interface. To better understand this assumption, we review the general structure of CEMs, examine how different choices of boundary conditions and physical moduli profiles alter the predicted bilayer thickness profiles around gramicidin A (gA) and mitochondrial voltage-dependent anion channels (VDAC), respectively, and compare these profiles with those obtained from all-atom molecular dynamics simulations. We find that the profiles differ qualitatively in the first lipid shell around the channels, indicating that the CEMs do not capture accurately the consequences of the protein-induced local changes in lipid bilayer dynamics. Therefore, one needs to be careful when interpreting the results of CEM-based analyses of lipid bilayer-membrane protein interactions. PMID- 23348555 TI - Nurse presence enhanced through Equus. AB - PURPOSE: The purpose of this study was for nurses to experience equine-assisted learning and for them to describe their being in the moment with their horse. The aims of the study were to assist clinicians in recognizing their ability and skill at being present--that is, calm and centered--as they engage with horses and to determine if interaction with horses is a valid representation in recognizing presence in the participants. DESIGN: Descriptive phenomenology was used to explore this lived experience. FINDINGS: Five themes emerged: The Experienced Novice, Present in the Moment, Discovery of Self, Team Building, and Leadership. CONCLUSIONS: Equine-assisted learning can be a meaningful venue for nurses to self-discover their ability to be present. PMID- 23348556 TI - A retrospective pattern analysis. AB - The purpose of this article was to explore the application of pattern analysis retrospectively to a 2-year relationship between me and a young mother of a small child with spina bifida. Five patterns are presented within the context of movement, time, space, and consciousness, followed by analysis of transitions, transforming experiences, and choice points. Finally connectedness with client is discussed along with implications for praxis. PMID- 23348557 TI - Cortisol response to challenge involving low controllability: the role of control beliefs and age. AB - Cortisol responses are typically more pronounced under low controllability conditions, yet little is known about the role of individual differences. This study examined whether cortisol response to a situation with low controllability differs as a function of preexisting control beliefs and age. We manipulated level of controllability using a driving simulator. Control beliefs were assessed prior to the lab session. Salivary cortisol was measured before and after the driving simulation. Participants were 152 adults aged 22-84 from a Boston area sample. In comparison to the normal controllability condition, those in the low controllability condition reported less perceived control over driving, supporting the effectiveness of the manipulation. In the low controllability condition those with higher control beliefs showed a greater cortisol response than those with low control beliefs. Older adults showed a greater cortisol response than younger adults during the challenge. Implications of acute cortisol responses for performance outcomes are discussed. PMID- 23348558 TI - Longitudinal associations in adolescence between cortisol and persistent aggressive or rule-breaking behavior. AB - Although several studies have associated antisocial behavior with decreased cortisol awakening responses (CAR), studies in adolescent samples yielded inconsistent results. In adolescence however, the CAR develops and antisocial behavior is heterogeneous in type and persistence. Therefore this longitudinal study compared persistent aggressive and rule-breaking adolescents to low aggressive and rule-breaking adolescents on the development of the CAR from ages 15 to 17 (N=390). Persistently high aggressive adolescents showed decreased cortisol levels at awakening consistently over the years (Deltachi(2)(1)=6.655, p=.01) as compared to low aggressive adolescents. No differences between adolescents showing persistent high rule-breaking and low rule-breaking were found. This longitudinal study is the first to show that persistent aggression, but not rule-breaking behavior, is related to neurobiological alterations. Moreover, despite development of the CAR over adolescence, the decrease in cortisol is consistent over time in persistent high aggressive adolescents, which is an important prerequisite for the prediction of persistent aggression. PMID- 23348560 TI - Diagnosis of malignant melanoma and basal cell carcinoma by in vivo NIR-FT Raman spectroscopy is independent of skin pigmentation. AB - There is a general need for methods to obtain fast in vivo diagnosis of skin tumours. Raman spectroscopy measures molecular structure and may thus have potential as a tool for skin tumour diagnosis. The purpose of this study was to investigate how skin pigmentation influenced the Raman spectra and skin tumour diagnostics in vivo. We obtained Raman spectra in vivo from the normal skin of 55 healthy persons with different skin pigmentation (Fitzpatrick skin type I-VI) and in vivo from 25 basal cell carcinomas, 41 pigmented nevi and 15 malignant melanomas. Increased skin pigmentation resulted in a higher spectral background caused by fluorescence, which could be removed by background correction. After background correction, we found only a negligible effect of pigmentation on the major spectral bands, and the comparison of the intensity of these bands allowed us to differentiate between normal skin and the different skin lesions independent of skin type. The diagnosis of skin lesions is possible due to significant (p < 0.05) differences found in the water band around 3250 cm(-1), the protein specific band around 1250 cm(-1) (amide-III) and the amide-III ratio that describes the protein/lipid ratio by comparing bands around 1250 cm(-1) with bands around 1300 cm(-1). We have shown that NIR-FT Raman spectroscopy is useable for malignant melanoma and basal cell carcinoma diagnostics in vivo and that pigmentation of the skin or lesion does not influence the diagnosis, but larger data sets are required to establish accurate diagnostic power. PMID- 23348567 TI - IF1 limits the apoptotic-signalling cascade by preventing mitochondrial remodelling. AB - Mitochondrial structure has a central role both in energy conversion and in the regulation of cell death. We have previously shown that IF1 protects cells from necrotic cell death and supports cristae structure by promoting the oligomerisation of the F1Fo-ATPsynthase. As IF1 is upregulated in a large proportion of human cancers, we have here explored its contribution to the progression of apoptosis and report that an increased expression of IF1, relative to the F1Fo-ATPsynthase, protects cells from apoptotic death. We show that IF1 expression serves as a checkpoint for the release of Cytochrome c (Cyt c) and hence the completion of the apoptotic program. We show that the progression of apoptosis engages an amplification pathway mediated by: (i) Cyt c-dependent release of ER Ca(2+), (ii) Ca(2+)-dependent recruitment of the GTPase Dynamin related protein 1 (Drp1), (iii) Bax insertion into the outer mitochondrial membrane and (iv) further release of Cyt c. This pathway is accelerated by suppression of IF1 and delayed by its overexpression. IF1 overexpression is associated with the preservation of mitochondrial morphology and ultrastructure, consistent with a central role for IF1 as a determinant of the inner membrane architecture and with the role of mitochondrial ultrastructure in the regulation of Cyt c release. These data suggest that IF1 is an antiapoptotic and potentially tumorigenic factor and may be a valuable predictor of responsiveness to chemotherapy. PMID- 23348566 TI - Mapping kainate activation of inner neurons in the rat retina. AB - Kainate receptors mediate fast, excitatory synaptic transmission for a range of inner neurons in the mammalian retina. However, allocation of functional kainate receptors to known cell types and their sensitivity remains unresolved. Using the cation channel probe 1-amino-4-guanidobutane agmatine (AGB), we investigated kainate sensitivity of neurochemically identified cell populations within the structurally intact rat retina. Most inner retinal neuron populations responded to kainate in a concentration-dependent manner. OFF cone bipolar cells demonstrated the highest sensitivity of all inner neurons to kainate. Immunocytochemical localization of AGB and macromolecular markers confirmed that type 2 bipolar cells were part of this kainate-sensitive population. The majority of amacrine (ACs) and ganglion cells (GCs) showed kainate responses with different sensitivities between major neurochemical classes (gamma-aminobutyric acid [GABA]/glycine ACs > glycine ACs > GABA ACs; glutamate [Glu]/weakly GABA GCs > Glu GCs). Conventional and displaced cholinergic ACs were highly responsive to kainate, whereas dopaminergic ACs do not appear to express functional kainate receptors. These findings further contribute to our understanding of neuronal networks in complex multicellular tissues. PMID- 23348569 TI - Two-year results of X-stop interspinous implant for the treatment of lumbar spinal stenosis: a prospective study. AB - STUDY DESIGN: Prospective Observational Study. OBJECTIVE: To prospectively assess the clinical outcome of patients treated for symptomatic spinal stenosis with the X-stop device. SUMMARY OF BACKGROUND DATA: The X-stop device is used in the treatment of symptomatic lumbar spinal stenosis. The preliminary results of this study of 40 patients at 1 year were published in 2007. The 2-year results of 57 patients are reported in this paper. Zucherman et al report 60% significant improvement at 1 year and 48.4% at 2 years. METHODS: Fifty-seven consecutive patients with radiologically confirmed lumbar spinal stenosis were enrolled and treated with the X-stop device. The device was implanted at a maximum of 2 affected levels. Clinical response was evaluated with the Zurich Claudication Questionnaire (ZCQ), Oswestry Disability Index, and Short Form-36 questionnaires preoperatively and 6, 12, and 24 months postoperatively. RESULTS: Of the 57 patients enrolled, 54 completed the ZCQ questionnaire at 1 year and 46 patients at 2 years. Clinically significant improvement was attained by 65% at 1 year and 57% at 2 years and 70% were satisfied with the outcome of the surgery. Single level and double level insertions did not have significant difference in clinical outcome. CONCLUSION: This study demonstrates with the use of ZCQ scores as primary outcome measures that improved clinical outcomes are maintained at 2 years after X-stop implantation. PMID- 23348570 TI - Natural antisense transcript-targeted regulation of inducible nitric oxide synthase mRNA levels. AB - Natural antisense transcripts (asRNAs) are frequently transcribed from mammalian genes. Recently, we found that non-coding asRNAs are transcribed from the 3' untranslated region (3'UTR) of the rat and mouse genes encoding inducible nitric oxide synthase (iNOS), which catalyzes the production of the inflammatory mediator nitric oxide. The iNOS asRNA stabilizes iNOS mRNA by interacting with the mRNA 3'UTR. Furthermore, single-stranded 'sense' oligonucleotides corresponding to the iNOS mRNA sequence were found to reduce iNOS mRNA levels by interfering with mRNA-asRNA interactions in rat hepatocytes. This method was named natural antisense transcript-targeted regulation (NATRE) technology. In this study, we detected human iNOS asRNA expressed in hepatocarcinoma and colon carcinoma tissues. The human iNOS asRNA harbored a sequence complementary to an evolutionarily conserved region of the iNOS mRNA 3'UTR. When introduced into hepatocytes, iNOS sense oligonucleotides that were modified by substitution with partial phosphorothioate bonds and locked nucleic acids or 2'-O-methyl nucleic acids greatly reduced levels of iNOS mRNA and iNOS protein. Moreover, sense oligonucleotides and short interfering RNAs decreased iNOS mRNA to comparable levels. These results suggest that NATRE technology using iNOS sense oligonucleotides could potentially be used to treat human inflammatory diseases and cancers by reducing iNOS mRNA levels. PMID- 23348571 TI - Serum albumin: accuracy and clinical use. AB - Albumin is the major plasma protein and its determination is used for the prognostic assessment of several diseases. Clinical guidelines call for monitoring of serum albumin with specific target cut-offs that are independent of the assay used. This requires accurate and equivalent results among different commercially available methods (i.e., result standardization) through a consistent definition and application of a reference measurement system. This should be associated with the definition of measurement uncertainty goals based on medical relevance of serum albumin to make results reliable for patient management. In this paper, we show that, in the current situation, if one applies analytical goals for serum albumin measurement derived from its biologic variation, the uncertainty budget derived from each step of the albumin traceability chain is probably too high to fulfil established quality levels for albumin measurement and to guarantee the accuracy needed for clinical usefulness of the test. The situation is further worsened if non-specific colorimetric methods are used for albumin measurement as they represent an additional random source of uncertainty. PMID- 23348568 TI - USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase. AB - A large number of patients are resistant to taxane-based chemotherapy. Functional mitotic checkpoints are essential for taxane sensitivity. Thus, mitotic regulators are potential markers for therapy response and could be targeted for anticancer therapy. In this study, we identified a novel function of ubiquitin (Ub)-specific processing protease-7 (USP7) that interacts and cooperates with protein death domain-associated protein (Daxx) in the regulation of mitosis and taxane resistance. Depletion of USP7 impairs mitotic progression, stabilizes cyclin B and reduces stability of the mitotic E3 Ub ligase, checkpoint with forkhead and Ring-finger (CHFR). Consequently, cells with depleted USP7 accumulate Aurora-A kinase, a CHFR substrate, thus elevating multipolar mitoses. We further show that these effects are independent of the USP7 substrate p53. Thus, USP7 and Daxx are necessary to regulate proper execution of mitosis, partially via regulation of CHFR and Aurora-A kinase stability. Results from colony formation assay, in silico analysis across the NCI60 platform and in breast cancer patients suggest that USP7 levels inversely correlate with response to taxanes, pointing at the USP7 protein as a potential predictive factor for taxane response in cancer patients. In addition, we demonstrated that inhibition of Aurora-A attenuates USP7-mediated taxane resistance, suggesting that combinatorial drug regimens of Taxol and Aurora-A inhibitors may improve the outcome of chemotherapy response in cancer patients resistant to taxane treatment. Finally, our study offers novel insights on USP7 inhibition as cancer therapy. PMID- 23348572 TI - Green synthetic approach for Ti3+ self-doped TiO(2-x) nanoparticles with efficient visible light photocatalytic activity. AB - Rice-shaped Ti(3+) self-doped TiO(2-x) nanoparticles were synthesized by mild hydrothermal treatment of TiH(2) in H(2)O(2) aqueous solution. The structure, crystallinity, morphology, and other properties of the as-prepared samples were characterized by X-ray diffraction, transmission electron microscopy, high resolution transmission electron microcopy and X-ray photoelectron spectra. Electron paramagnetic resonance spectra confirm the presence of high concentration of paramagnetic Ti(3+) in the bulk and surface of the as-prepared samples. The particles showed a strong absorption across the UV to the visible light region and retained their light-blue color upon storage in ambient atmosphere or water for one month at 40 degrees C. The formation mechanism of Ti(3+) self-doped TiO(2-x) nanoparticles was discussed. Under visible light irradiation, the samples exhibit higher photocatalytic activity for hydrogen evolution and photooxidation of methylene blue than that of the commercial P25 TiO(2) nanoparticles. The sample obtained at 160 degrees C for 27 h showed a 9 fold enhancement for the visible light decomposition of methylene blue and 12.5 times higher for H(2) production in comparison to P25 TiO(2). The samples also showed an excellent cycling stability of the photocatalytic activity. PMID- 23348573 TI - Thyroid hormone-responsive SPOT 14 homolog promotes hepatic lipogenesis, and its expression is regulated by liver X receptor alpha through a sterol regulatory element-binding protein 1c-dependent mechanism in mice. AB - The protein, thyroid hormone-responsive SPOT 14 homolog (Thrsp), has been reported to be a lipogenic gene in cultured hepatocytes, implicating an important role of Thrsp in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Thrsp expression is known to be regulated by a variety of transcription factors, including thyroid hormone receptor, pregnane X receptor, and constitutive androstane receptor. Emerging in vitro evidence also points to a critical role of liver X receptor (LXR) in regulating Thrsp transcription in hepatocytes. In the present study, we showed that Thrsp was up-regulated in livers of db/db mice and high-fat-diet-fed mice, two models of murine NAFLD. Hepatic overexpression of Thrsp increased triglyceride accumulation with enhanced lipogenesis in livers of C57Bl/6 mice, whereas hepatic Thrsp gene silencing attenuated the fatty liver phenotype in db/db mice. LXR activator TO901317 induced Thrsp expression in livers of wild-type (WT) and LXR-beta gene-deficient mice, but not in LXR-alpha or LXR-alpha/beta double-knockout mice. TO901317 treatment significantly enhanced hepatic sterol regulatory element-binding protein 1c (SREBP-1c) expression and activity in WT mice, but failed to induce Thrsp expression in SREBP-1c gene deficient mice. Sequence analysis revealed four LXR response-element-like elements and one sterol regulatory element (SRE)-binding site within a -2,468 ~+1 base-pair region of the Thrsp promoter. TO901317 treatment and LXR-alpha overexpression failed to induce, whereas overexpression of SREBP-1c significantly increased Thrsp promoter activity. Moreover, deletion of the SRE site completely abolished SREBP-1c-induced Thrsp transcription. CONCLUSION: Thrsp is a lipogenic gene in the liver that is induced by the LXR agonist through an LXR-alpha mediated, SREBP-1c-dependent mechanism. Therefore, Thrsp may represent a potential therapeutic target for the treatment of NAFLD. PMID- 23348574 TI - Biomolecule-functionalized polymer brushes. AB - Functional polymer brushes have been utilized extensively for the immobilization of biomolecules, which is of crucial importance for the development of biosensors and biotechnology. Recent progress in polymerization methods, in particular surface-initiated atom transfer radical polymerization (ATRP), has provided a unique means for the design and synthesis of new biomolecule-functionalized polymer brushes. This current review summarizes such recent research activities. The different preparation strategies for biomolecule immobilization through polymer brush spacers are described in detail. The functional groups of the polymer brushes used for biomolecule immobilization include epoxide, carboxylic acid, hydroxyl, aldehyde, and amine groups. The recent research activities indicate that functional polymer brushes become versatile and powerful spacers for immobilization of various biomolecules to maximize their functionalities. This review also demonstrates that surface-initiated ATRP is used more frequently than other polymerization methods in the designs of new biomolecule functionalized polymer brushes. PMID- 23348575 TI - Evaluation of pulse rate variability obtained by the pulse onsets of the photoplethysmographic signal. AB - This work presents the evaluation of pulse rate variability (PRV) obtained from pulse onsets of photoplethysmographic (PPG) signals. Three published algorithms were used to determine the pulse onsets: diastolic point, maximum second derivative and tangent intersection. Temporal series of pulse onsets were obtained for each method, and several variability indices were derived from these series. Simultaneous ECG and PPG records were acquired from 37 healthy volunteers to evaluate the interchangeability between PRV indices and heart rate variability (HRV) indices by the Bland-Altman method. Furthermore, the concordance correlation coefficient was used to correlate the indices. In all the cases, PRV indices obtained through the tangent intersection method showed better accuracy and precision (Bland-Altman analysis, bias +/- 1.96 standard deviation: low frequency, LF(ms)(2) = -28.06 +/- 72.68; high frequency, HF(ms)(2) = -68.23 +/- 192.85; high frequency in normalized units, HF(nu) =-2.02 +/- 7.08; LF/HF = 0.17 +/- 0.71) and higher correlation (concordance correlation coefficients: low frequency, LF(ms)(2) = 0.99; high frequency, HF(ms)(2) = 0.98; high frequency in normalized units, HF(nu) = 0.97; LF/HF = 0.90) with HRV indices than other methods, and could be used as a good surrogate of HRV. PMID- 23348576 TI - Case study: developing nursing partnerships to support a successful electronic medical record implementation. PMID- 23348579 TI - Randomness in self-organized phenomena. A case study: retinal angiogenesis. AB - This note presents a review of recent work by the authors on angiogenesis, as a case study for analyzing the role of randomness in the formation of biological patterns. The mathematical description of the formation of new vessels is presented, based on a system of stochastic differential equations, coupled with a branching process, both of them driven by a set of relevant chemotactic underlying fields. A discussion follows about the possible reduction of complexity of the above approach, by mean field approximations of the underlying fields. The crucial role of randomness at the microscale is observed in order to obtain nontrivial realistic vessel networks. PMID- 23348581 TI - Novel anti(lymph)angiogenic treatment strategies for corneal and ocular surface diseases. AB - The cornea is one of the few tissues which actively maintain an avascular state, i.e. the absence of blood and lymphatic vessels (corneal [lymph]angiogenic privilege). Nonetheless do several diseases interfere with this privilege and cause pathologic corneal hem- and lymphangiogenesis. The ingrowths of pathologic blood and lymphatic vessels into the cornea not only reduce transparency and thereby visual acuity up to blindness, but also significantly increases the rate of graft rejections after subsequent corneal transplantation. Therefore great interest exists in new strategies to target pathologic corneal (lymph)angiogenesis to promote graft survival. This review gives an overview on the vascular anatomy of the normal ocular surface, on the molecular mechanisms contributing to the corneal (lymph)angiogenic privilege and on the cellular and molecular mechanisms occurring during pathological neovascularization of the cornea. In addition we summarize the current preclinical and clinical evidence for three novel treatment strategies against ocular surface diseases based on targeting pathologic (lymph)angiogenesis: (a) modulation of the immune responses after (corneal) transplantation by targeting pathologic (lymph)angiogenesis prior to and after transplantation, (b) novel concepts against metastasis and recurrence of ocular surface tumors such as malignant melanoma of the conjunctiva by anti(lymph)angiogenic therapy and (c) new ideas on how to target ocular surface inflammatory diseases such as dry eye by targeting conjunctival and corneal lymphatic vessels. Based on compelling preclinical evidence and early data from clinical trials the novel therapeutic concepts of promoting graft survival, inhibiting tumor metastasis and dampening ocular surface inflammation and dry eye disease by targeting (lymph)angiogenesis are on their way to translation into the clinic. PMID- 23348582 TI - Sequential Cdk1 and Plk1 phosphorylation of protein tyrosine phosphatase 1B promotes mitotic cell death. AB - Mitotic cell death following prolonged arrest is an important death mechanism that is not completely understood. This study shows that Protein Tyrosine Phosphatase 1B (PTP1B) undergoes phosphorylation during mitotic arrest induced by microtubule-targeting agents (MTAs) in chronic myeloid leukaemia cells. Inhibition of cyclin-dependent kinase 1 (Cdk1) or polo-like kinase 1 (Plk1) during mitosis prevents PTP1B phosphorylation, implicating these kinases in PTP1B phosphorylation. In support of this, Cdk1 and Plk1 co-immunoprecipitate with endogenous PTP1B from mitotic cells. In addition, active recombinant Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B. Furthermore, overexpression of wild-type PTP1B induced mitotic cell death, which is potentiated by MTAs. Moreover, mutation of serine 286 abrogates the cell death induced by PTP1B, whereas mutation of serine 393 does not, highlighting the importance of serine 286 phosphorylation in the execution of mitotic cell death. Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. Collectively, these data reveal that PTP1B activity promotes mitotic cell death and is regulated by the co-operative action of Cdk1 and Plk1 during mitotic arrest. PMID- 23348583 TI - Identification of the novel differentiation marker MS4A8B and its murine homolog MS4A8A in colonic epithelial cells lost during neoplastic transformation in human colon. AB - The CD20-homolog Ms4a8a has recently been shown to be a marker for alternatively activated macrophages but its expression is not restricted to hematopoietic cells. Here, MS4A8A/MS4A8B expression was detected in differentiated intestinal epithelium in mouse and human, respectively. Interestingly, no MS4A8B expression was found in human colon carcinoma. Forced overexpression of MS4A8A in the murine colon carcinoma cell line CT26 led to a reduced proliferation and migration rate. In addition, MS4A8A-expressing CT26 cells displayed an increased resistance to hydrogen peroxide-induced apoptosis, which translated in an increased end weight of subcutaneous MS4A8A+ CT26 tumors. Gene profiling of MS4A8A+ CT26 cells revealed a significant regulation of 225 genes, most of them involved in cytoskeletal organization, apoptosis, proliferation, transcriptional regulation and metabolic processes. Thereby, the highest upregulated gene was the intestinal differentiation marker cytokeratin 20. In conclusion, we show that MS4A8A/MS4A8B is a novel differentiation marker of the intestinal epithelium that supports the maintenance of a physiological barrier function in the gut by modulating the transcriptome and by conferring an increased resistance to reactive oxygen species. The absence of MS4A8B in human colonic adenocarcinomas shown in this study might be a helpful tool to differentiate between healthy and neoplastic tissue. PMID- 23348584 TI - The plasma membrane channel ORAI1 mediates detrimental calcium influx caused by endogenous oxidative stress. AB - The mouse hippocampal cell line HT22 is an excellent model for studying the consequences of endogenous oxidative stress. Addition of extracellular glutamate depletes the cells of glutathione (GSH) by blocking the glutamate-cystine antiporter system x(c)(-). GSH is the main antioxidant in neurons and its depletion induces a well-defined program of cell death called oxytosis, which is probably synonymous with the iron-dependent form of non-apoptotic cell death termed ferroptosis. Oxytosis is characterized by an increase of reactive oxygen species and a strong calcium influx preceding cell death. We found a significant reduction in store-operated calcium entry (SOCE) in glutamate-resistant HT22 cells caused by downregulation of the Ca(2+) channel ORAI1, but not the Ca(2+) sensors STIM1 or STIM2. Pharmacological inhibition of SOCE mimicked this protection similarly to knockdown of ORAI1 by small interfering RNAs. Long-term calcium live-cell imaging after induction of the cell death program showed a specific reduction in Ca(2+)-positive cells by ORAI1 knockdown. These results suggest that dysregulated Ca(2+) entry through ORAI1 mediates the detrimental Ca(2+) entry in programmed cell death induced by GSH depletion. As this detrimental Ca(2+) influx occurs late in the course of the cell death program, it might be amenable to therapeutic intervention in diseases caused by oxidative stress. PMID- 23348585 TI - Salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis through DR5 and survivin-dependent mechanisms. AB - Ras activation is a frequent event in human hepatocarcinoma that may contribute to resistance towards apoptosis. Salirasib is a ras and mTOR inhibitor that induces a pro-apoptotic phenotype in human hepatocarcinoma cell lines. In this work, we evaluate whether salirasib sensitizes those cells to TRAIL-induced apoptosis. Cell viability, cell death and apoptosis were evaluated in vitro in HepG2, Hep3B and Huh7 cells treated with DMSO, salirasib and YM155 (a survivin inhibitor), alone or in combination with recombinant TRAIL. Our results show that pretreatment with salirasib sensitized human hepatocarcinoma cell lines, but not normal human hepatocytes, to TRAIL-induced apoptosis. Indeed, FACS analysis showed that 25 (Huh7) to 50 (HepG2 and Hep3B) percent of the cells treated with both drugs were apoptotic. This occurred through activation of the extrinsic and the intrinsic pathways, as evidenced by a marked increase in caspase 3/7 (five to ninefold), caspase 8 (four to sevenfold) and caspase 9 (eight to 12-fold) activities in cells treated with salirasib and TRAIL compared with control. Survivin inhibition had an important role in this process and was sufficient to sensitize hepatocarcinoma cells to apoptosis. Furthermore, TRAIL-induced apoptosis in HCC cells pretreated with salirasib was dependent on activation of death receptor (DR) 5. In conclusion, salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis by a mechanism involving the DR5 receptor and survivin inhibition. These results in human hepatocarcinoma cell lines and primary hepatocytes provide a rationale for testing the combination of salirasib and TRAIL agonists in human hepatocarcinoma. PMID- 23348587 TI - Optical imaging of cell death in traumatic brain injury using a heat shock protein-90 alkylator. AB - Traumatic brain injury is a major public health concern and is characterised by both apoptotic and necrotic cell death in the lesion. Anatomical imaging is usually used to assess traumatic brain injuries and there is a need for imaging modalities that provide complementary cellular information. We sought to non invasively image cell death in a mouse model of traumatic brain injury using a near-infrared fluorescent conjugate of a synthetic heat shock protein-90 alkylator, 4-(N-(S-glutathionylacetyl) amino) phenylarsonous acid (GSAO). GSAO labels both apoptotic and necrotic cells coincident with loss of plasma membrane integrity. The optical GSAO specifically labelled apoptotic and necrotic cells in culture and did not accumulate in healthy organs or tissues in the living mouse body. The conjugate is a very effective imager of cell death in brain lesions. The optical GSAO was detected by fluorescence intensity and GSAO bound to dying/dead cells was detected from prolongation of the fluorescence lifetime. An optimal signal-to-background ratio was achieved as early as 3 h after injection of the probe and the signal intensity positively correlated with both lesion size and probe concentration. This optical GSAO offers a convenient and robust means to non-invasively image apoptotic and necrotic cell death in brain and other lesions. PMID- 23348586 TI - Resveratrol potentiates rapamycin to prevent hyperinsulinemia and obesity in male mice on high fat diet. AB - High doses of rapamycin, an antiaging agent, can prevent obesity in mice on high fat diet (HFD). Obesity is usually associated with hyperinsulinemia. Here, we showed that rapamycin given orally, at doses that did not affect weight gain in male mice on HFD, tended to decrease fasting insulin levels. Addition of resveratrol, which alone did not affect insulin levels, potentiated the effect of rapamycin, so that the combination decreased obesity and prevented hyperinsulinemia. Neither rapamycin nor resveratrol, and their combination affected fasting levels of glucose (despite lowering insulin levels), implying that the combination might prevent insulin resistance. We and others previously reported that resveratrol at high doses inhibited the mTOR (Target of Rapamycin) pathway in cell culture. Yet, as we confirmed here, this effect was observed only at super-pharmacological concentrations. At pharmacological concentrations, resveratrol did not exert 'rapamycin-like effects' on cellular senescence and did not inhibit the mTOR pathway in vitro, indicating nonoverlapping therapeutic mechanisms of actions of rapamycin and resveratrol in vivo. Although, like rapamycin, resveratrol decreased insulin-induced HIF-1-dependent transcription in cell culture, resveratrol did not inhibit mTOR at the same concentrations. Given distinct mechanisms of action of rapamycin and resveratrol at clinically relevant doses, their combination warrants further investigation as a potential antiaging, antiobesity and antidiabetic modality. PMID- 23348589 TI - The 2nd international workshop 'Novel Therapeutic Strategies in Cancer' in St Petersburg. PMID- 23348588 TI - TRAIL (TNF-related apoptosis-inducing ligand) regulates adipocyte metabolism by caspase-mediated cleavage of PPARgamma. AB - Tumor necrosis factor alpha (TNFalpha) and other members of the TNF family affect adipose tissue metabolism and contribute to the obesity-related inflammation of adipose tissue. Here, we sought to identify the effects of TRAIL (TNF-related apoptosis-inducing ligand) on fat cell biology. TRAIL-receptor 2 (TRAIL-R2) and its mouse homolog DR5 were regulated upon acute and chronic energy imbalance in murine and human adipose tissue. TRAIL inhibited insulin-stimulated glucose uptake and de novo lipogenesis in human adipocytes. Interestingly, TRAIL did not interfere with the phosphorylation of insulin-stimulated kinases such as Akt or Erk and did not activate the NF-kappaB pathway. Instead, TRAIL activated cleavage of caspase-8 and caspase-3. The subsequent cleavage of PPARgamma led to its inactivation and resulted in reduced expression of lipogenic genes, such as Glut 4, FASN, and ACC. Taken together, we discovered a so far unknown function of the death ligand TRAIL in regulating adipocyte metabolism. Our results imply that TRAIL/TRAIL-R system might provide a new target for the prevention and treatment of obesity and its co-morbidities. PMID- 23348590 TI - Cooperative role of RanBP9 and P73 in mitochondria-mediated apoptosis. AB - Mitochondrial dysfunction and synaptic damage are critical early features of Alzheimer's disease (AD) associated with amyloid beta (Abeta) and tau. We previously reported that the scaffolding protein RanBP9, which is overall increased in AD, simultaneously promotes Abeta generation and focal adhesion disruption by accelerating the endocytosis of APP and beta1-integrin, respectively. Moreover, RanBP9 induces neurodegeneration in vitro and in vivo and mediates Abeta-induced neurotoxicity. However, little is known regarding the mechanisms underlying such neurotoxic processes. Here, we show that RanBP9 induces the loss of mitochondrial membrane potential and increase in mitochondrial superoxides associated with decrease in Bcl-2, increase in Bax protein and oligomerization, fragmentation of mitochondria, and cytochrome c release. RanBP9-induced neurotoxic changes are significantly prevented by the mitochondrial fission inhibitor Mdivi-1 and by classical inhibitors of the mitochondrial apoptosis, XIAP, Bcl-2, and Bcl-xl. RanBP9 physically interacts with the tumor suppressor p73 and increases endogenous p73alpha levels at both transcriptional and post-translational levels;moreover, the knockdown of endogenous p73 by siRNA effectively blocks RanBP9 and Abeta1-42-induced mitochondria-mediated cell death. Conversely, siRNA knockdown of endogenous RanBP9 also suppresses p73-induced apoptosis, suggesting that RanBP9 and p73 have cooperative roles in inducing cell death. Taken together, these finding implicate the RanBP9/p73 complex in mitochondria-mediated apoptosis in addition to its role in enhancing Abeta generation. PMID- 23348593 TI - Electroencephalogram gamma-band activity during the perception of music key levels. AB - An interdisciplinary research field, music perception involves various disciplines, such as psychology, neuroscience, and even physics. Research on music perception offers us a window into the mechanism of the brain. In music perception, the same distance of key shift in different directions tends to be perceived as different degrees of change. It, however, still remains unclear whether directional asymmetry is specific to key shift perception or a general phenomenon of key perception. Using both behavioral and electroencephalogram methods, this study examined Chinese nonmusicians' subjective ratings and electroencephalogram gamma-band activity related to a piece of music performed at three different key levels and presented in three separate performances, none of which contained a key shift. This study showed that directional asymmetry is a general phenomenon of key level perception rather than specific to key shift perception. Furthermore, a counterclockwisely modulated key is related to stronger gamma-band spectral power than a clockwisely modulated key. PMID- 23348592 TI - Sex-specific differences in pain response by dopamine in the bed nucleus of the stria terminalis in rats. AB - The formalin test for nociception shows characteristic sex differences in the pain response during the interphase period of the test. However, the mechanism underlying these differences remains unclear. We have recently reported the sex specific involvement of the lateral subdivision of the bed nucleus of the stria terminalis (BSTL) in the formalin test in rats. Here, we evaluated whether sex specific differences in the pain response were modulated by the dopamine system in the BSTL. We first examined the effects of injecting a dopamine D1 receptor agonist, dihydrexidine, or antagonist, SCH23390, into the BSTL on the formalin test. During the interphase of the formalin test, injection of the D1 receptor agonist exerted no effect in male or female rats. The antagonist significantly enhanced the nociceptive response in female rats but not in males, indicating a sex difference in the involvement of the dopamine system in the formalin test. Next, we examined the expression of dopamine D1 receptors in the BSTL. Immunohistochemical analysis showed that the dopamine D1 receptor was expressed in the BSTL in both sexes but showed stronger immunoreactivity in male rats than in females. These results suggest sex-specific differences in the formalin test in which the response of dopamine neurons projecting to the BSTL plays a role in attenuating pain in female rats. PMID- 23348591 TI - Sensitization of melanoma cells for TRAIL-induced apoptosis by BMS-345541 correlates with altered phosphorylation and activation of Bax. AB - Resistance to TRAIL (TNF-related apoptosis-inducing ligand)- induced apoptosis limits its therapeutic use. Different strategies of TRAIL sensitization and a dependency on Bax have been reported, but common principles of TRAIL resistance and the way of Bax activation remained poorly understood. Applying a melanoma model of TRAIL-sensitive and -resistant cell lines, efficient sensitization for TRAIL-induced apoptosis is demonstrated by the kinase inhibitor BMS-345541 (N (1,8-dimethylimidazo(1,2-a)quinoxalin-4-yl)-1,2-ethanediamine hydrochloride), which targets IkappaB (inhibitor of kappaB proteins) kinase beta (IKKbeta). This effect was completely abrogated by Bax knockout as well as by Bcl-2 overexpression, in accordance with a Bax dependency. Early loss of the mitochondrial membrane potential, release of cytochrome c and Smac (second mitochondria-derived activator of caspases) clearly indicated the activation of mitochondrial apoptosis pathways. Of note, BMS-345541 alone resulted in an early Bax activation, seen by conformational changes and by Bax translocation. The synergistic effects can be explained by Bid activation through TRAIL, which inhibits Bcl-2, and the activation of Bax through BMS-345541. The critical roles of XIAP (X-chromosome-linked inhibitor of apoptosis protein), Smac and Bid were clearly proven by overexpression and siRNA knockdown, respectively. The way of Bax activation by BMS-345541 was unraveled by establishing new assays for Bax activation. These showed reduction of the inactivating Bax phosphorylation at serine-184, while the activating Bax phosphorylation at threonine-167 was enhanced. Thus, modulation of Bax phosphorylation appeared as tightly related to TRAIL sensitivity/resistance in melanoma cells, and therapeutic strategies may be considered. PMID- 23348595 TI - Quiescent-inflow single-shot magnetic resonance angiography using a highly undersampled radial k-space trajectory. AB - PURPOSE: We hypothesized that high undersampling factors could be used in conjunction with radial quiescent-inflow single-shot magnetic resonance angiography (MRA) to accelerate the data acquisition and enable multislice acquisitions. METHODS: Seven subjects were imaged on a 1.5 T MRI system. For multislice quiescent-inflow single-shot MRA, the venous saturation radiofrequency pulse, in-plane saturation radiofrequency pulse, and quiescent interval were applied only once before the first slice. RESULTS: The mean (standard deviation) measurements for the intra-arterial signal-to-noise ratio were as follows: Cartesian 1 slice-29.3 (5.5); radial 1 slice, 92 views-22.3 (3.6); radial 1 slice, 46 views-18.5 (2.0); radial 2 slices, 46 views-18.3 (3.2); and radial 3 slices, 32 views-21.7 (3.9), normalized for pixel size to 15.8. Horizontal striping was present with multislice radial quiescent-inflow single-shot MRA (especially with the three-slice acquisition) due to variable T1 relaxation between the concurrently acquired slices, but the image quality remained diagnostic. Vascular pathology in patients with peripheral arterial disease was well shown by all techniques. CONCLUSION: Very high undersampling factors in excess of 18 have been demonstrated for nonenhanced MRA using a radial quiescent inflow single-shot technique, enabling the acquisition of two to three slices per cardiac cycle. Scan time for a complete peripheral MRA could be shortened to 2 min or less. PMID- 23348594 TI - In vivo characterization of a bigenic fluorescent mouse model of Alzheimer's disease with neurodegeneration. AB - The loss of cognitive function in Alzheimer's disease (AD) patients is strongly correlated with the loss of neurons in various regions of the brain. We have created a new fluorescent bigenic mouse model of AD by crossing "H-line" yellow fluorescent protein (YFP) mice with the 5xFAD mouse model, which we call the 5XY mouse model. The 5xFAD mouse has been shown to have significant loss of L5 pyramidal neurons by 12 months of age. These neurons are transgenically labeled with YFP in the 5XY mouse, which enable longitudinal imaging of structural changes. In the 5XY mice, we observed an appearance of axonal dystrophies, with two distinct morphologies in the early stages of the disease progression. Simple swelling dystrophies are transient in nature and are not directly associated with amyloid plaques. Rosette dystrophies are more complex structures that remained stable throughout all imaging sessions, and always surrounded an amyloid plaque. Plaque growth was followed over 4 weeks, and significant growth was seen between weekly imaging sessions. In addition to axonal dystrophy appearance and plaque growth, we were able to follow spine stability in 4-month old 5XY mice, which revealed no significant loss of spines. 5XY mice also showed a striking shrinkage of the neocortex at older ages (12-14 months). The 5XY mouse model may be a valuable tool for studying specific events in the degeneration of the neocortex, and may suggest new avenues for therapeutic intervention. PMID- 23348596 TI - The antimalarial ferroquine is an inhibitor of hepatitis C virus. AB - Hepatitis C virus (HCV) is a major cause of chronic liver disease. Despite recent success in improving anti-HCV therapy, additional progress is still needed to develop cheaper and interferon (IFN)-free treatments. Here, we report that ferroquine (FQ), an antimalarial ferrocenic analog of chloroquine, is a novel inhibitor of HCV. FQ potently inhibited HCV infection of hepatoma cell lines by affecting an early step of the viral life cycle. The antiviral activity of FQ on HCV entry was confirmed with pseudoparticles expressing HCV envelope glycoproteins E1 and E2 from six different genotypes. In addition to its effect on HCV entry, FQ also inhibited HCV RNA replication, albeit at a higher concentration. We also showed that FQ has no effect on viral assembly and virion secretion. Using a binding assay at 4 degrees C, we showed that FQ does not prevent attachment of the virus to the cell surface. Furthermore, virus internalization was not affected by FQ, whereas the fusion process was impaired in the presence of FQ as shown in a cell-cell fusion assay. Finally, virus with resistance to FQ was selected by sequential passage in the presence of the drug, and resistance was shown to be conferred by a single mutation in E1 glycoprotein (S327A). By inhibiting cell-free virus transmission using a neutralizing antibody, we also showed that FQ inhibits HCV cell-to-cell spread between neighboring cells. Combinations of FQ with IFN, or an inhibitor of HCV NS3/4A protease, also resulted in additive to synergistic activity. CONCLUSION: FQ is a novel, interesting anti-HCV molecule that could be used in combination with other direct-acting antivirals. PMID- 23348597 TI - Behavior of respiratory muscle strength in morbidly obese women by using different predictive equations. AB - BACKGROUND: Studies on the behavior of respiratory muscle strength (RMS) in morbidly obese patients have found conflicting results. OBJECTIVES: To evaluate RMS in morbidly obese women and to compare the results by using different predictive equations. METHOD: This is a cross-sectional study that recruited 30 morbidly obese women and a control group of 30 normal-weight women. The subjects underwent anthropometric and maximal respiratory pressure measurement. Visual inspection of the Bland-Altman plots was performed to evaluate the correlation between the different equations, with a p value lower than 0.05 considered as statistically significant. RESULTS: The obese women showed a significant increase in maximal inspiratory pressure (MIP) values (-87.83+/-21.40 cmH(2)O) compared with normal-weight women (-72+/-15.23 cmH(2)O) and a significant reduction of MIP (-87.83+/-21.40 cmH(2)O) according to the values predicted by the EHarik equation (-130.71+/-11.98 cmH(2)O). Regarding the obtained maximal expiratory pressure (MEP), there were no between-group differences (p>0.05), and no agreeement was observed between obtained and predicted values of MEP and the ENeder and ECosta equations. CONCLUSIONS: Inspiratory muscle strength was greater in the morbidly obese subjects. The most appropriate equation for calculating the predicted MIP values for the morbidly obese seems to be Harik-Khan equation. There seem to be similarities between the respiratory muscle strength behavior of morbidly obese and normal-weight women, however, these findings are still inconclusive. PMID- 23348598 TI - Translation of the Children Helping Out--Responsibilities, Expectations and Supports (CHORES) questionnaire into Brazilian-Portuguese: semantic, idiomatic, conceptual and experiential equivalences and application in normal children and adolescents and in children with cerebral palsy. AB - BACKGROUND: The participation of children with disabilities in daily chores in different environments has been a therapeutic goal shared by both parents and rehabilitation professionals, leading to increased demand for instrument development. The Children Helping Out: Responsibilities, Expectations and Supports (CHORES) questionnaire was created with the objective of measuring child and teenager participation in daily household tasks. OBJECTIVES: To translate the CHORES questionnaire into Brazilian Portuguese, evaluate semantic, idiomatic, experiential, and conceptual equivalences, apply the questionnaire to children and teenagers with and without disabilities, and test its test-retest reliability. METHOD: Methodological study developed through the following stages: (1) translation of the questionnaire by two different translators; (2) synthesis of translations; (3) back-translation into English; (4) analysis by an expert committee to develop the pre-final version; (5) test-retest reliability; (6) administration to a sample of 50 parents of children with and without disabilities. RESULTS: The CHORES translation was validated in all stages. The implemented adaptations aimed to improve the understanding of the instrument's content by families of different socioeconomic and educational levels. The questionnaire showed strong consistency within a 7 to 14-day interval (ICCs=0.93 a 0.97; p=0.0001). After application, there was no need to change any items in the questionnaire. CONCLUSIONS: The translation of the CHORES questionnaire into Brazilian Portuguese offers a unique instrument for health professionals in Brazil, enabling the documentation of child and teenager participation in daily household tasks and making it possible to develop scientific investigation on the topic. PMID- 23348599 TI - Clinical trial registration in physical therapy journals: recommendations from the International Society of Physiotherapy Journal Editors. PMID- 23348600 TI - Familiarity, objectivity--and misconduct. Counterstatement to Shaw DM. The Swiss Report on homoeopathy: a case study of research misconduct. Swiss Med Wkly. 2012;142:w13594. PMID- 23348601 TI - Gelation in protein extracts from cold acclimated and non-acclimated winter rye (Secale cereale L. cv Musketeer). AB - A protein gel is a three-dimensional network consisting of molecular interactions between biopolymers that entrap a significant volume of a continuous liquid phase (water). Molecular interactions in gels occur at junction zones within and between protein molecules through electrostatic forces, hydrogen bonding, hydrophobic associations (van der Waals attractions) and covalent bonding. Gels have the physicochemical properties of both solids and liquids, and are extremely important in the production and stability of a variety of foods, bioproducts and pharmaceuticals. In this study, gelation was induced in phenol extracted protein fractions from non-acclimated (NA) and cold-acclimated (CA) winter rye (Secale cereale L. cv Musketeer) leaf tissue after repeated freeze-thaw treatments. Gel formation only occurred at high pH (pH 12.0) and a minimum of 3-4 freeze-thaw cycles were required. The gel was thermally stable and only a specific combination of chemical treatments could disrupt the gel network. SDS-PAGE analysis identified ribulose-1,5-bisphosphate carboxylase oxygenase (Rubisco) as the major protein component in the gel, although Rubisco itself did not appear to be a factor in gelation. Raman spectroscopy suggested changes in protein secondary structure during freeze-thaw cycles. Overall, the NA and CA gels were similar in composition and structure, with the exception that the CA gel appeared to be amyloidic in nature based on thioflavin T (ThT) fluorescence. Protein gelation, particularly in the apoplast, may confer protection against freeze induced dehydration and potentially have a commercial application to improve frozen food quality. PMID- 23348602 TI - Mesoporous yolk-shell SnS2-TiO2 visible photocatalysts with enhanced activity and durability in Cr(VI) reduction. AB - A novel mesoporous yolk-shell SnS(2)-TiO(2) visible photocatalyst (ST-is) was synthesized by in situ doping TiO(2) with SnO(2) through solvothermal alcoholysis, followed by sulfurization under hydrothermal conditions. The ST-is displayed higher activity in photocatalytic reduction of Cr(VI) owing to the strong photosensitizing effect of SnS(2) in uniform nanoparticles and the enhanced light harvesting via multiple reflections in yolk-shell chambers. Meanwhile, the strong SnS(2)-TiO(2) interaction could generate more heterojunctions which facilitated photoelectron transfer from SnS(2) to TiO(2), leading to the enhanced activity by inhibiting photoelectron-hole recombination. Moreover, the ST-is displayed strong durability owing to the strong SnS(2)-TiO(2) interaction and the encapsulation of SnS(2) nanoparticles in the yolk-shell chamber, which could inhibit SnS(2) leaching. Furthermore, because of the electronegative surface and high surface area, the ST-is could thoroughly purify wastewater by completely adsorbing Cr(3+) resulting from Cr(VI) reduction. In addition, the presence of photocatalytic degradation of organic compounds promoted Cr(VI) reduction owing to inhibition of photoelectron-hole recombination by consuming holes. PMID- 23348603 TI - Patients' perspective of wide-awake hand surgery--100 consecutive cases. AB - The wide-awake hand surgery (WAHS) technique involves injecting lidocaine with adrenaline for hand surgical procedures that are done without the use of tourniquets, sedation, regional or general anaesthetic. This is a retrospective review of the first 100 consecutive patients who underwent operations using this technique at our centre. The operations included carpal and cubital tunnel decompression, trapeziectomy, tendon transfer, and tenolysis. A questionnaire adapted from Lalonde's previous work on wide-awake surgery was used to assess patients' experiences. Sixty-five percent of the patients responded to the postal questionnaire, the majority reporting a high satisfaction level. Ninety-one percent of responders reported that the operation was less painful or comparable with a procedure at the dentist; 86% would prefer to be wide-awake if they needed to have hand surgery again, and 90% stated they would recommend WAHS to a friend. PMID- 23348604 TI - Label-free luminescent oligonucleotide-based probes. AB - Breakthrough advances in chemistry and biology over the last two decades have vastly expanded the repertoire of nucleic acid structure and function with potential application in multiple areas of science and technology, including sensing and analytical applications. DNA oligonucleotides represent popular tools for the development of sensing platforms due to their low cost, rich structural polymorphism, and their ability to bind to cognate ligands with sensitivity and specificity rivaling those for protein enzymes and antibodies. In this review, we give an overview of the "label-free" approach that has been a particular focus of our group and others for the construction of luminescent DNA-based sensing platforms. The label-free strategy aims to overcome some of the drawbacks associated with the use of covalently-labeled oligonucleotides prevalent in electrochemical and optical platforms. Label-free DNA-based probes harness the selective interaction between luminescent dyes and functional oligonucleotides that exhibit a "structure-switching" response upon binding to analytes. Based on the numerous examples of label-free luminescent DNA-based probes reported recently, we envisage that this field would continue to thrive and mature in the years to come. PMID- 23348605 TI - Head and neck injuries in professional soccer. AB - OBJECTIVE: To investigate the rate of and risk factors for head and neck injury in male soccer. DESIGN: Prospective cohort study. SETTING: Professional soccer. PARTICIPANTS: Twenty-six European teams between 2001/2002 and 2009/2010. ASSESSMENT OF RISK FACTORS: Simple and multiple risk factor analyses were evaluated using Cox regression for player-related variables and logistic regression for match-related variables. MAIN OUTCOME MEASURES: Injury rate (number of time loss injuries per 1000 hours). RESULTS: A total of 136 head and neck injuries were recorded (2.2% of all injuries). The head and neck injury rate was 0.17 (0.06 concussions) per 1000 hours. There was a 20-fold higher rate of head and neck injury during match play compared with training (rate ratio [RR], 20.2; 95% confidence interval [CI], 13.3-30.6) and a 78-fold higher rate of concussions (RR, 78.5; 95% CI, 24.4-252.5). Mean layoff for concussion was 10.5 days, but 27% of the concussed players returned to play within 5 days. Defender was the only significant player-related risk factor for head and neck injuries in the multiple analysis (RR, 1.8; 95% CI, 1.0-3.1), whereas no significant variables were identified for concussions. CONCLUSIONS: Head and neck injuries were relatively uncommon in professional soccer. Defender was the playing position most at risk. More than one-quarter of the concussed players returned to play before what is recommended in the consensus statements by the major sports governing bodies. PMID- 23348606 TI - The effect of knee braces on tibial rotation in anterior cruciate ligament deficient knees during high-demand athletic activities. AB - OBJECTIVE: To examine if bracing can restrict tibial rotation in anterior cruciate ligament (ACL)-deficient patients during high loading activities. DESIGN: Repeated measures. Kinematic data were collected with an 8-camera Vicon system while each patient performed 2 tasks that are known to cause increased rotational and translational loads on the knee: (1) descending from a stair and subsequent pivoting, and (2) landing from a platform and subsequent pivoting. The tasks were repeated under 3 brace conditions for the ACL-deficient knee: (1) wearing a prophylactic brace (braced condition), (2) wearing a patellofemoral brace (sleeved condition), and (3) without brace (unbraced condition). SETTING: Biomechanical laboratory study. PATIENTS: Twenty-one male subjects with a confirmed unilateral ACL rupture were assessed in vivo. MAIN OUTCOME MEASURES: Tibial internal rotation. Two repeated measures ANOVAs tested for differences in tibial internal rotation among the 3 conditions of the ACL-deficient knee and the unbraced condition of the intact knee. RESULTS: In both tasks, tibial rotation was significantly lower in the intact knee compared with all 3 conditions of the ACL-deficient knee (P <= 0.031). Bracing the ACL-deficient knee resulted in lower rotation than the unbraced (P <= 0.001) and sleeved (P <= 0.033) conditions. The sleeved condition resulted in lower tibial rotation in the drop landing and pivoting task compared with the unbraced condition (P = 0.019) but not in the stair descending and pivoting task (P = 0.256). CONCLUSIONS: Bracing decreased the excessive tibial rotation in ACL-deficient patients during high-demand activities but failed to fully restore normative values. If knee braces can enhance rotational knee stability in ACL-deficient patients, then they could possibly play an important role in preventing further knee pathology in such patients. PMID- 23348608 TI - Bioimpedance system for monitoring muscle and cardiovascular activity in the stump of lower-limb amputees. AB - A bioimpedance system for the continuous measurement of non-invasive physiological parameters in lower-limb amputees is presented. The aim of the system is to monitor as many physiological parameters as possible from a single bioimpedance electrode configuration. In this way, a simple, low-cost and low size autonomous system is developed that is able to continuously monitor the amputee in different environments (home, work, etc). The system measures both electrical impedance myography and electrical impedance plethysmography in the stump with electrodes placed in the inside face of a silicone interface. Such a system allows for the monitoring of a patient's muscle activity, and heart and breath rate, thus enabling the study and continuous monitoring of prosthesis adaptation and improvement of patient's gait to reduce physiological stress. Additionally, it can prevent cardiovascular problems due to the effort involved in the use of prostheses, which can decrease the life expectancy of amputees with previous vascular diseases. Experimental results obtained from different amputees' test validate the purpose of the system. PMID- 23348609 TI - Comparative pharmacokinetics study of three anthraquinones in rat plasma after oral administration of Radix et Rhei Rhizoma extract and Dahuang Fuzi Tang by high performance liquid chromatography-mass spectrometry. AB - A specific and sensitive high performance liquid chromatography-mass spectrometric (HPLC-MS) method has been developed and validated for simultaneous determination of three anthraquinones of rhein, aloe-emodin and emodin in rat plasma after oral administration of Radix et Rhei Rhizoma extract and Dahuang Fuzi Tang. The analytes were separated on a Kromaisl((r)) C(18) column within a total running time of 12min with a mobile phase of methanol:ammonium acetate (3mM) (75:25, v/v). The calibration curves for all the anthraquinones showed good linearity in the measured range with correlation coefficient (r) higher than 0.9978. The precision, accuracy, recovery and stability were deemed acceptable. The method was successfully applied to the comparative pharmacokinetics study of the anthraquinones in rat plasma after oral administration of Radix et Rhei Rhizoma extract and Dahuang Fuzi Tang. PMID- 23348610 TI - European survey on the content of lead in lip products. AB - 223 lip articles (representing 55 brands) were purchased in 15 European Union Member States and analysed for lead content. Various lip products (lipsticks and lip glosses), shades (red, brown, purple and pink) and price ranges (3 categories) were investigated. The analytical method employed a microwave assisted acid digestion followed by ICP-MS determination. The results revealed that 49 samples (22%) contained lead at a level higher than 1mg/kg, representing 31% of the tested lipsticks and 4% of the lip glosses. On average, the lead content found in lipsticks (0.75mg/kg) was nearly double that found in lip glosses (0.38mg/kg) and this difference was judged statistically significant at 95% probability. Apart from brown, statistically significant higher levels of lead were also found when comparing the average lead contents in lipsticks and lip glosses of the same shade: pink (0.81 and 0.38mg/kg), purple (0.88 and 0.37mg/kg) and red (0.58 and 0.25mg/kg). The influence of price on lead content was studied on the two lip product types separately. In the case of lip glosses no differences were found. In the case of lipsticks, the more expensive items (price category III) contained a significantly lower quantity of lead in comparison to the cheapest articles (price category I). The lipsticks containing the highest levels of lead belonged to the price category II. In all cases, however, the actual lead concentration measured in the finished products is far below the recommended limits for Germany (20mg/kg) or Canada (10mg/kg). The outcome of this work delivers information about the current situation on the European market and provides information to policy-makers about the quantities of lead in lip articles and technically achievable levels. PMID- 23348611 TI - Simultaneous determination and pharmacokinetic study of stachydrine and leonurine in rat plasma after oral administration of Herba Leonuri extract by LC-MS/MS. AB - A simple, sensitive and specific method was developed for simultaneous determination of stachydrine and leonurine in rat plasma using diphenhydramine as an internal standard (IS). The separation was performed on an Agilent ZORBAX Eclipse XDB-C(18) column (150mm*4.6mm, i.d., 5MUm) at a flow rate of 0.6mL/min, and the mixture of methanol-water containing 0.1% formic acid was used as the mobile phase. The lower limits of quantitation (LLOQs) in rat plasma were 0.895 and 0.287ng/mL for stachydrine and leonurine, respectively. Intra- and inter-day precisions were within 14.4% and accuracies were not more than 3.0%. After single oral administration of 14.5g/kg Herba Leonuri extract, C(max) of stachydrine and leonurine in rat plasma were respectively 1608+/-267 and 43.3+/-8.2ng/mL, while T(max) values were respectively 0.75+/-0.27 and 0.83+/-0.26h. The results demonstrated that the present LC-MS/MS method was sensitive enough for pharmacokinetic study of stachydrine and leonurine following oral administration of Herba Leonuri extract. PMID- 23348607 TI - Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. AB - OBJECTIVE: The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Data from a planned 12-month interim analysis are reported. METHODS: In this double-blind, parallel-group, placebo controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily. At month 3, nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above; remaining placebo-treated patients were advanced at 6 months. Four primary efficacy end points were all analyzed in a step-down procedure. RESULTS: At month 6, response rates according to the American College of Rheumatology 20% improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo (51.5% and 61.8%, respectively, versus 25.3%; both P < 0.0001). At month 6, least squares mean (LSM) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06, respectively, versus 0.47 for placebo (P = 0.0792 and P <= 0.05, respectively). At month 3, LSM changes in the Health Assessment Questionnaire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 (significance not declared due to step-down procedure) and -0.54 (P < 0.0001), respectively, versus -0.15 for placebo. At month 6, rates of remission (defined as a value <2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate) for tofacitinib at 5 mg and 10 mg twice daily were 7.2% (significance not declared due to step-down procedure) and 16.0% (P < 0.0001), respectively, versus 1.6% for placebo. The safety profile was consistent with findings in previous studies. CONCLUSION: Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX. PMID- 23348612 TI - Simultaneous determination of ascorbic acid and rutin in pharmaceutical preparations with electrochemical method based on multi-walled carbon nanotubes chitosan composite film modified electrode. AB - In this paper, the simultaneous voltammetric determination of ascorbic acid (AA) and rutin (Ru) has been achieved at an acetylene black paste electrode modified with multi-walled carbon nanotubes-chitosan composite film (denoted as MWCNTs CHIT/ABPE). Compared with bare electrode, the peak currents of AA and Ru at MWCNTs-CHIT/ABPE increased greatly and the anodic peak potential difference (DeltaE(pa)) between AA and Ru are up to 342mV, which is undoubtedly attributed to the unique characteristics of AB and MWCNTs such as excellent electric conductivity, high surface area and strong adsorptive abilities, resulting in higher accumulation efficiency to AA and Ru. The influences of some experimental conditions on the oxidation of AA and Ru were tested and the calibration plot was examined. Under the optimized condition, a good linearity was obtained in the concentration range of 1MUM-0.4mM for AA in the presence of 10MUM Ru and 20nM 10MUM for Ru in the presence of 1mM AA. The detection limits (S/N=3) of AA and Ru are 0.8MUM and 10nM, respectively. The proposed method was successfully applied to the simultaneous determination of AA and Ru in pharmaceutical samples with reliable recovery. PMID- 23348613 TI - Prolyl oligopeptidase is a glyceraldehyde-3-phosphate dehydrogenase-binding protein that regulates genotoxic stress-induced cell death. AB - Prolyl oligopeptidase is a serine protease that cleaves peptides shorter 30-mer at carboxyl side of an internal proline. This enzyme has been proposed to be involved in the maturation and degradation of peptide hormones and neuropeptides. However, conclusive results have not yet been reported, and the primary physiological role remains to be elucidated. Here, we describe the identification of a novel protein that interacts with prolyl oligopeptidase in a human neuroblastoma cell line NB-1. Using an affinity column with immobilized recombinant human prolyl oligopeptidase as ligand, we identified glyceraldehyde-3 phosphate dehydrogenase as a novel prolyl oligopeptidase binding protein in NB-1 cell extracts. The interaction between prolyl oligopeptidase and glyceraldehyde-3 phosphate dehydrogenase was confirmed by immunoprecipitation both in vitro and in vivo. To study the functional relevance of prolyl oligopeptidase-glyceraldehyde-3 phosphate dehydrogenase interactions, we investigated whether this interaction was involved in cytosine arabinoside-induced glyceraldehyde-3-phosphate dehydrogenase nuclear translocation and cell death. Prolyl oligopeptidase inhibitor, SUAM-14746, and prolyl oligopeptidase knockdown successfully inhibited glyceraldehyde-3-phosphate dehydrogenase translocation and promoted the survival of cytosine arabinoside-treated NB-1 cells. We also found that the interactions between prolyl oligopeptidase and glyceraldehyde-3-phosphate dehydrogenase in the cytoplasm but not in nuclei of NB-1 cell treated with cytosine arabinoside using an in situ proximity ligation assay. These results indicate that the interaction between prolyl oligopeptidase and glyceraldehyde-3-phosphate dehydrogenase is required for cytosine arabinoside-induced glyceraldehyde-3-phosphate dehydrogenase nuclear translocation and cell death. Therefore, the results of the present study demonstrate a novel function for prolyl oligopeptidase in cell death. PMID- 23348614 TI - MiR-122 modulates type I interferon expression through blocking suppressor of cytokine signaling 1. AB - MiR-122 is a liver-specific miRNA. Recent studies demonstrated that the interferon (IFN) therapy efficacy is poor in the hepatitis C virus (HCV)-infected patients with lower miR-122 abundance in the livers. The hepatocarcinoma patients also have low miR-122 levels in their livers. We previously found that the IFN expression was reduced when miR-122 was knocked down in human oligodendrocytes. The mechanism is unclear. In this study, the miR-122-abundant cell Huh7 was used to explore the regulatory mechanism of miR-122 on type I IFN expression. We found that miR-122 significantly increased the type I IFN expression in Huh7 cells, while knocking down miR-122 decreased the type I IFN expression. By screening potential miR-122 targets among the negative regulators in IFN signaling pathways, we found that there were putative miR-122 targets in the suppressor of cytokine signaling 1 (SOCS1) mRNA. Over-expressing miR-122 decreased the SOCS1 expression by 50.55% in Huh7 cells, while knocking down miR-122 increased SOCS1 expression by 62.56%. Using a green fluorescence protein (EGFP) fused SOCS1 expressing plasmid, the SOCS1-EGFP fluorescence intensity and protein were lower in miR-122 mimic-treated cells than those in mock-miRNA-treated cells, while miR 122 knockdown significantly increased the SOCS1-EGFP fluorescence intensity and protein expression. Mutations in the nt359-nt375 region abandoned the impact of miR-122 on SOCS1-EGFP expression. Taken together, SOCS1 is a target of miR-122. MiR-122 can regulate the type I IFN expression through modulating the SOCS1 expression. PMID- 23348616 TI - Early remodeling of Muller cells in the rd/rd mouse model of retinal dystrophy. AB - We studied the anatomical remodeling and gliosis of retinal Muller cells in the rd/rd mouse model of photoreceptor degeneration. A computational calculation of glutamine synthetase immunoreactivity was developed so we could specifically quantify changes in Muller cell anatomy between control mice (C57Bl/6) and the dystrophic strain. We found no change in the number of Muller cell somata between mice strains, indicating no cell proliferation as a function of development and degeneration. The retinal area occupied by the total Muller cell body (soma and processes) was significantly less in the rd/rd mouse retina compared with control mice. When only the outer retina was considered, we found rd/rd Muller cell processes were dramatically reduced during the cone phase of photoreceptor degeneration. However, at older ages an increase in Muller cell processes was seen. Conversely, glial fibrillary acidic protein (GFAP) expression showed a significant increase during cone degeneration followed by a reduction in older ages. Muller cell electrophysiology, particularly K(+) currents and membrane potential, was similar between rd/rd and control Muller cells during cone degeneration. Together, these results show that glial remodeling in the rd/rd retina follows separate phases-an initial conservative glial response involving the loss of Muller cells processes, hyperexpression of GFAP, and preservation of normal electrophysiology followed by an active growth of Muller cell processes, glial seal formation, and attenuation of GFAP expression after complete photoreceptor loss. PMID- 23348617 TI - Enzyme nanoarchitectonics: organization and device application. AB - Fabrication of ultrasmall functional machines and their integration within ultrasmall areas or volumes can be useful for creation of novel technologies. The ultimate goal of the development of ultrasmall machines and device systems is to construct functional structures where independent molecules operate as independent device components. To realize exotic functions, use of enzymes in device structures is an attractive solution because enzymes can be regarded as efficient machines possessing high reaction efficiencies and specificities and can operate even under ambient conditions. In this review, recent developments in enzyme immobilization for advanced functions including device applications are summarized from the viewpoint of micro/nano-level structural control, or nanoarchitectonics. Examples are roughly classified as organic soft matter, inorganic soft materials or integrated/organized media. Soft matter such as polymers and their hybrids provide a medium appropriate for entrapment and encapsulation of enzymes. In addition, self-immobilization based on self-assembly and array formation results in enzyme nanoarchitectures with soft functions. For the confinement of enzymes in nanospaces, hard inorganic mesoporous materials containing well-defined channels play an important role. Enzymes that are confined exhibit improved stability and controllable arrangement, which are useful for formation of functional relays and for their integration into artificial devices. Layer-by-layer assemblies as well as organized lipid assemblies such as Langmuir-Blodgett films are some of the best media for architecting controllable enzyme arrangements. The ultrathin forms of these films facilitate their connection with external devices such as electrodes and transistors. Artificial enzymes and enzyme-mimicking catalysts are finally briefly described as examples of enzyme functions involving non-biological materials. These systems may compensate for the drawbacks of natural enzymes, such as their instabilities under harsh conditions. We believe that enzymes and their mimics will be freely coupled, organized and integrated upon demand in near future technologies. PMID- 23348618 TI - In situ synthesis and surface functionalization of gold nanoparticles with curcumin and their antioxidant properties: an experimental and density functional theory investigation. AB - Curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is an active component of turmeric; it is responsible for its characteristic yellow color and therapeutic potential, but its poor bioavailability remains a major challenge. In order to improve the bioavailability of curcumin, various approaches have been used. One of the possible approaches to increase the bioavailability of curcumin is its conjugation on the surface of metal nanoparticles. Therefore, in the present study, we report the binding of curcumin on the surface of gold nanoparticles (AuNPs). The AuNPs were synthesized by the direct reduction of HAuCl(4) using curcumin in the aqueous phase, without the use of any other reducing agents. We found that curcumin acts both as a reducing and capping agent, stabilizing the gold sol for many months. Moreover, these curcumin capped AuNPs also show good antioxidant activity which was confirmed by the DPPH (2,2-diphenyl-l-picrylhydrazyl) radical test. Thus, the surface functionalization of AuNPs with curcumin may pave a new way of using the curcuminoids towards possible drug delivery and therapeutics. Apart from the experimental study, a detailed quantum chemical calculation using density functional theory (DFT) has been performed, in order to investigate the formation of a complex of curcumin with Au(3+) ions in different possible conformational isomeric forms. Our theoretical calculations indicate the evidence of electron transfer from curcumin into the Au center and essentially indicate that as a consequence of complexation, Au(3+) ions are reduced to Au(0). Our theoretical results also propose that it is the breakage of intramolecular H-bonding that probably leads to the increased availability of curcumin in the presence of gold ions and water molecules. PMID- 23348619 TI - Dielectrophoresis of lambda-DNA using 3D carbon electrodes. AB - Carbon electrodes have recently been introduced as an alternative to metal electrodes and insulator structures for dielectrophoretic applications. Here, an experimental and theoretical study employing an array of 3D carbon electrodes contained in a microfluidic channel for the dielectrophoretic manipulation of DNA is presented. First evidence that carbon-electrode DEP can be used for the manipulation and trapping of biomolecules such as DNA is reported. In particular, the dielectrophoretic response of lambda-DNA (48.5 kbp) under various frequencies and flow conditions necessary for retention of lambda-DNA are studied. Negative DEP is observed at frequencies above 75 kHz and positive DEP is present in the range below 75 kHz and down to 5 kHz. We further implement a theoretical model to capture the experimental findings in sufficient detail. Our theoretical considerations based on reported scaling laws for linear and supercoiled DNA further suggest that carbon-electrode DEP devices could be employed in future analytical applications such as DNA preconcentration and fractionation. PMID- 23348620 TI - A novel adipokine C1q/TNF-related protein 1 (CTRP1) regulates chondrocyte proliferation and maturation through the ERK1/2 signaling pathway. AB - Adipose tissue-derived adipokines play important roles as regulators of skeletal growth and development. CTRP1, a paralog of adiponectin, is a member of the C1q and tumor necrosis factor (TNF)-related protein (CTRP) superfamily. It is expressed at high levels in adipose tissue and has recently emerged as a novel adipokine. In the present study, we provide the first evidence for a physiological role of the CTRP1 in chondrocyte proliferation and maturation using a mouse chondrocytic cell line, N1511. The CTRP1 protein was strongly expressed and predominantly distributed in the reserve and proliferative chondrocytes in the fetal growth plate and its mRNA decreased during the maturation of N1511 chondrocytes. Recombinant CTRP1 promoted proliferation of immature proliferating N1511 chondrocytes in a dose-dependent manner, whereas it inhibited maturation of maturing N1511 chondrocytes. The stimulatory effect of CTRP1 on chondrocyte proliferation was associated with activation of the extracellular signal regulated kinases 1/2 (ERK1/2) signaling pathway. On the other hand, the inhibitory effect of CTRP1 on chondrocyte maturation is associated with suppression of the ERK1/2 pathway. These results suggest a novel physiological role for CTRP1 in endochondral ossification. PMID- 23348622 TI - The future looks bright. PMID- 23348623 TI - Transitioning new leaders: seven steps for success. PMID- 23348624 TI - Stop going in circles! Break the barriers to hourly rounding. PMID- 23348625 TI - Improving the patient experience through bedside shift report. PMID- 23348627 TI - The road less traveled. PMID- 23348628 TI - Learning from grief: group therapy in a simulation center. PMID- 23348629 TI - A closer look at hybrid nurses. PMID- 23348630 TI - Leadership's "triple chance". PMID- 23348631 TI - Boots on the ground: the role of the Magnet(r) project director. PMID- 23348632 TI - Nurses as value analysis facilitators. PMID- 23348633 TI - Making the grade. PMID- 23348634 TI - CD16(+) monocyte subsets are increased in large abdominal aortic aneurysms and are differentially related with circulating and cell-associated biochemical and inflammatory biomarkers. AB - Proinflammatory components are present in abdominal aortic aneurysm (AAA). Circulating monocytes display heterogeneity, and three subsets have been identified, based on the differential expression for CD14 and CD16 receptors: CD14(+)CD16(-), classical, CD14(+)CD16(+), intermediate and CD14(dim)CD16(+), non classical monocytes. Increased proinflammatory CD16+ monocytes with high expression of CD143 are present in CKD patients. D-dimer is increased in AAA patients, and might contribute to the pro-inflammatory response associated to circulating monocytes. We aimed to investigate the frequency of CD14(+)CD16(+), CD14(dim)CD16(+) monocytes and monocyte CD143 expression in AAA patients, and their relationship with Ddimer, eGFR and other inflammatory parameters. Blood from 74 AAA patients and 30 healthy controls was analyzed to determine the frequency of CD14(+)CD16(+), CD14(dim)CD16(+) monocytes and the monocyte CD143 expression by means of flow-cytometry. AAA patients had expanded CD16+ subsets (CD14(+)CD16(+): 7.66 +/- 0.31% vs 5.42 +/- 0.27%; CD14(dim)CD16(+): 7.43 +/- 0.48% vs 5.54 +/- 0.38%, AAA vs controls, mean +/- SE, both p < 0.05). CD14(+)CD16(+) cells were associated to D-dimer and age, and to reduced eGFR. CD14(dim)CD16(+) cells were associated to uric acid, surface CD143, and reduced count of total leukocytes and neutrophils. Within AAA patients, the two CD16(+) subsets and the monocyte CD143 expression display different relationships with D dimer, parameters of renal function and circulating biochemical and inflammatory biomarkers. PMID- 23348635 TI - Concurrent chemotherapy inhibits herpes simplex virus-1 replication and oncolysis. AB - Herpes simplex virus-1 (HSV-1) replication in cancer cells leads to their destruction (viral oncolysis) and has been under investigation as an experimental cancer therapy in clinical trials as single agents, and as combinations with chemotherapy. Cellular responses to chemotherapy modulate viral replication, but these interactions are poorly understood. To investigate the effect of chemotherapy on HSV-1 oncolysis, viral replication in cells exposed to 5 fluorouracil (5-FU), irinotecan (CPT-11), methotrexate (MTX) or a cytokine (tumor necrosis factor-alpha (TNF-alpha)) was examined. Exposure of colon and pancreatic cancer cells to 5-FU, CPT-11 or MTX in vitro significantly antagonizes both HSV-1 replication and lytic oncolysis. Nuclear factor-kappaB (NF-kappaB) activation is required for efficient viral replication, and experimental inhibition of this response with an IkappaBalpha dominant-negative repressor significantly antagonizes HSV-1 replication. Nonetheless, cells exposed to 5-FU, CPT-11, TNF alpha or HSV-1 activate NF-kappaB. Cells exposed to MTX do not activate NF kappaB, suggesting a possible role for NF-kappaB inhibition in the decreased viral replication observed following exposure to MTX. The role of eukaryotic initiation factor 2alpha (eIF-2alpha) dephosphorylation was examined; HSV-1 mediated eIF-2alpha dephosphorylation proceeds normally in HT29 cells exposed to 5-FU, CPT-11 or MTX. This report demonstrates that cellular responses to chemotherapeutic agents provide an unfavorable environment for HSV-1-mediated oncolysis, and these observations are relevant to the design of both preclinical and clinical studies of HSV-1 oncolysis. PMID- 23348637 TI - Two-phase designs to follow-up genome-wide association signals with DNA resequencing studies. AB - Genome-wide association studies (GWAS) of complex traits have generated many association signals for single nucleotide polymorphisms (SNPs). To understand the underlying causal genetic variant(s), focused DNA resequencing of targeted genomic regions is commonly used, yet the current cost of resequencing limits sample sizes for resequencing studies. Information from the large GWAS can be used to guide choice of samples for resequencing, such as the SNP genotypes in the targeted genomic region. Viewing the GWAS tag-SNPs as imperfect surrogates for the underlying causal variants, yet expecting that the tag-SNPs are correlated with the causal variants, a reasonable approach is a two-phase case control design, with the GWAS serving as the first-phase and the resequencing study serving as the second-phase. Using stratified sampling based on both tag SNP genotypes and case-control status, we explore the gains in power of a two phase design relative to randomly sampling cases and controls for resequencing (i.e., ignoring tag-SNP genotypes). Simulation results show that stratified sampling based on both tag-SNP genotypes and case-control status is not likely to have lower power than stratified sampling based only on case-control status, and can sometimes have substantially greater power. The gain in power depends on the amount of linkage disequilibrium between the tag-SNP and causal variant alleles, as well as the effect size of the causal variant. Hence, the two-phase design provides an efficient approach to follow-up GWAS signals with DNA resequencing. PMID- 23348638 TI - [The timing of the Surgeon General]. PMID- 23348636 TI - PROPEL: a randomized trial of mericitabine plus peginterferon alpha-2a/ribavirin therapy in treatment-naive HCV genotype 1/4 patients. AB - Mericitabine is a nucleoside analog polymerase inhibitor of hepatitis C virus (HCV). Treatment-naive HCV genotype 1 or 4 patients were randomized to double blind treatment with oral mericitabine at a dosage of 500 mg twice-daily (BID) for 12 weeks (A), 1,000 mg BID for 8 (B) or 12 weeks (C and D), or placebo BID for 12 weeks (E). All patients received pegylated interferon alpha-2a (Peg IFNalpha-2a; 40 kD)/ribavirin (RBV) at standard doses for 24 or 48 weeks during and after mericitabine/placebo therapy. Patients in arms A-C who maintained a virologic response (VR) (HCV RNA <15 IU/mL) from weeks 4 to 22 stopped all treatment at week 24; all other patients (arms A-E) continued Peg-IFNalpha-2a/RBV to complete 48 weeks. The primary outcome was sustained VR (SVR) (HCV RNA <15 IU/mL after 24 weeks of untreated follow-up; SVR-24). VR rates were higher in arms A-D than in arm E at weeks 4 and 12 overall, in patients with and without cirrhosis and in patients with CC and non-CC IL28B genotypes. However, the overall SVR-24 rate in arms D (50.6%) and E (placebo, 51.2%) was similar and those in the response-guided therapy arms A, B, and C were lower (48.8%, 42.0%, and 32.9%, respectively). No viral breakthrough or mericitabine-resistance mutations (S282T) were observed during mericitabine therapy. CONCLUSION: Treatment with mericitabine plus Peg-IFNalpha-2a/RBV for 8 or 12 weeks provided potent suppression of HCV RNA, was well tolerated, and did not select resistant variants, but did not increase SVR rates, compared to placebo. IFN-free and IFN containing trials of mericitabine of longer treatment duration are ongoing. PMID- 23348639 TI - Ingestion of glutamine and maltodextrin two hours preoperatively improves insulin sensitivity after surgery: a randomized, double blind, controlled trial. AB - OBJECTIVE: To investigate whether the abbreviation of preoperative fasting with a drink containing glutamine and dextrinomaltose improves organic response to surgical trauma. METHODS: Thirty-six female patients adult (18-62 years) candidates for elective laparoscopic cholecystectomy were randomly divided into three groups: conventional fasting (fasting group), and two groups receiving two different diets, eight hours (400ml) and two hours before induction of anesthesia (200ml): carbohydrate (CHO) group (12.5% dextrinomaltose) and the glutamine (GLN) group (12.5% dextrinomaltose and 40 and 10g of glutamine, respectively). Blood samples were collected pre and postoperatively. RESULTS: Twenty-eight patients completed the study. No pulmonary complication occurred. Gastric residual volume was similar between groups (p = 0.95). Postoperatively, all patients from the fasting group had abnormal glucose (> 110mg/dl), this abnormality being of 50% when compared to the CHO group (p = 0.14), and of 22.2% when compared to the GLN group (p = 0.01). All patients who had the fasting period shortened (CHO + GLN) had normal postoperative insulin, contrasting with 66.7% in the fasted group (p = 0.02). The abnormal sensitivity to insulin postoperatively rose from 32.1% to 46.4% of cases (p = 0.24), and it occurred in only 11.1% of patients in GLN group when compared to 55.5% in the fasting group (p = 0.02). CONCLUSION: the abbreviation of preoperative fasting for two hours with dextrinomaltose and glutamine improves insulin sensitivity in patients undergoing elective laparoscopic cholecystectomy. PMID- 23348640 TI - Procalcitonin as a prognostic biomarker of severe sepsis and septic shock. AB - OBJECTIVE: To evaluate the tendency of the plasma concentration and clearance of procalcitonin (PCT-c) as biomarkers of prognosis of patients with severe sepsis and septic shock, compared to another early prognosis marker, the number of SIRS criteria at sepsis diagnosis. METHODS: We conducted a prospective, observational, cohort study, with patients with severe sepsis and septic shock. The serum procalcitonin was determined at diagnosis of sepsis and after 24 and 48 hours. Demographic data, APACHE IV, SOFA score on arrival, number of SIRS criteria at diagnosis, site of infection and microbiological results were recorded. RESULTS: Twenty-eight patients were included, 19 clinical and nine surgical. In 13 (46.4%) the source of sepsis was pulmonary, abdominal in seven (25.0%), urinary in five (17.9%) and soft tissue in three cases (10.7%). Fifteen patients had severe sepsis and 13 septic shock. Overall mortality was 17.9% (five patients), three with septic shock. Twenty-eight PCT determinations were performed at sepsis diagnosis, 27 after 24 hours and 26 after 48 hours. The initial concentration was not significantly different between survivors and non-survivors groups, but the differences between the two groups after 24 and 48 hours were statistically significant. There was no difference in the number of SIRS criteria. The 24-hour procalcitonin clearance proved to be significantly higher in the group of survivors (-3.0 versus -300.0, p = 0.028). Although the 48-hour procalcitonin clearance has shown to be higher in the group of survivors when compared to non survivors, the difference did not reach statistical significance. CONCLUSION: Persistently high procalcitonin concentrations in plasma, as well as reduced 24 hours PCT clearence, were associated with a significant increase in mortality in patients with severe sepsis and septic shock. PMID- 23348641 TI - Curative ablation of atrial fibrillation: comparison between deep sedation and general anesthesia. AB - OBJECTIVE: To compare deep sedation with general anesthesia for curative ablation of atrial fibrillation. METHODS: We conducted a prospective, randomized study with 32 patients, aged between 18 and 65 years, ASA 2 and 3, BMI d" 30 kg/m2, divided into two groups: deep sedation (G1) and general anesthesia (G2). All patients received intravenous midazolam (0.5 mg / kg). G1 received propofol (1mg/kg) and O2 by facemask, followed by continuous infusion of propofol (25 50mg/kg/min) and remifentanil (0.01-0.05 mg / kg / min). G2 received propofol (2mg/kg) and laryngeal mask with built-in drain tube, followed by continuous infusion of propofol (60-100mg/kg/min) and remifentanil (0.06 to 0.1g/kg/min). We compared heart rate, invasive blood pressure, arterial blood gases, complications and recurrence (outcome) in three months. RESULTS: G1 patients had arterial blood gas with higher PaCO2 levels and lower pH (p = 0.001) and higher incidence of cough. There was a decrease in Mean Arterial Pressure (MAP) and Heart Rate (HR) in G2. Except cough, complications and recurrence were similar in both groups. CONCLUSION: Both techniques can be used for the curative ablation of atrial fibrillation. General anesthesia provided smaller respiratory changes and greater immobility of the patient. PMID- 23348642 TI - Non-palpable breast lesions marked with coal suspension: evaluation of anatomopathological aspects, viability of interpretation and inflammatory response. AB - OBJECTIVE: To analyze the efficiency of labeling impalpable breast lesions with inert charcoal suspension; to evaluate the morphological alterations associated with its use and to determine whether the use of charcoal labeling hampers the diagnostic interpretation of the pathologist. METHODS: Was evaluated a total of 135 cases of impalpable breast lesions previously labeled with charcoal suspension. Histological H&E stained slides containing charcoal pigments were analyzed using optical microscopy, by which both quantitative and qualitative evaluations with regards to inflammatory response and interference in diagnosis were performed. Lymphocyte, giant cells and neutrophils were evaluated and quantified. Moreover, the distribution of the charcoal suspension present in the lesions was evaluated. RESULTS: As to the quantitative and qualitative evaluation of the inflammatory response caused by the use of charcoal labeling, granulomas were present in all samples regardless of the quantity of injected charcoal. Lymphocytic inflammatory response was absent in only 5.19% of the samples, 82.22% exhibited discrete intensity and 12.59% were moderate. With regards to acute inflammatory response, 42.96% showed total absence of neutrophilic exudate, whereas 42.22% contained discrete and 11.11% moderate neutrophilic exudate, and only 3.7% of cases had intense neutrophilic exudate. CONCLUSION: This study corroborates the utility and easiness of the charcoal method as a mean of efficient labeling of impalpable breast lesions; this technique is easy to use, has a low cost, high efficiency and does not interfere with the histological analysis. Moreover, it is comfortable for the patient and is of great help in finding and localizing the lesions for both the surgeon and pathologist. PMID- 23348643 TI - Predictors factors for post-thyroidectomy hypocalcaemia. AB - OBJECTIVE: To evaluate the incidence and predictors of post-thyroidectomy definitive hypocalcemia and hypoparathyroidism. METHODS: We assessed ionic calcium preoperatively and postoperatively (first, second and 30th day) in 333 patients undergoing thyroidectomy. In those presenting hypocalcemia, measurements were also made 90 and 180 days after surgery, when parathormone was also dosed. Patients were grouped according to the presence or absence of hypocalcemia and evaluated according to age, gender, thyroid function, thyroid volume, number of parathyroid glands identified and need to parathyroid reimplantation, type of operation, operative time, and histopathological diagnosis. RESULTS: The incidence of temporary hypocalcemia was 40.8% (136 patients), and of definitive hypoparathyroidism 4.2% (14 patients). Reoperation or total thyroidectomy, neck dissection, hyperthyroidism, operative time and age above 50 years were factors related to higher incidence of hypocalcemia and definitive hypoparathyroidism (p <0.05). CONCLUSION: predictors of postoperative hypocalcemia included age (> 50 years), total thyroidectomy, reoperation, neck dissection and operative time. The predictors of post-thyroidectomy definitive hypoparathyroidism included type of operation, histological diagnosis and hyperthyroidism. PMID- 23348644 TI - Laparoscopic liver resection: personal experience with 107 cases. AB - OBJECTIVE: To analyze our experience after 107 laparoscopic hepatectomies and discuss the technical evolution of laparoscopic hepatectomy in the last five years. METHODS: Between April 2007 and April 2012 we performed 107 laparoscopic hepatectomies in 105 patients. The mean age was 53.9 years (17 to 85). Fifty three patients were male. All interventions were performed by the authors. RESULTS: from the total of 107 operations, there was need for conversion to open technique in three cases (2.8%). Sixteen patients (14.9%) had complications. Two patients died, a mortality of 1.87%. One death was due to massive myocardial infarction, unrelated to the procedure, which was uneventful and showed no conversion or bleeding. The other death was due to failure of the stapler. Twenty patients (18.7%) required blood transfusion. The most frequent type of hepatectomy was bisegmentectomy of segments 2-3, (33 cases), followed by right hepatectomy (22 cases). Seventy-two procedures (67.3%) were performed by the technique of Glissonian access. CONCLUSION: The dissemination of results is of utmost importance. The technical difficulties, complications and even death, inherent in this complex type of surgery, need to be clearly disclosed. This procedure should be performed in a specialized center with knowledgeable staff. The technique of laparoscopic Glissonian access, described by our staff, facilitates the realization of anatomical hepatectomies. PMID- 23348645 TI - Correlation between Doppler of the right hepatic vein with ultrasound transcutaneous guided biopsy in liver diseases. AB - OBJECTIVE: To correlate chronic liver disease diagnosed by transcutaneous liver biopsy guided by ultrasound, with ultrasound findings with B-mode and Doppler of the right hepatic vein; 2) to compare the wave patterns between the study group and the control group; 3) to compare the right hepatic vein Doppler findings with histopathology findings as a possible marker of chronic liver disease. METHODS: Were studied 38 patients with chronic liver disease diagnosed by biopsy and serology (study group) and 10 persons without serologic liver disease (control group), assessed only by ultrasound B-mode and Doppler. The criteria were based on histology classification of the Brazilian Society of Pathology for chronic hepatitis. Chi-square, Fisher's exact and Student t tests were used. RESULTS: The B-mode and Doppler ultrasound were useful in inferring the differentiation between individuals with chronic liver disease from normal. There were significant differences between the study group and the controls when comparing the histopathology findings, ultrasound B-mode and Doppler in relationship to the wave patterns of the right hepatic vein. CONCLUSION: The correlation of liver biopsies with ultrasound B-mode and Doppler of hepatic vein was positive; 2) individuals with liver disease showed alterations in the flow of the right hepatic vein and normal subjects not, being the wave pattern in normal triphasic and in patients with chronic liver disease monophasic or biphasic; 3) Doppler of the right hepatic vein is useful marker for chronic liver disease. PMID- 23348646 TI - Predictive factors of morbidity in distal pancreatic resections. AB - OBJECTIVE: To evaluate the postoperative morbidity of distal pancreatic resections and to investigate its predictive factors. METHODS: The study was conducted retrospectively from a prospectively database maintained. From 1994 to 2008, 100 consecutive patients underwent left pancreatic resections. The primary variable of interest was postoperative morbidity, and various other characteristics of the population were simultaneously recorded. Later, for the analysis of predictors of postoperative morbidity, the subgroup of patients who underwent distal pancreatectomy with spleen preservation (n = 65) was separately analyzed with regards to the different techniques of section of the pancreatic parenchyma, as well as to other possible predictors of postoperative morbidity. RESULTS: Considering all left pancreatic resections performed, the occurrence of overall, relevant and serious complications was 55%, 42% and 20%, respectively. The factors predictive of postoperative morbidity after distal pancreatectomy with spleen preservation were the technique employed for section of the pancreatic parenchyma, age, body mass index and the performance of concomitant abdominal operations. CONCLUSION: The morbidity associated with pancreatic resections to the left of the superior mesenteric vessels was high. According to the stratification adopted based on the severity of complications, some predictive factors have been identified. Future studies with larger cohorts of patients are needed to confirm these results. PMID- 23348647 TI - Influence of cholestatic jaundice on the weight variance in an experimental model. AB - OBJECTIVE: To evaluate the influence of cholestatic jaundice in weight variation. METHODS: We used 64 adult rats divided into six groups: F1 (n = 6): normal females; F2 (n = 6): laparotomy females; F3 (n = 20): jaundiced females; M1 (n = 6): normal males; M2 (n = 6): laparotomy males; M3 (n = 20): jaundiced males. Jaundice was obtained by ligation and section of the biliopancreatic duct. The animal weights were recorded weekly for seven weeks. On the 14th day of the experiment, bilirubin and gonadal hormones were assessed. After the seventh week a histological study of the liver was performed. RESULTS: The animals in groups F3 and M3 showed elevated bilirubin and decreased body mass when compared to the other groups. The weight differences were significant from the fourth week on amongst females and from the fifth in males. In Jaundiced animals there was increased estradiol and decreased progesterone and testosterone. Perivenular septa and periportal fibrosis, cholangitis and bile duct hyperplasia occurred in the liver of jaundiced rats. No animal showed cirrhosis. CONCLUSION: There was decrease in murine body weight in the presence of cholestatic jaundice in both genders. PMID- 23348648 TI - Analysis of adhesions resulted from mesh fixation with fibrin sealant and suture: experimental intraperitoneal model. AB - OBJECTIVE: To compare surgical fixation of polypropylene mesh (PP) and coated polypropylene mesh (PCD) using polypropylene suture and fibrin glue, as for the formation of intraperitoneal adhesions. METHODS: A sample of 46 female Wistar rats were randomized into six groups: two control groups, with five rats each, were subjected to one medial incision (MI) and the other to a U-shaped incision (UI), none of these groups received the mesh. Two groups of PP mesh, with ten rats, fixed with suture (PPF), the other with six rats, fixed with biological glue (PPC). And two groups of PCD mesh, at first, with ten animals, the mesh was fixed with sutures (PCDFs) and the second with ten animals with biological glue (PCDC). RESULTS: After 21 days, the control groups showed no significant adhesions. The PPC group showed a lower degree of adhesion than the PPF group (p = 0.01). There was no difference between the groups with PCD. CONCLUSION: Comparison of fixation was statistically different only with PP mesh, with lesser degrees of adherence when using the glue. Adhesions were predominantly located at the extremities of the meshes studied. PMID- 23348649 TI - Comparative study of topical green and red propolis in the repair of wounds induced in rats. AB - OBJECTIVE: To evaluate the healing action of green and red propolis, correlating it with the content of flavonoids. METHODS: We performed quantification of total flavonoids of green and red propolis ethanol extracts for subsequent incorporation in ointment base to 20%. We used 20 Wistar rats divided into four groups: 0.9% saline (S), ointment base (B), green propolis ointment (G) and red propolis ointment (R). All animals were submitted to excisional lesions in the midian back region. The rats were treated daily for 15 days. During this period we observed weight, body temperature and diameters of the wounds. For histological analysis, samples were collected from wounds. At the end of the experiment we performed blood collection and removal of the kidney and liver for biochemical and histological analyzes. RESULTS: The levels of total flavonoids of green (4.50%) and red (5.92%) propolis were high (> 2%), but, while the latter showed a content larger than the former, the evolution of green propolis was better in the repair of wounds, both macroscopically and histologically. There were no nephrotoxicity or hepatotoxicity, a result confirmed by biochemical tests (ALT and albumin). Propolis influenced the reduction of total cholesterol, triglycerides and glucose. CONCLUSION: There was no correlation between total flavonoid contents and the healing action of propolis. This reveals the need for elucidation of the flavonoids found in each class of propolis to unravel which one(s) would be important for the healing process. PMID- 23348650 TI - Analysis of the diversity of the intestinal microbiota of rats subjected to resection of the ileocecal valve and creation of artificial sphincter. AB - OBJECTIVE: To analyze, through molecular biology, the diversity of the intestinal microbiota before and after resection of the ileocecal junction and reconstruction of intestinal transit with and without the creation of a neosphincter. METHODS: Fourteen Wistar rats were divided into two groups: Group A (n = 7), submitted to resection of the ileocecal valve and end-to-end, single layer ileocolic anastomosis; and Group B (n = 7) with resection of the ileocecal valve and end-to-end, single-layer ileocolic anastomosis followed by construction of an artificial sphincter. Intraluminal contents were collected from both groups. The animals were reoperated 20 days after the first procedure, with new collection of intraluminal contents of the ileum and colon. From the samples collected, DNA was extracted for PCR-DGGE. The electrophoretic banding patterns generated in the reaction were analyzed for similarities and diversities of the microbiota. RESULTS: The diversity of microorganisms was larger and in more samples when collected from the ileum than from the colon. The group with the neosphincter showed the highest variation in the colon, from 2.11 to 2.93. In three animals from each group was established comparing the similarity and not resembled the control. CONCLUSION: ileocecal resection led to changes in ileal microbiota and, with the creation of new sphincter, the changes were even greater. PMID- 23348651 TI - Protective effect of remote ischemic per-conditioning in the ischemia and reperfusion-induce renal injury in rats. AB - OBJECTIVE: To evaluate the protective effect of remote ischemic per-conditioning in ischemia and reperfusion-induced renal injury. METHODS: Fifteen rats (Rattus norvegicus) were randomized into three groups (n = 5): Group Normality (GN), Control Ischemia and Reperfusion (GIR) and Group remote ischemic per-conditioning (GPER). With the exception of the GN group, all others underwent renal ischemia for 30 minutes. In group GPER we performed the ischemic remote per-conditioning, consisting of three cycles of ischemia and reperfusion applied every five minutes during the ischemic period, to the left hindlimb of the rats by means of a tourniquet. To quantify the lesions we measured serum levels of creatinine and urea, as well as analyzed renal histopathology. RESULTS: The GPER group presented with better levels of urea (83.74 +/- 14.58%) and creatinine (0.72 +/- 26.14%) when compared to GIR group, approaching the GN group. Histopathologically, the lower levels of medullary congestion and hydropic degeneration were found in group GPER. CONCLUSION: The remote ischemic per-conditioning had a significant protective effect on renal ischemia and reperfusion. PMID- 23348652 TI - Advances in the management of early esophageal carcinoma. AB - Esophageal squamous cell cancer (ESCC) has a dismal prognosis mainly because its recognition in Western countries usually occurs in late stages, when the possibilities of cure are minimal. However, in recent years, several advances have been observed in the management of ESSC, such as the identification of high risk patients, the use of high-resolution endoscopy and lugol chromoscopy favoring the diagnosis of early stage ESCC, and the development of endoluminal techniques of en-block tumor resection, namely endoscopic submucosal dissection (ESD). These factors have enabled the application of endoscopic minimally invasive curative interventions in selected patients with superficial ESCC. This review article, designed by a multicenter international group, has the primary objective to provide a comprehensive overview of the most important recent advances in the management of ESCC. Secondarily it intends to provide a detailed and practical description of the technical approach to ESD in order to facilitate the dissemination of this concept and the incorporation of this new technologies in Brazil and in Latin-America. PMID- 23348653 TI - [Two-stage hepatectomy for hepatic metastasis and supra renal vena cava reconstruction]. AB - Two-stage hepatectomy uses compensatory liver regeneration after a first noncurative hepatectomy to enable a second curative resection. Herein we report the tecnical aspects of the management of a thirty-seven years-old woman with colorectal metastasis to the liver eligible because single resection could not achieve complete treatment, even in combination with chemotherapy, portal embolization, or radiofrequency, but tumors could be totally removed by two sequential resections. PMID- 23348654 TI - [Assessment of preceptorship in general surgery residency in the operating room, comparison between a teaching hospital and a non teaching hospital]. AB - BACKGROUND: Medical residency is well known as the best training method after graduation. It is a moment when, in addition to receiving technical guidance, residents should also develop attitudes, ethics, and professionalism. In order for that to occur, preceptors should be prepared for their task. OBJECTIVE: To evaluate and compare the preceptorship in the Medical Residency in General Surgery program, in the operating room of a Teaching Hospital (TH) and a Non teaching Hospital (NTH), from the viewpoint of the residents who entered in 2010 and 2011. METHODS: A questionnaire was applied to the residents, adapted from Sarker, Vincent and Darzi, and the Likert scale was used to qualify the survey items on the preceptors' attitudes. RESULTS: At the TH, 12 preceptors were evaluated by 7 residents. One of the residents did not answer the questionnaire. At the NTH, 11 preceptors were evaluated by 13 residents. The comparison of the distribution of responses between hospitals was analyzed using the chi-squared test for trend. Significance level was set at 5%. The statistical analysis was processed by the statistical software SAS(r) System version 6.11 (SAS Institute, Inc., Cary, North Carolina). The NTH showed a greater trend for discordant and indifferent responses than the TH. Only one question resulted in statistical significance between the hospitals. No significant difference was found between hospitals in the comparison of the responses to the remaining CONCLUSION: Only question 4 ("Keeps focused on the operation") showed a significant difference (p=0.010) in the distribution of responses. The two hospitals exhibited similar preceptorship quality. PMID- 23348655 TI - Venous thromboembolism prophylaxis in patients with traumatic brain injury. AB - Traumatic brain injury (TBI) with associated intracranial hemorrhage (ICH) occurs frequently in trauma. Trauma patients are also at high risk of developing venous thromboembolic (VTE) complications. Low Molecular Weight Heparin (LMWH) is used in trauma patients as prophylaxis to reduce the risk of VTE events. It remains unclear, however, if LMWH is safe to use in trauma patients with ICH for fear of hematoma progression. The "Evidence-based telemedicine: trauma & acute care surgery (EBT-TACS)" Journal Club performed a critical appraisal of 3 recent and most relevant studies on timing to initiate, safety and use of LMWH in trauma patients with ICH. Specifically, we appraised a i) critical literature review on the topic, ii) a multicenter, retrospective cohort study assessing the safety of LMWH in trauma patients with ICH and iii) a randomized, pilot study assessing the feasibility and event rates of ICH progression, laying the groundwork for future randomized controlled trials (RCT) on the topic. Some results are conflicting, with the highest level of evidence being the pilot RCT demonstrating the safety for early use of LMWH in TBI with ICH. Much of this research, however, was generated by a single center and consequently lacks external validity. Furthermore, clinical recommendations cannot be generated based on pilot studies. Evidence-based guidelines and recommendations could not be made at this time, until the completion of further studies on this challenging topic. PMID- 23348656 TI - [Popliteal artery pseudoaneurysm caused by a femoral osteochondorma: case report]. AB - Osteochondromas are the most common benign tumor of the bone. They are sometimes responsible for vascular complications involving either veins or arteries, principally around the knee. Pseudoaneurysms are considered a rare condition. The authors describe the occurrence of a pseudoaneurysm of the popliteal artery in association with a femoral osteochondroma in a 30-years-old man. PMID- 23348657 TI - [Urethral leiomyoma during pregnancy: a case report]. AB - The authors report a case of urethral leiomyoma diagnosed during pregnancy, which was conservatively treated up to the 38th week, when the pregnancy was interrupted. Thirty days after delivery, exeresis of the lesion was performed from the upper border of the urethral meatus and sutured with interrupted delayed absorbable suture. The patient evolved favorably and presented no lesion recurrence during three months of follow up. PMID- 23348658 TI - A multicentre weight loss study using a low-calorie diet over 8 weeks: regional differences in efficacy across eight European cities. AB - PRINCIPLES: The efficacy of low-calorie diets (LCDs) has not been investigated in large-scale studies or among people from different regions, who are perhaps unaccustomed to such methods of losing weight. The aim of the present study was to investigate changes in obesity measures among overweight/obese adults from eight European cities (from Northern, Central and Southern Europe) during the 8 week LCD phase of the DiOGenes study (2006-2007), a family-based, randomised, controlled dietary intervention. METHODS: 938 overweight/obese adults completed baseline examinations and underwent an 8-week LCD, providing 3.3-4.2 MJ/day to replace all meals. Anthropometric measurements and body composition were assessed at baseline and post-LCD. RESULTS: 773 (82.4%) adults (mean age, 43.1 y) completed the LCD successfully. The highest drop-out rate was observed in Southern (24.9%) and the lowest in Northern (13.3%) European cities. Overall, the LCD induced favourable changes in all outcomes, including an approximate 11.0% reduction in body weight and body fat percentage. Changes in outcomes differed significantly between regions, with North- and Central-European cities generally achieving higher percentage reductions in most anthropometric measurements assessed. Nonetheless, participants in Southern Europe reduced their body fat percentage significantly more than participants in Northern Europe (-11.8 vs. 9.5%, P = 0.017). CONCLUSIONS: The LCD significantly improved anthropometric and body composition measurements in all cities participating in DiOGenes. PMID- 23348659 TI - Confirmatory factor analysis of the Chinese version of the Pediatric Quality-of Life Inventory Cancer Module. AB - BACKGROUND: Before the Chinese version of the Pediatric Quality-of-Life Inventory Cancer Module can be used to assess the multidimensional construct of quality of life among Hong Kong Chinese pediatric patients with cancer, its psychometric properties need to be further empirically tested. OBJECTIVE: The objectives of the study were to establish the construct validity, including hypothesis testing and a confirmatory factor analysis of factor structure, of the Chinese version of the Pediatric Quality-of-Life Inventory Cancer Module. METHODS: A cross-sectional study was used; 200 children hospitalized with cancer (9- to 16-year-olds) were recruited. Participants were asked to respond to the Chinese version of the Cancer Module, Therapy-Related Symptom Checklist, and Rosenberg's Self-esteem Scale. RESULTS: The results showed that there was a strong positive correlation between children's self-esteem and quality of life (r = 0.50) and a strong negative correlation between children's therapy-related symptoms and quality of life (r = -0.65). Confirmatory factor analysis indicated that there were 7 factors underlying the Chinese version of the Cancer Module. CONCLUSION: The study added further evidence of the construct validity of the Chinese version of the Cancer Module, patient version. IMPLICATION FOR PRACTICE: The Cancer Module can be used to assess and evaluate psychological interventions directed toward promoting the quality of life of children hospitalized with cancer. PMID- 23348660 TI - "Cautiously optimistic that today will be another day with my disease under control": understanding women's lived experiences of ovarian cancer. AB - BACKGROUND: Women diagnosed with ovarian cancer face a multitude of physical, psychological, and social issues. However, existing research has typically focused on those newly diagnosed with an initial occurrence or recurrence or women with advanced disease. As such, few studies have examined women's experiences across the illness trajectory and the impact of ovarian cancer on their everyday lives. OBJECTIVE: This research explores women's lived experiences of ovarian cancer and how they negotiate and make sense of illness-related issues. METHODS: Sixteen women participated in face-to-face interviews and e-mail follow-ups that were informed by hermeneutic and social phenomenological approaches. RESULTS: Five broad themes emerged from data analysis related to changes in health status and the body, disruptions to everyday activities and relationships, uncertainty, and coping and finding meaning in illness. These themes reflect the structures of participants' experiences and constitute the essence of living with ovarian cancer, "cautious optimism." CONCLUSIONS: This research contributes to our understanding of women's lived experiences of ovarian cancer across the illness trajectory; specifically, the findings indicate that embodiment and relationships were a central focus for participants as they sought to cope with myriad issues resulting from ovarian cancer. IMPLICATIONS FOR PRACTICE: Insight into women's ovarian cancer experiences can help nurses in their provision of care to this population. Furthermore, the findings can inform support interventions for affected women across the illness trajectory, as participants' experiences show that support needs often persist following treatment as women negotiate survivorship or recurrence. PMID- 23348661 TI - Meeting reality: young adult cancer survivors' experiences of reentering everyday life after cancer treatment. AB - BACKGROUND: Cancer in young adults is rare, but the intensity of cancer treatment increases the risk of physical and psychosocial impacts on patients' entire lives. Young adult survivors are underrepresented in research, and knowledge of cancer survivors in this age group is scarce, especially knowledge of transition from cancer treatment to everyday life. OBJECTIVE: The objective of this study was to explore how young adult cancer survivors experience reentering everyday life after cancer treatment. METHODS: A qualitative, phenomenological approach was used and included 20 young adult survivors (aged 24-35 years) with different cancer diagnoses allocated to a rehabilitation program. Semistructured interviews were conducted, and the transcripts were analyzed qualitatively using Systematic Text Condensation method. RESULTS: "Meeting reality" was identified as a bridging theme, explained by 4 main themes important to the informants: (1) lack of preparation, (2) late effects, (3) lack of understanding, and (4) being neither sick nor healthy. CONCLUSIONS: Informants were unprepared for reentering everyday life after cancer treatment and experienced a mismatch of their expectations with reality, particularly in the holistic impact of late effects. Moreover, reentering everyday life was characterized by a lack of understanding from their network and even healthcare providers who conducted follow-ups. The informants experienced reentering everyday life as being much harder than expected, and they felt isolated as well as neither sick nor healthy. IMPLICATIONS FOR PRACTICE: The results suggest a major shortcoming in both preparation for survivorship, multidisciplinary follow-ups, and knowledge. A shift to a more holistic perspective in survivorship care is suggested. PMID- 23348662 TI - Virtual reality bringing a new reality to postthoracotomy lung cancer patients via a home-based exercise intervention targeting fatigue while undergoing adjuvant treatment. AB - BACKGROUND: Little is known about rehabilitation for postthoracotomy non-small cell lung cancer (NSCLC) patients. This research uses a perceived self-efficacy enhancing light-intensity exercise intervention targeting a priority symptom, cancer-related fatigue (CRF), for postthoracotomy NSCLC patients. This article reports on phase II of a 2-phase study. Phase I focused on initiation and tolerance of exercise during the 6 weeks immediately after thoracotomy, whereas phase II addressed maintenance of exercise for an additional 10 weeks including participants initiating and completing chemotherapy and/or radiation therapy. OBJECTIVE: The objective of this study was to investigate the feasibility, acceptability, and preliminary efficacy of an exercise intervention for postthoracotomy NSCLC patients to include those initiating and completing adjuvant therapy. INTERVENTIONS/METHODS: A single-arm design composed of 7 participants postthoracotomy for NSCLC performed light-intensity exercises using an efficacy-enhancing virtual-reality approach using the Nintendo Wii Fit Plus. RESULTS: Despite most participants undergoing chemotherapy and/or radiation therapy, participants adhered to the intervention at a rate of 88% with no adverse events while giving the intervention high acceptability scores on conclusion. Likewise, participants' CRF scores improved from initiation through the conclusion of the intervention with perceived self-efficacy for walking at a light intensity continuously for 60 minutes, improving significantly upon conclusion over presurgery values. CONCLUSIONS: Postthoracotomy NSCLC patients maintained exercise for an additional 10 weeks while undergoing adjuvant therapy showing rehabilitation potential because the exercise intervention was feasible, safe, well tolerated, and highly acceptable showing positive changes in CRF self management. IMPLICATIONS FOR PRACTICE: A randomized controlled trial is needed to further investigate these relationships. PMID- 23348663 TI - Living with advanced breast cancer: perceptions of Pakistani women on life expectations and fears. AB - BACKGROUND: Pakistan has the highest rate of breast cancer in Asia. Many women delay seeking heath advice and treatment for breast cancer, and between 50% and 70% of women will present when the disease in is in an advanced, aggressive form, particularly young women. The psychological impact of breast cancer is challenged by the negative public perception of cancer. OBJECTIVES: This qualitative study explored the psychological impact of advanced breast cancer in women receiving follow-up care in an oncology hospital in Pakistan. METHODS: This qualitative study used semistructured interviews to explore women's experiences of living with advanced breast cancer and the impact that this had on their lives as women, mothers, and wives. Twenty-one women were interviewed. Data were analyzed using thematic analysis. RESULTS: The majority of 21 women interviewed were diagnosed between 1 and 11 years, and 15 women had a history of metastases. Four themes emerged from the data. These were reaction to the diagnosis, change in outlook, living life positively, and motivating factors. CONCLUSION: Women acknowledged the significance of their illness on their health and longevity. Their individual cancer journey was multilayered and imbued with the hope of cure, remission, and an emotional catalog of feelings. All married women wished for sufficient time to visualize their children reach adulthood and marry. Single women wished to care for their mothers and families. IMPLICATIONS FOR PRACTICE: Through education and support, nurses can provide women with advanced breast cancer and their families educational, spiritual, and psychological care. PMID- 23348664 TI - Open communication with terminally ill cancer patients about illness and death: a comparison between spouses of Ashkenazi and Sephardi ethnic origins. AB - BACKGROUND: Studies document that caregivers face severe difficulties in communicating with their loved ones about both illness and death. To date, a paucity of studies has examined caregiver-patient communication at the end of life within the context of ethnic origin. OBJECTIVE: This study compares the level of open communication between caregivers from 2 ethnic groups and examines the contribution of different caregiver characteristics and situational variables to the explanation of open communication. METHODS: A total of 77 spouse caregivers of terminally ill cancer patients (comprising 41 Jews of Sephardi origin and 36 Jews of Ashkenazi origin) participated in the study. The questionnaire included measures of caregiver communication, caregiver characteristics (ie, age, gender, education level, optimism, self-efficacy), and situational variables (ie, duration and intensity of care). RESULTS: Spouses of Ashkenazi origin communicated more with their loved ones about illness and death compared with their Sephardi counterparts. Ethnic origin accounted for 16.6% of the explained variance, caregiver characteristics added 20.3%, and situation variables lent a modest contribution of 3.5%. Four variables emerged as significant predictors of caregivers' level of open communication: self-efficacy (beta = .33, P < .05), gender (beta = .32, P < .01), ethnic origin (beta = .25, P <.05), and duration of care (beta = .20, P < .05). CONCLUSIONS: These findings demonstrate the importance of ethnic origin to caregivers' open communication with terminal cancer patients about illness and death. Moreover, communication level with patients is mostly explained by the caregiver characteristics. IMPLICATIONS FOR PRACTICE: Caregiver characteristics should be considered by nurses when developing intervention programs for increasing caregivers' level of open communication with dying patients. PMID- 23348665 TI - The quality of life of male spouses of women with breast cancer: hope, self efficacy, and perceptions of guilt. AB - BACKGROUND: The quality of life of male spouses of partners with breast cancer may determine the support they are able to give their wives. Little is known about the factors associated with their quality of life. OBJECTIVE: The purpose of this study was to examine the relationship of the quality of life of male spouses of partners with breast cancer with the following factors: (a) demographic variables of male spouses and their partners, (b) levels of hope of male spouses and their partners, (c) self-efficacy and loss and grief of male spouses, and (d) quality of life of partners with breast cancer. METHODS: Six hundred surveys were mailed to women with breast cancer (stage 1-3) and their male spouses. A total of 110 surveys were completed. RESULTS: With the use of generalized linear modeling, participating male spouses with higher quality of life scores: (a) were older (P = .01), (b) had higher hope scores (P = .01), (c) had lower feelings of guilt scores (P < .01) (subscale of loss and grief), (d) had higher general self-efficacy scores (P < .01), and (e) had partners with breast cancer with higher quality of life scores (P < .01). CONCLUSIONS: Hope, self-efficacy, feelings of guilt, age, and their partners' quality of life were significantly related to quality of life of the male spouses of women with breast cancer. IMPLICATIONS FOR PRACTICE: The findings underscore the importance of assessing for and fostering hope and self-efficacy as well as decreasing guilt in male spouses of women with breast cancer to improve their quality of life. PMID- 23348666 TI - Bereaved Jewish mothers of children who died of cancer: the relationship between the mother and the deceased child and the mother's perceived functioning. AB - BACKGROUND: Coping with grief after a child's death is a complex and dynamic process. The Two-Track Model of Bereavement, which served as the theoretical framework for this study, examines biopsychosocial reactions to bereavement (track I) and attachment to the deceased (track II). OBJECTIVES: The objectives of this study were to identify differences in mothers' perceived functioning between bereaved mothers and mothers of children with cancer, describe mother child relationships and relationship development over the course of illness and death, and describe the association between the 2 tracks. METHODS: A quantitative cross-sectional study of 50 Jewish bereaved mothers and a matched comparison group of 50 Jewish mothers to children with cancer aged 6 to 18 years completed structured questionnaires. RESULTS: No difference was found between the groups in overall maternal functioning. Bereaved mothers keep a relationship with their deceased child. Among mothers of currently ill children, there was a difference in the mean score of the mother-child relationship with the child before and after the cancer diagnosis. A negative correlation was found between the bereaved mother's relationship with the deceased child and her functioning; this was not found in the comparison group. CONCLUSIONS: Mother-child relationships become closer following the cancer diagnosis and change further following the child's death. The relationship with the deceased child is an integral part of the bereaved mother's life and influences her functioning. IMPLICATIONS FOR PRACTICE: Training programs for nurses need to be developed to help nurses be sensitive to maternal loss and grief and to incorporate the bereaved mother's relationship with her deceased child into interventions. PMID- 23348667 TI - Poor communication in cancer care: patient perspectives on what it is and what to do about it. AB - BACKGROUND: Communication in cancer care is a recognized problem for patients. Research to date has provided limited relevant knowledge toward solving this problem. OBJECTIVE: Our research program aims to understand helpful and unhelpful communication from the patient perspective and to document changes in patient needs and priorities over time. In this analysis, we focus on patient perceptions of poor communication. METHODS: Using a qualitative longitudinal approach informed by interpretive description methodology, we are following a cohort of adult cancer patients across their cancer journey. We used constant comparative analysis of repeated interviews to examine thematic patterns in their perceptions and interpret both commonalities and diversities. RESULTS: Patient accounts reveal 3 types of poor communication. "Ordinary misses" are everyday missteps for which maturation and socialization may be an adequate solution. "Systemic misunderstandings" are assumptive gaps between patients and professionals, which may be addressed through qualitative research. "Repeat offenders" are a subset of clinicians whose communication patterns become a particular source of patient distress. CONCLUSIONS: This typology offers a novel way to conceptualize the problem of poor communication in cancer care toward more effective solutions for the communication problem. Managing the communication of a problematic subset of clinicians will likely require strategic interventions at the level of organizational culture and models of care. IMPLICATIONS FOR PRACTICE: Nurses can play a meaningful role in detecting and buffering sources of poor communication in the practice context. Addressing poor communication may be a further reason to advocate for interprofessional team-based care models. PMID- 23348668 TI - Heini, a personal recollection and appreciation. PMID- 23348670 TI - Hydration shells with a pinch of salt. AB - The discovery of extreme halophile microorganisms in the Dead Sea, which are specifically dependent on a multimolar salt environment to survive, stimulated major developments in biology and physical chemistry. The minireview focuses on the molecular level. After a brief introduction to the history of halophile studies, protein and nucleic acid solvent interactions and their influence on macromolecular structure stabilization and dynamics are discussed. PMID- 23348669 TI - Chromatin structure outside and inside the nucleus. AB - The structure of the 30-nm chromatin fiber has provided, over the years, an important reference in chromatin studies. Originally derived from electron microscopic studies of soluble chromatin fibers released by restriction digestion, the gross structural features of such fragments have been supported by biophysical methods such as low angle X-ray and neutron scattering, sedimentation, light scattering, and electric dichroism. Electron microscopy and sedimentation velocity measurements demonstrated that reconstituted chromatin fibers, prepared from repeating arrays of high affinity nucleosome positioning sequences, retain the same overall features as observed for native chromatin fibers. It had been suggested that the 30 nm fiber might be the form assumed in vivo by transcriptionally silent chromatin, but individual gene or genome-wide studies of chromatin released from nuclei do not reveal any such simple correlation. Furthermore, even though the 30 nm fiber has been thought to represent an intermediate in the hierarchical folding of DNA into chromosomes, most analyses of chromatin folding within the nucleus do not detect any regular extended compact structures. However, there are important exceptions in chicken erythroid cell nuclei as well as in transcribed regions that form extended loops. Localized domains within the nucleus, either at the surface of chromosome domains or constrained as a specialized kind of constitutive heterochromatin by specific DNA binding proteins, may adopt 30 nm fiber-like structures. PMID- 23348671 TI - Quantitative assessment of the relative contributions of steric repulsion and chemical interactions to macromolecular crowding. AB - The term "macromolecular crowding" denotes the combined effects of high volume fractions of nominally unrelated macromolecules upon the equilibrium and transport properties of all macrosolutes, dilute as well as concentrated, in the crowded medium. We present a formal partitioning of the total crowding effect into contributions from steric exclusion (excluded volume) and weak, nonspecific attractive interactions between a concentrated "crowding agent" and reactant and product species present at trace concentration. A numerical example of the combined effect of both steric and chemical interactions between crowder and tracer upon the reversible dimerization of tracer is presented, based upon reasonable estimates of the magnitude of both repulsive and attractive interactions between tracer and crowder species. PMID- 23348673 TI - Interaction of oil sands tailings particles with polymers and microbial cells: First steps toward reclamation to soil. AB - Production of bitumen by surface mining of Alberta's oil sands has given rise to tailings ponds, containing large volumes of finely dispersed clays (10(8) m(3)), which settle only slowly. The mature fine tailings (MFT) in these ponds are operationally defined as consisting of particles smaller than 44 MUm with a solids content in excess of 30% (w/w). Increasing the rate of densification of MFT is a rate-limiting step in tailings pond reclamation. Accelerated densification has been achieved through mixing of MFT with sand in the presence of calcium sulfate as a binding agent to generate consolidated tailings. Addition of negatively charged polymer, together with either calcium or magnesium ions, is similarly effective. Although toxic to higher aquatic life, tailings ponds harbour a wide variety of mainly anaerobic microbes. These convert residual hydrocarbon, causing methane emissions of up to 10(4) m(3) day(-1). Interestingly, anaerobic microbial activity also accelerates tailings pond densification. Hence, many technologies designed to accelerate densification move tailings, at least conceptually, towards soil in which sand and clay particles are linked by large amounts of humic and fulvic acid polymers supporting large numbers of microbes in a mechanically stable structure. PMID- 23348672 TI - ATP and ADP actin states. AB - This minireview is dedicated to the memory of Henryk Eisenberg and honors his major contributions to many areas of biophysics and to the analysis of macromolecular states and interactions in particular. This work reviews the ATP and ADP states of a ubiquitous protein, actins, and considers the present evidence for and against unique, nucleotide-dependent conformations of this protein. The effects of ATP and ADP on specific structural elements of actins, its loops and clefts, as revealed by mutational, crosslinking, spectroscopic, and EPR methods are discussed. It is concluded that the existing evidence points to dynamic equilibria of these structural elements among various conformational states in both ATP- and ADP-actins, with the nucleotides impacting the equilibria distributions. PMID- 23348674 TI - Evolution of the concept of conformational dynamics of enzyme functions over half of a century: A personal view. AB - To most physicists, it was always evident that conformational fluctuation is an inherent property of all molecules. Its existence in proteins was mentioned first by Linderstrom-Lang and Schellman in 1959 based on their hydrogen-deuterium exchange experiments. The "induced fit" mechanism to explain ligand-induced conformational changes was suggested by Koshland in 1958. Straub combined these two concepts in his "fluctuation fit" theory in 1964. The era of protein X-ray crystallography imposed a static view of protein structures. With proteins becoming accessible to NMR analysis, conformational dynamics could be mapped, and a new wave of dynamic interpretation of enzymatic catalysis and molecular recognition appeared. Energy landscapes, energy funnels, conformational selection, conformational distribution shifts are now frequent terms in interpreting biomolecular recognition and enzymatic catalysis. All these interpretations are based on the concept that evolution uses the conformational fluctuations of enzymes to develop efficient and dynamic catalytic machines. In a resurrection of the original "fluctuation fit" concept, it is generally recognized now that spatial and temporal events of catalysis are equally important to describe its mechanism. This special issue, dedicated to the memory of Henryk Eisenberg, prompted us to look back at the last 50 years of development of a concept that-like other important concepts-appeared, evolved and became accepted during the period covered by the scientific lifespan of Henryk. PMID- 23348675 TI - Henryk (Heini) Eisenberg (1921-2009): From polymer chemistry to halophilic enzymes to chromatin and back. PMID- 23348677 TI - Germ cells are required to maintain a stable sexual phenotype in adult zebrafish. AB - Sex in zebrafish is not determined by a major chromosomal locus, but instead relies on a mechanism that is influenced by a germ cell-derived signal, as animals that lack germ cells, or specifically oocytes, develop as phenotypic males. These data suggest that during primary sex determination, an oocyte derived signal acts on the bipotential somatic gonad to promote the female specific program. However, it is not known if germ cells are required only during the primary sex-determining window, or if they are required throughout adult life to maintain the female sexual phenotype. Here, we show that while wild-type zebrafish do not switch sex as adults, germ cell-depleted adult females readily convert to a male phenotype. Notably, when oocytes are depleted, but germline stem cells remain, adult females sex-revert to sperm-producing males, indicating that a germ cell-derived signal acts on the somatic gonad to promote female development directly or indirectly by repressing male-specific gene expression. These results also confirm that signals from the somatic gonad in turn ensure that the sex appropriate gamete is produced. PMID- 23348679 TI - Targeting the epithelial cells in fibrosis: a new concept for an old disease. AB - Fibrosis, which affects millions of individuals worldwide, is a leading cause of organ failure. For 40 years myofibroblasts have been recognized to be the key cellular players in fibrosis. Currently, several pharmaceutical targets are under investigation that may contribute to the activation of myofibroblasts. Recent preclinical and clinical evidence suggests that other components in the fibrotic microenvironment can trigger myofibroblast activation, providing new targets for pharmaceutical intervention. Epithelial cells may represent the most promising cellular phenotype that could be exploited in the design of new anti-fibrotic medicines through their paracrine action on myofibroblasts. The present review briefly highlights this hypothesis and discusses some interesting related pharmacological targets. PMID- 23348678 TI - Acute dietary zinc deficiency before conception compromises oocyte epigenetic programming and disrupts embryonic development. AB - Recent findings show that zinc is an important factor necessary for regulating the meiotic cell cycle and ovulation. However, the role of zinc in promoting oocyte quality and developmental potential is not known. Using an in vivo model of acute dietary zinc deficiency, we show that feeding a zinc deficient diet (ZDD) for 3-5 days before ovulation (preconception) dramatically disrupts oocyte chromatin methylation and preimplantation development. There was a dramatic decrease in histone H3K4 trimethylation and global DNA methylation in zinc deficient oocytes. Moreover, there was a 3-20 fold increase in transcript abundance of repetitive elements (Iap, Line1, Sineb1, Sineb2), but a decrease in Gdf9, Zp3 and Figla mRNA. Only 53% and 8% of mature eggs reached the 2-cell stage after IVF in animals receiving a 3 and 5 days ZDD, respectively, while a 5 day ZDD in vivo reduced the proportion of 2-cells to 49%. In vivo fertilized 2-cell embryos cultured in vitro formed fewer (38%) blastocysts compared to control embryos (74%). Likewise, fewer blastocyst and expanded blastocyst were collected from the reproductive tract of zinc deficient animals on day 3.5 of pregnancy. This could be due to a decrease in Igf2 and H19 mRNA in ZDD blastocyst. Supplementation with a methyl donor (SAM) during IVM restored histone H3K4me3 and doubled the IVF success rate from 17% to 43% in oocytes from zinc deficient animals. Thus, the terminal period of oocyte development is extremely sensitive to perturbation in dietary zinc availability. PMID- 23348680 TI - Profiles of sibling bullying. AB - Considerable research has been done on childhood bullying, including its antecedents and consequences. Yet, with all of the attention on bullying, particularly school bullying, sibling bullying has been vastly overlooked. Sibling bullying is a type of violence prevalent in the lives of most children, but little is known about the phenomenon. The purpose of this study was to profile sibling bullying by examining prevalence rates, the extent to which siblings perceive sibling bullying to be normative, and victim-perpetrator differences in perceptions of sibling bullying. Twenty-seven sibling pairs who wrote stories about personal experiences of sibling bullying and victimization completed questionnaires about these experiences and responded to their sibling partners' stories. Of the siblings surveyed, 78% reported being bullied by their sibling and 85% reported bullying their sibling during their childhood. This is far greater than published statistics on peer bullying. Not surprisingly, victims viewed sibling bullying more negatively than perpetrators. Sadly, there was a norm of acceptance of sibling bullying among most of the sibling pairs. Practical implications are discussed. PMID- 23348681 TI - EphA7 expression identifies a unique neuronal compartment in the rat striatum. AB - Prior studies have identified two anatomically and neurochemically distinct cellular compartments within the mammalian striatum, termed striosomes and matrix, which express MU-opioid receptors (MUOR) and EphA4, respectively. Here we identify and characterize an additional compartment in the rat striatum composed of neurons that express EphA7. In situ hybridization and immunohistochemical data indicate that neurons expressing EphA7 mRNA and protein are arranged in a banded "matrisome-like" pattern confined to the matrix in the dorsal striatum. Within the ventral striatum, EphA7-positive (+) neurons have a less organized mosaic pattern that partially overlaps areas expressing MUOR. Immunolabeling data demonstrate that EphA7+ striatofugal axons form distinct fascicles leaving the striatum. Within the globus pallidus, EphA7+ axons terminate primarily within ventromedial areas of the nucleus and along its striatal border. EphA7+ axons avoid regions containing dopamine neurons within the substantia nigra and preferentially innervate areas near the rostral and caudal margins of the nucleus. Within both nuclei, EphA7+ axons have similar but more restricted terminal fields than the entire population of EphA4+ matrix axons, indicating that EphA7+ axons comprise a subpopulation of matrix axons. Ligand binding data demonstrate that ephrin-A5 selectively binds areas of the striatum, globus pallidus, and substantia nigra containing EphA7+ neurons and axons, but not areas expressing only EphA4. Our findings demonstrate that EphA7 expression identifies a novel "matrisome" compartment within the matrix that binds ephrin-A5 and possesses unique axonal projections. Our findings also suggest that EphA7 and ephrin-A5 may participate in the formation of this matrisome subcompartment and its striatofugal projections. PMID- 23348682 TI - Assembly of three-dimensional networks based upon silver-ethynide complexes bearing pyridyl and carboxylate groups. AB - Two ligands with different geometries have been prepared to synthesize new silver ethynide complexes bearing pyridyl and carboxylate groups. Reactions of 5 ethynylnicotinic acid (H(2)L1) and 5-ethynylpicolinic acid (H(2)L2) with silver nitrate afforded [Ag(2)(L1).AgNO(3)](n) (1) and {[Ag(12)(L2)(6).12AgNO(3)].5H(2)O}(n) (2), respectively. Crystallographic studies revealed that in 1, the L1 ligands connect linear silver chains to form a 2D layer through silver-ethynide interactions and Ag-carboxylate coordination bonds, and subsequently the layers are further linked through Ag-N(pyridyl) coordination bonds to generate a 3D network; however in 2, the L2 ligand interacts with Ag(8) units through Ag-N, Ag-O coordination bonds, silver-ethynide interactions and pi pi stacking directly to assemble a 3D network. In the solid state, both complexes are luminescent at room temperature, assigned as the intraligand n-pi* and pi-pi* transitions. PMID- 23348683 TI - Manipulation of bacteriophages with dielectrophoresis on carbon nanofiber nanoelectrode arrays. AB - This work describes efficient manipulation of bacteriophage virus particles using a nanostructured DEP device. The nonuniform electric field for DEP is created by utilizing a nanoelectrode array (NEA) made of vertically aligned carbon nanofibers versus a macroscopic indium tin oxide electrode in a "points-and-lid" configuration integrated in a microfluidic channel. The capture of the virus particles has been systematically investigated versus the flow velocity, sinusoidal AC frequency, peak-to-peak voltage, and virus concentration. The DEP capture at all conditions is reversible and the captured virus particles are released immediately when the voltage is turned off. At the low virus concentration (8.9 * 10(4) pfu/mL), the DEP capture efficiency up to 60% can be obtained. The virus particles are individually captured at isolated nanoelectrode tips and accumulate linearly with time. Due to the comparable size, it is more effective to capture virus particles than larger bacterial cells with such NEA based DEP devices. This technique can be potentially utilized as a fast sample preparation module in a microfluidic chip to capture, separate, and concentrate viruses and other biological particles in small volumes of dilute solutions in a portable detection system for field applications. PMID- 23348684 TI - Breeding and Genetics Symposium: systems biology in animal breeding: Identifying relationships among markers, genes, and phenotypes. PMID- 23348685 TI - Effects of feeding dried distillers grains with supplemental starch on fecal shedding of Escherichia coli O157:H7 in experimentally inoculated steers. AB - Distillers grains (DG), a co-product of ethanol production used as protein and energy supplements in cattle diets, have been shown to increase fecal shedding of Escherichia coli O157:H7, a major foodborne pathogen. The reason for the positive association is not known. Because DG often replaces grain in the diet, decreased starch content and flow to the hindgut may create a favorable environment for E. coli O157:H7. Our objective was to determine whether the addition of starch to a corn DG-supplemented diet negates the effects of DG on fecal shedding of E. coli O157:H7. We conducted a study with 21 steers fed 1 of 3 diets: a corn grain-based basal diet (CON), basal diet supplemented with 25% corn dried DG (DDG), and basal diet supplemented with 25% DDG with corn starch (DDG+S) added at a level intended to increase starch concentration to that of the CON diet. Steers, housed individually in a biosafety level 2 animal facility, were randomly allocated to treatment diets and orally inoculated with a 5-strain mixture (10(9) cfu per steer) of nalidixic acid-resistant (Nal(R)) E. coli O157:H7. Fecal samples were collected for 5 wk, and on d 35, steers were euthanized and necropsied to collect gut content samples. Fecal or gut samples were cultured to determine prevalence and concentrations of Nal(R) E. coli O157:H7. Dietary starch concentrations, based on feed analysis, were 46.3% in the CON compared with 43.3 and 41.3% in the DDG and DDG+S diets, respectively. Steers fed DDG or DDG+S diets shed Nal(R) E. coli O157:H7 more often (P = 0.0027 and 0.0003, respectively) and at greater concentrations (1.9 or 2.0 cfu/g; P = 0.0025 and 0.0006) than those fed CON diet (1.4 cfu/g), but no difference was observed between DDG and DDG+S diets. Cumulative prevalence and concentrations of Nal(R) E. coli O157:H7 were greater in gut samples collected at necropsy in steers fed DDG and DDG+S diets compared with those fed CON diet, but no difference was observed between DDG and DDG+S diets. The lack of effect of starch addition to the DDG diet on fecal shedding of E. coli O157:H7 may be because either the decreased starch content in the DG supplemented diet is not a factor in the increased shedding of E. coli O157:H7 or inclusion of pure starch in the diet may not have achieved our intended goal to have starch flow into the hindgut similar to that of corn grain. The study confirms our previous finding of the positive association between feeding DG and fecal shedding of E. coli O157:H7. PMID- 23348686 TI - Body composition and amino acid concentrations of select birds and mammals consumed by cats in northern and central California. AB - The diet of the feral domestic cat consists of primarily birds and small mammals, but the nutritional composition is relatively unknown. Because of the increasing popularity of natural diets for cats and other wild captive carnivores, the purpose of this study was to describe the body composition and AA concentrations of select birds and small mammals in northern and central California: wild-caught mice (n = 7), Norway rats (n = 2), roof rats (n = 2), voles (n = 4), moles (n = 2), gophers (n = 3), and birds (n = 4). Body water, crude fat (CFa), CP, ash, and AA composition for each specimen were determined. Results are reported as mean +/ SD. All results are reported on a DM basis except body water (as-is basis) and AA (g/16 g N). Combined, carcasses had this mean composition: 67.35 +/- 3.19% water, 11.72 +/- 6.17% CFa, 62.19 +/- 7.28% CP, and 14.83 +/- 2.66% ash. Concentrations of Arg, Tau, Cys, and Met were 5.63 +/- 0.46, 0.92 +/- 0.33, 1.91 +/- 0.89, and 1.82 +/- 0.19 g/16 g N, respectively. Using NRC physiologic fuel values for CP, CFa, and carbohydrate by difference, the combined average energy content of the carcasses was 3,929 kcal/kg DM, but the fiber content was not determined. With the exception of mice and rats, little historical data exist regarding the body and AA composition of many of the species analyzed in this study. Wild-caught mice and rats were composed of less fat but more ash compared with previously reported data in their purpose-bred counterparts. The CP content of mice in this study was similar to previous reports in purpose-bred mice. The CP content of rats was similar or slightly greater compared with historical findings in purpose-bred rats. The N content of rats and AA concentrations on a per-N basis for both rats and mice were similar to previously published data on purpose-bred rodents. The discrepancies in nutrient composition, especially fat concentration, indicate that using purpose-bred animals to represent the diet of the feral domestic cat may not be valid in many instances. When consumed to meet energy needs, the nutrient content of the species reported in the present study exceed the NRC (2006) recommended allowances (RA) for total fat, CP, and essential AA for felines at all life stages. PMID- 23348687 TI - Foraging behavior of two cattle breeds, a whole-year study: I. Heat production, activity, and energy costs. AB - The foraging behavior and energy costs of activity of 19 large-frame Beefmaster * Simford (BS) cross mature cows and 14 small-frame Baladi (BA) mature cows was determined. Cows were allocated to the same paddock of a Mediterranean pasture and were monitored during 5 seasons throughout 2006 and 2007: spring (April 2006), summer (June 2006), autumn (September 2006), winter (February 2007), and early spring (March 2007). Cows were given poultry litter (25% CP, DM basis) as supplemental feed during autumn only. The cows were fitted for 3 to 4 d in each season with global positioning system (GPS) monitors, activity monitors attached to 1 of their hind legs, and heart rate (HR) monitors harnessed to their chests. Oxygen consumption per heart beat was determined for each cow during each season to enable conversion of the diurnal HR patterns to heat production (HP) units. All GPS data of cattle locations and activity and the HR and HP data were synchronized to produce simultaneous 5-min interval records; step length also was calculated for each record. These records provided summaries of partitioning among activities: lying down, standing, foraging, and walking without foraging as well as horizontal and vertical distances walked per day and number of steps taken per day. These attributes were analyzed using multiple regression models to relate these activities to HP and to estimate specific HP costs per unit of each activity. Accordingly, the daily energy costs of activity were calculated for the 2 cattle types in each season as the product of the specific activity and the number of units of each activity per day. The HP level of the large-frame BS cows was greater than that of the small-frame BA cows in winter and lower in spring (P < 0.001); however, the respective HP levels were much closer in summer and autumn, with BA cows having values greater by 3% than those of BS cows. The BA cows were more active than the BS cows during all seasons: they foraged for more hours per day (P < 0.001) and walked longer distances (P < 0.001). The mean specific costs of activity of BA cows were 20% less than those of BS cows (P < 0.001). The BA cows took longer steps during foraging and walking idle compared with BS cows despite their much smaller frame. The BA cows were more efficient in conditions of low herbage quality whereas metabolic rate of BS cows was greater in conditions of high herbage quality. PMID- 23348688 TI - [Incorporation monitoring of employees of a radioiodine therapy ward. Is incorporation monitoring required for routine?]. AB - Aim of the study was to determine the annual incorporation of staff on a radioiodine therapy ward and the resulting annual effective dose (aed). Following the German incorporation guideline (gig), incorporation monitoring is not necessary for potential aed below 0.5 mSv/a. For aed > 0.5 mSv/a adherence to the 1 mSv dose limit must be verified. For doses > 1 mSv/a incorporation has to be monitored by the authority. Furthermore, the (131)I incorporation factor from the gig should be verified. METHODS: To determine the actual work related incorporation, the (131)I activity concentration in urine samples (collection over 24 h) of 14 employees of different professions were examined over a period of 27 months. RESULTS: Measured activity concentrations were related to the individual time of exposure. A constant activity supply for at least three days was assumed. The mean annual effective doses were 2.4 . 10-1 mSv/a (nursing staff; n = 3), 5.6 . 10-2 mSv/a (cleaning staff; n = 2), 2.8 . 10-3 mSv/a (technical staff; n = 2) and 5.2 . 10-3 mSv/a (physicians; n = 7). All aed were below the dose limits of the gig. The calculated mean incorporation factors ranged from 3.0 . 10-8 for the nursing staff to 3.6 . 10-10 for the technical staff (cleaning staff: 7 . 10-9; physicians: 6.5 . 10-10) and were therefore well below the (131)I incorporation factor defined by the gig. CONCLUSIONS: To estimate the aed caused by incorporation of (131)I it has to be subdivided for the different requirements in the diverse fields of activity of the employees. Regarding those who spend most of their time nearby the patient an incorporation monitoring by the authority might be required. The (131)I incorporation factor from the guideline (10-6) can be reduced by a factor of 10. For (99m)Tc and (18)F an incorporation factor of 10-7 is accepted. PMID- 23348689 TI - New practical tools for the implementation and use of ultrafast 2D NMR experiments. AB - Ultrafast (UF) 2D NMR is a very promising methodology enabling the acquisition of 2D spectra in a single scan. In the last few years, the analytical performance of UF 2D NMR has been highly increased, consequently maximizing its range of applications. However, its implementation and use by non-specialists are far from being straightforward, because of the specific acquisition and processing procedures and parameters characterizing UF NMR. To make this methodology implementable and applicable by non-specialists, we developed a simple routine capable of translating conventional parameters (spectral widths and transmitter frequencies) into specific UF parameters (gradient and chirp pulse parameters). This macro was subsequently implemented in a Web page, which is available for external users. Although the algorithm was designed for two widely used 2D experiments, COSY and HSQC, it can easily be extended to any other pulse sequence. The robustness of this routine was verified successfully on a variety of small molecules. We believe that this tool will eliminate much of the technical difficulties related to UF 2D NMR and will make the technique accessible to a wider audience of organic and analytical chemists. PMID- 23348690 TI - TACC3 promotes epithelial-mesenchymal transition (EMT) through the activation of PI3K/Akt and ERK signaling pathways. AB - Transforming acidic coiled-coil protein 3 (TACC3) is a member of the TACC family, essential for mitotic spindle dynamics and centrosome integrity during mitosis. Mounting evidence suggests that deregulation of TACC3 is associated with various types of human cancer. However, the molecular mechanisms by which TACC3 contributes to the development of cancer remain largely unknown. Here, we propose a novel mechanism by which TACC3 regulates epithelial-mesenchymal transition (EMT). By modulating the expression of TACC3, we found that overexpression of TACC3 leads to changes in cell morphology, proliferation, transforming capability, migratory/invasive behavior as well as the expression of EMT-related markers. Moreover, phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated protein kinases (ERKs) signaling pathways are critical for TACC3 mediated EMT process. Notably, depletion of TACC3 is sufficient to suppress EMT phenotype. Collectively, our findings identify TACC3 as a driver of tumorigenesis as well as an inducer of oncogenic EMT and highlight its overexpression as a potential therapeutic target for preventing EMT-associated tumor progression and invasion. PMID- 23348691 TI - Brucine, an indole alkaloid from Strychnos nux-vomica attenuates VEGF-induced angiogenesis via inhibiting VEGFR2 signaling pathway in vitro and in vivo. AB - In this study, we investigated the mechanism of brucine in tumor angiogenesis. We found that brucine inhibits VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures in HUVECs in a dose dependent manner. Brucine suppresses VEGF- induced p-VEGFR2 kinase activity and inhibits neovascularization in vivo. Brucine inhibits the downstream protein kinases of VEGFR2, including Src, FAK, ERK, AKT and mTOR. And further downregulates levels of VEGF, NO, IL-6, IL-8, TNF-alpha and IFN-gamma in HUVECs. Taken together, our study suggests that brucine potently suppresses angiogenesis by targeting VEGFR2 activation and may be a viable drug candidate in anti angiogenesis and anti-cancer therapies. PMID- 23348692 TI - OT-404, multi-targeted anti-cancer agent affecting tumor proliferation, chemo resistance, and angiogenesis. AB - There is a need for a comprehensive anti-cancer strategy that simultaneously targets abnormal proliferation, angiogenesis rates, and development of chemotherapy resistance. We have identified a small molecule, OT-404, that effectively inhibited proliferation and angiogenesis of either chemo-sensitive or -resistant human cancer cells and enhanced cancer cell sensitivity to different chemotherapy. In vivo studies of human tumor xenografts in nude mice showed that OT-404, used alone or encapsulated into nanoparticles, inhibited the growth of doxorubicin-resistant breast cancer MCF-7 by more than 80%, and by 95% when combined with doxorubicin. These findings provide evidence for the potential of OT-404 in cancer management. PMID- 23348693 TI - Comprehensive gene expression profiles of NK cell neoplasms identify vorinostat as an effective drug candidate. AB - NK cell neoplasms are lymphoid malignancies with an aggressive clinical course. In the present study, we analyzed gene expression profiling of NK cell neoplasms and attempted to identify important molecular pathways and new effective drugs. Pathway analysis of gene expression profiles suggested the important roles of the JAK-STAT pathway, NF-kappaB pathway or Wnt pathways in NK cell neoplasms. Notably, western blot analysis revealed that STAT3 was expressed and phosphorylated at a higher level in NK cell lines than in normal NK cells or other cell lines. These findings indicate the occurrence of JAK-STAT activation in NK cell neoplasms. Connectivity Map (CMAP) analysis of gene expression profiles identified candidate drugs against NK cell neoplasms. Among the drugs suggested by CMAP analysis, we focused on puromycin, phenoxybenzamine, LY294002, wortmannin, vorinostat and trichostatin A because they exhibited high enrichment scores. We added these drugs to NK cell lines and other cell lines. Among the drugs, vorinostat suppressed NK cell line proliferation at a significantly lower concentration compared to other cell lines. Suppression of the JAK-STAT pathway appeared to contribute to this effect. Vorinostat may be a good candidate for use in the therapy against NK cell neoplasms. PMID- 23348695 TI - Combination chemotherapy of serine protease inhibitor nafamostat mesilate with oxaliplatin targeting NF-kappaB activation for pancreatic cancer. AB - In this study, we assessed if nafamostat mesilate may enhance anti-tumor effects of oxaliplatin on Panc-1 cells and pancreatic cancer mouse model. In combination treatment with nafamostat mesilate and oxaliplatin, NF-kappaB activation was inhibited by suppressing IkappaBalpha phosphorylation, and caspase-8-mediated apoptosis was more prominent than that treated with oxaliplatin alone, both in vitro and in vivo. Nafamostat mesilate reduced proliferation rate of Panc-1 cells as compared with oxaliplatin alone in vitro and enhanced oxaliplatin-induced tumor growth inhibition in vivo. Combination chemotherapy using nafamostat mesilate and oxaliplatin induces synergistic cytotoxicity in pancreatic cancer and could be a novel strategy for treatment. PMID- 23348696 TI - Entrapped doxorubicin nanoparticles for the treatment of metastatic anoikis resistant cancer cells. AB - Metastasized and chemoresistant secondary breast cancer treatment commonly shows very low efficacy. A new efficient treatment method is required to overcome the limitation against the secondary breast cancer. In this study, anoikis-resistant breast cancer cells, MDA-MB-231 and MCF-7 were developed as models of chemoresistant and metastatic breast cancer. Doxorubicin encapsulating human serum albumin nanoparticles (HSA+DOX NPs) were fabricated to confirm the benefits of nanoparticles at the treatment of anoikis-resistant breast cancer cells. The side population (SP) fraction in the anoikis-resistant cancer cells was higher than the parental cells. HSA+DOX NPs were more cytotoxic to anoikis-resistant cancer cells than free doxorubicin. The confocal microscope images demonstrated HSA+DOX NPs to deliver more doxorubicin into cells compared to the free doxorubicin by bypassing the drug efflux pump systems of anoikis-resistant cancer cells. In this study, a nanomedicine-based drug delivery carrier shows a potential in treating a metastasized and chemoresistant breast cancer. PMID- 23348694 TI - KRC-408, a novel c-Met inhibitor, suppresses cell proliferation and angiogenesis of gastric cancer. AB - Among many cancer therapeutic targets, c-Met receptor tyrosine kinase has recently given particular attention. This kinase and its ligand, hepatocyte growth factor (HGF), play a central role in cell proliferation and the survival of several human cancers. Thus, we developed KRC-408 as a novel c-Met inhibitor and investigated its anti-cancer effects on human gastric cancer. KRC-408 inhibited the phosphorylation of c-Met and its constitutive downstream effectors such as phosphatidylinositol 3-kinase (PI3K), Akt, Mek, and Erk. This compound was found to exert anti-cancer effects stronger than those of 5-fluorouracil (5 FU) on gastric cancer cells, especially cell lines that overexpressed c-Met. Interestingly, cytotoxicity of KRC-408 was lower than that of 5-FU in normal gastric cells. Apoptosis induced by KRC-408 was accompanied by increased levels of cleaved caspase-3 and PARP as well as DNA condensation and fragmentation. Flow cytometry analysis showed an accumulation of gastric cancer cells in the G2/M phase with concomitant loss of cells in the S phase following treatment with this drug. In the angiogenesis studies, KRC-408 inhibited tube formation and migration of human umbilical vein endothelial cells (HUVECs), and suppressed microvessel sprouting from rat aortic rings ex vivo along with blood vessel formation in a Matrigel plug assay in mice. Results of an in vivo mouse xenograft experiment showed that the administration of KRC-408 significantly delayed tumor growth in a dose-dependent manner, and suppressed Akt and Erk phosphorylation as well CD34 expression in tumor tissues. These findings indicate that KCR-408 may exert anti tumor effects by directly affecting tumor cell growth or survival via the c-Met receptor tyrosine kinase pathway. We therefore suggest that KRC-408 is a novel therapeutic candidate effective against gastric cancers that overexpress c-Met. PMID- 23348697 TI - Nodal promotes aggressive phenotype via Snail-mediated epithelial-mesenchymal transition in murine melanoma. AB - Nodal, an important embryonic morphogen, has been reported to function in tumorigenesis. Here we report for the first time that Nodal promotes malignancy by inducing epithelial-mesenchymal transition (EMT) in B16 murine melanoma. These cells displayed increased migration and invasion abilities upon treating with Nodal, accompanying with typical phenotype changes of EMT. In contrast, Nodal knockdown or blocking Nodal signaling using a specific antagonist SB431542 repressed the EMT phenotype as well as reduced cell motility and invasiveness. Treatment with Nodal also induced expression of transcription factor Snail. Snail knockdown abolished the Nodal-induced EMT in B16 cells. We further show that Snail expression is mediated by the Nodal-regulated AKT/GSK-3beta signaling. Taken together, these results revealed that Nodal promotes the aggressive phenotype of B16 murine melanoma cells by inducing EMT via up-regulation of Snail. This study provides a better understanding of Nodal function in melanoma, and suggests a potential novel target for clinical therapeutic research. PMID- 23348698 TI - miR-206 inhibits gastric cancer proliferation in part by repressing cyclinD2. AB - In this study, we detected miR-206 expression in gastric cancer (GC) and further investigated its effects on GC cell growth in vitro and in vivo. miR-206 expression was found to be significantly decreased in 30 GC samples and GC cell lines by real time-PCR. Restoration of miR-206 reduced cell growth and colony forming ability in GC cells with G0/G1 cell cycle arrest. Further studies demonstrated that miR-206 could suppress GC cells proliferation at least partially through targeting the cyclinD2 (CCND2). Therefore, we provided evidence that miR-206 was a potential tumor suppressor and may be used as a therapeutic target for gastric cancer. PMID- 23348699 TI - Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer. AB - Breast cancer development largely depends upon the essential contributions from the tumor microenvironment, where several inflammatory cell populations (e.g. macrophages) orchestrate breast cancer development. The majority of tumor associated macrophages (TAMs) exhibit alternatively activated M2 properties, produce abundant anti-inflammatory factors and facilitate tumor development. Clinical evidences compellingly indicate the association between high TAMs influx and poor prognosis in patients with breast cancers. The pan-macrophage marker CD68 is now generally utilized to identify TAMs in diagnostic biopsy samples, and some other TAM-related biomarkers are also utilized in prognosis prediction, including CD163, vascular endothelial growth factor (VEGF), hypoxia-inducible factors (HIFs), proliferating cellular nuclear antigen (PCNA), ferritin light chain (FTL) and C-C motif chemokine ligand 18 (CCL18). In this review, we highlight the recent progress made in understanding the relationship between TAMs and clinicopathological parameters in human breast cancer and address the potential value of TAMs as diagnostic and prognostic biomarkers. PMID- 23348701 TI - Genetic susceptibility to multiple primary neoplasms in the upper aero-digestive tract: genotype score and phenotype correlation. AB - Early detection and treatment of head and neck cancer has led to increased patient survival. However such patients are at a high risk for multiple primary neoplasm(s) (MPN). In order to study the genetic susceptibility to MPN, 22 candidate SNPs were genotyped based on which a distinctive Genotype Score was created using Additive, Dominant and Recessive models. Using lymphoblastoid cell lines (LCLs) generated from these individuals, the Genotype Score was correlated with carcinogen sensitivity in vitro. LCLs from MPN patients exhibited significantly higher Genotype Score and showed resistance to genotoxic agents compared to matched controls. This report demonstrates quantitative assessment of cumulative effect of gene polymorphisms and its correlation with carcinogen sensitivity for predicting susceptibility to MPN. PMID- 23348700 TI - A novel antitumor activity of deguelin targeting the insulin-like growth factor (IGF) receptor pathway via up-regulation of IGF-binding protein-3 expression in breast cancer. AB - In this study, we investigated the antitumor effects of deguelin in several human breast cancer cells in vitro and in vivo. Deguelin inhibited cell viability and the anchorage-dependent and anchorage-independent colony formation of triple negative (MDA-MB-231 and MDA-MB-468) and triple-positive (MCF-7) breast cancer cells, and it significantly reduced the growth of MCF-7 cell xenograft tumors. The induction of apoptosis, inhibition of insulin-like growth factor-1 receptor (IGF-1R) signaling activation, and up-regulation of IGF-binding protein-3 (IGFBP 3) expression may be associated with deguelin-mediated antitumor effects. Our findings suggest a potential therapeutic use for deguelin in patients with triple negative breast cancer and for those with breast cancers who are sensitive to endocrine- and HER2-targeted therapies. PMID- 23348702 TI - Pharmacological inhibition of carbonic anhydrase XII interferes with cell proliferation and induces cell apoptosis in T-cell lymphomas. AB - The membrane-bound carbonic anhydrase isoforms CAIX and CAXII, underpin a pH regulating system that enables hypoxic tumor cell survival. Here, we observed for the first time an upregulation of CAXII in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LL) cells. First we showed that CAXII is overexpressed in thymocytes from tPTEN-/- mice suffering of T lymphoma and that its pharmacological inhibition decreased cell proliferation and induced apoptosis. The same results were observed with the SupT1 human T cell lymphoma line. In addition we observed an upregulation of CAXII in human T-ALL samples supporting the case that CAXII may represent a new therapeutic target for T-ALL/LL. PMID- 23348703 TI - PRDM1 is directly targeted by miR-30a-5p and modulates the Wnt/beta-catenin pathway in a Dkk1-dependent manner during glioma growth. AB - The transcriptional regulator PRDM1 controls cell-fate decisions and has been implicated in human tumorigenesis as a tumor suppressor. However, its pathological role in glioma remains elusive. In this study, we showed that PRDM1 protein levels were inversely correlated with the pathological grade of gliomas and were predictive of patient survival in a retrospective analysis. Restored expression of PRDM1 inhibited proliferation and suppressed invasion by glioma cells. Mechanistic investigation revealed that PRDM1 attenuated glioma malignancy by negatively modulating Wnt/beta-catenin signaling and this modulation was dependent on the Wnt inhibitor Dkk1. Using bioinformatics and biological approaches, we found that PRDM1 was a direct target of miR-30a-5p, and PRDM1 dysfunction was attributable to miR-30a-5p-mediated repression. Our results provide evidence that PRDM1 deficiency contributes to the phenotype maintenance and pathogenesis of gliomas. PMID- 23348705 TI - A diacetylene-containing wedge-shaped compound: synthesis, morphology, and photopolymerization. AB - A novel wedge-shaped compound containing two diacetylene tails, namely, methyl 3,5-bis(trideca-2,4-diyn-1yloxyl)benzoate (DDABM), was synthesized. As shown by UV/Vis spectroscopy this compound can be polymerized under UV irradiation. The crystalline structure of DDABM was investigated by grazing-incidence wide-angle X ray diffraction on oriented crystalline films deposited on PTFE-rubbed silicon wafer substrates. Furthermore, the spherulites formed in thicker films were analyzed by wide-angle X-ray diffraction. A molecular packing model of DDABM based on the X-ray diffraction data is proposed. The diacetylene units are oriented along a defined lattice direction with a reticular distance of 4.85 A, which fulfills the requirements for topochemical polymerization. It was observed that UV polymerization does not affect the phase behavior of the compound, but mainly alters its optical properties. PMID- 23348706 TI - SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3beta/beta catenin signaling. AB - Sirtuin 1 (SIRT1) has been implicated in telomere maintenance and the growth of hepatocellular carcinoma (HCC). Nevertheless, the role of other sirtuins in the pathogenesis of HCC remains elusive. We found that sirtuin 2 (SIRT2), another member of the sirtuin family, also contributes to cell motility and invasiveness of HCC. SIRT2 is up-regulated in HCC cell lines and in a subset of human HCC tissues (23/45). Up-regulations of SIRT2 in primary HCC tumors were significantly correlated with the presence of microscopic vascular invasion (P = 0.001), a more advanced tumor stage (P = 0.004), and shorter overall survival (P = 0.0499). Functional studies by short hairpin RNA-mediated suppression of SIRT2 expression in HCC cell lines revealed significant inhibition of motility and invasiveness. Depletion of SIRT2 also led to the regression of epithelial-mesenchymal transition (EMT) phenotypes, whereas the ectopic expression of SIRT2 in the immortalized hepatocyte cell line L02 promoted cell motility and invasiveness. Mechanistic studies revealed that SIRT2 regulates the deacetylation and activation of protein kinase B, which subsequently impinges on the glycogen synthase kinase-3beta/beta-catenin signaling pathway to regulate EMT. CONCLUSIONS: Our findings have uncovered a novel role for SIRT2 in HCC metastasis, and provide a rationale to explore the use of sirtuin inhibitors in HCC therapy. (HEPATOLOGY 2013;). PMID- 23348707 TI - Interleukin-1 receptor antagonist improves normoglycemia and insulin sensitivity in diabetic Goto-Kakizaki-rats. AB - Type 2 diabetes mellitus has been considered as an auto-inflammatory syndrome. Interleukin-1 receptor antagonist (IL-1Ra) has attained considerable attention due to its broad spectrum anti-inflammatory therapeutic effects against various auto-immune diseases. The purpose of our study was to investigate its therapeutic effects of IL-1Ra on none-obese diabetic Goto-Kakizaki (GK) rats. We administered IL-1Ra subcutaneously for one month into GK rats. Insulin sensitivity and beta cell function was calculated by homeostatic model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) models. IL-1Ra decreased the onset of hyperglycemia and did not impact the body weight and/or food intake. Insulin tolerance test (ITT) and intraperitoneal glucose tolerance test (IPGTT) results showed that IL-1Ra improved insulin sensitivity and glucose tolerance. The results of HOMA and QUICKI models revealed that IL-1Ra improved insulin sensitivity and beta-cell function. Moreover, significant reduction of pro insulin/insulin ratio and lipid profiles also exhibited significant therapeutic effects of IL-1Ra. Immunohistochemical analysis showed minimal macrophage infiltration in pancreatic islets demonstrating decreased intra-islet inflammation in IL-1Ra treated GK rats. The results of our present study revealed that IL-1Ra has broad spectrum therapeutic potentials but due to its short biological half-life (6-8h) high doses with frequent dosing intervals are required. Therefore, there is a need for the development of such dosage form that may prolong its half-life via extended release. PMID- 23348708 TI - p38 Mitogen-activated protein kinase and extracellular signal-regulated kinase signaling pathways are not essential regulators of formyl peptide-stimulated p47(phox) activation in neutrophils. AB - Three structurally unrelated p38 mitogen-activated protein kinase (MAPK) inhibitors, (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole (SB203580), 1-5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl ethoxy)naphthalen-1-yl] urea (BIRB 796) and 5-(2,6-dichlorophenyl)-2-[2,4 difluorophenyl]thio]-6H-pyrimido[1,6-b]pyridazin-6-one (VX 745) showed approximately 40% inhibition of formyl-Met-Leu-Phe (fMLP)-stimulated neutrophil superoxide anion (O2(*-)) generation at concentrations that greatly diminished p38 MAPK activity. However, a significant inhibition of p47(phox) activation occurred at concentrations much higher than the corresponding IC50 values of these inhibitors in blocking p38 MAPK activity. 4-Ethyl-2(p-methoxyphenyl)-5-(4' pyridyl)-IH-imidazole (SB202474), an inactive analogue of SB203580, at a concentration (30MUM) which significantly attenuated p38 MAPK activity, had no effect on p47(phox) activation, whereas it inhibited O2(*-) generation with an IC50 value of approximately 16MUM. Moreover, both SB203580 and BIRB 796 had no effect on protein kinase B (PKB)/Akt Ser473 phosphorylation and S100A9 protein membrane translocation at concentrations that effectively blocked p38 MAPK activity. Pretreatment of cells with two structurally unrelated MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitors, 2-(2 amino-3-methoxy-phenyl)-chromen-4-one (PD 98059) and 1,4-diamino-2,3-dicyano-1,4 bis(2-aminophenylthio)butadiene (U0126), at concentrations that effectively blocked MEK activity, attenuated p47(phox) phosphorylation but did not affect the recruitment of p47(phox) to p22(phox) or O2(*-) generation. Both p47(phox) activation and O2(*-) generation were attenuated by a protein kinase C (PKC) inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide (GF 109203X) in the concentration range that effectively blocked PKC activity. Taken together, these results suggest that the ERK-mediated Ser phosphorylation of p47(phox) is not implicated in the assembly of NADPH oxidase or O2(*-) generation, and that O2(*-) generation is partly attributable to p38 MAPK signaling through mechanisms other than p47(phox) activation, Akt activation and S100A9 membrane recruitment in fMLP-stimulated neutrophils. PMID- 23348709 TI - Protective effects of coenzyme Q10 against angiotensin II-induced oxidative stress in human umbilical vein endothelial cells. AB - Angiotensin II is the major effector in the renin-angiotensin system, and angiotensin II-induced oxidative stress and endothelial dysfunction are profoundly implicated in the pathogenesis of hypertension and cardiovascular disease. In the present study, we investigated the effect of an antioxidant reagent, coenzyme Q10, on angiotensin II-induced oxidative stress in human umbilical vein endothelial cells (HUVEC) to assess its potential usefulness for antioxidant therapy. Treatment of HUVEC with coenzyme Q10 (1-10MUM) increased its intracellular levels in a concentration-dependent manner. Coenzyme Q10 (10MUM) prevented the actions of angiotensin II (100nM): overproduction of reactive oxygen species, increases in expression of p22(phox) and Nox2 subunits of NADPH oxidase, and inhibition of insulin-induced nitric oxide production. In addition, coenzyme Q10 prevented angiotensin II-induced upregulation of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in HUVEC, and inhibited their adhesion to U937 monocytic cells. Moreover, treatment of HUVEC with coenzyme Q10 effectively ameliorated angiotensin II-induced increases in expression of Nox2 subunit of NADPH oxidase, ICAM-1, and VCAM-1. These results provide the first in vitro evidence that coenzyme Q10 is an efficient antioxidant reagent to improve angiotensin II-induced oxidative stress and endothelial dysfunction, possibly relevant to the causes of cardiovascular disease. PMID- 23348710 TI - Hypertrophic cardiomyopathy: do sudden death prevention strategies in children differ between Europe and North America? AB - PURPOSE OF REVIEW: Hypertrophic cardiomyopathy (HCM) is the second most common childhood heart muscle disease and is the most common cause of unexpected sudden cardiac death in young people. The purpose of this review is to describe the risk of sudden death, to assess which of the criteria conventionally used as indication for a primary prevention defibrillator placement in adults are applicable in children with HCM, and to review differences in management between Europe and North America. RECENT FINDINGS: There is no uniform 'annual mortality rate' in childhood, and the risk of sudden death is at its highest level between 8 and 16 years. There are no significant differences between sudden death fatality rates in childhood HCM in Europe, North America and Australia when patients presenting with sudden death as the first sign of disease are excluded. The criteria for primary prevention defibrillator placement in adults with HCM are, with the exception of previous cardiac arrest and ventricular tachycardia on Holter monitoring, not predictive of risk in childhood HCM, and further research is required to establish better criteria for primary prevention in children. SUMMARY: Most children diagnosed with HCM have a favorable prognosis with life style modification with additional medical therapy, surgical therapy, and/or defibrillator placement in selected patients. The challenges inherent in identification of the patients most likely to benefit from invasive therapies and avoidance of these therapies in those least likely to benefit (and most likely to experience harm) exist on both sides of the Atlantic. PMID- 23348711 TI - A counterstatement to a counterstatement--reply to the letter to the editor "Familiarity, objectivity--and misconduct. Counterstatement to Shaw: Swiss Report". PMID- 23348712 TI - A scoring algorithm for predicting the presence of adult asthma: a prospective derivation study. AB - BACKGROUND: To predict the presence of asthma in adult patients with respiratory symptoms, we developed a scoring algorithm using clinical parameters. METHODS: We prospectively analysed 566 adult outpatients who visited Kinki University Hospital for the first time with complaints of nonspecific respiratory symptoms. Asthma was comprehensively diagnosed by specialists using symptoms, signs, and objective tools including bronchodilator reversibility and/or the assessment of bronchial hyperresponsiveness (BHR). Multiple logistic regression analysis was performed to categorise patients and determine the accuracy of diagnosing asthma. RESULTS: A scoring algorithm using the symptom-sign score was developed, based on diurnal variation of symptoms (1 point), recurrent episodes (2 points), medical history of allergic diseases (1 point), and wheeze sound (2 points). A score of >3 had 35% sensitivity and 97% specificity for discriminating between patients with and without asthma and assigned a high probability of having asthma (accuracy 90%). A score of 1 or 2 points assigned intermediate probability (accuracy 68%). After providing additional data of forced expiratory volume in 1 second/forced vital capacity (FEV(1)/FVC) ratio <0.7, the post-test probability of having asthma was increased to 93%. A score of 0 points assigned low probability (accuracy 31%). After providing additional data of positive reversibility, the post-test probability of having asthma was increased to 88%. CONCLUSIONS: This pragmatic diagnostic algorithm is useful for predicting the presence of adult asthma and for determining the appropriate time for consultation with a pulmonologist. PMID- 23348713 TI - Functional mannose-binding lectin haplotype variants are associated with Alzheimer's disease. AB - Mannan-Binding lectin (MBL) is a serum lectin and an important constituent of the innate immune system. Processes linked to the innate immune response have previously been implicated in Alzheimer's disease (AD). MBL is associated with blood vessels in the brain and AD patients demonstrate lower MBL levels in the cerebrospinal fluid compared to controls. We investigated six single nucleotide polymorphisms, linked to MBL deficiency, in the corresponding MBL2 gene in AD patients and controls. Two MBL2 haplotypes, LXP and LYQ, were significantly associated with AD risk (OR = 1.6, p = 0.01 and OR = 1.5, p = 0.02, respectively). The present study is the first investigating MBL2 genotypes and haplotypes in relation to AD. Our findings support that the MBL2 gene impact the disease risk. PMID- 23348714 TI - Dielectrophoresis: applications and future outlook in point of care. AB - Dielectrophoresis (DEP) is a label free, noninvasive, stand alone, rapid, and sensitive particle manipulation and characterization technique. Improvements in micro-electro-mechanical systems technology have enabled the biomedical applications of DEP over the past decades. By this way, integration of DEP into lab-on-a-chip systems has become achievable, creating a potential tool for point of-care (POC) systems. DEP can be utilized in many different POC applications including early detection and prognosis of various cancer types, diagnosis of infectious diseases, blood cell analysis, and stem cell therapy. However, there are still some challenges to be resolved to have DEP-based devices available in POC market. Today, researchers have focused on these challenges to have this powerful theory as a solution for many POC applications. Here, DEP theory, cell modeling, and most common device structures are introduced briefly. Next, POC applications of DEP theory, such as cell (blood, cancer, stem, and fetal) and microorganism separation, manipulation, and enrichment for diagnosis and prognosis, are explained. Integration of DEP with other detection techniques to have more sensitive systems is summarized. Finally, future outlook for DEP-based systems are discussed with some challenges, which are currently preventing these systems to be a common tool for POC applications, and possible solutions. PMID- 23348715 TI - Expression of the ghrelin receptor gene in neurons of the medulla oblongata of the rat. AB - There is ambiguity concerning the distribution of neurons that express the ghrelin receptor (GHSR) in the medulla oblongata. In the current study we used a sensitive nonradioactive method to investigate GHSR mRNA distribution by in situ hybridization. Strong expression of the GHSR gene was confirmed in neurons of the facial nucleus (FacN, 7), the dorsal vagal complex (DVC), and the semicompact (but not compact) nucleus ambiguus (AmbSC and AmbC). In addition, expression of GHSR was found in other regions, where it had not been described before. GHSR positive neurons were observed in the gustatory rostral nucleus tractus solitarius and in areas involved in vestibulo-ocular processing (such as the medial vestibular nucleus and the nucleus abducens). GHSR expression was also noted in ventral areas associated with cardiorespiratory control, including the gigantocellular reticular nucleus, the lateral paragigantocellular nucleus, the rostral and caudal ventrolateral medulla, the (pre)-Botzinger complex, and the rostral and caudal ventrolateral respiratory group. However, GHSR-positive neurons in ventrolateral areas did not express markers for cardiovascular presympathetic vasomotor neurons, respiratory propriobulbar rhythmogenic neurons, or sensory interneurons. GHSR-positive cells were intermingled with catecholamine neurons in the dorsal vagal complex but these populations did not overlap. Thus, the ghrelin receptor occurs in the medulla oblongata in 1) second-order sensory neurons processing gustatory, vestibulo-ocular, and visceral sensation; 2) cholinergic somatomotor neurons of the FacN and autonomic preganglionic neurons of the DMNX and AmbSC; 3) cardiovascular neurons in the DVC, Gi, and LPGi; 4) neurons of as yet unknown function in the ventrolateral medulla. PMID- 23348716 TI - Aggregates of a triphenylene based chemosensing ensemble for sensitive detection of cyanide ions in an aqueous medium. AB - Nanoaggregates of a supramolecular ensemble of triphenylene derivative 3 and Cu(2+) ions exhibit 'turn-on' response towards CN(-) ions in an aqueous medium and can detect the trace amount of inorganic cyanide ions (NaCN) in tap water and blood serum milieu. PMID- 23348717 TI - Essential role of Ubr11, but not Ubr1, as an N-end rule ubiquitin ligase in Schizosaccharomyces pombe. AB - The N-end rule pathway degrades proteins bearing a destabilization-inducing amino acid at the N-terminus. In this proteolytic system, Ubr ubiquitin ligases recognize and ubiquitylate substrates intended for degradation. Schizosaccharomyces pombe has two similar Ubr proteins, Ubr1 and Ubr11. Both proteins have unique roles in various cellular processes, although the ubr1? strain shows more severe defects. However, their involvement in the N-end rule pathway is unclear, and even the N-end rule pathway-dependent proteolytic activity has not been demonstrated in Sz. pombe. Here, we show that: (a) Sz. pombe has the N-end rule pathway in which only Ubr11, but not Ubr1, is responsible; and (b) the C-terminal fragment of the meiotic cohesin Rec8 (denoted as Rec8c) generated by separase-mediated cleavage is an endogenous substrate of the N-end rule pathway. Forced overexpression of stable Rec8c was deleterious in mitosis and caused a loss of the mini-chromosome. In unperturbed mitosis without overexpression, the rate of mini-chromosome loss was five-fold higher in the ubr11? strain. Since Rec8 is normally produced in meiosis, we examined whether meiosis and sporulation were affected in the ubr11? strain. In unperturbed meiosis, chromosome segregation occurred almost normally and viable spores were produced in the ubr11? cells, irrespective of the presence of undegraded endogenous Rec8c peptides. PMID- 23348718 TI - From "magic bullets" to specific cancer immunotherapy. AB - The immune system is able to specifically target antigen-expressing cancer cells. The promise of immunotherapy was to eliminate cancer cells without harming normal tissue and, therefore, with no or very few side effects. Immunotherapy approaches have, for several decades, been tested against several tumours, most often against malignant melanoma. However, although detectable immune responses have regularly been induced, the clinical outcome has often been disappointing. The development of molecular methods and an improved understanding of tumour immunosurveillance led to novel immunotherapy approaches in the last few years. First randomised phase III trials proved that immunotherapy can prolong survival of patients with metastatic melanoma or prostate cancer. The development in the field is very rapid and various molecules (mainly monoclonal antibodies) that activate the immune system are currently being tested in clinical trials and will possibly change our treatment of cancer. The ultimate goal of any cancer therapy and also immunotherapy is to cure cancer. However, this depends on the elimination of the disease originating cancer stem cells. Unfortunately, cancer stem cells seem resistant to most available treatment options. Recent developments in immunotherapy may allow targeting these cancer stem cells specifically in the future. In this review, we summarise the current state of immunotherapy in clinical routine and the expected developments in the near future. PMID- 23348719 TI - Influence of PET reconstruction parameters on the TrueX algorithm. A combined phantom and patient study. AB - With the increasing use of functional imaging in modern radiotherapy (RT) and the envisaged automated integration of PET into target definition, the need for reliable quantification of PET is growing. Reconstruction algorithms in new PET scanners employ point-spread-function (PSF) based resolution recovery, however, their impact on PET quantification still requires thorough investigation. PATIENTS, MATERIAL, METHODS: Measurements were performed on a Siemens PET/CT using an IEC phantom filled with varying activity. Data were reconstructed using the OSEM (Gauss filter) and the PSF TrueX (Gauss and Allpass filter) algorithm with all available products of iterations (i) and subsets (ss). The recovery coeffcient (RC) and threshold defining the real sphere volume were determined for all settings and compared to the clinical standard (4i21ss). PET acquisitions of eight lung patients were reconstructed using all algorithms with 4i21ss. Volume size and tracer uptake were determined with different segmentation methods. RESULTS: The threshold for the TrueX was lower (up to 40%) than for the OSEM. The RC for the different algorithms and filters varied. TrueX was more sensitive to permutations of i and ss and only the RC of the OSEM stabilised with increasing number. For patient scans the difference of the volume and activity between TrueX and OSEM could be reduced by applying an adapted threshold and activity correction. CONCLUSION: The TrueX algorithm results in excellent diagnostic image quality, however, guidelines for native algorithms have to be extended for PSF based reconstruction methods. For appropriate tumour delineation, for the TrueX a lower threshold than the 42% recommended for the OSEM is necessary. These filter dependent thresholds have to be verified for different scanners prior to using them in multicenter trials. PMID- 23348720 TI - Deciduous vegetation (Betula glandulosa) as a biomonitor of airborne PCB contamination from a local source in the Arctic. AB - Concentrations of polychlorinated biphenyls (PCBs) were measured in the new-year growth of dwarf birch (Betula glandulosa) before (2001-2002), during (2003-2004), and for six years after (2005-2010) the screening and containerization of PCB contaminated soils (>50 MUg/g PCBs) at a remote Arctic radar site. During the remediation activities, ambient air PCB concentrations were measured using active air samplers for comparison to the passive samplers (dwarf birch). PCB concentrations measured by the active samplers reached a maximum of 0.037 MUg/m(3) which was below the project criteria of 0.15 MUg/m(3) indicating minimal source emissions. During the same time period, PCB concentrations in the dwarf birch (passive samplers) showed significant increases of 2-14 fold compared to the baseline data from previous years. The birch data also showed significant changes between monitoring events within the 2003 and 2004 sampling seasons (June to September) and decreases when ambient air concentrations were low, indicating the sensitivity of new-year growth to reflect net accumulation and ambient conditions at a temporal scale of approximately two weeks. The dwarf birch PCB concentrations remained elevated compared to baseline levels for two years after the remediation was completed. In the third year following remediation, concentrations decreased to below baseline levels reflecting the overall remediation and source removal at the site. Spatial variations observed in dwarf birch PCB concentrations are likely due to the influence of wind direction on contaminant dispersal and deposition. PMID- 23348721 TI - Evaluation of growth, biochemical and bioaccumulation parameters in Pelophylax perezi tadpoles, following an in-situ acute exposure to three different effluent ponds from a uranium mine. AB - Mining activities invariably produce metal contaminated effluents. Depending on factors such as pH and metal concentration the toxicity of the effluent may vary. To assess the effects of three characteristically different effluent ponds from a deactivated uranium mine, with toxicologically relevant data, an in situ exposure with Pelophylax perezi tadpoles, was conducted. Tadpoles were exposed to the three effluent ponds, ranked by increasing order of metals concentrations (REF, M1, M2). Survival, growth, metal accumulation, antioxidant enzymes (catalase, glutathione peroxidase and glutathione reductase) and lipid peroxidation (LPO) were determined in tadpoles. As well, physical and chemical variables of the effluents were measured. Death percentage in the effluents was 3.17 (REF), 9.84 (M1) and 42.86% (M2) and was not coincident with metal accumulation which was highest in tadpoles exposed to M1, while metal contents in M2 tadpoles were quite similar to those recorded in REF tadpoles. However, high mortality in M2 was attributed to the extremely low pH (~3.77). From the three effluents M2 tadpoles had the lowest growth and the antioxidant enzymatic activity was only affected in the case glutathione peroxidase (GPx) with significantly higher activity in M1, being in accordance with the highest accumulation of metals. LPO, usually associated with metal accumulation, had the following pattern M1>REF>M2. Overall, effluent toxicity in tadpoles exposed to M2 effluent seems to be primarily an effect of pH while in M1 toxicity is mainly owed to high metal concentrations. The effluent acidity seems to reduce metal accumulation probably due to damage in the integument, affecting ion uptake. The results obtained bring a better understanding of the toxicological processes that local P. perezi population is subjected to, mainly in the early life stages. Furthermore this study highlights the influence of pH in the toxicity of metal rich effluents. PMID- 23348722 TI - Prognostic significance of von willebrand factor in cirrhosis: a possible mechanism. PMID- 23348723 TI - Prediction of mutant mRNA splice isoforms by information theory-based exon definition. AB - Mutations that affect mRNA splicing often produce multiple mRNA isoforms, resulting in complex molecular phenotypes. Definition of an exon and its inclusion in mature mRNA relies on joint recognition of both acceptor and donor splice sites. This study predicts cryptic and exon-skipping isoforms in mRNA produced by splicing mutations from the combined information contents (R(i), which measures binding-site strength, in bits) and distribution of the splice sites defining these exons. The total information content of an exon (R(i),total) is the sum of the R(i) values of its acceptor and donor splice sites, adjusted for the self-information of the distance separating these sites, that is, the gap surprisal. Differences between total information contents of an exon (DeltaR(i,total)) are predictive of the relative abundance of these exons in distinct processed mRNAs. Constraints on splice site and exon selection are used to eliminate nonconforming and poorly expressed isoforms. Molecular phenotypes are computed by the Automated Splice Site and Exon Definition Analysis (http://splice.uwo.ca) server. Predictions of splicing mutations were highly concordant (85.2%; n = 61) with published expression data. In silico exon definition analysis will contribute to streamlining assessment of abnormal and normal splice isoforms resulting from mutations. PMID- 23348724 TI - Lipid modification in Wnt structure and function. AB - PURPOSE OF REVIEW: Wnt proteins are morphogens encoded by 19 mammalian genes that play essential roles in embryonic development, stem cell renewal, and adult tissue homeostasis. The recent publication of the first crystal structure of a Wnt protein represents a key step in the study of Wnt signaling. RECENT FINDINGS: We discuss the basic aspects of Wnt signaling, provide historical background for why the proteins have been so challenging to study from a biochemical perspective, describe the lipid modifications that occur to Wnt proteins, and then discuss the implications of the recently reported crystal structure. SUMMARY: The recent determination of the Wnt8-Fz8 structure has created new opportunities to better understand the mechanisms by which Wnt proteins activate downstream signaling pathways and has further clarified why lipid modification of Wnt is required for activation. PMID- 23348725 TI - Association of LIPC and advanced age-related macular degeneration. AB - PURPOSE: To determine whether there is an association between hepatic lipase (LIPC) and age-related macular degeneration (AMD) in two independent Caucasian cohorts. METHODS: A discovery cohort of 1626 patients with advanced AMD and 859 normal controls and a replication cohort of 2159 cases and 1150 controls were genotyped for two single-nucleotide polymorphisms (SNPs) in the promoter region of LIPC. The associations between the SNPs and AMD were examined by chi(2) tests. RESULTS: In the discovery cohort, rs493258 and rs10468017 were both associated with advanced AMD (P=9.63E-3 and P=0.048, respectively). The association was corroborated in the replication cohort (P=4.48E-03 for rs493258 and P=0.015 for rs10468017). Combined analysis resulted in even more significant associations (P=1.21E-04 for rs493258 and P=1.67E-03 for rs10468017). CONCLUSION: The LIPC promoter variants rs493258 and rs10468017 were associated with advanced AMD in two independent Caucasian populations, confirming that LIPC polymorphisms may be a genetic risk factor for AMD in the Caucasian population. PMID- 23348726 TI - Intraorbital corticosteroid injection for orbital reactive lymphoid hyperplasia. AB - PURPOSE: The purpose of this study is to assess the utility of intraorbital injection of triamcinolone acetonide as a primary treatment option for orbital reactive lymphoid hyperplasia (RLH). PATIENTS AND METHOD: Retrospective, single centre, interventional case series. RESULTS: Intraorbital injection of triamcinolone acetonide was associated with complete resolution of all symptoms and signs in four cases (80%). This was achieved with a single injection in two cases and with two injections in another two cases. Radiological resolution was confirmed in one case. One case developed bilateral multifocal orbital RLH lesions 1 month after the second injection. CONCLUSION: Intraorbital injection of corticosteroid may be a useful treatment option for orbital RLH, and may have a role as a first-line therapy in RLH of the anterior orbit. A significant proportion of patients may require repeat injections to achieve resolution. A larger prospective study is required to validate our findings. PMID- 23348727 TI - Endothelial keratoplasty in the management of irido-corneal endothelial syndrome. AB - PURPOSE: To describe the results of endothelial keratoplasty (EK) in the management of irido-corneal endothelial (ICE) syndrome. DESIGN: Retrospective, consecutive, interventional case series. METHODS: Eight eyes of seven patients underwent EK for corneal edema owing to ICE syndrome. Simultaneous cataract surgery was performed in five eyes. The charts were reviewed for demographics, clinical findings, and outcomes after EK. RESULTS: Mean age was 50.4 years (range 35-59 years). Mean follow-up was 12.5 months (range 6-24 months). Corneal clarity was restored in all eyes and was maintained till the last follow-up. Four patients had acute rise in the intraocular pressure in the post-operative period, which was well controlled on medical treatment. One patient who was non-compliant with medications and regular follow-up advice had progression of glaucomatous disc changes and visual field loss. The best-corrected visual acuity ranged from 20/50-20/30. CONCLUSIONS: EK is a viable option in ICE syndrome. Adequate control of glaucoma is the paramount factor in maintaining good visual acuity in these eyes. PMID- 23348728 TI - Implantation of a customized toric intraocular lens for correction of post keratoplasty astigmatism. AB - PURPOSE: To report visual and refractive outcomes, and endothelial cell loss following primary and secondary 'piggyback' toric intraocular lens (IOL) implantation in patients with high post-penetrating keratoplasty (PK) astigmatism. METHODS: Prospective case series. Nine eyes of nine patients with post-PK astigmatism were consecutively recruited for implantation of a customized toric IOL. Six underwent simultaneous phacoemulsification (PE) and three pseudophakic eyes had a secondary 'piggyback' toric IOL implanted in the ciliary sulcus. Mean follow-up time was 17.2+/-7.7 months. Pre- and post-operative uncorrected (UDVA) and best-corrected (BDVA) distance visual acuities and refractive errors were collected for comparison. Cartesian astigmatic vectors were calculated to identify a change in the magnitude of astigmatism pre- compared to postoperatively. Pre- and post-operative endothelial cell counts were also collected for analysis. RESULTS: UDVA (logMAR) improved from 1.13+/-0.51 preoperatively to 0.48+/-0.24 postoperatively (P-value=0.003). There was no significant change in BDVA (P-value=0.905) from 0.31+/-0.27 to 0.26+/-0.19. Corneal astigmatism preoperatively was 6.57+/-4.40 diopters (D). Post-operative refractive cylinder was 0.83+/-1.09 D compared to 3.89+/-4.01 D preoperatively (P=0.039). Analysis of astigmatic Cartesian x and y coordinates found a significant reduction postoperatively compared to preoperatively (P=0.005 and P=0.002), respectively. Mean endothelial cell loss was 9.9%. CONCLUSION: Implantation of a customized primary or secondary 'piggyback' toric IOL serves as an effective modality in treating patients with high post-PK astigmatism. PMID- 23348730 TI - Nucleocytoplasmic connections and deafness. AB - The linker of nucleoskeleton and cytoskeleton (LINC) complex connects the nuclear lamina to the cytoskeleton, in part to aid in nuclear positioning. Mutations in genes encoding LINC complex and lamina components cause a range of human diseases. In this issue of the JCI, Horn et al. report that mutations in the gene SYNE4 encoding the LINC complex protein nesprin-4 lead to progressive high frequency hearing loss. Further, in mice deficient in nesprin-4 and Sun1, another LINC complex component, outer hair cells of the cochlea form normally during development, but die in the early postnatal weeks. These results link improper nuclear positioning specifically to the death of outer hair cells in the organ of Corti and ultimately to deafness. PMID- 23348729 TI - Andean and Tibetan patterns of adaptation to high altitude. AB - OBJECTIVES: High-altitude hypoxia, or decreased oxygen levels caused by low barometric pressure, challenges the ability of humans to live and reproduce. Despite these challenges, human populations have lived on the Andean Altiplano and the Tibetan Plateau for millennia and exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. We and others have identified natural selection candidate genes and gene regions for these adaptations using dense genome scan data. One gene previously known to be important in cellular oxygen sensing, egl nine homolog 1 (EGLN1), shows evidence of positive selection in both Tibetans and Andeans. Interestingly, the pattern of variation for this gene differs between the two populations. Continued research among Tibetan populations has identified statistical associations between hemoglobin concentration and single nucleotide polymorphism (SNP) genotype at EGLN1 and a second gene, endothelial PAS domain protein 1 (EPAS1). METHODS: To measure for the effects of EGLN1 and EPAS1 altitude genotypes on hemoglobin concentration among Andean highlanders, we performed a multiple linear regression analysis of 10 candidate SNPs in or near these two genes. RESULTS: Our analysis did not identify significant associations between EPAS1 or EGLN1 SNP genotypes and hemoglobin concentration in Andeans. CONCLUSIONS: These results contribute to our understanding of the unique set of adaptations developed in different highland groups to the hypoxia of high altitude. Overall, the results provide key insights into the patterns of genetic adaptation to high altitude in Andean and Tibetan populations. PMID- 23348731 TI - Ubiquitylation and the pathogenesis of hypertension. AB - Liddle syndrome is monogenic hypertension caused by mutations in the epithelial Na+ channel (ENaC) that interfere with its ubiquitylation by Nedd4-2. In this issue, Ronzaud and colleagues found that deleting Nedd4-2 from kidney tubules in adult mice led to ENaC accumulation, but not at the plasma membrane, as predicted from current models. Instead, abundance of the sodium chloride transporter NCC increased at the plasma membrane, and the mice have some features of increased NCC activity. Together, the results suggest that defective ubiquitylation of ENaC by Nedd4-2 may not fully explain Liddle syndrome and that Nedd4-2 modulates NCC more strongly. PMID- 23348732 TI - iRHOM2 takes control of rheumatoid arthritis. AB - The cytokine TNF-alpha is a major drug target for rheumatoid arthritis, an inflammatory joint disorder. An alternative approach is to target the protease TNF-alpha convertase (TACE), which releases TNF-alpha from cells. However, because TACE cleaves other proteins involved in development and cancer, a tissue specific inhibition of TACE in immune cells appears mandatory. In this issue of the JCI, Issuree et al. report that iRHOM2 is a TACE activator in immune cells. Loss of iRHOM2 largely protects mice from inflammatory arthritis, making iRHOM2 a potential drug target for this condition. PMID- 23348733 TI - Old King coal - molecular mechanisms underlying an ancient treatment for atopic eczema. AB - Traditional remedies for common disorders have been known for centuries, but insight into their mechanism of action is often limited. In this issue of the JCI, Joost Schalkwijk's research group at the Radboud University Nijmegen Medical Centre in The Netherlands advances our understanding of why topical coal tar is an effective treatment for atopic dermatitis (AD), both rationalizing the use of this traditional medicine, and providing the scientific basis for new therapeutic approaches. PMID- 23348734 TI - Cancer therapy combination: green tea and a phosphodiesterase 5 inhibitor? AB - The major constituent of green tea, (-)-epigallocatechin-3-O-gallate (EGCG), has been shown to have cancer-preventive and therapeutic activities. Numerous molecular targets for EGCG have been proposed, but the mechanisms of its anticancer activities are not clearly understood. In this issue of the JCI, Kumazoe et al. report that EGCG activates 67-kDa laminin receptor (67LR), elevates cGMP levels, and induces cancer cell apoptosis. Furthermore, a phosphodiesterase 5 inhibitor, vardenafil, synergizes with EGCG to induce cancer cell death. This is a provocative observation with important implications for cancer therapy. It also raises several issues for further investigation, such as the mechanism by which EGCG specifically activates 67LR. PMID- 23348735 TI - B4 androgen ablation: attacking the prostate cancer stem cell. AB - There is increasing evidence that prostate cancers in rodent models and in men contain a cellular subpopulation that displays stem cell properties. These prostate cancer stem cells (PCSCs) lack androgen receptor expression and are increased in castration-resistant disease. In this issue of the JCI, a study from Yoshioka et al. demonstrates that PCSCs are regulated by a pathway in which alpha6beta4 integrin amplifies signaling through ErbB2 and c-Met receptors. Targeting this pathway provides a novel therapeutic strategy for hormone refractory prostate cancer. PMID- 23348736 TI - Why stress is BAD for cancer patients. AB - Behavioral stress is known to promote tumor progression in experimental models, but the role of behavioral stress in cancer initiation is less clear. In this issue, Hassan et al. focus on the signaling and biological effects induced by stress hormones that lead to tumor cell evasion from apoptosis, resulting in prostate cancer progression. PMID- 23348737 TI - Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension. AB - The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis. Mutations in the human beta/gammaENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and high Na+ diets, conditional KO mice displayed decreased plasma aldosterone but normal Na+/K+ balance. Under a high-Na+ diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of betaENaC, gammaENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated thiazide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the alphaENaC subunit, was reduced and proteolytic cleavage of alphaENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of beta/gammaENaC, but not alphaENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK. PMID- 23348738 TI - Platelet ITAM signaling is critical for vascular integrity in inflammation. AB - Platelets play a critical role in maintaining vascular integrity during inflammation, but little is known about the underlying molecular mechanisms. Here we report that platelet immunoreceptor tyrosine activation motif (ITAM) signaling, but not GPCR signaling, is critical for the prevention of inflammation induced hemorrhage. To generate mice with partial or complete defects in these signaling pathways, we developed a protocol for adoptive transfer of genetically and/or chemically inhibited platelets into thrombocytopenic (TP) mice. Unexpectedly, platelets with impaired GPCR signaling, a crucial component of platelet plug formation and hemostasis, were indistinguishable from WT platelets in their ability to prevent hemorrhage at sites of inflammation. In contrast, inhibition of GPVI or genetic deletion of Clec2, the only ITAM receptors expressed on mouse platelets, significantly reduced the ability of platelets to prevent inflammation-induced hemorrhage. Moreover, transfusion of platelets without ITAM receptor function or platelets lacking the adapter protein SLP-76 into TP mice had no significant effect on vascular integrity during inflammation. These results indicate that the control of vascular integrity is a major function of immune-type receptors in platelets, highlighting a potential clinical complication of novel antithrombotic agents directed toward the ITAM signaling pathway. PMID- 23348739 TI - Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. AB - Topical application of coal tar is one of the oldest therapies for atopic dermatitis (AD), a T helper 2 (Th2) lymphocyte-mediated skin disease associated with loss-of-function mutations in the skin barrier gene, filaggrin (FLG). Despite its longstanding clinical use and efficacy, the molecular mechanism of coal tar therapy is unknown. Using organotypic skin models with primary keratinocytes from AD patients and controls, we found that coal tar activated the aryl hydrocarbon receptor (AHR), resulting in induction of epidermal differentiation. AHR knockdown by siRNA completely abrogated this effect. Coal tar restored filaggrin expression in FLG-haploinsufficient keratinocytes to wild type levels, and counteracted Th2 cytokine-mediated downregulation of skin barrier proteins. In AD patients, coal tar completely restored expression of major skin barrier proteins, including filaggrin. Using organotypic skin models stimulated with Th2 cytokines IL-4 and IL-13, we found coal tar to diminish spongiosis, apoptosis, and CCL26 expression, all AD hallmarks. Coal tar interfered with Th2 cytokine signaling via dephosphorylation of STAT6, most likely due to AHR-regulated activation of the NRF2 antioxidative stress pathway. The therapeutic effect of AHR activation herein described opens a new avenue to reconsider AHR as a pharmacological target and could lead to the development of mechanism-based drugs for AD. PMID- 23348740 TI - 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis. AB - The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCdelta/acid sphingomyelinase (PKCdelta/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death. PMID- 23348741 TI - The LINC complex is essential for hearing. AB - Hereditary hearing loss is the most common sensory deficit. We determined that progressive high-frequency hearing loss in 2 families of Iraqi Jewish ancestry was due to homozygosity for the protein truncating mutation SYNE4 c.228delAT. SYNE4, a gene not previously associated with hearing loss, encodes nesprin-4 (NESP4), an outer nuclear membrane (ONM) protein expressed in the hair cells of the inner ear. The truncated NESP4 encoded by the families' mutation did not localize to the ONM. NESP4 and SUN domain-containing protein 1 (SUN1), which localizes to the inner nuclear membrane (INM), are part of the linker of nucleoskeleton and cytoskeleton (LINC) complex in the nuclear envelope. Mice lacking either Nesp4 or Sun1 were evaluated for hair cell defects and hearing loss. In both Nesp4-/- and Sun1-/- mice, OHCs formed normally, but degenerated as hearing matured, leading to progressive hearing loss. The nuclei of OHCs from mutant mice failed to maintain their basal localization, potentially affecting cell motility and hence the response to sound. These results demonstrate that the LINC complex is essential for viability and normal morphology of OHCs and suggest that the position of the nucleus in sensory epithelial cells is critical for maintenance of normal hearing. PMID- 23348742 TI - Behavioral stress accelerates prostate cancer development in mice. AB - Prostate cancer patients have increased levels of stress and anxiety. Conversely, men who take beta blockers, which interfere with signaling from the stress hormones adrenaline and noradrenaline, have a lower incidence of prostate cancer; however, the mechanisms underlying stress-prostate cancer interactions are unknown. Here, we report that stress promotes prostate carcinogenesis in mice in an adrenaline-dependent manner. Behavioral stress inhibited apoptosis and delayed prostate tumor involution both in phosphatase and tensin homolog-deficient (PTEN deficient) prostate cancer xenografts treated with PI3K inhibitor and in prostate tumors of mice with prostate-restricted expression of c-MYC (Hi-Myc mice) subjected to androgen ablation therapy with bicalutamide. Additionally, stress accelerated prostate cancer development in Hi-Myc mice. The effects of stress were prevented by treatment with the selective beta2-adrenergic receptor (ADRB2) antagonist ICI118,551 or by inducible expression of PKA inhibitor (PKI) or of BCL2-associated death promoter (BAD) with a mutated PKA phosphorylation site (BADS112A) in xenograft tumors. Effects of stress were also blocked in Hi-Myc mice expressing phosphorylation-deficient BAD (BAD3SA). These results demonstrate interactions between prostate tumors and the psychosocial environment mediated by activation of an adrenaline/ADRB2/PKA/BAD antiapoptotic signaling pathway. Our findings could be used to identify prostate cancer patients who could benefit from stress reduction or from pharmacological inhibition of stress-induced signaling. PMID- 23348743 TI - Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation. AB - During sepsis, acute lung injury (ALI) results from activation of innate immune cells and endothelial cells by endotoxins, leading to systemic inflammation through proinflammatory cytokine overproduction, oxidative stress, and intracellular Ca2+ overload. Despite considerable investigation, the underlying molecular mechanism(s) leading to LPS-induced ALI remain elusive. To determine whether stromal interaction molecule 1-dependent (STIM1-dependent) signaling drives endothelial dysfunction in response to LPS, we investigated oxidative and STIM1 signaling of EC-specific Stim1-knockout mice. Here we report that LPS mediated Ca2+ oscillations are ablated in ECs deficient in Nox2, Stim1, and type II inositol triphosphate receptor (Itpr2). LPS-induced nuclear factor of activated T cells (NFAT) nuclear accumulation was abrogated by either antioxidant supplementation or Ca2+ chelation. Moreover, ECs lacking either Nox2 or Stim1 failed to trigger store-operated Ca2+ entry (SOCe) and NFAT nuclear accumulation. LPS-induced vascular permeability changes were reduced in EC-specific Stim1-/- mice, despite elevation of systemic cytokine levels. Additionally, inhibition of STIM1 signaling prevented receptor-interacting protein 3-dependent (RIP3 dependent) EC death. Remarkably, BTP2, a small-molecule calcium release-activated calcium (CRAC) channel blocker administered after insult, halted LPS-induced vascular leakage and pulmonary edema. These results indicate that ROS-driven Ca2+ signaling promotes vascular barrier dysfunction and that the SOCe machinery may provide crucial therapeutic targets to limit sepsis-induced ALI. PMID- 23348744 TI - iRHOM2 is a critical pathogenic mediator of inflammatory arthritis. AB - iRHOM2, encoded by the gene Rhbdf2, regulates the maturation of the TNF-alpha convertase (TACE), which controls shedding of TNF-alpha and its biological activity in vivo. TACE is a potential target to treat TNF-alpha-dependent diseases, such as rheumatoid arthritis, but there are concerns about potential side effects, because TACE also protects the skin and intestinal barrier by activating EGFR signaling. Here we report that inactivation of Rhbdf2 allows tissue-specific regulation of TACE by selectively preventing its maturation in immune cells, without affecting its homeostatic functions in other tissues. The related iRHOM1, which is widely expressed, except in hematopoietic cells, supported TACE maturation and shedding of the EGFR ligand TGF-alpha in Rhbdf2 deficient cells. Remarkably, mice lacking Rhbdf2 were protected from K/BxN inflammatory arthritis to the same extent as mice lacking TACE in myeloid cells or Tnfa-deficient mice. In probing the underlying mechanism, we found that two main drivers of K/BxN arthritis, complement C5a and immune complexes, stimulated iRHOM2/TACE-dependent shedding of TNF-alpha in mouse and human cells. These data demonstrate that iRHOM2 and myeloid-expressed TACE play a critical role in inflammatory arthritis and indicate that iRHOM2 is a potential therapeutic target for selective inactivation of TACE in myeloid cells. PMID- 23348746 TI - Synthesis of 2-hydroxy-1,4-oxazin-3-ones through ring transformation of 3-hydroxy 4-(1,2-dihydroxyethyl)-beta-lactams and a study of their reactivity. AB - The reactivity of 3-hydroxy-4-(1,2-dihydroxyethyl)-beta-lactams with regard to the oxidant sodium periodate was evaluated, unexpectedly resulting in the exclusive formation of new 2-hydroxy-1,4-oxazin-3-ones through a C3?C4 bond cleavage of the intermediate 4-formyl-3-hydroxy-beta-lactams followed by a ring expansion. This peculiar transformation stands in sharp contrast with the known NaIO(4)-mediated oxidation of 3-alkoxy- and 3-phenoxy-4-(1,2-dihydroxyethyl)-beta lactams, which exclusively leads to the corresponding 4-formyl-beta-lactams without a subsequent ring enlargement. In addition, this new class of functionalized oxazin-3-ones was further evaluated for its potential use as building blocks in the synthesis of a variety of differently substituted oxazin-3 ones, morpholin-3-ones and pyrazinones. Furthermore, additional insights into the mechanism and the factors governing this new ring-expansion reaction were provided by means of density functional theory calculations. PMID- 23348747 TI - Quantification of volume, mass, and density of thrombus formation using brightfield and differential interference contrast microscopy. AB - Flow chamber assays, in which blood is perfused over surfaces of immobilized extracellular matrix proteins, are used to investigate the formation of platelet thrombi and aggregates under shear flow conditions. Elucidating the dynamic response of thrombi/aggregate formation to different coagulation pathway perturbations in vitro has been used to develop an understanding of normal and pathological cardiovascular states. Current microscopy techniques, such as differential interference contrast (DIC) or fluorescent confocal imaging, respectively, do not provide a simple, quantitative understanding of the basic physical features (volume, mass, and density) of platelet thrombi/aggregate structures. The use of two label-free imaging techniques applied, for the first time, to platelet aggregate and thrombus formation are introduced: noninterferometric quantitative phase microscopy, to determine mass, and Hilbert transform DIC microscopy, to perform volume measurements. Together these techniques enable a quantitative biophysical characterization of platelet aggregates and thrombi formed on three surfaces: fibrillar collagen, fibrillar collagen +0.1 nM tissue factor (TF), and fibrillar collagen +1 nM TF. It is demonstrated that label-free imaging techniques provide quantitative insight into the mechanisms by which thrombi and aggregates are formed in response to exposure to different combinations of procoagulant agonists under shear flow. PMID- 23348745 TI - beta4 Integrin signaling induces expansion of prostate tumor progenitors. AB - The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the beta4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of beta4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed Pten loss-driven prostate tumorigenesis in tissue recombination experiments. We traced this defect back to an inability of signaling-defective beta4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant beta4 fails to promote transactivation of ErbB2 and c-Met in prostate tumor progenitor cells and human cancer cell lines. Pharmacological inhibition of ErbB2 and c-Met reduced the ability of prostate tumor progenitor cells to undergo self-renewal in vitro. Finally, we found that beta4 is often coexpressed with c-Met and ErbB2 in human prostate cancers and that combined pharmacological inhibition of these receptor tyrosine kinases exerts antitumor activity in a mouse xenograft model. These findings indicate that the beta4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c Met signaling in tumor progenitor cells. PMID- 23348748 TI - Neurochemical codes of sympathetic preganglionic neurons activated by glucoprivation. AB - Glucoprivation or hypoglycemia induces a range of counterregulatory responses, including glucose mobilization, reduced glucose utilization, and de novo glucose synthesis. These responses are mediated in part by the sympathetic nervous system. The aim of this study was to determine the chemical codes of sympathetic preganglionic neurons (SPN) activated by glucoprivation, induced by 2-deoxy-D glucose (2DG). SPN controlling the adrenal glands and celiac ganglia, which ultimately can innervate the liver and pancreas, were targeted together with the superior cervical ganglia (control). 23.9% +/- 1.3% of SPN in the T4-T11 region contained c-Fos immunoreactivity following 2DG; 70.3% +/- 1.8% of SPN innervating the adrenal glands and 37.4% +/- 3% of SPN innervating celiac ganglia were activated. 14.8% +/- 3.5% of SPN (C8-T3) innervating superior cervical ganglia were activated. In the C8-T3 region 55% +/- 10% of SPN activated contained PPCART, with only 12% +/- 3% expressing PPE mRNA, whereas, in the T4-T11 region, 78% +/- 4% contained PPE, with only 6.0% +/- 0.6% expressing PPCART mRNA. Thus CART is not involved in glucose mobilization. Two chemically distinct populations of SPN (PPE+ 57.4% +/- 5%, PPE- ~40%) were identified to regulate adrenaline release in response to glucoprivation. Multiple chemically distinct SPN populations innervating a specific target could suggest their graded recruitment. The two distinct populations of SPN (PPE+ 67.6% +/- 9%, PPE- ~30%) projecting to celiac ganglia activated by glucoprivation could direct pancreatic and hepatic or other counterregulatory responses. Nearly all SPN that expressed PPE mRNA and projected to the adrenal glands or celiac ganglia were activated, suggesting a role for the inhibitory peptide enkephalin in responses evoked by glucoprivation. PMID- 23348749 TI - Synthesis of 3,3-disubstituted oxindoles by one-pot integrated Bronsted base catalyzed trichloroacetimidation of 3-hydroxyoxindoles and Bronsted acid catalyzed nucleophilic substitution reaction. AB - Treatment of 3-hydroxyoxindoles with trichloroacetonitrile (1.3 equiv.) and a catalytic amount of DBU (0.1 equiv.) followed by addition of nucleophiles (1.5 equiv.) and diphenylphosphoric acid (0.2 equiv.) afforded the 3,3-disubstituted oxindoles in good to excellent yields. DFT computations supported the notion that the reaction went through the 1-alkyl-2-oxo-2H-indol-1-ium intermediate. PMID- 23348750 TI - Hydrothermal synthesis of an ortho-metallated Co(III) complex anchored by a carboxylate group with a selective oxidation catalytic property. AB - An air-stable and water-tolerant ortho-metallated complex [Co(tfb)(bpy)(2)](NO(3)).3H(2)O was obtained via hydrothermal synthesis. The mechanism for the formation of Co-C bond was studied using both DFT calculations and experimental analysis. This highly stable complex exhibits good catalytic performance for the selective oxidation of cyclohexane. PMID- 23348751 TI - A separability parameter for dielectrophoretic cell separation. AB - In this study, a separability parameter is introduced to determine the selection of optimum operating parameters for DEP separation of a cell pair. The separability parameter is defined as a function of cells' Clausius-Mossotti (CM) factors. T-cell leukemia Jurkat and mouse melanoma B16 cells are tested to validate the separability parameter. CM factors of cells are measured using a recently developed microfluidic impedance spectroscopy device. Separability maps are generated for varying values of field frequency and buffer conductivity. Cell separation is tested using a planar interdigitated electrode array at different buffer conductivities. Impedance measurements of the DEP device are performed at various buffer conductivities. Electrode polarization effects and energy allocation for dielectrophoretic manipulation of cells are computed from the impedance data utilizing an equivalent circuit model. Cell separation results are explained in the light of the impedance measurements. PMID- 23348752 TI - Role of adaptive and non-adaptive mechanisms forming complex patterns of genome size variation in six cytotypes of polyploid Allium oleraceum (Amaryllidaceae) on a continental scale. AB - BACKGROUND AND AIMS: Although the large variation in genome size among different species is widely acknowledged, the occurrence and extent of variation below the species level are still controversial and have not yet been satisfactorily analysed. The aim of this study was to assess genome size variation in six ploidy levels (2n = 3x-8x) of the polyploid Allium oleraceum over a large geographical gradient and to search for potential interpretations of the size variation. METHODS: The genome sizes of 407 individuals of A. oleraceum collected from 114 populations across Europe were determined by flow cytometry using propidium iodide staining. The genome size variation was correlated with spatial, climatic and habitat variables. KEY RESULTS: The mean holoploid genome size (2C DNA) was 42.49, 52.14, 63.34, 71.94, 85.51 and 92.12 pg at the tri-, tetra-, penta-, hexa , hepta- and octoploid levels, respectively. Genome size varied from a minimum of 2.3 % in the octoploids to a maximum of 18.3 % in the tetraploids. Spatial structuring of genome size was observed within the tetra- and pentaploids, where 2C DNA significantly increased with both latitude and longitude, and correlated with several climatic variables, suggesting a gradient of continentality. Genome size in hexaploids showed low variation, weak correlation with climatic variables and no spatial structuring. Downsizing in monoploid genome size was observed between all cytotypes except for heptaploids. Splitting populations into western and eastern European groups resulted in strong differences in monoploid genome size between groups in tetra- and pentaploids but not in hexaploids. The monoploid genome sizes of the cytotypes were similar in the western group but diverged in the eastern group. CONCLUSIONS: Complex patterns of holoploid and monoploid genome size variation found both within and between A. oleraceum cytotypes are most likely the result of several interacting factors, including different evolutionary origins of cytotypes via hybridization of parental combinations with different genome sizes in the south-western and south-eastern part of Europe, introgression between cytotypes, and antropic dispersal. The role of broad-scale and fine-scale environmental variables in shaping genome size is probably of minor importance in A. oleraceum. PMID- 23348754 TI - A brief history of oxytocin and its role in modulating psychostimulant effects. AB - Over the past century, the polypeptide oxytocin has played an important role in medicine with major highlights including the identification of its involvement in parturition and the milk let-down reflex. Oxytocin is now implicated in an extensive range of psychological phenomena including reward and memory processes and has been investigated as a treatment for several psychiatric disorders including addiction, anxiety, autism, and schizophrenia. In this review, we first provide an historical overview of oxytocin and describe key aspects of its physiological activity. We then outline some pharmacological limitations in this field of research before highlighting the role of oxytocin in a wide range of behavioral and neuronal processes. Finally, we review evidence for a modulatory role of oxytocin with regard to psychostimulant effects. Key findings suggest that oxytocin attenuates a broad number of cocaine and methamphetamine induced behaviors and associated neuronal activity in rodents. Evidence also outlines a role for oxytocin in the prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in both rodents and humans. Clinical trials should now investigate the effectiveness of oxytocin as a novel intervention for psychostimulant addiction and should aim to determine its specific role in the therapeutic properties of MDMA that are currently being investigated. PMID- 23348755 TI - The stereoisomer (+)-naloxone potentiates G-protein coupling and feeding associated with stimulation of mu opioid receptors in the parabrachial nucleus. AB - Classically, opioids produce their effects by activating Gi-proteins that inhibit adenylate cyclase activity. Previous studies proposed that mu-opioid receptors can also stimulate adenylate cyclase due to an initial transient coupling to Gs proteins. Treatment with ultra-low doses of the nonselective opioid antagonist ( )-naloxone or its inactive enantiomer (+)-naloxone blocks this excitatory effect and enhances Gi-coupling. Previously we reported that infusion of the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4, Glycinol5]-Enkephalin (DAMGO) into the mu opioid receptor expressing lateral parabrachial nucleus increases feeding. Pretreatment with (-)-naloxone blocks this effect. We used this parabrachial circuit as a model to assess cellular actions of ultra-low doses of (-)-naloxone and (+)-naloxone in modifying the effects of DAMGO. Our results showed that an ultra-low concentration of (-)-naloxone (0.001 nM) and several concentrations of (+)-naloxone (0.01-10 nM) enhanced DAMGO-stimulated guanosine-5'-0-(gamma-thio) triphosphate incorporation in parabrachial sections in vitro. Further, we analyzed the relevance of these effects in vivo. In the present study, we show that (+)-naloxone can potentiate DAMGO-induced feeding at doses at which (-) naloxone was an antagonist. These results implicated (+)-naloxone as a novel tool for studying mu-opioid receptor functions and suggest that (+)-naloxone may have therapeutic value to enhance clinical actions of opiate drugs. PMID- 23348753 TI - Metabolomics--a novel window into inflammatory disease. AB - Inflammation is an important component of normal responses to infection and injury. However, chronic activation of the immune system, due to aberrant responses to normal stimuli, can lead to the establishment of a persistent inflammatory state. Such inflammatory conditions are often debilitating, and are associated with a number of important co-morbidities including cardiovascular disease. Resting non-proliferative tissues have distinctive metabolic activities and requirements, which differ considerably from those in infiltrating immune cells, which are undergoing proliferation and differentiation. Immune responses in tissues may therefore be modulated by the relative abundance of substrates in the inflamed site. In turn immune cell activity can feed back and affect metabolic behaviour of the tissues, as most clearly demonstrated in cachexia - the loss of cellular mass driven by tumour necrosis factor-alpha (TNF-alpha) a key mediator of the inflammatory response. Here we discuss the potential for metabolomic analysis to clarify the interactions between inflammation and metabolic changes underlying many diseases. We suggest that an increased understanding of the interaction between inflammation and cellular metabolism, energy substrate use, tissue breakdown markers, the microbiome and drug metabolites, may provide novel insight into the regulation of inflammatory diseases. PMID- 23348756 TI - Response to desmopressin is strongly dependent on F8 gene mutation type in mild and moderate haemophilia A. AB - Desmopressin causes two- to six-fold increase of factor VIII (FVIII) in mild or moderate haemophilia A patients. However, responses are variable and little is known whether this is associated with F8 gene mutation. The study objective was to assess the relationship between F8 gene mutation and desmopressin response in haemophilia A patients. Desmopressin response (absolute and relative) was determined in 97 hemophilia A patients. Four amino acid changes (Arg2169His, Pro149Arg, Asn637Ser, and Arg612Cys) and a number of other mutations leading to an aberrant FVIII protein or FVIII deficiency were analysed. Patients with Arg2169His showed significantly lower FVIII levels before and after desmopressin compared to all other mutations (p<0.001). Pro149Arg amino acid change showed significantly lower FVIII levels 1 hour after desmopressin compared to all other mutations (p<0.005). An absolute response with FVIII>=0.50 IU/ml after 1 hour was observed in 41% (9 of 22) of patients with Arg2169His; however, this was not sustainable after 6 hours in any of these subjects. No patients with Pro149Arg mutation (n=6) showed an absolute response with FVIII>=0.50 I U/ml. Patients with other mutations showed significantly more complete and partial responses. Relative responses did not differ between mutations. Our study shows that haemophilia A patients with amino acid change Arg2169His or Pro149Arg have a decreased desmopressin response with regard to FVIII levels as compared to other mutations. Our results indicate that response to desmopressin is dependent on the F8 gene mutation type, despite the fact that multiple factors influence the desmopressin response, even within families. PMID- 23348757 TI - Factors influencing the patient with rheumatoid arthritis in their decision to seek podiatry. AB - INTRODUCTION: Despite the level of foot involvement in rheumatoid arthritis (RA), and the literature to support early assessment of foot care needs, local referral of patients to podiatry has been occurring too late to instigate certain preventative interventions. Preliminary fieldwork has highlighted that the primary responsibility for the instigation of this lies with the patient. The present study describes the factors that influence the patient with RA in their decision to self-report foot problems. METHOD: A case study research strategy was employed. Nine patients attending the outpatient rheumatology department participated in the study and data were gathered through semi-structured interviews. This information was analysed using a framework approach. RESULTS: The key themes derived from the data suggested that there are a variety of factors influencing the patient's decision to self-report foot concerns. Some will act to encourage the action and others will act to oppose it. Other factors can influence the decision either way, depending on the individual patient (psychological state, previous experience, body image changes). In addition, age, gender, and cultural and social aspects are also significant. CONCLUSION: Due to the multitude of factors influencing the individual's decision to seek help, the patient cannot be given sole responsibility for their foot health if we wish to achieve timely and appropriate podiatry, as recommended in the literature. Responsibility should be three-way; the patient, the members of the rheumatology team and, once in the podiatry service, the podiatrist should maintain this. PMID- 23348758 TI - Obesity and fracture in men and women: an epidemiologic perspective. AB - In Western societies, mean body weight has increased dramatically in older people, and a similar trend exists in Asia. Yet insufficient attention has been directed to the problem of osteoporotic fractures in the overweight and obese. Many, if not most, osteoporotic fractures occur in overweight or obese people, and obese men may be particularly susceptible. We discuss the potential implications of these findings, including the challenge of identifying individuals at highest risk, screening and treatment strategies, and future research directions. PMID- 23348759 TI - Dorsal thoracic arachnoid web and the "scalpel sign": a distinct clinical radiologic entity. AB - Arachnoid webs are intradural extramedullary bands of arachnoid tissue that can extend to the pial surface of the spinal cord, causing a focal dorsal indentation of the cord. These webs tend to occur in the upper thoracic spine and may produce a characteristic deformity of the cord that we term the "scalpel sign." We describe 14 patients whose imaging studies demonstrated the scalpel sign. Ten of 13 patients who underwent MR imaging demonstrated T2WI cord signal-intensity changes, and 7 of these patients also demonstrated syringomyelia adjacent to the level of indentation. Seven patients underwent surgery, with 5 demonstrating an arachnoid web as the cause of the dorsal indentation demonstrated on preoperative imaging. Although the webs themselves are rarely demonstrated on imaging, we propose that the scalpel sign is a reliable indicator of their presence and should prompt consideration of surgical lysis, which is potentially curative. PMID- 23348761 TI - Development of a standardized MRI scoring tool for CNS demyelination in children. AB - BACKGROUND AND PURPOSE: The degree to which MR imaging is useful in the diagnosis of MS is predicated on standardized and reliable evaluation of MR imaging parameters. We aimed to devise items for an MR imaging scoring tool that would have high inter-rater agreement and would be straightforward to apply. MATERIALS AND METHODS: On the basis of a literature search and consensus of an expert panel, we identified 48 parameters that describe acute CNS demyelination, predict MS diagnosis, or characterize demyelinating disorder mimics. MR images of children with clinically confirmed MS, monophasic ADEM, and angiography-negative biopsy-positive small-vessel primary angiitis of the CNS were scored by 2 neuroradiologists independently, using the preliminary 48-parameter tool. Parameters with Cohen kappa >= 0.6 and deemed important in predicting diagnosis were retained. Parameters not visualized on routine clinical imaging or not important in differentiating MS, ADEM, and SV-cPACNS were discarded. RESULTS: Of 65 eligible patients, 55 children were enrolled (16 with monophasic ADEM, 27 with MS, 12 with SV-cPACNS); 10 were excluded (6 had hard-copy films, 4 did not meet MR imaging quality requirements). Of the 48 parameters, 16 were retained in the final scoring tool. The remaining 28 parameters were discarded: 4 had kappa < 0.6 and were not deemed useful in predicting diagnosis; 9 were not visible on routinely acquired clinical images; and 15 had inter-rater agreement >=0.6 but were not useful in differentiating monophasic ADEM, MS, and SV-cPACNS. CONCLUSIONS: We propose a 16-parameter MR imaging scoring tool that is straightforward to apply in the clinical setting and demonstrates high inter rater agreement. PMID- 23348760 TI - Functional homotopic changes in multiple sclerosis with resting-state functional MR imaging. AB - BACKGROUND AND PURPOSE: CC is extensively involved in MS with interhemispheric dysfunction. The purpose of this study was to determine whether interhemispheric correlation is altered in MS by use of a recently developed RS-fMRI homotopy technique and whether these homotopic changes correlate with CC pathology. MATERIALS AND METHODS: Twenty-four patients with relapsing-remitting MS and 24 age-matched healthy volunteers were studied with RS-fMRI and DTI acquired at 3T. The Pearson correlation of each pair of symmetric interhemispheric voxels of RS fMRI time-series data was performed to compute VMHC, and z-transformed for subsequent group-level analysis. In addition, 5 CC segments in the midsagittal area and DTI-derived FA were measured to quantify interhemispheric microstructural changes and correlate with global and regional VMHC in MS. RESULTS: Relative to control participants, patients with MS exhibited an abnormal homotopic pattern with decreased VMHC in the primary visual, somatosensory, and motor cortices and increased VMHC in several regions associated with sensory processing and motor control including the insula, thalamus, pallidum, and cerebellum. The global VMHC correlates moderately with the average FA of the entire CC for all participants in both groups (r = 0.3; P = .03). CONCLUSIONS: Our data provide preliminary evidence of the potential usefulness of VMHC analyses for the detection of abnormalities of interhemispheric coordination in MS. We demonstrated that the whole-brain homotopic RS-fMRI pattern was altered in patients with MS, which was partially associated with the underlying structural degenerative changes of CC measured with FA. PMID- 23348763 TI - Differentiation of primary central nervous system lymphomas and glioblastomas: comparisons of diagnostic performance of dynamic susceptibility contrast-enhanced perfusion MR imaging without and with contrast-leakage correction. AB - BACKGROUND AND PURPOSE: Contrast leakage results in underestimation of the CBV of brain tumors. Our aim was to compare the diagnostic performance of DSC perfusion MR imaging without and with mathematic contrast-leakage correction in differentiating PCNSLs and glioblastomas. MATERIALS AND METHODS: Perfusion parameters-CBV, corrected CBV, and leakage coefficient-were measured in enhancing tumor portions and contralateral NAWM of 15 PCNSLs and 20 glioblastomas, respectively. The ratios of CBV and corrected CBV were calculated by dividing the tumor values by those obtained from contralateral NAWM. A paired t test was used to compare tumor K2 and NAWM K2, as well as tumor CBV ratios without and with leakage correction. Comparisons of CBV, corrected CBV, and K2 between PCNSLs and glioblastomas were done by using a 2-sample t test. The diagnostic performance of DSC perfusion MR imaging without and with contrast-leakage correction was assessed with receiver operating characteristic curve analysis. RESULTS: PCNSLs and glioblastomas demonstrated higher K2 than those in their contralateral NAWM. Corrected CBV ratios were significantly higher than the uncorrected ones for both tumors. PCNSLs had lower CBV ratios (P < .001), lower corrected CBV ratios (P < .001), and higher K2 (P = .001) compared with glioblastomas. In differentiating between PCNSLs and glioblastomas, the area under the curve of the CBV ratio, corrected CBV ratio, and K2 were 0.984, 0.940, and 0.788, respectively. CONCLUSIONS: PCNSL can be differentiated from glioblastoma with CBV ratios, corrected CBV ratios, and K2. CBV without contrast-leakage correction seems to have the best diagnostic performance in differentiating the 2 tumors. PMID- 23348762 TI - Bilateral posterior periventricular nodular heterotopia: a recognizable cortical malformation with a spectrum of associated brain abnormalities. AB - BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain malformations suggest specific subcategories. MATERIALS AND METHODS: We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA. RESULTS: Nodules were often noncontiguous (n = 28) and asymmetric (n = 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar malformations and posterior fossa cysts (n = 38). Corpus callosum abnormalities (n = 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased (n = 22), and colpocephaly was frequent (n = 26). Most (n = 40) had associated cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common (n = 27), and hippocampal abnormalities were frequent (n = 37). Four family cases were identified-2 with concordant malformation patterns and 2 with discordant malformation patterns. CONCLUSIONS: The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian malformations involving the posterior cerebral and hindbrain structures. PMID- 23348764 TI - Safety and efficacy of neuroform for treatment of intracranial aneurysms: a prospective, consecutive, French multicentric study. AB - BACKGROUND AND PURPOSE: Endovascular embolization of wide-neck intracranial aneurysms can be technically challenging, especially when the anatomy is complex. Stent reconstruction of the parent artery is commonly used to treat wide-neck and bifurcated aneurysms. The main objective of this study was to investigate the periprocedural and midterm morbidity and mortality results of this procedure. MATERIALS AND METHODS: SENAT is a consecutive, prospective, multicentric study. Patients with unruptured cerebral aneurysms who underwent endovascular treatment with the Neuroform stent system were recruited and recorded. Technical outcomes and complications were also assessed. The midterm anatomic results were re evaluated at 12-18 months. RESULTS: A total of 113 stents were used to treat the 107 aneurysms in 107 patients. The mean width of the aneurysm sac was 6.2 mm, and the mean diameter of aneurysm neck was 4.5 mm. The complete occlusion rate postprocedure was 66.4%. The rate of progressive occlusion at 12-18 months was 14%, and the rate of recurrence was 9.7%. The rate of subsequent treatment was 4%. The thromboembolic rate in the periprocedural period was 3.7%, and the rate of delayed TE events was 3%. Overall, the mortality rate at 12-18 months was 1%, and the permanent morbidity rate was 1%. CONCLUSIONS: Stent-assisted coiling with the Neuroform stent system provides a high level of occlusion with low rates of subsequent treatment despite a predominant population of patients with wide-neck aneurysms. Morbidity and thromboembolic rates were comparable to studies investigating stand-alone coiling. PMID- 23348765 TI - Novel germline GJA5/connexin40 mutations associated with lone atrial fibrillation impair gap junctional intercellular communication. AB - Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia worldwide. Here, we investigate the molecular and cellular mechanisms of lone AF linked germline mutations in the connexin40 (Cx40) gene, GJA5. The entire coding region of GJA5 was sequenced in 68 unrelated patients with lone AF. A novel germline heterozygous missense mutation in Cx40 (p.I75F) was identified in one index patient. The mutation was also present in the proband's father with lone AF but was not found in the unaffected family members who were examined and 200 unrelated healthy control individuals. Electrophysiological studies revealed no electrical coupling of the cell pairs expressing the mutant alone and a significant reduction in gap junction coupling conductance when the mutant was coexpressed with wild-type (wt) Cx40 or Cx43. Interestingly, another lone AF linked Cx40 mutant p.L229M did not show any apparent coupling defect when expressed alone or together with wt Cx40 but specifically reduced the gap junction coupling when coexpressed with wt Cx43. This study is the first to demonstrate that the germline familial mutations in Cx40 impair the gap junctions through different mechanisms, which may predispose the mutant carriers to AF. PMID- 23348766 TI - Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. AB - Cholesteryl ester storage disease (CESD), an inherited deficiency of lysosomal acid lipase (LAL), is an underappreciated cause of progressive liver disease with no approved therapy. Presenting features include dyslipidemia, elevated transaminases, and hepatomegaly. To assess the clinical effects and safety of the recombinant human LAL, sebelipase alfa, nine patients received four once-weekly infusions (0.35, 1, or 3 mg.kg(-1) ) in LAL-CL01, which is the first human study of this investigational agent. Patients completing LAL-CL01 were eligible to enroll in the extension study (LAL-CL04) in which they again received four once weekly infusions of sebelipase alfa (0.35, 1, or 3 mg.kg(-1) ) before transitioning to long-term every-other-week infusions (1 or 3 mg.kg(-1) ). Sebelipase alfa was well tolerated, with mostly mild adverse events unrelated to sebelipase alfa. No antidrug antibodies were detected. Transaminases decreased in patients in LAL-CL01 and increased between studies. In seven patients receiving ongoing sebelipase alfa treatment in LAL-CL04, the mean +/- standard deviation (SD) decreases for alanine transaminase and aspartate aminotransferase at week 12 compared to the baseline values in LAL-CL01 were 46 +/- 21 U/L (-52%) and 21 +/- 14 U/L (-36%), respectively (P <= 0.05). Through week 12 of LAL-CL04, these seven patients also showed mean decreases from baseline in total cholesterol of 44 +/- 41 mg/dL (-22%; P = 0.047), low density lipoprotein-cholesterol of 29 +/- 31 mg/dL (-27%; P = 0.078), and triglycerides of 50 +/- 38 mg/dL (-28%, P = 0.016) and increases in high density lipoprotein-cholesterol of 5 mg/dL (15%; P = 0.016). CONCLUSION: These data establish that sebelipase alfa, an investigational enzyme replacement, in patients with CESD is well tolerated, rapidly decreases serum transaminases, and that these improvements are sustained with long-term dosing and are accompanied by improvements in serum lipid profile. PMID- 23348768 TI - ACMG Policy Statement. Risk categorization for oversight of laboratory-developed tests for inherited conditions. PMID- 23348767 TI - Inhibin B response to testicular toxicants hexachlorophene, ethane dimethane sulfonate, di-(n-butyl)-phthalate, nitrofurazone, DL-ethionine, 17-alpha ethinylestradiol, 2,5-hexanedione, or carbendazim following short-term dosing in male rats. AB - BACKGROUND: Inhibin B is a heterodimer glycoprotein that downregulates follicle stimulating hormone and is produced predominantly by Sertoli cells. The potential correlation between changes in plasma Inhibin B and Sertoli cell toxicity was evaluated in male rats administered testicular toxicants in eight studies. Inhibin B fluctuations over 24 hr were also measured. METHODS: Adult rats were administered one of eight testicular toxicants for 1 to 29 days. The toxicants were DL-ethionine, dibutyl phthalate, nitrofurazone, 2,5-hexanedione, 17-alpha ethinylestradiol, ethane dimethane sulfonate, hexachlorophene, and carbendazim. In a separate study plasma was collected throughout a 24-hr period via an automatic blood sampler. RESULTS: Histomorphologic testicular findings included seminiferous tubule degeneration, round and elongate spermatid degeneration/necrosis, seminiferous tubule vacuolation, aspermatogenesis, and interstitial cell degeneration. There was a varying response of plasma Inhibin B levels to seminiferous tubule toxicity, with three studies showing high correlation, three studies with a response only at a certain time or dose, and two studies with no Inhibin B changes. In a receiver operating characteristics exclusion model analysis, where treated samples without histopathology were excluded, Inhibin B showed a sensitivity of 70% at 90% specificity in studies targeting seminiferous tubule toxicity. CONCLUSION: Decreases in Inhibin B correlated with Sertoli cell toxicity in the majority of studies evaluated, demonstrating the value of Inhibin B as a potential biomarker of testicular toxicity. There was no correlation between decreases in Inhibin B and interstitial cell degeneration. In addition, a pattern of Inhibin B secretion could not be identified over 24 hr. PMID- 23348769 TI - Cascade carrier testing after a child is diagnosed with cystic fibrosis through newborn screening: investigating why most relatives do not have testing. AB - PURPOSE: Newborn screening for cystic fibrosis is increasingly available, but cascade testing following the diagnosis in a child has received little attention. We previously reported low levels of cascade testing over time, and this study investigated motivators as well as barriers to testing. METHODS: Parents were interviewed about communicating the genetic information and also asked to recruit their relatives to receive a specifically developed questionnaire. RESULTS: Thirty parents were interviewed and addresses of 284 relatives were provided; completed questionnaires were received from 225 (79%). A relative's relationship to the child, as well as knowledge, is associated with having had carrier testing. Relatives' reasons for testing included curiosity and wanting information for other relatives and for reproductive planning. Reasons for not testing were perceived irrelevance, lacking awareness, and viewing it as something to do in the future. Parents communicated the genetic information to relatives in various ways, which contributed to whether relatives accessed carrier testing. CONCLUSION: Newborn screening programs should provide support to parents to aid communication of genetic information to relatives. (Ir)relevance of testing is often linked to life stage; ongoing support and communication may allow relatives to learn of their risk and then seek testing, if they wish, at a time perceived to be most relevant to them. PMID- 23348770 TI - Beyond the competition-colonization trade-off: linking multiple trait response to disturbance characteristics. AB - Disturbances' role in shaping communities is well documented but highly disputed. We suggest replacing the overused two-trait trade-off approach with a functional group scheme, constructed from combinations of four key traits that represent four classes of species' responses to disturbances. Using model results and field observations from sites affected by two highly different disturbances, we demonstrated that popular dichotomous trade-offs are not sufficient to explain community dynamics, even if some emerge under certain conditions. Without disturbances, competition was only sufficient to predict species survival but not relative success, which required some escape mechanism (e.g., long-term dormancy). With highly predictable and large-scale disturbances, successful species showed a combination of high individual tolerance to disturbance and, more surprisingly, high competitive ability. When disturbances were less predictable, high individual tolerance and long-term seed dormancy were favored, due to higher environmental uncertainty. Our study demonstrates that theories relying on a small number of predefined trade-offs among traits (e.g., competition-colonization trade-off) may lead to unrealistic results. We suggest that the understanding of disturbance-community relationships can be significantly improved by employing sets of relevant trait assemblies instead of the currently common approach in which trade-offs are assumed in advance. PMID- 23348771 TI - Genetic constraints on dishonesty and caste dimorphism in an ant. AB - The ultimate causes of honest signaling remain a subject of debate, with questions remaining over the relative importance of costs and constraints. Signal costs may make dishonesty prohibitively expensive, while genetic constraints could make it impossible. We investigated honest signaling using full-sib analysis and parent-offspring regression in the ant Lasius niger, in which queens produce a cuticular hydrocarbon-based pheromone that signals fertility and inhibits worker reproduction and aggression. We found multiple lines of evidence that cuticular hydrocarbon production is genetically correlated with oogenesis and that the queen pheromone 3-methylhentriacontane and other 3-methylalkanes have strong genetic links with fertility relative to other cuticular hydrocarbons. These genetic correlations may maintain honesty in the face of directional selection on signaling and explain the putatively widespread use of cuticular hydrocarbons in fertility signaling across the social insects. We also found evidence for a positive genetic correlation for fertility between the castes; that is, the most fertile queens produced especially fertile workers. These results highlight that intercaste genetic correlations could constrain the evolution of queen-worker dimorphism, such that worker reproduction may sometimes reflect a nonadaptive "caste load" rather than positively selected cheating. PMID- 23348772 TI - Brood size matching: a novel perspective on predator dilution. AB - A primary benefit of grouping is diluting the individual risk of attack by predators. However, the fact that groups are formed not always by solitary adults but also by subgroups (e.g., families) has been overlooked. The subgroup-specific benefit of predator dilution depends on its relative contribution to total group size. Therefore, the willingness of a subgroup to merge with others should increase the less it contributes to total group size, but the conflicting preferences of partners may result in the preferential merger of similar-sized subgroups. Here, we evaluate how the proportional contribution of subgroups to diluting risk affects group formation. We generate predictions using a bidding game over parental care and test them using data on common eiders (Somateria mollissima), in which females with variable-sized broods may form brood-rearing coalitions. The predictions (1) that size-matched subgroups should have a higher propensity to merge, (2) that predation should increase group formation propensity, and (3) that increased bargaining power, as proxied by female body condition, should increase the time needed to establish partnerships were all supported. Partners do negotiate over their relative contributions to predator dilution, accepting or rejecting partnerships on the basis of this criterion. Our results show that consideration of the size of subgroups before merger is critical in understanding the process of group formation under the threat of predation. PMID- 23348773 TI - How the informational environment shapes how prey estimate predation risk and the resulting indirect effects of predators. AB - Prey often behaviorally respond to changes in the intensity of predation risk, and these responses can often significantly shape community dynamics, but flexible responses to changes in predation risk require that prey have accurate and timely estimates of predation risk. We present a model of how a prey's environment should shape the cognitive rules they use to assess predation risk and present how these rules shape the effects predators have on prey and the prey's resources. In the model, prey can rely on a combination of a fixed estimate of predation risk and a flexible estimate of predation risk shaped by their recent experience. Prey relied more on their experience to estimate predation risk when predator cues were more reliable and when predator densities were lower. In addition, when the prey cognitive rules favored a greater use of their experience to estimate predation risk, the presence of predators caused larger nonconsumptive effects and generally smaller consumptive effects on prey and the prey's resources. These differences in prey cognition also altered the effects that alterations of cue reliability and predator densities had on prey and their resources. PMID- 23348774 TI - On the relationship between ontogenetic and static allometry. AB - Ontogenetic and static allometries describe how a character changes in size when the size of the organism changes during ontogeny and among individuals measured at the same developmental stage, respectively. Understanding the relationship between these two types of allometry is crucial to understanding the evolution of allometry and, more generally, the evolution of shape. However, the effects of ontogenetic allometry on static allometry remain largely unexplored. Here, we first show analytically how individual variation in ontogenetic allometry and body size affect static allometry. Using two longitudinal data sets on ontogenetic and static allometry, we then estimate variances and covariances for the different parameters of the ontogenetic allometry defined in our model and assess their relative contribution to the static allometric slope. The mean ontogenetic allometry is the main parameter that determines the static allometric slope, while the covariance between the ontogenetic allometric slope and body size generates most of the discrepancies between ontogenetic and static allometry. These results suggest that the apparent evolutionary stasis of the static allometric slope is not generated by internal (developmental) constraints but more likely results from external constraints imposed by selection. PMID- 23348775 TI - Female mate fidelity in a Lek mating system and its implications for the evolution of cooperative lekking behavior. AB - The extent and importance of female mate fidelity in polygynous mating systems are poorly known. Fidelity may contribute to high variance in male reproductive success when it favors attractive mates or may stabilize social interactions if females are faithful to mating sites rather than males. Using 12 years of data on genetic mate choice in the cooperatively lekking lance-tailed manakin (Chiroxiphia lanceolata), I investigated the frequency of fidelity within and between years, whether females were faithful to individual males or to mating sites across years, and whether fidelity favored attractive males. Mate fidelity occurred in 41.7% of 120 between-year comparisons and was observed for 41.1% of 73 individual females that had the opportunity to mate faithfully. Females were not more likely to mate at prior mating sites when previous mates were replaced. Faithful females mated with the same male in up to four consecutive years but were not disproportionately faithful to attractive partners. Mating history influences current mate choice, and fidelity in this lekking system apparently represents active mate choice by females but little is not cited in the text. Please provide a citation or mark this reference for deletion.consensus in mate choices among faithful females. This study underscores the prevalence of mate fidelity in polygynous mating systems and emphasizes the need to consider the larger context of lifetime reproductive behavior when interpreting patterns of female choice. PMID- 23348776 TI - Sexually antagonistic coevolution for sexual harassment can act as a barrier to further invasions by parthenogenesis. AB - The assumption of a twofold cost of sex not only complicates the maintenance of sex but also sets conditions for sexual conflict: in organisms with the twofold cost, males often sexually harass females. Sexual harassment is detrimental to female fitness and thus might help maintain sexual populations if male harassment inflicts a harsher cost on parthenogens than on sexual females (asymmetric harassment cost). However, the generality of this concept is now considered doubtful because selective harassment of parthenogens results in loss of mating opportunities for males. Using three mathematical models, I show here that sexual harassment still can impose the asymmetric cost on parthenogens. First, I apply the Lotka-Volterra model to show the degree of asymmetric harassment cost that permits sex to be maintained stably in the population. Second, using adaptive dynamics, I examine whether sexually antagonistic coevolution for sexual harassment, which occurs only in sexual populations, can promote the asymmetric harassment cost. Finally, an individual-based model, which assumes a spatial structure unlike that in the other two, demonstrates that the asymmetric evolution of harassment cost prevents further invasions of parthenogens from different patches into sexual lineages; these mechanisms may account for allopatric distributions of sexual and parthenogenetic lineages as well as the maintenance of sex. PMID- 23348777 TI - Environmental complexity influences association network structure and network based diffusion of foraging information in fish shoals. AB - Socially transmitted information can significantly affect the ways in which animals interact with their environments. We used network-based diffusion analysis, a novel and powerful tool for exploring information transmission, to model the rate at which sticklebacks (Gasterosteus aculeatus) discovered prey patches, comparing shoals foraging in open and structured environments. We found that for groups in the open environment, individuals tended to recruit to both the prey patch and empty comparison patches at similar times, suggesting that patch discovery was not greatly affected by direct social transmission. In contrast, in structured environments we found strong evidence that information about prey patch location was socially transmitted and moreover that the pathway of information transmission followed the shoals' association network structures. Our findings highlight the importance of considering habitat structure when investigating the diffusion of information through populations and imply that association networks take on greater ecological significance in structured than open environments. PMID- 23348778 TI - Limited oxygen availability in utero may constrain the evolution of live birth in reptiles. AB - Although viviparity (live birth) has evolved from oviparity (egg laying) at least 140 times in vertebrates, nearly 120 of these independent events occurred within a single reptile taxon. Surprisingly, only squamate reptiles (lizards and snakes) are capable of facilitating embryonic development to increasingly advanced stages inside the mother during extended periods of oviducal egg retention. Viviparity has never evolved in turtle lineages, presumably because embryos enter and remain in an arrested state until after eggs are laid, regardless of the duration of egg retention. Until now, the limiting factor that initiates and maintains developmental arrest has remained elusive. Here, we show that oviducal hypoxia arrests embryonic development. We demonstrate that hypoxia can maintain developmental arrest after oviposition and that subsequent exposure of arrested embryos to normoxia triggers resumption of their development. We discovered remarkably low oxygen partial pressure in the oviducts of gravid turtles and found that secretions produced by the oviduct retard oxygen diffusion. Our results suggest that an extremely hypoxic environment in the oviduct arrests embryonic development and may constrain the evolution of viviparity in turtles, with the reduced diffusive capacity of oviducal secretions possibly creating or contributing to this hypoxia. We anticipate that these findings will allow us to better understand the mechanisms underlying the evolutionary transition between reproductive modes. PMID- 23348779 TI - Large-scale natural disturbance alters genetic population structure of the sailfin molly, Poecilia latipinna. AB - Many inferences about contemporary rates of gene flow are based on the assumption that the observed genetic structure among populations is stable. Recent studies have uncovered several cases in which this assumption is tenuous. Most of those studies have focused on the effects that regular environmental fluctuations can have on genetic structure and gene flow patterns. Occasional catastrophic disturbances could also alter either the distribution of habitat or the spatial distribution of organisms in a way that affects population structure. However, evidence of such effects is sparse in the literature because it is difficult to obtain. Hurricanes, in particular, have the potential to exert dramatic effects on population structure of organisms found on islands or coral reefs or in near shore and coastal habitats. Here we draw on a historic genetic data set and new data to suggest that the genetic structure of sailfin molly (Poecilia latipinna) populations in north Florida was altered dramatically by an unusually large and uncommon type of storm surge associated with Hurricane Dennis in 2005. We compare the spatial pattern of genetic variation in these populations after Hurricane Dennis to the patterns described in an earlier study in this same area. We use comparable genetic data from another region of Florida, collected in the same two periods, to estimate the amount of change expected from typical temporal variation in population structure. The comparative natural history of sailfin mollies in these two regions indicates that the change in population structure produced by the storm surge is not the result of many local extinctions with recolonization from a few refugia but emerged from a pattern of mixing and redistribution. PMID- 23348780 TI - A novel report of hatching plasticity in the phylum Echinodermata. AB - Hatching plasticity occurs in response to a wide range of stimuli across many animal taxa, including annelids, arthropods, mollusks, and chordates. Despite the prominence of echinoderms in developmental biology and more than 100 years of detailed examination of their development under a variety of conditions, environmentally cued hatching plasticity has never been reported in the phylum Echinodermata. Here we report plasticity in the timing and stage of hatching of embryos of the sand dollar Echinarachnius parma in response to reductions in salinity. Embryos of E. parma increased their time to hatching more than twofold in response to ecologically relevant salinity reductions, while maintaining an otherwise normal developmental schedule. Embryos that experienced the greatest delay in hatching time emerged from the fertilization envelope as four-arm pluteus larvae rather than hatching as blastulae or early gastrulae. Salinity manipulations across multiple male-female pairs indicated high variability in hatching time both within and among clutches, suggesting significant intraspecific variation in developmental responses to salinity. PMID- 23348781 TI - How did the swiss cheese plant get its holes? AB - Adult leaf fenestration in "Swiss cheese" plants (Monstera Adans.) is an unusual leaf shape trait lacking a convincing evolutionary explanation. Monstera are secondary hemiepiphytes that inhabit the understory of tropical rainforests, where photosynthesis from sunflecks often makes up a large proportion of daily carbon assimilation. Here I present a simple model of leaf-level photosynthesis and whole-plant canopy dynamics in a stochastic light environment. The model demonstrates that leaf fenestration can reduce the variance in plant growth and thereby increase geometric mean fitness. This growth-variance hypothesis also suggests explanations for conspicuous ontogenetic changes in leaf morphology (heteroblasty) in Monstera, as well as the absence of leaf fenestration in co occurring juvenile tree species. The model provides a testable hypothesis of the adaptive significance of a unique leaf shape and illustrates how variance in growth rate could be an important factor shaping plant morphology and physiology. PMID- 23348782 TI - Taxon categories and the universal species-area relationship (a comment on Sizling et al., "between geometry and biology:the problem of universality of the species-area relationship"). AB - A theory of macroecology based on the maximum information entropy (MaxEnt) inference procedure predicts that the log-log slope of the species-area relationship (SAR) at any spatial scale is a specified function of the ratio of abundance, N(A), to species richness, S(A), at that scale. The theory thus predicts, in generally good agreement with observation, that all SARs collapse onto a specified universal curve when local slope, z(A), is plotted against N(A)/S(A). A recent publication, however, argues that if it is assumed that patterns in macroecology are independent of the taxonomic choices that define assemblages of species, then this principle of "taxon invariance" precludes the MaxEnt-predicted universality of the SAR. By distinguishing two dimensions of the notion of taxon invariance, we show that while the MaxEnt-based theory predicts universality regardless of the taxonomic choices that define an assemblage of species, the biological characteristics of assemblages should under MaxEnt, and do in reality, influence the realism of the predictions. PMID- 23348784 TI - The predictive adaptive response: modeling the life-history evolution of the butterfly Bicyclus anynana in seasonal environments. AB - A predictive adaptive response (PAR) is a type of developmental plasticity where the response to an environmental cue is not immediately advantageous but instead is later in life. The PAR is a way for organisms to maximize fitness in varying environments. Insects living in seasonal environments are valuable model systems for testing the existence and form of PAR. Previous manipulations of the larval and the adult environments of the butterfly Bicyclus anynana have shown that individuals that were food restricted during the larval stage coped better with forced flight during the adult stage compared to those with optimal conditions in the larval stage. Here, we describe a state-dependent energy allocation model, which we use to test whether such a response to food restriction could be adaptive in nature where this butterfly exhibits seasonal cycles. The results from the model confirm the responses obtained in our previous experimental work and show how such an outcome was facilitated by resource allocation patterns to the thorax during the pupal stage. We conclude that for B. anynana, early-stage cues can direct development toward a better adapted phenotype later in life and, therefore, that a PAR has evolved in this species. PMID- 23348785 TI - Distinguishing between indirect and direct modes of transmission using epidemiological time series. AB - Pathogen transmission can involve direct and/or indirect pathways. Using theoretical models, in this study we ask, "do directly and indirectly transmitted pathogens yield different population-level epidemiological dynamics?" and "can the transmission pathway be inferred from population-level epidemiological data?" Our approach involves comparing the continuous-time dynamics of a class of compartmental epidemiological models with direct versus environmentally mediated indirect transmission pathways. Combing analytical theory and numerical simulations we show that models with direct and indirect transmission can produce quantitatively similar time series when the pathogen cannot reproduce in the environment, particularly when the environmental pathogen dynamics are fast. We apply these results to a previous study on chronic wasting disease and show that identifying the transmission pathway is more difficult than previously acknowledged. Our analysis and simulations also yield conditions under which numerical differences can potentially identify the transmission route in oscillating endemic systems and systems where the environmental pathogen dynamics are not fast. This work begins to identify how differences in the transmission pathway can result in quantitatively different epidemiological dynamics and how those differences can be used to identify the transmission pathway from population level time series. PMID- 23348786 TI - RAMP: a bioinformatics framework for researching imaging agents through molecular pathways. AB - Signaling pathways are the fundamental grammar of cellular communication, yet few frameworks are available to analyze molecular imaging probes in the context of signaling pathways. Such a framework would aid in the design and selection of imaging probes for measuring specific signaling pathways and, vice versa, help illuminate which pathways are being assayed by a given probe. RAMP (Researching imaging Agents through Molecular Pathways) is a bioinformatics framework for connecting signaling pathways and imaging probes using a controlled vocabulary of the imaging targets. RAMP contains signaling pathway data from MetaCore, the Kyoto Encyclopedia of Genes and Genomes, and the Gene Ontology project; imaging probe data from the Molecular Imaging and Contrast Agent Database (MICAD); and tissue protein expression data from The Human Protein Atlas. The RAMP search tool is available at . Examples are presented to demonstrate the utility of RAMP for pathway-based searches of molecular imaging probes. PMID- 23348787 TI - In vivo imaging of brain infarct with the novel fluorescent probe PSVue 794 in a rat middle cerebral artery occlusion-reperfusion model. AB - The utility of PSVue 794 (PS794), a near-infrared fluorescent dye conjugated to a bis[zinc (II)-dipicolylamine] (Zn-DPA) targeting moiety, in imaging brain infarct was assessed in a rat middle cerebral artery occlusion-reperfusion model. Following reperfusion, 1 mM PS794 solution was administered intravenously via a tail vein. Fluorescence images were captured between 6 to 72 hours postinjection using a LI-COR Biosciences Pearl Imaging System. Strong fluorescence signals, which may represent the infarct core, were detected in the right hemisphere, ipsilateral to the injured site, and weaker signals in areas surrounding the core. In ischemia-reperfusion rats injected with a control dye not linked to a targeting agent, fluorescence was distributed diffusely throughout the brain. To address the issue of whether Zn-DPA targets apoptotic/necrotic cells, HT22 mouse hippocampal neurons were cultured in either Dulbecco's Modified Eagle's Medium, serum-deprived medium, Hank's Balanced Salt Solution, or L-glutamate (10 mM) containing medium for up to 33 hours. Cells were then double-labeled with PSVue 480 (Zn-DPA conjugated to fluorescein isothiocyanate) and propidium iodide, which labels necrotic cells. Microscopic examination revealed that PS480 targeted apoptotic and necrotic cells. The result indicates that PS794 is applicable to in vivo imaging of brain infarct and that Zn-DPA selectively targets apoptotic/necrotic cells. PMID- 23348788 TI - Development and characterization of 89Zr-labeled panitumumab for immuno-positron emission tomographic imaging of the epidermal growth factor receptor. AB - The epidermal growth factor receptor (EGFR) is overexpressed in the majority of malignancies and has been associated with poor outcomes. Panitumumab, an anti EGFR monoclonal antibody that binds to the extracellular binding domain of EGFR, is increasingly used with radiotherapy and chemotherapy but has associated toxicities. The purpose of this study was to develop and characterize a novel targeted imaging agent for the EGFR using radiolabeled panitumumab. Flow cytometry studies were performed to evaluate EGFR expression in several cell lines. Desferrioxamine-Bz-NCS (DFO) was conjugated to panitumumab and labeled with (89)Zr. Cell uptake studies were performed in four cell lines. For biodistribution studies and micro-positron emission tomography/computed tomography (PET/CT), mouse xenograft models were generated using the same cell lines. PET was performed, and tumors and select organs were harvested for biodistribution studies. Panitumumab was radiolabeled with (89)Zr with high radiochemical purity and specific activity and was found to be stable in serum. Cell binding studies demonstrated that radiotracer uptake in cells correlated with the degree of EGFR expression. MicroPET/CT imaging studies demonstrated a high intensity of (89)Zr-panitumumab in A431 and HCT 116 tumors in comparison with the EGFR-negative tumors. Biodistribution studies confirmed the results from the imaging studies. (89)Zr-panitumumab imaging of EGFR-positive tumors demonstrated levels of radiotracer uptake associated with EGFR expression. PMID- 23348789 TI - Flexible peritoneal windows for quantitative fluorescence and bioluminescence preclinical imaging. AB - At present, there is considerable interest in the use of in vivo fluorescence and bioluminescence imaging to track the onset and progression of pathologic processes in preclinical models of human disease. Optical quantitation of such phenomena, however, is often problematic, frequently complicated by the overlying tissue's scattering and absorption of light, as well as the presence of endogenous cutaneous and subcutaneous fluorophores. To partially circumvent this information loss, we report here the development of flexible, surgically implanted, transparent windows that enhance quantitative in vivo fluorescence and bioluminescence imaging of optical reporters. These windows are metal and glass free and thus compatible with computed tomography, magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography; they also permit visualization of much larger areas with fewer impediments to animal locomotion and grooming than those previously described. To evaluate their utility in preclinical imaging, we surgically implanted these windows in the abdominal walls of female athymic nude mice and subsequently inoculated each animal with 1 * 10(4) to 1 * 10(6) bioluminescent human ovarian cancer cells (SKOV3ip.1-luc). Longitudinal imaging studies of fenestrated animals revealed up to 48-fold gains in imaging sensitivity relative to nonfenestrated animals, with relatively few complications, allowing wide-field in vivo visualization of nascent metastatic ovarian cancer colonization. PMID- 23348790 TI - Monitoring glioma growth and tumor necrosis with the U-SPECT-II/CT scanner by targeting integrin alphavbeta3. AB - The purpose of this study was to validate (99m)Tc-3P-RGD(2) single-photon emission computed tomography/computed tomography (SPECT/CT) as an imaging tool to monitor alpha(v)beta(3) expression and tumor necrosis. The animal model was established by subcutaneous injection of 5 * 10(6) U87MG cells into the shoulder flank of each mouse. Imaging was performed using the U-SPECT-II/CT scanner (Milabs, Utrecht, the Netherlands). Tumor volumes were determined, and the tumor uptake of (99m)Tc-3P-RGD(2) was calculated on the basis of SPECT/CT and compared to that from biodistribution. Immunohistochemistry was performed to determine CD31 and alpha(v)beta(3) expression levels. We found that the tumor detection limit was ~ 0.5 mm(3) by (99m)Tc-3P-RGD(2) SPECT/CT. The tumor uptake of (99m)Tc 3P-RGD(2) from SPECT/CT was almost identical to that from biodistribution. The alpha(v)beta(3) was expressed mainly on blood vessels for the tumors of 0.2 to 0.5 cm(3). In larger tumors, tumor alpha(v)beta(3) expression increased due to more contribution from glioma cells. When tumors were > 0.5 cm(3), the %ID/cm(3) uptake of (99m)Tc-3P-RGD(2) decreased because of necrosis. The overall relationship between the tumor size and %ID of (99m)Tc-3P-RGD(2) was modeled as a quadratic polynomial fitting curve, with R(2) being > .95. (99m)Tc-3P-RGD(2) SPECT/CT is excellent for monitoring alpha(v)beta(3) expression and tumor necrosis during tumor growth and may become a screening tool for patient selection before anti-alpha(v)beta(3) therapy. PMID- 23348791 TI - Pharmacologic activation of tumor hypoxia: a means to increase tumor 2-deoxy-2 [18F]fluoro-D-glucose uptake? AB - Tumor hypoxia and tumor metabolism are linked through the activation of metabolic genes following hypoxia-inducible factor 1 (HIF-1) activation. This raises the question of whether this relationship can be exploited to improve 2-deoxy-2 [(18)F]fluoro-D-glucose positron emission tomography ([(18)F]FDG-PET). To do this, [(18)F]FDG uptake was investigated after chemical induction of hypoxia and chemical activation of HIF-1 in an in vitro and an in vivo model of a human colorectal carcinoma. [(18)F]FDG uptake, HIF-1alpha protein levels, and messenger ribonucleic acid expression of glucose transporter 1 (GLUT1), hexokinase 2, HIF 1alpha, and carbonic anhydrase IX (CA IX) were determined in HT29 cells after treatment with 200 MUM CoCl(2) and 500 MUM dimethyloxalylglycine (DMOG). In an HT29 xenograft, the distribution of endogenous and exogenous markers of hypoxia was investigated using immunohistochemistry, and tumor [(18)F]FDG uptake was determined after treatment with a single dose of 5 mg/kg hydralazine and 8 mg DMOG. Treatment of HT29 cells with CoCl(2) and DMOG induced functional HIF-1 and resulted in increased [(18)F]FDG uptake. In an HT29 xenograft, a similar spatial distribution of pimonidazole, CA IX, and GLUT1 was found, and treatment with DMOG resulted in significant increases in maximum and mean standardized uptake values using [(18)F]FDG-PET. Chemical activation of HIF-1 can increase in vitro and in vivo [(18)F]FDG uptake. Imaging after pharmacologic HIF-1 activation might increase tumor [(18)F]FDG uptake when using [(18)F]FDG-PET. PMID- 23348792 TI - Quantitative magnetic resonance imaging in the transgenic APC(Delta468) mouse model of hereditary colon cancer. AB - In this study, we investigated the use of high-resolution magnetic resonance imaging (MRI) methods for in vivo detection and quantitative characterization of colorectal tumors in the transgenic APC(Delta468) mouse model. High-resolution T(1)-weighted (T(1)W) images, T(2)-weighted (T(2)W) images, and dynamic contrast enhanced (DCE) measurements were performed using a 7.0 T small-animal imaging system (N = 10). Individual tumors were identified on both T(1)W and T(2)W images. Twenty-eight tumors (2.8 +/- 0.9 mm, mean +/- SD) were detected with high resolution MRI across a distance of roughly 3 cm from the rectum to the splenic flexure, whereas 29 tumors were found within corresponding colon tissue samples examined at gross necropsy in the same area. T(2) values were significantly different between tumor, skeletal muscle, and normal intestinal wall tissues (p < .05). For analysis of the vascular characteristics of colon tumor tissues using DCE measurements, the initial area under the curve (IAUC) for Gd contrast concentration curve (time) (C(Gd) [t]) was calculated with integration times of 60 and 120 seconds post-contrast infusion; two integration times were selected to capture both tracer wash-in and wash-out characteristics. IAUC measurements were significantly larger in tumor tissues compared to both normal intestinal wall and skeletal muscle tissues (p < .001). In vivo anatomic and quantitative MRI measurements were readily feasible in the transgenic APC(Delta468) mouse model. These noninvasive methods should improve experimental efficiencies during longitudinal survival studies that otherwise would require single-end-point necropsy measurements. PMID- 23348793 TI - Imaging of tumor vascularization using fluorescence molecular tomography to monitor arginine deiminase treatment in melanoma. AB - Based on their inability to express argininosuccinate synthetase (ASS), some cancer entities feature the characteristic of L-arginine (Arg) auxotrophy. This inability to intrinsically generate Arg makes them applicable for arginine deiminase (ADI) treatment, an Arg-depleting drug. Arg is also used for the synthesis of endothelial nitric oxide (NO), which mainly confers vasodilatation but is also considered to have a major influence on tumor vascularization. The purpose of this study was to define changes in tumor vasculature in an ADI treated melanoma xenograft mouse model using the blood pool agent AngioSense 750 and fluorescence molecular tomography (FMT). We used an ASS-negative melanoma xenograft mouse model and subjected it to weekly ADI treatment. Changes in tumor size were measured, and alterations in tumor vasculature were depicted by FMT and CD31 immunohistochemistry (IHC). On ADI treatment and effective antitumor therapy, we observed a drop in NO plasma levels and visualized changes in tumor vascularization with FMT and IHC. ADI treatment in melanoma xenografts has a tumor-reducing effect, which can be noninvasively imaged by quantifying tumor vascularization with FMT and IHC. PMID- 23348796 TI - Thermodynamic stability and relaxation studies of small, triaza-macrocyclic Mn(II) chelates. AB - Due to its favorable relaxometric properties, Mn(2+) is an appealing metal ion for magnetic resonance imaging (MRI) contrast agents. This paper reports the synthesis and characterization of three new triazadicarboxylate-type ligands and their Mn(2+) chelates (NODAHep, 1,4,7-triazacyclononane-1,4-diacetate-7-heptanil; NODABA, 1,4,7-triazacyclononane-1,4-diacetate-7-benzoic acid; and NODAHA, 1,4,7 triazacyclononane-1,4-diacetate-7-hexanoic acid). The protonation constants of the ligands and the stability constants of the chelates formed with Mn(2+) and the endogenous Zn(2+) ion have been determined by potentiometry. In overall, the thermodynamic stability of the chelates is lower than that of the corresponding NOTA analogues (NOTA = 1,4,7-triazacyclononane-1,4,7-triacetate), consistent with the decreased number of coordinating carboxylate groups. Variable temperature (1)H NMRD and (17)O NMR measurements have been performed on the paramagnetic chelates to provide information on the water exchange rates and the rotational dynamics. The values of the (17)O chemical shifts are consistent with the presence of one water molecule in the first coordination sphere of Mn(2+). The three complexes are in the slow to intermediate regime for the water exchange rate, and they all display relatively high rotational correlation times, which explain the relaxivity values between 4.7 and 5.8 mM(-1) s(-1) (20 MHz and 298 K). These relaxivities are higher than expected for Mn(2+) chelates of such size and comparable to those of small monohydrated Gd(3+) complexes. The amphiphilic [Mn(NODAHep)] forms micelles above 22 mM (its critical micellar concentration was determined by relaxometry and fluorescence), and interacts with HSA via its alkylic carbon chain providing a 60% relaxivity increase at 20 MHz due to a longer tumbling time. PMID- 23348797 TI - Highly selective sorption and luminescent sensing of small molecules demonstrated in a multifunctional lanthanide microporous metal-organic framework containing 1D honeycomb-type channels. AB - A rare, robust microporous lanthanide metal-organic framework with 1D honeycomb type channels is presented. Excellent adsorption capabilities for N(2), H(2), and CO(2) and significant selective sorption of CO(2) over N(2) and CH(4) were observed. Moreover, the guest-dependent luminescent behavior of these lanthanide materials shows a potential use for the sensing of small-molecule pollutants such as benzene and acetone. PMID- 23348798 TI - Plasmatic tissue factor pathway inhibitor is a major determinant of clotting in factor VIII inhibited plasma or blood. AB - Tissue factor pathway inhibitor (TFPI) is a major inhibitor of coagulation. We therefore hypothesised that high plasmatic TFPI levels are associated with impaired ex vivo clotting in a model of acquired haemophilia. Blood samples were collected in a prospective clinical study from 30 healthy volunteers. Coagulation in normal or factor VIII (FVIII)-inhibited human blood or plasma was measured by the calibrated automated thrombogram (CAT) and rotational thromboelastometry (ROTEM). Both methods are global haemostatic assays that provide insight into the whole coagulation process. Monoclonal mouse antibodies raised against either the C-terminus or the Kunitz domain 2 of TFPI were used to determine full-length (fl ) and total TFPI by an enzyme-immunoassay. Clotting times and parameters of thrombin generation correlated with TFPI levels. Subjects with low fl-TFPI levels had significantly shorter clotting times and a higher endogenous thrombin potential (ETP) compared to those with high fl-TFPI levels (p<=0.005 for all). An even stronger effect was seen in FVIII-inhibited blood/plasma: ROTEM clotting time was 26% shorter (p=0.01) and the ETP assessed by CAT was >2-fold higher in subjects with low fl-TFPI levels (p<=0.0001). Plasmatic TFPI is a major determinant of coagulation in global haemostatic tests particularly when FVIII is missing. Thus, inhibition of TFPI might be a promising novel treatment approach, especially in haemophilia patients with FVIII inhibitors. PMID- 23348799 TI - Electrorotation of titanium microspheres. AB - Electrorotation (ROT) data for solid titanium micrometer-sized spheres in an electrolyte are presented for three different ionic conductivities, over the frequency range of 10 Hz to 100 kHz. The direction of rotation was found to be opposite to the direction of rotation of the electric field vector (counterfield electrorotation), with a single rotation peak. The maximum rotation rate occurs at a frequency of the order of the reciprocal RC time constant for charging the particle double layer capacitance through the resistor of the electrolyte bulk. A model for the electrical torque acting on a metallic sphere is presented, using a constant phase element impedance to describe the metal/electrolyte interface. The titanium spheres are much denser than the electrolyte and rest on the bottom substrate. Therefore, the electrical and viscous torques near a wall are considered in the analysis. Good agreement is found between the predicted and measured rotational speed as a function of frequency. Theory shows that there is no effect of induced charge electroosmotic flow on the ROT, as observed experimentally. PMID- 23348800 TI - Cystatin C and neutrophil gelatinase-associated lipocalin: biomarkers for acute kidney injury after congenital heart surgery. AB - QUESTIONS UNDER STUDY: To evaluate the diagnostic value of serum Cystatin C and urine neutrophil gelatinase-associated lipocalin (NGAL) for the detection of acute kidney injury in patients undergoing congenital heart surgery. METHODS: Serial samples of serum Cystatin C and urine NGAL were collected from 139 consecutive patients with congenital heart defects aged 3 days to 30 years after admission to the intensive care unit, 2 and 6 hours after the end of cardiopulmonary bypass. Biomarker levels were compared to perioperative data retrospectively. Acute kidney injury was defined according to the paediatric modified RIFLE classification. RESULTS: According to the paediatric-modified RIFLE criteria 53% of patients developed evidence of acute kidney injury. Serum Cystatin C concentrations were strongly correlated with severity of acute kidney injury. Optimal sensitivity of 80% and specificity of 66% for the prediction of acute kidney injury occurred at a cut-off value of 0.995 mg/l, 2 hours after the end of cardiopulmonary bypass. The 2 hour urine NGAL concentration was significantly correlated to the duration of cardiopulmonary bypass, time of aortic cross clamping, and serum lactate concentration. Moreover a significant correlation was found between urine NGAL and both length of hospital stay and mechanical ventilation. CONCLUSIONS: In patients after congenital heart surgery, urine NGAL indicates the damaging force of cardiopulmonary bypass and serum Cystatin C is a valuable predictive biomarker for resulting acute kidney injury. PMID- 23348801 TI - When does combining markers improve classification performance and what are implications for practice? AB - When an existing standard marker does not have sufficient classification accuracy on its own, new markers are sought with the goal of yielding a combination with better performance. The primary criterion for selecting new markers is that they have good performance on their own and preferably be uncorrelated with the standard. Most often linear combinations are considered. In this paper, we investigate the increment in performance that is possible by combining a novel continuous marker with a moderately performing standard continuous marker under a variety of biologically motivated models for their joint distribution. We find that an uncorrelated continuous marker with moderate performance on its own usually yields only minimally improved performance. We identify other settings that lead to large improvements, including a novel marker that has very poor performance on its own but is highly correlated with the standard and a novel marker with poor to moderate performance that is highly correlated with the standard but only in one class category. These results suggest changing current strategies for identifying markers to be included in panels for possible combination. Using simulated and real datasets, we examine the merits of a broadened strategy that selects panels of markers as candidates on the basis of their joint performance with existing markers, compared with the standard strategy that selects markers on the basis of their marginal performance. We find that a broadened strategy can be fruitful but necessitates using studies with large numbers of subjects. PMID- 23348802 TI - Long-term changes in BMI and adiposity rebound among girls from Krakow (Poland) over the last 30 years (from 1983 to 2010). AB - BACKGROUND: Early adiposity rebound (AR, below 5 years) is an important predictor of adult obesity. OBJECTIVES: The main purpose of this study was to explore changes in body weight and height, BMI, body fat, and AR timing in girls from Krakow within the last 3 decades. METHODS: 1,970 girls were measured in 2010. Using the results of body height, weight and skin folds measurements, the BMI and %BF was calculated. The LMS method was used to constructed BMI and %BF centiles. Three fractions were distinguished in individual age groups of the subjects-below the 15th percentile (underweight girls), 50th percentile and above 85th percentile (overweight girls). These data were compared with the results from previous survey series (1983 and 2000). The mean age of the menarche onset were calculated by means of the probit method. RESULTS: The girls from last series are taller and heavier than girls measured in 1983. Before the time of AR, girls from last series have lowest BMI and %BF than girls from the first series. In spite of this, all girls measured in 2010 have the time of AR earlier than girls measured in 1983. The girls from the last series of measurements showed also acceleration of sexual maturation and the average menarche age was the earliest in them and equalled 12.68 years. CONCLUSIONS: AR cannot be explained only by changes in body adiposity. Early AR could be a marker of acceleration of development already in an early postnatal ontogenesis. PMID- 23348803 TI - Inducible NOS mediates CNP-induced relaxation of intestinal myofibroblasts. AB - Contraction of intestinal myofibroblasts (IMF) contributes to the development of strictures and fistulas seen in inflammatory bowel disease, but the mechanisms that regulate tension within these cells are poorly understood. In this study we investigated the role of nitric oxide (NO) signaling in C-type natriuretic peptide (CNP)-induced relaxation of IMF. We found that treatment with ODQ, a soluble guanylyl cyclase (sGC) inhibitor, or N(G)-nitro-L-arginine (L-NNA) or N(G)-monomethyl-L-arginine (L-NMMA), inhibitors of NO production, all impaired the relaxation of human and mouse IMF in response to CNP. ODQ, L-NNA, and L-NMMA also prevented CNP-induced elevations in cGMP concentrations, and L-NNA or L-NMMA blocked CNP-induced decreases in myosin light phosphorylation. IMF isolated from transgenic mice deficient in inducible nitric oxide synthase (iNOS) had reduced relaxation responses to CNP compared with IMF from control mice and were insensitive to the effects of ODQ, L-NNA, and L-NMMA on CNP treatment. Together these data indicate that stimulation of sGC though NO produced by iNOS activation is required for maximal CNP-induced relaxation in IMF. PMID- 23348805 TI - Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. AB - Maturity-onset diabetes of the young (MODY) is a monogenic disorder characterized by autosomal dominant inheritance of young-onset (typically <25 years), noninsulin-dependent diabetes due to defective insulin secretion. MODY is both clinically and genetically heterogeneous with mutations in at least 10 genes. Mutations in the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are the most common cause of MODY in most adult populations studied. The number of different pathogenic HNF1A mutations totals 414 in 1,247 families. Mutations in the HNF4A gene encoding hepatocyte nuclear factor-4 alpha are a rarer cause of MODY with 103 different mutations reported in 173 families to date. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The HNF4A MODY phenotype has been expanded by the reports of macrosomia in ~50% of babies, and more rarely, neonatal hyperinsulinemic hypoglycemia. The identification of an HNF1A or HNF4A gene mutation has important implications for clinical management in diabetes and pregnancy, but MODY is significantly underdiagnosed. Current research is focused on identifying biomarkers and developing probability models to identify those patients most likely to have MODY, until next generation sequencing technology enables cost effective gene analysis for all patients with young onset diabetes. PMID- 23348804 TI - Comparative outcomes of oncologic therapy in gastric extranodal marginal zone (MALT) lymphoma: analysis of the SEER-Medicare database. AB - BACKGROUND: Therapy for gastric marginal zone (MALT) lymphoma is largely based on single-arm trials. This observational study compared survival with radiotherapy, rituximab and combination chemoimmunotherapy in this disease. PATIENTS AND METHODS: Gastric MALT lymphoma cases diagnosed between 1997 and 2007 were selected from the Surveillance, Epidemiology and End Results-Medicare database. Propensity score analysis and competing risk models were used to compare survival in patients with stage IE treated with radiation or chemotherapy, and in patients of all stages treated with rituximab alone or with chemoimmunotherapy. RESULTS: Among 1134 patients, 21% underwent radiation and 24% chemotherapy as initial treatment. In the balanced cohort of 347 patients with stage IE, radiotherapy alone was associated with a better cause-specific survival [hazard ratio (HR) 0.27, P < 0.001]. Patients receiving systemic therapy had better survival if it incorporated rituximab (HR 0.53, P = 0.017). After adjustment for confounding, the outcomes of those who received rituximab alone or combination chemoimmunotherapy were not statistically different (P = 0.14). CONCLUSIONS: In elderly patients with stage IE gastric MALT lymphoma, radiotherapy was associated with lower risk of lymphoma-related death than chemotherapy. In those requiring systemic treatment, addition of cytotoxic chemotherapy to rituximab in the first line regimen was not associated with improved survival. PMID- 23348806 TI - Core-shell poly-methylmethacrylate nanoparticles as effective carriers of electrostatically loaded anionic porphyrin. AB - Among the medical applications of nanoparticles, their usage as photosensitizer (PS) carriers for photodynamic therapy (PDT) has attracted increasing attention. In the present study we explored the morphological and photophysical properties of core-shell PMMA nanoparticles (PMMA-NPs) electrostatically post-loaded with the synthetic, water soluble 5,10,15,20-tetrakis(4-sulphonatophenyl)-porphyrin (TPPS4). pH response and singlet oxygen analyses of differently loaded samples proved the high capability of the PMMA-NPs to shield the PS from the environment, while retaining the PS singlet oxygen production capability. Preliminary in vitro imaging and phototoxicity experiments on HepG2 cells demonstrated the efficacy of the system to trigger photoinduced cell death in the culture. PMID- 23348807 TI - Asthmatic children have increased specific anti-Mycoplasma pneumoniae IgM but not IgG or IgE-values independent of history of respiratory tract infection. AB - BACKGROUND: Bronchial asthma is exacerbated by Mycoplasma pneumoniae-induced upper respiratory tract infections (URTIs) in children. Specific IgM and IgG isotypes are involved in the immune response to M. pneumoniae, but little is known about the role of specific IgE antibodies against M. pneumoniae in asthma. OBJECTIVE: To investigate the role of IgM-, IgG- and IgE-specific antibody responses to M. pneumoniae in children with persistent asthma in relationship to history of URTI within the past 6 months. METHODS: Total or specific anti-M. pneumoniae IgM, IgG and IgE antibody responses were studied in stable asthmatic pediatric patients (M. pneumoniae positive and negative) without current exacerbation and nonasthmatic controls (N = 23 and 13, respectively) (UniCAP total IgE Fluoroenzymeimmunoassay, enzyme-linked immunosorbent assay). RESULTS: Values of specific IgM correlated with specific IgG (Spearman correlation, rho = 0.61, P < 0.0001) but not with specific IgE anti-M. pneumoniae antibodies (AMA) in asthmatic subjects compared with nonasthmatic controls. However, concentrations of specific IgG correlated with specific IgE AMA (rho = 0.49, P = 0.0017). Asthmatic subjects had higher levels of specific IgM AMA levels compared with nonasthmatics (median [interquartile range]: 0.57 [1.00] versus 0.21 [0.19]; Kruskal-Wallis test, P = 0.0008). In addition, IgM positivity was significantly higher in asthmatic compared with nonasthmatic subjects (39.1% versus 0.0%; Fisher's exact test, P = 0.01). These results were independent of URTI history in the past 6 months, which was not associated with higher IgM, IgG or IgE AMA levels compared with no URTI history (P = 0.25-0.64). CONCLUSIONS: Increased specific IgM anti-M. pneumoniae responses may indicate an important role for M. pneumoniae infection in asthma. PMID- 23348809 TI - Phase II study of a three-dose primary vaccination course of DTPa-IPV/Hib-MenC-TT followed by a 12-month Hib-MenC-TT booster in healthy infants. AB - AIM: To test for immunologic noninferiority of antibody responses to Hib and MenC using a 6-in-1 combination vaccine (DTPa-IPV/Hib-MenC-TT) compared with DTPa-IPV Hib plus MenC-CRM197, before and after a 12-month Hib-MenC-TT booster. METHODS: Pragmatic open-label, randomized, multicenter, UK study. "6-in-1" group received DTPa-IPV/Hib-MenC-TT at 2, 3 and 4 months; control group received DTPa-IPV-Hib at 2, 3 and 4 months and MenC-CRM197 at 3 and 4 months. Both groups received Hib MenC-TT at 12 months. Concomitant vaccines: pneumococcal conjugate vaccine at 2, 4 and 13 months, and measles, mumps and rubella vaccine at 13 months. RESULTS: One hundred forty-two children were randomized to each group. One hundred children in the "6-in-1" group and 112 control group children completed the study according-to-protocol. One month postprimary immunizations: 100% of "6-in-1" group and 93.3% of control children had anti-polyribosylribitol phosphate (PRP) IgG >=0.15 ug/mL; 96.2% and 100%, respectively, had rSBA-MenC titers >=1:8. One month after booster all children met these thresholds, with anti-PRP geometric mean concentrations of 66.7 (53.3; 83.5) in "6-in-1" recipients and 26.9 (20.9; 34.6) in control children (4.4 [3.5; 5.4] and 3.0 [2.2-4.2] postprimary immunizations, respectively,). rSBA-MenC geometric mean titers were 3062.9 (2421.2; 3874.6) and 954.0 (761.3; 1195.5), respectively, postbooster and 393.2 (292.5; 528.7) and 3110.5 (2612; 3704.2) postprimary. CONCLUSION: Noninferiority of DTPa-IPV/Hib-MenC-TT compared with DTPa-IPV/Hib plus MenC-CRM197 was demonstrated. In the "6-in-1" group, lower postprimary and greater postbooster rSBA-MenC geometric mean titers suggest memory B-cell priming may be favored by this vaccine over plasma cell induction. Furthermore, greater immunogenicity of TT conjugates used in both primary and booster vaccines in this group may be important. PMID- 23348810 TI - Investigation of an outbreak of osteoarticular infections caused by Kingella kingae in a childcare center using molecular techniques. AB - We describe an outbreak of 5 osteoarticular infections among 24 daycare center attendees. Polymerase chain reaction revealed Kingella kingae in the joint fluid of 1 child and in 85% of throat samples from healthy contacts. Multilocus sequence typing performed on the joint fluid and carriage isolates identified an unique sequence type. Rifampin failed to eradicate K. kingae carriage. PMID- 23348808 TI - Isoniazid-resistant tuberculosis in children: a systematic review. AB - BACKGROUND: Isoniazid resistance is an obstacle to the treatment of tuberculosis disease and latent tuberculosis infection in children. We aim to summarize the literature describing the risk of isoniazid-resistant tuberculosis among children with tuberculosis disease. METHODS: We did a systematic review of published reports of children with tuberculosis disease who had isolates tested for susceptibility to isoniazid. We searched PubMed, Embase and LILACS online databases up to January 12, 2012. RESULTS: Our search identified 3403 citations, of which 95 studies met inclusion criteria. These studies evaluated 8351 children with tuberculosis disease for resistance to isoniazid. The median proportion of children found to have isoniazid-resistant strains was 8%; the distribution was right-skewed (25th percentile: 0% and 75th percentile: 18%). CONCLUSIONS: High proportions of isoniazid resistance among pediatric tuberculosis patients have been reported in many settings suggesting that diagnostics detecting only rifampin resistance are insufficient to guide appropriate treatment in this population. Many children are likely receiving substandard tuberculosis treatment with empirical isoniazid-based regimens, and treating latent tuberculosis infection with isoniazid may not be effective in large numbers of children. Work is needed urgently to identify effective regimens for the treatment of children sick with or exposed to isoniazid-resistant tuberculosis and to better understand the scope of this problem. PMID- 23348811 TI - Polymicrobial acute respiratory infections in a hospital-based pediatric population. AB - BACKGROUND: The clinical impact of polymicrobial respiratory infections remains uncertain. Previous reports are contradictory regarding an association with severe disease. METHODS: Three hundred forty-six specimens from children with acute respiratory illness identified at the University of Iowa Hospitals and Clinics Clinical Microbiology Laboratory were evaluated by direct immunofluorescent assay and/or viral culture by Clinical Microbiology Laboratory and later by molecular study for the presence of influenza, parainfluenza, respiratory syncytial virus, adenovirus, human metapneumovirus, rhinovirus and human bocavirus. Demographic and clinical data were abstracted from medical records. RESULTS: Multiple viruses were detected in 46 (21.7%) of 212 virus positive specimens with the most frequent virus-virus combinations being HRV respiratory syncytial virus (n = 12), HRV-human bocavirus (n = 6) and HRV parainfluenza virus 3 (n = 4). Risk factors for coinfection included male gender (OR [odds ratio]: 1.70, 95% confidence interval [CI]: 0.83-3.46), 6 months to 1 year age (OR: 2.15, 95% CI: 0.75-6.19) and history of immunosuppression (OR: 2.05, 95% CI: 0.99-4.23). Children with viral coinfections were less likely than children with single virus infections to be admitted to an intensive care unit (OR: 0.32, 95% CI: 0.08-1.27); however, this may be explained by undetected viral bacterial coinfections. CONCLUSIONS: HRV, respiratory syncytial virus, human bocavirus, and polymicrobial infections were prevalent in this study. Although the cross-sectional design could not easily examine polymicrobial infection and disease severity, prospective, population-based research regarding the clinical impact of such infections is warranted. PMID- 23348812 TI - Serotypeo1 [corrected] childhood invasive pneumococcal disease has unique characteristics compared to disease caused by other streptococcus pneumoniae serotypes. AB - BACKGROUND: We aimed to determine whether serotype 1 (SP1) invasive pneumococcal disease (IPD) can be distinguished by demographic, clinical and laboratory characteristics from IPD caused by the other most common serotypes (MCS) in our region: 5, 14, 6A, 6B, 19A, 19F, 23F. METHODS: Data for all IPD episodes in children <18 years old treated at the Soroka University Medical Center during 2000 to 2009 were retrospectively retrieved. Episodes caused by SP1-IPD were compared with those caused by MCS-IPD (both grouped and individual serotypes). Analyses were adjusted for age and ethnicity. RESULTS: Ninety-four SP1-IPD and 250 MCS-IPD episodes were documented. SP1-IPD cases were older (68.3 +/- 52.6 months versus 30.4 +/- 39.2 months; P < 0.001) and more likely to be found in Bedouin children than MCS-IPD (87.5% versus 58.6%; P < 0.001). SP1 was less frequently isolated from patients with underlying disease than MCS (14.9% versus 31.6 %; P < 0.001; relative risk 0.15 [95% confidence interval: 0.07-0.32]). SP1 was more often associated with bacteremic pneumonia and primary peritonitis than MCS (66% versus 38.4% and 7.4% versus 0.8%, respectively; P < 0.001); the proportion of bacteremia without focus was higher in MCS-IPD (32.4% versus 12.5%; P < 0.001). There were no differences in hospitalization and mortality rates (70.2% versus 68.0% [P = 0.22] and 4.3% versus 5.6% [P = 0.26], respectively). CONCLUSIONS: SP1 was found less frequently than MCS in children with underlying diseases, but it was more frequent in older and Bedouin children with IPD. SP1 was more frequently associated with bacteremic pneumonia and primary peritonitis than MCS grouped. PMID- 23348813 TI - Development and validation of a new grading scale for otitis media. AB - BACKGROUND: Grading of acute otitis media (AOM) is important in clinical situations as well as in research. Current grading scales for AOM have used a 6 to 9 point scoring system primarily based on variation of redness and bulging of the tympanic membrane (TM). This study aimed to develop and validate a new scale for grading AOM. METHOD: The scale was developed in 3 stages based on 32 patients with images taken of the TM when a child attended healthcare centre with othalgia and at follow-up visits. Content validity was used as the method for the first 2 stages. An expert panel reviewed the scale and repeated the process on a revised scale. Reliability was tested with a different expert panel that used the final scale on a sample of TM images in a test-retest and inter-rater and intra-rater agreements were calculated. RESULTS: The scale was developed in 3 steps using expert committees. During the process the description of vascularization was judged to be of insufficient importance for our scale. Inter-rater agreement was moderate (kappa = 0.52) and intra-rater agreement was good (kappa = 0.66 to 0.89) in the test-retest of the final scale. CONCLUSIONS: The developed AOM image-based grading scale demonstrates substantial inter- and intra-rater reliability with potential use in clinical research and telemedicine applications. Furthermore, the parameter "redness of TM" is of less importance in our scale as compared with other available grading systems. PMID- 23348814 TI - One or two doses of quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine is immunogenic in 9- to 12-month-old children. AB - BACKGROUND: The incidence of invasive meningococcal disease is highest in infants. A quadrivalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT) was evaluated in children 9-12 months of age. METHODS: We randomized infants (1:1) to receive 1 dose of MenACWY-TT at 12 months of age (ACWY-1 group) or 2 doses at 9 and 12 months (ACWY-2). We measured immunogenicity after each dose and 1 year after completing vaccination using human serum bactericidal antibody (hSBA) assays according to prespecified criteria of >= 1:8. Local and general symptoms were solicited for 8 days after vaccination. Adverse events were recorded for 6 months after the last dose. RESULTS: We enrolled and vaccinated 349 subjects, of whom 248 reenrolled at Year 1 for evaluation of antibody persistence. Percentages of subjects with postvaccination hSBA >= 1:8 in the ACWY-1 group were 79.5%, 94.6%, 50.8% and 56.1% and in the 2-dose group (ACWY-2) were 88.4%, 100%, 99.3% and 99.3% postdose 2 for serogroups A, C, W-135 and Y, respectively. At Year 1, 80.0-99.1% in each group had hSBA >= 1:8, except for serogroup A, for which 20.6% (ACWY-1) and 25.9% (ACWY-2) retained hSBA >=1:8. Both schedules were well-tolerated, with no observed increase in reactogenicity after the second dose. CONCLUSIONS: MenACWY TT was immunogenic when administered as a single dose at 12 months of age, or as 2 doses at 9 and 12 months, and had a clinically acceptable safety profile. Good antibody persistence was observed through 12 months postvaccination after both treatment schedules for serogroups C, W-135, Y. PMID- 23348815 TI - Timing and predictors of fever and infection after craniotomy for epilepsy in children. AB - BACKGROUND: Fevers and leukocytosis after pediatric craniotomy trigger diagnostic evaluation and antimicrobial therapy for possible brain infection. This study determined the incidence and predictors of infection in infants and children undergoing epilepsy neurosurgery. METHODS: We reviewed the postoperative course of 100 consecutive surgeries for pediatric epilepsy, comparing those with and without infections for clinical variables and daily maximum temperatures, blood white blood cell (WBC) and differential and cerebrospinal fluid (CSF) studies. RESULTS: Infections were the most common adverse events after these surgeries. Four patients (4%) had CSF infections and 12 had non-CSF infections (including 1 with distinct CSF and bloodstream infections). Most (88%) infections occurred before postoperative day 12 and were associated with larger resections involving ventriculostomies. Fevers (T >= 38.5 degrees C) were observed in the first 12 days postsurgery in 43% of cases, and were associated with patients undergoing hemispherectomy and multilobar resections. Fevers in the first 3 days postsurgery identified infections with 73% sensitivity, 69% specificity and 70% accuracy; 2 (13%) patients with infections never developed fevers. Peripheral blood WBC >15,000 was found in 49% of patients and 5 cases of infections never had elevated WBC counts. WBC differential, CSF protein, red blood cell, WBC and red blood cell/WBC ratios were poor predictors of infections. Longer hospital stays were associated with infections and hemispherectomy and multilobar resections. Patients with and without infections were equally likely to be seizure free after surgery. CONCLUSIONS: Fevers and elevated blood WBC counts were common after pediatric epilepsy surgery, but CSF infections were uncommon. Positive cultures and other confirmatory microbiologic tests should drive changes in antimicrobial therapy after surgery. PMID- 23348816 TI - Nearly complete elimination of the 7-valent pneumococcal conjugate vaccine serotypes in Tennessee. AB - BACKGROUND: Invasive pneumococcal disease (IPD) rates decreased after 7-valent pneumococcal conjugate vaccine (PCV) introduction in 2000. We assessed whether previously described decreases were sustained. METHODS: Active laboratory-based surveillance identified IPD cases in 5 Tennessee Counties. For each case, clinical data were collected, and antibiotic susceptibility testing and serotyping were performed. Penicillin resistance was defined as intermediate- or high-level resistance to penicillin. Serotypes were classified as PCV7, PCV13 (6 additional serotypes not in PCV7), pneumococcal polysaccharide vaccine (PPV23, 11 additional serotypes not in PCV13 and nonvaccine serotypes. Total and penicillin resistant IPD rates were calculated for persons <2, 2-14 and >=15 years of age before (1998 to 1999) and after (2001 to 2008) PCV7 introduction. RESULTS: Annual IPD rates in children <2 years of age declined by 75% after PCV7 introduction (P < 0.001). Annual IPD rates in children 2-14 years of age declined by 51% after PCV7 introduction (P < 0.001). IPD rates in persons >=15 of age years initially decreased 40% from 22 to 13 per 100,000 person-years (from 1998 through 2004), and then increased to 18 per 100,000 person-years in 2008. Both IPD and penicillin-resistant IPD PCV7 serotypes were almost completely eliminated in all age groups by 2008. During 2005 to 2008, 52.5%, 58% and 38% of IPD serotypes in children <2, 2-14 and >=15 years of age, respectively, were the additional 6 serotypes in PCV13. CONCLUSIONS: Overall, 9 years after PCV7 introduction both penicillin-susceptible and resistant IPD rates PCV7 serotypes have been nearly eliminated in Tennessee in all age groups. Total IPD rates remain reduced in children <15 years of age, whereas total IPD rates in persons >=15 years of age have approached pre-PCV7 rates due to modest increases in nonvaccine serotypes. PMID- 23348817 TI - Evaluation of IgG anti-toxoplasma avidity and polymerase chain reaction in the postnatal diagnosis of congenital toxoplasmosis. AB - Confirmatory tests for congenital toxoplasmosis were evaluated in 23 infected and 31 uninfected newborns. Conventional polymerase chain reaction was better than real-time polymerase chain reaction, but did not identify additional cases. Avidity tests added 2 new cases that were not identified by other criteria. Overall sensitivity was 82.6%. Avidity assay, but not polymerase chain reaction, increased the sensitivity of confirmatory assays in congenital toxoplasmosis. PMID- 23348818 TI - Infective dermatitis associated with human T-cell lymphotropic virus type 1 in a child with bronchiectasis. AB - We report a case of infective dermatitis associated with human T lymphocyte virus type 1 in a South African child with associated stunting, anaemia and chronic lung disease. human T lymphocyte virus type 1 should always be considered in a patient with unexplained recurrent dermatitis. Chronic lung disease is a rare association. PMID- 23348819 TI - Perceptions of German GPs on benefits and risks of benzodiazepines and Z-drugs. AB - QUESTIONS UNDER STUDY: In many countries newer non-benzodiazepines, zolpidem and zopiclone ("Z-drugs"), are prescribed instead of benzodiazepine hypnotics. This is not supported by current evidence and guidelines. The aim of this study was to compare the perceptions of GPs on the benefits and harms of benzodiazepines and Z drugs. METHODS: A questionnaire was mailed to a random sample of 1,350 German GPs between May and June 2012. GPs were asked to rate their perceptions on a five point Likert scale for 12 items asked for both benzodiazepines and Z-drugs. Wilcoxon signed rank test for paired observations was used for comparison between groups. Due to multiple testing, only p values <=0.01 were considered statistically significant. RESULTS: A total of 458 questionnaires were returned (response 33.9%). The mean age of participants was 53.3 years (59.4% males). GPs perceived that Z-drugs were significantly more effective in terms of reduced night-time waking, feelings of being rested on waking and improved daytime functioning than benzodiazepines (p <0.0001 for all comparisons), but not in terms of reduced time to get to sleep and increased total sleep time. All studied side effects were believed to be less often for patients receiving Z-drugs (p <0.0001 for all comparisons). A total of 73.4% and 80.4% answered that tolerance or withdrawal effects on stopping occur often or very often/always for benzodiazepines, whereas these values were only 30.6% and 28.7% for Z-drugs. CONCLUSIONS: German GPs perceived that Z-drugs were more effective and safer compared to benzodiazepines, which is not supported by current evidence. The results are quite comparable to a British survey conducted seven years before. PMID- 23348820 TI - Comorbid conditions and outcomes in patients with pulmonary arterial hypertension: a REVEAL registry analysis. AB - BACKGROUND: Comorbidities can affect disease progression and/or response to treatment in various conditions. Comorbid conditions are prevalent in patients with pulmonary arterial hypertension (PAH); however, their effect on patient outcomes remains unknown. METHODS: We evaluated the effect on functional class (FC), 6-min walk test distance (6MWD), and survival of the seven most common, comorbid conditions at enrollment in patients with PAH from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry): hypertension, clinical depression, type 2 diabetes mellitus (diabetes), obesity, COPD, sleep apnea, and thyroid disease. RESULTS: Patients with COPD or diabetes had the shortest 6MWD at enrollment (304.5 and 304.6 m, respectively) vs other comorbidities. Adjusted linear regression for 6MWD at enrollment revealed significant reductions among patients who were hypertensive, obese, diabetic, or had COPD (P<.001). A larger proportion of patients who were obese or had COPD were FC III/IV vs FC I/II at enrollment (P<.001). There was a greater risk for death among patients with diabetes (hazard ratio [HR], 1.73; 95% CI, 1.40-2.13; P<.001) or COPD (HR, 1.59; 95% CI, 1.34-1.90; P<.001), but there was a reduced risk for death in patients who were obese (HR, 0.73; 95% CI, 0.61-0.86; P<.001). CONCLUSIONS: Compared with other analyzed comorbidities in patients with PAH, hypertension, obesity, diabetes, and COPD were associated with significantly worse 6MWD; obesity and COPD were associated with worse FC; and diabetes and COPD were associated with increased risk for death. Further investigation of the effects of treating these comorbidities in patients with PAH is warranted. TRIAL REGISTRY: ClinicalTrials.gov; Identifier: NCT00370214; URL: www.clinicaltrials.gov. PMID- 23348821 TI - Prenatal diagnosis of MPPH syndrome. AB - We report the prenatal sonographic detection of a fetus with megalencephaly, polymicrogyria, postaxial polydactyly and hydrocephaly. Only 14 patients have been reported in the literature so far, all but one were diagnosed postnatally. The polymicrogyria in the frontoparietal lobe was confirmed by prenatal magnetic resonance imaging. Additionally, a hypoplastic thymus as seen in a 22q11 deletion was present. Although polymicrogyria along with pre-axial polydactyly has been described in 22q11 deletion, the diagnosis of Di George syndrome was ruled out. The etiology of megalencephaly, polymicrogyria, postaxial polydactyly and hydrocephaly has not been revealed yet. A dominant as well as recessive inheritance has been suggested. PMID- 23348822 TI - Pyrophosphate selective fluorescent probe and molecular flip-flop. AB - Highly selective detection of pyrophosphate in the presence of inorganic phosphates, halides, acetate, ATP, other nucleotides in neutral aqueous solutions is achieved by a fluorescent Zn-ensemble based system. The implementation of the first molecule based JK-latch sequential logic function is also described. PMID- 23348823 TI - The inhibin B response to the testicular toxicant 1, 3 dinitrobenzene in male rats. AB - BACKGROUND: This study was conducted as part of an ILSI-HESI International Life Sciences Institute-Health & Environmental Sciences Institute consortium effort to assess the utility of circulating Inhibin B as an early biomarker of Sertoli cell specific testicular toxicity in rats. 1, 3-Dinitrobenzene (1,3-DNB) was selected as a testicular toxicant in this study as it is known to target Sertoli cells. METHODS: 1,3-DNB (2 and 6 mg/kg/day) or control (corn oil) was administered orally to male rats for two or five consecutive days. Blood was collected from rats treated for 2 days on days 1 and 2 and from rats treated for 5 days on days 1, 3, and 5. The resulting serum was evaluated for Inhibin B and follicle stimulating hormone. At the end of the treatment periods, the testes were removed, weighed, and examined histopathologically. RESULTS: Daily administration of 1,3-DNB resulted in decreased testis weight only on day 5 and only at the high dose (6 mg/kg/day). There was a time-dependent increase in incidence and severity of testicular findings characterized by degeneration of the germinal epithelium with loss of pachytene spermatocytes and vacuolization of the Sertoli cells in the seminiferous tubules at the high dose. Inhibin B levels in 1,3-DNB-treated animals were decreased with treatment only on day 5 at the high dose; there were no associated changes in follicle stimulating hormone. CONCLUSIONS: Changes in serum Inhibin B levels were detected only in association with moderate or severe testicular toxicity as evidenced by histopathology and is therefore considered to be of limited value as a biomarker for Sertoli cell toxicity. PMID- 23348824 TI - New year wishes and updates. PMID- 23348825 TI - A study on the use of Gumbel approximation with the Bernoulli spatial scan statistic. AB - The Bernoulli version of the spatial scan statistic is a well established method of detecting localised spatial clusters in binary labelled point data, a typical application being the epidemiological case-control study. A recent study suggests the inferential accuracy of several versions of the spatial scan statistic (principally the Poisson version) can be improved, at little computational cost, by using the Gumbel distribution, a method now available in SaTScan(TM) (www.satscan.org). We study in detail the effect of this technique when applied to the Bernoulli version and demonstrate that it is highly effective, albeit with some increase in false alarm rates at certain significance thresholds. We explain how this increase is due to the discrete nature of the Bernoulli spatial scan statistic and demonstrate that it can affect even small p-values. Despite this, we argue that the Gumbel method is actually preferable for very small p-values. Furthermore, we extend previous research by running benchmark trials on 12 000 synthetic datasets, thus demonstrating that the overall detection capability of the Bernoulli version (i.e. ratio of power to false alarm rate) is not noticeably affected by the use of the Gumbel method. We also provide an example application of the Gumbel method using data on hospital admissions for chronic obstructive pulmonary disease. PMID- 23348827 TI - Determinants of Alcohol, Khat, and Bhang Use in Rural Kenya. AB - The study investigated local determinants of substance use in rural Kenya. Over the years, there has been a growing concern over increased use of substances across ages, gender, religious persuasions, and social class in Kenya. It is still unclear what psychosocial individual and/or community factors might be that offer some explanation for the high levels of alcohol and drug use. The study investigated community members' social status in areas of gender, education, employment, self-esteem, and availability of substances. The sample was comprised of Kenyan rural participants, and included 153 men and 64 women with a mean age of 34.2 years. The participants completed a survey measuring possible psychosocial determinants of alcohol, khat and bhang (i.e., marijuana) use patterns. The sample evidenced high levels of substance use particularly involving the locally available substances (i.e., bottled beer, local brews, chewing khat, smoking bhang). Males in comparison to females were more likely to drink alcohol, chew khat, and smoke bhang. Women compared to men reported higher education and employment status, which were associated with less substance use. Females had higher self-esteem when they did not use bottled beer whereas males had higher self-esteem when they use bottled beer. The implications of these findings are discussed. PMID- 23348826 TI - The regio- and stereospecific intermolecular dehydrative alkoxylation of allylic alcohols catalyzed by a gold(I) N-heterocyclic carbene complex. AB - A 1:1 mixture of [AuCl(IPr)] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2 ylidine) and AgClO(4) catalyzes the intermolecular dehydrative alkoxylation of primary and secondary allylic alcohols with aliphatic primary and secondary alcohols to form allylic ethers. These transformations are regio- and stereospecific with preferential addition of the alcohol nucleophile at the gamma position of the allylic alcohol syn to the departing hydroxyl group and with predominant formation of the E stereoisomer. The minor alpha regioisomer is formed predominantly through a secondary reaction manifold involving regioselective gamma-alkoxylation of the initially formed allylic ether rather than by the direct alpha-alkoxylation of the allylic alcohol. PMID- 23348828 TI - Many roads lead to Parkinson's disease. PMID- 23348829 TI - Male body movements as possible cues to physical strength: a biomechanical analysis. AB - OBJECTIVES: Comparative research suggests that male courtship displays signal condition-dependent traits tofemales; these displays might also provide cues to potential male competitors. Although some associations betweenhuman movements and physical/behavioral qualities have been found, such research has typically only been conducted from a perspective of female mate choice. Here, using advanced motion capture and biomechanical analyses, we examine the extent to which male dancing provides cues about the dancer's physical qualities to both males and females. METHODS: Thirty men aged 19-37 were recorded using motion-capture technology as they danced to a standard rhythm. Participants also completed a vascular fitness test, assessments of upper- and lower-body strength, and biomechanical indices were extracted from their dance movements. Dance clips were converted into virtual humanoid characters (avatars) and rated by 27 women and 21 men on perceived dance quality. RESULTS: General linear mixed modeling revealed that both handgrip strength and arm movements of the dancer were statistically significant predictors of dance quality ratings; stronger males who displayed larger, more variable, and faster movements of their arms being rated as better dancers. There was no effect of the sex of the observer in predicting dance quality ratings, indicating that male and female observers rated dance quality equivalently. Physical fitness was not associated with perceived dance quality. CONCLUSIONS: Men and women are able to derive certain quality cues from observing male dance movements in the form of controlled stimuli. Thus, male dancing may form a condition-dependent ornament of certain aspects of mate quality. PMID- 23348830 TI - Welander distal myopathy caused by an ancient founder mutation in TIA1 associated with perturbed splicing. AB - Welander distal myopathy (WDM) is an adult onset autosomal dominant disorder characterized by distal limb weakness, which progresses slowly from the fifth decade. All WDM patients are of Swedish or Finnish descent and share a rare chromosome 2p13 haplotype. We restricted the WDM-associated haplotype followed by whole exome sequencing. Within the conserved haplotype, we identified a single heterozygous mutation c.1150G>A (p.E384K) in T-cell intracellular antigen-1 (TIA1) in all WDM patients investigated (n = 43). The TIA1 protein regulates splicing, and translation through direct interaction with mRNA and the p.E384K mutation is located in the C-terminal Q-rich domain that interacts with the U1-C splicing factor. TIA1 has been shown to prevent skipping of SMN2 exon 7, and we show that WDM patients have increased levels of spliced SMN2 in skeletal muscle cells when compared with controls. Immunostaining of WDM muscle biopsies showed accumulation of TIA1 and stress granulae proteins adjacent to intracellular inclusions, a typical finding in WDM. The combined findings strongly suggest that the TIA1 mutation causes perturbed RNA splicing and cellular stress resulting in WDM. The selection against the mutation is likely to be negligible and the age of the TIA1 founder mutation was calculated to approximately 1,050 years, which coincides with the epoch of early seafaring across the Baltic Sea. PMID- 23348833 TI - Increased mortality after infusion of "modern" hydroxyethyl starch. PMID- 23348832 TI - Biomolecular analysis and cancer diagnostics by negative mode probe electrospray ionization. AB - We have examined several combinations of solvents and probes with the aim of optimizing the ionization conditions for biomolecules e.g., proteins, peptides and lipids by negative mode probe electrospray ionization mass spectrometry (PESI MS). With the data presented in this study, negative-mode PESI-MS can be considered as a potential tool for biomolecular analysis and cancer diagnostics because of its simplicity in instrumental configuration. A sharper sampling probe was found to be better for obtaining high quality mass spectra because it can generate stable electrospray without the occurrence of gas breakdown. Although the best conditions may depend on each sample, aqueous organic solvent solutions, especially isopropanol-H(2)O (1/1) with a pH of >=7, are shown to be preferable for negative-mode PESI-MS, which was successfully applied to colon cancer diagnosis. PMID- 23348831 TI - Methicillin-resistant Staphylococcus aureus-induced thrombo-inflammatory response is reduced with timely antibiotic administration. AB - Methicillin-resistant Staphylococcus aureus (MRSA) induces a pro-thrombotic and pro-inflammatory milieu. Although timely antibiotic administration in MRSAsepsis may improve outcomes by arresting bacterial growth, the effects of antibiotics on mitigating injurious thrombo-inflammatory cellular responses remains unexplored. Using a newly developed human whole blood model and an in vivo mouse model of MRSAinfection, we examined how antibiotics inhibit MRSAinduced thrombo inflammatory pathways. Human whole blood was inoculated with MRSA. Thrombin generation and inflammatory cytokine synthesis was measured in the presence or absence of linezolid and vancomycin. C57BL/6 mice were injected with MRSA and the effect of vancomycin administration was examined. MRSAaccelerated thrombin generation in a time- and concentration-dependent manner andinduced the release of cytokines, including interleukin (IL)-6, IL-8, and monocyte chemotactic protein (MCP)-1. The increase in thrombin generation and inflammatory responses was mediated through the synthesis of tissue factor and cytokines, respectively, and the release of microparticles. The early administration of antibiotics restored normal thrombin generation patterns and significantly reduced the synthesis of cytokines. In contrast, when antibiotic administration was delayed, thrombin generation and cytokine synthesis were not significantly reduced. In mice infected with MRSA, early antibiotic administration reduced thrombin anti thrombin complexes and cytokine synthesis, whereas delayed antibiotic administration did not. These data provide novel mechanistic evidence of the importance of prompt antibiotic administration in infectious syndromes. PMID- 23348834 TI - White matter fractional anisotropy is inversely related to anxious symptoms in older adults with atherosclerosis. AB - OBJECTIVE: Clinical anxiety disorders are associated with white matter hyperintensities and diffusion abnormalities measured using diffusion tensor imaging. However, it is not known if this association extends into individuals with mild anxious symptoms without formal diagnosis, in those who are older, or in those who have atherosclerosis. The current study explores whether white matter integrity and/or organization significantly associates with anxious symptoms in older adults with and without atherosclerosis. METHODS: We recruited older adults (ages 55-90 years); 35 with clinically diagnosed atherosclerotic vascular disease (AVD) and 22 without AVD. Anxious symptoms were measured using the validated Symptom Checklist-90-Revised. Fractional anisotropy (FA), a proxy for white matter organization and health, was measured in the white matter globally, by lobe, and in several smaller regions of interest suggested by the literature. Partial correlations between anxious symptoms and FA were calculated, controlling for significant covariates. RESULTS: Participants with and without AVD did not differ in severity of anxious symptom endorsement. There was a unique inverse relationship between white matter health and anxious symptoms in the AVD participants, but not in healthy comparisons. Significant relationships were observed in the superior longitudinal fasciculus (r = -0.476, df = 32, p = 0.004), as well as the cingulum bundle, the frontal lobes, and the parietal lobes. CONCLUSIONS: Anxiety symptoms uniquely correlated with low FA in older adults with atherosclerosis. These findings may have implications for future research on the topic of anxiety in aging and vascular disease and warrant replication. PMID- 23348835 TI - Combining hidden Markov models for comparing the dynamics of multiple sleep electroencephalograms. AB - In this manuscript, we consider methods for the analysis of populations of electroencephalogram signals during sleep for the study of sleep disorders using hidden Markov models (HMMs). Notably, we propose an easily implemented method for simultaneously modeling multiple time series that involve large amounts of data. We apply these methods to study sleep-disordered breathing (SDB) in the Sleep Heart Health Study (SHHS), a landmark study of SDB and cardiovascular consequences. We use the entire, longitudinally collected, SHHS cohort to develop HMM population parameters, which we then apply to obtain subject-specific Markovian predictions. From these predictions, we create several indices of interest, such as transition frequencies between latent states. Our HMM analysis of electroencephalogram signals uncovers interesting findings regarding differences in brain activity during sleep between those with and without SDB. These findings include stability of the percent time spent in HMM latent states across matched diseased and non-diseased groups and differences in the rate of transitioning. PMID- 23348836 TI - Predictors of squamous cell carcinoma in high-risk patients in the VATTC trial. AB - Invasive squamous cell carcinoma (SCC) of the skin is one of the most common cancers in the United States, with no proven means for prevention other than systemic retinoids, which have significant toxicity, and sunscreen. We sought to determine the risk factors for invasive SCC on the face or ears in a high-risk population comprising 1,131 veterans in the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial. Participants were required to have been diagnosed with at least two keratinocyte carcinomas (KCs) in the 5 years prior to enrollment. The median duration of follow-up was 3.7 years. Twenty-three percent of the participants developed a new invasive SCC, and the cumulative risk of invasive SCC was 30% at 5 years. The following factors independently predicted for new invasive SCCs: number of invasive SCCs and number of in situ SCCs in the 5 years prior to enrollment, actinic keratoses count at enrollment, a history of ever use of topical 5-fluorouracil, and total occupational time spent outdoors. In contrast, the use of angiotensin-convering enzyme inhibitors or angiotensin receptor blockers during the study and a history of warts anywhere on the body were found to protect against new invasive SCCs. These independent predictors remained the same for all SCCs (invasive and in situ combined). The number of basal cell carcinomas in the 5 years prior to enrollment, sunburns, sun sensitivity, and recreational sun exposure were not associated with new SCCs. These findings identify key risk factors for additional SCCs in patients with multiple prior KCs, and suggest that a history of warts may be associated with reduced SCC risk. PMID- 23348837 TI - Location, location, location: it's all in the timing for replication origins. AB - The differential replication timing of eukaryotic replication origins has long been linked with epigenetic regulation of gene expression and more recently with genome stability and mutation rates; however, the mechanism has remained obscure. Recent studies have shed new light by identifying novel factors that determine origin timing in yeasts and mammalian cells and implicate the spatial organization of origins within nuclear territories in the mechanism. These new insights, along with recent findings that several initiation factors are limiting relative to licensed origins, support and shape an emerging model for replication timing control. The mechanisms that control the spatial organization of replication origins have potential impacts for genome regulation beyond replication. PMID- 23348840 TI - Centriole distal appendages promote membrane docking, leading to cilia initiation. AB - The distal appendages (DAPs) of centrioles have been proposed to anchor cilia to the plasma membrane, but their molecular composition, assembly, and exact function in ciliogenesis remain poorly understood. Using quantitative centrosome proteomics and superresolution microscopy, we identified five DAP components, including one previously described (CEP164), one partially characterized (CEP89 [ccdc123]), and three novel (CEP83 [ccdc41], SCLT1, and FBF1) DAP proteins. Analyses of DAP assembly revealed a hierarchy. CEP83 recruits both SCLT1 and CEP89 to centrioles. Subsequent recruitment of FBF1 and CEP164 is independent of CEP89 but mediated by SCLT1. All five DAP components are essential for ciliogenesis; loss of CEP83 specifically blocks centriole-to-membrane docking. Undocked centrioles fail to recruit TTBK2 or release CP110, the two earliest modifications found on centrioles prior to cilia assembly, revealing centriole-to membrane docking as a temporal and spatial cue promoting cilia initiation. PMID- 23348839 TI - Tricornered/NDR kinase signaling mediates PINK1-directed mitochondrial quality control and tissue maintenance. AB - Eukaryotes employ elaborate mitochondrial quality control (MQC) to maintain the function of the power-generating organelle. Parkinson's disease-associated PINK1 and Parkin actively participate in MQC. However, the signaling events involved are largely unknown. Here we show that mechanistic target of rapamycin 2 (mTORC2) and Tricornered (Trc) kinases act downstream from PINK1 to regulate MQC. Trc is phosphorylated in mTORC2-dependent and mTORC2-independent manners and is specifically localized to mitochondria in response to PINK1, which regulates mTORC2 through mitochondrial complex-I activity. Genetically, mTORC2 and Trc act upstream of Parkin. Thus, multiplex kinase signaling is acting between PINK1 and Parkin to regulate MQC, a process highly conserved in mammals. PMID- 23348838 TI - Pick one, but be quick: 5' splice sites and the problems of too many choices. AB - Splice site selection is fundamental to pre-mRNA splicing and the expansion of genomic coding potential. 5' Splice sites (5'ss) are the critical elements at the 5' end of introns and are extremely diverse, as thousands of different sequences act as bona fide 5'ss in the human transcriptome. Most 5'ss are recognized by base-pairing with the 5' end of the U1 small nuclear RNA (snRNA). Here we review the history of research on 5'ss selection, highlighting the difficulties of establishing how base-pairing strength determines splicing outcomes. We also discuss recent work demonstrating that U1 snRNA:5'ss helices can accommodate noncanonical registers such as bulged duplexes. In addition, we describe the mechanisms by which other snRNAs, regulatory proteins, splicing enhancers, and the relative positions of alternative 5'ss contribute to selection. Moreover, we discuss mechanisms by which the recognition of numerous candidate 5'ss might lead to selection of a single 5'ss and propose that protein complexes propagate along the exon, thereby changing its physical behavior so as to affect 5'ss selection. PMID- 23348841 TI - An unusual arrangement of two 14-3-3-like domains in the SMG5-SMG7 heterodimer is required for efficient nonsense-mediated mRNA decay. AB - The nonsense-mediated mRNA decay (NMD) pathway triggers the rapid degradation of aberrant mRNAs containing premature translation termination codons (PTCs). In metazoans, NMD requires three 14-3-3-like proteins: SMG5, SMG6, and SMG7. These proteins are recruited to PTC-containing mRNAs through the interaction of their 14-3-3-like domains with phosphorylated UPF1, the central NMD effector. Recruitment of SMG5, SMG6, and SMG7 causes NMD target degradation. In this study, we report the crystal structure of the Caenorhabditis elegans SMG5-SMG7 complex. The 14-3-3-like phosphopeptide recognition domains of SMG5 and SMG7 heterodimerize in an unusual perpendicular back-to-back orientation in which the peptide-binding sites face opposite directions. Structure-based mutants and functional assays indicate that the SMG5-SMG7 interaction is conserved and is crucial for efficient NMD in human cells. Notably, we demonstrate that heterodimerization increases the affinity of the SMG5-SMG7 complex for UPF1. Furthermore, we show that the degradative activity of the SMG5-SMG7 complex resides in SMG7 and that the SMG5-SMG7 complex and SMG6 play partially redundant roles in the degradation of aberrant mRNAs. We propose that the SMG5-SMG7 complex binds to phosphorylated UPF1 with high affinity and recruits decay factors to the mRNA target through SMG7, thus promoting target degradation. PMID- 23348842 TI - Kava for the treatment of generalized anxiety disorder RCT: analysis of adverse reactions, liver function, addiction, and sexual effects. AB - Presently, little is known about a number issues concerning kava (Piper methysticum), including (i) whether kava has any withdrawal or addictive effects; (ii) if genetic polymorphisms of the cytochrome (CYP) P450 2D6 liver enzyme moderates any potential adverse effects; and (iii) if medicinal application of kava has any negative or beneficial effect on sexual function and experience. The study design was a 6-week, double-blind, randomized controlled trial (n = 75) involving chronic administration of kava (one tablet of kava twice per day; 120 mg of kavalactones per day, titrated in non-response to two tablets of kava twice per day; 240 mg of kavalactones) or placebo for participants with generalized anxiety disorder. Results showed no significant differences across groups for liver function tests, nor were there any significant adverse reactions that could be attributed to kava. No differences in withdrawal or addiction were found between groups. Interesting, kava significantly increased female's sexual drive compared to placebo (p = 0.040) on a sub-domain of the Arizona Sexual Experience Scale (ASEX), with no negative effects seen in males. Further, it was found that there was a highly significant correlation between ASEX reduction (improved sexual function and performance) and anxiety reduction in the whole sample. PMID- 23348843 TI - Airway vascular endothelial function in healthy smokers without systemic endothelial dysfunction. AB - BACKGROUND: Cigarette smoking can lead to systemic endothelial dysfunction. Since the airway circulation is exposed to a high concentration of cigarette smoke constituents, we reasoned that airway vascular endothelial dysfunction could be present in healthy smokers without systemic endothelial dysfunction. OBJECTIVES: The purpose of this study was to compare airway and systemic endothelial function and measure markers of systemic inflammation in lung-healthy current smokers. Since endothelial dysfunction in smokers has been related to systemic inflammation, we also investigated its response to an inhaled glucocorticosteroid (ICS). METHODS: Fifteen healthy, current smokers and 17 healthy, lifetime nonsmokers were enrolled. Smokers were randomly assigned to 3-week treatments with inhaled fluticasone propionate or placebo in a crossover design. Vascular endothelial function was assessed in the airway by the airway blood-flow response to inhaled albuterol (DeltaQaw) and in the extrapulmonary circulation by brachial arterial flow-mediated vasodilation (FMD). Venous blood was collected for C reactive protein and IL-6. RESULTS: Baseline parameters did not differ between groups except for DeltaQaw, which was greater in nonsmokers (45% +/- 12%) than smokers (1% +/- 12%) (P = .001). In the smokers, ICS treatment increased Qaw to 41% +/- 7% (P < .001), but had no effect on FMD or inflammatory markers. There was an inverse relationship between baseline and ICS-induced changes in DeltaQaw. CONCLUSIONS: Healthy smokers with no signs of systemic inflammation or endothelial dysfunction display impaired airway vascular endothelial function, possibly preceding systemic endothelial dysfunction. Airway endothelial function was restored with an ICS, and the response was directly related to the severity of endothelial dysfunction. PMID- 23348844 TI - Synthesis and properties of phosphorescent iridium(III) complexes of delocalized ligands. AB - New Ir(III) complexes involving N,C-chelating difluorophenyl-pyridine (dfppy) or dibenzo[a,c]phenazine (dbpz) ligands along with either N,N-bound 5-ethynyl-2,2' bipyridine (e-bpy) or CO + Cl co-ligands have been obtained as [Ir(dfppy)(2)(e bpy)]PF(6), [Ir(dbpz)(2)(e-bpy)]PF(6) and cis-[Ir(dbpz)(2)(Cl)(CO)]. A single crystal X-ray diffraction study of cis-[Ir(dbpz)(2)(CO)Cl] has shown the Ir(III) centre to adopt a distorted octahedral coordination geometry with cis-CO/Cl and trans-N,N configurations. Pronounced pi-pi stacking interactions involving different dibenzo[a,c]phenazine units are evident. Electronic absorption and luminescence spectroscopy at 298 K and 77 K, along with cyclic voltammetry were used to study the three complexes. Excited state lifetimes varied from 1.4 to 2.9 MUs at rt with quantum yields ranging from 10.2 to 0.7%. With 5-ethynyl-2,2' bipyridine in the first coordination sphere, the lowest emitting state is that associated with the MLCT band, whereas in the bis-phenazine case the emission is ligand-centred. Importantly, the emission wavelength can be tuned from 552 to 640 nm by changing the conjugation length of the N,C ligand. PMID- 23348846 TI - Cognition, imagery and coping among adolescents with social anxiety and phobia: testing the Clark and Wells model in the population. AB - The Clark and Wells' cognitive model of social phobia suggests that self-focused attention, negative observer-perspective images of oneself and safety behaviours maintain anxiety in subjects with SP. Empirical research among adults supports the model, but limited evidence for it has been obtained in other age groups or in the general population. We examined automatic thoughts, imagery, safety behaviours and general coping of adolescents with social anxiety and phobia. These were elicited by a thought listing procedure in a recalled, distressing social situation. The target variables were compared between adolescents with high versus normal self-reported social anxiety (HSA/NSA) and between adolescents with clinical/subclinical SP (SP/SSP) versus no diagnosis. Adolescents with HSA reported overall negative thoughts, negative observer-perspective images and safety behaviours more frequently than adolescents with NSA. The SP/SSP group displayed the same difference, and clearer, relative to the no diagnosis group, but additionally reported negative thoughts focused more often on self. Minor differences in coping were found between the groups. The study suggests that adolescents with SP already display the negative self-focused cognitions, observer-perspective imagery and behavioural pattern found among adults with SP. KEY PRACTITIONER MESSAGE: Social anxiety associates with observer-perspective imagery and safety behaviours in adolescence. Adolescents with clinical social phobia report frequent negative self-focused thoughts. However, such negative cognitions focused on self do not associate to self-reported social anxiety. The cognitive model of social phobia (Clark & Wells, 1995) is applicable to adolescents. PMID- 23348847 TI - A colorimetric homogeneous immunoassay system for the C-reactive protein. AB - The C-reactive protein (CRP), which has a five repeat pentameric structure, is known to be a marker for acute inflammation and a potential risk predictor for cardiovascular disease. A simple and rapid homogeneous assay method for the detection of CRP, based on a gold nanoparticle (AuNP) aggregation induced colorimetric response, has been developed. In the technique, aggregation of CRP antibody-conjugated AuNPs is induced by addition of CRP as a consequence of its unique pentameric structure. CRP-promoted aggregation of the antibody-conjugated AuNPs results in a change of the wavelength maximum in the UV/Vis-spectrum. This homogeneous assay displays a typical hook effect, in which the signal level is directly proportional to CRP concentration until a critical concentration of CRP (the hook point) is reached. Above this concentration, the signal level decreases as the CRP concentration increases. The maximum shift in the absorption maximum was found to occur when the CRP antigen concentration is 100 ng mL(-1). In order to improve the linearity of the method, we employed a procedure, which takes advantage of a saturation phenomenon that leads to the hook effect, to increase the dynamic range of the CRP assay. Specifically, the use of CRP pre-spiked serum promotes maximum aggregation at the low CRP concentrations and, as a result, leads to an increase in the dynamic range for CRP detection. The applicability of the new homogenous assay system was demonstrated by its utilization for qualitative analysis of CRP in serum samples. The combined observations made in this effort show that the method using CRP antibody-conjugated AuNPs is both rapid and simple and, consequently, it can potentially be applied to onsite diagnosis. PMID- 23348848 TI - The inhibin B response to testicular toxicants ethylene glycol monomethyl ether or dibromoacetic acid in male rats. AB - BACKGROUND: This study was conducted as part of an ILSI-HESIconsortium effort to assess the utility of circulating inhibin B as an early biomarker of testicular toxicity in rats. METHODS: Two known testicular toxicants were selected for use in this study: ethylene glycol monomethyl ether (EGME) and dibromoacetic acid (DBAA). EGME (200 mg/kg/day), DBAA (250 mg/kg/day), or vehicle control (0.2% hydroxypropyl methylcellulose [HPMC]) was administered orally to male rats for 3, 6, or 14 consecutive days. On study days 4, 7, and 15, serum was collected for evaluation of inhibin B levels from all surviving animals and a subset of animals was necropsied from each of the control, EGME, and DBAAgroups. RESULTS: Administration of EGMEresulted in spermatocyte degeneration in late stage tubules and spermatocyte depletion to stage III on day 4, progressing to loss of spermatocytes and round spermatids to stage VI by day 7 and continued germ cell loss and degeneration of elongating spermatids by day 15. Inhibin B levels among EGME-treated animals progressively decreased relative to their respective controls at all time points. Administration of DBAA was associated with spermatid retention at all three time points and abnormal residual bodies at days 7 and 15. Inhibin B levels among DBAA-treated animals decreased progressively relative to their respective controls on days 7 and 15. CONCLUSIONS: Serum inhibin B levels in rats provided a signal of testicular toxicity for each of these known testicular toxicants administered at high levels; however, histopathology provided the earliest evidence of toxic effects. PMID- 23348845 TI - Factors affecting open-set word recognition in adults with cochlear implants. AB - OBJECTIVE: A great deal of variability exists in the speech-recognition abilities of postlingually deaf adult cochlear implant (CI) recipients. A number of previous studies have shown that duration of deafness is a primary factor affecting CI outcomes; however, there is little agreement regarding other factors that may affect performance. The objective of the present study was to determine the source of variability in CI outcomes by examining three main factors, biographic/audiologic information, electrode position within the cochlea, and cognitive abilities in a group of newly implanted CI recipients. DESIGN: Participants were 114 postlingually deaf adults with either the Cochlear or Advanced Bionics CI systems. Biographic/audiologic information, aided sentence recognition scores, a high resolution temporal bone CT scan and cognitive measures were obtained before implantation. Monosyllabic word recognition scores were obtained during numerous test intervals from 2 weeks to 2 years after initial activation of the CI. Electrode position within the cochlea was determined by three-dimensional reconstruction of pre- and postimplant CT scans. Participants' word scores over 2 years were fit with a logistic curve to predict word score as a function of time and to highlight 4-word recognition metrics (CNC initial score, CNC final score, rise time to 90% of CNC final score, and CNC difference score). RESULTS: Participants were divided into six outcome groups based on the percentile ranking of their CNC final score, that is, participants in the bottom 10% were in group 1; those in the top 10% were in group 6. Across outcome groups, significant relationships from low to high performance were identified. Biographic/audiologic factors of age at implantation, duration of hearing loss, duration of hearing aid use, and duration of severe-to-profound hearing loss were significantly and inversely related to performance as were frequency modulated tone, sound-field threshold levels obtained with the CI. That is, the higher-performing outcome groups were younger in age at the time of implantation, had shorter duration of severe-to-profound hearing loss, and had lower CI sound-field threshold levels. Significant inverse relationships across outcome groups were also observed for electrode position, specifically the percentage of electrodes in scala vestibuli as opposed to scala tympani and depth of insertion of the electrode array. In addition, positioning of electrode arrays closer to the modiolar wall was positively correlated with outcome. Cognitive ability was significantly and positively related to outcome; however, age at implantation and cognition were highly correlated. After controlling for age, cognition was no longer a factor affecting outcomes. CONCLUSION: There are a number of factors that limit CI outcomes. They can act singularly or collectively to restrict an individual's performance and to varying degrees. The highest performing CI recipients are those with the least number of limiting factors. Knowledge of when and how these factors affect performance can favorably influence counseling, device fitting, and rehabilitation for individual patients and can contribute to improved device design and application. PMID- 23348849 TI - [Antoine Augustin Parmentier (1737-1813), Science for public welfare]. PMID- 23348850 TI - [Diabesity and cardiovascular diseases: Novel mediators and novel targets]. PMID- 23348851 TI - [Calculation of the first dose of amikacine: evaluation of the current dosage recommendations]. AB - Aminoglycosides, including amikacin, are antibiotics with major interest in the management of sepsis, but with a high potential toxicity. The French national recommendations revised in 2011 recommend a dose of amikacin ranging from 15 to 30 mg/kg. The objective was to assess if such a dose interval allows reaching the efficiency target concentrations of 64 mg/L without exceeding the toxic threshold of 2.5mg/L. From a cohort of 100 patients treated with amikacin, the individual pharmacokinetic parameters were estimated using pharmacokinetic software (MM USCPACK). Peak and residual concentrations obtained after simulated doses ranging from 15 to 30 mg/kg were estimated and compared with the effective and toxic thresholds. The optimum dose to achieve precisely the efficiency target was calculated for each patient. Patients studied had a mean age of 79 years, mean weight of 58 kg, and mean creatinine clearance of 45 mL/min. The dose of 30 mg/kg allows the achievement of an effective peak in 98.7% of patients, but led to a potentially toxic through for 72.4% of them. The optimal dose was at mean of 1264 mg, significantly different than doses calculated with weight (P<0.0001). A weak correlation was found between weight and the optimal dose. A fixed dose of 30 mg/kg seems to be effective for most patients, but often excessive and leads to a toxic residual to 72% of patients, whereas 15 mg/kg was insufficient for most patients. The low correlation between optimal dose and patient weight shows that weight does not explain fully the interindividual variability. PMID- 23348852 TI - [Fat mass expansion, fatty acids and adipokines: metabolic markers and risk factors for cardiovascular pathologies]. AB - Obesity is described as an independent risk factor for cardiovascular disease. Fat mass expansion is often associated with occurrence of a pro-inflammatory state, which will interfere with cell metabolism in various tissues and alter noticeably insulin-signaling processes. This low-grade, systemic inflammatory response that characterizes obesity will develop towards dysfunctions which will include insulin-resistance, type 2 diabetes, dyslipidemia, hypertension and coronary and vascular pathologies and even toward some cancers. Metabolic and endocrine functions will be briefly considered as well as events related to fat mass expansion such as hypertrophy-related disturbances in adipocyte function and adipose tissue infiltration by immune cells (i.e., macrophages and lymphocytes which could secrete cytokines and chemokines). In addition to the well known function of storage and release on non esterified fatty acids (NEFAs), the adipocytes synthesize and secrete circulating hormones (called adipokines such as leptin, adiponectin and apelin) which are acting as signaling molecules and which are mediators/modulators of the inflammatory processes. The interest of adipose tissue productions as plasma metabolic markers and the dialogue and interactions between adipose tissue productions (i.e., NEFAs, adipokines and cytokines) and other target tissues will be considered. The objective of this paper is to describe adipose tissue dysfunctions observed in obesity and to delineate putative relationships, which could exist between adipose tissue dysfunctions and other tissues. The idea is to describe how adipose tissue dysfunction is involved in the development of type 2 diabetes and cardiovascular diseases. PMID- 23348853 TI - Drug treatments to restore vascular function and diabesity. AB - Over the last decades, an escalating rate of type 2 diabetes has paralleled an epidemic rise in the prevalence of obesity. Both diabetes and obesity confer an increased risk of cardiovascular comorbidities, including hypertension, coronary artery disease and stroke. Vascular dysfunction, represented by impaired endothelial release of vasodilator substances or defective smooth muscle vasodilator reactivity, is the early stage of the process leading to atherosclerosis and a common finding in patients with diabesity. It is understandable, therefore, that effective treatments for diabesity should restore vascular function to prevent the development of cardiovascular disease. Recent evidence from clinical studies supports the efficacy of incretin-based antidiabetic therapies for vascular protection. Thus, glucose control with either DDP-4 inhibitor or GLP-1 receptor therapies seems associated with favorable effects on vascular function in diabetes and the metabolic syndrome. Another mechanism to counter excess plasma glucose and reduce body weight in these patients may rely on drug therapies targeting gut hormones, as suggested by the efficacy of bariatric surgery to produce both sustained weight loss and high diabetes remission rates. Also, as knowledge of the multifaceted vascular actions of adipokines and their dysregulation in patients with diabesity increases, these substances become attractive targets for treatments aimed at cardiovascular prevention. The increasing coexistence of diabetes and obesity presents complex treatment challenges owing to the elevated risk of developing cardiovascular complications. Hence, therapeutic strategies integrating glycemic control, weight loss and vascular protection are of the greatest importance to successfully counteract the health and economic burden posed by diabesity. PMID- 23348854 TI - [Metabolic therapy at the edge between human hosts and gut microbes]. AB - Personalized medicine is becoming day-after-day more urgent taking into account the great diversity characterizing patients affected by a given pathology, especially metabolic diseases. In fact, antidiabetic/obesity treatments have shown a reduced or no effect at all in some patients, representing a major challenge physicians have to face worldwide. Therefore, efforts have to be put to identify individual factors affecting our susceptibility towards a given medication. In that regard, gut microbiota may stand for the missing piece of the metabolic puzzle regulating host response, since its role in the induction of metabolic diseases has now been achieved. In fact, we firstly provided a bacterial explanation for the low-grade chronic inflammation featuring metabolic diseases, by showing the lipopolysaccharide as a trigger and risk factor of such pathologies. However, despite similar lineages of microbes characterize the gut of people, important differences still remain, which may be responsible for opposite effect of treatments such as pre- or probiotics, whose efficacy seems to be governed by the own gut microbiota of subjects. We have recently shown that gut microbiota is associated to the inclination to resist or not high-fat diet induced type 2 diabetes in mice. In addition, the direct targeting of gut microbes by dietary fibers reversed the observed metabolic phenotype. These results, together with the literature, strongly suggest gut microbiota as a new target for the development of personalized metabolic therapy. PMID- 23348855 TI - [Endothelial dysfunction in obesity]. AB - The last decades have witnessed an explosive increase in the number of obese people in the Western world as well as in emerging countries. In obese subjects, the enlarged adipose tissues release more pro-inflammatory adipokines (in particular A-FABP and lipocalin-2) while the production of adiponectin, which exerts beneficial effects on insulin sensitivity, inflammation and cardiovascular function, is markedly reduced. As a consequence, as discussed in this article, obesity negatively affects the function of the endothelial cells and results in their progressive endothelial dysfunction with reduced release of relaxing signals (nitric oxide [NO]) and augmented production of vasoconstrictor prostaglandins (EDCF) which activate TP receptors on vascular smooth-muscle cells to cause their contraction. PMID- 23348856 TI - Parent's attitude toward prenatal diagnosis and termination of pregnancy could be influenced by other factors rather than by the severity of the condition. AB - OBJECTIVE: The aim of this study is to investigate whether the severity of a particular condition alone influences parents' attitudes toward prenatal diagnosis (PND) and termination of pregnancy (TOP) or are there other factors involved? METHODS: A questionnaire that mainly focuses on parent's attitude toward PND and TOP for 30 different hypothetical scenarios for a series of genetic, non-genetic, and non-medical conditions were completed by 400 Saudi parents. Results were compared and scored and parent comments were noted. Additionally, cross tabulation of thalassemia, considered the most severe and had the most favorable PND and TOP, against the 29 other conditions were carried out to find similarities and different views toward TOP and PND. RESULTS: We found that parents' attitudes toward PND and TOP for thalassemia are significantly associated with their attitudes in relation to all of the other conditions (p < 0.01). CONCLUSION: Saudi Parents' attitudes toward TOP and PND are not always influenced by the severity of the condition. PMID- 23348857 TI - Non-immediate, severe hypersensitivity reaction to iopamidol with cross reactivity to different radiocontrast agents. PMID- 23348858 TI - The pitfalls of FeNO testing. PMID- 23348859 TI - Aerosol characteristics of admixture of budesonide inhalation suspension with a beta2-agonist, procaterol. AB - BACKGROUND: Nebulized drugs for asthma treatment are often mixed together in order to simplify inhalation regimens, although not recommended. We therefore evaluated aerosol characteristics and physicochemical stability of the admixture of an inhaled corticosteroid suspension with a beta2-agonist solution. METHODS: An 8-stage cascade impactor was used to measure the particle size distribution of admixture of Pulmicort(r) Respules(r) (budesonide, 0.5mg/2mL) with Meptin(r) Inhalation Solution Unit (procaterol hydrochloride, 30MUg/0.3mL) from a jet nebulizer, PARI LC Plus(r). Concentration of each drug was assayed with high pressure liquid chromatography. Physicochemical compatibility was also assessed up to 24 hours after mixing. RESULTS: With regard to budesonide, impactor parameters such as mass median aerodynamic diameter (MMAD) and respirable mass (RM) were comparable between admixtures and single-drug preparations (2.92 +/- 0.03 vs 2.99 +/- 0.14MUm, 146.8 +/- 2.9 vs 147.6 +/- 8.2MUg, respectively). On the other hand, delivery rates of procaterol increased when admixed with budesonide suspension, resulting in significantly higher RM (15.1 +/- 0.8 vs 10.2 +/- 0.5MUg, p < 0.01). Variations from initial concentration in the percentages of drug remaining at any time point were less than 10%, and there were no appreciable changes in pH of the admixtures for up to 24 hours. CONCLUSIONS: There is a possibility that admixture might influence of aerodynamic characteristics of procaterol, but not budesonide. In vivo data will be needed for the clinical implications of our findings. PMID- 23348860 TI - Vascular graft infections. AB - Vascular procedures are rarely complicated by infection, but if prosthetic vascular graft infection (PVGI) occurs, morbidity and mortality are high. Several patient-related, surgery-related and postoperative risk factors are reported, but they are not well validated. PVGI is due to bacterial colonisation of the wound and the underlying prosthetic graft, generally as a result of direct contamination during the operative procedure, mainly from the patient's skin or adjacent bowel. There is no consensus on diagnostic criteria or on the best management of PVGI. On the basis of reported clinical studies and our own experience, we advocate a surgical approach combining repeated radical local debridement, with graft preservation whenever possible or partial excision of the infected graft, depending on its condition, plus simultaneous negative-pressure wound therapy (NPWT). In addition, antimicrobial therapy is recommended, but there is no consensus on which classes of agent are adequate for the treatment of PVGI and whether certain infections may be treated by means of NPWT alone. Since staphylococci and Gram-negative rods are likely to be isolated, empirical treatment might include a penicillinase-resistant beta-lactam or a glycopeptide, plus an aminoglycoside, the latter for Gram-negative coverage and synergistic treatment of Gram-positive cocci. Additionally, empirical treatment might include rifampicin since it penetrates well into biofilms. PMID- 23348861 TI - Y-linked microsatellites in Amazonian Amerindians applied to ancestry estimates in Brazilian Afro-derived populations. AB - OBJECTIVES: Proper ancestral populations are required to determine accurate ancestry estimates for Afro-derived Brazilian populations. Herein, we have genotyped Y-STRs in Amazonian Amerindians to determine the ancestral contribution in quilombo remnant communities. METHODS: The frequencies for five Y-chromosome linked microsatellites (DYS19, DYS390, DYS391, DYS392, and DYS393) were characterized in four Amerindian tribes from Brazilian Amazon (Tikuna, Baniwa, Kashinawa, and Kanamari), and in four quilombo remnants (Mimbo, Sitio Velho, Gaucinha, and Sao Goncalo) and two urban populations (Teresina and Jequie) from Northeastern Brazil. We then estimated the male genetic ancestry in each admixed population. Moreover, we performed analysis of molecular variance (AMOVA), FST , haplotype diversity, and principal component analysis. RESULTS: Lower haplotype diversity (h) values were observed for Tikuna compared with other tribes. Quilombo remnants exhibited higher h levels ranging from 0.893 +/- 0.027 in Sitio Velho to 0.963 +/- 0.033 in Sao Goncalo. African ancestry estimates ranged from 0.529 +/- 0.027 in Mimbo to 0.602 +/- 0.086 in Sitio Velho. Conversely, European contribution was 0.795 +/- 0.045 in Teresina and 0.826 +/- 0.040 in Jequie. CONCLUSIONS: FST and principal component analysis indicate homogeneity in the male genetic constitution among the quilombo remnants analyzed. Data on Amerindians allowed accurate ancestry estimates, which indicated a higher African contribution, followed by a considerable European contribution for these quilombo remnants. PMID- 23348863 TI - Incidence, morphology, and classification of epimacular membrane rip. AB - PURPOSE: To describe the incidence, associated factors, morphology, and visual characteristics of a series of patients with tears within an epimacular membrane (EMM). METHODS: Consecutive, prospective, observational case series of patients with EMM rip. Patients were evaluated with spectral domain optical coherence tomography, infrared photography, and fundus autofluorescence. Symptomatic patients were treated with pars plana vitrectomy and EMM removal. Follow-up imaging evaluation was performed at 3-month intervals. RESULTS: A total of 761 patients presented with EMM. Thirty-four eyes of 34 patients (4.5%) developed EMM rip. Frequent associated features included history of cataract extraction, diabetes mellitus, and retinal tear treated with photocoagulation. Morphologic characteristics included a scrolled torn edge of internal limiting membrane/EMM. Rip patterns include horseshoe shapes and patchy confluent striae and appeared as dark lines on infrared or fundus autofluorescence imaging. The EMM rips were classified as Type 1 if the rip occurred within 500 MUm of the foveola on spectral domain optical coherence tomography and Type 2 if extrafoveal. Foveal involvement was associated with worse presenting vision (P = 0.002) and visual outcome after EMM removal (P = 0.012). Previous retinal tear was associated with worse visual outcome. CONCLUSION: The EMM rip occurs in a small but significant minority of patients with EMM. Foveal involvement leads to increased visual deficit and may indicate a worse visual outcome at presentation and after intervention. Fundus autofluorescence and infrared imaging are useful in identifying EMM rip patterns. PMID- 23348862 TI - Revival of PFA-100--how far is it useful for the monitoring of ADP receptor antagonists? PMID- 23348864 TI - Spectral-domain optical coherence tomography of early onset large colloid drusen. AB - PURPOSE: Large colloid drusen (LCD) are a subgroup of early onset drusen recently reported. The aim of this study was to describe morphologic features in patients affected with LCD using high-resolution spectral-domain optical coherence tomography (SD-OCT). METHODS: A complete ophthalmologic examination including SD OCT was performed in 22 eyes of 11 consecutive patients. RESULTS: Mean age was 35 years old at diagnosis, and mean visual acuity was 20/25. In all eyes, SD-OCT showed multiple dome-shaped retinal pigment epithelium detachments corresponding to the drusen. Mean height of drusen was 199 MUm (range, 108-316 MUm) and mean width was 419 MUm (range, 190-681 MUm). Indocyanine green angiography hypofluorescent LCD were larger and more reflective on SD-OCT than indocyanine green angiography hyperfluorescent LCD. All drusen appeared convex with medium and homogeneous internal reflectivity. Retina overlying LCD appeared wavy and overall thinned. Prominent diffuse hyperreflective haze in the Henle fiber layer over drusen was noted in 73% of the eyes. No geographic atrophy or choroidal neovascularization was observed. CONCLUSION: The peculiar SD-OCT features reported in the current series give insight on the ultrastructure of LCD. Further studies with follow-up evaluation and possibly histologic evaluation are needed to clarify the clinical significance of LCD. PMID- 23348865 TI - Correlation of foveal microstructural changes with vision after anti-vascular endothelial growth factor therapy in age-related macular degeneration. AB - PURPOSE: To investigate the correlation of foveal microstructural changes with vision after intravitreal ranibizumab injection in eye with choroidal neovascularization (CNV) secondary to age-related macular degeneration. METHODS: We retrospectively studied 40 eyes of 40 patients with neovascular age-related macular degeneration who had no previous treatment history of age-related macular degeneration. All patients were treated with 3 monthly intravitreal ranibizumab (0.5 mg/0.05 mL) injections. One month after the third consecutive injection, best-corrected visual acuity (BCVA) was evaluated and the eyes were categorized into 2 groups according to the change in BCVA (good function group: BCVA improvement >= logarithm of minimum angle of resolution 0.3; poor function group: BCVA improvement < logarithm of minimum angle of resolution 0.3). Changes of foveal photoreceptor layer integrity, CNV size (diameter and thickness), central macular thickness, center point thickness, outer nuclear layer thickness, and subretinal fluid in each group were also evaluated using spectral-domain optical coherence tomography. RESULTS: The good function group is 20 eyes, and the poor function group is 20 eyes. No significant differences in baseline characteristics of variables including CNV type, initial BCVA, photoreceptor integrity, and CNV size were observed between the two groups. Best-corrected visual acuity in the good function group was 0.30 +/- 0.17 (logarithm of minimum angle of resolution) and that in the poor function group was 0.48 +/- 0.40 (logarithm of minimum angle of resolution). Decreased disrupted length of photoreceptor layer (1,020.80 +/- 974.60) and decreased CNV thickness (78.86 +/- 50.78) were found in the good function group at the end of follow-up. However, no significant differences in changes of CNV diameter, central macular thickness, center point thickness, outer nuclear layer thickness, and resolution of subretinal fluid were observed between the two groups. CONCLUSION: Restoration of foveal photoreceptor integrity and decreased CNV thickness are closely associated with visual improvement in neovascular age-related macular degeneration after treatment. PMID- 23348866 TI - Community pharmacists and people with dementia: a cross-sectional survey exploring experiences, attitudes, and knowledge of pain and its management. AB - OBJECTIVES: To explore community pharmacists' experiences with and attitudes towards people with dementia, and to determine the knowledge they have about pain and its management in this patient population. METHODS: A questionnaire comprising five sections, including the Approaches to Dementia Questionnaire, was mailed, on two occasions, during February and March 2011, to all community pharmacies in Northern Ireland (n = 530). RESULTS: The response rate was 34.3%. A greater proportion of pharmacists provided pharmaceutical care to people with dementia living at home (91.2%) than those living in care homes (40.1%). Respondents most frequently encountered queries relating to starting and stopping medications, compliance with medication, and availability of formulation types. The mean total score for the Approaches to Dementia Questionnaire measure was 72.8, indicating a positive attitude towards people with dementia, and respondents demonstrated a strong person-centred approach towards this patient population. The majority of respondents recognised the difficulty of assessing pain in people with dementia; however, younger pharmacists (p = 0.041) and pharmacists who provided pharmaceutical care to people with dementia (p = 0.012) were more likely to be aware of the pain assessment tools for use in people with dementia. Pharmacists appeared uncertain about how to appropriately manage pain in people with dementia. CONCLUSIONS: The study has revealed that community pharmacists often encounter people with dementia, especially those living in their own homes, and they have positive attitudes towards the patient population. However, training in the assessment and management of pain in people with dementia must be developed to further improve their knowledge in this area. PMID- 23348867 TI - Variations among US hospitals in counseling practices regarding prematurely born infants. AB - OBJECTIVE: We studied several counselor-independent elements of prenatal counseling regarding prematurely born infants. Elements studied include: indications to offer counseling, clinical settings in which counseling is offered, personnel assigned to counsel, availability of tools to assist counseling and post-counseling documentation requirements. METHOD: As the study aimed to explore system-based practices and not counselor-based practices, we surveyed Neonatal Intensive Care Unit medical directors. RESULT: Responses were received from 352 hospitals (53%) in 47 states. Analysis was based on responses from the 337 hospitals that routinely counseled women anticipating a premature birth. In 299 (~ 90%) hospitals, counseling was primarily performed by neonatal professionals. Premature labor was the most common indication to offer counseling; however, in 54 hospitals most counseling was offered before labor and based on maternal risk factors for preterm delivery. In nearly all (99.7%) hospitals information was provided verbally and face-to-face; a third of the hospitals also provided written information. For non-English-speaking Hispanic patients, 208 (62%) of the hospitals had certified hospital-based Spanish interpreters. Five (1%) hospitals provided specialized training to the designated prenatal counselors. The upper gestational age eligible for counseling at all 337 hospitals included 33 weeks; in 134 hospitals, gestational age of <23 weeks was not eligible for counseling. CONCLUSION: Antenatal parental counseling for premature delivery is a widely practiced intervention with substantial system based variability in execution. Interventions and strategies known to improve overall counseling effectiveness are not commonly utilized. We speculate that guidelines and tool-kits supported by Pediatric and Obstetric professional organizations may help improve system-based practices. PMID- 23348868 TI - Infant illness spanning the antenatal to early neonatal continuum in rural northern Ghana: local perceptions, beliefs and practices. AB - OBJECTIVE: To explore community understanding of perinatal illness in northern Ghana. STUDY DESIGN: A cross-sectional descriptive study design. RESULT: 253 community members participated in in-depth interviews and focus group discussions, including women with newborn infants, grandmothers and health care providers. Four overarching themes emerged: (1) Local understanding of illness affects treatment practices. Respondents recognized danger signs of illness spanning antenatal to early neonatal periods. Understanding of causation often had a distinctly local flavor, and thus treatment sometimes differed from mainstream recommendations; (2) Mothers are frequently blamed for their infant's illness; (3) Healthcare decisions regarding infant care are often influenced by community members aside from the infant's mother and (4) Confidence in healthcare providers is issue-specific, and many households use a blended approach to meet their health needs. CONCLUSION: Despite widespread recognition of danger signs and reported intentions to treat ill infants through the formal health care system, traditional approaches to perinatal illness remain common. Interventions need to be aligned with community perceptions if they are to succeed. PMID- 23348869 TI - Resource utilization in primary repair of cleft lip. AB - OBJECTIVE: To determine national variations in resource utilization for primary repair of cleft lip, identify patient and institutional factors associated with high resource use, and estimate the current incidence of cleft lip in the United States. STUDY DESIGN: Retrospective analysis of a national, pediatric database (2009 Kids' Inpatient Database [KID]). METHODS: Patients aged 1 year and younger were selected using international classification of disease codes for cleft lip and procedure codes for cleft lip repair. A number of demographic variables were analyzed, and hospital charges were considered as a measure of resource utilization. RESULTS: There were 1318 patients identified. The national incidence was 0.09%, with a male to female ratio of 1.8:1. Regional incidence varied from 0.07% (Northeast) to 0.10% (West). The mean age at surgery was 4.2 months. The average length of stay was 1.4 days. The national average hospital charge was $20,147, ranging from $14,635 (South) to $23,663 (West). Teaching hospitals charge an average of $9764 higher than nonteaching hospitals. The strongest predictor of charge was length of stay, increasing charge by $8102 for every additional hospital day (P < .01). CONCLUSION: Regional variations exist in resource utilization for primary cleft lip repair. Resource use is higher in the West and among teaching hospitals. PMID- 23348870 TI - Supportive care in early rehabilitation for advanced-stage radiated head and neck cancer patients. AB - OBJECTIVE: To investigate the health-related quality of life (HRQoL) and supportive follow-up care needs 1 month posttreatment for patients with advanced stage (stage III or IV) radiated head and neck cancer (HNC) who were treated with curative intent. STUDY DESIGN: An exploratory, descriptive analysis of HRQoL data obtained from 3 treatment groups: conventional radiotherapy (RT, n = 21), surgery + radiotherapy (SRT, n = 10), and chemoradiation (CRT, n = 21). SETTING: The head and neck oncology center of a university hospital. SUBJECTS AND METHODS: Fifty two patients completed the EORTC QLQ-C30 and EORTC QLQ H&N35 self-report questionnaires 1 month posttreatment. Descriptive statistics and clinically relevant differences between the groups were analyzed. RESULTS: The HRQoL outcomes between groups differed. Clinically relevant difference was observed in the RT and CRT groups with respect to dry mouth, coughing, feeling ill, use of painkillers, and the use of nutritional supplements. The RT group differed from the other groups with respect to pain and swallowing. The CRT group differed from the other groups regarding role functioning. CONCLUSION: Health-related quality of life differs between RT, SRT, and CRT patients 1 month posttreatment. The RT- and CRT-treated patients reported higher impairment than the patients who were treated with SRT. Nutritional intake and oral function emphasize the importance of providing supportive care to radiated advanced-stage HNC patients throughout the treatment trajectory and the need for continuation during the first few posttreatment months. PMID- 23348871 TI - Postoperative urinary tract infection and short-term outcomes and costs in head and neck cancer surgery. AB - OBJECTIVES: Catheter-associated urinary tract infections (UTIs) have been identified as a preventable "never event" by the Centers for Medicare & Medicaid Services. We sought to determine the relationship between UTI and in-hospital mortality, postoperative complications, length of stay, and costs in head and neck cancer (HNCA) surgery. STUDY DESIGN: Cross-sectional analysis using cross tabulations and multivariate regression modeling. SETTING: The Nationwide Inpatient Sample database. SUBJECTS AND METHODS: Discharge data for 93,663 patients who underwent an ablative procedure for a malignant oral cavity, laryngeal, hypopharyngeal, or oropharyngeal neoplasm in 2003-2008 were analyzed. RESULTS: Urinary tract infection was diagnosed in 2% of patients, with catheter associated UTI coded in only 20 patients. Patients with UTI were more likely to be older than 80 years (odds ratio [OR], 3.3; P = .008), be female (OR, 1.9; P < .001), have advanced comorbidity (OR, 1.8; P < .012), undergo major surgical procedures (OR, 1.7; P = .001), and have predisposing bladder and prostate conditions (OR, 3.8; P < .001), surgical complications (OR, 2.3; P < .001), and acute medical complications (OR, 3.1; P < .001). Urinary tract infection was associated with significantly increased length of hospitalization and hospital related costs, after controlling for all other variables. CONCLUSION: Urinary tract infection is unusual in HNCA surgical patients but is more common with extent of surgery and age and is significantly associated with postoperative complications, length of hospitalization, and hospital-related costs. Catheter associated UTI is likely underestimated because of difficulty in distinguishing between a catheter-associated UTI and postoperative UTI in patients undergoing major surgical procedures, who routinely undergo perioperative urinary catheterization. Patients with HNCA are a high-risk group for this "never event," particularly as the population ages. PMID- 23348872 TI - Biofilm formations in nasopharyngeal tissues of patients with nasopharyngeal osteoradionecrosis. AB - OBJECTIVE: Determine the presence of nasopharynx biofilms in patients with nasopharyngeal cancer (NPC) and osteoradionecrosis (ORN) and patients with NPC but no ORN. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary referral medical center. SUBJECTS AND METHODS: We enrolled 27 patients with NPC from our outpatient clinic during January 2010 to June 2012. These patients were diagnosed with NPC between 1980 and 2012, and all had received radiotherapy. Of these 27 patients, 15 presented with ORN, and 12 did not. The nasopharynx biopsied specimens were processed and analyzed within 2 hours of collection with the FilmTracer LIVE_DEAD Biofilm Viability Kit (Molecular Probes, Invitrogen, Carlsbad, California). A blinded investigator determined the formation of biofilms by fluorescence microscopy. Bacterial cultures were collected. RESULTS: Eleven of 15 (73%) ORN patients had biofilm formations in nasopharynx biopsy specimens. Five of these samples (45%) yielded positive cultures, and 4 of these cultures indicated the presence of methicillin-resistant Staphylococcus aureus (MRSA). Only 1 of 12 NPC patients without ORN had nasopharynx biofilm formation, and all culture results were negative. CONCLUSION: Biofilm formations were common in nasopharynx samples of NPC patients with ORN but rare in samples of NPC patients without ORN. The presence of biofilms, especially MRSA, may have a role in the disease progression of ORN or may contribute to the chronicity and resistance to antibiotic treatment. PMID- 23348873 TI - Middle ear effusion in patients with sinonasal cancer treated by surgery with or without radiotherapy. AB - OBJECTIVE: To identify the prevalence and risk factors of eustachian tube dysfunction after surgery for sinonasal cancer by observing the occurrence of middle ear effusion. STUDY DESIGN: Historical cohort study. SETTING: Academic university hospital. SUBJECTS AND METHODS: Clinical records of 112 patients surgically treated for sinonasal cancer over a 16-year period were evaluated. Initial bivariate analysis was followed by a multivariate logistic regression model. RESULTS: The best model included 2 variables: posterior extension of surgical resection (nasopharynx, soft palate, eustachian tube, pterygomaxillary fossa, parapharyngeal space) with an odds ratio of 5.662 (95% confidence interval [CI], 1.877-9.447) and postoperative radiotherapy with an odds ratio of 8.691 (95% CI, 4.187-13.194). CONCLUSION: Despite the limited number of patients, the study gives a prediction of middle ear effusion based on 2 well-defined factors: surgical resection of anatomic structures involved in tubal function and adjuvant radiotherapy. PMID- 23348875 TI - Temperature-dependent zero-field splitting in a copper(II) dimer studied by EPR. AB - We report on the synthesis and temperature-dependent magnetic properties observed in an exchange-coupled copper(II) dimer using X/Q-band Electron Paramagnetic Resonance (EPR) spectroscopy (9/34 GHz). It has been found that the zero-field splitting (D) in the dimer changes gradually by a factor close to two in the temperature range from T = 50 to 300 K. X-ray diffraction data show that this dimer consists of two five-coordinated copper ions, one of which has a highly asymmetric geometry intermediate between square pyramid and trigonal bipyramid. The copper-copper distance in the dimer is temperature-independent, whereas the degree of trigonality in an asymmetric unit decreases as the temperature is lowered. Therefore we suppose that the observed dependence D(T) originates from the interplay of different exchange interaction pathways driven by these thermal changes. Magnetic susceptibility measurements reveal weak ferromagnetic interactions, whose anisotropic parts should indeed be very sensitive to the subtle changes in the geometry and may result in apparent D(T). Apart from being a very unusual example of magneto-structural correlations, this and similar dimeric systems can be considered as an interesting type of new materials exhibiting strongly temperature-dependent magnetic properties. PMID- 23348874 TI - Prunella vulgaris attenuates prepulse inhibition deficit and attention disruption induced by MK-801 in mice. AB - Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and it has been traditionally used to treat inflammation or hypertension. In the present study, we investigated the effects of the ethanolic extract of the spikes of Prunella vulgaris var. lilacina (EEPV) on dizocilpine (MK-801)-induced schizophrenia-like phenotype behaviors such as the disruption of prepulse inhibition and attention deficits in mice. We also determined the effect of EEPV on MK-801-induced alterations in phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, phospho-glycogen synthase kinase 3-beta, and phosphorylated cAMP response element-binding protein levels in the cortex and hippocampus of mice. MK-801-induced prepulse inhibition deficits were ameliorated by the administration of EEPV, as shown in the acoustic startle response test. Furthermore, EEPV attenuated the MK-801-induced attention deficits in the water finding test. We also found that EEPV attenuated the increased phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, or phospho-glycogen synthase kinase 3-beta levels induced by MK-801 in the cortex but not in the hippocampus. These results suggest that EEPV could be useful for treating schizophrenia because EEPV ameliorates prepulse inhibition disruption and attention deficits induced by MK-801. PMID- 23348876 TI - Reversal of chronic to resolved infection by IL-10 blockade is LCMV strain dependent. AB - Chronic viral infections lead to CD8(+) T-cell exhaustion, characterized by impaired cytokine secretion. The immune-regulatory cytokine IL-10 promotes chronicity of infection with lymphocytic choriomeningitis virus (LCMV) Clone 13, as absence of IL-10 or blocking of IL-10R during early LCMV Clone 13 infection results in viral clearance. Thus, treatment of humans suffering from chronic viral infections with IL-10 neutralizing or IL-10R blocking antibodies was proposed to boost virus-specific T-cell responses to enhance control or even clear the viral infection. Here we demonstrate that although CD4(+) and CD8(+) T cells can produce elevated levels of cytokines in IL-10(-/-) mice early after infection compared with WT mice, IL-10(-/-) mice cannot clear an infection with the quicker replicating LCMV strain Docile, eventually resulting in T-cell exhaustion. These data suggest that the success of IL-10 blockade to control chronic viral infections may critically depend on the virulence of the infecting strain. PMID- 23348877 TI - Investigating the suspension culture on aggregation and function of mouse pancreatic beta-cells. AB - The integrity and hierarchical structure of islet influence beta-cells physiology dramatically. A culture substrate which can maintain or improve beta-cells aggregation shall benefit cell therapy for diabetics. In this study, nontreated, type IV collagen, Lipidure, and ultralow attachment dishes were used to culture a murine beta-cell line, MIN-6. The formation and biological performances of pseudoislets were investigated. Results showed that beta-cells formed loose and irregular aggregates on nontreated dishes. Oppositely, pseudoislets formed on other three substrates. Most pseudoislets on Lipidure and type IV collagen dishes had a diameter between 100-150 MUm with high survival rate, while large pseudoislets (>250 MUm) with seriously central necrosis were found on ultralow attachment dishes. Western blot analysis revealed that pseudoislets had relatively higher connexin 36 protein productions relative to single cells. The glucose-stimulated insulin secretion test showed pseudoislets on type IV collagen have high stimulation index. Monolayers from TCPS dishes and pseudoislets from type IV collagen or Lipidure dishes were further transplanted into diabetic mice. Animals received both single cells and pseudoislets had decreasing blood glucose level and regained body weight. Histologic examination revealed that all implants successfully engrafted with positive insulin staining. Interestingly, the area under curve for the intraperitoneal glucose tolerance test showed pseudoislets had superior glucose disappearance rate. This study reveals that isolated islets or insulin-producing cells can be cultured on type IV collagen or Lipidure dishes to improve/maintain integrity prior to transplantation. PMID- 23348878 TI - Serum bicarbonate and mortality in adults in NHANES III. AB - BACKGROUND: Low serum bicarbonate concentration is a risk factor for death in people with chronic kidney disease (CKD). Whether low serum bicarbonate is a mortality risk factor for people without CKD is unknown. METHODS: National Health and Nutrition Examination Survey III (NHANES III) adult participants were categorized into one of four serum bicarbonate categories: <22, 22-25, 26-30 and >= 31 mM. Cox models were used to determine the hazards of death in each serum bicarbonate category, using 26-30 mM as the reference group, in the (i) entire population, (ii) non-CKD subgroup and (iii) CKD subgroup. RESULTS: After adjusting for age, gender, race, estimated glomerular filtration rate, albuminuria, diuretic use, smoking, C-reactive protein, cardiovascular disease, protein intake, diabetes, hypertension, body mass index, lung disease and serum albumin, the hazards of death in the <22 mM serum bicarbonate category were 1.75 (95% CI: 1.12-2.74), 1.56 (95% CI: 0.78-3.09) and 2.56 (95% CI: 1.49-4.38) in the entire population, non-CKD subgroup and CKD subgroup, respectively, compared with the reference group. Hazard ratios in the other serum bicarbonate categories in the entire population and non-CKD and CKD subgroups did not differ from the reference group. CONCLUSIONS: Among the NHANES III participants, low serum bicarbonate was not observed to be a strong predictor of mortality in people without CKD. However, low serum bicarbonate was associated with a 2.6-fold increased hazard of death in people with CKD. PMID- 23348880 TI - Screening for depression: only one piece of the puzzle. AB - In this issue of NDT, van den Beukel et al. from the Netherlands suggest that a 5 item survey questionnaire might be used to replace the Beck Depression Index to screen patients with chronic kidney disease (CKD) for depression. The nephrology community is at a tipping point in terms of the assessment of outcomes, especially among patients on dialysis. Indeed, the entire healthcare community has begun to shift its focus to patient-reported outcomes (PROs), including quality of life, patient satisfaction and the psychosocial determinants of health. Beyond depression, there are a myriad of aspects of psychological distress that include anxiety, worrying, fear of progression of kidney disease and the fear of the future in general, death and dying, hopelessness, questions around the meaning of life and the experience of recurrent psychological and physical trauma through the CKD trajectory. We encourage the community and its researchers to embrace and research PROs, with the aim to create a holistic, patient-centered model of care for patients at all stages of CKD, including those on chronic dialysis and after transplantation, keeping the whole person-and their families-in mind. PMID- 23348879 TI - Correlates of parathyroid hormone concentration in hemodialysis patients. AB - BACKGROUND: The implications of chemical hyperparathyroidism on bone and mineral metabolism measures in maintenance hemodialysis (MHD) are not well known. We hypothesized that a higher serum intact parathyroid hormone (iPTH) level is associated with the higher likelihood of hyperphosphatemia, hyperphosphatasemia [high serum alkaline phosphatase (ALP) levels] and hypercalcemia. METHODS: Over an 8-year period (July 2001-June 2009), we identified 106 760 MHD patients with iPTH and calcium (Ca), phosphorous (P) and ALP data from a large dialysis clinic. Logistic regression models were examined to assess the association between serum iPTH increments and the likelihood of hyperphosphatemia (P >=5.5 mg/dL), hypercalcemia (Ca >=10.2 mg/dL) and hyperphosphatasemia (ALP >=120 U/L). RESULTS: Patients were 61 +/- 16 years old and included 45% women, 59% diabetics and 33% Blacks. Compared with an iPTH level of 100 to <200 pg/mL, patients with an iPTH level of 600-700, 700 to <800 and >=800 pg/mL had 122% (OR: 2.22, 95% CI: 2.04 2.41), 153% (OR: 2.53, 95% CI: 2.29-2.80) and 243% (OR: 3.43, 95% CI: 3.22-3.66) higher risk of hyperphosphatemia, respectively, and had 109% (OR: 2.09, 95% CI: 1.93-2.26), 130% (OR: 2.30, 95% CI: 2.10-2.52) and 376% (OR: 4.76, 95% CI: 4.50 5.04) higher risk of hyperphosphatasemia, respectively. Compared with an iPTH level of 100 to <200 pg/mL, both the low iPTH (<100 pg/mL, OR: 2.45, 95% CI: 2.27 2.64) and the high iPTH (>=800 pg/mL: OR: 2.13, 95% CI: 1.95-2.33) levels were associated with hypercalcemia. CONCLUSIONS: Higher levels of iPTH are incremental correlates of hyperphosphatemia and hyperphosphatasemia, whereas both very low and high PTH levels are linked to hypercalcemia. If these associations are causal, correction of hyperparathyroidism may have overarching implications on bone and mineral disorders in MHD patients. PMID- 23348881 TI - Shorter delivered dialysis times associate with a higher and more difficult to treat blood pressure. AB - BACKGROUND: Shorter delivered dialysis times are associated with increased all cause mortality. Whether shorter delivered dialysis times also associate with an increase in blood pressure (BP) and reduce the ability of probing dry weight to lower BP is unclear. METHODS: Among patients participating in the Dry-Weight Reduction in Hypertensive Hemodialysis Patients (DRIP) trial, interdialytic ambulatory BP was recorded at baseline, 4 weeks and 8 weeks. Median intradialytic BP was also calculated at each dialysis treatment and associated with the delivered daily dialysis time. RESULTS: The median time on dialysis at baseline was 3.6 h per treatment (range 2.5-4.5 h). At baseline, modeled median intradialytic systolic BPs were higher among those who received fewer hours of dialysis. Among subjects who did not have their dry weight probed (control group), the median intradialytic systolic BP continued to be elevated. Probing dry weight (ultrafiltration group) provoked a drop in median intradialytic systolic BP regardless of the delivered dialysis time. However, the reduction in BP was achieved after fewer sessions of dialysis when delivered dialysis was longer in duration. The pattern of change was confirmed using interdialytic ambulatory BP monitoring. CONCLUSIONS: Fewer hours of delivered dialysis are associated with a higher systolic BP. Upon probing dry weight, compared with shorter dialysis treatment times, 4 h of delivered dialysis per session provokes reductions in systolic BP over fewer dialysis treatment sessions. Reduction of BP may lag dry-weight reduction when shorter dialysis is delivered. PMID- 23348882 TI - Encapsulating peritoneal sclerosis in children on chronic PD: a survey from the European Paediatric Dialysis Working Group. AB - BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis (PD) that is associated with significant morbidity and mortality in adults. There are scarce data for children. We performed a 10-year survey to determine the prevalence, risk factors and outcome for EPS in children. METHODS: Chronic PD patients in 14 dialysis units participating in the European Paediatric Dialysis Working Group between January 2001 and December 2010 were included in this study. RESULTS: Twenty-two cases of EPS were reported (prevalence 1.5%; 8.7 per 1000 patient-years on PD). Median PD vintage was 5.9 (1.6-10.2) in EPS and 1.7 (0.7-7.7) years in the remainder of the PD population (P<0.0001). EPS patients had a significantly higher peritonitis rate than non-EPS patients (P=0.2). EPS was diagnosed while the child was on PD in 17 (77%), after conversion to haemodialysis (HD) in 3 and after transplantation in 2. Fifteen of 17 (88%) developed ultrafiltration (UF) failure. The median interval between UF failure and presentation with bowel obstruction was 2.8 (0.02-5.8) months. Twenty (91%) had clinical and radiological signs of bowel obstruction. Enterolysis was performed in 14 and 19 received immunosuppression or tamoxifen. Nine required parenteral nutrition. At final follow-up 4.8 (1.3-8.7) years after EPS diagnosis, 3 patients died, 11 had a functioning transplant and 8 were on HD. CONCLUSIONS: The prevalence of EPS in European children on PD is comparable with that of adult PD patients, but mortality from paediatric EPS is significantly lower. A high index of suspicion is required for the diagnosis of EPS in children with longer dialysis duration, a high peritonitis rate and UF failure. PMID- 23348883 TI - Urinary vesicles: in splendid isolation. PMID- 23348884 TI - Clinical and histological predictors of long-term kidney graft survival. AB - Renal transplantation is the best option for patients with end-stage renal disease (ESRD), but its half-life is limited to a decade. Clinical and histological markers measurable within the first year of transplantation can be used to predict its outcome. These markers are important for selecting kidneys for transplantation, for identifying the main causes of late allograft loss, for therapeutic decisions and as surrogate markers in therapeutic trials. 'Basal state' markers, such as age, glomerular filtration rate and fibrotic lesions, are highly predictive of allograft loss, showing that early and stable pathological mechanisms contribute considerably to this loss. On the other hand, some more dynamic predictors such as treatment, recurrence of the initial disease, inflammation and epithelial phenotypic changes offer clinicians and researchers opportunities to influence the fate of allografts. PMID- 23348885 TI - Defining reduced urine output in neonatal ICU: importance for mortality and acute kidney injury classification. AB - BACKGROUND: Acute kidney injury (AKI) is an independent risk factor for mortality in adults and children. Generally, urine output (UO) < 1 mL/kg/h is accepted as oliguria in neonates, although it has not been systematically studied. pRIFLE criteria suggest UO cut-offs similar to those of the adult population (0.3 and 0.5 mL/kg/h). The aim of the present study was to investigate UO in correlation with mortality in critically ill neonates and suggest changes in the pRIFLE definition of reduced diuresis. METHODS: A retrospective cohort study was performed in an eight-bed neonatal intensive care unit (NICU). UO was systematically measured by diaper weight each 3 h. Discriminatory capacity to predict mortality of UO was measured and patients were divided according to UO ranges: G1 > 1.5 mL/kg/h; G2 1.0-1.5 mL/kg/h; G3 0.7-1.0 mL/kg/h and G4 < 0.7 mL/kg/h. These ranges were incorporated to pRIFLEGFR criteria and its performance was evaluated. RESULTS: Of 384 patients admitted at the NICU during the study period, 72 were excluded and overall mortality was 12.8%. UO showed good performance for mortality prediction (area under the curve 0.789, P < 0.001). There was a stepwise increase in hospital mortality according to UO groups after controlling for SNAPPE-II and diuretic use. Using these UO ranges with pRIFLE improves its discriminatory capacity (area under the receiver operating characteristic curve 0.882 versus 0.693, P < 0.05). CONCLUSIONS: UO is a predictor of mortality in NICU. An association between a UO threshold < 1.5 mL/kg/h and mortality was observed, which is higher than the previously published pRIFLE thresholds. Adopting higher values of UO in pRIFLE criteria can improve its capacity to detect AKI severity in neonates. PMID- 23348886 TI - Is a strategy based on routine endotracheal cultures the best way to prescribe antibiotics in ventilator-associated pneumonia? AB - OBJECTIVES: The objectives of this study were to evaluate if a strategy based on routine endotracheal aspirate (ETA) cultures is better than using the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines to prescribe antimicrobials in ventilator-associated pneumonia (VAP). METHODS: This was a prospective, observational, cohort study conducted in a 15-bed ICU and comprising 283 patients who were mechanically ventilated for >=48 h. Interventions included twice-weekly ETA; BAL culture was done if VAP was suspected. BAL (collected at the time of VAP) plus ETA cultures (collected<=7 days before VAP) (n=146 different pairs) were defined. We compared two models of 10 days of empirical antimicrobials (ETA-based vs ATS/IDSA guidelines-based strategies), analyzing their impact on appropriateness of therapy and total antimicrobial-days, using the BAL result as the standard for comparison. RESULTS: Complete ETA and BAL culture concordance (identical pathogens or negative result) occurred in 52 pairs; discordance (false positive or false negative) in 67, and partial concordance in two. ETA predicted the etiology in 62.4% of all pairs, in 74.0% of pairs if ETA was performed<=2 days before BAL, and in 46.2% of pairs if ETA was performed 3 to 7 days before BAL (P=.016). Strategies based on the ATS/IDSA guidelines and on ETA results led to appropriate therapy in 97.9% and 77.4% of pairs, respectively (P<.001). The numbers of antimicrobial-days were 1,942 and 1,557 for therapies based on ATS/IDSA guidelines and ETA results, respectively (P<.001). CONCLUSIONS: The ATS/IDSA guidelines-based approach was more accurate than the ETA-based strategy for prescribing appropriate, initial, empirical antibiotics in VAP, unless a sample was available<=2 days of the onset of VAP. The ETA-based strategy led to fewer days on prescribed antimicrobials. PMID- 23348887 TI - Correction method for wireless electromagnetic localization of microcapsule devices. AB - BACKGROUND: In the development of a telemetry localization system for wireless tracking of a microcapsule medical device based on alternating current magnetic fields, further improvements are required in terms of localization accuracy and reductions in systematic error. METHODS: A new correction method is proposed based on an improved neural network algorithm for wireless localization. Based on the wireless localization model and its prototype, a single neural network with five input and five output neurons was designed for correction. Because the position and attitude angle are defined on different domains, both the input and output variables were normalized to improve network convergence. To prevent overfitting, the Levenberg-Marquardt Bayesian regularization algorithm was used as an effective learning algorithm for the neural network. RESULTS: Through experimental testing, the tracked and true locations were obtained, and the effects of neural network correction on improving localization accuracy were assessed. The experiments demonstrated reductions in localization errors when using the improved neural network correction algorithm. After correction, average errors of the X, Y, Z, alpha, and beta components reduced to 8.1 mm, 9.3 mm, 7.2 mm, 0.075 rad, and 0.071 rad, respectively. CONCLUSIONS: Compared with the basic back propagation algorithm, the Levenberg-Marquardt Bayesian regularization algorithm effectively improves the generalizability and convergence accuracy of neural networks in wireless localization correction. In addition, this method provides a feasible solution for improving the accuracy when wirelessly tracking a microcapsule device. PMID- 23348888 TI - A depropargylation-triggered fluorescence "turn-on" probe for the detection of Pd2+ based on a bispropargylamine-rhodamine conjugate. AB - A bis-propargyl-appended rhodamine B-based receptor BPRB has been synthesised that exhibits pronounced fluorescence enhancement in the presence of Pd2+ ions. The addition of Pd2+ enhanced the fluorescence intensity of BPRB by 113-fold (Phif = 0.37) and BPRB was found to exhibit high selectivity towards Pd2+ compared to a range of other metal ions. The enhancement of fluorescence was triggered by spirolactam ring opening followed by depropargylation of BPRB in the presence of Pd2+, as evidenced by FTIR and NMR analyses. BPRB was able to detect Pd0 without the addition of a reducing agent, and the emission intensity of BPRB Pd0 was almost identical to that of BPRB-Pd2+; however, a rapid fluorescence response was observed in the presence of PPh3. To explore the efficiency of the rhodamine unit, a bispropargyl derivative of cyclohexane (BPCH) was synthesised and the fluorescence response towards Pd2+ was examined and compared with BPRB, revealing that the rhodamine unit enhanced the fluorescence intensity by 500 fold. The fluorescence images of BPRB and BPRB-Pd2+ samples indicate that BPRB could be useful for imaging Pd2+ in living cells. PMID- 23348889 TI - Assessment and diagnosis of dementia in Hispanic and non-Hispanic white outpatients. AB - PURPOSE: We examined whether (a) neuropsychological test performance (NP) or (b) informant reports of patients' functional abilities or (c) behavioral and psychological symptoms (BPS) predicted dementia diagnoses to different degrees among Hispanic and non-Hispanic Whites (NHWs). DESIGN AND METHODS: Our sample included 444 Hispanic and 444 (randomly selected from 11,081) NHW outpatients diagnosed with normal cognition or dementia at their initial evaluations. We tested for significant ethnic-group differences in dementia diagnosis predictors using NP and the 2 informant reports, covarying for age, sex, and education. RESULTS: When using ethnic group-specific norms, NP and functional abilities predicted diagnosis in both groups with no significant differences but BPS was only significant in Hispanics. When using combined ethnic group norms, the only major difference was that BPS approached but did not meet statistical significance in Hispanics. IMPLICATIONS: Clinicians may be aware of the limitations of NP and may thus be informally adjusting their overall impressions of patients' NP among Hispanics and weighing certain tests differentially across ethnic groups when assessing dementia. Though these approaches may be aimed at reducing misdiagnosis, their effectiveness is questionable and they may be driving systematic differences in diagnosis within and across ethnicities. In addition, informant-reported functional abilities may be less sensitive to ethnicity-related influences and represent an important, ethnically neutral area in dementia assessment. The predictive value of informant-reported BPS in the diagnostic process across ethnic groups warrants further attention. PMID- 23348890 TI - First data on the Evolution duodenal stent for palliation of malignant gastric outlet obstruction (DUOLUTION study): a prospective multicenter study. AB - BACKGROUND AND STUDY AIMS: Enteral stent placement has emerged as a safe and effective palliative treatment option for patients with malignant gastric outlet obstruction (GOO). In an attempt to further optimize this treatment new enteral stents have been designed. This study is the first to describe the results regarding technical success, clinical success, complication rate, and stent dysfunction of the Evolution duodenal stent (Cook Medical, Limerick, Ireland). PATIENTS AND METHODS: A total of 46 patients with symptomatic malignant GOO were included in this prospective multicenter cohort study. All patients who successfully received an Evolution duodenal stent were followed until death. RESULTS: The technical and clinical success rates were 89 % (95 % confidence interval [CI] 77 % - 95 %) and 72 % (95 %CI 58 % - 83 %), respectively. The GOO Scoring System score, the Global Health Score, and the EuroQol visual analog scale improved significantly (GOOSS and Global Health Score P < 0.0001; EuroQol P = 0.005) when scores before stenting were compared with scores after stent placement. Median survival was 87 days, and stent patency was observed in 67 % for up to 395 days, accounting for death unrelated to the stent as a competing risk. Stent dysfunction occurred in 14 patients (30 %) (stent ingrowth n = 9; stent migration n = 2; extrinsic compression on the stent n = 2; food impaction n = 1). CONCLUSION: These first data on the new Evolution duodenal stent show that it is safe and effective for the palliative treatment of symptomatic malignant GOO. PMID- 23348891 TI - The inhibin B response in male rats treated with two drug candidates. AB - BACKGROUND: Serum Inhibin B was measured in two studies of known testis-toxic drug candidates. METHODS AND RESULTS: Study 1 was for a compound for Hepatitis C, and utilized a 10-week dosing period, followed by mating and necropsy of half of each group, and then a 12-week recovery period for the remaining animals. At the postmating necropsy, 6 of 15 high-dose males had testis lesions; Inhibin B was significantly reduced in all animals in that group. The mid-dose group had no lesions but significantly reduced serum Inhibin B. At recovery, 9 of 15 high-dose males showed damage in testes; serum Inhibin B levels were not different from controls. Inhibin B appeared to both overreport and underreport testis damage in Study 1. Study 2 was an acute pathogenesis study for an antibacterial compound, using control and two dose levels and multiple time points (days 5, 8, 15, 22, and then untreated until day 71). At each time point blood was sampled from all remaining rats and five/group were killed for histologic evaluation. The low-dose group had minimal to moderate lesions, while serum Inhibin B was never changed. The high-dose animals progressed quickly from minimal lesions to being broadly and moderately affected; serum Inhibin B levels were reduced at days 8 and 15 only. In Study 2, Inhibin B appeared less sensitive than histology, except at the extremes of testis damage, when Inhibin B was routinely low. CONCLUSION: We conclude that in these two studies there was a poor correlation between changes in serum levels of Inhibin B and testis histopathology. PMID- 23348892 TI - Symptoms and clinical relevance: a dilemma for clinical trials on prevention of venous thromboembolism. AB - The outcomes of thromboprophylactic trials have been debated for decades. Recently, the 9th edition of the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines based their strong recommendations only on patient-important outcomes. Practically, symptoms were considered the crucial element. Consequently, studies that primarily aimed at reducing venographic thrombi were considered less pertinent than studies that focused on symptomatic thrombosis. In the present viewpoint, we challenge the argument that "symptomatic" and "clinically relevant" are interchangeable. In particular, the case is made that asymptomatic events may be clinically relevant and that asymptomatic venographically detected thrombosis is a clinically relevant surrogate outcome for fatal pulmonary embolism. PMID- 23348893 TI - Asymmetric cytokinesis guide the development of pseudomonads in Rhynchospora pubera (Cyperaceae). AB - The late stages of microsporogenesis in the family Cyperaceae are marked by the formation of an asymmetrical tetrad, degeneration of three of the four nuclei resulting from meiosis and the formation of pseudomonads. In order to understand the cytological changes involved in the development of pseudomonads, a combination of 11 different techniques (conventional staining, cytochemistry procedures, immunofluorescence, FISH and transmission electron microscopy: TEM) were used to study the later stages of microsporogenesis in Rhynchospora pubera. The results demonstrated the occurrence of two cytoplasmic domains in the pseudomonads, one functional and the other degenerative, which are physically and asymmetrically separated by cell plate with an endomembrane system rich in polysaccharides. Other changes associated with endomembrane behaviour were observed, such as a large number of lipid droplets, vacuoles containing electron dense material and concentric layers of endoplasmic reticulum. Concomitant with the isolation of degenerative nuclei, the tapetal cells also showed evidence of degeneration, indicating that both tissues under programmed cell death (PCD), as indicated by immunofluorescence and TEM procedures. The results are significant because they associate cellular polarisation and asymmetry with different cytoplasmic domains, and hence open new possibilities for studying cellular compartmentalisation and PCD. PMID- 23348894 TI - Acute but transient release of terminal complement complex after reperfusion in clinical kidney transplantation. AB - BACKGROUND: Ischemia/reperfusion (I/R) injury has a major impact on kidney graft function and survival. Animal studies have suggested a role for complement activation in mediating I/R injury; however, results are not unambiguous. Whether complement activation is involved in clinical I/R injury in humans is still unclear. METHODS: In the present study, we assessed the formation and release of C5b-9 during early reperfusion in clinical kidney transplantation in living donor, brain-dead donor, and cardiac dead donor kidney transplantation. By arteriovenous measurements and histologic studies, local terminal complement activation in the reperfused kidney was assessed. RESULTS: There was no release of soluble C5b-9 (sC5b-9) from living donor kidneys, nor was there a release of C5a. In contrast, instantly after reperfusion, there was a significant but transient venous release of sC5b-9 from the reperfused kidney graft in brain-dead donor and cardiac dead donor kidney transplantation. This short-term activation of the terminal complement cascade in deceased-donor kidney transplantation was not reflected by renal tissue deposition of C5b-9 in biopsies taken 45 min after reperfusion. CONCLUSIONS: This systematic study in human kidney transplantation shows an acute but nonsustained sC5b-9 release on reperfusion in deceased-donor kidney transplantation. This instantaneous, intravascular terminal complement activation may be induced by intravascular cellular debris and hypoxic or injured endothelium. PMID- 23348895 TI - Study of the ophthalmic system of babies delivered to transplant recipients. AB - BACKGROUND: The aim of the study was the analysis of ophthalmologic disorders in children born to mothers after liver transplantation (LTx) or renal transplantation (RTx) with the assessment of certain neonatal parameters. METHODS: In the period between 01 January 2010 and 30 June 2012, ophthalmologic examinations were performed in 37 children born to mothers after LTx and 35 children after RTx, as well as 66 children from a control group, born at the 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, from 01 January 2001 to 30 June 2012. Certain parameters of the neonatal period of the child and the mother were retrospectively analyzed. RESULTS: Good first-minute states of neonates were observed in 89.2% LTx and 97.1% RTx but in the fifth minute in more than 97% of neonates in both groups. In the LTx and RTx groups, the percentage of preterm deliveries was 48.8% (68.8% in the RTx and 43.2% in the LTx; P=0.0306). There were differences in the immunosuppressant drug therapy in monotherapy as well as two to three drug combinations between the two groups. Children from the LTx, RTx, and control groups had no ophthalmologic disorders in more than 80%. In the LTx and RTx groups, there were convergence insufficiency (6 of 72), strabismus (2 of 72), and hyperopia (2 of 72). The differences in disorders between LTx and RTx groups, as well as LTx+RTx and control groups, were not statistically significant (P=1.00 vs. 0.6206). Retinopathy of prematurity was diagnosed in only two neonates in the RTx group. CONCLUSIONS: Immunosuppressive treatment during pregnancy, regardless of kind, did not affect the ocular organ's development. PMID- 23348896 TI - Objective radiologic assessment of body composition in patients with end-stage liver disease: going beyond the BMI. AB - BACKGROUND: Body mass index (BMI) is a commonly used but likely inexact measure of body composition for patients with end-stage liver disease. For this reason, we examined whether body composition measurements from direct visualization on computed tomography (CT) scans provide new insights in both the degree of malnutrition and the discordant combinations such as obesity with muscle mass loss. This technology is widely used in other medically ill populations but not yet in liver transplantation. METHODS: We examined actual body composition using abdominal CT scan data and software designed to measure fat and muscle compartments. RESULTS: In 234 liver transplant candidates, we found that BMI was highly and significantly correlated to subcutaneous and visceral fat. However, we additionally found that, even among obese patients, cachexia, as defined by muscle mass, was common, with 56% of those with BMI above 30 being cachexic. We also found that patients with nonalcoholic steatohepatitis, compared with other types of liver diseases, were significantly more likely to have larger amounts of visceral fat while also having less muscle. In an exploratory analysis, muscle mass corrected for height was a significant predictor of posttransplantation survival. CONCLUSIONS: Body composition by CT scan data provides a specific method to identify obesity and muscle wasting for end-stage liver disease patients. Whether these data can aid in the prognostication of outcomes and survival requires further investigation. PMID- 23348897 TI - A follow-up intervention in severely demented patients after discharge from a special Alzheimer acute care unit: impact on early emergency room re hospitalization rate. AB - BACKGROUND: Emergency room (ER) re-hospitalizations are prevalent in severe Alzheimer's disease affected older patients. DESIGN: Quasi-experimental before and after study. SETTING: Discharge of severely demented patients from a Special Alzheimer Acute Care Unit. PARTICIPANTS: A total of 390 patients hospitalized in the unit from 2007 through 2009, with at least one of the following characteristics: severe disruptive behavioral and psychological symptoms of dementia (BPSD) (agitation, aggressiveness, and psychotic symptoms), change of living arrangement related to BPSD, exhaustion of the principal caregiver, and discharge of a subject with anosognosia living alone in the community. INTERVENTION: The intervention consisted of an individualized care plan, targeting the problems observed during the hospital stay, implemented by the means of regular telephone contacts (in the first week after discharge, before the end of the first month, and then at 3 and 6 months) between a geriatric team and the patient's caregiver. Information was gathered on functional decline, BPSD, change of living arrangement and treatment. The calls were followed by a telephone intervention providing advice, support, and information to the caregiver. When required, these calls were followed by a consultation with a physician or psychologist, or by a consultation in the patient's home. MEASUREMENTS: The primary outcome measure was the ER re-hospitalization rate, defined as occurring within 31 days of discharge. RESULTS: The early ER re hospitalization rate was 8.39% in 2007 versus 8.02% in 2008 (p = 0.818) and 7.47% in 2009 (p = 0.563). Vocal disruptive behavior are more prevalent in re hospitalized patients (9.64% versus 3.97%, p = 0.05) than in non re-hospitalized patients. CONCLUSION: We found a nonsignificant decrease of early ER re hospitalization rate at 1 month after discharge. Interventions addressing severe dementia affected patients with BPSD are needed, as this is a major issue in the organization of health care systems. PMID- 23348898 TI - Semiquantitative histologic evaluation improves diagnosis of esophageal carcinoma cuniculatum on biopsy. AB - Carcinoma cuniculatum, a unique variant of well-differentiated squamous cell carcinoma, has been only rarely reported in the esophagus. The present study was undertaken to determine if a previously observed common histologic pattern for carcinoma cuniculatum is diagnostically useful in esophageal mucosal biopsy specimens. Thirty-five esophageal mucosal biopsies obtained from 25 procedures in 11 patients with a resection-proven diagnosis of carcinoma cuniculatum were compared with 92 esophageal biopsies from 69 patients with benign diagnoses. All biopsies were assessed for the presence of hyperkeratosis, acanthosis, dyskeratosis, deep keratinization, intraepithelial neutrophils, neutrophilic microabscess, focal cytologic atypia, koilocyte-like cells, and keratin-filled cyst/burrows. Each feature, if present, was given one point, and the final histologic score was calculated for each biopsy by summing the points. The mean histologic score was 6.66 (s.d. 1.88) in biopsies from carcinoma cuniculatum vs a mean score of 1.93 (s.d. 1.75) for biopsies with benign diagnoses (P<0.0001). Using a cutoff value of 7 for carcinoma cuniculatum, 57% of biopsies (20/35) from 64% esophagogastroduodenoscopy procedures (16/25) in 91% patients (10/11) would be diagnostic, in comparison to the initial diagnostic rates of carcinoma of 9, 12, and 27%, respectively (P<0.0001 for all). None of the 92 benign biopsies showed a score of >=7. Our results demonstrate that a semiquantitative histologic evaluation of mucosal biopsies taken from an esophageal mass greatly improves the diagnostic sensitivity from patients with carcinoma cuniculatum with 100% specificity. Larger studies are necessary to confirm the current findings. PMID- 23348899 TI - HER2 in gastric cancer: a digital image analysis in pre-neoplastic, primary and metastatic lesions. AB - The assessment of human epidermal growth factor receptor 2 (HER2) status in gastric cancer is crucial in selecting patients who may benefit from targeted therapy, yet heterogeneous expression could represent an important drawback for HER2 testing. We aimed to analyze (i) HER2 heterogeneity in primary gastric cancers, pre-neoplastic and metastatic lesions and (ii) HER2 prognostic role. We studied 292 surgically resected primary gastric carcinomas and constructed 21 tissue microarrays including tumor tissue cores, invasive front, paired lymph node metastasis, low- and high-grade dysplasia. Microarrays were immunohistochemically stained with HER2 antibody and digitally scanned. Novel digital analysis algorithms were developed to score HER2 expression. Fluorescence in situ hybridization was performed on equivocal cases. HER2-positive cases were 13% and heterogeneous HER2 expression was observed in 71% of positive samples. Analysis of HER2 status in tumor and tumor invasive front demonstrate concordance in 177 cases (88%). Comparison of HER2 expression in primary cancer and synchronous lymph node metastasis exhibited discordant status in 14% of cases. Dysplastic epithelium surrounding the tumor showed immunohistochemical score 2 or 3 in 19% of high-grade and in 9% of low-grade dysplastic samples. HER2 status was significantly associated with intestinal-type carcinomas (P=0.018) and prognosis since patients with primary HER2-positive tumor showed decreased overall survival (P=0.006). Intratumoral HER2 expression heterogeneity and variable lymph node metastases status strongly suggest evaluating more than one sample and, if available, metastatic foci for routinely HER2 testing. PMID- 23348900 TI - Distinguishing primary adenocarcinoma of the urinary bladder from secondary involvement by colorectal adenocarcinoma: extended immunohistochemical profiles emphasizing novel markers. AB - Glandular neoplasms involving the urinary bladder carry a challenging differential diagnosis including primary and secondary processes. We investigated the potential diagnostic utility of cadherin-17 and GATA3 in 25 primary adenocarcinomas of the urinary bladder, as compared with other commonly used markers including beta-catenin and p63. Urothelial carcinoma with glandular differentiation (11), colorectal adenocarcinoma secondarily involving the bladder (25), and primary colorectal adenocarcinoma (22) were also analyzed and the results were compared using a Fisher exact test. Cadherin-17 was expressed in 23/25 primary bladder adenocarcinomas (92%), 23/25 colorectal adenocarcinomas involving the bladder (92%), 21/22 primary colorectal adenocarcinomas (95%) and entirely negative (0/11) in both components of urothelial carcinoma with glandular differentiation (P<0.001). In urothelial carcinoma with glandular differentiation, positive nuclear staining for GATA3 was evident in the urothelial component for 18% (2/11) and the glandular component for 9% (1/11) with additional tumors showing only cytoplasmic staining. Nuclear reactivity for GATA3 was not present in primary bladder adenocarcinoma and primary/secondary colorectal adenocarcinoma (P<0.05). Positive nuclear and cytoplasmic immunostaining for beta-catenin was evident in 21/22 primary colorectal adenocarcinomas (95%) and 23/25 cases of secondary involvement by colorectal adenocarcinoma (92%). In contrast, positive membranous and cytoplasmic staining for beta-catenin was observed in 23/25 primary bladder adenocarcinomas (92%) and 11/11 urothelial carcinomas with glandular differentiation (100%, P<0.001). p63 was expressed only in the urothelial component of urothelial carcinoma with glandular differentiation and not in the glandular component (P<0.001). In summary, cadherin-17 is a relatively specific and sensitive marker for primary adenocarcinoma of the urinary bladder, distinguishing it from urothelial carcinoma with glandular differentiation. However, it does not distinguish primary bladder adenocarcinoma from secondary involvement by colorectal adenocarcinoma. The pattern of reactivity for beta-catenin remains the most useful marker for distinguishing these two tumors. PMID- 23348901 TI - Collagenous colitis in children and adolescents: study of 7 cases and literature review. AB - The aim of this study is to examine the clinical and pathologic characteristics of collagenous colitis (CC) in children and adolescents. Seven patients (five females and two males, median age: 13 years, ranging from 4 to 16) were included. Four (of 7, 57%) patients presented with non-bloody watery diarrhea, one with alternating constipation and diarrhea with rectal prolapse, one with constipation, and one with normal bowel movement. Abdominal pain and weight loss were manifested in 80 and 40% patients, respectively. Two patients had celiac disease in remission. None of the patients took non-steroidal antiinflammatory agents. All patients had normal colonoscopy, but had typical histologic features of CC in colon biopsies. Four patients had clinical follow-up (24-75 months duration, median 54 months): three patients had no gastrointestinal symptoms upon follow-up, but one patient had continued symptoms of alternating diarrhea and constipation. Two patients had follow-up biopsies: one showed persistence of CC, and one had complete histologic resolution. We conclude that while CC is rare in children and adolescents, the clinical presentation is similar to adults, with a female preponderance, presentation with diarrhea and abdominal pain, and an association with celiac disease and other autoimmune disorders. However, compared with adults, children and adolescents are more likely to have weight loss and an atypical presentation including alternating constipation and diarrhea, constipation alone or normal bowel movements. Treatment is less standardized in children and adolescents with CC. PMID- 23348902 TI - Novel dual-color immunohistochemical methods for detecting ERG-PTEN and ERG SPINK1 status in prostate carcinoma. AB - Identification of new molecular markers has led to the molecular classification of prostate cancer based on driving genetic lesions. The translation of these discoveries for clinical use necessitates the development of simple, reliable and rapid detection systems to screen patients for specific molecular aberrations. We developed two dual-color immunohistochemistry-based assays for the simultaneous assessment of ERG-PTEN and ERG-SPINK1 in prostate cancer. A total of 232 cases from 184 localized and 48 metastatic prostate cancers were evaluated for ERG-PTEN and 284 cases from 228 localized and 56 metastatic prostate cancers were evaluated for ERG-SPINK1. Of the 232 cases evaluated for ERG-PTEN, 81 (35%) ERG positive and 77 (33%) PTEN-deleted cases were identified. Of the 81 ERG-positive cases, PTEN loss was confirmed in 35 (15%) cases by fluorescence in situ hybridization (FISH). PTEN status was concordant in 203 cases (sensitivity 90% and specificity 87%; P<0.0001) by both immunohistochemisty and FISH; however, immunohistochemisty could not distinguish between heterozygous and homozygous deletion status of PTEN. Of the 284 cases evaluated for ERG-SPINK1, 111 (39%) cases were positive for ERG. In the remaining 173 ERG-negative cases, SPINK1 was positive in 26 (9%) cases. SPINK1 expression was found to be mutually exclusive with ERG expression; however, we identified two cases, of which one showed concomitant expression of ERG and SPINK1 in the same tumor foci, and in the second case ERG and SPINK1 were seen in two independent foci of the same tumor nodule. Unlike the homogenous ERG staining in cancer tissues, heterogeneous SPINK1 staining was observed in the majority of the cases. Further studies are required to understand the molecular heterogeneity of cases with concomitant ERG SPINK1 expression. Automated dual ERG-PTEN and ERG-SPINK1 immunohistochemisty assays are simple, reliable and portable across study sites for the simultaneous assessment of these proteins in prostate cancer. PMID- 23348903 TI - Prostate cancer cell phenotypes based on AGR2 and CD10 expression. AB - The combination of expression patterns of AGR2 (anterior gradient 2) and CD10 by prostate cancer provided four phenotypes that correlated with clinical outcome. Based on immunophenotyping, CD10(low)AGR2(high), CD10(high)AGR2(high), CD10(low)AGR2(low), and CD10(high)AGR2(low) were distinguished. AGR2(+) tumors were associated with longer recurrence-free survival and CD10(+) tumors with shorter recurrence-free survival. In high-stage cases, the CD10(low)AGR2(high) phenotype was associated with a ninefold higher recurrence-free survival than the CD10(high)AGR2(low) phenotype. The CD10(high)AGR2(high) and CD10(low)AGR2(low) phenotypes were intermediate. The CD10(high)AGR2(low) phenotype was most frequent in high-grade primary tumors. Conversely, bone and other soft tissue metastases, and derivative xenografts, expressed more AGR2 and less CD10. AGR2 protein was readily detected in tumor metastases. The CD10(high)AGR2(low) phenotype in primary tumors is predictive of poor outcome; however, the CD10(low)AGR2(high) phenotype is more common in metastases. It appears that AGR2 has a protective function in primary tumors but may have a role in the distal spread of tumor cells. PMID- 23348904 TI - Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features. AB - KRAS-mutated carcinomas comprise 35-40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O(6) methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wild-type carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; P<0.001), demonstrated mucinous differentiation (46 vs 31%; P=0.001) and were associated with different MSI status (P<0.001) and with MGMT methylation (47 vs 21%; P=0.001). Compared with tumors demonstrating neither BRAF nor KRAS mutation, KRAS-mutated carcinomas showed more frequent location in the proximal colon (41 vs 27%; P=0.001), mucinous differentiation (46 vs 25%; P<0.001), presence of a contiguous polyp (38 vs 22%; P<0.001), MGMT methylation (47 vs 26%; P=0.01) and loss of MGMT immunohistochemical expression (27 vs 19%; P=0.02). KRAS-mutated carcinomas were distributed in a bimodal pattern along the proximal-distal axis of the colorectum. Compared with male subjects, female subjects were more likely to have KRAS-mutated carcinoma in the transverse colon and descending colon (39 vs 15%; P=0.02). No difference in overall survival was observed in patients according to their tumor KRAS mutation status. In summary, KRAS-mutated carcinomas frequently develop in contiguity with a residual polyp and show molecular features distinct from other colorectal carcinomas, in particular from tumors with neither BRAF nor KRAS mutation. PMID- 23348905 TI - Immunohistochemical pitfalls and the importance of glypican 3 and arginase in the diagnosis of scirrhous hepatocellular carcinoma. AB - Scirrhous hepatocellular carcinoma is a rare ill-defined morphological subtype of hepatocellular carcinoma characterized by marked stromal fibrosis. This variant can be difficult to distinguish from intrahepatic cholangiocarcinoma and metastatic adenocarcinoma, especially on needle biopsies. We performed immunohistochemistry for hepatocellular and adenocarcinoma-associated markers on 20 scirrhous hepatocellular carcinoma cases and compared the results with classical hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Scirrhous hepatocellular carcinomas were significantly less likely to be HepPar-1 positive than classical hepatocellular carcinomas (26% and 74%, respectively; P<0.001) and were significantly more likely to express adenocarcinoma-associated markers such as epithelial cell adhesion molecule (63 vs 11%; P<0.001), cytokeratin 19 (26 vs 2%; P<0.001), and cytokeratin 7 (53 vs 2%; P<0.001). At least one of these adenocarcinoma-related markers was positive in 80% of scirrhous hepatocellular carcinoma cases. Glypican 3 and arginase were positive in 79% and 85% of cases of scirrhous hepatocellular carcinoma, respectively; the combined use of these two markers yielded 100% sensitivity for scirrhous hepatocellular carcinoma. In conclusion, the scirrhous morphology, absence of HepPar-1 staining, and frequent positivity with adenocarcinoma-related markers in scirrhous hepatocellular carcinoma can lead to an erroneous diagnosis of adenocarcinoma. Glypican 3 and arginase are the most reliable markers for identifying hepatocellular differentiation in this setting. PMID- 23348906 TI - FOXL2 molecular testing in ovarian neoplasms: diagnostic approach and procedural guidelines. AB - A single, recurrent somatic point mutation (402C->G) in FOXL2 has been described in almost all adult-type granulosa cell tumors but not other ovarian neoplasms. Histopathological features of adult-type granulosa cell tumors can be mimicked by a variety of other tumors, making diagnosis of adult-type granulosa cell tumor challenging. It has been suggested that molecular testing for FOXL2 mutation might be a useful tool in the diagnosis of adult-type granulosa cell tumors. The aim of this study was to demonstrate how testing for the FOXL2 mutation can be used in a gynecological pathology consultation service and to establish clear procedural guidelines for FOXL2 testing. Immunohistochemistry for FOXL2 was done using an anti-FOXL2 polyclonal antiserum. If immunohistochemistry was positive, FOXL2 mutation status was subsequently analyzed using a TaqMan assay. A dilution experiment was done to assess the sensitivity and minimum tumor cellularity requirements for our TaqMan assay. Twenty problematic cases were assessed, where the differential diagnosis after the initial investigations included adult-type granulosa cell tumors. Differential diagnoses included: thecoma, Sertoli-Leydig cell tumor, juvenile granulosa cell tumor, endometrial stromal sarcoma and others. In all cases, FOXL2 immunohistochemistry was positive and in six samples the FOXL2 mutation was detected, thus confirming a diagnosis of adult-type granulosa cell tumor. The TaqMan assay was able to reliably detect the FOXL2 mutation with input DNA in the range of 2.5-20 ng, and with a minimum of 25% tumor cell nuclei. The analysis of the FOXL2 mutational status in clinical samples is a useful diagnostic tool in situations where the differential diagnosis is between adult-type granulosa cell tumor and other ovarian tumors. The TaqMan assay requires a minimum of 2.5 ng DNA, with optimal assay performance for 5 to 10 ng DNA input. Laser capture or needle-macrodissection should be undertaken to enrich samples with tumor cell content below 25%. PMID- 23348907 TI - Thoracic and lumbar spinal cord diffusion tensor imaging in dogs. AB - PURPOSE: To analyze four clinically applicable diffusion tensor imaging (DTI) protocols (two each in the transverse and sagittal planes) in the normal dog. MATERIALS AND METHODS: Seven healthy Dachshund dogs were scanned with four DTI protocols. Within each plane, identical spatial resolution was used while the number of diffusion-encoding directions and averages varied. Agreement of measured fractional anisotropy (FA) and apparent diffusion coefficient (ADC) was analyzed with Bland-Altman methods, subjective image quality within each plane was compared, and FA and ADC were explored as a function of anatomic location. RESULTS: There was good agreement in FA and ADC values within each plane. FA had the smallest bias and most precision. No difference was detected in subjective image quality within each plane. FA and ADC were slightly higher cranial to the lumbar intumescence compared to within it. CONCLUSION: DTI is a promising tool in the assessment of spinal cord injury (SCI) in the study of dogs with intervertebral disk herniation as a preclinical model of human SCI. PMID- 23348908 TI - Bone integration capability of a series of strontium-containing hydroxyapatite coatings formed by micro-arc oxidation. AB - Strontium-containing hydroxyapatites (Sr-HA) combine the desirable bone regenerative properties of hydroxyapatites (HA) with anabolic and anti-catabolic effects of strontium cations. In the present work, a series of Sr(y)HA [Sr(y)Ca(10-y)(PO4)6(OH)2; y = 0, 0.5, 1, 2] coatings on titanium are produced by micro-arc oxidation (MAO), and the effects of the in vivo osseointegration ability of the coatings are investigated by using a rabbit model. All samples are subjected to biomechanical, surface elemental, micro-CT and histological analysis after 4 and 12 weeks of healing. The obtained results show that the MAO-formed coatings exhibit a microporous network structure composed of Sr(y)HA/Sr(y)HA Sr(x)Ca(1-x)TiO3/Sr(x)Ca(1-x)TiO3-TiO2 multilayers, in which the outer Sr(y)HA and intermediate Sr(y)HA-Sr(x)Ca(1-x)TiO3 layers have a nanocrystalline structure. All Sr-HA coated implants induce marked improvements in the behavior of bone formation, quantity and quality of bone tissue around the implants than the control HA implant and in particular, the 20%Sr-HA coating promotes early bone formation as identified by polyfluorochrome sequential labeling. The bone-to implant contact is increased by 46% (p < 0.05) and the pull-out strength is increased by 103% over the HA group (p < 0.01). Extensive areas of mineralized tissue densely deposit on the 20%Sr-HA coating after biomechanical testing, and the greatest improvement of bone microarchitecture are observed around the 20%Sr HA implant. The identified biological parameters successfully demonstrate the osteoconductivity of 20%Sr-HA surfaces, which results not only in an acceleration but also an improvement of bone-implant integration. The study demonstrates the immense potential of 20%Sr-HA coatings in dental and orthopedic applications. PMID- 23348909 TI - Alterations of regional spontaneous neuronal activity and corresponding brain circuit changes during resting state in migraine without aura. AB - Although previous resting-state studies have reported abnormal functional cerebral changes in patients with migraine without aura (MwoA), few have focused on alterations in both regional spontaneous neuronal activity and corresponding brain circuits in MwoA patients during rest. Eighteen MwoA patients and 18 age- and gender-matched healthy controls (HC) were recruited in the current study. Baseline cerebral alterations were investigated using amplitude of low-frequency fluctuation (ALFF) and region of interest (ROI)-based functional connectivity (FC) analyses. Compared with HC, MwoA patients showed decreased ALFF values in the left rostral anterior cingulate cortex (rACC) and bilateral prefrontal cortex (PFC) as well as increased ALFF values in the right thalamus. FC analysis also revealed abnormal FCs associated with these ROIs. In addition, ALFF values of the left rACC correlated with duration of disease in MwoA. Our findings could lead to a better understanding of intrinsic functional architecture of baseline brain activity in MwoA, providing both regional and brain circuit spontaneous neuronal activity properties. PMID- 23348911 TI - A crystallographic and spectroscopic study on the reactions of WCl6 with carbonyl compounds. AB - WCl6, 1, reacted with two equivalents of HC(O)NR2 (R = Me, Et) in CH2Cl2 to afford the W(VI) oxo-derivatives WOCl4(OCHNR2) (R = Me, 2a; R = Et, 2b) as main products. The hexachlorotungstate(V) salts [{O=C-N(Me)CH2CH2CH2}2(MU-H)][WCl6], 3, and [PhNHC(Me)N(Ph)C(O)Me][WCl6], 4, were isolated in moderate yields from the 1:2 molar reactions of 1 with N-methyl-2-pyrrolidone (in CH2Cl2) and acetanilide (in CDCl3), respectively. The additions of two equivalents of ketones/aldehydes to 1/CH2Cl2 yielded the complexes WOCl4[OC(R)(R')] (R = Me, R' = Ph, 5a; R = R' = Ph, 5b; R = R' = Me, 5c; R = R' = Et, 5d; R = H, R' = 2-Me-C6H4, 5e) and equimolar amounts of C(R)(R')Cl2. Analogously, WOCl3[kappa(2)-{1,2 C6H4(O)(CHO)}], 5f, and 1,2-C6H4(OH)(CHCl2) were obtained from 1 and salicylaldehyde. The 1:1 reaction of 1 with acetone in CH2Cl2 resulted in the clean formation of WOCl4 and 2,2-dichloropropane. Compounds 5a,b,f were isolated as crystalline solids, whereas 5c,d,e could be detected by solution NMR only. The interaction of 1/CH2Cl2 with isatin, in a 1:1 molar ratio, revealed to be a new, convenient route for the synthesis of 3,3-dichloro-2,3-dihydro-1H-indol-2-one, 6. The 1:1 reactions of 1 with R'OCH(R)CO2Me (R = H, R' = Me; R = Me, R' = H) in a chlorinated solvent afforded the tungsten(V) adducts WCl4[kappa(2)-OCH(R)CO2Me] (R = H, 7a; R = Me, 7b). 1/CH2Cl2 reacted sluggishly with equimolar quantities of trans-(CO2Et)CH=CH(CO2Et) and CH2(CO2Me)2 to give, respectively, the W(IV) derivatives WCl4[kappa(2)-CH2(CO2Me)2], 8a, and [WCl4-kappa(2)-{trans (CO2Et)CH=CH (CO2Et)}]n, 8b, in about 70% yields. The molecular structures of 2a, 3, 4, 5a, 5f, 7a and 7b were ascertained by X-ray diffraction studies. PMID- 23348912 TI - Brain infection and activation of neuronal repair mechanisms by the human pathogen Listeria monocytogenes in the lepidopteran model host Galleria mellonella. AB - Listeria monocytogenes the causative agent of the foodborne disease listeriosis in humans often involves fatal brainstem infections leading to meningitis and meningoencephalitis. We recently established the larvae of the greater wax moth (Galleria mellonella) as a model host for the investigation of L. monocytogenes pathogenesis and as a source of peptides exhibiting anti-Listeria-activity. Here we show that G. mellonella can be used to study brain infection and its impact on larval development as well as the activation of stress responses and neuronal repair mechanisms. The infection of G. mellonella larvae with L. monocytogenes elicits a cellular immune response involving the formation of melanized cellular aggregates (nodules) containing entrapped bacteria. These form under the integument and in the brain, resembling the symptoms found in human patients. We screened the G. mellonella transcriptome with marker genes representing stress responses and neuronal repair, and identified several modulated genes including those encoding heat shock proteins, growth factors, and regulators of neuronal stress. Remarkably, we discovered that L. monocytogenes infection leads to developmental shift in larvae and also modulates the expression of genes involved in the regulation of endocrine functions. We demonstrated that L. monocytogenes pathogenesis can be prevented by treating G. mellonella larvae with signaling inhibitors such as diclofenac, arachidonic acid, and rapamycin. Our data extend the utility of G. mellonella larvae as an ideal model for the high-throughput in vivo testing of potential compounds against listeriosis. PMID- 23348913 TI - Novel alterations in the epigenetic signature of MeCP2-targeted promoters in lymphocytes of Rett syndrome patients. AB - Rett syndrome (RTT) is a neurodevelopmental disorder with neurological symptoms, such as motor disorders and mental retardation. In most cases, RTT is caused by mutations in the DNA binding protein MeCP2. In mice, MeCP2 gene deletion has been reported to result in genome-wide increased histone acetylation. Transcriptional regulation of neurotrophic factor BDNF and transcription factor DLX5, essential for proper neurogenesis, is further altered in MeCP2-deleted animals. We therefore investigated the chromatin environment of MeCP2 target genes BDNF and DLX5 in lymphocytes from RTT patients and human controls, and analyzed the density of histones H3, H2B and H1, as well as the levels of methylation and acetylation on selected lysines of histone H3. Notably, we found a general increase in the density of histone H3 in RTT patients' lymphocytes compared with controls, and decreased levels of trimethylation of lysine 4 on histone H3 (H3K4me3), a modification associated with transcriptional activation. The levels of acetylation of lysine 9 (H3K9ac) and 27 (H3K27ac) did not show any statistically significant changes when normalized to the decreased histone H3 levels; nevertheless, an average decrease in acetylation was noted. Our results reveal an unexpected alteration of the chromatin state of established MeCP2 target genes in lymphocytes of human subjects with RTT. PMID- 23348914 TI - Docking of the da Vinci Si Surgical System(r) with single-site technology. AB - BACKGROUND: Strategies to spare operating room (OR) times are crucial to limiting the costs involved in robotic surgery. Among other factors, the pre-operative set up and docking phases have been incriminated at first to be time consuming. The docking process on the standard multiport da Vinci Surgical System has not been shown to significantly prolong the overall OR time. This study aims to analyse whether the length of the docking process on the new da Vinci Si Surgical System with Single-SiteTM technology remains acceptable. METHODS: We prospectively analysed all of the robotic single-incision cholecystectomies performed at our institution for docking and operating times during 2011-2012. The docking task load was assessed each time in a self-administered fashion by the docking surgeon using the NASA TLX visual scale. RESULTS: Sixty-four robotic single-incision cholecystectomies were included and analysed. The mean operative time was 78 min. Two surgeons with previous robotic surgery experience and a group of three less experienced robotic surgeons were responsible for docking the system. They performed 45, 10 and nine dockings, respectively. The overall mean docking time was 6.4 min with no significant difference between the groups. The docking process represented approximately 8% of the operating time. The surgeon with the most procedures showed significant progress in his docking times. The different task load parameters did not show a statistical difference between the three groups, with the exception of the frustration parameter, which was higher in the group of less experienced surgeons. There were significant correlations between docking times and the assessment of the various task load parameters. CONCLUSION: The docking process for a robotic single-incision cholecystectomy is learned rapidly and does not significantly increase the overall OR time. PMID- 23348915 TI - All-atom structural models of insulin binding to the insulin receptor in the presence of a tandem hormone-binding element. AB - Insulin regulates blood glucose levels in higher organisms by binding to and activating insulin receptor (IR), a constitutively homodimeric glycoprotein of the receptor tyrosine kinase (RTK) superfamily. Therapeutic efforts in treating diabetes have been significantly impeded by the absence of structural information on the activated form of the insulin/IR complex. Mutagenesis and photo crosslinking experiments and structural information on insulin and apo-IR strongly suggest that the dual-chain insulin molecule, unlike the related single chain insulin-like growth factors, binds to IR in a very different conformation than what is displayed in storage forms of the hormone. In particular, hydrophobic residues buried in the core of the folded insulin molecule engage the receptor. There is also the possibility of plasticity in the receptor structure based on these data, which may in part be due to rearrangement of the so-called CT-peptide, a tandem hormone-binding element of IR. These possibilities provide opportunity for large-scale molecular modeling to contribute to our understanding of this system. Using various atomistic simulation approaches, we have constructed all-atom structural models of hormone/receptor complexes in the presence of CT in its crystallographic position and a thermodynamically favorable displaced position. In the "displaced-CT" complex, many more insulin-receptor contacts suggested by experiments are satisfied, and our simulations also suggest that R-insulin potentially represents the receptor-bound form of hormone. The results presented in this work have further implications for the design of receptor-specific agonists/antagonists. PMID- 23348916 TI - Prognostic factors and the significance of treatment after recurrence in completely resected stage I non-small cell lung cancer. AB - OBJECTIVE: The objective of this study was to identify the clinicopathologic factors influencing postrecurrence survival (PRS) in and the effect of postrecurrence therapy (PRT) on patients with completely resected stage I non small cell lung cancer (NSCLC). METHODS: We reviewed the data of 919 patients in whom complete resection of stage I NSCLC had been performed. RESULTS: Of the 919 patients, 170 (18.5%) had recurrent disease. Initial PRT was performed in 118 patients (69.1%) (surgery in eight, chemotherapy in 79, radiotherapy in 10, and chemoradiotherapy in 21). On multivariate analyses, PRT (hazard ratio [HR], 0.542; 95% CI, 0.344-0.853; P = .008), female sex (HR, 0.487; 95% CI, 0.297 0.801; P = .005), and differentiation (HR, 1.810; 95% CI, 1.194-2.743; P = .005) demonstrated a statistically significant association with favorable PRS. Bone metastasis (HR, 3.288; 95% CI, 1.783-6.062; P < .001), liver metastasis (HR, 4.518; 95% CI, 1.793-11.379; P = .001), chemotherapy (HR, 0.478; 95% CI, 0.236 0.975; P = .040), epidermal growth factor receptor-tyrosine kinase inhibitors treatment (EGFR-TKIs) (HR, 0.460; 95% CI, 0.245-0.862; P = .015), and nonadenocarcinoma (HR, 2.136; 95% CI, 1.273-3.585; P = .004) were independently and significantly associated with PRS in the 118 patients who underwent any PRT. Subgroup analysis with a combination of these five PRS factors in the patients who underwent any PRT revealed median PRS times of 42.4 months for 20 patients lacking all five risk factors and 18.8 months for 98 patients with at least one of these risk factors (P = .001). CONCLUSIONS: PRT, sex, and differentiation were independently associated with PRS. In the patients who underwent any PRT, PRS was related to EGFR-TKIs, chemotherapy, histology, and initial recurrence sites. One challenge for the future will be to create systematic treatment strategies for recurrent NSCLC according to the risk factor status of individual patients. PMID- 23348917 TI - The inhibin B response to a motilin receptor agonist in male rats. AB - BACKGROUND: In a repeat oral dose toxicity study, all of 16 male rats given 100 mg/kg/day GSK1322888 sustained testicular injury after 4 weeks of treatment; the findings were not reversible after 12 weeks off-dose. The current study was conducted to further characterize testicular toxicity and to explore the possible relationship between onset of lesions, and changes in circulating hormone levels. METHODS: Male Sprague Dawley rats were orally administered 30 or 100 mg/kg/day GSK1322888 for 2 weeks with a 4-week off-dose period. Blood was collected via tail vein twice during the treatment period (days 4 and 11) and three times during the off-dose period (days 28, 36, and 42) for measurement of serum testosterone, dihydrotestosterone, and Inhibin B, luteinizing hormone, and follicle stimulating hormone concentrations. A histopathologic examination of testes was performed at the end of the treatment and off-dose periods. RESULTS: At 100 mg/kg/day, microscopic findings of the testis (degeneration of the germinal epithelium) were evident for 9 of 10 male rats on day 14 and all 10 rats at the end of the 4-week recovery period. There was no testicular toxicity observed at 30 mg/kg/day. During all stages of evaluation, there was no apparent difference among control and treated animals in hormone concentrations. CONCLUSION: There was poor correlation between changes in serum levels of Inhibin B and testis histopathology. Based on these observations, the utility of Inhibin B as a hormonal marker for germ cell toxicity is limited. PMID- 23348918 TI - Mechanical properties and crystallization behavior of hydroxyapatite/poly(butylenes succinate) composites. AB - Biodegradable synthetic polymers have attracted much attention nowadays, and more and more researches have been done on biodegradable polymers due to their excellent mechanical properties, biocompatibility, and biodegradability. In this work, hydroxyapatite (HA) particles were melt-mixing with poly (butylenes succinate) (PBS) to prepare the material, which could be used in the biomedical industry. To develop high-performance PBS for cryogenic engineering applications, it is necessary to investigate the cryogenic mechanical properties and crystallization behavior of HA/PBS composites. Cryogenic mechanical behaviors of the composites were studied in terms of tensile and impact strength at the glass transition temperature (-30 degrees C) and compared to their corresponding behaviors at room temperature. With the increase of HA content, the crystallization of HA/PBS composites decreased and crystallization onset temperature shifted to a lower temperature. The diameter of spherulites increased at first and decreased with a further HA content. At the same time, the crystallization rate became slow when the HA content was no more than 15wt% and increased when HA content reached 20wt%. In all, the results we obtained demonstrate that HA/PBS composites reveal a better tensile strength at -30 degrees C in contrast to the strength at room temperature. HA particles with different amount affect the crystallization of PBS in different ways. PMID- 23348919 TI - A heteroleptic cyclometalated iridium(III) fluorophenylpyridine complex from partial defluorohydrogenation reaction: synthesis, photophysical properties and mechanistic insights. AB - In this paper, a C-F bond activation reaction of a chloro-bridged iridium(III) dimer (dfppy)(2)Ir(MU-Cl)(2)Ir(dfppy)(2) (1) (dfppy denotes 2-(4,6 difluorophenyl)pyridyl) in the presence of sodium methoxide has been reported, leading to the formation of a heteroleptic cyclometalated iridium(III) fluorophenylpyridine complex 2. HPLC-mass analysis confirmed the release of formaldehyde in the product mixture. When sodium benzyloxide was used as the base, complex 2 was also generated with the release of a benzaldehyde derivative. Complex 2 has been fully characterized by (1)H-NMR, (19)F-NMR and X-ray crystallographic methods, confirming the partial loss of one of the fluorine atoms on one of the cyclometalated phenylpyridyl ligands. Photophysical studies of complex 2 show that it has a similar absorption spectrum to that of Ir(III)(dfppy)(3). However, the emission spectrum shows a red shift maximum emission band at 478 nm due to the loss of a single fluorine atom, highlighting the critical effect of fluorine on the photoluminescence of these Ir(III) complexes. Finally, intensive mechanistic studies including HPLC-mass analysis, (1)H-NMR, and (19)F-NMR studies demonstrate that the formation of complex 2 should involve a critical beta-hydride elimination of Ir(III)-alkoxide intermediate and the participation of Ir-hydride and/or Ir-fluoride intermediates. PMID- 23348920 TI - Carbon microarrays for the direct impedimetric detection of Bacillus anthracis using Gamma phages as probes. AB - A direct and efficient impedimetric method is presented for the detection of Bacillus anthracis Sterne vegetative cells, using Gamma phages as probes attached to screen-printed carbon electrode microarrays. The carbon electrodes were initially functionalized through cyclic-voltammetric reduction of a nitro-aryl diazonium moiety, followed by further reduction of nitro groups to amino groups, and finally by treatment with glutaraldehyde. Functionalization (probe immobilization) using Gamma phages was verified by XPS and TOF-SIM experiments. The Gamma phage-modified microarrays were then used to detect B. anthracis Sterne bacteria in aqueous electrolyte media. Faradaic impedimetric detection of bacteria in KCl solution containing the ferri/ferro cyanide redox couple shows a gradual increase in Z' (real impedance) values, taken from the extrapolation of the linear portion of Nyquist plots in the low frequency range, for sensors placed in contact with increasing concentrations of B. anthracis. DeltaZ' values vary from 700 to 5300 Ohms for bacteria concentrations ranging from 10(2) to 10(8) cfu mL(-1). These shifts in Z' are attributed to a decrease in diffusion controlled charge transfer to the electrode surface following capture of intact B. anthracis. No significant DeltaZ' was observed for control experiments using E. coli. K12 as a non-specific target, even at a concentration of 10(8) cfu mL( 1). PMID- 23348921 TI - Proteasix: a tool for automated and large-scale prediction of proteases involved in naturally occurring peptide generation. AB - In this study, we have developed Proteasix, an open-source peptide-centric tool that can be used to predict in silico the proteases involved in naturally occurring peptide generation. We developed a curated cleavage site (CS) database, containing 3500 entries about human protease/CS combinations. On top of this database, we built a tool, Proteasix, which allows CS retrieval and protease associations from a list of peptides. To establish the proof of concept of the approach, we used a list of 1388 peptides identified from human urine samples, and compared the prediction to the analysis of 1003 randomly generated amino acid sequences. Metalloprotease activity was predominantly involved in urinary peptide generation, and more particularly to peptides associated with extracellular matrix remodelling, compared to proteins from other origins. In comparison, random sequences returned almost no results, highlighting the specificity of the prediction. This study provides a tool that can facilitate linking of identified protein fragments to predicted protease activity, and therefore into presumed mechanisms of disease. Experiments are needed to confirm the in silico hypotheses; nevertheless, this approach may be of great help to better understand molecular mechanisms of disease, and define new biomarkers, and therapeutic targets. PMID- 23348922 TI - Do open label blinded outcome studies of novel anticoagulants versus warfarin have equivalent validity to those carried out under double-blind conditions? AB - Recent anticoagulants for stroke prevention in AF have been tested in active comparator controlled studies versus warfarin using two designs: double-blind, double-dummy and prospective randomised, open blinded endpoint (PROBE). The former requires elaborate procedures to maintain blinding, while PROBE does not. Outcomes of double-blind and PROBE designed studies of novel anticoagulants for AF, focusing on warfarin controls, were explored. Major, Phase III warfarin controlled trials for stroke prevention in AF were identified. Odds ratios (ORs) of key outcomes for active comparators versus VKA and event rates for VKA arms were compared between designs, in context of baseline demographics and inclusion criteria. Identified trials studied five novel anticoagulants in three each of PROBE and double-blind design. For ORs of results across studies and outcomes, there was little pattern differentiating the two designs. Among VKA-control subjects, event rates for the primary outcome (stroke or systemic embolism) in PROBE trials at 1.74 %/year (95% confidence interval: 1.54-1.95) was not significantly different from that in double-blind trials, at 1.88 (1.73-2.03). Among other outcomes, VKA-treated subjects in both trial designs had similar event rates, apart from higher all-cause mortality in ROCKET AF, and lower myocardial infarction rates among the PROBE study patients. Although there are differences in outcome between PROBE and double blind trials, they do not appear to be design-related. The exacting requirements of double-blinding in AF trials may not be necessary. PMID- 23348923 TI - High-Yield Production in Escherichia coli of Fungal Immunomodulatory Protein Isolated from Flammulina velutipes and Its Bioactivity Assay in Vivo. AB - A fungal immunomodulatory protein isolated from Flammulina velutipes (FIP-fve) has structural similarity to the variable region of the immunoglobulin heavy chain. In the present study, the recombinant bioactive FIP-fve protein with a His tag in N-terminal of recombinant protein was expressed in transetta (DE3) at a high level under the optimized culturing conditions of 0.2 mM IPTG and 28 degrees C. The efficiency of the purification was improved with additional ultrasonication to the process of lysozyme lysis. The yield of the bioactive FIP fve protein with 97.1% purity reached 29.1 mg/L with a large quantity for industrial applications. Enzyme-linked immunosorbent assay showed a maximum increase in interleukin-2 (IL-2) and gamma interferon (IFN-gamma) for the mice serum group of 5 mg/kg body mass (p < 0.01) with three doses of His-FIP-fve. However, the production of IL-4 had no apparent difference compared to the control. PMID- 23348924 TI - Advanced Glycation End Product (AGE)-AGE Receptor (RAGE) System Upregulated Connexin43 Expression in Rat Cardiomyocytes via PKC and Erk MAPK Pathways. AB - The remodeling of cardiac gap junction contributes to the arrhythmias in a diabetic heart. We previously reported that high glucose reduced Cx43 protein level in neonatal rat cardiomyocytes. But, the effect and mechanisms of advanced glycation end product (AGE) on Cx43 expression still remain unclear. In this study, we measured the AGE receptor (RAGE) and Cx43 expression by immunohistochemisty in AGE-infused Sprague-Dawley (SD) rats. In vitro, the Cx43 and RAGE levels were detected in AGE-treated cardiomyocytes by Western blot and real-time RT-PCR. The function of cells coupling was measured by Scrap loading dye transfer assay. Our results showed that the AGE-infused rat hearts exhibited increased cardiac RAGE and Cx43, as well as Cx43 redistribution. In cultured cardiomyocytes, AGE elevated RAGE expression in a time- and dose-dependent manner. Cx43 protein and mRNA levels were upregulated by AGE (200 mg/L, 24 h), but the gap junction function was not enhanced. RAGE-targeted knock-down or the addition of PKC, and Erk inhibitors abolished the effect of AGE on Cx43. Therefore, AGE-RAGE system might elevate Cx43 expression in rat cardiomyocytes by activating PKC and Erk MAPK pathways, and it also enhanced Cx43 redistribution in vivo, which might contribute to the arrhythmias in diabetes. PMID- 23348925 TI - Regulation of Erythropoietin Receptor Activity in Endothelial Cells by Different Erythropoietin (EPO) Derivatives: An in Vitro Study. AB - In endothelial cells, erythropoietin receptors (EPORs) mediate the protective, proliferative and angiogenic effects of EPO and its analogues, which act as EPOR agonists. Because hormonal receptors undergo functional changes upon chronic exposure to agonists and because erythropoiesis-stimulating agents (ESAs) are used for the long-term treatment of anemia, it is critical to determine the mechanism by which EPOR responsiveness is regulated at the vascular level after prolonged exposure to ESAs. Here, we investigated EPOR desensitization/resensitization in human umbilical vein endothelial cells (HUVECs) upon exposure to three ESAs with different pharmacokinetic profiles, epoetin alpha (EPOalpha), darbepoetin alpha (DarbEPO) and continuous EPOR activator (CERA). These agonists all induced activation of the transcription factor STAT-5, which is a component of the intracellular pathway associated with EPORs. STAT-5 activation occurred with either monophasic or biphasic kinetics for EPOalpha/DarbEPO and CERA, respectively. ESAs, likely through activation of the STAT-5 pathway, induced endothelial cell proliferation and stimulated angiogenesis in vitro, demonstrating a functional role for epoetins on endothelial cells. All epoetins induced EPOR desensitization with more rapid kinetics for CERA compared to EPOalpha and DarbEPO. However, the recovery of receptor responsiveness was strictly dependent on the type of epoetin, the agonist concentration and the time of exposure to the agonist. EPOR resensitization occurred with more rapid kinetics after exposure to low epoetin concentrations for a short period of desensitization. When the highest concentration of agonists was tested, the recovery of receptor responsiveness was more rapid with CERA compared to EPOalpha and was completely absent with DarbEPO. Our results demonstrate that these three ESAs regulate EPOR resensitization by very different mechanisms and that both the type of molecule and the length of EPOR stimulation are factors that are critical for the control of EPOR functioning in endothelial cells. The differences observed in receptor resensitization after stimulation with the structurally different ESAs are most likely due different control mechanisms of receptor turnover at the intracellular level. PMID- 23348926 TI - Thermotropic and barotropic phase behavior of phosphatidylcholine bilayers. AB - Bilayers formed by phospholipids are frequently used as model biological membranes in various life science studies. A characteristic feature of phospholipid bilayers is to undergo a structural change called a phase transition in response to environmental changes of their surroundings. In this review, we focus our attention on phase transitions of some major phospholipids contained in biological membranes, phosphatidylcholines (PCs), depending on temperature and pressure. Bilayers of dipalmitoylphosphatidylcholine (DPPC), which is the most representative lipid in model membrane studies, will first be explained. Then, the bilayer phase behavior of various kinds of PCs with different molecular structures is revealed from the temperature-pressure phase diagrams, and the difference in phase stability among these PC bilayers is discussed in connection with the molecular structure of the PC molecules. Furthermore, the solvent effect on the phase behavior is also described briefly. PMID- 23348927 TI - Molecular motions in functional self-assembled nanostructures. AB - The construction of "smart" materials able to perform specific functions at the molecular scale through the application of various stimuli is highly attractive but still challenging. The most recent applications indicate that the outstanding flexibility of self-assembled architectures can be employed as a powerful tool for the development of innovative molecular devices, functional surfaces and smart nanomaterials. Structural flexibility of these materials is known to be conferred by weak intermolecular forces involved in self-assembly strategies. However, some fundamental mechanisms responsible for conformational lability remain unexplored. Furthermore, the role played by stronger bonds, such as coordination, ionic and covalent bonding, is sometimes neglected while they can be employed readily to produce mechanically robust but also chemically reversible structures. In this review, recent applications of structural flexibility and molecular motions in self-assembled nanostructures are discussed. Special focus is given to advanced materials exhibiting significant performance changes after an external stimulus is applied, such as light exposure, pH variation, heat treatment or electromagnetic field. The crucial role played by strong intra- and weak intermolecular interactions on structural lability and responsiveness is highlighted. PMID- 23348929 TI - Connecting chromatin modifying factors to DNA damage response. AB - Cells are constantly damaged by factors that can induce DNA damage. Eukaryotic cells must rapidly load DNA repair proteins onto damaged chromatin during the DNA damage response (DDR). Chromatin-remodeling complexes use the energy from ATP hydrolysis to remodel nucleosomes and have well-established functions in transcription. Emerging lines of evidence indicate that chromatin-remodeling complexes are important and may remodel nucleosomes during DNA damage repair. New studies also reveal that ATP-dependent chromatin remodeling is involved in cell cycle progression, signal transduction pathways, and interaction and modification of DDR-related proteins that are specifically and intimately connected with the process of DNA damage. This article summarizes the recent advances in our understanding of the interplay between chromatin remodeling and DNA damage response. PMID- 23348930 TI - HER-2 Expression in Brain Metastases from Colorectal Cancer and Corresponding Primary Tumors: A Case Cohort Series. AB - Brain metastases (BM) from colorectal cancer (CRC) are a rare but increasing event. Surgical resection of oligometastatic disease, including BM, may produce a survival benefit in selected patients. Previous studies described the HER-2 expression patterns in CRC patients, but its prognostic role still remains controversial. Information on the HER-2 expression in BM from CRC is currently lacking. Among the over 500 patients treated at our Department of Neurosurgery in the last 13 years (1999-2012), we identified a cohort of 50 consecutive CRC patients resected for BM. Clinical data were retrospectively reviewed using electronic hospital charts and surgical notes. Formalin-fixed, paraffin-embedded tissue samples were retrieved and histologically reviewed. HER-2 status was assessed on 4-MUm sections by HerceptTestTM, and scored by two pathologists according to gastric cancer HER-2 status guidelines. In score 2+ cases HER-2 gene copy number was analyzed by FISH, performed using the PathVysion HER-2 DNA Probe Kit. Median age at time of BM resection was 65 years (35-82); most patients were males (60%) with a good performance status. The majority of the BM were single (74%) and sited in the supratentorial area (64%); 2-4 lesions were diagnosed in 9 patients (18%), and >4 in 3 patients (6%). The rate of HER-2 positivity (defined as IHC score 3+ or IHC score 2+ and FISH gene amplification) was 8.1% for the primary CRC tumors and 12% for their corresponding BM. The concordance rate between primary tumors and matched BM was 89%. Median overall survival after neurosurgery was 6.5 months for HER-2 IHC score 0 vs. 4.6 months for HER-2 IHC score 1+/2+/3+; the difference was statistically significant (p = 0.01, Log-rank test). HER-2 positivity of our case cohort was low but comparable to literature. Concordance rate of HER-2 expression between BM and corresponding primary tumors is high and similar to those reported for breast and gastric cancers. Our data suggest a potential negative prognostic value of HER-2 expression in brain lesions from CRC. PMID- 23348928 TI - Cell survival and apoptosis signaling as therapeutic target for cancer: marine bioactive compounds. AB - Inhibition of apoptosis leads to activation of cell survival factors (e.g., AKT) causes continuous cell proliferation in cancer. Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. A number of discoveries have clarified the molecular mechanism of apoptosis, thus clarifying the link between apoptosis and cell survival factors, which has a therapeutic outcome. Induction of apoptosis and inhibition of cell survival by anticancer agents has been shown to correlate with tumor response. Cellular damage induces growth arrest and tumor suppression by inducing apoptosis, necrosis and senescence; the mechanism of cell death depends on the magnitude of DNA damage following exposure to various anticancer agents. Apoptosis is mainly regulated by cell survival and proliferating signaling molecules. As a new therapeutic strategy, alternative types of cell death might be exploited to control and eradicate cancer cells. This review discusses the signaling of apoptosis and cell survival, as well as the potential contribution of marine bioactive compounds, suggesting that new therapeutic strategies might follow. PMID- 23348933 TI - Isometric handgrip exercise during cardiovascular magnetic resonance imaging: set up and cardiovascular effects. AB - PURPOSE: To establish a suitable setup for combining isometric handgrip exercise with cardiovascular magnetic resonance (CMR) imaging and to assess cardiovascular effects. MATERIALS AND METHODS: Fifty-three healthy volunteers (31 males, mean age 45 +/- 17 years) underwent handgrip exercise in a 3T scanner using a prototype handgrip system and a custom-made feedback system that displayed the force. Handgrip was sustained at 30% of the maximal contraction for 6-8 minutes. Heart rate, blood pressure (BP), and double product were determined sequentially. Stroke volume was quantified in a subgroup (n = 21) at rest and stress using phase contrast acquisitions. RESULTS: Heart rate increased significantly between rest and stress by 20 +/- 13%, systolic / diastolic / mean BP by 15 +/- 11% / 20 +/- 18% / 17 +/- 13%, double product by 37 +/- 21%, and cardiac output by 27 +/- 16% (each P < 0.001). Stroke volume did not significantly increase (3 +/- 9%; P = 0.215). Higher age was associated with reduced increase of stroke volume (P = 0.022) and cardiac output (P < 0.001). Overweight subjects showed less increases in heart rate (P = 0.021) and cardiac output (P = 0.002). CONCLUSION: The handgrip exercise during CMR with the presented set-up leads to considerable hemodynamic changes in healthy volunteers. PMID- 23348931 TI - Parkinson's disease: a complex interplay of mitochondrial DNA alterations and oxidative stress. AB - Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases. This pathology causes a significant loss of dopaminergic neurons in the Substantia Nigra. Several reports have claimed a role of defective nuclear and mitochondrial DNA repair pathways in PD etiology, in particular, of the Base Excision Repair (BER) system. In addition, recent findings, related to PD progression, indicate that oxidative stress pathways involving c-Abl and GST could also be implicated in this pathology. This review focuses on recently described networks most likely involved in an integrated manner in the course of PD. PMID- 23348934 TI - Preparation of Kupffer cell enriched non-parenchymal liver cells with high yield and reduced damage of surface markers by a modified method for flow cytometry. AB - The aim of this study was to optimise a collagenase perfusion protocol for the isolation of a liver non-parenchymal cell (NPC) suspension enriched for Kupffer cells that reduced damage to F4/80 antigen cell surface expression to allow analysis by flow cytometry. Kupffer cell-enriched liver NPCs were isolated from C57BL/6 mice using different protocols. Flow cytometry was used to examine the effect of collagenase digestion on F4/80 expression on Kupffer cells, and results were represented by the percentage of F4/80 positive cells and by the F4/80 mean fluorescence intensity (MFI). The perfusion temperature, concentration of collagenase solution and total dosage of collagenase for liver perfusion influenced the effect of collagenase perfusion on the expression of F4/80 antigen on Kupffer cells. Collagenase perfusion at 28 degrees C resulted in an increased percentage of F4/80 positive cells (P = 0.001) and MFI (P = 0.005) compared with 37 degrees C. Perfusion with a total dose of 1.0 g/kg BW collagenase (using a 0.75 mg/mL solution) resulted in the highest percentage of F4/80 positive cells (P = 0.001) compared with 0.8 g/kg BW and 1.2 g/kg BW collagenase. Isolation of cells using the modified protocol resulted in a higher percentage of Kupffer cells (P < 0.001) and a higher MFI of F4/80 antigen (P < 0.001) compared with the common protocol. PMID- 23348932 TI - Melatonin anticancer effects: review. AB - Melatonin (N-acetyl-5-methoxytryptamine, MLT), the main hormone produced by the pineal gland, not only regulates circadian rhythm, but also has antioxidant, anti-ageing and immunomodulatory properties. MLT plays an important role in blood composition, medullary dynamics, platelet genesis, vessel endothelia, and in platelet aggregation, leukocyte formula regulation and hemoglobin synthesis. Its significant atoxic, apoptotic, oncostatic, angiogenetic, differentiating and antiproliferative properties against all solid and liquid tumors have also been documented. Thanks, in fact, to its considerable functional versatility, MLT can exert both direct and indirect anticancer effects in factorial synergy with other differentiating, antiproliferative, immunomodulating and trophic molecules that form part of the anticancer treatment formulated by Luigi Di Bella (Di Bella Method, DBM: somatostatin, retinoids, ascorbic acid, vitamin D3, prolactin inhibitors, chondroitin-sulfate). The interaction between MLT and the DBM molecules counters the multiple processes that characterize the neoplastic phenotype (induction, promotion, progression and/or dissemination, tumoral mutation). All these particular characteristics suggest the use of MLT in oncological diseases. PMID- 23348935 TI - Nuclear magnetic resonance imaging of tumour growth and neovasculature performance in vivo reveals Grb7 as a novel antiangiogenic target. AB - Development of neovasculature is a necessary requirement for tumour growth and it provides additional opportunities for therapeutic intervention. However, current antiangiogenic therapies have limited efficacy, mostly because of the development of resistance. Hence, characterization of new antiangiogenic molecular targets is of considerable clinical interest. We report that a calmodulin-binding domain (CaM-BD) deletion mutant of the growth factor receptor bound protein 7 (Grb7) (denoted Grb7Delta) impairs tumour growth and associated angiogenesis in vivo. We implanted glioma C6 cells in rat brains transfected with an enhanced yellow fluorescent protein (EYFP) chimera of Grb7?, its EYFP-Grb7 wild type counterpart, and EYFP alone. We systematically followed intracerebral growth of the tumours, their cellularity and the functional performance of tumour-associated microvasculature using magnetic resonance imaging, including anatomical T1W and T2W images and functional diffusion and perfusion parameters. Tumours grown from implanted C6 cells expressing EYFP-Grb7Delta developed slower, became smaller and presented lower apparent cellularity than those derived from cells expressing EYFP-Grb7 and EYFP. Vascular perfusion measurements within tumours derived from EYFP-Grb7?-expressing cells showed significantly lower cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) values. These findings were independently validated by histological and immunohistochemical techniques. Taken together, these findings confirm that the CaM-BD of Grb7 plays an important role in tumour growth and associated angiogenesis in vivo, thus identifying this region of the protein as a novel target for antiangiogenic treatment. PMID- 23348936 TI - Molecular and functional characterization of hemocyanin of the giant African millipede, Archispirostreptus gigas. AB - In contrast to other terrestrial arthropods, where gaseous O2 that fuels aerobic metabolism diffuses to the tissues in tracheal tubes, and most other metazoans, where O2 is transported to tissues by circulating respiratory proteins, the myriapods (millipedes and centipedes) strikingly have tracheal systems as well as circulating hemocyanin (Hc). In order to elucidate the evolutionary origin and biological significance of millipede Hc, we report the molecular structure (subunit composition and amino acid sequence) of multimeric (36-mer) Hc from the forest floor-dwelling giant African millipede Archispirostreptus gigas and its allosteric oxygen-binding properties under various physico-chemical conditions. Archispirostreptus gigas Hc consists of only a single subunit type with differential glycosylation. Phylogenic analysis revealed that millipede Hc is a sister group to centipede HcA, which supports an early divergence of distinct Hc subunits in myriapods and an ancient origin of multimeric Hcs. Archispirostreptus gigas Hc binds O2 with a high affinity and shows a strong Bohr effect. O2 binding is, moreover, modulated by Ca(2+) ions, which increase the O2 affinity of the Hc in the tense (T; deoxygenated) as well as the relaxed (R; oxygenated) states, and by (l)-lactate, which modulates Hc-O2 affinity by changing the allosteric equilibrium constant, L. Cooperativity in O2 binding at half O2 saturation (n50) is pH dependent and maximal at ~pH 7.4, and the number of interacting O2-binding sites (q) is markedly increased by binding Ca(2+). The data are discussed in the light of the mutually supplementary roles of Hc and the tracheal system for tissue O2 supply. PMID- 23348937 TI - Invasion and adaptation of a warm-adapted species to montane localities: effect of acclimation potential. AB - Drosophila ananassae has successfully invaded the cold and dry montane localities of the Western Himalayas in recent years. The ability of this desiccation- and cold-sensitive tropical species to evolve in response to seasonal changes in montane localities is largely unknown. Here, we investigated how this sensitive species adapt to seasonally varying environmental conditions that are lethal to its survival. We observed change in the frequency of dark and light morphs of D. ananassae in five mid-altitude localities during the last decade (2000-2010). We document invasion of D. ananassae to montane localities and increase in frequency of the dark morph. The stress tolerance of morphs (dark and light) remained unaffected of developmental acclimation. However, adult acclimation has shown significant effects on tolerance to various environmental stresses in morphs and effect of this acclimation persist for long durations. Desiccation and cold stress tolerance was increased after adult acclimation for respective stress in the dark morph; while tolerance of the light morph was not affected. Further, heat tolerance of the light morph was increased after adult heat acclimation with no influence on heat tolerance of the dark morph. Our results suggest a possible role of adult acclimation in successful invasion and adaptation of D. ananassae to montane localities. Future experiments should be carried out to determine whether the survival in adverse conditions of low versus high temperature and humidity during seasonal changes is assisted by different acclimation abilities of the two morphs of D. ananassae. PMID- 23348938 TI - Gastrointestinal and renal responses to variable water intake in whitebellied sunbirds and New Holland honeyeaters. AB - Nectarivores face a constant challenge in terms of water balance, experiencing water loading or dehydration when switching between food plants or between feeding and fasting. To understand how whitebellied sunbirds and New Holland honeyeaters meet the challenges of varying preformed water load, we used the elimination of intramuscular-injected [(14)C]-l-glucose and (3)H2O to quantify intestinal and renal water handling on diets varying in sugar concentration. Both sunbirds and honeyeaters showed significant modulation of intestinal water absorption, allowing excess water to be shunted through the intestine when on dilute diets. Despite reducing their fractional water absorption, both species showed linear increases in water flux and fractional body water turnover as water intake increased (both afternoon and morning), suggesting that the modulation of fractional water absorption was not sufficient to completely offset dietary water loads. In both species, glomerular filtration rate was independent of water gain (but was higher for the afternoon), as was renal fractional water reabsorption (measured in the afternoon). During the natural overnight fast, both sunbirds and honeyeaters arrested whole kidney function. Evaporative water loss in sunbirds was variable but correlated with water gain. Both sunbirds and honeyeaters appear to modulate intestinal water absorption as an important component of water regulation to help deal with massive preformed water loads. Shutting down glomerular filtration rate during the overnight fast is another way of saving energy for osmoregulatory function. Birds maintain osmotic balance on diets varying markedly in preformed water load by varying both intestinal water absorption and excretion through the intestine and kidneys. PMID- 23348939 TI - Ontogenetic expression of metabolic genes and microRNAs in rainbow trout alevins during the transition from the endogenous to the exogenous feeding period. AB - As oviparous fish, rainbow trout change their nutritional strategy during ontogenesis. This change is divided into the exclusive utilization of yolk-sac reserves (endogenous feeding), the concurrent utilization of yolk reserves and exogenous feeds (mixed feeding) and the complete dependence on external feeds (exogenous feeding). The change in food source is accompanied by well characterized morphological changes, including the development of adipose tissue as an energy storage site, and continuous muscle development to improve foraging. The aim of this study was to investigate underlying molecular mechanisms that contribute to these ontogenetic changes between the nutritional phenotypes in rainbow trout alevins. We therefore analyzed the expression of marker genes of metabolic pathways and microRNAs (miRNAs) important in the differentiation and/or maintenance of metabolic tissues. In exogenously feeding alevins, the last enzyme involved in glucose production (g6pca and g6pcb) and lipolytic gene expression (cpt1a and cpt1b) decreased, while that of gk, involved in hepatic glucose use, was induced. This pattern is consistent with a progressive switch from the utilization of stored (gluconeogenic) amino acids and lipids in endogenously feeding alevins to a utilization of exogenous feeds via the glycolytic pathway. A shift towards the utilization of external feeds is further evidenced by the increased expression of omy-miRNA-143, a homologue of the mammalian marker of adipogenesis. The expression of its predicted target gene abhd5, a factor in triglyceride hydrolysis, decreased concurrently, suggesting a potential mechanism in the onset of lipid deposition. Muscle-specific omy-miRNA-1/133 and myod1 expression decreased in exogenously feeding alevins, a molecular signature consistent with muscle hypertrophy, which may be linked to nutritional cues or increased foraging. PMID- 23348940 TI - Adaptive evolution of fish hatching enzyme: one amino acid substitution results in differential salt dependency of the enzyme. AB - Embryos of medaka Oryzias latipes hatch in freshwater, while those of killifish Fundulus heteroclitus hatch in brackish water. Medaka and Fundulus possess two kinds of hatching enzymes, high choriolytic enzyme (HCE) and low choriolytic enzyme (LCE), which cooperatively digest their egg envelope at the time of hatching. Optimal salinity of medaka HCE was found in 0 mol l(-1) NaCl, and activity decreased with increasing salt concentrations. One of the two Fundulus HCEs, FHCE1, showed the highest activity in 0 mol l(-1) NaCl, and the other, FHCE2, showed the highest activity in 0.125 mol l(-1) NaCl. The results suggest that the salt dependencies of HCEs are well adapted to each salinity at the time of hatching. Different from HCE, LCEs of both species maintained the activity sufficient for egg envelope digestion in various salinities. The difference in amino acid sequence between FHCE1 and FHCE2 was found at only a single site at position 36 (Gly/Arg), suggesting that this single substitution causes the different salt dependency between the two enzymes. Superimposition of FHCE1 and FHCE2 with the 3-D structure model of medaka HCE revealed that position 36 was located on the surface of HCE molecule, far from its active site cleft. The results suggest a hypothesis that position 36 influences salt-dependent activity of HCE, not with recognition of primary structure around the cleavage site, but with recognition of higher ordered structure of egg envelope protein. PMID- 23348941 TI - Mobilization of ectopic yolk in Gallus gallus domesticus: a novel reverse lipid transport process. AB - In many oviparous animals, bursting type atresia of ovarian follicles occurs during the reproductive cycle, resulting in the escape of yolk into the extracellular compartment. In birds, this ectopic yolk is rapidly cleared by an unknown process that involves the appearance of yolk-engorged macrophage-like cells. To study this unique type of lipid transport, we injected young male chickens intra-abdominally with egg yolk. Absorption of egg yolk from the body cavity markedly increased the triacylglyceride-rich fraction (TRL) of plasma lipoproteins and was coincident with increased levels of plasma triacylglycerides (TAGs) but not non-esterified fatty acids (NEFAs). Thus, the transport of yolk lipids from the abdominal cavity appears to occur in lipoproteins and be more similar to the transport of hepatic TAGs to the periphery via lipoproteins than to transport of adipose TAGs to the periphery via NEFAs released by the action of lipases. When macrophages were exposed to yolk in vitro, they quickly phagocytized yolk; however, it is unclear whether this level of phagocytosis contributes significantly to total yolk clearance. Instead, the chicken macrophage may function more as a facilitator of yolk clearance through the modification of yolk lipoproteins and the regulation of the local and systemic immune response to ectopic yolk. Yolk appears to be anti-inflammatory in nature. Yolk did not increase levels of the inflammatory cytokines IL-1, IL-6 and IFNgamma either in vivo or in vitro; in fact, yolk dampened many inflammatory changes caused by lipopolysaccharide (LPS). Conversely, LPS-induced inflammation retarded yolk clearance from the abdominal cavity and plasma TAG levels. PMID- 23348942 TI - Antifreeze proteins in the primary urine of larvae of the beetle Dendroides canadensis. AB - To avoid freezing while overwintering beneath the bark of fallen trees, Dendroides canadensis (Coleoptera: Pyrochroidae) larvae produce a family of antifreeze proteins (DAFPs) that are transcribed in specific tissues and have specific compartmental fates. DAFPs and associated thermal hysteresis activity (THA) have been shown previously in hemolymph and midgut fluid, but the presence of DAFPs has not been explored in primary urine, a potentially important site that can contain endogenous ice-nucleating compounds that could induce freezing. A maximum mean THA of 2.65+/-0.33 degrees C was observed in primary urine of winter-collected D. canadensis larvae. THA in primary urine increased significantly through autumn, peaked in the winter and decreased through spring to levels of 0.2-0.3 degrees C in summer, in a pattern similar to that of hemolymph and midgut fluid. THA was also found in hindgut fluid and excreted rectal fluid, suggesting that these larvae not only concentrate AFPs in the hindgut, but also excrete AFPs from the rectal cavity. Based on dafp transcripts isolated from Malpighian tubule epithelia, cDNAs were cloned and sequenced, identifying the presence of transcripts encoding 24 DAFP isoforms. Six of these Malpighian tubule DAFPs were known previously, but 18 are new. We also provide functional evidence that DAFPs can inhibit ice nucleators present in insect primary urine. This is potentially critical because D. canadensis larvae die if frozen, and therefore ice formation in any body fluid, including the urine, would be lethal. PMID- 23348943 TI - An increase in minimum metabolic rate and not activity explains field metabolic rate changes in a breeding seabird. AB - The field metabolic rate (FMR) of a free-ranging animal can be considered as the sum of its maintenance costs (minimum metabolic rate, MMR) and additional costs associated with thermoregulation, digestion, production and activity. However, the relationships between FMR and BMR and how they relate to behaviour and extrinsic influences is not clear. In seabirds, FMR has been shown to increase during the breeding season. This is presumed to be the result of an increase in foraging activity, stimulated by increased food demands from growing chicks, but few studies have investigated in detail the factors that underlie these increases. We studied free-ranging Australasian gannets (Morus serrator) throughout their 5 month breeding season, and evaluated FMR, MMR and activity related metabolic costs on a daily basis using the heart rate method. In addition, we simultaneously recorded behaviour (flying and diving) in the same individuals. FMR increased steadily throughout the breeding season, increasing by 11% from the incubation period to the long chick-brooding period. However, this was not accompanied by either an increase in flying or diving behaviour, or an increase in the energetic costs of activity. Instead, the changes in FMR could be explained exclusively by a progressive increase in MMR. Seasonal changes in MMR could be due to a change in body composition or a decrease in body condition associated with changing the allocation of resources between provisioning adults and growing chicks. Our study highlights the importance of measuring physiological parameters continuously in free-ranging animals in order to understand fully the mechanisms underpinning seasonal changes in physiology and behaviour. PMID- 23348944 TI - Regulation of succinate-fuelled mitochondrial respiration in liver and skeletal muscle of hibernating thirteen-lined ground squirrels. AB - Hibernating ground squirrels (Ictidomys tridecemlineatus) alternate between two distinct metabolic states throughout winter: torpor, during which metabolic rate (MR) and body temperature (Tb) are considerably suppressed, and interbout euthermia (IBE), during which MR and Tb briefly return to euthermic levels. Previous studies showed suppression of succinate-fuelled respiration during torpor in liver and skeletal muscle mitochondria; however, these studies used only a single, saturating succinate concentration. Therefore, they could not address whether mitochondrial metabolic suppression occurs under physiological substrate concentrations or whether differences in the kinetics of mitochondrial responses to changing substrate concentration might also contribute to mitochondrial metabolic regulation during torpor. The present study confirmed that succinate oxidation is reduced during torpor in liver and skeletal muscle at 37 and 10 degrees C over a 100-fold range of succinate concentrations. At 37 degrees C, this suppression resulted from inhibition of succinate dehydrogenase (SDH), which had a greater affinity for oxaloacetate (an SDH inhibitor) during torpor. At 10 degrees C, SDH was not inhibited, suggesting that SDH inhibition initiates but does not maintain mitochondrial suppression during torpor. Moreover, in both liver and skeletal muscle, mitochondria from torpid animals maintained relatively higher respiration rates at low succinate concentrations, which reduces the extent of energy savings that can be achieved during torpor, but may also maintain mitochondrial oxidative capacity above some lower critical threshold, thereby preventing cellular and/or mitochondrial injury during torpor and facilitating rapid recruitment of oxidative capacity during arousal. PMID- 23348945 TI - Bat flight with bad wings: is flight metabolism affected by damaged wings? AB - Infection of North American bats with the keratin-digesting fungus Geomyces destructans often results in holes and ruptures of wing membranes, yet it is unknown whether flight performance and metabolism of bats are altered by such injuries. I conducted flight experiments in a circular flight arena with Myotis albescens and M. nigricans individuals with an intact or ruptured trailing edge of one of the plagiopatagial membranes. In both species, individuals with damaged wings were lighter, had a higher aspect ratio (squared wing span divided by wing area) and an increased wing loading (weight divided by wing area) than conspecifics with intact wings. Bats with an asymmetric reduction of the wing area flew at similar speeds to conspecifics with intact wings but performed fewer flight manoeuvres. Individuals with damaged wings showed lower metabolic rates during flight than conspecifics with intact wings, even when controlling for body mass differences; the difference in mass-specific metabolic rate may be attributable to the lower number of flight manoeuvres (U-turns) by bats with damaged wings compared with conspecifics with intact wings. Possibly, bats compensated for an asymmetric reduction in wing area by lowering their body mass and avoiding flight manoeuvres. In conclusion, it may be that bats suffer from moderate wing damage not directly, by experiencing increased metabolic rate, but indirectly, by a reduced manoeuvrability and foraging success. This could impede a bat's ability to gain sufficient body mass before hibernation. PMID- 23348946 TI - Production of chimeras between the Chinese soft-shelled turtle and Peking duck through transfer of early blastoderm cells. AB - Chimeras are useful models for studies of developmental biology and cell differentiation. Intraspecies and interspecies germline chimeras have been produced in previous studies, but the feasibility of producing chimeras between animals of two different classes remains unclear. To address this issue, we attempted to produce chimeras between the Chinese soft-shelled turtle and the Peking duck by transferring stage X blastoderm cells to recipient embryos. We then examined the survival and development of the PKH26-labeled donor cells in the heterologous embryos. At early embryonic stages, both turtle and duck donor cells that were labeled with PKH26 were readily observed in the brain, neural tube, heart and gonads of the respective recipient embryos. Movement of turtle donor-derived cells was observed in the duck host embryos after 48 h of incubation. Although none of the hatchlings presented a chimeric phenotype, duck donor-derived cells were detected in a variety of organs in the hatchling turtles, particularly in the gonads. Moreover, in the hatched turtles, mRNA expression of tissue-specific duck genes MEF2a and MEF2c was detected in many tissues, including the muscle, heart, small and large intestines, stomach and kidney. Similarly, SPAG6 mRNA was detected in a subset of turtle tissues, including the gonad and the small and large intestines. These results suggest that duck donor-derived cells can survive and differentiate in recipient turtles; however, no turtle-derived cells were detected in the hatched ducks. Our findings indicate that chimeras can be produced between animals of two different classes. PMID- 23348947 TI - Rapid cold hardening improves recovery of ion homeostasis and chill coma recovery time in the migratory locust, Locusta migratoria. AB - Chill tolerance of insects is defined as the ability to tolerate low temperature under circumstances not involving freezing of intracellular or extracellular fluids. For many insects chill tolerance is crucial for their ability to persist in cold environments and mounting evidence indicates that chill tolerance is associated with the ability to maintain ion and water homeostasis, thereby ensuring muscular function and preventing chill injury at low temperature. The present study describes the relationship between muscle and haemolymph ion homeostasis and time to regain posture following cold shock (CS, 2 h at -4 degrees C) in the chill-susceptible locust Locusta migratoria. This relationship was examined in animals with and without a prior rapid cold-hardening treatment (RCH, 2 h at 0 degrees C) to investigate the physiological underpinnings of RCH. CS elicited a doubling of haemolymph [K(+)] and this disturbance was greater in locusts pre-exposed to RCH. Recovery of ion homeostasis was, however, markedly faster in RCH-treated animals, which correlated well with whole-organism performance as hardened individuals regained posture faster than non-hardened individuals following CS. The present study indicates that loss and recovery of muscular function are associated with the resting membrane potential of excitable membranes as attested by the changes in the equilibrium potential for K(+) (EK) following CS. Both hardened and non-hardened animals regained movement once K(+) homeostasis had recovered to a fixed level (EK~-41 mV). RCH is therefore not associated with altered sensitivity to ion disturbance but instead is correlated to a faster recovery of haemolymph [K(+)]. PMID- 23348948 TI - Rapid postnatal development of myoglobin from large liver iron stores in hooded seals. AB - Hooded seals (Cystophora cristata) rely on large stores of oxygen, either bound to hemoglobin or myoglobin (Mb), to support prolonged diving activity. Pups are born with fully developed hemoglobin stores, but their Mb levels are only 25-30% of adult levels. We measured changes in muscle [Mb] from birth to 1 year of age in two groups of captive hooded seal pups, one being maintained in a seawater pool and one on land during the first 2 months. All pups fasted during the first month, but were fed from then on. The [Mb] of the swimming muscle musculus longissimus dorsi (LD) doubled during the month of fasting in the pool group. These animals had significantly higher levels and a more rapid rise in LD [Mb] than those kept on land. The [Mb] of the shoulder muscle, m. supraspinatus, which is less active in both swimming and hauled-out animals, was consistently lower than in the LD and did not differ between groups. This suggests that a major part of the postnatal rise in LD [Mb] is triggered by (swimming) activity, and this coincides with the previously reported rapid early development of diving capacity in wild hooded seal pups. Liver iron concentration, as determined from another 25 hooded seals of various ages, was almost 10 times higher in young pups (1-34 days) than in yearling animals and adults, and liver iron content of pups dropped during the first month, implying that liver iron stores support the rapid initial rise in [Mb]. PMID- 23348949 TI - Snapshots in ants? New interpretations of paradigmatic experiments. AB - Ants can use visual information to guide long idiosyncratic routes and accurately pinpoint locations in complex natural environments. It has often been assumed that the world knowledge of these foragers consists of multiple discrete views that are retrieved sequentially for breaking routes into sections controlling approaches to a goal. Here we challenge this idea using a model of visual navigation that does not store and use discrete views to replicate the results from paradigmatic experiments that have been taken as evidence that ants navigate using such discrete snapshots. Instead of sequentially retrieving views, the proposed architecture gathers information from all experienced views into a single memory network, and uses this network all along the route to determine the most familiar heading at a given location. This algorithm is consistent with the navigation of ants in both laboratory and natural environments, and provides a parsimonious solution to deal with visual information from multiple locations. PMID- 23348950 TI - Thermal tolerance breadths among groundwater crustaceans living in a thermally constant environment. AB - The climate variability hypothesis assumes that the thermal tolerance breadth of a species is primarily determined by temperature variations experienced in its environment. If so, aquatic invertebrates living in thermally buffered environments would be expected to exhibit narrow thermal tolerance breadths (stenothermy). We tested this prediction by studying the thermal physiology of three isopods (Asellidae, Proasellus) colonizing groundwater habitats characterized by an annual temperature amplitude of less than 1 degrees C. The species responses to temperature variation were assessed in the laboratory using five physiological variables: survival, locomotor activity, aerobic respiration, immune defense and concentrations of total free amino acids and sugars. The three species exhibited contrasted thermal physiologies, although all variables were not equally informative. In accordance with the climate variability hypothesis, two species were extremely sensitive even to moderate changes in temperature (2 degrees C) below and above their habitat temperature. In contrast, the third species exhibited a surprisingly high thermal tolerance breadth (11 degrees C). Differences in response to temperature variation among Proasellus species indicated that their thermal physiology was not solely shaped by the current temperature seasonality in their natural habitats. More particularly, recent gene flow among populations living in thermally constant yet contrasted habitats might explain the occurrence of eurytherm species in thermally buffered environments. PMID- 23348951 TI - The Chinese soft-shelled turtle, Pelodiscus sinensis, decreases nitrogenous excretion, reduces urea synthesis and suppresses ammonia production during emersion. AB - The objective of this study was to examine the effects of 6 days of emersion on nitrogen metabolism and excretion in the Chinese soft-shelled turtle, Pelodiscus sinensis. Despite having a soft shell with a cutaneous surface that is known to be water permeable, P. sinensis lost only ~2% of body mass and was able to maintain its hematocrit and plasma osmolality, [Na(+)] and [Cl(-)] during 6 days of emersion. During emersion, it ameliorated water loss by reducing urine output, which led to a reduction (by 29-76%) in ammonia excretion. In comparison, there was a more prominent reduction (by 82-99%) in urea excretion during emersion due to a lack of water to flush the buccopharyngeal epithelium, which is known to be the major route of urea excretion. Consequently, emersion resulted in an apparent shift from ureotely to ammonotely in P. sinensis. Although urea concentration increased in several tissues, the excess urea accumulated could only account for 13-22% of the deficit in urea excretion. Hence, it can be concluded that a decrease (~80%) in urea synthesis occurred in P. sinensis during the 6 days of emersion. Indeed, emersion led to significant decreases in the activity of some ornithine-urea cycle enzymes (argininosuccinate synthetase/argininosuccinate lyase and arginase) from the liver of P. sinensis. As a decrease in urea synthesis occurred without the accumulation of ammonia and total free amino acids, it can be deduced that ammonia production through amino acid catabolism was suppressed with a proportional reduction in proteolysis in P. sinensis during emersion. Indeed, calculated results revealed that there could be a prominent decrease (~88%) in ammonia production in turtles after 6 days of emersion. In summary, despite being ureogenic and ureotelic in water, P. sinensis adopted a reduction in ammonia production, instead of increased urea synthesis, as the major strategy to ameliorate ammonia toxicity and problems associated with dehydration during terrestrial exposure. PMID- 23348952 TI - Pheromones exert top-down effects on visual recognition in the jumping spider Lyssomanes viridis. AB - In diverse and productive habitats, predaceous arthropods are expected to frequently encounter dangerous conspecifics and heterospecifics. This should make quick and accurate discriminations between species and sexes adaptive. By simultaneously sampling both visual cues and pheromones, and by utilizing stringent species- and sex-specific visual recognition templates, an individual should be able to increase both its speed and accuracy in making such discriminations. We tested for the use and stringency of visual recognition templates in the jumping spider Lyssomanes viridis by presenting males with animated images of conspecifics, heterospecifics and composite images that combined the facial coloration and morphology of one sex or species with the leg coloration of another. Males' courtship versus threat displays indicated whether a stimulus was perceived as a potential mate or a threat. By comparing males' visual inspection times of, and display types towards, the various images in the presence versus absence of female pheromones, we were able to deduce whether males tend to inspect a subset of the color pattern and morphological features that make up their conspecific recognition templates (i.e. those on just the face or just the legs), or all features, and whether this changes in the presence of pheromones. We found that the male recognition template for conspecific female was surprisingly coarse, whereas the recognition template for conspecific male, and especially the male face, was more specific. Pheromones hastened the recognition of images with coloration and morphology closely matching those of conspecifics, presumably by activating conspecific visual recognition templates. When males were presented with an image that was, overall, a poor match to a conspecific female, but that contained a subset of female or female-like features, female pheromones usually did not hasten recognition, but did increase the likelihood that the image would be identified as a female. Taken together, our data suggest that males examined features on both the face and the legs in both the presence and absence of pheromones, and that female pheromones tipped the balance in favor of a female identification when a male was unsure how to categorize an incongruous set of visual features. PMID- 23348953 TI - Foxp3+ regulatory T cells are activated in spite of B7-CD28 and CD40-CD40L blockade. AB - Costimulatory signals are required for priming and activation of naive T cells, while it is less clear how they contribute to induction of regulatory T (Treg) cell activity. We previously reported that the blockade of the B7-CD28 and CD40L CD40 interaction efficiently suppresses allogeneic T-cell activation in vivo. This was characterized by an initial rise in Foxp3(+) cells, followed by depletion of host-reactive T cells. To further investigate effects of costimulatory blockade on Treg cells, we used an in vitro model of allogeneic CD4(+) cell activation. When CTLA-4Ig and anti-CD40L mAb (MR1) were added to the cultures, T-cell proliferation and IL-2 production were strongly reduced. However, Foxp3(+) cells proliferated and acquired suppressive activity. They suppressed activation of syngeneic CD4(+) cells much more efficiently than did freshly isolated Treg cells. CD4(+) cells activated by allogeneic cells in the presence of MR1 and CTLA-4Ig were hyporesponsive on restimulation, but their response was restored to that of naive CD4(+) cells when Foxp3(+) Treg cells were removed. We conclude that natural Treg cells are less dependent on B7-CD28 or CD40-CD40L costimulation compared with Foxp3(-) T cells. Reduced costimulation therefore alters the balance between Teff and Treg-cell activation in favor of Treg-cell activity. PMID- 23348954 TI - Cardiovascular and respiratory effects of the degree of head-down angle during robot-assisted laparoscopic radical prostatectomy. AB - BACKGROUND: Robot-assisted laparoscopic radical prostatectomy (RALP) requires a steep Trendelenburg position and CO2 pneumoperitoneum for several hours to secure the surgical visual field. The present study was performed to investigate the influence of each angle of Trendelenburg position during RALP on cardiovascular and respiratory homeostasis. METHODS: Forty-seven ASA physical status 1 and 2 patients underwent open retropubic radical prostatectomy (RRP) or RALP. Patients receiving RALP were randomized to undergo the operation in the 20 degrees , 25 degrees or 30 degrees Trendelenburg position. Heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR), end-tidal CO2 pressure (PetCO2 ), tidal volume (Vt), peak inspiratory pressure (PIP) and dynamic compliance (Cdyn) were recorded during the operation. RESULTS: Angle of head-down tilt was significantly correlated with MAP, PIP and Cdyn, but not with HR, RR or PetCO2 . MAP decreased gradually over time in each group in the Trendelenburg position with pneumoperitoneum. As the angle of head-down tilt became stronger, MAP, RR, PetCO2 and PIP tended to increase and Cdyn tended to decrease. CONCLUSIONS: This study demonstrated that the degree of the head-down angle at RALP affected the cardiovascular and respiratory parameters. Pneumoperitoneum with head-down position in RALP influenced the cardiovascular and respiratory system to a greater extent than RRP, and these effects were stronger with deeper head-down angle. PMID- 23348955 TI - The inhibin B (InhB) response to the testicular toxicants mono-2-ethylhexyl phthalate (MEHP), 1,3 dinitrobenzene (DNB), or carbendazim (CBZ) following short term repeat dosing in the male rat. AB - OBJECTIVE: The objective of this study was to evaluate the utility of plasma Inhibin B (InhB) as a biomarker of testicular injury in adult rats following short-term exposure to the known Sertoli cell toxicants mono-2-ethylhexyl phthalate (MEHP), 1,3 dinitrobenzene (DNB), or carbendazim (CBZ). METHODS: Following oral gavage administration of the compounds for 2 or 7 days, the rats were evaluated for clinical signs, body weight, food consumption, organ weights, plasma hormone levels, and gross and microscopic pathology. RESULTS: MEHP, DNB, and CBZ produced a range of testicular toxicity characterized by minimal exfoliation of germ cells as demonstrated by increased cellular debris in the epididymis (MEHP) to more severe and dose/duration responsive Sertoli cell vacuolation, germ cell degeneration, and multinucleated giant cells of germ cell origin (DNB and CBZ). The slight to moderate Sertoli and germinal cell injuries did not correlate with significant changes in plasma InhB levels following 2- or 7-day exposures. However, more severe injury to germinal epithelium following up to 7 days of exposure, but not after 2 days of exposure, correlated with decreased plasma InhB levels and less consistently with increases in plasma follicle stimulating hormone. CONCLUSION: In conclusion, under the conditions of these studies, changes in InhB were not an effective early onset marker of testicular toxicity or an effective marker for slight to moderate levels of acute injury, and only reflected more severe disruption of spermatogenesis. Changes in plasma InhB and follicle stimulating hormone were poorly correlated except in some instances of moderate to marked testicular toxicity. PMID- 23348957 TI - Double parallel dynamic resolution through lipase-catalyzed asymmetric transformation. AB - Dynamic systems based on double parallel reactions have been generated and resolved in situ by secondary lipase-catalyzed asymmetric transformation, resulting in high chemo- and enantioselectivities. PMID- 23348956 TI - Molecular dynamics simulations of transitions for ECD epidermal growth factor receptors show key differences between human and drosophila forms of the receptors. AB - Recent X-ray structural work on the Drosophila epidermal growth factor receptor (EFGR) has suggested an asymmetric dimer that rationalizes binding affinity measurements that go back decades (Alvarado et al., Cell 2010;142:568-579; Dawson et al., Structure 2007;15:942-954; Lemmon et al., Embo J 1997;16:281-294; Mattoon et al., Proc Natl Acad Sci USA 2004;101:923-928; Mayawala et al., Febs Lett 2005;579:3043-3047; Ozcan et al., Proc Natl Acad Sci USA 2006;103:5735-5740). This type of asymmetric structure has not been seen for the human EGF receptor family and it may or may not be important for function in that realm. We hypothesize that conformational changes in the Drosophila system have been optimized for the transition, whereas the barrier for the same transition is much higher in the human forms. To address our hypothesis we perform dynamic importance sampling (DIMS) (Perilla et al., J Comput Chem 2010;32:196-209) for barrier crossing transitions in both Drosophila and human EFGRs. For each set of transitions, we work from the hypothesis, based on results from the AdK system, that salt-bridge pairs making and breaking connections are central to the conformational change. To evaluate the effectiveness of the salt-bridges as drivers for the conformational change, we use the effective transfer entropy based on stable state MD calculations (Kamberaj and Der Vaart, Biophys J 2009;97:1747-1755) to define a reduced subset of degrees of freedom that seem to be important for driving the transition (Perilla and Woolf, J Chem Phys 2012;136:164101). Our results suggest that salt-bridge making and breaking is not the dominant factor in driving the symmetric to asymmetric transition, but that instead it is a result of more concerted and correlated functional motions within a subset of the dimer structures. Furthermore, the analysis suggests that the set of residues involved in the transitions from the Drosophila relative to the human forms differs and that this difference in substate distributions relates to why the asymmetric form may be more common to Drosophila than to the human forms. We close with a discussion about the residues that may be changed in the human and the Drosophila forms to potentially shift the kinetics of the symmetric to asymmetric transition. PMID- 23348958 TI - Sr, Mg cosubstituted HA porous macro-granules: potentialities as resorbable bone filler with antiosteoporotic functions. AB - Porous macro-granules of nanostructured apatite with Ca ions partially cosubstituted with Mg and Sr ions in different ratios (SrMgHAs), were synthesized at 37 degrees C and compared with Mg and/or Sr free apatites (MgHAs and HA). Strontium improved the Mg substitution extent in the apatite and the chemical physical and thermal stability of the resulting cosubstituted apatite. Porous macro-granules of 400-600 micron with selected composition were tested for the ionic release in synthetic body fluid and the data were related with the results of preliminary cell investigation in vitro. As compared to the corresponding Sr free granulate, the SrMgHA could be exploited to prolong the beneficial Mg release during the bone regeneration process. In addition the contemporary in situ supply of Sr, an antiosteoporotic and anticarie ion, could influence the quality of new hard tissues. The ionic multirelease created a more favorable environment for human osteoblasts, demonstrated by a proliferative effect for each dose tested in the range 0.1-10 mg/mL. PMID- 23348959 TI - [Benign vocal fold lesions]. AB - Benign vocal fold lesions are grouped in lesions arising from the epithelium like papillomas, lesions affecting the Reinke's space (nodules, polyps, cysts, Reinkes's edema as a form of chronic laryngitis) and lesions affecting the arytenoid (granulomas). A multifactorial genesis is assumed. Main symptoms are dysphonia and hyperfunctional vocal behavior that might also be a cause of these lesions. PMID- 23348960 TI - Prevention and treatment of colon cancer by peroral administration of HAMLET (human alpha-lactalbumin made lethal to tumour cells). AB - BACKGROUND: Most colon cancers start with dysregulated Wnt/beta-catenin signalling and remain a major therapeutic challenge. Examining whether HAMLET (human alpha-lactalbumin made lethal to tumour cells) may be used for colon cancer treatment is logical, based on the properties of the complex and its biological context. OBJECTIVE: To investigate if HAMLET can be used for colon cancer treatment and prevention. Apc(Min)(/+) mice, which carry mutations relevant to hereditary and sporadic human colorectal tumours, were used as a model for human disease. METHOD: HAMLET was given perorally in therapeutic and prophylactic regimens. Tumour burden and animal survival of HAMLET-treated and sham-fed mice were compared. Tissue analysis focused on Wnt/beta-catenin signalling, proliferation markers and gene expression, using microarrays, immunoblotting, immunohistochemistry and ELISA. Confocal microscopy, reporter assay, immunoprecipitation, immunoblotting, ion flux assays and holographic imaging were used to determine effects on colon cancer cells. RESULTS: Peroral HAMLET administration reduced tumour progression and mortality in Apc(Min)(/+) mice. HAMLET accumulated specifically in tumour tissue, reduced beta-catenin and related tumour markers. Gene expression analysis detected inhibition of Wnt signalling and a shift to a more differentiated phenotype. In colon cancer cells with APC mutations, HAMLET altered beta-catenin integrity and localisation through an ion channel-dependent pathway, defining a new mechanism for controlling beta-catenin signalling. Remarkably, supplying HAMLET to the drinking water from the time of weaning also significantly prevented tumour development. CONCLUSIONS: These data identify HAMLET as a new, peroral agent for colon cancer prevention and treatment, especially needed in people carrying APC mutations, where colon cancer remains a leading cause of death. PMID- 23348961 TI - Yin Yang 1 promotes hepatic steatosis through repression of farnesoid X receptor in obese mice. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is characterised by accumulation of excessive triglycerides in the liver. Obesity is usually associated with NAFLD through an unknown mechanism. OBJECTIVE: To investigate the roles of Yin Yang 1 (YY1) in the progression of obesity-associated hepatosteatosis. METHODS: Expression levels of hepatic YY1 were identified by microarray analysis in high-fat-diet (HFD)-induced obese mice. Liver triglyceride metabolism was analysed in mice with YY1 overexpression and suppression. RESULTS: YY1 expression was markedly upregulated in HFD-induced obese mice and NAFLD patients. Overexpression of YY1 in healthy mice promoted hepatosteatosis under high-fat dietary conditions, whereas liver-specific ablation of YY1 using adenoviral shRNA ameliorated triglyceride accumulation in obese mice. At the molecular level, YY1 suppressed farnesoid X receptor (FXR) expression through binding to the YY1 responsive element at intron 1 of the FXR gene. CONCLUSIONS: These findings indicate that YY1 plays a crucial role in obesity-associated hepatosteatosis, through repression of FXR expression. PMID- 23348962 TI - Bacterial lipopolyshaccaride inhibits CB2 receptor expression in human monocytic cells. PMID- 23348963 TI - Validation of an interventional pulmonary examination. AB - BACKGROUND: Interventional pulmonology (IP) is an emerging subspecialty with a dedicated 12 months of additional training after traditional pulmonary and critical care fellowships with fellowships across the country. A multiple-choice question (MCQ) examination was developed to measure didactic knowledge acquired in IP fellowships. METHODS: Interventional pulmonologists from 10 academic centers developed a MCQ-based examination on a proposed curriculum for IP fellowships. The 75 multiple-choice question examination was proctored, time limited (120 min), and computer-based. The examination was administered to IP faculty, IP fellows in their last month of fellowship, graduating pulmonary and critical care fellows in their last month of training, and incoming first-year pulmonary and critical care fellows. RESULTS: The mean score for IP faculty was 87% (range, 83%-94%), 74% for IP fellows (range, 61%-81%, SD 5.09, median 76%), 62% for graduating pulmonary and critical care fellows (range 52% to 73%), and 50% for incoming pulmonary/critical care fellows (range, 35%-65%). There was a graduated increase in mean scores with level of IP training. Scores differed significantly across the four groups (P = .001). CONCLUSION: A validated MCQ examination can measure IP knowledge. There is a difference in IP knowledge based on IP training exposure. PMID- 23348964 TI - Neural responses to visual food cues: insights from functional magnetic resonance imaging. AB - The aim of this paper is to describe the patterns of functional magnetic resonance imaging activation produced by visual food stimuli in healthy participants, as well as in those with anorexia nervosa, bulimia nervosa, binge eating disorder and obesity. We conducted a systematic review of studies published in the last decade on normal and abnormal eating. This review suggested the existence of neural differences in response to the sight of food between healthy individuals, those with an eating disorder and obese subjects. Differences were identified in two brain circuits: (i) limbic and paralimbic areas associated with salience and reward processes and (ii) prefrontal areas supporting cognitive control processes. PMID- 23348965 TI - A conditional two-hybrid (C2H) system for the detection of protein-protein interactions that are mediated by post-translational modification. AB - The original bacterial two-hybrid system is widely used but does not permit the study of interactions regulated by PTMs. Here, we have built a conditional two hybrid (C2H) system, in which bait and prey proteins can be co-expressed in the presence of a modifying enzyme such as a methyltransferase, acetyltransferase, or kinase. Any increase or decrease in interaction due to the modification of the proteins can be measured by an increased or decreased level of reporter gene expression. The C2H system is comprised of eight new vectors based on the Novagen Duet co-expression plasmids. These vectors include two multiple cloning sites per vector as well as a hexahistidine tag or S-tag to aid in purification, if desired. We demonstrate the use of the C2H system to study the dimerization of the yeast protein Npl3, which is increased when methylated by the methyltransferase Hmt1. PMID- 23348966 TI - Cis association of leukocyte Ig-like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18. AB - Leukocyte Ig-like receptor (LIR) 1 (CD85j/ILT2/LILRB1) is an inhibitory receptor with broad specificity for MHC class I (MHC-I) and the human CMV MHC-I homologue UL18. LIR-1 can inhibit NK cells through the conventional interaction with MHC-I expressed on a target cell (in trans) but the nature and the effects of LIR-1 interactions with MHC-I in cis are not well understood. Here we show that MHC-I expressed in cis has an impact on the detection of LIR-1 with various antibodies. We found the cis interaction alters recognition by only one of two antibodies known to block functional trans recognition by LIR-1 on NK cells. Specifically, we observed an enhancement of recognition with GHI/75 in the presence of various MHC-I alleles on 721.221 cells. We found that blocking the LIR-1 contact site with anti-MHC-I antibodies decreased detection of LIR-1 with GHI/75. We also observed a decrease in GHI/75 following acid denaturation of MHC-I. Finally, disruption of LIR-1 cis interactions with MHC-I significantly enhanced UL18-Fc binding to NK92 cells and enhanced the relative inhibition of NK92 cells by HLA G. These results have implications for LIR-1 function in scenarios such as infection when MHC-I levels on effector cells may be increased by IFNs. PMID- 23348967 TI - The classification of personality disorders in ICD-11: implications for forensic psychiatry. PMID- 23348968 TI - Race/Ethnicity, nativity, and tobacco use among US young adults: results from a nationally representative survey. AB - INTRODUCTION: A growing body of research documents racial/ethnic disparities in U.S. cigarette smoking. To date, however, few studies have examined the influence of nativity, in addition to race/ethnicity, on current and ever use of cigarettes as well as other tobacco products among young adults. Here, racial/ethnic and nativity disparities in tobacco use and self-identified smoking status are documented for U.S. women and men aged 18-34, both unadjusted and adjusted for socioeconomic status. METHODS: The Legacy Young Adult Cohort Study (N = 3,696) was used to examine gender-specific tobacco use and smoking status differences among foreign-born Hispanics, U.S.-born Hispanics, U.S.-born non-Hispanic Blacks, and U.S.-born non-Hispanic Whites. Prevalence estimates and multivariable models of ever tobacco use, current tobacco use, and self-identified smoking status were calculated. RESULTS: U.S.-born Hispanics, Blacks, and Whites exhibit the highest levels of ever and current use across a range of tobacco products, whereas foreign-born Hispanics, particularly women, exhibit the lowest ever and current use of most products and are least likely to describe themselves as smokers. Controlling for socioeconomic covariates, current tobacco use is generally lower for most minority groups relative to Whites. Social or occasional smoking, however, is higher among U.S.-born Hispanics and Blacks. CONCLUSIONS: The high level of tobacco use among U.S.-born young adults foreshadows substantial tobacco related morbidity and mortality in the coming decades. Foreign-born Hispanic young adults, particularly women, exhibit the lowest levels of tobacco use. Future studies of tobacco use must differentiate racial/ethnic groups by nativity to better understand patterns of tobacco use. PMID- 23348969 TI - Pilot RCT results of stop my smoking USA: a text messaging-based smoking cessation program for young adults. AB - INTRODUCTION: To address the lack of smoking cessation programs available to young adults, Stop My Smoking (SMS) USA, a text messaging-based smoking cessation program, was developed and pilot tested. METHODS: This was a two-arm randomized controlled trial with adaptive randomization (arms were balanced by sex and smoking level [heavy vs. light]), conducted nationally in the United States. One hundred sixty-four 18- to 25-year-old daily smokers who were seriously thinking about quitting in the next 30 days were randomized to either (a) the 6-week SMS USA intervention (n = 101) or (b) an attention-matched control group aimed at improving sleep and physical activity (n = 63). The main outcome measure was 3 month continuous abstinence, verified by a significant other. Participants but not researchers were blinded to study arm allocation. RESULTS: Based upon intent to-treat analyses, intervention participants (39%) were significantly more likely than control participants (21%) to have quit at 4 weeks postquit (adjusted odds ratio [aOR] = 3.33, 95% confidence interval [CI]: 1.48, 7.45). Findings were not sustained at 3 months postquit, although rates in the SMS USA group were favored (40% vs. 30%, respectively; aOR = 1.59, 95% CI: 0.78, 3.21). Subsequent analyses suggested that among intervention participants, SMS USA might be more influential for youth not currently enrolled in a higher education (p = .06). CONCLUSIONS: Consistent with pilot studies, the sample was underpowered. Data suggest, however, that the SMS USA program affects smoking cessation rates at 4 weeks postquit. More research is needed before conclusions can be made about long-term impact. Identifying profiles of users for whom the program may be particularly beneficial also will be important. PMID- 23348970 TI - Efficient approximate k-fold and leave-one-out cross-validation for ridge regression. AB - In model building and model evaluation, cross-validation is a frequently used resampling method. Unfortunately, this method can be quite time consuming. In this article, we discuss an approximation method that is much faster and can be used in generalized linear models and Cox' proportional hazards model with a ridge penalty term. Our approximation method is based on a Taylor expansion around the estimate of the full model. In this way, all cross-validated estimates are approximated without refitting the model. The tuning parameter can now be chosen based on these approximations and can be optimized in less time. The method is most accurate when approximating leave-one-out cross-validation results for large data sets which is originally the most computationally demanding situation. In order to demonstrate the method's performance, it will be applied to several microarray data sets. An R package penalized, which implements the method, is available on CRAN. PMID- 23348971 TI - Familial risk of venous thromboembolism in first-, second- and third-degree relatives: a nationwide family study in Sweden. AB - Venous thromboembolism (VTE) clusters in families, but the familial risk of VTE has only been determined in first-degree relatives. This nationwide study aimed to determine the familial risk of VTE in first-, second- and third-degree relatives of affected individuals. The Swedish Multi-Generation Register was linked to Hospital Discharge Register data for the period 1987-2009. This was a case-cohort study. Odds ratios (ORs) for VTE were calculated for individuals whose relatives were hospitalised for VTE, as determined by the International Classification of Diseases (ICD), and those whose relatives were unaffected by VTE. The familial OR for VTE was 2.49 in siblings (95% confidence interval [CI] 2.40-2.58), 2.65 in children (2.50-2.80), 2.09 in parents (2.03-2.15), 1.52 in maternal half-siblings (1.26-1.85), 2.34 in paternal half-siblings (2.00-2.73), 1.69 in nieces/nephews (1.57-1.82), 1.47 in cousins (1.33-1.64), and 1.14 in spouses of individuals diagnosed with VTE (1.09-1.18). Familial clustering was stronger at young ages. The familial transmission was slightly stronger for males compared with females but was only significant for siblings 1.13 (1.05-1.22) and parents 1.11 (1.05-1.78) of probands. The present data showing an increased VTE risk among not only first-degree relatives but also second- and third-degree relatives indicate that the genetic component of the familial clustering of VTE is strong. Family history is a potentially useful genetic surrogate marker for clinical VTE risk assessment, even in second- and third degree-relatives. PMID- 23348973 TI - beta2-agonist therapy in lung disease. AB - beta2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of beta2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between beta2-agonists. Traditional inhaled short acting beta2-agonists albuterol, fenoterol, and terbutaline provide rapid as needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily beta2 agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer beta2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, beta2-agonists have an acceptable safety profile, although there is still controversy as to whether long acting beta2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of beta2-adrenoceptors that occurs during the first few days of regular use of beta2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of beta2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily beta2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID- 23348972 TI - Lung microbiota and bacterial abundance in patients with bronchiectasis when clinically stable and during exacerbation. AB - RATIONALE: Characterization of bacterial populations in infectious respiratory diseases will provide improved understanding of the relationship between the lung microbiota, disease pathogenesis, and treatment outcomes. OBJECTIVES: To comprehensively define lung microbiota composition during stable disease and exacerbation in patients with bronchiectasis. METHODS: Sputum was collected from patients when clinically stable and before and after completion of antibiotic treatment of exacerbations. Bacterial abundance and community composition were analyzed using anaerobic culture and 16S rDNA pyrosequencing. MEASUREMENTS AND MAIN RESULTS: In clinically stable patients, aerobic and anaerobic bacteria were detected in 40 of 40 (100%) and 33 of 40 (83%) sputum samples, respectively. The dominant organisms cultured were Pseudomonas aeruginosa (n = 10 patients), Haemophilus influenzae (n = 12), Prevotella (n = 18), and Veillonella (n = 13). Pyrosequencing generated more than 150,000 sequences, representing 113 distinct microbial taxa; the majority of observed community richness resulted from taxa present in low abundance with similar patterns of phyla distribution in clinically stable patients and patients at the onset of exacerbation. After treatment of exacerbation, there was no change in total (P = 0.925), aerobic (P = 0.917), or anaerobic (P = 0.683) load and only a limited shift in community composition. Agreement for detection of bacteria by culture and pyrosequencing was good for aerobic bacteria such as P. aeruginosa (kappa = 0.84) but poorer for other genera including anaerobes. Lack of agreement was largely due to bacteria being detected by pyrosequencing but not by culture. CONCLUSIONS: A complex microbiota is present in the lungs of patients with bronchiectasis and remains stable through treatment of exacerbations, suggesting that changes in microbiota composition do not account for exacerbations. PMID- 23348974 TI - Effects of prone positioning on lung protection in patients with acute respiratory distress syndrome. AB - RATIONALE: Positive end-expiratory pressure (PEEP) and prone positioning may induce lung recruitment and affect alveolar dynamics in acute respiratory distress syndrome (ARDS). Whether there is interdependence between the effects of PEEP and prone positioning on these variables is unknown. OBJECTIVES: To determine the effects of high PEEP and prone positioning on lung recruitment, cyclic recruitment/derecruitment, and tidal hyperinflation and how these effects are influenced by lung recruitability. METHODS: Mechanically ventilated patients (Vt 6 ml/kg ideal body weight) underwent whole-lung computed tomography (CT) during breath-holding sessions at airway pressures of 5, 15, and 45 cm H2O and Cine-CTs on a fixed thoracic transverse slice at PEEP 5 and 15 cm H2O. CT images were repeated in supine and prone positioning. A recruitment maneuver at 45 cm H2O was performed before each PEEP change. Lung recruitability was defined as the difference in percentage of nonaerated tissue between 5 and 45 cm H2O. Cyclic recruitment/de-recruitment and tidal hyperinflation were determined as tidal changes in percentage of nonaerated and hyperinflated tissue, respectively. MEASUREMENTS AND MAIN RESULTS: Twenty-four patients with ARDS were included. Increasing PEEP from 5 to 15 cm H2O decreased nonaerated tissue (501 +/- 201 to 322 +/- 132 grams; P < 0.001) and increased tidal-hyperinflation (0.41 +/- 0.26 to 0.57 +/- 0.30%; P = 0.004) in supine. Prone positioning further decreased nonaerated tissue (322 +/- 132 to 290 +/- 141 grams; P = 0.028) and reduced tidal hyperinflation observed at PEEP 15 in supine patients (0.57 +/- 0.30 to 0.41 +/- 0.22%). Cyclic recruitment/de-recruitment only decreased when high PEEP and prone positioning were applied together (4.1 +/- 1.9 to 2.9 +/- 0.9%; P = 0.003), particularly in patients with high lung recruitability. CONCLUSIONS: Prone positioning enhances lung recruitment and decreases alveolar instability and hyperinflation observed at high PEEP in patients with ARDS. PMID- 23348975 TI - Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. AB - RATIONALE: The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined. OBJECTIVES: To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death. METHODS: Light and electron microscopy and immunohistochemical staining for markers of cellular injury and stress, including connexin-43 and kidney-injury-molecule-1 (Kim-1), were used in this study. MEASUREMENTS AND MAIN RESULTS: Rapid postmortem cardiac and renal harvest was performed in 44 septic patients. Control hearts were obtained from 12 transplant and 13 brain-dead patients. Control kidneys were obtained from 20 trauma patients and eight patients with cancer. Immunohistochemistry demonstrated low levels of apoptotic cardiomyocytes (<1-2 cells per thousand) in septic and control subjects and revealed redistribution of connexin-43 to lateral membranes in sepsis (P < 0.020). Electron microscopy showed hydropic mitochondria only in septic specimens, whereas mitochondrial membrane injury and autophagolysosomes were present equally in control and septic specimens. Control kidneys appeared relatively normal by light microscopy; 3 of 20 specimens showed focal injury in approximately 1% of renal cortical tubules. Conversely, focal acute tubular injury was present in 78% of septic kidneys, occurring in 10.3 +/- 9.5% and 32.3 +/- 17.8% of corticomedullary-junction tubules by conventional light microscopy and Kim-1 immunostains, respectively (P < 0.01). Electron microscopy revealed increased tubular injury in sepsis, including hydropic mitochondria and increased autophagosomes. CONCLUSIONS: Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs. Renal tubular injury is common in sepsis but presents focally; most renal tubular cells appear normal. The degree of cell injury and death does not account for severity of sepsis-induced organ dysfunction. PMID- 23348976 TI - Exercise-induced pulmonary hypertension: physiological basis and methodological concerns. AB - Exercise stresses the pulmonary circulation through increases in cardiac output (.Q) and left atrial pressure. Invasive as well as noninvasive studies in healthy volunteers show that the slope of mean pulmonary artery pressure (mPAP)-flow relationships ranges from 0.5 to 3 mm Hg.min.L(-1). The upper limit of normal mPAP at exercise thus approximates 30 mm Hg at a .Q of less than 10 L.min(-1) or a total pulmonary vascular resistance at exercise of less than 3 Wood units. Left atrial pressure increases at exercise with an average upstream transmission to PAP in a close to one-for-one mm Hg fashion. Multipoint PAP-flow relationships are usually described by a linear approximation, but present with a slight curvilinearity, which is explained by resistive vessel distensibility. When mPAP is expressed as a function of oxygen uptake or workload, plateau patterns may be observed in patients with systolic heart failure who cannot further increase .Q at the highest levels of exercise. Exercise has to be dynamic to avoid the increase in systemic vascular resistance and abrupt changes in intrathoracic pressure that occur with resistive exercise and can lead to unpredictable effects on the pulmonary circulation. Postexercise measurements are unreliable because of the rapid return of pulmonary vascular pressures and flows to the baseline resting state. Recent studies suggest that exercise-induced increase in PAP to a mean higher than 30 mm Hg may be associated with dyspnea-fatigue symptomatology. PMID- 23348977 TI - Characteristics of lung cancers detected by computer tomography screening in the randomized NELSON trial. AB - RATIONALE: The NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek) trial is, with 15,822 participants, the largest European lung cancer computer tomography screening trial. A volumetry-based screening strategy, stringent criteria for a positive screening, and an increasing length of screening interval are particular features of the NELSON trial. OBJECTIVES: To determine the effect of stringent referral criteria and increasing screening interval on the characteristics of screen-detected lung cancers, and to compare this across screening rounds, between sexes, and with other screening trials. METHODS: All NELSON participants with screen-detected lung cancer in the first three rounds were included. Lung cancer stage at diagnosis, histological subtype, and tumor localization were compared between the screening rounds, the sexes, and with other screening trials. MEASUREMENTS AND MAIN RESULTS: In the first three screening rounds, 200 participants were diagnosed with 209 lung cancers. Of these lung cancers, 70.8% were diagnosed at stage I and 8.1% at stage IIIB-IV, and 51.2% were adenocarcinomas. There was no significant difference in cancer stage, histology, or tumor localization across the screening rounds. Women were diagnosed at a significantly more favorable cancer stage than men. Compared with other trials, the screen-detected lung cancers of the NELSON trial were relatively more often diagnosed at stage I and less often at stage IIIB-IV. CONCLUSIONS: Despite stringent criteria for a positive screening, an increasing length of screening interval, and few female participants, the screening strategy of the NELSON trial resulted in a favorable cancer stage distribution at diagnosis, which is essential for the effectiveness of our screening strategy. Clinical trial registered with www.trialregister.nl (ISRCTN63545820). PMID- 23348978 TI - Hemodynamic predictors of mortality in adults with sickle cell disease. AB - BACKGROUND: Pulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality, but no prior studies have evaluated quantitative relationships of mortality to physiological measures of pre- and postcapillary PH. OBJECTIVES: To identify risk factors associated with mortality and to estimate the expected survival in a cohort of patients with SCD with PH documented by right heart catheterization. METHODS: Nine-year follow-up data (median, 4.7 yr) from the National Institutes of Health SCD PH screening study are reported. A total of 529 adults with SCD were screened by echocardiography between 2001 and 2010 with no exclusion criteria. Hemodynamic data were collected from 84 patients. PH was defined as mean pulmonary artery pressure (PAP) >= 25 mm Hg. Survival rates were estimated by the Kaplan-Meier method, and mortality risk factors were analyzed by the Cox proportional hazards regression. MEASUREMENTS AND MAIN RESULTS: Specific hemodynamic variables were independently related to mortality: mean PAP (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.05 2.45 per 10 mm Hg increase; P = 0.027), diastolic PAP (HR, 1.83; 95% CI, 1.09 3.08 per 10 mm Hg increase; P = 0.022), diastolic PAP - pulmonary capillary wedge pressure (HR, 2.19; 95% CI, 1.23-3.89 per 10 mm Hg increase; P = 0.008), transpulmonary gradient (HR, 1.78; 95% CI, 1.14-2.79 per 10 mm Hg increase; P = 0.011), and pulmonary vascular resistance (HR, 1.44; 95% CI, 1.09-1.89 per Wood unit increase; P = 0.009) as risk factors for mortality. CONCLUSIONS: Mortality in adults with SCD and PH is proportional to the physiological severity of precapillary PH, demonstrating its prognostic and clinical relevance despite anemia-induced high cardiac output and less severely elevated pulmonary vascular resistance. PMID- 23348979 TI - Early identification of patients at risk for difficult intubation in the intensive care unit: development and validation of the MACOCHA score in a multicenter cohort study. AB - RATIONALE: Difficult intubation in the intensive care unit (ICU) is a challenging issue. OBJECTIVES: To develop and validate a simplified score for identifying patients with difficult intubation in the ICU and to report related complications. METHODS: Data collected in a prospective multicenter study from 1,000 consecutive intubations from 42 ICUs were used to develop a simplified score of difficult intubation, which was then validated externally in 400 consecutive intubation procedures from 18 other ICUs and internally by bootstrap on 1,000 iterations. MEASUREMENTS AND MAIN RESULTS: In multivariate analysis, the main predictors of difficult intubation (incidence = 11.3%) were related to patient (Mallampati score III or IV, obstructive sleep apnea syndrome, reduced mobility of cervical spine, limited mouth opening); pathology (severe hypoxia, coma); and operator (nonanesthesiologist). From the beta parameter, a seven-item simplified score (MACOCHA score) was built, with an area under the curve (AUC) of 0.89 (95% confidence interval [CI], 0.85-0.94). In the validation cohort (prevalence of difficult intubation = 8%), the AUC was 0.86 (95% CI, 0.76-0.96), with a sensitivity of 73%, a specificity of 89%, a negative predictive value of 98%, and a positive predictive value of 36%. After internal validation by bootstrap, the AUC was 0.89 (95% CI, 0.86-0.93). Severe life-threatening events (severe hypoxia, collapse, cardiac arrest, or death) occurred in 38% of the 1,000 cases. Patients with difficult intubation (n = 113) had significantly higher severe life-threatening complications than those who had a nondifficult intubation (51% vs. 36%; P < 0.0001). CONCLUSIONS: Difficult intubation in the ICU is strongly associated with severe life-threatening complications. A simple score including seven clinical items discriminates difficult and nondifficult intubation in the ICU. Clinical trial registered with www.clinicaltrials.gov (NCT 01532063). PMID- 23348981 TI - Effect of glutamine supplementation on neutrophil function in male judoists. AB - Glutamine is an important amino acid for immune function. Though high intensity and prolonged exercise decreases plasma glutamine concentration and causes immune suppression, the relationship between neutrophil functions and glutamine has not yet been found. The purpose of this study was to investigate the impacts of glutamine supplementation on neutrophil function. Twenty-six male university judoists were recruited. Subjects were classified into glutamine and control groups. The glutamine group ingested 3000 mg of glutamine per day and the control group ingested placebo for 2 weeks. Examinations were performed at the start of preunified loading exercise (pre-ULE), then 1 and 2 weeks after ULE (post-ULE). Reactive oxygen species (ROS) production, phagocytic activity, serum opsonic activity and serum myogenic enzymes were measured. Differences between the levels obtained in pre-ULE and post-ULE for the two groups were compared. In the glutamine group, ROS production activity increased 1 week after ULE, whereas it was not observed in the control group (P < 0.001). Though myogenic enzymes increased significantly after ULE (P < 0.001), the glutamine group remained unchanged by supplementation during ULE. Glutamine supplementation has prevented excessive muscle damage and suppression of neutrophil function, especially in ROS production activity, even during an intensive training period. PMID- 23348982 TI - Emotional mimicry as social regulation. AB - Emotional mimicry is the imitation of the emotional expressions of others. According to the classic view on emotional mimicry (the Matched Motor Hypothesis), people mimic the specific facial movements that comprise a discrete emotional expression. However, little evidence exists for the mimicry of discrete emotions; rather, the extant evidence supports only valence-based mimicry. We propose an alternative Emotion Mimicry in Context view according to which emotional mimicry is not based on mere perception but rather on the interpretation of signals as emotional intentions in a specific context. We present evidence for the idea that people mimic contextualized emotions rather than simply expressive muscle movements. Our model postulates that (implicit or explicit) contextual information is needed for emotional mimicry to take place. It takes into account the relationship between observer and expresser, and suggests that emotional mimicry depends on this relationship and functions as a social regulator. PMID- 23348980 TI - A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis. AB - RATIONALE: Observational studies link statin therapy with improved outcomes in patients with severe sepsis. OBJECTIVES: To test whether atorvastatin therapy affects biologic and clinical outcomes in critically ill patients with severe sepsis. METHODS: Phase II, multicenter, prospective, randomized, double-blind, placebo-controlled trial stratified by site and prior statin use. A cohort of 250 critically ill patients (123 statins, 127 placebo) with severe sepsis were administrated either atorvastatin (20 mg daily) or matched placebo. MEASUREMENTS AND MAIN RESULTS: There was no difference in IL-6 concentrations (primary end point) between the atorvastatin and placebo groups (P = 0.76) and no interaction between treatment group and time to suggest that the groups behaved differently over time (P = 0.26). Baseline plasma IL-6 was lower among previous statin users (129 [87-191] vs. 244 [187-317] pg/ml; P = 0.01). There was no difference in length of stay, change in Sequential Organ Failure Assessment scores or mortality at intensive care unit discharge, hospital discharge, 28- or 90-day (15% vs. 19%), or adverse effects between the two groups. Cholesterol was lower in patients treated with atorvastatin (2.4 [0.07] vs. 2.6 [0.06] mmol/L; P = 0.006). In the predefined group of 77 prior statin users, those randomized to placebo had a greater 28-day mortality (28% vs. 5%; P = 0.01) compared with those who received atorvastatin. The difference was not statistically significant at 90 days (28% vs. 11%; P = 0.06). CONCLUSIONS: Atorvastatin therapy in severe sepsis did not affect IL-6 levels. Prior statin use was associated with a lower baseline IL-6 concentration and continuation of atorvastatin in this cohort was associated with improved survival. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12607000028404). PMID- 23348983 TI - The social distance theory of power. AB - We propose that asymmetric dependence between individuals (i.e., power) produces asymmetric social distance, with high-power individuals feeling more distant than low-power individuals. From this insight, we articulate predictions about how power affects (a) social comparison, (b) susceptibility to influence, (c) mental state inference and responsiveness, and (d) emotions. We then explain how high power individuals' greater experienced social distance leads them to engage in more abstract mental representation. This mediating process of construal level generates predictions about how power affects (a) goal selection and pursuit, (b) attention to desirability and feasibility concerns, (c) subjective certainty, (d) value-behavior correspondence, (e) self-control, and (f) person perception. We also reassess the approach/inhibition theory of power, noting limitations both in what it can predict and in the evidence directly supporting its proposed mechanisms. Finally, we discuss moderators and methodological recommendations for the study of power from a social distance perspective. PMID- 23348987 TI - Might diet play a role in autism?: research explores genetic mutations behind nutritional deficiencies linked to the disorder. PMID- 23348984 TI - MR imaging of the yucatan pig head and neck vasculature. AB - PURPOSE: To evaluate the cerebral venous drainage system of the swine as a probable model to test whether extracranial venous abnormalities may play a role in neurodegenerative diseases as reported recently in multiple sclerosis. MATERIALS AND METHODS: Three Yucatan micropigs, 5 to 7 months old, were scanned with a comprehensive MRI protocol at 3 Tesla. The vascular anatomy of the head and neck was imaged using conventional and angiographic MR sequences. Phase contrast MR images were collected at multiple levels of the neck and intracranial space to monitor flow. RESULTS: Three large cervical veins were observed; the external jugular vein draining the olfactory and gustatory tissues; the internal jugular vein (IJV) draining the cavernous sinus as well as surrounding soft tissues in the neck; and the ventral vertebral venous plexus (VVVP) surrounding the dural sac and paraspinal region. The majority of the cerebral blood flow in the pig appears to drain through the VVVP. Flow through the IJV comprised a nondominant component. Anastamoses were observed connecting the major veins of the neck bilaterally. CONCLUSION: The dominance of outflow from the brain to the VVVP may be analogous to the typical dominance of the IJVs in humans in the supine position. PMID- 23348988 TI - Experimental therapy for neurofibromatosis I shows promise: cancer drug shrinks some plexiform neuromas. PMID- 23348990 TI - Case studies of the synthesis of bioactive cyclodepsipeptide natural products. AB - Cyclodepsipeptide natural products often display intriguing biological activities that along with their complex molecular scaffolds, makes them interesting targets for chemical synthesis. Although cyclodepsipeptides feature highly diverse chemical structures, their synthesis is often associated with similar synthetic challenges such as the establishment of a suitable macrocyclization methodology. This review therefore compiles case studies of synthetic approaches to different bioactive cyclodepsipeptide natural products, thereby illustrating obstacles of cyclodepsipeptide synthesis as well as their overcomings. PMID- 23348991 TI - Profiling and characterization of volatile components from non-fumigated and sulfur-fumigated Flos Lonicerae Japonicae using comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry coupled with chemical group separation. AB - Flos Lonicerae Japonicae (FLJ) is a popular herb used for many centuries in Traditional Chinese Medicine as a treatment of fever and inflammation. Non fumigated processing of FLJ has been the traditional approach used in post harvest preparation of the commodity for commercial use. However, in recent years, natural drying processing of FLJ has been replaced by sulfur-fumigation for efficiency and pest control. Sulfur-fumigation can induce changes in the volatile compounds of the herb, altering its medicinal properties. A comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC*GC-TOF/MS) method was established for the resolution and determination of volatile components in non-fumigated and sulfur-fumigated FLJ. In this paper, analysis of the volatile oils in non-fumigated and sulfur-fumigated (including lab-prepared sulfur-fumigated and industrial sulfur-fumigated) FLJ was performed using GC*GC-TOF/MS. Seventy-three representative volatile components were identified, including furans, alkalies, acids, aldehydes, ketones, alcohols, terpenes, esters, and others, as the main components of FLJ volatile oils. The proposed method was successfully applied for rapid and accurate quality evaluation of FLJ and its related medicinal materials and preparations. PMID- 23348992 TI - Antioxidants improve the phenotypes of dilated cardiomyopathy and muscle fatigue in mitochondrial superoxide dismutase-deficient mice. AB - Redox imbalance elevates the reactive oxygen species (ROS) level in cells and promotes age-related diseases. Superoxide dismutases (SODs) are antioxidative enzymes that catalyze the degradation of ROS. There are three SOD isoforms: SOD1/CuZn-SOD, SOD2/Mn-SOD, and SOD3/EC-SOD. SOD2, which is localized in the mitochondria, is an essential enzyme required for mouse survival, and systemic knockout causes neonatal lethality in mice. To investigate the physiological function of SOD2 in adult mice, we generated a conditional Sod2 knockout mouse using a Cre-loxP system. When Sod2 was specifically deleted in the heart and muscle, all mice exhibited dilated cardiomyopathy (DCM) and died by six months of age. On the other hand, when Sod2 was specifically deleted in the skeletal muscle, mice showed severe exercise disturbance without morphological abnormalities. These provide useful model of DCM and muscle fatigue. In this review, we summarize the impact of antioxidants, which were able to regulate mitochondrial superoxide generation and improve the phenotypes of the DCM and the muscle fatigue in mice. PMID- 23348993 TI - Synthesis and structure-activity relationships of novel amino/nitro substituted 3-arylcoumarins as antibacterial agents. AB - A new series of amino/nitro-substituted 3-arylcoumarins were synthesized and their antibacterial activity against clinical isolates of Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) was evaluated. Some of these molecules exhibited antibacterial activity against S. aureus comparable to the standards used (oxolinic acid and ampicillin). The preliminary structure-activity relationship (SAR) study showed that the antibacterial activity against S. aureus depends on the position of the 3-arylcoumarin substitution pattern. With the aim of finding the structural features for the antibacterial activity and selectivity, in the present manuscript different positions of nitro, methyl, methoxy, amino and bromo substituents on the 3-arylcoumarin scaffold were reported. PMID- 23348994 TI - Cytotoxic and radical scavenging nor-dammarane triterpenoids from Viburnum mongolicum. AB - The ethanol extract of the whole plants of Viburnum mongolicum afforded six new nor-dammarane triterpenoids: 3beta,12beta-dihydroxy-25,26,27-trinordammara-22-en 24,20-olide (1), 3beta,12beta-dihydroxy-24alpha-methoxy-25,26,27-trinordammara 20,24-epoxy (2), 3beta-O-acetyl-12beta-hydroxy-23,24,25,26,27-hexanordammarane-20 one (3), 12beta-O- acetyl-15alpha-hydroxy-17beta-methoxy-3-oxo-20,21,22 23,24,25,26,27-octanordammanrane (4), 12beta-O-acetyl-15alpha,17beta-dihydroxy-3 oxo-20,21,22-23,24,25,26,27-octanordammanrane (5), and 12beta,15alpha-dihydroxy-3 oxo-17-en-20,21,22-23,24,25,26,27-octanordammanrane (6), together with two known nor-dammarane triterpenoids, 12beta-hydroxy-3-oxo-24alpha-methoxy- 25,26,27 trinordammara-20,24-epoxy (7) and 3beta,12beta-dihydroxy-23,24,25,26,27- hexanordammarane-20-one (8). The structures of the isolated compounds were established based on 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated compounds were tested in vitro for cytotoxic potential against seven tumor cell lines and radical scavenging activities. Compounds 4-6 exhibited significant cytotoxic activities against all tested tumor cell lines and radical scavenging activities against ABTS.+ radicals comparable with the standard drug Trolox. PMID- 23348995 TI - Induction of apoptosis by costunolide in bladder cancer cells is mediated through ROS generation and mitochondrial dysfunction. AB - Despite the availability of several therapeutic options, a safer and more effective modality is urgently needed for treatment of bladder cancer. Costunolide, a member of sesquiterpene lactone family, possesses potent anticancer properties. In this study, for the first time we investigated the effects of costunolide on the cell viability and apoptosis in human bladder cancer T24 cells. Treatment of T24 cells with costunolide resulted in a dose dependent inhibition of cell viability and induction of apoptosis which was associated with the generation of ROS and disruption of mitochondrial membrane potential (Deltapsim). These effects were significantly blocked when the cells were pretreated with N-acetyl- cysteine (NAC), a specific ROS inhibitor. Exposure of T24 cells to costunolide was also associated with increased expression of Bax, down-regulation of Bcl-2, survivin and significant activation of caspase-3, and its downstream target PARP. These findings provide the rationale for further in vivo and clinical investigation of costunolide against human bladder cancer. PMID- 23348996 TI - Cytotoxicity and anti-inflammatory activity of methylsulfanyl triazoloquinazolines. AB - A series of twenty five 2-methylsulfanyl-[1,2,4]triazolo[1,5-a]quinazoline derivatives 1-25 was previously synthesized. We have now investigated their cytotoxic effects against hepatocellular Hep-G2 and colon HCT-116 carcinoma cells and effect on the macrophage growth, in addition to their influence of the inflammatory mediators [nitric oxide (NO), tumor necrosis factor-alpha (TNF alpha), prostaglandin E-2 (PGE-2) and in bacterial lipopolysachharide (LPS) stimulated macrophages]. The findings revealed that compounds 13 and 17 showed the highest cytotoxicity and that 3, 6-8 and 25 are promising multi-potent anti inflammatory agents. PMID- 23348997 TI - Degradation kinetics of atorvastatin under stress conditions and chemical analysis by HPLC. AB - Atorvastatin is an antilipemic drug belonging to the statins class, whose reference drug is Pfizer's Lipitor(r). It is used to reduce the levels of lipoproteins rich in cholesterol and reduce the risk of coronary artery disease. It is well-known that calcium atorvastatin (ATV), C66H68CaF2N4O10*3H2O, presents polymorphism. The drug in question is commonly sought after by pharmaceutical industries that produce generic drugs, due to the fact that the drug has a high value price, it is consumed globally, and its patent expired in late 2010. Many questions concerning this drug's pharmaceutical scope demonstrate its importance regarding stability studies and the identification of degradation products of drugs and pharmaceutical formulations. ATV has been found to degrade under acid and basic conditions, including a first order kinetic degradation under acid conditions, as compared to a zero order kinetic degradation under basic conditions, which tends to be less stable when studied within acid mediums. The rate constant (k) for degradation in acid medium was 1.88 * 10-2 s-1 (first order), while for basic medium k = 2.35 * 10-4 mol L-1 s-1 (zero order), demonstrating a lower stability of the drug within acid mediums. PMID- 23348998 TI - Degradation of methyl blue using Fe-tourmaline as a novel photocatalyst. AB - This study investigated the photocatalytic activity of tourmaline by itself. Under irradiation of a 13 W, 254 nm UV lamp, 50% of methyl blue disappeared in the presence of 130 mg.L-1 tourmaline. The reaction was inhibited by the addition of ethanol, Cl-, SO42- and Cu2+, and promoted a little by addition of 50 mg/L Mg2+, which supports the inference of involvement of *OH radicals. This is the first proposal of tourmaline as a single photocatalyst without the need to add any artificial chemical products. Results from this study might contribute to the broadened usage of this mineral to approach the goals of saving energy and eliminate direct or indirect environmental pollution. PMID- 23348999 TI - Crystal structure, antibacterial and cytotoxic activities of a new complex of bismuth(III) with sulfapyridine. AB - A new complex of Bi(III) and sulfapyridine was synthesized and characterized by elemental analysis, atomic absorption spectrometry, conductivity analysis, electrospray ionization mass spectrometry (ESI-MS), infrared spectroscopy, and single crystal X-ray diffraction methods. The antimicrobial and the cytotoxic activities of the compound were investigated. Elemental and conductivity analyses are in accordance to the formulation [BiCl3(C11H11N3O2S)3]. The structure of the complex reveals a distorted octahedral geometry around the bismuth atom, which is bound to three sulfonamidic nitrogens from sulfapyridine, acting as a monodentate ligand, and to three chloride ions. The presence of the compound in solution was confirmed by ESI-MS studies. The complex is 3 times more potent than the ligand against Salmonella typhimurium, 4 times against Staphylococcus aureus, Shigella dysenteriae, and Shigella sonnei and 8 times more potent against Pseudomonas aeruginosa and Escherichia coli. The compound inhibits the growth of chronic myelogenous leukemia cells with an IC50 value of 44 MUM whereas the free ligand has no effect up to 100 MUM. PMID- 23349000 TI - Unintentional role models: links between maternal eating psychopathology and the modelling of eating behaviours. AB - This study explored the relationships between maternal modelling of eating behaviours with reported symptoms of maternal eating psychopathology, anxiety and depression. Mothers (N = 264) with a child aged 1.5 to 8 years completed three self-report measures designed to assess modelling of eating behaviours, eating psychopathology and levels of anxiety and depression. The study found that higher levels of maternal eating psychopathology were positively associated with eating behaviours that were unintentionally modelled by mothers but that maternal eating psychopathology was not associated with more overt/intentional forms of parental modelling. In addition, higher levels of maternal depression were associated with lower levels of both unintentional and intentional forms of maternal modelling, whereas maternal anxiety was not found to correlate with modelling behaviours. This study highlights the possible detrimental influences of maternal mental health in relation to mothers providing their child with a positive parental role model around eating and feeding. PMID- 23349001 TI - Novel hypomyelinating leukoencephalopathy affecting early myelinating structures: clinical course in two brothers. AB - A novel leukoencephalopathy, termed hypomyelinating leukoencephalopathy affecting early myelinating structures (HEMS), was recently described. Here we report on two patients affected by HEMS with a clinical picture characterized by early onset nystagmus and thereafter progressive cerebellar signs and mild spasticity predominantly affecting the legs. In one patient, who has the longest follow-up described to date, we detected a mild worsening of the clinical and neuroradiologic picture after a long period of stability lasting until age 6 years. The most recent magnetic resonance image, performed at the age of 11 years, showed a more severe neuroradiologic picture characterized by involvement of almost the entire supratentorial white matter, with relative sparing of the subcortical fibers. We also provide spectroscopy results, not previously reported in this disorder, that support the idea of a progressive disease course on neuroimaging. Our findings suggest that HEMS patients should undergo a new magnetic resonance imaging evaluation after a certain interval to look for possible progression of the abnormalities. PMID- 23349003 TI - The inhibin B response in male rats treated with a GnRH agonist and an endothelin receptor antagonist. AB - BACKGROUND: This study examined the correlation between Inhibin B and testicular pathology. METHODS: Male Han Wistar rats (approximately 10 weeks old) were administered either vehicle or an endothelin receptor antagonist (ET-An) orally for 28 days or a Gonadotropin Releasing Hormone (GnRH) agonist (GnRH-A) as a subcutaneous implant on day 1. Ten animals/group/time point were killed on days 4, 8, 15, and 29 (controls on days 15 and 29) for testes weights and histopathology. In-life blood samples were taken on days 4, 8, 15, and 29 to measure Inhibin B, Follicle-Stimulating Hormone (FSH), and Lutenising Hormone (LH), and at necropsy for the same hormones plus testosterone. RESULTS: Plasma Inhibin B showed a wide concentration range in controls (group means 76.4-184.2 pg/ml; individual animals 17.8-381 pg/ml). GnRH-A caused decreased testes weights plus degenerative testicular pathology from day 4 with partial recovery by day 29. Statistically significant reductions in Inhibin B were observed at all time points and appeared to track the development and partial recovery of the pathology (generally <50 pg/ml on days 4-15; group mean 92 pg/ml on day 29). ET An produced an increase in testes weights and a nondegenerative lesion of minimal tubular dilatation. There was a trend for lower Inhibin B values (30-50%) at all time points, including on day 4 when tubular dilatation was not yet evident. CONCLUSION: Inhibin B showed a good correlation with testicular pathology for GnRH-A, and following ET-An administration appeared to give a signal that might reflect changes in tubular function in the absence of degenerative pathology. PMID- 23349002 TI - Simultaneous prediction of protein secondary structure and transmembrane spans. AB - Prediction of transmembrane spans and secondary structure from the protein sequence is generally the first step in the structural characterization of (membrane) proteins. Preference of a stretch of amino acids in a protein to form secondary structure and being placed in the membrane are correlated. Nevertheless, current methods predict either secondary structure or individual transmembrane states. We introduce a method that simultaneously predicts the secondary structure and transmembrane spans from the protein sequence. This approach not only eliminates the necessity to create a consensus prediction from possibly contradicting outputs of several predictors but bears the potential to predict conformational switches, i.e., sequence regions that have a high probability to change for example from a coil conformation in solution to an alpha-helical transmembrane state. An artificial neural network was trained on databases of 177 membrane proteins and 6048 soluble proteins. The output is a 3 * 3 dimensional probability matrix for each residue in the sequence that combines three secondary structure types (helix, strand, coil) and three environment types (membrane core, interface, solution). The prediction accuracies are 70.3% for nine possible states, 73.2% for three-state secondary structure prediction, and 94.8% for three-state transmembrane span prediction. These accuracies are comparable to state-of-the-art predictors of secondary structure (e.g., Psipred) or transmembrane placement (e.g., OCTOPUS). The method is available as web server and for download at www.meilerlab.org. PMID- 23349004 TI - Photoaffinity casting of a coumarin flag for rapid identification of ligand binding sites within protein. AB - A photo-switchable fluorescent flagging approach has been developed to identify photoaffinity-labeled peptides in target protein. Upon photochemical release of the ligand, the protein was newly modified with a coumarin in place of the previously attached biotin. It allowed us to simplify complex identification processes for labeled sites. PMID- 23349005 TI - A high-confidence reference dataset of differentially expressed proteins in elongating cotton fiber cells. AB - In our previous study, we used a comparative proteomic approach based on 2DE to profile dynamic proteomes of cotton fibers and found 235 protein spots differentially expressed during the elongation process ranging from 5 to 25 days post-anthesis. Of them, only 106 differentially expressed proteins (DEPs) were identified by MS due to database limitations at the time. In the present work, we successfully identified the remaining 129 DEPs from the same experimental system using high-resolution MS with an updated database. Bioinformatic analysis revealed that proteins involved in carbohydrate and protein metabolism, transport, and redox homeostasis are the most abundant, and glycolysis was found to be the most significantly regulated process during fiber elongation. Our high confidence reference dataset, composed of 235 DEPs, provides a valuable resource for future studies on the molecular mechanism of cotton fiber elongation. PMID- 23349006 TI - Validation of the new comprehensive cytogenetic scoring system (NCCSS) on 630 consecutive de novo MDS patients from a single institution. AB - This study evaluated whether the NCCSS truly improves the prognostic stratification of 630 consecutive de novo MDS patients and established which cytogenetic grouping [NCCSS or International Prognostic Scoring System (IPSS)], when combined with the WHO classification, best predicted the clinical outcome of myelodysplastic syndromes (MDS). The frequency of chromosomal defects was 53.8%. Clinical parameters, including number of cytopenias, WHO classification, IPSS cytogenetic categories and scores, NCCSS were all relevant for overall survival (OS) and leukemia-free survival (LFS) and were included in six distinct multivariate models compared by the Akaike Information Criterion (AIC). The most effective model to predict OS included the number of cytopenias, the WHO classification and the NCCSS, whereas the model including the number of cytopenias, blast cell percentage and the NCCSS and the model including the number of cytopenias the WHO classification and the NCCSS were almost equally effective to predict LFS. In conclusion, the NCCS (i) improves the prognostic stratification of the good and poor IPSS cytogenetic categories by introducing the very good and the very poor categories; (ii) is still incomplete in establishing the prognostic relevance of rare/double defects, (ii) applied to patients who receive supportive treatment only identifies five different prognostic subgroups, but applied to patients treated with specific therapies reveals only a trend toward a significantly different OS and LFS when patients of the poor and intermediate cytogenetic categories are compared, (iii) combined with the WHO classification is much more effective than the IPSS in predicting MDS clinical outcome. PMID- 23349007 TI - Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management. AB - DISEASE OVERVIEW: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. DIAGNOSIS: Diagnosis is based on bone marrow morphology. The presence of fibrosis, JAK2/MPL mutation, or +9/13q- cytogenetic abnormality is supportive but not essential for diagnosis. Prefibrotic PMF mimics essential thrombocythemia in its presentation and the distinction is prognostically relevant. Differential diagnosis of myelofibrosis should include chronic myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. RISK STRATIFICATION: The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) prognostic model for PMF can be applied at any point during the disease course and uses eight independent predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 * 109/L, circulating blasts >= 1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 * 109/L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement). The presence of 0, 1, "2 or 3," and >= 4 adverse factors defines low, intermediate-1, intermediate-2, and high-risk disease with median survivals of approximately 15.4, 6.5, 2.9, and 1.3 years, respectively. A >80% two-year mortality is predicted by monosomal karyotype, inv(3)/i(17q) abnormalities, or any two of circulating blasts >9%, leukocytes >= 40 * 109/L or other unfavorable karyotype. Most recently, mutations involving ASXL1, SRSF2, EZH2, and IDH1/2 or increased plasma IL-2R, IL-8, or serum-free light chain levels have been shown to adversely affect survival. RISK-ADAPTED THERAPY: Observation alone is adequate for asymptomatic low/intermediate-1 risk disease. Allogeneic stem cell transplantation (ASCT) is often considered for high risk disease. Conventional or experimental drug therapy is reasonable for symptomatic intermediate-1 or intermediate-2 risk disease; however, ASCT is an acceptable treatment option for such patients in the presence of ASXL1 or other prognostically adverse mutations. Splenectomy and low-dose radiotherapy are used for drug-refractory splenomegaly. Radiotherapy is also used for the treatment of non-hepatosplenic EMH, PMF associated pulmonary hypertension, and extremity bone pain. PMID- 23349008 TI - First de novo mutation in RPS19 gene as the cause of hydrops fetalis in Diamond Blackfan anemia. PMID- 23349009 TI - Nodular lymphocyte predominant Hodgkin lymphoma with non-invasive or early invasive growth pattern suggests an early step of the disease with a highly favorable outcome. PMID- 23349010 TI - Analysis of Mogroside V in Siraitia grosvenorii with micelle-mediated cloud-point extraction. AB - INTRODUCTION: Mogroside V is the main effective ingredient of Siraitia grosvenorii used as a natural sweet food as well as a traditional Chinese medicine. The sample pre-treatment prior to chromatographic analysis requires large amounts of toxic organic solvents and is time consuming. OBJECTIVE: To develop an effective and simple method for extracting and determining mogroside V of Siraitia grosvenorii. METHODS: Mogroside V was extracted and preconcentrated by micelle-mediated cloud-point extraction with nonionic surfactant isotridecyl poly (ethylene glycol) ether (Genapol(r) X-080). The obtained solutions containing mogroside V were analysed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The chromatographic separation was performed on a C18 -column using gradient elution with acetonitrile and water at 203 nm. RESULTS: The cloud-point extraction yield was 80.7% while the pre concentration factor was about 10.8. The limit of detection was 0.75 ug/mL and the limit of quantification was 2 ug/mL. The relative standard deviations for intra- and interday precisions of mogroside V were less than 8.68% and 5.78%, respectively, and the recoveries were between 85.1% and 103.6%. CONCLUSION: The HPLC-UV method based on micelle-mediated cloud-point extraction for determination mogroside V in Siraitia grosvenorii was environmentally friendly, simple and sensitive. PMID- 23349012 TI - Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in human keratinocytes and ex vivo skin. AB - Nicotinamide (vitamin B3) protects from ultraviolet (UV) radiation-induced carcinogenesis in mice and from UV-induced immunosuppression in mice and humans. Recent double-blinded randomized controlled Phase 2 studies in heavily sun damaged individuals have shown that oral nicotinamide significantly reduces premalignant actinic keratoses, and may reduce new non-melanoma skin cancers. Nicotinamide is a precursor of nicotinamide adenine dinucleotide (NAD(+)), an essential coenzyme in adenosine triphosphate (ATP) production. Previously, we showed that nicotinamide prevents UV-induced ATP decline in HaCaT keratinocytes. Energy-dependent DNA repair is a key determinant of cellular survival after exposure to DNA-damaging agents such as UV radiation. Hence, in this study we investigated whether nicotinamide protection from cellular energy loss influences DNA repair. We treated HaCaT keratinocytes with nicotinamide and exposed them to low-dose solar-simulated UV (ssUV). Excision repair was quantified using an assay of unscheduled DNA synthesis. Nicotinamide increased both the proportion of cells undergoing excision repair and the repair rate in each cell. We then investigated ssUV-induced cyclobutane pyrimidine dimers (CPDs) and 8-oxo-7,8-dihydro-2' deoxyguanosine (8oxoG) formation and repair by comet assay in keratinocytes and with immunohistochemistry in human skin. Nicotinamide reduced CPDs and 8oxoG in both models and the reduction appeared to be due to enhancement of DNA repair. These results show that nicotinamide enhances two different pathways for repair of UV-induced photolesions, supporting nicotinamide's potential as an inexpensive, convenient and non-toxic agent for skin cancer chemoprevention. PMID- 23349011 TI - Anatomy of a blastocyst: cell behaviors driving cell fate choice and morphogenesis in the early mouse embryo. AB - The preimplantation period of mouse early embryonic development is devoted to the specification of two extraembryonic tissues and their spatial segregation from the pluripotent epiblast. During this period two cell fate decisions are made while cells gradually lose their totipotency. The first fate decision involves the segregation of the extraembryonic trophectoderm (TE) lineage from the inner cell mass (ICM); the second occurs within the ICM and involves the segregation of the extraembryonic primitive endoderm (PrE) lineage from the pluripotent epiblast (EPI) lineage, which eventually gives rise to the embryo proper. Multiple determinants, such as differential cellular properties, signaling cues and the activity of transcriptional regulators, influence lineage choice in the early embryo. Here, we provide an overview of our current understanding of the mechanisms governing these cell fate decisions ensuring proper lineage allocation and segregation, while at the same time providing the embryo with an inherent flexibility to adjust when perturbed. PMID- 23349014 TI - Low-dose aspirin delays an inflammatory tumor progression in vivo in a transgenic mouse model of neuroblastoma. AB - Tumor-associated inflammation is a driving force in several adult cancers and intake of low-dose aspirin has proven to reduce cancer incidence. Little is known about tumor-associated inflammation in pediatric neoplasms and no in vivo data exists on the effectiveness of low-dose aspirin on established tumors. The present study employs the transgenic TH-MYCN mouse model for neuroblastoma (NB) to evaluate inflammatory patterns paralleling tumor growth in vivo and low-dose aspirin as a therapeutic option for high-risk NB. Spontaneously arising abdominal tumors were monitored for tumor-associated inflammation ex vivo at various stages of disease and homozygous mice received daily low-dose aspirin (10mg/kg) using oral gavage or no treatment, from 4.5 to 6 weeks of age. Using flow cytometry, a transition from an adaptive immune response predominated by CD8(+) T cell in early neoplastic lesions, towards enrichment in immature cells of the innate immune system, including myeloid-derived suppressor cells, dendritic cells and tumor-associated macrophages, was detected during tumor progression. An M1 to M2 transition of tumor-associated macrophages was demonstrated, paralleled by a deterioration of dendritic cell status. Treatment with low-dose aspirin to mice homozygous for the TH-MYCN transgene significantly reduced the tumor burden (P < 0.01), the presence of tumor-associated cells of the innate immune system (P < 0.01), as well as the intratumoral expression of transforming growth factor-beta, thromboxane A2 (P < 0.05) and prostaglandin D2 (P < 0.01). In conclusion, tumor associated inflammation appears as a potential therapeutic target in NB and low dose aspirin reduces tumor burden in the TH-MYCN transgenic mouse model of NB, hence warranting further studies on aspirin in high-risk NB. PMID- 23349016 TI - Reduced mitochondrial DNA copy number in peripheral blood leukocytes increases the risk of soft tissue sarcoma. AB - Mitochondrial DNA (mtDNA) has increased susceptibility to damage due to its close proximity to the site of reactive oxygen species production, lack of introns and protective histones, and less efficient DNA repair mechanisms than nuclear DNA. The relationship between mtDNA copy number in peripheral blood leukocytes (PBLs) and the risk of soft tissue sarcoma (STS) has not been investigated. In this study, we determined the relative mtDNA copy number in PBLs of 325 patients (cases) with histologically confirmed STS and 330 healthy controls that were frequency matched to cases according to age, sex and ethnicity. Cases had a significantly lower mtDNA copy number than controls (0.93 +/- 0.49 for cases versus 1.23 +/- 0.59 for controls; P < 0.001). In analyses stratified by sex, ethnicity and smoking status, mtDNA copy number was lower in the cases than in controls in any stratum. Using the median mtDNA copy number in controls as a cutoff, individuals with lower mtDNA copy number were associated with a significantly increased risk of STS compared with those with higher mtDNA copy number (adjusted odds ratio, 2.71; 95% confidence interval, 1.94-3.82). There was a significant dose-response relationship between reduced mtDNA copy number and increased risk of STS in tertile and quartile analyses. The present study provides the first epidemiologic evidence that reduced mtDNA copy number in PBLs is significantly associated with an increased risk of STS, thereby suggesting an important role of mtDNA in STS development. PMID- 23349015 TI - Lymphotoxin beta receptor mediates caspase-dependent tumor cell apoptosis in vitro and tumor suppression in vivo despite induction of NF-kappaB activation. PMID- 23349018 TI - DICER1, DROSHA and miRNAs in patients with non-small cell lung cancer: implications for outcomes and histologic classification. AB - The clinical and functional significance of RNA-interference machinery in lung cancer is poorly understood. Besides, microRNAs (miRNA) have the potential to serve both as biomarkers and therapeutic agents, by personalizing diagnosis and therapy. In this study, we investigated whether the expression levels of DICER1 and DROSHA, components of the RNA-interference machinery, can predict survival, and whether the miRNA expression profiles can differentiate histologic subtypes in non-small cell lung cancer (NSCLC). Levels of DICER1, DROSHA and five different miRNAs were measured in NSCLC specimens (N = 115) by qRT-PCR assay and correlated with clinical outcomes. Low expression of DROSHA was associated with an increased median survival (154.2 versus 39.8 months, P = 0.016). Also, high DROSHA expression was associated with decreased median survival in the following subgroups: adenocarcinoma (P = 0.011), grade III tumors (P = 0.038) and low-stage patients (P = 0.014). In multivariate analyses, we found two independent predictors of reduced disease-specific survival: high DROSHA expression [hazards ratio = 2.24; P = 0.04] and advanced tumor stage (hazards ratio = 1.29, P = 0.02). In general, the overall tumor miRNA expression was downregulated in our cohort compared with normal tissues. Expression levels of hsa-let-7a (P = 0.005) and miR-16 (P = 0.003) miRNA were significantly higher in squamous cell carcinoma than in adenocarcinoma samples. This study supports the value of the expression profiling of the components of the miRNA-processing machinery in the prognosis of NSCLC patients, especially DROSHA expression levels. In addition, differential expression of miRNAs, such as hsa-let-7a and miR-16 may be helpful tools in the histologic subclassification of NSCLC. PMID- 23349017 TI - LGR5 promotes survival in human colorectal adenoma cells and is upregulated by PGE2: implications for targeting adenoma stem cells with NSAIDs. AB - Cyclooxygenase-2 is overexpressed in the majority of colorectal tumours leading to elevated levels of prostaglandin E2 (PGE2), promoting many hallmarks of cancer. Importantly, PGE2 is reported to enhance Wnt/beta-catenin signalling in colorectal carcinoma cells and in normal haematopoietic stem cells where it promotes stem cell function. Although Wnt signalling plays a crucial role in intestinal stem cells, the relationship between PGE2 and intestinal stem cells is unclear. Given that the key intestinal cancer stem cell marker LGR5 (leucine-rich G-protein coupled receptor 5) is a Wnt target and PGE2 enhances Wnt signalling, the focus of this study was to investigate whether PGE2 regulated LGR5 expression in colorectal adenoma cells and whether LGR5 was important for tumour cell survival. PGE2 upregulated LGR5 protein in adenoma (RG/C2) and carcinoma (DLD-1) cell lines. LGR5 knockdown induced cell death in RG/C2 and AA/C1 adenoma cells, suggesting that LGR5 has an important survival-promoting role in adenoma cells. Indeed, we detected LGR5 protein expression in 4 of 4 human adenoma cell lines. Furthermore, LGR5 small interfering RNA inhibited the survival-promoting effects of PGE2 in RG/C2, suggesting that PGE2 promotes adenoma cell survival, at least in part, by increasing LGR5 expression. These studies, therefore, show the first link between PGE2 and LGR5 in human colorectal adenoma and carcinoma cells and demonstrate a survival-promoting role of LGR5. As non-steroidal anti-inflammatory drugs (NSAIDs) cause adenomas to regress in FAP patients, these studies could have important implications for the mechanism by which NSAIDs are chemopreventive, as lowering PGE2 levels could reduce LGR5 expression and survival of LGR5(+) adenoma stem cells. PMID- 23349019 TI - Association of polymorphisms and haplotype in the region of TRIT1, MYCL1 and MFSD2A with the risk and clinicopathological features of gastric cancer in a southeast Chinese population. AB - To explore the association of polymorphisms in the region of three neighboring genes TRIT1, MYCL1 and MFSD2A with risk and clinicopathological features of gastric cancer, 19 tagging SNPs in this region were genotyped using matrix assisted laser desorption/ionization time-of-flight mass spectrometry in a case control study of 610 Chinese gastric cancer patients and 608 cancer-free controls. MFSD2A rs4233508 T>C CC genotype was associated with an increased risk of gastric cancer in younger patients and an increased risk of moderately/well differentiated intestinal-type gastric cancer (adjusted odds ratio [OR], 1.74 and 1.50, respectively). TRIT1 rs11581557 T>G TG was associated with lymph node metastasis (TG versus TT/GG, adjusted OR, 1.64). MFSD2A rs12083239 GC genotype and TRIT1 rs2172362 or rs230310 homozygous genotype were associated with Lauren's classification (GC versus GG, adjusted OR, 1.69; GC versus GG/CC, adjusted OR, 1.74) and tumor site (rs2172362: CC versus CT, adjusted OR, 1.71; CC/TT versus CT, adjusted OR, 1.62; rs230310: CC versus CT, adjusted OR, 1.75; CC/TT versus CT, adjusted OR, 1.67) of gastric cancer, respectively. One TRIT1 haplotype, CCGT, was associated with lymph node metastasis and tumor site of gastric cancer (CCGT versus TTTT, adjusted OR, 1.91 and 1.55). This is believed to be the first report that several tagging SNPs and haplotypes in TRIT1, MYCL1 and MFSD2A region are significantly associated with risk and clinicopathological features of gastric cancer in a Chinese population. The findings might be useful for risk assessment and prognosis prediction of gastric cancer. PMID- 23349020 TI - Valproic acid inhibits the proliferation of cancer cells by re-expressing cyclin D2. AB - In this study, primary murine prostate cancer (PCa) cells were derived using the well-established TRAMP model. These PCa cells were treated with the histone deacetylase inhibitor, valproic acid (VPA), and we demonstrated that VPA treatment has an antimigrative, antiinvasive and antiproliferative effect on PCa cells. Using microarray analyses, we discovered several candidate genes that could contribute to the cellular effects we observed. In this study, we could demonstrate that VPA treatment of PCa cells causes the re-expression of cyclin D2, a known regulator that is frequently lost in PCa as we could show using immunohistochemical analyses on PCa specimens. We demonstrate that VPA specifically induces the re-expression of cyclin D2, one of the highly conserved D-type cyclin family members, in several cancer cell lines with weak or no cyclin D2 expression. Interestingly, VPA treatment had no effect in fibroblasts, which typically have high basal levels of cyclin D2 expression. The re-expression of cyclin D2 observed in PCa cells is activated by increased histone acetylation in the promoter region of the Ccnd2 gene and represents one underlying molecular mechanism of VPA treatment that inhibits the proliferation of cancer cells. Altogether, our results confirm that VPA is an anticancer therapeutic drug for the treatment of tumors with epigenetically repressed cyclin D2 expression. PMID- 23349013 TI - Genetic susceptibility to lung cancer--light at the end of the tunnel? AB - Lung cancer is one of the most common and deadliest cancers in the world. The major socio-environmental risk factor involved in the development of lung cancer is cigarette smoking. Additionally, there are multiple genetic factors, which may also play a role in lung cancer risk. Early work focused on the presence of relatively prevalent but low-penetrance alterations in candidate genes leading to increased risk of lung cancer. Development of new technologies such as genomic profiling and genome-wide association studies has been helpful in the detection of new genetic variants likely involved in lung cancer risk. In this review, we discuss the role of multiple genetic variants and review their putative role in the risk of lung cancer. Identifying genetic biomarkers and patterns of genetic risk may be useful in the earlier detection and treatment of lung cancer patients. PMID- 23349021 TI - Areca nut-induced buccal mucosa fibroblast contraction and its signaling: a potential role in oral submucous fibrosis--a precancer condition. AB - Betel quid (BQ) chewing is an oral habit that increases the risk of oral cancer and oral submucous fibrosis (OSF), a precancerous condition showing epithelial atrophy and tissue fibrosis. Persistent fibroblast contraction may induce the fibrotic contracture of tissue. In this study, we found that areca nut extract (ANE) (200-1200 ug/ml) stimulated buccal mucosa fibroblast (OMF)-populated collagen gel contraction. Arecoline but not arecaidine-two areca alkaloids, slightly induced the OMF contraction. Exogenous addition of carboxylesterase (2U/ml) prevented the arecoline- but not ANE-induced OMF contraction. OMF expressed inositol triphosphate (IP3) receptors. ANE-induced OMF (800 ug/ml) contraction was inhibited by U73122 [phospholipase C (PLC) inhibitor] and 2 aminoethoxydiphenyl borate (IP3 receptor antagonist), respectively. Ethylene glycol tetraacetic acid and verapamil, two calcium mobilization modulators, also suppressed the ANE-induced OMF contraction. ANE induced calcium/calmodulin kinase II and myosin light chain (MLC) phosphorylation in OMF. Moreover, W7 (a Ca(2+)/calmodulin inhibitor), HA1077 (Rho kinase inhibitor), ML-7 (MLC kinase inhibitor) and cytochalasin B (actin filament polymerization inhibitor) inhibited the ANE-induced OMF contraction. Although ANE elevated reactive oxygen species (ROS) level in OMF, catalase, superoxide dismutase and N-acetyl-L-cysteine showed no obvious effect on ANE-elicited OMF contraction. These results indicate that BQ chewing may affect the wound healing and fibrotic processes in OSF via inducing OMF contraction by ANE and areca alkaloids. AN components-induced OMF contraction was related to PLC/IP3/Ca(2+)/calmodulin and Rho signaling pathway as well as actin filament polymerization, but not solely due to ROS production. PMID- 23349022 TI - Phenotype of Williams-Beuren syndrome in Brazilian patients: comments on the article by Patil et al. [2012] and discussion of variable phenotypes in distinct populations. PMID- 23349023 TI - Protective effect of Paeonia anomala extracts and constituents against tert butylhydroperoxide-induced oxidative stress in HepG2 cells. AB - The fruit and root parts of Paeonia anomala L. are used for the treatment of many kinds of disorders in Mongolian traditional medicine. The protective effect of a fruit extract from P. anomala against tert-butylhydroperoxide-induced cell damage was evaluated in human hepatoma HepG2 cells and compared to that of a root extract from P. anomala on the basis of cell viability, generation of intracellular reactive oxygen species, cellular total glutathione concentration, and anti-genotoxicity. The fruit extract of P. anomala showed excellent protection against the oxidative stress when compared to the root extract, through free radical scavenging, enhancing cellular glutathione concentration, and inhibiting DNA damage. Chemical constituents in the fruit extract of P. anomala were investigated and two novel compounds, 2-hydroxy-6-methoxy-4-O-(6'-O alpha-L-arabinofuranosyl-beta-D-glucopyranosyl)acetophenone (1) and 3,3'-di-O methyl-4-O-(3''-O-galloyl-beta-D-glucopyranosyl)ellagic acid (2), along with 18 other known compounds were identified. Compound 2 showed better cytoprotection against tert-butylhydroperoxide than compound 1. Among other compounds isolated from the fruit extract, ellagic acid, methyl gallate, ethyl gallate, fischeroside B, and quercetin derivatives showed potent protective effects against tert butylhydroperoxide-induced oxidative stress via inhibiting reactive oxygen species generation and increasing total glutathione levels in HepG2 cells. PMID- 23349024 TI - Egr-2 transcription factor is required for Blimp-1-mediated IL-10 production in IL-27-stimulated CD4+ T cells. AB - Interleukin-27 (IL-27) suppresses immune responses through inhibition of the development of IL-17 producing Th17 cells and induction of IL-10 production. We previously showed that forced expression of early growth response gene 2 (Egr-2), a transcription factor required for T-cell anergy induction, induces IL-10 and lymphocyte activation gene 3 expression and confers regulatory activity on CD4(+) T cells in vivo. Here, we evaluated the role of Egr-2 in IL-27-induced IL-10 production. Among various IL-10-inducing factors, only IL-27 induced high levels of Egr-2 and lymphocyte activation gene 3 expression. Intriguingly, IL-27 failed to induce IL-10 in Egr-2-deficient T cells. IL-27-mediated induction of Prdm1 that codes B lymphocyte induced maturation protein-1, a transcriptional regulator important for IL-10 production in CD4(+) T cells, was also impaired in the absence of Egr-2. Although IL-27-mediated IL-10 induction was dependent on both STAT1 and STAT3, only STAT3 was required for IL-27-mediated Egr-2 induction. These results suggest that IL-27 signal transduction through Egr-2 and B lymphocyte induced maturation protein-1 plays an important role in IL-10 production. Furthermore, Egr-2-deficient CD4(+) T cells showed dysregulated production of IFN-gamma and IL-17 in response to IL-27 stimulation. Therefore, Egr-2 may play key roles in controlling the balance between regulatory and effector cytokines. PMID- 23349025 TI - Temperature-dependent conformational change affecting Tyr11 and sweetness loops of brazzein. AB - The sweet protein brazzein, a member of the Csbetaalpha fold family, contains four disulfide bonds that lend a high degree of thermal and pH stability to its structure. Nevertheless, a variable temperature study has revealed that the protein undergoes a local, reversible conformational change between 37 and 3 degrees C with a midpoint about 27 degrees C that changes the orientations and side-chain hydrogen bond partners of Tyr8 and Tyr11. To test the functional significance of this effect, we used NMR saturation transfer to investigate the interaction between brazzein and the amino terminal domain of the sweet receptor subunit T1R2; the results showed a stronger interaction at 7 degrees C than at 37 degrees C. Thus the low temperature conformation, which alters the orientations of two loops known to be critical for the sweetness of brazzein, may represent the bound state of brazzein in the complex with the human sweet receptor. PMID- 23349026 TI - Cognitive dysfunction in patients hospitalized with acute exacerbation of COPD. AB - BACKGROUND: Cognitive impairment is one of the least well-studied COPD comorbidities. It is known to occur in hypoxemic patients, but its presence during acute exacerbation is not established. OBJECTIVES: The purpose of this study was to assess neuropsychological performance in patients with COPD who were awaiting discharge from hospital following acute exacerbation and recovery and to compare them with stable outpatients with COPD and with healthy control subjects. METHODS: We recruited 110 participants to the study: 30 inpatients with COPD who were awaiting discharge following an exacerbation, 50 outpatients with stable COPD, and 30 control subjects. Neuropsychological tests measured episodic memory, executive function, visuospatial function, working memory, processing speed, and an estimate of premorbid abilities. Follow-up cognitive assessments for patients who were stable and those with COPD exacerbation were completed at 3 months. RESULTS: Patients with COPD exacerbation were significantly worse (P<.05) than stable patients over a range of measures of cognitive function, independent of hypoxemia, disease severity, cerebrovascular risk, or pack-years smoked. Of the patients with COPD exacerbation, up to 57% were in the impaired range and 20% were considered to have suffered a pathologic loss in processing speed. Impaired cognition was associated with worse St. George's Respiratory Questionnaire score (r=-0.40-0.62, P<=.02) and longer length of stay (r=0.42, P=.02). There was no improvement in any aspect of cognition at recovery 3 months later. CONCLUSIONS: In patients hospitalized with an acute COPD exacerbation, impaired cognitive function is associated with worse health status and longer hospital length of stay. A significant proportion of patients are discharged home with unrecognized mild to severe cognitive impairment, which may not improve with recovery. PMID- 23349027 TI - Mouse brain fixation to preserve In vivo manganese enhancement for ex vivo manganese-enhanced MRI. AB - PURPOSE: To develop a tissue fixation method that preserves in vivo manganese enhancement for ex vivo magnetic resonance imaging (MRI). The needs are clear, as conventional in vivo manganese-enhanced MRI (MEMRI) applied to live animals is time-limited, hence limited in spatial resolution and signal-to-noise ratio (SNR). Ex vivo applications can achieve superior spatial resolution and SNR through increased signal averaging and optimized radiofrequency coil designs. A tissue fixation method that preserves in vivo Mn(2+) enhancement postmortem is necessary for ex vivo MEMRI. MATERIALS AND METHODS: T1 measurements and T1 weighted MRI were performed on MnCl2 -administered mice. The mice were then euthanized and the brains were fixed using one of two brain tissue fixation methods: aldehyde solution or focused beam microwave irradiation (FBMI). MRI was then performed on the fixed brains. RESULTS: T1 values and T1 -weighted signal contrasts were comparable between in vivo and ex vivo scans on aldehyde-fixed brains. FBMI resulted in the loss of Mn(2+) enhancement. CONCLUSION: Aldehyde fixation, not FBMI, maintained in vivo manganese enhancement for ex vivo MEMRI. PMID- 23349028 TI - Quantitative proteomic analysis reveals induction of premature senescence in human umbilical vein endothelial cells exposed to chronic low-dose rate gamma radiation. AB - Chronic low-dose ionizing radiation induces cardiovascular disease in human populations but the mechanism is largely unknown. We suggested that chronic radiation exposure may induce endothelial cell senescence that is associated with vascular damage in vivo. We investigated whether chronic radiation exposure is causing a change in the onset of senescence in endothelial cells in vitro. Indeed, when exposed to continuous low-dose rate gamma radiation (4.1 mGy/h), primary human umbilical vein endothelial cells (HUVECs) initiated senescence much earlier than the nonirradiated control cells. We investigated the changes in the protein expression of HUVECs before and during the onset of radiation-induced senescence. Cellular proteins were quantified using isotope-coded protein label technology after 1, 3, and 6 weeks of radiation exposure. Several senescence related biological pathways were influenced by radiation, including cytoskeletal organization, cell-cell communication and adhesion, and inflammation. Immunoblot analysis showed an activation of the p53/p21 pathway corresponding to the progressing senescence. Our data suggest that chronic radiation-induced DNA damage and oxidative stress result in induction of p53/p21 pathway that inhibits the replicative potential of HUVECs and leads to premature senescence. This study contributes to the understanding of the increased risk of cardiovascular diseases seen in populations exposed to chronic low-dose irradiation. PMID- 23349029 TI - Inhibin B as a marker of sertoli cell damage and spermatogenic disturbance in the rat. AB - This study was designed to determine the effects of Compound A on spermatogenesis including assessment of inhibin B levels and on fertility in the male rat over a 15 to 19 weeks treatment and a 19 weeks treatment-free period in control and 30, 60, and 180 mg/kg dose groups (n = 22/group). Compound A in a dose-dependent manner induced various degrees of spermatogenic alterations compatible with Sertoli cells being the primary target, for example, inter- and intracellular Sertoli cell vacuolization and altered cellular morphology followed by germ cell degeneration and marked reduction of epididymidal sperm numbers. Blood-testis barrier remained intact (electron microscopy and hyperosmotic fixation test) until germ cells disappeared. Mating behavior and weights of androgen-dependent prostate and seminal vesicles remained unaffected. Inhibin B levels correlated only with moderate to severe spermatogenic alterations. Ten animals with inhibin B levels below detection limit were encountered and five of these animals were fertile in week 19 but following 19 weeks without treatment, another five animals were rendered infertile and inhibin B levels remained undetectable. In the rat, inhibin B only reflects major spermatogenic alterations and markedly reduced inhibin B levels might indicate irreversibility of these alterations and even infertility. PMID- 23349030 TI - The effect of birth cohort on well-being: the legacy of economic hard times. AB - In the present research, we examined the effects of age, cohort, and time of measurement on well-being across adulthood. Cross-sectional and longitudinal analyses of two independent samples-one with more than 10,000 repeated assessments across 30 years (mean assessments per participant = 4.44, SD = 3.47) and one with nationally representative data-suggested that well-being declines with age. This decline, however, reversed when we controlled for birth cohort. That is, once we accounted for the fact that older cohorts had lower levels of well-being, all cohorts increased in well-being with age relative to their own baseline. Participants tested more recently had higher well-being, but time of measurement, unlike cohort, did not change the shape of the trajectory. Although well-being increased with age for everyone, cohorts that lived through the economic challenges of the early 20th century had lower well-being than those born during more prosperous times. PMID- 23349033 TI - Effect of concentrate supplementation on feed consumption, nutrient utilization and blood metabolite profile in captive spotted deer (Axis axis) fed oat (Avena sativa) and berseem (Trifolium alexandrinum) fodders based diet. AB - This experiment was conducted to determine the optimum level of a maize-soybean meal-wheat bran concentrate supplement fed to captive spotted deer fed an oat and berseem fodder-based diet. Twelve adult spotted deer [64-76 kg body weight (BW)] were distributed into three groups of four each and were housed individually. A diet consisting of 5 kg of oat fodder and 5.5 kg of berseem fodder was offered to each one of the experimental animals. The animal in group I received no supplementary concentrate, whereas, those in groups II and III received 0.5 and 1 kg of supplementary concentrate, respectively. A 60 days digestibility trial was conducted with a 5 days collection period on Days 55-59 of the trial. Blood samples were collected from all animals on Day 60 of the experiment. Average daily dry matter intake (DMI) was 1,224, 1,613, and 1,574 g/day in groups I, II, and III, respectively. Dry matter (DM) and organic matter (OM) intake was lowest (P < 0.01) in group I. Intake of P, Cu, and Zn was highest (P < 0.01) in group III, followed by groups II and I. Digestibility of neutral detergent fiber was highest (P < 0.05) in group II. Digestibility of OM and CP was lowest (P < 0.05) in group I. Digestibility of gross energy was highest (P < 0.01) in group III (74.9%), followed by groups II (69.3%) and I (66.2%). Digestible energy (DE) intake (kcal/kg BW(0.75) ) was highest (P < 0.01) in group III (195.4), followed by groups II (180.9) and I (129.8). Initial BW was 72.7, 72.5, and 71.0 kg, whereas, final BW was 71.0, 72.7, and 73.5 kg, in groups I, II and III, respectively. Average daily change in body mass was significantly (P < 0.01) different among the groups. The body mass was lost (-29.2 g/day), maintained (4.1 g/day) and gained (41.6 g/day) in groups I, II, and III, respectively. Blood glucose and cholesterol concentration was highest (P < 0.05) in group III, followed by groups II and I. Serum concentration of Cu and Zn was highest (P < 0.05) in group III, followed by groups II and I. Supplementation of forage only diet with 0.5 kg of concentrate mixture increased intake and digestibility of nutrients, without change in body mass. Animals fed 1 kg of supplementary concentrate received energy in excess of requirements, were consistently gaining body mass and were prone to obesity. Thus, it is a right strategy to supplement forage only diet of captive spotted deer with 0.5 kg of concentrate. PMID- 23349032 TI - A nanobody-based method for tracking factor XII activation in plasma. AB - The physiological role of the plasma protein factor XII (FXII), as well as its involvement in human pathology, is poorly understood. While FXII is implicated in thrombotic pathology as a coagulation factor, it can contribute to inflammatory conditions without triggering coagulation. We recently generated nanobodies against the catalytic domain of activated FXII (FXIIa). Here, we describe two of these nanobodies, A10 and B7, both of which do not recognise FXII. Nanobody A10 recognises the catalytic domain of purified alpha-FXIIa (80 kDa), but not that of purified beta-FXIIa (28 kDa), whereas nanobody B7 recognises both. This suggests minute differences in the catalytic domain between these isoforms of FXIIa. The detection of FXIIa by these nanobodies in plasma can become compromised through inactivation by serine protease inhibitors. This effect can be efficiently countered through the addition of the small-molecular protease inhibitor PPACK. Finally, we show that our nanobody-based assays in vitro distinguish various activation products of FXII that differ with the type of activator present: whereas procoagulant activators solely trigger the formation of a species that is captured by B7, proinflammatory activators first generate a species that is recognised by B7, which is later converted into a species that is recognised by A10. These findings suggest that a progressive proteolysis of FXIIa results in the generation a non-procoagulant form of FXIIa, whereas retention of intermediate forms triggers coagulation. Moreover, our findings indicate the development of nanobodies against activated enzymes offers improved opportunities to investigate their contribution to health and disease. PMID- 23349034 TI - Spleen size measured on enhanced MRI for quantitatively staging liver fibrosis in minipigs. AB - PURPOSE: To investigate whether and how spleen size measured on magnetic resonance imaging (MRI) could be used to stage liver fibrosis. MATERIALS AND METHODS: Sixteen minipigs were used to prospectively model liver fibrosis staged by biopsy. Abdominal gadolinium-enhanced MRI was performed on the 0, 5th, 9th, 16th, and 21st weekend after beginning of the modeling. Splenic maximal width (W), thickness (T), length (L), and area (S) together with spleen volume (SV) and liver volume (LV) were measured on enhanced MRI and the ratio of SV to LV (SV/LV) was calculated. Spleen multidimensional indexes 1 and 2 were obtained by W * T * L and S * L, respectively. Statistical analyses were performed to determine which parameter could best stage the fibrosis. RESULTS: W, T, L, S, SV, index 1 and 2, and SV/LV tended to increase with increasing stages of fibrosis (r = 0.46-0.796, all P < 0.001), and might predict liver fibrosis stage >=1, >=2, >=3, and 4 (area under receiver operating characteristic curve [AUC] = 0.697-1.0, all P < 0.05). Among the parameters, splenic index 1, SV, and SV/LV might be best for predicting stage >=1 (AUC = 0.941), >=2 or >=3 (AUC = 0.875 or 0.978, respectively), and 4 (AUC = 1.0), respectively. CONCLUSION: Spleen size measured on MRI could be used for staging liver fibrosis. PMID- 23349035 TI - Visualization of inactive X chromosome in preimplantation embryos utilizing MacroH2A-EGFP transgenic mouse. AB - One of the two X chromosomes is inactivated in female eutherian mammals. MacroH2A, an unusual histone variant, is known to accumulate on the inactive X chromosome (Xi) during early embryo development, and can thus be used as a marker of the Xi. In this study, we produced a transgenic mouse line expressing the mouse MacroH2A1.2-enhanced green fluorescent protein (EGFP) fusion protein (MacroH2A-EGFP) under the control of a CAG promoter and verified whether MacroH2A EGFP would be useful for tracing the process of X chromosome inactivation by visualizing Xi noninvasively in preimplantation embryos. In transgenic female mice, MacroH2A-EGFP formed a fluorescent focus in nuclei throughout the body. In female blastocysts, the MacroH2A-EGFP focus colocalized with Xist RNA, well known as a marker of Xi. Fluorescence marking of Xi was first observed in some embryonic cells between the 4- and 8-cell stages. These results demonstrate that MacroH2A can bind to the Xi by around the 8-cell stage in female mouse embryos. These MacroH2A-EGFP transgenic mice might be useful to elucidate the process of X chromosome inactivation during the mouse life cycle. PMID- 23349031 TI - Max Bergmann lecture protein epitope mimetics in the age of structural vaccinology. AB - This review highlights the growing importance of protein epitope mimetics in the discovery of new biologically active molecules and their potential applications in drug and vaccine research. The focus is on folded beta-hairpin mimetics, which are designed to mimic beta-hairpin motifs in biologically important peptides and proteins. An ever-growing number of protein crystal structures reveal how beta hairpin motifs often play key roles in protein-protein and protein-nucleic acid interactions. This review illustrates how using protein structures as a starting point for small-molecule mimetic design can provide novel ligands as protein protein interaction inhibitors, as protease inhibitors, and as ligands for chemokine receptors and folded RNA targets, as well as novel antibiotics to combat the growing health threat posed by the emergence of antibiotic-resistant bacteria. The beta-hairpin antibiotics are shown to target a beta-barrel outer membrane protein (LptD) in Pseudomonas sp., which is essential for the biogenesis of the outer cell membrane. Another exciting prospect is that protein epitope mimetics will be of increasing importance in synthetic vaccine design, in the emerging field of structural vaccinology. Crystal structures of protective antibodies bound to their pathogen-derived epitopes provide an ideal starting point for the design of synthetic epitope mimetics. The mimetics can be delivered to the immune system in a highly immunogenic format on the surface of synthetic virus-like particles. The scientific challenges in molecular design remain great, but the potential significance of success in this area is even greater. PMID- 23349036 TI - Proteomic and bioinformatic analysis of membrane proteome in type 2 diabetic mouse liver. AB - Type 2 diabetes mellitus (T2DM) is the most prevalent and serious metabolic disease affecting people worldwide. T2DM results from insulin resistance of the liver, muscle, and adipose tissue. In this study, we used proteomic and bioinformatic methodologies to identify novel hepatic membrane proteins that are related to the development of hepatic insulin resistance, steatosis, and T2DM. Using FT-ICR MS, we identified 95 significantly differentially expressed proteins in the membrane fraction of normal and T2DM db/db mouse liver. These proteins are primarily involved in energy metabolism pathways, molecular transport, and cellular signaling, and many of them have not previously been reported in diabetic studies. Bioinformatic analysis revealed that 16 proteins may be related to the regulation of insulin signaling in the liver. In addition, six proteins are associated with energy stress-induced, nine proteins with inflammatory stress induced, and 14 proteins with endoplasmic reticulum stress-induced hepatic insulin resistance. Moreover, we identified 19 proteins that may regulate hepatic insulin resistance in a c-Jun amino-terminal kinase-dependent manner. In addition, three proteins, 14-3-3 protein beta (YWHAB), Slc2a4 (GLUT4), and Dlg4 (PSD-95), are discovered by comprehensive bioinformatic analysis, which have correlations with several proteins identified by proteomics approach. The newly identified proteins in T2DM should provide additional insight into the development and pathophysiology of hepatic steatosis and insulin resistance, and they may serve as useful diagnostic markers and/or therapeutic targets for these diseases. PMID- 23349037 TI - pi-pi Stacking mediated drug-drug interactions in human CYP2E1. AB - Because of having many low molecular mass substrates, CYP2E1 is of particular interests to the pharmaceutical industry. Many evidences showed that this enzyme can adopt multiple substrates to significantly reduce the oxidation rate of the substrates. The detailed mechanism for this observation is still unclear. In the current study, we employed GPU-accelerated molecular dynamics simulations to study the multiple-binding mode of human CYP2E1, with an aim of offering a mechanistic explanation for the unexplained multiple-substrate binding. Our results showed that Thr303 and Phe478 were key factors for the substrate recognition and multiple-substrate binding. The former can form a significant hydrogen bond to recognize and position the substrate in the productive binding orientation in the active site. The latter acted as a mediator for the substrate communications via pi-pi stacking interactions. In the multiple-binding mode, the aforementioned pi-pi stacking interactions formed by the aromatic rings of both substrates and Phe478 drove the first substrate far away from the catalytic center, orienting in an additional binding position and going against the substrate metabolism. All these findings could give atomic insights into the detailed mechanism for the multiple-substrate binding in human CYP2E1, providing useful information for the drug metabolism mechanism and personalized use of clinical drugs. PMID- 23349038 TI - S14G-humanin inhibits Abeta1-42 fibril formation, disaggregates preformed fibrils, and protects against Abeta-induced cytotoxicity in vitro. AB - The aggregation of soluble amyloid-beta (Abeta) peptide into oligomers/fibrils is one of the key pathological features in Alzheimer's disease (AD). The Abeta aggregates are considered to play a pivotal role in the pathogenesis of AD. Therefore, inhibiting Abeta aggregation and destabilizing preformed Abeta fibrils would be an attractive therapeutic target for prevention and treatment of AD. S14G-humanin (HNG), a synthetic derivative of Humanin (HN), has been shown to be a strong neuroprotective agent against various AD-related insults. Recent studies have shown that HNG can significantly improve cognitive deficits and reduce insoluble Abeta levels as well as amyloid plaque burden without affecting amyloid precursor protein processing and Abeta production in transgenic AD models. However, the potential mechanisms by which HNG reduces Abeta-related pathology in vivo remain obscure. In the present study, we found that HNG could significantly inhibit monomeric Abeta1-42 aggregation into fibrils and destabilize preformed Abeta1-42 fibrils in a concentration-dependent manner by Thioflavin T fluorescence assay. In transmission electron microscope study, we observed that HNG was effective in inhibiting Abeta1-42 fibril formation and disrupting preformed Abeta1-42 fibrils, exhibiting various types of amorphous aggregates without identifiable Abeta fibrils. Furthermore, HNG-treated monomeric or fibrillar Abeta1-42 was found to significantly reduce Abeta1-42-mediated cytotoxic effects on PC12 cells in a dose-dependent manner by MTT assay. Collectively, our results demonstrate for the first time that HNG not only inhibits Abeta1-42 fibril formation but also disaggregates preformed Abeta1-42 fibrils, which provides the novel evidence that HNG may have anti-Abeta aggregation and fibrillogenesis, and fibril-destabilizing properties. Together with previous studies, we concluded that HNG may have promising therapeutic potential as a multitarget agent for the prevention and/or treatment of AD. PMID- 23349039 TI - Biodegradable cisplatin-eluting tracheal stent for malignant airway obstruction: in vivo and in vitro studies. AB - BACKGROUND: Self-expandable metallic stents (SEMSs) are effective in the palliation of malignant airway obstruction. Tumor ingrowth, however, frequently occurs because of a shortage of effective local therapy. Additionally, SEMSs are frequently associated with problems of fracture, migration, and difficult removals. Our goal was to develop a novel bioabsorbable stent with cisplatin elution to circumvent such problems. METHODS: Biodegradable stents made of polycaprolactone were fabricated by a laboratory-made, microinjection molding machine. In vitro mechanical strength of the stents was compared with the strength of Ultraflex SEMSs. Polylactide-polyglycolide copolymer and cisplatin were coated onto the surfaces of the stents. Elution method and high-performance liquid chromatography (HPLC) analysis were used to examine the in vitro cisplatin release characteristics. In vivo, the stents were surgically implanted into the cervical trachea of 15 New Zealand white rabbits. Bronchoscopic examination was performed weekly (1 to approximately 5 weeks) before killing. Cisplatin concentrations in trachea, lung, and blood were analyzed by HPLC. Histologic examination was also performed. RESULTS: The biodegradable stent exhibited mechanical strength comparable to the strength of Ultraflex SEMSs and provided a steady release of cisplatin for >4 weeks in vitro. The in vivo study showed sustained cisplatin levels in rabbit trachea for >5 weeks with a minimum drug level in blood. Histologic examination showed an intact ciliated epithelium and marked leukocyte infiltration in the submucosa of the stented area. CONCLUSIONS: Our study demonstrated that the biodegradable stents provided physical properties comparable to the properties of SEMSs and a sustained release of cisplatin for >5 weeks, which showed great potential in the treatment of malignant airway obstruction. PMID- 23349040 TI - Analytic evaluation of a human ELISA kit for measurement of inhibin B in rat samples. AB - BACKGROUND: A cross-laboratory analytic evaluation of a commercially available human inhibin B ELISA for measuring inhibin B in rat serum and plasma has been undertaken. METHODS: Dilution linearity, spiked recovery, intra- and inter-assay precision, functional sensitivity, matrix effects, and frozen stability were assessed across five laboratories. Reference ranges were generated for male Sprague Dawley and Han Wistar rats. RESULTS: Acceptable performance was defined as an overall assay coefficient of variation <= 20% with an intraday LLOQ <= 20 pg/ml. Intra- and inter-assay precision and functional sensitivity (<=6.4 pg/ml) generally met these criteria, but with occasional evidence of greater variability, particularly at lower concentrations. Dilution linearity was acceptable with occasional low recovery. Acceptable recovery of kit calibrators from rat serum confirmed the absence of matrix effects. Matched serum and plasma samples gave comparable results. The signal increased on freezing, remained constant for >=3 freeze-thaw cycles and was generally stable for at least 8 weeks. Mean inhibin B ranged from 33.5 to 140.6 pg/ml in adult rats across laboratories, with some evidence for a decline from 6 to 9 weeks of age. Power calculations using preliminary reference range data indicated 10 animals/group would generally detect a 40% decrease in inhibin B at AstraZeneca, but laboratories with lower control values would require larger groups. CONCLUSIONS: The assay meets the analytical performance criteria; however, precision at the low end of the standard curve, biological variability, and low control values observed in some laboratories indicate that the utility of the assay may be limited in some laboratories. PMID- 23349041 TI - The identification of microRNAs in calcisponges: independent evolution of microRNAs in basal metazoans. AB - We present the discovery of microRNAs (miRNAs) in the calcisponges Sycon and Leucosolenia (phylum Calcarea), and potential miRNAs in the homoscleromorph Oscarella carmela (Phylum Homoscleromorpha), expanding the complement of poriferan miRNAs previously known only from the siliceous sponges (demosponges and hexactinellids). Comparison of these miRNAs with those previously described from silicisponges and eumetazoans reveals that these newly described miRNAs are novel, with each metazoan lineage (Silicea, Calcarea, Homoscleromorpha, and Eumetazoa) characterized by a unique and non-overlapping repertoire of miRNAs (or potential miRNAs as in the case of the homoscleromorphs). Because each group is characterized by a unique repertoire of miRNAs, miRNAs cannot be used to help resolve the contentious issue of sponge mono- versus paraphyly. Further, because all sponges are characterized by a similar repertoire of tissue types and body plan organisation, we hypothesize that the lack of conserved miRNAs amongst the three primary sponge lineages is evidence that cellular differentiation and cell type specificity in sponges are not dependent upon conserved miRNAs, contrary to many known cases in eumetazoans. Finally, we suggest that miRNAs evolved multiple times independently not only among eukaryotes, but even within animals, independently evolved miRNAs representing molecular exaptations of RNAi machinery into pre-existing gene regulatory networks. The role(s) miRNAs play though in sponge biology and evolution remains an open question. PMID- 23349042 TI - Imatinib-induced Stevens-Johnsons syndrome. AB - Imatinib mesylate is a tyrosine kinase inhibitor used widely as the first-line treatment for chronic myeloid leukaemia (CML). The side-effect profile of this drug includes fluid retention, muscle cramps, diarrhoea, myelosuppression and skin rashes. Of these, rashes of the type maculo-papular eruptions and oedema developed most commonly. The cutaneous adverse reactions other than maculo papular eruptions are rare with imatinib. Severe and life-threatening cutaneous reactions can occur in 5% cases. Here, the author reports a case of newly diagnosed CML that developed Steven-Johnsons syndrome due to imatinib therapy. Patient responded and discharged successfully on withdrawal of the culminating drug. PMID- 23349043 TI - Prevention of restenosis: medical treatment and procedures for iliac occlusive disease. AB - The treatment of occlusive vascular disease has evolved considerably over the past decades, with management strategies shifting from open surgical approaches toward less-invasive endovascular solutions or hybrid open and endovascular therapies. The treatment of aortoiliac occlusive disease has followed a similar pattern, with a more aggressive, minimally invasive approach being used even for long-segment iliac artery occlusions. Regardless of the type of treatment, however, optimal results are still limited by restenosis. This is also true in virtually all locations undergoing treatment of arterial occlusive disease. The current review seeks to explore the medical therapy and treatment options available for preventing restenosis in the iliac artery following intervention. Here we include data regarding prevention of restenosis in other arterial locations. Finally, novel therapies not currently available for iliac artery use but showing promise in prevention of arterial restenosis are reviewed. PMID- 23349044 TI - Acute enhancement of non-rapid eye movement sleep in rats after drinking water contaminated with cadmium chloride. AB - Cadmium (Cd) is a heavy metal widely used or effused by industries. Serious environmental Cd pollution has been reported over the past two centuries, whereas the mechanisms underlying Cd-mediated diseases are not fully understood. Interestingly, an increase in reactive oxygen species (ROS) after Cd exposure has been shown. Our group has demonstrated that sleep is triggered via accumulation of ROS during neuronal activities, and we thus hypothesize the involvement of Cd poisoning in sleep-wake irregularities. In the present study, we analyzed the effects of Cd intake (1-100 ppm CdCl2 in drinking water) on rats by monitoring sleep encephalograms and locomotor activities. The results demonstrated that 100 ppm CdCl2 administration for 28 h was sufficient to increase non-rapid-eye movement (non-REM) sleep and reduce locomotor activities during the night (the rat active phase). In contrast, free-running locomotor rhythms under constant dim red light and their re-entrainment to 12:12-h light/dark cycles were intact under chronic (1 month) 100 ppm CdCl2 administrations, suggesting a limited influence on circadian clock movements at this dosage. The relative amount of oxidized glutathione increased in the brain after the 28-h 100 ppm CdCl2 administrations similar to the levels in cultured astrocytes receiving H2O2 or CdCl2 in culture medium. Therefore, we propose Cd-induced sleep as a consequence of oxidative stress. As oxidized glutathione is an endogenous sleep substance, we suggest that Cd rapidly induces sleepiness and influences activity performance by occupying intrinsic sleep-inducing mechanisms. In conclusion, we propose increased non-REM sleep during the active phase as an index of acute Cd exposure. PMID- 23349045 TI - HDlive imaging of a serous borderline ovarian tumor. PMID- 23349046 TI - Optimizing MRI scan time in the computation of pharmacokinetic parameters (K(trans) ) in breast cancer diagnosis. AB - PURPOSE: To assess the effects of reduced scan time in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of breast for the evaluation of pharmacokinetic parameters (K(trans) , ve , and kep ). MATERIALS AND METHODS: High temporal resolution DCE-MRI was performed for calculation of pharmacokinetic parameters (K(trans) , ve , and kep ) at different timepoints using an in-house developed computation scheme adopting the standard model (SM). RESULTS: The receiver operating characteristic (ROC) curve analysis revealed an area under the ROC curve (AUC) of 0.994 for K(trans) at 90 seconds and 0.987 for K(trans) at 60 seconds with a significant decrease in the AUC for K(trans) at 30 seconds (0.669). While ve showed a consistently higher AUC (>0.9) at timepoints >=40 seconds, the AUC for kep showed a consistent decline with reduced acquisition times. CONCLUSION: Reducing the acquisition time for the K(trans) and ve measurement up to 60 seconds yields reasonable accuracy for both and can be incorporated in the routine DCE-MRI protocol for evaluation of enhancing breast lesions. PMID- 23349047 TI - Proteomics of the milk fat globule membrane from Camelus dromedarius. AB - Camel milk has been widely characterized with regards to casein and whey proteins. However, in camelids, almost nothing is known about the milk fat globule membrane (MFGM), the membrane surrounding fat globules in milk. The purpose of this study was thus to identify MFGM proteins from Camelus dromedarius milk. Major MFGM proteins (namely, fatty acid synthase, xanthine oxidase, butyrophilin, lactadherin, and adipophilin) already evidenced in cow milk were identified in camel milk using MS. In addition, a 1D-LC-MS/MS approach led us to identify 322 functional groups of proteins associated with the camel MFGM. Dromedary MFGM proteins were then classified into functional categories using DAVID (the Database for Annotation, Visualization, and Integrated Discovery) bioinformatics resources. More than 50% of MFGM proteins from camel milk were found to be integral membrane proteins (mostly belonging to the plasma membrane), or proteins associated to the membrane. Enriched GO terms associated with MFGM proteins from camel milk were protein transport (p-value = 1.73 * 10(-14)), translation (p-value = 1.08 * 10(-11)), lipid biosynthetic process (p-value = 6.72 * 10(-10)), hexose metabolic process (p-value = 1.89 * 10(-04)), and actin cytoskeleton organization (p-value = 2.72 * 10(-04)). These findings will help to contribute to a better characterization of camel milk. Identified MFGM proteins from camel milk may also provide new insight into lipid droplet formation in the mammary epithelial cell. PMID- 23349048 TI - The role of serum VCAM-1 and TNF-alpha as predictors of mortality and morbidity in patients with chronic heart failure. AB - BACKGROUND: To assess the prognostic significance of four inflammatory markers (TNF-alpha, high sensitive C-reactive protein (hs-CRP), intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1)) in chronic heart failure (CHF) patients with respect to individual outcomes, especially disease exacerbation and mortality. METHODS: Plasma adhesion molecules, ICAM-1, and VCAM-1, together with TNF-alpha and hs-CRP were determined in 120 CHF patients and 69 healthy controls. Endothelial function was also estimated by flow-mediated brachial artery dilatation. RESULTS: Increased levels of all investigated inflammatory markers were found in CHF patients compared to controls, with the rise more pronounced in New York Heart association (NYHA) functional IV class. Significant correlations were obtained for VCAM-1 and brain natriuretic peptide (r = 0.191; P = 0.038), as well as, ICAM-1 and endothelium dependent vasodilatation (r = -0.235; P = 0.01). Kaplan-Meier analysis showed disease exacerbation in patients with TNF-alpha levels >2.78 pg/ml significantly shorter compared to those with TNF-alpha levels <2.78 pg/ml (log-rank test = 8.270; P = 0.004), while similar association was observed for patients with hs CRP levels >4.76 mg/l (log-rank test = 5.052; P = 0.025) and VCAM-1 levels >1200 ng/l (log-rank test = 5.45; P = 0.020) with respect to mortality. Cox regression analysis demonstrated only VCAM-1 (HR = 4.7; 95% confidence interval (CI): 1.1 18.7; P = 0.030) as independent death predictor, while TNF-alpha was associated with disease exacerbation (HR = 8.2; 95%CI: 1.1-23.0; P = 0.045). CONCLUSIONS: VCAM-1 appears to be useful in risk stratification of CHF patients and in screening, to identify subjects at risk for heart failure related events. PMID- 23349049 TI - GABAergic neurons regulate lateral ventricular development via transcription factor Pax5. AB - Postmortem studies have revealed a downregulation of the transcription factor Pax5 in GABAergic neurons in bipolar disorder, a neurodevelopmental disorder, raising the question whether Pax5 in GABAergic neurons has a role in normal brain development. In a genetic approach to study functions of Pax5 in GABAergic neurons, Pax5 was specifically deleted in GABAergic neurons from Pax5 floxed mice using a novel Gad1-Cre transgenic mouse line expressing Cre recombinase in Gad1 positive, that is, GABAergic neurons. Surprisingly, these mice developed a marked enlargement of the lateral ventricles at approximately 7 weeks of age, which was lethal within 1-2 weeks of its appearance. This hydrocephalus phenotype was observed in mice homozygous or heterozygous for the Pax5 conditional knockout, with a gene dosage-dependent penetrance. By QTL (quantitative trait loci) mapping, a 3.5 Mb segment on mouse chromosome 4 flanked by markers D4Mit237 and D4Mit214 containing approximately 92 genes including Pax5 has previously been linked to differences in lateral ventricular size. Our findings are consistent with Pax5 being a relevant gene underlying this QTL phenotype and demonstrate that Pax5 in GABAergic neurons is essential for normal ventricular development. PMID- 23349050 TI - Protein kinase A-Ialpha regulates Na,K-ATPase endocytosis in alveolar epithelial cells exposed to high CO(2) concentrations. AB - Elevated concentrations of CO2 (hypercapnia) lead to alveolar epithelial dysfunction by promoting Na,K-ATPase endocytosis. In the present report, we investigated whether the CO2/HCO3(-) activated soluble adenylyl cyclase (sAC) regulates this process. We found that hypercapnia increased the production of cyclic adenosine monophosphate (cAMP) and stimulated protein kinase A (PKA) activity via sAC, which was necessary for Na,K-ATPase endocytosis. During hypercapnia, cAMP was mainly produced in specific microdomains in the proximity of the plasma membrane, leading to PKA Type Ialpha activation. In alveolar epithelial cells exposed to high CO2 concentrations, PKA Type Ialpha regulated the time-dependent phosphorylation of the actin cytoskeleton component alpha adducin at serine 726. Cells expressing small hairpin RNA for PKAc, dominant negative PKA Type Ialpha, small interfering RNA for alpha-adducin, and alpha adducin with serine 726 mutated to alanine prevented Na,K-ATPase endocytosis. In conclusion, we provide evidence for a new mechanism by which hypercapnia via sAC, cAMP, PKA Type Ialpha, and alpha-adducin regulates Na,K-ATPase endocytosis in alveolar epithelial cells. PMID- 23349053 TI - Fine characterization of the recurrent c.1584+18672A>G deep-intronic mutation in the cystic fibrosis transmembrane conductance regulator gene. AB - Splicing mutations account for approximately 12% of the 1,890 cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations described in cystic fibrosis (CF). However, their impact on pre-mRNA processing frequently remains unclear. An interesting opportunity to study CFTR transcripts in vivo involves the use of RNA from nasal brushings. Through this approach we previously identified a deep-intronic mutation (c.1584+18672A>G) that activates a 104-base pair (bp) out-of-frame pseudoexon by creating a donor splice site. The screening of 230 patients with CF identified c.1584+18672A>G in three additional individuals, demonstrating that it is a recurrent, and potentially overlooked, mutation among Italian patients. Haplotype analysis suggests that it originated from at least two independent events. To characterize the mutation further, a genomic region, including the activated pseudoexon and surrounding intronic sequences, was cloned into an expression vector and transfected into HeLa cells. RT-PCR analysis identified two alternative splicing products, produced by the activation of two different cryptic acceptor splice sites. One included the 104 bp pseudoexon (78.7% of transcripts), and the other led to the inclusion of a 65 bp pseudoexon (21.3% of mRNAs). The allele-specific measurement of wild-type and aberrant splicings from the nasal-brushing RNA of the three probands with genotype F508del/c.1584+18672A>G demonstrated: (1) a low level of pseudoexon inclusion in the F508del transcript (not containing the splicing mutation); (2) residual wild-type splicing in the c.1584+18672A>G mRNA; (3) the degradation of aberrant transcripts; and (4) the relative strength of the different cryptic splice sites. Interestingly, the residual wild-type splicing detected in transcripts bearing the c.1584+18672A>G mutation correlates well with the milder clinical phenotype of patients. PMID- 23349052 TI - Pulmonary natural killer T cells play an essential role in mediating hyperoxic acute lung injury. AB - Critically ill patients are routinely exposed to high concentrations of supplemental oxygen for prolonged periods of time, which can be life-saving in the short term, but such exposure also causes severe lung injury and increases mortality. To address this therapeutic dilemma, we studied the mechanisms of the tissue-damaging effects of oxygen in mice. We show that pulmonary invariant natural killer T (iNKT) cells are unexpectedly crucial in the development of acute oxygen-induced lung injury. iNKT cells express high concentrations of the ectonucleotidase CD39, which regulates their state of activation. Both iNKT cell deficient (Jalpha18(-/-)) and CD39-null mice tolerate hyperoxia, compared with wild-type control mice that exhibit severe lung injury. An adoptive transfer of wild-type iNKT cells into Jalpha18(-/-) mice results in hyperoxic lung injury, whereas the transfer of CD39-null iNKT cells does not. Pulmonary iNKT cell activation and proliferation are modulated by ATP-dependent purinergic signaling responses. Hyperoxic lung injury can be induced by selective P2X7-receptor blockade in CD39-null mice. Our data indicate that iNKT cells are involved in the pathogenesis of hyperoxic lung injury, and that tissue protection can be mediated through ATP-induced P2X7 receptor signaling, resulting in iNKT cell death. In conclusion, our data suggest that iNKT cells and purinergic signaling should be evaluated as potential novel therapeutic targets to prevent hyperoxic lung injury. PMID- 23349051 TI - Macrophage A2A adenosinergic receptor modulates oxygen-induced augmentation of murine lung injury. AB - Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality. Exacerbating factors increasing the risk of ARDS remain unknown. Supplemental oxygen is often necessary in both mild and severe lung disease. The potential effects of supplemental oxygen may include augmentation of lung inflammation by inhibiting anti-inflammatory pathways in alveolar macrophages. We sought to determine oxygen-derived effects on the anti-inflammatory A2A adenosinergic (ADORA2A) receptor in macrophages, and the role of the ADORA2A receptor in lung injury. Wild-type (WT) and ADORA2A(-/-) mice received intratracheal lipopolysaccharide (IT LPS), followed 12 hours later by continuous exposure to 21% oxygen (control mice) or 60% oxygen for 1 to 3 days. We measured the phenotypic endpoints of lung injury and the alveolar macrophage inflammatory state. We tested an ADORA2A-specific agonist, CGS-21680 hydrochloride, in LPS plus oxygen-exposed WT and ADORA2A(-/-) mice. We determined the specific effects of myeloid ADORA2A, using chimera experiments. Compared with WT mice, ADORA2A(-/ ) mice exposed to IT LPS and 60% oxygen demonstrated significantly more histologic lung injury, alveolar neutrophils, and protein. Macrophages from ADORA2A(-/-) mice exposed to LPS plus oxygen expressed higher concentrations of proinflammatory cytokines and cosignaling molecules. CGS-21680 prevented the oxygen-induced augmentation of lung injury after LPS only in WT mice. Chimera experiments demonstrated that the transfer of WT but not ADORA2A(-/-) bone marrow cells into irradiated ADORA2A(-/-) mice reduced lung injury after LPS plus oxygen, demonstrating myeloid ADORA2A protection. ADORA2A is protective against lung injury after LPS and oxygen. Oxygen after LPS increases macrophage activation to augment lung injury by inhibiting the ADORA2A pathway. PMID- 23349054 TI - Identification of novel isoforms of vitellogenin expressed in ascidian eggs. AB - Vitellogenin is a precursor of yolk protein that is necessary for embryonic development. This protein is a large multi-domain protein consisting of a signal peptide, a heavy-chain lipovitellin, a phosvitin, a light-chain lipovitellin, a von Willebrand factor type D domain (vWF-D), and a C-terminal coding region (CT), which are processed to respective domains after uptake into oocytes. It is currently believed that only lipovitellin and phosvitin domains are necessary for nutrient supply to oocytes. Thus, molecular species of vitellogenin lacking these domains are not known. Here, we show that two novel isoforms of vitellogenin, both of which possess vWF-D and CT domains but not a lipovitellin or phosvitin domain, are expressed in the gonad of the ascidian Halocynthia roretzi. In situ hybridization revealed that mRNAs of these proteins are specifically expressed in oocytes and test cells, accessory cells in the perivitelline space of ascidian eggs. Immunohistochemistry showed that these proteins are localized around the surface of test cells in immature oocytes. Immunoelectron microscopy revealed that vitellogenin associates with vesicles located beneath the vitelline coat (VC) before fertilization but that it dissociates from the VC after fertilization. These results, together with our previous results showing that vWF D and CT domains are capable of binding to the two sperm proteases HrProacrosin and HrSpermosin, led us to propose that novel isoforms of vitellogenin, which are expressed in oocytes and test cells and released to the perivitelline space during oocyte maturation, may participate in gamete interaction upon fertilization. PMID- 23349055 TI - Introduction to the HESI-sponsored inhibin consortium. PMID- 23349056 TI - Towards high-siderophore-content foods: optimisation of coprogen production in submerged cultures of Penicillium nalgiovense. AB - BACKGROUND: Fungal siderophores are likely to possess atheroprotective effects in humans, and therefore studies are needed to develop siderophore-rich food additives or functional foods to increase the siderophore uptake in people prone to cardiovascular diseases. In this study the siderophore contents of mould ripened cheeses and meat products were analysed and the coprogen production by Penicillium nalgiovense was characterised. RESULTS: High concentrations of hexadentate fungal siderophores were detected in penicillia-ripened Camembert- and Roquefort-type cheeses and also in some sausages. In one sausage fermented by P. nalgiovense, the siderophore content was comparable to those found in cheeses. Penicillium nalgiovense produced high concentrations of coprogen in submerged cultures, which were affected predominantly by the available carbon and nitrogen sources under iron starvation. Considerable coprogen yields were still detectable in the presence of iron when the fermentation medium was supplemented with the iron chelator Na2-EDTA or when P. nalgiovense was co-cultivated with Saccharomyces cerevisiae. CONCLUSION: These data may be exploitable in the future development of high-siderophore-content foods and/or food additives. Nevertheless, the use of P. nalgiovense fermentation broths for these purposes may be limited by the instability of coprogen in fermentation media and by the beta-lactam production by the fungus. PMID- 23349057 TI - Outcomes of morbidly obese patients receiving invasive mechanical ventilation: a nationwide analysis. AB - BACKGROUND: Critically ill, morbidly obese patients (BMI>=40 kg/m2) are at high risk of respiratory failure requiring invasive mechanical ventilation (IMV). It is not clear if outcomes of critically ill, obese patients are affected by obesity. Due to limited cardiopulmonary reserve, they may have poor outcomes. However, literature to this effect is limited and conflicted. METHODS: We used the Nationwide Inpatient Sample from 2004 to 2008 to examine the outcomes of morbidly obese people receiving IMV and compared them to nonobese people. We identified hospitalizations requiring IMV and morbid obesity using International Classification of Diseases, 9th Revision, Clinical Modification codes. Primary outcomes studied were inhospital mortality, rates of prolonged mechanical ventilation (>=96 h), and tracheostomy. Multivariable logistic regression was used to adjust for potential confounding variables. We also examined outcomes stratified by number of organs failing. RESULTS: Of all hospitalized, morbidly obese people, 2.9% underwent IMV. Mean age, comorbidity score, and severity of illness were lower in morbidly obese people. The adjusted mortality was not significantly different in morbidly obese people (OR 0.89; 95% CI, 0.74-1.06). When stratified by severity of disease, there was a stepwise increase in risk for mortality among morbidly obese people relative to nonobese people (range: OR, 0.77; 95% CI, 0.58-1.01 for only respiratory failure, to OR, 4.14; 95% CI, 1.11 15.3 for four or more organs failing). Rates of prolonged mechanical ventilation were similar, but rate of tracheostomy (OR 2.19; 95% CI, 1.77-2.69) was significantly higher in patients who were morbidly obese. CONCLUSIONS: Morbidly obese people undergoing IMV have a similar risk for death as nonobese people if only respiratory failure is present. When more organs fail, morbidly obese people have increased risk for mortality compared with nonobese people. PMID- 23349058 TI - Pain increases motivational drive to obtain reward, but does not affect associated hedonic responses: a behavioural study in healthy volunteers. AB - BACKGROUND: Pain and reward have been suggested to interact, and some evidence is provided by a rodent study showing that acutely injured animals are more motivated to reach a food reward while they do not increase food consumption, pointing at unaltered reward liking. Since no data exist in humans, we conducted a psychophysical experiment to test the effects of experimentally induced tonic pain on (1) the motivation to receive reward and (2) hedonic responses when being rewarded. METHODS: Forty healthy participants underwent two experimental sessions: in one, painful heat stimulation was continuously applied while participants played a monetary reward task; in the other, participants experienced non-painful warm stimulation while playing the task. In the task, participants needed to react quickly enough to a target cue to win the money associated with the particular trial ($0.04, $1 or $4). Reaction time to the target cue served as measure of motivation. Ratings after each trial on how much the participant liked the trial's outcome served as a measure of hedonic responses. RESULTS: Pain increased the motivation to obtain reward when the incentive was high, indexed by decreased reaction times (repeated-measures analysis of variance, interaction pain * incentive; p = 0.009). In contrast to motivational drive, hedonic ratings of the rewarding stimuli were not influenced by pain. CONCLUSION: Similar to existing rodent data, our results suggest a pain induced mismatch of increased motivational drive with a lack of increased hedonic responses. This mismatch is discussed as perhaps reflecting a failed coping attempt, which is potentially relevant for chronic pain patients. PMID- 23349059 TI - Early fetoscopic tracheal occlusion for extremely severe pulmonary hypoplasia in isolated congenital diaphragmatic hernia: preliminary results. AB - OBJECTIVE: To evaluate the effect of early fetoscopic tracheal occlusion (FETO) (22-24 weeks' gestation) on pulmonary response and neonatal survival in cases of extremely severe isolated congenital diaphragmatic hernia (CDH). METHODS: This was a multicenter study involving fetuses with extremely severe CDH (lung-to-head ratio < 0.70, liver herniation into the thoracic cavity and no other detectable anomalies). Between August 2010 and December 2011, eight fetuses underwent early FETO. Data were compared with nine fetuses that underwent standard FETO and 10 without fetoscopic procedure from January 2006 to July 2010. FETO was performed under maternal epidural anesthesia, supplemented with fetal intramuscular anesthesia. Fetal lung size and vascularity were evaluated by ultrasound before and every 2 weeks after FETO. Postnatal therapy was equivalent for both treated fetuses and controls. Primary outcome was infant survival to 180 days and secondary outcome was fetal pulmonary response. RESULTS: Maternal and fetal demographic characteristics and obstetric complications were similar in the three groups (P > 0.05). Infant survival rate was significantly higher in the early FETO group (62.5%) compared with the standard group (11.1%) and with controls (0%) (P < 0.01). Early FETO resulted in a significant improvement in fetal lung size and pulmonary vascularity when compared with standard FETO (P < 0.01). CONCLUSIONS: Early FETO may improve infant survival by further increases of lung size and pulmonary vascularity in cases with extremely severe pulmonary hypoplasia in isolated CDH. This study supports formal testing of the hypothesis with a randomized controlled trial. PMID- 23349060 TI - Regional difference in GABA levels between medial prefrontal and occipital cortices. AB - PURPOSE: To avoid the confounding effects of variations in tissue composition this study measured regional GABA differences using two voxels with the same tissue composition. MATERIALS AND METHODS: Eighteen healthy adult volunteers were scanned using a 3 Tesla GE clinical scanner with a J-coupling based editing sequence. Spectroscopy voxels were placed in the medial prefrontal (MPFC) and occipital cortex (OCC) with essentially the same gray and white matter fractions. RESULTS: A 16% (P = 0.0001) significantly higher GABA to creatine ratio was found in the OCC (0.1103 +/- 0.0050) compared with the MPFC (0.0953 +/- 0.0041). When normalized to tissue water, GABA concentrations in the OCC were 14% higher than in the MPFC. CONCLUSION: A difference in GABA concentration was found between the OCC and MPFC voxels in healthy subjects which is attributable to differences other than tissue composition. PMID- 23349061 TI - Predominance of Enterobacteriaceae isolates in early positive anaerobic blood culture bottles in BacT/Alert system. AB - We collected and analyzed the time to detection (TTD) of blood cultures in the BacT/Alert automated system from 2002 to 2007. Among the 10,893 monomicrobial isolates from a total of 133,735 blood culture sets, the recoveries of aerobic bottles were compared with those of anaerobic bottles in this study. Significantly more Gram-positive cocci (except Staphylococcus aureus and enterococci), glucose nonfermentative Gram-negative bacteria, and yeast were recovered from aerobic bottles than from anaerobic bottles. The average TTD was 19.0 hr and 20.1 hr for the aerobic and anaerobic bottles, respectively, and 96.8% of the microorganisms were detected within the first 72 hr. Of the 5,489 microorganisms recovered from both of the blood culture bottle pair, microbial growth was significantly more often detected first in the anaerobic bottles than the aerobic bottles for Enterobacteriaceae except Serratia marcescens, while S. aureus, coagulase-negative staphylococci and Pseudomonas aeruginosa were more often detected first in the aerobic bottles. According to these data, we conclude that the earlier positivity of anaerobic bottles is a useful marker for rapid presumptive identification of Enterobacteriaceae infection. PMID- 23349062 TI - Effect of silk protein processing on drug delivery from silk films. AB - Sericin removal from the core fibroin protein of silkworm silk is a critical first step in the use of silk for biomaterial-related applications, but degumming can affect silk biomaterial properties, including molecular weight, viscosity, diffusivity and degradation behavior. Increasing the degumming time (10, 30, 60, and 90 min) decreases the average molecular weight of silk protein in solution, silk solution viscosity, and silk film glass-transition temperature, and increases the rate of degradation of a silk film by protease. Model compounds spanning a range of physical-chemical properties generally show an inverse relationship between degumming time and release rate through a varied degumming time silk coating. Degumming provides a useful control point to manipulate silk's material properties. PMID- 23349063 TI - A novel reporter rat strain that expresses LacZ upon Cre-mediated recombination. AB - The recent widespread application of Cre/loxP technology has resulted in a new generation of conditional animal models that can better recapitulate many salient features of human disease. These models benefit from the ability to monitor the expression and functionality of Cre protein. We have generated a conditional (Cre/loxP dependent) LacZ reporter rat (termed the LacZ541 rat) to monitor Cre in transgenic rats. When LacZ541 rats were bred with another transgenic rat line expressing Cre recombinase under the control of the CAG promoter, LacZ/Cre double transgenic embryos displayed ubiquitous expression of LacZ, and when LacZ541 rats were bred with transgenic rats expressing Cre/loxP-dependent oncogenic H- or K ras, LacZ was expressed in the lesions resulting from the activation of the oncogene. The LacZ541 rat enables evaluation of the performance of Cre-expressing systems which are based upon transgenic rats or somatic gene transfer vectors and provides efficient and simple lineage marking. PMID- 23349064 TI - Inhibin B in plasma samples from male volunteer panel selected for health but not fertility: sources of variability. AB - BACKGROUND: Inhibin B was measured in plasma samples obtained from 34 healthy male subjects selected on criteria typical for a phase I clinical trial across a wide age range (19-70 years). METHODS: Mutiple samples (up to seven per subject) were obtained as a set consisting of one baseline sample then three pairs of morning and evening samples. This allowed assessment of the fed/fasted state and diurnal effects. Samples were analyzed using a commercially available inhibin B ELISA assay. Across all time points, the mean plasma inhibin B was 197 pg/ml +/- 67pg/ml. RESULTS: The results confirmed a diurnal effect where inhibin B concentration is on average about 40 pg/ml greater in the morning and showed a negative influence of age on inhibin B concentrations. There was no overt influence of body mass index on inhibin B. A variance components analysis revealed that more than 80% of the total variability was due to the variability observed between individuals. Within the fed-fasted sampling schedule of this study, inhibin B levels were slightly lower when volunteers had eaten but the magnitude of this effect was within the variance encountered between occasions. CONCLUSION: These results illustrate that when undertaking longitudinal monitoring of inhibin B in clinical trials as means of monitoring testicular function, it is important to obtain samples from an individual at the same time of day and to use statistical methods which analyze the magnitude of deviation of an individual from their personal baseline as well as looking at group means and influence of study duration. PMID- 23349065 TI - Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. AB - SCOPE: Plant secondary metabolites, such as phenolic acids are commonly associated with benefits for human health. Two of the most abundant phenylpropanoid-derived compounds detected in human faecal samples are phenylacetic acid (PAA) and 4-hydroxylphenylacetic acid (4-hydroxyPAA). Although they have the potential to be derived from diets rich in plant-based foods, evidence suggests that these compounds can be derived from the microbial fermentation of aromatic amino acids (AAAs) in the colon. METHODS AND RESULTS: To identify the bacteria responsible, 26 strains representing 25 of the dominant human colonic species were screened for phenyl metabolite formation. Seven strains produced significant amounts of both PAA and 4-hydroxyPAA. These included five out of seven Bacteroidetes (Bacteroides thetaiotaomicron, Bacteroides eggerthii, Bacteroides ovatus, Bacteroides fragilis, Parabacteroides distasonis), and two out of 17 Firmicutes (Eubacterium hallii and Clostridium bartlettii). These species also produced indole-3-acetic acid (IAA), the corresponding tryptophan metabolite, but C. bartlettii showed 100 times higher IAA production than the other six strains. Four strains were further tested and PAA formation was substantially increased by phenylalanine, 4-hydroxyPAA by tyrosine and IAA by tryptophan. CONCLUSION: This study demonstrates that certain microbial species have the ability to ferment all three AAAs and that protein fermentation is the likely source of major phenylpropanoid-derived metabolites in the colon. PMID- 23349066 TI - New insight into motor adaptation to pain revealed by a combination of modelling and empirical approaches. AB - BACKGROUND: Movement changes in pain. Unlike the somewhat stereotypical response of limb muscles to pain, trunk muscle responses are highly variable when challenged by pain in that region. This has led many to question the existence of a common underlying theory to explain the adaptation. Here, we tested the hypotheses that (1) adaptation in muscle activation in acute pain leads to enhanced spine stability, despite variation in the pattern of muscle activation changes; and (2) individuals would use a similar 'signature' pattern for tasks with different mechanical demands. METHODS: In 17 healthy individuals, electromyography recordings were made from a broad array of anterior and posterior trunk muscles while participants moved slowly between trunk flexion and extension with and without experimentally induced back pain. Hypotheses were tested by estimating spine stability (Stability Index) with an electromyography driven spine model and analysis of individual and overall (net) adaptations in muscle activation. RESULTS: The Stability Index (P < 0.017) and net muscle activity (P < 0.021) increased during pain, although no two individuals used the same pattern of adaptation in muscle activity. For most, the adaptation was similar between movement directions despite opposite movement demands. CONCLUSIONS: These data provide the first empirical confirmation that, in most individuals, acute back pain leads to increased spinal stability and that the pattern of muscle activity is not stereotypical, but instead involves an individual-specific response to pain. This adaptation is likely to provide short term benefit to enhance spinal protection, but could have long-term consequences for spinal health. PMID- 23349067 TI - Alcohol outlet business hours and violent crime in New York state. AB - AIMS: Alcohol-related harm places a significant strain on victims, perpetrators and society. The present research reports on how licensed alcohol outlet business hours may influence the reported incidence of interpersonal violence and the associated burden of disease. METHODS: We examined the relationship between alcohol outlet business hours and violent crime in 2009 in New York State (excluding New York City). Regression analyses modeled the burden of disease for the violence associated with outlet business hours. RESULTS: Every 1 h increase in weekly outlet business hours was associated with a greater reported incidence of violent crimes generally, more reported aggravated assaults and more reported non-gun violence. The estimated cost from having licensed premises open after 1 a.m. was $194 million in 2009. CONCLUSION: The findings suggest that alcohol outlet business hours affect the incidence of reported violence even in regions that would not be considered to have severe problems with alcohol-fueled violence. PMID- 23349068 TI - Standardized fetal anatomical examination using magnetic resonance imaging: a feasibility study. AB - OBJECTIVE: To determine whether a standard complete fetal anatomical survey, as recommended for ultrasound examination guidelines, is feasible using a standardized magnetic resonance imaging (MRI) protocol. METHODS: Based on guidelines for ultrasound examination, we created a specific MRI protocol for fetal anatomical survey. This protocol was then tested prospectively in 100 women undergoing fetal MRI examination for various specific indications at a median gestational age of 30 weeks. The feasibility of using MRI to perform the fetal anatomical survey was analyzed by two reviewers (A and B) based on 26 predefined anatomical criteria, yielding a score ranging from 0 to 26 (26 meaning successful complete anatomical study). Reproducibility was analyzed using percentage agreement and modified kappa statistics. RESULTS: The mean score for the standardized MRI anatomical survey was 24.6 (SD, 1.4; range, 15-26) for Reviewer A and 24.2 (SD, 1.7; range, 15-26) for Reviewer B (P = 0.1). Twenty-two, two and two criteria could be assessed in > 95%, 80-95% and < 80% of cases by Reviewer A and 19, four and three criteria could be assessed in > 95%, 80-95% and < 80% of cases by Reviewer B. For both reviewers, the two most difficult criteria to evaluate were aorta and pulmonary artery. Inter-reviewer agreement was above 90% for 22 of the 26 anatomical criteria and adjusted kappa coefficients for each criterion demonstrated good, moderate and poor agreement for 22, two and two criteria, respectively. CONCLUSION: Our data support the hypothesis that standardized fetal anatomical examination might be achieved and reproducible using MRI, although improvement is required for the cardiac part of the examination. PMID- 23349069 TI - Psychological change mechanisms in anorexia nervosa treatments: how much do we know? AB - OBJECTIVE: Anorexia nervosa (AN) is a debilitating and often chronic and treatment-resistant disorder. Despite decades of theoretical progress and research, many questions remain with regard to the psychological mechanisms explaining why and how some AN patients respond to treatment whereas others do not. Based on the premise that the broader, noneating disorders psychotherapy research literature, and particularly the common factors literature, can inform AN treatment development efforts, we review a set of selected psychological change mechanisms and describe how they might be relevant in the context of AN treatment response. Specifically, we suggest that a systematic consideration of constructs such as basic psychological needs, expectancies, the therapeutic alliance, experiential avoidance, and patient motivation for change might help illuminate how patients do or do not benefit from AN treatment. We briefly describe an ongoing multicenter trial in which the constructs introduced here are being measured on a weekly basis and are examined as potential mediators of treatment response. The article aims to contribute to the AN literature by introducing a set of potentially important change constructs that we think ought to be studied in greater depth by AN researchers. PMID- 23349071 TI - Synthesis, photochromic, and computational studies of dithienylethene-containing beta-diketonate derivatives and their near-infrared photochromic behavior upon coordination of a boron(III) center. AB - A series of dithienylethene-containing 1-thienyl-3-aryl-propane-1,3-diones (aryl = phenyl (Ph), thienyl (Th), and 4,5-bis(2,5-dimethylthiophen-3-yl)thiophen-2-yl (DTE-Th)) and the corresponding boron(III) diketonates, (O^O)BR(2) (R = F, C(6)F(5), and Ph), have been designed and synthesized. Their photophysical, electrochemical, and photochromic properties have been studied. Upon coordination of a boron(III) center, the closed forms of the dithienylethene-containing beta diketonates show near-infrared response and the photochromic behavior was also found to be affected by the aryl substituents at the 3-position of the beta diketonates. Moreover, computational studies have been performed that help to provide an understanding of the effect of substituents on the photophysical and photochromic properties. PMID- 23349070 TI - Anisotropic analysis of multi-component T2 and T1rho relaxations in achilles tendon by NMR spectroscopy and microscopic MRI. AB - PURPOSE: To study the anisotropic characteristics of both multi-component T2 and T1rho relaxation times in tendon. MATERIALS AND METHODS: T2 and T1rho were measured in tendon by NMR spectroscopy at different orientations and by microscopic MRI at the magic angle. Several experimental issues in the multi component relaxation measurements were investigated, including the effects of echo spacing, the resolution of MRI experiments, the influence of the specimen orientations, and the strengths of different spin-lock frequencies in T1rho experiments. RESULTS: Both the values and fractions of T2 in tendon showed significant orientational dependence. The values and fractions of T1rho strongly depended on both the specimen orientation and the spin-lock strength. The imaging resolution (35-280 MUm) had little influence in the T2 experiments. Both the echo spacings (0.6-3.0 ms) in the T2 experiment and the spin-lock strengths (0.5-5 kHz) in the T1rho experiment affected the quantification of the multi-component relaxation. Up to three T2 and T1rho components were resolved in tendon. CONCLUSION: Multi-component relaxations could be attributed to different populations of water in the tissue. The transitions between a mono-component and multi-component result call for the caution in interpreting the relaxation results. PMID- 23349072 TI - Monitoring nutrient transport in tissue-engineered grafts. AB - Limited nutrient diffusion in three-dimensional (3D) constructs is a major concern in tissue engineering. Therefore, monitoring nutrient availability and diffusion within a scaffold is an important asset. Since nutrients come in various forms, we have investigated the diffusion of the oxygen, luciferin and dextran molecules within tissue-engineered constructs using optical imaging technologies. First, oxygen availability and diffusion were investigated, using transgenic cell lines in which a hypoxia-responsive element drives expression of the green fluorescent protein gene. Using confocal imaging, we observed oxygen limitation, starting at around 200 um from the periphery in the context of agarose gel with 1 million CHO cells. Diffusion of luciferin was monitored real time in agarose gels using a cell line in which the luciferase gene was driven by a constitutively active CMV promoter. Gel concentration affected the diffusion rate of luciferin. Furthermore, we assessed the diffusion rates of fluorescent dextran molecules of different molecular weights in biomaterials by fluorescence recovery after photobleaching (FRAP) and observed that diffusion depended on both molecular size and gel concentration. In conclusion, we have validated a set of efficient tools to investigate molecular diffusion of a range of molecules and to optimize biomaterials design in order to improve nutrient delivery. PMID- 23349074 TI - Enhancement of biomechanical behavior on osseointegration of implant with SLAffinity. AB - The purpose of this study was to investigate stresses resulting from different thicknesses of hydroxyapatite- and titanium dioxide (TiO(2))-treated layers at the interface between temporomandibular joint (TMJ) implants and bones using three-dimensional finite element models. For ensuring osseointegration of implant treatment, one must examine the stresses of interface between implant and bone tissue. Treated layers on TMJ implants are a very important factor in clinical application. Several studies have investigated finite element models for TMJs, but few have examined a model for TMJ implants with treated layers. In this study, TMJ models were reconstructed using computer tomography data, and the effects of treated layer thickness on the stress field during jaw movement were investigated; this index has not yet been reported with respect to TMJ implant. The maximum stresses in the bone occurred at the position of the first screw. Data analysis indicated a greater decrease in this stress in the case of using TMJ implants with TiO(2)-treated layers, and the stresses decreased with increasing layer thicknesses. Results confirmed that the treated layers improve biomechanical properties of the TMJ implants and release abnormal stress concentration in them. The results of our study offer the potential clinical benefit of inducing superior biomechanical behavior in TMJ implants. PMID- 23349073 TI - Microbiota diversity and stability of the preterm neonatal ileum and colon of two infants. AB - The composition of the microbiota associated with the human ileum and colon in the early weeks of life of two preterm infants was examined, with particular emphasis on the Lactobacillus and Bifidobacterium members. Culturing work showed that bifidobacteria and lactobacilli in the ileostomy changed over time, compared with the colostomy effluent where there was far less variation. The colostomy infant was dominated by two phyla, Actinobacteria and Firmicutes, while in the ileostomy samples, Proteobacteria emerged at the expense of Actinobacteria. Bacteroidetes were only detected following the reversal of the ileostomy in the final fecal sample and were not detected in any colonic fluid samples. Clostridia levels were unstable in the colostomy fluid, suggesting that the ileostomy/colostomy itself influenced the gut microbiota, in particular the strict anaerobes. Pyrosequencing analysis of microbiota composition indicated that bifidobacteria and lactobacilli are among the dominant genera in both the ileal and colonic fluids. Bifidobacteria and lactobacilli levels were unstable in the ileostomy fluid, with large reductions in numbers and relative proportions of both observed. These decreases were characterized by an increase in proportions of Streptococcus and Enterobacteriaceae. Clostridium was detected only in the colonic effluent, with large changes in the relative proportions over time. PMID- 23349075 TI - Generation and characterization of ScxCre transgenic mice. AB - Scleraxis (Scx) is a basic helix-loop-helix transcription factor that is a marker for the tendon/ligament cell lineage. The ~11 kb genomic region from the mouse Scx gene locus faithfully recapitulates the endogenous Scx expression pattern in ScxGFP transgenic (Tg) mice. We have established two Tg mouse lines expressing Cre-recombinase (Cre) using this regulatory region (ScxCre-L and ScxCre-H). The specificity and efficiency of Cre recombination in these Tg lines are evaluated by crossing with Rosa-CAG-LSL-tdTomato (Ai14) or ROSA26R (R26R) reporter mice. The recombination in ScxCre-H;Ai14 mice is efficiently achieved in the endogenous Scx expression domains including the branchial arches, the syndetome, and the lateral plate mesoderm. Further analysis of ScxCre-H;Ai14;ScxGFP embryos reveal that expression of the ScxGFP transgene largely overlaps with Cre activity detected by tdTomato at embryonic day 12.5 (E12.5). In ScxCre-L;R26R or ScxCre H;R26R neonates, Cre activity is detected in tendons, ligaments, intervertebral discs, joints, and cartilage around the chondro-tendinous/ligamentous junction, the prospective enthesis. The present results suggest that ScxCre Tg lines are useful for targeting the gene specifically in the Scx-expressing domains. PMID- 23349076 TI - Neuromedin U receptor 2 does not play a role in the development of neuropathic pain following nerve injury in mice. AB - BACKGROUND: Previous studies have identified neuromedin U receptor 2 (NMUR2) as the subtype mediating the effects of neuromedin U on acute chemo-nociception induced by capsaicin or formalin injection. The aims of this study were to determine whether NMUR2 is required for the development of mechanical hypersensitivity after nerve injury or heat hypersensitivity after inflammation and whether there is a gender difference in the contribution of NMUR2 to nociception. METHODS: Mechanical sensitivity was assessed with von Frey filaments in wild type (WT) and NMUR2-null mice at baseline and following spared tibial nerve (STN) injury. Heat sensitivity was also assessed at baseline and after induction of inflammation with Freund's complete adjuvant (FCA). RESULTS: The response to von Frey filaments at baseline was similar for WT and NMUR2-null mice and for males and females. The response of male NMUR2-null mice was slightly but significantly decreased when exposed to 52 degrees C but not 58 degrees C heat stimuli. There was no difference between the stimulus-response curve for WT and NMUR2-null mice 7, 13 and 16 days after nerve injury. Similarly, after FCA induced inflammation, there was no significant difference in heat hyperalgesia between WT and NMUR2-null mice or male or female mice in responses to temperatures ranging from 44 to 48 degrees C. CONCLUSIONS: The present data do not support a significant contribution of NMUR2 to the development of hypersensitivity after nerve injury or tissue inflammation, suggesting that pharmacological intervention aimed at the NMUR2 receptor might not be a valuable approach for the treatment of chronic pain. PMID- 23349077 TI - 3-Caffeoyl, 4-dihydrocaffeoylquinic acid from Salicornia herbacea attenuates high glucose-induced hepatic lipogenesis in human HepG2 cells through activation of the liver kinase B1 and silent information regulator T1/AMPK-dependent pathway. AB - SCOPE: Increasing evidence indicates that polyphenols may protect against metabolic disease through activating AMP-activated protein kinase (AMPK). The aims of our study were to provide new data on the molecular mechanism(s) underlying the role of the phenolic compound, 3-caffeoyl, 4-dihydrocaffeoylquinic acid (CDCQ) from Salicornia herbacea, in the prevention of high glucose-induced lipogenesis in human HepG2 cells. METHODS AND RESULTS: Nile red staining assays were used to demonstrate lipid accumulation in the cells. Expression of sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) gene at the levels of promoter activity, mRNA, and protein was demonstrated using transient transfection assays, quantitative RT-PCR, and Western blot analyses, respectively. We found that CDCQ suppressed high glucose-induced lipid accumulation in HepG2 cells. CDCQ strongly inhibited high glucose-induced FAS expression by modulating SREBP-1c activation. Moreover, the use of both a specific inhibitor and liver kinase B1 (LKB1)-siRNA transfected HepG2 cells showed that CDCQ activated AMPK via silent information regulator T1 (SIRT1) or LKB1 in HepG2 cells. CONCLUSION: These results indicate that CDCQ prevented lipid accumulation by blocking the expression of SREBP-1c and FAS through LKB1/SIRT1 and AMPK activation in HepG2 cells, suggesting that CDCQ plays a potential role in the prevention of lipogenesis by AMPK activation. PMID- 23349078 TI - Sonographic imaging of fetal tympanic rings. AB - OBJECTIVE: To examine the feasibility of ultrasonographic imaging of fetal tympanic rings. METHODS: This was an observational cohort study of 80 healthy fetuses in low-risk pregnancies, divided into four gestational-age subgroups (12, 16, 23 and 32 weeks), each comprising 20 consecutive fetuses. Tympanic ring visualization was achieved by two-dimensional and three-dimensional (3D) sonography. A standard algorithm for tympanic ring examination was constructed using 3D multiplanar reconstruction. The volume acquisition plane was directed to the inferolateral aspect of the fetal temporal bone. Transvaginal scans were carried out in the 12-week and 16-week subgroups, and transabdominal scans in the 23-week and 32-week subgroups. Study parameters included the inferomedial inclination angle (IMIA) of the tympanic ring relative to the vertical skull axis, the anteromedial inclination angle (AMIA) of the tympanic ring relative to the anteroposterior skull axis and the longest (LTRD) and shortest (STRD) tympanic ring diameter, the latter measured perpendicular to the LTRD. The feasibility of tympanic ring demonstration was assessed in each gestational-age subgroup. RESULTS: Tympanic rings appeared as round-oval, thin, echogenic structures in a plane tangential to the inferolateral surface of the fetal skull below the inferior border of the squamous part of the temporal bone. Higher demonstration rates were achieved in the 16-week and 23-week subgroups (90% and 80%, respectively) than in the others. LTRD and STRD each showed a linear correlation with gestational age (r = 0.96 for both measurements; P < 0.01). Mean IMIA ranged from 41.0 to 60.4 degrees and mean AMIA from 17.3 to 23.4 degrees across the different gestational-age subgroups. The malleal manubrium was observed only in examinations in the second half of pregnancy, appearing as a bright echo within the upper area of the tympanic ring in 56% (9/16) and 82% (9/11) of cases with tympanic ring imaging appropriate for measurement of the study parameters in the 23-week and 32-week subgroups, respectively. CONCLUSION: This is the first report of sonographic imaging of fetal tympanic rings and shows that this is feasible in the second trimester. We discuss the possible implications of our findings for the prenatal diagnosis of congenital hearing loss. PMID- 23349080 TI - Federated queries of clinical data repositories: the sum of the parts does not equal the whole. AB - BACKGROUND AND OBJECTIVE: In 2008 we developed a shared health research information network (SHRINE), which for the first time enabled research queries across the full patient populations of four Boston hospitals. It uses a federated architecture, where each hospital returns only the aggregate count of the number of patients who match a query. This allows hospitals to retain control over their local databases and comply with federal and state privacy laws. However, because patients may receive care from multiple hospitals, the result of a federated query might differ from what the result would be if the query were run against a single central repository. This paper describes the situations when this happens and presents a technique for correcting these errors. METHODS: We use a one-time process of identifying which patients have data in multiple repositories by comparing one-way hash values of patient demographics. This enables us to partition the local databases such that all patients within a given partition have data at the same subset of hospitals. Federated queries are then run separately on each partition independently, and the combined results are presented to the user. RESULTS: Using theoretical bounds and simulated hospital networks, we demonstrate that once the partitions are made, SHRINE can produce more precise estimates of the number of patients matching a query. CONCLUSIONS: Uncertainty in the overlap of patient populations across hospitals limits the effectiveness of SHRINE and other federated query tools. Our technique reduces this uncertainty while retaining an aggregate federated architecture. PMID- 23349079 TI - Pulmonary perfusion MRI using interleaved variable density sampling and HighlY constrained cartesian reconstruction (HYCR). AB - PURPOSE: To demonstrate the feasibility of performing single breathhold, noncardiac gated, ultrafast, high spatial-temporal resolution whole chest MR pulmonary perfusion imaging in humans. MATERIALS AND METHODS: Eight subjects (five male, three female) were scanned with the proposed method on a 3 Tesla clinical scanner using a 32-channel phased-array coil. Seven (88%) were healthy volunteers, and one was a patient volunteer with sarcoidosis. The peak lung enhancement phase for each subject was scored for gravitational effect, peak parenchymal enhancement and severity of artifacts by three cardiothoracic radiologists independently. RESULTS: All studies were successfully performed by MR technologists without any additional training. Mean parenchymal signal was very good, measuring 0.78 +/- 0.13 (continuous scale, 0 = "none" -> 1 = "excellent"). Mean level of motion artifacts was low, measuring 0.13 +/- 0.08 (continuous scale, 0 = "none" -> 1 = "severe"). CONCLUSION: It is feasible to perform single breathhold, noncardiac gated, ultrafast, high spatial-temporal resolution whole chest MR pulmonary perfusion imaging in humans. PMID- 23349081 TI - An additive manufacturing-based PCL-alginate-chondrocyte bioprinted scaffold for cartilage tissue engineering. AB - Regenerative medicine is targeted to improve, restore or replace damaged tissues or organs using a combination of cells, materials and growth factors. Both tissue engineering and developmental biology currently deal with the process of tissue self-assembly and extracellular matrix (ECM) deposition. In this investigation, additive manufacturing (AM) with a multihead deposition system (MHDS) was used to fabricate three-dimensional (3D) cell-printed scaffolds using layer-by-layer (LBL) deposition of polycaprolactone (PCL) and chondrocyte cell-encapsulated alginate hydrogel. Appropriate cell dispensing conditions and optimum alginate concentrations for maintaining cell viability were determined. In vitro cell based biochemical assays were performed to determine glycosaminoglycans (GAGs), DNA and total collagen contents from different PCL-alginate gel constructs. PCL alginate gels containing transforming growth factor-beta (TGFbeta) showed higher ECM formation. The 3D cell-printed scaffolds of PCL-alginate gel were implanted in the dorsal subcutaneous spaces of female nude mice. Histochemical [Alcian blue and haematoxylin and eosin (H&E) staining] and immunohistochemical (type II collagen) analyses of the retrieved implants after 4 weeks revealed enhanced cartilage tissue and type II collagen fibril formation in the PCL-alginate gel (+TGFbeta) hybrid scaffold. In conclusion, we present an innovative cell-printed scaffold for cartilage regeneration fabricated by an advanced bioprinting technology. PMID- 23349082 TI - The influence of demand characteristics and social desirability on clients' ratings of the therapeutic alliance. AB - OBJECTIVE: To examine demand characteristics, social desirability on clients' rating of working alliance using the Session Rating Scale (SRS; Miller, Duncan, & Johnson, 2000). METHOD: Clients (N = 102) at two sites were randomly assigned to one of three alliance feedback conditions: (a) IF--SRS completed in presence of therapist and the results discussed immediately afterward; (b) Next Session Feedback--SRS completed alone and results discussed next session; or (c) No Feedback--SRS completed alone and results not available to therapist. Clients completed the SRS for the first three sessions of treatment. RESULTS: No statistically significant differences in SRS scores across the feedback conditions were found. Additionally, the analysis showed that SRS scores were not correlated with a measure of social desirability but were correlated with an established alliance measure. CONCLUSIONS: The results indicate that alliance scores were not inflated due to the presence of a therapist or knowing that the scores would be observed by the therapist. PMID- 23349083 TI - Immediate force loss after eccentric contractions is increased with L-NAME administration, a nitric oxide synthase inhibitor. AB - INTRODUCTION: Nitric oxide (NO) signaling regulates many biological processes in skeletal muscle, wherein aberrant signaling contributes to myopathic conditions (e.g., Duchenne muscular dystrophy). NO has been shown to play a role in muscle regeneration after injury. However, less is known about its role during injury. In this study we aimed to determine whether NO synthase (NOS) inhibition exacerbates functional deficits immediately after the performance of eccentric contractions. METHODS: Wild-type mouse extensor digitorum longus (EDL) muscles underwent in vitro functional testing in the presence or absence of a non specific NOS inhibitor (L-NAME, 10 mM) before and after performance of 10 eccentric contractions. RESULTS: After eccentric contractions, P(o) was reduced by ?25% for muscle in regular physiological solution but by ?50% with the addition of L-NAME (P = 0.009). CONCLUSIONS: Non-specific blockade of NOS exacerbates functional deficits immediately after eccentric contractions, suggesting that NO signaling protects skeletal muscle from excessive injury in healthy muscle. PMID- 23349084 TI - Noninvasive respiratory management and diaphragm and electrophrenic pacing in neuromuscular disease and spinal cord injury. AB - The purpose of this monograph is to describe noninvasive management of respiratory muscle weakness/paralysis for patients with neuromuscular disease (NMD) and spinal cord injury (SCI). Noninvasive ventilation (NIV) assists and supports inspiratory muscles, whereas mechanically assisted coughing (MAC) simulates an effective cough. Long-term outcomes will be reviewed as well as the use of NIV, MAC, and electrophrenic pacing (EPP) and diaphragm pacing (DP) to facilitate extubation and decannulation. Although EPP and DP can facilitate decannulation and maintain alveolar ventilation for high-level SCI patients when they cannot use NIV because of lack of access to oral interfaces, there is no evidence that they have any place in the management of NMD. PMID- 23349085 TI - Aquaporin-4 antibody seropositivity in myasthenia gravis patients with thymoma. PMID- 23349086 TI - Myotonia congenita in a patient who presented with diplopia and ptosis. PMID- 23349087 TI - Case study of sporadic mitochondrial disease with myotonic discharges and optic atrophy. PMID- 23349093 TI - Cytokine secretion from human peripheral blood mononuclear cells cultured in vitro with metal particles. AB - The failure of implanted medical devices can be associated with changes in the production of cytokines by cells of the immune system. Cytokines released by peripheral blood mononuclear cells upon contact with metal particles were quantified to understand their role in implantation intergration and their importance as messengers in the recruitment of T-lymphocytes at the implantation site. Opsonization was utilised to understand the influence of serum proteins on particle-induced cytokine production and release. Different metal compositions were used in the particulate format, Titanium (Ti), Titanium alloy (Ti6Al4V), and Stainless Steel 316L (SS), and were cultured in vitro with a mixed population of monocytes/macrophages and lymphocytes. The cells were also exposed to an exogenous stimulant mixture of phytohemagglutinin-P and interferon-gamma (IFN gamma) and opsonized particles with human serum. Interleukins, IL-1alpha, IL 1beta, IL-2, IL-4, IL-6, IL-8, IFN-gamma, and tumor necrosis factor-alpha (TNF alpha) were investigated using enzyme-linked immunosorbent assay as they are an indicator of the inflammation evoked by particulate metals. It has been experimentally evidenced that metal particles induced higher amounts of IL-6 and IL-1 but very low amounts of TNF-alpha. T-lymphocyte activation was evaluated by the quantification of IL-2 and IFN-gamma levels. The results showed that nonopsonized and opsonized metal particles did not induce the release of increased levels of IL-2 and IFN-gamma. PMID- 23349094 TI - Interspecific variations in the gastrointestinal microbiota in penguins. AB - Despite the enormous amount of data available on the importance of the gastrointestinal (GI) microbiota in vertebrate (especially mammals), information on the GI microbiota of seabirds remains incomplete. As with many seabirds, penguins have a unique digestive physiology that enables them to store large reserves of adipose tissue, protein, and lipids. This study used quantitative real-time polymerase chain reaction (qPCR) and 16S rRNA gene pyrosequencing to characterize the interspecific variations of the GI microbiota of four penguin species: the king, gentoo, macaroni, and little penguin. The qPCR results indicated that there were significant differences in the abundance of the major phyla Firmicutes, Bacteroides, Actinobacteria, and Proteobacteria. A total of 132,340, 18,336, 6324, and 4826 near full-length 16S rRNA gene sequences were amplified from fecal samples collected from king, gentoo, macaroni, and little penguins, respectively. A total of 13 phyla were identified with Firmicutes, Bacteroidetes, Proteobacteria, and Fusobacteria dominating the composition; however, there were major differences in the relative abundance of the phyla. In addition, this study documented the presence of known human pathogens, such as Campylobacter, Helicobacter, Prevotella, Veillonella, Erysipelotrichaceae, Neisseria, and Mycoplasma. However, their role in disease in penguins remains unknown. To our knowledge, this is the first study to provide an in-depth investigation of the GI microbiota of penguins. PMID- 23349095 TI - The effectiveness of varenicline medication guide for conveying safety information to patients: a REMS assessment survey. AB - PURPOSE: Risk Evaluation and Mitigation Strategies (REMS) include various mechanisms to enhance safe use of medications, including a patient medication guide (MG) that provides key information regarding the potential risks associated with the medication. To evaluate the effectiveness of the varenicline MG as a REMS tool for educating patients, we undertook a survey among patients who were dispensed varenicline. METHODS: Varenicline recipients within the Optum Research Database, a large U.S. administrative claims database, were invited to participate in a self-administered survey. Survey questions were general (receipt and reading of the MG) and specific regarding patient's understanding of the potential varenicline risks outlined in the MG (neuropsychiatric symptoms, skin reactions, and allergic reactions). RESULTS: From 3568 varenicline recipients invited, 640 (18%) responded, with 633 completing at least one of three risk comprehension questions. The majority (93%) indicated receiving the MG, and 86% read all or part of it. Ninety-one percent, 41%, and 53% correctly answered at least one question on neuropsychiatric symptoms, skin reactions, and allergic reactions, respectively. A higher proportion who read the MG had correct responses to the risk-comprehension questions than those who did not read it. CONCLUSIONS: The varenicline MG was widely received and read among survey respondents, and the information conveyed was generally well understood regarding potential risk of neuropsychiatric symptoms. This study provides an assessment of the effectiveness of the varenicline MG in communicating information about potential risks associated with varenicline. This assessment method may apply to the evaluation of the effectiveness of other MGs. PMID- 23349096 TI - Mx1-cre mediated Rgs12 conditional knockout mice exhibit increased bone mass phenotype. AB - Regulators of G-protein Signaling (Rgs) proteins are the members of a multigene family of GTPase-accelerating proteins (GAP) for the Galpha subunit of heterotrimeric G-proteins. Rgs proteins play critical roles in the regulation of G protein couple receptor (GPCR) signaling in normal physiology and human diseases such as cancer, heart diseases, and inflammation. Rgs12 is the largest protein of the Rgs protein family. Some in vitro studies have demonstrated that Rgs12 plays a critical role in regulating cell differentiation and migration; however its function and mechanism in vivo is largely unknown. Here, we generated a floxed Rgs12 allele (Rgs12(flox/flox) ) in which the exon 2, containing both PDZ and PTB_PID domains of Rgs12, was flanked with two loxp sites. By using the inducible Mx1-cre and Poly I:C system to specifically delete Rgs12 at postnatal 10 days in interferon-responsive cells including monocyte and macrophage cells, we found that Rgs12 mutant mice had growth retardation with the phenotype of increased bone mass. We further found that deletion of Rgs12 reduced osteoclast numbers and had no significant effect on osteoblast formation. Thus, Rgs12(flox/flox) conditional mice provide a valuable tool for in vivo analysis of Rgs12 function and mechanism through time- and cell-specific deletion of Rgs12. PMID- 23349097 TI - Toward a "structural BLAST": using structural relationships to infer function. AB - We outline a set of strategies to infer protein function from structure. The overall approach depends on extensive use of homology modeling, the exploitation of a wide range of global and local geometric relationships between protein structures and the use of machine learning techniques. The combination of modeling with broad searches of protein structure space defines a "structural BLAST" approach to infer function with high genomic coverage. Applications are described to the prediction of protein-protein and protein-ligand interactions. In the context of protein-protein interactions, our structure-based prediction algorithm, PrePPI, has comparable accuracy to high-throughput experiments. An essential feature of PrePPI involves the use of Bayesian methods to combine structure-derived information with non-structural evidence (e.g. co-expression) to assign a likelihood for each predicted interaction. This, combined with a structural BLAST approach significantly expands the range of applications of protein structure in the annotation of protein function, including systems level biological applications where it has previously played little role. PMID- 23349099 TI - Glutathione exposes sequential IgE-epitopes in ovomucoid relevant in persistent egg allergy. AB - SCOPE: Patients with persistent egg allergy have more immunoglobulin E (IgE) against sequential than conformational epitopes of ovomucoid (OVO). Here, we aimed to identify compounds capable to render sequential epitopes in egg. METHODS AND RESULTS: Glutathione was used for in vitro reduction of OVO and circular dichroism analyses were performed. Glutathione reduced OVO in a concentration dependent manner. Egg white was analyzed for reduced proteins with a thiol probe and by MALDI-TOF/TOF. In unprocessed total egg white, several reduced proteins were detected by the thiol probe, among them reduced ovalbumin could be confirmed with MS analyses. Egg-allergics or sensitized controls were tested serologically (n = 19) for IgE against native and reduced OVO and in skin prick tests (n = 9). More patients had IgE against reduced than native OVO in Western blots. In skin prick test, five out of seven persistent egg-allergics and none of the controls reacted with reduced OVO. CONCLUSION: Reduced egg proteins are present in natural egg white. Glutathione, which is present in egg and furthermore is used as texture-improving additive in processed food, is capable of reducing OVO. Patients with persistent egg allergy reacted rather to reduce the native OVO. Hence, our data indicate that reduction is a novel natural and processing associated principle, which contributes to the allergenicity of food. PMID- 23349100 TI - Demineralized bone matrix and human cancellous bone enhance fixation of porous coated titanium implants in sheep. AB - Allogenic bone graft has been considered the gold standard in connection with bone graft material in revision joint arthroplasty. However, the lack of osteogenic potential and the risk of disease transmission are clinical challenges. The use of osteoinductive materials, such as demineralized bone matrix (DBM), alone or in combination with allograft or commercially available human cancellous bone (CB), may replace allografts, as they have the capability of inducing new bone and improving implant fixation through enhancing bone ongrowth. The purpose of this study was to investigate the effect of DBM alone, DBM with CB, or allograft on the fixation of porous-coated titanium implants. DBM100 and CB produced from human tissue were included. Both materials are commercially available. DBM granules are placed in pure DBM and do not contain any other carrier. Titanium alloy implants, 10 mm long * 10 mm diameter, were inserted bilaterally into the femoral condyles of eight skeletally mature sheep. Thus, four implants with a concentric gap of 2 mm were implanted in each sheep. The gap was filled with: (a) DBM; (b) DBM:CB at a ratio of 1:3; (c) DBM:allograft at a ratio of 1:3; or (d) allograft (gold standard), respectively. A standardized surgical procedure was used. At sacrifice 6 weeks after implantation, both distal femurs were harvested. The implant fixation was evaluated by mechanical push-out testing to test shear mechanical properties between implant and the host bone and by histomorphometry. Non-parametric tests were applied; p < 0.05 was considered significant. Mechanical fixation showed that the strengths among the DBM/CB, DBM/allograft and allograft groups were not statistically different. The strength of the DBM group was 0.01 MPa, which was statistical significantly lower than the other three groups (p < 0.05). Histomorphometry results showed that the bone ongrowth in the DBM group was statistically significantly lower than the other three groups, while the volume fraction of new bone showed no significant difference among all the groups. Our data revealed that adding DBM to CB or to allograft resulted in comparable mechanical properties relative to the gold standard, allograft. We found inferior early effects of DBM alone on the fixation of porous-coated titanium implant in this animal model, while the long-term effects have to be investigated. The combination of DBM with CB, which can be used off the shelf, may represent an alternative to allograft. A cost-benefit analysis is necessary before application in clinical trial. PMID- 23349098 TI - Evidence for distinct genetic effects associated with response to 35% CO2. AB - BACKGROUND: Carbon dioxide (CO2 ) hypersensitivity represents an individual difference response to breathing CO2 enriched air. People with a history of panic attacks or panic disorder are particularly prone to anxious response, suggesting that CO2 hypersensitivity is a robust risk marker of panic spectrum vulnerability. METHODS: Twin pairs (n = 346) from the general population-based Norwegian NIPH Mental Health Study completed a measure of anxiety before and after vital capacity inhalation of 35% CO2 air and before and after inhalation of regular air. Three hypotheses regarding genetic factors for CO2 hypersensitivity were examined: (1) a single set of genetic risk factors impacts anxiety before exposure to CO2 and these same genes constitute the only genetic influences on anxiety in response to CO2 , (2) the genetic effects on pre-CO2 anxiety are entirely different from the genetic effects on anxiety in response to exposure to CO2 (i.e., new genetic effects), and (3) pre-CO2 anxiety influences anxiety in response to CO2 as well as unique genetic factors that become activated by respiratory stimulation. RESULTS: Our results support the latter hypothesis for response to 35% CO2 , with additive genetic and unique environmental factors best fitting the data. Evidence of new genetic effects was observed, accounting for 20% unique variance in post 35% CO2 anxiety response. New genetic effects were not observed for anxiety ratings made post regular air where only preregular air anxiety ratings explained significant variance in this outcome. CONCLUSIONS: These data suggest that there are distinct genetic factors associated with responsivity to respiratory stimulation via 35% CO2 . PMID- 23349101 TI - Reduced toxicity and superior cellular response of preosteoblasts to Ti-6Al-7Nb alloy and comparison with Ti-6Al-4V. AB - There are serious concerns on the toxicity of vanadium in Ti-6Al-4V alloy. In this regard, we describe the biological footprint of Ti-6Al-4V and compare with a viable alternate Ti-6Al-7Nb alloy, in terms of novel experimentation pertaining to cellular activity that include qualitative and quantitative analysis of Feret's diameter of cells, area, and perimeter, and proteins-actin, vinculin, and fibronectin. Interestingly, Ti-6Al-7Nb was characterized by superior cell attachment, proliferation, viability, morphology, and spread, which were significantly different from Ti-6Al-4V alloy. Additionally, immunofluorescence studies demonstrated stronger vinculin signals associated with actin stress fibers in the outer regions of the cells and cellular extensions in Ti-6Al-7Nb alloy. These striking observations suggest enhanced cell-substrate interaction and activity on the surface of niobium-containing titanium alloy. The significant differences in the cellular response between the two alloys clearly point to the determining role of alloying element (Nb versus V) in a conclusive manner. Based on this study, next generation of titanium alloys is proposed to focus on niobium containing alloy. PMID- 23349102 TI - Modulation of Nrf2-dependent gene transcription by bilberry anthocyanins in vivo. AB - In a human pilot intervention study (healthy + ileostomy probands), the questions were addressed whether in vivo consumption of an anthocyanin-rich bilberry (Vaccinium myrtillius L.) pomace extract (BE) affects (i) the transcription of Nrf2-dependent genes in peripheral blood mononuclear cells (PBMC), indicative for systemic effects, and (ii) the level of oxidative DNA damage in these cells. In healthy test subjects transcripts of NAD(P)H quinone oxidoreductase 1 (NQO1) were significantly elevated throughout the observation period (1-8 h), whereas transcription of heme oxygenase 1 (HO-1) and Nrf2 was significantly decreased. NQO1 and HO-1 transcription remained unchanged in the ileostomy probands, whereas Nrf2-transcription was suppressed in both groups. Decrease in oxidative DNA damage was observed 2 h after BE consumption again only in healthy subjects. In vitro studies using a reporter gene approach (CHO) and qPCR (HT29) indicate that not the intact anthocyanins/anthocyanidins are the activating constituents but the intestinal degradation product phloroglucinol aldehyde (PGA). Taken together, consumption of anthocyanin-rich BE was found to modulate Nrf2-dependent gene expression in PBMCs indicative for systemic activity. Limitation of the effect to healthy test subjects suggests a role of colonic processes for bioactivity, supported by the results on Nrf2-activating properties of the intestinal anthocyanin degradation product PGA. PMID- 23349103 TI - Professional confidence: conceptions held by novice occupational therapists in South Africa. AB - This study aimed to explore how novice occupational therapists conceptualized professional confidence. Professional confidence is a dynamic personal belief that matures over time. It is closely linked to both competence and professional identity ensuring fitness for practice. Although professional confidence has been defined and a number of its attributes have been identified, how practitioners understand or conceptualize the phenomenon is not clearly understood. Eight novice occupational therapists undertaking their community service year in South Africa during 2011 participated in the study. Data, collected during semi structured interviews, were analyzed using phenomenographic methodology. From the participant's descriptions, three qualitatively different ways of understanding professional confidence emerged from the data, namely knowing as an occupational therapist, believing you are an occupational therapist and being an occupational therapist. The outcome space was also described. The study did not purport to gauge whether the novice therapists were in fact confident. As professional confidence is a maturing self-belief, the findings are limited to novice occupational therapists. The findings contribute to a growing understanding of professional confidence in occupational therapy. Further research is needed in terms of what informs the conceptions held by novice therapists and how professional confidence can be assessed in graduates on completion of their educational programme. PMID- 23349104 TI - Factors influencing the prescription of drugs of different price levels. AB - PURPOSE: Socioeconomic factors have been suggested to influence the prescribing of newer and more expensive drugs. In the present study, individual and health care provider factors were studied in relation to the prevalence of differently priced drugs. METHODS: Register data for dispensed drugs were retrieved for 18 486 individuals in a county council in Sweden. The prevalence of dispensed drugs was combined with data for the individual's gender, age, education, income, foreign background, and type of caregiver. For each of the diagnostic groups (chronic obstructive pulmonary disease [COPD], depression, diabetes, and osteoporosis), selected drugs were dichotomized into cost categories, lower and higher price levels. Univariate and multivariate logistic regressions were performed using cost category as the dependent variable and the individual and provider factors as independent variables. RESULTS: In all four diagnostic groups, differences were observed in the prescription of drugs of lower and higher price levels with regard to the different factors studied. Age and gender affected the prescription of drugs of lower and higher price levels more generally, except for gender in the osteoporosis group. Income, education, foreign background, and type of caregiver affected prescribing patterns but in different ways for the different diagnostic groups. CONCLUSIONS: Certain individual and provider factors appear to influence the prescribing of drugs of different price levels. Because the average price for the cheaper drugs versus more costly drugs in each diagnostic group was between 19% and 69%, there is a risk that factors other than medical needs are influencing the choice of drug. PMID- 23349105 TI - Fabrication of FITC-doped silica nanoparticles and study of their cellular uptake in the presence of lectins. AB - Fluorescent silica nanoparticles are reported to be highly stable and biocompatible materials with high water solubility, which make them ideal candidates for biological applications. These nanoparticles can also be modified with biocompatible and targeting moieties and can be used for a variety of in vitro and in vivo applications, such as targeting, particle tracking, cargo carrier, and as contrast agents. In this study, fluorescent dye-doped silica nanoparticles were prepared by a modified Stober method. The nanoparticles produced were surface functionalized with amine moieties for their conjugation with glucose-derived and galactose-based residues. The amine, glucose-derived, and galactose-based functionalized fluorescent silica nanoparticles were analyzed for their physiochemical properties such as sizes, polydispersities, organic layer content, and surface chemistries. The nanoparticles produced were then studied for their interactions with carbohydrate-specific lectins. These lectin bioconjugates have helped in understanding their interactions with cell-surface receptors. As expected, galactose-functionalized nanoparticles were found to specifically interact with RCA120 , as compared to other nanoparticles. These specific interactions of galactose-lectin conjugates were further studied on the hepatocytes cell surface in vitro. The aggregation of galactose-lectins conjugates on the plasma membrane was possibly due to the specific interactions of carbohydrates with cell-surface glycoproteins, hence preventing the uptake of these nanoparticles. The study has provided an interesting approach to mark the cell-surface glycoproteins with fluorescent probes using a combination of lectin carbohydrate conjugates. PMID- 23349106 TI - Youth genetic vulnerability to maternal depressive symptoms: 5-HTTLPR as moderator of intergenerational transmission effects in a multiwave prospective study. AB - BACKGROUND: Maternal depressive symptoms are a strong predictor of increases in depressive symptoms in offspring, yet knowledge of individual differences that may moderate the association between youth and maternal symptoms is still relatively scant. Youth genetic susceptibility to maternal depressive symptoms in particular is a nearly unexplored area of research. METHODS: This study used a multiwave prospective design and lagged hierarchical linear modeling analyses to examine whether youth 5-HTTLPR genotype moderated the longitudinal association between mother and youth depressive symptoms in a community sample (N = 241 youth). Maternal and youth symptoms were assessed every 3 months over 1 year (five waves of data). RESULTS: Youth 5-HTTLPR interacted with idiographic elevations in maternal depressive symptoms (elevations relative to mothers' average level of symptoms) to predict prospective increases in youth symptoms 3 months later. Youth with the SS genotype experienced greatest increases in depressive symptoms when exposed to elevations in maternal symptoms. Youth 5 HTTLPR did not interact with maternal nomothetic elevations in depressive symptoms (severity of symptoms compared to the sample as a whole). CONCLUSION: These findings advance knowledge on genetic susceptibility for intergenerational transmission of depression between mothers and their children. PMID- 23349107 TI - Greater scaffold permeability promotes growth of osteoblastic cells in a perfused bioreactor. AB - Pore size and porosity have been widely acknowledged as important structural factors in tissue-engineered scaffolds. In fact, scaffolds with similar pore size and porosity can provide important and varied permeability due to different pore shape, interconnectivity and tortuosity. However, the effects of scaffold permeability on seeded cells remains largely unknown during tissue regeneration in vitro. In this study, we measured the Darcy permeability (K) of tri-calcium phosphate scaffolds by distributed them into three groups: Low, Medium and High. As a result, the effects of scaffold permeability on cell proliferation, cellular activity and growth in the inner pores were investigated in perfused and static cultures in vitro. Results demonstrated that higher permeable scaffolds exhibited superior performance during bone regeneration in vitro and the advantages of higher scaffold permeability were amplified in perfused culture. Based on these findings, scaffold permeability should be considered in future scaffold fabrications. PMID- 23349108 TI - An improved SPE method for fractionation and identification of phospholipids. AB - This work reports an efficient and universal SPE method developed for separation and identification of phospholipids derived from complex biological samples. For the separation step, sequential combination of silica gel-aminopropyl-silica gel SPE cartridges is applied. This setup enables separation of phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylinositol, phosphatidylserine, cardiolipin, and sphingomyelin into four fractions according to the polarity of their headgroups. Sample acquisition of the SPE fractions is performed by a high-resolution LC-MS system consisting of a hybrid linear IT Fourier transform ion cyclotron resonance mass spectrometer coupled to RP-HPLC. The unequivocal advantage of our SPE sample preparation setup is avoidance of analyte peak overlapping in the determination step done by RP-HPLC. Overlapping phospholipid signals would otherwise exert adverse ion suppression effects. An additional benefit of this method is the elimination of polar and nonpolar (e.g. neutral lipids) contaminants from the phospholipid fractions, which highly reduces contamination of the LC-MS system. The method was validated with fermentation samples of organic waste, where 78 distinct phospholipid and sphingomyelin species belonging to six lipid classes were successfully identified. PMID- 23349109 TI - Human breast milk sugars and polyols over the first 10 puerperium days. AB - OBJECTIVE: The transition from colostrum to mature breast milk during early puerperium is associated with significant concentration changes of numerous compounds. However, it is not known whether the free sugars, aminohexoses, and polyols are affected. Therefore, in this study, we aimed to determine their concentrations in human colostrum and milk during the first 10 days postpartum. METHODS: This prospective longitudinal study in a sample of normal consecutive obstetric patients was conducted as a collaboration between two academic centers Polish and American. Participants were 13 women after uncomplicated pregnancy and delivery at term of a singleton, appropriate-for-gestational-age fetus. Lactose, galactose, glucose, mannose, galactosamine, glucosamine, glycerol, and myo inositol concentrations were measured using high performance liquid chromatography. RESULTS: During the first 3 days postpartum, the concentrations of lactose and glucose increased significantly (P < 0.001), to steady-state values thereafter. In contrast, the concentrations of myo-inositol and glycerol decreased significantly (P < 0.001) over the first 4 days, to reach relatively low stable values. ANOVA analysis indicated that the postpartum day at which early changes ceased to be significantly different from their plateau values was Day 4. myo-Inositol concentrations were significantly higher (P = 0.022) in multiparas than in primiparas. CONCLUSIONS: The colostrum-to-milk transition is associated with significant changes in concentrations of free sugars and polyols, changes which are completed by the fourth postpartum day. Parity influences the concentrations of some compounds in the breast milk. PMID- 23349110 TI - Polylactic-co-glycolic acid mesh coated with fibrin or collagen and biological adhesive substance as a prefabricated, degradable, biocompatible, and functional scaffold for regeneration of the urinary bladder wall. AB - The chief obstacle for reconstructing the bladder is the absence of a biomaterial, either permanent or biodegradable, that will function as a suitable scaffold for the natural process of regeneration. In this study, polylactic-co glycolic acid (PLGA) plus collagen or fibrin was evaluated for its suitability as a scaffold for urinary bladder construct. Human adipose-derived stem cells (HADSCs) were cultured, followed by incubation in smooth muscle cells differentiation media. Differentiated HADSCs were then seeded onto PLGA mesh supported with collagen or fibrin. Evaluation of cell-seeded PLGA composite immersed in culture medium was performed under a light and scanning microscope. To determine if the composite is compatible with the urodynamic properties of urinary bladder, porosity and leaking test was performed. The PLGA samples were subjected to tensile testing was pulled until PLGA fibers break. The results showed that the PLGA composite is biocompatible to differentiated HADSCs. PLGA collagen mesh appeared to be optimal as a cell carrier while the three-layered PLGA-fibrin composite is better in relation to its leaking/ porosity property. A biomechanical test was also performed for three-layered PLGA with biological adhesive and three-layered PLGA alone. The tensile stress at failure was 30.82 +/ 3.80 (MPa) and 34.36 +/- 2.57 (MPa), respectively. Maximum tensile strain at failure was 19.42 +/- 2.24 (mm) and 23.06 +/- 2.47 (mm), respectively. Young's modulus was 0.035 +/- 0.0083 and 0.043 +/- 0.012, respectively. The maximum load at break was 58.55 +/- 7.90 (N) and 65.29 +/- 4.89 (N), respectively. In conclusion, PLGA-Fibrin fulfils the criteria as a scaffold for urinary bladder reconstruction. PMID- 23349111 TI - Determination of thiol compounds by HPLC and fluorescence detection with 1,3,5,7 tetramethyl-8-bromomethyl-difluoroboradiaza-s-indacene. AB - Altered levels of thiols in biological fluids are considered to be an important indicator for several diseases. In this article, 1,3,5,7-tetramethyl-8 bromomethyl-difluoroboradiaza-s-indacene is proposed as a fluorescent derivatization reagent for the determination of thiols including glutathione, cysteine, N-acetylcysteine, and homocysteine by HPLC. Under the optimized derivatization and separation conditions, a baseline separation of all the four derivatives has been achieved using isocratic elution on an RP C(8) column within 26 min. With fluorescence detection at 505 and 525 nm for the excitation and emission, respectively, the LODs (S/N = 3) are from 0.2 nM (glutathione) to 0.8 nM (cysteine). The feasibility of this method in real samples has been evaluated by the determination of thiols in human plasma from the healthy persons and hypertensive patients with recoveries of 92-105.3%. PMID- 23349112 TI - Efficacy and acceptability of high frequency repetitive transcranial magnetic stimulation (rTMS) versus electroconvulsive therapy (ECT) for major depression: a systematic review and meta-analysis of randomized trials. AB - Clinical trials comparing the efficacy and acceptability of high frequency repetitive transcranial magnetic stimulation (HF-rTMS) and electroconvulsive therapy (ECT) for treating major depression (MD) have yielded conflicting results. As this may have been the result of limited statistical power, we have carried out this meta-analysis to examine this issue. We searched the literature for randomized trials on head-to-head comparisons between HF-rTMS and ECT from January 1995 through September 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, and SCOPUS. The main outcome measures were remission rates, pre-post changes in depression ratings, as well as overall dropout rates at study end. We used a random-effects model, Odds Ratios (OR), Number Needed to Treat (NNT), and Hedges' g effect sizes. Data were obtained from 7 randomized trials, totalling 294 subjects with MD. After an average of 15.2 HF rTMS and 8.2 ECT sessions, 33.6% (38/113) and 52% (53/102) of subjects were classified as remitters (OR = 0.46; p = 0.04), respectively. The associated NNT for remission was 6 and favoured ECT. Also, reduction of depressive symptomatology was significantly more pronounced in the ECT group (Hedges' g = 0.93; p = 0.007). No differences on dropout rates for HF-rTMS and ECT groups were found. In conclusion, ECT seems to be more effective than HF-rTMS for treating MD, although they did not differ in terms of dropout rates. Nevertheless, future comparative trials with larger sample sizes and better matching at baseline, longer follow-ups and more intense stimulation protocols are warranted. PMID- 23349113 TI - Determinants of western food adoption among Hindu Nepalese women living in the Kathmandu Valley. AB - OBJECTIVES: The purpose of this study was to characterize western food adopters among Nepalese women and to investigate whether caste and class play an important role as a barrier to food adoption, thus limiting access to the globalizing market. It was hypothesized that women who consumed and prepared above average amounts of western foods would be taller and heavier. METHODS: A convenience sample of 508 Nepalese women of mixed castes, 18-60 years, was purposefully recruited. A Food Adoption Instrument was developed, tested, and used to assess the consumption of western foods. Women were grouped as western food adopters (>= 12.5)-those consuming equal or more western food than Nepalese foods and western food non-adopters (<= 12.5). Using student t-tests, sample characteristics and body mass index (BMI) were compared between western food adopters and non-western food adopters. RESULTS: Nearly a quarter of the women identified as western food adopters (n = 118) and 76% identified as western food non-adopters (n = 399). Using student t-test analysis, stepwise regression, and Pearson correlation analyses, it was found that western food adopters were significantly younger (P < 0.000), better educated (P < 0.000), had fewer children (P < 0.003), had higher incomes (P < 0.000), and watched more TV (P < 0.000) than western food non adopters. They were taller and had lower BMIs than their western food non-adopter counterparts. Caste was also associated with western food adoption. CONCLUSIONS: Lack of education and low paying jobs appear to prevent access to the globalizing food system, suggesting that the centuries old sociopolitical and caste infrastructure indirectly prevents western food adoption for those failing to achieve financial security. PMID- 23349114 TI - Secretomes: the fungal strike force. AB - Microorganisms, although being very diverse because they comprise prokaryotic organisms such as bacteria or eukaryotic organisms such as fungi, all share an essential exodigester function. The consequence is their essential need to have a secretome adapted to their environment. The selection pressure exerted by environmental constraints led to the emergence of species with varying complexity in terms of composition of their secretomes. This review on fungal secretomes highlights the extraordinary variability among these organisms, even within the same species, and hence the absolute necessity to fully characterize all their components in the aims of understanding the fundamental mechanisms responsible for secretome plasticity and developing applications notably toward a better control of diseases caused by these pathogens. PMID- 23349116 TI - Recyclable synthesis, characterization, and antimicrobial activity of chitosan based polysaccharide composite materials. AB - We have successfully developed a simple and totally recyclable method to synthesize novel, biocompatible, and biodegradable composite materials from cellulose (CEL) and chitosan (CS). In this method, [BMIm(+) Cl(-) ], an ionic liquid (IL), was used as a green solvent to dissolve and synthesize the [CEL+CS] composites. Since, the IL can be removed from the composites by washing them with water, and recovered by distilling the washed solution, the method is totally recyclable. Spectroscopic and imaging techniques including XRD, FTIR, NIR, and SEM were used to monitor the dissolution, to characterize and to confirm that CEL and CS were successfully regenerated. More importantly, we have successfully demonstrated that [CEL+CS] composite is particularly suited for many applications including antimicrobial property. This is because the composites have combined advantages of their components, namely superior chemical and mechanical stability (from CEL) and bactericide (from CS). Results of tensile strength measurements clearly indicate that adding CEL into CS substantially increase its tensile strength. Up to 5* increase in tensile strength can be achieved by adding 80% of CEL into CS. Results of in vitro antibacterial assays confirm that CS retains its antibacterial property in the composite. More importantly, the composites reported here can inhibit growth of wider range of bacteria than other CS-based materials prepared by conventional methods; that is over 24 h period, the composites substantially inhibited growth of bacteria such as MRSA, VRE, S. aureus, E. coli. These are bacteria that are often found to have the highest morbidity and mortality associated with wound infections. PMID- 23349117 TI - "Let's get physical": advantages of a physical model over 3D computer models and textbooks in learning imaging anatomy. AB - Three-dimensional (3D) information plays an important part in medical and veterinary education. Appreciating complex 3D spatial relationships requires a strong foundational understanding of anatomy and mental 3D visualization skills. Novel learning resources have been introduced to anatomy training to achieve this. Objective evaluation of their comparative efficacies remains scarce in the literature. This study developed and evaluated the use of a physical model in demonstrating the complex spatial relationships of the equine foot. It was hypothesized that the newly developed physical model would be more effective for students to learn magnetic resonance imaging (MRI) anatomy of the foot than textbooks or computer-based 3D models. Third year veterinary medicine students were randomly assigned to one of three teaching aid groups (physical model; textbooks; 3D computer model). The comparative efficacies of the three teaching aids were assessed through students' abilities to identify anatomical structures on MR images. Overall mean MRI assessment scores were significantly higher in students utilizing the physical model (86.39%) compared with students using textbooks (62.61%) and the 3D computer model (63.68%) (P < 0.001), with no significant difference between the textbook and 3D computer model groups (P = 0.685). Student feedback was also more positive in the physical model group compared with both the textbook and 3D computer model groups. Our results suggest that physical models may hold a significant advantage over alternative learning resources in enhancing visuospatial and 3D understanding of complex anatomical architecture, and that 3D computer models have significant limitations with regards to 3D learning. PMID- 23349118 TI - Human adaptability studies at high altitude: research designs and major concepts during fifty years of discovery. AB - OBJECTIVES: This report presents a perspective on the broad research trends in the biology of human populations at high-altitude and their contributions to the improved understanding of evolution and adaptation. A focus is on the research that has occurred over the past 50 years of anthropological fieldwork on the Andean, Tibetan, and, to a lesser extent, the East African plateaus. METHODS: With an emphasis on fieldwork studies, this report presents and illustrates major concepts and research designs in published high-altitude studies. RESULTS: Early use of a single population-multiple stress research design focused on Andean Quechua, sometimes in comparison with European or admixed Andean-European samples. That design identified physical and sociocultural environmental factors including cold and under nutrition as well as high-altitude hypobaric hypoxia. Researchers accumulated evidence supporting the hypothesis of four modes of adaptation to a complex Andean highland environment: cultural, acclimatization, developmental, and genetic. The discovery that Andean biological patterns were not replicated among Tibetan highlanders stimulated research on the extent and origins of the contrasts. It also shifted emphasis to a multiple population - single stress study design. The discovery of oxygen-homeostasis-associated genetic loci and traits in all multicellular animals has transformed high altitude research. Paradoxically, genomic analyses identifying the pertinent biological pathways are likely to return interest to environmental factors other than hypoxia. CONCLUSIONS: Details of the proximate mechanisms, the biochemical, and physiological processes underlying the three modes of biological adaptation are accumulating. Better understanding of oxygen-homeostasis processes leads to questions about crossadaptation with other environmental factors. The particulars of the ultimate mechanisms, the evolutionary, and microevolutionary history underlying the population differences are also emerging. For example, similar hemoglobin phenotypes among Tibetan and Ethiopian Amhara highlanders associate with different genetic loci and the variants at those loci are present in most populations regardless of altitude. Continuing fieldwork is urgent because modernization and migration are changing the traditional ways of life and patterns of exposure to the environment among highlanders everywhere. PMID- 23349115 TI - Pesticides, microglial NOX2, and Parkinson's disease. AB - Accumulating evidence indicates that pesticide exposure is associated with an increased risk for developing Parkinson's disease (PD). Several pesticides known to damage dopaminergic (DA) neurons, such as paraquat, rotenone, lindane, and dieldrin also demonstrate the ability to activate microglia, the resident innate immune cell in the brain. While each of these environmental toxicants may impact microglia through unique mechanisms, they all appear to converge on a common final pathway of microglial activation: NADPH oxidase 2 (NOX2) activation. This review will detail the role of microglia in selective DA neurotoxicity, highlight what is currently known about the mechanism of microglial NOX2 activation in these key pesticides, and describe the importance for DA neuron survival and PD etiology. PMID- 23349119 TI - One size does not fit all: investigating doctors' stated preference heterogeneity for job incentives to inform policy in Thailand. AB - This study investigates heterogeneity in Thai doctors' job preferences at the beginning of their career, with a view to inform the design of effective policies to retain them in rural areas. A discrete choice experiment was designed and administered to 198 young doctors. We analysed the data using several specifications of a random parameter model to account for various sources of preference heterogeneity. By modelling preference heterogeneity, we showed how sensitivity to different incentives varied in different sections of the population. In particular, doctors from rural backgrounds were more sensitive than others to a 45% salary increase and having a post near their home province, but they were less sensitive to a reduction in the number of on-call nights. On the basis of the model results, the effects of two types of interventions were simulated: introducing various incentives and modifying the population structure. The results of the simulations provide multiple elements for consideration for policy-makers interested in designing effective interventions. They also underline the interest of modelling preference heterogeneity carefully. PMID- 23349120 TI - Subcutaneous tissue response to titanium, poly(epsilon-caprolactone), and carbonate-substituted hydroxyapatite-coated poly(epsilon-caprolactone) plates: a rabbit study. AB - The aim of this study was to evaluate the soft tissue response to poly(epsilon caprolactone) (PCL) implants with and without carbonate-substituted hydroxyapatite (CHA) coating compared to the commonly used titanium alloy (Ti-6Al 4V)-machined surface. Experimental materials were implanted subcutaneously in New Zealand white rabbits for 5 weeks. The tissue attachment strength, as evaluated by a tissue peel test, histological and histomorphology analysis, as well as scanning electron microscopy were compared between groups. The peel test result revealed no statistically significant difference between groups. Histological analysis found fibrous capsule formation around all implant materials. The fibrous capsule around PCL implants with and without CHA coating was significantly thinner compared with the capsule thickness around the titanium implants. However, the inflammatory cells, as present at the fibrous capsule implant interface, were found to be significantly lower in the Ti-group. In conclusion, the current data do not prove that PCL or PCL with a CHA coating results in a superior soft tissue response compared with a machined titanium implant. PMID- 23349122 TI - Learning anatomy enhances spatial ability. AB - Spatial ability is an important factor in learning anatomy. Students with high scores on a mental rotation test (MRT) systematically score higher on anatomy examinations. This study aims to investigate if learning anatomy also oppositely improves the MRT-score. Five hundred first year students of medicine (n = 242, intervention) and educational sciences (n = 258, control) participated in a pretest and posttest MRT, 1 month apart. During this month, the intervention group studied anatomy and the control group studied research methods for the social sciences. In the pretest, the intervention group scored 14.40 (SD: +/- 3.37) and the control group 13.17 (SD: +/- 3.36) on a scale of 20, which is a significant difference (t-test, t = 4.07, df = 498, P < 0.001). Both groups show an improvement on the posttest compared to the pretest (paired samples t-test, t = 12.21/14.71, df = 257/241, P < 0.001). The improvement in the intervention group is significantly higher (ANCOVA, F = 16.59, df = 1;497, P < 0.001). It is concluded that (1) medical students studying anatomy show greater improvement between two consecutive MRTs than educational science students; (2) medical students have a higher spatial ability than educational sciences students; and (3) if a MRT is repeated there seems to be a test effect. It is concluded that spatial ability may be trained by studying anatomy. The overarching message for anatomy teachers is that a good spatial ability is beneficial for learning anatomy and learning anatomy may be beneficial for students' spatial ability. This reciprocal advantage implies that challenging students on spatial aspects of anatomical knowledge could have a twofold effect on their learning. PMID- 23349123 TI - The demand for preventive and restorative dental services. AB - Chronic tooth decay is the most common chronic condition in the United States among children ages 5-17 and also affects a large percentage of adults. Oral health conditions are preventable, but less than half of the US population uses dental services annually. We seek to examine the extent to which limited dental coverage and high out-of-pocket costs reduce dental service use by the nonelderly privately insured and uninsured. Using data from the 2001-2006 Medical Expenditure Panel Survey and an American Dental Association survey of dental procedure prices, we jointly estimate the probability of using preventive and both basic and major restorative services through a correlated random effects specification that controls for endogeneity. We found that dental coverage increased the probability of preventive care use by 19% and the use of restorative services 11% to 16%. Both conditional and unconditional on dental coverage, the use of dental services was not sensitive to out-of-pocket costs. We conclude that dental coverage is an important determinant of preventive dental service use, but other nonprice factors related to consumer preferences, especially education, are equal if not stronger determinants. PMID- 23349125 TI - Identification of (2-aminopropyl)benzofuran (APB) phenyl ring positional isomers in internet purchased products. AB - 5-(2-Aminopropyl)benzofuran (5-APB), a 'research chemical' that was first reported by UK authorities to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) in 2010, is anecdotally reported to produce a combination of stimulant and entactogenic effects. More recently, in 2011, 6-(2 aminopropyl)benzofuran (6-APB) was identified by Hungarian authorities. To confirm positional isomer identity in Internet purchased products, 4- 5- 6- and 7 APBs were synthesized and found to be separable by gas chromatography (as heptafluorobutyramide derivatives) and liquid chromatography. The analyses of products purchased from online vendors of 'research chemicals' identified the presence of 5- or 6-APBs. These findings were further confirmed by liquid chromatography-mass spectrometry and (1) H nuclear magnetic resonance spectroscopy. In products containing 6-APB, the 4- positional isomer was also identified and this may have arisen during the manufacturing process. PMID- 23349126 TI - Effect of silver content on the antibacterial and bioactive properties of silver substituted hydroxyapatite. AB - The long-term success of a biomaterial used during surgery may be compromised by infection. A possible effective solution is to make the biomaterial osteoconductive and antibacterial. A range of silver-substituted hydroxyapatite (AgHA) of up to 1.1 wt. % of Ag was synthesized. AgHA displayed a rod-like morphology of dimensions ~50 nm in length and ~15 nm in width. Phase-pure AgHA was demonstrated in the X-ray diffraction patterns and Fourier transform infrared spectroscopy spectra. Comparing with hydroxyaptite (HA), 0.5AgHA exhibited a 3 log reduction in the number of bacteria. Diffusion of the entrapped Ag(+) ions towards the crystal structure surface was revealed by an increase of 6 at. % Ag in the X-ray photoelectron spectroscopy results. Furthermore, less than 0.5 ppm of Ag(+) ions being released from 0.5AgHA into the deionized water medium was evidenced from the inductively coupled plasma mass spectrometry results. AgHA produced by co-precipitation gave rise to minimal release of Ag(+) ions. It was hypothesized that the diffused surface Ag(+) ions damaged the bacteria cell membrane and impede its replication. With the culturing time, significant increase in the number of human mesenchymal stem cells (p < 0.05) was demonstrated on 0.5AgHA. PMID- 23349127 TI - Embodying racism: race, rhinoplasty, and self-esteem in Venezuela. AB - In this article, I examine how race motivates women's decisions to undergo aesthetic rhinoplasty in Caracas, Venezuela. Through a combination of cultural domain analysis and thematic analysis of qualitative interviews, I explore how the preference for whiteness and associated facial features dovetail with the aesthetic ideals promoted by cosmetic surgeons. Rhinoplasty is offered by physicians and interpreted by patients as a resolution to body dissatisfaction and low self-esteem. The clinical ethos of objectivity established by cosmetic surgeons fails to acknowledge how perceptions of the self and body are strongly tied to racial marginalization: patients' efforts to alter the nose reveal attempts to change not only how the body looks, but how it is lived. As a result, cosmetic surgery only acts as a stop-gap measure to heighten one's self-esteem and body image. PMID- 23349128 TI - Chronological reading of radiographs in rheumatoid arthritis increases efficiency and does not lead to bias. AB - OBJECTIVES: To evaluate the difference between chronological and random sequence reading in a series of radiographs with 11 years' follow-up. In addition, the influence of the starting point and length of series was evaluated. METHODS: Two experienced readers independently and repeatedly scored digitised radiographs of 62 patients at time points 0, 2, 5, 8 and 11 years of follow-up from the COBRA follow-up database according to the Sharp/van der Heijde method. A linear mixed model was fitted to the data. RESULTS: Over 11 years the mean scores increased by 3.8 points per year. Compared to random reading, chronological reading resulted in a slightly increased progression rate of 0.4 points per year (p=0.008) and a lower standard error of the mean total progression rate of 0.30 (compared to 0.35 for random reading). Over 11 years, this results in a small difference in progression estimates of about five points, but a highly relevant difference of over 25% of patients needed in a study to find a difference in radiological outcome between two groups. Reading of short series, or series including a baseline radiograph, results in a significantly higher yearly progression rate compared to reading of long series, or series not including a baseline measurement. CONCLUSIONS: Chronological reading of radiographs is preferred above random reading, due to decreased variability around the estimation of the progression rate; this increased efficiency translates into smaller sample sizes, or increased power to detect small differences. For studies with long-term follow up, the same two readers should read all radiographs, including baseline. PMID- 23349130 TI - Metric properties of advanced imaging methods in osteoarthritis of the hand: a systematic review. AB - OBJECTIVE: To assess the value of advanced imaging techniques in the detection of hand osteoarthritis (OA) and hand OA progression. METHODS: PubMed/Medline and Embase were searched until April 2012 for studies on imaging of hand OA that presented quantitative data on validity, reliability or responsiveness. Articles presenting only data on conventional radiography (CR) were excluded. Methodological quality was assessed by the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist for validity, the Quality Appraisal of Reliability Studies (QAREL) for reliability and the COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) for responsiveness. RESULTS: Of 627 citations, 25 studies on ultrasonography (US), MRI or scintigraphy were included. No studies on CT, positron emission tomography or single photon emission CT met our eligibility criteria. Validity was generally assessed against healthy controls, CR or clinical examination. Overall, US and MRI detected more disease than CR and found significant differences between patients and healthy controls. Scintigraphy detected fewer pathological joints than CR. Intra- and inter-reader reliability varied for US (kappa=0.01-1.0) and MRI (kappa=0.15-0.84 and intraclass correlation coefficient=0.21-0.99) and was good for scintigraphy (kappa=0.61-0.84). There were no responsiveness studies for MRI. US responsiveness studies showed a reduction of soft-tissue changes after treatment which correlated with decrease in pain (r=0.7-0.8). For scintigraphy, scores decreased over time while CR showed progression of hand OA. CONCLUSIONS: MRI and US seem to be the most promising candidates for early detection of hand OA and for future use in clinical trials. However, further research is needed to improve scoring methods, to compare US with MRI, to confirm reliability of MRI and to further determine the responsiveness of US and MRI. PMID- 23349129 TI - Aryl hydrocarbon receptor antagonism mitigates cytokine-mediated inflammatory signalling in primary human fibroblast-like synoviocytes. AB - OBJECTIVES: Rheumatoid Arthritis (RA) is a chronic inflammatory disease of unclear aetiology, which is associated with inflamed human fibroblast-like synoviocytes (HFLS). Epidemiological studies have identified a positive correlation between tobacco smoking (a rich source of aryl hydrocarbon receptor (AHR) agonists) and aggressive RA phenotype. Thus, we hypothesise that antagonism of AHR activity by a potent AHR antagonist GNF351 can attenuate the inflammatory phenotype of HFLS-RA cells. METHODS: Quantitative PCR was used to examine IL1B induced mRNA expression in primary HFLS-RA cells. A structurally diverse AHR antagonist CH223191 and transient AHR repression using AHR small interfering RNA (siRNA) in primary HFLS-RA cells were used to demonstrate that effects observed by GNF351 are AHR-mediated. The levels of PTGS2 were determined by western blot and secretory cytokines such as IL1B and IL6 by ELISA. Chromatin immunoprecipitation was used to assess occupancy of the AHR on the promoters of IL1B and IL6. RESULTS: Many of the chemokine and cytokine genes induced by IL1B in HFLS-RA cells are repressed by co-treatment with GNF351 at both the mRNA and protein level. Pretreatment of HLFS-RA cells with CH223191 or transient gene ablation of AHR by siRNA confirmed that the effects of GNF351 are AHR-mediated. GNF351 inhibited the recruitment of AHR to the promoters of IL1B and IL6 confirming occupancy of AHR at these promoters is required for enhanced inflammatory signalling. CONCLUSIONS: These data suggest that AHR antagonism may represent a viable adjuvant therapeutic strategy for the amelioration of inflammation associated with RA. PMID- 23349132 TI - Changing sulphasalazine to methotrexate does not improve the 2-year outcomes of the initial single DMARD treatment in early rheumatoid arthritis: subanalysis of the FIN-RACo trial. PMID- 23349131 TI - Expert consensus for performing right heart catheterisation for suspected pulmonary arterial hypertension in systemic sclerosis: a Delphi consensus study with cluster analysis. AB - OBJECTIVE: To establish an expert consensus on which criteria are the most appropriate in clinical practice to refer patients with systemic sclerosis (SSc) for right heart catheterisation (RHC) when pulmonary hypertension (PH) is suspected. METHODS: A three stage internet based Delphi consensus exercise involving worldwide PH experts was designed. In the first stage, a comprehensive list of domains and items combining evidence based indications and expert opinions were obtained. In the second and third stages, experts were asked to rate each item selected in the list. After each of stages 2 and 3, the number of items and criteria were reduced according to a cluster analysis. RESULTS: A literature search and the opinions of 47 experts participating in Delphi stage 1 provided a list of seven domains containing 142 criteria. After stages 2 and 3, these domains and tools were reduced to three domains containing eight tools: clinical (progressive dyspnoea over the past 3 months, unexplained dyspnoea, worsening of WHO dyspnoea functional class, any finding on physical examination suggestive of elevated right heart pressures and any sign of right heart failure), echocardiography (systolic pulmonary artery pressure >45 mm Hg and right ventricle dilation) and pulmonary function tests (diffusion lung capacity for carbon monoxide <50% without pulmonary fibrosis). CONCLUSIONS: Among experts in pulmonary arterial hypertension-SSc, a core set of criteria for clinical practice to refer SSc patients for RHC has been defined by Delphi consensus methods. Although these indications are recommended by this expert group to be used as an interim tool, it will be necessary to formally validate the present tools in further studies. PMID- 23349133 TI - Population-specific influence of SLC2A9 genotype on the acute hyperuricaemic response to a fructose load. AB - BACKGROUND: SLC2A9 is a strong genetic risk factor for hyperuricaemia and gout. SLC2A9 (GLUT9) is a high capacity urate transporter and reportedly transports glucose and fructose. Intake of fructose-containing beverages is associated with development of hyperuricaemia and gout. OBJECTIVE: To determine whether genetic variation in SLC2A9 influences the acute serum urate response to a fructose load. METHODS: Following an overnight fast, 76 healthy volunteers (25 Maori, 26 Pacific, 25 European Caucasian) drank a solution containing 64 g fructose. Serum and urine were obtained immediately before and then 30, 60, 120 and 180 min after ingestion. The SLC2A9 single nucleotide polymorphism (SNP) rs11942223 was genotyped and data were analysed based on the presence or absence of the gout protective minor allele (C). RESULTS: The rs11942223 C allele was present in 17 participants (22%). In the entire group, fructose intake led to an increase in serum urate, which peaked 60 min following fructose ingestion (analysis of variance p=0.006). The presence of the C allele was associated with an attenuated hyperuricaemic response (p(SNP)<0.0001) and increased fractional excretion of uric acid (FEUA) (p(SNP)<0.0001) following the fructose load. The effects of rs11942223 variants on serum urate and FEUA in response to fructose were present only in Caucasian ancestral subgroups but not in the Maori and Pacific ancestral subgroup. CONCLUSIONS: Variation in SLC2A9 influences acute serum urate and FEUA responses to a fructose load. SLC2A9 genotype may influence the development of gout on exposure to fructose-containing beverages, particularly in European Caucasian populations. PMID- 23349135 TI - The bifactor model of the Maslach Burnout Inventory-Human Services Survey (MBI HSS)--an alternative measurement model of burnout. AB - The purpose of the present study was to examine the construct validity of the Hungarian language version of the Maslach Burnout Inventory-Human Services Survey (MBI-HSS). A sample of 653 healthcare professionals (420 physicians and 233 nurses and nursing assistants) completed the MBI-HSS. A series of confirmatory factor analyses showed that a hierarchical bifactor model including a global burnout factor and three specific factors of emotional exhaustion, depersonalization and reduced personal accomplishment had the closest fit to the data, compared with an alternative second-order three-factor hierarchical model as well as to non-hierarchical one-factor, two-factor, three-factor, four-factor and five-factor models. However, only the global burnout factor and the specific personal accomplishment factor explained a considerable unique proportion of variance in observed scores. Our study confirms the validity of the MBI-HSS and suggests an alternative structural model, which may contribute to further understanding of the burnout construct. PMID- 23349134 TI - Suppression of elevations in serum C reactive protein levels by anti-IL-6 autoantibodies in two patients with severe bacterial infections. PMID- 23349136 TI - The significance of CP29 reversible phosphorylation in thylakoids of higher plants under environmental stresses. AB - Reversible phosphorylation of proteins is a key event in many fundamental cellular processes. Under stressful conditions, many thylakoid membrane proteins in photosynthetic apparatus of higher plants undergo rapid phosphorylation and dephosphorylation in response to environmental changes. CP29 is the most frequently phosphorylated protein among three minor antennae complexes in higher plants. CP29 phosphorylation in dicotyledons has been known for several decades and is well characterized. However, CP29 phosphorylation in monocotyledons is less studied and appears to have a different phosphorylation pattern. In this review, we discuss recent advancements in CP29 phosphorylation and dephosphorylation studies and its physiological significance under environmental stresses in higher plants, especially in the monocotyledonous crops. Physiologically, the phosphorylation of CP29 is likely to be a prerequisite for state transitions and the disassembly of photosystem II supercomplexes, but not involved in non-photochemical quenching (NPQ). CP29 is phosphorylated in monocots exposed to environmental cues, with its subsequent lateral migration from grana stacks to stroma lamellae. However, neither CP29 phosphorylation nor its lateral migration occurs in dicotyledonous plants after drought, cold, or salt stress. Since the molecular mechanisms of differential CP29 phosphorylation under stresses are not fully understood, this review provides insights for future studies regarding the physiological function of CP29 reversible phosphorylation. PMID- 23349137 TI - Gametophytic and zygotic selection leads to segregation distortion through in vivo induction of a maternal haploid in maize. AB - Production of maternal haploids via a male inducer can greatly accelerate maize breeding and is an interesting biological phenomenon in double fertilization. However, the mechanism behind haploid induction remains elusive. Segregation distortion, which is increasingly recognized as a potentially powerful evolutionary force, has recently been observed during maternal haploid induction in maize. The results present here showed that both male gametophytic and zygotic selection contributed to severe segregation distortion of a locus, named segregation distortion 1 (sed1), during maternal haploid induction in maize. Interestingly, analysis of reciprocal crosses showed that sed1 is expressed in the male gametophyte. A novel mapping strategy based on segregation distortion has been used to fine-map this locus. Strong selection for the presence of the sed1 haplotype from inducers in kernels with haploid formation and defects could be detected in the segregating population. Dual-pollination experiments showed that viable pollen grains from inducers had poor pollen competitive ability against pollen from normal genotypes. Although defective kernels and haploids have different phenotypes, they are most probably caused by the sed1 locus, and possible mechanisms for production of maternal haploids and the associated segregation distortion are discussed. This research also provides new insights into the process of double fertilization. PMID- 23349138 TI - TGA transcription factors and jasmonate-independent COI1 signalling regulate specific plant responses to reactive oxylipins. AB - Jasmonates and phytoprostanes are oxylipins that regulate stress responses and diverse physiological and developmental processes. 12-Oxo-phytodienoic acid (OPDA) and phytoprostanes are structurally related electrophilic cyclopentenones, which activate similar gene expression profiles that are for the most part different from the action of the cyclopentanone jasmonic acid (JA) and its biologically active amino acid conjugates. Whereas JA-isoleucine signals through binding to COI1, the bZIP transcription factors TGA2, TGA5, and TGA6 are involved in regulation of gene expression in response to phytoprostanes. Here root growth inhibition and target gene expression were compared after treatment with JA, OPDA, or phytoprostanes in mutants of the COI1/MYC2 pathway and in different TGA factor mutants. Inhibition of root growth by phytoprostanes was dependent on COI1 but independent of jasmonate biosynthesis. In contrast, phytoprostane-responsive gene expression was strongly dependent on TGA2, TGA5, and TGA6, but not dependent on COI1, MYC2, TGA1, and TGA4. Different mutant and overexpressing lines were used to determine individual contributions of TGA factors to cyclopentenone responsive gene expression. Whereas OPDA-induced expression of the cytochrome P450 gene CYP81D11 was primarily regulated by TGA2 and TGA5, the glutathione S transferase gene GST25 and the OPDA reductase gene OPR1 were regulated by TGA5 and TGA6, but less so by TGA2. These results support the model that phytoprostanes and OPDA regulate differently (i) growth responses, which are COI1 dependent but jasmonate independent; and (ii) lipid stress responses, which are strongly dependent on TGA2, TGA5, and TGA6. Identification of molecular components in cyclopentenone signalling provides an insight into novel oxylipin signal transduction pathways. PMID- 23349139 TI - Plastid genome evolution across the genus Cuscuta (Convolvulaceae): two clades within subgenus Grammica exhibit extensive gene loss. AB - The genus Cuscuta (Convolvulaceae, the morning glory family) is one of the most intensely studied lineages of parasitic plants. Whole plastome sequencing of four Cuscuta species has demonstrated changes to both plastid gene content and structure. The presence of photosynthetic genes under purifying selection indicates that Cuscuta is cryptically photosynthetic. However, the tempo and mode of plastid genome evolution across the diversity of this group (~200 species) remain largely unknown. A comparative investigation of plastid genome content, grounded within a phylogenetic framework, was conducted using a slot-blot Southern hybridization approach. Cuscuta was extensively sampled (~56% of species), including groups previously suggested to possess more altered plastomes compared with other members of this genus. A total of 56 probes derived from all categories of protein-coding genes, typically found within the plastomes of flowering plants, were used. The results indicate that two clades within subgenus Grammica (clades 'O' and 'K') exhibit substantially more plastid gene loss relative to other members of Cuscuta. All surveyed members of the 'O' clade show extensive losses of plastid genes from every category of genes typically found in the plastome, including otherwise highly conserved small and large ribosomal subunits. The extent of plastid gene losses within this clade is similar in magnitude to that observed previously in some non-asterid holoparasites, in which the very presence of a plastome has been questioned. The 'K' clade also exhibits considerable loss of plastid genes. Unlike in the 'O' clade, in which all species seem to be affected, the losses in clade 'K' progress phylogenetically, following a pattern consistent with the Evolutionary Transition Series hypothesis. This clade presents an ideal opportunity to study the reduction of the plastome of parasites 'in action'. The widespread plastid gene loss in these two clades is hypothesized to be a consequence of the complete loss of photosynthesis. Additionally, taxa that would be the best candidates for entire plastome sequencing are identified in order to investigate further the loss of photosynthesis and reduction of the plastome within Cuscuta. PMID- 23349140 TI - Translational downregulation of RBCL is operative in the coordinated expression of Rubisco genes in senescent leaves in rice. AB - Rubisco gene expression was examined in detail in rice (Oryza sativa L.) leaves at different positions, i.e. expanding, mature, and senescent leaves. Rubisco small subunit (RBCS) synthesis and RBCS mRNA levels were maximal in expanding leaves and gradually became lower in mature and senescent leaves, with declines in those of the large subunit (RBCL) being relatively slower. The amount of synthesized RBCL per unit level of RBCL mRNA and polysome loading of RBCL mRNA declined in senescent leaves, whereas such phenomena were not observed for RBCS. These results suggested that gene expression of RBCL is downregulated at the level of its translation when a balance between RBCL and RBCS expression is disturbed by leaf senescence. It has been suggested that RBCS protein is a positive regulator for RBCL mRNA level in expanding rice leaves, as judged from their stoichiometric relationship in RBCS transgenic rice plants. However, the ratio of the RBCL mRNA level to the amount of synthesized RBCS in senescent leaves was significantly higher than that in expanding leaves. Therefore, it is suggested that the decline in RBCL mRNA level in senescent leaves is not fully accounted for by that in the amount of synthesized RBCS. Effects of other factors such as the stability of RBCL mRNA may come into play. PMID- 23349142 TI - Pollination induces autophagy in petunia petals via ethylene. AB - Autophagy is one of the main mechanisms of degradation and remobilization of macromolecules, and it appears to play an important role in petal senescence. However, little is known about the regulatory mechanisms of autophagy in petal senescence. Autophagic processes were observed by electron microscopy and monodansylcadaverine staining of senescing petals of petunia (Petunia hybrida); autophagy-related gene 8 (ATG8) homologues were isolated from petunia and the regulation of expression was analysed. Nutrient remobilization was also examined during pollination-induced petal senescence. Active autophagic processes were observed in the mesophyll cells of senescing petunia petals. Pollination induced the expression of PhATG8 homologues and was accompanied by an increase in ethylene production. Ethylene inhibitor treatment in pollinated flowers delayed the induction of PhATG8 homologues, and ethylene treatment rapidly upregulated PhATG8 homologues in petunia petals. Dry weight and nitrogen content were decreased in the petals and increased in the ovaries after pollination in detached flowers. These results indicated that pollination induces autophagy and that ethylene is a key regulator of autophagy in petal senescence of petunia. The data also demonstrated the translocation of nutrients from the petals to the ovaries during pollination-induced petal senescence. PMID- 23349141 TI - Towards understanding vacuolar antioxidant mechanisms: a role for fructans? AB - Recent in vitro, in vivo, and theoretical experiments strongly suggest that sugar (like) molecules counteract oxidative stress by acting as genuine reactive oxygen species (ROS) scavengers. A concept was proposed to include the vacuole as a part of the cellular antioxidant network. According to this view, sugars and sugar like vacuolar compounds work in concert with vacuolar phenolic compounds and the 'classic' cytosolic antioxidant mechanisms. Among the biologically relevant ROS (H(2)O(2), O(2).(-), and .OH), hydroxyl radicals are the most reactive and dangerous species since there are no enzymatic systems known to neutralize them in any living beings. Therefore, it is important to study in more detail the radical reactions between .OH and different biomolecules, including sugars. Here, Fenton reactions were used to compare the .OH-scavenging capacities of a range of natural vacuolar compounds to establish relationships between antioxidant capacity and chemical structure and to unravel the mechanisms of .OH-carbohydrate reactions. The in vitro work on the .OH-scavenging capacity of sugars and phenolic compounds revealed a correlation between structure and .OH-scavenging capacity. The number and position of the C=C type of linkages in phenolic compounds greatly influence antioxidant properties. Importantly, the splitting of disaccharides and oligosaccharides emerged as a predominant outcome of the .OH carbohydrate interaction. Moreover, non-enzymatic synthesis of new fructan oligosaccharides was found starting from 1-kestotriose. Based on these and previous findings, a working model is proposed describing the putative radical reactions involving fructans and secondary metabolites at the inner side of the tonoplast and in the vacuolar lumen. PMID- 23349143 TI - The mesophyll anatomy enhancing CO2 diffusion is a key trait for improving rice photosynthesis. AB - Increases in rates of individual leaf photosynthesis (P(n)) are critical for future increases in yields of rice plants. Although many efforts have been made to improve rice P(n) with transgenic technology, the desired increases in P(n) have not yet been achieved. Two rice lines with extremely high values of P(n) were identified among the backcrossed inbred lines derived from the indica variety Takanari, one of the most productive varieties in Japan, and the elite japonica variety Koshihikari (Koshihikari/Takanari//Takanari). The P(n) values of the two lines at an ambient CO(2) concentration of 370MUmol mol(-1) as well as at a saturating concentration of CO(2) were 20-50% higher than those of the parental varieties. Compared with Takanari, these lines had neither a higher content nor a higher activity of ribulose 1,5-bisphosphate carboxylase/oxygenase when the leaf nitrogen contents were similar, but they did have high mesophyll conductance with respect to CO(2) flux due to their higher density and more highly developed lobes of mesophyll cells. These lines also had higher electron transport rates. The plant growth rates of these lines were higher than that of Takanari. The findings show that it is possible to increase P(n) significantly, both at the current atmospheric concentration of CO(2) and at the increased concentration of CO(2) expected in the future, using appropriate combinations of genetic resources that are available at present. PMID- 23349144 TI - Influence of alkyl chain length on calcium phosphate deposition onto titanium surfaces modified with alkylphosphonic acid monolayers. AB - Much attention has been paid to the modification of a titanium surface with an alkylphosphonic acid (PA)-based self-assembled monolayer (SAM) to accelerate hydroxyapatite (HA) deposition on the surface. In order to further accelerate the rate of HA deposition, we examined here the effect of alkyl chain length of SAMs on the formation of a HA layer. PAs with three different alkyl chain lengths (3, 6, and 16 methylene units) were used for the preparation of a SAM on titanium. The titanium specimens with monolayers were soaked in a simulated body fluid under physiological conditions for 4 weeks. The deposited substances were analyzed by scanning electron microscopy, X-ray photoelectron spectroscopy, and X ray diffraction. These analyses revealed that the formation of PA SAMs accelerate the deposition of poorly crystallized HA, in an alkyl chain length-dependent manner. Among PAs studied here, PA containing a 16-carbon alkyl chain gave rise to the titanium surface most effective for the deposition of HA. PMID- 23349145 TI - Comparison of LUCIO(r)-direct ELISA with CEDIA immunoassay for 'zero tolerance' drug screening in urine as required by the German re-licensing guidelines. AB - The performance of the previously validated LUCIO((r))-Direct-enzyme linked immunosorbent assay (direct ELISA) screening tests according to forensic guidelines is compared to that of cloned enzyme donor immunoassays (CEDIA) test for drugs of abuse in urine as defined in the new re-licensing German medical and psychological assessment (MPA) guidelines. The MPA screening cut-offs correspond to 10 ng/ml 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), 50 ng/ml amphetamine and designer amphetamines, 25 ng/ml morphine, codeine and dihydrocodeine, 30 ng/ml benzoylecgonine, 50 ng/ml methadone metabolite, 2 ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and metabolites of diazepam, oxazepam, bromazepam, alprazolam, flunitrazepam and lorazepam at 50 ng/ml. Average relative sensitivities and relative specificities were 99.7 % and 98.4 % for direct ELISA and 66 % and 91.4 % for CEDIA, respectively. PMID- 23349146 TI - Modeling and biomechanical analysis of craniosynostosis correction with the use of finite element method. AB - Craniosynostosis is a skull malformation because of premature fusing of one or more cranial sutures. The most common types of craniosynostosis are scaphocephaly (with the sagittal suture fused) and trigonocephaly (with the metopic suture fused). In this paper we describe and discuss how finite element analysis and three-dimensional modeling can be used for preoperative planning of the correction of craniosynostosis and for the postoperative evaluation of the treatment results. We used the engineering software MIMICS MATERIALISE to obtain three-dimensional geometry from computed tomography scans, and applied finite element method for the sake of biomechanical analysis. These simulations help to improve the surgical treatment, making it more accurate, safer, and faster. PMID- 23349147 TI - An unusual cause of non-weight bearing. PMID- 23349148 TI - Numerical simulation of particle dynamics in an orifice-electrode system. Application to counting and sizing by impedance measurement. AB - This paper describes how to numerically tackle the problem of counting and sizing particles by impedance measurement in an orifice-electrode system. The model allows to simulate the particle dynamics submitted to strong hydrodynamic stresses through a microorifice and to compute the voltage pulses generated by the modification of the inner dielectric medium. This approach gives important information about particles size distribution and allows to quantify the role of trajectory and orientation of particles on the size measurement. PMID- 23349149 TI - GPR40 modulators: new kid on the block. PMID- 23349150 TI - Twenty-first century behavioral medicine: a context for empowering clinicians and patients with diabetes: a consensus report. PMID- 23349151 TI - Association between physical activity and risk of all-cause mortality and cardiovascular disease in patients with diabetes: a meta-analysis. AB - OBJECTIVE: The association between habitual physical activity (PA) and lowered risk of all-cause mortality (ACM) and cardiovascular disease (CVD) has been suggested in patients with diabetes. This meta-analysis summarizes the risk reduction in relation to PA, focusing on clarifying dose-response associations. RESEARCH DESIGN AND METHODS: Electronic literature searches were conducted for cohort studies that examined relative risk (RR) of ACM or CVD in relation to PA in patients with diabetes. For the qualitative assessment, RR for the highest versus the lowest PA category in each study was pooled with a random-effects model. We added linear and spline regression analyses to assess the quantitative relationship between increases in PA and ACM and CVD risk. RESULTS: There were 17 eligible studies. Qualitatively, the highest PA category had a lower RR [95% CI] for ACM (0.61 [0.52-0.70]) and CVD (0.71 [0.60-0.84]) than the lowest PA category. The linear regression model indicated a high goodness of fit for the risk of ACM (adjusted R(2) = 0.44, P = 0.001) and CVD (adjusted R(2) = 0.51, P = 0.001), with the result that a 1 MET-h/day incrementally higher PA was associated with 9.5% (5.0-13.8%) and 7.9% (4.3-11.4%) reductions in ACM and CVD risk, respectively. The spline regression model was not significantly different from the linear model in goodness of fit (P = 0.14 for ACM risk; P = 0.60 for CVD risk). CONCLUSIONS: More PA was associated with a larger reduction in future ACM and CVD risk in patients with diabetes. Nevertheless, any amount of habitual PA was better than inactivity. PMID- 23349154 TI - The big blue test: effects of 14 minutes of physical activity on blood glucose levels. PMID- 23349152 TI - A systematic review and meta-analysis of the association between depression and insulin resistance. AB - OBJECTIVE: Depression is associated with the onset of type 2 diabetes. A systematic review and meta-analysis of observational studies, controlled trials, and unpublished data was conducted to examine the association between depression and insulin resistance (IR). RESEARCH DESIGN AND METHODS: Medline, EMBASE, and PsycINFO were searched for studies published up to September 2011. Two independent reviewers assessed the eligibility of each report based on predefined inclusion criteria (study design and measure of depression and IR, excluding prevalent cases of diabetes). Individual effect sizes were standardized, and a meta-analysis was performed to calculate a pooled effect size using random effects. Subgroup analyses and meta-regression were conducted to explore any potential source of heterogeneity between studies. RESULTS: Of 967 abstracts reviewed, 21 studies met the inclusion criteria of which 18 studies had appropriate data for the meta-analysis (n = 25,847). The pooled effect size (95% CI) was 0.19 (0.11-0.27) with marked heterogeneity (I(2) = 82.2%) using the random-effects model. Heterogeneity between studies was not explained by age or sex, but could be partly explained by the methods of depression and IR assessments. CONCLUSIONS: A small but significant cross-sectional association was observed between depression and IR, despite heterogeneity between studies. The pathophysiology mechanisms and direction of this association need further study using a purposively designed prospective or intervention study in samples at high risk for diabetes. PMID- 23349155 TI - Repeated hypoglycemia caused by the overproduction of anti-insulin antibodies and isolated ACTH deficiency in a type 2 diabetic patient receiving insulin therapy. PMID- 23349156 TI - Comment on: Hardikar et al. Spuriously high prevalence of prediabetes diagnosed by HbA(1c) in young indians partly explained by hematological factors and iron deficiency anemia. Diabetes Care 2012;35:797-802. PMID- 23349157 TI - Response to comment on: Hardikar et al. Spuriously high prevalence of prediabetes diagnosed by HbA(1c) in young indians partly explained by hematological factors and iron deficiency anemia. Diabetes Care 2012;35:797-802. PMID- 23349158 TI - Comment on: Hanssen et al. Associations between the ankle-brachial index and cardiovascular and all-cause mortality are similar in individuals without and with type 2 diabetes: nineteen-year follow-up of a population-based cohort study. Diabetes Care 2012;35:1731-1735. PMID- 23349159 TI - Comment on: Pan et al. Bidirectional association between depression and metabolic syndrome: a systematic review and meta-analysis of epidemiological studies. Diabetes Care 2012;35:1171-1180. PMID- 23349160 TI - Response to comment on: Pan et al. Bidirectional association between depression and metabolic syndrome: a systematic review and meta-analysis of epidemiological studies. Diabetes Care 2012;35:1171-1180. PMID- 23349161 TI - Comment on: Chang et al. A 25-year longitudinal evaluation of gastric emptying in diabetes. Diabetes Care 2012;35:2594-2596. PMID- 23349162 TI - Response to comment on: Chang et al. A 25-year longitudinal evaluation of gastric emptying in diabetes. Diabetes Care 2012;35:2594-2596. PMID- 23349163 TI - Comment on: Khurana et al. The diagnosis of neonatal diabetes in a mother at 25 years of age. Diabetes Care 2012;35:e59. PMID- 23349164 TI - Association between mothers' and fathers' depressive symptoms, sense of coherence and perception of their child's temperament in early parenthood in Sweden. AB - AIMS: To examine whether there was any association between mothers' and fathers' post-partum depressive symptoms and sense of coherence and perception of their child's temperament. The hypotheses were that parents with depressive symptoms: 1) have more often a poor sense of coherence, and 2) perceive their child's temperament to be more difficult than parents without depressive symptoms. METHODS: A total of 401 Swedish-speaking couples, who were the parents of children born through the years 2004-2006 in the northern part of the county of Vastmanland, Sweden, were invited to participate in the study. The parents answered 3 questionnaires including: at inclusion of the study: demographic data (n = 393 couples); at 3 months: the Edinburgh Postnatal Depression Scale and the Sense of Coherence Scale (n = 308 couples); and at 18 months: the Infant Characteristics Questionnaire (n = 272 couples). RESULTS: Depressive symptoms measured at 3 months, were reported by 17.7% of mothers and 8.7% of fathers, and correlated significantly between mothers and fathers within couples (rho = 0.165, p = 0.003). Mothers and fathers with depressive symptoms had a poorer sense of coherence (p < 0.001, p < 0.001) and perceived their child's temperament as more difficult than mothers and fathers without depressive symptoms at 3 (p = 0.028, p < 0.001) and 18 months (p = 0.145, p = 0.012 respectively). CONCLUSIONS: Early parenthood has been studied thoroughly in mothers, but few studies have included fathers. Identifying problems in early parenthood could help predict later problems exhibited by the preschool child, which might be prevented by supportive programmes. PMID- 23349165 TI - Drinking contexts and the legitimacy of alcohol use: findings from a focus group study on alcohol use in Denmark. AB - AIM: To examine the perceptions and meanings of alcohol use in Denmark with specific focus on drinking contexts. METHODS: A qualitative study using focus group interviews. The sample consisted of five focus groups of adults with one group for each of the following age groups: 16-20; 21-34; 35-44; 45-64; and 65-82 years. The groups consisted of both men and women with five to six participants in each group (27 in total). RESULTS: Alcohol use is perceived as legitimate in many social contexts with few being defined as inappropriate. Drinking alone is mostly associated with having alcohol-related problems, but considered legitimate if it is characterized by activity. Drinking socially plays an important role in people's considerations of legitimate use and seems to overrule the actual alcohol amount consumed. Different contexts influence different meanings of drinking with context and purpose changing with age and life stages. CONCLUSIONS: The social drinking context is pivotal in people's perception of the legitimacy of their alcohol use, leaving the alcohol amount less important. This calls for the need to focus on and incorporate the drinking context within public health initiatives aimed at reducing high risk drinking, just as the focus on the actual amount of alcohol people consume or their frequency of use. PMID- 23349166 TI - Income and health in different welfare contexts: a comparison of Sweden, East and West Germany. AB - BACKGROUND: The aim of the present study is to explore whether the association between income and self-rated health in Sweden is similar to that in Germany. Both countries represent relatively similar economic contexts, but also different welfare traditions and historic experiences. Thus, the study compares Sweden with East Germany and West Germany in order to incorporate the aftereffects of reunification in East Germany. METHODS: The association between adjusted disposable household income and self-rated health is investigated by exploring cross-sectional survey data for the year 2000. In a sequence of logistic regression models, the risk for poor self-rated health across income quintiles is analysed, controlling for educational status and occupational position. Data sources are the Swedish Level-of-Living Survey and the German Socio-Economic Panel. RESULTS: A relationship between income and health was observed for Sweden, East Germany and West Germany, before as well as after controlling for education and occupational position. The associations were somewhat stronger for women than for men. Similar magnitudes of income-related poor health were detected across the investigated subsamples, but patterns were distinct in the three regions. The highest estimates were not always found in groups with the lowest income position. CONCLUSIONS: Given the variation in the results, we found neither advantages nor disadvantages that can be linked to the effectiveness of the welfare contexts under study. We could also not identify an income threshold for poor health across the investigated countries and settings. Nevertheless, the association between income and health persists, although the patterns vary across regional contexts. PMID- 23349167 TI - The youth sports club as a health-promoting setting: an integrative review of research. AB - AIMS: The aims of this review is to compile and identify key issues in international research about youth sports clubs as health-promoting settings, and then discuss the results of the review in terms of a framework for the youth sports club as a health-promoting setting. METHODS: The framework guiding this review of research is the health-promoting settings approach introduced by the World Health Organization (WHO). The method used is the integrated review. Inclusion criteria were, first, that the studies concerned sports clubs for young people, not professional clubs; second, that it be a question of voluntary participation in some sort of ongoing organized athletics outside of the regular school curricula; third, that the studies consider issues about youth sports clubs in terms of health-promoting settings as described by WHO. The final sample for the review consists of 44 publications. RESULTS: The review shows that youth sports clubs have plentiful opportunities to be or become health-promoting settings; however this is not something that happens automatically. To do so, the club needs to include an emphasis on certain important elements in its strategies and daily practices. The youth sports club needs to be a supportive and healthy environment with activities designed for and adapted to the specific age-group or stage of development of the youth. CONCLUSIONS: To become a health-promoting setting, a youth sports club needs to take a comprehensive approach to its activities, aims, and purposes. PMID- 23349169 TI - Heart failure in the new born; vein of Galen aneurysmal malformation. AB - We narrate the case of a term baby who presented at 30 h of age in congestive cardiac failure due to vein of Galen aneurysmal malformation. A successful interventional radiology embolisation of the feeding vessels to the aneurysm was performed on day 5. Twenty hours following the procedure, the baby developed significant intraventricular haemorrhage with extension into the brain parenchyma; care was reoriented on day 7 of life after discussion with the parents. Vein of Galen aneurysmal malformation is a rare congenital vascular malformation. It usually manifests in the newborn period with high-output cardiac failure. The death rate is higher in those who present early in the neonatal period. The management of this condition requires a multidisciplinary approach. PMID- 23349168 TI - Shelbourne's update of the O'Donoghue knee triad in a 17-year-old male Rugby player. AB - Acute athletic knee injuries are often caused by a combination of valgus impact with external rotation of the tibia leading to a triad of injuries involving medial collateral and anterior cruciate ligament disruption with associated meniscal damage. This injury pattern has been greatly discussed in the literature with conflicts of opinion and evidence as to whether medial or lateral meniscal pathology has a higher incidence. This case report introduces a 17-year-old male athlete with this unhappy triad It will evaluate the clinical assessment which suggested a medial meniscal lesion follow the patient through arthroscopy revealing a lateral meniscal tear in addition to complete anterior cruciate ligament rupture and grade 2 medial collateral ligament tear. It will go on to look at the evidence base for the relative incidence of lateral and medial meniscal injuries and will evaluate the role of MRI in assessing acute athletic knee injuries. PMID- 23349170 TI - Renal malakolpkia followed by chronic myelogenous leukaemia: treatment challenges case report and literature review. AB - Malakoplakia is a rare granulomatous disorder of unknown aetiology and usually affects patients with underlying immunosuppression. This disorder usually involves the genitourinary tract but has been reported in a wide array of anatomical sites. We are presenting, what is to our knowledge, the first case in the literature in which a patient was diagnosed with malakoplakia and after his successful management; he was diagnosed with chronic meylomoncytic leukaemia. All cases of malakoplakia reported in the literature were either preceded or accompanied by an immunosuppressive state. PMID- 23349171 TI - Quadricuspid aortic valve with aortic regurgitation: a rare echocardiographic finding. AB - We report on a middle-aged woman treated for chronic hepatitis C virus infection with pegylated interferon. Auscultation revealed a diastolic murmur and the peripheral signs of aortic regurgitation. She had shortness of breath on moderate exertion for the past 4 months, which she attributed to her liver disease. Echocardiogram showed a quadricuspid aortic valve with severe aortic regurgitation. She was referred to a cardiothoracic surgeon for aortic valve replacement (AVR). However, she decided against AVR despite detailed counselling, and opted for medical treatment. PMID- 23349172 TI - Cervical spine arterio venous malformation. AB - We present an unusual case of a young patient who presented to our emergency department with a history of sudden onset of pain on the left side of the neck and numbness to the left arm after lifting a small weight. Patient continued to work as normal for approximately 30 min after the event and then attended the emergency department as numbness in the left arm was not resolving. On examination there was no sensorymotor deficit in the lower limbs but neurological deficits were found in the upper limbs which made us suspect a diagnosis of cervical spine injury/brachial plexus. The patient then rapidly developed numbness in both upper and lower limbs and eventually became aphasic and developed a rapid, shallow respiration and was unable to maintain the airway. The patient was then intubated and ventilated. The patient was then transferred to a neurosurgical centre after the relevant investigations was found to have an arteriovenous malformation of spinal cord. PMID- 23349173 TI - Congestive hepatopathy secondary to large renal arteriovenous malformation. AB - A 75-year-old woman presented with acute onset dyspnoea, and was found to have signs of pulmonary congestion on clinical examination. Imaging revealed cardiomegaly and coincident congestive hepatopathy, secondary to a left renal arteriovenous malformation. The presence of a high flow vascular shunt in the left kidney was possibly the causative factor behind both the high-output cardiac failure and congestive hepatopathy. PMID- 23349174 TI - An interesting case of screen-detected breast cancer encasing a ventriculoperitoneal shunt. AB - A 67-year-old woman was diagnosed with a breast cancer via screening encasing the ventriculoperitoneal shunt. Triple assessment including MRI scan of the breast confirmed the presence of a breast mass and the tubing of the ventriculoperitoneal shunt was running directly through the mass. She underwent wide local excision of the breast cancer as well as rerouting of VP shunt as a joint procedure with the neurosurgery team and recovered uneventfully. This is a very rare and an interesting case and required management involving a different specialty. PMID- 23349175 TI - Oral manifestations of epidermolysis bullosa dystrophica: a rare genetic disease. AB - Epidermolysis bullosa (EB) constitutes a group of phenotypically diverse genodermatoses, which manifests with blistering and erosions of the skin and mucous membranes as the unifying diagnostic feature. It is an acquired disease or inherited as either autosomal-dominant or recessive with an incidence of 1/50 000. The prominent clinical characteristic of the disease is the development of bullae or vesicles in mucosa or skin in response to minor trauma. It is a chronic mechanobullous disease characterised by auto antibodies against Type VII collagen. This paper documents a case of a man diagnosed with dominant dystrophic EB; describing the measures that dentists and healthcare providers should adopt in order to provide a safe and effective dental treatment. Early prevention protocols for these patients have also been discussed. PMID- 23349177 TI - Lumbar synovial cyst calcification after facet joint steroid injection. PMID- 23349176 TI - Concomitant amyotrophic lateral sclerosis and paraclinical laboratory features of multiple sclerosis: coincidence or causal relationship? AB - We report a 55-year-old patient, presenting with paresis, muscle atrophy and dysarthria, all symptoms accordable to definite amyotrophic lateral sclerosis (ALS). However, MRI and cerebrospinal fluid show abnormalities typical of multiple sclerosis (MS). On the basis of this case report, we discuss possible overlaps between both diseases by comparing clinical and paraclinical features including laboratory, radiological and electrophysiological diagnostics. As genetic, as well as environmental, factors are assumed to be involved in the development of both the diseases, literature is reviewed according to similar cases, results of autopsies and possible parallels in pathogenesis. In summary, based on the data currently available, the hypothesis of ALS being a neurodegenerative multisystem disorder, a common pathophysiological pathway or, alternatively, a random comorbidity of ALS and MS in this patient has to be discussed. PMID- 23349178 TI - Oral contraceptive causing renal artery thrombosis. AB - A young female presented with acute left lower quadrant pain followed by nausea and vomiting. She was found to have haematuria and elevated serum creatine. CT scan revealed a wedge-shaped hypodensity along with an intraluminal filling defect on the left kidney. Renal artery duplex showed no evidence for stenosis and MRI was negative for any atherosclerotic disease. Technetium scan confirmed the diagnosis of left renal infarct. Following day the patient became febrile and was noted to have leucocytosis and elevated serum lactate dehydrogenase. She was started on enoxaparin and low-dose aspirin. Blood cultures were negative. The oral contraceptive was stopped. Fever and leucocytosis resolved in the following 3 days. Extensive thrombophilic work-up was negative. No recurrence of thrombosis was found during a 6-month follow-up period. To the best of our knowledge, this is the first report of renal artery thrombosis leading to acute renal infarction associated with oral contraceptive use. PMID- 23349179 TI - Hair-on-end appearance in a case of thalassemia intermedia. PMID- 23349180 TI - Double migration of a schwannoma of thoracic spine. AB - Mobile intraspinal tumours have rarely been reported. In most cases, mobile tumours such as schwannomas or ependymomas were located in the cauda equina. Perusal of the literature revealed only two reports of mobile schwannomas in the cervical and thoracic regions. We report a case of thoracic schwannoma which migrated twice in successive operations resulting in negative exploration in the expected area. The aim of this report is to remind the surgeons about the possibility of migration of intradural-extramedullary tumour. PMID- 23349181 TI - Not all T wave inversions are ischaemic. PMID- 23349182 TI - Endodontic management of middle mesial canal of the mandibular molar. AB - Thorough knowledge of root canal morphology and unusual anatomy of the tooth is critical for successful endodontic treatment. Although the most common configuration is two roots and three root canals, mandibular molars might have many different combinations. In the literature, it is less described about three mesial canals and two distal canals in mandibular second molars, indicating a rare anatomical configuration. A case of unusual root canal morphology is presented to demonstrate anatomical variations in mandibular molars. Endodontic therapy was performed in a mandibular second molar with five separate canals, three mesial and two distal. This report points out the importance of looking for additional canals and unusual canal morphology, because knowledge of their existence might occasionally enable clinicians to treat a case successfully that otherwise might have ended in failure. In conclusion, every attempt should be made to find and treat all root canals of a tooth. PMID- 23349183 TI - PET-CT confirms the diagnosis of pyogenic spondylodiscitis complicated by psoas abscess. PMID- 23349184 TI - Fungal interface keratitis by Candida orthopsilosis following deep anterior lamellar keratoplasty. AB - A 39-year-old male patient underwent uncomplicated deep anterior lamellar keratoplasty due to keratoconus. On day 5 after surgery, small whitish infiltrates developed in the corneal interface. The diagnosis of fungal keratitis was made when the culture medium of the graft grew Candida after the surgical intervention. Despite intensive antimycotic treatment and irrigation of the interface, the infiltrates persisted and eventually enlarged. Therefore, revision surgery with penetrating keratoplasty was performed. Microbiological analysis showed Candida orthopsilosis in the culture of the excised graft button. Histopathological staining of the excised graft showed periodic acid-Schiff positive and Grocott methenamine silver-positive clusters of yeast between Descemet's membrane and the deep corneal stroma with focal perforations through Descemet's membrane. The treatment of mycotic keratitis caused by C orthopsilosis is challenging. Antimycotic treatment was unsuccessful in this case. Progression of the keratitis and perforation of Descemet's membrane suggest that early surgical intervention by penetrating keratoplasty is required. PMID- 23349185 TI - Interleukins-12 and -23 do not alter expression or activity of multiple cytochrome P450 enzymes in cryopreserved human hepatocytes. AB - Psoriasis is a T-cell-mediated autoimmune disease involving the skin. Two cytokines, interleukin-12 (IL-12) and IL-23 have been shown to play a pivotal role in the pathogenesis of the disease. Ustekinumab (Stelara) is a therapeutic monoclonal antibody (mAb) targeted against the p40 shared subunit of IL-12 and IL 23. Recently the ability of therapeutic proteins (TP) including mAbs that target either cytokines directly (e.g., Pegasys; peginterferon alpha-2a) or their respective cell surface receptors [e.g., tocilizumab (Actemra); anti IL-6R] to desuppress cytochrome P450 (P450) enzymes in vitro and in the clinic, has been demonstrated. In the present study the ability of IL-12 and IL-23 to suppress multiple P450 enzymes was investigated in vitro using six separate lots of cultured human hepatocytes. Following exposure of 10 ng/ml IL-12 and IL-23 for 48 hours, either alone or in combination, no change in CYP2B6, 2C9, 2C19, or 3A4 gene expression or functional activity was observed. None of the untreated hepatocyte donors showed appreciable expression of the IL-12 or IL-23 receptors. Similar results were seen with whole human liver samples. Exposure of hepatocytes to IL-12 and/or IL-23, known P450 suppressors (IL-6 and tumor necrosis factor alpha) or known P450 inducers (beta-naphthoflavone, phenobarbital, and rifampicin) did not appreciably alter the expression of the IL-12 and IL-23 receptors either. Finally, in contrast to the positive control IL-6, expression of the acute phase C-reactive protein was unaltered following IL-12 and/or IL-23 treatment. Together, these data suggest a negligible propensity for IL-12 or IL 23 to directly alter P450 enzymes in human hepatocytes. PMID- 23349186 TI - Novel role of copper transport protein antioxidant-1 in neointimal formation after vascular injury. AB - OBJECTIVE: Vascular smooth muscle cell (VSMC) migration is critically important for neointimal formation after vascular injury and atherosclerosis lesion formation. Copper (Cu) chelator inhibits neointimal formation, and we previously demonstrated that Cu transport protein antioxidant-1 (Atox1) is involved in Cu induced cell growth. However, role of Atox1 in VSMC migration and neointimal formation after vascular injury is unknown. APPROACH AND RESULTS: Here, we show that Atox1 expression is upregulated in injured vessel, and it is colocalized with the Cu transporter ATP7A, one of the downstream targets of Atox1, mainly in neointimal VSMCs at day 14 after wire injury. Atox1(-/-) mice show inhibition of neointimal formation and extracellular matrix expansion, which is associated with a decreased VSMCs accumulation within neointima and lysyl oxidase activity. Mechanistically, in cultured VSMC, Atox1 depletion with siRNA inhibits platelet derived growth factor-induced Cu-dependent VSMC migration by preventing translocation of ATP7A and small G protein Rac1 to the leading edge, as well as Cu- and Rac1-dependent lamellipodia formation. Furthermore, Atox1(-/-) mice show decreased perivascular macrophage infiltration in wire-injured vessels, as well as thioglycollate-induced peritoneal macrophage recruitment. CONCLUSIONS: Atox1 is involved in neointimal formation after vascular injury through promoting VSMC migration and inflammatory cell recruitment in injured vessels. Thus, Atox1 is a potential therapeutic target for VSMC migration and inflammation-related vascular diseases. PMID- 23349187 TI - Thioredoxin 1 is essential for sodium sulfide-mediated cardioprotection in the setting of heart failure. AB - OBJECTIVE: The aim of this study was to determine whether thioredoxin 1 (Trx1) mediates the cardioprotective effects of hydrogen sulfide (H2S) in a model of ischemic-induced heart failure (HF). APPROACH AND RESULTS: Mice with a cardiac specific overexpression of a dominant negative mutant of Trx1 and wild-type littermates were subjected to ischemic-induced HF. Treatment with H2S as sodium sulfide (Na2S) not only increased the gene and protein expression of Trx1 in the absence of ischemia but also augmented the HF-induced increase in both. Wild-type mice treated with Na2S experienced less left-ventricular dilatation, improved left-ventricular function, and less cardiac hypertrophy after the induction of HF. In contrast, Na2S therapy failed to improve any of these parameters in the dominant negative mutant of Trx1 mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na2S therapy inhibited HF-induced apoptosis signaling kinase-1 signaling and nuclear export of histone deacetylase 4 in a Trx1-dependent manner. CONCLUSIONS: These findings provide novel information that the upregulation of Trx1 by Na2S therapy in the setting of HF sets into motion events, such as the inhibition of apoptosis signaling kinase-1 signaling and histone deacetylase 4 nuclear export, which ultimately leads to the attenuationof left-ventricular remodeling. PMID- 23349188 TI - Intramuscular fat and associations with metabolic risk factors in the Framingham Heart Study. AB - OBJECTIVE: Intramuscular fat accumulates between muscle fibers or within muscle cells. We investigated the association of intramuscular fat with other ectopic fat deposits and metabolic risk factors. APPROACH AND RESULTS: Participants (n=2945; 50.2% women; mean age 50.8 years) from the Framingham Heart Study underwent multidetector computed tomography scanning of the abdomen. Regions of interest were placed on the left and right paraspinous muscle, and the muscle attenuation (MA) in Hounsfield units was averaged. We examined the association between MA and metabolic risk factors in multivariable models, and additionally adjusted for body mass index (BMI) and visceral adipose tissue (VAT) in separate models. MA was associated with dysglycemia, dyslipidemia, and hypertension in both sexes. In women, per standard deviation decrease in MA, there was a 1.34 (95% confidence interval, 1.10-1.64) increase in the odds of diabetes mellitus, a 1.40 (95% confidence interval, 1.22-1.61) increase in the odds of high triglycerides, and a 1.29 (95% confidence interval, 1.12-1.48) increase in the odds of hypertension. However, none of these associations persisted after adjustment for BMI or VAT. In men, we observed similar patterns for most risk factors. The exception was metabolic syndrome, which retained association in women even after adjustment for BMI and VAT, and low high density lipoprotein and high triglycerides in men, whose associations also persisted after adjustment for BMI and VAT. CONCLUSIONS: MA was associated with metabolic risk factors, but most of these associations were lost after adjustment for BMI or VAT. However, a unique association remained for metabolic syndrome in women and lipids in men. PMID- 23349189 TI - Group X secreted phospholipase A2 limits the development of atherosclerosis in LDL receptor-null mice. AB - OBJECTIVE: Several secreted phospholipases A2 (sPLA2s), including group IIA, III, V, and X, have been linked to the development of atherosclerosis, which led to the clinical testing of A-002 (varespladib), a broad sPLA2 inhibitor for the treatment of coronary artery disease. Group X sPLA2 (PLA2G10) has the most potent hydrolyzing activity toward phosphatidylcholine and is believed to play a proatherogenic role. METHODS AND RESULTS: Here, we show that Ldlr(-/-) mice reconstituted with bone marrow from mouse group X-deficient mice (Pla2g10(-/-)) unexpectedly display a doubling of plaque size compared with Pla2g10(+/+) chimeric mice. Macrophages of Pla2g10(-/-) mice are more susceptible to apoptosis in vitro, which is associated with a 4-fold increase of plaque necrotic core in vivo. In addition, chimeric Pla2g10(-/-) mice show exaggerated T lymphocyte (Th)1 immune response, associated with enhanced T-cell infiltration in atherosclerotic plaques. Interestingly, overexpression of human PLA2G10 in murine bone marrow cells leads to significant reduction of Th1 response and to 50% reduction of lesion size. CONCLUSIONS: PLA2G10 expression in bone marrow cells controls a proatherogenic Th1 response and limits the development of atherosclerosis. The results may provide an explanation for the recently reported inefficacy of A-002 (varespladib) to treat patients with coronary artery disease. Indeed, A-002 is a nonselective sPLA2 inhibitor that inhibits both proatherogenic (groups IIA and V) and antiatherogenic (group X) sPLA2s. Our results suggest that selective targeting of individual sPLA2 enzymes may be a better strategy to treat cardiovascular diseases. PMID- 23349190 TI - Experimental pediatric arterial ischemic stroke model reveals sex-specific estrogen signaling. AB - BACKGROUND AND PURPOSE: Pediatric stroke, birth to 18 years, is a significant cause of long-term disability in the United States; however, there is currently little experimental data on the pathophysiology of childhood stroke owing to lack of animal models. We developed a novel mouse model of experimental childhood onset arterial ischemic stroke to characterize the sex-specific response of the adolescent brain to cerebral ischemia and assess the neuroprotective effect of estrogen at this developmental stage. METHODS: Postnatal day 20 to 25 mice were subjected to 90 minutes experimental stroke via the intraluminal filament middle cerebral artery occlusion model and ischemic damage assessed 22 hours after reperfusion. Real-time quantitative real-time polymerase chain reaction was performed 22 hours after middle cerebral artery occlusion to determine the effects of ischemia and estrogen treatment on the proapoptotic gene Bax. RESULTS: Ischemic injury did not differ between male and female juvenile (postnatal day 20 25) mice after middle cerebral artery occlusion. However, estrogen reduced ischemic injury in female mice, whereas having no effect in juvenile males. No differences in estrogen receptor expression were observed on postnatal day between 20 males and females. In contrast, estrogen minimized the ischemia induced increase in the proapoptotic gene Bax in female mice, whereas having no effect on Bax induction in the male brain. CONCLUSIONS: Focal ischemia has fundamentally different effects in the juvenile brain compared with the adult, as evidenced by the lack of sex difference in ischemic injury in the murine postnatal day 20 to 25 middle cerebral artery occlusion model and the sexually dimorphic response to estrogen neuroprotection. PMID- 23349191 TI - Mitigation of murine focal cerebral ischemia by the hypocretin/orexin system is associated with reduced inflammation. AB - BACKGROUND AND PURPOSE: Brain ischemia causes immediate and delayed cell death that is exacerbated by inflammation. Recent studies show that hypocretin-1/orexin A (Hcrt-1) reduces ischemic brain injury, and Hcrt-positive neurons modulate infection-induced inflammation. Here, we tested the hypothesis that Hcrt plays a protective role against ischemia by modulating inflammation. METHODS: Orexin/ataxin-3 (AT) mice, a transgenic strain in which Hcrt-producing neurons degenerate in early adulthood, and wild-type mice were subjected to transient middle cerebral artery occlusion (MCAO). Infarct volume, neurological score, and spontaneous home cage activity were assessed. Inflammation was measured using immunohistochemistry, ELISA, and assessment of cytokine mRNA levels. RESULTS: Infarct volumes 24 and 48 hours after MCAO were significantly larger, neurological score was worse, and spontaneous activity decreased in AT compared with wild-type mice. Macrophage/microglial infiltration and myeloperoxidase positive cells were higher in AT compared with wild-type mice. Pre-MCAO intracerebroventricular injection of Hcrt-1 significantly reduced infarct volume and macrophage/microglial infiltration in both genotypes and improved neurological score in AT mice. Post-MCAO treatment decreased infarct size in both wild-type and AT mice, but had no effect on neurological score in either genotype. Microglia express the Hcrt-1 receptor after MCAO. Tumor necrosis factor alpha production by lipopolysaccharide-stimulated microglial BV2 cells was significantly reduced by Hcrt-1 pretreatment. Sham AT mice exhibit increased brain tumor necrosis factor-alpha and interleukin-6 mRNA, suggesting chronic inflammation. CONCLUSIONS: Loss of Hcrt neurons in AT mice resulted in worsened stroke outcomes, which were reversed by administration of exogenous Hcrt-1. The mechanism underlying Hcrt-mediated neuroprotection includes attenuation of inflammatory responses after ischemic insult. PMID- 23349192 TI - Hyperbranched polyglycerol: a future alternative to polyglucose in peritoneal dialysis fluids? PMID- 23349193 TI - Nonuremic indication for peritoneal dialysis for refractory heart failure in cardiorenal syndrome type II: review and perspective. AB - Cardiorenal syndrome (CRS) type II is a serious condition in which chronic cardiac abnormalities cause worsening kidney function, leading to permanent chronic kidney damage. Management of CRS type II coupled with diuretic-resistant congestive heart failure (CHF) has been an issue of dispute. However, since the early 1990s, reports indicating the clinical usefulness of peritoneal dialysis (PD) as maintenance therapy for intractable CHF in this population have been accumulating. The present manuscript reviews the mechanisms by which kidney dysfunction develops within CHF, and then examines recent experiences of PD as chronic supportive therapy for intractable CRS type II, reviews the contributing mechanisms, and discusses the rationale for using PD as a new therapeutic approach in the nonuremic setting of CHF. PMID- 23349194 TI - Hyperbranched polyglycerol is an efficacious and biocompatible novel osmotic agent in a rodent model of peritoneal dialysis. AB - OBJECTIVES: To enhance the effectiveness of peritoneal dialysis (PD), new biocompatible PD solutions may be needed. The present study was designed to test the efficacy and biocompatibility of hyperbranched polyglycerol (HPG)-a nontoxic, nonimmunogenic water-soluble polyether polymer-in PD. METHODS: Adult Sprague Dawley rats were instilled with 30 mL HPG solution (molecular weight 3 kDa; 2.5% 15%) or control glucose PD solution (2.5% Dianeal: Baxter Healthcare Corporation, Deerfield, IL, USA), and intraperitoneal fluid was recovered after 4 hours. Peritoneal injury and cellular infiltration were determined by histologic and flow cytometric analysis. Human peritoneal mesothelial cells were assessed for viability in vitro after 3 hours of PD fluid exposure. RESULTS: The 15% HPG solution achieved a 4-hour dose-related ultrafiltration up to 43.33 +/- 5.24 mL and a dose-related urea clearance up to 39.17 +/- 5.21 mL, results that were superior to those with control PD solution (p < 0.05). The dialysate-to-plasma (D/P) ratios of urea with 7.5% and 15% HPG solution were not statistically different from those with control PD solution. Compared with fluid recovered from the control group, fluid recovered from the HPG group contained proportionally fewer neutrophils (3.63% +/- 0.87% vs 9.31% +/- 2.89%, p < 0.0001). Detachment of mesothelial cells positive for human bone marrow endothelial protein 1 did not increase in the HPG group compared with the stain control (p = 0.1832), but it was elevated in the control PD solution group (1.62% +/- 0.68% vs 0.41% +/- 0.31%, p = 0.0031). Peritoneal biopsies from animals in the HPG PD group, compared with those from control PD animals, demonstrated less neutrophilic infiltration and reduced thickness. Human peritoneal mesothelial cell survival after HPG exposure was superior in vitro (p < 0.0001, 7.5% HPG vs control; p < 0.01, 15% HPG vs control). Exposure to glucose PD solution induced cytoplasmic vacuolation and caspase 3-independent necrotic cell death that was not seen with HPG solution. CONCLUSIONS: Our novel HPG PD solution demonstrated effective ultrafiltration and waste removal with reduced peritoneal injury in a rodent model of PD. PMID- 23349195 TI - Recommendations for fasting in Ramadan for patients on peritoneal dialysis. AB - INTRODUCTION: The month of Ramadan holds great religious and social significance for Muslims all over the world. The aim of the present study was to provide a modified dialysis schedule for peritoneal dialysis (PD) patients that allows for fasting and that minimizes the effect on the patient's general health and volume status. METHODS: We observed 31 patients under treatment at the PD unit of King Khalid University Hospital, King Saud University, Riyadh. During the 3 - 4 weeks before the start of Ramadan, all patients were counseled individually and in detail about the possibility of fasting. They were also provided with clear instructions about fluid intake (up to 1 L daily) and avoiding a high-potassium diet. Of the 31 patients, 18 (10 women, 8 men) elected to fast during the month of Ramadan. The mean duration of fast in the study year (2009) in Riyadh, Saudi Arabia, was about 14 hours: from 0415 h (before sunrise) to 1800 h (after sunset). Depending on membrane type and patient preference, the fasting group was shifted to one of two regimens: Modified continuous ambulatory PD (8 patients): 3 exchanges during the night (1.36% or 2.27%), and icodextrin for a long dwell during the day. The first dialysis exchange was performed immediately after breaking the fast (1900 h), and the next at 2300 h. The final exchange was performed in the early morning before sunrise (0300 h), when the icodextrin was infused. Modified continuous cycling PD (10 patients): exchanges (1.36% or 2.27%) were performed over 6 - 7 hours, and icodextrin was infused for a long dwell during the day. The patient connected to the cycler at 2000 h or 2100 h, and therapy finished at nearly 0300 h, with icodextrin as the last fill. RESULTS: Of the study patients, 2 were admitted because of peritonitis (1 in each modality group), and the modified therapy was discontinued. In the modified CCPD group, 1 patient (on PD for 1 month before Ramadan) developed PD-related pleural effusion (proved by pleural fluid analysis), and PD was consequently discontinued. Hypotension developed in 2 patients of the CAPD group and 1 of the CCPD group during the first 2 weeks. In the CCPD group, 1 patient presented with lower limb edema and mild fluid overload. Overall, PD patients that opted to fast during Ramadan did not experience any serious morbidity or deterioration in renal function during their period of observance. No biochemical parameters or clearance studies showed a statistically significant p value. CONCLUSIONS: In view of the study findings, we conclude that most stable patients on PD can fast, provided that they strictly adhere to their medications and dialysis therapy in addition to the dietary restrictions. These patients should be followed closely to detect any complications and to ensure that adequate fluid and electrolyte balance are maintained. PMID- 23349196 TI - Intraperitoneal voriconazole in a patient with Aspergillus peritoneal dialysis peritonitis. PMID- 23349197 TI - Peritoneal dialysis catheters with back exit sites. PMID- 23349198 TI - Use of home hemodialysis after peritoneal dialysis technique failure. PMID- 23349200 TI - Ofloxacin solution for persistent exit-site and tunnel infection in peritoneal dialysis. PMID- 23349199 TI - Lactococcus garvieae peritoneal dialysis peritonitis. PMID- 23349202 TI - Chemical peritonitis after intraperitoneal sodium thiosulfate. PMID- 23349201 TI - Sphingobium olei peritonitis: peritoneal dialysis in turmoil? PMID- 23349203 TI - CAPD-related peritonitis caused by Morganella morganii. PMID- 23349204 TI - Adrenal insufficiency in a peritoneal dialysis patient taking megestrol acetate. PMID- 23349205 TI - First identification of Gordonia sputi in a continuous ambulatory peritoneal dialysis patient with Peritonitis. PMID- 23349206 TI - Hepatic retinoid stores are required for normal liver regeneration. AB - Preliminary studies of liver regeneration induced by partial hepatectomy (PHE) identified a substantial depletion of hepatic retinoid stores, by greater than 70%, in regenerating livers of wild-type C57Bl/6J mice. To understand this, we compared responses of wild-type and lecithin:retinol acyltransferase (Lrat) deficient mice, which totally lack hepatic retinoid stores, to PHE. The Lrat deficient livers showed delayed regeneration in the first 24 h after PHE. At 12 h after PHE, we observed significantly less mRNA expression for growth factors and cytokines implicated in regulating the priming phase of liver regeneration, specifically for Hgf and Tgfalpha, but not Tgfbeta. Compared with wild-type mice, the changes in mRNA levels for p21 and cyclins E1, B1, and A2 mRNAs and for hepatocellular BrdU incorporation and mitoses were delayed (i.e., shifted to later times) in regenerating Lrat(-/-) livers. Concentrations of all-trans retinoic acid were significantly lower in the livers of Lrat(-/-) mice following PHE, and this was accompanied by diminished expression of known retinoid responsive genes. At later times after PHE, the rate of liver weight restoration for Lrat(-/-) mice was parallel to that of wild-type mice, although additional biochemical differences were observed. Thus, hepatic retinoid stores are required for maintaining expression of signaling molecules that regulate cell proliferation and differentiation immediately after hepatic injury, accounting for the delayed restoration of liver mass in Lrat(-/-) mice. PMID- 23349207 TI - The low-resolution structure of nHDL reconstituted with DMPC with and without cholesterol reveals a mechanism for particle expansion. AB - Small-angle neutron scattering (SANS) with contrast variation was used to obtain the low-resolution structure of nascent HDL (nHDL) reconstituted with dimyristoyl phosphatidylcholine (DMPC) in the absence and presence of cholesterol, [apoA1:DMPC (1:80, mol:mol) and apoA1:DMPC:cholesterol (1:86:9, mol:mol:mol)]. The overall shape of both particles is discoidal with the low-resolution structure of apoA1 visualized as an open, contorted, and out of plane conformation with three arms in nascent HDL/dimyristoyl phosphatidylcholine without cholesterol (nHDL(DMPC)) and two arms in nascent HDL/dimyristoyl phosphatidylcholine with cholesterol (nHDL(DMPC+Chol)). The low-resolution shape of the lipid phase in both nHDL(DMPC) and nHDL(DMPC+Chol) were oblate ellipsoids, and fit well within their respective protein shapes. Modeling studies indicate that apoA1 is folded onto itself in nHDL(DMPC), making a large hairpin, which was also confirmed independently by both cross-linking mass spectrometry and hydrogen deuterium exchange (HDX) mass spectrometry analyses. In nHDL(DMPC+Chol), the lipid was expanded and no hairpin was visible. Importantly, despite the overall discoidal shape of the whole particle in both nHDL(DMPC) and nHDL(DMPC+Chol), an open conformation (i.e., not a closed belt) of apoA1 is observed. Collectively, these data show that full length apoA1 retains an open architecture that is dictated by its lipid cargo. The lipid is likely predominantly organized as a bilayer with a micelle domain between the open apoA1 arms. The apoA1 configuration observed suggests a mechanism for accommodating changing lipid cargo by quantized expansion of hairpin structures. PMID- 23349209 TI - Bag of worms in coronary angiogram: an interesting case of right coronary artery collateral circulation. PMID- 23349208 TI - Evaluation of suppressive and pro-resolving effects of EPA and DHA in human primary monocytes and T-helper cells. AB - Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but DHA to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of cytokine expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)gamma dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both EPA and DHA increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-alpha and IL-6. Cellular incorporation of EPA and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro resolving responses. PMID- 23349210 TI - Necrotising fasciitis caused by P aeruginosa in a male patient with chronic lymphocytic leukaemia. AB - A 53-year-old man with chronic lymphocytic leukaemia and multiple comorbidities presented with a 2-day history of increasing pain and swelling in his left leg following a minor trauma, associated with signs of systemic sepsis and worsening multiorgan failure. The clinical picture was consistent with necrotising fasciitis and he was taken to the theatre for an above-knee amputation. Blood and tissue cultures grew Pseudomonas aeruginosa only, which is very rare as a monomicrobial infection, with relatively few cases being reported in the literature. The combination of aggressive timely surgical intervention, broad spectrum antibiotics and treatment on the intensive care unit yielded a successful outcome from this acute episode. PMID- 23349211 TI - Calcium handling in porcine coronary endothelial cells by gastrin-17. AB - In porcine coronary artery endothelial cells (PCAEC), gastrin-17 has recently been found to increase nitric oxide (NO) production by the endothelial NO synthase (eNOS) isoform through cholecystokinin 1/2 (CCK1/2) receptors and the involvement of protein kinase A (PKA), PKC and the beta2-adrenoreceptor-related pathway. As eNOS is the Ca(2)(+)-dependent isoform of the enzyme, we aimed to examine the effects of gastrin-17 on Ca(2)(+) movements. Thus, experiments were performed in Fura-2-acetoxymethyl-ester-loaded PCAEC, where changes of cytosolic Ca(2)(+) ([Ca(2)(+)]c) caused by gastrin-17 were analysed and compared with those of CCK receptors and beta2-adrenoreceptors agonists/antagonists. In addition, some experiments were performed by stimulating cells with gastrin-17 in the presence or absence of cAMP/PKA activator/inhibitor and of phospholipase C (PLC) and Ca(2)(+)-calmodulin dependent protein kinase II (CaMKII) blockers. The results have shown that gastrin-17 can promote a transient increase in [Ca(2)(+)]c mainly originating from an intracellular pool sensitive to thapsigargin and from the extracellular space. In addition, the response of cells to gastrin-17 was increased by the adenylyl cyclase activator and the beta2 adrenoreceptor agonists and affected mainly by the CCK2 receptor agonists/antagonists. Moreover, the effects of gastrin-17 were prevented by beta2 adrenoreceptors and CaMKII blockers and the adenylyl cyclase/PKA and PLC inhibitors. Finally, in PCAEC cultured in Na(+)-free medium or loaded with the plasma membrane Ca(2)(+) pump inhibitor, the gastrin-17-evoked Ca(2)(+) transient was long lasting. In conclusion, this study shows that gastrin-17 affected intracellular Ca(2)(+) homeostasis in PCAEC by both promoting a discharge of an intracellular pool and by interfering with the operation of store-dependent channels through mainly CCK2 receptors and PKA/PLC- and CaMKII-related signalling downstream of beta2-adrenoreceptor stimulation. PMID- 23349212 TI - Graphlet-based measures are suitable for biological network comparison. AB - MOTIVATION: Large amounts of biological network data exist for many species. Analogous to sequence comparison, network comparison aims to provide biological insight. Graphlet-based methods are proving to be useful in this respect. Recently some doubt has arisen concerning the applicability of graphlet-based measures to low edge density networks-in particular that the methods are 'unstable'-and further that no existing network model matches the structure found in real biological networks. RESULTS: We demonstrate that it is the model networks themselves that are 'unstable' at low edge density and that graphlet based measures correctly reflect this instability. Furthermore, while model network topology is unstable at low edge density, biological network topology is stable. In particular, one must distinguish between average density and local density. While model networks of low average edge densities also have low local edge density, that is not the case with protein-protein interaction (PPI) networks: real PPI networks have low average edge density, but high local edge densities, and hence, they (and thus graphlet-based measures) are stable on these networks. Finally, we use a recently devised non-parametric statistical test to demonstrate that PPI networks of many species are well-fit by several models not previously tested. In addition, we model several viral PPI networks for the first time and demonstrate an exceptionally good fit between the data and theoretical models. PMID- 23349213 TI - essaMEM: finding maximal exact matches using enhanced sparse suffix arrays. AB - We have developed essaMEM, a tool for finding maximal exact matches that can be used in genome comparison and read mapping. essaMEM enhances an existing sparse suffix array implementation with a sparse child array. Tests indicate that the enhanced algorithm for finding maximal exact matches is much faster, while maintaining the same memory footprint. In this way, sparse suffix arrays remain competitive with the more complex compressed suffix arrays. PMID- 23349214 TI - Tiotropium bromide triple combination therapy improves lung function and decreases asthma exacerbations. PMID- 23349215 TI - Prophylactic antiretroviral HIV therapy prevents infection in heterosexual men and women. PMID- 23349216 TI - Tools to assess evidence-based practice behaviour among healthcare professionals. AB - OBJECTIVE: To identify and compare tools to assess Evidence-Based Practice (EBP) behaviour among healthcare professionals. DESIGN: Systematic review. DATA SOURCES: MEDLINE, EMBASE, Cochrane Library, PsychInfo and CINAHL up to July 2011. STUDY SELECTION: Titles, abstracts and eligible full text articles were screened by two reviewers independently. DATA EXTRACTION: Relevant data were extracted by one reviewer and checked by a second reviewer. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: original studies among all healthcare professionals that described the development or use of EBP behaviour assessment tools. RESULTS: Of 19 310 identified articles, 172 studies were included. We identified 117 questionnaires, 10 interviews or focus groups, nine observational studies, 27 chart evaluations and nine studies used a combination of methods. Psychometric properties of the questionnaires used were reported in about half of the studies, in seven studies that assess a single EBM step and in six studies that assess a combination of EBM steps. One of these assessed all five steps of EBP. CONCLUSIONS: Valid and reliable EBP behaviour assessment tools are available. However, only one questionnaire validly assessed all five EBP steps, covering the entire concept of EBP. PMID- 23349217 TI - An unusual case of haemoptysis. PMID- 23349218 TI - Life-threatening haemoptysis due to tracheal varices secondary to pulmonary vein obstruction. PMID- 23349219 TI - Macrolides for yet another chronic airway disease: severe asthma? PMID- 23349220 TI - 3D contrast-enhanced lung perfusion MRI is an effective screening tool for chronic thromboembolic pulmonary hypertension: results from the ASPIRE Registry. AB - BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism potentially curable by surgery. Perfusion scintigraphy is currently advocated as the imaging modality of choice to exclude CTEPH due to its high sensitivity. We have evaluated the diagnostic utility of lung perfusion MRI. METHODS: Consecutive patients attending a pulmonary hypertension referral centre undergoing lung perfusion MRI, perfusion scintigraphy, CT pulmonary angiography (CTPA) and right heart catheterisation within 14 days were identified. RESULTS: Of 132 patients, 78 were diagnosed as having CTEPH. Lung perfusion MRI correctly identified 76 patients as having CTEPH with an overall sensitivity of 97%, specificity 92%, positive predictive value 95% and negative predictive value 96% compared with perfusion scintigraphy (sensitivity 96%, specificity 90%) and CTPA (sensitivity 94%, specificity 98%). No cases of surgically accessible CTEPH were missed with either modality. CONCLUSIONS: Lung perfusion MRI has high sensitivity equivalent to perfusion scintigraphy in diagnosing CTEPH but does not require ionising radiation, making it an attractive initial imaging modality to assess patients with suspected CTEPH. PMID- 23349221 TI - Manipulation of object choice by electrical microstimulation in macaque frontal eye fields. AB - For each saccade, we select an object to direct gaze and to specify the direction and amplitude of eye movement. Although these 2 processes are inevitably interdependent when visual stimuli are held stationary, several lines of evidence suggest that the neuronal signals in the frontal eye fields (FEF) that underlie the selection of visual objects are distinct from those underlying the selection of saccades. In the present study, we overtly dissociated these 2 processes spatially and temporally using the covert object-tracking paradigm, in which 4 identical objects moved randomly for 3 s before monkeys made a saccade to a previously selected target. To assess the causal role of the FEF in the 2 selection processes, we applied electrical microstimulation to the FEF at various times during the motion period. When stimulation was delivered at the motion onset, animals tended to choose an object that was initially presented at a particular location depending on the stimulation site. In contrast, the same stimulation delivered at the motion end failed to alter saccade end points. These results indicate that manipulation of FEF activity can change the selection of a visual object without affecting saccade goals, suggesting the existence of neurons solely regulating visual selection. PMID- 23349222 TI - Involvement of human internal globus pallidus in the early modulation of cortical error-related activity. AB - The detection and assessment of errors are a prerequisite to adapt behavior and improve future performance. Error monitoring is afforded by the interplay between cortical and subcortical neural systems. Ample evidence has pointed to a specific cortical error-related evoked potential, the error-related negativity (ERN), during the detection and evaluation of response errors. Recent models of reinforcement learning implicate the basal ganglia (BG) in early error detection following the learning of stimulus-response associations and in the modulation of the cortical ERN. To investigate the influence of the human BG motor output activity on the cortical ERN during response errors, we recorded local field potentials from the sensorimotor area of the internal globus pallidus and scalp electroencephalogram representing activity from the posterior medial frontal cortex in patients with idiopathic dystonia (hands not affected) during a flanker task. In error trials, a specific pallidal error-related potential arose 60 ms prior to the cortical ERN. The error-related changes in pallidal activity characterized by theta oscillations-were predictive of the cortical error-related activity as assessed by Granger causality analysis. Our findings show an early modulation of error-related activity in the human pallidum, suggesting that pallidal output influences the cortex at an early stage of error detection. PMID- 23349223 TI - Efficiency of a "small-world" brain network depends on consciousness level: a resting-state FMRI study. AB - It has been revealed that spontaneous coherent brain activity during rest, measured by functional magnetic resonance imaging (fMRI), self-organizes a "small world" network by which the human brain could sustain higher communication efficiency across global brain regions with lower energy consumption. However, the state-dependent dynamics of the network, especially the dependency on the conscious state, remain poorly understood. In this study, we conducted simultaneous electroencephalographic recording with resting-state fMRI to explore whether functional network organization reflects differences in the conscious state between an awake state and stage 1 sleep. We then evaluated whole-brain functional network properties with fine spatial resolution (3781 regions of interest) using graph theoretical analysis. We found that the efficiency of the functional network evaluated by path length decreased not only at the global level, but also in several specific regions depending on the conscious state. Furthermore, almost two-thirds of nodes that showed a significant decrease in nodal efficiency during stage 1 sleep were categorized as the default-mode network. These results suggest that brain functional network organizations are dynamically optimized for a higher level of information integration in the fully conscious awake state, and that the default-mode network plays a pivotal role in information integration for maintaining conscious awareness. PMID- 23349224 TI - NMDA and AMPA/kainate glutamatergic receptors in the prelimbic medial prefrontal cortex modulate the elaborated defensive behavior and innate fear-induced antinociception elicited by GABAA receptor blockade in the medial hypothalamus. AB - The aim of the present study was to investigate the involvement of N-methyl-d aspartate (NMDA) and amino-3-hydroxy-5-methyl-isoxazole-4-proprionate (AMPA)/kainate receptors of the prelimbic (PL) division of the medial prefrontal cortex (MPFC) on the panic attack-like reactions evoked by gamma-aminobutyric acid-A receptor blockade in the medial hypothalamus (MH). Rats were pretreated with NaCl 0.9%, LY235959 (NMDA receptor antagonist), and NBQX (AMPA/kainate receptor antagonist) in the PL at 3 different concentrations. Ten minutes later, the MH was treated with bicuculline, and the defensive responses were recorded for 10 min. The antagonism of NMDA receptors in the PL decreased the frequency and duration of all defensive behaviors evoked by the stimulation of the MH and reduced the innate fear-induced antinociception. However, the pretreatment of the PL cortex with NBQX was able to decrease only part of defensive responses and innate fear-induced antinociception. The present findings suggest that the NMDA glutamatergic system of the PL is critically involved in panic-like responses and innate fear-induced antinociception and those AMPA/kainate receptors are also recruited during the elaboration of fear-induced antinociception and in panic attack-related response. The activation of the glutamatergic neurotransmission of PL division of the MPFC during the elaboration of oriented behavioral reactions elicited by the chemical stimulation of the MH recruits mainly NMDA receptors in comparison with AMPA/kainate receptors. PMID- 23349226 TI - Mutations in TMEM231 cause Meckel-Gruber syndrome. AB - BACKGROUND: Meckel-Gruber syndrome (MKS) is a genetically heterogeneous severe ciliopathy characterised by early lethality, occipital encephalocele, polydactyly, and polycystic kidney disease. PURPOSE: To report genetic analysis results in two families in which all known MKS diseases genes have been excluded. METHODS: In two consanguineous families with classical MKS in which autozygome guided sequencing of previously reported MKS genes was negative, we performed exome sequencing followed by autozygome filtration. RESULTS: We identified one novel splicing mutation in TMEM231, which led to complete degradation of the mutant transcript in one family, and a novel missense mutation in the other, both in the homozygous state. CONCLUSIONS: TMEM231 represents a novel MKS locus. The very recent identification of TMEM231 mutations in Joubert syndrome supports the growing appreciation of the overlap in the molecular pathogenesis between these two ciliopathies. PMID- 23349225 TI - Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture. AB - BACKGROUND: Osteoporotic fracture (OF) as a clinical endpoint is a major complication of osteoporosis. To screen for OF susceptibility genes, we performed a genome-wide association study and carried out de novo replication analysis of an East Asian population. METHODS: Association was tested using a logistic regression analysis. A meta-analysis was performed on the combined results using effect size and standard errors estimated for each study. RESULTS: In a combined meta-analysis of a discovery cohort (288 cases and 1139 controls), three hospital based sets in replication stage I (462 cases and 1745 controls), and an independent ethnic group in replication stage II (369 cases and 560 for controls), we identified a new locus associated with OF (rs784288 in the MECOM gene) that showed genome-wide significance (p=3.59*10(-8); OR 1.39). RNA interference revealed that a MECOM knockdown suppresses osteoclastogenesis. CONCLUSIONS: Our findings provide new insights into the genetic architecture underlying OF in East Asians. PMID- 23349228 TI - Indirect protection of adults from rotavirus by pediatric rotavirus vaccination. AB - BACKGROUND: Pediatric vaccination has resulted in declines in disease in unvaccinated individuals through decreasing pathogen circulation in the community. About 2 years after implementation of pediatric rotavirus vaccination in the United States, dramatic declines in rotavirus disease were observed in both vaccinated and unvaccinated children. Whether this protection extends to adults is unknown. METHODS: The prevalence of rotavirus, as determined by Rotaclone enzyme immunoassay, in adults who had stools submitted for bacterial stool culture (BSC) between February to May to Northwestern Memorial Hospital, Chicago, was compared between the prepediatric impact era (2006-2007) and the pediatric impact era (2008-2010). Isolates were genotyped and clinical characteristics of those with rotavirus were compared. RESULTS: Of the 5788 BSC sent, 4725 met inclusion criteria and 3530 of these (74.7%) were saved for rotavirus testing. The prevalence of rotavirus among adults who had stool sent for BSC declined from 4.35% in 2006-2007 to 2.24% in 2008-2010 (a relative decline of 48.4%; P = .0007). The decline in the prevalence of rotavirus was of similar significant magnitude in both outpatients and inpatients. Marked year-to year variability was observed in circulating rotavirus genotypes, with strain G2P[4] accounting for 24%; G1P[8], 22%; G3P[8], 11%; and G12P[6], 10% overall. About 30% of adults from whom rotavirus was isolated were immunocompromised and this remained constant. CONCLUSIONS: Pediatric rotavirus vaccination correlated with a relative decline of almost 50% in rotavirus identified from adult BSC during the peak rotavirus season, suggesting that pediatric rotavirus vaccination protects adults from rotavirus. PMID- 23349227 TI - Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis. AB - BACKGROUND: Corneal intraepithelial dyskeratosis is an extremely rare condition. The classical form, affecting Native American Haliwa-Saponi tribe members, is called hereditary benign intraepithelial dyskeratosis (HBID). Herein, we present a new form of corneal intraepithelial dyskeratosis for which we identified the causative gene by using deep sequencing technology. METHODS AND RESULTS: A seven member Caucasian French family with two corneal intraepithelial dyskeratosis affected individuals (6-year-old proband and his mother) was ascertained. The proband presented with bilateral complete corneal opacification and dyskeratosis. Palmoplantar hyperkeratosis and laryngeal dyskeratosis were associated with the phenotype. Histopathology studies of cornea and vocal cord biopsies showed dyskeratotic keratinisation. Quantitative PCR ruled out 4q35 duplication, classically described in HBID cases. Next generation sequencing with mean coverage of 50* using the Illumina Hi Seq and whole exome capture processing was performed. Sequence reads were aligned, and screened for single nucleotide variants and insertion/deletion calls. In-house pipeline filtering analyses and comparisons with available databases were performed. A novel missense mutation M77T was discovered for the gene NLRP1 which maps to chromosome 17p13.2. This was a de novo mutation in the proband's mother, following segregation in the family, and not found in 738 control DNA samples. NLRP1 expression was determined in adult corneal epithelium. The amino acid change was found to destabilise significantly the protein structure. CONCLUSIONS: We describe a new corneal intraepithelial dyskeratosis and how we identified its causative gene. The NLRP1 gene product is implicated in inflammation, autoimmune disorders, and caspase mediated apoptosis. NLRP1 polymorphisms are associated with various diseases. PMID- 23349230 TI - Marketing 'less harmful, low-tar' cigarettes is a key strategy of the industry to counter tobacco control in China. AB - While the 'low-tar' scheme has been widely recognised as a misleading tactic used by the tobacco industry to deceive the public about the true risks of cigarette smoking, a similar campaign using the slogan of 'less harmful, low tar' was launched by the Chinese tobacco industry, that is, State Tobacco Monopoly Administration/China National Tobacco Corporation and began to gain traction during the last decade. Despite the fact that no sufficient research evidence supports the claims made by the industry that these cigarettes are safer, the Chinese tobacco industry has continued to promote them using various health claims. As a result, the production and sales of 'less harmful, low-tar' cigarettes have increased dramatically since 2000. Recently, a tobacco industry senior researcher, whose main research area is 'less harmful, low-tar' cigarettes, was elected as an Academician to the prestigious Chinese Academy of Engineering for his contribution to developing 'less harmful, low-tar' cigarettes. The tobacco researcher's election caused an outcry from the tobacco control community and the general public in China. This paper discusses the Chinese tobacco industry's 'less harmful, low-tar' initiatives and calls for the Chinese government to stop the execution of this deceptive strategy for tobacco marketing. PMID- 23349229 TI - Biomarkers of secondhand smoke exposure in automobiles. AB - OBJECTIVES: The objectives of this study were: (1) to characterise the exposure of non-smokers exposed to secondhand smoke (SHS) in a vehicle using biomarkers, (2) to describe the time course of the biomarkers over 24 h, and (3) to examine the relationship between tobacco biomarkers and airborne concentrations of SHS markers. METHODS: Eight non-smokers were individually exposed to SHS in cars with fully open front windows and closed back windows over an hour from a smoker who smoked three cigarettes at 20 min intervals. The non-smokers sat in the back seat on the passenger side, while the smoker sat in the driver's seat. Plasma cotinine and urine cotinine, 3-hydroxycotinine (3HC) and 4-(methylnitrosoamino)-(3 pyridyl)-1-butanol (NNAL) were compared in samples taken at baseline (BL) and several time-points after exposure. Nicotine, particulate matter (PM2.5) and carbon monoxide (CO) were measured inside and outside the vehicle and ventilation rates in the cars were measured. RESULTS: Average plasma cotinine and the molar sum of urine cotinine and 3HC (COT+3HC) increased four-fold, urine cotinine increased six-fold and urine NNAL increased ~27 times compared to BL biomarker levels. Plasma cotinine, urine COT+3HC and NNAL peaked at 4-8 h post-exposure while urine cotinine peaked within 4 h. Plasma cotinine was significantly correlated to PM2.5 (Spearman correlation rs=0.94) and CO (rs=0.76) but not to air nicotine. The correlations between urine biomarkers, cotinine, COT+3HC and NNAL, and air nicotine, PM2.5 and CO were moderate but non-significant (rs range = 0.31-0.60). CONCLUSIONS: Brief SHS exposure in cars resulted in substantial increases in levels of tobacco biomarkers in non-smokers. For optimal characterisation of SHS exposure, tobacco biomarkers should be measured within 4 8 h post-exposure. Additional studies are needed to better describe the relationship between tobacco biomarkers and environmental markers of SHS. PMID- 23349233 TI - Regulation of cyclin D2 expression and degradation by follicle-stimulating hormone during rat granulosa cell proliferation in vitro. AB - Cyclin D2 (CCND2, encoded by Ccnd2) plays an important role in the induction of early-to-mid G1 phase transition and is required for granulosa cell proliferation during ovarian folliculogenesis. In the present study, we investigated the role of follicle-stimulating hormone (FSH) in the regulation of cyclin D2 expression and degradation during rat granulosa cell proliferation in vitro. FSH acutely increased granulosa cell Ccnd2 mRNA abundance and CCND2 protein content as well as proliferation. FSH-induced granulosa cell CCND2 protein content and proliferation were mimicked by forskolin and attenuated by inhibitors of protein kinase A (PKA; H89) and phosphatidylinositol 3-kinase (PI3K; LY294002) as well as PKA catalytic subunit (PRKACA) small interfering RNA (siRNA) and dominant negative Akt (dn-Akt) but were not affected by mitogen-activated protein kinase kinase 1/2 (MEK1/2; U0126). Interestingly, FSH also enhanced CCND2 protein degradation in granulosa cells, a process involving a PKA-mediated ubiquitin proteasome degradation pathway. Taken together, these results demonstrate that FSH acutely regulated CCND2 expression through both PKA and PI3K signaling pathways during granulosa cell proliferation and also accelerated its ubiquitination-proteasomal degradation, which may prevent overstimulation of granulosa cell proliferation and follicular growth. PMID- 23349232 TI - DMRT1 owner's manual: synchronized installation required to operate. PMID- 23349231 TI - Dual-energy computed tomography imaging of atherosclerotic plaques in a mouse model using a liposomal-iodine nanoparticle contrast agent. AB - BACKGROUND: The accumulation of macrophages in inflamed atherosclerotic plaques has long been recognized. In an attempt to develop an imaging agent for detection of vulnerable plaques, we evaluated the feasibility of a liposomal-iodine nanoparticle contrast agent for computed tomography imaging of macrophage-rich atherosclerotic plaques in a mouse model. METHODS AND RESULTS: Liposomal-iodine formulations varying in particle size and polyethylene glycol coating were fabricated and shown to stably encapsulate the iodine compound. In vitro uptake studies using optical and computed tomography imaging in the RAW 264.7 macrophage cell line identified the formulation that promoted maximal uptake. Dual-energy computed tomography imaging using this formulation in apolipoprotein E-deficient (ApoE(-/-)) mice (n=8) and control C57BL/6 mice (n=6) followed by spectral decomposition of the dual-energy images enabled imaging of the liposomes localized in the plaque. Imaging cytometry confirmed the presence of liposomes in the plaque and their colocalization with a small fraction (~2%) of the macrophages in the plaque. CONCLUSIONS: The results demonstrate the feasibility of imaging macrophage-rich atherosclerotic plaques using a liposomal-iodine nanoparticle contrast agent and dual-energy computed tomography. PMID- 23349235 TI - Human endometrial stromal cell-trophoblast interactions: mutual stimulation of chemotactic migration and promigratory roles of cell surface molecules CD82 and CEACAM1. AB - We have previously shown that the presence of trophoblast cells enhances invasiveness of decidualizing human endometrial stromal cells. The metastasis suppressor CD82, which has antimigratory function in tumor cells, is up-regulated in decidualizing endometrial stromal cells. CEACAM1 is expressed in trophoblast cells at the invasion front in early placenta and is considered proinvasive. Here, we investigate the role of CD82 and CEACAM1 in cocultures of the endometrial stromal cell line T-HESC and AC-1M88 trophoblast cells. In transwell migration assays, chemotaxis of AC-1M88 cells was stimulated by coplated T-HESC in the lower compartment or by the combination of heparin-binding EGF-like growth factor (HB-EGF), interleukin-1 beta (IL-1beta), and leukemia inhibitory factor (LIF), local factors present at the time of implantation. In an implantation model of AC-1M88 trophoblast spheroids on a monolayer of T-HESC, spheroid expansion was enhanced in the presence of HB-EGF/IL-1beta/LIF. Silencing of CEACAM1 in AC-1M88 blunted this response. Chemotactic migration of T-HESC was stimulated by trophoblast secretions or HB-EGF/IL-1beta/LIF. These responses were suppressed by CD82 depletion in T-HESC. Proteome profiling revealed the presence of platelet-derived growth factor (PDGF)-AA in trophoblast supernatant. Chemotaxis of T-HESC toward PDGF-AA was significantly inhibited by CD82 silencing. Neutralization of PDGF-AA in AC-1M88 conditioned media reduced the chemotactic effect on T-HESC. In summary, we demonstrate a mutual stimulation of chemotactic migration between trophoblast and endometrial stromal cells and promigratory roles for the cell surface molecules CEACAM1 and CD82, which may serve to support tissue remodeling at the implantation site. PMID- 23349234 TI - Massively parallel sequencing for chromosomal abnormality testing in trophectoderm cells of human blastocysts. AB - Preimplantation genetic diagnosis and screening are widely accepted for chromosomal abnormality identification to avoid transferring embryos with genetic defects. Massively parallel sequencing (MPS) is a rapidly developing approach for genome analysis with increasing application in clinical practice. The purpose of this study was to use MPS for identification of aneuploidies and unbalanced chromosomal rearrangements after blastocyst biopsy. Trophectoderm (TE) samples of 38 blastocysts from 16 in vitro fertilization cycles were subjected to analysis. Low-coverage whole genome sequencing was performed using the Illumina HiSeq2000 platform with a novel algorithm purposely created for chromosomal analysis. The efficiency of this MPS approach was estimated by comparing results obtained by an Affymetrix single-nucleotide polymorphism (SNP) array. Whole genome amplification (WGA) products of TE cells were detected by MPS, with an average of 0.07* depth and 5.5% coverage of the human genome. Twenty-six embryos (68.4%) were detected as euploid, while six embryos (15.8%) contained uniform aneuploidies. Four of these (10.5%) were with solely unbalanced chromosomal rearrangements, whereas the remaining two embryos (5.3%) showed both aneuploidies and unbalanced rearrangements. Almost all these results were confirmed by the SNP array, with the exception of one sample, where different sizes of unbalanced rearrangements were detected, possibly due to chromosomal GC bias in array analysis. Our study demonstrated MPS could be applied to accurately detect embryonic chromosomal abnormality with a flexible and cost-effective strategy and higher potential accuracy. PMID- 23349236 TI - Lcn5 promoter directs the region-specific expression of cre recombinase in caput epididymidis of transgenic mice. AB - Epididymis plays a crucial role in regulating the development of sperm motility and fertilizing capacity. To study the function of genes in the caput epididymidis using the Cre/loxP system, we generated Lcn5-Cre transgenic mice in which the expression of Cre recombinase is driven by the 1.8-kb Lcn5 promoter. A total of 11 founder mice carrying the Lcn5-Cre transgene were identified by PCR from 38 offspring, and the integration efficiency was 28.9%. However, only 1 of the 11 transgenic mouse lines were revealed with the Cre recombinase expressed specifically in caput epididymidis. Furthermore, expression of Cre mRNA was first observed on Postnatal Day 30 and continued to increase during development. Subsequently, Cre protein distribution was assessed by crossing Lcn5-Cre transgenic mice into the mT/mG reporter line. As expected, the Cre recombinase activity was only found in principal cells of the middle/distal caput epididymidis. The tissue-specific expression of Cre protein in the caput epididymidis was further confirmed using Lcn5-Cre mice crossed with a mouse strain carrying Aip1 conditional alleles (Aip1(flox/+)). In summary, a transgenic mouse line expressing Cre recombinase in principal cells of caput epididymidis was established. This transgenic mouse line can be used to generate conditional, caput epididymidis-specific knockout mouse models by crossing with mice harboring floxed (LoxP flanked) genes. PMID- 23349237 TI - Atypical antipsychotics not associated with improved hospitalisation outcomes compared with typical antipsychotics in people with schizophrenia in real practice. PMID- 23349238 TI - Death rate in older people with schizophrenia elevated compared with the general population. PMID- 23349239 TI - Review: No clear benefit from information and communication technology-delivered support and education compared with standard care in people with schizophrenia. PMID- 23349240 TI - Behavioural infant sleep intervention does not have long-lasting effects on children's emotions or behaviour, or maternal outcomes. PMID- 23349241 TI - Sample heating system for spin-polarized scanning electron microscopy. AB - A sample-heating system for spin-polarized scanning electron microscopy (spin SEM) has been developed and used for microscopic magnetization analysis at temperatures up to 500 degrees C. In this system, a compact ceramic heater and a preheating operation keep the ultra-high vacuum conditions while the sample is heated during spin SEM measurement. Moreover, the secondary-electron collector, which is arranged close to the sample, was modified so that it is not damaged at high temperatures. The system was used to heat a Co(1000) single-crystal sample from room temperature up to 500 degrees C, and the magnetic-domain structures were observed. Changes of the domain structures were observed around 220 and 400 degrees C, and these changes are considered to be due to phase transitions of this sample. PMID- 23349242 TI - A review of fine structures of nanoporous materials as evidenced by microscopic methods. AB - This paper reviews diverse capabilities offered by modern electron microscopy techniques in studying fine structures of nanoporous crystals such as zeolites, silica mesoporous crystals, metal organic frameworks and yolk-shell materials. For the case of silica mesoporous crystals, new approaches that have been developed recently to determine the three-dimensionally periodic average structure, e.g., through self-consistent analysis of electron microscope images or through consideration of accidental extinctions, are presented. Various structural deviations in nanoporous materials from their average structures including intergrowth, surface termination, incommensurate modulation, quasicrystal and defects are demonstrated. Ibidem observations of the scanning electron microscope and atomic force microscope give information about the zeolite-crystal-growth mechanism, and an energy for unstitching a building-unit from a crystal surface is directly observed by an anatomic force microscope. It is argued how these observations lead to a deeper understanding of the materials. PMID- 23349243 TI - Adjusting for observational secondary treatments in estimating the effects of randomized treatments. AB - In randomized clinical trials, for example, on cancer patients, it is not uncommon that patients may voluntarily initiate a secondary treatment postrandomization, which needs to be properly adjusted for in estimating the "true" effects of randomized treatments. As an alternative to the approach based on a marginal structural Cox model (MSCM) in Zhang and Wang [(2012). Estimating treatment effects from a randomized trial in the presence of a secondary treatment. Biostatistics 13, 625-636], we propose methods that treat the time to start a secondary treatment as a dependent censoring process, which is handled separately from the usual censoring such as the loss to follow-up. Two estimators are proposed, both based on the idea of inversely weighting by the probability of having not started a secondary treatment yet. The second estimator focuses on improving efficiency of inference by a robust covariate-adjustment that does not require any additional assumptions. The proposed methods are evaluated and compared with the MSCM-based method in terms of bias and variance tradeoff using simulations and application to a cancer clinical trial. PMID- 23349244 TI - General health checks may not reduce morbidity or mortality but do increase the number of new diagnoses. PMID- 23349246 TI - Influence of single-fraction Gamma-Knife radiosurgery on ocular surface and tear function in choroidal melanoma patients. AB - AIM: To evaluate ocular surface and tear function in patients with choroidal melanoma treated with single-fraction radiosurgery. METHODS: 36 patients (median age 62 years; range 26-84 years) were enrolled between 2001 and 2006 at a single institution. They were treated with the Leksell Gamma Knife in one fraction with a median dose of 30 Gy (range 25-35 Gy). In both eyes of all patients treated subjective symptom score (visual analogue scale) was evaluated, central corneal sensitivity testing, Schirmer test without local anaesthesia, and corneal and conjunctival staining were performed before therapy and 3, 6, 12, 24 and 36 months thereafter. The respective untreated fellow eye served as control. RESULTS: Three months after radiosurgery, the subjective dry eye symptom score and lissamine green staining score of the ocular surface were significantly higher in the treated eyes compared with the fellow eyes (p<0.001, p=0.028, respectively). After 12 months, a significant difference between the treated and the fellow eyes in corneal sensitivity (p=0.041) and corneal fluorescein staining (p=0.002) was found when compared with pretreatment values. After 24 months Schirmer test values without local anaesthesia were significantly reduced in the treated eyes vis-a-vis untreated fellow eyes and pretreatment values (p=0.004). The dose applied to the lacrimal gland was significantly correlated to ocular surface staining scores (p=0.001) and Schirmer test values (p=0.026) at 24 months after irradiation. CONCLUSIONS: Stereotactic single-fraction Gamma-Knife radiotherapy of choroidal melanoma with a median dose of 30 Gy significantly affected ocular surface and tear function and increased dry eye symptoms and signs. PMID- 23349245 TI - Store-independent Orai1/3 channels activated by intracrine leukotriene C4: role in neointimal hyperplasia. AB - RATIONALE: Through largely unknown mechanisms, Ca(2+) signaling plays important roles in vascular smooth muscle cell (VSMC) remodeling. Orai1-encoded store operated Ca(2+) entry has recently emerged as an important player in VSMC remodeling. However, the role of the exclusively mammalian Orai3 protein in native VSMC Ca(2+) entry pathways, its upregulation during VSMC remodeling, and its contribution to neointima formation remain unknown. OBJECTIVE: The goal of this study was to determine the agonist-evoked Ca(2+) entry pathway contributed by Orai3; Orai3 potential upregulation and role during neointima formation after balloon injury of rat carotid arteries. METHODS AND RESULTS: Ca(2+) imaging and patch-clamp recordings showed that although the platelet-derived growth factor activates the canonical Ca(2+) release-activated Ca(2+) channels via store depletion in VSMC, the pathophysiological agonist thrombin activates a distinct Ca(2+)-selective channel contributed by Orai1, Orai3, and stromal interacting molecule1 in the same cells. Unexpectedly, Ca(2+) store depletion is not required for activation of Orai1/3 channel by thrombin. Rather, the signal for Orai1/3 channel activation is cytosolic leukotrieneC4 produced downstream thrombin receptor stimulation through the catalytic activity of leukotrieneC4 synthase. Importantly, Orai3 is upregulated in an animal model of VSMC neointimal remodeling, and in vivo Orai3 knockdown inhibits neointima formation. CONCLUSIONS: These results demonstrate that distinct native Ca(2+)-selective Orai channels are activated by different agonists/pathways and uncover a mechanism whereby leukotrieneC4 acts through hitherto unknown intracrine mode to elicit store-independent Ca(2+) signaling that promotes vascular occlusive disease. Orai3 and Orai3-containing channels provide novel targets for control of VSMC remodeling during vascular injury or disease. PMID- 23349247 TI - Altered activation of endothelial anti- and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling. AB - BACKGROUND: Endothelial dysfunction and injury are thought to play an important role in the progression of coronary artery disease (CAD). High-density lipoprotein from healthy subjects (HDL(Healthy)) has been proposed to exert endothelial antiapoptotic effects that may represent an important antiatherogenic property of the lipoprotein. The present study therefore aimed to compare effects of HDL(CAD) and HDL(Healthy) on the activation of endothelial anti- and proapoptotic pathways and to determine which changes of the lipoprotein are relevant for these processes. METHODS AND RESULTS: HDL was isolated from patients with stable CAD (HDL(sCAD)), an acute coronary syndrome (HDL(ACS)), and healthy subjects. HDL(Healthy) induced expression of the endothelial antiapoptotic Bcl-2 protein Bcl-xL and reduced endothelial cell apoptosis in vitro and in apolipoprotein E-deficient mice in vivo. In contrast, HDL(sCAD) and HDL(ACS) did not inhibit endothelial apoptosis, failed to activate endothelial Bcl-xL, and stimulated endothelial proapoptotic pathways, in particular, p38-mitogen activated protein kinase-mediated activation of the proapoptotic Bcl-2 protein tBid. Endothelial antiapoptotic effects of HDL(Healthy) were observed after inhibition of endothelial nitric oxide synthase and after delipidation, but not completely mimicked by apolipoprotein A-I or reconstituted HDL, suggesting an important role of the HDL proteome. HDL proteomics analyses and subsequent validations and functional characterizations suggested a reduced clusterin and increased apolipoprotein C-III content of HDL(sCAD) and HDL(ACS) as mechanisms leading to altered effects on endothelial apoptosis. CONCLUSIONS: The present study demonstrates for the first time that HDL(CAD) does not activate endothelial antiapoptotic pathways, but rather stimulates potential endothelial proapoptotic pathways. HDL-proteome remodeling plays an important role for these altered functional properties of HDL. These findings provide novel insights into mechanisms leading to altered vascular effects of HDL in coronary disease. PMID- 23349249 TI - Prevalence and bacterial colonisation of fundic ulcerations in veal calves. PMID- 23349250 TI - Out-of-pocket costs in the year after early breast cancer among Canadian women and spouses. AB - BACKGROUND: We lack comprehensive information about the extent of out-of-pocket costs after diagnosis of early breast cancer and their effects on the family's financial situation. METHODS: This longitudinal study assessed out-of-pocket costs and wage losses during the first year after diagnosis of early breast cancer among Canadian women and spouses. Out-of-pocket costs for treatments and follow-up, consultations with other practitioners, home help, clothing, and natural health products were estimated, with information collected from telephone interviews. Generalized linear models were used to identify women at risk of having higher costs and the effects of out-of-pocket costs on perceptions of the family's financial situation. RESULTS: Overall, 829 women (participation, 86.2%) and 391 spouses participated. Women's median net out-of-pocket costs during the year after diagnosis were $1002 (2003 Canadian dollars; mean = $1365; SD = $1238), and 74.4% of these costs resulted from treatments and follow-up. Spouses' median costs were $111 (mean = $234; SD = $320), or 9% of couples' total expenses. In multivariable analyses, the percentage of women with out-of-pocket costs of $1773 or more (upper quartile) was statistically significantly associated with higher education, working at diagnosis, living more than 50 km from the hospital where surgery was performed, and having two and three different types of adjuvant treatment (all 2-sided P values <= .01). However, when considered simultaneously with wage losses, out-of-pocket costs were not associated with perceived deterioration in the family's financial situation; rather, wage losses were the driving factor. CONCLUSIONS: Overall, out-of-pocket costs from breast cancer for the year after diagnosis are probably not unmanageable for most women. However, some women were at higher risk of experiencing financial burden resulting from these costs. PMID- 23349251 TI - Out of pocket, out of sight? An unmeasured component of the burden of cancer. PMID- 23349253 TI - Fruit and vegetable intake and breast cancer risk: a case for subtype-specific risk? PMID- 23349255 TI - They never saw it coming. PMID- 23349248 TI - Recent insights into the cell biology of thyroid angiofollicular units. AB - In thyrocytes, cell polarity is of crucial importance for proper thyroid function. Many intrinsic mechanisms of self-regulation control how the key players involved in thyroid hormone (TH) biosynthesis interact in apical microvilli, so that hazardous biochemical processes may occur without detriment to the cell. In some pathological conditions, this enzymatic complex is disrupted, with some components abnormally activated into the cytoplasm, which can lead to further morphological and functional breakdown. When iodine intake is altered, autoregulatory mechanisms outside the thyrocytes are activated. They involve adjacent capillaries that, together with thyrocytes, form the angiofollicular units (AFUs) that can be considered as the functional and morphological units of the thyroid. In response to iodine shortage, a rapid expansion of the microvasculature occurs, which, in addition to nutrients and oxygen, optimizes iodide supply. These changes are triggered by angiogenic signals released from thyrocytes via a reactive oxygen species/hypoxia-inducible factor/vascular endothelial growth factor pathway. When intra- and extrathyrocyte autoregulation fails, other forms of adaptation arise, such as euthyroid goiters. From onset, goiters are morphologically and functionally heterogeneous due to the polyclonal nature of the cells, with nodules distributed around areas of quiescent AFUs containing globules of compact thyroglobulin (Tg) and surrounded by a hypotrophic microvasculature. Upon TSH stimulation, quiescent AFUs are activated with Tg globules undergoing fragmentation into soluble Tg, proteins involved in TH biosynthesis being expressed and the local microvascular network extending. Over time and depending on physiological needs, AFUs may undergo repetitive phases of high, moderate, or low cell and tissue activity, which may ultimately culminate in multinodular goiters. PMID- 23349254 TI - Influence of Aloe arborescens Mill. extract on selected parameters of pro-oxidant antioxidant equilibrium and cytokine synthesis in rowers. AB - This investigation examined the effect of supplementation with Biostimine, extract from Aloe arborescens Mill. leaves, on the levels of pro-oxidant antioxidant equilibrium markers and anti- and proinflammatory cytokines in rowers subjected to exhaustive exercise. This double-blind study included 18 members of the Polish Rowing Team. Subjects were randomly assigned to the supplemented group (n = 9), which received one ampoule of Biostimine once daily for 4 weeks, or to the placebo group (n = 9). Subjects performed a 2,000-meter-maximum test on a rowing ergometer at the beginning and end of the preparatory camp. Blood samples were obtained from the antecubital vein before each exercise test, 1 min after completing the test and after a 24-hr recovery period. Superoxide dismutase and glutathione peroxidase activity as well as the concentration of thiobarbituric acid reactive substances (TBARS) were assessed in erythrocytes. In addition, total antioxidant capacity (TAC) and creatine kinase activity were measured in plasma samples, and cytokine (IL-6, IL-10) concentrations were determined in the serum. Before and after Biostimine supplementation, exercise significantly increased the values of SOD, IL-6, IL-10, and TBARS in both groups. However, postexercise and recovery levels of TBARS were significantly lower in athletes receiving Biostimine than in controls. After supplementation, TAC was the only variable with the level being significantly higher in the supplemented group than in the placebo group. Consequently, we can conclude that Biostimine supplementation reduces the postexercise level of TBARS by increasing the antioxidant activity of plasma but has no effect on inflammatory markers. PMID- 23349260 TI - Public health. Gun control agenda is a call to duty for scientists. PMID- 23349261 TI - Global warming. Soot is warming the world even more than thought. PMID- 23349252 TI - Fruit and vegetable intake and risk of breast cancer by hormone receptor status. AB - BACKGROUND: Estrogen receptor-negative (ER(-)) breast cancer has few known or modifiable risk factors. Because ER(-) tumors account for only 15% to 20% of breast cancers, large pooled analyses are necessary to evaluate precisely the suspected inverse association between fruit and vegetable intake and risk of ER( ) breast cancer. METHODS: Among 993 466 women followed for 11 to 20 years in 20 cohort studies, we documented 19 869 estrogen receptor positive (ER(+)) and 4821 ER(-) breast cancers. We calculated study-specific multivariable relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression analyses and then combined them using a random-effects model. All statistical tests were two-sided. RESULTS: Total fruit and vegetable intake was statistically significantly inversely associated with risk of ER(-) breast cancer but not with risk of breast cancer overall or of ER(+) tumors. The inverse association for ER(-) tumors was observed primarily for vegetable consumption. The pooled relative risks comparing the highest vs lowest quintile of total vegetable consumption were 0.82 (95% CI = 0.74 to 0.90) for ER(-) breast cancer and 1.04 (95% CI = 0.97 to 1.11) for ER(+) breast cancer (P (common-effects) by ER status < .001). Total fruit consumption was non-statistically significantly associated with risk of ER(-) breast cancer (pooled multivariable RR comparing the highest vs lowest quintile = 0.94, 95% CI = 0.85 to 1.04). CONCLUSIONS: We observed no association between total fruit and vegetable intake and risk of overall breast cancer. However, vegetable consumption was inversely associated with risk of ER(-) breast cancer in our large pooled analyses. PMID- 23349262 TI - Europe. 'Brussels ranking' of universities off to a rocky start. PMID- 23349263 TI - Field research. Foreigners run afoul of China's tightening secrecy rules. PMID- 23349264 TI - Shaking up science. PMID- 23349265 TI - 2013 Society for Integrative and Comparative Biology Annual Meeting. Eating was tough for early tetrapods. PMID- 23349266 TI - 2013 Society for Integrative and Comparative Biology Annual Meeting. Nervous system may have evolved twice. PMID- 23349267 TI - 2013 Society for Integrative and Comparative Biology Annual Meeting. Snapshots from the meeting. PMID- 23349268 TI - Accidental island voyagers. PMID- 23349269 TI - Accidental island voyagers--response. PMID- 23349271 TI - Extend data exclusivity to save drug development. PMID- 23349272 TI - Comment on "Radiative absorption enhancements due to the mixing state of atmospheric black carbon". AB - Cappa et al. (Reports, 31 August 2012, p. 1078) suggest that black carbon (BC) in a mixture absorbs only ~6% more sunlight than when volatile chemicals are evaporated from the mixture, and state that "many climate models may overestimate warming by BC." However, the authors misinterpret at least some model results and omit optical focusing at high relative humidity and of involatile components. Thus, their conclusion about model error is not demonstrated. PMID- 23349273 TI - Response to comment on "Radiative absorption enhancements due to the mixing state of atmospheric black carbon". AB - Jacobson argues that our statement that "many climate models may overestimate warming by BC" has not been demonstrated. Jacobson challenges our results on the basis that we have misinterpreted some model results, omitted optical focusing under high relative humidity conditions and by involatile components, and because our measurements consist of only two locations over short atmospheric time periods. We address each of these arguments, acknowledging important issues and clarifying some misconceptions, and stand by our observations. We acknowledge that Jacobson identified one detail in our experimental technique that places an additional constraint on the interpretation of our observations and reduces somewhat the potential consequences of the stated implications. PMID- 23349274 TI - Science education. Science learning progressions. PMID- 23349275 TI - Structural biology. Membrane protein twists and turns. PMID- 23349276 TI - Structural biology. (Pseudo-)symmetrical transport. PMID- 23349277 TI - Materials science. Ferroelectric organic materials catch up with oxides. PMID- 23349278 TI - Cell biology. Deconstructing dimensionality. PMID- 23349279 TI - Chemistry. Corralling positively charged molecular radicals. PMID- 23349280 TI - Physics. How big is the proton? PMID- 23349281 TI - Neuroscience. Chaperones that SNARE neurotransmitter release. PMID- 23349282 TI - IBI series winner. Keeping an eye on biology. PMID- 23349283 TI - Can we name Earth's species before they go extinct? AB - Some people despair that most species will go extinct before they are discovered. However, such worries result from overestimates of how many species may exist, beliefs that the expertise to describe species is decreasing, and alarmist estimates of extinction rates. We argue that the number of species on Earth today is 5 +/- 3 million, of which 1.5 million are named. New databases show that there are more taxonomists describing species than ever before, and their number is increasing faster than the rate of species description. Conservation efforts and species survival in secondary habitats are at least delaying extinctions. Extinction rates are, however, poorly quantified, ranging from 0.01 to 1% (at most 5%) per decade. We propose practical actions to improve taxonomic productivity and associated understanding and conservation of biodiversity. PMID- 23349284 TI - Proton structure from the measurement of 2S-2P transition frequencies of muonic hydrogen. AB - Accurate knowledge of the charge and Zemach radii of the proton is essential, not only for understanding its structure but also as input for tests of bound-state quantum electrodynamics and its predictions for the energy levels of hydrogen. These radii may be extracted from the laser spectroscopy of muonic hydrogen (MUp, that is, a proton orbited by a muon). We measured the 2S(1/2)(F=0)-2P(3/2)(F=1) transition frequency in MUp to be 54611.16(1.05) gigahertz (numbers in parentheses indicate one standard deviation of uncertainty) and reevaluated the 2S(1/2)(F=1)-2P(3/2)(F=2) transition frequency, yielding 49881.35(65) gigahertz. From the measurements, we determined the Zemach radius, r(Z) = 1.082(37) femtometers, and the magnetic radius, r(M) = 0.87(6) femtometer, of the proton. We also extracted the charge radius, r(E) = 0.84087(39) femtometer, with an order of magnitude more precision than the 2010-CODATA value and at 7sigma variance with respect to it, thus reinforcing the proton radius puzzle. PMID- 23349285 TI - Diisopropylammonium bromide is a high-temperature molecular ferroelectric crystal. AB - Molecular ferroelectrics are highly desirable for their easy and environmentally friendly processing, light weight, and mechanical flexibility. We found that diisopropylammonium bromide (DIPAB), a molecular crystal processed from aqueous solution, is a ferroelectric with a spontaneous polarization of 23 microcoulombs per square centimeter [close to that of barium titanate (BTO)], high Curie temperature of 426 kelvin (above that of BTO), large dielectric constant, and low dielectric loss. DIPAB exhibits good piezoelectric response and well-defined ferroelectric domains. These attributes make it a molecular alternative to perovskite ferroelectrics and ferroelectric polymers in sensing, actuation, data storage, electro-optics, and molecular or flexible electronics. PMID- 23349286 TI - A radically configurable six-state compound. AB - Most organic radicals possess short lifetimes and quickly undergo dimerization or oxidation. Here, we report on the synthesis by radical templation of a class of air- and water-stable organic radicals, trapped within a homo[2]catenane composed of two rigid and fixed cyclobis(paraquat-p-phenylene) rings. The highly energetic octacationic homo[2]catenane, which is capable of accepting up to eight electrons, can be configured reversibly, both chemically and electrochemically, between each one of six experimentally accessible redox states (0, 2+, 4+, 6+, 7+, and 8+) from within the total of nine states evaluated by quantum mechanical methods. All six of the observable redox states have been identified by electrochemical techniques, three (4+, 6+, and 7+) have been characterized by x ray crystallography, four (4+, 6+, 7+, and 8+) by electron paramagnetic resonance spectroscopy, one (7+) by superconducting quantum interference device magnetometry, and one (8+) by nuclear magnetic resonance spectroscopy. PMID- 23349287 TI - Identification of the long-sought common-envelope events. AB - Common-envelope events (CEEs), during which two stars temporarily orbit within a shared envelope, are believed to be vital for the formation of a wide range of close binaries. For decades, the only evidence that CEEs actually occur has been indirect, based on the existence of systems that could not be otherwise explained. Here we propose a direct observational signature of CEEs arising from a physical model where emission from matter ejected in a CEE is controlled by a recombination front as the matter cools. The natural range of time scales and energies from this model, as well as the expected colors, light-curve shapes, ejection velocities, and event rate, match those of a recently recognized class of red transient outbursts. PMID- 23349289 TI - To favor survival under food shortage, the brain disables costly memory. AB - The brain regulates energy homeostasis in the organism. Under resource shortage, the brain takes priority over peripheral organs for energy supply. But can the brain also down-regulate its own consumption to favor survival? We show that the brain of Drosophila specifically disables the costly formation of aversive long term memory (LTM) upon starvation, a physiological state required for appetitive LTM formation. At the neural circuit level, the slow oscillations normally triggered in two pairs of dopaminergic neurons to enable aversive LTM formation were abolished in starved flies. Transient artificial activation of these neurons during training restored LTM formation in starved flies but at the price of a reduced survival. LTM formation is thus subject to adaptive plasticity that helps survival under food shortage. PMID- 23349288 TI - Synchronous x-ray and radio mode switches: a rapid global transformation of the pulsar magnetosphere. AB - Pulsars emit from low-frequency radio waves up to high-energy gamma-rays, generated anywhere from the stellar surface out to the edge of the magnetosphere. Detecting correlated mode changes across the electromagnetic spectrum is therefore key to understanding the physical relationship among the emission sites. Through simultaneous observations, we detected synchronous switching in the radio and x-ray emission properties of PSR B0943+10. When the pulsar is in a sustained radio-"bright" mode, the x-rays show only an unpulsed, nonthermal component. Conversely, when the pulsar is in a radio-"quiet" mode, the x-ray luminosity more than doubles and a 100% pulsed thermal component is observed along with the nonthermal component. This indicates rapid, global changes to the conditions in the magnetosphere, which challenge all proposed pulsar emission theories. PMID- 23349290 TI - Fasting launches CRTC to facilitate long-term memory formation in Drosophila. AB - Canonical aversive long-term memory (LTM) formation in Drosophila requires multiple spaced trainings, whereas appetitive LTM can be formed after a single training. Appetitive LTM requires fasting prior to training, which increases motivation for food intake. However, we found that fasting facilitated LTM formation in general; aversive LTM formation also occurred after single-cycle training when mild fasting was applied before training. Both fasting-dependent LTM (fLTM) and spaced training-dependent LTM (spLTM) required protein synthesis and cyclic adenosine monophosphate response element-binding protein (CREB) activity. However, spLTM required CREB activity in two neural populations- mushroom body and DAL neurons--whereas fLTM required CREB activity only in mushroom body neurons. fLTM uses the CREB coactivator CRTC, whereas spLTM uses the coactivator CBP. Thus, flies use distinct LTM machinery depending on their hunger state. PMID- 23349291 TI - The human THAP9 gene encodes an active P-element DNA transposase. AB - The human genome contains ~50 genes that were derived from transposable elements or transposons, and many are now integral components of cellular gene expression programs. The human THAP9 gene is related to the Drosophila P-element transposase. Here, we show that human THAP9 can mobilize Drosophila P-elements in both Drosophila and human cells. Chimeric proteins formed between the Drosophila P-element transposase N-terminal THAP DNA binding domain and the C-terminal regions of human THAP9 can also mobilize Drosophila P elements. Our results indicate that human THAP9 is an active DNA transposase that, although "domesticated," still retains the catalytic activity to mobilize P transposable elements across species. PMID- 23349292 TI - Tunable signal processing through modular control of transcription factor translocation. AB - Signaling pathways can induce different dynamics of transcription factor (TF) activation. We explored how TFs process signaling inputs to generate diverse dynamic responses. The budding yeast general stress-responsive TF Msn2 acted as a tunable signal processor that could track, filter, or integrate signals in an input-dependent manner. This tunable signal processing appears to originate from dual regulation of both nuclear import and export by phosphorylation, as mutants with one form of regulation sustained only one signal-processing function. Versatile signal processing by Msn2 is crucial for generating distinct dynamic responses to different natural stresses. Our findings reveal how complex signal processing functions are integrated into a single molecule and provide a guide for the design of TFs with "programmable" signal-processing functions. PMID- 23349293 TI - An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. AB - Mitochondrial fission is fundamentally important to cellular physiology. The dynamin-related protein Drp1 mediates fission, and interaction between mitochondrion and endoplasmic reticulum (ER) enhances fission. However, the mechanism for Drp1 recruitment to mitochondria is unclear, although previous results implicate actin involvement. Here, we found that actin polymerization through ER-localized inverted formin 2 (INF2) was required for efficient mitochondrial fission in mammalian cells. INF2 functioned upstream of Drp1. Actin filaments appeared to accumulate between mitochondria and INF2-enriched ER membranes at constriction sites. Thus, INF2-induced actin filaments may drive initial mitochondrial constriction, which allows Drp1-driven secondary constriction. Because INF2 mutations can lead to Charcot-Marie-Tooth disease, our results provide a potential cellular mechanism for this disease state. PMID- 23349294 TI - Country- and individual-level socioeconomic determinants of depression: multilevel cross-national comparison. AB - BACKGROUND: The prevalence and correlates of depression vary across countries. Contextual factors such as country-level income or income inequalities have been hypothesised to contribute to these differences. AIMS: To investigate associations of depression with socioeconomic factors at the country level (income inequality, gross national income) and individual (education, employment, assets and spending) level, and to investigate their relative contribution in explaining the cross-national variation in the prevalence of depression. METHOD: Multilevel study using interview data of 187 496 individuals from 53 countries participating in the World Health Organization World Health Surveys. RESULTS: Depression prevalence varied between 0.4 and 15.7% across countries. Individual level factors were responsible for 86.5% of this variance but there was also reasonable variation at the country level (13.5%), which appeared to increase with decreasing economic development of countries. Gross national income or country-level income inequality had no association with depression. At the individual level, fewer material assets, lower education, female gender, economic inactivity and being divorced or widowed were associated with increased odds of depression. Greater household spending, unlike material assets, was associated with increasing odds of depression (adjusted analysis). CONCLUSIONS: The variance of depression prevalence attributable to country-level factors seemed to increase with decreasing economic development of countries. However, country-level income inequality or gross national income explained little of this variation, and individual-level factors appeared more important than contextual factors as determinants of depression. The divergent relationship of assets and spending with depression emphasise that different socioeconomic measures are not interchangeable in their associations with depression. PMID- 23349295 TI - Treatment in a specialised out-patient mood disorder clinic v. standard out patient treatment in the early course of bipolar disorder: randomised clinical trial. AB - BACKGROUND: Little is known about whether treatment in a specialised out-patient mood disorder clinic improves long-term prognosis for patients discharged from initial psychiatric hospital admissions for bipolar disorder. AIMS: To assess the effect of treatment in a specialised out-patient mood disorder clinic v. standard decentralised psychiatric treatment among patients discharged from one of their first three psychiatric hospital admissions for bipolar disorder. METHOD: Patients discharged from their first, second or third hospital admission with a single manic episode or bipolar disorder were randomised to treatment in a specialised out-patient mood disorder clinic or standard care (ClinicalTrials.gov: NCT00253071). The primary outcome measure was readmission to hospital, which was obtained from the Danish Psychiatric Central Register. RESULTS: A total of 158 patients with mania/bipolar disorder were included. The rate of readmission to hospital was significantly decreased for patients treated in the mood disorder clinic compared with standard treatment (unadjusted hazard ratio 0.60, 95% CI 0.37-0.97, P = 0.034). Patients treated in the mood disorder clinic more often used a mood stabiliser or an antipsychotic and satisfaction with treatment was more prevalent than among patients who received standard care. CONCLUSIONS: Treatment in a specialised mood disorder clinic early in the course of bipolar disorder substantially reduces readmission to a psychiatric hospital and increases satisfaction with care. PMID- 23349296 TI - Prevention of contrast-induced nephropathy with Na/K citrate. AB - AIMS: Contrast-induced nephropathy (CIN) is a frequent complication of many radiological procedures involving the application of contrast media. It represents a significant health problem that causes the increase in mortality, morbidity, and medical costs. For the prevention of CIN, a number of methods have been proposed to be effective. Among them, alkalinization of urine takes an important place. Although the Na/K citrate is a well-known agent for urine alkalinization, it has not been studied in the prevention of CIN. METHODS AND RESULTS: Two hundred and two patients who underwent coronary angiography were included in the study. They were randomized into groups receiving the drug Na/K citrate per os and to the control group. Serum creatinine and glomerular filtration rate were determined in all patients immediately before coronary angiography, and 48 h after the procedure. CIN criteria were a creatinine increase of >25%, reduction in the glomerular filtration rate by >25%, or an increase in serum creatinine of >44 MUmol/L. The incidence of CIN in the group receiving Na/K citrate was significantly lower when compared with the control group (4% compared with 20%, P = 0.0001). Patients who had a urine pH <6 had a more than ten-fold higher incidence of contrast nephropathy compared with patients whose urine pH was >6. CONCLUSION: Alkalinization of urine using the Na/K citrate may reduce the incidence of CIN. PMID- 23349297 TI - Circulating angiopoietins and cardiovascular mortality in cardiogenic shock. AB - AIMS: Vascular integrity is disturbed in shock contributing to clinical appearance and serious outcomes. While angiopoietin (Ang)-1 protects from vascular inflammation and leakage, Ang-2 disrupts endothelial barrier function. The imbalance of Ang-1 and Ang-2, their association to haemodynamic deterioration, and their prognostic relevance are not known and, thus, were prospectively evaluated in patients with cardiogenic shock (CS) in this study. METHODS AND RESULTS: Plasma Ang-1 and Ang-2 were determined by the enzyme immunoassay in patients with CS (n = 96), uncomplicated acute myocardial infarction (AMI, n = 20) and age-matched healthy controls (HC, n = 20). Angiopoietin-2 was three-fold elevated in CS compared with HC (P < 0.001), remained elevated in non-survivors, and decreased in survivors (P < 0.001). In contrast, Ang-1 decreased up to 35-fold in CS (P < 0.001). Angiopoietin-1 was correlated and Ang-2 was inversely related to a cardiac power index and mixed venous oxygen saturation, respectively (P < 0.001 for all). To assess the prognostic relevance, two outcome variables were considered: the 28-day mortality and the survival time (follow-up time 1 year). For Ang-2 at admission a cut-off point of 2500 pg/mL had a sensitivity of 61% and a specificity of 80% to determine 28-day mortality in CS (confirmed by receiver operating characteristic analysis, area under the curve = 0.71 +/- 0.06, P < 0.001). Angiopoietin-2 levels >2500 pg/mL at admission were observed to be an independent predictor for 1-year mortality in CS confirmed by Cox proportional hazard analysis [hazard ratio (HR) 2.11; 95% confidence interval (CI) 1.03-4.36; P = 0.042]. CONCLUSION: Circulating Angs are closely related to outcome and severity in CS. Angiopoietin-2 emerged as an independent predictor of 28-day and 1-year mortality in CS. Larger studies are required to define the cut-off and predictive values for Ang-2. Angiopoietins may be prognostic biomarkers for survival in CS and might represent a novel therapeutic target. PMID- 23349298 TI - Oral creatine supplementation augments the repeated bout effect. AB - PURPOSE: We examined the effects of creatine supplementation on the response to repeated bouts of resistance exercise. METHODS: Young men (24.1 +/- 5.2 yr) were divided into Creatine (CM, n = 9) and Placebo (PL, n = 9) groups. On day (D) 1 and D15, subjects performed four sets of bicep curls at 75% 1-RM to concentric failure. On D8-D13, subjects consumed either 20g/d creatine monohydrate or placebo. Muscle soreness and elbow joint range of motion (ROM) were assessed on D1-D5 and D15-D19. Serum creatine kinase activity (CK) was assessed on D1, D3, D5, D15, D17, and D19. RESULTS: The first exercise bout produced increases in muscle soreness and CK, and decreases in ROM in both groups (p < .001). The second bout produced lesser rises in serum CK, muscle soreness, and a lesser decrease in ROM (bout effect, p < .01 for all), with greater attenuation of these damage markers in CM than PL. CK levels on D17 were lower (+110% over D15 for CM vs. +343% for PL), muscle soreness from D15-19 was lower (-75% for CM vs. -56% for PL compared with first bout), and elbow ROM was decreased in PL, but not CM on D16 (p < .05 for all). CONCLUSIONS: Creatine supplementation provides an additive effect on blunting the rise of muscle damage markers following a repeated bout of resistance exercise. The mechanism by which creatine augments the repeated bout effect is unknown but is likely due to a combination of creatine's multifaceted functions. PMID- 23349299 TI - Cord blood-derived CD34+ hematopoietic cells with low mitochondrial mass are enriched in hematopoietic repopulating stem cell function. AB - The homeostasis of the hematopoietic stem/progenitor cell pool relies on a fine tuned balance between self-renewal, differentiation and proliferation. Recent studies have proposed that mitochondria regulate these processes. Although recent work has contributed to understanding the role of mitochondria during stem cell differentiation, it remains unclear whether the mitochondrial content/function affects human hematopoietic stem versus progenitor function. We found that mitochondrial mass correlates strongly with mitochondrial membrane potential in CD34(+) hematopoietic stem/progenitor cells. We, therefore, sorted cord blood CD34(+) cells on the basis of their mitochondrial mass and analyzed the in vitro homeostasis and clonogenic potential as well as the in vivo repopulating potential of CD34(+) cells with high (CD34(+) Mito(High)) versus low (CD34(+) Mito(Low)) mitochondrial mass. The CD34(+) Mito(Low) fraction contained 6-fold more CD34(+)CD38(-) primitive cells and was enriched in hematopoietic stem cell function, as demonstrated by its significantly greater hematopoietic reconstitution potential in immuno-deficient mice. In contrast, the CD34(+) Mito(High) fraction was more enriched in hematopoietic progenitor function with higher in vitro clonogenic capacity. In vitro differentiation of CD34(+) Mito(Low) cells was significantly delayed as compared to that of CD34(+) Mito(High) cells. The eventual complete differentiation of CD34(+) Mito(Low) cells, which coincided with a robust expansion of the CD34(-) differentiated progeny, was accompanied by mitochondrial adaptation, as shown by significant increases in ATP production and expression of the mitochondrial genes ND1 and COX2. In conclusion, cord blood CD34(+) cells with low levels of mitochondrial mass are enriched in hematopoietic repopulating stem cell function whereas high levels of mitochondrial mass identify hematopoietic progenitors. A mitochondrial response underlies hematopoietic stem/progenitor cell differentiation and proliferation of lineage-committed CD34(-) cells. PMID- 23349300 TI - Different effects of HLA disparity on transplant outcomes after single-unit cord blood transplantation between pediatric and adult patients with leukemia. AB - Recent advances in unrelated cord blood transplantation have increased chances and options available in allogeneic stem cell transplantation. The effect of HLA disparity on outcomes after cord blood transplantation was studied recently in mainly pediatric populations. Results showed that HLA matching in combination with total nucleated cell dose positively affects survival. The effect of HLA disparity after single-unit cord blood transplantation may be different in adults because their total nucleated cell dose is much lower compared to pediatric patients. We investigated the effect of HLA disparity on the outcome of single unit unrelated cord blood transplantation separately in 498 children aged 15 years or under (HLA-A, HLA-B low-resolution, and HLA-DRB1 high-resolution matched [6/6], n=82, and one locus- [5/6], n=222, two loci- [4/6], n=158, three loci- [3/6] mismatched, n=36) and 1,880 adults (6/6, n=71; 5/6, n=309; 4/6, n=1,025; 3/6, n=475) with leukemia. With adjusted analyses, in children, 4/6 showed significantly increased risks of overall mortality (relative risk [RR]=1.61, P=0.042) and transplant-related mortality (RR=3.55, P=0.005) compared to 6/6. The risk of grade 2 to 4 acute GVHD was increased in 5/6 (RR=2.13, P=0.004) and 4/6 (RR=2.65, P<0.001). In adults, the risk of mortality did not increase with the number of mismatched loci (RR=0.99, P=0.944 for 5/6; RR=0.88, P=0.436 for 4/6). The risk of relapse was significantly decreased in 4/6 (RR=0.67, P=0.034). The risk of transplant-related mortality (TRM) or acute GVHD was not increased in 5/6 or 4/6. The effect of HLA disparity on transplant outcome differed between children and adults. In children, an increased number of mismatched HLA loci correlated with an increased risk of mortality. In adults, there was no increase in mortality with an increase in the number of mismatched HLA loci. PMID- 23349301 TI - Elevated lipoprotein (a), small apolipoprotein (a), and the risk of arterial ischemic stroke in North American children. AB - Lipoprotein (a) is a risk factor for adult cardiovascular events, in which the apolipoprotein (a) component is thought to promote atherogenesis and impair fibrinolysis. We investigated whether elevated plasma lipoprotein (a) concentration and small predominant apolipoprotein (a) isoform size (number of kringle-4 domains) are risk factors for childhood arterial ischemic stroke and correlate with plasma fibrinolytic function. Patients who had had an arterial ischemic stroke in childhood (29 days - <21 years at onset; n=43) and healthy controls (n=127) were recruited for plasma sampling and laboratory determinations. Cases were followed for recurrence in a prospective cohort study. The median lipoprotein (a) concentration did not differ between groups [cases: median 18.0 nmol/L (7.5 mg/dL) and observed range 0.9-259 nmol/L (0.38-108.0 mg/dL), controls: 20.4 nmol/L (8.5 mg/dL) and 0.2-282 nmol/L (0.08-117.5 mg/dL); P=0.62]. While odds of incident stroke were not significantly increased, risks of recurrent arterial ischemic stroke were each more than ten-times increased for lipoprotein(a) >90(th) percentile of race-specific reference values and apolipoprotein (a) <10(th) percentiles [odds ratio=14.0 (95% confidence interval: 1.0-184), P=0.05 and odds ratio=12.8 (1.61-101), P=0.02]. Statistically significant but weak correlations were observed between euglobulin lysis time and both lipoprotein (a) level (r=0.18, P=0.03) and apolipoprotein (a) size (r= 0.26, P=0.002). In conclusion, elevated lipoprotein (a) and small apolipoprotein (a) potently increase the risk of recurrent arterial ischemic stroke in children, with a mechanism only partially attributable to impaired fibrinolysis. Collaborative studies are warranted to investigate these findings further and, more broadly, to establish key risk factors for incident and recurrent arterial ischemic stroke in children. PMID- 23349302 TI - The monocytic population in chronic lymphocytic leukemia shows altered composition and deregulation of genes involved in phagocytosis and inflammation. AB - Macrophages reside in tissues infiltrated by chronic lymphocytic leukemia B cells and the extent of infiltration is associated with adverse prognostic factors. We studied blood monocyte population by flow cytometry and whole-genome microarrays. A mixed lymphocyte reaction was performed to evaluate proliferation of T cells in contact with monocytes from patients and normal donors. Migration and gene modulation in normal monocytes cultured with CLL cells were also evaluated. The absolute number of monocytes increased in chronic lymphocytic leukemia patients compared to the number in normal controls (792 +/- 86 cells/MUL versus 485 +/- 46 cells/MUL, P=0.003). Higher numbers of non-classical CD14(+)CD16(++) and Tie-2 expressing monocytes were also detected in patients. Furthermore, we performed a gene expression analysis of monocytes in chronic lymphocytic leukemia patients, showing up-regulation of RAP1GAP and down-regulation of tubulins and CDC42EP3, which would be expected to result in impairment of phagocytosis. We also detected gene alterations such as down-regulation of PTGR2, a reductase able to inactivate prostaglandin E2, indicating immunosuppressive activity. Accordingly, the proliferation of T cells in contact with monocytes from patients was inhibited compared to that of cells in contact with monocytes from normal controls. Finally, normal monocytes in vitro increased migration and up-regulated CD16, RAP1GAP, IL-10, IL-8, MMP9 and down-regulated PTGR2 in response to leukemic cells or conditioned media. In conclusion, altered composition and deregulation of genes involved in phagocytosis and inflammation were found in blood monocytes obtained from chronic lymphocytic leukemia patients, suggesting that leukemia mediated "education" of immune elements may also include the establishment of a skewed phenotype in the monocyte/macrophage population. PMID- 23349303 TI - NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia. AB - Despite improvements in treatment results for pediatric T-cell acute lymphoblastic leukemia, approximately 20% of patients relapse with dismal prognosis. PTEN inactivation and NOTCH1 activation are known frequent leukemogenic events but their effect on outcome is still controversial. We analyzed the effect of PTEN inactivation and its interaction with NOTCH1 activation on treatment response and long-term outcome in 301 ALL-BFM treated children with T-cell acute lymphoblastic leukemia. We identified PTEN mutations in 52 of 301 (17.3%) of patients. In univariate analyses this was significantly associated with increased resistance to induction chemotherapy and a trend towards poor long-term outcome. By contrast, patients with inactivating PTEN and activating NOTCH1 mutations showed marked sensitivity to induction treatment and excellent long-term outcome, which was similar to patients with NOTCH1 mutations only, and more favorable than in patients with PTEN mutations only. Notably, in the subgroup of patients with a prednisone- and minimal residual disease (MRD) response based medium risk profile, PTEN-mutations without co-existing NOTCH1 mutations represented an MRD-independent highly significant high-risk biomarker. Mutations of PTEN highly significantly indicate a poor prognosis in T-ALL patients who have been stratified to the medium risk group of the BFM-protocol. This effect is clinically neutralized by NOTCH1 mutations. Although these results have not yet been explained by an obvious molecular mechanism, they contribute to the development of new molecularly defined stratification algorithms. Furthermore, these data have unexpected potential implications for the development of NOTCH1 inhibitors in the treatment of T-cell acute lymphoblastic leukemia in general, and in those with a combination of PTEN and NOTCH1 mutations in particular. PMID- 23349305 TI - Mutational analysis of therapy-related myelodysplastic syndromes and acute myelogenous leukemia. AB - Therapy-related myelodysplastic syndromes and acute myelogenous leukemia comprise a poor-risk subset of myelodysplastic syndromes and acute myelogenous leukemia. Large-scale mutation profiling efforts in de novo myelodysplastic syndromes have identified mutations that correlate with clinical features, but such mutations have not been investigated in therapy-related myelodysplastic syndromes and acute myelogenous leukemia. Genomic DNA from 38 patient samples were subjected to high throughput polymerase chain reaction and sequenced for TP53, TET2, DNMT3A, ASXL1, IDH1, IDH2, EZH2, EED, SUZ12, RBBP4, SRSF2, U2AF35, and SF3B1. We identified somatic mutations in 16 of 38 (42%) patients. TP53 mutations were the most common lesion, detected in 8 of 38 (21%) patients, followed by TET2 in 4 of 38 (10.5%). Cases with a TP53 mutation or loss of the TP53 locus had a worse overall survival compared to those with wild-type TP53 (8.8 vs. 37.4 months; P=0.0035). PMID- 23349304 TI - Microsatellite instability induced mutations in DNA repair genes CtIP and MRE11 confer hypersensitivity to poly (ADP-ribose) polymerase inhibitors in myeloid malignancies. AB - Inactivation of the DNA mismatch repair pathway manifests as microsatellite instability, an accumulation of mutations that drives carcinogenesis. Here, we determined whether microsatellite instability in acute myeloid leukemia and myelodysplastic syndrome correlated with chromosomal instability and poly (ADP ribose) polymerase (PARP) inhibitor sensitivity through disruption of DNA repair function. Acute myeloid leukemia cell lines (n=12) and primary cell samples (n=18), and bone marrow mononuclear cells from high-risk myelodysplastic syndrome patients (n=63) were profiled for microsatellite instability using fluorescent fragment polymerase chain reaction. PARP inhibitor sensitivity was performed using cell survival, annexin V staining and cell cycle analysis. Homologous recombination was studied using immunocytochemical analysis. SNP karyotyping was used to study chromosomal instability. RNA silencing, Western blotting and gene expression analysis was used to study the functional consequences of mutations. Acute myeloid leukemia cell lines (4 of 12, 33%) and primary samples (2 of 18, 11%) exhibited microsatellite instability with mono-allelic mutations in CtIP and MRE11. These changes were associated with reduced expression of mismatch repair pathway components, MSH2, MSH6 and MLH1. Both microsatellite instability positive primary acute myeloid leukemia samples and cell lines demonstrated a downregulation of homologous recombination DNA repair conferring marked sensitivity to PARP inhibitors. Similarly, bone marrow mononuclear cells from 11 of 56 (20%) patients with de novo high-risk myelodysplastic syndrome exhibited microsatellite instability. Significantly, all 11 patients with microsatellite instability had cytogenetic abnormalities with 4 of them (36%) possessing a mono allelic microsatellite mutation in CtIP. Furthermore, 50% reduction in CtIP expression by RNA silencing also down-regulated homologous recombination DNA repair responses conferring PARP inhibitor sensitivity, whilst CtIP differentially regulated the expression of homologous recombination modulating RecQ helicases, WRN and BLM. In conclusion, microsatellite instability dependent mutations in DNA repair genes, CtIP and MRE11 are detected in myeloid malignancies conferring hypersensitivity to PARP inhibitors. Microsatellite instability is significantly correlated with chromosomal instability in myeloid malignancies. PMID- 23349306 TI - The trithorax protein partner menin acts in tandem with EZH2 to suppress C/EBPalpha and differentiation in MLL-AF9 leukemia. AB - Trithorax and polycomb group proteins antagonistically regulate the transcription of many genes, and cancer can result from the disruption of this regulation. Deregulation of trithorax function occurs through chromosomal translocations involving the trithorax gene MLL, leading to the expression of MLL fusion proteins and acute leukemia. It is poorly understood how MLL fusion proteins block differentiation, a hallmark of leukemogenesis. We analyzed the effect of acute depletion of menin, a close partner of MLL that is critical for MLL and MLL AF9 recruitment to target genes, on MLL-AF9 leukemia cell differentiation using an in vivo model. We performed cDNA microarray analysis of menin-regulated genes from primary leukemia cells to determine menin-regulated pathways involved in suppressing MLL-AF9 leukemia cell differentiation. We found that menin binds the promoter of the polycomb gene Ezh2, and promotes its expression. EZH2 interacts with the differentiation-promoting transcription factor C/EBPalpha and represses C/EBPalpha target genes. Menin depletion reduces MLL binding to the Ezh2 locus, EZH2 expression, and EZH2 binding and repressive H3K27 methylation at C/EBPalpha target genes, thereby inducing the expression of pro-differentiation C/EBPalpha targets. In conclusion, our results show that in contrast to its classical role antagonizing trithorax function, the polycomb group protein EZH2 collaborates with trithorax-associated menin to block MLL-AF9 leukemia cell differentiation, uncovering a novel mechanism for suppression of C/EBPalpha and leukemia cell differentiation, through menin-mediated upregulation of EZH2. PMID- 23349307 TI - Constant activation of the RAF-MEK-ERK pathway as a diagnostic and therapeutic target in hairy cell leukemia. AB - The BRAF-V600E mutation defines genetically hairy cell leukemia among B-cell leukemias and lymphomas. In solid tumors, BRAF-V600E is known to aberrantly activate the oncogenic MEK-ERK pathway, and targeted BRAF and/or MEK inhibitors have shown remarkable efficacy in clinical trials in melanoma patients. However, the MEK-ERK pathway status in hairy cell leukemia has not been thoroughly investigated. We assessed phospho-ERK expression in 37 patients with hairy cell leukemia and 44 patients with neoplasms mimicking hairy cell leukemia (40 splenic marginal zone lymphoma, 2 hairy cell leukemia-variant and 2 splenic lymphoma/leukemia unclassifiable) using immunohistochemistry on routine biopsies and/or Western blotting on purified leukemic cells, and correlated the phospho ERK status with the BRAF-V600E mutation status. Besides confirming the constant presence of BRAF-V600E in all patients with hairy cell leukemia, we observed ubiquitous phospho-ERK expression in this malignancy. Conversely, all 44 cases with neoplasms mimicking hairy cell leukemia were devoid of BRAF-V600E and none expressed phospho-ERK. Furthermore, the two exceptionally rare cases of non-hairy cell leukemia unclassifiable chronic B-cell neoplasms previously reported to be BRAF-V600E(+) on allele-specific polymerase chain reaction lacked phospho-ERK expression as well, suggesting the presence of the mutation in only a small part of the leukemic clone in these cases. In conclusion, our findings support the use of phospho-ERK immunohistochemistry in the differential diagnosis between hairy cell leukemia and its mimics, and establish the MEK-ERK pathway as a rational therapeutic target in this malignancy. PMID- 23349308 TI - ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders. AB - The liver, pancreas, and heart are particularly susceptible to iron-related disorders. These tissues take up plasma iron from transferrin or non-transferrin bound iron, which appears during iron overload. Here, we assessed the effect of iron status on the levels of the transmembrane transporters, ZRT/IRT-like protein 14 and divalent metal-ion transporter-1, which have both been implicated in transferrin- and non-transferrin-bound iron uptake. Weanling male rats (n=6/group) were fed an iron-deficient, iron-adequate, or iron-overloaded diet for 3 weeks. ZRT/IRT-like protein 14, divalent metal-ion transporter-1 protein and mRNA levels in liver, pancreas, and heart were determined by using immunoblotting and quantitative reverse transcriptase polymerase chain reaction analysis. Confocal immunofluorescence microscopy was used to localize ZRT/IRT like protein 14 in the liver and pancreas. ZRT/IRT-like protein 14 and divalent metal-ion transporter-1 protein levels were also determined in hypotransferrinemic mice with genetic iron overload. Hepatic ZRT/IRT-like protein 14 levels were found to be 100% higher in iron-loaded rats than in iron-adequate controls. By contrast, hepatic divalent metal-ion transporter-1 protein levels were 70% lower in iron-overloaded animals and nearly 3-fold higher in iron deficient ones. In the pancreas, ZRT/IRT-like protein 14 levels were 50% higher in iron-overloaded rats, and in the heart, divalent metal-ion transporter-1 protein levels were 4-fold higher in iron-deficient animals. At the mRNA level, ZRT/IRT-like protein 14 expression did not vary with iron status, whereas divalent metal-ion transporter-1 expression was found to be elevated in iron deficient livers. Immunofluorescence staining localized ZRT/IRT-like protein 14 to the basolateral membrane of hepatocytes and to acinar cells of the pancreas. Hepatic ZRT/IRT-like protein 14, but not divalent metal-ion transporter-1, protein levels were elevated in iron-loaded hypotransferrinemic mice. In conclusion, ZRT/IRT-like protein 14 protein levels are up-regulated in iron loaded rat liver and pancreas and in hypotransferrinemic mouse liver. Divalent metal-ion transporter-1 protein levels are down-regulated in iron-loaded rat liver, and up-regulated in iron-deficient liver and heart. Our results provide insight into the potential contributions of these transporters to tissue iron uptake during iron deficiency and overload. PMID- 23349309 TI - The clinical characteristics, therapy and outcome of 85 adults with acute lymphoblastic leukemia and t(4;11)(q21;q23)/MLL-AFF1 prospectively treated in the UKALLXII/ECOG2993 trial. AB - The biology and outcome of adult t(4;11)(q21;q23)/MLL-AFF1 acute lymphoblastic leukemia are poorly understood. We describe the outcome and delineate prognostic factors and optimal post-remission therapy in 85 consecutive patients (median age 38 years) treated uniformly in the prospective trial UKALLXII/ECOG2993. The immunophenotype of this leukemia was pro-B (CD10(NEG)). Immaturity was further suggested by high expression of the stem-cell antigens, CD133 and CD135, although CD34 expression was significantly lower than in t(4;11)-negative patients. Complete remission was achieved in 77 (93%) patients but only 35% survived 5 years (95% CI: 25-45%); the relapse rate was 45% (95% CI: 33-58%). Thirty-one patients underwent allogeneic transplantation in first remission (15 sibling donors and 16 unrelated donors): with 5-year survival rates of 56% and 67% respectively, only 2/31 patients relapsed. This compares with a 24% survival rate and 59% relapse rate in 46 patients who received post-remission chemotherapy. A major determinant of outcome was age with 71% of patients aged <25 years surviving. Younger patients had lower relapse rates (19%) but most received allografts in first complete remission. In conclusion, multivariate analysis did not demonstrate an advantage of allografting over chemotherapy but only five younger patients received chemotherapy. Prospective trials are required to determine whether poor outcomes in older patients can be improved by reduced intensity conditioning allografts. NCT00002514 www.clinicaltrials.gov. PMID- 23349310 TI - Multipotent stromal cells skew monocytes towards an anti-inflammatory interleukin 10-producing phenotype by production of interleukin-6. AB - Multipotent stromal cells have immunomodulatory capacities and have been used in transplantation and autoimmune diseases. One of the effects of multipotent stromal cells involves the inhibition of dendritic cell differentiation. Since interleukin-6 and interleukin-10 are known to play a role in inhibiting immature dendritic cell differentiation, we hypothesized that these cytokines may also mediate the inhibitory effect of human multipotent stromal cells in immature dendritic cell differentiation. In order to test this hypothesis monocytes were cultured with interleukin-4 and granulocyte-monocyte colony-stimulating factor in the presence or absence of culture-expanded bone marrow-derived multipotent stromal cells. Neutralization and cytokine-depletion strategies were applied to reveal the cellular source and effect of interleukin-6 and interleukin-10. Addition of multipotent stromal cells to monocyte cultures significantly reduced the generation of immature dendritic cells (CD14(-)CD1a(+)) and resulted in the generation of CD14(+)CD1a(-) cells that displayed a significantly reduced immunostimulatory effect. We found that culture supernatants of co-cultures of multipotent stromal cells and monocytes contained higher concentrations of interleukin-6 and interleukin-10. Multipotent stromal cells produced interleukin 6 and neutralizing this interleukin-6 reversed the inhibitory effect of the multipotent cells. Interleukin-10 was not produced by multipotent stromal cells, but exclusively by monocytes after exposure to multipotent stromal cell-produced interleukin-6. In conclusion, through constitutive production of interleukin-6, multipotent stromal cells prevent the differentiation of monocytes towards antigen-presenting immunogenic cells and skew differentiation towards an anti inflammatory interleukin-10-producing cell type. PMID- 23349311 TI - Messengers without borders: mediators of systemic inflammatory response in AKI. AB - The list of signals sent by an injured organ to systemic circulation, so-called danger signals, is growing to include multiple metabolites and secreted moieties, thus revealing a highly complex and integrated network of interlinked systemic proinflammatory and proregenerative messages. Emerging new data indicate that, apart from the well established local inflammatory response to AKI, danger signaling unleashes a cascade of precisely timed, interdependent, and intensity gradated mediators responsible for development of the systemic inflammatory response. This fledgling realization of the importance of the systemic inflammatory response to the localized injury and inflammation is at the core of this brief overview. It has a potential to explain the additive effects of concomitant diseases or preexisting chronic conditions that can prime the systemic inflammatory response and exacerbate it out of proportion to the actual degree of acute kidney damage. Although therapies for ameliorating AKI per se remain limited, a potentially powerful strategy that could reap significant benefits in the future is to modulate the intensity of danger signals and consequently the systemic inflammatory response, while preserving its intrinsic proregenerative stimuli. PMID- 23349312 TI - Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. AB - Few prospective, randomized controlled clinical trials address the diagnosis and management of patients with Alport syndrome or thin basement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18 recommendations are based on Level D (Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles-National Health Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees-U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstration of its mode of inheritance; the need to identify and follow all affected members of a family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and consideration of genetic testing to exclude X-linked Alport syndrome in some individuals with thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further. PMID- 23349313 TI - Compression garments: no enhancement of high-intensity exercise in hot radiant conditions. AB - PURPOSE: To establish the thermal and performance effects of wearing a lower-body graduated compression garment (GCG) in a hot environment (35.2 degrees C +/- 0.1 degrees C) with a representative radiant heat load (~800 W/m2) in contrast to a control (running shorts) and sham condition (a compression garment 1 size larger than that recommended by the manufacturer), with the latter included to establish any placebo effect. METHOD: Eight participants (mean +/- SD; age 21 +/- 2 y, height 1.77 +/- 0.06 m, mass 72.8 +/- 7.1 kg, surface area, 1.89 +/- 0.10 m2) completed 3 treadmill tests at a fixed speed for 15 min followed by a self-paced 5-km time trial. Performance (completion time) and pacing (split time), thermal responses (aural, skin, and mean body temperature, cardiac frequency), and perceptual responses (rating of perceived exertion [RPE], thermal sensation, thermal comfort) were measured. RESULTS: Performance in the compression group was not different than in either sham or control at any stage (P > .05); completion time 26.08 +/- 4.08, 26.05 +/- 3.27, and 25.18 +/- 3.15 min, respectively. At the end of the 5-km time trial, RPE was not different; it was 19 +/- 1 across conditions. In general, thermal and perceptual responses were not different, although the radiant heat load increased site-specific skin temperature (quadriceps) in the garment conditions. CONCLUSION: GCG did not enhance performance in a hot environment with a representative radiant heat load. The sham treatment did not benefit perception. GCG provided no evidence of performance enhancement. PMID- 23349314 TI - Molecular photoacoustic imaging of follicular thyroid carcinoma. AB - PURPOSE: To evaluate the potential of targeted photoacoustic imaging as a noninvasive method for detection of follicular thyroid carcinoma. EXPERIMENTAL DESIGN: We determined the presence and activity of two members of matrix metalloproteinase family (MMP), MMP-2 and MMP-9, suggested as biomarkers for malignant thyroid lesions, in FTC133 thyroid tumors subcutaneously implanted in nude mice. The imaging agent used to visualize tumors was MMP-activatable photoacoustic probe, Alexa750-CXeeeeXPLGLAGrrrrrXK-BHQ3. Cleavage of the MMP activatable agent was imaged after intratumoral and intravenous injections in living mice optically, observing the increase in Alexa750 fluorescence, and photoacoustically, using a dual-wavelength imaging method. RESULTS: Active forms of both MMP-2 and MMP-9 enzymes were found in FTC133 tumor homogenates, with MMP 9 detected in greater amounts. The molecular imaging agent was determined to be activated by both enzymes in vitro, with MMP-9 being more efficient in this regard. Both optical and photoacoustic imaging showed significantly higher signal in tumors of mice injected with the active agent than in tumors injected with the control, nonactivatable, agent. CONCLUSIONS: With the combination of high spatial resolution and signal specificity, targeted photoacoustic imaging holds great promise as a noninvasive method for early diagnosis of follicular thyroid carcinomas. PMID- 23349315 TI - Inactivation or loss of TTP promotes invasion in head and neck cancer via transcript stabilization and secretion of MMP9, MMP2, and IL-6. AB - PURPOSE: Invasion is the critical step in progression of a precancerous lesion to squamous cell carcinoma of the head and neck (HNSCC). Invasion is regulated by multiple proinflammatory mediators. Tristetraprolin (TTP) is an mRNA-degrading protein that regulates multiple proinflammatory mediators. TTP may serve as an excellent treatment target. Rap1 is a ras-like oncoprotein that induces critical signaling pathways. In this study, the role of rap1 in TTP-mediated invasion was investigated. EXPERIMENTAL DESIGN: Using complementary approaches, we modulated TTP and altered expression of interleukin (IL)-6 and matrix metalloproteinase (MMP) 2/9, which were quantified by ELISA and zymogram. Invasion was evaluated in vitro using the oral-cancer-equivalent (OCE) three-dimensional model and in vivo in the chick chorioallantoic membrane (CAM). The role of rap1 and p38 were established using knockdown strategies. RESULTS: Downregulation of TTP significantly increased invasion via secretion of MMP9/2 and IL-6. In the novel OCE and CAM invasion models of HNSCC, cells with downregulated TTP destroyed the basement membrane to invade the underlying connective tissue. Rap1 induces p38 mitogen-activated protein kinase (p38)-mediated inactivation of TTP. Inactive TTP enhances transcript stability via binding to the 3'-untranslated region (UTR). High IL-6 and MMP9 are prognostic for poor clinical outcomes in patients with HNSCC. CONCLUSIONS: Targeting the rap1-p38-TTP cascade is an attractive novel treatment strategy in HNSCC to concurrently suppress multiple mediators of invasion. PMID- 23349316 TI - Castration therapy results in decreased Ku70 levels in prostate cancer. AB - PURPOSE: Neoadjuvant castration improves response to radiotherapy of prostate cancer. Here, we determine whether castration therapy impairs nonhomologous end joining (NHEJ) repair of DNA double-strand breaks (DSB) by downregulating Ku70 protein expression. EXPERIMENTAL DESIGN: Twenty patients with locally advanced prostate cancer were enrolled, and 6 to 12 needle core biopsy specimens were taken from the prostate of each patient before treatment. Bilateral orchidectomy was conducted in eight patients and 12 patients were treated with a GnRH agonist. After castration, two to four similar biopsies were obtained, and the levels of Ku70 and gamma-H2AX foci were determined by immunofluorescence in verified cancer tissues. RESULTS: We observed that the androgen receptor binds directly to Ku70 in prostate tissue. We also found a reduction of the Ku70 protein levels in the cell nuclei in 12 of 14 patients (P < 0.001) after castration. The reduction in Ku70 expression correlated significantly with decreased serum prostate-specific antigen (PSA) levels after castration, suggesting that androgen receptor activity regulates Ku70 protein levels in prostate cancer tissue. Furthermore, a significant correlation between the reductions of Ku70 after castration versus changes induced of castration of gamma-H2AX foci could be seen implicating a functional linkage of decreased Ku70 levels and impaired DNA repair. CONCLUSIONS: Castration therapy results in decreased levels of the Ku70 protein in prostate cancer cells. Because the Ku70 protein is essential for the NHEJ repair of DSBs and its downregulation impairs DNA repair, this offers a possible explanation for the increased radiosensitivity of prostate cancer cells following castration. PMID- 23349317 TI - Phase I study of GRN1005 in recurrent malignant glioma. AB - PURPOSE: GRN1005 is a peptide-drug conjugate with the ability to penetrate the blood-brain barrier (BBB) and tumor cells by targeting the low-density lipoprotein receptor-related protein-1. We conducted a first-in-human phase I trial of GRN1005 in patients with recurrent glioma. METHODS: Patients received GRN1005 by intravenous infusion every 3 weeks. Doses were escalated using a modified Fibonacci scheme. Study objectives included safety, tolerability, identification of the maximum tolerated dose (MTD), pharmacokinetics, and preliminary evidence of efficacy. Tumor extracted from patients undergoing surgery following administration of GRN1005 was analyzed to determine whether therapeutic concentrations of GRN1005 were achieved. RESULTS: Sixty-three patients received GRN1005 at doses of 30 to 700 mg/m(2) every 3 weeks. Therapy was well tolerated with neutropenia, leucopenia, and fatigue as the most frequent drug-associated grade 3/4 or higher toxicities. The MTD was 650 mg/m(2) every 3 weeks. Dose-limiting toxicities were grade 3 mucositis and grade 4 neutropenia. There was no evidence of central nervous system toxicity or antibody production. Pharmacokinetic analysis showed that exposure to GRN1005 was dose proportional. We observed one complete and two partial responses. Eight of 27 patients dosed >= 420 mg/m(2) had stable disease, which lasted a median of 51 days. Therapeutic concentrations of GRN1005 and free paclitaxel were shown in tumor tissue of surgical patients dosed with >= 200 mg/m(2). CONCLUSION: GRN1005 delivers paclitaxel across the BBB and achieves therapeutic concentrations in tumor tissue. It has similar toxicity to paclitaxel and appears to have activity in recurrent glioma. The recommended phase II dose is 650 mg/m(2) every 3 weeks. PMID- 23349318 TI - Safety performance evaluation of taekwondo headgear. AB - BACKGROUND: With over 20 years of taekwondo concussion research highlighting the high incidence of injury, previous studies recommend an investigation of headgear impact attenuation performance. OBJECTIVE: To examine impact attenuation differences between the anterior, posterior and sides of selected taekwondo headgear brands. DESIGN: Between-groups. SETTING: Biomechanics laboratory. METHODS: Five different commercially available taekwondo headgear were selected for impact testing. A 50th percentile Hybrid II Dummy Crash Test head and neck was fitted with the selected helmet and was bolted to a 25 kg steel torso-like structure. Each headgear model was impacted eight times to the anterior, posterior and sides by a 6.75 kg bowling ball at three heights to produce 52.25, 85 and 144 J strikes. MAIN OUTCOME MEASUREMENTS: Resultant head linear acceleration. RESULTS: Two-way (Helmet*Location) mixed analysis of variance with repeated measures on the second factor was performed to determine the differences between headgear by location of impact. There was a two-way (Helmet*Location) interaction for acceleration (eta(2)=0.368). CONCLUSIONS: Taekwondo headgear manufacturers and sport governing bodies must consider improving the design of especially anterior helmet properties. PMID- 23349319 TI - From consensus to action: knowledge transfer, education and influencing policy on sports concussion. AB - OBJECTIVE: To: (1) provide a review of knowledge transfer (KT) and related concepts; (2) look at the impact of traditional and emerging KT strategies on concussion knowledge and education; (3) discuss the value and impact of KT to organisations and concussion-related decision making and (4) make recommendations for the future of concussion education. DESIGN: Qualitative literature review of KT and concussion education literature. INTERVENTION: PubMed, Medline and Sport Discus databases were reviewed and an internet search was conducted. The literature search was restricted to articles published in the English language, but not restricted to any particular years. Altogether, 67 journal articles, 21 websites, 1 book and 1 report were reviewed. RESULTS: The value of KT as part of concussion education is increasingly becoming recognised. Target audiences benefit from specific learning strategies. Concussion tools exist, but their effectiveness and impact require further evaluation. The media is valuable in drawing attention to concussion, but efforts need to ensure that the public is aware of the right information. Social media as a concussion education tool is becoming more prominent. Implementation of KT models is one approach which organisations can use to assess knowledge gaps; identify, develop and evaluate education strategies and use the outcomes to facilitate decision-making. CONCLUSIONS: Implementing KT strategies requires a defined plan. Identifying the needs, learning styles and preferred learning strategies of target audiences, coupled with evaluation, should be a piece of the overall concussion education puzzle to have an impact on enhancing knowledge and awareness. PMID- 23349321 TI - Evaluating the health impacts of participation in Australian community arts groups. AB - This study evaluates the impacts of three well-established community arts programmes in Victoria, Australia, on the mental health and well-being outcomes of participants typically from disadvantaged backgrounds during 2006-07. It employs a theoretical framework that reconciles evidence-based practice in health and the phenomenological nature of community arts practice. Self-determination theory (SDT) was used to do this with SDT-derived psychometric instruments [arts climate and Basic Psychological Needs Scales (BPNS)]. Self-administered surveys using these instruments as well as a measure of social support were undertaken on two occasions. Two overlapping but distinct samples were defined and analysed cross-sectionally. These were a (pre-)survey at the commencement of rehearsals for the annual performance (n = 103) and a (post-)survey following the performance (n = 70). The most significant change (MSC) technique was used to study the arts-making process and how it contributes to outcomes. Using these mixed-methods approach, impacts on the climate of the arts organizations, participant access to supportive relationships and participant's mental health and well-being were studied. There were positive changes in the BPNS (p = 0.00), as well as its autonomy (p = 0.04) and relatedness (p = 0.00) subscales. Social support increased from 65.3% in the pre-survey to 82.4% in the post-survey (p = 0.03). MSC data indicated that the supportive, collaborative environment provided by the arts organizations was highly valued by participants and was perceived to have mental health benefits.Overall, the study demonstrated the potential health promoting effects of community arts programmes in disadvantaged populations. Its multi-method approach should be further studied in evaluating other community arts programmes. PMID- 23349320 TI - Clinical, genetic, neurophysiological and functional study of new mutations in episodic ataxia type 1. AB - BACKGROUND AND OBJECTIVE: Heterozygous mutations in KCNA1 cause episodic ataxia type 1 (EA1), an ion channel disorder characterised by brief paroxysms of cerebellar dysfunction and persistent neuromyotonia. This paper describes four previously unreported families with EA1, with the aim of understanding the phenotypic spectrum associated with different mutations. METHODS: 15 affected individuals from four families underwent clinical, genetic and neurophysiological evaluation. The functional impact of new mutations identified in the KCNA1 gene was investigated with in vitro electrophysiology and immunocytochemistry. RESULTS: Detailed clinical documentation, dating back to 1928 in one family, indicates that all patients manifested episodic ataxia of varying severity. Four subjects from three families reported hearing impairment, which has not previously been reported in association with EA1. New mutations (R167M, C185W and I407M) were identified in three out of the four families. When expressed in human embryonic kidney cells, all three new mutations resulted in a loss of K(v)1.1 channel function. The fourth family harboured a previously reported A242P mutation, which has not been previously described in association with ataxia. CONCLUSIONS: The genetic basis of EA1 in four families is established and this report presents the earliest documented case from 1928. All three new mutations caused a loss of K(v)1.1 channel function. The finding of deafness in four individuals raises the possibility of a link between K(v)1.1 dysfunction and hearing impairment. Our findings broaden the phenotypic range associated with mutations in KCNA1. PMID- 23349322 TI - Nature and impact of European anti-stigma depression programmes. AB - Stigma associated with depression is a major public health issue in the EU, with over 20 million people experiencing depression and its associated personal distress each year. While most programmes against stigma related to mental health problems are of a general nature, the knowledge about programmes tackling stigma against people with depression is limited. This study therefore aims to assess the nature and impact of depression-specific programmes in EU countries. Using a web-based tool, 26 programmes were identified across the 18 EU countries taking part in the study. Most were universal and targeted the whole population, while many also targeted specific population groups or settings, such as young people or health professionals. The most common programme aim was improving literacy, although reducing stigmatizing attitudes and discriminatory behaviour and promoting help-seeking were also common. Most programmes originated from professional bodies, or as grassroots initiatives from service user groups/NGOs, rather than as part of national and local policy. The approaches used were primarily different forms of education/information, with some, but very limited, use of positive personal contact. Overall, the quality and extent of impact of the programmes was limited, with few leading to peer-reviewed publications. Specific programmes were identified with evidence of positive impact, and we drew on these examples to develop a framework to be used for future programmes against stigma and discrimination associated with depression. These findings are provided in full in the Anti-Stigma Partnership European Network Toolkit available at www.antistigma.eu. PMID- 23349323 TI - Changes in pulmonary function tests predict radiological response to chemotherapy in malignant pleural mesothelioma. AB - OBJECTIVES: Response to chemotherapy in malignant pleural mesothelioma (MPM) is usually evaluated by radiological criteria, but no common agreement exists on their validity, yet. The cytoreductive effect of chemotherapy on pleural thickening may make the lung more expansible, reducing the restrictive ventilatory impairment. The aim of this study was to evaluate the changes in pulmonary function following chemotherapy in patients with MPM and to correlate these findings with radiological changes. METHODS: Between 2004 and 2011, 62 consecutive patients (74% males, median age 63 years) were prospectively investigated. Modified RECIST criteria were used for radiological evaluation of response to chemotherapy. All patients underwent pulmonary function tests before and after three cycles of platinum-based chemotherapy. Changes between baseline and post-chemotherapy pulmonary function values (Delta) and their differences were assessed by means of Student's paired and unpaired t-test, respectively. Receiver operating characteristic (ROC) curve analysis was performed on spirometric parameters significantly associated with response. RESULTS: Thirty (48.4%) patients had a radiological stable disease (S), 23 (37.1%) a partial response (R) and 9 (14.5%) a progressive disease (P). DeltaFEV1%pred (R: 18.1 +/- 18.5%; S: 0.5 +/- 9.3%; P: -11 +/- 13.5%; P < 0.0001), DeltaFVC%pred (R: 16.1 +/- 11.8%; S: 0.4 +/- 11.2%; P: -9.2 +/- 14.6%; P < 0.0001) and DeltaVC%pred (R: 12.9 +/- 15.7%; S: 1.5 +/- 12.1%; P: -6.1 +/- 13.2%; P = 0.001) were significantly associated with radiological response. A significant correlation was observed between DeltaFEV1%pred (r = 0.46, P = 0.01), DeltaFVC%pred (r = 0.43, P = 0.02) and % change in linear tumour measurement. ROC curve analysis using dichotomized radiological response (P/S vs R) as classification variables showed AUC = 0.88 (95%CI: 0.77-0.95) for DeltaFEV1%pred (optimal cut-off value: +7%, sensitivity: 83%, specificity: 82%, PPV: 73%, NPV: 89%) and AUC = 0.86 (95%CI: 0.75-0.94) for DeltaFVC%pred (optimal cut-off value: +6%, sensitivity: 82%, specificity: 74%, PPV: 64%, NPV: 88%). CONCLUSIONS: Dynamic lung volumes and radiological changes after chemotherapy seem directly related. Lung function changes could be an additional tool to better evaluate the response to chemotherapy in MPM. PMID- 23349324 TI - Debranching of the arch in aortic aneurysms. PMID- 23349325 TI - Reply to Ugur et al. PMID- 23349326 TI - Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. AB - Despite excellent short-term results, long-term survival of transplanted kidneys has not improved accordingly. Although alloimmune responses and calcineurin inhibitor-related nephrotoxicity have been identified as main drivers of fibrosis, no effective treatment options have emerged. In this perspective, mesenchymal stromal cells (MSCs) are an interesting candidate because of their immunosuppressive and regenerative properties. Of importance, no other clinical studies have investigated their effects in allograft rejection and fibrosis. We performed a safety and feasibility study in kidney allograft recipients to whom two intravenous infusions (1 million cells per kilogram) of autologous bone marrow (BM) MSCs were given, when a protocol renal biopsy at 4 weeks or 6 months showed signs of rejection and/or an increase in interstitial fibrosis/tubular atrophy (IF/TA). Six patients received MSC infusions. Clinical and immune monitoring was performed up to 24 weeks after MSC infusions. MSCs fulfilled the release criteria, infusions were well-tolerated, and no treatment-related serious adverse events were reported. In two recipients with allograft rejection, we had a clinical indication to perform surveillance biopsies and are able to report on the potential effects of MSCs in rejection. Although maintenance immunosuppression remained unaltered, there was a resolution of tubulitis without IF/TA in both patients. Additionally, three patients developed an opportunistic viral infection, and five of the six patients displayed a donor-specific downregulation of the peripheral blood mononuclear cell proliferation assay, not reported in patients without MSC treatment. Autologous BM MSC treatment in transplant recipients with subclinical rejection and IF/TA is clinically feasible and safe, and the findings are suggestive of systemic immunosuppression. PMID- 23349327 TI - Concise review: immunologic lessons from solid organ transplantation for stem cell-based therapies. AB - Clinical organ transplantation became possible only after powerful immunosuppressive drugs became available to suppress the alloimmune response. After decades of solid organ transplantation, organ rejection is still a major challenge. However, significant insight into allorecognition has emerged from this vast experience and should be used to inform future stem cell-based therapies. For this reason, we review the current understanding of selected topics in transplant immunology that have not been prominent in the stem cell literature, including immune responses to ischemia/reperfusion injuries, natural killer cells, the adaptive immune response, some unresolved issues in T-cell allorecognition, costimulatory molecules, and the anticipated role of regulatory T cells in graft tolerance. PMID- 23349329 TI - Inhibition of 72 kDa inositol polyphosphate 5-phosphatase E improves insulin signal transduction in diet-induced obesity. AB - The 72 kDa inositol polyphosphate 5-phosphatase E (72k-5ptase) controls signal transduction through the catalytic dephosphorylation of the 5-position of membrane-bound phosphoinositides. The reduction of 72k-5ptase expression in the hypothalamus results in improved hypothalamic insulin signal transduction and reduction of food intake and body mass. Here, we evaluated the tissue distribution and the impact of obesity on the expression of 72k-5ptase in peripheral tissues of experimental animals. In addition, insulin signal transduction and action were determined in an animal model of obesity and insulin resistance treated with an antisense (AS) oligonucleotide that reduces 72k-5ptase expression. In lean Wistar rats, 72k-5ptase mRNA and protein are found in highest levels in heart, skeletal muscle, and white adipose tissue. In three distinct models of obesity, Wistar rats, Swiss mice fed on high-fat diet, and leptin deficient ob/ob mice, the expression of 72k-5ptase is increased in skeletal muscle and adipose tissue. The treatment of obese Wistar rats with an anti-72k 5ptase AS oligonucleotide results in significant reduction of 72k-5ptase catalytic activity, which is accompanied by reduced food intake and body mass and improved insulin signal transduction and action as determined by immunoblotting and clamp studies respectively. 72k-5ptase expression is increased in obesity and its AS inhibition resulted in a significant improvement in insulin signal transduction and restoration of glucose homeostasis. PMID- 23349328 TI - Concise review: preleukemic stem cells: molecular biology and clinical implications of the precursors to leukemia stem cells. AB - Recent experimental evidence has shown that acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) arise from transformed immature hematopoietic cells following the accumulation of multiple stepwise genetic and epigenetic changes in hematopoietic stem cells and committed progenitors. The series of transforming events initially gives rise to preleukemic stem cells (pre-LSC), preceding the formation of fully transformed leukemia stem cells (LSC). Despite the established use of poly-chemotherapy, relapse continues to be the most common cause of death in AML and MDS. The therapeutic elimination of all LSC, as well as pre-LSC, which provide a silent reservoir for the re-formation of LSC, will be essential for achieving lasting cures. Conventional sequencing and next generation genome sequencing have allowed us to describe many of the recurrent mutations in the bulk cell populations in AML and MDS, and recent work has also focused on identifying the initial molecular changes contributing to leukemogenesis. Here we review recent and ongoing advances in understanding the roles of pre-LSC, and the aberrations that lead to pre-LSC formation and subsequent LSC transformation. PMID- 23349330 TI - Endocrine tumours: epidemiology of malignant digestive neuroendocrine tumours. AB - Little is known about patients with malignant digestive neuroendocrine tumours (MD-NETs). Although their incidence is increasing, MD-NETs remain a rare cancer, representing 1% of digestive cancers. Most MD-NETs are well-differentiated. MD NET poorly differentiated carcinomas account for 20% of cases on average. Anatomical localisation of MD-NETs varied according to geographic region. Stage at diagnosis and prognosis for patients with MD-NETs in the general population are considerably worse than often reported from small hospital case series. Prognosis varies with tumour differentiation, anatomic site and histological subtype. There are significant differences in survival from MD-NETs among European countries, independent of other prognostic factors. Early diagnosis is difficult; new therapeutic options appear to represent the best approach to improving prognosis. PMID- 23349331 TI - The outcomes of patients with ESRD and ANCA-associated vasculitis in Australia and New Zealand. AB - BACKGROUND AND OBJECTIVES: This study aimed to evaluate dialysis and transplant outcomes of patients with ESRD secondary to ANCA-associated vasculitis (AAV). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All ESRD patients who commenced renal replacement therapy in Australia and New Zealand between 1996 and 2010 were included. Outcomes were assessed by Kaplan-Meier, multivariable Cox regression, and competing-risks regression survival analyses. RESULTS: Of 36,884 ESRD patients, 228 had microscopic polyangiitis (MPA) and 221 had granulomatosis with polyangiitis (GPA). Using competing-risks regression, compared with other causes of ESRD, MPA patients (hazard ratio [HR], 0.89; 95% confidence interval [95% CI], 0.73-1.08; P=0.24) and GPA patients (HR, 0.94; 95% CI, 0.74-1.19; P=0.62) experienced comparable survival on dialysis. Forty-six MPA patients (21%) and 47 GPA (20%) patients received 98 renal allografts. Respective 10-year first graft survival rates in MPA, GPA, and non-AAV patients were 50%, 62%, 70%, whereas patient survival rates were 68%, 85% and 83%, respectively. Compared with non-AAV patients, MPA transplant recipients had higher risks of graft failure (HR, 1.87; 95% CI, 1.07-3.25; P=0.03) and death (HR, 1.94; 95% CI, 1.02-3.69; P=0.04), whereas GPA transplant recipients experienced comparable renal allograft survival (HR, 0.91; 95% CI, 0.43-1.93; P=0.81) and patient survival (HR, 0.58; 95% CI, 0.23-2.27; P=0.58). AAV recurrence was observed in two renal allografts (2%). CONCLUSIONS: Compared with ESRD patients without AAV, those with GPA have comparable renal replacement therapy outcomes, whereas MPA patients have comparable dialysis survival but poorer renal transplant allograft and patient survival rates. PMID- 23349332 TI - Initiation of dialysis at higher levels of estimated GFR and subsequent withdrawal. PMID- 23349333 TI - Breastfeeding and tacrolimus: serial monitoring in breast-fed and bottle-fed infants. AB - BACKGROUND AND OBJECTIVES: Women have traditionally been advised not to breastfeed while taking tacrolimus, based on theoretical risks of neonatal immunosuppression and assumed secretion into breast milk, rather than clinical data suggesting neonatal absorption. The aim of this study was to assess tacrolimus levels in breast milk and neonatal exposure during breastfeeding. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: An observational cohort study was performed in two tertiary referral high-risk obstetric medicine clinics. Fourteen women taking tacrolimus during pregnancy and lactation, and their 15 infants, 11 of whom were exclusively breast-fed, were assessed. Tacrolimus levels were analyzed by liquid chromatography-tandem mass spectrometry. Samples from mothers and cord blood were collected at delivery and from mothers, infants, and breast milk postnatally where possible. RESULTS: All infants with serial sampling had a decline in tacrolimus level, which was approximately 15% per day (ratio of geometric mean concentrations 0.85; 95% confidence interval, 0.82-0.88; P<0.001). Breast-fed infants did not have higher tacrolimus levels compared with bottle-fed infants (median 1.3 MUg/L [range, 0.0-4.0] versus 1.0 MUg/L [range, 0.0-2.3], respectively; P=0.91). Maximum estimated absorption from breast milk is 0.23% of maternal dose (weight-adjusted). CONCLUSIONS: Ingestion of tacrolimus by infants via breast milk is negligible. Breastfeeding does not appear to slow the decline of infant tacrolimus levels from higher levels present at birth. Women taking tacrolimus should not be discouraged from breastfeeding if monitoring of infant levels is available. PMID- 23349334 TI - Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome. AB - BACKGROUND AND OBJECTIVES: Up to 95% of children presenting with steroid resistant nephrotic syndrome in early life will have a pathogenic single-gene mutation in 1 of 24 genes currently associated with this disease. Others may be affected by polymorphic variants. There is currently no accepted diagnostic algorithm for clinical genetic testing. The hypothesis was that the increasing reliability of next generation sequencing allows comprehensive one-step genetic investigation of this group and similar patient groups. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study used next generation sequencing to screen 446 genes, including the 24 genes known to be associated with hereditary steroid-resistant nephrotic syndrome. The first 36 pediatric patients collected through a national United Kingdom Renal Registry were chosen with comprehensive phenotypic detail. Significant variants detected by next generation sequencing were confirmed by conventional Sanger sequencing. RESULTS: Analysis revealed known and novel disease-associated variations in expected genes such as NPHS1, NPHS2, and PLCe1 in 19% of patients. Phenotypically unexpected mutations were also detected in COQ2 and COL4A4 in two patients with isolated nephropathy and associated sensorineural deafness, respectively. The presence of an additional heterozygous polymorphism in WT1 in a patient with NPHS1 mutation was associated with earlier-onset disease, supporting modification of phenotype through genetic epistasis. CONCLUSIONS: This study shows that next generation sequencing analysis of pediatric steroid-resistant nephrotic syndrome patients is accurate and revealing. This analysis should be considered part of the routine genetic workup of diseases such as childhood steroid-resistant nephrotic syndrome, where the chance of genetic mutation is high but requires sequencing of multiple genes. PMID- 23349336 TI - Inconsistent condom use among women veterans and active duty servicewomen. PMID- 23349335 TI - Positional isomers of aspirin are equally potent in inhibiting colon cancer cell growth: differences in mode of cyclooxygenase inhibition. AB - We compared the differential effects of positional isomers of acetylsalicylic acid (o-ASA, m-ASA, and p-ASA) on cyclooxygenase (COX) inhibition, gastric prostaglandin E2 (PGE2), malondialdehyde, tumor necrosis factor-alpha (TNF-alpha) levels, superoxide dismutase (SOD) activity, human adenocarcinoma colon cancer cell growth inhibition, cell proliferation, apoptosis, and cell-cycle progression. We also evaluated the gastric toxicity exerted by ASA isomers. All ASA isomers inhibit COX enzymes, but only the o-ASA exerted an irreversible inhibitory profile. We did not observe a significant difference between ASA isomers in their ability to decrease the in vivo synthesis of PGE2 and SOD activity. Furthermore, all isomers increased the levels of gastric and TNF-alpha when administered orally at equimolar doses. We observed a dose-dependent cell growth inhibitory effect; the order of potency was p-ASA > m-ASA ~ o-ASA. There was a dose-dependent decrease in cell proliferation and an increase in apoptosis, with a concomitant Go/G1 arrest. The ulcerogenic profile of the three ASA isomers showed a significant difference between o-ASA (aspirin) and its two positional isomers when administered orally at equimolar doses (1 mmol/kg); the ulcer index (UI) for o-ASA indicated extensive mucosal injury (UI = 38), whereas m-ASA and p ASA produced a significantly decreased toxic response (UI = 12 and 8, respectively) under the same experimental conditions. These results suggest that the three positional isomers of ASA exert practically the same biologic profile in vitro and in vivo but showed different safety profiles. The mechanism of gastric ulcer formation exerted by aspirin and its two isomers warrants a more detailed and thorough investigation. PMID- 23349337 TI - Prevalence and morbidity of urethral Trichomonas vaginalis in Japanese men with or without urethritis. AB - OBJECTIVES: Trichomonas vaginalis is one of the pathogens causing sexually transmitted infections. This microorganism is a common pathogen among women, but its significance as a cause of morbidity among men remains uncertain. We sought to determine the prevalence and morbidity of T. vaginalis infection in Japanese men with and without urethritis. METHODS: We examined urine specimens from 215 men with urethritis and 98 men without urethritis for the presence of urethral T. vaginalis by PCR assay. RESULTS: Only four patients-one with gonococcal urethritis, one with non-gonococcal chlamydial urethritis, one with non gonococcal non-chlamydial urethritis and one without urethritis-were positive for T. vaginalis. The prevalence of T. vaginalis was 1.4% in men with urethritis and 1.0% in men without urethritis. A possible relation between the appearance of T. vaginalis and clinical symptoms was not confirmed. CONCLUSIONS: In the present study, the incidence of urethral T. vaginalis infection appears to be rare in Japanese men with or without urethritis, and T. vaginalis may be an uncommon pathogen in male urethritis in Japan. PMID- 23349338 TI - ru2hot?: A public health education campaign for men who have sex with men to increase awareness of symptoms of acute HIV infection. AB - OBJECTIVES: Teach HIV-negative men who have sex with men (MSM) symptoms of acute HIV infection (AHI) and direct them to nucleic acid amplification testing (NAAT) though Public Health--Seattle & King County (PHSKC). DESIGN: Cross-sectional surveys, retrospective database analysis and chart review. METHODS: Beginning in June 2009, the ru2hot? campaign described AHI symptoms and NAAT. Two preintervention and two postintervention surveys assessed campaign visibility, symptom knowledge, and healthcare-seeking behaviour. Regression analyses evaluated secular trends in case-finding. RESULTS: 366 MSM completed surveys. In survey 4, 23% of 100 men reported seeing the campaign, and 25% knew 'ru2hot?' referred to AHI. From survey 1 to survey 4, the proportion of subjects who knew >=2 symptoms or that AHI was a 'flu-like' illness was unchanged (61% vs 57%, p=0.6). However, in survey 4, 13 (72%) of 18 subjects who saw the campaign named fever as a symptom of AHI compared with 19 (35%) of 55 subjects who had not seen the campaign (p=0.005). From 9/2003 to 12/2010, 622 (2.2%) of 27 661 MSM tested HIV-positive, and 111 (18%) were identified by the Public Health--Seattle & King County NAAT programme. In terms of the impact of the campaign on case-finding, diagnosis of EIA-negative/NAAT-positive and OraQuick-negative/EIA-positive cases increased from six in 2004 to 20 in 2010 (p=0.01), but postcampaign numbers were unchanged. 23 (51%) of 45 cases identified before and 8 (44%) of 18 cases identified after the campaign reported symptoms at initial testing (p=0.6). CONCLUSIONS: Although a quarter of MSM surveyed saw the campaign and knowledge of fever (the symptom of emphasis) was high, case-finding was unchanged. Increasing campaign visibility could have had greater impact. PMID- 23349339 TI - Evaluation of dosimetric variance in whole breast forward-planned intensity modulated radiotherapy based on 4DCT and 3DCT. AB - This study was performed to explore and compare the dosimetric variance caused by respiratory movement in the breast during forward-planned IMRT after breast conserving surgery. A total of 17 enrolled patients underwent the 3DCT simulation scans followed by 4DCT simulation scans during free breathing. The treatment planning constructed using the 3DCT images was copied and applied to the end expiration (EE) and end inspiration (EI) scans and the dose distributions were calculated separately. CTV volume variance amplitude was very small (11.93 +/- 28.64 cm(3)), and the percentage change of CTV volumes receiving 50 Gy and 55 Gy between different scans were all less than 0.8%. There was no statistically significant difference between EI and EE scans (Z =-0.26, P = 0.795). However, significant differences were found when comparing the Dmean at 3DCT planning with the EI and EE planning (P = 0.010 and 0.019, respectively). The homogeneity index at EI, EE and 3D plannings were 0.139, 0.141 and 0.127, respectively, and significant differences existed between 3D and EI, and between 3D and EE (P = 0.001 and 0.006, respectively). The conformal index (CI) increased significantly in 3D treatment planning (0.74 +/- 0.07) compared with the EI and EE phase plannings (P = 0.005 and 0.005, respectively). The V30, V40, V50 and Dmean of the ipsilateral lung for EE phase planning were significantly lower than for EI (P = 0.001-0.042). There were no significant differences in all the DVH parameters for the heart among these plannings (P = 0.128-0.866). The breast deformation during respiration can be disregarded in whole breast IMRT. 3D treatment planning is sufficient for whole breast forward-planned IMRT on the basis of our DVH analysis, but 4D treatment planning, breath-hold, or respiratory gate may ensure precise delivery of radiation dose. PMID- 23349340 TI - Ectopic expression of miR-34a enhances radiosensitivity of non-small cell lung cancer cells, partly by suppressing the LyGDI signaling pathway. AB - miR-34a is transcriptionally induced by the tumor suppressor gene p53, which is often downregulated in non-small cell lung cancer (NSCLC). To address whether the downstream signal of miR-34a is sufficient to induce apoptosis and to alter cellular radiosensitivity, a chemical synthetic miR-34a mimic was delivered into A549 and H1299 cells, with or without co-treatment of gamma-irradiation. Results showed that ectopic expression of miR-34a induced dose-dependent cell growth inhibition and apoptosis in a p53-independent manner in both NSCLC cell lines. Interestingly, LyGDI was discovered as a new target gene of miR-34a, and downregulation of LyGDI promoted Rac1 activation and membrane translocation, resulting in cell apoptosis. Furthermore, restoration of miR-34a indirectly reduced cyclooxygenase-2 (COX-2) expression. Taken together, these results demonstrate that restoration of miR-34a expression enhances radiation-induced apoptosis, partly by suppressing the LyGDI signaling pathway, and miR-34a could possibly be used as a radiosensitizer for non-small cell lung cancer therapy. PMID- 23349342 TI - A successful switch from transdermal fentanyl to transdermal buprenorphine in a patient with neuropathic pain: a case report. AB - Buprenorphine is a frequently used opioid in the treatment of neuropathic pain component that is often present in patients with cancer. A case of a 41-year-old patient was depicted whose pain syndrome was associated with the chondrosarcoma growth originating from the sacral bone and numerous surgical interventions and radiotherapy. Improvement in analgesia and good toleration of therapy were observed after switching from transdermal fentanyl to transdermal buprenorphine while maintaining treatment with antidepressants and anticonvulsants. This case report indicates a possibility of a safe switch of transdermal opioids at home, which may provide benefits in terms of analgesia and adverse effects and in consequence have positive impact on the patients' quality of life. This is also accompanied by constant psychological, social, and spiritual support provided to the patient and family. PMID- 23349341 TI - Sodium orthovanadate (vanadate), a potent mitigator of radiation-induced damage to the hematopoietic system in mice. AB - Previous in vitro and in vivo studies have shown that sodium orthovanadate (vanadate), an inorganic vanadium compound, could effectively suppress radiation induced p53-mediated apoptosis via both transcription-dependent and transcription independent pathways. As a potent radiation protector administered at a dose of 20 mg/kg body weight (20 mg/kg) prior to total body irradiation (TBI) by intra peritoneal (ip) injection, it completely protected mice from hematopoietic syndrome and partially from gastrointestinal syndrome. In the present study, radiation mitigation effects from vanadate were investigated by ip injection of vanadate after TBI in mice. Results showed that a single administration of vanadate at a dose of 20 mg/kg markedly improved the 30-day survival rate and the peripheral blood hemogram, relieved bone marrow aplasia and decreased occurrence of the bone marrow micronucleated erythrocytes in the surviving animals. The dose reduction factor was 1.2 when a single dose of 20 mg/kg was administered 15 min after TBI in mice using the 30-day survival test as the endpoint. Results also showed that either doubling the vanadate dose (40 mg/kg) in a single administration or continuing the vanadate treatment (after a single administration at 20 mg/kg) from the following day at a dose of 5 mg/kg per day for 4 consecutive days further significantly improved the efficacy for rescuing bone marrow failure in the 30-day survival test. Taken together, these findings indicate that vanadate would be a potent mitigator suppressing the acute lethality (hematopoietic syndrome) and minimizing the detrimental effects (anhematopoiesis and delayed genotoxic effects) induced by TBI in mice. PMID- 23349343 TI - Attitude toward euthanasia scale: psychometric properties and relations with religious orientation, personality, and life satisfaction. AB - End-of-life decisions (ELDs) represent a controversial subject, with ethical dilemmas and empirical ambiguities that stand at the intersection of ethics and medicine. In a non-Western population, we examined individual differences in perceiving ELDs that end the life of a patient as acceptable and found that an attitude toward euthanasia (ATE) scale consists of 2 factors representing voluntary and nonvoluntary euthanasia. Also, acceptance of ELDs that end the life of a patient negatively correlated with life satisfaction, honesty-humility, conscientiousness, and intrinsic and extrinsic personal motivation toward religion. These findings provided additional construct validity of the ATE scale. PMID- 23349344 TI - Cardiac resynchronisation therapy for chronic heart failure: predicting and measuring 'response'. PMID- 23349345 TI - Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors. AB - OBJECTIVE: Although adjuvant trastuzumab improves survival in patients with HER2 positive early breast cancer, there is growing concern about the long-term effect of trastuzumab-induced cardiotoxicity (TIC). We retrospectively assessed the incidence of TIC and heart failure (HF) to identify possible risk and protective factors. DESIGN: Retrospective study. SETTING: Institute for Cancer Research and Treatment, Medical Oncology Department. PATIENTS: Consecutive patients who started adjuvant trastuzumab between 2007 and 2010. MAIN OUTCOME: Measures TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease >= 15 points from baseline or a LVEF<50%. Logistic regression was used to estimate OR and their 95% CI in order to evaluate the risk of TIC, considering potential cardiac risk factors (hypertension, hypercholesterolaemia, diabetes mellitus, smoke, cardiac ischaemia and previous chest radiotherapy) and protective factors (beta-blockers, ACE inhibitors and/or angiotensin receptor blockers). RESULTS: Among 179 patients, 78 cases of TIC (44%, 95% CI 37% to 51%) and four cases of HF (2%, 95% CI 0% to 4%) were reported. 14 patients stopped trastuzumab as a result of TIC. None of the cardiac risk factors or concomitant cardiovascular medications altered the risk of TIC. A previous cumulative dose >240 mg/m(2) of doxorubicin or >500 mg/m(2) of epirubicin increased the risk of TIC compared with lower doses (OR 3.07; 95% CI 1.29 to 7.27, p=0.0011). CONCLUSIONS: TIC is a frequent, albeit generally mild, adverse event in clinical practice. Further studies are warranted to better define the risk of and protective factors for TIC. PMID- 23349346 TI - Prognostic value of B-type natriuretic peptide in elderly patients with aortic valve stenosis: the COFRASA-GENERAC study. AB - OBJECTIVE: Previous studies suggested an independent prognostic value of B-type natriuretic peptide (BNP) in aortic valve stenosis (AS) but were impeded by small sample sizes and inclusion of relatively selected young patients. We aimed to evaluate the relationship among N-terminal fragment of proBNP (Nt-proBNP), AS severity, symptoms and outcome in a large cohort of elderly patients with AS. DESIGN: Observational cohort study, COhorte Francaise de Retrecissement Aortique du Sujet Age (clinicalTrial.gov number-NCT00338676) and GENEtique du Retrecissement Aortique (clinicalTrial.gov number-NCT00647088). SETTING: Single centre study. PATIENTS: Patients older than 70 years with at least mild AS. INTERVENTIONS: None. MEASUREMENTS: A comprehensive clinical, biological and echocardiographic evaluation was performed at study entry. Asymptomatic patients were prospectively followed on a 6-months basis and AS-related events (sudden death, congestive heart failure or new onset of AS-related symptoms) collected. RESULTS: We prospectively enrolled 361 patients (79+/-6 years, 230 severe AS). Nt proBNP increased with the grade of AS severity and the NYHA class (all p<0.0001) but there was an important overlap between grades/classes. Consequently, diagnostic value of Nt-proBNP for the diagnosis of severe symptomatic AS was only modest (area under the curve of the receiver operator characteristic analysis=0.73). At 2 years, 28 AS-related events occurred among 142 asymptomatic patients prospectively followed. Nt-proBNP was associated with outcome in univariate analysis (p=0.04) but not after adjustment for age, gender and AS severity (p=0.40). CONCLUSIONS: The present study clearly highlights the limitations of Nt-proBNP for the evaluation and management of AS patients. Our results suggest that Nt-proBNP should be considered cautiously, at least as a single criterion, in the decision-making process of AS patients especially in the elderly population. PMID- 23349347 TI - Plaques with high lipid burden: keeping the fat out of the fire. PMID- 23349349 TI - Molecular targets of current and prospective heart failure therapies. AB - Heart failure (HF) is a vicious circle in which an original insult leading to mechanical cardiac dysfunction initiates multiple morphological, biochemical and molecular pathological alterations referred to as cardiac remodelling. Remodelling leads to further deterioration of cardiac function and functional reserve. Interrupting or reversing cardiac remodelling is a major therapeutic goal of HF therapies. The role of molecules and molecular pathways in cardiac remodelling and HF has been extensively studied. Multiple approaches are now used or investigated in HF therapy, including pharmacological therapy, device therapy, gene therapy, cell therapy and biological therapy targeting cytokines and growth factors. This review explores the molecular targets and molecular bases of current and prospective therapies in HF. PMID- 23349348 TI - Human non-contrast T1 values and correlation with histology in diffuse fibrosis. AB - BACKGROUND: Aortic stenosis (AS) leads to diffuse fibrosis in the myocardium, which is linked to adverse outcome. Myocardial T1 values change with tissue composition. OBJECTIVE: To test the hypothesis that our recently developed non contrast cardiac magnetic resonance (CMR) T1 mapping sequence could identify myocardial fibrosis without contrast agent. DESIGN, SETTING AND PATIENTS: A prospective CMR non-contrast T1 mapping study of 109 patients with moderate and severe AS and 33 age- and gender-matched controls. METHODS: CMR at 1.5 T, including non-contrast T1 mapping using a shortened modified Look-Locker inversion recovery sequence, was carried out. Biopsy samples for histological assessment of collagen volume fraction (CVF%) were obtained in 19 patients undergoing aortic valve replacement. RESULTS: There was a significant correlation between T1 values and CVF% (r=0.65, p=0.002). Mean T1 values were significantly longer in all groups with severe AS (972 +/- 33 ms in severe asymptomatic, 1014 +/- 38 ms in severe symptomatic) than in normal controls (944 +/- 16 ms) (p<0.05). The strongest associations with T1 values were for aortic valve area (r=-0.40, p=0.001) and left ventricular mass index (LVMI) (r=0.36, p=0.008), and these were the only independent predictors on multivariate analysis. CONCLUSIONS: Non-contrast T1 values are increased in patients with severe AS and further increase in symptomatic compared with asymptomatic patients. T1 values lengthened with greater LVMI and correlated with the degree of biopsy-quantified fibrosis. This may provide a useful clinical assessment of diffuse myocardial fibrosis in the future. PMID- 23349350 TI - Inconsistent echocardiographic grading of aortic stenosis: is the left ventricular outflow tract important? AB - OBJECTIVE: Discrepancy in the echocardiographic severity grading of aortic stenosis (AS) based on current guidelines has been reported. We sought to investigate the left ventricular outflow tract diameter (LVOTd) as a source of inconsistencies, and to explore hypothetical alternatives for discrepancy improvement. DESIGN: Retrospective echocardiographic cross-sectional analysis. SETTING: From 2000 to 2010, we identified all AS patients with left ventricular EF >=50%, mean gradient (MG) >=20 mm Hg, aortic valve area (AVA) <=2.5 cm(2), =2.3 cm. In each group, inconsistency of data for classification of severity of AS was assessed and alternative thresholds explored. RESULTS: Of 9488 total patients, 58% were men, LVOTd 2.18+/-0.19 cm, peak velocity (Vmax) 3.9+/-0.8 m/s, MG 37+/-16 mm Hg, and AVA 1.09+/-0.34 cm(2). Small LVOTd patients were older women (91%) with worse systemic haemodynamics and more prevalent paradoxical low flow, compared with average and large LVOTd patients (all parameters p <0.001). Despite clinically similar MG and Vmax across all groups, mean AVA ranged from 0.88 to 1.25 cm(2) (p <0.001), classifying small LVOTd patients as severe, average LVOTd as moderate-severe and large LVOTd as moderate. For patients with large, average and small LVOTd, an AVA of 1 cm(2) corresponded to MG of 42, 35 and 29 mm Hg, Vmax of 4.1, 3.8 and 3.5 m/s and dimensionless index (DI) of 0.22, 0.29 and 0.36, respectively. An AVA cut-off of 0.8 cm(2) reduced severe AS inconsistency from 48% to 26% for small LVOTd patients. An AVA cut-off of 0.9 cm(2) reduced severe AS inconsistency from 37% to 26% for average LVOTd patients. The current AVA cut-off of 1 cm(2) was consistent for large LVOTd patients. CONCLUSIONS: The LVOTd is associated with significant inconsistencies in AS assessment by current guidelines. For patients with normal EF and normal flow, current guideline definition of severe AS is most consistent for patients with large LVOTd, but not so for patients with average or small LVOTd in whom lower AVA cut-offs should be further studied. The DI cut-off for severe AS is highly variable depending on the LVOTd and guideline revision of this threshold should be considered. PMID- 23349352 TI - Case studies in prehospital care from London HEMS: pre-hospital administration of prothrombin complex concentrate to the head-injured patient. AB - A case of pre-hospital administration of prothrombin complex concentrate to a patient anticoagulated with warfarin and with suspected intracranial haemorrhage is described. Effective, early reversal of anticoagulation by the time of arrival at hospital was achieved. PMID- 23349351 TI - Critical incident reporting in emergency medicine: results of the prehospital reports. AB - BACKGROUND: Medical errors frequently contribute to morbidity and mortality. Prehospital emergency medicine is prone to incidents that can lead to immediate deadly consequences. Critical incident reporting can identify typical problems and be the basis for structured risk management in order to reduce and mitigate these incidents. METHODS: We set up a free access internet website for German speaking countries, with an anonymous reporting system for emergency medical services personnel. After a 7-year study period, an expert team analysed and classified the incidents into staff related, equipment related, organisation and tactics, or other. RESULTS: 845 reports were entered in the study period. Physicians reported 44% of incidents, paramedics 42%. Most patients were in a life-threatening or potentially life-threatening situation (82%), and only 53% of all incidents had no influence on the outcome of the patient. Staff-related problems were responsible for 56% of the incidents, when it came to harm, 78% of these incidents were staff related. CONCLUSIONS: Incident reporting in prehospital emergency medicine can identify system weaknesses. Most of the incidents were reported during care of patients in life-threatening conditions with a high impact on patient outcome. Staff-related problems contributed to the most frequent and most severe incidents. PMID- 23349353 TI - Methoxetamine toxicity reported to the National Poisons Information Service: clinical characteristics and patterns of enquiries (including the period of the introduction of the UK's first Temporary Class Drug Order). AB - OBJECTIVE: To report the demographic and clinical characteristics of cases of methoxetamine toxicity reported to The National Poisons Information Service (NPIS) by healthcare professionals. To assess the pattern of enquiries from health professionals to the UK NPIS related to methoxetamine, including the period of the making of the UK first Temporary Class Drug Order (TCDO). METHODS: All telephone enquiries to and user sessions for TOXBASE, the NPIS on-line information resource, related to methoxetamine (and synonyms 'MXE', 'mket' and '2 (3-methoxyphenyl)-2-(ethylamino)cyclohexanone') were reviewed from 1 April 2010 to 1 August 2012. Data were compared for the 3 months before and after the TCDO. RESULTS: There were 47 telephone enquiries and 298 TOXBASE sessions regarding methoxetamine during the period of study. Comparing the 3 months before and after the TCDO, TOXBASE sessions for methoxetamine fell by 79% (from 151 to 32) and telephone enquiries by 80% (from 15 to 3). Clinical features reported by enquirers were consistent with case reports of analytically confirmed methoxetamine toxicity and typical toxidromes were of stimulant (36%), reduced consciousness (17%), dissociative (11%) and cerebellar (6.4%) types, but also particularly featured acute disturbances in mental heath (43%). CONCLUSIONS: Structured NPIS data may reveal trends in drugs of abuse use and toxicity when interpreted within their limitations. Since April 2012, there have been fewer enquiries to NPIS from clinicians, indicating reduced presentations with suspected methoxetamine toxicity to healthcare services. It is unclear if this is related to the TCDO made on 5 April 2012. PMID- 23349354 TI - Craniotomy unplugged. PMID- 23349355 TI - Atrial fibrillation in acute pulmonary embolism: prognostic considerations. AB - AIMS: Although it is accepted that atrial fibrillation (AF) may be both the contributing factor and the consequence of pulmonary embolism (PE), data on the prognostic role of AF in patients with acute venous thromboembolism are scarce. Our aim was to study whether AF had a prognostic role in patients with acute PE. METHODS: Retrospective cohort study involving 270 patients admitted for acute PE. Collected data: past medical history, analytic/gasometric parameters, admission ECG and echocardiogram, thoracic CT angiography. Patients followed for 6 months. An analysis was performed in order to clarify whether history of AF, irrespective of its timing, helps predict intrahospital, 1-month and 6-month all-cause mortality. RESULTS: Patients with history of AF, irrespective of its timing (n=57, 21.4%), had higher intrahospital (22.8% vs 13.1%, p=0.052, OR 2.07, 95% CI 0.98 to 4.35), 1-month (35.1% vs 16.9%, p=0.001, OR 3.16, 95% CI 1.61 to 6.21) and 6-month (45.6% vs 17.4%, p<0.001, OR 4.67, 95% CI 2.37 to 9.21) death rates. The prognostic power of AF was independent of age, NT-proBNP values, renal function and admission blood pressure and heart rate and additive to mortality prediction ability of simplified PESI (AF: p=0.021, OR 2.31, CI 95% 1.13 to 4.69; simplified PESI: p=0.002, OR 1.47, CI 95% 1.15 to 1.89). The presence of AF at admission added prognostic value to previous history of AF in terms of 1-month and 6-month all-cause mortality prediction, although it did not increase risk for intrahospital mortality. CONCLUSIONS: The presence of AF, irrespective of its timing, may independently predict mortality in patients with acute PE. These data should be tested and validated in prospective studies using larger cohorts. PMID- 23349356 TI - Features and predictors of myocardial injury in carbon monoxide poisoned patients. AB - BACKGROUND AND PURPOSE: By contrast with neurologic injury, myocardial injury associated with carbon monoxide (CO) poisoning has not been well investigated. Therefore, this study assessed features and predictors of myocardial injury in CO poisoned patients. SUBJECTS AND METHODS: 250 CO poisoning cases that were diagnosed and treated by the emergency department of Wonju Christian Hospital from January 2006 to February 2012 were retrospectively reviewed. RESULTS: Fifty (20%) out of 250 patients with CO poisoning developed myocardial injury. Among those with elevated troponin I (Tn I), peak levels occurred at 11.0 (IQR, 4.5 18.5) h normalising by 65.0 (IQR 44.0-96.0) h. CO exposure time, and total and ICU admission length was longer (7.5 (IQR 3.7-10.0) h vs 3.0 (IQR 1.0-7.5) h, p<0.001; 3.5 (IQR 0.0-7.0) days and 0.0 (IQR 0.0-1.25) days vs 0.0 (IQR 0.0-2.0) days and 0.0 (IQR 0.0-0.0) days, p<0.001, respectively) in the myocardial vs non myocardial injury group. The predictors of myocardial injury were male gender, Glasgow Coma Scale (GCS) <=14, and CO exposure time >=2 h (OR (95% CI) of 3.341 (1.171 to 9.531), 9.920 (3.763 to 26.150), and 7.743 (1.610 to 37.238), respectively). CONCLUSIONS: Myocardial injury developed in 20% of CO poisoned patients. Time to normalisation and of peak Tn I level in elevated Tn I group was 65.0 (IQR 44.0-96.0) h and 11.0 (IQR 4.5-18.5) h. Presence of myocardial injury was associated with poorer prognosis. Predictors of myocardial injury included male gender, GCS of 14 or less, or CO exposure times greater than 2 h. PMID- 23349357 TI - Lightning and its association with the frequency of headache in migraineurs: an observational cohort study. AB - AIM: The aim of this article is to determine if lightning is associated with the frequency of headache in migraineurs. METHODS: Participants fulfilling diagnostic criteria for International Headache Society-defined migraine were recruited from sites located in Ohio ( N = 23) and Missouri ( N = 67). They recorded headache activity in a daily diary for three to six months. A generalized estimating equations (GEE) logistic regression determined the odds ratio (OR) of headache on lightning days compared to non-lightning days. Other weather factors associated with thunderstorms were also added as covariates to the GEE model to see how they would attenuate the effect of lightning on headache. RESULTS: The mean age of the study population was 44 and 91% were female. The OR for headache was 1.31 (95% confidence limits (CL); 1.07, 1.66) during lighting days as compared to non lightning days. The addition of thunderstorm-associated weather variables as covariates were only able to reduce the OR for headache on lightning days to 1.18 (95% CL; 1.02, 1.37). The probability of having a headache on lightning days was also further increased when the average current of lightning strikes for the day was more negative. CONCLUSION: This study suggests that lightning represents a trigger for headache in migraineurs that cannot be completely explained by other meteorological factors. It is unknown if lightning directly triggers headaches through electromagnetic waves or indirectly through production of bioaerosols (e.g. ozone), induction of fungal spores or other mechanisms. These results should be interpreted cautiously until replicated in a second dataset. PMID- 23349358 TI - En'lightning' the impact of atmospheric conditions in headache. PMID- 23349359 TI - From neuroimaging to the bedside: take the sheets off the thalamus. PMID- 23349360 TI - Hypoxia-inducible factor 1a is a Tsc1-regulated survival factor in newborn neurons in tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in TSC1 or TSC2 resulting in hyperactivity of the mammalian target of rapamycin and disabling brain lesions. These lesions contain misplaced neurons enriched in hypoxia-inducible factor 1a (HIF1a). However, the relationship between TSC1/2 and HIF1a and the function of HIF1a in TSC neurons remain unexplored. Here, we examine the degree of HIF1a activity and its function in newborn Tsc1(null) neurons in a mouse model of TSC. Using single cell electroporation in the neurogenic subventricular zone (SVZ) of neonatal mice, we deleted Tsc1 and generated olfactory lesions containing misplaced Tsc1(null) neurons as previously reported. These newborn neurons displayed elevated HIF1a-mediated transcriptional activity when compared with Tsc1 heterozygote neurons and a marked resistance to cell death induced by a HIF1a antagonist. Electroporation of Hif1a targeting short hairpin RNA (shRNA) or dominant negative HIF1a constructs resulted in 80 90% loss of Tsc1(null) newborn neurons although sparing SVZ stem cells. Consistent with this later finding, induction of Hif1a shRNA expression during synaptic integration thus bypassing neuron production also resulted in newborn neuron death. Collectively, these results suggest that HIF1a acts as a molecular determinant of newborn neuron survival and that its TSC1-dependent up-regulation gave Tsc1(null) neurons a survival advantage, despite their misplacement in a novel microenvironment. PMID- 23349362 TI - A fasciclin-like arabinogalactan protein, GhFLA1, is involved in fiber initiation and elongation of cotton. AB - Arabinogalactan proteins (AGPs) are involved in many aspects of plant development. In this study, biochemical and genetic approaches demonstrated that AGPs are abundant in developing fibers and may be involved in fiber initiation and elongation. To further investigate the role of AGPs during fiber development, a fasciclin-like arabinogalactan protein gene (GhFLA1) was identified in cotton (Gossypium hirsutum). Overexpression of GhFLA1 in cotton promoted fiber elongation, leading to an increase in fiber length. In contrast, suppression of GhFLA1 expression in cotton slowed down fiber initiation and elongation. As a result, the mature fibers of the transgenic plants were significantly shorter than those of the wild type. In addition, expression levels of GhFLAs and the genes related to primary cell wall biosynthesis were remarkably enhanced in the GhFLA1 overexpression transgenic fibers, whereas the transcripts of these genes were dramatically reduced in the fibers of GhFLA1 RNA interference plants. An immunostaining assay indicated that both AGP composition and primary cell wall composition were changed in the transgenic fibers. The levels of glucose, arabinose, and galactose were also altered in the primary cell wall of the transgenic fibers compared with those of the wild type. Together, our results suggested that GhFLA1 may function in fiber initiation and elongation by affecting AGP composition and the integrity of the primary cell wall matrix. PMID- 23349363 TI - Fever literacy and fever phobia. AB - OBJECTIVE: To identify the percentage of parents who define the threshold for fever between 38.0 degrees C and 38.3 degrees C, which has not been reported previously, and to describe parental attitudes toward fever and antipyretic use. STUDY DESIGN: Thirteen-question survey study of caregivers. RESULTS: Overall, 81% of participants defined the threshold for fever as <38.0 degrees C, 0% correctly defined fever between 38.0 degrees C and 38.3 degrees C, and 19% defined fever as >38.3 degrees C. Twenty percent of children brought to clinic for a chief complaint of fever were never truly febrile. Ninety-three percent of participants believed that high fever can cause brain damage. For a comfortable-appearing child with fever, 89% of caregivers reported that they would give antipyretics and 86% would schedule a clinic visit. CONCLUSION: Our finding that 0% of parents correctly defined fever is both surprising and unsettling, and it should inform future discussions of fever between parents and clinicians. PMID- 23349361 TI - Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain. AB - Tc1 mouse model of Down syndrome (DS) is functionally trisomic for ~120 human chromosome 21 (HSA21) classical protein-coding genes. Tc1 mice display features relevant to the DS phenotype, including abnormalities in learning and memory and synaptic plasticity. To determine the molecular basis for the phenotypic features, the levels of 90 phosphorylation-specific and phosphorylation independent proteins were measured by Reverse Phase Protein Arrays in hippocampus and cortex, and 64 in cerebellum, of Tc1 mice and littermate controls. Abnormal levels of proteins involved in MAP kinase, mTOR, GSK3B and neuregulin signaling were identified in trisomic mice. In addition, altered correlations among the levels of N-methyl-D-aspartate (NMDA) receptor subunits and the HSA21 proteins amyloid beta (A4) precursor protein (APP) and TIAM1, and between immediate early gene (IEG) proteins and the HSA21 protein superoxide dismutase-1 (SOD1) were found in the hippocampus of Tc1 mice, suggesting altered stoichiometry among these sets of functionally interacting proteins. Protein abnormalities in Tc1 mice were compared with the results of a similar analysis of Ts65Dn mice, a DS mouse model that is trisomic for orthologs of 50 genes trisomic in the Tc1 plus an additional 38 HSA21 orthologs. While there are similarities, abnormalities unique to the Tc1 include increased levels of the S100B calcium-binding protein, mTOR proteins RAPTOR and P70S6, the AMP-kinase catalytic subunit AMPKA, the IEG proteins FBJ murine osteosarcoma viral oncogene homolog (CFOS) and activity regulated cytoskeleton-associated protein (ARC), and the neuregulin 1 receptor ERBB4. These data identify novel perturbations, relevant to neurological function and to some seen in Alzheimer's disease, that may occur in the DS brain, potentially contributing to phenotypic features and influencing drug responses. PMID- 23349364 TI - Impact of vegetarian diet on serum immunoglobulin levels in children. AB - BACKGROUND: Nutrition plays an important role in immune response. We evaluated the effect of nutrient intake on serum immunoglobulin levels in vegetarian and omnivore children. METHODS: Serum immunoglobulin levels and iron status were estimated in 22 vegetarian and 18 omnivore children. Seven-day food records were used to assess the diet. RESULTS: There were no significant differences in serum IgA, IgM, and IgG levels between groups of children. Serum immunoglobulin levels were lower in vegetarian children with iron deficiency in comparison with those without iron deficiency. In the vegetarians, IgG level correlated positively with energy, zinc, copper, and vitamin B(6) intake. In the omnivores, these correlations were stronger with IgM level. CONCLUSIONS: Despite negligible differences in serum immunoglobulin levels between vegetarian and omnivore children, the impact of several nutrient intakes on IgM and IgG levels differed between groups. Low iron status in vegetarian children can lead to decreased immunoglobulin levels. PMID- 23349368 TI - Diabetes mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology. AB - BACKGROUND: It is unclear whether diabetes mellitus (DM) is an adverse prognostic factor in chronic heart failure (CHF) of ischaemic and non-ischaemic aetiology managed with contemporary evidence-based care. METHODS: In total, 1091 outpatients with CHF with reduced ejection fraction were prospectively observed for a mean of 960 days. Total and cardiovascular mortality was quantified after accounting for potential confounders. RESULTS: In total, 25.7% of patients had DM; this group was more likely to have CHF of ischaemic aetiology and was more symptomatic. Patients with DM received comparable medical- and device-based therapies, except for greater doses of loop diuretic. DM was associated with approximately doubled crude and adjusted risk of total and cardiovascular mortality. The association of diabetes with these outcomes in patients with ischaemic and non-ischaemic cardiomyopathies was of similar magnitude. CONCLUSIONS: In spite of advances in the management of CHF, DM remains a major adverse prognostic feature, irrespective of ischaemic/non-ischaemic aetiology. PMID- 23349369 TI - Is there benefit in dual renin-angiotensin-aldosterone system blockade? No, yes and maybe: a guide for the perplexed. AB - Since the initial discovery of Angiotensin converting enzyme inhibitors (ACEI) in the 1960s and the launch of Captopril as the first available for clinical use in the 1970s, there now exist three other classes of drugs that block the renin angiotensin aldosterone system (RAAS): the angiotensin II receptor blockers (ARB), aldosterone antagonists (AA) and direct renin inhibitors (DRI). With the proven efficacy of RAAS blockers as monotherapy in many arenas there has been considerable interest in the use of dual therapy combinations of these medications that target different points in the pathway. By potentially offering a more complete RAAS blockade with a commensurate enhanced clinical effect, the strong biological rationale for dual therapy has led to it being embraced by clinicians as a treatment option, for hypertension and nephroprotection in particular. However, the initial enthusiasm for this treatment has been tempered by the recent results from several large trials such as ONTARGET and ALTITUDE, which do not support a specific dual therapy approach. In contrast, there is supportive evidence for dual blockade of specific combinations in selected patient groups and data are lacking for others. In the wake of this complex contemporary evidence, the conundrum now faced by clinicians committed to individualised care is, for which patients dual therapy could still be of benefit. This review examines for the practising clinician the current 'state of play' for dual blockade of various combinations and a perspective on its use in cardio-renal disease and diabetic complications. PMID- 23349370 TI - Moving T memory stem cells to the clinic. PMID- 23349371 TI - Surprisingly variable "dangers, toils, and snares" faced by humans and mice. PMID- 23349372 TI - Gas6 gains entry into the coagulation cascade. PMID- 23349374 TI - Proapoptotic Bak and Bax guard against fatal systemic and organ-specific autoimmune disease. AB - Dysregulation of the "intrinsic" apoptotic pathway is associated with the development of cancer and autoimmune disease. Bak and Bax are two proapoptotic members of the Bcl-2 protein family with overlapping, essential roles in the intrinsic apoptotic pathway. Their activity is critical for the control of cell survival during lymphocyte development and homeostasis, best demonstrated by defects in thymic T-cell differentiation and peripheral lymphoid homeostasis caused by their combined loss. Because most bak(-/-)bax(-/-) mice die perinatally, the roles of Bax and Bak in immunological tolerance and prevention of autoimmune disease remain unclear. We show that mice reconstituted with a Bak/Bax doubly deficient hematopoietic compartment develop a fatal systemic lupus erythematosus-like autoimmune disease characterized by hypergammaglobulinemia, autoantibodies, lymphadenopathy, glomerulonephritis, and vasculitis. Importantly, these mice also develop a multiorgan autoimmune disease with autoantibodies against most solid glandular structures and evidence of glandular atrophy and necrotizing vasculitis. Interestingly, similar albeit less severe pathology was observed in mice containing a hematopoietic compartment deficient for only Bak, a phenotype reminiscent of the disease seen in patients with point mutations in BAK. These studies demonstrate a critical role for Bak and an ancillary role for Bax in safeguarding immunological tolerance and prevention of autoimmune disease. This suggests that direct activators of the intrinsic apoptotic pathway, such as BH3 mimetics, may be useful for treatment of diverse autoimmune diseases. PMID- 23349378 TI - Soft tissue defects of the foot and ankle. PMID- 23349379 TI - Design comparison of the INBONE I versus INBONE II total ankle system. AB - Degenerative joint disease of the ankle is a debilitating etiology, in which treatment has been disputed in the literature among healthy active patients. Total ankle arthroplasty had recently gained popularity as long-term outcomes are being reported and advancement in the design of the implants themselves evolves. Multiple implants are available on today's market including the INBONE (Wright Medical technologies, Arlington, TN) Total Ankle System. The second generation INBONE total ankle arthroplasty was launched and approved for use in the United States by the FDA in 2005. The second generation INBONE implant has a talar sulcus, allowing for a more biomechanically stable articulation between the polyethelene insert and the talar component (Figure 1). The initial INBONE implant had a flat articulation with the poly leading to instability. This paper will help to demonstrate the advantages of INBONE II versus INBONE I Total Ankle System in management of arthrosis of the ankle joint. LEVEL OF EVIDENCE: Level V: Expert opinion. PMID- 23349380 TI - Management of degloving injuries of the lower extremity: a case report of a forklift injury. AB - Soft-tissue injuries of the foot and ankle can vary from crushing to penetrating mechanisms. Degloving injuries of the lower extremity are the result of an entrapment between a fixed surface and a moving object. These injuries pose significant morbidity and potential complications (eg, infection) to the patient if prompt wound coverage is not initiated. The authors present a case of an extensive degloving injury to the foot, ankle, and lower leg from a forklift accident. With the collaborative effort of the podiatry and plastic surgery teams, the patient underwent serial debridements, application of a small intestine submucosa wound matrix, negative-pressure wound therapy, and skin grafting. This case presentation demonstrates the benefit of procedure staging and early wound coverage for improved patient outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV, Case Study. PMID- 23349381 TI - Intermediate and long-term outcomes of the suture bridge technique for the management of insertional achilles tendinopathy. AB - INTRODUCTION: Insertional Achilles tendinopathy is a problem frequently encountered by the foot and ankle surgeon. Conservative care yields mixed results, and this condition is often treated surgically. Our hypothesis is that the suture bridge technique through a central posterior incision allows adequate visualization for thorough debridement and exostectomy and provides a stable tendon-to-bone interface for healing. MATERIAL AND METHODS: The medical records of 35 patients who underwent surgical treatment for insertional Achilles tendinopathy with the suture bridge technique, by a single surgeon, between 2006 and 2012 were retrospectively reviewed. American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot instruments as well as a subjective questionnaire were utilized. RESULTS: In all, 30 individuals who met the inclusion criteria for the treatment of insertional Achilles tendinopathy were evaluated at a mean follow-up of 28.93 +/- 16.99 months. We included 10 men and 20 women, with a mean age of 49.1 +/- 9.2 years. The mean preoperative AOFAS score was 56.6 +/- 14.0. The average postoperative AOFAS score significantly increased to 91.7 +/- 10.4 (P < .0001). One participant required revisional surgery, consisting of a flexor hallucis longus transfer performed by another physician. There were no wound complications or infections. Overall, there was a 97% (28/29) satisfaction rate. CONCLUSION: The central incision with complete detachment of the Achilles tendon and reattachment with the suture bridge technique for the treatment of insertional Achilles tendinopathy provides an effective treatment with good to excellent clinical outcomes in 97% of patients, with a mean follow-up of 29 months. PMID- 23349382 TI - Lawn mower injuries to the lower extremity: a 10-year retrospective review. AB - INTRODUCTION: Lawn mower injuries occur frequently in the United States and oftentimes result in extensive trauma to the lower extremities. These injuries can be quite devastating and cause there to be loss of function and amputation. The purpose of this study was to determine if there are specific factors that would help determine the best treatment protocol, patient outcomes, and prognosis after lawn mower injury to the foot and ankle. MATERIAL AND METHODS: A retrospective review of medical records was performed on all patients treated at a university level 1 trauma center from 2000 to 2010. Only subjects 18 years or older who sustained an injury below the level of the knee were included for review. RESULTS: Seventy-three patients were included in this review. The results revealed that patients who developed a complication were significantly older than the group of patients without complications (P = .03). Digits were found to be injured most often but the odds of developing a complication were much higher if these injuries involved the plantar foot, dorsal foot, or ankle. Interestingly, patients on prolonged antibiotic therapy had a significantly higher risk of developing complications. The presence of comorbidities significantly increased the risk of complication (P = .008); the greatest risk factors were cardiovascular disease (P = .001) and diabetes (P = .06). DISCUSSION: The authors present the largest cohort of lawn mower injuries in the medical literature, which demonstrates that factors such as age, location of injury, and the presence of comorbidities influence the outcome and increase the risk of injury to the foot and ankle. These results may be useful in determining the best treatment plan possible for patients with these severe injuries. LEVELS OF EVIDENCE: Therapeutic, Level IV, Retrospective case series. PMID- 23349383 TI - Pulmonary-renal syndrome: a life threatening but treatable condition. AB - Pulmonary renal syndrome (PRS) describes the occurrence of renal failure in association with respiratory failure, characterised by autoimmune-mediated rapidly progressive glomerulonephritis (RPGN) and diffuse alveolar haemorrhage (DAH), respectively. PRS is associated with significant morbidity and mortality, and prompt diagnosis and treatment significantly improve outcomes. Prompt diagnosis of PRS requires a high index of suspicion, as clinical features are non specific, and immunological testing aids the diagnosis in many cases. The diagnostic evaluation of DAH and RPGN is outlined in the context of the important differential diagnoses. The commonest causes of PRS include antineutrophil cytoplasm antibody (ANCA)-associated vasculitis and antiglomerular basement membrane disease. As such, more emphasis has been placed on these two conditions in addition to an overview of the less common causes of PRS. We provide a practical review of the diagnostic evaluation, current treatment strategies and clinical outcomes of PRS for renal, respiratory and general physicians. PMID- 23349384 TI - Dual embedded agency: physicians implement integrative medicine in health-care organizations. AB - The paradox of embedded agency addresses the question of how embedded agents are able to conceive of new ideas and practices and then implement them in institutionalized organizations if social structures exert so powerful an influence on behavior, and agents operate within a framework of institutional constraints. This article proposes that dual embedded agency may provide an explanation of the paradox. The article draws from an ethnographic study that examined the ways in which dual-trained physicians, namely medical doctors trained also in some modality of complementary and alternative medicine, integrate complementary and alternative medicine into the biomedical fortress of mainstream health-care organizations. Participant observations were conducted during the years 2006-2011. The observed physicians were found to be embedded in two diverse medical cultures and to have a hybrid professional identity that comprised two sets of health-care values. Seeking to introduce new ideas and practices associated with complementary and alternative medicine to medical institutions, they maneuvered among the constraints of institutional structures while using these very structures, in an isomorphic mode of action, as a platform for launching complementary and alternative medicine practices and values. They drew on the complementary and alternative medicine philosophical principle of interconnectedness and interdependency of seemingly polar opposites or contrary forces and acted to achieve change by means of nonadversarial strategies. By addressing the structure-agency dichotomy, this study contributes to the literature on change in institutionalized health-care organizations. It likewise contributes both theoretically and empirically to the study of integrative medicine and to the further development of this relatively new area of inquiry within the sociology of medicine. PMID- 23349385 TI - Finding the patient in patient safety. AB - In the last decade, the field of patient safety has grappled with the complexity of health-care systems by attending to the activity of frontline clinicians. This article extends the field by highlighting the activity of patients and their carers in determining the safety of these systems. We draw on data from three studies exploring patients' accounts of their health-care experiences in Australia and internationally, to show how patients and carers are currently contributing to the safety of their own care. Furthermore, we emphasise the importance of patient-clinician collaboration in ensuring the success of these activities. We argue that it is no longer sufficient to discuss if patients should be involved with ensuring their own safety. Given that patients are already involved, we propose a new conceptualisation of safety and systems that acknowledges their involvement and supports patient-provider collaboration to achieve safer care. PMID- 23349386 TI - High performance teamwork training and systems redesign in outpatient oncology. AB - BACKGROUND: Oncology care is delivered largely in ambulatory settings by interdisciplinary teams. Treatments are often complex, extended in time, dispersed geographically and vulnerable to teamwork failures. To address this risk, we developed and piloted a team training initiative in the breast cancer programme at a comprehensive cancer centre. METHODS: Based on clinic observations, interviews with key staff and analyses of incident reports, we developed interventions to address four high-risk areas: (1) miscommunication of chemotherapy order changes on the day of treatment; (2) missing orders on treatment days without concurrent physician appointments; (3) poor follow-up with team members about active patient issues; and (4) conflict between providers and staff. The project team developed protocols and agreements to address team members' roles, responsibilities and behaviours. RESULTS: Using a train-the trainer model, 92% of breast cancer staff completed training. The incidence of missing orders for unlinked visits decreased from 30% to 2% (p<0.001). Patient satisfaction scores regarding coordination of care improved from 93 to 97 (p=0.026). Providers, infusion nurses and support staff reported improvement in efficiency (75%, 86%, 90%), quality (82%, 93%, 93%) and safety (92%, 92%, 90%) of care, and more respectful behaviour (92%, 79%, 83%) and improved relationships among team members (91%, 85%, 92%). Although most clinicians reported a decrease in non-communicated changes, there was insufficient statistical power to detect a difference. CONCLUSIONS: Team training improved communication, task coordination and perceptions of efficiency, quality, safety and interactions among team members as well as patient perception of care coordination. PMID- 23349387 TI - Harnessing the cloud of patient experience: using social media to detect poor quality healthcare. AB - Recent years have seen increasing interest in patient-centred care and calls to focus on improving the patient experience. At the same time, a growing number of patients are using the internet to describe their experiences of healthcare. We believe the increasing availability of patients' accounts of their care on blogs, social networks, Twitter and hospital review sites presents an intriguing opportunity to advance the patient-centred care agenda and provide novel quality of care data. We describe this concept as a 'cloud of patient experience'. In this commentary, we outline the ways in which the collection and aggregation of patients' descriptions of their experiences on the internet could be used to detect poor clinical care. Over time, such an approach could also identify excellence and allow it to be built on. We suggest using the techniques of natural language processing and sentiment analysis to transform unstructured descriptions of patient experience on the internet into usable measures of healthcare performance. We consider the various sources of information that could be used, the limitations of the approach and discuss whether these new techniques could detect poor performance before conventional measures of healthcare quality. PMID- 23349388 TI - Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease. AB - Chronic inflammation has emerged as an important pathogenic mechanism in sickle cell disease (SCD). One component of this inflammatory response is oxidant stress mediated by reactive oxygen species (ROS) generated by leukocytes, endothelial cells, plasma enzymes, and sickle red blood cells (RBC). Sickle RBC ROS generation has been attributed to sickle hemoglobin auto-oxidation and Fenton chemistry reactions catalyzed by denatured heme moieties bound to the RBC membrane. In this study, we demonstrate that a significant part of ROS production in sickle cells is mediated enzymatically by NADPH oxidase, which is regulated by protein kinase C, Rac GTPase, and intracellular Ca(2+) signaling within the sickle RBC. Moreover, plasma from patients with SCD and isolated cytokines, such as transforming growth factor beta1 and endothelin-1, enhance RBC NADPH oxidase activity and increase ROS generation. ROS-mediated damage to RBC membrane components is known to contribute to erythrocyte rigidity and fragility in SCD. Erythrocyte ROS generation, hemolysis, vaso-occlusion, and the inflammatory response to tissue damage may therefore act in a positive-feedback loop to drive the pathophysiology of sickle cell disease. These findings suggest a novel pathogenic mechanism in SCD and may offer new therapeutic targets to counteract inflammation and RBC rigidity and fragility in SCD. PMID- 23349389 TI - The diversity of the immune response to the A2 domain of human factor VIII. AB - Approximately 30% of patients with severe hemophilia A develop inhibitory anti factor VIII (fVIII) antibodies (Abs). We characterized 29 anti-human A2 monoclonal Abs (mAbs) produced in a murine hemophilia A model. A basis set of nonoverlapping mAbs was defined by competition enzyme-linked immunosorbent assay, producing 5 major groups. The overlapping epitopes covered nearly the entire A2 surface when mapped by homolog-scanning mutagenesis. Most group A mAbs recognized a previously described epitope bounded by Arg484-Ile508 in the N-terminal A2 subdomain, resulting in binding to activated fVIII and noncompetitive inhibition of the intrinsic fXase complex. Group B and C mAbs displayed little or no inhibitory activity. Group D and E mAbs recognized epitopes in the C-terminal A2 subdomain. A subset of group D mAbs inhibited the activation of fVIII by interfering with thrombin-catalyzed cleavage at Arg372 at the A1-A2 domain junction. Other group D mAbs displayed indeterminate or no inhibitory activity despite inhibiting cleavage at Arg740 at the A2-B domain junction. Group E mAbs inhibited fVIII light-chain cleavage at Arg1689. Inhibition of cleavages at Arg372 and Arg1689 represent novel mechanisms of inhibitor function and, along with the extensive epitope spectrum identified in this study, reveal hitherto unrecognized complexity in the immune response to fVIII. PMID- 23349390 TI - AML cells are differentially sensitive to chemotherapy treatment in a human xenograft model. AB - As acute myeloid leukemia (AML) xenograft models improve, the potential for using them to evaluate novel therapeutic strategies becomes more appealing. Currently, there is little information on using standard chemotherapy regimens in AML xenografts. Here we have characterized the immunodeficient mouse response to combined Ara-C (cytarabine) and doxorubicin treatment. We observed significant toxicity associated with doxorubicin that required optimization of the route of injection as well as the maximum-tolerated dose for immunodeficient strains. Mice treated with an optimized 5-day induction protocol showed transient weight loss, short-term reduction of peripheral blood cell and platelet counts, and slight anemia. Considerable cytotoxicity was observed in the bone marrow (BM), with primitive LSK cells having a significant survival advantage relative to more mature cells, consistent with the idea of chemotherapy targeting actively growing cells. Treated leukemic mice demonstrated reduced disease burden and increased survival, demonstrating efficacy. AML cells showed significantly increased sensitivity to doxorubicin-containing therapy compared with murine BM cells. Although early treatment could result in some cures, mice with significant leukemia grafts were not cured by using induction therapy alone. Overall, the data show that this model system is useful for the evaluation of novel chemotherapies in combination with standard induction therapy. PMID- 23349391 TI - The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-induced anemia in cynomolgus monkeys. AB - Anemia of chronic inflammation is the most prevalent form of anemia in hospitalized patients. A hallmark of this disease is the intracellular sequestration of iron. This is a consequence of hepcidin-induced internalization and subsequent degradation of ferroportin, the hepcidin receptor and only known iron-export protein. This study describes the characterization of novel anti hepcidin compound NOX-H94, a structured L-oligoribonucleotide that binds human hepcidin with high affinity (Kd = 0.65 +/- 0.06 nmol/L). In J774A.1 macrophages, NOX-H94 blocked hepcidin-induced ferroportin degradation and ferritin expression (half maximal inhibitory concentration = 19.8 +/- 4.6 nmol/L). In an acute cynomolgus monkey model of interleukin 6 (IL-6)-induced hypoferremia, NOX-H94 inhibited serum iron reduction completely. In a subchronic model of IL-6-induced anemia, NOX-H94 inhibited the decrease in hemoglobin concentration. We conclude that NOX-H94 protects ferroportin from hepcidin-induced degradation. Therefore, this pharmacologic approach may represent an interesting treatment option for patients suffering from anemia of chronic inflammation. PMID- 23349393 TI - Nonredundant and locus-specific gene repression functions of PRC1 paralog family members in human hematopoietic stem/progenitor cells. AB - The Polycomb group (PcG) protein BMI1 is a key factor in regulating hematopoietic stem cell (HSC) and leukemic stem cell self-renewal and functions in the context of the Polycomb repressive complex 1 (PRC1). In humans, each of the 5 subunits of PRC1 has paralog family members of which many reside in PRC1 complexes, likely in a mutually exclusive manner, pointing toward a previously unanticipated complexity of Polycomb-mediated silencing. We used an RNA interference screening approach to test the functionality of these paralogs in human hematopoiesis. Our data demonstrate a lack of redundancy between various paralog family members, suggestive of functional diversification between PcG proteins. By using an in vivo biotinylation tagging approach followed by liquid chromatography-tandem mass spectrometry to identify PcG interaction partners, we confirmed the existence of multiple specific PRC1 complexes. We find that CBX2 is a nonredundant CBX paralog vital for HSC and progenitor function that directly regulates the expression of the cyclin-dependent kinase inhibitor p21, independently of BMI1 that dominantly controls expression of the INK4A/ARF locus. Taken together, our data show that different PRC1 paralog family members have nonredundant and locus-specific gene regulatory activities that are essential for human hematopoiesis. PMID- 23349392 TI - VWF propeptide and ratios between VWF, VWF propeptide, and FVIII in the characterization of type 1 von Willebrand disease. AB - During posttranslational modifications of von Willebrand factor (VWF), the VWF propeptide (VWFpp) is cleaved. The ratio between VWFpp and VWF antigen (VWF:Ag) and the ratio between factor VIII (FVIII:C) and VWF:Ag may be used to assess synthesis and clearance of VWF. We analyzed the contribution of VWFpp and ratios of VWFpp/VWF:Ag and FVIII:C/VWF:Ag in the pathophysiological characterization of type 1 von Willebrand disease (VWD) in the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 VWD (MCMDM-1VWD) study. The VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios were increased among patients compared with unaffected family members and healthy controls. The VWFpp/VWF:Ag ratio was higher in individuals heterozygous for missense mutations than in those heterozygous for null alleles. In contrast, the FVIII:C/VWF:Ag ratio was highest among heterozygotes for VWF null alleles. The ratios of VWFpp/VWF:Ag and FVIII:C/VWF:Ag indicate that the pathophysiological mechanisms of type 1 VWD include reduced production and accelerated clearance of VWF, but that often a combination of both mechanisms is implicated. PMID- 23349394 TI - Lenalidomide reduces survival of chronic lymphocytic leukemia cells in primary cocultures by altering the myeloid microenvironment. AB - Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental stimuli for their survival, provided for example by monocyte-derived nurse-like cells (NLCs). The immunomodulatory drug lenalidomide shows therapeutic effects in subgroups of CLL patients, and is believed to act via the microenvironment. To investigate the effects of lenalidomide on the survival support of NLCs, cocultures of monocytes and CLL cells were treated for 14 days with lenalidomide, which resulted in significantly decreased viability of CLL cells. Among the changes induced by this drug, we observed reduced expression of HLA-DR in NLCs as well as increased secretion of interleukin-10 (IL-10), indicating an altered inflammatory milieu in the cocultures. The increase in IL-10 levels lead to an induction of STAT1 phosphorylation in CLL cells and to enhanced cell-surface expression of intercellular adhesion molecule 1 and altered expression of cytoskeletal and migration-related genes. Chemotaxis assays with lenalidomide-treated CLL cells revealed an impaired migration capability. Our data show that lenalidomide reduces the survival support of NLCs for CLL cells in vitro, suggesting that this drug affects the myeloid microenvironment in CLL in vivo. Furthermore, lenalidomide acts on the migratory potential of CLL cells, which may affect circulation and homing of CLL cells in vivo. PMID- 23349396 TI - Relationship between the linguistic environments and early bilingual language development of hearing children in deaf-parented families. AB - We explored variation in the linguistic environments of hearing children of Deaf parents and how it was associated with their early bilingual language development. For that purpose we followed up the children's productive vocabulary (measured with the MCDI; MacArthur Communicative Development Inventory) and syntactic complexity (measured with the MLU10; mean length of the 10 longest utterances the child produced during videorecorded play sessions) in both Finnish Sign Language and spoken Finnish between the ages of 12 and 30 months. Additionally, we developed new methodology for describing the linguistic environments of the children (N = 10). Large variation was uncovered in both the amount and type of language input and language acquisition among the children. Language exposure and increases in productive vocabulary and syntactic complexity were interconnected. Language acquisition was found to be more dependent on the amount of exposure in sign language than in spoken language. This was judged to be related to the status of sign language as a minority language. The results are discussed in terms of parents' language choices, family dynamics in Deaf-parented families and optimal conditions for bilingual development. PMID- 23349397 TI - Understanding of emotions and false beliefs among hearing children versus deaf children. AB - Emotion understanding and theory of mind (ToM) are two major aspects of social cognition in which deaf children demonstrate developmental delays. The current study investigated these social cognition aspects in two subgroups of deaf children-those with cochlear implants who communicate orally (speakers) and those who communicate primarily using sign language (signers)-in comparison to hearing children. Participants were 53 Israeli kindergartners-20 speakers, 10 signers, and 23 hearing children. Tests included four emotion identification and understanding tasks and one false belief task (ToM). Results revealed similarities among all children's emotion labeling and affective perspective taking abilities, similarities between speakers and hearing children in false beliefs and in understanding emotions in typical contexts, and lower performance of signers on the latter three tasks. Adapting educational experiences to the unique characteristics and needs of speakers and signers is recommended. PMID- 23349395 TI - ATM-dependent spontaneous regression of early EMU-myc-induced murine B-cell leukemia depends on natural killer and T cells. AB - Mechanisms of spontaneous tumor regression have been difficult to characterize in a systematic manner due to their rare occurrence and the lack of model systems. Here, we provide evidence that early-stage B cells in EMU-myc mice are tumorigenic and sharply regress in the periphery between 41 and 65 days of age. Regression depended on CD4(+), CD8(+), NK1.1(+) cells and the activation of the DNA damage response, which has been shown to provide an early barrier against cancer. The DNA damage response can induce ligands that enhance immune recognition. Blockade of DNAM-1, a receptor for one such ligand, impaired tumor regression. Hence, EMU-myc mice provide a model to study spontaneous regression and possible mechanisms of immune evasion or suppression by cancer cells. PMID- 23349398 TI - Health literacy and community empowerment: it is more than just reading, writing and counting. AB - The concept of health literacy is evolving. The re-emergence of Freireian inspired health literacy projects moves the conceptualisation of health literacy from merely the ability to apply functional literacy skills in a health-care context to a wider ability to exert control over the determinants of health. This article presents an example of a community-based project that adopts an empowerment education model in health literacy. Based within a small indigenous community in the Philippines, participants were engaged in critical reflection to gain a better understanding of how health is conceptualised within their socio economic and political environment and its implications for practice, power relations and subjective experiences. The article concludes with the assertion that although developing health literacy skills is important, we must never lose sight of unbalanced power relations and unfair structures that hinder positive social change. PMID- 23349399 TI - Needed action in health literacy. AB - Insights for action in the relatively new field of health literacy have been constrained by the emphasis on the literacy skills of the individuals. Early studies into the relationship between literacy and health outcomes were not appropriately balanced with examinations of individuals' skills and health system demands. Most studies focused on the measures of patients' reading skills without due attention to the health tasks undertaken, the health materials used, or the skills of providers with whom patients were interacting. Furthermore, public health is founded on the epidemiologic notion of the reciprocal relationship between individuals and environments. Early studies in health literacy did not attend to context-the physical and social environment of health-care settings. New initiatives in health literacy must bring attention to the demands and expectations of health systems and to the proficiencies of the various health professionals who prepare documents and information for the public and who interact with communities and patients. PMID- 23349400 TI - Survey mode matters: adults' self-reported statistical confidence, ability to obtain health information, and perceptions of patient-health-care provider communication. AB - This study examined adults' self-reported understanding and formatting preferences of medical statistics, confidence in self-care and ability to obtain health advice or information, and perceptions of patient-health-care provider communication measured through dual survey modes (random digital dial and mail). Even while controlling for sociodemographic characteristics, significant differences in regard to adults' responses to survey variables emerged as a function of survey mode. While the analyses do not allow us to pinpoint the underlying causes of the differences observed, they do suggest that mode of administration should be carefully adjusted for and considered. PMID- 23349401 TI - African American and Latina community health workers engage PhotoPAR as a resource in a post-disaster context: Katrina at 5 years. AB - This article reports on participatory action and photo elicitation research conducted by community health workers and university-based researchers in post Katrina New Orleans between August 2007 and 2010. It documents how 11 African American and Latina women community health workers forged ties and developed a model for responding to some of the personal, familial, and community effects of this "unnatural disaster." We identify and analyze two of the health literacies they developed and deployed: (1) intragroup and intergroup empathy skills and (2) capacity to critically analyze structural causes of health inequities. We argue that the participatory processes and outcomes analyzed herein offer one possible model through which local communities and health workers can creatively respond to health disparities in post-disaster contexts. PMID- 23349403 TI - Exploration of health anxiety among individuals with diabetes: prevalence and implications. AB - Health anxiety has been infrequently examined in individuals with diabetes. In this study, individuals with Type 1 or 2 diabetes (n = 414) completed questionnaires assessing health anxiety and related constructs. Elevated health anxiety was reported by 24.1 percent of the sample and was greater among younger individuals, females, unmarried participants, and those recently diagnosed with diabetes. The construct was related to trait anxiety, fear of diabetes complications, poorer adherence to dietary and exercise self-care activities as well as lower physical quality of life. The research improves our understanding of health anxiety among individuals with diabetes. PMID- 23349402 TI - A randomized trial comparing two approaches to weight loss: differences in weight loss maintenance. AB - This study compared treatment outcomes for a new weight loss program that emphasized reducing unhealthy relationships with food, body image dissatisfaction, and internalized weight bias (New Perspectives) to a weight loss program that emphasizes environmental modification and habit formation and disruption (Transforming Your Life). Fifty-nine overweight and obese adults (body mass index >= 27 kg/m(2)) were randomly assigned to either a 12-week New Perspectives or Transforming Your Life intervention. Despite equivalent outcomes at the end of treatment, the Transforming Your Life participants were significantly more effective at maintaining their weight loss than New Perspectives participants during the 6-month no-treatment follow-up period. PMID- 23349404 TI - Metformin for patients with diabetes and concomitant renal restrictions--is there an evidence base? AB - Despite its array of benefits that comparatively outweigh alternative oral anti glycaemic agents, the ability of clinicians to prescribe metformin is restricted. There are numerous contra-indications and cautions concerning the putative risks of metformin-related side effects that necessitate cessation of metformin. Notably the often stated, yet completely unsubstantiated, heightened risk for development of lactic acidosis in the context of renal insufficiency or a kidney transplant is particularly contentious. In this article, I will critique current regulatory advice and argue for further research to evaluate the safety and efficacy of metformin use in populations where the benefits of metformin are likely to far outweigh any infinitesimal risk (such as advanced chronic kidney disease and those after kidney transplantation). The only way to settle this debate is for well-designed trials and registry analyses to ascertain the safety and efficacy of metformin in these 'high-risk' populations. That is what evidence based medicine demands and unfortunately is long overdue. PMID- 23349405 TI - Pseudomelanosis of the stomach. PMID- 23349406 TI - Death rates for acquired hypothyroidism and thyrotoxicosis in English populations (1979-2010): comparison of underlying cause and all certified causes. AB - BACKGROUND: Overt hypothyroidism and thyrotoxicosis have widespread systemic effects and are associated with increased mortality. Most death certificates that include them do not have the thyroid disease coded as the underlying cause of death. AIM: To describe regional (1979-2010) and national (1995-2010) trends in mortality rates for acquired hypothyroidism and thyrotoxicosis, analysing all certified causes of death (termed 'mentions') and not just the underlying cause. DESIGN: Analysis of death registration data. METHODS: Analysis of data for the Oxford region (mentions available from 1979) and English national data (mentions available from 1995). The data were grouped in periods defined by different national rules for selecting the underlying cause of death (1979-83, 1984-92, 1993-2000 and 2001-10) and were also analysed as single calendar years. RESULTS: Mentions mortality for acquired hypothyroidism in the Oxford region declined significantly from 1979 to 2010: the average annual percentage change (AAPC) was 2.6% (95% confidence intervals -3.5, -1.8). Most of the decrease occurred during the 1980s. The AAPC in rates for later years in England (1995-2010) was non significant at 0.2% (-0.7, 1.0). Mortality rates for thyrotoxicosis decreased significantly: the AAPC was -2.8% (-4.1, -1.5) in the Oxford region and -3.8% ( 4.7, -3.0) in England. In England, between 2001 and 2010, hypothyroidism or thyrotoxicosis was coded as the underlying cause of death on, respectively, 17 and 24% of death certificates that included them. CONCLUSION: Mortality rates for hypothyroidism and thyrotoxicosis have fallen substantially. The fall is probably wholly or mainly a result of improved care. PMID- 23349407 TI - Treatment for acute anterior cruciate ligament tear: five year outcome of randomised trial. AB - OBJECTIVE: To compare, in young active adults with an acute anterior cruciate ligament (ACL) tear, the mid-term (five year) patient reported and radiographic outcomes between those treated with rehabilitation plus early ACL reconstruction and those treated with rehabilitation and optional delayed ACL reconstruction. DESIGN: Extended follow-up of prospective randomised controlled trial. SETTING: Orthopaedic departments at two hospitals in Sweden. PARTICIPANTS: 121 young, active adults (mean age 26 years) with acute ACL injury to a previously uninjured knee. One patient was lost to five year follow-up. INTERVENTION: All patients received similar structured rehabilitation. In addition to rehabilitation, 62 patients were assigned to early ACL reconstruction and 59 were assigned to the option of having a delayed ACL reconstruction if needed. MAIN OUTCOME MEASURE: The main outcome was the change from baseline to five years in the mean value of four of the five subscales of the knee injury and osteoarthritis outcome score (KOOS(4)). Other outcomes included the absolute KOOS(4) score, all five KOOS subscale scores, SF-36, Tegner activity scale, meniscal surgery, and radiographic osteoarthritis at five years. RESULTS: Thirty (51%) patients assigned to optional delayed ACL reconstruction had delayed ACL reconstruction (seven between two and five years). The mean change in KOOS(4) score from baseline to five years was 42.9 points for those assigned to rehabilitation plus early ACL reconstruction and 44.9 for those assigned to rehabilitation plus optional delayed reconstruction (between group difference 2.0 points, 95% confidence interval -8.5 to 4.5; P=0.54 after adjustment for baseline score). At five years, no significant between group differences were seen in KOOS(4) (P=0.45), any of the KOOS subscales (P >= 0.12), SF-36 (P >= 0.34), Tegner activity scale (P=0.74), or incident radiographic osteoarthritis of the index knee (P=0.17). No between group differences were seen in the number of knees having meniscus surgery (P=0.48) or in a time to event analysis of the proportion of meniscuses operated on (P=0.77). The results were similar when analysed by treatment actually received. CONCLUSION: In this first high quality randomised controlled trial with minimal loss to follow-up, a strategy of rehabilitation plus early ACL reconstruction did not provide better results at five years than a strategy of initial rehabilitation with the option of having a later ACL reconstruction. Results did not differ between knees surgically reconstructed early or late and those treated with rehabilitation alone. These results should encourage clinicians and young active adult patients to consider rehabilitation as a primary treatment option after an acute ACL tear. TRIAL REGISTRATION: Current Controlled Trials ISRCTN84752559. PMID- 23349408 TI - Postpartum fever and shortness of breath. PMID- 23349409 TI - Learning from Winterbourne View. PMID- 23349410 TI - beta blockers for heart failure: which works best? PMID- 23349411 TI - Increased risk of preterm birth in singleton pregnancies after blastocyst versus Day 3 embryo transfer: Canadian ART Register (CARTR) analysis. AB - STUDY QUESTION: Are the fetal outcomes of singleton pregnancies that result from cleavage stage embryo transfer (ET) different from the outcomes from Day 5/6 blastocyst stage ET? SUMMARY ANSWER: There was a significantly higher risk of preterm birth (<37 weeks) in singletons after extended embryo culture (Day 5/6) compared with cleavage stage (Day 3) transfer. WHAT IS KNOWN ALREADY: Two recent studies, from Sweden and the USA, reported an increased risk of preterm birth in singleton pregnancies after Day 5/6 ET compared with Day 3 ET. The US study also showed increased early preterm births and the Swedish study showed increased fetal malformations in this group. STUDY DESIGN, SIZE AND DURATION: A retrospective cohort study was performed. Data were collected from the Canadian ART Register database for all singleton births after fresh IVF/ICSI ET cycles (2001-2009). PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 12 712 singleton births were included. Of these, 9506 resulted from a Day 3 ET and 3206 resulted from a blastocyst (Day 5/6) ET. MAIN RESULTS AND THE ROLE OF CHANCE: Preterm birth rate <37 weeks (unadjusted by potential confounding factors) was higher with Day 5/6 versus Day 3 transfers (17.2 versus 14.1%, P < 0.001). Using logistic regression analysis to adjust for confounding factors, preterm birth rate <37 weeks was the only outcome significantly increased after Day 5/6 compared with Day 3 transfer (odds ratio 1.32, 95% confidence interval 1.17 1.49). The following confounding factors were adjusted for: year of treatment (2001-2009), maternal age (continuous), parity (0 versus >=1 birth), diagnosis category, number of oocytes retrieved [<=20 versus >20 (high responder group)], insemination method (IVF versus ICSI), number of embryos transferred (1, 2 or >=3) and the presence of a vanishing twin (>=1 fetal heart on the initial ultrasonographic examination). LIMITATIONS, REASONS FOR CAUTION: Post-natal follow-up studies will be required to determine if this difference we observed translates into adverse long-term effects on these offspring. The rate of early preterm births (<32 weeks) was higher in Day 5/6 versus Day 3, but the low number of cases in this category did not have the power to show a difference (3.0 versus 2.7%, P = 0.34). WIDER IMPLICATIONS OF THE FINDINGS: We found a significantly higher risk of preterm birth (<37 weeks) in singletons after extended embryo culture (Day 5/6) compared with cleavage stage (Day 3) transfer, even when adjusting for confounding factors. Our findings are in agreement with the previous two studies; however, we did not show a difference in the very preterm deliveries (unlike the US study) or in fetal malformations (as in the Swedish study). We hypothesize that there may be a deleterious effect of prolonged in vitro embryo culture on subsequent placentation. Longer term follow-up studies will be required to determine if prolonged in vitro culture to the blastocyst stage has an adverse effect on the long-term health of offspring when compared with shorter cleavage stage culture. STUDY FUNDING/COMPETING INTEREST(S): None. PMID- 23349412 TI - New Indian visa rules exclude single people and gay couples from child surrogacy. PMID- 23349413 TI - On the edge. PMID- 23349415 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: Cricoid pressure in emergency rapid sequence induction. AB - A short-cut review was carried out to establish whether the application of cricoid pressure during the induction of general anaesthesia reduced the incidence of regurgitation and aspiration of gastric contents. One good quality review article, two studies and two abstracts provided the best evidence to answer the clinical question. The authors, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated (table 1). It is concluded that although there is a theoretical advantage to providing cricoid pressure during induction, there is little evidence of any benefit at this time. PMID- 23349416 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: Dexamethasone for reduction of migraine recurrence. AB - A short-cut review was carried out to establish whether the administration of dexamethasone reduced the risk of recurrence of migraine headaches at 24 h. Three hundred and fifteen articles were found using the reported search including two systematic reviews and meta-analyses. A total of nine trials was included between the two meta-analyses. One trial was included in both analyses from the abstract data but had subsequently been published with further patient data. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated (table 2). It is concluded that the administration of dexamethasone reduces the risk of recurrence at 24 h in patients presenting to an emergency department with a migraine headache. PMID- 23349417 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: Management of paediatric minor head injuries: safe discharge? AB - A short-cut review was carried out to establish whether the finding of a normal cranial CT scan, in a child with a history of minor head injury, a Glasgow coma scale (GCS) score of 15 and normal neurological examination could facilitate safe discharge from hospital. Ninety-eight articles were found using the reported search and a further two papers were found from the references of selected papers. A total of 11 trials were included with one prospective cohort study including 13,543 patients. The authors, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated (table 3). It is concluded that in the absence of any coagulation problems, a child who presents following a minor head injury with a GCS of 15, normal neurological examination and a normal CT scan can be safely discharged to the care of a capable parent. PMID- 23349418 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 4: Alpha blockers v calcium blockers to increase spontaneous passage of renal calculi. AB - A short cut review was carried out to establish the administration of an alpha-1 receptor antagonist or a calcium channel blocker would facilitate the most rapid and successful expulsion of a stone from a patient with uncomplicated renal colic. 597 articles were found using the reported search, of which five trials were selected as providing the best evidence to answer this question. The authors, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. It is concluded that in a patient with an uncomplicated ureteric calculus tamsulosin is more effective than nifedipine in promoting speedy and successful expulsion of the stone. PMID- 23349419 TI - Short answer question case series: symptomatic first-trimester pregnancy. PMID- 23349421 TI - Road traffic injuries in conflict areas. PMID- 23349422 TI - Palatally impacted maxillary canines: choice of surgical-orthodontic treatment method does not influence post-treatment periodontal status. A controlled prospective study. AB - SUMMARY There is lack of consensus with respect to the preferred surgical procedure for the treatment of palatally impacted maxillary canines. The aim of this study was to evaluate post-treatment periodontal status of palatally impacted canines treated by open technique with free eruption and closed flap technique and compare it with naturally erupted canines. The subjects comprised 43 patients treated for unilateral palatally impacted maxillary canines and examined 4.19+/-1.44 months (3-6 months) after removal of the fixed appliance. The group 1 comprised subjects treated by open technique with free eruption (n = 22) and group 2 by closed technique (n = 21). Post-treatment examination comprised periodontal and radiographic examination. There were no significant intergroup differences with respect to periodontal pocket depth or bone support. However, compared with contralateral quadrants with normally erupted canines, quadrants with impacted canines exhibited significant bone loss at the distal contact point of the lateral incisor and the mesial contact point of the canine. The duration of treatment was 28.41+/-4.96 months for group 1 and 32.19+/-11.73 months for group 2 (P > 0.05). The mean treatment time required to achieve eruption/extrusion of the impacted canine was 3.05+/-1.07 months for group 1 and 6.86+/-4.53 months (P < 0.01) for group 2. It is concluded that choice of surgical method is not associated with any significant differences in post treatment periodontal status of palatally impacted canines and adjacent teeth. PMID- 23349423 TI - Commentary: Haldanes and trends in phenotypic change in humans. PMID- 23349425 TI - Identifying risk factors for stillbirth. PMID- 23349424 TI - Maternal and fetal risk factors for stillbirth: population based study. AB - OBJECTIVE: To assess the main risk factors associated with stillbirth in a multiethnic English maternity population. DESIGN: Cohort study. SETTING: National Health Service region in England. POPULATION: 92,218 normally formed singletons including 389 stillbirths from 24 weeks of gestation, delivered during 2009-11. MAIN OUTCOME MEASURE: Risk of stillbirth. RESULTS: Multivariable analysis identified a significant risk of stillbirth for parity (para 0 and para >= 3), ethnicity (African, African-Caribbean, Indian, and Pakistani), maternal obesity (body mass index >= 30), smoking, pre-existing diabetes, and history of mental health problems, antepartum haemorrhage, and fetal growth restriction (birth weight below 10th customised birthweight centile). As potentially modifiable risk factors, maternal obesity, smoking in pregnancy, and fetal growth restriction together accounted for 56.1% of the stillbirths. Presence of fetal growth restriction constituted the highest risk, and this applied to pregnancies where mothers did not smoke (adjusted relative risk 7.8, 95% confidence interval 6.6 to 10.9), did smoke (5.7, 3.6 to 10.9), and were exposed to passive smoke only (10.0, 6.6 to 15.8). Fetal growth restriction also had the largest population attributable risk for stillbirth and was fivefold greater if it was not detected antenatally than when it was (32.0% v 6.2%). In total, 195 of the 389 stillbirths in this cohort had fetal growth restriction, but in 160 (82%) it had not been detected antenatally. Antenatal recognition of fetal growth restriction resulted in delivery 10 days earlier than when it was not detected: median 270 (interquartile range 261-279) days v 280 (interquartile range 273-287) days. The overall stillbirth rate (per 1000 births) was 4.2, but only 2.4 in pregnancies without fetal growth restriction, increasing to 9.7 with antenatally detected fetal growth restriction and 19.8 when it was not detected. CONCLUSION: Most normally formed singleton stillbirths are potentially avoidable. The single largest risk factor is unrecognised fetal growth restriction, and preventive strategies need to focus on improving antenatal detection. PMID- 23349426 TI - Timeliness of cancer care from diagnosis to treatment: a comparison between patients with breast, colon, rectal or lung cancer. AB - OBJECTIVE: The purpose of this study was to assess the value in measuring specific time intervals across cancer sites to identify potentially important variation in the timeliness of cancer care that may inform needed changes and/or improvements in coordination of care. DESIGN: Retrospective population-level study. Demographic and treatment information were obtained from the Alberta Cancer Registry. Date of oncologist-consult was obtained from cancer medical records. SETTING: Alberta, Canada. PARTICIPANTS: All patients diagnosed in 2005 with breast, colon, rectal or lung cancer who were residents of Alberta, Canada. MAIN OUTCOME MEASURES: (i) Number of days from diagnosis to first treatment by treatment modality and cancer site, (ii) number of days from surgery to post surgery consultation and subsequent treatment and (iii) relationship between clinical and demographic factors and the cancer-specific provincial median time for outcome measures (i) and (ii). RESULTS: Time from diagnosis to surgery, if first treatment, was ~4 months for lung cancer compared with 1-2 months for breast and colorectal cancers. Factors associated with this time interval for breast and colorectal cancers was stage at diagnosis but was region of residence for lung cancer. CONCLUSIONS: Important variation within and across cancer sites identified in the care intervals evaluated in this study provides relevant information to inform local areas for improvement. Comparisons of these intervals across healthcare systems may also provide insights into strengths of different models for coordinating care. PMID- 23349427 TI - The dynamic relationship between physical function and cognition in longitudinal aging cohorts. AB - On average, older people remember less and walk more slowly than do younger persons. Some researchers argue that this is due in part to a common biologic process underlying age-related declines in both physical and cognitive functioning. Only recently have longitudinal data become available for analyzing this claim. We conducted a systematic review of English-language research published between 2000 and 2011 to evaluate the relations between rates of change in physical and cognitive functioning in older cohorts. Physical functioning was assessed using objective measures: walking speed, grip strength, chair rise time, flamingo stand time, and summary measures of physical functioning. Cognition was measured using mental state examinations, fluid cognition, and diagnosis of impairment. Results depended on measurement type: Change in grip strength was more strongly correlated with mental state, while change in walking speed was more strongly correlated with change in fluid cognition. Examining physical and cognitive functioning can help clinicians and researchers to better identify individuals and groups that are aging differently and at different rates. In future research, investigators should consider the importance of identifying different patterns and rates of decline, examine relations between more diverse types of measures, and analyze the order in which age-related declines occur. PMID- 23349429 TI - Keratoconus diagnosis using anterior segment polarization-sensitive optical coherence tomography. AB - PURPOSE: To investigate the tissue properties of keratoconic and normal corneas in vivo by using polarization-sensitive optical coherence tomography (PS-OCT), and to evaluate early keratoconus by the area under the receiver operating characteristic curve (AUROC) and Mahalanobis distance analysis. METHODS: Thirty one eyes of 20 patients with keratoconus, 7 eyes of 7 patients with keratoconus suspect, and 25 eyes of 25 normal subjects were investigated by PS-OCT and corneal and anterior segment (CAS)-OCT. Average of en face phase retardation of the posterior surface of the cornea, curvature, videokeratographic parameters, regular and irregular astigmatism, pachymetry map, and elevation were measured. The AUROC of each parameter was calculated to evaluate the diagnostic power to detect keratoconus and keratoconus suspect. RESULTS: While in normal controls, the center of the en face phase retardation map showed low and homogeneous birefringence, in keratoconic corneas the birefringence increased with disease severity. Some keratoconus suspects had apparent high birefringence values without displaying morphologic signs of keratoconus in the anterior surface. The phase retardation values for normal, keratoconus suspect, and keratoconus subjects were, respectively, 0.20 +/- 0.06, 0.35 +/- 0.06, and 0.50 +/- 0.14 radians in 3 mm diameter and 0.29 +/- 0.22, 0.33 +/- 0.13, and 0.74 +/- 0.45 radians in 6 mm diameter. Outer morphological parameters such as curvature, videokeratographic parameters, regular and irregular astigmatism, and elevation showed high AUROCs for discriminating keratoconus from normal controls. On the other hand, using Mahalanobis distance, the AUROC of phase retardation, which represents microstructural properties of tissue, showed high value (0.989-1.000) for discriminating between keratoconus suspects and normal controls. CONCLUSIONS: Average of en face phase retardation of the posterior surface of the cornea was increased in keratoconus patients due to changes in the lamellar structure of collagen fibers. Phase retardation was sensitive with regard to discriminating keratoconus suspect and might be useful for detecting very early or even subclinical keratoconus. PMID- 23349430 TI - Correlation of OCT characteristics and retinal sensitivity in neovascular age related macular degeneration in the course of monthly ranibizumab treatment. AB - PURPOSE: To evaluate the functional treatment response 3 months and 12 months after monthly ranibizumab in neovascular age-related macular degeneration (NAMD). METHODS: Twenty-six eyes showing treatment-naive NAMD were examined with the Heidelberg Spectralis OCT (SD-OCT) and the Nidek MP-1 microperimeter (MP) at baseline, after 3 months, and after 12 months of monthly ranibizumab therapy. Each test point of light sensitivity was transferred to the corresponding location on SD-OCT, and subsequently the microperimetric results were evaluated with respect to the following oct findings: neovascular complex (NVC), subretinal fluid (SRF), intraretinal fluid (IRF), intraretinal cystoid space (IRCS), serous pigment epithelium detachment (SPED), and fibrovascular pigment epithelium detachment (FPED). RESULTS: Loci of an initial NVC improved significantly from a mean retinal sensitivity value of 2.6 dB +/- 0.8 dB at baseline to 7.4 dB +/- 0.9 dB (P < 0.0001) at month 12. Initial SRF, IRF, and IRCS improved significantly from a mean value of 5.1 dB +/- 0.9 dB to 12.4 dB +/- 0.9 dB (P < 0.0001), 4.0 dB +/-1.0 dB to 9.3 dB +/- 0.9 dB (P < 0.0001), and 3.4 dB +/- 0.9 dB to 8.2 dB +/- 0.9 dB (P < 0.0001), respectively. An initial SPED improved significantly from a mean retinal sensitivity value of 1.9 dB +/- 1.1 dB at baseline to 9.4 dB +/- 1.1 dB (P < 0.0001) at month 12; a FPED improved significantly from 5.2 dB +/- 0.9 dB at baseline to 7.6 dB +/- 0.9 dB (P < 0.0001) at month 12. CONCLUSIONS: Functional benefit could be detected at all locations of macular pathology, with a lower benefit in the case of FPED and in the case of additional IRCS, and a marked benefit for all types of macular edema. (https://eudract.ema.europa.eu/, number 2006-005684-26.). PMID- 23349431 TI - Proteomics and phosphoproteomics analysis of human lens fiber cell membranes. AB - PURPOSE: The human lens fiber cell insoluble membrane fraction contains important membrane proteins, cytoskeletal proteins, and cytosolic proteins that are strongly associated with the membrane. The purpose of this study was to characterize the lens fiber cell membrane proteome and phosphoproteome from human lenses. METHODS: HPLC-mass spectrometry-based multidimensional protein identification technology (MudPIT), without or with phosphopeptide enrichment, was applied to study the proteome and phosphoproteome of lens fiber cell membranes, respectively. RESULTS: In total, 951 proteins were identified, including 379 integral membrane and membrane-associated proteins. Enriched gene categories and pathways based on the proteomic analysis include carbohydrate metabolism (glycolysis/gluconeogenesis, pentose phosphate pathway, pyruvate metabolism), proteasome, cell-cell signaling and communication (GTP binding, gap junction, focal adhesion), glutathione metabolism, and actin regulation. The combination of TiO(2) phosphopeptide enrichment and MudPIT analysis revealed 855 phosphorylation sites on 271 proteins, including 455 phosphorylation sites that have not been previously identified. PKA, PKC, CKII, p38MAPK, and RSK are predicted as the major kinases for phosphorylation on the sites identified in the human lens membrane fraction. CONCLUSIONS: The results presented herein significantly expand the characterized proteome and phosphoproteome of the human lens fiber cell and provide a valuable reference for future research in studies of lens development and disease. PMID- 23349432 TI - Semiautomated segmentation of the choroid in spectral-domain optical coherence tomography volume scans. AB - PURPOSE: Changes in the choroid, in particular its thickness, are believed to be of importance in the pathophysiology of a number of retinal diseases. The purpose of this study was to adapt the graph search algorithm to semiautomatically identify the choroidal layer in spectral-domain optical coherence tomography (SD OCT) volume scans and compare its performance to manual delineation. METHODS: A graph-based multistage segmentation approach was used to identify the choroid, defined as the layer between the outer border of the RPE band and the choroid sclera junction. Thirty randomly chosen macular SD-OCT (1024 * 37 * 496 voxels, Heidelberg Spectralis) volumes were obtained from 20 healthy subjects and 10 subjects with non-neovascular AMD. The positions of the choroidal borders and resultant thickness were compared with consensus manual delineation performed by two graders. For consistency of the statistical analysis, the left eyes were horizontally flipped in the x-direction. RESULTS: The algorithm-defined position of the outer RPE border and choroid-sclera junction was consistent with the manual delineation, resulting in highly correlated choroidal thickness values with r = 0.91 to 0.93 for the healthy subjects and 0.94 for patients with non neovascular AMD. Across all cases, the mean and absolute differences between the algorithm and manual segmentation for the outer RPE boundary was -0.74 +/- 3.27 MUm and 3.15 +/- 3.07 MUm; and for the choroid-sclera junction was -3.90 +/- 15.93 MUm and 21.39 +/- 10.71 MUm. CONCLUSIONS: Excellent agreement was observed between the algorithm and manual choroidal segmentation in both normal eyes and those with non-neovascular AMD. The choroid was thinner in AMD eyes. Semiautomated choroidal thickness calculation may be useful for large-scale quantitative studies of the choroid. PMID- 23349428 TI - Can infections cause Alzheimer's disease? AB - Late-onset Alzheimer's disease (AD) is the most prevalent cause of dementia among older adults, yet more than a century of research has not determined why this disease develops. One prevailing hypothesis is that late-onset AD is caused by infectious pathogens, an idea widely studied in both humans and experimental animal models. This review examines the infectious AD etiology hypothesis and summarizes existing evidence associating infectious agents with AD in humans. The various mechanisms through which different clinical and subclinical infections could cause or promote the progression of AD are considered, as is the concordance between putative infectious agents and the epidemiology of AD. We searched the PubMed, Web of Science, and EBSCO databases for research articles pertaining to infections and AD and systematically reviewed the evidence linking specific infectious pathogens to AD. The evidence compiled from the literature linking AD to an infectious cause is inconclusive, but the amount of evidence suggestive of an association is too substantial to ignore. Epidemiologic, clinical, and basic science studies that could improve on current understanding of the associations between AD and infections and possibly uncover ways to control this highly prevalent and debilitating disease are suggested. PMID- 23349434 TI - Estimation of ocular rigidity in glaucoma using ocular pulse amplitude and pulsatile choroidal blood flow. AB - PURPOSE: Theoretical models and animal studies have suggested that scleral rigidity plays an important role in the pathogenesis of glaucoma. The aim of this study was to present a noninvasive technique for estimating ocular rigidity (E) in vivo, and to compare the estimated rigidity between patients with open-angle glaucoma (OAG); ocular hypertension (OHT); suspect glaucomatous disc (GS); and normal subjects (N). We hypothesized that OHT patients would have higher rigidity. METHODS: All patients underwent measurements of ocular pulse amplitude (OPA) using dynamic contour tonometry, pulsatile choroidal blood flow (ChBFP) using laser Doppler flowmetry; axial length (AL); and assessment of automated visual field mean deviation (MD). The ratio between OPA and ChBFP was calculated according to the Friedenwald's equation of ocular rigidity. The calculated ratio is denoted as (ER). The average ER values of the four diagnostic groups were compared using nonparametric tests. The relationship between ER and other ocular and systemic factors was examined using correlation and regression analysis. RESULTS: A total of 257 subjects were included in the study (56 N, 108 OAG, 48 GS, and 45 OHT). ER correlated negatively with AL and positively with MD, signifying that a lower rigidity was associated with a longer eye and a worse (more negative) MD. ER was also found to be highest in OHT (0.235 +/- 0.16) and lowest in OAG (0.188 +/- 0.14; P = 0.01). CONCLUSIONS: Estimated coefficient of ocular rigidity by OPA and ChBFP suggested that glaucoma patients had the lowest rigidity and OHT the highest. It supports the idea that a more compliant ocular shell may predispose the optic nerve head to intraocular pressure (IOP)-related damage. PMID- 23349435 TI - New crosslinkers for electrospun chitosan fibre mats. Part II: mechanical properties. AB - Few studies exist on the mechanical performance of crosslinked electrospun chitosan (CS) fibre mats. In this study, we show that the mat structure and mechanical performance depend on the different crosslinking agents genipin, epichlorohydrin (ECH), and hexamethylene-1,6-diaminocarboxysulphonate (HDACS), as well as the post-electrospinning heat and base activation treatments. The mat structure was imaged by field emission scanning electron microscopy and the mechanical performance was tested in tension. The elastic modulus, tensile strength, strain at failure and work to failure were found to range from 52 to 592 MPa, 2 to 30 MPa, 2 to 31 per cent and 0.041 to 3.26 MJ m(-3), respectively. In general, neat CS mats were found to be the stiffest and the strongest, though least ductile, while CS-ECH mats were the least stiff, weakest, but the most ductile, and CS-HDACS fibre mats exhibited intermediary mechanical properties. The mechanical performance of the mats is shown to reflect differences in the fibre diameter, number of fibre-fibre contacts formed within the mat, as well as varying intermolecular bonding and moisture content. The findings reported here complement the chemical properties of the mats, described in part I of this study. PMID- 23349433 TI - Series length used during trend analysis affects sensitivity to changes in progression rate in the ocular hypertension treatment study. AB - PURPOSE: Trend analysis techniques to detect glaucomatous progression typically assume a constant rate of change. This study uses data from the Ocular Hypertension Treatment Study to assess whether this assumption decreases sensitivity to changes in progression rate, by including earlier periods of stability. METHODS: Series of visual fields (mean 24 per eye) completed at 6 month intervals from participants randomized initially to observation were split into subseries before and after the initiation of treatment (the "split-point"). The mean deviation rate of change (MDR) was derived using these entire subseries, and using only the window length (W) tests nearest the split-point, for different window lengths of W tests. A generalized estimating equation model was used to detect changes in MDR occurring at the split-point. RESULTS: Using shortened subseries with W = 7 tests, the MDR slowed by 0.142 dB/y upon initiation of treatment (P < 0.001), and the proportion of eyes showing "rapid deterioration" (MDR <-0.5 dB/y with P < 5%) decreased from 11.8% to 6.5% (P < 0.001). Using the entire sequence, no significant change in MDR was detected (P = 0.796), and there was no change in the proportion of eyes progressing (P = 0.084). Window lengths 6 <= W <= 9 produced similar benefits. CONCLUSIONS: Event analysis revealed a beneficial treatment effect in this dataset. This effect was not detected by linear trend analysis applied to entire series, but was detected when using shorter subseries of length between six and nine fields. Using linear trend analysis on the entire field sequence may not be optimal for detecting and monitoring progression. Nonlinear analyses may be needed for long series of fields. (ClinicalTrials.gov number, NCT00000125.). PMID- 23349436 TI - Population dynamics of normal and leukaemia stem cells in the haematopoietic stem cell niche show distinct regimes where leukaemia will be controlled. AB - Haematopoietic stem cells (HSCs) are responsible for maintaining immune cells, red blood cells and platelets throughout life. HSCs must be located in their ecological niche (the bone marrow) to function correctly, that is, to regenerate themselves and their progeny; the latter eventually exit the bone marrow and enter circulation. We propose that cells with oncogenic potential cancer/leukaemia stem cells (LSC)-and their progeny will also occupy this niche. Mathematical models, which describe the dynamics of HSCs, LSCs and their progeny allow investigation into the conditions necessary for defeating a malignant invasion of the niche. Two such models are developed and analysed here. To characterize their behaviour, we use an inferential framework that allows us to study regions in parameter space that give rise to desired behaviour together with an assessment of the robustness of the dynamics. Using this approach, we map out conditions under which HSCs can outcompete LSCs. In therapeutic applications, we clearly want to drive haematopoiesis into such regimes and the current analysis provide some guidance as to how we can identify new therapeutic targets. Our results suggest that maintaining a viable population of HSCs and their progenies in the niche may often already be nearly sufficient to eradicate LSCs from the system. PMID- 23349437 TI - Tracking the long-distance dispersal of marine organisms: sensitivity to ocean model resolution. AB - Ocean circulation models are widely used to simulate organism transport in the open sea, where challenges of directly tracking organisms across vast spatial and temporal scales are daunting. Many recent studies tout the use of 'high resolution' models, which are forced with atmospheric data on the scale of several hours and integrated with a time step of several minutes or seconds. However, in many cases, the model's outputs that are used to simulate organism movement have been averaged to considerably coarser resolutions (e.g. monthly mean velocity fields). To examine the sensitivity of tracking results to ocean circulation model output resolution, we took the native model output of one of the most sophisticated ocean circulation models available, the Global Hybrid Coordinate Ocean Model, and averaged it to commonly implemented spatial and temporal resolutions in studies of basin-scale dispersal. Comparisons between simulated particle trajectories and in situ near-surface drifter trajectories indicated that 'over averaging' model output yields predictions inconsistent with observations. Further analyses focused on the dispersal of juvenile sea turtles indicate that very different inferences regarding the pelagic ecology of these animals are obtained depending on the resolution of model output. We conclude that physical processes occurring at the scale of days and tens of kilometres should be preserved in ocean circulation model output to realistically depict the movement marine organisms and the resulting ecological and evolutionary processes. PMID- 23349438 TI - Yeast gene CMR1/YDL156W is consistently co-expressed with genes participating in DNA-metabolic processes in a variety of stringent clustering experiments. AB - The binarization of consensus partition matrices (Bi-CoPaM) method has, among its unique features, the ability to perform ensemble clustering over the same set of genes from multiple microarray datasets by using various clustering methods in order to generate tunable tight clusters. Therefore, we have used the Bi-CoPaM method to the most synchronized 500 cell-cycle-regulated yeast genes from different microarray datasets to produce four tight, specific and exclusive clusters of co-expressed genes. We found 19 genes formed the tightest of the four clusters and this included the gene CMR1/YDL156W, which was an uncharacterized gene at the time of our investigations. Two very recent proteomic and biochemical studies have independently revealed many facets of CMR1 protein, although the precise functions of the protein remain to be elucidated. Our computational results complement these biological results and add more evidence to their recent findings of CMR1 as potentially participating in many of the DNA-metabolism processes such as replication, repair and transcription. Interestingly, our results demonstrate the close co-expressions of CMR1 and the replication protein A (RPA), the cohesion complex and the DNA polymerases alpha, delta and epsilon, as well as suggest functional relationships between CMR1 and the respective proteins. In addition, the analysis provides further substantial evidence that the expression of the CMR1 gene could be regulated by the MBF complex. In summary, the application of a novel analytic technique in large biological datasets has provided supporting evidence for a gene of previously unknown function, further hypotheses to test, and a more general demonstration of the value of sophisticated methods to explore new large datasets now so readily generated in biological experiments. PMID- 23349439 TI - Predictability of spatio-temporal patterns in a lattice of coupled FitzHugh Nagumo oscillators. AB - In many biological systems, variability of the components can be expected to outrank statistical fluctuations in the shaping of self-organized patterns. In pioneering work in the late 1990s, it was hypothesized that a drift of cellular parameters (along a 'developmental path'), together with differences in cell properties ('desynchronization' of cells on the developmental path) can establish self-organized spatio-temporal patterns (in their example, spiral waves of cAMP in a colony of Dictyostelium discoideum cells) starting from a homogeneous state. Here, we embed a generic model of an excitable medium, a lattice of diffusively coupled FitzHugh-Nagumo oscillators, into a developmental-path framework. In this minimal model of spiral wave generation, we can now study the predictability of spatio-temporal patterns from cell properties as a function of desynchronization (or 'spread') of cells along the developmental path and the drift speed of cell properties on the path. As a function of drift speed and desynchronization, we observe systematically different routes towards fully established patterns, as well as strikingly different correlations between cell properties and pattern features. We show that the predictability of spatio-temporal patterns from cell properties contains important information on the pattern formation process as well as on the underlying dynamical system. PMID- 23349440 TI - High-dose induction liposomal amphotericin B followed by de-escalation is effective in experimental Aspergillus terreus pneumonia. AB - OBJECTIVES: Aspergillus terreus is considered to be resistant to amphotericin B (AMB). However, it is unknown whether higher daily doses of liposomal AMB (L-AMB) can overcome this resistance in vivo. We evaluated the efficacy and total lung homogenate AMB concentrations of escalating intravenous doses of L-AMB (3-20 mg/kg daily) versus an induction-de-escalation dosing strategy (10 mg/kg/day *3 days, then 3 mg/kg/day) in an experimental neutropenic murine model of A. terreus pneumonia. METHODS: BALB/c mice were rendered neutropenic with cyclophosphamide and administered cortisone acetate prior to intranasal inoculation (3.5 * 10(6) conidia) with A. terreus (Etest MIC 8 mg/L). Mice were then treated with L-AMB regimens for 5-7 days. The efficacy was assessed by animal survival and quantitative PCR lung fungal burden. Total AMB lung homogenate concentrations were determined by HPLC. RESULTS: Compared with untreated controls, 10 mg/kg/day L-AMB prolonged survival (mean >7 versus 3-4 days, P < 0.003) and reduced A. terreus lung fungal burden (median log10 conidial DNA 5.0 versus 6.7, P < 0.05). Daily L-AMB regimens >10 mg/kg/day were associated with poorer survival and higher lung fungal burden. The induction-de-escalation strategy of 10 mg/kg/day *3 days followed by 3 mg/kg/day was as effective as 10 mg/kg daily dosing, and resulted in higher mean AMB lung homogenate concentrations compared with a continuous 10 mg/kg regimen (23.2 +/- 6.7 versus 16.4 +/- 4.4 MUg/g, P = 0.09). CONCLUSIONS: A high-dose induction-de-escalation L-AMB dosing strategy was an effective treatment for experimental A. terreus pneumonia in neutropenic mice. PMID- 23349441 TI - Genetic characterization of tigecycline resistance in clinical isolates of Enterobacter cloacae and Enterobacter aerogenes. AB - OBJECTIVES: The intrinsically encoded ramA gene has been linked to tigecycline resistance through the up-regulation of efflux pump AcrAB in Enterobacter cloacae. The molecular basis for increased ramA expression in E. cloacae and Enterobacter aerogenes, as well as the role of AraC regulator rarA, has not yet been shown. To ascertain the intrinsic molecular mechanism(s) involved in tigecycline resistance in Enterobacter spp., we analysed the expression levels of ramA and rarA and corresponding efflux pump genes acrAB and oqxAB in Enterobacter spp. clinical isolates. METHODS: The expression levels of ramA, rarA, oqxA and acrA were tested by quantitative real-time RT-PCR. The ramR open reading frames of the ramA-overexpressing strains were sequenced; strains harbouring mutations were transformed with wild-type ramR to study altered ramA expression and tigecycline susceptibility. RESULTS: Tigecycline resistance was mediated primarily by increased ramA expression in E. cloacae and E. aerogenes. Only the ramA-overexpressing E. cloacae isolates showed increased rarA and oqxA expression. Upon complementation with wild-type ramR, all Enterobacter spp. containing ramR mutations exhibited decreased ramA and acrA expression and increased tigecycline susceptibility. Exceptions were one E. cloacae strain and one E. aerogenes strain, where a decrease in ramA levels was not accompanied by lower acrA expression. CONCLUSIONS: Increased ramA expression due to ramR deregulation is the primary mediator of tigecycline resistance in clinical isolates of E. cloacae and E. aerogenes. However, some ramA-overexpressing isolates do not show changes in ramR, suggesting alternate pathways of ramA regulation; the rarA regulator and the oqxAB efflux pump may also play a role in tigecycline resistance in E. cloacae. PMID- 23349442 TI - Three-dimensional culture model to distinguish normal from malignant human bronchial epithelial cells. AB - In the present study, we have developed an in vitro three-dimensional model to differentiate normal lung cells from lung cancer cells in order to study the mechanisms resulting in lung cancer. Using a reconstituted laminin-rich basement membrane (Matrigel), we were able to culture normal human bronchial epithelial cells and a subset of malignant cells. The two cell types can be readily distinguished by the ability of normal cells to express a structurally and functionally differentiated phenotype within Matrigel. Human bronchial epithelial cells embedded in Matrigel as single cells were able to form multi-cellular spherical colonies with a final size close to that of true acini in situ. Sections of mature spheres revealed a central lumen surrounded by polarised epithelial cells. In contrast, none of malignant cells tested, cell lines and lung biopsies responded to basement membrane by lumen formation. These results demonstrated that this in vitro glandular tumour model can be useful for studies of bronchial oncogene. Indeed, these findings may provide the basis for a rapid assay to discriminate normal human bronchial epithelial cells from their malignant counterparts. In conclusion, the three-dimensional tumour bronchial epithelial acinar-like sphere represents a novel in vitro model to further investigate pathophysiological functions resulting in lung cancer. PMID- 23349443 TI - Sample sizes for clinical trials using sputum eosinophils as a primary outcome. AB - Clinical trials do not report sputum eosinophil data in a consistent method and this makes it difficult to compare across studies and to evaluate the sample sizes estimated in these studies. The objectives of the paper are: 1) to systematically review reporting of effect size and sample calculations in randomised controlled trials using sputum eosinophil count as a primary outcome and 2) to illustrate sample size estimation under different methods of data representation using data from an effective anti-eosinophil treatment strategy (mepolizumab). Randomised controlled trials in adults (excluding allergen provocation models) of treatment of asthma and chronic obstructive pulmonary disease for the past 10 years were searched in Ovid MEDLINE and 20 studies were identified that met all the inclusion criteria. Only nine studies discussed sample size calculation. Change from baseline was used as an outcome in 11 studies and was expressed as change in absolute percentage count, percentage change from baseline or as fold changes. Assuming a minimal clinically important reduction of 15% in absolute terms, 18 subjects in each arm will be required to achieve 80% power using an ANCOVA analysis, which we recommend, to detect significance with an alpha error of 0.05. PMID- 23349444 TI - Biomarker-enhanced triage in respiratory infections: a proof-of-concept feasibility trial. AB - Concerns about inadequate performance and complexity limit routine use of clinical risk scores in lower respiratory tract infections. Our aim was to study feasibility and effects of adding the biomarker proadrenomedullin (proADM) to the confusion, urea>7 mmol.L(-1), respiratory rate>=30 breaths.min(-1), blood pressure<90 mmHg (systolic) or <=60 mmHg (diastolic), age>=65 years (CURB-65) score on triage decisions and length of stay. In a randomised controlled proof-of concept intervention trial, triage and discharge decisions were made for adults with lower respiratory tract infection according to interprofessional assessment using medical and nursing risk scores either without (control group) or with (proADM group) knowledge of proADM values, measured on admission, and on days 3 and 6. An adjusted generalised linear model was calculated to investigate the effect of our intervention. On initial presentation the algorithms were overruled in 123 (39.3%) of the cases. Mean length of stay tended to be shorter in the proADM (n=154, 6.3 days) compared with the control group (n=159, 6.8 days; adjusted regression coefficient -0.19, 95% CI -0.41-0.04; p=0.1). This trend was robust in subgroup analyses and for overall length of stay within 90 days (7.2 versus 7.9 days; adjusted regression coefficient -0.18, 95% CI -0.40-0.05; p=0.13). There were no differences in adverse outcomes or readmission. Logistic obstacles and overruling are major challenges to implement biomarker-enhanced algorithms in clinical settings and need to be addressed to shorten length of stay. PMID- 23349445 TI - Dried plasma spots in the diagnosis of tuberculosis: IP-10 release assay on filter paper. AB - Interferon (IFN)-gamma release assays (IGRAs) are probably the most accurate tests for the detection of latent Mycobacterium tuberculosis infection, but IGRAs are labour intensive and the transport of samples over longer distances is difficult. IFN-gamma-induced protein (IP)-10 is expressed at 100-fold higher levels than IFN-gamma, and IP-10 release assays have comparable performance to IGRAs. The aim of this study was to explore the diagnostic potential of a novel IP-10 release assay based on dried plasma spots (DPS). The presence of IP-10 and IFN-gamma was determined in plasma and in DPS by ELISA. Diagnostic algorithms for plasma and DPS tests for IP-10 were developed on a training cohort comprising 60 tuberculosis (TB) patients and 59 healthy controls. Diagnostic accuracy was assessed in a validation cohort comprising 78 TB patients and 98 healthy controls. Plasma was measured in Spain and DPS samples were sent to Denmark using the conventional postal service for analysis. IP-10 was readily detectable in both plasma and DPS, and correlation was excellent (r(2) = 0.95). QuantiFERON-TB Gold In-Tube (QFT-TB) and IP-10 in DPS and plasma rendered comparable sensitivity (78%, 82% and 84%, respectively), specificity (100%, 97% and 97%, respectively) and indeterminate rates (p>0.55). The DPS-based IP-10 test has comparable diagnostic accuracy to the QFT-TB and samples can be sent via conventional mail over long distances for analysis without affecting the results. PMID- 23349447 TI - Airway and systemic inflammation in obese children with asthma. AB - Obese asthma presents via altered airway and systemic inflammation in adults. This has not been comprehensively described in children. The aim of the present study was to compare airway and systemic inflammation in obese and nonobese asthmatic children and controls. In a cross-sectional study, children aged 8-17 years were assigned to one of four groups: obese asthma (OA, n=74); nonobese asthma (NOA, n=249); obese control (OC, n=9); nonobese control (NOC, n=29). Lung function, and both sputum and systemic inflammatory biomarkers were measured. Non eosinophilic asthma was more prevalent among OA females (60.0%) versus OA males (30.8%). However, there were no differences in the percentage of eosinophils or neutrophils between OA and NOA. Leptin was higher in OC, but not OA, versus NOA and NOC, while adiponectin was reduced in OA versus NOC only. Expiratory reserve volume was reduced in OA, versus NOC. Residual volume (RV) and RV/total lung capacity were reduced in OC versus OA, and OC versus OA and NOA, respectively. Obesity was associated with significant lung restriction in children with and without asthma. Obesity was not associated with significantly altered airway or systemic inflammation in asthmatic children. However, the higher prevalence of non-eosinophilic asthma in female obese asthmatics, compared to males, warrants further investigation. PMID- 23349446 TI - High-risk patients following hospitalisation for an acute exacerbation of COPD. AB - The aim of this study was to assess long-term mortality and predictive factors of death after hospital admission for acute exacerbation of chronic obstructive pulmonary disease (COPD). 1824 patients (23.2% female; mean age 70.3+/-11.3 years) consecutively admitted for acute exacerbation of COPD in the respiratory medicine departments of 68 general hospitals between October 2006 and June 2007 were prospectively enrolled in a follow-up cohort. Their vital status was documented between October 2010 and April 2011. Vital status was available for 1750 patients (95.9%), among whom 787 (45%) died during follow-up. Multivariate analysis found that age (60-80 years and >=80 years versus <60 years, relative risk 2.99, 95% CI 2.31-3.89), lower body mass index (25-30 kg.m(-2) versus <=20 kg.m(-2), relative risk 0.80, 95% CI 0.66-0.97), lung cancer (relative risk 2.08, 95% CI 1.43-3.01), cardiovascular comorbidity (relative risk 1.35, 95% CI 1.16 1.58), previous hospital admissions for acute exacerbation of COPD (four or more versus none, relative risk 1.91, 95% CI 1.44-2.53), use of accessory respiratory muscles (relative risk 1.19, 95% CI 1.01-1.40) or lower-limb oedema (relative risk 1.74, 95% CI (1.44-2.12)) at admission and treatment by long-term oxygen therapy at discharge (relative risk 2.09, 95% CI 1.79-2.45) were independent risk factors of death. Mortality rate during the 4 years following hospital admission for acute exacerbation of COPD was high (45%). Simple clinical information relating to respiratory and general status can help in identifying high-risk patients and targeting more intensive follow-up and care. Interestingly, cardiovascular comorbidities and past hospitalisations for acute exacerbation of COPD, but not forced expiratory volume in 1 s, independently predicted the risk of death. PMID- 23349448 TI - Early patterns of wheezing in asthmatic and nonasthmatic children. AB - The aim of this study was to describe the time patterns of wheezing in both asthmatic and nonasthmatic children during the first 36 months of life, and to determine whether there are asthma-related breakpoints in the incidence of wheezing. Data from a historical cohort of children followed from birth to 6 years (SLAM cohort) were used. Wheezing episodes until 36 months and asthma at 6 years were both recorded by a doctor. Monthly mean incidence rate of wheezing and rate ratio were calculated. Joinpoint regression models were built to identify breakpoints in the risk of wheeze. Complete information was available for 3739 children. Wheezing in the first 36 months was more frequent in asthmatic than in nonasthmatic children (rate ratio 2.62, 95% CI 1.81-3.78). Differences were appreciable within the first months and increased steadily thereafter because of a persistently high rate in asthmatic children. No breakpoint in the rate ratio could be identified. Asthmatic children exhibited a one-phase curve of incidence and nonasthmatic children exhibited a two-phase curve. However, children with allergic asthma also displayed a two-phase curve. There is no identifiable breakpoint during the first 36 months of life at which the incidence of wheezing in asthmatic children begins to stand out. PMID- 23349449 TI - Lung function indices for predicting mortality in COPD. AB - Chronic obstructive pulmonary disease (COPD) is characterised by high morbidity and mortality. It remains unknown which aspect of lung function carries the most prognostic information and if simple spirometry is sufficient. Survival was assessed in COPD outpatients whose data had been added prospectively to a clinical audit database from the point of first full lung function testing including spirometry, lung volumes, gas transfer and arterial blood gases. Variables univariately associated with survival were entered into a multivariate Cox proportional hazard model. 604 patients were included (mean +/- SD age 61.9 +/- 9.7 years; forced expiratory volume in 1 s 37 +/- 18.1% predicted; 62.9% males); 229 (37.9%) died during a median follow-up of 83 months. Median survival was 91.9 (95% CI 80.8-103) months with survival rates at 3 and 5 years 0.83 and 0.66, respectively. Carbon monoxide transfer factor % pred quartiles (best quartile (>51%): HR 0.33, 95% CI 0.172-0.639; and second quartile (51-37.3%): HR 0.52, 95% CI 0.322-0.825; versus lowest quartile (<27.9%)), age (HR 1.04, 95% CI 1.02-1.06) and arterial oxygen partial pressure (HR 0.85, 95% CI 0.77-0.94) were the only parameters independently associated with mortality. Measurement of gas transfer provides additional prognostic information compared to spirometry in patients under hospital follow-up and could be considered routinely. PMID- 23349451 TI - Anaesthesia for positron emission tomography scanning of animal brains. AB - Positron emission tomography (PET) provides a means of studying physiological and pharmacological processes as they occur in the living brain. Mice, rats, dogs, cats, pigs and non-human primates are often used in studies using PET. They are commonly anaesthetized with ketamine, propofol or isoflurane in order to prevent them from moving during the imaging procedure. The use of anaesthesia in PET studies suffers, however, from the drawback of possibly altering central neuromolecular mechanisms. As a result, PET findings obtained in anaesthetized animals may fail to correctly represent normal properties of the awake brain. Here, we review findings of PET studies carried out either in both awake and anaesthetized animals or in animals given at least two different anaesthetics. Such studies provide a means of estimating the extent to which anaesthesia affects the outcome of PET neuroimaging in animals. While no final conclusion can be drawn concerning the 'best' general anaesthetic for PET neuroimaging in laboratory animals, such studies provide findings that can enhance an understanding of neurobiological mechanisms in the living brain. PMID- 23349450 TI - Diagnosing pneumonia in patients with acute cough: clinical judgment compared to chest radiography. AB - Pneumonia is often diagnosed and treated empirically. We set out to determine the diagnostic accuracy of clinical judgment based on signs and symptoms to detect radiographic pneumonia in patients presenting with acute cough in primary care. In 2810 European patients with acute cough, general practitioners (GPs) recorded whether they considered pneumonia to be present ("yes" or "no") immediately after history and physical examination. Chest radiography was performed within 1 week by local radiologists blind to other patient characteristics. 140 patients had radiographic pneumonia (5%), of whom 41 (29%) had been diagnosed as such. 31 (1%) patients had a clinical diagnosis that was not confirmed by radiography (n=2670). In clinically suspected pneumonia, 57% of subjects were subsequently diagnosed with radiographic pneumonia. Negative predictive value (NPV), sensitivity and specificity of GPs' clinical judgment were 96%, 29% and 99%, respectively. Compared to patients with a clinical diagnosis of pneumonia, less severe symptoms were found in radiographic pneumonia cases not suspected clinically (p<0.05). The predictive values of GPs' clinical judgment, particularly the high NPVs, are helpful in routine care. Nonetheless, the majority of diagnoses of radiographic pneumonias was not suspected on clinical grounds. There is a need to further support the detection of clinically relevant pneumonia in primary care. PMID- 23349452 TI - Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience. AB - AIMS: With more than 40 dilated cardiomyopathy (DCM)-related genes known, genetic analysis of patients with idiopathic DCM is costly and time-consuming. We describe the yield from genetic analysis in DCM patients in a large Dutch cohort. METHODS AND RESULTS: We collected cardiological and neurological evaluations, family screenings, and genetic analyses for 418 index patients with idiopathic DCM. We identified 35 (putative) pathogenic mutations in 82 index patients (20%). The type of DCM influenced the yield, with mutations found in 25% of familial DCM cases, compared with 8% of sporadic DCM cases and 62% of cases where DCM was accompanied by neuromuscular disease. A PLN founder mutation (43 cases) and LMNA mutations (19 cases, 16 different mutations) were most prevalent and often demonstrated a specific phenotype. Other mutations were found in: MYH7, DES, TNNT2, DMD, TPM1, DMPK, SCN5A, SGCB (homozygous), and TNNI3. After a median follow-up of 40 months, the combined outcome of death from any cause, heart transplantation, or malignant ventricular arrhythmias in patients with a mutation was worse than in those without an identified mutation (hazard ratio 2.0, 95% confidence interval 1.4-3.0). This seems to be mainly attributable to a high prevalence of malignant ventricular arrhythmias and end-stage heart failure in LMNA and PLN mutation carriers. CONCLUSION: The yield of identified mutations in DCM index patients with clinical clues, such as associated neuromuscular disease or familial occurrence, is higher compared with those without these clues. For sporadic DCM, specific clinical characteristics may be used to select cases for DNA analysis. PMID- 23349453 TI - A simplified method for determining phenotypic traits in patients with obstructive sleep apnea. AB - We previously published a method for measuring several physiological traits causing obstructive sleep apnea (OSA). The method, however, had a relatively low success rate (76%) and required mathematical modeling, potentially limiting its application. This paper presents a substantial revision of that technique. To make the measurements, continuous positive airway pressure (CPAP) was manipulated during sleep to quantify 1) eupneic ventilatory demand, 2) the level of ventilation at which arousals begin to occur, 3) ventilation off CPAP (nasal pressure = 0 cmH(2)O) when the pharyngeal muscles are activated during sleep, and 4) ventilation off CPAP when the pharyngeal muscles are relatively passive. These traits could be determined in all 13 participants (100% success rate). There was substantial intersubject variability in the reduction in ventilation that individuals could tolerate before having arousals (difference between ventilations #1 and #2 ranged from 0.7 to 2.9 liters/min) and in the amount of ventilatory compensation that individuals could generate (difference between ventilations #3 and #4 ranged from -0.5 to 5.5 liters/min). Importantly, the measurements accurately reflected clinical metrics; the difference between ventilations #2 and #3, a measure of the gap that must be overcome to achieve stable breathing during sleep, correlated with the apnea-hypopnea index (r = 0.9, P < 0.001). An additional procedure was added to the technique to measure loop gain (sensitivity of the ventilatory control system), which allowed arousal threshold and upper airway gain (response of the upper airway to increasing ventilatory drive) to be quantified as well. Of note, the traits were generally repeatable when measured on a second night in 5 individuals. This technique is a relatively simple way of defining mechanisms underlying OSA and could potentially be used in a clinical setting to individualize therapy. PMID- 23349455 TI - Automated open flow respirometry in continuous and long-term measurements: design and principles. AB - Sustaining high-quality respirometry measurements on animals for estimating metabolic rate and fuel use is challenging. I present a general discussion and selected methods for automated measurements spanning over >4 mo with little need for adjustments or maintenance. 1) Lack of compensation for respiratory volume change may cause 6% error in the results on a fasting animal. The Haldane transformation provides the simplest calculation method for both O(2) and CO(2) measurements. 2) Use of Nafion tube dryers configured as countercurrent moisture exchangers provides maintenance-free drying of gases, with typical outlet dew points at -25 to -38 degrees C and no CO(2) adsorption. The accuracy is improved by low dead space, making it feasible to pass gases though the same dryer. 3) A software algorithm employing a triple interpolation technique allows corrections for automated calibrations of O(2) and CO(2) with both zero-reference and span gas. 4) Burning known amounts of 100% ethanol provides total system verification of both O(2) consumption and respiratory quotient. A calculation method to supply instant CO(2) calibration gas from an alcohol burn is presented. 5) Automatic flow switching triggered by low/high O(2) thresholds improves accuracy of measurements and safety for the animals experiencing large ranges of O(2) consumption; this is a special requirement for recording metabolism in small hibernating mammals. PMID- 23349454 TI - Differential effects of aging and exercise on intra-abdominal adipose arteriolar function and blood flow regulation. AB - Adipose tissue (AT), which typically comprises an increased percentage of body mass with advancing age, receives a large proportion of resting cardiac output. During exercise, an old age-associated inability to increase vascular resistance within the intra-abdominal AT may compromise the ability of the cardiovascular system to redistribute blood flow to the active musculature, contributing to the decline in exercise capacity observed in this population. We tested the hypotheses that 1) there would be an elevated perfusion of AT during exercise with old age that was associated with diminished vasoconstrictor responses of adipose-resistance arteries, and 2) chronic exercise training would mitigate the age-associated alterations in AT blood flow and vascular function. Young (6 mo; n = 40) and old (24 mo; n = 28) male Fischer 344 rats were divided into young sedentary (YSed), old sedentary (OSed), young exercise trained (YET), or old exercise trained (OET) groups, where training consisted of 10-12 wk of treadmill exercise. In vivo blood flow at rest and during exercise and in vitro alpha adrenergic and myogenic vasoconstrictor responses in resistance arteries from AT were measured in all groups. In response to exercise, there was a directionally opposite change in AT blood flow in the OSed group (~ 150% increase) and YSed (~ 55% decrease) vs. resting values. Both alpha-adrenergic and myogenic vasoconstriction were diminished in OSed vs. YSed AT-resistance arteries. Exercise training resulted in a similar AT hyperemic response between age groups during exercise (YET, 9.9 +/- 0.5 ml . min(-1) . 100(-1) g; OET, 8.1 +/- 0.9 ml . min(-1) . 100(-1) g) and was associated with enhanced myogenic and alpha adrenergic vasoconstriction of AT-resistance arteries from the OET group relative to OSed. These results indicate that there is an inability to increase vascular resistance in AT during exercise with old age, due, in part, to a diminished vasoconstriction of AT arteries. Furthermore, the results indicate that exercise training can augment vasoconstriction of AT arteries and mitigate age-related alterations in the regulation of AT blood flow during exercise. PMID- 23349456 TI - Pharmacological inhibition of S-nitrosoglutathione reductase improves endothelial vasodilatory function in rats in vivo. AB - Nitric oxide (NO) exerts a wide range of cellular effects in the cardiovascular system. NO is short lived, but S-nitrosoglutathione (GSNO) functions as a stable intracellular bioavailable NO pool. Accordingly, increased levels can facilitate NO-mediated processes, and conversely, catabolism of GSNO by the regulatory enzyme GSNO reductase (GSNOR) can impair these processes. Because dysregulated GSNOR can interfere with processes relevant to cardiovascular health, it follows that inhibition of GSNOR may be beneficial. However, the effect of GSNOR inhibition on vascular activity is unknown. To study the effects of GSNOR inhibition on endothelial function, we treated rats with a small-molecule inhibitor of GSNOR (N6338) that has vasodilatory effects on isolated aortic rings and assessed effects on arterial flow-mediated dilation (FMD), an NO-dependent process. GSNOR inhibition with a single intravenous dose of N6338 preserved FMD (15.3 +/- 5.4 vs. 14.2 +/- 6.3%, P = nonsignificant) under partial NO synthase inhibition that normally reduces FMD by roughly 50% (14.1 +/- 2.9 vs. 7.6 +/- 4.4%, P < 0.05). In hypertensive rats, daily oral administration of N6338 for 14 days reduced blood pressure (170.0 +/- 5.3/122.7 +/- 6.4 vs. 203.8 +/- 1.9/143.7 +/- 7.5 mmHg for vehicle, P < 0.001) and vascular resistance index (1.5 +/- 0.4 vs. 3.2 +/- 1.0 mmHg . min . l(-1) for vehicle, P < 0.001), and restored FMD from an initially impaired state (7.4 +/- 1.7%, day 0) to a level (13.0 +/- 3.1%, day 14, P < 0.001) similar to that observed in normotensive rats. N6338 also reversed the pathological kidney changes exhibited by the hypertensive rats. GSNOR inhibition preserves FMD under conditions of impaired NO production and protects against both microvascular and conduit artery dysfunction in a model of hypertension. PMID- 23349457 TI - A heartless brain. PMID- 23349458 TI - The right recommendations for the wrong reasons? PMID- 23349459 TI - 'Patient choice' concept in AF ESC Guidelines: is the clinician giving up? PMID- 23349460 TI - The rescue of dentin matrix protein 1 (DMP1)-deficient tooth defects by the transgenic expression of dentin sialophosphoprotein (DSPP) indicates that DSPP is a downstream effector molecule of DMP1 in dentinogenesis. AB - Dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP) are essential for the formation of dentin. Previous in vitro studies have indicated that DMP1 might regulate the expression of DSPP during dentinogenesis. To examine whether DMP1 controls dentinogenesis through the regulation of DSPP in vivo, we cross-bred transgenic mice expressing normal DSPP driven by a 3.6-kb rat Col1a1 promoter with Dmp1 KO mice to generate mice expressing the DSPP transgene in the Dmp1 KO genetic background (referred to as "Dmp1 KO/DSPP Tg mice"). We used morphological, histological, and biochemical techniques to characterize the dentin and alveolar bone of Dmp1 KO/DSPP Tg mice compared with Dmp1 KO and wild type mice. Our analyses showed that the expression of endogenous DSPP was remarkably reduced in the Dmp1 KO mice. Furthermore, the transgenic expression of DSPP rescued the tooth and alveolar bone defects of the Dmp1 KO mice. In addition, our in vitro analyses showed that DMP1 and its 57-kDa C-terminal fragment significantly up-regulated the Dspp promoter activities in a mesenchymal cell line. In contrast, the expression of DMP1 was not altered in the Dspp KO mice. These results provide strong evidence that DSPP is a downstream effector molecule that mediates the roles of DMP1 in dentinogenesis. PMID- 23349461 TI - Proteomic and functional analyses reveal the role of chromatin reader SFMBT1 in regulating epigenetic silencing and the myogenic gene program. AB - SFMBT1 belongs to the malignant brain tumor domain-containing chromatin reader family that recognizes repressive histone marks and represses transcription. The biological functions and molecular basis underlying SFMBT1-mediated transcriptional repression are poorly elucidated. Here, our proteomic analysis revealed that SFMBT1 is associated with multiple transcriptional corepressor complexes, including CtBP/LSD1/HDAC complexes, polycomb repressive complexes, and malignant brain tumor family proteins, that collectively contribute to SFMBT1 repressor activity. During myogenesis, Sfmbt1 represses myogenic differentiation of cultured and primary myoblasts. Mechanistically, Sfmbt1 interacts with MyoD and mediates epigenetic silencing of MyoD target genes via recruitment of its associated corepressors and subsequent induction of epigenetic modifications and chromatin compaction. Therefore, our study identified novel mechanisms accounting for SFMBT1-mediated transcription repression and revealed an essential role of Sfmbt1 in regulating MyoD-mediated transcriptional silencing that is required for the maintenance of undifferentiated states of myogenic progenitor cells. PMID- 23349462 TI - The MukB-ParC interaction affects the intramolecular, not intermolecular, activities of topoisomerase IV. AB - Proper chromosome organization is accomplished through binding of proteins such as condensins that shape the DNA and by modulation of chromosome topology by the action of topoisomerases. We found that the interaction between MukB, the bacterial condensin, and ParC, a subunit of topoisomerase IV, enhanced relaxation of negatively supercoiled DNA and knotting by topoisomerase IV, which are intramolecular DNA rearrangements but not decatenation of multiply linked DNA dimers, which is an intermolecular DNA rearrangement required for proper segregation of daughter chromosomes. MukB DNA binding and a specific chiral arrangement of the DNA was required for topoisomerase IV stimulation because relaxation of positively supercoiled DNA was unaffected. This effect could be attributed to a more effective topological reconfiguration of the negatively supercoiled compared with positively supercoiled DNA by MukB. These data suggest that the MukB-ParC interaction may play a role in chromosome organization rather than in separation of daughter chromosomes. PMID- 23349463 TI - Binding interactions with the complementary subunit of nicotinic receptors. AB - The agonist-binding site of nicotinic acetylcholine receptors (nAChRs) spans an interface between two subunits of the pentameric receptor. The principal component of this binding site is contributed by an alpha subunit, and it binds the cationic moiety of the nicotinic pharmacophore. The other part of the pharmacophore, a hydrogen bond acceptor, has recently been shown to bind to the complementary non-alpha subunit via the backbone NH of a conserved Leu. This interaction was predicted by studies of ACh-binding proteins and confirmed by functional studies of the neuronal (CNS) nAChR, alpha4beta2. The ACh-binding protein structures further suggested that the hydrogen bond to the backbone NH is mediated by a water molecule and that a second hydrogen bonding interaction occurs between the water molecule and the backbone CO of a conserved Asn, also on the non-alpha subunit. Here, we provide new insights into the nature of the interactions between the hydrogen bond acceptor of nicotinic agonists and the complementary subunit backbone. We studied both the nAChR of the neuromuscular junction (muscle-type) and a neuronal subtype, (alpha4)2(beta4)3. In the muscle type receptor, both ACh and nicotine showed a strong interaction with the Leu NH, but the potent nicotine analog epibatidine did not. This interaction was much attenuated in the alpha4beta4 receptor. Surprisingly, we found no evidence for a functionally significant interaction with the backbone carbonyl of the relevant Asn in either receptor with an array of agonists. PMID- 23349464 TI - Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases. AB - Cullin-RING ligases are multisubunit E3 ubiquitin ligases that recruit substrate specific adaptors to catalyze protein ubiquitylation. Cul3-based Cullin-RING ligases are uniquely associated with BTB adaptors that incorporate homodimerization, Cul3 assembly, and substrate recognition into a single multidomain protein, of which the best known are BTB-BACK-Kelch domain proteins, including KEAP1. Cul3 assembly requires a BTB protein "3-box" motif, analogous to the F-box and SOCS box motifs of other Cullin-based E3s. To define the molecular basis for this assembly and the overall architecture of the E3, we determined the crystal structures of the BTB-BACK domains of KLHL11 both alone and in complex with Cul3, along with the Kelch domain structures of KLHL2 (Mayven), KLHL7, KLHL12, and KBTBD5. We show that Cul3 interaction is dependent on a unique N terminal extension sequence that packs against the 3-box in a hydrophobic groove centrally located between the BTB and BACK domains. Deletion of this N-terminal region results in a 30-fold loss in affinity. The presented data offer a model for the quaternary assembly of this E3 class that supports the bivalent capture of Nrf2 and reveals potential new sites for E3 inhibitor design. PMID- 23349465 TI - Biochemical analysis of histone deacetylase-independent transcriptional repression by MeCP2. AB - MeCP2 is an abundant methyl-cytosine-guanine (CG)-binding protein and transcriptional repressor. We developed a biochemical system that exhibits CG methylation-specific transcriptional repression by purified human MeCP2. MeCP2 represses transcription by histone deacetylase (HDAC)-dependent and HDAC independent mechanisms. Our system appears to recreate the HDAC-independent component of MeCP2-mediated repression and occurs via inhibition of the assembly of transcription preinitiation complexes. At a ratio of approximately one molecule of MeCP2 per two methyl-CG dinucleotides, as found in mammalian neurons, the magnitude of methylation-specific repression was greater than 10-fold. Notably, the HDAC inhibitor trichostatin A had no effect on MeCP2-mediated repression with either naked DNA or chromatin templates. We designed a CG deficient core promoter that is resistant to MeCP2-mediated repression when placed in a plasmid lacking CG dinucleotides. By using this CG-deficient reporter as a reference, we found that eight CG dinucleotides in the core promoter region are sufficient for strong methylation-specific repression by MeCP2. In contrast, MeCP2 does not repress a construct with 13 CG dinucleotides located ~1.7 kbp upstream of the promoter. Furthermore, by analysis of C-terminally truncated MeCP2 proteins, we found that binding of MeCP2 to methyl-CG dinucleotides is not sufficient for transcriptional repression. Hence, MeCP2-mediated repression is not due to the simple steric blockage of the transcriptional machinery. These experiments suggest that MeCP2 can function as a global methyl-CG-specific, HDAC independent repressor. This HDAC-independent mechanism of MeCP2-mediated repression may be important in cells, such as mammalian neurons, that have high levels of CG methylation and MeCP2. PMID- 23349466 TI - Expression and significance of E-cadherin and beta-catenins in pituitary adenoma. AB - This study used immunohistochemical methods for detecting the expression of E cadherin and beta-catenin in pituitary adenoma. Specimens were collected from 91 cases. EnVision was used for immunohistochemical staining. The results were graded depending on the staining intensity and range. Associations between E cadherin and beta-catenin expression and tumor subtype, invasiveness, and postoperative recurrence were investigated. There was a significant downregulation of E-cadherin and beta-catenin in growth hormone (GH)-type tumors when compared with prolactin-type tumors (u(c) = 2.693 and 2.109, respectively; P < .05). E-cadherin and beta-catenin were downregulated in invasive pituitary adenomas (u(c) = 3.563 and 4.166, respectively; P < .05) and in clinically recurring pituitary adenomas (u(c) = 2.871 and 3.866, respectively; P < .05). There was no difference in the percentage of invasive prolactin and GH secreting tumors (28.57% and 22.86%, respectively; P > .05). The expression of E-cadherin and beta-catenin in pituitary adenoma was significantly downregulated and related to subtype, invasiveness, and postoperative recurrence. PMID- 23349467 TI - Salivary gland pleomorphic adenoma with giant cell tumor component. PMID- 23349468 TI - Dilated high endothelial venules in lymph nodes simulating metastatic thyroid carcinoma. AB - When examining microscopically lymph nodes removed as part of the surgical therapy for thyroid carcinoma, one should be aware of the fact that high endothelial venules, when dilated and near the capsule, can lead to a wrong diagnosis of metastasis. We present a case in which such a situation arose. PMID- 23349469 TI - Microinvasive lobular carcinoma arising in a fibroadenoma. AB - A 51-year-old woman had a 35 mm circumscribed calcified lesion identified on screening mammography, designated R4. Excision showed a fibroadenoma with multiple foci of lobular neoplasia (atypical lobular hyperplasia and classical lobular carcinoma in situ [LCIS]). A focus of microinvasive lobular carcinoma (MILC) was also present, confirmed on immunohistochemistry. The MILC cells were ER positive, Her-2-negative, and e-cadherin negative. Microinvasive carcinoma, defined as "invasive carcinoma with no focus measuring >1 mm" (TNM UICC 7th edition) is usually encountered in ductal carcinoma in situ but may occur with classical, florid, or pleomorphic LCIS. In one series MILC constituted 0.4% of all invasive lobular carcinomas and was present in 0.4% of all LCIS. MILC is a histologically subtle lesion, the identification of which lends further weight to the concept of lobular neoplasia as a precursor lesion. MILC has been observed in hamartoma but, to our knowledge, has not previously been reported in fibroadenoma. PMID- 23349470 TI - Podoplanin and E-cadherin expression in preoperative incisional biopsies of oral squamous cell carcinoma is related to lymph node metastases. AB - Metastases to cervical lymph nodes (LNs) are an important independent adverse indicator in the prognosis of oral squamous cell carcinoma (OSCC). An accurate evaluation of molecular patterns favoring the metastatic process can be helpful in predicting cases of OSCC with elevated probability of early or late metastases and, moreover, in planning the proper therapeutic procedures before surgery. To this end, immunohistochemical expressions of both E-cadherin and podoplanin were evaluated on preoperative incisional biopsies of OSCC from 102 patients. The probability to have or develop metastases was very low when high E-cadherin expression was found in a preoperative sample or when a low podoplanin expression was found. Therefore, because of the strong association with LN metastases, high E-cadherin/low podoplanin immunohistochemical expression should also be assessed on preoperative incisional biopsies as a useful tool for evaluating the probability of early or late LN metastases of OSCCs. PMID- 23349471 TI - Oral leiomyomatous hamartoma of the median maxillary gingiva: a case report and review of the literature. AB - Oral leiomyomatous hamartoma (OLH) is a rare lesion seen in the oral cavity. It mainly presents on the median maxilla and tongue. In the literature in English, there are only 10 reported cases of OLH of the median maxilla. Most of the cases were found in patients of Japanese and Latin American origin. We report a case of OLH in an 18-month-old boy of Middle Eastern ancestry. The lesion presented as a pedunculated, light pink, soft swelling that was located on the labial gingiva of tooth number 21. Microscopically, it showed proliferative smooth-muscle fascicles dispersed in loose fibrous stroma and multiple small vessels. The lesional cells looked mature and elongated and were deeply eosinophilic spindle cells with basophilic, central "cigar-shaped" nuclei. The diagnosis of OLH was supported by positive immunohistochemical reactivity of smooth-muscle actin and desmin. To our knowledge, this is the first reported case of OLH in a Middle Eastern patient. PMID- 23349472 TI - Cribriform-morular variant of papillary thyroid carcinoma displaying poorly differentiated features. AB - Cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) usually occurs in the setting of familial adenomatous polyposis (FAP) although it can rarely arise sporadically. Poorly differentiated thyroid carcinoma (PDTC) is a follicular cell-derived neoplasm with more aggressive behavior than well differentiated carcinomas such as CMVPTC. We report the case of a 35-year-old woman without FAP history who presented a left neck mass and complained of back pain. Imagiological examinations revealed a nodule in the left lobe of thyroid and multiple nodular lesions in the bone and lungs suggestive of metastases. The patient was submitted to total thyroidectomy and radioactive iodine. The tumor was composed of CMVPTC and PDTC components that shared the same somatic APC gene mutation (p.Cys520Tyr_fsX534). Besides this mutation, no CTNNB1, BRAF, N-RAS, and H-RAS gene mutations were detected in any of the 2 components. To the best of our knowledge, this is the first report of a sporadic CMVPTC with transformation into PDTC. Although the majority of CMVPTCs carry an indolent clinical outcome, the coexistence of poorly differentiated areas may justify the aggressiveness of the CMVPTC reported here. PMID- 23349473 TI - UbcH10 and its emerging role in systemic carcinogenesis. PMID- 23349474 TI - Multiple cystic brain metastases from papillary thyroid carcinoma mimicking neurocysticercosis. AB - The papillary carcinoma of the thyroid gland is the most common type of tumor of the thyroid gland with good prognosis and low incidence of distant metastasis. The brain metastases of thyroid gland carcinoma are extremely rare. We report a patient with multiple cystic brain lesions and satisfying criteria for diagnosis of neurocysticercosis. Brain biopsy revealed brain metastases from papillary thyroid carcinoma. The tumor originated from mediastinal thyroid tissue. Even in cases when neuroimaging suggests neurocysticercosis with great accuracy, it is important to exclude metastasis. Extensive brain metastases of primary papillary thyroid carcinoma are extremely rare. PMID- 23349476 TI - Global analysis of condition-specific subcellular protein distribution and abundance. AB - Cellular control of protein activities by modulation of their abundance or compartmentalization is not easily measured on a large scale. We developed and applied a method to globally interrogate these processes that is widely useful for systems-level analyses of dynamic cellular responses in many cell types. The approach involves subcellular fractionation followed by comprehensive proteomic analysis of the fractions, which is enabled by a data-independent acquisition mass spectrometry approach that samples every available mass to charge channel systematically to maximize sensitivity. Next, various fraction-enrichment ratios are measured for all detected proteins across different environmental conditions and used to group proteins into clusters reflecting changes in compartmentalization and relative conditional abundance. Application of the approach to characterize the response of yeast proteins to fatty acid exposure revealed dynamics of peroxisomes and novel dynamics of MCC/eisosomes, specialized plasma membrane domains comprised of membrane compartment occupied by Can1 (MCC) and eisosome subdomains. It also led to the identification of Fat3, a fatty acid transport protein of the plasma membrane, previously annotated as Ykl187. PMID- 23349477 TI - PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice. AB - The pregnane X receptor (PXR), along with its sister receptor constitutive androstane receptor (CAR), was initially characterized as a xenobiotic receptor that regulates drug metabolism. In this study, we have uncovered an unexpected endobiotic role of PXR in obesity and type 2 diabetes. PXR ablation inhibited high-fat diet (HFD)-induced obesity, hepatic steatosis, and insulin resistance, which were accounted for by increased oxygen consumption, increased mitochondrial beta-oxidation, inhibition of hepatic lipogenesis and inflammation, and sensitization of insulin signaling. In an independent model, introducing the PXR( /-) allele into the ob/ob background also improved body composition and relieved the diabetic phenotype. The ob/ob mice deficient of PXR showed increased oxygen consumption and energy expenditure, as well as inhibition of gluconeogenesis and increased rate of glucose disposal during euglycemic clamp. Mechanistically, the metabolic benefits of PXR ablation were associated with the inhibition of c-Jun NH2-terminal kinase activation and downregulation of lipin-1, a novel PXR target gene. The metabolic benefit of PXR ablation was opposite to the reported prodiabetic effect of CAR ablation. Our results may help to establish PXR as a novel therapeutic target, and PXR antagonists may be used for the prevention and treatment of obesity and type 2 diabetes. PMID- 23349478 TI - Activation of islet autoreactive naive T cells in infants is influenced by homeostatic mechanisms and antigen-presenting capacity. AB - Islet autoimmunity precedes type 1 diabetes onset. We previously found that islet autoimmunity rarely starts before 6 months of age but reaches its highest incidence already at ~1 year of age. We now examine whether homeostatic expansion and immune competence changes seen in a maturating immune system may account for this marked variation in islet autoimmunity risk in the first year of life. We found naive proinsulin- and GAD65-responsive T cells in cord blood (CB) of healthy newborns, with highest responses observed in children with type 1 diabetes-susceptible HLA-DRB1/DQB1 genotypes. Homeostatic expansion characteristics with increased IL-7 concentrations and enhanced T-cell responsiveness to IL-7 were observed throughout the first year of life. However, the ability of antigen-presenting cells to activate naive T cells was compromised at birth, and CB monocytes had low surface expression of CD40 and HLA class II. In contrast, antigen presentation and expression of these molecules had reached competent adult levels by the high incidence age of 8 months. We propose that temporal changes in islet autoimmunity seroconversion in infants are a consequence of the changing balance between homeostatic drive and antigen presentation competence. These findings are relevant for early prevention of type 1 diabetes. PMID- 23349479 TI - Myocardial adipose triglyceride lipase overexpression protects diabetic mice from the development of lipotoxic cardiomyopathy. AB - Although diabetic cardiomyopathy is associated with enhanced intramyocardial triacylglycerol (TAG) levels, the role of TAG catabolizing enzymes in this process is unclear. Because the TAG hydrolase, adipose triglyceride lipase (ATGL), regulates baseline cardiac metabolism and function, we examined whether alterations in cardiomyocyte ATGL impact cardiac function during uncontrolled type 1 diabetes. In genetic (Akita) and pharmacological (streptozotocin) murine models of type 1 diabetes, cardiac ATGL protein expression and TAG content were significantly increased. To determine whether increased ATGL expression during diabetes is detrimental or beneficial to cardiac function, we studied streptozotocin-diabetic mice with heterozygous ATGL deficiency and cardiomyocyte specific ATGL overexpression. After diabetes, streptozotocin-diabetic mice with heterozygous ATGL deficiency displayed increased TAG accumulation, lipotoxicity, and diastolic dysfunction comparable to wild-type mice. In contrast, myosin heavy chain promoter (MHC)-ATGL mice were resistant to diabetes-induced increases in intramyocardial TAG levels, lipotoxicity, and cardiac dysfunction. Moreover, hearts from diabetic MHC-ATGL mice exhibited decreased reliance on palmitate oxidation and blunted peroxisome proliferator--activated receptor-alpha activation. Collectively, this study shows that after diabetes, increased cardiac ATGL expression is an adaptive, albeit insufficient, response to compensate for the accumulation of myocardial TAG, and that overexpression of ATGL is sufficient to ameliorate diabetes-induced cardiomyopathy. PMID- 23349480 TI - Liver sinusoidal endothelial cells link hyperinsulinemia to hepatic insulin resistance. AB - Insulin signaling in vascular endothelial cells (ECs) is critical to maintain endothelial function but also to mediate insulin action on peripheral glucose disposal. However, gene knockout studies have reached disparate conclusions. Thus, insulin receptor inactivation in ECs does not impair insulin action, whereas inactivation of Irs2 does. Previously, we have shown that endothelial ablation of the three Foxo genes protects mice from atherosclerosis. Interestingly, here we show that mice lacking FoxO isoforms in ECs develop hepatic insulin resistance through excessive generation of nitric oxide (NO) that impairs insulin action in hepatocytes via tyrosine nitration of insulin receptors. Coculture experiments demonstrate that NO produced in liver sinusoidal ECs impairs insulin's ability to suppress glucose production in hepatocytes. The effects of liver sinusoidal ECs can be mimicked by NO donors and can be reversed by NO inhibitors in vivo and ex vivo. The findings are consistent with a model in which excessive, rather than reduced, insulin signaling in ECs predisposes to systemic insulin resistance, prompting a reevaluation of current approaches to insulin sensitization. PMID- 23349481 TI - Antidiabetic actions of an estrogen receptor beta selective agonist. AB - The estrogen receptor beta (ERbeta) is emerging as an important player in the physiology of the endocrine pancreas. We evaluated the role and antidiabetic actions of the ERbeta selective agonist WAY200070 as an insulinotropic molecule. We demonstrate that WAY200070 enhances glucose-stimulated insulin secretion both in mouse and human islets. In vivo experiments showed that a single administration of WAY200070 leads to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Two-week treatment administration increased glucose-induced insulin release and pancreatic beta-cell mass and improved glucose and insulin sensitivity. In addition, streptozotocin nicotinamide-induced diabetic mice treated with WAY200070 exhibited a significant improvement in plasma insulin levels and glucose tolerance as well as a regeneration of pancreatic beta-cell mass. Studies performed in db/db mice demonstrated that this compound restored first-phase insulin secretion and enhanced pancreatic beta-cell mass. We conclude that ERbeta agonists should be considered as new targets for the treatment of diabetes. PMID- 23349482 TI - Activation of PPARalpha ameliorates hepatic insulin resistance and steatosis in high fructose-fed mice despite increased endoplasmic reticulum stress. AB - Endoplasmic reticulum (ER) stress is suggested to cause hepatic insulin resistance by increasing de novo lipogenesis (DNL) and directly interfering with insulin signaling through the activation of the c-Jun N-terminal kinase (JNK) and IkappaB kinase (IKK) pathway. The current study interrogated these two proposed mechanisms in a mouse model of hepatic insulin resistance induced by a high fructose (HFru) diet with the treatment of fenofibrate (FB) 100 mg/kg/day, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist known to reduce lipid accumulation while maintaining elevated DNL in the liver. FB administration completely corrected HFru-induced glucose intolerance, hepatic steatosis, and the impaired hepatic insulin signaling (pAkt and pGSK3beta). Of note, both the IRE1/XBP1 and PERK/eIF2alpha arms of unfolded protein response (UPR) signaling were activated. While retaining the elevated DNL (indicated by the upregulation of SREBP1c, ACC, FAS, and SCD1 and [3H]H2O incorporation into lipids), FB treatment markedly increased fatty acid oxidation (indicated by induction of ACOX1, p-ACC, beta-HAD activity, and [14C]palmitate oxidation) and eliminated the accumulation of diacylglycerols (DAGs), which is known to have an impact on insulin signaling. Despite the marked activation of UPR signaling, neither JNK nor IKK appeared to be activated. These findings suggest that lipid accumulation (mainly DAGs), rather than the activation of JNK or IKK, is pivotal for ER stress to cause hepatic insulin resistance. Therefore, by reducing the accumulation of deleterious lipids, activation of PPARalpha can ameliorate hepatic insulin resistance against increased ER stress. PMID- 23349483 TI - Reduction of reactive oxygen species ameliorates metabolism-secretion coupling in islets of diabetic GK rats by suppressing lactate overproduction. AB - We previously demonstrated that impaired glucose-induced insulin secretion (IS) and ATP elevation in islets of Goto-Kakizaki (GK) rats, a nonobese model of diabetes, were significantly restored by 30-60-min suppression of endogenous reactive oxygen species (ROS) overproduction. In this study, we investigated the effect of a longer (12 h) suppression of ROS on metabolism-secretion coupling in beta-cells by exposure to tempol, a superoxide (O2(-)) dismutase mimic, plus ebselen, a glutathione peroxidase mimic (TE treatment). In GK islets, both H2O2 and O2(-) were sufficiently reduced and glucose-induced IS and ATP elevation were improved by TE treatment. Glucose oxidation, an indicator of Krebs cycle velocity, also was improved by TE treatment at high glucose, whereas glucokinase activity, which determines glycolytic velocity, was not affected. Lactate production was markedly increased in GK islets, and TE treatment reduced lactate production and protein expression of lactate dehydrogenase and hypoxia-inducible factor 1alpha (HIF1alpha). These results indicate that the Warburg-like effect, which is characteristic of aerobic metabolism in cancer cells by which lactate is overproduced with reduced linking to mitochondria metabolism, plays an important role in impaired metabolism-secretion coupling in diabetic beta-cells and suggest that ROS reduction can improve mitochondrial metabolism by suppressing lactate overproduction through the inhibition of HIF1alpha stabilization. PMID- 23349484 TI - Nox2 NADPH oxidase has a critical role in insulin resistance-related endothelial cell dysfunction. AB - Insulin resistance is characterized by excessive endothelial cell generation of potentially cytotoxic concentrations of reactive oxygen species. We examined the role of NADPH oxidase (Nox) and specifically Nox2 isoform in superoxide generation in two complementary in vivo models of human insulin resistance (endothelial specific and whole body). Using three complementary methods to measure superoxide, we demonstrated higher levels of superoxide in insulin resistant endothelial cells, which could be pharmacologically inhibited both acutely and chronically, using the Nox inhibitor gp91ds-tat. Similarly, insulin resistance-induced impairment of endothelial-mediated vasorelaxation could also be reversed using gp91ds-tat. siRNA-mediated knockdown of Nox2, which was specifically elevated in insulin-resistant endothelial cells, significantly reduced superoxide levels. Double transgenic mice with endothelial-specific insulin resistance and deletion of Nox2 showed reduced superoxide production and improved vascular function. This study identifies Nox2 as the central molecule in insulin resistance-mediated oxidative stress and vascular dysfunction. It also establishes pharmacological inhibition of Nox2 as a novel therapeutic target in insulin resistance-related vascular disease. PMID- 23349485 TI - Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high fat diet-induced obesity and insulin resistance in mice. AB - A nonsense mutation in cereblon (CRBN) causes a mild type of mental retardation in humans. An earlier study showed that CRBN negatively regulates the functional activity of AMP-activated protein kinase (AMPK) in vitro by binding directly to the alpha1-subunit of the AMPK complex. However, the in vivo role of CRBN was not studied. For elucidation of the physiological functions of Crbn, a mouse strain was generated in which the Crbn gene was deleted throughout the whole body. In Crbn-deficient mice fed a normal diet, AMPK in the liver showed hyperphosphorylation, which indicated the constitutive activation of AMPK. Since Crbn-deficient mice showed significantly less weight gain when fed a high-fat diet and their insulin sensitivity was considerably improved, the functions of Crbn in the liver were primarily investigated. These results provide the first in vivo evidence that Crbn is a negative modulator of AMPK, which suggests that Crbn may be a potential target for metabolic disorders of the liver. PMID- 23349486 TI - Reduced adipose tissue macrophage content is associated with improved insulin sensitivity in thiazolidinedione-treated diabetic humans. AB - Obesity is associated with increased adipose tissue macrophage (ATM) infiltration, and rodent studies suggest that inflammatory factors produced by ATMs contribute to insulin resistance and type 2 diabetes. However, a relationship between ATM content and insulin resistance has not been clearly established in humans. Since thiazolidinediones attenuate adipose tissue inflammation and improve insulin sensitivity, we examined the temporal relationship of the effects of pioglitazone on these two parameters. The effect of 10 and 21 days of pioglitazone treatment on insulin sensitivity in 26 diabetic subjects was assessed by hyperinsulinemic-euglycemic clamp studies. Because chemoattractant factors, cytokines, and immune cells have been implicated in regulating the recruitment of ATMs, we studied their temporal relationship to changes in ATM content. Improved hepatic and peripheral insulin sensitivity was seen after 21 days of pioglitazone. We found early reductions in macrophage chemoattractant factors after only 10 days of pioglitazone, followed by a 69% reduction in ATM content at 21 days and reduced ATM activation at both time points. Although markers for dendritic cells and neutrophils were reduced at both time points, there were no significant changes in regulatory T cells. These results are consistent with an association between adipose macrophage content and systemic insulin resistance in humans. PMID- 23349487 TI - Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion. AB - BTBR mice develop severe diabetes in response to genetically induced obesity due to a failure of the beta-cells to compensate for peripheral insulin resistance. In analyzing BTBR islet gene expression patterns, we observed that Pgter3, the gene for the prostaglandin E receptor 3 (EP3), was upregulated with diabetes. The EP3 receptor is stimulated by prostaglandin E2 (PGE2) and couples to G-proteins of the Gi subfamily to decrease intracellular cAMP, blunting glucose-stimulated insulin secretion (GSIS). Also upregulated were several genes involved in the synthesis of PGE2. We hypothesized that increased signaling through EP3 might be coincident with the development of diabetes and contribute to beta-cell dysfunction. We confirmed that the PGE2-to-EP3 signaling pathway was active in islets from confirmed diabetic BTBR mice and human cadaveric donors, with increased EP3 expression, PGE2 production, and function of EP3 agonists and antagonists to modulate cAMP production and GSIS. We also analyzed the impact of EP3 receptor activation on signaling through the glucagon-like peptide (GLP)-1 receptor. We demonstrated that EP3 agonists antagonize GLP-1 signaling, decreasing the maximal effect that GLP-1 can elicit on cAMP production and GSIS. Taken together, our results identify EP3 as a new therapeutic target for beta cell dysfunction in T2D. PMID- 23349488 TI - The type 2 diabetes-associated gene ide is required for insulin secretion and suppression of alpha-synuclein levels in beta-cells. AB - Genome-wide association studies have identified several type 2 diabetes (T2D) risk loci linked to impaired beta-cell function. The identity and function of the causal genes in these susceptibility loci remain, however, elusive. The HHEX/IDE T2D locus is associated with decreased insulin secretion in response to oral glucose stimulation in humans. Here we have assessed beta-cell function in Ide knockout (KO) mice. We find that glucose-stimulated insulin secretion (GSIS) is decreased in Ide KO mice due to impaired replenishment of the releasable pool of granules and that the Ide gene is haploinsufficient. We also show that autophagic flux and microtubule content are reduced in beta-cells of Ide KO mice. One important cellular role for IDE involves the neutralization of amyloidogenic proteins, and we find that alpha-synuclein and IDE levels are inversely correlated in beta-cells of Ide KO mice and T2D patients. Moreover, we provide evidence that both gain and loss of function of alpha-synuclein in beta-cells in vivo impair not only GSIS but also autophagy. Together, these data identify the Ide gene as a regulator of GSIS, suggest a molecular mechanism for beta-cell degeneration as a consequence of Ide deficiency, and corroborate and extend a previously established important role for alpha-synuclein in beta-cell function. PMID- 23349489 TI - beta-Cells are not generated in pancreatic duct ligation-induced injury in adult mice. AB - The existence of adult beta-cell progenitors remains the most controversial developmental biology topic in diabetes research. It has been reported that beta cell progenitors can be activated by ductal ligation-induced injury of adult mouse pancreas and apparently act in a cell-autonomous manner to double the functional beta-cell mass within a week by differentiation and proliferation. Here, we demonstrate that pancreatic duct ligation (PDL) does not activate progenitors to contribute to beta-cell mass expansion. Rather, PDL stimulates massive pancreatic injury, which alters pancreatic composition and thus complicates accurate measurement of beta-cell content via traditional morphometry methodologies that superficially sample the pancreas. To overcome this potential bias, we quantified beta-cells from the entire pancreas and observed that beta cell mass and insulin content are totally unchanged by PDL-induced injury. Lineage-tracing studies using sequential administration of thymidine analogs, rat insulin 2 promoter-driven cre-lox, and low-frequency ubiquitous cre-lox reveal that PDL does not convert progenitors to the beta-cell lineage. Thus, we conclude that beta-cells are not generated in injured adult mouse pancreas. PMID- 23349490 TI - Enhanced NF-kappaB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes. AB - Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor-kappaB (NF-kappaB) signaling contributes to vascular dysfunction in T2D. We treated type 2 diabetic (db(-)/db(-)) and control (db(-)/db(+)) mice with two NF-kappaB inhibitors (6 mg/kg dehydroxymethylepoxyquinomicin twice a week and 500 MUg/kg/day IKK-NBD peptide) for 4 weeks. Pressure-induced myogenic tone was significantly potentiated, while endothelium-dependent relaxation (EDR) was impaired in small coronary arterioles and mesenteric resistance artery from diabetic mice compared with controls. Interestingly, diabetic mice treated with NF-kappaB inhibitors had significantly reduced myogenic tone potentiation and improved EDR. Importantly, vascular function was also rescued in db(-)/db(-p50NF-kappaB-/-) and db(-)/db(-PARP-1-/-) double knockout mice compared with db(-)/db(-) mice. Additionally, the acute in vitro downregulation of NF-kappaB-p65 using p65NF-kappaB short hairpin RNA lentivirus in arteries from db(-)/db(-) mice also improved vascular function. The NF-kappaB inhibition did not affect blood glucose level or body weight. The RNA levels for Sp-1 and eNOS phosphorylation were decreased, while p65NF-kappaB phosphorylation, cleaved poly(ADP-ribose) polymerase (PARP)-1, and cyclooxygenase (COX)-2 expression were increased in arteries from diabetic mice, which were restored after NF-kappaB inhibition and in db(-)/db(-p50NF-kappaB-/-) and db( )/db(-PARP-1-/-) mice. In the current study, we provided evidence that enhanced NF-kappaB activity impairs vascular function by PARP-1-, Sp-1-, and COX-2 dependent mechanisms in male type 2 diabetic mice. Therefore, NF-kappaB could be a potential target to overcome diabetes-induced vascular dysfunction. PMID- 23349491 TI - Reduction of circulating neutrophils precedes and accompanies type 1 diabetes. AB - Human type 1 diabetes (T1D) is an autoimmune disease associated with major histocompatibility complex polymorphisms, beta-cell autoantibodies, and autoreactive T cells. However, there is increasing evidence that innate cells may also play critical roles in T1D. We aimed to monitor peripheral immune cells in early stages of T1D (i.e., in healthy autoantibody-positive subjects) and in more advanced phases of the disease (i.e., at disease onset and years after diagnosis). We found a mild but significant and reproducible peripheral neutropenia that both precedes and accompanies the onset of T1D. This reduction was not due to peripheral neutrophil cell death, impaired differentiation, or the presence of anti-neutrophil antibodies. Neutrophils were observed by electron microscopy and immunohistochemical analysis in the exocrine pancreas of multiorgan donors with T1D (both at onset and at later stages of the disease) and not in that of multiorgan donors with type 2 diabetes or nondiabetic donors. These pancreas-infiltrating neutrophils mainly localized at the level of very small blood vessels. Our findings suggest the existence of a hitherto unrecognized clinical phenotype that might reflect unexplored pathogenic pathways underlying T1D. PMID- 23349492 TI - Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance. AB - Increased deposition of specific extracellular matrix (ECM) components is a characteristic of insulin-resistant skeletal muscle. Hyaluronan (HA) is a major constituent of the ECM. The hypotheses that 1) HA content is increased in the ECM of insulin-resistant skeletal muscle and 2) reduction of HA in the muscle ECM by long-acting pegylated human recombinant PH20 hyaluronidase (PEGPH20) reverses high-fat (HF) diet-induced muscle insulin resistance were tested. We show that muscle HA was increased in HF diet-induced obese (DIO) mice and that treatment of PEGPH20, which dose-dependently reduced HA in muscle ECM, decreased fat mass, adipocyte size, and hepatic and muscle insulin resistance in DIO mice at 10 mg/kg. Reduced muscle insulin resistance was associated with increased insulin signaling, muscle vascularization, and percent cardiac output to muscle rather than insulin sensitization of muscle per se. Dose-response studies revealed that PEGPH20 dose-dependently increased insulin sensitivity in DIO mice with a minimally effective dose of 0.01 mg/kg. PEGPH20 at doses of 0.1 and 1 mg/kg reduced muscle HA to levels seen in chow-fed mice, decreased fat mass, and increased muscle glucose uptake. These findings suggest that ECM HA is a target for treatment of insulin resistance. PMID- 23349493 TI - Galectin-3 deficiency accelerates high-fat diet-induced obesity and amplifies inflammation in adipose tissue and pancreatic islets. AB - Obesity-induced diabetes is associated with low-grade inflammation in adipose tissue and macrophage infiltration of islets. We show that ablation of galectin-3 (Gal-3), a galactoside-binding lectin, accelerates high-fat diet-induced obesity and diabetes. Obese LGALS3(-/-) mice have increased body weight, amount of total visceral adipose tissue (VAT), fasting blood glucose and insulin levels, homeostasis model assessment of insulin resistance, and markers of systemic inflammation compared with diet-matched wild-type (WT) animals. VAT of obese LGALS3(-/-) mice exhibited increased incidence of type 1 T and NKT lymphocytes and proinflammatory CD11c(+)CD11b(+) macrophages and decreased CD4(+)CD25(+)FoxP3(+) regulatory T cells and M2 macrophages. Pronounced mononuclear cell infiltrate, increased expression of NLRP3 inflammasome and interleukin-1beta (IL-1beta) in macrophages, and increased accumulation of advanced glycation end products (AGEs) and receptor for AGE (RAGE) expression were present in pancreatic islets of obese LGALS3(-/-) animals accompanied with elevated phosphorylated nuclear factor-kappaB (NF-kappaB) p65 and mature caspase 1 protein expression in pancreatic tissue and VAT. In vitro stimulation of LGALS3(-/-) peritoneal macrophages with lipopolysaccharide (LPS) and saturated fatty acid palmitate caused increased caspase-1-dependent IL-1beta production and increased phosphorylation of NF-kappaB p65 compared with WT cells. Transfection of LGALS3(-/-) macrophages with NLRP3 small interfering RNA attenuated IL-1beta production in response to palmitate and LPS plus palmitate. Obtained results suggest important protective roles for Gal-3 in obesity-induced inflammation and diabetes. PMID- 23349494 TI - Disruption of the cerebral white matter network is related to slowing of information processing speed in patients with type 2 diabetes. AB - Patients with type 2 diabetes often show slowing of information processing. Disruptions in the brain white matter network, possibly secondary to vascular damage, may underlie these cognitive disturbances. The current study reconstructed the white matter network of 55 nondemented individuals with type 2 diabetes (mean age, 71 +/- 4 years) and 50 age-, sex-, and education-matched controls using diffusion magnetic resonance imaging-based fiber tractography. Graph theoretical analysis was then applied to quantify the efficiency of these networks. Patients with type 2 diabetes showed alterations in local and global network properties compared with controls (P < 0.05). These structural network abnormalities were related to slowing of information processing speed in patients. This relation was partly independent of cerebrovascular lesion load. This study shows that the approach of characterizing the brain as a network using diffusion magnetic resonance imaging and graph theory can provide new insights into how abnormalities in the white matter affect cognitive function in patients with diabetes. PMID- 23349495 TI - VASP increases hepatic fatty acid oxidation by activating AMPK in mice. AB - Activation of AMP-activated protein kinase (AMPK) signaling reduces hepatic steatosis and hepatic insulin resistance; however, its regulatory mechanisms are not fully understood. In this study, we sought to determine whether vasodilator stimulated phosphoprotein (VASP) signaling improves lipid metabolism in the liver and, if so, whether VASP's effects are mediated by AMPK. We show that disruption of VASP results in significant hepatic steatosis as a result of significant impairment of fatty acid oxidation, VLDL-triglyceride (TG) secretion, and AMPK signaling. Overexpression of VASP in hepatocytes increased AMPK phosphorylation and fatty acid oxidation and reduced hepatocyte TG accumulation; however, these responses were suppressed in the presence of an AMPK inhibitor. Restoration of AMPK phosphorylation by administration of 5-aminoimidazole-4-carboxamide riboside in Vasp(-/-) mice reduced hepatic steatosis and normalized fatty acid oxidation and VLDL-TG secretion. Activation of VASP by the phosphodiesterase-5 inhibitor, sildenafil, in db/db mice reduced hepatic steatosis and increased phosphorylated (p-)AMPK and p-acetyl CoA carboxylase. In Vasp(-/-) mice, however, sildendafil treatment did not increase p-AMPK or reduce hepatic TG content. These studies identify a role of VASP to enhance hepatic fatty acid oxidation by activating AMPK and to promote VLDL-TG secretion from the liver. PMID- 23349496 TI - TSG-6 produced by hMSCs delays the onset of autoimmune diabetes by suppressing Th1 development and enhancing tolerogenicity. AB - Genetic and immunological screening for type 1 diabetes has led to the possibility of preventing disease in susceptible individuals. Here, we show that human mesenchymal stem/stromal cells (hMSCs) and tumor necrosis factor-alpha stimulated gene 6 (TSG-6), a protein produced by hMSCs in response to signals from injured tissues, delayed the onset of spontaneous autoimmune diabetes in NOD mice by inhibiting insulitis and augmenting regulatory T cells (Tregs) within the pancreas. Importantly, hMSCs with a knockdown of tsg-6 were ineffective at delaying insulitis and the onset of diabetes in mice. TSG-6 inhibited the activation of both T cells and antigen-presenting cells (APCs) in a CD44 dependent manner. Moreover, multiple treatments of TSG-6 rendered APCs more tolerogenic, capable of enhancing Treg generation and delaying diabetes in an adoptive transfer model. Therefore, these results could provide the basis for a novel therapy for the prevention of type 1 diabetes. PMID- 23349497 TI - In vivo JNK activation in pancreatic beta-cells leads to glucose intolerance caused by insulin resistance in pancreas. AB - Insulin resistance is a key condition in the development of type 2 diabetes. It is well established that exacerbated Jun NH2-terminal kinase (JNK) activity is involved in promoting insulin resistance in peripheral insulin-target tissues; however, this involvement is less documented in pancreatic beta-cells. Using a transgenic mouse model, here we show that JNK activation in beta-cells led to glucose intolerance as a result of impaired capacity to increase insulinemia in response to hyperglycemia. Pancreatic islets from these mice showed no obvious morphostructural abnormalities or decreased insulin content. In contrast, these islets failed to secrete insulin in response to glucose or insulin but were competent in succinate-, ketoisocaproate-, 3-isobutyl-1-methylxanthine (IBMX-), KCl-, and tolbutamide-induced insulin secretion. At the molecular level, JNK activation in beta-cells inhibited insulin-induced Akt phosphorylation, pancreatic and duodenal homeobox 1 nucleocytoplasmic shuttling, and transcription of insulin-target genes. Remarkably, rosiglitazone restored insulin secretion in response to hyperglycemia in mice and insulin-induced insulin secretion and signaling in isolated islets. In conclusion, the mere activation of JNK suffices to induce insulin resistance in pancreatic beta-cells by inhibition of insulin signaling in these cells, but it is not sufficient to elicit beta-cell death. In addition, we provide the first evidence that thiazolidinediones exert insulin sensitizing action directly on pancreatic beta-cells. PMID- 23349498 TI - Link between GIP and osteopontin in adipose tissue and insulin resistance. AB - Low-grade inflammation in obesity is associated with accumulation of the macrophage-derived cytokine osteopontin (OPN) in adipose tissue and induction of local as well as systemic insulin resistance. Since glucose-dependent insulinotropic polypeptide (GIP) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate OPN expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13 +/- 0.04 vs. 0.04 +/- 0.01, P < 0.05) and correlated inversely with measures of insulin sensitivity (r = -0.24, P = 0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with a lower amount of the exon 9-containing isoform required for transmembrane activity. Carriers of the A allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of the GIPR rs10423928 A allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions. PMID- 23349499 TI - Promotion of autoimmune diabetes by cereal diet in the presence or absence of microbes associated with gut immune activation, regulatory imbalance, and altered cathelicidin antimicrobial Peptide. AB - We are exposed to millions of microbial and dietary antigens via the gastrointestinal tract, which likely play a key role in type 1 diabetes (T1D). We differentiated the effects of these two major environmental factors on gut immunity and T1D. Diabetes-prone BioBreeding (BBdp) rats were housed in specific pathogen-free (SPF) or germ-free (GF) conditions and weaned onto diabetes promoting cereal diets or a protective low-antigen hydrolyzed casein (HC) diet, and T1D incidence was monitored. Fecal microbiota 16S rRNA genes, immune cell distribution, and gene expression in the jejunum were analyzed. T1D was highest in cereal-SPF (65%) and cereal-GF rats (53%) but inhibited and delayed in HC-fed counterparts. Nearly all HC-GF rats remained diabetes-free, whereas HC-fed SPF rats were less protected (7 vs. 29%). Bacterial communities differed in SPF rats fed cereal compared with HC. Cereal-SPF rats displayed increased gut CD3(+) and CD8alpha(+) lymphocytes, ratio of Ifng to Il4 mRNA, and Lck expression, indicating T-cell activation. The ratio of CD3(+) T cells expressing the Treg marker Foxp3(+) was highest in HC-GF and lowest in cereal-SPF rats. Resident CD163(+) M2 macrophages were increased in HC-protected rats. The cathelicidin antimicrobial peptide (Camp) gene was upregulated in the jejunum of HC diet protected rats, and CAMP(+) cells colocalized with CD163. A cereal diet was a stronger promoter of T1D than gut microbes in association with impaired gut immune homeostasis. PMID- 23349500 TI - beta-Cell-specific protein kinase A activation enhances the efficiency of glucose control by increasing acute-phase insulin secretion. AB - Acute insulin secretion determines the efficiency of glucose clearance. Moreover, impaired acute insulin release is characteristic of reduced glucose control in the prediabetic state. Incretin hormones, which increase beta-cell cAMP, restore acute-phase insulin secretion and improve glucose control. To determine the physiological role of the cAMP-dependent protein kinase (PKA), a mouse model was developed to increase PKA activity specifically in the pancreatic beta-cells. In response to sustained hyperglycemia, PKA activity potentiated both acute and sustained insulin release. In contrast, a glucose bolus enhanced acute-phase insulin secretion alone. Acute-phase insulin secretion was increased 3.5-fold, reducing circulating glucose to 58% of levels in controls. Exendin-4 increased acute-phase insulin release to a similar degree as PKA activation. However, incretins did not augment the effects of PKA on acute-phase insulin secretion, consistent with incretins acting primarily via PKA to potentiate acute-phase insulin secretion. Intracellular calcium signaling was unaffected by PKA activation, suggesting that the effects of PKA on acute-phase insulin secretion are mediated by the phosphorylation of proteins involved in beta-cell exocytosis. Thus, beta-cell PKA activity transduces the cAMP signal to dramatically increase acute-phase insulin secretion, thereby enhancing the efficiency of insulin to control circulating glucose. PMID- 23349501 TI - Impaired local production of proresolving lipid mediators in obesity and 17-HDHA as a potential treatment for obesity-associated inflammation. AB - Obesity-induced chronic low-grade inflammation originates from adipose tissue and is crucial for obesity-driven metabolic deterioration, including insulin resistance and type 2 diabetes. Chronic inflammation may be a consequence of a failure to actively resolve inflammation and could result from a lack of local specialized proresolving lipid mediators (SPMs), such as resolvins and protectins, which derive from the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We assessed obesity induced changes of n-3-derived SPMs in adipose tissue and the effects of dietary EPA/DHA thereon. Moreover, we treated obese mice with SPM precursors and investigated the effects on inflammation and metabolic dysregulation. Obesity significantly decreased DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA, resolvin D1 precursor) and protectin D1 (PD1) levels in murine adipose tissue. Dietary EPA/DHA treatment restored endogenous biosynthesis of n-3-derived lipid mediators in obesity while attenuating adipose tissue inflammation and improving insulin sensitivity. Notably, 17-HDHA treatment reduced adipose tissue expression of inflammatory cytokines, increased adiponectin expression, and improved glucose tolerance parallel to insulin sensitivity in obese mice. These findings indicate that impaired biosynthesis of certain SPM and SPM precursors, including 17-HDHA and PD1, contributes to adipose tissue inflammation in obesity and suggest 17 HDHA as a novel treatment option for obesity-associated complications. PMID- 23349502 TI - Cbl-b is a critical regulator of macrophage activation associated with obesity induced insulin resistance in mice. AB - We previously reported the potential involvement of casitas B-cell lymphoma-b (Cbl-b) in aging-related murine insulin resistance. Because obesity also induces macrophage recruitment into adipose tissue, we elucidated here the role of Cbl-b in obesity-related insulin resistance. Cbl-b(+/+) and Cbl-b(-/-) mice were fed a high-fat diet (HFD) and then examined for obesity-related changes in insulin signaling. The HFD caused recruitment of macrophages into adipose tissue and increased inflammatory reaction in Cbl-b(-/-) compared with Cbl-b(+/+) mice. Peritoneal macrophages from Cbl-b(-/-) mice and Cbl-b-overexpressing RAW264.7 macrophages were used to examine the direct effect of saturated fatty acids (FAs) on macrophage activation. In macrophages, Cbl-b suppressed saturated FA-induced Toll-like receptor 4 (TLR4) signaling by ubiquitination and degradation of TLR4. The physiological role of Cbl-b in vivo was also examined by bone marrow transplantation and Eritoran, a TLR4 antagonist. Hematopoietic cell-specific depletion of the Cbl-b gene induced disturbed responses on insulin and glucose tolerance tests. Blockade of TLR4 signaling by Eritoran reduced fasting blood glucose and serum interleukin-6 levels in obese Cbl-b(-/-) mice. These results suggest that Cbl-b deficiency could exaggerate HFD-induced insulin resistance through saturated FA-mediated macrophage activation. Therefore, inhibition of TLR4 signaling is an attractive therapeutic strategy for treatment of obesity related insulin resistance. PMID- 23349505 TI - What is mental health? PMID- 23349503 TI - Spillover of Fatty acids during dietary fat storage in type 2 diabetes: relationship to body fat depots and effects of weight loss. AB - Spillover of lipoprotein lipase-generated fatty acids from chylomicrons into the plasma free fatty acid (FFA) pool is an important source of FFA and reflects inefficiency in dietary fat storage. We measured spillover in 13 people with type 2 diabetes using infusions of a [(3)H]triolein-labeled lipid emulsion and [U (13)C]oleate during continuous feeding, before and after weight loss. Body fat was measured with dual energy X-ray absorptiometry and computed tomography. Participants lost ~14% of body weight. There was an ~38% decrease in meal suppressed FFA concentration (P < 0.0001) and an ~23% decrease in oleate flux (P = 0.007). Fractional spillover did not change (P = NS). At baseline, there was a strong negative correlation between spillover and leg fat (r = -0.79, P = 0.001) and a positive correlation with the trunk-to-leg fat ratio (R = 0.56, P = 0.047). These correlations disappeared after weight loss. Baseline leg fat (R = -0.61, P = 0.027) but not trunk fat (R = -0.27, P = 0.38) negatively predicted decreases in spillover with weight loss. These results indicate that spillover, a measure of inefficiency in dietary fat storage, is inversely associated with lower body fat in type 2 diabetes. PMID- 23349504 TI - LKB1 regulates lipid oxidation during exercise independently of AMPK. AB - Lipid metabolism is important for health and insulin action, yet the fundamental process of regulating lipid metabolism during muscle contraction is incompletely understood. Here, we show that liver kinase B1 (LKB1) muscle-specific knockout (LKB1 MKO) mice display decreased fatty acid (FA) oxidation during treadmill exercise. LKB1 MKO mice also show decreased muscle SIK3 activity, increased histone deacetylase 4 expression, decreased NAD+ concentration and SIRT1 activity, and decreased expression of genes involved in FA oxidation. In AMP activated protein kinase (AMPK)alpha2 KO mice, substrate use was similar to that in WT mice, which excluded that decreased FA oxidation in LKB1 MKO mice was due to decreased AMPKalpha2 activity. Additionally, LKB1 MKO muscle demonstrated decreased FA oxidation in vitro. A markedly decreased phosphorylation of TBC1D1, a proposed regulator of FA transport, and a low CoA content could contribute to the low FA oxidation in LKB1 MKO. LKB1 deficiency did not reduce muscle glucose uptake or oxidation during exercise in vivo, excluding a general impairment of substrate use during exercise in LKB1 MKO mice. Our findings demonstrate that LKB1 is a novel molecular regulator of major importance for FA oxidation but not glucose uptake in muscle during exercise. PMID- 23349506 TI - Alert for suicide prevention in Greece: remember lessons from Eastern Europe! PMID- 23349508 TI - Dotting the I's and crossing the T's: autonomy and/or beneficence? The 'fetus as a patient' in maternal-fetal surgery. AB - Chervenak and McCullough, authors of the most acknowledged ethical framework for maternal-fetal surgery, rely on the 'ethical-obstetrical' concept of the fetus as a patient in order to determine what is morally owed to fetuses by both physicians and the women who gestate them in the context of prenatal surgery. In this article, we reconstruct the argumentative structure of their framework and present an internal criticism. First, we analyse the justificatory arguments put forward by the authors regarding the moral status of the fetus qua patient. Second, we discuss the internal coherence and consistency of the moral obligations those authors derive from that concept. We claim that some of the dilemmas their approach is purported to avoid, such as the debate about the independent moral status of the fetus, and the foundation of the moral obligations of pregnant women (towards the fetuses they gestate) are not, all things considered, avoided. Chervenak and McCullough construct the obligations of physicians as obligations towards entities with equal moral status. But, at the same time, they assume that the woman has an independent moral status while the moral status of the fetus is dependent on the decision of the woman to present it to a physician for care. According to the logic of their own argumentation, Chervenak and McCullough implicitly admit a different moral status of the woman and the fetus, which will lead to different ascription of duties of the physician than those they ascribed. PMID- 23349507 TI - The active recruitment of health workers: a commentary. PMID- 23349511 TI - You cannot have your normal functioning cake and eat it too. AB - Does biomedical enhancement challenge justice in health care? This paper argues that health care justice based on the concept of normal functioning is inadequate if enhancements are widespread. Two different interpretations of normal functioning are distinguished: the "species typical" vs. the "normal cooperator" account, showing that each version of the theory fails to account for certain egalitarian intuitions about help and assistance owed to people with health needs, where enhancements are widespread. PMID- 23349512 TI - Is it ethical to invite compatible pairs to participate in exchange programmes? AB - Living kidney transplantation offers the best results for patients with end-stage renal disease (ESRD). This form of transplantation is no longer restricted to genetically or emotionally related donors, as shown by the acceptance of non directed living anonymous donors, and the development of exchange programmes (EPs). EPs make it possible to perform living kidney transplantation among incompatible pairs, but while such programmes can help increase living organ donation, they can also create a degree of unfairness. Kidney transplant recipients in the O blood group are at a disadvantage when it comes to EPs because they can only receive organs from O donors, whereas O donors are universal donors. This poses a major challenge in terms of distributive justice and equity. A way to remedy this situation is through altruistic unbalanced paired kidney exchange (AUPKE), in which a compatible pair consisting of an O blood group donor and a non-O recipient is invited to participate in an EP. Although the AUPKE approach appears fairer for O recipients, it still raises ethical questions. How does this type of exchange affect the donor/recipient gift relationship? Should recipients in compatible pairs receive a 'better organ' than the one they would otherwise have received from their intended donor? Finally, what is the role of transplant teams in AUPKE? This article will examine the organisational and ethical challenges associated with EPs and AUPKE, and compare different EP policies in countries where such programmes exist. PMID- 23349510 TI - Comprehension of a simplified assent form in a vaccine trial for adolescents. AB - INTRODUCTION: Future HIV vaccine efficacy trials with adolescents will need to ensure that participants comprehend study concepts in order to confer true informed assent. A Hepatitis B vaccine trial with adolescents offers valuable opportunity to test youth understanding of vaccine trial requirements in general. METHODS: Youth reviewed a simplified assent form with study investigators and then completed a comprehension questionnaire. Once enrolled, all youth were tested for HIV and confirmed to be HIV-negative. RESULTS: 123 youth completed the questionnaire (mean age=15 years; 63% male; 70% Hispanic). Overall, only 69 (56%) youth answered all six questions correctly. CONCLUSIONS: Youth enrolled in a Hepatitis B vaccine trial demonstrated variable comprehension of the study design and various methodological concepts, such as treatment group masking. PMID- 23349514 TI - Identifying the patient in George W Lambert's Chesham Street. AB - This paper takes as its focus one of the Edwardian period's most dramatic and little-understood paintings of a medical examination: George Washington Lambert's Chesham Street (1910). The painting shows an upper-class male patient lifting his shirt to reveal a muscular torso for examination by the doctor in the scene and the viewers outside it. The subject of a medical examination, I argue, legitimised the scrutiny of exposed male flesh and offered an opportunity for sensual pleasure between men. By way of a comparison with other portraits of the artist from around the same period, I interpret Chesham Street as a patient self portrait, which reveals the artist's dual personalities of bohemian artist and Australian boxer: two personae that did not combine seamlessly, as revealed by the composite nature of the patient in Chesham Street. From a discussion of the artist as patient, I move to an analysis of other self-portraits by Lambert in which the artist is shown flexing his muscles, especially in the context of his passion for boxing. I consider how these portraits serve as complex inscriptions of illness and health and how this relates to the experience of living and working as an Australian expatriate artist in London in the early twentieth century. PMID- 23349513 TI - In hindsight: urban exposure explains the association between prior migration and current health of older adults in Mexico. AB - OBJECTIVE: This study examines sex differences in the association between migration and exposure to an urban environment and overweight, hypertension and diabetes in later life. METHODS: Interviews were conducted with 3,604 adults aged 50 and older in the Mexican Family Life Survey (MxFLS). Logistic regression analyses were used to examine the association between previous migration, urban exposure, and risk of overweight, hypertension, and diabetes. RESULTS: Migration itself was not associated with health outcomes after controlling for urban exposure. The risk of overweight and diabetes associated with urban exposure appeared to be greater for men. Sex differences were found in the covariates that helped explain differences in health between those with high and low urban exposure. DISCUSSION: These findings underscore the need to consider heterogeneity in health by urban exposure and by sex. PMID- 23349517 TI - A novel glycine decarboxylase gene mutation in an Indian family with nonketotic hyperglycinemia. AB - Nonketotic hyperglycinemia is an inborn error of glycine metabolism. It manifests mostly as an acute encephalopathy in the neonatal period, although later, atypical presentations have also been reported. Mutations in 3 different genes have been implicated in nonketotic hyperglycinemia. Here we report a novel mutation, c.2296G>T (p.Gly766Cys), in exon 19 of the glycine decarboxylase (GLDC) gene (Refseq accession number NM_000170.2) in a consanguineous Indian couple with a history of 4 neonatal deaths. PMID- 23349518 TI - Is idiopathic toe walking really idiopathic? The motor skills and sensory processing abilities associated with idiopathic toe walking gait. AB - This study aimed to investigate any differences between the motor skills and sensory processing abilities of children between the ages of 4 and 8, who do and do not have an idiopathic toe walking gait. Children in each cohort were tested with a number of norm referenced assessments. A total of 60 children participated, 30 within each cohort. Those with an idiopathic toe walking gait were found to have different Sensory Profile quadrant scores (P = .002), poorer performance on the Bruininks-Oseretsky Test of Motor Proficiency (P <= .001), a lower vibration perception threshold (P = .001), and poorer performance on the Standing Walking Balance subtest of the Sensory Integration and Praxis Test (P = .047), compared with non-toe walking peers. Although this research does not give a causative factor for toe walking gait, it provides a number of theories as to why this gait may not be idiopathic in nature. PMID- 23349519 TI - Levodopa does not improve function in individuals with dystonic cerebral palsy. AB - Although levodopa is the main treatment for dystonia, its role in cerebral palsy has not been assessed. We hypothesized that levodopa will improve upper limb function in individuals with cerebral palsy. Nine participants (age 16.8 +/- 5.6 years) with quadriplegic cerebral palsy and upper limb dystonia were enrolled in this randomized, double-blind, placebo-controlled, crossover study. Function was assessed before and after 2 weeks of treatment of levodopa and placebo using box and-blocks, 9-hole pegs, dynamometer recordings, and Quality of Upper Extremity Skills Test. No benefits for upper limb functional performance were found following levodopa (6.65 +/- 1.66 mg/kg/d) treatment compared to placebo. No side effects were reported. PMID- 23349520 TI - IADR Global Oral Health Inequalities Research Agenda (IADR-GOHIRA(R)): a call to action. PMID- 23349523 TI - Minireview: endoplasmic reticulum stress: control in protein, lipid, and signal homeostasis. AB - Endoplasmic reticulum (ER) stress is a regulatory mechanism that allows cells to adapt to a series of metabolic, redox, and other environmental changes. The role of ER stress was first identified in the maintenance of proteostasis. It has since been shown that ER stress is also critical to the regulation of lipid homeostasis, membrane turnover, and autophagy. ER stress initiates an intrinsic signaling network, the unfolded protein response, one component of the multifold and complex cellular signaling process system, which leads to major changes in the profiles of transcription factors. The unfolded protein response affects several other signaling routes through direct connections and also by indirect means. It directly influences hormone formation and life/death decisions at a cellular level; this relationship also involves connections to nutrient and environmental sensing-biotransformation processes. In conclusion, ER stress represents an integrated complex organelle response that makes an essential contribution to the maintenance of intracellular homeostasis. PMID- 23349526 TI - Evaluation of the clinical use of tepoxalin and meloxicam in cats. AB - Medical records where tepoxalin (Zubrin) or meloxicam (Metacam) were prescribed in cats were reviewed and data extracted. Comparisons were performed for exploring changes between pre- and post-non-steroidal anti-inflammatory drug course laboratory tests. Seventy-nine medical records fit the inclusion criteria (n = 57 and n = 22, tepoxalin and meloxicam, respectively). The median dosages administered were 13 and 0.029 mg/kg(/)day (tepoxalin and meloxicam, respectively). Median prescription durations were 11 (2-919) and 93 (4-1814) days for tepoxalin and meloxicam, respectively. Suspected adverse events were reported for tepoxalin (9%, 5/57 cats) and meloxicam (18%, 4/22 cats) a median of 774 and 448 days, respectively, after the prescription started. For cats prescribed meloxicam, there were several statistically significant changes for serum biochemistry and hematology parameters, but median values were within normal limits. These valuable clinical data suggest that tepoxalin and meloxicam are well tolerated in the clinical setting at the doses prescribed in this study. PMID- 23349527 TI - Effect of background region of interest and time-interval selection on glomerular filtration ratio estimation by percentage dose uptake of (99m)Tc-DTPA in comparison with (51)Cr-EDTA clearance in healthy cats. AB - Evaluation of glomerular function is a useful part of the diagnostic approach in animals suspected of having renal disease. Time-interval and background region of interest (bg ROI) selection are determining factors when calculating the glomerular filtration ratio (GFR) based on percentage uptake of (99m)technetium labelled diethylene triamine penta-acetic acid ((99m)Tc-DTPA). Therefore, three different time intervals (60-120 s, 120-180 s, 60-180 s) and three different bg ROIs (C-shape, caudolateral, cranial + caudal) were investigated. In addition, global GFRs based on percentage dose uptake of (99m)Tc-DTPA for the different time-intervals and bg ROIs were compared with the global GFR based on (51)chromium-ethylene diaminic tetra-acetic acid ((51)Cr-EDTA) plasma clearance in nine healthy European domestic shorthair cats. Paired Student's t-tests and linear regression analysis were used to analyse the data. Different time intervals seemed to cause significant variation (P <0.01) in absolute GFR values, regardless of the choice of bg ROI. Significant differences (P <0.01) between bg ROIs were only observed in the 120-180s time interval between the C-shape and cranial + caudal bg ROI, and between the caudolateral and cranial + caudal bg ROI. The caudolateral bg ROI in the 60-180 s time interval showed the highest correlation coefficient (r = 0.882) between (99m)Tc-DTPA and (51)Cr-EDTA, although a significant difference (P <0.05) was present between both techniques. PMID- 23349525 TI - Minireview: miRomics in endocrinology: a novel approach for modeling endocrine diseases. AB - MicroRNAs (miRNAs) are small (16-24 nucleotides) noncoding RNAs that negatively regulate gene expression. Growing evidence demonstrates that miRNAs participate in the regulation of numerous physiological and pathological processes. The clinical utility of the cell-type-specific miRNA expression profile (miRomics) has been directly demonstrated in molecular classification of tumor samples and in prediction of prognosis or therapeutic responsiveness. Identification of the relevant miRNAs and their targets requires both in silico and molecular biological methods. In this review, we summarize the methodological arsenal used in miRNA-related research, and through our own data on adrenal tumors, we present how miRNA could be integrated into omics-based networks. The expanding knowledge obtained from miRNA research may lead to the development of novel diagnostic and treatment modalities in future. PMID- 23349524 TI - The role of GH in adipose tissue: lessons from adipose-specific GH receptor gene disrupted mice. AB - GH receptor (GHR) gene-disrupted mice (GHR-/-) have provided countless discoveries as to the numerous actions of GH. Many of these discoveries highlight the importance of GH in adipose tissue. For example GHR-/- mice are insulin sensitive yet obese with preferential enlargement of the sc adipose depot. GHR-/- mice also have elevated levels of leptin, resistin, and adiponectin, compared with controls leading some to suggest that GH may negatively regulate certain adipokines. To help clarify the role that GH exerts specifically on adipose tissue in vivo, we selectively disrupted GHR in adipose tissue to produce Fat GHR Knockout (FaGHRKO) mice. Surprisingly, FaGHRKOs shared only a few characteristics with global GHR-/- mice. Like the GHR-/- mice, FaGHRKO mice are obese with increased total body fat and increased adipocyte size. However, FaGHRKO mice have increases in all adipose depots with no improvements in measures of glucose homeostasis. Furthermore, resistin and adiponectin levels in FaGHRKO mice are similar to controls (or slightly decreased) unlike the increased levels found in GHR-/- mice, suggesting that GH does not regulate these adipokines directly in adipose tissue in vivo. Other features of FaGHRKO mice include decreased levels of adipsin, a near-normal GH/IGF-1 axis, and minimal changes to a large assortment of circulating factors that were measured such as IGF-binding proteins. In conclusion, specific removal of GHR in adipose tissue is sufficient to increase adipose tissue and decrease circulating adipsin. However, removal of GHR in adipose tissue alone is not sufficient to increase levels of resistin or adiponectin and does not alter glucose metabolism. PMID- 23349528 TI - Not different is not the same as the same: how can we tell? PMID- 23349529 TI - Do as you would be done by: write as you would wish to read. PMID- 23349530 TI - The heart on fire: inflammasome and cardiomyopathy. PMID- 23349532 TI - Does a full bladder assist insertion of intrauterine contraception? A randomised trial. AB - BACKGROUND: Bladder distension is thought to cause the uterine axis to become more aligned with the cervical canal. Among women undergoing assisted conception it has been demonstrated that having a full bladder facilitates the passage of an intrauterine catheter for embryo transfer. OBJECTIVE: To determine if insertion of intrauterine contraceptive devices is easier in women who have a full bladder at the time of insertion. METHODS: 200 women requesting intrauterine contraception with a pre-filled bladder were randomised to delayed emptying (after insertion; n=100) or immediate emptying (before insertion; n=100). Comparisons were made between doctors' reported ease of insertion and women's pain scores. RESULTS: There was no significant difference with reported ease of insertion between the groups. Doctors reported that insertions were either 'very easy' or 'quite easy' in 82% and 83% of women in the immediate and delayed emptying groups, respectively (95% CIs for difference -10% to +11%). There was no significant difference in reported pain scores, with mean pain scores (out of 10) of 3.8 and 4.4 in the delayed and immediate emptying groups, respectively. CONCLUSIONS: Bladder filling does not have a significant effect on ease of insertion of an intrauterine method of contraception. Insertion is mostly associated with low levels of discomfort, even in the presence of a full bladder. PMID- 23349533 TI - The role of ambulatory hysteroscopy in reproduction. AB - Hysteroscopy is a mainstay of modern gynaecologic practice. However, the role of ambulatory hysteroscopy and associated procedures has increased dramatically in recent years. The outpatient setting has associated benefits, both for the patient and economically. The advent of less invasive vaginoscopic techniques means that diagnostic hysteroscopy is achievable safely, comfortably and efficiently in almost all women and avoids the risk of a general anaesthetic. This review aims to summarise first the role for ambulatory hysteroscopy in diagnosis of conditions contributing to reproductive failure. The second section of the review concentrates on the therapeutic interventions that can be performed hysteroscopically in the ambulatory setting such as tubal catheterisation, tubal occlusion and uteroplasty. Lastly, we discuss the role outpatient hysteroscopy plays in established contraceptive techniques such as intrauterine device placement, and the more recent advent of hysteroscopic sterilisation. PMID- 23349534 TI - Understanding barriers to sexual health service access among substance-misusing women on the South East coast of England. AB - OBJECTIVES: Evidence suggests substance-misusing women (SMW) experience disproportionate sexual health morbidity and poor uptake of interventions including contraception and cervical screening, yet there has been little investigation of sexual health service access issues for this population. METHODS: Twenty women with problem drug use in Hastings in South East England, UK participated in a one-to-one interview with a researcher to explore experiences and beliefs surrounding access to a range of sexual health service interventions. Transcripts were open-coded and themes were elicited and organised concerning barriers to access. RESULTS: Drug-use lifestyles, trauma and low self-worth framed the lives of SMW and hindered sexual health service access through: depleted practical and emotional resources to enable attendance; high perceived emotional cost of discussing sexual histories, and coping with tests and unfavourable results; and low anticipated value of sexual health interventions due to low perception and minimisation of risk and perceived incompatibility between drug use and sexual well-being. CONCLUSIONS: A range of practical, social and emotional barriers to sexual health service access exist for this population, presenting a context from within which use of services may come at considerable personal cost to SMW. Interventions addressing anticipated stigma and emotional, hygiene and fiscal concerns are warranted for this population. PMID- 23349535 TI - Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease? AB - Two-thirds of adults in the U.S. are overweight or obese, and another 26 million have type 2 diabetes (T2D). Patients with diabetes and/or the metabolic syndrome have a significantly increased risk of heart attack and stroke compared with people with normal insulin sensitivity. Decreased insulin sensitivity in cardiovascular tissues as well as in traditional targets of insulin metabolic signaling, such as skeletal muscle, is an underlying abnormality in obesity, hypertension, and T2D. In the vasculature, insulin signaling plays a critical role in normal vascular function via endothelial cell nitric oxide production and modulation of Ca(2+) handling and sensitivity in vascular smooth muscle cells. Available evidence suggests that impaired vascular insulin sensitivity may be an early, perhaps principal, defect of vascular function and contributor to the pathogenesis of vascular disease in persons with obesity, hypertension, and T2D. In the overweight and obese individual, as well as in persons with hypertension, systemic and vascular insulin resistance often occur in concert with elevations in plasma aldosterone. Indeed, basic and clinical studies have demonstrated that elevated plasma aldosterone levels predict the development of insulin resistance and that aldosterone directly interferes with insulin signaling in vascular tissues. Furthermore, elevated plasma aldosterone levels are associated with increased heart attack and stroke risk. Conversely, renin-angiotensin-aldosterone system and mineralocorticoid receptor (MR) antagonism reduces cardiovascular risk in these patient populations. Recent and accumulating evidence in this area has implicated excessive Ser phosphorylation and proteosomal degradation of the docking protein, insulin receptor substrate, and enhanced signaling through hybrid insulin/IGF-1 receptor as important mechanisms underlying aldosterone mediated interruption of downstream vascular insulin signaling. Prevention or restoration of these changes via blockade of aldosterone action in the vascular wall with MR antagonists (i.e., spironolactone, eplerenone) may therefore account for the clinical benefit of these compounds in obese and diabetic patients with cardiovascular disease. This review will highlight recent evidence supporting the hypothesis that aldosterone and MR signaling represent an ideal candidate pathway linking early promoters of diabetes, especially overnutrition and obesity, to vascular insulin resistance, dysfunction, and disease. PMID- 23349536 TI - Diabetes research: a perspective from the National Institute of Diabetes and Digestive and Kidney Diseases. PMID- 23349538 TI - Novel insights into the regulation of postprandial lipemia by glucagon-like peptides: significance for diabetes. PMID- 23349537 TI - beta-Cell failure in type 2 diabetes: a case of asking too much of too few? AB - The islet in type 2 diabetes (T2DM) is characterized by a deficit in beta-cells, increased beta-cell apoptosis, and extracellular amyloid deposits derived from islet amyloid polypeptide (IAPP). In the absence of longitudinal studies, it is unknown if the low beta-cell mass in T2DM precedes diabetes onset (is a risk factor for diabetes) or develops as a consequence of the disease process. Although insulin resistance is a risk factor for T2DM, most individuals who are insulin resistant do not develop diabetes. By inference, an increased beta-cell workload results in T2DM in some but not all individuals. We propose that the extent of the beta-cell mass that develops during childhood may underlie subsequent successful or failed adaptation to insulin resistance in later life. We propose that a low innate beta-cell mass in the face of subsequent insulin resistance may expose beta-cells to a burden of insulin and IAPP biosynthetic demand that exceeds the cellular capacity for protein folding and trafficking. If this threshold is crossed, intracellular toxic IAPP membrane permeant oligomers (cylindrins) may form, compromising beta-cell function and inducing beta-cell apoptosis. PMID- 23349539 TI - LADA: time for a new definition. PMID- 23349540 TI - Understanding the diabetic brain: new technologies but old challenges. PMID- 23349541 TI - Microvascular contributions to insulin resistance. PMID- 23349542 TI - Aging and insulin resistance: just say iNOS. PMID- 23349543 TI - Targeted metabolomics finds its mark in diabetes research. PMID- 23349544 TI - Plasma ceramides target skeletal muscle in type 2 diabetes. PMID- 23349547 TI - Impact of admission glycemic variability, glucose, and glycosylated hemoglobin on major adverse cardiac events after acute myocardial infarction. AB - OBJECTIVE: Dysglycemia is associated with poorer prognosis in patients with acute myocardial infarction (AMI). Whether admission glycemic variability (GV) has important value in prognosis of AMI patients is still unknown. The aim of the study is to investigate the prognostic value of admission GV, glucose, and glycosylated hemoglobin (HbA(1c)) in AMI patients. RESEARCH DESIGN AND METHODS: We measured blood glucose, HbA(1c), and GV on admission in 222 consecutive patients with diagnosed AMI. GV, indicated as the mean amplitude of glycemic excursions (MAGE), was determined by a continuous glucose monitoring system. MAGE was categorized as >=3.9 or <3.9 mmol/L, admission glucose as >=8.61 or <8.61 mmol/L, and HbA(1c) as >=6.5 or <6.5%. Participants were followed up prospectively for 12 months. The relationship of admission MAGE, glucose, and HbA(1c) to the major adverse cardiac event (MACE) of AMI patients was analyzed. RESULTS: In 222 enrolled patients with AMI, the rate of MACE by MAGE category (<3.9 or >=3.9 mmol/L) was 8.4 and 24.1%, respectively (P = 0.001), by admission glucose category (<8.61 or >=8.61 mmol/L) was 10.1 and 21.6%, respectively (P = 0.020), and by HbA(1c) category (<6.5 vs. >=6.5%) was 10.7 versus 18.7%, respectively (P = 0.091). In multivariate analysis, high MAGE level was significantly associated with incidence of MACE (hazard ratio 2.419 [95% CI 1.273 9.100]; P = 0.017) even after adjusting for Global Registry of Acute Coronary Events risk score, but admission glucose and HbA(1c) was not. CONCLUSIONS: Elevated admission GV appears more important than admission glucose and prior long-term abnormal glycometabolic status in predicting 1-year MACE in patients with AMI. PMID- 23349549 TI - Habitually higher dietary glycemic index during puberty is prospectively related to increased risk markers of type 2 diabetes in younger adulthood. AB - OBJECTIVE: Carbohydrate nutrition during periods of physiological insulin resistance such as puberty may affect future risk of type 2 diabetes. This study examined whether the amount or the quality (dietary glycemic index [GI], glycemic load [GL], and added sugar, fiber, and whole-grain intake) of carbohydrates during puberty is associated with risk markers of type 2 diabetes in younger adulthood. RESEARCH DESIGN AND METHODS: The analysis was based on 226 participants (121 girls and 105 boys) from the Dortmund Nutritional and Anthropometric Longitudinally Designed Study (DONALD) with an average of five 3 day weighed dietary records (range 2-6) during puberty (girls, age 9-14 years; boys, age 10-15 years) and fasting blood samples in younger adulthood (age 18-36 years) (average duration of follow-up 12.6 years). Multivariable linear regression was used to analyze the associations between carbohydrate nutrition and homeostasis model assessment-insulin resistance (HOMA-IR) as well as the liver enzymes alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) (n = 214). RESULTS: A higher dietary GI was prospectively related to greater values of HOMA-IR (P(trend) = 0.03), ALT (P(trend) = 0.02), and GGT (P(trend) = 0.04). After adjustment for sex, adult age, baseline BMI, and early life and socioeconomic factors as well as protein and fiber intake, predicted mean HOMA-IR values in energy-adjusted tertiles of GI were 2.37 (95% CI 2.16-2.60), 2.47 (2.26 2.71), and 2.59 (2.35-2.85). The amount of carbohydrates, GL, and added sugar, fiber, and whole-grain intake were not related to the analyzed markers. CONCLUSIONS: Our data indicate that a habitually higher dietary GI during puberty may adversely affect risk markers of type 2 diabetes in younger adulthood. PMID- 23349550 TI - Bacterial resistance mechanism: what proteomics can elucidate. AB - Antibiotics are important therapeutic agents commonly used for the control of bacterial infectious diseases; however, resistance to antibiotics has become a global public health problem. Therefore, effective therapy in the treatment of resistant bacteria is necessary and, to achieve this, a detailed understanding of mechanisms that underlie drug resistance must be sought. To fill the multiple gaps that remain in understanding bacterial resistance, proteomic tools have been used to study bacterial physiology in response to antibiotic stress. In general, the global analysis of changes in the protein composition of bacterial cells in response to treatment with antibiotic agents has made it possible to construct a database of proteins involved in the process of resistance to drugs with similar mechanisms of action. In the past few years, progress in using proteomic tools has provided the most realistic picture of the infective process, since these tools detect the end products of gene biosynthetic pathways, which may eventually determine a biological phenotype. In most bacterial species, alterations occur in energy and nitrogen metabolism regulation; glucan biosynthesis is up-regulated; amino acid, protein, and nucleotide synthesis is affected; and various proteins show a stress response after exposing these microorganisms to antibiotics. These issues have been useful in identifying targets for the development of novel antibiotics and also in understanding, at the molecular level, how bacteria resist antibiotics. PMID- 23349548 TI - The effect of real-time continuous glucose monitoring in pregnant women with diabetes: a randomized controlled trial. AB - OBJECTIVE: To assess whether intermittent real-time continuous glucose monitoring (CGM) improves glycemic control and pregnancy outcome in unselected women with pregestational diabetes. RESEARCH DESIGN AND METHODS: A total of 123 women with type 1 diabetes and 31 women with type 2 diabetes were randomized to use real time CGM for 6 days at 8, 12, 21, 27, and 33 weeks in addition to routine care, including self-monitored plasma glucose seven times daily, or routine care only. To optimize glycemic control, real-time CGM readings were evaluated by a diabetes caregiver. HbA1c, self-monitored plasma glucose, severe hypoglycemia, and pregnancy outcomes were recorded, with large-for-gestational-age infants as the primary outcome. RESULTS: Women assigned to real-time CGM (n = 79) had baseline HbA1c similar to that of women in the control arm (n = 75) (median 6.6 [range 5.3 10.0] vs. 6.8% [5.3-10.7]; P = 0.67) (49 [34-86] vs. 51 mmol/mol [34-93]). Forty nine (64%) women used real-time CGM per protocol. At 33 weeks, HbA1c (6.1 [5.1 7.8] vs. 6.1% [4.8-8.2]; P = 0.39) (43 [32-62] vs. 43 mmol/mol [29-66]) and self monitored plasma glucose (6.2 [4.7-7.9] vs. 6.2 mmol/L [4.9-7.9]; P = 0.64) were comparable regardless of real-time CGM use, and a similar fraction of women had experienced severe hypoglycemia (16 vs. 16%; P = 0.91). The prevalence of large for-gestational-age infants (45 vs. 34%; P = 0.19) and other perinatal outcomes were comparable between the arms. CONCLUSIONS: In this randomized trial, intermittent use of real-time CGM in pregnancy, in addition to self-monitored plasma glucose seven times daily, did not improve glycemic control or pregnancy outcome in women with pregestational diabetes. PMID- 23349551 TI - Preserved adiposity in the Fischer 344 rat devoid of gut microbiota. AB - The gut microbiota is implicated in host metabolism and energy regulation. Germ free (GF) C57BL/6 mice display decreased adiposity, an effect associated with increased intestinal fasting-induced adipose factor (FIAF) and decreased hepatic lipogenesis. However, whether the altered metabolism observed in the absence of gut microbiota extends to other species, commonly used to examine energy metabolism, is unknown. Thus, we used the GF Fischer 344 rat to examine adiposity and associated alterations in intestinal nutrient chemoreceptors, gut peptide levels, and FIAF expression, as well as markers of hepatic and adipose lipogenesis and adipogenesis. We found that GF rats displayed similar body weights and adiposity relative to controls. GF state was associated with up regulation of intestinal and hepatic FIAF, decreased expression of hepatic FAS, ACC-1, and SREBP, and increased pAMPK and pACC. However, GF rats displayed reduced adipocyte FIAF, increased lipogenic enzymes, and decreased pAMPK, accompanied by an increase in adipocyte size. These findings show that, despite increased intestinal FIAF and reduced hepatic lipogenesis, adiposity is preserved in the Fisher 344 GF rat, unlike the C57Bl/6J GF mouse, with a shift in increased adipocyte lipogenesis. This also demonstrates that adipose, rather than intestinal, FIAF may have a more prominent role in adiposity. PMID- 23349552 TI - Computer-based Learning of Neuroanatomy: A Longitudinal Study of Learning, Transfer, and Retention. AB - A longitudinal experiment was conducted to evaluate the effectiveness of new methods for learning neuroanatomy with computer-based instruction. Using a 3D graphical model of the human brain, and sections derived from the model, tools for exploring neuroanatomy were developed to encourage adaptive exploration. This is an instructional method which incorporates graphical exploration in the context of repeated testing and feedback. With this approach, 72 participants learned either sectional anatomy alone or whole anatomy followed by sectional anatomy. Sectional anatomy was explored either with perceptually continuous navigation through the sections or with discrete navigation (as in the use of an anatomical atlas). Learning was measured longitudinally to a high performance criterion. Subsequent tests examined transfer of learning to the interpretation of biomedical images and long-term retention. There were several clear results of this study. On initial exposure to neuroanatomy, whole anatomy was learned more efficiently than sectional anatomy. After whole anatomy was mastered, learners demonstrated high levels of transfer of learning to sectional anatomy and from sectional anatomy to the interpretation of complex biomedical images. Learning whole anatomy prior to learning sectional anatomy led to substantially fewer errors overall than learning sectional anatomy alone. Use of continuous or discrete navigation through sectional anatomy made little difference to measured outcomes. Efficient learning, good long-term retention, and successful transfer to the interpretation of biomedical images indicated that computer-based learning using adaptive exploration can be a valuable tool in instruction of neuroanatomy and similar disciplines. PMID- 23349553 TI - Efficient, Low-Cost Synthesis of Retinal (Vitamin A Aldehyde). AB - Inexpensive retinyl acetate has been subjected to transesterification followed by allylic oxidation to give retinal in 98% yield as a 92:8 mixture of all-trans/13 cis isomers after chromatographic separation. More convenient methods of isolating the all-trans isomer have also been employed. PMID- 23349555 TI - Head and neck cancer in elderly patients: is microsurgical free-tissue transfer a safe procedure? AB - The safety and success of microvascular transfer have been well documented in the general population, but the good results achieved with the use of free flaps in elderly patients have received little attention. This study sought to identify differences in complications, morbidity and functional outcomes between elderly (>= 75 years) and younger (< 75 years) patients treated surgically for advanced head and neck cancer using the Head and Neck 35 module of the European Organisation for Research and Treatment of Cancer quality of life questionnaire. Patient treatment consisted of composite resection, including excision of the primary tumour with ipsilateral or bilateral neck dissection and microvascular reconstruction. Eighty-five microvascular tissue transfers were performed to reconstruct major surgical defects. Postoperative radiation therapy was performed when indicated. Total flap loss occurred in three cases in elderly patients and two cases in younger patients. The rates of major surgical complication were 9% in young patients and 11% in elderly patients. No significant difference was observed between the two groups in the rates of major and minor flap complications, morbidity or long-term functional outcome. The results of the present analysis indicate that free-flap microvascular reconstruction can be considered a safe procedure in elderly patients with head and neck cancer. PMID- 23349554 TI - Infant hearing loss: from diagnosis to therapy Official Report of XXI Conference of Italian Society of Pediatric Otorhinolaryngology. AB - Hearing loss is one of the most common disabilities and has lifelong consequences for affected children and their families. Both conductive and sensorineural hearing loss (SNHL) may be caused by a wide variety of congenital and acquired factors. Its early detection, together with appropriate intervention, is critical to speech, language and cognitive development in hearing-impaired children. In the last two decades, the application of universal neonatal hearing screening has improved identification of hearing loss early in life and facilitates early intervention. Developments in molecular medicine, genetics and neuroscience have improved the aetiological classification of hearing loss. Once deafness is established, a systematic approach to determining the cause is best undertaken within a dedicated multidisciplinary setting. This review addresses the innovative evidences on aetiology and management of deafness in children, including universal neonatal screening, advances in genetic diagnosis and the contribution of neuroimaging. Finally, therapy remains a major challenge in management of paediatric SNHL. Current approaches are represented by hearing aids and cochlear implants. However, recent advances in basic medicine which are identifying the mechanisms of cochlear damage and defective genes causing deafness, may represent the basis for novel therapeutic targets including implantable devices, auditory brainstem implants and cell therapy. PMID- 23349556 TI - Shoulder function after selective and superselective neck dissections: clinical and functional outcomes. AB - The aim of this work is to assess the clinical and functional outcome of patients who underwent different types of neck dissection, with special regards to the spinal accessory nerve, trapezius muscle and shoulder function. From February 2008 to July 2010, we evaluated 17 cases of neck dissection in patients affected by laryngeal carcinoma clinically staged N0. We performed selective neck dissection (IIA-IIBIII- IV) in 11 cases (group A) and superselective neck dissection in 6 cases (group B). All patients underwent clinical examination before surgery to evaluate shoulder function. They also underwent functional evaluation of the spinal accessory nerve through electromyography (study of muscular activity) and electroneurography (study of motor action potential). Patients were evaluated before surgery (T0), 8 days after surgery (T1) and 21 days after surgery (T2). In all cases, at the end of surgery it was possible to assess the integrity of the spinal accessory nerve. The average value of the MAP was 13.06 in group A and 10.98 in group B at T0. Eight days after surgery (T1) the value of MAP was reduced to 1.35 in group A and 6.15 in group B. Electromyography evaluation showed signs of denervation in 6 cases in group A and in 2 cases in group B. Voluntary activity was not detectable in 6 cases in group A, while it was present, even if reduced, in all cases in group B. At 21 days after surgery (T2), we found a value of MAP of 1.03 in group A and 6.43 in group B. Electromyography showed signs of denervation in 10 patients in group A and in 3 cases in group B. Voluntary activity was not detectable in 10 cases in group A, while it was present in all cases in group B. The arm abduction test was 2.5 in group A and 4.0 in group B. Neck dissection quality of life questionnaire showed a value of 24.17 in group A and a value of 25.5 in group B. Our data thus confirm that surgical manipulation of the nerve may be associated with severe impairment of nerve conduction when sublevel IIB is involved in the dissection. PMID- 23349557 TI - The effect of alpha-lipoic acid on temporary threshold shift in humans: a preliminary study. AB - Noise-induced hearing loss (NHIL) is a significant source of hearing loss in industrialized countries. Recent research on the cellular bases of NIHL has led to new avenues for protection through prophylactic drugs. Although in experimental animal models several compounds have shown a protective effect in NIHL, limited data are available in humans. Many authors are focusing their attention on the role of antioxidant on hearing protection. Alpha-lipoic acid (ALA), an essential cofactor in mitochondrial enzymes, is a novel biological antioxidant and a potent free radical scavenger and, in animal models, it has been shown to protect from age-induced and cisplatin-induced hearing loss. The aim of our study was to evaluate the effect of alpha-lipoic acid on temporary threshold shift measured 2 minutes after the end of exposure (TTS(2)) induced by a 3 kHz tone in young normally hearing subjects. Thirty young normal hearing volunteers served as control subjects. Individuals were randomly assigned to three groups. Group A (10 subjects) subjects were exposed to a 90 dB HL 3 kHz pure tone for 10 min. Group B (10 subjects) subjects were exposed to a 90 dB HL 3 kHz pure tone one hour after oral ingestion of 600 mg of ALA. Group C (10 subjects) were exposed to a 90 dB HL 3 kHz pure tone after 10 days of oral ingestion of 600 mg of ALA. Statistical analysis showed that prior to the exposure the hearing thresholds did not differ significantly among the three groups. TTS(2) of group C was significantly lower that TTS2 of Groups A and B at 6 kHz (p 0.03), and TEOAEs amplitude change after noise exposure was lower for group C compared to Groups A (p = 0.089) and B (p = 0.03). ALA is a powerful lipophilic antioxidant and free radical scavenger currently used in clinical practice. A single dose of 600 mg of dose ALA did not induce any protection on the TTS(2) induced by a 90 dB HL 3 kHz tone, while 10 days of therapeutic dosage assumption of ALA was associated with significant protection at 6 kHz. The results of this study show that a short course of ALA protects from TTS(2) in humans, and therefore further studies are needed to better define the role of ALA in the prevention of noise induced hearing loss. PMID- 23349558 TI - The role of High Mobility Group Box 1 chromosomal protein in the pathogenesis of chronic sinusitis and nasal polyposis. AB - Chronic rhinosinusitis with nasal polyposis is considered to be a multifactorial disease where different stimuli (mechanical, viral, bacterial, fungal infection, immunological disorders or dysreactivity, environmental pollution), acting on the mucosa of nasal cavities and paranasal sinuses, lead to epithelial damage and mucosal inflammation. Inflammatory cell infiltration (predominantly eosinophils, but also neutrophils, mast cells, macrophages and lymphocytes), cytokine release and sub-epithelial oedema are the histological pictures that are associated, from the clinical point of view, with nasal congestion, secretion and/or post-nasal drip and facial pain/headache. Recently, the importance of the HMG B-1 protein in the pathogenesis of several inflammatory diseases has been demonstrated. This protein is released from necrotic/damaged cells or immune-activated cells, and by acting on specific membrane receptors causes the release of pro-inflammatory mediators, endothelial activation and the survival of inflammatory cells. The objective of the present study was: i) to determine whether HMG B1 is augmented in chronic rhinosinusitis with nasal polyps; ii) if its expression is associated with eosinophils, TNF-alpha, IL 5 and IL 8 cytokines typically present in chronic inflammation of the nose and paranasal sinuses; iii) to investigate a hypothetical role of this protein in the pathogenesis of nasal polyposis. Nasal polyps tissue from 21 patients affected by CRSwNP and nasal mucosa from 8 controls was collected at the ENT Department of the Chinese PLA General Hospital and underwent immunohistological staining for detection of HMG B1 protein and IL 5, IL -8 and TNF-alpha inflammatory cytokines. The degree of HMG B1 protein expression was evaluated by dividing the stained sections in 4 portions: 1) nucleus of epithelial cells, 2) cytoplasm of epithelial cells, 3) focal extracellular infiltration, 4) inflammatory cells. HMG B1 was more expressed in the nucleus of epithelial cells of patients compared with controls. In contrast, epithelial cytoplasm HMG B1 staining was significant lower in patients. Sub epithelial focal infiltration of HMG B1 protein expression was lower in controls, whereas the expression of HMG B1 in the inflammatory cells in patients was significantly increased in comparison with controls. These data, together with the correlation we found between HMG B1 protein expression in different portions and the number of eosinophils infiltrating cells, or IL -5, IL -8 and TNF-alpha positive cells in patients, suggest that HMG B1 may play a crucial role in the pathogenesis of chronic rhinosinusitis with nasal polyps. PMID- 23349560 TI - The ENT's role in sinus lift management doesn't need misleading messages. PMID- 23349559 TI - Effect of a fixed combination of nimodipine and betahistine versus betahistine as monotherapy in the long-term treatment of Meniere's disease: a 10-year experience. AB - Despite an abundance of long-term pharmacological treatments for recurrent vertigo attacks due to Meniere's disease, there is no general agreement on the their efficacy. We present the results of a retrospective study based on a 10 year experience with two long-term medical protocols prescribed to patients affected by Meniere's disease (diagnosed according to the American Academy of Otolaryngology-Head and Neck Surgery Committee on Hearing and Equilibrium guidelines) who completed treatments in the period 1999-2009. A total of 113 medical records were analysed; 53 patients received betahistine-dihydrochloride at on-label dosage (32 mg die) for six months, and 60 patients were treated with the same regimen and nimodipine (40 mg die) as an add-therapy during the same period. Nimodipine, a 1,4-dihydropyridine that selectively blocks L-type voltage sensitive calcium channels, has previously been tested as a monotherapy for recurrent vertigo of labyrinthine origin in a multinational, double-blind study with positive results. A moderate reduction of the impact of vertigo on quality of life (as assessed by the Dizziness Handicap Inventory) was obtained in patients after therapy with betahistine (p < 0.05), but a more significant effect was achieved in patients treated by combined therapy (p < 0.005). In the latter group, better control of vertigo was seen with a greater reduction of frequency of attacks (p < 0.005). Both protocols resulted in a significant improvement of static postural control, although a larger effect on body sway area in all tests was obtained by the fixed combination of drugs. In contrast, no beneficial effect on either tinnitus annoyance (as assessed by the Tinnitus Handicap Inventory) and hearing loss (pure-tone average at 0.5, 1, 2, 3 kHz frequencies of the affected ear) was recorded in patients treated with betahistine as monotherapy (p > 0.05), whereas the fixed combination of betahistine and nimodipine was associated with a significant reduction of tinnitus annoyance and improvement of hearing loss (p < 0.005). It was concluded that nimodipine represents not only a valid add-therapy for Meniere's disease, and that it may also exert a specific effect on inner ear disorders. Further studies to investigate this possibility are needed. PMID- 23349561 TI - Step-by-step mandibular reconstruction with free fibula flap modelling. AB - The functional and aesthetic outcomes after segmental mandibular resection are closely related to the technique used during mandibular reconstruction with bone graft. The fibula free flap approach allows the possibility of using bone with/without skin for restoring the defect. Here, we aimed to establish the preplating technique for oromandibular reconstruction in a step-by-step fashion, based on 41 patients. The surgical technique is expounded in 8-10 steps. Preplating, plate removal, resection, replating, template modelling, contouring and fixation of the fibula represent the key points of the procedure. In this report, we show that the preplating and template modelling method is easy, does not incur extra costs and can be successfully used for mandibular reconstruction with bone graft. Functional and aesthetic results confirm the feasibility and reproducibility of the technique. PMID- 23349562 TI - Are brown tumours a forgotten disease in developed countries? AB - Brown tumours (BT), an expression of osteitis fibrosa cystic due to primary hyperparathyroidism (pHPT), can occasionally be mistaken for malignancy. Among 615 patients who underwent parathyroidectomy for pHPT in our institution, the medical records of three patients affected by BT were reviewed. The first patient underwent surgical removal of the orbital mass for a suspected lachrymal gland neoplasm. The remaining two patients underwent, respectively, leg amputation and femur resection for a suspected bone malignancy. Final histology showed a BT in three cases. All three patients were admitted to our Division and underwent successful parathyroidectomy for parathyroid adenoma in two cases and for parathyroid carcinoma in the remaining case. When faced with an osteolithic bone lesion, complete evaluation of medical history, biochemical and radiographic findings can help to reach a correct diagnosis and avoid unnecessary bone resections. PMID- 23349563 TI - Pseudomonas and Aspergillus interaction in malignant external otitis: risk of treatment failure. AB - Malignant external otitis (MEO) is a rare infection of the temporal bone primarily affecting elderly patients and diabetics or immunocompromised individuals, which may have dismal prognosis if treatment is not prompt and adequate. Almost 95% of MEO cases reported in the literature are attributed to Pseudomonas aeruginosa, and this pathogen is isolated from aural drainage in > 90% of cases. However, in recent years fungal and polymicrobial temporal bone infections have been reported with increasing frequency. The aim of this paper is to discuss a possible pitfall in MEO treatment using an unusual clinical case. In this patient, bacteriological data positive for Pseudomonas delayed correct diagnosis of Aspergillus infection, which was obtained after surgical debridement and biopsy of the infra-temporal space. PMID- 23349564 TI - Synthesis of beta-Glycosyl Amides from N-Glycosyl Dinitrobenzenesulfonamides. AB - The N-glycosyl-2,4-dinitrobenzenesulfonamides were accessed via benzoyl-protected beta-glycosyl azides. The azides were reduced with Adams' catalyst to the corresponding amines. The glycosylamines were sulfonated with 2,4 dinitrobenzenesulfonyl chloride to form N-glycosyl-2,4-dinitrobenzenesulfonamides in moderate yields. beta-Glycosyl amides were then prepared in 67 - 81 % yields by treatment of the sulfonamides with thioacetic acid and cesium carbonate. The conversion of the glycosylsulfonamide to the glycosyl amide proceeded with high stereoselectivity. PMID- 23349565 TI - Configuration and Performance of a Mobile (129)Xe Polarizer. AB - A stand-alone, self-contained and transportable system for the polarization of (129)Xe by spin exchange optical pumping with Rb is described. This mobile polarizer may be operated in batch or continuous flow modes with medium amounts of hyperpolarized (129)Xe for spectroscopic or small animal applications. A key element is an online nuclear magnetic resonance module which facilitates continuous monitoring of polarization generation in the pumping cell as well as the calculation of the absolute (129)Xe polarization. The performance of the polarizer with respect to the crucial parameters temperature, xenon and nitrogen partial pressures, and the total gas flow is discussed. In batch mode the highest (129)Xe polarization of P(Xe) = 40 % was achieved using 0.1 mbar xenon partial pressure. For a xenon flow of 6.5 and 26 mln/min, P(Xe) = 25 % and P(Xe) = 13 % were reached, respectively. The mobile polarizer may be a practical and efficient means to make the applicability of hyperpolarized (129)Xe more widespread. PMID- 23349566 TI - Antiferromagnetic Ordering of Magnetic Clusters Units in Nb(6)F(15). AB - We have studied the magnetic cluster compound Nb(6)F(15) which has an odd number of 15 valence electrons per (Nb(6)F(12))(3+) cluster core, as a function of temperature using nuclear magnetic resonance, magnetic susceptibility, electron magnetic resonance and neutron powder diffraction. Nuclear magnetic resonance of the (19)F nuclei shows two lines corresponding to the apical F(a-a) nucleus, and to the inner F(i) nuclei. The temperature dependence of the signal from the F(i) nuclei reveals an antiferromagnetic ordering at T < 5 K, with a hyperfine field of ~2 mT. Magnetic susceptibility exhibits a Curie-Weiss behavior with T(N) ~5 K, and MU(eff) ~1.57 MU(B) close to the expected theoretical value for one unpaired electron (1.73 MU(B)). Electron magnetic resonance linewidth shows a transition at 5 K. Upon cooling from 10 to 1.4 K, the neutron diffraction shows a decrease in the intensity of the low-angle diffuse scattering below Q ~0.27 A(-1). This decrease is consistent with emergence of magnetic order of large magnetic objects (clusters). This study shows that Nb(6)F(15) is paramagnetic at RT and undergoes a transition to antiferromagnetic order at 5 K. This unique antiferromagnetic ordering results from the interaction between magnetic spins delocalized over each entire (Nb(6)F(12) (i))(3+) cluster core, rather than the common magnetic ordering. PMID- 23349567 TI - The "write" approach to publish. PMID- 23349568 TI - Tooth resorption part I - pathogenesis and case series of internal resorption. AB - Resorption is a pathologic process that often eludes the clinician with its varied etiologic factors and diverse clinical presentations. The key cells involved in tooth resorption are odontoclasts which are multinucleated cells that produce resorption lacunae. Resorption can be classified as internal and external resorption. Internal resorption has been described as a rare occurrence as compared to external resorption. This article describes the pathogenesis of tooth resorption and various forms of internal resorption along with some clinical cases. Early diagnosis is the key factor in the successful management of resorptive lesions. PMID- 23349569 TI - The antibacterial activity of sodium hypochlorite and chlorhexidine against Enterococcus faecalis: A review on agar diffusion and direct contact methods. AB - Complete debridement and disinfection of the root canal system are fundamental requirements for successful endodontic treatment. Despite the morphological challenges of the internal root anatomy, root canal irrigants play an important role in the optimization of the root canal preparation, which is essentially a chemo-mechanical procedure. Enterococcus faecalis is one of the most resistant microorganisms that dominants the microbial ecosystem of persistent periradicular lesions in retreatment cases. For that reason, many in vitro and in vivo studies evaluated and compared the antibacterial activity of sodium hypochlorite and chlorhexidine at varying concentrations using different experimental models against this microorganism. However, many controversies with regard to the ideal irrigant and concentration do in fact exist. Hence, this review aims to discuss the antibacterial activity of these two main root canal irrigants against Enterococcus faecalis using the agar diffusion and direct contact methods and the possible modulating factors responsible for inconsistent findings among different studies. In addition, the disinfection potential of both chemical agents on gutta percha and Resilon cones are also discussed. The source of this review was conducted through an electronic literature search using PubMed database from December 1997 until December 2011, which analyze the related laboratory investigations of both irrigants, published in major endodontic journals. PMID- 23349570 TI - The effect of bleaching on toothbrush abrasion of resin composites. AB - AIM: This experimental study was designed to focus on the effects of bleaching on toothbrush abrasion in three types of composites with different filler size. MATERIALS AND METHODS: Forty eight disks were prepared from three types of composite and divided into 6 groups. In the first three groups the abrasion test was done. The remaining groups were bleached and the abrasion test was performed. The weight of the samples before and after abrasion was measured. Statistical analysis was done with one-way ANOVA and Duncan test. RESULTS: There was a significant difference in abrasion of composites with different filler size (P < 0.05). The most amount of abrasion was observed in Z100 after being bleached. An increase in abrasion was noticed in all three types of tested composite after bleaching. CONCLUSION: According to the findings, it is suggested to use a nano filled resin composite for restoration if the bleaching treatment is required. PMID- 23349571 TI - Informative promotional outcome on school teachers' knowledge about emergency management of dental trauma. AB - AIM: To assess awareness of school teachers concerning the emergency management of traumatized teeth. MATERIALS AND METHODS: This is a prospective intervention study conducted with 1000 teachers (500 urban, 500 rural) randomly selected from the entire government and private, primary (elementary) as well as secondary (high) schools of Nellore district of Andhra Pradesh, India. Study was carried out in three phases; the first phase being an initial survey conducted to assess the existing knowledge of teachers on management of traumatic injuries by using self-administered questionnaire. This was followed by a comprehensive informative promotion regarding the initial management of the traumatic dental injuries for the teachers. A post-promotion follow-up review was conducted 3 months later to evaluate the effect of the informative promotion, using the same set of questionnaires. Study was completed over a period of 9 months. STATISTICAL METHODS: Data analysis was done using SPSS software version 14.0, and Chi-square test was used to compare the knowledge of teachers prior to and after the informative promotion. The level of significance was set at P <= 0.05. RESULTS: The teachers' overall knowledge with respect to the emergency management of the traumatic injuries was deficient and significant differences were found in the knowledge of teachers before and after the informative promotion. CONCLUSION: Informative promotion programs to improve the knowledge and awareness of this group of community, who are generally the first line of assistance in case of dental trauma in schools, are mandatory. PMID- 23349572 TI - Influence of restorative technique, Bevelling and aging on composite bonding to sectioned incisal edges: A comparative in vitro study. AB - AIM: To evaluate the effect of direct and indirect technique, bevel placement, and aging on the fracture resistance of composite restorations bonded to sectioned incisal edges. MATERIALS AND METHODS: Incisal thirds of 80 human maxillary incisors were sectioned. Four treatment groups of 20 teeth each were formed as follows: Direct composite with bevel and without bevel (Adper single bond 2/Filtek Z350); indirect composite with bevel and without bevel (prepolymerized Filtek Z350 cemented with Adper single bond 2/Relay * ARC). Ten teeth from each group were stored in distilled water for 24 h. The remaining ten teeth were stored in distilled water for 180 days with two thermocycling treatments. The specimens were subjected to shear testing using universal testing machine. Fractured specimens were examined with a stereomicroscope at *10 magnification to evaluate the failure patterns. The obtained data were statistically analyzed by using ANOVA, Bonferroni test, and Student's t-test. RESULTS: Beveled restorations exhibited higher fracture resistance values than nonbeveled restorations. Long-term water storage decreased the fracture resistance. CONCLUSION: The use of bevels resulted in improved fracture resistance of composite restorations and reduced the impact of aging. PMID- 23349573 TI - Evaluation of light transmission through different esthetic posts and its influence on the degree of polymerization of a dual cure resin cement. AB - AIM: To measure the light transmission through different esthetic posts and to evaluate the degree of polymerization of dual cure resin cement cured through these posts. MATERIALS AND METHODS: The posts were divided into two experimental groups i.e. Group A (D.T. Light post); Group B (D.T. White post) and control i.e. Group C (metal post), each group having 10 samples. Posts of each group were illuminated with curing light and photographs were taken keeping the parameters standardized to evaluate the intensity of light transmission at different levels. The degree of polymerization of dual cure resin cement was evaluated using Fourier Transform Infrared spectroscopy. The data obtained was subjected to statistical analysis. RESULTS: D.T. Light post showed highest light transmission and degree of polymerization. The light intensity decreased from cervical to apical for both esthetic post but the decrease from middle to apical third was insignificant for D.T. White post group. No light transmission was detected in metal post but the degree of polymerization decreased significantly from cervical to middle third. CONCLUSION: Cementation of fibre post with superior light transmitting ability using dual cured resin cement resulted in increased degree of polymerization. PMID- 23349574 TI - Evaluation of biocompatibility of a new root canal irrigant Q MixTM 2 in 1- An in vivo study. AB - AIM: To evaluate the biocompatibility of a new root canal irrigant Q mixTM 2 in 1 in comparison to 0.9% sterile saline, 3% sodium hypochlorite (NaOCl), 2% chlorhexidine (CHX), and 17% ethylenediaminetetraacetic acid (EDTA). MATERIALS AND METHODS: Six circles were drawn on the dorsal skin of 24 male Wistar Albino rats, leaving 2cm between each circle. Using a syringe, 0.1mL of each root canal irrigant was injected subcutaneously into five circles. In the sixth circle, the needle of an empty syringe was introduced into the skin, but no irrigant was injected (control group). Evaluations were done at 2 hours, 48 hours, 14 days, and 30 days postprocedure. Tissue samples were excised, embedded in paraffin blocks, and 3 MUm thick sections were obtained and stained with hematoxylin and eosin. The areas of inflammatory reaction were evaluated. From each tissue sample, five sections presenting the greatest inflammatory reactions were examined under a light microscope, and analyzed statistically by analysis of variance (ANOVA) and Tukey's test. RESULTS: At the two-hour examination period, all the irrigants showed a slight increase in the number of inflammatory cells, at 48 hours, the number of inflammatory cells were increased significantly, and after 14 and 30 days, they were decreased gradually. QmixTM 2 in 1 showed a smaller number of inflammatory cells than other irrigants tested. CONCLUSION: QMixTM 2 in 1 was shown to be less toxic to the rat subcutaneous tissue than 3% NaOCl, 2% CHX, and 17% EDTA. PMID- 23349575 TI - Comparison between phosphoric acid and hydrochloric acid in microabrasion technique for the treatment of dental fluorosis. AB - PURPOSE: To compare the effectiveness of phosphoric acid (H(3)PO(4))-pumice compound with conventional hydrochloric acid (HCl)-pumice compound in treating different severities of dental fluorosis with the microabrasion technique. MATERIALS AND METHODS: Sixty-seven anterior teeth from seven patients with different severities of dental fluorosis were treated. In each patient, half of the teeth were treated with HCl-pumice compound and the other half with H(3)PO(4) pumice compound (split-mouth design). Both treatment compounds were applied for 30-second periods and treatment continued up to 10 minutes. Before and after treatment, standardized photographs were taken. The photographs were compared by two experienced observers unaware of the modality of treatment. Two indices of aesthetics, improvement in appearance (IA) and degree of stain removal (DSR), were determined according to a visual analog scale. The inter- and intra correlation coefficients were made; then, statistical analyses were calculated using Mann-Whitney and t-test. RESULTS: There were no significant differences in interobserver evaluation. Improvements in aesthetic indices were observed in all fluorotic teeth by both compounds; however, the mean treatment time with HCl pumice was significantly lower than H(3)PO(4)-pumice. CONCLUSION: The H(3)PO(4) pumice compound improved aesthetic indices in fluorotic teeth similar to the HCl pumice compound. PMID- 23349576 TI - Effect of bleaching with two different concentrations of hydrogen peroxide containing sweet potato extract as an additive on human enamel: An in vitro spectrophotometric and scanning electron microscopy analysis. AB - OBJECTIVES: To evaluate the color change in teeth bleached with two different concentrations of hydrogen peroxide, containing sweet potato extract as an additive, using a spectrophotometer, and to evaluate the surface changes in enamel using a scanning electron microscope (SEM). MATERIALS AND METHODS: Baseline color values of 24 artificially stained incisors were obtained using a spectrophotometer. The specimens were divided into two groups of 12 teeth, each based on the concentration of hydrogen peroxide (H(2)O(2)) as follows: Group I - 35% H(2)O(2) and Group II - 10% H(2)O(2). One-half of the tooth was bleached with H(2)O(2) alone (Subgroup A) and the other half was bleached with a combination of H(2)O(2) and sweet potato extract (Subgroup B). Post bleaching the Commission Internationale de l' Eclairage L(*), a(*), b(*) (CIEL(*)a(*)b(*)) values were obtained and DeltaE was calculated. The surfaces of the samples were examined using SEM. RESULTS: The mean DeltaE values of groups IB (72.52 +/- 2.03) and IIB (71.50 +/- 1.81) were significantly higher than those of groups IA (65.24 +/- 1.02) and IIA (64.19 +/- 1.88), respectively, (P < 0.05). The SEM images of groups IB and IIB showed lesser surface irregularities and morphological alterations in enamel. CONCLUSION: The addition of sweet potato extract to hydrogen peroxide not only resulted in the restoration of the natural tooth color, but also decreased the effects of bleaching on the enamel morphology, compared to the use of hydrogen peroxide alone. PMID- 23349577 TI - Idiopathic dental pulp calcifications in a tertiary care setting in South India. AB - BACKGROUND: Dental pulp calcifications are unique and represent the dental pulp regenerative process. Dental pulp calcifications are sometimes routine findings in oral radiographs and may later serve as an important diagnostic criterion for a hidden aspect of systemic illness. OBJECTIVE: The purpose of this study was to assess the patterns and prevalence of idiopathic dental pulp calcifications in a tertiary care setting in South India. MATERIALS AND METHODS: A total of 227 patients were included in the study fulfilling the inclusion criteria. Age range of the study population was from 15 to 70 years. Teeth were examined under digital panoramic radiograph. The presence or absence of pulp stones was recorded. The presence of pulp stone were categorized according to the types classified as Type I, Type IA, Type II, Type IIA, Type II B, and Type III. The frequency of occurrence of pulp stones with sex, tooth type, dental arches, and types were compared with the types of calcification. RESULTS: Total no. of patients with pulpal calcification were 227 [females 133 (58.59%) and males 94 (41.40%)]. The most common type between both sexes was Type I (48%). Total no. of teeth with calcification was 697; maxilla (48%), mandible (52%). The prevalence of pulp stone was found to be higher in the molars in both the arches. Most no. of pulp stones are reported at the third and fourth decade of life. CONCLUSION: Idiopathic dental pulp calcifications are incidental radiographic findings of the pulp tissue and also may be an indicator of underlying disease. PMID- 23349578 TI - Comparison of the efficacy of ethylene diamine tetraacetic acid and maleic acid in the removal of three calcium hydroxide intra-canal dressings: A spiral computerized tomography volumetric analysis. AB - AIM: To assess the efficacy of 17% ethylene diamine tetra acetic acid and 7% maleic acid in the removal of 3 calcium hydroxide preparations placed as intracanal medicaments. MATERIALS AND METHODS: The root canals of 60 single rooted premolars were prepared with a step back technique and randomly assigned into 3 experimental groups (n= 20). Group A was filled with plain calcium hydroxide mixed with distilled water in which barium sulfate was added for radio opacity, Group B was filled with Apexcal and Group C was filled with Metapex. After 7 days each group was divided into 2 sub groups (n= 10). The medicaments were retrieved with 17% EDTA (first sub group) and 7% maleic acid (second sub group). Along with the above irrigants manual and ultrasonic agitation was used. The pre and post removal volume of medicaments in root canals were measured using spiral computerized tomography. The percentage difference was calculated and statistically analyzed using Kruskal Wallis and Mann Whitney U test. RESULTS: 17% EDTA and 7% maleic acid efficiently removed calcium hydroxide, distilled water mixture (P= 0.218) and Apexcal (P= 0.684), whereas 7% maleic acid showed better retrieval capability of Metapex than 17% EDTA (P= 0.002). CONCLUSION: Calcium hydroxide, distilled water mixture and polyethylene glycol based calcium hydroxide were efficiently removed by 17% EDTA and 7% maleic acid. 7% maleic acid removed silicone oil based calcium hydroxide preparation better than 17% EDTA. PMID- 23349579 TI - Effect of eugenol-containing sealer and post diameter on the retention of fiber reinforced composite posts. AB - BACKGROUND: Fiber reinforced composite (FRC) posts are cemented with resin cements. It is reported that using resin cements in canals sealed with eugenol containing sealers reduces the post retention. However, there is controversy on the subject. AIMS: The aim was to investigate the influence of eugenol-containing sealers and the amount of dentin removal from root canal with different post diameters on retention of FRC posts. SETTINGS AND DESIGN: It was an in vitro study MATERIALS AND METHODS: The roots of sixty teeth were cut with 14 mm distance from the apex and were instrumented to the working-length of 13 mm. The teeth were randomly distributed into 2 groups (n = 30). Following storage in normal saline for 7 days, the samples in both the groups were further divided into 3 subgroups (n = 10). Canals in the experimental subgroups (I, II, III) were obturated by gutta-percha and eugenol-containing sealer; and in the control subgroups (IV, V, VI) without any sealer. After storage in normal saline for 7 days, the post space was prepared by #3, #2, and #1 drills of DT Light-Post system. Post was cemented with Panavia-F2.0 resin-cement. A composite core was built for each sample. All samples were thermo cycled for 1000 cycles. The samples were tested for post retention with a mechanical testing machine. STATISTICAL ANALYSIS: Data were analyzed by two-way ANOVA and Tukey-HSD test. RESULTS: There was not a significant difference in retention between FRC posts #1 and #2 (P > 0.05). Post #3 was more retentive than posts #1and #2 (P < 0.05). ZOE sealer significantly reduced the retention of posts (P = 0.024), however, increasing post-space diameter significantly increased post retention in canals coated with ZOE sealer (P = 0.002). CONCLUSIONS: Eugenol-containing sealer reduced the retention of FRC posts cemented with resin cement. Removing more dentin from root-canals treated with eugenol-containing sealer for placing larger diameter posts caused an increase in post retention. PMID- 23349580 TI - Evaluation of antimicrobial efficacy of calcium hydroxide paste, chlorhexidine gel, and a combination of both as intracanal medicament: An in vivo comparative study. AB - AIM: To compare the antimicrobial efficacy of calcium hydroxide (CH), 2% chlorhexidine gel (CHX) and a combination of both, on obligate anaerobes, facultative anaerobes and Candida spp . MATERIALS AND METHODS: 90 single rooted permanent teeth were included in the study. After complete disinfection and access opening, the first microbiological pre-treatment sample (S1) was collected. After completion of instrumentation, a post-instumentation sample (S2) was taken and the teeth were divided into three groups: Group I: CH, Group II: 2% CHX, Group III: 2% CHX with CH. After 1 week, a post-medication sample (S3) was collected. RESULTS: All three medicaments were effective in the elimination of obligate anaerobes. CHX and combination showed higher antimicrobial effect against facultative anaerobes and Candida spp. in comparison with CH. But there was no statistical significant difference between Group II and Group III. CONCLUSION: CHX with or without CH was more effective than CH alone against all the tested micro-organisms. PMID- 23349581 TI - Evaluation and comparison of efficacy of three different storage media, coconut water, propolis, and oral rehydration solution, in maintaining the viability of periodontal ligament cells. AB - BACKGROUND: Two of the most critical factors affecting the prognosis of an avulsed tooth after replantation are extra oral dry time and the storage medium in which the tooth is placed before treatment is rendered. However, the ability of a storage/transport medium to support cell viability can be more important than the extra oral time to prevent ankylosis and replacement resorption. AIM: Purpose of this study was evaluation and comparison of efficacy of a new storage medium, oral rehydration solution (ORS) with coconut water, and propolis in maintaining the viability of periodontal ligament (PDL) cells by using a collagenase-dispase assay. MATERIALS AND METHODS: 40 teeth were selected with intact crown which were advised for Orthodontic extraction having healthy PDL. Teeth were then randomly divided into three experimental storage solution groups. Other 10 were divided into positive and negative control groups (5 each). STATISTICAL ANALYSIS AND RESULT: The results were statistically analyzed with analysis of variance and multiple range by using post hoc tests. The results of the prevailing study indicated that coconut water group demonstrated a significantly higher number of viable PDL cells than propolis 50%, and ORS. There was no significant difference between coconut water and propolis 50% groups. PMID- 23349583 TI - Cleaning capacity promoted by motor-driven or manual instrumentation using ProTaper Universal system: Histological analysis. AB - AIM: The aim of this study was to assess the cleaning capacity of the Protaper system using motor-driven or manual instrumentation. MATERIALS AND METHODS: Ten mandibular molars were randomly separated into 2 groups (n = 5) according to the type of instrumentation performed, as follows: Group 1 - instrumentation with rotary nickel-titanium (Ni-Ti) files using ProTaper Universal System (Dentsply/Maillefer); and, Group 2 - instrumentation with Ni-Ti hand files using ProTaper Universal (Dentsply-Maillefer). Afterwards, the teeth were sectioned transversely and submitted to histotechnical processing to obtain histological sections for microscopic evaluation. The images were analyzed by the Corel Photo Paint X5 program (Corel Corporation) using an integration grid superimposed on the image. RESULTS: Statistical analysis (U-Mann-Whitney - P < 0.05) demonstrated that G1 presented higher cleaning capacity when compared to G2. CONCLUSIONS: The rotary technique presented better cleaning results in the apical third of the root canal system when compared to the manual technique. PMID- 23349582 TI - Evaluation of the sealing ability of two sealers after using chlorhexidine as a final irrigant: An in vitro study. AB - AIMS AND OBJECTIVES: The aim of this study was to evaluate the effect of the precipitate formed by using sodium hypochlorite and chlorhexidine as a root canal irrigant on the sealing ability of different root canal sealers, using a push-out bond strength test. MATERIALS AND METHODS: Twenty single rooted premolars were used for this study. The teeth were divided into two groups (Groups I and II) of ten teeth each, according to the obturation done with AH Plus with GuttaPercha and Resilon with epiphany, respectively. The groups were in turn divided into two subgroups of five teeth each (Subgroups A and B) according to the irrigation protocol, and were evaluated using a micro push-out bond strength, with the help of a universal testing machine. Statistical analysis was done using the paired t test. RESULTS: The mean value of the AH Plus GuttaPercha group with precipitate formation (17.66 +/- 0.56) showed the highest mean value for the bond strength, which was statistically higher (P < 0.05) than the rest of the groups. In the Resilon Epiphany group, the samples with precipitate formation showed (13.28 +/- 1.35) the least bond strength, which was statistically lower than all the groups, except the Resilon samples without precipitate (13.99 +/- 0.48). CONCLUSION: The precipitate formed by a combination of sodium hypochlorite and chlorhexidine tends to affect the bond strength of the sealers used for obturation. PMID- 23349584 TI - Indirect pulp therapy in a symptomatic mature molar using calcium enriched mixture cement. AB - Dental pulp has the ability of repair/regeneration. Indirect pulp therapy (IPT) is recommended for pulp preservation in asymptomatic teeth with extremely deep caries as well as teeth with clinical symptoms of reversible pulpitis. In this case study, we performed IPT with calcium enriched mixture (CEM) cement on a symptomatic permanent molar. After clinical/radiographic examinations the tooth was diagnosed with irreversible pulpitis and associated apical periodontitis. IPT involved partial caries removal, the placement of CEM cement pulp cap and overlying adhesive permanent restoration. At the 1 week follow-up, patient's spontaneous symptoms had resolved. One-year follow-up demonstrated pulp vitality, clinical function, as well as the absence of pain/tenderness to percussion/palpation/cold sensitivity tests; periapical radiograph showed a healing periradicular lesion with newly formed bone, that is normal pulp with normal periodontium. These favorable results indicate that IPT/CEM may be a good treatment option in comparison to endodontic treatment in young patients. IPT of deep-caries lesion is an easier, more practical and valuable treatment plan than complete caries removal. PMID- 23349585 TI - Endodontic management of four rooted mandibular first premolar. AB - Mandibular premolars have earned the reputation for having aberrant anatomy. The literature is replete with reports of extra canals in mandibular first premolars, but reports about the incidence of extra roots in these teeth are quite rare. This paper attempts at explaining a rare case of successful endodontic management of a four-rooted mandibular first premolar with diagnostic, interoperative and postoperative radiographic records along with a substantial data on the incidence of extra roots in these teeth. The standard method of radiographic appraisal was maintained as the criteria for determining the presence of extra roots. PMID- 23349586 TI - Hippocampus in health and disease: An overview. AB - Hippocampus is a complex brain structure embedded deep into temporal lobe. It has a major role in learning and memory. It is a plastic and vulnerable structure that gets damaged by a variety of stimuli. Studies have shown that it also gets affected in a variety of neurological and psychiatric disorders. In last decade or so, lot has been learnt about conditions that affect hippocampus and produce changes ranging from molecules to morphology. Progresses in radiological delineation, electrophysiology, and histochemical characterization have made it possible to study this archicerebral structure in greater detail. Present paper attempts to give an overview of hippocampus, both in health and diseases. PMID- 23349588 TI - Subacute onset fluctuating sensorium, mimetic facial palsy and vertical supranuclearophthalmoplegia in an young female. PMID- 23349587 TI - The therapeutic value of yoga in neurological disorders. AB - BACKGROUND: The ancient mind and body healing methods of yoga recently sparked fervor in the scientific community as an alternative and complementary means of therapy. Since the World Health Organization officially began promoting yoga in developing countries in 1978, yoga has been cited for its therapeutic potential and has been widely recognized in Western culture. However, as an increasing number of people practice yoga for remedial purposes, researchers raise two important questions: 1) Is yoga a valid complementary management and rehabilitation treatment modality? 2) What conditions show promise of treatment with this intervention?. OBJECTIVE: This review article uses comprehensive scientific, evidence-based studies to analyze the efficacy of various basic and applied aspects of yoga in disease prevention and health promotion. It specifically intends to expose the effects of yoga in neurological disorders, particularly epilepsy, stroke, multiple sclerosis, Alzheimer's disease, peripheral nervous system disease, and fibromyalgia. MATERIALS AND METHODS: Information was gathered from various resources including PubMed, Ovid, MD Consult, USC, and U.C.L.A. libraries. Studies were selected and reviewed on the basis of sample size, control, randomization, double-blinding, and statistical analysis of results. RESULTS: The pratice of yoga and meditation demonstrates statistically encouraging physiological and psychological improvements in the aforementioned neurological disorders. However, there were certain flaws and inadequacies in the study designs employed to evaluate the same. A critical analysis of these studies is presented. CONCLUSIONS: With the aim to focus attention on this widespread yet largely unexamined treatment modality, this paper seeks to provide direction and support for further research necessary to validate yoga as an integrative, alternative, and complementary therapy. PMID- 23349589 TI - Quantitative thermal sensory testing and sympathetic skin response in primary Restless legs syndrome - A prospective study on 57 Indian patients. AB - Patients with restless leg syndrome present with sensory symptoms similar to peripheral neuropathy. While there is evidence of abnormalities of dopaminergic pathways, the peripheral nervous system has been studied infrequently. We studied conventional nerve conduction studies, quantitative thermal sensory testing and sympathetic skin response in 57 patients with primary restless leg syndrome. Almost two third patients demonstrated abnormalities in the detailed testing of the peripheral nervous system. Sbtle abnormalities of the peripheral nervous system may be more common than previously believed. PMID- 23349590 TI - Etiology and outcome determinants of intracerebral hemorrhage in a south Indian population, A hospital-based study. AB - BACKGROUND: There is paucity of methodologically sound published studies on intracerebral hemorrhage (ICH) from India, on pub med/embase search. AIMS: To explore etiology of ICH and correlate the causes, location, and size of hemorrhage to clinical outcome. MATERIALS AND METHODS: A hospital-based descriptive study from South Indian eastern coastal town of Puducherry; 60 consecutive subjects aged > 12 years, predominantly of inbred Tamil population, with head CT evidence of intracerebral hemorrhage not associated with trauma and brain tumors, were recruited. Outcome at three months was measured using Glasgow Outcome scale, NIHSS and mortality. SPSS v 19 was used for statistical analysis. RESULTS: Commonest etiological factor was hypertension, followed by bleeding diathesis, thrombolysis for myocardial infarction, and cortical vein thrombosis. Most frequent locations of hematoma were basal ganglia, thalamus, internal capsule, and cerebral and cerebellar parenchyma. Hematoma volume correlated significantly with systolic and mean arterial pressure but not with diastolic blood pressure. Poor outcome was correlated to size (P < 0.05) and intraventricular extension of hematoma (P < 0.05), and to systolic, diastolic and mean arterial pressure, but not to age, gender, smoking, alcoholism, ischemic heart disease, and blood sugar level. Among diabetic patients with ICH, the size of hematoma (P = 0.04) and severity of coma (P = 0.01) at admission were significantly worse compared to the non-diabetic, but not the outcome at three months [Glasgow outcome scale or mortality (P = 0.94 and 0.14)]. CONCLUSIONS: The location of hemorrhage and correlation with outcome agreed with the patterns described for the non-white races in prior reports. Independence of outcome to diabetic status despite a more severe initial presentation may indicate importance of good care, even in high risk groups. PMID- 23349591 TI - Effects of augmented proprioceptive cues on the parameters of gait of individuals with Parkinson's disease. AB - CONTEXT: Impairment of initiating sequential movements and processing of proprioception contribute to characteristic Parkinson's disease (PD) gait abnormalities. Many studies have used a single external cue or 2 different cues to correct PD gait. AIM: An aim of this study was to determine the influence of paired proprioceptive cues on gait parameters of individuals with PD. SETTING AND DESIGN: Double-blind randomized controlled trial. MATERIALS AND METHODS: Subjects were 30 PD patients who had mild to moderate impairment according to the United Parkinson's Disease Rating Scale (UPDRS). They were randomly assigned to either a routine physiotherapy program or treadmill training with vibratory stimuli applied to the feet plantar surfaces and proprioceptive neuromuscular facilitation (PNF) as well as the same physiotherapy program. All Participants received a 45-minutes session of low intensity physiotherapy program, 3 times a week, for 8 weeks. The duration of treadmill training was 5 minutes at baseline and 25 minutes at the end of treatment. Walking speed and distance were recorded from the treadmill control panel for both groups before and immediately after the end of treatment. The Qualysis ProReflex motion analysis system was used to measure cadence, stride length, hip, knee, and ankle joints' angular excursion. RESULTS: The cadence, stride length, and lower limb joints' angular excursion showed a significant improvement in both groups (P <= 0.05). These improvements in spatio-temporal parameters and angular excursion were higher in the study group than in the control group (P <= 0.05). CONCLUSION: Potentiated proprioceptive feedback improves parkinsonian gait kinematics, the hip, knee, and ankle joints' angular excursion. PMID- 23349592 TI - Neuroimaging observations in a cohort of elderly manifesting with new onset seizures: Experience from a university hospital. AB - BACKGROUND: The occurrence of epilepsy is higher among elderly patients. The clinical manifestations of seizures, causes of epilepsy, and choice of anti epileptic drugs (AEDs) are different in elderly people with epilepsy compared to the young. AIM: To evaluate the imaging (CT/MRI) observations in elderly patients manifesting with new-onset seizures. MATERIALS AND METHODS: Two hundred and one elderly patients with new onset seizures, >60 years (age: 68.0 +/- 7.5 years; M:F = 1.8:1) from Jan' 07 to Jan' 09, were prospectively recruited. Observations of cranial CT scan (n = 201) and MR imaging (n = 43) were analyzed. RESULTS: THE TYPE OF SEIZURES INCLUDED: Simple partial (42%), generalized tonic-clonic (30.3%), and complex partial (27.4%). The pattern of epilepsy syndromes were acute symptomatic (42.3%), remote symptomatic (18.4%), cryptogenic (37.8%), and idiopathic (1.5%). Seizures were controlled with monotherapy in 85%. The CT scan (n = 201) revealed cerebral atrophy (139), mild (79), moderate (43), and severe (18); focal lesions (98), infarcts (45), hemorrhages (18), granuloma (16), tumor (15) and gliosis (4), and hemispheric atrophy (1), white matter changes (75) and diffuse edema (21). An MRI (n = 43) showed variable degree of cerebral atrophy (31); white matter changes (20); focal cerebral lesions (24); - infarct (7); intracranial hemorrhage (6); granuloma (5); tumor (6); gliosis (1); hemispheric atrophy (1); and prominent Virchow-Robin spaces (7); and UBOs (12). Patients with focal lesions in neuroimaging more often had partial seizures, symptomatic epilepsy, past stroke, focal deficit, absence of diffuse atrophy, focal EEG slowing, abnormal CSF, seizure recurrence at follow-up (P < 0.05). CONCLUSIONS: Brain imaging observations in elderly patients with new-onset seizures revealed underlying symptomatic nature, hence the etiology and thereby assisted in deciding the specific therapy. PMID- 23349594 TI - Appraisal of Kernig's and Brudzinski's sign in meningitis. PMID- 23349593 TI - Oxidative stress is increased in women with epilepsy: Is it a potential mechanism of anti-epileptic drug-induced teratogenesis? AB - CONTEXT: Oxidative stress can be a final common pathway for AED-induced teratogenesis. AIMS: To compare the oxidative stress of women with epilepsy (WWE) and unfavorable pregnancy outcome (fetal malformation or spontaneous abortion - group EM) with that of WWE with normal pregnancy outcome (group ENM) and healthy women with normal pregnancy outcome (group C). MATERIALS AND METHODS: We identified WWE under group EM (n = 43) and group ENM (n = 22) from the Kerala Registry of Epilepsy and Pregnancy (KREP). Group C was constituted of healthy volunteers (N = 20). Oxidative stress was assessed by estimating serum levels of malondialdehyde (MDA) and isoprostane (ISP). The antioxidant profile was evaluated as activity of superoxide dismutase (SOD), glutathione reductase (GR), catalase (CAT), total antioxidant status (TAO), and glutathione (GSH) content. RESULTS: The MDA and ISP levels for group EM (3.46 + 0.82 and 17.77 + 3.0) were higher than that of group ENM (3.07 + 1.02 and 14.0 + 5.3), and both were significantly higher than that of group C (2.42 + 0.51 and 10.77 + 4.1). Their levels of SOD (146.82 + 42.64 vs. 175.81 + 42.61) and GSH (0.98 + 0.98 vs. 1.55 + 1.3) were significantly lower than those of controls. No significant changes were seen in TAO and GR. WWE on polytherapy showed significant increase in MDA when compared to monotherapy group. CONCLUSION: WWE (group EM and ENM) had higher oxidative stress and reduced antioxidant activity. The subgroup of WWE with unfavorable pregnancy outcome (group EM) had higher oxidative stress. Excess oxidative stress can be a final common pathway, by which AEDs exert teratogenic effects. PMID- 23349595 TI - Antiepileptic drugs prescription utilization behavior and direct costs of treatment in a national hospital of India. AB - BACKGROUND AND OBJECTIVES: The present study evaluated the direct costs of active epilepsy and looked at the pattern of drug prescription and utilization in epileptic patients visiting the neuroscience centre of a national hospital of India. MATERIALS AND METHODS: A total of 134 epileptic patients were studied over a period of 4 months. Patients demography, commonly prescribed antiepileptic drugs (AEDs), socioeconomic status, direct costs, response ratio (RR) for newer drugs, and quality of life (QOLIE-10) was evaluated. RESULTS AND DISCUSSION: We found a higher percentage of male patients (67.9%) as compared with females. Most of the patients were in the age group 11-30 years and majority of them (39.6%) belonged to lower middle group. A higher percentage (68.7) of drugs was prescribed as polytherapy. Higher monthly cost was observed for some of the newer AEDs including the lamotrigine, levetiracetam, and lacosamide as compared with older drugs. Among the newer drugs, clobazam had the lowest cost. RR was calculated for 12 patients out of which 8 had a RR < -0.50. The QOL domains, following conventional or newer drugs, were not much affected. CONCLUSION: The study indicates an increasing trend toward clinical usage of newer AEDs, increasing trend of poly-therapy with significant escalations in the cost of therapy. PMID- 23349596 TI - Knowledge of Parkinson's disease among patients and caregivers attending movement disorder clinic at a tertiary care centre in north India. AB - CONTEXT: Few studies have been done to see the level of knowledge among patients and caregivers about Parkinson's disease (PD). AIMS: The aim of the current study was to determine the knowledge of PD among patients and caregivers at a movement disorder clinic in India. SETTINGS AND DESIGN: A tertiary care neurology facility in north India. MATERIALS AND METHODS: We conducted a questionnaire based interview among the subjects collected on the annual PD day in 2006. RESULTS: Out of 200 questionnaires that were distributed 172 subjects responded. Of these, there were 103 (59.8%) patients with PD and 69 (40.11%) caregivers. Mean age of the patients and caregivers was 55.4 +/- 13.3 years and 49.4 +/- 15.9 years respectively. Mean duration of PD was 6.8 +/- 4.7 years (range-21). Ninety nine patients out of the 103 (96.1%) and 57 caregivers out of 69 (82.6%) had previously attended the PD education program. High scores (>90%) were obtained to questions on body parts affected, pathology in PD, main drug treatment, epidemiology and effect of exercise. Low scores were seen to questions on surgery in PD and biochemical abnormality in PD. No significant difference was noted in correct answers among patients and caregivers on duration of PD. CONCLUSION: Patients and caregivers had adequate knowledge about PD. Patient and caregiver education programs may be useful in imparting knowledge about PD. PMID- 23349597 TI - Jean-martin charcot pathologist, neurologist, psychiatrist and physician. AB - Jean-Martin Charcot is known as father of modern neurology. Before him, neurology was only limited to select disorders like chorea. His contributions were not limited to neurology only, as he was instrumental in many new developments in the field of pathology, psychiatry, and internal medicine. Even after 100 years, Charcot's clinical methods remain the pillar of modern neurology. PMID- 23349598 TI - A report of a probable case of familial Guillain Barre syndrome. AB - Although it is a sporadic disease, few studies have reported cases of Guillain Barre Syndrome (GBS) in families which postulate a genetic susceptibility. Human leukocyte antigen (HLA) typing is an area of discussion in GBS though none of them are considered definitive. In recent years, more studies have evaluated HLA typing in sporadic cases while rarely it has been assessed in familial ones. We report a woman and her daughter experiencing GBS and their HLA typing in a 2-year interval. PMID- 23349599 TI - Chronic meningitis and central nervous system vasculopathy related to Epstein Barr virus. AB - Chronic active Epstein Barr virus (EBV) infection causes a wide spectrum of manifestation, due to meningeal, parenchymal and vascular involvement. An 11-year old boy presented with chronic headache, fever and seizures of 18 months duration. His magnetic resonance imaging Brain showed fusiform aneurysmal dilatations of arteries of both the anterior and posterior cerebral circulation. Cerebrospinal fluid (CSF) showed persistent lymphocytic pleocytosis, raised proteins and low sugar with positive polymerase chain reaction for EBV. He later developed pancytopenia due to bone marrow aplasia, with secondary infection and expired. From clinical, imaging and CSF findings, he had chronic lymphocytic meningitis with vasculopathy, which was isolated to the central nervous system. He later had marrow aplasia probably due to X-linked lymphoproliferative disorder related to EBV infection. Vasculopathy, especially diffuse fusiform aneurysmal dilatation associated with chronic EBV infection, is rare, but has been described, similar to our case report. PMID- 23349600 TI - Stroke and skin rash: A rare case of Henoch-Schonlein purpura. AB - Henoch-Schonlein purpura (HSP) is a small vessel vasculitis that is rare in adults. Here, we present a case of a woman who presented with palpable purpura, abdominal pain, arthritis and ischemic stroke. The patient met the diagnostic criteria of HSP. However, cerebrovascular disease is reported as an uncommon, yet fatal, complication of HSP. The patient responded to aggressive immunosuppression with pulses of corticosteroids and cyclophosphamide. In the absence of an established protocol of treatment of such neurologic emergency in HSP patients, this report demonstrates a successful outcome. PMID- 23349601 TI - An interesting case of Leigh-like syndrome. AB - A 12-year-old female child with motor developmental delay presented with persistent vomiting, recurrent falls and unsteadiness in dark since 2 years of age. There was decline in scholastic performance, bulbar symptoms and aggravation of symptoms during intercurrent illness. Clinically, she had frontal and parietal lobar dysfunction, dysarthria, optic atrophy and LMN VII, IX, X, XII cranial nerve involvement. There was generalized hypotonia, distal muscle wasting, weakness, cerebellar signs and impaired vibration/position sense in distal extremities. Biochemical investigations revealed elevated serum/cerebrospinal fluid (CSF) lactate and CSF lactate pyruvate ratio. Neuroimaging demonstrated bilateral symmetrical T2 hyperintensities in basal ganglia, subcortical white matter, cerebellar hemispheres and posterior aspect of spinal cord. As certain atypical features like bilateral symmetrical T2 hyperintensities in subcortical white matter were also seen, metachromatic leukodystrophy was considered in differential diagnosis but ruled out by nerve biopsy. This case is reported for the presence of atypical neuroimaging features that are rarely found in Leigh's disease. PMID- 23349602 TI - Olanzapine-induced electroencephalographic changes reversed by lamotrigine. AB - The atypical neuroleptic, olanzapine (OLZ), may induce electroencephalographic (EEG) abnormalities. The anticonvulsant, lamotrigine (LMG), reduces interictal epileptiform discharges and is effective in seizures in patients with both primary and partial epilepsy syndromes. The effect of LMG on neuroleptic-induced EEG abnormalities has not been previously reported. We describe the case of a 13 year-old male with paroxysmal nonepileptic spells who underwent diagnostic video EEG telemetry, whose abnormal OLZ-induced EEG findings were strikingly affected by LTG withdrawal and reintroduction. The effect of LTG in normalizing EEG changes in suspected epilepsy caused by atypical neuroleptics is discussed. PMID- 23349603 TI - Massive scalp hematoma: An unusual presentation of valproic acid toxicity. AB - Valproic acid (VPA) is a commonly used broad-spectrum antiepileptic drug especially in children, with various side-effects reported with its usage. Hematologic toxicity is dose related and intracranial bleeding complications have been reported. We are reporting a rare case of massive scalp hematoma requiring surgical intervention, following a trivial fall associated with high-VPA levels. PMID- 23349604 TI - Pulmonary thromboembolism in a patient with myotonic dystrophy type 1. AB - Thromboembolism is a rare complication in patients with myotonic dystrophy. While immobilization of patients with advanced disease predisposes to high risk for venous thromboembolism, hypercoagulability could account for venous thromboembolism in patients without impaired mobilization. We report a patient with myotonic dystrophy type 1 who developed pulmonary thromboembolism unrelated to immobilization. PMID- 23349605 TI - Intravenous immunoglobulin in the treatment of drug rash eosinophilia and systemic symptoms caused by phenytoin. AB - A 32 year old Asian female on 300 mg per day of phenytoin following meningioma excision developed a fever with a diffuse maculopapular rash, lymphadenopathy and splenomegaly after12 days. A diagnosis of DRESS (Drug Rash Eosinophilia and Systemic Symptoms) syndrome was made. Patient was started on prednisolone at a dose of 1 mg/kg but since there was further deterioration in her condition, intravenous immunoglobulin was started. Clinical and blood parameters began to improve by the next day with liver functions returning to normal by the third week. DRESS syndrome is a drug hypersensitivity syndrome which can be fatal and therefore needs to be recognized early for the appropriate treatment to be started. The use of Intravenous immunoglobulins is anecdotal and the dramatic improvement noted in this case indicates that it is another treatment choice. The case and a brief review of the literature are discussed. PMID- 23349606 TI - Bilateral thoracic outlet syndrome: An uncommon presentation of a rare condition in children. AB - We report an adolescent girl who had left-sided neurogenic thoracic outlet syndrome (TOS) due to impingement of the scalenus anterior muscle with bilateral changes on nerve conduction studies and responded well to surgical decompression. A 13-year-old Caucasian girl presented with intermittent pain, swelling, erythema, tingling and numbness of the palmar aspect of her left hand. Nerve conduction studies revealed bilateral ulnar sensory and motor conduction abnormalities, suggesting early compressive neuropathy in the asymptomatic arm as well. She underwent surgical exploration when it was noted that the scalenus anterior itself was impinging on the brachial plexus. She had a good clinical response to scalenectomy. The diagnosis of neurogenic TOS remains difficult as no single test has been accepted as a gold standard. But, once diagnosed using clinical symptoms, nerve conduction studies, electromyography and radiological investigations, it is a treatable condition with good prognosis. PMID- 23349607 TI - Communicating hydrocephalus due to cerebral venous sinus thrombosis treated with ventriculoperitoneal shunt. AB - Cerebral venous sinus thrombosis (CVT) is a rare cerebrovascular disease with variable presentation. CVT rarely causes hydrocephalus. Communicating hydrocephalus due to CVT is extremely rare. We describe a patient of CVT presenting with chronic headache and communicating hydrocephalus. The patient was successfully treated with ventriculoperitoneal (VP) shunt. A 40 year old man presented with moderate to severe headache since six months and progressive visual loss since two months. Head Computed tomogram showed mild hydrocephalus without obstruction. Lumbar puncture (LP) demonstrated elevated pressure but was otherwise normal. Magnetic resonance venogram showed extensive CVT. Repeated CSF drainage and thecoperitoneal shunt did not relieve the severe headache hence a VP shunt was placed. Post shunt headache subsided with resolution of hydrocephalus. CVT can present as communicating hydrocephalus. Gradual reduction of intra ventricular pressure by repeated LPs followed by VP shunt can safely treat hydrocephalus due to CVT. PMID- 23349608 TI - Subacute sclerosing panencephalitis with bilateral inferior collicular hyperintensity on magnetic resonance imaging brain. AB - Subacute sclerosing panencephalitis (SSPE) is chronic encephalitis occurring after infection with measles virus. An 8-year-old boy presented with progressive behavioral changes, cognitive decline and myoclonic jerks, progressing to a bed bound state over 2 months. Magnetic resonance imaging (MRI) brain showed T2 weighted hyperintensities in the subcortical areas of the left occipital lobe and brachium of the inferior colliculus on both sides. EEG showed bilateral, synchronous periodic discharges. Serum/cerebrospinal fluid measles IgG titer was significantly positive. The overall features were suggestive of SSPE. MRI finding of bilateral inferior colliculus changes on MRI without significant involvement of other commonly involved areas suggests an uncommon/rare imaging pattern of SSPE. PMID- 23349609 TI - Lipid storage myopathy with clinical markers of Marfan syndrome: A rare association. AB - Disorders of lipid metabolism can cause variable clinical presentations, often involving skeletal muscle, alone or together with other tissues. A 19-year-old boy presented with a 2-year history of muscle pain, cramps, exercise intolerance and progressive weakness of proximal lower limbs. Examination revealed skeletal markers of Marfan syndrome in the form of increased arm span compared with height, Kyphoscoliois, moderate pectus excavatum, high arched palate and wrist sign. He also had mild neck flexor weakness and proximal lower limb weakness with areflexia. Pathologic findings revealed lipid-laden fine vacuoles in the muscle fibers. Possibility of carnitine deficiency myopathy was considered and the patient was started on carnitine and Co Q. The patient made remarkable clinical improvement over the next 2 months. This case is reported for rarity of the association of clinical markers of Marfan syndrome and lipid storage myopathy and sparse literature on lipid storage myopathy in the Indian context. PMID- 23349610 TI - The diagnostic role of 18-fluorodeoxyglucocose-positron emission tomography/computed tomography in occult bacteremia searching underlying primary disease. AB - 18-Fluoro-2-deoxy-D-glucose(FDG) is a structural analog of 2-deoxyglucose and accumulates in malignant tissues but also at sites of infection and inflammation. For this reason, FDG PET or PET/CT has great advantage in understanding of underlying pathology in assessment of FUO (Fever of unknown origin). However, till today, there are limited studies about the role of FDG PET or PET/CT in evaluation of FUO. Conventional diagnostic methods are still not adequate to reveal underlying reason in approximately 50% of patients with FUO especially in cases presenting with diagnostic challenges i.e. involvement of two or more organ systems with seemingly no correlation. We report a case of two years old Indian female child who presented with fever of one month duration, CT and MRI reported nonspecific findings. She underwent Whole body 18 FDG PET/CT for further evaluation, which revealed FDG avid rim lesion with central photopenic defect suspicious of pyogenic abscess in high parietal cortex along with bilateral lung nodules. This confirmed the diagnosis of a brain abscess secondary to pulmonary infection. We emphasize the utility of 18 FDG PET/CT as imaging modality, highlight the diagnostic difficulties using current serological and radiological measures, and propose managing FUO with 18 FDG PET/CT in cases empirically prior to more invasive measures. PMID- 23349611 TI - Reversible electrophysiological abnormalities in acute secondary hyperkalemic paralysis. AB - Hyperkalemia manifests clinically with acute neuromuscular paralysis, which can simulate Guillain Barre syndrome (GBS) and other causes of acute flaccid paralysis. Primary hyperkalemic paralysis occurs from genetic defects in the sodium channel, and secondary hyperkalemic paralysis (SHP) from diverse causes including renal dysfunction, potassium retaining drugs, Addison's disease, etc. Clinical characteristics of SHP have been addressed in a number of publications. However, electrophysiological evaluations of these patients during neuromuscular paralysis are infrequently reported and have demonstrated features of demyelination. The clinical features and electrophysiological abnormalities in secondary hyperkalemia mimic GBS, and pose diagnostic challenges. We report the findings of nerve conduction studies in a middle-aged man who was admitted with rapidly reversible acute quadriplegia resulting from secondary hyperkalemic paralysis. PMID- 23349612 TI - An Indian family with an Emery-Dreifuss myopathy and familial dilated cardiomyopathy due to a novel LMNA mutation. AB - Emery-Dreifuss myopathy can be associated with a cardiomyopathy and cardiac dysrhythmias. The inheritance pattern of Emery-Dreifuss muscular dystrophy (EDMD) is X linked, whereas EDMD2 is autosomal dominant. EDMD2 is caused by lamin A/C gene (LMNA) mutations that produce alterations in the lamin proteins that are integral to nuclear and cell integrity. A 53-year-old man was brought to us with a right internal carotid artery dissection. Detailed work-up of the patient and family members revealed some unusual features, and genetic sequencing of the LMNA gene was undertaken. A novel mutation was identified in two of the samples sent for analysis. We present the first Indian family of EDMD2 with familial dilated cardiomyopathy and cardiac dysrhythmias in whom LMNA gene sequencing was performed. A novel mutation was identified and additional unusual clinical features were described. PMID- 23349613 TI - Evolution of mobile plaque to complete division of carotid lumen. PMID- 23349614 TI - Hypothesis and "metahypothesis". PMID- 23349615 TI - Author's reply. PMID- 23349616 TI - Long sleep duration and frequent day-time naps of the infants can be protective for vigabatrin-induced visual field defects. PMID- 23349617 TI - Epidemiology and treatment gap of epilepsy in India. PMID- 23349618 TI - Electroencephalographers: A different breed. PMID- 23349619 TI - Green, Palladium-Catalyzed Synthesis of Benzylic H-phosphinates from Hypophosphorous Acid and Benzylic Alcohols. AB - Benzylic alcohols cross-couple directly with concentrated H(3)PO(2) using Pd/xantphos (1 or 2 mol-%). Depending on the substrate, DMF at 110 degrees C, or t-AmOH at reflux with a Dean-Stark trap, can be used. A broad range of benzylic alcohols reacted successfully in moderate to good yields. The preparation of other organophosphorus compounds (phosphinic and phosphonic acids) is also demonstrated.Asymmetric reaction with (R)-1-(2-naphthyl)ethanol provided the corresponding H-phosphinic acid in 77% ee. The methodology provides a green, PCl(3)-free, entry into benzylic-H-phosphinic acids. PMID- 23349620 TI - Radial glial neural progenitors regulate nascent brain vascular network stabilization via inhibition of Wnt signaling. AB - The cerebral cortex performs complex cognitive functions at the expense of tremendous energy consumption. Blood vessels in the brain are known to form stereotypic patterns that facilitate efficient oxygen and nutrient delivery. Yet little is known about how vessel development in the brain is normally regulated. Radial glial neural progenitors are well known for their central role in orchestrating brain neurogenesis. Here we show that, in the late embryonic cortex, radial glial neural progenitors also play a key role in brain angiogenesis, by interacting with nascent blood vessels and regulating vessel stabilization via modulation of canonical Wnt signaling. We find that ablation of radial glia results in vessel regression, concomitant with ectopic activation of Wnt signaling in endothelial cells. Direct activation of Wnt signaling also results in similar vessel regression, while attenuation of Wnt signaling substantially suppresses regression. Radial glial ablation and ectopic Wnt pathway activation leads to elevated endothelial expression of matrix metalloproteinases, while inhibition of metalloproteinase activity significantly suppresses vessel regression. These results thus reveal a previously unrecognized role of radial glial progenitors in stabilizing nascent brain vascular network and provide novel insights into the molecular cascades through which target neural tissues regulate vessel stabilization and patterning during development and throughout life. PMID- 23349622 TI - Why do women not use antenatal services in low- and middle-income countries? A meta-synthesis of qualitative studies. AB - BACKGROUND: Almost 50% of women in low- and middle-income countries (LMICs) don't receive adequate antenatal care. Women's views can offer important insights into this problem. Qualitative studies exploring inadequate use of antenatal services have been undertaken in a range of countries, but the findings are not easily transferable. We aimed to inform the development of future antenatal care programmes through a synthesis of findings in all relevant qualitative studies. METHODS AND FINDINGS: Using a predetermined search strategy, we identified robust qualitative studies reporting on the views and experiences of women in LMICs who received inadequate antenatal care. We used meta-ethnographic techniques to generate themes and a line-of-argument synthesis. We derived policy-relevant hypotheses from the findings. We included 21 papers representing the views of more than 1,230 women from 15 countries. Three key themes were identified: "pregnancy as socially risky and physiologically healthy", "resource use and survival in conditions of extreme poverty", and "not getting it right the first time". The line-of-argument synthesis describes a dissonance between programme design and cultural contexts that may restrict access and discourage return visits. We hypothesize that centralised, risk-focused antenatal care programmes may be at odds with the resources, beliefs, and experiences of pregnant women who underuse antenatal services. CONCLUSIONS: Our findings suggest that there may be a misalignment between current antenatal care provision and the social and cultural context of some women in LMICs. Antenatal care provision that is theoretically and contextually at odds with local contextual beliefs and experiences is likely to be underused, especially when attendance generates increased personal risks of lost family resources or physical danger during travel, when the promised care is not delivered because of resource constraints, and when women experience covert or overt abuse in care settings. PMID- 23349623 TI - Reducing vulnerability to climate change in sub-Saharan Africa: the need for better evidence. PMID- 23349621 TI - The effectiveness of mobile-health technology-based health behaviour change or disease management interventions for health care consumers: a systematic review. AB - BACKGROUND: Mobile technologies could be a powerful media for providing individual level support to health care consumers. We conducted a systematic review to assess the effectiveness of mobile technology interventions delivered to health care consumers. METHODS AND FINDINGS: We searched for all controlled trials of mobile technology-based health interventions delivered to health care consumers using MEDLINE, EMBASE, PsycINFO, Global Health, Web of Science, Cochrane Library, UK NHS HTA (Jan 1990-Sept 2010). Two authors extracted data on allocation concealment, allocation sequence, blinding, completeness of follow-up, and measures of effect. We calculated effect estimates and used random effects meta-analysis. We identified 75 trials. Fifty-nine trials investigated the use of mobile technologies to improve disease management and 26 trials investigated their use to change health behaviours. Nearly all trials were conducted in high income countries. Four trials had a low risk of bias. Two trials of disease management had low risk of bias; in one, antiretroviral (ART) adherence, use of text messages reduced high viral load (>400 copies), with a relative risk (RR) of 0.85 (95% CI 0.72-0.99), but no statistically significant benefit on mortality (RR 0.79 [95% CI 0.47-1.32]). In a second, a PDA based intervention increased scores for perceived self care agency in lung transplant patients. Two trials of health behaviour management had low risk of bias. The pooled effect of text messaging smoking cessation support on biochemically verified smoking cessation was (RR 2.16 [95% CI 1.77-2.62]). Interventions for other conditions showed suggestive benefits in some cases, but the results were not consistent. No evidence of publication bias was demonstrated on visual or statistical examination of the funnel plots for either disease management or health behaviours. To address the limitation of the older search, we also reviewed more recent literature. CONCLUSIONS: Text messaging interventions increased adherence to ART and smoking cessation and should be considered for inclusion in services. Although there is suggestive evidence of benefit in some other areas, high quality adequately powered trials of optimised interventions are required to evaluate effects on objective outcomes. PMID- 23349624 TI - Prioritizing congenital syphilis control in south China: a decision analytic model to inform policy implementation. AB - BACKGROUND: Syphilis is a major public health problem in many regions of China, with increases in congenital syphilis (CS) cases causing concern. The Chinese Ministry of Health recently announced a comprehensive 10-y national syphilis control plan focusing on averting CS. The decision analytic model presented here quantifies the impact of the planned strategies to determine whether they are likely to meet the goals laid out in the control plan. METHODS AND FINDINGS: Our model incorporated data on age-stratified fertility, female adult syphilis cases, and empirical syphilis transmission rates to estimate the number of CS cases associated with prenatal syphilis infection on a yearly basis. Guangdong Province was the focus of this analysis because of the availability of high-quality demographic and public health data. Each model outcome was simulated 1,000 times to incorporate uncertainty in model inputs. The model was validated using data from a CS intervention program among 477,656 women in China. Sensitivity analyses were performed to identify which variables are likely to be most influential in achieving Chinese and international policy goals. Increasing prenatal screening coverage was the single most effective strategy for reducing CS cases. An incremental increase in prenatal screening from the base case of 57% coverage to 95% coverage was associated with 106 (95% CI: 101, 111) CS cases averted per 100,000 live births (58% decrease). The policy strategies laid out in the national plan led to an outcome that fell short of the target, while a four pronged comprehensive syphilis control strategy consisting of increased prenatal screening coverage, increased treatment completion, earlier prenatal screening, and improved syphilis test characteristics was associated with 157 (95% CI: 154, 160) CS cases averted per 100,000 live births (85% decrease). CONCLUSIONS: The Chinese national plan provides a strong foundation for syphilis control, but more comprehensive measures that include earlier and more extensive screening are necessary for reaching policy goals. PMID- 23349625 TI - Oroxylin A inhibits hemolysis via hindering the self-assembly of alpha-hemolysin heptameric transmembrane pore. AB - Alpha-hemolysin (alpha-HL) is a self-assembling, channel-forming toxin produced by most Staphylococcus aureus strains as a 33.2-kDa soluble monomer. Upon binding to a susceptible cell membrane, the monomer self-assembles to form a 232.4-kDa heptamer that ultimately causes host cell lysis and death. Consequently, alpha-HL plays a significant role in the pathogenesis of S. aureus infections, such as pneumonia, mastitis, keratitis and arthritis. In this paper, experimental studies show that oroxylin A (ORO), a natural compound without anti-S. aureus activity, can inhibit the hemolytic activity of alpha-HL. Molecular dynamics simulations, free energy calculations, and mutagenesis assays were performed to understand the formation of the alpha-HL-ORO complex. This combined approach revealed that the catalytic mechanism of inhibition involves the direct binding of ORO to alpha-HL, which blocks the conformational transition of the critical "Loop" region of the alpha-HL protein thereby inhibiting its hemolytic activity. This mechanism was confirmed by experimental data obtained from a deoxycholate-induced oligomerization assay. It was also found that, in a co-culture system with S. aureus and human alveolar epithelial (A549) cells, ORO could protect against alpha-HL-mediated injury. These findings indicate that ORO hinders the lytic activity of alpha-HL through a novel mechanism, which should facilitate the design of new and more effective antibacterial agents against S. aureus. PMID- 23349626 TI - Metallochaperones regulate intracellular copper levels. AB - Copper (Cu) is an important enzyme co-factor that is also extremely toxic at high intracellular concentrations, making active efflux mechanisms essential for preventing Cu accumulation. Here, we have investigated the mechanistic role of metallochaperones in regulating Cu efflux. We have constructed a computational model of Cu trafficking and efflux based on systems analysis of the Cu stress response of Halobacterium salinarum. We have validated several model predictions via assays of transcriptional dynamics and intracellular Cu levels, discovering a completely novel function for metallochaperones. We demonstrate that in addition to trafficking Cu ions, metallochaperones also function as buffers to modulate the transcriptional responsiveness and efficacy of Cu efflux. This buffering function of metallochaperones ultimately sets the upper limit for intracellular Cu levels and provides a mechanistic explanation for previously observed Cu metallochaperone mutation phenotypes. PMID- 23349629 TI - Make it, take it, or leave it: heme metabolism of parasites. PMID- 23349630 TI - Biosafety Level-4 laboratories in Europe: opportunities for public health, diagnostics, and research. PMID- 23349628 TI - Transcription of a cis-acting, noncoding, small RNA is required for pilin antigenic variation in Neisseria gonorrhoeae. AB - The strict human pathogen Neisseria gonorrhoeae can utilize homologous recombination to generate antigenic variability in targets of immune surveillance. To evade the host immune response, N. gonorrhoeae promotes high frequency gene conversion events between many silent pilin copies and the expressed pilin locus (pilE), resulting in the production of variant pilin proteins. Previously, we identified a guanine quartet (G4) structure localized near pilE that is required for the homologous recombination reactions leading to pilin antigenic variation (Av). In this work, we demonstrate that inactivating the promoter of a small non-coding RNA (sRNA) that initiates within the G4 forming sequence blocks pilin Av. The sRNA promoter is conserved in all sequenced gonococcal strains, and mutations in the predicted transcript downstream of the G4 forming sequence do not alter pilin Av. A mutation that produces a stronger promoter or substitution of the pilE G4-associated sRNA promoter with a phage promoter (when the phage polymerase was expressed) produced wild-type levels of pilin Av. Altering the direction and orientation of the pilE G4-associated sRNA disrupted pilin Av. In addition, expression of the sRNA at a distal site on the gonococcal chromosome in the context of a promoter mutant did not support pilin Av. We conclude that the DNA containing the G-rich sequence can only form the G4 structure during transcription of this sRNA, thus providing a unique molecular step for the initiation of programmed recombination events. PMID- 23349627 TI - SIVagm infection in wild African green monkeys from South Africa: epidemiology, natural history, and evolutionary considerations. AB - Pathogenesis studies of SIV infection have not been performed to date in wild monkeys due to difficulty in collecting and storing samples on site and the lack of analytical reagents covering the extensive SIV diversity. We performed a large scale study of molecular epidemiology and natural history of SIVagm infection in 225 free-ranging AGMs from multiple locations in South Africa. SIV prevalence (established by sequencing pol, env, and gag) varied dramatically between infant/juvenile (7%) and adult animals (68%) (p<0.0001), and between adult females (78%) and males (57%). Phylogenetic analyses revealed an extensive genetic diversity, including frequent recombination events. Some AGMs harbored epidemiologically linked viruses. Viruses infecting AGMs in the Free State, which are separated from those on the coastal side by the Drakensberg Mountains, formed a separate cluster in the phylogenetic trees; this observation supports a long standing presence of SIV in AGMs, at least from the time of their speciation to their Plio-Pleistocene migration. Specific primers/probes were synthesized based on the pol sequence data and viral loads (VLs) were quantified. VLs were of 10(4) 10(6) RNA copies/ml, in the range of those observed in experimentally-infected monkeys, validating the experimental approaches in natural hosts. VLs were significantly higher (10(7)-10(8) RNA copies/ml) in 10 AGMs diagnosed as acutely infected based on SIV seronegativity (Fiebig II), which suggests a very active transmission of SIVagm in the wild. Neither cytokine levels (as biomarkers of immune activation) nor sCD14 levels (a biomarker of microbial translocation) were different between SIV-infected and SIV-uninfected monkeys. This complex algorithm combining sequencing and phylogeny, VL quantification, serology, and testing of surrogate markers of microbial translocation and immune activation permits a systematic investigation of the epidemiology, viral diversity and natural history of SIV infection in wild African natural hosts. PMID- 23349631 TI - Adaptive immunity alters distinct host feeding pathways during nematode induced inflammation, a novel mechanism in parasite expulsion. AB - Gastrointestinal infection is often associated with hypophagia and weight loss; however, the precise mechanisms governing these responses remain poorly defined. Furthermore, the possibility that alterations in feeding during infection may be beneficial to the host requires further study. We used the nematode Trichinella spiralis, which transiently inhabits the small intestine before migrating to skeletal muscle, as a biphasic model of infection to determine the cellular and molecular pathways controlling feeding during enteric and peripheral inflammation. Through the infection of genetically modified mice lacking cholecystokinin, Tumor necrosis factor alpha receptors and T and B-cells, we observed a biphasic hypophagic response to infection resulting from two separate immune-driven mechanisms. The enteroendocrine I-cell derived hormone cholecystokinin is an essential mediator of initial hypophagia and is induced by CD4+ T-cells during enteritis. In contrast, the second hypophagic response is extra-intestinal and due to the anorectic effects of TNFalpha during peripheral infection of the muscle. Moreover, via maintaining naive levels of the adipose secreted hormone leptin throughout infection we demonstrate a novel feedback loop in the immunoendocrine axis. Immune driven I-cell hyperplasia and resultant weight loss leads to a reduction in the inflammatory adipokine leptin, which in turn heightens protective immunity during infection. These results characterize specific immune mediated mechanisms which reduce feeding during intestinal or peripheral inflammation. Importantly, the molecular mediators of each phase are entirely separate. The data also introduce the first evidence that I-cell hyperplasia is an adaptively driven immune response that directly impinges on the outcome to infection. PMID- 23349632 TI - The hepatitis B virus ribonuclease H is sensitive to inhibitors of the human immunodeficiency virus ribonuclease H and integrase enzymes. AB - Nucleos(t)ide analog therapy blocks DNA synthesis by the hepatitis B virus (HBV) reverse transcriptase and can control the infection, but treatment is life-long and has high costs and unpredictable long-term side effects. The profound suppression of HBV by the nucleos(t)ide analogs and their ability to cure some patients indicates that they can push HBV to the brink of extinction. Consequently, more patients could be cured by suppressing HBV replication further using a new drug in combination with the nucleos(t)ide analogs. The HBV ribonuclease H (RNAseH) is a logical drug target because it is the second of only two viral enzymes that are essential for viral replication, but it has not been exploited, primarily because it is very difficult to produce active enzyme. To address this difficulty, we expressed HBV genotype D and H RNAseHs in E. coli and enriched the enzymes by nickel-affinity chromatography. HBV RNAseH activity in the enriched lysates was characterized in preparation for drug screening. Twenty one candidate HBV RNAseH inhibitors were identified using chemical structure activity analyses based on inhibitors of the HIV RNAseH and integrase. Twelve anti-RNAseH and anti-integrase compounds inhibited the HBV RNAseH at 10 uM, the best compounds had low micromolar IC(50) values against the RNAseH, and one compound inhibited HBV replication in tissue culture at 10 uM. Recombinant HBV genotype D RNAseH was more sensitive to inhibition than genotype H. This study demonstrates that recombinant HBV RNAseH suitable for low-throughput antiviral drug screening has been produced. The high percentage of compounds developed against the HIV RNAseH and integrase that were active against the HBV RNAseH indicates that the extensive drug design efforts against these HIV enzymes can guide anti-HBV RNAseH drug discovery. Finally, differential inhibition of HBV genotype D and H RNAseHs indicates that viral genetic variability will be a factor during drug development. PMID- 23349633 TI - Centromere-like regions in the budding yeast genome. AB - Accurate chromosome segregation requires centromeres (CENs), the DNA sequences where kinetochores form, to attach chromosomes to microtubules. In contrast to most eukaryotes, which have broad centromeres, Saccharomyces cerevisiae possesses sequence-defined point CENs. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) reveals colocalization of four kinetochore proteins at novel, discrete, non-centromeric regions, especially when levels of the centromeric histone H3 variant, Cse4 (a.k.a. CENP-A or CenH3), are elevated. These regions of overlapping protein binding enhance the segregation of plasmids and chromosomes and have thus been termed Centromere-Like Regions (CLRs). CLRs form in close proximity to S. cerevisiae CENs and share characteristics typical of both point and regional CENs. CLR sequences are conserved among related budding yeasts. Many genomic features characteristic of CLRs are also associated with these conserved homologous sequences from closely related budding yeasts. These studies provide general and important insights into the origin and evolution of centromeres. PMID- 23349634 TI - A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity. AB - Methylation is a post-translational modification that can affect numerous features of proteins, notably cellular localization, turnover, activity, and molecular interactions. Recent genome-wide analyses have considerably extended the list of human genes encoding putative methyltransferases. Studies on protein methyltransferases have revealed that the regulatory function of methylation is not limited to epigenetics, with many non-histone substrates now being discovered. We present here our findings on a novel family of distantly related putative methyltransferases. Affinity purification coupled to mass spectrometry shows a marked preference for these proteins to associate with various chaperones. Based on the spectral data, we were able to identify methylation sites in substrates, notably trimethylation of K135 of KIN/Kin17, K561 of HSPA8/Hsc70 as well as corresponding lysine residues in other Hsp70 isoforms, and K315 of VCP/p97. All modification sites were subsequently confirmed in vitro. In the case of VCP, methylation by METTL21D was stimulated by the addition of the UBX cofactor ASPSCR1, which we show directly interacts with the methyltransferase. This stimulatory effect was lost when we used VCP mutants (R155H, R159G, and R191Q) known to cause Inclusion Body Myopathy with Paget's disease of bone and Fronto-temporal Dementia (IBMPFD) and/or familial Amyotrophic Lateral Sclerosis (ALS). Lysine 315 falls in proximity to the Walker B motif of VCP's first ATPase/D1 domain. Our results indicate that methylation of this site negatively impacts its ATPase activity. Overall, this report uncovers a new role for protein methylation as a regulatory pathway for molecular chaperones and defines a novel regulatory mechanism for the chaperone VCP, whose deregulation is causative of degenerative neuromuscular diseases. PMID- 23349635 TI - Genome-wide analysis reveals selection for important traits in domestic horse breeds. AB - Intense selective pressures applied over short evolutionary time have resulted in homogeneity within, but substantial variation among, horse breeds. Utilizing this population structure, 744 individuals from 33 breeds, and a 54,000 SNP genotyping array, breed-specific targets of selection were identified using an F(ST)-based statistic calculated in 500-kb windows across the genome. A 5.5-Mb region of ECA18, in which the myostatin (MSTN) gene was centered, contained the highest signature of selection in both the Paint and Quarter Horse. Gene sequencing and histological analysis of gluteal muscle biopsies showed a promoter variant and intronic SNP of MSTN were each significantly associated with higher Type 2B and lower Type 1 muscle fiber proportions in the Quarter Horse, demonstrating a functional consequence of selection at this locus. Signatures of selection on ECA23 in all gaited breeds in the sample led to the identification of a shared, 186-kb haplotype including two doublesex related mab transcription factor genes (DMRT2 and 3). The recent identification of a DMRT3 mutation within this haplotype, which appears necessary for the ability to perform alternative gaits, provides further evidence for selection at this locus. Finally, putative loci for the determination of size were identified in the draft breeds and the Miniature horse on ECA11, as well as when signatures of selection surrounding candidate genes at other loci were examined. This work provides further evidence of the importance of MSTN in racing breeds, provides strong evidence for selection upon gait and size, and illustrates the potential for population-based techniques to find genomic regions driving important phenotypes in the modern horse. PMID- 23349636 TI - Coordinated degradation of replisome components ensures genome stability upon replication stress in the absence of the replication fork protection complex. AB - The stabilization of the replisome complex is essential in order to achieve highly processive DNA replication and preserve genomic integrity. Conversely, it would also be advantageous for the cell to abrogate replisome functions to prevent inappropriate replication when fork progression is adversely perturbed. However, such mechanisms remain elusive. Here we report that replicative DNA polymerases and helicases, the major components of the replisome, are degraded in concert in the absence of Swi1, a subunit of the replication fork protection complex. In sharp contrast, ORC and PCNA, which are also required for DNA replication, were stably maintained. We demonstrate that this degradation of DNA polymerases and helicases is dependent on the ubiquitin-proteasome system, in which the SCF(Pof3) ubiquitin ligase is involved. Consistently, we show that Pof3 interacts with DNA polymerase epsilon. Remarkably, forced accumulation of replisome components leads to abnormal DNA replication and mitotic catastrophes in the absence of Swi1. Swi1 is known to prevent fork collapse at natural replication block sites throughout the genome. Therefore, our results suggest that the cell elicits a program to degrade replisomes upon replication stress in the absence of Swi1. We also suggest that this program prevents inappropriate duplication of the genome, which in turn contributes to the preservation of genomic integrity. PMID- 23349637 TI - Telomerase is required for zebrafish lifespan. AB - Telomerase activity is restricted in humans. Consequentially, telomeres shorten in most cells throughout our lives. Telomere dysfunction in vertebrates has been primarily studied in inbred mice strains with very long telomeres that fail to deplete telomeric repeats during their lifetime. It is, therefore, unclear how telomere shortening regulates tissue homeostasis in vertebrates with naturally short telomeres. Zebrafish have restricted telomerase expression and human-like telomere length. Here we show that first-generation tert(-/-) zebrafish die prematurely with shorter telomeres. tert(-/-) fish develop degenerative phenotypes, including premature infertility, gastrointestinal atrophy, and sarcopaenia. tert(-/-) mutants have impaired cell proliferation, accumulation of DNA damage markers, and a p53 response leading to early apoptosis, followed by accumulation of senescent cells. Apoptosis is primarily observed in the proliferative niche and germ cells. Cell proliferation, but not apoptosis, is rescued in tp53(-/-)tert(-/-) mutants, underscoring p53 as mediator of telomerase deficiency and consequent telomere instability. Thus, telomerase is limiting for zebrafish lifespan, enabling the study of telomere shortening in naturally ageing individuals. PMID- 23349638 TI - Switchgrass genomic diversity, ploidy, and evolution: novel insights from a network-based SNP discovery protocol. AB - Switchgrass (Panicum virgatum L.) is a perennial grass that has been designated as an herbaceous model biofuel crop for the United States of America. To facilitate accelerated breeding programs of switchgrass, we developed both an association panel and linkage populations for genome-wide association study (GWAS) and genomic selection (GS). All of the 840 individuals were then genotyped using genotyping by sequencing (GBS), generating 350 GB of sequence in total. As a highly heterozygous polyploid (tetraploid and octoploid) species lacking a reference genome, switchgrass is highly intractable with earlier methodologies of single nucleotide polymorphism (SNP) discovery. To access the genetic diversity of species like switchgrass, we developed a SNP discovery pipeline based on a network approach called the Universal Network-Enabled Analysis Kit (UNEAK). Complexities that hinder single nucleotide polymorphism discovery, such as repeats, paralogs, and sequencing errors, are easily resolved with UNEAK. Here, 1.2 million putative SNPs were discovered in a diverse collection of primarily upland, northern-adapted switchgrass populations. Further analysis of this data set revealed the fundamentally diploid nature of tetraploid switchgrass. Taking advantage of the high conservation of genome structure between switchgrass and foxtail millet (Setaria italica (L.) P. Beauv.), two parent-specific, synteny based, ultra high-density linkage maps containing a total of 88,217 SNPs were constructed. Also, our results showed clear patterns of isolation-by-distance and isolation-by-ploidy in natural populations of switchgrass. Phylogenetic analysis supported a general south-to-north migration path of switchgrass. In addition, this analysis suggested that upland tetraploid arose from upland octoploid. All together, this study provides unparalleled insights into the diversity, genomic complexity, population structure, phylogeny, phylogeography, ploidy, and evolutionary dynamics of switchgrass. PMID- 23349639 TI - POWERDRESS and diversified expression of the MIR172 gene family bolster the floral stem cell network. AB - Termination of the stem cells in the floral meristem (also known as floral determinacy) is critical for the reproductive success of plants, and the molecular activities regulating floral determinacy are precisely orchestrated during the course of floral development. In Arabidopsis thaliana, regulators of floral determinacy include several transcription factor genes, such as APETALA2 (AP2), AGAMOUS (AG), SUPERMAN (SUP), and CRABSCLAW (CRC), as well as a microRNA (miRNA), miR172, which targets AP2. How the transcription factor and miRNA genes are coordinately regulated to achieve floral determinacy is unknown. A mutation in POWERDRESS (PWR), a previously uncharacterized gene encoding a SANT-domain containing protein, was isolated in this study as an enhancer of the weakly indeterminate ag-10 allele. PWR was found to promote the transcription of CRC, MIR172a, b, and c and/or enhance Pol II occupancy at their promoters, without affecting MIR172d or e. A mutation in mature miR172d was additionally found to enhance the determinacy defects of ag-10 in an AP2-dependent manner, providing direct evidence that miR172d is functional in repressing AP2 and thereby contributes to floral determinacy. Thus, while PWR promotes floral determinacy by enhancing the expression of three of the five MIR172 members as well as CRC, MIR172d, whose expression is PWR-independent, also functions in floral stem cell termination. Taken together, these findings demonstrate how transcriptional diversification and functional redundancy of a miRNA family along with PWR mediated co-regulation of miRNA and transcription factor genes contribute to the robustness of the floral determinacy network. PMID- 23349640 TI - Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies. AB - The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (P(LYM) = 3.89*10(-8), OR = 1.29) and rs948562 (P(LYM) = 5.85*10(-7), OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, P(NHL) = 5.72*10(-7)) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (P(FL) = 2.69*10(-12), OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy. PMID- 23349641 TI - Function and regulation of AUTS2, a gene implicated in autism and human evolution. AB - Nucleotide changes in the AUTS2 locus, some of which affect only noncoding regions, are associated with autism and other neurological disorders, including attention deficit hyperactivity disorder, epilepsy, dyslexia, motor delay, language delay, visual impairment, microcephaly, and alcohol consumption. In addition, AUTS2 contains the most significantly accelerated genomic region differentiating humans from Neanderthals, which is primarily composed of noncoding variants. However, the function and regulation of this gene remain largely unknown. To characterize auts2 function, we knocked it down in zebrafish, leading to a smaller head size, neuronal reduction, and decreased mobility. To characterize AUTS2 regulatory elements, we tested sequences for enhancer activity in zebrafish and mice. We identified 23 functional zebrafish enhancers, 10 of which were active in the brain. Our mouse enhancer assays characterized three mouse brain enhancers that overlap an ASD-associated deletion and four mouse enhancers that reside in regions implicated in human evolution, two of which are active in the brain. Combined, our results show that AUTS2 is important for neurodevelopment and expose candidate enhancer sequences in which nucleotide variation could lead to neurological disease and human-specific traits. PMID- 23349642 TI - Transcription of the major neurospora crassa microRNA-like small RNAs relies on RNA polymerase III. AB - Most plant and animal microRNAs (miRNAs) are transcribed by RNA polymerase II. We previously discovered miRNA-like small RNAs (milRNAs) in the filamentous fungus Neurospora crassa and uncovered at least four different pathways for milRNA production. To understand the evolutionary origin of milRNAs, we determined the roles of polymerases II and III (Pol II and Pol III) in milRNA transcription. Our results show that Pol III is responsible for the transcription of the major milRNAs produced in this organism. The inhibition of Pol III activity by an inhibitor or by gene silencing abolishes the production of most abundant milRNAs and pri-milRNAs. In addition, Pol III associates with these milRNA producing loci. Even though silencing of Pol II does not affect the synthesis of the most abundant milRNAs, Pol II or both Pol II and Pol III are associated with some milRNA-producing loci, suggesting a regulatory interaction between the two polymerases for some milRNA transcription. Furthermore, we show that one of the Pol III-transcribed milRNAs is derived from a tRNA precursor, and its biogenesis requires RNase Z, which cleaves the tRNA moiety to generate pre-milRNA. Our study identifies the transcriptional machinery responsible for the synthesis of fungal milRNAs and sheds light on the evolutionary origin of eukaryotic small RNAs. PMID- 23349643 TI - Ethnic Differences in Family Stress Processes Among African-Americans and Black Caribbeans. AB - Several theories of stress exposure, including the stress process and the family stress model for economically disadvantaged families, suggest that family processes work similarly across race/ethnic groups. Much of this research, however, treats African-Americans as a monolithic group and ignores potential differences in family stress processes within race that may emerge across ethnic groups. This study examines whether family stress processes differ intraracially in African-American and Black Caribbean families. Using data from the National Survey of American Life, a national representative data set of African-American and Black Caribbean families, we assess the extent to which parents' stress appraisals and psychological adjustment are related to their adolescent children's stress appraisals, psychological adjustment, and depressive symptoms. Our study illustrates that stress processes differ by ethnicity and operate through varying pathways in African-American and Black Caribbean families. The implications of intraracial variations in stress processes are discussed. PMID- 23349644 TI - Influence of Organic Solvents on Enzymatic Asymmetric Carboligations. AB - The asymmetric mixed carboligation of aldehydes with thiamine diphosphate (ThDP) dependent enzymes is an excellent example where activity as well as changes in chemo- and stereoselectivity can be followed sensitively. To elucidate the influence of organic additives in enzymatic carboligation reactions of mixed 2 hydroxy ketones, we present a comparative study of six ThDP-dependent enzymes in 13 water-miscible organic solvents under equivalent reaction conditions. The influence of the additives on the stereoselectivity is most pronounced and follows a general trend. If the enzyme stereoselectivity in aqueous buffer is already >99.9% ee, none of the solvents reduces this high selectivity. In contrast, both stereoselectivity and chemoselectivity are strongly influenced if the enzyme is rather unselective in aqueous buffer. For the S-selective enzyme with the largest active site, we were able to prove a general correlation of the solvent-excluded volume of the additives with the effect on selectivity changes: the smaller the organic solvent molecule, the higher the impact of this additive. Further, a correlation to log P of the additives on selectivity was detected if two additives have almost the same solvent-excluded volume. The observed results are discussed in terms of structural, biochemical and energetic effects. This work demonstrates the potential of medium engineering as a powerful additional tool for varying enzyme selectivity and thus engineering the product range of biotransformations. It further demonstrates that the use of cosolvents should be carefully planned, as the solvents may compete with the substrate(s) for binding sites in the enzyme active site. PMID- 23349645 TI - Living emotions, avoiding emotions: behavioral investigation of the regulation of socially driven emotions. AB - Emotion regulation is important for psychological well-being. Although it is known that alternative regulation strategies may have different emotional consequences, the effectiveness of such strategies for socially driven emotions remains unclear. In this study we investigated the efficacy of different forms of reappraisal on responses to the selfish and altruistic behavior of others in the Dictator Game. In Experiment 1, subjects mentalized the intentions of the other player in one condition, and took distance from the situation in the other. Emotion ratings were recorded after each offer. Compared with a baseline condition, mentalizing led subjects to experience their emotions more positively when receiving both selfish and altruistic proposals, whereas distancing decreased the valence when receiving altruistic offers, but did not affect the perception of selfish behavior. In Experiment 2, subjects played with both computer and human partners while reappraising the meaning of the player's intentions (with a human partner) or the meaning of the situation (with a computer partner). Results showed that both contexts were effectively modulated by reappraisal, however a stronger effect was observed when the donor was a human partner, as compared to a computer partner. Taken together, these results demonstrate that socially driven emotions can be successfully modulated by reappraisal strategies that focus on the reinterpretation of others' intentions. PMID- 23349647 TI - Contrast-enhanced ultrasound as support for prostate brachytherapy treatment planning. AB - PURPOSE: To investigate the possibility of localization of intraprostatic lesions (IL) with contrast-enhanced ultrasound (CEUS) to support the brachytherapy treatment planning of temporary implants. MATERIAL AND METHODS: Two brachytherapy treatment plans were generated for 8 patients treated with external beam radiotherapy and pulsed-dose rate brachytherapy boost for prostate cancer. The first and second brachytherapy treatment plan was without and with knowledge of the localization of the ILs, respectively. Pairwise comparison was performed on prostate, rectum, and urethra dose-volume parameters and total reference air kerma (TRAK)-values. RESULTS: Coverage of the ILs by the 140% isodose was increased from mean 66.0-67.7% for the standard plan to mean 92.5-95.7% for the adapted plan. The mean D90 of the ILs increased from 1.49-1.57 Gy/pulse to 1.76 1.81 Gy/pulse. Dose-volume parameters for the prostate, rectum, and urethra and the TRAK did not change. CONCLUSIONS: CEUS technique is a promising method for IL localization to aid in brachytherapy treatment planning. Dose coverage on the IL could be improved without any increase of dose in organs at risk. PMID- 23349648 TI - Case series analysis of post-brachytherapy prostate edema and its relevance to post-implant dosimetry. Post-implant prostate edema and dosimetry. AB - PURPOSE: We evaluated the post-operative pattern of prostate volume (PV) changes following prostate brachytherapy (PB) and analyzed variables which affect swelling. MATERIAL AND METHODS: Twenty-nine patients treated with brachytherapy (14) or combined brachytherapy and external beam radiotherapy modality (15) underwent pre- and post-implant computed tomography (CT). Prostate volume measurements were done on post-operative days 1, 9, 30, and 60. An observer performed 139 prostate volume (PV) measurements. We analyzed the influence of pre implant PV, number of needles and insertion attempts, number and activity of seeds, Gleason score, use of hormonal therapy and external beam radiation therapy on the extent of edema. We computed a volume correction factor (CF) to account for dosimetric changes between day 1 and day 30. Using the calculated CF, the dose received by 90% (D(90)) of the prostate on day 30 (D(90)Day30) was obtained by dividing day 1 (D(90)Day1) by the CF. RESULTS: The mean PV recorded on post operative day 1 was 67.7 cm(3), 18.8 cm(3) greater than average pre-op value (SD 15.6 cm(3)). Swelling returned to pre-implant volume by day 30. Seed activity, treatment modality, and Gleason score were significant variables. The calculated CF was 0.76. After assessment using the CF, the mean difference between estimated and actual D(90)Day30 was not significant. CONCLUSIONS: We observed maximum prostate size on post-operative day 1, returning to pre-implant volume by day 30. This suggests that post-implant dosimetry should be obtained on or after post operative day 30. If necessary, day 30 dosimetry can be estimated by dividing D(90)Day1 by a correction factor of 0.76. PMID- 23349646 TI - Cognitive and neuroplasticity mechanisms by which congenital or early blindness may confer a protective effect against schizophrenia. AB - Several authors have noted that there are no reported cases of people with schizophrenia who were born blind or who developed blindness shortly after birth, suggesting that congenital or early (C/E) blindness may serve as a protective factor against schizophrenia. By what mechanisms might this effect operate? Here, we hypothesize that C/E blindness offers protection by strengthening cognitive functions whose impairment characterizes schizophrenia, and by constraining cognitive processes that exhibit excessive flexibility in schizophrenia. After briefly summarizing evidence that schizophrenia is fundamentally a cognitive disorder, we review areas of perceptual and cognitive function that are both impaired in the illness and augmented in C/E blindness, as compared to healthy sighted individuals. We next discuss: (1) the role of neuroplasticity in driving these cognitive changes in C/E blindness; (2) evidence that C/E blindness does not confer protective effects against other mental disorders; and (3) evidence that other forms of C/E sensory loss (e.g., deafness) do not reduce the risk of schizophrenia. We conclude by discussing implications of these data for designing cognitive training interventions to reduce schizophrenia-related cognitive impairment, and perhaps to reduce the likelihood of the development of the disorder itself. PMID- 23349650 TI - A novel method for vaginal cylinder treatment planning: a seamless transition to 3D brachytherapy. AB - PURPOSE: Standard treatment plan libraries are often used to ensure a quick turn around time for vaginal cylinder treatments. Recently there is increasing interest in transitioning from conventional 2D radiograph based brachytherapy to 3D image based brachytherapy, which has resulted in a substantial increase in treatment planning time and decrease in patient through-put. We describe a novel technique that significantly reduces the treatment planning time for CT-based vaginal cylinder brachytherapy. MATERIAL AND METHODS: Oncentra MasterPlan TPS allows multiple sets of data points to be classified as applicator points which has been harnessed in this method. The method relies on two hard anchor points: the first dwell position in a catheter and an applicator configuration specific dwell position as the plan origin and a soft anchor point beyond the last active dwell position to define the axis of the catheter. The spatial location of various data points on the applicator's surface and at 5 mm depth are stored in an Excel file that can easily be transferred into a patient CT data set using window operations and then used for treatment planning. The remainder of the treatment planning process remains unaffected. RESULTS: The treatment plans generated on the Oncentra MasterPlan TPS using this novel method yielded results comparable to those generated on the Plato TPS using a standard treatment plan library in terms of treatment times, dwell weights and dwell times for a given optimization method and normalization points. Less than 2% difference was noticed between the treatment times generated between both systems. Using the above method, the entire planning process, including CT importing, catheter reconstruction, multiple data point definition, optimization and dose prescription, can be completed in ~5-10 minutes. CONCLUSION: The proposed method allows a smooth and efficient transition to 3D CT based vaginal cylinder brachytherapy planning. PMID- 23349649 TI - Physics-aspects of dose accuracy in high dose rate (HDR) brachytherapy: source dosimetry, treatment planning, equipment performance and in vivo verification techniques. AB - This study provides a review of recent publications on the physics-aspects of dosimetric accuracy in high dose rate (HDR) brachytherapy. The discussion of accuracy is primarily concerned with uncertainties, but methods to improve dose conformation to the prescribed intended dose distribution are also noted. The main aim of the paper is to review current practical techniques and methods employed for HDR brachytherapy dosimetry. This includes work on the determination of dose rate fields around brachytherapy sources, the capability of treatment planning systems, the performance of treatment units and methods to verify dose delivery. This work highlights the determinants of accuracy in HDR dosimetry and treatment delivery and presents a selection of papers, focusing on articles from the last five years, to reflect active areas of research and development. Apart from Monte Carlo modelling of source dosimetry, there is no clear consensus on the optimum techniques to be used to assure dosimetric accuracy through all the processes involved in HDR brachytherapy treatment. With the exception of the ESTRO mailed dosimetry service, there is little dosimetric audit activity reported in the literature, when compared with external beam radiotherapy verification. PMID- 23349651 TI - Impact of interfraction seroma collection on breast brachytherapy dosimetry - a mathematical model. AB - PURPOSE: Balloon brachytherapy is a widely accepted modality for delivery of accelerated partial breast irradiation (APBI). Our hypothesis was that inter fraction seroma collection around the balloon surface would have an adverse effect on dosimetry of the target. MATERIAL AND METHODS: This is a dosimetric re planning study using two volumetric models (30 cc and 45 cc) in a Contura((r)) multi-lumen balloon (MLB) catheter. In a previously treated patient, two customized baseline plans were generated using multiple channels of the Contura((r)) catheter prescribed to the Planning Target Volume Evaluation (PTV_Eval). Symmetric expansions of 1.0 mm (0-9 mm) increments around the balloon surface were performed to simulate a "Virtual Seroma" (VS) accumulation for both balloon volumes and plans were obtained for each expansion using Eclipse BrachyvisionTM. An analysis of these plans was then performed to evaluate the effect of seroma accumulation on dosimetric parameters of V100 and V90. RESULTS: 20 plans were generated and analyzed (10 plans for each balloon volume), representing VS of 6.0-66.0 cc. There was a commensurate decrease in the dose delivered to the PTV_Eval V100 and V90 (as defined by the original treatment plan) with increasing VS accumulation leading to a sub-optimal coverage of the PTV_Eval. For 30 cc MLB catheter, V100 decreased by 1.4% and V90 decreased by 0.9% for every 1 cc of VS. For 45cc MLB catheter, V100 decreased by 1.3% and V90 decreased by 1.15% for every 1.0 cc accumulation of VS. CONCLUSIONS: Balloon catheter-tissue adherence ensures daily dose delivery to the planned PTV_Eval. Accumulation of seroma, hematoma or air between HDR fractions can significantly impact PTV_Eval dosimetry. Vacuum-port aspiration prior to delivery of each fraction, if available, should be considered to minimize the risk of geographic under dosing. PMID- 23349653 TI - Vaginal cuff dehiscence after intracavitary brachytherapy for endometrial cancer. AB - We describe 2 unusual cases of vaginal dehiscence after intracavitary brachytherapy performed following robotic laparoscopic hysterectomy (RLH) along with their management. This unusual complication, which may be more common because of the robotic procedures, can be prevented by careful examination and possible delay of the onset of brachytherapy, if indicated. Our report reviews techniques of avoiding this complication and suggests that these complications should be discussed with the patients. PMID- 23349652 TI - Dose correction in lung for HDR breast brachytherapy. AB - PURPOSE: To evaluate the dosimetric impact of lung tissue in Ir-192 APBI. MATERIAL AND METHODS: In a 40 * 40 * 40 cm(3) water tank, an Accelerated Partial Breast Irradiation (APBI) brachytherapy balloon inflated to 4 cm diameter was situated directly below the center of a 30 * 30 * 1 cm(3) solid water slab. Nine cm of solid water was stacked above the 1 cm base. A parallel plate ion chamber was centered above the base and ionization current measurements were taken from the central HDR source dwell position for channels 1, 2, 3 and 5 of the balloon. Additional ionization data was acquired in the 9 cm stack at 1 cm increments. A comparable data set was also measured after replacing the 9 cm solid water stack with cork slabs. The ratios of measurements in the two phantoms were calculated and compared to predicted results of a commercial treatment planning system. RESULTS: Lower dose was measured in the cork within 1 cm of the cork/solid water interface possibly due to backscatter effects. Higher dose was measured beyond 1 cm from the cork/solid water interface, increasing with path length up to 15% at 9 cm depth in cork. The treatment planning system did not predict either dose effect. CONCLUSIONS: This study investigates the dosimetry of low density material when the breast is treated with Ir-192 brachytherapy. HDR dose from Ir 192 in a cork media is shown to be significantly different than in unit density media. These dose differences are not predicted in most commercial brachytherapy planning systems. Empirical models based on measurements could be used to estimate lung dose associated with HDR breast brachytherapy. PMID- 23349654 TI - Comparison of the GTV coverage by PTV and isodose of 90% in 2D and 3D planning during endobronchial brachytherapy in the palliative treatment of patients with advanced lung cancer. Pilot study. AB - PURPOSE: Endobronchial brachytherapy (EB) is one way of treatment of patients with advanced lung cancer. Technological progress and the introduction of computed tomography for use in 3D planning allows one to define the area being treated very precisely, which gives an opportunity to extend survival, even in groups of patients receiving palliative care. MATERIAL AND METHODS: In 2011, in the Brachytherapy Department of the Subcarpathian Oncological Center, a group of 12 consecutive patients with advanced cancer of the bronchus underwent palliative EB. We compared the coverage of GTV (gross tumor volume), seen in the computed tomography study with intravenous contrast, by the PTV (planning target volume) planned in 3D and 2D. RESULTS: In 2D planning GTV coverage ranged from 15% to 89%. By analyzing the isodose of 90%, it was found that 2D planning covered GTV in 15-35% of the dose. In 3D planning, this coverage changed positively, and ranged from 85% to 100%. The GTV coverage in 3D planning was 100% by definition. In addition, it should be noted that in the 3D planning one can spare critical organs or pacemakers. CONCLUSIONS: Planning for HDR brachytherapy in all locations should be based on dynamic imaging at present, especially in centers that are equipped with CT. Evaluation should be a routine test in treatment planning. The use of CT, even in palliative treatment planning, allows for much better coverage of GTV areas as well, which is very important to reduce radiation doses to critical organs and thereby reduce the toxic effects of treatment. PMID- 23349655 TI - Prostate cancer brachytherapy: guidelines overview. AB - Prostate cancer, due to wide availability of PSA tests, is very often diagnosed in early stage, nowadays. This makes management of this disease even harder in every day oncology care. There is a wide range of treatment options including surgery, radiotherapy and active surveillance, but essential question is which treatment patient and oncologist should decide for. Due to recent publication of Prostate Cancer Results Study Group, in which brachytherapy is one of supreme curative options for prostate cancer, we decided to overview most present european and north american recommendations. National Comprehensive Cancer Network, American Society for Radiation Oncology, American Brachytherapy Society, European Association of Urology and Groupe Europeen de Curietherapie of European Society for Therapeutic Radiation Oncology guidelines are overviewed, particularly focusing on HDR and LDR brachytherapy. PMID- 23349656 TI - Divergent trends in abortion and birth control practices in belarus, Russia and Ukraine. AB - CONTEXT: The last decade witnessed growing differences in abortion dynamics in Belarus, Russia, and Ukraine despite demographic, social, and historical similarities of these nations. This paper investigates changes in birth control practices in the three countries and searches for an explanation of the diverging trends in abortion. METHODS: Official abortion and contraceptive use statistics, provided by national statistical agencies, were analysed. Respective laws and other legal documents were examined and compared between the three countries. To disclose inter-country differences in prevalence of the modern methods of contraception and its association with major demographic and social factors, an analysis of data from national sample surveys was performed, including binary logistic regression. RESULTS: The growing gap in abortion rate in Belarus, Russia, and Ukraine is a genuine phenomenon, not a statistical artefact. The examination of abortion and prevalence of contraception based on official statistics and three national sample surveys did not reveal any unambiguous factors that could explain differences in abortion dynamics in Belarus, Russia, and Ukraine. However, it is very likely that the cause of the inter-country discrepancies lies in contraceptive behavior itself, in adequacies of contraceptive knowledge and practices. Additionally, large differences in government policies, which are very important in shaping contraceptive practices of the population, were detected. CONCLUSION: Since the end of the 1990s, the Russian government switched to archaic ideology in the area of reproductive health and family planning and neglects evidence-based arguments. Such an extreme turn in the governmental position is not observed in Belarus or Ukraine. This is an important factor contributing to the slowdown in the decrease of abortion rates in Russia. PMID- 23349657 TI - Left atrial and right atrial deformation in patients with coronary artery disease: a velocity vector imaging-based study. AB - BACKGROUND: Impaired left ventricular (LV) function has been shown by strain rate (SR) imaging in patients with coronary artery disease (CAD). Our aim was to investigate global and regional, systolic and diastolic left atrial (LA) and right atrial (RA) longitudinal deformation in CAD using velocity vector imaging. METHODS: Echocardiographic and velocity vector imaging studies were performed in 20 patients with mild CAD, 40 patients with severe CAD and 25 controls. Maximal atrial volume, peak atrial longitudinal strain (epsilon(s)) and SR during LV systole (SRs), SR during early LV filling (SRe) and late LV filling (SRa) were measured. Longitudinal strain during atrial contraction (epsilon(a)) was obtained at the onset of P-wave on electrocardiography, and epsilon(a)/epsilon(s) was calculated. RESULTS: Longitudinal peak epsilon(s) and SRs of LA showed decreased trend among CAD patients. The global and lateral LA SRe were prominently lower, while RA epsilon(a), SRa and epsilon(a)/epsilon(s) were prominently higher in 2 CAD groups than control group (P value <0.05). As compared with controls and patients with other single-vessel disease, LA SRa and epsilon(a)/epsilon(s) ratio were significantly increased among patients with exclusively left anterior descending coronary artery (LAD) stenosis (SRa 1.14+/-0.38 s(-1), 1.10+/-0.41 s( 1), 1.45+/-0.46 s(-1), P value<0.05; epsilon(a)/epsilon(s) 0.44+/-0.11, 0.44+/ 0.20, 0.57+/-0.12, P value<0.01). CONCLUSIONS: Apparently decreased SRe of LA and increased epsilon(a), SRa and epsilon(a)/epsilon(s) of RA were found in CAD patients with preserved LVEF and E/E' in gray zone. SRa and epsilon(a)/epsilon(s) of LA were found to significantly increase in those with LAD stenosis. PMID- 23349658 TI - Regulation of cel genes of C. cellulolyticum: identification of GlyR2, a transcriptional regulator regulating cel5D gene expression. AB - Transcription and expression regulation of some individual cel genes (cel5A, cel5I, cel5D and cel44O) of Clostridium cellulolyticum were investigated. Unlike the cip-cel operon, these genes are transcribed as monocistronic units of transcription, except cel5D. The location of the transcription initiation sites was determined using RT-PCR and the mRNA 5'-end extremities were detected using primer extension experiments. Similarly to the cip-cel operon, cel5A and cel5I expressions are regulated by a carbon catabolite repression mechanism, whereas cel44O and cel5D expressions do not seem to be submitted to this regulation. The role of the putative transcriptional regulator GlyR2 in the regulation of cel5D expression was investigated. The recombinant protein GlyR2 was produced and was shown to bind in vitro to the cel5D and glyR2 promoter regions, suggesting that besides regulating its own expression, GlyR2 may regulate cel5D expression. To test this hypothesis in vivo, an insertional glyR2 mutant was generated and the effect of this disruption on cel5D expression was evaluated. Levels of cel5D mRNAs in the mutant were 16 fold lower than that of the wild-type strain suggesting that GlyR2 acts as an activator of cel5D expression. PMID- 23349659 TI - Molecular epidemiology and disease severity of human respiratory syncytial virus in Vietnam. AB - Respiratory syncytial virus (RSV) is a major cause of acute respiratory infections (ARIs) in children worldwide and can cause high mortality, especially in developing countries. However, information on the clinical and molecular characteristics of RSV infection in developing countries is limited. From April 2010 to May 2011, 1,082 nasopharyngeal swabs were collected from children with ARI admitted to the Children's Hospital 2, Ho Chi Minh City, Vietnam. Samples were screened for RSV and genotyped by reverse transcription-PCR and sequencing. Demographic and clinical data was also recorded. RSV was found in 23.8% (257/1,082) of samples. RSV A was the dominant subgroup, accounting for 91.4% (235/257), followed by RSV B, 5.1% (13/257), and 9 cases (3.5%) were mixed infection of these subgroups. The phylogenetic analysis revealed that all group A strains belonged to the GA2 genotype. All group B strains belonged to the recently identified BA genotype, and further clustered into 2 recently described subgenotypes BA9 and BA10. One GA2 genotype strain had a premature stop codon which shortened the G protein length. RSV infection was significantly associated with younger age and higher severity score than those without. Co-infection with other viruses did not affect disease severity. RSV A caused more severe disease than RSV B. The results from this study will not only contribute to the growing database on the molecular diversity of RSV circulating worldwide but may be also useful in clinical management and vaccine development. PMID- 23349660 TI - The silent period of evidence integration in fast decision making. AB - In a typical experiment on decision making, one out of two possible stimuli is displayed and observers decide which one was presented. Recently, Stanford and colleagues (2010) introduced a new variant of this classical one-stimulus presentation paradigm to investigate the speed of decision making. They found evidence for "perceptual decision making in less than 30 ms". Here, we extended this one-stimulus compelled-response paradigm to a two-stimulus compelled response paradigm in which a vernier was followed immediately by a second vernier with opposite offset direction. The two verniers and their offsets fuse. Only one vernier is perceived. When observers are asked to indicate the offset direction of the fused vernier, the offset of the second vernier dominates perception. Even for long vernier durations, the second vernier dominates decisions indicating that decision making can take substantial time. In accordance with previous studies, we suggest that our results are best explained with a two-stage model of decision making where a leaky evidence integration stage precedes a race-to threshold process. PMID- 23349661 TI - De novo transcriptome assembly in chili pepper (Capsicum frutescens) to identify genes involved in the biosynthesis of capsaicinoids. AB - The capsaicinoids are a group of compounds produced by chili pepper fruits and are used widely in many fields, especially in medical purposes. The capsaicinoid biosynthetic pathway has not yet been established clearly. To understand more knowledge in biosynthesis of capsaicinoids, we applied RNA-seq for the mixture of placenta and pericarp of pungent pepper (Capsicum frutescens L.). We have assessed the effect of various assembly parameters using different assembly software, and obtained one of the best strategies for de novo assembly of transcriptome data. We obtained a total 54,045 high-quality unigenes (transcripts) using Trinity software. About 92.65% of unigenes showed similarity to the public protein sequences, genome of potato and tomato and pepper (C. annuum) ESTs databases. Our results predicted 3 new structural genes (DHAD, TD, PAT), which filled gaps of the capsaicinoid biosynthetic pathway predicted by Mazourek, and revealed new candidate genes involved in capsaicinoid biosynthesis based on KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. A significant number of SSR (Simple Sequence Repeat) and SNP (Single Nucleotide Polymorphism) markers were predicted in C. frutescens and C. annuum sequences, which will be helpful in the identification of polymorphisms within chili pepper populations. These data will provide new insights to the pathway of capsaicinoid biosynthesis and subsequent research of chili peppers. In addition, our strategy of de novo transcriptome assembly is applicable to a wide range of similar studies. PMID- 23349662 TI - The effects of methionine acquisition and synthesis on Streptococcus pneumoniae growth and virulence. AB - Bacterial pathogens need to acquire nutrients from the host, but for many nutrients their importance during infection remain poorly understood. We have investigated the importance of methionine acquisition and synthesis for Streptococcus pneumoniae growth and virulence using strains with gene deletions affecting a putative methionine ABC transporter lipoprotein (Sp_0149, metQ) and/or methionine biosynthesis enzymes (Sp_0585 - Sp_0586, metE and metF). Immunoblot analysis confirmed MetQ was a lipoprotein and present in all S. pneumoniae strains investigated. However, vaccination with MetQ did not prevent fatal S. pneumoniae infection in mice despite stimulating a strong specific IgG response. Tryptophan fluorescence spectroscopy and isothermal titration calorimetry demonstrated that MetQ has both a high affinity and specificity for L methionine with a K(D) of ~25 nM, and a DeltametQ strain had reduced uptake of C(14)-methionine. Growth of the DeltametQ/DeltametEF strain was greatly impaired in chemically defined medium containing low concentrations of methionine and in blood but was partially restored by addition of high concentrations of exogenous methionine. Mixed infection models showed no attenuation of the DeltametQ, DeltametEF and DeltametQ/DeltametEF strains in their ability to colonise the mouse nasopharnyx. In a mouse model of systemic infection although significant infection was established in all mice, there were reduced spleen bacterial CFU after infection with the DeltametQ/DeltametEF strain compared to the wild-type strain. These data demonstrate that Sp_0149 encodes a high affinity methionine ABC transporter lipoprotein and that Sp_0585 - Sp_0586 are likely to be required for methionine synthesis. Although Sp_0149 and Sp_0585-Sp_0586 make a contribution towards full virulence, neither was essential for S. pneumoniae survival during infection. PMID- 23349664 TI - Robust short-term memory without synaptic learning. AB - Short-term memory in the brain cannot in general be explained the way long-term memory can--as a gradual modification of synaptic weights--since it takes place too quickly. Theories based on some form of cellular bistability, however, do not seem able to account for the fact that noisy neurons can collectively store information in a robust manner. We show how a sufficiently clustered network of simple model neurons can be instantly induced into metastable states capable of retaining information for a short time (a few seconds). The mechanism is robust to different network topologies and kinds of neural model. This could constitute a viable means available to the brain for sensory and/or short-term memory with no need of synaptic learning. Relevant phenomena described by neurobiology and psychology, such as local synchronization of synaptic inputs and power-law statistics of forgetting avalanches, emerge naturally from this mechanism, and we suggest possible experiments to test its viability in more biological settings. PMID- 23349663 TI - Angiotensin II reduces cardiac AdipoR1 expression through AT1 receptor/ROS/ERK1/2/c-Myc pathway. AB - Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2) mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII) on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1) receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS) scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII. PMID- 23349665 TI - Schizophrenia as a network disease: disruption of emergent brain function in patients with auditory hallucinations. AB - Schizophrenia is a psychiatric disorder that has eluded characterization in terms of local abnormalities of brain activity, and is hypothesized to affect the collective, "emergent" working of the brain. Indeed, several recent publications have demonstrated that functional networks in the schizophrenic brain display disrupted topological properties. However, is it possible to explain such abnormalities just by alteration of local activation patterns? This work suggests a negative answer to this question, demonstrating that significant disruption of the topological and spatial structure of functional MRI networks in schizophrenia (a) cannot be explained by a disruption to area-based task-dependent responses, i.e. indeed relates to the emergent properties, (b) is global in nature, affecting most dramatically long-distance correlations, and (c) can be leveraged to achieve high classification accuracy (93%) when discriminating between schizophrenic vs control subjects based just on a single fMRI experiment using a simple auditory task. While the prior work on schizophrenia networks has been primarily focused on discovering statistically significant differences in network properties, this work extends the prior art by exploring the generalization (prediction) ability of network models for schizophrenia, which is not necessarily captured by such significance tests. PMID- 23349666 TI - Phosphorylation of STAT-1 serine 727 is prolonged in HLA-B27-expressing human monocytic cells. AB - A tissue antigen, HLA-B27, is strongly associated with a group of rheumatic diseases called spondyloarthritides. Despite the intensive research, the exact role of HLA-B27 in the pathogenesis of these diseases is still unclear. Here we studied whether HLA-B27 modulates the phosphorylation of signal transducer and activator of transcription 1 (STAT-1) serine 727 residue and the localization of STAT-1 in Salmonella-infected human monocytic cells. In addition, we studied the role of signaling molecule double-stranded RNA activated protein kinase (PKR) in these modulatory effects. U937 human monocytic cell transfectants stably expressing wild type HLA-B27 or mutated HLA-B27 heavy chains with amino acid substitutions in the B pocket were prepared. The PMA-differentiated cells were infected with S. enteritidis. Western blotting was used to detect the phosphorylation of STAT-1, and to visualize the localization of STAT-1 in the cells confocal microscopy was used. Specific inhibitors were employed to study the role of PKR in STAT-1 phosphorylation. We discovered that the phosphorylation of STAT-1 serine 727 is prolonged in cells expressing misfolding forms of HLA-B27 after S. enteritidis infection, whereas in mock cells and in cells expressing mutated, non-misfolding HLA-B27 the phosphorylation of serine 727 is transient. Interestingly, STAT-1 serine 727 phosphorylation is partly dependent on PKR. In addition, more STAT-1 is localized in the nucleus of HLA-B27-expressing cells, even before an external trigger, when compared to mock cells. In conclusion, our results show that the phosphorylation of STAT-1 serine 727 residue is prolonged in HLA-B27-expressing monocyte-macrophage U937 cells after bacterial infection. This is of interest since the phosphorylation of serine 727 on STAT-1 is suggested to contribute to macrophage activation and promote inflammatory responses. Therefore, our results provide a mechanism which explains how the expression of an HLA-B27 molecule can impact the course of Salmonella infection and reactive arthritis. PMID- 23349667 TI - Estimating the true accuracy of diagnostic tests for dengue infection using bayesian latent class models. AB - BACKGROUND: Accuracy of rapid diagnostic tests for dengue infection has been repeatedly estimated by comparing those tests with reference assays. We hypothesized that those estimates might be inaccurate if the accuracy of the reference assays is not perfect. Here, we investigated this using statistical modeling. METHODS/PRINCIPAL FINDINGS: Data from a cohort study of 549 patients suspected of dengue infection presenting at Colombo North Teaching Hospital, Ragama, Sri Lanka, that described the application of our reference assay (a combination of Dengue IgM antibody capture ELISA and IgG antibody capture ELISA) and of three rapid diagnostic tests (Panbio NS1 antigen, IgM antibody and IgG antibody rapid immunochromatographic cassette tests) were re-evaluated using bayesian latent class models (LCMs). The estimated sensitivity and specificity of the reference assay were 62.0% and 99.6%, respectively. Prevalence of dengue infection (24.3%), and sensitivities and specificities of the Panbio NS1 (45.9% and 97.9%), IgM (54.5% and 95.5%) and IgG (62.1% and 84.5%) estimated by bayesian LCMs were significantly different from those estimated by assuming that the reference assay was perfect. Sensitivity, specificity, PPV and NPV for a combination of NS1, IgM and IgG cassette tests on admission samples were 87.0%, 82.8%, 62.0% and 95.2%, respectively. CONCLUSIONS: Our reference assay is an imperfect gold standard. In our setting, the combination of NS1, IgM and IgG rapid diagnostic tests could be used on admission to rule out dengue infection with a high level of accuracy (NPV 95.2%). Further evaluation of rapid diagnostic tests for dengue infection should include the use of appropriate statistical models. PMID- 23349668 TI - Mixing plants from different origins to restore a declining population: ecological outcomes and local perceptions 10 years later. AB - Populations of the Large-flowered Sandwort (Arenaria grandiflora L.) in the Fontainebleau forest (France) have declined rapidly during the last century. Despite the initiation of a protection program in 1991, less than twenty individuals remained by the late 1990s. The low fitness of these last plants, which is likely associated with genetic disorders and inbreeding depression, highlighted the need for the introduction of non-local genetic material to increase genetic diversity and thus restore Fontainebleau populations. Consequently, A. grandiflora was introduced at three distant sites in the Fontainebleau forest in 1999. Each of these populations was composed of an identical mix of individuals of both local and non-local origin that were obtained through in vitro multiplication. After establishment, the population status (number of individuals, diameter of the plants, and number of flowers) of the introduced populations was monitored. At present, two populations (one of which is much larger than the other) persist, while the third one became extinct in 2004. Analyses of the ecological parameters of the introduction sites indicated that differences in soil pH and moisture might have contributed to the differences in population dynamics. This introduction plan and its outcome attracted interest of local community, with those who supported the plan and regarded its 10-year result as a biological success (i.e., persistent populations were created), but also those who expressed reservations or disapproval of the plan and its outcome. To understand this controversy, a sociological study involving 27 semi-structured interviews was carried out. From these interviews emerged three areas of controversy: alteration of the identity of the plant, alteration of the identity of its territory, and the biological and ethical consequences of the techniques used for the experimental conservation. PMID- 23349669 TI - Stereoselective phytotoxicity of HCH mediated by photosynthetic and antioxidant defense systems in Arabidopsis thaliana. AB - BACKGROUND: Hexachlorocyclohexane (HCH) has been used for plant protection and sanitation world-widely, and its isomers have been detected in water, soil, and air as well as in vegetation. As a sink for lipophilic pollutants, vegetation is very important for the degradation and fate of organic contamination; however, little was known about their phytotoxicity and mechanisms of toxic effect. In this study, the stereoselective phototoxicity of four isomers (alpha, beta, gamma, and delta) of HCHs mediated by independent as well as interconnecting systems of photosynthesis and enzymatic antioxidant defense system in Arabidopsis thaliana were assessed. PRINCIPAL FINDINGS: Our results revealed that all the HCHs not only stimulated the activities of catalase (CAT) and peroxidase (POD), but also inhibited the activity of superoxide dismutase (SOD). In photosynthesis system, the photosynthetic efficiency of PSI and PSII were all down regulated. Meanwhile, results from both systems showed that delta-HCH was the most toxic one, while alpha-HCH the least in Arabidopsis thaliana. CONCLUSIONS: For the first time, stereoselective effects of different isomers of HCH in plant were demonstrated. And the results suggest that it requires further research to fully elucidate the environmental toxicity and their mechanisms. PMID- 23349670 TI - Rapid diagnosis of Mycobacterium tuberculosis with Truenat MTB: a near-care approach. AB - BACKGROUND: Control of the global Tuberculosis (TB) burden is hindered by the lack of a simple and effective diagnostic test that can be utilized in resource limited settings. METHODS: We evaluated the performance of Truenat MTBTM, a chip based nucleic acid amplification test in the detection of Mycobacterium tuberculosis (MTB) in clinical sputum specimens from 226 patients with suspected pulmonary tuberculosis (TB). The test involved sputum processing using Trueprep MAGTM (nanoparticle-based protocol run on a battery-operated device) and real time PCR performed on the Truelab UnoTM analyzer (handheld, battery-operated thermal cycler). Specimens were also examined for presence of MTB using smear microscopy, liquid culture and an in-house nested PCR protocol. Results were assessed in comparison to a composite reference standard (CRS) consisting of smear and culture results, clinical treatment and follow-up, and radiology findings. RESULTS: Based on the CRS, 191 patients had "Clinical-TB" (Definite and Probable-TB). Of which 154 patients are already on treatment, and 37 were treatment naive cases. Remaining 35 were confirmed "Non-TB" cases which are treatment naive cases. The Truenat MTB test was found to have sensitivity and specificity of 91.1% (CI: 86.1-94.7) and 100% (CI: 90.0-100) respectively, in comparison to 90.58% (CI: 85.5-94.3) and 91.43% (CI: 76.9-98.2) respectively for the in-house nested PCR protocol. CONCLUSION: This preliminary study shows that the Truenat MTB test allows detection of TB in approximately one hour and can be utilized in near-care settings to provide quick and accurate diagnosis. PMID- 23349671 TI - Phylogeny of the Archiborborinae (Diptera: Sphaeroceridae) based on combined morphological and molecular analysis. AB - The Archiborborinae is a diverse Neotropical subfamily of Sphaeroceridae, with many undescribed species. The existing generic classification includes three genera consisting of brachypterous species, with all other species placed in the genus Archiborborus. We present the first phylogenetic hypothesis for the subfamily based on morphological, molecular, and combined datasets. Morphological data include 53 characters and cover all valid described taxa (33 species in 4 genera) in the subfamily, as well as 83 undescribed species. Molecular data for five genes (mitochondrial 12S rDNA, cytochrome c oxidase subunit I, and cytochrome B, and nuclear alanyl-tRNA synthetase and 28S rDNA) were obtained for 21 ingroup taxa. Data support the separation of the Archiborborinae from the Copromyzinae, with which they were formerly combined. Analyses support consistent groups within the subfamily, but relationships between groups are poorly resolved. The validity of the brachypterous genera Penola Richards and Frutillaria Richards is supported. The former genus Archiborborus Duda is paraphyletic, and will be divided into monophyletic genera on the basis of this work. Aptery and brachyptery have evolved multiple times in the subfamily. Antrops Enderlein, previously including a single brachypterous species, is a senior synonym of Archiborborus. PMID- 23349672 TI - Willingness to participate in clinical trials among patients of Chinese heritage: a meta-synthesis. AB - BACKGROUND: Subjects of Chinese heritage have been found to participate in clinical research at lower rates than other groups despite growing in numbers as a population. While much research has examined research participants' motivation, there has not been a comprehensive synthesis of this information with respect to participants of Chinese descent. We sought to identify the factors that promote and hinder participation in clinical research among participants of Chinese heritage. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a systematic review of the literature in Pubmed, OpenJGATE, SCIRUS, and COCHRANE databases and performed a meta-synthesis of retrieved articles. We extracted qualitative data, such as quotes to identify emerging themes. We identified five studies that met our selection criteria. Of them, only one (1/5) was conducted in China while other studies involved Chinese emigrants in USA (3/5) and Singapore (1/5). Participants from China were similar to emigrants with regard to factors that either promoted or decreased research participation. Four studies reported data exclusively on Chinese subjects. Three of the five studies involved qualitative interviews while the others were conducted using a survey design. Six themes favoring research participation were identified: Personal Benefit to Participants, Financial Incentives, Participant Sense of Altruism, Family or Physician Recommendations, Advertisements, and Convenience to the Participant. Five factors were seen as a barrier to participation in clinical trials: Mistrust of Researchers, Language Barrier, Lack of Financial and Other Support, Cultural and Social Barriers, Lack of Knowledge about Clinical Trials. CONCLUSIONS/SIGNIFICANCE: Chinese heritage clinical research participants value personal benefit, financial incentives, the ability to help others, recommendations of others, advertisements, and convenience when considering clinical research participation. In addition, the establishment of trust and addressing knowledge deficits are important factors to them. Investigators seeking to optimize enrolment in these populations should incorporate these findings into their study design and subject handouts. PMID- 23349673 TI - An epigenetic feedback regulatory loop involving microRNA-195 and MBD1 governs neural stem cell differentiation. AB - BACKGROUND: Epigenetic mechanisms, including DNA methylation, histone modification, and microRNAs, play pivotal roles in stem cell biology. Methyl-CpG binding protein 1 (MBD1), an important epigenetic regulator of adult neurogenesis, controls the proliferation and differentiation of adult neural stem/progenitor cells (aNSCs). We recently demonstrated that MBD1 deficiency in aNSCs leads to altered expression of several noncoding microRNAs (miRNAs). METHODOLOGY/PRINCIPAL FINDINGS: Here we show that one of these miRNAs, miR-195, and MBD1 form a negative feedback loop. While MBD1 directly represses the expression of miR-195 in aNSCs, high levels of miR-195 in turn repress the expression of MBD1. Both gain-of-function and loss-of-function investigations show that alterations of the MBD1-miR-195 feedback loop tip the balance between aNSC proliferation and differentiation. CONCLUSIONS/SIGNIFICANCE: Therefore the regulatory loop formed by MBD1 and miR-195 is an important component of the epigenetic network that controls aNSC fate. PMID- 23349675 TI - The impact of Bevacizumab (Avastin) on survival in metastatic solid tumors--a meta-analysis and systematic review. AB - PURPOSE: To evaluate the effect of Bevacizumab in combination with chemotherapy on overall survival of patients with metastatic solid tumors. DESIGN: A systematic literature search to identify randomized trials comparing chemotherapy with and without Bevacizumab in metastatic cancer. The primary end point was overall survival (OS) and the secondary end points were progression free survival (PFS) and toxicity. A meta-analysis was performed for each tumor type and for the combination of all tumors. RESULTS: 24 randomized trials with 8 different types of malignancies were included in this meta-analysis. Patients treated with Bevacizumab had an OS benefit, hazard ratio (HR) 0.89 (95% CI 0.84-0.93, P<0.00001 I(2)-4%). The combined analysis showed a PFS benefit with a HR 0.71 (95% CI 0.68-0.74, P<0.00001, I(2)-54%). The toxicity analysis showed a statistically significant increase in fatal adverse events (FAEs) in the Bevacizumab treatment arm, risk ratio (RR) 1.47 (95% CI 1.1-1.98). A separate analysis of the lung cancer trials showed an increased risk of fatal pulmonary hemorrhage with a RR of 5.65 (95% CI 1.26-25.26). The risk of G3-4 adverse events was increased: RR 1.2 (95% CI 1.15-1.24). CONCLUSION: in this combined analysis Bevacizumab improved OS (with little heterogeneity) and PFS. These results should be considered in the light of lack of markers predictive of response and the increased severe and fatal toxicity seen with Bevacizumab treatment. PMID- 23349674 TI - Arsenic exposure and calpain-10 polymorphisms impair the function of pancreatic beta-cells in humans: a pilot study of risk factors for T2DM. AB - The incidence of type 2 diabetes mellitus (T2DM) is increasing worldwide and diverse environmental and genetic risk factors are well recognized. Single nucleotide polymorphisms (SNPs) in the calpain-10 gene (CAPN-10), which encodes a protein involved in the secretion and action of insulin, and chronic exposure to inorganic arsenic (iAs) through drinking water have been independently associated with an increase in the risk for T2DM. In the present work we evaluated if CAPN 10 SNPs and iAs exposure jointly contribute to the outcome of T2DM. Insulin secretion (beta-cell function) and insulin sensitivity were evaluated indirectly through validated indexes (HOMA2) in subjects with and without T2DM who have been exposed to a gradient of iAs in their drinking water in northern Mexico. The results were analyzed taking into account the presence of the risk factor SNPs SNP-43 and -44 in CAPN-10. Subjects with T2DM had significantly lower beta-cell function and insulin sensitivity. An inverse association was found between beta cell function and iAs exposure, the association being more pronounced in subjects with T2DM. Subjects without T2DM who were carriers of the at-risk genotype SNP-43 or -44, also had significantly lower beta-cell function. The association of SNP 43 with beta-cell function was dependent on iAs exposure, age, gender and BMI, whereas the association with SNP-44 was independent of all of these factors. Chronic exposure to iAs seems to be a risk factor for T2DM in humans through the reduction of beta-cell function, with an enhanced effect seen in the presence of the at-risk genotype of SNP-43 in CAPN-10. Carriers of CAPN-10 SNP-44 have also shown reduced beta-cell function. PMID- 23349676 TI - Cigarette smoke decreases airway epithelial FABP5 expression and promotes Pseudomonas aeruginosa infection. AB - Cigarette smoking is the primary cause of Chronic Obstructive Pulmonary Disease (COPD), which is characterized by chronic inflammation of the airways and destruction of lung parenchyma. Repeated and sustained bacterial infections are clearly linked to disease pathogenesis (e.g., exacerbations) and a huge burden on health care costs. The airway epithelium constitutes the first line of host defense against infection and our previous study indicated that Fatty Acid Binding Protein 5 (FABP5) is down regulated in airway epithelial cells of smokers with COPD as compared to smokers without COPD. We hypothesized that cigarette smoke (CS) exposure down regulates FABP5, thus, contributing to a more sustained inflammation in response to bacterial infection. In this report, we show that FABP5 is increased following bacterial infection but decreased following CS exposure of primary normal human bronchial epithelial (NHBE) cells. The goal of this study was to address FABP5 function by knocking down or overexpressing FABP5 in primary NHBE cells exposed to CS. Our data indicate that FABP5 down regulation results in increased P. aeruginosa bacterial load and inflammatory cytokine levels (e.g., IL-8) and decreased expression of the anti-bacterial peptide, beta defensin-2. On the contrary, FABP5 overexpression exerts a protective function in airway epithelial cells against P. aeruginosa infection by limiting the production of IL-8 and increasing the expression of beta defensin-2. Our study indicates that FABP5 exerts immunomodulatory functions in the airway epithelium against CS exposure and subsequent bacterial infection through its modulation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma activity. These findings support the development of FABP5/PPAR-gamma-targeted therapeutic approach to prevent airway inflammation by restoring antimicrobial immunity during COPD exacerbations. PMID- 23349677 TI - Biological stoichiometry in tumor micro-environments. AB - Tumors can be viewed as evolving ecological systems, in which heterogeneous populations of cancer cells compete with each other and somatic cells for space and nutrients within the ecosystem of the human body. According to the growth rate hypothesis (GRH), increased phosphorus availability in an ecosystem, such as the tumor micro-environment, may promote selection within the tumor for a more proliferative and thus potentially more malignant phenotype. The applicability of the GRH to tumor growth is evaluated using a mathematical model, which suggests that limiting phosphorus availability might promote intercellular competition within a tumor, and thereby delay disease progression. It is also shown that a tumor can respond differently to changes in its micro-environment depending on the initial distribution of clones within the tumor, regardless of its initial size. This suggests that composition of the tumor as a whole needs to be evaluated in order to maximize the efficacy of therapy. PMID- 23349679 TI - Chemical memory reactions induced bursting dynamics in gene expression. AB - Memory is a ubiquitous phenomenon in biological systems in which the present system state is not entirely determined by the current conditions but also depends on the time evolutionary path of the system. Specifically, many memorial phenomena are characterized by chemical memory reactions that may fire under particular system conditions. These conditional chemical reactions contradict to the extant stochastic approaches for modeling chemical kinetics and have increasingly posed significant challenges to mathematical modeling and computer simulation. To tackle the challenge, I proposed a novel theory consisting of the memory chemical master equations and memory stochastic simulation algorithm. A stochastic model for single-gene expression was proposed to illustrate the key function of memory reactions in inducing bursting dynamics of gene expression that has been observed in experiments recently. The importance of memory reactions has been further validated by the stochastic model of the p53-MDM2 core module. Simulations showed that memory reactions is a major mechanism for realizing both sustained oscillations of p53 protein numbers in single cells and damped oscillations over a population of cells. These successful applications of the memory modeling framework suggested that this innovative theory is an effective and powerful tool to study memory process and conditional chemical reactions in a wide range of complex biological systems. PMID- 23349678 TI - Revision of MELD to include serum albumin improves prediction of mortality on the liver transplant waiting list. AB - BACKGROUND: Allocation of donor livers for transplantation in most regions is based on the Model for End-Stage Liver Disease (MELD) or MELD-sodium (MELDNa). Our objective was to assess revisions to MELD and MELDNa that include serum albumin for predicting waiting list mortality. METHODS: Adults registered for liver transplantation in the United States (2002-2007) were identified from the United Network for Organ Sharing (UNOS) database. Cox regression was used to determine the association between serum albumin and 3-month mortality, and to derive revised MELD and MELDNa scores incorporating albumin ('MELD-albumin' and '5-variable MELD [5vMELD]'). RESULTS: Among 40,393 patients, 9% died and 24% underwent transplantation within 3 months of listing. For serum albumin concentrations between 1.0 and 4.0 g/dL, a linear, inverse relationship was observed between albumin and 3-month mortality (adjusted hazard ratio per 1 g/dL reduction in albumin: 1.44; 95% CI 1.35-1.54). The c-statistics for 3-month mortality of MELD-albumin and MELD were 0.913 and 0.896, respectively (P<0.001); 5vMELD was superior to MELDNa (c-statistics 0.922 vs. 0.912, P<0.001). The potential benefit of 5vMELD was greatest in patients with low MELD (<15). Among low MELD patients who died, 27% would have gained >=10 points with 5vMELD over MELD versus only 4-7% among low MELD survivors and high MELD (>=15) candidates (P<0.0005). CONCLUSION: Modification of MELD and MELDNa to include serum albumin is associated with improved prediction of waiting list mortality. If validated and shown to be associated with reduced mortality, adoption of 5vMELD as the basis for liver allograft allocation may improve outcomes on the liver transplant waiting list. PMID- 23349680 TI - Clinical utility of the UPOINT phenotype system in Chinese males with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): a prospective study. AB - BACKGROUND: Recent data showed that a six-domain UPOINT is a flexible and responsive new classification system that has the clinical applicability in CP/CPPS. However, the utility of UPOINT algorithm in men in China with CP/CPPS has not been comprehensively studied. For international validation and adoption, we evaluated this clinical phenotype system for a large cohort of Chinese CP/CPPS patients and correlated it with patient symptoms and erectile dysfunction (ED). We also investigated the addition of an ED domain in regard to symptom correlation. METHODS: A total of 389 Chinese males with CP/CPPS were prospectively collected and classified in each domain of the UPOINT system. Symptom severity was measured using the NIH-CPSI and IPSS. The erectile function was evaluated using the IIEF-5. Clinically relevant associations were calculated. RESULTS: The percentage of patients positive for each domain was 54.0%, 42.1%, 41.9%, 20.8%, 26.7%, and 40.4% for the Urinary, Psychosocial, Organ-specific, Infection, Neurological/systemic, and Tenderness, respectively. There were significant correlations between the number of positive UPOINT domains and total NIH-CPSI (r = 0.706, p<0.001), IPSS (r = 0.682, p<0.001) and IIEF-5 scores (r = 0.631, P = 0.007) in Chinese cohort. Except for patients age, symptom duration was associated with a significantly greater number of positive domains (r = 0.638, P = 0.005). After adding an ED domain to create a modified UPOINT system, the correlation between the number of phenotypic domains and symptom severity was improved (0.706 to 0.844, p<0.001). CONCLUSIONS: The clinical applicability of using UPOINT phenotyping system has been validated in the Chinese patients with CP/CPPS. In our cohort, the number of positive domains was also correlated with ED symptoms and the significant association between the number of UPOINT domains and NIH-CPSI scores was further refined by adding a domain for ED. Our findings presented here support the utility of using ED as a stand-alone item in the UPOINT domain. PMID- 23349681 TI - Muscle activity and inactivity periods during normal daily life. AB - Recent findings suggest that not only the lack of physical activity, but also prolonged times of sedentary behaviour where major locomotor muscles are inactive, significantly increase the risk of chronic diseases. The purpose of this study was to provide details of quadriceps and hamstring muscle inactivity and activity during normal daily life of ordinary people. Eighty-four volunteers (44 females, 40 males, 44.1+/-17.3 years, 172.3+/-6.1 cm, 70.1+/-10.2 kg) were measured during normal daily life using shorts measuring muscle electromyographic (EMG) activity (recording time 11.3+/-2.0 hours). EMG was normalized to isometric MVC (EMG(MVC)) during knee flexion and extension, and inactivity threshold of each muscle group was defined as 90% of EMG activity during standing (2.5+/-1.7% of EMG(MVC)). During normal daily life the average EMG amplitude was 4.0+/-2.6% and average activity burst amplitude was 5.8+/-3.4% of EMG(MVC) (mean duration of 1.4+/-1.4 s) which is below the EMG level required for walking (5 km/h corresponding to EMG level of about 10% of EMG(MVC)). Using the proposed individual inactivity threshold, thigh muscles were inactive 67.5+/-11.9% of the total recording time and the longest inactivity periods lasted for 13.9+/-7.3 min (2.5-38.3 min). Women had more activity bursts and spent more time at intensities above 40% EMG(MVC) than men (p<0.05). In conclusion, during normal daily life the locomotor muscles are inactive about 7.5 hours, and only a small fraction of muscle's maximal voluntary activation capacity is used averaging only 4% of the maximal recruitment of the thigh muscles. Some daily non-exercise activities such as stair climbing produce much higher muscle activity levels than brisk walking, and replacing sitting by standing can considerably increase cumulative daily muscle activity. PMID- 23349682 TI - Decision-making under risk of loss in children. AB - In human adults, judgment errors are known to often lead to irrational decision making in risky contexts. While these errors can affect the accuracy of profit evaluation, they may have once enhanced survival in dangerous contexts following a "better be safe than sorry" rule of thumb. Such a rule can be critical for children, and it could develop early on. Here, we investigated the rationality of choices and the possible occurrence of judgment errors in children aged 3 to 9 years when exposed to a risky trade. Children were allocated with a piece of cookie that they could either keep or risk in exchange of the content of one cup among 6, visible in front of them. In the cups, cookies could be of larger, equal or smaller sizes than the initial allocation. Chances of losing or winning were manipulated by presenting different combinations of cookie sizes in the cups (for example 3 large, 2 equal and 1 small cookie). We investigated the rationality of children's response using the theoretical models of Expected Utility Theory (EUT) and Cumulative Prospect Theory. Children aged 3 to 4 years old were unable to discriminate the profitability of exchanging in the different combinations. From 5 years, children were better at maximizing their benefit in each combination, their decisions were negatively induced by the probability of losing, and they exhibited a framing effect, a judgment error found in adults. Confronting data to the EUT indicated that children aged over 5 were risk-seekers but also revealed inconsistencies in their choices. According to a complementary model, the Cumulative Prospect Theory (CPT), they exhibited loss aversion, a pattern also found in adults. These findings confirm that adult-like judgment errors occur in children, which suggests that they possess a survival value. PMID- 23349683 TI - Switchable gene expression in Escherichia coli using a miniaturized photobioreactor. AB - We present a light-switchable gene expression system for both inducible and switchable control of gene expression at a single cell level in Escherichia coli using a previously constructed light-sensing system. The lambda cI repressor gene with an LVA degradation tag was expressed under the control of the ompC promoter on the chromosome. The green fluorescent protein (GFP) gene fused to a lambda repressor-repressible promoter was used as a reporter. This light-switchable system allows rapid and reversible induction or repression of expression of the target gene at any desired time. This system also ensures homogenous expression across the entire cell population. We also report the design of a miniaturized photobioreactor to be used in combination with the light-switchable gene expression system. The miniaturized photobioreactor helps to reduce unintended induction of the light receptor due to environmental disturbances and allows precise control over the duration of induction. This system would be a good tool for switchable, homogenous, strong, and highly regulatable expression of target genes over a wide range of induction times. Hence, it could be applied to study gene function, optimize metabolic pathways, and control biological systems both spatially and temporally. PMID- 23349684 TI - Silencing mutant ataxin-3 rescues motor deficits and neuropathology in Machado Joseph disease transgenic mice. AB - Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly-inherited neurodegenerative disorder caused by the over repetition of a CAG codon in the MJD1 gene. This expansion translates into a polyglutamine tract that confers a toxic gain-of-function to the mutant protein- ataxin-3, leading to neurodegeneration in specific brain regions, with particular severity in the cerebellum. No treatment able to modify the disease progression is available. However, gene silencing by RNA interference has shown promising results. Therefore, in this study we investigated whether lentiviral-mediated allele-specific silencing of the mutant ataxin-3 gene, after disease onset, would rescue the motor behavior deficits and neuropathological features in a severely impaired transgenic mouse model of MJD. For this purpose, we injected lentiviral vectors encoding allele-specific silencing-sequences (shAtx3) into the cerebellum of diseased transgenic mice expressing the targeted C-variant of mutant ataxin-3 present in 70% of MJD patients. This variation permits to discriminate between the wild-type and mutant forms, maintaining the normal function of the wild-type allele and silencing only the mutant form. Quantitative analysis of rotarod performance, footprint and activity patterns revealed significant and robust alleviation of gait, balance (average 3-fold increase of rotarod test time), locomotor and exploratory activity impairments in shAtx3-injected mice, as compared to control ones injected with shGFP. An important improvement of neuropathology was also observed, regarding the number of intranuclear inclusions, calbindin and DARPP-32 immunoreactivity, fluorojade B and Golgi staining and molecular and granular layers thickness. These data demonstrate for the first time the efficacy of gene silencing in blocking the MJD-associated motor-behavior and neuropathological abnormalities after the onset of the disease, supporting the use of this strategy for therapy of MJD. PMID- 23349685 TI - Automated in vivo platform for the discovery of functional food treatments of hypercholesterolemia. AB - The zebrafish is becoming an increasingly popular model system for both automated drug discovery and investigating hypercholesterolemia. Here we combine these aspects and for the first time develop an automated high-content confocal assay for treatments of hypercholesterolemia. We also create two algorithms for automated analysis of cardiodynamic data acquired by high-speed confocal microscopy. The first algorithm computes cardiac parameters solely from the frequency-domain representation of cardiodynamic data while the second uses both frequency- and time-domain data. The combined approach resulted in smaller differences relative to manual measurements. The methods are implemented to test the ability of a methanolic extract of the hawthorn plant (Crataegus laevigata) to treat hypercholesterolemia and its peripheral cardiovascular effects. Results demonstrate the utility of these methods and suggest the extract has both antihypercholesterolemic and postitively inotropic properties. PMID- 23349686 TI - Timing of umbilical cord blood derived mesenchymal stem cells transplantation determines therapeutic efficacy in the neonatal hyperoxic lung injury. AB - Intratracheal transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) attenuates the hyperoxia-induced neonatal lung injury. The aim of this study was to optimize the timing of MSCs transplantation. Newborn Sprague-Dawley rats were randomly exposed to hyperoxia (90% for 2 weeks and 60% for 1 week) or normoxia after birth for 21 days. Human UCB-derived MSCs (5*10(5) cells) were delivered intratracheally early at postnatal day (P) 3 (HT3), late at P10 (HT10) or combined early+late at P3+10 (HT3+10). Hyperoxia induced increase in mortality, TUNEL positive cells, ED1 positive alveolar macrophages, myeloperoxidase activity and collagen levels, retarded growth and reduced alveolarization as evidenced by increased mean linear intercept and mean alveolar volume were significantly better attenuated in both HT3 and HT3+10 than in HT10. Hyperoxia-induced up-regulation of both cytosolic and membrane p47(phox) indicative of oxidative stress, and increased inflammatory markers such as tumor necrosis factor-alpha, interleukin (IL) -1alpha, IL-1beta, IL-6, and transforming growth factor-beta measured by ELISA, and tissue inhibitor of metalloproteinase 1, CXCL7, RANTES, L-selectin and soluble intercellular adhesion molecule-1 measured by protein array were consistently more attenuated in both HT3 and HT3+10 than in HT10. Hyperoxia-induced decrease in hepatocyte growth factor and vascular endothelial growth factor was significantly up-regulated in both HT3 and HT3+10, but not in HT10. In summary, intratracheal transplantation of human UCB derived MSCs time-dependently attenuated hyperoxia-induced lung injury in neonatal rats, showing significant protection only in the early but not in the late phase of inflammation. There were no synergies with combined early+late MSCs transplantation. PMID- 23349687 TI - Superficial nephrons in BALB/c and C57BL/6 mice facilitate in vivo multiphoton microscopy of the kidney. AB - Multiphoton microscopy (MPM) offers a unique approach for addressing both the function and structure of an organ in near-real time in the live animal. The method however is limited by the tissue-specific penetration depth of the excitation laser. In the kidney, structures in the range of 100 um from the surface are accessible for MPM. This limitation of MPM aggravates the investigation of the function of structures located deeper in the renal cortex, like the glomerulus and the juxtaglomerular apparatus. In view of the relevance of gene-targeted mice for investigating the function of these structures, we aimed to identify a mouse strain with a high percentage of superficially located glomeruli. The mean distance of the 30 most superficial glomeruli from the kidney surface was determined in 10 commonly used mouse strains. The mean depth of glomeruli was 118.4+/-3.4, 123.0+/-2.7, 133.7+/-3.0, 132.3+/-2.6, 141.0+/-4.0, 145.3+/-4.3, 148.9+/-4.2, 151.6+/-2.7, 167.7+/-3.9, and 207.8+/-3.2 um in kidney sections from 4-week-old C3H/HeN, BALB/cAnN, SJL/J, C57BL/6N, DBA/2N, CD1 (CRI), 129S2/SvPas, CB6F1, FVB/N and NMRI (Han) mice, respectively (n = 5 animals from each strain). The mean distance from the kidney surface of the most superficial glomeruli was significantly lower in the strains C3H/HeN Crl, BALB/cAnN, DBA/2NCrl, and C57BL/6N when compared to a peer group consisting of all the other strains (p<.0001). In 10-week-old mice, the most superficial glomeruli were located deeper in the cortex when compared to 4-week-old animals, with BALB/cAnN and C57BL/6N being the strains with the highest percentage of superficial glomeruli (25% percentile 116.7 and 121.9 um, respectively). In summary, due to significantly more superficial glomeruli compared to other commonly used strains, BALB/cAnN and C57BL/6N mice appear to be particularly suitable for the investigation of glomerular function using MPM. PMID- 23349688 TI - Allelic expression imbalance of JAK2 V617F mutation in BCR-ABL negative myeloproliferative neoplasms. AB - The discovery of a single point mutation in the JAK2 gene in patients with BCR/ABL-negative myeloproliferative neoplasms (MPNs) has not only brought new insights and pathogenesis, but also has made the diagnosis of MPNs much easier. Although, to date, several mechanisms for the contribution of single JAK2V617F point mutation to phenotypic diversity of MPNs have been suggested in multiple studies, but it is not clear how a unique mutation can cause the phenotypic diversity of MPNs. In this study, our results show that allelic expression imbalance of JAK2 V617F mutant frequently occurs and contributes to phenotypic diversity of BCR-ABL-negative MPNs. The proportion of JAK2 V617F mutant allele was significantly augmented in RNA levels as compared with genomic DNA differently by distinct MPNs subtypes. In detail, preferential expression of JAK2 mutant allele showed threefold increase from the cDNA compared with the genomic DNA from patients with essential thrombocythemia and twofold increase in polycythemia vera. In conclusion, allelic expression imbalance of JAK2 V617F mutant proposes another plausible mechanism for the contribution of single JAK2 point mutation to phenotypic diversity of MPNs. PMID- 23349689 TI - The totally extraperitoneal method versus Lichtenstein's technique for inguinal hernia repair: a systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. AB - BACKGROUND: Lichtenstein's technique is considered the reference technique for inguinal hernia repair. Recent trials suggest that the totally extraperitoneal (TEP) technique may lead to reduced proportions of chronic pain. A systematic review evaluating the benefits and harms of the TEP compared with Lichtenstein's technique is needed. METHODOLOGY/PRINCIPAL FINDINGS: The review was performed according to the 'Cochrane Handbook for Systematic Reviews'. Searches were conducted until January 2012. Patients with primary uni- or bilateral inguinal hernias were included. Only trials randomising patients to TEP and Lichtenstein were included. Bias evaluation and trial sequential analysis (TSA) were performed. The error matrix was constructed to minimise the risk of systematic and random errors. Thirteen trials randomized 5404 patients. There was no significant effect of the TEP compared with the Lichtenstein on the number of patients with chronic pain in a random-effects model risk ratio (RR 0.80; 95% confidence interval (CI) 0.61 to 1.04; p = 0.09). There was also no significant effect on number of patients with recurrences in a random-effects model (RR 1.41; 95% CI 0.72 to 2.78; p = 0.32) and the TEP technique may or may not be associated with less severe adverse events (random-effects model RR 0.91; 95% CI 0.73 to 1.12; p = 0.37). TSA showed that the required information size was far from being reached for patient important outcomes. CONCLUSIONS/SIGNIFICANCE: TEP versus Lichtenstein for inguinal hernia repair has been evaluated by 13 trials with high risk of bias. The review with meta-analyses, TSA and error matrix approach shows no conclusive evidence of a difference between TEP and Lichtenstein on the primary outcomes chronic pain, recurrences, and severe adverse events. PMID- 23349690 TI - The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma. AB - PURPOSE: To examine the effect of riboflavin/UVA corneal crosslinking on stromal ultrastructure and hydrodynamic behaviour. METHODS: One hundred and seventeen enucleated ungulate eyes (112 pig and 5 sheep) and 3 pairs of rabbit eyes, with corneal epithelium removed, were divided into four treatment groups: Group 1 (28 pig, 2 sheep and 3 rabbits) were untreated; Group 2 (24 pig) were exposed to UVA light (3.04 mW/cm(2)) for 30 minutes and Group 3 (29 pig) and Group 4 (31 pig, 3 sheep and 3 rabbits) had riboflavin eye drops applied to the corneal surface every 5 minutes for 35 minutes. Five minutes after the initial riboflavin instillation, the corneas in Group 4 experienced a 30 minute exposure to UVA light (3.04 mW/cm(2)). X-ray scattering was used to obtain measurements of collagen interfibrillar spacing, spatial order, fibril diameter, D-periodicity and intermolecular spacing throughout the whole tissue thickness and as a function of tissue depth in the treated and untreated corneas. The effect of each treatment on the hydrodynamic behaviour of the cornea (its ability to swell in saline solution) and its resistance to enzymatic digestion were assessed using in vitro laboratory techniques. RESULTS: Corneal thickness decreased significantly following riboflavin application (p<0.01) and also to a lesser extent after UVA exposure (p<0.05). With the exception of the spatial order factor, which was higher in Group 4 than Group 1 (p<0.01), all other measured collagen parameters were unaltered by cross-linking, even within the most anterior 300 microns of the cornea. The cross-linking treatment had no effect on the hydrodynamic behaviour of the cornea but did cause a significant increase in its resistance to enzymatic digestion. CONCLUSIONS: It seems likely that cross-links formed during riboflavin/UVA therapy occur predominantly at the collagen fibril surface and in the protein network surrounding the collagen. PMID- 23349691 TI - Small RNA modules confer different stabilities and interact differently with multiple targets. AB - Bacterial Hfq-associated small regulatory RNAs (sRNAs) parallel animal microRNAs in their ability to control multiple target mRNAs. The small non-coding MicA RNA represses the expression of several genes, including major outer membrane proteins such as ompA, tsx and ecnB. In this study, we have characterised the RNA determinants involved in the stability of MicA and analysed how they influence the expression of its targets. Site-directed mutagenesis was used to construct MicA mutated forms. The 5'linear domain, the structured region with two stem loops, the A/U-rich sequence or the 3' poly(U) tail were altered without affecting the overall secondary structure of MicA. The stability and the target regulation abilities of the wild-type and the different mutated forms of MicA were then compared. The 5' domain impacted MicA stability through an RNase III mediated pathway. The two stem-loops showed different roles and disruption of stem-loop 2 was the one that mostly affected MicA stability and abundance. Moreover, STEM2 was found to be more important for the in vivo repression of both ompA and ecnB mRNAs while STEM1 was critical for regulation of tsx mRNA levels. The A/U-rich linear sequence is not the only Hfq-binding site present in MicA and the 3' poly(U) sequence was critical for sRNA stability. PNPase was shown to be an important exoribonuclease involved in sRNA degradation. In addition to the 5' domain of MicA, the stem-loops and the 3' poly(U) tail are also shown to affect target-binding. Disruption of the 3'U-rich sequence greatly affects all targets analysed. In conclusion, our results have shown that it is important to understand the "sRNA anatomy" in order to modulate its stability. Furthermore, we have demonstrated that MicA RNA can use different modules to regulate its targets. This knowledge can allow for the engineering of non-coding RNAs that interact differently with multiple targets. PMID- 23349692 TI - An improved Ras sensor for highly sensitive and quantitative FRET-FLIM imaging. AB - Ras is a signaling protein involved in a variety of cellular processes. Hence, studying Ras signaling with high spatiotemporal resolution is crucial to understanding the roles of Ras in many important cellular functions. Previously, fluorescence lifetime imaging (FLIM) of fluorescent resonance energy transfer (FRET)-based Ras activity sensors, FRas and FRas-F, have been demonstrated to be useful for measuring the spatiotemporal dynamics of Ras signaling in subcellular micro-compartments. However the predominantly nuclear localization of the sensors' acceptor has limited its sensitivity. Here, we have overcome this limitation and developed two variants of the existing FRas sensor with different affinities: FRas2-F (K(d)~1.7 uM) and FRas2-M (K(d)~0.5 uM). We demonstrate that, under 2-photon fluorescence lifetime imaging microscopy, FRas2 sensors provide higher sensitivity compared to previous sensors in 293T cells and neurons. PMID- 23349693 TI - Reduction of splenic immunosuppressive cells and enhancement of anti-tumor immunity by synergy of fish oil and selenium yeast. AB - Growing evidence has shown that regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) abnormally increase in cancer cachectic patients. Suppressions of Tregs and MDSCs may enhance anti-tumor immunity for cancer patients. Fish oil and selenium have been known to have many biological activities such as anti-inflammation and anti-oxidation. Whether fish oil and/or selenium have an additional effect on population of immunosuppressive cells in tumor-bearing hosts remained elusive and controversial. To gain insights into their roles on anti-tumor immunity, we studied the fish oil- and/or selenium mediated tumor suppression and immunity on lung carcinoma, whereof cachexia develops. Advancement of cachexia in a murine lung cancer model manifested with such indicative symptoms as weight loss, chronic inflammation and disturbed immune functionality. The elevation of Tregs and MDSCs in spleens of tumor bearing mice was positively correlated with tumor burdens. Consumption of either fish oil or selenium had little or no effect on the levels of Tregs and MDSCs. However, consumption of both fish oil and selenium together presented a synergistic effect--the population of Tregs and MDSCs decreased as opposed to increase of anti-tumor immunity when both fish oil and selenium were supplemented simultaneously, whereby losses of body weight and muscle/fat mass were alleviated significantly. PMID- 23349694 TI - The role of statins in prevention and treatment of community acquired pneumonia: a systematic review and meta-analysis. AB - BACKGROUND: Emerging epidemiological evidence suggests that statins may reduce the risk of community-acquired pneumonia (CAP) and its complications. PURPOSE: Performed a systematic review to address the role of statins in the prevention or treatment of CAP. DATA SOURCE: Ovid MEDLINE, Cochrane, EMBASE, ISI Web of Science, and Scopus from inception through December 2011 were searched for randomized clinical trials, cohort and case-control studies. STUDY SELECTION: Two authors independently reviewed studies that examined the role of statins in CAP. DATA EXTRACTION: Data about study characteristics, adjusted effect-estimates and quality characteristics was extracted. DATA SYNTHESIS: Eighteen studies corresponding to 21 effect-estimates (eight and 13 of which addressed the preventive and therapeutic roles of statins, respectively) were included. All studies were of good methodological quality. Random-effects meta-analyses of adjusted effect-estimates were used. Statins were associated with a lower risk of CAP, 0.84 (95% CI, 0.74-0.95), I(2) = 90.5% and a lower short-term mortality in patients with CAP, 0.68 (95% CI, 0.59-0.78), I(2) = 75.7%. Meta-regression did not identify sources of heterogeneity. A funnel plot suggested publication bias in the treatment group, which was adjusted by a novel regression method with a resultant effect-estimate of 0.85 (95% CI, 0.77-0.93). Sensitivity analyses using the rule-out approach showed that it is unlikely that the results were due to an unmeasured confounder. CONCLUSIONS: Our meta-analysis reveals a beneficial role of statins for the risk of development and mortality associated with CAP. However, the results constitute very low quality evidence as per the GRADE framework due to observational study design, heterogeneity and publication bias. PMID- 23349695 TI - Integron gene cassettes: a repository of novel protein folds with distinct interaction sites. AB - Mobile gene cassettes captured within integron arrays encompass a vast and diverse pool of genetic novelty. In most cases, functional annotation of gene cassettes directly recovered by cassette-PCR is obscured by their characteristically high sequence novelty. This inhibits identification of those specific functions or biological features that might constitute preferential factors for lateral gene transfer via the integron system. A structural genomics approach incorporating x-ray crystallography has been utilised on a selection of cassettes to investigate evolutionary relationships hidden at the sequence level. Gene cassettes were accessed from marine sediments (pristine and contaminated sites), as well as a range of Vibrio spp. We present six crystal structures, a remarkably high proportion of our survey of soluble proteins, which were found to possess novel folds. These entirely new structures are diverse, encompassing all alpha, alpha+beta and alpha/beta fold classes, and many contain clear binding pocket features for small molecule substrates. The new structures emphasise the large repertoire of protein families encoded within the integron cassette metagenome and which remain to be characterised. Oligomeric association is a notable recurring property common to these new integron-derived proteins. In some cases, the protein-protein contact sites utilised in homomeric assembly could instead form suitable contact points for heterogeneous regulator/activator proteins or domains. Such functional features are ideal for a flexible molecular componentry needed to ensure responsive and adaptive bacterial functions. PMID- 23349696 TI - Wnt5a is associated with cigarette smoke-related lung carcinogenesis via protein kinase C. AB - Wnt5a is overexpressed during the progression of human non-small cell lung cancer. However, the roles of Wnt5a during smoking-related lung carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related lung cancer using human bronchial epithelial (HBE) cells (NHBE, BEAS-2B, 1799, 1198 and 1170I) at different malignant stages established by exposure to cigarette smoke condensate (CSC). Abnormal up-regulation of Wnt5a mRNA and proteins was detected in CSC exposed transformed 1198 and tumorigenic 1170I cells as compared with other non CSC exposed HBE cells. Tumor tissues obtained from smokers showed higher Wnt5a expressions than matched normal tissues. In non-CSC exposed 1799 cells, treatment of recombinant Wnt5a caused the activations of PKC and Akt, and the blockage of Wnt5a and PKC significantly decreased the viabilities of CSC-transformed 1198 cells expressing high levels of Wnt5a. This reduced cell survival rate was associated with increased apoptosis via the down-regulation of Bcl2 and the induction of cleaved poly ADP-ribose polymerase. Moreover, CSC-treated 1799 cells showed induction of Wnt5a expression and enhanced colony-forming capacity. The CSC-induced colony forming efficiency was suppressed by the co-incubation with a PKC inhibitor. In conclusion, these results suggest that cigarette smoke induces Wnt5a-coupled PKC activity during lung carcinogenesis, which causes Akt activity and anti-apoptosis in lung cancer. Therefore, current study provides novel clues for the crucial role of Wnt5a in the smoking-related lung carcinogenesis. PMID- 23349697 TI - CC-chemokine ligand 18 induces epithelial to mesenchymal transition in lung cancer A549 cells and elevates the invasive potential. AB - Lung cancer is one of the leading causes of cancer related death worldwide with more than a million deaths per year. The poor prognosis is due to its high aggressiveness and its early metastasis. Although the exact mechanisms are still unknown, the process of epithelial to mesenchymal transition (EMT) seems to be involved in these neoplastic processes. We already demonstrated that serum levels of CCL18, a primate specific chemokine, are highly elevated in patients with lung cancer and correlate with their survival time of patients with adenocarcinoma of the lung. Therefore, we hypothesized that CCL18 may be directly involved in pathological processes of lung cancer, e.g. EMT. We investigated the effect of CCL18 on A549, an adenocarcinoma cell line of the lung, on EMT and other cell functions like proliferation, chemotaxis, invasion, chemoresistance and proliferation. Exposure of A549 lung cancer cells to CCL18 in various concentrations decreases the epithelial marker E-cadherin, whereas FSP-1, a marker of the mesenchymal phenotype increases. Accordingly, CCL18 induced the transcriptional EMT regulator SNAIL1 in a dose dependent fashion. In contrast, an increasing CCL18 concentration was associated with a decline of cell proliferation rate. In addition, CCL18 induced chemotaxis of these cells and increased their chemoresistance. Therefore, CCL18 may be an interesting therapeutic target for NSCLC. PMID- 23349699 TI - Percolation centrality: quantifying graph-theoretic impact of nodes during percolation in networks. AB - A number of centrality measures are available to determine the relative importance of a node in a complex network, and betweenness is prominent among them. However, the existing centrality measures are not adequate in network percolation scenarios (such as during infection transmission in a social network of individuals, spreading of computer viruses on computer networks, or transmission of disease over a network of towns) because they do not account for the changing percolation states of individual nodes. We propose a new measure, percolation centrality, that quantifies relative impact of nodes based on their topological connectivity, as well as their percolation states. The measure can be extended to include random walk based definitions, and its computational complexity is shown to be of the same order as that of betweenness centrality. We demonstrate the usage of percolation centrality by applying it to a canonical network as well as simulated and real world scale-free and random networks. PMID- 23349698 TI - The transcriptional and gene regulatory network of Lactococcus lactis MG1363 during growth in milk. AB - In the present study we examine the changes in the expression of genes of Lactococcus lactis subspecies cremoris MG1363 during growth in milk. To reveal which specific classes of genes (pathways, operons, regulons, COGs) are important, we performed a transcriptome time series experiment. Global analysis of gene expression over time showed that L. lactis adapted quickly to the environmental changes. Using upstream sequences of genes with correlated gene expression profiles, we uncovered a substantial number of putative DNA binding motifs that may be relevant for L. lactis fermentative growth in milk. All available novel and literature-derived data were integrated into network reconstruction building blocks, which were used to reconstruct and visualize the L. lactis gene regulatory network. This network enables easy mining in the chrono transcriptomics data. A freely available website at http://milkts.molgenrug.nl gives full access to all transcriptome data, to the reconstructed network and to the individual network building blocks. PMID- 23349700 TI - Effects of catchment and riparian landscape setting on water chemistry and seasonal evolution of water quality in the upper Han River basin, China. AB - Six-year (2005-2010) evolution of water chemistry (Cl(-), NO(3)(-), SO(4)(2-), HCO(3)(-), Na(+), K(+), Ca(2+) and Mg(2+)) and their interactions with morphological properties (i.e., slope and area), land cover, and hydrological seasonality were examined to identify controlling factors and processes governing patterns of stream water quality in the upper Han River, China. Correlation analysis and stepwise multiple regression models revealed significant correlations between ions (i.e., Cl(-), SO(4)(2-), Na(+) and K(+)) and land cover (i.e., vegetation and bare land) over the entire catchment in both high- and low flow periods, and in the buffer zone the correlation was much more stronger in the low-flow period. Catchment with steeper slope (>15 degrees ) was negatively correlated with major ions, largely due to multicollinearity of basin characteristics. Land cover within the buffer zone explained slightly less of major elements than at catchment scale in the rainy season, whereas in the dry season, land cover along the river networks in particular this within 100 m riparian zone much better explained major elements rather than this over the entire catchment. Anthropogenic land uses (i.e., urban and agriculture) however could not explain water chemical variables, albeit EC, TDS, anthropogenic markers (Cl(-), NO(3)(-), SO(4)(2)), Na(+), K(+) and Ca(2+) significantly increased during 2005-2010, which was corroborated by principal component analyses (PCA) that indicated anthropogenic inputs. Observations demonstrated much higher solute concentrations in the industrial-polluted river. Our results suggested that seasonal evolution of water quality in combined with spatial analysis at multiple scales should be a vital part of identifying the controls on spatio-temporal patterns of water quality. PMID- 23349701 TI - First fossil record of Alphonsea Hk. f. & T. (Annonaceae) from the Late Oligocene sediments of Assam, India and comments on its phytogeography. AB - A new fossil leaf impression of Alphonsea Hk. f. & T. of the family Annonaceae is described from the Late Oligocene sediments of Makum Coalfield, Assam, India. This is the first authentic record of the fossil of Alphonsea from the Tertiary rocks of South Asia. The Late Oligocene was the time of the last significant globally warm climate and the fossil locality was at 10 degrees -15 degrees N palaeolatitude. The known palaeoflora and sedimentological studies indicate a fluvio-marine deltaic environment with a mosaic of mangrove, fluvial, mire and lacustrine depositional environments. During the depositional period the suturing between the Indian and Eurasian plates was not complete to facilitate the plant migration. The suturing was over by the end of the Late Oligocene/beginning of Early Miocene resulting in the migration of the genus to Southeast Asia where it is growing profusely at present. The present study is in congruence with the earlier published palaeofloral and molecular phylogenetic data. The study also suggests that the Indian plate was not only a biotic ferry during its northward voyage from Gondwana to Asia but also a place for the origin of several plant taxa. PMID- 23349702 TI - SPARC fusion protein induces cellular adhesive signaling. AB - Secreted protein, acidic and rich in cysteine (SPARC) has been described as a counteradhesive matricellular protein with a diversity of biological functions associated with morphogenesis, remodeling, cellular migration, and proliferation. We have produced mouse SPARC with a FLAG-tag at the N-terminus of SPARC (Flag SPARC, FSP) in a Bac-to-Bac baculoviral expression system. After affinity purification, this procedure yields SPARC of high purity, with an electrophoretic mobility of ~44 kDa under reducing conditions, and ~38-39 kDa under non-reducing conditions. Unexpectedly, FSP adsorbed to plastic supported cell attachment and spreading, in a calcium-dependent manner. The adhesive activity of native FSP was inhibited by prior incubation with anti-SPARC IgG. Cell adhesion to FSP induced the formation of filopodia and lamellipodia but not focal adhesions that were prominent on cells that were attached to fibronectin. In addition, FSP induced the tyrosine phosphorylation of FAK and paxillin in attached epithelial cells. Erk1/2 and Rac were also activated in cells attached to FSP, but at a lower level in comparison to cells on fibronectin. This study provides new insight into the biological functions of SPARC, a matricellular protein with important roles in cell-extracellualr matrix interactions. PMID- 23349703 TI - Variants in the 15q24/25 locus associate with lung function decline in active smokers. AB - Genetic variation in nicotinic acetylcholine receptor subunit genes (nAChRs) is associated with lung function level and chronic obstructive pulmonary disease (COPD). It is unknown whether these variants also predispose to an accelerated lung function decline. We investigated the association of nAChR susceptibility variants with lung function decline and COPD severity. The rs1051730 and rs8034191 variants were genotyped in a population-based cohort of 1,226 heavy smokers (COPACETIC) and in an independent cohort of 883 heavy smokers, of which 653 with COPD of varying severity (LEUVEN). Participants underwent pulmonary function tests at baseline. Lung function decline was assessed over a median follow-up of 3 years in COPACETIC. Current smokers homozygous for the rs1051730 A allele or rs8034191 G-allele had significantly greater FEV(1)/FVC decline than homozygous carriers of wild-type alleles (3.3% and 4.3%, p = 0.026 and p = 0.009, respectively). In the LEUVEN cohort, rs1051730 AA-carriers and rs8034191 GG carriers had a two-fold increased risk to suffer from COPD GOLD IV (OR 2.29, 95% confidence interval [CI] = 1.11-4.75; p = 0.025 and OR = 2.42, 95% [CI] = 1.18 4.95; p = 0.016, respectively). The same risk alleles conferred, respectively, a five- and four-fold increased risk to be referred for lung transplantation because of end-stage COPD (OR = 5.0, 95% [CI] = 1.68-14.89; p = 0.004 and OR = 4.06, 95% [CI] = 1.39-11.88; p = 0.010). In Europeans, variants in nAChRs associate with an accelerated lung function decline in current smokers and with clinically relevant COPD. PMID- 23349704 TI - Absence of platelet phenotype in mice lacking the motor protein myosin Va. AB - BACKGROUND: The motor protein myosin Va plays an important role in the trafficking of intracellular vesicles. Mutation of the Myo5a gene causes Griscelli syndrome type 1 in humans and the dilute phenotype in mice, which are both characterised by pigment dilution and neurological defects as a result of impaired vesicle transport in melanocytes and neuroendocrine cells. The role of myosin Va in platelets is currently unknown. Rab27 has been shown to be associated with myosin Va cargo vesicles and is known to be important in platelet dense granule biogenesis and secretion, a crucial event in thrombus formation. Therefore, we hypothesised that myosin Va may regulate granule secretion or formation in platelets. METHODOLOGY/PRINCIPAL FINDINGS: Platelet function was studied in vitro using a novel Myo5a gene deletion mouse model. Myo5a(-/-) platelets were devoid of myosin Va, as determined by immunoblotting, and exhibited normal expression of surface markers. We assessed dense granule, alpha granule and lysosomal secretion, integrin alpha(IIb)beta(3) activation, Ca(2+) signalling, and spreading on fibrinogen in response to collagen-related peptide or the PAR4 agonist, AYPGKF in washed mouse platelets lacking myosin Va or wild type platelets. Surprisingly, Myo5a(-/-) platelets showed no significant functional defects in these responses, or in the numbers of dense and alpha granules expressed. CONCLUSION: Despite the importance of myosin Va in vesicle transport in other cells, our data demonstrate this motor protein has no non redundant role in the secretion of dense and alpha-granules or other functional responses in platelets. PMID- 23349705 TI - Phytoplankton-specific response to enrichment of phosphorus-rich surface waters with ammonium, nitrate, and urea. AB - Supply of anthropogenic nitrogen (N) to the biosphere has tripled since 1960; however, little is known of how in situ response to N fertilisation differs among phytoplankton, whether species response varies with the chemical form of N, or how interpretation of N effects is influenced by the method of analysis (microscopy, pigment biomarkers). To address these issues, we conducted two 21 day in situ mesocosm (3140 L) experiments to quantify the species- and genus specific responses of phytoplankton to fertilisation of P-rich lake waters with ammonium (NH(4)(+)), nitrate (NO(3)(-)), and urea ([NH(2)](2)CO). Phytoplankton abundance was estimated using both microscopic enumeration of cell densities and high performance liquid chromatographic (HPLC) analysis of algal pigments. We found that total algal biomass increased 200% and 350% following fertilisation with NO(3)(-) and chemically-reduced N (NH(4)(+), urea), respectively, although 144 individual taxa exhibited distinctive responses to N, including compound specific stimulation (Planktothrix agardhii and NH(4)(+)), increased biomass with chemically-reduced N alone (Scenedesmus spp., Coelastrum astroideum) and no response (Aphanizomenon flos-aquae, Ceratium hirundinella). Principle components analyses (PCA) captured 53.2-69.9% of variation in experimental assemblages irrespective of the degree of taxonomic resolution of analysis. PCA of species level data revealed that congeneric taxa exhibited common responses to fertilisation regimes (e.g., Microcystis aeruginosa, M. flos-aquae, M. botrys), whereas genera within the same division had widely divergent responses to added N (e.g., Anabaena, Planktothrix, Microcystis). Least-squares regression analysis demonstrated that changes in phytoplankton biomass determined by microscopy were correlated significantly (p<0.005) with variations in HPLC-derived concentrations of biomarker pigments (r(2) = 0.13-0.64) from all major algal groups, although HPLC tended to underestimate the relative abundance of cyanobacteria. Together, these findings show that while fertilisation of P-rich lakes with N can increase algal biomass, there is substantial variation in responses of genera and divisions to specific chemical forms of added N. PMID- 23349706 TI - Association of +331G/A PgR polymorphism with susceptibility to female reproductive cancer: evidence from a meta-analysis. AB - The progesterone receptor (PgR), a sex steroid hormone receptor that binds progesterone is critical for normal breast development. The PgR (+331G/A, rs10895068) promoter polymorphism is associated with cancer risk possibly by altering the expression of progesterone receptor B isoform. Previous studies have provided inconsistent results. To validate the association between the PgR +331G/A polymorphism and female reproductive cancer risk (breast, endometrial and ovarian cancer), we performed a meta-analysis of 19 studies (19,978 cases and 24,525 controls) by using the CMA Version 2 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. The overall results indicated that the variant allele and genotypes were associated with a mild increase in overall female reproductive cancer risk (A vs. G: OR = 1.063, 95% CI = 1.001-1.129; AA+AG vs. GG: OR = 1.067, 95% CI = 1.002 1.136). The results suggest that the PgR +331G/A polymorphism might be associated with an increased female reproductive cancer risk. PMID- 23349707 TI - Reward optimization in the primate brain: a probabilistic model of decision making under uncertainty. AB - A key problem in neuroscience is understanding how the brain makes decisions under uncertainty. Important insights have been gained using tasks such as the random dots motion discrimination task in which the subject makes decisions based on noisy stimuli. A descriptive model known as the drift diffusion model has previously been used to explain psychometric and reaction time data from such tasks but to fully explain the data, one is forced to make ad-hoc assumptions such as a time-dependent collapsing decision boundary. We show that such assumptions are unnecessary when decision making is viewed within the framework of partially observable Markov decision processes (POMDPs). We propose an alternative model for decision making based on POMDPs. We show that the motion discrimination task reduces to the problems of (1) computing beliefs (posterior distributions) over the unknown direction and motion strength from noisy observations in a bayesian manner, and (2) selecting actions based on these beliefs to maximize the expected sum of future rewards. The resulting optimal policy (belief-to-action mapping) is shown to be equivalent to a collapsing decision threshold that governs the switch from evidence accumulation to a discrimination decision. We show that the model accounts for both accuracy and reaction time as a function of stimulus strength as well as different speed accuracy conditions in the random dots task. PMID- 23349708 TI - The PrePex device is unlikely to achieve cost-savings compared to the forceps guided method in male circumcision programs in sub-Saharan Africa. AB - BACKGROUND: Male circumcision (MC) reduces the risk of heterosexual HIV acquisition in men by approximately 60%. MC programs for HIV prevention are currently being scaled-up in fourteen countries in sub-Saharan Africa. The current standard surgical technique for MC in many sub-Saharan African countries is the forceps-guided male circumcision (FGMC) method. The PrePex male circumcision (PMC) method could replace FGMC and potentially reduce MC programming costs. We compared the potential costs of introducing the PrePex device into MC programming to the cost of the forceps-guided method. METHODS: Data were obtained from the Nyanza Reproductive Health Society (NRHS), an MC service delivery organization in Kenya, and from the Kenya Ministry of Health. Analyses are based on 48,265 MC procedures performed in four Districts in western Kenya from 2009 through 2011. Data were entered into the WHO/UNAIDS Decision Makers Program Planning Tool. The tool assesses direct and indirect costs of MC programming. Various sensitivity analyses were performed. Costs were discounted at an annual rate of 6% and are presented in United States Dollars. RESULTS: Not including the costs of the PrePex device or referral costs for men with phimosis/tight foreskin, the costs of one MC surgery were $44.54-$49.02 and $54.52-$55.29 for PMC and FGMC, respectively. CONCLUSION: The PrePex device is unlikely to result in significant cost-savings in comparison to the forceps guided method. MC programmers should target other aspects of the male circumcision minimum package for improved cost efficiency. PMID- 23349709 TI - IKKi deficiency promotes pressure overload-induced cardiac hypertrophy and fibrosis. AB - The inducible IkappaB kinase (IKKi/IKKepsilon) is a recently described serine threonine IKK-related kinase. Previous studies have reported the role of IKKi in infectious diseases and cancer. However, its role in the cardiac response to pressure overload remains elusive. In this study, we investigated the effects of IKKi deficiency on the development of pathological cardiac hypertrophy using in vitro and in vivo models. First, we developed mouse models of pressure overload cardiac hypertrophy induced by pressure overload using aortic banding (AB). Four weeks after AB, cardiac function was then assessed through echocardiographic and hemodynamic measurements. Western blotting, real-time PCR and histological analyses were used to assess the pathological and molecular mechanisms. We observed that IKKi-deficient mice showed significantly enhanced cardiac hypertrophy, cardiac dysfunction, apoptosis and fibrosis compared with WT mice. Furthermore, we recently revealed that the IKKi-deficient mice spontaneously develop cardiac hypertrophy. Moreover, in vivo experiments showed that IKKi deficiency-induced cardiac hypertrophy was associated with the activation of the AKT and NF-kappaB signaling pathway in response to AB. In cultured cells, IKKi overexpression suppressed the activation of this pathway. In conclusion, we demonstrate that IKKi deficiency exacerbates cardiac hypertrophy by regulating the AKT and NF-kappaB signaling pathway. PMID- 23349710 TI - Survival of patients with oral cavity cancer in Germany. AB - The purpose of the present study was to describe the survival of patients diagnosed with oral cavity cancer in Germany. The analyses relied on data from eleven population-based cancer registries in Germany covering a population of 33 million inhabitants. Patients with a diagnosis of oral cavity cancer (ICD-10: C00 06) between 1997 and 2006 are included. Period analysis for 2002-2006 was applied to estimate five-year age-standardized relative survival, taking into account patients' sex as well as grade and tumor stage. Overall five-year relative survival for oral cavity cancer patients was 54.6%. According to tumor localization, five-year survival was 86.5% for lip cancer, 48.1% for tongue cancer and 51.7% for other regions of the oral cavity. Differences in survival were identified with respect to age, sex, tumor grade and stage. The present study is the first to provide a comprehensive overview on survival of oral cavity cancer patients in Germany. PMID- 23349711 TI - Solving hard computational problems efficiently: asymptotic parametric complexity 3-coloring algorithm. AB - Many practical problems in almost all scientific and technological disciplines have been classified as computationally hard (NP-hard or even NP-complete). In life sciences, combinatorial optimization problems frequently arise in molecular biology, e.g., genome sequencing; global alignment of multiple genomes; identifying siblings or discovery of dysregulated pathways. In almost all of these problems, there is the need for proving a hypothesis about certain property of an object that can be present if and only if it adopts some particular admissible structure (an NP-certificate) or be absent (no admissible structure), however, none of the standard approaches can discard the hypothesis when no solution can be found, since none can provide a proof that there is no admissible structure. This article presents an algorithm that introduces a novel type of solution method to "efficiently" solve the graph 3-coloring problem; an NP complete problem. The proposed method provides certificates (proofs) in both cases: present or absent, so it is possible to accept or reject the hypothesis on the basis of a rigorous proof. It provides exact solutions and is polynomial-time (i.e., efficient) however parametric. The only requirement is sufficient computational power, which is controlled by the parameter alpha?N. Nevertheless, here it is proved that the probability of requiring a value of alpha>k to obtain a solution for a random graph decreases exponentially: P(alpha>k)<=2(-(k+1)), making tractable almost all problem instances. Thorough experimental analyses were performed. The algorithm was tested on random graphs, planar graphs and 4 regular planar graphs. The obtained experimental results are in accordance with the theoretical expected results. PMID- 23349712 TI - Temperature-dependent structural changes of Parkinson's alpha-synuclein reveal the role of pre-existing oligomers in alpha-synuclein fibrillization. AB - Amyloid fibrils of alpha-synuclein are the main constituent of Lewy bodies deposited in substantial nigra of Parkinson's disease brains. alpha-Synuclein is an intrinsically disordered protein lacking compact secondary and tertiary structures. To enhance the understanding of its structure and function relationship, we utilized temperature treatment to study alpha-synuclein conformational changes and the subsequent effects. We found that after 1 hr of high temperature pretreatment, >80 degrees C, alpha-synuclein fibrillization was significantly inhibited. However, the temperature melting coupled with circular dichroism spectra showed that alpha-synuclein was fully reversible and the NMR studies showed no observable structural changes of alpha-synuclein after 95 degrees C treatment. By using cross-linking and analytical ultracentrifugation, rare amount of pre-existing alpha-synuclein oligomers were found to decrease after the high temperature treatment. In addition, a small portion of C-terminal truncation of alpha-synuclein also occurred. The reduction of pre-existing oligomers of alpha-synuclein may contribute to less seeding effect that retards the kinetics of amyloid fibrillization. Overall, our results showed that the pre existing oligomeric species is a key factor contributing to alpha-synuclein fibrillization. Our results facilitate the understanding of alpha-synuclein fibrillization. PMID- 23349713 TI - Co-culture of hematopoietic stem/progenitor cells with human osteblasts favours mono/macrophage differentiation at the expense of the erythroid lineage. AB - Hematopoietic stem cells (HSCs) are located in the bone marrow in a specific microenvironment referred as the hematopoietic stem cell niche, where HSCs interact with a variety of stromal cells. Though several components of the stem cell niche have been identified, the regulatory mechanisms through which such components regulate the stem cell fate are still unknown. In order to address this issue, we investigated how osteoblasts (OBs) can affect the molecular and functional phenotype of Hematopoietic Stem/Progenitor Cells (HSPCs) and vice versa. For this purpose, human CD34+ cells were cultured in direct contact with primary human OBs. Our data showed that CD34+ cells cultured with OBs give rise to higher total cell numbers, produce more CFUs and maintain a higher percentage of CD34+CD38- cells compared to control culture. Moreover, clonogenic assay and long-term culture results showed that co-culture with OBs induces a strong increase in mono/macrophage precursors coupled to a decrease in the erythroid ones. Finally, gene expression profiling (GEP) allowed us to study which signalling pathways were activated in the hematopoietic cell fraction and in the stromal cell compartment after coculture. Such analysis allowed us to identify several cytokine-receptor networks, such as WNT pathway, and transcription factors, as TWIST1 and FOXC1, that could be activated by co-culture with OBs and could be responsible for the biological effects reported above. Altogether our results indicate that OBs are able to affect HPSCs on 2 different levels: on one side, they increase the immature progenitor pool in vitro, on the other side, they favor the expansion of the mono/macrophage precursors at the expense of the erythroid lineage. PMID- 23349714 TI - Unveiling distribution patterns of freshwater phytoplankton by a next generation sequencing based approach. AB - The recognition and discrimination of phytoplankton species is one of the foundations of freshwater biodiversity research and environmental monitoring. This step is frequently a bottleneck in the analytical chain from sampling to data analysis and subsequent environmental status evaluation. Here we present phytoplankton diversity data from 49 lakes including three seasonal surveys assessed by next generation sequencing (NGS) of 16S ribosomal RNA chloroplast and cyanobacterial gene amplicons and also compare part of these datasets with identification based on morphology. Direct comparison of NGS to microscopic data from three time-series showed that NGS was able to capture the seasonality in phytoplankton succession as observed by microscopy. Still, the PCR-based approach was only semi-quantitative, and detailed NGS and microscopy taxa lists had only low taxonomic correspondence. This is probably due to, both, methodological constraints and current discrepancies in taxonomic frameworks. Discrepancies included Euglenophyta and Heterokonta that were scarce in the NGS but frequently detected by microscopy and Cyanobacteria that were in general more abundant and classified with high resolution by NGS. A deep-branching taxonomically unclassified cluster was frequently detected by NGS but could not be linked to any group identified by microscopy. NGS derived phytoplankton composition differed significantly among lakes with different trophic status, showing that our approach can resolve phytoplankton communities at a level relevant for ecosystem management. The high reproducibility and potential for standardization and parallelization makes our NGS approach an excellent candidate for simultaneous monitoring of prokaryotic and eukaryotic phytoplankton in inland waters. PMID- 23349715 TI - The liver X receptor agonist GW3965 improves recovery from mild repetitive traumatic brain injury in mice partly through apolipoprotein E. AB - Traumatic brain injury (TBI) increases Alzheimer's disease (AD) risk and leads to the deposition of neurofibrillary tangles and amyloid deposits similar to those found in AD. Agonists of Liver X receptors (LXRs), which regulate the expression of many genes involved in lipid homeostasis and inflammation, improve cognition and reduce neuropathology in AD mice. One pathway by which LXR agonists exert their beneficial effects is through ATP-binding cassette transporter A1 (ABCA1) mediated lipid transport onto apolipoprotein E (apoE). To test the therapeutic utility of this pathway for TBI, we subjected male wild-type (WT) and apoE-/- mice to mild repetitive traumatic brain injury (mrTBI) followed by treatment with vehicle or the LXR agonist GW3965 at 15 mg/kg/day. GW3965 treatment restored impaired novel object recognition memory in WT but not apoE-/- mice. GW3965 did not significantly enhance the spontaneous recovery of motor deficits observed in all groups. Total soluble Abeta(40) and Abeta(42) levels were significantly elevated in WT and apoE-/- mice after injury, a response that was suppressed by GW3965 in both genotypes. WT mice showed mild but significant axonal damage at 2 d post-mrTBI, which was suppressed by GW3965. In contrast, apoE-/- mice showed severe axonal damage from 2 to 14 d after mrTBI that was unresponsive to GW3965. Because our mrTBI model does not produce significant inflammation, the beneficial effects of GW3965 we observed are unlikely to be related to reduced inflammation. Rather, our results suggest that both apoE-dependent and apoE-independent pathways contribute to the ability of GW3965 to promote recovery from mrTBI. PMID- 23349716 TI - Sympatric speciation: when is it possible in bacteria? AB - According to theory, sympatric speciation in sexual eukaryotes is favored when relatively few loci in the genome are sufficient for reproductive isolation and adaptation to different niches. Here we show a similar result for clonally reproducing bacteria, but which comes about for different reasons. In simulated microbial populations, there is an evolutionary tradeoff between early and late stages of niche adaptation, which is resolved when relatively few loci are required for adaptation. At early stages, recombination accelerates adaptation to new niches (ecological speciation) by combining multiple adaptive alleles into a single genome. Later on, without assortative mating or other barriers to gene flow, recombination generates unfit intermediate genotypes and homogenizes incipient species. The solution to this tradeoff may be simply to reduce the number of loci required for speciation, or to reduce recombination between species over time. Both solutions appear to be relevant in natural microbial populations, allowing them to diverge into ecological species under similar constraints as sexual eukaryotes, despite differences in their life histories. PMID- 23349717 TI - Transcriptomic analyses of sexual dimorphism of the zebrafish liver and the effect of sex hormones. AB - The liver is one of the most sex-dimorphic organs in both oviparous and viviparous animals. In order to understand the molecular basis of the difference between male and female livers, high-throughput RNA-SAGE (serial analysis of gene expression) sequencing was performed for zebrafish livers of both sexes and their transcriptomes were compared. Both sexes had abundantly expressed genes involved in translation, coagulation and lipid metabolism, consistent with the general function of the liver. For sex-biased transcripts, from in addition to the high enrichment of vitellogenin transcripts in spawning female livers, which constituted nearly 80% of total mRNA, it is apparent that the female-biased genes were mostly involved in ribosome/translation, estrogen pathway, lipid transport, etc, while the male-biased genes were enriched for oxidation reduction, carbohydrate metabolism, coagulation, protein transport and localization, etc. Sexual dimorphism on xenobiotic metabolism and anti-oxidation was also noted and it is likely that retinol x receptor (RXR) and liver x receptor (LXR) play central roles in regulating the sexual differences of lipid and cholesterol metabolisms. Consistent with high ribosomal/translational activities in the female liver, female-biased genes were significantly regulated by two important transcription factors, Myc and Mycn. In contrast, Male livers showed activation of transcription factors Ppargc1b, Hnf4a, and Stat4, which regulate lipid and glucose metabolisms and various cellular activities. The transcriptomic responses to sex hormones, 17beta-estradiol (E2) or 11-keto testosterone (KT11), were also investigated in both male and female livers and we found that female livers were relatively insensitive to sex hormone disturbance, while the male livers were readily affected. E2 feminized male liver by up-regulating female-biased transcripts and down-regulating male-biased transcripts. The information obtained in this study provides comprehensive insights into the sexual dimorphism of zebrafish liver transcriptome and will facilitate further development of the zebrafish as a human liver disease model. PMID- 23349718 TI - Proteome regulation during Olea europaea fruit development. AB - BACKGROUND: Widespread in the Mediterranean basin, Olea europaea trees are gaining worldwide popularity for the nutritional and cancer-protective properties of the oil, mechanically extracted from ripe fruits. Fruit development is a physiological process with remarkable impact on the modulation of the biosynthesis of compounds affecting the quality of the drupes as well as the final composition of the olive oil. Proteomics offers the possibility to dig deeper into the major changes during fruit development, including the important phase of ripening, and to classify temporal patterns of protein accumulation occurring during these complex physiological processes. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we started monitoring the proteome variations associated with olive fruit development by using comparative proteomics coupled to mass spectrometry. Proteins extracted from drupes at three different developmental stages were separated on 2-DE and subjected to image analysis. 247 protein spots were revealed as differentially accumulated. Proteins were identified from a total of 121 spots and discussed in relation to olive drupe metabolic changes occurring during fruit development. In order to evaluate if changes observed at the protein level were consistent with changes of mRNAs, proteomic data produced in the present work were compared with transcriptomic data elaborated during previous studies. CONCLUSIONS/SIGNIFICANCE: This study identifies a number of proteins responsible for quality traits of cv. Coratina, with particular regard to proteins associated to the metabolism of fatty acids, phenolic and aroma compounds. Proteins involved in fruit photosynthesis have been also identified and their pivotal contribution in oleogenesis has been discussed. To date, this study represents the first characterization of the olive fruit proteome during development, providing new insights into fruit metabolism and oil accumulation process. PMID- 23349719 TI - Analysis of quality of clinical practice guidelines for otorhinolaryngology in China. AB - OBJECTIVE: To evaluate the quality of clinical practice guidelines (CPGs) for otorhinolaryngology in China. MATERIALS AND METHODS: A systematic search of relevant literature databases (CBM, WANFANG, VIP, CNKI, China Guideline Clearinghouse) published between 1978 and March 2012 was undertaken to identify and select CPGs related to otorhinolaryngology. Four independent reviewers assessed the eligible guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. Their degree of agreement was evaluated using the intraclass correlation coefficient (ICC). RESULT: From 170 citations, 21 relevant guidelines were included. The overall agreement among reviewers was moderate (ICC = 0.87; 95% confidence interval [CI], 0.78-0.91). The scores for each of the AGREE domains were the following: "scope and purpose" (mean +/- standard error [SE] = 45.4+/-4.4; ICC = 0.92), "stakeholder involvement" (mean +/ SE = 30.4+/-3.1; ICC = 0.81), "rigor of development" (mean +/- SE = 20.9+/-2.8; ICC = 0.87), "clarity of presentation" (mean +/- SE = 48.8+/-3.7; ICC = 0.80), "applicability" (mean +/- SE = 12.6+/-1.7; ICC = 0.72), and "editorial independence" (mean +/- SE = 6.2+/-0.8; ICC = 0.76). Three guidelines (14%) mentioned updates, and the average update frequency was 7 years. None used the GRADE system. CONCLUSION: The quality of otorhinolaryngology guidelines in China is low. Greater efforts are needed to provide high-quality guidelines that serve as a useful and reliable tool for clinical decision-making in this field. PMID- 23349720 TI - Confounding effects of phase delays on causality estimation. AB - Linear and non-linear techniques for inferring causal relations between the brain signals representing the underlying neuronal systems have become a powerful tool to extract the connectivity patterns in the brain. Typically these tools employ the idea of Granger causality, which is ultimately based on the temporal precedence between the signals. At the same time, phase synchronization between coupled neural ensembles is considered a mechanism implemented in the brain to integrate relevant neuronal ensembles to perform a cognitive or perceptual task. Phase synchronization can be studied by analyzing the effects of phase-locking between the brain signals. However, we should expect that there is no one-to-one mapping between the observed phase lag and the time precedence as specified by physically interacting systems. Specifically, phase lag observed between two signals may interfere with inferring causal relations. This could be of critical importance for the coupled non-linear oscillating systems, with possible time delays in coupling, when classical linear cross-spectrum strategies for solving phase ambiguity are not efficient. To demonstrate this, we used a prototypical model of coupled non-linear systems, and compared three typical pipelines of inferring Granger causality, as established in the literature. Specifically, we compared the performance of the spectral and information-theoretic Granger pipelines as well as standard Granger causality in their relations to the observed phase differences for frequencies at which the signals become synchronized to each other. We found that an information-theoretic approach, which takes into account different time lags between the past of one signal and the future of another signal, was the most robust to phase effects. PMID- 23349721 TI - Infection-induced bystander-apoptosis of monocytes is TNF-alpha-mediated. AB - Phagocytosis induced cell death (PICD) is crucial for controlling phagocyte effector cells, such as monocytes, at sites of infection, and essentially contributes to termination of inflammation. Here we tested the hypothesis, that during PICD bystander apoptosis of non-phagocyting monocytes occurs, that apoptosis induction is mediated via tumor necrosis factor-alpha (TNF-alpha and that TNF-alpha secretion and -signalling is causal. Monocytes were infected with Escherichia coli (E. coli), expressing green fluorescent protein (GFP), or a pH sensitive Eos-fluorescent protein (EOS-FP). Monocyte phenotype, phagocytic activity, apoptosis, TNF-receptor (TNFR)-1, -2-expression and TNF-alpha production were analyzed. Apoptosis occured in phagocyting and non-phagocyting, bystander monocytes. Bacterial transport to the phagolysosome was no prerequisite for apoptosis induction, and desensitized monocytes from PICD, as confirmed by EOS-FP expressing E. coli. Co-cultivation with non-infected carboxyfluorescein succinimidyl-ester- (CFSE-) labelled monocytes resulted in significant apoptotic cell death of non-infected bystander monocytes. This process required protein de novo synthesis and still occurred in a diminished way in the absence of cell-cell contact. E. coli induced a robust TNF-alpha production, leading to TNF-mediated apoptosis in monocytes. Neutralization with an anti-TNF-alpha antibody reduced monocyte bystander apoptosis significantly. In contrast to TNFR2, the pro apoptotic TNFR1 was down-regulated on the monocyte surface, internalized 30 min. p.i. and led to apoptosis predominantly in monocytes without phagocyting bacteria by themselves. Our results suggest, that apoptosis of bystander monocytes occurs after infection with E. coli via internalization of TNFR1, and indicate a relevant role for TNF-alpha. Modifying monocyte apoptosis in sepsis may be a future therapeutic option. PMID- 23349722 TI - Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington's disease. AB - Huntington's disease (HD) is a neuropsychiatric disorder characterized by choreiform movement of the limbs, cognitive disability, psychosis and dementia. It is invariably associated with an abnormally long CAG expansion within the IT15 gene on human chromosome 4. Although the mutant huntingtin protein is ubiquitously expressed in HD patients, cellular degeneration occurs predominantly in neurons within the corpus striatum and cerebral cortex. The Ras homolog Rhes is expressed very selectively in the precise brain areas affected by HD. Recent in vitro work suggests that Rhes may be a co-factor with mutant huntingtin in cell death. The objective of the present study was to examine whether the inhibition of Rhes would attenuate or delay the symptoms of HD in vivo. We used a transgenic mouse model of HD crossed with Rhes knockout mice to show that the behavioral symptoms of HD are regulated by Rhes. HD(+)/Rhes(-/-) mice showed significantly delayed expression of HD-like symptoms in this in vivo model. Drugs that block or inhibit the actions of Rhes may be useful as the first treatments for HD. PMID- 23349723 TI - Association properties and unfolding of a betagamma-crystallin domain of a Vibrio specific protein. AB - The betagamma-crystallin superfamily possesses a large number of versatile members, of which only a few members other than lens betagamma-crystallins have been studied. Understanding the non-crystallin functions as well as origin of crystallin-like properties of such proteins is possible by exploring novel members from diverse sources. We describe a novel betagamma-crystallin domain with S-type (Spherulin 3a type) Greek key motifs in protein vibrillin from a pathogenic bacterium Vibrio cholerae. This domain is a part of a large Vibrio specific protein prevalent in Vibrio species (found in at least fourteen different strains sequenced so far). The domain contains two canonical N/D-N/D-X X-S/T-S Ca(2+)-binding motifs, and bind Ca(2+). Unlike spherulin 3a and other microbial homologues studied so far, betagamma-crystallin domain of vibrillin self-associates forming oligomers of various sizes including dimers. The fractionated dimers readily form octamers in concentration-dependent manner, suggesting an association between these two major forms. The domain associates/dissociates forming dimers at the cost of monomeric populations in the presence of Ca(2+). No such effect of Ca(2+) has been observed in oligomeric species. The equilibrium unfolding of both forms follows a similar pattern, with the formation of an unfolding intermediate at sub-molar concentrations of denaturant. These properties exhibited by this betagamma-crystallin domain are not shown by any other domain studied so far, demonstrating the diversity in domain properties. PMID- 23349724 TI - Role of baseline HIV-1 DNA level in highly-experienced patients receiving raltegravir, etravirine and darunavir/ritonavir regimen (ANRS139 TRIO trial). AB - OBJECTIVE: In the ANRS 139 TRIO trial, the use of 3 new active drugs (raltegravir, etravirine, and darunavir/ritonavir), resulted in a potent and sustained inhibition of viral replication in multidrug-resistant treatment experienced patients. The aim of this virological sub-study of the ANRS 139 TRIO trial was to assess: (i) the evolution of HIV-1 DNA over the first year; and (ii) the association between baseline HIV-1 DNA and virological outcome. METHODS: Among the 103 HIV-1-infected patients included in the ANRS-139 TRIO trial, HIV-1 DNA specimens were available for 92, 84, 88, and 83 patients at Week (W)0, W12, W24, and W48, respectively. Quantification of total HIV-1 DNA was performed by using the commercial kit "Generic HIV DNA Cell" (Biocentric, Bandol, France). RESULTS: Baseline median HIV-1 DNA of patients displaying virological success (n= 61), viral blip (n= 20), and virological failure (n = 11) were 2.34 log(10) copies/10(6) PBMC (IQR= 2.15-2.66), 2.42 (IQR = 2.12-2.48), and 2.68 (IQR= 2.46 2.83), respectively. Although not statistically significant, patients exhibiting virological success or viral blip had a tendency to display lower baseline HIV-1 DNA than patients experiencing virological failure (P = 0.06). Median decrease of HIV-1 DNA between baseline and W48 was -0.13 log(10) copies/10(6) PBMC (IQR = 0.34 to +0.10), mainly explained by the evolution from W0 to W4. No more changes were observed in the W4-W48 period. CONCLUSIONS: In highly-experienced multidrug resistant patients, HIV-1 DNA slightly decreased during the first month and then remained stable during the first year of highly potent antiretroviral regimen. In this population, baseline HIV-1 DNA might help to better predict the virological response and to tailor clinical therapeutic management as more aggressive therapeutic choices in patients with higher baseline HIV-1 DNA. PMID- 23349726 TI - Estimating how inflated or obscured effects of climate affect forecasted species distribution. AB - Climate is one of the main drivers of species distribution. However, as different environmental factors tend to co-vary, the effect of climate cannot be taken at face value, as it may be either inflated or obscured by other correlated factors. We used the favourability models of four species (Alytes dickhilleni, Vipera latasti, Aquila fasciata and Capra pyrenaica) inhabiting Spanish mountains as case studies to evaluate the relative contribution of climate in their forecasted favourability by using variation partitioning and weighting the effect of climate in relation to non-climatic factors. By calculating the pure effect of the climatic factor, the pure effects of non-climatic factors, the shared climatic effect and the proportion of the pure effect of the climatic factor in relation to its apparent effect (rho), we assessed the apparent effect and the pure independent effect of climate. We then projected both types of effects when modelling the future favourability for each species and combination of AOGCM-SRES (two Atmosphere-Ocean General Circulation Models: CGCM2 and ECHAM4, and two Special Reports on Emission Scenarios (SRES): A2 and B2). The results show that the apparent effect of climate can be either inflated (overrated) or obscured (underrated) by other correlated factors. These differences were species specific; the sum of favourable areas forecasted according to the pure climatic effect differed from that forecasted according to the apparent climatic effect by about 61% on average for one of the species analyzed, and by about 20% on average for each of the other species. The pure effect of future climate on species distributions can only be estimated by combining climate with other factors. Transferring the pure climatic effect and the apparent climatic effect to the future delimits the maximum and minimum favourable areas forecasted for each species in each climate change scenario. PMID- 23349725 TI - Analysis of V2 antibody responses induced in vaccinees in the ALVAC/AIDSVAX HIV-1 vaccine efficacy trial. AB - The RV144 clinical trial of a prime/boost immunizing regimen using recombinant canary pox (ALVAC-HIV) and two gp120 proteins (AIDSVAX B and E) was previously shown to have a 31.2% efficacy rate. Plasma specimens from vaccine and placebo recipients were used in an extensive set of assays to identify correlates of HIV 1 infection risk. Of six primary variables that were studied, only one displayed a significant inverse correlation with risk of infection: the antibody (Ab) response to a fusion protein containing the V1 and V2 regions of gp120 (gp70 V1V2). This finding prompted a thorough examination of the results generated with the complete panel of 13 assays measuring various V2 Abs in the stored plasma used in the initial pilot studies and those used in the subsequent case-control study. The studies revealed that the ALVAC-HIV/AIDSVAX vaccine induced V2 specific Abs that cross-react with multiple HIV-1 subgroups and recognize both conformational and linear epitopes. The conformational epitope was present on gp70-V1V2, while the predominant linear V2 epitope mapped to residues 165-178, immediately N-terminal to the putative alpha4beta7 binding motif in the mid-loop region of V2. Odds ratios (ORs) were calculated to compare the risk of infection with data from 12 V2 assays, and in 11 of these, the ORs were <=1, reaching statistical significance for two of the variables: Ab responses to gp70-V1V2 and to overlapping V2 linear peptides. It remains to be determined whether anti-V2 Ab responses were directly responsible for the reduced infection rate in RV144 and whether anti-V2 Abs will prove to be important with other candidate HIV vaccines that show efficacy, however, the results support continued dissection of Ab responses to the V2 region which may illuminate mechanisms of protection from HIV 1 infection and may facilitate the development of an effective HIV-1 vaccine. PMID- 23349727 TI - The different role of Notch1 and Notch2 in astrocytic gliomas. AB - It is well known that Notch signaling plays either oncogenic or tumor suppressive role in a variety of tumors, depending on the cellular context. However, in our previous study, we found that Notch1 was overexpressed while Notch2 downregulated in the majority of astrocytic gliomas with different grades as well as in glioblastoma cell lines U251 and A172. We had knocked down Notch1 by siRNA in glioblastoma cells, and identified that the cell growth and invasion were inhibited, whereas cell apoptosis was induced either in vitro or in vivo. For further clarification of the role of Notch2 in pathogenesis of gliomas, enforced overexpression of Notch2 was carried out with transfection of Notch2 expression plasmid in glioma cells and the cell growth, invasion and apoptosis were examined in vitro and in vivo in the present study, and siRNA targeting Notch1 was used as a positive control in vivo. The results showed that upregulating Notch2 had the effect of suppressing cell growth and invasion as well as inducing apoptosis, just the same as the results of knocking down Notch1. Meanwhile, the activity of core signaling pathway-EGFR/PI3K/AKT in astrocytic glioma cells was repressed. Thus, the present study reveals, for the first time, that Notch1 and Notch2 play different roles in the biological processes of astrocytic gliomas. Knocking down the Notch1 or enforced overexpression of Notch2 both modulate the astrocytic glioma phenotype, and the mechanism by which Notch1 and 2 play different roles in the glioma growth should be further investigated. PMID- 23349728 TI - Choroidal thickness and biometric markers for the screening of lacquer cracks in patients with high myopia. AB - OBJECTIVES: Validation of choroidal thickness and other biometrics measured by spectral domain optical coherence tomography (SD-OCT) in predicting lacquer cracks formation in highly myopic eyes. METHODS: Patients with a refractive error worse than -8 diopters and moderate myopic maculopathy were recruited into two groups based on the presence or absence of lacquer cracks (36 eyes without and 33 eyes with lacquer cracks). Choroidal thickness, refractive error, and axial length were measured and subjected to receiver operating characteristic curve analysis to identify the optimal cutoff values at predicting lacquer crack formation. The width of the retinal pigment epithelium (RPE), RPE to the inner segment/outer segment line, RPE to the external limiting membrane were also measured and compared to the subfoveal choroidal thickness to assess their relationships as potential markers of lacquer crack formation. RESULTS: Lacquer crack is associated with decreased choroidal thickness, lower best-corrected visual acuity, longer axial length and higher refractive errors. Choroidal thickness has the strongest association with lacquer crack formation versus axial length and refractive error. In eyes with lacquer cracks, stellate lacquer cracks are associated with thinner choroidal thickness compared to eyes with linear lacquer cracks. Subfoveal choroidal thickness less than the width of the retinal pigment epithelium to the inner segment/outer segment line is also associated with lacquer crack formation (sensitivity 78.8%, specificity 88.3%, and accuracy 81.2%). CONCLUSIONS: This study suggests that choroidal thickness and other SD OCT measurements could be employed clinically to predict the development and severity of lacquer cracks in patients with high myopia. PMID- 23349729 TI - Characterization of epicardial-derived cardiac interstitial cells: differentiation and mobilization of heart fibroblast progenitors. AB - The non-muscular cells that populate the space found between cardiomyocyte fibers are known as 'cardiac interstitial cells' (CICs). CICs are heterogeneous in nature and include different cardiac progenitor/stem cells, cardiac fibroblasts and other cell types. Upon heart damage CICs soon respond by initiating a reparative response that transforms with time into extensive fibrosis and heart failure. Despite the biomedical relevance of CICs, controversy remains on the ontogenetic relationship existing between the different cell kinds homing at the cardiac interstitium, as well as on the molecular signals that regulate their differentiation, maturation, mutual interaction and role in adult cardiac homeostasis and disease. Our work focuses on the analysis of epicardial-derived cells, the first cell type that colonizes the cardiac interstitium. We present here a characterization and an experimental analysis of the differentiation potential and mobilization properties of a new cell line derived from mouse embryonic epicardium (EPIC). Our results indicate that these cells express some markers associated with cardiovascular stemness and retain part of the multipotent properties of embryonic epicardial derivatives, spontaneously differentiating into smooth muscle, and fibroblast/myofibroblast-like cells. Epicardium-derived cells are also shown to initiate a characteristic response to different growth factors, to display a characteristic proteolytic expression profile and to degrade biological matrices in 3D in vitro assays. Taken together, these data indicate that EPICs are relevant to the analysis of epicardial-derived CICs, and are a god model for the research on cardiac fibroblasts and the role these cells play in ventricular remodeling in both ischemic or non/ischemic myocardial disease. PMID- 23349730 TI - Integrin-linked kinase regulates interphase and mitotic microtubule dynamics. AB - Integrin-linked kinase (ILK) localizes to both focal adhesions and centrosomes in distinct multiprotein complexes. Its dual function as a kinase and scaffolding protein has been well characterized at focal adhesions, where it regulates integrin-mediated cell adhesion, spreading, migration and signaling. At the centrosomes, ILK regulates mitotic spindle organization and centrosome clustering. Our previous study showed various spindle defects after ILK knockdown or inhibition that suggested alteration in microtubule dynamics. Since ILK expression is frequently elevated in many cancer types, we investigated the effects of ILK overexpression on microtubule dynamics. We show here that overexpressing ILK in HeLa cells was associated with a shorter duration of mitosis and decreased sensitivity to paclitaxel, a chemotherapeutic agent that suppresses microtubule dynamics. Measurement of interphase microtubule dynamics revealed that ILK overexpression favored microtubule depolymerization, suggesting that microtubule destabilization could be the mechanism behind the decreased sensitivity to paclitaxel, which is known to stabilize microtubules. Conversely, the use of a small molecule inhibitor selective against ILK, QLT-0267, resulted in suppressed microtubule dynamics, demonstrating a new mechanism of action for this compound. We further show that treatment of HeLa cells with QLT-0267 resulted in higher inter-centromere tension in aligned chromosomes during mitosis, slower microtubule regrowth after cold depolymerization and the presence of a more stable population of spindle microtubules. These results demonstrate that ILK regulates microtubule dynamics in both interphase and mitotic cells. PMID- 23349731 TI - Staphylococcus aureus and Pseudomonas aeruginosa express and secrete human surfactant proteins. AB - Surfactant proteins (SP), originally known from human lung surfactant, are essential to proper respiratory function in that they lower the surface tension of the alveoli. They are also important components of the innate immune system. The functional significance of these proteins is currently reflected by a very large and growing number of publications. The objective goal of this study was to elucidate whether Staphylococcus aureus and Pseudomonas aeruginosa is able to express surfactant proteins. 10 different strains of S. aureus and P. aeruginosa were analyzed by means of RT-PCR, Western blot analysis, ELISA, immunofluorescence microscopy and immunoelectron microscopy. The unexpected and surprising finding revealed in this study is that different strains of S. aureus and P. aeruginosa express and secrete proteins that react with currently commercially available antibodies to known human surfactant proteins. Our results strongly suggest that the bacteria are either able to express 'human-like' surfactant proteins on their own or that commercially available primers and antibodies to human surfactant proteins detect identical bacterial proteins and genes. The results may reflect the existence of a new group of bacterial surfactant proteins and DNA currently lacking in the relevant sequence and structure databases. At any rate, our knowledge of human surfactant proteins obtained from immunological and molecular biological studies may have been falsified by the presence of bacterial proteins and DNA and therefore requires critical reassessment. PMID- 23349732 TI - Structural basis of the gamma-lactone-ring formation in ascorbic acid biosynthesis by the senescence marker protein-30/gluconolactonase. AB - The senescence marker protein-30 (SMP30), which is also called regucalcin, exhibits gluconolactonase (GNL) activity. Biochemical and biological analyses revealed that SMP30/GNL catalyzes formation of the gamma-lactone-ring of L gulonate in the ascorbic acid biosynthesis pathway. The molecular basis of the gamma-lactone formation, however, remains elusive due to the lack of structural information on SMP30/GNL in complex with its substrate. Here, we report the crystal structures of mouse SMP30/GNL and its complex with xylitol, a substrate analogue, and those with 1,5-anhydro-D-glucitol and D-glucose, product analogues. Comparison of the crystal structure of mouse SMP30/GNL with other related enzymes has revealed unique characteristics of mouse SMP30/GNL. First, the substrate binding pocket of mouse SMP30/GNL is designed to specifically recognize monosaccharide molecules. The divalent metal ion in the active site and polar residues lining the substrate-binding cavity interact with hydroxyl groups of substrate/product analogues. Second, in mouse SMP30/GNL, a lid loop covering the substrate-binding cavity seems to hamper the binding of L-gulonate in an extended (or all-trans) conformation; L-gulonate seems to bind to the active site in a folded conformation. In contrast, the substrate-binding cavities of the other related enzymes are open to the solvent and do not have a cover. This structural feature of mouse SMP30/GNL seems to facilitate the gamma-lactone-ring formation. PMID- 23349733 TI - Effects of oral L-carnitine administration in narcolepsy patients: a randomized, double-blind, cross-over and placebo-controlled trial. AB - Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement (REM) sleep abnormalities. A genome-wide association study (GWAS) identified a novel narcolepsy-related single nucleotide polymorphism (SNP), which is located adjacent to the carnitine palmitoyltransferase 1B (CPT1B) gene encoding an enzyme involved in beta oxidation of long-chain fatty acids. The mRNA expression levels of CPT1B were associated with this SNP. In addition, we recently reported that acylcarnitine levels were abnormally low in narcolepsy patients. To assess the efficacy of oral L-carnitine for the treatment of narcolepsy, we performed a clinical trial administering L-carnitine (510 mg/day) to patients with the disease. The study design was a randomized, double-blind, cross-over and placebo-controlled trial. Thirty narcolepsy patients were enrolled in our study. Two patients were withdrawn and 28 patients were included in the statistical analysis (15 males and 13 females, all with HLA-DQB1*06:02). L-carnitine treatment significantly improved the total time for dozing off during the daytime, calculated from the sleep logs, compared with that of placebo-treated periods. L-carnitine efficiently increased serum acylcarnitine levels, and reduced serum triglycerides concentration. Differences in the Japanese version of the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF 36) vitality and mental health subscales did not reach statistical significance between L-carnitine and placebo. This study suggests that oral L-carnitine can be effective in reducing excessive daytime sleepiness in narcolepsy patients. TRIAL REGISTRATION: University hospital Medical Information Network (UMIN) UMIN000003760. PMID- 23349735 TI - The afterlife of interspecific indirect genetic effects: genotype interactions alter litter quality with consequences for decomposition and nutrient dynamics. AB - Aboveground-belowground linkages are recognized as divers of community dynamics and ecosystem processes, but the impacts of plant-neighbor interactions on these linkages are virtually unknown. Plant-neighbor interactions are a type of interspecific indirect genetic effect (IIGE) if the focal plant's phenotype is altered by the expression of genes in a neighboring heterospecific plant, and IIGEs could persist after plant senescence to affect ecosystem processes. This perspective can provide insight into how plant-neighbor interactions affect evolution, as IIGEs are capable of altering species interactions and community composition over time. Utilizing genotypes of Solidago altissima and Solidago gigantea, we experimentally tested whether IIGEs that had affected living focal plants would affect litter decomposition rate, as well as nitrogen (N) and phosphorous (P) dynamics after the focal plant senesced. We found that species interactions affected N release and genotype interactions affected P immobilization. From a previous study we knew that neighbor genotype influenced patterns of biomass allocation for focal plants. Here we extend those previous results to show that these changes in biomass allocation altered litter quality, that then altered rates of decomposition and nutrient cycling. Our results provide insights into above- and belowground linkages by showing that, through their effects on plant litter quality (e.g., litter lignin:N), IIGEs can have afterlife effects, tying plant-neighbor interactions to ecosystem processes. This holistic approach advances our understanding of decomposition and nutrient cycling by showing that evolutionary processes (i.e., IIGEs) can influence ecosystem functioning after plant senescence. Because plant traits are determined by the combined effects of genetic and environmental influences, and because these traits are known to affect decomposition and nutrient cycling, we suggest that ecosystem processes can be described as gene-less products of genetic interactions among the species comprising ecological communities. PMID- 23349734 TI - AlgiMatrixTM based 3D cell culture system as an in-vitro tumor model for anticancer studies. AB - BACKGROUND: Three-dimensional (3D) in-vitro cultures are recognized for recapitulating the physiological microenvironment and exhibiting high concordance with in-vivo conditions. Taking the advantages of 3D culture, we have developed the in-vitro tumor model for anticancer drug screening. METHODS: Cancer cells grown in 6 and 96 well AlgiMatrixTM scaffolds resulted in the formation of multicellular spheroids in the size range of 100-300 um. Spheroids were grown in two weeks in cultures without compromising the growth characteristics. Different marketed anticancer drugs were screened by incubating them for 24 h at 7, 9 and 11 days in 3D cultures and cytotoxicity was measured by AlamarBlue(r) assay. Effectiveness of anticancer drug treatments were measured based on spheroid number and size distribution. Evaluation of apoptotic and anti-apoptotic markers was done by immunohistochemistry and RT-PCR. The 3D results were compared with the conventional 2D monolayer cultures. Cellular uptake studies for drug (Doxorubicin) and nanoparticle (NLC) were done using spheroids. RESULTS: IC(50) values for anticancer drugs were significantly higher in AlgiMatrixTM systems compared to 2D culture models. The cleaved caspase-3 expression was significantly decreased (2.09 and 2.47 folds respectively for 5-Fluorouracil and Camptothecin) in H460 spheroid cultures compared to 2D culture system. The cytotoxicity, spheroid size distribution, immunohistochemistry, RT-PCR and nanoparticle penetration data suggested that in vitro tumor models show higher resistance to anticancer drugs and supporting the fact that 3D culture is a better model for the cytotoxic evaluation of anticancer drugs in vitro. CONCLUSION: The results from our studies are useful to develop a high throughput in vitro tumor model to study the effect of various anticancer agents and various molecular pathways affected by the anticancer drugs and formulations. PMID- 23349736 TI - Sequencing ASMT identifies rare mutations in Chinese Han patients with autism. AB - Melatonin is involved in the regulation of circadian and seasonal rhythms and immune function. Prior research reported low melatonin levels in autism spectrum disorders (ASD). ASMT located in pseudo-autosomal region 1 encodes the last enzyme of the melatonin biosynthesis pathway. A previous study reported an association between ASD and single nucleotide polymorphisms (SNPs) rs4446909 and rs5989681 located in the promoter of ASMT. Furthermore, rare deleterious mutations were identified in a subset of patients. To investigate the association between ASMT and autism, we sequenced all ASMT exons and its neighboring region in 398 Chinese Han individuals with autism and 437 healthy controls. Although our study did not detect significant differences of genotypic distribution and allele frequencies of the common SNPs in ASMT between patients with autism and healthy controls, we identified new rare coding mutations of ASMT. Among these rare variants, 4 were exclusively detected in patients with autism including a stop mutation (p.R115W, p.V166I, p.V179G, and p.W257X). These four coding variants were observed in 6 of 398 (1.51%) patients with autism and none in 437 controls (Chi-Square test, Continuity Correction p = 0.032, two-sided). Functional prediction of impact of amino acid showed that p.R115W might affect protein function. These results indicate that ASMT might be a susceptibility gene for autism. Further studies in larger samples are needed to better understand the degree of variation in this gene as well as to understand the biochemical and clinical impacts of ASMT/melatonin deficiency. PMID- 23349737 TI - The CD3 versus CD7 plot in multicolor flow cytometry reflects progression of disease stage in patients infected with HTLV-I. AB - PURPOSE: In a recent study to purify adult T-cell leukemia-lymphoma (ATL) cells from acute-type patients by flow cytometry, three subpopulations were observed in a CD3 versus CD7 plot (H: CD3(high)CD7(high); D: CD3(dim)CD7(dim); L: CD3(dim)CD7(low)). The majority of leukemia cells were enriched in the L subpopulation and the same clone was included in the D and L subpopulations, suggesting clonal evolution. In this study, we analyzed patients with indolent type ATL and human T-cell leukemia virus type I (HTLV-I) asymptomatic carriers (ACs) to see whether the CD3 versus CD7 profile reflected progression in the properties of HTLV-I-infected cells. EXPERIMENTAL DESIGN: Using peripheral blood mononuclear cells from patient samples, we performed multi-color flow cytometry. Cells that underwent fluorescence-activated cell sorting were subjected to molecular analyses, including inverse long PCR. RESULTS: In the D(%) versus L(%) plot, patient data could largely be categorized into three groups (Group 1: AC; Group 2: smoldering- and chronic-type ATL; and Group 3: acute-type ATL). Some exceptions, however, were noted (e.g., ACs in Group 2). In the follow-up of some patients, clinical disease progression correlated well with the CD3 versus CD7 profile. In clonality analysis, we clearly detected a major clone in the D and L subpopulations in ATL cases and, intriguingly, in some ACs in Group 2. CONCLUSION: We propose that the CD3 versus CD7 plot reflects progression of disease stage in patients infected with HTLV-I. The CD3 versus CD7 profile will be a new indicator, along with high proviral load, for HTLV-I ACs in forecasting disease progression. PMID- 23349738 TI - A systematic review of recent clinical practice guidelines on the diagnosis, assessment and management of hypertension. AB - BACKGROUND: Despite the availability of clinical practice guidelines (CPGs), optimal hypertension control is not achieved in many parts of the world; one of the challenges is the volume of guidelines on this topic and their variable quality. To systematically review the quality, methodology, and consistency of recommendations of recently-developed national CPGs on the diagnosis, assessment and the management of hypertension. METHODOLOGY/PRINCIPAL FINDINGS: MEDLINE, EMBASE, guidelines' websites and Google were searched for CPGs written in English on the general management of hypertension in any clinical setting published between January 2006 and September 2011. Four raters independently appraised each CPG using the AGREE-II instrument and 2 reviewers independently extracted the data. Conflicts were resolved by discussion or the involvement of an additional reviewer. Eleven CPGs were identified. The overall quality ranged from 2.5 to 6 out of 7 on the AGREE-II tool. The highest scores were for "clarity of presentation" (44.4%-88.9%) and the lowest were for "rigour of development" (8.3% 30% for 9 CGPs). None of them clearly reported being newly developed or adapted. Only one reported having a patient representative in its development team. Systematic reviews were not consistently used and only 2 up-to-date Cochrane reviews were cited. Two CPGs graded some recommendations and related that to levels (but not quality) of evidence. The CPGs' recommendations on assessment and non-pharmacological management were fairly consistent. Guidelines varied in the selection of first-line treatment, adjustment of therapy and drug combinations. Important specific aspects of care (e.g. resistant hypertension) were ignored by 6/11 CPGs. The CPGs varied in methodological quality, suggesting that their implementation might not result in less variation of care or in better health related outcomes. CONCLUSIONS/SIGNIFICANCE: More efforts are needed to promote the realistic approach of localization or local adaptation of existing high quality CPGs to the national context. PMID- 23349739 TI - Characterization of a stable, metronidazole-resistant Clostridium difficile clinical isolate. AB - BACKGROUND: Clostridium difficile are gram-positive, spore forming anaerobic bacteria that are the leading cause of healthcare-associated diarrhea, usually associated with antibiotic usage. Metronidazole is currently the first-line treatment for mild to moderate C. difficile diarrhea however recurrence occurs at rates of 15-35%. There are few reports of C. difficile metronidazole resistance in the literature, and when observed, the phenotype has been transient and lost after storage or exposure of the bacteria to freeze/thaw cycles. Owing to the unstable nature of the resistance phenotype in the laboratory, clinical significance and understanding of the resistance mechanisms is lacking. METHODOLOGY/PRINCIPAL FINDINGS: Genotypic and phenotypic characterization was performed on a metronidazole resistant clinical isolate of C. difficile. Whole genome sequencing was used to identify potential genetic contributions to the phenotypic variation observed with molecular and bacteriological techniques. Phenotypic observations of the metronidazole resistant strain revealed aberrant growth in broth and elongated cell morphology relative to a metronidazole susceptible, wild type NAP1 strain. Comparative genomic analysis revealed single nucleotide polymorphism (SNP) level variation within genes affecting core metabolic pathways such as electron transport, iron utilization and energy production. CONCLUSIONS/SIGNIFICANCE: This is the first characterization of stable, metronidazole resistance in a C. difficile isolate. The study provides an in-depth genomic and phenotypic analysis of this strain and provides a foundation for future studies to elucidate mechanisms conferring metronidazole resistance in C. difficile that have not been previously described. PMID- 23349740 TI - Telomerase reverse transcriptase synergizes with calorie restriction to increase health span and extend mouse longevity. AB - Caloric restriction (CR), a reduction of food intake while avoiding malnutrition, can delay the onset of cancer and age-related diseases in several species, including mice. In addition, depending of the genetic background, CR can also increase or decrease mouse longevity. This has highlighted the importance of identifying the molecular pathways that interplay with CR in modulating longevity. Significant lifespan extension in mice has been recently achieved through over-expression of the catalytic subunit of mouse telomerase (mTERT) in a cancer protective background. Given the CR cancer-protective effects in rodents, we set to address here whether CR impacts on telomere length and synergizes with mTERT to extend mouse longevity. CR significantly decreased tumor incidence in TERT transgenic (TgTERT) mice and extended their lifespan compared to wild-type (WT) controls under the same diet, indicating a synergy between TgTERT and CR in increasing mouse longevity. In addition, longitudinal telomere length measurements in peripheral blood leukocytes from individual mice showed that CR resulted in maintenance and/or elongation telomeres in a percentage of WT mice, a situation that mimics telomere dynamics in TgTERT cohorts. These results demonstrate that CR attenuates telomere erosion associated to aging and that synergizes with TERT over-expression in increasing "health span" and extending mouse longevity. PMID- 23349741 TI - Efficacy of quinine, artemether-lumefantrine and dihydroartemisinin-piperaquine as rescue treatment for uncomplicated malaria in Ugandan children. AB - BACKGROUND: The treatment of falciparum malaria poses unique challenges in settings where malaria transmission intensity is high because recurrent infections are common. These could be new infections, recrudescences, or a combination of the two. Though several African countries continue to use quinine as the second line treatment for patients with recurrent infections, there is little information on its efficacy when used for rescue therapy. Moreover, such practice goes against the World Health Organisation (WHO) recommendation to use combination therapy for uncomplicated malaria. METHODS: We conducted a nested, randomized, open label, three-arm clinical trial of rescue therapy in children 6 59 months old with recurrent malaria infection during 28 days post treatment with artemisinin combination treatment (ACT). Patients were randomly assigned to receive either quinine, artemether-lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPQ), and actively followed up for 28 days. FINDINGS: Among 220 patients enrolled, 217 (98.6%) were assigned an efficacy outcome and 218 (99.1%) were assessed for safety. The risk of recurrent infection was significantly higher in patients treated with quinine (70%, 74/110, HR = 3.9; 95% CI: 2.4-6.7, p<0.0001) and AL (60%, 21/35, HR = 3.3; 95% CI: 1.8-6.3, p<0.0002), compared to DHAPQ (25%, 18/72). Recrudescence tended to be lower in the DHAPQ (1%, 1/72) than in the quinine (7%, 8/110) or AL (6%, 2/35) group, though it was not statistically significant. No serious adverse events were reported. CONCLUSION: Recurrent infections observed after the administration of an ACT can be successfully treated with an alternative ACT rather than with quinine. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99046537. PMID- 23349742 TI - Reversible behavioral deficits in rats during a cycle of demyelination remyelination of the fimbria. AB - Traumatic brain injury (TBI) selectively damages white matter. White matter damage does not produce deficits in many behavioral tests used to analyze experimental TBI. Rats were impaired on an active place avoidance task following inactivation of one hippocampal injection of tetrodotoxin. The need for both hippocampi suggests that acquisition of the active place avoidance task may require interhippocampal communication. The controlled cortical impact model of TBI demyelinates midline white matter and impairs rats on the active place avoidance task. One white matter region that is demyelinated is the fimbria that contains hippocampal commissural fibers. We therefore tested whether demyelination of the fimbria produces deficits in active place avoidance. Lysophosphatidylcholine (LPC) was injected stereotaxically to produce a cycle of demyelination-remyelination of the fimbria. At 4 days, myelin loss was observed in the fimbria of LPC-, but not saline-injected rats. Fourteen days after injection, myelin content increased in LPC-, but not saline-injected rats. Three days after injection, both saline- and LPC-injected rats had similar performance on an open field and passive place avoidance task in which the rat avoided a stationary shock zone on a stationary arena. The following day, on the active place avoidance task, LPC-injected rats had a significantly higher number of shock zone entrances suggesting learning was impaired. At 14 days after injection, saline- and LPC-injected rats had similar performance on open field and passive place avoidance. On active place avoidance, however, saline- and LPC injected rats had a similar number of total entrances suggesting that the impairment seen at 4 days was no longer present at 14 days. These data suggest that active place avoidance is highly sensitive to white matter injury. PMID- 23349743 TI - Cloning, annotation and developmental expression of the chicken intestinal MUC2 gene. AB - Intestinal mucin 2 (MUC2) encodes a heavily glycosylated, gel-forming mucin, which creates an important protective mucosal layer along the gastrointestinal tract in humans and other species. This first line of defense guards against attacks from microorganisms and is integral to the innate immune system. As a first step towards characterizing the innate immune response of MUC2 in different species, we report the cloning of a full-length, 11,359 bp chicken MUC2 cDNA, and describe the genomic organization and functional annotation of this complex, 74.5 kb locus. MUC2 contains 64 exons and demonstrates distinct spatiotemporal expression profiles throughout development in the gastrointestinal tract; expression increases with gestational age and from anterior to posterior along the gut. The chicken protein has a similar domain organization as the human orthologue, with a signal peptide and several von Willebrand domains in the N terminus and the characteristic cystine knot at the C-terminus. The PTS domain of the chicken MUC2 protein spans ~1600 amino acids and is interspersed with four CysD motifs. However, the PTS domain in the chicken diverges significantly from the human orthologue; although the chicken domain is shorter, the repetitive unit is 69 amino acids in length, which is three times longer than the human. The amino acid composition shows very little similarity to the human motif, which potentially contributes to differences in the innate immune response between species, as glycosylation across this rapidly evolving domain provides much of the musical barrier. Future studies of the function of MUC2 in the innate immune response system in chicken could provide an important model organism to increase our understanding of the biological significance of MUC2 in host defense and highlight the potential of the chicken for creating new immune-based therapies. PMID- 23349744 TI - Phase contrast imaging reveals low lung volumes and surface areas in the developing marsupial. AB - Marsupials are born with immature lungs when compared to eutherian mammals and rely, to various extents, on cutaneous gas exchange in order to meet metabolic requirements. Indeed, the fat-tailed dunnart is born with lungs in the canalicular stage of development and relies almost entirely on the skin for gas exchange at birth; consequently undergoing the majority of lung development in air. Plane radiographs and computed tomography data sets were acquired using phase contrast imaging with a synchrotron radiation source for two marsupial species, the fat-tailed dunnart and the larger tammar wallaby, during the first weeks of postnatal life. Phase contrast imaging revealed that only two lung sacs contain air after the first hour of life in the fat-tailed dunnart. While the lung of the tammar wallaby was comparatively more developed, both species demonstrated massive increases in air sac number and architectural complexity during the postnatal period. In addition, both the tammar wallaby and fat-tailed dunnart had lower lung volumes and parenchymal surface areas than were expected from morphometrically determined allometric equations relating these variables to body mass during the neonatal period. However, lung volume is predicted to scale with mass as expected after the neonatal marsupial reaches a body mass of ~1 g and no longer relies on the skin for gas exchange. Decreased lung volume in the marsupial neonate further supports the maxim that cutaneous gas exchange occurs in the marsupial neonate because the respiratory apparatus is not yet capable of meeting the gas exchange requirements of the newborn. PMID- 23349745 TI - Female sex workers, male circumcision and HIV: a qualitative study of their understanding, experience, and HIV risk in Zambia. AB - Several sub-Saharan African countries, including Zambia, have initiated national voluntary medical male circumcision (MC) programs to reduce HIV incidence. In depth interviews were conducted with twenty female sex workers (FSWs) in Lusaka to examine their understanding of MC and experiences with circumcised clients. Knowledge of MC was derived primarily through informal sources, with very few FSWs reporting exposure to MC educational campaigns. MC was not widely believed to be protective against HIV, however it was viewed by some as protective against STIs. Three FSWs reported having sex with recently circumcised clients, and most reported that men often used their MC status to try to convince FSWs to forego condoms. Findings suggest that FSWs, already at high risk for HIV infection, may face additional pressure toward higher risk behavior as a result of MC. As MC services are expanded, programs should support FSWs' efforts to protect themselves by providing information about what MC can--and cannot--offer for HIV/STI infection prevention. PMID- 23349746 TI - Biologically inspired information processing and synchronization in ensembles of non-identical threshold-potential nanostructures. AB - Nanotechnology produces basic structures that show a significant variability in their individual physical properties. This experimental fact may constitute a serious limitation for most applications requiring nominally identical building blocks. On the other hand, biological diversity is found in most natural systems. We show that reliable information processing can be achieved with heterogeneous groups of non-identical nanostructures by using some conceptual schemes characteristic of biological networks (diversity, frequency-based signal processing, rate and rank order coding, and synchronization). To this end, we simulate the integrated response of an ensemble of single-electron transistors (SET) whose individual threshold potentials show a high variability. A particular experimental realization of a SET is a metal nanoparticle-based transistor that mimics biological spiking synapses and can be modeled as an integrate-and-fire oscillator. The different shape and size distributions of nanoparticles inherent to the nanoscale fabrication procedures result in a significant variability in the threshold potentials of the SET. The statistical distributions of the nanoparticle physical parameters are characterized by experimental average and distribution width values. We consider simple but general information processing schemes to draw conclusions that should be of relevance for other threshold-based nanostructures. Monte Carlo simulations show that ensembles of non-identical SET may show some advantages over ensembles of identical nanostructures concerning the processing of weak signals. The results obtained are also relevant for understanding the role of diversity in biophysical networks. PMID- 23349747 TI - Efficient and comprehensive representation of uniqueness for next-generation sequencing by minimum unique length analyses. AB - As next generation sequencing technologies are getting more efficient and less expensive, RNA-Seq is becoming a widely used technique for transcriptome studies. Computational analysis of RNA-Seq data often starts with the mapping of millions of short reads back to the genome or transcriptome, a process in which some reads are found to map equally well to multiple genomic locations (multimapping reads). We have developed the Minimum Unique Length Tool (MULTo), a framework for efficient and comprehensive representation of mappability information, through identification of the shortest possible length required for each genomic coordinate to become unique in the genome and transcriptome. Using the minimum unique length information, we have compared different uniqueness compensation approaches for transcript expression level quantification and demonstrate that the best compensation is achieved by discarding multimapping reads and correctly adjusting gene model lengths. We have also explored uniqueness within specific regions of the mouse genome and enhancer mapping experiments. Finally, by making MULTo available to the community we hope to facilitate the use of uniqueness compensation in RNA-Seq analysis and to eliminate the need to make additional mappability files. PMID- 23349748 TI - A common neurodynamical mechanism could mediate externally induced and intrinsically generated transitions in visual awareness. AB - The neural correlates of conscious visual perception are commonly studied in paradigms of perceptual multistability that allow multiple perceptual interpretations during unchanged sensory stimulation. What is the source of this multistability in the content of perception? From a theoretical perspective, a fine balance between deterministic and stochastic forces has been suggested to underlie the spontaneous, intrinsically driven perceptual transitions observed during multistable perception. Deterministic forces are represented by adaptation of feature-selective neuronal populations encoding the competing percepts while stochastic forces are modeled as noise-driven processes. Here, we used a unified neuronal competition model to study the dynamics of adaptation and noise processes in binocular flash suppression (BFS), a form of externally induced perceptual suppression, and compare it with the dynamics of intrinsically driven alternations in binocular rivalry (BR). For the first time, we use electrophysiological, biologically relevant data to constrain a model of perceptual rivalry. Specifically, we show that the mean population discharge pattern of a perceptually modulated neuronal population detected in electrophysiological recordings in the lateral prefrontal cortex (LPFC) during BFS, constrains the dynamical range of externally induced perceptual transitions to a region around the bifurcation separating a noise-driven attractor regime from an adaptation-driven oscillatory regime. Most interestingly, the dynamical range of intrinsically driven perceptual transitions during BR is located in the noise-driven attractor regime, where it overlaps with BFS. Our results suggest that the neurodynamical mechanisms of externally induced and spontaneously generated perceptual alternations overlap in a narrow, noise-driven region just before a bifurcation where the system becomes adaptation-driven. PMID- 23349749 TI - Gene regulation of iron-deficiency responses is associated with carbon monoxide and heme oxydase 1 in Chlamydomonas reinhardtii. AB - Carbon monoxide (CO) as an endogenous gaseous molecule regulates a variety of biological processes in animals. However, CO regulating nutrient stress responses in green alga is largely unknown. On the other hand, heme oxydase (HO1 as a rate limiting enzyme of the first step for heme degration and to catalyze heme into biliverdin (BV), which is concomitant with releasing of CO and ferrous ions, probably participates in the process of CO-regulating response to nutrient stress in green alga. In this paper, we described an observation that CO could regulate iron-homeostasis in iron-starving Chlamydomonas reinhardtii. Exogenous CO at 8 uM was able to prevent the iron deficient-inducing chlorosis and improve chlorophyll accumulation. Expression pattern of FOX1, FTR1 and ferredoxin was up-regulated by CO exposure in iron-deficient mediam. treatment with external CO increasing iron accumulation in iron-deficient C. reinhardtii. Moreover, to get insights into the regulatory role of HO1, we constructed a transgenic alga overexpressing HO1 and HO1 knock-out mutants. The results show that there was no significant influence on chlorosis with HO1 overexpression of C. reinhardtii under iron-deficiency and the chlorophyll accumulation, and gene expression associated with iron deficiency of mutant were greatly improved. Otherwise, those results from HO1 knock-out mutants were opposite to HO1 overexpression mutants. Finally, CO exposure induced NO accumulation in cells. However, such an action could be blocked by NO scavenger cPTIO. These results indicate that CO/HO1 may play an important role in improving green algae adaptation to iron deficiency or cross-talking with NO under the iron deficiency. PMID- 23349751 TI - The effect of the small Indian mongoose (Urva auropunctatus), island quality and habitat on the distribution of native and endemic birds on small islands within Fiji. AB - This study investigated the effect of the presence of introduced mongoose, environmental quality and habitat on the distribution of native and endemic birds on 16 small islands within Fiji. In total, 9055 birds representing 45 species were observed within four key habitats (forest, villages, crop land and coastal vegetation) on the 16 islands, half of which had mongoose present. Previous studies attribute bird declines and extirpation anecdotally to the mongoose. The presence of mongoose, environmental quality and habitat type had a measurable influence on observed extant native and endemic bird communities. We conclude that three ground birds; Gallirallus phillipensis, Anas supericiliosa and Porphyrio porhyrio were negatively influenced by the presence of mongoose and that Ptilinopus perousii, Phigys solitarius, Chrysoenas victor, Ducula latrans, Clytorhyrchus vitiensis, Pachycephala pectoralis, Prospeia tabunesis, and Foulehaio carunculata were particularly dependent on good quality forest habitat. Conservation priorities in relation to protecting Fiji's endemic birds from the effect of mongoose are discussed and preventative measures suggested. PMID- 23349750 TI - Distinct distal gut microbiome diversity and composition in healthy children from Bangladesh and the United States. AB - BACKGROUND: Our current understanding of the composition and stability of the human distal gut microbiota is based largely on studies of infants and adults living in developed countries. In contrast, little is known about the gut microbiota and its variation over time in older children and adolescents, especially in developing countries. METHODOLOGY/PRINCIPAL FINDINGS: We compared the diversity, composition, and temporal stability of the fecal microbiota of healthy children, ages 9 to 14 years, living in an urban slum in Bangladesh with that of children of the same age range in an upper-middle class suburban community in the United States. We analyzed >8,000 near full-length 16S rRNA gene sequences and over 845,000 pyrosequencing reads of the 16S rRNA V1-V3 region. The distal gut of Bangladeshi children harbored significantly greater bacterial diversity than that of U.S. children, including novel lineages from several bacterial phyla. Bangladeshi and U.S. children had distinct fecal bacterial community membership and structure; the microbiota of Bangladeshi children was enriched in Prevotella, Butyrivibrio, and Oscillospira and depleted in Bacteroides relative to U.S. children (although similar to Bangladeshi adults). Furthermore, community membership and structure in Bangladeshi children was significantly less stable month-to-month than U.S. children. CONCLUSIONS/SIGNIFICANCE: Together, these results suggest that differing environmental or genetic factors may shape the microbiota of healthy children in the two countries. Further investigation is necessary to understand the mechanisms and factors that underlie these differences, and to incorporate these findings into new strategies for the prevention and treatment of childhood and adolescent diseases. PMID- 23349752 TI - Categories of auditory performance and speech intelligibility ratings of early implanted children without speech training. AB - OBJECTIVE: To assess whether speech therapy can lead to better results for early cochlear implantation (CI) children. PATIENTS: A cohort of thirty-four congenitally profoundly deaf children who underwent CI before the age of 18 months at the Sixth Hospital affiliated with Shanghai Jiaotong University from January 2005 to July 2008 were included. Nineteen children received speech therapy in rehabilitation centers (ST), whereas the remaining fifteen cases did not (NST), but were exposed to the real world, as are normal hearing children. METHODS: All children were assessed before surgery and at 6, 12, and 24 months after surgery with the Categories of Auditory Performance test (CAP) and the Speech Intelligibility Rating (SIR). Each assessment was given by the same therapist who was blind to the situation of the child at each observation interval. CAP and SIR scores of the groups were compared at each time point. RESULTS: Our study showed that the auditory performance and speech intelligibility of trained children were almost the same as to those of untrained children with early implantation. The CAP and SIR scores of both groups increased with increased time of implant use during the follow-up period, and at each time point, the median scores of the two groups were about equal. CONCLUSIONS: These results indicate that great communication benefits are achieved by early implantation (<18 months) without routine speech therapy. The results exemplify the importance of enhanced social environments provided by everyday life experience for human brain development and reassure parents considering cochlear implants where speech training is unavailable. PMID- 23349753 TI - Effects of stresscopin on rat hypothalamic paraventricular nucleus neurons in vitro. AB - The effects of stresscopin (SCP) on rat paraventricular nucleus (PVN) neurons were examined using whole-cell patch-clamp recordings and single-cell reverse transcription multiplex polymerase chain reaction (SC-RT-mPCR) techniques. Under current-clamp conditions, bath application of SCP (100 nM) induced inhibition in 35.2% (37/105) of putative magnocellular neurons and 24.7% (20/81) of putative parvocellular neurons, and excitation in 5.7% (6/105) of putative magnocellular neurons and 18.5% (15/81) of putative parvocellular neurons. SCP-induced inhibition persisted in the presence of a mixture of TTX, a voltage-gated Na+ channel blocker, CNQX, an AMPA/kainate receptor antagonist and bicuculline, a GABA(A) receptor antagonist, whereas SCP-induced excitation of PVN neurons was reversed by the mixture. The SCP-induced inhibition of PVN neurons was abolished by bath application of antisauvagine-30, a selective CRF receptor 2 (CRF-R2) antagonist. Under voltage-clamp conditions, SCP evoked outward currents at the holding potential (-60 mV), which reversed near the potassium equilibrium potential. The SCP-evoked membrane currents were completely blocked by bath application of tertiapin-Q, a selective blocker of G protein-activated inwardly rectifying potassium (GIRK) channels. SC-RT-mPCR analysis indicated that all the SCP-sensitive PVN neurons (57 SCP-inhibited neurons, 21 SCP-excited neurons) expressed CRF-R1 and CRF-R2 mRNAs. Among SCP-hyperpolarized PVN neurons, oxytocin (OT) mRNA was detected in 91.8% of putative magnocellular neurons and 45.0% of putative parvocellular neurons. OT mRNA was also detected in 26.6% of SCP depolarized parvocellular neurons, but not in SCP-depolarized magnocellular neurons. These results indicate that SCP inhibits a subpopulation of PVN neurons, especially OTergic magnocellular neurons, by enhancing the activity of GIRK channels via CRF-R2. PMID- 23349754 TI - Impact of rotavirus vaccination on hospitalisations in Belgium: comparing model predictions with observed data. AB - BACKGROUND: Published economic assessments of rotavirus vaccination typically use modelling, mainly static Markov cohort models with birth cohorts followed up to the age of 5 years. Rotavirus vaccination has now been available for several years in some countries, and data have been collected to evaluate the real-world impact of vaccination on rotavirus hospitalisations. This study compared the economic impact of vaccination between model estimates and observed data on disease-specific hospitalisation reductions in a country for which both modelled and observed datasets exist (Belgium). METHODS: A previously published Markov cohort model estimated the impact of rotavirus vaccination on the number of rotavirus hospitalisations in children aged <5 years in Belgium using vaccine efficacy data from clinical development trials. Data on the number of rotavirus positive gastroenteritis hospitalisations in children aged <5 years between 1 June 2004 and 31 May 2006 (pre-vaccination study period) or 1 June 2007 to 31 May 2010 (post-vaccination study period) were analysed from nine hospitals in Belgium and compared with the modelled estimates. RESULTS: The model predicted a smaller decrease in hospitalisations over time, mainly explained by two factors. First, the observed data indicated indirect vaccine protection in children too old or too young for vaccination. This herd effect is difficult to capture in static Markov cohort models and therefore was not included in the model. Second, the model included a 'waning' effect, i.e. reduced vaccine effectiveness over time. The observed data suggested this waning effect did not occur during that period, and so the model systematically underestimated vaccine effectiveness during the first 4 years after vaccine implementation. CONCLUSIONS: Model predictions underestimated the direct medical economic value of rotavirus vaccination during the first 4 years of vaccination by approximately 10% when assessing hospitalisation rates as compared with observed data in Belgium. PMID- 23349755 TI - A clinical evaluation of statin pleiotropy: statins selectively and dose dependently reduce vascular inflammation. AB - Statins are thought to reduce vascular inflammation through lipid independent mechanisms. Evaluation of such an effect in atherosclerotic disease is complicated by simultaneous effects on lipid metabolism. Abdominal aortic aneurysms (AAA) are part of the atherosclerotic spectrum of diseases. Unlike atherosclerotic occlusive disease, AAA is not lipid driven, thus allowing direct evaluation of putative anti-inflammatory effects. The anti-inflammatory potency of increasing doses (0, 20 or 40 mg/day) simvastatin or atorvastatin was evaluated in 63 patients that were at least 6 weeks on statin therapy and who underwent open AAA repair. A comprehensive analysis using immunohistochemistry, mRNA and protein analyses was applied on aortic wall samples collected during surgery. The effect of statins on AAA growth was analyzed in a separate prospective study in incorporating 142 patients. Both statins equally effectively and dose-dependently reduced aortic wall expression of NFkappaB regulated mediators (i.e. IL-6 (P<0.001) and MCP-1 (P<0.001)); shifted macrophage polarization towards a M2 phenotype (P<0.0003); selectively reduced macrophage related markers such as cathepsin K and S (P<0.009 and 0.0027 respectively), and ALOX5 (P<0.0009), and reduced vascular wall NFkappaB activity (40 mg/day group, P<0.016). No effect was found on other cell types. Evaluation of the clinical efficacy of statins to reduce AAA progression did not indicate an effect of statins on aneurysm growth (P<0.337). Hence, in the context of AAA the clinical relevance of statins pleiotropy appears minimal. PMID- 23349756 TI - The predisposition, infection, response and organ failure (Piro) sepsis classification system: results of hospital mortality using a novel concept and methodological approach. AB - INTRODUCTION: PIRO is a conceptual classification system in which a number of demographic, clinical, biological and laboratory variables are used to stratify patients with sepsis in categories with different outcomes, including mortality rates. OBJECTIVES: To identify variables to be included in each component of PIRO aiming to improve the hospital mortality prediction. METHODS: Patients were selected from the Portuguese ICU-admitted community-acquired sepsis study (SACiUCI). Variables concerning the R and O component included repeated measurements along the first five days in ICU stay. The trends of these variables were summarized as the initial value at day 1 (D1) and the slope of the tendency during the five days, using a linear mixed model. Logistic regression models were built to assess the best set of covariates that predicted hospital mortality. RESULTS: A total of 891 patients (age 60+/-17 years, 64% men, 38% hospital mortality) were studied. Factors significantly associated with mortality for P component were gender, age, chronic liver failure, chronic renal failure and metastatic cancer; for I component were positive blood cultures, guideline concordant antibiotic therapy and health-care associated sepsis; for R component were C-reactive protein slope, D1 heart rate, heart rate slope, D1 neutrophils and neutrophils slope; for O component were D1 serum lactate, serum lactate slope, D1 SOFA and SOFA slope. The relative weight of each component of PIRO was calculated. The combination of these four results into a single-value predictor of hospital mortality presented an AUC-ROC 0.84 (IC(95%):0.81-0.87) and a test of goodness-of-fit (Hosmer and Lemeshow) of p = 0.368. CONCLUSIONS: We identified specific variables associated with each of the four components of PIRO, including biomarkers and a dynamic view of the patient daily clinical course. This novel approach to PIRO concept and overall score can be a better predictor of mortality for patients with community-acquired sepsis admitted to ICUs. PMID- 23349757 TI - Development and validation of a questionnaire assessing fears and beliefs of patients with knee osteoarthritis: the Knee Osteoarthritis Fears and Beliefs Questionnaire (KOFBeQ). AB - OBJECTIVE: We aimed to develop a questionnaire assessing fears and beliefs of patients with knee OA. DESIGN: We sent a detailed document reporting on a qualitative analysis of interviews of patients with knee OA to experts, and a Delphi procedure was adopted for item generation. Then, 80 physicians recruited 566 patients with knee OA to test the provisional questionnaire. Items were reduced according to their metric properties and exploratory factor analysis. Reliability was tested by the Cronbach alpha coefficient. Construct validity was tested by divergent validity and confirmatory factor analysis. Test-retest reliability was assessed by the intra-class correlation coefficient (ICC) and the Bland and Altman technique. RESULTS: 137 items were extracted from analysis of the interview data. Three Delphi rounds were needed to obtain consensus on a 25 item provisional questionnaire. The item-reduction process resulted in an 11-item questionnaire. Selected items represented fears and beliefs about daily living activities (3 items), fears and beliefs about physicians (4 items), fears and beliefs about the disease (2 items), and fears and beliefs about sports and leisure activities (2 items). The Cronbach alpha coefficient of global score was 0.85. We observed expected divergent validity. Confirmation factor analyses confirmed higher intra-factor than inter-factor correlations. Test-retest reliability was good, with an ICC of 0.81, and Bland and Altman analysis did not reveal a systematic trend. CONCLUSIONS: We propose an 11-item questionnaire assessing patients' fears and beliefs concerning knee OA with good content and construct validity. PMID- 23349758 TI - When the seasons don't fit: speedy molt as a routine carry-over cost of reproduction. AB - The failure of animals to fit all life-cycle stages into an annual cycle could reduce the chances of successful breeding. In some cases, non-optimal strategies will be adopted in order to maintain the life-cycle within the scope of one year. We studied trade-offs made by a High Arctic migrant shorebird, the red knot Calidris canutus islandica, between reproduction and wing feather molt carried out in the non-breeding period in the Dutch Wadden Sea. We compared primary molt duration between birds undertaking the full migratory and breeding schedule with birds that forego breeding because they are young or are maintained in captivity. Molt duration was ca. 71 days in breeding adults, which was achieved by an accelerated feather replacement strategy. Second-year birds and captive adults took ca. 22% and 27% longer, respectively. Second-year birds start molt in late June, more than four weeks before captive adults, and almost seven weeks before adults that return from breeding in late July-August. Adults finish molt in October when steeply increasing thermostatic costs and reductions in food availability occur. Primary molt duration was longer in female than in male knots (all ages), which was accordance with the somewhat larger body size of females. Since fast growth leads to lower quality feathers, the speedy wing molt shown by Arctic-breeding birds may represent a time constraint that is an unavoidable and routine cost of reproduction. So far it was hypothesized that only birds over 1 kg would have difficulty fitting molt within a year. Here we show that in birds an order of magnitude smaller, temporal imperatives may impose the adoption of non-optimal life-cycle routines in the entire actively breeding population. PMID- 23349759 TI - Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation. AB - CONTEXT: KISS1R mutations have been reported in few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). OBJECTIVE: To describe in detail nCHH patients with biallelic KISS1R mutations belonging to 2 unrelated families, and to functionally characterize a novel KISS1R mutation. RESULTS: An original mutant, p.Tyr313His, was found in the homozygous state in 3 affected kindred (2 females and 1 male) from a consanguineous Portuguese family. This mutation, located in the seventh transmembrane domain, affects a highly conserved amino acid, perturbs the conformation of the transmembrane segment, and impairs MAP kinase signaling and intracellular calcium release. In the second family, a French Caucasian male patient with nCHH was found to carry two recurrent mutations in the compound heterozygous state (p.Leu102Pro/Stop399Arg). In this man, pulsatile GnRH (Gonadotropin Releasing Hormone) administration restored pulsatile LH (Luteinizing Hormone) secretion and testicular hormone secretion. Later, long-term combined gonadotropin therapy induced spermatogenesis, enabling 3 successive pregnancies that resulted in 2 miscarriages and the birth of a healthy boy. CONCLUSION: We show that a novel loss-of-function mutation (p.Tyr313His) in the KISS1R gene can cause familial nCHH, revealing the crucial role of this amino acid in KISS1R function. The observed restoration of gonadotropin secretion by exogenous GnRH administration further supports, in humans, the hypothalamic origin of the gonadotropin deficiency in this genetic form of nCHH. PMID- 23349760 TI - Modelling BMI trajectories in children for genetic association studies. AB - BACKGROUND: The timing of associations between common genetic variants and changes in growth patterns over childhood may provide insight into the development of obesity in later life. To address this question, it is important to define appropriate statistical models to allow for the detection of genetic effects influencing longitudinal childhood growth. METHODS AND RESULTS: Children from The Western Australian Pregnancy Cohort (Raine; n=1,506) Study were genotyped at 17 genetic loci shown to be associated with childhood obesity (FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, SEC16B, LYPLAL1, TFAP2B, MTCH2, BCDIN3D, NRXN3, SH2B1, MRSA) and an obesity-risk-allele-score was calculated as the total number of 'risk alleles' possessed by each individual. To determine the statistical method that fits these data and has the ability to detect genetic differences in BMI growth profile, four methods were investigated: linear mixed effects model, linear mixed effects model with skew-t random errors, semi parametric linear mixed models and a non-linear mixed effects model. Of the four methods, the semi-parametric linear mixed model method was the most efficient for modelling childhood growth to detect modest genetic effects in this cohort. Using this method, three of the 17 loci were significantly associated with BMI intercept or trajectory in females and four in males. Additionally, the obesity risk-allele score was associated with increased average BMI (female: beta=0.0049, P=0.0181; male: beta=0.0071, P=0.0001) and rate of growth (female: beta=0.0012, P=0.0006; male: beta=0.0008, P=0.0068) throughout childhood. CONCLUSIONS: Using statistical models appropriate to detect genetic variants, variations in adult obesity genes were associated with childhood growth. There were also differences between males and females. This study provides evidence of genetic effects that may identify individuals early in life that are more likely to rapidly increase their BMI through childhood, which provides some insight into the biology of childhood growth. PMID- 23349761 TI - Microplate-test for the rapid determination of bacteriophage-susceptibility of Campylobacter isolates-development and validation. AB - A simple susceptibility test using 800 isolates of one Campylobacter strain with different degrees of susceptibility and four bacteriophages of the British phage typing scheme was developed and examined for its suitability. The test presented is economically cheaper and less time consuming than the conventional agar overlay plate assay and therefore enables the monitoring of changes in the susceptibility pattern during phage therapy under practical field conditions. The main objective of this study was to compare the simplified test with the conventional agar overlay plate assay. The conventional test describes for a population of Campylobacter: i. the rate of resistant isolates (0 plaques) and ii. the degree of susceptibility, also called relative efficiency of plating (EOP), for the remaining isolates. The simplified test divides the isolates into four susceptibility ranks, which are easily distinguishable to the naked eye. Ten Campylobacter isolates out of each rank were subjected to the conventional method for validation of the simplified test. Each resistance rank contained isolates showing certain degrees of susceptibility, reflecting decreasing susceptibility by an increase of the rank. Thus, the simplified test correlated well with the conventional method. Nevertheless, it can be suggested for a clear cut to summarise the first thee ranks as "high susceptible" and to mark out the fourth rank as reduced susceptible. Further test improvements will enable the monitoring of the degree of susceptibility and potentially also of resistance during phage therapy in the field. To ensure a long-lasting successful use of phage therapy, further studies on both the loss of susceptibility and the development of resistance of Campylobacter against phages combined with their impact on phage therapy will be necessary. PMID- 23349762 TI - STK295900, a dual inhibitor of topoisomerase 1 and 2, induces G(2) arrest in the absence of DNA damage. AB - STK295900, a small synthetic molecule belonging to a class of symmetric bibenzimidazoles, exhibits antiproliferative activity against various human cancer cell lines from different origins. Examining the effect of STK295900 in HeLa cells indicates that it induces G(2) phase arrest without invoking DNA damage. Further analysis shows that STK295900 inhibits DNA relaxation that is mediated by topoisomerase 1 (Top 1) and topoisomerase 2 (Top 2) in vitro. In addition, STK295900 also exhibits protective effect against DNA damage induced by camptothecin. However, STK295900 does not affect etoposide-induced DNA damage. Moreover, STK295900 preferentially exerts cytotoxic effect on cancer cell lines while camptothecin, etoposide, and Hoechst 33342 affected both cancer and normal cells. Therefore, STK295900 has a potential to be developed as an anticancer chemotherapeutic agent. PMID- 23349763 TI - The multifaceted effects of agmatine on functional recovery after spinal cord injury through Modulations of BMP-2/4/7 expressions in neurons and glial cells. AB - Presently, few treatments for spinal cord injury (SCI) are available and none have facilitated neural regeneration and/or significant functional improvement. Agmatine (Agm), a guanidinium compound formed from decarboxylation of L-arginine by arginine decarboxylase, is a neurotransmitter/neuromodulator and been reported to exert neuroprotective effects in central nervous system injury models including SCI. The purpose of this study was to demonstrate the multifaceted effects of Agm on functional recovery and remyelinating events following SCI. Compression SCI in mice was produced by placing a 15 g/mm(2) weight for 1 min at thoracic vertebra (Th) 9 segment. Mice that received an intraperitoneal (i.p.) injection of Agm (100 mg/kg/day) within 1 hour after SCI until 35 days showed improvement in locomotor recovery and bladder function. Emphasis was made on the analysis of remyelination events, neuronal cell preservation and ablation of glial scar area following SCI. Agm treatment significantly inhibited the demyelination events, neuronal loss and glial scar around the lesion site. In light of recent findings that expressions of bone morphogenetic proteins (BMPs) are modulated in the neuronal and glial cell population after SCI, we hypothesized whether Agm could modulate BMP- 2/4/7 expressions in neurons, astrocytes, oligodendrocytes and play key role in promoting the neuronal and glial cell survival in the injured spinal cord. The results from computer assisted stereological toolbox analysis (CAST) demonstrate that Agm treatment dramatically increased BMP- 2/7 expressions in neurons and oligodendrocytes. On the other hand, BMP- 4 expressions were significantly decreased in astrocytes and oligodendrocytes around the lesion site. Together, our results reveal that Agm treatment improved neurological and histological outcomes, induced oligodendrogenesis, protected neurons, and decreased glial scar formation through modulating the BMP- 2/4/7 expressions following SCI. PMID- 23349764 TI - Obesity and risk of colorectal cancer: a systematic review of prospective studies. AB - BACKGROUND: Mounting evidence indicates that obesity may be associated with the risk of colorectal cancer (CRC). To conduct a systematic review of prospective studies assessing the association of obesity with the risk of CRC using meta analysis. METHODOLOGY/PRINCIPAL FINDINGS: Relevant studies were identified by a search of MEDLINE and EMBASE databases before January 2012, with no restrictions. We also reviewed reference lists from retrieved articles. We included prospective studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the association between general obesity [measured using body mass index (BMI)] or central obesity [measured using waist circumference (WC)] and the risk of colorectal, colon, or rectal cancer. Approximately 9, 000, 000 participants from several countries were included in this analysis. 41 studies on general obesity and 13 studies on central obesity were included in the meta-analysis. The pooled RRs of CRC for the obese vs. normal category of BMI were 1.334 (95% CI, 1.253-1.420), and the highest vs. lowest category of WC were 1.455 (95% CI, 1.327 1.596). There was heterogeneity among studies of BMI (P<0.001) but not among studies of WC (P=0.323). CONCLUSIONS: Both of general and central obesity were positively associated with the risk of CRC in this meta-analysis. PMID- 23349765 TI - Antigenic proteins involved in occupational rhinitis and asthma caused by obeche wood (Triplochiton scleroxylon). AB - BACKGROUND: Obeche wood dust is a known cause of occupational asthma where an IgE mediated mechanism has been demonstrated. OBJECTIVE: To characterize the allergenic profile of obeche wood dust and evaluate the reactivity of the proteins by in vitro, ex vivo and in vivo assays in carpenters with confirmed rhinitis and/or asthma MATERIALS AND METHODS: An in-house obeche extract was obtained, and two IgE binding bands were purified (24 and 12 kDa) and sequenced by N-terminal identity. Specific IgE and IgG, basophil activation tests and skin prick tests (SPTs) were performed with whole extract and purified proteins. CCD binding was analyzed by ELISA inhibition studies. RESULTS: Sixty-two subjects participated: 12 with confirmed occupational asthma/rhinitis (ORA+), 40 asymptomatic exposed (ORA-), and 10 controls. Of the confirmed subjects, 83% had a positive SPT to obeche. There was a 100% recognition by ELISA in symptomatic subjects vs. 30% and 10% in asymptomatic exposed subjects and controls respectively (p<0.05). Two new proteins were purified, a 24 kDa protein identified as a putative thaumatin-like protein and a 12 kDa gamma-expansin. Both showed allergenic activity in vitro, with the putative thaumatin being the most active, with 92% recognition by ELISA and 100% by basophil activation test in ORA+ subjects. Cross-reactivity due to CCD was ruled out in 82% of cases. CONCLUSIONS: Two proteins of obeche wood were identified and were recognized by a high percentage of symptomatic subjects and by a small proportion of asymptomatic exposed subjects. Further studies are required to evaluate cross reactivity with other plant allergens. PMID- 23349766 TI - Improved discovery of molecular interactions in genome-scale data with adaptive model-based normalization. AB - BACKGROUND: High throughput molecular-interaction studies using immunoprecipitations (IP) or affinity purifications are powerful and widely used in biology research. One of many important applications of this method is to identify the set of RNAs that interact with a particular RNA-binding protein (RBP). Here, the unique statistical challenge presented is to delineate a specific set of RNAs that are enriched in one sample relative to another, typically a specific IP compared to a non-specific control to model background. The choice of normalization procedure critically impacts the number of RNAs that will be identified as interacting with an RBP at a given significance threshold - yet existing normalization methods make assumptions that are often fundamentally inaccurate when applied to IP enrichment data. METHODS: In this paper, we present a new normalization methodology that is specifically designed for identifying enriched RNA or DNA sequences in an IP. The normalization (called adaptive or AD normalization) uses a basic model of the IP experiment and is not a variant of mean, quantile, or other methodology previously proposed. The approach is evaluated statistically and tested with simulated and empirical data. RESULTS AND CONCLUSIONS: The adaptive (AD) normalization method results in a greatly increased range in the number of enriched RNAs identified, fewer false positives, and overall better concordance with independent biological evidence, for the RBPs we analyzed, compared to median normalization. The approach is also applicable to the study of pairwise RNA, DNA and protein interactions such as the analysis of transcription factors via chromatin immunoprecipitation (ChIP) or any other experiments where samples from two conditions, one of which contains an enriched subset of the other, are studied. PMID- 23349767 TI - Promoter hypermethylation of ARID1A gene is responsible for its low mRNA expression in many invasive breast cancers. AB - ARID1A (AT-rich interactive domain 1A) has recently been identified as a tumor suppressor gene. Its mRNA expression is significantly low in many breast cancers; this is often associated with more aggressive phenotypes. However, the underlying molecular mechanism for its low expression has not been fully understood. This study was undertaken to evaluate the contribution of gene copy number variation, mutations, promoter methylation and histone modification to ARID1A's low expression. 38 pairs of breast invasive ductal carcinomas and their normal breast tissue counterparts from the same patients were randomly selected for gene expression and copy number variation detection. Promoter methylation and histone modification levels were evaluated by MeDIP-qPCR and ChIP-qPCR, respectively. PCR product Sanger sequencing was carried out to detect the exon mutation rate. Twenty-two out of 38 invasive ductal carcinomas in the study (57.9%) revealed ARID1A mRNA low expression by realtime RT-PCR. The relative promoter methylation level was, significantly higher in ARID1A mRNA low expression group compared with its high expression group (p<0.001). In the low expression group, nineteen out of 22 invasive ductal carcinomas (86.4%) exhibited ARID1A promoter hypermthylation. In addition, the promoter hypermethylation was accompanied with repressive histone modification (H3K27Me3). Although five out of 38 invasive ductal carcinomas (13.2%) exhibited loss of ARID1A gene copy number by realtime PCR and nine exon novel mutations are seen from eight out of 33 invasive ductal carcinomas (24.2%), there was no statistically significant difference in both ARID1A mRNA low and high expression groups (p=0.25,and p=0.68, respectively). We demonstrate that promoter hypermethylation was the main culprit for ARID1A mRNA low expression in invasive ductal carcinomas. The influence of mutation and copy number variation on the expression were statistically insignificant at mRNA level, and were, therefore, not considered the main causes for ARID1A mRNA low expression in invasive breast cancer. PMID- 23349768 TI - Evaluation of a novel non-destructive catch and release technology for harvesting autologous adult stem cells. AB - BACKGROUND: Cell based therapies are required now to meet the critical care needs of paediatrics and healthy ageing in an increasingly long-lived human population. Repair of compromised tissue by supporting autologous regeneration is a life changing objective uniting the fields of medical science and engineering. Adipose stem cells (adSCs) are a compelling candidate for use in cell based medicine due to their plasticity and residence in numerous tissues. Adipose found in all animals contains a relatively high concentration of stem cells and is easily isolated by a minimally invasive clinical intervention; such as liposuction. METHODS: This study utilised primary rat adipose to validate a novel strategy for selecting adult stem cells. Experiments explored the use of large, very dense cell-specific antibody loaded isolation beads (diameter 5x-10x greater than target cells) which overcome the problem of endocytosis and have proved to be very effective in cell isolation from minimally processed primary tissue. The technique also benefited from pH mediated release, which enabled elution of captured cells using a simple pH shift. RESULTS: Large beads successfully captured and released adSCs from rat adipose, which were characterised using a combination of microscopy, flow cytometry and PCR. The resultant purified cell population retains minimal capture artefact facilitating autologous reperfusion or application in in vitro models. CONCLUSION: Although evidenced here for adSCs, this approach provides a technological advance at a platform level; whereby it can be applied to isolate any cell population for which there is a characterised surface antigen. PMID- 23349769 TI - Glucocorticoid repression of inflammatory gene expression shows differential responsiveness by transactivation- and transrepression-dependent mechanisms. AB - Binding of glucocorticoid to the glucocorticoid receptor (GR/NR3C1) may repress inflammatory gene transcription via direct, protein synthesis-independent processes (transrepression), or by activating transcription (transactivation) of multiple anti-inflammatory/repressive factors. Using human pulmonary A549 cells, we showed that 34 out of 39 IL-1beta-inducible mRNAs were repressed to varying degrees by the synthetic glucocorticoid, dexamethasone. Whilst these repressive effects were GR-dependent, they did not correlate with either the magnitude of IL 1beta-inducibility or the NF-kappaB-dependence of the inflammatory genes. This suggests that induction by IL-1beta and repression by dexamethasone are independent events. Roles for transactivation were investigated using the protein synthesis inhibitor, cycloheximide. However, cycloheximide reduced the IL-1beta dependent expression of 13 mRNAs, which, along with the 5 not showing repression by dexamethasone, were not analysed further. Of the remaining 21 inflammatory mRNAs, cycloheximide significantly attenuated the dexamethasone-dependent repression of 11 mRNAs that also showed a marked time-dependence to their repression. Such effects are consistent with repression occurring via the de novo synthesis of a new product, or products, which subsequently cause repression (i.e., repression via a transactivation mechanism). Conversely, 10 mRNAs showed completely cycloheximide-independent, and time-independent, repression by dexamethasone. This is consistent with direct GR transrepression. Importantly, the inflammatory mRNAs showing attenuated repression by dexamethasone in the presence of cycloheximide also showed a significantly greater extent of repression and a higher potency to dexamethasone compared to those mRNAs showing cycloheximide-independent repression. This suggests that the repression of inflammatory mRNAs by GR transactivation-dependent mechanisms accounts for the greatest levels of repression and the most potent repression by dexamethasone. In conclusion, our data indicate roles for both transrepression and transactivation in the glucocorticoid-dependent repression of inflammatory gene expression. However, transactivation appears to account for the more potent and efficacious mechanism of repression by glucocorticoids on these IL-1beta-induced genes. PMID- 23349770 TI - De novo transcriptome sequencing and analysis for Venturia inaequalis, the devastating apple scab pathogen. AB - Venturia inaequalis is the causal agent of apple scab, one of the most devastating diseases of apple. Due to several distinct features, it has emerged as a model fungal pathogen to study various aspects of hemibiotrophic plant pathogen interactions. The present study reports de novo assembling, annotation and characterization of the transcriptome of V. inaequalis. Venturia transcripts expressed during its growth on laboratory medium and that expressed during its biotrophic stage of infection on apple were sequenced using Illumina RNAseq technology. A total of 94,350,055 reads (50 bp read length) specific to Venturia were obtained after filtering. The reads were assembled into 62,061 contigs representing 24,571 unique genes. GO analysis suggested prevalence of genes associated with biological process categories like metabolism, transport and response to stimulus. Genes associated with molecular function like binding, catalytic activities and transferase activities were found in majority. EC and KEGG pathway analyses suggested prevalence of genes encoding kinases, proteases, glycoside hydrolases, cutinases, cytochrome P450 and transcription factors. The study has identified several putative pathogenicity determinants and candidate effectors in V. inaequalis. A large number of transcripts encoding membrane transporters were identified and comparative analysis revealed that the number of transporters encoded by Venturia is significantly more as compared to that encoded by several other important plant fungal pathogens. Phylogenomics analysis indicated that V. inaequalis is closely related to Pyrenophora tritici-repentis (the causal organism of tan spot of wheat). In conclusion, the findings from this study provide a better understanding of the biology of the apple scab pathogen and have identified candidate genes/functions required for its pathogenesis. This work lays the foundation for facilitating further research towards understanding this host-pathogen interaction. PMID- 23349771 TI - Association study of 25 type 2 diabetes related Loci with measures of obesity in Indian sib pairs. AB - Obesity is an established risk factor for type 2 diabetes (T2D) and they are metabolically related through the mechanism of insulin resistance. In order to explore how common genetic variants associated with T2D correlate with body mass index (BMI), we examined the influence of 25 T2D associated loci on obesity risk. We used 5056 individuals (2528 sib-pairs) recruited in Indian Migration Study and conducted within sib-pair analysis for six obesity phenotypes. We found associations of variants in CXCR4 (rs932206) and HHEX (rs5015480) with higher body mass index (BMI) (beta=0.13, p=0.001) and (beta=0.09, p=0.002), respectively and weight (beta=0.13, p=0.001) and (beta=0.09, p=0.001), respectively. CXCR4 variant was also strongly associated with body fat (beta=0.10, p=0.0004). In addition, we demonstrated associations of CXCR4 and HHEX with overweight/obesity (OR=1.6, p=0.003) and (OR=1.4, p=0.002), respectively, in 1333 sib-pairs (2666 individuals). We observed marginal evidence of associations between variants at six loci (TCF7L2, NGN3, FOXA2, LOC646279, FLJ39370 and THADA) and waist hip ratio (WHR), BMI and/or overweight which needs to be validated in larger set of samples. All the above findings were independent of daily energy consumption and physical activity level. The risk score estimates based on eight significant loci (including nominal associations) showed associations with WHR and body fat which were independent of BMI. In summary, we establish the role of T2D associated loci in influencing the measures of obesity in Indian population, suggesting common underlying pathophysiology across populations. PMID- 23349772 TI - In vivo facilitated diffusion model. AB - Under dilute in vitro conditions transcription factors rapidly locate their target sequence on DNA by using the facilitated diffusion mechanism. However, whether this strategy of alternating between three-dimensional bulk diffusion and one-dimensional sliding along the DNA contour is still beneficial in the crowded interior of cells is highly disputed. Here we use a simple model for the bacterial genome inside the cell and present a semi-analytical model for the in vivo target search of transcription factors within the facilitated diffusion framework. Without having to resort to extensive simulations we determine the mean search time of a lac repressor in a living E. coli cell by including parameters deduced from experimental measurements. The results agree very well with experimental findings, and thus the facilitated diffusion picture emerges as a quantitative approach to gene regulation in living bacteria cells. Furthermore we see that the search time is not very sensitive to the parameters characterizing the DNA configuration and that the cell seems to operate very close to optimal conditions for target localization. Local searches as implied by the colocalization mechanism are only found to mildly accelerate the mean search time within our model. PMID- 23349773 TI - Nutritional basis for colonization resistance by human commensal Escherichia coli strains HS and Nissle 1917 against E. coli O157:H7 in the mouse intestine. AB - Escherichia coli is a single species consisting of many biotypes, some of which are commensal colonizers of mammals and others that cause disease. Humans are colonized on average with five commensal biotypes, and it is widely thought that the commensals serve as a barrier to infection by pathogens. Previous studies showed that a combination of three pre-colonized commensal E. coli strains prevents colonization of E. coli O157:H7 in a mouse model (Leatham, et al., 2010, Infect Immun 77: 2876-7886). The commensal biotypes included E. coli HS, which is known to successfully colonize humans at high doses with no adverse effects, and E. coli Nissle 1917, a human commensal strain that is used in Europe as a preventative of traveler's diarrhea. We hypothesized that commensal biotypes could exert colonization resistance by consuming nutrients needed by E. coli O157:H7 to colonize, thus preventing this first step in infection. Here we report that to colonize streptomycin-treated mice E. coli HS consumes six of the twelve sugars tested and E. coli Nissle 1917 uses a complementary yet divergent set of seven sugars to colonize, thus establishing a nutritional basis for the ability of E. coli HS and Nissle 1917 to occupy distinct niches in the mouse intestine. Together these two commensals use the five sugars previously determined to be most important for colonization of E. coli EDL933, an O157:H7 strain. As predicted, the two commensals prevented E. coli EDL933 colonization. The results support a model in which invading pathogenic E. coli must compete with the gut microbiota to obtain the nutrients needed to colonize and establish infection; accordingly, the outcome of the challenge is determined by the aggregate capacity of the native microbiota to consume the nutrients required by the pathogen. PMID- 23349774 TI - Extended postinterventional tumor necrosis-implication for outcome in liver transplant patients with advanced HCC. AB - BACKGROUND: Locoregional interventional bridging therapy (IBT) is an accepted neoadjuvant approach in liver transplant candidates with hepatocellular carcinoma (HCC). However, the prognostic value of IBT in patients with advanced HCC is still undefined. AIM: The aim of this trial was to evaluate the impact of postinterventional tumor necrosis on recurrence-free long-term survival after liver transplantation (LT) in patients with HCC, especially focusing on those exceeding the Milan criteria on pretransplant radiographic imaging. PATIENTS AND METHODS: A total of 93 consecutive liver transplant candidates with HCC were included in this trial. In 36 patients, tumors were clinically staged beyond Milan criteria prior LT. Fifty-nine patients underwent IBT by transarterial chemoembolization or radiofrequency ablation pretransplantation. Postinterventional tumor necrosis rate as assessed at liver explant pathology was correlated with outcome post-LT. RESULTS: There was no significant difference in 5-year tumor-free survival rate between the IBT- and the non-IBT subpopulation (78% versus 68%, P=0.25). However, tumor response following IBT (>= 50% tumor necrosis rate at explant pathology) resulted in a significantly better outcome 5 years post-LT (96%) than tumor non-response to IBT (<50% tumor necrosis rate at explant pathology; 21%; P<0.001). Five-year recurrence-free survival rate was 80% in Milan Out patients with extended post-IBT tumor necrosis versus 0% in Milan Out patients without tumor response to IBT (P<0.001). None of macromorphological HCC features, but only the absence of increased (18)F-fluoro-deoxy-glucose ((18)FDG) uptake on pretransplant positron emission tomography (PET) was identified as independent predictor of postinterventional tumor response (P<0.001). CONCLUSION: Our results implicate that extended postinterventional tumor necrosis promotes recurrence-free long-term survival in patients with HCC beyond standard criteria. Pretransplant PET assessment may identify those patients with advanced HCC that will benefit from post-IBT tumor response and may, thereby, achieve excellent posttransplant outcome. PMID- 23349775 TI - FIM, a novel FTIR-based imaging method for high throughput locomotion analysis. AB - We designed a novel imaging technique based on frustrated total internal reflection (FTIR) to obtain high resolution and high contrast movies. This FTIR based Imaging Method (FIM) is suitable for a wide range of biological applications and a wide range of organisms. It operates at all wavelengths permitting the in vivo detection of fluorescent proteins. To demonstrate the benefits of FIM, we analyzed large groups of crawling Drosophila larvae. The number of analyzable locomotion tracks was increased by implementing a new software module capable of preserving larval identity during most collision events. This module is integrated in our new tracking program named FIMTrack which subsequently extracts a number of features required for the analysis of complex locomotion phenotypes. FIM enables high throughput screening for even subtle behavioral phenotypes. We tested this newly developed setup by analyzing locomotion deficits caused by the glial knockdown of several genes. Suppression of kinesin heavy chain (khc) or rab30 function led to contraction pattern or head sweeping defects, which escaped in previous analysis. Thus, FIM permits forward genetic screens aimed to unravel the neural basis of behavior. PMID- 23349777 TI - The repertoire of glycosphingolipids recognized by Vibrio cholerae. AB - The binding of cholera toxin to the ganglioside GM1 as the initial step in the process leading to diarrhea is nowadays textbook knowledge. In contrast, the knowledge about the mechanisms for attachment of Vibrio cholerae bacterial cells to the intestinal epithelium is limited. In order to clarify this issue, a large number of glycosphingolipid mixtures were screened for binding of El Tor V. cholerae. Several specific interactions with minor complex non-acid glycosphingolipids were thereby detected. After isolation of binding-active glycosphingolipids, characterization by mass spectrometry and proton NMR, and comparative binding studies, three distinct glycosphingolipid binding patterns were defined. Firstly, V. cholerae bound to complex lacto/neolacto glycosphingolipids with the GlcNAcbeta3Galbeta4GlcNAc sequence as the minimal binding epitope. Secondly, glycosphingolipids with a terminal Galalpha3Galalpha3Gal moiety were recognized, and the third specificity was the binding to lactosylceramide and related compounds. V. cholerae binding to lacto/neolacto glycosphingolipids, and to the other classes of binding-active compounds, remained after deletion of the chitin binding protein GbpA. Thus, the binding of V. cholerae to chitin and to lacto/neolacto containing glycosphingolipids represents two separate binding specificities. PMID- 23349776 TI - Self-renewal and differentiation capacity of urine-derived stem cells after urine preservation for 24 hours. AB - Despite successful approaches to preserve organs, tissues, and isolated cells, the maintenance of stem cell viability and function in body fluids during storage for cell distribution and transportation remains unexplored. The aim of this study was to characterize urine-derived stem cells (USCs) after optimal preservation of urine specimens for up to 24 hours. A total of 415 urine specimens were collected from 12 healthy men (age range 20-54 years old). About 6 * 10(4) cells shed off from the urinary tract system in 24 hours. At least 100 USC clones were obtained from the stored urine specimens after 24 hours and maintained similar biological features to fresh USCs. The stored USCs had a "rice grain" shape in primary culture, and expressed mesenchymal stem cell surface markers, high telomerase activity, and normal karyotypes. Importantly, the preserved cells retained bipotent differentiation capacity. Differentiated USCs expressed myogenic specific proteins and contractile function when exposed to myogenic differentiation medium, and they expressed urothelial cell-specific markers and barrier function when exposed to urothelial differentiation medium. These data demonstrated that up to 75% of fresh USCs can be safely persevered in urine for 24 hours and that these cells stored in urine retain their original stem cell properties, indicating that preserved USCs could be available for potential use in cell-based therapy or clinical diagnosis. PMID- 23349778 TI - Evidence for the role of Epstein Barr Virus infections in the pathogenesis of acute coronary events. AB - BACKGROUND: The role of viral infections in the pathogenesis of atherosclerosis remains controversial largely due to inconsistent detection of the virus in atherosclerotic lesions. However, viral infections elicit a pro-inflammatory cascade known to be atherogenic and to precipitate acute ischemic events. We have published in vitro data that provide the foundation for a mechanism that reconciles these conflicting observations. To determine the relation between an early viral protein, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), produced following reactivation of Epstein Barr Virus (EBV) to circulating pro inflammatory cytokines, intercellular adhesion molecule-1 (ICAM-1) and acute coronary events. METHODOLOGY/PRINCIPAL FINDINGS: Blood samples were obtained from 299 patients undergoing percutaneous coronary intervention for stable angina (SA), unstable angina (UA), or acute myocardial infarction (AMI). Plasma concentrations of pro-inflammatory cytokines and neutralizing antibody against EBV-encoded dUTPase were compared in the three patient groups. AMI was associated with the highest measures of interleukin-6 (ANOVA p<0.05; 4.6 +/- 2.6 pg/mL in patients with AMI vs. 3.2 +/- 2.3 pg/mL in SA). ICAM-1 was significantly higher in patients with AMI (ANOVA p<0.05; 304 +/- 116 pg/mL in AMI vs. 265 +/- 86 pg/mL SA). The highest values of ICAM-1 were found in patients having an AMI and who were antibody positive for dUTPase (ANOVA p=0.008; 369 +/- 183 pg/mL in AMI and positive for dUTPase vs. 249 +/- 70 pg/mL in SA negative for dUTPase antibody). CONCLUSIONS/SIGNIFICANCE: These clinical data support a model, based on in vitro studies, by which EBV may precipitate AMI even under conditions of low viral load through the pro-inflammatory action of the early protein dUTPase that is produced even during incomplete viral replication. They further support the putative role of viral infections in the pathogenesis of atherosclerosis and coronary artery events. PMID- 23349779 TI - Deciphering the metabolic changes associated with diapause syndrome and cold acclimation in the two-spotted spider mite Tetranychus urticae. AB - Diapause is a common feature in several arthropod species that are subject to unfavorable growing seasons. The range of environmental cues that trigger the onset and termination of diapause, in addition to associated hormonal, biochemical, and molecular changes, have been studied extensively in recent years; however, such information is only available for a few insect species. Diapause and cold hardening usually occur together in overwintering arthropods, and can be characterized by recording changes to the wealth of molecules present in the tissue, hemolymph, or whole body of organisms. Recent technological advances, such as high throughput screening and quantification of metabolites via chromatographic analyses, are able to identify such molecules. In the present work, we examined the survival ability of diapausing and non-diapausing females of the two-spotted spider mite, Tetranychus urticae, in the presence (0 or 5 degrees C) or absence of cold acclimation. Furthermore, we examined the metabolic fingerprints of these specimens via gas chromatography-mass spectrophotometry (GC MS). Partial Least Square Discriminant Analysis (PLS-DA) of metabolites revealed that major metabolic variations were related to diapause, indicating in a clear cut-off between diapausing and non-diapausing females, regardless of acclimation state. Signs of metabolic depression were evident in diapausing females, with most amino acids and TCA cycle intermediates being significantly reduced. Out of the 40 accurately quantified metabolites, seven metabolites remained elevated or were accumulated in diapausing mites, i.e. cadaverine, gluconolactone, glucose, inositol, maltose, mannitol and sorbitol. The capacity to accumulate winter polyols during cold-acclimation was restricted to diapausing females. We conclude that the induction of increased cold hardiness in this species is associated with the diapause syndrome, rather than being a direct effect of low temperature. Our results provide novel information about biochemical events related to the cold hardening process in the two-spotted spider mite. PMID- 23349780 TI - Prunus pananensis (Rosaceae), a new species from Pan'an of central Zhejiang, China. AB - Prunus pananensis Z. L. Chen, W. J. Chen & X. F. Jin, a new species of Rosaceae from central Zhejiang, China is described and illustrated. Micromorphological characters of the indumentum on young shoots, leaves, petioles and peduncles, including scanning electron microscope [SEM] images, are provided. This new species is morphologically similar to P. schneiderianae Koehne in having its young shoots, petioles and pedicels all densely villose, but differs in having bracts persistent, styles glabrous, stipules 8-9 mm long, stamens 28-30 of per flower, and drupes glabrous. The new species is also similar to P. discoidea (Yu & C. L. Li) Yu & C. L. Li ex Z. Wei & Y. B. Chang in having 2 or 3 flowers in an umbellate inflorescence, and bracts persistent and marginally glandular, but it differs in having young shoots and petioles densely covered with yellowish-brown villose trichomes; leaves rounded or slightly cordate at base, the mid-ribs and lateral veins abaxially densely covered with yellowish-brown villose trichomes; and hypanthium ca. 3 mm long, shorter than sepals. The atpB-rbcL and trnL-F intergenic chloroplast spacers are selected for identification of the new and its similar species. PMID- 23349781 TI - Modulating membrane composition alters free fatty acid tolerance in Escherichia coli. AB - Microbial synthesis of free fatty acids (FFA) is a promising strategy for converting renewable sugars to advanced biofuels and oleochemicals. Unfortunately, FFA production negatively impacts membrane integrity and cell viability in Escherichia coli, the dominant host in which FFA production has been studied. These negative effects provide a selective pressure against FFA production that could lead to genetic instability at industrial scale. In prior work, an engineered E. coli strain harboring an expression plasmid for the Umbellularia californica acyl-acyl carrier protein (ACP) thioesterase was shown to have highly elevated levels of unsaturated fatty acids in the cell membrane. The change in membrane content was hypothesized to be one underlying cause of the negative physiological effects associated with FFA production. In this work, a connection between the regulator of unsaturated fatty acid biosynthesis in E. coli, FabR, thioesterase expression, and unsaturated membrane content was established. A strategy for restoring normal membrane saturation levels and increasing tolerance towards endogenous production of FFAs was implemented by modulating acyl-ACP pools with a second thioesterase (from Geobacillus sp. Y412MC10) that primarily targets medium chain length, unsaturated acyl-ACPs. The strategy succeeded in restoring membrane content and improving viability in FFA producing E. coli while maintaining FFA titers. However, the restored fitness did not increase FFA productivity, indicating the existence of additional metabolic or regulatory barriers. PMID- 23349782 TI - TFPP: an SVM-based tool for recognizing flagellar proteins in Trypanosoma brucei. AB - Trypanosoma brucei is a unicellular flagellated eukaryotic parasite that causes African trypanosomiasis in human and domestic animals with devastating health and economic consequences. Recent studies have revealed the important roles of the single flagellum of T. brucei in many aspects, especially that the flagellar motility is required for the viability of the bloodstream form T. brucei, suggesting that impairment of the flagellar function may provide a promising cure for African sleeping sickness. Knowing the flagellum proteome is crucial to study the molecular mechanism of the flagellar functions. Here we present a novel computational method for identifying flagellar proteins in T. brucei, called trypanosome flagellar protein predictor (TFPP). TFPP was developed based on a list of selected discriminating features derived from protein sequences, and could predict flagellar proteins with ~92% specificity at a ~84% sensitivity rate. Applied to the whole T. brucei proteome, TFPP reveals 811 more flagellar proteins with high confidence, suggesting that the flagellar proteome covers ~10% of the whole proteome. Comparison of the expression profiles of the whole T. brucei proteome at three typical life cycle stages found that ~45% of the flagellar proteins were significantly changed in expression levels between the three life cycle stages, indicating life cycle stage-specific regulation of flagellar functions in T. brucei. Overall, our study demonstrated that TFPP is highly effective in identifying flagellar proteins and could provide opportunities to study the trypanosome flagellar proteome systematically. Furthermore, the web server for TFPP can be freely accessed at http:/wukong.tongji.edu.cn/tfpp. PMID- 23349784 TI - Imaging of metastatic lymph nodes by X-ray phase-contrast micro-tomography. AB - Invasive cancer causes a change in density in the affected tissue, which can be visualized by x-ray phase-contrast tomography. However, the diagnostic value of this method has so far not been investigated in detail. Therefore, the purpose of this study was, in a blinded manner, to investigate whether malignancy could be revealed by non-invasive x-ray phase-contrast tomography in lymph nodes from breast cancer patients. Seventeen formalin-fixed paraffin-embedded lymph nodes from 10 female patients (age range 37-83 years) diagnosed with invasive ductal carcinomas were analyzed by X-ray phase-contrast tomography. Ten lymph nodes had metastatic deposits and 7 were benign. The phase-contrast images were analyzed according to standards for conventional CT images looking for characteristics usually only visible by pathological examinations. Histopathology was used as reference. The result of this study was that the diagnostic sensitivity of the image analysis for detecting malignancy was 100% and the specificity was 87%. The positive predictive value was 91% for detecting malignancy and the negative predictive value was 100%. We conclude that x-ray phase-contrast imaging can accurately detect density variations to obtain information regarding lymph node involvement previously inaccessible with standard absorption x-ray imaging. PMID- 23349783 TI - Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR-dependent manner. AB - Opiates are among the most prescribed drugs for pain management. However, morphine use or abuse results in significant gut bacterial translocation and predisposes patients to serious infections with gut origin. The mechanism underlying this defect is still unknown. In this report, we investigated the mechanisms underlying compromised gut immune function and bacterial translocation following morphine treatment. We demonstrate significant bacterial translocation to mesenteric lymph node (MLN) and liver following morphine treatment in wild type (WT) animals that was dramatically and significantly attenuated in Toll-like receptor (TLR2 and 4) knockout mice. We further observed significant disruption of tight junction protein organization only in the ileum but not in the colon of morphine treated WT animals. Inhibition of myosin light chain kinase (MLCK) blocked the effects of both morphine and TLR ligands, suggesting the role of MLCK in tight junction modulation by TLR. This study conclusively demonstrates that morphine induced gut epithelial barrier dysfunction and subsequent bacteria translocation are mediated by TLR signaling and thus TLRs can be exploited as potential therapeutic targets for alleviating infections and even sepsis in morphine-using or abusing populations. PMID- 23349785 TI - Major cardiovascular risk factors in Latin America: a comparison with the United States. The Latin American Consortium of Studies in Obesity (LASO). AB - BACKGROUND: Limited knowledge on the prevalence and distribution of risk factors impairs the planning and implementation of cardiovascular prevention programs in the Latin American and Caribbean (LAC) region. METHODS AND FINDINGS: Prevalence of hypertension, diabetes mellitus, abnormal lipoprotein levels, obesity, and smoking were estimated from individual-level patient data pooled from population based surveys (1998-2007, n=31,009) from eight LAC countries and from a national survey of the United States (US) population (1999-2004) Age and gender specific prevalence were estimated and age-gender adjusted comparisons between both populations were conducted. Prevalence of diabetes mellitus, hypertension, and low high-density lipoprotein (HDL)-cholesterol in LAC were 5% (95% confidence interval [95% CI]: 3.4, 7.9), 20.2% (95% CI: 12.5, 31), and 53.3% (95% CI: 47, 63.4), respectively. Compared to LAC region's average, the prevalence of each risk factor tended to be lower in Peru and higher in Chile. LAC women had higher prevalence of obesity and low HDL-cholesterol than men. Obesity, hypercholesterolemia, and hypertriglyceridemia were more prevalent in the US population than in LAC population (31 vs. 16.1%, 16.8 vs. 8.9%, and 36.2 vs. 26.5%, respectively). However, the prevalence of low HDL-cholesterol was higher in LAC than in the US (53.3 vs. 33.7%). CONCLUSIONS: Major cardiovascular risk factors are highly prevalent in LAC region, in particular low HDL-cholesterol. In addition, marked differences do exist in this prevalence profile between LAC and the US. The observed patterns of obesity-related risk factors and their current and future impact on the burden of cardiovascular diseases remain to be explained. PMID- 23349786 TI - Reducing stock-outs of life saving malaria commodities using mobile phone text messaging: SMS for life study in Kenya. AB - BACKGROUND: Health facility stock-outs of life saving malaria medicines are common across Africa. Innovative ways of addressing this problem are urgently required. We evaluated whether SMS based reporting of stocks of artemether lumefantrine (AL) and rapid diagnostic tests (RDT) can result in reduction of stock-outs at peripheral facilities in Kenya. METHODS/FINDINGS: All 87 public health facilities in five Kenyan districts were included in a 26 week project. Weekly facility stock counts of four AL packs and RDTs were sent via structured incentivized SMS communication process from health workers' personal mobile phones to a web-based system accessed by district managers. The mean health facility response rate was 97% with a mean formatting error rate of 3%. Accuracy of stock count reports was 79% while accuracy of stock-out reports was 93%. District managers accessed the system 1,037 times at an average of eight times per week. The system was accessed in 82% of the study weeks. Comparing weeks 1 and 26, stock-out of one or more AL packs declined by 38 percentage-points. Total AL stock-out declined by 5 percentage-points and was eliminated by the end of the project. Stock-out declines of individual AL packs ranged from 14 to 32 percentage-points while decline in RDT stock-outs was 24 percentage-points. District managers responded to 44% of AL and 73% of RDT stock-out signals by redistributing commodities between facilities. In comparison with national trends, stock-out declines in study areas were greater, sharper and more sustained. CONCLUSIONS: Use of simple SMS technology ensured high reporting rates of reasonably accurate, real-time facility stock data that were used by district managers to undertake corrective actions to reduce stock-outs. Future work on stock monitoring via SMS should focus on assessing response rates without use of incentives and demonstrating effectiveness of such interventions on a larger scale. PMID- 23349787 TI - Plexin A3 and turnout regulate motor axonal branch morphogenesis in zebrafish. AB - During embryogenesis motor axons navigate to their target muscles, where individual motor axons develop complex branch morphologies. The mechanisms that control axonal branching morphogenesis have been studied intensively, yet it still remains unclear when branches begin to form or how branch locations are determined. Live cell imaging of individual zebrafish motor axons reveals that the first axonal branches are generated at the ventral extent of the myotome via bifurcation of the growth cone. Subsequent branches are generated by collateral branching restricted to their synaptic target field along the distal portion of the axon. This precisely timed and spatially restricted branching process is disrupted in turnout mutants we identified in a forward genetic screen. Molecular genetic mapping positioned the turnout mutation within a 300 kb region encompassing eight annotated genes, however sequence analysis of all eight open reading frames failed to unambiguously identify the turnout mutation. Chimeric analysis and single cell labeling reveal that turnout function is required cell non-autonomously for intraspinal motor axon guidance and peripheral branch formation. turnout mutant motor axons form the first branch on time via growth cone bifurcation, but unlike wild-type they form collateral branches precociously, when the growth cone is still navigating towards the ventral myotome. These precocious collateral branches emerge along the proximal region of the axon shaft typically devoid of branches, and they develop into stable, permanent branches. Furthermore, we find that null mutants of the guidance receptor plexin A3 display identical motor axon branching defects, and time lapse analysis reveals that precocious branch formation in turnout and plexin A3 mutants is due to increased stability of otherwise short-lived axonal protrusions. Thus, plexin A3 dependent intrinsic and turnout dependent extrinsic mechanisms suppress collateral branch morphogenesis by destabilizing membrane protrusions before the growth cone completes navigation into the synaptic target field. PMID- 23349788 TI - Activation of thromboxane A2 receptor (TP) increases the expression of monocyte chemoattractant protein -1 (MCP-1)/chemokine (C-C motif) ligand 2 (CCL2) and recruits macrophages to promote invasion of lung cancer cells. AB - Thromboxane synthase (TXAS) and thromboxane A(2) receptor (TP), two critical components for thromboxane A(2) (TXA(2)) signaling, have been suggested to be involved in cancer invasion and metastasis. However, the mechanisms by which TXA(2) promotes these processes are still unclear. Here we show that TXA(2) mimetic, I-BOP, induced monocyte chemoattractant protein -1(MCP-1)/chemokine (C-C motif) ligand 2 (CCL2) expression at both mRNA and protein levels in human lung adenocarcinoma A549 cells stably over-expressing TP receptor alpha isoform (A549 TPalpha). The induction of MCP-1 was also found in other lung cancer cells H157 and H460 that express relatively high levels of endogenous TP. Using specific inhibitors of several signaling molecules and promoter/luciferase assay, we identified that transcription factor SP1 mediates I-BOP-induced MCP-1 expression. Furthermore, supernatants from I-BOP-treated A549-TPalpha cells enhanced MCP-1 dependent migration of RAW 264.7 macrophages. Moreover, co-culture of A549 cells with RAW 264.7 macrophages induced expression of MMPs, VEGF and MCP-1 genes, and increased the invasive potential in A549 cells. These findings suggest that TXA(2) may stimulate invasion of cancer cells through MCP-1-mediated macrophage recruitment. PMID- 23349789 TI - SDF-1 promotes endochondral bone repair during fracture healing at the traumatic brain injury condition. AB - PURPOSES: The objective of this study was to investigate the role of stromal cell derived factor-1 (SDF-1) and its receptor, CXCR4, on bone healing and whether SDF 1 contributes to accelerating bone repair in traumatic brain injury (TBI)/fracture model. MATERIALS AND METHODS: Real-time polymerase chain reaction and immunohistochemical analysis were used to detect the expression of SDF-1 during the repair of femoral bone in TBI/fracture model. The TBI/fracture model was treated with anti-SDF-1 neutralizing antibody or AMD3100, an antagonist for CXCR4, and evaluated by histomorphometry. In vitro and in vivo migration assays were used to evaluate the functional effect of SDF-1 on primary mesenchymal stem cells. RESULTS: The expression of SDF1 and CXCR4 messenger RNA was increased during the bone healing in TBI/fracture model but was less increased in fracture only model. High expression of SDF-1 protein was observed in the surrounding tissue of the damaged bone. Treated with anti-SDF-1 antibody or AMD3100 could inhibit new bone formation. SDF-1 increased mesenchymal stem cell chemotaxis in vitro in a dose-dependent manner. The in vivo migration study demonstrated that mesenchymal stem cells recruited by SDF-1 participate in endochondral bone repair. CONCLUSION: The SDF-1/CXCR4 axis plays a crucial role in the accelerating fracture healing under the condition of TBI and contributes to endochondral bone repair. PMID- 23349790 TI - Diversity of cacao trees in Waslala, Nicaragua: associations between genotype spectra, product quality and yield potential. AB - The sensory quality and the contents of quality-determining chemical compounds in unfermented and fermented cocoa from 100 cacao trees (individual genotypes) representing groups of nine genotype spectra (GG), grown at smallholder plantings in the municipality of Waslala, Nicaragua, were evaluated for two successive harvest periods. Cocoa samples were fermented using a technique mimicking recommended on-farm practices. The sensory cocoa quality was assessed by experienced tasters, and seven major chemical taste compounds were quantified by near infrared spectrometry (NIRS). The association of the nine, partially admixed, genotype spectra with the analytical and sensory quality parameters was tested. The individual parameters were analyzed as a function of the factors GG and harvest (including the date of fermentation), individual trees within a single GG were used as replications. In fermented cocoa, significant GG-specific differences were observed for methylxanthines, theobromine-to-caffeine (T/C) ratio, total fat, procyanidin B5 and epicatechin, as well as the sensory attributes global score, astringency, and dry fruit aroma, but differences related to harvest were also apparent. The potential cocoa yield was also highly determined by the individual GG, although there was significant tree-to-tree variation within every single GG. Non-fermented samples showed large harvest-to harvest variation of their chemical composition, while differences between GG were insignificant. These results suggest that selection by the genetic background, represented here by groups of partially admixed genotype spectra, would be a useful strategy toward enhancing quality and yield of cocoa in Nicaragua. Selection by the GG within the local, genetically segregating populations of seed-propagated cacao, followed by clonal propagation of best performing individuals of the selected GG could be a viable alternative to traditional propagation of cacao by seed from open pollination. Fast and gentle air-drying of the fermented beans and their permanent dry storage were an efficient and comparatively easy precondition for high cocoa quality. PMID- 23349791 TI - Mismatch negativity and cognitive performance for the prediction of psychosis in subjects with at-risk mental state. AB - BACKGROUND: A shorter duration of untreated psychosis has been associated with better prognosis in schizophrenia. In this study, we measured the duration mismatch negativity (dMMN), an event-related potential, and cognitive performance in subjects with at-risk mental state (ARMS), patients with first-episode or chronic schizophrenia, and healthy volunteers. The main interest was to determine if these neurocognitive measures predict progression to overt schizophrenia in ARMS subjects. METHODOLOGY/PRINCIPAL FINDINGS: Seventeen ARMS subjects, meeting the criteria of the Comprehensive Assessment of At-Risk Mental State, 31 schizophrenia patients (20 first-episode and 11 chronic) and healthy controls (N=20) participated in the study. dMMN was measured by an auditory odd-ball paradigm at baseline. Neuropsychological performance was evaluated by the Japanese version of the Brief assessment of cognitive function of schizophrenia (BACS-J). The first-episode schizophrenia group showed significantly smaller amplitudes at frontal electrodes than did control subjects whereas chronic patients elicited smaller amplitudes at frontal and central electrodes, consistent with previous reports. During the follow-up period, 4 out of the 17 ARMS subjects transitioned to schizophrenia (converters) while 13 did not (non converters). Specifically, dMMN amplitudes of non-converters did not differ from those of healthy controls, while converters showed significantly smaller dMMN amplitudes at some electrodes compared to control subjects. Converters performed significantly worse on tests of working memory, verbal fluency, and attention/information processing than did non-converters. There was a significant positive correlation between dMMN amplitudes at the frontal electrodes and verbal fluency, as measured by the BACS, in the AMRS subjects as a whole. CONCLUSIONS/SIGNIFICANCE: ARMS subjects who later developed schizophrenia elicited smaller dMMN amplitudes to begin with, compared to non-converters. Notably, we have provided the first evidence for the ability of verbal fluency to predict dMMN amplitudes in ARMS subjects. These findings are expected to add to the efforts for early diagnosis and intervention of schizophrenia. PMID- 23349792 TI - Binding action and emotion in social understanding. AB - In social life actions are tightly linked with emotions. The integration of affective- and action-related information has to be considered as a fundamental component of appropriate social understanding. The present functional magnetic resonance imaging study aimed at investigating whether an emotion (Happiness, Anger or Neutral) dynamically expressed by an observed agent modulates brain activity underlying the perception of his grasping action. As control stimuli, participants observed the same agent either only expressing an emotion or only performing a grasping action. Our results showed that the observation of an action embedded in an emotional context (agent's facial expression), compared with the observation of the same action embedded in a neutral context, elicits higher neural response at the level of motor frontal cortices, temporal and occipital cortices, bilaterally. Particularly, the dynamic facial expression of anger modulates the re-enactment of a motor representation of the observed action. This is supported by the evidence that observing actions embedded in the context of anger, but not happiness, compared with a neutral context, elicits stronger activity in the bilateral pre-central gyrus and inferior frontal gyrus, besides the pre-supplementary motor area, a region playing a central role in motor control. Angry faces not only seem to modulate the simulation of actions, but may also trigger motor reaction. These findings suggest that emotions exert a modulatory role on action observation in different cortical areas involved in action processing. PMID- 23349793 TI - The case of Watson vs. James: effect-priming studies do not support ideomotor theory. AB - In this paper we show that response facilitation in choice reaction tasks achieved by priming the (previously perceived) effect is based on stimulus response associations rather than on response-effect associations. The reduced key-press response time is not accounted for by earlier established couplings between the key-press movement and its subsequent effect, but instead results from couplings between this effect and the contingent key-release movement. This key-release movement is an intrinsic part of the entire performed response action in each trial of a reaction-time task, and always spontaneously follows the key press movement. Eliminating the key-release movement from the task leads to the disappearance of the response facilitation, which raises the question whether response-effect associations actually play a role in studies that use the effect priming paradigm. Together the three experiments presented in the paper cast serious doubts on the claim that action-effect couplings are acquired and utilized by the cognitive system in the service of action selection, and that the priming paradigm by itself can provide convincing evidence for this claim. As a corollary, we question whether the related two-step model for the ideomotor principle holds a satisfying explanation for how anticipation of future states guides action planning. The results presented here may have profound implications for priming studies in other disciplines of psychology as well. PMID- 23349794 TI - Activation of p21 by HDAC inhibitors requires acetylation of H2A.Z. AB - Differential positioning of the histone variant H2A.Z in a p53 dependent manner was shown to regulate p21 transcription. Whether H2A.Z is involved in p21 activity in the absence of p53 is not known. The p21 gene is repressed in estrogen receptor (ER) negative cell lines that are p53-/- and hormone independent for their growth. Here we demonstrate that class I and II pan Histone deacetylase inhibitors (HDACi) induce p21 transcription and reduce cell proliferation of MDA-MB231, an ERalpha-negative mammary tumor cell line, in a H2A.Z dependent manner. H2A.Z is associated with the transcription start site (TSS) of the repressed p21 gene. Depleting H2A.Z did not lead to transcription of p21 but annihilated the stimulating effect of HDACi on this gene. Acetylation of H2A.Z but not of H3K9 at the p21 promoter correlated with p21 activation. We further show that HDACi treatment reduced the presence of the p400 chromatin remodeler at the p21 TSS. We propose a model in which association of p400 negatively affects p21 transcription by interfering with acetylation of H2A.Z. PMID- 23349795 TI - Description and predictive factors of individual outcomes in a refugee camp based mental health intervention (Beirut, Lebanon). AB - BACKGROUND: There is little evidence on the effectiveness of services for the care of people with mental disorders among refugee populations. Medecins sans Frontieres (MSF) has established a mental health centre in a mixed urban-refugee population in Beirut to respond to the significant burden of mental health problems. Patients received comprehensive care through a multidisciplinary team. A cohort of people with common and severe mental disorders has been analysed between December 2008 and June 2011 to evaluate individual outcomes of treatment in terms of functionality. METHODS: All patients diagnosed with mental disorders were included in the study. The Global Assessment of Functioning (GAF) and the Self Reporting Questionnaire-20 items (SRQ 20) were used as tools for baseline assessment, monitoring and evaluation of patients. Predictors of evolution of SRQ20 and GAF over visits were explored using a linear mixed model. RESULTS: Up to June 2011, 1144 patients were followed, 63.7% of them Lebanese, 31.8% Palestinians and 1.2% Iraqis. Females represented 64.2% of the patient population. Mean age was 39.2 years (28.5-46.5). The most frequent primary diagnoses were depressive disorders (28.8%), anxiety disorders (15.6%) and psychosis (11.5%). A lower baseline SRQ20 score/higher baseline GAF score (indicators of severity), being diagnosed with anxiety (compared to being diagnosed with depression or psychosis) and a higher level of education were associated with better outcomes. DISCUSSION: In this MSF program, we observed a significant decrease of SRQ20 individual scores and a significant increase of individual GAF scores. This corresponded to an improvement in the functionality of our patients. Analysis of the predictors of this positive evolution indicates that we need to adapt our model for the more severe and less educated patients. It also makes us reflect on the length of the individual follow-up. Further research could include a qualitative evaluation of the intervention. Results of this study have been presented at the World Congress of the World Federation for Mental Health in Cape Town, October 2011. PMID- 23349796 TI - MITF-independent pro-survival role of BRG1-containing SWI/SNF complex in melanoma cells. AB - Metastasized malignant melanoma has a poor prognosis because of its intrinsic resistance to chemotherapy and radiotherapy. The central role in the melanoma transcriptional network has the transcription factor MITF (microphthalmia associated transcription factor). It has been shown recently that the expression of MITF and some of its target genes require the SWI/SNF chromatin remodeling complex. Here we demonstrate that survival of melanoma cells requires functional SWI/SNF complex not only by supporting expression of MITF and its targets and but also by activating expression of prosurvival proteins not directly regulated by MITF. Microarray analysis revealed that besides the MITF-driven genes, expression of proteins like osteopontin, IGF1, TGFbeta2 and survivin, the factors known to be generally associated with progression of tumors and the antiapoptotic properties, were reduced in acute BRG1-depleted 501mel cells. Western blots and RT-PCR confirmed the microarray findings. These proteins have been verified to be expressed independently of MITF, because MITF depletion did not impair their expression. Because these genes are not regulated by MITF, the data suggests that loss of BRG1-based SWI/SNF complexes negatively affects survival pathways beyond the MITF cascade. Immunohistochemistry showed high expression of both BRM and BRG1 in primary melanomas. Exogenous CDK2, osteopontin, or IGF1 each alone partly relieved the block of proliferation imposed by BRG1 depletion, implicating that more factors, besides the MITF target genes, are involved in melanoma cell survival. Together these results demonstrate an essential role of SWI/SNF for the expression of MITF-dependent and MITF-independent prosurvival factors in melanoma cells and suggest that SWI/SNF may be a potential and effective target in melanoma therapy. PMID- 23349797 TI - DNA methylation in the malignant transformation of meningiomas. AB - Meningiomas are central nervous system tumors that originate from the meningeal coverings of the brain and spinal cord. Most meningiomas are pathologically benign or atypical, but 3-5% display malignant features. Despite previous studies on benign and atypical meningiomas, the key molecular pathways involved in malignant transformation remain to be determined, as does the extent of epigenetic alteration in malignant meningiomas. In this study, we explored the landscape of DNA methylation in ten benign, five atypical and four malignant meningiomas. Compared to the benign tumors, the atypical and malignant meningiomas demonstrate increased global DNA hypomethylation. Clustering analysis readily separates malignant from atypical and benign tumors, implicating that DNA methylation patterns may serve as diagnostic biomarkers for malignancy. Genes with hypermethylated CpG islands in malignant meningiomas (such as HOXA6 and HOXA9) tend to coincide with the binding sites of polycomb repressive complexes (PRC) in early developmental stages. Most genes with hypermethylated CpG islands at promoters are suppressed in malignant and benign meningiomas, suggesting the switching of gene silencing machinery from PRC binding to DNA methylation in malignant meningiomas. One exception is the MAL2 gene that is highly expressed in benign group and silenced in malignant group, representing de novo gene silencing induced by DNA methylation. In summary, our results suggest that malignant meningiomas have distinct DNA methylation patterns compared to their benign and atypical counterparts, and that the differentially methylated genes may serve as diagnostic biomarkers or candidate causal genes for malignant transformation. PMID- 23349798 TI - Association of HK2 and NCK2 with normal tension glaucoma in the Japanese population. AB - Although family studies and genome-wide association studies have shown that genetic factors play a role in glaucoma, it has been difficult to identify the specific genetic variants involved. We tested 669 single nucleotide polymorphisms (SNPs) from the region of chromosome 2 that includes the GLC1B glaucoma locus for association with primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) in the Japanese population. We performed a two-stage case-control study. The first cohort consisted of 123 POAG cases, 121 NTG cases and 120 controls: the second cohort consisted of 187 POAG cases, 286 NTG cases, and 271 controls. Out of six SNPs showing significant association with POAG in the first round screening, seven SNPs were tested in the second round. Rs678350 in the HK2 gene coding sequence showed significant allelic (p=0.0027 in Stage Two, 2.7XE-4 in meta-analysis) association with POAG, and significant allelic (p=4.7XE-4 in Stage Two, 1.0XE-5 in meta-analysis) association with NTG. Although alleles in the TMEM182 gene did not show significant association with glaucoma in the second round, subjects with the A/A allele in TMEM182 rs869833 showed worse visual field mean deviation (p=0.01). Even though rs2033008 in the NCK2 gene coding sequence did not show significant association in the first round, it had previously shown association with NTG so it was tested for association with NTG in round 2 (p=0.0053 in Stage Two). Immunohistochemistry showed that both HK2 and NCK2 are expressed in the retinal ganglion cell layer. Once multi-testing was taken into account, only HK2 showed significant association with POAG and NTG in Stage Two. Our data also support previous reports of NCK2 association with NTG, and raise questions about what role TMEM182 might play in phenotypic variability. Our data suggest that HK2 may play an important role in NTG in the Japanese population. PMID- 23349799 TI - A C-repeat binding factor transcriptional activator (CBF/DREB1) from European bilberry (Vaccinium myrtillus) induces freezing tolerance when expressed in Arabidopsis thaliana. AB - Freezing stress affects all plants from temperate zones to the poles. Global climate change means such freezing events are becoming less predictable. This in turn reduces the ability of plants to predict the approaching low temperatures and cold acclimate. This has consequences for crop yields and distribution of wild plant species. C-repeat binding factors (CBFs) are transcription factors previously shown to play a vital role in the acclimation process of Arabidopsis thaliana, controlling the expression of hundreds of genes whose products are necessary for freezing tolerance. Work in other plant species cements CBFs as key determinants in the trait of freezing tolerance in higher plants. To test the function of CBFs from highly freezing tolerant plants species we cloned and sequenced CBF transcription factors from three Vaccinium species (Vaccinium myrtillus, Vaccinium uliginosum and Vaccinium vitis-idaea) which we collected in the Arctic. We tested the activity of CBF transcription factors from the three Vaccinium species by producing transgenic Arabidopsis lines overexpressing them. Only the Vaccinium myrtillus CBF was able to substantially activate COR (CBF target) gene expression in the absence of cold. Correspondingly, only the lines expressing the Vaccinium myrtillus CBF were constitutively freezing tolerant. The basis for the differences in potency of the three Vaccinium CBFs was tested by observing cellular localisation and protein levels. All three CBFs were correctly targeted to the nucleus, but Vaccinium uliginosum CBF appeared to be relatively unstable. The reasons for lack of potency for Vaccinium vitis-idaea CBF were not due to stability or targeting, and we speculate that this was due to altered transcription factor function. PMID- 23349800 TI - Identification of novel protein-protein interactions of Yersinia pestis type III secretion system by yeast two hybrid system. AB - Type III secretion system (T3SS) of the plague bacterium Y. pestis encodes a syringe-like structure consisting of more than 20 proteins, which can inject virulence effectors into host cells to modulate the cellular functions. Here in this report, interactions among the possible components in T3SS of Yersinia pestis were identified using yeast mating technique. A total of 57 genes, including all the pCD1-encoded genes except those involved in plasmid replication and partition, pseudogenes, and the putative transposase genes, were subjected to yeast mating analysis. 21 pairs of interaction proteins were identified, among which 9 pairs had been previously reported and 12 novel pairs were identified in this study. Six of them were tested by GST pull down assay, and interaction pairs of YscG-SycD, YscG-TyeA, YscI-YscF, and YopN-YpCD1.09c were successfully validated, suggesting that these interactions might play potential roles in function of Yersinia T3SS. Several potential new interactions among T3SS components could help to understand the assembly and regulation of Yersinia T3SS. PMID- 23349801 TI - Protein kinase C regulates human pluripotent stem cell self-renewal. AB - BACKGROUND: The self-renewal of human pluripotent stem (hPS) cells including embryonic stem and induced pluripotent stem cells have been reported to be supported by various signal pathways. Among them, fibroblast growth factor-2 (FGF 2) appears indispensable to maintain self-renewal of hPS cells. However, downstream signaling of FGF-2 has not yet been clearly understood in hPS cells. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we screened a kinase inhibitor library using a high-throughput alkaline phosphatase (ALP) activity-based assay in a minimal growth factor-defined medium to understand FGF-2-related molecular mechanisms regulating self-renewal of hPS cells. We found that in the presence of FGF-2, an inhibitor of protein kinase C (PKC), GF109203X (GFX), increased ALP activity. GFX inhibited FGF-2-induced phosphorylation of glycogen synthase kinase 3beta (GSK-3beta), suggesting that FGF-2 induced PKC and then PKC inhibited the activity of GSK-3beta. Addition of activin A increased phosphorylation of GSK 3beta and extracellular signal-regulated kinase-1/2 (ERK-1/2) synergistically with FGF-2 whereas activin A alone did not. GFX negated differentiation of hPS cells induced by the PKC activator, phorbol 12-myristate 13-acetate whereas Go6976, a selective inhibitor of PKCalpha, beta, and gamma isoforms could not counteract the effect of PMA. Intriguingly, functional gene analysis by RNA interference revealed that the phosphorylation of GSK-3beta was reduced by siRNA of PKCdelta, PKCepsilon, and zeta, the phosphorylation of ERK-1/2 was reduced by siRNA of PKCepsilon and zeta, and the phosphorylation of AKT was reduced by PKCepsilon in hPS cells. CONCLUSIONS/SIGNIFICANCE: Our study suggested complicated cross-talk in hPS cells that FGF-2 induced the phosphorylation of phosphatidylinositol-3 kinase (PI3K)/AKT, mitogen-activated protein kinase/ERK 1/2 kinase (MEK), PKC/ERK-1/2 kinase, and PKC/GSK-3beta. Addition of GFX with a MEK inhibitor, U0126, in the presence of FGF-2 and activin A provided a long-term stable undifferentiated state of hPS cells even though hPS cells were dissociated into single cells for passage. This study untangles the cross-talk between molecular mechanisms regulating self-renewal and differentiation of hPS cells. PMID- 23349802 TI - IKKbeta in myeloid cells controls the host response to lethal and sublethal Francisella tularensis LVS infection. AB - BACKGROUND: The NF-kappaB activating kinases, IKKalpha and IKKbeta, are key regulators of inflammation and immunity in response to infection by a variety of pathogens. Both IKKalpha and IKKbeta have been reported to modulate either pro- or anti- inflammatory programs, which may be specific to the infectious organism or the target tissue. Here, we analyzed the requirements for the IKKs in myeloid cells in vivo in response to Francisella tularensis Live Vaccine Strain (Ft. LVS) infection. METHODS AND PRINCIPAL FINDINGS: In contrast to prior reports in which conditional deletion of IKKbeta in the myeloid lineage promoted survival and conferred resistance to an in vivo group B streptococcus infection, we show that mice with a comparable conditional deletion (IKKbeta cKO) succumb more rapidly to lethal Ft. LVS infection and are unable to control bacterial growth at sublethal doses. Flow cytometry analysis of hepatic non-parenchymal cells from infected mice reveals that IKKbeta inhibits M1 classical macrophage activation two days post infection, which has the collateral effect of suppressing IFN-gamma(+) CD8(+) T cells. Despite this early enhanced inflammation, IKKbeta cKO mice are unable to control infection; and this coincides with a shift toward M2a polarized macrophages. In comparison, we find that myeloid IKKalpha is dispensable for survival and bacterial control. However, both IKKalpha and IKKbeta have effects on hepatic granuloma development. IKKalpha cKO mice develop fewer, but well contained granulomas that accumulate excess necrotic cells after 9 days of infection; while IKKbeta cKO mice develop numerous micro-granulomas that are less well contained. CONCLUSIONS: Taken together our findings reveal that unlike IKKalpha, IKKbeta has multiple, contrasting roles in this bacterial infection model by acting in an anti-inflammatory capacity at early times towards sublethal Ft. LVS infection; but in spite of this, macrophage IKKbeta is also a critical effector for host survival and efficient pathogen clearance. PMID- 23349803 TI - Cigarette smoke induced airway inflammation is independent of NF-kappaB signalling. AB - RATIONALE: COPD is an inflammatory lung disease largely associated with exposure to cigarette smoke (CS). The mechanism by which CS leads to the pathogenesis of COPD is currently unclear; it is known however that many of the inflammatory mediators present in the COPD lung can be produced via the actions of the transcription factor Nuclear Factor-kappaB (NF-kappaB) and its upstream signalling kinase, Inhibitor of kappaB kinase-2 (IKK-2). Therefore the NF kappaB/IKK-2 signalling pathway may represent a therapeutic target to attenuate the inflammation associated with COPD. AIM: To use a range of assays, genetically modified animals and pharmacological tools to determine the role of NF-kappaB in CS-induced airway inflammation. METHODS: NF-kappaB pathway activation was measured in pre-clinical models of CS-induced airway inflammation and in human lung tissue from COPD patients. This data was complemented by employing mice missing a functional NF-kappaB pathway in specific cell types (epithelial and myeloid cells) and with systemic inhibitors of IKK-2. RESULTS: We showed in an airway inflammation model known to be NF-kappaB-dependent that the NF-kappaB pathway activity assays and modulators were functional in the mouse lung. Then, using the same methods, we demonstrated that the NF-kappaB pathway appears not to play an important role in the inflammation observed after exposure to CS. Furthermore, assaying human lung tissue revealed that in the clinical samples there was also no increase in NF-kappaB pathway activation in the COPD lung, suggesting that our pre-clinical data is translational to human disease. CONCLUSIONS: In this study we present compelling evidence that the IKK-2/NF kappaB signalling pathway does not play a prominent role in the inflammatory response to CS exposure and that this pathway may not be important in COPD pathogenesis. PMID- 23349805 TI - Optimising homing endonuclease gene drive performance in a semi-refractory species: the Drosophila melanogaster experience. AB - Homing endonuclease gene (HEG) drive is a promising insect population control technique that employs meganucleases to impair the fitness of pest populations. Our previous studies showed that HEG drive was more difficult to achieve in Drosophila melanogaster than Anopheles gambiae and we therefore investigated ways of improving homing performance in Drosophila. We show that homing in Drosophila responds to increased expression of HEGs specifically during the spermatogonia stage and this could be achieved through improved construct design. We found that 3'-UTR choice was important to maximise expression levels, with HEG activity increasing as we employed Hsp70, SV40, vasa and betaTub56D derived UTRs. We also searched for spermatogonium-specific promoters and found that the Rcd-1r promoter was able to drive specific expression at this stage. Since Rcd-1 is a regulator of differentiation in other species, it suggests that Rcd-1r may serve a similar role during spermatogonial differentiation in Drosophila. Contrary to expectations, a fragment containing the entire region between the TBPH gene and the bgcn translational start drove strong HEG expression only during late spermatogenesis rather than in the germline stem cells and spermatogonia as expected. We also observed that the fraction of targets undergoing homing was temperature-sensitive, falling nearly four-fold when the temperature was lowered to 18 degrees C. Taken together, this study demonstrates how a few simple measures can lead to substantial improvements in the HEG-based gene drive strategy and reinforce the idea that the HEG approach may be widely applicable to a variety of insect control programs. PMID- 23349804 TI - Genetic interactions underlying the biosynthesis and inhibition of beta-diketones in wheat and their impact on glaucousness and cuticle permeability. AB - Cuticular wax composition greatly impacts plant responses to dehydration. Two parallel pathways exist in Triticeae for manipulating wax composition: the acyl elongation, reduction, and decarbonylation pathway that is active at the vegetative stage and yields primary alcohols and alkanes, and the beta-diketone pathway that predominates at the reproductive stage and synthesizes beta diketones. Variation in glaucousness during the reproductive stage of wheat is mainly controlled by the wax production genes, W1 and W2, and wax inhibitor genes, Iw1 and Iw2. Little is known about the metabolic and physiological effects of the genetic interactions among these genes and their roles in shifting wax composition during plant development. We characterized the effect of W1, W2, Iw1, and Iw2 and analyzed their interaction using a set of six near-isogenic lines (NILs) by metabolic, molecular and physiological approaches. Loss of functional alleles of both W genes or the presence of either Iw gene depletes beta-diketones and results in the nonglaucous phenotype. Elimination of beta-diketones is compensated for by an increase in aldehydes and primary alcohols in the Iw NILs. Accordingly, transcription of CER4-6, which encodes an alcohol-forming fatty acyl CoA reductase, was elevated 120-fold in iw1Iw2. CER4-6 was transcribed at much higher levels in seedlings than in adult plants, and showed little difference between the glaucous and nonglaucous NILs, suggesting that Iw2 counteracts the developmental repression of CER4-6 at the reproductive stage. While W1 and W2 redundantly function in beta-diketone biosynthesis, a combination of both functional alleles led to the beta-diketone hydroxylation. Consistent with this, transcription of MAH1-9, which encodes a mid-chain alkane hydroxylase, increased seven-fold only in W1W2. In parallel with the hydroxyl-beta-diketone production patterns, glaucousness was intensified and cuticle permeability was reduced significantly in W1W2 compared to the other NILs. This suggests that both W1 and W2 are required for enhancing drought tolerance. PMID- 23349806 TI - Rapid two-temperature formalin fixation. AB - Formalin fixation is a mainstay of modern histopathologic analysis, yet the practice is poorly standardized and a significant potential source of preanalytical errors. Concerns of workflow and turnaround time drive interest in developing shorter fixation protocols, but rapid protocols can lead to poor histomorphology or inadequate downstream assay results. Additionally, assays such as immunohistochemistry for phosphorylated epitopes have historically been challenging in the context of formalin-fixed tissue, indicating that there may be room for improvement in this process that is fundamental to the practice of anatomic pathology. With these issues in mind, we studied basic formalin biochemistry to develop a novel formalin fixation protocol that involves a pre incubation in subambient temperature formalin prior to a brief exposure to heated formalin. This new protocol is more rapid than standard protocols yet preserves histomorphology and yields tissue that is compatible with an expanded set of downstream clinical and research assays, including immunohistochemistry for phosphorylated epitopes. PMID- 23349807 TI - Children's and adults' on-line processing of syntactically ambiguous sentences during reading. AB - While there has been a fair amount of research investigating children's syntactic processing during spoken language comprehension, and a wealth of research examining adults' syntactic processing during reading, as yet very little research has focused on syntactic processing during text reading in children. In two experiments, children and adults read sentences containing a temporary syntactic ambiguity while their eye movements were monitored. In Experiment 1, participants read sentences such as, 'The boy poked the elephant with the long stick/trunk from outside the cage' in which the attachment of a prepositional phrase was manipulated. In Experiment 2, participants read sentences such as, 'I think I'll wear the new skirt I bought tomorrow/yesterday. It's really nice' in which the attachment of an adverbial phrase was manipulated. Results showed that adults and children exhibited similar processing preferences, but that children were delayed relative to adults in their detection of initial syntactic misanalysis. It is concluded that children and adults have the same sentence parsing mechanism in place, but that it operates with a slightly different time course. In addition, the data support the hypothesis that the visual processing system develops at a different rate than the linguistic processing system in children. PMID- 23349808 TI - Fission yeast Nod1 is a component of cortical nodes involved in cell size control and division site placement. AB - Most cells enter mitosis once they have reached a defined size. In the fission yeast Schizosaccharomyces pombe, mitotic entry is orchestrated by a geometry sensing mechanism that involves the Cdk1/Cdc2-inhibiting Wee1 kinase. The factors upstream of Wee1 gather together in interphase to form a characteristic medial and cortical belt of nodes. Nodes are also considered to be precursors of the cytokinesis contractile actomyosin ring (CAR). Here we describe a new component of the interphase nodes and cytokinesis rings, which we named Nod1. Consistent with its role in cell size control at division, nod1Delta cells were elongated and epistatic with regulators of Wee1. Through biochemical and localisation studies, we placed Nod1 in a complex with the Rho-guanine nucleotide exchange factor Gef2. Nod1 and Gef2 mutually recruited each other in nodes and Nod1 also assembles Gef2 in rings. Like gef2Delta, nod1Delta cells showed a mild displacement of their division plane and this phenotype was severely exacerbated when the parallel Polo kinase pathway was also compromised. We conclude that Nod1 specifies the division site by localising Gef2 to the mitotic cell middle. Previous work showed that Gef2 in turn anchors factors that control the spatio temporal recruitment of the actin nucleation machinery. It is believed that the actin filaments originated from the nodes pull nodes together into a single contractile ring. Surprisingly however, we found that node proteins could form pre-ring helical filaments in a cdc12-112 mutant in which nucleation of the actin ring is impaired. Furthermore, the deletion of either nod1 or gef2 created an un expected situation where different ring components were recruited sequentially rather than simultaneously. At later stages of cytokinesis, these various rings appeared inter-fitted rather than merged. This study brings a new slant to the understanding of CAR assembly and function. PMID- 23349809 TI - A PKS/NRPS/FAS hybrid gene cluster from Serratia plymuthica RVH1 encoding the biosynthesis of three broad spectrum, zeamine-related antibiotics. AB - Serratia plymuthica strain RVH1, initially isolated from an industrial food processing environment, displays potent antimicrobial activity towards a broad spectrum of Gram-positive and Gram-negative bacterial pathogens. Isolation and subsequent structure determination of bioactive molecules led to the identification of two polyamino antibiotics with the same molecular structure as zeamine and zeamine II as well as a third, closely related analogue, designated zeamine I. The gene cluster encoding the biosynthesis of the zeamine antibiotics was cloned and sequenced and shown to encode FAS, PKS as well as NRPS related enzymes in addition to putative tailoring and export enzymes. Interestingly, several genes show strong homology to the pfa cluster of genes involved in the biosynthesis of long chain polyunsaturated fatty acids in marine bacteria. We postulate that a mixed FAS/PKS and a hybrid NRPS/PKS assembly line each synthesize parts of the backbone that are linked together post-assembly in the case of zeamine and zeamine I. This interaction reflects a unique interplay between secondary lipid and secondary metabolite biosynthesis. Most likely, the zeamine antibiotics are produced as prodrugs that undergo activation in which a nonribosomal peptide sequence is cleaved off. PMID- 23349810 TI - Industrial systems biology of Saccharomyces cerevisiae enables novel succinic acid cell factory. AB - Saccharomyces cerevisiae is the most well characterized eukaryote, the preferred microbial cell factory for the largest industrial biotechnology product (bioethanol), and a robust commerically compatible scaffold to be exploitted for diverse chemical production. Succinic acid is a highly sought after added-value chemical for which there is no native pre-disposition for production and accmulation in S. cerevisiae. The genome-scale metabolic network reconstruction of S. cerevisiae enabled in silico gene deletion predictions using an evolutionary programming method to couple biomass and succinate production. Glycine and serine, both essential amino acids required for biomass formation, are formed from both glycolytic and TCA cycle intermediates. Succinate formation results from the isocitrate lyase catalyzed conversion of isocitrate, and from the alpha-keto-glutarate dehydrogenase catalyzed conversion of alpha-keto glutarate. Succinate is subsequently depleted by the succinate dehydrogenase complex. The metabolic engineering strategy identified included deletion of the primary succinate consuming reaction, Sdh3p, and interruption of glycolysis derived serine by deletion of 3-phosphoglycerate dehydrogenase, Ser3p/Ser33p. Pursuing these targets, a multi-gene deletion strain was constructed, and directed evolution with selection used to identify a succinate producing mutant. Physiological characterization coupled with integrated data analysis of transcriptome data in the metabolically engineered strain were used to identify 2(nd)-round metabolic engineering targets. The resulting strain represents a 30 fold improvement in succinate titer, and a 43-fold improvement in succinate yield on biomass, with only a 2.8-fold decrease in the specific growth rate compared to the reference strain. Intuitive genetic targets for either over-expression or interruption of succinate producing or consuming pathways, respectively, do not lead to increased succinate. Rather, we demonstrate how systems biology tools coupled with directed evolution and selection allows non-intuitive, rapid and substantial re-direction of carbon fluxes in S. cerevisiae, and hence show proof of concept that this is a potentially attractive cell factory for over-producing different platform chemicals. PMID- 23349811 TI - p68/DdX5 supports beta-catenin & RNAP II during androgen receptor mediated transcription in prostate cancer. AB - The DEAD box RNA helicase p68 (Ddx5) is an important androgen receptor (AR) transcriptional co-activator in prostate cancer (PCa) and is over-expressed in late stage disease. beta-Catenin is a multifunctional protein with important structural and signalling functions which is up-regulated in PCa and similar to p68, interacts with the AR to co-activate expression of AR target genes. Importantly, p68 forms complexes with nuclear beta-Catenin and promotes gene transcription in colon cancer indicating a functional interplay between these two proteins in cancer progression. In this study, we explore the relationship of p68 and beta-Catenin in PCa to assess their potential co-operation in AR-dependent gene expression, which may be of importance in the development of castrate resistant prostate cancer (CRPCa). We use immunoprecipitation to demonstrate a novel interaction between p68 and beta-Catenin in the nucleus of PCa cells, which is androgen dependent in LNCaP cells but androgen independent in a hormone refractory derivative of the same cell line (representative of the CRPCa disease type). Enhanced AR activity is seen in androgen-dependent luciferase reporter assays upon transient co-transfection of p68 and beta-Catenin as an additive effect, and p68-depleted Chromatin-Immunoprecipitation (ChIP) showed a decrease in the recruitment of the AR and beta-Catenin to androgen responsive promoter regions. In addition, we found p68 immunoprecipitated with the processive and non processive form of RNA polymerase II (RNAP II) and show p68 recruited to elongating regions of the AR mediated PSA gene, suggesting a role for p68 in facilitating RNAP II transcription of AR mediated genes. These results suggest p68 is important in facilitating beta-Catenin and AR transcriptional activity in PCa cells. PMID- 23349812 TI - Functional modulation of vascular adhesion protein-1 by a novel splice variant. AB - Vascular Adhesion Protein-1 (VAP-1) is an endothelial adhesion molecule belonging to the primary amine oxidases. Upon inflammation it takes part in the leukocyte extravasation cascade facilitating transmigration of leukocytes into the inflamed tissue. Screening of a human lung cDNA library revealed the presence of an alternatively spliced shorter transcript of VAP-1, VAP-1Delta3. Here, we have studied the functional and structural characteristics of VAP-1Delta3, and show that the mRNA for this splice variant is expressed in most human tissues studied. In comparison to the parent molecule this carboxy-terminally truncated isoform lacks several of the amino acids important in the formation of the enzymatic groove of VAP-1. In addition, the conserved His684, which takes part in coordinating the active site copper, is missing from VAP-1Delta3. Assays using the prototypic amine substrates methylamine and benzylamine demonstrated that VAP 1Delta3 is indeed devoid of the semicarbazide-sensitive amine oxidase (SSAO) activity characteristic to VAP-1. When VAP-1Delta3-cDNA is transfected into cells stably expressing VAP-1, the surface expression of the full-length molecule is reduced. Furthermore, the SSAO activity of the co-transfectants is diminished in comparison to transfectants expressing only VAP-1. The observed down-regulation of both the expression and enzymatic activity of VAP-1 may result from a dominant negative effect caused by heterodimerization between VAP-1 and VAP-1Delta3, which was detected in co-immunoprecipitation studies. This alternatively spliced transcript adds thus to the repertoire of potential regulatory mechanisms through which the cell-surface expression and enzymatic activity of VAP-1 can be modulated. PMID- 23349813 TI - Spatial patterns of high Aedes aegypti oviposition activity in northwestern Argentina. AB - BACKGROUND: In Argentina, dengue has affected mainly the Northern provinces, including Salta. The objective of this study was to analyze the spatial patterns of high Aedes aegypti oviposition activity in San Ramon de la Nueva Oran, northwestern Argentina. The location of clusters as hot spot areas should help control programs to identify priority areas and allocate their resources more effectively. METHODOLOGY: Oviposition activity was detected in Oran City (Salta province) using ovitraps, weekly replaced (October 2005-2007). Spatial autocorrelation was measured with Moran's Index and depicted through cluster maps to identify hot spots. Total egg numbers were spatially interpolated and a classified map with Ae. aegypti high oviposition activity areas was performed. Potential breeding and resting (PBR) sites were geo-referenced. A logistic regression analysis of interpolated egg numbers and PBR location was performed to generate a predictive mapping of mosquito oviposition activity. PRINCIPAL FINDINGS: Both cluster maps and predictive map were consistent, identifying in central and southern areas of the city high Ae. aegypti oviposition activity. A logistic regression model was successfully developed to predict Ae. aegypti oviposition activity based on distance to PBR sites, with tire dumps having the strongest association with mosquito oviposition activity. A predictive map reflecting probability of oviposition activity was produced. The predictive map delimitated an area of maximum probability of Ae. aegypti oviposition activity in the south of Oran city where tire dumps predominate. The overall fit of the model was acceptable (ROC=0.77), obtaining 99% of sensitivity and 75.29% of specificity. CONCLUSIONS: Distance to tire dumps is inversely associated with high mosquito activity, allowing us to identify hot spots. These methodologies are useful for prevention, surveillance, and control of tropical vector borne diseases and might assist National Health Ministry to focus resources more effectively. PMID- 23349814 TI - Characteristics of high risk people with cardiovascular disease in Chinese rural areas: clinical indictors, disease patterns and drug treatment. AB - BACKGROUND AND AIMS: Current cardiovascular disease (CVD) prevention is based on diagnosis and treatment of specific disease. Little is known for high risk people with CVD at the community level. In rural China, health records of all residents were established after the recent health reforms. This study aims to describe the characters of the rural population with high CVD risk regarding their clinical indicators, disease patterns, drug treatment and adherence. METHODS AND RESULTS: 17042 (87%) of all the 19500 rural residents in the two townships had valid health records in 2009. We employed a validated tool, the Asian Equation, to screen 8182 (48%) resident health records of those aged between 40-75 years in 2010. Those who were identified with a CVD risk of 20% or higher were selected for a face-to-face questionnaire survey regarding their diagnosed disease and drug treatment. 453 individuals were identified as high risk of CVD, with an average age of 53 years, 62% males, 50% smoking rate and average systolic blood pressure of 161 mmHg. 386 (85%) participated in the survey, while 294 (76%) were diagnosed with and 88 (23%) were suspects of CVD, hypertension, diabetes or hyperlipidaemia. 75 (19%) took drug regularly and 125 (32%) either stopped treatment or missed drugs. The most often used drugs were calcium channel blockers (20%). Only 2% used aspirins and 0.8% used statins. The median costs of drugs were 17 RMB (USD2.66) per month. CONCLUSION: The majority of the high risk population in our setting of rural China had already been diagnosed with a CVD related disease, but very few took any drugs, and less still took highly effective drugs to prevent CVD. A holistic strategy focused on population with high risk CVD and based on the current China public health reform is suggested in the context of primary care. PMID- 23349815 TI - Variation of genetic diversity in a rapidly expanding population of the greater long-tailed hamster (Tscherskia triton) as revealed by microsatellites. AB - Genetic diversity is essential for persistence of animal populations over both the short- and long-term. Previous studies suggest that genetic diversity may decrease with population decline due to genetic drift or inbreeding of small populations. For oscillating populations, there are some studies on the relationship between population density and genetic diversity, but these studies were based on short-term observation or in low-density phases. Evidence from rapidly expanding populations is lacking. In this study, genetic diversity of a rapidly expanding population of the Greater long-tailed hamsters during 1984 1990, in the Raoyang County of the North China Plain was studied using DNA microsatellite markers. Results show that genetic diversity was positively correlated with population density (as measured by % trap success), and the increase in population density was correlated with a decrease of genetic differentiation between the sub-population A and B. The genetic diversity tended to be higher in spring than in autumn. Variation in population density and genetic diversity are consistent between sub-population A and B. Such results suggest that dispersal is density- and season-dependent in a rapidly expanding population of the Greater long-tailed hamster. For typically solitary species, increasing population density can increase intra-specific attack, which is a driving force for dispersal. This situation is counterbalanced by decreasing population density caused by genetic drift or inbreeding as the result of small population size. Season is a major factor influencing population density and genetic diversity. Meanwhile, roads, used to be considered as geographical isolation, have less effect on genetic differentiation in a rapidly expanding population. Evidences suggest that gene flow (Nm) is positively correlated with population density, and it is significant higher in spring than that in autumn. PMID- 23349816 TI - Chemotaxis of Dictyostelium discoideum: collective oscillation of cellular contacts. AB - Chemotactic responses of Dictyostelium discoideum cells to periodic self generated signals of extracellular cAMP comprise a large number of intricate morphological changes on different length scales. Here, we scrutinized chemotaxis of single Dictyostelium discoideum cells under conditions of starvation using a variety of optical, electrical and acoustic methods. Amebas were seeded on gold electrodes displaying impedance oscillations that were simultaneously analyzed by optical video microscopy to relate synchronous changes in cell density, morphology, and distance from the surface to the transient impedance signal. We found that starved amebas periodically reduce their overall distance from the surface producing a larger impedance and higher total fluorescence intensity in total internal reflection fluorescence microscopy. Therefore, we propose that the dominant sources of the observed impedance oscillations observed on electric cell substrate impedance sensing electrodes are periodic changes of the overall cell substrate distance of a cell. These synchronous changes of the cell-electrode distance were also observed in the oscillating signal of acoustic resonators covered with amebas. We also found that periodic cell-cell aggregation into transient clusters correlates with changes in the cell-substrate distance and might also contribute to the impedance signal. It turned out that cell-cell contacts as well as cell-substrate contacts form synchronously during chemotaxis of Dictyostelium discoideum cells. PMID- 23349817 TI - Manus track preservation bias as a key factor for assessing trackmaker identity and quadrupedalism in basal ornithopods. AB - BACKGROUND: The Las Cerradicas site (Tithonian-Berriasian), Teruel, Spain, preserves at least seventeen dinosaur trackways, some of them formerly attributed to quadrupedal ornithopods, sauropods and theropods. The exposure of new track evidence allows a more detailed interpretation of the controversial tridactyl trackways as well as the modes of locomotion and taxonomic affinities of the trackmakers. METHODOLOGY/PRINCIPAL FINDINGS: Detailed stratigraphic analysis reveals four different levels where footprints have been preserved in different modes. Within the tridactyl trackways, manus tracks are mainly present in a specific horizon relative to surface tracks. The presence of manus tracks is interpreted as evidence of an ornithopod trackmaker. Cross-sections produced from photogrammetric digital models show different depths of the pes and manus, suggesting covariance in loading between the forelimbs and the hindlimbs. CONCLUSIONS/SIGNIFICANCE: Several features (digital pads, length/width ratio, claw marks) of some ornithopod pes tracks from Las Cerradicas are reminiscent of theropod pedal morphology. This morphological convergence, combined with the shallow nature of the manus tracks, which reduces preservation potential, opens a new window into the interpretation of these tridactyl tracks. Thus, trackmaker assignations during the Jurassic-Cretaceous interval of purported theropod trackways may potentially represent ornithopods. Moreover, the Las Cerradicas trackways are further evidence for quadrupedalism among some basal small- to medium-sized ornithopods from this time interval. PMID- 23349818 TI - Assessing community-level and single-species models predictions of species distributions and assemblage composition after 25 years of land cover change. AB - To predict the impact of environmental change on species distributions, it has been hypothesized that community-level models could give some benefits compared to species-level models. In this study we have assessed the performance of these two approaches. We surveyed 256 bird communities in an agricultural landscape in southwest France at the same locations in 1982 and 2007. We compared the ability of CQO (canonical quadratic ordination; a method of community-level GLM) and GLMs (generalized linear models) to i) explain species distributions in 1982 and ii) predict species distributions, community composition and species richness in 2007, after land cover change. Our results show that models accounting for shared patterns between species (CQO) slightly better explain the distribution of rare species than models that ignore them (GLMs). Conversely, the predictive performances were better for GLMs than for CQO. At the assemblage level, both CQO and GLMs overestimated species richness, compared with that actually observed in 2007, and projected community composition was only moderately similar to that observed in 2007. Species richness projections tended to be more accurate in sites where land cover change was more marked. In contrast, the composition projections tended to be less accurate in those sites. Both modelling approaches showed a similar but limited ability to predict species distribution and assemblage composition under conditions of land cover change. Our study supports the idea that our community-level model can improve understanding of rare species patterns but that species-level models can provide slightly more accurate predictions of species distributions. At the community level, the similar performance of both approaches for predicting patterns of assemblage variation suggests that species tend to respond individualistically or, alternatively, that our community model was unable to effectively account for the emergent community patterns. PMID- 23349819 TI - BIRB796, the inhibitor of p38 mitogen-activated protein kinase, enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cells. AB - ATP-binding-cassette family membrane proteins play an important role in multidrug resistance. In this study, we investigated BIRB796, an orally active inhibitor of p38 mitogen-activated protein kinase, reversed MDR induced by ABCB1, ABCG2 and ABCC1. Our results showed that BIRB796 could reverse ABCB1-mediated MDR in both the drug selected and transfected ABCB1-overexpressing cell models, but did not enhance the efficacy of substrate-chemotherapeutical agents in ABCC1 or ABCG2 overexpression cells and their parental sensitive cells. Furthermore, BIRB796 increased the intracellular accumulation of the ABCB1 substrates, such as rhodamine 123 and doxorubicin. Moreover, BIRB796 bidirectionally mediated the ATPase activity of ABCB1, stimulating at low concentration, inhibiting at high concentration. However, BIRB796 did not alter the expression of ABCB1 both at protein and mRNA level. The down-regulation of p38 by siRNA neither affected the expression of ABCB1 nor the cytotoxic effect of paclitaxel on KBV200. The binding model of BIRB796 within the large cavity of the transmembrane region of ABCB1 may form the basis for future lead optimization studies. Importantly, BIRB796 also enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1 overexpressing KBV200 cell xenografts in nude mice. Overall, we conclude that BIRB796 reverses ABCB1-mediated MDR by directly inhibiting its transport function. These findings may be useful for cancer combinational therapy with BIRB796 in the clinic. PMID- 23349820 TI - A school-based study with Rome III criteria on the prevalence of functional gastrointestinal disorders in Chinese college and university students. AB - BACKGROUND: Functional gastrointestinal disorders, including functional dyspepsia, irritable bowel syndrome and functional constipation are very common worldwide. OBJECTIVE: This research aims to estimate the prevalence and associated factors involved in functional gastrointestinal disorders in Chinese college and university students using the Rome III criteria. METHODS: A total of 5000 students from Shandong University in China were asked in January-May 2012 to complete questionnaires, including the Rome III questionnaire, hospital anxiety and depression scale, and negative life events scale. RESULTS: Based on the 4638 students who completed the questionnaire, the prevalence of functional dyspepsia, irritable bowel syndrome and functional constipation in college and university students of North China worked out to be 9.25%, 8.34% and 5.45% respectively. They were more frequent in female students. The factors of anxiety (OR 1.07; 95% CI 0.99 to 1.16, P=0.002<0.05) and depression (OR 0.55; 95% CI 0.15 to 1.05, P=0.045<0.05) indicated a high risk of causing irritable bowel syndrome. CONCLUSION: Functional dyspepsia, irritable bowel syndrome and functional constipation were common in college and university students of North China. Psychological disorders such as anxiety and depression provide significant risk factors for irritable bowel syndrome patients. PMID- 23349821 TI - Residue-specific annotation of disorder-to-order transition and cathepsin inhibition of a propeptide-like crammer from D. melanogaster. AB - Drosophila melanogaster crammer is a novel cathepsin inhibitor involved in long term memory formation. A molten globule-to-ordered structure transition is required for cathepsin inhibition. This study reports the use of alanine scanning to probe the critical residues in the two hydrophobic cores and the salt bridges of crammer in the context of disorder-to-order transition and cathepsin inhibition. Alanine substitution of the aromatic residues W9, Y12, F16, Y20, Y32, and W53 within the hydrophobic cores, and charged residues E8, R28, R29, and E67 in the salt bridges considerably decrease the ability of crammer to inhibit Drosophila cathepsin B (CTSB). Far-UV circular dichroism (CD), intrinsic fluorescence, and nuclear magnetic resonance (NMR) spectroscopies show that removing most of the aromatic and charged side-chains substantially reduces thermostability, alters pH-dependent helix formation, and disrupts the molten globule-to-ordered structure transition. Molecular modeling indicates that W53 in the hydrophobic Core 2 is essential for the interaction between crammer and the prosegment binding loop (PBL) of CTSB; the salt bridge between R28 and E67 is critical for the appropriate alignment of the alpha-helix 4 toward the CTSB active cleft. The results of this study show detailed residue-specific dissection of folding transition and functional contributions of the hydrophobic cores and salt bridges in crammer, which have hitherto not been characterized for cathepsin inhibition by propeptide-like cysteine protease inhibitors. Because of the involvements of cathepsin inhibitors in neurodegenerative diseases, these structural insights can serve as a template for further development of therapeutic inhibitors against human cathepsins. PMID- 23349822 TI - Casein kinase 1delta activity: a key element in the zebrafish circadian timing system. AB - Zebrafish have become a popular model for studies of the circadian timing mechanism. Taking advantage of its rapid development of a functional circadian clock and the availability of light-entrainable clock-containing cell lines, much knowledge has been gained about the circadian clock system in this species. However, the post-translational modifications of clock proteins, and in particular the phosphorylation of PER proteins by Casein kinase I delta and epsilon (CK1delta and CK1epsilon), have so far not been examined in the zebrafish. Using pharmacological inhibitors for CK1delta and CK1epsilon, a pan CK1delta/epsilon inhibitor PF-670462, and a CK1epsilon -selective inhibitor PF 4800567, we show that CK1delta activity is crucial for the functioning of the circadian timing mechanism of zebrafish, while CK1epsilon plays a minor role. The CK1delta/epsilon inhibitor disrupted circadian rhythms of promoter activity in the circadian clock-containing zebrafish cell line, PAC-2, while the CK1epsilon inhibitor had no effect. Zebrafish larvae that were exposed to the CK1delta/epsilon inhibitor showed no rhythms of locomotor activity while the CK1epsilon inhibitor had only a minor effect on locomotor activity. Moreover, the addition of the CK1delta/epsilon inhibitor disrupted rhythms of aanat2 mRNA expression in the pineal gland. The pineal gland is considered to act as a central clock organ in fish, delivering a rhythmic hormonal signal, melatonin, which is regulated by AANAT2 enzymatic activity. Therefore, CK1delta plays a key role in the circadian timing system of the zebrafish. Furthermore, the effect of CK1delta inhibition on rhythmic locomotor activity may reflect its effect on the function of the central clock in the pineal gland as well as its regulation of peripheral clocks. PMID- 23349823 TI - Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature. AB - INTRODUCTION: Inherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms underlying this process may result in the development of novel agents to enhance the sensitivity of cisplatin. METHODS: An isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460). Over a period of twelve months, cisplatin resistant (CisR) cell lines were derived from original, age matched parent cells (PT) and subsequently characterized. Proliferation (MTT) and clonogenic survival assays (crystal violet) were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and beta catenin. Cisplatin-DNA adduct formation, DNA damage (gammaH2AX) and cellular platinum uptake (ICP-MS) was also assessed. RESULTS: Characterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c Met and beta-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased gammaH2AX foci were observed compared to parental cell lines. CONCLUSION: Our results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing a further understanding of the cellular events associated with the cisplatin resistance phenotype in lung cancer. PMID- 23349824 TI - Imaging conditioned fear circuitry using awake rodent fMRI. AB - Functional magnetic resonance imaging (fMRI) is a powerful method for exploring emotional and cognitive brain responses in humans. However rodent fMRI has not previously been applied to the analysis of learned behaviour in awake animals, limiting its use as a translational tool. Here we have developed a novel paradigm for studying brain activation in awake rats responding to conditioned stimuli using fMRI. Using this method we show activation of the amygdala and related fear circuitry in response to a fear-conditioned stimulus and demonstrate that the magnitude of fear circuitry activation is increased following early life stress, a rodent model of affective disorders. This technique provides a new translatable method for testing environmental, genetic and pharmacological manipulations on emotional and cognitive processes in awake rodent models. PMID- 23349825 TI - Stabilization of the skeletal muscle ryanodine receptor ion channel-FKBP12 complex by the 1,4-benzothiazepine derivative S107. AB - Activation of the skeletal muscle ryanodine receptor (RyR1) complex results in the rapid release of Ca(2+) from the sarcoplasmic reticulum and muscle contraction. Dissociation of the small FK506 binding protein 12 subunit (FKBP12) increases RyR1 activity and impairs muscle function. The 1,4-benzothiazepine derivative JTV519, and the more specific derivative S107 (2,3,4,5,-tetrahydro-7 methoxy-4-methyl-1,4-benzothiazepine), are thought to improve skeletal muscle function by stabilizing the RyR1-FKBP12 complex. Here, we report a high degree of nonspecific and specific low affinity [(3)H]S107 binding to SR vesicles. SR vesicles enriched in RyR1 bound ~48 [(3)H]S107 per RyR1 tetramer with EC(50) ~52 uM and Hillslope ~2. The effects of S107 and FKBP12 on RyR1 were examined under conditions that altered the redox state of RyR1. S107 increased FKBP12 binding to RyR1 in SR vesicles in the presence of reduced glutathione and the NO-donor NOC12, with no effect in the presence of oxidized glutathione. Addition of 0.15 uM FKBP12 to SR vesicles prevented FKBP12 dissociation; however, in the presence of oxidized glutathione and NOC12, FKBP12 dissociation was observed in skeletal muscle homogenates that contained 0.43 uM myoplasmic FKBP12 and was attenuated by S107. In single channel measurements with FKBP12-depleted RyR1s, in the absence and presence of NOC12, S107 augmented the FKBP12-mediated decrease in channel activity. The data suggest that S107 can reverse the harmful effects of redox active species on SR Ca(2+) release in skeletal muscle by binding to RyR1 low affinity sites. PMID- 23349826 TI - Finding protein-coding genes through human polymorphisms. AB - Human gene catalogs are fundamental to the study of human biology and medicine. But they are all based on open reading frames (ORFs) in a reference genome sequence (with allowance for introns). Individual genomes, however, are polymorphic: their sequences are not identical. There has been much research on how polymorphism affects previously-identified genes, but no research has been done on how it affects gene identification itself. We computationally predict protein-coding genes in a straightforward manner, by finding long ORFs in mRNA sequences aligned to the reference genome. We systematically test the effect of known polymorphisms with this procedure. Polymorphisms can not only disrupt ORFs, they can also create long ORFs that do not exist in the reference sequence. We found 5,737 putative protein-coding genes that do not exist in the reference, whose protein-coding status is supported by homology to known proteins. On average 10% of these genes are located in the genomic regions devoid of annotated genes in 12 other catalogs. Our statistical analysis showed that these ORFs are unlikely to occur by chance. PMID- 23349827 TI - A lectin with highly potent inhibitory activity toward breast cancer cells from edible tubers of Dioscorea opposita cv. nagaimo. AB - A 70-kDa galactose-specific lectin was purified from the tubers of Dioscorea opposita cv. nagaimo. The purification involved three chromatographic steps: anion exchange chromatography on a Q-Sepharose column, FPLC-anion exchange chromatography on a Mono Q column, and FPLC-gel filtration on a Superdex 75 column. The purified nagaimo lectin presented as a single 35-kDa band in reducing SDS-PAGE while it exhibited a 70-kDa single band in non-reducing SDS-PAGE suggesting its dimeric nature. Nagaimo lectin displayed moderate thermostability, retaining full hemagglutinating activity after heating up to 62 degrees C for 30 minutes. It also manifested stability over a wide pH range from pH 2 to 13. Nagaimo lectin was a galactose-specific lectin, as evidenced by binding with galactose and galactose-containing sugars such as lactose and raffinose. The minimum concentration of galactose, lactose and raffinose required to exert an inhibitory effect on hemagglutinating activity of nagaimo lectin was 20 mM, 5 mM and 40 mM, respectively. Nagaimo lectin inhibited the growth of some cancer cell lines including breast cancer MCF7 cells, hepatoma HepG2 cells and nasopharyngeal carcinoma CNE2 cells, with IC(50) values of 3.71 uM, 7.12 uM and 19.79 uM, respectively, after 24 hour treatment with nagaimo lectin. The induction of phosphatidylserine externalization and mitochondrial depolarization indicated that nagaimo lectin evoked apoptosis in MCF7 cells. However, the anti proliferative activity of nagaimo lectin was not blocked by application of galactose, signifying that the activity was not related to the carbohydrate binding specificity of the lectin. PMID- 23349829 TI - Predicting the impact of climate change on threatened species in UK waters. AB - Global climate change is affecting the distribution of marine species and is thought to represent a threat to biodiversity. Previous studies project expansion of species range for some species and local extinction elsewhere under climate change. Such range shifts raise concern for species whose long-term persistence is already threatened by other human disturbances such as fishing. However, few studies have attempted to assess the effects of future climate change on threatened vertebrate marine species using a multi-model approach. There has also been a recent surge of interest in climate change impacts on protected areas. This study applies three species distribution models and two sets of climate model projections to explore the potential impacts of climate change on marine species by 2050. A set of species in the North Sea, including seven threatened and ten major commercial species were used as a case study. Changes in habitat suitability in selected candidate protected areas around the UK under future climatic scenarios were assessed for these species. Moreover, change in the degree of overlap between commercial and threatened species ranges was calculated as a proxy of the potential threat posed by overfishing through bycatch. The ensemble projections suggest northward shifts in species at an average rate of 27 km per decade, resulting in small average changes in range overlap between threatened and commercially exploited species. Furthermore, the adverse consequences of climate change on the habitat suitability of protected areas were projected to be small. Although the models show large variation in the predicted consequences of climate change, the multi-model approach helps identify the potential risk of increased exposure to human stressors of critically endangered species such as common skate (Dipturus batis) and angelshark (Squatina squatina). PMID- 23349828 TI - The sequence structures of human microRNA molecules and their implications. AB - The count of the nucleotides in a cloned, short genomic sequence has become an important criterion to annotate such a sequence as a miRNA molecule. While the majority of human mature miRNA sequences consist of 22 nucleotides, there exists discrepancy in the characteristic lengths of the miRNA sequences. There is also a lack of systematic studies on such length distribution and on the biological factors that are related to or may affect this length. In this paper, we intend to fill this gap by investigating the sequence structure of human miRNA molecules using statistics tools. We demonstrate that the traditional discrete probability distributions do not model the length distribution of the human mature miRNAs well, and we obtain the statistical distribution model with a decent fit. We observe that the four nucleotide bases in a miRNA sequence are not randomly distributed, implying that possible structural patterns such as dinucleotide (trinucleotide or higher order) may exist. Furthermore, we study the relationships of this length distribution to multiple important factors such as evolutionary conservation, tumorigenesis, the length of precursor loop structures, and the number of predicted targets. The association between the miRNA sequence length and the distributions of target site counts in corresponding predicted genes is also presented. This study results in several novel findings worthy of further investigation that include: (1) rapid evolution introduces variation to the miRNA sequence length distribution; (2) miRNAs with extreme sequence lengths are unlikely to be cancer-related; and (3) the miRNA sequence length is positively correlated to the precursor length and the number of predicted target genes. PMID- 23349830 TI - Ferulic acid attenuates the injury-induced decrease of protein phosphatase 2A subunit B in ischemic brain injury. AB - BACKGROUND: Ferulic acid provides a neuroprotective effect during cerebral ischemia through its anti-oxidant function. Protein phosphatase 2A (PP2A) is a serine and threonine phosphatase that contributes broadly to normal brain function. This study investigated whether ferulic acid regulates PP2A subunit B in a middle cerebral artery occlusion (MCAO) animal model and glutamate toxicity induced neuronal cell death. METHODOLOGY/PRINCIPAL FINDINGS: MCAO was surgically induced to yield permanent cerebral ischemic injury in rats. The rats were treated with either vehicle or ferulic acid (100 mg/kg, i.v.) immediately after MCAO, and cerebral cortex tissues were collected 24 h after MCAO. A proteomics approach, RT-PCR, and Western blot analyses performed to identification of PP2A subunit B expression levels. Ferulic acid significantly reduced the MCAO-induced infarct volume of the cerebral cortex. A proteomics approach elucidated the reduction of PP2A subunit B in MCAO-induced animals, and ferulic acid treatment prevented the injury-induced reduction in PP2A subunit B levels. RT-PCR and Western blot analyses also showed that ferulic acid treatment attenuates the injury-induced decrease in PP2A subunit B levels. Moreover, the number of PP2A subunit B-positive cells was reduced in MCAO-induced animals, and ferulic acid prevented these decreases. In cultured neuronal cells, ferulic acid treatment protected cells against glutamate toxicity and prevented the glutamate-induced decrease in PP2A subunit B. CONCLUSIONS/SIGNIFICANCE: These results suggest that the maintenance of PP2A subunit B by ferulic acid in ischemic brain injury plays an important role for the neuroprotective function of ferulic acid. PMID- 23349831 TI - Two strains of male-killing Wolbachia in a ladybird, Coccinella undecimpunctata, from a hot climate. AB - Ladybirds are a hot-spot for the invasion of male-killing bacteria. These maternally inherited endosymbionts cause the death of male host embryos, to the benefit of female sibling hosts and the bacteria that they contain. Previous studies have shown that high temperatures can eradicate male-killers from ladybirds, leaving the host free from infection. Here we report the discovery of two maternally inherited sex ratio distorters in populations of a coccinellid, Coccinella undecimpunctata, from a hot lowland region of the Middle East. DNA sequence analysis indicates that the male killing is the result of infection by Wolbachia, that the trait is tetracycline sensitive, and that two distinct strains of Wolbachia co-occur within one beetle population. We discuss the implications of these findings for theories of male-killing and suggest avenues for future field-work on this system. PMID- 23349832 TI - MicroRNA-22 (miR-22) overexpression is neuroprotective via general anti-apoptotic effects and may also target specific Huntington's disease-related mechanisms. AB - BACKGROUND: Whereas many causes and mechanisms of neurodegenerative diseases have been identified, very few therapeutic strategies have emerged in parallel. One possible explanation is that successful treatment strategy may require simultaneous targeting of more than one molecule of pathway. A new therapeutic approach to have emerged recently is the engagement of microRNAs (miRNAs), which affords the opportunity to target multiple cellular pathways simultaneously using a single sequence. METHODOLOGY/PRINCIPAL FINDINGS: We identified miR-22 as a potentially neuroprotective miRNA based on its predicted regulation of several targets implicated in Huntington's disease (histone deacetylase 4 (HDAC4), REST corepresor 1 (Rcor1) and regulator of G-protein signaling 2 (Rgs2)) and its diminished expression in Huntington's and Alzheimer's disease brains. We then tested the hypothesis that increasing cellular levels of miRNA-22 would achieve neuroprotection in in vitro models of neurodegeneration. As predicted, overexpression of miR-22 inhibited neurodegeneration in primary striatal and cortical cultures exposed to a mutated human huntingtin fragment (Htt171-82Q). Overexpression of miR-22 also decreased neurodegeneration in primary neuronal cultures exposed to 3-nitropropionic acid (3-NP), a mitochondrial complex II/III inhibitor. In addition, miR-22 improved neuronal viability in an in vitro model of brain aging. The mechanisms underlying the effects of miR-22 included a reduction in caspase activation, consistent with miR-22's targeting the pro apoptotic activities of mitogen-activated protein kinase 14/p38 (MAPK14/p38) and tumor protein p53-inducible nuclear protein 1 (Tp53inp1). Moreover, HD-specific effects comprised not only targeting HDAC4, Rcor1 and Rgs2 mRNAs, but also decreasing focal accumulation of mutant Htt-positive foci, which occurred via an unknown mechanism. CONCLUSIONS: These data show that miR-22 has multipartite anti neurodegenerative activities including the inhibition of apoptosis and the targeting of mRNAs implicated in the etiology of HD. These results motivate additional studies to evaluate the feasibility and therapeutic efficacy of manipulating miR-22 in vivo. PMID- 23349833 TI - Could public restrooms be an environment for bacterial resistomes? AB - Antibiotic resistance in bacteria remains a major problem and environments that help to maintain such resistance, represent a significant problem to infection control in the community. Restrooms have always been regarded as potential sources of infectious diseases and we suggest they have the potential to sustain bacterial "resistomes". Recent studies have demonstrated the wide range of different bacterial phyla that can be found in non-healthcare restrooms. In our study we focused on the Staphylococci. These species are often skin contaminants on man and have been reported as common restroom isolates in recent molecular studies. We collected samples from 18 toilets sited in 4 different public buildings. Using MALDI-TOF-MS and other techniques, we identified a wide range of antibiotic resistant Staphylococci and other bacteria from our samples. We identified 19 different Staphylococcal species within our isolates and 37.8% of the isolates were drug resistant. We also identified different Staphylococcal species with the same antibiograms inhabiting the same restrooms. Bacterial "resistomes" are communities of bacteria often localised in specific areas and within these environments drug resistance determinants may be freely transferred. Our study shows that non-healthcare restrooms are a source of antibiotic resistant bacteria where a collection of antibiotic resistance genes in pathogenic and non-pathogenic bacteria could form a resistome containing a "nexus of genetic diversity" PMID- 23349834 TI - Genome-wide landscapes of human local adaptation in Asia. AB - Genetic studies of human local adaptation have been facilitated greatly by recent advances in high-throughput genotyping and sequencing technologies. However, few studies have investigated local adaptation in Asian populations on a genome-wide scale and with a high geographic resolution. In this study, taking advantage of the dense population coverage in Southeast Asia, which is the part of the world least studied in term of natural selection, we depicted genome-wide landscapes of local adaptations in 63 Asian populations representing the majority of linguistic and ethnic groups in Asia. Using genome-wide data analysis, we discovered many genes showing signs of local adaptation or natural selection. Notable examples, such as FOXQ1, MAST2, and CDH4, were found to play a role in hair follicle development and human cancer, signal transduction, and tumor repression, respectively. These showed strong indications of natural selection in Philippine Negritos, a group of aboriginal hunter-gatherers living in the Philippines. MTTP, which has associations with metabolic syndrome, body mass index, and insulin regulation, showed a strong signature of selection in Southeast Asians, including Indonesians. Functional annotation analysis revealed that genes and genetic variants underlying natural selections were generally enriched in the functional category of alternative splicing. Specifically, many genes showing significant difference with respect to allele frequency between northern and southern Asian populations were found to be associated with human height and growth and various immune pathways. In summary, this study contributes to the overall understanding of human local adaptation in Asia and has identified both known and novel signatures of natural selection in the human genome. PMID- 23349835 TI - Development of a simple reliable radiographic scoring system to aid the diagnosis of pulmonary tuberculosis. AB - RATIONALE: Chest radiography is sometimes the only method available for investigating patients with possible pulmonary tuberculosis (PTB) with negative sputum smears. However, interpretation of chest radiographs in this context lacks specificity for PTB, is subjective and is neither standardized nor reproducible. Efforts to improve the interpretation of chest radiography are warranted. OBJECTIVES: To develop a scoring system to aid the diagnosis of PTB, using features recorded with the Chest Radiograph Reading and Recording System (CRRS). METHODS: Chest radiographs of outpatients with possible PTB, recruited over 3 years at clinics in South Africa were read by two independent readers using the CRRS method. Multivariate analysis was used to identify features significantly associated with culture-positive PTB. These were weighted and used to generate a score. RESULTS: 473 patients were included in the analysis. Large upper lobe opacities, cavities, unilateral pleural effusion and adenopathy were significantly associated with PTB, had high inter-reader reliability, and received 2, 2, 1 and 2 points, respectively in the final score. Using a cut-off of 2, scores below this threshold had a high negative predictive value (91.5%, 95%CI 87.1,94.7), but low positive predictive value (49.4%, 95%CI 42.9,55.9). Among the 382 TB suspects with negative sputum smears, 229 patients had scores <2; the score correctly ruled out active PTB in 214 of these patients (NPV 93.4%; 95%CI 89.4,96.3). The score had a suboptimal negative predictive value in HIV infected patients (NPV 86.4, 95% CI 75,94). CONCLUSIONS: The proposed scoring system is simple, and reliably ruled out active PTB in smear-negative HIV uninfected patients, thus potentially reducing the need for further tests in high burden settings. Validation studies are now required. PMID- 23349837 TI - Alteration of JNK-1 signaling in skeletal muscle fails to affect glucose homeostasis and obesity-associated insulin resistance in mice. AB - Obesity and associated metabolic disturbances, such as increased circulating fatty acids cause prolonged low grade activation of inflammatory signaling pathways in liver, skeletal muscle, adipose tissue and even in the CNS. Activation of inflammatory pathways in turn impairs insulin signaling, ultimately leading to obesity-associated type 2 diabetes mellitus. Conventional JNK-1 knock out mice are protected from high fat diet-induced insulin resistance, characterizing JNK-1-inhibition as a potential approach to improve glucose metabolism in obese patients. However, the cell type-specific role of elevated JNK-1 signaling as present during the course of obesity has not been fully elucidated yet. To investigate the functional contribution of altered JNK-1 activation in skeletal muscle, we have generated a ROSA26 insertion mouse strain allowing for Cre-activatable expression of a JNK-1 constitutive active construct (JNK(C)). To examine the consequence of skeletal muscle-restricted JNK-1 overactivation in the development of insulin resistance and glucose metabolism, JNK(C) mice were crossed to Mck-Cre mice yielding JNK(SM-C) mice. However, despite increased muscle-specific JNK activation, energy homeostasis and glucose metabolism in JNK(SM-C) mice remained largely unaltered compared to controls. In line with these findings, obese mice with skeletal muscle specific disruption of JNK-1, did not affect energy and glucose homeostasis. These experiments indicate that JNK-1 activation in skeletal muscle does not account for the major effects on diet-induced, JNK-1-mediated deterioration of insulin action and points towards a so far underappreciated role of JNK-1 in other tissues than skeletal muscle during the development of obesity-associated insulin resistance. PMID- 23349836 TI - Directed pancreatic acinar differentiation of mouse embryonic stem cells via embryonic signalling molecules and exocrine transcription factors. AB - Pluripotent embryonic stem cells (ESC) are a promising cellular system for generating an unlimited source of tissue for the treatment of chronic diseases and valuable in vitro differentiation models for drug testing. Our aim was to direct differentiation of mouse ESC into pancreatic acinar cells, which play key roles in pancreatitis and pancreatic cancer. To that end, ESC were first differentiated as embryoid bodies and sequentially incubated with activin A, inhibitors of Sonic hedgehog (Shh) and bone morphogenetic protein (BMP) pathways, fibroblast growth factors (FGF) and retinoic acid (RA) in order to achieve a stepwise increase in the expression of mRNA transcripts encoding for endodermal and pancreatic progenitor markers. Subsequent plating in Matrigel(r) and concomitant modulation of FGF, glucocorticoid, and folllistatin signalling pathways involved in exocrine differentiation resulted in a significant increase of mRNAs encoding secretory enzymes and in the number of cells co-expressing their protein products. Also, pancreatic endocrine marker expression was down regulated and accompanied by a significant reduction in the number of hormone expressing cells with a limited presence of hepatic marker expressing-cells. These findings suggest a selective activation of the acinar differentiation program. The newly differentiated cells were able to release alpha-amylase and this feature was greatly improved by lentiviral-mediated expression of Rbpjl and Ptf1a, two transcription factors involved in the maximal production of digestive enzymes. This study provides a novel method to produce functional pancreatic exocrine cells from ESC. PMID- 23349838 TI - Serotonin receptor 2C and insulin secretion. AB - Type 2 diabetes mellitus (T2DM) describes a group of metabolic disorders characterized by defects in insulin secretion and insulin sensitivity. Insulin secretion from pancreatic beta-cells is an important factor in the etiology of T2DM, though the complex regulation and mechanisms of insulin secretion from beta cells remains to be fully elucidated. High plasma levels of serotonin (5 hydroxytryptamine; 5-HT) have been reported in T2DM patients, though the potential effect on insulin secretion is unclear. However, it is known that the 5 HT receptor 2C (5-HT(2C)R) agonist, mCPP, decreases plasma insulin concentration in mice. As such, we aimed to investigate the expression of the 5-HT(2C)R in pancreatic islets of diabetic mice and the role of 5-HT(2C)R signaling in insulin secretion from pancreatic beta-cells. We found that 5-HT(2C)R expression was significantly increased in pancreatic islets of db/db mice. Furthermore, treatment with a 5-HT(2C)R antagonist (SB242084) increased insulin secretion from pancreatic islets isolated from db/db mice in a dose-dependent manner, but had no effect in islets from control mice. The effect of a 5-HT(2C)R agonist (mCPP) and antagonist (SB242084) were further studied in isolated pancreatic islets from mice and Min-6 cells. We found that mCPP significantly inhibited insulin secretion in Min-6 cells and isolated islets in a dose-dependent manner, which could be reversed by SB242084 or RNA interference against 5-HT(2C)R. We also treated Min-6 cells with palmitic acid for 24 h, and found that the expression of 5-HT(2C)R increased in a dose-dependent manner; furthermore, the inhibition of insulin secretion in Min-6 cells induced by palmitic acid could be reversed by SB242084 or RNA interference against 5-HT(2C)R. Taken together, our data suggests that increased expression of 5-HT(2C)R in pancreatic beta-cells might inhibit insulin secretion. This unique observation increases our understanding of T2DM and suggests new avenues for potential treatment. PMID- 23349840 TI - Cyclic AMP enhances TGFbeta responses of breast cancer cells by upregulating TGFbeta receptor I expression. AB - Cellular functions are regulated by complex networks of many different signaling pathways. The TGFbeta and cAMP pathways are of particular importance in tumor progression. We analyzed the cross-talk between these pathways in breast cancer cells in 2D and 3D cultures. We found that cAMP potentiated TGFbeta-dependent gene expression by enhancing Smad3 phosphorylation. Higher levels of total Smad3, as observed in 3D-cultured cells, blocked this effect. Two Smad3 regulating proteins, YAP (Yes-associated protein) and TbetaRI (TGFbeta receptor 1), were responsive to cAMP. While YAP had little effect on TGFbeta-dependent expression and Smad3 phosphorylation, a constitutively active form of TbetaRI mimicked the cAMP effect on TGFbeta signaling. In 3D-cultured cells, which show much higher levels of TbetaRI and cAMP, TbetaRI was unresponsive to cAMP. Upregulation of TbetaRI expression by cAMP was dependent on transcription. A proximal TbetaRI promoter fragment was moderately, but significantly activated by cAMP suggesting that cAMP increases TbetaRI expression at least partially by activating TbetaRI transcription. Neither the cAMP-responsive element binding protein (CREB) nor the TbetaRI-regulating transcription factor Six1 was required for the cAMP effect. An inhibitor of histone deacetylases alone or together with cAMP increased TbetaRI expression by a similar extent as cAMP alone suggesting that cAMP may exert its effect by interfering with histone acetylation. Along with an additive stimulatory effect of cAMP and TGFbeta on p21 expression an additive inhibitory effect of these agents on proliferation was observed. Finally, we show that mesenchymal stem cells that interact with breast cancer cells can simultaneously activate the cAMP and TGFbeta pathways. In summary, these data suggest that combined effects of cAMP and TGFbeta, as e.g. induced by mesenchymal stem cells, involve the upregulation of TbetaRI expression on the transcriptional level, likely due to changes in histone acetylation. As a consequence, cancer cell functions such as proliferation are affected. PMID- 23349839 TI - Surveillance of bovine tuberculosis and risk estimation of a future reservoir formation in wildlife in Switzerland and Liechtenstein. AB - Bovine tuberculosis (bTB) caused by Mycobacterium bovis or M. caprae has recently (re-) emerged in livestock and wildlife in all countries bordering Switzerland (CH) and the Principality of Liechtenstein (FL). Comprehensive data for Swiss and Liechtenstein wildlife are not available so far, although two native species, wild boar (Sus scrofa) and red deer (Cervus elaphus elaphus), act as bTB reservoirs elsewhere in continental Europe. Our aims were (1) to assess the occurrence of bTB in these wild ungulates in CH/FL and to reinforce scanning surveillance in all wild mammals; (2) to evaluate the risk of a future bTB reservoir formation in wild boar and red deer in CH/FL. Tissue samples collected from 2009 to 2011 from 434 hunted red deer and wild boar and from eight diseased ungulates with tuberculosis-like lesions were tested by direct real-time PCR and culture to detect mycobacteria of the Mycobacterium tuberculosis complex (MTBC). Identification of suspicious colonies was attempted by real-time PCR, genotyping and spoligotyping. Information on risk factors for bTB maintenance within wildlife populations was retrieved from the literature and the situation regarding identified factors was assessed for our study areas. Mycobacteria of the MTBC were detected in six out of 165 wild boar (3.6%; 95% CI: 1.4-7.8) but none of the 269 red deer (0%; 0-1.4). M. microti was identified in two MTBC positive wild boar, while species identification remained unsuccessful in four cases. Main risk factors for bTB maintenance worldwide, including different causes of aggregation often resulting from intensive wildlife management, are largely absent in CH and FL. In conclusion, M. bovis and M. caprae were not detected but we report for the first time MTBC mycobacteria in Swiss wild boar. Present conditions seem unfavorable for a reservoir emergence, nevertheless increasing population numbers of wild ungulates and offal consumption may represent a risk. PMID- 23349841 TI - Immunogenicity and cross protective ability of the central VP2 amino acids of infectious pancreatic necrosis virus in Atlantic salmon (Salmo salar L.). AB - Infectious pancreatic necrosis virus (IPNV) is a member of the family Birnaviridae that has been linked to high mortalities in juvenile salmonids and postsmolt stages of Atlantic salmon (Salmo salar L.) after transfer to seawater. IPN vaccines have been available for a long time but their efficacy has been variable. The reason for the varying immune response to these vaccines has not well defined and studies on the importance of using vaccine trains homologous to the virulent field strain has not been conclusive. In this study we prepared one vaccine identical to the virulent Norwegian Sp strain NVI-015 (NCBI: 379740) (T(217)A(221)T(247) of VP2) and three other vaccine strains developed using the same genomic backbone altered by reverse genetics at three residues yielding variants, T(217)T(221)T(247), P(217)A(221)A(247), P(217)T(221)A(247). These 4 strains, differing in these three positions only, were used as inactivated, oil adjuvanted vaccines while two strains, T(217)A(221)T(247) and P(217)T(221)A(247), were used as live vaccines. The results show that these three residues of the VP2 capsid play a key role for immunogenicity of IPNV vaccines. The virulent strain for inactivated vaccines elicited the highest level of virus neutralization (VN) titers and ELISA antibodies. Interestingly, differences in immunogenicity were not reflected in differences in post challenge survival percentages (PCSP) for oil-adjuvanted, inactivated vaccines but clearly so for live vaccines (TAT and PTA). Further post challenge viral carrier state correlated inversely with VN titers at challenge for inactivated vaccines and prevalence of pathology in target organs inversely correlated with protection for live vaccines. Overall, our findings show that a few residues localized on the VP2-capsid are important for immunogenicity of IPNV vaccines. PMID- 23349842 TI - Homocysteine inhibits hepatocyte proliferation via endoplasmic reticulum stress. AB - Homocysteine is an independent risk factor for coronary, cerebral, and peripheral vascular diseases. Recent studies have shown that levels of homocysteine are elevated in patients with impaired hepatic function, but the precise role of homocysteine in the development of hepatic dysfunction is unclear. In this study, we examined the effect of homocysteine on hepatocyte proliferation in vitro. Our results demonstrated that homocysteine inhibited hepatocyte proliferation by up regulating protein levels of p53 as well as mRNA and protein levels of p21(Cip1) in primary cultured hepatocytes. Homocysteine induced cell growth arrest in p53 positive hepatocarcinoma cell line HepG2, but not in p53-null hepatocarcinoma cell line Hep3B. A p53 inhibitor pifithrin-alpha inhibited the expression of p21(Cip1) and attenuated homocysteine-induced cell growth arrest. Homocysteine induced TRB3 expression via endoplasmic reticulum stress pathway, resulting in Akt dephosphorylation. Knock-down of endogenous TRB3 significantly suppressed the inhibitory effect of homocysteine on cell proliferation and the phosphorylation of Akt. LiCl reversed homocysteine-mediated cell growth arrest by inhibiting TRB3 mediated Akt dephosphorylation. These results demonstrate that both TRB3 and p21(Cip1) are critical molecules in the homocysteine signaling cascade and provide a mechanistic explanation for impairment of liver regeneration in hyperhomocysteinemia. PMID- 23349843 TI - Integrating HIV care into primary care services: quantifying progress of an intervention in South Africa. AB - BACKGROUND: Integration of human immunodeficiency virus (HIV) care into primary care services is one strategy proposed to achieve universal access to antiretroviral treatment (ART) for HIV-positive patients in high burden countries. There is a need for controlled studies of programmes to integrate HIV care with details of the services being integrated. METHODS: A semi-quantitative questionnaire was developed in consultation with clinic staff, tested for internal consistency using Cronbach's alpha coefficients and checked for inter observer reliability. It was used to conduct four assessments of the integration of HIV care into referring primary care clinics (mainstreaming HIV) and into the work of all nurses within ART clinics (internal integration) and the integration of pre-ART and ART care during the Streamlining Tasks and Roles to Expand Treatment and Care for HIV (STRETCH) trial in South Africa. Mean total integration and four component integration scores at intervention and control clinics were compared using one way analysis of variance (ANOVA). Repeated measures ANOVA was used to analyse changes in scores during the trial. RESULTS: Cronbach's alpha coefficients for total integration, pre-ART and ART integration and mainstreaming HIV and internal integration scores showed good internal consistency. Mean total integration, mainstreaming HIV and ART integration scores increased significantly at intervention clinics by the third assessment. Mean pre ART integration scores were almost maximal at the first assessment and showed no further change. There was no change in mean internal integration score. CONCLUSION: The questionnaire developed in this study is a valid tool with potential for monitoring integration of HIV care in other settings. The STRETCH trial interventions resulted in increased integration of HIV care, particularly ART care, by providing HIV care at referring primary care clinics, but had no effect on integrating HIV care into the work of all nurses with the ART clinic. PMID- 23349844 TI - Physiological and cellular responses caused by RNAi- mediated suppression of Snf7 orthologue in western corn rootworm (Diabrotica virgifera virgifera) larvae. AB - Ingestion of double stranded RNA (dsRNA) has been previously demonstrated to be effective in triggering RNA interference (RNAi) in western corn rootworm (WCR, Diabrotica virgifera virgifera LeConte), providing potential novel opportunities for insect pest control. The putative Snf7 homolog of WCR (DvSnf7) has previously been shown to be an effective RNAi target for insect control, as DvSnf7 RNAi leads to lethality of WCR larvae. Snf7 functions as a part of the ESCRT (Endosomal Sorting Complex Required for Transport) pathway which plays a crucial role in cellular housekeeping by internalization, transport, sorting and lysosomal degradation of transmembrane proteins. To understand the effects that lead to death of WCR larvae by DvSnf7 RNAi, we examined some of the distinct cellular processes associated with ESCRT functions such as de-ubiquitination of proteins and autophagy. Our data indicate that ubiquitinated proteins accumulate in DvSnf7 dsRNA-fed larval tissues and that the autophagy process seems to be impaired. These findings suggest that the malfunctioning of these cellular processes in both midgut and fat body tissues triggered by DvSnf7 RNAi were the main effects leading to the death of WCR. This study also illustrates that Snf7 is an essential gene in WCR and its functions are consistent with biological functions described for other eukaryotes. PMID- 23349845 TI - Influence of rhythmic grouping on duration perception: a novel auditory illusion. AB - This study investigated a potential auditory illusion in duration perception induced by rhythmic temporal contexts. Listeners with or without musical training performed a duration discrimination task for a silent period in a rhythmic auditory sequence. The critical temporal interval was presented either within a perceptual group or between two perceptual groups. We report the just-noticeable difference (difference limen, DL) for temporal intervals and the point of subjective equality (PSE) derived from individual psychometric functions based on performance of a two-alternative forced choice task. In musically untrained individuals, equal temporal intervals were perceived as significantly longer when presented between perceptual groups than within a perceptual group (109.25% versus 102.5% of the standard duration). Only the perceived duration of the between-group interval was significantly longer than its objective duration. Musically trained individuals did not show this effect. However, in both musically trained and untrained individuals, the relative difference limens for discriminating the comparison interval from the standard interval were larger in the between-groups condition than in the within-group condition (7.3% vs. 5.6% of the standard duration). Thus, rhythmic grouping affected sensitivity to duration changes in all listeners, with duration differences being harder to detect at boundaries of rhythm groups than within rhythm groups. Our results show for the first time that temporal Gestalt induces auditory duration illusions in typical listeners, but that musical experts are not susceptible to this effect of rhythmic grouping. PMID- 23349846 TI - Role of GalNAc4S-6ST in astrocytic tumor progression. AB - N-Acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S-6ST) is the sulfotransferase responsible for biosynthesis of highly sulfated chondroitin sulfate CS-E. Although involvements of CS-E in neuronal cell functions have been extensively analyzed, the role of GalNAc4S-6ST in astrocytic tumor progression remains unknown. Here, we reveal that GalNAc4S-6ST transcripts were detected in astrocytic tumors derived from all 30 patients examined using quantitative reverse transcription-PCR analysis. Patients with high GalNAc4S-6ST mRNA expression had significantly worse outcome compared with patients with low expression, and multivariate survival analysis disclosed that GalNAc4S-6ST is an independent poor prognostic factor for astrocytic tumors. We then tested whether CS-E enhanced haptotaxic migration of glioblastoma U251-MG cells that endogenously express both the CS-E's scaffold tyrosine phosphatase zeta (PTPzeta) and GalNAc4S-6ST, in the presence of CS-E's preferred ligands, pleiotrophin (PTN) or midkine (MK), using a modified Boyden chamber method. Haptotaxic stimulation of cell migration by PTN was most robust on control siRNA-transfected U251-MG cells, while that enhancing effect was cancelled following transduction of GalNAc4S-6ST siRNA. Similar results were obtained using MK, suggesting that both PTN and MK enhance migration of U251-MG cells by binding to CS-E. We also found that PTPzeta as well as PTN and MK were frequently expressed in astrocytic tumor cells. Thus, our findings indicate that GalNAc4S-6ST mRNA expressed by astrocytic tumor cells is associated with poor patient prognosis likely by enhancing CS-E mediated tumor cell motility in the presence of PTN and/or MK. PMID- 23349847 TI - HeurAA: accurate and fast detection of genetic variations with a novel heuristic amplicon aligner program for next generation sequencing. AB - Next generation sequencing (NGS) of PCR amplicons is a standard approach to detect genetic variations in personalized medicine such as cancer diagnostics. Computer programs used in the NGS community often miss insertions and deletions (indels) that constitute a large part of known human mutations. We have developed HeurAA, an open source, heuristic amplicon aligner program. We tested the program on simulated datasets as well as experimental data from multiplex sequencing of 40 amplicons in 12 oncogenes collected on a 454 Genome Sequencer from lung cancer cell lines. We found that HeurAA can accurately detect all indels, and is more than an order of magnitude faster than previous programs. HeurAA can compare reads and reference sequences up to several thousand base pairs in length, and it can evaluate data from complex mixtures containing reads of different gene segments from different samples. HeurAA is written in C and Perl for Linux operating systems, the code and the documentation are available for research applications at http://sourceforge.net/projects/heuraa/ PMID- 23349848 TI - Rehmannia glutinosa extract activates endothelial progenitor cells in a rat model of myocardial infarction through a SDF-1 alpha/CXCR4 cascade. AB - OBJECTIVES: Endothelial progenitor cells (EPCs) can be used to repair tissues after myocardial infarction (MI) but EPC activators have adverse reactions. Rehmannia glutinosa is a herb used in traditional Chinese medicine, which can promote bone-marrow proliferation and protect the ischemic myocardium. We investigated the effects of Rehmannia glutinosa extract (RGE) on EPCs in a rat model of MI. METHODS: A total of 120 male Wistar rats were randomized to 2 groups (n=60 each) for treatment: high-dose RGE (1.5 g.kg(-1).day(-1) orally) for 8 weeks, then left anterior descending coronary artery ligation, mock surgery or no treatment, then RGE orally for 4 weeks; or normal saline (NS) as the above protocol. The infarct region of the left ventricle was assessed by serial sectioning and morphology. EPCs were evaluated by number and function. Protein and mRNA levels of CD133, vascular endothelial growth factor receptor 2 (VEGFR2), chemokine C-X-C motif receptor 4 (CXCR4), stromal cell-derived factor-1alpha (SDF 1alpha) were measured by immunohistochemistry, Western blot and quantitative PCR analysis. RESULTS: RGE significantly improved left ventricular function, decreased the ischemic area and the apoptotic index in the infarct myocardium, also decreased the concentration of serum cardiac troponin T and brain natriuretic peptide at the chronic stage after MI (from week 2 to week 4). RGE increased EPC number, proliferation, migration and tube-formation capacity. It was able to up-regulate the expression of angiogenesis-associated ligand/receptor, including CD133, VEGFR2 and SDF-1alpha/CXCR4. In vitro, the effect of RGE on SDF-1alpha/CXCR4 cascade was reversed by the CXCR4 specific antagonist AMD3100. CONCLUSION: RGE may enhance the mobilization, migration and therapeutic angiogenesis of EPCs after MI by activating the SDF-1alpha/CXCR4 cascade. PMID- 23349849 TI - Flavonoids, flavonoid subclasses and breast cancer risk: a meta-analysis of epidemiologic studies. AB - BACKGROUND: Studies have suggested the chemopreventive effects of flavonoids on carcinogenesis. Yet numbers of epidemiologic studies assessing dietary flavonoids and breast cancer risk have yielded inconsistent results. The association between flavonoids, flavonoid subclasses (flavonols, flavan-3-ols, etc.) and the risk of breast cancer lacks systematic analysis. OBJECTIVE: We aimed to examine the association between flavonoids, each flavonoid subclass (except isoflavones) and the risk of breast cancer by conducting a meta-analysis. DESIGN: We searched for all relevant studies with a prospective cohort or case-control study design published before July 1(st), 2012, using Cochrane library, MEDLINE, EMBASE and PUBMED. Summary relative risks (RR) were calculated using fixed- or random effects models. All analyses were performed using STATA version 10.0. RESULTS: Twelve studies were included, involving 9 513 cases and 181 906 controls, six of which were prospective cohort studies, and six were case-control studies. We calculated the summary RRs of breast cancer risk for the highest vs lowest categories of each flavonoid subclass respectively. The risk of breast cancer significantly decreased in women with high intake of flavonols (RR=0.88, 95% CI 0.80-0.98) and flavones (RR=0.83, 95% CI: 0.76-0.91) compared with that in those with low intake of flavonols and flavones. However, no significant association of flavan-3-ols (RR=0.93, 95% CI: 0.84-1.02), flavanones (summary RR=0.95, 95% CI: 0.88-1.03), anthocyanins (summary RR=0.97, 95% CI: 0.87-1.08) or total flavonoids (summary RR=0.98, 95% CI: 0.86-1.12) intake with breast cancer risk was observed. Furthermore, summary RRs of 3 case-control studies stratified by menopausal status suggested flavonols, flavones or flavan-3-ols intake is associated with a significant reduced risk of breast cancer in post-menopausal while not in pre menopausal women. CONCLUSIONS: The present study suggests the intake of flavonols and flavones, but not other flavonoid subclasses or total flavonoids, is associated with a decreased risk of breast cancer, especially among post menopausal women. PMID- 23349850 TI - Accommodating species climate-forced dispersal and uncertainties in spatial conservation planning. AB - Spatial conservation prioritization should seek to anticipate climate change impacts on biodiversity and to mitigate these impacts through the development of dynamic conservation plans. Here, we defined spatial priorities for the conservation of amphibians inhabiting the Atlantic Forest Biodiversity Hotspot that overcome the likely impacts of climate change on the distribution of this imperiled fauna. First, we built ecological niche models (ENMs) for 431 amphibian species both for current time and for the mid-point of a 30-year period spanning 2071-2099 (i.e. 2080). For modeling species' niches, we combined six modeling methods and three different climate models. We also quantified and mapped model uncertainties. Our consensus models forecasted range shifts that culminate with high species richness in central and eastern Atlantic Forest, both for current time and for 2080. Most species had a significant range contraction (up to 72%) and 12% of species were projected to be regionally extinct. Most species would need to disperse because suitable climatic sites will change. Therefore, we identified a network of priority sites for conservation that minimizes the distance a given species would need to disperse because of changes in future habitat suitability (i.e. climate-forced dispersal) as well as uncertainties associated to ENMs. This network also maximized complementary species representation across currently established protected areas. Priority sites already include possible dispersal corridors linking current and future suitable habitats for amphibians. Although we used the a top-ranked Biodiversity Hotspot and amphibians as a case study for illustrating our approach, our study may help developing more effective conservation strategies under climate change, especially when applied at different spatial scales, geographic regions, and taxonomic groups. PMID- 23349851 TI - Evaluation of physical and functional protein-protein interaction prediction methods for detecting biological pathways. AB - BACKGROUND: Cellular activities are governed by the physical and the functional interactions among several proteins involved in various biological pathways. With the availability of sequenced genomes and high-throughput experimental data one can identify genome-wide protein-protein interactions using various computational techniques. Comparative assessments of these techniques in predicting protein interactions have been frequently reported in the literature but not their ability to elucidate a particular biological pathway. METHODS: Towards the goal of understanding the prediction capabilities of interactions among the specific biological pathway proteins, we report the analyses of 14 biological pathways of Escherichia coli catalogued in KEGG database using five protein-protein functional linkage prediction methods. These methods are phylogenetic profiling, gene neighborhood, co-presence of orthologous genes in the same gene clusters, a mirrortree variant, and expression similarity. CONCLUSIONS: Our results reveal that the prediction of metabolic pathway protein interactions continues to be a challenging task for all methods which possibly reflect flexible/independent evolutionary histories of these proteins. These methods have predicted functional associations of proteins involved in amino acids, nucleotide, glycans and vitamins & co-factors pathways slightly better than the random performance on carbohydrate, lipid and energy metabolism. We also make similar observations for interactions involved among the environmental information processing proteins. On the contrary, genetic information processing or specialized processes such as motility related protein-protein linkages that occur in the subset of organisms are predicted with comparable accuracy. Metabolic pathways are best predicted by using neighborhood of orthologous genes whereas phyletic pattern is good enough to reconstruct central dogma pathway protein interactions. We have also shown that the effective use of a particular prediction method depends on the pathway under investigation. In case one is not focused on specific pathway, gene expression similarity method is the best option. PMID- 23349852 TI - A platform for the remote conduct of gene-environment interaction studies. AB - BACKGROUND: Gene-environment interaction studies offer the prospect of robust causal inference through both gene identification and instrumental variable approaches. As such they are a major and much needed development. However, conducting these studies using traditional methods, which require direct participant contact, is resource intensive. The ability to conduct gene environment interaction studies remotely would reduce costs and increase capacity. AIM: To develop a platform for the remote conduct of gene-environment interaction studies. METHODS: A random sample of 15,000 men and women aged 50+ years and living in Cardiff, South Wales, of whom 6,012 were estimated to have internet connectivity, were mailed inviting them to visit a web-site to join a study of successful ageing. Online consent was obtained for questionnaire completion, cognitive testing, re-contact, record linkage and genotyping. Cognitive testing was conducted using the Cardiff Cognitive Battery. Bio-sampling was randomised to blood spot, buccal cell or no request. RESULTS: A heterogeneous sample of 663 (4.5% of mailed sample and 11% of internet connected sample) men and women (47% female) aged 50-87 years (median=61 yrs) from diverse backgrounds (representing the full range of deprivation scores) was recruited. Bio-samples were donated by 70% of those agreeing to do so. Self report questionnaires and cognitive tests showed comparable distributions to those collected using face-to face methods. Record linkage was achieved for 99.9% of participants. CONCLUSION: This study has demonstrated that remote methods are suitable for the conduct of gene-environment interaction studies. Up-scaling these methods provides the opportunity to increase capacity for large-scale gene-environment interaction studies. PMID- 23349853 TI - Dynamics of Streptococcus pneumoniae serotypes causing acute otitis media isolated from children with spontaneous middle-ear drainage over a 12-year period (1999-2010) in a region of northern Spain. AB - The aim of this study was to determine the serotype and clonal distribution of pneumococci causing acute otitis media (AOM) and their relationship with recurrences and mixed infections with other microorganisms under the influence of the 7-valent pneumococcal conjugate vaccine (PCV7). To do this, all pneumococcal isolates collected from the spontaneous middle-ear drainage of children <5 years old diagnosed of AOM by their pediatrician or their general practitioner from 1999 to 2010 were phenotypically characterized and the most frequent serotypes were genotyped. In the 12-year study, 818 episodes of pneumococcal AOM were detected, mostly (70.5%) in children younger than 2 years old. In 262 episodes (32%), the pneumococci were isolated with another bacterium, mainly (n=214) Haemophilus influenzae. Mixed infections were similar in children under or over 2 years old. The most frequent serotypes were 19A (n=227, 27.8%), 3 (n=92, 11.2%) and 19F (n=74, 9%). Serotypes included in the PCV7 sharply decreased from 62.4% in the pre-vaccination (1999-2001) to 2.2% in the late post-vaccination period (2008-2010). Serotype diversity steadily increased after the introduction of the PCV7 but decreased from 2008-2010 due to the predominant role of serotype 19A isolates, mostly ST276 and ST320. The prevalence of serotype 3 doubled from 6.1% (20/326) in 1999-2004 to 14.6% (72/492) in 2005-2010. Relapses mainly occurred in male infants infected with isolates with diminished antimicrobial susceptibility. Reinfections caused by isolates with the same serotype but different genotype were frequent, highlighting the need for genetic studies to differentiate among similar strains. In conclusion, the main change in pneumococcal AOM observed after the introduction of the PCV7 was the sharp decrease in vaccine serotypes. Also notable was the high burden of serotype 19A in total pneumococcal AOM before and especially after the introduction of the PCV7, as well as in relapses and reinfections. PMID- 23349854 TI - NA proteins of influenza A viruses H1N1/2009, H5N1, and H9N2 show differential effects on infection initiation, virus release, and cell-cell fusion. AB - Two surface glycoproteins of influenza virus, haemagglutinin (HA) and neuraminidase (NA), play opposite roles in terms of their interaction with host sialic acid receptors. HA attaches to sialic acid on host cell surface receptors to initiate virus infection while NA removes these sialic acids to facilitate release of progeny virions. This functional opposition requires a balance. To explore what might happen when NA of an influenza virus was replaced by one from another isolate or subtype, in this study, we generated three recombinant influenza A viruses in the background of A/PR/8/34 (PR8) (H1N1) and with NA genes obtained respectively from the 2009 pandemic H1N1 virus, a highly pathogenic avian H5N1 virus, and a lowly pathogenic avian H9N2 virus. These recombinant viruses, rPR8-H1N1NA, rPR8-H5N1NA, and rPR8-H9N2NA, were shown to have similar growth kinetics in cells and pathogenicity in mice. However, much more rPR8 H5N1NA and PR8-wt virions were released from chicken erythrocytes than virions of rPR8-H1N1NA and rPR8-H9N2NA after 1 h. In addition, in MDCK cells, rPR8-H5N1NA and rPR8-H9N2NA infected a higher percentage of cells, and induced cell-cell fusion faster and more extensively than PR8-wt and rPR8-H1N1NA did in the early phase of infection. In conclusion, NA replacement in this study did not affect virus replication kinetics but had different effects on infection initiation, virus release and fusion of infected cells. These phenomena might be partially due to NA proteins' different specificity to alpha2-3/2-6-sialylated carbohydrate chains, but the exact mechanism remains to be explored. PMID- 23349855 TI - Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors. AB - Human implantation involves extensive tissue remodeling at the fetal-maternal interface. It is becoming increasingly evident that not only trophoblast, but also decidualizing endometrial stromal cells are inherently motile and invasive, and likely contribute to the highly dynamic processes at the implantation site. The present study was undertaken to further characterize the mechanisms involved in the regulation of endometrial stromal cell motility and to identify trophoblast-derived factors that modulate migration. Among local growth factors known to be present at the time of implantation, heparin-binding epidermal growth factor-like growth factor (HB-EGF) triggered chemotaxis (directed locomotion), whereas platelet-derived growth factor (PDGF)-BB elicited both chemotaxis and chemokinesis (non-directed locomotion) of endometrial stromal cells. Supernatants of the trophoblast cell line AC-1M88 and of first trimester villous explant cultures stimulated chemotaxis but not chemokinesis. Proteome profiling for cytokines and angiogenesis factors revealed neither PDGF-BB nor HB-EGF in conditioned media from trophoblast cells or villous explants, while placental growth factor, vascular endothelial growth factor and PDGF-AA were identified as prominent secretory products. Among these, only PDGF-AA triggered endometrial stromal cell chemotaxis. Neutralization of PDGF-AA in trophoblast conditioned media, however, did not diminish chemoattractant activity, suggesting the presence of additional trophoblast-derived chemotactic factors. Pathway inhibitor studies revealed ERK1/2, PI3 kinase/Akt and p38 signaling as relevant for chemotactic motility, whereas chemokinesis depended primarily on PI3 kinase/Akt activation. Both chemotaxis and chemokinesis were stimulated upon inhibition of Rho-associated, coiled-coil containing protein kinase. The chemotactic response to trophoblast secretions was not blunted by inhibition of isolated signaling cascades, indicating activation of overlapping pathways in trophoblast endometrial communication. In conclusion, trophoblast signals attract endometrial stromal cells, while PDGF-BB and HB-EGF, although not identified as trophoblast derived, are local growth factors that may serve to fine-tune directed and non directed migration at the implantation site. PMID- 23349856 TI - Characterization of adult alpha- and beta-globin elevated by hydrogen peroxide in cervical cancer cells that play a cytoprotective role against oxidative insults. AB - OBJECTIVES: Hemoglobin (Hgb) is the main oxygen and carbon dioxide carrier in cells of erythroid lineage and is responsible for oxygen delivery to the respiring tissues of the body. However, Hgb is also expressed in nonerythroid cells. In the present study, the expression of Hgb in human uterine cervix carcinoma cells and its role in cervical cancer were investigated. METHODOLOGY: The expression level of Hgb in cervical cancer tissues was assessed by quantitative reverse transcriptase-PCR (qRT-PCR). We applied multiple methods, such as RT-PCR, immunoblotting, and immunohistochemical analysis, to confirm Hgb expression in cervical cancer cells. The effects of ectopic expression of Hgb and Hgb mutants on oxidative stress and cell viability were investigated by cellular reactive oxygen species (ROS) analysis and lactate dehydrogenase (LDH) array, respectively. Both Annexin V staining assay by flow cytometry and caspase-3 activity assay were used, respectively, to evaluate cell apoptosis. RESULTS: qRT PCR analysis showed that Hgb-alpha- (HBA1) and Hgb-beta-globin (HBB) gene expression was significantly higher in cervical carcinoma than in normal cervical tissues, whereas the expression of hematopoietic transcription factors and erythrocyte specific marker genes was not increased. Immunostaining experiments confirmed the expression of Hgb in cancer cells of the uterine cervix. Hgb mRNA and protein were also detected in the human cervical carcinoma cell lines SiHa and CaSki, and Hgb expression was up-regulated by hydrogen peroxide-induced oxidative stress. Importantly, ectopic expression of wild type HBA1/HBB or HBA1, rather than mutants HBA1(H88R)/HBB(H93R) unable to bind hemo, suppressed oxidative stress and improved cell viability. CONCLUSIONS: The present findings show for the first time that Hgb is expressed in cervical carcinoma cells and may act as an antioxidant, attenuating oxidative stress-induced damage in cervical cancer cells. These data provide a significant impact not only in globin biology but also in understanding of cervical cancer pathogenesis associated with oxidative stress. PMID- 23349857 TI - Local adaptation to altitude underlies divergent thermal physiology in tropical killifishes of the genus Aphyosemion. AB - In watersheds of equatorial West Africa, monophyletic groups of killifish species (genus Aphyosemion) occur in discrete altitudinal ranges, low altitude species (LA, sea level to ~350 m) or high altitude species (HA, 350 to 900 m). We investigated the hypothesis that local adaptation to altitude by the LA and HA species would be revealed as divergent effects of temperature on their physiological energetics. Two species from each group (mass ~350 mg) were acclimated to 19, 25 and 28 degrees C, with 19 and 28 degrees C estimated to be outside the thermal envelope for LA or HA, respectively, in the wild. Wild-caught animals (F0 generation) were compared with animals raised in captivity at 25 degrees C (F1 generation) to investigate the contribution of adaptation versus plasticity. Temperature significantly increased routine metabolic rate in all groups and generations. However, LA and HA species differed in the effects of temperature on their ability to process a meal. At 25 degrees C, the specific dynamic action (SDA) response was completed within 8 h in all groups, but acclimation to temperatures beyond the thermal envelope caused profound declines in SDA performance. At 19 degrees C, the LA required ~14 h to complete the SDA, whereas the HA required only ~7 h. The opposite effect was observed at 28 degrees C. This effect was evident in both F0 and F1. Reaction norms for effects of temperature on SDA therefore revealed a trade-off, with superior performance at warmer temperatures by LA being associated with inferior performance at cooler temperatures, and vice-versa in HA. The data indicate that divergent physiological responses to temperature in the LA and HA species reflect local adaptation to the thermal regime in their habitat, and that local adaptation to one thermal environment trades off against performance in another. PMID- 23349858 TI - Mechanistic evaluation of a novel small molecule targeting mitochondria in pancreatic cancer cells. AB - BACKGROUND: Pancreatic cancer is one of the deadliest cancers with a 5-year survival rate of 6%. Therapeutic options are very limited and there is an unmet medical need for safe and efficacious treatments. Cancer cell metabolism and mitochondria provide unexplored targets for this disease. We recently identified a novel class of triphenylphosphonium salts, TP compounds, with broad- spectrum anticancer properties. We examined the ability of our prototypical compound TP421 chosen for its fluorescent properties - to inhibit the growth of pancreatic cancer cells and further investigated the molecular mechanisms by which it exerts its anticancer effects. METHODOLOGY/PRINCIPAL FINDINGS: TP421 exhibited sub micromolar IC(50) values in all the pancreatic cancer cell lines tested using MTT and colony formation assays. TP421 localized predominantly to mitochondria and induced G(0)/G(1) arrest, ROS accumulation, and activation of several stress regulated kinases. Caspase and PARP-1 cleavage were observed indicating an apoptotic response while LC3B-II and p62 were accumulated indicating inhibition of autophagy. Furthermore, TP421 induced de-phosphorylation of key signaling molecules involved in FAK mediated adhesion that correlated with inhibition of cell migration. CONCLUSIONS/SIGNIFICANCE: TP421 is a representative compound of a new promising class of mitochondrial-targeted agents useful for pancreatic cancer treatment. Because of their unique mechanism of action and efficacy further development is warranted. PMID- 23349859 TI - Passive exercise of the hind limbs after complete thoracic transection of the spinal cord promotes cortical reorganization. AB - Physical exercise promotes neural plasticity in the brain of healthy subjects and modulates pathophysiological neural plasticity after sensorimotor loss, but the mechanisms of this action are not fully understood. After spinal cord injury, cortical reorganization can be maximized by exercising the non-affected body or the residual functions of the affected body. However, exercise per se also produces systemic changes - such as increased cardiovascular fitness, improved circulation and neuroendocrine changes - that have a great impact on brain function and plasticity. It is therefore possible that passive exercise therapies typically applied below the level of the lesion in patients with spinal cord injury could put the brain in a more plastic state and promote cortical reorganization. To directly test this hypothesis, we applied passive hindlimb bike exercise after complete thoracic transection of the spinal cord in adult rats. Using western blot analysis, we found that the level of proteins associated with plasticity - specifically ADCY1 and BDNF - increased in the somatosensory cortex of transected animals that received passive bike exercise compared to transected animals that received sham exercise. Using electrophysiological techniques, we then verified that neurons in the deafferented hindlimb cortex increased their responsiveness to tactile stimuli delivered to the forelimb in transected animals that received passive bike exercise compared to transected animals that received sham exercise. Passive exercise below the level of the lesion, therefore, promotes cortical reorganization after spinal cord injury, uncovering a brain-body interaction that does not rely on intact sensorimotor pathways connecting the exercised body parts and the brain. PMID- 23349860 TI - Expression and functional role of Sox9 in human epidermal keratinocytes. AB - In this study, we investigated the expression and putative role of Sox9 in epidermal keratinocyte. Immunohistochemical staining showed that Sox9 is predominantly expressed in the basal layer of normal human skin epidermis, and highly expressed in several skin diseases including psoriasis, basal cell carcinoma, keratoacanthoma and squamous cell carcinoma. In calcium-induced keratinocyte differentiation model, the expression of Sox9 was decreased in a time dependent manner. When Sox9 was overexpressed using a recombinant adenovirus, cell growth was enhanced, while the expression of differentiation related genes such as loricrin and involucrin was markedly decreased. Similarly, when rat skin was intradermally injected with the adenovirus expressing Sox9, the epidermis was thickened with increase of PCNA positive cells, while the epidermal differentiation was decreased. Finally, UVB irradiation induced Sox9 expression in cultured human epidermal keratinocytes, and keratinocytes are protected from UVB-induced apoptosis by Sox9 overexpression. Together, these results suggest that Sox9 is an important regulator of epidermal keratinocytes with putative pro proliferation and/or pro-survival functions, and may be related to several cutaneous diseases that are characterized by abnormal differentiation and hyperproliferation. PMID- 23349861 TI - Electrical vs manual acupuncture stimulation in a rat model of polycystic ovary syndrome: different effects on muscle and fat tissue insulin signaling. AB - In rats with dihydrotestosterone (DHT)-induced polycystic ovary syndrome (PCOS), repeated low-frequency electrical stimulation of acupuncture needles restores whole-body insulin sensitivity measured by euglycemic hyperinsulinemic clamp. We hypothesized that electrical stimulation causing muscle contractions and manual stimulation causing needle sensation have different effects on insulin sensitivity and related signaling pathways in skeletal muscle and adipose tissue, with electrical stimulation being more effective in DHT-induced PCOS rats. From age 70 days, rats received manual or low-frequency electrical stimulation of needles in abdominal and hind limb muscle five times/wk for 4-5 wks; controls were handled but untreated rats. Low-frequency electrical stimulation modified gene expression (decreased Tbc1d1 in soleus, increased Nr4a3 in mesenteric fat) and protein expression (increased pAS160/AS160, Nr4a3 and decreased GLUT4) by western blot and increased GLUT4 expression by immunohistochemistry in soleus muscle; glucose clearance during oral glucose tolerance tests was unaffected. Manual stimulation led to faster glucose clearance and modified mainly gene expression in mesenteric adipose tissue (increased Nr4a3, Mapk3/Erk, Adcy3, Gsk3b), but not protein expression to the same extent; however, Nr4a3 was reduced in soleus muscle. The novel finding is that electrical and manual muscle stimulation affect glucose homeostasis in DHT-induced PCOS rats through different mechanisms. Repeated electrical stimulation regulated key functional molecular pathways important for insulin sensitivity in soleus muscle and mesenteric adipose tissue to a larger extent than manual stimulation. Manual stimulation improved whole-body glucose tolerance, an effect not observed after electrical stimulation, but did not affect molecular signaling pathways to the same extent as electrical stimulation. Although more functional signaling pathways related to insulin sensitivity were affected by electrical stimulation, our findings suggest that manual stimulation of acupuncture needles has a greater effect on glucose tolerance. The underlying mechanism of the differential effects of the intermittent manual and the continuous electrical stimulation remains to be elucidated. PMID- 23349862 TI - Wdr68 requires nuclear access for craniofacial development. AB - Wdr68 is a highly conserved scaffolding protein required for craniofacial development and left-right asymmetry. A Ras-Map3k-Wdr68-Dyrk1 signaling relay may mediate these and other diverse signaling events important in development and disease. While the sub-cellular localization of Wdr68 has been shown to be dependent on that of its interaction partners, it is not clear where Wdr68 activity is required during development. Here we show that while a GFP-Wdr68 fusion functionally substituted for craniofacial development in the zebrafish, that a Nuclear Export Signal (NES) fusion protein (GFPNESWdr68) failed to support craniofacial development. As control for NES activity, we show that while GFP Wdr68 exhibited a pan-cellular distribution in C2C12 cells, the GFPNESWdr68 fusion predominantly localized to the cell cytoplasm, as expected. Interestingly, while GFP-Wdr68 and RFP-Dyrk1a co-localized to the cell nucleus as expected based on the known sub-cellular localization for Dyrk1a, we found that the GFPNESWdr68 fusion redistributed RFP-Dyrk1a to the cell cytoplasm potentially disconnecting the Ras/Dyrk1 signal relay from further downstream targets. Consistent with a nuclear role in gene regulation, we also found that while a transcriptional activation domain fusion, CebpFlagWdr68, functionally substituted for endogenous Wdr68 for craniofacial development, that a transcriptional repression domain fusion, MadFlagWdr68, failed to support craniofacial development. Dyrk1b is required for myogenin (myog) expression in differentiating mouse C2C12 cells and here we report that wdr68 is also important for myog expression in differentiating C2C12 cells. Using a C2C12 cell myog promoter-reporter system, we found that Wdr68 overexpression increased reporter activity while moderate expression levels of MadFlagWdr68 interfered with reporter activity. Taken together, these findings support a nuclear role for Wdr68-containing complexes. PMID- 23349863 TI - The SIRT1 modulators AROS and DBC1 regulate HSF1 activity and the heat shock response. AB - The heat shock response, the cellular response to protein damaging stress, is critical in maintaining proteostasis. The heat shock response is regulated by the transcription factor HSF1, which is activated upon heat shock and other stresses to induce the expression of molecular chaperones. SIRT1 has previously been shown to activate HSF1 by deacetylating it, leading to increased DNA binding ability. We have investigated how the heat shock response may be controlled by factors influencing SIRT1 activity. We found that heat shock results in an increase in the cellular NAD(+)/NADH ratio and an increase in recruitment of SIRT1 to the hsp70 promoter. Furthermore, we found that the SIRT1 modulators AROS and DBC1 have an impact on hsp70 transcription, HSF1 acetylation status, and HSF1 recruitment to the hsp70 promoter. Therefore, AROS and DBC1 are now two new targets available for therapeutic regulation of the heat shock response. PMID- 23349864 TI - Separate developmental programs for HLA-A and -B cell surface expression during differentiation from embryonic stem cells to lymphocytes, adipocytes and osteoblasts. AB - A major problem of allogeneic stem cell therapy is immunologically mediated graft rejection. HLA class I A, B, and Cw antigens are crucial factors, but little is known of their respective expression on stem cells and their progenies. We have recently shown that locus-specific expression (HLA-A, but not -B) is seen on some multipotent stem cells, and this raises the question how this is in other stem cells and how it changes during differentiation. In this study, we have used flow cytometry to investigate the cell surface expression of HLA-A and -B on human embryonic stem cells (hESC), human hematopoietic stem cells (hHSC), human mesenchymal stem cells (hMSC) and their fully-differentiated progenies such as lymphocytes, adipocytes and osteoblasts. hESC showed extremely low levels of HLA A and no -B. In contrast, multipotent hMSC and hHSC generally expressed higher levels of HLA-A and clearly HLA-B though at lower levels. IFNgamma induced HLA-A to very high levels on both hESC and hMSC and HLA-B on hMSC. Even on hESC, a low expression of HLA-B was achieved. Differentiation of hMSC to osteoblasts downregulated HLA-A expression (P = 0.017). Interestingly HLA class I on T lymphocytes differed between different compartments. Mature bone marrow CD4(+) and CD8(+) T cells expressed similar HLA-A and -B levels as hHSC, while in the peripheral blood they expressed significantly more HLA-B7 (P = 0.0007 and P = 0.004 for CD4(+) and CD8(+) T cells, respectively). Thus different HLA loci are differentially regulated during differentiation of stem cells. PMID- 23349865 TI - Coevolution of Drosophila melanogaster mtDNA and Wolbachia genotypes. AB - Maternally inherited microorganisms can influence the mtDNA pattern of variation in hosts. This influence is driven by selection among symbionts and can cause the frequency of mitochondrial variants in the population to eventually increase or decrease. Wolbachia infection is common and widespread in Drosophila melanogaster populations. We compared genetic variability of D. melanogaster mitotypes with Wolbachia genotypes among isofemale lines associated with different geographic locations and time intervals to study coevolution of the mtDNA and Wolbachia. Phylogenetic analysis of D. melanogaster mtDNA revealed two clades diverged in Africa, each associated with one of the two Wolbachia genotype groups. No evidence of horizontal transmission of Wolbachia between maternal lineages has been found. All the mtDNA variants that occur in infected isofemale lines are found in uninfected isofemale lines and vice versa, which is indicative of a recent loss of infection from some maternal fly lineages and confirms a significant role of Wolbachia in the D. melanogaster mtDNA pattern of variation. Finally, we present a comparative analysis of biogeographic distribution of D. melanogaster mitotypes all over the world. PMID- 23349866 TI - Exposure to extremely low-frequency electromagnetic fields modulates Na+ currents in rat cerebellar granule cells through increase of AA/PGE2 and EP receptor mediated cAMP/PKA pathway. AB - Although the modulation of Ca(2+) channel activity by extremely low-frequency electromagnetic fields (ELF-EMF) has been studied previously, few reports have addressed the effects of such fields on the activity of voltage-activated Na(+) channels (Na(v)). Here, we investigated the effects of ELF-EMF on Na(v) activity in rat cerebellar granule cells (GCs). Our results reveal that exposing cerebellar GCs to ELF-EMF for 10-60 min significantly increased Na(v) currents (I(Na)) by 30-125% in a time- and intensity-dependent manner. The Na(v) channel steady-state activation curve, but not the steady-state inactivation curve, was significantly shifted (by 5.2 mV) towards hyperpolarization by ELF-EMF stimulation. This phenomenon is similar to the effect of intracellular application of arachidonic acid (AA) and prostaglandin E(2) (PGE(2)) on I(Na) in cerebellar GCs. Increases in intracellular AA, PGE(2) and phosphorylated PKA levels in cerebellar GCs were observed following ELF-EMF exposure. Western blottings indicated that the Na(V) 1.2 protein on the cerebellar GCs membrane was increased, the total expression levels of Na(V) 1.2 protein were not affected after exposure to ELF-EMF. Cyclooxygenase inhibitors and PGE(2) receptor (EP) antagonists were able to eliminate this ELF-EMF-induced increase in phosphorylated PKA and I(Na). In addition, ELF-EMF exposure significantly enhanced the activity of PLA(2) in cerebellar GCs but did not affect COX-1 or COX 2 activity. Together, these data demonstrate for the first time that neuronal I(Na) is significantly increased by ELF-EMF exposure via a cPLA2 AA PGE(2) EP receptors PKA signaling pathway. PMID- 23349867 TI - Detergent/nanodisc screening for high-resolution NMR studies of an integral membrane protein containing a cytoplasmic domain. AB - Because membrane proteins need to be extracted from their natural environment and reconstituted in artificial milieus for the 3D structure determination by X-ray crystallography or NMR, the search for membrane mimetic that conserve the native structure and functional activities remains challenging. We demonstrate here a detergent/nanodisc screening study by NMR of the bacterial alpha-helical membrane protein YgaP containing a cytoplasmic rhodanese domain. The analysis of 2D [(15)N,(1)H]-TROSY spectra shows that only a careful usage of low amounts of mixed detergents did not perturb the cytoplasmic domain while solubilizing in parallel the transmembrane segments with good spectral quality. In contrast, the incorporation of YgaP into nanodiscs appeared to be straightforward and yielded a surprisingly high quality [(15)N,(1)H]-TROSY spectrum opening an avenue for the structural studies of a helical membrane protein in a bilayer system by solution state NMR. PMID- 23349868 TI - When health systems are barriers to health care: challenges faced by uninsured Mexican kidney patients. AB - BACKGROUND: Chronic Kidney Disease disproportionately affects the poor in Low and Middle Income Countries (LMICs). Mexico exemplifies the difficulties faced in supporting Renal Replacement Therapy (RRT) and providing equitable patient care, despite recent attempts at health reform. The objective of this study is to document the challenges faced by uninsured, poor Mexican families when attempting to access RRT. METHODS: The article takes an ethnographic approach, using interviewing and observation to generate detailed accounts of the problems that accompany attempts to secure care. The study, based in the state of Jalisco, comprised interviews with patients, their caregivers, health and social care professionals, among others. Observations were carried out in both clinical and social settings. RESULTS: In the absence of organised health information and stable pathways to renal care, patients and their families work extraordinarily hard and at great expense to secure care in a mixed public-private healthcare system. As part of this work, they must navigate challenging health and social care environments, negotiate treatments and costs, resource and finance healthcare and manage a wide range of formal and informal health information. CONCLUSIONS: Examining commonalities across pathways to adequate healthcare reveals major failings in the Mexican system. These systemic problems serve to reproduce and deepen health inequalities. A system, in which the costs of renal care are disproportionately borne by those who can least afford them, faces major difficulties around the sustainability and resourcing of RRTs. Attempts to increase access to renal therapies, therefore, need to take into account the complex social and economic demands this places on those who need access most. This paper further shows that ethnographic studies of the concrete ways in which healthcare is accessed in practice provide important insights into the plight of CKD patients and so constitute an important source of evidence in that effort. PMID- 23349869 TI - Description of the L76V resistance protease mutation in HIV-1 B and "non-B" subtypes. AB - OBJECTIVE: To describe the prevalence of the L76V protease inhibitors resistance associated mutation (PI-RAM) in relation with patients' characteristics and protease genotypic background in HIV-1 B- and "non-B"-infected patients. METHODS: Frequency of the L76V mutation between 1998 and 2010 was surveyed in the laboratory database of 3 clinical centers. Major PI-RAMs were identified according to the IAS-USA list. Fisher's and Wilcoxon tests were used to compare variables. RESULTS: Among the overall 29,643 sequences analyzed, the prevalence of L76V was 1.50%, while was 5.42% in PI-resistant viruses. Since 2008 the prevalence of L76V was higher in "non-B"-infected than in B-infected patients each year. Median time since diagnosis of HIV-1 infection and median time under antiretroviral-based regimen were both shorter in "non-B"- than in B-infected patients (8 vs 11 years, P<0.0001; and 7 vs 8 years, P = 0.004). In addition, "non-B"-infected patients had been pre-exposed to a lower number of PI (2 vs 3, P = 0.016). The L76V was also associated with a lower number of major PI-RAMs in "non-B" vs B samples (3 vs 4, P = 0.0001), and thus it was more frequent found as single major PI-RAM in "non-B" vs B subtype (10% vs 2%, P = 0.014). CONCLUSIONS: We showed an impact of viral subtype on the selection of the L76V major PI-RAM with a higher prevalence in "non-B" subtypes observed since 2008. In addition, in "non-B"-infected patients this mutation appeared more rapidly and was associated with less PI-RAM. PMID- 23349870 TI - CK2 phosphorylates Sec31 and regulates ER-To-Golgi trafficking. AB - Protein export from the endoplasmic reticulum (ER) is an initial and rate limiting step of molecular trafficking and secretion. This is mediated by coat protein II (COPII)-coated vesicles, whose formation requires small GTPase Sar1 and 6 Sec proteins including Sec23 and Sec31. Sec31 is a component of the outer layer of COPII coat and has been identified as a phosphoprotein. The initiation and promotion of COPII vesicle formation is regulated by Sar1; however, the mechanism regulating the completion of COPII vesicle formation followed by vesicle release is largely unknown. Hypothesizing that the Sec31 phosphorylation may be such a mechanism, we identified phosphorylation sites in the middle linker region of Sec31. Sec31 phosphorylation appeared to decrease its association with ER membranes and Sec23. Non-phosphorylatable mutant of Sec31 stayed longer at ER exit sites and bound more strongly to Sec23. We also found that CK2 is one of the kinases responsible for Sec31 phosphorylation because CK2 knockdown decreased Sec31 phosphorylation, whereas CK2 overexpression increased Sec31 phosphorylation. Furthermore, CK2 knockdown increased affinity of Sec31 for Sec23 and inhibited ER-to-Golgi trafficking. These results suggest that Sec31 phosphorylation by CK2 controls the duration of COPII vesicle formation, which regulates ER-to-Golgi trafficking. PMID- 23349871 TI - In vitro secondary structure of the genomic RNA of satellite tobacco mosaic virus. AB - Satellite tobacco mosaic virus (STMV) is a T = 1 icosahedral virus with a single stranded RNA genome. It is widely accepted that the RNA genome plays an important structural role during assembly of the STMV virion. While the encapsidated form of the RNA has been extensively studied, less is known about the structure of the free RNA, aside from a purported tRNA-like structure at the 3' end. Here we use selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) analysis to examine the secondary structure of in vitro transcribed STMV RNA. The predicted secondary structure is unusual in the sense that it is highly extended, which could be significant for protecting the RNA from degradation. The SHAPE data are also consistent with the previously predicted tRNA-like fold at the 3' end of the molecule, which is also known to hinder degradation. Our data are not consistent with the secondary structure proposed for the encapsidated RNA by Schroeder et al., suggesting that, if the Schroeder structure is correct, either the RNA is packaged as it emerges from the replication complex, or the RNA undergoes extensive refolding upon encapsidation. We also consider the alternative, i.e., that the structure of the encapsidated STMV RNA might be the same as the in vitro structure presented here, and we examine how this structure might be organized in the virus. This possibility is not rigorously ruled out by the available data, so it remains open to examination by experiment. PMID- 23349872 TI - Effect of virulence factors on the photodynamic inactivation of Cryptococcus neoformans. AB - Opportunistic fungal pathogens may cause an array of superficial infections or serious invasive infections, especially in immunocompromised patients. Cryptococcus neoformans is a pathogen causing cryptococcosis in HIV/AIDS patients, but treatment is limited due to the relative lack of potent antifungal agents. Photodynamic inactivation (PDI) uses the combination of non-toxic dyes called photosensitizers and harmless visible light, which produces singlet oxygen and other reactive oxygen species that produce cell inactivation and death. We report the use of five structurally unrelated photosensitizers (methylene blue, Rose Bengal, selenium derivative of a Nile blue dye, a cationic fullerene and a conjugate between poly-L-lysine and chlorin(e6)) combined with appropriate wavelengths of light to inactivate C. neoformans. Mutants lacking capsule and laccase, and culture conditions that favoured melanin production were used to probe the mechanisms of PDI and the effect of virulence factors. The presence of cell wall, laccase and melanin tended to protect against PDI, but the choice of the appropriate photosensitizers and dosimetry was able to overcome this resistance. PMID- 23349873 TI - ATP-mediated transactivation of the epidermal growth factor receptor in airway epithelial cells involves DUOX1-dependent oxidation of Src and ADAM17. AB - The respiratory epithelium is subject to continuous environmental stress and its responses to injury or infection are largely mediated by transactivation of the epidermal growth factor receptor (EGFR) and downstream signaling cascades. Based on previous studies indicating involvement of ATP-dependent activation of the NADPH oxidase homolog DUOX1 in epithelial wound responses, the present studies were performed to elucidate the mechanisms by which DUOX1-derived H(2)O(2) participates in ATP-dependent redox signaling and EGFR transactivation. ATP mediated EGFR transactivation in airway epithelial cells was found to involve purinergic P2Y(2) receptor stimulation, and both ligand-dependent mechanisms as well as ligand-independent EGFR activation by the non-receptor tyrosine kinase Src. Activation of Src was also essential for ATP-dependent activation of the sheddase ADAM17, which is responsible for liberation and activation of EGFR ligands. Activation of P2Y(2)R results in recruitment of Src and DUOX1 into a signaling complex, and transient siRNA silencing or stable shRNA transfection established a critical role for DUOX1 in ATP-dependent activation of Src, ADAM17, EGFR, and downstream wound responses. Using thiol-specific biotin labeling strategies, we determined that ATP-dependent EGFR transactivation was associated with DUOX1-dependent oxidation of cysteine residues within Src as well as ADAM17. In aggregate, our findings demonstrate that DUOX1 plays a central role in overall epithelial defense responses to infection or injury, by mediating oxidative activation of Src and ADAM17 in response to ATP-dependent P2Y(2)R activation as a proximal step in EGFR transactivation and downstream signaling. PMID- 23349874 TI - Incidence of end-stage renal disease in the Turkish-Cypriot population of Northern Cyprus: a population based study. AB - BACKGROUND: This is the first report of the incidence and causes of end-stage renal disease (ESRD) of the Turkish-Cypriot population in Northern Cyprus. METHODS: Data were collected over eight consecutive years (2004-2011) from all those starting renal replacement therapy (RRT) in this population. Crude and age standardised incidence at 90 days was calculated and comparisons made with other national registries. We collected DNA from the entire prevalent population. As an initial experiment we looked for two genetic causes of ESRD that have been reported in Greek Cypriots. RESULTS: Crude and age-standardised incidence at 90 days was 234 and 327 per million population (pmp) per year, respectively. The mean age was 63, and 62% were male. The age-adjusted prevalence of RRT in Turkish Cypriots was 1543 pmp on 01/01/2011. The incidence of RRT is higher than other countries reporting to the European Renal Association - European Dialysis and Transplant Association, with the exception of Turkey. Diabetes is a major cause of ESRD in those under 65, accounting for 36% of incident cases followed by 30% with uncertain aetiology. 18% of the incident population had a family history of ESRD. We identified two families with thin basement membrane nephropathy caused by a mutation in COL4A3, but no new cases of CFHR5 nephropathy. CONCLUSIONS: This study provides the first estimate of RRT incidence in the Turkish-Cypriot population, describes the contribution of different underlying diagnoses to ESRD, and provides a basis for healthcare policy planning. PMID- 23349875 TI - Risk factors for severe cholera among children under five in rural and urban Bangladesh, 2000-2008: a hospital-based surveillance study. AB - BACKGROUND: Children under five bear the largest cholera burden. We therefore sought to identify modifiable risk factors among Bangladeshi children. METHODOLOGY/PRINCIPAL FINDINGS: We used multivariate Poisson regression to assess risk factors for severe cholera among diarrheal patients presenting at hospitals in Matlab (rural) and Dhaka (urban), Bangladesh. Risk increased with age. Compared to those under one, rural and urban four-year-olds had adjusted risk ratios (aRR) of 4.17 (95% confidence interval (CI) 2.43-7.15) and 6.32 (95% CI: 4.63-8.63), respectively. Breastfeeding halved the risk in both rural (aRR = 0.49, 95% CI: 0.35-0.67) and urban (aRR = 0.51, 95% CI: 0.41-0.62) settings. Rural children's risk decreased with maternal education (P-trend: <0.001) and increased among those with a family member with diarrhea in the past week (aRR = 1.61, 95% CI: 1.22-2.14) and those with prior vitamin A supplementation (aRR = 1.65, 95% CI: 1.12-2.43). Urban children whose mothers daily (aRR = 0.41, 95% CI: 0.21-0.79) or occasionally (aRR = 0.55, 95% CI: 0.36-0.84) read a newspaper experienced reduced risk. Urban children from households with incomes between 34 84 USD/month had a 30% increased risk compared to those from households with incomes >84 USD/month. CONCLUSION/SIGNIFICANCE: Increasing age, lower socioeconomic status, and lack of breastfeeding are key correlates of increased risk for cholera hospitalization among those under five in rural and urban Bangladesh. In addition, having a family member with diarrhea in the past week was associated with increased risk among rural children. Continued attention should be directed to the promotion of breastfeeding. Further research is needed to elucidate the relationship between maternal education and cholera risk. Renewed research regarding the use of chemoprophylaxis among family members of cholera cases may be warranted in rural endemic settings. PMID- 23349876 TI - Does trophic status enhance or reduce the thermal tolerance of scleractinian corals? A review, experiment and conceptual framework. AB - Global warming, and nutrient and sediment runoff from coastal development, both exert increasing pressures on coastal coral reefs. The objective of this study was to resolve the question of whether coastal eutrophication may protect corals from thermal stress by improving their nutritional status, or rather diminish their thermal tolerance through the synergy of dual stressors. A review of previous studies on the topic of combined trophic status and heat exposure on the thermal tolerance of corals reveals a broad range of outcomes, including synergistic, additive and antagonistic effects. We conducted a 90-day long experiment exposing corals to realistic levels of elevated nutrients and sediments, and heat stress. Colonies of two common scleractinian corals (Acropora millepora and Montipora tuberculosa) were kept in coastal seawater, or coastal seawater that was further organically and nutrient enriched (OE), and/or enriched with nitrate. Batches of OE were created daily, facilitating nutrient uptake, plankton succession and organic enrichment as observed in coastal waters. After 10 days of acclimation, 67% of the colonies had their temperature gradually increased from 27 degrees to 31.2 degrees C. After 3-7 weeks of heat stress, colonies of both species had significantly greater reductions in fluorescence yields and lower survival in OE than without addition of OE. Furthermore, photophysiological recovery was incomplete 31-38 days after ending the heat stress only in the OE treatments. Nitrate alone had no measurable effect on survival, bleaching and recovery in either species. Skeletal growth rates were reduced by 45% in heat-stressed A. millepora and by 24% in OE-exposed M. tuberculosa. We propose a conceptual trophic framework that resolves some of the apparently contradictory outcomes revealed by the review. Our study shows that management actions to reduce coastal eutrophication can improve the resistance and resilience of vulnerable coastal coral reefs to warming temperatures. PMID- 23349877 TI - Toll-like receptor ligands induce expression of the costimulatory molecule CD155 on antigen-presenting cells. AB - Genotoxic stress and RAS induce the expression of CD155, a ligand for the immune receptors DNAM-1, CD96 and TIGIT. Here we show that antigen-presenting cells upregulate CD155 expression in response to Toll-like receptor activation. Induction of CD155 by Toll-like receptors depended on MYD88, TRIF and NF-kappaB. In addition, IRF3, but not IRF7, modulated CD155 upregulation in response to TLR3 signals. Immunization of CD155-deficient mice with OVA and the TLR9 agonist CpG resulted in increased OVA-specific IgG2a/c titers when compared to wild type mice. Splenocytes of immunized CD155-deficient mice secreted lower levels of IL-4 and fewer IL-4 and GATA-3 expressing CD4(+) T cells were present in the spleen of Cd155(-/-) mice. Our data suggest that CD155 regulates T(h)2 differentiation. Targeting of CD155 in immunization protocols using peptides may represent a promising new approach to boost protective humoral immunity in viral vaccines. PMID- 23349878 TI - Prospective surveillance for cardiac adverse events in healthy adults receiving modified vaccinia Ankara vaccines: a systematic review. AB - BACKGROUND: Vaccinia-associated myo/pericarditis was observed during the US smallpox vaccination (DryVax) campaign initiated in 2002. A highly-attenuated vaccinia strain, modified vaccinia Ankara (MVA) has been evaluated in clinical trials as a safer alternative to DryVax and as a vector for recombinant vaccines. Due to the lack of prospectively collected cardiac safety data, the US Food and Drug Administration required cardiac screening and surveillance in all clinical trials of MVA since 2004. Here, we report cardiac safety surveillance from 6 phase I trials of MVA vaccines. METHODS: Four clinical research organizations contributed cardiac safety data using common surveillance methods in trials administering MVA or recombinant MVA vaccines to healthy participants. 'Routine cardiac investigations' (ECGs and cardiac enzymes obtained 2 weeks after injections of MVA or MVA-HIV recombinants, or placebo-controls), and 'Symptom driven cardiac investigations' are reported. The outcome measure is the number of participants who met the CDC-case definition for vaccinia-related myo/pericarditis or who experienced cardiac adverse events from an MVA vaccine. RESULTS: Four hundred twenty-five study participants had post-vaccination safety data analyzed, 382 received at least one MVA-containing vaccine and 43 received placebo; 717 routine ECGs and 930 cardiac troponin assays were performed. Forty five MVA recipients (12%) had additional cardiac testing performed; 22 for cardiac symptoms, 19 for ECG/laboratory changes, and 4 for cardiac symptoms with an ECG/laboratory change. No participant had evidence of symptomatic or asymptomatic myo/pericarditis meeting the CDC-case definition and judged to be related to an MVA vaccine. CONCLUSIONS: Prospective surveillance of MVA recipients for myo/pericarditis did not detect cardiac adverse reactions in 382 study participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT00082446 NCT003766090 NCT00252148 NCT00083603 NCT00301184 NCT00428337. PMID- 23349880 TI - Survey of Naegleria fowleri in geothermal recreational waters of Guadeloupe (French West Indies). AB - In 2008 a fatal case of primary amoebic meningoencephalitis, due to the amoeboflagellate Naegleria fowleri, occurred in Guadeloupe, French West Indies, after a child swam in a bath fed with geothermal water. In order to improve the knowledge on free-living amoebae in this tropical part of France, we investigated on a monthly basis, the presence of Naegleria spp. in the recreational baths, and stream waters which feed them. A total of 73 water samples, 48 sediments and 54 swabs samples were collected from 6 sampling points between June 2011 and July 2012. The water samples were filtered and the filters transferred to non-nutrient agar plates seeded with a heat-killed suspension of Escherichia coli while sediment and swab samples were placed directly on these plates. The plates were incubated at 44 degrees C for the selective isolation of thermophilic Naegleria. To identify the Naegleria isolates the internal transcribed spacers, including the 5.8S rDNA, were amplified by polymerase chain reaction and the sequence of the PCR products was determined. Thermophilic amoebae were present at nearly all collection sites. The pathogenic N. fowleri was the most frequently encountered thermophilic species followed by N. lovaniensis. The concentration of N. fowleri was rather low in most water samples, ranging from 0 to 22 per liter. Sequencing revealed that all N. fowleri isolates belonged to a common Euro-American genotype, the same as detected in the human case in Guadeloupe. These investigations need to be continued in order to counsel the health authorities about prevention measures, because these recreational thermal baths are used daily by local people and tourists. PMID- 23349879 TI - Requirement for Dlgh-1 in planar cell polarity and skeletogenesis during vertebrate development. AB - The development of specialized organs is tightly linked to the regulation of cell growth, orientation, migration and adhesion during embryogenesis. In addition, the directed movements of cells and their orientation within the plane of a tissue, termed planar cell polarity (PCP), appear to be crucial for the proper formation of the body plan. In Drosophila embryogenesis, Discs large (dlg) plays a critical role in apical-basal cell polarity, cell adhesion and cell proliferation. Craniofacial defects in mice carrying an insertional mutation in Dlgh-1 suggest that Dlgh-1 is required for vertebrate development. To determine what roles Dlgh-1 plays in vertebrate development, we generated mice carrying a null mutation in Dlgh-1. We found that deletion of Dlgh-1 caused open eyelids, open neural tube, and misorientation of cochlear hair cell stereociliary bundles, indicative of defects in planar cell polarity (PCP). Deletion of Dlgh-1 also caused skeletal defects throughout the embryo. These findings identify novel roles for Dlgh-1 in vertebrates that differ from its well-characterized roles in invertebrates and suggest that the Dlgh-1 null mouse may be a useful animal model to study certain human congenital birth defects. PMID- 23349881 TI - Mutations in the hedgehog pathway genes SMO and PTCH1 in human gastric tumors. AB - The causal role of the hedgehog pathway in cancer has been best documented in basal cell carcinoma of the skin. To assess potential DNA alterations of the hedgehog pathway in gastric cancer, we sequenced SMO and PTCH1 genes in a set of 39 gastric tumors. Tumors were classified by histology based on the Lauren classification and Sanger sequencing was performed to obtain full length coding sequences. Genomic instability was evident in these tumors as a number of silent or missense mutations were found. In addition to those that are potential germline polymorphisms, we found three SMO missense mutations, and one PTCH1 frameshift mutation that are novel and have not been documented in basal cell carcinoma. Mutations were found in both intestinal and diffuse type gastric tumors as well as in tumors that exhibit both intestinal and diffuse features. mRNA expression of hedgehog pathway genes was also examined and their levels do not indicate unequivocal higher pathway activity in tumors with mutations than those without. In summary, SMO and/or PTCH1 mutations are present at low frequency in different histologic subtypes of gastric tumors and these do not appear to be driver mutations. PMID- 23349882 TI - Alpha-tocopherol and MRI outcomes in multiple sclerosis--association and prediction. AB - OBJECTIVE: Alpha-tocopherol is the main vitamin E compound in humans, and has important antioxidative and immunomodulatory properties. The aim of this study was to study alpha-tocopherol concentrations and their relationship to disease activity in Norwegian multiple sclerosis (MS) patients. METHODS: Prospective cohort study in 88 relapsing-remitting MS (RRMS) patients, originally included in a randomised placebo-controlled trial of omega-3 fatty acids (the OFAMS study), before and during treatment with interferon beta. The patients were followed for two years with repeated 12 magnetic resonance imaging (MRI) scans and nine serum measurements of alpha-tocopherol. RESULTS: During interferon beta (IFNB) treatment, each 10 umol/L increase in alpha-tocopherol reduced the odds (CI 95%) for simultaneous new T2 lesions by 36.8 (0.5-59.8) %, p = 0.048, and for combined unique activity by 35.4 (1.6-57.7) %, p = 0.042, in a hierarchical regression model. These associations were not significant prior to IFNB treatment, and were not noticeably changed by gender, age, body mass index, HLA-DRB1*15, treatment group, compliance, or the concentrations of 25-hydroxyvitamin D, retinol, neutralising antibodies against IFNB, or the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. The corresponding odds for having new T1 gadolinium enhancing lesions two months later was reduced by 65.4 (16.5-85.7) %, p = 0.019, and for new T2 lesions by 61.0 (12.4-82.6) %, p = 0.023. CONCLUSION: During treatment with IFNB, increasing serum concentrations of alpha-tocopherol were associated with reduced odds for simultaneous and subsequent MRI disease activity in RRMS patients. PMID- 23349883 TI - Wheat chloroplast targeted sHSP26 promoter confers heat and abiotic stress inducible expression in transgenic Arabidopsis Plants. AB - The small heat shock proteins (sHSPs) have been found to play a critical role in physiological stress conditions in protecting proteins from irreversible aggregation. To characterize the hloroplast targeted sHSP26 promoter in detail, deletion analysis of the promoter is carried out and analysed via transgenics in Arabidopsis. In the present study, complete assessment of the importance of CCAAT box elements along with Heat shock elements (HSEs) in the promoter of sHSP26 was performed. Moreover, the importance of 5' untranslated region (UTR) has also been established in the promoter via Arabidopsis transgenics. An intense GUS expression was observed after heat stress in the transgenics harbouring a full length promoter, confirming the heat-stress inducibility of the promoter. Transgenic plants without UTR showed reduced GUS expression when compared to transgenic plants with UTR as was confirmed at the RNA and protein levels by qRT PCR and GUS histochemical assays, thus suggesting the possible involvement of some regulatory elements present in the UTR in heat-stress inducibility of the promoter. Promoter activity was also checked under different abiotic stresses and revealed differential expression in different deletion constructs. Promoter analysis based on histochemical assay, real-time qPCR and fluorimetric analysis revealed that HSEs alone could not transcribe GUS gene significantly in sHSP26 promoter and CCAAT box elements contribute synergistically to the transcription. Our results also provide insight into the importance of 5'UTR of sHsp26 promoter thus emphasizing the probable role of imperfect CCAAT-box element or some novel cis-element with respect to heat stress. PMID- 23349884 TI - STED nanoscopy with time-gated detection: theoretical and experimental aspects. AB - In a stimulated emission depletion (STED) microscope the region in which fluorescence markers can emit spontaneously shrinks with continued STED beam action after a singular excitation event. This fact has been recently used to substantially improve the effective spatial resolution in STED nanoscopy using time-gated detection, pulsed excitation and continuous wave (CW) STED beams. We present a theoretical framework and experimental data that characterize the time evolution of the effective point-spread-function of a STED microscope and illustrate the physical basis, the benefits, and the limitations of time-gated detection both for CW and pulsed STED lasers. While gating hardly improves the effective resolution in the all-pulsed modality, in the CW-STED modality gating strongly suppresses low spatial frequencies in the image. Gated CW-STED nanoscopy is in essence limited (only) by the reduction of the signal that is associated with gating. Time-gated detection also reduces/suppresses the influence of local variations of the fluorescence lifetime on STED microscopy resolution. PMID- 23349885 TI - Human papillomavirus up-regulates MMP-2 and MMP-9 expression and activity by inducing interleukin-8 in lung adenocarcinomas. AB - Human papillomavirus (HPV) infection is associated with non-smoking female lung cancer. Our previous report demonstrated that HPV 16 promotes lung tumor cell progression by up-regulating interleukin-17 (IL-17). IL-17 and its downstream signaling mediator, interleukin-8 (IL-8), have been implicated to modulate a variety of pro-angiogenic factors and play important roles in tumor angiogenesis and metastasis. Accordingly, we hypothesized that HPV infection may potentiate tumorigenic and metastatic characteristics of the infected cells through IL-8. The goal of the present study was to determine whether HPV infection in lung adenocarcinoma cells can promote the expression of IL-8 and metalloproteinases (MMPs) to make the transformed cells equipped with angiogenic and metastatic characteristics. The expression of IL-8 and MMPs in HPV 16 E6-transfected H1299 cells was analyzed to examine the hypothesis. HPV 16 E6 up-regulates pro angiogenic MMP-2 and MMP-9 through inducing IL-8 expression in lung cancer cells. The results indicate that, in addition to cell proliferation-related machinery, HPV infection promotes the expression and activities of angiogenic and metastatic molecules in lung adenocarcinoma cells. The cytokines induced by HPV infection may work together to confer the malignant and tumorigenic potentials on the infected cells by promoting machineries of growth, angiogenic and metastatic characteristics. PMID- 23349886 TI - Evaluation of multiple-locus variable number of tandem repeats analysis for typing livestock-associated methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: The increasing occurrence of livestock-associated (LA) methicillin resistant Staphylococcus aureus (MRSA) associated with the clonal complex (CC) 398 within the past years shows the importance of standardized and comparable typing methods for the purposes of molecular surveillance and outbreak detection. Multiple-locus variable number of tandem repeats analysis (MLVA) has recently been described as an alternative and highly discriminative tool for S. aureus. However, until now the applicability of MLVA for the typing of LA-MRSA isolates from different geographic origin has not been investigated in detail. We therefore compared MLVA and S. aureus protein A (spa) typing for characterizing porcine MRSA from distinct Dutch and German farms. METHODOLOGY/PRINCIPAL FINDINGS: Overall, 134 MRSA isolates originating from 21 different pig-farms in the Netherlands and 36 farms in Germany comprising 21 different spa types were subjected to MLVA-typing. Amplification and subsequent automated fragment sizing of the tandem repeat loci on a capillary sequencer differentiated these 134 isolates into 20 distinct MLVA types. Whereas overall MLVA and spa typing showed the same discriminatory power to type LA-MRSA (p = 0.102), MLVA was more discriminatory than spa typing for isolates associated with the prevalent spa types t011 and t034 (Simpson's Index of Diversity 0.564 vs. 0.429, respectively; p<0.001). CONCLUSION: Although the applied MLVA scheme was not more discriminatory than spa typing in general, it added valuable information to spa typing results for specific spa types (t011, t034) which are highly prevalent in the study area, i.e. Dutch-German border area. Thus, both methods may complement each other to increase the discriminatory power to resolute highly conserved clones such as CC398 (spa types t011, t034) for the detection of outbreaks and molecular surveillance of zoonotic MRSA. PMID- 23349887 TI - Differential effects of rapamycin and dexamethasone in mouse models of established allergic asthma. AB - The mammalian target of rapamycin (mTOR) plays an important role in cell growth/differentiation, integrating environmental cues, and regulating immune responses. Our lab previously demonstrated that inhibition of mTOR with rapamycin prevented house dust mite (HDM)-induced allergic asthma in mice. Here, we utilized two treatment protocols to investigate whether rapamycin, compared to the steroid, dexamethasone, could inhibit allergic responses during the later stages of the disease process, namely allergen re-exposure and/or during progression of chronic allergic disease. In protocol 1, BALB/c mice were sensitized to HDM (three i.p. injections) and administered two intranasal HDM exposures. After 6 weeks of rest/recovery, mice were re-exposed to HDM while being treated with rapamycin or dexamethasone. In protocol 2, mice were exposed to HDM for 3 or 6 weeks and treated with rapamycin or dexamethasone during weeks 4-6. Characteristic features of allergic asthma, including IgE, goblet cells, airway hyperreactivity (AHR), inflammatory cells, cytokines/chemokines, and T cell responses were assessed. In protocol 1, both rapamycin and dexamethasone suppressed goblet cells and total CD4(+) T cells including activated, effector, and regulatory T cells in the lung tissue, with no effect on AHR or total inflammatory cell numbers in the bronchoalveolar lavage fluid. Rapamycin also suppressed IgE, although IL-4 and eotaxin 1 levels were augmented. In protocol 2, both drugs suppressed total CD4(+) T cells, including activated, effector, and regulatory T cells and IgE levels. IL-4, eotaxin, and inflammatory cell numbers were increased after rapamycin and no effect on AHR was observed. Dexamethasone suppressed inflammatory cell numbers, especially eosinophils, but had limited effects on AHR. We conclude that while mTOR signaling is critical during the early phases of allergic asthma, its role is much more limited once disease is established. PMID- 23349888 TI - Dispersal, mating events and fine-scale genetic structure in the lesser flat headed bats. AB - Population genetic structure has important consequences in evolutionary processes and conservation genetics in animals. Fine-scale population genetic structure depends on the pattern of landscape, the permanent movement of individuals, and the dispersal of their genes during temporary mating events. The lesser flat headed bat (Tylonycteris pachypus) is a nonmigratory Asian bat species that roosts in small groups within the internodes of bamboo stems and the habitats are fragmented. Our previous parentage analyses revealed considerable extra-group mating in this species. To assess the spatial limits and sex-biased nature of gene flow in the same population, we used 20 microsatellite loci and mtDNA sequencing of the ND2 gene to quantify genetic structure among 54 groups of adult flat-headed bats, at nine localities in South China. AMOVA and F(ST) estimates revealed significant genetic differentiation among localities. Alternatively, the pairwise F(ST) values among roosting groups appeared to be related to the incidence of associated extra-group breeding, suggesting the impact of mating events on fine-scale genetic structure. Global spatial autocorrelation analyses showed positive genetic correlation for up to 3 km, indicating the role of fragmented habitat and the specialized social organization as a barrier in the movement of individuals among bamboo forests. The male-biased dispersal pattern resulted in weaker spatial genetic structure between localities among males than among females, and fine-scale analyses supported that relatedness levels within internodes were higher among females than among males. Finally, only females were more related to their same sex roost mates than to individuals from neighbouring roosts, suggestive of natal philopatry in females. PMID- 23349889 TI - Development of adult worms and granulomatous pathology are collectively regulated by T- and B-cells in mice infected with Schistosoma japonicum. AB - Schistosoma blood flukes, which cause schistosomiasis affecting 200 million people in the world, are dependent on signals from host CD4(+) T cells to facilitate parasite growth and development in the mammalian host and to induce Th2-biased inflammatory granulomas. B cells, however, are reported to down regulate granulomatous pathology in schistosomiasis, but not to affect the development of blood flukes together with CD4(+) T lymphocytes. Thus it is not clear whether B cells mediate parasite development, reproduction and egg granuloma formation of schistosomes without the help of CD4(+) T lymphocytes. Using mice that have severe combined immunodeficiency (scid) and mice lacking T cells (nude), we found that the absence of B cells can more seriously hamper the development and paring of adult worms, but granuloma formation of Schistosoma japonicum in scid mice was not down-regulated comparing with that in nude mice. The level of IL-10 in the sera of nude mice was significantly higher than of scid mice at 43 days post infection (p.i.). Thus multiple mechanisms of immune modulation seem to be involved in parasite development and reproduction by helminth-induced regulatory B cells. Our findings have significance for understanding the molecular connections between schistosomes and T- and B-cells, indicating that more research is needed to develop efficient vaccine-based therapies for schistosomiasis. PMID- 23349890 TI - Snord 3A: a molecular marker and modulator of prion disease progression. AB - Since preventive treatments for prion disease require early identification of subjects at risk, we searched for surrogate peripheral markers characterizing the asymptomatic phases of such conditions. To this effect, we subjected blood mRNA from E200K PrP CJD patients and corresponding family members to global arrays and found that the expression of Snord3A, a non-coding RNA transcript, was elevated several times in CJD patients as compared to controls, while asymptomatic carriers presented intermediate Snord3A levels. In the brains of TgMHu2ME199K mice, a mouse model mimicking for E200K CJD, Snord 3A levels were elevated in an age and disease severity dependent manner, as was the case for brains of these mice in which disease was exacerbated by copper administration. Snord3A expression was also elevated in scrapie infected mice, but not in PrP(0/0) mice, indicating that while the expression levels of this transcript may reflect diverse prion etiologies, they are not related to the loss of PrP(C)'s function. Elevation of Snord3A was consistent with the activation of ATF6, representing one of the arms of the unfolded protein response system. Indeed, SnoRNAs were associated with reduced resistance to oxidative stress, and with ER stress in general, factors playing a significant role in this and other neurodegenerative conditions. We hypothesize that in addition to its function as a disease marker, Snord3A may play an important role in the mechanism of prion disease manifestation and progression. PMID- 23349892 TI - Growth and spectral assessment of Yb(3+)-doped KBaGd(MoO4)3 crystal: a candidate for ultrashort pulse and tunable lasers. AB - In order to explore new more powerful ultrashort pulse laser and tunable laser for diode-pumping, this paper reports the growth and spectral assessment of Yb(3+)-doped KBaGd(MoO(4))(3) crystal. An Yb(3+):KBaGd(MoO(4))(3) crystal with dimensions of 50*40*9 mm(3) was grown by the TSSG method from the K(2)Mo(2)O(7) flux. The investigated spectral properties indicated that Yb(3+):KBaGd(MoO(4))(3) crystal exhibits broad absorption and emission bands, except the large emission and gain cross-sections. This feature of the broad absorption and emission bands is not only suitable for the diode pumping, but also for the production of ultrashort pulses and tunability. Therefore, Yb(3+):KBaGd(MoO(4))(3) crystal can be regarded as a candidate for the ultrashort pulse and tunable lasers. PMID- 23349891 TI - Effect of maternal lipopolysaccharide administration on the development of dopaminergic receptors and transporter in the rat offspring. AB - Epidemiological evidence supports that maternal infection during gestation are notable risk factors for developmental mental illnesses including schizophrenia and autism. In prenatal lipopolysaccharide (LPS) model of immune activation in rats, the offspring exhibit significant impairments in behaviors mediated by central dopamine (DA) system. This study aimed to examine the temporal and regional pattern of postnatal DA development in the male offspring of pregnant Sprague-Dawley rats administered with 100 ug/kg LPS or saline at gestational days 15/16. Using ligand autoradiography, D1 and D2 dopamine receptors (D1R, D2R) and dopamine transporter (DAT) binding levels were measured in the prefrontal cortex (PFC) and sub cortical regions (dorsal striatum and nucleus accumbens core and shell) at pre pubertal (P35) and post pubertal ages (P60). We found a significant decrease in D2R ligand [(3)H] YM-90151-2 binding in the medial PFC (mPFC) in prenatal LPS-treated animals at P35 and P60 compared to respective saline groups. The decrease in D2R levels was not observed in the striatum or accumbens of maternal LPS-treated animals. No significant changes were observed in [(3)H] SCH23390 binding to D1R. However, the level of [(125)I] RTI-121 binding to DAT was selectively reduced in the nucleus accumbens core and shell at P35 in the prenatal LPS group. Immunohistochemical analysis showed that number of D2R immunopositive cells in infralimbic/prelimbic (IL/PL) part of mPFC was significantly reduced in the LPS group at P60. Prenatal LPS treatment did not significantly affect either the total number of mature neurons or parvalbumin (PV)-immunopositive interneurons in this region. However the number of PV and D2R co-labeled neurons was significantly reduced in the IL/PL subregion of PFC of LPS treated animals. Our data suggests D2R deficit in the PFC and PV interneurons may be relevant to understanding mechanisms of cortical dysfunctions described in prenatal infection animal models as well as schizophrenia. PMID- 23349893 TI - HIV-1 fusion is blocked through binding of GB Virus C E2-derived peptides to the HIV-1 gp41 disulfide loop [corrected]. AB - A strategy for antiviral drug discovery is the elucidation and imitation of viral interference mechanisms. HIV-1 patients benefit from a coinfection with GB Virus C (GBV-C), since HIV-positive individuals with long-term GBV-C viraemia show better survival rates than HIV-1 patients without persisting GBV-C. A direct influence of GBV-C on HIV-1 replication has been shown in coinfection experiments. GBV-C is a human non-pathogenic member of the flaviviridae family that can replicate in T and B cells. Therefore, GBV-C shares partly the same ecological niche with HIV-1. In earlier work we have demonstrated that recombinant glycoprotein E2 of GBV-C and peptides derived from the E2 N-terminus interfere with HIV entry. In this study we investigated the underlying mechanism. Performing a virus-cell fusion assay and temperature-arrested HIV-infection kinetics, we provide evidence that the HIV-inhibitory E2 peptides interfere with late HIV-1 entry steps after the engagement of gp120 with CD4 receptor and coreceptor. Binding and competition experiments revealed that the N-terminal E2 peptides bind to the disulfide loop region of HIV-1 transmembrane protein gp41. In conjunction with computational analyses, we identified sequence similarities between the N-termini of GBV-C E2 and the HIV-1 glycoprotein gp120. This similarity appears to enable the GBV-C E2 N-terminus to interact with the HIV-1 gp41 disulfide loop, a crucial domain involved in the gp120-gp41 interface. Furthermore, the results of the present study provide initial proof of concept that peptides targeted to the gp41 disulfide loop are able to inhibit HIV fusion and should inspire the development of this new class of HIV-1 entry inhibitors. PMID- 23349894 TI - Sod1 deficiency reduces incubation time in mouse models of prion disease. AB - Prion infections, causing neurodegenerative conditions such as Creutzfeldt-Jakob disease and kuru in humans, scrapie in sheep and BSE in cattle are characterised by prolonged and variable incubation periods that are faithfully reproduced in mouse models. Incubation time is partly determined by genetic factors including polymorphisms in the prion protein gene. Quantitative trait loci studies in mice and human genome-wide association studies have confirmed that multiple genes are involved. Candidate gene approaches have also been used and identified App, Il1 r1 and Sod1 as affecting incubation times. In this study we looked for an association between App, Il1-r1 and Sod1 representative SNPs and prion disease incubation time in the Northport heterogeneous stock of mice inoculated with the Chandler/RML prion strain. No association was seen with App, however, significant associations were seen with Il1-r1 (P = 0.02) and Sod1 (P<0.0001) suggesting that polymorphisms at these loci contribute to the natural variation observed in incubation time. Furthermore, following challenge with Chandler/RML, ME7 and MRC2 prion strains, Sod1 deficient mice showed highly significant reductions in incubation time of 20, 13 and 24%, respectively. No differences were detected in Sod1 expression or activity. Our data confirm the protective role of endogenous Sod1 in prion disease. PMID- 23349895 TI - Cholecystokinin revisited: CCK and the hunger trap in anorexia nervosa. AB - OBJECTIVE: Despite a number of studies in the past decades, the role of Cholecystokinin (CCK) in anorexia nervosa (AN) has remained uncertain. In this study a highly specific assay for the biologically active part of CCK was used in patients with bulimic as well as with the restricting type of AN who were followed over the course of weight gain. METHODS: Ten patients with restricting and 13 with bulimic AN were investigated upon admission (T0), after a weight gain of at least 2 kg on two consecutive weighting dates (T1), and during the last week before discharge (T2) from inpatient treatment in a specialized clinic. Blood samples were drawn under fasting conditions and 20 and 60 minutes following a standard meal (250 kcal). Data were compared to those of eight controls matched for sex and age. Gastrointestinal complaints of patients were measured by a questionnaire at each of the follow-up time points. RESULTS: At admission, AN patients exhibited CCK-levels similar to controls both prior to and after a test meal. Pre and post-meal CCK levels increased significantly after an initial weight gain but decreased again with further weight improvement. CCK release was somewhat lower in bulimic than in restricting type AN but both subgroups showed a similar profile. There was no significant association of CCK release to either initial weight or BMI, or their changes, but CCK levels at admission predicted gastrointestinal symptom improvement during therapy. CONCLUSIONS: Normal CCK profiles in AN at admission indicates hormonal responses adapted to low food intake while change of eating habits and weight gain results in initially increased CCK release (counteracting the attempts to alter eating behavior) that returns towards normal levels with continuous therapy. PMID- 23349896 TI - The insulin-like growth factor 1 receptor is essential for axonal regeneration in adult central nervous system neurons. AB - Axonal regeneration is an essential condition to re-establish functional neuronal connections in the injured adult central nervous system (CNS), but efficient regrowth of severed axons has proven to be very difficult to achieve. Although significant progress has been made in identifying the intrinsic and extrinsic mechanisms involved, many aspects remain unresolved. Axonal development in embryonic CNS (hippocampus) requires the obligate activation of the insulin-like growth factor 1 receptor (IGF-1R). Based on known similarities between axonal growth in fetal compared to mature CNS, we decided to examine the expression of the IGF-1R, using an antibody to the betagc subunit or a polyclonal anti-peptide antibody directed to the IGF-R (C20), in an in vitro model of adult CNS axonal regeneration, namely retinal ganglion cells (RGC) derived from adult rat retinas. Expression of both betagc and the beta subunit recognized by C20 antibody were low in freshly isolated adult RGC, but increased significantly after 4 days in vitro. As in embryonic axons, betagc was localised to distal regions and leading growth cones in RGC. IGF-1R-betagc co-localised with activated p85 involved in the phosphatidylinositol-3 kinase (PI3K) signaling pathway, upon stimulation with IGF-1. Blocking experiments using either an antibody which neutralises IGF-1R activation, shRNA designed against the IGF-1R sequence, or the PI3K pathway inhibitor LY294002, all significantly reduced axon regeneration from adult RGC in vitro (~40% RGC possessed axons in controls vs 2-8% in the different blocking studies). Finally, co-transfection of RGC with shRNA to silence IGF-1R together with a vector containing a constitutively active form of downstream PI3K (p110), fully restored axonal outgrowth in vitro. Hence these data demonstrate that axonal regeneration in adult CNS neurons requires re-expression and activation of IGF-1R, and targeting this system may offer new therapeutic approaches to enhancing axonal regeneration following trauma. PMID- 23349898 TI - Peptide-fluorescent bacteria complex as luminescent reagents for cancer diagnosis. AB - Currently in clinic, people use hematoxylin and eosin stain (H&E stain) and immunohistochemistry methods to identify the generation and genre of cancers for human pathological samples. Since these methods are inaccurate and time consuming, developing a rapid and accurate method to detect cancer is urgently demanded. In our study, binding peptides for lung cancer cell line A549 were identified using bacteria surface display method. With those binding peptides for A549 cells on the surface, the fluorescent bacteria (Escherichia coli with stably expressed green fluorescent protein) were served as specific detecting reagents for the diagnosis of cancers. The binding activity of peptide-fluorescent bacteria complex was confirmed by detached cancer cells, attached cancer cells and mice tumor xenograft samples. A unique fixation method was developed for peptide-bacteria complex in order to make this complex more feasible for the clinic use. This peptide-fluorescent bacteria complex has great potential to become a new diagnostic tool for clinical application. PMID- 23349897 TI - A naturally-occurring histone acetyltransferase inhibitor derived from Garcinia indica impairs newly acquired and reactivated fear memories. AB - The study of the cellular and molecular mechanisms underlying the consolidation and reconsolidation of traumatic fear memories has progressed rapidly in recent years, yet few compounds have emerged that are readily useful in a clinical setting for the treatment of anxiety disorders such as post-traumatic stress disorder (PTSD). Here, we use a combination of biochemical, behavioral, and neurophysiological methods to systematically investigate the ability of garcinol, a naturally-occurring histone acetyltransferase (HAT) inhibitor derived from the rind of the fruit of the Kokum tree (Garcina indica), to disrupt the consolidation and reconsolidation of Pavlovian fear conditioning, a widely studied rodent model of PTSD. We show that local infusion of garcinol into the rat lateral amygdala (LA) impairs the training and retrieval-related acetylation of histone H3 in the LA. Further, we show that either intra-LA or systemic administration of garcinol within a narrow window after either fear conditioning or fear memory retrieval significantly impairs the consolidation and reconsolidation of a Pavlovian fear memory and associated neural plasticity in the LA. Our findings suggest that a naturally-occurring compound derived from the diet that regulates chromatin function may be useful in the treatment of newly acquired or recently reactivated traumatic memories. PMID- 23349899 TI - Distinct protein classes in human red cell proteome revealed by similarity of phylogenetic profiles. AB - The minimal set of proteins necessary to maintain a vertebrate cell forms an interesting core of cellular machinery. The known proteome of human red blood cell consists of about 1400 proteins. We treated this protein complement of one of the simplest human cells as a model and asked the questions on its function and origins. The proteome was mapped onto phylogenetic profiles, i.e. vectors of species possessing homologues of human proteins. A novel clustering approach was devised, utilising similarity in the phylogenetic spread of homologues as distance measure. The clustering based on phylogenetic profiles yielded several distinct protein classes differing in phylogenetic taxonomic spread, presumed evolutionary history and functional properties. Notably, small clusters of proteins common to vertebrates or Metazoa and other multicellular eukaryotes involve biological functions specific to multicellular organisms, such as apoptosis or cell-cell signaling, respectively. Also, a eukaryote-specific cluster is identified, featuring GTP-ase signalling and ubiquitination. Another cluster, made up of proteins found in most organisms, including bacteria and archaea, involves basic molecular functions such as oxidation-reduction and glycolysis. Approximately one third of erythrocyte proteins do not fall in any of the clusters, reflecting the complexity of protein evolution in comparison to our simple model. Basically, the clustering obtained divides the proteome into old and new parts, the former originating from bacterial ancestors, the latter from inventions within multicellular eukaryotes. Thus, the model human cell proteome appears to be made up of protein sets distinct in their history and biological roles. The current work shows that phylogenetic profiles concept allows protein clustering in a way relevant both to biological function and evolutionary history. PMID- 23349900 TI - Prevalence of tick-borne pathogens in Ixodes ricinus and Dermacentor reticulatus ticks from different geographical locations in Belarus. AB - Worldwide, ticks are important vectors of human and animal pathogens. Besides Lyme Borreliosis, a variety of other bacterial and protozoal tick-borne infections are of medical interest in Europe. In this study, 553 questing and feeding Ixodes ricinus (n = 327) and Dermacentor reticulatus ticks (n = 226) were analysed by PCR for Borrelia, Rickettsia, Anaplasma, Coxiella, Francisella and Babesia species. Overall, the pathogen prevalence in ticks was 30.6% for I. ricinus and 45.6% for D. reticulatus. The majority of infections were caused by members of the spotted-fever group rickettsiae (24.4%), 9.4% of ticks were positive for Borrelia burgdorferi sensu lato, with Borrelia afzelii being the most frequently detected species (40.4%). Pathogens with low prevalence rates in ticks were Anaplasma phagocytophilum (2.2%), Coxiella burnetii (0.9%), Francisella tularensis subspecies (0.7%), Bartonella henselae (0.7%), Babesia microti (0.5%) and Babesia venatorum (0.4%). On a regional level, hotspots of pathogens were identified for A. phagocytophilum (12.5-17.2%), F. tularensis ssp. (5.5%) and C. burnetii (9.1%), suggesting established zoonotic cycles of these pathogens at least at these sites. Our survey revealed a high burden of tick borne pathogens in questing and feeding I. ricinus and D. reticulatus ticks collected in different regions in Belarus, indicating a potential risk for humans and animals. Identified hotspots of infected ticks should be included in future surveillance studies, especially when F. tularensis ssp. and C. burnetii are involved. PMID- 23349901 TI - Altered network communication following a neuroprotective drug treatment. AB - Preconditioning is defined as a range of stimuli that allow cells to withstand subsequent anaerobic and other deleterious conditions. While cell protection under preconditioning is well established, this paper investigates the influence of neuroprotective preconditioning drugs, 4-aminopyridine and bicuculline (4 AP/bic), on synaptic communication across a broad network of in vitro rat cortical neurons. Using a permutation test, we evaluated cross-correlations of extracellular spiking activity across all pairs of recording electrodes on a 64 channel multielectrode array. The resulting functional connectivity maps were analyzed in terms of their graph-theoretic properties. A small-world effect was found, characterized by a functional network with high clustering coefficient and short average path length. Twenty-four hours after exposure to 4-AP/bic, small world properties were comparable to control cultures that were not treated with the drug. Four hours following drug washout, however, the density of functional connections increased, while path length decreased and clustering coefficient increased. These alterations in functional connectivity were maintained at four days post-washout, suggesting that 4-AP/bic preconditioning leads to long-term effects on functional networks of cortical neurons. Because of their influence on communication efficiency in neuronal networks, alterations in small-world properties hold implications for information processing in brain systems. The observed relationship between density, path length, and clustering coefficient is captured by a phenomenological model where connections are added randomly within a spatially-embedded network. Taken together, results provide information regarding functional consequences of drug therapies that are overlooked in traditional viability studies and present the first investigation of functional networks under neuroprotective preconditioning. PMID- 23349902 TI - A potential role for plasma uric acid in the endothelial pathology of Plasmodium falciparum malaria. AB - BACKGROUND: Inflammatory cytokinemia and systemic activation of the microvascular endothelium are central to the pathogenesis of Plasmodium falciparum malaria. Recently, 'parasite-derived' uric acid (UA) was shown to activate human immune cells in vitro, and plasma UA levels were associated with inflammatory cytokine levels and disease severity in Malian children with malaria. Since UA is associated with endothelial inflammation in non-malaria diseases, we hypothesized that elevated UA levels contribute to the endothelial pathology of P. falciparum malaria. METHODOLOGY/PRINCIPAL FINDINGS: We measured levels of UA and soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-Selectin), thrombomodulin (sTM), tissue factor (sTF) and vascular endothelial growth factor (VEGF) in the plasma of Malian children aged 0.5-17 years with uncomplicated malaria (UM, n = 487) and non-cerebral severe malaria (NCSM, n = 68). In 69 of these children, we measured these same factors once when they experienced a malaria episode and twice when they were healthy (i.e., before and after the malaria transmission season). We found that levels of UA, sICAM-1, sVCAM-1, sE-Selectin and sTM increase during a malaria episode and return to basal levels at the end of the transmission season (p<0.0001). Plasma levels of UA and these four endothelial biomarkers correlate with parasite density and disease severity. In children with UM, UA levels correlate with parasite density (r = 0.092, p = 0.043), sICAM-1 (r = 0.255, p<0.0001) and sTM (r = 0.175, p = 0.0001) levels. After adjusting for parasite density, UA levels predict sTM levels. CONCLUSIONS/SIGNIFICANCE: Elevated UA levels may contribute to malaria pathogenesis by damaging endothelium and promoting a procoagulant state. The correlation between UA levels and parasite densities suggests that parasitized erythrocytes are one possible source of excess UA. UA-induced shedding of endothelial TM may represent a novel mechanism of malaria pathogenesis, in which activated thrombin induces fibrin deposition and platelet aggregation in microvessels. This protocol is registered at clinicaltrials.gov (NCT00669084). PMID- 23349903 TI - Identification of two evolutionarily conserved 5' cis-elements involved in regulating spatiotemporal expression of Nolz-1 during mouse embryogenesis. AB - Proper development of vertebrate embryos depends not only on the crucial funtions of key evolutionarily conserved transcriptional regulators, but also on the precisely spatiotemporal expression of these transcriptional regulators. The mouse Nolz-1/Znf503/Zfp503 gene is a mammalian member of the conserved zinc finger containing NET family. The expression pattern of Nolz-1 in mouse embryos is highly correlated with that of its homologues in different species. To study the spatiotemporal regulation of Nolz-1, we first identified two evolutionarily conserved cis-elements, UREA and UREB, in 5' upstream regions of mouse Nolz-1 locus. We then generated UREA-LacZ and UREB-LacZ transgenic reporter mice to characterize the putative enhancer activity of UREA and UREB. The results indicated that both UREA and UREB contained tissue-specific enhancer activity for directing LacZ expression in selective tissue organs during mouse embryogensis. UREA directed LacZ expression preferentially in selective regions of developing central nervous system, including the forebrain, hindbrain and spinal cord, whereas UREB directed LacZ expression mainly in other developing tissue organs such as the Nolz-1 expressing branchial arches and its derivatives, the apical ectodermal ridge of limb buds and the urogenital tissues. Both UREA and UREB directed strong LacZ expression in the lateral plate mesoderm where endogenous Nolz-1 was also expressed. Despite that the LacZ expression pattern did not full recapitulated the endogenous Nolz-1 expression and some mismatched expression patterns were observed, co-expression of LacZ and Nolz-1 did occur in many cells of selective tissue organs, such as in the ventrolateral cortex and ventral spinal cord of UREA-LacZ embryos, and the urogenital tubes of UREB-LacZ embryos. Taken together, our study suggests that UREA and UREB may function as evolutionarily conserved cis-regulatory elements that coordinate with other cis elements to regulate spatiotemporal expression of Nolz-1 in different tissue organs during mouse embryogenesis. PMID- 23349904 TI - Naturally occurring mutations in large surface genes related to occult infection of hepatitis B virus genotype C. AB - Molecular mechanisms related to occult hepatitis B virus (HBV) infection, particularly those based on genotype C infection, have rarely been determined thus far in the ongoing efforts to determine infection mechanisms. Therefore, we aim to elucidate the mutation patterns in the surface open reading frame (S ORF) underlying occult infections of HBV genotype C in the present study. Nested PCRs were applied to 624 HBV surface antigen (HBsAg) negative Korean subjects. Cloning and sequencing of the S ORF gene was applied to 41 occult cases and 40 control chronic carriers. Forty-one (6.6%) of the 624 Korean adults with HBsAg-negative serostatus were found to be positive for DNA according to nested PCR tests. Mutation frequencies in the three regions labeled here as preS1, preS2, and S were significantly higher in the occult subjects compared to the carriers in all cases. A total of two types of deletions, preS1 deletions in the start codon and preS2 deletions as well as nine types of point mutations were significantly implicated in the occult infection cases. Mutations within the "a" determinant region in HBsAg were found more frequently in the occult subjects than in the carriers. Mutations leading to premature termination of S ORF were found in 16 occult subjects (39.0%) but only in one subject from among the carriers (2.5%). In conclusion, our data suggest that preS deletions, the premature termination of S ORF, and "a" determinant mutations are associated with occult infections of HBV genotype C among a HBsAg-negative population. The novel mutation patterns related to occult infection introduced in the present study can help to broaden our understanding of HBV occult infections. PMID- 23349905 TI - RNA-Seq for enrichment and analysis of IRF5 transcript expression in SLE. AB - Polymorphisms in the interferon regulatory factor 5 (IRF5) gene have been consistently replicated and shown to confer risk for or protection from the development of systemic lupus erythematosus (SLE). IRF5 expression is significantly upregulated in SLE patients and upregulation associates with IRF5 SLE risk haplotypes. IRF5 alternative splicing has also been shown to be elevated in SLE patients. Given that human IRF5 exists as multiple alternatively spliced transcripts with distinct function(s), it is important to determine whether the IRF5 transcript profile expressed in healthy donor immune cells is different from that expressed in SLE patients. Moreover, it is not currently known whether an IRF5-SLE risk haplotype defines the profile of IRF5 transcripts expressed. Using standard molecular cloning techniques, we identified and isolated 14 new differentially spliced IRF5 transcript variants from purified monocytes of healthy donors and SLE patients to generate an IRF5 variant transcriptome. Next generation sequencing was then used to perform in-depth and quantitative analysis of full-length IRF5 transcript expression in primary immune cells of SLE patients and healthy donors by next-generation sequencing. Evidence for additional alternatively spliced transcripts was obtained from de novo junction discovery. Data from these studies support the overall complexity of IRF5 alternative splicing in SLE. Results from next-generation sequencing correlated with cloning and gave similar abundance rankings in SLE patients thus supporting the use of this new technology for in-depth single gene transcript profiling. Results from this study provide the first proof that 1) SLE patients express an IRF5 transcript signature that is distinct from healthy donors, 2) an IRF5-SLE risk haplotype defines the top four most abundant IRF5 transcripts expressed in SLE patients, and 3) an IRF5 transcript signature enables clustering of SLE patients with the H2 risk haplotype. PMID- 23349906 TI - Th inducing POZ-Kruppel Factor (ThPOK) is a key regulator of the immune response since the early steps of colorectal carcinogenesis. AB - We purposed to evaluate the role of Th inducing POZ-Kruppel Factor (ThPOK), a transcriptional regulator of T cell fate, in tumour-induced immune system plasticity in colorectal carcinogenesis. The amounts of CD4+, CD8+ and CD56+ and ThPOK+ cells infiltrate in normal colorectal mucosa (NM), in dysplastic aberrant crypt foci (microadenomas, MA), the earliest detectable lesions in colorectal carcinogenesis, and in colorectal carcinomas (CRC), were measured, and the colocalization of ThPOK with the above-mentioned markers of immune cells was evaluated using confocal microscopy. Interestingly, ThPOK showed a prominent increase since MA. A strong colocalization of ThPOK with CD4 both in NM and in MA was observed, weaker in carcinomas. Surprisingly, there was a peak in the colocalization levels of ThPOK with CD8 in MA, which was evident, although to a lesser extent, in carcinomas, too. In conclusion, according to the data of the present study, ThPOK may be considered a central regulator of the earliest events in the immune system during colorectal cancer development, decreasing the immune response against cancer cells. PMID- 23349907 TI - Comparative proteomic analysis of gallbladder bile proteins related to cholesterol gallstones. AB - BACKGROUND: Nucleation of cholesterol monohydrate crystals following the aggregation and fusion of cholesterol-enriched vesicles is a critical procedure in the formation of cholesterol gallstone. Biliary proteins play important roles in the process. It is inefficient to screen pro-nucleating or anti-nucleating proteins with routine physiochemical techniques, by which we discovered several pro-nucleating proteins. METHODOLOGY/PRINCIPAL FINDINGS: Based on comparative proteomic technologies, we investigated the differentially expressed proteins between the cholesterol gallstone and control groups, and between the vesicular phase and micellar phase. There are 401+/-75 spots detected on the cholesterol gallstone group and 389+/-94 spots on the control group gels, 120+/-24 spots detected on vesicular phase and 198+/-37 on micellar phase gels, and accordingly 22 and 8 differentially expressed proteins were identified successfully, respectively. Three of them, HSA, Profilin and Retinol Binding Protein, were validated by Western blot. CONCLUSION/SIGNIFICANCE: Some of the identified proteins are in good agreement with proteins reported to be involved in the gallstone formation before. The information from this study might provide some important clues to uncover the key proteins involved in the formation of cholesterol gallstone. PMID- 23349908 TI - Detection of copy number variants reveals association of cilia genes with neural tube defects. AB - BACKGROUND: Neural tube defects (NTDs) are one of the most common birth defects caused by a combination of genetic and environmental factors. Currently, little is known about the genetic basis of NTDs although up to 70% of human NTDs were reported to be attributed to genetic factors. Here we performed genome-wide copy number variants (CNVs) detection in a cohort of Chinese NTD patients in order to exam the potential role of CNVs in the pathogenesis of NTDs. METHODS: The genomic DNA from eighty-five NTD cases and seventy-five matched normal controls were subjected for whole genome CNVs analysis. Non-DGV (the Database of Genomic Variants) CNVs from each group were further analyzed for their associations with NTDs. Gene content in non-DGV CNVs as well as participating pathways were examined. RESULTS: Fifty-five and twenty-six non-DGV CNVs were detected in cases and controls respectively. Among them, forty and nineteen CNVs involve genes (genic CNV). Significantly more non-DGV CNVs and non-DGV genic CNVs were detected in NTD patients than in control (41.2% vs. 25.3%, p<0.05 and 37.6% vs. 20%, p<0.05). Non-DGV genic CNVs are associated with a 2.65-fold increased risk for NTDs (95% CI: 1.24-5.87). Interestingly, there are 41 cilia genes involved in non DGV CNVs from NTD patients which is significantly enriched in cases compared with that in controls (24.7% vs. 9.3%, p<0.05), corresponding with a 3.19-fold increased risk for NTDs (95% CI: 1.27-8.01). Pathway analyses further suggested that two ciliogenesis pathways, tight junction and protein kinase A signaling, are top canonical pathways implicated in NTD-specific CNVs, and these two novel pathways interact with known NTD pathways. CONCLUSIONS: Evidence from the genome wide CNV study suggests that genic CNVs, particularly ciliogenic CNVs are associated with NTDs and two ciliogenesis pathways, tight junction and protein kinase A signaling, are potential pathways involved in NTD pathogenesis. PMID- 23349909 TI - Transforming growth factor beta neutralization ameliorates pre-existing hepatic fibrosis and reduces cholangiocarcinoma in thioacetamide-treated rats. AB - Considerable evidence has demonstrated that transforming growth factor beta (TGF beta) plays a key role in hepatic fibrosis, the final common pathway for a variety of chronic liver diseases leading to liver insufficiency. Although a few studies have reported that blocking TGF-beta with soluble receptors or siRNA can prevent the progression of hepatic fibrosis, as yet no evidence has been provided that TGF-beta antagonism can improve pre-existing hepatic fibrosis. The aim of this study was to examine the effects of a murine neutralizing TGF-beta monoclonal antibody (1D11), in a rat model of thioacetamide (TAA)-induced hepatic fibrosis. TAA administration for 8 weeks induced extensive hepatic fibrosis, whereupon 1D11 dosing was initiated and maintained for 8 additional weeks. Comparing the extent of fibrosis at two time points, pre- and post-1D11 dosing, we observed a profound regression of tissue injury and fibrosis upon treatment, as reflected by a reduction of collagen deposition to a level significantly less than that observed before 1D11 dosing. Hepatic TGF-beta1 mRNA, tissue hydroxyproline, and plasminogen activator inhibitor 1 (PAI-1) levels were significantly elevated at the end of the 8 week TAA treatment. Vehicle and antibody control groups demonstrated progressive injury through 16 weeks, whereas those animals treated for 8 weeks with 1D11 showed striking improvement in histologic and molecular endpoints. During the course of tissue injury, TAA also induced cholangiocarcinomas. At the end of study, the number and area of cholangiocarcinomas were significantly diminished in rats receiving 1D11 as compared to control groups, presumably by the marked reduction of supporting fibrosis/stroma. The present study demonstrates that 1D11 can reverse pre existing hepatic fibrosis induced by extended dosing of TAA. The regression of fibrosis was accompanied by a marked reduction in concomitantly developed cholangiocarcinomas. These data provide evidence that therapeutic dosing of a TGF beta antagonist can diminish and potentially reverse hepatic fibrosis and also reduce the number and size of attendant cholangiocarcinomas. PMID- 23349910 TI - Sulodexide decreases albuminuria and regulates matrix protein accumulation in C57BL/6 mice with streptozotocin-induced type I diabetic nephropathy. AB - OBJECTIVE: Sulodexide is a mixture of glycosaminoglycans that may reduce proteinuria in diabetic nephropathy (DN), but its mechanism of action and effect on renal histology is not known. We investigated the effect of sulodexide on disease manifestations in a murine model of type I DN. METHODS: Male C57BL/6 mice were rendered diabetic with streptozotocin. After the onset of proteinuria, mice were randomized to receive sulodexide (1 mg/kg/day) or saline for up to 12 weeks and renal function, histology and fibrosis were examined. The effect of sulodexide on fibrogenesis in murine mesangial cells (MMC) was also investigated. RESULTS: Mice with DN showed progressive albuminuria and renal deterioration over time, accompanied by mesangial expansion, PKC and ERK activation, increased renal expression of TGF-beta1, fibronectin and collagen type I, III and IV, but decreased glomerular perlecan expression. Sulodexide treatment significantly reduced albuminuria, improved renal function, increased glomerular perlecan expression and reduced collagen type I and IV expression and ERK activation. Intra-glomerular PKC-alpha activation was not affected by sulodexide treatment whereas glomerular expression of fibronectin and collagen type III was increased. MMC stimulated with 30 mM D-glucose showed increased PKC and ERK mediated fibronectin and collagen type III synthesis. Sulodexide alone significantly increased fibronectin and collagen type III synthesis in a dose-dependent manner in MMC and this increase was further enhanced in the presence of 30 mM D-glucose. Sulodexide showed a dose-dependent inhibition of 30 mM D-glucose-induced PKC betaII and ERK phosphorylation, but had no effect on PKC-alpha or PKC-betaI phosphorylation. CONCLUSIONS: Our data demonstrated that while sulodexide treatment reduced proteinuria and improved renal function, it had differential effects on signaling pathways and matrix protein synthesis in the kidney of C57BL/6 mice with DN. PMID- 23349911 TI - MicroRNA-mediated suppression of oncolytic adenovirus replication in human liver. AB - MicroRNAs (miRNAs) are important and ubiquitous regulators of gene expression that can suppress their target genes by translational inhibition as well as mRNA destruction. Cell type-specific miRNA expression patterns have been successfully exploited for targeting the expression of experimental and therapeutic gene constructs, for example to reduce pathogenic effects of cancer virotherapy in normal tissues. In order to avoid liver damage associated with systemic or intrahepatic delivery of oncolytic adenoviruses we have introduced the concept of suppressing adenovirus replication in hepatic cells by inserting target elements for the liver-specific miR122 into the viral genome. Here we show using ex vivo cultured tissue specimens that six perfectly complementary miR122 target sites in the 3' untranslated region of the viral E1A gene are sufficient in the absence of any other genetic modifications to prevent productive replication of serotype 5 adenovirus (Ad5) in normal human liver. This modification did not compromise the replicative capacity of the modified virus in cancer tissue derived from a colon carcinoma liver metastasis or its oncolytic potency in a human lung cancer xenograft mouse model. Unlike wild-type Ad5, the modified virus did not result in increased serum levels of liver enzymes in infected mice. These results provide a strong preclinical proof of concept for the use of miR122 target sites for reducing the risk of liver damage caused by oncolytic adenoviruses, and suggest that ectopic miR122 target elements should be considered as an additional safety measure included in any therapeutic virus or viral vector posing potential hazard to the liver. PMID- 23349912 TI - Wide range of mercury contamination in chicks of southern ocean seabirds. AB - Using top predators as sentinels of the marine environment, Hg contamination was investigated within the large subantarctic seabird community of Kerguelen Islands, a remote area from the poorly known Southern Indian Ocean. Chicks of 21 sympatric seabirds presented a wide range of Hg concentrations, with the highest contaminated species containing ~102 times more feather Hg than the less contaminated species. Hence, Kerguelen seabirds encompass the whole range of chick feather Hg values that were previously collected worldwide in poorly industrialized localities. Using stable isotopes, the effects of foraging habitats (reflected by delta(13)C) and trophic positions (reflected by delta(15)N) on Hg concentrations were investigated. Species-related Hg variations were highly and positively linked to feather delta(15)N values, thus highlighting the occurrence of efficient Hg biomagnification processes within subantarctic marine trophic webs. By contrast, Hg contamination overall correlated poorly with feeding habitats, because of the pooling of species foraging within different isotopic gradients corresponding to distinct seabird habitats (benthic, pelagic, neritic and oceanic). However, when focusing on oceanic seabirds, Hg concentration was related to feather delta(13)C values, with species feeding in colder waters (lower delta(13)C values) south of Kerguelen Islands being less prone to be contaminated than species feeding in northern warmer waters (higher delta(13)C values). Within the context of continuous increase in global Hg emissions, Kerguelen Islands that are located far away from anthropogenic sources can be considered as an ideal study site to monitor the temporal trend of global Hg contamination. The present work helps selecting some seabird species as sentinels of environmental pollution according to their high Hg concentrations and their contrasted foraging ecology. PMID- 23349913 TI - Identification of the cancer cell proliferation and survival functions of proHB EGF by using an anti-HB-EGF antibody. AB - PURPOSE: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the epidermal growth factor family. The membrane-bound proHB-EGF is known to be a precursor of the soluble form of HB-EGF (sHB-EGF), which promotes cell proliferation and survival. While the functions of sHB-EGF have been extensively studied, it is not yet fully understood if proHB-EGF is also involved in cellular signaling events. In this study, we utilized the anti-HB-EGF monoclonal antibodies Y-142 and Y-073, which have differential specificities toward proHB-EGF, in order to elucidate proHB-EGF functions in cancer cells. EXPERIMENTAL DESIGN: The biological activities of proHB-EGF were assessed in cell proliferation, caspase activation, and juxtacrine activity assays by using a 3D spheroid culture of NUGC-3 cells. RESULTS: Y-142 and Y-073 exhibited similar binding and neutralizing activities for sHB-EGF. However, only Y-142 bound to proHB-EGF. We could detect the function of endogenously expressed proHB-EGF in a 3D spheroid culture. Blocking proHB-EGF with Y-142 reduced spheroid formation, suppressed cell proliferation, and increased caspase activation in the 3D spheroid culture of NUGC-3 cells. CONCLUSIONS: Our results show that proHB-EGF acts as a cell proliferation and cell survival factor in cancer cells. The results suggest that proHB-EGF may play an important role in tumor progression. PMID- 23349914 TI - Seizures induced by pentylenetetrazole in the adult zebrafish: a detailed behavioral characterization. AB - Pentylenetetrazole (PTZ) is a common convulsant agent used in animal models to investigate the mechanisms of seizures. Although adult zebrafish have been recently used to study epileptic seizures, a thorough characterization of the PTZ induced seizures in this animal model is missing. The goal of this study was to perform a detailed temporal behavior profile characterization of PTZ-induced seizure in adult zebrafish. The behavioral profile during 20 min of PTZ immersion (5, 7.5, 10, and 15 mM) was characterized by stages defined as scores: (0) short swim, (1) increased swimming activity and high frequency of opercular movement, (2) erratic movements, (3) circular movements, (4) clonic seizure-like behavior, (5) fall to the bottom of the tank and tonic seizure-like behavior, (6) death. Animals exposed to distinct PTZ concentrations presented different seizure profiles, intensities and latencies to reach all scores. Only animals immersed into 15 mM PTZ showed an increased time to return to the normal behavior (score 0), after exposure. Total mortality rate at 10 and 15 mM were 33% and 50%, respectively. Considering all behavioral parameters, 5, 7.5, 10, and 15 mM PTZ, induced seizures with low, intermediate, and high severity, respectively. Pretreatment with diazepam (DZP) significantly attenuated seizure severity. Finally, the brain PTZ levels in adult zebrafish immersed into the chemoconvulsant solution at 5 and 10 mM were comparable to those described for the rodent model, with a peak after a 20-min of exposure. The PTZ brain levels observed after 2.5-min PTZ exposure and after 60-min removal from exposure were similar. Altogether, our results showed a detailed temporal behavioral characterization of a PTZ epileptic seizure model in adult zebrafish. These behavioral analyses and the simple method for PTZ quantification could be considered as important tools for future investigations and translational research. PMID- 23349915 TI - A recombinant fusion toxin based on enzymatic inactive C3bot1 selectively targets macrophages. AB - BACKGROUND: The C3bot1 protein (~23 kDa) from Clostridium botulinum ADP ribosylates and thereby inactivates Rho. C3bot1 is selectively taken up into the cytosol of monocytes/macrophages but not of other cell types such as epithelial cells or fibroblasts. Most likely, the internalization occurs by a specific endocytotic pathway via acidified endosomes. METHODOLOGY/PRINCIPAL FINDINGS: Here, we tested whether enzymatic inactive C3bot1E174Q serves as a macrophage selective transport system for delivery of enzymatic active proteins into the cytosol of such cells. Having confirmed that C3bot1E174Q does not induce macrophage activation, we used the actin ADP-ribosylating C2I (~50 kDa) from Clostridium botulinum as a reporter enzyme for C3bot1E174Q-mediated delivery into macrophages. The recombinant C3bot1E174Q-C2I fusion toxin was cloned and expressed as GST-protein in Escherichia coli. Purified C3bot1E174Q-C2I was recognized by antibodies against C2I and C3bot and showed C2I-specific enzyme activity in vitro. When applied to cultured cells C3bot1E174Q-C2I ADP-ribosylated actin in the cytosol of macrophages including J774A.1 and RAW264.7 cell lines as well as primary cultured human macrophages but not of epithelial cells. Together with confocal fluorescence microscopy experiments, the biochemical data indicate the selective uptake of a recombinant C3-fusion toxin into the cytosol of macrophages. CONCLUSIONS/SIGNIFICANCE: In summary, we demonstrated that C3bot1E174Q can be used as a delivery system for fast, selective and specific transport of enzymes into the cytosol of living macrophages. Therefore, C3-based fusion toxins can represent valuable molecular tools in experimental macrophage pharmacology and cell biology as well as attractive candidates to develop new therapeutic approaches against macrophage-associated diseases. PMID- 23349916 TI - Neural progenitor cell implants modulate vascular endothelial growth factor and brain-derived neurotrophic factor expression in rat axotomized neurons. AB - Axotomy of central neurons leads to functional and structural alterations which largely revert when neural progenitor cells (NPCs) are implanted in the lesion site. The new microenvironment created by NPCs in the host tissue might modulate in the damaged neurons the expression of a high variety of molecules with relevant roles in the repair mechanisms, including neurotrophic factors. In the present work, we aimed to analyze changes in neurotrophic factor expression in axotomized neurons induced by NPC implants. For this purpose, we performed immunofluorescence followed by confocal microscopy analysis for the detection of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor (NGF) on brainstem sections from rats with axotomy of abducens internuclear neurons that received NPC implants (implanted group) or vehicle injections (axotomized group) in the lesion site. Control abducens internuclear neurons were strongly immunoreactive to VEGF and BDNF but showed a weak staining for NT-3 and NGF. Comparisons between groups revealed that lesioned neurons from animals that received NPC implants showed a significant increase in VEGF content with respect to animals receiving vehicle injections. However, the immunoreactivity for BDNF, which was increased in the axotomized group as compared to control, was not modified in the implanted group. The modifications induced by NPC implants on VEGF and BDNF content were specific for the population of axotomized abducens internuclear neurons since the neighboring abducens motoneurons were not affected. Similar levels of NT-3 and NGF immunolabeling were obtained in injured neurons from axotomized and implanted animals. Among all the analyzed neurotrophic factors, only VEGF was expressed by the implanted cells in the lesion site. Our results point to a role of NPC implants in the modulation of neurotrophic factor expression by lesioned central neurons, which might contribute to the restorative effects of these implants. PMID- 23349917 TI - A topography analysis incorporated optimization method for the selection and placement of best management practices. AB - Best Management Practices (BMPs) are one of the most effective methods to control nonpoint source (NPS) pollution at a watershed scale. In this paper, the use of a topography analysis incorporated optimization method (TAIOM) was proposed, which integrates topography analysis with cost-effective optimization. The surface status, slope and the type of land use were evaluated as inputs for the optimization engine. A genetic algorithm program was coded to obtain the final optimization. The TAIOM was validated in conjunction with the Soil and Water Assessment Tool (SWAT) in the Yulin watershed in Southwestern China. The results showed that the TAIOM was more cost-effective than traditional optimization methods. The distribution of selected BMPs throughout landscapes comprising relatively flat plains and gentle slopes, suggests the need for a more operationally effective scheme, such as the TAIOM, to determine the practicability of BMPs before widespread adoption. The TAIOM developed in this study can easily be extended to other watersheds to help decision makers control NPS pollution. PMID- 23349918 TI - Effect of mannitol dry powder challenge on exhaled nitric oxide in children. AB - BACKGROUND: Fractional exhaled nitric oxide (FENO), a non-invasive marker of eosinophilic airway inflammation, is increasingly used for diagnostic and therapeutic decisions in adult and paediatric asthma. Standardized guidelines for the measurement of FENO recommend performing FENO measurements before rather than after bronchial provocation tests. OBJECTIVE: To investigate whether FENO levels decrease after a Mannitol dry powder (MDP) challenge in a clinical setting, and whether the extent of the decrease is influenced by number of MDP manoeuvres, baseline FENO, atopy and doctor diagnosed asthma. METHODS: Children aged 6-16 years, referred for possible reactive airway disease to a respiratory outpatient clinic, performed an MDP challenge (Aridol(r), Pharmaxis, Australia). FENO was measured in doublets immediately before and after the challenge test using the portable NIOX MINO(r) device (Aerocrine, Stockholm, Sweden). We analysed the data using Kruskal-Wallis rank tests, Wilcoxon signed rank tests and multivariable linear regressions. RESULTS: One hundred and seven children completed both tests (mean+/-SD age 11.5+/-2.8 years). Overall, median (interquartile range) FENO decreased slightly by -2.5 ppb (-7.0, -0.5), from 18.5 ppb (10.5, 45.5) before the MDP challenge to 16.5 ppb thereafter (8.5, 40.5; p<0.001). In all participants, the change in FENO was smaller than one standard deviation of the baseline mean. The % fall in FENO was smaller in children with less MDP manoeuvres (e.g. higher bronchial responsiveness; p = 0.08) but was not influenced by levels of baseline FENO (p = 0.68), atopy (p = 0.84) or doctor diagnosed asthma (p = 0.93). CONCLUSION: MDP challenge test influences FENO values but differences are small and clinically barely relevant. PMID- 23349919 TI - A kinetic-based model of radiation-induced intercellular signalling. AB - It is now widely accepted that intercellular communication can cause significant variations in cellular responses to genotoxic stress. The radiation-induced bystander effect is a prime example of this effect, where cells shielded from radiation exposure see a significant reduction in survival when cultured with irradiated cells. However, there is a lack of robust, quantitative models of this effect which are widely applicable. In this work, we present a novel mathematical model of radiation-induced intercellular signalling which incorporates signal production and response kinetics together with the effects of direct irradiation, and test it against published data sets, including modulated field exposures. This model suggests that these so-called "bystander" effects play a significant role in determining cellular survival, even in directly irradiated populations, meaning that the inclusion of intercellular communication may be essential to produce robust models of radio-biological outcomes in clinically relevant in vivo situations. PMID- 23349920 TI - Neuronal Goalpha and CAPS regulate behavioral and immune responses to bacterial pore-forming toxins. AB - Pore-forming toxins (PFTs) are abundant bacterial virulence factors that attack host cell plasma membranes. Host defense mechanisms against PFTs described to date all function in the host tissue that is directly attacked by the PFT. Here we characterize a rapid and fully penetrant cessation of feeding of Caenorhabditis elegans in response to PFT attack. We demonstrate via analyses of C. elegans mutants that inhibition of feeding by PFT requires the neuronal G protein Goalpha subunit goa-1, and that maintenance of this response requires neuronally expressed calcium activator for protein secretion (CAPS) homolog unc 31. Independently from their role in feeding cessation, we find that goa-1 and unc-31 are additionally required for immune protection against PFTs. We thus demonstrate that the behavioral and immune responses to bacterial PFT attack involve the cross-talk between the nervous system and the cells directly under attack. PMID- 23349921 TI - Gold coated lanthanide phosphate nanoparticles for targeted alpha generator radiotherapy. AB - Targeted radiotherapies maximize cytotoxicty to cancer cells. In vivo alpha generator targeted radiotherapies can deliver multiple alpha particles to a receptor site dramatically amplifying the radiation dose delivered to the target. The major challenge with alpha-generator radiotherapies is that traditional chelating moieties are unable to sequester the radioactive daughters in the bioconjugate which is critical to minimize toxicity to healthy, non-target tissue. The recoil energy of the (225)Ac daughters following alpha decay will sever any metal-ligand bond used to form the bioconjugate. This work demonstrates that an engineered multilayered nanoparticle-antibody conjugate can deliver multiple alpha radiations and contain the decay daughters of (225)Ac while targeting biologically relevant receptors in a female BALB/c mouse model. These multi-shell nanoparticles combine the radiation resistance of lanthanide phosphate to contain (225)Ac and its radioactive decay daughters, the magnetic properties of gadolinium phosphate for easy separation, and established gold chemistry for attachment of targeting moieties. PMID- 23349922 TI - Assessment of microalbuminuria for early diagnosis and risk prediction in dengue infections. AB - BACKGROUND: Dengue is the most important arboviral infection of humans. Following an initial febrile period, a small proportion of infected patients develop a vasculopathy, with children at particular risk for severe vascular leakage and shock. Differentiation between dengue and other common childhood illnesses is difficult during the early febrile phase, and risk prediction for development of shock is poor. The presence of microalbuminuria is recognized as a useful early predictor for subsequent complications in a number of other disorders with vascular involvement. Significant proteinuria occurs in association with dengue shock syndrome and it is possible that early-phase microalbuminuria may be helpful both for diagnosis of dengue and for identification of patients likely to develop severe disease. METHODOLOGY/PRINCIPAL FINDINGS: We measured formal urine albumin to creatinine ratios (UACRs) in daily samples obtained from a large cohort of children with suspected dengue recruited at two outpatient clinics in Ho Chi Minh City, Vietnam. Although UACRs were increased in the 465 confirmed dengue patients, with a significant time trend showing peak values around the critical period for dengue-associated plasma leakage, urine albumin excretion was also increased in the comparison group of 391 patients with other febrile illnesses (OFI). The dengue patients generally had higher UACRs than the OFI patients, but microalbuminuria, using the conventional cutoff of 30 mg albumin/g creatinine discriminated poorly between the two diagnostic groups in the early febrile phase. Secondly UACRs did not prove useful in predicting either development of warning signs for severe dengue or need for hospitalization. CONCLUSION/SIGNIFICANCE: Low-level albuminuria is common, even in relatively mild dengue infections, but is also present in many OFIs. Simple point-of-care UACR tests are unlikely to be useful for early diagnosis or risk prediction in dengue endemic areas. PMID- 23349923 TI - Habitat selection and behaviour of a reintroduced passerine: linking experimental restoration, behaviour and habitat ecology. AB - Habitat restoration can play an important role in recovering functioning ecosystems and improving biodiversity. Restoration may be particularly important in improving habitat prior to species reintroductions. We reintroduced seven brown treecreeper (Climacteris picumnus) social groups into two nature reserves in the Australian Capital Territory in south-eastern Australia. This study provided a unique opportunity to understand the interactions between restoration ecology, behavioural ecology and habitat ecology. We examined how experimental restoration treatments (addition of coarse woody debris, variations in ground vegetation cover and nest box installation) influenced the behaviour and microhabitat use of radio-tracked individuals to evaluate the success of restoration treatments. The addition of coarse woody debris benefited the brown treecreeper through increasing the probability of foraging on a log or on the ground. This demonstrated the value of using behaviour as a bio-indicator for restoration success. Based on previous research, we predicted that variations in levels of ground vegetation cover would influence behaviour and substrate use, particularly that brown treecreepers would choose sites with sparse ground cover because this allows better access to food and better vigilance for predators. However, there was little effect of this treatment, which was likely influenced by the limited overall use of the ground layer. There was also little effect of nest boxes on behaviour or substrate use. These results somewhat confound our understanding of the species based on research from extant populations. Our results also have a significant impact regarding using existing knowledge on a species to inform how it will respond to reintroduction and habitat restoration. This study also places great emphasis on the value of applying an experimental framework to ecological restoration, particularly when reintroductions produce unexpected outcomes. PMID- 23349924 TI - Simultaneous measurement of amyloid fibril formation by dynamic light scattering and fluorescence reveals complex aggregation kinetics. AB - An apparatus that combines dynamic light scattering and Thioflavin T fluorescence detection is used to simultaneously probe fibril formation in polyglutamine peptides, the aggregating subunit associated with Huntington's disease, in vitro. Huntington's disease is a neurodegenerative disorder in a class of human pathologies that includes Alzheimer's and Parkinson's disease. These pathologies are all related by the propensity of their associated protein or polypeptide to form insoluble, beta-sheet rich, amyloid fibrils. Despite the wide range of amino acid sequence in the aggregation prone polypeptides associated with these diseases, the resulting amyloids display strikingly similar physical structure, an observation which suggests a physical basis for amyloid fibril formation. Thioflavin T fluorescence reports beta-sheet fibril content while dynamic light scattering measures particle size distributions. The combined techniques allow elucidation of complex aggregation kinetics and are used to reveal multiple stages of amyloid fibril formation. PMID- 23349925 TI - Role of salt-inducible kinase 1 in the activation of MEF2-dependent transcription by BDNF. AB - Substantial evidence supports a role for myocyte enhancer factor 2 (MEF2) mediated transcription in neuronal survival, differentiation and synaptic function. In developing neurons, it has been shown that MEF2-dependent transcription is regulated by neurotrophins. Despite these observations, little is known about the cellular mechanisms by which neurotrophins activate MEF2 transcriptional activity. In this study, we examined the role of salt-inducible kinase 1 (SIK1), a member of the AMP-activated protein kinase (AMPK) family, in the regulation of MEF2-mediated transcription by the neurotrophin brain-derived neurotrophic factor (BDNF). We show that BDNF increases the expression of SIK1 in primary cultures of rat cortical neurons through the extracellular signal regulated kinase 1/2 (ERK1/2)-signaling pathway. In addition to inducing SIK1 expression, BDNF triggers the phosphorylation of SIK1 at Thr182 and its translocation from the cytoplasm to the nucleus of cortical neurons. The effects of BDNF on the expression, phosphorylation and, translocation of SIK1 are followed by the phosphorylation and nuclear export of histone deacetylase 5 (HDAC5). Blockade of SIK activity with a low concentration of staurosporine abolished BDNF-induced phosphorylation and nuclear export of HDAC5 in cortical neurons. Importantly, stimulation of HDAC5 phosphorylation and nuclear export by BDNF is accompanied by the activation of MEF2-mediated transcription, an effect that is suppressed by staurosporine. Consistent with these data, BDNF induces the expression of the MEF2 target genes Arc and Nur77, in a staurosporine-sensitive manner. In further support of the role of SIK1 in the regulation of MEF2 dependent transcription by BDNF, we found that expression of wild-type SIK1 or S577A SIK1, a mutated form of SIK1 which is retained in the nucleus of transfected cells, is sufficient to enhance MEF2 transcriptional activity in cortical neurons. Together, these data identify a previously unrecognized mechanism by which SIK1 mediates the activation of MEF2-dependent transcription by BDNF. PMID- 23349926 TI - Does the benefit on survival from leisure time physical activity depend on physical activity at work? A prospective cohort study. AB - PURPOSE: To investigate if persons with high physical activity at work have the same benefits from leisure time physical activity as persons with sedentary work. METHODS: In the Copenhagen City Heart Study, a prospective cohort of 7,411 males and 8,916 females aged 25-66 years without known cardiovascular disease at entry in 1976-78, 1981-83, 1991-94, or 2001-03, the authors analyzed with sex stratified multivariate Cox proportional hazards regression the association between leisure time physical activity and cardiovascular and all-cause mortality among individuals with different levels of occupational physical activity. RESULTS: During a median follow-up of 22.4 years, 4,003 individuals died from cardiovascular disease and 8,935 from all-causes. Irrespective of level of occupational physical activity, a consistently lower risk with increasing leisure time physical activity was found for both cardiovascular and all-cause mortality among both men and women. Compared to low leisure time physical activity, the survival benefit ranged from 1.5-3.6 years for moderate and 2.6-4.7 years for high leisure time physical activity among the different levels of occupational physical activity. CONCLUSION: Public campaigns and initiatives for increasing physical activity in the working population should target everybody, irrespective of physical activity at work. PMID- 23349927 TI - Psychological factors, including alexithymia, in the prediction of cardiovascular risk in HIV infected patients: results of a cohort study. AB - BACKGROUND: Psychological factors are known predictors of cardiovascular disease in many clinical settings, but data are lacking for HIV infection. We carried out a prospective cohort study to evaluate potential psychological predictors of preclinical and clinical vascular disease in HIV patients. METHODOLOGY/PRINCIPAL FINDINGS: HIV patients were consecutively enrolled. Demographics, viral and immune parameters and traditional cardiovascular predictors were considered; Intima-Media Thickness (c-IMT, continuous measure) and Carotid Plaques (CPs, focal thickening >=1.5 mm) were investigated by B-mode ultrasonography; depressive symptoms by the Beck Depression Inventory (BDI-II), Type D personality (Distressed Personality or Type D) by the DS14, alexithymia by the Toronto Alexithymia Scale (TAS-20). Vascular outcomes included transient ischemic attacks or stroke, acute coronary syndrome, myocardial or other organ infarction. We enrolled 232 HIV subjects, 73.9% males, aged 44.5+/-9.9 y, 38.2% with AIDS diagnosis, 18.3% untreated. Mean Nadir CD4 T-cell counts were 237.5+/-186.2/mmc. Of them, 224 (96.5%) attended IMT measurements; 201 (86.6%) attended both IMT assessment and psychological profiling. Mean follow-up was 782+/-308 days. Fifty nine patients (29.4%) had CPs at baseline. Nineteen patients (9.5%) had >=1 vascular event; 12 (6.0%) died due to such events (n = 4) or any cause. At baseline cross-sectional multivariate analysis, increasing age, total cholesterol, current smoking and Alexithymia score>=50 were significantly associated with both increased cIMT (linear regression) and CPs (logistic regression). At follow-up analysis, log-rank tests and Cox's regression revealed that only older age (p = 0.001), current smoking (p = 0.019) and alexithymia score>=50 (p = 0.013) were independently associated with vascular events. CONCLUSIONS/SIGNIFICANCE: In HIV-infected subjects, the Alexithymic trait emerges as a strong predictor of increased IMT, presence of CPs and vascular events. Such results are preliminary and require confirmation from studies with larger sample size and longer follow-up. PMID- 23349928 TI - Nutrient-mediated architectural plasticity of a predatory trap. AB - BACKGROUND: Nutrients such as protein may be actively sought by foraging animals. Many predators exhibit foraging plasticity, but how their foraging strategies are affected when faced with nutrient deprivation is largely unknown. In spiders, the assimilation of protein into silk may be in conflict with somatic processes so we predicted web building to be affected under protein depletion. METHODOLOGY/PRINCIPAL FINDINGS: To assess the influence of protein intake on foraging plasticity we fed the orb-web spiders Argiope aemula and Cyclosa mulmeinensis high, low or no protein solutions over 10 days and allowed them to build webs. We compared post-feeding web architectural components and major ampullate (MA) silk amino acid compositions. We found that the number of radii in webs increased in both species when fed high protein solutions. Mesh size increased in A. aemula when fed a high protein solution. MA silk proline and alanine compositions varied in each species with contrasting variations in alanine between the two species. Glycine compositions only varied in C. mulmeinensis silk. No spiders significantly lost or gained mass on any feeding treatment, so they did not sacrifice somatic maintenance for amino acid investment in silk. CONCLUSIONS/SIGNIFICANCE: Our results show that the amount of protein taken in significantly affects the foraging decisions of trap-building predators, such as orb web spiders. Nevertheless, the subtle differences found between species in the association between protein intake, the amino acids invested in silk and web architectural plasticity show that the influence of protein deprivation on specific foraging strategies differs among different spiders. PMID- 23349929 TI - Distinct profiles of effector cytokines mark the different phases of Crohn's disease. AB - OBJECTIVE: Crohn's Disease (CD)-associated inflammation is supposed to be driven by T helper (Th)1/Th17 cell-derived cytokines, even though there is evidence that the mucosal profile of cytokine may vary with the evolution of the disease. We aimed at comparing the pattern of effector cytokines in early and established lesions of CD. DESIGN: Mucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with (early lesions) or without post-operative recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (established lesions). Inflammatory cell infiltrate was examined by immunofluorescence and cytokine expression was analysed by real-time PCR, flow-cytometry and ELISA. RESULTS: Before the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of T cells and macrophages, elevated levels of Th1-related cytokines and TNF-alpha and slightly increased IL-17A expression. Transition from this stage to endoscopic recurrence was marked by abundance of Th1 cytokines, marked increase in IL-17A, and induction of IL-6 and IL-23, two cytokines involved in the control of Th17 cell responses. In samples with established lesions, there was a mixed Th1/Th17 response with no TNF-alpha induction. Expression of IL-4 and IL-5 was up-regulated in both early and established lesions even though the fraction of IL-4-producing cells was lower than that of cells producing either interferon-gamma or IL-17A. CONCLUSIONS: Distinct mucosal profiles of cytokines are produced during the different phases of CD. A better understanding of the cytokines temporally regulated in CD tissue could help optimize therapeutic interventions in CD. PMID- 23349930 TI - Effector protein translocation by the Coxiella burnetii Dot/Icm type IV secretion system requires endocytic maturation of the pathogen-occupied vacuole. AB - The human pathogen Coxiella burnetii encodes a type IV secretion system called Dot/Icm that is essential for intracellular replication. The Dot/Icm system delivers bacterial effector proteins into the host cytosol during infection. The effector proteins delivered by C. burnetii are predicted to have important functions during infection, but when these proteins are needed during infection has not been clearly defined. Here, we use a reporter system consisting of fusion proteins that have a beta-lactamase enzyme (BlaM) fused to C. burnetii effector proteins to study protein translocation by the Dot/Icm system. Translocation of BlaM fused to the effector proteins CBU0077, CBU1823 and CBU1524 was not detected until 8-hours after infection of HeLa cells, which are permissive for C. burnetii replication. Translocation of these effector fusion proteins by the Dot/Icm system required acidification of the Coxiella-containing vacuole. Silencing of the host genes encoding the membrane transport regulators Rab5 or Rab7 interfered with effector translocation, which indicates that effectors are not translocated until bacteria traffic to a late endocytic compartment in the host cell. Similar requirements for effector translocation were discerned in bone marrow macrophages derived from C57BL/6 mice, which are primary cells that restrict the intracellular replication of C. burnetii. In addition to requiring endocytic maturation of the vacuole for Dot/Icm-mediated translocation of effectors, bacterial transcription was required for this process. Thus, translocation of effector proteins by the C. burnetii Dot/Icm system occurs after acidification of the CCV and maturation of this specialized organelle to a late endocytic compartment. This indicates that creation of the specialized vacuole in which C. burnetii replicates represents a two-stage process mediated initially by host factors that regulate endocytic maturation and then by bacterial effectors delivered into host cells after bacteria establish residency in a lysosome derived organelle. PMID- 23349931 TI - Towards tricking a pathogen's protease into fighting infection: the 3D structure of a stable circularly permuted onconase variant cleavedby HIV-1 protease. AB - Onconase(r) is a highly cytotoxic amphibian homolog of Ribonuclease A. Here, we describe the construction of circularly permuted Onconase(r) variants by connecting the N- and C-termini of this enzyme with amino acid residues that are recognized and cleaved by the human immunodeficiency virus protease. Uncleaved circularly permuted Onconase(r) variants are unusually stable, non-cytotoxic and can internalize in human T-lymphocyte Jurkat cells. The structure, stability and dynamics of an intact and a cleaved circularly permuted Onconase(r) variant were determined by Nuclear Magnetic Resonance spectroscopy and provide valuable insight into the changes in catalytic efficiency caused by the cleavage. The understanding of the structural environment and the dynamics of the activation process represents a first step toward the development of more effective drugs for the treatment of diseases related to pathogens expressing a specific protease. By taking advantage of the protease's activity to initiate a cytotoxic cascade, this approach is thought to be less susceptible to known resistance mechanisms. PMID- 23349932 TI - Tumor cells positive and negative for the common cancer stem cell markers are capable of initiating tumor growth and generating both progenies. AB - The cancer stem cell (CSC) model depicts that tumors are hierarchically organized and maintained by CSCs lying at the apex. CSCs have been "identified" in a variety of tumors through the tumor-forming assay, in which tumor cells distinguished by a certain cell surface marker (known as a CSC marker) were separately transplanted into immunodeficient mice. In such assays, tumor cells positive but not negative for the CSC marker (hereby defined as CSC(+) and CSC(-) cells, respectively) have the ability of tumor-forming and generating both progenies. However, here we show that CSC(+) and CSC(-) cells exhibit similar proliferation in the native states. Using a cell tracing method, we demonstrate that CSC(-) cells exhibit similar tumorigenesis and proliferation as CSC(+) cells when they were co-transplanted into immunodeficient mice. Through serial single cell derived subline construction, we further demonstrated that CSC(+) and CSC(-) cells from CSC marker expressing tumors could invariably generate both progenies, and their characteristics are maintained among different generations irrespective of the origins (CSC(+)-derived or CSC(-)-derived). These findings demonstrate that tumorigenic cells cannot be distinguished by common CSC markers alone and we propose that cautions should be taken when using these markers independently to identify cancer stem cells due to the phenotypic plasticity of tumor cells. PMID- 23349933 TI - What is the cost of diagnosis and management of drug resistant tuberculosis in South Africa? AB - BACKGROUND: Drug-resistant tuberculosis (DR-TB) is undermining TB control in South Africa. However, there are hardly any data about the cost of treating DR-TB in high burden settings despite such information being quintessential for the rational planning and allocation of resources by policy-makers, and to inform future cost-effectiveness analyses. METHODOLOGY: We analysed the comparative 2011 United States dollar ($) cost of diagnosis and treatment of drug sensitive TB (DS TB), MDR-TB and XDR-TB, based on National South African TB guidelines, from the perspective of the National TB Program using published clinical outcome data. PRINCIPAL FINDINGS: Assuming adherence to national DR-TB management guidelines, the per patient cost of XDR-TB was $26,392, four times greater than MDR-TB ($6772), and 103 times greater than drug-sensitive TB ($257). Despite DR-TB comprising only 2.2% of the case burden, it consumed ~32% of the total estimated 2011 national TB budget of US $218 million. 45% and 25% of the DR-TB costs were attributed to anti-TB drugs and hospitalization, respectively. XDR-TB consumed 28% of the total DR-TB diagnosis and treatment costs. Laboratory testing and anti TB drugs comprised the majority (71%) of MDR-TB costs while hospitalization and anti-TB drug costs comprised the majority (92%) of XDR-TB costs. A decentralized XDR-TB treatment programme could potentially reduce costs by $6930 (26%) per case and reduce the total amount spent on DR-TB by ~7%. CONCLUSION/SIGNIFICANCE: Although DR-TB forms a very small proportion of the total case burden it consumes a disproportionate and substantial amount of South Africa's total annual TB budget. These data inform rational resource allocation and selection of management strategies for DR-TB in high burden settings. PMID- 23349934 TI - Sustained oxidative stress causes late acute renal failure via duplex regulation on p38 MAPK and Akt phosphorylation in severely burned rats. AB - BACKGROUND: Clinical evidence indicates that late acute renal failure (ARF) predicts high mortality in severely burned patients but the pathophysiology of late ARF remains undefined. This study was designed to test the hypothesis that sustained reactive oxygen species (ROS) induced late ARF in a severely burned rat model and to investigate the signaling mechanisms involved. MATERIALS AND METHODS: Rats were exposed to 100 degrees C bath for 15 s to induce severe burn injury (40% of total body surface area). Renal function, ROS generation, tubular necrosis and apoptosis, and phosphorylation of MAPK and Akt were measured during 72 hours after burn. RESULTS: Renal function as assessed by serum creatinine and blood urea nitrogen deteriorated significantly at 3 h after burn, alleviated at 6 h but worsened at 48 h and 72 h, indicating a late ARF was induced. Apoptotic cells and cleavage caspase-3 in the kidney went up slowly and turned into significant at 48 h and 72 h. Tubular cell ROS production shot up at 6 h and continuously rose during the 72-h experiment. Scavenging ROS with tempol markedly attenuated tubular apoptosis and renal dysfunction at 72 h after burn. Interestingly, renal p38 MAPK phosphorylation elevated in a time dependent manner whereas Akt phosphorylation increased during the first 24 h but decreased at 48 h after burn. The p38 MAPK specific inhibitor SB203580 alleviated whereas Akt inhibitor exacerbated burn-induced tubular apoptosis and renal dysfunction. Furthermore, tempol treatment exerted a duplex regulation through inhibiting p38 MAPK phosphorylation but further increasing Akt phosphorylation at 72 h postburn. CONCLUSIONS: These results demonstrate that sustained renal ROS overproduction induces continuous tubular cell apoptosis and thus a late ARF at 72 h after burn in severely burned rats, which may result from ROS-mediated activation of p38 MAPK but a late inhibition of Akt phosphorylation. PMID- 23349935 TI - Grafting of a single donor myofibre promotes hypertrophy in dystrophic mouse muscle. AB - Skeletal muscle has a remarkable capability of regeneration following injury. Satellite cells, the principal muscle stem cells, are responsible for this process. However, this regenerative capacity is reduced in muscular dystrophies or in old age: in both these situations, there is a net loss of muscle fibres. Promoting skeletal muscle muscle hypertrophy could therefore have potential applications for treating muscular dystrophies or sarcopenia. Here, we observed that muscles of dystrophic mdx nude host mice that had been acutely injured by myotoxin and grafted with a single myofibre derived from a normal donor mouse exhibited increased muscle area. Transplantation experiments revealed that the hypertrophic effect is mediated by the grafted fibre and does not require either an imposed injury to the host muscle, or the contribution of donor cells to the host muscle. These results suggest the presence of a crucial cross-talk between the donor fibre and the host muscle environment. PMID- 23349937 TI - T-type Ca2+ current activity during oocyte growth and maturation in the ascidian Styela plicata. AB - Voltage-dependent calcium currents play a fundamental role during oocyte maturation, mostly L-type calcium currents, whereas T-type calcium currents are involved in sperm physiology and cell growth. In this paper, using an electrophysiological and pharmacological approach, we demonstrated, for the first time in oocytes, that T-type calcium currents are present with functional consequences on the plasma membrane of growing immature oocytes of the ascidian Styela plicata. We classified three subtypes of immature oocytes at the germinal vesicle stage on the basis of their size, morphology and accessory cellular structures. These stages were clearly associated with an increased activity of T type calcium currents and hyperpolarization of the plasma membrane. We also observed that T-type calcium currents oscillate in the post-fertilization embryonic stages, with minimal amplitude of the currents in the zygote and maximal at 8-cell stage. In addition, chemical inhibition of T-type calcium currents, obtained by applying specific antagonists, induced a significant reduction in the rate of cleavage and absence of larval formation. We suggest that calcium entry via T-type calcium channels may act as a potential pacemaker in regulating cytosolic calcium involved in fertilization and early developmental events. PMID- 23349936 TI - Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. AB - BACKGROUND AND AIM: Assessment of serum concentration of lipopolysaccharide (LPS) binding protein (LBP) has been suggested as a useful biomarker to indicate activation of innate immune responses to microbial products. We investigated LBP concentrations and associations with demographics, lifestyle factors, and common metabolic abnormalities in adults. We also examined if LBP concentrations were associated with common polymorphisms in genes coding for LBP (rs2232618), CD14 (rs2569190), and TLR4 (rs4986790), the molecules responsible for the innate immune response to LPS, or serum levels of soluble CD14 (sCD14) and proinflammatory cytokines. METHODS: Serum LBP was measured with a commercial immunoassay in a random sample of the adult population (n = 420, 45% males, age 18-92 years) from a single municipality. RESULTS: Serum LBP concentrations increased with age (P<0.001) and were higher in individuals who were overweight or obese than in normal-weight individuals (P<0.001). Similarly, LBP concentrations were higher in individuals with metabolic syndrome than in individuals without it (P<0.001). Among metabolic syndrome components, LBP concentrations were independently associated with abdominal obesity (P = 0.002) and low concentrations of HDL-cholesterol (P<0.001). Serum LBP concentrations tended to be independently associated with smoking (P = 0.05), but not with alcohol consumption. Likewise, there was not significant association between LBP concentrations and gene polymorphisms. Concentrations of LBP significantly correlated with serum levels of proinflammatory cytokines (IL-6 and IL-8), sCD14, and with liver enzymes. CONCLUSIONS: Serum LBP concentrations increased with age. Overweight, obesity, and having metabolic syndrome (particularly, low HDL cholesterol levels) were associated with higher LBP concentrations. These findings are consistent with microbial exposure playing a role in these inflammatory, metabolic abnormalities. PMID- 23349938 TI - A novel role for Lh3 dependent ECM modifications during neural crest cell migration in zebrafish. AB - During vertebrate development, trunk neural crest cells delaminate along the entire length of the dorsal neural tube and initially migrate as a non-segmented sheet. As they enter the somites, neural crest cells rearrange into spatially restricted segmental streams. Extracellular matrix components are likely to play critical roles in this transition from a sheet-like to a stream-like mode of migration, yet the extracellular matrix components and their modifying enzymes critical for this transition are largely unknown. Here, we identified the glycosyltransferase Lh3, known to modify extracellular matrix components, and its presumptive substrate Collagen18A1, to provide extrinsic signals critical for neural crest cells to transition from a sheet-like migration behavior to migrating as a segmental stream. Using live cell imaging we show that in lh3 null mutants, neural crest cells fail to transition from a sheet to a stream, and that they consequently enter the somites as multiple streams, or stall shortly after entering the somites. Moreover, we demonstrate that transgenic expression of lh3 in a small subset of somitic cells adjacent to where neural crest cells switch from sheet to stream migration restores segmental neural crest cell migration. Finally, we show that knockdown of the presumptive Lh3 substrate Collagen18A1 recapitulates the neural crest cell migration defects observed in lh3 mutants, consistent with the notion that Lh3 exerts its effect on neural crest cell migration by regulating post-translational modifications of Collagen18A1. Together these data suggest that Lh3-Collagen18A1 dependent ECM modifications regulate the transition of trunk neural crest cells from a non-segmental sheet like migration mode to a segmental stream migration mode. PMID- 23349939 TI - The non-peptidic part determines the internalization mechanism and intracellular trafficking of peptide amphiphiles. AB - BACKGROUND: Peptide amphiphiles (PAs) are a class of amphiphilic molecules able to self-assemble into nanomaterials that have shown efficient in vivo targeted delivery. Understanding the interactions of PAs with cells and the mechanisms of their internalization and intracellular trafficking is critical in their further development for therapeutic delivery applications. METHODOLOGY/PRINCIPAL FINDINGS: PAs of a novel, cell- and tissue-penetrating peptide were synthesized possessing two different lipophilic tail architectures and their interactions with prostate cancer cells were studied in vitro. Cell uptake of peptides was greatly enhanced post-modification. Internalization occurred via lipid-raft mediated endocytosis and was common for the two analogs studied. On the contrary, we identified the non-peptidic part as the determining factor of differences between intracellular trafficking and retention of PAs. PAs composed of di stearyl lipid tails linked through poly(ethylene glycol) to the peptide exhibited higher exocytosis rates and employed different recycling pathways compared to ones consisting of di-palmitic-coupled peptides. As a result, cell association of the former PAs decreased with time. CONCLUSIONS/SIGNIFICANCE: Control over peptide intracellular localization and retention is possible by appropriate modification with synthetic hydrophobic tails. We propose this as a strategy to design improved peptide-based delivery systems. PMID- 23349940 TI - Association between serum leptin concentrations and insulin resistance: a population-based study from China. AB - BACKGROUND: Insulin resistance contributes to the cardio-metabolic risk. The effect of leptin in obese and overweight population on insulin resistance was seldom reported. METHODS: A total of 1234 subjects (572 men and 662 women) aged >=18 y was sampled by the procedure. Adiposity measures included BMI, waist circumference, hip circumference, WHR, upper arm circumference, triceps skinfold and body fat percentage. Serum leptin concentrations were measured by an ELISA method. The homeostasis model (HOMA-IR) was applied to estimate insulin resistance. RESULTS: In men, BMI was the variable which was most strongly correlated with leptin, whereas triceps skinfold was most sensitive for women. More importantly, serum leptin levels among insulin resistant subjects were almost double compared to the subjects who had normal insulin sensitivity at the same level of adiposity in both men and women, after controlling for potential confounders. In addition, HOMA-IR increased significantly across leptin quintiles after adjustment for age, BMI, total energy intake, physical activity and smoking status in both men and women (p for trend <0.0001). CONCLUSIONS: There was a significant association between HOMA-IR and serum leptin concentrations in Chinese men and women, independently of adiposity levels. This may suggest that serum leptin concentration is an important predictor of insulin resistance and other metabolic risks irrespective of obesity levels. Furthermore, leptin levels may be used to identify the cardio-metabolic risk in obese and overweight population. PMID- 23349941 TI - Prognostic significance of Capn4 overexpression in intrahepatic cholangiocarcinoma. AB - BACKGROUND: Calpain small subunit 1 (Capn4) has been shown to correlate with the metastasis/invasion of hepatocellular carcinoma. This study aimed to investigate the role of Capn4 in intrahepatic cholangiocarcinoma (ICC). METHODS: Capn4 expression was measured in 33 ICC tissues by quantitative real-time polymerase chain reaction and western blot. The role of Capn4 in the migration, invasion and proliferation of ICC cells and matrix metalloproteinase 2 (MMP2) expression were assessed after Capn4 depletion by specific small interfering RNA. Capn4 expression was further examined by immunohistochemistry in a tissue microarray consisting of 140 ICC patients and 13 normal liver tissues, and the prognostic role of Capn4 in ICC was evaluated by Kaplan-Meier and Cox regression analyses. RESULTS: Capn4 expression was significantly higher in the ICC tissues compared to the peritumor tissues. Capn4 down-regulation impaired the migration/invasion ability of HCCC-9810 and QBC939 cells in vitro and decreased MMP2 expression. Capn4 overexpression significantly correlated with the presence of lymphatic metastasis of ICC (p = 0.026) and the tumor-node-metastasis (TNM) stage (p = 0.009). The postoperative 2- and 5-year overall survivals in patients with Capn4(low) were higher than those in the Capn4(high) group. The cumulative recurrence rate in patients with Capn4(low) was much lower than in the Capn4(high) group. Multivariate analysis showed that Capn4 overexpression was an independent prognostic marker in ICC. CONCLUSIONS: Capn4 overexpression was implicated in ICC metastasis/invasion, and Capn4 overexpression may be used as a molecular therapeutic target for ICC. PMID- 23349942 TI - The immunosuppressive agent mizoribine monophosphate is an inhibitor of the human RNA capping enzyme. AB - Mizoribine monophosphate (MZP) is a specific inhibitor of the cellular inosine-5' monophosphate dehydrogenase (IMPDH), the enzyme catalyzing the rate-limiting step of de novo guanine nucleotide biosynthesis. MZP is a highly potent antagonistic inhibitor of IMPDH that blocks the proliferation of T and B lymphocytes that use the de novo pathway of guanine nucleotide synthesis almost exclusively. In the present study, we investigated the ability of MZP to directly inhibit the human RNA capping enzyme (HCE), a protein harboring both RNA 5'-triphosphatase and RNA guanylyltransferase activities. HCE is involved in the synthesis of the cap structure found at the 5' end of eukaryotic mRNAs, which is critical for the splicing of the cap-proximal intron, the transport of mRNAs from the nucleus to the cytoplasm, and for both the stability and translation of mRNAs. Our biochemical studies provide the first insight that MZP can inhibit the formation of the RNA cap structure catalyzed by HCE. In the presence of MZP, the RNA 5' triphosphatase activity appears to be relatively unaffected while the RNA guanylyltransferase activity is inhibited, indicating that the RNA guanylyltransferase activity is the main target of MZP inhibition. Kinetic studies reveal that MZP is a non-competitive inhibitor that likely targets an allosteric site on HCE. Mizoribine also impairs mRNA capping in living cells, which could account for the global mechanism of action of this therapeutic agent. Together, our study clearly demonstrates that mizoribine monophosphate inhibits the human RNA guanylyltransferase in vitro and impair mRNA capping in cellulo. PMID- 23349943 TI - Vitamin D deficiency induces high blood pressure and accelerates atherosclerosis in mice. AB - Multiple epidemiological studies link vitamin D deficiency to increased cardiovascular disease (CVD), but causality and possible mechanisms underlying these associations are not established. To clarify the role of vitamin D deficiency in CVD in vivo, we generated mouse models of diet-induced vitamin D deficiency in two backgrounds (LDL receptor- and ApoE-null mice) that resemble humans with diet-induced hypertension and atherosclerosis. Mice were fed vitamin D-deficient or -sufficient chow for 6 weeks and then switched to high fat (HF) vitamin D-deficient or -sufficient diet for 8-10 weeks. Mice with diet-induced vitamin D deficiency showed increased systolic and diastolic blood pressure, high plasma renin, and decreased urinary sodium excretion. Hypertension was reversed and renin was suppressed by returning chow-fed vitamin D-deficient mice to vitamin D-sufficient chow diet for 6 weeks. On a HF diet, vitamin D-deficient mice had ~2-fold greater atherosclerosis in the aortic arch and ~2-8-fold greater atherosclerosis in the thoracic and abdominal aorta compared to vitamin D sufficient mice. In the aortic root, HF-fed vitamin D-deficient mice had increased macrophage infiltration with increased fat accumulation and endoplasmic reticulum (ER) stress activation, but a lower prevalence of the M1 macrophage phenotype within atherosclerotic plaques. Similarly, peritoneal macrophages from vitamin D-deficient mice displayed an M2-predominant phenotype with increased foam cell formation and ER stress. Treatment of vitamin D-deficient mice with the ER stress reliever PBA during HF feeding suppressed atherosclerosis, decreased peritoneal macrophage foam cell formation, and downregulated ER stress proteins without changing blood pressure. Thus, we suggest that vitamin D deficiency activates both the renin angiotensin system and macrophage ER stress to contribute to the development of hypertension and accelerated atherosclerosis, highlighting vitamin D replacement as a potential therapy to reduce blood pressure and atherosclerosis. PMID- 23349944 TI - Mast cells express 11beta-hydroxysteroid dehydrogenase type 1: a role in restraining mast cell degranulation. AB - Mast cells are key initiators of allergic, anaphylactic and inflammatory reactions, producing mediators that affect vascular permeability, angiogenesis and fibrosis. Glucocorticoid pharmacotherapy reduces mast cell number, maturation and activation but effects at physiological levels are unknown. Within cells, glucocorticoid concentration is modulated by the 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). Here we show expression and activity of 11beta HSD1, but not 11beta-HSD2, in mouse mast cells with 11beta-HSD activity only in the keto-reductase direction, regenerating active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone). Mast cells from 11beta-HSD1-deficient mice show ultrastructural evidence of increased activation, including piecemeal degranulation and have a reduced threshold for IgG immune complex-induced mast cell degranulation. Consistent with reduced intracellular glucocorticoid action in mast cells, levels of carboxypeptidase A3 mRNA, a glucocorticoid-inducible mast cell-specific transcript, are lower in peritoneal cells from 11beta-HSD1-deficient than control mice. These findings suggest that 11beta-HSD1-generated glucocorticoids may tonically restrain mast cell degranulation, potentially influencing allergic, anaphylactic and inflammatory responses. PMID- 23349945 TI - Blood cues induce antipredator behavior in Nile tilapia conspecifics. AB - In this study, we show that the fish Nile tilapia displays an antipredator response to chemical cues present in the blood of conspecifics. This is the first report of alarm response induced by blood-borne chemical cues in fish. There is a body of evidence showing that chemical cues from epidermal 'club' cells elicit an alarm reaction in fish. However, the chemical cues of these 'club' cells are restricted to certain species of fish. Thus, as a parsimonious explanation, we assume that an alarm response to blood cues is a generalized response among animals because it occurs in mammals, birds and protostomian animals. Moreover, our results suggest that researchers must use caution when studying chemically induced alarm reactions because it is difficult to separate club cell cues from traces of blood. PMID- 23349946 TI - Brightness discrimination in budgerigars (Melopsittacus undulatus). AB - Birds have excellent spatial acuity and colour vision compared to other vertebrates while spatial contrast sensitivity is relatively poor for unknown reasons. Contrast sensitivity describes the detection of gratings of varying spatial frequency. It is unclear whether bird brightness discrimination between large uniform fields is poor as well. Here we show that budgerigars (Melopsittacus undulatus) need a Michelson contrast of 0.09 to discriminate between large spatially separated achromatic fields in bright light conditions. This is similar to the peak contrast sensitivity of 10.2 (0.098 Michelson contrast) for achromatic grating stimuli established in earlier studies. The brightness discrimination threshold described in Weber fractions is 0.18, which is modest compared to other vertebrates. PMID- 23349947 TI - Mucuna pruriens and its major constituent L-DOPA recover spermatogenic loss by combating ROS, loss of mitochondrial membrane potential and apoptosis. AB - BACKGROUND: The Ayurvedic medicinal system claims Mucuna pruriens (MP) to possess pro-male fertility, aphrodisiac and adaptogenic properties. Some scientific evidence also supports its pro-male fertility properties; however, the mechanism of its action is not yet clear. The present study aimed at demonstrating spermatogenic restorative efficacy of MP and its major constituent L-DOPA (LD), and finding the possible mechanism of action thereof in a rat model. METHODOLOGY/FINDINGS: Ethinyl estradiol (EE) was administered at a rate of 3 mg/kg body weight (BW)/day for a period of 14 days to generate a rat model with compromised spermatogenesis. MP and LD were administered in two separate groups of these animals starting 15(th) day for a period of 56 days, and the results were compared with an auto-recovery (AR) group. Sperm count and motility, testis histo-architecture, level of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), apoptosis, peripheral hormone levels and testicular germ cell populations were analysed, in all experimental groups. We observed efficient and quick recovery of spermatogenesis in MP and LD groups in comparison to the auto-recovery group. The treatment regulated ROS level, apoptosis, and mitochondrial membrane potential (MMP), recovered the hypothalamic-pituitary gonadal axis and the number of testicular germ cells, ultimately leading to increased sperm count and motility. CONCLUSION/SIGNIFICANCE: M. pruriens efficiently recovers the spermatogenic loss induced due to EE administration. The recovery is mediated by reduction in ROS level, restoration of MMP, regulation of apoptosis and eventual increase in the number of germ cells and regulation of apoptosis. The present study simplified the complexity of mechanism involved and provided meaningful insights into MP/LD mediated correction of spermatogenic impairment caused by estrogens exposure. This is the first study demonstrating that L-DOPA largely accounts for pro-spermatogenic properties of M. pruriens. The manuscript bears CDRI communication number 8374. PMID- 23349948 TI - Incidence and determinants of tuberculosis among adults initiating antiretroviral therapy--Mozambique, 2004-2008. AB - BACKGROUND: In Mozambique, tuberculosis (TB) is thought to be the most common cause of death among antiretroviral therapy (ART) enrollees. Monitoring proportions of enrollees screened for TB, and incidence and determinants of TB during ART can help clinicians and program managers identify program improvement opportunities. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a retrospective cohort study among a nationally representative sample of the 79,500 adults (>14 years old) initiating ART during 2004-2007 to estimate clinician compliance with TB screening guidelines, factors associated with active TB at ART initiation, and incidence and predictors of documented TB during ART follow-up. Of 94 sites enrolling >50 adults on ART, 30 were selected using probability-proportional-to size sampling; 2,596 medical records at these sites were randomly selected for abstraction and analysis. At ART initiation, median age of patients was 34, 62% were female, median baseline CD4(+) T-cell count was 153/uL, and 11% were taking TB treatment. Proportions of records with TB screening documentation before ART initiation improved from 31% to 66% during 2004-2007 (p<0.001). TB screening compliance varied widely by ART clinic [n = 30, 2%-98% (p<0.001)] and supporting non-Governmental Organization (NGO) [n = 7, 27%-83% (p<0.001)]. Receiving TB treatment at ART enrollment was associated with male sex (p<0.001), weight <45 kg (p<0.001) and CD4<50/uL (p = 0.001). Isoniazid preventive therapy (IPT) was prescribed to <1% of ART enrollees not taking TB treatment. TB incidence during ART was 2.32 cases per 100 person-years. Factors associated with TB incidence included adherence to ART <95% (AHR 2.06; 95% CI, 1.32-3.21). CONCLUSION: Variations in TB screening by clinic and NGO may reflect differing investments in TB screening activities. Future scale-up should target under-performing clinics. Scale-up of TB screening at ART initiation, IPT, and ART adherence interventions could significantly reduce incident TB during ART. PMID- 23349949 TI - Controlled release of simvastatin from biomimetic beta-TCP drug delivery system. AB - Simvastatin have been shown to induce bone formation and there is currently a urgent need to develop an appropriate delivery system to sustain the release of the drug to increase therapeutic efficacy whilst reducing side effects. In this study, a novel drug delivery system for simvastatin by means of hydrothermally converting marine exoskeletons to biocompatible beta-tricalcium phosphate was investigated. Furthermore, the release of simvastatin was controlled by the addition of an outer apatite coating layer. The samples were characterized by x ray diffraction analysis, fourier transform infrared spectroscopy, scanning electron microscopy and mass spectroscopy confirming the conversion process. The in-vitro dissolution of key chemical compositional elements and the release of simvastatin were measured in simulated body fluid solution showing controlled release with reduction of approximately 25% compared with un-coated samples. This study shows the potential applications of marine structures as a drug delivery system for simvastatin. PMID- 23349950 TI - Effects of response force parameters on medial-frontal negativity. AB - The response-related medial-frontal activity (MFN) is often supposed to reflect action-monitoring and error-processing activity. The present force-production task was designed to investigate the effects of two response parameters (i.e., peak response force and time-to-peak, TTP) on the MFN separately. In a 2 * 2 design (high vs. low target force and short vs. long TTP), 22 participants had to produce isometric force pulses to match one of four conditions (e.g., a high target force with a long TTP). Significant main effects of both target force and target TTP were revealed. As previously shown, the MFN amplitude was higher in the high target-force condition than in the low target-force condition. Contrary to the initial expectations, a long TTP had the effect of reducing the MFN amplitude. There was no error-specific effect on the MFN. The force-unit monitoring model (FUMM) is suggested to account for the force- and TTP- specific variations of MFN amplitude, latency and slope. PMID- 23349951 TI - Endoglin haploinsufficiency promotes fibroblast accumulation during wound healing through Akt activation. AB - Accurate regulation of dermal fibroblast function plays a crucial role in wound healing. Many fibrotic diseases are characterized by a failure to conclude normal tissue repair and the persistence of fibroblasts inside lesions. In the present study we demonstrate that endoglin haploinsufficiency promotes fibroblast accumulation during wound healing. Moreover, scars from endoglin-heterozygous (Eng(+/-)) mice show persisting fibroblasts 12 days after wounding, which could lead to a fibrotic scar. Endoglin haploinsufficiency results in increased proliferation and migration of primary cultured murine dermal fibroblasts (MDFs). Moreover, Eng(+/-) MDF have diminished responses to apoptotic signals compared with control cells. Altogether, these modifications could explain the augmented presence of fibroblasts in Eng(+/-) mice wounds. We demonstrate that endoglin expression regulates Akt phosphorylation and that PI3K inhibition abolishes the differences in proliferation between endoglin haploinsufficient and control cells. Finally, persistent fibroblasts in Eng(+/-) mice wound co-localize with a greater degree of Akt phosphorylation. Thus, endoglin haploinsufficiency seems to promote fibroblast accumulation during wound healing through the activation of the PI3K/Akt pathway. These studies open new non-Smad signaling pathway for endoglin regulating fibroblast cell function during wound healing, as new therapeutic opportunities for the treatment of fibrotic wounds. PMID- 23349952 TI - Parallel patterns of morphological and behavioral variation among host-associated populations of two gall wasp species. AB - A powerful approach to address the general factors contributing to ecological speciation is to compare distantly related taxa that inhabit the same selective environments. In this design, similarities among taxa can elucidate general mechanisms of the process whereas differences may uncover specific factors important to the process for individual taxa. Herein, we present evidence of parallel patterns of morphological and behavioral variation among host-associated populations of two species of cynipid gall wasps, Belonocnema treatae and Disholcaspis quercusvirens, that each exhibit a life cycle intimately tied to the same two host plant environments, Quercus geminata and Q. virginiana. Across both gall-former species we find consistent differences in body size and gall morphology associated with host plant use, as well as strong differences in host plant preference, a measure of habitat isolation among populations. These consistent differences among taxa highlight the important role of host plant use in promoting reproductive isolation and morphological variation among herbivorous insect populations-a prerequisite for ecological speciation. PMID- 23349953 TI - Negative affect reduces performance in implicit sequence learning. AB - BACKGROUND: It is well documented that positive rather than negative moods encourage integrative processing of conscious information. However, the extent to which implicit or unconscious learning can be influenced by affective states remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: A Serial Reaction Time (SRT) task with sequence structures requiring integration over past trials was adopted to examine the effect of affective states on implicit learning. Music was used to induce and maintain positive and negative affective states. The present study showed that participants in negative rather than positive states learned less of the regularity. Moreover, the knowledge was shown by a Bayesian analysis to be largely unconscious as participants were poor at recognizing the regularity. CONCLUSIONS/SIGNIFICANCE: The results demonstrated that negative rather than positive affect inhibited implicit learning of complex structures. Our findings help to understand the effects of affective states on unconscious or implicit processing. PMID- 23349954 TI - Epidemiology, microbiology and mortality associated with community-acquired bacteremia in northeast Thailand: a multicenter surveillance study. AB - BACKGROUND: National statistics in developing countries are likely to underestimate deaths due to bacterial infections. Here, we calculated mortality associated with community-acquired bacteremia (CAB) in a developing country using routinely available databases. METHODS/PRINCIPAL FINDINGS: Information was obtained from the microbiology and hospital database of 10 provincial hospitals in northeast Thailand, and compared with the national death registry from the Ministry of Interior, Thailand for the period between 2004 and 2010. CAB was defined in patients who had pathogenic organisms isolated from blood taken within 2 days of hospital admission without a prior inpatient episode in the preceding 30 days. A total of 15,251 CAB patients identified, of which 5,722 (37.5%) died within 30 days of admission. The incidence rate of CAB between 2004 and 2010 increased from 16.7 to 38.1 per 100,000 people per year, and the mortality rate associated with CAB increased from 6.9 to 13.7 per 100,000 people per year. In 2010, the mortality rate associated with CAB was lower than that from respiratory tract infection, but higher than HIV disease or tuberculosis. The most common causes of CAB were Escherichia coli (23.1%), Burkholderia pseudomallei (19.3%), and Staphylococcus aureus (8.2%). There was an increase in the proportion of Extended-Spectrum Beta-Lactamases (ESBL) producing E. coli and Klebsiella pneumoniae over time. CONCLUSIONS: This study has demonstrated that national statistics on causes of death in developing countries could be improved by integrating information from readily available databases. CAB is neglected as an important cause of death, and specific prevention and intervention is urgently required to reduce its incidence and mortality. PMID- 23349955 TI - Mitochondrial translocation of vitamin D receptor is mediated by the permeability transition pore in human keratinocyte cell line. AB - BACKGROUND: Vitamin D receptor (VDR) is a well known transcriptional regulator, active as heterodimer in association with coactivators and corepressors. In addition it has been described the extranuclear distribution of the receptor and in particular the recently reported mitochondrial localization in platelets and megakaryocytes is intriguing because it appears to be a common feature of steroid receptors. Whereas for other members of the steroid receptor family the mitochondrial function has been explored, up to now nothing is known about a mitochondrial form of VDR in human proliferating cells. METHODOLOGY/PRINCIPAL FINDINGS: In this study we characterized for the first time the mitochondrial localization of VDR in the human keratinocyte cell line HaCaT. In proliferating HaCaT cells VDR was abundantly expressed in mitochondria in association with its binding partner RXRalpha and the import was ligand-independent. By immunoprecipitation studies we demonstrated the interaction of VDR with proteins of the permeability transition pore (PTP), VDAC and StAR. We then adopted different pharmacological and silencing approaches with the aim of hampering PTP function, either affecting PTP opening or abating the expression of the complex member StAR. By all means the impairment of pore function led to a reduction of mitochondrial levels of VDR. CONCLUSIONS: The results reported here demonstrate a ligand-independent mitochondrial import of VDR through the permeability transition pore, and open interesting new perspectives on PTP function as transporter and on VDR role in mitochondria. PMID- 23349956 TI - Microsatellites for the marsh fritillary butterfly: de novo transcriptome sequencing, and a comparison with amplified fragment length polymorphism (AFLP) markers. AB - BACKGROUND: Until recently the isolation of microsatellite markers from Lepidoptera has proved troublesome, expensive and time-consuming. Following on from a previous study of Edith's checkerspot butterfly, Euphydryas editha, we developed novel microsatellite markers for the vulnerable marsh fritillary butterfly, E. aurinia. Our goal was to optimize the process in order to reduce both time and cost relative to prevailing techniques. This was accomplished by using a combination of previously developed techniques: in silico mining of a de novo assembled transcriptome sequence, and genotyping the microsatellites found there using an economic method of fluorescently labelling primers. PRINCIPAL FINDINGS: In total, we screened nine polymorphic microsatellite markers, two of which were previously published, and seven that were isolated de novo. These markers were able to amplify across geographically isolated populations throughout Continental Europe and the UK. Significant deviations from Hardy Weinberg equilibrium were evident in some populations, most likely due to the presence of null alleles. However, we used an F(st) outlier approach to show that these markers are likely selectively neutral. Furthermore, using a set of 128 individuals from 11 populations, we demonstrate consistency in population differentiation estimates with previously developed amplified fragment length polymorphism (AFLP) markers (r = 0.68, p<0.001). SIGNIFICANCE: Rapid development of microsatellite markers for difficult taxa such as Lepidoptera, and concordant results with other putatively neutral molecular markers, demonstrate the potential of de novo transcriptional sequencing for future studies of population structure and gene flow that are desperately needed for declining species across fragmented landscapes. PMID- 23349957 TI - Skin collagen fiber molecular order: a pattern of distributional fiber orientation as assessed by optical anisotropy and image analysis. AB - BACKGROUND: Birefringence can reveal much of the morphology, molecular order, heterogeneity of fiber orientation, and nonlinear optical properties of biopolymers such as collagen. However, the detailed characterization of skin collagen fibers using optical anisotropy methods remains elusive. A clear understanding of collagen fiber organization in skin tissues may be important in the interpretation of their structural-functional relationships under normal and pathological conditions. In this study, fiber orientation in collagen bundles (CBs) and their supramolecular organization were examined in rat skin using polarization microscopy and image analysis. METHODOLOGY/PRINCIPAL FINDINGS: Image variations with rotation of the microscope stage and selection of the in-depth focus plane were investigated in unstained sections of varying thicknesses from rat skin fragments. Total birefringence (image analysis) and form and intrinsic birefringence (Senarmont's method) were estimated. Based on the birefringent images, CBs were found to contain intercrossing points with a twisted helical distribution of collagen fibers (chiral elements) and frequently presented circular structures. Collagen fibers were observed to extend from the surface level to deeper planes, creating a 3D-network of oriented intertwined CBs. At least three levels of birefringent brilliance intensity were revealed by image analysis, indicating a heterogeneous spatial organization of the CBs. Slight differences in optical retardations were found for CBs immersed in some of the fluids used in a comparison of 170- and 240-day old rats. CONCLUSION/SIGNIFICANCE: Polarization microscopy studies provide detailed high quality structural information on rat skin CBs. A 3D-network structure based on image analysis and birefringence compensation for collagen fibers is suggested for CBs. Form and intrinsic birefringence evaluation can reveal differences in the rat skin associated with age at the levels of collagen fiber crystallinity and macromolecular organization. These findings may inspire future studies of the feedback mechanisms by which spatial, bioelectrical and biomechanical information is transmitted from CBs to skin cells. PMID- 23349958 TI - A survey of congenital heart disease and other organic malformations associated with different types of orofacial clefts in Eastern China. AB - BACKGROUND: A high incidence of orofacial clefts is reported in China, but no data has shown the relation between cleft types and the incidence of other defects so far. The aim of this study is to assess the incidence of congenital heart diseases and other organic defects associated with different types of orofacial clefts. METHODOLOGY AND PRINCIPAL FINDINGS: All children with orofacial clefts, which were sought out from the Health Information System of Shanghai Ninth People's Hospital between 1(st) Jan 2009 and 30(th) Dec 2011, were enrolled in this study. All subjects underwent a thorough examination and grouped by the cleft phenotype. The numbers and types of other organic defects were recorded and analyzed statistically using SPSS 17.0. Of 2180 cases reported as having orofacial clefts, 657 (30.1%) had other congenital abnormalities, which were significantly more common in cleft palate (47.9% (329/687)) than that in cleft lip (10.6% (80/755)) or cleft lip and palate (33.6% (248/738)) (P<0.01). In subgroups, unilateral cleft lip and palate had a statistically higher incidence of associated abnormalities than bilateral cleft lip and palate (P<0.01). The most common malformation was congenital heart disease, which counted 45.1% (296/657) of all malformations. Disorders of the central nervous system (14.3%(94/657)) and Skeletal anomalies (13.1%(86/657)) were also frequently associated. Additionally, the most common defect in heart was atrial septal defect, which was 39.7% (118/296) of all congenital heart diseases. CONCLUSIONS AND SIGNIFICANCE: As the high incidence of heart defects and other organic abnormalities in the children with cleft palate in Eastern China, special attention should be paid to them and echocardiography should be a proposed examination in the evaluation of children with cleft palate before any surgical correction being executed. PMID- 23349959 TI - Differential effects of serum heat treatment on chemotaxis and phagocytosis by human neutrophils. AB - Neutrophils, in cooperation with serum, are vital gatekeepers of a host's microbiome and frontline defenders against invading microbes. Yet because human neutrophils are not amenable to many biological techniques, the mechanisms governing their immunological functions remain poorly understood. We here combine state-of-the-art single-cell experiments with flow cytometry to examine how temperature-dependent heat treatment of serum affects human neutrophil interactions with "target" particles of the fungal model zymosan. Assessing separately both the chemotactic as well as the phagocytic neutrophil responses to zymosan, we find that serum heat treatment modulates these responses in a differential manner. Whereas serum treatment at 52 degrees C impairs almost all chemotactic activity and reduces cell-target adhesion, neutrophils still readily engulf target particles that are maneuvered into contact with the cell surface under the same conditions. Higher serum-treatment temperatures gradually suppress phagocytosis even after enforced cell-target contact. Using fluorescent staining, we correlate the observed cell behavior with the amounts of C3b and IgG deposited on the zymosan surface in sera treated at the respective temperatures. This comparison not only affirms the critical role of complement in chemotactic and adhesive neutrophil interactions with fungal surfaces, but also unmasks an important participation of IgGs in the phagocytosis of yeast-like fungal particles. In summary, this study presents new insight into fundamental immune mechanisms, including the chemotactic recruitment of immune cells, the adhesive capacity of cell-surface receptors, the role of IgGs in fungal recognition, and the opsonin-dependent phagocytosis morphology of human neutrophils. Moreover, we show how, by fine-tuning the heat treatment of serum, one can selectively study chemotaxis or phagocytosis under otherwise identical conditions. These results not only refine our understanding of a widely used laboratory method, they also establish a basis for new applications of this method. PMID- 23349960 TI - Erlotinib preserves renal function and prevents salt retention in doxorubicin treated nephrotic rats. AB - Nephrotic syndrome is associated with up-regulation of the heparin-binding epidermal growth factor (HB-EGF). Erlotinib blocks the activation of the epidermal growth factor receptor (EGFR) in response to HB-EGF. This study investigates the effect of Erlotinib on the progression of proteinuria, renal dysfunction, and salt retention in doxorubicin treated nephrotic rats. Male rats were divided into 3 pair-fed groups (n = 13/group) as follows: Control rats (Ctrl); rats receiving intravenous doxorubicin (Dox); and rats receiving intravenous doxorubicin followed by daily oral Erlotinib (Dox + Erl). Upon establishment of high grade proteinuria, urine sodium and creatinine clearance were measured. Kidney tissue was dissected and analyzed for gamma-epithelial sodium channel (gammaENaC), sodium-potassium -chloride co-transporter 2 (NKCC2), sodium chloride co-transporter (NCC), aquaporin 2 (AQP2), and EGFR abundances using western blot. Creatinine clearance was preserved in the Dox + Erl rats as compared to the Dox group (in ml/min: Ctrl: 5.2+/-.5, Dox: 1.9+/-0.3, Dox + Erl: 3.6+/-0.5). Despite a minimal effect on the degree of proteinuria, Erlotinib prevented salt retention (Urinary Na in mEq/d: Ctrl: 2.2+/-0.2, Dox: 1.8+/-0.3, Dox + Erl: 2.2+/-0.2). The cleaved/uncleaved gammaENaC ratio was increased by 41+/-16% in the Dox group but unchanged in the Dox + Erl group when compared to Ctrl. The phosphorylated EGFR/total EGFR ratio was reduced by 74+/-7% in the Dox group and by 77+/-4% in the Dox + Erl group. In conclusion, Erlotinib preserved renal function and prevented salt retention in nephrotic rats. The observed effects do not appear to be mediated by direct blockade of EGFR. PMID- 23349961 TI - Activate to eradicate: inhibition of Clostridium difficile spore outgrowth by the synergistic effects of osmotic activation and nisin. AB - BACKGROUND: Germination is the irreversible loss of spore-specific properties prior to outgrowth. Because germinating spores become more susceptible to killing by stressors, induction of germination has been proposed as a spore control strategy. However, this strategy is limited by superdormant spores that remain unaffected by germinants. Harsh chemicals and heat activation are effective for stimulating germination of superdormant spores but are impractical for use in a hospital setting, where Clostridium difficile spores present a challenge. Here, we tested whether osmotic activation solutes will provide a mild alternative for stimulation of superdormant C. difficile spores in the presence of germinants as previously demonstrated in several species of Bacillus. In addition, we tested the hypothesis that the limitations of superdormancy can be circumvented with a combined approach using nisin, a FDA-approved safe bacteriocin, to inhibit outgrowth of germinated spores and osmotic activation solutes to enhance outgrowth inhibition by stimulating superdormant spores. PRINCIPAL FINDINGS: Exposure to germination solution triggered ~1 log(10) colony forming units (CFU) of spores to germinate, and heat activation increased the spores that germinated to >2.5 log(10)CFU. Germinating spores, in contrast to dormant spores, became susceptible to inhibition by nisin. The presence of osmotic activation solutes did not stimulate germination of superdormant C. difficile spores exposed to germination solution. But, in the absence of germination solution, osmotic activation solutes enhanced nisin inhibition of superdormant spores to >3.5 log(10)CFU. The synergistic effects of osmotic activation solutes and nisin were associated with loss of membrane integrity. CONCLUSIONS: These findings suggest that the synergistic effects of osmotic activation and nisin bypass the limitations of germination as a spore control strategy, and might be a novel method to safely and effectively reduce the burden of C.difficile spores on skin and environmental surfaces. PMID- 23349962 TI - Astrocytes enhance the invasion potential of glioblastoma stem-like cells. AB - Glioblastomas (GBMs) are characterized as highly invasive; the contribution of GBM stem-like cells (GSCs) to the invasive phenotype, however, has not been completely defined. Towards this end, we have defined the invasion potential of CD133+ GSCs and their differentiated CD133- counterparts grown under standard in vitro conditions and in co-culture with astrocytes. Using a trans-well assay, astrocytes or astrocyte conditioned media in the bottom chamber significantly increased the invasion of GSCs yet had no effect on CD133- cells. In addition, a monolayer invasion assay showed that the GSCs invaded farther into an astrocyte monolayer than their differentiated progeny. Gene expression profiles were generated from two GSC lines grown in trans-well culture with astrocytes in the bottom chamber or directly in contact with astrocyte monolayers. In each co culture model, genes whose expression was commonly increased in both GSC lines involved cell movement and included a number of genes that have been previously associated with tumor cell invasion. Similar gene expression modifications were not detected in CD133- cells co-cultured under the same conditions with astrocytes. Finally, evaluation of the secretome of astrocytes grown in monolayer identified a number of chemokines and cytokines associated with tumor cell invasion. These data suggest that astrocytes enhance the invasion of CD133+ GSCs and provide additional support for a critical role of brain microenvironment in the regulation of GBM biology. PMID- 23349963 TI - Signal oscillation is another reason for variability in microarray-based gene expression quantification. AB - Microarrays have been widely used for various biological applications, such as, gene expression profiling, determination of SNPs, and disease profiling. However, quantification and analysis of microarray data have been a challenge. Previously, by taking into account translational and rotational diffusion of the target DNA, we have shown that the rate of hybridization depends on its size. Here, by mathematical modeling of surface diffusion of transcript, we show that the dynamics of hybridization on DNA microarray surface is inherently oscillatory and the amplitude of oscillation depends on fluid velocity. We found that high fluid velocity enhances the signal without affecting the background, and reduces the oscillation, thereby reducing likelihood of inter- and intra-experiment variability. We further show that a strong probe reduces dependence of signal-to noise ratio on probe strength, decreasing inter-microarray variability. On the other hand, weaker probes are required for SNP detection. Therefore, we recommend high fluid velocity and strong probes for all microarray applications except determination of SNPs. For SNP detection, we recommend high fluid velocity with weak probe on the spot. We also recommend a surface with high adsorption and desorption rates of transcripts. PMID- 23349964 TI - In silico identification of IgE-binding epitopes of osmotin protein. AB - The identification of B-cell epitopes is an important step to study the antigen- antibody interactions for diagnosis and therapy. The present study aimed to identify B- cell epitopes of osmotin using bioinformatic tools and further modify these regions to study the allergenic property. B-cell epitopes were predicted based on amino acid physicochemical properties. Three single point mutations M1, M2, and M3 and a multiple point mutant (M123) were selected to disrupt the IgE binding. These mutants were cloned, expressed and proteins purified to homogeneity. The IgE binding of the purified proteins was evaluated by ELISA and ELISA inhibition with patients' sera. Three regions of osmotin M1 (57-70 aa), M2 (72-85 aa) and M3 (147-165 aa) were identified as potential antibody recognition sites using in silico tools. The sequence similarity search of the predicted epitopes of osmotin using Structural Database of Allergenic proteins (SDAP) showed similarity with known allergens from tomato, kiwifruit, bell pepper, apple, mountain cedar and cypress. Mutants M1, M2 and M3 showed up to 72%, 60% and 76% reduction, respectively in IgE binding whereas M123 showed up to 90% reduction with patients' sera. The immunoblot of M123 mutant showed 40% reduction in spot density as compared to osmotin. All mutants showed decreased inhibition potency with M123 exhibiting lowest potency of 32% with osmotin positive pooled patients' sera. The three B- cell epitopes of osmotin predicted by in silico method correlated with the experimental approach. The mutant M123 showed a reduction of 90% in IgE binding. The present method may be employed for prediction of B- cell epitopes of allergenic proteins. PMID- 23349965 TI - The structure of the karrikin-insensitive protein (KAI2) in Arabidopsis thaliana. AB - KARRIKIN INSENSITIVE 2 (KAI2) is an alpha/beta hydrolase involved in seed germination and seedling development. It is essential for plant responses to karrikins, a class of butenolide compounds derived from burnt plant material that are structurally similar to strigolactone plant hormones. The mechanistic basis for the function of KAI2 in plant development remains unclear. We have determined the crystal structure of Arabidopsis thaliana KAI2 in space groups P2(1) 2(1) 2(1) (a =63.57 A, b =66.26 A, c =78.25 A) and P2(1) (a =50.20 A, b =56.04 A, c =52.43 A, beta =116.12 degrees ) to 1.55 and 2.11 A respectively. The catalytic residues are positioned within a large hydrophobic pocket similar to that of DAD2, a protein required for strigolactone response in Petunia hybrida. KAI2 possesses a second solvent-accessible pocket, adjacent to the active site cavity, which offers the possibility of allosteric regulation. The structure of KAI2 is consistent with its designation as a serine hydrolase, as well as previous data implicating the protein in karrikin and strigolactone signalling. PMID- 23349966 TI - Connective tissue fibroblast properties are position-dependent during mouse digit tip regeneration. AB - A key factor that contributes to the regenerative ability of regeneration competent animals such as the salamander is their use of innate positional cues that guide the regeneration process. The limbs of mammals has severe regenerative limitations, however the distal most portion of the terminal phalange is regeneration competent. This regenerative ability of the adult mouse digit is level dependent: amputation through the distal half of the terminal phalanx (P3) leads to successful regeneration, whereas amputation through a more proximal location, e.g. the subterminal phalangeal element (P2), fails to regenerate. Do the connective tissue cells of the mammalian digit play a role similar to that of the salamander limb in controlling the regenerative response? To begin to address this question, we isolated and cultured cells of the connective tissue surrounding the phalangeal bones of regeneration competent (P3) and incompetent (P2) levels. Despite their close proximity and localization, these cells show very distinctive profiles when characterized in vitro and in vivo. In vitro studies comparing their proliferation and position-specific interactions reveal that cells isolated from the P3 and P2 are both capable of organizing and differentiating epithelial progenitors, but with different outcomes. The difference in interactions are further characterized with three-dimension cultures, in which P3 regenerative cells are shown to lack a contractile response that is seen in other fibroblast cultures, including the P2 cultures. In in vivo engraftment studies, the difference between these two cell lines is made more apparent. While both P2 and P3 cells participated in the regeneration of the terminal phalanx, their survival and proliferative indices were distinct, thus suggesting a key difference in their ability to interact within a regeneration permissive environment. These studies are the first to demonstrate distinct positional characteristics of connective tissue cells that are associated with their regenerative capabilities. PMID- 23349967 TI - Long-term prognostic value of restitution slope in patients with ischemic and dilated cardiomyopathies. AB - BACKGROUND: An action potential duration (APD) restitution curve with a steep slope >=1 has been associated with increased susceptibility for malignant ventricular arrhythmias. We aimed to evaluate the "restitution hypothesis" and tested ventricular APD restitution slope as well as effective refractory period (ERP)/APD ratio for long-term prognostic value in patients with ischemic (ICM) or dilated cardiomyopathy (DCM). METHODOLOGY/PRINCIPAL FINDINGS: Monophasic action potentials were recorded in patients with ICM (n = 32) and DCM (n = 42) undergoing routine programmed ventricular stimulation (PVS). Left ventricular ejection fraction was 32+/-7% and 28+/-9%, respectively. APD and ERP were measured at baseline stimulation (S(1)) and upon introduction of one to three extrastimuli (S(2)-S(4)). ERP/APD ratios and the APD restitution curve were calculated and the maximum restitution slope was determined. After a mean follow up of 6.1+/-3.0 years, the combined end-point of mortality and and/or implantable cardioverter-defibrillator shock was not predicted by restitution slope or ERP/APD ratios. Comparing S(2) vs. S(3) vs. S(4) extrastimuli for restitution slope (1.5+/-0.6 vs. 1.4+/-0.4 vs. 1.3+/-0.5; p = NS), additional extrastimuli did not lead to a steepening restitution slope. ERP/APD ratio decreased with additional extrastimuli (0.98+/-0.09 [S(1)] vs. 0.97+/-0.10 [S(2)] vs. 0.93+/ 0.11 [S(3)]; p = 0.03 S(1) vs. S(3)). Positive PVS was strongly predictive of outcome (p = 0.006). CONCLUSIONS/SIGNIFICANCE: Neither ventricular APD restitution slope nor ERP/APD ratios predict outcome in patients with ICM or DCM. PMID- 23349968 TI - Women with multiple chemical sensitivity have increased harm avoidance and reduced 5-HT(1A) receptor binding potential in the anterior cingulate and amygdala. AB - Multiple chemical sensitivity (MCS) is a common condition, characterized by somatic distress upon exposure to odors. As in other idiopathic environmental intolerances, the underlying mechanisms are unknown. Contrary to the expectations it was recently found that persons with MCS activate the odor-processing brain regions less than controls, while their activation of the anterior cingulate cortex (ACC) is increased. The present follow-up study was designed to test the hypotheses that MCS subjects have increased harm avoidance and deviations in the serotonin system, which could render them intolerant to environmental odors. Twelve MCS and 11 control subjects, age 22-44, all working or studying females, were included in a PET study where 5-HT(1A) receptor binding potential (BP) was assessed after bolus injection of [(11)C]WAY100635. Psychological profiles were assessed by the Temperament and Character Inventory and the Swedish universities Scales of Personality. All MCS and 12 control subjects were also tested for emotional startle modulation in an acoustic startle test. MCS subjects exhibited significantly increased harm avoidance, and anxiety compared to controls. They also had a reduced 5-HT(1A) receptor BP in amygdala (p = 0.029), ACC (p = 0.005) (planned comparisons, significance level 0.05), and insular cortex (p = 0.003; significance level p<0.005 with Bonferroni correction), and showed an inverse correlation between degree of anxiety and the BP in the amygdala (planned comparison). No group by emotional category difference was found in the startle test. Increased harm avoidance and the observed changes in the 5-HT(1A) receptor BP in the regions processing harm avoidance provides a plausible pathophysiological ground for the symptoms described in MCS, and yields valuable information for our general understanding of idiopathic environmental intolerances. PMID- 23349969 TI - Altered protozoan and bacterial communities and survival of Escherichia coli O157:H7 in monensin-treated wastewater from a dairy lagoon. AB - Surviving predation is a fitness trait of Escherichia coli O157:H7 (EcO157) that provides ample time for the pathogen to be transported from reservoirs (e.g. dairies and feedlots) to farm produce grown in proximity. Ionophore dietary supplements that inhibit rumen protozoa may provide such a selective advantage for EcO157 to proliferate in lagoons as the pathogen is released along with the undigested supplement as manure washings. This study evaluated the fate of an outbreak strain of EcO157, protozoan and bacterial communities in wastewater treated with monensin. Although total protozoa and native bacteria were unaffected by monensin, the time for 90% decrease in EcO157 increased from 0.8 to 5.1 days. 18S and 16S rRNA gene sequencing of wastewater samples revealed that monensin eliminated almost all colpodean and oligohymenophorean ciliates, probably facilitating the extended survival of EcO157. Total protozoan numbers remained high in treated wastewater as monensin enriched 94% of protozoan sequences undetected with untreated wastewater. Monensin stimulated 30-fold increases in Cyrtohymena citrina, a spirotrichean ciliate, and also biflagellate bicosoecids and cercozoans. Sequences of gram-negative Proteobacteria increased from 1% to 46% with monensin, but gram-positive Firmicutes decreased from 93% to 46%. It is noteworthy that EcO157 numbers increased significantly (P<0.01) in Sonneborn medium containing monensin, probably due to monensin-inhibited growth of Vorticella microstoma (P<0.05), a ciliate isolated from wastewater. We conclude that dietary monensin inhibits ciliate protozoa that feed on EcO157. Feed supplements or other methods that enrich these protozoa in cattle manure could be a novel strategy to control the environmental dissemination of EcO157 from dairies to produce production environments. PMID- 23349970 TI - Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme. AB - Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Delta(9) Tetrahydrocannabinol (THC) and Cannabidiol (CBD) - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-epsilon-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies. PMID- 23349971 TI - A psychophysical investigation of differences between synchrony and temporal order judgments. AB - BACKGROUND: Synchrony judgments involve deciding whether cues to an event are in synch or out of synch, while temporal order judgments involve deciding which of the cues came first. When the cues come from different sensory modalities these judgments can be used to investigate multisensory integration in the temporal domain. However, evidence indicates that that these two tasks should not be used interchangeably as it is unlikely that they measure the same perceptual mechanism. The current experiment further explores this issue across a variety of different audiovisual stimulus types. METHODOLOGY/PRINCIPAL FINDINGS: Participants were presented with 5 audiovisual stimulus types, each at 11 parametrically manipulated levels of cue asynchrony. During separate blocks, participants had to make synchrony judgments or temporal order judgments. For some stimulus types many participants were unable to successfully make temporal order judgments, but they were able to make synchrony judgments. The mean points of subjective simultaneity for synchrony judgments were all video-leading, while those for temporal order judgments were all audio-leading. In the within participants analyses no correlation was found across the two tasks for either the point of subjective simultaneity or the temporal integration window. CONCLUSIONS: Stimulus type influenced how the two tasks differed; nevertheless, consistent differences were found between the two tasks regardless of stimulus type. Therefore, in line with previous work, we conclude that synchrony and temporal order judgments are supported by different perceptual mechanisms and should not be interpreted as being representative of the same perceptual process. PMID- 23349972 TI - Environmental enrichment and gut inflammation modify stress-induced c-Fos expression in the mouse corticolimbic system. AB - Environmental enrichment (EE) has a beneficial effect on rodent behaviour, neuronal plasticity and brain function. Although it may also improve stress coping, it is not known whether EE influences the brain response to an external (psychological) stressor such as water avoidance stress (WAS) or an internal (systemic) stressor such as gastrointestinal inflammation. This study hence explored whether EE modifies WAS-induced activation of the mouse corticolimbic system and whether this stress response is altered by gastritis or colitis. Male C67BL/6N mice were housed under standard or enriched environment for 9 weeks, after which they were subjected to a 1-week treatment with oral iodoacetamide to induce gastritis or oral dextran sulfate sodium to induce colitis. Following exposure to WAS the expression of c-Fos, a marker of neuronal activation, was measured by immunocytochemistry. EE aggravated experimentally induced colitis, but not gastritis, as shown by an increase in the disease activity score and the colonic myeloperoxidase content. In the brain, EE enhanced the WAS-induced activation of the dentate gyrus and unmasked an inhibitory effect of gastritis and colitis on WAS-evoked c-Fos expression within this part of the hippocampus. Conversely, EE inhibited the WAS-evoked activation of the central amygdala and prevented the inhibitory effect of gastritis and colitis on WAS-evoked c-Fos expression in this region. EE, in addition, blunted the WAS-induced activation of the infralimbic cortex and attenuated the inhibitory effect of gastritis and colitis on WAS-evoked c-Fos expression in this area. These data reveal that EE has a region-specific effect on stress-induced c-Fos expression in the corticolimbic system, which is likely to improve stress resilience. The response of the prefrontal cortex - amygdala - hippocampus circuitry to psychological stress is also modified by the systemic stress of gut inflammation, and this interaction between external and internal stressors is modulated by the housing environment. PMID- 23349973 TI - Two functional motifs define the interaction, internalization and toxicity of the cell-penetrating antifungal peptide PAF26 on fungal cells. AB - The synthetic, cell penetrating hexapeptide PAF26 (RKKWFW) is antifungal at low micromolar concentrations and has been proposed as a model for cationic, cell penetrating antifungal peptides. Its short amino acid sequence facilitates the analysis of its structure-activity relationships using the fungal models Neurospora crassa and Saccharomyces cerevisiae, and human and plant pathogens Aspergillus fumigatus and Penicillium digitatum, respectively. Previously, PAF26 at low fungicidal concentrations was shown to be endocytically internalized, accumulated in vacuoles and then actively transported into the cytoplasm where it exerts its antifungal activity. In the present study, two PAF26 derivatives, PAF95 (AAAWFW) and PAF96 (RKKAAA), were designed to characterize the roles of the N-terminal cationic and the C-terminal hydrophobic motifs in PAF26's mode-of action. PAF95 and PAF96 exhibited substantially reduced antifungal activity against all the fungi analyzed. PAF96 localized to fungal cell envelopes and was not internalized by the fungi. In contrast, PAF95 was taken up into vacuoles of N. crassa, wherein it accumulated and was trapped without toxic effects. Also, the PAF26 resistant Deltaarg1 strain of S. cerevisiae exhibited increased PAF26 accumulation in vacuoles. Live-cell imaging of GFP-labelled nuclei in A. fumigatus showed that transport of PAF26 from the vacuole to the cytoplasm was followed by nuclear breakdown and dissolution. This work demonstrates that the amphipathic PAF26 possesses two distinct motifs that allow three stages in its antifungal action to be defined: (i) its interaction with the cell envelope; (ii) its internalization and transport to vacuoles mediated by the aromatic hydrophobic domain; and (iii) its transport from vacuoles to the cytoplasm. Significantly, cationic residues in PAF26 are important not only for the electrostatic attraction and interaction with the fungal cell but also for transport from the vacuole to the cytoplasm, which coincides with cell death. Peptide containment within vacuoles preserves fungal cells from peptide toxicity. PMID- 23349974 TI - Application of a qPCR assay in the investigation of susceptibility to malaria infection of the M and S molecular forms of An. gambiae s.s. in Cameroon. AB - Plasmodium falciparum is the causative agent of malaria, a disease that kills almost one million persons each year, mainly in sub-Saharan Africa. P. falciparum is transmitted to the human host by the bite of an Anopheles female mosquito, and Anopheles gambiae sensus stricto is the most tremendous malaria vector in Africa, widespread throughout the afro-tropical belt. An. gambiae s.s. is subdivided into two distinct molecular forms, namely M and S forms. The two molecular forms are morphologically identical but they are distinct genetically, and differ by their distribution and their ecological preferences. The epidemiological importance of the two molecular forms in malaria transmission has been poorly investigated so far and gave distinct results in different areas. We have developed a real-time quantitative PCR (qPCR) assay, and used it to detect P. falciparum at the oocyst stage in wild An. gambiae s.s. mosquitoes experimentally infected with natural isolates of parasites. Mosquitoes were collected at immature stages in sympatric and allopatric breeding sites and further infected at the adult stage. We next measured the infection prevalence and intensity in female mosquitoes using the qPCR assay and correlated the infection success with the mosquito molecular forms. Our results revealed different prevalence of infection between the M and S molecular forms of An. gambiae s.s. in Cameroon, for both sympatric and allopatric populations of mosquitoes. However, no difference in the infection intensity was observed. Thus, the distribution of the molecular forms of An. gambiae s.s. may impact on the malaria epidemiology, and it will be important to monitor the efficiency of malaria control interventions on the two M and S forms. PMID- 23349975 TI - Identification of a binding site for ASF/SF2 on an RNA fragment derived from the hepatitis delta virus genome. AB - The hepatitis delta virus (HDV) is a small (~1700 nucleotides) RNA pathogen which encodes only one open reading frame. Consequently, HDV is dependent on host proteins to replicate its RNA genome. Recently, we reported that ASF/SF2 binds directly and specifically to an HDV-derived RNA fragment which has RNA polymerase II promoter activity. Here, we localized the binding site of ASF/SF2 on the HDV RNA fragment by performing binding experiments using purified recombinant ASF/SF2 combined with deletion analysis and site-directed mutagenesis. In addition, we investigated the requirement of ASF/SF2 for HDV RNA replication using RNAi mediated knock-down of ASF/SF2 in 293 cells replicating HDV RNA. Overall, our results indicate that ASF/SF2 binds to a purine-rich region distant from both the previously published initiation site of HDV mRNA transcription and binding site of RNAP II, and suggest that this protein is not involved in HDV replication in the cellular system used. PMID- 23349976 TI - A systematic survey of expression and function of zebrafish frizzled genes. AB - Wnt signaling is crucial for the regulation of numerous processes in development. Consistent with this, the gene families for both the ligands (Wnts) and receptors (Frizzleds) are very large. Surprisingly, while we have a reasonable understanding of the Wnt ligands likely to mediate specific Wnt-dependent processes, the corresponding receptors usually remain to be elucidated. Taking advantage of the zebrafish model's excellent genomic and genetic properties, we undertook a comprehensive analysis of the expression patterns of frizzled (fzd) genes in zebrafish. To explore their functions, we focused on testing their requirement in several developmental events known to be regulated by Wnt signaling, convergent extension movements of gastrulation, neural crest induction, and melanocyte specification. We found fourteen distinct fzd genes in the zebrafish genome. Systematic analysis of their expression patterns between 1 somite and 30 hours post-fertilization revealed complex, dynamic and overlapping expression patterns. This analysis demonstrated that only fzd3a, fzd9b, and fzd10 are expressed in the dorsal neural tube at stages corresponding to the timing of melanocyte specification. Surprisingly, however, morpholino knockdown of these, alone or in combination, gave no indication of reduction of melanocytes, suggesting the important involvement of untested fzds or another type of Wnt receptor in this process. Likewise, we found only fzd7b and fzd10 expressed at the border of the neural plate at stages appropriate for neural crest induction. However, neural crest markers were not reduced by knockdown of these receptors. Instead, these morpholino knockdown studies showed that fzd7a and fzd7b work co operatively to regulate convergent extension movement during gastrulation. Furthermore, we show that the two fzd7 genes function together with fzd10 to regulate epiboly movements and mesoderm differentiation. PMID- 23349977 TI - Zebrafish 20beta-hydroxysteroid dehydrogenase type 2 is important for glucocorticoid catabolism in stress response. AB - Stress, the physiological reaction to a stressor, is initiated in teleost fish by hormone cascades along the hypothalamus-pituitary-interrenal (HPI) axis. Cortisol is the major stress hormone and contributes to the appropriate stress response by regulating gene expression after binding to the glucocorticoid receptor. Cortisol is inactivated when 11beta-hydroxysteroid dehydrogenase (HSD) type 2 catalyzes its oxidation to cortisone. In zebrafish, Danio rerio, cortisone can be further reduced to 20beta-hydroxycortisone. This reaction is catalyzed by 20beta-HSD type 2, recently discovered by us. Here, we substantiate the hypothesis that 20beta HSD type 2 is involved in cortisol catabolism and stress response. We found that hsd11b2 and hsd20b2 transcripts were up-regulated upon cortisol treatment. Moreover, a cortisol-independent, short-term physical stressor led to the up regulation of hsd11b2 and hsd20b2 along with several HPI axis genes. The morpholino-induced knock down of hsd20b2 in zebrafish embryos revealed no developmental phenotype under normal culture conditions, but prominent effects were observed after a cortisol challenge. Reporter gene experiments demonstrated that 20beta-hydroxycortisone was not a physiological ligand for the zebrafish glucocorticoid or mineralocorticoid receptor but was excreted into the fish holding water. Our experiments show that 20beta-HSD type 2, together with 11beta HSD type 2, represents a short pathway in zebrafish to rapidly inactivate and excrete cortisol. Therefore, 20beta-HSD type 2 is an important enzyme in stress response. PMID- 23349979 TI - Clinical value of NGAL, L-FABP and albuminuria in predicting GFR decline in type 2 diabetes mellitus patients. AB - OBJECTIVES: Neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid binding protein (L-FABP) are emerging as excellent biomarkers in the urine and plasma for the early prediction of acute and chronic kidney injury. The aims of this prospective study were to determine the role of albuminuria, and that of serum and urine levels of NGAL and L-FABP as predictors of a decline in the glomerular filtration rate (GFR) in patients with type 2 diabetes. METHODS: A longitudinal cohort study with one hundred forty type 2 diabetic patients was conducted. Serum and urine levels of NGAL and L-FABP, and the urine albumin excretion rate were determined. The correlation between the kidney injury biomarkers and rate of GFR decline was analyzed. RESULTS: The eGFR of study subjects decreased significantly as the study progressed (86.4+/-31.1 vs. 74.4+/ 27.3 ml/min/1.73 m(2), P<0.001), and the urine albumin excretion rate increased significantly (264.9+/-1060.3 vs. 557.7+/-2092.5 mg/day, P = 0.009). The baseline urine albumin excretion rate and serum L-FABP level were significantly correlated with baseline eGFR (P<0.05). The results of regression analysis for the correlations between the rate of eGFR change and the baseline levels of NGAL and L-FABP, and the urine albumin excretion rate showed that only the urine albumin excretion rate was significantly correlated with the rate of eGFR change (standardized coefficients: -0.378; t: -4.298; P<0.001). CONCLUSIONS: Tubular markers, such as NGAL and L-FABP, may not be predictive factors associated with GFR decline in type 2 diabetic patients. PMID- 23349978 TI - Conditional inactivation of TNFalpha-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones. AB - TNFalpha-converting enzyme (TACE) is a membrane-bound proteolytic enzyme with essential roles in the functional regulation of TNFalpha and epidermal growth factor receptor (EGFR) ligands. Previous studies have demonstrated critical roles for TACE in vivo, including epidermal development, immune response, and pathological neoangiogenesis, among others. However, the potential contribution of TACE to skeletal development is still unclear. In the present study, we generated a Tace mutant mouse in which Tace is conditionally disrupted in chondrocytes under the control of the Col2a1 promoter. These mutant mice were fertile and viable but all exhibited long bones that were approximately 10% shorter compared to those of wild-type animals. Histological analyses revealed that Tace mutant mice exhibited a longer hypertrophic zone in the growth plate, and there were fewer osteoclasts at the chondro-osseous junction in the Tace mutant mice than in their wild-type littermates. Of note, we found an increase in osteoprotegerin transcripts and a reduction in Rankl and Mmp-13 transcripts in the TACE-deficient cartilage, indicating that dysregulation of these genes is causally related to the skeletal defects in the Tace mutant mice. Furthermore, we also found that phosphorylation of EGFR was significantly reduced in the cartilage tissue lacking TACE, and that suppression of EGFR signaling increases osteoprotegerin transcripts and reduces Rankl and Mmp-13 transcripts in primary chondrocytes. In accordance, chondrocyte-specific abrogation of Egfr in vivo resulted in skeletal defects nearly identical to those observed in the Tace mutant mice. Taken together, these data suggest that TACE-EGFR signaling in chondrocytes is involved in the turnover of the growth plate during postnatal development via the transcriptional regulation of osteoprotegerin, Rankl, and Mmp 13. PMID- 23349980 TI - Active RNA replication of hepatitis C virus downregulates CD81 expression. AB - So far how hepatitis C virus (HCV) replication modulates subsequent virus growth and propagation still remains largely unknown. Here we determine the impact of HCV replication status on the consequential virus growth by comparing normal and high levels of HCV RNA expression. We first engineered a full-length, HCV genotype 2a JFH1 genome containing a blasticidin-resistant cassette inserted at amino acid residue of 420 in nonstructural (NS) protein 5A, which allowed selection of human hepatoma Huh7 cells stably-expressing HCV. Short-term establishment of HCV stable cells attained a highly-replicating status, judged by higher expressions of viral RNA and protein as well as higher titer of viral infectivity as opposed to cells harboring the same genome without selection. Interestingly, maintenance of highly-replicating HCV stable cells led to decreased susceptibility to HCV pseudotyped particle (HCVpp) infection and downregulated cell surface level of CD81, a critical HCV entry (co)receptor. The decreased CD81 cell surface expression occurred through reduced total expression and cytoplasmic retention of CD81 within an endoplasmic reticulum -associated compartment. Moreover, productive viral RNA replication in cells harboring a JFH1 subgenomic replicon containing a similar blasticidin resistance gene cassette in NS5A and in cells robustly replicating full-length infectious genome also reduced permissiveness to HCVpp infection through decreasing the surface expression of CD81. The downregulation of CD81 surface level in HCV RNA highly-replicating cells thus interfered with reinfection and led to attenuated viral amplification. These findings together indicate that the HCV RNA replication status plays a crucial determinant in HCV growth by modulating the expression and intracellular localization of CD81. PMID- 23349982 TI - Identification of a nonsense mutation in CWC15 associated with decreased reproductive efficiency in Jersey cattle. AB - With the recent advent of genomic tools for cattle, several recessive conditions affecting fertility have been identified and selected against, such as deficiency of uridine monophosphate synthase, complex vertebral malformation, and brachyspina. The current report refines the location of a recessive haplotype affecting fertility in Jersey cattle using crossover haplotypes, discovers the causative mutation using whole genome sequencing, and examines the gene's role in embryo loss. In an attempt to identify unknown recessive lethal alleles in the current dairy population, a search using deep Mendelian sampling of 5,288 Jersey cattle was conducted for high-frequency haplotypes that have a deficit of homozygotes at the population level. This search led to the discovery of a putative recessive lethal in Jersey cattle on Bos taurus autosome 15. The haplotype, denoted JH1, was associated with reduced fertility, and further investigation identified one highly-influential Jersey bull as the putative source ancestor. By combining SNP analysis of whole-genome sequences aligned to the JH1 interval and subsequent SNP validation a nonsense mutation in CWC15 was identified as the likely causative mutation underlying the fertility phenotype. No homozygous recessive individuals were found in 749 genotyped animals, whereas all known carriers and carrier haplotypes possessed one copy of the mutant allele. This newly identified lethal has been responsible for a substantial number of spontaneous abortions in Jersey dairy cattle throughout the past half century. With the mutation identified, selection against the deleterious allele in breeding schemes will aid in reducing the incidence of this defect in the population. These results also show that carrier status can be imputed with high accuracy. Whole-genome resequencing proved to be a powerful strategy to rapidly identify a previously mapped deleterious mutation in a known carrier of a recessive lethal allele. PMID- 23349981 TI - Dact2 represses PITX2 transcriptional activation and cell proliferation through Wnt/beta-catenin signaling during odontogenesis. AB - Dact proteins belong to the Dapper/Frodo protein family and function as cytoplasmic attenuators in Wnt and TGFbeta signaling. Previous studies show that Dact1 is a potent Wnt signaling inhibitor by promoting degradation of beta catenin. We report a new mechanism for Dact2 function as an inhibitor of the canonical Wnt signaling pathway by interacting with PITX2. PITX2 is a downstream transcription factor in Wnt/beta-catenin signaling, and PITX2 synergizes with Lef 1 to activate downstream genes. Immunohistochemistry verified the expression of Dact2 in the tooth epithelium, which correlated with Pitx2 epithelial expression. Dact2 loss of function and PITX2 gain of function studies reveal a feedback mechanism for controlling Dact2 expression. Pitx2 endogenously activates Dact2 expression and Dact2 feeds back to repress Pitx2 transcriptional activity. A Topflash reporter system was employed showing PITX2 activation of Wnt signaling, which is attenuated by Dact2. Transient transfections demonstrate the inhibitory effect of Dact2 on critical dental epithelial differentiation factors during tooth development. Dact2 significantly inhibits PITX2 activation of the Dlx2 and amelogenin promoters. Multiple lines of evidence conclude the inhibition is achieved by the physical interaction between Dact2 and Pitx2 proteins. The loss of function of Dact2 also reveals increased cell proliferation due to up regulated Wnt downstream genes, cyclinD1 and cyclinD2. In summary, we have identified a novel role for Dact2 as an inhibitor of the canonical Wnt pathway in embryonic tooth development through its regulation of cell proliferation and differentiation. PMID- 23349983 TI - The frequency response of the vibrissae of harp seal, Pagophilus Groenlandicus, to sound in air and water. AB - The motion of isolated seal vibrissae due to low frequency sound in air has been measured using a microscope with a video camera and modeled using an FEM method with good agreement between the measurements and the model; the model has also been used to predict the motion of seal vibrissae in water. The shape of the seal vibrissae is that of a tapered right rectangular prism, unlike that of the previously studied rat vibrissae which are conical in shape. Moreover, unlike rat vibrissae which oscillate in the direction of the sound stimulus, two different modes of vibration of seal vibrissae were observed - one corresponding to the wider side being stimulated and one with the narrow side stimulated. The tuning of the seal vibrissae was much sharper than those of rat vibrissae, with quality factors about three times as large as those of rat vibrissae. As shown by the model, this increased sharpness is caused by the larger cross-sectional areas (by more than a factor of ten) of the seal vibrissae. This increased sharpness may be necessary for seal vibrissae so that they can have tuning in water, where the drag more heavily dampens the tuning than in air. The results suggest that vibrissae tuning may be important in the seal's ability to track the wake of its prey. PMID- 23349984 TI - Ectopic overexpression of SlHsfA3, a heat stress transcription factor from tomato, confers increased thermotolerance and salt hypersensitivity in germination in transgenic Arabidopsis. AB - Plant heat stress transcription factors (Hsfs) are the critical components involved in mediating responses to various environmental stressors. However, the detailed roles of many plant Hsfs are far from fully understood. In this study, an Hsf (SlHsfA3) was isolated from the cultivated tomato (Solanum lycopersicum, Sl) and functionally characterized at the genetic and developmental levels. The nucleus-localized SlHsfA3 was basally and ubiquitously expressed in different plant organs. The expression of SlHsfA3 was induced dramatically by heat stress, moderately by high salinity, and slightly by drought, but was not induced by abscisic acid (ABA). The ectopic overexpression of SlHsfA3 conferred increased thermotolerance and late flowering phenotype to transgenic Arabidopsis plants. Moreover, SlHsfA3 played a negative role in controlling seed germination under salt stress. RNA-sequencing data demonstrated that a number of heat shock proteins (Hsps) and stress-associated genes were induced in Arabidopsis plants overexpressing SlHsfA3. A gel shift experiment and transient expression assays in Nicotiana benthamiana leaves demonstrated that SlHsfA3 directly activates the expression of SlHsp26.1-P and SlHsp21.5-ER. Taken together, our results suggest that SlHsfA3 behaves as a typical Hsf to contribute to plant thermotolerance. The late flowering and seed germination phenotypes and the RNA-seq data derived from SlHsfA3 overexpression lines lend more credence to the hypothesis that plant Hsfs participate in diverse physiological and biochemical processes related to adverse conditions. PMID- 23349985 TI - Fms-like tyrosine kinase 3 ligand controls formation of regulatory T cells in autoimmune arthritis. AB - Fms-like tyrosine kinase 3 ligand (Flt3L) is known as the primary differentiation and survival factor for dendritic cells (DCs). Furthermore, Flt3L is involved in the homeostatic feedback loop between DCs and regulatory T cell (Treg). We have previously shown that Flt3L accumulates in the synovial fluid in rheumatoid arthritis (RA) and that local exposure to Flt3L aggravates arthritis in mice, suggesting a possible involvement in RA pathogenesis. In the present study we investigated the role of Flt3L on DC populations, Tregs as well as inflammatory responses in experimental antigen-induced arthritis. Arthritis was induced in mBSA-immunized mice by local knee injection of mBSA and Flt3L was provided by daily intraperitoneal injections. Flow cytometry analysis of spleen and lymph nodes revealed an increased formation of DCs and subsequently Tregs in mice treated with Flt3L. Flt3L-treatment was also associated with a reduced production of mBSA specific antibodies and reduced levels of the pro-inflammatory cytokines IL-6 and TNF-alpha. Morphological evaluation of mBSA injected joints revealed reduced joint destruction in Flt3L treated mice. The role of DCs in mBSA arthritis was further challenged in an adoptive transfer experiment. Transfer of DCs in combination with T-cells from mBSA immunized mice, predisposed naive recipients for arthritis and production of mBSA specific antibodies. We provide experimental evidence that Flt3L has potent immunoregulatory properties. Flt3L facilitates formation of Treg cells and by this mechanism reduces severity of antigen-induced arthritis in mice. We suggest that high systemic levels of Flt3L have potential to modulate autoreactivity and autoimmunity. PMID- 23349986 TI - Cryopreservation in trehalose preserves functional capacity of murine spermatogonial stem cells. AB - Development of techniques to isolate, culture, and transplant human spermatogonial stem cells (SSCs) has the future potential to treat male infertility. To maximize the efficiency of these techniques, methods for SSC cryopreservation need to be developed to bank SSCs for extended periods of time. Although, it has been demonstrated that SSCs can reinitiate spermatogenesis after freezing, optimal cryopreservation protocols that maximize SSC proliferative capacity post-thaw have not been identified. The objective of this study was to develop an efficient cryopreservation technique for preservation of SSCs. To identify efficient cryopreservation methods for long-term preservation of SSCs, isolated testis cells enriched for SSCs were placed in medium containing dimethyl sulfoxide (DMSO) or DMSO and trehalose (50 mM, 100 mM, or 200 mM), and frozen in liquid nitrogen for 1 week, 1 month, or 3 months. Freezing in 50 mM trehalose resulted in significantly higher cell viability compared to DMSO at all thawing times and a higher proliferation rate compared to DMSO for the 1 week freezing period. Freezing in 200 mM trehalose did not result in increased cell viability; however, proliferation activity was significantly higher and percentage of apoptotic cells was significantly lower compared to DMSO after freezing for 1 and 3 months. To confirm the functionality of SSCs frozen in 200 mM trehalose, SSC transplantation was performed. Donor SSCs formed spermatogenic colonies and sperm capable of generating normal progeny. Collectively, these results indicate that freezing in DMSO with 200 mM trehalose serves as an efficient method for the cryopreservation of SSCs. PMID- 23349987 TI - Toxocariasis in waste pickers: a case control seroprevalence study. AB - BACKGROUND: The epidemiology of Toxocara infection in humans in Mexico has been poorly explored. There is a lack of information about Toxocara infection in waste pickers. AIMS: Determine the seroepidemiology of Toxocara infection in waste pickers. METHODS: Through a case control study design, the presence of anti Toxocara IgG antibodies was determined in 90 waste pickers and 90 age- and gender matched controls using an enzyme-linked immunoassay. Associations of Toxocara exposure with socio-demographic, work, clinical, and behavioral data of the waste pickers were also evaluated. RESULTS: The seroprevalence of anti-Toxocara IgG antibodies was significantly higher in waste pickers (12/90: 13%) than in control subjects (1/90: 1%) (OR = 14; 95% CI: 2-288). The seroprevalence was not influenced by socio-demographic or work characteristics. In contrast, increased seroprevalence was found in waste pickers suffering from gastritis, and reflex and visual impairments. Multivariate analysis showed that Toxocara exposure was associated with a low frequency of eating out of home (OR = 26; 95% CI: 2-363) and negatively associated with consumption of chicken meat (OR = 0.03; 95% CI: 0.003-0.59). Other behavioral characteristics such as animal contacts or exposure to soil were not associated with Toxocara seropositivity. CONCLUSIONS: 1) Waste pickers are a risk group for Toxocara infection. 2) Toxocara is impacting the health of waste pickers. This is the first report of Toxocara exposure in waste pickers and of associations of gastritis and reflex impairment with Toxocara seropositivity. Results warrant for further research. PMID- 23349988 TI - Dietary proportions of carbohydrates, fat, and protein and risk of oesophageal cancer by histological type. AB - BACKGROUND: Dietary habits influence the risk of cancer of the oesophagus and oesophago-gastric junction, but the role of proportions of the main dietary macronutrients carbohydrates, fats and proteins is uncertain. METHODS: Data was derived from a nationwide Swedish population-based case-control study conducted in 1995-1997, in which case ascertainment was rapid, and all cases were uniformly classified. Information on the subjects' history of dietary intake was collected in personal interviews. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression, with adjustment for potentially confounding factors. RESULTS: Included were 189 oesophageal adenocarcinomas, 262 oesophago gastric adenocarcinomas, 167 oesophageal squamous cell carcinomas, and 820 control subjects. Regarding oesophageal or oesophago-gastric junctional adenocarcinoma, a high dietary proportion of carbohydrates decreased the risk (OR 0.50, CI 0.34-0.73), and a high portion of fat increased the risk (OR 1.96, CI 1.34-2.87), while a high proportion of protein did not influence the risk (OR 1. 08, 95% CI 0.75-1.56). Regarding oesophageal squamous cell carcinoma, the single macronutrients did not influence the risk statistically significantly. CONCLUSIONS: A diet with a low proportion of carbohydrates and a high proportion of fat might increase the risk of oesophageal adenocarcinoma. PMID- 23349989 TI - A comparison of Ku0063794, a dual mTORC1 and mTORC2 inhibitor, and temsirolimus in preclinical renal cell carcinoma models. AB - Rapamycin analogs, temsirolimus and everolimus, are approved for the treatment of advance renal cell carcinoma (RCC). Currently approved agents inhibit mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). However, the mTOR kinase exists in two distinct multiprotein complexes, mTORC1 and mTORC2, and both complexes may be critical regulators of cell metabolism, growth and proliferation. Furthermore, it has been proposed that drug resistance develops due to compensatory activation of mTORC2 signaling during treatment with temsirolimus or everolimus. We evaluated Ku0063794, which is a small molecule that inhibits both mTOR complexes. Ku0063794 was compared to temsirolimus in preclinical models for renal cell carcinoma. Ku0063794 was effective in inhibiting the phosphorylation of signaling proteins downstream of both mTORC1 and mTORC2, including p70 S6K, 4E-BP1 and Akt. Ku0063794 was more effective than temsirolimus in decreasing the viability and growth of RCC cell lines, Caki-1 and 786-O, in vitro by inducing cell cycle arrest and autophagy, but not apoptosis. However, in a xenograft model there was no difference in the inhibition of tumor growth by Ku0063794 or temsirolimus. A potential explanation is that temsirolimus has additional effects on the tumor microenvironment. Consistent with this possibility, temsirolimus, but not Ku0063794, decreased tumor angiogenesis in vivo, and decreased the viability of HUVEC (Human Umbilical Vein Endothelial Cells) cells in vitro at pharmacologically relevant concentrations. Furthermore, expression levels of VEGF and PDGF were lower in Caki-1 and 786-O cells treated with temsirolimus than cells treated with Ku0063794. PMID- 23349990 TI - Disruption of spatial task performance in anorexia nervosa. AB - In anorexia nervosa (AN), body distortions have been associated with parietal cortex (PC) dysfunction. The PC is the anatomical substrate for a supramodal reference framework involved in spatial orientation constancy. Here, we sought to evaluate spatial orientation constancy and the perception of body orientation in AN patients. In the present study, we investigated the effect of passive lateral body inclination on the visual and tactile subjective vertical (SV) and body Z axis in 25 AN patients and 25 healthy controls. Subjects performed visual- and tactile-spatial judgments of axis orientations in an upright position and tilted 90 degrees clockwise or counterclockwise. We observed a significant deviation of the tactile and visual SV towards the body (an A-effect) under tilted conditions, suggesting a multisensory impairment in spatial orientation. Deviation of the Z axis in the direction of the tilt was also observed in the AN group. The greater A-effect in AN patients may reflect reduced interoceptive awareness and thus inadequate consideration of gravitational inflow. Furthermore, marked body weight loss could decrease the somatosensory inputs required for spatial orientation. Our study results suggest that spatial references are impaired in AN. This may be due to particular integration of visual, tactile and gravitational information (e.g. vestibular and proprioceptive cues) in the PC. PMID- 23349991 TI - Xylella fastidiosa differentially accumulates mineral elements in biofilm and planktonic cells. AB - Xylella fastidiosa is a bacterial plant pathogen that infects numerous plant hosts. Disease develops when the bacterium colonizes the xylem vessels and forms a biofilm. Inductively coupled plasma optical emission spectroscopy was used to examine the mineral element content of this pathogen in biofilm and planktonic states. Significant accumulations of copper (30-fold), manganese (6-fold), zinc (5-fold), calcium (2-fold) and potassium (2-fold) in the biofilm compared to planktonic cells were observed. Other mineral elements such as sodium, magnesium and iron did not significantly differ between biofilm and planktonic cells. The distribution of mineral elements in the planktonic cells loosely mirrors the media composition; however the unique mineral element distribution in biofilm suggests specific mechanisms of accumulation from the media. A cell-to-surface attachment assay shows that addition of 50 to 100 uM Cu to standard X. fastidiosa media increases biofilm, while higher concentrations (>200 uM) slow cell growth and prevent biofilm formation. Moreover cell-to-surface attachment was blocked by specific chelation of copper. Growth of X. fastidiosa in microfluidic chambers under flow conditions showed that addition of 50 uM Cu to the media accelerated attachment and aggregation, while 400 uM prevented this process. Supplementation of standard media with Mn showed increased biofilm formation and cell-to-cell attachment. In contrast, while the biofilm accumulated Zn, supplementation to the media with this element caused inhibited growth of planktonic cells and impaired biofilm formation. Collectively these data suggest roles for these minerals in attachment and biofilm formation and therefore the virulence of this pathogen. PMID- 23349992 TI - Time will show: real time predictions during interpersonal action perception. AB - Predictive processes are crucial not only for interpreting the actions of individual agents, but also to predict how, in the context of a social interaction between two agents, the actions of one agent relate to the actions of a second agent. In the present study we investigated whether, in the context of a communicative interaction between two agents, observers can use the actions of one agent to predict when the action of a second agent will take place. Participants observed point-light displays of two agents (A and B) performing separate actions. In the communicative condition, the action performed by agent B responded to a communicative gesture performed by agent A. In the individual condition, agent A's communicative action was substituted with a non communicative action. For each condition, we manipulated the temporal coupling of the actions of the two agents, by varying the onset of agent A's action. Using a simultaneous masking detection task, we demonstrated that the timing manipulation had a critical effect on the communicative condition, with the visual discrimination of agent B increasing linearly while approaching the original interaction timing. No effect of the timing manipulation was found for the individual condition. Our finding complements and extends previous evidence for interpersonal predictive coding, suggesting that the communicative gestures of one agent can serve not only to predict what the second agent will do, but also when his/her action will take place. PMID- 23349993 TI - Evaluation of chemotherapy response with serum squamous cell carcinoma antigen level in cervical cancer patients: a prospective cohort study. AB - MRI does not always reflect tumor response after chemotherapy. Therefore, it is necessary to explore additional parameters to more accurately evaluate tumor response for the subsequent clinical determination about radiotherapy or radical surgery. A training cohort and an external validation cohort were used to examine the predictive performance of SCC-ag to evaluate tumor response from teaching hospital of Harbin Medical University. The study included 397 women with SCC (age: 28-73 years). Patients consecutively enrolled between August 2008 and January 2010 (n = 205) were used as training cohort. Patients consecutively enrolled between February 2010 and May 2011 (n = 192) were used as validation cohort. A multivariate regression analysis of the data from the training cohort indicated that serum SCC-ag level is an independent factor for neo-adjuvant chemotherapy (NACT) response. Analysis of the data from the validation cohort suggested that chemotherapy response could be more accurately predicted by SCC-ag than by magnetic resonance imaging (MRI) (sensitivity (Se): 0.944 vs. 0.794; specificity (Sp): 0.727 vs. 0.636; positive predictive value (PPV): 0.869 vs. 0.806; negative predictive value (NPV): 0.873 vs. 0.618; the area under ROC curve (AUC): 0.898 vs. 0.734). Combining SCC-ag with MRI was more powerful than MRI alone (Se: 0.952 vs. 0.794; Sp: 0.833 vs. 0.636; PPV: 0.916 vs. 0.806; NPV: 0.902 vs. 0.618; AUC: 0.950 vs. 0.734). Our study indicates that serum SCC-ag level is a sensitive and reliable measure to evaluate cervical cancer response to chemotherapy. Using SCC-ag in combination with MRI findings further improves the predictive power. PMID- 23349994 TI - Real-time loop-mediated isothermal amplification (RealAmp) for the species specific identification of Plasmodium vivax. AB - Plasmodium vivax infections remain a major source of malaria-related morbidity and mortality. Early and accurate diagnosis is an integral component of effective malaria control programs. Conventional molecular diagnostic methods provide accurate results but are often resource-intensive, expensive, have a long turnaround time and are beyond the capacity of most malaria-endemic countries. Our laboratory has recently developed a new platform called RealAmp, which combines loop-mediated isothermal amplification (LAMP) with a portable tube scanner real-time isothermal instrument for the rapid detection of malaria parasites. Here we describe new primers for the detection of P. vivax using the RealAmp method. Three pairs of amplification primers required for this method were derived from a conserved DNA sequence unique to the P. vivax genome. The amplification was carried out at 64 degrees C using SYBR Green or SYTO-9 intercalating dyes for 90 minutes with the tube scanner set to collect fluorescence signals at 1-minute intervals. Clinical samples of P. vivax and other human-infecting malaria parasite species were used to determine the sensitivity and specificity of the primers by comparing with an 18S ribosomal RNA based nested PCR as the gold standard. The new set of primers consistently detected laboratory-maintained isolates of P. vivax from different parts of the world. The primers detected P. vivax in the clinical samples with 94.59% sensitivity (95% CI: 87.48-98.26%) and 100% specificity (95% CI: 90.40-100%) compared to the gold standard nested-PCR method. The new primers also proved to be more sensitive than the published species-specific primers specifically developed for the LAMP method in detecting P. vivax. PMID- 23349995 TI - Analysis of four aberrometers for evaluating lower and higher order aberrations. AB - PURPOSE: To compare the measurements of lower and higher order aberrations (HOA) of 4 commonly used aberrometers. SETTING: Massachusetts Eye & Ear Infirmary, Boston, USA. DESIGN: Prospective, cross-sectional study, in a controlled, single blinded fashion. METHODS: Multiple readings were obtained in 42 eyes of 21 healthy volunteers, at a single visit, with each of the following aberrometers: Alcon LADARWave(r), Visx WaveScan(r), B & L Zywave(r), and Wavelight Allegro Analyzer(r). Results were compared and analyzed in regards to the lower and HOA, to the different wavefront sensing devices and software, Tscherning and Hartmann Shack and between the Fourier and Zernike algorithms. Statistical analysis included Bland-Altman plots, Intraclass Correlation Coefficient (ICC), multiple comparison tests with Analysis of Variance and Kruskal-Wallis. Significant level was set to p<0.05 and alpha level correction was adjusted under the Bonferroni criteria. RESULTS: Most measurements of all 4 aberrometers were comparable. However, statistically significant differences were found between the aberrometers in total HOA (tHOA), spherical aberration (SA), horizontal coma and astigmatism (2,2). LADARwave and Wavescan showed significant differences in tHOA (P<0.001, ICC = 0.549, LoA = 0.19+/-0.5) and in SA (P<0.001, ICC = 0.733, LoA = 0.16+/-0.37). Wavescan showed a significant difference compared to Zywave (p<0.001, ICC = 0.920, LoA = 0.09+/-0.13) in SA. Comparisons between Allegro Analyzer and Zywave demonstrated significant differences in both Horizontal Coma (3,1) (p<0.001, ICC = -0.207, LoA = -0.15+/-0.48) and Astigmatism (2,2) (P = 0.003, ICC = -0.965, LoA = 0.2+/-2.5). Allegro Analyzer also differed from Wavescan in Horizontal Coma (3,1) (P<0.001, ICC = 0.725, LoA = -0.07+/-0.25). CONCLUSIONS: Although some measurements were comparable predominately in the lower order aberrations, significant differences were found in the tHOA, SA, horizontal coma and astigmatism. Our analysis suggests that sensor design contributes to agreement in lower order aberrations, and Fourier and Zernike expansion might disagree in higher order aberrations. Therefore, comparison between aberrometers was generally possible with some exceptions in higher order measurements. PMID- 23349996 TI - Construction of improved tools for protein localization studies in Streptococcus pneumoniae. AB - We have constructed a set of plasmids that allow efficient expression of both N- and C-terminal fusions of proteins of interest to fluorescent proteins mCherry, Citrine, CFP and GFP in the Gram-positive pathogen Streptococcus pneumoniae. In order to improve expression of the fluorescent fusions to levels that allow their detection by fluorescence microscopy, we have introduced a 10 amino acid tag, named i-tag, at the N-terminal end of the fluorescent proteins. This caused increased expression due to improved translation efficiency and did not interfere with the protein localization in pneumococcal bacteria. Localizing fluorescent derivatives of FtsZ, Wzd and Wze in dividing bacteria validated the developed tools. The availability of the new plasmids described in this work should greatly facilitate studies of protein localization in an important clinical pathogen. PMID- 23349997 TI - Improving access to anti-schistosome treatment and care in nonendemic areas of China: lessons from one case of advanced schistosomiasis japonica. PMID- 23349998 TI - Immunosuppression and Chagas disease: a management challenge. AB - Immunosuppression, which has become an increasingly relevant clinical condition in the last 50 years, modifies the natural history of Trypanosoma cruzi infection in most patients with Chagas disease. The main goal in this setting is to prevent the consequences of reactivation of T. cruzi infection by close monitoring. We analyze the relationship between Chagas disease and three immunosuppressant conditions, including a description of clinical cases seen at our center, a brief review of the literature, and recommendations for the management of these patients based on our experience and on the data in the literature. T. cruzi infection is considered an opportunistic parasitic infection indicative of AIDS, and clinical manifestations of reactivation are more severe than in acute Chagas disease. Parasitemia is the most important defining feature of reactivation. Treatment with benznidazole and/or nifurtimox is strongly recommended in such cases. It seems reasonable to administer trypanocidal treatment only to asymptomatic immunosuppressed patients with detectable parasitemia, and/or patients with clinically defined reactivation. Specific treatment for Chagas disease does not appear to be related to a higher incidence of neoplasms, and a direct role of T. cruzi in the etiology of neoplastic disease has not been confirmed. Systemic immunosuppressive diseases or immunosuppressants can modify the natural course of T. cruzi infection. Immunosuppressive doses of corticosteroids have not been associated with higher rates of reactivation of Chagas disease. Despite a lack of evidence-based data, treatment with benznidazole or nifurtimox should be initiated before immunosuppression where possible to reduce the risk of reactivation. Timely antiparasitic treatment with benznidazole and nifurtimox (or with posaconazole in cases of therapeutic failure) has proven to be highly effective in preventing Chagas disease reactivation, even if such treatment has not been formally incorporated into management protocols for immunosuppressed patients. International consensus guidelines based on expert opinion would greatly contribute to standardizing the management of immunosuppressed patients with Chagas disease. PMID- 23349999 TI - Arginase activity in the blood of patients with visceral leishmaniasis and HIV infection. AB - BACKGROUND: Visceral leishmaniasis is a parasitic disease associated with high mortality. The most important foci of visceral leishmaniasis in Ethiopia are in the Northwest and are predominantly associated with high rates of HIV co infection. Co-infection of visceral leishmaniasis patients with HIV results in higher mortality, treatment failure and relapse. We have previously shown that arginase, an enzyme associated with immunosuppression, was increased in patients with visceral leishmaniasis and in HIV seropositive patients; further our results showed that high arginase activity is a marker of disease severity. Here, we tested the hypothesis that increased arginase activities associated with visceral leishmaniasis and HIV infections synergize in patients co-infected with both pathogens. METHODOLOGY/PRINCIPAL FINDINGS: We recruited a cohort of patients with visceral leishmaniasis and a cohort of patients with visceral leishmaniasis and HIV infection from Gondar, Northwest Ethiopia, and recorded and compared their clinical data. Further, we measured the levels of arginase activity in the blood of these patients and identified the phenotype of arginase-expressing cells. Our results show that CD4(+) T cell counts were significantly lower and the parasite load in the spleen was significantly higher in co-infected patients. Moreover, our results demonstrate that arginase activity was significantly higher in peripheral blood mononuclear cells and plasma of co-infected patients. Finally, we identified the cells-expressing arginase in the PBMCs as low-density granulocytes. CONCLUSION: Our results suggest that increased arginase might contribute to the poor disease outcome characteristic of patients with visceral leishmaniasis and HIV co-infection. PMID- 23350000 TI - Frequent in-migration and highly focal transmission of dengue viruses among children in Kamphaeng Phet, Thailand. AB - Revealing the patterns and determinants of the spread of dengue virus (DENV) at local scales is central to understanding the epidemiology and evolution of this major human pathogen. We performed a phylogenetic analysis of the envelope (E) genes of DENV-1, -2, -3, and -4 isolates (involving 97, 23, 5, and 74 newly collected sequences, respectively) sampled from school-based cohort and village based cluster studies in Kamphaeng Phet, Thailand, between 2004 and 2007. With these data, we sought to describe the spatial and temporal patterns of DENV spread within a rural population where a future vaccine efficacy trial is planned. Our analysis revealed considerable genetic diversity within the study population, with multiple lineages within each serotype circulating for various lengths of time during the study period. These results suggest that DENV is frequently introduced into both semi-urban and rural areas in Kamphaeng Phet from other populations. In contrast, the persistence of viral lineages across sampling years was observed less frequently. Analysis of phylogenetic clustering indicated that DENV transmission was highly spatially and temporally focal, and that it occurred in homes rather than at school. Overall, the strength of temporal clustering suggests that seasonal bottlenecks in local DENV populations facilitate the invasion and establishment of viruses from outside of the study area, in turn reducing the extent of lineage persistence. PMID- 23350001 TI - Point-of-care laboratory of pathogen diagnosis in rural Senegal. AB - BACKGROUND: In tropical Africa, where the spectrum of the bacterial pathogens that cause fevers is poorly understood and molecular-based diagnostic laboratories are rare, the time lag between test results and patient care is a critical point for treatment of disease. METHODOLOGY/PRINCIPAL FINDINGS: We implemented POC laboratory in rural Senegal to resolve the time lag between test results and patient care. During the first year of the study (February 2011 to January 2012), 440 blood specimens from febrile patients were collected in Dielmo and Ndiop villages. All samples were screened for malaria, dengue fever, Borrelia spp., Coxiella burnetii, Tropheryma whipplei, Rickettsia conorii, R. africae, R. felis, and Bartonella spp. CONCLUSIONS/SIGNIFICANCE: We identified DNA from at least one pathogenic bacterium in 80/440 (18.2%) of the samples from febrile patients. B. crocidurae was identified in 35 cases (9.5%), and R. felis DNA was found in 30 cases (6.8%). The DNA of Bartonella spp. was identified in 23/440 cases (4.3%), and DNA of C. burnetii was identified in 2 cases (0.5%). T. whipplei (0.2%) was diagnosed in one patient. No DNA of R. africae or R. conorii was identified. Among the 7 patients co-infected by two different bacteria, we found R. felis and B. crocidurae in 4 cases, B. crocidurae and Bartonella spp. in 2 cases, and B. crocidurae and C. burnetii in 1 case. Malaria was diagnosed in 54 cases. In total, at least one pathogen (bacterium or protozoa) was identified in 127/440 (28.9%) of studied samples. Here, the authors report the proof of concept of POC in rural tropical Africa. Discovering that 18.2% of acute infections can be successfully treated with doxycycline should change the treatment strategy for acute fevers in West Africa. PMID- 23350002 TI - Analytical performance of a multiplex Real-Time PCR assay using TaqMan probes for quantification of Trypanosoma cruzi satellite DNA in blood samples. AB - BACKGROUND: The analytical validation of sensitive, accurate and standardized Real-Time PCR methods for Trypanosoma cruzi quantification is crucial to provide a reliable laboratory tool for diagnosis of recent infections as well as for monitoring treatment efficacy. METHODS/PRINCIPAL FINDINGS: We have standardized and validated a multiplex Real-Time quantitative PCR assay (qPCR) based on TaqMan technology, aiming to quantify T. cruzi satellite DNA as well as an internal amplification control (IAC) in a single-tube reaction. IAC amplification allows rule out false negative PCR results due to inhibitory substances or loss of DNA during sample processing. The assay has a limit of detection (LOD) of 0.70 parasite equivalents/mL and a limit of quantification (LOQ) of 1.53 parasite equivalents/mL starting from non-boiled Guanidine EDTA blood spiked with T. cruzi CL-Brener stock. The method was evaluated with blood samples collected from Chagas disease patients experiencing different clinical stages and epidemiological scenarios: 1- Sixteen Venezuelan patients from an outbreak of oral transmission, 2- Sixty three Bolivian patients suffering chronic Chagas disease, 3- Thirty four Argentinean cases with chronic Chagas disease, 4- Twenty seven newborns to seropositive mothers, 5- A seronegative receptor who got infected after transplantation with a cadaveric kidney explanted from an infected subject. CONCLUSIONS/SIGNIFICANCE: The performing parameters of this assay encourage its application to early assessment of T. cruzi infection in cases in which serological methods are not informative, such as recent infections by oral contamination or congenital transmission or after transplantation with organs from seropositive donors, as well as for monitoring Chagas disease patients under etiological treatment. PMID- 23350003 TI - Field cage studies and progressive evaluation of genetically-engineered mosquitoes. AB - BACKGROUND: A genetically-engineered strain of the dengue mosquito vector Aedes aegypti, designated OX3604C, was evaluated in large outdoor cage trials for its potential to improve dengue prevention efforts by inducing population suppression. OX3604C is engineered with a repressible genetic construct that causes a female-specific flightless phenotype. Wild-type females that mate with homozygous OX3604C males will not produce reproductive female offspring. Weekly introductions of OX3604C males eliminated all three targeted Ae. aegypti populations after 10-20 weeks in a previous laboratory cage experiment. As part of the phased, progressive evaluation of this technology, we carried out an assessment in large outdoor field enclosures in dengue endemic southern Mexico. METHODOLOGY/PRINCIPAL FINDINGS: OX3604C males were introduced weekly into field cages containing stable target populations, initially at 10:1 ratios. Statistically significant target population decreases were detected in 4 of 5 treatment cages after 17 weeks, but none of the treatment populations were eliminated. Mating competitiveness experiments, carried out to explore the discrepancy between lab and field cage results revealed a maximum mating disadvantage of up 59.1% for OX3604C males, which accounted for a significant part of the 97% fitness cost predicted by a mathematical model to be necessary to produce the field cage results. CONCLUSIONS/SIGNIFICANCE: Our results indicate that OX3604C may not be effective in large-scale releases. A strain with the same transgene that is not encumbered by a large mating disadvantage, however, could have improved prospects for dengue prevention. Insights from large outdoor cage experiments may provide an important part of the progressive, stepwise evaluation of genetically-engineered mosquitoes. PMID- 23350004 TI - The laboratory diagnosis and follow up of strongyloidiasis: a systematic review. AB - BACKGROUND: Strongyloidiasis is frequently under diagnosed since many infections remain asymptomatic and conventional diagnostic tests based on parasitological examination are not sufficiently sensitive. Serology is useful but is still only available in reference laboratories. The need for improved diagnostic tests in terms of sensitivity and specificity is clear, particularly in immunocompromised patients or candidates to immunosuppressive treatments. This review aims to evaluate both conventional and novel techniques for the diagnosis of strongyloidiasis as well as available cure markers for this parasitic infection. METHODOLOGY/PRINCIPAL FINDINGS: The search strategy was based on the data-base sources MEDLINE, Cochrane Library Register for systematic review, EmBase, Global Health and LILACS and was limited in the search string to articles published from 1960 to August 2012 and to English, Spanish, French, Portuguese and German languages. Case reports, case series and animal studies were excluded. 2003 potentially relevant citations were selected for retrieval, of which 1649 were selected for review of the abstract. 143 were eligible for final inclusion. CONCLUSIONS: Sensitivity of microscopic-based techniques is not good enough, particularly in chronic infections. Furthermore, techniques such as Baermann or agar plate culture are cumbersome and time-consuming and several specimens should be collected on different days to improve the detection rate. Serology is a useful tool but it might overestimate the prevalence of disease due to cross reactivity with other nematode infections and its difficulty distinguishing recent from past (and cured) infections. To evaluate treatment efficacy is still a major concern because direct parasitological methods might overestimate it and the serology has not yet been well evaluated; even if there is a decline in antibody titres after treatment, it is slow and it needs to be done at 6 to 12 months after treatment which can cause a substantial loss to follow-up in a clinical trial. PMID- 23350005 TI - Syndromic algorithms for detection of gambiense human African trypanosomiasis in South Sudan. AB - BACKGROUND: Active screening by mobile teams is considered the best method for detecting human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense but the current funding context in many post-conflict countries limits this approach. As an alternative, non-specialist health care workers (HCWs) in peripheral health facilities could be trained to identify potential cases who need testing based on their symptoms. We explored the predictive value of syndromic referral algorithms to identify symptomatic cases of HAT among a treatment-seeking population in Nimule, South Sudan. METHODOLOGY/PRINCIPAL FINDINGS: Symptom data from 462 patients (27 cases) presenting for a HAT test via passive screening over a 7 month period were collected to construct and evaluate over 14,000 four item syndromic algorithms considered simple enough to be used by peripheral HCWs. For comparison, algorithms developed in other settings were also tested on our data, and a panel of expert HAT clinicians were asked to make referral decisions based on the symptom dataset. The best performing algorithms consisted of three core symptoms (sleep problems, neurological problems and weight loss), with or without a history of oedema, cervical adenopathy or proximity to livestock. They had a sensitivity of 88.9-92.6%, a negative predictive value of up to 98.8% and a positive predictive value in this context of 8.4-8.7%. In terms of sensitivity, these out-performed more complex algorithms identified in other studies, as well as the expert panel. The best-performing algorithm is predicted to identify about 9/10 treatment-seeking HAT cases, though only 1/10 patients referred would test positive. CONCLUSIONS/SIGNIFICANCE: In the absence of regular active screening, improving referrals of HAT patients through other means is essential. Systematic use of syndromic algorithms by peripheral HCWs has the potential to increase case detection and would increase their participation in HAT programmes. The algorithms proposed here, though promising, should be validated elsewhere. PMID- 23350006 TI - Chikungunya fever: a clinical and virological investigation of outpatients on Reunion Island, South-West Indian Ocean. AB - BACKGROUND: Chikungunya virus (CHIKV) is responsible for acute febrile polyarthralgia and, in a proportion of cases, severe complications including chronic arthritis. CHIKV has spread recently in East Africa, South-West Indian Ocean, South-Asia and autochthonous cases have been reported in Europe. Although almost all patients are outpatients, medical investigations mainly focused on hospitalised patients. METHODOLOGY/PRINCIPAL FINDINGS: Here, we detail clinico biological characteristics of Chikungunya (CHIK) outpatients in Reunion Island (2006). 76 outpatients with febrile arthralgia diagnosed within less than 48 hours were included by general practitioners during the CuraChik clinical trial. CHIK was confirmed in 54 patients and excluded in 22. A detailed clinical and biological follow-up was organised, that included analysis of viral intrahost diversity and telephone survey until day 300. The evolution of acute CHIK included 2 stages: the 'viral stage' (day 1-day 4) was associated with rapid decrease of viraemia and improvement of clinical presentation; the 'convalescent stage' (day 5-day 14) was associated with no detectable viraemia but a slower clinical improvement. Women and elderly had a significantly higher number of arthralgia at inclusion and at day 300. Based on the study clinico-biological dataset, scores for CHIK diagnosis in patients with recent febrile acute polyarthralgia were elaborated using arthralgia on hands and wrists, a minor or absent myalgia and the presence of lymphopenia (<1G/L) as major orientation criteria. Finally, we observed that CHIKV intra-host genetic diversity increased over time and that a higher viral amino-acid complexity at the acute stage was associated with increased number of arthralgia and intensity of sequelae at day 300. CONCLUSIONS/SIGNIFICANCE: This study provided a detailed picture of clinico biological CHIK evolution at the acute phase of the disease, allowed the elaboration of scores to assist CHIK diagnosis and investigated for the first time the impact of viral intra-host genetic diversity on the disease course. PMID- 23350007 TI - Bispidine-amino acid conjugates act as a novel scaffold for the design of antivirals that block Japanese encephalitis virus replication. AB - BACKGROUND: Japanese encephalitis virus (JEV) is a major cause of viral encephalitis in South and South-East Asia. Lack of antivirals and non availability of affordable vaccines in these endemic areas are a major setback in combating JEV and other closely related viruses such as West Nile virus and dengue virus. Protein secondary structure mimetics are excellent candidates for inhibiting the protein-protein interactions and therefore serve as an attractive tool in drug development. We synthesized derivatives containing the backbone of naturally occurring lupin alkaloid, sparteine, which act as protein secondary structure mimetics and show that these compounds exhibit antiviral properties. METHODOLOGY/PRINCIPAL FINDINGS: In this study we have identified 3,7 diazabicyclo[3.3.1]nonane, commonly called bispidine, as a privileged scaffold to synthesize effective antiviral agents. We have synthesized derivatives of bispidine conjugated with amino acids and found that hydrophobic amino acid residues showed antiviral properties against JEV. We identified a tryptophan derivative, Bisp-W, which at 5 uM concentration inhibited JEV infection in neuroblastoma cells by more than 100-fold. Viral inhibition was at a stage post entry and prior to viral protein translation possibly at viral RNA replication. We show that similar concentration of Bisp-W was capable of inhibiting viral infection of two other encephalitic viruses namely, West Nile virus and Chandipura virus. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that the amino acid conjugates of 3,7-diazabicyclo[3.3.1]nonane can serve as a molecular scaffold for development of potent antivirals against encephalitic viruses. Our findings will provide a novel platform to develop effective inhibitors of JEV and perhaps other RNA viruses causing encephalitis. PMID- 23350008 TI - Naphthoquinone derivatives exert their antitrypanosomal activity via a multi target mechanism. AB - BACKGROUND AND METHODOLOGY: Recently, we reported on a new class of naphthoquinone derivatives showing a promising anti-trypanosomatid profile in cell-based experiments. The lead of this series (B6, 2-phenoxy-1,4 naphthoquinone) showed an ED(50) of 80 nM against Trypanosoma brucei rhodesiense, and a selectivity index of 74 with respect to mammalian cells. A multitarget profile for this compound is easily conceivable, because quinones, as natural products, serve plants as potent defense chemicals with an intrinsic multifunctional mechanism of action. To disclose such a multitarget profile of B6, we exploited a chemical proteomics approach. PRINCIPAL FINDINGS: A functionalized congener of B6 was immobilized on a solid matrix and used to isolate target proteins from Trypanosoma brucei lysates. Mass analysis delivered two enzymes, i.e. glycosomal glycerol kinase and glycosomal glyceraldehyde-3 phosphate dehydrogenase, as potential molecular targets for B6. Both enzymes were recombinantly expressed and purified, and used for chemical validation. Indeed, B6 was able to inhibit both enzymes with IC(50) values in the micromolar range. The multifunctional profile was further characterized in experiments using permeabilized Trypanosoma brucei cells and mitochondrial cell fractions. It turned out that B6 was also able to generate oxygen radicals, a mechanism that may additionally contribute to its observed potent trypanocidal activity. CONCLUSIONS AND SIGNIFICANCE: Overall, B6 showed a multitarget mechanism of action, which provides a molecular explanation of its promising anti trypanosomatid activity. Furthermore, the forward chemical genetics approach here applied may be viable in the molecular characterization of novel multitarget ligands. PMID- 23350009 TI - Perceptions on the effectiveness of treatment and the timeline of Buruli ulcer influence pre-hospital delay reported by healthy individuals. AB - BACKGROUND: Delay in seeking treatment at the hospital is a major challenge in current Buruli ulcer control; it is associated with severe sequelae and functional limitations. Choosing alternative treatment and psychological, social and practical factors appear to influence delay. Objectives were to determine potential predictors for pre-hospital delay with Leventhal's commonsense model of illness representations, and to explore whether the type of available dominant treatment modality influenced individuals' perceptions about BU, and therefore, influenced pre-hospital delay. METHODOLOGY: 130 healthy individuals aged >18 years, living in BU-endemic areas in Benin without any history of BU were included in this cross-sectional study. Sixty four participants from areas where surgery was the dominant treatment and sixty six participants from areas where antibiotic treatment was the dominant treatment modality were recruited. Using a semi-structured interview we measured illness perceptions (IPQ-R), knowledge about BU, background variables and estimated pre-hospital delay. PRINCIPAL FINDINGS: The individual characteristics 'effectiveness of treatment' and 'timeline acute-chronic' showed the strongest association with pre-hospital delay. No differences were found between regions where surgery was the dominant treatment and regions where antibiotics were the dominant treatment modality. CONCLUSIONS: Individual characteristics, not anticipated treatment modality appeared predictors of pre-hospital delay. PMID- 23350010 TI - PARK2 mediates interleukin 6 and monocyte chemoattractant protein 1 production by human macrophages. AB - Leprosy is a persistent infectious disease caused by Mycobacterium leprae that still affects over 200,000 new patients annually. The host genetic background is an important risk factor for leprosy susceptibility and the PARK2 gene is a replicated leprosy susceptibility candidate gene. The protein product of PARK2, Parkin, is an E3 ubiquitin ligase that is involved in the development of various forms of Parkinsonism. The human macrophage is both a natural host cell of M. leprae as well as a primary mediator of natural immune defenses, in part by secreting important pro-inflammatory cytokines and chemokines. Here, we report that down-regulation of Parkin in THP-1 macrophages, human monocyte-derived macrophages and human Schwann cells resulted in a consistent and specific decrease in interleukin-6 (IL-6) and monocyte chemoattractant protein 1 (MCP 1/CCL2) production in response to mycobacteria or LPS. Interestingly, production of IL-6 at 6 hours by THP-1 cells stimulated with live M. leprae and M. bovis BCG was dependent on pretreatment with 1,25-dihydroxyvitamin D(3) (VD). Parkin knockdown in VD-treated cells blocked IL-6 induction by mycobacteria. However, IkappaB-alpha phosphorylation and levels of IkappaB-xi, a nuclear protein required for IL-6 expression, were not affected by Parkin silencing. Phosphorylation of MAPK ERK1/2 and p38 was unaffected by Parkin silencing while JNK activation was promoted but did not explain the altered cytokine production. In a final set of experiments we found that genetic risk factors of leprosy located in the PARK2 promoter region were significantly correlated with M. leprae sonicate triggered CCL2 and IL6 transcript levels in whole blood assays. These results associated genetically controlled changes in the production of MCP-1/CCL2 and IL-6 with known leprosy susceptibility factors. PMID- 23350011 TI - A multiplex PCR for the simultaneous detection and genotyping of the Echinococcus granulosus complex. AB - Echinococcus granulosus is characterized by high intra-specific variability (genotypes G1-G10) and according to the new molecular phylogeny of the genus Echinococcus, the E. granulosus complex has been divided into E. granulosus sensu stricto (G1-G3), E. equinus (G4), E. ortleppi (G5), and E. canadensis (G6-G10). The molecular characterization of E. granulosus isolates is fundamental to understand the spatio-temporal epidemiology of this complex in many endemic areas with the simultaneous occurrence of different Echinococcus species and genotypes. To simplify the genotyping of the E. granulosus complex we developed a single tube multiplex PCR (mPCR) allowing three levels of discrimination: (i) Echinococcus genus, (ii) E. granulosus complex in common, and (iii) the specific genotype within the E. granulosus complex. The methodology was established with known DNA samples of the different strains/genotypes, confirmed on 42 already genotyped samples (Spain: 22 and Bulgaria: 20) and then successfully applied on 153 unknown samples (Tunisia: 114, Algeria: 26 and Argentina: 13). The sensitivity threshold of the mPCR was found to be 5 ng Echinoccoccus DNA in a mixture of up to 1 ug of foreign DNA and the specificity was 100% when template DNA from closely related members of the genus Taenia was used. Additionally to DNA samples, the mPCR can be carried out directly on boiled hydatid fluid or on alkaline-lysed frozen or fixed protoscoleces, thus avoiding classical DNA extractions. However, when using Echinococcus eggs obtained from fecal samples of infected dogs, the sensitivity of the mPCR was low (<40%). Thus, except for copro analysis, the mPCR described here has a high potential for a worldwide application in large-scale molecular epidemiological studies on the Echinococcus genus. PMID- 23350013 TI - Utilities and limitations of the World Health Organization 2009 warning signs for adult dengue severity. AB - BACKGROUND: In 2009, the World Health Organization (WHO) proposed seven warning signs (WS) as criteria for hospitalization and predictors of severe dengue (SD). We assessed their performance for predicting dengue hemorrhagic fever (DHF) and SD in adult dengue. METHOD: DHF, WS and SD were defined according to the WHO 1997 and 2009 dengue guidelines. We analyzed the prevalence, sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of WS before DHF and SD onset. RESULTS: Of 1507 cases, median age was 35 years (5(th)-95(th) percentile, 17-60), illness duration on admission 4 days (5(th)-95(th) percentile, 2-6) and length of hospitalization 5 days (5(th)-95(th) percentile, 3-7). DHF occurred in 298 (19.5%) and SD in 248 (16.5%). Of these, WS occurred before DHF in 124 and SD in 65 at median of two days before DHF or SD. Three commonest warning signs were lethargy, abdominal pain/tenderness and mucosal bleeding. No single WS alone or combined had Sn >64% in predicting severe disease. Specificity was >90% for both DHF and SD with persistent vomiting, hepatomegaly, hematocrit rise and rapid platelet drop, clinical fluid accumulation, and any 3 or 4 WS. Any one of seven WS had 96% Sn but only 18% Sp for SD. CONCLUSIONS: No WS was highly sensitive in predicting subsequent DHF or SD in our confirmed adult dengue cohort. Persistent vomiting, hepatomegaly, hematocrit rise and rapid platelet drop, and clinical fluid accumulation, as well as any 3 or 4 WS were highly specific for DHF or SD. PMID- 23350012 TI - Antigenicity and diagnostic potential of vaccine candidates in human Chagas disease. AB - BACKGROUND: Chagas disease, caused by Trypanosoma cruzi, is endemic in Latin America and an emerging infectious disease in the US and Europe. We have shown TcG1, TcG2, and TcG4 antigens elicit protective immunity to T. cruzi in mice and dogs. Herein, we investigated antigenicity of the recombinant proteins in humans to determine their potential utility for the development of next generation diagnostics for screening of T. cruzi infection and Chagas disease. METHODS AND RESULTS: Sera samples from inhabitants of the endemic areas of Argentina-Bolivia and Mexico-Guatemala were analyzed in 1(st)-phase for anti-T. cruzi antibody response by traditional serology tests; and in 2(nd)-phase for antibody response to the recombinant antigens (individually or mixed) by an ELISA. We noted similar antibody response to candidate antigens in sera samples from inhabitants of Argentina and Mexico (n=175). The IgG antibodies to TcG1, TcG2, and TcG4 (individually) and TcG(mix) were present in 62-71%, 65-78% and 72-82%, and 89-93% of the subjects, respectively, identified to be seropositive by traditional serology. Recombinant TcG1- (93.6%), TcG2- (96%), TcG4- (94.6%) and TcG(mix)- (98%) based ELISA exhibited significantly higher specificity compared to that noted for T. cruzi trypomastigote-based ELISA (77.8%) in diagnosing T. cruzi infection and avoiding cross-reactivity to Leishmania spp. No significant correlation was noted in the sera levels of antibody response and clinical severity of Chagas disease in seropositive subjects. CONCLUSIONS: Three candidate antigens were recognized by antibody response in chagasic patients from two distinct study sites and expressed in diverse strains of the circulating parasites. A multiplex ELISA detecting antibody response to three antigens was highly sensitive and specific in diagnosing T. cruzi infection in humans, suggesting that a diagnostic kit based on TcG1, TcG2 and TcG4 recombinant proteins will be useful in diverse situations. PMID- 23350014 TI - Age at diagnosis of sickle cell anaemia in lagos, Nigeria. AB - BACKGROUND: Sickle cell anaemia is the most common genetic disorder worldwide as well as in Nigeria. Delay in the diagnosis of the condition constitutes an important cause of concern for caretakers of affected children. OBJECTIVE: To determine the age at diagnosis in a population of children with sickle cell anaemia in Lagos, Nigeria. METHODOLOGY: The study was conducted between October and December 2009 at the sickle cell clinic of the Department of Paediatrics of Lagos State University Teaching Hospital, Ikeja, Lagos in South west Nigeria. By convenience sampling, a total of 192 children with sickle cell anaemia aged six months to 15 years were interviewed with the aid of a structured questionnaire. RESULTS: Overall, the mean age at confirmation of haemoglobin genotype was 27.33 months (+/- 26. 36 months). The mean age at diagnosis was significantly lower among males than females (25.59 +/- 27.74 Vs. 29.14 +/- 24.85, p = 0.04). A quarter of the children were diagnosed before infancy and three-quarters before three years of age. Upper social stratum and small family size were significantly associated with earlier diagnosis of sickle cell anaemia. CONCLUSION: Too few subjects are diagnosed in infancy. Routine screening should ideally be done at birth and neonatal period or at the latest, between six and nine months. PMID- 23350015 TI - Beta thalassemia major in a developing country: epidemiological, clinical and evolutionary aspects. AB - Beta-thalassemia major (TM) remains to be one of the major health problems particularly in developing countries. Tunisia is a part of the Mediterranean countries mostly affected by this disease which is highly concentrated in small towns in families with low-income earners. The main objectives of this study are to provide a description of the demographic, clinical features and transfusion related complications in patients with TM living in Tunisia. A standardized questionnaire was sent to clinicians throughout 33 different medical institutions caring for thalassemic patients. 391 transfusion dependant thalassemic patients with a median age of 10.7 years (range 3 months- 31 years) were included in the study. The majority originated from the north west of the country. A moderate iron overload between 1501 and 2500 ng/ml was found in 61patients, while 81 patients (26.9%) had a ferritin level more than 2500 ng/ml and greater than 5000ng/ml in 21 patients (6.9%). 51 patients died from complications related to their disease. Heart failure was the main cause of death. The incidence of cardiac, endocrine, and infectious complications will be reviewed. Preventive measures such as health education, carrier screening and premarital screening remain the best ways for lowering the incidence of these diseases, which might be reflected in financial saving, social s and health benefits. PMID- 23350016 TI - Genetic Heterogeneity of Beta Globin Mutations among Asian-Indians and Importance in Genetic Counselling and Diagnosis. AB - There are an estimated 45 million carriers of beta-thalassemia trait and about 12,000-15,000 infants with beta-thalassemia major are born every year in India. Thalassemia major constitutes a significant burden on the health care system. The burden of thalassemia major can be decreased by premarital screening and prenatal diagnosis. The success of prenatal diagnosis requires proper knowledge of spectrum of beta-thalassemia mutations. In present study, beta-thalassemia mutations were characterized in 300 thalassemia cases from 2007 to 2010 using ARMS-PCR and DNA sequencing. The five most common mutations accounted 78.9% of the studied chromosomes that includes IVS1-5(G>C), Cod 41-42(-TCTT), Cod8-9(+G), Cod16(-C) and 619bp del. Though IVS1-5(G>C) is most common mutation in all the communities, the percentage prevalence were calculated on sub caste basis and found that IVS1-5(G>C) percentage prevalence varied from 25 to 60 in Aroras & Khatris and Thakur respectively. Interestingly Cod41-42(-TCTT) mutation which is the second commonest among the mutations reported was totally absent in Kayasthas and Muslim community. These findings have implications for providing molecular diagnosis, genetic counseling and prenatal diagnosis to high risk couples of beta thalassemia. PMID- 23350017 TI - Circumcision in males with bleeding disorders. AB - INTRODUCTION: Male circumcision practice is an invasive procedure that is using worldwide. It makes challenges to haemostatic system and its possible haemorrhagic side effects are more serious in bleeding individuals than normal subjects. In most cases, it can be complete controlled using infusion of appropriate amount of coagulation factors before and post circumcision. AIM: We aim to documentation type of coagulation therapy and post circumcision practice haemorrhagic presentation among 463 bleeder males of both common and rare bleeding disorders in north eastern part of country. METHODS: We retrospectively gathered information using evaluation medical records in 3 major hospitals during last 15 years and list of patients with bleeding disorders that obtained from haemophilia center. Also a call phone established for each bleeder person to complete data and updating of them. The survey took time from Sep 2009 - Mar 2011. The designed question form included data on doing circumcision or not, types of treatment before and post the procedure and occurrence of bleeding episodes after the surgery. RESULTS: Overall among 424 cases with various common and rare bleeding disorders who had circumcised, 239 cases (56.3%) had passed the procedure with bleeding experience (indication of undiagnosed cases who underwent circumcision or inadequacy of coagulation therapy), while 185 cases (43.7%) had passed it successfully and without noticeable bleeding experience. The types of coagulation therapy in each group have been cited. CONCLUSION: The circumcision practice in unequipped medical center for bleeder ones may make challenges for them and medical services. Also it needed supervision of expert haematologist for. PMID- 23350018 TI - Skin involvement in primary systemic amyloidosis. AB - Primary systemic amyloidosis is a rare disease. It primarily involves kidney, heart, peripheral nerves and liver. Intracutaneous hemorrhage manifesting in the form of petechiae, purpura and ecchymoses due to infiltration of blood vessel walls by amyloid deposits are the most common skin lesions. We report a case of primary systemic amyloidosis with multiple, non-itchy, papular lesions in lower eyelids and lower chest wall bilaterally. Diagnosis was confirmed in this case by biopsy of skin lesions using congo red staining. Papular eruptions as seen in index patient are relatively uncommon form of skin manifestations. PMID- 23350019 TI - Successful Treatment of Gastric Relapse in Multiple Myeloma with Bortezomib after Autologous Hematopoietic Stem Cell Transplantation (autoHSCT). AB - We report a case of 59-year-old Turkish man with history of mitral valve replacement (MVR) and chronic obstructive pulmonary disease (COPD) who was diagnosed with stage IIIA IgG lambda multiple myeloma (MM) in 1997. He underwent autologous hematopoietic stem cell transplantation after a conditioning regimen with melphalan 200mg per body area (m(2)) in February 2006. On February 2011, he was admitted to the emergency service of university hospital with complaints of hematemesis and melena. Pathological evaluation of gastric biopsy, obtained from a lesion of small gastric curvature, showed the gastric mucosa infiltrated by neoplastic plasma cells, monoclonal lambda light chain positive. The patient was considered as having local gastric relapsed disease and was treated with 2 cycles of bortezomib. He achieved an excellent local response after 2 cycles of bortezomib, cyclophosphamide and prednisone (BEP) regimen, with healing of gastric ulcer and no recurrence of the hematemesis or melena. PMID- 23350020 TI - Early Application of High Cut-Off Haemodialysis for de-Novo Myeloma Nephropathy is Associated with Long-Term Dialysis-Independency and Renal Recovery. AB - BACKGROUND: Multiple myeloma (MM) is a haematological malignancy associated with kidney injury resulting from cast nephropathy, which can be caused by monoclonal free light chains (FLC). It has been demonstrated that early reduction of FLC can lead to a higher proportion of patients recovering renal function with a better outcome, especially if high cut-off haemodialysis (HCO-HD) combined with chemotherapy is used. PATIENTS AND METHODS: In this study, four cases with MM nephropathy were treated with HCO-HD and chemotherapy at a single institution during the period from August 2009 to August 2011. All of the patients presented with acute renal failure and high serum FLC. All patients underwent a bone marrow biopsy to confirm the diagnosis of MM, according to the WHO criteria. Three patients had de novo MM and one patient had relapsed light chain myeloma disease. All patients underwent HCO-HD concomitantly with specific myeloma therapy once the diagnosis or relapse of MM was established. RESULTS: After a medial follow up of 26 months, (range, 13-36) our data showed that all patients had a significant decrease in serum FLC through HCO-HD, proving the effectiveness of HCO-HD in managing MM. De-novo MM patients restored their renal function and achieved low level FLC early in the treatment and became dialysis-independent. One patient with relapsed myeloma remained dialysis-dependent. CONCLUSION: In summary, our study suggests that in myeloma nephropathy associated with light-chain MM, HCO-HD should be initiated as early as possible. At the same time a specific MM treatment should be initiated to gain control of the disease and salvage the kidneys in order to achieve dialysis-independency. Further randomized trials to confirm our results are warranted. PMID- 23350021 TI - An urologic face of chronic lymphocytic leukemia: sequential prostatic and penis localization. AB - We report a patient with chronic lymphocytic leukemia (CLL) in whom a leukemic involvement of prostate and penis occurred in the advanced phase of his disease. Obstructive urinary symptoms were indicative of prostatic CLL infiltration, followed by the occurrence of an ulcerative lesion on the glans. Histologic examination confirmed the neoplastic B-cell infiltration. Both localizations responded to conventional treatments. A review of the literature confirms that leukemic involvement of the genito-urinary system is uncommon in CLL patients. However, it should be considered in CLL patients with urologic symptoms and a long history of the disease. PMID- 23350022 TI - Role of haematological parameters as an indicator of acute malarial infection in uttarakhand state of India. AB - BACKGROUND: Malaria may be associated with complications which may be avoided by early diagnosis and treatment. Microscopic diagnosis showing presence of malarial parasites is needed for confirmation which at times may be unreliable and requires technical expertise. The present study was conducted to statistically analyze the haematological parameters including platelet indices which can give initial hint for malarial infection and therefore prompt the laboratory physician for active search of the parasite microscopically. METHODS: A retrospective study was conducted which included 334 cases of acute malaria caused by Plasmodium vivax, falciparum and dual infection along with 100 cases of control. Routine haematological parameters along with platelet indices (MPV and PDW) which are easily available on automated cell counter were statistically analyzed to assess their role as indicators for malaria. RESULTS: Leukocyte count and platelet count were significantly lower in cases of acute malaria in comparison to controls (p value <0.001). Platelet count<150*109/l showed 87.2% sensitivity, 65% specificity, 89.3% positive predictive value and 2.49 likelihood ratio for the infection. PDW of 6-10 and MPV>8 fl had 71.9% and 61.5% sensitivity and 78.2% and 77.7% positive predictive value respectively for infection. Platelet count <150*109/l and MPV>8 fl was comparatively more sensitive indicator for vivax (88% and 70.8% respectively) than falciparum (84.8% and 50.4% respectively) and PDW 6 10 was more sensitive indicator for falciparum (82.6%) than vivax (69.5%) infection. CONCLUSION: Thrombocytopenia (<150*109/l) and low leukocyte count (<4*109/l) may be used as probable indicator for malaria in endemic countries. Higher MPV (>8 fl) and PDW of 6-10 also show considerable sensitivity for malarial infection. In addition, thrombocytopenia (<150*109/l) and higher MPV (>8 fl) was more sensitive for vivax infection while PDW 6-10 was more sensitive for falciparum infection. PMID- 23350024 TI - Russeting in apple and pear: a plastic periderm replaces a stiff cuticle. AB - BACKGROUND AND AIMS: Russeting in apples (Malus * domestica Borkh.) and pears (Pyrus communis L.) is a disorder of the fruit skin that results from microscopic cracks in the cuticle and the subsequent formation of a periderm. To better understand russeting, rheological properties of cuticular membranes (CM) and periderm membranes (PM) were studied from the russet-sensitive apple 'Karmijn de Sonnaville' and from 'Conference' pear. METHODOLOGY: The CM and PM were isolated enzymatically, investigated by microscopy and subjected to tensile tests, creep/relaxation tests and to stepwise creep tests using a material testing machine. PRINCIPAL RESULTS: The isolated CM formed a continuous polymer, whereas the PM represented a cellular structure of stacked cork cells. Tensile tests revealed higher plasticity of the hydrated PM compared with the CM, as indicated by a higher strain at the maximum force (E(max)) and a lower modulus of elasticity (E). In apple, the maximum force (F(max)) was higher in the CM than in the PM but in pear the higher F(max) value was found for the PM. In specimens obtained from the CM : PM transition zone, the weak point in apple was found to be at the CM : PM borderline but in pear it was within the CM. In both apple and pear, creep/relaxation tests revealed elastic strain, creep strain, viscoelastic strain and viscous strain components in both the PM and CM. For any particular force, strains were always greater in the PM than in the CM and were also greater in pear than in apple. The E(max) and F(max) values of the CM and PM were lower than those of non-russeted and russeted whole-fruit skin segments, which included adhering tissue. CONCLUSIONS: In russeting, stiff CM are replaced by more plastic PM. Further, the cell layers underlying the CM and PM represent the load-bearing structure in the fruit skin in apple and pear. PMID- 23350023 TI - Malaria in pregnancy. AB - Pregnant women have a higher risk of malaria compared to non-pregnant women. This review provides an update on knowledge acquired since 2000 on P. falciparum and P.vivax infections in pregnancy. Maternal risk factors for malaria in pregnancy (MiP) include low maternal age, low parity, and low gestational age. The main effects of MIP include maternal anaemia, low birth weight (LBW), preterm delivery and increased infant and maternal mortality.P. falciparum infected erythrocytes sequester in the placenta by expressing surface antigens, mainly variant surface antigen (VAR2CSA), that bind to specific receptors, mainly chondroitin sulphate A. In stable transmission settings, the higher malaria risk in primigravidae can be explained by the non-recognition of these surface antigens by the immune system. Recently, placental sequestration has been described also for P.vivax infections. The mechanism of preterm delivery and intrauterine growth retardation is not completely understood, but fever (preterm delivery), anaemia, and high cytokines levels have been implicated.Clinical suspicion of MiP should be confirmed by parasitological diagnosis. The sensitivity of microscopy, with placenta histology as the gold standard, is 60% and 45% for peripheral and placental falciparum infections in African women, respectively. Compared to microscopy, RDTs have a lower sensitivity though when the quality of microscopy is low RDTs may be more reliable. Insecticide treated nets (ITN) and intermittent preventive treatment in pregnancy (IPTp) are recommended for the prevention of MiP in stable transmission settings. ITNs have been shown to reduce malaria infection and adverse pregnancy outcomes by 28-47%. Although resistance is a concern, SP has been shown to be equivalent to MQ and AQ for IPTp. For the treatment of uncomplicated malaria during the first trimester, quinine plus clindamycin for 7 days is the first line treatment and artesunate plus clindamycin for 7 days is indicated if this treatment fails; in the 2(nd) and 3(rd) trimester first line treatment is an artemisinin-based combination therapy (ACT) known to be effective in the region or artesunate and clindamycin for 7 days or quinine and clindamycin. For severe malaria, in the second and third trimester parenteral artesunate is preferred over quinine. In the first trimester, both artesunate and quinine (parenteral) may be considered as options. Nevertheless, treatment should not be delayed and should be started immediately with the most readily available drug. PMID- 23350026 TI - Visualizing hippocampal neurons with in vivo two-photon microscopy using a 1030 nm picosecond pulse laser. AB - In vivo two-photon microscopy has revealed vital information on neural activity for brain function, even in light of its limitation in imaging events at depths greater than several hundred micrometers from the brain surface. We developed a novel semiconductor-laser-based light source with a wavelength of 1030 nm that can generate pulses of 5-picosecond duration with 2-W output power, and a 20-MHz repetition rate. We also developed a system to secure the head of the mouse under an upright microscope stage that has a horizontal adjustment mechanism. We examined the penetration depth while imaging the H-Line mouse brain and demonstrated that our newly developed laser successfully images not only cortex pyramidal neurons spreading to all cortex layers at a superior signal-to background ratio, but also images hippocampal CA1 neurons in a young adult mouse. PMID- 23350027 TI - Carbon microfibers with hierarchical porous structure from electrospun fiber-like natural biopolymer. AB - Electrospinning offers a powerful route for building one-dimensional (1D) micro/nanostructures, but a common requirement for toxic or corrosive organic solvents during the preparation of precursor solution has limited their large scale synthesis and broad applications. Here we report a facile and low-cost way to prepare 1D porous carbon microfibers by using an electrospun fiber-like natural product, i.e., silk cocoon, as precursor. We surprisingly found that by utilizing a simple carbonization treatment, the cocoon microfiber can be directly transformed into 1D carbon microfiber of ca. 6 MUm diameter with a unique three dimensional porous network structure composed of interconnected carbon nanoparticles of 10~40 nm diameter. We further showed that the as-prepared carbon product presents superior electrochemical performance as binder-free electrodes of supercapacitors and good adsorption property toward organic vapor. PMID- 23350028 TI - Mass production of chemicals from biomass-derived oil by directly atmospheric distillation coupled with co-pyrolysis. AB - Production of renewable commodity chemicals from bio-oil derived from fast pyrolysis of biomass has received considerable interests, but hindered by the presence of innumerable components in bio-oil. In present work, we proposed and experimentally demonstrated an innovative approach combining atmospheric distillation of bio-oil with co-pyrolysis for mass production of renewable chemicals from biomass, in which no waste was produced. It was estimated that 51.86 wt.% of distillate just containing dozens of separable organic components could be recovered using this approach. Ten protogenetic and three epigenetic compounds in distillate were qualitatively identified by gas chromatography/mass spectrometry and quantified by gas chromatography. Among them, the recovery efficiencies of acetic acid, propanoic acid, and furfural were all higher than 80 wt.%. Formation pathways of the distillate components in this process were explored. This work opens up a fascinating prospect for mass production of chemical feedstock from waste biomass. PMID- 23350029 TI - Equilibrious strand exchange promoted by DNA conformational switching. AB - Most of DNA strand exchange reactions in vitro are based on toehold strategy which is generally nonequilibrium, and intracellular strand exchange mediated by proteins shows little sequence specificity. Herein, a new strand exchange promoted by equilibrious DNA conformational switching is verified. Duplexes containing c-myc sequence which is potentially converted into G-quadruplex are designed in this strategy. The dynamic equilibrium between duplex and G4-DNA is response to the specific exchange of homologous single-stranded DNA (ssDNA). The SER is enzyme free and sequence specific. No ATP is needed and the displaced ssDNAs are identical to the homologous ssDNAs. The SER products and exchange kenetics are analyzed by PAGE and the RecA mediated SER is performed as the contrast. This SER is a new feature of G4-DNAs and a novel strategy to utilize the dynamic equilibrium of DNA conformations. PMID- 23350030 TI - The interaction of asbestos and iron in lung tissue revealed by synchrotron-based scanning X-ray microscopy. AB - Asbestos is a potent carcinogen associated with malignant mesothelioma and lung cancer but its carcinogenic mechanisms are still poorly understood. Asbestos toxicity is ascribed to its particular physico-chemical characteristics, and one of them is the presence of and ability to adsorb iron, which may cause an alteration of iron homeostasis in the tissue. This observational study reports a combination of advanced synchrotron-based X-ray imaging and micro-spectroscopic methods that provide correlative morphological and chemical information for shedding light on iron mobilization features during asbestos permanence in lung tissue. The results show that the processes responsible for the unusual distribution of iron at different stages of interaction with the fibres also involve calcium, phosphorus and magnesium. It has been confirmed that the dominant iron form present in asbestos bodies is ferritin, while the concurrent presence of haematite suggests alteration of iron chemistry during asbestos body permanence. PMID- 23350031 TI - Citrullination as early-stage indicator of cell response to single-walled carbon nanotubes. AB - Single-walled carbon nanotubes (SWCNTs) have been widely explored as potential technologies for information systems and medical applications. The impact of SWCNTs on human health is of prime concern, if SWCNTs have a future in the manufacturing industry. This study proposes a novel, inflammation-independent paradigm of toxicity for SWCNTs, identifying the protein citrullination process as early-stage indicator of inflammatory responses of macrophages (THP-1) and of subtle phenotypic damages of lung epithelial (A549) cells following exposure to chemically-treated SWCNTs. Our results showed that, while most of the cellular responses of A549 cells exposed to SWCNTs are different to those of similarly treated THP-1 cells, the protein citrullination process is triggered in a dose- and time-dependent manner in both cell lines, with thresholds comparable between inflammatory (THP-1) and non-inflammatory (A549) cell types. The cellular mechanism proposed herein could have a high impact in predicting the current risk associated with environmental exposure to SWCNTs. PMID- 23350032 TI - Evaluation of Ca3Co2O6 as cathode material for high-performance solid-oxide fuel cell. AB - A cobalt-based thermoelectric compound Ca(3)Co(2)O(6) (CCO) has been developed as new cathode material with superior performance for intermediate-temperature (IT) solid-oxide fuel cell (SOFC). Systematic evaluation has been carried out. Measurement of thermal expansion coefficient (TEC), thermal-stress (sigma) and interfacial shearing stress (tau) with the electrolyte show that CCO matches well with several commonly-used IT electrolytes. Maximum power density as high as 1.47 W cm(-2) is attained at 800 degrees C, and an additional thermoelectric voltage of 11.7 mV is detected. The superior electrochemical performance, thermoelectric effect, and comparable thermal and mechanical behaviors with the electrolytes make CCO to be a promising cathode material for SOFC. PMID- 23350033 TI - Predictions of avian Plasmodium expansion under climate change. AB - Vector-borne diseases are particularly responsive to changing environmental conditions. Diurnal temperature variation has been identified as a particularly important factor for the development of malaria parasites within vectors. Here, we conducted a survey across France, screening populations of the house sparrow (Passer domesticus) for malaria (Plasmodium relictum). We investigated whether variation in remotely-sensed environmental variables accounted for the spatial variation observed in prevalence and parasitemia. While prevalence was highly correlated to diurnal temperature range and other measures of temperature variation, environmental conditions could not predict spatial variation in parasitemia. Based on our empirical data, we mapped malaria distribution under climate change scenarios and predicted that Plasmodium occurrence will spread to regions in northern France, and that prevalence levels are likely to increase in locations where transmission already occurs. Our findings, based on remote sensing tools coupled with empirical data suggest that climatic change will significantly alter transmission of malaria parasites. PMID- 23350034 TI - Chaotic Ising-like dynamics in traffic signals. AB - The green and red lights of a traffic signal can be viewed as the up and down states of an Ising spin. Moreover, traffic signals in a city interact with each other, if they are controlled in a decentralised way. In this paper, a simple model of such interacting signals on a finite-size two-dimensional lattice is shown to have Ising-like dynamics that undergoes a ferromagnetic phase transition. Probabilistic behaviour of the model is realised by chaotic billiard dynamics that arises from coupled non-chaotic elements. This purely deterministic model is expected to serve as a starting point for considering statistical mechanics of traffic signals. PMID- 23350035 TI - Handedness helps homing in swimming and flying animals. AB - Swimming and flying animals rely on their ability to home on mobile targets. In some fish, physiological handedness and homing correlate, and dolphins exhibit handedness in their listening response. Here, we explore theoretically whether the actuators, sensors, and controllers in these animals follow similar laws of self-regulation, and how handedness affects homing. We find that the acoustic sensor (combined hydrophone-accelerometer) response maps are similar to fin force maps-modeled by Stuart-Landau oscillators-allowing localization by transitional vortex-propelled animals. The planar trajectories of bats in a room filled with obstacles are approximately reproduced by the states of a pair of strong and weak olivo-cerebellar oscillators. The stereoscopy of handedness reduces ambiguity near a mobile target, resulting in accelerated homing compared to even handedness. Our results demonstrate how vortex-propelled animals may be localizing each other and circumventing obstacles in changing environments. Handedness could be useful in time-critical robot-assisted rescues in hazardous environments. PMID- 23350036 TI - Novel TPR-containing subunit of TOM complex functions as cytosolic receptor for Entamoeba mitosomal transport. AB - Under anaerobic environments, the mitochondria have undergone remarkable reduction and transformation into highly reduced structures, referred as mitochondrion-related organelles (MROs), which include mitosomes and hydrogenosomes. In agreement with the concept of reductive evolution, mitosomes of Entamoeba histolytica lack most of the components of the TOM (translocase of the outer mitochondrial membrane) complex, which is required for the targeting and membrane translocation of preproteins into the canonical aerobic mitochondria. Here we showed, in E. histolytica mitosomes, the presence of a 600 kDa TOM complex composed of Tom40, a conserved pore-forming subunit, and Tom60, a novel lineage-specific receptor protein. Tom60, containing multiple tetratricopeptide repeats, is localized to the mitosomal outer membrane and the cytosol, and serves as a receptor of both mitosomal matrix and membrane preproteins. Our data indicate that Entamoeba has invented a novel lineage specific shuttle receptor of the TOM complex as a consequence of adaptation to an anaerobic environment. PMID- 23350037 TI - Beating the heat--fast scanning melts silk beta sheet crystals. AB - Beta-pleated-sheet crystals are among the most stable of protein secondary structures, and are responsible for the remarkable physical properties of many fibrous proteins, such as silk, or proteins forming plaques as in Alzheimer's disease. Previous thinking, and the accepted paradigm, was that beta-pleated sheet crystals in the dry solid state were so stable they would not melt upon input of heat energy alone. Here we overturn that assumption and demonstrate that beta-pleated-sheet crystals melt directly from the solid state to become random coils, helices, and turns. We use fast scanning chip calorimetry at 2,000 K/s and report the first reversible thermal melting of protein beta-pleated-sheet crystals, exemplified by silk fibroin. The similarity between thermal melting behavior of lamellar crystals of synthetic polymers and beta-pleated-sheet crystals is confirmed. Significance for controlling beta-pleated-sheet content during thermal processing of biomaterials, as well as towards disease therapies, is envisioned based on these new findings. PMID- 23350038 TI - Terrestrial pesticide exposure of amphibians: an underestimated cause of global decline? AB - Amphibians, a class of animals in global decline, are present in agricultural landscapes characterized by agrochemical inputs. Effects of pesticides on terrestrial life stages of amphibians such as juvenile and adult frogs, toads and newts are little understood and a specific risk assessment for pesticide exposure, mandatory for other vertebrate groups, is currently not conducted. We studied the effects of seven pesticide products on juvenile European common frogs (Rana temporaria) in an agricultural overspray scenario. Mortality ranged from 100% after one hour to 40% after seven days at the recommended label rate of currently registered products. The demonstrated toxicity is alarming and a large scale negative effect of terrestrial pesticide exposure on amphibian populations seems likely. Terrestrial pesticide exposure might be underestimated as a driver of their decline calling for more attention in conservation efforts and the risk assessment procedures in place do not protect this vanishing animal group. PMID- 23350040 TI - Estimation of clinical predictive factors in treating patients with globus. PMID- 23350041 TI - Is easier the better in a feasibility study of questionnaires? PMID- 23350039 TI - N-acetylglucosamine (GlcNAc) functions in cell signaling. AB - The amino sugar N-acetylglucosamine (GlcNAc) is well known for the important structural roles that it plays at the cell surface. It is a key component of bacterial cell wall peptidoglycan, fungal cell wall chitin, and the extracellular matrix of animal cells. Interestingly, recent studies have also identified new roles for GlcNAc in cell signaling. For example, GlcNAc stimulates the human fungal pathogen Candida albicans to undergo changes in morphogenesis and expression of virulence genes. Pathogenic E. coli respond to GlcNAc by altering the expression of fimbriae and CURLI fibers that promote biofilm formation and GlcNAc stimulates soil bacteria to undergo changes in morphogenesis and production of antibiotics. Studies with animal cells have revealed that GlcNAc influences cell signaling through the post-translational modification of proteins by glycosylation. O-linked attachment of GlcNAc to Ser and Thr residues regulates a variety of intracellular proteins, including transcription factors such as NFkappaB, c-myc and p53. In addition, the specificity of Notch family receptors for different ligands is altered by GlcNAc attachment to fucose residues in the extracellular domain. GlcNAc also impacts signal transduction by altering the degree of branching of N-linked glycans, which influences cell surface signaling proteins. These emerging roles of GlcNAc as an activator and mediator of cellular signaling in fungi, animals, and bacteria will be the focus of this review. PMID- 23350042 TI - Electrogastrography: methodology, validation and applications. AB - Electrogastrography (EGG) is a non-invasive method for the measurement of gastric myoelectrical activity. It was first discovered in 1921 and popularized in 1990s. EGG is attractive because it is non-invasive. However, due to its non-invasive nature, there have also been controversies regarding validity and applications of EGG. The aim of this review is to discuss the methodologies, validation and applications of EGG. Pros and cons of EGG will also be discussed in detail. First, the gastric slow wave and its correlation with gastric motility are presented. The association between gastric dysrhythmia and impaired gastric motility is reviewed. Secondly the method for recording the electrogastrogram is presented in detail and pitfalls in the recording and analysis of EGG are discussed. Thirdly, findings reported in the literature demonstrating the accuracy of EGG in recording gastric slow waves and gastric dysrhythmia are reviewed and discussed. The correlation of the electrogastrogram with gastric contraction is carefully discussed. Finally, applications of EGG in a few major areas are reviewed. PMID- 23350043 TI - Recent advances in the pathophysiology and treatment of gastroparesis. AB - Gastroparesis is a clinical disorder characterized by upper gastrointestinal symptoms related with delayed gastric emptying of solids and liquids in the absence of mechanical obstruction. Diabetes mellitus has been the most common cause of gastroparesis and idiopathic gastroparesis also accounts for a third of all chronic cases. The most important mechanisms of gastroparesis, as understood to date, are loss of expression of neuronal nitric oxide synthase and loss of the interstitial cells of Cajal. However, the pathogenesis of gastroparesis is poorly understood. There have been several studies on specific molecules related to the pathogenesis of gastroparesis. Additionally, the Gastroparesis Clinical Research Consortium of the National Institutes of Health has achieved several promising results regarding the pathophysiology of gastroparesis. As the progress in the pathophysiology of gastroparesis has been made, a promising new drug therapy has been found. The pathophysiology and drug therapy of gastroparesis are focused in this review. Until now, the real-world medication options for treatment of gastroparesis are limited. However, it is expected to be substantially improved as the pathophysiology of gastroparesis is elucidated. PMID- 23350044 TI - Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. AB - Proton pump inhibitor (PPI) is a prodrug which is activated by acid. Activated PPI binds covalently to the gastric H(+), K(+)-ATPase via disulfide bond. Cys813 is the primary site responsible for the inhibition of acid pump enzyme, where PPIs bind. Omeprazole was the first PPI introduced in market, followed by pantoprazole, lansoprazole and rabeprazole. Though these PPIs share the core structures benzimidazole and pyridine, their pharmacokinetics and pharmacodynamics are a little different. Several factors must be considered in understanding the pharmacodynamics of PPIs, including: accumulation of PPI in the parietal cell, the proportion of the pump enzyme located at the canaliculus, de novo synthesis of new pump enzyme, metabolism of PPI, amounts of covalent binding of PPI in the parietal cell, and the stability of PPI binding. PPIs have about 1hour of elimination half-life. Area under the plasmic concentration curve and the intragastric pH profile are very good indicators for evaluating PPI efficacy. Though CYP2C19 and CYP3A4 polymorphism are major components of PPI metabolism, the pharmacokinetics and pharmacodynamics of racemic mixture of PPIs depend on the CYP2C19 genotype status. S-omeprazole is relatively insensitive to CYP2C19, so better control of the intragastric pH is achieved. Similarly, R-lansoprazole was developed in order to increase the drug activity. Delayed-release formulation resulted in a longer duration of effective concentration of R-lansoprazole in blood, in addition to metabolic advantage. Thus, dexlansoprazole showed best control of the intragastric pH among the present PPIs. Overall, PPIs made significant progress in the management of acid-related diseases and improved health-related quality of life. PMID- 23350045 TI - Effects of ramosetron on gastrointestinal transit of Guinea pig. AB - BACKGROUND/AIMS: A selective 5-hydroxytryptamine (5-HT) type 3 receptor antagonist, ramosetron, inhibits stress-induced abnormal defecation in animals and is currently used as a therapeutic drug for irritable bowel syndrome with diarrhea. The aim of this study is to investigate the effect of ramosetron on altered gastrointestinal (GI) transit. METHODS: Male guinea pigs weighing approximately 300 g were used. The effect of ramosetron was investigated on altered GI transit induced by thyrotropin-releasing hormone (TRH), 5-HT, or mustard oil (MO). GI transit was evaluated by the migration of charcoal mixture from the pylorus to the most distal point, and expressed as a percentage (%) of charcoal migration (cm) of the total length of total small intestine (cm). RESULTS: The average charcoal transit was 51.3 +/- 20.1% in the control (vehicle) group, whereas in the ramosetron group charcoal moved 56.6 +/- 21.9%, 46.9 +/- 9.14% and 8.4 +/- 5.6% of the total small intestine at the concentrations of 10, 30 and 100 ug/kg, respectively. GI transit after administration of TRH (100 ug/kg), 5-HT (10 mg/kg) or MO (10 mg/kg) was accelerated compared to vehicle (5 HT, 94.9 +/- 9.22%; TRH, 73.4 +/- 14.7%; MO, 81.0 +/- 13.7%). Ramosetron inhibited GI transit altered by 5-HT, TRH or MO. CONCLUSIONS: Ramosetron modulated GI transit. We suggest that ramosetron may be therapeutically useful for those with accelerated upper GI transit. PMID- 23350046 TI - Observations of Acid Reflux and Motor Function in Distal Esophagus Using Simultaneous Measurements of Intra-esophageal pH and Pressure in 8 Directions With Novel Sensor Catheter - A Feasibility Study. AB - BACKGROUND/AIMS: Esophagogastric junctional lesions, such as mucosal breaks with Los Angeles grade A or B reflux esophagitis, lacerations in Mallory Weiss syndrome, and short segment Barrett's esophagus, are mainly found in the right anterior wall of the distal esophagus. Asymmetrical lower esophageal sphincter pressure and resting radial asymmetrical acid reflux may be causes of this asymmetrical distribution of reflux esophagitis and short segment Barrett's esophagus. We developed a novel pH and pressure catheter to investigate the asymmetrical distributions of pH and intra-esophageal pressure in the distal esophagus. METHODS: One healthy male volunteer was enrolled in this study. Acid reflux and motor function in distal esophagus was investigated using simultaneous measurements of intra-esophageal pH and pressure in 8 directions with novel sensor catheter. RESULTS: Thirty-six acid and weak acid reflux events were observed, of which 22 were circumferential refluxes with pH drops in all channels and 14 were partial refluxes with pH drops in some channels. Increase in transient circumferential intraesophageal pressure was observed just after 72.7% of the circumferential reflux and 42.9% of the partial reflux events. CONCLUSIONS: Using a novel sensor catheter, 2 different types of acid reflux events were identified in the present study. PMID- 23350047 TI - Clinical predictors for response to proton pump inhibitor treatment in patients with globus. AB - BACKGROUND/AIMS: Globus is a persistent or intermittent non-painful sensation of a lump or foreign body in the throat. Given the benign nature of the condition and the association of gastroesophageal reflux disease, empirical therapy with proton pump inhibitor seems reasonable for patients with typical globus. The aim of this study was to investigate the clinical predictors for symptom response to short-term proton pump inhibitor treatment in patients with globus symptom. METHODS: Fifty-four patients with globus symptom were enrolled prospectively. All patients were treated with pantoprazole 40 mg daily for 4 weeks. Treatment response was defined as a > 50% reduction in symptom scores between symptom assessments. Univariate and multivariate logistic regression analysis between responders and non-responders was performed to identify variables predicting response to pantoprazole treatment. RESULTS: Of the 54 consecutive patients considered, 13 were excluded on the basis of exclusion criteria and/or refusal to participate in the study. Finally, 41 patients were included in this study. After 4-week pantoprazole treatment, 22 patients (53.7%) were classified as responders. On multivariate analysis, the presence of reflux symptom was associated with a higher response rate to 4-week pantoprazole treatment (OR, 68.56; P = 0.043), and long symptom duration (>= 3 months) were associated with a lower response rate to pantoprazole treatment (OR, 0.03; P = 0.034). CONCLUSIONS: Presence of reflux symptom and short symptom duration were independent predictors of responsiveness to 4-week pantoprazole treatment in patients with globus. PMID- 23350048 TI - Comparative Study of 2 Different Questionnaires in Japanese Patients: The Quality of Life and Utility Evaluation Survey Technology Questionnaire (QUEST) Versus the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease Questionnaire (FSSG). AB - BACKGROUND/AIMS: The aim of this study was to examine the convenience of the quality of life and utility evaluation survey technology (QUEST) questionnaire and the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) questionnaire as self-assessment diagnostic instrument. METHODS: This was a two-way crossover study conducted over 6 weeks from September 2010 to November 2010. The subjects were 60 consecutive patients admitted to the Hiratsuka city hospital with a gastrointestinal condition, regardless of the coexistence of heartburn. They were assigned to fill in both the QUEST and FSSG questionnaires in random order. We analyzed the time taken to complete the questionnaires, whether subjects asked any questions as they filled in the questionnaire, and the questionnaire scores. RESULTS: Comparison of the QUEST and the FSSG revealed significant differences in the completion time (196.5 vs. 97.5 seconds, respectively; P < 0.0001) and in whether subjects asked any questions (37 vs. 15 subjects, respectively; P < 0.0001). Completion time in QUEST scores of >= 4 was lower than < 4 (170.5 vs. 214.0 seconds, respectively; P = 0.022), and the QUEST score was significantly higher without questions than with question (3 vs. 1 points, respectively; P = 0.025). CONCLUSIONS: This study revealed that the FSSG questionnaire may be easier for Japanese subjects to complete than the QUEST questionnaire. PMID- 23350049 TI - Comparison of gastroesophageal reflux disease symptoms and proton pump inhibitor response using gastroesophageal reflux disease impact scale questionnaire. AB - BACKGROUND/AIMS: To compare gastroesophageal reflux disease (GERD) symptoms and response to proton pump inhibitor (PPI) in patients with erosive esophagitis (EE), non-erosive reflux disease (NERD) or functional heartburn (FH) using GERD impact scale (GIS) questionnaire. METHODS: Total 126 patients with GERD symptoms were diagnosed as EE (n = 62), NERD (n = 34) and FH (n = 30) by endoscopy, 24 hour esophageal pH testing and Bernstein test, prospectively. Analysis of risk factors and GIS questionnaire for GERD symptoms and quality of life were performed before and 8 weeks after PPI treatment. RESULTS: EE group had a higher proportion of men, frequent alcohol consumption, smoking, hiatal hernia, body mass index >= 25 kg/m(2) and triglyceride levels (>= 150 mg/dL) than the other groups (all P < 0.05). On the other hand, both psychiatric treatment and psychopharmacotherapy were more frequent in patients with FH than in those with EE and NERD (both P < 0.05). Among GERD symptoms, chest pain was more frequent in FH group than in EE and NERD groups (P < 0.05). Eating problems and limitation of productive daily activities occurred frequently in FH group and NERD group, respectively. GIS after 8 week PPI treatment showed improvement in all of the GERD symptoms in EE (all P < 0.05) and in acid regurgitation, epigastric pain and hoarseness in NERD group (all P < 0.05). In terms of quality of life, PPI treatment improved sleep disturbance in EE (P = 0.031) and limitation of productive activity in the NERD group (P = 0.001). CONCLUSIONS: GIS questionnaire showed that different characteristics and symptoms improved after PPI therapy among patients with EE, NERD and FH, demonstrating the usefulness of the GIS questionnaire. PMID- 23350051 TI - Successful outcome of refractory chronic constipation by surgical treatment: a series of 34 patients. AB - BACKGROUND/AIMS: Chronic constipation is commonly managed medically, and surgical options have been advocated in patients with refractory symptoms. We aimed to study the role of surgical procedures in patients with constipation, refractory to medical therapy. METHODS: Data on 34 surgically managed patients with refractory chronic constipation during a 6-year period (March 2003 to May 2009) were retrospectively analyzed. RESULTS: All the 34 patients (24 males and 10 females, median age of 45 years [range, 18-77 years]) had symptoms for a long period (median 96 months [range, 12-360 months]) without response to medical treatment including biofeedback. Preopertive investigations included barium enema, colonoscopy, colonic transit study, defecography and anorectal manometry as indicated. Eight patients (23.5%) had slow transit constipation, 4 (11.8%) had Hirschsprung's disease and 22 (64.7%) had rectal prolapse. Total colectomy and ileo-rectal anastomosis, anterior resection, Delorme's procedure, resection rectopexy and Duhamel's operation were the surgical procedures performed. Though 7 (20.6%) patients had post operative complications, there was no mortality. One patient whose symptoms recurred following anterior resection was successfully treated by total colectomy and ileo-rectal anastomosis. Median spontaneous bowel movements increased following surgical treatment compared to that while on medical treatment (1 per week [range, 0 to 3 per week] vs. 14 per week [range, 7 28 per week], P < 0.00001). Patients remained well during 3-60 months follow-up (n = 27). CONCLUSIONS: Spontaneous bowel movements significantly increased following surgical operation for refractory chronic constipation, nature of which is dependent on underlying etiology and the expertise available. Careful preoperative work-up and selection of patients are critical for obtaining good functional results. PMID- 23350050 TI - The Prevalence of Erosive Esophagitis Is Not Significantly Increased in a Healthy Korean Population - Could It Be Explained?: A Multi-center Prospective Study. AB - BACKGROUND/AIMS: Researches on the potential risk factors for the development of erosive esophagitis have been conducted extensively, however, the results are conflicting. The aim of this multicenter study was to identify the prevalence rate and risk factors of erosive esophagitis and their interactions with residency status. METHODS: A total of 4,023 eligible subjects at 8 tertiary health care centers were evaluated using questionnaires, laboratory tests and endoscopy. Univariate and multivariate analyses were conducted to identify independent risk factors for erosive esophagitis. RESULTS: The prevalence rate of reflux esophagitis was 8.8%. Los Angeles grade A was common type of erosive esophagitis. Residence in a large urban areas was negatively associated with the development of erosive esophagitis (OR, 0.60; 95% CI, 0.40-0.90). The high body mass index (>= 25 kg/m(2)) was more frequent in residents of small and medium sized cities than those in big cities (38.8% and 26.9%, respectively; P < 0.001). Seronegativity of Helicobacter pylori was associated with increased erosive esophagitis (OR, 1.91; 95% CI, 1.48-2.46). Triglyceride >= 150 mg/dL (OR, 1.65; 95% CI, 1.08-2.07), fasting glucose level >= 126 mg/dL (OR, 1.73; 95% CI, 1.06 2.81), and hiatal hernia (OR, 3.11; 95% CI, 1.87-5.16) were also associated with erosive esophagitis. CONCLUSIONS: The prevalence rate of erosive esophagitis and its risk factors in this study were similar to the result of 8.0% of nationwide study in 2006. Residency and obesity are more important independent risk factors than H. pylori infection status for development of erosive esophagitis in Korea. These results suggest that the prevalence rate of erosive esophagitis in Korea might not increase as in the Western countries. PMID- 23350052 TI - Surgical correction is ineffective for improvement of dyssynergic defecation in patients with rectal prolapse. AB - BACKGROUND/AIMS: The patients with rectal prolapse suffer from not only a prolapse rectum but also associated dysfunction. However, most surgical techniques are successful regarding the prolapse, but either do not solve or even worsen defecation dysfunction. The purpose of this study was to investigate the functional and physiological results after surgical correction in patients with rectal prolapse. METHODS: This study is a retrospective review of a single institution experience. Patients with rectal prolapse who underwent anorectal manometry before and after Delorme's procedure were included. The primary outcomes measured were improvement of clinical symptoms and physiologic study. RESULTS: Consecutive 19 patients with rectal prolapse (17 females, mean age of 68.1 +/- 10.8 years) underwent anorectal manometry before and after Delorme's procedure. The two most prevalent symptoms before operation were rectal tenesmus (15/19, 78.9%) and excessive straining (13/19, 68.4%). The two most prevalent symptoms after operation were rectal tenesmus (14/19, 73.6%) and excessive straining (13/19, 68.4%). No significant differences in resting anal pressure, squeezing anal pressure, defecation index, and rectal sense were found postoperatively. However, vector asymmetry index before surgery was higher than that after surgery (35.0 vs. 32.0, P = 0.018). Ten patients (52.5%) had type I dyssynergic defecation before surgery. No improvement of dyssynergic pattern occurred after surgery. CONCLUSIONS: In conclusion, dyssynergic defecation was not improved after reduction of rectal prolapse in patients with rectal prolapse. Further study about combination treatment with biofeedback therapy in these subgroups may be necessary. PMID- 23350053 TI - The Incidence of Irritable Bowel Syndrome in Children Using the Rome III Criteria and the Effect of Trimebutine Treatment. AB - BACKGROUND/AIMS: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders and when compared to the vast knowledge pertaining to adults with IBS, very little is known about IBS in children and adolescents. We aimed to explore the prevalence of IBS, identify symptoms and contributing factors and also to examine the efficacy of trimebutine maleate in children and adolescents. METHODS: The study involved 345 children and adolescents (4-18 years) and parents were requested to fill in a questionnaire, Rome III criteria was used to diagnose IBS. To exclude organic disease, all patients underwent medical investigations. Half of the randomly selected IBS patients were treated with trimebutine maleate while the rest of IBS patients were not. The IBS patients were reevaluated at the end of 3 weeks. RESULTS: The prevalence of IBS according to Rome III criteria in children and adolescents was 22.6% and IBS with constipation was the predominant subtype. Back pain (OR, 6.68), headache (OR, 4.72) and chronic fatigue (OR, 3.74) were significantly higher in IBS group. The prevalence of IBS in both parents and depression in mothers was greater for the patient group than the healthy controls (P < 0.0001). The prevalence of functional dyspepsia in IBS group was 80.8% and was significantly higher than control group. Clinical recovery was seen in 94.9% of the trimebutine maleate group versus spontaneous recovery in 20.5% of the non medicated group. The difference was significant (P < 0.0001). CONCLUSIONS: IBS is a common disorder in children and adolescents. IBS is closely associated with somatic and familial factors. Trimebutine maleate is effective for pediatric IBS patients. PMID- 23350054 TI - Opioids and the gastrointestinal tract - a case of narcotic bowel syndrome and literature review. AB - The worldwide use of opiates is increasing yet there is little evidence that in long-term, non-cancer patients, they have an efficacious effect on functional outcomes and quality of life measures. Although it seems paradoxical, chronic opiate use may lead to a pro-nociceptive state. Mechanisms for the development of the hyperalgesic state include activation of the opiate bimodal regulatory systems, dynorphin and spinal cord glia. A potential consequence of chronic opiate usage is the development of narcotic bowel syndrome, which is characterized by chronic or intermittent colicky abdominal pain or discomfort that worsens after the narcotic effects of opiates wear off. It is likely that this is an under-recognized diagnosis. We describe here a case of 26-year old female who had visited our institution multiple times with intractable chronic abdominal pain in the context of normal findings on haematological, biochemical, metabolic, endoscopic and radiological investigations. She had been treated with a multitude of opioid agonists with escalating doses. A diagnosis of narcotic bowel syndrome was made. On elective admission her daily analgesic requirements were 150 ug/hr fentanyl, 100 mg oramorph and 400 mg tramadol (equating to 740 mg oral morphine/24 hr). A detoxification regimen was prescribed which included rapid opiate withdrawal couple with the commencement of methadone, lorazepam, clonidine and duloxetine. She was discharged opiate free, with no abdominal pain, 14 days after admission. Clinicians must be aware of narcotic bowel syndrome, which is often erroneously labelled as a functional gastrointestinal disorder, in patients who have been on long-term opiates. PMID- 23350055 TI - How to perform and interpret upper esophageal sphincter manometry. AB - Manometry of the pharynx and the upper esophageal sphincter (UES) provides important information on the swallowing mechanism, especially about details on the pharyngeal contraction and relaxation of the UES. However, UES manometry is challenging because of the radial asymmetry of the sphincter, and upward movement of the UES during swallowing. In addition, the rapidity of contraction of the pharyngoesophageal segment requires high frequency recording for capturing these changes in pressure; this is best done with the use of solid state transducers and high-resolution manometry. UES manometry is not required for routine patient care, when esophageal manometry is being performed. The major usefulness of UES manometry in clinical practice is in the evaluation of patients with oropharyngeal dysphagia. PMID- 23350056 TI - Magnifying endoscopy with narrow band imaging and endoscopic ultrasonography for assessing eosinophilic esophagitis. PMID- 23350057 TI - Interesting Findings of High-resolution Manometry Before and After Treatment in a Case of Diffuse Esophageal Spasm. PMID- 23350058 TI - Increased Expression of Brain-derived Neurotrophic Factor in Irritable Bowel Syndrome and Its Correlation With Abdominal Pain (Gut 2012;61:685-694). PMID- 23350059 TI - Are major basic protein, eotaxin-3 and leukotriene enzyme staining useful for diagnosing eosinophilic esophagitis? (Am j gastroenterol 2012;107:1503-1511). PMID- 23350060 TI - Esophageal Disorders Not Yet Addressed by High-resolution Manometry. PMID- 23350061 TI - Gastric emptying in patients with functional dyspepsia and patients with migraine. PMID- 23350062 TI - Gastric Emptying in Patients With Functional Dyspepsia and Patients With Migrain: Author's Reply. PMID- 23350063 TI - Computed tomography mimics of acute appendicitis: predictors of appendiceal disease confirmed at pathology. AB - PURPOSE: Imaging and pathology findings are used to analyze the capability of computed tomography (CT) to distinguish between acute appendicitis and radiological mimickers. MATERIALS AND METHODS: A retrospective review of 5861 patients undergoing abdominopelvic CT from 2000 to 2008 for suspicion of acute appendicitis was performed. Appendix diameter, surrounding inflammation, appendicolith, and location were assessed. Only those cases were included where patients underwent surgery for acute appendicitis on CT findings. Pathology specimens were examined and those indicative of acute appendicitis were identified. Statistical analysis was performed to correlate pathology and CT signs. RESULTS: A total of 969 of the 5681 patients were included in the study. Acute appendicitis was verified in 870/969 (89%) cases, while 99/969 (11%) demonstrated either chronic findings (i.e., fibrosis [32%], granulomatous disease [16%], lymphoid hyperplasia [11%]) or no abnormality. In regression models, appendiceal diameter >7 mm (odds ratio [OR] = 3.98, P < 0.0001) and mesenteric fat stranding (OR = 6.04, P < 0.0001) were associated with acute appendicitis. Nearly 87% (754/870) of acute appendicitis cases showed both signs on CT, compared with 53% (52/99) of those with other pathologic finding (P < 0.0001). In cases with non-appendicitis findings, 39% (39/99) had only one of these signs compared with 13% (112/870) of those with acute appendicitis (P < 0.0001). CONCLUSION: Diseases of the appendix other than acute appendicitis may manifest with isolated radiological findings and should be considered as part of the differential diagnosis in cases of borderline acute appendicitis. PMID- 23350064 TI - Differential impact of body mass index and its change on the risk of breast cancer by molecular subtype: A case-control study in Japanese women. AB - Body mass index (BMI) is an independent risk factor for luminal-type breast cancer in Western populations. However, it is unclear whether the impact of BMI differs according to breast cancer subtype in Japanese populations. We conducted a case-control study with 715 cases and 1430 age- and menopausal status-matched controls to evaluate the associations of BMI and its change (from age 20 years to the current age) with breast cancer risk. We applied conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Tumor subtypes were divided into four subtypes, namely the luminal, luminal/HER2, HER2-rich, and triple-negative subtypes. Current BMI and BMI change were positively associated with postmenopausal breast cancer risk. On stratified analysis by tumor subtype, we observed associations between current BMI and BMI change and postmenopausal breast cancer risk for the luminal subtype, with OR for each 1 kg/m(2) increase in current BMI of 1.14 (95% CI: 1.07 - 1.20) and the corresponding OR of BMI change of 1.16 (1.09 - 1.23) (each P(trend) < 0.001). Additionally, we found the same tendency for the triple-negative subtype, with the OR for a 1 kg/m(2) increase in current BMI of 1.21 (1.05 - 1.39) and that for BMI change of 1.18 (1.02 - 1.36) (P(trend) was 0.008 and 0.024, respectively). In premenopausal women, a suggestive inverse association was observed between BMI change and breast cancer risk for the luminal subtype only, with OR of BMI change of 0.93 (0.87 - 1.00, P(trend) = 0.054). No association was seen between BMI at age 20 years and risk of any tumor subtype. In conclusion, BMI and its change are associated with the risk of both luminal and triple-negative breast cancer among postmenopausal Japanese women. These findings suggest the etiological heterogeneity of breast cancer among tumor subtypes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2193-1801-1-39) contains supplementary material, which is available to authorized users. PMID- 23350065 TI - New synthesis method for 4-MAPBA monomer and using for the recognition of IgM and mannose with MIP-based QCM sensors. AB - Quartz crystal microbalance (QCM) sensors coated with molecularly imprinted polymers (MIP) have been developed for the recognition of immunoglobulin M (IgM) and mannose. In this method, methacryloylamidophenylboronic acid (MAPBA) was used as a monomer and mannose was used as a template. For this purpose, initially, QCM electrodes were modified with 2-propene-1-thiol to form mannose-binding regions on the QCM sensor surface. In the second step, the methacryloylamidophenylboronic acid-mannose [MAPBA-mannose], pre-organized monomer system, was prepared using the MAPBA monomer. Then, a molecularly imprinted film was coated on to the QCM electrode surface under UV light using ethylene glycol dimethacrylate (EDMA), and azobisisobutyronitrile (AIBN) as a cross-linking agent and an initiator, respectively. The mannose can be simultaneously bound to MAPBA and fitted into the shape-selective cavities. The binding affinity of the mannose-imprinted sensors was investigated using the Langmuir isotherm. The mannose-imprinted QCM electrodes have shown homogeneous binding sites for mannose (K(a): 3.3 * 10(4) M( 1)) and heterogeneous binding sites for IgM (K(a1): 1.0 * 10(4) M(-1); K(a2): 3.3 * 10(3) M(-1)). PMID- 23350066 TI - A strategy to decorate porous polymer monoliths with graphene oxide and graphene nanosheets. AB - Graphene oxide (GO)/graphene (GN) nanosheets were coated onto the poly(glycidyl methacrylate-ethylene dimethacrylate) monolithic bed synthesized inside the capillary in order to prepare a promising polymer monolith microextraction (PMME) material (GO/GN@poly(GMA-EDMA)). Various techniques, including Fourier transform infrared spectroscopy, atomic force microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, and scanning electron microscopy, were employed to characterize the synthesized GO/GN@poly(GMA-EDMA) monoliths, confirming that GO/GN was effectively functionalized on the poly(GMA-EDMA) monolithic materials. Furthermore, a new method was developed for the analysis of sarcosine (identified as a potential prostate cancer biomarker) using PMME coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Under the preoptimized conditions, the monolithic column afforded satisfactory enhancement factor (32 fold) and low limits of detection (1.0 ng mL(-1)) were obtained. In comparison to several other commercialized solid phase extraction adsorbents, GN@poly(GMA-EDMA) monoliths exhibited excellent performance with recoveries of sarcosine approaching 93% with relative standard deviations less than 11.5%. PMID- 23350067 TI - Transient myeloproliferative disorder. PMID- 23350068 TI - Like son, like father. PMID- 23350069 TI - Genotoxic effects and oxidative stress induced by organic extracts of particulate matter(PM 10)collected from a subway tunnel in Seoul, Korea. AB - Particulate matter (PM) has become an important health risk factor in our society. PM can easily deposit in the bronchi and lungs, causing diverse diseases such as respiratory infections, lung cancers and cardiovascular diseases. In recent days, more and more toxicological studies have been dealing with air particles in distinctive areas including industrial areas, transportation sites, or indoors. Studies on subway PM in particular, have been recognizing PM as an important health risk factor because many people use subways as a major mode of public transportation (4 million people a day in Korea). The main aim of the present study was to evaluate the genotoxic effects of organic extract (OE) of subway PM10 and potential attribution of PAHs to these effects. Particles were collected in the subway tunnel at Kil-eum station(Line 4) for one month and then extracted with Dichloromethane (DCM). Chinese Hamster Ovary cells(CHO-K1) and human normal bronchial cells (BEAS-2B) were exposed to OE, and MN and Comet assays were conducted to analyze the genotoxicity. The results showed that OE increased DNA or chromosome damages in both cell lines. In the modified Comet assay and MN assay with free radical scavengers, we confirmed that the genotoxic effect of OE was partially due to the oxidative damage on DNA. DCFHD Aassay also indicated that OE induced ROS generation in BEAS-2B cells. PAHs [benzo(a)anthracene,benzo(k)fluoranthrene, etc.], the most well-known carcinogens in polluted air, were detected in Kil-eum PM10. In conclusion, our findings confirmed that OE of subway PM10 has genotoxic effects on normal human lung cells, and oxidative stress could be one of the major mechanisms of these genotoxic effects.In addition, some genotoxic and carcinogenic PAHs were detected in OE by GC/MS/MS, even though PAHs level was not enough to increase CYP1A1 gene. Therefore, we suggest that additive or synergistic effects by unidentified chemicals as well as PAHs contained in OE of subway PM10 may induce genotoxic effects and further researches are needed to identify the genotoxic compounds in subway PM. PMID- 23350070 TI - Clinical research: Conducting a trial. PMID- 23350072 TI - We can all be healthy achieving health equity for adolescents and young adults. Abstracts of a meeting. February 2013. Atlanta, Georgia, USA. PMID- 23350071 TI - Effects of reduced measurement independence on Bell-based randomness expansion. AB - With the advent of quantum information, the violation of a Bell inequality is used to witness the absence of an eavesdropper in cryptographic scenarios such as key distribution and randomness expansion. One of the key assumptions of Bell's theorem is the existence of experimental "free will," meaning that measurement settings can be chosen at random and independently by each party. The relaxation of this assumption potentially shifts the balance of power towards an eavesdropper. We consider a no-signaling model with reduced "free will" and bound the adversary's capabilities in the task of randomness expansion. PMID- 23350073 TI - Abstracts of the 113th National Congress of the Italian Society of Internal Medicine. Rome, Italy. October 20-22, 2012. PMID- 23350074 TI - Genetic privacy. PMID- 23350075 TI - Vigilance needed. PMID- 23350076 TI - Science stakes. PMID- 23350077 TI - Knowledge and attitudes of psychiatrists towards eating disorders. AB - OBJECTIVE: This study examined the eating disorder mental health literacy of psychiatrists. METHOD: A sample of psychiatrists completed a questionnaire measuring knowledge of and attitudes towards eating disorders. Knowledge questions were based on the academic literature, standard diagnostic criteria and national guidelines on the management of eating disorders. Attitude items covered beliefs about the aetiology and treatment of eating disorders, confidence levels in diagnosis and management and the use of compulsory measures in anorexia nervosa. RESULTS: Psychiatrists' knowledge of eating disorders was variable with specific gaps in both diagnosis and management. Psychiatrists felt more confident in diagnosing eating disorders than managing these conditions. Attitudes towards eating disorders were less stigmatizing than those seen in other health professionals. DISCUSSION: There is a clear need for greater education of psychiatrists regarding the diagnosis and management of eating disorders. Implementing training programmes and making information readily available could contribute to addressing these issues. PMID- 23350079 TI - The straight and narrow words of medicine. PMID- 23350078 TI - How do we know when a medication works? PMID- 23350080 TI - Hypergravity effects on pregnancy and parturition. AB - The events of mammalian parturition (labor and birth) were analyzed in Norway rats exposed to either 1.0-g, 1.5-g or 2.0-g hypergravity (hg) beginning at the approximate midpoint of their pregnancies. Pregnant dams were 24h timelapse videorecorded during parturition (days 22-23). Compared with 1-g controls, hg dams displayed one-half as many lordosis contractions, the predominant labor contraction type in rats. The timing of birth, duration of delivery and number of neonates born was comparable in hg and 1-g control dams. Results are discussed in relation to earlier findings that, following spaceflight during pregnancy, lordosis contractions are doubled in frequency. The importance of labor in the transition from prenatal to postnatal life is discussed. Together, these results provide evidence that gravitational load varies inversely with lordosis contraction frequency and support the view that certain biological systems show a continuum of response across gravitational vectors. PMID- 23350081 TI - Computational intelligence in health technologies. PMID- 23350082 TI - Good news on alternatives to the femoral approach for hemodynamic support. PMID- 23350083 TI - The reduction of physical restraints in nursing homes: the impact of nursing research on clinical practice and health care policy. PMID- 23350084 TI - [20 years editorial assistance]. PMID- 23350085 TI - Complementary and alternative medicine merits further exploration. PMID- 23350086 TI - [The major achievements of medicine in XX-early XXI centuries and their significance for the near future]. AB - Among major achievements of medicine in XX-early XXI centuries considered as the most outstanding contribution are the development of theory of system of control of functions of organism and its integrity by I.P. Pavlov and his disciples and followers: the concept of psycho-somatic medicine by Z. Freud and social psychology; the theory of stress and general adaptive syndrome by H. Selye and the discovering of nature of many infectious and parasitic diseases. Then establishment of pathogenic impact of extra-environmental factors, decoding of gene chromosomal structure of organism, development of genetic engineering, effective pharmaceuticals, and techniques of treatment and prevention of various inherent and acquired diseases also can be put into this category. The achievements and discoveries in the area of public health, social medicine and hygiene and development of concept of healthy life-style are discussed too. PMID- 23350087 TI - [The social hygienic assessment of pathological affectedness of population]. AB - The article considers the indicator of pathological affectedness to assess population health. This technique enables to forecast beforehand the occurrence of problematic situations in population health and development of diseases. The main elements of social hygienic evaluation of pathological affectedness of population including the results of mass diagnostics of population pathology on the basis of objective (macro-diagnostic, micro-diagnostic and functional analysis) and subjective (counseling, health self-assessment) assessments and the results of autopsy of the deceased from bureau of forensic medical examination and departments of morbid anatomy of large-size hospitals. The need in development of corresponding classifiers and prognostic criteria is declared to determine the relationship of pathological affectedness, the medical technologies demand, the optimization of organizational functional structure of public health, medical services and organizations. PMID- 23350088 TI - [The medical social characteristics of patients with joint tuberculosis and HIV infection]. AB - The survey of 335 patients with joint tuberculosis and HIV-infection was carried out to establish the main medical social characteristics of the given category of patients. The sample consisted of persons characterized by of able-bodied age, education of not high level, no profession or occupied in entry-level professions, low or unstable level of income and having no family and children. The distinctive characteristic of patients with joint tuberculosis and HIV infection is high prevalence of alcohol and drugs abuse. The concurrence of both alcohol and drug dependence was established in every one often respondent. The survey revealed very low level of medical activity of respondents. Almost half of the respondents were never examined on the subject of tuberculosis in the AIDS Center Only one third of respondents undergo the preventive fluorography timely. PMID- 23350089 TI - [The dynamics of gender-age indicators of lethality in population of Omsk as a result of acute and chemical intoxications in 2001-2010]. AB - The article demonstrates that in Omsk, during 2001-1010, the indicators of lethality of population as a result of acute chemical intoxications were reliably higher in females. At that, significant decrease of corresponding indicator of lethality in males was observed. In contrary, a slight increase of lethality was established in females. The significant differences in indicators of lethality due to acute chemical intoxications between age groups made it possible to draw a conclusion about the impact of age-related factor to the forecast and outcome of chemical intoxication. This data is to be considered during the development of standards, protocols and treatment algorithms relating to patients with the mentioned pathology. PMID- 23350090 TI - [The health condition of workers of enterprises with different level of ecological pollution]. AB - The article considers the functional conditions of organism of workers depending on the location of enterprise. The dependencies of values of indicators of functional conditions and health on different enterprises from ecological pollution of their locations are established The subjective opinion of workers concerning their health conditions and capacity for work was found out. The relationship between workers' morbidity and percentage of persons systematically engaged in physical training is determined. The prospective decrease of morbidity of workers of enterprises was calculated for case of 100% coverage of all working persons with physical training PMID- 23350091 TI - [The implementation of innovations in public health]. AB - Nowadays, the innovative activities are considered as the mechanism of implementation of public policy to increase effectiveness of public health system on the basis of achievements of modern medicine and technical sciences. The development, elaboration and implementation of products being in line with corresponding to criteria of innovation, promote the concurrency of medical institutions at the medical services market. The administrators of health departments and medical science professionals are to become aware about the problems of implementation of innovations into medical practice to develop the mechanisms of overcoming these issues. PMID- 23350092 TI - [The communicative skills of physicians in ambulatory practice]. AB - The effectiveness of medical care in most cases depends on the quality of information exchange between patient and physician. The knowledge of communicative skills makes it possible for physician to settle more effectively the curative diagnostic and organizational issues in the process of providing medical care to patients. The information support and fundamental theoretical training of physicians not always correspond to modern considerations on patient physician relationship. The long-standing traditions and profound development of theoretical issues of effective exchange of information between patient and physician provide researchers, practical physicians and teachers large possibilities in significant progressing in the field of development of communication technologies in the system of national public health system. PMID- 23350093 TI - [The legal awareness of medical workers in the system of medical care quality management]. AB - The article presents the results of comprehensive study of the level of legal awareness of medical workers. The knowledge of physicians, paramedical personnel and health administrators concerning the rights of patients was assessed. The role of factor of legal awareness in the system of medical care quality management was analyzed. The effective system of measures of development of legal competence of medical personnel was marked out. PMID- 23350094 TI - [The implementation of diagnostic and curative technologies of improvement of population health in ambulatory polyclinic conditions]. AB - The article deals with the main groups of diseases as a reason for adult population to consult a municipal polyclinics for diagnostics and ambulatory treatment. These diseases are arterial hypertension, diabetes mellitus, gastritis, duodenitis, influenza and acute respiratory disease. It is established that the leading groups of technologies on the implementation of diagnostic process are the laboratory clinical analyses and common diagnostics measures which comprise 72.7% of all diagnostic technologies. In polyclinics, the foundation of treatment process is the common treatment measures which comprise 68.6% of all treatment technologies. This fact testifies the non-significant percentage of implementation of high-technology diagnostics technique and treatment in the ambulatory polyclinic conditions. PMID- 23350095 TI - [The development of specialized hospital care to children of early age]. AB - The study was carried out in 2009-2010 on the basis of the Republican children clinical hospital of the Republic of Dagestan. The structure of hospitalized children aged 0-3 years was analyzed using the data from of medical records of hospital patients. The sampling consisted of 17 368 cases. The morbidity of children of the first year of life and morbidity of newborns in maternity hospitals was analyzed. It is established that the morbidity of children of the first year of life made 2258.6 to 1 000 children of corresponding age. The morbidity of newborns in maternity hospitals made 290 to 1 000 newborns. Thy indicator is slightly higher in urban area (295) than in rural area (272.3). In the structure of classes of diseases of hospitalized children of early age the first position is for particular states of perinatal period (40.4%), second position for respiratory diseases (18.1%), third position for inherited malformations (15.3%) and forth position for neoplasms (6.8%). The analysis of hospital lethality demonstrated that the major percentage of deceased (88.9%) go to the first year of life. PMID- 23350096 TI - [The characteristics of sanitary educative work of physicians in urban and rural territories of the Republic of Dagestan]. AB - The study covers the issues of organization of sanitary educative work in the Republic of Dagestan. It is established that both physicians of urban medical institutions and specialists in rural medical institutions consider this sector of their professional activities in a formal way. About 16% of physicians are not involved into sanitary educative work at all and 84% of respondents consider the formation of healthy life-style as a direct output of increase of salary of medical specialists. PMID- 23350097 TI - [The medical social aspects of ambulatory medical care to victims of road traffic accidents]. AB - The article discusses the issues of the organization of medical care to victims of road traffic accidents. The analysis of primary appealability of patients to the first-aid center of Stavropol and Novorossiysk during 2008-2010 is presented. The sampling consisted of 904 cases of this kind of trauma. It is established that among victims of road traffic accident appealed to first-aid centers the pedestrians consist the major part. The traumas of limbs are among the most frequently occurred cases. The victims with cranio-cerebral injuries are among those who appealed most frequently for medical aid. Besides that in most cases (63.4%) the victims with cranio-cerebral injuries were transported not to the neurologic surgery clinic but to the first-aid center This action increased the number of transport stages and duration of time gap before specialized medical care was applied. The conclusion is made concerning the need of further development of out-patient urgent medical care to victims of road traffic accidents. PMID- 23350098 TI - [On the results of sociological survey of feldshers of emergency medical service]. AB - The article deals with the results of sociological survey of feldshers of emergency medical service concerning satisfaction of conditions of professional work. The complex of activities of development of organization of feldsher activities is substantiated. PMID- 23350099 TI - [The issues of organization of medical care delivery to region population within unfavorable allergic status]. AB - The increasing imbalance between allergic diseases morbidity, severity of this pathology and deficiency of allergic care is established Hence the organization of this type of medical support becomes an important issue in the region. The solution is possible through the establishment of allergic care on the municipal level. PMID- 23350100 TI - [The mean timing of periodontic care rendering]. AB - The time-studies demonstrated that the periodontologist spend 30.3 +/- 2.6 minutes on the primary ambulatory visit of patient and 16.4 +/- 0.9 minutes on the revisit of patient (non-registering time spending on preventive and curative activities). Time spending on curative preventive activities in each group of patients with periodontal diseases depended on both the severity of inflammatory destructive processes in periodontium and therapy stage. PMID- 23350101 TI - [The international experience of involvement of state and private sectors in reformation of health care]. AB - The article considers the issues of development of state (public) private partnership in public health of particular foreign countries in the late XX-early Xxi centuries. It is demonstrated that the implementation of partnership in practice unduly leave behind its studying and evaluation of results. PMID- 23350102 TI - [The origination of preventive medicine in the process of reforming of practical medicine in XVII-XIX centuries: report three. The development and implementation of the new approach in investigating the epidemics and its role in the reformation of hygiene is discussed]. AB - The present report considers the ideas of T. Sydenham regarding the causes and essence of epidemics and their role in origin of new methodological approach to studying epidemics. The corresponding issues of health maintenance and disease prevention are also discussed. PMID- 23350103 TI - [The organization of surgical care in Russian army during 1812 Great Patriotic War]. AB - The article considers the characteristics of surgical care to warriors of Russian army during 1812 Great Patriotic War. Such conditions are analyzed as damaging action of French weapons, types of combat wounds, organization and forces of military sanitary service of Russian troops, surgeons' support with means of supplying surgical care to the wounded and arsenal of surgical aids. On the basis of given materials analysis a preliminary conclusion is made that surgical care in Russian army in 1812 not only was on the sufficiently high level but it played a specified role in the victory of Russian weapon. PMID- 23350104 TI - [The A.N. Kriukov scientific therapeutic school]. AB - The article deals with the additions and specifications to the biography of A.N. Kryukov. For the first time, the general therapeutic scientific school created by him is analyzed. The formation within this school of the comprehensive clinical hematological school of Kryukov-Kassirsky which took a leadership in national hematology of XX century is considered. PMID- 23350105 TI - [Zinaida Iakovlevna El'tsyna--the first Russian woman-syphilidolologist]. AB - The article demonstrates that the graduates of the first woman physician courses left their mark in medicine. Z. Ya. Yeltsyna, as the first woman syphilidolologist, takes up aforeground in the struggle against syphilis. She mostly contributed into the organization of care to women and children with syphilis. She also inputted into popularization of ideas concerning the struggle against syphilis among rural and urban population. PMID- 23350115 TI - [Development of postgraduate education for doctors-internists]. AB - Medical progress and to optimize the management of health is largely dependent upon the effectiveness of the modernization of education and science. The primary objective in this regard is the creation of a new management model clinics. International experience has confirmed the effectiveness of the cluster approach. Another important development is the transition to single-channel financing, improving the monitoring of the quality of medical care. To solve these problems it is necessary to develop a model management model clinic based on modern technologies of strategic management and information technology, optimizations of economic activity, social monitoring system of public satisfaction with the quality of medical care. PMID- 23350116 TI - [Postgraduate studies on reflexotherapy: prospects of improved methods of rehabilitation]. AB - Formation adaptive effect of reflexology is one of the most important non specific mechanisms of action to ensure implementation of its sacrificial, sanohenetichnoho and preventive effects. Today, basic education in acupuncture should focus on common international standards, including anatomical, physiological, biochemical and biophysical basis. Based on primary specialization of reflexology should be in continuous improvement of the methods of acupuncture in various fields of clinical medicine aggregate of not less than 350 hours, which is usually carried out intermittently for several years. PMID- 23350117 TI - [Mildronat--treatment of cardio-neurologic pathology in ischemia and hypoxia]. AB - Cerebrovascular pathology has long moved from the category of a single medical problem in the social problem. Progression of vascular lesions of the brain results in significant disability, and in the later stages interfere with the ability to self-service and significantly reduces the quality of life. The key link is ischemic brain damage, or glutamate cascade, which many researchers believe trigger excitotoxic damage and a major cause of neuronal death. One important component of effective control of the effects of ischemic disorders is complex neuro-cytoprotective therapy. To correct for the effects of both acute and chronic ischemia of the brain need to effectively act in several directions simultaneously, normalizing metabolic changes, eliminating the cytokine imbalance transcription violations, reducing the severity of oxidative stress and excitotoxicity. PMID- 23350118 TI - [Relevance of restorative treatment and rehabilitation of patients with cerebrovascular disease]. AB - Reducing treatment and rehabilitation of patients with cerebrovascular disease (TSVB) for many years has been one of the priorities of the national health care, which is largely due to a significant increase in the incidence and severity of medical, economic and social consequences of the disease for patients and their relatives, and for society as a whole. The objectives of rehabilitation include: restoring consumer opportunities patient, ie, mobility, self-care and the implementation of simple homework, rehabilitation, ie lost disability skills through the use and development of the skeletal system functionality, preventing the development of pathological processes that lead to temporary or permanent disability, that is, implementation of secondary prevention. PMID- 23350119 TI - [Stage-by-stage medical rehabilitation of patients with stroke]. AB - Actuality of medical rehabilitation of patients that carried a stroke is important (see text)--by a social problem. The special value a medical rehabilitation has after the consequences of stroke in connection with large (see text) of such patients. Proceeding in a capacity for patients that survived after a stroke, problematic. For determination of volume of rehabilitation interventions it is necessary to take into account weight of motion of stroke, his variants (ischemic, hemorragic) and stages (terms) of development. PMID- 23350120 TI - [Medical and socio-economic effects of early rehabilitation of patients with acute cerebral vascular accidents]. AB - Acute ischemic brain injury (stroke, stroke), a leader among the causes of morbidity and mortality in the world. This pathology is one of the most pressing health and social problems that cause enormous economic damage to society, due to the high fatality rate, significant disability and social maladjustment of patients, which is based in most cases are the motor and cognitive impairment. Despite the fact that, currently established risk factors and pathophysiological basis of this disease, the availability of effective methods of diagnosing illness, still a practicing neurologist in some cases difficult to find adequate therapy that could effectively reach a well-established neurological deficit. Therefore the search for treatments that effectively reduce the health and social consequences of vascular damage to the brain, is one of the priority areas of neurology. PMID- 23350121 TI - [Vertigo: patient management tactics]. AB - To avoid serious causes of dizziness and establishing preliminary diagnosis is usually enough sighting history taking and physical examination of the patient. Great importance is self-presenting patients with complaints of dizziness. In recent years, for treatment of various types vestybulopatiy, but also for the prevention of attacks, successfully used betahistyn hydrochloride, which improves the quality of care and well-being of the patient. PMID- 23350122 TI - [The role of neuroprotection in complex rehabilitation of patients with ischemic stroke]. AB - In this review we considered some questions of early rehabilitation in ischemic stroke. Rehabilitation tactics such patients provides non-medical (treatment status, developmental kinesitherapy, early vertical integration and activation of the patient), and medications (antiplatelet, nootropic, antioxidant and vascular therapy) methods. It was examined the data on the pathogenesis of acute ischemia and the role of neuroprotection in early rehabilitation. We analyzed the rationale for the use of citicoline in the most acute period of stroke. PMID- 23350123 TI - [Rehabilitation of radiculopathy of the spine lumbosacral region complicated with herniated disc depending on the type of hernia]. AB - The article presents the results of treatment of 168 patients with radiculopathy lumbosacral spine, complicated hernias of intervertebral disc nucleus on the developed technique. The results show high efficacy of the treatment of this disease. PMID- 23350124 TI - [Effect of cytoprotectors on lipid metabolism and C-reactive protein in patients with coronary heart disease]. AB - The results of the study parameters lipid profile and C-reactive protein (C-RP) in patients with angina pectoris after applying meksykoru. Combined treatment with meksykoru to correct the atherogenic lipid profile and CRP helped reduce content CRP, total cholesterol, low-density lipoprotein cholesterol, triglycerides, factor aterohenosti and raise HDL cholesterol. PMID- 23350125 TI - [Experience of continuous educational process in training of doctors specializing in reflexotherapy]. AB - Highlights the experience of the Department of Neurology and Reflexology to organize continuous education process in preparing doctors with specialization reflexology. PMID- 23350126 TI - [Changing of the expression of VEGF genes encoded important regulators of angiogenesis and neurogenesis under hypoxic and ischemic conditions]. AB - The study of cellular and molecular processes that underlie the regeneration of nerve tissue is one of the most important problems of modern neuroscience. The solution of this problem is associated with the development of the new methods for the treatment of ischemic stroke. This paper investigated one of the key regulators of angio- and neurogenesis--vascular endothelial growth factor (VEGF). We stadied changes in the expression of VEGF genes under ischemia and hypoxic conditions in glioma cell lines U87 and its dependence on the ERN1 gene function. We found that the expression of VEGF genes in glioma cell lines U87 is significantly changed under hypoxia and ischemic conditions. Its expression depends upon the blockade of the ERN1 gene function. PMID- 23350127 TI - [Effect of rehabilitation using antihomotoxic drug together with energy stabilizing electromagnetic therapy on morphological, biochemical, and system immunity indices in children with recurrent bronchitis]. AB - There is now good evidence that the use of electromagnetic millimeter waves the following curative effects: analgesic, normalization of relations or increased formation of neurohumoral substances. The introduction of a therapeutic practice complex biological drugs that trigger, not overwhelming the body auxiliary immunological reaction, based on the activation of the regulation clones of T lymphocytes and helper functions, is an important step in achieving a qualitatively level of health patients with chronic disease. PMID- 23350128 TI - [Depressive disorders after closed craniocerebral injury]. AB - 71 patients were under the observation (37 male and 34 female) aged 30-74 years old (average age 51). Depression developed after 3-6 months after the cranial injury. 20 patients with vertebrogeneous lumbargy without injury were included into the comparing group. Neurological, pathopsycological and psychometric examination were carried out (according to Gamilton's, Bek's, Spilberger-Hanyn's scales). It was demonstrated that average depression level in patiens after cranial injury was the same as in patients without injury and it didn't depend on injury terms and neurological deficiency. Clinicaly manifested, severe, depression was noticed in 22% patients. Its degree was higher in cases of the right hemisphere localization of traumatic process. It was determined that psycosocial factors (lonlines) were the most significant for depression pathogenesis. Conditions of depression occurences were aftertraumatic intellect and high anxiety level. Loss of job didn't influence the patients condition. PMID- 23350129 TI - [Medical care to patients with remote consequences of traumatic craniocerebral injury using methods of reflexology]. AB - Head injury--is an important medical and social problem. In recent years Ukraine prevalence rate of patients with TBI is growing and now is 4-4,2 cases per 100 thousand population. In 50-80% or 2 of the 3 victims formed long-term consequences of closed head injuries that occur with frequent decompensation states with a temporary disability, often (11-12% of patients) have a strong disability. Use in osnovnovnomu acupuncture points of general application, segmental acupuncture points in the head, neck and scalp area. Treatment ought to be lengthy, with mnohorazovym conducting repeated courses. Most often, the following AND: VB(XI)20, VB(XI)21, T(XII)14, T(XII)20, GI(II)11, GI(II)15, GI(II)10, IG(VI)3, IG(VI)15, IG(VI)16, TR(X)5, TR(X)9, C(V)5, MC(IX)5, MC(IX)6, V(VII)40, V(VII)62, VB(XI)34, VB(XI)30, E(III)36, RP(IV)6. Take Effect braking method. PMID- 23350130 TI - [Stages of kinetotherapy and therapeutic massage for long time bedridden patients]. AB - Rehabilitation of stroke patients, is a complex chain of consistently conducted medical and social measures aimed at rehabilitation, health or possible adaptation to self-service in the presence of a persistent neurological defect. Already in acute stroke patient needs not only to drug therapy and care, but also in the emotional and psychological support for the type of "cautious optimism." It should be explained to the patient a temporary, reversible nature of its existing motor and other violations. With relatives patient should discuss the real situation, prognosis, rehabilitation opportunities, the need for hospitalization or appropriate treatment at home, put them in front of clear objectives for the near future. Activity and the amount of rehabilitation expanded in young children with satisfactory prognosis, consideration being given to their professional and social status. PMID- 23350131 TI - [Subacute inflammatory demyelinating polyradiculopathy associated with Epstein Barr viral infection: a clinical case]. AB - The clinical case of treatment a patient for subacute inflammatory demyelinating polyradiculopathy associated with Epstein-Barr viral infection is presented. It is showed that the period of rehabilitation after the indicated disease lasts long enough. It requires the differentiated approach in acute and recovery treatment period with using of different rehabilitation measures. PMID- 23350132 TI - [Rehabilitative treatment of obesity and overweight]. AB - The article presents epidemiological data, etiology, pathogenesis, classification, diagnostic criteria of obesity and overweight. Informed complex treatment of patients with obesity and overweight drug-free means and the results of treatment. The results show high efficacy of the treatment of this disease. PMID- 23350133 TI - [Analysis of single-photon emission computed tomography in patients with hypertensive encephalopathy complicated with previous hypertensive crisis]. AB - In cerebrovascular diseases pefuzionnaya single photon emission computed tomography with lipophilic amines used for the diagnosis of functional disorders of cerebral blood flow. Quantitative calculations helps clarify the nature of vascular disease and clarify the adequacy and effectiveness of the treatment. In this modern program for SPECT ensure conduct not only as to the calculation of blood flow, but also make it possible to compute also the absolute values of cerebral blood flow. PMID- 23350134 TI - [Venous insufficiency: clinical features, diagnosis and treatment]. AB - Cerebrovascular disease is a major public health problem. In recent years there has been a significant increase in cerebrovascular disease. These problems are related to improve the prevention and early detection methods for selecting the appropriate treatment. Treatment depends on the clinical manifestations: there are several major pathogenetic mechanisms such as brain edema, intracranial hypertension, vasospasm, increased vascular permeability. PMID- 23350135 TI - [Principles of post stroke rehabilitation]. AB - Clinical management of patients with acute cerebral blood flow depends on the cause and location of violation, clinical manifestations of the disease. Acute stroke patients during the course conducted in specialized intensive care and neurological departments of hospitals. The most frequent problems in patients who have had a stroke, is a violation of the motor and koordinatornye functions, language, vision and sensitivity, loss of skills and self-service moves. It is with these effects occur patients after discharge from hospital. PMID- 23350136 TI - [Criteria of limitation of vital functions in remote consequences of closed craniocerebral trauma]. AB - On the basis of international classification of functioning, limitations of vital functions and health (MKF) were conducted inspections patients with the remote consequences of the closed craniocerebral trauma. All of patients passed a standard clinical neurological inspection and testing with a help MKF. It is well proven that adaptation MKF allows to apply it at expert diagnostics, and also to estimate rehabilitation potential and efficiency of leadthrough of rehabilitation measures at patients with the remote consequences of the closed craniocerebral trauma. PMID- 23350137 TI - [Teaching rehabilitation in neurology for general practitioners of family medicine]. AB - In the article the educational and pedagogical and organizational measures designed and implemented in practice staff of the Department of Neurology and reflexology to improve the training of doctors cycle "general practice family medicines". OBJECTIVE: To optimize teaching process for doctors neurology "General practice - family medicine". We recommend using the following methods for diagnosing the level of training of cadets: Control of practical skills--the ability to explore the neurological status and interpret it in different neurological diseases, questionnaires, computer tests, solving situational problems. PMID- 23350138 TI - [Acupuncture in the treatment of neurasthenia]. AB - Neurasthenia--is the exhaustion of the nervous system, mental disorder that belongs to a group of neuroses. Doctors sometimes briefly describing him "irritable weakness" or "irritable fatigue." This term is justified: a person who suffers asthenic-neurotic syndrome, while experiencing fatigue and increased nervous excitability. Reasons neurasthenia quite a lot. Unfortunately, the lifestyle of modern man gives many reasons for the emergence of asthenic-neurotic syndrome. PMID- 23350140 TI - [Glutamate antagonists in treatment and rehabilitation of patients with postherpetic neuralgia]. AB - The article is devoted to modern views of the pathogenesis of postherpetic neuralgia, the risks of its occurrence in patients with herpetic ganglionitis and treatment in the acute period to prevent the development of chronic pain, as well as in the treatment of already developed postherpetic neuralgia with the use of glutamate receptors antagonists. PMID- 23350139 TI - [Cognitive impairments in early restorative period of ischemic stroke]. AB - The aim was to study prevalence and peculiarity of cognitive impairments in patients with ischemic stroke. 76 patients with stroke were examined in early restorative period of disease. Neurologic status of the patients was examined with NIHSS scale, Renkin scale was employed for measuring the degree of disability, MMSE and FAB was used to estimate cognitive functions. 24-hour, non invasive ambulatory blood pressure (BP) monitoring was used to reveal arterial hypertension and impairment of circadian rhythm of ABP. Considerable prevalence of cognitive impairments was shown. 34.2% patients suffered from dementia. The most impaired cognitive functions were memory, calculation, repetition and writing. Risk factors of cognitive impairments in patients with ischemic stroke were advanced age, severe neurological impairments, increasing SBP, minimal DBP. Examination cognitive function after stroke is necessary to plan treatment, prevention and reablement. PMID- 23350141 TI - [Carpal tunnel syndrome: diagnostics and conservative treatment]. AB - The Carpal tunnel syndrome is the most frequent entrapment neuropaphy of human. The Article is dedicated to diagnostics and conservative treatment this pathology. The early diagnostics and in time fixed treatment prevents the progress of the disease, raises the quality of life and allows to avoid surgical procedure. Big attention is given acupuncture reflexotherepy and infrared latherotherepy, which use raises the quality of the therapeutic influences. PMID- 23350142 TI - [Connective tissue dysplasia]. AB - The article presents a diagnosis of dysplasia of connective tissue in athletes, where the most important are the methods of clinical assessment using diagnostic tests and rating scales manifestation of connective tissue dysplasia. Evaluation of patients with suspected connective tissue dysplasia should include inspection of an ophthalmologist, orthopedic trauma, cardiology. Should also be carried out by criteria diagnosis degree of connective tissue dysplasia by T. Y. Smolnova (2003) (Large and small diagnostic criteria), which include: increased skin extensibility, joint hypermobility (sprain, dislocation and subluxation, flat feet), muscle hypotonia, a hereditary predisposition to the disease, evaluation of signs joint hypermobility (Beighton criteria). If during routine medical examination revealed athletes with manifestations of connective tissue dysplasia, they are subject to a more in-depth examination and observation. Early diagnosis of connective tissue dysplasia allows not only to plan the training process, but also reduces the trauma of athletes. PMID- 23350144 TI - [Reflexotherapy and evidence-based medicine]. AB - Assessment of the role and place of nontraditional methods of treatment and reflexotherapy, widely applied in hospitals is presented in the article. Besides, we become alerted regarding not serious approach of some scientists and health service managers to reflexotherapy as a whole and to one of its methods acupuncture. PMID- 23350143 TI - [Vertical integration--an important component of rehabilitation of patients with stroke]. AB - Today it is proved that the reduction of mortality from cardiovascular disease is achieved through the implementation of a coordinated set of measures, the most important of which is to increase public awareness of the risk factors for cardiovascular diseases and their prevention, implementation of effective prevention programs and improve the system of care for stroke. PMID- 23350145 TI - [Complex treatment of patients with chronic cerebrovascular insufficiency]. AB - Chronic cerebrovascular insufficiency is the most common manifestation of chronic diseases of the nervous system. Its main causes are hypertension and atherosclerosis. Diseases debut mainly on 5-6th decade of life. The condition prohreiyentnyy, but the degree of progression can be varied--from slow to galloping. Therefore, when studying the effectiveness of treatment programs, in our opinion, it is important to include the medical complex of different methods of reflexology. PMID- 23350146 TI - [Importance of vascular factors for cognitive rehabilitation in Parkinson's disease patients]. AB - The examination of the Parkinson's disease patients, patients with subcortical encephalopathy and their combination, using neuropsychological testings and definitions of the gait and balance disturbance degree, the dependence of balance impairment and cognitive functions from concomitant cerebrovascular patology has been revealed. PMID- 23350147 TI - [Rehabilitation of patients with herpetic neuroinfection]. AB - The clinical and etiopathogenetic heterogenity of herpes infection tropic to the nervous tissue are presented in this article. Filed basis of classification according to nosology, shape, type and period of the current herpes neuroinfection. Modern concepts of clinical laboratory and instrumental diagnostics of neuroinfections are presented. Highlight the major approaches to etiopathogenic therapy. PMID- 23350148 TI - [The clinic, diagnosis, complex treatment of diabetic polyneuropathy]. AB - Distal symmetric sensory-motor diabetic polyneuropathy (DPN)--the most common variant of diabetic neuropathy, which is expressed by more than 50% of patients with diabetes mellitus (DM) 1 and type 2. The pathogenesis of DPN is the damaging effect of chronic hyperglycemia. Based on this key trends in the pathogenetic treatment of DPN are the normal levels of blood glucose, improved tissue perfusion and oxygen consumption, improve the rheological properties of blood, to restore normal energy balance, reducing the severity of oxidative stress. PMID- 23350149 TI - [Headache in pregnant women]. AB - Headache (cephalgia) is one of the most common presenting complaints pregnant. Patients who report having had the same problem for some time prior to pregnancy do not usually have a neurological emergency. Chronic and recurrent headaches may be due to tension, migraine, sinusitis, pseudotumor cerebri or in many cases be unexplained. A patient with a neurological emergency does not present with a diagnosis but rather with one or several clinical manifestations. The nature of the presentation, sequence of events, and constellation of signs and symptoms suggests a differential diagnosis. Starting from the presentation, the physician must select diagnostic tests and procedures and then, once a diagnosis is made, initiate treatment. PMID- 23350150 TI - [Optimization of medical-diagnostic process in patients with traumatic brain injury during early rehabilitation]. AB - The problem of cardiovascular disease and cancer, the effects of traumatic brain injury is now one of the major health and social problems. Every year in Ukraine registered 200 thousand cases of the victims of traumatic brain injury. Of these, 30% of people then have persistent signs of disability that results in a disability, sometimes painful existence the patient and his relatives. Therefore, in order to bring man back into society after a traumatic brain injury, to the rehabilitation phase of treatment, immediately after the stabilization of the patient. PMID- 23350151 TI - [Multiple sclerosis: new approaches to comprehensive treatment and rehabilitation using methods of reflexotherapy]. AB - The article raises the question of integrated approaches to the treatment of multiple sclerosis, depending on the phase of the disease, type of course and comorbidity. The features of rehabilitation in this disease, discussed the feasibility of reflexology techniques in complex medical and rehabilitation measures. PMID- 23350152 TI - Craniofacial morphologic and anthropometric features of Croatian schizophrenia patients and non-psychiatric controls--a pilot study. AB - AIM: to evaluate differences in craniofacial morphologic features and several anthropometric measures between schizophrenia patients and non-psychiatric controls, and to find the best-fit model to differentiate between two groups. METHODS: 40 morphologic features of the head and face, and 5 craniofacial anthropometric measures were evaluated using the Lane Dysmorphology Scale in 58 patients and 46 controls. Total MPA score and subscores for different craniofacial regions were calculated. Individual items were examined using logistic regression analyses to define a model that can discriminate between patient vs. control status. RESULTS: total MPA score, and several subscores (general asymmetry, nasal, lip, ear and tongue) were significantly higher in the patient group. Patients were distinguished by significantly higher measures of maxillary and mandibular facial arcs, general and subtle facial asymmetries presented as deviation of facial landmarks from the vertical facial midline and horizontals, more variable vermilion of the upper lip, tongue surface, frenulum and anterior hair margin, and more adherent and underdeveloped earlobes. A final regression model including maxillary are, facial asymmetry, and adherent earlobes as independent predictors proved useful to efficiently recognize schizophrenia patients (specificity and positive prediction value of 100% when all the three items were present in an individual) or to exclude risk for schizophrenia (sensitivity and negative prediction value of 96.6% and 84.6%, respectively, in cases no one of the three items was present). CONCLUSIONS: schizophrenia patients evidenced significantly more craniofacial dysmorphology than controls. The model revealed in the study needs to be verified in larger samples and other populations. PMID- 23350153 TI - Menopausal complaints in Slovak midlife women and the impact of CYP1B1 polymorphism on their incidence. AB - A wide variety of symptoms have been attributed to menopause, negatively influencing women's physical and psychological health. In addition to lifestyle parameters and personal history, genetic factors are considered to be the main source of this variation. This study aims to investigate the incidence of menopausal symptoms among midlife women according to their menopausal status, and to evaluate the contribution to their manifestation from CYP1B1 Leu432Val polymorphism as a predisposing factor for menopausal symptoms. The studied cohort consisted of 299 women ranging from 39 to 59 years of age. Women were recruited from the western and middle parts of Slovakia, and all participants completed a menopause-specific questionnaire and provided blood or saliva samples for genotyping. Our results indicated that all women are at risk of typical menopausal symptoms, but there is a higher number of postmenopausal women affected than premenopausal ones. Regression analysis showed that the CYP1B1 Leu/Leu genotype can increase the experience of bloated stomach and facial hair increase in all the sampled women, while the Leu/Leu genotype may increase experience of palpitations and involuntary urination in the premenopausal women. The Leu/Leu genotype may increase the experience of nausea, bloated stomach, and vaginal dryness in peri- and postmenopausal women. We determined that women with the Leu/Leu, or Leu/Val genotypes were approximately five times more likely to suffer from vaginal dryness than the Val/Val women (OR = 4.948; 95% CI, 1.259 19.447). We therefore suggest that CYP1B1 Leu432Val polymorphism could be involved in individual susceptibility to menopausal symptoms in Slovak midlife women. PMID- 23350154 TI - Further evidence supporting a genetic background for Paget's disease of bone in Spain. AB - The aim of this paper is to investigate heritable factors that might be related to the recognised genetic susceptibility for developing Paget's disease of bone (PD). This was a hospital-based, case-control study of a systematically selected group of PD patients and a group of controls drawn from the same health setting. In these populations we assessed surname pattern, parental consanguinity and constitutional physical traits. In a separate case-control analysis, genetically based features and pathological traits of interest for genetic inference in 43 demonstrated familial cases were then compared to those in 24 sporadic cases. Results showed coincidence of three or four surnames (Odds Ratio [OR] = 5.6; 95% CI = 1.7-18.5), degree of parental consanguinity (OR = 4.1; 95% CI = 2.1-1.8), and green or blue eye colour (OR = 1.5; 95% CI = 1.1-2.1) were significantly associated with PD. Comparison of proven familial and sporadic PD cases showed that the former had a stronger association with Monckeberg-type vascular calcifications (32% vs. 4%; p = 0.02), percentage of skeleton affected (13.1 vs. 9.0), and green and blue eye colour (82% vs. 25%; p = 0.006), with Monckeberg type vascular calcifications being the main variable of interest (OR = 30.9; 95% CI = 12.75-347.00) in the multivariate analysis. In conclusion, heritable factors are crucial in the pathogenesis of PD and, in line with other data sources, might account for the ethnic predisposition observed in different countries. PMID- 23350155 TI - Multiplex analysis of genetic markers related to body mass index (BMI) and bone mineral density (BMD). AB - The multiplex analysis system described here allows simultaneous typing of one short tandem repeat (STR) and three single nucleotide polymorphisms (SNPs) that are associated with obesity and/or osteoporosis. Genes that are related to a high body mass index (BMI) and/or a high bone mineral density (BMD) are presumed to give an advantage in surviving famines. This analysis system makes it possible to genotype the (TTTA)n polymorphism of CYP19 and three SNPs, namely the rs1800795 polymorphism of IL6, the rs373 6228 polymorphism of LRP5 and the rs993 9609 polymorphism of FTO, in a single PCR amplification in recent and ancient DNA samples. Furthermore, it allows a synchronous authentication of the results with the (TATC)n polymorphism of D13S317, the (TCTA)n polymorphism of D21S11 and the (TTTC)n polymorphism of FGA in a partial genetic fingerprinting. For this purpose, PCR products for fragment-length analysis, as well as those for sequence analysis, were amplified together. After amplification, the PCR product was split into two aliquots. The first aliquot was used for fragment-length analysis and the second one for sequence analysis. The analysis system described here has been optimized for analysing ancient samples, since only minimal amounts of material are available. PMID- 23350156 TI - The temperature of cremation and its effect on the microstructure of the human rib compact bone. AB - The presented study deals with the effect of the cremation temperature on the microstructure and morphology of the human compact bone. The biological material consisted of samples from ribs of recent Central European origin belonging to individuals of known age, sex and cause of death. Each bone sample was divided into several sections. One section remained unburned and the rest were burned at 700, 800 and 1000 degrees C. A few samples were burned also at the temperature of 600 degrees C. The undecalcified unstained ground cross-sections were made from burned and unburned bones; photographed and analysed using the SigmaScan Pro 5 programme. During burning, both the macroscopic and microscopic dimensions of the bone shrink, including the measures of the individual microstructures. The percentual representation of the area of individual microstructures on the area of the cross-section decreases. The number of individual microstructures per mm2 of the compact bone cross-section increases. Most microstructural variables demonstrated statistically significant differences at the individual temperatures of cremation. The burned bones showed a large scale of the colours, especially at 700 degrees C. PMID- 23350157 TI - A detection of microevolutionary changes by the analysis of qualitative dermatoglyphic traits: an example of Albanians from Kosovo. AB - In this study we analyzed the qualitative dermatoglyphic traits in the Albanians from three Kosovo distinct regions. We aimed to detect possible microevolutionary changes, which could have happened as a consequence of geographical and cultural isolation. The dermatoglyphic traits were analyzed for total 641 Albanians of both sexes. The analysis included 4 variables on fingers, 8 on palms and terminations of A, B, C, D and T main-lines. The differences in patterns incidence were tested using the chi-square test. The frequencies of several pattern types varied to a great extent between distinct groups with statistically significant difference in most of the cases. Our results indicated that the Albanians from South Morava valley and from Kosovo plain were genetically close, and the population from Dukagjini valley is less close to any of them. The analysis of qualitative dermatoglyphic patterns may be utilized effectively to track the microevolutionary changes. This is especially useful in a developing country like Kosovo, since it is an inexpensive and effective tool for screening and studying the patterns influenced by the divergence of population. PMID- 23350158 TI - Anthropological examination of the chronologically separated groups of the 11th 13th century Zalavar-Chapel (Zalavar-Kapolna) cemetery from Hungary. AB - SUMMARY: The Zalavar-Chapel (Hungarian: Zalavar-Kapolna) cemetery was found near the village Zalavar, located in the western part of the Lake Balaton, in the area of the Little-Balaton (in Hungarian: Kis-Balaton) in Hungary. Burial around the chapel started in the second half of the 11th century and was finished in the 13th century. During this period, significant changes occurred in the burial customs, thus the graves can be divided into four groups (horizons) chronologically. The first horizon includes the earliest, while the third and fourth the latest burials. Earlier, it was assumed that the differences in the burial customs were signs of population changes in that area. However, based on the results of our examination, it was used most probably by the same population throughout the whole time. The craniometric comparison of the skeletons of the Zalavar-Chapel cemetery by Euclidean and Penrose distance analysis with the skeletons of other 114 cemeteries--mainly from the Carpathian-basin--showed that the majority of the population of the studied cemetery originated from the 9th century population of the area. PMID- 23350159 TI - A review on post-puberty hypothyroidism: a glance at myxedema. AB - Hypothyroidism, is a thyroid disorder accompanied by serum thyroid hormone reduction when thyroxin T4, the main thyroid hormone, reduced, it is followed by disruption of a negative-feed back auto regulatory mechanism on pituitary gland and subsequent thyroid stimulating hormone (TSH) which is released into the blood circulation to stimulate the thyroid gland to produce enough thyroid hormone to compensate for the body hormone requirements. Therefore, reduced serum thyroxin(T4) in principle, triidothyronine (T3) and elevated TSH are laboratory indices for the diagnosis of hypothyroidism. At early stage of hypothyroidism although laboratory measurements of thyroid function test are manifest the thyroid disorder but the patient clinical signs and symptoms may remain unnoticed. If the patient undiagnosed and untreated the condition of hypothyroidism worsen and the clinical manifestation begin to show itself and myxedema is a definition given to the whole picture of untreated hypothyroidism at very end stage the patients enter into myxedema comma with eventual death due to the sever symptoms of hypothyroidism. Among important causative factors leading to catastrophic events in myxedema is life threatening hypothermia, heart and cerebral dysfunctions. PMID- 23350160 TI - Interaction between heavy metals and thiol-linked redox reactions in germination. AB - Thioredoxin (TRX) proteins perform important biological functions in cells by changing the redox state of proteins via dithiol disulfide exchange. Several systems are able to control the activity, stability, and correct folding of enzymes through dithiol/disulfide isomerization reactions including the enzyme protein disulfide-isomerase, the glutathione-dependent glutaredoxin system, and the thioredoxin systems. Plants have devised sophisticated mechanisms to cope with biotic and abiotic stresses imposed by their environment. Among these mechanisms, those collectively referred to as redox reactions induced by endogenous systems. This is of agronomical importance since a better knowledge of the involved mechanisms can offer novel means for crop protection. In the plant life cycle, the seed and seedling stages are key developmental stages conditioning the final yield of crops. Both are very sensitive to heavy metal stress. Plant redox reactions are principally studied on adult plant organs and there is only very scarce informations about the onset of redox regulation at the level of seed germination. In the here presented study, we discussed the importance of redox proteins in plant cell metabolism and defence. Special focus is given to TRX, which are involved in detoxification of ROS and also to their targets. PMID- 23350161 TI - A comparison of effects of ABVD and ChlVPP chemotherapeutic protocols for Hodgkin's disease on rats' epididiymal and testicular tissues. AB - The goal of this study was to determine the effects of ABVD and ChlVPP chemotherapeutic protocols for Hodgkin's disease on the structure of testis and epididymis of male rat. After determining tolerance dose of drugs in pilot study, 24 male rats were divided to four groups: ABVD (doxorubicin, bleomycine, vinblastin, dacarbazine) group, ChlVPP (chlorambucil, vinblastin, procarbazine, prednisolone) group and two control groups one for each treatment group. One half of the lethal dose for 50% of population (LD50) was used for treatment of animals in each protocol. Testes and epididymis tissues were examined for structural changes and serum testosterone level was measured by Lission (chemiluminescence method). Body weight, testis and epididymis weights, in treated rats were significantly less than their control groups specifically in ABVD group was less than ChlVPP group. Decreasing of mean diameter of seminiferous tubules, height of spermatogenic cells and diameter of epididymis in caput, corpus and cauda in ABVD group were significantly more than ChlVPP and control group. The serum testosterone level in ABVD group was significantly less than ChlVPP and control group. According to this study results, the ChlVPP had fewer impairment effects than ABVD on testis and epididymis tissue in tolerance doses on male rats' reproductive system. More clinical trial studies are suggested on Hodgkin's patients. With equal treatment effectiveness, it will be better to use the most reliable and safe treatment especially in young patients. PMID- 23350162 TI - Bone mineral content measured by DEXA scan in preterm neonates receiving total parentral nutrition with and without phosphorus supplementation. AB - Intravenous phosphorus preparation was not available in Egypt till recently. So we aimed to prove the positive effect of adding intravenous phosphorus to total parentral nutrition (TPN) on calcium (Ca) and phosphorus (PO4) metabolism ofpreterm neonates by measuring bone mineral content (BMC) using DEXA scan. A case-control study was conducted in NICU of Obstetric and Gynecology Hospital of Ain Shams University which is a tertiary care unit in Cairo. Thirty preterm infants were prospectively enrolled in the study divided into 2 groups; 15 preterm infants received TPN with phosphorus supplementation (group 1) and 15 preterm received TPN without phosphorus supplementation (group 2). Serum Ca, PO4 and alkaline phosphatase (ALP) assay were done together with urinary calcium/creatinine (Ca/Cr) ratio, abdominal ultrasound and DEXA scan. There were no significant difference regarding serum Ca and PO4 between group 1 and 2. Yet there were highly significant increase in serum ALP and urinary Ca/Cr ratio in group 2 compared to group 1 (p = 0.001). Also group 1 had significantly higher BMC compared to group 2 even with TPN duration less than 15 days (p = 0.001). BMC was significantly positively correlated with G.A and B.W in both groups and was significantly negatively correlated with serum ALP in group 2 and with urinary calcium/creatinine ratio in group 1. Duration of TPN as short as 2 weeks can affect negatively the BMC as documented by DEXA scan in preterm infants receiving TPN without phosphorus supplementation. PMID- 23350163 TI - Embryo-feto-toxicity of anticancer drug, heptaplatin in laboratory mice. AB - The present study was conducted to test the possible teratogenic and toxic effects of anti-cancer drug heptaplatin (SKI 2053) on developing embryos and fetuses in gestating SWR/J mice. Dose levels of 5.0, 10.0 and 12.5 mg heptaplatin/kg b.wt. were intraperitoneally administered to pregnant mice on days 6-8, 9-11 and 12-14 of gestation. On day 17 of gestation, all fetuses were removed and examined for toxic phenomena (embryo-fetal toxicity) by taking observation on live fetuses and embryonic resorption. Fetuses were also examined for external, internal and skeletal malformations. None of the dams treated with heptaplatin at any of the dose levels used in the present study died during the experimental period. Higher doses of heptaplatin caused greater embryonic resorption and reduced number of live fetuses. However, no loss of body weight was noticed in fetuses at any of the dose levels administered. At highest dose of heptaplatin (12.5 mg kg(-1)), tail deformity was observed in the form of short and curve tails whereas no other anatomical or skeletal malformations were noticed in any of the fetuses. In addition to mild embryo-fetotoxicity, the study indicates mild teratogenic effects of hetaplatin as reflected in fetal abnormalities at low frequency. These results have significant implications for protracted use of this drug. PMID- 23350164 TI - Comparison the effects of two educational methods on knowledge, attitude and practices of Arak physicians about breast cancer. AB - Breast cancer is the most common and most preventable cancer in women and early detection has the important role in reducing its morbidity and mortality, so increase 95% survival time. The present study conducted to compare the effects of two educational methods on knowledge, attitude and practices of Arak physicians. An interventional study after randomized allocation of each 64 physician to any of two different educational methods (video and systematic review) used to compare knowledge; attitude and practices score variation about breast cancer screening skills. Data collection carried out with structured questionnaire and entered to SPSS software. Data analyzed by t-test, paired t-test and Man-Whitney test in significant level of 0.05. Mean of total score of knowledge, attitude and practices (KAP) showed a significant difference before and after training and the total score of KAP increase (p < 0.05). But KAP score variation and their subscales were same in two groups and didn't show any significant difference (p > 0.05). Although KAP in Arak physician is appropriate and any educational program increase their KAP level, but continuing and repetition of educational courses seems to be necessary. PMID- 23350165 TI - Features of premature ejaculation in infertile men. AB - Premature ejaculation (PE) is the most common form of sexual dysfunction and is one of the causes of male factor infertility. The aim of this study was assay of frequency and features of PE in a group of infertile men. This cross-sectional study was carried out since December 2006 to January 2008 on a sequential sample of 300 male patients complaining of infertility referring to the only infertility research center of Tabriz al-Zahra hospital. Data were collected by a designed questionnaire in which there were questions about age, age of marriage, history of sexual transmitted disease, drug use, previous sexual contacts, systemic diseases, masturbation, erectile dysfunction and frequency of intercourse. The mean age of studied patients was 30.39 +/- 5.76 and 43% of patients had PE, that in 74.4% primary PE and in 25.6% secondary PE seen. The most common form of ejaculation latency time was about less than 1 min that was seen in 51.2% of patients with PE. Mean of masturbation times was 5.13 +/- 3.19 times per month, and there is significant relation between the age of patients and type of PE, (p = 0.001) and ejaculation latency time and type of PE (p = 0.035). The high frequency rate of PE in Iranian men with complaint of infertility and also relatively lower age of these patients reflects the necessity of attention and management of this imperative psycho-organic disorder. PMID- 23350166 TI - A hospital reborn. Replacement facility gives organization a new beginning. AB - Having delivered more than 297,000 babies since it opened in 1968, it's no wonder that Woman's Hospital in Baton Rouge, La., calls itself "the birthplace of Baton Rouge". Now, with the construction of a replacement facility, Woman's Hospital is experiencing a new beginning of its own. n PMID- 23350167 TI - Practice makes perfect. Planning considerations for medical simulation centers. PMID- 23350168 TI - Senior settings. How some facilities are accommodating the aged. PMID- 23350169 TI - 'Code blue': Planning and managing emergency water systems. PMID- 23350170 TI - Carpeting concepts. PMID- 23350171 TI - Watching for hot spots. Advice on pest control in the health care environment. PMID- 23350172 TI - Employment-based retiree health benefits: trends in access and coverage, 1997 2010. PMID- 23350173 TI - "Nursing strategy success depends on everyone". PMID- 23350174 TI - Strategy calls for action on staffing. PMID- 23350175 TI - "Give nurses the skills to create transparent and safe cultures". PMID- 23350176 TI - "It may be Christmas but we can't extend goodwill to all men". PMID- 23350177 TI - "A methodical approach can help manage difficult patients". PMID- 23350178 TI - Supporting young people to move to adult services. AB - Young people with chronic kidney disease can have poor treatment outcomes and struggle to come to terms with their condition. They may also find the transition from paediatric to adult services difficult. A support service is taking an evidence-based approach to these issues, recording outcome data to measure the efficacy of its interventions. PMID- 23350179 TI - Working with families to boost children's continence. AB - This article discusses a new care model for managing idiopathic paediatric continence problems. A key aspect of the innovation is empowering the child and family to self-manage the problem. This resulted in improved treatment outcomes and reduced both "did not attend" rates and waiting lists. It was also cost effective. PMID- 23350181 TI - Updated RCN guidance on digital rectal examination. PMID- 23350180 TI - Crohn's disease in adults and children. PMID- 23350182 TI - End-of-life care for people with urological cancer. AB - The National End of Life Care Intelligence Network has produced its first report looking at differences in where people with urological cancers die--at home, in hospital, hospices or nursing homes--depending on the type of cancer they have and other factors such as age, sex and socioeconomic status. This article summarises the key findings of the report and their implication so for urology nursing practice. PMID- 23350183 TI - Non-blanching rash in an infant with bronchiolitis. PMID- 23350184 TI - Improving services for long-term conditions. AB - Providing services by personal need, rather than by specialty, could improve services and make better use of NHS resources. NHS Improvement's long-term conditions pathway recognises nurses' key role in planning care and responding to need, and offers four key steps for better care. PMID- 23350185 TI - 60 seconds with Jenny Kay. PMID- 23350186 TI - Time to go back to school. PMID- 23350187 TI - Write your way to a winning funding bid. PMID- 23350188 TI - [Streptomyces sp. 17, an organism producing oligomycin SC-iI (culture characteristics and antibiotic biological properties)]. AB - Under the screening programme for organisms producing substances with hypolipidemic and antifungal activity Streptomyces sp. 17 was isolated. The taxonomic properties of the strain were investigated. Active compounds, i.e. oligomycin A and oligomycin SC-II were isolated from a complex biosynthetic product. Oligomycin A showed high antifungal activity whereas oligomycin SC-II had also moderate antibacterial activity. PMID- 23350189 TI - [Submerged cultivation and chemical composition of Hericium erinaceus mycelium]. AB - Submerged cultivation of Hericium erinaceus in various media was studied. The yield of the biomass was shown to depend mainly on the carbon source, whereas the content of water soluble polysaccharides depended mainly on the nitrogen source. The optimal medium composition provided the biomass yield of 21-23 g/l in 7 days. The biomass was characterized by the content of total protein, lipids and carbohydrates. In addition, the amino acid composition of the biomass was determined and shown to meet all the requirements of FAO/WHO concerning the amounts of essential amino acids (with exception of tryptophane). Oleinic and linoleic acids were identified as the main components of the fatty acids. Two water soluble polysaccharide fractions differing in solubility in aqueous ethanol were isolated and shown to contain rhamnose, fucose, xylose, glucose and galactose in different proportions. Vitamins B1, B2, B6, PP and E, ergosterol and coenzyme Q were also detected in the biomass of H. erinaceus. PMID- 23350190 TI - [Experimental and clinicolaboratory evaluation of complex therapy efficacy in arboviral infections]. AB - Search for drugs efficient in prophylaxis and treatment of dangerous infections (especially arboviral ones) is rather actual, since no specific therapy is available. Many-year investigations of interferon inductors showed that they had immunomodulating, antiviral and antiinflammatory effects and were low toxic. The present study demonstrated that the protective effect was the following: Venezuelan equine encephalitis (VEE)--cycloferon > amixin = ridostin, Rift Valley fever (RVF)--cycloferon > amixin > ridostin, predator pox (PP)--cycloferon > amixin = ridostin, that was obvious that cycloferon was the most active agent in the treatment of VEE, RVF and PP, thus making it possible to acknowledge its priority in prophylaxis and therapy of dangerous viral infections (DVI). Ribavirin in combination with cycloferon solution or cycloferon tablets provided shorter periods of the fever, minimized the intoxication syndrome, promoted earlier resolution of hemorrhagic eruption and lowered the frequency of complications, which was in favour of the disease prognosis. PMID- 23350191 TI - [Ergoferon and oseltamivir in treatment of influenza: results of multicentre randomized comparative clinical trial]. AB - The narrow range of choice and virus resistance to the most common drugs require search and introduction of new drugs with proven efficacy and safety for the treatment of influenza. Ergoferon is a new combined medicine containing release active antibodies to interferon-gamma (anti-IFNgamma), CD4-coreceptor and histamine. The formulation influences various links of antiviral defense and provides antiinflammatory effect. The efficacy of the drug is related to its production process during which multiple reduction of the initial concentration of every component leads to release of special release activity. Previous experimental studies showed that anti-IFNgamma had antiviral activity against pandemic influenza virus A (H1N1) 2009 comparable to that ofoseltamivir (suppression of virus replication in the lung tissue, increase of the lifespan and reduction of the laboratory animals mortality). The aim of the multicentre randomized clinical trial was to compare (versus oseltamivir) the efficacy and safety of ergoferon in the treatment of influenza in adults. 213 patients with flu-like symptoms were examined in 8 medical centres of Russia during two epidemiological seasons (2010-11 and 2011-12). The inclusion criteria were: the first 48 hours after the onset; fever > or =37.8 degrees C, at least one common symptom and at least one respiratory symptom. Influenza was confirmed in 52 patients by QuickVue rapid diagnosis. 23 patients received ergoferon according to the treatment scheme and 29 received oseltamivir (daily dose 150 mg). Duration of the treatment was 5 days. The patients were followed up for 7 days. The primary endpoint was the percentage of the patients with the body temperature normalization for 2-5 days of the treatment. The maximum efficacy of ergoferon was observed on the second day of the treatment: almost half (48%) of the initially febrile patients had normal body temperature (versus 28% in the patients treated with oseltamivir). The comparison of the two groups of the patients by the morning and evening measurements of the body temperature every five days of the treatment by Cochran-Mantel-Haenszel revealed a significant difference between the two groups (chi2 = 7.1; p = 0.008). The average duration of the fever in the group of ergoferon was 2.3 +/- 1.2 days, in the group of oseltamivir--2.6 +/- 1.3 days (the efficacy of oseltamivir in the present study was comparable with the previously published data). The percentage of the patients treated with antipyretics because of hyperthermia on the second day of the treatment lowered 3 times and amounted to 17% (versus 41% in the oseltamivir group). The severity of common and respiratory symptoms (nose/throat/chest) significantly decreased on the third day of the treatment in both groups, the majority of the patients had either minimum severity or no signs of influenza. The clinical improvement was associated with positive changes in the life quality. No cases of the disease aggravation were recorded. Complications requiring antibiotic treatment or hospitalization were not observed during the followup. There were no adverse events recorded due to the drug use. No deviations in the laboratory indices were stated. Ergoferon is a new safe drug for the treatment of influenza. Its clinical efficacy was comparable to that of oseltamivir. The therapeutic effects of the drug were evident from: significant reduction of the disease severity, duration of febricity and general toxicity and respiratory flu symptoms, lower percentage of the patients with fever for 2 days. The febrile period in most of the patients did not exceed 2 days. PMID- 23350192 TI - [Remaxol hepatoprotective therapy of patients with tuberculosis and HIV infection in day unit of tuberculosis dispensary]. AB - To improve the treatment of hepatotoxic responses to antituberculosis polychemotherapy, the impact of remaxol on the biochemical indices and parameters of the antioxidant system in patients with tuberculosis and HIV infection was estimated. The use of remaxol having cytoprotective, anticholestatic, antihypoxitic and antioxidant effects in the treatment of patients with tuberculosis and HIV infection and liver drug damage due to tuberculosis polychemotherapy significantly improved the biochemical indices and lowered the level of the cytolytic and cholestatic syndromes. Remaxol increased the antioxidant system potential and had an antihypoxitic effect. PMID- 23350193 TI - [Role and place of antibacterial therapy in prophylaxis of disturbances in reproductive function of women]. AB - One-stage retrospective analysis of 350 primary medical documents of the female patients treated under hospital conditions for salpingo-oophoritis in 2010-2011 was performed. The results were compared with those of the investigation of the present etiological pattern of pelvic inflammatory diseases (PID) by the data of the microbiological examination of 117 patients with PID and susceptibility of the isolates to the antibacterials. The frequency and efficiency of the use of antibacterials alone or in combinations were analysed in the treatment of various clinical forms of PID. The ovarian reserve was estimated in 87 patients after recovery from salpingo-oophoritis. 52 of them had an episode of the chronic process exacerbation and 35 had the first episode of acute PID. The ovarian reserve was estimated by determination of the anti-Mullerian hormone (AMH), basal FSH level, ovarian volume and antral follicle count. A statistically significant decrease of the ovarian reserve in the patients with chronic salpingo-oophoritis confirmed the necessity of rational treatment of the acute inflammatory process. PMID- 23350194 TI - [Biologically active nonribosomal peptides. III. Mechanism of biosynthesis of nonribosomal peptides]. AB - The third part of the review is concerned with investigation of nonribosomal peptides. PMID- 23350195 TI - [Current methods of cytochrome p450 analysis]. AB - Current review describes recent approaches of cytochrome P450 concentration and activity evaluation. Special attention paid to modem methods of proteomic analysis such as electrophoresis and chromato-mass-spectrometry. Methods of targeted proteomic applicable for quantitative and qualitative study of P450s in biological samples as well as methods for the enzyme activity measurements are reviewed. Finally, data on correlation between certain P450 isoform content and its specific enzymatic activities were described and discussed in the review. PMID- 23350196 TI - [Biochemical markers predicting response to radiation- and radiochemo-therapy in cancer patients]. AB - In last years there is increasing interest in radiogenomics and the characterization of DNA array molecular profiles that can predict tumor and no tumor tissues radioresponse. Ongoing studies carried out worldwide in the banking of tumor and no tumor samples give evidence that perspective markers for response prediction in individual patient to intended radiation therapy can be some apoptotic indexes, spectrum a number of specific proteins, and DNA-based microarray molecular profiling analysis as well determination of single nucleotide polymorphisms in genome of the patients. So far there are only a few robust reports of molecular markers predicting tumor and no tumor tissues response to radiation. The results of new studies, which in future should be validated in larger definitive trials, are likely to see in nearest years. It is needed to determine technologies of methods and to define more precisely areas of its applications. PMID- 23350197 TI - [Analysis of complex formation of human recombinant HSP70 with tumor-associated peptides]. AB - Molecular chaperones of HSP70 family assists presentation of exogenous antigenic peptides by antigen-presenting cells (APC). HSP70-peptide complexes are powerful immunotherapeutic agents, which enhance cross-presentation of captured antigen in dendritic cells and macrophages. Several clinical trials have shown that HSP based cancer vaccines possess good efficacy and safety. However, sometime it is impossible to isolate sufficient amount of vaccine. These make us to pay attention for recombinant HSP70-based vaccines and to optimize in vitro complex formation mechanism. Here we have investigated two human recombinant proteins HSP70(HYB) and HSC70. Optimal values of ADP concentration, pH, temperature and peptides excess are determined in this work. We have also shown that proposed complex formation method enriches eluted from HSP70-complexes peptide repertoire compared to in vivo assembled ones. PMID- 23350198 TI - [Thermosensitization of tumor cells with inhibitors of chaperone activity and expression]. AB - Effects of inhibitors of the heat shock protein 90 (HSP90) chaperone activity and inhibitors of the heat shock protein (HSP) expression on sensitivity of HeLa tumor cells to hyperthermia were studied. It was found that nanomolar concentrations of inhibitors of the HSP90 activity (17AAG or radicicol) slowed down chaperone-dependent reactivation of a thermo-labile reporter (luciferase) in heat-stressed HeLa cells and slightly enhanced their death following incubation for 60 min at 43 degrees C. Herein, the inhibitors of HSP90 activity stimulated de novo induction of additional chaperones (HSP70 and HSP27) that significantly increased the intracellular HSP levels. If the cells were treated with 17AAG or radicicol along with an inhibitor of the HSP induction (e.g. quercetin or triptolid, or NZ28), this fully prevented the increase in intracellular chaperone levels resulting from the inhibition of HSP90 activity and subsequent heating. Importantly, in the case of conjunction of all the three treatments (an inhibitor of the HSP90 activity + an inhibitor of the HSP induction + 43 degrees C for 60 min), the reporter reactivation was retarded yet stronger while the cell death was sharply (2-3-fold) enhanced. Such an enhancement of the cytotoxicity appears to occur owing to the "chaperone deficiency" when prior to heat stress both the functional activity of constitutive HSP90 and the expression of additional (inducible) chaperones are blocked in the cells. PMID- 23350199 TI - [Cell-free DNA fragments increase transcription in human mesenchymal stem cells, activate TLR-dependent signal pathway and supress apoptosis]. AB - Human mesenchymal stem cells (MSCs) are now widely adopted in regenerative medicine. However, many questions on the role of different signaling pathways in the regulation of stem cell (SC) functional activity within the organism remain unaswered. In damaged regions the level of cell death increases and DNA fragments from dead cells (cell-free DNA, cfDNA) are accumulated in blood. We showed that in adipose-derived MSCs exposed in vitro to cfDNA fragments the transcription level increased (the total amount of cellular RNA and the rRNA amount rose). GC rich CfDNA fragments (GC-DNA) activated the TLR9-dependent signal pathway: the expression of TLR9 and of TLR9-signaling pathway adapter--MyD88--was up regulated. AT-rich DNA fragments did not increase the TLR9 expression, though, the MyD88 expression level rose. So we suggest that AT-DNA acts via some other receptors that nevertheless activate MyD88-dependent signalling in MSCs. We also showed that cfDNA fragments decreased the activity of caspase, an apoptotic enzyme. So, ctDNA can significantly influence the functional activity ofMSC by activating TLR9- and MyD88-dependent signal pathways and lowering the apoptosis level. PMID- 23350200 TI - [The change in the structural and functional organization of the Guerin's carcinoma cytochrome part of respiratory chain in tumor carriers in the conditions of preliminary low-level irradiation]. AB - The effect of low-level irradiation of tumor-bearing rats on the structural and functional organization of the cytochrome part of respiratory chain of mitochondria isolated from Guerin's carcinoma has been investigated. The maximal reduction in the mitochondrial cytochromes a, b and c content was observed at the terminal stage of Guerin's carcinoma. A low-level irradiation during initial stages of oncogenesis produced opposite changes in the mitochondrial cytochrome content. The possible mechanism of mitochondrial haem-containing cytochromes content reduction may be attributed to impairment in their formation caused by inhibition of the key enzyme of haem synthesis, 5-aminolevulinate synthase. The determined changes of the mitochondrial cytochromes quantitative content were accompanied by decreased activity of cytochrome oxidase. The preliminary low level irradiation of the tumor-bearing animals produced further reduction in the cytochrome oxidase activity observed in all experimental periods. PMID- 23350201 TI - [Activity of endogenous aldehydes catabolism enzymes in subcellular fractions of liver, heart and brain of rats at pubertal age under stress]. AB - Activities of enzymes involved in redox transformation of endogenous aldehydes have been investigated in subcellular fractions of liver, heart, and brain of pubertal rats exposed to prolonged immobilization stress. In the liver aldo-keto reductase (AKR) activity in the postmitochondrial fraction and aldehyde dehydrogenase (ALDH) acivity of the mitochondrial fraction demonstrated a more pronounced decrease in 2-month-old rats. Rat heart postmitochondrial AKR and ALDH demonstrated opposite changes in their enzymatic activities, while activity of mitochondrial ALDH remained unchanged. Brain cells create conditions that favor effective utilization of endogenous aldehydes in metabolic redox pathways. PMID- 23350202 TI - [The influence of inhibiting no formation on metabolic recovery of ischemic rat heart by apelin-12]. AB - Apelin 12 (A-12) was synthesized by the automatic solid phase method with use of Fmoc 1H-NMR spectroscopy and mass spectrometry. Effects of apelin-12 (a peptide comprised of 12 aminoacids, A-12) on recovery of energy metabolism and cardiac function were studied in isolated working rat hearts perfused with Krebs buffer (KB) containing 11 mM glucose that were subjected to global ischemia and reperfusion. A short-term infusion of microM 140 A-12 in KB prior to ischemia enhanced myocardial ATP, the total adenine nucleotide pool (SigmaAN = ATP + ADP + AMP) and the energy charge of cardiomyocites ((ATP + 0.5ADP)/SigmaAN) at the end of reperfusion compared with control (KB infusion) and reduced lactate content and lactate/pyruvate ratio in reperfused myocardium to the initial values. This effect was accompanied by improved recovery of coronary flow and cardiac function. Coadministration of 140 microM A-12 and 100 microM L-NAME (the nonspecific NOS inhibitor) profoundly attenuated the peptide influence on metabolic and functional recovery of reperfused hearts. The results indicate involvement of NO, formed under the peptide action, in mechanisms of cardioprotection that are tightly associated with recovery of energy metabolism in postischemic heart. PMID- 23350203 TI - [The antiradical activity of plant extracts and healthful preventive combinations of these exrtacts with the phospholipid complex]. AB - Using the chemiluminescence method, the effective concentration of antioxidants (AO) and its reactivity toward peroxyl radicals (ARA, the k7 constant) have been measured for 13 plant extracts. In fact all extracts demonstrated ARA higher than ionol. Larix dahurica, Hypericum perforatum, Potentilla fruticosa, Aronia melanocarpa and Rhaponticum carthamoides extracts showed the highest values of ARA. The combinations Aronia + Raponticum extracts; Larix + Hibiscus extracts; Schizandra +Aronia extracts were synergistic (the synergism effect beta of 38%, 33% and 22%). Apparently this phenomenon is the result of the synergistic interaction between compounds present in plant extracts. The Phospholipid complex -Lipoid S40, lacting any antioxidant effect alone, showed a potent synergistic effect with Aronia extract (beta3 = 60%), Silybum extract (beta3 = 41%). Clinical trials demonstrated, that combinations "Lipoid + Aronia extract", "Lipoid + Larix extract + Hibiscus extract", "Lipoid + Silybum extract", "Lipoid + Q10 + Rosa majalis extract" may be used as an additional component in the medicinal treatment, or as an individual prophylactic agent. PMID- 23350205 TI - [Study of the interaction between antigen-antibody complexes for label-free sensor application]. AB - Nanomechanical cantilever systems have a great potential in design of the new type of label-free imunnosensors. They are based on the conversion of free energy change of the surface layer of the receptor by the reaction of molecular recognition between the antigen and antibody into mechanical deformation of microcantilever. But the mechanisms of molecular interactions in the layer are still not clear. PMID- 23350204 TI - [The influence of natural dicarbonils on the antioxidant enzymes activity in vitro and in vivo]. AB - Natural dicarbonyls, which may be accumulated during oxidative stress in atherosclerosis (e.g. malondialdehyde) or carbonyl stress in diabetes mellitus (glyoxal and methylglyoxal) effectively inhibited the activities of commercial preparations of antioxidant enzymes: catalase, Cu, Zn-superoxide dismutase (Cu, Zn-SOD) and Se-contained glutathione peroxidase from human and bovine erythrocytes and also rat liver glutathione-S-transferase. After incubation of human erythrocytes with 10 mM of each investigated dicarbonyls the decrease of intracellular Cu, Zn-SOD was observed. The decreased activity of erythrocyte Cu, Zn-SOD was also detected in diabetic patients with carbohydrate metabolism disturbance but effective sugar-lowered therapy was accompanied by the increase of this enzyme activity. The increase of erythrocytes activity of Cu, Zn-SOD of diabetic patients theated with metformin (which may utilize methylglyoxal) was higher than in erythrocytase of diabetic patients subjected to traditional therapy. PMID- 23350206 TI - [Critical evaluation of interaction screening software available in pharmacies]. AB - Due to the increasing complexity of medication regimens it is not always easy for the pharmacist to quickly and effectively screen the drug use of a particular patient for interactions. By means of a survey and a comparison, the advantages and disadvantages of the most common software packages available in Flanders were analysed. Major stumbling blocks of the currently available software are the high number of false positive signals, the absence of a history regarding the management of interactions, the lack of timely updates of the database and the absence of clear guidelines for the management of an interaction. Based on this research, we make the following recommendations: (1) signal fatigue should be reduced by interaction screening based on the duration of therapy in addition to the ability to suppress signals, (2) a log, coupled with the prescription register, should be implemented, (3) software companies should help pharmacists more in configuring software preferences and provide them with better information bout the available options, (4) the underlying databases must be updated more quickly. (5) OTC medications, especially in the context of polypharmacy, should be registered in the patient record by the pharmacist, (6) note that food supplements are not included in the interaction screening software, unlike registered medication. (7) the knowledge of pharmacists regarding interactions should be maintained and improved. PMID- 23350207 TI - [Comment of the Delphi Care editors on Critical evaluation of interaction screening software available in pharmacies]. PMID- 23350208 TI - [Does 5-methyltetrahydrofolate offer any advantage over folic acid?]. AB - Almost half of the women do not follow the guidelines around folate suppletion before and during pregnancy, despite the proven benefit in the prevention of neural tube defects, miscarriages and premature births. The Belgian Superior Health Council recommends a minimum of 400 micrograms of folic acid or folate suppletion per day from 4 weeks before conception to 8 weeks thereafter. Many studies point to the importance of a wider intake period, more particularly at least 3 months before conception and throughout pregnancy and lactation. In high risk women 4 mg is recommended until after the first 3 months of pregnancy. Afterwards the usual dose of 400 micrograms is sufficient. About half of the European population appears to have a gene mutation on the gene coding for the production of methylenetetrahydrofolate reductase, the enzyme that is involved in the formation of 5-methyltetrahydrofolate, which is, in his turn, responsible for the conversion of the toxic homocysteine in methionine. Women with such a gene polymorphism have a significantly higher risk to have a miscarriage or a baby with neural tube defects. For this reason, a search for an alternative form of synthetic folic acid supplement "pteroylmonoglutamic acid (PMG)" was conducted, particularly the calcium salt of 5-methyltetrahydrofolate (Metafolin). This offers the possibility to deliver the reduced folate immediately, which no longer needs to be converted by the reductase enzyme. Furthermore, this avoids free PMG in the circulation, lowers the risk for drug interactions and a vitamin B2 deficiency will not be masked. Despite clear guidelines regarding dietary supplements before and during pregnancy, their implementation is poor. Not only gynecologists but also GPs and pharmacists, should make more efforts to provide women of childbearing age with personal information. Especially risk groups such as adolescents, low-skilled or less well-off women and immigrants deserve special attention. PMID- 23350209 TI - [Approach of dry cough in community pharmacy]. AB - Cough is a common symptom, often experienced as troublesome. The cough reflex is a physiological defense of the respiratory tract, most often triggered by irritation or obstruction of the airways. Productive cough can expel bronchial secretions. This cough is certainly useful. An irritating, dry cough however, has no purpose and can justify the temporary use of a cough suppressant to relieve symptoms. The pharmacist is often the first person to whom the patient turns. Persistent cough generally indicates an underlying condition that requires a causal treatment. In this case, the pharmacist should refer the patient to the doctor. This article aims to provide guidelines for dealing with dry cough in the pharmacy. PMID- 23350210 TI - [Pharmacy compounding of medicinal shampoos: an update]. AB - Delivery of magistral (extemporaneous) preparations must comply with quality standards, as described in the "Guide to Good Officinal Pharmaceutical Practice" and the pharmacy's Quality Manual (Royal Decree of 21 January 2009). In this study, the shampoo Simplex Herdewijn, prepared with Texapon NSO, is compared with commercially available basic shampoos (Shampoo Fagron and Shampoo Simplex Conforma) with respect to its composition as well as its physicochemical properties. These basic shampoos were used to develop medicinal shampoos. The active compounds of these shampoos were: 0.5% hexachlorophene, 1% ichtammol, 1% cade oil or 2% liquor carbonis detergens. The necessary concentration of Cetomacrogol 1000, required to solubilise the active compounds was determined, as well as the amount of sodium chloride needed to adjust the viscosity of the shampoo. The viscosity of the basic and medicinal shampoos was determined by means of rheograms and by calculating their apparent viscosity. Additionally, a number of fundamental aspects of the formulation of shampoos are discussed in this paper. The results can be useful to pharmacists as guidelines for the preparation of medicinal shampoos. Beside patient instruction and pharmaceutical care, the intrinsic quality of magistral preparations is a prerequisite for therapeutic activity. PMID- 23350211 TI - [Racecadotril (Tiorfix), oral]. PMID- 23350212 TI - [Bilastine [Bellozal), oral]. PMID- 23350213 TI - New editor of Human Reproduction and Genetic Ethics. PMID- 23350214 TI - Courts, legislators and human embryo research: lessons from Ireland. AB - When it comes to the matter of human embryo research law plays a crucial role in its development by helping to set the boundaries of what may be done, the sanctions for acting outside those boundaries and the rights and responsibilities of key parties. Nevertheless, the philosophical challenges raised by human embryo research, even with the best will of all concerned, may prove too great for satisfactory resolution through the legal process. Taking as its focus the position of Ireland, this paper explores the distinctive constitutional approach taken on this issue and addresses the difficulty of translating sound philosophy into judicial decrees and the difficulty of establishing expert commissions to make law reform proposals on matters of profound normative controversy. It concludes that the Irish experience does have useful lessons for those in other countries who are concerned with the legal approach to research on human embryos and points to the desirability of a diversity of normative positions in order to enrich the quality of the analysis so as to encourage more informed debate in society. PMID- 23350215 TI - Embryo research in Italy: the bioethical and biojuridical debate. AB - This article deals with the discussion on the status of the human embryo in Italy on a philosophical, socio-ethical and juridical level before, during and after the law (n. 40/2004). Different lines of thought are outlined and critically discussed. The focus is the debate over the so-called embryonic stem cells, pointing out the ethical premises and the juridical implications. The regulations in Italy are analysed in detail, referring to legislation and jurisprudence (showing analogies and differences). In particular the author includes evidence for the debate after the law came in, with specific attention on the question of the use of imported embryonic stem cells and public financing for research and the problem of the use of frozen and non-implantable embryos. PMID- 23350216 TI - The law and politics of embryo research in America. AB - The moral, legal, and public policy dispute over embryonic stem cell research (and related matters, such as human cloning) is the most prominent issue in American public bioethics of the past decade. The primary moral question raised by the practice of embryonic stem cell research is whether it is defensible to disaggregate (and thus destroy) living human embryos in order to derive pluripotent cells (stem cells) for purposes of basic research that may someday yield regenerative therapies. This essay will explain the legal and political dimensions of the embryonic stem cell debate as it has unfolded at the national level in the United States, contrasting the position and thinking of President Clinton's administration with that of George W Bush. Building upon this, a set of brief reflections is offered on the form and substance of the American federal approach to this public matter and whether it is ultimately sustainable to join the issue in this particular way. PMID- 23350217 TI - Believing in the dignity of human embryos. AB - After showing that despite being inherently flawed the concept of dignity cannot be replaced without loss by ethical principles such as "respect for persons," it is argued that, if dignity be not understood as dignitas, but as bonitas, which emphasizes connectedness rather than excellence and to which the proper response is not respect, but awe, there is no reason not to ascribe it to the human embryo. The question whether or not human embryos have dignity can then be answered in the affirmative on the same pragmatist grounds that ultimately lead us to respect other human persons as possessors of dignity, that is, a special moral worth. PMID- 23350218 TI - The "special status" of the human embryo in the United Kingdom: an exploration of the use of language in public policy. AB - There is an apparent gap between public policy on embryo research in the United Kingdom and its ostensible justification. The rationale is respect for the "special status" of the embryo, but the policy actively promotes research in which embryos are destroyed Richard Harries argues that this is consistent because, the "special status" of the human embryo is less than the absolute status of persons. However this intermediate moral status does no evident work in decisions relating to the human embryo. Rather, public policy seems to be based on a different account of "special status": that developed by Mary Warnock. According to this, the embryo has no inherent status and the language of "special status" serves rather to accommodate the feelings of those who object to embryo research. This "emotivist" account is highly problematic, not so much for its attitude to the embryo as for its subversion of public moral reasoning. PMID- 23350219 TI - The Commons Science and Technology Committee inquiry into hybrid embryo research 2007: credible, reliable and objective? AB - In 2006 the Government issued a white paper in which it proposed a ban on human animal embryo research pending greater clarity on its potential. The Commons Select Committee on Science and Technology initiated an Inquiry and concluded that such research was necessary and should be permitted immediately. The Government agreed and this is reflected in revised legislation. The Government has issued guidelines on the gathering and use of scientific advice and evidence, designed to ensure that these are "credible, reliable and objective." This article tests the Committee's approach in the light of its remit and these, and other, relevant guidelines and concludes that it failed to meet these standards. Rather it effectively ceded to an interest group the regulation of its own activities. The article ends by suggesting alterations to the Committee's remit and composition designed to ensure that the public interest is better protected in future. PMID- 23350220 TI - The ethics of commercial surrogate mothering: a response to Casey Humbyrd. AB - This article critically examines the argument advanced by Casey Humbyrd in support of international commercial surrogate mothering. It finds her arguments unconvincing especially at the point of implementation. This is because the author was unable to demonstrate how regulation and her notion offair compensation would not lead to undue inducement and exploitation in resource-poor settings where urgent needs often exist. In fact, the argument advanced in this article is that commercial surrogate mothering cannot but be exploitative in so far as urgent and compelling needs exist. To logically drive home this point, the elements of exploitation were discussed in order to show that regulation and fair compensation cannot prevent exploitative transaction in commercial surrogate mothering arrangements. This may happen in the same way as regulation and compensation framework have not been successful in preventing the allegations of exploitation in the research context especially where studies are conducted in resource-poor countries. PMID- 23350221 TI - Doubts about a classic defence of abortion. AB - Professor Judith Jarvis Thomson's seminal paper "A defence of abortion" published in 1971 has formed part of higher education syllabi for decades. In the paper Thomson criticizes one of the fundamental arguments against abortion, that is, the right of the foetus to life by denying that the foetus is a person. This article argues that her thought experiments do not compare to the reality of abortion and focuses on the influence of the paper on arguments concerning personhood. PMID- 23350222 TI - Changing the paradigm: a novel framework for the study of resilience. PMID- 23350223 TI - Improving resistance and resiliency through crisis intervention training. AB - To our knowledge no research has been done on the impact of crisis intervention training programs on resistance and resiliency. This paper describes the use of a localized crisis intervention course and its impact on resistance and resiliency in the participants after 2 days of training. Participants attending the localized version of ICISF Individual Crisis Intervention and Peer Support courses participated in a pre-course quiz and a post-course quiz. The overall resistance and resiliency scores improved at the end of the localized 2-Day Individual Crisis Intervention and Peer Support course. Organizations should view the training of employees in mental health and crisis intervention as contributing to the overall resiliency of the organization, in addition to providing services that facilitate the resilience and recovery of employees affected by personal or workplace stress or critical incidents. PMID- 23350224 TI - Seven characteristics of highly resilient people: insights from Navy SEALs to the "greatest generation". AB - Having reviewed investigative methods such as structural equation modeling, seminal manuals of war (von Clausewitz, 1976, rev. 1984; Clavell, 1983), as well as individual interviews and focus groups with highly resilient people such as Navy SEALs, law enforcement professionals, and the "children of the Great Depression" now commonly referred to as the "greatest generation," we sought to discover the common themes, or characteristics, of highly resilient people. In this paper, we present our initial impressions that there exist seven important characteristics that seem to be associated with enhanced human resilience. PMID- 23350225 TI - The Johns Hopkins model of psychological first aid (RAPID-PFA): curriculum development and content validation. AB - There appears to be virtual universal endorsement of the need for and value of acute "psychological first aid" (PFA) in the wake of trauma and disasters. In this paper, we describe the development of the curriculum for The Johns Hopkins RAPID-PFA model of psychological first aid. We employed an adaptation of the basic framework for the development of a clinical science as recommended by Millon which entailed: historical review, theoretical development, and content validation. The process of content validation of the RAPID-PFA curriculum entailed the assessment of attitudes (confidence in the application of PFA interventions, preparedness in the application of PFA); knowledge related to the application of immediate mental health interventions; and behavior (the ability to recognize clinical markers in the field as assessed via a videotape recognition exercise). Results of the content validation phase suggest the six hour RAPID-PFA curriculum, initially based upon structural modeling analysis, can improve confidence in the application of PFA interventions, preparedness in the application of PFA, knowledge related to the application of immediate mental health interventions, and the ability to recognize clinical markers in the field as assessed via a videotape recognition exercise. PMID- 23350226 TI - Reciprocal peer support (RPS): a decade of not so random acts of kindness. AB - A model entitled "reciprocal peer support" (RPS) is introduced in this article to describe the peer support activity provided at University Behavioral HealthCare University of Medicine and Dentistry of New Jersey (UMDNJ) in a variety of peer programs. More than 10 years of peer support have been developed, reviewed, and assessed by this writer in an attempt to clarify the "lessons learned" and encourage RPS as an effective approach to peer support service in the future. The Cop 2 Cop, NJ Vet 2 Vet, and several other UBHC peer support programs, which conform to "best practices" criteria, have been sustained and expanded based on the RSP principles discussed in this article. PMID- 23350227 TI - Community capacity-building in disaster mental health resilience: a pilot study of an academic/faith partnership model. AB - We describe an academic/faith partnership approach for enhancing the capacity of communities to resist or rebound from the impact of terrorism and other mass casualty events. Representatives of several academic health centers (AHCs) collaborated with leaders of urban Christian-, Jewish-, and Muslim faith-based organizations (FBOs) to design, deliver, and preliminarily evaluate a train-the trainer approach to enhancing individual competencies in the provision of psychological first aid and in disaster planning for their respective communities. Evidence of partner commitment to, and full participation in, project implementation responsibilities confirmed the feasibility of the overall AHC/FBO collaborative model, and individual post-training, self-report data on perceived effectiveness of the program indicated that the majority of community trainees evaluated the interventions as having significantly increased their: (a) knowledge of disaster mental health concepts; (b) skills (self-efficacy) as providers of psychological first aid and bereavement support services, and (c) (with somewhat less confidence because of module brevity) capabilities of leading disaster preparedness planning efforts within their communities. Notwithstanding the limitations of such early-phase research in ensuring internal and external validity of the interventions, the findings, particularly when combined with those of earlier and subsequent work, support the rationale for continuing to refine this participatory approach to fostering community disaster mental health resilience, and to promoting the translational impact of the model. An especially important (recent) example of the latter is the formal recognition by local and state health departments of program-trained lay volunteers as a vital resource in the continuum of government assets for public health emergency preparedness planning and response. PMID- 23350229 TI - The role of law in addressing mental health-related aspects of disasters and promoting resilience. AB - Law plays a critical role in emergency preparedness and disaster response by establishing an infrastructure for the response and facilitating coordination among the federal, state, and local governments. Once a disaster occurs, certain legal mechanisms are activated to ensure that individuals' needs for mental health care are met, both for pre-existing and emergent conditions. This includes the rapid deployment of mental health care personnel and the implementation of crisis counseling programs in affected regions. By facilitating an influx of resources, including personnel, supplies, and financial assistance, the law can help communities quickly rebound and return to a sense of normal. Drawing on examples from the United States, this article illustrates the diverse ways in which the law simultaneously addresses mental health-related aspects of disasters and promotes resilience within affected communities. PMID- 23350228 TI - Assessment of psychological preparedness and emergency response willingness of local public health department and hospital workers. AB - This study sought to investigate the relationship between psychologically-related attitudes/beliefs toward public health emergency response among local health department (LHD) and hospital workers and their willingness to respond to a pandemic influenza emergency scenario and a radiological 'dirty' bomb scenario, to inform workforce resilience-building interventions. LHD and hospital workers participated in a survey based on an established threat- and efficacy-oriented behavioral model (the extended parallel process model) that focused on collection of the aforementioned attitudes, beliefs, and self-reported response willingness. Odds ratios associating psychologically-related attitudes and beliefs with self reported response willingness were computed Perceived levels of psychological preparedness and support were shown to impact response willingness, with more pronounced effects in the radiological 'dirty' bomb scenario. Compared to those who did not perceive themselves to be psychologically prepared, those who did perceive themselves as prepared had higher odds of self-reported response willingness. The relationship of these perceptions and self-reported willingness to respond in all contexts, both scenarios, and both cohorts was influenced by perceived self-efficacy andperceived family preparedness. PMID- 23350230 TI - [Design and quality control of short interfering RNAs]. AB - Review is devoted to analysis of design rules as well as quality controls in development of high effective and specific short interfering RNA (siRNA). Four crucial steps in development of such siRNAs are discussed: choice of target RNA, design of sense and antisense strands as well as assessment of activity and specificity of corresponding siRNAs. The special consideration is given to siRNA construction principles which are based on both structural and thermodynamical features and nucleotide composition of siRNAs as well as structural and thermodynamical properties of target RNA and features of experiment performance. Bioinformatics resources for development of siRNAs are also discussed. The information from this review can be useful for development of high effective and specific siRNA, short hairpin RNA (shRNA) and/or artificial microRNA (amiRNA) sequences for gene therapy and functional genomics purposes. PMID- 23350231 TI - [Transcription factor RUNX1]. AB - Transcription factor RUNX1 is one of the key regulatory proteins in vertebrates. It controls hematopoiesis and angiogenesis. It is indispensable during embryogenesis for the emergence of sites of definitive hematopoiesis and later in mature organisms for bone marrow blood stem cells differentiation. Moreover, RUNX1 gene is a frequent target for chromosomal translocations which cause acute forms of leukemia. A lot of types of human leukemia are somehow associated with mutations in this gene. Nevertheless, to this day the precise mechanism guiding the tissue-specific manner of the RUNX1 gene expression remains unknown. In this review we tried to summarize all the experimental data accumulated during the past twenty years beginning from the date when the cDNA sequence of the RUNX1 gene was first annotated. In the first part of the review we shall focus on structure, isoforms, covalent modifications of the RUNX1 transcription factor and its participation in different regulatory cascades. In the second part we shall discuss expression regulation, mutations and chromosomal translocations of the RUNX1 gene. PMID- 23350232 TI - [Anti-HIV nucleoside drugs: retrospective view at future]. AB - This review provides data on the design of antiretroviral drugs based on nucleoside analogs. About 30 drugs were approved for the treatment of HIV infected patients over 25 years. Seven nucleoside drugs are inhibitors of HIV reverse transcriptase and clinically used in combination with inhibitors of other viral enzymes, integrase and protease, and non-nucleoside inhibitors of reverse transcriptase. Toxicity of nucleoside drugs and approaches to obtaining of safe anti-HIV drugs are discussed. The results of developing of domestic anti-HIV drugs are presented. The future prospects of anti-HIV investigations are considered. PMID- 23350233 TI - [Oncolytic viruses in the therapy of gliomas]. AB - Despite the advances of modern medicine, malignant glioblastoma cure remains an elusive goal. Both the invasive nature and location in vital areas of the brain make this type of tumors difficult for surgical treatment, while the current adjuvant therapy is not as successful as expected. Frequent recurrence and invasiveness of malignant gliomas is due to resistance of glioma stem cells to conventional radiation and chemotherapy. Technological advances in constructing recombinant viruses have allowed creating strains with high oncolytic activity toward glial tumors. Many of these strains have passed Phase I of clinical trials and demonstrated high safety. Despite the obvious potential of the approach, efficiency of the existing strains is still far from being sufficient for effectively curing the disease and require further improvement. The review summarizes results obtained with the most successful variants of oncolytic viruses that come down to the clinical trials and discusses the prospects for new approaches in virotherapy of malignant gliomas. PMID- 23350234 TI - [Diversity of polyketide synthase genes (PKS) in metagenomic community of the freshwater sponge]. AB - Screening of metagenomic DNA of microbial community, associated with Baikalian sponge Lubomirskia baicalensis, was made to show the presence of polyketide synthase genes (PKS). PKS enzymatic systems take part in synthesis of a great number of biologically-active substances. Cloning and sequencing of amplified products of the ketosynthase domain section of PKS gene cluster has revealed 15 fragments of PKS genes differing from each other's on 35-65% by aminoacid sequences. BLASTX analysis has shown that all these sequences belong to the KS domains identified in various groups of microorganisms: alpha-, beta-, delta Proteobacteria, Verrucomicrobia, Cyanobacteria, Chlorophyta. Some sequences were related to the genes which are taking part in biosynthesis of curacin A (CurI, CurJ), stigmatellin (StiC, StiG), nostophycin (NpnB), and cryptophycins (CrpB). The homology of the found sequences with those of the EMBL database varies within 50-82% confirming the presence in fresh-water sponge community the genes for synthesis of the new, yet not studied polyketide substances, possessing the biotechnological potential. PMID- 23350235 TI - The influence of opioid peptides on matrix metalloproteinase-9 and urokinase plasminogen activator expression in three cancer cell lines. AB - Matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA) regulate proteolysis of the extracellular matrix (ECM) and as a consequence are involved in a number of physiological and pathological states, including cancer. A crucial feature of cancer progression and metastasis is the disruption of the ECM and spreading of proliferating cancer cells. Over-expression of MMPs and uPA is common for most types of cancers and correlates well with the adverse prognosis. Compounds able to modulate the activity of these proteolytic enzymes may become important agents in cancer therapy. In the present study, we examined the effect of the mu-opioid receptor selective peptide, morphiceptin, and its two synthetic analogs on mRNA and protein levels of MMP-9 and uPA in three human cancer cell lines: MCF-7, HT-29, and SH-SY5Y. Our findings indicate that in all three cell lines morphiceptin and its analogs attenuated MMP-9 expression and secretion and that this effect is not mediated by opioid receptors but is under control of the nitric oxide system. On the other hand, tested opioids up regulated uPA levels through a mechanism that involved opioid-receptors. Different pathways by which opioid peptides exert their actionin cancer cells can explain their contradictory influence on the level of cancer markers. PMID- 23350236 TI - Expression and regulation of Ang-2 in murine ovaries during sexual maturation and development of corpus luteum. AB - The aim of this study was to examine the expression and regulation of angiopoietin-2 (Ang-2) in murine ovaries during sexual maturation, gonadotropin treatment and luteal development by in situ hybridization and RT-PCR. By in situ hybridization Ang-2 mRNA was mainly localized in granulosa cells, thecal cells and corpus luteum, otherwise in oocytes. Moreover, Ang-2 mRNA was highly expressed in corpus luteum and granulosa cells of atretic follicles. According to RT-PCR data, Ang-2 mRNA was lowly expressed on day 10 after birth, then expression levels gradually increased and reached their highest values on day 25 after birth. In the superovulated model of immature mice, Ang-2 expression was strongly induced by equine chorionic gonadotropin (eCG) 48 h post the eCG injection, and was high from 0.5 to 13 h after hCG treatment. In situ hybridization showed that Ang-2 mRNA was highly expressed in corpus luteum from day 2 to 9 post the hCG injection, then the expression levels gradually declined on days 11 and 13 after hCG treatment. According to RT-PCR data, the levels of Ang-2 mRNA expression showed a decline after the hCG injection, with a nadir on day 3, followed by an increase, reaching the highest level on day 9 post-hCG injection. Then again Ang-2 expression gradually declined from day 11 to 15 after hCG injection. These results suggest that Ang-2 may be involved in follicular development, atresia, ovulation, and corpus luteum formation and regression. PMID- 23350237 TI - Characterization of the E-box binding affinity to snag-zinc finger proteins. AB - Members of the Snail/Gfi-1 domain family of zinc finger proteins are known to recognize the E-box sequence CANNTG, such as that found in the promoter of E cadherin, however, no studies have shown that the internal "NN" dinucleotides can play a role in different binding affinities. We show via gel shift assays that only the sequences CACCTG and CAGGTG can be recognized more strongly by the SNAG ZFP members such as Slug, Smuc, Snail, and Scratch while the other combinations of the internal nucleotides were bound weakly. All 16 possible dinucleotide combinations were tested by competition EMSAs to determine their relative binding affinities. The Kd value for the best-binding sequences was approximately 1.25 x 10(-6) M, while the other interactions were less effective. Our study has shown for the first time how different internal dinucleotide combinations of the E-box can be recognized differently by different transcription factors and also sheds light into how this transcription factor binding site may participate in DNA protein interactions. PMID- 23350238 TI - [The properties of four C-terminal carbohydrate-binding modules (CBM4) of laminarinase Lic16A of Clostridium thermocellum]. AB - At the C-terminus of multimodular laminarinase Lic16A Clostridium thermocellum four carbohydrate-binding modules (CBM), belonging to family 4, were found. The isolated CBM - CBM4_1, CBM4_2, CBM4_3, CBM4_4 and the tandem CBM4_(1-4) were obtained. None of the recombinant proteins did have the affinity to soluble beta 1,3-1,4-glucans--laminarin and lihenan--the main specific substrates of Licl6A. All modules, except CBM4_4, had the ability to bind bacterial crystalline cellulose, that was atypical for the family 4 CBMs. We found that all CBMs 4 of Licl6A had affinity for xylan, chitin, beta-glucan from yeast cell wall and Avicel, while CBM4_3 and CBM4_4 had additional affinity to chitosan. The tandem CBM4_(1-4) had the highest affinity to yeast cell wall beta-glucan, avicel and pustulan. The binding constants for these substrates were about 100 times higher than that of the individual modules, suggesting a synergy in the process of absorption to these polysaccharides. This finding helps to explain the evolutionary process of CBM multiplication. PMID- 23350239 TI - [Characteristics of complex formation between monomeric and dimeric bisbenzimidazoles and AT-containing polynucleotide]. AB - Double-stranded DNA is a one of the most important intracellular anticancer agent targets. Disturbance of DNA functions as well as DNA structure lead to disorder of such processes as transcription and/or translation thus inducing tumor cells death. Complex formation between novel dimeric bisbenzimidazole DB(7) and poly(dA dT) duplex in comparison with known monomeric bisbenzimidazole MB(Ac) was investigated in this study. DB(7)-poly(dA-dT) binding constant was determined by fluorescence spectroscopy using Scatchard plot and it values 1.18 x 10(8) M(-1) that is two orders of magnitude larger than MB(Ac) one (2.06 x 10(6) M(-1)). Thus, from findings mentioned above it could be concluded that the presence of two bisbenzimidazole moieties in the ligand structure significantly increases its affinity to the polynucleotide which motivates the synthesis of new potential anticancer drugs based on dimeric bisbenzimidazoles. PMID- 23350240 TI - [Clinical evaluation of Graves ophthalmopathy]. AB - INTRODUCTION: Graves ophthalmopathy is an autoimmune disease, which is the consequence of thyroid dysfunction. Ocular manifestations occur in 50% of patients with Graves disease. The changes occur due to the inflammatory cell infiltration of retrobulbar fat tissue and extraocular muscles. Ultrasonography of eye orbit provides important information about the condition of retrobulbar adipose tissue and the thickness of extraocular muscles. OBJECTIVE: The aim of our study was to show the clinical significance of orbital ultrasonography in the diagnostics and follow-up of patients with Graves disease. METHODS: The authors examined 154 patients with Graves ophthalmopathy at the Clinic of Ophthalmology of the Clinical Centre in Kragujevac during the period 2008-2010. Ophthalmological examination included visual acuity testing (Snellen chart), biomicroscopy and applanation tonometry, direct and indirect ophthalmoscopy, dry eye testing and exophthalmometry (Hertel). Orbital ultrasonography examination and extraorbital muscle measurement was done by ultrasound B-scan. RESULTS: The disease was more frequent in women (79.87%) aged from 36-45 years. Most patients had hyperthyreoidism (54.55%). In relation to the duration of the disease, the most frequent clinical signs were bilateral ptosis, conjunctival chemosis and periorbital edema. According to our data the highest number of patients had enlarged medial straight muscle. CONCLUSION: Graves ophthalmopathy is the most frequent sign of thyroid disease. By orbital ultrasonography we detected extended echogram and measured the thickness of the extraocular muscle. Computerized tomography and magnetic resonance scan were utilized for cases of insufficiently manifested clinical signs of the disease. The advantages of ultrasonography lie in easy handling, patients' comfort, short time of examination and possibilities of repetition. PMID- 23350241 TI - [Comparison of normal tension and high tension glaucoma patients (corrected) according to age and sex]. AB - INTRODUCTION: According to the level of intraocular pressure (IOP), open angle glaucoma is divided into high tension glaucoma (HTG) and normal tension glaucoma (NTG). OBJECTIVE: To determine if there are differences in the distribution of patients by age and sex between NTG and HTG. METHODS: Our prospective study included 30 patients with NTG and 30 with HTG. A complete eye examination was performed. The examination included measuring of intraocular pressure by Goldmann applanation tonometry, examination of optic disc head by indirect ophthalmoscopy with Volk 90 D lens and visual field examination using the Octopus program. RESULTS: The average damage of visual field in the group of patients with NTG was 8.14 +/- 4.43 dB, while in the group with HTG it was 7.40 +/- 2.84 dB (p > 0.05). The average age of the group of patients with NTG was 66 +/- 11.58 years, while among those with HTG the average age was 59.7 +/- 11.63 years (p < 0.01). Among the patients with NTG there were three times more women than men (chi2 = 9.124; p < 0.01), while in the group of patients with HTG there were more men than women, but without statistically significant difference between the tested groups (chi2 = 1.851; p > 0.05). CONCLUSION: Open angle glaucoma is a disease of elderly population. According to our results, risk factors for this disease can be age and sex. NTG is more frequently present than HTG among elderly population and females. PMID- 23350242 TI - [The effects of orthognathic surgery on mandibular movements in patients with mandibular prognathism]. AB - INTRODUCTION: Mandibular prognathism, one of the most severe dentofacial deformities, affects the person's appearance, psychological health and the quality of life in the most sensitive age period. OBJECTIVE: The aim of this study was to evaluate the effects of sagittal split ramus osteotomy on the range of mandibular border movements in the early postoperative period. METHODS: The study was conducted on 20 patients, of mean age 20.8 years, with mandibular prognathism. All patients included in this study were operated on by bilateral sagittal spliting ramus osteotomy according to Obwegeser and Dal Pont followed by mandibular immobilization during eight weeks. In all patients mandibular border movements were recorded before and six months after surgery using the computerized pantograph Arcus-Digma (KaVo EWL GmbH, Leutkirch, Germany). RESULTS: The analysis of the chosen kinematic parameters revealed that sagittal split ramus osteotomy followed by eight weeks of mandibular immobilization had severe effects on the mouth opening. Six months after surgery the range of maximal mouth opening decreased for approximately 13.9 mm in relation to the preoperative stage. On the contrary, the ranges of maximal protrusion and the border of laterotrusive excursions increased significantly after surgery. CONCLUSION: In patients with mandibular prognathism where enormous mandibular growth was the main causal factor of the deformity, the sagittal split ramus osteotomy yielded good results. The rigid fixation of bone fragments and reduced period of mandibular immobilization followed by appropriate physical therapy could considerably contribute to a more rapid recovery of mandibular kinematics in the postoperative period. PMID- 23350243 TI - Short QT interval is unreliable marker of anabolic androgenic steroid abuse in competitive athletes. AB - INTRODUCTION: Previous animal and human studies provided the evidence that testosterone may affect ventricular repolarization by shortening of the QT interval. Synthetic derivatives of testosterone, modified to enhance its anabolic properties, are occasionally abused by some competitive athletes. OBJECTIVE: We assessed whether the QT interval duration could discriminate androgenic anabolic steroids (AAS)-using strength athletes (SA) from drug-free endurance athletes (EA), by comparing 25 formulas for QT interval correction. METHODS: We recruited 22 elite male athletes involved in long-term strength or endurance training and 20 sedentary controls. All elite SA reported AAS abuse, whereas EA and controls were AAS-free. RESULTS: AAS-using SA had markedly shorter QT-interval than AAS free EA (348 +/- 42.3 vs. 400 +/- 34.2 ms; p < 0.001). Also, drug-free EA had a significantly longer QT-interval than sedentary persons (400 +/- 34.2 vs. 358 +/- 18.9 ms; p < 0.01). In contrast, no significant difference in the QT-interval duration was observed between AAS users and control group (348 +/- 42.3 vs. 358 +/- 18.9 ms; p = 0.394). After the QT interval was adjusted for heart rate (HR) according to 25 different formulas, only the Ashman equation yielded considerable differences among the groups that were in line with those observed before correction. CONCLUSION: Inconsistent results obtained by different correction formulas along with inability to discriminate QT (QTc) interval duration between AAS-misusing athletes and control group do not support the use of QT (QTc) interval for anti-doping purposes. PMID- 23350244 TI - [Quality of treatment in gouty patients considering EULAR recommendations]. AB - INTRODUCTION: There are 12 recommendations for gout treatment, based on evidence and opinion of experts. OBJECTIVE: To assess the quality of therapy in patients with gout analyzing adherence to four selected recommendations. METHODS: Retrospective cross sectional study of 111 patients with gouty flare was conducted. Adherence to selected recommendation was defined as odds ratio between the number of patients whose therapy adhered to treatment recommendation and the number of patients eligible for the relevant recommendation. These recommendations refer to indications for allopurinol treatment (R1), prophylaxis of induced gouty flares in the first month of allopurinol treatment (R2), treatment goals (R3), and treatment monitoring regime (R4). RESULTS: Out of 111 patients with gout, 25 with tophi, 87 with frequent gouty flares and 46 with CUA or X-ray erosions were indicated for allopurinol treatment. The adherence to R1 was 76% for tophi patients, 54% for patients with frequent gouty flares, and 63% for patients with CUA. None of the patients starting allopurinol was either recruited for gouty prophylaxis or monitored properly; adherence to R2 as well as to R4 was 0%. Target serum uric acid (SUc) rating below 360 micromol/L was achieved in 13/50 patients treated with allopurinol, while the adherence to R3 was 26%. Therapeutic monitoring in accordance with P4 was not done in any of the patients on allopurinol. There were no differences in mean levels of the SUc between allopurinol users and non-users: 471.3 +/- 164.4 vs. 460.0 +/- 103.5 micromol/L (p = 0.067). Therefore, almost every second patient with gouty flares was on allopurinol therapy (50/111). CONCLUSION: The degree of deviation in relation to the key principles of correct treatment in patients with gout ranged from a relatively high (24%) to that of absolute digression (100%). PMID- 23350246 TI - Results and experiences after 2000 performed hysteroscopies. AB - INTRODUCTION: Hysteroscopy is one of the oldest endoscopic procedures which uses the cervix for introducing a telescope to place a camera into the uterine cavity. OBJECTIVE: The aim of the study was to present our experiences with this procedure during the long-term work starting from the time when hysteroscopic method of treatment was first introduced at this Clinic until today. METHODS: This prospective study involved 2000 female patients referred to the Clinic for Gynecology and Obstetrics in Novi Sad from January 2005 till January 2011 for diagnostic and operative hysteroscopy. The following parameters were analyzed: the presence of minor and major pathology of the endometrium, type of anesthesia, technique of operative work, instruments and energy used during hysteroscopy and complications. RESULTS: Seventy-eight percent of all procedures were done under intravenous anesthesia. The most common operative procedure was polypectomy and the most complicated one was myomectomy. By histopathological examination of hysteroscopic biopsy specimens four endometrial carcinomas were revealed. The combination of mechanical instrument and bipolar energy were used in most of the cases, while the percentage of complications was extremely low. CONCLUSION: Hysteroscopy is a safe, highly sensitive, precise diagnostic and operative endoscopic procedure. Our experiences and dilemmas open a field for discussion and offer salutations to everyday problems. The introduction of this procedure into out-patients conditions has contributed to the efficiency of the treatment of vaginal pathological processes, thus enabling that the method has become available to all gynecologists. This fact requires further study and new results. PMID- 23350245 TI - Efficacy and safety of once-monthly ibandronate treatment in patients with low bone mineral density-ESTHER Study: 24 months of follow-up. AB - INTRODUCTION: Osteoporosis is a major health and economic problem worldwide. The use of new drugs, such as ibandronate, is aimed at improving treatment of osteoporosis and currently poor compliance with BP therapy. OBJECTIVE: To investigate efficacy and safety of ibandronate applied monthly, orally, in women with low bone mineral density (BMD). METHODS: The prospective study was conducted in 34 centers in Serbia and included 77 women treated for 24 months with monthly ibandronate. The efficacy of treatment was assessed by change in bone mass values obtained by BMD measurement at the end of 24 months follow-up versus baseline and 12-months follow-up values. Compliance and safety, i.e. adverse effects (AE) were recorded. RESULTS: Participants were postmenopausal (96%), osteoporotic (79.7%) females, diagnosed by lumbar spine DXA measurement (81%), with history of prior BP therapy in 33.8% women. The physical activity level significantly increased to the substantial level of activity (5.2% vs. 21.3%, p = 0.003) during the study. After 12 and 24 months of treatment, BMD values significantly increased (p = 0.002 and p < 0.001). BP experienced patients improved more than BP naive patients at both time points (p = 0.012 and p = 0.027, respectively). During the second 12 months of treatment the adherence was 96%; AE were recorded as mild gastrointestinal disturbances in 3.9%. CONCLUSION: Treatment by using ibandronate once monthly for 24 months was generally well tolerated and led to a significant increase in BMD in women with low BMD. PMID- 23350247 TI - [Open segmental fractures of the tibia treated by external fixation]. AB - INTRODUCTION: Open segmental fractures of the tibia are rare but severe injuries. In these fractures the wide zone of injury (damage of all structures of the lower leg) creates very unsuitable biological conditions for healing of the fracture. OBJECTIVE: The aim of our work was to present the results of treatment of patients with segmental open fractures of the tibia treated by external fixation. METHODS: We analyzed treatment results of 21 patients with open segmental tibial fractures who were treated using the method of external fixation at the Clinical Center Nis from January 1, 1995 to July 31, 2010. The average age of the patients was 53 years; the youngest patient was 27 years and the oldest one 80 years. According to the Gustilo open fracture classification, there were 3 (14.3%) type 1, 6 (28.6%) type 11, 8 (38.1%) type IIIA, and 4 (19.0%) type IIIB. All the patients were treated by a unilateral type Mitkovic external fixator by Traffix Company. RESULTS: Union was attained in 16 (76.2%) fractures without severe complications (pseudoarthrosis, chronic osteitis and angular deformities of over 10 degrees). Among severe complications associated with open segmental tibial fractures, in two cases we registered septic pseudoarthrosis, in one aseptic pseudoarthrosis and in two large angular deformities of the tibia after union, with a valgus of over 10 degrees and extremity shortening of over 2 cm which required additional surgery. CONCLUSION: External fixation by the use of Mitkovic external fixator is one of the methods of choice in the treatment of open segmental tibial fractures, which incorporated with antibiotic therapy provides good biomehanical conditions for segmental fracture healing that enables good stability of the segmental tibial fracture and decreases the risk of deep infections. PMID- 23350248 TI - Morphological characteristics of the developing proximal femur: a biomechanical perspective. AB - INTRODUCTION: In contrast to a plethora of studies on the proximal femur in adults, its external and internal morphology in growing children has not been sufficiently analyzed. OBJECTIVE: We analyzed changes in external and internal morphology of the proximal femur during growth and development to interpret the links between them and concepts of the human femoral biomechanics. METHODS: We assessed external geometry, internal trabecular and cortical arrangement, and bone mineral density (BMD) of the proximal femur in 29 children (age at death from 1 month to 14 years) from archaeological context by using microscopic and radiographic methods. Results The results showed that both the femoral neck width and length increased with age, with the femoral neck becoming more elongated, while the collo-diaphyseal angle decreased. A strong relationship between age and adjusted areal BMD was found, showing continuous increase during childhood. Parallel trabecular pattern at birth changed to mature three distinct trabecular groups (longitudinal-principal compressive, transversal-tensile and randomly scattered) starting from the age of 8 months. In older children the superior and inferior aspects of the femoral neck differently changed with growth, with medial neck having thicker cortex and trabeculae. CONCLUSION: In the light of bone adaptation principle, the observed changes in external and internal morphology are governed by mechanical forces acting on the developing femur. Our findings on the development of trabecular pattern and cortical distribution are compatible with recent views on the femoral biomechanics which point out the predominance of compressive stresses in the femoral neck, adaptation to shear stresses, multiaxial loading perspective, prevalence of muscle effects over body weight, and existence of adaptational eccentricity. PMID- 23350249 TI - [Aquatic exercise in the treatment of children with cerebral palsy]. AB - INTRODUCTION: Aquatic exercise is one of the most popular supplementary treatments for children with neuro-motor impairment, especially for cerebral palsy (CP). As water reduces gravity force which increases postural stability, a child with CP exercises more easily in water than on land. OBJECTIVE: The aim of the study was to examine aquatic exercise effects on gross motor functioning, muscle tone and cardiorespiratory endurance in children with spastic CP. METHODS: The study included 19 children of both sexes, aged 6 to 12 years, with spastic CP. They were included in a 12-week aquatic exercise program, twice a week. Measurements of GMFM (gross motor function measurement), spasticity (MAS-Modified Ashworth Scale), heart rate (HR) and maximal oxygen consumption (VO2max) were carried out before and after treatment. The measurement results were compared before and after treatment. RESULTS: GMFM mean value before therapy was 80.2% and statistically it was significantly lower in comparison to the same value after therapy, which was 86.2% (p < 0.05). The level of spasticity was considerably decreased after therapy; the mean value before treatment was 3.21 according to MAS, and after treatment it was 1.95 (p < 0.001). After treatment there was a statistically significant improvement of cardiorespiratory indurance, i.e., there was a significant decrease in the mean value of HR and a significant increase of VO2max (p < 0.001). CONCLUSION: Aquatic exercise program can be useful in improving gross motor functioning, reducing spasticity and increasing cardiorespiratory endurance in children with spastic CP. PMID- 23350250 TI - Seroprevalence study in Vojvodina (Serbia) following 2009 pandemic influenza A(H1N1)V. AB - INTRODUCTION: The seroprevalence study was performed in Vojvodina during May and June 2010 in order to asses the effects of the 2009 pandemic influenza A(H1N1)v epidemic on herd immunity. It was a part of the Serbian Ministry of Health funded nationwide study. OBJECTIVE: Prevalence of antibodies against 2009 pandemic influenza A(H1N1)v was determined in a 1% sample of the population monitored for influenza-like illness and acute respiratory infections in Vojvodina through sentinel surveillance system. METHODS: The study sample involved a total of 1004 inhabitants of Vojvodina. The control group consisted of randomly selected and age-adjusted 1054 sera collected in the pre-pandemic period. Sera were tested by the reaction of hemagglutination inhibition using influenza A/California/7/2009 (H1N1) antigen in dilution from 1:8 to 1:256. Antibody titers > or = 1:32 and > or = 1:8 were considered protective and diagnostic, respectively. RESULTS: The differences between control and study sera in all age groups were significant for both diagnostic > or = 1/8 and protective titres > or = 1/32 of hemagglutination inhibition antibodies (chi square test, p < 0.001). The highest percentage of seropositive subjects was registered in the age group 15-19 years followed by children aged 5-14 years. Both diagnostic and protective titres were about twice higher in the vaccinated as compared to the non-vaccinated group. There were no statistically significant differences in seroprevalence between seven districts of Vojvodina. CONCLUSION: The 2009 pandemic influenza A(H1N1)v epidemic significantly influenced the herd immunity in our population regardless of low immunization coverage with highest immunity levels in adolescents aged 15-19 years and with similar herd immunity levels in all the regions in the province six months after the outbreak. PMID- 23350251 TI - [Vesicovaginal fistulas: results of surgical treatment during ten years]. AB - INTRODUCTION: Vesicovaginal fistulas (VVF) are the most common and the most frequent type of urogenital fistulas. They may have a different etiology. In most cases, surgery is required for treatment. OBJECTIVE: The aim of the study was to analyze the results of surgical therapy of VVF in a tertiary level institution over the last decade. METHODS: The retrospective study of results was conducted involving a total number of 99 women who were surgically treated for VVF at the Clinic of Urology of the Clinical Center of Serbia in Belgrade in the period from 2001-2010. RESULTS: Over the past ten years VVF occurred after hysterectomy in 74.7% of cases, and almost twice more frequently after hysterectomy for a benign gynecological disease. In the surgical treatment of primary VVF transvesical approach was used in 53.53% (52/99) of cases. Relapses were treated surgically using transperitoneal approach in all cases. No significant difference was found in respect to the applied approach in the surgical treatment of primary fistulas. In even 94% (93/99) of cases the problem of VVF was solved by a single surgical intervention only. In total, in 107 interventions 8 (7.4%) relapses were recorded. CONCLUSION: The study showed that VVF occurred after hysterectomy in three quarters of cases, more frequently after hysterectomy due to a benign gynecological disease. Early detection with timely and appropriate treatment of gynecological diseases will reduce the number of conditions that may lead to VVF. Surgical treatment of VVF yielded satisfactory results; it was shown that even in 94% of cases the problem of VVF was solved by a single surgical intervention only, however further improvement is certainly necessary. PMID- 23350252 TI - [Family paracentric inversion of the short arm of chromosome X (Xp21.2p11.23) and connection with autism spectrum disorders]. AB - INTRODUCTION: Autism spectrum disorders (ASDs) are a group of complex pervasive developmental disorders characterized by impairments in communication, social interaction and behavior. In most cases autism is caused by a combination of genetic factors and environmental risk factors. In 10% to 20% of cases it has been shown that the cause of ASD is genetic. CASE OUTLINE: We are describing a 2 year-old boy who was referred to genetic counseling because of speech delay and certain autism-like behavior. By cytogenetic analysis the karyotype 46, inv(X),Y was obtained. The boy was a carrier of a paracentric inversion of the short arm of the chromosome X. After cytogenetic analysis of parental blood, it was detected that mother was a carrier of identical aberration, but had no clinical signs. The method of fluorescent in situ hybridization (FISH) yielded the precise breakpoint in the region (p21.2p11.23). Mother and son were carriers of identical X chromosome. CONCLUSION: Breakpoints are located in the regions that have already been linked to autism, which indicates that the positional effect of the gene could have been a possible cause of the patient's genotype. In addition to positional effects, in order to better understand the etiology of autism other genetic and environmental factors should be always taken into consideration. PMID- 23350253 TI - [Ascending aorta false aneurysm as a late complication of aortic valve surgery]. AB - INTRODUCTION: False aneurysms of the ascending aorta represent a rare but potentially fatal complication of cardiac surgical procedures. Predisposing factors are aortic dissection, infection, connective tissue disorders, chronic hypertension, aortic calcifications and aortotomy dehiscence. At the beginning they are usually asymptomatic, but later various symptoms arise as a consequence of vital structures compression. Potential risk of rupture rises with time and pseudoaneurysm enlargement. From surgical point of view treatment of such cases represents a unique challenge because of the great danger of inadvertent opening of the aneurysm during resternotomy. CASE OUTLINE: A 58-year-old female patient underwent aortic valve replacement due to severe aortic stenosis in 2004. Operation and postoperative recovery were uneventful.Three years later she started complaining about chest pain. On chest X-ray there was upper mediastinal widening. CT scan showed a pseudoaneurysm of the ascending aorta located in front of the right atrium and right ventricle, which was subsequently verified by angiography. During redo operation the pseudoaneurysm was successfully resected and aorta closed with separate ethybond sutures with pledgets. CONCLUSION: Postoperative pseudoaneurysms of the ascending aorta mostly arise from the suture lines. The most useful diagnostic procedures are contrast CT scan, echocardiography, angiography and MRI. Surgical intervention is absolutely indicated. The institution of cardiopulmonary bypass by alternative ways before chest opening is strongly recommended. PMID- 23350254 TI - Mystery called sarcoidosis: forty-four years follow-up of chronic systemic disease. AB - INTRODUCTION: This is a presentation of a 61-year-old female patient. Since 44 years have passed from the onset of her first symptoms until the final diagnosis of sarcoidosis, this was the reason of our decision to publish the case. CASE OUTLINE: During the follow-up period of 44 years the patient had ocassional polymorphic complains, such as adynamia, nausea, abdominal pains, myalgia, arthralgia, body weight loss (8-10 kg) etc. The clinical course was predominated by splenomegaly, hepatitis and arthralgia, and later chronic renal failure also developed. Laboratory findings showed elevated markers of acute inflammation and autoantibodies. The patient was hospitalized in different university internal hospitals (gastroenterology, allergology, rheumatology, nephrology and pulmology). Liver biopsy was performed three times, rectum and kidney biopsy once each and finally bronchoscopy and pulmonary biopsy was done. At last, about 40 years from the onset of the first symptoms, in 2006 the diagnosis of lung sarcoidosis was established. CONCLUSION: The final diagnosis of spleen sarcoidosis was confirmed by pathologically verified sarcoidosis of the lungs. This case is particularly interesting because of the presence of familial sarcoidosis (the patient's son also had recurrent pulmonary sarcoidosis). PMID- 23350255 TI - [Biliobronchial fistula secondary to percutaneous dilatation of the benign biliary stricture]. AB - INTRODUCTION: Biliobronchial fistula is rare. Very rarely it may be congenital, more frequently it is acquired as a complication of the hydatide cyst of the liver, pyogenic abscess, serious trauma and resection of the liver as well as recurrent cholangitis due to benign bile duct stricture or cholangiolithiasis. The main causes of the biliobronchial fistula are billiary obstruction and infectious lesion (abscess) in the liver. CASE OUTLINE: We present a 56-year-old man with benign stricture of the hepaticojejunostomy performed after operative common bile duct injury, who developed biliobronchial fistula following repeated percutaneous drainage of the liver abscess and percutaneous dilatation of the strictured anastomosis. Over the years the patient developed atrophy/hypertrophy complex, portal hypertension, grade II esophageal varicosities, ascites and splenomegaly. Although biliobronchial fistula was solved by a successful surgical reconstruction (new wide hepaticojejunostomy), the operation had a limited value as it was performed late after permanent lesions of the liver and intrahepatic bile ducts had already developed. CONCLUSION: Surgical reconstruction of strictured biliodigestive anastomosis should be considered on time as a possibly better solution than percutaneous dilatation. According to the authors' knowledge, a similar case of biliobronchial fistula as a complication of percutaneous dilatation of the benign biliary stricture has not been reported before in the literature. PMID- 23350256 TI - Combined lymphangioma and hemangioma of the spleen in a patient with Klippel Trenaunay syndrome. AB - INTRODUCTION: Klippel-Trenaunay syndrome (KTS) is a very rare congenital anomaly of blood vessels, characterized by the following clinical triad: varicose superficial veins, port-wine stain and usually bony and soft tissue hypertophy of extremities, most often located in the lower extremities. It is often accompanied by visceral manifestations, and rarely combined with splenomegaly. CASE OUTLINE: A 30-year-old female patient came to the Surgery Clinic because of occasional left hypochondrial pain. After she was diagnosed with KTS combined with splenomegaly, splenectomy was performed. Macroscopic and microscopic spleen examination indicated the presence of tumor of vascular origin, presenting a combination of lymphangioma and hemangioma. CONCLUSION: Diagnosed KTS demands a thorough clinical examination of the patient because of the potential presence of visceral manifestations. When splenomegaly is present, even though being often benign, splenectomy is usually performed to alleviate accompanying symptoms which occur as a result of organ enlargement and compression, to prevent rupture and consequential bleeding when the vascular spleen tumor is large, and finally to avoid a possibility of malignant transformation. PMID- 23350257 TI - PFA-100 test in the detection of platelet dysfunction and monitoring DDAVP in a patient with liver cirrhosis undergoing inguinal hernia repair. AB - INTRODUCTION: Hemostatic abnormalities in liver cirrhosis are complex and multifactorial and may predispose to prolonged hemorrhage following invasive procedures. Due to increased perioperative bleeding risks, patients with cirrhosis should undergo elective surgery after making medical preparations. It has been shown that 1-deamino-8-D-arginine vasopressin (DDAVP), desmopressin, can be used as a safe and effective remedy in preventing and treating bleeding in cirrhotics. However, there is still scarce information of adequate test(s) for assessing effects of DDAVP in platelet dysfunction. The use of platelet function analyzer-100 (PFA-100) allows more reliable assessment of impaired primary hemostasis as well as follow-up of hemostatic changes induced by DDAVP effects. CASE OUTLINE: In a 49-year-old male with ethylic liver cirrhosis and prolonged bleeding time scheduled for elective left side inguinal hernia repair, we carried out PFA-100 testing to investigate the patients platelet functional status. Results were affirmative for the presence of platelet functional problems. By standard coagulation tests the patient was also identified as having secondary hemostasis. Preoperatively, PFA-100 was used to test the patient's response to a standard dose of DDAVP, which was favorable. The patient was operated after medical preparations with DDAVP and vitamin K. Neither bleeding complications nor side effects of DDAVP were recorded in the perioperative period. CONCLUSION: The PFA-100 is a simple and reliable test for the assessment of primary hemostasis as well as in monitoring of DDAVP therapy. PMID- 23350258 TI - [Manifestations of contact allergy]. AB - Contact allergy (sensibilization, hypersensitivity) is a state of specific immune response in the skin occurring after repeated contact of the skin or mucous membrane with various environmental substances. At the Allergy Department of the Clinic of Dermatovenereology Diseases in Novi Sad, we patch tested the patients who were referred with a suspected contact allergy and who had been also coming for check-ups as outpatients over the last two years. Contact allergy was assessed in respect to the fact that not only allergic contact dermatitis, but also the whole spectrum of different clinical entities where allergic contact dermatitis and contact urticaria are only the two extremes, should be included. Our results provide further insight into etiology and pathogenesis of contact allergy, offering a better diagnostic and therapeutic approach to patients and opening new horizons to further researches. PMID- 23350259 TI - Endovascular aortic repair: first twenty years. AB - Endovascular aortic/aneurysm repair (EVAR) was introduced into clinical practice at the beginning of the nineties. Its fast development had a great influence on clinicians, vascular surgeons and interventional radiologists, educational curriculums, patients, industry and medical insurance. The aim of this paper is to present the contribution of clinicians and industry to the development and advancement of endovascular aortic repair over the last 20 years. This review article presents the development of EVAR by focusing on the contribution of physicians, surgeons and interventional radiologists in the creation of the new field of vascular surgery termed hybrid vascular surgery, and also the contribution of technological advancement by a significant help of industrial representatives--engineers and their counselors. This article also analyzes studies conducted in order to compare the successfulness of EVAR with up-to-now applied open surgical repair of aortic aneurysms, and some treatment techniques of other aortic diseases. During the first two decades of its development the EVAR method was rapidly progressing and was adopted concurrently with the expansion of technology. Owing to large randomized studies, early and long-term results indicate specific complications of this method, thus influencing further technological improvement and defining risk patients groups in whom the use of the technique should be avoided. Good results are insured only in centers, specialized in vascular surgery, which have on their disposal adequate conditions for solving all complications associated with this method. PMID- 23350260 TI - [Fifty years of subclinical primary aldosteronism: importance of early diagnosis]. AB - Clinical presentation of excessive aldosterone secretion is often not specific. The presence of resistant severe hypertension (HT) and signs of hypokalemia is useful but inconsistent characteristic. Plasma aldosterone level in primary aldosteronism (PA) could be normal, although inappropriately high for a low plasma renin activity and not suppressed by sodium. Screening of hypertensive population with no obvious signs of PA has revealed an increased prevalence of idiopathic adrenal hyperplasia as a cause of aldosterone excess. Nowadays, PA is the most common endocrine form of secondary HT, with an estimated prevalence 5 10% of hypertensive population. The diagnosis of PA can lead to surgical cure in the case of aldosterone producing adenoma and unilateral adrenal hyperplasia. The aldosterone excess is responsible for vascular inflammation and end-organ damage. Left ventricular hypertrophy, cardiac arrhythmia and cerebral insult are frequently seen in PA and preventable by mineralocorticoid receptor blockers. For this reason, screening for PA in patients with HT and hypokalemia and/or adrenal incidentaloma, resistant and severe HT, and in patients with the onset of HT at young age is advisable.The most widely accepted screening for PA is serum aldosterone to plasma rennin activity (aldosterone: PRA) ratio, with the cut-off of 30 ng/dl:ng/ml/h. Serum aldosterone level could be included as an additional screening parameter. Confirmatory tests are crucial for the diagnosis of PA in patients with an increased aldosterone: PRA ratio and subtype differentiation for the choice of treatment. PMID- 23350261 TI - Premature ovarian failure. AB - Premature ovarian failure (POF) is the occurrence of hypergonadotropic hypoestrogenic amenorrhea in women under the age of forty years. It is idiopathic in 74-90% patients. Known cases can be divided into primary and secondary POF. In primary POF genetic aberrations can involve the X chromosome (monosomy, trisomy, translocations, deletions) or autosomes. Genetic mechanisms include reduced gene dosage and non-specific chromosome effects impairing meiosis, decreasing the pool of primordial follicles and increasing atresia due to apoptosis or failure of follicle maturation. Autoimmune ovarian damage is caused by alteration of T-cell subsets and T-cell mediated injury, increase of autoantibody producing B-cells, a low number of effector/cytotoxic lymphocyte, which decreases the number and activity of natural killer cells. Bilateral oophorectomy, chemotherapy, radiotherapy and infections cause the secondary POF. Symptoms of POF include irritability, nervousness, loss of libido, depression, lack of concentration, hot flushes, weight gaining, dry skin, vaginal dryness, frequent infections etc.The diagnosis is confirmed by the level of FSH of over 40 IU/L and estradiol below 50 pmol/L in women aged below 40 years. Biochemical and other hormonal analysis (free thyroxin, TSH, prolactin, testosterone), karyotype (<30 years of age), ultrasound of the breasts and pelvis are advisable. Optimal therapy is combined estrogen progestagen therapy given in a sequential rhythm, after excluding absolute contraindications. Testosterone can be added to adnexectomized women and those with a low libido. Sequential estrogen progestagen replacement therapy is the first line therapy for ovulation induction in those looking for pregnancy and after that oocyte donation will be advised. Appropriate estro-progestagen therapy improves the quality of life and prevents complications such as cardiovascular diseases, osteoporosis, stroke etc. PMID- 23350263 TI - High-tech, high-touch: use or abuse? PMID- 23350262 TI - Risk factors for acute respiratory distress syndrome in H1N1. PMID- 23350264 TI - FOCUS on: Restorative dentistry. PMID- 23350265 TI - Crown and bridge cements: clinical applications. AB - Cement selection can be confusing because factors such as substrate, the type of restoration, and patient needs must be considered. Some substrates require additional treatment before cementation. This article describes the most commonly used traditional crown and bridge cements (GI and RMGI) used for metal and metal ceramic restorations, and resin cements used for all-ceramic restorations. Advantages, disadvantages, indications, and contraindications of cements have been reviewed. Recommended uses of cements for metal, ceramic, and laboratory composite restorations have been presented. General guidelines for surface treatment ot silica- and zirconia-based restorations when using resin cements have been discussed. PMID- 23350266 TI - An aesthetic application for lithium disilicate. Treatment of missing maxillary lateral incisors and canine substitution. PMID- 23350267 TI - Endodontic diagnosis: there's an app for that! PMID- 23350268 TI - The CT/CBCT-based team approach to care. Part 3: Identifying prosthetic options through team communication. PMID- 23350270 TI - A new approach to implant provisionalization. PMID- 23350269 TI - Titanium-zirconium implants: Case report. Immediate provisional and restoration using a small-diameter system. AB - This article presented the immediate provisional and definitive restoration at 6 weeks of a novel small-diameter titanium-zirconium implant, with a 6-month follow up. The manufacturer purports that the implant described herein has superior mechanical and biological properties that could expand treatment options for small-diameter implants, thus benefiting accelerated protocols by further shortening the total treatment time. Human studies are needed to validate these claims. PMID- 23350271 TI - Monolithic zirconia: minimizing adjustments. PMID- 23350272 TI - Biting into sound. PMID- 23350273 TI - A minimally invasive smile restoration. A case report describing a multitechnique approach over time. PMID- 23350274 TI - GbWRKY1, a novel cotton (Gossypium barbadense) WRKY gene isolated from a bacteriophage full-length cDNA library, is induced by infection with Verticillium dahliae. AB - WRKY transcription factor proteins play important roles in diverse stress responses. In this study, we first cloned a novel WRKY from our constructed bacteriophage full-length cDNA library for cotton (Gossypium barbadense). The plants were stressed by exposure to a defoliating strain of Verticillium dahliae. The capacity of primary cDNA library was 1.28 x 10(6) PFU and the titer of the amplified cDNA library was > 10(10) PFU mL(-1). The recombination rate of the library was 94% and average insert size was about 1.1 kb. This novel gene, named GbWRKY1 was 1971 bp long and encodes a protein of 489 amino acids. It contains two characteristic WRKY domains and two zinc finger motifs. The sub-cellular assay indicated that GbWRKY1-GFP fusion protein was localized in the nucleus. Furthermore, Northern blot analysis showed that expression pattern of GbWRKY1 was similar among tissue types (roots, stems and leaves), but differed between pathogen-infiltrated and Czapek medium-infiltrated (untreated control) plants. Quantitative real-time PCR showed that GbWRKY1 could also be induced by salicylic acid (SA), methyl jasmonate (MeJA) and 1-aminocyclopropane-1-carboxylic acid (ACC). These findings clearly suggest that as a pathogen-inducible transcription factor GbWRKY1 plays an important role in plant defense responses. PMID- 23350275 TI - Homocysteine in occlusive vascular disease: a risk marker or risk factor. AB - Homocysteine has emerged as a significant marker for occlusive vascular disease, but there has been some debate as to whether it is just an association (risk marker) or actually a causative factor (risk factor). To elucidate this, a retrospective statistical analysis was done of data generated in the course of our study on homocysteine and vascular disease. Homocysteine, lipid profile components and lipoprotein(a) were estimated in fasting blood samples drawn from 252 controls and 536 patients of occlusive vascular disease. The data were analyzed by SPSS version 17. Mean homocysteine levels were significantly higher (p < 0.001) in all patients categories, as compared to controls. In fact, homocysteine level was the most significant biochemical risk factor for vascular disease. The odds ratios due to hyperhomocysteinemia varied from 3.170-4.153. When the cut-off was increased by 5 micromol/L, the odds ratio became almost three-fold. The prevalence of hyperhomocysteinemia increased by approximately equal to 20%, when the cut-off was reduced by 5 micromol/L. Statistical analysis of our data revealed that homocysteine conformed to Hill's criteria of causation. Moreover, hyperhomocysteinemia was treatable by the administration of B-vitamins, even if the cause was genetic. Hence morbidity due to vascular disease could be reduced by identification and treatment of hyperhomocysteinemia. PMID- 23350276 TI - Propeptide processing and proteolytic activity of proenzymes of the staphylococcal and enterococcal GluV8-family protease. AB - Proenzymes with various lengths of propeptides have been observed in GluV8 from Staphylococcus aureus and GluSE from S. epidermidis. However, the production mechanism of these proenzymes and roles of truncated propeptides have yet to be elucidated. Here we demonstrate that shortening of propeptide commonly occurs in an auto-catalytic manner in GluV8-family members, including those from coagulase negative Staphylococci and Enterococcus faecalis. Accompanied with propeptide shortening, the pro-mature junction (Asn/Ser_1-Val1) becomes more susceptible towards the hetero-catalytic maturation enzymes. The auto-catalytic propeptide truncation is not observed in Ser169Ala inert molecules of GluV8-family members. A faint proteolytic activity of proenzymes from Staphylococcus caprae and E. faecalis is detected. In addition, proteolytic activity of proenzyme of GluV8 carrying Arg-3AlaAsn.1 is demonstrated with synthetic peptide substrates LLE/Q MCA. These results suggest that GluV8-family proenzymes with shortened propeptides intrinsically possess proteolytic activity and are involved in the propeptide shortening that facilitates the final hetero-catalytic maturation. PMID- 23350277 TI - Effects of low intensity electromagnetic irradiation of 70.6 and 73 GHz frequencies and antibiotics on energy-dependent proton and potassium ion transport by E. coli. AB - The effects of low intensity (flux capacity 0.06 mW/cm2) coherent electromagnetic irradiation (EMI) of 70.6 and 73 GHz frequencies and their combined effects with antibiotics--ceftriaxone or kanamycin (0.4 or 15 microM, correspondingly) on E. coli K12 growth and survival have been reported previously. To further study the effects of EMI and antibiotics and mechanisms, decrease in overall energy (glucose)-dependent H+ and K+ fluxes across the cell membrane was investigated in E. coli. The depression of H+ and K+ fluxes rate was maximally achieved with the 73 GHz frequency. The EMI strengthened the effect of N,N'-dicyclohexycarbodiimide (DCCD, an inhibitor of the F0F1-ATPase). The 73 GHz EMI had more influence on H+ efflux inhibition, whereas 70.6 GHz on K+ influx. Also, EMI strengthened the depressive effects of ceftriaxone and kanamycin on the overall and DCCD-inhibited H+ and K+ fluxes. The 73 GHz EMI strengthened the effect of ceftriaxone on both ions fluxes. Kanamycin depressed H+ efflux more as compared to ceftriaxone, which was also strengthened with EMI. The results of E. coli H+ and K+ transport systems activities depression by irradiation and the irradiation effect on DCCD and antibiotics action indicated the EMI and antibiotics causing primary changes in the bacterial membrane. PMID- 23350278 TI - Docking studies on novel alkaloid tryptanthrin and its analogues against enoyl acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis. AB - Isoniazid resistance is a serious threat in the battle against the treatment of multi-drug resistant tuberculosis (MDR-TB) and extremely drug-resistant tuberculosis (XDR-TB). Isoniazid is an inhibitor of enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis, which is an important and functional enzyme of the type II fatty acid synthesis system and important therapeutic target. Natural alkaloid tryptanthrin and its analogues have shown anti-tubercular activity against MDR-TB, but their cellular target is unknown. In this work, in silico molecular docking was performed using docking server in order to see the interaction of tryptanthrin and its 15 analogues with InhA of M. tuberculosis. Results showed that among tryptanthrin and its 15 analogues, tryptanthrin and its two analogues exhibited good affinity to the binding site of InhA with free binding energy of -7.94 kcal/mol and inhibition constant (Ki) of 1.50 microm. Active site residues of InhA interacting with tryptanthrin were Ser13, Thr39, Phe41, Leu63, Asp64, Val65, Ile95, Phe97 and Ile122. In binding mode, polar bond were found between O1 (1) with Asp64 of bond length (3.34 A) and hydrophobic bonds were found between Leu63 with C15 and C12, Val65 with C7, Val65 with C12 and C4, Ile95 with C6 and C7, Ile95 with C10, C12 and C14. Important pi pi bonds were found between Phe41 with C2, C5, C7, C12, C4, C6, C8, C9, C13 and Phe97 with C9. These interactions indicated stability of tryptanthrin in active residue and suggested it as a potential drug candidate. Thus, good affinity of tryptanthrin to binding site of InhA may lead to synthesis of anti-tubercular drug capable of combating MDR strains of M. tuberculosis. PMID- 23350279 TI - Probing the evolutionary conserved regions within functional site of drug resistant target proteins of Staphylococcus aureus: In silico phylogenetic motif profiling approach. AB - Staphylococcus aureus is one of the major causes of clinical infections and increasing mortality due to multi-drug resistance. In this study, eight drug resistant genes, beta-lactamase, metallo-beta-lactamase, vanB, mecA, norA, qacA, qacB and qacC of S. aureus strain Mu50 (vancomycin resistant) were studied to predict the evolutionary conserved functional site residues in their protein sequences. It was found that in beta-lactamase, Tyr, Gly, Thr, Asn and in metallo beta-lactamase, Thr, His, Gly, Leu, Arg and Asp residues were highly conserved. In vanB, Gly, His and Asp residues were highly conserved. Whereas in mecA, His, Val, Phe, Gln, Lys and in norA, Ser, Leu and Ala residues showed conservedness at moderate level. In the multi-drug efflux pump (corresponding to qacA, qacB and qacC), Gly residue was found to be highly conserved. The homology clustering of target proteins through SCI-PHY algorithm and homologues identified through PSI BLAST were compared to identify the degree of conservation of functional residues. The phylogenetic motifs identified using homologues of target proteins were validated through domain search to locate their site and functionality in the protein sequences. Interactome analysis was performed to understand the possible mode of interaction of target proteins with their functional partners. PMID- 23350280 TI - Anti-proliferative effect of leaf extracts of Eucalyptus citriodora against human cancer cells in vitro and in vivo. AB - Six different extracts from Eucalyptus citriodora leaves were investigated for their anticancer effect. Extracts were prepared using a range of polar and non polar solvents to leach out maximum active components. Phytochemical analysis of the extracts revealed the presence of anthraquinones, cardiac glycosides, flavonoids, saponins and tannins. Cytotoxic activity of different extracts was tested in vitro against seven human cancer cell lines from seven different tissues, such as SW-620 (colon), HOP-62 (lung), PC-3 (prostate), OVCAR-5 (ovary), HeLa (cervix), IMR-32 (neuroblastoma) and HEP-2 (liver). The ethyl acetate, chloroform and 50% methanolic extract displayed highest anti-proliferative effect in a dose-dependent manner. In vivo anti-tumor activity was evaluated against murine tumor (solid) model of Ehrlich ascites carcinoma and Sarcoma 180. The results showed that ethyl acetate and aqueous extracts suppressed the growth of Ehrlich ascites carcinoma (29.79% and 18.48%, respectively), but showed little growth inhibition in case of Sarcoma 180 (13. 86% and 8.57%, respectively). The activity might be due to the flavonoids, tannins and saponins that are present in all the extracts of the plant. Further investigation is required for the isolation of active principle(s) from the ethyl acetate extract, which has shown significant in vitro and in vivo anticancer potential. PMID- 23350281 TI - Protective effect of Withania somnifera roots extract on hematoserological profiles against lead nitrate-induced toxicity in mice. AB - The in vivo protective role of hydro-methanolic root extract of Withania somnifera (WS) was evaluated in alleviating lead nitrate (LN)-induced toxicity in male Swiss albino mice by measuring hematoserological profiles. The lead-treated (20 mg/kg body wt, p.o.) albino mice (25-30 g) concurrently received the root extract (200 and 500 mg/kg body wt, p.o.) once daily for the duration of six weeks. Animals exposed to LN showed significant (P < 0.001) decline in haemoglobin content, red blood cell count, white blood cell count, packed cell volume and insignificant decrease in mean corpuscular haemoglobin and mean corpuscular haemoglobin content, while mean corpuscular volume and platelet count were increased. A significant elevation (P < 0.001) in serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, alkaline phosphatase, acid phosphatase and total cholesterol were also observed, when compared with control mice. Thus, the study demonstrated that the concurrent daily administration of root extract of WS protected the adverse effects of LN intoxication in mice. PMID- 23350282 TI - Anti-inflammatory and antipyretic activities of the ethanolic extract of Shorea robusta Gaertn. f. resin. AB - Shorea robusta Gaertn. f. (Sal) is one of the most important traditional Indian medicinal plants. The resin of the plant has been used in the treatment of inflammation in folklore medicine. In the present study, ethanolic extract (70%) of S. robusta resin (SRE) was investigated for its anti-inflammatory and antipyretic activities. Acute inflammation was produced by carrageenan-induced hind paw edema and sub-acute by cotton pellet-induced granuloma in male Wistar rats. The antipyretic activity of SRE was studied using Brewer's yeast-induced pyrexia in rats. The rats were divided into five groups with five animals in each group. Group I was treated with vehicle i.e. 1% v/v Tween-80 and served as control. Groups II to IV were treated with three different doses of SRE (30, 100 and 300 mg/kg orally). Group V was treated with standard drug etoricoxib (10 mg/kg orally). The anti-inflammatory activity of SRE was assessed by per cent reduction in edema volume of carrageenan-induced hind paw edema and by per cent decrease in granuloma formation in cotton pellet-induced granuloma test. SRE (100 and 300 mg/kg) produced a significant reduction in edema volume and decrease in granulation tissue formation in rats. Significant reduction in pyrexia was observed at all the dose levels of SRE i.e. 30, 100 and 300 mg/kg. The results of the present study demonstrated anti-inflammatory and antipyretic activities of S. robusta resin and supported its traditional therapeutic use in painful inflammatory conditions and fever. PMID- 23350283 TI - Nanoactivator mediated modifications in thermostable amylase from Bacillus licheniformis. AB - Gram-positive rod-shaped thermophilic bacteria were isolated using samples collected from terrestrial natural thermal spring located at Unkeshwar (Longitude 78.22 degree East to 78.34 degree East, Latitude 19 degree 34' North to 19 degree 40' North), District Nanded, Maharashtra State, India. The isolates were then cultivated using selective media and identified using culture-dependent techniques. One prominent isolate (UN1) exhibited high temperature stability and remarkable amylase production and was identified as Bacillus licheniformis. Amylase production was carried out in starch media and the enzyme was partially purified and characterized for optimization of pH and temperature. Amylolytic activity of the enzyme was determined. Nanoactivator-mediated modifications were carried out to enhance amylolytic activity of the partially purified amylase. Three-fold increase in catalytic efficiency of amylase was obtained after modification. PMID- 23350284 TI - [Part-time residency training in Israel]. AB - Full-time work has long been perceived as a cornerstone of medical residency, the consensus being that a resident must apply the bulk of his time and attention to his professional training. Demographic and cultural changes that have taken place over the last several years, specifically the rise in the number of female doctors and the importance of leisure time to the younger generation, have intensified the need to find new and innovative ways to deal with the plight of the resident population. One idea, already in effect in many Western countries, is the institution of part-time residency programs. The possibility of fulfilling residency requirements on a part-time basis is intended to assist medical residents in integrating their professional development with their personal and family life, without compromising the quality of their training. A number of research studies conducted over the last several years in countries that allow part-time residency, among them the United States, England and Switzerland, aimed to examine the quality of part-time training. The various studies evinced a high level of satisfaction from the program both by the residents themselves and their supervisors, and in many aspects those doing residency part-time received higher appraisals than their full-time colleagues. Some of the residents polled noted that they would have totally foregone the practice of medicine had there not been an option to complete residency part-time. In light of the experience throughout the world and the changing landscape in Israel, the Scientific Council of the Israeli Medical Association decided to examine the issue and its various aspects, and weighed all the considerations in favor and against part-time residency. Recently, the Scientific Council approved the launch of a pilot program to allow part-time residency in several fields that were carefully selected according to specific criteria. Once the Ministry of Health completes the LegisLation process, part-time residency will officially begin in Israel. PMID- 23350285 TI - [Moshe Silman's suicide and Werther effect]. PMID- 23350286 TI - [Pediatric infectious diseases--an ongoing battle]. AB - Eleven articles are included in this special issue of Harefuah dedicated to pediatric infectious diseases. Herein, they present the problems and dilemmas pediatricians, as well as general practitioners, face in current practice. In spite of tremendous achievements in prevention, diagnosis and treatment, infectious diseases remain a major concern in pediatrics. Additional efforts are urgently needed including judicious use of antibiotics to reduce resistance, development of modern vaccines and antibiotics and public health measures in order to overcome the battle against infections. This can be possible only with robust governmental support. PMID- 23350287 TI - [Compliance and safety of oseltamivir treatment in children and infants less than one year of age]. AB - BACKGROUND: Data regarding the compliance and safety of oseltamivir in infants < 1-year-old are limited. AIM: To compare the rates of adverse effects and compliance with oseltamivir treatment among hospitalized children aged < 1-year old with suspected influenza and older children. METHODS: A telephone follow-up was carried out with parents of children admitted to hospital during the 2009 influenza pandemic within a week after their discharge, and their medical records were reviewed. RESULTS: A total of 89 children were included (median age was 1.3 years old); 38.2% were < 1-year-old. Only 9% were diagnosed with pH1N1 influenza. The mean duration of therapy was 3 days. Difficulty in the administration of oseltamivir was reported in 52.8% of the children. Adverse effects were reported in 53.9% of the children. The most common were vomiting and/or diarrhea (32.6%) followed by restlessness (31.8%), and rash (6.7%). Treatment of only one child was discontinued due to a possible adverse event. The rates of adverse effects and difficulties in oseltamivir administration were similar among infants < 1-yr old and older children. CONCLUSIONS: The compliance and safety of oseltamivir therapy were similar among infants < 1-yr-old and older children. Difficulties in oseltamivir administrating and/or possible adverse effects have rarely influenced compliance. Liberal treatment with oseltamivir has led to prominent overuse of the medication. PMID- 23350288 TI - [Combination antifungal therapy in hematopoietic stem cell transplantation patients]. AB - Invasive fungal infections are a major cause of morbidity and mortality in hematopoietic stem cell transplantation patients. In recent years, new resistant fungal strains have emerged, requiring physicians to use new generation antifungal drugs or drug combinations. We report a case of invasive Fusarium infection involving the nasopharynx, skin and lungs, following haploidentical hematopoietic stem cell transplantation in an 8-year old patient with recurrent leukemia. The patient was treated with combination antifungal treatment of amphotericin B and voriconazole, as well as supportive care, with the improvement of his symptoms and home discharge. We reviewed the history of combination antifungal therapy. Combination antifungal treatment has been used since 1979, especially in immunocompromised patients. Although randomized controlled trials are lacking, reports favoring combination, especially for invasive mold infections, are increasingly published. PMID- 23350289 TI - [Cutaneous leishmaniasis treated with ambisome (liposomal amphotericin B)]. AB - Cutaneous leishmaniasis, caused mainly by Leishmania major, is endemic in southern Israel. It is characterized by multiple skin lesions on the skin's patient. The treatment often includes only topical treatment, and treatment failures are not uncommon. Liposomal amphotericin B, a drug approved for visceral leishmaniasis treatment, has rarely been used for the cutaneous disease, especially for Old World cutaneous leishmaniasis. We report a 1-year-old patient with multiple skin Lesions, diagnosed as leishmania major infection. The patient's parents refused topical treatment, as they were concerned regarding the possibility of treatment failure and residual facial scars. The patient was treated with intravenous liposomal amphotericin B, given as a 6 dose regimen and was cured clinically without any complications. Post-treatment evaluation, including direct microscopy, culture and polymerase chain reaction (PCR) revealed no evidence of residual disease. We believe that liposomal amphotericin B, although expensive, should be considered for cutaneous leishmaniasis treatment, when systemic treatment is needed, such as in cases with multiple facial skin lesions. PMID- 23350290 TI - [Spasmodic left waist pain in a six years old child--cat scratch disease]. AB - Cat scratch disease is caused by Bartonella henselae, a bacterium transmitted to humans from cats through a scratch or by fleas. In 90% of cases, the clinical presentation is that of classical cat scratch disease where an adjacent lymph node is infected. Atypical manifestations include prolonged fever, liver and spleen abscesses, infective endocarditis, central nervous system involvement etc. We present a 6 years old girl who suffered from L2 vertebral osteomyelitis and epidural abscess, initially presenting as colic left waist pain, with no back pain or high fevers. During the process of diagnosis, she recovered without surgical intervention or antibiotic treatment. A review of the literature indicates that among the wide spectrum of clinical manifestations of cat scratch disease, skeletal involvement is rare. However, in cases of osteomyelitis, vertebrae are a common site as well as formation of a contiguous phlegmon. Although no studies have investigated the efficacy of different treatment regimens, all patients presented were treated with antimicrobial combinations and recovery rates were high. In view of the patient presented here, it is questioned whether the high recovery rates are a result of efficient antibiotic treatment or due to a benign natural course of the disease. PMID- 23350291 TI - [Trends in pediatric infective endocarditis in a tertiary pediatric center in Israel]. AB - INTRODUCTION: The characteristics of pediatric infective endocarditis (IE) are continuously changing. OBJECTIVES: To describe trends in pediatric IE over a period of 25 years. STUDY METHODS: Children (< 18 years old] treated at Schneider Children's Medical Center during 1992-2004 who met Duke criteria for definite or possible IE were included in the study. Demographic, clinical and laboratory data were collected and compared to data gathered during 1980-1991. RESULTS: Compared to 1980-1991, during 1992-2004 we noted a decrease in the mean age from 6.5 to 4 years and in the incidence of congenital heart defects from 96% to 61% (p = 0.001). Incidence of significant underlying diseases and non-cardiac predisposing factors rose from 4% to 43%. Significantly Less children presented with fever, splenomegaly and murmur during 1992-2004; a 4-fold increase in surgical intervention [p = 0.024) and a 3-fold increase in mortality p = 0.257 were observed. Viridans streptococci (37.5%), Staphylococcus aureus (20.8%) and gram negative bacilli 2.5%] caused most of IE during 1980-1992, whereas viridians streptococci (19.1%), Candida spp (17%), S. aureus (17%) and coagulase-negative staphylococci (12.8%) were the common causes during 1992-2004. CONCLUSIONS: Considerable changes in pediatric IE were observed. DISCUSSION AND SUMMARY: Pediatric IE became an infection of young children, especially those with significant noncardiac underlying diseases. It is less commonly caused by viridans streptococci and is increasingly caused by Candida spp and coagulase negative staphylococci. These trends may affect the management of pediatric IE. PMID- 23350292 TI - [Prevalence of H1N1 A influenza virus infection among hospitalized patients with bronchiolitis twelve months old and younger]. AB - BACKGROUND: Many pathogens have been reported to ause bronchiolitis during the winter season including he respiratory syncytial virus (RSV), influenza, oetapneumovirus, etc. The last H1N1 A influenza pandemic ccurred during the respiratory syncytial virus (RSV) eason. The role of the pandemic influenza strain as a ause of bronchiolitis was not documented. OBJECTIVE: Assessment of the prevalence of co-infections of RSV and H1N1 influenza virus among children aged 12 months and younger, hospitalized with bronchiolitis. METHODS: A retrospective study design was used. Clinical data on 93 infants, 12 months old and younger, hospitalized for bronchiolitis, were retrospectively collected, including test results for RSV and H1N1 A influenza infection. RESULTS: Sixty-six out of the 90 (73.3 %) patients tested were positive for RSV; 2 out of the 81 patients tested (2.5%) were positive for H1N1 influenza. No patient was positive for both. CONCLUSIONS: The results of the present study clearly show that in infants younger than one year of age, who suffer from upper and lower respiratory tract infection (bronchiolitis), the main pathogen is RSV (also appeared in the middle of he H1N1 A influenza pandemic last winter). We conclude that the H1N1 A influenza infection is uncommon in infants hospitalized with bronchiolitis during the winter season. PMID- 23350293 TI - [Congenital skull base defect causing recurrent bacterial meningitis]. AB - Bacterial meningitis is a life threatening disease. Most patients will experience only one episode throughout life. Children who experience bacterial meningitis more than once, require further immunologic or anatomic evaluation. We report a 9 year old child with five episodes of bacterial meningitis due to a congenital defect of the skull base. A two and a half year old boy first presented to our medical center with pneumococcal meningitis. He was treated with antibiotics and fully recovered. Two months later he presented again with a similar clinical picture. Streptococcus pneumoniae grew in cerebrospinal fluid (CSF) culture. CT scan and later MRI of the brain revealed a defect in the anterior middle fossa floor, with protrusion of brain tissue into the sphenoidal sinus. Corrective surgery was recommended but the parents refused. Three months later, a third episode of pneumococcal meningitis occurred. The child again recovered with antibiotics and this time corrective surgery was performed. Five years later, the boy presented once again with clinical signs and symptoms consistent with bacterial meningitis. CSF culture was positive, but the final identification of the bacteria was conducted by broad spectrum 16S ribosomal RNA PCR (16S rRNA PCR) which revealed a sequence of Neisseria lactamica. CT and MRI showed recurrence of the skull base defect with encephalocele in the sphenoid sinus. The parents again refused neurosurgical intervention. A year later the patient presented with bacterial meningitis. CSF culture obtained after initiation of antibiotics was negative, but actinobacillus was identified in the CSF by 16S rRNA PCR. The patient is scheduled for neurosurgical intervention. In patients with recurrent bacterial meningitis caused by organisms colonizing the oropharynx or nasopharynx, an anatomical defect should be carefully sought and surgically repaired. PMID- 23350294 TI - [Primary cutaneous Nocardia brasiliensis cellulitis in immunocompetent child]. AB - Primary cutaneous nocardiosis is an infrequent infection among children, generally affecting immunocompromised hosts. It is caused by Gram positive bacteria, partially alcohol and acid resistant which are saprophytes of the soil, water and organic matter. In most cases the causal agent enters through inhalation, and hematogenous dissemination may occur mainly among the immune compromised patients. Direct cutaneous inoculation is less frequent, especially among children. We report an 8-year old female who lives in an urban house with a small garden, who presented with an ulcer on her right shin accompanied by surrounding cellulitis, pain, swelling and fever. The patient's medical history was unremarkable, with no exposure to animals or travelling, except for rafting on the Jordan River the previous week. Culture from the ulcer grew Nocardia brasiliensis, and she recovered after 8 weeks of therapy with trimethoprim sulphamethoxazole. PMID- 23350295 TI - [Legionella pneumonia in a child with leukemia]. AB - Legionnaires' disease is a rare cause of community acquired pneumonia in children and is exceedingly rare in infants and neonates. We describe a case of a 15 years old female, with lymphoblastic leukemia and legionella pneumophila pneumonia. Diagnosis was made by specific culture and polymerase chain reaction method from sputum and bronchoalveolar ravage specimens. Treatment was prolonged because of slow resolution and the fact that she underwent bone marrow transplantation. This emphasizes the importance of considering this rare entity in cases of severe pneumonia, especially in the immunocompromised host. PMID- 23350296 TI - [Infectious diseases--new horizons]. AB - During the last decade we have witnessed important developments in the field of infectious diseases. These developments have in a large part been made possible due to our entry into the genomic period. The main areas of progress include diagnosis, understanding of the pathophysiology, genetics, anti-microbial therapy and the prevention of disease by new vaccines. The diagnosis of infection using Polymerase Chain Reaction (PCR), contributes today to the early identification of a pathogen, long before the culture and serology. In the future, we will be able to utilize molecular methodologies based on the unique response of the host to a specific infection--the genetic signature. This method will enable very early identification of the pathogen, institution of optimal treatment, and will prevent the excessive use of antibiotics. Another area that has developed in recent years is the genetics of infectious diseases. Accumulated data shows that changes in the genome, polymorphism, result in different reactions by people to different infections. As a result of these changes some people are resistant to certain infections whilst others are especially sensitive to other infections. Introduction of this knowledge into clinical practice will enable more rational medical management with an emphasis on personalized medicine. After a long period without the development of new antibiotics, there are now signs of conceptual and practical breakthroughs in the development of antibiotic agents whose activity is based on new principles and directed against sites different from those of existing antibiotics. These advances are predominantly due to progress in the field of genomics. Similarly, in the development of future vaccines, more and more vaccines will be developed using genomic methods, enabling the creation of vaccines against diseases that we have not yet succeeded to eradicate. Genomic methods will enable the design of vaccines tailored to the specific genomic structure of the host--personal vaccines. All these four aspects of progress in the field of infectious diseases are not science fiction, and it can be stated with confidence that the future is already here. PMID- 23350297 TI - [Infectious diseases in children--dreams came true, however]. PMID- 23350298 TI - [Perspectives from the 9th Annual Conference on Health Technology Assessment- dealing with personalized medicine in the community, hospitals and organizing knowledge]. PMID- 23350299 TI - Influence of G. Stanley Hall on Yuzero Motora, the first psychology professor in Japan: how the kymograph powered Motora's career in psychology. AB - Yuzero Motora was the founder of psychology in Japan, acting as an organizer, executive, and administrator of psychological science and practice and as a vocal link between psychology and the larger philosophical and pedagogical community. He studied under Professor G. Stanley Hall and earned his PhD at Johns Hopkins University. An article coauthored by Hall and Motora was published in the first issue of The American Journal of Psychology. Findings presented herein are based partially on the biographical records, articles, and books written by Motora and partially on Motora's personal documents and course curriculum from Johns Hopkins University. We focus on Motora's life and work with Hall at Johns Hopkins, the research described in the article coauthored with Hall and the impact that it had, and the influence of Hall on Motora's career after he returned to Japan. PMID- 23350300 TI - Emotion and mood: over 120 years of contemplation and exploration in the American Journal of Psychology. AB - Emotional states derived from stimuli such as visual objects, scenes, and films, linguistic input such as words and phrases, and other inputs such as music and humor have been examined over many decades in an attempt to understand how feelings are aroused and, in turn, how they influence behavior. From early introspectionists to modern-day social, clinical, and cognitive researchers studying the ways in which affect is derived from everyday conscious and unconscious experiences and how those experiences frame our perceptions for processing future encounters with emotional stimuli, over 120 years of work has been reported in The American Journal of Psychology. The current article provides an overview of the more salient and influential of those works and articulates the ways in which the reported findings influence our current explorations of emotion and mood. PMID- 23350301 TI - From classic to current: a look back on attention research in the American Journal of Psychology. AB - This review examines attention research appearing in The American Journal of Psychology over the journal's rich 125-year history. In particular, the review examines studies focused on selective attention's role in modulating the influence of distraction and the methods used to capture the nature of selective attention. Special attention is given to classic articles by Treisman (1964a, 1964b), Neisser (1963), and Eriksen and Rohrbaugh (1970), whose methods and results are examined in detail in light of current theory and research in selective attention. PMID- 23350302 TI - The vital role of the American Journal of Psychology in the early and continuing history of mental chronometry. AB - The American Journal of Psychology (AJP) was founded in 1887 by G. Stanley Hall during what Edwin G. Boring (1950) called the Period of Mental Chronometry and, consistent with the prevailing interests of the time, featured articles of relevance to scientists in this research domain. Contained in the early volumes of AJP were several articles that examined what have become some of the enduring issues faced by researchers studying the structure and timing of mental processing using reaction time (RT) procedures. Collectively, RT research published in AJP during its early years contributed to establishing mental chronometry as an important subfield of psychology. From 1900 to 1950 interest in mental chronometry waned, during what has been called its Dark Age. Nonetheless, interest in the effects of factors such as age and intelligence on total RT continued unabated. Numerous articles pertinent to these effects appeared in AJP. Finally, with the publication of Neisser's (1963) seminal work on visual search, AJP played an important role in reviving interest in mental chronometry in the latter half of the 20th century and continues in its 125th year of existence to contribute pertinent articles on contemporary research in mental chronometry. PMID- 23350303 TI - Neuropsychological status in older adults influences susceptibility to false memories. AB - In 2 experiments we examined the influence of frontal lobe function on older adults' susceptibility to false memory in a categorized list paradigm. Using a neuropsychological battery of tests developed by Glisky, Polster, and Routhieaux (1995), we designated older adults as having high- or low-frontal function. Young and older adults studied and were tested on categorized lists using free report cued recall and forced report cued recall instructions, with the latter requiring participants to produce responses even if they had to guess. Under free report cued recall instructions, frontal lobe function was a strong predictor of false memories in older adults: Older adults who scored low on tests of frontal functioning demonstrated much higher levels of false recall than younger adults, whereas levels of false recall in high-frontal older adults were more similar to those of young adults. However, after forced report cued recall, high- and low frontal older adults performed similarly to each other, and both demonstrated higher levels of false recall than young adults. On a final recognition test, high-frontal older adults in both the free report cued recall and forced report cued recall conditions were more successful than low-frontal older adults in using source information to reduce memory errors. The results indicate that older adults show higher levels of false recall than younger adults, but type of test (free report or forced report) and neuropsychological status of older adults mediate these effects. Low-frontal older adults are particularly susceptible to producing false memories on free report tests that entail source monitoring. PMID- 23350304 TI - Analyzing the components of face-name forgetting across 4 weeks. AB - The present studies investigated forgetting processes across 4 weeks of names learned in response to faces. Our theoretical model assumes that there were 4 separate but interdependent aspects to a learned face-name unit. Each of these components (faces, names, face-name connections, and encoding cues to names that are stored during the original learning of names) has different forgetting rates across time. During retrieval, successful matching of faces with names depends on available memories for the first 3 components, whereas available memories for all 4 are necessary for successful recall of names. Results of the first study showed different forgetting curves for the 4 components, particularly the latter 2. Experiments 2 and 3 showed that cues associated with faces that serve as later retrieval cues for the recall of names are forgotten more quickly than face-name connections used to make identifying matches, and there was a very strong relationship between congruent cues at encoding and retrieval and the ability to recall target names after a 4-week interval. These results suggest that a profitable way to look at the learning of faces and names is to look at the components that break apart during forgetting. PMID- 23350305 TI - Relational versus absolute representation in categorization. AB - This study explores relational-like and absolute-like representations in categorization. Although there is much evidence that categorization processes can involve information about both the particular physical properties of studied instances and abstract (relational) properties, there has been little work on the factors that lead to one kind of representation as opposed to the other. We tested 370 participants in 6 experiments, in which participants had to classify new items into predefined artificial categories. In 4 experiments, we observed a predominantly relational-like mode of classification, and in 2 experiments we observed a shift toward an absolute-like mode of classification. These results suggest 3 factors that promote a relational-like mode of classification: fewer items per group, more training groups, and the presence of a time delay. Overall, we propose that less information about the distributional properties of a category or weaker memory traces for the category exemplars (induced, e.g., by having smaller categories or a time delay) can encourage relational-like categorization. PMID- 23350306 TI - [Causes of depression]. AB - This paper describes four nosological categories of depressive disorder according to the fundamental or prime cause: endogen depression, situative depression, psychogen depression and somatogen (also pharmacogen or addictive) depression. Recent advances in neurobiology provide the commun pathogenic mechanism distribuited in neurochemical, neuroendocrine and neuroinmune factors, with at the end a cellular and molecular sequence beyond the synapse. There is an increased risk of depression multiplied by three or four in the elderly, obese, unemployed and inmigrant and it is very frequent in terminally ill patients with a pervasive desire for death. Finally, eight personalized preventive guidelines enable to decrease the individual risk of depression in more than a fifty per cent. PMID- 23350307 TI - [Outlining the limits of salvageability in severe head injury]. AB - Severe head injury is one of the most important health, social, and economic problems in industrialized countries. The percentages of mortality and unfavourable outcomes are very similar to those reported in the last quarter of century. In order to make predictions, different "prognostic formulas or models" have been carried out. These models will be constructed on the one hand, by a group of "prognostic indicators or factors" and on the other hand, by different "prognostic scales" that are useful for measuring the final outcome of these patients. Several "statistical techniques or methods" are necessary to develop these ones. PMID- 23350308 TI - [The remote origin of metabolic diseases (obesity and type 2 diabetes mellitus) thrifty phenotype vs. thrifty genotype]. PMID- 23350309 TI - [Hormones, politics and sport in the German Democratic Republic (1949-1989)]. AB - The author shows his deep knowledge on State doping at the GDR during its brief existence as a Nation. Outstands the null concern of the communist authorities about the lifes of the athletes and the effects of the anabolic steroids in the survivors. The author regrets that the 'fake sport' was the only well known reason of the GDR's sport reputation. PMID- 23350310 TI - [Robotic surgery in gynecology: is it the future?]. AB - Gynecologic surgery has been undergone a significant change in the last decade thanks to innovation in health technology. The appearance of the Da Vinci Surgical System has revolutionized the concept of minimally invasive surgery, due to add advantages over conventional laparoscopic surgery, such us three dimensional vision, wristed forceps and a complete control of the instruments by the surgeon. The evidence published reflects that robotic surgery is preferable to laparotomy and laparoscopic approach, because it is more accurate, versatile, intuitive, and reduces perioperative morbidity. The future of Gynecologic Surgery is linked to the robotic approach. PMID- 23350311 TI - [Margins in oncology surgery]. AB - The author describes, within the important frequency of the cancer in current population, the fact that the surgery continues being the first step of therapeutic action in most cases. Furthermore, he describes how these surgeries have changed from the former big exeresis with amputations and alterations of the corporal silhouette to more effective conservative surgeries of the organ without producing the harmful effects of the previous ones. These conservative surgeries entail the extirpation of the tumor keeping some margins, which should be understood as the distance between the tumor and the end of the piece found. The procedures which are currently used to achieve some acceptable negative margins in the different parts of the organism and specially in breasts are listed below. PMID- 23350312 TI - [Cytogenetic biomarkers and health status]. AB - Cytogenetic aberrations are a biomarker for early effect that indicate the cell or the organism has undergone chromosomal damage as a result of his exposure to an external mutagenic/carcinogenic agent. The story begins with the description of the cytogenetic effects of ionizing radiation in 1927, but was not until 1956, with the description of the cytogenetic technique in humans, when genotoxic effects induced by mutagenic or carcinogenic chemical and physical agents are known. Induced chromosomal damage in humans by genotoxic agents is analyzed in human cells in vitro to check the genotoxicity of a suspected agent or in vivo in lymphocytes of individuals exposed to a genotoxic agent. The biomarker may be chromosomal breakage, sister chromatids exchanges, or micronucleus when the exposure has been recent, or chromosomal translocations for delayed or continuing exposures. The above, has allowed establishing that genotoxic damage accumulates with age and lifestyles such as smoking or occupational exposures. Recently, after checking the health status and survival of several European cohorts of normal individuals who years earlier were analyzed their cytogenetics biomarkers, has been established the cancer predictive value of the biomarker chromosome aberrations. PMID- 23350313 TI - [The sick individual as a concept]. AB - We start from the premise, shared by some current philosophical movements and by the author, which states that philosophy is not contemplation, or reflection, or introspection or communication. Philosophy is the art of shaping, inventing and creating concepts. It is an explicit way of introducing new differences in life, a different reading level, a specific jargon, which may imply revealing the flip side of the coin, or a dissimilar view of the side facing us. The philosopher is the friend of the concept, he holds it in his power, which means, basically and in all honesty, that philosophy is the discipline of creating concepts. Let us remember the brilliant idea of the Russian director Tarkovsky, who announced his greatest ambition as an artist: "To capture time". At the same time, we must recall one of the sayings of this director: "Every film I have directed and I intend to direct is always tied to characters who have something to overcome". The healthy individual lives in a specific time, with precise coordinates, aware that his life consists only of living that time. That is, living as defined by Josep Maria Esquirol: "Then we could also see that the best way of living the present is not to run after the fleeing time, but to see and live the opportunity that appears before us". One of the many circumstances that can intercept the way we see and live the opportunity that appears before us is sickness, one of those inescapable experiences we have not been taught how to pay an adequate attention to, and the meaning of which can, in a way, go unnoticed. As "time" goes by, the circumstance that we consider to be the basis on which existence is founded, sickness can appear, thus introducing a new dimension in the time of the healthy individual. For this reason we, as doctors and professionals, know that sickness "is tied to characters who have something to overcome". In view of the fact that a sickness invades a healthy individual and transforms him into a sick one, this paper supports the philosophical idea of the creation of a new concept: We have to create the concept of the sick with a philosophical basis, we must establish the idea that the sick individual lives, since the very moment he starts being sick, in a new and different time. The sick individual lives in a different time and, if we identify--with a certain boldness, just as Esquirol points out--"time" and "life", then we shall be bold enough to create a new entity, the sick individual, whose circumstances and new supports turn him into a new concept, they turn him into an idea--which shall be well defined and better shaped--after which we can think and act according to the belief of the sick individual as a concept, which is radically different from the healthy individual as a concept. The sick individual has nothing to do, if we can say so with a certain emphasis, with the healthy individual. They live in different times, although those times are not entirely unknown for each other. Every individual has the ability of thought. I think that the doctor, now become philosopher, must integrate the creation in its routine in order to be a better professional. He must create the concept of the sick individual, whose time has more different connotations than those found in the healthy individual. Accordingly, we want to think that the fabricated reality of the time of the healthy individual is not useful anymore, because the sick individual is an entity "in the distance", in which the course of time is fragmented as soon as he assimilates the crisis brought by the sickness. We have to properly shape and define that crisis and use it to philosophically establish the concept of the sick individual. Our plan is to produce a book after this conference. PMID- 23350314 TI - [Epidemic of Serratia marcescens in a tertiary neonatal intensive care unit: multivariate analysis of risk factors in a case-control study]. AB - An epidemic of Serratia marcescens was studied in a neonatal intensive care unit in a tertiary hospital by evaluating both infections and colonizations by this microorganism. Over a 14-month period, 26 infants were infected with S. marcescens (bacteriemias or bronchopneumonias). All the S. marcescens isolates studied by PFGE were identical, although their antimicrobial resistance varied. No environmental reservoirs were found. In the concurrent case-control study, the risk factors for infection were stay of more than 1 month, mechanical ventilation and anemia. PMID- 23350315 TI - [Effect of pretreatment with melatonin on the oxidative and inflammatory damage induced by hepatic ischemia/reperfusion in Zucker rats]. AB - The limiting factor of the viability of hepatic transplants has been the ischemia reperfusion damage where oxidative stress induced lesion after reperfusion plays a fundamental role. Melatonin is a substance that has demonstrated protective effects against oxidative stress. The aim of the present study is to demonstrate that the intraperitoneal or oral administration of melatonin before and during experimental hepatic ischemia reperfusion in young and old Wistar and Zucker rats could reduce the oxidative stress and inflammation induced lesion, responsible of the poor initial function after ischemia in the old or steatosic livers. The mRNA expression in hepatic tissue of cytokines, markers of oxidative stress and apoptosis as well as plasma transaminase levels were analyzed. Results showed an increase in both plasma transaminase as well as cytokines or oxidative stress and proapoptotic parameters. The elevation was higher in old and Zucker rats. Treatment with melatonin significantly reduced hepatic damage, being oral administration more effective. In conclusion melatonin was able to reduce liver damage after ischemia reperfusion being the effect more important in old and Zucker animals. PMID- 23350316 TI - [Differences in atrial remodelling between right and left atria in patients with chronic atrial fibrillation]. AB - Atrial fibrillation starts in the left atrium and from there the activity invades the atrial tissues and causes an inhomogeneous shortening the duration of atrial action potential duration and refractoriness. The purpose of this study was to compare the voltage-dependent potassium currents in human cells isolated from the right and left atria and to determine whether electrical remodeling produced by chronic atrial fibrillation (CAF) differentially affects voltage-dependent potassium currents involved in atrial repolarization in each atrium as compared to sinus rhythm (SR). The currents were recorded using the whole-cell configuration of the patch-clamp technique. We found that in atrial cardiomyocytes of patients both in SR and in CAF there are three types of cells according to their main voltage-dependent repolarizing potassium current: the Ca(2+)-independent 4-aminopyridine sensitive component of the transient outward current (I(to1)) and the ultrarapid (I(Kur)), rapid (I(Kr)) and slow (I(Ks)) components of the delayed rectifier current. CAF differentially modified the proportion of these 3 types of cells on each atrium: CAF reduced the I(to1) more markedly in the left than in the right atria, while I(Kur) was more markedly reduced in the right than in the left atria. Interestingly, in both atria, CAF markedly increased the I(Ks). This increase was enhanced by isoproterenol and suppressed by atenolol. These changes produce a non-uniform shortening of atrial repolarization that facilitates the reentry of the cardiac impulse and the perpetuation of the arrhythmia. PMID- 23350317 TI - [Rodriguez Lafora's in the academy]. AB - A chapter of Gonzalo Rodriguez Lafora's life is analyzed. His short but controversial academic period (the renewal of Cajal's chair in the Academy after his death) widely ignored by his biographs, is studied, on the light of documentation from the Archives of the Academy. PMID- 23350318 TI - [Circulating tumor cells: a new efficacy marker in the treatment of metastatic colorectal cancer]. AB - Colorectal cancer metastasis is the result of several interacting processes at the end of which cancer cells survive in distant organs. Penetration of primary tumor cells into blood is central to the whole phenomenon of metastasis and is a common step in all cancer types. The detection of circulating tumor cells (CTC) in peripheral blood of patients with colorectal cancer could have clinical usefulness in three aspects: 1) as evidence of early dissemination, and then as a risk factor of clinical recurrence, 2) as a relevant risk factor for metastatic progression and worse prognosis, and 3) as predictive marker of response to treatment. PMID- 23350319 TI - [Vitamina D. A wonderful drug?]. AB - During the last years vitamina D receptors have been found in a vast number of tissues and cell types. In paralel, the therapeutic utility of vitamina D has expanded to the prophylaxis of muscular, oncologic, cardiovascular and autoinmmune disorders. PMID- 23350320 TI - [Reutilization of wastewater]. AB - The problem of the reutilization of waste water is dealt with, in general and with a global vision, without scientific (physical, chemical and biological) or technical details, in the context of the serious situation that humanity suffers due to the widespread water shortage in quantity and quality. PMID- 23350321 TI - [Welcome speech for the new corresponding academicians]. PMID- 23350322 TI - [Speech in behalf of the new corresponding academicians]. PMID- 23350323 TI - [Concluding remarks of the President]. PMID- 23350324 TI - [New surgery for complicated renal anomalies]. AB - The indications for "ex vivo" surgery and autotransplantation have been broadened o complicated renal anomalies; particularly in the cases of the horseshoe kikney and kidney malrotation. This position is justified as conventional techniques do not correct the multiple causes that are responsible for these complications. These complications requiere a surgical strategy that simultaneously deals with the pathology of the renal anomaly itself and that of its excretory tract. The aforementioned means that the abnormal kidney orientation and position must be retified to permit a large resectioning of the dysplasic or dystrophic excretory conduct in order to achieve normal urinary drainage while conserving all the renal parenchyma. It has been achieved in thirteen out of the 14 cases operated on that correspond to distinct types of complicated anomalies. The excellent results demonstrate that this new and innovative surgery has resolved the complex and difficult issue of kidney malformations. The surgical method and long-therm results in the adult and child, the first in the literature, are presented here. PMID- 23350325 TI - [Morphogenesis and clinical anatomy of the petrotympanic and petrosquamosal fissure]. AB - Petrotympanic and petrosquamosal fissures are located in the temporal bone, in a complex area of the base of the skull, closely related to the evolutionary development of mammals. However, until now we do not have a comprehensive descriptions about how the formation of these fissures were formed. Recent researches have allowed us to determine the factors involved in their development, and consequently how the closure of the middle takes place and its separation of the temporomandibular joint. The mechanisms and structures involved in their morphogenesis determine the variability and anatomoclinical implications. PMID- 23350326 TI - [The event and contribution of Spanish medicine at Mexico]. AB - We are invited to solemnize the Event of 1810 Bicentenary of Mexican Independence and Centenary of UNAM and the Medical National Academy. We remembered the Constitution 1812 of Liberal Constitution at Cadiz, and the influence of Spanish Medical Doctors in Mexican Institution and The Academy. We consider the role of human rights advancing in global health, due to multidisciplinary nature. The Political Epidemiology help to increase scientific knowledge on social determinants of Health, in the consideration of the decision taken, and effective ways to reduce inequality (poverty, unemployed, handicapped), that focuses more broadly in social justice. PMID- 23350327 TI - [Descemet anterior lamellar keratoplasty (DALK). Indications, surgical technique and results]. AB - Although the cornea and the anterior chamber maintain an immune privilege that guarantees the survival of the majority of the corneal grafts in patients treated with penetrating keratoplasty, there are some cases in which the ocular surface status or the baseline conditions of the patient determine an immune rejection in the recipient which means graft failure. DALK technique preserves the endothelium (avoiding the majority of the anterior chamber immune reactions) and restores the anterior surface of the cornea to obtain a good visual acuity. We describe the surgical technique step by step, indications and possible intraoperative and postoperative complications. PMID- 23350328 TI - [Generation of bioartificial organs. The cornea as a model]. AB - The development of bioartificial organs is a new target in the development of tissue engineering. It consists in the use of stem cells in a decellularized stroma of other organs. In this paper we present our previous experience in the construction of a complete artificial cornea using cell cultures and biomaterials and compare it with the construction of a bioartificial cornea using a decellularized porcine stroma. The results, in building this new type of cornea, showed that 1.5 M NaCl treatment of porcine corneas is able to generate an acellular corneal stroma with adequate histologic and optical properties and that human keratocytes are able to penetrate and spread within this scaffold with proper levels of cell differentiation. In contrast, 0.1% SDS treatment of porcine corneas resulted in high levels of fibril disorganization and poor optical behavior of these corneas. PMID- 23350329 TI - [Social impact of epidemic or pandemic infectious contagion. The repercussion on the sanitary control of the health area]. AB - The social impact originated from the threat or presence of an infectious outbreak of epidemic and pandemic character is analyzed, using several diseases of big epidemiological relevance, such as AIDS, rabies, listeriosis, bovine spongiform encephalopathy, avian and human type A influenza of porcine origin. Once that the updated historical scheme has been established, the social reaction and the consequences of the fear and anxiety attitudes are studied, as well as the consequences that these states of mind may have, due to diverse reasons, on the health management of an epidemic or pandemic situation. PMID- 23350330 TI - [Reflecting on pain]. AB - A reflection on pain as a scourge of mankind, analysing the different types or ways of appearance and the various theories about the creation mechanisms arisen in the course of time. We consider the doctor/patient communication problems, faced with the different languages spoken by the two main characters of this drama. The progresses made in the two types of units which are currenfly aimed at treating acute or chronic pain are referred to, concluding that the problem of pain persists despite the constant therapeutic improvements, and advising the inclusion of Algiology into university curricula in order to facilitate the training of true superspecialists, capable of putting an end to pain. PMID- 23350331 TI - [The "thalamus-cerebral cortex" anatomofunctinal unit in the waking state]. AB - The "thalamus-cerebral cortex unit" is awakened by the "ascending reticular activating system", which originates from neuronal groups located within the brainstem, hypothalamus and basal forebrain, all of which use known neurotransmitters and whose neurons are more active during wakefulness than during the other behavioral states. Synergies among several of these neurotransmitters are necessary to generate the cortical and thalamic activation that is characteristic of wakefulness. During the wakefulness the complex interrelated structures of the "thalamus-cerebral cortex unit" provide the pathway that interconnects cortex and thalamus and allow the modulation, and organization of the mechanisms producing the adequate activity of the different thalamic and cortical formations and the organization of cognitive processes and performance of appropriate behavioral responses. PMID- 23350332 TI - [Where does Parkinson's disease start?]. AB - Parkinson's disease concept is classically restricted to a rigid-akinetic syndrome due to a nigro-striatal dopaminergic depletion. This concept ignored the widespread extension of neuropathologic findings across the CNS. Moreover detailed clinical studies showed that patients suffer a constellation of other symptoms and signs such as anosmia, constipation, cardiovascular disautonomia, neuropsychologic and neuropsychiatric disorders, dementia and sleep changes. Taken together these evidences have lead to the idea that Parkinson's disease is a multisystemic disease of the nervous system. Braak et al. have proposed first, a staging system for the neuropathologic burden into the CNS and second, a "dual hit" pathogenic hypothesis implicating a putative exogenous agent acquired through nasal route passing into the digestive tube and reaching the medulla following the vagus nerve. This hypothesis has received many criticisms. Our own findings in a family carrying a single aminoacid change (E46K) in alpha-synuclein segregating with a severe autosomal dominant Parkinson's disease phenotype, suggest that cardiac sympathetic denervation is the first step in this disease. PMID- 23350333 TI - [Mirror neurons]. AB - Mirror neurons were recently discovered in frontal brain areas of the monkey. They are activated when the animal makes a specific movement, but also when the animal observes the same movement in another animal. Some of them also respond to the emotional expression of other animals of the same species. These mirror neurons have also been found in humans. They respond to or "reflect" actions of other individuals in the brain and are thought to represent the basis for imitation and empathy and hence the neurobiological substrate for "theory of mind", the potential origin of language and the so-called moral instinct. PMID- 23350334 TI - [The segmentary classification of complex congenital heart disease or how the embryology simplified the study of these cardiopathies. The morphology of side by syde great arteries]. AB - In the 60-70 years of last century began the systematic study of complex congenital heart disease. The group of Dr. de la Cruz at the National Heart Institute of Mexico, based the segmental analysis of these heart in experimental study of embryological development. We could include exceptions to the complex cadiopathies, adding to the segmental classification, atrial situs, ventricular loop pedicle of the great arteries, the infundibular analysis. This presentation describes for the first time as a separate entity in the segmental analysis cadiopathies with great arteries side by side as a group with a different developmental mechanism to transposition and normally related or crossed great arteries. PMID- 23350335 TI - [Santiago Tamames Escobar - January 11, 2011), in memoriam]. PMID- 23350336 TI - [Biomarkers in tumor pathology]. AB - The process of malignant transformation requires the accumulation of multiple genetic alterations, a process which is usually years, where hundreds of genes may be involved. This enormous complexity is best understood through the work of Hanahan and Weinberg, which suggested that the most important functional impairment of various biochemical pathways (senescence, apoptosis, cell signaling and growth autonomy, ...), where many genes can be involved. All molecular advances are translated in the study of biomarkers. These factors, which range from genetic alterations, proteins, microRNAs, ... are basic to the study of neoplastic disease in all its phases. From risk assessment to have a certain type of tumor, with more than 30 genes already known to be inherited mutated and increase the likelihood of developing tumors (colon, breast, thyroid, ..), factors that can serve for serological screening of early tumors and especially also to outline more specific treatments. Continually new factors / biomarkers are being discovered, that may be therapeutic targets or associated with prognosis or resistance to certain treatments. The combination of specific treatments for each patient, in a stratified manner according to the molecular alterations, is assuming a very significant advance in the survival of some tumor types and has opened a great hope for the future of Oncology. PMID- 23350337 TI - [Giant cell in maxillary pseudotumors]. AB - A research on lesions apparently tumorous that appear on jawbones and are not exactly tumors is developed. These lesions are clinically silent, although they produce deformity and, perhaps because of that, an early diagnosis with biopsy or other procedures is needed. The image research can be very characteristic or otherwise, it can be very complex, non specific and not provide everything expected to make the diagnosis. The difference between radiolucent and radiopaque images that produce the querubism-fibrous displasia, prove both extremes in which the diagnosis judgment made by image can or cannot be significant. We have to highlight the presence of giant cells with an osteoclastic nature in most of these pseudo tumorous lesions. PMID- 23350338 TI - [History and poetry in women's biological twilight: menopause and old age]. AB - This is a poetical and historical approach to the last biological stages of the evolutive development of women, namely menopause and old age. It starts with the passages found in Egyptian Papirii such as Ebers or Smith, dated 1500-2000 BC, which describe, among other symptoms, the sweating and hig body temperatures caused by the diminishing hormon secretion of the ovaries. Other important works on the subject, some of them written in the 20th century and some others composed before that date, are also quoted, such as the Edad Critica (Critical Age) by Dr. Maranon. The final stage of a woman's life, old age, is presented through the famous sonet "Alfa y Omega" (Alpha and Omega) by poet Manuel Machado. Using poetical strokes, the author conveys an image of the many phisiopatological consequences of old age in women: osteoporosis, genital prolapse, urine incontinence and "wrinkles" ("old age is neither shown by white hair nor by wrinkles but by the heart"). The work finishes with the famous statement uttered by Napoleon Bona-parte: "God wanted to be a writer: Man is His prose; His poetry, Women". The same poetry that Dr. Cruz y Hermida has found through the complexities of the evolutive process of feminine biology. PMID- 23350339 TI - [Gastroesophageal reflux disease in obesity]. AB - Obesity is currently one of the top health problems worldwide. Its prevalence is markedly increasing in developed countries, but it is becoming a problem even in developing countries. In fact, the epidemic magnitude of obesity leads the WHO to coin the term globesity. Obesity is commonly associated with other diseases, like diabetes (diabesity) and other metabolic disorders. However, many organs and systems are affected, including the gastrointestinal tract. Gastroesophageal reflux disease is associated with obesity, as many studies showed. Several factors are involved in this association; among them, the onset of GERD has been related to weight gain, placing obesity in a critical point at the beginning of the natural history of GERD. PMID- 23350340 TI - [Splenic-thoracic transit: a rare evolution of hydatid disease]. AB - We report a case of splenic hydatid cyst, an unfrequent localization of hydatid disease that usually presents with hydatid cysts in other organs (but not in this case). Primary spleen infestation generally occurs trough arterial blood supply, after the oncosphere of Echinococcus granulosus travels from host's digestive tube to the left atrium, passing trhough hepatic and pulmonar filters; other routes are also possible. Migration of an abdominal hydatid cyst into the thoracic cavity (phenomena called abdominal thoracic hydatid transit) occurs in 3.5% to 5% of liver cysts, and is quite exceptional in splenic cysts. Clinical manifestations are mainly thoracic, the diagnosis is based on serological tests and imaging studies, and surgical treatment is always required. Taking advantage of this unusual case, we remember the pathogenesis of splenic hydatid disease as well as the pathophysiology of transdiaphragmatic transit of abdominal hydatid disease. PMID- 23350341 TI - [State of the medicine 2011]. AB - During many centuries the scientific knowledge has advanced in a slow and discontinue manner, with much time to deposit the established things and to generate theories and hypothesis about the unexplained and unknown matters. However, in the last decades happened an exponential increase in the knowledge of Medicine, because the technological advance and the contribution of several disciplines, which produce the development of Health Sciences. In the last 60 years Medicine has progressed faster than in the previous twenty centuries, which make very difficult to describe the events happened in this period. Thus, we have established a relationship between the development of communication in different facets of our own life and the biocommunication facts happening in our cell molecules to generate its functions. Alterations of these activities may explain the pathological modifications observed in disease. Also, we have considered this topic under general aspects, such as, role of the image in the Medicine development, appearance and development of Molecular Biology, human genome project, Molecular Medicine, animal models to study human diseases, molecular basis of cancer, genic and cell therapies and genes and aging. Also, we have analyzed the great technical and conceptual advance of Medicine through several specialities such as, Biochemistry,Hematology, Microbiology, Immunology, Histology, Pathology,Pharmacology, Radiology, Surgery, Obstetrics and Gynecology, Pediatrics and Oftalmology. PMID- 23350342 TI - [Etidronate and calcitonin to PTH (1-84) in postmenopausal osteoporosis]. AB - Postmenopausal osteoporosis is now a major health problem. The advancement of knowledge on the role preferred cellular osteocytes, osteoblasts and osteoclasts in bone tissue, the biochemical activity and gene expression, interaction with physical activity, diet and nutritional measures, as well as various currently available drugs are disclosed in interaction with clinical studies of etidronate and calcitonin, parathyroid hormone and recombinant 1-84. It is concluded in relation to its activity at eighteen months of the administration and its assessment by bone mineral density, biochemical markers and production of fractures. PMID- 23350343 TI - Changes in leisure styles and satisfaction of older people: a five years follow up. AB - The present study examines the leisure style and leisure satisfaction of a sample of older people at baseline and after a period of 5 years. Three groups were identified by factorial and cluster analyses and labelled under the headings of: organised style, surrounding style and indoor style. Each group represented a different typology of leisure, according to the demand for physical and organizational commitment. Results indicated that the Organized Style group was the most active and satisfied with their leisure time, and differed from the other two by being predominantly male, younger, better educated and in good health. Follow-up analyses revealed a decline in the size of both the organised style and surrounding style groups, and an increase in the size of the less active group, suggesting that advancing very old age with deteriorating health influenced older peoples' choices toward an increment of indoor activities. This pattern may be softened through the implementation of mechanisms of selection and optimisation. PMID- 23350344 TI - Development of the gerotranscendence scale type 2: Japanese version. AB - This study developed the Japanese version of the gerotranscendence scale type 2 (the GST2) and examined reliability and validity of the scale. In Japan, 525 community-dwelling older adults (male = 260, female = 265) answered a questionnaire. An exploratory factor analysis of the Japanese version of the GST2 revealed the same three-factor structure including the Dimensions of the Cosmic, the Coherence, and the Solitude, which had been reported by Tornstam with the omission of item 1. Reliability and construct validity of the Japanese version of the GST2 were confirmed. These findings provide support for use of the Japanese version of the GST2 as a measure of lifespan development among the oldest old in Japan. The GST2 can be applicable not only for older adults in Sweden but also for older adults in Japan. PMID- 23350345 TI - Jump into the void? Factors related to a preferred retirement age: gender, social interests, and leisure activities. AB - Using the frameworks of the life course perspective and continuity theory, this study focuses on the association among working people between gender and specific leisure activities, social interests and individuals' preferred retirement age. The study is based on the first wave of the Norwegian Life Course, Aging and Generation (NorLAG) study, concentrating on workers 40-61 years old, thinking about retirement (n=2339). Results indicate that some leisure activities and interests are associated with preferences for early retirement, while other activities and interests are associated with preferences for later retirement. Different leisure activities and interests are related to men's and women's retirement preferences. Single women prefer to retire later than married women. Findings suggest that leisure activities and social interests have different relevance for men's and women's preferences for leaving the labor force. Women active in voluntary work prefer later retirement, while men engaged in fishing and hunting prefer early retirement. PMID- 23350346 TI - Beliefs about promoting cognitive health among Filipino Americans who care for persons with dementia. AB - We examined beliefs about promoting cognitive health among Filipino Americans who care for persons with dementia, their awareness of media information about cognitive health, and their suggestions for communicating such information to other caregivers. We conducted three focus groups (25 participants). The constant comparison method compared themes across focus groups. Caregivers most frequently described cognitive health benefits of social engagement and leisure; next in emphasis were benefits of healthy diets. There was less emphasis on physical activity. Participants had heard from television that avoiding smoking, alcohol, and drugs might promote cognitive health. Ways to inform others about cognitive health included information in Filipino newspapers, and handouts in Filipino languages, distributed in Filipino stores, workplaces, community organizations, and health care facilities. Findings suggest an opportunity to develop public health messages promoting cognitive health that are in-language, published in ethnic-specific media, and that are culturally appropriate for Filipino and other Asian Americans. PMID- 23350347 TI - Chemoprotective and immunomodulatory effect of Acacia nilotica during cyclophosphamide induced toxicity. AB - Most of the synthetic chemotherapeutic agents used today are immunosuppressant and lead to numerous side effects. Plant based immunomodulators are employed as supportive therapy to counteract the undesirable side effects of chemotherapy. In the present study, the immunomodulatory and chemoprotective effect of methanolic extract of Acacia nilotica was investigated in mice. Intraperitoneal administration of the extract was found to significantly increase the Total WBC count, bone marrow cellularity and alpha-esterase positive cells. Cyclophosphamide is a chemotherapeutic drug and induces acute myelosuppression but treatment with the extract was beneficial in ameliorating chemically induced toxicity. The administration of the extract considerably increased the Total WBC count (6800 +/- 733.9 cells/cm2), bone marrow cellularity (43.6 x 10(5) +/- 14.33 cells/femur) and alpha-esterase positive cells (808.6 +/- 8.57 cells/4000 cells) in CTX treated mice when compared to CTX alone treated control mice. Weight of lymphoid organs such as spleen and thymus reduced by CTX were enhanced by treatment with Acacia nilotica extract. It can be concluded that the extract possess immunostimulatory properties. PMID- 23350348 TI - The tumour suppressive role of metastasis suppressor-1, MTSS1, in human kidney cancer, a possible connection with the SHH pathway. AB - BACKGROUND: Metastasis suppressor 1 (MTSS1), a cytoskeletal associated protein, has been indicated in certain types of human cancers, but its role in kidney cancer remains unknown. We have investigated the expression of MTSS1 in normal and malignant human kidney tissues and its molecular interaction within kidney cancer cells. MATERIALS AND METHODS: The expression of MTSS1 in human kidney tissues and kidney cancer cell lines was assessed at both the mRNA and protein levels using RT-PCR and immunohistochemistry, respectively. Full-length MTSS1 cDNA expression vector was used to generate MTSS1 over-expressing cells. Effect of MTSS1 overexpression on cellular functions, was examined in kidney cancer cells of MTSS1 being over-expressed using a variety of in vitro assays. Involvement of Sonic Hedgehog (SHH) pathway was tested by using Shh small inhibitors. RESULTS: Epithelial cells at proximal tubules of kidney tissues were stained positively for MTSS1, while the staining was weak or absent from cells at corpuscles and cancer cells of tumour tissues. Similarly, in kidney cancer cell lines, CAKI-2 and UMRC-2, expressed very low level of MTSS1. Over-expression of MTSS1 reduced the growth, invasion, adhesion and migration of kidney cell lines in vitro. Shh inhibitors diminished the inhibitory effect of MTSS1 on cell migration. CONCLUSION: MTSS1 expression is reduced in human kidney cancer cells. MTSS1 levels are inversely correlated with the growth, invasion, adhesion and migration of kidney cancer cells in vitro. MTSS1 suppresses migration of kidney cancer cells via SHH pathway, and is a putative tumour suppressor of kidney cancer. PMID- 23350349 TI - Chemo protective activity of carotenoid meso-zeaxanthin against doxorubicin induced cardio toxicity. AB - Carotenoid meso-zeaxanthin (MZ) was evaluated for its protective effect against doxorubicin (DOX) induced cardio toxicity in Wistar rats. Oral administration of MZ was started 15 days prior to doxorubicin (30mg/kg b.wt, i.p, single dose) injection. Animals in all groups were sacrificed 24 hours after doxorubicin administration. Serum markers of cardiac injury-LDH, CPK, SGOT and SGPT levels, which were increased drastically by doxorubicin treatment, were decreased to normal level by MZ pre-treatment. MZ significantly mitigated DOX-provoked reductions of cardiac activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as depletion of glutathione (GSH).Pretreatment of MZ significantly guarded against DOX-induced rise of oxidative stress markers like lipid peroxidation (LPO), tissue hydroperoxides (HP) and conjugated dienes (CD) in cardiac tissue. Moreover, DOX-induced myocardial injury, which was manifested by arrhythmias and conduction abnormalities in ECG (increased ST, QT interval and ST elevation), was reversed significantly by MZ pre-treatment. Histopathological analysis further confirmed cardio-protective potential of this carotenoid. PMID- 23350350 TI - Relation between nitrate and nitrite food habits with lung cancer. AB - Nitrites, a probable human carcinogen, generate reactive nitrogen species that may cause damage to the lung. We evaluated the association between nutritional habits related to nitrite and nitrate intake and risk of lung cancer in Mazandaran, Northern Province of Iran. In this case-control study the two groups were matched for gender and age (+/- 5 years). A semi -quantitative food frequency questionnaire (FFQ) was used to collect dietary data about nutritional habits related to nitrate, nitrite, vitamins E and C intake, from 40 lung cancer cases and 40 control subjects admitted at Mazanaran hospitals. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of lung cancer using logistic regression. Mean score of nutritional habits in case group was significantly lower than that in control group (P less than or equal 0.001). We observed a positive association between animal sources of nitrate and nitrite intake (OR = 2.7, 95% CI: 0.13-0.96) and risk of lung cancer. Decreased risk of lung cancer was also observed with fruit intake (OR = 0.26, 95% CI: 1.3-11). Our results indicate a probable association between nutritional habits related to animal sources of nitrate and nitrite intake and the risk of lung cancer that requires to be confirmed by other studies. PMID- 23350351 TI - A novel strategy of cancer therapy by enucleation. AB - Current modalities of cancer therapy utilize different agents to block key steps involved in cell division. Newer agents also block specific parts of molecular pathways that are vital for survival of the cancer cells but cells may develop resistance to all these agents and their use may also be limited by toxic effects on healthy normal cells. There is increasing evidence that the seat of cancer may be located in cancer stem cells which seldom divide. This property protects them from most of the chemotherapeutic agents which act on dividing cells. Identification of markers for cancer stem cells has been difficult and targeted therapy towards them has been elusive. The hypothesis proposed here utilizes the phenomenon of enucleation that is commonly observed in maturing red blood cells. Specifically, by utilizing protein fragment complementation it proposes that cancer cells may be induced to undergo enucleation. The specific advantage of this system is that the cells lose their nucleus and hence the emergence of resistance is very unlikely. The system also utilizes the binding of cytoplasmic cancer specific proteins to render it specific to cancer cells. It has the advantage of potentially being effective in cancer stem cells which may be resistant to conventional modes of therapy. PMID- 23350352 TI - Discovery and development of anticancer agents from marine sponges: perspectives based on a chemistry-experimental therapeutics collaborative program. AB - A collaborative program was initiated in 1990 between the natural product chemistry laboratory of Dr. Phillip Crews at the University of California Santa Cruz and the experimental therapeutics laboratory of Dr. Fred Valeriote at the Henry Ford Hospital in Detroit. The program focused on the discovery and development of anticancer drugs from sponge extracts. A novel in vitro disk diffusion, solid tumor selective assay was used to examine 2,036 extracts from 683 individual sponges. The bioassay-directed fractionation discovery component led to the identification of active pure compounds from many of these sponges. In most cases, pure compound was prepared in sufficient quantities to both chemically identify the active compound(s) as well as pursue one or more of the biological development components. The latter included IC50, clonogenic survival concentration exposure, maximum tolerated dose, pharmacokinetics and therapeutic assessment studies. Solid tumor selective compounds included fascaplysin and 10 bromofascaplysin (Fascaplysinopsis), neoamphimedine, 5-methoxyneoamphimedine and alpkinidine (Xestospongia), makaluvamine C and makaluvamine H (Zyzzya), psymberin (Psammocinia and Ircinia), and ethylplakortide Z and ethyldidehydroplakortide Z (Plakortis). These compounds or analogs thereof continue to have therapeutic potential. PMID- 23350353 TI - Embryonal rhabdomyosarcoma of the female genital tract: 5 years' experience. AB - OBJECTIVES: To present our single institution experience with 10 cases of embryonal rhabdomyosarcoma diagnosed over 5 years. METHODS: Retrospective analysis of the medical records of 10 patients. The initial presenting data as age, complains and staging were analyzed. Surgical interference of all cases was studied. The follow up data regarding survival and recurrences were analyzed. RESULTS: The mean age at diagnosis was 4.3 years (range: 2-12). Six cases (60%) were subjected to "True Cut" biopsy and 4 cases (40%) were subjected to complete surgical excision of the tumor. All cases received chemotherapy. "Vincristine, Actinomycin D, Cyclophosphamide" combination was the most commonly used. Radiation therapy was used in 3 patients (30%) in the form of external beam radiation. The 5-year overall survival of our studied cases were 80%. CONCLUSION: The recurrence rate of our retrospectively studied 10 cases of embryonal rhabdomyosarcoma of vagina and cervix was high (70%). However, five-year survival was 80%. Combined modality treatment is essential to improve prognosis. PMID- 23350354 TI - PKI 166 induced redox signalling and apoptosis through activation of p53, MAP kinase and caspase pathway in epidermoid carcinoma. AB - Cellular redox changes have emerged as a pivotal and proximal event in cancer. PKI 166 is used to determine the effects of redox sensitive inhibition of EGFR, metastasis and apoptosis in epidermoid carcinoma. Cytotoxicity study of PKI 166 (IC50 1.0 microM) treated A431 cells were performed by MTT assay for 48 and 72 hrs. Morphological analysis of PKI 166 treated A431 cells for 48 hrs. revealed the cell shrinkage, loss of filopodia and lamellipodia by phase contrast and SEM images in dose dependent manner. It has cytotoxic effects through inhibiting cellular proliferation, leads to the induction of apoptosis, as increased fraction of sub-G1 phase of the cell cycle, chromatin condensation and DNA ladder. It inhibited cyclin-D1 and cyclin-E expression and induced p53, p21 expression in dose dependent manner. Consequently, an imbalance of Bax/Bcl-2 ratio triggered caspase cascade and subsequent cleavage of PARP, thereby shifting the balance in favour of apoptosis. PKI 166 treatment actively stimulated reactive oxygen species (ROS) and mitochondrial membrane depolarization. It inhibited some metastatic properties of A431 cells supressing colony formation by soft agar assay and inhibition of MMP 9 activity by gelatin zymography and western blot analysis. PKI 166 inhibited growth factor induced phosphorylation of EGFR, Akt, MAPK, JNK and colony formation in A431 cells. Thus the inhibition of proliferation was associated with redox regulation of the caspase cascade, EGFR, Akt/PI3K, MAPK/ ERK and JNK pathway. On the other hand, increased antioxidant activity leads to decreased ROS generation inhibit the anti-proliferative and apoptotic properties of PKI 166 in A431 cells. These observations indicated PKI 166 induced redox signalling dependent inhibition of cell proliferation, metastatic properties and induction of apoptotic potential in epidermoid carcinoma. PMID- 23350356 TI - PTTG1 expression and it's rapidly evolving role in the progression and development of systemic malignancies. PMID- 23350357 TI - [Tradition and prospect of pathological diagnosis]. PMID- 23350355 TI - A phosphopeptide mimetic prodrug targeting the SH2 domain of Stat3 inhibits tumor growth and angiogenesis. AB - Signal transducer and activator of transcription 3 (Stat3) is constitutively activated in a number of human cancers and cancer cell lines. Via its Src homology 2 (SH2) domain, Stat3 is recruited to phosphotyrosine residues on intracellular domains of cytokine and growth factor receptors, whereupon it is phosphorylated on Tyr705, dimerizes, translocates to the nucleus and is reported to participate in the expression of genes related to angiogenesis, metastasis, growth and survival. To block this process, we are developing cell-permeable, phosphatase-stable phosphopeptide mimics, targeted to the SH2 domain of Stat3, that inhibit the phosphorylation of Tyr705 of Stat3 in cultured tumor cells (Mandal et al., J. Med. Chem. 54, 3549-5463, 2011). At concentrations that inhibit tyrosine phosphorylation, these materials were not cytotoxic, similar to recent reports on JAK inhibitors. At higher concentrations, cytotoxicity was accompanied by off-target effects. We report that treatment of MDA-MB-468 human breast cancer xenografts in mice with peptidomimetic PM-73G significantly inhibited tumor growth, which was accompanied by reduction in VEGF production and microvessel density. No evidence of apoptosis or changes in the expression of the canonical genes cyclin D1 or survivin were observed. Thus selective inhibition of Stat3 Tyr705 phosphorylation may be a novel anti-angiogenesis strategy for the treatment of cancer. PMID- 23350359 TI - [Survey of the history and the future for breast cancer radiotherapy]. PMID- 23350358 TI - [History and future of surgical treatment]. PMID- 23350360 TI - [Transition and perspective of chemotherapy in breast cancer]. PMID- 23350361 TI - [Change and perspective in endocrine therapy]. PMID- 23350362 TI - [Recent trends of breast cancer epidemiology in Japan]. PMID- 23350363 TI - [Epidemiological features of breast cancer with special reference of global pattern]. PMID- 23350364 TI - [Risk factors of breast cancer (life style and environmental factors)]. PMID- 23350365 TI - [Familial breast cancer and hereditary breast cancer]. PMID- 23350366 TI - ['Molecular biology' of breast cancer]. PMID- 23350367 TI - [Oncogene and tumor suppressor gene]. PMID- 23350368 TI - [LOH and genetic polymorphysms of breast cancer]. PMID- 23350369 TI - [Breast cancer stem cells]. PMID- 23350370 TI - [The significance of microRNA in breast cancer cells]. PMID- 23350371 TI - [Chemoprevention for breast cancer]. PMID- 23350372 TI - [Mechanisms of human breast cancer tumorigenesis: outline (including the molecular mechanism and multi-step of breast carcinogenesis)]. PMID- 23350373 TI - [Second malignancies in breast cancer patients after radiotherapy]. PMID- 23350374 TI - [Genetic polymorphisms and breast cancer]. PMID- 23350375 TI - [Mechanisms of invasion and metastasis in human breast carcinoma]. PMID- 23350376 TI - [Clinical characteristics of bone metastases of breast cancer]. PMID- 23350377 TI - [Clinical features of hepatic metastasis from breast cancer]. PMID- 23350378 TI - [Clinical features of lung metastases from breast cancer]. PMID- 23350379 TI - [Clinical characteristic of brain metastases from breast cancer]. PMID- 23350380 TI - [Clinical significances of metastasis to stomach or uterus, from breast cancers]. PMID- 23350381 TI - [The clinical features of meningeal dissemination from breast cancer]. PMID- 23350382 TI - [Outline of prognostic factors and their clinical relevance in breast cancer]. PMID- 23350383 TI - [Prognostic significance of the number of axillary lymph nodes examined in breast cancer]. PMID- 23350384 TI - [Bmi-1 expression in breast cancer]. PMID- 23350385 TI - [The significance for prognostic factor of pathological complete response (pCR) after neoadjuvant chemotherapy]. PMID- 23350386 TI - [HOXB9 as a novel prognostic factor in breast cancer]. PMID- 23350387 TI - [MicroRNA-210 in breast cancer]. PMID- 23350388 TI - [Loss of heterozygosity (LOH) at BRCA1 loci in primary breast cancers]. PMID- 23350389 TI - [Ki-67 labeling index as prognostic in breast cancer]. PMID- 23350390 TI - [General view on classifications, staging systems and treatment guidelines]. PMID- 23350391 TI - [Comparison among Japanese general rules for clinical and pathological recording of breast cancer 16th eds and UICC TNM classification 7th eds]. PMID- 23350392 TI - [Comparison of clinical guidelines between Japanese Breast Cancer Society and National Comprehensive Cancer Network]. PMID- 23350393 TI - [Epithelial-mesenchymal transition and tumor microenvironment propose the seed and soil theory of the present age]. PMID- 23350394 TI - [Mechanistic analysis of the antitumor efficacy of TRAIL-positive human natural killer cells]. PMID- 23350395 TI - [Activation of aromatase gene expression by RORalpha and GR expression in breast cancer tissue]. PMID- 23350396 TI - [Application of microRNA to breast cancer diagnosis]. PMID- 23350397 TI - [Gene expression profiling studies in breast cancer]. PMID- 23350398 TI - [Clinical implementation of the immunohistochemical intrinsic subtypes of breast cancer]. PMID- 23350399 TI - [Genetic diagnosis of familial breast cancer]. PMID- 23350400 TI - [Therapeutic strategy for breast cancer stem cells]. PMID- 23350401 TI - [Breast imaging analysis and diagnosis: introduction]. PMID- 23350402 TI - [Diagnosis procedures for breast cancer]. PMID- 23350403 TI - [Diagnostic process of the distorted lesion detected by mammography]. PMID- 23350404 TI - [Close examination of mammographically detected microcalcifications]. PMID- 23350405 TI - [Medical relations in breast cancer screening program]. PMID- 23350406 TI - [Diagnosis of metachronous bilateral breast cancer]. PMID- 23350407 TI - [Are the images for delineating tumor extent inside breast for breast cancer patients necessary ?--Challenges by the multiinstitutional prospective study on breast CT]. PMID- 23350408 TI - [Ultra early phase MRI for non-palpable breast cancer microcalcification in supine position]. PMID- 23350409 TI - [Assessment of ductal spread extent of breast cancer with MDCT]. PMID- 23350410 TI - [VAB (vacuum-assisted breast biopsy system)]. PMID- 23350411 TI - [Accuracy for a diagnosis of breast cancer spread using 3.0T MRI]. PMID- 23350412 TI - [MRI and sonography imaging fusion system with magnetic position tracking system using real-time virtual sonography (RVS) for second-look US of the breast]. PMID- 23350413 TI - [Ultrasound features of triple negative breast cancer]. PMID- 23350414 TI - [3D mammography]. PMID- 23350415 TI - [Photoacoustic mammography for the diagnosis of breast cancer]. PMID- 23350416 TI - [Contrast-enhanced ultrasonography using by sonazoid (spread diagnosis)]. PMID- 23350417 TI - [Ductal carcinoma in situ (DCIS) on B-mode breast ultrasound sonography (US)]. PMID- 23350418 TI - [The utility of FDG-PET/CT for pre/post operative diagnosis]. PMID- 23350419 TI - [Dedicated breast PET scanners]. PMID- 23350420 TI - [Sentinel lymph node biopsy under local anaesthesia for outpatient]. PMID- 23350421 TI - [Sentinel lymph node biopsy with predict factors to omit axillary lymph node dissection]. PMID- 23350422 TI - [Dye-guided sentinel node biopsy for breast cancer]. PMID- 23350423 TI - [Sentinel lymph node biopsy using ICG fluorescence navigation method]. PMID- 23350424 TI - [Sentinel lymph node biopsy in the neoadjuvant setting]. PMID- 23350425 TI - [3D-CT mammary lymphography for sentinel node biopsy]. PMID- 23350426 TI - [Intra-operative rapid diagnosis of sentinel lymph node metastases by the one step nucleic acid amplification]. PMID- 23350427 TI - [Base of pathological reporting for breast carcinoma and appropriate management for the excised specimen]. PMID- 23350428 TI - [Atypical lobular hyperplasia (ALH)]. PMID- 23350429 TI - [Management for treatment of lobular carcinoma in situ (LCIS)]. PMID- 23350430 TI - [Imprint cytology from core biopsies for breast lesions]. PMID- 23350431 TI - [Histopathological diagnosis of surgical margins and sentinel lymph nodes]. PMID- 23350432 TI - [Assessment of histopathological markers for response to primary systemic therapy]. PMID- 23350433 TI - [Indeterminate case of breast fine-needle aspiration biopsy]. PMID- 23350434 TI - [Quality assurance in HER2 testing]. PMID- 23350436 TI - [Ki67 immunohistochemical staining: the present situation of diagnostic criteria]. PMID- 23350435 TI - [Dual color in situ hybridization in HER2 testing]. PMID- 23350437 TI - [Endocrine responsiveness based on expression levels of ki67]. PMID- 23350438 TI - [FOXA1 expression in luminal-type breast cancer]. PMID- 23350439 TI - [L-type amino acid transporter 1 (LAT1)]. PMID- 23350440 TI - [Galectin-9 as a possible suppressor for metastasis of breast cancer]. PMID- 23350441 TI - [ALDH1-positive cells in axillary lymph node metastases after chemotherapy as a prognostic factor in patients with node-positive breast cancer]. PMID- 23350442 TI - [Identification of a novel serum marker for early breast cancer detection by proteomic approach]. PMID- 23350443 TI - [Circulating endothelial cells(CECs), circulating endothelial progenitors (CEPs)]. PMID- 23350444 TI - [Predictive factors for endocrine responsiveness in stage IV breast cancer]. PMID- 23350445 TI - [Importance and practice of UGT1A1 polymorphisms]. PMID- 23350446 TI - [Problem of the hereditary breast cancer screening; including the genetic diagnosis]. PMID- 23350447 TI - [Breast cancer practice guideline 2011]. PMID- 23350448 TI - [Surgical treatment strategy for early breast cancer]. PMID- 23350449 TI - [Video-assisted surgery for early breast cancer]. PMID- 23350450 TI - [Ipsilateral breast tumor recurrence after breast conserving surgery]. PMID- 23350451 TI - [Oncoplastic surgery for patients with ptotic breast cancer]. PMID- 23350452 TI - [MRI diagnosis for the planning of breast-conserving surgery]. PMID- 23350453 TI - [Radioguided occult lesion localization for non palpable breast cancer]. PMID- 23350454 TI - [Surgical methods and indications for local recurrence of breast cancer]. PMID- 23350455 TI - [A novel method to determine the suitable dissection line using sutures in breast conserving surgery]. PMID- 23350456 TI - [Breast-conserving surgery for ductal carcinoma in situ of the breast]. PMID- 23350457 TI - [Role of radiotherapy in breast-conserving therapy]. PMID- 23350458 TI - [Intraoperative radiotherapy for early breast cancer]. PMID- 23350459 TI - [PMRT(post-mastectomy radiation therapy)]. PMID- 23350460 TI - [Indication of chemoradiotherapy in patients with unresectable T4 breast tumors]. PMID- 23350461 TI - [Proposed measures for the complication after breast irradiation]. PMID- 23350462 TI - [Implication of radiotherapy for locoregional recurrence of breast cancer]. PMID- 23350463 TI - [Radiofrequency ablation for early breast cancer]. PMID- 23350464 TI - [Prediction of therapeutic efficacy for preoperative chemotherapy]. PMID- 23350465 TI - [Multidisciplinary treatment of chemotherapy and surgical therapy]. PMID- 23350466 TI - [Principal strategy for metastatic breast cancer]. PMID- 23350467 TI - [Treatment of inoperable breast cancer]. PMID- 23350468 TI - [Oral chemotherapy for advanced breast cancer]. PMID- 23350469 TI - [Oral combination chemotherapy with capecitabine and cyclophosphamide in combination with endocrine therapy and anti-HER2 therapy for advanced and metastatic breast cancer]. PMID- 23350470 TI - [Clinical utility of adjuvant TC regimen]. PMID- 23350471 TI - [Individualized treatment of breast cancer chemotherapy]. PMID- 23350472 TI - [Anti-Her2 therapy in breast cancer]. PMID- 23350473 TI - [Anti-angiogenic therapy for breast cancer--problems and future directions]. PMID- 23350474 TI - [Targeting therapy perspectives]. PMID- 23350475 TI - [Adjuvant endocrine therapy in premenopausal breast cancer]. PMID- 23350476 TI - [Adjuvant endocrine therapy for postmenopausal women]. PMID- 23350477 TI - [Endocrine therapy for advanced breast cancer]. PMID- 23350478 TI - [Evaluation of cohesive silicone breast implants]. PMID- 23350479 TI - [Immediate mammoplasty using lateral tissue flap after breast-conserving surgery]. PMID- 23350480 TI - [Immediate latissimus breast reconstruction with nipple reconstruction]. PMID- 23350481 TI - [Immediate breast reconstruction after mastectomy using tissue expandable implants]. PMID- 23350482 TI - [Utility of skin-sparing mastectomy]. PMID- 23350483 TI - [Dry skin of breast after breast conserving therapy (frequency and measures)]. PMID- 23350484 TI - [Management for treatment-induced adverse reaction--chemotherapy]. PMID- 23350485 TI - [Supports for the toxicity of the molecular target medicine]. PMID- 23350486 TI - [Stage I-III breast cancer in elderly patients]. PMID- 23350487 TI - [Chemotherapy for elderly breast cancer]. PMID- 23350488 TI - [Hemodialysis patients]. PMID- 23350489 TI - [Management of the breast cancer in patients with mental illness]. PMID- 23350490 TI - [Breast surgery and biopsy in anticoagulated patients]. PMID- 23350491 TI - [Experimental basic research on mammary cancer gene therapy for metastasis inhibition]. PMID- 23350492 TI - [Today and future perspectives in breast cancer immunotherapy]. PMID- 23350493 TI - [Measuring quality of life in patients with breast cancer]. PMID- 23350494 TI - [Late adverse effects and QOL after breast conserving therapy]. PMID- 23350495 TI - [QOL of young breast cancer patients]. PMID- 23350496 TI - [Financial difficulties and health-related quality of life in breast cancer patients]. PMID- 23350497 TI - [Areal medical cooperation for the treatment of breast cancer to improve quality of life of patients]. PMID- 23350498 TI - [Elements of informed consent in patients with diagnosed breast cancer]. PMID- 23350499 TI - [Point of informed consent on breast cancer surgical treatments]. PMID- 23350500 TI - [The point of the informed consent in a breast cancer chemotherapy]. PMID- 23350501 TI - [Current activities and perspective of JBCRG (Japan Breast Cancer Research Group)]. PMID- 23350502 TI - [The significance of JROSG (Japanese Radiation Oncology Study group) 05-5 Study]. PMID- 23350503 TI - [Significance of participation of global clinical trial]. PMID- 23350504 TI - [Current status and problems of breast cancer screening in Japan]. PMID- 23350505 TI - [Collaboration between oncologist and family physicians for the use of a regional cooperation booklet]. PMID- 23350506 TI - [Interdisciplinary team clinical practice in recurrent breast cancer]. PMID- 23350507 TI - [Economic evaluation of treatment on breast cancer]. PMID- 23350508 TI - [From kidney development toward regeneration]. PMID- 23350509 TI - [Royalactin induces queen differentiation in honeybees]. PMID- 23350510 TI - [Molecular basis for tRNA(Ile) agmatinylation essential for AUA codon decoding]. PMID- 23350511 TI - [Transgenic approaches to the pathogenesis of autoimmune disease with mouse models of the human disease]. PMID- 23350512 TI - [Cytoskeletal control of CD36 diffusion promotes its receptor and signaling function in human primary macrophage]. PMID- 23350513 TI - [Regulation and role of the arachidonate cascade at different life stages of adipocytes]. PMID- 23350514 TI - [Synaptic modulation in spinal pain transmission]. PMID- 23350515 TI - [Fluorescence cross-correlation spectroscopy for molecular fluorescence cross correlation spectroscopy for molecular dynamics in the living cell]. PMID- 23350516 TI - [Evaluation of tuberculosis transmission routes in an outbreak among young adults for developing an effective method for contact investigations]. AB - PURPOSE: To evaluate the various transmission routes of tuberculosis in an outbreak among young adults in order to develop an effective method for contact investigations. METHOD: We reviewed the records of 21 tuberculosis patients involved in an outbreak of tuberculosis; the records were collected by conventional epidemiological studies. Mycobacterium tuberculosis isolates were genotyped using IS6110-based restriction fragment length polymorphism (RFLP). RESULT: The index patient was a 26-year-old man whose 32-year-old brother was identified as the source patient of tuberculosis through a contact investigation. Investigation of their contacts led to the identification of 10 tuberculosis patients. Further, 5 more patients with only casual contact with the index or source patients developed tuberculosis 18-25 months after identification of the index patient. The RFLP analysis of strains obtained from these 5 patients as well as the index and source patients revealed an identical pattern. Further, 4 persons, among those who had epidemiological links with some of the above mentioned 5 patients, developed tuberculosis 22-34 months after identification of the index patient. All 21 patients were relatively young. In total, 15 strains obtained from these patients were sent for the RFLP analysis, all of which showed an identical pattern. The epidemiological links were categorized into a household environment, an entertainment area, a university, a music band, and a construction site. CONCLUSION: Molecular epidemiology can provide insights into the process of tuberculosis transmission, which may otherwise go unrecognized by conventional contact investigations. Additionally, it can play an important role in identifying places of tuberculosis outbreaks and routes of transmission in a contact investigation. PMID- 23350517 TI - [A case of tuberculous peritonitis accompanied by lymphadenitis in a patient with liver cirrhosis in which lymph node biopsy was useful for establishing the diagnosis]. AB - A 62-year-old woman with liver cirrhosis developed ascites. She had been previously treated with a combination of interferon and ribavirin therapy. The ascites was bloody and of exudative nature. Radiological examinations showed supraclavicular, axillar, and mediastinal lymphadenopathy. Biopsy of the axillar lymph node was performed because of suspected malignancy, and the results showed that the lymph node had granulomatous inflammation with caseous necrosis and Langhans giant cells, suggestive of mycobacterial infection. Furthermore, a DNA sequence specific to Mycobacterium tuberculosis was recovered from the same lesion, leading to a diagnosis of tuberculous lymphadenitis. The ascites and the lymphadenopathy subsided with anti-tuberculosis chemotherapy. Although bacilli were not detected in the ascites, a high level of adenosine deaminase in the ascites, the coexistence of tuberculous lymphadenitis, and the response to anti tuberculosis agents supported the diagnosis of tuberculous peritonitis. Although tuberculous peritonitis is often difficult to diagnose, lymph node biopsy was useful to establish the diagnosis in the present case. PMID- 23350518 TI - [A case of miliary tuberculosis complicated by disseminated intravascular coagulation and acute respiratory distress syndrome successfully treated with recombinant human soluble thrombomodulin]. AB - A 67-year-old woman was referred to our hospital for persistent fever and dyspnea. Chest X-ray revealed diffuse reticulonodular shadows and high-resolution computed tomography showed randomly distributed small nodules. Examination of sputum and urine revealed acid-fast bacilli, which were later confirmed as Mycobacterium tuberculosis sensitive to all drugs. Laboratory tests revealed thrombocytopenia, an elevated concentration of fibrin degradation products, and severe hypoxemia. We therefore diagnosed her with miliary tuberculosis complicated by acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC). After admission, her status rapidly worsened and she required mechanical ventilation. Treatment with recombinant human soluble thrombomodulin (rTM) and high-dose methylprednisolone was started in addition to the antituberculosis chemotherapy. The patient's condition gradually improved and she was weaned from ventilation on day 30. She was discharged on day 92. It is generally thought that prognosis of miliary tuberculosis complicated by DIC and ARDS is very poor. A recent report suggested that rTM is effective for DIC and ARDS secondary to sepsis. This is the first report of miliary tuberculosis complicated by DIC and ARDS successfully treated with rTM. PMID- 23350519 TI - [A case of atypical drug-induced hypersensitivity syndrome caused by isoniazid]. AB - A 43-year-old man developed fever, systemic erythema, and hepatic dysfunction approximately 1 month after initiating treatment with oral allopurinol and anti TB drugs. The high fever, skin rash, headache, vomiting, and general malaise aggravated even after discontinuation of the anti-TB drugs and allopurinol, and they continued for more than 2 weeks. Hence, the patient was diagnosed with atypical drug-induced hypersensitivity syndrome. Oral prednisolone was introduced at a dosage of 65 mg, and the systemic symptoms rapidly subsided. Drug lymphocyte stimulation test was positive for isoniazid and oxypurinol, a metabolite of allopurinol. The prednisolone dosage was gradually reduced with 3-7 day intervals, and the patient was discharged on day 31 without any recurrence of the symptoms. Although high fever and erythema occurred again upon resumption of isoniazid, the symptoms gradually improved with oral prednisolone. Finally, the patient was diagnosed with atypical drug-induced hypersensitivity syndrome caused by isoniazid. PMID- 23350520 TI - [Present and future of tuberculosis care in regions]. AB - As the incidence of active tuberculosis in Japan declines and the healthcare environment changes, restructuring of the medical care system for tuberculosis is required. According to a questionnaire survey in Hiroshima Prefecture, experiences in tuberculosis (TB) care and knowledge, such as standard treatment and DOT, is insufficient in the local medical institutions designated for tuberculosis care. Regional coordination between the tuberculosis hospital and the regional private practitioners will be one of the important issues in proper TB care. In order to strengthen coordination, Higashi-hiroshima Medical Center (HMC) collaborated with Onomichi Medical Association and the health center having jurisdiction over the area (Tobu Health Center) to create liaison clinical paths for doctors, a booklet for patient education and a medication record named "DOTS note". These liaison paths were provided to the regional practitioner from the health center on discharge and referral from HMC. After the start of regional cooperation, treatment outcome of the cohort of sputum smear positive pulmonary tuberculosis in the region were improved: success; 37.0% to 53.3% (cured; 0% to 40.0%, completed; 37.0% to 13.3%), treatment more than 12 months; 17.4% to 6.7%, died 37.0% to 26.7%. It is considered from experience of the regional cooperation in Hiroshima that regional medical cooperation using liaison paths is helpful to provide proper TB care. Treatment of patients with serious complication(s) is another issue in TB care. For example, only a few TB hospitals can treat the patient who needs hemodialysis, on the other hand, most general hospitals do not treat TB patients, because they have no beds and little knowledge. I think the following measures are effective and necessary for the future TB care: 1) one or more of the general hospitals in each region should provide one or more air controlled bed(s) to treat TB patients, which can be also used for patients with suspected airborne infectious disease, 2) cooperation between tuberculosis experts and general physicians is necessary to provide standard TB care, 3) Rapid communication between TB experts and regional health centers to provide concrete information such as liaison clinical paths, and finally, 4) government commitment is needed to promote the above measures. PMID- 23350521 TI - [Patient-centered medicine for tuberculosis medical services]. AB - The 2011 edition of Specific Guiding Principles for Tuberculosis Prevention calls for a streamlined medical services system capable of providing medical care that is customized to the patient's needs. The new 21st Century Japanese version of the Directly Observed Treatment Short Course (DOTS) expands the indication of DOTS to all tuberculosis (TB) patients in need of treatment. Hospital DOTS consists of comprehensive, patient-centered support provided by a DOTS care team. For DOTS in the field, health care providers should select optimal administration support based on patient profiles and local circumstances. In accordance with medical fee revisions for 2012, basic inpatient fees have been raised and new standards for TB hospitals have been established, the result of efforts made by the Japanese Society for Tuberculosis and other associated groups. It is important that the medical care system be improved so that patients can actively engage themselves as a member of the team, for the ultimate goal of practicing patient-centered medicine. We have organized this symposium to explore the best ways for practicing patient-centered medicine in treating TB. It is our sincere hope that this symposium will lead to improved medical treatment for TB patients. 1. Providing patient-centered TB service via utilization of collaborative care pathway: Akiko MATSUOKA (Hiroshima Prefectural Tobu Public Health Center) We have been using two types of collaborative care pathway as one of the means of providing patient-centered TB services since 2008. The first is the clinical pathway, which is mainly used by TB specialist doctors to communicate with local practitioners on future treatment plan (e.g. medication and treatment duration) of patients. The clinical pathway was first piloted in Onomichi district and its use was later expanded to the whole of Hiroshima prefecture. The second is the regional care pathway, which is used to share treatment progress, test results and other necessary patient information among the relevant parties. The regional care pathway was developed by the Tobu Public Health Center. It is currently being used by several other public health centers in Hiroshima. Utilization of these two pathways has resulted in improved adherence, treatment being offered at local clinics, shorter hospitalization and better treatment outcomes. 2. Patient centered DOTS in Funabashi-city: Akiko UOZUMI (Funabashi-city Public Health Center) In Funabashi-city, all TB patients, including those with LTBI, are treated under DOTS which recognizes and tries to accommodate the various different needs of each individual patient. For example, various types of DOTS are offered, such as pharmacy-based DOTS and DOTS supported by caregivers of nursing homes. This enables public health nurses to take into consideration both the results of risk assessment and convenience for the patient, and choose DOTS which most effectively support the patient. Furthermore, DOTS in principle is offered face-to-face, so that DOTS providers may not only build relationship of trust with the patient, but also to collect and analyze the necessary information regarding the patient and respond timely when problems arise. Such effort has directly contributed to improved default and treatment rate. 3. Hospital DOTS and clinical path for the treatment of tuberculosis: Kentaro SAKASHITA, Akira FUJITA (Tokyo Metropolitan Tama Medical Center) We introduced a version of hospital DOTS at Tama Medical Center (formerly Fuchu Hospital) in 2004. As part of this three stage version, patients are allowed to progress to the next stage if they meet the step-up criteria. Following the introduction of this hospital DOTS, the occurrence of drug administration-related incidents decreased and support for patient adherence became easier for health care workers than before. In 2006, we developed a clinical path based on this hospital DOTS with consistent eligibility criteria for patients. This clinical path helped increase the efficiency of medical services in the TB ward. In conclusion, a patient's initiative for tuberculosis treatment can be supported through our hospital's TB treatment system. 4. Survey of TB patients' understanding and satisfaction of hospital DOTS: Yoko NAGATA, Minako URAKAWA, Noriko KOBAYASHI, Seiya KATO (Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association) We surveyed the satisfaction and understanding of recently discharged TB patients regarding DOTS to analyze how to better implement DOTS. The questionnaire consisted of nine items covering knowledge of TB, comfort in talking to and asking questions of the medical staff, explanations given to family members, and motivation for continuing medication. Two hundred and eight of the 228 patients who accepted the questionnaire responded (response rate: 91.2%). The level of understanding and satisfaction tended to be higher among patients in hospitals that employed a primary nursing system, more coverage and duration of DOT, and audiovisual materials for patient education. The level of understanding and satisfaction also tended to be slightly higher among institutions that conducted in-hospital conferences and collaborated with public health centers more frequently. 5. Medical cooperative system against tuberculosis elimination: Dai YOSHIZAWA (Tuberculosis and Infectious disease control division, Ministry of Health, Labour and Welfare) There are 3 points we should consider. First, despite one of the intermediate burden countries, emphasis for infectious incidence is insufficient. Besides new incidence decreases gradually, increased ratio of the elderly causes necessity of implementation against each complications. The second is how find infectious one, especially from high burden countries, before they spread it. Final, unspecific symptoms suffer the patients and medical staff. It's the key of implementation that spread of tuberculosis must be caused by delayed diagnosis. PMID- 23350522 TI - [Follow-up discussion on restructuring the medical-service system]. AB - The Japan Tuberculosis Society organized symposia on restructuring the medical service system at the 84th and 86th annual meetings. These symposia clarified the following issues and concerns. It is becoming difficult to maintain tuberculosis beds in wards in many areas, since beds required for tuberculosis are declining due to the decreasing incidence of tuberculosis and shortened hospitalization periods. The extremely poor profitability of medical practices has caused closure of tuberculosis wards. A highly urbanized area may have a shortage of tuberculosis beds, while some rural areas have the problem of poor access to hospitalization. Aging of tuberculosis patients causes an increase in the number of patients with serious complications that are sometimes difficult to treat within a prefectural jurisdiction. Infection control for multi-drug resistant tuberculosis needs to be solid. To address these issues and challenges, it will be necessary to restructure the medical-service system for tuberculosis. The Prevention Guideline addressed in May 2011 by the Ministry of Health, Labour, and Welfare mentions that the medical-service system should seek to ensure enough tuberculosis beds and to realize patient-centered medical service. The future directions should be 1) ensuring a core hospital for tuberculosis treatment at the prefectural level, 2) ensuring a principal hospital for treating tuberculosis patients with serious complications in an area, 3) ensuring the treatment environment is suitable to individual patient conditions, 4) formulating a regional coordination mechanism with a core hospital at the center in each area, and 5) achieving complete infection control. This symposium was organized based on discussions in the previous symposia to present points necessary to realize the future medical-service system described in the Prevention Guideline. When constructing a new hospital or renovating a ward, attention must be paid to infection control and amenities for tuberculosis patients whose hospitalization is often longer than patients of other diseases. There is no official standard for a facility with tuberculosis beds at this moment. Professor Atsuo Kakehi, a hospital architectural expert, discussed the points in a draft of the standard he proposed in his report. Aging of tuberculosis patients increases the number of patients with serious complications. Ensuring medical service for such patients is a major challenge. The new National Hospital Organization Hokkaido Medical Center was built in March 2010 with tuberculosis wards. Dr. Arisu Kamada reported on infection control and medical practice for patients with serious complications in a general hospital. Psychiatric diseases including senile dementia are among the largest problems among tuberculosis complications. The National Hospital Organization Kamo Psychiatric Center, which has model beds for tuberculosis, produced successful outcomes by collaborating with the National Hospital Organization Higashihiroshima Medical Center tuberculosis hospital. Dr. Masahiro Nomura reported on the implementation of DOT and regional collaboration as well as medical practice in his hospital. An important point in the National Guideline is regional collaboration. Dr. Tadatoshi Suruda from the National Hospital Organization Wakayama National Hospital discussed the status and outcomes from their regional collaboration system in Wakayama Prefecture, the top runner in this area. Thanks to solid presentation from the speakers and thoughtful comments from the floor, the symposium was very useful for promoting patient-centered medical service, a keyword in the National Guideline. 1. Environment of hospital beds for treating TB patients: Atsuo KAKEHI (Department of Architectural Design, School of Architecture, Kogakuin University) It is becoming more difficult to configure wards since the number of tuberculosis beds is decreasing. It is therefore necessary to mix general beds and tuberculosis beds in one ward, making it necessary to develop criteria for designing facilities as part of a general ward for isolated space. This paper describes the current care environment of tuberculosis patients and the draft guidelines for a more appropriate hospital environment. 2. Treatment to complications in the patients in the tuberculosis hospital: Arisu KAMADA (National Hospital Organization Hokkaido Medical Center) Recently, many patients with tuberculosis, especially the elderly, have been exhibiting various complications. It is often difficult to treat complications at a tuberculosis hospital, especially at the old sanatorium hospital. Our hospital is both a tuberculosis hospital and a general hospital in which various complications can be treated. However, such general hospitals are very rare in Japan. Many patients passed away immediately after transferring to a tuberculosis hospital due to inadequate treatment of complications. To avoid repeating such tragedies, continuing treatment of complications without transferring to a tuberculosis hospital should be considered. Kamo Psychiatric Center has eight model beds for tuberculosis patients with psychiatric diseases. We retrospectively studied 71 cases of hospital DOTS from 2006 to 2011. There were 33 dementia cases and 30 schizophrenia cases. The standard regimens (A or B) were performed for 68 of the 71 cases. The median duration of hospitalization was six months. Some schizophrenia cases taking antipsychotic medications experienced worse mental symptoms when they started tuberculosis treatment. 4. Medical collaboration for tuberculosis patients' care in region: Tadatoshi SURUDA (National Hospital Organization Wakayama National Hospital) Complete medical collaboration for tuberculosis patients' care is possible by close cooperation utilizing coordination tools such as the regional critical path among TB hospitals, other medical facilities, welfare organizations, and health centers that function as a coordinator in an area. TB hospitals and health centers, both major role players in the collaboration scheme, should maintain good ties and share responsibilities. Through establishing close collaboration, medical service for TB patients will be a part of primary practice. It is expected to raise TB awareness among general medical staff and result in early case detection in the area. PMID- 23350525 TI - Composition- and band-gap-tunable synthesis of wurtzite-derived Cu2ZnSn(S(1 x)Se(x))4 nanocrystals: theoretical and experimental insights. AB - The wurtzite-derived Cu2ZnSn(S(1-x)Se(x))4 alloys are studied for the first time through combining theoretical calculations and experimental characterizations. Ab initio calculations predict that wurtzite-derived Cu2ZnSnS4 and Cu2ZnSnSe4 are highly miscible, and the band gaps of the mixed-anion alloys can be linearly tuned from 1.0 to 1.5 eV through changing the composition parameter x from 0 to 1. A synthetic procedure for the wurtzite-derived Cu2ZnSn(S(1-x)Se(x))4 alloy nanocrystals with tunable compositions has been developed. A linear tunable band gap range of 0.5 eV is observed in the synthesized alloy nanocrystals, which shows good agreement with the ab initio calculations. PMID- 23350524 TI - Introduction to the special section on genomics. PMID- 23350526 TI - The complete mitochondrial genome sequence of Schizothorax wangchiachii (Cypriniformes: Cyprinidae). AB - In this study, the complete mitochondrial DNA (mtDNA) sequence of Schizothorax wangchiachii has been determined. The mitogenome is 16,593 bp in length. It consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 2 non coding regions: origin of light-strand replication (OL) and control region (D loop). The complete mtDNA sequence of S. wangchiachii can contribute to elucidate the evolutionary mechanisms and biogeography of Schizothorax and is useful to stock evaluation and conservation genetics for S. wangchiachii. PMID- 23350527 TI - Expanding the chemical structure space of opto-electronic molecular materials: unprecedented push-pull chromophores by reaction of a donor-substituted tetracyanofulvene with electron-rich alkynes. AB - The reaction of a 3,5-bis(N,N-dimethylanilino)-substituted 2,4,6,6 tetracyanopentafulvene (TCPF) with mono- and bis(N,N-dimethylanilino)acetylene provides facile access to push-pull chromophores with diverse new scaffolds. The starting TCPF reacts with bis(N,N-dimethylanilino)acetylene in a formal [2+2] cycloaddition at the exocyclic double bond, followed by retroelectrocyclization, to yield an ethenylene-extended push-pull pentafulvene. The transformation with 4 ethynyl-N,N-dimethylaniline also yields a similar extended pentafulvene as well as two other products that required X-ray analysis for their structure elucidation. One features an 8,8-dicyanoheptafulvene core formed by formal [2+2] cycloaddition, followed by ring opening via fragmentation. The second is a chiral cyclobutenylated tetrahydropentalene, resulting from a cascade of formal [6+2] and [2+2] cycloadditions. All new nonplanar push-pull chromophores display amphoteric redox behavior with both strong electron-donating and -accepting potency. Notably, the N,N-dimethylanilino-substituted extended pentafulvenes show remarkably low oxidation potentials (0.27/0.28 V vs Fc/Fc(+) reference) that are lower than those for N,N-dimethylaniline itself. The push-pull-substituted extended pentafulvenes feature intense electronic absorption bands, extending over the entire visible spectral range into the near infrared, and low highest occupied molecular orbital-lowest unoccupied molecular orbital gaps. These properties, together with high thermal stability and good solubility, suggest the potential use of the new chromophores as advanced materials in molecular electronics devices. PMID- 23350528 TI - Improvement of carcinogenicity prediction performances based on sensitivity analysis in variable selection of SVM models. AB - A new sensitivity analysis (SA) method for variable selection in support vector machine (SVM) was proposed to improve the performance level of the QSAR model to predict carcinogenicity based on the correlation coefficient (CC) method used in our preceding study. The performances of both methods were also compared with that of the F-score (FS) method proposed by Chang and Lin. The 911 non-congeneric chemicals were classified into 20 mutually overlapping groups according to contained substructures, and a specific SVM model created on chemicals belonging to each group was optimized by searching the best set of SVM parameters while successively omitting descriptors of lower absolute values of sensitivity, CC or FS until the maximum predictive performance was obtained. The SA method improves the overall accuracy from 80% of CC and FS to 84%, which is considerably higher than those of existing models for predicting the carcinogenicity of non congeneric chemicals. It selects the optimum sets of effective descriptors fewer than the CC and FS methods, and is not time-consuming and can be applied to a large set of initial descriptors. It is concluded that SA is superior as a variable selection method in SVM models. PMID- 23350529 TI - Engineering bacterial two-component system PmrA/PmrB to sense lanthanide ions. AB - The Salmonella PmrA/PmrB two-component system uses an iron(III)-binding motif on the cell surface to sense the environmental or host ferric level and regulate PmrA-controlled gene expression. We replaced the iron(III)-binding motif with a lanthanide-binding peptide sequence that is known to selectively recognize trivalent lanthanide ions. The newly engineered two-component system (PmrA/PmrB) can effectively sense lanthanide ion and regulate gene expression in E. coli . This work not only provides the first known lanthanide-based sensing and response in live cells but also demonstrates that the PmrA/PmrB system is a suitable template for future synthetic biology efforts to construct bacteria that can sense and respond to other metal ions in remediation or sequestration. PMID- 23350530 TI - Intracellular drug release from curcumin-loaded PLGA nanoparticles induces G2/M block in breast cancer cells. AB - PLGA nanoparticles are among the most studied polymer nanoformulations for several drugs against different kinds of malignant diseases, thanks to their in vivo stability and tumor localization exploiting the well-documented "enhanced permeation and retention" (EPR) effect. In this paper, we have developed uniform curcumin-bearing PLGA nanoparticles by a single-emulsion process, which exhibited a curcumin release following a Fickian-law diffusion over 10 days in vitro. PLGA nanoparticles were about 120 nm in size, as determined by dynamic light scattering, with a surface negative charge of -30 mV. The loading ratio of encapsulated drug in our PLGA nanoformulation was 8 wt%. PLGA encapsulation provided efficient protection of curcumin from environment, as determined by fluorescence emission experiments. Next, we have investigated the possibility to study the intracellular degradation of nanoparticles associated with a specific G2/M blocking effect on MCF7 breast cancer cells caused by curcumin release in the cytoplasm, which provided direct evidence on the mechanism of action of our nanocomplex. This study was carried out using Annexin V-based cell death analysis, MTT assessment of proliferation, flow cytometry, and confocal laser scanning microscopy. PLGA nanoparticles proved to be completely safe, suggesting a potential utilization of this nanocomplex to improve the intrinsically poor bioavailability of curcumin for the treatment of severe malignant breast cancer. PMID- 23350531 TI - Wide field-of-view on-chip Talbot fluorescence microscopy for longitudinal cell culture monitoring from within the incubator. AB - Time-lapse or longitudinal fluorescence microscopy is broadly used in cell biology. However, current available time-lapse fluorescence microscopy systems are bulky and costly. The limited field-of-view (FOV) associated with the microscope objective necessitates mechanical scanning if a larger FOV is required. Here we demonstrate a wide FOV time-lapse fluorescence self-imaging Petri dish system, termed the Talbot Fluorescence ePetri, which addresses these issues. This system's imaging is accomplished through the use of the Fluorescence Talbot Microscopy (FTM). By incorporating a microfluidic perfusion subsystem onto the platform, we can image cell cultures directly from within an incubator. Our prototype has a resolution limit of 1.2 MUm and an FOV of 13 mm(2). As demonstration, we obtained time-lapse images of HeLa cells expressing H2B-eGFP. We also employed the system to analyze the cells' dynamic response to an anticancer drug, camptothecin (CPT). This method can provide a compact and simple solution for automated fluorescence imaging of cell cultures in incubators. PMID- 23350532 TI - Fusion rates in multilevel, instrumented anterior cervical fusion for degenerative disease with and without the use of bone morphogenetic protein. AB - OBJECT: The goal of this study was to compare the rates of solid arthrodesis and complications following multilevel, instrumented anterior cervical fusion in patients treated with and without bone morphogenetic protein (BMP). METHODS: The authors conducted a retrospective cohort study of patients who underwent multilevel (2+ level) anterior cervical fusions performed for degenerative disc disease with or without the concurrent use of BMP-2 from 1997 to 2012. The dosage throughout the study ranged from 2.1 to 0.26 mg/level (mean 1.0 mg/level). All patients were evaluated postoperatively by means of radiographs and CT scans to determine fusion status. RESULTS: The overall fusion rate for the patients treated without BMP (n = 23) was 82.6% compared with a 100% fusion rate in the group treated with BMP (n = 22) (p = 0.04). The pseudarthrosis rates increased with number of fusion levels in patients who did not receive BMP, whereas all patients in the group treated with BMP had solid arthrodesis. Furthermore, there were 2 instrumentation failures in the non-BMP group. There was a direct correlation between the incidence of complications and the dosage of BMP used per level, with no complications reported at doses equal to or less than 1.1 mg/level. CONCLUSIONS: The overall rate of bony arthrodesis was increased following the use of BMP in multilevel anterior cervical fusion. Traditional methods without BMP had a high rate of pseudarthrosis. The complications associated with the use of BMP appeared to be dose related and of low incidence when BMP is used in doses equal to or less than 1.1 mg/level. PMID- 23350533 TI - An incomplete paraplegia following the dislocation of an artificial cervical total disc replacement. AB - Replacement of the cervical intervertebral disc by artificial implants, known as cervical total disc replacement (CTDR), is becoming a generally applied method instead of using the gold standard of the anterior cervical discectomy and fusion. Hypothetically, the preserved mobility results in the protection of the neighboring segments. There is growing evidence that results in patients who underwent CTDR were not inferior when compared to results in patients who underwent anterior cervical discectomy and fusion. The authors report a case of a healthy 53-year-old man who suffered an incomplete paraplegia below C-6 following the dislocation of an artificial CTDR device into the spinal canal with consequent compression of the spinal cord. PMID- 23350534 TI - Comparison of population and 454 "deep" sequence analysis for HIV type 1 tropism versus the original trofile assay in non-B subtypes. AB - HIV-1 tropism can be predicted using V3 genotypic algorithms. The performance of these prediction algorithms for non-B subtypes is poorly characterized. Here, we use these genotypic algorithms to predict viral tropism of HIV-1 subtype A, B, C, and D to find apparent sensitivity, specificity, and concordance against a recombinant phenotypic assay, the original Trofile assay. This is a substudy of an epidemiological study (Pfizer A4001064). Plasma samples were selected to represent a large number of DM/X4 and R5 viruses. The HIV-1 env gene V3 loop was genotyped by Sanger sequencing (N=260) or 454 "deep" sequencing (N=280). Sequences were scored with g2p[coreceptor], PSSM X4/R5, PSSM SI/NSI, and PSSM subtype C matrices. Overall, non-B subtypes tropism prediction had similar concordance and apparent sensitivity and specificity as subtype B in predicting Trofile's results in both population sequencing (81.3%, 65.6%, and 90.5% versus 84.2%, 78.5%, and 88.2%) and 454 "deep" sequencing (82.3%, 80.0%, and 83.6% versus 86.8%, 92.0%, and 82.6%) using g2p[coreceptor]. By population sequencing, subtype A had lower sensitivity, whereas subtype D had lower specificity for non R5 predictions, both in comparison to subtype B. 454 "deep" sequencing improved subtype A sensitivity but not subtype D. Subtype C had greater concordance than subtype B regardless of sequencing methods. In conclusion, genotypic tropism prediction algorithms may be applied to non-B HIV-1 subtypes with caution. Collective analysis of non-B subtypes revealed a performance similar to subtype B, whereas a subtype-specific analysis revealed overestimation (subtype D) or underestimation (subtype A). PMID- 23350535 TI - Strategies to promote safe medication administration in assisted living settings. AB - Assisted living (AL) provides lower cost, less institutional environments than skilled nursing facilities, yet less professional oversight, despite the high prevalence of chronic conditions among residents. Unlicensed staff administer large quantities of medications daily, and medication management is one of the three top quality issues in AL, with error rates ranging from 10% to 40%. This qualitative study described AL provider views on medication safety and strategies used to promote safety in medication administration. The sample included 96 participants representing all parties involved in medication administration (i.e., medication aides, administrators, RNs, consulting pharmacists, primary care providers) in 12 AL settings in three states. Core themes were the importance of medication safety, unique contextual factors in AL, and strategies used to promote medication safety. This study has implications for research on interventions to improve medication safety at the individual, facility, and policy levels. PMID- 23350536 TI - Current perspectives on children and youth who sexually abuse. PMID- 23350537 TI - Adolescent and young adult male sex offenders: understanding the role of recidivism. AB - The current review explores the complex paths that can lead to adolescent and young adult males becoming sexually abusive. Because sexual abuse is an ongoing issue in our society that is often oversimplified, this article distinguishes between the various risk factors that predict sexually abusive behavior and types of sex offenders, particularly recidivistic offenders. It is imperative to focus on adolescents and young adults who sexually abuse because they represent a particularly important intervention point in preventing sexual abuse in comparison to older age groups and address the importance of differentiating among youths who sexually abuse, particularly between one-time offenders and recidivistic offenders. Implications for addressing these differences are discussed. PMID- 23350538 TI - Denying denial in children with sexual behavior problems. AB - Denial in some form is almost always present in the assessment and therapy of children with sexual behavior problems. Although it can be a major element in the therapeutic interaction, denial has received scant attention, both in teaching programs and professional literature. It is as if the clinical community is "denying denial." Despite its seemingly resistant nature, denial can be used to produce impressive inroads in data collection and in developing insight. This article offers an in-depth look at the construct of denial, especially its expression among children with sexual behavior problems. It will be argued that a more informed understanding of denial dynamics can creatively inform and direct treatment of children and adolescents with sexual behavior problems and considerably improve treatment outcome. PMID- 23350539 TI - Arab parents' reactions to child sexual abuse: a review of clinical records. AB - This paper addresses parents' reactions to sexual abuse cases in their families. The study analyzed the clinical records of individual and family therapy sessions with 35 cases of Arab Palestinian clients, citizens of Israel (27 individuals and 8 families). Families were categorized as either functional or dysfunctional. It was concluded that the degree and type of relatedness of the perpetrator to the victim's family influences the type of reaction more than the family's level of functionality or the type of harm caused to the victim. Functional families consider the mental welfare of the victim as a serious concern. However, when the abuser is a relative or an acquaintance, functional families balance between support for the victim and the maintenance of correct relations with the abuser's family. Dysfunctional families offer solutions that in the short-term and/or the long-term usually harm the victim. PMID- 23350540 TI - Maltreatment and depression in adolescent sexual offenders with an autism spectrum disorder. AB - This study examined the self-reported presence and severity of abuse, neglect, and depressive symptoms for 43 adolescents adjudicated delinquent due to a sexual offense. Twenty-seven of the adolescent sexual offenders were also diagnosed with an autism spectrum disorder, and 16 did not carry an autism spectrum disorder diagnosis. Both groups reported moderate to high levels of abuse and neglect. Adolescent sexual offenders with an autism spectrum disorder reported significantly higher depressive symptoms than those without an autism spectrum disorder. Furthermore, of the group with an autism spectrum disorder, those reporting severe levels of emotional abuse and/or emotional neglect were more likely to also have depressive symptoms. Results suggest a need to tailor treatment programs to match the unique needs of sexual offenders. PMID- 23350541 TI - Parents of minors who have sexually abused: legal liability and clinical interventions. AB - While children and adolescents generally do not have the right to vote, marry, or sign contracts independently, they are often held responsible for their crimes. In spite of this, some parents of minor victims file civil suits against parents of the youth responsible for the harm. The courts must then decide to what extent, if any, parents are legally liable when their minor children commit offenses. Since parents are essential to the successful rehabilitation of minors who have sexually offended, the impact of legal liability on parental engagement in therapy must be examined. This article will explore the conflicting issues of age, legal responsibility, parental responsibility, and therapeutic effectiveness in the Israeli context and propose a means for resolution. PMID- 23350542 TI - Knowledge of juvenile sex offender registration laws predicts adolescent sexual behavior. AB - Because juveniles can now be registered as sex offenders, we conducted a pilot study to investigate awareness of these policies and sexual behavior histories in a convenience sample of 53 young adults (ages 18 to 23, 79% women). These preliminary data revealed that 42% percent of participants were unaware that youth under the age of 18 can be registered as sex offenders, and when informed that they can be, participants were unaware of the breadth of adolescent sexual behavior that warrants registration. Furthermore, those unaware of juvenile registration policies, compared to those who were aware, were marginally more likely to have had sex prior to age 18. Thus, youth most at risk of registration were least aware of this possibility, suggesting that juvenile registration likely does little to deter many behaviors that are considered to be juvenile sex offenses. PMID- 23350543 TI - Young people who sexually abuse: a historical perspective and future directions. AB - This article presents a historical overview of research on sexually abusive youth. The evolution of the field over the past 30 years is discussed-from the initial development of treatment interventions to contemporary efforts of professionals to move from traditional, adult-oriented interventions toward developmentally sensitive assessment strategies and practice models. Focus is on two critical areas: risk assessment and trauma-informed care. The article reviews contemporary research on risk assessment tools, stressing the need for validated tools that can accurately assess youth and follow changes in risk over time. Etiological models for understanding effects of trauma (Trauma Outcome Process Assessment and Family Lovemap) are presented. Discussed are new ecologically based therapy models for working with sexually abusive youth that approach the youth holistically and are attuned to youths' needs, including providing interventions to address effects of past trauma. PMID- 23350544 TI - Conservative management of placenta previa complicated by abnormal placentation. AB - OBJECTIVE: Abnormal implantation of placenta previa is life-threatening condition. The purpose of this study was to evaluate the impact of the conservative management of pregnancies with such complication on maternal morbidity rate and the chance for uterine preservation (fertility). METHODS: Eleven patients with abnormal implantation of placenta previa were analyzed prospectively. This complication was diagnosed antenatally by two-dimensional ultrasound and color flow Doppler. The following outcomes were analyzed: need for blood transfusion, admission and duration of stay in intensive care unit, infections, coagulopathies, time between cesarean section and delivery of placenta, hysterectomy and preservation of uterus. RESULTS: Among the 20 085 women who had a singleton gestation, 11 (0.054%) were identified with placenta previa with abnormal placentation. In five patients (group A), hysterectomy was performed because of hemorrhage or placenta ablation. In six patients (group B), conservative management succeeded and placenta were preserved. In group A, placenta were delivered earlier (2 d-8 weeks) in comparison with group B (6-15 weeks). Estimated blood loss during the delayed delivery of placenta was higher in the group with hysterectomy (respectively, 450-1600 and 300-500 ml). CONCLUSIONS: Conservative management of placenta previa with abnormal implantation decreases the risk of severe hemorrhage at the time of delivery and can preserve fertility. PMID- 23350545 TI - A c-fos-monomeric red fluorescent protein 1 fusion transgene is differentially expressed in rat forebrain and brainstem after chronic dehydration and rehydration. AB - We have previously shown that an acute osmotic stimulation induces the expression of a c-fos and monomeric red fluorescent protein 1 (mRFP1) fusion transgene in osmosensitive rat brain areas, including the supraoptic (SON) and paraventricular nuclei (PVN). However, the effects of chronic stimuli, such as dehydration, have not been investigated. In the present study, the expression patterns of the c-fos mRFP1 fusion gene in the forebrain and the brainstem of male and female transgenic rats were studied in seven experimental groups: ad lib. water (euhydration), water deprivation for 12, 24 or 48 h (dehydration) and water deprivation for 46 h + ad lib. water for 2, 6 or 12 h (rehydration). The number of cells that express nuclear mRFP1 fluorescence was quantified in the hypothalamus, the circumventricular organs and the brainstem. Compared to the euhydrated state, the number of transgene expressing cells significantly increased in all forebrain areas and in the rostral ventrolateral medulla after dehydration and 2 h of rehydration. In the nucleus of the solitary tract and area postrema, the number of mRFP1 fluorescent cells was markedly increased after 2 h of rehydration. Although the number of mRFP1 fluorescent cells in the organum vasculosum laminae terminalis, median preoptic nucleus and subfornical organ remained significantly increased after 6 h of rehydration, reaching control levels after 12 h of rehydration, the number of mRFP1 fluorescent cells in the SON and the PVN reached control levels after 6 h of rehydration. There were no significant differences between male and female rats. These results show that the expression of the c-fos-mRFP1 fusion gene changes in the forebrain and the brainstem not only after acute osmotic stimulation, but also after chronic osmotic stimulation. Interestingly, these studies reveal the differential activation of different neuronal groups over the time course of dehydration and rehydration. PMID- 23350546 TI - Endothelial cells actively concentrate insulin during its transendothelial transport. AB - OBJECTIVE: We examined insulins uptake and transendothelial transport by endothelial cells in order to: (i) ascertain whether insulin accumulates within the cells to concentrations greater than in the media; (ii) compare trans endothelial insulin transport to that of inulin (using the latter as a tracer for passive transport or leaked); and; (iii) determine whether insulins transported depended on insulin action. METHODS: Using 125I-insulin at physiologic concentrations we measured both the uptake and trans endothelial transport of insulin by bovine aortic endothelial cells and measured cell volume using tritiated 3-O-methylglucose. RESULTS: Bovine aortic endothelial cells accumulate insulin to > five-fold above the media concentrations and the trans endothelial transport of insulin, but not inulin, is saturable and requires intact PI-3 kinase and MEK signaling. CONCLUSION: The insulin receptor and downstream signaling from the receptor regulates endothelial insulin transport. Insulin is accumulated against a concentration gradient by the endothelial cell. We suggest that insulin uptake is rate limiting for insulin trans endothelial transport. PMID- 23350548 TI - In vivo regenerative properties of coralline-derived (biocoral) scaffold grafts in human maxillary defects: demonstrative and comparative study with Beta tricalcium phosphate and biphasic calcium phosphate by synchrotron radiation x ray microtomography. AB - BACKGROUND: In recent years, there has been interest on the fabrication of systems using particulates or block-based approach for bone tissue engineering (TE) scaffolds, possessing porous interconnected structures. In fact, these particular morphologies greatly increase the surface area for more chemical and biological reactions to take place. PURPOSE: This study was designed to demonstrate the unique capability of the synchrotron radiation x-ray microtomography (micro-CT) in offering an advanced characterization of coralline derived (Biocoral) biomaterials placed in human maxillary defects as it allows, in a nondestructive way, a complete, precise, and high-resolution three dimensional analysis of their microstructural parameters. Moreover, the comparison between Biocoral and other biomaterials was explored to understand the mechanism of their biological behavior as bone substitute. MATERIALS AND METHODS: Implant survival, bone regeneration, graft resorption, neovascularization, and morphometric parameters (including anisotropy and connectivity index of the structures) were evaluated by micro-CT in Biocoral and the other biomaterials after 6 to 7 months from implantation in human maxillary bone defects. RESULTS: After the in vivo tests, a huge amount of bone was detected in the retrieved Biocoral-based samples, coupled with a good rate of biomaterial resorption and the formation of a homogeneous and rich net of new vessels. The morphometric parameters were comparable to those obtained in the biphasic calcium phosphate based control, with the exception of the connectivity index for which this control exhibited the most well-connected structure. This last result, together with those referred to the poor performances of the beta-tricalcium phosphate block-based sample, suggests that the particular scaffold morphology may play a role in the hunt the optimal scaffold structure to be implanted. CONCLUSION: In this limited study, implant success rate seems not strictly dependent on the biomaterial that is used, but on the scaffold morphology. Micro-CT technique was demonstrated to play a fundamental role in advanced characterization of bone TE constructs. PMID- 23350547 TI - The cytosolic adaptor AP-1A is essential for the trafficking and function of Niemann-Pick type C proteins. AB - Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by over-accumulation of low-density lipoprotein-derived cholesterol and glycosphingolipids in late endosomes/lysosomes (LE/L) throughout the body. Human mutations in either NPC1 or NPC2 genes have been directly associated with impaired cholesterol efflux from LE/L. Independent from its role in cholesterol homeostasis and its NPC2 partner, NPC1 was unexpectedly identified as a critical player controlling intracellular entry of filoviruses such as Ebola. In this study, a yeast three-hybrid system revealed that the NPC1 cytoplasmic tail directly interacts with the clathrin adaptor protein AP-1 via its acidic/di leucine motif. Consequently, a nonfunctional AP-1A cytosolic complex resulted in a typical NPC-like phenotype mainly due to a direct impairment of NPC1 trafficking to LE/L and a partial secretion of NPC2. Furthermore, the mislocalization of NPC1 was not due to cholesterol accumulation in LE/L, as it was not rescued upon treatment with Mbeta-cyclodextrin, which almost completely eliminated intracellular free cholesterol. Our cumulative data demonstrate that the cytosolic clathrin adaptor AP-1A is essential for the lysosomal targeting and function of NPC1 and NPC2. PMID- 23350549 TI - Research in prisons: an eye for equity. PMID- 23350550 TI - Optic neuropathy among a prison population in Papua New Guinea. AB - PURPOSE: To estimate the prevalence of optic neuropathy (ON) among prisoners in a provincial prison in Papua New Guinea, and to explore risk factors for this condition among this population. METHODS: Cross-sectional observation study of 148 male prisoners aged >=18 years using an interview-based questionnaire, assessment of visual and nervous system function, ocular examination, and blood analysis (alpha-tocopherol, beta-carotene, lutein, folate, homocysteine, holotranscobalamin II, riboflavin, selenium, thiamin, and vitamins A, B(12) and C). Likelihood of the presence of ON was based on ordered groups determined by weighted combination of optic nerve head appearance and visual dysfunction (acuity, field, color perception). Main outcome measures were prevalence and associations of ON. RESULTS: Sample prevalence of clinical ON was 10.4% (95% confidence interval [CI], 6.2-16.8). No cases were found of unexplained non visual nervous system dysfunction, including peripheral neuropathy. Increasing age (p = 0.001), length of current (p = 0.002) and lifetime (p = 0.03) incarceration, and duration of smoking by current smokers (p = 0.001) were associated with increased ON likelihood. However, when age-controlled, the smoking duration association was not maintained (p = 0.6). Prisoners were folate deficient. Adjusting for age and duration of current incarceration, whole blood (p = 0.02) and red blood cell (p = 0.04) folate concentrations were inversely associated with ON likelihood. No association was found for any other assessed demographic, lifestyle or biochemical measure. CONCLUSIONS: A cluster of ON associated with folate deficiency has been identified. Recommendations for dietary change and micronutrient supplementation have been made. PMID- 23350552 TI - Prevalence and causes of visual impairment and blindness, cataract surgical coverage and outcomes of cataract surgery in Libya. AB - PURPOSE: To assess the major causes of avoidable blindness, and outcomes and barriers to cataract services in Libya. METHODS: A stratified multistage cluster random sample study was conducted in the four regions of Libya. Visual acuity and lens assessment were performed on all subjects. Those with presenting visual acuity <6/18 in either or both eyes were further investigated to determine cause(s) of impairment. Barriers to cataract surgery were investigated. Visual outcomes of subjects with surgery performed were assessed. RESULTS: A total of 8538 persons aged >=50 years were examined across the four regions. The prevalence of blindness was 3.25% (3.15% with best correction), which varied across the regions (2.94-3.80%); after adjustment for age and sex, the prevalence was 2.66%. Major causes of blindness were cataract (29%), glaucoma (24%) and other corneal scars (14%). Causes were similar across all regions except in the south. Avoidable causes were responsible for 60.6% of blindness. Major causes of visual impairment were cataract (31.2%), diabetic retinopathy (16.6%) and posterior segment diseases (15.1%). Cataract surgical coverage among those with visual acuity <3/60 was 95.4%, with no sex differences. About 38% of cataract operated eyes had poor outcome even after best correction (35%). There was poor outcome in 33% of pseudophakic eyes with best correction. The major barriers to service uptake were "waiting for maturity" (26%), "unaware of treatment" (24%) and "God's will/destiny" (17%). CONCLUSION: Libya needs to improve the quality of cataract surgery across all the regions. The southern region needs improvement in both quality and coverage of services. PMID- 23350551 TI - Relative frequencies of inherited retinal dystrophies and optic neuropathies in Southern France: assessment of 21-year data management. AB - PURPOSE: Inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are rare diseases defined by specific clinical and molecular features. The relative prevalence of these conditions was determined in Southern France. METHODS: Patients recruited from a specialized outpatient clinic over a 21-year period underwent extensive clinical investigations and 107 genes were screened by polymerase chain reaction/sequencing. RESULTS: There were 1957 IRD cases (1481 families) distributed in 70% of pigmentary retinopathy cases (56% non-syndromic, 14% syndromic), 20% maculopathies and 7% stationary conditions. Patients with retinitis pigmentosa were the most frequent (47%) followed by Usher syndrome (10.8%). Among non-syndromic pigmentary retinopathy patients, 84% had rod-cone dystrophy, 8% cone-rod dystrophy and 5% Leber congenital amaurosis. Macular dystrophies were encountered in 398 cases (30% had Stargardt disease and 11% had Best disease). There were 184 ION cases (127 families) distributed in 51% with dominant optic neuropathies, 33% with recessive/sporadic forms and 16% with Leber hereditary optic neuropathy. Positive molecular results were obtained in 417/609 families with IRDs (68.5%) and in 27/58 with IONs (46.5%). The sequencing of 5 genes (ABCA4, USH2A, MYO7A, RPGR and PRPH2) provided a positive molecular result in 48% of 417 families with IRDs. Except for autosomal retinitis pigmentosa, in which less than half the families had positive molecular results, about 75% of families with other forms of retinal conditions had a positive molecular diagnosis. CONCLUSIONS: Although gene discovery considerably improved molecular diagnosis in many subgroups of IRDs and IONs, retinitis pigmentosa, accounting for almost half of IRDs, remains only partly molecularly defined. PMID- 23350554 TI - Prevalence and causes of patient dropout after glaucoma surgery. AB - PURPOSE: To determine the prevalence of patient dropout after glaucoma surgery and reasons for the same based on patient attitudes and beliefs. DESIGN: A hospital-based retrospective case-control study. METHODS: Clinical and demographic data of patients who failed to attend follow-up within 12 months of their last scheduled appointment after glaucoma surgery were analyzed. These patients were issued recall letters and those who returned were interviewed to establish the reasons for their dropout. A structured interview was conducted to assess the educational and socioeconomic status of the patients, their knowledge and belief regarding glaucoma, their attitude towards surgery and the specific reason for their inability to follow up post-operatively. Control subjects who were regularly followed-up post-operatively were also interviewed. RESULTS: Of 312 patients operated on from 2004-2006, only 92 (30%) patients maintained a 5 year follow-up. Of patients who dropped out, 43 patients responded to the recall letters and were interviewed along with 45 control patients. The demographic profile of those who dropped out was statistically similar to the controls; however, the controls had a significantly better awareness of glaucoma and higher monthly income (p < 0.001 and p = 0.01, respectively). Among those who dropped out, 38 (88%) believed surgery was the cure to the disease in comparison to 12 (46%) controls (p < 0.001). CONCLUSIONS: Dropout after glaucoma surgery is high among patients from lower socioeconomic strata. Misconceptions regarding surgery as a cure to glaucoma and situational factors are the most common reasons for patient dropout in this population. PMID- 23350553 TI - New systematic review methodology for visual impairment and blindness for the 2010 Global Burden of Disease study. AB - PURPOSE: To describe a systematic review of population-based prevalence studies of visual impairment (VI) and blindness worldwide over the past 32 years that informs the Global Burden of Diseases, Injuries and Risk Factors Study. METHODS: A systematic review (Stage 1) of medical literature from 1 January 1980 to 31 January 2012 identified indexed articles containing data on incidence, prevalence and causes of blindness and VI. Only cross-sectional population-based representative studies were selected from which to extract data for a database of age- and sex-specific data of prevalence of four distance and one near vision loss categories (presenting and best-corrected). Unpublished data and data from studies using rapid assessment methodology were later added (Stage 2). RESULTS: Stage 1 identified 14,908 references, of which 204 articles met the inclusion criteria. Stage 2 added unpublished data from 44 rapid assessment studies and four other surveys. This resulted in a final dataset of 252 articles of 243 studies, of which 238 (98%) reported distance vision loss categories. A total of 37 studies of the final dataset reported prevalence of mild VI and four reported near VI. CONCLUSION: We report a comprehensive systematic review of over 30 years of VI/blindness studies. While there has been an increase in population-based studies conducted in the 2000s compared to previous decades, there is limited information from certain regions (eg, Central Africa and Central and Eastern Europe, and the Caribbean and Latin America), and younger age groups, and minimal data regarding prevalence of near vision and mild distance VI. PMID- 23350555 TI - Changing barriers to use of eye care services in Timor-Leste: 2005 to 2010. AB - PURPOSE: To determine barriers to seeking eye care services in Timor-Leste in 2010, and compare this to similar analyses undertaken 5 years previously. METHODS: An interview-based questionnaire used in a 2005 survey was re administered as part of a population-based cross-sectional survey of adults selected by multistage random sampling from those aged >=40 years in Timor-Leste in 2010. RESULTS: The participation rate for the 2010 survey was 89.5% (n = 2014). The sex-age-domicile-adjusted prevalence of a history of at least one previous or current ophthalmic problem in the population aged >=40 years was 92.6% (95% confidence interval [CI], 91.4-93.7%). Of these, 75.4% (95% CI 73.4 77.3%) had not consulted a care provider. In multivariate analysis, rural domicile, illiteracy and subsistence farming were associated with having not sought care for an eye problem. The most frequently cited reasons were "service too far away" (36.3%), "no time/other priorities" (21.7%) and "unaware of eye care service" (20.7%). More people reported a history of an eye problem in 2010 than in 2005, but the proportion seeking care was no different. Social barriers became more prevalent for urban dwellers in 2010, while attitudinal barriers decreased. For rural residents, social and service-related barriers increased and awareness and attitudinal barriers decreased. CONCLUSION: Barriers to eye health service use in Timor-Leste are not universal or static. Monitoring the extent and nature of barriers, as well as the prevalence and causes of vision impairment, will help plan appropriate interventions for vulnerable groups. PMID- 23350556 TI - Lack of awareness of common eye conditions in the community. AB - PURPOSE: Awareness of eye conditions aids health promotion activities and leads to better outcomes. We examined factors influencing the lack of awareness of common eye conditions in a population. METHODS: The Singapore Malay Eye Study examined 3280 (78.7% response) Malays aged 40-80 years. We included 2112 (64.4%) participants with at least one of five eye conditions: 1504 (71.2%) with cataract, 1013 (47.8%) with myopia, 270 (12.8%) with diabetic retinopathy, 181 (8.6%) with age-related macular degeneration and 150 (7.1%) with glaucoma. Lack of awareness was defined in the questionnaire as not answering "yes" to previously being told by a doctor of having the eye condition. RESULTS: Among 2112 participants, 83.2% were unaware of at least one of their eye conditions. After controlling for age, sex and socioeconomic factors, participants unaware of their eye condition were older (odds ratio, OR, 1.03, per 1 year, p < 0.001), had better visual acuity (OR 1.32, p = 0.04), lower education (OR 1.89, p < 0.001), poorer literacy (OR 1.44, p = 0.02), lower income (OR 1.73, p = 0.009), higher blood glucose (OR 1.08, per 1 mmol/L, p < 0.001), higher serum cholesterol (OR 1.20, per 1 mmol/L, p = 0.003), lower annual eye examination attendance (OR 2.08, p < 0.001) and were less likely to wear glasses (OR 2.90, p < 0.001) than those who were aware of their condition. CONCLUSIONS: In this community-based population, 80% of those with common eye conditions were unaware of their condition. PMID- 23350557 TI - The Yazd Eye Study-a population-based survey of adults aged 40-80 years: rationale, study design and baseline population data. AB - PURPOSE: To describe the rationale, methodology and baseline data of the Yazd Eye Study, a study in the urban and rural areas of Yazd, a district in the center of Iran. METHODS: This population-based cross-sectional study included adults aged 40-80 years from the non-institutionalized population of the Yazd district, in 2010-2011. Using multi-stage, systematic cluster random sampling and a probability proportional to size strategy, 58 clusters of 40 subjects were selected from 251 clusters in different enumeration areas. A detailed interview and eye examination were performed for each eligible participant. The eye examination included refraction testing, uncorrected and best corrected visual acuity testing, slit lamp biomicroscopy, Goldmann applanation tonometry, gonioscopy, dilated fundus examination, visual field, determination of central corneal thickness, and stereoscopic fundus photography. General health assessments and laboratory tests including hemoglobin, hematocrit, glycosylated hemoglobin, fasting blood sugar, serum lipids, and urine albumin to creatinine ratio were also performed to assess anthropometric and systemic risk factors. RESULTS: Of 2320 eligible individuals, 2098 (response rate 90.4%) participated in the study. The mean +/- standard deviation age of participants was 54.1 +/- 10.0 years, and included 994 men (47.4%) and 1104 women (52.6%). Most participants lived in urban regions (89.2%) and were younger than 60 years old (72.0%). Among the participants, 20.1% were illiterate, and 40.9%, 28.0%, and 11.0% had primary, secondary and college or university level education, respectively. CONCLUSION: This study is expected to provide an estimate of the prevalence and risk factors of major eye diseases and normal eye indices in the Yazd district. PMID- 23350559 TI - Necrotizing fasciitis in a patient with bullous pemphigoid treating with systemic steroid. AB - Necrotizing fasciitis (NF) is a rarely seen, life-threatening soft tissue infection characterized by progressive necrosis of skin, subcutaneous tissues and fasciae. Herein, we present a case of NF in a patient with bullous pemphigoid. A 78-year-old female patient was admitted with the left leg pain, swelling, redness and blistering. Streptococcus pyogenes was isolated from the wound culture. In the skin biopsy and the left leg magnetic resonance imaging, signs of NF were observed. The diagnosis of NF was considered. Then, urgent surgical debridement was performed by the department of plastic surgery. While under treatment with intravenous antibiotics therapy, unfortunately the patient died of acute renal insufficiency. PMID- 23350560 TI - Bacillus and Streptomyces were selected as broad-spectrum antagonists against soilborne pathogens from arid areas in Egypt. AB - Plant protection via disease-suppressive bacteria in desert farming requires specific biological control agents (BCAs) adapted to the unique arid conditions. We performed an ecological study of below-ground communities in desert farm soil and untreated desert soil, and based on these findings, selected antagonists were hierarchically evaluated. In contrast to the highly specific 16S rRNA fingerprints of bacterial communities in soil and cultivated medicinal plants, internal transcribed spacer profiles of fungal communities were less discriminative and mainly characterised by potential pathogens. Therefore, we focused on in vitro bacterial antagonists against pathogenic fungi. Based on the antifungal potential and genomic diversity, 45 unique strains were selected and characterised in detail. Bacillus/Paenibacillus were most frequently identified from agricultural soil, but antagonists from the surrounding desert soil mainly belonged to Streptomyces. All strains produced antibiotics against the nematode Meloidogyne incognita, and one-third showed additional activity against the bacterial pathogen Ralstonia solanacearum. Altogether, 13 broad-spectrum antagonists with antibacterial, antifungal and nematicidal activity were found. They belong to seven different bacterial species of the genera Bacillus and Streptomyces. These Gram-positive, spore-forming bacteria are promising drought resistant BCAs and a potential source for antibiotics. Their rhizosphere competence was shown by fluorescence in situ hybridisation combined with laser scanning microscopy. PMID- 23350561 TI - Local recurrence after prone vs supine abdominoperineal excision for low rectal cancer. AB - AIM: Tumour-involved circumferential resection margins (CRMs) and intra-operative perforation (IOP) are well known risk factors for local recurrence after surgery for low rectal cancer. In conventional abdominoperineal excision (APE) the patient remains in the supine position for the perineal part of the procedure. However, turning the patient to the prone position may improve visualization which potentially might reduce the risk of involved CRMs and IOP and thus improve local control. The study was carried out to assess local recurrence rates after APE in relation to the positioning of the patient during the perineal part of the procedure. METHOD: This cohort study includes 466 patients having APE for low rectal cancer between 2001 and December 2010. Data were retrieved from the regional rectal cancer registry in Stockholm and from a retrospective review of patient files. RESULTS: An incomplete resection was reported in 12.4% after APE in the supine position and in 6.8% after APE in the prone position (P = 0.038). Corresponding figures for IOP were 12.4% and 4.0% (P < 0.001). Prone APE was associated with a 39% relative reduction in local recurrence events compared with APE in the supine position, although the difference was not statistically significant (hazard ratio 0.61, 95% CI 0.27-1.37). CONCLUSION: APE in the prone position reduced the incidence of incomplete resection and IOP, but the study did not find a statistically significant difference in local failure rates related to the position of the patient. PMID- 23350562 TI - ITS1 versus ITS2 as DNA metabarcodes for fungi. AB - The nuclear ribosomal Internal Transcribed Spacer ITS region is widely used as a DNA metabarcoding marker to characterize the diversity and composition of fungal communities. In amplicon pyrosequencing studies of fungal diversity, one of the spacers ITS1 or ITS2 of the ITS region is normally used. In this methodological study we evaluate the usability of ITS1 vs. ITS2 as a DNA metabarcoding marker for fungi. We analyse three data sets: two comprising ITS1 and ITS2 sequences of known taxonomic affiliations and a third comprising ITS1 and ITS2 environmental amplicon pyrosequencing data. Clustering analyses of sequences with known taxonomy using the bioinformatics pipeline ClustEx revealed that a 97% similarity cut-off represent a reasonable threshold for estimating the number of known species in the data sets for both ITS1 and ITS2. However, no single threshold value worked well for all fungi at the same time within the curated UNITE database, and we found that the Operational Taxonomic Unit (OTU) concept is not easily translated into the level of species because many species are distributed over several clusters. Clustering analyses of the 134 692 ITS1 and ITS2 pyrosequences using a 97% similarity cut-off revealed a high similarity between the two data sets when it comes to taxonomic coverage. Although some groups are under- or unrepresented in the two data sets due to, e.g. primer mismatches, our results indicate that ITS1 and ITS2 to a large extent yield similar results when used as DNA metabarcodes for fungi. PMID- 23350564 TI - The transformed political world of older boomers. PMID- 23350563 TI - Proteome-wide analysis of nonsynonymous single-nucleotide variations in active sites of human proteins. AB - An enzyme's active site is essential to normal protein activity such that any disruptions at this site may lead to dysfunction and disease. Nonsynonymous single-nucleotide variations (nsSNVs), which alter the amino acid sequence, are one type of disruption that can alter the active site. When this occurs, it is assumed that enzyme activity will vary because of the criticality of the site to normal protein function. We integrate nsSNV data and active site annotations from curated resources to identify all active-site-impacting nsSNVs in the human genome and search for all pathways observed to be associated with this data set to assess the likely consequences. We find that there are 934 unique nsSNVs that occur at the active sites of 559 proteins. Analysis of the nsSNV data shows an over-representation of arginine and an under-representation of cysteine, phenylalanine and tyrosine when comparing the list of nsSNV-impacted active site residues with the list of all possible proteomic active site residues, implying a potential bias for or against variation of these residues at the active site. Clustering analysis shows an abundance of hydrolases and transferases. Pathway and functional analysis shows several pathways over- or under-represented in the data set, with the most significantly affected pathways involved in carbohydrate metabolism. We provide a table of 32 variation-substrate/product pairs that can be used in targeted metabolomics experiments to assay the effects of specific variations. In addition, we report the significant prevalence of aspartic acid to histidine variation in eight proteins associated with nine diseases including glycogen storage diseases, lacrimo-auriculo-dento-digital syndrome, Parkinson's disease and several cancers. PMID- 23350565 TI - Conceptualizing age-friendly community characteristics in a sample of urban elders: an exploratory factor analysis. AB - Accurate conceptualization and measurement of age-friendly community characteristics would help to reduce barriers to documenting the effects on elders of interventions to create such communities. This article contributes to the measurement of age-friendly communities through an exploratory factor analysis of items reflecting an existing US Environmental Protection Agency policy framework. From a sample of urban elders (n = 1,376), we identified 6 factors associated with demographic and health characteristics: access to business and leisure, social interaction, access to health care, neighborhood problems, social support, and community engagement. Future research should explore the effects of these factors across contexts and populations. PMID- 23350566 TI - Comparing supports for LGBT aging in rural versus urban areas. AB - Studies of rural populations typically underrepresent lesbian, gay, bisexual, and transgender (LGBT) older adults. This secondary analysis examined data from a nationwide sample of LGBT baby boomers (n = 1201). Geographic differences with respect to self-reported outness, acceptance of sexual identity, social and familial support, and household income were assessed with one-way analyses of variance. Guardedness about one's sexual identity and household asset levels were assessed with chi-square analyses. Rural individuals reported lower levels of outness, guardedness with people including siblings and close friends, and lower levels of household income. Providers should consider strategies for connecting older rural LGBT adults for potential care and support. PMID- 23350567 TI - Nursing home social services directors who report thriving at work. AB - Nationally representative data from a sample (n = 928) of full-time nursing home social services directors were used to investigate whether knowing characteristics of the social environment at work can help to explain which directors report job thriving. Two-thirds of directors reported they were thriving in their jobs. Multiple regression results show that thriving is increased by job autonomy, being treated like an important part of the team, having enough time to identify and meet resident psychosocial needs, not having to do things that others could do, and being clear what the social services role is. Findings suggest that addressing these aspects of the social environment and social services role will likely contribute to increasing a sense of thriving at work among social services staff members. PMID- 23350568 TI - Older adults navigating medicare: when benefits are denied. AB - Guided by Bourdieu's theory of practice and symbolic violence, this qualitative study explored experiences and perceptions of elderly beneficiaries who had been denied rehabilitation services by Medicare. In semistructured interviews, 12 beneficiaries or family members told of the physical, psychological, and financial consequences of service denial/termination. The resulting perception of Medicare was as a cumbersome, difficult to negotiate system. Findings have implications for future research on service denial and indicate the need for better communication with, and support of, consumers by health care professionals when this occurs. PMID- 23350569 TI - The transformative potential of social work's evolving practice in dementia care. AB - Social workers in diverse service systems throughout the United States encounter many opportunities for improving quality of life for people with dementia and their families. Yet practice with this population is unclearly defined and a core set of competencies for such practice does not yet exist. Instead, it is shaped by roles within aging and health systems. These roles are informed by a biomedical disease model of dementia. This article examines social work practice and its connection to evolving views on aging and senility throughout the 20th century. New directions for practice are recommended to improve services for individuals with dementia. PMID- 23350571 TI - 'What mother wouldn't want to save her baby?' HIV testing and counselling practices in a rural Ugandan antenatal clinic. AB - Drawing on an exploratory qualitative case study investigating everyday practices within an antenatal clinic in rural Uganda, this paper investigates the dynamics of consent and counselling within a prevention of mother-to-child HIV transmission (PMTCT) programme, from the perspectives of various health professionals involved at different stages of the PMTCT trajectory. The paper contributes to the existing literature by focusing not on clients' views but, rather, by elucidating how different cadres of health workers view and practice the human rights principles of informed consent and opting out, that are reflected in Uganda's HIV testing policies. By investigating the roles and responsibilities of community counsellors, post-test counsellors, and midwives, we illustrate how the practice of counselling in PMTCT is influenced by two hegemonic discourses: the health of a child should be protected, and the health worker knows best. As a result, a directive form of counselling in PMTCT settings, with its focus on the health of the baby, silences women's right to opt out of HIV tests. PMID- 23350572 TI - The triggering role of allergic contact dermatitis in discoid lupus erythematosus. AB - BACKGROUND: The onset and exacerbations of discoid lupus erythematosus (DLE) can be precipitated by several factors like needling, scratches, trauma, X-rays, heat, cold, pressure, tattooing, scars, allergic and irritant dermatitis and inflammatory dermatoses. OBJECTIVE: To investigate the role of allergic contact dermatitis (ACD) in devolopment and triggering of the lesions of DLE. MATERIALS AND METHODS: This study was performed on 30 patients with DLE. European baseline series and cosmetic patch test series were used. At least 1+ reaction was accepted as meaningful. RESULTS: Twenty-three (76.7%) of 30 DLE patients and 16 (40%) of 40 control group patients were allergic to at least one allergen on standard patch test series. The difference between the groups were found statistically significant. Seventeen (56.7%) of 30 DLE patients and 6 (15%) of 40 control group patients were allergic to at least one allergen on cosmetic patch test series. The difference between the groups were statistically significant. The most sensitized allergens in both the groups were nickel sulphate, paraphenylen diamine, potassium dichromate from standard patch test series; quaternium 15, cocamidopropyl betain from cosmetic patch test series, in order. CONCLUSION: This study is distinctive since it is the first study to determine the eliciting role of ACD on DLE by imposing standard and cosmetic patch test series on DLE and control group patients. Worldwide, there is no study based on this subject. In the DLE group, the results of sensitization on standard and cosmetic patch test series were higher and statistically significant. Larger studies are required to reveal the exact role. PMID- 23350573 TI - Outcome from consecutive ICSI cycles in patients treated with recombinant human LH and those supplemented with urinary hCG-based LH activity during controlled ovarian stimulation in the long GnRH-agonist protocol. AB - Clinical results were compared in a well-established, assisted reproduction program during the cross-over from highly purified (HP)-human menopausal gonadotropin (hMG) to rhFSH/rhLH. We included the last 33 patients treated with HP-hMG and the first 33 patients receiving rhFSH/rhLH for ovarian stimulation in their first intracytoplasmic sperm injection cycle. Patient baseline characteristics were almost identical in the two groups. Ovarian stimulation characteristics (days of stimulation, total amount of FSH administered using a modest initial loading dose of 150 IU/d, patients with oocyte retrieval) were similar for the two groups. However, the number of total and leading follicles and E2 serum levels on the human chorionic gonadotropin injection day were significantly higher in the rhFSH/rhLH group. The oocyte yield was significantly higher in the rhFSH/rhLH group as well as the number of metaphase II oocytes, difference almost reaching the statistical significance. The number of oocytes fertilized was also higher in patients receiving rhFSH/rhLH treatment. Implantation and clinical pregnancy rates were similar in both the study groups. It is concluded that in women undergoing controlled ovarian hyperstimulation under pituitary suppression for ART, the recombinant combined product containing FSH and LH in a fixed 2:1 ratio is more effective than HP-hMG in terms of follicle development, oocyte yield and quality, and fertilization rates. PMID- 23350574 TI - Ethnic differences in drug utilization pattern during pregnancy: a cross sectional study. AB - OBJECTIVE: To investigate the differences in exposure to medications in a cohort of multi-ethnic pregnant women. METHODS: Six hundred and forty-one pregnant women of Western, Arab/Turkish and "other origins" participated in this cross-sectional study using a questionnaire in a university hospital in Brussels, Belgium. Assessment of the drug safety was done using the food and drug administration (FDA) risk classification system. Data analysis was performed using SPSS (Chicago, IL). RESULTS: In overall cohort, 83.8% used at least one preparation (including multivitamins) during pregnancy and 37.0% of women used at least one drug (excluding multivitamins). Significantly more Western women (43.7%) used one or more medications compared to Arab/Turkish women (28.7%; p = 0.000). This difference in exposure was most pronounced for over-the-counter (OTC) drugs for occasional and pregnancy-related complaints, and was observed for potentially unsafe drugs or drugs with unknown safety. None of the women reported use of FDA X category drugs. CONCLUSIONS: The use of drugs known to be harmful was not observed, but a higher prevalence of exposure to potentially harmful drugs (FDA C/D) was found among Western women who also consumed more OTC drugs. This highlights the need for cautious prescribing for women in the fertile age in general and for continuous monitoring of medication use during pregnancy. PMID- 23350576 TI - Mitochondrial DNA response to high altitude: a new perspective on high-altitude adaptation. AB - Mitochondria are the energy metabolism centers of the cell. More than 95% of cellular energy is produced by mitochondrial oxidative phosphorylation. Hypoxia affects a wide range of energy generation and consumption processes in animals. The most important mechanisms limiting ATP consumption increase the efficiency of ATP production and accommodate the reduced production of ATP by the body. All of these mechanisms relate to changes in mitochondrial function. Mitochondrial function can be affected by variations in mitochondrial DNA, including polymorphisms, content changes, and deletions. These variations play an important role in acclimatization or adaptation to hypoxia. In this paper, the association between mitochondrial genome sequences and high-altitude adaptation is reviewed. PMID- 23350575 TI - Why mitochondria must fuse to maintain their genome integrity. AB - SIGNIFICANCE: The maintenance of mitochondrial genome integrity is a major challenge for cells to sustain energy production by respiration. RECENT ADVANCES: Recently, mitochondrial membrane dynamics emerged as a key process contributing to prevent mitochondrial DNA (mtDNA) alterations. Indeed, both fundamental and clinical data suggest that disruption of mitochondrial fusion, related to mutations in the OPA1, MFN2, PINK1, and PARK2 genes, leads to the accumulation of mutations in the mitochondrial genome. CRITICAL ISSUES: We discuss here the possibility that mitochondrial fusion acts as a direct mechanism to prevent the generation of altered mtDNA and to eliminate mutated deleterious genomes either by trans-complementation or by mitophagy. FUTURE DIRECTIONS: Finally, we conclude this review with a short evolutionary comparison between the mechanisms involved in mitochondrial and bacterial modes of genome distribution and plasticity, highlighting possible common conserved processes required for the maintenance of their genome integrity, which should inspire our future investigations. PMID- 23350577 TI - Increased risk of prosthetic joint infection associated with esophago-gastro duodenoscopy with biopsy. AB - BACKGROUND: There are no prospective data regarding the risk of prosthetic joint infection following routine gastrointestinal endoscopic procedures. We wanted to determine the risk of prosthetic hip or knee infection following gastrointestinal endoscopic procedures in patients with joint arthroplasty. METHODS: We conducted a prospective, single-center, case-control study at a single, tertiary-care referral center. Cases were defined as adult patients hospitalized for prosthetic joint infection of the hip or knee between December 1, 2001 and May 31, 2006. Controls were adult patients with hip or knee arthroplasties but without a diagnosis of joint infection, hospitalized during the same time period at the same orthopedic hospital. The main outcome measure was the odds ratio (OR) of prosthetic joint infection after gastrointestinal endoscopic procedures performed within 2 years before admission. RESULTS: 339 cases and 339 controls were included in the study. Of these, 70 cases (21%) cases and 82 controls (24%) had undergone a gastrointestinal endoscopic procedure in the preceding 2 years. Among gastrointestinal procedures that were assessed, esophago-gastro-duodenoscopy (EGD) with biopsy was associated with an increased risk of prosthetic joint infection (OR = 3, 95% CI: 1.1-7). In a multivariable analysis adjusting for sex, age, joint age, immunosuppression, BMI, presence of wound drain, prior arthroplasty, malignancy, ASA score, and prothrombin time, the OR for infection after EGD with biopsy was 4 (95% CI: 1.5-10). INTERPRETATION: EGD with biopsy was associated with an increased risk of prosthetic joint infection in patients with hip or knee arthroplasties. This association will need to be confirmed in other epidemiological studies and adequately powered prospective clinical trials prior to recommending antibiotic prophylaxis in these patients. PMID- 23350578 TI - Monitoring of the first stages of bone healing with microdialysis. AB - BACKGROUND AND PURPOSE: Bone healing is a complex process influenced by growth factors, cytokines, and other mediators. The regulation of this process is not well understood. In this pilot study, we used microdialysis technology in a critical-size bone defect in rat femurs to determine the feasibility of measuring cytokines and growth factors in the first 24 h after injury. METHODS: A 5-mm defect, stabilized by a plate, was created in the femurs of 30 male Wistar rats. The microdialysis probe (with 100 kDa molecular weight cutoff) was inserted into the defect and microdialysates were collected continuously for up to 24 h. Total protein concentration, interleukin-6 (IL-6) concentration, and transforming growth factor-beta1 (TGF-beta1) concentration were assessed under different conditions. RESULTS: Microdialysis allowed continuous and consistent protein collection over 24 h from a critical-size bone defect starting at the time of injury. IL-6 was secreted within the first 3 h after the injury. The highest IL-6 concentration (344 pg/mL) was measured between 12 and 15 h after surgery. Addition of bovine serum albumin to the perfusate resulted in detectable concentrations of TGF-beta1 ranging from 10 to 23 pg/mL. INTERPRETATION: Continuous sampling over 24 h of proteins from a bone defect directly after the injury is feasible and provides the opportunity for a detailed analysis of the initial stages of bone healing. PMID- 23350579 TI - No effect of fibrin sealant on drain output or functional recovery following simultaneous bilateral total knee arthroplasty: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND AND PURPOSE: Blood loss after total knee arthroplasty (TKA) may lead to anemia, blood transfusions, and increased total costs. Also, bleeding into the periarticular tissue may cause swelling and a reduction in quadriceps strength, thus impairing early functional recovery. In this randomized, double-blind, placebo-controlled study, we analyzed the possible effect of fibrin sealant on blood loss and early functional recovery in a fast-track setting. METHODS: 24 consecutive patients undergoing bilateral simultaneous TKA were included. 10 mL of fibrin sealant (Evicel) was sprayed onto one knee whereas the contralateral knee had saline. Drain output, the primary outcome, was measured from knee drains removed exactly 24 h after surgery. Secondary outcomes (knee swelling, pain, strength of knee extension, and range of movement (ROM)) were evaluated up to 21 days after surgery. RESULTS: The drain output in knees treated with fibrin sealant and placebo was similar (582 mL and 576 mL, respectively). Likewise, no statistically significant differences were found between groups regarding swelling, pain, strength of knee extension, and ROM. INTERPRETATION: Fibrin sealant as a local hemostatic in TKA showed no benefit in reducing drain output or in facilitating early functional recovery when used with a tourniquet, tranexamic acid, and a femoral bone plug. PMID- 23350580 TI - The uptake and outcome of prenatal and pre-implantation genetic diagnosis for Huntington's disease in the Netherlands (1998-2008). AB - We aimed to study reproductive behaviour of couples opting for prenatal diagnosis (PND) and pre-implantation genetic diagnosis (PGD) for Huntington's disease (HD). In the Netherlands, exclusion PND is available for persons at 50% risk, whereas exclusion PGD is not allowed. All 162 couples who underwent PND or PGD for HD between 1998 and 2008 and referrals for exclusion PGD to Belgium were included. Couples' reproductive information was collected until December 2010; 132 couples (81.5%) underwent PND in 262 pregnancies, 54 (33.3%) started PGD, and 25 used both. Sixteen percent of PND couples used exclusion PND and 6% used exclusion PGD. The outcomes were 76.5% of PND couples delivered >=1 unaffected child(ren) after PND, and 44.4% of PGD couples delivered >=1 PGD child(ren) (mean 2.5 cycles/couple). Couples opting for PGD secondarily (after a previous pregnancy) had more frequently terminated a pregnancy for HD (87.0%) compared with couples secondarily opting for PND (55.2%; p = 0.015). At-risk or HD expansion carrier males were underrepresented in the group of couples primarily opting for PGD (25%) and overrepresented in the secondary PGD group (64%). We conclude that couples reconsider their choices in every subsequent pregnancy based on their previous experience, personal beliefs and the gender of the at-risk partner. PMID- 23350581 TI - Microfluidic mixing triggered by an external LED illumination. AB - The mixing of confined liquids is a central yet challenging operation in miniaturized devices. Microfluidic mixing is usually achieved with passive mixers that are robust but poorly flexible, or active mixers that offer dynamic control but mainly rely on electrical or mechanical transducers, which increase the fragility, cost, and complexity of the device. Here, we describe the first remote and reversible control of microfluidic mixing triggered by a light illumination simply provided by an external LED illumination device. The approach is based on the light-induced generation of water microdroplets acting as reversible stirrers of two continuous oil phase flows containing samples to be mixed. We demonstrate many cycles of reversible photoinduced transitions between a nonmixing behavior and full homogenization of the two oil phases. The method is cheap, portable, and adaptable to many device configurations, thus constituting an essential brick for the generation of future all-optofluidic chip. PMID- 23350583 TI - Anomalous manganese activation of a pyrophosphate cathode in sodium ion batteries: a combined experimental and theoretical study. AB - Sodium ion batteries (SIBs) have many advantages such as the low price and abundance of sodium raw materials that are suitable for large-scale energy storage applications. Herein, we report an Mn-based pyrophosphate, Na(2)MnP(2)O(7), as a new SIB cathode material. Unlike most Mn-based cathode materials, which suffer severely from sluggish kinetics, Na(2)MnP(2)O(7) exhibits good electrochemical activity at ~3.8 V vs Na/Na(+) with a reversible capacity of 90 mAh g(-1) at room temperature. It also shows an excellent cycling and rate performance: 96% capacity retention after 30 cycles and 70% capacity retention at a c-rate increase from 0.05C to 1C. These electrochemical activities of the Mn containing cathode material even at room temperature with relatively large particle sizes are remarkable considering an almost complete inactivity of the Li counterpart, Li(2)MnP(2)O(7). Using first-principles calculations, we find that the significantly enhanced kinetics of Na(2)MnP(2)O(7) is mainly due to the locally flexible accommodation of Jahn-Teller distortions aided by the corner sharing crystal structure in triclinic Na(2)MnP(2)O(7). By contrast, in monoclinic Li(2)MnP(2)O(7), the edge-sharing geometry causes multiple bonds to be broken and formed during charging reaction with a large degree of atomic rearrangements. We expect that the similar computational strategy to analyze the atomic rearrangements can be used to predict the kinetics behavior when exploring new cathode candidates. PMID- 23350582 TI - Trends in quetiapine use and non-fatal quetiapine-related ambulance attendances. AB - INTRODUCTION AND AIMS: Concern about the non-medical use of quetiapine and related acute harms is growing. Case series cite quetiapine as a potential drug of misuse, while recent research questions its relative safety in comparison with other atypical antipsychotic preparations. This paper explores population-level patterns of quetiapine-related ambulance attendances over time, identifying associated risk factors and potential subpopulations at-risk of acute harms. DESIGN AND METHODS: A retrospective analysis of quetiapine-, olanzapine- and risperidone-related ambulance attendances in metropolitan Melbourne and prescription data in Victoria, Australia. Trends in ambulance attendance and prescription rates, attendance characteristics, and associated risk factors were explored from 2001 to 2010. RESULTS: Quetiapine was consistently associated with substantially higher rates of ambulance attendances relative to prescription availability than olanzapine or risperidone. Quetiapine prescribing rates increased at a significantly greater magnitude than olanzapine or risperidone, leading to substantial increases in quetiapine attendances by population. Quetiapine-related attendances were associated with concurrent heroin and opioid replacement therapy toxicity, history of heroin and alcohol misuse, mood disorders, low Glasgow Coma Scale and women. DISCUSSION AND CONCLUSIONS: Trends in quetiapine-related ambulance attendances indicate rising community-level harms and greater harm relative to other atypical antipsychotics, while prescription patterns suggest increasing quetiapine availability. The association of quetiapine-related attendances with concurrent heroin and opioid replacement therapy toxicity as well as previous heroin and alcohol misuse suggest illicit and poly-drug users are a subpopulation at greater risk of quetiapine-related harms, consistent with emerging evidence of the use, misuse and diversion of quetiapine. PMID- 23350584 TI - Impact of HER-2-targeted therapy on overall survival in patients with HER-2 positive metastatic breast cancer. AB - Upon disease progression on trastuzumab-based therapy, patients with HER-2 positive metastatic breast cancer (MBC) may switch to lapatinib or continue on trastuzumab. We aimed to assess the impact of both strategies on overall survival (OS) in all patients treated for HER-2 positive MBC at the Medical University Vienna from 1999 until 2009. A total of 201 patients were identified from a breast cancer data base. Of these 115 (57.2%) received multiple lines of trastuzumab-based therapy, whereas 58 (28.9%) were treated with a single line. A control group of 28 patients (13.9%) had never received trastuzumab as they were treated before 1999, when trastuzumab was registered. OS from diagnosis of metastatic disease was defined as primary study endpoint. Trastuzumab significantly prolonged OS in HER-2 positive MBC (41 versus 13 months; p < 0.001). Administration of multiple lines further improved OS; this, however, did not reach statistical significance (47 versus 28 months; p = 0.069). Positive estrogen receptor (ER) status (HR 1.6; 95% CI 1.13-2.27) was associated with better outcome compared to negative estrogen receptor status (p = 0.02). Addition of lapatinib did not improve OS significantly in patients with prior trastuzumab based therapy (62 versus 47 months; p = n.s.). Patients receiving lapatinib after diagnosis of BM, however, experienced an improvement of OS (22 versus 5 months; p = 0.022). Trastuzumab improves OS in patients with HER-2 positive MBC with further nonsignificant improvement when administered in multiple lines. Lapatinib did not further improve OS in the entire population; however, lapatinib might improve OS in patients with BM. PMID- 23350585 TI - Rotation and generation of mental imagery in children with specific language impairment. AB - AIM: To investigate the relationship between mental imagery and specific language impairment (SLI) and explore the assumption that children with SLI are less able to generate mental images and/or convert them, when compared to typical development (TD) children of the same age. METHODS: Twenty-four children, aged six to eight, took part in two tests to see how well they generated and rotated mental images. The participants were 12 SLI children (six boys and six girls) and 12 TD children (six boys and six girls), matched by age and gender. RESULTS: The statistical analysis showed a significant difference between the two groups when it came to generating mental imagery. However, there were no significant differences with regard to rotating mental imagery. CONCLUSION: The results suggest imagery deficit in language-impaired children is not caused by mental rotation, but by other aspects of image processing, such as generation, maintenance and interpretation of visual images. PMID- 23350586 TI - Aptamer-based cantilever array sensors for oxytetracycline detection. AB - We present a new method for specific detection of oxytetracycline (OTC) at nanomolar concentrations based on a microfabricated cantilever array. The sensing cantilevers in the array are functionalized with self-assembled monolayers (SAMs) of OTC-specific aptamer, which acts as a recognition molecule for OTC. While the reference cantilevers in the array are functionalized with 6-mercapto-1-hexanol SAMs to eliminate the influence of environmental disturbances. The cantilever sensor shows a good linear relationship between the deflection amplitude and the OTC concentration in the range of 1.0-100 nM. The detection limit of the cantilever array sensor is as low as 0.2 nM, which is comparable to some traditional methods. Other antibiotics such as doxycycline and tetracycline do not cause significant deflection of the cantilevers. It is demonstrated that the cantilever array sensors can be used as a powerful tool to detect drugs with high sensitivity and selectivity. PMID- 23350587 TI - Improved glycemic control and acute complications among children with type 1 diabetes mellitus in Moshi, Tanzania. AB - OBJECTIVE: There are an estimated 1000 children with diabetes in Tanzania. Recently, the first two pediatric endocrinologists, trained in the European Society for Paediatric Endocrinology (ESPE)/International Society for Paediatric and Adolescent Diabetes (ISPAD) program in Nairobi, Kenya, entered practice. The purpose of this study was to prospectively assess the impact of a 6-month diabetes management and education program on glycemic control and acute complications in children and adolescents in Tanzania. RESEARCH DESIGN AND METHODS: Eighty-one patients aged 3-19 yr were enrolled. All were on split-dose Insulatard (Neutral Protamine Hagedorn) and Actrapid (soluble, regular) insulin, and were given three glucose test strips per week. Children were seen in clinic an average of six times over 6 months and received 3 h of diabetes education. A structured questionnaire evaluated social demographic data and acute complications. RESULTS: Despite regular clinic attendance, diabetes education, and provision of insulin, hemoglobin A1c (HbA1c) levels did not improve. Four children (5%) had HbA1c 7.5%, 22 (28%) HbA1c 7.5-10%, 9 (24%) HbA1c 11-12.5%, and 36 (44%) HbA1c >12.5%. There was a substantial reduction in severe hypoglycemia, with 17% of subjects experiencing this acute complication compared to 52% in the 6 months prior to study enrolment. Six children were admitted in diabetic ketoacidosis during the study compared to three during the previous 6 months. Twenty-six children (36%) reported missing >6 doses of insulin (but only two lacked insulin). CONCLUSIONS: Diabetes education significantly reduced the risk of severe hypoglycemia, but better glycemic control of diabetes was not attained. Further study is needed to explore factors to improve glycemic control including increased testing, or perhaps different insulin regimens. PMID- 23350588 TI - Retinol binding protein as early marker of fetal growth restriction in first trimester maternal serum. AB - BACKGROUND: Serum retinol binding protein (RBP4) is the binding protein for retinol, being delivered into the circulation through the carrier protein transthyretin (TTR) together with thyroxin (T4). RBP4 has also been recently indicated as a new adipokine implicated in insulin resistance and metabolism regulation. OBJECTIVE: To investigate the role of RBP4 as early markers of fetal growth restriction (FGR) and preeclampsia (PE) in maternal serum during the first trimester of pregnancy. MATERIALS AND METHODS: Retrospective case control study in patients between the 12th and the 14th week of gestation. RBP4, TTR and T4 concentration was assessed in maternal serum of three groups of women: 15 and 14 patients later developing respectively FGR and PE were compared with 11 patients having a normal pregnancy. RESULTS: All women were Caucasian and the mean maternal age was 33.62 years (+/-5.50). RBP4 resulted lower in the FGR than in the control group (11.00 versus 16.00 ug/ml, p < 0.05) and than in the PE group (15.00 ug/ml, p = 0.075), both in bivariate and multivariate analysis. No difference was observed in TTR and T4 concentration. CONCLUSIONS: RBP4 seems to play a role as early marker of FGR but not PE in first trimester maternal serum. PMID- 23350589 TI - Block allograft technique versus standard guided bone regeneration: a randomized clinical trial. AB - PURPOSE: The aim of this randomized clinical trial was to compare the potential of deproteinized bovine bone added to autologous bone or corticocancellous allograft block with or without the addition of recombinant human platelet derived growth factor-BB (rhPDGF-BB) to regenerate mandibular atrophic ridges. MATERIALS AND METHODS: TRIAL DESIGN: parallel, allocation ratio of 1:1 using a split-mouth model. Eligibility criteria for patients: adult patients; bilateral atrophic edentulous areas in the posterior area of the mandible; a preoperatory cone beam computed tomography scan; and absence of systemic diseases affecting the bone metabolism. Bone graft intervention for control group consisted of bone chips collected with a scraper mixed with deproteinized bovine bone covered with a resorbable membrane. Bone graft intervention for test group consisted of a corticocancellous allograft block, shaped before surgery, and protected with a collagen membrane. In addition, both groups received rhPDGF-BB or a saline solution as control. As primary outcome quantity, bone variation after a 1-year healing period was considered. A p-value of.05 was considered statistically significant. RESULTS: Sixteen patients were enrolled in this trial. A total of 50 implants and 32 bone grafts were placed. All patients concluded the study (no dropouts). Change at 1 year in bone volume was not significantly different between the two groups (p-value = .25). Effect of treatment in terms of change in bone volume at 1 year was not significant (p-value = .89) when saline solution was used while was at limit of significance when rhPDGF-BB was used (p-value = .052). After 1 year, all the implants were successfully integrated. CONCLUSIONS: The block allograft and the standard regenerative procedure showed similar results in terms of regenerated bone volume after 1 year of functional loading. The rhPDGF-BB positively influenced soft-tissue healing. PMID- 23350590 TI - Catalysis by doped oxides. PMID- 23350591 TI - Predictive value of lingua/pharynx ratio for retroglossal obstruction in patients with obstructive sleep apnea hypopnea syndrome. AB - CONCLUSIONS: The lingua/pharynx (L/P) ratio has high sensitivity and specificity in predicting the severity of retroglossal obstruction in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). OBJECTIVE: To evaluate the diagnostic value of the L/P ratio in predicting the severity of retroglossal obstruction in patients with OSAHS. METHODS: Airway computed tomography (CT) was performed in 115 patients with OSAHS. The retroglossal cross-sectional area (RCSA) was measured at the axial level of the hypopharynx, immediately superior to the tip of the epiglottis. Moreover, nine lines, which were lined up in the order of n = 1, 2, 3, ..., 9, were drawn from the genial tubercle (point G) to nine points (point P n ) proximally on the posterior pharyngeal wall and hard palate in the sagittal plane. Meanwhile, the nine lines intersected the lingual surface at point Ln, respectively. The L/P ratios of the lingual segment (G to L n distance) to the pharyngeal segment (G to P n distance) were measured. We analyzed the correlations between nine L/P values (L/P n ) and RCSA. RESULTS: Both simple linear correlation analysis and multiple linear regression analysis showed that L/P6 and L/P9 had significant negative correlations with RCSA. PMID- 23350592 TI - Effect of severity of vestibular dysfunction on postural instability in idiopathic bilateral vestibulopathy. AB - CONCLUSIONS: Foam posturography reveals that idiopathic bilateral vestibulopathy (IBV) significantly affects postural stability. Instability was more severe in patients with damage to both of the vestibular nerve systems. Residual function in the spared vestibular nerve system might contribute to postural stability in IBV. OBJECTIVE: Postural stability was assessed using foam posturography in patients with IBV according to whether the inferior, superior or both of the vestibular nerve systems were affected. METHODS: Two-legged stance tasks were performed by patients with IBV (n = 29) in four conditions: eyes open with and without foam rubber, and eyes closed with and without foam rubber. We examined six variables: the velocity of movement of the center of pressure (COP), the envelopment area traced by the movement of the COP, Romberg's ratio of velocity and area, and the foam ratios of velocity and area. RESULTS: The presence of IBV was significantly positively related to all the variables in adjusting for the subjects' gender and age (p < 0.001). Five of the 29 patients (17%) with IBV required assistance to prevent falling with eyes closed/foam rubber. Four of these five patients showed bilateral canal paresis in caloric testing and bilaterally no responses in cervical vestibular evoked myogenic potential testing. PMID- 23350593 TI - Multidrug resistance in mucoepidermoid carcinoma of the parotid gland- immunohistochemical investigations of P-glycoprotein expression. AB - Abstract Conclusion: P-glycoprotein is abundantly expressed in certain parotid mucoepidermoid carcinoma tissues, known historically to be multidrug resistant. This discovery may be important in incrementally advancing our ability to develop alternative pharmacologic strategies to improve multi-modality tumor control. OBJECTIVE: P-glycoprotein plays a functional role in promoting the efflux of drug metabolites in certain malignant tumors. With this understanding we immunohistochemically investigated the expression of P-glycoprotein in parotid mucoepidermoid carcinoma tissues and examined prognostic factors that contribute to the treatment of parotid cancer. METHODS: Thirteen patients with mucoepidermoid carcinoma of the parotid gland were included. P-glycoprotein expression was immunohistochemically investigated by a modified avidin-biotin peroxidase complex method using four different antibodies. RESULTS: P glycoprotein expression was observed in a higher percentage of patients with higher grade malignancy. The tumor size-related difference in P-glycoprotein expression was only significant for staining with one antibody, and no significant differences were observed with or without induction chemotherapy. PMID- 23350594 TI - Usefulness of the BAST-24 smell and taste test in the study of diabetic patients: a new approach to the determination of renal function. AB - CONCLUSION: A reduction in the percentage of correct responses in the olfactory test indirectly indicated increased albuminuria and worse glomerular filtration rate (GFR) in diabetic patients. The olfactory function test is an indirect indicator of early microvascular complications in diabetic patients. OBJECTIVES: Diabetes mellitus is a highly prevalent disease that causes numerous complications. The aim of this study was to determine whether olfactory and taste sensations are related to renal failure in diabetic patients. METHODS: We studied 61 patients diagnosed with diabetes mellitus, mean age = 65.9 years (SD = 16.8), 54.1% male. We evaluated olfactory and taste sensations by determining the capacity of detection, identification and percentage of correct responses of the 29 components of the Barcelona Smell-taste Test-24 (BAST-24). We determined the relationship between these results and glycosylated haemoglobin (HbA1c), creatinine, albumin/creatinine, albuminuria and GFR (normal = GFR >= 60 ml/min/1.73 m(2); impaired renal function = GFR < 60 ml/min/1.73 m(2)). RESULTS: There was no significant relationship between HbA1c and olfactory and taste sensations. There was a significant relationship between the percentage of correct responses and albuminuria (p = 0.03) and between identification of odours through the olfactory nerve and GFR (p = 0.029), and the percentage of correct responses and GFR (p = 0.03). There was no significant relationship between taste and renal failure. PMID- 23350595 TI - Tenotomy of the stapedius and tensor tympani muscles reduces subjective dizziness handicap in definite Meniere's disease. AB - CONCLUSION: Tenotomy is a promising surgical alternative with a high reduction in dizziness handicap in the short and long term. OBJECTIVES: To investigate the immediate and the long-term effect of tenotomy of the stapedius and tensor tympani muscles on subjective dizziness as measured by the Dizziness Handicap Inventory (DHI). METHODS: A retrospective follow-up study of 42 patients with definite, unilateral Meniere's disease (19 males, 23 females, average age = 58.1 +/- 14.1 years) had undergone tenotomy under general anesthesia through an endaural approach. Pre- and postoperative DHI values were compared for all patients, with postoperative follow-up ranging from 6 months to 9 years. Additionally, results were divided into three postoperative subgroups (A = 0-3 years, B = 3-6 years, C = 6-9 years). RESULTS: A statistically significant reduction of 48 DHI points, from a median preoperative DHI = 52 to DHI = 4 postoperatively, was noted (p < 0. 001). In all, 40/42 patients reported a reduction of dizziness handicap, while in 33/42 the difference was > 12 points. A statistically significant reduction of DHI scores was noted (A = 60, B = 34, C = 33) in all subgroups. It was also noted that the higher the preoperative DHI score, the greater the subjective success of the surgery. PMID- 23350596 TI - Morphological and morphometric study on human Scarpa ganglion development. AB - CONCLUSION: In Scarpa neurons the cell and nuclear area increases and nuclear/cytoplasm ratio decreases with fetal age (p < 0.0001). There are statistically significant differences in cell area between all fetal groups, except for the interval 45-74 mm crown-rump-length (CRL). Displacement of a neuron within the internal auditory meatus (IAM) occurs from 9 weeks in the fetus until the neonate. METHODS: A light microscopic histomorphometric study of the Scarpa ganglion in human fetuses from spontaneous abortions measuring 45, 74, 90, 134, 145 and 270 mm CRL and a from a 1-day-old neonate (360 mm) was carried out. Cell and nuclear area, ganglion area and distances from the Scarpa ganglion neurons to the endocranial porus of the IAM were measured. RESULTS: In the 45, 74, 90 and 134 mm CRL human fetuses the cartilaginous labyrinthine capsule appears divided by the facial nerve and the Scarpa ganglion into two compartments: rostral and dorsal. Ovoidal Scarpa ganglion in the 45 mm CRL lies within the IAM near its endocranial porus (15 um). In the otic capsule of the 145 mm CRL fetus an endochondral ossification appears in the IAM base, where Scarpa ganglion neurons are displayed in two groups: superior and inferior divided by a vascular-connective septum. This anatomy remains from this specimen until the neonate specimen. PMID- 23350597 TI - Human papillomavirus and head and neck squamous cell carcinomas in the South-East of France: prevalence, viral expression, and prognostic implications. AB - CONCLUSION: Human papillomavirus (HPV) infection, especially by HPV 16, is frequently detected in oropharyngeal squamous cell carcinoma (OSCC). The expression of viral oncoproteins in tumoral tissues of OSCCs suggests the implication of HPV in tumorogenesis. It should now be systematically detected and considered in each patient's treatment and outcome. OBJECTIVES: To investigate the prevalence of HPV infection, the oncogenic role of HPV in patients from the South-East of France with head and neck squamous cell carcinoma (HNSCC), and the resulting clinical implications. METHODS: Biopsy samples from 200 patients with HNSCC were analyzed. For each patient, one or two biopsies of tumoral tissue were analyzed simultaneously with a biopsy of healthy tissue. Fresh frozen tissues were tested by molecular techniques for HPV DNA detection and genotyping as well as mRNA expression of oncoproteins E6 and E7. Expression of p16 was also analyzed by immunohistochemical staining. RESULTS: HPV DNA tested positive in 11.5% of biopsy samples. The HPV prevalence was higher in OSCCs (91.3 vs 27.3, p < 0.0001) and in patients not consuming tobacco (65.2% vs 95.4%, p < 0.0001). The estimated 3-year overall survival rates were 67.0% for HPV-infected patients versus 39.9% for non-infected patients. The high-risk HPV 16 was the most common type detected (65.2%). In 12 of 18 patients exhibiting DNA of high-risk HPV in their tumor tissue, the same viral genome was also present in normal tissue. E6 and E7 expression was found in 9 of 14 tumoral biopsies tested for these markers. PMID- 23350598 TI - Treatment outcomes of closed reduction of arytenoid dislocation. AB - CONCLUSION: Closed reduction is an effective and safe treatment method for arytenoid dislocation. Early closed reduction of arytenoid cartilage plays an important role in voice recovery. OBJECTIVE: The study reviewed the clinical characteristics of arytenoid dislocation with the aim of identifying factors influencing voice recovery in the closed reduction of arytenoid dislocation. METHODS: A retrospective chart review was performed at Chonnam National University Hospital for the period from January 2007 to March 2012. RESULTS: Eleven patients with arytenoid dislocation were identified. The causes of arytenoid dislocation were intubation (n = 9) and blunt trauma (n = 2). All cases of arytenoid dislocations were treated by closed reduction. There were no major complications resulting from surgical intervention. Six of the 11 patients (54.5%) regained normal voice and vocal fold movement after closed reduction. Five patients (45.5%) had significant voice improvement postoperatively. In arytenoid dislocation due to blunt trauma, the duration between injury and voice improvement was much longer than in other causes of arytenoid dislocation (p = 0.012). PMID- 23350599 TI - Salvage transoral laser microsurgery for early recurrent glottic carcinoma after primary laser treatment. AB - CONCLUSION: Salvage transoral laser microsurgery (TLM) may be a curative organ preserving treatment for early recurrent glottic carcinoma after primary laser resection. However, failure after TLM seems to be associated with decrease of survival and larynx preservation rates. OBJECTIVE: To evaluate the oncological results of salvage TLM for early recurrent glottic carcinoma after primary laser treatment. METHODS: Records of 50 patients with local recurrences of glottic carcinoma treated by salvage TLM between January 1994 and December 2008 were retrospectively analyzed. RESULTS: Thirty-six rT1 and 14 rT2 lesions were treated with salvage TLM. Mean follow-up was 68.3 months. Thirty-one patients were cured by first salvage TLM and four by further laser procedures. The other 15 patients were finally salvaged by laryngectomy or radiotherapy. Five-year overall survival, disease-specific survival, local control, and loco-regional control rates were 89.9%, 97.9%, 62.3%, and 60.1%, respectively. Larynx preservation rate after long-term follow-up was 86%. In univariate analysis, second local recurrence showed a statistically significant impact on disease-specific survival rate ( p = 0.049) and larynx preservation rate ( p = 0.006). In multivariate analysis, it was associated with a statistically significant decrease in larynx preservation rate ( p = 0.016). There was no statistically significant difference in oncological results between patients with and without anterior commissure involvement. PMID- 23350600 TI - Cervical lymph node metastasis from early-stage squamous cell carcinoma of the oral tongue. AB - CONCLUSIONS: The findings of this study demonstrated that the wait-and-watch strategy for neck metastasis from squamous cell carcinoma (SCC) of oral tongue is a reliable option and that salvage by surgical treatment is effective. However, younger patients should be closely monitored for recurrence. Adjuvant therapy may be recommended for patients with pathologically advanced disease. OBJECTIVES: Metastatic involvement of cervical lymph nodes is the most important prognostic indicator in patients with oral tongue SCC. With the objective of determining the most appropriate treatment strategy for regional recurrence, we conducted a retrospective review of clinicopathologic factors. METHODS: The clinicopathologic features of 103 patients with oral tongue SCC, in whom the local lesions were treated successfully by low-dose interstitial brachytherapy (LD-IBT), but who subsequently developed cervical lymph node metastases and were treated by salvage surgery, were reviewed. RESULTS: In the patients who underwent surgical treatment at our hospital, 5-year disease-free survival and regional control rates were 69.3% and 85.3%, respectively. The clinicopathologic factors significantly associated with unfavorable disease-free survival were the presence of extracapsular spread (hazard ratio (HR) = 3.005, p = 0.045), multiple and large lymph nodes (HR = 2.850, p = 0.010 and HR = 3.112, p = 0.007, respectively), younger age (HR = 2.429, p = 0.048), and shorter interval from the LD-IBT to detection of neck metastasis (HR = 1.749, p = 0.013). PMID- 23350601 TI - BLOG 2.0: a software system for character-based species classification with DNA Barcode sequences. What it does, how to use it. AB - BLOG (Barcoding with LOGic) is a diagnostic and character-based DNA Barcode analysis method. Its aim is to classify specimens to species based on DNA Barcode sequences and on a supervised machine learning approach, using classification rules that compactly characterize species in terms of DNA Barcode locations of key diagnostic nucleotides. The BLOG 2.0 software, its fundamental modules, online/offline user interfaces and recent improvements are described. These improvements affect both methodology and software design, and lead to the availability of different releases on the website http://dmb.iasi.cnr.it/blog downloads.php. Previous and new experimental tests show that BLOG 2.0 outperforms previous versions as well as other DNA Barcode analysis methods. PMID- 23350602 TI - Specific detection and quantification of virulent/avirulent Phytophthora infestans isolates using a real-time PCR assay that targets polymorphisms of the Avr3a gene. AB - Molecular tools that allow intraspecific quantification and discrimination of pathogen isolates are useful to assess fitness of competitors during mixed infections. However, methods that were developed for quantifying Phytophthora infestans are only specific at the species level. Here, we reported a TaqMan based real-time PCR assay allowing, according to the specificity of the used probes, an accurate quantification of different proportions of two genetically distinct clones of P. infestans in mixed fractions. Indeed, in addition to a primer specific to P. infestans, two primers and two TaqMan((r)) probes that target single-nucleotide polymorphisms located in the Avr3a/avr3a virulence gene sequence were designed. The reliability of the method was tested on serially diluted fractions containing plasmid DNA with either the Avr3a or the avr3a sequences at concentrations ranging from 10(2) to 10(8) copies per MUl. Based on its specificity, sensitivity and repeatability, the proposed assay allowed a quantification of the targeted DNA sequence in fractions with a Avr3a/avr3a ratio in the range 1/99 to 99/1. The reliability of the test was also checked for counting zoospores. Applications for future research in P. infestans/host quantitative interactions were also discussed. PMID- 23350604 TI - Colonic inflammatory myofibroblastic tumours: an institutional review. AB - AIM: The aim of the study was to present the largest series of colonic inflammatory myofibroblastic tumour (C-IMFT) in the literature so far and to provide a review of this condition. METHOD: A retrospective review was carried out of a consecutive series of patients diagnosed with a C-IMFT at a community based hospital with a specialized gastrointestinal unit between 2002 and 2011. The main outcome measures were success rate and postoperative complications. Using a set of terms we searched the PubMed database for papers published on C IMFT. We reviewed the data from these studies and case reports. RESULTS: There were seven patients with a histopathologically proven C-IMFT. The patients' mean age was 39 +/- 11.3 years. Four presented with clinical features of intestinal obstruction of varying severity and three with symptoms of anaemia. Complete surgical resection with end-to-end anastomosis was performed. The gross morphology included polypoidal myxoid tumours that served as a lead point for intussusception in two cases, a whorled mass in two and a circumferential infiltrative tumour in three. Microscopically, all tumours had typical features of IMFT with a variable expression of anaplastic lymphoma kinase (ALK-1) and tumour-free resection margins. All patients were well without local recurrence or metastasis at a mean follow-up of 46.8 +/- 11.9 months. CONCLUSION: Surgical resection is effective for this rare tumour which mostly behaves in a benign manner. Our review supports the need for patients to be followed up for long periods because of the possibility of metastasis or late recurrence. PMID- 23350603 TI - The cysteine dioxgenase knockout mouse: altered cysteine metabolism in nonhepatic tissues leads to excess H2S/HS(-) production and evidence of pancreatic and lung toxicity. AB - AIMS: To define the consequences of loss of cysteine dioxygenase (CDO) on cysteine metabolism at the tissue level, we determined levels of relevant metabolites and enzymes and evidence of H2S/HS(-) (gaseous hydrogen sulfide and its conjugate base) toxicity in liver, pancreas, kidney, and lung of CDO(-/-) mice that were fed either a taurine-free or taurine-supplemented diet. RESULTS: CDO(-/-) mice had low tissue and serum taurine and hypotaurine levels and high tissue levels of cysteine, consistent with the loss of CDO. CDO(-/-) mice had elevated urinary excretion of thiosulfate, high tissue and serum cystathionine and lanthionine levels, and evidence of inhibition and destabilization of cytochrome c oxidase, which is consistent with excess production of H2S/HS(-). Accumulation of cystathionine and lanthionine appeared to result from cystathionine beta-synthase (CBS)-mediated cysteine desulfhydration. Very high levels of hypotaurine in pancreas of wild-type mice and very high levels of cystathionine and lanthionine in pancreas of CDO(-/-) mice were observed, suggesting a unique cysteine metabolism in the pancreas. INNOVATION: The CDO(-/-) mouse model provides new insights into tissue-specific cysteine metabolism, particularly the role of pancreas in metabolism of excess cysteine by CBS catalyzed reactions, and will be a useful model for studying the effects of excess endogenous production of H2S/HS(-). CONCLUSION: The CDO(-/-) mouse clearly demonstrates that H2S/HS(-) production in tissues can exceed the capacity of the animal to oxidize sulfide to sulfate and demonstrates that pancreas and lung are more susceptible to toxicity from endogenous H2S/HS(-)production than are liver and kidney. PMID- 23350605 TI - Diversity and cold adaptation of culturable endophytic fungi from bryophytes in the Fildes Region, King George Island, maritime Antarctica. AB - Endophytic fungi associated with three bryophyte species in the Fildes Region, King George Island, maritime Antarctica, that is, the liverwort Barbilophozia hatcheri, the mosses Chorisodontium aciphyllum and Sanionia uncinata, were studied by culture-dependent method. A total of 128 endophytic fungi were isolated from 1329 tissue segments of 14 samples. The colonization rate of endophytic fungi in three bryophytes species were 12.3%, 12.1%, and 8.7%, respectively. These isolates were identified to 21 taxa, with 15 Ascomycota, 5 Basidiomycota, and 1 unidentified fungus, based on morphological characteristics and sequence analyses of ITS region and D1/D2 domain. The dominant fungal endophyte was Hyaloscyphaceae sp. in B. hatcheri, Rhizoscyphus sp. in C. aciphyllum, and one unidentified fungus in S. uncinata; and their relative frequencies were 33.3%, 32.1%, and 80.0%, respectively. Furthermore, different Shannon-Weiner diversity indices (0.91-1.99) for endophytic fungi and low endophytic fungal composition similarities (0.19-0.40) were found in three bryophyte species. Growth temperature tests indicated that 21 taxa belong to psychrophiles (9), psychrotrophs (11), and mesophile (1). The results herein demonstrate that the Antarctic bryophytes are an interesting source of fungal endophytes and the endophytic fungal composition is different among the bryophyte species, and suggest that these fungal endophytes are adapted to cold stress in Antarctica. PMID- 23350606 TI - Predicting saturated fat consumption: exploring the role of subjective well being. AB - Consumption of saturated fat (SF) is associated with obesity, cardiovascular disease and cancer; which are among the leading causes of death in Australia and worldwide. A causal relationship between subjective well-being and positive health outcomes has been established, although few studies have specifically focused on health-enhancing or health-risk behaviours. The aim of this research was to develop an improved understanding of the processes underlying SF consumption by exploring the relationship between subjective well-being and SF consumption, within the Theory of Planned Behaviour framework. Questionnaires related to the TPB variables, subjective well-being and SF intake were administered online to 96 participants. Perceived behavioural control (PBC) was found to be a significant predictor of intention to limit SF intake. Intention and PBC accounted for 25% of variance in behaviour; with PBC the only significant predictor of SF consumption. While subjective well-being variables were not significant unique predictors of SF consumption, these variables contributed an additional 2% to the prediction of behaviour, and this model was significant. The addition of subjective well-being to the TPB is novel and the results partially support the potential of subjective well-being in improving the prediction of this health-risk behaviour. Future research will need to replicate and extend these preliminary findings before such a framework may be translated into an intervention targeting SF consumption. PMID- 23350607 TI - Effect of sheet morphology on the scalability of graphene-based ultracapacitors. AB - Graphene is considered a promising ultracapacitor material toward high power and energy density because of its high conductivity and high surface area without pore tortuosity. However, the two-dimensional (2D) sheets tend to aggregate during the electrode fabrication process and align perpendicular to the flow direction of electrons and ions, which can reduce the available surface area and limit the electron and ion transport. This makes it hard to achieve scalable device performance as the loading level of the active material increases. Here, we report a strategy to solve these problems by transforming the 2D graphene sheet into a crumpled paper ball structure. Compared to flat or wrinkled sheets, the crumpled graphene balls can deliver much higher specific capacitance and better rate performance. More importantly, devices made with crumpled graphene balls are significantly less dependent on the electrode mass loading. Performance of graphene-based ultracapacitors can be further enhanced by using flat graphene sheets as the binder for the crumpled graphene balls, thus eliminating the need for less active binder materials. PMID- 23350608 TI - Photoinduced electron transfer facilitates tautomerization of the conserved signaling glutamine side chain in BLUF protein light sensors. AB - The BLUF domain (sensor of blue light using flavin adenine dinucleotide) from a bacterial photoreceptor protein AppA undergoes a cascade of chemical transformations, including hydrogen bond rearrangements around the flavin adenine dinucleotide (FAD) chromophore, in response to light illumination. These transformations are initiated by photoinduced electron and proton transfer from a tyrosine residue to the photoexcited flavin which is assisted by a glutamine residue. According to the recent studies, the proton-coupled electron transfer leads to formation of a radical-pair intermediate Tyr*...FADH* and a tautomeric EE form of glutamine in the ground electronic state. This intermediate is a precursor of the light-induced state of the BLUF photoreceptor implicated in biological signaling. In order to describe evolution of the radical pair, we computed reaction pathways on the ground state potential energy surface employing quantum-chemical calculations in the DFT PBE0/cc-pVDZ approximation for a molecular cluster mimicking the chromophore containing pocket of the AppA BLUF protein. We found a minimum-energy pathway comprised of the following consecutive reaction steps: (1) rotation of the imidic group of the EE glutamine side chain around the Cgamma-Cdelta bond; (2) flip of the OepsilonH group and formation of the ZE form of the glutamine side chain; and (3) biradical recombination via coupled proton and electron transfer, leading to the ZZ form of the glutamine side chain. The potential-energy barriers for stages 1-3 do not exceed 9 kcal/mol. Energy barrier 3 describing the ZE to ZZ glutamine tautomerization is significantly smaller in the BLUF model than in isolated glutamine, since tautomerization in BLUF is facilitated by electron transfer and radical recombination. Thus, our study shows that tautomerization of the conserved glutamine is coupled to the light-induced electron transfer process in BLUF and, thus, is a viable candidate for the photoactivation mechanism which at present is very much debated. PMID- 23350609 TI - Factors contributing to inconsistent condom use among heterosexual men in Curacao. AB - This study explored, from a public health perspective, factors that contribute to inconsistent condom use by men in Curacao through semi-structured face-to-face interviews with 21 heterosexual men. The findings show that there is an important disconnect between what is considered culturally appropriate sexual behaviour for men and women and condom use, that diverging from prescribed notions of masculinity and femininity in order to use condoms consistently is difficult, and that condom use is particularly problematic in the context of concurrent partnerships and sexual economic exchanges. Participants further reported that Caribbean family structures, whereby mothers assume the role as primary caregiver and fathers contribute biologically but, to a much lesser extent socially, also have an impact on condom use. Additionally, consistent condom use was reported to be impeded by a cultural taboo on talking seriously about sex and sexual health. In their totality, findings provide important input from men for the development of sexual health promotion interventions that are cognizant of the cultural context in which inconsistent condom use occurs, and that are geared not only to the individual level but also to the interpersonal and structural levels. PMID- 23350610 TI - Can peritoneal dialysis be used in preterm infants with congenital diaphragmatic hernia? AB - Peritoneal dialysis (PD) is considered as the most common form of renal replacement therapy for newborns including preterms with acute kidney injury (AKI). Although there are several reports describing successful PD performed for AKI in preterm infants, there is no data describing the use of PD to treat AKI in preterm newborns with congenital diaphragmatic hernia (CDH), which is one of the contraindications for PD. We present a preterm newborn with CDH, truncus arteriosus and AKI treated with PD and emphasize that PD may be successfully performed with caution even in cases of contraindications when other renal replacement therapies cannot be used. PMID- 23350611 TI - Fused dithienogermolodithiophene low band gap polymers for high-performance organic solar cells without processing additives. AB - We report the synthesis of a novel ladder-type fused ring donor, dithienogermolodithiophene, in which two thieno[3,2-b]thiophene units are held coplanar by a bridging dialkyl germanium. Polymerization of this extended monomer with N-octylthienopyrrolodione by Stille polycondensation afforded a polymer, pDTTG-TPD, with an optical band gap of 1.75 eV combined with a high ionization potential. Bulk heterojunction solar cells based upon pDTTG-TPD:PC(71)BM blends afforded efficiencies up to 7.2% without the need for thermal annealing or processing additives. PMID- 23350612 TI - Conventional and unconventional cardiovascular risk factors in men with erectile dysfunction. PMID- 23350613 TI - A national network to advance the field of cancer and female sexuality. AB - INTRODUCTION: Understanding sexual health issues in cancer patients is integral to care for the continuously growing cancer survivor population. AIM: To create a national network of active clinicians and researchers focusing on the prevention and treatment of sexual problems in women and girls with cancer. METHODS: Interdisciplinary teams from the University of Chicago and Memorial Sloan Kettering Cancer Center jointly developed the mission for a national conference to convene clinicians and researchers in the field of cancer and female sexuality. The invitee list was developed by both institutions and further iterated through suggestions from invitees. The conference agenda focused on three high-priority topics under the guidance of a professional facilitator. Breakout groups were led by attendees recognized by collaborators as experts in those topics. Conference costs were shared by both institutions. MAIN OUTCOME MEASURE: Development of Scientific Working Groups (SWGs). RESULTS: One hundred two clinicians and researchers were invited to attend the 1st National Conference on Cancer and Female Sexuality. Forty-three individuals from 20 different institutions across 14 states attended, including representation from eight National Cancer Institute (NCI)-funded cancer centers. Attendees included PhD researchers (N = 19), physicians (N = 16), and other healthcare professionals (N = 8). Breakout groups included (i) Defining key life course sexuality issues; (ii) Building a registry; and (iii) Implementing sexual health assessment. Breakout group summaries incorporated group consensus on key points and priorities. These generated six SWGs with volunteer leaders to accelerate future research and discovery: (i) Technology-based interventions; (ii) Basic science; (iii) Clinical trials; (iv) Registries; (v) Measurement; and (vi) Secondary data analysis. Most attendees volunteered for at least one SWG (N = 35), and many volunteered for two (N = 21). CONCLUSION: This 1st National Conference demonstrated high motivation and broad participation to address research on cancer and female sexuality. Areas of need were identified, and SWGs established to help promote research in this field. PMID- 23350614 TI - Prenatal testing for Huntington's disease in the Netherlands from 1998 to 2008. AB - This study aims to give an overview of the number of prenatal tests for Huntington's disease (HD), test results, and pregnancy outcomes in the Netherlands between 1998 and 2008 and to compare them with available data from the period 1987 to 1997. A total of 126 couples underwent prenatal diagnosis (PND) on 216 foetuses: 185 (86%) direct tests and 31 (14%) exclusion tests. In 9% of direct tests the risk for the foetus was 25%. Four at-risk parents (4%) carried intermediate alleles. Ninety-one foetuses had CAG expansions >=36% or 50% risk haplotypes: 75 (82%) were terminated for HD, 12 (13%) were carried to term; four pregnancies were miscarried, terminated for other reasons or lost to follow up. Unaffected pregnancies (122 foetuses) resulted in the birth of 112 children. The estimated uptake of PND was 22% of CAG expansion carriers (>=36 repeats) at reproductive age. PND was used by two new subgroups: carriers of intermediate alleles and 50% at-risk persons opting for a direct prenatal test of the foetus. A significant number of HD expansion or 50% risk pregnancies were continued. Speculations were made on causative factors contributing to these continuations. Further research on these couples' motives is needed. PMID- 23350615 TI - A plant-specific in vitro ubiquitination analysis system. AB - Protein ubiquitination requires the concerted action of three enzymes: ubiquitin activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin ligase (E3). These ubiquitination enzymes belong to an abundant protein family that is encoded in all eukaryotic genomes. Describing their biochemical characteristics is an important part of their functional analysis. It has been recognized that various E2/E3 specificities exist, and that detection of E3 ubiquitination activity in vitro may depend on the recruitment of E2s. Here, we describe the development of an in vitro ubiquitination system based on proteins encoded by genes from Arabidopsis. It includes most varieties of Arabidopsis E2 proteins, which are tested with several RING-finger type E3 ligases. This system permits determination of E3 activity in combination with most of the E2 sub-groups that have been identified in the Arabidopsis genome. At the same time, E2/E3 specificities have also been explored. The components used in this system are all from plants, particularly Arabidopsis, making it very suitable for ubiquitination assays of plant proteins. Some E2 proteins that are not easily expressed in Escherichia coli were transiently expressed and purified from plants before use in ubiquitination assays. This system is also adaptable to proteins of species other than plants. In this system, we also analyzed two mutated forms of ubiquitin, K48R and K63R, to detect various types of ubiquitin conjugation. PMID- 23350616 TI - The complete mitochondrial genome of the hybrid of Ctenopharyngodon idella (?) * Squaliobarbus curriculus (?). AB - The complete mitochondrial genome sequence of the hybrid of Ctenopharyngodon idella (?) * Squaliobarbus curriculus (?) was determined using PCR-based method. The total length of the mitogenome is 16,609 bp. It contains the typical structure as that of most other vertebrates, including 2 ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes, and 1 non-coding control region (D loop region). The overall composition of the mitogenome was estimated to be 31.86% for A, 26.08% for T, 26.38% for C, and 15.68% for G, respectively, indicating that an A+T (57.94%)-rich feature occurs in the hybrid mitogenome. Both the termination-associated sequence and three conserved sequence blocks (CSB1, CSB2, and CSB3) were also detected in the D-loop region. PMID- 23350617 TI - Polycaprolactone for the correction of nasolabial folds: a 24-month, prospective, randomized, controlled clinical trial. AB - BACKGROUND: In this study, we examined two polycaprolactone (PCL)-based dermal filler formulas (PCL-1; PCL-2) for safety, patient satisfaction, likelihood to return, efficacy, and duration of correction. OBJECTIVE: This 40-patient, 24 month, prospective, randomized, controlled study evaluated the efficacy, safety, longevity, and volume of two PCL formulas for correction of nasolabial folds. METHODS: Patients enrolled in a medical clinic in Europe received two injections 1 month apart and returned at 3, 6, 9, 12, 15, 18, and 24 months for blinded patient evaluation using accepted aesthetic rating scales. RESULTS: At 12 months, the efficacy outcomes on Wrinkle Severity Rating Scale (WSRS) and Global Aesthetic Improvement Scale (GAIS) of PCL-1 and PCL-2 were consistently maintained, with sustained improvement in 90% and 91.4% of patients, respectively. At 24 months, PCL-2 was found to be more effective than PCL-1 with respect to GAIS and WSRS, showing sustained improvement for the entire 2-year study period (linear p = .52; quadratic p > .99). Patient satisfaction at 24 months was 72.4% for PCL-1 and 81.7% for PCL-2. Both products were found to be safe and well tolerated. CONCLUSIONS: PCL-1 and PCL-2 are safe and have sustained efficacy and high patient satisfaction, with PCL-2 demonstrating longer-lasting results than PCL-1. PMID- 23350618 TI - Prevalence of congenital heart disease at live birth: an accurate assessment by echocardiographic screening. AB - AIM: To determine the true prevalence of congenital heart disease (CHD) at live birth using echocardiographic screening. METHODS: A total of 5190 consecutive newborns from two secondary hospitals were included. Each neonate had a complete clinical evaluation with echocardiographic diagnosis at average 47 h of age. Newborns with persistent CHD underwent at least 4 months of follow-up, and the temporal trend of prevalence of mild CHD was assessed. RESULTS: Overall live birth prevalence of CHD was 26.60/00 (severe 3.50/00, moderate 5.40/00 and mild 17.70/00), and prevalence of CHD that could be detected by clinical evaluation was 12.10/00. The most common CHD was ventricular septal defect (VSD, 17.30/00), followed by atrial septal defect (ASD, 6.20/00), patent ductus arteriosus (PDA, 1.30/00), tetralogy of Fallot (TOF, 0.40/00), single ventricle (SV, 0.40/00), atrioventricular septal defect (AVSD, 0.20/00) and double outlet right ventricle (DORV, 0.20/00). Female predominance was observed in mild CHD (VSD, ASD), and male predominance was observed in severe CHD. The prevalence of CHD was reduced to 19.50/00 at the 4-month follow-up, which was largely caused by spontaneous closure rate of muscular VSD. CONCLUSION: Prevalence of CHD determined by echocardiography screening was higher but more accurate than that obtained from birth defect registries. PMID- 23350619 TI - Activatable cell penetrating peptide-conjugated nanoparticles with enhanced permeability for site-specific targeting delivery of anticancer drug. AB - Based on the powerful cell-penetrating ability of low molecular weight protamine (LMWP) and the overexpression of matrix metalloproteinases in the tumor sites, we constructed an activatable low molecular weight protamine (ALMWP) and modified it onto the surface of poly(ethylene glycol)-poly(lactic acid) nanoparticles to develop a "smart" drug delivery system with enhanced permeability for facilitating site-specific targeting delivery of anticancer drug. The obtained ALMWP-functionalized nanoparticles (ALMWP-NP) with a particle size of 134.0 +/- 4.59 nm and a zeta potential of -34.4 +/- 2.7 mV, exhibited an enhanced MMP dependent accumulation in HT-1080 cells via both energy-independent direct translocation and clathrin-mediated, cytoskeleton-dependent endocytosis. Pharmacokinetic and biodistribution study in HT-1080 tumor-bearing mice showed that ALMWP-NP significantly increased the accumulation of paclitaxel (PTX) in the tumor site but not the nontarget tissues. In addition, intratumor distribution analysis demonstrated that more ALMWP-NP penetrated deeply into the tumor parenchyma. As a result, PTX loaded by ALMWP-NP exhibited improved antitumor efficacy over that by unmodified nanoparticles and LMWP-functionalized nanoparticles. The findings suggested that ALMWP-NP could be used as a safe and effective tumor-targeting drug delivery system and opened a new gateway to the application of cell-penetrating peptides for targeted antitumor therapy. PMID- 23350620 TI - Copper-catalyzed enantioselective allyl-allyl cross-coupling. AB - A Cu(I)-phosphoramidite-based catalytic system that allows asymmetric allyl-allyl cross-coupling with high enantioselectivity is reported. This transformation tolerates a large variety of functionalized substrates. The versatility of this new reaction is illustrated in the catalytic asymmetric synthesis of the Martinelline alkaloids chromene derivative core. PMID- 23350621 TI - Leptin levels and adipose tissue percentage in adolescents with polycystic ovary syndrome. AB - The main purpose of the research is to compare serum leptin (Lep) levels and adipose tissue percentage in adolescents diagnosed with polycystic ovary syndrome (PCOS) and those in healthy subjects. The results showed a greater percentage of patients with increased adipose tissue and significantly higher serum Lep levels in the PCOS group compared to the healthy controls. It was proved that there is a correlation between Lep and body mass index, body adipose tissue, waist circumference and HOMA index. PCOS in adolescents is a condition related to highly predominant overweight and obesity with exceeding level of body adipose tissue and higher serum Lep levels compared to healthy age-matched controls. PMID- 23350622 TI - Maternal depressive symptoms predict acute hospitalization among children with type 1 diabetes. AB - OBJECTIVES: The aim of this study is to examine the impact of a mother's depressive symptoms on the risk of hospital admission of her child due to severe hypoglycemia or diabetic ketoacidosis. MATERIALS AND METHODS: One hundred sixty six mothers of children with type 1 diabetes (T1DM) were evaluated using the Hamilton Depression Rating Scale (HDRS). All of the children were studied prospectively for acute diabetic complications. The optimal thresholds of HDRS mother's scores for prediction of the risk of child hospitalization were identified using the Receiver Operating Characteristic curve analysis. The time to hospital admissions were compared using the log-rank test for univariate and Cox's proportional hazard models for multivariate analysis of risk factors for hospitalization. RESULTS: At study entry age, diabetes duration and glycated hemoglobin (HbA1c) of the children equaled 13.5 +/- 2.6 years, 4.1 +/- 1.9 years and 7.8 +/- 1.7%, respectively. Throughout the observation period 56 patients required at least one hospitalization due to acute complications. Median time of observation and time to the hospital admission were 46.3 [interquartile range (IQR) 32.2-57.7] and 13.2 (IQR 6.6-20.0) months, respectively. The best cutoff value of maternal depression in HDRS predictive for the risk of child hospitalization was above 12 points. The hazard ratio for hospitalization offered by the cutoff score for mother's depressive symptoms above threshold was 2.73 (95% confidence interval: 1.39-5.36). CONCLUSION: Children with T1DM whose mothers show high level of depressive symptoms are at an elevated risk for hospitalization due to acute diabetic complication. PMID- 23350624 TI - Combined osteotome-induced ridge expansion and guided bone regeneration simultaneous with implant placement: a biometric study. AB - PURPOSE: To evaluate the long-term outcome of a single-step ridge expansion osteotome procedure and implant placement combined with guided bone regeneration in patients presenting narrow maxillary alveolar ridges. MATERIALS AND METHODS: During the period 1999 to 2010, 41 patients aged 19 to 77 years (18 males; 23 females) suffering from partial or full edentulism associated with horizontal resorption of the maxillary ridges (2.5-5 mm) were treated using the combined ridge expansion and guided bone-regeneration techniques to obtain an improved bony base for implant placement. Implant survival, bone width measurements, clinical and radiologic implant success, and clinical complications were recorded and analyzed. RESULTS: Achievement of primary stability of the implant was impossible at six sites; these were recorded as failures. In the remaining 35 patients, one hundred sixteen endosseous titanium implants were simultaneously placed. Follow-up time varied between 6 and 144 months (mean 52.4); of these, 36% were followed up for periods of time longer than 60 months. Implant diameter and lengths varied between 3.3 to 4.8 and 12 to 16 mm, respectively. In the 35 successful procedures (one hundred sixteen implants), the overall implant survival rate was 100%. An average gain in ridge width was 3.5 +/- 0.93 (p < .0001) and an average enlargement of the buccal bone was 1.91 +/- 0.6 (p < .0001). The mean vertical mesial bone loss was 1.81 mm +/- 1.07 (ranging from 0.3 to 4.2 mm), and the mean vertical distal bone loss was 1.74 mm +/- 1.12 (ranging from 0.4 to 4.5 mm). In eight patients (32%), at least one implant presented bone loss of >=3 mm. CONCLUSIONS: Within the limitations of this study, we suggest that the combined osteotome-induced ridge expansion and guided bone regeneration simultaneous with implant placement is a reliable procedure with reduced morbidity and may offer an alternative in suitable situations. PMID- 23350626 TI - Supplemental description of Myxobolus squamalis (Myxozoa). AB - Myxobolus squamalis is a myxozoan skin parasite first reported from rainbow trout (Oncorhynchus mykiss). Identification of the parasite based on myxospore morphology is unreliable because M. squamalis is similar to several other myxobolids that share host species and geographic ranges. The only ssrRNA gene sequence available for M. squamalis is from Chinook salmon, Oncorhynchus tschawytscha, but these data are not linked with any information on spore morphology. Here we provide a supplemental description of M. squamalis from its type host, O. mykiss, using myxospore morphology, morphometry, and ssrRNA gene sequence data. Our ssrRNA sequence data were only 78% similar to the GenBank M. squamalis sequence from Chinook salmon, which raises the possibility of misidentification. We suggest that Chinook salmon are not a host of the parasite, as no infections were found in current stocks or in >30 yr of historical data from hatchery fish held in waters that harbored M. squamalis in rainbow trout, and we could find no well-identified report of M. squamalis from Chinook salmon. Our complementary morphological and molecular data sets will facilitate unambiguous future identification of M. squamalis. PMID- 23350627 TI - Photocatalytic properties of graphdiyne and graphene modified TiO2: from theory to experiment. AB - The chemical structure and electronic properties of two-dimensional (2D) carbon supported TiO2, TiO2-graphdiyne, and TiO2-graphene composites have been studied by first-principles density functional theory. Calculation results show that TiO2(001)-graphdiyne composites possess superior charge separation and oxidation properties, having the longest lifetimes of photoexcited carriers among all of the 2D composites containing TiO2 of different facets. Our experimental results further proved that TiO2(001)-graphdiyne composites could be a promising photocatalyst. For photocatalytic degradation of methylene blue, the rate constant of the TiO2(001)-graphdiyne composite is 1.63 +/- 0.15 times that of the pure TiO2(001) and 1.27 +/- 0.12 times that of the TiO2(001)-graphene composite. PMID- 23350625 TI - Regulation of cell death by transfer RNA. AB - SIGNIFICANCE: Both transfer RNA (tRNA) and cytochrome c are essential molecules for the survival of cells. tRNA decodes mRNA codons into amino-acid-building blocks in protein in all organisms, whereas cytochrome c functions in the electron transport chain that powers ATP synthesis in mitochondrion-containing eukaryotes. Additionally, in vertebrates, cytochrome c that is released from mitochondria is a potent inducer of apoptosis, activating apoptotic proteins (caspases) in the cytoplasm to dismantle cells. A better understanding of both tRNA and cytochrome c is essential for an insight into the regulation of cell life and death. RECENT ADVANCES: A recent study showed that the mitochondrion released cytochrome c can be removed from the cell-death pathway by tRNA molecules. The direct binding of cytochrome c by tRNA provides a mechanism for tRNA to regulate cell death, beyond its role in gene expression. CRITICAL ISSUES: The nature of the tRNA-cytochrome c binding interaction remains unknown. The questions of how this interaction affects tRNA function, cellular metabolism, and apoptotic sensitivity are unanswered. FUTURE DIRECTIONS: Investigations into the critical issues raised above will improve the understanding of tRNA in the fundamental processes of cell death and metabolism. Such knowledge will inform therapies in cell death-related diseases. PMID- 23350628 TI - Mechanistic insights into amplification of specific ion effect in water nonaqueous solvent mixtures. AB - Ethylene glycol (EG) and hydrogen peroxide (H2O2) can act as both hydrogen-bond donors and acceptors in the formation of solvent complexes with water molecules. In the present work, we have systematically investigated the ion-specific lower critical solution temperature (LCST) behavior of poly(N-isopropylacrylamide) (PNIPAM) in H2O-EG and H2O-H2O2 mixtures. The results obtained from turbidity measurements show that the specific anion effect is amplified with the increasing molar fraction of EG (x(EG)) but is independent of the molar fraction of H2O2 (x(H2O2)). The studies of Raman spectra and differential scanning calorimetry indicate that the discrepancy in amplification of specific anion effect between H2O-EG and H2O-H2O2 mixtures is due to the difference in the anion-solvent complex interactions rather than the anion-polymer or solvent-polymer interactions. On the other hand, the specific cation effect can also be amplified with the increasing x(EG) but changes only slightly with the x(H2O2). The discrepancy in amplification of specific cation effect between the two types of solvent mixtures is attributed to the difference in the solvent-polymer interactions. PMID- 23350629 TI - In vitro antimicrobial activity of pistachio (Pistacia vera L.) polyphenols. AB - We investigated the antimicrobial properties of polyphenol-rich fractions derived from raw shelled and roasted salted pistachios. American Type Culture Collection (ATCC), food and clinical isolates, of Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Pseudomonas mirabilis), Gram-positive bacteria (Listeria monocytogenes, Enterococcus hirae, Enterococcus faecium, Bacillus subtilis, Staphylococcus epidermidis, Staphylococcus aureus), the yeasts Candida albicans and Candida parapsilosis and the fungus Aspergillus niger were used. Pistachio extracts were active against Gram-positive bacteria with a bactericidal effect observed against L. monocytogenes (ATCC strains and food isolates), S. aureus and MRSA clinical isolates. Extracts from raw shelled pistachios were more active than those from roasted salted pistachios. The bactericidal activity of pistachio extracts could be used to help control the growth of some microorganisms in foods to improve safety and may find application as a topical treatment for S. aureus. PMID- 23350631 TI - Self-assembled nanoscale DNA-porphyrin complex for artificial light harvesting. AB - Mimicking green plants' and bacteria's extraordinary ability to absorb a vast number of photons and harness their energy is a longstanding goal in artificial photosynthesis. Resonance energy transfer among donor dyes has been shown to play a crucial role on the overall transfer of energy in the natural systems. Here, we present artificial, self-assembled, light-harvesting complexes consisting of DNA scaffolds, intercalated YO-PRO-1 (YO) donor dyes and a porphyrin acceptor anchored to a lipid bilayer, conceptually mimicking the natural light-harvesting systems. A model system consisting of 39-mer duplex DNA in a linear wire configuration with the porphyrin attached in the middle of the wire is primarily investigated. Utilizing intercalated donor fluorophores to sensitize the excitation of the porphyrin acceptor, we obtain an effective absorption coefficient 12 times larger than for direct excitation of the porphyrin. On the basis of steady-state and time-resolved emission measurements and Markov chain simulations, we show that YO-to-YO resonance energy transfer substantially contributes to the overall flow of energy to the porphyrin. This increase is explained through energy migration along the wire allowing the excited state energy to transfer to positions closer to the porphyrin. The versatility of DNA as a structural material is demonstrated through the construction of a more complex, hexagonal, light-harvesting scaffold yielding further increase in the effective absorption coefficient. Our results show that, by using DNA as a scaffold, we are able to arrange chromophores on a nanometer scale and in this way facilitate the assembly of efficient light-harvesting systems. PMID- 23350630 TI - Nonsteady state oxygen transport in engineered tissue: implications for design. AB - Engineered tissue constructs are limited in size, and thus clinical relevance, when diffusion is the primary mode of oxygen transport. Understanding the extent of oxygen diffusion and cellular consumption is necessary for the design of engineered tissues, particularly those intended for implantation into hypoxic wound sites. This study presents a combined experimental and computation model to predict design constraints for cellularized fibrin tissues subjected to a step change in the oxygen concentration to simulate transplantation. Nonsteady state analysis of oxygen diffusion and consumption was used to estimate the diffusion coefficient of oxygen (mean+/-SD, 1.7*10(-9)+/-8.4*10(-11) m(2)/s) in fibrin hydrogels as well as the Michaelis-Menten parameters, Vmax (1.3*10(-17)+/-9.2*10( 19) mol.cell(-1).s(-1)), and Km (8.0*10(-3)+/-3.5*0(-3) mol/m(3)), of normal human lung fibroblasts. Nondimensionalization of the governing diffusion-reaction equation enabled the creation of a single dimensionless parameter, the Thiele modulus (phi), which encompasses the combined effects of oxygen diffusion, consumption, and tissue dimensions. Tissue thickness is the design parameter with the most pronounced influence on the distribution of oxygen within the system. Additionally, tissues designed such that phi<1 achieve a near spatially uniform and adequate oxygen concentration following the step change. Understanding and optimizing the Thiele modulus will improve the design of engineered tissue implants. PMID- 23350632 TI - Adjunctive treatment with lodenafil carbonate for erectile dysfunction in outpatients with schizophrenia and spectrum: a randomized, double-blind, crossover, placebo-controlled trial. AB - INTRODUCTION.: Evidence is accumulating to support the presence of erectile dysfunction in patients with schizophrenia. This dysregulation may be amenable to therapeutic intervention to improve adherence and quality of life of patients who suffer from schizophrenia and schizoaffective disorders. AIM.: We aimed to evaluate the use of adjunctive medication lodenafil for the treatment of erectile dysfunction in outpatients with schizophrenia and spectrum. METHODS.: The design was a randomized, double-blind, crossover, placebo-controlled trial with lodenafil and it was carried at the Schizophrenia Outpatients Program. MAIN OUTCOME MEASURES.: The measures used to assess sexual dysfunction were Arizona Sexual Experiences Scale (ASEX) and International Index of Erectile Function (IIEF). The Positive and Negative Syndrome Scale (PANSS) and the Quality of Life Scale (QLS) were also used. The measures included the levels of prolactin, estradiol, luteinizing hormone, sex hormone-binding globulin, free testosterone, and total testosterone at baseline and end point. Lodenafil and placebo pills were used by the patients for 16 weeks. RESULTS.: Fifty male outpatients fulfilled the criteria and 94% of the participants completed the study. Lodenafil and placebo produced improvement in ASEX, IIEF scale, PANSS, and QLS, and there was no statistical difference between lodenafil and placebo groups in all sexual domains in the results of PANSS and QLS and in the results of hormone levels. CONCLUSION.: These results indicate that both lodenafil and placebo were effective in the treatment of erectile dysfunction for schizophrenia. Placebo effect is very important in patients with schizophrenia and this study showed the importance of discussing sexuality and trying to treat these patients. Further studies designed to test treatments of erectile dysfunction in patients who suffer from schizophrenia are necessary. PMID- 23350633 TI - Survival of patients with Stage III colon cancer is improved in hereditary non polyposis colorectal cancer compared with sporadic cases. A Danish registry based study. AB - AIM: Patients with hereditary non-polyposis colorectal cancer (HNPCC) seem to have a better prognosis than those with sporadic colorectal cancer (CRC). The aim was to compare survival after Stage III CC in patients with HNPCC with those having sporadic CC. METHOD: A total of 230 patients with hereditary cancer from the Danish HNPCC Register and 3557 patients with sporadic CC from the Danish Colorectal Cancer Database, diagnosed during May 2001-December 2008, were included. HNPCC patients were classified according to mismatch repair mutation status and family pedigree. Sporadic cases had no known family history of cancer. Patient characteristics, geographical differences and survival data were analysed. RESULTS: The overall survival (OS) was better in HNPCC patients compared with sporadic CC after stratification for sex and age (P = 0.02; CI 1.04 1.7). The 5-year survival was 70% in HNPCC patients compared with 56% in sporadic CC (P < 0.001). No survival difference was found between HNPCC subgroups but a tendency to better OS was seen in patients with Lynch syndrome. No geographical differences in OS were found. The median follow-up was 3.9 (0-9.5) years for HNPCC vs 3.2 (0-9.6) years for sporadic CC. CONCLUSION: HNPCC patients with Stage III CC have a better OS compared with sporadic CC. No significant difference in OS was found within HNPCC subgroups. PMID- 23350634 TI - Mitochondrial DNA sequence of the hybrid of Squaliobarbus curriculus (?) * Ctenopharyngodon idella (?). AB - In this work, we reported the complete mitochondrial DNA sequence of the hybrid of Squaliobarbus curriculus (?) * Ctenopharyngodon idella (?), which was obtained by artificial hybridization. The total length of the mitochondrial genome is 16,616 bp, with the base composition of 31.15% A, 25.02% T, 27.66% C, and 16.17% G. It contains 2 ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes, and a major non-coding control region (D-loop region). The arrangement of these genes is the same as that found in the teleosts. All the protein initiation codons are ATG, except for COX1 that begins with GTG. The complete mitogenome of the hybrid of S. curriculus (?) * C. idella (?) provides an important data set for the study in genetic mechanism. PMID- 23350635 TI - CA-MRSA puerperal mastitis and breast abscess: a potential problem emerging in Europe with many unanswered questions. AB - Puerperal mastitis and breast abscess caused by community-acquired methicillin resistant Staphylococcus aureus (CA-MRSA) is a condition rarely described in Europe to date. We report and comment on a case of CA-MRSA puerperal breast abscess in a 22-year-old primiparous mother. This aetiology was suspected before the antibiotic susceptibility profile of the strain isolated from the abscess was known on account of a history of previous skin colonisation detected in her baby. Additionally, the most striking epidemiological and therapeutic aspects, potential consequences of cross-infection between mother and child, and infection control management of this entity are briefly reviewed and discussed. PMID- 23350636 TI - 'Did they think I would understand all that on my own?' A questionnaire study about sexuality with Swedish cancer patients. AB - This study investigates information about the sexual effects of cancer on patients, irrespective of age or diagnosis, in terms of fertility, sexual desire and sexual function. A quantitative study was conducted and the results are based on responses from 106 questionnaires. The results show that 48% of respondents had not received any information in the areas of inquiry. There was a difference between information wished for and provided, and the largest difference was in the question of whether sexual activity should be avoided. A significantly higher number of men than women received information about effects on fertility and sexual desire. The results also showed that information about sexuality needs to be taken into account to a greater extent than is presently being done. PMID- 23350637 TI - A coeliac child presenting with bleeding. PMID- 23350638 TI - The biomechanical properties of the skin. AB - BACKGROUND: The skin possesses unique biochemical properties that allow it to protect and conform to the body that it covers. Elements constituting the dermis collagen and elastin-primarily afford these properties. OBJECTIVES: To define these properties and explore their relevance with regard to aging skin and dermatologic surgery. MATERIALS AND METHODS: In the first part of this review, the determinants of mechanical properties of the skin will be outlined, through an extensive review of the literature. General physical properties that explain the behavior of skin will be defined, and diseases that manifest the extremes of those properties will be discussed. In the second half of this discussion, the surgical implications of skin biomechanics will be reviewed. RESULTS: Emphasis will be placed on understanding how dermatologic surgeons may optimally use skin properties to produce the best cosmetic and functional outcomes possible. CONCLUSION: Understanding of the biomechanical properties of skin is paramount to obtain the best cosmetic outcomes in dermatologic surgery. PMID- 23350639 TI - Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci. AB - Synaptopathies constitute a group of neurological diseases including autism spectrum disorders (ASD) and intellectual disability (ID). They have been associated with mutations in genes encoding proteins important for the formation and stabilization of synapses, such as SHANK1-3. Loss-of-function mutations in the SHANK genes have been identified in individuals with ASD and ID suggesting that other factors modify the neurological phenotype. We report a boy with severe ID, behavioral anomalies, and language impairment who carries a balanced de novo triple translocation 46,XY,t(11;17;19)(q13.3;q25.1;q13.42). The 11q13.3 breakpoint was found to disrupt the SHANK2 gene. The patient also carries copy number variations at 15q13.3 and 10q22.11 encompassing ARHGAP11B and two synaptic genes. The CHRNA7 gene encoding alpha7-nicotinic acetylcholine receptor subunit and the GPRIN2 gene encoding G-protein-regulated inducer of neurite growth 2 were duplicated. Co-occurrence of a de novo SHANK2 mutation and a CHRNA7 duplication in two reported patients with ASD and ID as well as in the patient with t(11;17;19), severe ID and behavior problems suggests convergence of these genes on a common synaptic pathway. Our results strengthen the oligogenic inheritance model and highlight the presence of a large effect mutation and modifier genes collectively determining phenotypic expression of the synaptopathy. PMID- 23350641 TI - Isolation, molecular characterization and antibiotic resistance of Shiga Toxin Producing Escherichia coli (STEC) from buffalo in India. AB - In total, 363 Escherichia coli were isolated from 165 faecal samples of healthy buffaloes in West Bengal, India. Twenty-four of these isolates (6.61%) were found to carry at least one gene characteristic for Shiga toxin-producing Escherichia coli (STEC). These STEC strains belonged to 13 different O-serogroups. The stx1 gene was present in 23 (95.8%) of total STEC isolates, whereas 20 (83.3%) STEC isolates carried the gene stx2. Twelve strains of E. coli (50% of total STEC isolates) possessed enterohaemolysin (ehxA) gene in combination with others. Fourteen (58.33%) isolates found to possess saa gene. However, no E. coli was detected harbouring gene for intimin protein (eaeA). Of 23 stx1 -positive isolates, seven (30.43%) were positive for genes of the stx1C subtype. Of the 20 isolates with the stx2 gene, 25% (5/20) possessed stx2C and 10% (2/20) possessed stx2d gene. The phylogenetic analysis after RAPD of STEC strains revealed six major clusters. The isolated STEC strains were resistant most frequently to erythromycin (95.83%), cephalothin (62.5%), amikacin (54.17%), kanamycin (45.83%) and gentamicin (41.67%) group of antibiotics. No ESBL-producing (blaCTXM , blaTEM , blaSHV ) or quinolone resistance gene (qnrA) was detected in the STEC isolates. PMID- 23350642 TI - Trihydroxamate siderophore-fluoroquinolone conjugates are selective sideromycin antibiotics that target Staphylococcus aureus. AB - Siderophores are multidentate iron(III) chelators used by bacteria for iron assimilation. Sideromycins, also called siderophore-antibiotic conjugates, are a unique subset of siderophores that enter bacterial cells via siderophore uptake pathways and deliver the toxic antibiotic in a "Trojan horse" fashion. Sideromycins represent a novel antibiotic delivery technology with untapped potential for developing sophisticated microbe-selective antibacterial agents that limit the emergence of bacterial resistance. The chemical synthesis of a series of mono-, bis-, and trihydroxamate sideromycins are described here along with their biological evaluation in antibacterial susceptibility assays. The linear hydroxamate siderophores used for the sideromycins in this study were derived from the ferrioxamine family and inspired by the naturally occurring salmycin sideromycins. The antibacterial agents used were a beta-lactam carbacepholosporin, Lorabid, and a fluoroquinolone, ciprofloxacin, chosen for the different locations of their biological targets, the periplasm (extracellular) and the cytoplasm (intracellular). The linear hydroxamate-based sideromycins were selectively toxic toward Gram-positive bacteria, especially Staphylococcus aureus SG511 (MIC = 1.0 MUM for the trihydroxamate-fluoroquinolone sideromycin). Siderophore-sideromycin competition assays demonstrated that only the fluoroquinolone sideromycins required membrane transport to reach their cytoplasmic biological target and that a trihydroxamate siderophore backbone was required for protein-mediated active transport of the sideromycins into S. aureus cells via siderophore uptake pathways. This work represents a comprehensive study of linear hydroxamate sideromycins and teaches how to build effective hydroxamate based sideromycins as Gram-positive selective antibiotic agents. PMID- 23350640 TI - PMEL: a pigment cell-specific model for functional amyloid formation. AB - PMEL is a pigment cell-specific protein responsible for the formation of fibrillar sheets within the pigment organelle, the melanosome. The fibrillar sheets serve as a template upon which melanins polymerize as they are synthesized. The PMEL fibrils are required for optimal pigment cell function, as animals that either lack PMEL expression or express mutant PMEL variants show varying degrees of hypopigmentation and pigment cell inviability. The PMEL fibrils have biophysical properties of amyloid, a protein fold that is frequently associated with neurodegenerative and other diseases. However, PMEL is one of a growing number of non-pathogenic amyloid proteins that contribute to the function of the cell and/or organism that produces them. Understanding how PMEL generates amyloid in a non-pathogenic manner might provide insights into how to avoid toxicity due to pathological amyloid formation. In this review, we summarize and reconcile data concerning the fate of PMEL from its site of synthesis in the endoplasmic reticulum to newly formed melanosomes and the role of distinct PMEL subdomains in trafficking and amyloid fibril formation. We then discuss how its progression through the secretory pathway into the endosomal system might allow for the regulated and non-toxic conversion of PMEL into an ordered amyloid polymer. PMID- 23350644 TI - The effect of different doses of vitamin D supplementation on insulin resistance during pregnancy. AB - Low serum vitamin D levels are correlated with insulin resistance during pregnancy. We have assessed the effects of different doses of vitamin D on insulin resistance during pregnancy. A randomized clinical trial was done on 120 women with a gestational age of less than 12 weeks. The women were divided into three groups randomly. Group A received 200 IU vitamin D daily, group B 50,000 IU vitamin D monthly and group C 50,000 IU vitamin D every 2 weeks from 12 weeks of pregnancy until delivery. The serum levels of fasting blood sugar (FBS), insulin, calcium and 25-hydroxyvitamin D were measured before and after intervention. We used the homeostatic model assessment of insulin resistance (HOMA-IR) as a surrogate measure of insulin resistance. The mean +/- standard deviation of serum 25-hydroxyvitamin D increased in group C from 7.3 +/- 5.9 to 34.1 +/- 11.5 ng/ml and in group B it increased from 7.3 +/- 5.3 to 27.23 +/- 10.7 ng/ml, but the level of vitamin D in group A increased from 8.3 +/- 7.8 to 17.7 +/- 9.3 ng/ml (p < 0.001). The mean differences of insulin and HOMA-IR before and after intervention in groups A and C were significant (p = 0.01, p = 0.02). This study has shown that supplementation of pregnant women with 50 000 IU vitamin D every 2 weeks improved insulin resistance significantly. PMID- 23350643 TI - A novel approach to monitoring pulmonary congestion in heart failure: initial animal and clinical experiences using remote dielectric sensing technology. AB - Despite current therapies and disease management approaches, rates of heart failure (HF) rehospitalization remain high. New tools are needed to assess preclinical (asymptomatic) pulmonary congestion to enable outpatient management. Hence, a novel monitoring system based on noninvasive remote dielectric sensing (ReDS) technology was developed. Validation of the ReDS technology was conducted in preclinical and clinical studies. In a porcine HF model, acute fluid overload followed by administration of diuretics were performed. Changes in ReDS values were correlated to serial computed tomographic (CT) assessments of lung fluid concentrations. In hospitalized decompensated HF patients, changes in ReDS values were correlated to net fluid balance changes. A nearly linear pattern between the changes in ReDS and CT fluid concentration values was observed in 6 discrete experiments (Intraclass correlation=0.95). Results from 24 patients demonstrated a reduction in ReDS values of 17.53%+/-11% throughout hospitalization, consistent with a reduction in pulmonary congestion. This finding strongly correlated with changes in net fluid balance (Pearson correlation=0.86; 95% confidence interval, 0.68-0.94; R(2) =0.74). These findings suggest that ReDS technology accurately quantifies lung fluid concentration and has potential for monitoring HF patients through hospitalization and possibly at home. PMID- 23350645 TI - Resilience in systemic lupus erythematosus. AB - Resilience (RS) concerns human beings' capacity to respond positively to adverse situations they face, enabling individuals to achieve, maintain, or recover physical or emotional health after devastating illness, losses, or other stressful situations. RS can be an important factor in health promotion. The aim of this study was to evaluate RS in patients with systemic lupus erythematosus (SLE). Forty-five SLE patients participated in this study and were evaluated by both Mini International Neuropsychiatric and Wagnild and Young scales. Of these, 8.9% had low RS (score < 121), 71% medium score (between 121 and 146), and 20% high RS (score > 146). Patients over 35 years of age had the highest scores on the RS scale and patients at risk of committing suicide presented the lowest RS scores, possibly due to high level of depression. Identifying risk and protective factors is important for developing psychological support strategies. PMID- 23350646 TI - Chondroitin sulfate, a major component of the perineuronal net, elicits inward currents, cell depolarization, and calcium transients by acting on AMPA and kainate receptors of hippocampal neurons. AB - Chondroitin sulfate (CS) proteoglycans (CSPGs) are the most abundant PGs of the brain extracellular matrix (ECM). Free CS could be released during ECM degradation and exert physiological functions; thus, we aimed to investigate the effects of CS on voltage- and current-clamped rat embryo hippocampal neurons in primary cultures. We found that CS elicited a whole-cell Na(+)-dependent inward current (ICS) that produced drastic cell depolarization, and a cytosolic calcium transient ([Ca(2+)]c). Those effects were similar to those elicited by alpha amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate, were completely blocked by NBQX and CNQX, were partially blocked by GYKI, and were unaffected by MK801 and D-APV. Furthermore, ICS and AMPA currents were similarly potentiated by cyclothiazide, a positive allosteric modulator of AMPA receptors. Because CSPGs have been attributed Ca(2) (+) -dependent roles, such as neural network development, axon pathfinding, plasticity and regeneration after CNS injury, CS action after ECM degradation could be contributing to the mediation of these effects through its interaction with AMPA and kainate receptors. PMID- 23350648 TI - Carbohydrate mimetics as potential drug candidates. PMID- 23350647 TI - Combined surgical therapy of advanced peri-implantitis lesions with concomitant soft tissue volume augmentation. A case series. AB - OBJECTIVES: Mucosal recessions are a common finding following surgical treatment of peri-implantitis, thus compromising the overall esthetic outcome of implant therapy. This case series aimed at evaluating the clinical outcome of a combined surgical therapy of advanced peri-implantitis lesions with concomitant soft tissue volume augmentation. MATERIAL AND METHODS: Ten patients (n = 13 implants exhibiting combined supra- and intrabony defects) underwent access flap surgery, implantoplasty at bucally and supracrestally exposed implant parts, and augmentation of the intrabony components using a natural bone mineral and a native collagen membrane after surface decontamination. A subepithelial connective tissue graft was harvested from the palate and adapted to the wound area to support transmucosal healing. Clinical parameters (i.e. bleeding on probing--BOP; probing depths--PD; mucosal recession--MR; clinical attachment level--CAL) were recorded at baseline and after 6 months. RESULTS: At 6 months, the combined surgical procedure was associated with a significant reduction in mean BOP (74.39 +/- 28.52%), PD (2.53 +/- 1.80 mm), and CAL (2.07 +/- 1.93 mm) values. Site-level analysis has pointed to a slight increase in mean mucosal height (0.07 +/- 0.5 mm) at the buccal aspects (i.e. mb, b, db). CONCLUSION: The combined surgical procedure investigated may be effective in controlling advanced peri-implantitis lesions without compromising the overall esthetic outcome in the short term. PMID- 23350649 TI - Two ABC transporter systems participate in siderophore transport in the marine pathogen Vibrio anguillarum 775 (pJM1). AB - ORF40 (named fatE) in the Vibrio anguillarum pJM1 plasmid-encoding anguibactin iron transport systems is a homolog of ATPase genes involved in ferric siderophore transport. Mutation of fatE did not affect ferric-anguibactin transport, indicating that there must be other ATPase gene(s) in addition to fatE. By searching the genomic sequence of V. anguillarum 775(pJM1), we identified a homolog of fatE named fvtE on chromosome 2. It is of interest that in this locus, we also identified homologs of fatB, fatC, and fatD that we named fvtB, fvtC and fvtD, respectively. The fvtE mutant still showed ferric anguibactin transport, while the double fatE and fvtE mutation completely abolished the ferric-anguibactin transport indicating that fatE and fvtE are functional ATPase homologs for ferric-anguibactin transport. Furthermore, we demonstrate that fvtB, fvtC, fvtD, and fvtE are essential for ferric vanchrobactin and ferric-enterobactin transport. PMID- 23350651 TI - Synthesis of long T1 silicon nanoparticles for hyperpolarized 29Si magnetic resonance imaging. AB - We describe the synthesis, materials characterization, and dynamic nuclear polarization (DNP) of amorphous and crystalline silicon nanoparticles for use as hyperpolarized magnetic resonance imaging (MRI) agents. The particles were synthesized by means of a metathesis reaction between sodium silicide (Na4Si4) and silicon tetrachloride (SiCl4) and were surface functionalized with a variety of passivating ligands. The synthesis scheme results in particles of diameter ~10 nm with long size-adjusted 29Si spin-lattice relaxation (T1) times (>600 s), which are retained after hyperpolarization by low-temperature DNP. PMID- 23350650 TI - Frataxin deficiency leads to defects in expression of antioxidants and Nrf2 expression in dorsal root ganglia of the Friedreich's ataxia YG8R mouse model. AB - AIMS: Oxidative stress is thought to be involved in Friedreich's ataxia (FRDA), yet it has not been demonstrated in the target neurons that are first to degenerate. Using the YG8R mouse model of FRDA, microarray and neuritic growth experiments were carried out in the dorsal root ganglion (DRG), the primary site of neurodegeneration in this disease. RESULTS: YG8R hemizygous mice exhibited defects in movement, and DRG neurites had growth defects. Microarray of DRG tissue identified decreased transcripts encoding the antioxidants, including peroxiredoxins, glutaredoxins, and glutathione S-transferase, and these were confirmed by immunoblots and quantitative real-time PCR. Because the decreased gene transcripts are the known targets of the antioxidant transcription factor nuclear factor-E2-related factor-2 (Nrf2), Nrf2 expression was measured; it was significantly decreased at the transcript and protein level in both the DRG and the cerebella of the YG8R hemizygous mouse; further, frataxin expression was significantly correlated with Nrf2 expression. Functionally, in YG8R hemizygous DRG, the total glutathione levels were reduced and explanted cells were more sensitive to the thioredoxin reductase (TxnRD) inhibitor auranofin, a thiol oxidant. In cell models of FRDA, including Schwann and the DRG, frataxin deficiency caused a decreased expression of the Nrf2 protein level in the nucleus, but not a defect in its translocation from the cytosol. Further, frataxin-deficient cells had decreased enzyme activity and expression of TxnRD, which is regulated by Nrf2, and were sensitive the TxnRD inhibitor auranofin. INNOVATION AND CONCLUSION: These results support a mechanistic hypothesis in which frataxin deficiency decreases Nrf2 expression in vivo, causing the sensitivity to oxidative stress in target tissues the DRG and the cerebella, which contributes to the process of neurodegeneration. PMID- 23350652 TI - Permanent neonatal diabetes due to a novel insulin signal peptide mutation. AB - We report a rare case of permanent neonatal diabetes (PND) due to insulin (INS) gene mutation in a 51-month-old girl who presented with hyperglycemia in the neonatal period. Mutational analysis of KCNJ11 and INS was performed and this detected a novel heterozygous c.38T>G (p.Leu13Arg) INS de novo mutation. The non conservative change substitutes the highly conserved L(13) residue within the hydrophobic core region of the preproinsulin signal peptide. Given the frequent tendency of heterozygous INS mutations to exhibit dominant negative disease pathogenesis, it is likely that the mutant preproinsulin perturbed the non-mutant counterpart progression and processing within the beta-cells, and this resulted to a permanent form of congenital diabetes. PMID- 23350653 TI - Type 2 congenital pulmonary airway malformation and congenital nephrotic syndrome: report of a new association. AB - Type 2 congenital pulmonary airway malformation (CPAM) has been reported in association with many other congenital anomalies. To the best of our knowledge, however, an association of type 2 CPAM with congenital nephrotic syndrome has not been heretofore reported. We present the 1st report of such an association in a boy who had a prenatal diagnosis of cystic lung malformation and was found to have congenital nephrotic syndrome (diffuse mesangial sclerosis) at 1 month of age. A prenatal ultrasonogram had also shown oligohydramnios, and additionally the child had cleft lip and palate. There was no family history of childhood renal or pulmonary disease, and genetic testing for genes mutated in congenital nephrotic syndrome was negative. PMID- 23350655 TI - Gene expression patterns of vascular endothelial growth factor (VEGF-A) in human placenta from pregnancies with intrauterine growth restriction. AB - OBJECTIVE: In this study, we describe changes in gene expression pattern of vascular endothelial growth factor (VEGF)-A in human placenta obtained from pregnancies with intrauterine growth restriction using placenta from normal pregnancies as control. METHODS: We compared gene expression of VEGF-A in placental samples from Intrauterine growth restriction (IUGR) pregnancies versus placenta obtained from normal pregnancies. Among potential confounders, important clinical informations were also analyzed. RESULTS: In the IUGR group, the VEGF-A gene was overexpressed compared to the normal pregnancy group (Ln 2(alpha)beta actin: 1.32; Ln 2(alpha)GADPH: 1.56). There was no correlation between the degree of growth restriction and VEGF-A gene expression (Ln 2(alpha)(0-5)percentile: 0.58; Ln 2(alpha)(5-10)percentile: 0.64). Within the IUGR group, there was a trend toward a positive correlation between placental VEGF-A gene activity and gestational age at delivery (Ln 2(alpha)< 33 weeks: 1.09; Ln 2(alpha)33-37 weeks: 1.27; Ln 2(alpha)> 37 weeks: 1.35). CONCLUSIONS: Our findings suggest that the increase in placental expression of the VEGF-A gene and the resultant stimulation of angiogenesis are a response to hypoxic environment developing in the placental tissue in IUGR. Thus, it appears to be a secondary event rather than a primary factor in the development of IUGR There is a trend toward a positive correlation between gestational age and placental VEGF-A gene activity. PMID- 23350656 TI - 'Living under assault': men making sense of cancer. AB - In accepting illness as a subjective experience, there is value in examining how individuals perceive, interpret and understand its challenges, knowledge critical to understanding patterns of response. Although researchers have considered how prostate cancer can challenge 'embodied masculinities' few studies have considered gendered dynamics in men's cancer experiences more broadly. This article helps attends to this gap by examining how men with a variety of cancers made sense of the challenges of their illness. The results, part of a grounded theory study including 30 Canadian adult men, highlight how the men perceived a troubled future and a discordant present, a profound sense of uncertainty, and feelings of isolation. These patterns, infused with societal expectations for male bodies and lives, move beyond the particular needs varying by medical, demographic and situational diversities. More specifically, they are recognised as consistent with a 'biographical disruption' or an ongoing problematic situation destabilising how the men made sense of their individual selves and the world around them. Focused on commonalities and considerate of diversities, findings are reviewed in relation to existing work on illness and gender identity and work specific to men with cancer. Implications are discussed. PMID- 23350654 TI - Aromatic sulfonyl fluorides covalently kinetically stabilize transthyretin to prevent amyloidogenesis while affording a fluorescent conjugate. AB - Molecules that bind selectively to a given protein and then undergo a rapid chemoselective reaction to form a covalent conjugate have utility in drug development. Herein a library of 1,3,4-oxadiazoles substituted at the 2 position with an aryl sulfonyl fluoride and at the 5 position with a substituted aryl known to have high affinity for the inner thyroxine binding subsite of transthyretin (TTR) was conceived of by structure-based design principles and was chemically synthesized. When bound in the thyroxine binding site, most of the aryl sulfonyl fluorides react rapidly and chemoselectively with the pKa-perturbed K15 residue, kinetically stabilizing TTR and thus preventing amyloid fibril formation, known to cause polyneuropathy. Conjugation t50s range from 1 to 4 min, ~1400 times faster than the hydrolysis reaction outside the thyroxine binding site. X-ray crystallography confirms the anticipated binding orientation and sheds light on the sulfonyl fluoride activation leading to the sulfonamide linkage to TTR. A few of the aryl sulfonyl fluorides efficiently form conjugates with TTR in plasma. Eleven of the TTR covalent kinetic stabilizers synthesized exhibit fluorescence upon conjugation and therefore could have imaging applications as a consequence of the environment sensitive fluorescence of the chromophore. PMID- 23350657 TI - Study of ion diffusional motion in ionic liquid-based polymer electrolytes by simultaneous solid state NMR and DTA. AB - Polymer electrolytes containing ionic liquid (IL), 2-methyl-1,3 dipropylimidazolium dihydrogenphosphate (MDPImH2PO4) have been studied by (1)H solid state NMR and differential thermal analysis (DTA) simultaneously by using a specially designed probe. To the best of our knowledge, this is the first report of its kind for IL based polymer electrolytes. The variation of NMR line width with temperature for the IL and polymer electrolytes shows line narrowing at the glass transition and melting temperature. The onset of long-range ion diffusional motion also takes place at these temperatures and is accompanied by a sudden increase in ionic conductivity value by 2-3 orders of magnitude. The presence of amorphous and crystalline phases in IL-based polymer electrolytes has been observed from X-ray diffraction (XRD) studies, and the amorphous phase is the high conducting phase in these polymer electrolytes. The IL-based polymer electrolytes have been observed to be thermally stable up to 200 degrees C. The results obtained from ion transport studies have also been supported by Fourier transform infrared (FTIR), XRD, and cyclic voltammetry (CV) studies. PMID- 23350658 TI - Association of PTPN22 rs2476601 and EGFR rs17337023 Gene polymorphisms and rheumatoid arthritis in Zahedan, Southeast Iran. AB - In this study we aimed to evaluate the possible association of PTPN22 rs2476601 as well as epidermal growth factor receptor (EGFR) rs17337023 gene polymorphism and rheumatoid arthritis (RA) in a sample of Iranian population. This case control study was performed on 120 patients with RA and 120 healthy subjects. Genomic DNA was extracted from whole blood and PTPN22 rs2476601 and EGFR rs17337023 polymorphisms were determined using tetra amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR). The results showed that PTPN22 rs2476601 CT genotype as well as rs2476601 T allele was a risk factor for susceptibility to RA (OR=5.89 95%CI = 1.78-19.48, P = 0.004 and OR = 4.78, 95%CI = 1.59-14.35, P = 0.003, respectively). We also found that EGFR rs17337023 AT and rs17337023 TT genotypes were risk factor for susceptibility to RA (OR = 9.94 95%CI = 3.65-26.73, P < 0.001 and OR = 3.66, 95%CI = 1.46-9.15, P = 0.005, respectively). In addition the EGFR rs17337023 T allele was a risk for predisposition to RA (OR = 1.56, 95%CI=1.06-2.30, P = 0.030). In conclusion, we found an association between PTPN22 rs2476601 and EGFR rs17337023 polymorphisms and the risk of RA in a sample of Iranian population. PMID- 23350659 TI - Decolorization of salt-alkaline effluent with industrial reactive dyes by laccase producing Basidiomycetes strains. AB - The discharge of highly coloured synthetic dye effluents into rivers and lakes is harmful to the water bodies, and therefore, intensive researches have been focussed on the decolorization of wastewater by biological, physical or chemical treatments. In the present study, 12 basidiomycetes strains from the genus Pleurotus, Trametes, Lentinus, Peniophora, Pycnoporus, Rigidoporus, Hygrocybe and Psilocybe were evaluated for decolorization of the reactive dyes Cibacron Brilliant Blue H-GR and Cibacron Red FN-2BL, both in solid and liquid media. Among the evaluated fungi, seven showed great ability to decolorize the synthetic textile effluent, both in vivo (74-77%) or in vitro (60-74%), and laccase was the main ligninolytic enzyme involved on dyes decolorization. Pleurotus ostreatus, Trametes villosa and Peniophora cinerea reduced near to 60% of the effluent colour after only 1 h of treatment. The decolorization results were still improved by establishing the nitrogen source and amount to be used during the fungal strains cultivation in synthetic medium previous their action on the textile effluent, with yeast extract being a better nitrogen source than ammonium tartarate. These results contribute for the development of an effective microbiological process for decolorization of dye effluents with reduced time of treatment. PMID- 23350660 TI - Effect of preoperative two-dimensional animation information on perioperative anxiety and knowledge retention in patients undergoing bowel surgery: a randomized pilot study. AB - AIM: The use of multimedia information provided preoperatively can potentially reduce anxiety in patients and improve the hospital experience. However, the use of two-dimensional (2D) animation (cartoon) to provide information to patients undergoing colorectal surgery has not been investigated. This study investigated the effect of preoperative 2D information on anxiety and knowledge retention in patients undergoing bowel surgery. METHOD: Patients were randomized to one of two groups; the video group watched a 13-min cartoon animation whereas the nonvideo group did not. Anxiety levels were measured at the preadmission clinic, postvideo, on the day of admission for surgery, within 24-h after surgery and before discharge using the Spielberger state-trait anxiety inventory and visual analogue scale. Both groups completed a knowledge retention questionnaire and the video group completed a feedback questionnaire about the animation. RESULTS: Thirty-one patients (16 video, 15 nonvideo) participated in the study. There was no significant difference in baseline anxiety score between two groups. An immediate reduction (P = 0.03) in anxiety score was observed in the video group after watching the video compared with baseline. There was a significant reduction in anxiety score in the video group at discharge compared with the nonvideo group (P = 0.03). There was no significant difference in knowledge retention between two groups. Eighty-eight per cent of patients who watched the video found it beneficial. CONCLUSION: 2D animation is an effective medium for delivering information to patients undergoing bowel surgery and can potentially reduce anxiety related to surgery and improve the hospital experience. PMID- 23350661 TI - Peptide-based glioma-targeted drug delivery vector gHoPe2. AB - Gliomas are therapeutically challenging cancers with poor patient prognosis. New drug delivery strategies are needed to achieve a more efficient chemotherapy based approach against brain tumors. The current paper demonstrates development of a tumor-targeted delivery vector that is based on a cell-penetrating peptide pVEC and a novel glioma-targeting peptide sequence gHo. The unique tumor-homing peptide gHo was identified using in vitro phage display technology. The novel delivery vector, which we designated as gHoPe2, was constructed by a covalent conjugation of pVEC, gHo, and a cargo; the latter could be either a labeling moiety (such as a fluorescent marker) or a cytostatic entity. Using a fluorescent marker, we demonstrate efficient uptake of the vector in glioma cells and selective labeling of glioma xenograft tumors in a mouse model. This is the first time that we know where in vitro phage display has yielded an efficient, in vivo working vector. We also demonstrate antitumor efficacy of the delivery vector gHoPe2 using a well-characterized chemotherapeutic drug doxorubicin. Vectorized doxorubicin proved to be more efficient than the free drug in a mouse glioma xenograft model after systemic administration of the drugs. In conclusion, we have characterized a novel glioma-homing peptide gHo, demonstrated development of a new and potential glioma-targeted drug delivery vector gHoPe2, and demonstrated the general feasibility of the current approach for constructing cell-penetrating peptide-based targeted delivery systems. PMID- 23350663 TI - Brazilin isolated from Caesalpinia sappan L. acts as a novel collagen receptor agonist in human platelets. AB - BACKGROUND: Brazilin, isolated from the heartwood of Caesalpinia sappan L., has been shown to possess multiple pharmacological properties. METHODS: In this study, platelet aggregation, flow cytometry, immunoblotting analysis, and electron spin resonance (ESR) spectrometry were used to investigate the effects of brazilin on platelet activation ex vivo. Moreover, fluorescein sodium-induced platelet thrombi of mesenteric microvessels was also used in in vivo study. RESULTS: We demonstrated that relatively low concentrations of brazilin (1 to 10 MUM) potentiated platelet aggregation induced by collagen (0.1 MUg/ml) in washed human platelets. Higher concentrations of brazilin (20 to 50 MUM) directly triggered platelet aggregation. Brazilin-mediated platelet aggregation was slightly inhibited by ATP (an antagonist of ADP). It was not inhibited by yohimbine (an antagonist of epinephrine), by SCH79797 (an antagonist of thrombin protease-activated receptor [PAR] 1), or by tcY-NH2 (an antagonist of PAR 4). Brazilin did not significantly affect FITC-triflavin binding to the integrin alphaIIbbeta(3) in platelet suspensions. Pretreatment of the platelets with caffeic acid phenethyl ester (an antagonist of collagen receptors) or JAQ1 and Sam.G4 monoclonal antibodies raised against collagen receptor glycoprotein VI and integrin alpha2beta(1), respectively, abolished platelet aggregation stimulated by collagen or brazilin. The immunoblotting analysis showed that brazilin stimulated the phosphorylation of phospholipase C (PLC)gamma2 and Lyn, which were significantly attenuated in the presence of JAQ1 and Sam.G4. In addition, brazilin did not significantly trigger hydroxyl radical formation in ESR analysis. An in vivo mouse study showed that brazilin treatment (2 and 4 mg/kg) significantly shortened the occlusion time for platelet plug formation in mesenteric venules. CONCLUSION: To the best of our knowledge, this study provides the first evidence that brazilin acts a novel collagen receptor agonist. Brazilin is a plant-based natural product, may offer therapeutic potential as intended anti-thrombotic agents for targeting of collagen receptors or to be used a useful tool for the study of detailed mechanisms in collagen receptors-mediated platelet activation. PMID- 23350664 TI - Impact of human migrations on diversity of Helicobacter pylori in Cambodia and New Caledonia. AB - BACKGROUND: Helicobacter pylori is a major gastric bacterial pathogen, presumed to have established itself in the human stomach approximately 100,000 years ago. Helicobacter pylori co-evolved with its host, and human migrations shaped the expansion and the diversity of strains around the world. Here, we investigated the population structure and the genomic diversity of H. pylori in New Caledonia and Cambodia, where humans of different origins are living. METHODS: Both multilocus sequence typing (MLST) and macro-array experiments were performed to assess polymorphism of housekeeping genes and to compare differences in gene contents among strains of H. pylori. RESULTS: The macro-array analysis based on variations of the flexible gene pools was consistent with the contribution of ancestral H. pylori populations to modern strains. Most of the CDS variably present encode proteins of unknown function, selfish DNA, and transposases. In New Caledonia-where humans are of several ethnic origins-strains belonged to four different genetic populations, reflecting the diversity of human populations. Melanesians and Polynesians were infected mainly by strains assigned to hspMaori, whereas Caucasians were infected by hspWAfrica, hpEurope, and hpNEAfrica strains. In contrast, strains from Khmer patients belonged to only two subpopulations: hspEAsia and hpEurope. In the two countries, both ancient and recent human migrations may have influenced the diversity of H. pylori. CONCLUSION: Our present results are consistent with the possibility of admixture of strains in multiethnic communities. This increases the global polymorphism of H. pylori without evidence of functional change or impact on fitness and virulence. PMID- 23350662 TI - Tailoring adipose stem cell trophic factor production with differentiation medium components to regenerate chondral defects. AB - Recent endeavors to use stem cells as trophic factor production sources have the potential to translate into viable therapies for damaged or diseased musculoskeletal tissues. Adipose stem cells (ASCs) can be differentiated into chondrocytes using the chondrogenic medium (CM), but it is unknown if this approach can optimize ASC growth factor secretion for cartilage regeneration by increasing the chondrogenic factor production, while decreasing angiogenic and hypertrophic factor production. The objective of this study was to determine the effects the CM and its components have on growth factor production from ASCs to promote cartilage regeneration. ASCs isolated from male Sprague-Dawley rats and cultured in monolayer or alginate microbeads were treated with either the growth medium (GM) or the CM for 5 days. In subsequent studies, ASC monolayers were treated with either the GM supplemented with different combinations of 50 MUg/mL ascorbic acid-2-phosphate (AA2P), 100 nM dexamethasone (Dex), 10 ng/mL transforming growth factor (TGF)-beta1, and 100 ng/mL bone morphogenetic protein (BMP)-6 or with the CM excluding different combinations of AA2P, Dex, TGF-beta1, and BMP-6. mRNA levels and growth factor production were quantified at 8 and 24 h after the last media change, respectively. The CM increased chondrogenic factor secretion (TGF-beta2, TGF-beta3, and insulin-like growth factor [IGF]-I) and decreased angiogenic factor production (the vascular endothelial growth factor [VEGF]-A, the fibroblast growth factor [FGF]-2). Microencapsulation in the GM increased production of the chondrogenic (IGF-I, TGF-beta2) and angiogenic (VEGF A) factors. AA2P increased secretion of chondrogenic factors (IGF-I, TGF-beta2), and decreased angiogenic factor (VEGF-A) secretion, in addition to decreasing mRNA levels for factors associated with chondrocyte hypertrophy (FGF-18). Dex increased mRNA levels for hypertrophic factors (BMP-2, FGF-18) and decreased angiogenic factor secretion (VEGF-A). TGF-beta1 increased angiogenic factor production (FGF-2, VEGF-A) and decreased chondrogenic factor mRNA levels (IGF-I, PTHrP). BMP-6 increased hypertrophic mRNA levels (FGF-18) and chondrogenic factor production (TGF-beta2). When ASC microbeads preconditioned with the CM were implanted in a focal cartilage defect and immobilized within an RGD-conjugated hydrogel, tissue infiltration from the edges of the defect and perichondrium was observed. These results show that differentiation media components have distinct effects on ASC's production of angiogenic, chondrogenic, and hypertrophic factors and that AA2P may be the most beneficial CM component for preconditioning ASCs to stimulate cartilage regeneration. PMID- 23350665 TI - Analysis of low-lying gerade Rydberg states of acetylene using two-photon resonance fluorescence excitation spectroscopy. AB - The np gerade Rydberg states of acetylene were analyzed using two-photon resonance fluorescence excitation spectroscopy in the 72,000-93,000 cm(-1) energy region. The nppi(1)Sigma(g)(+) and nppi(1)Delta(g) Rydberg series (n = 3-5) were identified in the fluorescence excitation spectrum measured by monitoring the C(2) d(3)Pi(g)-a(3)Pi(u) Swan system. Some vibronic bands were assigned to the nppi(1)Delta(g)-X(1)Sigma(g)(+) transition on the basis of rotational analysis. The 5psigma(1)Pi(g) state was observed, which is the first such observation in an npsigma(1)Pi(g) series. Rotational analysis of the 5psigma(1)Pi(g) X(1)Sigma(g)(+) transition showed e/f-symmetry dependent predissociation of acetylene in the 5psigma(1)Pi(g) state. The 0(0)(0) band of the deuterated acetylene (C(2)D(2)) 4ppi(1)Sigma(g)(+)-X(1)Sigma(g)(+) transition exhibits an atypical structure, which was satisfactorily reproduced by a simple model of quantum interference between the discrete and quasi-continuum states. The predissociative lifetimes of the nppigerade Rydberg states were estimated from the spectral profiles. The predissociation mechanism of acetylene in the Rydberg states is discussed. PMID- 23350666 TI - Hypermineralized whale rostrum as the exemplar for bone mineral. AB - Although bone is a nanocomposite of mineral and collagen, mineral has been the more elusive component to study. A standard for bone mineral clearly is needed. We hypothesized that the most natural, least-processed bone mineral could be retrieved from the most highly mineralized bone. We therefore studied the rostrum of the toothed whale Mesoplodon densirostris, which has the densest recognized bone. Essential to establishment of a standard for bone mineral is documentation that the proposed tissue is bone-like in all properties except for its remarkably high concentration of mineral. Transmitted-light microscopy of unstained sections of rostral material shows normal bone morphology in osteon geometry, lacunae concentration, and vasculature development. Stained sections reveal extremely low density of thin collagen fibers throughout most of the bone, but enrichment in and thicker collagen fibers around vascular holes and in a minority of osteons. FE-SEM shows the rostrum to consist mostly of dense mineral prisms. Most rostral areas have the same chemical-structural features, Raman spectroscopically dominated by strong bands at ~962 Deltacm(-1) and weak bands at ~2940 Deltacm( 1). Spectral features indicate that the rostrum is composed mainly of the calcium phosphate mineral apatite and has only about 4 wt.% organic content. The degree of carbonate substitution (~8.5 wt.% carbonate) in the apatite is in the upper range found in most types of bone. We conclude that, despite its enamel-like extraordinarily high degree of mineralization, the rostrum is in all other features bone-like. Its mineral component is the long-sought uncontaminated, unaltered exemplar of bone mineral. PMID- 23350667 TI - Fertility preservation: current prospects and future challenges. AB - Due to remarkable advances in cancer therapies, we have seen great improvements in survival rates of pediatric and reproductive-age male patients. Unfortunately, fertility in adult life might be severely impaired by these treatments. Gonadotoxic therapy is also used to cure a variety of non-malignant disorders. Providing young people undergoing gonadotoxic treatment with adequate fertility preservation options is a challenging area of reproductive medicine and merits broader diffusion in clinical practice. This paper, therefore, aims to review current concepts and perspectives to restore fertility from germ cells or gonadal tissue cryostored prior to gonadotoxic therapies in pre- and post-pubertal patients. For patients rendered sterile after treatment, who did not benefit from fertility preservation measures before therapy, the reproductive potential of alternative sources of stem cells is also examined, although this is at the research stage. PMID- 23350668 TI - Electrical impedance spectroscopy as a potential adjunct diagnostic tool for cutaneous melanoma. AB - BACKGROUND: Previous studies have shown statistically significant differences in electrical impedance between various cutaneous lesions. Electrical impedance spectroscopy (EIS) may therefore be able to aid clinicians in differentiating between benign and malignant skin lesions. OBJECTIVES: The aim of the study was to develop a classification algorithm to distinguish between melanoma and benign lesions of the skin with a sensitivity of at least 98% and a specificity approximately 20 per cent higher than the diagnostic accuracy of dermatologists. PATIENTS/METHODS: A total of 1300 lesions were collected in a multicentre, prospective, non-randomized clinical trial from 19 centres around Europe. All lesions were excised and subsequently evaluated independently by a panel of three expert dermatopathologists. From the data two classification algorithms were developed and verified. RESULTS: For the first classification algorithm, approximately 40% of the data were used for calibration and 60% for testing. The observed sensitivity for melanoma was 98.1% (101/103), non-melanoma skin cancer 100% (25/25) and dysplastic nevus with severe atypia 84.2% (32/38). The overall observed specificity was 23.6% (66/280). For the second classification algorithm, approximately 55% of the data were used for calibration. The observed sensitivity for melanoma was 99.4% (161/162), for non-melanoma skin cancer was 98.0% (49/50) and dysplastic nevus with severe atypia was 93.8% (60/64). The overall observed specificity was 24.5% (116/474). CONCLUSION: EIS has the potential to be an adjunct diagnostic tool to help clinicians differentiate between benign and malignant (melanocytic and non-melanocytic) skin lesions. Further studies are needed to confirm the validity of the automatic assessment algorithm. PMID- 23350669 TI - Physarum polycephalum mutants in the photocontrol of sporulation display altered patterns in the correlated expression of developmentally regulated genes. AB - Physarum polycephalum is a lower eukaryote belonging to the amoebozoa group of organisms that forms macroscopic, multinucleate plasmodial cells during its developmental cycle. Plasmodia can exit proliferative growth and differentiate by forming fruiting bodies containing mononucleate, haploid spores. This process, called sporulation, is controlled by starvation and visible light. To genetically dissect the regulatory control of the commitment to sporulation, we have isolated plasmodial mutants that are altered in the photocontrol of sporulation in a phenotypic screen of N-ethyl-N-nitrosourea (ENU) mutagenized cells. Several non sporulating mutants were analyzed by measuring the light-induced change in the expression pattern of a set of 35 genes using GeXP multiplex reverse transcription-polymerase chain reaction with RNA isolated from individual plasmodial cells. Mutants showed altered patterns of differentially regulated genes in response to light stimulation. Some genes clearly displayed pairwise correlation in terms of their expression level as measured in individual plasmodial cells. The pattern of pairwise correlation differed in various mutants, suggesting that different upstream regulators were disabled in the different mutants. We propose that patterns of pairwise correlation in gene expression might be useful to infer the underlying gene regulatory network. PMID- 23350670 TI - Localized in situ generation of diazonium cations by electrocatalytic formation of a diazotization reagent. AB - A new one-step electrochemical approach for the localized generation of diazonium cations in the diffusion layer of an electrode by taking advantage of the electrocatalytic properties of the electrode for the formation of the diazotization agent (nitrite) is proposed. Once nitrite anions are formed by electrocatalytic reduction of nitrate, they immediately react with an arylamine to produce the corresponding diazonium cations, which can be electrochemically readily reduced at the electrode surface. By this method, spontaneous modification of the electrode surface can be avoided. Furthermore, because the potential of the electrochemical nitrate reduction depends strongly on the nature of the electrode material, we also demonstrate that selective grafting can be achieved on a surface, which consists of two different materials: copper-gold or copper-glassy carbon substrates. PMID- 23350671 TI - Evaluation of glycated hemoglobin and fetal hemoglobin-adjusted HbA1c measurements in infants. AB - BACKGROUND: As the presence of fetal hemoglobin (HbF) affects the accuracy of hemoglobin A1c (HbA1c) analysis methods, HbA1c measurement may not be a good indicator for patients with neonatal diabetes mellitus, whereas glycated albumin (GA) may be a good indicator. OBJECTIVE: To investigate whether total glycated hemoglobin (GHb) or HbF-adjusted HbA1c (adj-HbA1c) can act as a glycemic control marker in infants. SUBJECTS AND METHODS: Plasma glucose (PG), GA, HbF, GHb measured using the affinity method, and HbA1c measured using the latex immunoturbidimetry (LA) or the high-performance liquid chromatography (HPLC) methods were determined in 26 full-term newborn infants aged 4-234 d. Adj-HbA1c was calculated as HbA1c/(total Hb - HbF). RESULTS: GHb, adj-HbA1c measured using the LA and the HPLC methods were 4.8 +/- 0.5%, 4.5 +/- 0.5%, and 4.7 +/- 0.6%, respectively. GA was most positively correlated with PG (r = 0.696, p < 0.0001). GHb was positively correlated with both PG (r = 0.479, p = 0.013) and GA (r = 0.727, p < 0.0001). Adj-HbA1c measured using the LA method was positively correlated with GA (r = 0.465, p = 0.017), but not PG (r = 0.304, p = 0.132). Adj HbA1c measured using the HPLC method was correlated with neither PG (r = -0.077, p = 0.710) nor GA (r = 0.360, p = 0.071). CONCLUSIONS: GHb measured using the affinity method may be a useful glycemic control marker in infants. Although adj HbA1c measured using the LA method was correlated with GA, it may not be a practical measure because it was not correlated with PG and determining HbF levels using HPLC method can be troublesome. Adj-HbA1c measured using the HPLC method should not be used as a glycemic marker in infants. PMID- 23350673 TI - Asia-Pacific consensus recommendations for endoscopic and interventional management of hilar cholangiocarcinoma. AB - Hilar cholangiocarcinoma (HCCA) is one of the most common types of hepatobiliary cancers reported in the world including Asia-Pacific region. Early HCCA may be completely asymptomatic. When significant hilar obstruction develops, the patient presents with jaundice, pale stools, dark urine, pruritus, abdominal pain, and sometimes fever. Because no single test can establish the definite diagnosis then, a combination of many investigations such as tumor markers, tissue acquisition, computed tomography scan, magnetic resonance imaging/magnetic resonance cholangiopancreatography, endoscopic ultrasonography/intraductal ultrasonography, and advanced cholangioscopy is required. Surgery is the only curative treatment. Unfortunately, the majority of HCCA has a poor prognosis due to their advanced stage on presentation. Although there is no survival advantage, inoperable HCCA managed by palliative drainage may benefit from symptomatic improvement. Currently, there are three techniques of biliary drainage which include endoscopic, percutaneous, and surgical approaches. For nonsurgical approaches, stent is the most preferred device and there are two types of stents i.e. plastic and metal. Type of stent and number of stent for HCCA biliary drainage are subjected to debate because the decision is made under many grounds i.e. volume of liver drainage, life expectancy, expertise of the facility, etc. Recently, radio-frequency ablation and photodynamic therapy are promising techniques that may extend drainage patency. Through a review in the literature and regional data, the Asia-Pacific Working Group for hepatobiliary cancers has developed statements to assist clinicians in diagnosing and managing of HCCA. After voting anonymously using modified Delphi method, all final statements were determined for the level of evidence quality and strength of recommendation. PMID- 23350672 TI - Mechanisms of neuroprotection by hemopexin: modeling the control of heme and iron homeostasis in brain neurons in inflammatory states. AB - Hemopexin provides neuroprotection in mouse models of stroke and intracerebral hemorrhage and protects neurons in vitro against heme or reactive oxygen species (ROS) toxicity via heme oxygenase-1 (HO1) activity. To model human brain neurons experiencing hemorrhages and inflammation, we used human neuroblastoma cells, heme-hemopexin complexes, and physiologically relevant ROS, for example, H(2)O(2) and HOCl, to provide novel insights into the underlying mechanism whereby hemopexin safely maintains heme and iron homeostasis. Human amyloid precursor protein (hAPP), needed for iron export from neurons, is induced ~twofold after heme-hemopexin endocytosis by iron from heme catabolism via the iron-regulatory element of hAPP mRNA. Heme-hemopexin is relatively resistant to damage by ROS and retains its ability to induce the cytoprotective HO1 after exposure to tert butylhydroperoxide, although induction is impaired, but not eliminated, by exposure to high concentrations of H(2)O(2) in vitro. Apo-hemopexin, which predominates in non-hemolytic states, resists damage by H(2)O(2) and HOCl, except for the highest concentrations likely in vivo. Heme-albumin and albumin are preferential targets for ROS; thus, albumin protects hemopexin in biological fluids like CSF and plasma where it is abundant. These observations provide strong evidence that hemopexin will be neuroprotective after traumatic brain injury, with heme release in the CNS, and during the ensuing inflammation. Hemopexin sequesters heme, thus preventing unregulated heme uptake that leads to toxicity; it safely delivers heme to neuronal cells; and it activates the induction of proteins including HO1 and hAPP that keep heme and iron at safe levels in neurons. PMID- 23350674 TI - Lactobacillus casei Zhang modulate cytokine and toll-like receptor expression and beneficially regulate poly I:C-induced immune responses in RAW264.7 macrophages. AB - Lactobacilli are frequently used as probiotics due to their beneficial effects on health. Lactobacillus casei Zhang (LcZ), which has favorable probiotic properties, was first isolated from koumiss. In this study, the immunomodulating effects of LcZ on cytokine and toll-like receptor expression in RAW264.7 macrophages was assessed and it was found that live LcZ promotes production of nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and interferon (IFN)-beta. Transcription of inducible nitric oxide synthase (iNOS) was also enhanced by viable LcZ. The immunostimulating effects of live LcZ are significantly attenuated in heat-killed LcZ. Live LcZ promotes TLR2 mRNA transcription, whereas heat-killed LcZ enhances transcription of TLR2, TLR3, TLR4 and TLR9. Furthermore, live LcZ significantly suppresses polyinosinic:polycytidylic acid (poly I:C)-stimulated NO, iNOS and TNF-alpha expression while enhancing expression of IFN-beta. It was also found that poly I:C-induced interferon regulatory factor 3 (IRF-3) reporter gene activity was significantly up-regulated by live LcZ. These results suggest that LcZ keeps the innate immune system alert by increasing transcription of Toll-like receptors and enhancing production of pro-inflammatory mediators and type I IFN in macrophages. The synergistic effect of live LcZ with poly I:C on IFN-beta expression is associated with increased activity of IRF-3. LcZ has the potential to be used as an adjuvant against viral infections. PMID- 23350675 TI - Effect of guanine to inosine substitution on stability of canonical DNA and RNA duplexes: molecular dynamics thermodynamics integration study. AB - Guanine to inosine (G -> I) substitution has often been used to study various properties of nucleic acids. Inosine differs from guanine only by loss of the N2 amino group, while both bases have similar electrostatic potentials. Therefore, G -> I substitution appears to be optimally suited to probe structural and thermodynamics effects of single H-bonds and atomic groups. However, recent experiments have revealed substantial difference in free energy impact of G -> I substitution in the context of B-DNA and A-RNA canonical helices, suggesting that the free energy changes reflect context-dependent balance of energy contributions rather than intrinsic strength of a single H-bond. In the present study, we complement the experiments by free energy computations using thermodynamics integration method based on extended explicit solvent molecular dynamics simulations. The computations successfully reproduce the basic qualitative difference in free energy impact of G -> I substitution in B-DNA and A-RNA helices although the magnitude of the effect is somewhat underestimated. The computations, however, do not reproduce the salt dependence of the free energy changes. We tentatively suggest that the different effect of G -> I substitution in A-RNA and B-DNA may be related to different topologies of these helices, which affect the electrostatic interactions between the base pairs and the negatively charged backbone. Limitations of the computations are briefly discussed. PMID- 23350676 TI - Beyond the helix pitch: direct visualization of native DNA in aqueous solution. AB - The DNA double helix was first elucidated by J.D. Watson and F.H.C. Crick over a half century ago. However, no one could actually "see" the well-known structure ever. Among all real-space observation methods, only atomic force microscopy (AFM) enables us to visualize the biologically active structure of natural DNA in water. However, conventional AFM measurements often caused the structural deformation of DNA because of the strong interaction forces acting on DNA. Moreover, large contact area between the AFM probe and DNA hindered us from imaging sub-molecular-scale features smaller than helical periodicity of DNA. Here, we show the direct observation of native plasmid DNA in water using an ultra-low-noise AFM with the highly sensitive force detection method (frequency modulation AFM: FM-AFM). Our micrographs of DNA vividly exhibited not only overall structure of the B-form double helix in water but also local structures which deviate from the crystallographic structures of DNA without any damage. Moreover, the interaction force area in the FM-AFM was small enough to clearly discern individual functional groups within DNA. The technique was also applied to explore the synthesized DNA nanostructures toward the current nanobiotechnology. This work will be essential for considering the structure function relationship of biomolecular systems in vivo and for in situ analysis of DNA-based nanodevices. PMID- 23350677 TI - Drug delivery with a calixpyrrole--trans-Pt(II) complex. AB - A meso-p-nitroaniline-calix[4]pyrrole derivative trans-coordinated to a Pt(II) center was synthesized and its structure solved by X-ray analysis. Adenosine monophosphate (AMP) was used as a model compound to evaluate the potential for the assisted delivery of the metal to the DNA nucleobases via the phosphate anion binding properties of the calix[4]pyrrole unit. An NMR investigation of the kinetics of AMP complexation in the absence of an H-bonding competing solvent (dry CD(3)CN) was consistent with this hypothesis, but we could not detect the interaction of the calix[4]pyrrole with phosphate in the presence of water. However, in vitro tests of the new trans-calixpyrrole-Pt(II) complex on different cancer cell lines indicate a cytotoxic activity that is unquestionably derived from the coexistence of both the trans-Pt(II) fragment and the calix[4]pyrrole unit. PMID- 23350678 TI - Multidisciplinary staged surgical management of bifrontal meningoencephalocele with long-term follow-up. AB - The authors report on an infant with a bifrontal encephalocele that was associated with multisuture craniosynostosis, spasticity, and a progressively severe epilepsy. They describe the initial presentation, genetic screening results, staged multidisciplinary operative plans, clinical course, complications, and long-term surgical and developmental follow-up. To their knowledge, the comprehensive surgical management of this type of complicated congenital cranial anomaly has not been previously described. Surgical management was staged and multidisciplinary and required careful attention to all 3 components of the condition: 1) hydrocephalus, 2) frontal meningoencephalocele, and 3) epilepsy. PMID- 23350679 TI - Pediatric perimedullary arteriovenous fistula of the conus medullaris supplied by the artery of Desproges-Gotteron. AB - The cone artery, or artery of Desproges-Gotteron, is sometimes seen arising from the internal iliac artery. The authors describe a case of a symptomatic perimedullary arteriovenous fistula (AVF) of the conus medullaris in an 8-year old boy who presented with a protracted history of urinary difficulty and severe sudden-onset right lumbosciatic pain that evolved to severe paraparesis with compromise of the sphincter muscles. The spinal AVF, which was supplied by the cone artery and a thoracic radiculomedullary artery that joined at the fistula site in a large partially thrombosed varix, was completely occluded with Onyx liquid embolic. The patient's clinical condition improved rapidly after embolization. As shown in this patient, urgent endovascular embolization of spinal AVFs can be very rewarding, even in patients with severe neurological presentation. The artery of Desproges-Gotteron appears to be a rare arterial variation. To the authors' knowledge, this is the first pediatric case of a conal AVF supplied by this artery. PMID- 23350680 TI - Filum terminale. PMID- 23350681 TI - Adipose stromal vascular fraction cells isolated using an automated point of care system improve the patency of expanded polytetrafluoroethylene vascular grafts. AB - We evaluated the use of an automated, point-of-care instrument to derive canine adipose stromal vascular fraction cells, and the subsequent deposition of these cells onto the luminal surface of an expanded polytetrafluoroethylene (ePTFE) vascular graft for use as a bypass graft. The hypothesis evaluated was that an instrument requiring minimal user interface will provide a therapeutic dose of cells to improve the patency of synthetic vascular grafts in an autologous animal model of graft patency. The stromal vascular fraction (SVF) cells were isolated using an automated adipose tissue processing and cell isolation system and cells sodded onto the surface of an ePTFE vascular graft. Control grafts, used off-the shelf without cell treatment were used as a control to assess patency effects. Each animal received a control, untreated graft implanted in one carotid artery, and the cell-treated graft implanted in the carotid artery on the contralateral side. The grafts were implanted for 6 months utilizing 12 animals. Results indicate a fully automated adipose tissue processing system will consistently produce functional autologous cells for immediate use in the operating room. Cell sodded polymeric grafts exhibited improved patency compared to control grafts after 6 month implantation in the canine carotid artery model. PMID- 23350682 TI - Identification and isolation of stimulator of interferon genes (STING): an innate immune sensory and adaptor gene from camelids. AB - The mechanism by which type I interferon-mediated antiviral response is mounted by hosts against invading pathogen is an intriguing one. Of late, an endoplasmic reticulum transmembrane protein encoded by a gene called stimulator of interferon genes (STING) is implicated in the innate signalling pathways and has been identified and cloned in few mammalian species including human, mouse and pig. In this article, we report the identification of STING from three different species of a highly conserved family of mammals - the camelids. cDNAs encoding the STING of Old World camels - dromedary camel (Camelus dromedarius) and bactrian camel (Camelus bactrianus) and a New World camel - llama (Llama glama) were amplified using conserved primers and RACE. The complete STING cDNA of dromedary camel is 2171 bp long with a 706-bp 5' untranslated regions (UTR), an 1137-bp open reading frame (ORF) and a 328-bp 3' UTR. Sequence and phylogenetic analysis of the ORF of STING from these three camelids indicate high level of similarity among camelids and conservation of critical amino acid residues across different species. Quantitative real-time PCR analysis revealed high levels of STING mRNA expression in blood, spleen, lymph node and lung. The identification of camelid STING will help in better understanding of the role of this molecule in the innate immunity of the camelids and other mammals. PMID- 23350684 TI - Improved detection of Helicobacter pylori DNA in formalin-fixed paraffin-embedded (FFPE) tissue of patients with hepatocellular carcinoma using laser capture microdissection (LCM). PMID- 23350683 TI - Left ventricular remodeling: one small step for the extracellular matrix will translate to a giant leap for the myocardium. PMID- 23350685 TI - International online survey: female ejaculation has a positive impact on women's and their partners' sexual lives. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Genital secretions during female orgasm (female ejaculation) have been a matter of controversy for centuries. Scientific work on this essential part of female sexual function has been able to differentiate between female ejaculation, urinary incontinence and vaginal transudate. According to earlier studies, less than 50% of women actually do ejaculate during sexual stimulation. Few affected women discuss female ejaculation with their physician--partly because of its physiological nature, partly through embarrassment. To gain knowledge on the characteristics of female ejaculation and its impact on women's sexual lives, an online questionnaire has been designed and published internationally. In this way, data from 320 women who perceive ejaculation could be acquired. Most women and their partners perceive female ejaculation as an enrichment of their sexual lives. OBJECTIVE: To study characteristics of female ejaculation as perceived by healthy women. To evaluate whether fluid emission during sexual activity has an impact on women's or their partners' sexual lives. MATERIALS AND METHODS: An online questionnaire consisting of 23 questions addressing the participants' characteristics, aspects of perceived female ejaculation, and its impact on women's and their partners' lives was published internationally on various online platforms. RESULTS: Over a period of 18 months, 320 women from all over the world were included in the study (excluding women below the age of 18 years and double entries). The women's mean age was 34.1 years (+/-11.1) and their mean age at first ejaculation was 25.4 years. Most women ejaculate a few times a week. The volume of ejaculation is approximately 2 oz (29.1%), and the fluid is usually clear as water (83.1%). For most women (78.8%) and their partners (90.0%), female ejaculation is an enrichment of their sexual lives, whereas 14 women (4.4%) stated that their partners were unaware of their potential ejaculation. CONCLUSIONS: Perceived female ejaculation--and its onset--occurs in women of all ages. Most women who ejaculate do so on a regular basis. Female ejaculation is an enrichment of the sexual lives of women as well as their partners. PMID- 23350686 TI - Parietal peritoneal closure versus non-closure at caesarean section: which technique is feasible to perform? AB - OBJECTIVE: To evaluate short-term effects of closure versus non-closure of the parietal peritoneum at caesarean section. METHODS: A randomized controlled study of women undergoing caesarean section was conducted at the obstetrics department of a research and education hospital between October 2010 and May 2011. Patients were randomly assigned to have closure of parietal peritoneal layer (Group I, n = 55), and non-closure of parietal peritoneal layer (Control, Group II, n = 55). Intra-operative and post-operative outcomes were compared between the groups. RESULTS: Groups were similar for baseline characteristics. Although there was statistically significant difference between Group 1 and Group 2 in terms of time to oral intake and mobilization time [12 (8-12) versus 8 (8-10) h; p < 0.001; 12 (8-12) versus 8 (8-10) h; p < 0.001]; the other variables, such as drop in hemoglobin concentration, estimate of blood loss, intra-operative additional sutures, operating time and time to passage of flatus [1.13 +/- 0.86 versus 1.41 +/- 0.82 g/dL; 487.9 +/- 217.01 versus 544.87 +/- 237.64 mL; 0 (0-1) versus 0 (0 1); 30.8 +/- 7.63 versus 31.6 +/- 10.38 h; 18.2 +/- 6.04 versus 18.2 +/- 4.23 h, p > 0.05] were not statistically different between Group 1 and Group 2. CONCLUSIONS: Closure of the parietal peritoneum has no benefit over non-closure of parietal peritoneum and non-closure is associated with rapid post-operative recovery. PMID- 23350687 TI - The complete mitochondrial genome of Gynaephora menyuanensis (Lepidoptera: Lymantriidae) from the Qinghai-Tibetan Plateau. AB - We sequenced and annotated the complete mitochondrial genome (mitogenome) of Gynaephora menyuanensis (Lepidoptera: Lymantriidae), which is a major pest in alpine meadows and endemic to the Qinghai-Tibetan Plateau. This mitogenome is 15,770 bp in length with an A+T content of 81.48%, and contains 37 typical animal mitochondrial genes that are arranged in the same order as that of other lepidopteran species. All protein-coding genes (PCGs) start with a typical ATN codon, with the exception of cox1, which begins with CGA. Eleven PCGs stop with termination codon TAA, whereas cox2 and nad4 have single T as the incomplete stop codon. All of the 22 transfer RNA genes present the typical clover leaf secondary structure. The A+T-rich region is located between rrnS and trnM with a length of 449 bp, and contains a 19 bp poly-T stretch as found in other lepidopteran mitogenomes. This is the second completely sequenced mitogenome from the family Lymantriidae of Lepidoptera, providing important molecular information to phylogenetic and population genetic researches. PMID- 23350688 TI - A synthetic peptide from transforming growth factor-beta1 type III receptor inhibits NADPH oxidase and prevents oxidative stress in the kidney of spontaneously hypertensive rats. AB - AIMS: The NADPH oxidases constitute a major source of superoxide anion (.O2(-)) in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by transforming growth factor-beta1 (TGF-beta1). We investigated whether a chronic treatment with P144, a peptide synthesized from type III TGF-beta1 receptor, inhibited NADPH oxidases in the renal cortex of spontaneously hypertensive rats (SHR). RESULTS: Here, we show that chronic administration of P144 significantly reduced the NADPH oxidase expression and activity as well as the oxidative stress observed in control vehicle-treated SHR (V-SHR). In addition, P144 was also able to reduce the significant increase in the renal fibrosis and in mRNA expression of different components of collagen metabolism, as well as in the levels of connective tissue growth factor observed in V-SHR. Finally, TGF-beta1-stimulated NRK52E exhibited a significant increase in NADPH oxidase expression and activity as well as a TGF-beta1-dependent intracellular pathway that were inhibited in the presence of P144. INNOVATION: Our experimental evidence suggests that reversing oxidative stress may be therapeutically useful in preventing fibrosis-associated renal damage. We show here that (i) the TGF-beta1-NADPH oxidases axis is crucial in the development of fibrosis in an experimental hypertensive renal disease animal model, and (ii) the use of P144 reverses TGF-beta1-dependent NADPH oxidase activity; thus, P144 may be considered a novel therapeutic tool in kidney disease associated with hypertension. CONCLUSION: We demonstrate that P144 inhibits NADPH oxidases and prevents oxidative stress in kidneys from hypertensive rats. Our data also suggest that these effects are associated with the renal antifibrotic effect of P144. PMID- 23350689 TI - Extending the honey bee venome with the antimicrobial peptide apidaecin and a protein resembling wasp antigen 5. AB - Honey bee venom is a complex mixture of toxic proteins and peptides. In the present study we tried to extend our knowledge of the venom composition using two different approaches. First, worker venom was analysed by liquid chromatography mass spectrometry and this revealed the antimicrobial peptide apidaecin for the first time in such samples. Its expression in the venom gland was confirmed by reverse transcription PCR and by a peptidomic analysis of the venom apparatus tissue. Second, genome mining revealed a list of proteins with resemblance to known insect allergens or venom toxins, one of which showed homology to proteins of the antigen 5 (Ag5)/Sol i 3 cluster. It was demonstrated that the honey bee Ag5-like gene is expressed by venom gland tissue of winter bees but not of summer bees. Besides this seasonal variation, it shows an interesting spatial expression pattern with additional production in the hypopharyngeal glands, the brains and the midgut. Finally, our immunoblot study revealed that both synthetic apidaecin and the Ag5-like recombinant from bacteria evoke no humoral activity in beekeepers. Also, no IgG4-based cross-reactivity was detected between the honey bee Ag5-like protein and its yellow jacket paralogue Ves v 5. PMID- 23350690 TI - In vivo microdialysis for the evaluation of transfersomes as a novel transdermal delivery vehicle for cinnamic acid. AB - In this study, cinnamic acid-loaded transfersomes were prepared and dermal microdialysis sampling was used in Sprague-Dawley rats to compare the amount of drug released into the skin using transfersomes as transdermal carriers with that released on using conventional liposomes. The formulation of cinnamic acid-loaded transfersomes was optimized by a uniform design through in vitro transdermal permeation studies. Hydration time was confirmed as a significant factor influencing the entrapment efficiency of transfersomes, further affecting their transdermal flux in vitro. The fluxes of cinnamic acid from transfersomes were all higher than those from conventional liposomes, and the flux from the optimal transfersome formulation was 3.01-fold higher than that from the conventional liposomes (p < 0.05). An in vivo microdialysis sampling method revealed that the dermal drug concentrations from transfersomes applied on various skin regions were much lower than those required with conventional liposomes. After the administration of drug-containing transfersomes and liposomes on abdominal skin regions of rats for a period of 10 h, the Cmax of cinnamic acid from the compared liposomes was 3.21 +/- 0.25 MUg/mL and that from the transfersomes was merely 0.59 +/- 0.02 MUg/mL. The results suggest that transfersomes can be used as carriers to enhance the transdermal delivery of cinnamic acid, and that these vehicles may penetrate the skin in the complete form, given their significant deformability. PMID- 23350691 TI - Biological artificial fluid-induced non-lamellar phases in glyceryl monooleate: the kinetics pathway and its digestive process by bile salts. AB - BACKGROUND: The cubic (Q(II)) phase is a promising sustained-release system. However, its rigid gel-like propensity is highly viscous, which makes it difficult to handle in pharmaceutical applications. To circumvent this problem, a less viscous lamellar (L(alpha)) phase that could spontaneously transform to Q(II) phase by the introduction of water or biological artificial fluid can be used. However, the kinetics pathway of phase transition, susceptibility to digestive processes and impact of the transition on drug release are not yet well understood. METHOD: We investigated various biological artificial fluid-induced L(alpha) to inverse Q(II) phase transition over time in glyceryl monooleate (GMO) by water penetration scan and light polarizing microscopy. To reveal the structure stability, fluorescence spectroscopy studies were conducted using pyrene as a probe. Furthermore, the release mechanism of pyrene as a lipophilic drug model in the spontaneously formed Q(II) was investigated. RESULT: Although hexagonal (H(II)) mesophases occurred when phosphate buffered saline (PBS) 7.4, 0.1 M HCl or sodium taurocholate (NaTC) solutions were introduced to GMO at room temperature, they disappear with the exception of 0.1 M HCl at 37 degrees C. Compared with 25 degrees C, L(alpha) to Q(II) phase transition was in a faster rate as almost completely transforms were observed after 2 h post-immersion. The spontaneously formed mesophases were stable over 24 h immersions in PBS or pancreatic lipase solutions as proven by the extremely low fluorescence signal, however they were digestible by bile salts. This result indicated that digestion by bile salts was the major pathway instead of digestion by lipases. Moreover, pyrene fluorescence spectroscopy confirmed that the digestion by bile salts induced the formation of GMO-bile salt mixed micelles whose performance depended on the bile salt concentrations. This dependence influenced the drug release from the spontaneously formed Q(II) phase. CONCLUSION: All the results concluded that temperature, pH and ionic strength tendencies for the formation of non-lamellar structures greatly influenced the self-assembly process, thereby affecting the final mesophase structure. The results of this study are important to understand the lamellar to non-lamellar lipid-phase transitions and their possible pharmaceutical applications. PMID- 23350692 TI - Iontophoresis of amoxicillin and cefuroxime: rapid therapeutic concentrations in skin. AB - CONTEXT: Amoxicillin (AMX) and cefuroxime (CFX) are antibiotics used often to treat skin bacterial infections. Typically, high oral doses are required to achieve minimum inhibitory concentration (MIC) at the site of infection that may affect only a very small area of skin. OBJECTIVES: To lower side effects and increase therapeutic effectiveness, the percutaneous absorption and retention of AMX and CFX administered by iontophoresis was investigated in a rabbit model by measuring dermis concentrations via microdialysis. METHODS: Iontophoresis was performed using a stainless steel electrode and a non-woven polypropylene pad. The cartridge pad was soaked with a solution of AMX in glycerin or of CFX in glycerin/water (60:40). Constant current density of 0, 100, 200 or 300 uA/cm(2) was applied for 60 min. RESULTS: For AMX, therapeutically effective skin concentrations were detected immediately after the application of electrical current for any of the current density tested and remained above it for at least 2 h from the end of iontophoresis. For CFX, skin concentrations rose above MIC only at the higher current densities and fell below the MIC by the end of the experiment. CONCLUSION: Iontophoresis is a promising method to obtain a fast and sustained concentration of AMX and CFX in skin. PMID- 23350693 TI - Ground state proton transfer in phenol-(NH3)(n) (n <= 11) clusters studied by mid IR spectroscopy in 3-10 MUm range. AB - The infrared (IR) spectra of size-selected phenol-ammonia clusters, PhOH (NH(3))(n) (n <= 11) in the 3-10 MUm wavelength region were measured to investigate the critical number of solvent molecules necessary to promote the ground state proton transfer (GSPT) reaction. While the N-H stretching vibrations did not provide clear information, characteristic changes that are assigned to the GSPT reaction were observed in the skeletal vibrational region. The production of phenolate anion (PhO(-)), which is a product of the GSPT reaction, was established from the appearance of characteristic bands assignable to C-C stretching and C-H bending vibrations of PhO(-) and from the corresponding disappearance of C-O-H bending vibration of PhOH at n = 9. The mid-IR spectroscopy directly proves the structural change induced by the deprotonation from the O-H bond and thus establishes the GSPT reaction as complete at n = 9. No such absorptions were observed for n <= 5 in line with a previous report. For n = 6-8, both the proton transferred and the nontransferred signatures were observed in the spectra, showing coexistence of both species for the first time. PMID- 23350694 TI - Site-specific PEGylation of human thyroid stimulating hormone to prolong duration of action. AB - Recombinant human thyroid stimulating hormone (rhTSH or Thyrogen) has been approved for thyroid cancer diagnostics and treatment under a multidose regimen due to its short circulating half-life. To reduce dosing frequency, PEGylation strategies were explored to increase the duration of action of rhTSH. Lysine and N-terminal PEGylation resulted in heterogeneous product profiles with 40% or lower reaction yields of monoPEGylated products. Eleven cysteine mutants were designed based on a structure model of the TSH-TSH receptor (TSHR) complex to create unique conjugation sites on both alpha and beta subunits for site-specific conjugation. Sequential screening of mutant expression level, oligomerization tendency, and conjugation efficiency resulted in the identification of the alphaG22C rhTSH mutant for stable expression and scale-up PEGylation. The introduced cysteine in the alphaG22C rhTSH mutant was partially blocked when isolated from conditioned media and could only be effectively PEGylated after mild reduction with cysteine. This produced a higher reaction yield, ~85%, for the monoPEGylated product. Although the mutation had no effect on receptor binding, PEGylation of alphaG22C rhTSH led to a PEG size-dependent decrease in receptor binding. Nevertheless, the 40 kDa PEG alphaG22C rhTSH showed a prolonged duration of action compared to rhTSH in a rat pharmacodynamics model. Reverse phase HPLC and N-terminal sequencing experiments confirmed site-specific modification at the engineered Cys 22 position on the alpha-subunit. This work is another demonstration of successful PEGylation of a cysteine-knot protein by an engineered cysteine mutation. PMID- 23350695 TI - The potential impact of washing machines on laundry malodour generation. AB - A multidisciplinary approach has been adopted to investigate and identify the source of malodour in washing machines and the potential for cross-contamination of laundry. Four washing machines were olfactively graded, and the number of colony-forming units (CFUs) bacteria was determined in four specific locations. Then, samples of terry-towel and fleece were washed, without the use of detergent, in the machines, and the occurrence of malodour over a 52-h period was assessed. Analysis of the scrapings from the four locations in the two malodorous machines identified a plethora of volatile organic compounds (VOCs) by either olfactory detection or mass spectral identification post-gas chromatographic separation. In addition, microbiological analysis from the swabs from the four locations within all four washing machines was carried out. Quantitative analysis of VOCs from 66 microbiological isolates from either the washing machines or fabrics was carried out. In total, 10 VOCs were identified: dimethyl disulfide, 3 methyl-1-butanol, 2,4-dithiapentane, dimethyl trisulfide, 2-tridecanone, indole, 2-phenylethanol, isovaleric acid, isobutyric acid and 1-undecene. PMID- 23350696 TI - Effect of the approach to insulin therapy on glycaemic fluctuations and autonomic tone in hospitalized patients with diabetes. AB - AIMS: Glycaemic variability (GV) is associated with mortality in acutely ill patients, but the mechanism is unknown. The objective of this study is to determine whether common approaches to insulin therapy have distinct effects on GV and autonomic tone. METHODS: Hospitalized patients with diabetes were randomized to short-term intravenous (IV) or physiologic subcutaneous (SQ) insulin. Heart rate variability (HRV) and cardiac impedance (pre-ejection period, PEP) were used to estimate parasympathetic and sympathetic tone, respectively. GV was measured using a continuous glucose monitor. RESULTS: Mean glucose tended to be lower initially in the SQ group (N = 16) compared with the IV group (N = 17) on day 1 (10.5 vs. 8.6 mmol/l, p = 0.05), but became non-significant during the transition off of the infusion. There was no difference in glycaemic lability index (GLI), continuous overlapping net glycaemic action (CONGA) or coefficient of variation (CV) on day 1, but by day 2, these measures were higher in the IV group (p < 0.05 for all). PEP was higher in the SQ group during (110 vs. 123 ms, p = 0.02) and after the intervention (104 vs. 126 ms, p = 0.004). Hypoglycaemia was similar in both groups. There were only small differences in HRV. Post treatment PEP was inversely correlated with log GLI (r = -0.41, p = 0.03) but not other measures. CONCLUSIONS: Short-term IV insulin is associated with an increase in multiple GV measures compared with optimal SQ insulin. However, GLI was the only predictor of PEP. Further research is needed to determine if interventions that minimize GV improve outcomes in the hospital. PMID- 23350697 TI - Tailoring crystal structure and morphology of LiFePO4/C cathode materials synthesized by heterogeneous growth on nanostructured LiFePO4 seed crystals. AB - Porous and coarse (5-10 MUm) LiFePO4/C composites with excellent electrochemical performance were synthesized by a growth technology using nanostructured (100-200 nm) LiFePO4 as seed crystals for the 2nd crystallization process. The porous and coarse LiFePO4/C presented a high initial discharge capacity (~155 mA h g-1 at 0.1 C), superior rate-capability (~100 mA h g-1 at 5 C, ~65 % of the discharge capacity at 0.1 C), and excellent cycling performance (~131 mA h g-1, ~98 % of its initial discharge capacity after 100 cycles at 1 C). The improvement in the rate-capability of the LiFePO4/C was attributed to the high reaction area resulted from the pore tunnels formed inside LiFePO4 particles and short Li-ion diffusion length. The improved cycling performance of the LiFePO4/C resulted from the enhanced structural stability against Li-deficient LiFePO4 phase formation after cycling by the expansion of the 1D Li-ion diffusion channel in the LiFePO4 crystal structure. PMID- 23350698 TI - A small peptide mimetic of brain-derived neurotrophic factor promotes peripheral myelination. AB - The expression of the neurotrophins and their receptors is essential for peripheral nervous system development and myelination. We have previously demonstrated that brain-derived neurotrophic factor (BDNF) exerts contrasting influences upon Schwann cell myelination in vitro - promoting myelination via neuronally expressed p75NTR, but inhibiting myelination via neuronally expressed TrkB. We have generated a small peptide called cyclo-dPAKKR that structurally mimics the region of BDNF that binds p75NTR. Here, we have investigated whether utilizing cyclo-dPAKKR to selectively target p75NTR is an approach that could exert a unified promyelinating response. Like BDNF, cyclo-dPAKKR promoted myelination of nerve growth factor-dependent neurons in vitro, an effect dependent on the neuronal expression of p75NTR. Importantly, cyclo-dPAKKR also significantly promoted the myelination of tropomyosin-related kinase receptor B expressing neurons in vitro, whereas BDNF exerted a significant inhibitory effect. This indicated that while BDNF exerted a contrasting influence upon the myelination of distinct subsets of dorsal root ganglion (DRG) neurons in vitro, cyclo-dPAKKR uniformly promoted their myelination. Local injection of cyclo dPAKKR adjacent to the developing sciatic nerve in vivo significantly enhanced myelin protein expression and significantly increased the number of myelinated axons. These results demonstrate that cyclo-dPAKKR promotes peripheral myelination in vitro and in vivo, suggesting it is a strategy worthy of further investigation for the treatment of peripheral demyelinating diseases. PMID- 23350699 TI - ALG-2-interacting Tubby-like protein superfamily member PLSCR3 is secreted by an exosomal pathway and taken up by recipient cultured cells. AB - PLSCRs (phospholipid scramblases) are palmitoylated membrane-associating proteins. Regardless of the given names, their physiological functions are not clear and thought to be unrelated to phospholipid scrambling activities observed in vitro. Using a previously established cell line of HEK-293 (human embryonic kidney-293) cells constitutively expressing human Scr3 (PLSCR3) that interacts with ALG-2 (apoptosis-linked gene 2) Ca2+-dependently, we found that Scr3 was secreted into the culture medium. Secretion of Scr3 was suppressed by 2-BP (2 bromopalmitate, a palmitoylation inhibitor) and by GW4869 (an inhibitor of ceramide synthesis). Secreted Scr3 was recovered in exosomal fractions by sucrose density gradient centrifugation. Palmitoylation sites and the N-terminal Pro-rich region were necessary for efficient secretion, but ABSs (ALG-2-binding sites) were dispensable. Overexpression of GFP (green fluorescent protein)-fused VPS4B(E235Q), a dominant negative mutant of an AAA (ATPase associated with various cellular activities) ATPase with a defect in disassembling ESCRT (endosomal sorting complex required for transport)-III subunits, significantly reduced secretion of Scr3. Immunofluorescence microscopic analyses showed that Scr3 was largely localized to enlarged endosomes induced by overexpression of a GFP-fused constitutive active mutant of Rab5A (GFP-Rab5A(Q79L)). Secreted Scr3 was taken up by HeLa cells, suggesting that Scr3 functions as a cell-to-cell transferable modulator carried by exosomes in a paracrine manner. PMID- 23350701 TI - Serum orexin-A (OXA) level decreases in polycystic ovarian syndrome. AB - AIM: In the current study, we aimed to investigate whether serum orexin-A (OXA) levels are different in polycystic ovary syndrome (PCOS) subjects. MATERIALS AND METHODS: Thirty-six women with PCOS and 40 healthy, age and body mass index matched controls were included in the prospective cross-sectional study. All subjects underwent venous blood draws during the early follicular phase after overnight fasting. Serum OXA levels were measured with an enzyme immunoassay (EIA). The relationships between the serum OXA levels and the anthropometric and metabolic parameters were also assessed. RESULTS: The serum OXA levels were lower in the women with PCOS compared to the control group. The serum OXA levels were correlated negatively with systolic blood pressure, the Ferriman-Gallway score and LH and free testosterone levels. CONCLUSION: Our results indicate that serum OXA levels decrease in the serum of women with PCOS. PMID- 23350700 TI - Divergent requirements for fibroblast growth factor signaling in zebrafish maxillary barbel and caudal fin regeneration. AB - The zebrafish maxillary barbel is an integumentary organ containing skin, glands, pigment cells, taste buds, nerves, and endothelial vessels. The maxillary barbel can regenerate (LeClair & Topczewski 2010); however, little is known about its molecular regulation. We have studied fibroblast growth factor (FGF) pathway molecules during barbel regeneration, comparing this system to a well-known regenerating appendage, the zebrafish caudal fin. Multiple FGF ligands (fgf20a, fgf24), receptors (fgfr1-4) and downstream targets (pea3, il17d) are expressed in normal and regenerating barbel tissue, confirming FGF activation. To test if specific FGF pathways were required for barbel regeneration, we performed simultaneous barbel and caudal fin amputations in two temperature-dependent zebrafish lines. Zebrafish homozygous for a point mutation in fgf20a, a factor essential for caudal fin blastema formation, regrew maxillary barbels normally, indicating that the requirement for this ligand is appendage-specific. Global overexpression of a dominant negative FGF receptor, Tg(hsp70l:dn-fgfr1:EGFP)(pd1) completely blocked fin outgrowth but only partially inhibited barbel outgrowth, suggesting reduced requirements for FGFs in barbel tissue. Maxillary barbels expressing dn-fgfr1 regenerated peripheral nerves, dermal connective tissue, endothelial tubes, and a glandular epithelium; in contrast to a recent report in which dn-fgfr1 overexpression blocks pharyngeal taste bud formation in zebrafish larvae (Kapsimali et al. 2011), we observed robust formation of calretinin positive tastebuds. These are the first experiments to explore the molecular mechanisms of maxillary barbel regeneration. Our results suggest heterogeneous requirements for FGF signaling in the regeneration of different zebrafish appendages (caudal fin versus maxillary barbel) and taste buds of different embryonic origin (pharyngeal endoderm versus barbel ectoderm). PMID- 23350702 TI - Exogenous insulin requirements do not differ between youth and adults with cystic fibrosis related diabetes. AB - OBJECTIVE: To examine whether insulin requirements and diabetes control differ between adolescents and adults with cystic fibrosis related diabetes (CFRD). METHODS: All CFRD patients on insulin therapy seen at the University of Minnesota outpatient clinic from 1 January 2011 to 1 June 2012 were identified. Hemoglobin A1c (HbA1c) levels obtained during this period were averaged for each patient, and the most recent outpatient insulin dose was obtained. In addition, retrospective chart review was performed in order to obtain longitudinal data on insulin requirements during the transition from adolescence to adulthood. RESULTS: Eighteen youth aged 14-19 yr and 137 adults aged 20-67 yr were identified to be currently on insulin therapy. The average insulin dose was 0.38 +/- 0.29 units/kg/d for adolescents and 0.46 +/- 0.30 units/kg/d for adults (p = 0.20). In adults, insulin doses were significantly higher in transplant recipients: Tx = 0.58 +/- 0.29, no Tx = 0.43 +/- 0.30 (p = 0.005). Average HbA1c was 6.9 +/- 2.1% in youth and 6.9 +/- 1.5% in adults (p = 0.35). There were no changes in the insulin dosage when adolescents transitioned to adulthood with diabetes were not on higher doses of insulin compared to when they were adolescents with diabetes. CONCLUSION: Modest insulin requirements suggest the persistence of endogenous insulin secretion in both youth and adults with CFRD. In adolescents, residual endogenous insulin secretion likely compensates for the insulin resistance during puberty, keeping insulin requirements low. PMID- 23350703 TI - A comparative study of colour and perfusion between two different post surgical scars. Do the laser Doppler imager and the colorimeter measure the same features of a scar? AB - BACKGROUND/PURPOSE: The purpose of this study was to investigate the influence of different located post surgical scars on both perfusion and redness. The pattern of change and correlation between perfusion and redness of post surgical scars is also examined. METHODS: In this study, we measured redness and perfusion of the abdominal and breast scar of 24 women undergoing breast reconstruction with Deep Inferior Epigastric Perforator Free Flap surgery with the Minolta Chromameter CR 400/410 and the Moor Instruments laser Doppler imager 12IR, respectively, at different intervals post-operatively. RESULTS: The laser Doppler imager gives significantly higher values for the abdominal compared with the breast scar. There was no consistent correlation found between perfusion and redness at the different test moments for both locations. The scores of both parameters were significantly associated after 9 months follow-up for both locations. CONCLUSION: Scars closed with higher mechanical force show higher perfusion and prolonged activity; and more redness is associated with more perfusion for both post surgical scars. Nevertheless, there was no consistent correlation found between these parameters making the laser Doppler imager and the Colorimeter still non replaceable instruments. PMID- 23350705 TI - Redox-controlled selective docking in a [2]catenane host. AB - The docking by neutral and charged guests selectively in two geometrically different binding pockets in a dynamic [2]catenane host is demonstrated in the solid state by manipulating its redox chemistry. The change in redox properties, not only alters the affinity of the host toward neutral and charged guests, but it also induces a profound change in the geometry of the host to accommodate them. X-ray crystallography, performed on the two different 1:1 complexes, demonstrates unambiguously the fact that the [2]catenane host provides a uniquely different binding pocket wherein a methyl viologen dication is stabilized by interacting with a bipyridinium radical cation, despite the presence of Coulombic repulsions. PMID- 23350704 TI - Determining in-patient diabetes treatment satisfaction in the UK--the DIPSat study. AB - AIMS: To measure in-patient diabetes treatment satisfaction and its relationship to in-patient diabetes care. METHODS: In a cross-sectional study, diabetes in patient specialist nurses at 58 UK hospitals asked insulin-treated in-patients with diabetes to complete the recently updated Diabetes Treatment Satisfaction Questionnaire for In-patients and a general questionnaire; 1319 in-patients completed these questionnaires. RESULTS: Satisfaction with the general diabetes treatment items in the Diabetes Treatment Satisfaction Questionnaire for In patients was high, but there were high levels of extreme dissatisfaction with meal choices, meal quality and lack of similarity of hospital meals to normal domestic choices--23% would never or rarely have made similar meal choices at home. Hyperglycaemia or hypoglycaemia was reported for much of the in-patient stay (20% and 7%, respectively) and 26% reported at least one severe hypoglycaemic episode; these groups had lower satisfaction with the timing of medication in relation to meals (P < 0.003). More frequent in-patient hyperglycaemia or hypoglycaemia were associated with significantly poorer overall satisfaction scores and negative well-being scores (both P < 0.0001). Previous experience of a multiple daily insulin injection regimen was associated with more dissatisfaction than other regimens (P < 0.01). Multiple regression models explained 36% of variability in overall treatment satisfaction, with most (22.4%) accounted for by satisfaction with time spent with a diabetes in-patient specialist nurse (P < 0.0001). Self-administration of insulin was independently associated with higher treatment satisfaction (P < 0.006) in this model. CONCLUSIONS: The DIPSat programme describes the complex relationships between diabetes in-patient treatment satisfaction and in-patient diabetes care. PMID- 23350706 TI - Molecular reorganization in organic field-effect transistors and its effect on two-dimensional charge transport pathways. AB - Charge transport in organic thin film transistors takes place in the first few molecular layers in contact with the gate dielectric. Here we demonstrate that the charge transport pathways in these devices are extremely sensitive to the orientational defects of the first monolayers, which arise from specific growth conditions. Although these defects partially heal during the growth, they cause depletion of charge carriers in the first monolayer, and drive the current to flow in the monolayers above the first one. Moreover, the residual defects induce lower crystalline order and charge mobility. These results, which are not intuitively explained by electrostatics arguments, have been obtained by combining in situ real time structural and electrical characterization together with ex situ AFM measurements, on thin films of a relevant n-type organic semiconductor, N,N'-bis(n-octyl)-dicyanoperylene-3,4:9,10-bis dicarboximide grown by sublimation in a quasi-layer-by-layer mode at different substrate temperatures. PMID- 23350707 TI - Physicochemical properties and applications of poly(lactic-co-glycolic acid) for use in bone regeneration. AB - Poly(lactic-co-glycolic acid) (PLGA) is the most often used synthetic polymer within the field of bone regeneration owing to its biocompatibility and biodegradability. As a consequence, a large number of medical devices comprising PLGA have been approved for clinical use in humans by the American Food and Drug Administration. As compared with the homopolymers of lactic acid poly(lactic acid) and poly(glycolic acid), the co-polymer PLGA is much more versatile with regard to the control over degradation rate. As a material for bone regeneration, the use of PLGA has been extensively studied for application and is included as either scaffolds, coatings, fibers, or micro- and nanospheres to meet various clinical requirements. PMID- 23350708 TI - Protective effect of standardized extract of Cleome viscosa against experimentally induced gastric lesions in the rat. AB - CONTEXT: Cleome viscosa Linn. (Capparidaceae) is used traditionally in the Indian system of medicine as a carminative, anthelmintic, and diuretic, and used for healing wounds, ulcers and diarrhea. OBJECTIVE: A 70% ethanol (EtOH) extract of the aerial parts of Cleome viscosa extract (CVE) was investigated for gastroprotective activity in different gastric ulcer models in order to validate ethnobotanical claims regarding the plant use in ulcers. MATERIALS AND METHODS: CVE (100, 200 and 400 mg/kg body weight) was administered orally, twice daily for 5 d, for prevention from EtOH, pylorus ligation (PL) and cold restraint stress (CRS)-induced ulcers in rats. Estimation of H(+)K(+)ATPase activity and gastric wall mucous were performed in EtOH-induced ulcer, antioxidant enzyme activities in supernatant mitochondrial fraction of CRS-induced ulcer, and gastric secretion parameters were estimated in PL-induced ulcer model. RESULTS: CVE showed significant (p < 0.01) dose-dependent inhibition of lesion index in EtOH 15.93 42.30%, PL 26.34-59.28% and CRS 22.58-54.03%, respectively. CVE prevents the oxidative damage of gastric mucosa by blocking lipid peroxidation and by a significant (p < 0.001) decrease in superoxide dismutase, and an increase in catalase activity. A significant (p < 0.01) decrease occurred in the level of H(+)K(+)ATPase, volume of gastric juice and total acidity. Simultaneously, the level of gastric wall mucus and pH were increased significantly (p < 0.05). High performance thin layer chromatography analysis showed the presence of quercetin and gallic acid (0.3% and 0.25% w/w, respectively) in CVE. CONCLUSIONS: Results of our study showed that C. viscosa possesses significant gastroprotective activity, probably due to free radical scavenging activity, and validates the folklore claim. PMID- 23350709 TI - Compounding pharmacies: who is in charge? AB - Compounding pharmacies play an increasing and increasingly important role in our healthcare system, but recent media attention has exposed limited regulatory control over these organizations at the same time their role is expanding. Compounding pharmacies are not regulated in the same manner as pharmaceutical companies and are governed largely by Chapter <797>, a monograph on the pharmaceutical compounding of sterile products, issued but not enforced by the U.S. Pharmacopeial Convention. Not all states require adherence to Chapter <797>, and those that do may choose not to enforce it stringently. Furthermore, Chapter <797> is not a strong standard--for example, it does not require documentation of drug lot numbers or cross-references for patient identification. Thus, there have long been many potential quality issues associated with compounding pharmacies. As these compounding pharmacies provide important products and services, better regulation is urgently needed. Moreover, clinicians should be better aware that some injectable products they use may have been prepared by a compounding pharmacy. PMID- 23350710 TI - Sulfated small molecules targeting eBV in Burkitt lymphoma: from in silico screening to the evidence of in vitro effect on viral episomal DNA. AB - Epstein-Barr virus (EBV) infects more than 90% of the world population. Following primary infection, Epstein-Barr virus persists in an asymptomatic latent state. Occasionally, it may switch to lytic infection. Latent EBV infection has been associated with several diseases, such as Burkitt lymphoma (BL). To date, there are no available drugs to target latent EBV, and the existing broad-spectrum antiviral drugs are mainly active against lytic viral infection. Thus, using computational molecular docking, a virtual screen of a library of small molecules, including xanthones and flavonoids (described with potential for antiviral activity against EBV), was carried out targeting EBV proteins. The more interesting molecules were selected for further computational analysis, and subsequently, the compounds were tested in the Raji (BL) cell line, to evaluate their activity against latent EBV. This work identified three novel sulfated small molecules capable of decreasing EBV levels in a BL. Therefore, the in silico screening presents a good approach for the development of new anti-EBV agents. PMID- 23350711 TI - Acidemia at birth in the vigorous infant as a trigger incident to assess intrapartum care with regard to CTG patterns. AB - OBJECTIVE: To evaluate if acidemia in vigorous infants is a useful variable in the assessment of intrapartum care with regard to cardiotocographic (CTG) patterns during the second stage. METHODS: Cases (n = 241) were infants with an umbilical artery pH < 7.05, controls (n = 482) were infants with pH >= 7.05. Apgar score was >= 7 at 5 min in both groups. CTGs during the last two hours of labor were assessed and neonatal outcomes compared. A sub-analysis of cases with metabolic acidemia: pH < 7.00 and base deficit >= 12 mmol/L and acidemia: 7.00 < pH < 7.05 was performed. RESULTS: 63% of cases had a pathological CTG versus 26% of controls (p < 0.001). Patterns with severe variable decelerations had a significantly longer duration in cases. Metabolic acidemia was significantly associated with severe variable decelerations and decreased variability. Infants to cases were admitted to neonatal care in 19% versus 2% of controls (p < 0.001). With metabolic acidemia, 32% were admitted. CONCLUSION: An umbilical artery pH < 7.05 at birth of vigorous infants may be a useful variable for quality control of intrapartum management with regard to the assessment of second-stage CTGs. Differences in duration of pathological patterns indicate passiveness in academic cases. PMID- 23350713 TI - Utilization of surgery in trimodality-eligible patients with locally advanced esophageal adenocarcinoma in a nonprotocol setting. AB - Trimodality therapy with neoadjuvant chemoradiation followed by surgery significantly improves the survival of locally advanced (clinical stage IIA-III) esophageal cancer patients compared to treatment with surgery alone. This has resulted in an increased use of neoadjuvant therapy in recent years, yet little is known regarding how this increase has impacted the utilization of surgery in the treatment of locally advanced disease. Although previous reports of experimental protocols suggest that 90-95% of patients complete trimodality therapy including a surgical resection, trimodality therapy completion among adenocarcinoma patients eligible for curative resection has not been evaluated in a nonprotocol setting. We sought to (i) assess the completion of trimodality therapy among locally advanced esophageal adenocarcinoma patients; (ii) characterize the reasons for avoiding surgery; and (iii) identify factors associated with failure to complete trimodality therapy. We identified 296 patients with locally advanced esophageal adenocarcinoma eligible for trimodality therapy at our institution. All patients were evaluated in a multidisciplinary setting and considered eligible for curative resection after initial staging and physiologic assessment. Multivariable logistic regression was used to identify factors associated with failure to complete trimodality therapy. Of 296 trimodality-eligible patients, 33% (97/296) did not complete trimodality therapy. Reasons for not undergoing surgery included patient choice (27.8%, 27/97), distant progression of disease during chemoradiation (23.7%, 23/97), and physician preference for surveillance (23.7%, 23/97). In addition, 17.5% (17/97) of patients had physical deterioration in performance status, and treatment related deaths occurred in 7.2% (7/97) prior to surgery. In the total study population (n = 296), multivariable logistic regression identified older age (>=70 years: odds ratio [OR] = 6.611, 95% confidence interval [CI]: 2.900 15.071), pretreatment standard uptake value (6.8-10.1: OR = 2.393, 95% CI: 1.050 5.455; >=15.8: OR = 3.623, 95% CI: 1.604-8.186), and a radiation dose of 50.4 Gy (OR = 5.312, 95% CI: 2.365-11.929) as being significantly associated with failure to complete trimodality therapy. Among the subgroup of patients that successfully completed chemoradiation (n = 266), older patients (>=70 years: OR = 9.606, 95% CI: 3.637-25.372), those with a comorbidity score of 2 or higher (OR = 4.059, 95% CI: 1.257-13.103), and those that received a radiation dose of 50.4 Gy (OR = 4.878, 95% CI: 1.974-12.054) were at a significantly higher risk of not completing trimodality therapy. Trimodality therapy completion among patients with locally advanced esophageal adenocarcinoma in a nonprotocol setting is considerably lower than what has previously been reported in clinical trials. Our findings suggest that a selective approach to surgery is commonly utilized in clinical practice. Trimodality-eligible patients that are older and have a higher comorbidity score are at risk for not completing trimodality therapy. PMID- 23350712 TI - Presence or absence of a positive pathological margin outperforms any other margin-associated variable in predicting clinically relevant biochemical recurrence in Gleason 7 prostate cancer. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The presence of a positive pathological margin is an independent risk factor for clinically significant disease recurrence only in intermediate-risk disease when the a priori risk of micrometastatic disease is accounted for. The study examines patients with Gleason 7 prostate cancer to assess the relative importance of various margin-related variables (focality, linear length, tumour grade at margin, presence of diathermy artifact and plane of tumour) with regard to biochemical recurrence. We found that the presence or absence of a positive pathological margin outperforms any other margin-associated variable in predicting significant disease recurrence. OBJECTIVE: To determine the influence of pathological margin variables on the risk of clinically significant biochemical recurrence in Gleason 7 prostate cancer. MATERIALS AND METHODS: Patients with Gleason 7 prostate cancer with complete clinical and pathological data and detailed follow-up were identified from a prospectively recorded prostatectomy database. Slides from all patients with positive pathological margins were reviewed by a single expert uropathologist and the following information recorded: multifocality, linear length, predominant Gleason grade at the margin, diathermy artifact and margin plane. Cox regression models were generated to determine the impact of positive pathological margins on the risk of biochemical recurrence (using various definitions thereof). RESULTS: Of 1048 patients with Gleason 7 prostate cancer, 238 (23%) patients had positive margins. With a median follow-up of 11 months, biochemical recurrence occurred in 9.7% of patients with negative surgical margins and 28.4% of patients with positive margins. Positive margins were significantly associated with higher serum prostate-specific antigen (PSA) level, tumour grade, stage and volume. In patients with positive pathological margins, controlling for other factors, no margin-derived variable (focality, linear length, tumour grade at margin, diathermy artifact or plane of tumour) was a consistent predictor of biochemical recurrence, although the presence of Gleason score 4 or tertiary Gleason score 5 tumour at the margin edge was an independent predictor of recurrence with PSA doubling times <= 6 and <=9 months. Similarly, in the cohort as a whole, the pathological margin status was a more important predictor of recurrence than any other margin-derived variable. CONCLUSIONS: In Gleason 7 prostate cancer, positive pathological margin status was the only consistent margin-derived variable determining biochemical failure. The presence of high-grade disease at the margin may also have an impact on the development of clinically significant biochemical recurrence. PMID- 23350714 TI - Association of thymidylate synthase gene 3'-untranslated region polymorphism with sensitivity of non-small cell lung cancer to pemetrexed treatment: TS gene polymorphism and pemetrexed sensitivity in NSCLC. AB - BACKGROUND: Thymidylate synthase (TS) is a key enzyme responsible for DNA synthesis and repair. Altered expression of TS protein or TS gene polymorphisms has been associated with cancer progression and treatment response. This study investigated the expressions of TS and its gene SNPs in non-small cell lung cancer (NSCLC), and then its association with sensitivity to pemetrexed treatment. Immunohistochemistry and qRT-PCR were performed on 160 resected NSCLC specimens and corresponding normal tissues to assess the expressions of TS protein and TS mRNA, and for associations with clinicopathological data. Blood samples of 106 lung adenocarcinoma patients were examined for polymorphisms of the TS gene 3'-UTR 1494del 6 bp, which was then investigated for associations with responses of the patients to pemetrexed treatment and survival. RESULTS: Expression of both TS protein and its mRNA was elevated in NSCLC tissues compared with matched normal tissues, and significantly higher in lung squamous cell carcinoma than in lung adenocarcinoma. TS expression was associated with poor tumor differentiation. Furthermore, the genotyping data showed that 56% of lung adenocarcinoma patients had the TS gene 3'-UTR 1494 bp (-6 bp/-6 bp) genotype and the rest had TS gene 3'-UTR 1494 bp (-6 bp/+6 bp). There was no TS 3'-UTR 1494 bp (+6 bp/+6 bp) genotype in any patients. Statistical analysis revealed that gender, tumor stage, and TS 3'-UTR 1494del 6 bp polymorphism were significant prognostic factors after short-term pemetrexed treatment. Log-rank analysis revealed that patients with the (-6 bp/-6 bp) genotype had significantly better progression-free and overall survival than patients with (-6 bp/+6 bp). CONCLUSIONS: This study showed that TS protein is highly expressed in NSCLC and that polymorphisms of TS 3'-UTR 1494del 6 bp are associated with sensitivity of lung adenocarcinoma patients to pemetrexed treatment. This suggests that TS gene polymorphisms should be further evaluated as prognostic markers for personalized therapy in lung adenocarcinoma. PMID- 23350715 TI - The corneal endothelium after keratoplasty for keratoconus. AB - BACKGROUND: The aim was to assess the corneal endothelium, post-operative visual outcome and complications following keratoplasty for keratoconus. METHODS: Seventy-six corneal grafts (57 per cent penetrating keratoplasties and 43 per cent deep anterior lamellar keratoplasties) were assessed as part of routine follow-up at the Ophthalmology Department at Gartnavel General Hospital in Glasgow. Routine ophthalmic assessment included visual acuity, slitlamp biomicroscopy and scanning slit confocal microscopy of the central cornea. Case records were reviewed and demographic, surgical and post-operative data retrieved. Linear and logistic regression models were used to determine associations between endothelial cell density, visual acuity and post-operative complications. Kaplan-Meier analysis was used to estimate the probability for grafts to retain more than 700 endothelial cells per mm(2) and to have 0.3 logMAR or better vision. Odds ratios were calculated to assess the risk for low cell counts and poor visual outcome. RESULTS: The mean and standard deviation of the endothelial cell count was predictably higher in lamellar (2033 +/- 643 cells per mm(2)) than penetrating keratoplasties (898 +/- 380 cells per mm(2)) and the mean post-operative cell count for grafts without post-operative complications was higher (1585 +/- 775) than those with complications (1312 +/- 747 cells per mm(2)). Mean visual acuity was 0.25 +/- 0.20 and 0.29 +/- 0.41 for lamellar and penetrating keratoplasties, respectively. A higher number of post-operative events was associated with an increased risk for graft rejection (odds ratio 2.40, p = 0.008, multiple logistic regression) and with poorer visual outcome (odds ratio 1.38, p = 0.044). After keratoplasty, the visual outcome and endothelial cell density were not associated, either in penetrating or deep anterior lamellar grafts (p > 0.05). CONCLUSIONS: In keratoplasties performed for keratoconus, visual outcome cannot be predicted reliably by post-operative endothelial cell density but post-operative events can lead to poorer visual outcomes in both types of grafts. PMID- 23350716 TI - Accumulation of mutations over the complete mitochondrial genome in tobacco related oral cancer from northeast India. AB - Northeast India has one of the world's highest incidences of oral cancer and 90% of them are related to tobacco. We examined the complete mitochondrial genome to determine hot spot mutations in oral cancer. The complete mitochondrial genome was sequenced using PGMTM from 10 patients matched blood and tumour tissue. Overall, 26 somatic mutations were found of which nine mutations in d-loop and 17 mutations in the coding region. The mutations at nucleotide positions 16294, 16325 and 16463 in d-loop and 4136, 13542 and 13869 in coding region are probably an indication to be a hot spot mutation in oral cancer. The knowledge about role, patterns and timing of mitochondrial mutations may serve to be facilitating clinical applications and hot spot mutations may be helpful in assessing cancer risk in tumour. PMID- 23350717 TI - Vibrational spectra and structures of Ti-N2O and OTi-N2: a combined IR matrix isolation and theoretical study. AB - The reaction of atomic titanium with nitrous oxide has been reinvestigated using matrix isolation in solid neon coupled to infrared spectroscopy and by quantum chemical methods. Our technique of sublimation of Ti atoms from a filament heated at about 1500 degrees C allowed the formation of three species: one Ti-N(2)O pair of van der Waals (vdW) type characterized by small red shift with respect to N(2)O monomer, and two isomers of OTi-N(2) pair where N(2) is in interaction with the OTi moiety either with end-on or side-on structure. Interconversion between these structures has been performed with several wavelengths. In the visible and near-ultraviolet the conversion vdW -> OTi-N(2) (end-on) is observed with characteristic times strongly varying according to the wavelength. In the near infrared the conversion OTi-N(2) (end-on) -> OTi-N(2) (side-on) occurs, the vdW species remaining unchanged. These selectivities allow 8, 6, and 4 vibrational transitions to be assigned for vdW, (3)[OTi(eta(1)-NN)] (end-on), and (1)[OTi(eta(2)-NN)] (side-on), respectively. Electronic and geometrical structures are also investigated with double-hybrid functionals. It has been shown that the side-on geometry corresponds to the ground state of (1)[OTi(eta(2) NN)] in the singlet electronic state. The theoretical vibrational analysis supports well the experimental attributions. PMID- 23350718 TI - Sleep-disordered breathing in major depressive disorder. AB - Individuals with major depressive disorder often experience obstructive sleep apnea. However, the relationship between depression and less severe sleep disordered breathing is unclear. This study examined the rate of sleep-disordered breathing in depression after excluding those who had clinically significant sleep apnea (>5 apneas?h-1). Archival data collected between 1991 and 2005 were used to assess the prevalence of sleep-disordered breathing events in 60 (31 depressed; 29 healthy controls) unmedicated participants. Respiratory events were automatically detected using a program developed in-house measuring thermal nasal air-flow and chest pressure. Results show that even after excluding participants with clinically significant sleep-disordered breathing, individuals with depression continue to exhibit higher rates of sleep-disordered breathing compared with healthy controls (depressed group: apnea-hypopnea index mean = 0.524, SE = 0.105; healthy group: apnea-hypopnea index mean = 0.179, SE = 0.108). Exploratory analyses were also conducted to assess for rates of exclusion in depression studies due to sleep-disordered breathing. Study exclusion of sleep disordered breathing was quantified based on self-report during telephone screening, and via first night polysomnography. Results from phone screening data reveal that individuals reporting depression were 5.86 times more likely to report a diagnosis of obstructive sleep apnea than presumptive control participants. Furthermore, all of the participants excluded for severe sleep disordered breathing detected on the first night were participants with depression. These findings illustrate the importance of understanding the relationship between sleep-disordered breathing and depression, and suggest that screening and quantification of sleep-disordered breathing should be considered in depression research. PMID- 23350719 TI - Tracing the genetic roots of the indigenous White Park Cattle. AB - The White Park Cattle (WPC) is an indigenous ancient breed from the British Isles which has a long-standing history in heroic sagas and documents. The WPC has retained many primitive traits, especially in their grazing behaviour and preferences. Altogether, the aura of this breed has led to much speculation surrounding its origin. In this study, we sequenced the mitogenomes from 27 WPC and three intronic fragments of genes from the Y chromosome of three bulls. We observed six novel mitogenomic lineages that have not been found in any other cattle breed so far. We found no evidence that the WPC is a descendant of a particular North or West European branch of aurochs. The WPC mitogenomes are grouped in the T3 cluster together with most other domestic breeds. Nevertheless, both molecular markers support the primitive position of the WPC within the taurine breeds. PMID- 23350720 TI - Neuroprotection conferred by post-ischemia ethanol therapy in experimental stroke: an inhibitory effect on hyperglycolysis and NADPH oxidase activation. AB - Ethanol provides neuroprotection following ischemia/reperfusion. This study assessed ethanol's effect on hyperglycolysis and NADPH oxidase (NOX) activation. Adult, male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Three sets of experiments were conducted to determine ethanol's effect on (i) conferring neuroprotection by measuring infarct volume and neurological deficits 24 h post reperfusion; (ii) cerebral glucose metabolism and lactic acidosis by measuring brain and blood glucose concentrations and protein expression of glucose transporter 1 and 3 (GLUT1, GLUT3), phosphofructokinase (PFK), as well as lactic acidosis by measuring lactate dehydrogenase (LDH), and lactate; and (iii) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activation by detecting enzymatic activity and subunit expression at 3 h after reperfusion. When administered upon reperfusion, ethanol (1.5 g/kg) reduced infarct volume by 40% (p < 0.01) and neurological deficits by 48% at 24 h post reperfusion while reducing (p < 0.01) elevations in glycolytic protein expression and lactate levels during early reperfusion (3 h). Ethanol increased the reductions in cerebral glucose concentration at 3 h post reperfusion by 64% (p < 0.01) while enhancing (p < 0.01) post stroke blood glucose concentration, suggesting a reduced cellular glucose uptake and utilization. Ethanol decreased (p < 0.01) stroke-induced NOX activation by reducing enzymatic activity and gp91(phox) expression by 45% and 38%, respectively. Post-ischemia ethanol treatment exerts neuroprotection through attenuation of hyperglycolysis and associated NOX activation. Because of the lack of associated hypoglycemia and selectivity toward decreasing cerebral metabolism, further investigation of ethanol's use as a post-stroke therapy, especially in the context of hyperglycemia, seems warranted. PMID- 23350721 TI - Tumor-targeting antibody-anticalin fusion proteins for in vivo pretargeting applications. AB - Pretargeting approaches rely on the injection of bispecific antibodies capable of recognizing both an accessible disease marker and a small ligand, which is typically administered at a later stage and which serves as delivery vehicle for a payload for imaging or therapy applications. In the oncology field, pretargeting strategies have exhibited extremely promising biodistribution results and in vivo selectivity, but have often relied on the cumbersome preparation of multispecific antibodies by chemical conjugation techniques. Here, we describe the design, production, and characterization of a novel class of bispecific multivalent antibody products, which contain both antibody fragments and an anticalin moiety for the simultaneous recognition of tumor-associated antigens and a small organic molecule. Anticalins are derivatives of the naturally occurring binding proteins lipocalins, which have been engineered to recognize a target molecule with high affinity. In particular, we produced and compared in vitro and in vivo different fusion proteins, which contained the anticalin FluA that selectively recognizes various different fluorescein derivatives and the F8 antibody specific to the alternatively spliced EDA domain of fibronectin (a marker of tumor angiogenesis). The selective accumulation of the most promising fusion-protein scFv(F8)-FluA-scFv(F8) on solid tumors and simultaneous binding of fluorescein derivatives could be visualized in vivo using a fluorescein-near-infrared fluorescent dye conjugate, confirming the potential of antibody-anticalin fusion proteins for pretargeting applications. PMID- 23350722 TI - Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. AB - The purpose of this report was to update the 2006 International League Against Epilepsy (ILAE) report and identify the level of evidence for long-term efficacy or effectiveness for antiepileptic drugs (AEDs) as initial monotherapy for patients with newly diagnosed or untreated epilepsy. All applicable articles from July 2005 until March 2012 were identified, evaluated, and combined with the previous analysis (Glauser et al., 2006) to provide a comprehensive update. The prior analysis methodology was utilized with three modifications: (1) the detectable noninferiority boundary approach was dropped and both failed superiority studies and prespecified noninferiority studies were analyzed using a noninferiority approach, (2) the definition of an adequate comparator was clarified and now includes an absolute minimum point estimate for efficacy/effectiveness, and (3) the relationship table between clinical trial ratings, level of evidence, and conclusions no longer includes a recommendation column to reinforce that this review of efficacy/evidence for specific seizure types does not imply treatment recommendations. This evidence review contains one clarification: The commission has determined that class I superiority studies can be designed to detect up to a 20% absolute (rather than relative) difference in the point estimate of efficacy/effectiveness between study treatment and comparator using an intent-to-treat analysis. Since July, 2005, three class I randomized controlled trials (RCT) and 11 class III RCTs have been published. The combined analysis (1940-2012) now includes a total of 64 RCTs (7 with class I evidence, 2 with class II evidence) and 11 meta-analyses. New efficacy/effectiveness findings include the following: levetiracetam and zonisamide have level A evidence in adults with partial onset seizures and both ethosuximide and valproic acid have level A evidence in children with childhood absence epilepsy. There are no major changes in the level of evidence for any other subgroup. Levetiracetam and zonisamide join carbamazepine and phenytoin with level A efficacy/effectiveness evidence as initial monotherapy for adults with partial onset seizures. Although ethosuximide and valproic acid now have level A efficacy/effectiveness evidence as initial monotherapy for children with absence seizures, there continues to be an alarming lack of well designed, properly conducted epilepsy RCTs for patients with generalized seizures/epilepsies and in children in general. These findings reinforce the need for multicenter, multinational efforts to design, conduct, and analyze future clinically relevant adequately designed RCTs. When selecting a patient's AED, all relevant variables and not just efficacy and effectiveness should be considered. PMID- 23350723 TI - PVP and surfactant combined carrier as an effective absorption enhancer of poorly soluble astilbin in vitro and in vivo. AB - CONTEXT: Astilbin is considered to be a new and promising immunosuppressant for immune related diseases, but limited in clinical application due to its poor water solubility, difficult oral absorption and low bioavailability. OBJECTIVE: The present work studied the effect of PVP and surfactant combined carrier on its capability to improve drug absorption. MATERIALS AND METHODS: PVP K30-Tween 80 combined carries was applied into the astilbin solid dispersions, tested both in vivo in beagle dogs and in vitro in transport experiments across Caco-2 cell monolayers. RESULTS AND DISCUSSION: In the animal studies a many fold increase in plasma AUC was observed for the solid dispersions of drug in PVP K30-Tween 80 combined carries compared to active pharmaceutical ingredient (API). The applicability of Caco-2 monolayers as a tool for predicting the in vivo transport behavior of Astilbin in combination with a solubility enhancing carries was shown. In vitro transport studies confirmed the effect of combined carries on the absorption behavior of the astilbin. MTT studies showed the cell viability gradually decreased with the increase of the drug concentration in a dose dependent manner for astilbin and that in solid dispersions. The permeability and apparent permeability coefficients (Papp) increased with drug in the Caco-2 cell. CONCLUSION: In this study, it was found that PVP K30 and Tween 80 promoted the permeability of drugs best within a certain amount. For astilbin PVP K30 and surfactant combined carrier had a strong potential to improve oral bioavailability. PMID- 23350724 TI - Solid-state stability studies of faropenem based on chromatography, spectroscopy and theoretical analysis. AB - AIM: The purpose of this study was to investigate the stability of faropenem in solid state. RESULTS: The kinetic and thermodynamic parameters of degradation of faropenem were studied using an RP-HPLC method while the changes of spectral properties were investigated using derivative UV and FT-IR. Quantum-chemical calculations, based on the density functional theory, were carried out to support the estimation of the intra-ring stresses of faropenem and for theoretical interpretation of the spectra. The degradation of faropenem was a first-order reaction depending on the substrate concentration at an increased relative humidity and in dry air. The dependence ln k = f(1/T) became the ln k = (2.03 +/- 3.22) * 10(4)-(9761 +/- 3052)(1/T) in dry air and ln k = (1.25 +/- 0.22) * 10(5) (9004 +/- 3479)(1/T ) at 90.0% RH. The thermodynamic parameters Ea, DeltaH(?a), and DeltaS(?a) of the degradation of faropenem were calculated. The dependence ln k = f(RH%) assumed the form ln k = (7.58 +/- 1.88) * 10(-2) (RH%) - (5.90 +/- 3.90) * 10(-8). CONCLUSIONS: Stability studies of faropenem showed that the fusion of beta-lactam and thiazolidine rings reduces the intra-ring stress, leading to a lower susceptibility to degradation in dry air and at increased RH. PMID- 23350725 TI - Genome wide association studies for diabetes: perspective on results and challenges. AB - Recent results of genome wide association study (GWAS) for diabetes genes, while reaching impressive technical milestones and implicating new findings for research, have been uniformly disappointing in terms of immediate clinical utility. The relative risk associated with any of the newly reported genetic loci, or even considering all of them together, is far less than simply that which can be obtained by taking a history and a physical exam. For type 2 diabetes (T2D), GWAS have implicated novel pathways, supported previously known associations, and highlighted the importance of the beta cell and insulin secretion. Monogenic forms of diabetes, on the other hand, continue to yield interesting insights into genes controlling human beta cell function but most cases of monogenic diabetes are simply not diagnosed. Here, we briefly review recent results related to type 1, type 2 and maturity onset diabetes of youth (MODY) diabetes and suggest that future studies emphasizing quantitative traits are likely to yield even more insights. PMID- 23350726 TI - A nine country study of the burden of non-severe nocturnal hypoglycaemic events on diabetes management and daily function. AB - AIMS: The purpose of this study was to explore the burden and impact of non severe nocturnal hypoglycaemic events (NSNHEs) on diabetes management, patient functioning and well-being in order to better understand the role that NSNHEs play in caring for persons with diabetes and facilitate optimal diabetes treatment management strategies. METHODS: A 20-min survey assessing the impact of NSNHEs was administered to patients with self-reported diabetes age 18 or older via the Internet in nine countries (USA, UK, Germany, Canada, France, Italy, Spain, The Netherlands and Sweden) who experienced an NSNHE in the last month. Questions captured reasons for and length of the event, and impacts on diabetes management, daily function, sleep and well-being. RESULTS: A total of 20 212 persons with Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM) were screened of which 2108 respondents were eligible. Respondents initiated, on average, an additional 3.6 glucose monitoring tests, and did not resume usual functioning for an average of 3.4 hours after the NSNHE. Of the respondents using insulin, 15.8% decreased their insulin dose over an average of 3.6 days. NSNHEs also impacted sleep, with 10.4% not returning to sleep that night. Next day functioning was affected with 60.3% (n = 1273) feeling the need to take a nap and/or rest (with 65.5% of those actually taking a nap/rest) and 40.2% (n = 848) wanting to go to bed earlier than usual. A total of 21.4% were restricted in their driving the next day. These events also resulted in decreased well-being with 39.6% of respondents feeling 'emotional low' the following day. CONCLUSIONS: NSNHEs have serious consequences for patients. Greater attention to patient and physician education regarding the burden of NSNHEs and incorporation of corrective actions in treatment plans is needed to facilitate patients reaching optimal glycaemic control. PMID- 23350727 TI - Apoe, Mbl2, and Psp plasma protein levels correlate with diabetic phenotype in NZO mice--an optimized rapid workflow for SRM-based quantification. AB - Male New Zealand Obese (NZO) mice progress through pathophysiological stages similar to humans developing obesity-associated type 2 diabetes (T2D). The current challenge is to establish quantitative proteomics from small plasma sample amounts. We established an analytical workflow that facilitates a reproducible depletion of high-abundance proteins, has high throughput applicability, and allows absolute quantification of proteins from mouse plasma samples by LC-SRM-MS. The ProteoMiner equalizing technology was adjusted to the small sample amount, and reproducibility of the identifications was monitored by spike proteins. Based on the label-free relative quantification of proteins in depleted plasma of a test set of NZO mice, assays for potential candidates were designed for the setup of a targeted selected reaction monitoring (SRM) approach and absolute quantification. We could demonstrate that apolipoprotein E (Apoe), mannose-binding lectin 2 (Mbl2), and parotid secretory protein (Psp) are present at significantly different quantities in depleted plasma of diabetic NZO mice compared to non-diabetic controls using AQUA peptides. Quantification was validated for Mbl2 using the ELISA technology on non-depleted plasma. We conclude that the depletion technique is applicable to restricted sample amounts and suitable for the identification of T2D signatures in plasma. PMID- 23350728 TI - Response to Akilen et al. Efficacy and safety of 'true' cinnamon (Cinnamomum zeylanicum) as a pharmaceutical agent in diabetes: a systematic review and meta analysis. PMID- 23350729 TI - The new HLA-B*58:21 allele is predicted to be functionally similar to the B*58:01P group of alleles. AB - The new human leukocyte antigen (HLA)-B*58:21 allele differs from B*58:01:01 by an amino acid exchange at codon 90. PMID- 23350730 TI - Parathyroid and calcium metabolism disorders during pregnancy. AB - Parathyroid disorders are not common among pregnant women, but harbor a significant morbidity and mortality potential if they remain unrecognized and untreated. The symptoms caused by abnormally low or high blood free calcium level are mostly non-specific in the initial stages, thus when recognized might pose a real danger. Here we will survey the alterations in calcium metabolism induced by pregnancy, and describe the clinical manifestations, diagnosis and treatment of parathyroid and other calcium metabolism disorders during pregnancy. The current literature on the impact of calcium and vitamin D deficiency during pregnancy will also be reviewed. PMID- 23350731 TI - High-risk human papillomaviruses in two different primary tumors in the same patient. AB - Two cases of patients with high-risk human papillomavirus-related squamous cell carcinomas of the penis are reported. In both patients, a second high-risk human papillomavirus-related squamous cell carcinoma, of the same type (genotype 16), was detected: a carcinoma of the oropharynx 2 years after treatment of the squamous cell carcinomas of the penis in the first patient, and a carcinoma of the esophagus 1 year after the treatment of the squamous cell carcinomas of the penis in the second patient. To the best of our knowledge, this is the first time that multiple human papillomavirus-related tumors in the same patient are reported. It is suggested that a careful clinical investigation is necessary in patients with tumors attributable to high-risk human papillomavirus for the early detection of a possible second neoplasm related to this virus in a different organ. PMID- 23350732 TI - Structural complexity meets transport and magnetic anisotropy in single crystalline Ln30Ru4Sn31 (Ln = Gd, Dy). AB - We present the structure of Ln(30)Ru(4+x)Sn(31-y) (Ln = Gd, Dy) and the anisotropic resistivity, magnetization, thermopower, and thermal conductivity of single crystal Ln(30)Ru(4+x)Sn(31-y) (Ln = Gd, Tb). Gd(30)Ru(4.92)Sn(30.54) crystallizes in a new structure-type with space group Pnnm and dimensions of a = 11.784(1) A, b = 24.717(1) A, and c = 11.651(2) A, and V = 3394(1) A(3). Magnetic anisotropy and highly anisotropic electrical transport behavior were observed in the single crystals of Gd(30)Ru(4.92)Sn(30.54) and Tb(30)Ru(6)Sn(29.5). Additionally, the lattice thermal conductivity of Tb(30)Ru(6)Sn(29.5) is quite low, and a comparison is made to other Sn-containing compounds. PMID- 23350733 TI - Potent elastase inhibitors from cyanobacteria: structural basis and mechanisms mediating cytoprotective and anti-inflammatory effects in bronchial epithelial cells. AB - We discovered new structural diversity to a prevalent, yet medicinally underappreciated, cyanobacterial protease inhibitor scaffold and undertook comprehensive protease profiling to reveal potent and selective elastase inhibition. Structure-activity relationship (SAR) studies and X-ray cocrystal structure analysis allowed a detailed assessment of critical and tunable structural elements. To realize the therapeutic potential of these cyclodepsipeptides, we probed the cellular effects of a novel and representative family member, symplostatin 5 (1), which attenuated the downstream cellular effects of elastase in an epithelial lung airway model system, alleviating clinical hallmarks of chronic pulmonary diseases such as cell death, cell detachment, and inflammation. This compound attenuated the effects of elastase on receptor activation, proteolytic processing of the adhesion protein ICAM-1, NF kappaB activation, and transcriptomic changes, including the expression of pro inflammatory cytokines IL1A, IL1B, and IL8. Compound 1 exhibited activity comparable to the clinically approved elastase inhibitor sivelestat in short-term assays and demonstrated superior sustained activity in longer-term assays. PMID- 23350734 TI - Endotoxins-the invisible companion in biomaterials research. AB - Metal implants and polymeric devices for the application in the clinical treatment of orthopedic tissue injuries are increasingly coated with bioactive biomaterials derived from natural substances to induce desirable biological effects. Many metals and polymers used in biomaterials research show high affinity for endotoxins, which are abundant in the environment. Endotoxin contamination is indicated in the pathology of periodontitis and aseptic implant loosening, but may also affect the evaluation of a biomaterial's bioactivity by inducing strong inflammatory reactions. In this review, we discuss the high affinity of three commonly used implant biomaterials for endotoxins and how the contamination can affect the outcome of the orthopedic fixation. The chemical nature of bacterial endotoxins and some of the clinical health implications are described, as this knowledge is critically important to tackle the issues associated with the measurement and removal of endotoxins from medical devices. Commonly used methods for endotoxin testing and removal from natural substances are examined and the lack of standard guidelines for the in vitro evaluation of biomaterials is discussed. PMID- 23350735 TI - The association between low 50 g glucose challenge test result and fetal growth restriction. AB - OBJECTIVE: To determine whether a low-GCT result is predictive of low birthweight and to identify the lower GCT threshold for prediction of fetal growth restriction. METHODS: A retrospective cohort study of 12,899 women who underwent a GCT (24-28 weeks). Women with a low-GCT result (<10th percentile (70 mg/dL) were compared to women with normal-GCT result (70-140 mg/dL). ROC analysis was used to determine the optimal lower GCT threshold for the prediction of growth restriction. RESULTS: Women in the low GCT had significant lower rates of cesarean delivery (18.7% versus 22.5%), shoulder dystocia (0.0% versus 0.3%), mean birthweight (3096 +/- 576 versus 3163 +/- 545) and birthweight percentile (49.1 +/- 27.0 versus 53.1 +/- 26.7) and significant higher rates of birthweight <2500 g (11.3% versus 8.5%), below the 10th percentile (8.3% versus 6.5%) and 3rd percentile (2.3% versus 1.4%). Low GCT was independently associated with an increased risk for birthweight <2500 g (OR = 1.6, 1.2-2.0), birthweight <10th percentile (OR = 1.3, 1.1-1.6), birthweight <3rd percentile (OR = 1.7, 1.2-2.5) and neonatal hypoglycemia (OR = 1.4, 1.02-2.0). The optimal GCT threshold for the prediction of birthweight <10th percentile was 88.5 mg/dL (sensitivity 48.5%, specificity 58.1%). CONCLUSION: Low-GCT result is independently associated with low birthweight and can be used in combination with additional factors for the prediction of fetal growth restriction. PMID- 23350736 TI - Chromosomal instability and bladder cancer: the UroVysion(TM) test in the UroScreen study. AB - What's known on the subject? and what does the study add?: UroVysionTM is a multicolour fluorescence in situ hybridisation assay that detects DNA gain at chromosomes 3, 7 and 17 and loss at the 9p21 locus in exfoliated urothelial cells. This cell-based test is time-consuming and costly compared with voided urine cytology or other molecular markers for the early detection of bladder cancer. We determined copy number changes at chromosomes 3, 7 and 17 and at the 9p21 locus with UroVysion in a prospective screening study among chemical workers. Strong correlations between DNA gains yield a similar performance in detecting bladder cancer with just one of the probes for chromosomes 3, 7 or 17 instead of all, supporting the development of a simpler and cheaper assay. OBJECTIVE: To explore changes at chromosomes 3, 7, 17 and 9p21 in order to assess associations with bladder cancer for possible improvements of the UroVysionTM assay regarding screening. SUBJECTS AND METHODS: In all, 1609 men took part in the prospective study UroScreen. Annual screening for bladder cancer was offered to male chemical workers with former exposure to aromatic amines as a voluntary surveillance programme between 2003 and 2010. In all, 191 434 cells in 6517 UroVysion tests were analysed for copy number variations (CNV) at chromosome 3, 7, 17 (gains) and 9p21 (deletions) in 1595 men. We assessed CNVs at single or multiple loci using polysomy indices (PIs, called multiple PI and PI 3, PI 7 and PI 17). We calculated Spearman's rank correlation coefficients (rs ) between these PIs and receiver operating characteristic (ROC) curves with areas under the curves (AUCs). We applied Cox regression to estimate hazard ratios (HRs) to assess the risk of developing bladder cancer. RESULTS: Nine out of 21 bladder tumours detected in 20 participants ('cases') had a positive UroVysion test, including seven high-grade carcinomas and seven overlapping results with a positive cytology. Four cases with negative test results did not attend screening annually. No case was found because of a complete loss of 9p21 in at least 12 cells. There were strong correlations between pairwise combinations of gains at chromosome 3, 7 or 17, ranging between rs = 0.98 and rs = 0.99 in cases and between rs = 0.84 and rs = 0.88 in non-cases (P < 0.001). Associations were less pronounced with CNVs at 9p21 among cases and were lacking in non-cases. Estimates of the relative risk of DNA gain for developing a bladder tumour assessed with PIs (threshold 10% of cells) were 47.7 (95% confidence interval [CI] 18.3-124.1) for the multiple PI, 44.5 (95%CI 16.5-119.9) for PI 3, 34.7 (95%CI 13.1-92.1) for PI 7 and 52.4 (95%CI 20.7-132.6) for PI 17, as well as 7.9 (95%CI 3.0-20.6) for a complete loss of 9p21 (threshold 2.5% of cells), respectively. ROC analyses showed similar AUCs for multiple PI compared with PIs of single chromosomes 3, 7 and 17 (all AUCs between 0.79 and 0.80) and a lower AUC for a homozygous loss of 9p21 (AUC 0.72). CONCLUSIONS: The UroVysion assay showed a reasonable performance in detecting bladder cancer in the present study population and shared positive test results with cytology, which is much cheaper. A simpler, faster and cheaper version of the UroVysion assay might rely on the very strong correlations between gains at chromosomes 3, 7 and 17, resulting in a similar performance in detecting bladder cancer with single-probe PIs compared with the full set of these probes. Loss of 9p21 was less predictive for developing bladder cancer in UroScreen. PMID- 23350737 TI - Chiral bicyclic tetramates as non-planar templates for chemical library synthesis. AB - Chemoselective Dieckmann cyclization reactions may be used on oxazolidine and thiazolidine templates derived from various aldehydes to access bicyclic tetramates, which have potential as templates for chemical library construction. Bioassay against Staphylococcus aureus and Escherichia coli showed that these systems have little or no intrinsic antibacterial bioactivity. PMID- 23350738 TI - The weave technique for nipple reconstruction. AB - Traditional nipple reconstruction relies on local flap techniques. However, there are several problems associated with local flap reconstruction including loss of projection, widening of the base width, and difficulty working around the mastectomy scar. This study presents a variation of traditional local flap nipple reconstruction, which is termed the weave technique. Rather than using two flaps to create base width, the weave technique uses one. By controlling the base width, this may serve to sustain long-term projection. Second, filling the inside of the nipple with the second flap may contribute to longer term projection. Because there is no third flap, it is easier to orient the nipple with respect to the mastectomy scar. To date, the senior author has used this method to reconstruct 55 nipples in 40 patients, with 415 days (range 191-733) mean follow up time. This includes 45 (82%) nipple reconstructions after tissue expander implant reconstruction. The use of this technique has produced excellent aesthetic results with nipple projection and site healing. The majority of patients have been satisfied with their nipple reconstruction. Three patients had wound healing difficulties, including two (3.6%) that healed with conservative wound care and one (1.8%) in a radiated patient requiring surgical revision. There were no other revisions necessary and no infections. In summary, the weave technique is a suitable modification to the popular C-V technique that maintains the benefits and simplicity of the aforementioned flap while potentially reducing projection loss, conserving base width, and allowing greater flexibility for nipple placement. PMID- 23350739 TI - Use of the tabbed expander in latissimus dorsi breast reconstruction. AB - Latissimus dorsi (LD) myocutaneous flap breast reconstruction with a tissue expander/implant is a post-mastectomy option often used as a salvage procedure for a failed tissue expander (TE). The patient is traditionally placed in the lateral decubitus position for flap dissection and is re-prepped and re-draped in the supine position for placement of the tissue expander. A new generation of anatomically-shaped, tabbed tissue expanders are increasingly being used in place of traditional untabbed expanders. The innovative suture tabs allow for more predictable and controlled expander placement while the patient is in the lateral decubitus position, eliminating the need to reposition the patient intraoperatively. The objective of this study was to evaluate the use of tabbed tissue expanders in latissimus dorsi breast reconstruction, with respect to total operative time, complication rates, and aesthetic outcomes. The outcomes of 34 LD breast reconstruction procedures with tissue expanders were evaluated. Eight patients received tabbed tissue expanders with no position change, while 26 patients underwent an intraoperative position change. Demographic information, total operative time, and follow-up complication data were collected. Aesthetic outcomes were evaluated by three blinded individuals using a validated scoring scale. The mean operative time for procedures with no position change was 107 minutes. The mean operative time for position change cohort was 207 minutes. There was no statistical difference in complication rates or aesthetic outcomes between the two groups. In conclusion, tabbed tissue expanders decrease operative time by eliminating the need for an intraoperative position change without influencing complication rates while maintaining equivalent aesthetic outcomes. PMID- 23350740 TI - Immediate reconstruction of the chest wall by latissimus dorsi and vertical rectus abdominis musculocutaneous flaps after radical mastectomy for a huge pleomorphic liposarcoma. AB - We describe a 53-year-old woman who had a huge pleomorphic liposarcoma of the left breast. She had a left Halstead mastectomy, which left a huge defect in the chest wall. We did an immediate reconstruction of the chest wall with combined latissimuss dorsi musculocutaneous (for the upper half of the defect) and vertical rectus abdominis musculocutaneous flaps (for the lower half of the defect). She then had radiotherapy and chemotherapy during which time the flaps remained viable and provided satisfactory coverage for the irradiated area. Unfortunately four months later she was diagnosed with spinal cord and lung metastases and died seven months after the operation. PMID- 23350741 TI - A simple dynamic external fixator for complex phalangeal fractures. AB - Complex compound and comminuted phalangeal fractures are often surrounded by soft tissue injuries. Stabilising such fractures is not easy but is essential before early mobilisation to prevent stiffness and regaining hand function. Several designs of external fixators have been advocated but could not simultaneously offer simplicity, affordability, stability, and freedom of movement. We propose a design that is easy to make without expert assistance. It is cheap, available in most theatres, and offers required stability and freedom of movement in the immediate postoperative period. Our claim is strongly supported by long-term follow-up results. PMID- 23350742 TI - Synthesis, fungicidal activity, and sterol 14alpha-demethylase binding interaction of 2-azolyl-3,4-dihydroquinazolines on Penicillium digitatum. AB - A series of new 2-azolyl-3,4-dihydroquinazolines 6 was synthesized by direct cyclization of imidazole or 1,2,4-triazole with carbodiimides 4, which were obtained from aza-Wittig reaction of iminophosphorane 3 with isocyanate. The preliminary bioassay results demonstrated that most of the 2-imidazolyl-3,4 dihydroquinazolines 6a-6i exhibited good to significant fungicidal activity against Penicillium digitatum , whereas 2-triazolyl-3,4-dihydroquinazolines 6j 6t exhibited low fungicidal activity. Some of the 2-imidazolyl-3,4 dihydroquinazolines 6a-6i also exhibited strong binding interaction with the cytochrome P450-dependent sterol 14alpha-demethylase (CYP51). For example, compound 6e showed the best fungicidal activity against P. digitatum with IC(50) = 4.14 MUg/mL and the best CYP51 binding activity with K(d) = 0.34 MUg/mL, both superior to those of the agricultural fungicide triadimefon. PMID- 23350743 TI - How long to treat with antibiotics following amputation in patients with diabetic foot infections? Are the 2012 IDSA DFI guidelines reasonable? AB - WHAT IS KNOWN AND OBJECTIVE: To the best of our knowledge, there has been no published study designed to identify the most appropriate duration of antibiotic therapy in lower extremity skin and skin structure infections in diabetic patients [aka "diabetic foot infections" (DFI)] post-amputation. However, recent guidelines published by the Infectious Diseases Society of America (IDSA) provide recommendations for treatment duration in these patients. Therefore, our objective is to review the literature evaluating antibiotic treatment in DFI to determine if the IDSA guidelines are reasonable. COMMENT: Evidence for the use of antibiotics after amputation comes largely from perioperative surgical prophylaxis studies evaluating the rate of infection after amputation. Three such studies were identified; 2 found a 5-day course of antibiotics post-amputation resulted in a reduction of infection rate, while 1 found no additional benefit. Comparative antibiotic studies in DFI also offers evidence for treatment duration, of which, 10 studies were identified. Five included patients who received amputations; however, only 1 reported treatment outcomes in a subset of diabetics requiring amputation. In this study, the authors concluded that antibiotic treatment is likely necessary after amputation. WHAT IS NEW AND CONCLUSION: Given the general lack of data, we recommend that post-operative treatment duration be individualized, and, until further studies are done, it seems reasonable to adhere to the recommendation provided by the 2012 IDSA DFI guidelines for a 2-5 day course of antibiotic therapy post-operatively when no residual infected tissue remains. PMID- 23350744 TI - Extracellular chaperones and proteostasis. AB - There exists a family of currently untreatable, serious human diseases that arise from the inappropriate misfolding and aggregation of extracellular proteins. At present our understanding of mechanisms that operate to maintain proteostasis in extracellular body fluids is limited, but it has significantly advanced with the discovery of a small but growing family of constitutively secreted extracellular chaperones. The available evidence strongly suggests that these chaperones act as both sensors and disposal mediators of misfolded proteins in extracellular fluids, thereby normally protecting us from disease pathologies. It is critically important to further increase our understanding of the mechanisms that operate to effect extracellular proteostasis, as this is essential knowledge upon which to base the development of effective therapies for some of the world's most debilitating, costly, and intractable diseases. PMID- 23350745 TI - Antimicrobial resistance genes in multidrug-resistant Salmonella enterica isolated from animals, retail meats, and humans in the United States and Canada. AB - Salmonella enterica is a prevalent foodborne pathogen that can carry multidrug resistance (MDR) and pose a threat to human health. Identifying the genetics associated with MDR in Salmonella isolated from animals, foods, and humans can help determine sources of MDR in food animals and their impact on humans. S. enterica serovars most frequently carrying MDR from healthy animals, retail meats, and human infections in the United States and Canada were identified and isolates resistant to the largest number of antimicrobials were chosen. Isolates were from U.S. slaughter (n=12), retail (9), and humans (9), and Canadian slaughter (9), retail (9), and humans (8; total n=56). These isolates were assayed by microarray for antimicrobial resistance and MDR plasmid genes. Genes detected encoded resistance to aminoglycosides (alleles of aac, aad, aph, strA/B); beta-lactams (bla(TEM), bla(CMY), bla(PSE-1)); chloramphenicol (cat, flo, cmlA); sulfamethoxazole (sulI); tetracycline (tet(A, B, C, D) and tetR); and trimethoprim (dfrA). Hybridization with IncA/C plasmid gene probes indicated that 27/56 isolates carried one of these plasmids; however, they differed in several variable regions. Cluster analysis based on genes detected separated most of the isolates into two groups, one with IncA/C plasmids and one without IncA/C plasmids. Other plasmid replicons were detected in all but one isolate, and included I1 (25/56), N (23/56), and FIB (10/56). The presence of different mobile elements along with similar resistance genes suggest that these genetic elements may acquire similar resistance cassettes, and serve as multiple sources for MDR in Salmonella from food animals, retail meats, and human infections. PMID- 23350747 TI - Nanostructured catalysts for organic transformations. AB - The development of green, sustainable and economical chemical processes is one of the major challenges in chemistry. Besides the traditional need for efficient and selective catalytic reactions that will transform raw materials into valuable chemicals, pharmaceuticals and fuels, green chemistry also strives for waste reduction, atomic efficiency and high rates of catalyst recovery. Nanostructured materials are attractive candidates as heterogeneous catalysts for various organic transformations, especially because they meet the goals of green chemistry. Researchers have made significant advances in the synthesis of well defined nanostructured materials in recent years. Among these are novel approaches that have permitted the rational design and synthesis of highly active and selective nanostructured catalysts by controlling the structure and composition of the active nanoparticles (NPs) and by manipulating the interaction between the catalytically active NP species and their support. The ease of isolation and separation of the heterogeneous catalysts from the desired organic product and the recovery and reuse of these NPs further enhance their attractiveness as green and sustainable catalysts. This Account reviews recent advances in the use of nanostructured materials for catalytic organic transformations. We present a broad overview of nanostructured catalysts used in different types of organic transformations including chemoselective oxidations and reductions, asymmetric hydrogenations, coupling reactions, C-H activations, oxidative aminations, domino and tandem reactions, and more. We focus on recent research efforts towards the development of the following nanostructured materials: (i) nanostructured catalysts with controlled morphologies, (ii) magnetic nanocomposites, (iii) semiconductor-metal nanocomposites, and (iv) hybrid nanostructured catalysts. Selected examples showcase principles of nanoparticle design such as the enhancement of reactivity, selectivity and/or recyclability of the nanostructured catalysts via control of the structure, composition of the catalytically active NPs, and/or nature of the support. These principles will aid researchers in the rational design and engineering of new types of multifunctional nanocatalysts for the achievement of green and sustainable chemical processes. Although the past decade has brought many advances, there are still challenges in the area of nanocatalysis that need to be addressed. These include loss of catalytic activity during operation due to sintering, leaching of soluble species from the nanocatalysts under harsh reaction conditions, loss of control over well-defined morphologies during the scale-up synthesis of the nanocomposites, and limited examples of enantioselective nanocatalytic systems. The future of nanocatalyst research lies in the judicious design and development of nanocomposite catalysts that are stable and resistant to sintering and leaching, and yet are highly active and enantioselective for the desired catalytic organic transformations, even after multiple runs. The successful generation of such multifunctional nanocatalysts especially in tandem, domino, or cascade reactions would provide a powerful tool for the establishment of green and sustainable technologies. PMID- 23350746 TI - Decreased core muscle size is associated with worse patient survival following esophagectomy for cancer. AB - Preoperative risk assessment, particularly for patient frailty, remains largely subjective. This study evaluated the relationship between core muscle size and patient outcomes following esophagectomy for malignancy. Using preoperative computed tomography scans in 230 subjects who had undergone transhiatal esophagectomy for cancer between 2001 and 2010, lean psoas area (LPA), measured at the fourth lumbar vertebra, was determined. Cox proportional hazards regression was employed to analyze overall survival (OS) and disease-free survival (DFS) adjusted for age, gender, and stage, and the Akaike information criterion was used to determine each covariate contribution to OS and DFS. Univariate analysis demonstrated that increasing LPA correlated with both OS (P = 0.017) and DFS (P = 0.038). In multivariate analysis controlling for patient and tumor characteristics, LPA correlated with OS and DFS in patients who had not received neoadjuvant treatment (n = 64), with higher LPA associated with improved OS and DFS. Moreover, LPA was of equivalent, or slightly higher importance than pathologic stage. These measures were not predictive among patients (n = 166) receiving neoadjuvant chemoradiation. Core muscle size appears to be an independent predictor of both OS and DFS, as significant as tumor stage, in patients following transhiatal esophagectomy. Changes in muscle mass related to preoperative treatment may confound this effect. Assessment of core muscle size may provide an additional objective measure for risk stratification prior to undergoing esophagectomy. PMID- 23350748 TI - Split Spy0128 as a potent scaffold for protein cross-linking and immobilization. AB - Site-specific cross-linking techniques between proteins and additional functional groups have become increasingly important for expanding the utility of proteins in biochemistry and biotechnology. In order to explore powerful techniques for practical bioconjugation applications, we have validated a technique mediated by a unique property of Streptcoccus pyogenes pilin subunit Spy0128, an autocatalytic intramolecular isopeptide formation in Spy0128. Recently, it has been revealed that Spy0128 can be split into two fragments (split-Spy0128 (residues 18-299 of Spy0128) and isopeptag (residues 293-308 of Spy0128)) that were capable of forming an intermolecular covalent complex. We focused on this unique reconstitution property and first studied the bioconjugation of blue and green fluorescent proteins, enabling the direct monitoring of cross-linking reactions by Forster resonance energy transfer (FRET). A fluorescence lifetime study shows that spatial control of two proteins on the Spy0128 scaffold is possible when one protein is fused to the N-terminus of split-Spy0128 and another one is tethered at the N- or C-terminus of the isopeptag. Furthermore, we demonstrated site-specific protein immobilization mediated by the reconstitution of split-Spy0128 and isopeptag. In this case, a split-Spy0128 mutant with a free N-terminal Cys residue was first immobilized onto beads chemically modified with a maleimide group through a Michael addition process. Then, an isopeptagged protein was successfully immobilized onto the split-Spy0128-immobilized beads. These results suggest that Spy0128 is a potent proteinaceous scaffold available for bioconjugation both in solution and at a solid surface. PMID- 23350749 TI - Mesenchymal stem cells promote alveolar epithelial cell wound repair in vitro through distinct migratory and paracrine mechanisms. AB - BACKGROUND: Mesenchymal stem cells (MSC) are in clinical trials for widespread indications including musculoskeletal, neurological, cardiac and haematological disorders. Furthermore, MSC can ameliorate pulmonary fibrosis in animal models although mechanisms of action remain unclear. One emerging concept is that MSCs may have paracrine, rather than a functional, roles in lung injury repair and regeneration. METHODS: To investigate the paracrine role of human MSC (hMSC) on pulmonary epithelial repair, hMSC-conditioned media (CM) and a selected cohort of hMSC-secretory proteins (identified by LC-MS/MS mass spectrometry) were tested on human type II alveolar epithelial cell line A549 cells (AEC) and primary human small airway epithelial cells (SAEC) using an in vitro scratch wound repair model. A 3D direct-contact wound repair model was further developed to assess the migratory properties of hMSC. RESULTS: We demonstrate that MSC-CM facilitates AEC and SAEC wound repair in serum-dependent and -independent manners respectively via stimulation of cell migration. We also show that the hMSC secretome contains an array of proteins including Fibronectin, Lumican, Periostin, and IGFBP-7; each capable of influencing AEC and SAEC migration and wound repair stimulation. In addition, hMSC also show a strong migratory response to AEC injury as, supported by the observation of rapid and effective AEC wound gap closure by hMSC in the 3D model. CONCLUSION: These findings support the notion for clinical application of hMSCs and/or their secretory factors as a pharmacoregenerative modality for the treatment of idiopathic pulmonary fibrosis (IPF) and other fibrotic lung disorders. PMID- 23350750 TI - Epidemiology of epilepsy in rural Benin: prevalence, incidence, mortality, and follow-up. AB - PURPOSE: Epilepsy is a major clinical and social issue in Africa. This study was conducted to estimate the prevalence, incidence, mortality, and therapeutic outcome in rural Djidja in Benin. METHODS: This was a two-phase study with a cross-sectional phase and 18 months of follow-up. In the first phase, information was obtained using door-to-door surveys, reports from key informants, and medical sources. People were interviewed using a validated screening questionnaire for epilepsy in tropical regions. The diagnosis of epilepsy was confirmed by a neurologist. We used a capture-recapture method to estimate the number of people with epilepsy (PWE). PWE were followed every month for 18 months after the cross sectional survey. We asked the health services, the general population, and village leaders in the study area to identify suspected cases of epilepsy occurring during the follow-up. New cases were updated every month after confirmation. Antiepileptic drugs were prescribed to PWE. KEY FINDINGS: We surveyed 11,668 subjects (male-to-female ratio 0.9) and identified 123 PWE, yielding a prevalence of 10.5 per 1,000 (95% confidence interval (CI) 8.8 12.6/1,000). Combining the three sources, we found 148 PWE and a prevalence of 12.7 per 1,000 (95% CI 10.7-14.9/1,000). After application of the capture recapture method, the prevalence was estimated to be as high as 38.4 per 1,000 (95% CI 34.9-41.9/1,000). The cumulative incidence was 104.2 per 100,000 and the mean annual incidence was 69.4 per 100,000. The mean annual mortality was 20.8 per 1,000. After treatment, 45% of PWE had total seizure remission and 35% had a decrease in the number of seizures. SIGNIFICANCE: This study shows that door-to door survey findings could be improved by using information from other sources. The follow-up suggests that epilepsy could be controlled. Continuous drug delivery and regular follow-up are key. PMID- 23350751 TI - [Sc2(MU-OH)2(H2O)6(NO3)2](NO3)2: aqueous synthesis and characterization. AB - [Sc(2)(MU-OH)(2)(H(2)O)(6)(NO(3))(2)](NO(3))(2) has been synthesized from an aqueous scandium nitrate solution by using zinc powder as a reducing agent for nitric acid, which drives an increase in pH and forces the condensation of aqua scandium cations. This preparative route readily produces gram-scale samples with yields near 65%. A single-crystal X-ray diffraction study reveals a structure characterized by a hydroxo-bridged Sc dimer. The FTIR spectrum of the compound has been modeled via ab initio computations, allowing the identification of signature IR peaks. Some initial observations on the thermal transformation of the compound to Sc(2)O(3) are also reported. PMID- 23350752 TI - Anomeric effect in halogenated methanols: a quantum theory of atoms in molecules study. AB - The quantum theory of atoms in molecules (QTAIM) has been used to analyze the gauche conformational preference of fluoromethanol and chloromethanol. The analysis of the total atomic population and localization and delocalization indices show trends that are not in line with the hyperconjugative explanation. Energy terms arising from the QTAIM partitioning have been obtained for fluoromethanol, revealing that (i) C-O interaction plays the most significant role in stabilizing the gauche rotamer and (ii) the summation of exchange terms (the only ones that could be related to hyperconjugation) has a smaller weight than electrostatic ones in the energy balance among gauche, anti, and syn conformations; however, they are far from being negligible. PMID- 23350753 TI - Multiple symptoms in patients with chronic obstructive pulmonary disease in Norway. AB - This paper examines the prevalence of multiple symptoms and the relationships between future expectations and multiple symptoms in a cross-sectional study of 100 patients with chronic obstructive pulmonary disease. A questionnaire was used to examine the patients' symptoms of breathlessness, anxiety, depression, sleeplessness, fatigue, and pain, and their outlook for the future. All patients reported breathlessness, 64% anxiety, 69% depression, 28% sleeplessness, 72% fatigue, and 45% pain. Those with anxiety reported significant depression (P < 0.001), and those with fatigue reported significant depression (P = 0.004). Patients who reported pain also reported significant sleeplessness (P = 0.022). A negative outlook for the future was reported by 42% of patients who also reported significantly more anxiety, depression, sleeplessness, fatigue, and pain (P <= 0.049). Multiple symptoms are common in chronic obstructive pulmonary disease, and patients with a pessimistic view of the future reported more symptoms. Those with multiple symptoms and a negative outlook toward the future may benefit from interventions to help them achieve a more positive outlook for the future, which may relieve symptom burden. PMID- 23350754 TI - Identifying successful outcomes and important factors to consider in upper limb amputation rehabilitation: an international web-based Delphi survey. AB - PURPOSE: To identify and gain agreement on successful outcomes of and important factors to consider in rehabilitation following upper limb absence (ULA). METHOD: Fifty-three participants consisting of multi-disciplinary rehabilitation professionals, and individuals with ULA were invited to complete a three-round modified Delphi iterative survey. Following three Delphi questionnaire rounds, participants clarified the definitions of success in three areas (prosthesis use, activities and participation and self-image). In addition, participants identified and agreed the important factors to consider in rehabilitation after ULA. RESULTS: Results showed that participants reached agreement (having a SD <1) over the three rounds on 78 out of 81 rated items. Of these, 54 rated items were "accepted" as important by panel members (mean score of 4 on a five-point Likert scale). Twenty-four items were rejected. Only three rated items had not reached agreement by the third round. CONCLUSIONS: Clarification of successful outcomes and factors that should be taken into consideration in a patient's rehabilitation allows a clearer evaluation of what should be the focus of rehabilitation. The findings from the Delphi study can help form the basis for a screening tool for clinicians to be able to identify areas of concern and subsequent treatment for a patient in their care. Implications for Rehabilitation To date, there has been no definitive guidance on which outcomes should be assessed in amputation rehabilitation. This study identified the seven core domains of importance regarding the rehabilitation of individuals with ULA and created a starting point for developing a new portfolio of research that aims to address all relevant aspects of patients' rehabilitation. This study reached a consensus and enabled an insight into what defines successful prosthesis use, self-image and activities and participation, and provided evidence that the current definition of prosthesis use in the literature does not sufficiently capture what RPs and individuals with ULA consider important, such as specific use of the prosthesis, as often as an individual wishes, while using it as intended. This study provided RPs and individuals with ULA an opportunity to communicate their opinions and knowledge anonymously regarding the important areas to consider in rehabilitation. PMID- 23350755 TI - Car driving in schizophrenia: can visual memory and organization make a difference? AB - PURPOSE: Driving is a meaningful occupation which is ascribed to functional independence in schizophrenia. Although it is estimated that individuals with schizophrenia have two times more traffic accidents, little research has been done in this field. Present research explores differences in mental status, visual working memory and visual organization between drivers and non-drivers with schizophrenia in comparison to healthy drivers. METHODS: There were three groups in the study: 20 drivers with schizophrenia, 20 non-driving individuals with schizophrenia and 20 drivers without schizophrenia (DWS). Visual perception was measured with Rey-Osterrieth Complex Figure test and a general cognitive status with Mini-Mental State Examination. RESULTS: The general cognitive status predicted actual driving situation in people with schizophrenia. No statistically significant differences were found between driving and non-driving persons with schizophrenia on any of the visual parameters tested, although these abilities were significantly lower than those of DWS. CONCLUSION: The research demonstrates that impairment of visual abilities does not prevent people with schizophrenia from driving and emphasizes the importance of general cognitive status for complex and multidimensional everyday tasks. The findings support the need for further investigation in the field of car driving for this population - a move that will considerably contribute to the participation and well-being. Implication for Rehabilitation Unique approach for driving evaluation in schizophrenia should be designed since direct applications of knowledge and practice acquired from other populations are not reliable. This research demonstrates that visual perception deficits in schizophrenia do not prevent clients from driving, and general cognitive status appeared to be a valid determinant for actual driving. We recommended usage of a general test of cognition such as Mini-Mental State Examination, or conjunction number of cognitive factors such as executive functions (e.g., Trail Making Test) and attention (e.g., Continuous Performance Test) in addition to spatial-visual ability tests (e.g., Rey-Osterrieth Complex Figure test) for considering driving status in schizophrenia. PMID- 23350756 TI - Environmental opportunities questionnaire: development of a measure of the environment supporting early motor development in the first year of life. AB - PURPOSE: The development and testing of a measure evaluating the quality and variability in the home environment as it relates to the motor development of infants during the first year of life. METHODS: A sample of 112 boys and 95 girls with a mean age of 7.1 months (SD 1.8) and GA of 39.6 weeks (SD 1.5) participated in the study. The measurement development process was divided into three phases: measurement development (item generation or selection of items from existing measurement tools), pilot testing to determine acceptability and feasibility to parents, and exploratory factor analysis to organize items into meaningful concepts. Test-retest reliability and internal consistency were also determined. RESULTS: The environmental opportunities questionnaire (EOQ) is a feasible 21 item measure comprised of three factors including opportunities in the play space, sensory variety and parental encouragement. Overall, test-retest reliability was 0.92 (CI 0.84-0.96) and the internal consistency is 0.79. The EOQ emphasizes quality of the environment and access to equipment and toys that have the potential to facilitate early motor development. CONCLUSION: The preliminary analyses reported here suggest more work could be done on the EOQ to strengthen its use for research or clinical purposes; however, it is adequate for use in its current form. Implications for Rehabilitation New and feasible 21-item questionnaire that enables identification of malleable environmental factors that serve as potential points of intervention for children that are not developing typically. Therapeutic tool for use by therapists to inform and guide discussions with caregivers about potential influences of environmental, social and attitudinal factors in their child's early development. PMID- 23350757 TI - Sexuality in people with a lower limb amputation: a topic too hot to handle? AB - PURPOSE: The purpose of this study was to analyze whether, and by whom sexuality is discussed in amputation departments. The focus was on whether professionals received questions about sexuality from their patients with a lower limb amputation and whether they addressed sexuality themselves, as well as on the knowledge and comfort level, approach and attitudes toward sexuality of these professionals. METHOD: An online questionnaire, including questions on self perceived sexological competence and the Knowledge, Comfort, Approach and Attitudes towards Sexuality Scale. RESULTS: Seventy-eight percent of the professionals had not received questions about sexuality from their patients and 67% had not addressed sexuality. Self-perceived knowledge about sexuality and self-perceived ability to recognize sexual problems increased the odds of receiving a question about sexuality and the odds of addressing this issue. CONCLUSIONS: Sexuality is rarely discussed by professionals in the amputation department. It is, however, the responsibility of the professional to do so. By addressing sexuality in a systematic way and discussing this as a common topic professionals "give permission" to patients and other team members to discuss eventual sexual problems or concerns. Therefore, the professionals' self perceived sexological competence and feeling of comfort with the topic of sexuality need to be increased. Implications for Rehabilitation Sexuality is rarely discussed by professionals in the amputation department, even though sexual problems do occur in patients with a lower limb amputation (LLA). By addressing sexuality in a systematic way and discussing this as a common topic professionals "give permission" to patients and other team members to discuss eventual sexual problems or concerns. Our study shows that self-perceived knowledge about sexuality and self-perceived ability to recognize sexual problems increases the odds of receiving a question about sexuality and the odds of addressing this issue. Investing in courses that focus on increasing the knowledge and feeling of comfort concerning sexuality of professionals working with people with a LLA is therefore of important value. PMID- 23350758 TI - Intellectual disability in Africa: implications for research and service development. AB - Although intellectual disability (ID) is probably the largest impairment grouping on the African continent, few indigenous research and evaluation studies have been undertaken. This article is an initial attempt to relate service delivery issues to an African research agenda. We critically analysed the available literature, drawing on academic publications and those of non-governmental agencies. In this process we identified several key issues for further investigation, namely: understanding ID in African contexts, access to education and health care, the provision of appropriate assistance and support, and income generation. We relate our analysis to the recommendations made in the World Report on Disability but with a specific focus on ID in Africa. The need for mainstreaming and prioritising ID in non-disability related and across impairment programmes is highlighted. We note the importance of families and emphasise the need to draw on informal and traditional forms of care and participation. The need for reliable research evidence to support practice is highlighted. We conclude with a call to action by and on behalf of individuals with ID to be included in the development priorities of the continent. Implications for Rehabilitation Service provision for people with intellectual disabilities in Africa is not always well served by insights obtained from western research agendas. Appropriate and effective rehabilitation requires an understanding of the context and the environment in which the disabled person operates. Indigenous research into the provision of support to families and the inclusion of persons with intellectual disability into mainstream programmes as well as disability specific provision is recommended. PMID- 23350759 TI - The effect of the environment on participation of children and youth with disabilities: a scoping review. AB - OBJECTIVE: The study's purpose was to identify and synthesize research evidence regarding the effect of the environment on community participation of children with disabilities. METHODS: A scoping review of peer-reviewed studies published from 1990 to 2011 was performed. Two independent reviewers selected studies based on a systematic procedure. Inclusion criteria for studies were: participants with a disability, aged 5-21 years, whose environment was examined in relation to participation in out-of-school activities. Data were organized and synthesized based on environmental domains within the International Classification of Functioning, Disability and Health (ICF): Natural Environment/Products and Technology; Support and Relationships; Attitudes; and Services, Systems and Policies. RESULTS: Searching identified 1232 articles and 31 met the inclusion criteria. Each domain of the environment within the ICF influenced participation as a facilitator and/or barrier. The most common facilitators involved social support of family and friends and geographic location. The most common barriers included attitudes, physical environment, transportation, policies and the lack of support from staff and service providers. CONCLUSIONS: Knowledge derived from this review can assist practitioners in addressing the specific environmental domains that influence children's participation. Such awareness can also foster new research questions and assist policy makers in identifying the factors influencing participation. IMPLICATIONS FOR REHABILITATION: All domains of the environment, suggested by the ICF, have an influence on children's participation.Evidence regarding the effect of the environment on participation is focused primarily on children with physical disabilities; more studies are needed involving various health conditions and age groups. Practitioners and decision-makers can focus attention on specific aspects of the environment, e.g. attitudinal challenges and social support, in order to foster inclusion and participation-based communities. PMID- 23350760 TI - The lived experience of engaging in everyday occupations in persons with mild to moderate aphasia. AB - PURPOSE: Impairment of language ability, aphasia, can cause barriers to communication and hence impact on participation in many life situations. This study aimed to describe and explore how persons with aphasia following stroke experience engaging in everyday occupations. METHOD: Six persons from Southwest Finland who had aphasia due to stroke one to four years previously were interviewed for the study. A modified form of the empirical phenomenological psychological method was used for data analysis. RESULTS: Three main characteristics of experiences of engaging in everyday occupations were identified: (1) encountering new experiences in everyday occupations, (2) striving to handle everyday occupations and (3) going ahead with life. The participants had experienced an altering life-world. Engagement in occupations affected their perceptions of competence and identity, and experiences of belonging and well-being. It was also through engagement in everyday occupations that they had discovered and learnt to handle changes in their everyday life. CONCLUSION: Aphasia can have a long-term impact on engagement in everyday occupations and participation in society, but conversely, engagement in meaningful occupations can also contribute to adaptation to disability and life changes. IMPLICATIONS FOR REHABILITATION: Aphasia can have a long-term impact on engagement in everyday occupations and participation in society. Health care professionals need to determine what clients with aphasia think about their occupations and life situations in spite of difficulties they may have verbalizing their thoughts. Experiences of engaging in meaningful occupations can help clients with aphasia in reconstructing their life stories, thereby contributing to adaptation to disability and life changes. PMID- 23350761 TI - What predicts a poor outcome in older stroke survivors? A systematic review of the literature. AB - PURPOSE: To identify factors in the early post-stroke period that have a predictive value for a poor outcome, defined as institutionalization or severe disability. METHODS: MEDLINE, PSYCINFO, EMBASE and CINAHL were systematically searched for observational cohort studies in which adult and/or elderly stroke patients were assessed <= 1 month post-stroke and poor outcome was determined after a follow-up of >= 3 months. RESULTS: Thirty three articles were selected from 4063 records, describing 27 independent cohort studies. There are rather consistent findings that greater age, a more severe stroke (measured through a clinical evaluation scale), the presence of urinary incontinence (with impaired awareness) and a larger stroke volume (measured through brain imaging techniques) predict poor stroke outcome. In contrast to clinical expectations, the prognostic value of ADL-dependency and impaired cognition remains unclear, and factors in the domains of emotional and communicative functioning rarely feature. Studies using a selected group of stroke patients tended to identify different predictors. CONCLUSIONS: The current evidence is insufficient for the development of a clinical prediction tool that is better than physicians' informal predictions. Future research should focus on the selection of optimal screening instruments in multiple domains of functioning, including the timing of assessment. We suggest developing prediction tools stratified by more homogeneous, clinically distinguished stroke subtypes. IMPLICATIONS FOR REHABILITATION: A reliable prognosis soon after a stroke is highly relevant to patients who ultimately have a poor outcome, because it enables early planning of care tailored to their needs. In view of the development of a clinical prediction tool that is better than physicians' informal predictions, future research should focus on optimal screening instruments in multiple domains of functioning, including emotional and communicative functioning. Clinical prediction tools stratified by more homogeneous, clinically distinguished stroke subtypes, could enable more accurate prognosis in individual stroke patients. PMID- 23350762 TI - Patterns of participation in school-related activities and settings in children with spina bifida. AB - PURPOSE: To evaluate how children with spina bifida (SB) participate in school related activities and to explore if their motor and process skills in task performance were related to their level of active participation in school. METHOD: Fifty children from a geographical cohort of children with SB (aged 6-14 years) and their teachers rated the children's frequency of participation in school-related activities using a Swedish adaptation of the Availability and Participation Scale. The teachers also rated each child's level of active participation with the School Function Assessment, part one. Each child's motor and process skills were evaluated with the Assessment of Motor and Process Skills. The relation between levels of active participation and motor and process skills was subjected to binary logistic regression analysis. RESULTS: The children participated very frequently in school activities, but their level of active participation was restricted, particularly in the recess/playground setting. There was a highly significant relation between full active participation in most school settings and the children's motor and process skills. CONCLUSION: Children with SB need support to become more actively involved, particularly in unstructured peer activities. The school staff need to be informed that not only the motor skills but also the process skills have an impact on the children's active participation. IMPLICATIONS FOR REHABILITATION: The children with spina bifida (SB) showed a low level of active participation and involvement in school settings even though their frequency of participation was high. It is of highest importance to enable children with SB to be actively involved in peer-related and unstructured activities and to encourage them to participate in both academic and societal learning. To achieve active participation, it is important to inform the school staff about how this issue is affected not only by the level of the child's motor skills but also, and probably even more so, by the level of his/her process skills. From this knowledge, individual strategies can be worked out. PMID- 23350763 TI - Identifying employees at risk for job loss during sick leave. AB - PURPOSE: To examine the associations between medical, work-related, organizational and sociodemographic factors and job loss during sick leave in a Dutch population of 4132 employees on sick leave. METHODS: Data were assessed by occupational health physicians (OHPs) on sociodemographic, medical, work-related and organizational factors. Odds ratios for job loss were calculated in logistic regression models. RESULTS: Job loss during sick leave is associated with mental disorder, a history of sick leave due to these disorders, lack of co-worker and supervisor support, job insecurity and working as a civil servant or a teacher. Associations vary for gender and for company size. CONCLUSIONS: Job loss during sick leave is associated with medical, work-related, organizational and socio demographic factors. The findings of this study might help the OHP or other health professionals involved in the management of employees on sick leave to identify those employees who are at risk for job loss during sick leave, and might help policymakers to decide on priorities in prevention and treatment. Future studies should have a longitudinal, prospective design and include information about the type of contract, possible causes for job loss, severity and treatment of the disorder causing the sick leave. IMPLICATIONS FOR REHABILITATION: The labor market moves to more and more flexible and temporary contracts. This leads to more precarious types of employment. The risk of job loss during sick leave is associated with medical, work-related, organizational and sociodemographic factors. Occupational health physicians and other professionals in the field of work rehabilitation should be aware of these associations to prevent job loss due to these factors. PMID- 23350764 TI - Nordic walking and its clinical benefits in different disorders. PMID- 23350765 TI - Representations of disability in the Canadian news media: a decade of change? AB - PURPOSE: To assess stability and change in representations of disability and persons with disability in the Canadian news media between 1998 and 2008. METHOD: The study replicated research conducted in 1998 that assessed the representation of disability in the Canadian news media. Following the earlier study, three newspapers were selected (Globe and Mail, Toronto Star and Toronto Sun) and all articles from a three-month period in 1998 and 2008 were assessed for disability content. In total, 362 articles were found in the two time periods. These were coded for structure and content using a schema developed in the earlier research. RESULTS: Between 1998 and 2008, there was a significant increase in the proportion of stories using "person first" language, and a significant increase in the proportion of "progressively" themed articles (e.g. dealing with barriers to participation, or disability awareness and inclusion). At the same time, there were significant differences between newspapers, with the Toronto Sun (a tabloid) maintaining a strong focus on "traditional" themes (e.g. special education, charitable provision). CONCLUSIONS: The differences in news media representations between 1998 and 2008 suggest a positive change in the way people with disabilities are represented, with greater attention to the complexity of their identity and their multiple social roles. IMPLICATIONS FOR REHABILITATION: The participation of persons with disabilities in society continues to be limited by negative attitudes. Media reporting has a significant influence on public attitudes toward disability. In a content analysis of three Canadian newspapers, this study found several significant changes in the language and content of disability-related articles. Together, these changes provide some evidence of more favorable media representations of disability. Further research in rehabilitation is needed to understand how such changes may both reflect and facilitate ongoing efforts to enhance people with disabilties' participation in social life. PMID- 23350766 TI - Diabetes and driving. AB - The principal safety concern for driving for people treated with insulin or insulin secretagogues is hypoglycaemia, which impairs driving performance. Other complications, such as those causing visual impairment and peripheral neuropathy, are also relevant to medical fitness to drive. Case control studies have suggested that drivers with diabetes pose a modestly increased but acceptable and measurable risk of motor vehicle accidents compared to non-diabetic drivers, but many studies are limited and of poor quality. Factors which have been shown to increase driving risk include previous episodes of severe hypoglycaemia, previous hypoglycaemia while driving, strict glycaemic control (lower HbA1c) and absence of blood glucose monitoring before driving. Impaired awareness of hypoglycaemia may be counteracted by frequent blood glucose testing. The European Union Third directive on driving (2006) has necessitated changes in statutory regulations for driving licences for people with diabetes in all European States, including the UK. Stricter criteria have been introduced for Group 1 vehicle licences while those for Group 2 licences have been relaxed. Insulin-treated drivers can now apply to drive Group 2 vehicles, but in the UK must meet very strict criteria and be assessed by an independent specialist to be issued with a 1-year licence. PMID- 23350767 TI - Response to Kawada: Self-rated health and depression of patients with diabetes: how to handle with wide range of ageing and diabetic status? PMID- 23350768 TI - Design, synthesis, and pharmacological properties of new heteroarylpyridine/heteroarylpyrimidine derivatives as CB(2) cannabinoid receptor partial agonists. AB - Recent developments indicate that CB(2) receptor ligands have the potential to become therapeutically important. To explore this potential, it is necessary to develop compounds with high affinity for the CB(2) receptor. Very recently, we have identified the oxazinoquinoline carboxamides as a novel class of CB(2) receptor full agonists. In this paper we describe the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7-oxopyrimidine derivatives. Some of the reported compounds showed high affinity and potency at the CB(2) receptor while showing only modest affinity for the centrally expressed CB(1) cannabinoid receptor. Moreover, we found that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series show dose-dependent effects on the modulation of forskolin-induced cAMP production, revealing different behaviors as full agonists, partial agonists, and inverse agonists. PMID- 23350769 TI - Hb Treviso [alpha91(FG3)Leu->Phe (alpha2)]: a new slightly unstable hemoglobin variant with moderately decreased oxygen affinity. AB - We report a new hemoglobin (Hb) variant, found in a North-East Italian family living in the city of Treviso. The proband, a non anemic 60-year-old male with a history of chronic rhinitis, allergy to Parietaria and suspected obstructive sleep apnea syndrome, was referred for blood gas analysis. Determination of the oxygen affinity revealed a p50 of 32.5 mmHg (control 27.5 mmHg) indicating a moderate decrease in oxygen affinity. An abnormal pattern compatible with an alpha Hb variant was observed on high performance liquid chromatography (HPLC); direct sequencing revealed a transition at codon 91 of the alpha2 gene (HBA2: c.274C>T) changing leucine into phenylalanine. Characterization and phenotype studies are reported. PMID- 23350770 TI - Childhood catatonia, autism and psychosis past and present: is there an 'iron triangle'? AB - OBJECTIVE: To explore the possibility that autism, catatonia and psychoses in children are different manifestations of a single underlying form of brain pathology - a kind of 'Iron Triangle' of symptomatology - rather than three separate illnesses. METHOD: Systematic evaluation of historical case literature on autism to determine if catatonic and psychotic symptoms accompanied the diagnosis, as is found in some challenging present-day cases. RESULTS: It is clear from the historical literature that by the 1920s all three diagnoses in the Iron Triangle - catatonia, autism and childhood schizophrenia - were being routinely applied to children and adolescents. Furthermore, it is apparent that children diagnosed with one of these conditions often qualified for the other two as well. Although conventional thinking today regards these diagnoses as separate entities, the presence of catatonia in a variety of conditions is being increasingly recognized, and there is also growing evidence of connections between childhood-onset psychoses and autism. CONCLUSION: Recognition of a mixed form of catatonia, autism and psychosis has important implications for both diagnosis and treatment. None of the separate diagnoses provides an accurate picture in these complex cases, and when given single diagnoses such as 'schizophrenia', the standard treatment options may prove markedly ineffective. PMID- 23350772 TI - Early-stage microvascular alterations of a new model of controlled cortical traumatic brain injury: 3D morphological analysis using scanning electron microscopy and corrosion casting. AB - OBJECT: This study was performed to study the microvascular changes that occur during the first 12 hours after traumatic brain injury (TBI) using the corrosion casting technique. METHODS: The authors performed a qualitative and quantitative morphological study of the changes in cerebral vessels at acute (3 hours) and subacute (12 hours) stages after experimental TBI. They used a model of controlled cortical impact (CCI) injury induced by a recently developed electromagnetic device (impactor), focusing their observations mainly on the microvascular alterations responsible for the formation and maintenance of tissue edema and consequent brain swelling during the first hours after TBI. They used corrosion casting, scanning electron microscopy (SEM), light microscopy, and transmission electron microscopy (TEM) to obtain a morphological qualitative map with both 2D and 3D details. RESULTS: Scanning electron microscopy analysis of vascular casts documented in 3 dimensions the typical injuries occurring after a TBI: subdural, subarachnoid, and intraparenchymal hemorrhages, along with alterations of the morphological characteristics and architecture of both medium sized and capillary vessels, including ectasia of pial vessels, sphincter constrictions at the origin of the perforating vessels, focal swelling of perforating vessels, widening of intercellular junctions, and some indirect evidence of structural impairment of endothelial cells. All of these vascular alterations were confirmed in 2D analyses using light microscopy and TEM. CONCLUSIONS: The corrosion casting-SEM technique applied to a CCI experimental model proved to be a reliable method for studying the pathophysiology of the vascular alterations occurring at acute and subacute stages after CCI injury. It was also possible to obtain topographical localization of the vascular and cellular events that usually lead to hyperemia, edema, and brain swelling. Moreover, by applying informatic software to anatomical images it was possible to perform quantification and statistical analysis of the observed events. PMID- 23350771 TI - Amniotic fluid-derived stem cells for cardiovascular tissue engineering applications. AB - Recent research has demonstrated that a population of stem cells can be isolated from amniotic fluid removed by amniocentesis that are broadly multipotent and nontumorogenic. These amniotic fluid-derived stem cells (AFSC) could potentially provide an autologous cell source for treatment of congenital defects identified during gestation, particularly cardiovascular defects. In this review, the various methods of isolating, sorting, and culturing AFSC are compared, along with techniques for inducing differentiation into cardiac myocytes and endothelial cells. Although research has not demonstrated complete and high-yield cardiac differentiation, AFSC have been shown to effectively differentiate into endothelial cells and can effectively support cardiac tissue. Additionally, several tissue engineering and regenerative therapeutic approaches for the use of these cells in heart patches, injection after myocardial infarction, heart valves, vascularized scaffolds, and blood vessels are summarized. These applications show great promise in the treatment of congenital cardiovascular defects, and further studies of isolation, culture, and differentiation of AFSC will help to develop their use for tissue engineering, regenerative medicine, and cardiovascular therapies. PMID- 23350773 TI - Temporal trends and volume-outcome associations after traumatic brain injury: a 12-year study in Taiwan. AB - OBJECT: The purpose of this study was to evaluate temporal trends in traumatic brain injury (TBI); the impact of hospital volume and surgeon volume on length of stay (LOS), hospitalization cost, and in-hospital mortality rate; and to explore predictors of these outcomes in a nationwide population in Taiwan. METHODS: This population-based patient cohort study retrospectively analyzed 16,956 patients who had received surgical treatment for TBI between 1998 and 2009. Bootstrap estimation was used to derive 95% confidence intervals for differences in effect sizes. Hierarchical linear regression models were used to predict outcomes. RESULTS: Patients treated in very-high-volume hospitals were more responsive than those treated in low-volume hospitals in terms of LOS (-0.11; 95% CI -0.20 to 0.03) and hospitalization cost (-0.28; 95% CI -0.49 to -0.06). Patients treated by high-volume surgeons were also more responsive than those treated by low volume surgeons in terms of LOS (-0.19; 95% CI -0.37 to -0.01) and hospitalization cost (-0.43; 95% CI -0.81 to -0.05). The mean LOS was 24.3 days and the average LOS for very-high-volume hospitals and surgeons was 61% and 64% shorter, respectively, than that for low-volume hospitals and surgeons. The mean hospitalization cost was US $7,292.10, and the average hospitalization cost for very-high-volume hospitals and surgeons was 19% and 22% lower, respectively, than that for low-volume hospitals and surgeons. Advanced age, male sex, high Charlson Comorbidity Index score, treatment in a low-volume hospital, and treatment by a low-volume surgeon were significantly associated with adverse outcomes (p < 0.001). CONCLUSIONS: The data suggest that annual surgical volume is the key factor in surgical outcomes in patients with TBI. The results improve the understanding of medical resource allocation for this surgical procedure, and can help to formulate public health policies for optimizing hospital resource utilization for related diseases. PMID- 23350774 TI - Editorial: traumatic brain injury. PMID- 23350775 TI - Editorial: arteriovenous malformation and embolization. PMID- 23350776 TI - The failure of preoperative ethylene-vinyl alcohol copolymer embolization to improve outcomes in arteriovenous malformation management: case series. AB - OBJECT: Ethylene-vinyl alcohol copolymer embolization is increasingly used preoperatively in the resection of brain arteriovenous malformations (AVMs). However, the case for embolization improving the outcome of resection has not been evaluated. In this paper the authors set out to compare outcomes after surgery for brain AVMs in 2 consecutive periods of practice. In the first period, selective embolization was used without the use of ethylene-vinyl alcohol copolymer. In the second period, selective embolization with ethylene-vinyl alcohol copolymer was performed. METHODS: A consecutive case series (prospectively collected data) was retrospectively analyzed. Adverse outcomes were considered to be an outcome modified Rankin Scale score greater than 2 due to embolization or surgery. RESULTS: A total of 538 surgical cases were included. The percentages of adverse outcomes were as follows: 0.34% for Spetzler-Martin AVMs less than Grade III (1 of 297 cases); 5.23% (95% CI 2.64%-9.78%) for Grade III AVMs (9 of 172 cases); and 17% (95% CI 10%-28%) for AVMs greater than Grade III (12 of 69 cases). There was no improvement in outcomes from the first period to the second period. The adverse outcome for Grade III brain AVMs in the first period was 5.2% (7 of 135 cases) and in the second period (after ethylene-vinyl alcohol copolymer was introduced) it was 5.4% (2 of 37 cases). For AVMs greater than Grade III, the adverse outcome was 12% (6 of 49 cases) in the first period and 30% (6 of 20 cases) in the second period. CONCLUSIONS: Outcomes for brain AVM surgery were not improved by ethylene-vinyl alcohol copolymer embolization. Preoperative embolization of high-grade AVMs with an ethylene-vinyl alcohol copolymer did not prevent those hemorrhagic complications which embolization is hypothesized to prevent based on theoretical speculations but not demonstrated in practice. PMID- 23350777 TI - Prospective study of carmustine wafers in combination with 6-month metronomic temozolomide and radiation therapy in newly diagnosed glioblastoma: preliminary results. AB - OBJECT: Locoregional chemotherapy with carmustine wafers, positioned at surgery and followed by radiation therapy, has been shown to prolong survival in patients with newly diagnosed glioblastoma, as has concomitant radiochemotherapy with temozolomide. A combination of carmustine wafers with the Stupp treatment regimen has only been investigated in retrospective studies. METHODS: In a single institution prospective study, the authors assessed 12-month progression-free survival (PFS), toxicity, and overall survival in patients with glioblastoma treated with surgery, carmustine wafers, radiotherapy, and 6-month metronomic temozolomide chemotherapy. Thirty-five patients with de novo glioblastoma, between the ages of 18 and 70 years, and with Karnofsky Performance Scale scores of at least 70, were included in the study. Patients were followed monthly and assessed using MRI every 2 months. RESULTS: After a median follow-up of 15 months, the median time to tumor progression was 12.5 months and median survival was 17.8 months. Due to toxicity (mostly hematological), 7 patients had to prematurely stop temozolomide treatment. Twenty-two patients developed Grade 3 CD4(+) lymphocytopenia. Three patients developed oral-esophageal candidiasis, 2 developed pneumonia, and 1 developed a dorsolumbar zoster. Early intracranial hypertension was observed in 1 patient, and 1 was treated empirically for suspected brain abscess. One patient died of Legionella pneumonia soon after repeat surgery. CONCLUSIONS: Overall, this treatment schedule produced promising results in terms of PFS without a marked increase in toxicities as compared with the Stupp regimen. However, the gain in median survival using this schedule was less clear. Only prospective comparative trials will determine whether these preliminary results will translate into a long-term survival advantage with an acceptable toxicity profile. PMID- 23350778 TI - Endovascular treatment of proximal and distal posterior inferior cerebellar artery aneurysms. AB - OBJECT: Surgical clipping of posterior inferior cerebellar artery (PICA) aneurysms can be challenging and carries a potentially significant risk of morbidity and mortality. Experience with endovascular therapy has been limited to a few studies. The authors assess the feasibility, safety, and efficacy of endovascular therapy in the largest series of proximal and distal PICA aneurysms to date. METHODS: A total of 76 patients, 54 with proximal and 22 with distal PICA aneurysms, underwent endovascular treatment at Jefferson Hospital for Neuroscience between 2001 and 2011. RESULTS: Endovascular treatment was successful in 52 patients (96.3%) with proximal aneurysms and 19 patients (86.4%) with distal aneurysms. Treatment consisted of selective aneurysm coiling in 60 patients (84.5%) (including 4 with stent assistance and 4 with balloon assistance) and parent vessel trapping in 11 patients (15.5%). Specifically, a deconstructive procedure was necessary in 9.6% of proximal aneurysms (5 of 52) and 31.6% of distal aneurysms (6 of 19). There were 9 overall procedural complications (12.7%), 6 infarcts (8.5%; 4 occurring after deliberate occlusion of the PICA), and 3 intraprocedural ruptures (4.2%). The rate of procedure related permanent morbidity was 2.8%. Complete aneurysm occlusion was achieved in 63.4% of patients (45 of 71). One patient (1.4%) treated with selective aneurysm coiling suffered a rehemorrhage on postoperative Day 15. The mean angiographic follow-up time was 17.2 months. Recurrence and re-treatment rates were, respectively, 20% and 17.1% for proximal aneurysms compared with 30.8% and 23.1% for distal aneurysms. Favorable outcomes (moderate, mild, or no disability) at follow-up were seen in 93% of patients with unruptured aneurysms and in 78.7% of those with ruptured aneurysms. CONCLUSIONS: Endovascular therapy is a feasible, safe, and effective treatment in patients with proximal and distal PICA aneurysms, providing excellent patient outcomes and adequate protection against rehemorrhage. The long-term incidence of aneurysm recanalization appears to be high, especially in distal aneurysms, and requires careful angiographic follow up. PMID- 23350779 TI - Muscle and nerve transfer in tetraplegia. PMID- 23350780 TI - Intracranial phosphaturic mesenchymal tumors: report of 2 cases. AB - Hypophosphatemia with osteomalacia may be due to a neoplasm that produces fibroblast growth factor 23 (FGF-23), which inhibits phosphate reabsorption in the kidneys. Most of these tumors occur in bone or soft tissue and occasionally in the head, although intracranial occurrence is very rare. This report describes a tumor that caused hypophosphatemia and osteomalacia and was located entirely in the right anterior cranial fossa. Radiologically, the tumor resembled a meningioma; histologically, it was a low-grade phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT). After gross-total resection, the patient's symptoms abated and laboratory values normalized. The authors also studied another PMTMCT initially diagnosed as a hemangiopericytoma that involved the left anterior cranial fossa and ethmoid sinus, and reviewed reports of 6 other intracranial tumors that induced osteomalacia, 3 entirely in the anterior cranial fossa, 2 involving the anterior cranial fossa and ethmoid sinus, and 1 in the cavernous sinus. In older children or adults who have hypophosphatemia with osteomalacia and no personal or family history of metabolic, renal, or malabsorptive disease, a neoplasm should be suspected and an imaging workup that includes the brain is warranted, with particular attention to the anterior cranial fossa. Additionally, because there are some overlapping histological features between PMTMCTs and hemangiopericytomas, it may be helpful to assess tumoral FGF-23 expression by reverse transcriptase polymerase chain reaction or immunohistochemical analysis in patients with oncogenic osteomalacia from an intracranial tumor diagnosed as, or resembling, hemangiopericytoma. PMID- 23350781 TI - Prevention of postoperative cerebrospinal fluid leaks with multilayered reconstruction using titanium mesh-hydroxyapatite cement cranioplasty after translabyrinthine resection of acoustic neuroma. AB - OBJECT: Several prophylactic surgical methods have been tried to prevent CSF leakage after translabyrinthine resection of acoustic neuroma (TLAN). The authors report an improvised technique for multilayer watertight closure using titanium mesh-hydroxyapatite cement (HAC) cranioplasty in addition to dural substitute and abdominal fat graft after TLAN. METHODS: The study was limited to 42 patients who underwent TLAN at University Hospitals Case Medical Center using this new technique from 2006 to 2012. Systematic closure of the surgical wound in layers using temporalis fascia, dural substitute, dural sealant, adipose graft, titanium mesh, and then HAC was performed in each case. Temporalis muscle and eustachian tube obliteration were not used. The main variables studied were patient age, tumor size, tumor location, cosmetic outcome, length of hospitalization, and the incidence of CSF leak, pseudomeningocele, and infection. RESULTS: Excellent cosmetic outcome was achieved in all patients. There were no cases of postoperative CSF rhinorrhea, incisional CSF leak, or meningitis. Cosmetic results were comparable to those achieved using HAC alone. This cost-effective technique used only a third of the HAC required for traditional closure in which the entire mastoid defect is filled with cement, predisposing to infection. Postoperative CT and MRI showed excellent bony contouring and dural reconstitution, respectively. CONCLUSIONS: The authors report on successful use of titanium mesh-HAC cranioplasty in preventing postoperative CSF leak after TLAN in all cases in their series. The titanium mesh provides a well-defined anatomical dissection plane that would make reoperation easier than working through scarred soft tissue. The mesh bolsters the fat graft and keeps HAC out of direct contact with mastoid air cells, thereby reducing the risk of infection. The cement cranioplasty does not preclude subsequent implantation of a bone anchored hearing aid. PMID- 23350782 TI - Intraventricular silicone oil. AB - The authors report a case in which intravitreous silicone oil migrated into the ventricles. They note that intraventricular silicone oil can be misdiagnosed as intraventricular hemorrhage and neurosurgeons should be aware of this possibility. This 58-year-old woman with a history of Type II diabetic mellitus and retinal detachment (resulting from diabetic retinopathy), which had been treated with intravitreous silicone tamponade, presented with dizziness and headache approximately 10 years after the intravitreous silicone treatment. Over the next 6 years she underwent 2 non-contrast-enhanced brain CT studies and 1 MRI study for evaluation of her symptoms. On CT scan, extension of the intraocular silicone along the optic nerve was evident. Two hyperdense nodules were observed freely floating in the right lateral and fourth ventricles, remaining in the nondependent portion of ventricles in both supine and prone positions. On T2 weighted MRI, the left orbital content and the intraventricular nodules all demonstrated chemical shift artifacts typically associated with silicone. The imaging findings were characteristic for intraventricular silicone after silicone oil tamponade. The patient's dizziness and headache were treated symptomatically and she was followed up at the outpatient department. Migration of intravitreous silicone oil into the cerebral ventricles is a rare complication. Intraventricular silicone oil can mimic intraventricular hemorrhage. Radiographically, intraventricular silicone oil can be distinguished from hemorrhage as silicone oil tends to stay in the nondependent portion of the ventricle. Chemical shift artifacts on MRI may help establishing the diagnosis of intraventricular silicone oil. Currently, there is no consensus on surgical removal of intraventricular silicone oil, and in the majority of cases reported in the literature, the patients were asymptomatic. PMID- 23350783 TI - Isolation and identification of antioxidant peptides from jinhua ham. AB - The antioxidant activities of the peptides extracted from Jinhua ham were evaluated on the basis of hydroxyl radical scavenging activity, DPPH radical scavenging activity, and Fe(2+) chelating ability. The peptide extracts exhibited great hydroxyl radical scavenging activity and DPPH radical scavenging activity as well as Fe(2+) chelating ability at the concentration of 1 mg/mL, which suggested the presence of peptides with antioxidant activity. The peptides were separated using size exclusion chromatography and reversed-phase HPLC. The fraction with highest DPPH radical scavenging activity was further purified and identified using liquid chromatography tandem matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (HPLC-MALDI TOF/TOF-MS). The sequence of the antioxidant peptide was identified as Gly-Lys Phe-Asn-Val. The assessment of fractions indicated that the hydrophobic fractions contributed more to free radical scavenging activities than the hydrophilic peptides. It was concluded that natural peptides extracted and isolated from the Jinhua ham by several chromatographic techniques have antioxidant activities. PMID- 23350784 TI - Relative accuracy and availability of an Irish National Database of dispensed medication as a source of medication history information: observational study and retrospective record analysis. AB - WHAT IS KNOWN AND OBJECTIVE: The medication reconciliation process begins by identifying which medicines a patient used before presentation to hospital. This is time-consuming, labour intensive and may involve interruption of clinicians. We sought to identify the availability and accuracy of data held in a national dispensing database, relative to other sources of medication history information. METHODS: For patients admitted to two acute hospitals in Ireland, a Gold Standard Pre-Admission Medication List (GSPAML) was identified and corroborated with the patient or carer. The GSPAML was compared for accuracy and availability to PAMLs from other sources, including the Health Service Executive Primary Care Reimbursement Scheme (HSE-PCRS) dispensing database. RESULTS: Some 1111 medication were assessed for 97 patients, who were median age 74 years (range 18 92 years), median four co-morbidities (range 1-9), used median 10 medications (range 3-25) and half (52%) were male. The HSE-PCRS PAML was the most accurate source compared to lists provided by the general practitioner, community pharmacist or cited in previous hospital documentation: the list agreed for 74% of the medications the patients actually used, representing complete agreement for all medications in 17% of patients. It was equally contemporaneous to other sources, but was less reliable for male than female patients, those using increasing numbers of medications and those using one or more item that was not reimbursable by the HSE. WHAT IS NEW AND CONCLUSION: The HSE-PCRS database is a relatively accurate, available and contemporaneous source of medication history information and could support acute hospital medication reconciliation. PMID- 23350785 TI - A novel approach to active compounds identification based on support vector regression model and mean impact value. AB - Traditionally, active compounds were discovered from natural product extracts by bioassay-guided fractionation, which was with high cost and low efficiency. A well-trained support vector regression model based on mean impact value was used to identify lead active compounds on inhibiting the proliferation of the HeLa cells in curcuminoids from Curcuma longa L. Eight constituents possessing the high absolute mean impact value were identified to have significant cytotoxicity, and the cytotoxic effect of these constituents was partly confirmed by subsequent MTT (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays and previous reports. In the dosage range of 0.2-211.2, 0.1-140.2, 0.2-149.9 MUm, 50% inhibiting concentrations (IC50 ) of curcumin, demethoxycurcumin, and bisdemethoxycurcumin were 26.99 +/- 1.11, 19.90 +/- 1.22, and 35.51 +/- 7.29 MUm, respectively. It was demonstrated that our method could successfully identify lead active compounds in curcuminoids from Curcuma longa L. prior to bioassay guided separation. The use of a support vector regression model combined with mean impact value analysis could provide an efficient and economical approach for drug discovery from natural products. PMID- 23350786 TI - Negative pressure wound therapy for surgical site infection associated with artificial urinary sphincter implantation. PMID- 23350787 TI - Multiple cores of Gleason score 6 correlate with favourable findings at radical prostatectomy. AB - OBJECTIVE: To establish whether the good prognosis of Gleason score 6 (GS6) is maintained in the setting of multiple involved cores. PATIENTS AND METHODS: In total, 6156 men (from 1 April 2000 to 30 April 2007) with GS6 on biopsy underwent radical prostatectomy (RP) at our institution. The number of positive cores was correlated with the outcome at RP. RESULTS: More positive cores correlated with less organ-confined disease (P < 0.001), positive margins (P < 0.012), increasing RP grade (P < 0.001) and increased seminal vesicles/lymph node involvement (P = 0.012). For men with data available, the actuarial risk of being biochemically free of disease at 5 years was 93.2% when <=6 cores were positive (812 men followed to 5 years) vs 89.1% if >6 cores were positive (41 men followed to 2 years) (P = 0.6). Although the predicted 'cure rate' of >75% probability of a tumour showing no evidence of biochemical recurrence at 10 years after RP was statistically different between cases with <=6 vs >6 positive cores (P < 0.0001), the outcome in both groups was still favourable (90.5% vs 84%). Partin-like tables were generated factoring in the number of positive cores to predict organ confined disease as a guide for urologists to perform nerve-sparing surgery. For example, with T1c disease, there was a >=75% probability of organ-confined disease with one to three positive cores regardless of prostate-specific antigen (PSA) level, and the same probability was present with four to six positive cores and a PSA level of 0-4 ng/mL. CONCLUSION: A low Gleason score on biopsy is a powerful prognostic finding, such that this favourable outcome is maintained even in the setting of multiple positive cores with GS6. PMID- 23350788 TI - Effect sizes in memory research. AB - Effect sizes are omitted from many research articles and are rarely discussed. To help researchers evaluate effect sizes we collected values for the more commonly reported effect size measures (partial eta squared and d) from papers reporting memory research published in 2010. Cohen's small, medium, and large generic guideline values for d mapped neatly onto the observed distributions, but his values for partial eta squared were considerably lower than those observed in current memory research. We recommend interpreting effect sizes in the context of either domain-specific guideline values agreed for an area of research or the distribution of effect size estimates from published research in the domain. We provide cumulative frequency tables for both partial eta squared and d enabling authors to report and consider not only the absolute size of observed effects but also the percentage of reported effects that are larger or smaller than those observed. PMID- 23350789 TI - Time-resolved radiation chemistry: photoelectron imaging of transient negative ions of nucleobases. AB - Time-resolved photoelectron imaging has been utilized to probe the energetics and dynamics of the transient negative ion of the nucleobase uracil. This species was created through charge transfer from an iodide anion within a binary iodide uracil complex using a UV pump pulse; the ensuing dynamics were followed by photodetachment with a near-IR probe pulse. The photoelectron spectra show two time-dependent features, one from probe-induced photodetachment of the transient anion state and another from very low energy electron signal attributed to autodetachment. The transient anion was observed to decay biexponentially with time constants of hundreds of femtoseconds and tens of picoseconds, depending on the excitation energy. These dynamics are interpreted in terms of autodetachment from the initially excited state and a second, longer-lived species relaxed by iodine loss. Hydrogen loss from the N1 position may also occur in parallel. PMID- 23350790 TI - Systematic review on heparin-induced thrombocytopenia in children: a call to action. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) has increasingly been reported in children as an indication for use of new alternative anticoagulant drugs (NAADs). OBJECTIVES: To systematically review the literature regarding: (i) the incidence and prevalence of seroconversion and HIT and (ii) the clinical/laboratory findings and management of HIT in children. DESIGN/METHODS: MEDLINE and EMBASE databases were searched for studies that reported pediatric cases of HIT. Methodological reliability assessment of studies was performed with the Loney scale. RESULTS: The incidence of seroconversion in neonates ranged between 0% and 1.7%. There were no cases of neonatal HIT in the included cohorts. The incidence range of seroconversion in the non-neonatal population was 1.3-52%. The incidence of HIT in non-neonates after cardiopulmonary bypass was 0.33% (95%CI, < 0.01-2.04). Whereas more than half of pediatric cases labeled as HIT (30/52) did not include pivotal features of this syndrome, 80% of them received NAADs. CONCLUSION: The incidence of HIT is likely to have been overestimated in children, leading to potential misuse of NAADs in many cases. Clinical findings and laboratory assessment of pediatric cases are poorly described in the literature at present. Thorough laboratory investigation, proper reporting of cases and adequate design of studies are mandatory to elucidate the clinical/laboratory picture of pediatric HIT. PMID- 23350791 TI - Left ventricular thrombectomy using video-assisted thoracoscopy. AB - We report a case of a 40-year-old male who had a left ventricular thrombus with impaired cardiac function. The thrombus was completely removed using a video assisted thoracoscopy via a right mini-thoracotomy. This approach is less invasive, avoiding sternotomy and ventriculotomy which can cause postoperative complications. PMID- 23350792 TI - Increasing the rate of heating: a potential therapeutic approach for achieving synergistic tumour killing in combined hyperthermia and chemotherapy. AB - PURPOSE: A synergistic cancer cell killing effect of sub-lethal hyperthermia and chemotherapy has been reported extensively. In this study, in vitro cell culture experiments with a uterine cancer cell line (MES-SA) and its multidrug resistant (MDR) variant MES-SA/Dx5 were conducted in order to investigate the role of heating rate in achieving a synergistic effect. The mode of cell death, induction of thermal tolerance and P-glycoprotein (P-gp) mediated MDR following two different rates of heating were studied. MATERIALS AND METHODS: Doxorubicin (DOX) was used as the chemotherapy drug. A rapid rate hyperthermia was achieved by near infrared laser (NIR) excited indocyanine green (ICG) dye (absorption maximum at 808 nm, ideal for tissue penetration). A slow rate hyperthermia was provided by a cell culture incubator. RESULTS: The potentiating effect of hyperthermia to chemotherapy can be maximised by increasing the rate of heating. When delivered at the same thermal dose, a rapid increase in temperature from 37 degrees C to 43 degrees C caused more cell membrane damage than gradually heating the cells from 37 degrees C to 43 degrees C and thus allowed for more intracellular accumulation of DOX. Meanwhile, the rapid rate laser-ICG hyperthermia at 43 degrees C caused cell necrosis whereas the slow rate incubator hyperthermia at 43 degrees C induced mild apoptosis. At 43 degrees C a positive correlation between thermal tolerance and the length of hyperthermia exposure is identified. CONCLUSIONS: This study shows that by increasing the rate of heating, less thermal dose is needed in order to overcome P-gp mediated MDR. PMID- 23350793 TI - Toxicity assessment of transgenic papaya ringspot virus of 823-2210 line papaya fruits. AB - The transgenic papaya is a valuable strategy for creating plants resistant to papaya ringspot virus (PRSV) infection and increasing production. This study was further performed to evaluate the comparative toxicity effects of the newly developed transgenic line of the fruits of two backcross transgenic papaya lines (2210 and 823) and one hybrid line (823-2210) and compare to their parent non transgenic (TN-2) counterparts. The stability analysis of coat protein (CP) of PRSV was investigated using the digestion stability assays in simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and bile salts to detect the CP fragments. Results revealed that the CP fragments were rapidly hydrolyzed in SGF and were undetectable in organs and gastrointestinal contents in rats. For the genotoxicity, three in vitro assays were conducted and exhibited that non transgenic and backcross transgenic papaya fruits were negative. Moreover, a repeated animal feeding study was conducted by feeding 2 g/kg of body weight (bw) of non-transgenic and backcross transgenic papaya fruits for 28 days in rats. There were no biological or toxicological significances between non-transgenic and backcross transgenic papaya fruits in rats. The results demonstrated that the backcross transgenic papaya fruit can be recognized as an equivalent substitution for traditional papaya in food safety. PMID- 23350794 TI - Intrinsic relative scales of electrophilicity and nucleophilicity. AB - The formulation of the second-order perturbation approach to the stabilization energy of the A-B interacting species due to charge transfer is revisited. Intrinsic (i.e., electronic) theoretical indices for both relative electrophilicity and nucleophilicity are proposed for any electrophile (A) nucleophile (B) pairs of combining species. By using the new descriptors, an electronic analogue to the Mayr-Patz linear free relationship has been successfully tested in the context of available experimental evidence reported for reactions of primary and secondary amines with benzhydrylium ions. PMID- 23350795 TI - Clinical predictors of risk of hypoglycaemia during addition and titration of insulin glargine for type 2 diabetes mellitus. AB - AIM: Addition and titration of basal insulin is usually effective in improving glycaemic control in type 2 diabetes, but fear of hypoglycaemia remains a barrier. Ability to predict which patients might be at greatest risk of hypoglycaemia might facilitate individualization of treatment and improve safety. The aim of this study was to obtain information about clinical characteristics which might predict risk of hypoglycaemia during initiation of basal insulin. METHODS: Patient-level data from 2251 participants in 11 studies in which insulin glargine was started and titrated using similar treat-to-target methods was pooled and analysed with logistic regression models. RESULTS: Participants had mean age 58 years, diabetes duration 8.9 years, body mass index 31.0 and baseline A1c 8.8%. They attained mean A1c 7.1% during 6 months of treatment with final mean glargine dosage 0.44 units/kg. Symptomatic hypoglycaemia occurred in 52%, glucose-confirmed hypoglycaemia (blood glucose <50 mg/dl) in 17%, repeated glucose-confirmed events in 7% and severe hypoglycaemia in 1.5%. Independent predictors of glucose-confirmed hypoglycaemia were younger age, lower body mass index, use of a sulphonylurea in addition to metformin, lower attained A1c and lower dosage of glargine. CONCLUSIONS: These findings confirm low rates of clinically important hypoglycaemia using this method, and suggest that higher risk of hypoglycaemia may be suspected when patients needing insulin are younger, less obese and taking metformin and a sulphonylurea, and especially when A1c levels <=7.0% are attained with glargine dosage <=0.4 units/kg. PMID- 23350796 TI - Plasma brain-derived neurotrophic factor and prefrontal white matter integrity in late-onset depression and normal aging. AB - OBJECTIVE: To explore the relationship between brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), cerebral deep white matter lesions (DWMLs), and measures of white matter integrity in patients with late onset depression, with respect to vascular risk factors. METHOD: We examined 22 patients with late-onset depression and 22 matched controls. Quantification of plasma BDNF and VEGF levels were performed with enzyme-linked immunosorbent assay (ELISA) kits. Measures of white matter integrity comprised apparent diffusion coefficient (ADC) and fractional anisotropy (FA), obtained by diffusion tensor imaging (DTI). Effects of DWMLs, FA, ADC, and vascular risk factors on BDNF and VEGF were assessed using multiple linear regression. RESULTS: The BDNF and VEGF levels did not differ significantly between groups. With pooled data for patients and controls, the BDNF level was positively associated with both number (t = 2.14, P = 0.039) and volume (t = 2.04, P = 0.048) of prefrontal DWMLs and negatively associated with FA in prefrontal normal-appearing white matter (t = 2.40, P = 0.02), adjusted for age and gender. Smoking and hypercholesterolemia was positively associated with the BDNF (t = 2.36, P = 0.023) and VEGF levels (t = 2.28, P = 0.028), respectively. CONCLUSION: Our results suggest a role for BDNF in the complex pathophysiologic mechanisms underlying DWMLs in both normal aging and late-onset depression. PMID- 23350797 TI - 7-Chloro-4-quinolinyl hydrazones: a promising and potent class of antileishmanial compounds. AB - In this work, we report the antileishmanial evaluation of twenty 7-chloro-4 quinolinyl hydrazone derivatives (1-20). Firstly, the compounds were tested against promastigotes of four different Leishmania species. After that, all derivatives were assayed against L. braziliensis amastigotes and murine macrophages. Furthermore, it was investigated whether the antiamastigote L. braziliensis effect of the compounds could be associated with nitric oxide production. Compounds 6 and 7 showed a strong leishmanicidal activity against intracellular parasite with IC50 in nanogram levels (30 and 20 ng/mL, respectively). Appreciable activity of three compounds tested can be considered an important finding for the rational design of new leads for antileishmanial compounds. PMID- 23350798 TI - The evolution of phenylpropanoid metabolism in the green lineage. AB - Phenolic secondary metabolites are only produced by plants wherein they play important roles in both biotic and abiotic defense in seed plants as well as being potentially important bioactive compounds with both nutritional and medicinal benefits reported for animals and humans as a consequence of their potent antioxidant activity. During the long evolutionary period in which plants have adapted to the environmental niches in which they exist (and especially during the evolution of land plants from their aquatic algal ancestors), several strategies such as gene duplication and convergent evolution have contributed to the evolution of this pathway. In this respect, diversity and redundancy of several key genes of phenolic secondary metabolism such as polyketide synthases, cytochrome P450s, Fe(2+)/2-oxoglutarate-dependent dioxygenases and UDP glycosyltransferases have played an essential role. Recent technical developments allowing affordable whole genome sequencing as well as a better inventory of species-by-species chemical diversity have resulted in a dramatic increase in the number of tools we have to assess how these pathways evolved. In parallel, reverse genetics combined with detailed molecular phenotyping is allowing us to elucidate the functional importance of individual genes and metabolites and by this means to provide further mechanistic insight into their biological roles. In this review, phenolic metabolite-related gene sequences (for a total of 65 gene families including shikimate biosynthetic genes) are compared across 23 independent species, and the phenolic metabolic complement of various plant species are compared with one another, in attempt to better understand the evolution of diversity in this crucial pathway. PMID- 23350799 TI - Judging veracity impairs eyewitnesses' memory of a perpetrator. AB - Witnesses to crimes sometimes perform cognitively demanding tasks while simultaneously observing a perpetrator. This division of attentional resources can cause witnesses to remember the perpetrator less accurately. We hypothesised that judging the veracity of a target individual can impair subsequent memory for his or her appearance and message. In Experiment 1, we demonstrated that the veracity judgement task is cognitively demanding by having participants perform a concurrent secondary task. In three additional experiments, we confirmed that witnesses who judged the veracity of a target remembered his or her appearance and message less accurately than witnesses who simply observed the target. We also extended this result by showing that suspicion amplified the memory impairment effect, apparently by inducing witnesses to allocate even more resources to the judgement task (Experiments 2a and b), and that witnesses' memory was less accurate when they used a cue within the message content rather than a nonverbal cue to judge veracity (Experiment 3). Contrary to our prediction, however, witnesses who monitored two cues versus one did not display worse memory performance. PMID- 23350800 TI - Nominal association with CHRNA4 variants and nicotine dependence. AB - Nicotine binds to nicotinic acetylcholine receptors and studies in animal models have shown that alpha4beta2 receptors mediate many behavioral effects of nicotine. Human genetics studies have provided support that variation in the gene that codes for the alpha4 subunit influences nicotine dependence (ND), but the evidence for the involvement of the beta2 subunit gene is less convincing. In this study, we examined the genetic association between variation in the genes that code for the alpha4 (CHRNA4) and beta2 (CHRNB2) subunits of the nicotinic acetylcholine receptor and a quantitative measure of lifetime DSM-IV ND symptom counts. We performed this analysis in two longitudinal family-based studies focused on adolescent antisocial drug abuse: the Center on Antisocial Drug Dependence (CADD, N = 313 families) and Genetics of Antisocial Drug Dependence (GADD, N = 111 families). Family-based association tests were used to examine associations between 14 single nucleotide polymorphisms (SNPs) in CHRNA4 and CHRNB2 and ND symptoms. Symptom counts were corrected for age, sex and clinical status prior to the association analysis. Results, when the samples were combined, provided modest evidence that SNPs in CHRNA4 are associated with ND. The minor allele at both rs1044394 (A; Z = 1.988, P = 0.047, unadjusted P-value) and rs1044396 (G; Z = 2.398, P = 0.017, unadjusted P-value) was associated with increased risk of ND symptoms. These data provide suggestive evidence that variation in the alpha4 subunit of the nicotinic acetylcholine receptor may influence ND liability. PMID- 23350801 TI - Development of an improved three-dimensional in vitro intestinal mucosa model for drug absorption evaluation. AB - Human epithelial cell culture models of monolayer Caco-2 cells have been widely employed to assess the absorption of drug molecules across intestinal mucosa. However, cautions should be taken when interpreting the conclusions from those models due to their undesirable phenotype and functionality when compared with the native intestinal tissue. In the present study, an improved, more physiologically relevant three-dimensional (3D) culture model of the intestinal mucosa was developed to study drug absorption, in which a coculture of epithelial cells, including Caco-2 cells and HT29-methotrexate cells, was indirectly seeded on a Transwell filter insert with collagen gel and stromal cells (fibroblasts and immunocytes) incorporation. This setting-up provided a compatible environment to improve the phenotype and functionality of the epithelial cells. Compared with the monolayer culture of Caco-2 cells, the reconstructed 3D model displayed more physiologically relevant characteristics evidenced by its decreased TEER value and mucus-like layer formation. A decreased expression of P-gp and an increased expression of BCRP were also observed in the current 3D culture model, leading to a changed secretory permeability of their substrates. More importantly, an improved correlation (R(2)=0.843) was obtained between the absorptive permeability across the 3D coculture model and the human absorption fraction especially for those model compounds with moderate or high permeability. Thus, this engineered 3D coculture model presents a unique, improved opportunity to evaluate drug permeability in vitro. PMID- 23350802 TI - Patient satisfaction: the name of the game? PMID- 23350803 TI - New magnetic resonance imaging techniques identify cortical changes in glaucoma. PMID- 23350804 TI - Elastic hysteresis in human eyes is an age-dependent value. AB - BACKGROUND: The elastic hysteresis phenomenon is observed when cyclic loading is applied to a viscoelastic system. The purpose of this study was to quantitatively evaluate elastic hysteresis in living human eyes against an external force. DESIGN: Prospective case series. PARTICIPANTS: Twenty-four eyes of 24 normal human subjects (mean age: 41.5 +/- 10.6 years) were recruited. METHODS: A non contact tonometry process was recorded with a high-speed camera. Central corneal thickness, corneal thickness at 4 mm from the centre, corneal curvature and anterior chamber depth were measured. Intraocular pressure was also measured using Goldmann applanation tonometry and dynamic contour tonometer. MAIN OUTCOME MEASURES: Energy loss due to elastic hysteresis was calculated and graphed. RESULTS: The mean central corneal thickness was 552.5 +/- 36.1 um, corneal curvature was 7.84 +/- 0.26 mm and anterior chamber depth was 2.83 +/- 0.29 mm. The mean Goldmann applanation tonometry-intraocular pressure was 14.2 +/- 2.7 mmHg and dynamic contour tonometer-intraocular pressure was 16.3 +/- 3.5 mmHg. The mean energy loss due to elastic hysteresis was 3.90 * 10(-6) +/- 2.49 * 10( 6) Nm. Energy loss due to elastic hysteresis correlated significantly with age (Pearson correlation coefficient = 0.596, P = .0016). There were no significant correlations between energy loss due to elastic hysteresis and other measurements. CONCLUSION: Energy loss due to elastic hysteresis in the eyes of subjects was found to positively correlate with age, independent of anterior eye structure or intraocular pressure. Therefore, it is believed that the viscosity of the eye increases with age. PMID- 23350805 TI - Structural characterization and physical properties of the new transition metal oxyselenide La2O2ZnSe2. AB - The quaternary transition metal oxyselenide La(2)O(2)ZnSe(2) has been shown to adopt a ZrCuSiAs-related structure with Zn(2+) cations in a new ordered arrangement within the [ZnSe(2)](2-) layers. This cation-ordered structure can be derived and described using the symmetry-adapted distortion mode approach. La(2)O(2)ZnSe(2) is an direct gap semiconductor with an experimental optical band gap of 3.4(2) eV, consistent with electronic structure calculations. PMID- 23350806 TI - Clinical, biochemical, and molecular studies in pyridoxine-dependent epilepsy. Antisense therapy as possible new therapeutic option. AB - PURPOSE: Pyridoxine-dependent epilepsy seizure (PDE; OMIM 266100) is a disorder associated with severe seizures that can be controlled pharmacologically with pyridoxine. In the majority of patients with PDE, the disorder is caused by the deficient activity of the enzyme alpha-aminoadipic semialdehyde dehydrogenase (antiquitin protein), which is encoded by the ALDH7A1 gene. The aim of this work was the clinical, biochemical, and genetic analysis of 12 unrelated patients, mostly from Spain, in an attempt to provide further valuable data regarding the wide clinical, biochemical, and genetic spectrum of the disease. METHODS: The disease was confirmed based on the presence of alpha-aminoadipic semialdehyde (alpha-AASA) in urine measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) and pipecolic acid (PA) in plasma and/or cerebrospinal fluid (CSF) measured by high performance liquid chromatography (HPLC)/MS/MS and by sequencing analysis of messenger RNA (mRNA) and genomic DNA of ALDH7A1. KEY FINDINGS: Most of the patients had seizures in the neonatal period, but they responded to vitamin B6 administration. Three patients developed late-onset seizures, and most patients showed mild-to-moderate postnatal developmental delay. All patients had elevated PA and alpha-AASA levels, even those who had undergone pyridoxine treatment for several years. The clinical spectrum of our patients is not limited to seizures but many of them show associated neurologic dysfunctions such as muscle tone alterations, irritability, and psychomotor retardation. The mutational spectrum of the present patients included 12 mutations, five already reported (c.500A>G, c.919C>T, c.1429G>C c.1217_1218delAT, and c.1482-1G>T) and seven novel sequence changes (c.75C>T, c.319G>T, c.554_555delAA, c.757C>T, c.787 + 1G>T, c.1474T>C, c.1093-?_1620+?). Only one mutation, p.G477R (c.1429G>C), was recurrent; this was detected in four different alleles. Transcriptional profile analysis of one patient's lymphoblasts and ex vivo splicing analysis showed the silent nucleotide change c.75C>T to be a novel splicing mutation creating a new donor splice site inside exon 1. Antisense therapy of the aberrant mRNA splicing in a lymphoblast cell line harboring mutation c.75C>T was successful. SIGNIFICANCE: The present results broaden our knowledge of PDE, provide information regarding the genetic background of PDE in Spain, afford data of use when making molecular-based prenatal diagnosis, and provide a cellular proof-of concept for antisense therapy application. PMID- 23350807 TI - In vitro and in vivo investigation of low molecular weight heparin-alginate beads for oral administration. AB - Low molecular weight heparin (LMWH) and standard heparin are widely used anticoagulants. However, they have very poor oral bioavailability and have to be administered by the parenteral route. Alginates are biodegradable, biocompatible and mucoadhesive polymers which can be used for advantage for the oral administration of LMWH. The aim of the study was to develop LMWH-alginate beads for oral delivery. Alginate beads were prepared based on the 2(3) factorial design. In vitro characterization studies of the beads were carried out. In vivo studies were performed on rabbits. The LMWH solutions (5000 IU/kg, with and without 5% dimethyl-beta-cyclodextrin), as well as the LMWH-alginate beads were administered to rabbits. The IV solution was also administered (100 IU/kg). The anti-Xa activity was measured in plasma. Area under curve (AUC) and Cmax values were determined. Histological investigations were also carried out. The formulation consisting of a 1:2 drug/alginate ratio and cured using 0.5 M CaCl2 for 15 min gave the best result in terms of encapsulation efficiency and the time for 50% of the drug to be released (t50%). A significantly higher bioavailability was observed for LMWH-alginate beads than for LMWH solutions. It was concluded that, anticoagulant effectiveness was achieved using alginate beads containing LMWH after oral administration to the rabbits. PMID- 23350808 TI - Aptamer-based nanoparticles for cancer targeting. AB - BACKGROUND: The use of mesoporous silica for cancer targeting is increasing rapidly. The association between rigid model of nanoparticles such as mesoporous silica and biological compounds with affinity for oncological diseases is a very promising drug targeting system nowadays. METHODS: In this study, we used the mesoporous silica (SBA-15) associated with aptamer (functionalized for the tumor marker MUC-1). RESULTS: The results obtained in the characterization were quite interesting and demonstrated that the silica produced were very uniform and with a size range of 50-100 nm. Thus, the results of cytotoxicity demonstrated that there is no cytotoxicity related to the nanoparticle. CONCLUSION: We conclude that although further studies are required, the nanoparticle mesoporous silica model loaded with aptamer is very functional and its use can be widespread for other application especially in nuclear medicine. PMID- 23350809 TI - Association between metabolic syndrome and carotid atherosclerosis: a community based study in Hong Kong. AB - BACKGROUND: Carotid atherosclerosis should not be neglected as a cause for stroke in China, despite its low prevalence. This study was performed to evaluate the association between ultrasonographic markers for different stages of carotid atherosclerosis and metabolic syndrome. METHODS: This was a community-based study in Hong Kong. Metabolic syndrome was defined as having three or more of the following conditions or receiving specific treatment for these conditions: Abdominal obesity, elevated triglycerides, low high-density lipoprotein cholesterol, hypertension, and impaired fasting blood glucose. All subjects underwent carotid duplex ultrasonography. Mean carotid intima media thickness (CIMT) of bilateral common carotid arteries was used as the CIMT value for a single subject. CIMT within the 4(th) quartile was regarded as increased CIMT. Carotid plaque was defined as a focal CIMT of >1.5 mm. A carotid plaque obstructing >=50% of vessel lumen was considered as carotid stenosis. RESULTS: A total of 653 subjects (mean age 55.1+/-10.4; 47.2% male) were recruited. Metabolic syndrome was found in 188 (28.8%) subjects (30.8% in males and 27.0% in females). Mean CIMT was 0.74+/-0.12 mm. Increased CIMT, carotid plaque, and carotid stenosis were detected in 163 (25.0%), 95 (14.5%), and 6 (1.4%) subjects, respectively. In multivariate linear regression, CIMT significantly increased with increasing numbers of metabolic syndrome components (P<0.001). In multivariate logistic regression analysis, metabolic syndrome was independently associated with increased CIMT [odds ratio (OR) 1.17; 95% confidence interval (CI) 1.11-2.64; P=0.014), but not presence of carotid plaque (OR 1.50; 95% CI 0.92-2.46; P=0.108). CONCLUSIONS: Metabolic syndrome may be independently associated with the early stage but not the later and advanced stages of carotid atherosclerosis in community residents in China. PMID- 23350810 TI - The role of phosphatidylcholine and choline metabolites to cell proliferation and survival. AB - The reorganization of metabolic pathways in cancer facilitates the flux of carbon and reducing equivalents into anabolic pathways at the expense of oxidative phosphorylation. This provides rapidly dividing cells with the necessary precursors for membrane, protein and nucleic acid synthesis. A fundamental metabolic perturbation in cancer is the enhanced synthesis of fatty acids by channeling glucose and/or glutamine into cytosolic acetyl-CoA and upregulation of key biosynthetic genes. This lipogenic phenotype also extends to the production of complex lipids involved in membrane synthesis and lipid-based signaling. Cancer cells display sensitivity to ablation of fatty acid synthesis possibly as a result of diminished capacity to synthesize complex lipids involved in signaling or growth pathways. Evidence has accrued that phosphatidylcholine, the major phospholipid component of eukaryotic membranes, as well as choline metabolites derived from its synthesis and catabolism, contribute to both proliferative growth and programmed cell death. This review will detail our current understanding of how coordinated changes in substrate availability, gene expression and enzyme activity lead to altered phosphatidylcholine synthesis in cancer, and how these changes contribute directly or indirectly to malignant growth. Conversely, apoptosis targets key steps in phosphatidylcholine synthesis and degradation that are linked to disruption of cell cycle regulation, reinforcing the central role that phosphatidylcholine and its metabolites in determining cell fate. PMID- 23350811 TI - Docking-based virtual screening of covalently binding ligands: an orthogonal lead discovery approach. AB - In pharmaceutical industry, lead discovery strategies and screening collections have been predominantly tailored to discover compounds that modulate target proteins through noncovalent interactions. Conversely, covalent linkage formation is an important mechanism for a quantity of successful drugs in the market, which are discovered in most cases by hindsight instead of systematical design. In this article, the implementation of a docking-based virtual screening workflow for the retrieval of covalent binders is presented considering human cathepsin K as a test case. By use of the docking conditions that led to the best enrichment of known actives, 44 candidate compounds with unknown activity on cathepsin K were finally selected for experimental evaluation. The most potent inhibitor, 4-(N phenylanilino)-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile (CP243522), showed a K(i) of 21 nM and was confirmed to have a covalent reversible mechanism of inhibition. The presented approach will have great potential in cases where covalent inhibition is the desired drug discovery strategy. PMID- 23350812 TI - Phase IIa randomized double-blind, placebo-controlled study of inhaled apomorphine as acute challenge for rescuing 'off' periods in patients with established Parkinson's disease. AB - BACKGROUND AND PURPOSE: In this first study of inhaled apomorphine (VR040) in patients with Parkinson's disease, the primary objective was to find the minimum efficacious dose of apomorphine that was useful in rescuing patients during 'off' periods. Safety, tolerability and pharmacokinetics of inhaled apomorphine were assessed during the study. METHODS: A double-blind, placebo-controlled, randomized trial of three escalating single doses of inhaled apomorphine (0.2, 0.5 and 0.8 mg fine particle dose) versus placebo (3 : 1 active:placebo) was performed. Parkinson's motor severity assessments by a clinician, and disease state assessment by the patient, were performed at baseline during an 'off' state, and at specified times after test drug administration. Safety assessments (including vital signs, electrocardiogram and forced expiratory volume) were performed, and plasma apomorphine levels measured. RESULTS: All 24 patients completed the study, and considering the three dose levels together, inhaled apomorphine did not significantly increase the proportion of patients switching from 'off' to 'on' (0/6 at 0.2 mg, 3/6 at 0.5 mg and 2/6 at 0.8 mg vs. 1/6 for placebo), or decrease the time from 'off' to 'on' post-treatment (10 min for 0.5 mg, 40 min for 0.8 mg, vs. 20 min for placebo). However, there was a suggestion of benefit at the higher doses (5/12 switched 'on' at the 0.5 or 0.8 mg doses, vs. 1/6 for placebo). There were no serious adverse events and treatment was well tolerated. Peak plasma concentration was 1-3 min post-dose, and plasma level dose proportionality was observed. CONCLUSIONS: Inhaled apomorphine was safe and well tolerated at the doses tested for an acute challenge to rescue 'off' periods, but efficacy at these doses was limited. A follow-up study at higher doses is appropriate given these initial findings. PMID- 23350813 TI - Investigation of the heating properties of platinum nanoparticles under a radiofrequency current. AB - PURPOSE: For the potential application of platinum nanoparticles (PtNPs) in hyperthermia therapy, the heating efficiency of PtNPs in the presence of radiofrequency (RF) current generated by a capacitive electric transfer (CET) system was compared with that of gold nanoparticles (AuNPs). MATERIALS AND METHODS: PtNPs and AuNPs synthesised by citrate capping (5 nm) were exposed to an RF current of 0.35 +/- 0.05 MHz in a CET system. The temperature of the solution containing various concentrations of platinum or gold NPs was monitored for 5 min at various power ranges. RESULTS: When both NP solutions were exposed to an RF field at a fixed power, the temperature of the NP solution increased continuously over the 5 min of measurement. In contrast, the NP-free solutions did not show any temperature change. Both PtNPs and AuNPs can be heated in a concentration- and power-dependent manner. However, PtNPs showed a higher efficiency in generating heat compared with AuNPs in both water and the physiological buffer. CONCLUSIONS: The heat generating efficiency of 5-nm PtNPs was about 50% higher than that of AuNPs when they were exposed to electric current through RF. This result suggests that PtNPs are promising nanomaterials for RF-induced hyperthermia therapy. PMID- 23350814 TI - Collagen/beta(1) integrin interaction is required for embryoid body formation during cardiogenesis from murine induced pluripotent stem cells. AB - BACKGROUND: The interactions between stem cells and extracellular matrix (ECM) mediated by integrins play important roles in the processes that determine stem cell fate. However, the role of ECM/integrin interaction in the formation of embryoid bodies (EBs) during cardiogenesis from murine induced pluripotent stem cells (miPSCs) remains unclear. RESULTS: In the present study, collagen type I and beta(1) integrin were expressed and upregulated synergistically during the formation of miPSC-derived EBs, with a peak expression at day 3 of differentiation. The blockage of collagen/beta(1) integrin interaction by beta(1) integrin blocking antibody resulted in the production of defective EBs that were characterized by decreased size and the absence of a shell-like layer composed of primitive endoderm cells. The quantification of spontaneous beating activity, cardiac-specific gene expression and cardiac troponin T (cTnT) immunostaining showed that the cardiac differentiation of these defective miPSC-derived EBs was lower than that of control EBs. CONCLUSIONS: These findings indicate that collagen/beta(1) integrin interaction is required for the growth and cardiac differentiation of miPSC-derived EBs and will be helpful in future engineering of the matrix microenvironment within EBs to efficiently direct the cardiac fate of pluripotent stem cells to promote cardiovascular regeneration. PMID- 23350815 TI - Cholesterol lowering with bile salt hydrolase-active probiotic bacteria, mechanism of action, clinical evidence, and future direction for heart health applications. AB - INTRODUCTION: Cardiovascular diseases (CVD) are the leading cause of global mortality and morbidity. Current CVD treatment methods include dietary intervention, statins, fibrates, niacin, cholesterol absorption inhibitors, and bile acid sequestrants. These formulations have limitations and, thus, additional treatment modalities are needed. Probiotic bacteria, especially bile salt hydrolase (BSH)-active probiotic bacteria, have demonstrated cholesterol-lowering efficacy in randomized controlled trials. AREAS COVERED: This review describes the current treatments for CVD and the need for additional therapeutics. Gut microbiota etiology of CVD, cholesterol metabolism, and the role of probiotic formulations as therapeutics for the treatment and prevention of CVD are described. Specifically, we review studies using BSH-active bacteria as cholesterol-lowering agents with emphasis on their cholesterol-lowering mechanisms of action. Potential limitations and future directions are also highlighted. EXPERT OPINION: Numerous clinical studies have concluded that BSH active probiotic bacteria, or products containing them, are efficient in lowering total and low-density lipoprotein cholesterol. However, the mechanisms of action of BSH-active probiotic bacteria need to be further supported. There is also the need for a meta-analysis to provide better information regarding the therapeutic use of BSH-active probiotic bacteria. The future of BSH-active probiotic bacteria most likely lies as a combination therapy with already existing treatment options. PMID- 23350816 TI - Zwitterions and unobserved intermediates in organocatalytic Diels-Alder reactions of linear and cross-conjugated trienamines. AB - The Diels-Alder reactions of cyclic linear and cross-conjugated trienamines with oxindoles have been studied with density functional theory [M06-2X/def2 TZVPP/IEFPCM//B97D/6-31+G(d,p)/IEFPCM]. These reactions are found to proceed in a stepwise fashion. Computations revealed that these transformations involve complex mechanisms including zwitterionic intermediates and several unstable alternate cycloadducts arising from (2 + 2) cycloadditions and hetero-Diels-Alder reactions. The observed regio- and stereochemistry can be rationalized by a combination of kinetic and thermodynamic control. PMID- 23350817 TI - Photosensitivity and photodynamic events in black, red and blue tattoos are common: A 'Beach Study'. AB - OBJECTIVES: To find the prevalence of complaints in people having tattoos, with emphasis on chronic complaints, photosensitivity and photodynamic events. METHODS: Individuals sunbathing from June to September 2011 at the beaches of Denmark were invited to participate as they are prone to report tattoos and sun habits reliably. Sun-related and non-sun-related problems in tattoos were determined along with participants' use of sunscreen. Skin type was categorized, as were motifs and colours associated with problems. RESULTS: Of 467 sunbathers, 146 (31.3%) had tattoos. A total of 144 sunbathers with 301 tattoos accepted inclusion. Complaints were experienced in 60/144 (42%), of which 31/60 (52%) were sun related, such as swelling (58%), itching/stinging/pain (52%) and redness (26%). Reactions independent of sun were 29/60 (48%), such as reactions to heat 12/29 (41%) and cold 1/29 (4%). Red, blue and black tattoos predominantly caused sun-related complaints followed by the remaining colours. By number, problems in black tattoos dominated as black was far more frequent. DISCUSSION/CONCLUSION: Complaints such as swelling, itching, stinging, pain and redness are common, predominantly in black and red tattoos, but also frequent in blue tattoos, thus, not confined to one specific colour or chemical entity or class of pigment. Symptoms may switch on and off in seconds, typically not of the weal-and-flare type. Photochemical reactions to pigment or pigment-breakdown products in situ in the skin with induction of reactive oxygen species (ROS) is presumed to be one causative mechanism. Another possible mechanism especially relevant in black may be induction of ROS due to effects of aggregation of carbon black nanoparticles. PMID- 23350818 TI - Upper airway changes in Pierre Robin sequence from childhood to adulthood. AB - OBJECTIVES: To investigate pharyngeal airway changes in patients with Pierre Robin sequence (PRS) longitudinally from childhood to adulthood. SETTING AND SAMPLE POPULATION: Cleft Lip and Palate Unit, Clinic of Orthodontics, University of Zurich. Twenty-four patients born between 1970 and 1990 with non-syndromic PRS. MATERIALS AND METHODS: Lateral cephalograms at age 5 (T1), 10 (T2), 15 (T3) and 20 (T4) years were available. Variables describing pharyngeal airway dimensions, soft palate morphology, tongue and hyoid position, skeletal morphology and head posture were assessed. RESULTS: A significant increase in nasopharyngeal depth was found over the entire observation period (T1 10.7 to T4 19.1 mm, p < 0.001), especially between T2 and T3 (change 3.8 mm, p < 0.001), and was mainly due to adenoid recession (r = -0.75, p < 0.001; variation explained by 56%). Increase in velopharyngeal depth mainly took place between T3 and T4 (change 2.3 mm, p < 0.01). It was due to more anterior tongue posture (r = 0.65, p < 0.001; 42.5% of variation explained), in turn allowing the soft palate to take a more vertical position (r = -0.52, p < 0.001). Increase in oropharyngeal depth was associated with head extension and anterior mandibular positioning (36% of variation explained). However, significance was not reached (T1 8.3 to T4 9.8 mm, p > 0.05). CONCLUSIONS: Upper airway dimensions in children with PRS improve with time, except for the oropharyngeal airway. Despite large interindividual variation, the mean remained in the lower reaches of normality described in other studies. Thus, further research should investigate the prevalence of obstructive sleep apnoea in adults with PRS. PMID- 23350819 TI - Can questions about social interaction correctly identify preschool aged children with autism? AB - AIM: We developed a questionnaire to assess social development (SIQ) in preschool children. Social development is often not included in medical assessment, though it may assist in early identification of autism spectrum disorder (ASD). METHODS: Parents of 108 children with ASD, speech and language disorders, or 'developmental concerns', recruited from a clinical developmental assessment and community child health service, completed the SIQ, and also a Childhood Autism Rating Scale (CARS) assessment. Receiver Operator Characteristic (ROC) curves were generated to assess the performance of different questionnaire score thresholds in correctly identifying children with a CARS score of 30 or more. Logistic regression models were used to identify the questions which had the most predictive value for a CARS score of 30 or more. RESULTS: An SIQ score of 14 or more correctly identified children with a CARS >= 30 with a sensitivity of 85%, specificity 85%, positive likelihood ratio (LR) 8.3 and negative LR 0.2. Two questions were identified as most predictive of ASD. CONCLUSIONS: The SIQ may assist clinicians in assessing social development and in making decisions about referral for autism assessment. Evaluation of the SIQ at the point of entry to a clinical service is needed. PMID- 23350823 TI - Self-rated health and depression of patients with diabetes: how to handle with wide range of ageing and diabetic status? PMID- 23350824 TI - Tunable graphene-silicon heterojunctions for ultrasensitive photodetection. AB - We present the photodetection properties of graphene/Si heterojunctions both in the photocurrent and photovoltage modes. Monolayer graphene/Si junctions were found to be excellent weak-signal detectors with photovoltage responsivity exceeding 10(7) V/W and with noise-equivalent-power reaching ~1 pW/Hz(1/2), potentially capable of distinguishing materials with transmittance, T = 0.9995 in a 0.5 s integration time. In the photocurrent mode, the response was found to remain linear over at least six decades of incident power (P), with tunable responsivity up to 435 mA/W (corresponding to incident photon conversion efficiency (IPCE) > 65%) obtained by layer thickening and doping. With millisecond-scale responses and ON/OFF ratios exceeding 10(4), these photodiodes are highly suitable for tunable and scalable broadband (400 < lambda < 900 nm) photodetectors, photometers, and millisecond-response switching, spectroscopic and imaging devices, and further, and are architecturally compatible with on-chip low-power optoelectronics. PMID- 23350825 TI - Eliciting general practitioners' salient beliefs towards prescribing: a qualitative study based on the Theory of Planned Behaviour in Greece. AB - WHAT IS KNOWN AND OBJECTIVE: Prescribing represents an important medical action especially in primary care. However, irrational prescribing is common and has an impact on clinical and economic outcomes. Therefore, there is a growing need to rationalize prescribing. Knowledge of influential factors is crucial for achieving this. The aim of the present study was to identify the behavioural, normative and control beliefs of GPs regarding prescribing in Greece. METHODS: Focus group sessions were conducted in three geographically defined areas in Greece. GPs working in the private and public sector in primary care settings were invited to participate. Transcripts from focus groups were content analysed using the Theory of Planned Behaviour (TPB) as the theoretical framework. RESULTS AND DISCUSSION: GPs acknowledged prescribing as the most important method for treating diseases in primary health care, with significant impact on patient's health and quality of life. The expectations of patients and their families were extremely influential during prescribing. Pharmaceutical sales representatives, other GPs and specialists, as well as public health authorities influenced prescribing. GPs admitted that factors such as the income of the patient, the limited time available and special situations such as prescribing through a third person or prescribing following patients' prescription requests for medicines that they have previously purchased over the counter through pharmacies may facilitate or hinder their prescribing decision. WHAT IS NEW AND CONCLUSION: This elicitation study shed light into GPs' beliefs regarding prescribing. Factors that are not common in the usual European setting were revealed, such as the influence of the patients' family and special situations during prescribing. Thus, various issues were highlighted that should inform the development of items for inclusion in a forthcoming TPB-based questionnaire. The results of this study revealed also certain issues that can affect the design of policies aiming at the rationalization of prescribing. PMID- 23350827 TI - Diameter-dependent bending modulus of individual multiwall boron nitride nanotubes. AB - The mechanical properties of individual multiwall boron nitride nanotubes (MWBNNTs) synthesized by a growth-vapor-trapping chemical vapor deposition method are investigated by a three-point bending technique via atomic force microscopy. Multiple locations on suspended tubes are probed in order to determine the boundary conditions of the supported tube ends. The bending moduli (EB) calculated for 20 tubes with diameters ranging from 18 to 58 nm confirm the exceptional mechanical properties of MWBNNTs, with an average EB of 760 +/- 30 GPa. For the first time, the bending moduli of MWBNNTs are observed to increase with decreasing diameter, ranging from 100 +/- 20 GPa to as high as 1800 +/- 300 GPa. This diameter dependence is evaluated by Timoshenko beam theory. The Young's modulus and shear modulus were determined to be 1800 +/- 300 and 7 +/- 1 GPa, respectively, for a trimmed data set of 16 tubes. The low shear modulus of MWBNNTs is the reason for the detected diameter-dependent bending modulus and is likely due to the presence of interwall shearing between the crystalline and faceted helical nanotube structures of MWBNNTs. PMID- 23350826 TI - Internet-based treatment of stress urinary incontinence: a randomised controlled study with focus on pelvic floor muscle training. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Stress urinary incontinence (SUI) affects 10-35% of women, and it is sometimes very distressful. Pelvic floor exercises are the first line of treatment, but access barriers or embarrassment may prevent women from seeking help. There is a need for new, simple, and effective ways to deliver treatment. Management of SUI without face to-face contact is possible, and Internet-based treatment is a new, promising treatment alternative. OBJECTIVE: To compare two treatment programmes for stress urinary incontinence (SUI) without face-to-face contact: one Internet-based and one sent by post. PATIENTS AND METHODS: Randomised, controlled trial conducted in Sweden 2009-2011. Computer-generated block-randomisation, allocation by independent administrator. No 'blinding'. The study included 250 community dwelling women aged 18-70 years, with SUI >=1 time/week. Consecutive online recruitment. The women had 3 months of either; (i) An Internet-based treatment programme (124 women), including e-mail support and cognitive behavioural therapy assignments or (ii) A treatment programme sent by post (126). Both programmes focused mainly on pelvic floor muscle training. PRIMARY OUTCOMES: symptom-score (International Consultation on Incontinence Questionnaire Short Form, ICIQ-UI SF) and condition-specific quality of life (ICIQ-Lower Urinary Tract Symptoms Quality of Life, ICIQ-LUTSQoL). SECONDARY OUTCOMES: (i) Patient Global Impression of Improvement, (ii) Incontinence aids, (iii) Patient satisfaction, (iv) Health specific QoL (EQ5D-Visual Analogue Scale), and (v) Incontinence episode frequency. Follow-up after 4 months via self-assessed postal questionnaires. RESULTS: In all, 12% (30 women) were lost to follow-up. Intention-to-treat analysis showed highly significant improvements (P < 0.001) with large effect sizes (>0.8) with both interventions, but there were no significant differences between groups in primary outcomes. The mean (sd) changes in symptom-score were: Internet 3.4 (3.4), Postal 2.9 (3.1) (P = 0.27). The mean (sd) changes in condition-specific QoL were: Internet 4.8 (6.1), Postal 4.6 (6.7) (P = 0.52). Compared with the postal-group, more participants in the Internet-group perceived they were much or very much improved (40.9% (43/105) vs 26.5% (30/113), P = 0.01), reported reduced usage of incontinence aids (59.5% (47/79) vs 41.4% (34/82), P = 0.02) and were satisfied with the treatment programme (84.8% (89/105) vs 62.9% (71/113), P < 0.001). Health-specific QoL improved in the Internet-group (mean change 3.7 (10.9), P = 0.001), but not in the postal-group (1.9 (13.0), P = 0.13). Overall, 69.8% (120/172) of participants reported complete lack of leakage or reduced number of leakage episodes by >50%. CONCLUSIONS: Concerning primary outcomes, treatment effects were similar between groups whereas for secondary outcomes the Internet-based treatment was more effective. Internet-based treatment for SUI is a new, promising treatment alternative. PMID- 23350828 TI - Long-term outcome and quality of life after arterial switch operation: a prospective study with a historical comparison. AB - AIM.: The study aims to describe the long-term cardiological and psychological results of our first surgical cohort of arterial switch operation (ASO) patients and compare the results with our earlier series of Mustard patients. METHODS.: Twenty-four survivors of ASO operated in our center (1985-1990) were evaluated by electrocardiography, echocardiography, magnetic resonance imaging, exercise testing, 24-hour Holter-monitoring, and health-related quality of life questionnaire. The results were compared with 58 adult Mustard patients who were evaluated in 2001 using the same study protocol. RESULTS.: Arterial switch operation was performed at a median age of 13 days and Mustard operation at 2 years. Median follow-up was 22 years (range 20-25) and 25 years (22-29), respectively. After ASO, survival was better (P =.04). The event-free survival after 22 years was 77% after ASO vs. 44% after Mustard (P =.03). Good systemic ventricular function was present in 93% after ASO vs. 6% after Mustard (P <.01). Exercise capacity in ASO was 85% of predicted, compared with 72% in Mustard patients (P =.01). Aortic regurgitation was found in 21% of ASO patients vs. 16% in Mustard patients. Arterial switch patients vs. Mustard patients reported significantly better quality of life and less somatic complaints. CONCLUSION.: The progression made in surgical treatment for transposition of the great arteries from Mustard to ASO has had a positive impact on survival, cardiac function, exercise capacity, and also self-reported quality of life and somatic complaints. Longer follow-up is warranted to monitor aortic regurgitation. PMID- 23350830 TI - Minnesota Rural Palliative Care Initiative: building palliative care capacity in rural Minnesota. AB - BACKGROUND: Significant gaps exist in the availability of palliative care in rural hospitals and communities, even though rural populations are often disproportionately elderly and chronically ill. Few studies have examined what models of palliative care would be sustainable in a rural community. METHODS: We studied the effects of a novel approach to palliative care program development with 10 rural Minnesota community teams over 18 months. The Minnesota Rural Palliative Care Initiative (MRPCI) included a three-prong framework consisting of community capacity theory, a learning collaborative model, and the National Quality Forum (NQF) Preferred Practices for Palliative and Hospice Care Quality. RESULTS: MRPCI confirmed the feasibility of building palliative care capacity in rural communities using this framework. By the end of the 18 months, all 10 teams had identified a target population, developed and refined an action plan, and included at least two strategies to address community needs or gaps related to NQF preferred practices. Only one community had an existing palliative care program at the start of the MRPCI. During the course of the collaborative, five additional communities built a core team to implement a palliative care program. CONCLUSIONS: Palliative care development is necessary in rural communities, and envisioning a program that combines structure, accountability, customized guidance, tools, and networking across settings is essential for success. PMID- 23350831 TI - Suffering assessment: a review of available instruments for use in palliative care. AB - BACKGROUND: The prevention and relief of suffering in palliative care are critical to the well-being and quality of life of patients and families facing life-threatening diseases. Many tools to assess different issues in health care are available, but few are specifically designed to evaluate suffering, which is essential for its prevention, early management, and treatment. OBJECTIVE: The purpose of this review was to identify and describe existing instruments developed to assess suffering in palliative care, as well as to comment on their psychometric properties. METHODS: A review of articles indexed in MEDLINE, PsycINFO, and SciELO up to June 2011 was conducted. All articles reporting the development, description, or psychometric properties of instruments that assess suffering were included. An assessment of their psychometric quality was performed following a structured checklist. RESULTS: Ten instruments that assess suffering were identified. Their main features and psychometric properties are described in order to facilitate the selection of the appropriate one given each patient's context. CONCLUSION: By taking into consideration all features of the assessment instruments under review, the evaluation of suffering can be made easier. A wide and ever expanding range of approaches is now available, which facilitates the selection of the suffering-assessment instrument that is best suited to the needs of the specific patient. One of the challenges ahead will be to further analyze the psychometric properties of some existing instruments. PMID- 23350832 TI - Test-retest reliability of computational network measurements derived from the structural connectome of the human brain. AB - Structural magnetic resonance (MR) connectomics holds promise for the diagnosis, outcome prediction, and treatment monitoring of many common neurodevelopmental, psychiatric, and neurodegenerative disorders for which there is currently no clinical utility for MR imaging (MRI). Before computational network metrics from the human connectome can be applied in a clinical setting, their precision and their normative intersubject variation must be understood to guide the study design and the interpretation of longitudinal data. In this work, the reproducibility of commonly used graph theoretic measures is investigated, as applied to the structural connectome of healthy adult volunteers. Two datasets are examined, one consisting of 10 subjects scanned twice at one MRI facility and one consisting of five subjects scanned once each at two different facilities using the same imaging platform. Global graph metrics are calculated for unweighed and weighed connectomes, and two levels of granularity of the connectome are evaluated: one based on the 82-node cortical and subcortical parcellation from FreeSurfer and one based on an atlas-free parcellation of the gray-white matter boundary consisting of 1000 cortical nodes. The consistency of the unweighed and weighed edges and the module assignments are also computed for the 82-node connectomes. Overall, the results demonstrate good-to-excellent test retest reliability for the entire connectome-processing pipeline, including the graph analytics, in both the intrasite and intersite datasets. These findings indicate that measurements of computational network metrics derived from the structural connectome have sufficient precision to be tested as potential biomarkers for diagnosis, prognosis, and monitoring of interventions in neurological and psychiatric diseases. PMID- 23350833 TI - Flexible-dose fesoterodine in elderly adults with overactive bladder: results of the randomized, double-blind, placebo-controlled study of fesoterodine in an aging population trial. AB - OBJECTIVES: To assess the efficacy and safety of flexible-dose fesoterodine in elderly adults with overactive bladder (OAB). DESIGN: Twelve-week, randomized, double-blind, placebo-controlled trial. SETTING: Sixty-one outpatient clinics in Europe, Israel, and Turkey. PARTICIPANTS: Seven hundred ninety-four individuals aged 65 and older (47% male) with OAB symptoms for 3 months or longer, mean of eight or more micturitions and three or more urgency episodes per 24 hours, at least some moderate problems on Patient Perception of Bladder Condition (PPBC), and Mini-Mental State Examination (MMSE) score of 20 or greater. INTERVENTIONS: Participants were randomized to fesoterodine or placebo for 12 weeks, with stratification according to age (>75 vs <= 75) and dosing time (morning vs evening). Participants receiving fesoterodine started on 4 mg and could increase to 8 mg at week 4 or 8 and de-escalate to 4 mg at week 8 (sham escalation for placebo). MEASUREMENTS: Changes from baseline in bladder-diary variables (primary endpoint, urgency episodes) and patient-reported outcomes including OAB Questionnaire, Treatment Benefit Scale (TBS), PPBC, Urgency Perception Scale (UPS), and OAB Satisfaction Questionnaire (OAB-S); all observed or reported adverse events. RESULTS: By week 8, 64% of fesoterodine-treated and 71% of placebo-treated participants opted for dose escalation. At week 12, the fesoterodine group had statistically significantly greater improvement than the placebo group in urgency episodes, micturitions, nocturnal micturitions, incontinence pad use, and OAB Questionnaire scores but not urgency urinary incontinence episodes. Responder rates on TBS, PPBC, UPS, and OAB-S were statistically significantly higher with fesoterodine. Improvements in most diary variables and participant-reported outcomes were greater with fesoterodine than placebo in participants in both age groups and when administered in the morning and evening. Rates of dry mouth and constipation were 34% and 9% with fesoterodine and 5% and 3% with placebo, respectively. Rates of adverse events and discontinuations were generally similar in participants in both age groups. There was no change in MMSE score. CONCLUSION: Fesoterodine was associated with significantly greater improvements in most diary variables and participant reported outcomes than placebo and was generally well tolerated in older people. PMID- 23350834 TI - An unprecedented Fe(36) phosphonate cage. AB - The reaction of 2-pyridylphosphonic acid (LH(2)) with iron(II) perchlorate and iron(III) nitrate afforded an interconnected, double-layered, cationic iron cage, [{Fe(36)L(44)(H(2)O)(48)}](20+) (1a), the largest interconnected, polynuclear ferric cage reported to date. Magnetic studies on 1a revealed antiferromagnetic coupling between the spins on adjacent Fe(III) ions. PMID- 23350835 TI - Advanced and recurrent rectal cancer. PMID- 23350836 TI - Evidence-based postoperative pain management after laparoscopic colorectal surgery. AB - AIM: The aim of this systematic review was to evaluate the available literature on the management of pain after laparoscopic colorectal surgery. METHOD: Randomized studies, published in English between January 1995 and July 2011, assessing analgesic and anaesthetic interventions in adults undergoing laparoscopic colorectal surgery, and reporting pain scores, were retrieved from the Embase and MEDLINE databases. The efficacy and adverse effects of the analgesic techniques was assessed. The recommendations were based on procedure specific evidence from a systematic review and supplementary transferable evidence from other relevant procedures. RESULTS: Of the 170 randomized studies identified, 12 studies were included. Overall, all approaches including ketorolac, methylprednisolone, intraperitoneal instillation of ropivacaine, intravenous lidocaine infusion, intrathecal morphine and epidural analgesia improved pain relief, reduced opioid requirements and improved bowel function. However, there were significant differences in the study designs and the variables evaluated, precluding quantitative analysis. The L'Abbe plots of the data from the epidural analgesia studies included in this review indicate that the pain scores in the nonepidural groups, although higher than those in the epidural groups, were within an acceptable level (i.e. < 4/10). CONCLUSION: Infiltration of surgical incisions with local anaesthetic at the end of surgery, systemic steroids, conventional nonsteroidal anti-inflammatory drugs or cyclooxygenase-2-selective inhibitors in combination with paracetamol with opioid used as rescue are recommended. Intravenous lidocaine infusion is recommended, but not as the first line of therapy. However, neuraxial blocks (i.e. epidural analgesia and spinal morphine) are not necessary based on high risk:benefit ratio. PMID- 23350841 TI - Fostering reflective capacity with interactive reflective writing in medical education: Using formal analytic frameworks to guide formative feedback to students' reflective writing. PMID- 23350840 TI - Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy. AB - PURPOSE: Structural variations disrupting the gene encoding the neuron-specific splicing regulator RBFOX1 have been reported in three patients exhibiting epilepsy in comorbidity with other neuropsychiatric disorders. Consistently, the Rbfox1 knockout mouse model showed an increased susceptibility of seizures. The present candidate gene study tested whether exon-disrupting deletions of RBFOX1 increase the risk of idiopathic generalized epilepsies (IGEs), representing the largest group of genetically determined epilepsies. METHODS: Screening of microdeletions (size: >40 kb, coverage >20 markers) affecting the genomic sequence of the RBFOX1 gene was carried out by high-resolution single-nucleotide polymorphism (SNP) arrays in 1,408 European patients with idiopathic generalized epilepsy (IGE) and 2,256 population controls. Validation of RBFOX1 deletions and familial segregation analysis were performed by quantitative polymerase chain reaction (qPCR). KEY FINDINGS: We detected five exon-disrupting RBFOX1 deletions in the IGE patients, whereas none was observed in the controls (p = 0.008, Fisher's exact test). The size of the exonic deletions ranged from 68 to 896 kb and affected the untranslated 5'-terminal RBFOX1 exons. Segregation analysis in four families indicated that the deletions were inherited, display incomplete penetrance, and heterogeneous cosegregation patterns with IGE. SIGNIFICANCE: Rare deletions affecting the untranslated 5'-terminal RBFOX1 exons increase risk of common IGE syndromes. Variable expressivity, incomplete penetrance, and heterogeneous cosegregation patterns suggest that RBFOX1 deletions act as susceptibility factor in a genetically complex etiology, where heterogeneous combinations of genetic factors determine the disease phenotype. PMID- 23350842 TI - Crystal structure of peanut (Arachis hypogaea) allergen Ara h 5. AB - Profilins from numerous species are known to be allergens, including food allergens, such as peanut ( Arachis hypogaea ) allergen Ara h 5, and pollen allergens, such as birch allergen Bet v 2. Patients with pollen allergy can also cross-react to peanut. Structural characterization of allergens will allow a better understanding of the allergenicity of food allergens and their cross reactivities. The three-dimensional structures of most known food allergens remain to be elucidated. Here, we report the first crystallographic study of a food allergen in the profilin family. The structure of peanut allergen Ara h 5 was determined, and the resolution of the final refined structure was 1.1 A. Structure alignment revealed that Ara h 5 is more similar to Bet v 2 than to Hev b 8, although sequence alignment suggested that Ara h 5 is more closely related to Hev b 8 than to Bet v 2, indicating that homology-model-based prediction of immunoglobulin E epitopes needs to be interpreted with caution. PMID- 23350843 TI - Organic single molecular structures for light induced spin-pump devices. AB - We present theoretical results on molecular structures for realistic spin-pump applications. Taking advantage of the electron spin resonance concept, we find that interesting candidates constitute triplet biradicals with two strongly spatially and energetically separated singly occupied molecular orbitals (SOMOs). Building on earlier reported stable biradicals, particularly bis(nitronyl nitroxide) based biradicals, we employ density functional theory to design a selection of potential molecular spin-pumps which should be persistent at ambient conditions. We estimate that our proposed molecular structures will operate as spin-pumps using harmonic magnetic fields in the MHz regime and optical fields in the infrared to visible light regime. PMID- 23350844 TI - Complex oral sensitivity disorder: a reappraisal of current classification of burning mouth syndrome. PMID- 23350845 TI - Palladium-catalyzed picolinamide-directed alkylation of unactivated C(sp3)-H bonds with alkyl iodides. AB - We report an efficient method for the alkylation of gamma-C(sp(3))-H bonds of picolinamide-protected aliphatic amine substrates with primary alkyl iodides via palladium catalysis. Ag(2)CO(3) and dibenzyl phosphate, (BnO)(2)PO(2)H, are critical promoters of this reaction. These reactions provide a convenient and straightforward method for the preparation of high-value N-containing products from readily available amine and alkyl iodide precursors. PMID- 23350847 TI - Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors. AB - We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series. PMID- 23350849 TI - Hybrid repair of simultaneous multiple mycotic aortic aneurysms. AB - Simultaneous mycotic aortic aneurysms are a rare but life-threatening complication. We describe the technique of one stage hybrid open debranching and endovascular repair using three thoracic stent-graft devices deployed to cover the whole aorta to exclude multiple mycotic aneurysms. PMID- 23350846 TI - Genome sequence reveals that Pseudomonas fluorescens F113 possesses a large and diverse array of systems for rhizosphere function and host interaction. AB - BACKGROUND: Pseudomonas fluorescens F113 is a plant growth-promoting rhizobacterium (PGPR) isolated from the sugar-beet rhizosphere. This bacterium has been extensively studied as a model strain for genetic regulation of secondary metabolite production in P. fluorescens, as a candidate biocontrol agent against phytopathogens, and as a heterologous host for expression of genes with biotechnological application. The F113 genome sequence and annotation has been recently reported. RESULTS: Comparative analysis of 50 genome sequences of strains belonging to the P. fluorescens group has revealed the existence of five distinct subgroups. F113 belongs to subgroup I, which is mostly composed of strains classified as P. brassicacearum. The core genome of these five strains is highly conserved and represents approximately 76% of the protein-coding genes in any given genome. Despite this strong conservation, F113 also contains a large number of unique protein-coding genes that encode traits potentially involved in the rhizocompetence of this strain. These features include protein coding genes required for denitrification, diterpenoids catabolism, motility and chemotaxis, protein secretion and production of antimicrobial compounds and insect toxins. CONCLUSIONS: The genome of P. fluorescens F113 is composed of numerous protein coding genes, not usually found together in previously sequenced genomes, which are potentially decisive during the colonisation of the rhizosphere and/or interaction with other soil organisms. This includes genes encoding proteins involved in the production of a second flagellar apparatus, the use of abietic acid as a growth substrate, the complete denitrification pathway, the possible production of a macrolide antibiotic and the assembly of multiple protein secretion systems. PMID- 23350850 TI - Antiviral activity of the interferon alpha family: biological and pharmacological aspects of the treatment of chronic hepatitis C. AB - INTRODUCTION: Type I interferons (IFNs) comprise a group of at least 13 structurally related subtypes of IFN-alpha with similar, but not identical, biological activities. Each subtype displays a unique activity profile; only IFN alpha2a and IFN-alpha2b subtypes together with natural IFN-alpha preparations are currently used in the clinical practice, so that the remaining IFN-alpha subtypes are a still unexploited reservoir of opportunity also in the new era of direct acting antiviral agents for the treatment of hepatitis C virus (HCV). AREAS COVERED: This paper reviews recent progress in the study of the biology of IFN family, the antiviral action mechanism and the strategies employed by HCV to evade IFN action. Currently available IFN preparations for the treatment of chronic hepatitis C infection are described and what is currently known on the pharmacokinetics, pharmacodynamics and immunogenicity of IFN-alpha preparations used in clinical practice are summarized. EXPERT OPINION: The characterization of multifunctional nature of IFN system together with recent advances in the identification of HCV IFN evasion strategies and the variety of host factors influencing IFN treatment response should be considered to improve HCV and other infectious diseases treatment in the future. PMID- 23350851 TI - Development and in-house validation of an LC-MS/MS method for the quantification of the mycotoxins deoxynivalenol, zearalenone, T-2 and HT-2 toxin, ochratoxin A and fumonisin B1 and B2 in vegetable animal feed. AB - Animal feed can be contaminated with various mycotoxins. To ensure animal health and safe food and feed production, the European Commission has recommended increased monitoring of the co-occurrence of deoxynivalenol, zearalenone, ochratoxin A, fumonisin B(1) and B(2), T-2 and HT-2 toxin in feed. Thus, there is a need for an analytical method that enables their simultaneous detection and quantification. This paper describes the development and in-house validation of such a method, in which the mycotoxins were extracted from spiked and naturally contaminated cereal-based compound feed, corn and wheat. The extracts were divided into two aliquots where one was diluted and then analysed directly and the other was cleaned by using MultiSep((r))226 and then diluted and analysed. Separation and detection was achieved with LC-ESI-MS/MS by using a triple quadrupole instrument in the SRM mode. The precision (in terms of intra-day repeatability and inter-day reproducibility), accuracy, linearity, apparent recovery and expanded measurement uncertainty in feed, corn and wheat were evaluated. The LODs ranged from 1.0 to 72 MUg/kg, and the LOQs ranged from 2.5 to 115 MUg/kg. The apparent recovery was higher than 86% for all the mycotoxins, and the precision was better than that defined by the Horwitz equation for all concentrations. Proficiency test materials were analysed to assess the accuracy of the method, and the results were satisfactory for all seven mycotoxins. The method will be used to monitor the occurrence of these mycotoxins in products intended for animal feeding in Sweden. PMID- 23350848 TI - Proteomics and metabolomics in renal transplantation-quo vadis? AB - The improvement of long-term transplant organ and patient survival remains a critical challenge following kidney transplantation. Proteomics and biochemical profiling (metabolomics) may allow for the detection of early changes in cell signal transduction regulation and biochemistry with high sensitivity and specificity. Hence, these analytical strategies hold the promise to detect and monitor disease processes and drug effects before histopathological and pathophysiological changes occur. In addition, they will identify enriched populations and enable individualized drug therapy. However, proteomics and metabolomics have not yet lived up to such high expectations. Renal transplant patients are highly complex, making it difficult to establish cause-effect relationships between surrogate markers and disease processes. Appropriate study design, adequate sample handling, storage and processing, quality and reproducibility of bioanalytical multi-analyte assays, data analysis and interpretation, mechanistic verification, and clinical qualification (=establishment of sensitivity and specificity in adequately powered prospective clinical trials) are important factors for the success of molecular marker discovery and development in renal transplantation. However, a newly developed and appropriately qualified molecular marker can only be successful if it is realistic that it can be implemented in a clinical setting. The development of combinatorial markers with supporting software tools is an attractive goal. PMID- 23350852 TI - Regioselective bromination of fused heterocyclic N-oxides. AB - A mild method for the regioselective C2-bromination of fused azine N-oxides is presented, employing tosic anhydride as the activator and tetra-n-butylammonium bromide as the nucleophilic bromide source. The C2-brominated compounds are produced in moderate to excellent yields and with excellent regioselectivity in most cases. The potential extension of this method to other halogens, effecting C2-chlorination with Ts(2)O/TBACl is also presented. Finally, this method could be incorporated into a viable one-pot oxidation/bromination process, using methyltrioxorhenium/urea hydropgen peroxide as the oxidant. PMID- 23350853 TI - A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is expected to grow. A genetic predisposition for AF has long been recognized, but its manifestation in these patients likely involves a combination of rare and common genetic variants. Identifying genetic variants that associate with a high penetrance for AF would represent a significant breakthrough for understanding the mechanisms that associate with disease. METHOD AND RESULTS: Candidate gene sequencing in 5 unrelated families with familial AF identified the KCNQ1 missense mutation p.Arg231His (R231H). In addition to AF, several of the family members have abnormal QTc intervals, syncope or experienced sudden cardiac arrest or death. KCNQ1 encodes the voltage-gated K(+) channel that conducts the slowly activating delayed rectifier K(+) current in the heart. Functional and computational analyses suggested that R231H increases KCNQ1 current (I(KCNQ1)) to shorten the atrial action potential (AP) duration. R231H is predicted to minimally affect ventricular excitability, but it prevented the increase in I(KCNQ1) following PKA activation. The unique properties of R231H appeared to be caused by a loss in voltage-dependent gating. CONCLUSIONS: The R231H variant causes a high penetrance for interfamilial early-onset AF. Our study indicates R231H likely shortens atrial refractoriness to promote a substrate for reentry. Additionally, R231H might cause abnormal ventricular repolarization by disrupting PKA activation of IKCNQ1 . We conclude genetic variants, which increase IKs during the atrial AP, decrease the atrial AP duration, and/or shorten atrial refractoriness, present a high risk for interfamilial AF. PMID- 23350854 TI - Adoptive immunotherapy with redirected T cells produces CCR7- cells that are trapped in the periphery and benefit from combined CD28-OX40 costimulation. AB - Adoptive therapy of cancer with genetically redirected T cells showed spectacular efficacy in recent trials. A body of preclinical and clinical data indicate that young effector and central memory T cells perform superior in a primary antitumor response; repetitive antigen engagement, however, drives T-cell maturation to terminally differentiated cells associated with the loss of CCR7, which enables T cells to persist in peripheral tissues. In this work, we explored the antitumor efficacy of CCR7(-) T cells when redirected in an antigen-dependent fashion by a chimeric antigen receptor (CAR) toward tumors in the periphery. CAR-engineered CCR7(-) T cells more efficiently accumulated at the tumor site, secreted more IFN gamma, expressed higher amounts of cytotoxic molecules, and showed superior tumor cell lysis compared to the younger CCR7(+) cells. CCR7(-) T cells, however, were more prone to spontaneous and activation-induced cell death, which could be counteracted by simultaneous CD28 and OX40 (CD134) costimulation. Consequently, the combined CD28-zeta-OX40 signaling CAR rescued CCR7(-) T cells from apoptosis, which then produced more efficient antitumor efficacy than CCR7(+) T cells redirected by the same CAR. Data suggest that T-cell therapy will benefit from combined CD28-zeta-OX40 stimulation in the long-term by rescuing continuously generated CCR7(-) T cells for an antitumor attack. PMID- 23350855 TI - Actinobaculum schaalii, a commensal of the urogenital area. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Actinobaculum schaalii is considered to be a part of the normai flora in the genital and urinary tract area. It has been associated to urinary tract infection (UTI), sepsis, osteomyelitis, endocarditis and Foumier's gangrene. So far it has mainly been isolated from urine, blood and pus, and predominantly in elderly patients. This study examined the habitat of A. schaalii by collecting samples from skin and urine in patients with kidney or ureter stones before and after treatment with Extracorporeal Shock Wave Lithotripsy (ESWL). Additionally faeces and vaginal swabs from routine specimen in patients not undergoing ESWL and without known urinary calculi were also analysed. The study does not find A. schaalii in faeces but shows it to be presents on skin and mucosa in the genital area. A. schaalii is also shown a possible pathogen in the stone-patient group undergoing ESWL. OBJECTIVE: To study the habitat of Actinobaculum schaalii by examing groin swabs, faeces samples and vaginal swabs, and to determine whether it is a common uropathogen in patients with kidney or ureter stones. PATIENTS AND METHODS: A quantitative real-time PCR assay was used to analyse all samples, which were collected between 2010 and 2011. A total of 38 patients (24 men and 14 women), with kidney or ureter stones and undergoing extracorporeal shock wave lithotripsy (ESWL), provided urine samples and had groin swabs taken. In addition, 30 faecal samples and 19 vaginal swabs that had been sent for routine microbiological examinations from patients outside the ESWL group were analysed. A chi-squared test was used to analyse the differences between patient groups, studying samples from urine, faeces samples, groin swabs and vaginal swabs. RESULTS: Actinobaculum schaalii was found in the urine samples from 14 (37%) patients undergoing ESWL, and in both urine and groin swabs from seven (18%) patients. Actinobaculum schaalii was not found in faeces samples but it was found in six (32%) of the vaginal swabs, predominantly in patients >50 years (P = 0.06). CONCLUSION: The study indicates that A. schaalii is a commensal found on skin, urine and vaginal mucosa in the human urogenital area and supports other investigations in its finding that the elderly are at greatest risk of being colonized with A. schaalii. PMID- 23350856 TI - Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. AB - AIMS: Pioglitazone, a thiazolidinedione, was approved for treatment of Type 2 diabetes. However, several observational studies suggest an association of pioglitazone with an increased risk of bladder cancer in patients with diabetes. Therefore, we sought to perform a systematic review and meta-analysis to evaluate the magnitude of this association and the quality of the supporting evidence. METHODS: Electronic databases were queried to identify controlled studies of pioglitazone that measured the risk of bladder cancer. RESULTS: Six studies involving 215 142 patients using pioglitazone were included, with a median period of follow-up of 44 months. The hazard of developing bladder cancer was significantly higher in patients using pioglitazone (hazard ratio 1.23; 95% CI 1.09-1.39; I2 = 0%) compared with control groups. The risk of bias was moderate across the six studies. Considering an incidence rate of 20.8 per 100 000 person years, the number needed to harm was five additional cases of bladder cancer per 100 000 person years. CONCLUSIONS: Patients treated with pioglitazone have a slight increased risk of bladder cancer compared to general population. Patient involvement and weighing treatment benefits versus risks should be discussed with patient toward shared decision. Patients with type 2 diabetes with risk factors, such as family history, smoking, or exposure to certain forms of chemotherapy may need to consider other anti-hyperglycemic agents. Also, pioglitazone should be discontinued in type 2 diabetes patients with newly diagnosed bladder cancer. PMID- 23350857 TI - Drug-induced liver injury in the Australian setting. AB - WHAT IS KNOWN AND OBJECTIVE: The causes of drug-induced liver injury vary worldwide, with limited data regarding drug-induced hepatotoxicity in Australia. This study sought to provide information about the incidence, causes and clinical manifestations of drug-induced hepatotoxicity. METHODS: A retrospective study was performed on all adult inpatients with abnormal liver function tests, defined as an increase of more than twice the upper limit of the normal range in either serum alanine aminotransferase or alkaline phosphatase, over a 12-month period at the major hospital in Tasmania, Australia. A random sample of individual medical records was reviewed and clinical data extracted. The causality of suspected drug induced liver injury cases was assessed using the Roussel Uclaf Causality Assessment Method. RESULTS: A total of 264 cases were included. Drug-induced liver injury with at least a possible causal relationship was found in 24 cases (9.1%). The mean age at presentation in the 17 patients with possible or probable hepatotoxicity not related to paracetamol or cancer chemotherapy was 60 +/- 20.0 years, and 9 (53%) were men. The frequencies of cholestatic, hepatocellular and mixed patterns of liver damage were 9 (53%), 2 (12%) and 6 (35%) respectively. The most common cause was antibiotics (11 of 17; 65%), while flucloxacillin (4 of 17; 24%) was the single agent most often implicated. WHAT IS NEW AND CONCLUSION: Nearly 10% of cases of abnormal liver function could be associated with adverse effects of drugs. The possibility of drug-induced liver injury should always be considered when there is an absence of other apparent hepatic disease. PMID- 23350859 TI - Factors influencing time to diagnosis after abnormal mammography in diverse women. AB - BACKGROUND: Abnormal mammograms are common, and the risk of false positives is high. We surveyed women in order to understand the factors influencing the efficiency of the evaluation of an abnormal mammogram. METHODS: Women aged 40-80 years, identified from lists with Breast Imaging Reporting and Data System (BIRADS) classifications of 0, 3, 4, or 5, were surveyed. Telephone surveys asked about the process of evaluation, and medical records were reviewed for tests and timing of evaluation. RESULTS: In this study, 970 women were surveyed, and 951 had chart reviews. Overall, 36% were college graduates, 68% were members of a group model health plan, 18% were Latinas, 25% were African Americans, 15% were Asian, and 43% were white. Of the 352 women who underwent biopsies, 151 were diagnosed with cancer (93 invasive). Median time to diagnosis was 183 days for BIRADS 3 compared to 29 days for BIRADS 4/5 and 27 days for BIRADS 0. At 60 days, 84% of BIRADS 4/5 women had a diagnosis. Being African American (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.49-0.97, p=0.03), income < $10,000 (HR 0.55, 95% CI 0.31-0.98, p<0.04), perceived discrimination (HR 0.22, 95% CI 0.09 0.52, p<0.001), not fully understanding the results of the index mammogram (HR 0.49, 95% CI 0.32-0.75, p=0.001), and being notified by letter (HR 0.66, 95% CI 0.48-0.90, p=0.01) or telephone (HR 0.62, 95% CI 0.42-0.92, p=0.02) rather than in person were all associated with significant delays in diagnosis. CONCLUSIONS: Evaluation of BIRADS 0, 4, or 5 abnormal mammograms was completed in most women within the recommended 60 days. Even within effective systems, correctible communication factors may adversely affect time to diagnosis. PMID- 23350860 TI - Occupation as a risk factor for hypertensive disorders of pregnancy. AB - BACKGROUND: Hypertensive disorders of pregnancy (HDP) are leading causes of morbidity and mortality and have been rising in incidence. Little is known about the effects of worker classifications on HDP. This large-scale study examines associations between occupational classifications and HDP. METHODS: We examined 385,537 Texas Electronic Registrar Birth Registration 2005 birth certificates. Maternal occupations were coded using the Standard Occupational Classification (SOC). Crude and adjusted risks for HDP among working women within occupational groupings were analyzed and compared with risks of nonemployed women. RESULTS: The risk of developing HDP varies across SOC occupational classifications. After controlling for known confounders, women employed in business, management, and the legal and social services, teaching, counseling, and healthcare professions are at higher risk for developing HDP than women employed in support industries, such as food preparation, housekeeping, cosmetic and personal care services, or nonemployed women. Women employed in computer, engineering, architectural, and scientific occupations also carry greater risks, although these increased risks do not affect women of normal weight. CONCLUSIONS: Worker classification is an independent risk factor for HDP. Additional work must be done to examine the complex interactions among individual maternal genetics, biology, and physical and mental abilities and how they affect adverse health outcomes. Examining job stressors may shed light on these occupational variations and their potential HDP associations. Strategies to mitigate job stressors in the workplace should be considered. PMID- 23350861 TI - Attitudes and practices regarding late preterm birth among American obstetrician gynecologists. AB - BACKGROUND: Late preterm birth (LPTB) accounts for most preterm births and has been increasing, associated with increases in cesarean sections and inductions at this gestational age. METHODS: A self-administered survey, consisting of questions about opinions, knowledge, and practices regarding LPTB, was mailed to 1232 American College of Obstetricians and Gynecologists (ACOG) Fellows and Junior Fellows in Practice in May-July 2010. RESULTS: Surveys were returned by 520 practicing obstetricians.Two thirds of respondents defined LPTB as either 34 36 or 34-37 weeks gestation [corrected].Most responding physicians (87%) were aware of the evidence regarding morbidity and mortality of infants born at 34-36 weeks; 81% considered such evidence sufficient to make a clinical judgment. Although 84% were concerned about long-term health problems in these infants, many disagreed that LPTB infants were at increased risk of long-term neurodevelopmental outcomes. Most agreed that the increase in LPTB in the United States is due to increasing rates and complications of multifetal pregnancies and maternal disorders. Almost all responding physicians agreed that certain clinical indications (e.g., severe preeclampsia, placental abruption, premature rupture of the membranes [PROM]) were appropriate reasons for early delivery, and most disagreed with delivering late preterm infants for logistical reasons or convenience. Half of responding physicians reported that concerns about malpractice risks contribute to their decision to induce labor or perform a cesarean section at 34-36 weeks. CONCLUSIONS: Many obstetricians underestimate long-term neurodevelopmental outcomes among infants born late preterm and may have a lower threshold to deliver some infants late preterm for indications that are not evidence based. Additional educational efforts regarding LPTB are needed. PMID- 23350862 TI - Gender differences in mortality and CD4 count response among virally suppressed HIV-positive patients. AB - BACKGROUND: Treatment outcomes for antiretroviral therapy (ART) patients may vary by gender, but estimates from current evidence may be confounded by disease stage and adherence. We investigated the gender differences in treatment response among HIV-positive patients virally suppressed within 6 months of treatment initiation. METHODS: We analyzed data from 7,354 patients initiating ART between April 2004 and April 2010 at Themba Lethu Clinic, a large urban public sector treatment facility in South Africa. We estimated the relations among gender, mortality, and mean CD4 response in HIV-infected adults virally suppressed within 6 months of treatment initiation and used inverse probability of treatment weights to correct estimates for loss to follow-up. RESULTS: Male patients had a 20% greater risk of death at both 24 months and 36 months of follow-up compared to females. Older patients and those with a low hemoglobin level or low body mass index (BMI) were at increased risk of mortality throughout follow-up. Men gained fewer CD4 cells after treatment initiation than did women. The mean differences in CD4 count gains made by women and men between baseline and 12, 24, and 36 months were 28.2 cells/mm(3) (95% confidence interval [CI] 22.2-34.3), 60.8 cells/mm(3) (95% CI 71.1-50.5 cells/mm(3)), and 83.0 cells/mm(3) (95% CI 97.1-68.8 cells/mm(3)), respectively. Additionally, patients with a current detectable viral load (>400 copies/mL) and older patients had a lower mean CD4 increase at the same time points. CONCLUSIONS: In this initially virally suppressed population, women showed consistently better immune response to treatment than did men. Promoting earlier uptake of HIV treatment among men may improve their immunologic outcomes. PMID- 23350863 TI - Cryoablation and angiographic evidence of a concealed right atrial appendage to right ventricle accessory pathway in an infant. AB - We report a case of successful cryoablation of a concealed accessory pathway from the right atrial appendage to the right ventricle in an infant. A 4-month-old female who had previously undergone successful ablation of a left-sided accessory pathway was taken to the electrophysiology lab due to recurrent supraventricular tachycardia. While in this second supraventricular tachycardia, we found earliest atrial activation in the distal right atrial appendage. Angiography confirmed a connection between right atrial appendage and the right ventricle. Cryoablation at this location promptly terminated the supraventricular tachycardia. Following ablation, there were no further inducible arrhythmias and ventriculo-atrial dissociation was appreciated. PMID- 23350864 TI - High-pressure synthesis, structure, and photoluminescence of a new KSbO3-type bismuth germanate Bi3Ge3O10.5. AB - A new Bi(3)Ge(3)O(10.5) compound has been synthesized under high pressure, P = 7 GPa, and 700 degrees C. Instead of the pyrochlore that is normally stabilized under high pressure, the Bi(3)Ge(3)O(10.5) crystallizes in a KSbO(3)-ype crystal structure. The crystal structure has been refined by the Rietveld method from synchrotron X-ray diffraction data. Moreover, we have also characterized the Bi(3)Ge(3)O(10.5) by X-ray photoelectron spectroscopy, photoluminescence, and specific heat. PMID- 23350866 TI - Varenicline in autistic disorder: hypothesis and case report of single-patient crossover. PMID- 23350868 TI - Emergency transanal haemorrhoidal Doppler guided dearterialization for acute and persistent haemorrhoidal bleeding. PMID- 23350867 TI - Associations between visual, hearing, and dual sensory impairments and history of motor vehicle collision involvement of older drivers. AB - OBJECTIVES: To examine the association between visual and hearing impairment and motor vehicle collision (MVC) involvement in older drivers. DESIGN: Retrospective cohort study. SETTING: North central Alabama. PARTICIPANTS: Population-based sample of 2,000 licensed-drivers aged 70 and older. MEASUREMENTS: Visual acuity was measured using the Electronic Visual Acuity test. Contrast sensitivity was measured using the Pelli-Robson chart. Presence of subjective hearing loss and other health conditions were determined using a general health questionnaire. Information regarding MVCs for all participants spanning the 5 years before study enrollment was obtained from the Alabama Department of Public Safety. RESULTS: After adjustment for age, race, sex, number of miles driven, number of medical conditions, general cognitive status, and visual processing speed, older drivers with visual acuity and hearing impairment (rate ratio (RR) = 1.52, 95% confidence interval (CI) = 1.01-2.30), contrast sensitivity impairment alone (RR = 1.42, 95% CI = 1.00-2.02), and contrast sensitivity and hearing impairment (RR = 2.41, 95% CI = 1.62-3.57) had higher MVC rates than drivers with no visual or hearing impairments. Drivers with visual acuity loss alone or hearing loss alone did not have MVC rates that were significantly different from those of the no impairment group after adjustment for multiple variables. CONCLUSION: Older drivers with dual sensory impairment are at greater MVC risk than those with a visual acuity or hearing deficit alone. A combined screening approach of screening for hearing and visual impairment may be a useful tool to identify older drivers at risk of MVC involvement. PMID- 23350869 TI - Enzymatic production of zero-trans plastic fat rich in alpha-linolenic acid and medium-chain fatty acids from highly hydrogenated soybean oil, Cinnamomum camphora seed oil, and perilla oil by lipozyme TL IM. AB - In the present study, zero-trans alpha-linolenic acid (ALA) and medium-chain fatty acids (MCFA)-enriched plastic fats were synthesized through enzymatic interesterification reactions from highly hydrogenated soybean oil (HSO), Cinnamomum camphora seed oil (CCSO), and perilla oil (PO). The reactions were performed by incubating the blending mixtures of HSO, CCSO, and PO at different weight ratios (60:40:100, 70:30:100, 80:20:100) using 10% (total weight of substrate) of Lipozyme TL IM at 65 degrees C for 8 h. After reaction, the physical properties (fatty acids profile, TAG composition, solid fat content, slip melting point, contents of tocopherol, polymorphic forms, and microstructures) of the interesterified products and their physical blends were determined, respectively. Results showed that the fatty acid compositions of the interesterified products and physical blends had no significant changes, while the content of MCFA in both interesterified products and physical blends increased to 8.58-18.72%. Several new types of TAG species were observed in interesterified products (SSL/SLS, PLO/LLS, and OLLn/LnLO/LOLn). It should be mentioned that no trans fatty acids (TFA) were detected in all products. As the temperature increased, the solid fat content (SFC) of interesterified products was obviously lower than that of physical blends. The SFCs of interesterified products (60:40:100, 70:30:100, and 80:20:100, HSO:CCSO:PO) at 25 degrees C were 6.5%, 14.6%, and 16.5%, respectively, whereas the counterparts of physical blends were 32.5%, 38.5%, and 43.5%, respectively. Meanwhile, interesterified products showed more beta' polymorphs than physical blends, in which beta' polymorph is a favorite form for production of margarine and shortening. Such zero-trans ALA and MCFA-enriched fats may have desirable physical and nutritional properties for shortenings and margarines. PMID- 23350870 TI - Steering the patient mix of GP trainees: results of a randomized controlled intervention. AB - BACKGROUND: In studies exploring the patient mixes of general practitioner (GP) trainees, gaps were repeatedly found, as there were disparities between the patient mixes of GP trainers and trainees. This reduces the opportunities of trainees to acquire enough competence. AIMS: To investigate whether steering the patient mix can be effectuated by instructing medical receptionist, trainer and trainee, and to study the effects of this intervention on trainee's self-efficacy (SE) and knowledge. METHOD: Randomized Controlled Trial (RCT). After a six-month basic registration period, 73 trainees were randomized. Patients with skin conditions and psychosocial conditions were actively assigned to trainees in the intervention group (n=35) during two successive periods of three months. The patient mix was measured by extracting data from electronic patient records. Learning outcomes were measured by SE questionnaires and by a knowledge test. RESULTS: No increase was found in patient volume and diversity of the steered conditions in the intervention group as compared to the control group. However, the percentual increase of exposure to skin conditions was greater in the intervention group. No difference in skin SE and psychiatric knowledge was found. The increase of psychosocial SE was greater in the intervention group. In a regression analysis, patient volume was a significant predictor of both skin and psychosocial SE. CONCLUSIONS: Despite the difficulty in implementing steering in daily practice, tailoring the patient mix to the individual learning needs of trainees could be considered. PMID- 23350871 TI - Disparities in completion of substance abuse treatment between and within racial and ethnic groups. AB - OBJECTIVE: To evaluate disparities in substance abuse treatment completion between and within racial and ethnic groups in publicly funded treatment in Los Angeles County, California. DATA SOURCE: The Los Angeles County Participant Reporting System with multicross-sectional annual data (2006-2009) for adult participants (n = 16,637) who received treatment from publicly funded programs (n = 276) for the first time. STUDY DESIGN: Retrospective analyses of county discharge and admission data. Hierarchical linear regressions models were used to test the hypotheses. DATA COLLECTION: Client data were collected during personal interviews at admission and discharge for most participants. PRINCIPAL FINDINGS: African Americans and Latinos reported lower odds of completing treatment compared with Whites. Within-group analysis revealed significant heterogeneity within racial and ethnic groups, highlighting primary drug problem, days of drug use before admission, and homelessness as significant factors affecting treatment completion. Service factors, such as referral by the criminal justice system, enabled completion among Latinos and Whites only. CONCLUSIONS: These findings have implications for reducing health disparities among members of racial and ethnic minorities by identifying individual and service factors associated with treatment adherence, particularly for first-time clients. PMID- 23350872 TI - Termini of bottom-up fabricated graphene nanoribbons. AB - Atomically precise graphene nanoribbons (GNRs) can be obtained via thermally induced polymerization of suitable precursor molecules on a metal surface. This communication discusses the atomic structure found at the termini of armchair GNRs obtained via this bottom-up approach. The short zigzag edge at the termini of the GNRs under study gives rise to a localized midgap state with a characteristic signature in scanning tunneling microscopy (STM). By combining STM experiments with large-scale density functional theory calculations, we demonstrate that the termini are passivated by hydrogen. Our results suggest that the length of nanoribbons grown by this protocol may be limited by hydrogen passivation during the polymerization step. PMID- 23350873 TI - Adolescent predictors and associates of psychosocial functioning in young men and women: 11 year follow-up findings from the Nord-Trondelag Health Study. AB - The aim of this paper was to investigate whether psychosocial functioning in adulthood (e.g., friends support, cohabitation, community connectedness and work satisfaction) could be predicted by mental health, subjective well-being, social relations and behavior problems in adolescence, and whether gender was a moderator in these associations. Data were obtained from a major population-based Norwegian study, the Nord-Trondelag Health Study (HUNT), in which 517 men and 819 women completed an extensive self-report questionnaires at baseline (mean age 14.4 years) and at follow-up (mean age 26.9 years). Community connectedness as well as work satisfaction were predicted by subjective well-being. Cohabitation was predicted by male gender and frequency of meeting friends in adolescence, and friends support was predicted by frequency of meeting friends. Gender had a minor effect as a moderator. Frequency of meeting friends and subjective well-being seemed to be the strongest adolescent predictors of psychosocial functioning in young adulthood. These findings may have implications both for prevention and intervention in adolescence, as well as for future research. PMID- 23350874 TI - Temperature and urea have opposing impacts on polyproline II conformational bias. AB - The native states of globular proteins have been accessed in atomic detail by X ray crystallography and nuclear magnetic resonance spectroscopy, yet characterization of denatured proteins beyond global metrics has proven to be elusive. Denatured proteins have been observed to exhibit global geometric properties of a random coil polymer. However, this does not preclude the existence of nonrandom, local conformational bias that may be significant for protein folding and function. Indeed, circular dichroism (CD) spectroscopy and other methods have suggested that the denatured state contains considerable local bias to the polyproline II (PII) conformation. Here, we develop predictive models to determine the extent that temperature and the chemical denaturant urea modulate PII propensity. In agreement with our predictive model, PII propensity is observed experimentally to decrease with an increase in temperature. Conversely, urea appears to promote the PII conformation as determined by CD and isothermal titration calorimetry. Importantly, the calorimetric data are in quantitative agreement with a model that predicts the stability of the PII helix relative to other denatured state conformations based upon solvent accessible surface area and experimentally measured Gibbs transfer free energies. The ability of urea to promote the PII conformation can be attributed to the favorable interaction of urea with the peptide backbone. Thus, perturbing denatured states by temperature or cosolutes has subtle, yet opposing, impacts on local PII conformational biases. These results have implications for protein folding as well as for the function of signaling proteins that bind proline-rich targets in globular or intrinsically disordered proteins. PMID- 23350876 TI - Contingency bias in probability judgement may arise from ambiguity regarding additional causes. AB - In laboratory contingency learning tasks, people usually give accurate estimates of the degree of contingency between a cue and an outcome. However, if they are asked to estimate the probability of the outcome in the presence of the cue, they tend to be biased by the probability of the outcome in the absence of the cue. This bias is often attributed to an automatic contingency detection mechanism, which is said to act via an excitatory associative link to activate the outcome representation at the time of testing. We conducted 3 experiments to test alternative accounts of contingency bias. Participants were exposed to the same outcome probability in the presence of the cue, but different outcome probabilities in the absence of the cue. Phrasing the test question in terms of frequency rather than probability and clarifying the test instructions reduced but did not eliminate contingency bias. However, removal of ambiguity regarding the presence of additional causes during the test phase did eliminate contingency bias. We conclude that contingency bias may be due to ambiguity in the test question, and therefore it does not require postulation of a separate associative link-based mechanism. PMID- 23350875 TI - A colorectal cancer genome-wide association study in a Spanish cohort identifies two variants associated with colorectal cancer risk at 1p33 and 8p12. AB - BACKGROUND: Colorectal cancer (CRC) is a disease of complex aetiology, with much of the expected inherited risk being due to several common low risk variants. Genome-Wide Association Studies (GWAS) have identified 20 CRC risk variants. Nevertheless, these have only been able to explain part of the missing heritability. Moreover, these signals have only been inspected in populations of Northern European origin. RESULTS: Thus, we followed the same approach in a Spanish cohort of 881 cases and 667 controls. Sixty-four variants at 24 loci were found to be associated with CRC at p-values <10-5. We therefore evaluated the 24 loci in another Spanish replication cohort (1481 cases and 1850 controls). Two of these SNPs, rs12080929 at 1p33 (Preplication=0.042; Ppooled=5.523x10-03; OR (CI95%)=0.866(0.782-0.959)) and rs11987193 at 8p12 (Preplication=0.039; Ppooled=6.985x10-5; OR (CI95%)=0.786(0.705-0.878)) were replicated in the second Phase, although they did not reach genome-wide statistical significance. CONCLUSIONS: We have performed the first CRC GWAS in a Southern European population and by these means we were able to identify two new susceptibility variants at 1p33 and 8p12 loci. These two SNPs are located near the SLC5A9 and DUSP4 loci, respectively, which could be good functional candidates for the association signals. We therefore believe that these two markers constitute good candidates for CRC susceptibility loci and should be further evaluated in other larger datasets. Moreover, we highlight that were these two SNPs true susceptibility variants, they would constitute a decrease in the CRC missing heritability fraction. PMID- 23350877 TI - Prevention of periprocedural ischemic stroke and management of hemorrhagic complications in atrial fibrillation ablation under continuous warfarin administration. AB - INTRODUCTION: This study aimed to determine the effects of continuing warfarin administration during the periprocedural period of catheter ablation for atrial fibrillation (AF) on the prevention of stroke complications and to evaluate the management of hemorrhagic complications occurring with this approach. METHODS AND RESULTS: A total of 3,280 patients undergoing AF catheter ablation at our institution were divided into 2 groups: the first 1,953 patients who discontinued warfarin 3-4 days before AF ablation and were bridged with heparin (warfarin discontinued group), and the last 1,327 patients who continued warfarin throughout the periprocedural period (warfarin-continued group). Symptomatic stroke or transient ischemic attack occurred in 13/1,953 patients (0.67%) in the warfarin-discontinued group and in 2/1,327 patients (0.15%) in the warfarin continued group (P = 0.021). None of the patients with therapeutic international normalized ratio at the time of the procedure had periprocedural thromboembolism in the warfarin-continued group. Major hemorrhagic complications occurred in 26/1,953 patients in the warfarin-discontinued group (1.3%; 25 with cardiac tamponade and 1 with retroperitoneal bleeding), and in 15/1,327 patients in the warfarin-continued group (1.1%; 14 with cardiac tamponade and 1 with abdominal wall bleeding) (P = 0.80). Of the 14 warfarin-continued patients with cardiac tamponade, 13 were administered prothrombin complex concentrate (PCC) and vitamin K; the bleeding was stopped safely without surgical repair. CONCLUSION: The continuation of warfarin during the periprocedural period of AF ablation could reduce the incidence of stroke without increasing hemorrhagic complications. When cardiac tamponade occurred with this approach, it was safely treated with PCC and vitamin K. PMID- 23350878 TI - AsTeRICS: a new flexible solution for people with motor disabilities in upper limbs and its implication for rehabilitation procedures. AB - PURPOSE: To present the AsTeRICS construction set, and examine different combinations of sensors installed in the platform and how users interact with them. METHOD: Nearly 50 participants from Austria, Poland and Spain were included in the study. They had a heterogeneous range of diagnoses, but as a common feature all of them experienced motor limitations in their upper limbs. The study included a 1 h session with each participant where the user interacted with a personalized combination of sensors, based on a previous assessment on their motor capabilities performed by healthcare professionals. The sensors worked as substitutes for a standard QWERTY keyboard and a standard mouse. Semi-structured interviews were conducted to obtain participants' opinions. All collected data were analyzed based on the qualitative methodology. RESULTS: The findings illustrated that AsTeRICS is a flexible platform whose sensors can adapt to different degrees of users' motor capabilities, thus facilitating in most cases the interaction of the participants with a common computer. CONCLUSION: AsTeRICS platform can improve the interaction between people with mobility limitations and computers. It can provide access to new technologies and become a promising tool that can be integrated in physical rehabilitation programs for people with motor disabilities in their upper limbs. IMPLICATIONS FOR REHABILITATION: The AsTeRICS platform offers an interesting tool to interface and support the computerized rehabilitation program of the patients. Due to AsTeRICS platform high usability features, family and rehabilitation professionals can learn how to use the AsTeRICS platform quickly fostering the key role of their involvement on patients' rehabilitation. AsTeRICS is a flexible, extendable, adaptable and affordable technology adapted for using computer, environmental control, mobile phone, rehabilitation programs and mechatronic systems. AsTeRICS makes possible an easy reconfiguration and integration of new functionalities, such as biofeedback rehabilitation, without major changes in the system. PMID- 23350879 TI - Assistive obstacle detection and navigation devices for vision-impaired users. AB - Quality of life for the visually impaired is an urgent worldwide issue that needs to be addressed. Obstacle detection is one of the most important navigation tasks for the visually impaired. In this research, a novel range sensor placement scheme is proposed in this paper for the development of obstacle detection devices. Based on this scheme, two prototypes have been developed targeting at different user groups. This paper discusses the design issues, functional modules and the evaluation tests carried out for both prototypes. Implications for Rehabilitation Visual impairment problem is becoming more severe due to the worldwide ageing population. Individuals with visual impairment require assistance from assistive devices in daily navigation tasks. Traditional assistive devices that assist navigation may have certain drawbacks, such as the limited sensing range of a white cane. Obstacle detection devices applying the range sensor technology can identify road conditions with a higher sensing range to notify the users of potential dangers in advance. PMID- 23350880 TI - Consumer perspectives on assistive technology outcomes. AB - PURPOSE: The current study explored domains of assistive technology (AT) device outcomes that are most valued by AT users. A secondary objective was to identify elements in the device acquisition process that affect outcomes. METHOD: Focus groups were conducted at geographically dispersed locations within the USA. The groups were moderated by experienced AT practitioners who followed a detailed procedure emphasizing a nominal group facilitation technique. RESULTS: Twenty four adult AT users, representing a range of ages and disability populations, participated in four focus groups. Many had over 15 years of experience with multiple device types. Qualitative analysis yielded 13 threads that embodied salient outcome domains (e.g. independence, subjective well-being, participation in work and school, cost-effectiveness) and key factors associated with the device acquisition process (e.g. lengthy periods of frustration, variable quality of service providers). Ironically, these data were evoked only after the term "outcomes" was omitted from focus group questions. CONCLUSIONS: AT outcomes studies are needed that report data regarding (a) the impact of AT on participation, (b) costs of AT provision and (c) key elements in the AT service delivery process. Future studies will be further strengthened to the extent that their methodologies actively assimilate consumer perspectives. Implications for Rehabilitation Consumers highly value the impact of AT devices on their independence, subjective well-being and participation in work and school. The process of acquiring assistive technology devices is often lengthy and frustrating for consumers. Future AT outcomes research should report descriptive data regarding service delivery processes, as well as long-term impacts for consumers. Practitioners and researchers should avoid the use of potentially confusing professional jargon when administering surveys to consumers. PMID- 23350881 TI - Effects of synchronous versus asynchronous mode of propulsion on wheelchair basketball sprinting. AB - PURPOSE: This study aimed to first investigate synchronous (SYN) versus asynchronous (ASY) mode of propulsion and, second, investigate the wheel camber effects on sprinting performance as well as temporal parameters. METHOD: Seven wheelchair basketball players performed four maximal eight-second sprints on a wheelchair ergometer. They repeated the test according to two modes of propulsion (SYN and ASY) and two wheel cambers (9 degrees and 15 degrees ). RESULTS: The mean maximal velocity and push power output was greater in the synchronous mode compared to the asynchronous mode for both camber angles. However, the fluctuation in the velocity profile is inferior for ASY versus SYN mode for both camber angles. Greater push time/cycle time (Pt/Ct) and arm frequency (AF) for synchronous mode versus asynchronous mode and inversely, lesser Ct and rest time (Rt) values for the synchronous mode, for which greater velocity were observed. CONCLUSIONS: SYN mode leads to better performance than ASY mode in terms of maximal propulsion velocity. However, ASY propulsion allows greater continuity of the hand-rim force application, reducing fluctuations in the velocity profile. The camber angle had no effect on ASY and SYN mean maximal velocity and push power output. IMPLICATIONS FOR REHABILITATION: The study of wheelchair propulsion strategies is important for better understanding physiological and biomechanical impacts of wheelchair propulsion for individuals with disabilities. From a kinematical point of view, this study highlights synchronous mode of propulsion to be more efficient, with regards to mean maximal velocity reaching during maximal sprinting exercises. Even if this study focuses on well-trained wheelchair athletes, results from this study could complement the knowledge on the physiological and biomechanical adaptations to wheelchair propulsion and therefore, might be interesting for wheelchair modifications for purposes of rehabilitation. PMID- 23350882 TI - A product of a templated solid-state photodimerization acts as a template: single crystal reactivity in a single polymorph of a cocrystal. AB - The concept of using a product of a template-directed solid-state reaction as a template is demonstrated. A cyclobutane lined with four carboxylic acid groups is employed as the template in photoreactive cocrystals. The resulting material is shown to exhibit polymorphism. PMID- 23350883 TI - Complementary and alternative medicine use among patients with thyroid cancer. AB - BACKGROUND: To report on the incidence and predictors of use of complementary and alternative medicine (CAM) among patients with thyroid cancer. METHODS: Data were collected using a web-based online anonymous survey under Institutional Review Board approval from Boston University. This report is based on 1327 responses from subjects with thyroid cancer. Patient factors were compared by univariate and multivariate analyses. RESULTS: After excluding multivitamin and prayer use, 74% (n=941) used CAM. Respondents were primarily over age 40, white, and female and held a college degree. The top five modalities were massage therapy, chiropraxy, special diets, herbal tea, and yoga. Few patients reported perceiving a particular modality had a negative effect on treatment. CAM was more often used for treatment of symptoms (73%) than as part of thyroid cancer treatment (27%). Multivariable logistic regression demonstrated that patients reporting a poor health status, higher education, cardiovascular disease, pulmonary symptoms, or persistent, recurrent, or metastatic disease were more likely to use CAM for treatment of thyroid cancer symptoms. Nearly one third of respondents reported their CAM use was not known, prescribed, or asked about by their physicians. CONCLUSIONS: In comparison to national surveys of the general U.S. population, patients with thyroid cancer use CAM therapies twice as often and report their use far less often. Physicians who treat patients with thyroid cancer should be aware of these data to further assist in their assessment and care. PMID- 23350884 TI - Evaluation of the expression of p53, MDM2, and SUMO-1 in oral lichen planus. AB - OBJECTIVE: The objective of this study was to compare the expression of proteins p53, MDM2, and SUMO-1 in oral lichen planus (OLP) lesions, epithelial dysplasia, and squamous cell carcinoma. MATERIALS AND METHODS: The sample consisted of the following five groups of cheek mucosa lesions: normal mucosa (NM), inflammatory fibrous hyperplasia (IFH), lichen planus, epithelial dysplasia, and squamous cell carcinoma. The tissue samples were stained with hematoxylin-eosin and submitted to immunohistochemistry using anti-p53, anti-MDM2, and anti-SUMO-1 antibodies. RESULTS: The results of this study demonstrated similar expression of p53 and MDM2 between OLP, oral epithelial dysplasia and, to a lesser extent, between OLP and oral squamous cell carcinoma (OSCC). However, for SUMO-1 a similar expression was observed in OLP, NM, and IFH. CONCLUSIONS: The results demonstrated overexpression of important proteins (p53 and MDM2) related to regulatory mechanisms of apoptosis in OLP, suggesting that there is a favorable environment for malignant transformation. The expression of SUMO-1 in OLP was similar to NM and IFH, suggesting that alterations of this protein occur at later stages of carcinogenesis, because important overexpression occurred in oral epithelial dysplasia and OSCC. PMID- 23350885 TI - Effect of melatonin on chronic bladder-ischaemia-associated changes in rat bladder function. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There are many studies showing melatonin's potent endogenous free radical scavenging and antioxidative properties, which protect against oxidative insult, but there is no information about the effect of chronic treatment with melatonin on oxidative-stress-related bladder dysfunction caused by chronic ischaemia. The model used in this study shows that functional and morphological changes caused by chronic bladder ischaemia and oxidative stress were protected by chronic treatment with melatonin, resulting in improvement of bladder hyperactivity. OBJECTIVE: To investigate the potential therapeutic benefit of melatonin for chronic ischaemia related bladder dysfunction. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were divided into control, arterial injury (AI), AI with low-dose melatonin treatment (AI-ML) and AI with high-dose melatonin treatment (AI-MH) groups. The AI, AI-ML and AI-MH groups underwent a procedure to induce endothelial injury of the iliac arteries and received a 2% cholesterol diet after AI. The rats in the AI-ML and AI-MH groups were treated with melatonin 2.5 or 20 mg/kg/day orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, urodynamic investigations were performed. Bladder tissues and iliac arteries were processed for pharmacological studies, and for immunohistochemical and histological examination. RESULTS: Iliac arteries from AI, AI-ML and AI-MH rats displayed neo-intimal formation and luminal occlusion. In the AI group, the micturition interval was significantly shorter, and bladder capacity and voided volume were lower than in the controls. Contractile responses of bladder strips to KCl, electrical field stimulation and carbachol were significantly lower after AI than in the controls. The AI bladders were found to have a significantly increased collagen ratio, oxidative stress and inducible nitric oxide synthase (NOS) expression, and decreased constitutive NOS expression compared with the controls. In the AI-ML and AI-MH groups, neo-intimal formation was not prevented, but there were beneficial effects on bladder function and morphology. In the AI ML group, the beneficial effects failed to reach statistical significance. In the AI-MH group, melatonin significantly improved oxidative stress and NOS expression, and there were significant improvements in all the functional and morphological variables compared with the AI group. CONCLUSIONS: Arterial occlusive disease may lead to chronic bladder ischaemia and bladder hyperactivity associated with oxidative stress. In the model used, chronic treatment with melatonin protected bladder function and morphology, probably through its free radical scavenging and antioxidative properties. Melatonin may prevent oxidative damage and improve ischaemia-related bladder dysfunction. PMID- 23350886 TI - Effect of preoperative nursing visit on preoperative anxiety and postoperative complications in candidates for laparoscopic cholecystectomy: a randomized clinical trial. AB - BACKGROUND: Despite progress in surgery and anaesthesia techniques, anxiety remains an important problem that imposes tremendous barriers to postoperative recovery for surgery patients. AIMS: In this study, we investigated the effects of preoperative nursing visits on anxiety and postoperative complications in candidates for laparoscopic cholecystectomy. METHODS: One hundred consecutive patients were randomly assigned into two equal groups of 50 patients each. Anxiety was evaluated in both groups using a translated and validated Spielberger State-Trait Anxiety Inventory. Patients in the control group received routine nursing care. Patients in the intervention group received two preoperative interviews, one on the day before surgery and one just before entering the operating room. Pain, nausea, vomiting and other postoperative complications were compared. Pain was measured using a visual analogue scale. FINDINGS: All patients were women with a mean +/- standard deviation age of 46.8 +/- 10.6 years. At admission, state and trait anxiety measurements in the intervention and control groups were approximately 56 and 55 in both groups. Just before entering the operating room, these values reduced to 40.30 and 39.04 in the intervention group, with no significant change in the control group (p > 0.05). Mean time to reach an Aldrete consciousness score of 9, frequency of nausea and vomiting in the recovery room, level of postoperative pain, vital sign stabilization and time interval to get out of bed all improved significantly in the intervention group. CONCLUSIONS: Our study showed that preoperative nursing visits could decrease the level of preoperative anxiety and postoperative complications in this patient population. PMID- 23350887 TI - Extracorporeal membrane oxygenation as a temporizing approach in a patient with shock, myocardial infarct, and a large ventricle septal defect; successful repair after six days. AB - Rupture of the ventricular septum occurs in 1% to 2% of all acute myocardial infarctions (MI) requiring surgical intervention in the majority of cases. Furthermore, patch dehiscence and residual shunt are major problems following repair in the acute stage. A delay in repair may prevent patch dehiscence. We now describe the technique used for a successful repair of a ruptured ventricular septal defect following six days of extracorporeal membrane oxygenation support. PMID- 23350888 TI - Prediction of early allograft dysfunction using serum phosphorus level in living donor liver transplantation. AB - Serum phosphorus is greatly affected by liver surgeries, but its change after liver transplantation has not yet been clarified. We investigated the predictive role of serum phosphorus for early allograft dysfunction (EAD) after living donor liver transplantation (LDLT). Perioperative factors, including serum phosphorus level, of 304 patients who underwent LDLT were retrospectively studied and compared between patients with and without EAD after LDLT. Potentially significant factors (P < 0.15) in univariate comparisons were subjected to multivariate logistic regression analysis to develop a prediction model for EAD. A total of 48 patients (15.8%) met the EAD criteria. Patients with EAD experienced more severe preoperative disease conditions, higher one-month mortality and more elevated serum phosphorus concentrations during the first week after surgery compared with patients without EAD (P = 0.016). Multivariate analysis showed that a serum phosphorus level >=4.5 mg/dl on postoperative day 2 was an independent predictor of EAD occurrence after LDLT (relative risk: 2.36, 95% confidence interval [1.18-4.31], P = 0.017), together with a history of past abdominal surgery, emergency transplantation and preoperative continuous veno venous haemodiafiltration. These data indicate that hyperphosphataemia during the immediate postoperative days could be utilized as a predictor of EAD after LDLT. PMID- 23350889 TI - An upward trend in the age-specific incidence patterns for mantle cell lymphoma in the USA. AB - Although an increased incidence of mantle cell lymphoma (MCL) has been reported, age-specific incidence patterns have not been described. Further analyses could inform investigation into the etiology of this disease. We conducted an epidemiologic study using the 13 Surveillance, Epidemiology, and End Results (SEER) registries to evaluate MCL incidence from 1992 through 2009. We calculated the proportional changes in the incidence of MCL for subpopulations defined by age, race/ethnicity and gender over time and the racial/ethnic and gender disparities. We observed a 130.9% increase in MCL incidence from 1992-1994 to 2005-2009. The increase was strongest for males (199.0%) and for whites (153.0%). The incidence increased 161%, 200%, 398% and 429% from 1992-1994 to 2005-2009 in white men ages 50-59, 60-69, 70-79 and 80+, respectively, whereas the increase in white females was 86%, 82%, 50% and 193% in the corresponding age groups. We observed a male-to-female incidence rate ratio (IRR) of 2.65 and a white-to-black IRR of 2.21. Our analysis confirmed significant increases in MCL, and illustrated that the incidence is increasing more rapidly in elderly persons, particularly in white males. We also identified novel age-specific temporal trends by race/ethnicity and sex. In addition, we found that the gender and white-to-black disparities have grown over time. Our findings may impact MCL etiologic investigation and treatment research. PMID- 23350890 TI - Heterogeneity in the myelodysplastic syndromes: moving toward a better understanding. PMID- 23350891 TI - Vascular endothelial growth factor expression in acute myeloid leukemia: a biomarker ready for primetime? PMID- 23350892 TI - Pleurocidin-family cationic antimicrobial peptides mediate lysis of multiple myeloma cells and impair the growth of multiple myeloma xenografts. AB - Abstract Multiple myeloma is a common hematological malignancy that urgently requires new approaches to treatment, since the disease is not curable using current chemotherapeutic regimens. The aim of this study was to determine whether human and mouse multiple myeloma cells are killed by the pleurocidin-like cationic antimicrobial peptides NRC-03 and NRC-07, previously shown to be active against breast cancer cells. We demonstrate here that NRC-03 and NRC-07 bound to and rapidly killed multiple myeloma cells by causing extensive membrane damage, as well as DNA cleavage. NRC-03 showed greater binding to multiple myeloma cells and a more potent cytotoxic effect than NRC-07. In addition, intratumoral injections of NRC-03 impaired the growth of multiple myeloma xenografts in immune deficient mice. We conclude that NRC-03 warrants further investigation for its possible use in the treatment of multiple myeloma. PMID- 23350893 TI - Associations of HbA1c and educational level with risk of cardiovascular events in 32,871 drug-treated patients with Type 2 diabetes: a cohort study in primary care. AB - AIMS: To explore the association of HbA1c and educational level with risk of cardiovascular events and mortality in patients with Type 2 diabetes. METHODS: A cohort of 32 871 patients with Type 2 diabetes aged 35 years and older identified by extracting data from electronic patient records for all patients who had a diagnosis of Type 2 diabetes and had glucose-lowering agents prescribed between 1999 and 2009 at 84 primary care centres in Sweden. Associations of mean HbA1c levels and educational level with risks of cardiovascular events and all-cause mortality were analysed. RESULTS: The associations of HbA1c with risk of all cause and cardiovascular mortality were J-shaped, with the lowest risk observed for cardiovascular mortality at an HbA1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin-treated patients. The lowest risk observed for all-cause mortality was at an HbA1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin-treated patients. There was an increased risk for cardiovascular death [hazard ratio 1.6 (1.2-2.1), P = 0.0008] at the lowest HbA1c decile for subjects in the low education category. For subjects with higher education there was no evident J curve for cardiovascular death [hazard ratio 1.2 (0.8-1.6), P = 0.3873]. CONCLUSIONS: Our results lend support to the recent American Diabetes Association/ European Association for the Study of Diabetes position statement that emphasizes the importance of additional factors, including the propensity for hypoglycaemia, which should influence HbA1c targets and treatment choices for individual patients. (Clinical Trials Registry No; NCT 01121315). PMID- 23350895 TI - Investigation of therapeutic efficiency of bleomycin and bleomycin-glucuronide labeled with (131)I on the cancer cell lines. AB - The aim of this study is to determine the incorporations of radiolabeled bleomycin ((131)I-BLM) and bleomycin-glucuronide ((131)I-BLMGLU) on PC-3 (human prostate carcinoma cell line), Caco-2 (human colon adenocarcinoma cell line), Hutu-80 (Human Duodenum adenocarcinoma cell line), and A549 (Human lung adenocarcinoma epithelial cell line) cancerous cell lines. For this purpose, BLM and BLMGLU enyzmatically synthesized were labeled with (131)I, quality control studies were done and the incorporation yields of (131)I-BLM and (131)I-BLMGLU on these cell lines were measured. Quality-control studies showed that the radiolabeling yields were obtained as 95% and 90% for (131)I-BLM and (131)I BLMGLU, respectively. Also, as a result of the cell culture studies, it was found that (131)I-BLM and (131)I-BLMGLU had higher incorporation on PC-3 cells than that of other cell lines. In addition to this, it was reported that the incorporation yield of (131)I-BLMGLU was higher than that (131)I-BLM. At the end of the study, cytotoxicities of BLM and BLMGLU on PC-3 cancerous cell line were inspected and fluorescent images of BLM and BLMGLU were taken on PC-3 cells by using fluorescein isothiocyanate. In conclusion, cell culture studies demonstrated that the incorporation values of (131)I-BLMGLU on the four cell lines were about five to six times higher than (131)I-BLM. Radiolabeled glucuronide derivatives can be used in cancer therapy and tumor imaging, depending on the properties of radioiodine for the beta-glucuronidase-rich tissues because glucuronidation leads to rapid and higher incorporation on adenocarcinoma cells. PMID- 23350894 TI - Positron-emission tomography imaging of the TSPO with [(18)F]FEPPA in a preclinical breast cancer model. AB - The present study aims to image the 18-kDa translocator protein (TSPO; formerly known as the peripheral benzodiazepine receptor) in a preclinical human breast cancer (BC) xenograft mouse model with positron-emission tomography (PET). An automated radiosynthesis of [(18)F]-N-(2-(2-fluoroethoxy)benzyl)-N-(4 phenoxypyridin-3-yl)acetamide ([(18)F]FEPPA) was validated for human use using a commercial synthesis module and resulted in a high radiochemical yield (30%+/-8%, uncorrected; n=54) and specific activity (6+/-4 Ci/MUmol). Tumor uptake of [(18)F]FEPPA in mice bearing subcutaneous MDA-MB-231 BC xenografts was evaluated by PET-computed tomography imaging and ex vivo biodistribution studies. Although the tumor was successfully visualized, ex vivo biodistribution studies revealed low tumor uptake (0.7%ID/g), with the majority of radioactivity distributed in the spleen, muscle, and heart despite high TSPO expression in this cell line. Our laboratory routinely prepares [(18)F]FEPPA for human-imaging studies in the central nervous system, and we envision that radiopharmaceuticals that target the TSPO have the potential for imaging macrophages in the tumor microenvironment. PMID- 23350896 TI - Activator protein-1 inhibition by 3-[(dodecylthiocarbonyl)methyl]-glutamaride impairs invasion and radiosensitizes osteosarcoma cells in vitro. AB - Osteosarcoma (OS) is the most common primary malignant bone tumor. Despite advances in neoadjuvant multi-agent chemotherapy, the outcome of patients has not significantly improved in the last decades, making the search for more effective therapeutic agents imperative. In the present study, we explored the possibility of using activator protein-1 inhibition by 3-[(dodecylthiocarbonyl)methyl] glutarimide (DTCM-g) as a new therapeutic strategy in two OS cell lines, HOS and MG-63. Our results showed that low concentrations (2.5, 5, 10, and 20 MUg/mL) of the drug significantly decreased cell proliferation and clonogenic capacity, albeit it did not significantly induce cell death. DTCM-g also decreased cell invasiveness, and inhibited PDPN, MMP-2, TIMP1, and TIMP2 expressions. Moreover, our results showed that DTCM-g synergized with ionizing radiation in both cell lines while chemosensitized MG-63 cells to doxorubicin treatment. Even though additional laboratorial and preclinical tests are still needed to support our data, we demonstrate that DTCM-g inhibits growth in OS cells, increases the cytotoxicity of other commonly used agents, and may possess antimetastatic activity. PMID- 23350897 TI - Cucurbitacin B and its rapidly emerging role in the management of systemic malignancies besides lung carcinomas. PMID- 23350898 TI - Is colectomy for fulminant Clostridium difficile colitis life saving? A systematic review. AB - AIM: It is unclear whether colectomy for fulminant Clostridium difficile colitis (FCDC) leads to a improvement in survival compared with continued medical therapy for this moribund population. METHOD: Selected studies from 1994-2010 were identified through a comprehensive search theme applied to MEDLINE (OvidSP and PubMed), EMBASE and by hand searching. Data regarding mortality rates between medically and surgically treated patients were extracted. Risk of bias was assessed using a Newcastle-Ottawa Scale score. A meta-analysis of the odds ratios for mortality between surgical and medical treatment for FCDC was conducted using the Mantel-Haenszel method and fixed-effects modelling. RESULTS: Five hundred and ten patients with FCDC were identified in six studies. The pooled adjusted odds ratio of mortality comparing surgery with medical therapy was 0.70 (0.49-0.99), suggesting that surgery provided a survival benefit. CONCLUSION: Emergent colectomy for patients with FCDC provides a survival advantage compared with continuing antibiotics. Though there is selection bias of patients having surgery, the results of this systematic review suggest that colectomy has a therapeutic role in treating severe forms of C. difficile colitis. PMID- 23350901 TI - The (noncoding) RNA world. PMID- 23350899 TI - Antihypertensive therapy and cerebral hemodynamics in executive mild cognitive impairment: results of a pilot randomized clinical trial. AB - OBJECTIVES: To compare the effects of three antihypertensive medications on cerebral hemodynamic and cognitive function in hypertensive individuals with executive dysfunction. DESIGN: Double-blind randomized clinical trial. SETTING: Community. PARTICIPANTS: Fifty-three individuals aged 60 and older with hypertension and executive dysfunction. INTERVENTION: Lisinopril, candesartan, or hydrochlorothiazide for 1 year. MEASUREMENTS: Cerebral blood flow velocity (BFV; transcranial Doppler ultrasonography during rest, sitting, standing, hypercapnia, and hypocapnia), cognition, and blood pressure were measured at baseline and after 6 and 12 months. Linear mixed models were used to compare the three groups. RESULTS: Of the 53 participants, 47 had successful insonation (mean age 72; 70% white; 57% women). There was a tendency toward an increase in BFV in the candesartan group and a decrease in the lisinopril and hydrochlorothiazide groups (between-group P = .57) that was significant in those with low BFV at baseline (3 h dry intervals between voiding. According to DAN-PSS questionnaire only two of 11 patients with exstrophy and two of 13 with epispadias were fully continent and could void normally. In addition to storage symptoms, eight of 13 patients with epispadias and 10 of 12 with exstrophy had disturbing voiding symptoms. Moderate or severe LUTS was reported altogether by 12 of 15 (80%) males and by six of nine females. CONCLUSIONS: Continence rates in patients with BEE are very dependent on the evaluation method. Most LUTS become apparent only by using a detailed questionnaire. Moderate or severe LUTS appear to be common amongst patients with BEE. PMID- 23350916 TI - Immediate acoustic effects of straw phonation exercises in subjects with dysphonic voices. AB - Abstract This study sought to measure any acoustic changes in the speaking voice immediately after phonation exercises involving plastic straws versus phonation exercises with the open vowel /a/. Forty-one primary school teachers with slightly dysphonic voices were asked to participate in four phonatory tasks. Phonetically balanced text at habitual intensity level and speaking fundamental frequency was recorded. Acoustical analysis with long-term average spectrum was performed. Significant changes after therapy for the experimental group include the alpha ratio, L1-L0 ratio and ratio between 1-5 kHz and 5-8 kHz. The results indicate that the use of phonatory tasks with straw exercises can have immediate therapeutic acoustic effects in dysphonic voices. Long-term effects were not assessed in this study. PMID- 23350917 TI - Donation after cardiac death: results of the SUMMA 112 - Hospital 12 de Octubre Program. AB - BACKGROUND: In 2005, our center started a donation after cardiac death (DACD) program, by which patients who present an irreversible cardiac arrest outside hospital are brought to our center with the purpose of organ donation. We reviewed the outcomes of our program of kidney transplants from DACD. METHODS: We conducted a retrospective study of the DACD, and we reviewed the procedures carried out in our institution between July 2005 and December 2010 and descriptively analyzed the results obtained for kidney donation. RESULTS: One hundred and fifty-two of 274 potential donors were transferred to our hospital. Of them, 126 (82.8%) were connected to cardiopulmonary bypass machine, and organs were procured in 113 donors (74.3%). The discarded grafts were mainly due to inadequate perfusion. One hundred and fifty-six kidneys were transplanted (51.3%). Over a median follow-up period of 18 +/- 13.7 months, the median creatinine clearance was 78.2 +/- 10.2 ml/min. 8.6% of the grafts had no primary function, and 85% had a delayed graft function. Recipient survival and graft survival were 98% and 87%, respectively. CONCLUSIONS: DACD is an adequate source of organs for kidney transplantation. Our functional and survival results are encouraged in the short term, although further work is required to increase the program's benefits. PMID- 23350913 TI - Biological interplay between proteoglycans and their innate immune receptors in inflammation. AB - An emerging body of evidence indicates that secreted proteoglycans act as signaling molecules, in addition to their canonical function in maintaining and regulating the architecture of various extracellular matrices. Proteoglycans interact with a number of receptors that regulate growth, motility and immune response. In part, as a consequence of their complex structure, proteoglycans can induce crosstalk among various families of receptors and can also interact with natural receptor ligands, often blocking and sequestering their bioactivity. In their soluble form, originating from either partial proteolytic processing or through de novo synthesis by activated cells, some proteoglycans can become potent danger signals, denoting tissue stress and injury. Recently, it has been shown that proteoglycans, especially those belonging to the small leucine-rich and hyaluronan-binding gene families as well as the glycosaminoglycan hyaluronan, act as endogenous ligands of the toll-like receptors, a group of central receptors regulating innate immunity. Furthermore, proteoglycans can activate intracellular inflammasomes and trigger sterile inflammation. In this review, we critically assess the signaling events induced by the proteoglycans biglycan, decorin, lumican and versican as well as hyaluronan during inflammation. We discuss the intriguing emerging notion that, in spite of structural diversity of biglycan, decorin, versican and hyaluronan, all of them signal through the same toll-like receptors, albeit triggering differential responses and biological outcomes. Finally, we review the modes of action of these endogenous ligands of toll-like receptors and their ability to specifically modify the final signaling events and the inflammatory response. PMID- 23350918 TI - Transcapsular arterial neovascularization of liver transplants increases the risk of intraoperative bleeding during retransplantation. AB - Arterial neovascularization of liver grafts can be a source of significant blood loss during retransplantation. This study evaluated the effect of transcapsular arterial neovascularization on intraoperative blood loss during retransplantation and long-term follow-up. Eleven consecutive patients with transcapsular arterial neovascularization (seven male, four female; nine children, two adults; mean age 12.3 +/- 16.3 years) and the same number of matched control patients were analysed. Blood loss was calculated based on transfusion requirements. The volume of transfused units of red blood cells per kilogram bodyweight until hepatectomy and during the entire procedure was significantly higher in patients with neovascularization than in control patients (0.32 +/- 0.21 vs. 0.14 +/- 0.11, and 0.94 +/- 0.83 vs. 0.36 +/- 0.38 respectively; P-values 0.027). Neovascularization was associated with extensive intra-abdominal adhesions and a longer operating time until hepatectomy (175.6 +/- 52.1 min vs. 124.3 +/- 34.9 min, P-value 0.015). Postoperative revisions were performed more frequently in patients with neovessels. Graft survival did not differ between groups. Assessment for transcapsular arterial neovascularization should be included in preoperative Doppler ultrasound protocols to identify patients at risk of a complicated intra- and postoperative course in case of retransplantation. PMID- 23350919 TI - Loop-mediated isothermal amplification (LAMP)-based method for rapid mushroom species identification. AB - Toxic mushroom species, such as the death cap ( Amanita phalloides ), are responsible for most mushroom poisonings. In the present work, novel loop mediated isothermal amplification (LAMP) assays were used for the differentiation of even closely related edible and toxic mushroom species. The applicability of these methods was tested by cross-reaction studies and analysis of spiked mushroom samples (raw and fried material). Contaminations at the level of 2% (w/w) could be detected in different mushroom blends. Three detection methods were used: agarose gel analysis, fluorimetric real-time detection, and visual detection by lateral flow dipsticks (LFD). The LAMP assay combined with LFD detection allows the identification of A. phalloides in about 2 h (including DNA extraction) at a very low level of technical equipment (micropestle, water bath, and mobile centrifuge), which makes this technique perfectly suited for on site applications. PMID- 23350920 TI - Affective symptoms and change in diabetes self-efficacy and glycaemic control. AB - AIMS: To examine the role of baseline depression, anxiety and stress symptoms on post-intervention diabetes self-efficacy and glycaemic control (HbA(1c)). METHODS: The current study analysed data from patients (n = 85) with treated but uncontrolled Type 2 diabetes who participated in a comparative effectiveness study of two diabetes self-management interventions. Hierarchical linear regression was used to examine the relationships between baseline affective symptoms and post-intervention diabetes self-efficacy and the moderating effects of baseline affective symptoms on the relationship between changes in diabetes self-efficacy and post-intervention HbA(1c). RESULTS: Baseline depression was inversely associated with post-intervention diabetes self-efficacy (P = 0.0001) after adjusting for baseline characteristics including diabetes self-efficacy. In contrast, normal-mild levels of stress were associated with higher post intervention diabetes self-efficacy (P = 0.04). Anxiety and stress symptoms significantly and independently moderated the relationship between changes in diabetes self-efficacy and post-intervention HbA(1c) (P = 0.02 and P = 0.03, respectively). Further evaluation of these interactions demonstrated that changes in diabetes self-efficacy were associated with lower post-intervention HbA(1c), but only among those with higher baseline affective symptoms. CONCLUSIONS: We found a moderating effect across affective symptoms on the relationship between diabetes self-efficacy changes and post-intervention HbA1c in the context of a self-management intervention. Results suggest that patients with poorly controlled diabetes who have higher levels of depression, anxiety and stress symptoms may derive greater benefits from self-management interventions known to improve diabetes self-efficacy. PMID- 23350922 TI - Chemical shift correlations from hyperpolarized NMR using a single SHOT. AB - A significant challenge in realizing the promise of the dissolution dynamic nuclear polarization technique for signal enhancement in high-resolution NMR lies in the nonrenewability of the hyperpolarized spin state. This property prevents the application of traditional two-dimensional correlation spectroscopy, which relies on regeneration of spin polarization before each successive increment of the indirect dimension. Since correlation spectroscopy is one of the most important approaches for the identification and structural characterization of molecules by NMR, it is important to find easily applicable methods that circumvent this problem. Here, we introduce the application of scaling of heteronuclear couplings by optimal tracking (SHOT) to achieve this goal. SHOT decoupling pulses have been numerically optimized on the basis of optimal control algorithms to obtain chemical shift correlations in C-H groups, either by acquiring a single one-dimensional (13)C spectrum with (1)H off-resonance decoupling or vice versa. Vanillin, which contains a number of functional groups, was used as a test molecule, allowing the demonstration of SHOT decoupling tailored toward simplified and accurate data analysis. This strategy was demonstrated for two cases: First, a linear response to chemical shift offset in the correlated dimension was optimized. Second, a pulse with alternating linear responses in the correlated dimension was chosen as a goal to increase the sensitivity of the decoupling response to the chemical shift offset. In these measurements, error ranges of +/-0.03 ppm for the indirectly determined (1)H chemical shifts and of +/-0.4 ppm for the indirectly determined (13)C chemical shifts were found. In all cases, we show that chemical shift correlations can be obtained from information contained in a single scan, which maximizes the ratio of signal to stochastic noise. Furthermore, a comprehensive discussion of the robustness of the method toward nonideal conditions is included based on experimental and simulated data. Unique features of this technique include the abilities to control the accuracy of chemical shift determination in spectral regions of interest and to acquire such chemical shift correlations rapidly-the latter being of interest for potential application in real-time spectroscopy. PMID- 23350921 TI - Advance care planning and the quality of end-of-life care in older adults. AB - OBJECTIVES: To determine whether advance care planning influences quality of end of-life care. DESIGN: In this observational cohort study, Medicare data and survey data from the Health and Retirement Study (HRS) were combined to determine whether advance care planning was associated with quality metrics. SETTING: The nationally representative HRS. PARTICIPANTS: Four thousand three hundred ninety nine decedent subjects (mean age 82.6 at death, 55% women). MEASUREMENTS: Advance care planning (ACP) was defined as having an advance directive (AD), durable power of attorney (DPOA) or having discussed preferences for end-of-life care with a next of kin. Outcomes included previously reported quality metrics observed during the last month of life (rates of hospital admission, in-hospital death, >14 days in the hospital, intensive care unit admission, >1 emergency department visit, hospice admission, and length of hospice <= 3 days). RESULTS: Seventy-six percent of subjects engaged in ACP. Ninety-two percent of ADs stated a preference to prioritize comfort. After adjustment, subjects who engaged in ACP were less likely to die in a hospital (adjusted relative risk (aRR) = 0.87, 95% confidence interval (CI) = 0.80-0.94), more likely to be enrolled in hospice (aRR = 1.68, 95% CI = 1.43-1.97), and less likely to receive hospice for 3 days or less before death (aRR = 0.88, 95% CI = 0.85-0.91). Having an AD, a DPOA or an ACP discussion were each independently associated with a significant increase in hospice use (P < .01 for all). CONCLUSION: ACP was associated with improved quality of care at the end of life, including less in-hospital death and increased use of hospice. Having an AD, assigning a DPOA and conducting ACP discussions are all important elements of ACP. PMID- 23350923 TI - Preferential responses to extinguished face stimuli are preserved in frontal and occipito-temporal cortex at initial but not later stages of processing. AB - Magnetoencephalographic correlates of rapid emotional responses (50-80 ms) in frontal and occipito-temporal regions have recently been reported using a novel MultiCS Conditioning paradigm with odor-conditioned faces. As those short-latency responses were supposed to partially reflect initial access to nonextinguished emotional memories, it could be predicted that they outlast the extinction phase. To test this hypothesis, appetitively and aversively odor-conditioned faces were frequently presented during extinction while event-related magnetic fields were recorded. Affect-specific responses in frontal and occipito-temporal areas were found in the early (50-80 ms) but not in the later (130-190 ms) time interval following extinction learning. These results suggest that previously acquired emotional memories can be accessed at initial processing stages but become ineffective in modulating processing at later stages as extinction proceeds. PMID- 23350924 TI - Uniform thin films of CdSe and CdSe(ZnS) core(shell) quantum dots by sol-gel assembly: enabling photoelectrochemical characterization and electronic applications. AB - Optoelectronic properties of quantum dot (QD) films are limited by (1) poor interfacial chemistry and (2) nonradiative recombination due to surface traps. To address these performance issues, sol-gel methods are applied to fabricate thin films of CdSe and core(shell) CdSe(ZnS) QDs. High-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) imaging with chemical analysis confirms that the surface of the QDs in the sol-gel thin films are chalcogen-rich, consistent with an oxidative-induced gelation mechanism in which connectivity is achieved by formation of dichalcogenide covalent linkages between particles. The ligand removal and assembly process is probed by thermogravimetric, spectroscopic, and microscopic studies. Further enhancement of interparticle coupling via mild thermal annealing, which removes residual ligands and reinforces QD connectivity, results in QD sol-gel thin films with superior charge transport properties, as shown by a dramatic enhancement of electrochemical photocurrent under white light illumination relative to thin films composed of ligand-capped QDs. A more than 2-fold enhancement in photocurrent, and a further increase in photovoltage can be achieved by passivation of surface defects via overcoating with a thin ZnS shell. The ability to tune interfacial and surface characteristics for the optimization of photophysical properties suggests that the sol-gel approach may enable formation of QD thin films suitable for a range of optoelectronic applications. PMID- 23350925 TI - The influence of saturated fatty acids on complex index and in vitro digestibility of rice starch. AB - In Asia, rice and rice products are the main sources of carbohydrate contributing to both dietary energy and glycaemic load. It is known that complexation of starch with lipids could potentially reduce the availability of starch to enzymatic degradation. The aim of this study was to investigate the effect of capric, lauric, myristic, palmitic and stearic acids, ranging from 0 to 2 mmol/g starch, on complexing index and in vitro digestibility of gelatinized rice starch. The results revealed that the ability of rice starch to complex with saturated fatty acids increased with increasing concentration; but reduced with increasing lipid chain length. The complexation of rice starch with capric, lauric, myristic and stearic acids did not reduce the in vitro starch digestibility, except rice starch-palmitic acid complexes. PMID- 23350926 TI - Cleavage of DNA by proton-coupled electron transfer to a photoexcited, hydrated Ru(II) 1,10-phenanthroline-5,6-dione complex. AB - Visible light irradiation of a ruthenium(II) quinone-containing complex, [(phen)(2)Ru(phendione)](2+) (1(2+)), where phendione = 1,10-phenanthroline-5,6 dione, leads to DNA cleavage in an oxygen independent manner. A combination of NMR analyses, transient absorption spectroscopy, and fluorescence measurements in water and acetonitrile reveal that complex 1(2+) must be hydrated at the quinone functionality, giving [(phen)(2)Ru(phenH(2)O)](2+) (1H(2)O(2+), where phenH(2)O = 1,10-phenanthroline-6-one-5-diol), in order to access a long-lived (3)MLCT(hydrate) state (tau ~ 360 ns in H(2)O) which is responsible for DNA cleavage. In effect, hydration at one of the carbonyl functions effectively eliminates the low-energy (3)MLCT(SQ) state (Ru(III) phen-semiquinone radical anion) as the predominant nonradiative decay pathway. This (3)MLCT(SQ) state is very short-lived (<1 ns) as expected from the energy gap law for nonradiative decay, (1) and too short-lived to be the photoactive species. The resulting excited state in 1H(2)O(2+)* has photophysical properties similar to the (3)MLCT state in [Ru(phen)(3)](2+)* with the added functionality of basic sites at the ligand periphery. Whereas [Ru(phen)(3)](2+)* does not show direct DNA cleavage, the deprotonated form of 1H(2)O(2+)* does via a proton-coupled electron transfer (PCET) mechanism where the peripheral basic oxygen sites act as the proton acceptor. Analysis of the small molecule byproducts of DNA scission supports the conclusion that cleavage occurs via H-atom abstraction from the sugar moieties, consistent with a PCET mechanism. Complex 1(2+) is a rare example of a ruthenium complex which 'turns on' both reactivity and luminescence upon switching to a hydrated state. PMID- 23350927 TI - Predicting functional capacity in patients with a systemic right ventricle: subjective patient self-assessment is better than B-type natriuretic peptide levels and right ventricular systolic function. AB - BACKGROUND: Many adults with transposition of the great arteries have an anatomic right ventricle functioning as the systemic ventricle and are known to develop congestive heart failure, premature cardiac death, and need for cardiac transplantation. Predictors of poor clinical outcome and functional status in patients with left ventricular failure do not always apply to these patients. We aimed to identify predictors of poor functional status in those patients with a systemic right ventricle. METHODS: We performed a prospective study of 51 adults with transposition of the great arteries and systemic right ventricles. Demographic, clinical, laboratory, and imaging data were collected, and patients completed a Minnesota Living with Heart Failure Questionnaire (MLHFQ). Comparisons were made between those patients with d-type transposition of the great arteries (dTGA) who have undergone prior atrial switch and those with congenitally corrected transposition (ccTGA). A correlation analysis was performed to identify predictors of poor functional status, as determined by a 6 minute walk distance test. RESULTS: Median age was 30 years (range 19-65). Median B-type natriuretic peptide was 48 pg/mL (range 16-406). There were 27 patients (53%) with moderate-severe right ventricular dysfunction and 10 (20%) with moderate-severe tricuspid valve regurgitation. The median MLHFQ score was 9 (range 0-78) and 6-minute walk test was 510 m (range 231-703). Forty-one patients had a diagnosis of dTGA atrial switch and 11 patients had ccTGA. Patients with ccTGA were significantly older (40 vs. 28 years, P =.004) and had more tricuspid valve regurgitation (P =.02). Despite this, their MLHFQ scores were significantly lower (2.5 vs. 17, P =.04) and they walked further (635 vs. 504 m, P =.02). Predictors of a short 6-minute walk distance included short stature (P =.009) and dTGA (P =.002). The patient's self-assessment of poor health, as measured by an increased New York Heart Association class (P =.003) and a decreased MLHFQ score (P >.0001) also correlated. B-type natriuretic peptide levels, right ventricular dysfunction, severity of tricuspid valve regurgitation, need for pacemaker, and clinical signs of heart failure did not correlate with exercise tolerance. CONCLUSIONS: Traditional parameters used to predict outcomes in patients with left ventricular failure are not predictive in patients with a systemic right ventricle. Instead, patient's self-assessment of functional status did correlate with objective functional status. PMID- 23350928 TI - Judgment of Line Orientation: an examination of eight short forms. AB - The Judgment of Line Orientation (JLO) test is a commonly used measure of visuospatial perception. Because of its length, several short forms have appeared in the literature. We examined the internal consistency of the JLO and eight of its published short forms among 128 undergraduates, 203 healthy older adults, and 55 chronic kidney disease patients. The full test demonstrated good reliability for traditional neuropsychological assessment, but the majority of short forms were adequate only for screening purposes, where greater measurement error is typically permitted in exchange for brevity. In contrast, a recently developed short form based upon item response theory demonstrated promise as a stand-alone measure. PMID- 23350929 TI - Molecular diversity and high virulence of Legionella pneumophila strains isolated from biofilms developed within a warm spring of a thermal spa. AB - BACKGROUND: Several cases of legionellosis have been diagnosed in the same French thermal spa in 1986, 1994 and 1997. L. pneumophila serogroup 1 (Lp1) strains have been isolated from several patients, but the source of contamination was not identified despite the presence of different Lp1 in water samples of the three natural springs feeding the spa at this period. RESULTS: Our strategy was to investigate L. pneumophila (Lp) strains from natural biofilms developed in a sulphur-rich warm spring of this contaminated site. Biofilm analysis revealed the presence of three Lp serogroups (Lp1, Lp10 and Lp12). Surprisingly, Lp10 and Lp12 were not reported in the previous described studies from water samples. Besides, the new seven Lp1 we isolated exhibit a high molecular diversity and have been differentiated in five classes according to their DNA genome patterns obtained by PFGE and mip sequences. It must be noted that these DNA patterns are original and unknown in databases. Interestingly, the 27 Lp environmental strains we isolated display a higher cytotoxicity and virulence towards the amoeba Acanthamoeba castellanii than those of known Lp1 epidemic strains. CONCLUSION: The characteristics of Legionella pneumophila Lp1 strains isolated from the warm spring are in agreement with their presence in biofilms and their probable long term persistence in this ecosystem. PMID- 23350930 TI - Marriage as a risk factor for HIV: learning from the experiences of HIV-infected women in Malawi. AB - The gender inequalities that characterise intimate partner relationships in Malawi, a country with one of the highest HIV prevalence rates in the world, arguably place marriage as an important risk factor for HIV infection among women, yet few studies detail the complex interactions of marriage and risk. In order to develop HIV-prevention interventions that have lasting impacts in such communities, we need a deeper understanding of the intricacies of women's lives, how and why they are involved in marital relationships, and the implications of these relationships for HIV transmission or prevention. This article describes how women understand marriage's effects on their lives and their HIV risks. Drawing from focus group discussions with 72 women attending antiretroviral clinics in Malawi, we explore why women enter marriage, what women's experiences are within marriage and how they leave spouses for other relationships. Based on their narratives, we describe women's lives after separation, abandonment or widowhood, and report their reflections on marriage after being married two or three times. We then review women's narratives in light of published work on HIV, and provide recommendations that would minimise the risks of HIV attendant on marriage. PMID- 23350931 TI - The prevalence of right-sided colonic diverticulosis and diverticular haemorrhage. AB - AIM: The study was performed to determine the prevalence of right-sided diverticular disease in a western population and whether it is more likely to bleed than disease on the left side. METHOD: From January 2004 to June 2005, 796 consecutive patients were referred for total colonoscopy to 17 physicians. Data obtained included age, gender, and presence and localization of diverticula. This population was compared with a cohort of 133 consecutive patients who were admitted for colonic diverticular bleeding. RESULTS: Three-hundred and eighteen (40%) of the 796 patients presented with noncomplicated diverticulosis. Of these, 103 (32.4%) had right-sided diverticula. In univariate analysis, the presence of right diverticula in patients admitted for diverticular bleeding was about twice as frequent as in patients who had diverticula with no bleeding (65.2% vs 32.4%; P = 0.0001). In multivariate analysis, the right localization of the diverticulosis was associated with a risk of bleeding, which was independent of the patients' age (P = 0.0001, OR = 3.6). CONCLUSION: The prevalence of colonic diverticula increased from < 10% in adults under 40 years of age to about 75% in those over 75 years of age. Of these patients, nearly one-third presented with right-sided involvement. Right-sided localization was associated with a significant risk of bleeding, which was independent of the patients' age. PMID- 23350932 TI - TAF4b and TAF4 differentially regulate mouse embryonic stem cells maintenance and proliferation. AB - TAF4b is a cell type-specific subunit of the general transcription factor TFIID. Here, we show that TAF4b is highly expressed in embryonic stem cells (ESC) and is down-regulated upon differentiation. To examine the role of TAF4b in ESC, we applied a knockdown (KD) approach. TAF4b depletion is associated with morphological changes and reduced expression of the self-renewal marker alkaline phosphatase. In contrast, KD of TAF4, a ubiquitously expressed TAF4b paralog, retained and even stabilized ESC stemness. Retinoic acid-induced differentiation was facilitated in the absence of TAF4b but was significantly delayed by TAF4 KD. Furthermore, TAF4b supports, whereas TAF4 inhibits, ESC proliferation and cell cycle progression. We identified a subset of TAF4b target genes preferentially expressed in ESC and controlling the cell cycle. Among them are the germ cell specific transcription factor Sohlh2 and the protein kinase Yes1, which was recently shown to regulate ESC self-renewal. Interestingly, Sohlh2 and Yes1 are also targets of the pluripotency factor Oct4, and their regulation by Oct4 is TAF4b-dependent. Consistent with that, TAF4b but not TAF4 interacts with Oct4. Our findings suggest that TAF4b cooperates with Oct4 to regulate a subset of genes in ESC, whereas TAF4 is required for later embryonic developmental stages. PMID- 23350933 TI - An examination of pay-for-performance in general practice in Australia. AB - OBJECTIVE: This study examines the impact of Australia's pay-for-performance (P4P) program for general practitioners (GPs). The voluntary program pays GPs A$40 and A$100 in addition to fee-for-service payment for providing patients recommended diabetes and asthma treatment over a year, and A$35 for screening women for cervical cancer who have not been screened in 4 years. DESIGN: Three approaches were used to triangulate the program's impact: (1) analysis of trends in national claims for incentivized services pre- and postprogram implementation; (2) fixed effects panel regression models examining the impact of GPs' P4P program participation on provision of incentivized services; and (3) in-depth interviews to explore GPs' perceptions of their own response to the program. RESULTS: There was a short-term increase in diabetes testing and cervical cancer screens after program implementation. The increase, however, was for all GPs. Neither signing onto the program nor claiming incentive payments was associated with increased diabetes testing or cervical cancer screening. GPs reported that the incentive did not influence their behavior, largely due to the modest payment and the complexity of tracking patients and claiming payment. IMPLICATIONS: Monitoring and evaluating P4P programs is essential, as programs may not spark the envisioned impact on quality improvement. PMID- 23350934 TI - Synthesis of 3-acylindoles by palladium-catalyzed acylation of free (N-H) indoles with nitriles. AB - An efficient palladium-catalyzed synthesis of 3-acylindoles using free (N-H) indoles and nitriles has been developed. The acylation reaction proceeded well under the Pd(OAc)(2)/2,2'-bipyridine system and with D-(+)-camphorsulfonic acid as the additive. A possible mechanism involving carbopalladation of nitriles and subsequent hydrolysis of ketimines is proposed. PMID- 23350935 TI - Diabetes-induced changes in mannan-binding lectin levels and complement activation in a mouse model of type 1 diabetes. AB - Circulating mannan-binding lectin (MBL) levels are elevated in type 1 diabetes. Further, high MBL levels are associated with the development of diabetic nephropathy. In animals, a direct effect of MBL on diabetic kidney changes is observed. We hypothesized that MBL levels and detrimental complement activation increase as a consequence of diabetes. We measured plasma MBL before and 7 weeks after inducing diabetes by streptozotocin. Mice have two MBLs, MBL-A and MBL-C. Diabetes induction led to an increase in MBL-C concentration, whereas no change during the study was found in the control group. The increase in MBL-C was associated with the increasing plasma glucose levels. In accordance with the observed changes in circulating MBL levels, liver expression of Mbl2mRNA (encoding MBL-C) was increased in diabetes. Mbl1expression (encoding MBL-A) did not differ between diabetic and control animals. The estimated half-life of recombinant human MBL was significantly prolonged in mice with diabetes compared with control mice. Complement activation in plasma and glomeruli did not differ between groups. We demonstrate for the first time that MBL levels increase after induction of diabetes and in parallel with increasing plasma glucose. Our findings support the previous clinical observations of increased MBL in type 1 diabetes. This change may be explained by alternations in both MBL production and turnover. PMID- 23350936 TI - Why do five-membered heterocyclic compounds sometimes not participate in polar Diels-Alder reactions? AB - The reactions of bicyclic enone (BCE, 1) with cyclopentadiene (Cp, 2) and the five-membered heterocyclic compounds (FHCs) furan 3 and N-methyl pyrrole 4 for the construction of polycyclic heterocyclic compounds have been studied at the B3LYP/6-31G* level. No reaction takes place in the absence of Lewis acid (LA) catalysts as a consequence of the high activation energy associated with these reactions. Electrophilic activation of BCE 1 by formation of a complex with the BF3 LA, 1-BF3, and solvent effects favor the reactions. However, a different reactivity is manifested by Cp 2 and FHCs 3 and 4. Thus, while the reaction of 1 BF3 with Cp 2 yields the expected exo [4 + 2] cycloadduct, the reactions of these FHCs yield Michael adducts. In any case, the reactions are characterized by the nucleophilic/electrophilic interaction between the most nucleophilic centers of these dienes and the most electrophilic center of complex 1-BF3. The greater ability of FHCs 3 and 4 to stabilize positive charges opposed to Cp 2 favors a stepwise mechanism with formation of a zwitterionic intermediate. Although in most stepwise Diels-Alder reactions, the subsequent ring closure has unappreciable barriers, in these FHCs the abstraction of a proton with regeneration of the aromatic ring becomes competitive. Thermodynamic calculations suggest that the exergonic character of the formation of the Michael adducts could be the driving force for the reactions involving FHCs. PMID- 23350937 TI - Many young men with prostate-specific antigen (PSA) screen-detected prostate cancers may be candidates for active surveillance. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Little is known as to the potential for over-treatment of young men diagnosed with prostate cancer. We show that for men aged <=55 years with PSA screen-detected disease, 45% of the tumours are classified as very low risk and 85% of these have favourable pathology, yet most are actively treated. These findings raise the spectre of over-treatment for a group of men likely to be affected by treatment side effects. OBJECTIVE: To identify a population of young men (aged <55 years at diagnosis) with very-low-risk prostate cancer (stage cT1c, with prostate-specific antigen [PSA] density of <0.15 ng/mL/g, Gleason score <=6, and <=2 positive biopsy cores with <50% tumour involvement) that may be candidates for active surveillance (AS). PATIENTS AND METHODS: We queried a Department of Defense tumour registry and hard-copy records for servicemen diagnosed with prostate cancer from 1987 to 2010. Statistical analyses were undertaken using Fisher's exact and chi-square testing. RESULTS: From 1987-1991 and 2007-2010, PSA screen detected tumours diagnosed in men aged <=55 years rose >30-fold. Data for a subset of men (174) with PSA screen-detected cancer were evaluable for disease risk assessment. Of the 174 men with screen-detected disease, 81 (47%) had very low-risk disease. Of that group, 96% (78/81) selected treatment and, of 57 men undergoing radical prostatectomy (RP), the tumours of 49 (86%) carried favourable pathology (organ confined, <10% gland involvement, Gleason <=6). CONCLUSIONS: Nearly half of young men with PSA screen-detected prostate cancer are AS candidates but the overwhelming majority seek treatment. Considering that many tumours show favourable pathology at RP, there is a possibility that these patients may benefit from AS management. PMID- 23350938 TI - More donors or more delayed graft function? A cost-effectiveness analysis of DCD kidney transplantation. AB - Expansion of the donor pool with expanded criteria donors and donation after cardiac death (DCD) donors is essential. DCD grafts result in increased rates of primary non-function (PNF) and delayed graft function (DGF). However, long-term patient and graft survival is similar between donation after brain death (DBD) donors and DCD donors. The aim of this study was to evaluate the cost effectiveness of the use of DCD donors. A Markov-based decision analytic model was created to simulate outcomes for two wait list strategies: (i) wait list composed of only DBD organs and (ii) wait list combining DBD and DCD organs. Baseline values and ranges were determined from the Scientific Registry of Transplant Recipients (SRTR) database and literature review. Sensitivity analyses were conducted to test model strength and parameter variability. The wait list strategy consisting of DBD donors only provided recipients 5.4 Quality-adjusted life years (QALYs) at $65 000/QALY, whereas a wait list strategy combining DBD + DCD donors provided recipients 6.0 QALYs at a cost of $56 000/QALY. Wait lists with DCD donors provide adequate long-term survival despite more DGF. This equates to an improvement in quality of life and decreased cost when compared to remaining on dialysis for any period of time. PMID- 23350939 TI - A case with occurrence of antidromic tachycardia after ablation of idiopathic left fascicular tachycardia: mechanism of left upper septal ventricular tachycardia. AB - A 36-year-old male presented with verapamil-sensitive narrow QRS tachycardia. The patient underwent the catheter ablation of common idiopathic left fascicular ventricular tachycardia (ILVT) 2 years ago. During narrow QRS tachycardia, the diastolic and presystolic potentials (P1 and P2) were recorded at the left septum. Activation sequences of P1 and P2 were opposite from those in common ILVT. Entrainment of P1 at the upper septum exhibited concealed fusion and S-QRS equal to P1-QRS. Radiofrequency current to P1 suppressed VT. Idiopathic left upper septal VT might be the antidromic macroreentry of the common form of ILVT. PMID- 23350940 TI - Development of liposomes loaded with anti-leishmanial drugs for the treatment of cutaneous leishmaniasis. AB - Cutaneous leishmaniasis is caused by different species of Leishmania parasites and its available treatments have not yet provided a strong consistent result. The weak response of current chemotherapeutics is due to their deficient effects on stealth parasites inside macrophages, rapid clearance from the site of action and systemic side effects in high doses. Liposomal formulation of anti leishmanial drugs could overcome these problems. In this study, different liposomal formulations of three famous anti-leishmanial drugs: Glucantime(r), miltefosine and paromomycin were prepared by a modified freeze-drying double emulsion method. Liposome size, zeta potential and encapsulation efficiency were evaluated, and their imaging was carried out by means of atomic force microscopy. Three formulations were evaluated in vivo by subcutaneous injection into skin lesions caused by Leishmania major in BALB/c mice. Encapsulation efficiency of prepared liposomes was up to 90%; however, they inherited a bimodal size distribution that caused their encapsulation efficiency to decrease to 50% during filtering sterilization. Besides, the effect of surface charge was significant on preparation procedure, size and encapsulation efficiency. All three formulations reduced amastigote counts and lesion size but only miltefosine-loaded formulations had significant therapeutic effects compared with control group (p < 0.05). PMID- 23350941 TI - A pilot study of serum selenium, vitamin D, and thyrotropin concentrations in patients with thyroid cancer. AB - BACKGROUND: Low serum selenium concentrations have been associated with a diagnosis of differentiated thyroid cancer in small studies in selenium deficient areas. We conducted a pilot study to explore associations between selenium concentrations and the diagnosis of thyroid cancer in an area of selenium sufficiency in the United States. As low 25-hydroxyvitamin D concentrations have been associated with several malignancies, we also examined 25-hydroxyvitamin D levels. METHODS: This study was designed as a pilot study of prediagnostic selenium and 25-hydroxyvitamin D concentrations. We identified 65 euthyroid patients at an academic medical center who were scheduled for thyroidectomy for thyroid cancer, suspicion of thyroid cancer, or nodular disease. Blood samples were obtained two to four weeks prior to thyroidectomy. Samples were analyzed for thyrotropin (TSH), free thyroxine, total triiodothyronine, selenium, and 25 hydroxyvitamin D levels. Concentrations of these analytes were correlated with whether the patient was diagnosed with benign or malignant disease following their thyroidectomy. In patients with thyroid cancer, the concentrations of selenium and 25-hydroxyvitamin D were correlated with various prognostic features. RESULTS: Although selenium concentrations were not significantly lower in patients with thyroid cancer, serum selenium concentrations were inversely correlated with disease stage (p = 0.011). There were no associations between vitamin D concentration and a diagnosis of thyroid cancer. Within the thyroid cancer patients, vitamin D concentrations were not associated with disease stage or any other prognostic features. In contrast, TSH concentrations were significantly higher in patients with thyroid cancer, and were positively correlated with the number of involved lymph nodes (p = 0.011) and disease stage (p = 0.022). CONCLUSION: These data confirm the association between serum TSH and advanced thyroid cancer. In addition, they also suggest a potential association between selenium concentrations and higher thyroid cancer stage. No such association was seen for 25-hydroxyvitamin D concentrations. Larger prospective studies will be required to confirm this association. If confirmed, future studies would need to determine if the association is causative in nature. If causation exists, it seems likely that selenium concentrations would influence thyroid cancer development via an independent mechanism from that of TSH. PMID- 23350942 TI - L-serine deficiency caused by genetic Phgdh deletion leads to robust induction of 4E-BP1 and subsequent repression of translation initiation in the developing central nervous system. AB - Targeted disruption in mice of the gene encoding D-3-phosphoglycerate dehydrogenase (Phgdh) results in embryonic lethality associated with a striking reduction in free L-serine and growth retardation including severe brain malformation. We previously observed a severe impairment in neurogenesis of the central nervous system of Phgdh knockout (KO) embryos and a reduction in the protein content of their brains. Although these findings suggest that L-serine deficiency links attenuation of mRNA translation to severe developmental malformation of the central nervous system, the underlying key molecular event remains unexplored. Here we demonstrate that mRNA of Eif4ebp1 encoding eukaryotic initiation factor 4 binding protein 1 and its protein, 4E-BP1, are markedly induced in the central nervous system of Phgdh KO embryos, whereas a modest induction is observed in the liver. The increase in 4E-BP1 was associated with a decrease in the cap initiation complex in the brain, as shown by lower levels of eukaryotic translation initiation factor 4G bound to eukaryotic translation initiation factor 4E (eIF4E) and increased eIF4E interaction with 4E-BP1 based on 7-methyl-GTP chromatography. eIF4E protein and polysomes were also diminished in Phgdh KO embryos. Induction of Eif4ebp1 mRNA and of 4E-BP1 was reproduced in mouse embryonic fibroblasts established from Phgdh KO embryos under the condition of L-serine deprivation. Induction of Eif4ebp1 mRNA was suppressed only when L serine was supplemented in the culture medium, indicating that reduced L-serine availability regulates the induction of Eif4ebp1/4E-BP1. These data suggest that elevated levels of 4E-BP1 may be involved in a mechanism to arrest brain development in Phgdh KO embryos. PMID- 23350943 TI - Interventions for impaired bladders in paediatric renal transplant recipients with lower urinary tract dysfunction. AB - Dysfunctional bladders in paediatric patients were thought to be a contraindication for renal transplantation, but advances in surgical techniques have meant that surgical correction can allow safe transplantation. This study compares the outcomes of renal transplantation for different interventions, and the timing of such interventions, in relation to transplantation. We identified all paediatric renal transplant recipients with LUTD that received intervention for their impaired bladders at two hospitals between 2002 and 2010. Outcome measures included patient and graft survival, perioperative complications, UTI incidence, acute rejection episodes and serum creatinine levels. A total of 288 allografts were transplanted, 77 were in 75 children with LUTD, of which 46 received intervention. Patient survival was 100% in the intervention group and 97% in the nonintervention group (P = 0.815). Death-censored graft survival was 96% and 100% respectively (P = 0.688). In the groups receiving intervention pretransplant or post-transplant, graft survival rates were 95% and 100% respectively (P = 0.476). The follow-up serum creatinine levels were higher in the pretransplant intervention group (P < 0.001). Interventions for dysfunctional bladders can be performed safely in paediatric renal transplant recipients. The mode of intervention and timing of intervention, in relation to transplant, do not influence outcomes if guided by careful assessment and investigation. PMID- 23350944 TI - Genotypic variation of the glucosinolate profile in pak choi (Brassica rapa ssp. chinensis). AB - Thirteen different pak choi (Brassica rapa ssp. chinensis) cultivars were characterized regarding their glucosinolate profile analyzed by HPLC-DAD-MS. The identified glucosinolates were subjected to principal component analysis, and three distinct groups of pak choi sprouts were identified. Group differences were marked mainly by variations in the aliphatic glucosinolate profile such as differing levels of 3-butenyl glucosinolate and 2-hydroxy-3-butenyl glucosinolate as well as by their varying proportional ratios. In addition, the three groups of pak choi sprouts varied by the presence or absence of 2-hydroxy-4-pentenyl glucosinolate and in level and composition of butyl glucosinolates. This classification is reflected by relative mRNA expression level of 2-oxoacid dependent dioxygenase. As in sprouts, the major glucosinolates in mature leaves were found to be the aliphatic glucosinolates. However, unlike in sprouts, an additional aliphatic glucosinolate, 5-methylsulfinylpentyl glucosinolate, was detected as characteristic ontogenetic variation in mature leaves in 12 of the 13 pak choi cultivars analyzed. PMID- 23350945 TI - Investigation of the interaction of gamma-Al2O3 with aqueous solutions of dimethyl methylphosphonate using infrared multiple internal reflection spectroscopy. AB - The interaction of dilute solutions of dimethyl methylphosphonate (DMMP) in H(2)O with thin porous layers of gamma-Al(2)O(3) has been studied under steady-state conditions using infrared multiple-internal-reflection spectroscopy. Upon the initial introduction of the DMMP solution to a previously H(2)O-saturated surface, DMMP diffuses into the porous layer and displaces weakly hydrogen-bonded H(2)O molecules. This is accompanied by hydrolysis of the gamma-Al(2)O(3) to form Al(OH)(3) and/or AlO(OH). The P?O group of DMMP interacts predominantly with H(2)O and gives no clear indication of bonding to the oxide surface itself, from which it is inferred that the displacement of weakly adsorbed H(2)O results from the interaction of acidic Al-OH sites with the methoxy O atoms of DMMP. No hydrolysis of the DMMP, either in solution or in contact with the oxide, was detectable under the present conditions. The results have practical implications in the decontamination of materials following exposure to toxic reagents related to DMMP. PMID- 23350946 TI - Prognosis of diabetic gastroparesis--a 25-year evaluation. AB - AIM: To evaluate the prognosis of diabetic gastroparesis. METHODS: Eighty-six patients with diabetes had measurements of gastric emptying of a mixed meal using a dual isotope test of solid and liquid meal components, mean blood glucose levels, HbA1c , upper gastrointestinal symptoms and autonomic nerve function performed in 1984-1989. These patients were followed up in 2011, after a mean period of ~25 years. RESULTS: Of the 86 patients, gastric emptying of solid (the percentage remaining in the stomach at 100 min) was delayed in 35 (41%), and of liquid (the time taken for 50% of the liquid to empty) was delayed in 38 (44%). In 2011, 53 patients were known to be alive, 29 had died and four were lost to follow-up. In those who had died, both age at baseline (P < 0.001) and the score for autonomic nerve dysfunction (P < 0.001) were greater than those who were alive, while there was no difference in emptying of either the solid or liquid between the two groups. When patients with delayed gastric emptying were divided according to the median value ('delayed' and 'markedly delayed'), mortality tended to be greater in the 'markedly delayed' group for both solids (P = 0.12) and liquids (P = 0.09). Of the 82 patients who could be followed up, 23 of the 35 (66%) with delayed gastric emptying of solid and 25 of 38 (66%) with delayed gastric emptying of liquid were alive. After adjustment for age and autonomic dysfunction, there was no association between gastric emptying of either solid or liquid and death. CONCLUSIONS: Over a period of ~25 years, diabetic gastroparesis is apparently not usually associated with a poor prognosis, or increased mortality. ABBREVIATIONS: T100 min, the percentage remaining in the stomach at 100 mins; T50%, the time taken for 50% of the liquid to empty. PMID- 23350947 TI - Discriminative ability and predictive validity of the timed up and go test in identifying older people who fall: systematic review and meta-analysis. AB - OBJECTIVES: To investigate the discriminative ability and diagnostic accuracy of the Timed Up and Go Test (TUG) as a clinical screening instrument for identifying older people at risk of falling. DESIGN: Systematic literature review and meta analysis. SETTING AND PARTICIPANTS: People aged 60 and older living independently or in institutional settings. MEASUREMENTS: Studies were identified with searches of the PubMed, EMBASE, CINAHL, and Cochrane CENTRAL data bases. Retrospective and prospective cohort studies comparing times to complete any version of the TUG of fallers and non-fallers were included. RESULTS: Fifty-three studies with 12,832 participants met the inclusion criteria. The pooled mean difference between fallers and non-fallers depended on the functional status of the cohort investigated: 0.63 seconds (95% confidence (CI) = 0.14-1.12 seconds) for high functioning to 3.59 seconds (95% CI = 2.18-4.99 seconds) for those in institutional settings. The majority of studies did not retain TUG scores in multivariate analysis. Derived cut-points varied greatly between studies, and with the exception of a few small studies, diagnostic accuracy was poor to moderate. CONCLUSION: The findings suggest that the TUG is not useful for discriminating fallers from non-fallers in healthy, high-functioning older people but is of more value in less-healthy, lower-functioning older people. Overall, the predictive ability and diagnostic accuracy of the TUG are at best moderate. No cut-point can be recommended. Quick, multifactorial fall risk screens should be considered to provide additional information for identifying older people at risk of falls. PMID- 23350948 TI - BRAIN: a universal tool for high-throughput calculations of the isotopic distribution for mass spectrometry. AB - This Letter presents the R-package implementation of the recently introduced polynomial method for calculating the aggregated isotopic distribution called BRAIN (Baffling Recursive Algorithm for Isotopic distributioN calculations). The algorithm is simple, easy to understand, highly accurate, fast, and memory efficient. The method is based on the application of the Newton-Girard theorem and Viete's formulae to the polynomial coding of different aggregated isotopic variants. As a result, an elegant recursive equation is obtained for computing the occurrence probabilities of consecutive aggregated isotopic peaks. Additionally, the algorithm also allows calculating the center-masses of the aggregated isotopic variants. We propose an implementation which is suitable for high-throughput processing and easily customizable for application in different areas of mass spectral data analyses. A case study demonstrates how the R-package can be applied in the context of protein research, but the software can be also used for calculating the isotopic distribution in the context of lipidomics, metabolomics, glycoscience, or even space exploration. More materials, i.e., reference manual, vignette, and the package itself are available at Bioconductor online (http://www.bioconductor.org/packages/release/bioc/html/BRAIN.html). PMID- 23350949 TI - How to reduce mortality in ST-elevation myocardial infarction patients treated with primary percutaneous coronary interventions: cut the bleeding. AB - BACKGROUND: In-hospital mortality for ST-elevation myocardial infarction (STEMI) has declined thanks to a greater use of primary percutaneous coronary interventions (PCI) associated with more effective antiplatelet and anticoagulant drugs. In this regard, bivalirudin has been shown to decrease total and cardiac mortality as compared to unfractionated heparin (UFH). OBJECTIVE: The primary purpose of this analysis is to evaluate the hypothesis that the reduction of in hospital bleeding is the most plausible explanation for the improved survival of STEMI patients treated with bivalirudin during primary PCI. The secondary objective is to reconsider the prognostic significance of the radial access alone or in association with bivalirudin on the basis of the published data. METHODS: We have done a comprehensive evaluation of the main and related publications of the HORIZONS-AMI trial in addition to an extensive research by Medline of randomized trials evaluating the prognostic impact of radial access as compared with the femoral one in primary PCI. RESULTS: In the HORIZONS-AMI trial bivalirudin resulted in significantly lower rates of the 30 day primary endpoint (defined as major adverse ischemic outcomes plus major bleeding) over UFH plus GPI, largely due to the significantly lower rate of the protocol-defined major bleeding. All-cause and cardiac mortality were also reduced in the bivalirudin arm at 3 year follow-up. Recent studies have also shown that the use of the radial instead of the femoral approach for primary PCI is associated with reduced bleeding as well as reduced mortality. CONCLUSIONS: Our research suggests that decreasing bleeding by either a pharmacologic strategy (use of bivalirudin) or a technical approach (the transradial access) improves survival in STEMI patients undergoing primary PCI. The validity of this hypothesis should be confirmed by specific randomized trials. PMID- 23350950 TI - Electrocatalytic water oxidation with a copper(II) polypeptide complex. AB - A self-assembly-formed triglycylglycine macrocyclic ligand (TGG(4-)) complex of Cu(II), [(TGG(4-))Cu(II)-OH(2)](2-), efficiently catalyzes water oxidation in a phosphate buffer at pH 11 at room temperature by a well-defined mechanism. In the mechanism, initial oxidation to Cu(III) is followed by further oxidation to a formal "Cu(IV)" with formation of a peroxide intermediate, which undergoes further oxidation to release oxygen and close the catalytic cycle. The catalyst exhibits high stability and activity toward water oxidation under these conditions with a high turnover frequency of 33 s(-1). PMID- 23350951 TI - Highly transparent and flexible nanopaper transistors. AB - Renewable and clean "green" electronics based on paper substrates is an emerging field with intensifying research and commercial interests, as the technology combines the unique properties of flexibility, cost efficiency, recyclability, and renewability with the lightweight nature of paper. Because of its excellent optical transmittance and low surface roughness, nanopaper can host many types of electronics that are not possible on regular paper. However, there can be tremendous challenges with integrating devices on nanopaper due to its shape stability during processing. Here we demonstrate for the first time that flexible organic field-effect transistors (OFETs) with high transparency can be fabricated on tailored nanopapers. Useful electrical characteristics and an excellent mechanical flexibility were observed. It is believed that the large binding energy between polymer dielectric and cellulose nanopaper, and the effective stress release from the fibrous substrate promote these beneficial properties. Only a 10% decrease in mobility was observed when the nanopaper transistors were bent and folded. The nanopaper transistor also showed excellent optical transmittance up to 83.5%. The device configuration can transform many semiconductor materials for use in flexible green electronics. PMID- 23350952 TI - Circulating IL-6, IL-17 and vitamin D in hepatocellular carcinoma: potential biomarkers for a more favorable prognosis? AB - Hepatitis C virus (HCV) infects primarily hepatocytes, leads to development of fibrosis and/or cirrhosis of the liver and is a significant factor for developing hepatocellular carcinoma (HCC). Evidence indicates that liver fibrosis contains uncontrolled inflammation as a part of its etiology. Normal cell-mediated immunity plays a central role in the mechanisms involved in viral clearance/persistence in the liver. In this context, cytokines modulate the immune system and exert direct anti-viral activity. To this end, this study investigated potential associations of serum IL-17 and IL-6 with exacerbation of hepatic damage in chronic HCV patients to determine their utility as prognostic markers for potential development of HCC. Chronic HCV-patients were recruited, divided into groups according to degree of liver damage, i.e. patients with peri hepatic fibrosis, hepatic cirrhosis, or HCC, and had their blood collected for analysis of liver function and serum IL-6 and IL-17 levels. Interestingly, increases in serum IL-17 levels in the study groups were associated with aggravation of the clinical state from HCV to cirrhosis and then to HCC. Serum IL 6 levels followed a similar pattern. The association of both cytokines with progressive exacerbation of the initial HCV-induced liver damage was further confirmed by correlation analysis that revealed positive correlations between HCV RNA titer and IL-17 (+0.951, p < 0.05) and IL-6 (+0.85, p < 0.05). A receiver operating characteristics (ROC) analysis revealed their beneficial addition as promising biomarkers for a better prognostic profile of HCC. Interestingly, a significant progressive decline in the active vitamin D status was noted in all three clinical states, and these too were associated with progressive liver disease. This study confirms the necessity of adding screening for IL-6 and IL-17 and vitamin D to that of the classic marker AFP for patients with HCV and cirrhosis to hopefully permit clinicians to initiate measures that ultimately might mitigate/delay development of HCC in these infected patients. PMID- 23350953 TI - Anti-inflammatory effect of Mentha longifolia in lipopolysaccharide-stimulated macrophages: reduction of nitric oxide production through inhibition of inducible nitric oxide synthase. AB - Mentha longifolia is an aromatic plant used in flavoring and preserving foods and as an anti-inflammatory folk medicine remedy. The present study assessed the effects of M. longifolia extracts, including essential oil and crude methanol extract and its fractions (ethyl acetate, butanol and hexane), on nitric oxide (NO) production and inducible NO synthase (iNOS) mRNA expression in lipopolysaccharide (LPS)-stimulated J774A.1 cells using real-time polymerase chain reaction (PCR). The cytotoxic effects of the extracts on the cells were examined and non-cytotoxic concentrations (<0.2 mg/ml) were used to examine their effects on NO production and iNOS mRNA expression. Only the hexane fraction that contained high levels of phenolic and flavonoid compounds at concentrations from 0.05-0.20 mg/ml significantly reduced NO production in LPS-stimulated cells (p < 0.001). Real-time PCR analysis indicated the ability of this fraction at the same concentrations to significantly decrease iNOS as well as TNFalpha mRNA expression in the cells (p < 0.001). All extracts were able to scavenge NO radicals in a concentration-dependent manner. At concentrations greater than 0.2 mg/ml, total radicals were 100% scavenged. In conclusion, M. longifolia possibly reduces NO secretion in macrophages by scavenging NO and inhibiting iNOS mRNA expression, and also decreases TNFalpha pro-inflammatory cytokine expression, thus showing its usefulness in the inflammatory disease process. PMID- 23350954 TI - Pre-natal exposure to perfluoroalkyl substances may be associated with altered vaccine antibody levels and immune-related health outcomes in early childhood. AB - Perfluoroalkyl substances (PFAS) are suggested to have immunosuppressive effects; exposure in utero and in the first years of life is of special concern as fetuses and small children are highly vulnerable to toxicant exposure. The objective of this study was to investigate the effect of pre-natal exposure to PFAS on responses to pediatric vaccines and immune-related health outcomes in children up to 3 years of age. In the prospective birth-cohort BraMat, a sub-cohort of the Norwegian Mother and Child Cohort Study (MoBa), pregnant women from Oslo and Akershus, Norway, were recruited during 2007-2008. Three annual questionnaire based follow-ups were performed. Blood samples were collected from the mothers at the time of delivery and from the children at the age of 3 years. As a measure of pre-natal exposure to PFAS, the concentrations of perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) were determined in maternal blood from 99 BraMat participants. Main outcome measures were anti-vaccine antibody levels, common infectious diseases and allergy- and asthma-related health outcomes in the children up to the age of 3 years. There was an inverse association between the level of anti rubella antibodies in the children's serum at age 3 years and the concentrations of the four PFAS. Furthermore, there was a positive association between the maternal concentrations of PFOA and PFNA and the number of episodes of common cold for the children, and between PFOA and PFHxS and the number of episodes of gastroenteritis. No associations were found between maternal PFAS concentrations and the allergy- and asthma-related health outcomes investigated. The results indicate that pre-natal exposure to PFAS may be associated with immunosuppression in early childhood. PMID- 23350955 TI - Imaging and percutaneous occlusion of a large aneurysm of the ductus arteriosus in an infant with Loeys-Dietz syndrome. AB - Loeys-Dietz is a multisystem congenital syndrome that comprises craniofacial and cutaneous abnormalities as well as structural cardiac defects. One of its key pathological features is an aggressive widespread vasculopathy that can manifest as aortic or cerebral aneurysms, which is prone to dissection and rupture. We report a case of a large aneurysm of the ductus arteriosus in a patient with Loeys-Dietz syndrome, successfully occluded by interventional catheterization. PMID- 23350956 TI - Improving attention control in dysphoria through cognitive training: transfer effects on working memory capacity and filtering efficiency. AB - Impaired filtering of irrelevant information from working memory is thought to underlie reduced working memory capacity for relevant information in dysphoria. The current study investigated whether training-related gains in working memory performance on the adaptive dual n-back task could result in improved inhibitory function. Efficacy of training was monitored in a change detection paradigm allowing measurement of a sustained event-related potential asymmetry sensitive to working memory capacity and the efficient filtering of irrelevant information. Dysphoric participants in the training group showed training-related gains in working memory that were accompanied by gains in working memory capacity and filtering efficiency compared to an active control group. Results provide important initial evidence that behavioral performance and neural function in dysphoria can be improved by facilitating greater attentional control. PMID- 23350957 TI - Effect of sprint interval versus continuous cycling on postprandial lipaemia. AB - The present study compares the effect of a single bout of sprint interval cycling against continuous cycling on postprandial lipaemia. Participants were nine healthy volunteers (five male), aged 20-26 years. Each participant undertook three 2-d trials in a random order. On day 1, participants rested (control), undertook a single 20 minute bout of continuous cycling at 70% of maximum oxygen uptake or completed four 30-second bouts of sprint interval cycling on a cycle ergometer, separated by 4.5 minutes of recovery. On day 2, participants rested and consumed a test meal (75% fat). Triacylglycerol concentrations were measured fasting and for 6 hours after the meal. The total area under the triacylglycerol concentration against time curve was similar among trials (mean (SD): control, 9.51 (3.50) mmol . l(-1) compared with continuous cycling, 8.58 (3.08) mmol . l( 1) compared with sprint interval cycling, 9.28 (1.89) mmol . l(-1); P = 0.517). There was no difference in the pattern of TAG response to the test meal among trials (trial * time interaction, P = 0.637). The present study found no effect of sprint interval or continuous cycling on postprandial lipaemia, with the reason for this finding unclear. Future studies need to more precisely determine the relationship between exercise and postprandial lipaemia across different types of exercise. PMID- 23350958 TI - Colonic electrical stimulation: potential use for treatment of delayed colonic transit. AB - AIM: Recently there has been an increased interest in using electrical stimulation to regulate gut motility generally and particularly for the treatment of slow-transit constipation. In this preliminary canine study, we aimed to study the effects of colonic electrical stimulation (CES) on colonic motility and transit. METHOD: Nine dogs, each equipped with a pair of serosal colon electrodes and a proximal colon cannula were randomized to receive: (i) sham-CES, (ii) long pulse CES (20 cpm, 300 ms, 6 mA) or (iii) pulse train CES (40 Hz, 6 ms, 6 mA). Animals underwent assessment of colonic contractions via manometry, and of colonic transit by inserting 24 radiopaque markers via the colonic cannula and radiographically monitoring the markers at 2, 4 and 6 h following their insertion. The colonic transit was assessed by the geometric centre. RESULTS: We found that, compared with sham-CES, pulse train CES, but not long pulse CES, significantly increased the overall colonic motility index twofold and accelerated the colonic transit by 104% at 2 h, by 60% at 4 h and by 31% at 6 h (P = 0.01, P = 0.02 and P = 0.03 vs sham-CES at 2, 4 and 6 h, respectively). The accelerating effect of pulse train CES was found to be mediated via both cholinergic and nitrergic pathways. CONCLUSION: CES with pulse trains has prokinetic effects on colonic contractions and transit in healthy dogs, mediated via the cholinergic and nitrergic pathways. Further clinical studies are warranted to explore the therapeutic potential of CES for slow colonic transit constipation. PMID- 23350959 TI - The role of speed versus working memory in predicting learning new information in multiple sclerosis. AB - The most common cognitive impairments in multiple sclerosis (MS) have been documented in specific domains, including new learning and memory, working memory, and information processing speed. However, little attempt has been made to increase our understanding of their relationship to one another. While recent studies have shown that processing speed impacts new learning and memory abilities in MS, the role of working memory in this relationship has received less attention. The present study examines the relative contribution of impaired working memory versus processing speed in new learning and memory functions in MS. Participants consisted of 51 individuals with clinically definite MS. Participants completed two measures of processing speed, two measures of working memory, and two measures of episodic memory. Data were analyzed via correlational and multiple regression analysis. Results indicate that the variance in new learning abilities in this sample was primarily associated with processing speed, with working memory exerting much less of an influence. Results are discussed in terms of the role of cognitive rehabilitation of new learning and memory abilities in persons with MS. PMID- 23350961 TI - Evaluation of a theory of planned behaviour-based breastfeeding intervention in Northern Irish schools using a randomized cluster design. AB - OBJECTIVE: The aim of this research was to evaluate the effectiveness of a school based intervention designed to enhance young people's motivations to breastfeed. DESIGN: A cluster randomized controlled trial was conducted involving 50 post primary schools from across Northern Ireland. However, dropout and exclusion criteria utilized for the current study resulted in an effective sample size of 42 schools. METHODS: The intervention was delivered in two 35-min classroom sessions targeting those beliefs identified by the theory of planned behaviour (TPB) as significant in predicting motivation to breastfeed. Questionnaires incorporating the key components of the TPB were administered to all intervention and control schools at baseline, 1 and 6 months post-intervention. Multi-level modelling was used to analyse the data. RESULTS: Findings suggest that the intervention was effective in that it increased females' intentions to breastfeed, expanded their knowledge and led to more favourable attitudes and perceptions of subjective norms. Notably, females' knowledge increased more in secondary schools than in grammar schools irrespective of whether they were control or intervention schools. CONCLUSION: The research has provided evidence to support the use of the TPB in the design and evaluation of an intervention to increase females' intentions to breastfeed. PMID- 23350960 TI - Transcriptional programming during cell wall maturation in the expanding Arabidopsis stem. AB - BACKGROUND: Plant cell walls are complex dynamic structures that play a vital role in coordinating the directional growth of plant tissues. The rapid elongation of the inflorescence stem in the model plant Arabidopsis thaliana is accompanied by radical changes in cell wall structure and chemistry, but analysis of the underlying mechanisms and identification of the genes that are involved has been hampered by difficulties in accurately sampling discrete developmental states along the developing stem. RESULTS: By creating stem growth kinematic profiles for individual expanding Arabidopsis stems we have been able to harvest and pool developmentally-matched tissue samples, and to use these for comparative analysis of global transcript profiles at four distinct phases of stem growth: the period of elongation rate increase, the point of maximum growth rate, the point of stem growth cessation and the fully matured stem. The resulting profiles identify numerous genes whose expression is affected as the stem tissues pass through these defined growth transitions, including both novel loci and genes identified in earlier studies. Of particular note is the preponderance of highly active genes associated with secondary cell wall deposition in the region of stem growth cessation, and of genes associated with defence and stress responses in the fully mature stem. CONCLUSIONS: The use of growth kinematic profiling to create tissue samples that are accurately positioned along the expansion growth continuum of Arabidopsis inflorescence stems establishes a new standard for transcript profiling analyses of such tissues. The resulting expression profiles identify a substantial number of genes whose expression is correlated for the first time with rapid cell wall extension and subsequent fortification, and thus provide an important new resource for plant biologists interested in gene discovery related to plant biomass accumulation. PMID- 23350963 TI - Chloride-dependent spectral tuning mechanism of L-group cone visual pigments. AB - Most vertebrates have one type of rhodopsin and multiple types of cone visual pigments with different absorption maxima in their retinas. The spectral sensitivities of multiple cone visual pigments contribute to color discrimination in these animals. Vertebrate cone visual pigments are classified into four groups based on their amino acid sequences. Among these groups, many pigments in the longer wavelength-sensitive group (L-group) have a unique spectral tuning mechanism, that is, the red-shift of absorption maximum induced by the binding of chloride to His181 of the protein moiety (chloride effect). However, a few pigments such as mouse green and guinea pig green pigments in L-group have a tyrosine residue instead of a histidine at position 181. Interestingly, mouse green shows no chloride effect, whereas guinea pig green shows a significant chloride effect. In the present site-directed mutational analysis, we revealed that this difference in the chloride effect in rodent pigments is completely explained by the replacements of two residues at positions 289 and 292. In addition, mutations at positions 181, 289, and 292 abolished 80% of the chloride effect in monkey red and green. Further analysis with chimeras showed that the residual 20% of the chloride effect could be attributed to helical interactions within the pigments. Thus, we concluded that these three amino acid residues are the main determinants of the chloride-dependent spectral shift in L-group pigments. PMID- 23350962 TI - The nuclear factor-kappaB pathway down-regulates expression of the NKG2D ligand H60a in vitro: implications for use of nuclear factor-kappaB inhibitors in cancer therapy. AB - NKG2D ligands are cell surface proteins that activate NKG2D, a receptor used by natural killer (NK) cells to detect virus-infected and transformed cells. When tumour cells express high levels of NKG2D ligands, they are rejected by the immune system. Hence, reagents that increase NKG2D ligand expression on tumour cells can be important for tumour immunotherapy. To identify genes that regulate the NKG2D ligand H60a, we performed a microarray analysis of 3' methylcholanthrene-induced sarcoma cell lines expressing high versus low H60a levels. A20, an inhibitor of nuclear factor-kappaB (NF-kappaB) activation, was differentially expressed in H60a-hi sarcoma cells. Correspondingly, treatment of tumour cells with inhibitors of NF-kappaB activation, such as sulfasalazine (slz), BAY-11-7085, or a non-phosphorylatable IkappaB, led to increased levels of H60a protein, whereas transduction of cells with an active form of IkappaB kinase beta (IKKbeta) led to decreased levels of H60a. The regulation probably occurred at the transcriptional level, because NF-kappaB pathway inhibition led to increased H60a transcripts and promoter activity. Moreover, treatment of tumour cells with slz enhanced their killing by NK cells in vitro, suggesting that NF kappaB inhibition can lead to tumour cell rejection. Indeed, when we blocked the NF-kappaB pathway specifically in tumour cells, there was decreased tumour growth in wild-type but not immune-deficient mice. Our results suggest that reagents that can block NF-kappaB activity specifically in the tumour and not the host immune cells would be efficacious for tumour therapy. PMID- 23350964 TI - Aripiprazole in the treatment of Alzheimer's disease. AB - INTRODUCTION: Psychosis is a common and difficult to treat symptom in Alzheimer's disease (AD). It is a cause of diminished quality of life and caregiver distress. Atypical antipsychotics are frequently used for the treatment of dementia-related psychosis, despite FDA warnings because of increased mortality associated with the use of these medications in dementia patients. Aripiprazole is a newer atypical antipsychotic drug with partial agonist activity at dopamine receptors and antagonist activity at 5-HT(2A) receptors, with a low side-effect profile. AREAS COVERED: This descriptive review gives a short overview of the pathology and epidemiology of AD, including psychotic symptoms, and describes the mode of action of aripiprazole and results of preclinical studies. Finally, randomized controlled trials evaluating the use of aripiprazole in AD-related psychosis and agitation are discussed. Whenever relevant, meta-analytical data from literature are referred to. EXPERT OPINION: In randomized placebo-controlled clinical trials, aripiprazole shows modest efficacy in the treatment of AD-related psychosis. Neuropsychiatric symptoms alleviated were predominantly psychotic features and agitation. In individual trials, aripiprazole was generally well tolerated, serious side effects were seldom reported and included accidental injury and somnolence. Meta-analyses however demonstrated increased mortality as a class effect for atypical, but also for typical antipsychotics. No increased cardiovascular outcomes, cerebrovascular accidents, increased appetite or weight gain were demonstrated in meta-analyses for aripiprazole-treated patients with psychosis of dementia. Aripiprazole was found to induce sedation. Aripiprazole should only be used in selected patient populations resistant to non pharmacological treatment with persisting or severe psychotic symptoms and/or agitation, and in which symptoms lead to significant morbidity, patient suffering and potential self-harm. The indication for continuing treatment should be revised regularly. PMID- 23350965 TI - Long-term outcome of small, organ-confined renal cell carcinoma (RCC) is not always favourable. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Small, organ-confined renal cell carcinoma (RCC) generally has favourable pathological characteristics and a good prognosis. However, late recurrence is a known characteristic of the biological behaviour of RCC and no consensus has been established for surveillance protocols from 5 years after radical or partial nephrectomy. In the present study with long-term follow-up of patients with small RCCs, 18 of 172 patients (10.5%) with pT1a RCC developed recurrence and eight of these (4.7%) died from cancer. Patients with microvascular invasion had a higher risk for cancer death than those without (P < 0.001, Log-rank test). Therefore long-term follow-up is required after surgery, particularly when the disease has microvascular invasion. OBJECTIVES: To identify the long-term clinical course of small, organ-confined renal cell carcinoma (RCC). To detect the risk factors of recurrence and of cancer death in small RCC. PATIENTS AND METHODS: Retrospectively reviewed 172 patients who were pathologically diagnosed as having pT1a RCC without metastasis at our institution from 1980 to 2005. All pathology slides were re-reviewed by a single experienced pathologist. Associations of microvascular invasion (MVI), development of metastasis, and cancer death were evaluated using Cox proportional hazards analysis. RESULTS: During a median (range) follow-up of 104.5 (8-308) months, 18 patients (10.5%) developed progression and eight patients (4.7%) died from cancer. Kaplan-Meier curves showed higher cancer-specific survival (CSS) in patients without MVI (P < 0.001). In multivariate analysis, MVI was the only factor that reached statistical significance (P = 0.006). The 10-year CSS rates were 85.1% and 96.5% in patients with and without MVI, respectively. CONCLUSIONS: Patients with MVI have worse survival than those without MVI. This suggests that long-term follow-up of patients with small RCCs is needed because of the risk of recurrence and cancer death even 10 years after surgery, particularly when the disease has apparent MVI. PMID- 23350967 TI - Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): an on-treatment analysis. AB - BACKGROUND: In the Ventricular Tachycardia Ablation in Coronary Heart Disease (VTACH) study, an intention-to-treat approach was used and may have diminished the observed degree of treatment effect. We present a subanalysis of the VTACH study by treatment actually received. METHODS AND RESULTS: The VTACH study was a prospective, open, randomized controlled trial, undertaken in 16 European centers, comparing defibrillator implantation with and without ventricular tachycardia (VT) ablation in patients with stable VT, previous myocardial infarction, and reduced left-ventricular ejection fraction. Of the 52 patients in the ablation group, 7 (13%) did not receive VT ablation and 19% of patients assigned to implantable cardioverter defibrillator (ICD) only treatment group crossed over and had an ablation. The primary endpoint (first recurrence of any documented VT or ventricular fibrillation [VF]) was reached after a median of 19.5 months in the ablation group and 5.9 months in the ICD only group (P = 0.01). Overall, 685 VT/VF events occurred per year of follow-up in 22 patients of the ablation group and 4,986 events in 43 patients of the control group (P = 0.024). In the ICD only group, median numbers of VT/VF episodes were 25 (IQR 5.8 45.3) and 1.5 (IQR 0-24.8) per patient and year before and after crossover (n = 12), respectively. CONCLUSION: On-treatment analysis of the VTACH study emphasizes the effectiveness of VT ablation in patients receiving ICD treatment because of monomorphic VT post myocardial infarction. VT ablation clearly prolonged time to recurrence of VT/VF episodes and markedly decreased VT/VF burden. PMID- 23350966 TI - Inflammation in the setting of chronic allograft dysfunction post-kidney transplant: phenotype and genotype. AB - BACKGROUND: Chronic allograft dysfunction (CGD) is a common outcome in kidney transplants, but its pathogenesis is unclear. We investigated the CGD phenotype and single-nucleotide polymorphisms (SNPs) associated with CGD. METHOD: This prospective study enrolled 2336 transplants from seven transplant centers in North America. CGD was defined as a >25% rise in serum creatinine relative to a three-month post-transplant baseline, requiring a kidney biopsy. We genotyped 2724 SNPs in the initial 979 transplants, which form the test cohort. RESULTS: CGD occurred 11.2 times per 100 person-years at a median of 509 +/- 387 days from the three-month baseline. CGD was independently associated with death-censored, allograft failure, in an adjusted analysis [HR=20.6 (11.8-35.8, p < 0.001)]. Among 366 transplant recipients with CGD, 91% had inflammation on biopsy scores. 94 (26%) had inflammatory changes consistent with a diagnosis of concomitant acute rejection. SNPs in FM06 and FM03, potential drug metabolism genes, were associated with CGD, after accounting for multiple testing. CONCLUSION: CGD phenotype with concomitant inflammation is associated with increased risk of allograft failure. SNPs associated with CGD in novel drug metabolism and transport genes, will be validated in subsequent transplants. PMID- 23350968 TI - Excess nutrient supply in early life and its later metabolic consequences. AB - Suboptimal nutrition in early life, both in utero and during infancy, is linked to increased risk of adult obesity and its associated adverse metabolic health problems. Excess nutrient supply during early life can lead to metabolic programming in the offspring. Such overnutrition can occur in the offspring of obese mothers, the offspring of mothers who gain excess weight during gestation, infants of diabetic mothers and infants who undergo rapid growth, particularly weight gain, during early infancy. Postnatal overnutrition is particularly detrimental for infants who are born small for gestational age, who are overfed to attain 'catch-up growth'. Potential mechanisms underlying metabolic programming that results from excess nutrition during early life include resetting of hypothalamic energy sensing and appetite regulation, altered adipose tissue insulin sensitivity and impaired brown adipose tissue function. More detailed understanding of the mechanisms involved in metabolic programming could enable the development of therapeutic strategies for ameliorating its ill effects. Research in this field could potentially identify optimal and appropriate preventative interventions for a burgeoning population at risk of increased mortality and morbidity from obesity and its concomitant metabolic conditions. PMID- 23350969 TI - Primer effect in the detection of mitochondrial DNA point heteroplasmy by automated sequencing. AB - The correct detection of mitochondrial DNA (mtDNA) heteroplasmy by automated sequencing presents methodological constraints. The main goals of this study are to investigate the effect of sense and distance of primers in heteroplasmy detection and to test if there are differences in the accurate determination of heteroplasmy involving transitions or transversions. A gradient of the heteroplasmy levels was generated for mtDNA positions 9477 (transition G/A) and 15,452 (transversion C/A). Amplification and subsequent sequencing with forward and reverse primers, situated at 550 and 150 bp from the heteroplasmic positions, were performed. Our data provide evidence that there is a significant difference between the use of forward and reverse primers. The forward primer is the primer that seems to give a better approximation to the real proportion of the variants. No significant differences were found concerning the distance at which the sequencing primers were placed neither between the analysis of transitions and transversions. The data collected in this study are a starting point that allows to glimpse the importance of the sequencing primers in the accurate detection of point heteroplasmy, providing additional insight into the overall automated sequencing strategy. PMID- 23350970 TI - Zn(OTf)2-promoted chemoselective esterification of hydroxyl group bearing carboxylic acids. AB - Selective esterification of aliphatic and aromatic carboxylic acids with various alcohols is studied using triphenylphosphine, I2, and a catalytic amount of Zn(OTf)2. Use of this catalyst allows the formation of esters at a faster rate with good to excellent yield by activating the in situ generated acyloxyphosphonium ion intermediate. During the esterification process, both their aromatic and aliphatic hydroxyl groups are fully preserved from transesterification. The results show that the bulkiness and the reactivity of this doubly activated intermediate III control the selectivity and the rate of the reaction, respectively. The method is also useful for direct amidation reactions. PMID- 23350971 TI - Long-term oral administration of melatonin improves spatial learning and memory and protects against cholinergic degeneration in middle-aged Ts65Dn mice, a model of Down syndrome. AB - Ts65Dn mice (TS), the most commonly used model of Down syndrome (DS), exhibit phenotypic characteristics of this condition. Both TS mice and DS individuals present cognitive disturbances, age-related cholinergic degeneration, and increased brain expression of beta-amyloid precursor protein (AbetaPP). These neurodegenerative processes may contribute to the progressive cognitive decline observed in DS. Melatonin is a pineal indoleamine that has been reported to reduce neurodegenerative processes and improve cognitive deficits in various animal models. In this study, we evaluated the potentially beneficial effects of long-term melatonin treatment on the cognitive deficits, cholinergic degeneration, and enhanced AbetaPP and beta-amyloid levels of TS mice. Melatonin was administered for 5 months to 5- to 6-month-old TS and control (CO) mice. Melatonin treatment improved spatial learning and memory and increased the number of choline acetyltransferase (ChAT)-positive cells in the medial septum of both TS and CO mice. However, melatonin treatment did not significantly reduce AbetaPP or beta-amyloid levels in the cortex or the hippocampus of TS mice. Melatonin administration did reduce anxiety in TS mice without inducing sensorimotor alterations, indicating that prolonged treatment with this indoleamine is devoid of noncognitive behavioral side effects (e.g., motor coordination, sensorimotor abilities, or spontaneous activity). Our results suggest that melatonin administration might improve the cognitive abilities of both TS and CO mice, at least partially, by reducing the age-related degeneration of basal forebrain cholinergic neurons. Thus, chronic melatonin supplementation may be an effective treatment for delaying the age-related progression of cognitive deterioration found in DS. PMID- 23350972 TI - Laboratory adapted Escherichia coli K-12 becomes a pathogen of Caenorhabditis elegans upon restoration of O antigen biosynthesis. AB - Escherichia coli has been the leading model organism for many decades. It is a fundamental player in modern biology, facilitating the molecular biology revolution of the last century. The acceptance of E. coli as model organism is predicated primarily on the study of one E. coli lineage; E. coli K-12. However, the antecedents of today's laboratory strains have undergone extensive mutagenesis to create genetically tractable offspring but which resulted in loss of several genetic traits such as O antigen expression. Here we have repaired the wbbL locus, restoring the ability of E. coli K-12 strain MG1655 to express the O antigen. We demonstrate that O antigen production results in drastic alterations of many phenotypes and the density of the O antigen is critical for the observed phenotypes. Importantly, O antigen production enables laboratory strains of E. coli to enter the gut of the Caenorhabditis elegans worm and to kill C. elegans at rates similar to pathogenic bacterial species. We demonstrate C. elegans killing is a feature of other commensal E. coli. We show killing is associated with bacterial resistance to mechanical shear and persistence in the C. elegans gut. These results suggest C. elegans is not an effective model of human pathogenic E. coli infectious disease. PMID- 23350973 TI - Gold(I)-catalyzed rearrangement of N-aryl 2-alkynylazetidines to pyrrolo[1,2 a]indoles. AB - Various N-aryl-2-alkynylazetidines were very efficiently converted to pyrrolo[1,2 a]indoles with gold catalysts, especially the 2-biphenyl-dicyclohexylphosphino gold(I) hexafluoroantimonate, in dichloromethane at room temperature. Additionally, two formal syntheses of bioactive non-natural compounds, i.e. 7 methoxymitosene and an 5-HT(2C) receptor agonist, have been achieved. PMID- 23350974 TI - Indigenous health in Australia and New Zealand. PMID- 23350975 TI - Severe trauma in elderly patients. PMID- 23350976 TI - Introducing practical non-clinical skills for surgeons. PMID- 23350977 TI - Chemical myofascial necrosis: a rare complication of laparoscopic nephrectomy. PMID- 23350978 TI - Cruveilhier-Baumgarten syndrome: intriguing for the hepatologist, caveat for a surgeon. PMID- 23350979 TI - Uncommon site for a common lesion. PMID- 23350980 TI - How to write a paper. PMID- 23350981 TI - Novel use of Rose Bengal (PV-10) in two cases of refractory scalp sarcoma. PMID- 23350982 TI - Arteriovenous malformation: a potential cause of ischaemic colitis. PMID- 23350983 TI - Surgical training in private hospitals should be encouraged. PMID- 23350984 TI - Surgicel: an effective tool to avoid free flap pedicle kinking in the head and neck. PMID- 23350985 TI - Re: Spine surgery outcomes in a workers' compensation cohort. PMID- 23350986 TI - Acute abdomen caused by huge pedunculated uterine leiomyoma in torsion. PMID- 23350988 TI - Fast phenotyping of LFS-silenced (tearless) onions by desorption electrospray ionization mass spectrometry (DESI-MS). AB - Fast MS techniques have been applied to the analysis of sulfur volatiles in Allium species and varieties to distinguish phenotypes. Headspace sampling by proton transfer reaction (PTR) MS and surface sampling by desorption electrospray ionization (DESI) MS were used to distinguish lachrymatory factor synthase (LFS) silenced (tearless; LFS-) onions from normal, LFS-active (tear-inducing; LFS+), onions. PTR-MS showed lower concentrations of the lachrymatory factor (LF, 3) and dipropyl disulfide 12 from tearless onions. DESI-MS of the tearless onions confirmed the decreased LF 3 and revealed much higher concentrations of the sulfenic acid condensates. Using DESI-MS with MS(2) could distinguish zwiebelane ions from thiosulfinate ions. DESI-MS gave reliable fast phenotyping of LFS+ versus LFS- onions by simply scratching leaves and recording the extractable ions for <0.5 min. DESI-MS leaf compound profiles also allowed the rapid distinction of a variety of Allium cultivars to aid plant breeding selections. PMID- 23350989 TI - Prescience of a surgeon in 1980. PMID- 23350987 TI - Decorin induces rapid secretion of thrombospondin-1 in basal breast carcinoma cells via inhibition of Ras homolog gene family, member A/Rho-associated coiled coil containing protein kinase 1. AB - Pathological neovascularization relies on an imbalance between potent proangiogenic agents and equally effective antiangiogenic cues. Collectively, these factors contribute to an angiogenic niche within the tumor microenvironment. Oncogenic events and hypoxia contribute to augmented levels of angiokines, and thereby activate the so-called angiogenic switch to promote aggressive tumorigenic and metastatic growth. Soluble decorin functions as a paracrine pan-inhibitor of receptor tyrosine kinases, such as Met and epidermal growth factor receptor, and thus is capable of suppressing angiogenesis under normoxia. This leads to noncanonical repression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor A (VEGFA), and concurrent induction of thrombospondin-1. The substantial induction of endogenous tumor cell-derived thrombospondin-1, a potent antiangiogenic effector, led us to the discovery of an unexpected secretory phenotype occurring very rapidly (within 5 min) after decorin treatment of the triple-negative basal breast carcinoma cell line MDA-MB 231. Surprisingly, the effect was not mediated by Met receptor antagonism, as initially hypothesized, but required epidermal growth factor receptor signaling to achieve swift and robust thrombospondin-1 release. Furthermore, this effect was ultimately dependent on the prompt degradation of Ras homolog gene family member A, via the 26S proteasome, leading to direct inactivation of Rho associated coiled-coil containing protein kinase 1. The latter led to derepression of thrombospondin-1 secretion. Collectively, these data provide a novel mechanistic role for Rho-associated coiled-coil containing protein kinase 1, in addition to providing the first conclusive evidence of decorin exclusively targeting a receptor tyrosine kinase to achieve a specific effect. The overall effects of soluble decorin on the tumor microenvironment would cause an immediately-early as well as a sustained antiangiogenic response in vivo. PMID- 23350990 TI - The unknown profession: a geriatrician. AB - The term "plastic surgeon" is oddly uninformative, although it seems likely that most people know what plastic surgeons do. How well can a sample of individuals encountered on the street describe what geriatricians do? To answer this question, we strolled through downtown Baltimore's Inner Harbor, armed with a video camera and picture identification cards to ask the following question: "What is a geriatrician?" Two of us (PA, JY), from the Johns Hopkins Division of Geriatric Medicine and Gerontology, surveyed a convenience sample of people aged 18-80. To further enhance this survey, a video of the interviews was produced (available in online version of article). We entered this exercise having recently joined the ranks of geriatricians-prepared to improve the health and quality of care of our elderly patients. Our naive excitement at entering this noble specialty was trampled by the reality that virtually no one we interviewed knew what a geriatrician was. Answers like, "somebody who works for Ben and Jerry's ice cream" were amusing but at the same time typical and sobering. This simple survey reveals a distressing gap in the public's knowledge of the field of geriatrics and the need for better understanding of its importance to public health and individual health. After all, if people do not know what a geriatrician is, how can they support the growth of geriatrics or seek care from us? PMID- 23350991 TI - Segmentation of precursor mass range using "tiling" approach increases peptide identifications for MS1-based label-free quantification. AB - Label-free quantification is a powerful tool for the measurement of protein abundances by mass spectrometric methods. To maximize quantifiable identifications, MS(1)-based methods must balance the collection of survey scans and fragmentation spectra while maintaining reproducible extracted ion chromatograms (XIC). Here we present a method which increases the depth of proteome coverage over replicate data-dependent experiments without the requirement of additional instrument time or sample prefractionation. Sampling depth is increased by restricting precursor selection to a fraction of the full MS(1) mass range for each replicate; collectively, the m/z segments of all replicates encompass the full MS(1) range. Although selection windows are narrowed, full MS(1) spectra are obtained throughout the method, enabling the collection of full mass range MS(1) chromatograms such that label-free quantitation can be performed for any peptide in any experiment. We term this approach "binning" or "tiling" depending on the type of m/z window utilized. By combining the data obtained from each segment, we find that this approach increases the number of quantifiable yeast peptides and proteins by 31% and 52%, respectively, when compared to normal data-dependent experiments performed in replicate. PMID- 23350992 TI - Computed tomography has low sensitivity for the diagnosis of early colon cancer. AB - AIM: The accuracy of computed tomography (CT) in detecting local invasion (T status) and nodal metastasis (N status) of colon cancer was determined. METHOD: Data on the preoperative CT scan of 153 lesions from 152 patients with colon cancer were reviewed retrospectively. Evaluation included the T stage and N stage of the TNM system. The results were compared with those obtained by histopathological examination of the resected tumour. RESULTS: Of the 153 tumours, 117 (76.5%) were correctly classified as Stage T1 and T2 (33 tumours) and Stage T3 and T4 (84 tumours) by CT. The sensitivity and specificity were 70.2% and 79.2%, respectively, and the positive and negative predictive values were 85.7% and 60.0%. When analysed according to the individual T stage (Tx/Tis, T1, 2, 3, 4) and N stage (N0, 1, 2), the kappa coefficient with linear weighting was 0.208 (fair agreement) for T stage and 0.154 (slight agreement) for N stage. The estimation of tumour size showed good agreement with histopathology (Spearman correlation coefficient 0.865). CONCLUSION: CT scanning of colonic cancer showed 75% accuracy in identifying T1 and T2 cancers combined, but gave poor agreement between CT and histopathology for individual T stages. PMID- 23350993 TI - Face-specificity is robust across diverse stimuli and individual people, even when interstimulus variance is zero. AB - The N170 is a brain electrical potential proposed to index the earliest time of categorical perception of faces in occipitotemporal visual areas implicated in face cognition, being more negative for faces than nonface objects between 120 and 200 ms. The interstimulus variance (ISV) account instead explained N170 face specificity as an artifact due to objects varying more visually than faces. Ganis, Smith, and Schendan (2012) tested this account directly, finding that N170 face-specificity remains even when ISV is eliminated. Here, N170 peak amplitude and face-specificity is quantified for individual stimuli and participants, revealing that the right hemisphere N170 is especially sensitive to stimulus variability. Further, ISV contributes 0 to 37% to N170 face-specificity. These findings provide evidence for optimizing face processing science. The paradigm can apply to any research in which ISV may be uncontrolled (e.g., category comparisons). PMID- 23350994 TI - Effects of omalizumab in non-atopic asthma: results from a Spanish multicenter registry. AB - Aim. To evaluate the effectiveness of omalizumab in non-atopic asthma. Methods. Using data from a multicenter registry of severe asthma, we evaluated and compared the clinical outcome of 29 omalizumab-treated severe non-atopic asthmatics with 266 omalizumab-treated severe allergic asthmatics. Effectiveness was assessed by considering severe exacerbations, pulmonary function, the Global Evaluation of Treatment Effectiveness (GETE) scale, and Asthma Control Test (ACT). Results. Omalizumab demonstrated significant improvement in the clinical status of non-atopic asthmatics as measured by GETE, which rose from 1.6 +/- 1.1 to 2.8 +/- 0.9 [corrected] at 4 months (p = .0215) to 2.9 +/- 0.9 at 1 year (p = .0093) and to 3.4 +/- 0.6 at 2 years (p = .0078), and by the ACT, which increased from 13.3 +/- 5.5 [corrected] to 17.5 +/- 5.4 at 4 months (p = .0236) to 17.9 +/- 4.8 at 1 year (p = .0136) and to 20.6 +/- 3.9 at 2 years (p = .0024). Forced expiratory volume in 1 second (FEV1) improved from 61.0 +/- 19.4% to 65.1 +/- 17.2 at 4 months to 64.1 +/- 24.7 at 1 year and to 67.3 +/- 23.0% [corrected] at 2 years, but without significant differences between initial and follow-up measurements (p = .52, .91, and .45, respectively) and exacerbations decreased from 3.1 +/- 3.5 to 1.9 +/- 2.8 at 1 year (p = .1709) to 1.8 +/- 4.4 at 2 years (p = .2344). The results were not significantly different from those obtained in atopic asthmatics. Conclusion. Anti-IgE therapy can be effective in non-atopic severe asthma. PMID- 23350995 TI - Editorial. PMID- 23350996 TI - Cognitive aesthetics of alchemical imagery. AB - Jung's contribution to the understanding of the relevance of psychology to alchemy has become increasingly invalidated by the ahistorical nature of his approach, just as his tendency to ignore the importance of cognitive aesthetics for an improved comprehension of the functions of alchemical images has prevented Jungians from further extending Jung's insight of the importance of alchemy for psychology. This paper explores the history of the development of alchemical illustrations in Western Europe from the 14(th) to the 16(th) century, tracing the emergent processes over time. It is only when we take into consideration the historical dimension and the aesthetics of alchemical imagery that it becomes possible to demonstrate how the increasing use of certain aesthetic techniques such as the disjunction and recombination of separate metaphorical elements of previous illustrations, the use of compressive combinations and the use of framing devices worked to gradually increase the cognitive function and the symbolical power of the images. If alchemy is still relevant to psychotherapy it is exactly because it helps us to understand the importance of cognitive aesthetics in our approach to the images, metaphors and narratives of our patients. PMID- 23350997 TI - Nostalgia and lost identity. AB - Nostalgia for the Soviet Union is a major social phenomenon in Russia today due to the irrevocable losses of the recent past in which Soviet citizens involuntarily became immigrants in their own country. With reference to discussions of nostalgia in philosophical and psychoanalytic literature, I suggest that nostalgia may represent either a defensive regression to the past or a progressive striving for wholeness through re-connecting with what has been lost in the service of a greater integration. I compare this with the processes of adaptation seen in immigrants and provide a clinical illustration of a young man coming to terms with loss and change in the post-Soviet era. When nostalgia is recognized as a legitimate emotional experience it may facilitate mourning and enable the integration of the past with the present and the development of a new identity. PMID- 23350998 TI - Ego consciousness in the Japanese psyche: culture, myth and disaster. AB - With globalization, modern Western consciousness has spread across the world. This influx has affected the Japanese culture but ego consciousness has emerged through a long history and different course from that of the West. At a personal level, I have been interested in the establishment of a subject in a culture that values homogeneity and to understand this, I reflect on my own history of living in both the East and the West and on my experience practising psychotherapy. To show Japanese collective functioning at its best, I describe the human inter connectedness and collaboration during the 2011 disaster. I explore the 'Nothing' at the centre of the Japanese psyche, through a reading of Japanese myth, especially the most originary and almost pre-human stories that come before the anthropomorphized 'First Parents'. A retelling of this founding story, reveals the multiple iterations over time that manifest in embodied being; this gradual emergence of consciousness is contrasted with Western myths of origin that are more clear and specific. This study attempts to bring awareness of the value and meaning of Eastern consciousness and its centre in the 'Nothing'. PMID- 23350999 TI - Trauma and the transference-countertransference: working with the bad object and the wounded self. AB - This paper focuses on the transference-countertransference dynamics that manifest in work with those individuals who experienced severe early relational trauma and, in particular, childhood sexual abuse. The literature is surveyed from Davies and Frawley's (1992a) seminal paper through to more current trauma-related and sensorimotor approaches, which deepen our understanding greatly. The rapidly shifting, powerful, conflicting and kaleidoscopic transference countertransference dynamics are explored in the light of these views and in relation to a lengthy clinical example. The author elucidates the dual-aspect of the traumatic complex, whereby the abuser figure, which is disavowed by the patient, becomes manifest in prosecuting the analyst for the 'wounds' that the analysis evokes. The paper also explores the particular nature of the splitting processes, whereby pressure is put on the analyst to adopt an idealized role, in particular to act as a self-object, in order to enable the patient to safely express and 'be' themselves in an attempt to make up for what was not possible in childhood; the analyst will necessarily fail in this task. In the context of powerful masochisto-sadistic dynamics, the analyst's masochism is likely to be called up in the spirit of caring 'humanity' (another inevitable enactment), which can impede the progress of the analysis if not addressed. The extreme woundedness, intense affect and moral outrage associated with these dynamics are characteristic and compelling. Issues relating to disclosure, enactment and analytic attitude are also discussed. PMID- 23351000 TI - 'Black holes': escaping the void. AB - The 'black hole' is a metaphor for a reality in the psyche of many individuals who have experienced complex trauma in infancy and early childhood. The 'black hole' has been created by an absence of the object, the (m)other, so there is no internalized object, no (m)other in the psyche. Rather, there is a 'black hole' where the object should be, but the infant is drawn to it, trapped by it because of an intrinsic, instinctive need for a 'real object', an internalized (m)other. Without this, the infant cannot develop. It is only the presence of a real object that can generate the essential gravity necessary to draw the core of the self that is still in an undeveloped state from deep within the abyss. It is the moving towards a real object, a (m)other, that relativizes the absolute power of the black hole and begins a reformation of its essence within the psyche. PMID- 23351001 TI - Temperament and typology. AB - This paper takes a cue from Harvard neuroscientists Jerome Kagan and Nancy Snidman's (2004) comment that Jung's work on typology has remarkable relevance to their research on neurobiological correlates of temperament and develops the links between the theorists separated by almost a century. The paper begins with a brief review of temperament traits in personality psychology. Kagan and Snidman's 11-year longitudinal study is then analysed and correlated with Jung's psychological attitude types of introversion and extraversion, demonstrating that Jung's close empirical observations of human nature fit explicitly with objective measurements of neurobiological sensitivity thresholds and their expression in temperament. Emerging research on neurobiologically sensitive adults and children from Aron (1997, 2004, 2011) and differential susceptibility theory (DST) is presented as extrapolating the same links between temperament and physiological sensitivity found in Jung's introversion and Kagan and Snidman's high-reactive type. The paper concludes with a consideration of the subjective psyche as a necessary aspect to understanding the self and human consciousness as whole. PMID- 23351005 TI - Copper(I)-catalyzed borylative exo-cyclization of alkenyl halides containing unactivated double bond. AB - A borylative exo-cyclization of alkenyl halides has been reported. The reaction includes the regioselective addition of a borylcopper(I) intermediate to unactivated terminal alkenes, followed by the intramolecular substitution of the resulting alkylcopper(I) moiety for the halide leaving groups. Experimental and theoretical investigations of the reaction mechanism have also been described. This reaction provides a new method for the synthesis of alkylboronates containing strained cycloalkyl structures from simple starting materials. PMID- 23351006 TI - A kinetic model for the deterministic prediction of gel-based single-chirality single-walled carbon nanotube separation. AB - We propose a kinetic model that describes the separation of single-chirality semiconducting carbon nanotubes based on the chirality-selective adsorption to specific hydrogels. Experimental elution profiles of the (7,3), (6,4), (6,5), (8,3), (8,6), (7,5), and (7,6) species are well described by an irreversible, first-order site association kinetic model with a single rate constant describing the adsorption of each SWNT to the immobile gel phase. Specifically, we find first-order binding rate constants for seven experimentally separated nanotubes normalized by the binding site molarity (M(theta)): k7,3 = 3.5 * 10-5 M(theta)-1 s-1, k6,4 = 7.7 * 10-8 M(theta)-1 s-1, k8,3 = 2.3 * 10-9 M(theta)-1 s-1, k6,5 = 3.8 * 10-9 M(theta)-1 s-1, k7,5 = 1.9 * 10-11 M(theta)-1 s-1, k8,6 = 7.7 * 10-12 M(theta)-1 s-1, and k7,6 = 3.8 * 10-12 M(theta)-1 s-1. These results, as well as additional control experiments, unambiguously identify the separation process as a selective adsorption. Unlike certain chromatographic processes with retention time dependence, this separation procedure can be scaled to arbitrarily large volumes, as we demonstrate. This study provides a foundation for both the mechanistic understanding of gel-based SWNT separation as well as the potential industrial-scale realization of single-chirality production of carbon nanotubes. PMID- 23351007 TI - Impact of calcium binding and thionylation of S100A1 protein on its nuclear magnetic resonance-derived structure and backbone dynamics. AB - S100 proteins play a crucial role in multiple important biological processes in vertebrate organisms acting predominantly as calcium signal transmitters. S100A1 is a typical representative of this family of proteins. After four Ca(2+) ions bind, it undergoes a dramatic conformational change, resulting in exposure, in each of its two identical subunits, a large hydrophobic cleft that binds to target proteins. It has been shown that abnormal expression of S100A1 is strongly correlated with a number of severe human diseases: cardiomyopathy and neurodegenerative disorders. A few years ago, we found that thionylation of Cys 85, the unique cysteine in two identical S100A1 subunits, leads to a drastic increase of the affinity of the protein for calcium. We postulated that the protein activated by thionylation becomes a more efficient calcium signal transmitter. Therefore, we decided to undertake, using nuclear magnetic resonance methods, a comparative study of the structure and dynamics of native and thionylated human S100A1 in its apo and holo states. In this paper, we present the results obtained for both forms of this protein in its holo state and compare them with the previously published structure of native apo-S100. The main conclusion that we draw from these results is that the increased calcium binding affinity of S100A1 upon thionylation arises, most probably, from rearrangement of the hydrophobic core in its apo form. PMID- 23351008 TI - Cognitive biases in patients with chronic obstructive pulmonary disease and depression--a pilot study. AB - OBJECTIVES: Comorbid depression is highly prevalent in patients with chronic obstructive pulmonary disease (COPD) and associated with a worse course of disease; however, the exact mechanisms linking both remain unclear. In currently depressed individuals without lung disease, depression-specific biases in information processing have been suggested as risk factors for the development and maintenance of depression. We examined whether comparable biases in cognitive information processing might underlie depression in COPD. DESIGN: Different aspects of cognitive information processing were examined with computer-based tasks measuring selective attention and memory in patients with COPD who were compared with age-matched, currently depressed patients without lung disease and healthy control participants. METHODS: The Self-Referential Encoding and Incidental Recall Task as well as the emotion face dot-probe task was applied to 21 never-depressed COPD patients, 18 currently depressed COPD patients, 20 currently depressed patients without lung disease and 19 healthy controls to examine cognitive biases. RESULTS: In both patients with COPD who were never and who were currently depressed, depression-like cognitive biases were observed for some attention- and memory-related tasks, but not for all tested aspects of information processing. These biases were particularly prominent in patients with COPD and current depression and comparable to those observed in currently depressed patients without lung disease. CONCLUSIONS: The results of this pilot study suggest that patients with COPD may potentially show depression-like biases in some aspects of cognitive information processing. Future studies are required to examine whether these biases represent a vulnerability factor for the development of depression in patients with COPD. PMID- 23351009 TI - Use of an anti-CD200 antibody for prolonging the survival of allografts: a patent evaluation of WO2012106634A1. AB - BACKGROUND: Allograft rejection continues to be the biggest hurdle in successful organ transplantation. This application (WO2012106634A1) claims the use of blocking CD200 antibody to achieve long-term survival of allografts. CD200 is the ligand for the inhibitory CD200 receptor (CD200R). METHODS: In mouse allograft transplantation models, a blocking CD200 antibody was used to improve renal and cardiac graft survival. Similarly, in humans a blocking CD200 antibody would be administered to the organ recipient in combination with currently used immunosuppressive drugs or even as a monotherapy. RESULTS: In the presented animal experiments, anti-CD200 antibody application to the allograft recipient decreases SHIP expression in splenocytes. This is accompanied by a significant increase in renal or cardiac graft survival. Furthermore, anti-CD200 antibody has an immunosuppressive effect manifested by an increased production of T regulatory and myeloid-derived suppressor cells (MDSC) and a decrease in B cells and activated T cells. CONCLUSION: In vivo administration of anti-CD200 antibody has a remarkable positive effect on allograft survival. However, since this finding contradicts all previous effects of in vivo CD200 manipulation described in transplantation settings, future development of this invention is highly uncertain. PMID- 23351010 TI - General practitioners' hypertension knowledge and training needs: a survey in Xuhui district, Shanghai. AB - BACKGROUND: Hypertension prevalence is high in China, while patients' levels of hypertension awareness, treatment and control are low. General practitioners' knowledge and training relating to hypertension prevention may be an important related factor. We aimed to investigate general practitioners' knowledge of hypertension prevention and potential training needs. METHODS: A questionnaire survey was conducted among all general practitioners at five community health service centers selected by convenience sampling. A total of 160 questionnaires were distributed and 147 were returned (response rate 91.9%) The questionnaire included general information; 12 subjective questions on health promotion, education and training needs; and 19 objective questions in 5 domains (epidemiology, diagnosis, treatment, referral and community management) measuring knowledge of hypertension prevention and treatment. RESULTS: The major difficulties in health education practice for general practitioners were poor patient compliance (77.6%) and lack of medical consultation time (49.0%). The average accuracy rate of hypertension prevention knowledge was 49.2%, ranging from 10.5% to 94.7%. The factors associated with accuracy rate were physician's education level (medical university vs. professional school, beta = 13.3, P = 0.003), and type of center (training base vs. community healthcare center, beta = 12.3, P < 0.0001). Most physicians (87.8%) reported being willing to attend training courses regularly and the preferred frequency was once every 2 ~ 3 months (53.5%). The preferred course was medical treatment of hypertension (82.3%) and the most favored training approach was expert lectures (80.3%). CONCLUSIONS: The knowledge level of hypertension prevention is low among general practitioners in urban settings. Physicians working in community clinics where they participate in a series of teaching, assessing and evaluating systems for hypertension prevention perform better than those in general healthcare centers who lack specific training. Continuing hypertension education is urgently needed to ensure that physicians in general practice are aware of and adhere to the national hypertension prevention guidelines. PMID- 23351011 TI - Altered transcriptional regulation of cytokines, growth factors, and apoptotic proteins in the endometrium of infertile women with chronic endometritis. AB - PROBLEM: Chronic endometritis (CE) is a poorly investigated and probably underestimated pathology, which may cause abnormal uterine bleeding (AUB), pain, and reproductive failures. Due to undefined symptoms and the normal presence of leukocytes in the endometrial mucosa, diagnosis may be missed. Fluid hysteroscopy is a reliable technique for diagnosing this pathology. Few data exist on the biochemical and paracrine alterations that occur in the endometrium of women diagnosed with CE. The aim of the study was to find molecular modification in endometrium related to CE. METHOD OF STUDY: Sixteen women with hysteroscopic and histological diagnosis of CE and 10 healthy women as controls were enrolled. We compared the endometrial expression profile of 25 genes encoding proteins involved in the inflammatory response, proliferation, and apoptosis in endometrium during implantation window, using high-throughput real-time RT-PCR. RESULTS: In women with CE, the endometrial expression of some genes was significantly altered. In particular, IGFBP1, BCL2, and BAX were up-regulated, while IL11, CCL4, IGF1, and CASP8 were down-regulated. CONCLUSION: The altered gene endometrial expression may explain the impaired endometrial receptivity and the finding of endometrial hyperplastic lesions in women affected by CE. PMID- 23351012 TI - Synthesis of quinolones by nickel-catalyzed cycloaddition via elimination of nitrile. AB - Substituted quinolones were efficiently synthesized via the nickel-catalyzed cycloaddition of o-cyanophenylbenzamide derivatives with alkynes. The reaction involves elimination of a nitrile group by cleavage of the two independent aryl cyano and aryl-carbonyl C-C bonds of the amides. PMID- 23351013 TI - Long-term outcomes after cyclosporine or mycophenolate withdrawal in kidney transplantation - results from an aborted trial. AB - Long-term triple immunosuppressive therapy with cyclosporine (CsA), mycophenolate mofetil (MMF) and prednisolone may be excessively powerful for many transplant recipients. We compared withdrawal of either MMF or CsA in stable kidney transplants on triple immunosuppression. The study was a prospective, randomized, controlled 12-months trial in stable kidney transplants. The patients who withdrew CsA were given MMF 2 g/d, and CsA troughs were between 75 and 125 ng/mL in MMF withdrawal. Planned inclusion was 298 patients. The study was prematurely aborted after inclusion of 39 patients. Acute rejection rates were 6/20 (30%) in the MMF group compared with 0/19 (0%) in the CsA group (p = 0.02). Time to acute rejections was 4.0-28.7 months after withdrawal. Trough concentrations of mycophenolic acid (MPA) and CsA showed therapeutic levels. The subjects have been observed for eight yr, and of the 28 patients remaining on randomized therapy, the MMF patients preserved graft function better than CsA patients. Death censored graft survival was 75% and 95% (p = 0.18) and patient survival was 70% and 68% (p = 0.99) in the MMF and CsA groups, respectively, at the end of long term follow-up. CsA withdrawal was associated with a high rate of acute rejections. Initially, the treatment of acute rejections was successful. However, five of six lost their grafts in the long term. PMID- 23351015 TI - Dynamic postural stability for double-leg drop landing. AB - Dynamic postural stability has been widely studied for single-leg landing, but seldom considered for double-leg landing. This study aimed to evaluate the dynamic postural stability and the influence mechanism of muscle activities during double-leg drop landing. Eight recreationally active males and eight recreationally active females participated in this study and dropped individually from three heights (0.32 m, 0.52 m, and 0.72 m). Ground reaction force was recorded to calculate the time to stabilisation. Electromyographic activities were recorded for selected lower-extremity muscles. A multivariate analysis of variance was carried out and no significant influence was found in time to stabilisation between genders or limb laterals (P > 0.05). With increasing drop height, time to stabilisation decreased significantly in two horizontal directions and the lower-extremity muscle activities were enhanced. Vertical time to stabilisation was not significantly influenced by drop height. Dynamic postural stability improved by neuromuscular change more than that required due to the increase of drop height. Double-leg landing on level ground is a stable movement, and the body would often be injured before dynamic postural stability is impaired. It is understandable to protect tissues from mechanical injuries by the sacrifice of certain dynamic postural stability in the design of protective devices or athlete training. PMID- 23351014 TI - The complete mitochondrial genome of Japanese sandeel Ammodytes personatus (Perciformes, Ammodytidae): rare structure in control region compared. AB - The first complete mitochondrial genome (16,537 bp) of the suborder Ammodytoidei was determined for Ammodytes personatus. The genome includes 22 tRNAs, 2 rRNAs, and 13 protein-coding genes as well as the putative control region and O(L). The gene order and component are identical to those of canonical vertebrate mitochondrial genomes. In control region, all six central conserved sequence blocks (CSB-F to CSB-A) having been detected only in the order Pleuronectiformes were recognized in A. personatus, which might contribute to its taxonomic resolution. PMID- 23351016 TI - Effect of fatigue on laparoscopic skills: a comparative historical cohort study. AB - BACKGROUND: Fatigue has been shown to have a negative impact on surgical performance. However, there is a lack of research investigating its effect on laparoscopy, particularly in Australia. This study investigated whether fatigue associated with a surgeon's usual workday led to a measurable drop off in laparoscopic surgical skills as assessed on a laparoscopic simulator. METHODS: A comparative study involving two cohorts was undertaken: a study group whose data were collected prospectively was compared to a historical control group. Participants were required to reach a predetermined level of proficiency in each laparoscopic task on either a FLS or LapSim simulator. The participants in the study cohort were re-tested approximately 1 month after completing 10 h of work. The participants in the historical non-fatigued group were re-tested approximately 1 month after reaching proficiency. Comparisons between cohorts were made using a 'decrease in score per day elapsed' value to account for the natural attrition in skills over time and the variability in testing times within and between the two cohorts. RESULTS: The decrease in overall score per day elapsed for fatigued participants was significantly greater than for historical non-fatigued participants, irrespective of the simulator type. Fatigue had a greater impact on certain laparoscopic skills, including peg transfer and knot tying. Participants who self-reported higher level of fatigue demonstrated significantly better skills than those who self-reported lower levels. CONCLUSION: Overall laparoscopic skill proficiency was reduced in the fatigued participants compared to the historical non-fatigued participants, with certain laparoscopic skills more affected than others. PMID- 23351017 TI - Sweet's syndrome triggered by pneumococcal vaccination. AB - Sweet's syndrome is the most frequent category among the neutrophilic dermatosis and is diagnosed by clearly defined criteria. Vaccines are included as potential triggers of this syndrome. Nevertheless, there are few reports unveiling such association. Herein, we describe the case of a patient who developed Sweet's syndrome after pneumococcal vaccination. To our knowledge, this is the second case of Sweet's syndrome triggered by pneumococcal vaccine reported, and the first one specifically with the 13-valent conjugate vaccine. PMID- 23351018 TI - Impact of a multidisciplinary team training programme on rectal cancer outcomes in Spain. AB - AIM: The Spanish Rectal Cancer Project was established in 2006, inspired by the Norwegian Rectal Cancer Project. It consisted of an educational project aiming to introduce mesorectal excision surgery to surgeons, pathologists and radiologists. Its effect on local recurrence (LR) was compared with the Norwegian Project. METHOD: An observational cohort study was carried out including all patients (4700) with rectal cancer from a population of 19 329 992 inhabitants operated on in 51 Spanish hospitals between March 2006 and June 2010. Curative resection was defined as a resection with an uninvolved circumferential margin in patients without distant metastases and without intra-operative rectal perforation. The effectiveness of the programme was measured by a central registry with feedback to participating institutions of their own results compared with the national average. The main outcome measures were LR and adverse effects in curative resections. RESULTS: Of the 4700 patients, 3213 had a resection considered to be curative. LR rates were 4.7% (95% CI 0.03-0.59), metastasis rate was 16% (95% CI 0.14-0.17) and overall survival was 87.8% (95% CI 0.86-0.89). Multivariate analysis showed that advanced TNM stage and decreasing distance of the tumour from the anal verge had a negative influence on LR. CONCLUSION: This study shows that the results obtained in Norway have been reproduced in a larger population in Spain applying a similar methodology. PMID- 23351019 TI - Neuropsychological functioning in children and adolescents with restrictive-type anorexia nervosa: an in-depth investigation with NEPSY-II. AB - Several studies have investigated the neuropsychological functioning of patients with anorexia nervosa restrictive type (AN-r), but results are conflicting. Here we compared the neuropsychological profile of 23 female children and adolescents with AN-r and of 46 typical controls (aged 9-16 years) using the second edition of the NEPSY (a Developmental Neuropsychology Assessment) neuropsychological battery. AN-r patients presented subtle cognitive flexibility impairments in audiomotor responses (p = .033). Conversely, superior performance in verbal fluency (p = .024) and memory (p = .034) was observed only in AN-r patients with an associated unipolar mood disorder. This profile of marginally impaired and enhanced performance was independent from illness duration and starvation degree, suggesting that it may preexist and represent a vulnerability factor for the disease onset. PMID- 23351021 TI - Antifibrotic peptide N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP): opportunities for angiotensin-converting enzyme inhibitor design. AB - The renin-angiotensin system (RAS) is central to regulation of blood pressure and electrolyte homeostasis. Angiotensin-converting enzyme (ACE), a key protease in the RAS, has a range of substrates, including N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP). The peptide Ac-SDKP is cleared almost exclusively by ACE, and specifically by the N-domain active site of this enzyme. N-Acetyl-Ser-Asp-Lys-Pro is a negative regulator of haematopoietic stem cell differentiation and is a potent antifibrotic agent. In this review, the physiological actions of Ac-SDKP are presented, together with the potential clinical usefulness of raising Ac-SDKP levels. This emphasizes the possible opportunity of N-domain-selective ACE inhibitors or ACE-resistant Ac-SDKP analogues for the treatment of fibrosis. PMID- 23351020 TI - Dichotomy of decorin activity on the insulin-like growth factor-I system. AB - The stromal-specific proteoglycan decorin has emerged in recent years as a critical regulator of tumor initiation and progression. Decorin regulates the biology of various types of cancer by modulating the activity of several receptor tyrosine kinases coordinating growth, survival, migration, and angiogenesis. Decorin binds to surface receptors for epidermal growth factor and hepatocyte growth factor with high affinity, and negatively regulates their activity and signaling via robust internalization and eventual degradation. The insulin-like growth factor (IGF)-I system plays a critical role in the regulation of cell growth both in vivo and in vitro. The IGF-I receptor (IGF-IR) is also essential for cellular transformation, owing to its ability to enhance cell proliferation and protect cancer cells from apoptosis. Recent data have pointed to a role of decorin in regulating the IGF-I system in both nontransformed and transformed cells. Significantly, there is a surprising dichotomy in the mechanism of decorin action on IGF-IR signaling, which differs considerably between physiological and pathological cellular models. In this review, we summarize the current knowledge on decorin regulation of the IGF-I system in normal and transformed cells, and discuss possible decorin-based therapeutic approaches to target IGF-IR-driven tumors. PMID- 23351022 TI - Same size--same niche? Foraging niche separation between sympatric juvenile Galapagos sea lions and adult Galapagos fur seals. AB - 1. In vertebrates, patterns of resource utilization change throughout development according to age- and or size-specific abilities and requirements. Thus, interspecific competition affects different age classes differently. 2. Adults of sympatric species often show distinct foraging niche segregation, but juvenile resource use might overlap with adult competitors of similar body size. Resultant negative effects on juveniles can have important consequences for population dynamics, yet such interactions have received little attention in studies of mammalian communities. 3. Using GPS tracking devices, time-depth recorders and stable isotope data, we compared diving depth, activity time, trophic position and foraging habitat characteristics to investigate foraging niche overlap between similar-sized sympatric juvenile Galapagos sea lions (Zalophus wollebaeki) and adult Galapagos fur seals (Arctocephalus galapagoensis) and compared each group with much larger-bodied adult Galapagos sea lions. 4. We found little indication for direct competition but a complex pattern of foraging niche segregation: juvenile sea lions and adult fur seals dived to shallow depths at night, but foraged in different habitats with limited spatial overlap. Conversely, juvenile and adult sea lions employed different foraging patterns, but their foraging areas overlapped almost completely. 5. Consistency of foraging habitat characteristics between juvenile and adult sea lions suggests that avoidance of competition may be important in shaping foraging habitat utilization. Resultant specialization on a limited habitat could contribute to low sea lion numbers that contrast with high fur seal abundance. Our data suggest that exploitation by multiple predators within spatially restricted foraging ranges of juveniles might negatively impact juvenile foraging success and ultimately influence population dynamics. PMID- 23351023 TI - 2D correlation analysis: sequential order judging. AB - Using a two-dimensional (2D) correlation analysis technique to determine the sequential order of physical or chemical events has received keen interests in the past ten years. However, our continuous work demonstrates that the sequential order of events determined by the "sequential order" rules of this technique may lead to ambiguous or even wrong conclusions, because the physical significance of the sequential order in generalized 2D correlation analysis is neither well defined nor meaningful in general situations, and the word "occur" used in the "sequential order" rules may easily give rise to ambiguity. In contrast to the integrated sequential order derived from periodic changes as in mechanical perturbation based 2D correlation infrared spectroscopy, there is a local/chronological sequential order for nonperiodic changes in general situations. The current work shows that the integrated sequential order in 2D correlation analysis is a reflection of the sequential order of the phases, i.e., phase sequence/difference. The integrated sequential order may indicate the relative state of two events (one event occurs/exists before or after the other one) according to a specific reference, only if both are obtained under the same frequency for periodic changes or even speeds for nonperiodic changes in general situations. The integrated sequential order may not always be able to reveal whether one event occurs/happens before or after another one for nonperiodic changes in terms of timings of happenings. For nonperiodic changes, the integrated sequential order is not so meaningful and must be replaced by the local/chronological sequential order. To judge whether one event occurs/happens before or after another one for two nonperiodic changes in general situations, the original spectral intensity changes must be verified to determine if a chronological/local sequential order exists between two events. PMID- 23351024 TI - The developmental transition of ovine adipose tissue through early life. AB - AIM: Hypothermia induced by cold exposure at birth is prevented in sheep by the rapid onset of non-shivering thermogenesis in brown adipose tissue (BAT). Changes in adipose tissue composition in early life are therefore essential for survival but also influence adiposity in later life and were thus examined in detail during early development. METHODS: Changes in adipose composition were investigated by immunohistochemistry and qRT-PCR between the period from the first appearance of adipose in the mid gestation foetus, through birth and up to 1 month of age. RESULTS: We identified four distinct phases of development, each associated with pronounced changes in tissue histology and in distribution of the BAT specific uncoupling protein (UCP)1. At mid gestation, perirenal adipose tissue exhibited a dense proliferative, structure marked by high expression of KI 67 but with no UCP1 or visible lipid droplets. By late gestation large quantities of UCP1 were present, lipid storage was evident and expression of BAT-related genes were abundant (e.g. prolactin and beta3 receptors). Subsequently, within 12 h of birth, the depot was largely depleted of lipid and expression of genes such as UCP1, PGC1alpha, CIDEA peaked. By 30 days UCP1 was undetectable and the depot contained large lipid droplets; however, genes characteristic of BAT (e.g. PRDM16 and BMP7) and most characteristic of white adipose tissue (e.g. leptin and RIP140) were still abundant. CONCLUSION: Adipose tissue undergoes profound compositional changes in early life, of which an increased understanding could offer potential interventions to retain BAT in later life. PMID- 23351025 TI - Androgen deprivation therapy: evidence-based management of side effects. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The benefits of androgen deprivation therapy (ADT) are well recognized and a multitude of studies have documented the benefits of ADT in conjunction with other therapies. Given the widespread use of ADT due to its important clinical implications, it is imperative that clinicians understand the side effects to limit treatment-related morbidity. There are numerous well recognized adverse effects of ADT, including vasomotor flushing, loss of libido and impotence, fatigue, gynaecomastia, anaemia, osteoporosis and metabolic complications, as well as effects on cardiovascular health and bone density. Present study focuses on the most recent evidence-based treatment options for various side effects of ADT. OBJECTIVE: To familiarize clinicians with the various side effects of androgen deprivation therapy (ADT). The present study focuses on the most recent evidence-based treatment strategies for the common side effects of ADT. METHODS: A PubMed database search was conducted from 2000 to 2012. All prospective clinical studies were selected, including randomized and non-randomized clinical trials, as well as meta-analysis studies concerning preventive and therapeutic interventions for various side effects of ADT. 'The Oxford 2011 Levels of Evidence' classification system for treatment benefits was used to categorize selected studies. RESULTS: Gabapentin shows moderate efficacy for the long-term treatment of hot flashes in a dose-dependent manner. A combined resistance/aerobic exercise programme leads to significant improvement in fatigue, sexual function and cognitive function. A home-based/group exercise programme also improves fatigue and unfavourable metabolic changes. Denosumab increases lumbar spine, hip and radius bone mass density, and also reduces the risk of vertebral fractures in men receiving ADT for non-metastatic prostate cancer. Metformin coupled with lifestyle intervention is a safe, well-tolerated intervention for adverse metabolic changes. Toremifene improves the lipid profile. Intermittent ADT improves early side effects, such as hot flashes, sexual activity, fatigue, and quality of life, although its effect on long-term side effects remains inconclusive. CONCLUSION: Despite significant improvement in management strategies for the side effects of ADT, the best way of preventing side effects is to use ADT only when it is absolutely indicated. PMID- 23351026 TI - Pain and anxiety mediate the relationship between dizziness and falls in older people. AB - OBJECTIVES: To identify medical, psychological, and physiological mediators of the relationship between dizziness and falls in older adults. DESIGN: Secondary analysis of a prospective cohort study. SETTING: Community. PARTICIPANTS: Five hundred sixteen community-dwelling adults aged 73 to 92. MEASUREMENTS: Participants completed questionnaires related to health and psychological well being and underwent a tilt table blood pressure test, the Physiological Profile Assessment (PPA; vision, reaction time, proprioception, postural sway, and quadriceps strength), and leaning balance tests. Prospective falls data were collected using monthly calendars for 12 months. Participants were categorized into dizzy and nondizzy groups based on self-report of dizziness, vertigo, and light-headedness. RESULTS: Two hundred seventeen (42%) participants reported vertigo or dizziness (10%), light-headedness (16%), or both (16%). The dizzy participants were significantly more likely to report neck and back pain, past transient ischemic attacks, and feeling dizzy upon upright tilting. They also had poorer balance and less strength and scored higher on measures of depression and anxiety (P < .05). There were no blood pressure measurement-related differences between the groups. Dizziness increased the risk of multiple falls in an unadjusted analysis (relative risk (RR) = 1.55, 95% confidence interval = 1.08 2.23). After controlling for PPA scores, neck and back pain and anxiety were mediators that reduced the RR of the relationship between dizziness and faller status the most (14%) in a modified Poisson regression model. CONCLUSION: Suffering from neck and back pain and anxiety were mediators of the relationship between dizziness and falls after controlling for poor sensorimotor function and balance. Older people with dizziness might benefit from interventions targeting these mediators such as pain management and cognitive behavioral therapy. PMID- 23351028 TI - The role of B cells in pregnancy: the good and the bad. AB - B lymphocytes are pleiotropic cells belonging to the adaptive arm of the immune system. Although B cells were classically regarded for their capacity to produce antibodies, in the recent years, several other functions were attributed to these cells. B cells can uptake, process and present antigens as well as produce several cytokines that further influence immunity.Mammalian pregnancies represent a fascinating phenomenon in which the maternal immune system must be able to 'tolerate' the semi-allogenic fetus while simultaneously protecting the mother and the fetus against external pathogens. This requires a finely regulated balance between immune activation and tolerance. In this regard, B cells and the antibodies they produced were shown to actively participate in both, pregnancy well-being as well as pregnancy-associated pathologies.We discuss here the currently available information concerning the role of B cells in the context of pregnancy. PMID- 23351027 TI - Blunted cardiac stress reactivity relates to neural hypoactivation. AB - The present study compared neural activity in participants with blunted (N = 9) or exaggerated (N = 8) cardiac stress reactions. Neural activity was recorded with fMRI while participants performed a validated stress task and control task. Exaggerated reactors exhibited significant increases in heart rate from control to stress task, whereas blunted reactors had no change in heart rate. Blunted reactors also had reduced activation in the anterior midcingulate cortex and insula compared to exaggerated reactors during the stress condition, and a greater deactivation in the amygdala and posterior cingulate. The biological differences between groups in response to the stress task could not be explained by subjective measures of engagement, stressfulness, or difficulty. This study supports the notion that blunted peripheral physiological stress reactivity may be a marker of a corresponding under-recruitment of brain systems during behavioral states requiring motivated action. PMID- 23351029 TI - Association of general and central obesity and atopic and nonatopic asthma in US adults. AB - OBJECTIVE: To examine the association of body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR) with the prevalence of asthma by atopic status and sex using nationally representative data in the US. METHODS: The National Health and Nutrition Examination Survey 2005-2006 data were analyzed using areas under the receiver operating characteristic (ROC) curves (AUCs) and multivariate logistic regression models. RESULTS: Women had higher AUCs (0.59-0.64) than men (0.50-0.58) across anthropometric indices and asthma outcomes. After controlling for sociodemographic characteristics and smoking status, only WHtR was positively associated with atopic asthma in both sexes (odds ratio per 1 SD [95% confidence interval]: men, 1.018 [1.004, 1.032], p = .01; women, 1.018 [1.006, 1.030], p = .003), and the associations persisted after further adjustment of BMI. Only in women was nonatopic asthma significantly associated with every 1 SD increase of BMI (odds ratio [95% confidence interval]: 1.018 [1.006, 1.030], p = .003), WC (1.018 [1.006, 1.030], p = .004), and WHtR (1.016 [1.004, 1.028], p = .008). CONCLUSIONS: Using US national data, this study adds to the emerging evidence suggesting two possible distinct phenotypes: (1) obese men and women with atopic asthma and (2) obese women with nonatopic asthma. The mechanistic and therapeutic implications of these findings warrant further investigation. PMID- 23351030 TI - Characterization of multidrug-resistant Proteus mirabilis isolated from chicken carcasses. AB - This study investigated genotypic and phenotypic features of antimicrobial resistance of Proteus mirabilis isolated from chicken products. Resistance to a broad spectrum of antimicrobial agents was commonly observed in the test isolates: tetracycline (100%), sulfamethoxazole (80%), chloramphenicol (66%), nalidixic acid (66%), ampicillin (60%), streptomycin (56%), ciprofloxacin (52%), kanamycin (46%), gentamicin (38%), ceftriaxone (36%), cefotaxime (34%), ceftiofur (22%), and amoxicillin-clavulanic acid (16%). The beta-lactamases TEM-1 and OXA 1, and extended-spectrum beta-lactamases CTX-M-9 and CMY-2 were detected in beta lactam-resistant isolates. Single mutations in gyrA and parC were found to be contributing factors for fluoroquinolone resistance. Plasmid-mediated quinolone resistance (PMQR) genes qnrA and qnrD were detected in six fluoroquinolone resistant isolates and a superintegron element, SXT, was detected in 14 out of 50 isolates. The high-level of antimicrobial resistance of P. mirabilis isolated from food products may pose a potential threat to public health. PMID- 23351031 TI - Antibacterial activity of Sonoran propolis and some of its constituents against clinically significant Vibrio species. AB - The aim of the present study was to evaluate the anti-Vibrio activity of propolis collected from three different areas of the Sonoran Desert in northwestern, Mexico [Pueblo de Alamos (PAP), Ures (UP), and Caborca (CP)]. The anti-Vibrio spp. activity of Sonoran propolis was determined by the broth microdilution method. UP propolis showed the highest antibacterial activity [minimal inhibitory concentration (MIC(50))<50 MUg mL(-1)] against Vibrio spp. (UP>CP>PAP). UP propolis significantly inhibited the growth of Vibrio cholerae O1 serotype Inaba (MIC(50)<50 MUg mL(-1)), V. cholerae non-O1 (MIC(50)<50 MUg mL(-1)), V. vulnificus (MIC(50)<50 MUg mL(-1)), and V. cholerae O1 serotype Ogawa (MIC(50) 100 MUg mL(-1)), in a concentration-dependent manner. The UP propolis constituents, galangin and caffeic acid phenethyl ester (CAPE), exhibited a potent growth inhibitory activity (MIC(50) 0.05-0.1 mmol l(-1)) against V. cholerae strains (non-O1 and serotype Ogawa). The strong anti-Vibrio activity of Sonoran propolis and some of its chemical constituents (galangin and CAPE) support further studies on the clinical applications of this natural bee product against different Vibrio spp., mainly V. cholerae. PMID- 23351033 TI - Diastereoselective bromocyclization of O-allyl-N-tosyl-hydroxylamines. AB - The intramolecular bromoamination of O-allyl-N-tosyl-hydroxylamines results in the formation of isoxazolidines via selective 5-endo-tet cyclization. This process occurs trans-selectively in high yield and diastereoselectivity. The obtained bromo-isoxazolidines provide access to other useful building blocks, such as 2-azido-aminoalcohols, diaminoalcohols, and aziridines. PMID- 23351032 TI - Clostridium leptum group bacteria abundance and diversity in the fecal microbiota of patients with inflammatory bowel disease: a case-control study in India. AB - BACKGROUND: Alterations in the fecal bacterial flora occur in inflammatory bowel disease (IBD). We examined the abundance and diversity of Clostridium leptum group, an important group of carbohydrate-fermenting bacteria, in the feces of patients with IBD and compared them with healthy controls. METHODS: Seventeen healthy controls (HC), 20 patients with Crohn's disease (CD) and 22 patients with ulcerative colitis (UC) participated in the study. DNA extracted from fecal samples was amplified by PCR targeting 16S rRNA gene sequences specific to C. leptum group. The PCR product was subjected to temporal temperature gradient electrophoresis (TTGE) and the number and position of individual bands were noted and diversity was estimated. The identity of bands at different positions was confirmed by cloning and sequencing. Real time quantitative PCR with Mesa Green, targeted at specific 16S rRNA gene sequences, was used to quantitate C. leptum group and its most prominent constituent, Faecalibacterium prausnitzii. RESULTS: Twenty five different operational taxonomic units (OTUs, equivalent to species) were identified constituting the C. leptum group in these participants. Their sequences were deposited in GenBank [accession numbers GQ465348 to GQ465370]. OTU number was significantly reduced in CD (7.7 +/- 3.7, mean +/- SD) and UC (9.0 +/- 3.0) compared to HC (11.9 +/- 2.2) (P=0.0005). The Simpson D index of alpha diversity was not significantly different between the three groups. Total numbers of C. leptum group bacteria and F. prausnitzii were reduced in both CD and UC compared to HC (P=0.0036 and P<0.0001 respectively). Disease activity did not influence numbers of C. leptum or F. prausnitzii in patients with CD or UC. CONCLUSION: C. leptum numbers and diversity were significantly reduced in both CD and UC suggesting that alterations noted were not specific to one disease. This could contribute to reduced short chain fatty acid production in IBD. PMID- 23351034 TI - Nano-optomechanical actuator and pull-back instability. AB - This paper studies the nonlinear behavior of a nano-optomechanical actuator, consisting of a free-standing arc in a ring resonator that is coupled to a bus waveguide through evanescent waves. The arc deflects when a control light of a fixed wavelength and optical power is pumped into the bus waveguide, while the amount of deflection is monitored by measuring the transmission spectrum of a broadband probe light. This nanoactuator achieves a maximal deflection of 43.1 nm, with a resolution of 0.28 nm. The optical force is a nonlinear function of the deflection of the arc, leading to pull-back instability when the control light is red-tuned. This instability is studied by a combination of experiment and modeling. Potential applications of the nanoactuator include bio-nanomotor, optical switches, and optomechanical memories. PMID- 23351035 TI - Nicotine-motivated behavior in Caenorhabditis elegans requires the nicotinic acetylcholine receptor subunits acr-5 and acr-15. AB - Signaling at nicotinic acetylcholine receptors in Caenorhabditis elegans controls many behaviors, including egg-laying and locomotor activity. Here, we show that C. elegans approaches a point source of nicotine in a time-, concentration- and age-dependent manner. Additionally, nicotine paired with butanone under starvation conditions prevented the reduced approach to butanone that is observed when butanone is paired with starvation alone and pairing with nicotine generates a preference for the tastes of either sodium or chloride over baseline. These results suggest nicotine acts as a rewarding substance in C. elegans. Furthermore, the nicotinic receptor antagonist mecamylamine, the smoking cessation pharmacotherapy varenicline, mutation of the dop-1 and dop-2 dopamine receptors, and mutations of either acr-5 or acr-15, two nicotinic receptor subunit genes with sequence homology to the mammalian alpha7 subunit, all reduced the nicotine approach behavior. These two mutants also were defective at associating the presence of nicotine with butanone under starvation conditions and acr-5 mutation could obviate the effect of pairing nicotine with salts. Furthermore, the approach deficit in acr-15 mutants was rescued by selective re expression in a subset of neurons, but not in muscle. Caenorhabditis elegans may therefore serve as a useful model organism for nicotine-motivated behaviors that could aid in the identification of novel nicotine motivational molecular pathways and consequently the development of novel cessation aids. PMID- 23351036 TI - Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation. AB - AIMS: Given the similarities in QTc response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QTc interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin. METHODS: Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. A threshold of >=10 ms was used to explore the probability of prolongation after drug administration. RESULTS: A linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QTc prolongation >=10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans. CONCLUSIONS: Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug-induced QTc prolongation in humans. Furthermore, the risk of QTc prolongation can be expressed in terms of the probability associated with an increase >=10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule. PMID- 23351037 TI - The protective effects of caffeic acid phenethyl ester in isoniazid and ethambutol-induced ocular toxicity of rats. AB - PURPOSE: This study intended to examine the effect of caffeic acid phenethyl ester (CAPE) on isoniazid (INH) and/or ethambutol (ETM)-induced retina and optic nerve toxicity in a rat model. METHODS: This study included eight groups, each containing 10 rats. The groups were Control, INH, ETM, CAPE, INH+CAPE, ETM+CAPE, INH+ETM and INH+ETM+CAPE. Rats were given orally 50 mg/kg/d of INH and 50 mg/kg/d of ETM in tap water for 30 d. 10 MUmol/kg of CAPE were intraperitoneally injected for 30 d. The first dose of CAPE was given 24 h before the INH and ETM treatment and continued until sacrifice. Control group was given only tap water for 30 d. Rats were anaesthetized and sacrificed on the 30th day of experiment. Superoxide dismutase (SOD) activities, malondialdehyde (MDA), total anti-oxidant status (TAS), total oxidant status (TOS) were measured on the dissected and excised retina and optic nerve samples. Fellow eyes were used for histopathologic evaluation and the retinal ganglion cell (RGC) count. In addition, CAPE, INH and ETM interaction with SOD isoforms were calculated in silico. RESULTS: The SOD activity and TAS levels were found significantly higher in CAPE-treated groups compared to INH and/or ETM-treated groups (p < 0.0001). But the MDA, and TOS levels were significantly lower in CAPE-treated groups (p < 0.0001). The mean RGC count is significantly decreased in INH, ETM and INH+ETM groups compared with INH+CAPE, ETM+CAPE and INH+ETM+CAPE groups, respectively (p values 0.001, 0.042, and 0.001 respectively). Besides, in silico calculations showed that binding affinity of CAPE to SOD isotypes was higher than that of INH and ETM. CONCLUSION: This study demonstrates that CAPE treatment may decrease the oxidative stress in the retina and optic nerve of INH- and ETM-treated rats and may prevent RGC loss. As an underlying mechanism, CAPE and SOD interaction seems crucial for alleviation of ocular oxidative stress and RGCs toxicity. PMID- 23351038 TI - Inverse solvent isotope effects arising from substrate triggering in the factor inhibiting hypoxia inducible factor. AB - Oxygen homeostasis plays a critical role in angiogenesis, erythropoiesis, and cell metabolism. Oxygen homeostasis is set by the hypoxia inducible factor-1alpha (HIF-1alpha) pathway, which is controlled by factor inhibiting HIF-1alpha (FIH). FIH is a non-heme Fe(II), alpha-ketoglutarate (alphaKG)-dependent dioxygenase that inhibits HIF-1alpha by hydroxylating the C-terminal transactivation domain (CTAD) of HIF-1alpha at HIF-Asn(803). A tight coupling between CTAD binding and O2 activation is essential for hypoxia sensing, making changes in the coordination geometry of Fe(II) upon CTAD encounter a crucial feature of this enzyme. Although the consensus chemical mechanism for FIH proposes that CTAD binding triggers O2 activation by causing the Fe(II) cofactor to release an aquo ligand, experimental evidence of this has been absent. More broadly, this proposed coordination change at Fe(II) has not been observed during steady-state turnover in any alphaKG oxygenase to date. In this work, solvent isotope effects (SIEs) were used as a direct mechanistic probe of substrate-triggered aquo release in FIH, as inverse SIEs (SIE < 1) are signatures for pre-equilibrium aquo release from metal ions. Our mechanistic studies of FIH have revealed inverse solvent isotope effects in the steady-state rate constants at limiting concentrations of CTAD or alphaKG [(D2O)kcat/KM(CTAD) = 0.40 +/- 0.07, and (D2O)kcat/KM(alphaKG) = 0.32 +/- 0.08], providing direct evidence of aquo release during steady-state turnover. Furthermore, the SIE at saturating concentrations of CTAD and alphaKG was inverse ((D2O)kcat = 0.51 +/- 0.07), indicating that aquo release occurs after CTAD binds. The inverse kinetic SIEs observed in the steady state for FIH can be explained by a strong Fe-OH2 bond. The stable Fe-OH2 bond plays an important part in FIH's regulatory role over O2 homeostasis in humans and points toward a strategy for tightly coupling O2 activation with CTAD hydroxylation that relies on substrate triggering. PMID- 23351039 TI - The complete mitochondrial genome of Cermatobius longicornis (Chilopoda: Lithobiomorpha: Henicopidae). AB - The first complete mitogenome sequence of Henicopidae is reported herein. The mitochondrial genome of Cermatobius longicornis (Lithobiomorpha: Henicopidae) is a circular molecule of 16,833 bp in length. It contains 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs, a control region and a pseudo control region. The comparability of the last 396 bp between the control region and the pseudo control region is 70.3%. The alpha strand has the following nucleotide composition: A = 4858 (28.86%), T = 5813 (34.53%), C = 3184 (18.92%) and G = 2978 (17.69%). GC- and AT-skews for the alpha strand, which can reflect the base compositional differences between the two strands, are--0.03 and 0.09, respectively. The gene order of C. longicornis is identical to that of Limulus polyphemus, except for the extra pseudo control region. PMID- 23351040 TI - How do metabolites differ from their parent molecules and how are they excreted? AB - Understanding which physicochemical properties, or property distributions, are favorable for successful design and development of drugs, nutritional supplements, cosmetics, and agrochemicals is of great importance. In this study we have analyzed molecules from three distinct chemical spaces (i) approved drugs, (ii) human metabolites, and (iii) traditional Chinese medicine (TCM) to investigate four aspects determining the disposition of small organic molecules. First, we examined the physicochemical properties of these three classes of molecules and identified characteristic features resulting from their distinctive biological functions. For example, human metabolites and TCM molecules can be larger and more hydrophobic than drugs, which makes them less likely to cross membranes. We then quantified the shifts in physicochemical property space induced by metabolism from a holistic perspective by analyzing a data set of several thousand experimentally observed metabolic trees. Results show how the metabolic system aims to retain nutrients/micronutrients while facilitating a rapid elimination of xenobiotics. In the third part we compared these global shifts with the contributions made by individual metabolic reactions. For better resolution, all reactions were classified into phase I and phase II biotransformations. Interestingly, not all metabolic reactions lead to more hydrophilic molecules. We were able to identify biotransformations leading to an increase of logP by more than one log unit, which could be used for the design of drugs with enhanced efficacy. The study closes with the analysis of the physicochemical properties of metabolites found in the bile, faeces, and urine. Metabolites in the bile can be large and are often negatively charged. Molecules with molecular weight >500 Da are rarely found in the urine, and most of these large molecules are charged phase II conjugates. PMID- 23351041 TI - Clinical features and outcomes of tuberculosis in kidney transplant recipients in Brazil: a report of the last decade. AB - BACKGROUND: Among kidney transplant recipients (KTRs), tuberculosis is one of the most common opportunistic infections and is associated with high morbidity and mortality. The aim of this study was to describe the incidence, clinical features, and prognosis of tuberculosis in KTRs. METHODS: Retrospective single center observational study involving all cases of tuberculosis in KTRs between 2000 and 2010. RESULTS: Of the 1549 KTRs evaluated, 43 (2.8%) developed tuberculosis, translating to an annual incidence of 803 cases/100 000 patients, considerably higher than that reported for the general population of Brazil. The median time to tuberculosis (TB) onset after transplantation was 196 d (range, 19 3626 d). Of the KTRs with tuberculosis, 67% became infected within the first year post-transplant, 74% had pulmonary tuberculosis, and 7% had a previous history of active tuberculosis. No tuberculosis prophylaxis was employed before or after transplantation. The most common symptoms were fever (in 79%), cough (in 35%), and dyspnea (in 16%). The median time from the onset of symptoms to the start of treatment was 28 d. The median duration of antituberculosis therapy was 196 d. In 15 patients (35%), the immunosuppressive therapy was reduced, and the incidence of acute rejection was higher in patients with tuberculosis than in those without (44% vs. 28%). Mortality during tuberculosis treatment was 12% (5 cases), and all five deaths were attributed to tuberculosis. Ten-yr death-censored graft survival and patient survival were similar between patients with tuberculosis and those without. CONCLUSION: Among KTRs, symptoms of tuberculosis are often attenuated, which leads to delayed diagnosis, and tuberculosis-related mortality remains high. PMID- 23351042 TI - Inferring spatial memory and spatiotemporal scaling from GPS data: comparing red deer Cervus elaphus movements with simulation models. AB - 1. Increased inference regarding underlying behavioural mechanisms of animal movement can be achieved by comparing GPS data with statistical mechanical movement models such as random walk and Levy walk with known underlying behaviour and statistical properties. 2. GPS data are typically collected with >= 1 h intervals not exactly tracking every mechanistic step along the movement path, so a statistical mechanical model approach rather than a mechanistic approach is appropriate. However, comparisons require a coherent framework involving both scaling and memory aspects of the underlying process. Thus, simulation models have recently been extended to include memory-guided returns to previously visited patches, that is, site fidelity. 3. We define four main classes of movement, differing in incorporation of memory and scaling (based on respective intervals of the statistical fractal dimension D and presence/absence of site fidelity). Using three statistical protocols to estimate D and site fidelity, we compare these main movement classes with patterns observed in GPS data from 52 females of red deer (Cervus elaphus). 4. The results show best compliance with a scale-free and memory-enhanced kind of space use; that is, a power law distribution of step lengths, a fractal distribution of the spatial scatter of fixes and site fidelity. 5. Our study thus demonstrates how inference regarding memory effects and a hierarchical pattern of space use can be derived from analysis of GPS data. PMID- 23351043 TI - Increased protein sorption in poly(acrylic acid)-containing films through incorporation of comb-like polymers and film adsorption at low pH and high ionic strength. AB - In principle, incorporation of comb-like block copolymers in multilayer polyelectrolyte films can both increase film thickness relative to coatings containing linear polymers and provide more swollen films for increased sorption of proteins. In the absence of added salt, alternating adsorption of 5 bilayers of protonated poly(allylamine) (PAH) and comb-like poly(2-hydroxyethyl methacrylate)-graft-poly(acrylic acid) (PHEMA-g-PAA) leads to ~2-fold thicker coatings than adsorption of PAH and linear PAA, and the difference in the thicknesses of the two coatings increases with the number of bilayers. Moreover, the (PAH/PHEMA-g-PAA)n films sorb 2- to 4-fold more protein than corresponding films prepared with linear PAA, and coatings deposited at pH 3.0 sorb more protein than coatings adsorbed at pH 5.0, 7.0, or 9.0. In fact changes in deposition pH and addition of 0.5 M NaCl to polyelectrolyte adsorption solutions alter protein sorption more dramatically than variations in the constituent polymer architecture. When deposited from 0.5 M NaCl at pH 3.0, both (PAH/PHEMA-g PAA)5 and (PAH/PAA)5 films increase in thickness more than 400% upon adsorption of lysozyme. These films contain a high concentration of free -COOH groups, and subsequent deprotonation of these groups at neutral pH likely contributes to increased protein binding. Lysozyme sorption stabilizes these films, as without lysozyme films deposited at pH 3.0 from 0.5 M NaCl desorb at neutral pH. Films deposited at pH 9.0 from 0.5 M NaCl are more stable and also bind large amounts of lysozyme. The high binding capacities of these films make them attractive for potential applications in protein isolation or immobilization of enzymes. PMID- 23351044 TI - DNAzyme footprinting: detecting protein-aptamer complexation on surfaces by blocking DNAzyme cleavage activity. AB - A novel method to quantitatively measure the binding of proteins to single stranded DNA (ssDNA) aptamers that employs the inhibition of the DNAzyme hydrolysis of aptamer monolayers is described. A 28-base DNAzyme was designed to specifically bind to and cleave a 29-base ssDNA sequence that can fold into a G quartet aptamer and bind the protein thrombin. The binding strength of the DNAzyme to the aptamer sequence was designed to be less than the binding strength of the thrombin to the aptamer (DeltaG degrees = -43.1 and -51.8 kJ/mol, respectively). Formation of the thrombin-aptamer complex was found to block DNAzyme cleavage activity both in solution and in an ssDNA aptamer monolayer. We denote this method for detecting protein-aptamer complexation as "DNAzyme footprinting" in analogy to the process of DNase footprinting for the detection of protein-DNA interactions. By attaching a 40-base reporter sequence to the ssDNA aptamer monolayer, the detection of any protein-aptamer complexes remaining on the surface after DNAzyme activity can be greatly enhanced (down to one thrombin-aptamer complex per 10,000 ssDNA molecules corresponding to 100 fM thrombin in solution) by a subsequent surface RNA transcription amplification reaction followed by RNA detection with nanoparticle-enhanced SPR imaging. In addition to RNA transcription, DNAzyme footprinting can be coupled to a wide variety of other nucleic acid surface amplification schemes and thus is a powerful new route for the enzymatically amplified detection of proteins via protein-aptamer complex formation. PMID- 23351045 TI - In-line multipoint near-infrared spectroscopy for moisture content quantification during freeze-drying. AB - During the past decade, near-infrared (NIR) spectroscopy has been applied for in line moisture content quantification during a freeze-drying process. However, NIR has been used as a single-vial technique and thus is not representative of the entire batch. This has been considered as one of the main barriers for NIR spectroscopy becoming widely used in process analytical technology (PAT) for freeze-drying. Clearly it would be essential to monitor samples that reliably represent the whole batch. The present study evaluated multipoint NIR spectroscopy for in-line moisture content quantification during a freeze-drying process. Aqueous sucrose solutions were used as model formulations. NIR data was calibrated to predict the moisture content using partial least-squares (PLS) regression with Karl Fischer titration being used as a reference method. PLS calibrations resulted in root-mean-square error of prediction (RMSEP) values lower than 0.13%. Three noncontact, diffuse reflectance NIR probe heads were positioned on the freeze-dryer shelf to measure the moisture content in a noninvasive manner, through the side of the glass vials. The results showed that the detection of unequal sublimation rates within a freeze-dryer shelf was possible with the multipoint NIR system in use. Furthermore, in-line moisture content quantification was reliable especially toward the end of the process. These findings indicate that the use of multipoint NIR spectroscopy can achieve representative quantification of moisture content and hence a drying end point determination to a desired residual moisture level. PMID- 23351046 TI - Alvarado score: a guide to computed tomography utilization in appendicitis. AB - BACKGROUND: Although useful in evaluation of suspected appendicitis, not all patients require computed tomography (CT) evaluation. Clinical stratification of patients who benefit from CT evaluation is essential. We utilize the Alvarado score (AS) to stratify patients with suspected appendicitis into subgroups who benefit from CT evaluation and propose an objective algorithm with AS guiding CT utilization. METHODS: This study is a retrospective review of medical records of all patients admitted for suspected appendicitis over a 6-month duration. Relevant data were recorded. The AS for each patient was determined retrospectively and correlated with histological and CT findings. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were determined for various ASs and for CT. RESULTS: Three hundred fifty-eight patients were studied, with 167 males (46.6%) and 191 females (53.4%). Prevalence of appendicitis was 50% (179 patients). Two hundred fourteen patients (59.8%) had CT performed. Surgery was performed for 206 patients (57.5%). Overall negative appendicectomy rate was 13.1%. Patients who underwent CT evaluation had a negative appendicectomy rate of 5.7% compared to 17.9% in those without CT evaluation (P = 0.009). CT scan had a sensitivity and specificity of 92.6% and 96.9%, respectively. An AS greater than 3 had a sensitivity superior to CT (95.5%), while an AS of 9 or greater had a specificity superior to CT (100%). CONCLUSIONS: In suspected appendicitis, patients who benefit from CT evaluation are those with the AS ranging from 4 to 8. We propose a management algorithm with the AS guiding the necessity for CT evaluation. PMID- 23351047 TI - Dynamical analysis on duplicating-and-assimilating process: toward the understanding of mirror-neuron systems. AB - In this paper, we mathematically study a particular process for assimilation in the brain. The research aims to establish a theoretical model at computational level of the mechanism in a cognitive process operated by the mirror-neuron system, to generate a multi-dimensional system from this model, and to analyze the fundamentals of the related cognitive process in terms of dynamical systems. Finally, to understand the interactions between two individual mirror-neuron systems, we formulate and examine coupled systems that are composed of two distinct systems. We also carry out various numerical simulations to illustrate the assimilation process. PMID- 23351048 TI - When order matters: last-come first-served effect in sequential arithmetic operations. AB - Cognitive psychologists have relied on dual-task interference experiments to understand the low-capacity and serial nature of conscious mental operations. Two widely studied paradigms, the Attentional Blink (AB) and the Psychological Refractory Period (PRP) have demonstrated a first-come first-served policy; processing a stimulus either impedes conscious access (AB) or postpones treatment (PRP) of a concurrent stimulus. Here we explored the transition from dual-task paradigms to multi-step human cognition. We studied the relative weight of individual addends in a sequential arithmetic task, where number notation (symbolic/non-symbolic) and presentation speed were independently manipulated. For slow presentation and symbolic notation, the decision relied almost equally on all addends, whereas for fast or non-symbolic notation, the decision relied almost exclusively on the last item reflecting a last-come first-served policy. We suggest that streams of stimuli may be chunked in events in which the last stimuli may override previous items from sensory buffers. PMID- 23351049 TI - The effect of proprioceptive training on multisensory perception under visual uncertainty. AB - Most previous studies on multisensory integration concern mandatory integration. Moreover, no study has evaluated the effect of modality training on the result of integration. The purpose of this study is to evaluate the effect of training on visual-proprioceptive integration; i.e., we investigate the effect of proprioceptive modality training on the hand location estimation, when visual feedback exists. To achieve this goal, the effect of visual uncertainty on the estimation of hand position in visual-proprioceptive integration is studied in two groups: trained proprioception and untrained proprioception. The visual uncertainty is provided by an unpredictable spatial shift between visual and proprioceptive sensory feedbacks. The experiment was performed on nine subjects with trained proprioception and 11 subjects without proprioception training. The experiment had three phases: "familiarization", to draw participant's attention to a modality, "proprioception test", to estimate the hand position using only proprioception, and "vision-proprioception test", to investigate the effect of the visual uncertainty (bias) on hand position estimation. Our results indicate that: (i) modality training increases the subject reliance on the proprioceptive sensory information (i.e., bias decrement in sensory integration); and (ii) increasing the discrepancy between the modalities leads to more uncertainty (i.e., variance) in the estimation of hand position, but the variance of the final estimate is less than the variance of the proprioceptive estimate. This result confirms the theory that both senses contribute to the multisensory perception and in contrast to some studies, the dominant sense does not fully override the non-dominant one in the range of applied shift between the sensory sources. PMID- 23351050 TI - Intracellular capacitive effects of polarized proteins in dendrites. AB - Passive dendrites become active as a result of electrostatic interactions by dielectric polarization in proteins in a segment of a dendrite. The resultant nonlinear cable equation for a cylindrical volume representation of a dendritic segment is derived from Maxwell's equations under assumptions: (i) the electric field is restricted longitudinally along the cable length; (ii) extracellular isopotentiality; (iii) quasi-electrostatic conditions; (iv) isotropic membrane and homogeneous medium with constant conductivity; and (v) protein polarization contributes to intracellular capacitive effects through a well defined nonlinear capacity-voltage characteristic; (vi) intracellular resistance and capacitance in parallel are connected to the membrane in series. Under the above hypotheses, traveling wave solutions of the cable equation are obtained as propagating fronts of electrical excitation associated with capacitive charge-equalization and dispersion of continuous polarization charge densities in an Ohmic cable. The intracellular capacitative effects of polarized proteins in dendrites contribute to the conduction process. PMID- 23351051 TI - Inhibition of protein kinase C signal reduces ET receptor expression and basilar vasospasm after subarachnoid hemorrhage in rats. AB - Endothelin-1 (ET-1), acting through specific ET(A) and/or ET(B) receptors, plays an important role in cerebral vasospasm after subarachnoid hemorrhage (SAH). However, the mechanism remains unclear. In the present study, ET receptors' expression in the basiliar artery during cerebral vasospasm and the possible involvement of protein kinase C (PKC) were investigated using immunofluorescence staining and reverse transcriptase polymerase chain reaction (RT-PCR) in a rat SAH model of delayed cerebral vasospasm (DCVS). The cross-sectional area of the basilar artery in the SAH model group decreased in 2-3 days, and then gradually returned to normal. ET(A) receptor expression in endothelial cells of the basilar artery increased in day 2 after SAH, peaked at day 3 and remained increased till day 14. ET(B) receptor expression increased significantly in endothelial cells at day 3, peaked at day 7 and remained until day 14. RT-PCR result also revealed increased expressions of similar trends, but the expression of ET(B) receptor mRNA level tended to increase earlier than the protein level. When PKC inhibitor (RO-31-7549, 10(-6) mol/L, 50 MUl) was administered 1, 6, 24, 32, 48 and 70 hours before cisternal injection, the expressions of the two ET receptors after day 3 decreased to varying degrees, while the vascular cross-sectional area was significantly higher (P < 0.05). The results suggest that the ET(A)/ET(B) receptors play an important role in cerebral vasospasm after SAH. Application of RO-31-7549 reduced the expression of ET receptors and reduced cerebral vasospasm, suggesting that inhibition of PKC signaling pathway could effectively reduce DCVS after SAH. PMID- 23351052 TI - On the neural basis of rule-guided behavior. AB - Human behavior emerges from a complex dynamic interaction between graded and context-sensitive neural processes, the biomechanics of our bodies, and the vicissitudes of our environments. These coupled processes bear little resemblance to the iterated application of simple symbolic rules. Still, there are circumstances under which our behavior appears to be guided by explicit mental rules. A prototypical case is when succinct verbal instructions are communicated and are promptly followed by another. How does the brain support such rule-guided behavior? How are explicit rules represented in the brain? How are rule representations shaped by experience? What neural processes form the foundation of our ability to systematically represent and apply rules from the vast range of possible rules? This article reviews a line of research that has sought a computational cognitive neuroscience account of rule-guided behavior in terms of the functioning of the prefrontal cortex, the basal ganglia, and related brain systems. PMID- 23351053 TI - Gender, facial attractiveness, and early and late event-related potential components. AB - Facial attractiveness has been an interesting topic in cognitive psychology due to its key role in human communication and experience. The evaluation of attractiveness is adjusted by many factors including gender differences and cultural biases. In this paper, event-related potential (ERP) activity was recorded in an oddball paradigm from 10 Chinese men and 10 Chinese women who judged attractiveness of faces. Participants were told to detect faces with neutral expression and judge their attractiveness among a train of neutral objects that were presented more frequently than the faces. The ERP analyses showed that there was enhanced detection over early (P1, N170, P2, N300) and late (P3b) components in both genders. This suggests that a biased electrophysiological response to attractive faces compared to unattractive faces could indicate the involvement of emotion and reward pathways in judging facial attractiveness. Specifically, there were delayed P1 and P3b latencies in response to attractive faces with slower response times in men compared to women. From an evolutionary perspective, this may suggest that men attribute more value to facial appearances, especially attractive features, than women do, as evidenced by their cognitive load while processing attractive faces compared to unattractive faces. PMID- 23351055 TI - Aryl azide photochemistry in defined protein environments. AB - A genetically encoded precursor to an aryl nitrene, para-azidophenylalanine, was introduced site specifically into proteins to deduce if distinct environments were capable of caging a reactive organic intermediate. Following photolysis of mutant T4 lysozyme or green fluorescent proteins, EPR spectra showed, respectively, the presence of a triplet nitrene and an anilino radical. PMID- 23351056 TI - Functional and pharmacological consequences of the distribution of voltage-gated calcium channels in the renal blood vessels. AB - Calcium channel blockers are widely used to treat hypertension because they inhibit voltage-gated calcium channels that mediate transmembrane calcium influx in, for example, vascular smooth muscle and cardiomyocytes. The calcium channel family consists of several subfamilies, of which the L-type is usually associated with vascular contractility. However, the L-, T- and P-/Q-types of calcium channels are present in the renal vasculature and are differentially involved in controlling vascular contractility, thereby contributing to regulation of kidney function and blood pressure. In the preglomerular vascular bed, all the three channel families are present. However, the T-type channel is the only channel in cortical efferent arterioles which is in contrast to the juxtamedullary efferent arteriole, and that leads to diverse functional effects of L- and T-type channel inhibition. Furthermore, by different mechanisms, T-type channels may contribute to both constriction and dilation of the arterioles. Finally, P-/Q-type channels are involved in the regulation of human intrarenal arterial contractility. The calcium blockers used in the clinic affect not only L-type but also P-/Q- and T type channels. Therefore, the distinct effect obtained by inhibiting a given subtype or set of channels under experimental settings should be considered when choosing a calcium blocker for treatment. T-type channels seem to be crucial for regulating the GFR and the filtration fraction. Use of blockers is expected to lead to preferential efferent vasodilation, reduction of glomerular pressure and proteinuria. Therefore, renovascular T-type channels might provide novel therapeutic targets, and may have superior renoprotective effects compared to conventional calcium blockers. PMID- 23351057 TI - Health-related quality of life in colorectal cancer. AB - AIM: As a consequence of the improved survival of patients and of cost effectiveness requirements for new treatments, health-related quality of life (HRQoL) issues have gained increasing attention in colorectal cancer (CRC). This cross-sectional study assesses HRQoL in several health states of CRC and explores factors influencing HRQoL. METHOD: Five hundred and eight Finnish CRC patients (aged 26-96 years; colon cancer 56%; women 47%) assessed their HRQoL using generic 15D and EQ-5D and cancer-specific EORTC QLQ-C30 questionnaires. Patients were divided into five groups: primary treatment, rehabilitation, remission, metastatic disease and palliative care. The patients' HRQoL was compared with population reference values. Multivariate modelling was used to find factors associated with HRQoL scores. RESULTS: The HRQoL of CRC patients is fairly good and comparable with that of the standardized general population except for those under palliative care. The mean 15D score of patients in the primary treatment group was 0.889 (95% CI 0.869-0.914), in rehabilitation 0.877 (0.855-0.907), in remission 0.886 (0.875-0.903), in metastatic disease 0.860 (0.844-0.878) and in palliative care 0.758 (0.716-0.808). The respective EQ-5D scores were 0.760 (0.699-0.823), 0.835 (0.777-0.881), 0.850 (0.828-0.882), 0.820 (0.783-0.858) and 0.643 (0.546-0.747). Multivariate analysis showed that fatigue, pain, age and financial difficulties had a marked negative impact on HRQoL. CONCLUSION: The mean HRQoL scores of CRC patients varied considerably depending on the HRQoL instrument used, but remained surprisingly good up to the palliative stage. In addition to age- and cancer-related symptoms, financial difficulties also had a clear negative impact on HRQoL, which needs to be taken into consideration when supporting patient HRQoL. PMID- 23351058 TI - Human chorionic gonadotropin regulates endothelial cell responsiveness to interleukin 1 and amplifies the cytokine-mediated effect on cell proliferation, migration and the release of angiogenic factors. AB - PROBLEM: Successful embryonic implantation requires an appropriate communication network between the embryo and its near environment within the implantation site. Herein, we examined whether human chorionic gonadotropin (hCG), the major embryonic signal, targets endothelial cells and regulate their responsiveness to interleukin 1 (IL1), one of the earliest signals released by embryonic cells. METHOD OF STUDY: Human microvascular endothelial cell proliferation and migration following exposure to various concentrations of hCG and/or IL1B for different time periods were analyzed by BrdU incorporation and wound healing assays. The expression of soluble (s) and membrane-bound (mb) IL1 receptors (IL1Rs), IL1R antagonist (IL1RN), luteinizing hormone/choriogonadotropin receptor (LHCGR), and IL8 was determined by real-time PCR, Western blot, and ELISA. RESULTS: Cell proliferation and migration increased in response to IL1B and further in the presence of hCG. IL1B up-regulated both the signaling IL1R1 and the inhibitory IL1R2, while adding hCG further increased IL1R1 and significantly downregulated IL1R2. This translated into an increased secretion of IL8, which was inhibited in cells where IL1R2 was overexpressed. CONCLUSIONS: These findings reveal a new mechanism by which hCG may target endothelial cells to directly stimulate angiogenesis and favor embryonic growth. PMID- 23351059 TI - Continued widespread dissemination and increased poultry host fitness of Campylobacter jejuni ST-4526 and ST-4253 in Japan. AB - AIMS: Campylobacter jejuni is a major cause of foodborne gastroenteritis. We previously reported the widespread Camp. jejuni sequence type (ST)-4526 in Japan from 2005 to 2006. This study assesses the potential for this genotype to thrive thereafter. METHODS AND RESULTS: Fifty human Camp. jejuni isolates collected in 2010-2011 in Osaka, Japan, were genotyped by multilocus sequence typing (MLST). This approach identified 22 STs and 11 clonal complexes (CCs), including four novel STs. A comparative analysis to the previous data set showed the predominance of CC-21, in which ST-4526 and ST-4253 represented 39 and 63% in each of the two time frames, indicating their continued widespread presence. These two STs belong to close evolutionary lineages and are also isolated from chicken meat. The superior abilities of ST-4526/ST-4253 representatives to colonize chicken gut were demonstrated by co-infections with ST-21, ST-50 and ST 8 representatives. CONCLUSIONS: Data provide evidence for the continued widespread of ST-4526/ST-4253 among human clinical isolates in Japan. These STs showed adaptive fitness to chicken. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first evidence of the continued thriving of ST-4526/ST-4253 in Japan with their increased in vivo fitness. Our findings suggest that poultry mediates the microevolution of this pathogen, thereby enabling these STs to become widespread. PMID- 23351060 TI - Diastereoselective synthesis of C60/steroid conjugates. AB - The design and synthesis of fullerene-steroid hybrids by using Prato's protocol has afforded new fullerene derivatives endowed with epiandrosterone, an important naturally occurring steroid hormone. Since the formation of the pyrrolidine ring resulting from the 1,3-dipolar cyloaddition reaction takes place with generation of a new stereogenic center on the C2 of the five-membered ring, the reaction proceeds with formation of a diastereomeric mixture [compounds 6 and 7 in 70:30 ratio, 8 and 9 in 26:74 ratio (HPLC)] in which the formation of the major diasteroisomers 6 and 9 is consistent with an electrophilic attack of [60]fullerene on the Re face of the azomethine ylide directed by the steroidic unit. The chiroptical properties of these conjugates reveal typical Cotton effects in CD spectra that have been used to assign the absolute configuration of the new fulleropyrrolidines. The electrochemical study of the new compounds reveals the presence of four quasi-reversible reduction waves which are cathodically shifted in comparison with the parent C60, thus ascertaining the proposed structures. PMID- 23351062 TI - Osteoporosis knowledge, health beliefs, and healthy bone behaviours in patients on androgen-deprivation therapy (ADT) for prostate cancer. AB - OBJECTIVES: To describe in patients with prostate cancer, receiving androgen deprivation therapy (ADT): (i) knowledge, self-efficacy (SE), and health beliefs about osteoporosis (OP); (ii) current engagement in healthy bone behaviours (HBBs). To explore the relationships between knowledge, SE, and health beliefs, and engagement in HBBs. PATIENTS AND METHODS: 175 patients receiving ADT by injection completed questionnaires assessing current HBBs, OP knowledge, SE, and health beliefs (motivation, perceived susceptibility, and seriousness). Descriptive statistics and independent samples t-tests were used to assess relationships between knowledge, SE, health beliefs, and engagement in HBBs. RESULTS: Only 38% of patients had undergone a dual X-ray absorptiometry scan in the past 2 years. OP knowledge was low (mean [sd, range] 9.6 [4.4, 0-19]) and perceived SE moderate (84.7 [24.5, 0-120]). Health motivation was fairly high (23.6 [3.1, 6-30]), but perceived susceptibility (16.8 [4.3]) and seriousness (16.8 [4.2]) of OP were low. Few patients met the recommendations for vitamin D intake (42%) and exercise (31%), and 15% were at risk of over-supplementation of calcium. Patients taking calcium supplements (P = 0.04), and meeting guidelines for vitamin D (P = 0.008) and for exercise (P = 0.002) had significantly greater knowledge than those who did not. Patients who were engaging in less than four of five HBBs had lower knowledge (P < 0.001) and health motivation (P = 0.01) than those who were engaging in four or all five HBBs. CONCLUSIONS: Most patients who are receiving ADT are not receiving appropriate screening, lack basic information about bone health, and are not engaging in the appropriate HBBs. These findings support the application of the Health Belief Model in this population: interventions that teach patients about the implications of bone loss, encourage proper uptake of HBBs, and promote feelings of SE could increase engagement in HBBs to prevent and manage bone loss. PMID- 23351061 TI - Category-based inhibition of focused attention across consecutive trials. AB - The distractor previewing effect (DPE) refers to the behavioral phenomenon that search times increase for oddball targets containing features recently associated with the absence of a target. Previous work using a color-oddball search task showed that the DPE covaried with the N2pc component of the event-related potential (an index of attention allocation) but not with other components, suggesting that the DPE reflects shifts in attentional sets. We sought to determine whether the previous results could generalize to a category-oddball search task. Results showed that the DPE co-occurred with N2pc effects in about 60% of the participants, and the DPE occurred with no N2pc effects in the rest of the participants. These results support a domain-general, attention-based account of the DPE, but also suggest that the attention-based DPE account requires some modifications. PMID- 23351063 TI - The isomerase and hydratase reaction mechanism of the crotonase active site of the multifunctional enzyme (type-1), as deduced from structures of complexes with 3S-hydroxy-acyl-CoA. AB - The multifunctional enzyme, type-1 (MFE1) is involved in several lipid metabolizing pathways. It catalyses: (a) enoyl-CoA isomerase and (b) enoyl-CoA hydratase (EC 4.2.1.17) reactions in its N-terminal crotonase part, as well as (3) a 3S-hydroxy-acyl-CoA dehydrogenase (HAD; EC 1.1.1.35) reaction in its C terminal 3S-hydroxy-acyl-CoA dehydrogenase part. Crystallographic binding studies with rat peroxisomal MFE1, using unbranched and branched 2E-enoyl-CoA substrate molecules, show that the substrate has been hydrated by the enzyme in the crystal and that the product, 3S-hydroxy-acyl-CoA, remains bound in the crotonase active site. The fatty acid tail points into an exit tunnel shaped by loop-2. The thioester oxygen is bound in the classical oxyanion hole of the crotonase fold, stabilizing the enolate reaction intermediate. The structural data of these enzyme product complexes suggest that the catalytic base, Glu123, initiates the isomerase reaction by abstracting the C2-proton from the substrate molecule. Subsequently, in the hydratase reaction, Glu123 completes the catalytic cycle by reprotonating the C2 atom. A catalytic water, bound between the OE1-atoms of the two catalytic glutamates, Glu103 and Glu123, plays an important role in the enoyl CoA isomerase and the enoyl-CoA hydratase reaction mechanism of MFE1. The structural variability of loop-2 between MFE1 and its monofunctional homologues correlates with differences in the respective substrate preferences and catalytic rates. PMID- 23351064 TI - Frailty and fracture, disability, and falls: a multiple country study from the global longitudinal study of osteoporosis in women. AB - OBJECTIVES: To test whether women aged 55 and older with increasing evidence of a frailty phenotype would have greater risk of fractures, disability, and recurrent falls than women who were not frail, across geographic areas (Australia, Europe, and North America) and age groups. DESIGN: Multinational, longitudinal, observational cohort study. SETTING: Global Longitudinal Study of Osteoporosis in Women (GLOW). PARTICIPANTS: Women (N = 48,636) aged 55 and older enrolled at sites in Australia, Europe, and North America. MEASUREMENTS: Components of frailty (slowness and weakness, poor endurance and exhaustion, physical activity, and unintentional weight loss) at baseline and report of fracture, disability, and recurrent falls at 1 year of follow-up were investigated. Women also reported health and demographic characteristics at baseline. RESULTS: Women younger than 75 from the United States were more likely to be prefrail and frail than those from Australia, Canada, and Europe. The distribution of frailty was similar according to region for women aged 75 and older. Odds ratios from multivariable models for frailty versus nonfrailty were 1.23 (95% confidence interval (CI) = 1.07-1.42) for fracture, 2.29 (95% CI = 2.09-2.51) for disability, and 1.68 (95% CI = 1.54-1.83) for recurrent falls. The associations for prefrailty versus nonfrailty were weaker but still indicated statistically significantly greater risk of each outcome. Overall, associations between frailty and each outcome were similar across age and geographic region. CONCLUSION: Greater evidence of a frailty phenotype is associated with greater risk of fracture, disability, and falls in women aged 55 and older in 10 countries, with similar patterns across age and geographic region. PMID- 23351066 TI - The complete mitochondrial genome sequence of Pseudobagrus ussuriensis (Siluriformes: Bagridae). AB - The complete mitochondrial DNA genome sequence of Ussuri catfish (Pseudobagrus ussuriensis) was determined. The mitochondrial genome sequence is a circular molecule with 16,536 bp in length. It contains 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and 2 non-coding regions. The nucleotide acid composition of the entire mitogenome is 31.79% for A, 26.84% for T, 14.87% for G, and 26.50% for C, showing a high A+T content. The complete mitogenome sequence of P. ussuriensis can be used in the studies on molecular systematics, conservation genetics, and stock evaluation. PMID- 23351065 TI - Loop-loop interactions regulate KaiA-stimulated KaiC phosphorylation in the cyanobacterial KaiABC circadian clock. AB - The Synechococcus elongatus KaiA, KaiB, and KaiC proteins in the presence of ATP generate a post-translational oscillator that runs in a temperature-compensated manner with a period of 24 h. KaiA dimer stimulates phosphorylation of KaiC hexamer at two sites per subunit, T432 and S431, and KaiB dimers antagonize KaiA action and induce KaiC subunit exchange. Neither the mechanism of KaiA-stimulated KaiC phosphorylation nor that of KaiB-mediated KaiC dephosphorylation is understood in detail at present. We demonstrate here that the A422V KaiC mutant sheds light on the former mechanism. It was previously reported that A422V is less sensitive to dark pulse-induced phase resetting and has a reduced amplitude of the KaiC phosphorylation rhythm in vivo. A422 maps to a loop (422-loop) that continues toward the phosphorylation sites. By pulling on the C-terminal peptide of KaiC (A-loop), KaiA removes restraints from the adjacent 422-loop whose increased flexibility indirectly promotes kinase activity. We found in the crystal structure that A422V KaiC lacks phosphorylation at S431 and exhibits a subtle, local conformational change relative to wild-type KaiC. Molecular dynamics simulations indicate higher mobility of the 422-loop in the absence of the A-loop and mobility differences in other areas associated with phosphorylation activity between wild-type and mutant KaiCs. The A-loop-422-loop relay that informs KaiC phosphorylation sites of KaiA dimer binding propagates to loops from neighboring KaiC subunits, thus providing support for a concerted allosteric mechanism of phosphorylation. PMID- 23351068 TI - Effects of oxidative stress on the pharmacokinetics and hepatic metabolism of atazanavir in rats. AB - We studied the effects of oxidative stress (OS) on the pharmacokinetics of atazanavir (ATV), particularly the distribution of ATV in the plasma and its metabolism in hepatic microsomes, using a rat model of ferric-nitrilotriacetate induced OS (OS rats). The areas under the plasma concentration-time curves for intravenous bolus, oral, and intraportal administration of ATV in the OS rats were significantly greater than those in the control rats, whereas blood clearance of ATV after intravenous bolus injection in the OS rats (0.94 +/- 0.04 L/h/kg) was approximately half of that in the control rats (2.08 +/- 0.20 L/h/kg). Moreover, the intrinsic clearance (CLint), which is determined by in vitro metabolic studies using hepatic microsomal fractions of rats, was approximately 43% lower in the OS rats (0.489 +/- 0.017 mL/min/mg protein) than in the control rats (0.851 +/- 0.004 mL/min/mg protein). ATV concentrations in both the plasma-bound fraction and erythrocytes of the OS rats were significantly greater than those in the control rats. These results suggest that the hepatic metabolism of ATV may be reduced in patients under OS. PMID- 23351067 TI - Antimicrobial susceptibility and genetic characteristics of Neisseria gonorrhoeae isolates from Vietnam, 2011. AB - BACKGROUND: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major public health concern worldwide. In Vietnam, knowledge regarding N. gonorrhoeae prevalence and AMR is limited, and data concerning genetic characteristics of N. gonorrhoeae is totally lacking. Herein, we investigated the phenotypic AMR (previous, current and possible future treatment options), genetic resistance determinants for extended-spectrum cephalosporins (ESCs), and genotypic distribution of N. gonorrhoeae isolated in 2011 in Hanoi, Vietnam. METHODS: N. gonorrhoeae isolates from Hanoi, Vietnam isolated in 2011 (n = 108) were examined using antibiograms (Etest for 10 antimicrobials), Neisseria gonorrhoeae multi antigen sequence typing (NG-MAST), and sequencing of ESC resistance determinants (penA, mtrR and penB). RESULTS: The levels of in vitro resistance were as follows: ciprofloxacin 98%, tetracycline 82%, penicillin G 48%, azithromycin 11%, ceftriaxone 5%, cefixime 1%, and spectinomycin 0%. The MICs of gentamicin (0.023 6 mg/L), ertapenem (0.002-0.125 mg/L) and solithromycin (<0.016-0.25 mg/L) were relatively low. No penA mosaic alleles were found, however, 78% of the isolates contained an alteration of amino acid A501 (A501V (44%) and A501T (34%)) in the encoded penicillin-binding protein 2. A single nucleotide (A) deletion in the inverted repeat of the promoter region of the mtrR gene and amino acid alterations in MtrR was observed in 91% and 94% of the isolates, respectively. penB resistance determinants were detected in 87% of the isolates. Seventy-five different NG-MAST STs were identified, of which 59 STs have not been previously described. CONCLUSIONS: In Vietnam, the highly diversified gonococcal population displayed high in vitro resistance to antimicrobials previously recommended for gonorrhoea treatment (with exception of spectinomycin), but resistance also to the currently recommended ESCs were found. Nevertheless, the MICs of three potential future treatment options were low. It is essential to strengthen the diagnostics, case reporting, and epidemiologic surveillance of gonorrhoea in Vietnam. Furthermore, the surveillance of gonococcal AMR and gonorrhoea treatment failures is imperative to reinforce. Research regarding novel antimicrobial treatment strategies (e.g., combination therapy) and new antimicrobials is crucial for future treatment of gonorrhoea. PMID- 23351069 TI - Nanostructures of small-molecule organic crystals on capillary wave surfaces with controllable capillary lengths. AB - We report on the nanostructures of organic small-molecule pentacene crystals that have been vapor-deposited onto the capillary wave surfaces of thin liquid films. The characteristic lateral length of the capillary wave surface or the capillary length can be controlled by changing the thickness of the liquid films and, thus, the van der Waals interaction with the substrate. We find that the morphology of the organic crystals gradually varies from fractals to compact islands as the liquid film thickness increases. The square of average distance between organic crystal grains was also found to be proportional to the liquid film thickness. We discuss the possibility that these effects are driven by capillary fluctuations at the air-liquid interface. PMID- 23351070 TI - Evaluation of air sampling methods for abrasive blasting. PMID- 23351071 TI - Early retinal and retinal nerve fiber layer effects of hydroxychloroquine: a follow up study by sdOCT. AB - CONTEXT: The antimalarial drug hydroxychloroquine (HCQ), used in the treatment of rheumatologic disease, has been associated with the development of retinopathy. The long-term incidence of HCQ retinopathy has been estimated at 0.5% when recommended dosages (<=6.5 mg/kg per day) are used. OBJECTIVE: Evaluating the patients for whom HCQ treatment will be started before and after treatment prospectively with spectral domain (sd) optical coherence tomography (OCT) to observe possible early changes in the retinal and retinal nerve fiber layer thickness. MATERIALS AND METHODS: Thirty-six patients from rheumatology clinic who have been started HCQ therapy had clinical examination and sdOCT imaging before and 6 months after starting treatment. The baseline ophthalmological examinations and visual field analysis (on automated Humphrey visual field (HVF) 10-2 perimetry, Humphrey HFA II-i 750 i, Carl Zeiss Meditec AG, Jena, Germany) were completely normal. The sdOCT was performed with the Optovue technology according to the manufacturer's guidelines using EMM5, retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) scans. The retinal thickness values in central foveal, inferior and superior hemispheres, temporal, superior, nasal and inferior para- and perifoveal areas and the RNFL thickness of eyes were compared before and 6 months after starting treatment by the paired t test. RESULTS: The retinal thickness values in central parafoveal (p = 0.02), and superior hemisphere (p = 0.01) in parafoveal area, parafoveal superior (p = 0.02), temporal (p = 0.03) and nasal (p = 0.04) quadrants were significantly thicker after 6 months of treatment. The thickness of the perifoveal area and the average RNFL thickness was not significantly different in any of the quadrants before and after starting HCQ treatment. The GCC thickness also did not change significantly different in superior and inferior hemisphere after starting treatment. DISCUSSION AND CONCLUSION: We observe increased retinal thickness in parafoveal areas in patients on HCQ therapy at short term. Its clinical significance may be apparent in longer follow up studies. PMID- 23351072 TI - Denaturation-resistant bifunctional colloidal superstructures assembled via the proteinaceous barnase-barstar interface. AB - To date, a number of biomolecule-mediated nanoparticle self-assembly systems have been developed that are amenable to controllable disassembly under relatively gentle conditions. However, for some applications such as design of self assembled multifunctional theragnostic agents, high stability of the assembled structures can be of primary importance. Here, we report extraordinarily high durability of protein-assisted nanoparticle self-assembly systems yielding bifunctional colloidal superstructures resistant to extreme denaturing conditions intolerable for most proteins (e.g., high concentrations of chaotropic agents, high temperature). Among the tested systems (barnase-barstar (BBS), streptavidin biotin, antibody-antigen, and protein A-immunoglobulin), the BBS is notable due to the combination of its high resistance to severe chemical perturbation and unique advantages offered by genetic engineering of this entirely protein-based system. Comparison of the self-assembly systems shows that whereas in all cases the preassembled structures proved essentially resistant to extreme conditions, the ability of the complementary biomolecular pairs to mediate assembly of the initial biomolecule-particle conjugates differs substantially in these conditions. PMID- 23351073 TI - GPCR Retreat 2012: timing is everything. AB - In London, Ontario, the 13th Annual Joint meeting of the Great Lakes GPCR Retreat and the Club des Recepteurs a Sept Domaines Transmembranaires (known simply as the GPCR Retreat) was held on 17-19 October 2012, organized by Steve Ferguson and Peter Chidiac. This meeting gathered together a core group of investigators from Michigan, Ontario and Quebec and has steadily increased its attendance in both the eastern (Europe) and western (USA, Canada) directions. This year's buzz naturally centered around the Nobel Prize in Chemistry, which was won the week before by Brian Kobilka and Robert Lefkowitz for their work on receptor structure and function. Michel Bouvier provided a heartfelt tribute to one of the attendees, Marc Caron, a pioneer in the GPCR field, has made many contributions to the work that led to this year's Nobel Prize. The meeting featured interesting sessions on the physiological roles of GPCRs in the nervous system, circadian biology and cancer, dealing at the cellular and molecular level with GPCR, G protein and effector structure and function, regulation and trafficking--with an overall focus on how to move molecular pharmacology in vivo. PMID- 23351074 TI - The hydrophobic amino acid cluster at the cytoplasmic end of transmembrane helix III modulates the coupling of the beta(1)-adrenergic receptor to G(s). AB - Abstract A cluster of hydrophobic amino acids at the cytoplasmic end of trans membranal helix III (TM-III) is a common feature among class-A of G protein coupled receptors (GPCR). We mutagenized alanine 159(3.53) to glutamic acid and isoleucine160(3.54) to arginine (A159E/I160R) in TM-III of the human beta(1) adrenergic receptor (beta(1)-AR) to disrupt the function of the hydrophobic cluster. Structurally, the combined mutations of A159E/I160R caused an almost 90 degrees tilt in the rotation of Arg156(3.50) in the E/DRY motif of TM-III and displaced Tyr166(3.60) in intracellular loop 2. The A159E/I160R beta(1)-AR was uncoupled from G(s) as determined by cyclic AMP/adenylyl cyclase assays and by FRET-based proximity measurements between the beta(1)-AR and G(s)alpha. Isoproterenol induced beta-arrestin trafficking in cells expressing both the wild type beta(1)-AR and the A159E/I160R beta(1)-AR. Isoproterenol markedly increased the phosphorylation of ERK1/2 in cells expressing the WT beta(1)-AR and this effect was dependent on the activation of the G(s)-cyclic AMP-dependent protein kinase -> Rap -> B-raf axis. However, in cells bearing the A159E/I160R beta(1) AR, isoproterenol failed to increase the phosphorylation of ERK(1/2). These results indicate that mutations in the G(s)alpha-binding pocket of the GPCR interfered with receptor coupling to G(s) and with its downstream signaling cascades. PMID- 23351075 TI - Targeted multiplex next-generation sequencing: advances in techniques of mitochondrial and nuclear DNA sequencing for population genomics. AB - Next-generation sequencing (NGS) is emerging as an efficient and cost-effective tool in population genomic analyses of nonmodel organisms, allowing simultaneous resequencing of many regions of multi-genomic DNA from multiplexed samples. Here, we detail our synthesis of protocols for targeted resequencing of mitochondrial and nuclear loci by generating indexed genomic libraries for multiplexing up to 100 individuals in a single sequencing pool, and then enriching the pooled library using custom DNA capture arrays. Our use of DNA sequence from one species to capture and enrich the sequencing libraries of another species (i.e. cross species DNA capture) indicates that efficient enrichment occurs when sequences are up to about 12% divergent, allowing us to take advantage of genomic information in one species to sequence orthologous regions in related species. In addition to a complete mitochondrial genome on each array, we have included between 43 and 118 nuclear loci for low-coverage sequencing of between 18 kb and 87 kb of DNA sequence per individual for single nucleotide polymorphisms discovery from 50 to 100 individuals in a single sequencing lane. Using this method, we have generated a total of over 500 whole mitochondrial genomes from seven cetacean species and green sea turtles. The greater variation detected in mitogenomes relative to short mtDNA sequences is helping to resolve genetic structure ranging from geographic to species-level differences. These NGS and analysis techniques have allowed for simultaneous population genomic studies of mtDNA and nDNA with greater genomic coverage and phylogeographic resolution than has previously been possible in marine mammals and turtles. PMID- 23351076 TI - Prediction of ligand-induced structural polymorphism of receptor interaction sites using machine learning. AB - Protein functions are closely related to their three-dimensional structures. Various degrees of conformational changes in the main and side chains occur when binding with other molecules, such as small ligands or proteins. The ligand induced structural polymorphism of proteins is also referred to as "induced-fit", and it plays an important role in the recognition of a particular class of ligands as well as in signal transduction. We have developed new prediction models that discriminate conformationally fluctuant residues caused by ligand binding. The training and test data sets were obtained from the Protein Data Bank. The induced-fit residues were judged based on the Z values of the Calpha atom distances in each protein cluster. Moreover, we introduced various descriptors, such as the number of residues, accessible surface area (ASA), depth of the residue, and position-specific scoring matrix (PSSM), which were obtained from the 2D- or 3D-structural information for the protein. After the optimization of the parameters by 5-fold cross validation, the best prediction model was applied to some well-known induced-fit target proteins to verify its effectiveness. Especially in the validation for the DFG motif of a protein kinase family, we succeeded in the prediction of the DFG-out possibility from only the DFG-in conformation of each kinase structure. PMID- 23351077 TI - Mice lacking Period 1 and Period 2 circadian clock genes exhibit blue cone photoreceptor defects. AB - Many aspects of retinal physiology are modulated by circadian clocks, but it is unclear whether clock malfunction impinges directly on photoreceptor survival, differentiation or function. Eyes from wild-type (WT) and Period1 (Per1) and Period2 (Per2) mutant mice (Per1(Brdm1) Per2(Brdm1) ) were examined for structural (histology, in vivo imaging), phenotypical (RNA expression, immunohistochemistry) and functional characteristics. Transcriptional levels of selected cone genes [red/green opsin (Opn1mw), blue cone opsin (Opn1sw) and cone arrestin (Arr3)] and one circadian clock gene (RORb) were quantified by real-time polymerase chain reaction. Although there were no changes in general retinal histology or visual responses (electroretinograms) between WT and Per1(Brdm1) Per2(Brdm1) mice, compared with age-matched controls, Per1(Brdm1) Per2(Brdm1) mice showed scattered retinal deformations by fundus inspection. Also, mRNA expression levels and immunostaining of blue cone opsin were significantly reduced in mutant mice. Especially, there was an alteration in the dorsal-ventral patterning of blue cones. Decreased blue cone opsin immunoreactivity was present by early postnatal stages, and remained throughout maturation. General photoreceptor differentiation was retarded in young mutant mice. In conclusion, deletion of both Per1 and Per2 clock genes leads to multiple discrete changes in retina, notably patchy tissue disorganization, reductions in cone opsin mRNA and protein levels, and altered distribution. These data represent the first direct link between Per1 and Per2 clock genes, and cone photoreceptor differentiation and function. PMID- 23351079 TI - Gangliosides as regulators of cell signaling: ganglioside-protein interactions or ganglioside-driven membrane organization? PMID- 23351078 TI - IL-4 and IL-13 inhibit IL-1beta and TNF-alpha induced kinin B1 and B2 receptors through a STAT6-dependent mechanism. AB - BACKGROUND AND PURPOSE: Bone resorption induced by interleukin-1beta (IL-1beta) and tumour necrosis factor (TNF-alpha) is synergistically potentiated by kinins, partially due to enhanced kinin receptor expression. Inflammation-induced bone resorption can be impaired by IL-4 and IL-13. The aim was to investigate if expression of B1 and B2 kinin receptors can be affected by IL-4 and IL-13. EXPERIMENTAL APPROACH: We examined effects in a human osteoblastic cell line (MG 63), primary human gingival fibroblasts and mouse bones by IL-4 and IL-13 on mRNA and protein expression of the B1 and B2 kinin receptors. We also examined the role of STAT6 by RNA interference and using Stat6(-/-) mice. KEY RESULTS: IL-4 and IL-13 decreased the mRNA expression of B1 and B2 kinin receptors induced by either IL-1beta or TNF-alpha in MG-63 cells, intact mouse calvarial bones or primary human gingival fibroblasts. The burst of intracellular calcium induced by either bradykinin (B2 agonist) or des-Arg(10) -Lys-bradykinin (B1 agonist) in gingival fibroblasts pretreated with IL-1beta was impaired by IL-4. Similarly, the increased binding of B1 and B2 ligands induced by IL-1beta was decreased by IL-4. In calvarial bones from Stat6-deficient mice, and in fibroblasts in which STAT6 was knocked down by siRNA, the effect of IL-4 was decreased. CONCLUSIONS AND IMPLICATIONS: These data show, for the first time, that IL-4 and IL-13 decrease kinin receptors in a STAT6-dependent mechanism, which can be one important mechanism by which these cytokines exert their anti-inflammatory effects and impair bone resorption. PMID- 23351080 TI - Complete mitochondrial genome of Blue-crowned Parakeet (Aratinga acuticaudata)- phylogenetic position of the species among parrots group called Conures. AB - Blue-crowned Parakeet (Aratinga acuticaudata) is a South American parrot species with a taxonomic position not confirmed by molecular studies. We sequenced full mitochondrial genome and constructed phylogenetic tree using sequences of mitochondrial ND2 gene from A. acuticaudata and some other representatives of Conures group. Our results confirmed previously described distribution of Aratinga species into three clades, but surprisingly did not classify Blue crowned Parakeet to any of them. We found that A. acuticaudata shares the closest relationship with Diopsittaca nobilis and forms a separate clade together with Guaruba guarouba and Leptosittaca branickii species with a significant node. Our results confirm lack of monophyly of the genus Aratinga and underline the need of its taxonomic revision. PMID- 23351081 TI - Tracing patterns of chloroplast evolution in euglenoids: contributions from Colacium vesiculosum and Strombomonas acuminata (Euglenophyta). AB - The chloroplast genomes of two photosynthetic euglenoids, Colacium vesiculosum Ehrenberg (128,889 bp), and Strombomonas acuminata (Schmarda) Deflandre (144,167 bp) have been sequenced. These chloroplast genomes in combination with those of Euglena gracilis, Eutreptia viridis, and Eutreptiella gymnastica provide a snapshot of euglenoid chloroplast evolution allowing comparisons of gene content, arrangement, and expansion. The gene content of the five chloroplast genomes is very similar varying only in the presence or absence of, rrn5, roaA, psaI, psaM, rpoA, and two tRNAs. Large gene rearrangements have occurred within the C. vesiculosum and S. acuminata chloroplast genomes. Most of these rearrangements represent repositioning of entire operons rather than single genes. When compared with previously sequenced genomes, C. vesiculosum and S. acuminata chloroplast genomes more closely resemble the E. gracilis chloroplast genome in size of the genome, number of introns, and gene order than they do those of the Eutreptiales. Overall, the chloroplast genomes of these five species show an evolutionary trend toward increased intron number, a decrease in gene density, and substantial rearrangement of gene clusters. PMID- 23351082 TI - Contribution of lipids in honeybee (Apis mellifera) royal jelly to health. AB - Honeybee (Apis mellifera) royal jelly (RJ) has a long history in human medicine because of its health-protecting properties. To develop a fundamental and comprehensive understanding of lipids in RJ, this article reviews the available literature on lipid compounds identified from RJ extracts and in vitro pharmacological effects of 10-hydroxy-2-decenoic acid in RJ and other closely related compounds, some of which are also identified as lipid compounds in RJ. Overall, the lipids in RJ are composed of mostly (aliphatic) fatty acids, almost all of which are present as free fatty acids and scarcely any as esters. Most fatty acids in RJ are medium-chain fatty acids, whether hydroxylated in terminal and/or internal positions, terminated with mono- or dicarboxylic acid groups, and saturated or monounsaturated at the 2-position. Besides these fatty acids, lipids in RJ contain sterols in minor amounts. Lipids in RJ are useful as preventive and supportive medicines with functionalities that include potential inhibitors of cancer growth, immune system modulators, alternative therapies for menopause, skin-aging protectors, neurogenesis inducers, and more. Taken together, the evidence suggests that health-protecting properties of RJ can be, in part, ascribed to actions of lipids in RJ. PMID- 23351083 TI - Can the fetal fibronectin test be used by remote dwelling pregnant women to predict the onset of labour at term and delay transfer for birth in regional settings? AB - INTRODUCTION: The closure of rural maternity units in Australia means an increasing number of women are transferred into major centres to await birth. Accurately excluding the onset of labour could delay relocation. The fetal fibronectin (fFN) test is used to predict preterm birth; however, the accuracy of this test for determining impending term birth is unclear. METHODS: 75 women were recruited to this study from two remote maternity units. Eligibility criteria were: aged &#8805;18 years, singleton pregnancy, 37+0 40+3 weeks (37 weeks to 40 weeks and 3 days gestation) and no indication for induction of labour or caesarean section in next 7 days. The Quikcheck fFN(r) test was performed at 37 weeks and then repeated at 7 day intervals. Time-to birth from test date was modelled using linear regression. Logistic regression models estimated odds of birth within 7 days. Separate models considered first and last test results and those at 38 weeks; adjusted for use of lubricant and gestational age. RESULTS: A shorter time-to-birth was found in women with positive compared with negative fFN tests; significant at first fFN test (adjusted mean difference [AMD] 5.4 days, 95% CI 2.0-8.8) and 38 weeks (AMD 5.7 days, 95% CI 2.2-9.2 days). A positive test was also associated with a significant increase in the odds of birthing within 7 days: first fFN test adjusted odds ratio (AOR) 11.0 (95% CI 2.5-48.7), 38 weeks test AOR 14.4 (95% CI 3.4-60.2), last fFN test AOR 8.1 (95% CI 1.6-39.8). However, of women who gave birth within 7 days of testing a significant proportion had a negative fFN result; first fFN test 8/17(47.1%), 38 weeks test 4/14(28.6%) and last fFN test 29/58(50.0%). CONCLUSION: The presence of fFN in cervical secretions was associated with impending term birth but its absence did not reliably exclude the onset of birth. Delaying transfer based on these findings would result in some women birthing in their home communities. PMID- 23351084 TI - Palladium/norbornene catalytic system: chelation as a tool to control regioselectivity of Pd(IV) reductive elimination. AB - Palladium/norbornene joint catalysis gives rise to a unique system in which the three most common formal oxidation states of the metal are at work in the same cycle (0, II, and IV). This paper summarizes a selection of synthetic applications and the feasibility of Pd(IV) formation by oxidative addition of aryl halides. On this intermediate, the presence of a suitable chelating group could trigger unexpected aryl-norbornyl coupling, further broadening the scope of readily available polycyclic frameworks. PMID- 23351085 TI - Tethering complexes in the endocytic pathway: CORVET and HOPS. AB - Endocytosis describes the processes by which proteins, peptides and solutes, and also pathogens, enter the cell. Endocytosed material progresses to endosomes. Genetic studies in yeast, worms, flies and mammals have identified a set of universally conserved proteins that are essential for early-to-late endosome transition and lysosome biogenesis, and for endolysosomal trafficking pathways, including autophagy. The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. In addition, several of the CORVET and HOPS subunits have diversified in metazoans, and probably form additional specialized complexes to accomodate the higher complexity of trafficking pathways in these cells. Recent studies offer new insights into the complex relationships between CORVET and HOPS complexes and other factors of the endolysosomal pathway. Interactions with V-ATPase, the ESCRT machinery, phosphoinositides, the cytoskeleton and the Rab switch suggest an intricate cooperative network for endosome maturation. Accumulating evidence supports the view that endosomal tethering complexes implement a regulatory logic that governs endomembrane identity and dynamics. PMID- 23351086 TI - Intravesical bacille Calmette-Guerin (BCG) in immunologically compromised patients with bladder cancer. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Intravesical bacille Calmette-Guerin (BCG) is generally considered to be contraindicated in immunologically compromised patients with bladder cancer because it may be ineffective and potentially toxic. Therefore, there is little experience with BCG in individuals with impaired immune systems. The present study provides evidence that intravesical BCG is safe and effective in the short term against non-muscle invasive bladder cancer affecting patients who were receiving immunosuppressive medications. This included anti-rejection drugs to support a solid organ transplant, high-dose steroids for autoimmune inflammatory diseases, and the first description of BCG use in patients who were receiving concomitant systemic chemotherapy for unrelated malignant neoplasms. OBJECTIVE: To investigate the outcomes of bacille Calmette-Guerin (BCG) therapy in patients with bladder cancer who were immunologically compromised. PATIENTS AND METHODS: In all, 45 immunosuppressed patients with high-grade non-muscle-invasive bladder cancer received BCG therapy. Twelve had functioning organ transplants, 23 were undergoing systemic chemotherapy for unrelated cancers, and 10 were taking steroids for autoimmune or related diseases. Patients received a 6-week induction course of BCG therapy. Relapsing patients were eligible for retreatment. All patients were followed for median (range) of 40 (12-72) months. End points were response to BCG and 5-year recurrence-free, progression-free and overall survival rates. RESULTS: In all, nine of the 12 transplant patients responded completely to one or two cycles of BCG compared with 99% (32/33) of other immunosuppressed patients. Half the patients with unrelated cancers and autoimmune diseases recurred vs all but one of the transplant patients (P = 0.008). Of the 12 transplant patients, six of 12 progressed vs five of 33 (15%) of the other patient groups (P = 0.02). Five patients died (11%), two of bladder cancer (both in transplant patients), and three of unrelated causes. BCG was well tolerated. None of the patients developed bacterial or BCG sepsis. Although this is largest series evaluating BCG in transplant and other immune-suppressed patients, it represents few patients and results must be interpreted with caution. CONCLUSIONS: We conclude that intravesical BCG is safe and effective in immunologically compromised patients with bladder cancer. Transplant patients fare worse and should be considered for early cystectomy if they fail BCG therapy. PMID- 23351087 TI - Reduction of aflatoxin level in aflatoxin-induced rats by the activity of probiotic Lactobacillus casei strain Shirota. AB - AIMS: Aflatoxin B1 (AFB1 ) is considered as the most toxic food contaminant, and microorganisms, especially bacteria, have been studied for their potential to reduce the bioavailability of mycotoxins including aflatoxins. Therefore, this research investigated the efficacy of oral administration of Lactobacillus casei Shirota (LcS) in aflatoxin-induced rats. METHODS AND RESULTS: Sprague Dawley rats were divided into three groups of untreated control, the group induced with AFB1 only, and the group given probiotic in addition to AFB1. In the group induced with AFB1 only, food intake and body weight were reduced significantly. The liver and kidney enzymes were significantly enhanced in both groups induced with AFB1 , but they were lower in the group given LcS. AFB1 was detected from all serum samples except for untreated control group's samples. Blood serum level of AFB1 in the group induced with AFB1 only was significantly higher than the group which received probiotic as a treatment (P < 0.05), and there was no significant difference between the control group and the group treated with probiotic. CONCLUSIONS: LcS supplementation could improve the adverse effect of AFB1 induction on rats' body weight, plasma biochemical parameters and also could reduce the level of AFB1 in blood serum. SIGNIFICANCE AND IMPACT OF THE STUDY: This study's outcomes contribute to better understanding of the potential of probiotic to reduce the bioavailability ofAFB1 . Moreover, it can open an opportunity for future investigations to study the efficacy of oral supplementation of probiotic LcS in reducing aflatoxin level in human. PMID- 23351088 TI - In situ, real time monitoring of surface transformation: ellipsometric microscopy imaging of electrografting at microstructured gold surfaces. AB - Surface chemical reactivity is imaged by combining electrochemical activation of a surface transformation process with spatiotemporal ellipsometric microscopy. An imaging ellipsometric microscope is built, allowing ellipsometric images of surfaces with a lateral resolution of ~1 MUm and a thickness sensitivity of ~0.1 nm in air and 0.4 nm in a liquid. These performances are particularly adapted for using such optical setup as an in situ, real time chemical microscope to observe a chemical surface transformation. This microscope is tested for the monitoring of the electrochemically actuated diazonium grafting of a gold surface. Such reaction is a model system of organic material deposition on a gold surface induced by an electrochemical actuation. Using either plain or physically or chemically structured electrodes, it allows for the characterization of local phenomena associated with the electrografting process. This illustrates its potential to reveal the local (electro)chemical reactivity of surfaces. PMID- 23351089 TI - Pitfalls in the management of rectal cancer after male-to-female sex change procedure. PMID- 23351091 TI - Heterogeneous catalysts need not be so "heterogeneous": monodisperse Pt nanocrystals by combining shape-controlled synthesis and purification by colloidal recrystallization. AB - Well-defined surfaces of Pt have been extensively studied for various catalytic processes. However, industrial catalysts are mostly composed of fine particles (e.g., nanocrystals), due to the desire for a high surface to volume ratio. Therefore, it is very important to explore and understand the catalytic processes both at nanoscale and on extended surfaces. In this report, a general synthetic method is described to prepare Pt nanocrystals with various morphologies. The synthesized Pt nanocrystals are further purified by exploiting the "self cleaning" effect which results from the "colloidal recrystallization" of Pt supercrystals. The resulting high-purity nanocrystals enable the direct comparison of the reactivity of the {111} and {100} facets for important catalytic reactions. With these high-purity Pt nanocrystals, we have made several observations: Pt octahedra show higher poisoning tolerance in the electrooxidation of formic acid than Pt cubes; the oxidation of CO on Pt nanocrystals is structure insensitive when the partial pressure ratio p(O2)/p(CO) is close to or less than 0.5, while it is structure sensitive in the O(2)-rich environment; Pt octahedra have a lower activation energy than Pt cubes when catalyzing the electron transfer reaction between hexacyanoferrate (III) and thiosulfate ions. Through electrocatalysis, gas-phase-catalysis of CO oxidation, and a liquid-phase-catalysis of electron transfer reaction, we demonstrate that high quality Pt nanocrystals which have {111} and {100} facets selectively expose are ideal model materials to study catalysis at nanoscale. PMID- 23351090 TI - Comparative efficacy and tolerability of anti-epileptic drugs for refractory focal epilepsy: systematic review and network meta-analysis reveals the need for long term comparator trials. AB - AIMS: To evaluate the comparative efficacy (50% reduction in seizure frequency) and tolerability (premature withdrawal due to adverse events) of anti-epileptic drugs (AEDs) for refractory epilepsy. METHODS: We searched Cochrane Central Register of Controlled Trials (Cochrane Library 2009, issue 2) including Epilepsy Group's specialized register, MEDLINE (1950 to March 2009), EMBASE (1980 to March 2009), and Current Contents Connect (1998 to March 2009) to conduct a systematic review of published studies, developed a treatment network and undertook a network meta-analysis. RESULTS: Forty-three eligible trials with 6346 patients and 12 interventions, including placebo, contributed to the analysis. Only three direct drug comparator trials were identified, the remaining 40 trials being placebo-controlled. Conventional random-effects meta-analysis indicated all drugs were superior in efficacy to placebo (overall odds ratio (OR] 3.78, 95% CI 3.14, 4.55) but did not permit firm distinction between drugs on the basis of the efficacy or tolerability. A Bayesian network meta-analysis prioritized oxcarbazepine, topiramate and pregabalin on the basis of short term efficacy. However, sodium valproate, levetiracetam, gabapentin and vigabatrin were prioritized on the basis of short-term efficacy and tolerability, with the caveat that vigabatrin is recognized as being associated with serious visual disturbance with chronic use. CONCLUSION: Of the wide range of AEDs licensed for the treatment of refractory epilepsy, sodium valproate, levetiracetam and gabapentin demonstrated the best balance of efficacy and tolerability. Until regulators mandate greater use of active comparator trials with longer term follow-up, network meta-analysis provides the only available means to quantify these clinically important parameters. PMID- 23351093 TI - The problem of pattern and scale in ecology: what have we learned in 20 years? AB - Over the past 20 years, major advances have clarified how ecological patterns inform theory, and how in turn theory informs applied ecology. Also, there has been an increased recognition that the problem of scale at which ecological processes should be considered is critical if we are to produce general predictions. Ecological dynamics is always stochastic at small scales, but variability is conditional on the scale of description. The radical changes in the scope and aims of ecology over the past decades reflect in part the need to address pressing societal issues of environmental change. Technological advances in molecular biology, global positioning, sensing instrumentation and computational power should not be overlooked as an explanation for these radical changes. However, I argue that conceptual unification across ecology, genetics, evolution and physiology has fostered even more fertile questions. We are moving away from the view that evolution is played in a fixed ecological theatre: the theatre is being rapidly and relentlessly redesigned by the players themselves. The maintenance of ecosystem functions depends on shifts in species assemblages and on cellular metabolism, not only on flows of energy and matter. These findings have far reaching implications for our understanding of how ecosystem function and biodiversity will withstand (or not) environmental changes in the 21st century. PMID- 23351092 TI - Serum albumin level during intestinal exfoliative rejection: a potential predictor of graft recovery and patient outcome. AB - Exfoliative rejection is a severe complication after intestinal transplant. The assessment of mucosa histology is restricted to the area reached by endoscopy. We aim to evaluate the serum albumin (SA) value as a parameter of graft damage and clinical prognosis in intestinal exfoliative rejection (ExR). The present study is a retrospective analysis of 11 episodes of ExR occurred in a cohort of 26 patients. SA levels were measured 24 h after diagnosis and twice a week thereafter and then correlated with parameters of clinical and graft histological recovery (HR). During ExR, all patients had very low SA levels, reaching a minimum average of 1.9 +/- 0.3 g/dL. According to the value of albumin levels at ExR diagnosis, the patients were grouped finding a correlation with their clinical evolution. Six ExR episodes presented with severe hipoalbuminemia (<2.2 g/dL; p < 0.05) that correlated with worse patient and graft outcome, ranging from graft loss and need for re-transplantation to delayed clinical and HR. SA at ExR diagnosis may be an indicator of the severity of the ExR process, and it could also be used as an early predictor of patient and graft outcome. PMID- 23351094 TI - Gadolinium(III)-gold nanorods for MRI and photoacoustic imaging dual-modality detection of macrophages in atherosclerotic inflammation. AB - AIM: One of the features of high-risk atherosclerotic plaques is the preponderance of macrophages. Gadolinium(III)-gold nanorods (Gd(III)-GNRs) have been developed as a dual-modality probe for MRI and photoacoustic imaging (PAI) to trace macrophages for determining the degree of inflammation. MATERIALS & METHODS: Gd(III)-GNRs were utilized for MRI and PAI dual-modality detection of macrophages in living mice and ex vivo simulated macrophage-rich plaque. RESULTS: Gd(III)-GNRs were shown to be endocytosed by macrophages in vitro. Macrophages labeled with Gd(III)-GNRs were detected by both PAI and MRI. With Gd(III)-GNRs, it is possible to institute a multiscale complementary imaging protocol: MRI can screen to identify the location of the probe-phagocytosed macrophages, and intravascular PAI provides a subsequent precise morphology to quantify the infiltration area and invasion depth of macrophages in the arterial wall. CONCLUSION: This new dual-modality nanoparticle approach has promise for enabling quantitative detection of macrophages in atherosclerotic plaques. PMID- 23351096 TI - Stimuli-responsive magnetic nanomicelles as multifunctional heat and cargo delivery vehicles. AB - Hybrid nanoarchitectures are among the most promising nanotechnology-enabled materials for biomedical applications. Interfacing of nanoparticles with active materials gives rise to the structures with unique multiple functionality. Superparamagnetic iron oxide nanoparticles particles SPION are widely employed in the biology and in developing of advanced medical technologies. Polymeric micelles offer the advantage of multifunctional carriers which can serve as delivery vehicles carrying nanoparticles, hydrophobic chemotherapeutics and other functional materials and molecules. Stimuli-responsive polymers are especially attractive since their properties can be modulated in a controlled manner. Here we report on multifunctional thermo-responsive poly(N-isopropylacrylamide-co acrylamide)-block-poly(epsilon-caprolactone) random block copolymer micelles as magnetic hyperthermia-mediated payload release and imaging agents. The combination of copolymers, nanoparticles and doxorubicin drug was tailored the way that the loaded micelles were cable to respond to magnetic heating at physiologically-relevant temperatures. A surface functionalization of the micelles with the integrin beta4 antibody and consequent interfacing of the resulting nanobio hybrid with squamous head and neck carcinoma cells which is known to specifically over-express the A9 antigen resulted in concentration of the micelles on the surface of cells. No inherent cytotoxicity was detected for the magnetic micelles without external stimuli application. Furthermore, SPION loaded micelles demonstrate significant MRI contrast enhancement abilities. PMID- 23351095 TI - Derivation and isolation of NKX2.1-positive basal forebrain progenitors from human embryonic stem cells. AB - Gamma aminobutyric acid (GABA)-expressing interneurons are the major inhibitory cells of the cerebral cortex and hippocampus. These interneurons originate in the medial ganglionic eminence (MGE) and lateral ganglionic eminence of the ventral forebrain during embryonic development and show reduced survival and function in a variety of neurological disorders, including temporal lobe epilepsy. We and others have proposed that embryonic stem cell (ESC)-derived ventral forebrain progenitors might provide a source of new GABAergic interneurons for cell-based therapies. While human ESCs (hESCs) are readily differentiated in vitro into dorsal telencephalic neural progenitors, standard protocols for generating ventral subtypes of telencephalic progenitors are less effective. We now report efficient derivation of GABAergic progenitors using an established hESC reporter line that expresses green fluorescent protein (GFP) under the control of an endogenous NKX2.1 promoter. GABAergic progenitors were derived from this hESC line by a modified monolayer neural differentiation protocol. Consistent with sonic hedgehog (SHH)-dependent specification of NKX2.1-positive progenitors in the embryonic MGE, we show a dose-dependent increase in the generation of NKX2.1:GFP-positive progenitors after SHH treatment in vitro. Characterization of NKX2.1:GFP-positive cells confirms their identity as MGE-like neural progenitors, based on gene expression profiles and their ability to differentiate into GABAergic interneurons. We are also able to generate highly enriched populations of NKX2.1:GFP-positive progenitors, including cells with telencephalic identity, by fluorescence-activated cell sorting. These hESC-derived ventral forebrain progenitors are suitable candidates for cell-based therapies that aim at replacing dysfunctional or damaged cortical or hippocampal GABAergic interneurons. PMID- 23351098 TI - Does arousal per se account for the influence of appetitive stimuli on attentional scope and the late positive potential? AB - Past research suggests that high approach-motivated positive affects narrow attentional scope and cause greater late positive potential (LPP) amplitudes. However, because arousal is related to motivational intensity, arousal may be responsible for these past findings. The present research investigated whether arousal, manipulated independently of affect using physical exercise, would influence attentional and LPP responses to stimuli. Results revealed that appetitive (vs. neutral) pictures evoked larger LPPs over central and left frontal regions, and caused more attentional narrowing. Individual differences in approach motivation predicted more attentional narrowing following appetitive stimuli. However, manipulated arousal did not influence attentional scope or LPPs to neutral or appetitive stimuli. Results suggest that attentional narrowing and LPPs to appetitive stimuli are related to approach motivation rather than enhanced general arousal. PMID- 23351097 TI - Nutritional anemia in reproductive age women with postadolescent acne. AB - CONTEXT: Postadolescent acne has been defined as the presence of acne beyond the age of 25 years. Postadolescent acne affects approximately 14% of women between the ages of 25 and 50 years. Namely, postadolescent acne usually occurs in women of reproductive age. Nutritional anemia occurs from an insufficient intake of nutrients such as iron, folate and vitamin B12. It is very common in women of reproductive age. Nutritional anemia causes irritability, apathy, fatigue, depressive symptoms and difficulty in concentration. The major etiological factor in adult acne can be increased levels of emotional stress, leading to increase in adrenal androgens. Thus, nutritional anemia may aggravate the lesions of acne by affecting the emotional status in women of reproductive age. OBJECTIVE: We aimed to investigate the relationship between postadolescent acne and nutritional anemia in this study. MATERIALS AND METHODS: The study population comprised of 52 patients with postadolescent acne and 52 healthy control subjects. Hemogram, vitamin B12, folate, serum iron, ferritin and total iron-binding capacity (TIBC) were measured. RESULTS: No significant differences were observed between both groups in hemoglobin, vitamin B12, serum iron, ferritin and TIBC levels. Serum folate levels were significantly decreased in postadolescent acne patients (p < 0.001). There were no significant correlations between hemoglobin, vitamin B12, folate, serum iron, ferritin and TIBC levels and acne severity. DISCUSSION AND CONCLUSION: We could not find any relationship between postadolescent acne and nutritional anemia in our study. However, serum folate levels were decreased in postadolescent acne patients. Prospective research studies are needed to clarify the role of nutrition in the pathophysiology of postadolescent acne. We think that nutritional interventions can be inexpensive, safe, easy to administer and generally acceptable to patients with postadolescent acne. PMID- 23351099 TI - Consensus docking: improving the reliability of docking in a virtual screening context. AB - Structure-based virtual screening relies on scoring the predicted binding modes of compounds docked into the target. Because the accuracy of this scoring relies on the accuracy of the docking, methods that increase docking accuracy are valuable. Here, we present a relatively straightforward method for improving the probability of identifying accurately docked poses. The method is similar in concept to consensus scoring schemes, which have been shown to increase ranking power and thus hit rates, but combines information about predicted binding modes rather than predicted binding affinities. The pose prediction success rate of each docking program alone was found in this trial to be 55% for Autodock, 58% for DOCK, and 64% for Vina. By using more than one docking program to predict the binding pose, correct poses were identified in 82% or more of cases, a significant improvement. In a virtual screen, these more reliably posed compounds can be preferentially advanced to subsequent scoring stages to improve hit rates. Consensus docking can be easily introduced into established structure-based virtual screening methodologies. PMID- 23351101 TI - Introduction to the special edition on school & community contexts of youth and mental health. PMID- 23351100 TI - A conserved amphipathic ligand binding region influences k-path-dependent activity of cytochrome C oxidase. AB - A conserved, crystallographically defined bile acid binding site was originally identified in the membrane domain of mammalian and bacterial cytochrome c oxidase (CcO). Current studies show other amphipathic molecules including detergents, fatty acids, steroids, and porphyrins bind to this site and affect the already 50% inhibited activity of the E101A mutant of Rhodobacter sphaeroides CcO as well as altering the activity of wild-type and bovine enzymes. Dodecyl maltoside, Triton X100, C12E8, lysophophatidylcholine, and CHOBIMALT detergents further inhibit RsCcO E101A, with lesser inhibition observed in wild-type. The detergent inhibition is overcome in the presence of micromolar concentrations of steroids and porphyrin analogues including deoxycholate, cholesteryl hemisuccinate, bilirubin, and protoporphyrin IX. In addition to alleviating detergent inhibition, amphipathic carboxylates including arachidonic, docosahexanoic, and phytanic acids stimulate the activity of E101A to wild-type levels by providing the missing carboxyl group. Computational modeling of dodecyl maltoside, bilirubin, and protoporphyrin IX into the conserved steroid site shows energetically favorable binding modes for these ligands and suggests that a groove at the interface of subunit I and II, including the entrance to the K-path and helix VIII of subunit I, mediates the observed competitive ligand interactions involving two overlapping sites. Spectral analysis indicates that ligand binding to this region affects CcO activity by altering the K-path dependent electron transfer equilibrium between heme a and heme a(3). The high affinity and specificity of a number of compounds for this region, and its conservation and impact on CcO activity, support its physiological significance. PMID- 23351102 TI - Commentary by Drs. Hooven and Walsh. PMID- 23351103 TI - Development of a doula intervention for postpartum depressive symptoms: participants' recommendations. AB - PROBLEM: About 10-15% of women experience postpartum depression (PPD). Doulas provide support and education about PPD. METHODS: This qualitative study used focus groups with mothers, doulas, and doula trainers to develop educational materials for doulas to help mothers identify symptoms of depression and seek treatment. FINDINGS: All participants preferred materials that use simple language and avoid psychiatric jargon. Three themes emerged: someone to talk to, flexibility, and interactivity. Materials developed include tri-fold brochure and content for an application for smartphones and digital tablets. CONCLUSIONS: Doulas can use these interactive materials to provide supportive, relationship based care that complements nursing care. PMID- 23351104 TI - The neurobiology of risk and pre-emptive interventions for anorexia nervosa. AB - TOPIC: The neurobiology of risk and pre-emptive interventions for anorexia nervosa. PURPOSE: This article is based on a presentation at the March 2012 annual conference of the International Society of Psychiatric Mental Health Nurses. SOURCES: A review of literature and clinical practice experience. CONCLUSIONS: Advances in genetics and neuroimaging provide evidence of a recognizable phenotype of traits and neuropsychological characteristics that precede symptom onset in children at risk for anorexia nervosa. Early recognition of the phenotype and experiences that can potentiate symptom expression provides the basis for pre-emptive interventions that may avert or delay the onset and reduce symptom severity. PMID- 23351105 TI - COPE for depressed and anxious teens: a brief cognitive-behavioral skills building intervention to increase access to timely, evidence-based treatment. AB - TOPIC: Evidence-based cognitive-behavioral therapy skills building intervention- Creating Opportunities for Personal Empowerment (COPE)--for depressed and anxious teens in brief 30 min outpatient visits. PURPOSE: Based on COPE training workshops, this article provides an overview of the COPE program, its development, theoretical foundation, content of the sessions, and lessons learned for best delivery of COPE to individuals and groups in psychiatric settings, primary care settings, and schools. SOURCES: Published literature and clinical examples. CONCLUSION: With the COPE program, the advanced practice nurse in busy outpatient practice can provide timely, evidence-based therapy for adolescents and use the full extent of his/her advanced practice nursing knowledge and skills. PMID- 23351106 TI - The effectiveness of narrative therapy with young people with autism. AB - PROBLEM: The aim of this pilot study was to be the first step toward empirically determining whether narrative therapy is effective in helping young people with autism who present with emotional and behavioral problems. Autism is increasingly being recognized in young people with average and above intelligence. Because of the nature of autism, these young people have difficulty navigating the challenges of school and adolescence. Narrative therapy can help them with their current difficulties and also help them develop skills to address future challenges. Narrative therapy involves working with a person to examine and edit the stories the person tells himself or herself about the world. It is designed to promote social adaptation while working on specific problems of living. METHOD: This pilot intervention study used a convenience sample of 10 young people with autism (10-16 years) to evaluate the effectiveness of five 1 hr sessions of narrative therapy conducted over 10 weeks. The study used the parent rated Strengths and Difficulties Questionnaire (SDQ) as the primary outcome measure. Secondary outcome measures were the Kessler-10 Scale of Psychological Distress (K-10), the Beck Hopelessness Scale, and a stress biomarker, the salivary cortisol to dehydroepiandrosterone (DHEA) ratio. FINDINGS: Significant improvement in psychological distress identified through the K-10 was demonstrated. Significant improvement was identified on the Emotional Symptoms Scale of the SDQ. The cortisol:DHEA ratio was responsive and a power analysis indicated that further study is indicated with a larger sample. CONCLUSION: Narrative therapy has merit as an intervention with young people with autism. Further research is indicated. PMID- 23351107 TI - How to identify students for school-based depression intervention: can school record review be substituted for universal depression screening? AB - PROBLEM: Early identification and intervention are critical for reducing the adverse effects of depression on academic and occupational performance. Cost effective approaches are needed for identifying adolescents at high depression risk. This study evaluated the utility of school record review versus universal school-based depression screening for determining eligibility for an indicated depression intervention program implemented in the middle school setting. METHODS: Algorithms derived from grades, attendance, suspensions, and basic demographic information were evaluated with regard to their ability to predict students' depression screening scores. FINDINGS: The school information-based algorithms proved poor proxies for individual students' depression screening results. However, school records showed promise for identifying low, medium, and high-yield subgroups on the basis of which efficient screening targeting decisions could be made. CONCLUSIONS: Study results will help to guide school nurses who coordinate indicated depression intervention programs in school settings as they evaluate options of approaches for determining which students are eligible for participation. PMID- 23351108 TI - School-wide staff and faculty training in suicide risk awareness: successes and challenges. AB - PROBLEM: Rates of youth suicide and suicidal behavior remain high despite prevention efforts. Training high school personnel as gatekeepers is an important strategy. METHODS: Training was implemented in a school district's five comprehensive high schools. Surveys were conducted before and after training sessions, which targeted all adults working at the high school. Two hundred thirty-seven individuals completed the pretest and/or posttest. FINDINGS: Participants reported gains in knowledge, confidence, and feelings of competence in recognizing, approaching, and connecting distressed youth to school-based resources. Training was well received. CONCLUSION: Training is acceptable and appropriate for school personnel. Increasing the number of school personnel who participate in the training is challenging. PMID- 23351109 TI - Neighborhood perceptions and emotional well-being in young adulthood. AB - PROBLEM: While mounting research suggests that neighborhood environment impacts mental health outcomes, for adolescents and adults, there is scant research on how perceived neighborhood context affects young adults. In this article, we explore the role of perceived neighborhood characteristics, specifically indicators of perceived neighborhood stressors, on emotional well-being among young adults. METHOD: Using a regional sample of young adults, we estimate regression models to examine the relationship of perceived neighborhood stressors on three mental health outcomes (depressed affect, hopelessness, and anger), reflective of a general emotional well-being, while controlling for key individual characteristics related to mental health outcomes. FINDINGS: Results show perceived neighborhood effects for emotional well-being consistent with a stress process model where the scale of perceived neighborhood stressors is associated with poor emotional well-being for depressed affect and hopelessness. Specific perceived neighborhood measures were significant for each of the mental health outcomes whereby greater perceptions of unsafe conditions and economic hardship are positively associated with poor emotional well-being and greater social intervention and more social attachments are associated with better emotional well-being. CONCLUSION: For young adults, perceptions of neighborhood stressors are related to indicators of mental health. We discuss the implications of our findings for ongoing research on neighborhood contextual effects and mental health during the transition to adulthood. PMID- 23351110 TI - School difficulties and co-occurring health risk factors: substance use, aggression, depression, and suicidal behaviors. AB - PROBLEM: Effective prevention requires understanding vulnerable populations, early signs of health risks, and the impact of social contexts. We tested a model of co-occurring mental health risks among at-risk youth experiencing school difficulties. METHODS: We analyzed data from a random sample of 336 at-risk youth, grades 9-12, who completed a comprehensive risk/protective factors assessment. FINDINGS: Simultaneously controlling for correlations among health risks, we observed systematic associations among risk factors, with generally consistent patterns for males and females. CONCLUSIONS: The findings underscore the importance of developing interventions that incorporate contextual influences and of identifying common adaptable strategies for attenuating co-occurring health risks for at-risk youth. PMID- 23351111 TI - Parents-CARE: a suicide prevention program for parents of at-risk youth. AB - TOPIC: Families play an important role in youth suicide prevention, as both a source of protection and a source of risk, and thus are an important target for adolescent suicide prevention programs. PURPOSE: This article describes in detail Parents-CARE, a brief youth suicide prevention program for parents, for which effectiveness has been demonstrated. Engaging parents in preventive intervention can be challenging; therefore, the feasibility, acceptability, and relevance of the program to parents are examined. SOURCES USED: A total of 289 households participated in Parents-CARE. Parent attendance data and parent and interventionist process data are utilized to demonstrate the positive response by parents to the program. CONCLUSION: The Parents-CARE program was highly attended, and ratings demonstrate that parents were engaged in the program. Ratings show parents found the program both acceptable and relevant. Hence, the program described is promising for clinicians working with at-risk youth as they seek brief, accessible, and effective interventions that include parents in order to amplify the effects of an individual intervention approach. PMID- 23351112 TI - Watch what you cut from our children. PMID- 23351113 TI - Synthesis and properties of highly dispersed ionic silica-poly(ethylene oxide) nanohybrids. AB - We report an ionic hybrid based on silica nanoparticles as the anion and amine terminated poly(ethylene oxide) (PEO) as a cation. The charge on the nanoparticle anion is carried by the surface hydroxyls. SAXS and TEM reveal an exceptional degree of dispersion of the silica in the polymer and high degree of order in both thin film and bulk forms. In addition to better dispersion, the ionic hybrid shows improved flow characteristics compared to silica/PEO mixtures in which the ionic interactions are absent. PMID- 23351114 TI - Iron(III) chloride/diorganyl diselenides: a tool for intramolecular cyclization of alkynone O-methyloximes. AB - This report describes the synthesis of 4-organoselenylisoxazoles via FeCl(3)/RSeSeR-mediated intramolecular cyclization of alkynone O-methyloximes. The optimized conditions allowed the cyclization to proceed at room temperature under ambient atmosphere, and the reaction requires a short time to be completed. The reaction conditions tolerated neutral, electron-donating and electron withdrawing groups present in both substrates, alkynone O-methyloximes and diorganyl diselenides. Treatment of 4-organoselenylisoxazoles with n butyllithium, followed by trapping with electrophiles, furnished the functionalized isoxazoles in good yields. The obtained products also proved to be suitable substrates for the preparation of 4-bromoisoxazoles via Br/Se exchange reaction. PMID- 23351116 TI - Visuo-tactile integration and body ownership during self-generated action. AB - Although there is increasing knowledge about how visual and tactile cues from the hands are integrated, little is known about how self-generated hand movements affect such multisensory integration. Visuo-tactile integration often occurs under highly dynamic conditions requiring sensorimotor updating. Here, we quantified visuo-tactile integration by measuring cross-modal congruency effects (CCEs) in different bimanual hand movement conditions with the use of a robotic platform. We found that classical CCEs also occurred during bimanual self generated hand movements, and that such movements lowered the magnitude of visuo tactile CCEs as compared to static conditions. Visuo-tactile integration, body ownership and the sense of agency were decreased by adding a temporal visuo-motor delay between hand movements and visual feedback. These data show that visual stimuli interfere less with the perception of tactile stimuli during movement than during static conditions, especially when decoupled from predictive motor information. The results suggest that current models of visuo-tactile integration need to be extended to account for multisensory integration in dynamic conditions. PMID- 23351115 TI - Detailed analysis of biased histamine H4 receptor signalling by JNJ 7777120 analogues. AB - BACKGROUND AND PURPOSE: The histamine H4 receptor, originally thought to signal merely through Galphai proteins, has recently been shown to also recruit and signal via beta-arrestin2. Following the discovery that the reference antagonist indolecarboxamide JNJ 7777120 appears to be a partial agonist in beta-arrestin2 recruitment, we have identified additional biased hH4R ligands that preferentially couple to Galphai or beta-arrestin2 proteins. In this study, we explored ligand and receptor regions that are important for biased hH4R signalling. EXPERIMENTAL APPROACH: We evaluated a series of 48 indolecarboxamides with subtle structural differences for their ability to induce hH4R-mediated Galphai protein signalling or beta-arrestin2 recruitment. Subsequently, a Fingerprints for Ligands and Proteins three-dimensional quantitative structure activity relationship analysis correlated intrinsic activity values with structural ligand requirements. Moreover, a hH4R homology model was used to identify receptor regions important for biased hH4R signalling. KEY RESULTS: One indolecarboxamide (75) with a nitro substituent on position R7 of the aromatic ring displayed an equal preference for the Galphai and beta-arrestin2 pathway and was classified as unbiased hH4R ligand. The other 47 indolecarboxamides were beta arrestin2-biased agonists. Intrinsic activities of the unbiased as well as beta arrestin2-biased indolecarboxamides to induce beta-arrestin2 recruitment could be correlated with different ligand features and hH4R regions. CONCLUSION AND IMPLICATIONS: Small structural modifications resulted in diverse intrinsic activities for unbiased (75) and beta-arrestin2-biased indolecarboxamides. Analysis of ligand and receptor features revealed efficacy hotspots responsible for biased-beta-arrestin2 recruitment. This knowledge is useful for the design of hH4R ligands with biased intrinsic activities and aids our understanding of the mechanism of H4R activation. PMID- 23351118 TI - Formation of [3]catenanes from 10 precursors via multicomponent coordination driven self-assembly of metallarectangles. AB - We describe the formation of a suite of [3]catenanes via multicomponent coordination-driven self-assembly and host-guest complexation of a rectangular scaffold comprising a 90 degrees Pt-based acceptor building block with a pseudorotaxane bis(pyridinium)ethane/dibenzo-24-crown-8 linear dipyridyl ligand and three dicarboxylate donors. The doubly threaded [3]catenanes are formed from a total of 10 molecular components from four unique species. Furthermore, the dynamic catenation process is reversible and can be switched off and on in a controllable manner by successive addition of KPF(6) and 18-crown-6, as monitored by (1)H and (31)P NMR spectroscopy. PMID- 23351117 TI - Severe lower respiratory tract infection in infants and toddlers from a non affluent population: viral etiology and co-detection as risk factors. AB - BACKGROUND: Lower respiratory tract infection (LRTI) is a major cause of pediatric morbidity and mortality, especially among non-affluent communities. In this study we determine the impact of respiratory viruses and how viral co detections/infections can affect clinical LRTI severity in children in a hospital setting. METHODS: Patients younger than 3 years of age admitted to a tertiary hospital in Brazil during the months of high prevalence of respiratory viruses had samples collected from nasopharyngeal aspiration. These samples were tested for 13 different respiratory viruses through real-time PCR (rt-PCR). Patients were followed during hospitalization, and clinical data and population characteristics were collected during that period and at discharge to evaluate severity markers, especially length of hospital stay and oxygen use. Univariate regression analyses identified potential risk factors and multivariate logistic regressions were used to determine the impact of specific viral detections as well as viral co-detections in relation to clinical outcomes. RESULTS: We analyzed 260 episodes of LRTI with a viral detection rate of 85% (n = 222). Co detection was observed in 65% of all virus-positive episodes. The most prevalent virus was Respiratory Syncytial Virus (RSV) (54%), followed by Human Metapneumovirus (hMPV) (32%) and Human Rhinovirus (HRV) (21%). In the multivariate models, infants with co-detection of HRV + RSV stayed 4.5 extra days (p = 0.004), when compared to infants without the co-detection. The same trends were observed for the outcome of days of supplemental oxygen use. CONCLUSIONS: Although RSV remains as the main cause of LRTI in infants our study indicates an increase in the length of hospital stay and oxygen use in infants with HRV detected by RT-PCR compared to those without HRV. Moreover, one can speculate that when HRV is detected simultaneously with RSV there is an additive effect that may be reflected in more severe clinical outcome. Also, our study identified a significant number of children infected by recently identified viruses, such as hMPV and Human Bocavirus (HBov), and this is a novel finding for poor communities from developing countries. PMID- 23351119 TI - Complete mitochondrial genome of Chinese sleeper, Perccottus glenii. AB - Chinese sleeper (Perccottus glenii) belongs to the largest vertebrate order, Perciformes. In this study, the complete mitochondrial genome of P. glenii was determined to be 16,487 bp in length, including 13 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes. We also analysed the sequence structure of non-coding control region. Comparing the mitochondrial genome of P. glenii with its congener Rhyacichthys aspro showed sequence similarity and the identical gene arrangement. The complete mitochondrial genome of Chinese sleeper provides the basis for the studies in Perciformes evolution and conservation. PMID- 23351120 TI - Anthropometry-corrected exposure modeling as a method to improve trunk posture assessment with a single inclinometer. AB - Measuring trunk posture in the workplace commonly involves subjective observation or self-report methods or the use of costly and time-consuming motion analysis systems (current gold standard). This work compared trunk inclination measurements using a simple data-logging inclinometer with trunk flexion measurements using a motion analysis system, and evaluated adding measures of subject anthropometry to exposure prediction models to improve the agreement between the two methods. Simulated lifting tasks (n=36) were performed by eight participants, and trunk postures were simultaneously measured with each method. There were significant differences between the two methods, with the inclinometer initially explaining 47% of the variance in the motion analysis measurements. However, adding one key anthropometric parameter (lower arm length) to the inclinometer-based trunk flexion prediction model reduced the differences between the two systems and accounted for 79% of the motion analysis method's variance. Although caution must be applied when generalizing lower-arm length as a correction factor, the overall strategy of anthropometric modeling is a novel contribution. In this lifting-based study, by accounting for subject anthropometry, a single, simple data-logging inclinometer shows promise for trunk posture measurement and may have utility in larger-scale field studies where similar types of tasks are performed. PMID- 23351121 TI - The rationale and design of Insight into Nephrotic Syndrome: Investigating Genes, Health and Therapeutics (INSIGHT): a prospective cohort study of childhood nephrotic syndrome. AB - BACKGROUND: Nephrotic syndrome is one of the most commonly diagnosed kidney diseases in childhood and its progressive forms can lead to chronic kidney disease (CKD) and/or end-stage renal disease (ESRD). There have been few longitudinal studies among a multi-ethnic cohort to determine potential risk factors influencing disease susceptibility, treatment response, and progression of nephrotic syndrome. Temporal relationships cannot be studied through cross sectional study design. Understanding the interaction between various factors is critical to developing new strategies for treating children with kidney disease. We present the rationale and the study design of a longitudinal cohort study of children with nephrotic syndrome, the Insight into Nephrotic Syndrome: Investigating Genes, Health and Therapeutics (INSIGHT) study. The specific aims are to determine: 1) socio-demographic, environmental, and genetic factors that influence disease susceptibility; 2) rates of steroid treatment resistance and steroid treatment dependence, and identify factors that may modify treatment response; 3) clinical and genetic factors that influence disease susceptibility and progression to CKD and ESRD; and 4) the interaction between the course of illness and socio-demographic, environmental, and clinical risk factors. METHODS/DESIGN: INSIGHT is a disease-based observational longitudinal cohort study of children with nephrotic syndrome. At baseline, participants complete questionnaires and provide biological specimen samples (blood, urine, and toenail clippings). Follow-up questionnaires and repeat biological specimen collections are performed annually for up to five years. DISCUSSION: The proposed cohort will provide the structure to test various risk factors predicting or influencing disease susceptibility, treatment response, and progression to CKD among children with nephrotic syndrome. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01605266. PMID- 23351122 TI - Dementia knowledge transfer project in a rural area. AB - INTRODUCTION: Rural Scotland has an ageing population. There has been an increase in the number of people with dementia and as the proportion of people aged over 75 years continues to rise, this will increase still further. The Scottish Government has produced a dementia strategy and implementing this will be a challenge for rural Scotland. METHODS: Transferring academic knowledge into practice is challenging. A Knowledge Transfer Partnership was formed between NHS Highland and the University of Stirling. A literature review was undertaken of the rural dementia literature; local services were surveyed and described; and interviews were undertaken with people with dementia and carers. Work was conducted on training, diagnostic service provision and local policy. Throughout the project, a collaborative approach was used, which aimed at the joint production of knowledge. RESULTS: Involving University staff in local service development had a substantial impact. Reviewing existing research knowledge and setting it in the context of local services, and of experience of service use, allowed the relevant priorities to be identified. As well as identifying training needs and providing training, the work influenced local decisions on diagnostic service design and standards, and on policy. CONCLUSION: This embedded engagement model appeared to produce more rapid change than traditional models of use of academic knowledge. PMID- 23351123 TI - Chemical mapping of pharmaceutical cocrystals using terahertz spectroscopic imaging. AB - Terahertz (THz) spectroscopic imaging is a promising technique for distinguishing pharmaceuticals of similar molecular composition but differing crystal structures. Physicochemical properties, for instance bioavailability, are manipulated by altering a drug's crystal structure through methods such as cocrystallization. Cocrystals are molecular complexes having crystal structures different from those of their pure components. A technique for identifying the two-dimensional distribution of these alternate forms is required. Here we present the first demonstration of THz spectroscopic imaging of cocrystals. THz spectra of caffeine-oxalic acid cocrystal measured at low temperature exhibit sharp peaks, enabling us to visualize the cocrystal distribution in nonuniform tablets. The cocrystal distribution was clearly identified using THz spectroscopic data, and the cocrystal concentration was calculated with 0.3-1.3% w/w error from the known total concentration. From this result, THz spectroscopy allows quantitative chemical mapping of cocrystals and offers researchers and drug developers a new analytical tool. PMID- 23351124 TI - A benedictory ode to urological live surgery. PMID- 23351125 TI - Why join groups? Lessons from parasite-manipulated Artemia. AB - Grouping behaviours (e.g. schooling, shoaling and swarming) are commonly explicated through adaptive hypotheses such as protection against predation, access to mates or improved foraging. However, the hypothesis that aggregation can result from manipulation by parasites to increase their transmission has never been demonstrated. We investigated this hypothesis using natural populations of two crustacean hosts (Artemia franciscana and Artemia parthenogenetica) infected with one cestode and two microsporidian parasites. We found that swarming propensity increased in cestode-infected hosts and that red colour intensity was higher in swarming compared with non-swarming infected hosts. These effects likely result in increased cestode transmission to its final avian host. Furthermore, we found that microsporidian-infected hosts had both increased swarming propensity and surfacing behaviour. Finally, we demonstrated using experimental infections that these concurrent manipulations result in increased spore transmission to new hosts. Hence, this study suggests that parasites can play a prominent role in host grouping behaviours. PMID- 23351126 TI - Depletion of Aurora-A in zebrafish causes growth retardation due to mitotic delay and p53-dependent cell death. AB - Aurora-A is a serine/threonine mitotic kinase that is required for centrosome maturation. Many cancer cells over-express Aurora-A, and several reports have suggested that Aurora-A has prognostic value in the clinical treatment of cancer. Therefore, inhibitors for Aurora-A kinase have been developed. However, studies on Aurora-A are largely performed in cancer cell lines and are sometimes controversial. For effective evaluation of Aurora-A inhibitors in cancer treatment, it is essential to understand its function at the organism level. Here, we report the crucial functions of Aurora-A in homeostasis of spindle organization in mitosis using zebrafish embryogenesis as a model system. Using morpholino technology, we show that depletion of Aurora-A in zebrafish embryogenesis results in short bent trunks, accompanied by growth retardation and eventual cell death. Live-imaging and immunofluorescence analyses of the embryos revealed that the developmental defects are due to problems in mitosis, manifested through monopolar and disorganized spindle formation. Aurora-A depleted cells exhibited mitotic arrest with congression failure, leading to activation of the spindle assembly checkpoint. Cell death in the absence of Aurora-A was partially rescued by co-injection of the p53 morpholino, suggesting that apoptosis after Aurora-A depletion is p53-dependent. The clinical implications of these results relate to the indication that Aurora-A inhibitors may be effective towards cancers with intact p53. PMID- 23351127 TI - The effect of induced self-presentation concerns on cognitive appraisal and affect. AB - An experiment was conducted to investigate how self-presentation imperatives can influence cognition and affect. Participants were 70 collegiate and recreational athletes who were recruited because of the relevance of self-presentation processes in sport. Athletes were asked to read either a script which de emphasized self-presentation concerns (low self-presentation) or emphasized self presentation concerns (high self-presentation). The scripts were developed for the purpose of the study and depicted a pre-competition scenario. The low self presentation manipulation group reported more of a challenge state of appraisal, higher self-efficacy, lower avoidance goal focus, and more positive affect, while the high self-presentation manipulation group reported more of a threat state of cognitive appraisal and more negative affect. Nonsignificant differences were observed between groups for the perception of positive affect and negative affect. These findings provide preliminary evidence that self-presentation imperatives can impact the cognitive appraisal and affect of athletes as they prepare for competition. PMID- 23351128 TI - Development of high-density SNP genotyping arrays for white spruce (Picea glauca) and transferability to subtropical and nordic congeners. AB - High-density SNP genotyping arrays can be designed for any species given sufficient sequence information of high quality. Two high-density SNP arrays relying on the Infinium iSelect technology (Illumina) were designed for use in the conifer white spruce (Picea glauca). One array contained 7338 segregating SNPs representative of 2814 genes of various molecular functional classes for main uses in genetic association and population genetics studies. The other one contained 9559 segregating SNPs representative of 9543 genes for main uses in population genetics, linkage mapping of the genome and genomic prediction. The SNPs assayed were discovered from various sources of gene resequencing data. SNPs predicted from high-quality sequences derived from genomic DNA reached a genotyping success rate of 64.7%. Nonsingleton in silico SNPs (i.e. a sequence polymorphism present in at least two reads) predicted from expressed sequenced tags obtained with the Roche 454 technology and Illumina GAII analyser resulted in a similar genotyping success rate of 71.6% when the deepest alignment was used and the most favourable SNP probe per gene was selected. A variable proportion of these SNPs was shared by other nordic and subtropical spruce species from North America and Europe. The number of shared SNPs was inversely proportional to phylogenetic divergence and standing genetic variation in the recipient species, but positively related to allele frequency in P. glauca natural populations. These validated SNP resources should open up new avenues for population genetics and comparative genetic mapping at a genomic scale in spruce species. PMID- 23351129 TI - Tumor biology and pre-transplant locoregional treatments determine outcomes in patients with T3 hepatocellular carcinoma undergoing liver transplantation. AB - Liver transplantation is the optimal treatment for patients with hepatocellular carcinoma (HCC) and cirrhosis. This study was conducted to determine the impact of pre-transplant locoregional therapy (LRT) on HCC and our institution's experience with expansion to United Network of Organ Sharing Region 4 T3 (R4T3) criteria. Two hundred and twenty-five patients with HCC (176 meeting Milan and 49 meeting R4T3 criteria) underwent liver transplantation from 2002 to 2008. Compared with the Milan criteria, HCCs in R4T3 criteria displayed less favorable biological features such as higher median alpha-fetoprotein level (21.9 vs. 8.5 ng/mL, p = 0.01), larger tumor size, larger tumor number, and higher incidence of microvascular invasion (22% vs. 5%, p = 0.002). As a result, patients meeting Milan criteria had better five-yr survival (79% vs. 69%, p = 0.03) and a trend toward lower HCC recurrence rates (5% vs. 13%, p = 0.05). Pre-transplant LRT did not affect post-transplant outcomes in patients meeting Milan criteria but did result in lower three-yr HCC recurrence (7% vs. 75%, p < 0.001) and better three yr survival (p = 0.02) in patients meeting R4T3 criteria. Tumor biology and pre transplant LRT are important factors that determine the post-transplant outcomes in patients with HCC who meet R4T3 criteria. PMID- 23351130 TI - Spider bite-induced erythema multiforme. AB - Erythema multiforme (EM) is an immune-mediated mucocutaneous eruption characterized by symmetrically distributed, polymorphic targetoid lesions, mostly on the distal parts of the extremities. It occurs mostly in the setting of an infection in certain predisposed individuals. A 30-year-old pregnant woman was presented with a necrotic erythematous lesion on her right thigh following a spider bite. As she was pregnant for 16 weeks, no systemic medication was given. On the 8th day of the spider bite an erythematous vesicular and targetoid rash was seen on the distal parts of her extremities. Based on the clinical and histopathological findings, lesions were diagnosed as EM. She had not used any medication for 4 months and she gave no prior history of herpetic infection. So her EM lesions were thought to be an ID reaction most probably due to the spider bite. As far as we know, this is the first reported case of EM induced by a spider bite. PMID- 23351131 TI - Sensory suppression effects to self-initiated sounds reflect the attenuation of the unspecific N1 component of the auditory ERP. AB - The suppression of the auditory N1 event-related potential (ERP) to self initiated sounds became a popular tool to tap into sensory-specific forward modeling. It is assumed that processing in the auditory cortex is attenuated due to a match between sensory stimulation and a specific sensory prediction afforded by a forward model of the motor command. The present study shows that N1 suppression was dramatically increased with long (~ 3 s) stimulus onset asynchronies (SOA), whereas P2 suppression was equal in all SOA conditions (0.8, 1.6, 3.2 s). Thus, the P2 was found to be more sensitive to self-initiation effects than the N1 with short SOAs. Moreover, only the unspecific but not the sensory-specific N1 components were suppressed for self-initiated sounds suggesting that N1-suppression effects mainly reflect an attenuated orienting response. We argue that the N1-suppression effect is a rather indirect measure of sensory-specific forward models. PMID- 23351132 TI - Effective interprofessional collaboration in rural contexts: a research protocol. AB - AIM: To describe the research protocol that will be used to investigate factors contributing to effective interprofessional practice in a rural context in Australia. BACKGROUND: Interprofessional practice is a key strategy for overcoming rural health challenges; however, our knowledge of interprofessional initiatives and consequences in rural areas is limited. DESIGN: A modified realistic evaluation approach will be used to explore the structures, systems, and social processes contributing to effective interprofessional outcomes. This 'context-mechanism-outcome' approach provides a useful framework for identifying why and how interprofessional practice works in rural contexts. METHOD: Initial propositions regarding the factors that explain effective collaborative practice will be generated through interviews with lead clinicians, policy-makers, and clinician managers. Clinician interviews, document analysis, and multi participant focus groups will be used as evidence to support, refine, or redevelop the initial propositions. This will allow the development of a model of rural interprofessional practice that will explain how and why collaborative approaches work in rural environments. This study is funded by an Institute of Rural Clinical Services and Teaching grant (January 2010). DISCUSSION: Rural healthcare challenges are well documented; however, studies investigating the nature of interprofessional practice in rural contexts are not common. Rural contexts also present research design, particularly data collection, challenges. This proposed research is one of the first to identify the factors that facilitate or constrain effective interprofessional work in rural settings. This is particularly important, given the continuing workforce shortages and maldistribution and poorer health outcomes in rural communities globally. PMID- 23351133 TI - Surface-stabilized lopinavir nanoparticles enhance oral bioavailability without coadministration of ritonavir. AB - AIM: The aim of the present study was to prepare surface-stabilized nanoparticles (NPs) for oral bioavailability enhancement of lopinavir (LPN), a Biopharmaceutics Classification System class II antiretroviral drug that possesses low oral bioavailability due to its poor aqueous solubility and extensive metabolism by liver microsomal enzymes. MATERIALS & METHODS: Surfactant-stabilized LPN-NPs were prepared by combination of antisolvent precipitation and high-pressure homogenization techniques using polyvinyl alcohol as a suitable stabilizer. LPN NPs were freeze dried by a universal stepwise freeze-drying cycle using mannitol as the cryoprotectant. Pharmacokinetics after oral administration of LPN-NPs were evaluated in male Sprague-Dawley rats and were compared with free LPN coadministered with ritonavir (conventional formulation). RESULTS & CONCLUSION: Freeze-dried stabilized LPN-NPs possessed particle sizes of approximately 320 nm and a narrow particle size distribution (polydispersity index <0.2). The surface stabilized LPN-NPs (without ritonavir) demonstrated a 3.11-fold enhancement in bioavailability in comparison to free LPN with ritonavir (conventional formulation). PMID- 23351134 TI - Presence of virulence markers in environmental Vibrio vulnificus strains. AB - AIMS: This work aims to demonstrate the presence of several genes and factors associated with virulence in strains isolated from the environment at Pueblo Viejo Lagoon, State of Veracruz, Mexico. METHODS AND RESULTS: In this study, we investigated the production of V. vulnificus virulence factors, as cytolysin (haemolysin), RTX toxin, metalloprotease, siderophores, capsular polysaccharide, adhesion structures (like type IV pili), and polar and lateral flagella, involved in swimming and swarming (or, at least, the presence of genes encoding some of them) in 40 strains of V. vulnificus isolated from water and food. The results indicate that strains of environmental origin possess potential virulence characteristics. CONCLUSIONS: Caution should be exercised when consuming raw shellfish (especially by those more susceptible risk groups). SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first work focused on the evaluation of V. vulnificus virulence factors in Mexico. PMID- 23351135 TI - Incidental sonographic diagnosis of neonatal carotid occlusion. AB - Cranial ultrasonography including colour Doppler can detect neonatal carotid flow problems at an early stage, even before symptoms occur. Different pathogeneses can be identified. The condition is more frequent than previously reported. If the circle of Willis is fully developed, this can prevent brain injury even in case of total carotid flow obstruction CONCLUSION: Screening of the carotid artery in critically ill neonates may detect complications of treatment at an early stage. PMID- 23351136 TI - Chemogenomics approaches to rationalizing the mode-of-action of traditional Chinese and Ayurvedic medicines. AB - Traditional Chinese medicine (TCM) and Ayurveda have been used in humans for thousands of years. While the link to a particular indication has been established in man, the mode-of-action (MOA) of the formulations often remains unknown. In this study, we aim to understand the MOA of formulations used in traditional medicine using an in silico target prediction algorithm, which aims to predict protein targets (and hence MOAs), given the chemical structure of a compound. Following this approach we were able to establish several links between suggested MOAs and experimental evidence. In particular, compounds from the 'tonifying and replenishing medicinal' class from TCM exhibit a hypoglycemic effect which can be related to activity of the ingredients against the Sodium Glucose Transporters (SGLT) 1 and 2 as well as Protein Tyrosine Phosphatase (PTP). Similar results were obtained for Ayurvedic anticancer drugs. Here, both primary anticancer targets (those directly involved in cancer pathogenesis) such as steroid-5-alpha-reductase 1 and 2 were predicted as well as targets which act synergistically with the primary target, such as the efflux pump P-glycoprotein (P-gp). In addition, we were able to elucidate some targets which may point us to novel MOAs as well as explain side effects. Most notably, GPBAR1, which was predicted as a target for both 'tonifying and replenishing medicinal' and anticancer classes, suggests an influence of the compounds on metabolism. Understanding the MOA of these compounds is beneficial as it provides a resource for NMEs with possibly higher efficacy in the clinic than those identified by single-target biochemical assays. PMID- 23351137 TI - Clear cell sarcoma of the jejunum: a case report. AB - BACKGROUND: Clear cell sarcoma (CCS), also known as malignant melanoma of soft parts, is a rare type of soft tissue sarcoma which exhibits morphological, immunohistochemical and ultrastructural similarity with malignant melanoma. It is rarely localized in the intestine and the natural history of this tumor is not yet clear. CASE REPORT: A 49-year-old woman presented with diffuse abdominal colicky pain and vomitus over the previous seven days. An X-ray of the abdomen revealed obstruction of the small intestine. The patient underwent contrast enhanced abdominal computerized tomography (CT), which confirmed the obstruction at the jejunum and an associated circumferential wall thickening extending about 3 cm in length, causing concentric narrowing of the lumen. At laparotomy, a mass was recognized at the level of the jejunum in the small intestine, which caused almost complete obstruction of the lumen. At the point of obstruction, adhered loops of small intestine were found. A segmental small bowel resection was performed with 5 cm clear margins and its respective mesenteric lymph nodes. RESULTS: Histological examination of the specimen revealed a tumor (3*3*2 cm) with epithelioid cell characteristics and eosinophilic or clear cytoplasm and focal translucent nuclei. Immunohistochemistry was positive for S100, epithelial membrane antigen (EMA) and synaptophysin. The tumor was pankeratin AE1/AE2, GFAP, HMB45 and MART-1/Melan-A negative. Twelve lymph nodes were retrieved and were free of neoplastic infiltration. Cytogenetic examination revealed translocation of the EWSR1 gene. The patient had an uncomplicated postoperative course and left the hospital seven days after her admission in good general condition. After 20 months of follow-up the patient remains asymptomatic without any clinical or radiological evidence of recurrence. CONCLUSION: CCS sarcoma can be rarely localized in the jejunum. Due to its morphological similarity to malignant melanoma, cytogenetic examination is necessary for its diagnosis. Wide resection of the tumor and its respective lymph nodes was associated with a 20-month disease free survival in this patient. PMID- 23351138 TI - Covalency in metal-oxygen multiple bonds evaluated using oxygen K-edge spectroscopy and electronic structure theory. AB - Advancing theories of how metal-oxygen bonding influences metal oxo properties can expose new avenues for innovation in materials science, catalysis, and biochemistry. Historically, spectroscopic analyses of the transition metal MO(4)(x-) anions have formed the basis for new M-O bonding theories. Herein, relative changes in M-O orbital mixing in MO(4)(2-) (M = Cr, Mo, W) and MO(4)(-) (M = Mn, Tc, Re) are evaluated for the first time by nonresonant inelastic X-ray scattering, X-ray absorption spectroscopy using fluorescence and transmission (via a scanning transmission X-ray microscope), and time-dependent density functional theory. The results suggest that moving from Group 6 to Group 7 or down the triads increases M-O e* (pi*) mixing; for example, it more than doubles in ReO(4)(-) relative to CrO(4)(2-). Mixing in the t(2)* orbitals (sigma* + pi*) remains relatively constant within the same Group, but increases on moving from Group 6 to Group 7. These unexpected changes in orbital energy and composition for formally isoelectronic tetraoxometalates are evaluated in terms of periodic trends in d orbital energy and radial extension. PMID- 23351139 TI - Drug-induced nanocarrier assembly as a strategy for the cellular delivery of nucleotides and nucleotide analogues. AB - The natural nucleotide adenosine triphosphate (ATP) and nucleotide analogues such as azidothymidine triphosphate (AZT-TP) display important pharmacological activities for the treatment of ischemia and HIV infections, respectively. Their clinical use is, however, limited mostly due to their hydrophilicity, which highly restricts their diffusion into the target cells. Few nanocarriers have been proposed to address the challenge of ATP/AZT-TP cellular delivery, but the loading efficiency, preparation complexity, and efficient cellular delivery remain important barriers to their development. In this study, we propose an original, straightforward and versatile design of nucleotide and nucleotide analogue nanocarriers based on the natural polysaccharide chitosan (CS). We show that the drugs ATP and AZT-TP can induce ionotropic gelation of CS, leading to CS/ATP and CS/AZT-TP nanoparticles with high drug entrapment efficiency and loading rate-up to 44%. Such nanocarriers release ATP and AZT-TP in physiological media and allow an efficient in vitro cellular delivery of these molecules down to the cell cytoplasm. PMID- 23351140 TI - Ileocolic intussusception secondary to a type II low-grade appendiceal mucinous neoplasm. PMID- 23351142 TI - Synthesis of alpha-alkylated beta-ketoesters by alkoxycarbonylation/Michael addition domino reaction. AB - The palladium-catalyzed alkoxycarbonylation of an alpha-chloro ketone can be efficiently combined to a Michael addition reaction in a new two-step domino reaction, allowing the synthesis of original highly functionalized alpha alkylated beta-ketoesters. The scope of the reaction was extended to several alpha-chloro ketones and Michael acceptors with moderate to very good yields. PMID- 23351141 TI - Radiosensitization in prostate cancer: mechanisms and targets. AB - Prostate cancer is the second most commonly diagnosed cancer in American men over the age of 45 years and is the third most common cause of cancer related deaths in American men. In 2012 it is estimated that 241,740 men will be diagnosed with prostate cancer and 28,170 men will succumb to prostate cancer. Currently, radiation therapy is one of the most common definitive treatment options for localized prostate cancer. However, significant number of patients undergoing radiation therapy will develop locally persistent/recurrent tumours. The varying response rates to radiation may be due to 1) tumor microenvironment, 2) tumor stage/grade, 3) modality used to deliver radiation, and 4) dose of radiation. Higher doses of radiation has not always proved to be effective and have been associated with increased morbidity. Compounds designed to enhance the killing effects of radiation, radiosensitizers, have been extensively investigated over the past decade. The development of radiosensitizing agents could improve survival, improve quality of life and reduce costs, thus benefiting both patients and healthcare systems. Herin, we shall review the role and mechanisms of various agents that can sensitize tumours, specifically prostate cancer. PMID- 23351143 TI - Identification of key residues involved in adrenomedullin binding to the AM1 receptor. AB - BACKGROUND AND PURPOSE: Adrenomedullin (AM) is a peptide hormone whose receptors are members of the class B GPCR family. They comprise a heteromer between the GPCR, the calcitonin receptor-like receptor and one of the receptor activity modifying proteins 1-3. AM plays a significant role in angiogenesis and its antagonist fragment AM22-52 can inhibit blood vessel and tumour growth. The mechanism by which AM interacts with its receptors is unknown. EXPERIMENTAL APPROACH: We determined the AM22-52 binding epitope for the AM1 receptor extracellular domain using biophysical techniques, heteronuclear magnetic resonance spectroscopy and alanine scanning. KEY RESULTS: Chemical shift perturbation experiments located the main binding epitope for AM22-52 at the AM1 receptor to the C-terminal 8 amino acids. Isothermal titration calorimetry of AM22-52 alanine-substituted peptides indicated that Y52, G51 and I47 are essential for AM1 receptor binding and that K46 and P49 and R44 have a smaller role to play. Characterization of these peptides at the full-length AM receptors was assessed in Cos7 cells by cAMP assay. This confirmed the essential role of Y52, G51 and I47 in binding to the AM1 receptor, with their substitution resulting in >=100-fold reduction in antagonist potency compared with AM22-52 . R44A, K46A, S48A and P49A AM22-52 decreased antagonist potency by approximately 10-fold. CONCLUSIONS AND IMPLICATIONS: This study localizes the main binding epitope of AM22-52 to its C-terminal amino acids and distinguishes essential residues involved in this binding. This will inform the development of improved AM receptor antagonists. PMID- 23351144 TI - Transglial transmission at the dorsal root ganglion sandwich synapse: glial cell to postsynaptic neuron communication. AB - The dorsal root ganglion (DRG) contains a subset of closely-apposed neuronal somata (NS) separated solely by a thin satellite glial cell (SGC) membrane septum to form an NS-glial cell-NS trimer. We recently reported that stimulation of one NS with an impulse train triggers a delayed, noisy and long-lasting response in its NS pair via a transglial signaling pathway that we term a 'sandwich synapse' (SS). Transmission could be unidirectional or bidirectional and facilitated in response to a second stimulus train. We have shown that in chick or rat SS the NS to-SGC leg of the two-synapse pathway is purinergic via P2Y2 receptors but the second SGC-to-NS synapse mechanism remained unknown. A noisy evoked current in the target neuron, a reversal potential close to 0 mV, and insensitivity to calcium scavengers or G protein block favored an ionotropic postsynaptic receptor. Selective block by D-2-amino-5-phosphonopentanoate (AP5) implicated glutamatergic transmission via N-methyl-d-aspartate receptors. This agent also blocked NS responses evoked by puff of UTP, a P2Y2 agonist, directly onto the SGC cell, confirming its action at the second synapse of the SS transmission pathway. The N-methyl-d-aspartate receptor NR2B subunit was implicated by block of transmission with ifenprodil and by its immunocytochemical localization to the NS membrane, abutting the glial septum P2Y2 receptor. Isolated DRG cell clusters exhibited daisy-chain and branching NS-glial cell-NS contacts, suggestive of a network organization within the ganglion. The identification of the glial-to neuron transmitter and receptor combination provides further support for transglial transmission and completes the DRG SS molecular transmission pathway. PMID- 23351145 TI - Iridium-catalyzed [3 + 2] annulation of cyclic N-sulfonyl ketimines with 1,3 dienes via C-H activation. AB - Ir-catalyzed [3 + 2] annulation of cyclic N-sulfonyl ketimines with 1,3-dienes, in which an aryliridium intermediate is formed via C-H activation, gives aminoindane derivatives in high yields with high regio- and diastereoselectivity. PMID- 23351147 TI - Cytotoxic constituents of ethyl acetate fraction from Dianthus superbus. AB - The ethyl acetate fraction (EE-DS) from Dianthus superbus was found to possess the cytotoxic activity against cancer cells in previous study. To investigate cytotoxic constituents, the bioassay-guided isolation of compounds from EE-DS was performed. Two dianthramides (1 and 2), three flavonoids (3-5), two coumarins (6 and 7) and three other compounds (8-10) were obtained. Structures of isolated compounds were identified by spectroscopic analysis. Cytotoxicity of the compounds against HepG2 cells was evaluated. Compound 1 showed the strongest cytotoxicity, compounds 10, 4, 3 and 5 had moderate cytotoxicity. PMID- 23351146 TI - Associations of epicardial fat with coronary calcification, insulin resistance, inflammation, and fibroblast growth factor-23 in stage 3-5 chronic kidney disease. AB - BACKGROUND: Epicardial fat, quantified in a single multi-slice computed tomography (MSCT) slice, is a reliable estimate of total epicardial fat volume (EFV). We sought to determine risk factors for EFV detected in a single-slice MSCT measurement (ssEFV) in pre-dialysis chronic kidney disease (CKD) patients. Our primary objective was to determine the association between ssEFV and coronary artery calcification (CAC). METHODS: 94 pre-dialysis stage 3-5 CKD patients underwent MSCT to measure ssEFV and CAC. ssEFV was quantified at the level of the left main coronary artery. Measures of inflammation, traditional and kidney related cardiovascular disease risk factors were collected. RESULTS: Mean age: 63.7 +/- 14 years, 56% male, 39% had diabetes, and mean eGFR: 25.1 +/- 11.9 mL/min/1.73 m2. Mean ssEFV was 5.03 +/- 2.4 cm3. By univariate analysis, body mass index (BMI) (r = 0.53; P = <0.0001), abdominal obesity (r = 0.51; P < 0.0001), high density lipoprotein (HDL) cholesterol (r = - 0.39; P = <0.0001), insulin resistance (log homeostasis model assessment of insulin resistance (log HOMA-IR)) (r = 0.38, P = 0.001), log interleukin-6 (IL-6) (r = 0.34; P = 0.001), and log urinary albumin to creatinine ratio (UACR) (r = 0.30, P = 0.004) demonstrated the strongest associations with ssEFV. Log coronary artery calcification (log CAC score) (r = 0.28, P = 0.006), and log fibroblast growth factor-23 (log FGF-23) (r = 0.23, P = 0.03) were also correlated with ssEFV. By linear regression, log CAC score (beta =0.40; 95% confidence interval (CI), 0.01 0.80; P = 0.045), increasing levels of IL-6 (beta = 0.99; 95% CI, 0.38 - 1.61; P = 0.002), abdominal obesity (beta = 1.86; 95% CI, 0.94 - 2.8; P < 0.0001), lower HDL cholesterol (beta = -2.30; 95% CI, - 3.68 to -0.83; P = 0.002) and albuminuria (log UACR, beta = 0.81; 95% CI, 0.2 to 1.4; P = 0.01) were risk factors for increased ssEFV. CONCLUSIONS: In stage 3-5 CKD, coronary calcification and IL-6 and were predictors of ssEFV. Further studies are needed to clarify the mechanism by which epicardial fat may contribute to the pathogenesis of coronary disease, particularly in the CKD population. PMID- 23351148 TI - Standardized comparison of robot-assisted limited and extended pelvic lymphadenectomy for prostate cancer. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Extended pelvic lymphadenectomy is the present standard of care according to European Association of Urology guidelines. Extended dissection improves staging, removes more metastatic lymph nodes, and potentially has therapeutic benefits. Previous reports have examined the morbidity of extended dissection compared with a more limited dissection in the open and laparoscopic setting. While some have suggested an increased complication rate with extended node dissection, others have not. This represents the first study focused on comparing the complications associated with the extent of node dissection using the modified Clavien system and Martin criteria in the literature on robot-assisted surgery. In a single surgeon series, we found no statistically significant differences in complications. With careful anatomic dissection, robot-assisted extended lymph node dissection can be performed safely and effectively, although operating time and length of hospital of stay are slightly increased. OBJECTIVES: To compare the perioperative course of patients undergoing robot-assisted limited lymph node dissection (LLND) or extended lymph node dissection (ELND) for prostate cancer. To examine the differential lymph node counts and rates of detection of lymph node metastases. PATIENTS AND METHODS: Between 2008 and 2012, 406 consecutive patients with D'Amico intermediate- or high-risk prostate cancer underwent either bilateral LLND (n = 204) or ELND (n = 202) and robot-assisted laparoscopic radical prostatectomy by a single surgeon. The region of dissection was the obturator fossa for LLND, while ELND included, in addition, the common iliac, external iliac and internal iliac lymph nodes. All complications within 90 days of surgery were recorded according to a modified Clavien system. Clinical variables were summarized and compared. Logistic regression was used to identify predictors of complications. RESULTS: There were no differences in demographics when comparing patients who underwent ELND with those who underwent LLND. The median operating time was 3.0 h for the ELND cohort and 2.8 h in the LLND cohort (P < 0.001). Intraoperative blood loss was 200 mL in both cohorts. Hospital stay was longer for a small percentage of patients in the ELND cohort, with 75% of ELND patients and 85% of LLND patients staying 1 day (P = 0.004). No significant difference was found in the overall or major complication rates between LLND (21.6% overall; 6.9% major) and ELND (22.8% overall; 4.5% major). No difference was seen in the symptomatic lymphocele rate between LLND and ELND, 2.9 vs 2.5%, respectively. Overall, the lymph-node-positive rate was 12% compared with 4% for the ELND and LLND groups, respectively (P = 0.002). A higher Charlson comorbidity index score was associated with the development of major complications. CONCLUSIONS: ELND at the time of robot-assisted radical prostatectomy can be performed safely with minimal additional morbidity. Long-term oncological and functional outcomes require further study. PMID- 23351149 TI - Structural relationships and vasorelaxant activity of monoterpenes. AB - BACKGROUND AND PURPOSE OF THE STUDY: The hypotensive activity of the essential oil of Mentha x villosa and its main constituent, the monoterpene rotundifolone, have been reported. Therefore, our objective was to evaluate the vasorelaxant effect of monoterpenes found in medicinal plants and establish the structure activity relationship of rotundifolone and its structural analogues on the rat superior mesenteric artery. METHODS: Contractions of the vessels were induced with 10 MUM of phenylephine (Phe) in rings with endothelium. During the tonic phase of the contraction, the monoterpenes (10-8 - 10-3, cumulatively) were added to the organ bath. The extent of relaxation was expressed as the percentage of Phe-induced contraction. RESULTS: The results from the present study showed that both oxygenated terpenes (rotundifolone, (+)-limonene epoxide, pulegone epoxide, carvone epoxide, and (+)-pulegone) and non-oxygenated terpene ((+)-limonene) exhibit relaxation activity. The absence of an oxygenated molecular structure was not a critical requirement for the molecule to be bioactive. Also it was found that the position of ketone and epoxide groups in the monoterpene structures influence the vasorelaxant potency and efficacy. MAJOR CONCLUSION: The results suggest that the presence of functional groups in the chemical structure of rotundifolone is not essential for its vasorelaxant activity. PMID- 23351150 TI - Continuous intravenous anaesthesia with sufentanil and midazolam in medetomidine premedicated New Zealand White rabbits. AB - BACKGROUND: Anaesthesia in rabbits is associated with a high mortality rate, compared to that in cats and dogs. Total intravenous anaesthesia (TIVA) with drugs that provide cardiovascular stability and are rapidly metabolised could be of benefit for use in rabbits. The aim was to evaluate cardiorespiratory effects of TIVA with sufentanil-midazolam in eight New Zealand White rabbits. Subcutaneous premedication with medetomidine (0.1 mg/kg BW) was followed by IV administration of a mixture of 2.5 MUg/mL sufentanil and 0.45 mg/mL midazolam at a rate of 0.3 mL/kg BW/h for anaesthetic induction. Additionally, intravenous boluses of 0.1 mL of the mixture were administered every 20 s until the righting reflex was lost. Following endotracheal intubation, anaesthesia was maintained for 60 min with an infusion rate adjusted to supress the pedal withdrawal reflex. Air and oxygen (1:2) were delivered at 3 L/min. Physiological variables were recorded before induction and at predefined time points during and after anaesthesia. RESULTS: Righting and pedal withdrawal reflexes were lost within 3 and 5 min, respectively. Doses of sufentanil and midazolam were 0.48 MUg/kg BW and 0.09 mg/kg BW for induction, and 0.72 MUg/kg BW/h and 0.13 mg/kg BW/h for maintenance. Apnoea occurred in two rabbits. Induction of anaesthesia caused a significant increase in heart rate, cardiac output and arterial CO2 partial pressure and a decrease in mean arterial pressure, respiratory rate and pH. Mean time from stopping the infusion to endotracheal extubation was 5 min, and to return of the righting reflex 7 min. Anaesthesia was characterized by induction and recovery without excitation, with muscle relaxation, and absence of the pedal withdrawal reflex. CONCLUSIONS: TIVA with sufentanil-midazolam provided smooth induction and recovery of anaesthesia in rabbits but with marked hypotension and respiratory depression, requiring mechanical ventilation. Further evaluation is needed to establish if the protocol is useful for rabbits undergoing surgery. PMID- 23351151 TI - Identification of mimotopes of Mycobacterium leprae as potential diagnostic reagents. AB - BACKGROUND: An early diagnostic test for detecting infection in leprosy is fundamental for reducing patients' sequelae. The currently used lepromin is not adequate for disease diagnosis and, so far, no antigen to be used in intradermoreaction has proved to be sensitive and specific for that purpose. Aiming at identifying new reagents to be used in skin tests, candidate antigens were investigated. METHODS: Random peptide phage display libraries were screened by using antibodies from leprosy patients in order to identify peptides as diagnostic reagents. RESULTS: Seven different phage clones were identified using purified antibodies pooled from sera of leprosy patients. When the clones were tested with serum samples by ELISA, three of them, 5A, 6A and 1B, allowed detecting a larger number of leprosy patients when compared to controls. The corresponding peptides expressed by selected phage clones were chemically synthesized. A pilot study was undertaken to assess the use of peptides in skin tests. The intradermal challenge with peptides in animals previously sensitized with Mycobacterium leprae induced a delayed-type hypersensitivity with peptide 5A (2/5) and peptide 1B (1/5). In positive controls, there was a 3/5 reactivity for lepromin and a 4/5 reactivity of the sensitized animals with soluble extract of M. leprae. CONCLUSIONS: The preliminary data suggest that may be possible to develop reagents with diagnostic potential based on peptide mimotopes selected by phage display using polyclonal human antibodies. PMID- 23351152 TI - PRIMA-1 increases cisplatin sensitivity in chemoresistant ovarian cancer cells with p53 mutation: a requirement for Akt down-regulation. AB - BACKGROUND: Since ovarian cancer is associated with high frequency of p53 mutation, the availability of p53 reactivation and induction of massive apoptosis (PRIMA-1) offers a possible new therapeutic strategy for overcoming this devastating disease. Although Akt activation is believed to be a determinant in chemoresistance in ovarian cancer, whether Akt plays a role in regulating the effectiveness of PRIMA-1 in sensitizing chemoresistant ovarian cancer cells with p53 mutation to cisplatin (CDDP), remains to be determined. METHODS: In the present studies, we examined the influence of Akt down-regulation following dominant-negative (DN-Akt) expression on the ability of PRIMA-1 (0-10 MUM) to facilitate CDDP (0-10 MUM)-induced apoptosis in p53-mutated chemoresistant ovarian cancer cells (A2780cp). RESULTS: Apoptosis rate was significantly higher at the combined treatment of low PRIMA-1 concentrations (0.156 - 0.938 MUM) plus CDDP (10 MUM) in the DN-Akt groups than control (p<0.001). Apoptosis in cells treated with PRIMA-1 (0.156 MUM) and CDDP treatment (10 MUM) was significantly suppressed by p53-siRNA. PRIMA-1 increased phospho-p53 (Ser15) content in Akt down-regulated cells treated with CDDP. CONCLUSIONS: These results demonstrate that PRIMA-1 can sensitize chemoresistant ovarian cancer cells with p53 mutation to CDDP when Akt is down-regulated, and the action of PRIMA-1 is associated with p53 activation. Our findings raise the possibility that PRIMA-1 may be useful candidate for adjuvant therapy with CDDP in chemoresistant ovarian cancer with p53 mutation when Akt is down-regulated. PMID- 23351154 TI - Electrochemistry in an acoustically levitated drop. AB - Levitated drops show potential as microreactors, especially when radicals are present as reactants or products. Solid/liquid interfaces are absent or minimized, avoiding adsorption and interfacial reaction of conventional microfluidics. We report amperometric detection in an acoustically levitated drop with simultaneous ballistic addition of reactant. A gold microelectrode sensor was fabricated with a lithographic process; active electrode area was defined by a photosensitive polyimide mask. The microdisk gold working electrode of radius 19 MUm was characterized using ferrocenemethanol in aqueous buffer. Using cyclic voltammetry, the electrochemically active surface area was estimated by combining a recessed microdisk electrode model with the Randles-Sevcik equation. Computer controlled ballistic introduction of reactant droplets into the levitated drop was developed. Chronoamperometric measurements of ferrocyanide added ballistically demonstrate electrochemical monitoring using the microfabricated electrode in a levitated drop. Although concentration increases with time due to drop evaporation, the extent of concentration is predictable with a linear evaporation model. Comparison of diffusion-limited currents in pendant and levitated drops show that convection arising from acoustic levitation causes an enhancement of diffusion-limited current on the order of 16%. PMID- 23351153 TI - Perturbations of circulating levels of RANKL-osteoprotegerin axis in relation to lipids and progression of atherosclerosis in HIV-infected and -uninfected adults: ACTG NWCS 332/A5078 Study. AB - The receptor activator of the NF-kappaB ligand (RANKL)-osteoprotegerin (OPG) axis has been shown to play a role in the inflammatory process of atherogenesis and may be regulated by changes in levels of cholesterol. However, the interplay between HIV-1 infection, lipids, the RANKL-OPG axis, and atherosclerosis is poorly defined. Serum RANKL, OPG, and RANKL/OPG ratio were retrospectively assessed for 91 subjects from a 3-year study of carotid artery intima-media thickness (CIMT), which enrolled triads of risk factor-matched persons that were HIV-1 uninfected (n=36) or HIV-1(+) with (n=29) or without (n=26) continuous protease inhibitor (PI)-based therapy for >=2 years. Associations of serum RANKL, OPG, and RANKL/OPG ratio to the primary outcomes of levels of circulating lipids and atherosclerosis progression were determined using multivariate regression models. Serum RANKL and RANKL/OPG ratio were significantly lower in HIV-infected versus HIV-uninfected subjects (p<0.01). Multivariate models for HIV-1(+) subjects, but not in uninfected controls, demonstrated that perturbations in serum cholesterol levels were significantly associated (p<0.05) with perturbations in serum levels of RANKL and OPG, and their ratio (RANKL/OPG). There were no significant associations of serum RANKL, OPG, and RANKL/OPG with progression of atherosclerosis in HIV-1(+) subjects. Our results suggest that HIV 1 infection is associated with reductions in both serum RANKL and the RANKL/OPG ratio, and perturbations in the circulating levels of RANKL and OPG are significantly associated with increases in cholesterol levels, but not with progression of atherosclerosis. PMID- 23351155 TI - Post-hatch changes in the immunoexpression of desmin, smooth muscle actin and vimentin in the testicular capsule and interstitial tissue of the Japanese quail (Coturnix coturnix japonica). AB - The post-hatch development of immunoreactivity to desmin, smooth muscle actin (SMA) and vimentin in the testicular capsule and interstitial tissue of day-old to adult quails was described in this study. The tunica albuginea of the testicular capsule was composed mainly of myoid cells. A zonal arrangement of desmin and SMA immunostaining was observed in myoid cells of the tunica albuginea in 1- to 24-day-old quails. Immunostaining for SMA and desmin was uniform in the tunica albuginea of adult birds. Vimentin immunostaining in the testicular capsule was demonstrated in mesothelial cells, endothelial cells and fibroblasts. The interstitial tissue contained mesenchymal cells, peritubular myoid cells, Leydig cells and fibroblasts. Desmin-immunopositive mesenchymal cells were present in the interstitial tissue of 1- to 17-day-old quails. Peritubular myoid cells expressed strong desmin immunostaining in all developmental stages, while the intensity of SMA immunostaining increased with testicular maturation. Vimentin was demonstrated in Leydig cells and fibroblasts, while the peritubular myoid cells displayed strong vimentin immunostaining only in adult birds. Strong vimentin immunostaining was demonstrated in the endothelial cells of capsular and interstitial blood vessels. The tunica media of these blood vessels displayed desmin and SMA immunostaining. The results of the study have established that variability exists in the distribution and intensity of desmin, SMA and vimentin immunostaining in the testicular capsule and interstitial tissue of the post hatch Japanese quail. PMID- 23351156 TI - In vitro and in vivo activities of ticarcillin-loaded nanoliposomes with different surface charges against Pseudomonas aeruginosa (ATCC 29248). AB - BACKGROUND: Pseudomonas aeruginosa exhibits multiple antibiotic resistance mechanisms. Different studies have shown that entrapment of antibiotics into liposomes could increase their anti-Pseudomonas activity. The objectives of this study were to prepare ticarcillin loaded-nanoliposomes with variable surface charges and evaluate their in vitro and in vivo efficacies against Pseudomonas aeruginosa (ATCC 29248). METHODS: Ticarcillin-loaded nanoliposomes with positive, negative and neutral surface charges were prepared by extrusion method. Ticarcillin encapsulation efficacies for different formulations were measured by HPLC method. Minimum inhibitory concentration (MIC) of ticarcillin nanoliposomal forms against strain ATCC 29248 were determined by broth dilution method. The killing rate of Pseudomonas aeruginosa was exposed to various concentrations of ticarcillin in free and nanoliposomal forms were analyzed. Ultimately, in vivo therapeutic efficacy of nanoliposomes in burned mice skin infected with strain ATCC 29248 was investigated. RESULTS: The encapsulation efficacies for ticarcillin-loaded cationic nanoliposomes were significantly higher (76% +/- 0.17) than those of neutral (55% +/- 0.14) and anionic (43% +/- 0.14) nanoliposomes. The MIC of free, cationic, neutral and anionic nanoliposomal forms of ticarcillin against ATCC 29248 were to 24, 3, 6 and 48 mg/L, respectively. The killing rates of ticarcillin-loaded cationic nanoliposomes were higher than those of free and other drug formulations. Treatment by ticarcillin-loaded nanoliposomes with positive, neutral and negative surface charges resulted in almost 100, 60 and 20% survival rates, respectively. CONCLUSION: Our data suggested that cationic ticarcillin-loaded nanoliposomes because of high effectiveness would be a good choice to treatment of Pseudomonas aeruginosa infections. PMID- 23351157 TI - Interactions between autonomic cardiovascular regulation and cortical activity: a CNV study. AB - The study investigated interactions between autonomic cardiovascular regulation and cortical activity. In 54 healthy subjects, baroreflex sensitivity (BRS) and respiratory sinus arrhythmia (RSA) were assessed at resting conditions. As an EEG indicator of cortical excitability, the contingent negative variation (CNV) was induced using a constant foreperiod reaction time task. At bivariate level, only RSA showed a moderate positive correlation with the CNV recorded at frontal electrodes. However, when common variance of BRS and RSA was controlled for in multiple regression analysis, an inverse association between BRS and the frontal CNV also arose. The inverse association between BRS and the CNV is discussed as reflecting bottom-up modulation of cortical excitability by baroreceptor afferents. The positive correlation between RSA and the CNV may relate to the interplay between prefrontal processing and cardiac vagal tone. PMID- 23351159 TI - Somatic complaints and refrain from buying prescribed medications. Results from a cross-sectional study on people 60 years and older living in Kaunas (Lithuania). AB - BACKGROUND: The use of medicines by elderly people is a growing area of concern in social pharmacy. A significant proportion of older people do not follow the recommendations from physicians and refrain from buying prescribed medications. The aim of this study is to evaluate associations between self-rated health, somatic complaints and refraining from buying prescribed medications by elderly people. FINDINGS: Data was collected in a cross-sectional study in 2009. We received 624 completed questionnaires (response rate - 48.9%) from persons aged 60-84 years living in Kaunas (Lithuania). Somatic complaints were measured with the 24 item version of the Giessen Complaint List (GBB-24). Logistic regression (Enter model) was used for evaluation of the associations between refraining from buying medications and somatic complaints. These associations were measured using odds ratio (OR) and calculating the 95% confidence interval (CI).The mean scores in total for the GBB scale and sub-scales (exhaustion, gastrointestinal and cardiovascular) were lowest among respondents who did not refrain from buying prescribed medications (means for GBB-24 scale: 21.04 vs. 24.82; p=0.001). Logistic regression suggests that somatic complaints were associated with a increased risk of refraining from buying prescribed medications (OR=1.35, 95% CI=1.15-1.60). CONCLUSIONS: Somatic complaints were significantly associated with the decision to refrain from buying prescribed medications. PMID- 23351158 TI - Thymidine kinase 1 regulatory fine-tuning through tetramer formation. AB - Thymidine kinase 1 (TK1) provides a crucial precursor, deoxythymidine monophosphate, for nucleic acid synthesis, and the activity of TK1 increases by up to 200-fold during the S-phase of cell division in humans. An important part of the regulatory checkpoints is the ATP and enzyme concentration-dependent transition of TK1 from a dimer with low catalytic efficiency to a tetramer with high catalytic efficiency. This regulatory fine-tuning serves as an additional control to provide a balanced pool of nucleic acid precursors in the cell. We subcloned and over-expressed 10 different TK1s, originating from widely different organisms, and characterized their kinetic and oligomerization properties. Whilst bacteria, plants and Dictyostelium only exhibited dimeric TK1, we found that all animals had a tetrameric TK1. However, a clear ATP-dependent switch between dimer and tetramer was found only in higher vertebrates and was especially pronounced in mammalian and bird TK1s. We suggest that the dimer form is the original form and that the tetramer originated in the animal lineage after the split of Dictyostelium and the lineages leading to invertebrates and vertebrates. The efficient switching mechanism was probably first established in warm-blooded animals when they separated from the rest of the vertebrates. PMID- 23351160 TI - DNA barcoding reveals diversity of Hymenoptera and the dominance of parasitoids in a sub-arctic environment. AB - BACKGROUND: Insect diversity typically declines with increasing latitude, but previous studies have shown conflicting latitude-richness gradients for some hymenopteran parasitoids. However, historical estimates of insect diversity and species richness can be difficult to confirm or compare, because they may be based upon dissimilar methods. As a proxy for species identification, we used DNA barcoding to identify molecular operational taxonomic units (MOTUs) for 7870 Hymenoptera specimens collected near Churchill, Manitoba, from 2004 through 2010. RESULTS: We resolved 1630 MOTUs for this collection, of which 75% (1228) were ichneumonoids (Ichneumonidae + Braconidae) and 91% (1484) were parasitoids. We estimate the total number of Hymenoptera MOTUs in this region at 2624-2840. CONCLUSIONS: The diversity of parasitoids in this sub-Arctic environment implies a high diversity of potential host species throughout the same range. We discuss these results in the contexts of resolving interspecific interactions that may include cryptic species, and developing reproducible methods to estimate and compare species richness across sites and between surveys, especially when morphological specialists are not available to identify every specimen. PMID- 23351161 TI - Inactivation of internalized Salmonella Typhimurium in lettuce and green onion using ultraviolet C irradiation and chemical sanitizers. AB - AIMS: The internalized human pathogens in fresh produce are not effectively removed during conventional washing, and therefore, it may cause foodborne illness when the produce is consumed raw. Thus, effective nonthermal processes are needed to prevent this risk. METHODS AND RESULTS: Green fluorescence protein tagged Salmonella Typhimurium was either sprayed on the surface of iceberg lettuce or injected into the bottom part (bulb) of green onions to induce bacterial internalization. The contaminated vegetables were collected after 2 days and subjected to surface disinfection. Different fluencies of UV-C radiation (75-900 mJ cm(-2)) and two fluencies of UV-C (450, 900 mJ cm(-2)) combined with chlorine and peracetic acid (PAA) were applied to the produce to examine the inactivation efficiency of internalized bacteria. A range of 1.96-2.52 log reduction in the internalized Salmonella was achieved when the lettuce was treated with higher UV-C fluency (150, 450, 900 mJ cm(-2)) or UV-C combined with chemical disinfectants. Significant reduction (1.00-1.49 log CFU g(-1)) in internalized Salmonella was observed in green onion treated with UV-C with the fluency of 150 or 900 mJ cm(-2) or UV-C-chlorine/PAA. No significant reduction was observed in either lettuce or green onion treatments when chlorine or PAA was used alone. The food quality measured with firmness was not changed during any treatments. However, a slight colour change was observed in lettuce only when UV C was used at 900 mJ cm(-2). CONCLUSION: High fluency UV-C can significantly inactivate the internalized Salmonella in lettuce and green onion while maintaining the food quality. SIGNIFICANCE AND IMPACT OF THE STUDY: This research provides applicable research outcomes for developing nonthermal methods to inactivate internalized pathogens in fresh produce. PMID- 23351162 TI - Antioxidant as an anticancer: consideration. PMID- 23351164 TI - Bisphosphonate-related osteonecrosis of the jaw in four Nordic countries and an indication of under-reporting. AB - OBJECTIVE: To assess reported cases of bisphosphonate-related osteonecrosis of the jaw (BONJ) to Medicines Agencies (MAs) in four Nordic countries and to compare the Norwegian MA data with BONJ cases retrieved through an e-mail survey to Oral and Maxillofacial Surgeons (OMS) in Norway. MATERIAL AND METHODS: BONJ cases reported to the national MAs in each country from January 1st 2003 to September 30th 2010 were collected. An e-mail survey was sent to all active members of the Norwegian Association of Oral and Maxillofacial Surgeons (n = 54) included questions on total BONJ cases seen in practice and route of drug administration during January 1st 2003 to December 31st 2009. RESULTS: In total, 253 BONJ cases were reported to the MAs; 39 in Denmark, 44 in Finland, 51 in Norway and 119 in Sweden. These figures result in cumulative incidences (multiplied by 100,000) of 0.7, 0.8, 1.1 and 1.3, respectively. Intravenous administration was reported in 169 of the cases. The e-mail survey resulted in 35 responses reporting 214 BONJ cases, 4-times more cases than reported to the MA. CONCLUSIONS: Cumulative incidence of cases reported in this study differs to some degree in the four Nordic countries (Denmark < Finland < Norway < Sweden). In Norway, almost the same number of BONJ cases were reported through the questionnaire by OMS as in all four countries together (214 by OMSs vs 254 to MAs) and included a high number after per oral administration. The present results indicate a notable under-reporting in Norway and most likely in other Nordic countries. PMID- 23351165 TI - Effects of lithium on extraction socket healing in rats assessed with micro computed tomography. AB - OBJECTIVE: Lithium is an activator of beta-catenin signaling and beta-catenin plays an important role in regulating bone formation and remodeling. The purpose of this study was to investigate the effects of lithium on bone repair in tooth extraction sockets in rats. MATERIAL AND METHODS: Twenty male Wistar rats were subjected to maxillary left second molar extraction. The animals received a daily injection of lithium chloride (LiCl) or the same dose of sodium chloride (NaCl) starting 7 days before tooth extraction until sacrifice 14 days after extraction. Rats were randomly divided into: (1) a pre-treated group that received LiCl injection from 7 days before to 3 days after tooth extraction; (2) a post-treated group that received LiCl injection starting 4 days after tooth extraction; (3) a continuously treated group that received LiCl injection for the entire 21 days; and (4) a control group that received NaCl injection only. The volume of new bone and the bone density in the extraction socket were quantified by micro-computed tomography. RESULTS: The percentage of new bone formation in the extraction socket was as follows: 63.2 +/- 13.4% (pre-treated group), 53.9 +/- 9.8% (post treated), 23.8 +/- 8.0% (continuously treated) and 37.5 +/- 4.2% (control). The difference in percentage was statistically significant between each pair of groups. Pre- and post-treated groups also showed a significant increase in the density of new bone. CONCLUSIONS: Lithium enhances bone repair in extraction sockets when delivered before or after tooth extraction. Tooth extraction during lithium treatment may impair bone healing. PMID- 23351163 TI - Pharmacological fractionation of tetrodotoxin-sensitive sodium currents in rat dorsal root ganglion neurons by MU-conotoxins. AB - BACKGROUND AND PURPOSE: Adult rat dorsal root ganglion (DRG) neurons normally express transcripts for five isoforms of the alpha-subunit of voltage-gated sodium channels: NaV 1.1, 1.6, 1.7, 1.8 and 1.9. Tetrodotoxin (TTX) readily blocks all but NaV 1.8 and 1.9, and pharmacological agents that discriminate among the TTX-sensitive NaV 1-isoforms are scarce. Recently, we used the activity profile of a panel of MU-conotoxins in blocking cloned rodent NaV 1-isoforms expressed in Xenopus laevis oocytes to conclude that action potentials of A- and C-fibres in rat sciatic nerve were, respectively, mediated primarily by NaV 1.6 and NaV 1.7. EXPERIMENTAL APPROACH: We used three MU-conotoxins, MU-TIIIA, MU PIIIA and MU-SmIIIA, applied individually and in combinations, to pharmacologically differentiate the TTX-sensitive INa of voltage-clamped neurons acutely dissociated from adult rat DRG. We examined only small and large neurons whose respective INa were >50% and >80% TTX-sensitive. KEY RESULTS: In both small and large neurons, the ability of the toxins to block TTX-sensitive INa was MU TIIIA < MU-PIIIA < MU-SmIIIA, with the latter blocking ?90%. Comparison of the toxin-susceptibility profiles of the neuronal INa with recently acquired profiles of rat NaV 1-isoforms, co-expressed with various NaV beta-subunits in X. laevis oocytes, were consistent: NaV 1.1, 1.6 and 1.7 could account for all of the TTX sensitive INa , with NaV 1.1 < NaV 1.6 < NaV 1.7 for small neurons and NaV 1.7 < NaV 1.1 < NaV 1.6 for large neurons. CONCLUSIONS AND IMPLICATIONS: Combinations of MU-conotoxins can be used to determine the probable NaV 1-isoforms underlying the INa in DRG neurons. Preliminary experiments with sympathetic neurons suggest that this approach is extendable to other neurons. PMID- 23351166 TI - Patient safety incidents reported by Finnish dentists; results from an internet based survey. AB - BACKGROUND: Few data are available on dental patient safety (PS), as most PS studies have focused on other activities in health care. OBJECTIVE: To detect types and causes of dental PS incidents (PSIs), including adverse events (AEs) and near misses (NMs), in Finnish dental care. MATERIAL AND METHODS: Altogether 1041 privately or publicly employed dentists in southern Finland completed a structured questionnaire using an internet-based system (Webropol) in 2010. RESULTS: Nearly one third of the dentists reported some PSI in the previous 12 months. Of the 872 reported events, 53% were classified as AEs, 45% as NMs and 2% remained unclassified. Nearly half of the PSIs had occurred during some form of dental treatment. One third of the AEs were related to dental equipment, devices and supplies. Most of the reported AEs resulted in little or no permanent harm to patients. However, 13% of AEs were considered as serious enough to potentially cause severe harm or did in fact cause permanent harm. CONCLUSIONS: Reported dental PSIs in Finland are in many respects similar to those reported in other countries. Compared to all annual dental visits in Finland, severe dental AEs seem to be relatively rare. Less severe AEs and NMs are not uncommon, especially in dental surgery, endodontic and restorative treatment. The results of this retrospective study, however, reveal more about incident types than their true prevalence and that further studies on dental PS are needed. PMID- 23351167 TI - Genistein excitation of gonadotrophin-releasing hormone neurones in juvenile female mice. AB - We investigated the effects of the phytoestrogen genistein on gonadotrophin releasing hormone (GnRH) neurones using single-cell electrophysiology on GnRH green fluorescent protein (GFP) transgenic juvenile female mice. Perforated patch clamp recordings from GnRH-GFP neurones showed that approximately 83% of GnRH neurones responded to 30 MUm genistein with a markedly prolonged membrane depolarisation. This effect not only persisted in the presence of tetrodotoxin, but also in the presence of amino acid receptor antagonists, indicating the direct site of action on postsynaptic GnRH neurones. Using a voltage clamp technique, we found that 30 MUm genistein increased the frequency of synaptic current of GnRH neurones clamped at -60 mV in the presence of glutamate receptor blocker but not GABAA receptor blocker. Pre-incubation of GnRH neurones with 30 MUm genistein enhanced kisspeptin-induced membrane depolarisation and firing. GnRH neurones of juvenile mice injected with genistein in vivo showed an enhanced kisspeptin response compared to vehicle-injected controls. The transient receptor potential channel (TRPC) blocker 2-aminoethoxydiphenyl borate (75 MUm) blocked the genistein-mediated response on GnRH neurones. These results demonstrate that genistein acts on GnRH neurones in juvenile female mice to induce excitation via GABA neurotransmission and TRPCs to enhance kisspeptin-induced activation. PMID- 23351168 TI - Liposarcoma of the spermatic cord mimicking a left inguinal hernia: a case report and literature review. AB - Liposarcoma of the spermatic cord (LSC) is a rare condition characterized by a painless inguinal or scrotal mass. To our knowledge, only about 200 cases have been previously reported in the literature. These tumors are often mistaken for common scrotal swellings, such as hydroceles and hernias. We present a LSC case in which a definitive diagnosis was obtained upon histological examination. We also provide a literature review of other cases that have been reported. PMID- 23351169 TI - Biosynthesis and characterization of diblock copolymer of p(3-hydroxypropionate) block-p(4-hydroxybutyrate) from recombinant Escherichia coli. AB - Poly(4-hydroxybutyrate) (P4HB) is a highly elastic polymer, whereas poly(3 hydroxypropionate) (P3HP) is a polymer with enormous tensile strength. This study aimed to biosynthesize a block copolymer consisting of soft P4HB block with a strong P3HP block to gain unique and excellent material properties. A recombinant Escherichia coli strain that produces homopolymers of P3HP and P4HB was employed for the block copolymer synthesis. When the strain was grown in the presence of 1,4-butanediol (BDO) as a 4HB precursor, P4HB block was formed. Sequential supplementation of 1,3-propanediol (PDO) as a 3HP precursor allowed the strain to produce P3HP block. Thermal, NMR, fractionation, and mechanical characterizations confirmed the resulting polymer as a block copolymer of P3HP-b-P4HB. Two block copolymers were formed from this study, including the P3HP-b-29% P4HB and P3HP-b 37% P4HB, they showed superior properties over random copolymers P(3HP-co-4HB). The block copolymers had two glass transition temperatures (Tg) and two melting temperatures (Tm). In comparison to the homopolymers P3HP and P4HB, incorporation of block microstructure resulted in the lowering of Tm, block copolymers were revealed with higher Young's modulus, yield strengths, and tension strengths much better than the previously reported random copolymers of similar compositions. Block copolymerization of P3HP and P4HB adds a new vision on PHA polymerization by generation of new polymers with superior properties. PMID- 23351170 TI - Lewis acid-promoted ketene-alkene [2 + 2] cycloadditions. AB - Described are the first examples of ketene-alkene [2 + 2] cycloadditions promoted by Lewis acids. Notable features of this method include (1) substantial rate acceleration relative to traditional thermal reactions, (2) good diastereoselectivities and yields for the formation of the cyclobutanone products, and (3) inverse diastereoselectivity compared with related thermal cycloadditions for many examples. These studies not only provide access to synthetically versatile cyclobutanones that cannot be prepared by traditional thermal cycloadditions but also address important mechanistic questions regarding ketene-alkene [2 + 2] cycloaddition reactions. PMID- 23351171 TI - Development of a method for the measurement of primary cilia length in 3D. AB - BACKGROUND: Primary cilia length is an important measure of cell and tissue function. While accurate length measurements can be calculated from cells in 2D culture, measurements in tissue or 3D culture are inherently difficult due to optical distortions. This study uses a novel combination of image processing techniques to rectify optical distortions and accurately measure cilia length from 3D images. METHODS: Point spread functions and experimental resolutions were calculated from subresolution microspheres embedded in 3D agarose gels for both wide-field fluorescence and confocal laser scanning microscopes. The degree of axial smearing and spherical aberration was calculated from xy:xz diameter ratios of 3D image data sets of 4 MUm microspheres that had undergone deconvolution and/or Gaussian blurring. Custom-made 18 and 50 MUm fluorescent microfibers were also used as calibration objects to test the suitability of processed image sets for 3D skeletonization. Microfiber length in 2D was first measured to establish an original population mean. Fibers were then embedded in 3D agarose gels to act as ciliary models. 3D image sets of microfibers underwent deconvolution and Gaussian blurring. Length measurements within 1 standard deviation of the original 2D population mean were deemed accurate. Finally, the combined method of deconvolution, Gaussian blurring and skeletonization was compared to previously published methods using images of immunofluorescently labeled renal and chondrocyte primary cilia. RESULTS: Deconvolution significantly improved contrast and resolution but did not restore the xy:xz diameter ratio (0.80). Only the additional step of Gaussian blurring equalized xy and xz resolutions and yielded a diameter ratio of 1.02. Following image processing, skeletonization successfully estimated microfiber boundaries and allowed reliable and repeatable measurement of fiber lengths in 3D. We also found that the previously published method of calculating length from 2D maximum projection images significantly underestimated ciliary length. CONCLUSIONS: This study used commercial and public domain image processing software to rectify a long-standing problem of 3D microscopy. We have shown that a combination of deconvolution and Gaussian blurring rectifies optical distortions inherent in 3D images and allows accurate skeletonization and length measurement of microfibers and primary cilia that are bent or curved in 3D space. PMID- 23351172 TI - Autophagy and hypoxia in colonic adenomas related to aggressive features. AB - AIM: The study investigated whether autophagic activity and hypoxia parallel the adenoma-carcinoma sequence. METHOD: The study comprised 120 tubular adenomas with high-grade dysplasia, including 22 with questionable evidence of invasion, 37 with definite stromal invasion and 29 with severely dysplastic adenoma, 10 traditional serrated adenomas and 22 classical tubular adenomas lacking aggressive features. The samples were stained immunohistochemically for autophagy (LC3A and Beclin-1) and hypoxia-inducible factor1-alpha (HIF1alpha) markers. RESULTS: LC3A was detected as diffuse cytoplasmic staining and as dense "stone like" structures (SLS) within cytoplasmic vacuoles. Beclin-1 reactivity was purely cytoplasmic, whereas that of HIF1alpha was both cytoplasmic and nuclear. SLS counts in noninvasive, nontransformed areas of tubular adenomas were consistently low (median SLS = 0.5; 200* magnification), whereas a progressive increase was noted from areas of equivocal invasion (median SLS = 1.3; 200* magnification) and intramucosal carcinoma (median SLS = 1.4; 200* magnification) to unequivocal invasive foci (median SLS = 2.1; 200* magnification) (P < 0.0001). A similar association was shown for Beclin-1 and HIF1alpha expression (P < 0.05). Traditional serrated adenomas yielded low SLS counts and weak HIF1alpha reactivity, but high cytoplasmic LC3A and Beclin-1 expression (P < 0.01). CONCLUSION: A hypoxia-driven autophagy in adenomatous polyps, when particularly intense and localized, is commonly associated with early invasion or severely dysplastic adenoma. PMID- 23351173 TI - Centrosomes in the zebrafish (Danio rerio): a review including the related basal body. AB - Ever since Edouard Van Beneden and Theodor Boveri first formally described the centrosome in the late 1800s, it has captivated cell biologists. The name clearly indicated its central importance to cell functioning, even to these early investigators. We now know of its role as a major microtubule-organizing center (MTOC) and of its dynamic roles in cell division, vesicle trafficking and for its relative, the basal body, ciliogenesis. While centrosomes are found in most animal cells, notably it is absent in most oocytes and higher plant cells. Nevertheless, it appears that critical components of the centrosome act as MTOCs in these cells as well. The zebrafish has emerged as an exciting and promising new model organism, primarily due to the pioneering efforts of George Streisinger to use zebrafish in genetic studies and due to Christiane Nusslein-Volhard, Wolfgang Driever and their teams of collaborators, who applied forward genetics to elicit a large number of mutant lines. The transparency and rapid external development of the embryo allow for experiments not easily done in other vertebrates. The ease of producing transgenic lines, often with the use of fluorescent reporters, and gene knockdowns with antisense morpholinos further contributes to the appeal of the model as an experimental system. The added advantage of high-throughput screening of small-molecule libraries, as well as the ease of mass rearing together with low cost, makes the zebrafish a true frontrunner as a model vertebrate organism. The zebrafish has a body plan shared by all vertebrates, including humans. This conservation of body plan provides added significance to the existing lines of zebrafish as human disease models and adds an impetus to the ongoing efforts to develop new models. In this review, the current state of knowledge about the centrosome in the zebrafish model is explored. Also, studies on the related basal body in zebrafish and their relationship to ciliogenesis are reviewed. PMID- 23351174 TI - The frequency modulated auditory evoked response (FMAER), a technical advance for study of childhood language disorders: cortical source localization and selected case studies. AB - BACKGROUND: Language comprehension requires decoding of complex, rapidly changing speech streams. Detecting changes of frequency modulation (FM) within speech is hypothesized as essential for accurate phoneme detection, and thus, for spoken word comprehension. Despite past demonstration of FM auditory evoked response (FMAER) utility in language disorder investigations, it is seldom utilized clinically. This report's purpose is to facilitate clinical use by explaining analytic pitfalls, demonstrating sites of cortical origin, and illustrating potential utility. RESULTS: FMAERs collected from children with language disorders, including Developmental Dysphasia, Landau-Kleffner syndrome (LKS), and autism spectrum disorder (ASD) and also normal controls - utilizing multi-channel reference-free recordings assisted by discrete source analysis - provided demonstratrions of cortical origin and examples of clinical utility. Recordings from inpatient epileptics with indwelling cortical electrodes provided direct assessment of FMAER origin. The FMAER is shown to normally arise from bilateral posterior superior temporal gyri and immediate temporal lobe surround. Childhood language disorders associated with prominent receptive deficits demonstrate absent left or bilateral FMAER temporal lobe responses. When receptive language is spared, the FMAER may remain present bilaterally. Analyses based upon mastoid or ear reference electrodes are shown to result in erroneous conclusions. Serial FMAER studies may dynamically track status of underlying language processing in LKS. FMAERs in ASD with language impairment may be normal or abnormal. Cortical FMAERs can locate language cortex when conventional cortical stimulation does not. CONCLUSION: The FMAER measures the processing by the superior temporal gyri and adjacent cortex of rapid frequency modulation within an auditory stream. Clinical disorders associated with receptive deficits are shown to demonstrate absent left or bilateral responses. Serial FMAERs may be useful for tracking language change in LKS. Cortical FMAERs may augment invasive cortical language testing in epilepsy surgical patients. The FMAER may be normal in ASD and other language disorders when pathology spares the superior temporal gyrus and surround but presumably involves other brain regions. Ear/mastoid reference electrodes should be avoided and multichannel, reference free recordings utilized. Source analysis may assist in better understanding of complex FMAER findings. PMID- 23351175 TI - Evaluation of parenteral nutritional support in the surgical and medical wards of a referral teaching hospital. AB - BACKGROUND AND PURPOSE: Malnutrition is a common problem in patients who are hospitalized in surgical and medical wards. Surgical patients, geriatric populations and individuals with severe illness are more vulnerable to malnutrition during their hospitalization course.The purpose of this study was evaluation of parenteral nutrition services in a referral teaching hospital, Tehran, Iran. METHOD: Medical records of 72 patients who received parenteral nutrition during one year period in different surgical and medical wards of Imam Khomeini hospital were reviewed retrospectively by clinical pharmacists. Criteria for initiation of parenteral nutrition, selection of appropriate formulation and monitoring parameters were assessed based on the American Society of Parenteral and Enteral Nutrition recommendations. RESULTS: Based on the patients' anthropometric parameters and serum albumin levels, 4.2%, 75% and 20.8% of the patients were well-nourished, moderately malnourished and severely malnourished respectively at the hospital admission and before nutritional support. Adequate calorie, protein, carbohydrate and lipid supports were achieved in 21.1%, 32.4%, 23.7% and 10.5% of the patients respectively. About 91% of the patients experienced at least one complication of the nutritional support. CONCLUSION: In this evaluation, several errors in assessment, establishing goals, and monitoring of parenteral nutrition regimens have been detected. Approximately all of the patients did not receive to the trace elements supports goals. PMID- 23351176 TI - Formulation and evaluation of microsphere based oro dispersible tablets of itopride hcl. AB - BACKGROUND: The purpose of the present work is to mask the intensely bitter taste of Itopride HCl and to formulate an Oro dispersible tablet (ODT) of the taste-masked drug by incorporation of microspheres in the tablets for use in specific populations viz. pediatrics, geriatrics and patients experiencing difficulty in swallowing. METHODS: With this objective in mind, microspheres loaded with Itopride HCl were prepared by solvent evaporation method using acetone as solvent for pH-sensitive polymer, Eudragit EPO and light liquid paraffin as the encapsulating medium. The prepared microspheres were characterized with regard to yield, drug content, flow properties, particle size and size distribution, surface features, in vitro drug release and taste. The ODTs so prepared from these microspheres were evaluated for hardness, thickness, weight variation, friability, disintegration time, drug content, wetting time, water absorption ratio, moisture uptake, in vitro dispersion, in vitro disintegration, in vitro drug release and stability. RESULTS: The average size of microspheres was found to be satisfactory in terms of the size and size distribution. Microspheres prepared were of a regular spherical shape. Comparison of the dissolution profiles of microspheres in different pH media showed that microspheres having drug: polymer ratio of 1:2 produced a retarding effect in simulated salivary fluid (pH 6.8) and were further used for formulation into ODTs after addition of suitable amounts of excipients such as superdisintegrant, diluent, sweetener and flavor of directly compressible grade. CONCLUSIONS: Effective taste-masking was achieved for Itopride HCl by way of preparation of microspheres and ODTs of acceptable characteristics. PMID- 23351177 TI - Identification and characterisation of vaginal lactobacilli from South African women. AB - BACKGROUND: Bacterial vaginosis (BV), which is highly prevalent in the African population, is one of the most common vaginal syndromes affecting women in their reproductive age placing them at increased risk for sexually transmitted diseases including infection by human immunodeficiency virus-1. The vaginal microbiota of a healthy woman is often dominated by the species belonging to the genus Lactobacillus namely L. crispatus, L. gasseri, L. jensenii and L. iners, which have been extensively studied in European populations, albeit less so in South African women. In this study, we have therefore identified the vaginal Lactobacillus species in a group of 40 African women from Soweto, a township on the outskirts of Johannesburg, South Africa. METHODS: Identification was done by cultivating the lactobacilli on Rogosa agar, de Man-Rogosa-Sharpe (MRS) and Blood agar plates with 5% horse blood followed by sequencing of the 16S ribosomal DNA. BV was diagnosed on the basis of Nugent scores. Since some of the previous studies have shown that the lack of vaginal hydrogen peroxide (H2O2) producing lactobacilli is associated with bacterial vaginosis, the Lactobacillus isolates were also characterised for their production of H2O2. RESULTS: Cultivable Lactobacillus species were identified in 19 out of 21 women without BV, in three out of five women with intermediate microbiota and in eight out of 14 women with BV. We observed that L. crispatus, L. iners, L. jensenii, L. gasseri and L. vaginalis were the predominant species. The presence of L. crispatus was associated with normal vaginal microbiota (P = 0.024). High level of H2O2 producing lactobacilli were more often isolated from women with normal microbiota than from the women with BV, although not to a statistically significant degree (P = 0.064). CONCLUSION: The vaginal Lactobacillus species isolated from the cohort of South African women are similar to those identified in European populations. In accordance with the other published studies, L. crispatus is related to a normal vaginal microbiota. Hydrogen peroxide production was not significantly associated to the BV status which could be attributed to the limited number of samples or to other antimicrobial factors that might be involved. PMID- 23351178 TI - The study protocol for the LINC (LUCAS in cardiac arrest) study: a study comparing conventional adult out-of-hospital cardiopulmonary resuscitation with a concept with mechanical chest compressions and simultaneous defibrillation. AB - BACKGROUND: The LUCASTM device delivers mechanical chest compressions that have been shown in experimental studies to improve perfusion pressures to the brain and heart as well as augmenting cerebral blood flow and end tidal CO2, compared with results from standard manual cardiopulmonary resuscitation (CPR). Two randomised pilot studies in out-of-hospital cardiac arrest patients have not shown improved outcome when compared with manual CPR. There remains evidence from small case series that the device can be potentially beneficial compared with manual chest compressions in specific situations. This multicentre study is designed to evaluate the efficacy and safety of mechanical chest compressions with the LUCASTM device whilst allowing defibrillation during on-going CPR, and comparing the results with those of conventional resuscitation. METHODS/DESIGN: This article describes the design and protocol of the LINC-study which is a randomised controlled multicentre study of 2500 out-of-hospital cardiac arrest patients. The study has been registered at ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00609778?term=LINC&rank=1). RESULTS: Primary endpoint is four-hour survival after successful restoration of spontaneous circulation. The safety aspect is being evaluated by post mortem examinations in 300 patients that may reflect injuries from CPR. CONCLUSION: This large multicentre study will contribute to the evaluation of mechanical chest compression in CPR and specifically to the efficacy and safety of the LUCASTM device when used in association with defibrillation during on-going CPR. PMID- 23351180 TI - Why a successful task substitution in glaucoma care could not be transferred from a hospital setting to a primary care setting: a qualitative study. AB - BACKGROUND: Healthcare systems are challenged by a demand that exceeds available resources. One policy to meet this challenge is task substitution-transferring tasks to other professions and settings. Our study aimed to explore stakeholders' perceived feasibility of transferring hospital-based monitoring of stable glaucoma patients to primary care optometrists. METHODS: A case study was undertaken in the Rotterdam Eye Hospital (REH) using semi-structured interviews and document reviews. They were inductively analysed using three implementation related theoretical perspectives: sociological theories on professionalism, management theories, and applied political analysis. RESULTS: Currently it is not feasible to use primary care optometrists as substitutes for optometrists and ophthalmic technicians working in a hospital-based glaucoma follow-up unit (GFU). Respondents' narratives revealed that: the glaucoma specialists' sense of urgency for task substitution outside the hospital diminished after establishing a GFU that satisfied their professionalization needs; the return on investments were unclear; and reluctant key stakeholders with strong power positions blocked implementation. The window of opportunity that existed for task substitution in person and setting in 1999 closed with the institutionalization of the GFU. CONCLUSIONS: Transferring the monitoring of stable glaucoma patients to primary care optometrists in Rotterdam did not seem feasible. The main reasons were the lack of agreement on professional boundaries and work domains, the institutionalization of the GFU in the REH, and the absence of an appropriate reimbursement system. Policy makers considering substituting tasks to other professionals should carefully think about the implementation process, especially in a two-step implementation process (substitution in person and in setting) such as this case. Involving the substituting professionals early on to ensure all stakeholders see the change as a normal step in the professionalization of the substituting professionals is essential, as is implementing the task substitution within the window of opportunity. PMID- 23351181 TI - Antifungal activity of volatile organic compounds from Streptomyces alboflavus TD 1. AB - Streptomyces sp. TD-1 was identified as Streptomyces alboflavus based on its morphological characteristics, physiological properties, and 16S rDNA gene sequence analysis. The antifungal activity of the volatile-producing S. alboflavus TD-1 was investigated. Results showed that volatiles generated by S. alboflavus TD-1 inhibited storage fungi Fusarium moniliforme Sheldon, Aspergillus flavus, Aspergillus ochraceus, Aspergillus niger, and Penicillum citrinum in vitro. GC/MS analysis revealed that 27 kinds of volatile organic compounds were identified from the volatiles of S. alboflavus TD-1 mycelia, among which the most abundant compound was 2-methylisoborneol. Dimethyl disulfide was proved to have antifungal activity against F. moniliforme by fumigation in vitro. PMID- 23351182 TI - Neuroprotective properties of Melissa officinalis after hypoxic-ischemic injury both in vitro and in vivo. AB - BACKGROUND: Brain ischemia initiates several metabolic events leading to neuronal death. These events mediate large amount of damage that arises after some neurodegenerative disorders as well as transient brain ischemia. Melissa officinalis is considered as a helpful herbal plant in the prevention of various neurological diseases like Alzheimer that is related with oxidative stress. METHODS: We examined the effect of Melissa officinalis on hypoxia induced neuronal death in a cortical neuronal culture system as in vitro model and transient hippocampal ischemia as in vivo model. Transient hippocampal ischemia was induced in male rats by tow vessel-occlusion for 20 min. After reperfusion, the histopathological changes and the levels inflammation, oxidative stress status, and caspase-3 activity in hippocampus were measured. RESULTS: Cytotoxicity assays showed a significant protection of a 10 MUg/ml dose of Melissa against hypoxia in cultured neurons which was confirmed by a conventional staining (P<0.05). Melissa treatment decrease caspase3 activity (P<0.05) and TUNEL-positive cells significantly (P<0.01). Melissa oil has also inhibited malon dialdehyde level and attenuated decrease of Antioxidant Capacity in the hippocampus. Pro-inflammatory cytokines TNF-alpha, IL-1beta and HIF-1alpha mRNA levels were highly increased after ischemia and treatment with Melissa significantly suppressed HIF-1alpha gene expression (P<0.05). DISCUSSION: Results showed that Melissa officinalis could be considered as a protective agent in various neurological diseases associated with ischemic brain injury. PMID- 23351183 TI - Pleurodesis by erythromycin, tetracycline, AerosilTM 200, and erythromycin plus AerosilTM 200 in a rat model: a preliminary study. AB - BACKGROUND: None of the current pleurodesing agents fulfil all the criteria for best pleural sclerosant. Therefore, the search for the ideal agent for chemical pleurodesis still continues. The aim of the present study was to compare the effectiveness of erythromycin, tetracycline, AerosilTM 200 (hydrophilic fumed amorphous silica), and erythromycin plus AerosilTM 200 in producing pleurodesis in rats. In the present study, talc was not used as a pleurodesing agent due to an unavailability of its sterile and pure form in Iran. METHODS: Overall, 75 adult male Spraque-Dawley rats were randomized to 5 treatment groups. Each group received an intrapleural injection via 5 Fr Silastic tubes of one of the following sterile agents: 35mg/kg erythromycin in 2 ml of saline, 35mg/kg tetracycline in 2 ml of saline, 35mg/kg AerosilTM 200 in 2ml of saline, erythromycin (35mg/kg in 2 ml of saline) plus AerosilTM 200 (35mg/kg in 2 ml of saline), or 2 ml of saline as a control. The animals were euthanized and necropsied 30 days after injection. The pleurae were assessed for macroscopic and microscopic evidence of surrounding inflammation and fibrosis. RESULTS: The median macroscopic score in the AerosilTM 200 group was significantly higher than that in the erythromycin group (P < 0.005). The median microscopic score in the erythromycin group was significantly lower than that in the AerosilTM 200 and erythromycin plus AerosilTM 200 groups (P < 0.005). Furthermore, maximum and minimum pleural fibrosis was observed in the erythromycin plus AerosilTM 200 and erythromycin groups, respectively (P < 0.05). CONCLUSION: This study suggests that AerosilTM 200 with or without erythromycin may be more potent pleurodesis agent than erythromycin and tetracycline. PMID- 23351184 TI - Mentha longifolia syrup in secondary amenorrhea: a double-blind, placebo controlled, randomized trials. AB - BACKGROUND: Amenorrhea is defined as the cessation of menses. Hormone therapy is the most common treatment. Due to the contraindications and side effects of it and the increasing demand for alternative medicine substitutes, Mentha longifolia L. was used in this study. Mentha longifolia L. is a known medication in Iranian traditional medicine to induce menstrual bleeding in women with secondary amenorrhea and oligomenorrhea. METHODS: A double-blind, randomized, placebo controlled, multicenter study was conducted in 120 women with secondary amenorrhea and oligomenorrhea. Treatment consisted of sequential oral syrup, 45 ml (15 ml three times a day) for 2 weeks. If the patients did not have menstruation after 2 weeks of taking the medication, we would wait for two more weeks. If the patients had menstruation at each stage of using the drug, we started it one week after the end of menstruation. But if the patients had not menstruate after four weeks (two-week using of drug and waiting for two more weeks), the previous steps were repeated. The drug and placebo were repeated in three cycles of menstruation. Bleeding was documented by the patient on diary cards. The primary outcome variable was the occurrence (yes/no) of bleeding during the first treatment cycle. The secondary efficacy outcome was the regularity of bleeding pattern during the three cycles of the study. RESULTS: The number of women with bleeding during the first cycle were higher in the drug group as in the placebo group (68.3% vs. 13.6%; p < 0.001). The regularity of bleeding throughout the study was markedly better in the drug group compared with those given placebo (33.3% vs. 3.3%; p < 0.001). No notable complication or side effect was reported in relation to Mentha longifolia L. syrup. CONCLUSION: In conclusion, Mentha longifolia L. syrup is a safe, well-tolerated, and effective choice in inducing bleeding and maintaining regular bleeding in women with secondary amenorrhea and oligomenorrhea. PMID- 23351185 TI - Predictive factors of adrenal insufficiency in patients admitted to acute medical wards: a case control study. AB - BACKGROUND: Adrenal insufficiency is a rare and potentially lethal disease if untreated. Several clinical signs and biological markers are associated with glucocorticoid failure but the importance of these factors for diagnosing adrenal insufficiency is not known. In this study, we aimed to assess the prevalence of and the factors associated with adrenal insufficiency among patients admitted to an acute internal medicine ward. METHODS: Retrospective, case-control study including all patients with high-dose (250 MUg) ACTH-stimulation tests for suspected adrenal insufficiency performed between 2008 and 2010 in an acute internal medicine ward (n = 281). Cortisol values <550 nmol/l upon ACTH stimulation test were considered diagnostic for adrenal insufficiency. Area under the ROC curve (AROC), sensitivity, specificity, negative and positive predictive values for adrenal insufficiency were assessed for thirteen symptoms, signs and biological variables. RESULTS: 32 patients (11.4%) presented adrenal insufficiency; the others served as controls. Among all clinical and biological parameters studied, history of glucocorticoid withdrawal was the only independent factor significantly associated with patients with adrenal insufficiency (Odds Ratio: 6.71, 95% CI: 3.08 -14.62). Using a logistic regression, a model with four significant and independent variable was obtained, regrouping history of glucocorticoid withdrawal (OR 7.38, 95% CI [3.18 ; 17.11], p-value <0.001), nausea (OR 3.37, 95% CI [1.03 ; 11.00], p-value 0.044), eosinophilia (OR 17.6, 95% CI [1.02; 302.3], p-value 0.048) and hyperkalemia (OR 2.41, 95% CI [0.87; 6.69], p-value 0.092). The AROC (95% CI) was 0.75 (0.70; 0.80) for this model, with 6.3 (0.8 - 20.8) for sensitivity and 99.2 (97.1 - 99.9) for specificity. CONCLUSIONS: 11.4% of patients with suspected adrenal insufficient admitted to acute medical ward actually do present with adrenal insufficiency, defined by an abnormal response to high-dose (250 MUg) ACTH-stimulation test. A history of glucocorticoid withdrawal was the strongest factor predicting the potential adrenal failure. The combination of a history of glucocorticoid withdrawal, nausea, eosinophilia and hyperkaliemia might be of interest to suspect adrenal insufficiency. PMID- 23351186 TI - Caries experience after periodontal treatment in aggressive and chronic periodontitis: results of a 10-year follow-up. AB - OBJECTIVE: To compare the increase of DMF-T and DMF-S in patients with aggressive periodontitis (AgP) and chronic periodontitis (ChP) after active periodontal therapy. MATERIALS AND METHODS: One hundred and thirty-six periodontally treated patients were re-examined after 10 years. Dental and periodontal status was assessed and patients' charts were screened for diagnosis, compliance to supportive periodontal treatment (SPT) and DMF-T/-S at baseline and re examination. deltaDMF-T/-S was calculated and multi-level regression analyses were performed to identify factors contributing to increase of DMF-T/-S. RESULTS: Thirty patients with AgP, 37 with moderate ChP and 69 with severe ChP could be included. deltaDMF-T between first visit and re-examination was 2.07 (SD = 2.51, range = 0-14 teeth), mean deltaDMF-S = 14.66 (SD = 14.54, range = 0-83 surfaces). Patients with AgP showed a similar increase in DMF-T/-S to those with ChP. Regression analysis identified compliance as the only factor significantly accounting for preventing an increase of DMF-S (p = 0.017). No factor had a significant impact on DMF-T. CONCLUSIONS: DMF-T and DMF-S developed similarly in periodontally-treated patients with AgP and ChP during a follow-up of 10 years. SPT showed a positive influence on avoiding decline in DMF-S in periodontally compromised patients. No significant impact was detected for all other studied factors. PMID- 23351189 TI - Is it right to look for anti-cancer drugs amongst compounds having antioxidant effect? PMID- 23351187 TI - Safety, tolerability, and efficacy of raltegravir in a diverse cohort of HIV infected patients: 48-week results from the REALMRK Study. AB - The racial diversity and gender distribution of HIV-infected patients make it essential to confirm the safety and efficacy of raltegravir in these populations. A multicenter, open-label, single-arm observational study was conducted in a diverse cohort of HIV-infected patients (goals: >=25% women; >=50% blacks in the United States), enrolling treatment-experienced patients failing or intolerant to current antiretroviral therapy (ART) and treatment-naive patients (limited to <=20%). All patients received raltegravir 400 mg b.i.d. in a combination antiretroviral regimen for up to 48 weeks. A total of 206 patients received study treatment at 34 sites in the United States, Brazil, Dominican Republic, Jamaica, and South Africa: 97 (47%) were female and 153 (74%) were black [116 (56%) in the United States]. Of these, 185 patients were treatment experienced: 97 (47%) were failing and 88 (43%) were intolerant to current therapy; 21 patients (10%) were treatment naive. Among treatment-intolerant patients, 55 (63%) had HIV-1 RNA<50 copies/ml at baseline. Overall, 15% of patients discontinued: 13% of men, 18% of women, 14% of blacks, and 17% of nonblacks. At week 48, HIV RNA was <50 copies/ml in 60/94 (64%) patients failing prior therapy, 61/80 (76%) patients intolerant to prior therapy, and 16/21 (76%) treatment-naive patients. Response rates were similar for men vs. women and black vs. nonblack patients. Drug-related clinical adverse events were reported by 8% of men, 18% of women, 14% of blacks, and 9% of nonblacks. After 48 weeks of treatment in a diverse cohort of HIV-infected patients, raltegravir was generally safe and well tolerated with potent efficacy regardless of gender or race. PMID- 23351188 TI - Ganglioside-monosialic acid (GM1) prevents oxaliplatin-induced peripheral neurotoxicity in patients with gastrointestinal tumors. AB - BACKGROUND: Oxaliplatin, an effective antineoplastic agent againstgastrointestinal tumors, can cause severe peripheral neurotoxicity, which seriously limits its clinical application. To date, there are no effective treatments for this complication. Ganglioside-monosialic acid (GM1) has been shown to protect neurons against injuries and degeneration. The aim of this study was to evaluate the effects of GM1 on preventing oxaliplatin-induced neurotoxicity in patients with gastrointestinal tumors. METHODS: In this study, 120 patients with gastrointestinal tumors were enrolled, andthey received the treatment of XELOX (oxaliplatin and capecitabine) and FOLFOX4 (oxaliplatin, leukovolin and 5-fluorouracil). The patients were randomly divided into two groups, the experimental group and control group, with60 patients ineach. On the day chemotherapy was initiated, the experimental group received GM1 intravenously (100 mg once daily) for 3 days, while no neuroprotective agents were applied in the control group. The incidence rates and classification of neurotoxicity in the two groups were evaluated and the differences between the two groups were examined. Furthermore, whether GM1 affected the therapeutic effects of chemotherapy was also examined. RESULTS: The grade of neurotoxicity in the experimental group was significantly lower than in the control group (P<0.05, Mann-Whitney U test). The probability of occurrence of low-grade neurotoxicity (grade 0 and 1) in the experimental group was higher than that in the control group (logistic ordinal regression); whereas the probability of occurrence of high-grade neurotoxicity (grade 2 and 3) in the experimental group was lower than in the control group (logistic ordinal regression). CONCLUSION: The data suggested that GM1 could reduce the grade of oxaliplatin-induced neurotoxicity and was an effective neuroprotective agent against oxaliplatin-induced high-grade neurotoxicity in patients with gastrointestinal tumors. PMID- 23351190 TI - The effect of halothane and pentobarbital sodium on brain ependymal cilia. AB - BACKGROUND: The effect of anesthetic agents on ependymal ciliary function is unknown. The aim of this study was to determine the effect of halothane and pentobarbital sodium on brain ependymal ciliary function. METHODS: We used an ex vivo rat brain slice model to measure ependymal ciliary beat frequency by high speed video photography at 37 degrees C. RESULTS: Exposure to halothane caused a significant reduction in ciliary beat frequency of 2 % (P = 0.006), 15.5 % (P < 0.001), and 21.5 % (P < 0.001) for halothane concentrations of 1.8 %, 3.4 % and 4.4 %, respectively, compared to controls. Following a one-hour wash-out period, there was no significant difference between control samples and cilia that had been exposed to 1.8 % (P = 0.5) and 3.4 % (P = 0.3) halothane. The beat frequency of cilia exposed to 4.4 % halothane had increased following the wash-out period but cilia were still beating significantly more slowly than cilia from the control group (P = <0.001).Pentobarbitone at concentrations of 25 and 50 MUg/ml had no effect on ciliary beat frequency compared to controls (P = 0.6 and 0.4 respectively). A significant (P = 0.002) decrease in ciliary beat frequency was seen following incubation with a pentobarbitone concentration of 250 MUg/ml (mean (SD) frequency, 24(8) Hz compared to controls, 38(9) Hz). CONCLUSIONS: Halothane reversibly inhibits the rate at which ependymal cilia beat. Pentobarbitone has no effect on ciliary activity at levels used for anesthesia. It is unclear whether the slowing of ependymal ciliary by halothane is responsible for some of the secondary central nervous system effects of volatile anesthetic agents. PMID- 23351192 TI - Measurement of empathy levels in undergraduate paramedic students. AB - INTRODUCTION: Paramedics rely on establishing a health provider-patient relationship with patients that promotes two-way communication, patient satisfaction, and facilitates appropriate patient assessment and treatment. Paramedics also must have an ability to empathize with patients and their family members in order to develop a successful health provider-patient relationship. The objective of this study was to assess paramedics' empathy and attitudes toward patients with specific conditions. METHODS: This was a cross-sectional study using a convenience sample of first-, second-, and third-year, Australian undergraduate paramedic students. Student empathy levels were assessed using two standardized self-reporting instruments: the Jefferson Scale of Physician Empathy (JSPE) Health Professional (HP) version and the Medical Condition Regard Scale (MCRS). RESULTS: A total of 94 paramedic students participated in the study. The JSPE demonstrated that male paramedic students had higher mean empathy scores than did female paramedic students (113.25 and 107.5, respectively; P = .042). The JSPE empathy level scores were lowest among first-year paramedic students (mean = 107.53); age was not found to be a significant variable on empathy scores. The Medical Condition Regard Scale revealed lowest scores in compassion towards substance abuse (mean = 46.42). CONCLUSIONS: The results of this study provide the discipline of paramedic health care with useful data, and provide students, academics, and other educators with important information regarding the improvement of the health provider-patient relationship and paramedic education curriculum development. PMID- 23351191 TI - The association between interpregnancy interval and birth weight: what is the role of maternal polyunsaturated fatty acid status? AB - BACKGROUND: The objective of this study was to evaluate the mediating role of maternal early pregnancy plasma levels of long chain polyunsaturated fatty acids (LCPUFAs) in the association of interpregnancy interval (IPI) with birth weight and smallness for gestational age (SGA) at birth. METHODS: We analysed a subsample of the Amsterdam Born Children and their Development (ABCD) cohort, comprising 1,659 parous pregnant women recruited between January 2003 and March 2004. We used linear and logistic regression to evaluate the associations between fatty acid status, interpregnancy interval and pregnancy outcome. RESULTS: Low plasma phospholipids concentrations of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and dihomo-gamma-linolenic acid (DGLA), and high concentrations of arachidonic acid (AA) during early pregnancy were associated with reduced birth weight and/or an increased risk of SGA. Short IPIs (< 6 months, with 18-23 months as a reference) were associated with a mean decrease of 207.6 g (SE: +/- 73.1) in birth weight (p = 0.005) and a twofold increased risk of SGA (OR: 2.05; CI: 0.93-4.51; p = 0.074). Adjustment for maternal fatty acid concentrations did not affect these results to any meaningful extent. CONCLUSIONS: Despite the observed association of maternal early pregnancy LCPUFA status with birth weight and SGA, our study provides no evidence for the existence of an important role of maternal EPA, DHA, DGLA or AA in the association of short interpregnancy intervals with birth weight and SGA. PMID- 23351193 TI - An update on toxicology of aluminum phosphide. AB - Aluminum phosphide (AlP) is a cheap solid fumigant and a highly toxic pesticide which is commonly used for grain preservation. In Iran it is known as the "rice tablet". AlP has currently aroused interest with increasing number of cases in the past four decades due to increased use in agricultural and non-agricultural purposesand also its easy availability in the markets has increased its misuse to commit suicide. Upon contact with moisture in the environment, AlP undergoes a chemical reaction yielding phosphine gas, which is the active pesticidal component. Phosphine inhibits cellular oxygen utilization and can induce lipid peroxidation. It was reported that AlP has a mortality rate more than 50% of intoxication cases. Poisoning with AlP has usually occurred in attempts to suicide. It is a more common case in adults rather than teen agers. In some eastern countries it is a very common agent with rapid action for suicide. Up to date, there is no effective antidote or treatment for its intoxication. Also, some experimental results suggest that magnesium sulfate, N-acetyl cysteine (NAC), glutathione, vitamin C and E, beta-carotenes, coconut oil and melatonin may play an important role in reducing the oxidative outcomes of phosphine. This article reviews the experimental and clinical features of AlP intoxication and tries to suggest a way to encounter its poisoning. PMID- 23351194 TI - EWI-2wint promotes CD81 clustering that abrogates Hepatitis C Virus entry. AB - CD81 is a major receptor for Hepatitis C Virus (HCV). It belongs to the tetraspanin family whose members form dynamic clusters with numerous partner proteins and with one another, forming tetraspanin-enriched areas in the plasma membrane. In our study, we combined single-molecule microscopy and biochemistry experiments to investigate the clustering and membrane behaviour of CD81 in the context of cells expressing EWI-2wint, a natural inhibitor of HCV entry. Interestingly, we found that EWI-2wint reduces the global diffusion of CD81 molecules due to a decrease of the diffusion rate of mobile CD81 molecules and an increase in the proportion of confined molecules. Indeed, we demonstrated that EWI-2wint promotes CD81 clustering and confinement in CD81-enriched areas. In addition, we showed that EWI-2wint influences the colocalization of CD81 with Claudin-1 - a co-receptor required for HCV entry. Together, our results indicate that a change in membrane partitioning of CD81 occurs in the presence of EWI 2wint. This study gives new insights on the mechanism by which HCV enters into its target cells, namely by exploiting the dynamic properties of CD81. PMID- 23351195 TI - A comprehensive investigation of variants in genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1/R2), and their association with serum adiponectin, type 2 diabetes, insulin resistance and the metabolic syndrome. AB - BACKGROUND: Low levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ, the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors (ADIPOR1 and ADIPOR2) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals. METHODS: Sixty four tagging single nucleotide polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling. RESULTS: Meta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained <5% of the variance in serum adiponectin concentration. None of the ADIPOR1/R2 tagSNPs were associated with serum adiponectin. There was no association between any of the genetic variants and insulin resistance or metabolic syndrome. A multi-SNP genotypic risk score for ADIPOQ alleles revealed an association with 3 independent SNPs, rs12637534, rs16861209, rs17366568 and type 2 diabetes after adjusting for adiponectin levels (OR=0.86, 95% CI=(0.75, 0.99), P=0.0134). CONCLUSIONS: Genetic variation in ADIPOQ, but not its receptors, was associated with altered serum adiponectin. However, genetic variation in ADIPOQ and its receptors does not appear to contribute to the risk of insulin resistance or metabolic syndrome but did for type 2 diabetes in a European-Australian population. PMID- 23351197 TI - Chronic lead poisoning in Iran; a silent disease. PMID- 23351196 TI - Comparison of trunk and spine deformity in adolescent idiopathic scoliosis. AB - BACKGROUND: Cobb measurement of standing radiographs is the standard for clinical assessment of coronal spinal deformity. Angle of trunk inclination (ATI) is an accepted clinical measurement of trunk asymmetry, and has variable reported correlations with Cobb angles. Transverse plane spine deformity is most accurately measured using axial computed tomography. Aaro and Dahlbourn's technique for quantifying apical vertebral rotation with respect to the sagittal plane (RAsag) is commonly reported in the literature. To our knowledge no study has correlated ATI with RAsag. The purpose of this study was to determine the relationship between commonly used measures of trunk and spine deformity. METHODS: Sixteen females that underwent preoperative apical vertebra(e) CT scans were retrospectively studied. Thoracic and thoracolumbar RAsag measurements were date-matched to clinically obtained ATI and Cobb measurements. Two-tailed Pearson correlations were calculated; alpha = 0.01. RESULTS: Median patient age was 14.6 years (11-19); BMI 19.4 (16.0-25.5). Curve patterns: Lenke 1 (5); 2 (5); 3 (1); 4 (1); 5 (2): 6 (2). Twenty-six curves (15T; 11TL) with complete, date-matched data points were analyzed. In thoracic curves, ATI correlated with Cobb (r = 0.711, P < 0.004) and RAsag (r = 0.730, P <0.003). ATI was inversely correlated with Cobb flexibility (r = -0.647, P < 0.01). In thoracolumbar curves, ATI correlated with Cobb (r = 0.789, P < 0.005), and RAsag (r = 0.771, P < 0.006) but not Cobb flexibility (r = -0.452, P = 0.190). CONCLUSIONS: Trunk and spine thoracic and thoracolumbar transverse plane deformity are correlated, as are trunk transverse plane and spine coronal plane deformity. Increasing trunk deformity limits thoracic, but not thoracolumbar spine flexibility. PMID- 23351198 TI - Role of Omega-3 fatty acids in preventing metabolic disturbances in patients on olanzapine plus either sodium valproate or lithium: a randomized double-blind placebo-controlled trial. AB - BACKGROUND: Metabolic and cardiovascular side effects have been noted with the use of second generation antipsychotics (SGAs) and mood stabilizers. Since Omega 3 fatty acids have been known to prevent some cardiovascular risks, this preliminary study was designed to evaluate the cardiovascular benefits of omega-3 when added to the combinations of olanzapine with mood stabilizers. METHODS: This study was a randomized, double-blind, placebo-controlled, within-subject trial in adult psychiatric patients who were receiving olanzapine combined with lithium (Li) or valproate sodium (VPA). Omega-3 as fish oil with less than 1 g/day of EPA/DHA or its placebo was added to patients' olanzapine and mood stabilizer regimens for 6 weeks. Metabolic parameters including anthropometric variables, lipid profile, metabolic syndrome indices, C-reactive protein, fibrinogen and lipoprotein (a) [(Lp) (a)] were assessed for participants. RESULTS: Forty one participants completed this study; 20 patients received omega-3 and 21 patients received placebo, added to their regimen of SGA and mood stabilizer. Omega-3 addition did not modulate anthropometric, metabolic syndrome and lipid parameter changes in 6 weeks. However, fibrinogen levels significantly decreased, Lp (a) did not increase and non-high-density lipoprotein cholesterol (non-HDL-C) did not go beyond its target level after omega-3 supplementation. Additionally, a significant inter-group effect was noted for Lp(a). CONCLUSIONS: This study suggests that use of short-term omega-3 supplementation added to a combined regimen of olanzapine and mood stabilizer may have a small modulating effect on some cardiovascular risk factors. Trials in longer periods of time and with larger number of patients are needed to further evaluate the effects of omega-3 supplements on preventing cardiovascular risk factors.This trial is registered at irct.ir and its Identifier is as following: IRCT138712231764N1. PMID- 23351199 TI - The patient-physician relationship: classic questions and new directions. PMID- 23351200 TI - Requests for care from family members. PMID- 23351201 TI - Responsibility for patients after the handoff. PMID- 23351202 TI - A university physician's duty to nonpatient students. PMID- 23351203 TI - A longitudinal approach to handoff training. PMID- 23351205 TI - The AMA Code of Medical Ethics' opinion on physicians treating family members. PMID- 23351204 TI - Turfing revisited. PMID- 23351206 TI - The patient, the physician, and Dr. Google. PMID- 23351207 TI - When is a patient-physician relationship established? PMID- 23351208 TI - Assignment, attribution, and accountability: new responsibilities and relationships in accountable care organizations. PMID- 23351209 TI - Physician assistants and their role in primary care. PMID- 23351210 TI - Individualism, solidarity, and U.S. health care. PMID- 23351211 TI - A medical student-cadaver relationship. PMID- 23351212 TI - Follow-up after a health fair. PMID- 23351214 TI - Cilia, tubby mice, and obesity. AB - Primary cilia have been previously linked to the central regulation of satiety. The tubby mouse is characterized by maturity-onset obesity and blindness. A recent paper demonstrates molecular defects in trafficking of ciliary GPCRs in the central neurons of tubby mice, underscoring the role of ciliary signaling in the pathogenesis of this monogenic obesity syndrome. Please see related Research article by Li et al., http://www.ciliajournal.com/content/1/1/21. PMID- 23351215 TI - Insulin resistance and adipokines serum levels in a caucasian cohort of hiv positive patients undergoing antiretroviral therapy: a cross sectional study. AB - BACKGROUND: Insulin resistance is frequent in human immunodeficiency virus (HIV) infection and may be related to antiretroviral therapy. Cytokines secreted by adipose tissue (adipokines) are linked to insulin sensitivity. The present study is aimed to assess the prevalence of insulin resistance (IR) and its association with several adipokines, in a non-diabetic Romanian cohort of men and women with HIV-1 infection, undergoing combination antiretroviral therapy (cART). METHODS: A cross-sectional study was conducted in an unselected sample of 89 HIV-1-positive, non-diabetic patients undergoing stable cART for at least 6 months. Metabolic parameters were measured, including fasting plasma insulin, and circulating adiponectin, leptin, resistin, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) levels. Insulin resistance was estimated by measuring the Quantitative Insulin Sensitivity Check Index (QUICKI), using a cut-off value of 0.33. A linear regression model was fitted to QUICKI to test the association of IR and adipokines levels. RESULTS: A total of 89 patients (aged 18-65, median: 28 years) including 51 men (57.3%) and 38 women (42.7%) were included in the study. Fifty nine patients (66.3%) were diagnosed with IR based on QUICKI values lower than the cut-off point. IR prevalence was 72.5% in men and 57.6% in women. The presence of the IR was not influenced by either the time of the HIV diagnosis or by the duration of cART. Decreased adiponectin and increased serum triglycerides were associated with increased IR in men (R=0.43, p=0.007). Hyperleptinemia in women was demonstrated to be associated with the presence of IR (R=0.33, p=0.03). CONCLUSIONS: Given the significant prevalence of the IR in our young non-diabetic cohort with HIV infection undergoing antiretroviral therapy reported in our study and the consecutive risk of diabetes and cardiovascular events, we suggest that the IR management should be a central component of HIV-infection therapeutic strategy. As adipokines play major roles in regulating glucose homeostasis with levels varying according to the sex, we suggest that further studies investigating adipokines should base their analyses on gender differences. PMID- 23351216 TI - Short communication: lack of occult HIV infection among non-AIDS-defining cancer patients in three academic oncology clinics in the United States. AB - The Centers for Disease Control (CDC) testing recommendations suggest universal opt-out testing in all health care settings, including cancer clinics. The incidence of non-AIDS-defining cancers (NADCs) is on the rise among HIV patients. However, to date, no data exist on the prevalence of HIV infection among NADC patients in the United States. Knowledge of HIV infection may affect clinical management, prognosis, and overall patient survival and decrease new infections in the population. The purpose of this study was to determine the point seroprevalence of HIV infection in cancer patients being seen in medical oncology clinics. A total of 634 individuals (mean age=53.2 years) participated and were tested for HIV. None of the participants tested positive for HIV in any of the three clinics. Using a futility analysis, the upper end of the 95% confidence interval for prevalence of undiagnosed HIV in cancer patients was less than 0.3%. Most participants were female (59.2%) and non-Hispanic (96.6%). The majority of study participants were white (76.5%) or African-American (17.7%). Breast cancer (19.7%), colon cancer (10.3%), and melanoma (9.7%) were the most commonly reported non-AIDS-defining cancers. While our study suggested that there was no occurrence of undiagnosed HIV among NADC patients, it is important to note that our population was largely white, females with insurance and with a different distribution of cancer than the most prevalent NADC among HIV patients. Furthermore, one-third of the patients did not consent to participate and further studies are needed to assess reasons for their unwillingness along with other populations, specifically minorities and individuals with low socioeconomic status (SES). PMID- 23351217 TI - Nitric oxide modulates levels of salivary Lactobacilli. AB - OBJECTIVE: Nitric Oxide (NO) is one of the most powerful antibacterial compounds. The aim of this study was to determine the association between salivary NO, dental caries and cariogenic bacteria. MATERIALS AND METHODS: The salivary NO concentration of 257 Korean children was analyzed by the Griess colorimetric reaction method. Salivary mutans streptococci (MS) and Lactobacilli (LB) were counted using the Dentocult MS and Dentocult LB kit, respectively. Dental caries status was examined using the WHO criteria. Confounders were age, gender, salivary flow rate and salivary buffer capacity. Analysis of covariance (ANCOVA) was used to evaluate the association among NO, salivary MS level, salivary LB level and dental caries status after adjusting for the effects of confounders. RESULTS: A significant decrease was found in salivary NO levels as the salivary LB count increased after controlling for confounders (p = 0.049). However, the MS level, caries experience and active caries status showed no significant association. CONCLUSION: This result indicates that NO production might be a host defense mechanism against the growth of cariogenic bacteria. PMID- 23351218 TI - In vitro effect of paediatric liquid medicines on deciduous enamel exposed to biofilm. AB - OBJECTIVE: This study aimed to assess the in vitro effects of paediatric liquid medicines on deciduous enamel exposed to biofilms. METHODS: Fragments (n = 25) of first primary molars were covered by nail varnish, leaving a 22 mm(2) exposure area. Specimens were fixed in polystyrene plates containing BHI broth media. Pooled human saliva was added to form a mature biofilm on fragments over a 10-day period in microaerophilic conditions. Specimens were divided into groups (n = 5 per group) and treated (50 MUL) daily for 1 min over 1 week as follows: G1 = 10% sucrose solution (positive control); G2 = Dimetapp Elixir(r) (antihistamine); G3 = Claritin(r) (antihistamine); and G4 = Klaricid(r) (antibiotic). Five other fragments, without treatment and inoculum represented the blank controls. The covered area for each specimen represented the negative control. Cross-sectional hardness of the enamel was used as a demineralization indicator. RESULTS: All treatment groups showed hardness loss compared to the corresponding negative controls (p < 0.05). Among the treatment groups, G2 exhibited the greatest demineralization pattern (p < 0.05) followed by G3, G1 and G4. CONCLUSION: All medicines caused deciduous enamel demineralization in the presence of biofilm. The greatest hardness loss was observed after treatment with Dimetapp Elixir(r). PMID- 23351219 TI - Toxic effects of daily applications of 10% carbamide peroxide on odontoblast-like MDPC-23 cells. AB - BACKGROUND: bleaching has been widely studied, mainly due to the possible undesirable effects that can be caused by this esthetic procedure. The cytotoxicity of the bleaching agents and its components to pulp cells has been demonstrated in several researches. The aim of this study was to evaluate the toxic effects of successive applications of 10% carbamide peroxide (CP) gel on odontoblast-like cells. MATERIALS AND METHODS: Enamel-dentin discs obtained from bovine incisors were adapted to artificial pulp chambers (APCs). The groups were formed as follows: G1: Without treatment (control group); G2: 10% carbamide peroxide, CP (five applications/one per day); G3: 10% CP (one unique application); and G4: 35% hydrogen peroxide, HP (three applications of 15 min each). After treatment, cell metabolism (MTT), alkaline phosphatase (ALP) activity and plasma membrane damage (flow cytometry) were analyzed. RESULTS: Reductions in cell metabolism and alkaline phosphatase activity along with severe damage of the cytoplasmic membrane were noted in G2. In G3, no damage was observed, compared to the control group. Intermediary values of toxicity were obtained after 35% HP application. CONCLUSION: It can be concluded that one application of 10% CP did not cause toxic effects in odontoblast-like cells, but the successive application of this product promoted severe cytotoxic effects. The daily application of the bleaching agents, such as used in the at-home bleaching technique, can increase the damages caused by this treatment to the dental pulp cells. PMID- 23351220 TI - Dental caries experience and Molar-Incisor Hypomineralization. AB - OBJECTIVE: This cross-sectional study assessed the prevalence and severity of the enamel defects, known as Molar-Incisor Hypomineralization (MIH) and its relationship to dental caries. MATERIALS AND METHODS: A sample of 1157 schoolchildren (population based), aged 6-12 years, of the Araraquara city Brazil, was evaluated according to the European Academy of Paediatric Dentistry (EAPD) criteria by two trained examiners. The dental impact caused by MIH was evaluated with the Decayed, Missing and Filled Teeth (DMFT) index (WHO). Data were analyzed using ANOVA and Chi-square tests (p < 0.05). The socioeconomic status was collected using a questionnaire answered by parents. RESULTS: The prevalence of MIH was 12.3%. Mild impairment was the most frequent diagnosis. DMFT of children with MIH was 0.89 (+/- 1.18), which are higher than those of the unaffected group (0.43 +/- 1.01). An association was found between dental caries only in the permanent dentition of children with MIH (p = 0.0001). Family income was considered low in 85% of the families of children with MIH in the public system, while in private school it was 18% (p < 0.05). CONCLUSION: The prevalence of MIH in Araraquara was associated with greater caries experience in the permanent dentition. PMID- 23351221 TI - Short fiber reinforced composite in restoring severely damaged incisors. AB - OBJECTIVE: To evaluate the static-load-bearing capacity of severely damaged endodontically-treated incisors restored with short fiber composite (SFC) as a direct post-core-crown complex and to investigate the effect of SFC on the failure mode of the restorations. MATERIALS AND METHODS: The clinical crowns of 40 maxillary incisors were prepared by cutting 2/3 parts of the crown horizontally. Five groups were fabricated (n = 8) using the direct technique; Group A: Crown restorations from conventional composite (CC); Group B: FRC-posts with core-crown restorations from CC; Group C: Crown restorations from SFC; Group D: FRC-posts and core-crown restorations from SFC; Group E: Post-core-crown restorations from SFC. The posts were cemented with dual-cure resin cement. The restorations were polymerized with a hand-light curing unit. All restored teeth were stored in distilled water at 37 degrees C for 5 days before they were statically loaded. Initial fracture (IF) and final fracture (FF) were recorded. Failure modes were visually examined. RESULTS: ANOVA revealed that SFC restorations had greater IF (469.8 N) and FF load values (515.8 N) (p < 0.05) than the CC restorations (164.8 N). No significant difference for both IF and FF was observed among groups C, D and E. Group E revealed a more favorable fracture mode than any other material combination used. CONCLUSION: The use of SFC as a restorative material for fabricating the direct composite post-core-crown restorations of severely damaged incisors provided improved load-bearing capacity than CC used alone or with FRC post reinforcement. PMID- 23351222 TI - Adhesion of veneering resins to polymethylmethacrylate-based CAD/CAM polymers after various surface conditioning methods. AB - OBJECTIVES: The aims of this study were to test whether the bond strength of a hybrid composite and a PMMA-based veneer to CAD/CAM polymers would improve after pre-treatment and to evaluate the failure types after debonding. MATERIALS AND METHODS: Three types of PMMA-based (CAD-Temp, artBloc Temp and TelioCAD) CAD/CAM blocks were obtained (N = 360, n = 15 per test group). They were divided into four groups to be conditioned with the following methods: (a) no-treatment, (b) air-abrasion (50 MUm Al2O3), (c) air-abrasion (50 MUm Al2O3) + MPS-Silane (Monobond S) + Adhesive resin (StickResin) (for Gradia)/MMA (for Integral Esthetic Press) application, (d) Silica coating and silanization (CoJet-System). The conditioned surfaces were veneered with a hybrid composite (Gradia) or a PMMA based resin (Integral esthetic press). After water storage (1 week, 37 degrees C), the bond strength was measured. Data were analyzed using 3-way ANOVA and post hoc Scheffe test (alpha = 0.05). RESULTS: Surface-conditioning method, veneer type and CAD/CAM polymers significantly affected the results. Hybrid composite did not bond to non-conditioned CAD/CAM polymers. Regardless of the conditioning method, PMMA-based resin showed significantly higher bond strength to all CAD/CAM polymers compared to hybrid composite. Air-abrasion increased the bond strength in all tested groups. Additional silane application after air-abrasion did not significantly increase the bond strength of hybrid composite. While exclusively adhesive failures were observed between the hybrid composite and the CAD/CAM polymers, PMMA veneer demonstrated cohesive failures in the CAD/CAM polymers. CONCLUSION: CAD/CAM polymers could be veneered with only a PMMA-based veneer with and without air-abrasion. PMID- 23351223 TI - A 5-year retrospective case series evaluating Branemark Integration BioHelix (TM) dental implants placed in a private practice by a specialist. AB - OBJECTIVE: To evaluate, in a case series, survival rate and complications of Branemark Integration BioHelix(TM) dental implants, placed according to conventional procedures in patients treated consecutively in a Swedish specialist private practice after 5 years. MATERIALS AND METHODS: Eighty-three consecutively treated patients received 89 final fixed prostheses supported by 310 implants placed according to 'conventional' procedure, i.e. no implants shorter than 10 mm, no immediate post-extraction implants and no bone-grafting procedures. In 70 patients, implants were left to heal submerged, whereas 13 patients were treated according to the one-stage protocol. All implants were incorporated in a prosthetic restoration. Probing was only performed when clinical signs of inflammation were present and this was then evaluated further with intra-oral radiographic examination. Outcome measures were implant survival and prosthetic complications. RESULTS: Five years after implant placement, two fixtures were removed because of loosening. One fixture was lost after 12 months in the lower jaw in one patient and one fixture was lost in the upper jaw in another patient after 3 years, both inserted using the two-stage technique. No other prosthetic complications occurred, giving a 99.3% cumulative survival rate. CONCLUSIONS: Branemark Integration BioHelix(TM) dental implants placed according to one- or two-stage procedures in patients in a private practice produced excellent 5-year results. Randomized clinical trials with suitable controls are suggested to confirm these results. PMID- 23351224 TI - Microleakage effect on class V composite restorations with two adhesive systems using different bleaching methods. AB - OBJECTIVE: The main objective of this study was to evaluate the effects of an at home and two in-office (chemically activated and KTP laser-activated) bleaching methods on the microleakage of composite resin restorations bonded with etch-and rinse and self-etch adhesive systems. MATERIALS AND METHODS: Class V cavity preparations were performed on 96 premolars and teeth were divided into two groups according to the two adhesive systems (etch-and-rinse and self-etch). After cavities were restored with an adhesive systems and composite resin, they were submitted to thermocycling procedures. Teeth were divided into four sub groups according to the bleaching systems (control, at-home bleaching, chemically activated office bleaching and KTP laser-activated office bleaching). After the bleaching procedure, teeth were evaluated for marginal leakage. All data were analyzed using the Mann-Whitney U and Kruskal-Wallis tests (p < 0.05). RESULTS: The results of the present study showed that the control group presented lower microleakage values compared with the groups treated with bleaching agents, except for the chemically activated in-office bleaching. When the scores of microleakage at the enamel and gingival margins of the four groups were compared, the differences among the groups were found to be statistically significant (p < 0.05). Comparing the gingival and enamel margins in each group, statistically significant differences were found in the at-home group (p < 0.05) and no significant differences were seen in the other groups (p > 0.05). No significant difference was found between the adhesive systems after treatment with the same bleaching techniques. CONCLUSION: Under the conditions of this study, microleakage of composite resin restorations differs according to the bleaching methods used and no difference was found between the adhesive systems. PMID- 23351225 TI - Ciliary and non-ciliary expression and function of PACRG during vertebrate development. AB - BACKGROUND: Park2-co-regulated gene (PACRG) is evolutionarily highly conserved from green algae to mammals. In Chlamydomonas and trypanosomes, the PACRG protein associates with flagella. Loss of PACRG results in shortened or absent flagella. In mouse the PACRG protein is required for spermatogenesis. The purpose of the present study was to analyze (1) the expression patterns of PACRG during vertebrate embryogenesis, and (2) whether the PACRG protein was required for left right (LR) axis specification through cilia-driven leftward flow in Xenopus laevis. METHODS: PACRG cDNAs were cloned and expression was analyzed during early embryonic development of Xenopus, mouse, rabbit and zebrafish. Antisense morpholino oligonucleotide (MO) mediated gene knockdown was applied in Xenopus to investigate LR development at the level of tissue morphology, leftward flow and asymmetric marker gene expression, using timelapse videography, scanning electron microscopy (SEM) and whole-mount in situ hybridization. Results were statistically evaluated using Wilcoxon paired and chi2 tests. RESULTS: PACRG mRNA expression was found in cells and tissues harboring cilia throughout the vertebrates. Highly localized expression was also detected in the brain. During early development, PACRG was specifically localized to epithelia where leftward flow arises, that is, the gastrocoel roof plate (GRP) in Xenopus, the posterior notochord (PNC) in mammals and Kupffer's vesicle (KV) in zebrafish. Besides its association with ciliary axonemes, subcellular localization of PACRG protein was found around the nucleus and in a spotty pattern in the cytoplasm. A green fluorescent protein (GFP) fusion construct preferentially labeled cilia, rendering PACRG a versatile marker for live imaging. Loss-of-function in the frog resulted dose dependently in LR, neural tube closure and gastrulation defects, representing ciliary and non-ciliary functions of PACRG. CONCLUSIONS: The PACRG protein is a novel essential factor of cilia in Xenopus. PMID- 23351226 TI - Financial perspective of private pharmacies in Tehran (Iran); is it a lucrative business? AB - BACKGROUND AND PURPOSE OF THE STUDY: Pharmacies as direct providers of medicine and pharmaceutical services to patients have an important role in the health status of a society. The assessment of their financial situations by healthcare policy makers is necessary to prevent any negative effects on population's health. In this study we aim to analyze the financial status of pharmacies in Tehran, Iran. METHODS: This study is a cross-sectional study based on a survey. Two-hundred and eighty-eight private community daytime pharmacies in Tehran were selected by random sampling. We used two questionnaires to collect data regarding cost, expense and income factors of private pharmacies and the significance of each of them from these selected pharmacies. The data was collected in 2011 from Tehran pharmacies. Profitability of pharmacies in Tehran, Iran was calculated in its current situation and then estimated for three defined scenarios: 1. The dispensing fee is omitted (ceteris paribus), 2. Pharmacies are prohibited from selling hygienic & cosmetic products (ceteris paribus), 3. Scenarios 1 and 2 together (ceteris paribus). These data were analyzed by using SPSS and descriptive-analytic statistics. RESULTS: About 68% of interviewees responded to our questionnaires. Our analysis indicated that the average annual costs (and expenses), income and profits of pharmacies are 73,181; 106,301; and 33,120 United States Dollar (USD), respectively. The analysis indicated that omission of dispensing fee (scenario 1) and prohibition of pharmacies from selling hygienic & cosmetic products (scenario 2) would decrease income of pharmacies to 18438 and 14034 USD/year, respectively. According to respondents, the cost (or expense) of properties and buildings, energy, taxes, delays in reimbursement by insurance companies, and renting the place of pharmacy could be considered as cost factors and prescription medicines, OTC medicines, dispensing fees, hygienic & cosmetic products, and long-term payment to pharmaceutical distribution companies as income factors, which have significant effects on a pharmacy's economy. MAJOR CONCLUSIONS: According to the results of this study, regarding the pharmacies' cost (and expenses) and incomes, the omission of dispensing fees for prescriptions has considerable negative effects on the profitability of pharmacies and likely on society's health. PMID- 23351227 TI - Fluids and blood transfusions: the corner pillars of perioperative period. PMID- 23351228 TI - Physiology of hemodynamic homeostasis. AB - Homeostasis of hemodynamics refers to the regulation of the blood circulation to meet the demands of the different organ and tissue systems. This homeostasis involves an intimate interaction between peripheral metabolic needs, vascular adaptations to meet these needs and cardiac adaptation to provide the driving force to circulate the blood. The three variables that reflect the homeostasis of cardiovascular regulation are mean systemic arterial pressure, cardiac output and total systemic vascular resistance in the circulation. Regulation of the blood circulation depends on a static component, based on the physical properties of the different vessels and the characteristics of the fluid going through these vessels. Superimposed on this static regulation, is the dynamic regulation which is based on local control systems and the controls systems that adjust hemodynamic status to meet the needs of the body as a whole. This global circulation throughout the body is regulated by hormonal and neural control systems. All these systems closely interact to maintain blood pressure between the normal levels. PMID- 23351229 TI - Effects of perioperative fasting on haemodynamics and intravascular volumes. AB - Maintaining cardiac preload throughout the perioperative period is a generally accepted target. As perioperative fasting is believed to cause intravascular hypovolaemia it traditionally triggers aggressive preemptive intravenous fluid infusion. Physiology suggests that extracellular losses via urinary output and evaporation decrease the extracellular compartment. Representing a relevant part of the latter, the intravascular space is also affected, even without blood loss. Measurements in humans, however, have revealed that even a prolonged fasting period does not decrease absolute blood volume. Beyond that, modern fasting guidelines recommend to refrain from clear liquids only two hours prior to surgery. Nevertheless, an intravenous colloid challenge can increase stroke volume after induction of anaesthesia in the majority of surgical patients. While perioperative stroke volume maximisation in high-risk surgery probably improves outcome, the implication of this observation for the routine patient remains unclear. It appears as though there are two important targets to preserve cardiac preload: normovolaemia and vasotension. PMID- 23351230 TI - Pathophysiology of perioperative anaemia. AB - Perioperative anaemia is a common clinical entity. It is usually due to combination of various mechanisms, including: pre-existing anaemia prior to surgery; anaemia due to impaired erythropoiesis, including alterations of metabolism of iron and erythropoietin (EPO); anaemia due to increased destruction of red blood cells (RBCs); and anaemia due to iatrogenic causes. Postoperatively, anaemia resembles anaemia of chronic disease and is probably related to the effects of inflammatory mediators released during and after surgery on the production and survival of RBCs. Pro-inflammatory cytokines, such as tumour necrosis factor, impair erythropoietin-dependent signalling and iron homeostasis. Iatrogenic causes, notably excessive phlebotomies, remain a major cause of perioperative anaemia. With increasing emphasis on restrictive blood transfusion strategies, understanding these mechanisms is important for the clinician. PMID- 23351231 TI - Characteristics of fluids used for intravascular volume replacement. AB - In this review, the relative merits of the different fluid solutions used for fluid replacement will be discussed. Differences in chemical composition may have important implications on volume expansion capacities but also on organ function. Among crystalloids, differences in electrolyte composition, and in particular chloride load, alter acid base status but may also affect other aspects of organ function. Large observational cohorts suggest that chloride load may be associated with a poor outcome. Colloids provide greater expansion capacities than crystalloids. When colloids are indicated, albumin should be preferred as it is the only one that has been proved to be safe in a large randomized trial. Cumulative evidence suggests that starches, even of the new generations, are associated with development of acute kidney injury. Hypertonic solutions may represent an interesting option in some groups of patients but more research is needed in this field. PMID- 23351232 TI - Perioperative hemodynamic monitoring. AB - Hemodynamic monitoring is the cornerstone of perioperative anesthetic monitoring. In the unconscious patient, hemodynamic monitoring not only provides information relating to cardiac output, volume status and ultimately tissue perfusion, but also indicates depth of anesthesia and adequacy of pain control. In the 21st century the anesthesiologist has an array of devices to choose from. No single device provides a complete assessment of hemodynamic status, and the use of all devices in every situation is neither practical nor appropriate. This article aims to provide the reader with an overview of the devices currently available, and the information they provide, to assist anesthesiologists in the selection of the most appropriate devices for any given situation. PMID- 23351233 TI - Perioperative intravascular volume replacement and kidney insufficiency. AB - Perioperative acute kidney injury (AKI) occurrence is probably increased in recent years due to the increased level of complexity of surgical procedures and severity of illness of surgical patients. Perioperative AKI has a multifactorial aetiology (preoperative co-morbidities such as diabetes, heart failure and chronic kidney disease, emergent surgery, exposure to nephrotoxic drugs, haemodynamic instability, hypothermia, inflammatory response to surgery, hospital acquired infections and abdominal compartment syndrome). However, fluid choice for perioperative volume replacement might have a major role in perioperative AKI, as administration of crystalloid solutions, colloids or haemoderivates has the potential for kidney injury. This review focusses on the issue of fluid replacement quality and quantity and their association with renal dysfunction. PMID- 23351234 TI - Blood transfusion in the perioperative period. AB - Anemia is associated with perioperative mortality and morbidity. Since the presence of anemia and blood transfusion often go hand in hand, it can be difficult to separate the effects of anemia from the effects of perioperative transfusion. The role for blood transfusion in mitigating the mortality and morbidity associated with anemia is unclear. A restrictive transfusion strategy has been advocated for hemodynamically stable patients, as blood transfusion exposes the patient to both infectious and non-infectious complications. Further research is warranted in patients with the acute coronary syndrome, as there is insufficient evidence to make recommendations for this patient population. Additional multi-center randomized controlled trials need to be conducted in perioperative and critically ill patients with large enough sample sizes to examine differences in mortality and major complications between liberal and restrictive transfusion strategies. Further trials need to incorporate current practices in improved blood storage and leukoreduction techniques. PMID- 23351235 TI - Impact of intravascular volume replacement and transfusion on outcome: where are we now? AB - Intravenous fluid administration is often required to counteract haemodynamic instability during emergency and elective surgeries, as well as in the intensive care unit. However, the best type and the amount of fluid required are controversial. A recent meta-analysis suggested that there is no difference among different types of colloids on outcome. Furthermore, colloids and crystalloids seem to be comparable in terms of efficiency in reverting haemodynamic instability, as well as morbidity and mortality. The interpretation of the results of different randomised controlled trials is somewhat difficult - the context must be always kept in mind. For example, results may differ in septic as compared to non-septic patient populations. Another important aspect concerns the effects on the macro- versus microcirculation. More recent studies emphasise that the microcirculation has to be taken into account when studying and interpreting the interaction between fluid therapy and the underlying disease. Nevertheless, the macrocirculation and clinical parameters have to be considered as well. Given that red blood cells remain the most important oxygen carriers, recent evidence regarding blood age may stimulate new studies according to the actual range for blood storage. Artificial oxygen carriers may play a role in specific situations, where the transfusion is indicated but the access to blood is problematic, but there is doubt that they may replace blood transfusion. PMID- 23351236 TI - Application of nanomedicine in emergency medicine; Point-of-care testing and drug delivery in twenty - first century. AB - The application of emerging nanotechnology to the practice of medicine represents a frontier of nanomedicine. Nanomedicine has been defined as a science which emphasizes the use of nanoscale tools in conjunction with background knowledge of the human body for medical diagnosis and treatment. Application of nanomedicine in EM may give EM providers the opportunity to diagnose and treat life-threatening diseases in a shorter period of time. These applications include diagnostic utilities, preventive medicine, targeted pharmacotherapy, and tissue regeneration. PMID- 23351237 TI - Role of testosterone in memory impairment of Alzheimer disease induced by Streptozotocin in male rats. AB - BACKGROUND AND PURPOSE OF THE STUDY: Recent studies demonstrate that androgens, beyond regulating sexual behavior, exert several neuroprotective functions in the brain. The present study was designed to explore effect of testosterone in memory impairment induced by intra- cerebroventricular (icv) injection of streptozotocin (STZ) as a model of sporadic AD. METHODS: Study was carried out on male Wistar rats. Animals were randomly divided into 11 equal groups. Experimental model of AD was induced by bilateral icv injection of STZ at the dose of 750 MUg/Rat/10 MUl ACSF at days 1 and 3. STZ-induced memory impairment was assessed two weeks after the last dose of STZ by using a passive avoidance task (1 mA). The interval between the placement of animals in the illuminated chamber and the entry into the dark chamber was measured as a step-through latency (STL). Castration was performed by surgical removing of testis and behavioral study of memory impairment was done after 4 weeks. RESULTS: Results of this study showed that icv injection of STZ could induce marked (p < 0.05) memory impairment at the dose of 750 MUg/Rat/dissolve10 MUl CSF/bilateral/days 1 and 3. Therefore, we used this dose of STZ for induction of experimental model of AD. Memory was worsened in castrated rats (P < 0.05) when compared with normal and sham-operated animals. Testosterone replacement therapy (1 mg/kg, sc, for 6 days) in 4 week castrated rats restored memory up to the level of control groups. Testosterone had not any significant effect on memory impairments of non-castrated rats. MAJOR CONCLUSION: According to the obtained results it can be concluded that testosterone improves cognitive and memory impairment of AD. We suggest that testosterone replacement therapy may have beneficial effect in ameliorating memory impairments of senile patients suffering from AD. Further clinical studies should be carried out to prove possible useful effect of testosterone as an adjuvant therapy in AD. PMID- 23351239 TI - Predictors of discrepancies in Parkinson's disease patient and caregiver ratings of apathy, disinhibition, and executive dysfunction before and after diagnosis. AB - Parkinson's disease (PD) patient and caregiver reports of patient functioning are often used interchangeably in clinical and research settings; however, the consistency of these reports is largely unknown. This study aimed to investigate the consistency and predictors of discrepancy between self- and caregiver reports of patient apathy, disinhibition, and executive dysfunction. Fifty-one pairs of nondemented PD patients and their caregivers completed the frontal systems behavior scale (FrSBe). Patients were administered a neuropsychological battery, and mood and burden were assessed in a subset of caregivers. Patients and caregivers significantly differed in their ratings of all retrospective prediagnosis behaviors and current levels of disinhibition. Current levodopa equivalent dosages predicted patient-caregiver rating differences in prediagnosis and current apathy and current executive dysfunction, while patient motor function, cognition, and mood failed to predict any disparities in ratings. Caregiver burden and depression were associated with apathy rating discrepancies, while burden was associated with discrepancies in ratings of disinhibition. These results suggest that consistency of patient and caregiver behavioral ratings may vary depending on the behavior assessed; and underscore the importance of considering the reporter when using subjective measures, as discrepancies in behavioral reports may be influenced by specific patient and/or caregiver symptoms or factors. PMID- 23351238 TI - Single v. multiple measures of skin carotenoids by resonance Raman spectroscopy as a biomarker of usual carotenoid status. AB - Resonance Raman spectroscopy (RRS) is a non-invasive method of assessing carotenoid status in the skin, which has been suggested as an objective indicator of fruit/vegetable intake. The present study assessed agreement and identified predictors of single v. multiple RRS measures of skin carotenoid status. A total of seventy-four participants had their skin carotenoid status measured in the palm of the hand by RRS at six time points over 6 months. Questionnaires were administered to collect information on demographic, lifestyle and dietary data. Mean age of the participants was 36.6 years, 62.2% were female, 83.8% Caucasian and 85.1% were non-smoking at baseline. There was a good agreement between a single measure of skin carotenoids by RRS and multiple measures (weighted kappa = 0.80; 95% CI 0.72, 0.88). The same variables were significantly associated with carotenoid status based on single or multiple measures, including a positive association with intake of total carotenoids (P< 0.01) and an inverse association with season of measurement (P<= 0.05). The exception was recent sun exposure, which emerged as a significant predictor of lower carotenoid status only when using multiple RRS measures (P<= 0.01). A single RRS measure was reasonably accurate at classifying usual skin carotenoid status. Researchers using RRS may want to take into account other factors that are associated with the biomarker, including season of measurement and recent sun exposure. PMID- 23351240 TI - Prognostic analysis of early-stage squamous cell carcinoma of the vulva. AB - AIM: The aim of this study was to analyze prognostic factors of early-stage squamous cell carcinoma of the vulva. METHODS: A retrospective analysis was conducted on 35 patients who were treated for early-stage squamous cell carcinoma of the vulva at Sun Yat-sen University Cancer Center from January 1980 to December 2005. The Statistical Package for Social Science (SPSS) was used to compare the different strategies of operation and to analyze the prognostic factors. RESULTS: Thirty-five patients had early-stage squamous cell carcinoma of the vulva. Of these cases, 26 were well differentiated, seven were moderately differentiated, and two were poorly differentiated. The five-year survival rate was 77.1%. Five cases were in FIGO stage 1a and 30 cases were in stage 1b; median survival times were 182.3 months and 152.5 months, and the five-year survival rates were 100% and 81.5% (P >0.05), respectively. The five-year survival of the patients who underwent local excision; radical vulvectomy and en bloc resection of inguinofemoral lymphadenectomy; orradical vulvectomyen bloc resection of inguinofemoral lymphadenectomy, and pelvic lymph nodes was 50%, 81.8%, and 83.9%, respectively. For these cases, 74.3% of the tumors were medial while 25.7% were lateral, and the five-year survival rates of patients according to tumor location were 87.0% and 64.8% (P <0.05), respectively. The inguinal lymph node not increased and active were 16 cases (45.7%), and increased, active and hard were 17 cases (48.6%), and syncretic were two cases (5.7%), five-year survival rates were 73.3%, 92.9% and 50% (P <0.05), respectively. Of these cases, 74.3% of the tumors were cauliflower-like and 25.7% were nodular; five-year survival rates by tumor type were 91.3% and 66.7% (P <0.05), respectively. CONCLUSIONS: For patients with early-stage squamous cell carcinoma of the vulva, surgical operation is the primary, yet the best, treatment. The related prognostic factors were tumor location (lateral/medial), stage, gross morphology, and clinical state of the inguinal lymph node. PMID- 23351242 TI - Implementing a regional anesthesia block nurse team in the perianesthesia care unit increases patient safety and perioperative efficiency. AB - A lack of standardized nursing procedures regarding the management of patients receiving preoperative regional anesthesia in the perianesthesia setting raises a number of issues for perianesthesia nurses. In January 2010, Duke University Hospital's perianesthesia care unit implemented a regional anesthesia "block nurse" team in the preoperative holding area as a patient safety initiative. In January 2011, a retrospective data review was conducted. Results indicated that the implementation of the block nurse team not only increased patient safety but also increased perioperative efficiency and productivity, and decreased delays to operating room start times. This article describes the role of the regional anesthesia block nurse, the development of a block nurse team, and the early benefits of implementing a dedicated regional anesthesia block nurse team in the perianesthesia setting. PMID- 23351243 TI - Preanesthesia screening phone messages and rate of return based on the primary language of patient. AB - As a part of the surgical process, patients are screened in the preanesthesia services department before surgery. Often phone messages are left in English. The nurses will continue to make multiple calls trying to reach patients. As the patient population continues to diversify, problems in contacting patients have been noted. It was suspected that patients whose primary language was non-English were returning phone messages at a lower rate than patients whose primary language was English. The project was conducted over a 6-week period and a total of 1,438 documented cases were reviewed and included. A Chi-square analysis was performed on the data. Compared with English-speaking patients, non-English speaking patients required almost twice as many calls on average to make contact. In addition, non-English-speaking patients were less likely to return telephone calls than were the English-speaking patients (P<.001). Furthermore, the percentage of day of service interviews was higher for non-English-speaking patients compared with English-speaking patients (P<.01). Based on these findings, processes for identifying the linguistic needs of our patients have been changed in an effort to provide safer quality care. PMID- 23351244 TI - Implementing primary care in the perianesthesia setting using a relationship based care model. AB - As surgical patients pass through the perianesthesia continuum, the nurses they encounter rarely have time to develop a nurse-patient relationship, or identify patient needs and concerns and pass this information along to other providers. In the preprocedural period of the care continuum, however, patients and their families often express information that is important to the patient and should be included in the patient's perioperative plan of care. Three questions were developed and added to the existing preoperative nursing assessment to ascertain the needs and concerns of patients and their families in the presurgical setting. Responses were communicated to the postanesthesia care unit nurse. Through implementation of this simple process, patient needs were better recognized and communicated during recovery from anesthesia. Results suggest that this primary care nursing model, adapted for a perioperative setting, has been overwhelmingly successful in communicating and responding to patients' needs during their surgical experience. PMID- 23351245 TI - Evaluating the need for routine supplemental oxygen in postoperative total joint replacement patients. PMID- 23351246 TI - Mobile devices in the perianesthesia environment. PMID- 23351247 TI - The perianesthesia nurse's role in the prevention of opioid-related sentinel events. PMID- 23351248 TI - Distractions and interruptions in the perianesthesia environment: a real threat to patient safety. PMID- 23351249 TI - Research news: postdischarge nausea and vomiting. PMID- 23351250 TI - 2013: the year of best practice. PMID- 23351251 TI - Stress ulcer prophylaxis in critically ill poisoned patients. PMID- 23351252 TI - Reporting of adverse drug reactions: an exploratory study among nurses in a teaching hospital, Ajman, United Arab Emirates. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: Adverse drug reactions (ADRs) are important public health problem associated with morbidity, mortality and financial burden on the society. Nurses play important role in medication safety surveillance through the spontaneous voluntary reporting of ADRs. Nurses' knowledge, attitude and practice towards ADR reporting and factors affecting reporting was assessed in the study. METHODS: All nurses working in a tertiary care hospital, Ajman, UAE participated in this cross-sectional survey. A self administered questionnaire of four domains (knowledge, attitude, practice, factors affecting reporting) was distributed among nurses after obtaining informed consent. The knowledge and attitude components were assigned score of one for correct response. Data was analyzed using SPSS (version 19). Mann-Whitney U test was used to compare knowledge and attitude scores between subgroups; Spearman's correlation for any relationship between knowledge and attitude. RESULTS: Of the total participants, females constituted 92.3%; average duration of clinical experience 6.5 +/- 3.3 years; mean age 28.9 +/- 4.1 years. Median score for knowledge components of ADR reporting was 11(total score: 17) and for attitude components was 4(total score: 8). No difference noted in knowledge and attitude scores between gender, age group, educational qualification. A positive correlation between knowledge and attitude components was observed (r = 0.38). ADRs are important cause for morbidity and mortality was reported by (54.9%). 49.5% were aware of Pharmacovigilance centers'. Uncertainty of ADRs (49.5%); concern that the report may be wrong (46.2%) and inadequate knowledge of ADR reporting procedure were the major barriers to reporting. Training in ADR reporting as the key measure to improve reporting was suggested by (86.8%). MAJOR CONCLUSION: The results of the study strongly point out the need for interventional program among nurses focusing on the importance of ADR reporting and reporting procedure to encourage their active, voluntary participation in drug safety surveillance. PMID- 23351253 TI - Giant solitary synovial osteochondromatosis of the elbow causing ulnar nerve neuropathy: a case report and review of literature. AB - INTRODUCTION: Giant or solitary osteochondroma is part of a rare disorder known as synovial osteochondromatosis. It forms part of a spectrum of disease characterized by metaplastic changes within the joint synovium that are eventually extruded as loose bodies. It has been suggested that solitary synovial osteochondroma forms as progression of synovial osteochondromatosis through a process of either coalescence of multiple smaller bodies or the growth of a dominant synovial osteochondroma. Previous studies have shown that it occurs as a late phase of the disease. We report a rare case of giant synovial osteochondromatosis at the elbow causing ulnar nerve neuropathy and mechanical symptoms which has not been previously reported in the literature. CASE REPORT: We report a case of a 56 year old Western European gentleman who presented with ulnar nerve neuropathy and swelling behind the elbow. The patient underwent MR imaging and subsequent biopsy that demonstrated synovial osteochondromatosis. Initially the patient declined surgery and opted for a watch and wait approach. Five years later he returned with worsening symptoms and underwent successful surgical resection of a giant solitary synovial osteochondroma. CONCLUSION: The unique outcome in our patient despite the long interval between presentation and surgical treatment resulted in early full resolution of symptoms within a short period. It may suggest an improved prognosis as compared to multiple synovial osteochondromatosis in terms of mechanical and neurological outcomes. PMID- 23351254 TI - Psychiatry in a brave new world. The human condition in the twenty-first century. PMID- 23351255 TI - Monitoring blogs: a new dilemma for psychiatrists. PMID- 23351256 TI - Special protections for mental health treatment notes. PMID- 23351257 TI - Treating bereavement. PMID- 23351258 TI - Resources for teaching neuroethics. PMID- 23351260 TI - The ethics of genetic testing in psychiatry. PMID- 23351261 TI - Diagnostic brain imaging in psychiatry: current uses and future prospects. PMID- 23351262 TI - Predicting the risk of future dangerousness. PMID- 23351263 TI - Telepsychiatry: licensing and professional boundary concerns. PMID- 23351264 TI - Antidepressants and the FDA's black-box warning: determining a rational public policy in the absence of sufficient evidence. PMID- 23351265 TI - Determinism and advances in neuroscience. PMID- 23351266 TI - Mainstream anxieties about race in antipsychotic drug ads. PMID- 23351267 TI - What can physicians learn from the neurodiversity movement? PMID- 23351269 TI - Effect of a facility-based multifaceted intervention on the quality of obstetrical care: a cluster randomized controlled trial in Mali and Senegal. AB - BACKGROUND: Maternal mortality in referral hospitals in Mali and Senegal surpasses 1% of obstetrical admissions. Poor quality obstetrical care contributes to high maternal mortality; however, poor care is often linked to insufficient hospital resources. One promising method to improve obstetrical care is maternal death review. With a cluster randomized trial, we assessed whether an intervention, based on maternal death review, could improve obstetrical quality of care. METHODS: The trial began with a pre-intervention year (2007), followed by two years of intervention activities and a post-intervention year. We measured obstetrical quality of care in the post-intervention year using a criterion-based clinical audit (CBCA). We collected data from 32 of the 46 trial hospitals (16 in each trial arm) and included 658 patients admitted to the maternity unit with a trial of labour. The CBCA questionnaire measured 5 dimensions of care- patient history, clinical examination, laboratory examination, delivery care and postpartum monitoring. We used adjusted mixed models to evaluate differences in CBCA scores by trial arms and examined how levels of hospital human and material resources affect quality of care differences associated with the intervention. RESULTS: For all women, the mean percentage of care criteria met was 66.3 (SD 13.5). There were significantly greater mean CBCA scores in women treated at intervention hospitals (68.2) compared to control hospitals (64.5). After adjustment, women treated at intervention sites had 5 points' greater scores than those at control sites. This difference was mostly attributable to greater clinical examination and post-partum monitoring scores. The association between the intervention and quality of care was the same, irrespective of the level of resources available to a hospital; however, as resources increased, so did quality of care scores in both arms of the trial. PMID- 23351270 TI - Association of anaemia in primary care patients with chronic kidney disease: cross sectional study of quality improvement in chronic kidney disease (QICKD) trial data. AB - BACKGROUND: Anaemia is a known risk factor for cardiovascular disease and treating anaemia in chronic kidney disease (CKD) may improve outcomes. However, little is known about the scope to improve primary care management of anaemia in CKD. METHODS: An observational study (N = 1,099,292) with a nationally representative sample using anonymised routine primary care data from 127 Quality Improvement in CKD trial practices (ISRCTN5631023731). We explored variables associated with anaemia in CKD: eGFR, haemoglobin (Hb), mean corpuscular volume (MCV), iron status, cardiovascular comorbidities, and use of therapy which associated with gastrointestinal bleeding, oral iron and deprivation score. We developed a linear regression model to identify variables amenable to improved primary care management. RESULTS: The prevalence of Stage 3-5 CKD was 6.76%. Hb was lower in CKD (13.2 g/dl) than without (13.7 g/dl). 22.2% of people with CKD had World Health Organization defined anaemia; 8.6% had Hb <= 11 g/dl; 3% Hb <= 10 g/dl; and 1% Hb <= 9 g/dl. Normocytic anaemia was present in 80.5% with Hb <= 11; 72.7% with Hb <= 10 g/dl; and 67.6% with Hb <= 9 g/dl; microcytic anaemia in 13.4% with Hb <= 11 g/dl; 20.8% with Hb <= 10 g/dl; and 24.9% where Hb <= 9 g/dl. 82.7% of people with microcytic and 58.8% with normocytic anaemia (Hb <= 11 g/dl) had a low ferritin (<100 ug/mL). Hypertension (67.2% vs. 54%) and diabetes (30.7% vs. 15.4%) were more prevalent in CKD and anaemia; 61% had been prescribed aspirin; 73% non-steroidal anti-inflammatory drugs (NSAIDs); 14.1% warfarin 12.4% clopidogrel; and 53.1% aspirin and NSAID. 56.3% of people with CKD and anaemia had been prescribed oral iron. The main limitations of the study are that routine data are inevitably incomplete and definitions of anaemia have not been standardised. CONCLUSIONS: Medication review is needed in people with CKD and anaemia prior to considering erythropoietin or parenteral iron. Iron stores may be depleted in over >60% of people with normocytic anaemia. Prescribing oral iron has not corrected anaemia. PMID- 23351271 TI - Effect of vitamin D on insulin resistance and anthropometric parameters in Type 2 diabetes; a randomized double-blind clinical trial. AB - BACKGROUND & THE PURPOSE OF THE STUDY: Prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. To reduce its risk and progression, preventive strategies are needed. Vitamin supplementation such as vitamin D is one of the strategies. This study was designed to investigate the effect of injection of vitamin D on insulin resistance and anthropometric parameters in T2DM. METHODS: This randomized double-blind clinical trial was conducted with 42 diabetic patients in two groups; intervention group with single intramuscular injection of 300,000 International Unit (IU) of vitamin D3 and the placebo group. After recording demographic and anthropometric factors (waist circumference, blood pressure and body mass index), fasting blood samples was taken for measurement of blood glucose, 25-hydroxyvitamin D3 (25-OHD3), insulin, glycosylated hemoglobin A1c (HbA1c) and estimation of Homeostasis Model Assessment Index (HOMA) in two times; before study and after three months. RESULTS: Two groups had similar baseline characteristics (each group = 21 subjects). Three months after vitamin D injection, HbA1c, anthropometric factors and HOMA index in intervention group stayed constant, however, serum 25- OHD3 was significantly increased (p = 0.007). CONCLUSION: The present data is not convincing and further studies with large sample sizes are needed to show the definite effect of injection of vitamin D on control of diabetes and its risk. PMID- 23351272 TI - Antidiarrhoeal and antimicrobial activity of Calpurnia aurea leaf extract. AB - BACKGROUND: In Ethiopia, Calpurnia aurea is used for the treatment of syphilis, malaria, rabies, diabetes, hypertension, diarrhoea, leishmaniasis, trachoma, elephantiasis, fungal diseases and different swellings. However, despite its traditional usage as an antidiarrhoeal and antimicrobial agent, there is limited or no information regarding its effectiveness and mode of action in diarrhoea which may be caused by Shigella flexneri, Staphylococcus aureus, Escherichia coli and Salmonella typhi. Hence, we evaluated the 80% methanol (MeOH) extract of dried and powdered leaves of C. aurea for its antidiarrhoeal and antimicrobial activities. METHODS: Swiss albino mice of either sex were divided into five groups (five/group): Group I served as control and received vehicle (1% Tween 80) at a dose of 10 ml/kg orally; Group II served as standard and received loperamide at the dose of 3 mg/kg orally; Groups III, IV and V served as test groups and received the 80% MeOH leaf extract of C. aurea at doses of 100, 200 and 400 mg/kg orally, respectively. Diarrhoea was induced by oral administration of 0.5 ml castor oil to each mouse, 1 h after the above treatments. During an observation period of 4 h, time of onset of diarrhea, total number of faecal output (frequency of defecation) and weight of faeces excreted by the animals were recorded. Data were analyzed using one way analysis of variance followed by Tukey post test. Antimicrobial activity test was conducted using agar well diffusion assay. Clinical isolates tested were Salmonella typhi, Salmonella paratyphi, Salmonella typhimurium, Shigella species, Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli. RESULTS: In castor oil induced diarrhea model, the 80% methanol leaf extract of C. aurea at 100, 200 and 400 mg/kg and the standard drug loperamide (3 mg/kg) significantly reduced the time of onset of diarrhea, the frequency of defecation (total number of faecal output) and weight of faeces. C. aurea leaf extract also showed good antimicrobial activity against all tested organisms. CONCLUSIONS: C. aurea possesses good antidiarrhoeal and antimicrobial activity which support the traditional use of the plant in the treatment of diarrhea in Ethiopia. PMID- 23351273 TI - Compressive strength evaluation of structural lightweight concrete by non destructive ultrasonic pulse velocity method. AB - In this paper the compressive strength of a wide range of structural lightweight aggregate concrete mixes is evaluated by the non-destructive ultrasonic pulse velocity method. This study involves about 84 different compositions tested between 3 and 180 days for compressive strengths ranging from about 30 to 80 MPa. The influence of several factors on the relation between the ultrasonic pulse velocity and compressive strength is examined. These factors include the cement type and content, amount of water, type of admixture, initial wetting conditions, type and volume of aggregate and the partial replacement of normal weight coarse and fine aggregates by lightweight aggregates. It is found that lightweight and normal weight concretes are affected differently by mix design parameters. In addition, the prediction of the concrete's compressive strength by means of the non-destructive ultrasonic pulse velocity test is studied. Based on the dependence of the ultrasonic pulse velocity on the density and elasticity of concrete, a simplified expression is proposed to estimate the compressive strength, regardless the type of concrete and its composition. More than 200 results for different types of aggregates and concrete compositions were analyzed and high correlation coefficients were obtained. PMID- 23351274 TI - Chlamydia trachomatis infection prevents front-rear polarity of migrating HeLa cells. AB - Chlamydiae are obligate intracellular bacterial pathogens that cause trachoma, sexually transmitted diseases and respiratory infections in humans. Fragmentation of the host cell Golgi apparatus (GA) is essential for chlamydial development, whereas the consequences for host cell functions, including cell migration are not well understood. We could show that Chlamydia trachomatis-infected cells display decelerated migration and fail to repopulate monolayer scratch wounds. Furthermore, infected cells lost the ability to reorient the fragmented GA or the microtubule organization centre (MTOC) after a migratory stimulus. Silencing of golgin-84 phenocopied this defect in the absence of the infection. Interestingly, GA stabilization via knockdown of Rab6A and Rab11A improved its reorientation in infected cells and it was fully rescued after inhibition of Golgi fragmentation with WEHD-fmk. These results show that C. trachomatis infection perturbs host cell migration on multiple levels, including the alignment of GA and MTOC. PMID- 23351275 TI - Husband and wife with sarcoidosis: possible environmental factors involved. AB - Sarcoidosis is a granulomatous multisystem disorder of unclear etiology that involves any organ, most commonly the lung and the lymph nodes. It is hypothesized that the disease derives from the interaction between single or multiple environmental factors and genetically determined host factors. Multiple potential etiologic agents for sarcoidosis have been proposed without any definitive demonstration of causality.We report the case of two patients, husband (57 years old) and wife (55 years old), both suffering from sarcoidosis. They underwent a lymph node biopsy by mediastinoscopy which showed a "granulomatous epithelioid giant cell non-necrotising chronic lymphadenitis". They had lived up to 3 years ago in the country in a farm, in contact with organic dusts, animals such as dogs, chickens, rabbits, pigeons; now they have lived since about 3 years in an urban area where there are numerous chemical industries and stone quarries. The aim of this case report was to focus on environmental factors that might be related to the pathogenesis of the sarcoidosis. PMID- 23351276 TI - ciliaFA: a research tool for automated, high-throughput measurement of ciliary beat frequency using freely available software. AB - BACKGROUND: Analysis of ciliary function for assessment of patients suspected of primary ciliary dyskinesia (PCD) and for research studies of respiratory and ependymal cilia requires assessment of both ciliary beat pattern and beat frequency. While direct measurement of beat frequency from high-speed video recordings is the most accurate and reproducible technique it is extremely time consuming. The aim of this study was to develop a freely available automated method of ciliary beat frequency analysis from digital video (AVI) files that runs on open-source software (ImageJ) coupled to Microsoft Excel, and to validate this by comparison to the direct measuring high-speed video recordings of respiratory and ependymal cilia. These models allowed comparison to cilia beating between 3 and 52 Hz. METHODS: Digital video files of motile ciliated ependymal (frequency range 34 to 52 Hz) and respiratory epithelial cells (frequency 3 to 18 Hz) were captured using a high-speed digital video recorder. To cover the range above between 18 and 37 Hz the frequency of ependymal cilia were slowed by the addition of the pneumococcal toxin pneumolysin. Measurements made directly by timing a given number of individual ciliary beat cycles were compared with those obtained using the automated ciliaFA system. RESULTS: The overall mean difference (+/- SD) between the ciliaFA and direct measurement high-speed digital imaging methods was -0.05 +/- 1.25 Hz, the correlation coefficient was shown to be 0.991 and the Bland-Altman limits of agreement were from -1.99 to 1.49 Hz for respiratory and from -2.55 to 3.25 Hz for ependymal cilia. CONCLUSIONS: A plugin for ImageJ was developed that extracts pixel intensities and performs fast Fourier transformation (FFT) using Microsoft Excel. The ciliaFA software allowed automated, high throughput measurement of respiratory and ependymal ciliary beat frequency (range 3 to 52 Hz) and avoids operator error due to selection bias. We have included free access to the ciliaFA plugin and installation instructions in Additional file 1 accompanying this manuscript that other researchers may use. PMID- 23351277 TI - Pharmacokinetic comparison of acetaminophen elixir versus suppositories in vaccinated infants (aged 3 to 36 months): a single-dose, open-label, randomized, parallel-group design. AB - BACKGROUND: Because of practical problems and ethical concerns, few studies of the pharmacokinetics (PK) of acetaminophen (ACET) in infants have been published. OBJECTIVE: The goal of this study was to compare the PK of an ACET rectal suppository with a commercially available ACET elixir to complete a regulatory obligation to market the suppository. This study was not submitted previously because of numerous obstacles related to both the investigators and the commercial entities associated with the tested product. METHODS: Thirty infants (age 3-36 months) prescribed ACET for either fever, pain, or postimmunization prophylaxis of fever and discomfort were randomized to receive a single 10- to 15 mg/kg ACET dose either as the rectal suppository or oral elixir. Blood was collected at selected times for up to 8 hours after administration. ACET concentrations were measured by using a validated HPLC method, and PK behavior and bioavailability were compared for the 2 preparations. RESULTS: All 30 infants enrolled were prescribed ACET for postimmunization prophylaxis. PK samples were available in 27 of the 30 enrolled infants. Subject enrollment (completed in January 1995) was rapid (8.3 months) and drawn entirely from a vaccinated infant clinic population. There were no statistically significant differences between the subjects (elixir, n = 12; suppository, n = 15) in either mean (SD) age (10.0 [6.3] vs 12.4 [8.1] months), weight (8.6 [2.3] vs 9.4 [2.4] kg), sex (7 of 12 males vs 7 of 15 males), or racial distribution (5 white, 5 black, and 2 biracial vs 4 white and 11 black) between the 2 dosing groups (oral vs rectal, respectively). The oral and rectal preparations produced similar, rapid peak concentrations (T(max), 1.16 vs 1.17 hours; P = 0.98) and elimination t(1/2) (1.84 vs 2.10 hours; P = 0.14), respectively. No statistically significant differences were found between either C(max) (7.65 vs 5.68 MUg/mL) or total drug exposure (AUC(0-infinity), 23.36 vs 20.45 MUg-h/mL) for the oral versus rectal preparations. There were no serious treatment-related effects noted. Delays in submitting this work for publication were the result of a number of investigator and sponsor issues despite the study's positive outcome. CONCLUSIONS: No statistically significant differences were found between the rates or extent of absorption of the suppository and elixir preparations in this small, infant population. Both preparations were well tolerated. Vaccinated infants were a useful population in which to conduct a PK study of this antipyretic, analgesic product. Delays in publishing pediatric trials can occur as a result of a number of issues even when results are positive. PMID- 23351278 TI - Cost effectiveness of Iran national plasma contract fractionation program. AB - Plasma derived medicines (PDM) including immunoglobulins, clotting factors and albumin are life saving medicines which due to their high costs are inaccessible for many patients living in developing countries. By contrary substantial volume of plasma as raw materials for production of these medicines are discarded worldwide. Good quality recovered plasma, as a result of separation of donated blood into its components, could be used for production of PDM. In 2011 Iranian donors donated about 2 million units of blood. A shift from administration of whole blood to components therapy has resulted in the generation of over 250,000 liters of surplus of recovered plasma. This created a good opportunity for Iran's health care system to use this plasma for production of PDM. Therefore Iran national transfusion service has started a contract fractionation program for converting recovered plasma into PDM. This program not only provided essential PDM for Iran pharmaceutical market but also has created a direct saving of about 8.5 million Euros in 2011 for national health sector. In addition this program has drastically contributed to improvement of overall quality of working procedures and services provided by Iran national blood transfusion organization. PMID- 23351281 TI - Ontogenic expression of the amino acid transporter b(0,+)AT in suckling Huanjiang piglets: effect of intra-uterine growth restriction. AB - Intestinal amino acid (AA) transport is critical for the supply of AA to other tissues. Few studies regarding AA intestinal transport systems during the period from postnatal intense development of piglets until weaning are available. In the present study, we measured the intestinal expression of b(0,+)AT according to developmental stage using the suckling Huanjiang piglet model, and documented the effect of intra-uterine growth restriction (IUGR) on such expression using real time PCR and Western blot analysis. Suckling piglets that recovered after IUGR and those with normal body weights (NBW) were used after birth or at 7, 14 and 21 d of age. Blood samples were used for the measurement of plasma AA concentrations, and the jejunum was collected for the measurement of b(0,+)AT expression. In NBW piglets, b(0,+)AT expression was markedly decreased from days 0 to 21 (P< 0.01) and remained at a low level during all the suckling periods. In IUGR piglets, there was a marked decrease in b(0,+)AT expression at birth, which remained lower, when compared with NBW piglets, during the suckling period. These results coincided with decreased plasma arginine concentration at birth and decreased lysine concentration in 21-d-old piglets (P< 0.05). It is concluded that the high expression of b(0,+)AT at birth decreases during the suckling period, and that IUGR is associated with decreased expression of this apical AA transporter. The possible causal relationship between decreased b(0,+)AT expression and lower body weight of IUGR piglets in the suckling period is discussed. PMID- 23351282 TI - Commentary on: a review on delayed toxic effects of sulfur mustard in Iranian veterans. PMID- 23351279 TI - Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase. AB - OBJECTIVE: Sulfur mustard (SM) is one of the major potent chemical warfare and attractive weapons for terrorists. It has caused deaths to hundreds of thousands of victims in World War I and more recently during the Iran-Iraq war (1980-1988). It has ability to develop severe acute and chronic damage to the respiratory tract, eyes and skin. Understanding the acute and chronic biologic consequences of SM exposure may be quite essential for developing efficient prophylactic/therapeutic measures. One of the systems majorly affected by SM is the respiratory tract that numerous clinical studies have detailed processes of injury, diagnosis and treatments of lung. The low mortality rate has been contributed to high prevalence of victims and high lifetime morbidity burden. However, there are no curative modalities available in such patients. In this review, we collected and discussed the related articles on the preventive and therapeutic approaches to SM-induced respiratory injury and summarized what is currently known about the management and therapeutic strategies of acute and long term consequences of SM lung injuries. METHOD: This review was done by reviewing all papers found by searching following key words sulfur mustard; lung; chronic; acute; COPD; treatment. RESULTS: Mustard lung has an ongoing pathological process and is active disorder even years after exposure to SM. Different drug classes have been studied, nevertheless there are no curative modalities for mustard lung. CONCLUSION: Complementary studies on one hand regarding pharmacokinetic of drugs and molecular investigations are mandatory to obtain more effective treatments. PMID- 23351283 TI - Aortic valve replacement via right anterolateral thoracotomy in the case of a patient with extreme mediastinal right-shift following pneumonectomy. AB - We report on the case of a 68-year-old male patient with the history of right pneumonectomy due to bronchial carcinoma, who was referred for aortic valve replacement due to severe calcified aortic stenosis. Pre-operative chest X-ray and computed tomography (CT) revealed an unusually pronounced mediastinal shift to the right. Despite this unusual anatomy, we decided to perform surgery using the right anterolateral thoracotomy following thorough pre-operative planning using 3D-volume rendering of the CT data-set. This approach yielded excellent exposure of the aortic root and the ascending aorta, respectively. Following an uneventful operative and post-operative course the patient could be discharged on post-OP day 6.Although only occasionally described for aortic valve replacement a right anterolateral thoracotomy may represent a valuable surgical approach, particular in patients with unusual anatomy, e.g. a mediastinal right-shift. However, thorough pre-operative planning, i.e. using visualization and planning techniques such as 3D-volume rendering should be mandatory as it provides information crucial to facilitate surgical steps and thus, may help avoid severe surgical complications. PMID- 23351280 TI - Advances in toxicology and medical treatment of chemical warfare nerve agents. AB - Organophosphorous (OP) Nerve agents (NAs) are known as the deadliest chemical warfare agents. They are divided into two classes of G and V agents. Most of them are liquid at room temperature. NAs chemical structures and mechanisms of actions are similar to OP pesticides, but their toxicities are higher than these compounds. The main mechanism of action is irreversible inhibition of Acetyl Choline Esterase (AChE) resulting in accumulation of toxic levels of acetylcholine (ACh) at the synaptic junctions and thus induces muscarinic and nicotinic receptors stimulation. However, other mechanisms have recently been described. Central nervous system (CNS) depression particularly on respiratory and vasomotor centers may induce respiratory failure and cardiac arrest. Intermediate syndrome after NAs exposure is less common than OP pesticides poisoning. There are four approaches to detect exposure to NAs in biological samples: (I) AChE activity measurement, (II) Determination of hydrolysis products in plasma and urine, (III) Fluoride reactivation of phosphylated binding sites and (IV) Mass spectrometric determination of cholinesterase adducts. The clinical manifestations are similar to OP pesticides poisoning, but with more severity and fatalities. The management should be started as soon as possible. The victims should immediately be removed from the field and treatment is commenced with auto injector antidotes (atropine and oximes) such as MARK I kit. A 0.5% hypochlorite solution as well as novel products like M291 Resin kit, G117H and Phosphotriesterase isolated from soil bacterias, are now available for decontamination of NAs. Atropine and oximes are the well known antidotes that should be infused as clinically indicated. However, some new adjuvant and additional treatment such as magnesium sulfate, sodium bicarbonate, gacyclidine, benactyzine, tezampanel, hemoperfusion, antioxidants and bioscavengers have recently been used for OP NAs poisoning. PMID- 23351284 TI - Naturalistic assessment of everyday activities and prompting technologies in mild cognitive impairment. AB - Older adults with mild cognitive impairment (MCI) often have difficulty performing complex instrumental activities of daily living (IADLs), which are critical to independent living. In this study, amnestic multi-domain MCI (N = 29), amnestic single-domain MCI (N = 18), and healthy older participants (N = 47) completed eight scripted IADLs (e.g., cook oatmeal on the stove) in a smart apartment testbed. We developed and experimented with a graded hierarchy of technology-based prompts to investigate both the amount of prompting and type of prompts required to assist individuals with MCI in completing the activities. When task errors occurred, progressive levels of assistance were provided, starting with the lowest level needed to adjust performance. Results showed that the multi-domain MCI group made more errors and required more prompts than the single-domain MCI and healthy older adult groups. Similar to the other two groups, the multi-domain MCI group responded well to the indirect prompts and did not need a higher level of prompting to get back on track successfully with the tasks. Need for prompting assistance was best predicted by verbal memory abilities in multi-domain amnestic MCI. Participants across groups indicated that they perceived the prompting technology to be very helpful. PMID- 23351285 TI - Undifferentiated pleomorphic sarcoma with osteoclast-like giant cells of the female breast. AB - The authors describe a case of undifferentiated pleomorphic sarcoma of the breast occurring in a 50-year-old woman who presented with a palpable mass in her right breast. She first noticed the mass one month previously. Core needle biopsy showed connective tissue including epithelioid and spindle cells. The patient underwent total mastectomy without axillary lymph node dissection. Based on examination of the excised tumor, the initial pathologic diagnosis was atypical spindle-shaped and ovoid cells with uncertain malignant potential. Histological findings with immunomarkers led to the final diagnosis of undifferentiated pleomorphic sarcoma.This case highlights a rare and interesting variant of primary breast sarcoma and the important role of immunohistochemistry in defining histological type and differential diagnosis. Hence, undifferentiated pleomorphic sarcoma has been a diagnosis of exclusion performed through sampling and critical use of ancillary diagnostic techniques. PMID- 23351286 TI - Transforming the patient-physician relationship: the future of shared decision making. PMID- 23351287 TI - Discounting a surgical risk: data, understanding, and gist. PMID- 23351288 TI - When patients seem overly optimistic. PMID- 23351289 TI - The use of informed assent in withholding cardiopulmonary resuscitation in the ICU. PMID- 23351290 TI - Investing in each other--Balint groups and the patient-doctor relationship. PMID- 23351292 TI - Exploring physicians' attitudes about and behavior in communicating with patients. PMID- 23351293 TI - Do patient-accessible electronic medical records help or complicate shared decision making? PMID- 23351294 TI - Informed consent: what must a physician disclose to a patient? PMID- 23351295 TI - Vermont's single-payer health care system: an interview with Allan Ramsay. Interview by Claire K. Ankuda. PMID- 23351296 TI - The role of perception in quality communication. PMID- 23351297 TI - Informed consent for off-label use of prescription medications. PMID- 23351300 TI - Drug-drug co-crystals. PMID- 23351298 TI - Selective paternalism. PMID- 23351301 TI - Career choices for cardiology: cohort studies of UK medical graduates. AB - BACKGROUND: Cardiology is one of the most popular of the hospital medical specialties in the UK. It is also a highly competitive specialty in respect of the availability of higher specialty training posts. Our aims are to describe doctors' early intentions about seeking careers in cardiology, to report on when decisions about seeking a career in cardiology are made, to compare differences between men and women doctors in the choice of cardiology, and to compare early career choices with later specialty destinations. METHODS: Questionnaire surveys were sent to all UK medical graduates in selected qualification years from 1974 2009, at 1, 3, 5, 7 and 10 years after graduation. RESULTS: One year after graduation, the percentage of doctors specifying cardiology as their first choice of long-term career rose from the mid-1990s from 2.4% (1993 cohort) to 4.2% (2005 cohort) but then fell back to 2.7% (2009 cohort). Men were more likely to give cardiology as their first choice than women (eg 4.1% of men and 1.9% of women in the 2009 cohort). The percentage of doctors who gave cardiology as their first choice of career declined between years one and five after qualification: the fall was more marked for women. 34% of respondents who specified cardiology as their sole first choice of career one year post-graduation were later working in cardiology. 24% of doctors practising as cardiologists several years after qualification had given cardiology as their sole first choice in year one. The doctors' 'domestic circumstances' were a relatively unimportant influence on specialty choice for aspiring cardiologists, while 'enthusiasm/commitment', 'financial prospects', 'experiences of the job so far' and 'a particular teacher/department' were important. CONCLUSIONS: Cardiology grew as a first preference one year after graduation to 2005 but is now falling. It consistently attracts a higher percentage of men than women doctors. The correspondence between early choice and later destination was not particularly strong for cardiology, and was less strong than that for several other specialties. PMID- 23351302 TI - Cell-line-specific stimulation of tumor cell aggressiveness by wound healing factors - a central role for STAT3. AB - BACKGROUND: Local recurrence is a major factor affecting survival after treatment for head and neck squamous cell carcinoma (HNSCC). It is possible that the normal processes involved in wound healing after surgical removal of a primary tumor can boost the regrowth of residual cancer cells, thereby contributing to the recurrent growth. In this work, we collected human wound fluids and used them to investigate the effect of wound healing factors on HNSCC cell lines in vitro. METHODS: Wound fluids were collected from thyroidectomized patients diagnosed with benign disease and were included in assays of cell proliferation, migration, cell scattering, and invasion. The involvement of intracellular signaling pathways and membrane receptors were investigated by western blotting and the inclusion of specific inhibitors. RESULTS: One out of four cell lines was greatly stimulated in proliferation, migration, cell scattering, and invasion by the addition of wound fluid as compared with addition of fetal bovine or human serum. These effects were accompanied by a sharp increase in activation of signal transducer and activator of transcription 3 (STAT3). Inhibition of STAT3 activation abolished the wound fluid response, showing that STAT3 plays an important role in the wound healing response. Several of the observed phenotypic changes were epithelial-to-mesenchymal transition (EMT)-like, but the appropriate changes were not seen in any of the EMT markers investigated. The involvement of c-Met or epidermal growth factor receptor family members was excluded, while the interleukin-6 receptor was found to be partly responsible for the activation of STAT3. CONCLUSIONS: In conclusion, we found cell-line-specific effects of wound healing factors on HNSCC, setting the stage for therapy development and predictive opportunities. PMID- 23351303 TI - Monitoring and kinetic analysis of the molecular interactions by which a repressor protein, PhaR, binds to target DNAs and poly[(R)-3-hydroxybutyrate]. AB - The repressor protein PhaR, which is a component of poly[(R)-3-hydroxybutyrate] granules, functions as a repressor of the gene expression of the phasin PhaP and of PhaR itself. We used a quartz crystal microbalance to investigate the binding behavior by which PhaR in Ralstonia eutropha H16 targets DNAs and amorphous poly[(R)-3-hydroxybutyrate] thin films. Binding rate constants, dissociation rate constants, and dissociation constants of the binding of PhaR to DNA and to amorphous poly[(R)-3-hydroxybutyrate] suggested that PhaR bind to both in a similar manner. On the basis of the binding rate constant values, we proposed that the phaP gene would be derepressed in harmony with the ratio of the concentration of the target DNA to the concentration of amorphous poly[(R)-3 hydroxybutyrate] at the start of poly[(R)-3-hydroxybutyrate] synthesis in R. eutropha H16. PMID- 23351304 TI - 4-Aryl-4H-naphthopyrans derivatives: one-pot synthesis, evaluation of Src kinase inhibitory and anti-proliferative activities. AB - BACKGROUND: A series of 2-amino-4-aryl-4H-benzo[h or f]chromene-3-carbonitrile derivatives were synthesized and evaluated for inhibition of Src kinase and cell proliferation in breast carcinoma (BT-20) cell lines. METHODS: The one-pot, three component reaction of alpha or beta-naphthol, malonitrile and an aromatic aldehyde in the presence of diammonium hydrogen phosphate was afforded the corresponding 2-amino-4-aryl-4H-benzo[h or f]chromene-3-carbonitrile derivatives, All target compounds were evaluated for inhibition of Src kinase and cell proliferation in breast carcinoma (BT-20) cell lines. RESULTS: Among all tested compounds, unsubstituted 4-phenyl analog 4a showed Src kinas inhibitory effect with IC50 value of 28.1 MUM and was the most potent compound in this series. In general, the compounds were moderately active against BT-20. 3-Nitro-phenyl 4e and 3-pyridinyl 4h derivatives inhibited the cell proliferation of BT-20 cells by 33% and 31.5%, respectively, and found to be more potent compared to doxorubicin (25% inhibition of cell growth). CONCLUSION: The data indicate that 4-aryl-4H naphthopyrans scaffold has the potential to be optimized further for designing more potent Src kinase inhibitors and/or anticancer lead compounds. PMID- 23351305 TI - Silence, activate, poise and switch! Mechanisms of antigenic variation in Plasmodium falciparum. AB - Phenotypic variation in genetically identical malaria parasites is an emerging topic. Although antigenic variation is only part of a more global parasite strategy to create adaptation through epigenetically controlled transcriptional variability, it is the central mechanism enabling immune evasion and promoting pathogenesis. The var gene family is the best-studied example in a wide range of clonally variant gene families in Plasmodium falciparum. It is unique in its strict selection of a single member for activation, a process termed monoallelic expression. The conceptual advances that have emerged from studying var genes show striking common epigenetic features with many other clonally variant gene families or even single-copy genes that show a variegated expression in parasite populations. However, major mechanistic questions, such as the existence of a potential expression site and the identity of transcription factors or genetic elements driving singular gene choice, are still unanswered. In this review we discuss the recent findings in the molecular processes essential for clonal variation, namely silencing, activation, poising and switching. Integrating findings about all clonally variant gene families and other mutually exclusive expression systems will hopefully drive mechanistic understanding of antigenic variation. PMID- 23351306 TI - A new strategy based on pharmacophore-based virtual screening in adenosine deaminase inhibitors detection and in-vitro study. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: Adenosine deaminase (ADA) inhibition not only may be applied for the treatment of ischemic injury, hypertension, lymphomas and leukaemia, but also they have been considered as anti- inflammatory drugs. On the other hand according to literatures, ADA inhibitors without a nucleoside framework would improve pharmacokinetics and decrease toxicity. Hence we have carried out a rational pharmacophore design for non-nucleoside inhibitors filtration. METHODS: A merged pharmacophore model based on the most potent non nucleoside inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and natural products were generated and applied for compounds filtration. The effects of filtrated compounds based on pharmacophore and docking studies investigated on ADA by UV and Fluorescence spectroscopy techniques. RESULTS: Extracted compounds were find efficiently inhibit ADA, and the most potent (2) shows an inhibition constant equal to 20 MUM. Besides, Fluorescence spectroscopy studies revealed that enzyme 3D structure bear further change in lower concentrations of compound 2. CONCLUSION: 3 non-nucleoside inhibitors for ADA are presented. According to obtained results from UV and fluorescence spectroscopy, such interesting pharmacophore template with multiple approaches will help us to extract or design compound with desired properties. PMID- 23351307 TI - Primary cilia and aberrant cell signaling in epithelial ovarian cancer. AB - BACKGROUND: Ovarian cancer is the fourth leading cause of cancer-related deaths among women in Denmark, largely due to the advanced stage at diagnosis in most patients. Approximately 90% of ovarian cancers originate from the single-layered ovarian surface epithelium (OSE). Defects in the primary cilium, a solitary sensory organelle in most cells types including OSE, were recently implicated in tumorigenesis, mainly due to deregulation of ciliary signaling pathways such as Hedgehog (Hh) signaling. However, a possible link between primary cilia and epithelial ovarian cancer has not previously been investigated. METHODS: The presence of primary cilia was analyzed in sections of fixed human ovarian tissue as well as in cultures of normal human ovarian surface epithelium (OSE) cells and two human OSE-derived cancer cell lines. We also used immunofluorescence microscopy, western blotting, RT-PCR and siRNA to investigate ciliary signaling pathways in these cells. RESULTS: We show that ovarian cancer cells display significantly reduced numbers of primary cilia. The reduction in ciliation frequency in these cells was not due to a failure to enter growth arrest, and correlated with persistent centrosomal localization of aurora A kinase (AURA). Further, we demonstrate that ovarian cancer cells have deregulated Hh signaling and platelet-derived growth factor receptor alpha (PDGFRalpha) expression and that promotion of ciliary formation/stability by AURA siRNA depletion decreases Hh signaling in ovarian cancer cells. Lastly, we show that the tumor suppressor protein and negative regulator of AURA, checkpoint with forkhead-associated and ring finger domains (CHFR), localizes to the centrosome/primary cilium axis. CONCLUSIONS: Our results suggest that primary cilia play a role in maintaining OSE homeostasis and that the low frequency of primary cilia in cancer OSE cells may result in part from over-expression of AURA, leading to aberrant Hh signaling and ovarian tumorigenesis. PMID- 23351308 TI - Changes in gram negative microorganisms' resistance pattern during 4 years period in a referral teaching hospital; a surveillance study. AB - BACKGROUND AND PURPOSE: Surveillance studies evaluating antimicrobial susceptibilities are of great value in preventing the spread of resistant pathogens by elucidating the trend of resistance in commonly used antibiotics and as a consequence providing information for prescribing the most appropriate agent. This study is a longitudinal antimicrobial resistance surveillance study designed to evaluate the trend in antimicrobial resistance to gram negative microorganisms from 2007 to 2010. METHOD: During a four-year period (2007-2010) isolates derived from all patients admitted to infectious diseases ward of Imam Khomeini Hospital, the major referral center for infectious disease in Iran with the highest admission rates, were evaluated. Based on disk diffusion method and zone of inhibition size, the microorganism was regarded as to be sensitive, resistant or has intermediate susceptibility to the antimicrobial agents. RESULTS: The widest spread Gram-negative microorganism in all of isolates taken together in our study was E.coli (30%) followed by Stenotrophomonas maltophilia in 28.6% and Enterobacter spp. in 11.9%, respectively. The susceptibility to amikacin, imipenem, piperacillin/tazobactam, and nitrofurantoin was equal or above 50% for all microorganisms over four years. However, the susceptibility to ampicillin, ampicillin/sulbactam, cefotaxim, and ceftriaxone was less than 50% in derived isolates during the study period. CONCLUSION: In conclusion, the finding of the present study revealed that resistance rate to common antimicrobial agents in Iran is growing and isolates were susceptible mostly to broad-spectrum antibiotics including imipenem and piperacillin/tazobactam. PMID- 23351309 TI - Co-administration of methyl donors along with guanidinoacetic acid reduces the incidence of hyperhomocysteinaemia compared with guanidinoacetic acid administration alone. AB - Guanidinoacetic acid (GAA) is the natural biosynthetic precursor of creatine, in a metabolic reaction that requires only a methyl group transfer. The use of GAA as a food additive for restoring creatine load in human tissues is rather unexplored and data on efficacy and safety are limited. In particular, an increase in serum homocysteine after GAA administration can be regarded as critical and should be prevented. The present study evaluated the effects of orally administered GAA with and without methyl group donors on serum and urine creatine concentrations, and the occurrence of adverse events during an intervention in healthy human subjects. A total of twenty male and female volunteers were randomised in a double-blind design to receive either GAA (2.4 g/d) or GAA with methyl donors (2.4 g/d of GAA and 1.6 g/d of betaine HCl, 5 MUg/d of vitamin B12, 10 mg/d of vitamin B6 and 600 MUg/d of folic acid) by oral administration for 8 weeks. Serum and urine creatine increased significantly from before to after administration in both groups (P< 0.001). The proportion of participants who reported minor adverse events was 33.3 % in the GAA group, and 10.0 % in the GAA with methyl donors group (P= 0.30). Hyperhomocysteinaemia was found in 55.6 % of participants supplemented with GAA, while no participant experienced hyperhomocysteinaemia in the group supplemented with GAA and methyl donors (P= 0.01). In summary, both interventions strongly influenced creatine metabolism, resulting in a significant increase in fasting serum creatine. The concomitant supplementation of methyl donors along with GAA largely precluded the elevation of serum homocysteine caused by GAA administration alone. PMID- 23351310 TI - Midterm results after treatment of gram-positive deep sternal wound infections with daptomycin for cardiac surgery patients. AB - Daptomycin in combination with surgical therapy has shown to be effective for treatment of deep sternal wound infection in cardiac surgery. However, till now midterm results in terms of re-infection or re-operation in patients who were successfully treated with daptomycin for gram-positive deep sternal wound infection are not published. Herein, we present midterm results in patients treated successfully with daptomycin after cardiac surgery. PMID- 23351311 TI - Genistein abrogates G2 arrest induced by curcumin in p53 deficient T47D cells. AB - BACKGROUND: The high cost and low level of cancer survival urge the finding of new drugs having better mechanisms. There is a high trend of patients to be "back to nature" and use natural products as an alternative way to cure cancer. The fact is that some of available anticancer drugs are originated from plants, such as taxane, vincristine, vinblastine, pacitaxel. Curcumin (diferuloylmethane), a dietary pigment present in Curcuma longa rizhome is reported to induce cell cycle arrest in some cell lines. Other study reported that genistein isolated from Glycine max seed inhibited phosphorylation of cdk1, gene involved during G2/M transition and thus could function as G2 checkpoint abrogator. The inhibition of cdk1 phosphorylation is one of alternative strategy which could selectively kill cancer cells and potentially be combined with DNA damaging agent such as curcumin. METHODS: T47D cell line was treated with different concentrations of curcumin and genistein, alone or in combination; added together or with interval time. Flow Cytometry and MTT assay were used to evaluate cell cycle distribution and viability, respectively. The presence of apoptotic cells was determined using acridine orange-ethidium bromide staining. RESULTS: In this study curcumin induced G2 arrest on p53 deficient T47D cells at the concentration of 10 MUM. Increasing concentration up to 30 MUM increased the number of cell death. Whilst genistein alone at low concentration (<=10 MUM) induced cell proliferation, addition of genistein (20 MUM) 16 h after curcumin resulted in more cell death (89%), 34% higher than that administered at the same time (56%). The combination treatment resulted in apoptotic cell death. Combining curcumin with high dose of genistein (50 MUM) induced necrotic cells. CONCLUSIONS: Genistein increased the death of curcumin treated T47D cells. Appropriate timing of administration and concentration of genistein determine the outcome of treatment and this method could potentially be developed as an alternative strategy for treatment of p53 defective cancer cells. PMID- 23351312 TI - Getting personal: the promises and potential pitfalls of personalized medicine. PMID- 23351313 TI - Genetic testing: clinical and personal utility. PMID- 23351314 TI - Informed consent for biobank-dependent research. PMID- 23351315 TI - Genetic profiling of medical students. PMID- 23351316 TI - Genetic and genomic competency in medical practice. PMID- 23351318 TI - Personalizing medicine: beyond race. PMID- 23351319 TI - Advances in clinical genomics. PMID- 23351320 TI - Genetic diseases and the duty to disclose. PMID- 23351321 TI - Regulation and the fate of personalized medicine. PMID- 23351322 TI - Certificates of confidentiality and the Marshfield Clinic's Personalized Medicine Research Project. PMID- 23351323 TI - Will personalized medicine challenge or reify categories of race and ethnicity? PMID- 23351326 TI - Overexpression of aldo-keto-reductase in azole-resistant clinical isolates of Candida glabrata determined by cDNA-AFLP. AB - BACKGROUND: Candida glabrata causes significant medical problems in immunocompromised patients. Many strains of this yeast are intrinsically resistant to azole antifungal agents, and treatment is problematic, leading to high morbidity and mortality rates in immunosuppressed individuals. The primary goal of this study was to investigate the genes involved in the drug resistance of clinical isolates of C. glabrata. METHODS: The clinical isolates of C. glabrata were collected in an epidemiological survey of candidal infection in immunocompromised patients and consisted of four fluconazole and itraconazole resistant isolates, two fluconazole and itraconazole sensitive isolates, and C. glabrata CBS 138 as reference strain. Antifungal susceptibility patterns of the organisms were determined beforehand by the Clinical and Laboratory Standards Institute (CLSI). The potential gene(s) implicated in antifungal resistance were investigated using complementary DNA- Amplified Fragment Length Polymorphism (cDNA-AFLP). Semi-quantitative RT-PCR was carried out to evaluate the expression of gene(s) in resistant isolates as compared to sensitive and reference strains. RESULTS AND CONCLUSIONS: The aldo-keto-reductase superfamily (AKR gene) was upregulated in the resistant clinical isolates as assessed by cDNA-AFLP. Semi quantitative RT-PCR revealed AKR mRNA expression approximately twice that seen in the sensitive isolates. Overexpression of the AKR gene was associated with increased fluconazole and itraconazole resistance in C. glabrata. The data suggest that upregulation of the AKR gene might give a new insight into the mechanism of azole resistance. PMID- 23351327 TI - Compliance with clinical practice guidelines for breast cancer treatment: a population-based study of quality-of-care indicators in Italy. AB - BACKGROUND: It has been documented that variations exist in breast cancer treatment despite wide dissemination of clinical practice guidelines. The aim of this population-based study was to evaluate the impact of regional guidelines (Piedmont guidelines, PGL) for breast cancer diagnosis and treatment on quality of-care indicators in the Northwestern Italian region of Piedmont. METHODS: We included two samples of women aged 50-69 years with incident breast cancer treated in Piedmont before and after the introduction of PGL: 600 in 2002 (pre PGL) and 621 in 2004 (post-PGL). Patients were randomly selected among all incident breast cancer cases identified through the hospital discharge records database. We extracted clinical data on breast cancer cases from medical charts and ascertained vital status through linkage with town offices. We assessed compliance with 14 quality-of-care indicators from PGL recommendations, before and after their introduction in clinical practice. RESULTS: Among patients with invasive lesions, 77.1% (N = 368) and 77.5% (N = 383) in the pre-PGL and post-PGL groups, respectively, received breast conservative surgery (BCS) as a first-line treatment. Following BCS, 87.7% received radiotherapy in 2002, compared to 87.9% in 2004. Of all patients at medium-to-high risk of distant metastasis, 65.5% (N = 268) and 63.6% (N = 252) received chemotherapy in 2002 and in 2004, respectively. Among the 117 patients with invasive lesions and negative estrogen receptor status in 2002, hormonal therapy was prescribed in 23 of them (19.6%). The incorrect prescription of hormonal therapy decreased to 10.8% (N = 10) among the 92 estrogen receptor-negative patients in 2004 (p < 0.01).Compliance with PGL recommendations was already high in the pre-PGL group, although some quality-of care indicators did not reach the standard. In the pre/post analysis, 8 out of 14 quality-of-care indicators showed an improvement from 2002 to 2004, but only 4 out of 14 reached statistical significance. We did not find any change in the risk of mortality in the post-PGL versus the pre-PGL group (adjusted hazard ratio 0.94, 95%CI 0.56-1.56). CONCLUSIONS: These results highlight the need to continue to improve breast cancer care and to measure adherence to PGL. PMID- 23351328 TI - Synthesis, in vitro antifungal evaluation and in silico study of 3-azolyl-4 chromanone phenylhydrazones. AB - BACKGROUND: The currently available antifungal drugs suffer from toxicity, greatest potential drug interactions with other drugs, insufficient pharmacokinetics properties, and development of resistance. Thus, development of new antifungal agents with optimum pharmacokinetics and less toxicity is urgent task. In the search for new azole antifungals, we have been previously described azolylchromanone oxime ethers as rigid analogs of oxiconazole. In continuation of our work, we incorporated phenylhydrazone moiety instead of oxime ether fragment in azolylchromanone derivatives. METHODS: The 3-azolyl-4-chromanone phenylhydrazones were synthesized via ring closure of 2-azolyl-2' hydroxyacetophenones and subsequent reaction with phenylhydrazine. The biological activity of title compounds was evaluated against different pathogenic fungi including Candida albicans, Saccharomyces cerevisiae, Aspergillus niger, and Microsporum gypseum. Docking study, in silico toxicity risks and drug-likeness predictions were used to better define of title compounds as antifungal agents. RESULTS: The in vitro antifungal activity of compounds based on MIC values revealed that all compounds showed good antifungal activity against C. albicans, S. cerevisiae and M. gypseum at concentrations less than 16 MUg/mL. Among the test compounds, 2-methyl-3-imidazolyl derivative 3b showed the highest values of drug-likeness and drug-score. CONCLUSION: The 3-azolyl-4-chromanone phenylhydrazones considered as analogs of 3-azolyl-4-chromanone oxime ethers basically designed as antifungal agents. The antifungal activity of title compounds was comparable to that of standard drug fluconazole. The drug-likeness data of synthesized compounds make them promising leads for future development of antifungal agents. PMID- 23351329 TI - Daily physical activity predicts degree of insulin resistance: a cross-sectional observational study using the 2003-2004 National Health and Nutrition Examination Survey. AB - BACKGROUND: This study examined the independent association of objectively measured physical activity on insulin resistance while controlling for confounding variables including: cardiorespiratory fitness, adiposity, sex, age, and smoking status. METHODS: Data were obtained from National Health and Nutrition Examination Survey 2003-2004, a cross-sectional observational study conducted by the National Center for Health Statistics of the Centers for Disease Control that uses a stratified, multistage probability design to obtain a nationally representative sample of the U.S. population. The analysis included 402 healthy U.S. adults with valid accelerometer, cardiorespiratory fitness, and fasting plasma glucose and insulin concentrations. After controlling for relevant confounding variables we performed a multiple linear regression to predict homeostatic model of insulin resistance (HOMA-IR) based on average daily minutes of moderate-to-vigorous physical activity (MVPA). RESULTS: In our bivariate models, MVPA, cardiorespiratory fitness and body fat percentage were all significantly correlated with log HOMA-IR. In the complete model including MVPA and relevant confounding variables, there were strong and significant associations between MVPA and log HOMA-IR (beta= -0.1607, P=0.004). In contrast the association between cardiorespiratory fitness and log HOMA-IR was not significant. CONCLUSION: When using an objective measure of physical activity the amount of time engaged in daily physical activity was associated with lower insulin resistance, whereas higher cardiorespiratory fitness was not. These results suggest that the amount of time engaged in physical activity may be an important determinant for improving glucose metabolism. PMID- 23351330 TI - Impairments in social cognition following severe traumatic brain injury. AB - Severe traumatic brain injury (TBI) leads to physical, neuropsychological, and emotional deficits that interfere with the individual's capacity to return to his or her former lifestyle. This review focuses on social cognition, that is, the capacity to attend to, recognize and interpret interpersonal cues that guide social behavior. Social cognition entails ''hot'' processes, that is, emotion perception and emotional empathy and ''cold'' processes, that is, the ability to infer the beliefs, feelings, and intentions of others (theory of mind: ToM) to see their point of view (cognitive empathy) and what they mean when communicating (pragmatic inference). This review critically examines research attesting to deficits in each of these domains and also examines evidence for theorized mechanisms including specific neural networks, the role of simulation, and non social cognition. Current research is hampered by small, heterogeneous samples and the inherent complexity of TBI pathology. Nevertheless, there is evidence that facets of social cognition are impaired in this population. New assessment tools to measure social cognition following TBI are required that predict everyday social functioning. In addition, research into remediation needs to be guided by the growing empirical base for understanding social cognition that may yet reveal how deficits dissociate following TBI. PMID- 23351334 TI - Drying of a plasmid containing formulation: chitosan as a protecting agent. AB - BACKGROUND: The purpose of the study. Along with research on development of more efficient gene delivery systems, it is necessary to search on stabilization processes to extend their active life span. Chitosan is a nontoxic, biocompatible and available gene delivery carrier. The aim of this study was to assess the ability of this polymer to preserve transfection efficiency during spray-drying and a modified freeze-drying process in the presence of commonly used excipients. METHOD: Molecular weight of chitosan was reduced by a chemical reaction and achieved low molecular weight chitosan (LMWC) was complexed with pDNA. Obtained nanocomplex suspensions were diluted by solutions of lactose and leucine, and these formulations were spray dried or freeze dried using a modified technique. Size, polydispersity index, zeta potential, intensity of supercoiled DNA band on gel electrophoresis, and transfection efficiency of reconstituted nanocomplexes were compared with freshly prepared ones. RESULTS AND MAJOR CONCLUSION: Size distribution profiles of both freeze dried, and 13 out of 16 spray-dried nanocomplexes remained identical to freshly prepared ones. LMWC protected up to 100% of supercoiled structure of pDNA in both processes, although DNA degradation was higher in spray-drying of the nanocomplexes prepared with low N/P ratios. Both techniques preserved transfection efficiency similarly even in lower N/P ratios, where supercoiled DNA content of spray dried formulations was lower than freeze-dried ones. Leucine did not show a significant effect on properties of the processed nanocomplexes. It can be concluded that LMWC can protect DNA structure and transfection efficiency in both processes even in the presence of leucine. PMID- 23351331 TI - Prognostic significance of the expression of GFRalpha1, GFRalpha3 and syndecan-3, proteins binding ARTEMIN, in mammary carcinoma. AB - BACKGROUND: Artemin (ARTN) has been implicated in promoting oncogenicity, tumor growth and invasiveness in diverse human malignancies. However, the clinical and prognostic significance of upstream ligand binding components, potentially mediating ARTN oncogenicity, largely remain to be determined. METHODS: We determined the mRNA and protein expression of three proteins demonstrated to bind ARTN, namely GFRalpha1, GFRalpha3 and syndecan-3 (SDC3), in benign breast disease and mammary carcinoma by in situ hybridization and immunohistochemistry, respectively. Their prognostic significance combined with ARTN expression was also investigated in mammary carcinoma. RESULTS: The expression of GFRalpha1 and GFRalpha3, but not SDC3, was significantly increased in mammary carcinoma and positively associated with tumor lymph node metastases, higher clinical stage and HER-2 positivity. Moreover, both GFRalpha1 and GFRalpha3 expression were significantly associated with survival outcome of patients with mammary carcinoma by univariate and multivariate analyses, whereas expression of SDC3 was not. Co expression of ARTN with either GFRalpha1 or GFRalpha3, but not SDC3, produced synergistic increases in the odds ratio for both relapse-free and overall survival in patients with mammary carcinoma. Furthermore, significant association of GFRalpha1 and GFRalpha3 expression with survival outcome observed herein were restricted to ER negative or HER-2 negative mammary carcinoma. CONCLUSIONS: The expression of GFRalpha1 and/or GFRalpha3, especially when combined with ARTN expression, may be useful predictors of disease progression and outcome in specific subtypes of mammary carcinoma. PMID- 23351335 TI - IgG4-related disease: why high IgG4 and fibrosis? AB - The hallmarks of IgG4-related disease (IgG4-RD) are lymphoplasmacytic tissue infiltration with a predominance of IgG4-positive plasma cells, accompanied by fibrosis, obliterative phlebitis, dacryoadenitis, and elevated levels of IgG4. In a recent issue of Arthritis Research & Therapy, Tsuboi and colleagues demonstrated that regulatory T (Treg) cell-and T helper 2 (Th2) cell-derived cytokines contribute to the pathogenesis of Mikulicz's disease, an activation pathway that appears to be common for IgG4-RD. Additional organ-specific factors may account for the different organ involvement of IgG4-RD. PMID- 23351336 TI - Paramecium BBS genes are key to presence of channels in Cilia. AB - BACKGROUND: Changes in genes coding for ciliary proteins contribute to complex human syndromes called ciliopathies, such as Bardet-Biedl Syndrome (BBS). We used the model organism Paramecium to focus on ciliary ion channels that affect the beat form and sensory function of motile cilia and evaluate the effects of perturbing BBS proteins on these channels. METHODS: We used immunoprecipitations and mass spectrometry to explore whether Paramecium proteins interact as in mammalian cells. We used RNA interference (RNAi) and swimming behavior assays to examine the effects of BBS depletion on ciliary ion channels that control ciliary beating. Combining RNA interference and epitope tagging, we examined the effects of BBS depletion of BBS 7, 8 and 9 on the location of three channels and a chemoreceptor in cilia. RESULTS: We found 10 orthologs of 8 BBS genes in P. tetraurelia. BBS1, 2, 4, 5, 7, 8 and 9 co-immunoprecipitate. While RNAi reduction of BBS 7 and 9 gene products caused loss and shortening of cilia, RNAi for all BBS genes except BBS2 affected patterns of ciliary motility that are governed by ciliary ion channels. Swimming behavior assays pointed to loss of ciliary K+ channel function. Combining RNAi and epitope tagged ciliary proteins we demonstrated that a calcium activated K+ channel was no longer located in the cilia upon depletion of BBS 7, 8 or 9, consistent with the cells' swimming behavior. The TRPP channel PKD2 was also lost from the cilia. In contrast, the ciliary voltage gated calcium channel was unaffected by BBS depletion, consistent with behavioral assays. The ciliary location of a chemoreceptor for folate was similarly unperturbed by the depletion of BBS 7, 8 or 9. CONCLUSIONS: The co immunoprecipitation of BBS 1,2,4,5,7,8, and 9 suggests a complex of BBS proteins. RNAi for BBS 7, 8 or 9 gene products causes the selective loss of K+ and PKD2 channels from the cilia while the critical voltage gated calcium channel and a peripheral receptor protein remain undisturbed. These channels govern ciliary beating and sensory function. Importantly, in P. tetraurelia we can combine studies of ciliopathy protein function with behavior and location and control of ciliary channels. PMID- 23351337 TI - The effect of cassia fistula emulsion on pediatric functional constipation in comparison with mineral oil: a randomized, clinical trial. AB - BACKGROUND: The prevalence of Pediatric Functional Constipation (FC) has been reported between 0.7% to 29.6%. This study was conducted to compare the laxative effect of cassia fistula emulsion (CFE) with mineral oil (MO) on FC. Cassia fistula is named in Traditional Iranian Medicine (TIM) as "Folus". MATERIALS AND METHODS: A randomized clinical trial was carried on 81 children (age range: 4-13 years) with FC, according to Rome III criteria in Amirkola Children's Hospital, Babol, Iran. They received CFE or MO randomly for three weeks. CFE was produced according to the order of TIM references. Children were counted as improved when they exited from Rome III criteria of FC. Frequency of defecation, fecal incontinence, retentive posturing, severity of pain, consistency of stool and anal leakage of oily material were compared between the two groups and with baselines. An intent-to-treat analysis was used. Safety of drugs was assessed with the evaluation of clinical adverse effects. RESULTS: 41 children were assigned randomly to receive CFE and 40 children received MO. After three weeks of medication, 84% of children in CFE group and 50% in MO group (p = 0.002) exited from the criteria of FC, so called improved. All measurable criteria improved in both groups. The frequency of defecation in CFE group improved from 1.7 per week (before the study) to 10.6 per week (at the third week) while this parameter differed in MO group from 2 to 6.1 (p < 0.001). The severity of pain during defecation and consistency of stool improved significantly better in CFE group than MO group (p < 0.05), but there were not any significant differences between the two groups in fecal incontinence and retentive posturing. Anal leakage of oily material occurred as an important complication in MO group while the children in CFE group did not complaint it. Drug's compliances were not significantly different in the two groups. CFE and MO did not cause clinically significant side effects. CONCLUSIONS: CFE was most effective than MO in the 3 week treatment of children with FC. PMID- 23351339 TI - New anti-neoplastic drug test using in vitro model: what to be concern? PMID- 23351338 TI - Oral green tea catechin metabolites are incorporated into human skin and protect against UV radiation-induced cutaneous inflammation in association with reduced production of pro-inflammatory eicosanoid 12-hydroxyeicosatetraenoic acid. AB - Green tea catechins (GTC) reduce UV radiation (UVR)-induced inflammation in experimental models, but human studies are scarce and their cutaneous bioavailability and mechanism of photoprotection are unknown. We aimed to examine oral GTC cutaneous uptake, ability to protect human skin against erythema induced by a UVR dose range and impact on potent cyclo-oxygenase- and lipoxygenase produced mediators of UVR inflammation, PGE2 and 12-hydroxyeicosatetraenoic acid (12-HETE), respectively. In an open oral intervention study, sixteen healthy human subjects (phototype I/II) were given low-dose GTC (540 mg) with vitamin C (50 mg) daily for 12 weeks. Pre- and post-supplementation, the buttock skin was exposed to UVR and the resultant erythema quantified. Skin blister fluid and biopsies were taken from the unexposed and the UVR-exposed skin 24 h after a pro inflammatory UVR challenge (three minimal erythema doses). Urine, skin tissue and fluid were analysed for catechin content and skin fluid for PGE2 and 12-HETE by liquid chromatography coupled to tandem MS. A total of fourteen completing subjects were supplement compliant (twelve female, median 42.5 years, range 29-59 years). Benzoic acid levels were increased in skin fluid post-supplementation (P= 0.03), and methylated gallic acid and several intact catechins and hydroxyphenyl valerolactones were detected in the skin tissue and fluid. AUC analysis for UVR erythema revealed reduced response post-GTC (P= 0.037). Pre-supplementation, PGE2 and 12-HETE were UVR induced (P= 0.003, 0.0001). After GTC, UVR-induced 12-HETE reduced from mean 64 (sd 42) to 41 (sd 32) pg/MUl (P= 0.01), while PGE2 was unaltered. Thus, GTC intake results in the incorporation of catechin metabolites into human skin associated with abrogated UVR-induced 12-HETE; this may contribute to protection against sunburn inflammation and potentially longer-term UVR-mediated damage. PMID- 23351340 TI - The release behavior and kinetic evaluation of tramadol HCl from chemically cross linked Ter polymeric hydrogels. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: Hydrogels, being stimuli responsive are considered to be effective for targeted and sustained drug delivery. The main purpose for this work was to study the release behavior and kinetic evaluation of Tramadol HCl from chemically cross linked ter polymeric hydrogels. METHODS: Ter polymers of methacrylate, vinyl acetate and acrylic acid cross linked with ethylene glycol dimethacrylate (EGDMA) were prepared by free radical polymerization. The drug release rates, dynamic swelling behavior and pH sensitivity of hydrogels ranging in composition from 1-10 mol% EGDMA were studied. Tramadol HCl was used as model drug substance. The release behavior was investigated at pH 8 where all formulations exhibited non-Fickian diffusion mechanism. RESULTS AND MAJOR CONCLUSION: Absorbency was found to be more than 99% indicating good drug loading capability of these hydrogels towards the selected drug substance. Formulations designed with increasing amounts of EGDMA had a decreased equilibrium media content as well as media penetrating velocity and thus exhibited a slower drug release rate. Fitting of release data to different kinetic models indicate that the kinetic order shifts from the first to zero order as the concentration of drug was increased in the medium, showing gradual independency of drug release towards its concentration. Formulations with low drug content showed best fitness with Higuchi model whereas those with higher concentration of drug followed Hixson-Crowell model with better correlation values indicating that the drug release from these formulations depends more on change in surface area and diameter of tablets than that on concentration of the drug. Release exponent (n) derived from Korse-Meyer Peppas equation implied that the release of Tramadol HCl from these formulations was generally non-Fickian (n > 0.5 > 1) showing swelling controlled mechanism. The mechanical strength and controlled release capability of the systems indicate that these co-polymeric hydrogels have a great potential to be used as colon drug delivery device through oral administration. PMID- 23351341 TI - The effect of 12 weeks Anethum graveolens (dill) on metabolic markers in patients with metabolic syndrome; a randomized double blind controlled trial. AB - BACKGROUND: The clustering of metabolic abnormalities defined as metabolic syndrome is now both a public health and a clinical problem .While interest in herbal medicine has greatly increased, lack of human evidence to support efficacies shown in animals does exist. This clinical trial study designed to investigate whether herbal medicine, Anethum graveolens (dill) extract, could improve metabolic components in patients with metabolic syndrome. METHODS: A double-blind, randomized, placebo-controlled trial using a parallel design was conducted. 24 subjects who had metabolic syndrome diagnostic criteria (update of ATP III) were randomly assigned to either dill extract (n = 12) or placebo (n = 12) for 3 months. RESULTS: Across lipid component of metabolic syndrome, no significant differences in triglyceride (TG) concentration and high density lipoprotein cholesterol were seen between the two groups. However TG improved significantly from baseline (257.0 vs. 201.5p = 0.01) with dill treatment but such a significant effect was not observed in placebo group. Moreover, no significant differences in waist circumference, blood pressure and fasting blood sugar were seen between two groups after 3 months follow up period. CONCLUSION: In this small clinical trial in patients with metabolic syndrome, 12 weeks of dill extract treatment had a beneficial effect in terms of reducing TG from baseline. However dill treatment was not associated with a significant improvement in metabolic syndrome related markers compared to control group. Larger studies might be required to prove the efficacy and safety of long-term administration of dill to resolve metabolic syndrome components. PMID- 23351343 TI - Induction of G1 cell cycle arrest and cyclin D1 down-regulation in response to pericarp extract of Baneh in human breast cancer T47D cells. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: Natural products from plants have an important role in the development and production of new drugs mainly for cancer therapy. More recently, we have shown that the pericarp methanolic extract of Pistacia atlantica sub kurdica (with local name of Baneh) as a rich source of active biological components with high antioxidant and radical scavenging activities, has ability to cease proliferation and induce apoptosis in T47D human breast cancer cells. The present study aimed to clarify whether Baneh extract able to alter cell cycle progression of T47D cells or not. METHODS: In order to study the possible effect of Baneh extract on cell cycle of T47D cells, we evaluated cell cycle distribution and its regulatory proteins by flow cytometry and western blot analysis respectively. RESULTS: Baneh extract induced G0/G1 cell cycle arrest in conjunction with a marked decrease in expression of cyclin D1 and cdk4 that was strongly dependent on time of exposure. In parallel, Dox-treated T47D cells in early time points were accumulated on S phase, but after 48 h cell cycle progression was inhibited on G2/M. Dox promoted striking accumulation of cyclin B1 rapidly and enhanced cyclin A abundance. CONCLUSION: Taken together, our results establish that the antitumor activity of the pericarp extract of Baneh partly is mediated via cell cycle arrest and downregulation of cyclin D1 and cdk4 expression. These findings warrant further evaluation regarding the mechanism(s) of action of this promising anticancer agent. PMID- 23351344 TI - Defining the limits of confidentiality in the patient-physician relationship. PMID- 23351342 TI - Mitochondrial quality, dynamics and functional capacity in Parkinson's disease cybrid cell lines selected for Lewy body expression. AB - BACKGROUND: Lewy bodies (LB) are a neuropathological hallmark of Parkinson's disease (PD) and other synucleinopathies. The role their formation plays in disease pathogenesis is not well understood, in part because studies of LB have been limited to examination of post-mortem tissue. LB formation may be detrimental to neuronal survival or merely an adaptive response to other ongoing pathological processes. In a human cytoplasmic hybrid (cybrid) neural cell model that expresses mitochondrial DNA from PD patients, we observed spontaneous formation of intracellular protein aggregates ("cybrid LB" or CLB) that replicate morphological and biochemical properties of native, cortical LB. We studied mitochondrial morphology, bioenergetics and biogenesis signaling by creating stable sub-clones of three PD cybrid cell lines derived from cells expressing CLB. RESULTS: Cloning based on CLB expression had a differential effect on mitochondrial morphology, movement and oxygen utilization in each of three sub cloned lines, but no long-term change in CLB expression. In one line (PD63(CLB)), mitochondrial function declined compared to the original PD cybrid line (PD63(Orig)) due to low levels of mtDNA in nucleoids. In another cell line (PD61(Orig)), the reverse was true, and cellular and mitochondrial function improved after sub-cloning for CLB expression (PD61(CLB)). In the third cell line (PD67(Orig)), there was no change in function after selection for CLB expression (PD67(CLB)). CONCLUSIONS: Expression of mitochondrial DNA derived from PD patients in cybrid cell lines induced the spontaneous formation of CLB. The creation of three sub-cloned cybrid lines from cells expressing CLB resulted in differential phenotypic changes in mitochondrial and cellular function. These changes were driven by the expression of patient derived mitochondrial DNA in nucleoids, rather than by the presence of CLB. Our studies suggest that mitochondrial DNA plays an important role in cellular and mitochondrial dysfunction in PD. Additional studies will be needed to assess the direct effect of CLB expression on cellular and mitochondrial function. PMID- 23351345 TI - Repeating an attending physician's unseemly remarks. PMID- 23351346 TI - Confidential mental health treatment for adolescents. PMID- 23351347 TI - The student becomes the patient. PMID- 23351349 TI - The "decrepit concept" of confidentiality, 30 years later. PMID- 23351350 TI - Electronic health records: privacy, confidentiality, and security. PMID- 23351351 TI - Patient-physician confidentiality: till death do us part? PMID- 23351352 TI - Would patient ownership of health data improve confidentiality? PMID- 23351353 TI - Confidentiality: concealing "things shameful to be spoken about". PMID- 23351354 TI - The evolution of confidentiality in the United Kingdom and the West. PMID- 23351356 TI - Reading fluency estimates of current intellectual function: demographic factors and effects of type of stimuli. AB - The study explores the potential clinical value of reading fluency measures in complementing demographic variables as indices of current intellectual capacity. IQ estimates (based on the PPVT-R, WASI Vocabulary and Block Design subtests) were obtained from a representative, non-clinical sample of 386 Greek adults aged 48-87 years along with two measures of reading efficiency (one involving relatively high-frequency words-WRE-and the second comprised of phonotactically matched pseudowords-PsWRE). Both reading measures (number of items read correctly in 45 s) accounted for significant portions of variability in demographically adjusted verbal and performance IQ indices. Reading measures provided IQ estimates which were significantly closer to those predicted by demographic variables alone in up to 22% of individuals with fewer than 7 (across all ages) or 13 years of formal education (in the 70-87 year age range). PsWRE scores slightly outperformed WRE scores in predicting a person's estimated verbal or performance IQ. Results are discussed in the context of previous findings using reading accuracy measures for low-frequency words with exceptional spellings in less transparent orthographic systems such as English. PMID- 23351355 TI - The Prevention and Reactivation Care Program: intervention fidelity matters. AB - BACKGROUND: The Prevention and Reactivation Care Program (PReCaP) entails an innovative multidisciplinary, integrated and goal oriented approach aimed at reducing hospital related functional decline among elderly patients. Despite calls for process evaluation as an essential component of clinical trials in the geriatric care field, studies assessing fidelity lag behind the number of effect studies. The threefold purpose of this study was (1) to systematically assess intervention fidelity of the hospital phase of the PReCaP in the first year of the intervention delivery; (2) to improve our understanding of the moderating factors and modifications affecting intervention fidelity; and (3) to explore the feasibility of the PReCaP fidelity assessment in view of the modifications. METHODS: Based on the PReCaP description we developed a fidelity instrument incorporating nineteen (n=19) intervention components. A combination of data collection methods was utilized, i.e. data collection from patient records and individual Goal Attainment Scaling care plans, in-depth interviews with stakeholders, and non-participant observations. Descriptive analysis was performed to obtain levels of fidelity of each of the nineteen PReCaP components. Moderating factors were identified by using the Conceptual Framework for Implementation Fidelity. RESULTS: Ten of the nineteen intervention components were always or often delivered to the group of twenty elderly patients. Moderating factors, such as facilitating strategies and context were useful in explaining the non- or low-adherence of particular intervention components. CONCLUSIONS: Fidelity assessment was carried out to evaluate the adherence to the PReCaP in the Vlietland Ziekenhuis in the Netherlands. Given that the fidelity was assessed in the first year of PReCaP implementation it was commendable that ten of the nineteen intervention components were performed always or often. The adequate delivery of the intervention components strongly depended on various moderating factors. Since the intervention is still developing and undergoing continuous modifications, it has been concluded that the fidelity criteria should evolve with the modified intervention. Furthermore, repeated intervention fidelity assessments will be necessary to ensure a valid and reliable fidelity assessment of the PReCaP. TRIAL REGISTRATION: The Netherlands National Trial Register: NTR2317. PMID- 23351357 TI - Are screen-based sedentary behaviors longitudinally associated with dietary behaviors and leisure-time physical activity in the transition into adolescence? AB - BACKGROUND: There is a need for more longitudinal studies investigating the associations between screen-based sedentary behaviors (SB), dietary behaviors and leisure-time physical activity (PA). METHODS: In the HEIA cohort study, 908 children were followed from age 11 to age 13 (September 2007-May 2009). The children self-reported their intake of fruits, vegetables, soft drinks with sugar and snacks. TV/DVD use, computer/game use and leisure-time PA were also self reported. Multilevel generalized linear mixed model analysis was used to assess longitudinal associations between the screen-based SB and each of the two other behaviors. RESULTS: Twenty-month changes in TV/DVD use and computer/game use were positively associated with changes in the consumption of soft drinks with sugar and unhealthy snacks in the same period; and inversely associated with change in vegetable consumption. Change in computer/game use was also inversely related to change in fruit consumption. An inverse but non-substantive association was found between change in TV/DVD use and change in leisure-time PA. Change in computer/game use was not significantly associated with change in leisure-time PA. CONCLUSIONS: Changes in screen-based SB were associated with multiple unfavorable changes in dietary habits, although the associations were weak. These associations need to be further investigated in intervention/experimental studies, to assess whether changing screen-based SB will result in clinically relevant changes in dietary behaviors. However, the findings of this study suggest that screen-based SB and leisure-time PA are largely independent behaviors which should be addressed separately in health promotion activities. PMID- 23351359 TI - The effect of semelil (angipars(r)) on bone resorption and bone formation markers in type 2 diabetic patients. AB - BACKGROUND AND PURPOSE OF THE STUDY: Diabetes mellitus has been recognized as a major risk factor for osteoporosis in which bone turnover is affected by different mechanisms. As the morbidity, mortality and financial cost related to osteoporosis are expected to rise in Iran in coming years, and considering the efficacy of Angipars(r) for improvement of different ulcers which made it a new herbal drug in diabetic foot ulcer, there is a need to evaluate the effect of this new drug on different organs including bone resorption and bone formation markers. METHODS: In this randomized, double- blind clinical trial, 61 diabetic patients were included. The subjects were randomly divided into intervention and control groups. Subjects of intervention group received 100 mg of Angipars(r) twice a day. Laboratory tests including bone resorption and bone formation markers were performed at baseline and after 3 months. RESULT: 31 patients in study group and 30 patients in control group finished the study. The mean age of the study population and the mean disease duration was respectively 51.8 +/- 6.2 and 7.5 +/- 4.7 years with no significant differences between intervention and control patients. No statistically significant differences between patients and controls were observed in pyridinoline, osteocalcin, urine calcium, bone alkaline phosphatase and tumor necrosis factor (TNF-alpha). Only urine creatinine level significantly changed between two groups after 3 month of treatment (p-value: 0.029) CONCLUSION: In conclusion, the findings of this study indicate that Semelil (Angipars(r)) had no beneficial or harmful effects on bone. It might be other effects of this new component on bone turnover process which need more studies and more time to be discovered. PMID- 23351358 TI - Cytostasis and morphological changes induced by mifepristone in human metastatic cancer cells involve cytoskeletal filamentous actin reorganization and impairment of cell adhesion dynamics. AB - BACKGROUND: Changes in cell shape and plasticity in cytoskeletal dynamics are critically involved in cell adhesion, migration, invasion and the overall process of metastasis. Previous work in our laboratory demonstrated that the synthetic steroid mifepristone inhibited the growth of highly metastatic cancer cells, while simultaneously causing striking changes in cellular morphology. Here we assessed whether such morphological alterations developed in response to cytostatic concentrations of mifepristone are reversible or permanent, involve rearrangement of cytoskeletal proteins, and/or affect the adhesive capacity of the cells. METHODS: Cancer cell lines of the ovary (SKOV-3), breast (MDA-MB-231), prostate (LNCaP), and nervous system (U87MG) were exposed to cytostatic concentrations of mifepristone and studied by phase-contrast microscopy. The transient or permanent nature of the cytostasis and morphological changes caused by mifepristone was assessed, as well as the rearrangement of cytoskeletal proteins. De-adhesion and adhesion assays were utilized to determine if mifepristone-arrested and morphologically dysregulated cells had abnormal de adhesion/adhesion dynamics when compared to vehicle-treated controls. RESULTS: Mifepristone-treated cells displayed a long, thin, spindle-like shape with boundaries resembling those of loosely adhered cells. Growth arrest and morphology changes caused by mifepristone were reversible in SKOV-3, MDA-MB-231 and U87MG, but not in LNCaP cells that instead became senescent. All cancer cell types exposed to mifepristone displayed greatly increased actin ruffling in association with accelerated de-adhesion from the culture plate, and delayed adhesion capacity to various extracellular matrix components. CONCLUSIONS: Cytostatic concentrations of mifepristone induced alterations in the cellular structure of a panel of aggressive, highly metastatic cancer cells of different tissues of origin. Such changes were associated with re-distribution of actin fibers that mainly form non-adhesive membrane ruffles, leading to dysregulated cellular adhesion capacity. PMID- 23351360 TI - A rheumatoid factor paradox: inhibition of rituximab effector function. AB - INTRODUCTION: Rituximab (RTX) therapy of rheumatoid arthritis (RA) exhibits enhanced effectiveness in seropositive patients. Using patient sera, we tested if this improved efficacy was associated with enhanced RTX mediated complement dependent cytotoxicity (RTX-CDC). METHODS: We developed an in vitro assay for RTX CDC using patient sera and the Daudi human B cell line. Using propidium iodide uptake and flow cytometry, we compared RTX-CDC with rheumatoid factor (RF)+ sera relative to normal volunteer, non-RA and RF- sera. Additional studies examined mixing studies of RF+ and RF- sera, as well as the effect of monoclonal IgA or IgM RF. Finally, the effect of RF on RTX mediated trogocytosis of normal B cells was evaluated. RESULTS: Using human sera, addition of RTX resulted in rapid and profound (>50%) Daudi cell death that was complement dependent. Surprisingly, RF+ patient sera exhibited reduced RTX-CDC relative to RF- sera, with an inverse relationship of RTX-CDC and RF titer. Mixing studies indicated the presence of an inhibitor of RTX-CDC in RF+ sera. The addition of monoclonal IgM or IgA RF to RF- sera markedly inhibited RTX-CDC. This effect was specific for RF binding to the Fc portion of RTX as it was not apparent with the F(ab)' domains of RTX engineered onto IgG3 heavy chain. RF also modestly inhibited RTX mediated trogocytosis. CONCLUSIONS: Contrary to expectations, RF+ sera exhibits reduced RTX-CDC due to the presence of RF. The enhanced efficacy of RTX in seropositive RA patients cannot be attributed to improved B cell depletion through CDC. This result indicates that high RF levels may potentially modulate the efficacy of any therapeutic monoclonal antibody dependent on Fc effector function. PMID- 23351361 TI - Glutamine modifies immune responses of mice infected with porcine circovirus type 2. AB - The present study was conducted to evaluate the immune-enhancing effects of dietary L-glutamine supplementation in porcine circovirus type 2 (PCV2)-infected mice, and to examine the clearance effects of glutamine against PCV2 in experimentally infected mice. A total of sixty Kunming female mice were infected with PCV2 at a dose of 100 TCID(50) (50% tissue culture infection dose) by intraperitoneal injection after 2 weeks of dietary L-glutamine supplementation or L-alanine supplementation (as the control (isonitrogenous) group). The measured variables on 3rd, 5th, 7th, 9th and 11th d post-infection (dpi) included: (1) PCV2 virus loaded in the liver, spleen, heart, lung, kidney, ovary and serum was determined by real-time PCR; (2) IL-2, IL-6, IL-10, interferon (IFN)-alpha, IFN gamma and C-reactive protein levels in serum were measured by ELISA; (3) serum total superoxide dismutase activity was measured spectrophotometrically at 550nm absorbance. Dietary L-glutamine supplementation significantly increased serum IL 2 levels on the 3rd (P<0.01), 5th (P<0.01), 7th (P<0.05) and 9th dpi, significantly (P<0.05) increased serum IL-6 levels on 3rd dpi, significantly (P<0.05) increased serum IFN-g levels on the 9th and 11th dpi and significantly decreased (P<0.01) serum IL-10 levels on the 9th and 11th dpi, compared with those in the control group. Meanwhile, the PCV2 virus genome was detected sporadically throughout the experimental period in both groups. Taken together, the present results suggest that dietary L-glutamine supplementation enhances immune function in PCV2-infected mice. PMID- 23351362 TI - Terpenes From the Root of Salvia hypoleuca Benth. AB - BACKGROUND: The genus Salvia, with nearly 900 species, is one of the largest members of Lamiaceae family. In the Flora of Iran, the genus Salvia is represented by 58 species of which 17 species are endemic. Salvia hypoleuca Benth., is one of these species growing wildly in northern and central parts of Iran. Salvia species are well known in folk medicine and widely used for therapeutic purposes. Literature review shows that there is no report on phytochemical investigation of the roots of S. hypoleuca. RESULTS: The separation and purification process were carried out using various chromatographic methods. Structural elucidation was on the basis of NMR and MS data, in comparison with those reported in the literature. The isolated compounds were identified as sitosteryl oleate (1), beta-sitosterol (2), stigmasterol (3), manool (4), 7alpha acetoxy royleanone (5), ursolic acid (6), oleanolic acid (7), 3-epicorosolic acid (8), 3-epimaslinic acid (9) and coleonolic acid (10). CONCLUSIONS: In the present study, three sterols, two diterpenes and five triterpenes were isolated from the ethyl acetate extract of the roots of S. hypoleuca. As the chemotaxonomic significance, some of the isolated compounds (1-7, 9) have not been previously reported from the species S. hypoleuca, while the triterpenes 8 and 10 are now documented from Salvia genus for the first time. PMID- 23351363 TI - Urease inhibitory activities of beta-boswellic acid derivatives. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: Boswellia carterii have been used in traditional medicine for many years for management different gastrointestinal disorders. In this study, we wish to report urease inhibitory activity of four isolated compound of boswellic acid derivative. METHODS: 4 pentacyclic triterpenoid acids were isolated from Boswellia carterii and identified by NMR and Mass spectroscopic analysis (compounds 1, 3-O-acetyl-9,11-dehydro-beta boswellic acid; 2, 3-O-acetyl-11-hydroxy-beta-boswellic acid; 3. 3-O- acetyl-11 keto-beta-boswellic acid and 4, 11-keto-beta-boswellic acid. Their inhibitory activity on Jack bean urease were evaluated. Docking and pharmacophore analysis using AutoDock 4.2 and Ligandscout 3.03 programs were also performed to explain possible mechanism of interaction between isolated compounds and urease enzyme. RESULTS: It was found that compound 1 has the strongest inhibitory activity against Jack bean urease (IC50 = 6.27 +/- 0.03 MUM), compared with thiourea as a standard inhibitor (IC50 = 21.1 +/- 0.3 MUM). CONCLUSION: The inhibition potency is probably due to the formation of appropriate hydrogen bonds and hydrophobic interactions between the investigated compounds and urease enzyme active site and confirms its traditional usage. PMID- 23351364 TI - Emotional regulation impairments following severe traumatic brain injury: an investigation of the body and facial feedback effects. AB - The object of this study was to evaluate the combined effect of body and facial feedback in adults who had suffered from a severe traumatic brain injury (TBI) to gain some understanding of their difficulties in the regulation of negative emotions. Twenty-four participants with TBI and 28 control participants adopted facial expressions and body postures according to specific instructions and maintained these positions for 10 s. Expressions and postures entailed anger, sadness, and happiness as well as a neutral (baseline) condition. After each expression/posture manipulation, participants evaluated their subjective emotional state (including cheerfulness, sadness, and irritation). TBI participants were globally less responsive to the effects of body and facial feedback than control participants, F(1,50) = 5.89, p = .02, eta(2) = .11. More interestingly, the TBI group differed from the Control group across emotions, F(8,400) = 2.51, p = .01, eta(2) = .05. Specifically, participants with TBI were responsive to happy but not to negative expression/posture manipulations whereas control participants were responsive to happy, angry, and sad expression/posture manipulations. In conclusion, TBI appears to impair the ability to recognize both the physical configuration of a negative emotion and its associated subjective feeling. PMID- 23351365 TI - Trade-offs between horizontal and vertical velocities during triple jumping and the effect on phase distances. AB - The triple jump is an athletic event involving three ground contact phases during which athletes must trade off the maintenance of horizontal velocity against the generation of vertical velocity. Previous studies have indicated that individual athletes have a linear relationship between the loss in horizontal velocity and the gain in vertical velocity during each phase. This study used computer simulation to investigate the effects of constraining the takeoff velocities in the hop phase on the velocity trade-offs in this and subsequent phases. Kinematic data were obtained from an entire triple jump using a Vicon automatic motion capture system, and strength and anthropometric data were collected from the triple jumper. A planar 13-segment torque-driven subject-specific computer simulation model was used to maximise the distance of each phase by varying torque generator activation timings using a genetic algorithm. Vertical takeoff velocities in the hop phase were constrained to be 100%, +/-10%, +/-20%, and +/ 30% of the performance velocity, and subsequent phases were optimised with initial conditions calculated from the takeoff of the previous phase and with no constraints on takeoff velocity. The results showed that the loss in horizontal velocity during each contact phase was strongly related to the vertical takeoff velocity (R(2)=0.83) in that phase rather than the overall gain in vertical velocity as found in previous studies. Maximum overall distances were achieved with step phases which were 30% of the total distance of the triple jump confirming the results of experimental studies on elite triple jumpers. PMID- 23351366 TI - Sex-specific prediction of neck muscle volumes. AB - Biomechanical analyses of the head and neck system require knowledge of neck muscle forces, which are often estimated from neck muscle volumes. Here we use magnetic resonance images (MRIs) of 17 subjects (6 females, 11 males) to develop a method to predict the volumes of 16 neck muscles by first predicting the total neck muscle volume (TMV) from subject sex and anthropometry, and then predicting individual neck muscle volumes using fixed volume proportions for each neck muscle. We hypothesized that the regression equations for total muscle volume as well as individual muscle volume proportions would be sex specific. We found that females have 59% lower TMV compared to males (females: 510+/-43cm(3), males: 814+/-64cm(3); p<0.0001) and that TMV (in cm(3)) was best predicted by a regression equation that included sex (male=0, female=1) and neck circumference (NC, in cm): TMV=269+13.7NC-233Sex (adjusted R(2)=0.868; p<0.01). Individual muscle volume proportions were not sex specific for most neck muscles, although small sex differences existed for three neck muscles (obliqus capitis inferior, longus capitis, and sternocleidomastoid). When predicting individual muscle volumes in subjects not used to develop the model, coefficients of concordance ranged from 0.91 to 0.99. This method of predicting individual neck muscle volumes has the advantage of using only one sex-specific regression equation and one set of sex-specific volume proportions. These data can be used in biomechanical models to estimate muscle forces and tissue loads in the cervical spine. PMID- 23351367 TI - Simulation of peri-implant bone healing due to immediate loading in dental implant treatments. AB - The goal of this work was to investigate the role of immediate loading on the peri-implant bone healing in dental implant treatments. A mechano-regulatory tissue differentiation model that takes into account the stimuli through the solid and the fluid components of the healing tissue, and the diffusion of pluripotent stem cells into the healing callus was used. A two-dimensional axisymmetric model consisting of a dental implant, the healing callus tissue and the host bone tissue was constructed for the finite element analysis. Poroelastic material properties were assigned to the healing callus and the bone tissue. The effects of micro-motion, healing callus size, and implant thread design on the length of the bone-to-implant contact (BIC) and the bone volume (BV) formed in the healing callus were investigated. In general, the analysis predicted formation of a continuous layer of soft tissue along the faces of the implant which are parallel to the loading direction. This was predicted to be correlated with the high levels of distortional strain transferred through the solid component of the stimulus. It was also predicted that the external threads on the implant, redistribute the interfacial load, thus help reduce the high distortional stimulus and also help the cells to differentiate to bone tissue. In addition, the region underneath the implant apex was predicted to experience high fluid stimulus that results in the development of soft tissue. The relationship between the variables considered in this study and the outcome measures, BV and BIC, was found to be highly nonlinear. A three-way analysis of variance (ANOVA) of the results was conducted and it showed that micro-motion presents the largest hindrance to bone formation during healing. PMID- 23351368 TI - Consequences of nongenomic actions of estradiol on pathogenic genital tract response. AB - Estradiol is a steroid hormone that regulates the structure and function of the female reproductive system. In addition to its genomic effects, which are mediated by activated nuclear receptors, estradiol elicits a variety of rapid signaling events independently of transcriptional or genomic regulation. These nongenomic actions influence the milieu of the genital tract, which changes the ability of pathogens to infect the genital tract. This review discusses our current knowledge regarding the mechanisms and relevance of nongenomic estradiol signaling in the genital tract that could change the ability of pathogens to invade epithelial cells. PubMed was searched through January 1980 for papers related to estradiol actions in the ovary, fallopian tube, uterus and cervix. The mechanisms conveying these rapid effects consist of a multitude of signaling molecules and include cross-talk with slower transcriptional actions. The nongenomic actions of estradiol that influence the infectious abilities of pathogens occur either directly on the genital tract cells or indirectly by modulating the local and systemic immune systems. Additional in-depth characterization of the response is required before the normal and pathological reproductive functions of the nongenomic estradiol pathway can be targeted for pharmacological intervention. PMID- 23351369 TI - Disease transmission on fragmented contact networks: livestock-associated Methicillin-resistant Staphylococcus aureus in the Danish pig-industry. AB - Animal trade in industrialised livestock-production systems creates a complex, heterogeneous, contact network that shapes between-herd transmission of infectious diseases. We report the results of a simple mathematical model that explores patterns of spread and persistence of livestock-associated Methicillin resistant Staphylococcus aureus (LA-MRSA) in the Danish pig-industry associated with this trade network. Simulations show that LA-MRSA can become endemic sustained by animal movements alone. Despite the extremely low predicted endemic prevalence, eradication may be difficult, and decreasing within-farm prevalence, or the time it takes a LA-MRSA positive farm to recover a negative status, fails to break long-term persistence. Our results suggest that a low level of non movement induced transmission strongly affects MRSA dynamics, increasing endemic prevalence and probability of persistence. We also compare the model-predicted risk of 291 individual farms becoming MRSA positive, with results from a recent Europe-wide survey of LA-MRSA in holdings with breeding pigs, and find a significant correlation between contact-network connectivity properties and the model-estimated risk measure. PMID- 23351370 TI - Estimating risk over time using data from targeted surveillance systems: application to bovine tuberculosis in Great Britain. AB - For infections that are typically asymptomatic, targeted surveillance systems (whereby individuals at increased risk are tested more frequently) will detect infections earlier on average than systems with random testing or in systems where all individuals are tested at the same intervals. However, estimating temporal trends in infection risk using data from such targeted surveillance systems can be challenging. This is similarly a problem for targeted surveillance to detect faults of individual industrial components. The incidence of bovine tuberculosis (TB) in British cattle has been generally increasing in the last thirty years. Cattle herds are routinely tested for evidence of exposure to the aetiological bacteria Mycobacterium bovis, in a targeted surveillance programme in which the testing interval is determined by past local TB incidence and local veterinary discretion. The UK Department for Environment, Food and Rural Affairs (Defra) report the monthly percentage of tests on officially TB-free (OTF) herds resulting in a confirmed positive test for M. bovis (i.e. the percentage of tested herds with OTF status withdrawn), which contains substantial fluctuations (three years apart) within the increasing trend. As the number of herds tested changes over time, this cyclic trend is difficult to interpret. Here we evaluate an alternative to the Defra method in which we distribute each incident event across the period at risk to infer the underlying trends in infection incidence using a stochastic model of cattle herd incidence and testing frequencies fitted to data on the monthly number of herds tested and number of these with OTF status withdrawn in 2003-2010. We show that for an increasing underlying incidence trend, the current Defra approach can produce artefactual fluctuations whereas the alternative method described provides more accurate descriptions of the underlying risks over time. PMID- 23351371 TI - Pre-existence and emergence of drug resistance in a generalized model of intra host viral dynamics. AB - Understanding the source of drug resistance emerging within a treated patient is an important problem, from both clinical and basic evolutionary perspectives. Resistant mutants may arise de novo either before or after treatment is initiated, with different implications for prevention. Here we investigate this problem in the context of chronic viral diseases, such as human immunodeficiency virus (HIV) and hepatitis B and C viruses (HBV and HCV). We present a unified model of viral population dynamics within a host, which can capture a variety of viral life cycles. This allows us to identify which results generalize across various viral diseases, and which are sensitive to the particular virus's life cycle. Accurate analytical approximations are derived that allow for a solid understanding of the parameter dependencies in the system. We find that the mutation-selection balance attained prior to treatment depends on the step at which mutations occur and the viral trait that incurs the cost of resistance. Life cycle effects and key parameters, including mutation rate, infected cell death rate, cost of resistance, and drug efficacy, play a role in determining when mutations arising during treatment are important relative to those pre existing. PMID- 23351372 TI - Linking antimicrobial prescribing to antimicrobial resistance in the ICU: before and after an antimicrobial stewardship program. AB - Antimicrobials are an effective treatment for many types of infections, but their overuse promotes the spread of resistant microorganisms that defy conventional treatments and complicate patient care. In 2009, an antimicrobial stewardship program was implemented at Mount Sinai Hospital (MSH, Toronto, Canada). Components of this program were to alter the fraction of patients prescribed antimicrobials, to shorten the average duration of treatment, and to alter the types of antimicrobials prescribed. These components were incorporated into a mathematical model that was compared to data reporting the number of patients colonized with Pseudomonas aeruginosa and the number of patients colonized with antimicrobial-resistant P. aeruginosa first isolates before and after the antimicrobial stewardship program. Our analysis shows that the reported decrease in the number of patients colonized was due to treating fewer patients, while the reported decrease in the number of patients colonized with resistant P. aeruginosa was due to the combined effect of treating fewer patients and altering the types of antimicrobials prescribed. We also find that shortening the average duration of treatment was unlikely to have produced any noticeable effects and that further reducing the fraction of patients prescribed antimicrobials would most substantially reduce P. aeruginosa antimicrobial resistance in the future. The analytical framework that we derive considers the effect of colonization pressure on infection spread and can be used to interpret clinical antimicrobial resistance data to assess different aspects of antimicrobial stewardship within the ecological context of the intensive care unit. PMID- 23351373 TI - Local persistence and extinction of plague in a metapopulation of great gerbil burrows, Kazakhstan. AB - Speculation on how the bacterium Yersinia pestis re-emerges after years of absence in the Prebalkhash region in Kazakhstan has been ongoing for half a century, but the mechanism is still unclear. One of the theories is that plague persists in its reservoir host (the great gerbil) in so-called hotspots, i.e. small regions in which the conditions remain favourable for plague to persist during times where the conditions in the Prebalkhash region as a whole have become unfavourable for plague persistence. In this paper we use a metapopulation model that describes the dynamics of the great gerbil. With this model we study the minimum size of an individual hotspot and the combined size of multiple hotspots in the Prebalkhash region that would be required for Y. pestis to persist through an inter-epizootic period. We show that the combined area of hotspots required for plague persistence is so large that it would be unlikely to have been missed by existing plague surveillance. This suggests that persistence of plague in that region cannot solely be explained by the existence of hotspots, and therefore other hypotheses, such as survival in multiple host species, and persistence in fleas or in the soil should be considered as well. PMID- 23351374 TI - Drivers and consequences of influenza antiviral resistant-strain emergence in a capacity-constrained pandemic response. AB - Antiviral agents remain a key component of most pandemic influenza preparedness plans, but there is considerable uncertainty regarding their optimal use. In particular, concerns exist regarding the likelihood of wide-scale distribution to select for drug-resistant variants. We used a model that considers the influence of logistical constraints on diagnosis and drug delivery to consider achievable 'reach' of alternative antiviral intervention strategies targeted at cases of varying severity, with or without pre-exposure prophylaxis of contacts. To identify key drivers of epidemic mitigation and resistance emergence, we used Latin hypercube sampling to explore plausible ranges of parameters describing characteristics of wild type and resistant viruses, along with intervention efficacy, target coverage and distribution capacity. Within our model framework, 'real world' constraints substantially reduced achievable drug coverage below stated targets as the epidemic progressed. In consequence, predictions of both intervention impact and selection for resistance were more modest than earlier work that did not consider such limitations. Definitive containment of transmission was unlikely but, where observed, achieved through early liberal post-exposure prophylaxis of known contacts of treated cases. Predictors of resistant strain dominance were high intrinsic fitness relative to the wild type virus, and early emergence in the course of the epidemic into a largely susceptible population, even when drug use was restricted to severe case treatment. Our work demonstrates the importance of consideration of 'real world' constraints in scenario analysis modeling, and highlights the utility of models to guide surveillance activities in preparedness and response. PMID- 23351375 TI - Evaluation of the antinociceptive and anti-inflammatory effects of essential oil of Nepeta pogonosperma Jamzad et Assadi in rats. AB - BACKGROUND AND THE PURPOSE OF STUDY: Concerning the different effects of essential oils from Nepeta genus on the central nervous system including pain killing effect, this study was designed to evaluate the antinociceptive and anti inflammatory effects of essential oil of Nepeta pogonosperma Jamzad et Assadi (NP), a recently identified species. METHODS: Air-dried aerial parts of NP were hydrodistillated and GC-MS analysis of obtained essential oil was conducted. Total 24 male Wister rats weighing 225 +/- 25 gm were studied. Essential oil of NP was administered intraperitoneally at the doses of 50 mg/kg, 100 mg/kg and 200 mg/kg for the experimental groups. Control rats received equal volume (2 ml/kg) of normal saline. Antinociception was assessed by tail flick test (after 30 minutes) and formalin test (for further 60 minutes). Then the animal was sacrificed and the paw edema was measured using a water plethysmometer. RESULTS: 4aalpha,7alpha,7abeta-nepetalactone and 1,8-cineole were found as the main concentrated components of NP essential oil. All the doses of NP showed antinociception. NP 200 mg/kg reduced the pain sensation in tail flick (p <0.01) and formalin test (p <0.001 in both phases). In paw edema test, NP 100 and 200 mg/kg significantly reduced the inflammation (p <0.01 and p <0.05). CONCLUSION: This study reveals that the essential oil of NP may minimize both the acute and chronic forms of nociception and may have potent role against inflammation, but the dose should be maintained precisely to obtain the intended effect. PMID- 23351376 TI - Comparison of measures of comorbidity for predicting disability 12-months post injury. AB - BACKGROUND: Understanding the factors that impact on disability is necessary to inform trauma care and enable adequate risk adjustment for benchmarking and monitoring. A key consideration is how to adjust for pre-existing conditions when assessing injury outcomes, and whether the inclusion of comorbidity is needed in addition to adjustment for age. This study compared different approaches to modelling the impact of comorbidity, collected as part of the routine hospital episode data, on disability outcomes following orthopaedic injury. METHODS: 12 month Glasgow Outcome Scale - Extended (GOS-E) outcomes for 13,519 survivors to discharge were drawn from the Victorian Orthopaedic Trauma Outcomes Registry, a prospective cohort study of admitted orthopaedic injury patients. ICD-10-AM comorbidity codes were mapped to four comorbidity indices. Cases with a GOS-E score of 7-8 were considered "recovered". A split dataset approach was used with cases randomly assigned to development or test datasets. Logistic regression models were fitted with "recovery" as the outcome and the performance of the models based on each comorbidity index (adjusted for injury and age) measured using calibration (Hosmer-Lemshow (H-L) statistics and calibration curves) and discrimination (Area under the Receiver Operating Characteristic (AUC)) statistics. RESULTS: All comorbidity indices improved model fit over models with age and injuries sustained alone. None of the models demonstrated acceptable model calibration (H-L statistic p < 0.05 for all models). There was little difference between the discrimination of the indices for predicting recovery: Charlson Comorbidity Index (AUC 0.70, 95% CI: 0.68, 0.71); number of ICD-10 chapters represented (AUC 0.70, 95% CI: 0.69, 0.72); number of six frequent chronic conditions represented (AUC 0.70, 95% CI: 0.69, 0.71); and the Functional Comorbidity Index (AUC 0.69, 95% CI: 0.68, 0.71). CONCLUSIONS: The presence of ICD-10 recorded comorbid conditions is an important predictor of long term functional outcome following orthopaedic injury and adjustment for comorbidity is indicated when assessing risk-adjusted functional outcomes over time or across jurisdictions. PMID- 23351377 TI - Biochemistry and structure of phosphoinositide phosphatases. AB - Phosphoinositides are the phosphorylated derivatives of phosphatidylinositol, and play a very significant role in a diverse range of signaling processes in eukaryotic cells. A number of phosphoinositide-metabolizing enzymes, including phosphoinositide-kinases and phosphatases are involved in the synthesis and degradation of these phospholipids. Recently, the function of various phosphatases in the phosphatidylinositol signaling pathway has been of great interest. In the present review we summarize the structural insights and biochemistry of various phosphatases in regulating phosphoinositide metabolism. PMID- 23351378 TI - When a ribosome encounters a premature termination codon. AB - In mammalian cells, aberrant transcripts harboring a premature termination codon (PTC) can be generated by abnormal or inefficient biogenesis of mRNAs or by somatic mutation. Truncated polypeptides synthesized from these aberrant transcripts could be toxic to normal cellular functions. However, mammalian cells have evolved sophisticated mechanisms for monitoring the quality of mRNAs. The faulty transcripts harboring PTC are subject to nonsense-mediated mRNA decay (NMD), nonsense-mediated translational repression (NMTR), nonsense-associated alternative splicing (NAS), or nonsense-mediated transcriptional gene silencing (NMTGS). In this review, we briefly outline the molecular characteristics of each pathway and suggest mRNA quality control mechanisms as a means to regulate normal gene expression. PMID- 23351379 TI - Transcutaneous antigen delivery system. AB - Transcutaneous immunization refers to the topical application of antigens onto the epidermis. Transcutaneous immunization targeting the Langerhans cells of the skin has received much attention due to its safe, needle-free, and noninvasive antigen delivery. The skin has important immunological functions with unique roles for antigen-presenting cells such as epidermal Langerhans cells and dermal dendritic cells. In recent years, novel vaccine delivery strategies have continually been developed; however, transcutaneous immunization has not yet been fully exploited due to the penetration barrier represented by the stratum corneum, which inhibits the transport of antigens and adjuvants. Herein we review recent achievements in transcutaneous immunization, focusing on the various strategies for the enhancement of antigen delivery and vaccination efficacy. PMID- 23351380 TI - Connexin32 inhibits gastric carcinogenesis through cell cycle arrest and altered expression of p21Cip1 and p27Kip1. AB - Gap junctions and their structural proteins, connexins (Cxs), have been implicated in carcinogenesis. To explore the involvement of Cx32 in gastric carcinogenesis, immunochemical analysis of Cx32 and proliferation marker Ki67 using tissue-microarrayed human gastric cancer and normal tissues was performed. In addition, after Cx32 overexpression in the human gastric cancer cell line AGS, cell proliferation, cell cycle analyses, and p21(Cip1) and p27(Kip1) expression levels were examined by bromodeoxyuridine assay, flow cytometry, real-time RT PCR, and western blotting. Immunohistochemical study noted a strong inverse correlation between Cx32 and Ki67 expression pattern as well as their location. In vitro, overexpression of Cx32 in AGS cells inhibited cell proliferation significantly. G1 arrest, up-regulation of cell cycle-regulatory proteins p21(Cip1) and p27(Kip1) was also found at both mRNA and protein levels. Taken together, Cx32 plays some roles in gastric cancer development by inhibiting gastric cancer cell proliferation through cell cycle arrest and cell cycle regulatory proteins. PMID- 23351381 TI - Over-expression of OsHsfA7 enhanced salt and drought tolerance in transgenic rice. AB - Heat shock proteins play an important role in plant stress tolerance and are mainly regulated by heat shock transcription factors (Hsfs). In this study, we generated transgenic rice over-expressing OsHsfA7 and carried out morphological observation and stress tolerance assays. Transgenic plants exhibited less, shorter lateral roots and root hair. Under salt treatment, over-expressing OsHsfA7 rice showed alleviative appearance of damage symptoms and higher survival rate, leaf electrical conductivity and malondialdehyde content of transgenic plants were lower than those of wild type plants. Meanwhile, transgenic rice seedlings restored normal growth but wild type plants could not be rescued after drought and re-watering treatment. These findings indicate that over-expression of OsHsfA7 gene can increase tolerance to salt and drought stresses in rice seedlings. PMID- 23351382 TI - Altered sugar donor specificity and catalytic activity of pteridine glycosyltransferases by domain swapping or site-directed mutagenesis. AB - CY-007 and CY-049 pteridine glycosyltransferases (PGTs) that differ in sugar donor specificity to catalyze either glucose or xylose transfer to tetrahydrobiopterin were studied here to uncover the structural determinants necessary for the specificity. The importance of the C-terminal domain and its residues 218 and 258 that are different between the two PGTs was assessed via structure-guided domain swapping or single and dual amino acid substitutions. Catalytic activity and selectivity were altered in all the mutants (2 chimeric and 6 substitution) to accept both UDP-glucose and UDP-xylose. In addition, the wild type activities were improved 1.6-4.2 fold in 4 substitution mutants and activity was observed towards another substrate UDP-N-acetylglucosamine in all the substitution mutants from CY-007 PGT. The results strongly support essential role of the C-terminal domain and the two residues for catalysis as well as sugar donor specificity, bringing insight into the structural features of the PGTs. PMID- 23351383 TI - Partial AUC maximization for essential gene prediction using genetic algorithms. AB - Identifying genes indispensable for an organism's life and their characteristics is one of the central questions in current biological research, and hence it would be helpful to develop computational approaches towards the prediction of essential genes. The performance of a predictor is usually measured by the area under the receiver operating characteristic curve (AUC). We propose a novel method by implementing genetic algorithms to maximize the partial AUC that is restricted to a specific interval of lower false positive rate (FPR), the region relevant to follow-up experimental validation. Our predictor uses various features based on sequence information, protein-protein interaction network topology, and gene expression profiles. A feature selection wrapper was developed to alleviate the over-fitting problem and to weigh each feature's relevance to prediction. We evaluated our method using the proteome of budding yeast. Our implementation of genetic algorithms maximizing the partial AUC below 0.05 or 0.10 of FPR outperformed other popular classification methods. PMID- 23351384 TI - Heat shock protein 90beta inhibits apoptosis of intestinal epithelial cells induced by hypoxia through stabilizing phosphorylated Akt. AB - Intestinal epithelial cell (IEC) apoptosis induced by hypoxia compromise intestinal epithelium barrier function. Both Akt and Hsp90 have cytoprotective function. However, the specific role of Akt and Hsp90beta in IEC apoptosis induced by hypoxia has not been explored. We confirmed that hypoxia-induced apoptosis was reduced by Hsp90beta overexpression but enhanced by decreasing Hsp90beta expression. Hsp90beta overexpression enhanced BAD phosphorylation and thus reduced mitochondrial release of cytochrome C. Reducing Hsp90beta expression had opposite effects. The protective effect of Hsp90beta against apoptosis was negated by LY294002, an Akt inhibitor. Further study showed that Akt phosphorylation was enhanced by Hsp90beta, which was not due to the activation of upstream PI3K and PDK1 but because of stabilization of pAkt via direct interaction between Hsp90beta and pAkt. These results demonstrate that Hsp90beta may play a significant role in protecting IECs from hypoxia-induced apoptosis via stabilizing pAkt to phosphorylate BAD and reduce cytochrome C release. PMID- 23351385 TI - Biochemical characteristics of functional domains using feline foamy virus integrase mutants. AB - We constructed deletion mutants and seven point mutants by polymerase chain reaction to investigate the specificity of feline foamy virus integrase functional domains. Complementation reactions were performed for three enzymatic activities such as 3'-end processing, strand transfer, and disintegration. The complementation reactions with deletion mutants showed several activities for 3' end processing and strand transfer. The conserved central domain and the combination of the N-terminal or C-terminal domains increased disintegration activity significantly. In the complementation reactions between deletion and point mutants, the combination between D107V and deletion mutants revealed 3'-end processing activities, but the combination with others did not have any activity, including strand transfer activities. Disintegration activity increased evenly, except the combination with glutamic acid 200. These results suggest that an intact central domain mediates enzymatic activities but fails to show these activities in the absence of the N-terminal or C-terminal domains. PMID- 23351386 TI - Antiproliferative effect of gold(I) compound auranofin through inhibition of STAT3 and telomerase activity in MDA-MB 231 human breast cancer cells. AB - Signal transducer and activator of transcription 3 (STAT3) and telomerase are considered attractive targets for anticancer therapy. The in vitro anticancer activity of the gold(I) compound auranofin was investigated using MDA-MB 231 human breast cancer cells, in which STAT3 is constitutively active. In cell culture, auranofin inhibited growth in a dose-dependent manner, and N-acetyl-L cysteine (NAC), a scavenger of reactive oxygen species (ROS), markedly blocked the effect of auranofin. Incorporation of 5-bromo-2'-deoxyuridine into DNA and anchorage-independent cell growth on soft agar were decreased by auranofin treatment. STAT3 phosphorylation and telomerase activity were also attenuated in cells exposed to auranofin, but NAC pretreatment restored STAT3 phosphorylation and telomerase activity in these cells. These findings indicate that auranofin exerts in vitro antitumor effects in MDA-MB 231 cells and its activity involves inhibition of STAT3 and telomerase. Thus, auranofin shows potential as a novel anticancer drug that targets STAT3 and telomerase. PMID- 23351387 TI - The role of prophylactic ibuprofen and N-acetylcysteine on the level of cytokines in periapical exudates and the post-treatment pain. AB - BACKGROUND: Periapical lesions are inflammatory diseases that result in periapical bone destruction because of host defensive-microbial disturbances. OBJECTIVE: To evaluate the role of prophylactic ibuprofen and N-acetylcysteine (NAC) on the levels of tumor necrosis factor alpha (TNF- alpha), interleukin- 6(IL-6) and IL-17 and post-treatment pain level in chronic periapical lesions. MATERIALS AND METHODS: Eighty patients with chronic apical lesions less than 1 cm were randomly assigned to receive NAC tablets (400 mg), ibuprofen tablets (400 mg), NAC (400 mg)/ibuprofen (200 mg) combination and placebo 90 minutes prior to sampling. Periapical exudates were collected from root canals. TNF- alpha, IL-6 and IL-17 levels were determined by ELISA and post-treatment pain was assessed using a visual analog scale (VAS). RESULTS: There was a significant difference in IL-6 level between ibuprofen group and placebo (p = 0.019). Significant difference in IL-17 level was observed between NAC/ibuprofen combination group and placebo (p = 0.043). Four hours after treatment, a significant difference was observed in VAS pain score between ibuprofen group and placebo (p = 0.017). Eight hours post-treatment, VAS pain score for NAC group was statistically lower than placebo group (p = 0.033). After 12 hours VAS pain score showed a significant decrease in NAC group compared to placebo (p = 0.049). CONCLUSION: The prophylactic ibuprofen and NAC failed to clearly reflect their effect on cytokines levels in exudates of chronic periapical lesions. On the other hand it seems that NAC can be a substitute for ibuprofen in the management of post endodontic pain. PMID- 23351388 TI - Re: Hashemi HM, Beshkar M, Aghajani R. The effect of sutureless wound closure on postoperative pain and swelling after impacted mandibular third molar surgery. Br J Oral Maxillofac Surg. 2012;50(April(3)):256-258. http://dx.doi.org/10.1016/j.bjoms.2011.04.075. PMID- 23351389 TI - Neural stem cell-like cells derived from autologous bone mesenchymal stem cells for the treatment of patients with cerebral palsy. AB - BACKGROUND: Stem cell therapy is a promising treatment for cerebral palsy, which refers to a category of brain diseases that are associated with chronic motor disability in children. Autologous MSCs may be a better cell source and have been studied for the treatment of cerebral palsy because of their functions in tissue repair and the regulation of immunological processes. METHODS: To assess neural stem cell-like (NSC-like) cells derived from autologous marrow mesenchymal stem cells as a novel treatment for patients with moderate-to-severe cerebral palsy, a total of 60 cerebral palsy patients were enrolled in this open-label, non randomised, observer-blinded controlled clinical study with a 6-months follow-up. For the transplantation group, a total of 30 cerebral palsy patients received an autologous NSC-like cells transplantation (1-2 * 107 cells into the subarachnoid cavity) and rehabilitation treatments whereas 30 patients in the control group only received rehabilitation treatment. RESULTS: We recorded the gross motor function measurement scores, language quotients, and adverse events up to 6 months post-treatment. The gross motor function measurement scores in the transplantation group were significantly higher at month 3 (the score increase was 42.6, 95% CI: 9.8-75.3, P=.011) and month 6 (the score increase was 58.6, 95% CI: 25.8-91.4, P=.001) post-treatment compared with the baseline scores. The increase in the Gross Motor Function Measurement scores in the control group was not significant. The increases in the language quotients at months 1, 3, and 6 post-treatment were not statistically significant when compared with the baseline quotients in both groups. All the 60 patients survived, and none of the patients experienced serious adverse events or complications. CONCLUSION: Our results indicated that NSC-like cells are safe and effective for the treatment of motor deficits related to cerebral palsy. Further randomised clinical trials are necessary to establish the efficacy of this procedure. PMID- 23351390 TI - Characteristics of neutralizing antibodies to adenovirus capsid proteins in human and animal sera. AB - Although it is known that Ad5-specific neutralizing antibodies (NAbs) against three major viral capsid components (hexon, penton and fiber) are generated, differences in the frequency and nature of these pre-existing NAbs remain unclear. The results emphasized the contribution of anti-fiber antibodies to Ad5 neutralization responses generated during natural viral infection. Additionally, Ad5-specific NAbs against the fiber knob protein were present in over 90% of the positive serum samples while 42% of the sera had NAbs against hexon in this study based on neutralization assay of anti-HVR and anti-knob subtracted sera and Western blotting analysis. We also found that the trimeric knob was preferentially recognized by fiber-induced NAbs and it was serotype-specific in human adenovirus species C. Results indicated that the trimeric knob protein would be a good candidate antigen for detecting adenovirus serotype-specific NAbs in naturally infected sera. PMID- 23351392 TI - Leukocyte trafficking mechanisms in epilepsy. AB - Epilepsy is a chronic disorder that affects 1% of the world population and is characterized by chronically reoccurring seizures. Seizures are initiated by abnormal excessive or synchronous neuronal activity in the brain. Epilepsy requires life long anti-convulsant therapy and current therapies for epilepsy selectively target neuronal activity. In the last decade, cytokines and vascular alterations have been discussed in relation to the pathogenesis of epilepsy, suggesting a potential role for inflammation mechanisms in seizure induction. More recently, it has been shown that leukocyte trafficking plays a key role in seizure generation, and that anti-leukocyte adhesion therapy has therapeutic and preventative effects in an experimental model of human epilepsy. These results were supported by evidence in humans showing that leukocytes accumulate in the brain parenchyma of patients with different types of epilepsy. Finally, recent clinical observations suggest that therapies able to interfere with leukocyte trafficking may have a therapeutic effect in epilepsy. The emerging role for leukocytes and leukocyte adhesion mechanisms in seizure generation provides insight into the mechanisms of brain damage and may contribute to the development of novel therapeutic strategies in epilepsy. PMID- 23351391 TI - IRES-based Venezuelan equine encephalitis vaccine candidate elicits protective immunity in mice. AB - Venezuelan equine encephalitis virus (VEEV) is an arbovirus that causes periodic outbreaks that impact equine and human populations in the Americas. One of the VEEV subtypes located in Mexico and Central America (IE) has recently been recognized as an important cause of equine disease and death, and human exposure also appears to be widespread. Here, we describe the use of an Internal Ribosome Entry Site (IRES) from encephalomyocarditis virus to stably attenuate VEEV, creating a vaccine candidate independent of unstable point mutations. Mice infected with this virus produced antibodies and were protected against lethal VEEV challenge. This IRES-based vaccine was unable to establish productive infection in mosquito cell cultures or in intrathoracically injected Aedes taeniorhynchus, demonstrating that it cannot be transmitted from a vaccinee. These attenuation, efficacy and safety results justify further development for humans or equids of this new VEEV vaccine candidate. PMID- 23351393 TI - The predictive value of resting heart rate following osmotherapy in brain injury: back to basics. AB - BACKGROUND: The importance of resting heart rate as a prognostic factor was described in several studies. An elevated heart rate is an independent risk factor for adverse cardiovascular events and total mortality in patients with coronary artery disease, chronic heart failure, and the general population. Also heart rate is elevated in the Multi Organ Dysfunction Syndrome (MODS) and the mortality due to MODS is highly correlated with inadequate sinus tachycardia.To evaluate the value of resting heart rate in predicting mortality in patients with traumatic brain injury along scoring systems like Acute Physiology and Chronic Health Evaluation(APACHE II), Sequential Organ Failure Assessment (SOFA) and Glasgow Coma Score (GCS). METHOD: By analyzing data which was collected from an open labeled randomized clinical trial that compared the different means of osmotherapy (mannitol vs bolus or infusion hypertonic saline), heart rate, GCS, APACHE II and SOFA score were measured at baseline and daily for 7 days up to 60 days and the relationship between elevated heart rate and mortality during the first 7 days and 60th day were assessed. RESULTS: After adjustments for confounding factors, although there was no difference in mean heart rate between either groups of alive and expired patients, however, we have found a relative correlation between 60th day mortality rate and resting heart rate (P=0.07). CONCLUSION: Heart rate can be a prognostic factor for estimating mortality rate in brain injury patients along with APACHE II and SOFA scores in patients with brain injury. PMID- 23351395 TI - Quantitative criteria for needle trap device selection. AB - In this note the quantitative criteria for selection of parameters of the NTD system were derived. The conditions were formulated for the force exerted on syringe, the volume of tested solution, for the time of test and contact time of solution with the sorbent. The last two conditions allowed to establish limits for combinations of fundamental geometrical and macroscopic structural characteristics of the system. The practical reasons of testing and sampling effectiveness of the NTD systems were taken into account. PMID- 23351394 TI - Prevalence of low back pain in children and adolescents: a meta-analysis. AB - BACKGROUND: Low back pain (LBP) is common in children and adolescents, and it is becoming a public health concern. In recent years there has been a considerable increase in research studies that examine the prevalence of LBP in this population, but studies exhibit great variability in the prevalence rates reported. The purpose of this research was to examine, by means of a meta analytic investigation, the prevalence rates of LBP in children and adolescents. METHODS: Studies were located from computerized databases (ISI Web of Knowledge, MedLine, PEDro, IME, LILACS, and CINAHL) and other sources. The search period extended to April 2011. To be included in the meta-analysis, studies had to report a prevalence rate (whether point, period or lifetime prevalence) of LBP in children and/or adolescents (<= 18 years old). Two independent researchers coded the moderator variables of the studies, and extracted the prevalence rates. Separate meta-analyses were carried out for the different types of prevalence in order to avoid dependence problems. In each meta-analysis, a random-effects model was assumed to carry out the statistical analyses. RESULTS: A total of 59 articles fulfilled the selection criteria. The mean point prevalence obtained from 10 studies was 0.120 (95% CI: 0.09 and 0.159). The mean period prevalence at 12 months obtained from 13 studies was 0.336 (95% CI: 0.269 and 0.410), whereas the mean period prevalence at one week obtained from six studies was 0.177 (95% CI: 0.124 and 0.247). The mean lifetime prevalence obtained from 30 studies was 0.399 (95% CI: 0.342 and 0.459). Lifetime prevalence exhibited a positive, statistically significant relationship with the mean age of the participants in the samples and with the publication year of the studies. CONCLUSIONS: The most recent studies showed higher prevalence rates than the oldest ones, and studies with a better methodology exhibited higher lifetime prevalence rates than studies that were methodologically poor. Future studies should report more information regarding the definition of LBP and there is a need to improve the methodological quality of studies. PMID- 23351396 TI - Mussel inspired polydopamine functionalized poly(ether ether ketone) tube for online solid-phase microextraction-high performance liquid chromatography and its application in analysis of protoberberine alkaloids in rat plasma. AB - A novel and simple poly(ether ether ketone) (PEEK) tube-based solid-phase microextraction (SPME)-HPLC method was developed in this work. A mussel inspired polydopamine method was used to functionalize the chemically resistant surface of PEEK tube and a poly(acrylamide-ethylene glycol dimethacrylate) monolith was synthesized inside the PEEK tube and chemically bonded with its surface. The stability of the polydopamine layer was investigated and found to be well enduring to most of commonly used organic solvents and strong acidic conditions. The PEEK tube-based monolith was coupled with HPLC system through a six-port valve, and the performance of the online SPME-HPLC system was demonstrated by analyzing three protoberberine alkaloids in aqueous samples, namely jatrorrhizine (Jat), palmatine (Pal) and berberine (Ber). These analytes were well extracted and separated within 10 min, and enrichment factors of about 400 were obtained. The limit of detection of the proposed method was decreased to 0.01 ng/mL by using UV detection. Finally, the online SPME-HPLC method was applied for determining Jat, Pal and Ber in rat plasma samples. Reproducibility was obtained by evaluating the intra- and inter-day precisions with RSDs less than 6.1% and 8.5%, respectively, and recoveries of the analytes in spiked plasma samples ranged from 89.8% to 96.7%. The proposed method was also applied to determine the concentration of Jat, Pal and Ber in rat plasma after oral administration of Cortex Phellodendri Chinensis. PMID- 23351397 TI - Hydrophilic interaction liquid chromatography columns classification by effect of solvation and chemometric methods. AB - In the current work, a 14 different types of stationary phases with specific structural properties (eight commercially available stationary phases and six home-made) have been studied. We used the minor disturbance method to measure the excess adsorption isotherms of water onto surface of chemically bonded stationary phases from water-acetonitrile mixtures. The presence of polar and hydrophobic groups in the structures of adsorbents as well as changes in the mobile phase composition causes the excess adsorption of given solvent when its concentration in the mobile phase is low. The excess adsorption of water is observed in acetonitrile-rich mobile phase and the excess adsorption of acetonitrile is observed in water-rich mobile phase. The maximum excess of adsorbed water is connected with a negative excess of adsorbed acetonitrile. However, the scale of these excess adsorption depend on the type of the stationary bonded phases. The retention factors of three test solutes (tryptophan, glycine and proline) are correlated with the maximum amount of excessively adsorbed water on the stationary bonded phase surface. Linear dependence of retention factor with excess amount of water suggest, that the amount of adsorbed water ("hydrophilic pillow") play an important role in the retention mechanism in HILIC. All tested stationary phases were divided into several groups according to the retention factors of 16 different biologically active compounds (selected amino acids, pesticides, vitamin B6). Principal component analysis (PCA) and cluster analysis (CA) analysis were used in column comparison and grouping. CA results indicated that all stationary phases may be generally grouped into several clusters, due to structure and properties of stationary phases. Interesting results were obtained also with the use of PCA. Presented methodologycan provide useful information on the hydrophilic properties of various polar columns and their suitability for HILIC applications. PMID- 23351398 TI - Preparation and evaluation of inhalable itraconazole chitosan based polymeric micelles. AB - BACKGROUND: This study evaluated the potential of chitosan based polymeric micelles as a nanocarrier system for pulmonary delivery of itraconazole (ITRA). METHODS: Hydrophobically modified chitosan were synthesized by conjugation of stearic acid to the hydrophilic depolymerized chitosan. FTIR and 1HNMR were used to prove the chemical structure and physical properties of the depolymerized and the stearic acid grafted chitosan. ITRA was entrapped into the micelles and physicochemical properties of the micelles were investigated. Fluorescence spectroscopy, dynamic laser light scattering and transmission electron microscopy were used to characterize the physicochemical properties of the prepared micelles. The in vitro pulmonary profile of polymeric micelles was studied by an air-jet nebulizer connected to a twin stage impinger. RESULTS: The polymeric micelles prepared in this study could entrap up to 43.2+/-2.27 MUg of ITRA per milliliter. All micelles showed mean diameter between 120-200 nm. The critical micelle concentration of the stearic acid grafted chitosan was found to be 1.58*10-2 mg/ml. The nebulization efficiency was up to 89% and the fine particle fraction (FPF) varied from 38% to 47%. The micelles had enough stability to remain encapsulation of the drug during nebulization process. CONCLUSIONS: In vitro data showed that stearic acid grafted chitosan based polymeric micelles has a potential to be used as nanocarriers for delivery of itraconazole through inhalation. PMID- 23351399 TI - The utility of parent report in the assessment of working memory among childhood brain tumor survivors. AB - Childhood brain tumor survivors are at increased risk for neurocognitive impairments, including working memory (WM) problems. WM is typically assessed using performance measures. Little is known about the value of parent ratings for identifying WM difficulties, the relationship between rater and performance measures, or predictors of parent-reported WM problems in this population. Accordingly, the current study examined the utility of parent report in detecting WM difficulties among childhood brain tumor survivors treated with conformal radiation therapy (n = 50) relative to siblings (n = 40) and solid tumor survivors not receiving central nervous system-directed therapy (n = 40). Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). Participants were administered WM measures (digit span, self-ordered search tasks). Findings revealed parents rated brain tumor survivors as having significantly more WM problems (p < .01) compared to controls. However, the BRIEF WM scale demonstrated poor sensitivity and specificity for detecting performance based problems. Significant, albeit modest, correlations were found between the BRIEF-WM scale and performance measures (r = -.24-.22; p < .05) for the combined group. Age at testing, socioeconomic status, and IQ were significant predictors of parent reported WM problems. Rater and performance measures offer complimentary yet different information in assessing WM, which reiterates the importance of using both within the context of clinical assessment. PMID- 23351400 TI - Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies. AB - BACKGROUND: Meckel-Gruber syndrome (MKS) is an autosomal recessive lethal condition that is a ciliopathy. MKS has marked phenotypic variability and genetic heterogeneity, with mutations in nine genes identified as causative to date. METHODS: Families diagnosed with Meckel-Gruber syndrome were recruited for research studies following informed consent. DNA samples were analyzed by microsatellite genotyping and direct Sanger sequencing. RESULTS: We now report the genetic analyses of 87 individuals from 49 consanguineous and 19 non consanguineous families in an unselected cohort with reported MKS, or an associated severe ciliopathy in a kindred. Linkage and/or direct sequencing were prioritized for seven MKS genes (MKS1, TMEM216, TMEM67/MKS3, RPGRIP1L, CC2D2A, CEP290 and TMEM237) selected on the basis of reported frequency of mutations or ease of analysis. We have identified biallelic mutations in 39 individuals, of which 13 mutations are novel and previously unreported. We also confirm general genotype-phenotype correlations. CONCLUSIONS: TMEM67 was the most frequently mutated gene in this cohort, and we confirm two founder splice-site mutations (c.1546 + 1 G > A and c.870-2A > G) in families of Pakistani ethnic origin. In these families, we have also identified two separate founder mutations for RPGRIP1L (c. 1945 C > T p.R649X) and CC2D2A (c. 3540delA p.R1180SfsX6). Two missense mutations in TMEM67 (c. 755 T > C p.M252T, and c. 1392 C > T p.R441C) are also probable founder mutations. These findings will contribute to improved genetic diagnosis and carrier testing for affected families, and imply the existence of further genetic heterogeneity in this syndrome. PMID- 23351401 TI - Surgical management of external auditory canal lesions. AB - BACKGROUND: Lesions arising in the external auditory canal that require surgical excision are uncommon. They are associated with a range of pathologies, including bony abnormalities, infections, benign and malignant neoplasms, and epithelial disorders. METHODS: This paper describes a 10-year personal case series of external auditory canal lesions with chart, imaging and histopathology review. RESULTS: In total, 48 lesions required surgical management, consisting of: 13 bony lesions; 14 infective lesions; 14 neoplasms with 11 histological types (including ceruminous adenoma and the extremely rare cavernous haemangioma); 3 epithelial abnormalities; and 4 other benign lesions. The surgical management is described. CONCLUSION: This study emphasises the diagnostic differences between exostoses and osteomas, and between external auditory canal cholesteatoma and keratosis obturans. It also discusses the management of aural polyps, and highlights the need to excise external auditory canal masses for histology in order to guide subsequent treatment. PMID- 23351402 TI - Three-component synthesis of pyrano[2,3-d]-pyrimidine dione derivatives facilitated by sulfonic acid nanoporous silica (SBA-Pr-SO3H) and their docking and urease inhibitory activity. AB - BACKGROUND: A straightforward and efficient method for the synthesis of pyrano[2,3-d]pyrimidine diones derivatives from the reaction of barbituric acid, malononitrile and various aromatic aldehydes using SBA-Pr-SO3H as a nanocatalyst is reported. RESULTS: Reactions proceed with high efficiency under solvent free conditions. Urease inhibitory activity of pyrano[2,3-d]pyrimidine diones derivatives were tested against Jack bean urease using phenol red method. Three compounds of 4a, 4d and 4l were not active in urease inhibition test, but compound 4a displayed slight urease activation properties. Compounds 4b, 4k, 4f, 4e, 4j, 4g and 4c with hydrophobic substitutes on phenyl ring, showed good inhibitory activity (19.45-279.14 MUM). DISCUSSION: The compounds with electron donating group and higher hydrophobic interaction with active site of enzyme prevents hydrolysis of substrate. Electron withdrawing groups such as nitro at different position and meta-methoxy reduced urease inhibitory activity. Substitution of both hydrogen of barbituric acid with methyl group will convert inhibitor to activator. PMID- 23351403 TI - Development and characterization of chitosan-polycarbophil interpolyelectrolyte complex-based 5-fluorouracil formulations for buccal, vaginal and rectal application. AB - BACKGROUND OF THE STUDY: The present investigation was designed with the intention to formulate versatile 5-fluorouracil (5-FU) matrix tablet that fulfills the therapeutic needs that are lacking in current cancer treatment and aimed at minimizing toxic effect, enhancing efficacy and increasing patient compliance. The manuscript presents the critical issues of 5-FU associate with cancer and surpasses issues by engineering novel 5-FU matrix tablets utilizing chitosan- polycarbophil interpolyelectrolyte complex (IPEC). METHODS: Precipitation method is employed for preparation of chitosan and polycarbophil interpolyelectrolyte complex (IPEC) followed by characterization with Fourier transform infrared spectroscopy (FT-IR), Differential Scanning calorimeter (DSC) and X-ray Diffraction (XRD). 5-FU tablets were prepared by direct compression using IPEC. Six formulations were prepared with IPEC alone and in combination with chitosan, polycarbophil and Sodium deoxycholate. The formulations were tested for drug content, hardness, friability, weight variation, thickness, swelling studies, in vitro drug release (buccal, vaginal and rectal pH), ex vivo permeation studies, mucoadhesive strength and in vivo studies. RESULTS: FT-IR studies represent the change in spectra for the IPEC than single polymers.DSC study represents the different thermo gram for chitosan, polycarbophil and IPEC whereas in X-ray diffraction, crystal size alteration was observed. Formulations containing IPEC showed pH independent controlled 5-FU without an initial burst release effect in buccal, vaginal and rectal pH. Furthermore, F4 formulations showed controlled release 5-FU with highest bioadhesive property and satisfactory residence in both buccal and vaginal cavity of rabbit. 3% of SDC in formulation F6 exhibited maximum permeation of 5-FU. CONCLUSION: The suitable combination of IPEC, chitosan and polycarbophil demonstrated potential candidate for controlled release of 5-FU in buccal, vaginal and rectal pH with optimum swelling approaching zero order release. PMID- 23351404 TI - Relationship between energy dense diets and white adipose tissue inflammation in metabolic syndrome. AB - Metabolic syndrome (MS) is a widespread pathologic state that manifests as multiple intertwined diseases affecting the entire body. This review analyzes the contribution of adipose tissue inflammation to its development. The main factor in the appearance of MS is an excess of dietary energy (largely fats), eliciting insulin resistance and creating the problem of excess energy disposal. Under these conditions, amino acid catabolism is diminished, which indirectly alters the production of nitric oxide and affects blood flow regulation. The oxidation of nitric oxide to nitrite and nitrate affects microbiota composition and functions. Adipose tissue cannot incorporate excessive nutrients after cell enlargement and loss of function. Tissue damage is a form of aggression, and the response is proinflammatory cytokine release. Cytokines favor the massive penetration of immune system cells, such as macrophages, which unsuccessfully try to fight an elusive danger for which they are not prepared. The consequence is low-level maintenance of the inflammatory state, which affects endoplasmic reticulum function and the endothelial response to excess regulatory mechanisms affecting blood flow and substrate/oxygen supply. When inflammation becomes chronic, the pathologic consequences are disseminated throughout the body because unused substrates and signals from adipose tissue affect energy partitioning and organ function. This maintenance of an unbalanced state ultimately results in the establishment of MS and associated pathologies. New research should focus on identifying ways to disarm the inflammatory response of adipose tissue when the dangers of dietary excess have already been controlled. PMID- 23351405 TI - Short-term supplementation with active hexose correlated compound improves the antibody response to influenza B vaccine. AB - Administration of bioactive nutritional supplements near or at the time of immunization has been a recent approach to stimulate human immune response to vaccination. Active hexose correlated compound (AHCC), a mushroom extract, has been shown to protect mice against lethal primary influenza infection. Moreover, when AHCC was administered pre-vaccination in mice, they showed improved protection from lethal avian flu infection when compared to mice vaccinated alone. In this study, we hypothesized that AHCC will also improve the immune responses of healthy individuals to influenza vaccine. A randomized controlled study was performed with 30 healthy adults to evaluate the effects of AHCC supplementation on the immune response to the 2009-2010 seasonal influenza vaccine. Blood was drawn pre-vaccination and 3 wk post-vaccination. Immediately post-vaccination, the AHCC group began supplementation with AHCC (3 g/d). Flow cytometric analysis of lymphocyte subpopulations revealed that AHCC supplementation increased NKT cells (P < .1), and CD8 T cells (P < .05) post vaccination compared to controls. Analysis of antibody production 3 weeks post vaccination revealed that AHCC supplementation significantly improved protective antibody titers to influenza B, while the improvement was not significant in the control group. Overall, our study showed that AHCC supplementation improved some lymphocyte percentages and influenza B antibody titers over the control. Future studies are required to determine the kinetics of AHCC supplementation to improve the overall response to influenza vaccination. PMID- 23351406 TI - Yogurt consumption is associated with better diet quality and metabolic profile in American men and women. AB - The evidence-based Dietary Guidelines for Americans recommends increasing the intake of fat-free or low-fat milk and milk products. However, yogurt, a nutrient dense milk product, has been understudied. This cross-sectional study examined whether yogurt consumption was associated with better diet quality and metabolic profile among adults (n = 6526) participating in the Framingham Heart Study Offspring (1998-2001) and Third Generation (2002-2005) cohorts. A validated food frequency questionnaire was used to assess dietary intake, and the Dietary Guidelines Adherence Index (DGAI) was used to measure overall diet quality. Standardized clinical examinations and laboratory tests were conducted. Generalized estimating equations examined the associations of yogurt consumption with diet quality and levels of metabolic factors. Approximately 64% of women (vs 41% of men) were yogurt consumers (ie, consumed >0 servings/week). Yogurt consumers had a higher DGAI score (ie, better diet quality) than nonconsumers. Adjusted for demographic and lifestyle factors and DGAI, yogurt consumers, compared with nonconsumers, had higher potassium intakes (difference, 0.12 g/d) and were 47%, 55%, 48%, 38%, and 34% less likely to have inadequate intakes (based on Dietary Reference Intake) of vitamins B2 and B12, calcium, magnesium, and zinc, respectively (all P <= .001). In addition, yogurt consumption was associated with lower levels of circulating triglycerides, glucose, and lower systolic blood pressure and insulin resistance (all P < .05). Yogurt is a good source of several micronutrients and may help to improve diet quality and maintain metabolic well-being as part of a healthy, energy-balanced dietary pattern. PMID- 23351407 TI - The ratio of insulin-like growth factor-I/insulin-like growth factor-binding protein-3 in sera of patients with hepatitis C virus-related chronic liver disease as a predictive marker of insulin resistance. AB - Recent studies have elucidated a lower level of serum insulin-like growth factor I (IGF-I) or a decrease in the IGF-I/IGF-binding protein-3 (IGFBP-3) ratio in patients with type 2 diabetes mellitus or hepatic steatosis. Persistent hepatitis C virus (HCV) infection often evokes metabolic abnormalities including hepatic steatosis and insulin resistance. We hypothesized that the relationship between the ratio of IGF-I/IGFBP-3 and the severity of hepatic steatosis or insulin resistance would be observed in patients with HCV-related chronic liver disease (CLD). On the basis of the classifications proposed by Brunt and colleagues (Am J Gastroenterol 1999; 94: 2467-2474), among the 42 enrolled patients with HCV related CLD, 23 of them had no hepatic steatosis (grade 0), 14 had grade 1 steatosis, and 5 had grade 2 steatosis. The levels of serum IGF-I in the enrolled patients declined in proportion to the severity of hepatic steatosis, whereas serum IGFBP-3 levels did not affect its severity. Therefore, the ratio of IGF I/IGFBP-3, which corresponds to the circulating free IGF-I status, was significantly lower in those patients with hepatic steatosis (grades 1 and 2) than in those without hepatic steatosis. Serum IGF-I levels significantly correlated with serum zinc levels (r = 0.370, P = .0266), but IGFBP-3 levels did not. However, the linear regression analysis revealed an inverse correlation between the IGF/IGFBP-3 ratio and the value of homeostasis model for assessment of insulin resistance (r =-0.411, P = .0094). These findings suggest that the decline of the circulating free IGF-I level, which derives from zinc deficiency, may contribute to hepatic steatosis and insulin resistance in patients with HCV related CLD. PMID- 23351408 TI - Acute differential effects of dietary protein quality on postprandial lipemia in obese non-diabetic subjects. AB - Non-fasting triglyceridemia is much closer associated to cardiovascular risk compared to fasting triglyceridemia. We hypothesized that there would be acute differential effects of four common dietary proteins (cod protein, whey isolate, gluten, and casein) on postprandial lipemia in obese non-diabetic subjects. To test the hypothesis we conducted a randomized, acute clinical intervention study with crossover design. We supplemented a fat rich mixed meal with one of four dietary proteins i.e. cod protein, whey protein, gluten or casein. Eleven obese non-diabetic subjects (age: 40-68, body mass index: 30.3-42.0 kg/m(2)) participated and blood samples were drawn in the 8-h postprandial period. Supplementation of a fat rich mixed meal with whey protein caused lower postprandial lipemia (P = .048) compared to supplementation with cod protein and gluten. This was primarily due to lower triglyceride concentration in the chylomicron rich fraction (P = .0293). Thus, we have demonstrated acute differential effects on postprandial metabolism of four dietary proteins supplemented to a fat rich mixed meal in obese non-diabetic subjects. Supplementation with whey protein caused lower postprandial lipemia compared to supplementation with cod and gluten. As postprandial lipemia is closely correlated to cardiovascular disease, long-term dietary supplementation with whey protein may prove beneficial in preventing cardiovascular disease in obese non diabetic subjects. PMID- 23351409 TI - Evidence that cranberry juice may improve augmentation index in overweight men. AB - The stiffening of arteries is a key step in atherogenesis leading to cardiovascular disease. It has been suggested that dietary polyphenols may be cardioprotective through possible favorable effects on oxidative stress and vascular function. The present study was undertaken in order to examine the effect of consuming low-calorie cranberry juice cocktail (CJC), a source of polyphenols, on arterial stiffness in abdominally obese men. We hypothesize that regular CJC consumption will reduce circulating oxidized low-density lipoproteins concentrations and have a beneficial impact on endothelial function. Thirty-five men (mean age +/- SD: 45 +/- 10 years) were randomly assigned to drink 500 mL CJC/day (27% juice) or 500 mL placebo juice (PJ)/day for 4 weeks in a double blind crossover design. Augmentation index (AIx), an index of arterial stiffness, was measured by applanation tonometry of the radial artery and the cardiometabolic profile was assessed in each participant before and after each phase of the study. We found no significant difference in AIx changes between men who consumed CJC or PJ for 4 weeks (P = .5820). Furthermore, there was no between treatment difference in changes in AIx responses to salbutamol (P = .6303) and glyceryl trinitrate (P = .4224). No significant difference was noted in other cardiometabolic variables between men consuming PJ or CJC. However, a significant within group decrease in AIx (mean decrease +/- SE; -14.0 +/- 5.8%, P = .019) was noted following the consumption of 500 mL CJC/day for 4 weeks. Our results indicate that the effect of chronic consumption of CJC on AIx was not significantly different from changes associated with the consumption of PJ. However, the significant within-group decrease in AIx following CJC consumption in abdominally obese men may deserve further investigation. PMID- 23351410 TI - Positive association between dietary iron intake and iron status in HIV-infected children in Johannesburg, South Africa. AB - Anemia is a common complication of pediatric HIV infection and is associated with suboptimal cognitive performance and growth failure. Routine iron supplementation is not provided to South African HIV-infected children. We hypothesized that dietary iron intake without supplementation is sufficient to protect against iron deficiency (ID) in HIV-infected children receiving highly active antiretroviral therapy. In this prospective study, the difference between dietary intakes of iron-deficient children (soluble transferrin receptor >9.4 mg/L) and iron sufficient children after 18 months on highly active antiretroviral therapy was examined. The association between iron intake and hemoglobin (Hb) concentration was also assessed. Longitudinal data collected for 18 months from 58 HIV-infected African children were assessed by generalized estimation equations, with adjustment for demographic information, dietary intakes, growth parameters, and CD4%. After adjustment for covariates, the longitudinal association between dietary iron intake and Hb concentration remained significant. This association shows that for every 1-mg increase in iron intake per day, Hb increases by 1.1 g/L (P < .001). Mean Hb increased significantly after 18 months of follow-up (106 +/- 14 to 129 +/- 14 g/L, P < .01), but soluble transferrin receptor also increased (7.7 +/- 2.7 to 8.9 +/- 3.0 mg/L, P < .01). The incidence of ID increased from 15.2% at baseline to 37.2% after 18 months. Children with animal protein intakes greater than >20 g/d had significantly lower odds for ID at 18 months than did children with lower intakes (odds ratio, 0.40; 95% confidence interval, 0.21-0.77). Dietary iron intake was insufficient to protect against ID, pointing to a need for low-dose iron supplementation for iron-deficient HIV infected children and interventions to increase the consumption of animal protein. PMID- 23351411 TI - A milk and cereal dietary pattern is associated with a reduced likelihood of having a low bone mineral density of the lumbar spine in Korean adolescents. AB - The traditional rice-based Korean diet has been changing toward a Western-style diet. This change has been especially rapid among adolescents. The purpose of this study was to investigate the association between dietary patterns and bone health among Korean adolescents. This cross-sectional study was conducted on 196 adolescents aged 12 to 15 years. Information on the general characteristics of the subjects was obtained through a questionnaire, and dietary intake was assessed with 6-day food records. Bone mineral densities (BMDs) of the lumbar spine and femur were measured by dual-energy x-ray absorptiometry. Dietary patterns were derived from 24 food groups using factor analysis. Four distinct dietary patterns-traditional Korean, fast food, milk and cereal, and snacks-were identified and accounted for 28.4% of the total variance. After adjusting for sex, age, body mass index percentiles, weight loss attempts, pubertal status, and regular exercise, the adolescents in the highest tertile of the "milk and cereal" dietary pattern score had significantly a reduced likelihood of having low BMD compared with those in the lowest tertile of this diet at the lumbar spine (odds ratio, 0.36; 95% confidence interval, 0.14-0.93; P = .0461). The other dietary patterns were not associated with the BMD of Korean adolescents. These results indicate that the intake of milk and cereal is important for the bone health of Korean adolescents, whose diets are composed mainly of grains and vegetables. PMID- 23351412 TI - Young overweight and obese women with lower circulating osteocalcin concentrations exhibit higher insulin resistance and concentrations of C-reactive protein. AB - The role of the skeleton in the regulation of energy metabolism in humans is not clear. This study investigates the hypothesis that biomarkers of bone turnover are associated with indices of glucose homeostasis and systemic inflammation in young adults. A cross-sectional study investigating the relationships between biomarkers of bone turnover (serum total and uncarboxylated osteocalcin, bone specific alkaline phosphatase, C-telopeptide of type I collagen, urinary N telopeptide of type I collagen) and glucose metabolism (fasting plasma glucose [FPG], insulin, insulin resistance [homeostatic model assessment of insulin resistance]), systemic inflammation (high-sensitivity C-reactive protein [hsCRP] and interleukin-6), adipokines (leptin and adiponectin), and body composition was conducted in 268 young, nondiabetic overweight and obese adults aged 20 to 40 years (116 men, 152 women; body mass index, 27.5-32.5 kg/m(2)). Data on diet, physical activity, serum 25-hydroxyvitamin D, and parathyroid hormone were also collected. In women, there was a stepwise increase in lean body mass (P < .05) and a decrease in serum hsCRP (P < .001) across tertiles of total osteocalcin. Multiple linear regression analysis showed significant inverse associations between total osteocalcin and FPG (beta = -0.350; P = .016; 95% confidence interval [CI], -0.35 to -0.04), insulin (beta = -0.455; P = .002; 95% CI, -1.9 to -0.46), and homeostatic model assessment of insulin resistance (beta = -0.508; P = .001; 95% CI, -10.93 to -3.17) in women with total osteocalcin concentrations below the group median. Men in the lowest tertile of uncarboxylated osteocalcin had twice the concentration of hsCRP than did other men (P = .05). In this sample, women with less lean body mass had lower circulating total osteocalcin concentrations and exhibited higher FPG, insulin resistance, and hsCRP compared with their similarly sized counterparts, suggesting that associations between osteocalcin and systemic inflammation, glucose homeostasis, and insulin resistance may be influenced by differences in sex and body composition. PMID- 23351413 TI - Aqueous extracts of Lentinula edodes and Pleurotus sajor-caju exhibit high antioxidant capability and promising in vitro antitumor activity. AB - Mushroom extracts are increasingly sold as dietary supplements because of several of their properties, including the enhancement of immune function and antitumor activity. We hypothesized that soluble polar substances present in mushroom extracts may show antioxidant and anticancer properties. This report shows that Brazilian aqueous extracts of Lentinula edodes and Pleurotus sajor-caju exert inhibitory activity against the proliferation of the human tumor cell lines laryngeal carcinoma (Hep-2) and cervical adenocarcinoma (HeLa). Cell viability was determined after using 3 different temperatures (4 degrees C, 22 degrees C, and 50 degrees C) for mushroom extraction. Biochemical assays carried out in parallel indicated higher amounts of polyphenols in the L edodes extracts at all extraction temperatures investigated. The scavenging ability of the 2,2-diphenyl 1-picrylhydrazyl radical showed higher activity for L edodes extracts. Superoxide dismutase-like activity showed no statistically significant difference among the groups for the 2 tested extracts, and catalase-like activity was increased with the L edodes extracts at 4 degrees C. The results for the cytotoxic activity from P sajor-caju extracts at 22 degrees C revealed the half maximal inhibitory concentration values of 0.64% +/- 0.02% for Hep-2 and 0.25% +/- 0.02% for HeLa. A higher cytotoxic activity was found for the L edodes extract at 22 degrees C, with half maximal inhibitory concentration values of 0.78% +/- 0.02% for Hep-2 and 0.57% +/- 0.01% for HeLa. Substantial morphological modifications in cells were confirmed by Giemsa staining after treatment with either extract, suggesting inhibition of proliferation and induction of apoptosis with increasing extract concentrations. These results indicate that the aqueous extracts of Brazilian L edodes and P sajor-caju mushrooms are potential sources of antioxidant and anticancer compounds. However, further investigations are needed to exploit their valuable therapeutic uses and to elucidate their modes of action. PMID- 23351414 TI - To flavor or not to flavor the colonoscopy preparation solution? PMID- 23351415 TI - The role of estrogen in the survival of ovarian tumors--a study of the human ovarian adenocarcinoma cell lines OC-117-VGH and OVCAR3. AB - BACKGROUND: The role of estrogen in the growth and survival of ovarian cancer cells is controversial. In this study, we investigated the changes in cell-cycle regulatory proteins in ovarian cancer cell lines after estrogen treatment to explore the role of estrogen in ovarian cancers. METHODS: Two ovarian adenocarcinoma cell lines were used for the study: the first, OC-117-VGH, was deficient in estrogen receptors (ER)alpha and ERbeta, and the second, OVCAR3, was positive for ERalpha and ERbeta. Serial concentrations of estrogen were used to evaluate the effects of estrogen on the survival of ovarian cancer cells. The cell-cycle regulatory proteins, including cyclin D1, cyclin E, p16/INK4a, and p27/KIP1, were used to check the possible mechanism of an estrogen effect on survival of the cancer cell line. RESULTS: Estrogen 0.01-1.0 MUM inhibited the growth of both cell lines. There were no differences in cyclin D1 and E expression between the two cell lines after estrogen treatment, but the expression of p16/INK4a and p27/KIP1 was significantly higher in the OC-1170-VGH cell line than in the OVCAR3 cell line. CONCLUSION: Although the ER-positive and ER-negative ovarian cancer cell lines were inhibited by estrogen, the influence of cell-cycle regulatory proteins was different between the two, suggesting that the inhibitory effect of estrogen on ovarian cancer cell lines might be mediated through different pathways. PMID- 23351416 TI - The use and clinical outcomes of rotablation in challenging cases in the drug eluting stent era. AB - BACKGROUND: Rotational atherectomy (RA) has been advocated in the bare metal stent (BMS) era but is underused now due to technique demands and nonsuperior outcomes. The aim of this study was to evaluate the procedural and clinical outcomes of patients with very complex, severely calcified coronary lesions treated by RA and drug-eluting stents (DESs) in our current percutaneous coronary intervention (PCI) practice in a region where RA use has been limited by lack of insurance reimbursement. METHODS: From March 2004 to November 2010, all consecutive patients who required RA treatment for severely calcified de novo lesions of native coronary arteries followed by DES implantation were queried from the cath lab database and recruited. Their clinical and angiographic characteristics at the index PCI were analyzed and completed by a thorough review of the medical charts. RESULTS: A total of 67 consecutive patients with 71 very complex, heavily calcified coronary lesions treated with RA plus DES were recruited. Of these patients, 64% presented with acute coronary syndrome, 9.0% with cardiogenic shock, 43.3% with chronic renal failure, and 50.7% with diabetes. Multiple-vessel diseases were found in 92.5% of our patients, and the average coronary artery calcification (CAC) score was 3.6+/-1.4. Of the coronary lesions, 26.7% were either balloon-uncrossable or balloon-undilatable. The angiographic success rate was 100% with one non-Q myocardial infarction. Five patients (7.5%) died in hospital, all initially presenting with extensive myocardial infarction and/or cardiogenic shock. The out-of-hospital major adverse cardiac event was 17.9% at the mean follow-up of 23.2 months (range: 5-86), primarily due to high target-lesion revascularization and target-vessel revascularization rates of 10.4% and 10.4%, respectively. Only one (1.5%) probable subacute stent thrombosis was observed in the follow-up. CONCLUSION: RA with DES implantation in very complex, heavily calcified coronary lesions can achieve very low complication and low out-of-hospital major adverse cardiac event rates even in high-risk patients despite use limited by lack of insurance reimbursement. The study results convince us to sustain and even broaden the use of this novel, but underused, device in the DES era. PMID- 23351417 TI - Bacterial pneumonia following acute ischemic stroke. AB - BACKGROUND: The most common serious complication following acute ischemic stroke is pneumonia, which may increase mortality and worsen clinical outcomes. The purpose of this study was to investigate the predictors of 30-day mortality in patients with pneumonia following acute ischemic stroke. METHODS: From June 2006 to May 2011, we retrospectively included 51 patients with pneumonia following acute ischemic stroke. We analyzed the clinical features, microbiologic data, and outcomes. Predictors of 30-day mortality were investigated by univariate and multivariate analysis. RESULTS: The acute ischemic strokes were caused by large artery atherosclerosis in 37 (72.5%) of the 51 patients. We found that the most common pathogen responsible for poststroke pneumonia was Klebsiella pneumoniae, followed by Pseudomonas aeruginosa and Escherichia coli. Ultimately, 12 patients died of progressive sepsis due to pneumonia after the acute ischemic stroke. The 30-day mortality rate was 23.5%. In the univariate analysis, patients who died within 30 days had higher National Institutes of Health Stroke Scale scores, higher CURB-65 scores, elevated instability of hemodynamic status, and lower Glasgow Coma Scale (GCS) scores. In Cox regression analysis, a GCS score of <9 on the day of pneumonia onset was only significant indicator for 30-day mortality (hazard ratio, 6.72; 95% confidence interval, 2.12-21.30, p = 0.001). CONCLUSION: Pneumonia after acute ischemic stroke is a severe complication. Once stroke related pneumonia develops, neurologic assessment, CURB-65 score, and shock can be used to predict the ultimate prognosis. PMID- 23351418 TI - Early endovascular experience for treatments of Takayasu's arteritis. AB - BACKGROUND: Takayasu's arteritis (TA) is a chronic inflammatory disease that involves the aorta and its major branches; however, only limited data are available on TA in Taiwan. This study presents the clinical features, angiographic findings, and response to treatment of patients with TA at a single institute in Taiwan. METHODS: A search of the hospital database for ICD9 code 446.7 (Takayasu's disease) between 1990 and 2010 was performed. Seven cases fulfilled the 1990 American College of Rheumatology diagnostic criteria for Takayasu's disease. Angiographic classification was made according to the guidelines of the 1994 International TA Conference in Tokyo. RESULTS: All of our cases were female, and the median age at diagnosis was 27.5 years (range 14-36 years). Four patients had an angiographic classification of type I (57.1%), two were classified as type V (28.6%), and one was classified as type III (14.3%). The most common symptoms/signs were dizziness and vascular bruits. Two patients underwent bypass surgery, four endovascular stenting, and one hybrid bypass with stenting. After a mean follow-up period of 50.3 +/- 68.2 months (range 12.3-199.6 months), both the procedure success and survival rates were 100%. There were four restenosis cases (57.1%), one in the surgical bypass group without symptoms (33.3%), and three in the endovascular group (60%), five restenosis in 14 stents (35.7%). Also, these three patients received secondary endovascular procedure for percutaneous transluminal angioplasty or restenting. CONCLUSION: There have not been any case series reports about treatments of Takayasu's disease in Taiwan to date, based on a search of the PubMed/MEDLINE and Cochrane Library databases. Although endovascular treatment is becoming more prevalent, the restenosis rate is still high, and long-term follow-up and further strategy for restenosis management are the main challenges. PMID- 23351419 TI - Concomitant Bentall operation plus aortic arch replacement surgery. AB - BACKGROUND: The Bentall operation is recommended for thoracic aortic dissection or aneurysm involving the aortic root. However, if the lesion extends to the aortic arch, concomitant Bentall operation plus aortic arch replacement (CoBAAR) surgery is required. CoBAAR is challenging because of its complex cardiopulmonary procedure, prolonged cardiopulmonary bypass time, and demanding operative techniques. Therefore, surgical mortality and morbidity rates for CoBAAR are very high. However, the Bentall operation performed as a single procedure may lead to reoperation if the residual aneurysm progresses. Therefore, CoBAAR as a one-stage surgery can lower the need for reoperation and possible further complications. METHODS: Nine patients received CoBAAR during January 2005 to May 2010. Six patients were diagnosed with Sanford type A aortic dissection and three with nondissecting ascending aortic and arch aneurysm. Four patients received a Bentall operation plus hemiarch replacement. The others received a Bentall operation plus total arch replacement along with elephant trunk because of extensive lesions. RESULTS: The in-hospital mortality was 11.1% (1 patient with total arch replacement). Morbidity included stroke (2 patients), spinal cord injury (1 patient), mechanical ventilation for more than 72 hours (5 patients), and temporary renal dialysis (3 patients). Eight patients survived. CONCLUSION: CoBAAR is a demanding operative technique requiring complex cardiopulmonary bypass. However, surgeons can perform this procedure on extensive ascending aortic dissection or aneurysm patients, achieving satisfactory results. PMID- 23351420 TI - Alleviative effects of deep-seawater drinking water on hepatic lipid accumulation and oxidation induced by a high-fat diet. AB - BACKGROUND: Hepatic steatosis is defined as excessive amounts of triglyceride and other fats inside liver cells and has become an emergent liver disease in developed and developing countries. METHODS: Deep seawater (DSW)300, DSW900, and DSW1500 drinking waters were formulated via a combination of reverse osmosis and electrodialysis. Hamsters on a high-fat diet were assigned to drink the following solutions: (1) normal distilled water, (2) DSW300, (3) DSW900, or (4) DSW1500. Serum, liver, and fecal biochemical values, expression of hepatic genes related to fatty-acid homeostasis, as well as liver antioxidative levels were measured after a 6-week feeding period. Additionally, hematoxylin and eosin staining was used to investigate the liver histopathology. RESULTS: Serum/liver lipids, liver sizes, liver malondialdehyde content, and serum aspartate aminotransferase and alanine aminotransferase of high-fat diet hamsters were reduced (p < 0.05) by drinking DSW, while daily fecal lipid and bile acid outputs were increased (p < 0.05). DSW drinking water maintained (p < 0.05) higher liver glutathione and Trolox equivalent antioxidant capacity levels. Although hepatic sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase, fatty acid synthase, and malic enzyme gene expression were not (p > 0.05) altered, DSW drinking water upregulated (p < 0.05) hepatic peroxisome proliferator-activated receptor-alpha, retinoid X receptor alpha, and uncoupling protein-2 gene expression in high-fat diet hamsters. The lipid droplets in livers were also reduced in DSW-drinking water groups as compared to those only drinking distilled water. CONCLUSION: DSW shows a preventive effect on development of hepatosteatosis induced by a high-fat diet. PMID- 23351421 TI - The association of clinical guideline adherence and pay-for-performance among patients with diabetes. AB - BACKGROUND: Diabetes mellitus management is one of the most challenging health care issues in Taiwan. To improve guideline adherence and the quality of diabetes care, the diabetes mellitus pay-for-performance (DM-P4P) program was introduced in 2001. This study examined the effects of the DM-P4P program on guideline adherence among patients with diabetes. METHODS: This cross-sectional study used National Health Insurance (NHI) claim data to assess guideline adherence among three groups of patients with diabetes: patients enrolled in the DM-P4P program, patients not enrolled but treated by DM-P4P-participating physicians, and patients treated by non-P4P physicians. Guideline adherence measures included hemoglobin A1c, blood glucose, lipid, serum creatinine, alanine transaminase, urinalysis, and eye examinations. Multiple logistic regression with generalized estimated equation approach were used to assess the effect of the DM-P4P program while controlling for patient and physician characteristics. RESULTS: A total of 520,804 patients were included in the analysis. Patients enrolled in the DM-P4P program were more likely to receive all of the guideline-recommended tests/examinations than patients treated by non-P4P physicians. Patients who were not enrolled in the program but who were treated by DM-P4P-participating physicians were more likely to receive three of the seven recommended tests/examinations than were those treated by non-P4P physicians. CONCLUSION: When physicians participated in the P4P program, this increased the likelihood that patients would receive guideline-recommended tests or examinations. Increasing the DM-P4P participation rates for physicians and patients are important and worthwhile objectives that can assist in the effort to more effectively manage diabetes in the general population. PMID- 23351422 TI - Ectopic mediastinal parathyroid carcinoma presenting as acute pancreatitis. AB - Parathyroid carcinoma is a rare cause of hyperparathyroidism, accounting for fewer than 1% of cases. The incidence of acute pancreatitis in patients with hyperparathyroidism was reported to be only 1.5%. We report a very rare case of ectopic mediastinal parathyroid carcinoma presenting as acute pancreatitis. A 72 year-old man presented with acute pancreatitis and hypercalcemia. During the work up for hypercalcemia, a mediastinal parathyroid tumor was identified by (99m)Tc sestamibi scintigraphy and magnetic resonance imaging. The tumor was completely removed via a lower cervical collar incision. The histopathology revealed parathyroid carcinoma. There was no tumor recurrence or abdominal symptoms at 3 year follow-up. PMID- 23351423 TI - Treatment of ovarian endodermal sinus tumor to preserve fertility. AB - Endodermal sinus tumor, also known as yolk sac tumor (YST), is a malignant germ cell tumor that most frequently occurs in the testis, the ovary, and sacrococcygeal areas in children. YSTs are highly aggressive and because of the early metastatic or invasive pattern, their prognosis has been poor. Treatment methods for YSTs are usually intensive, including multiagent chemotherapy, and have shown to improve patient survival significantly; therefore, it is important to consider the reproductive function of these patients with long-term survival. Herein, we present the case of a 31-year-old female, who was diagnosed with unilateral ovarian YST at the age of 13. The patient was treated with fertility sparing surgery and postoperative adjuvant chemotherapy. During the subsequent long-term follow-up, she was not only free of disease, but also had a successful, naturally conceived pregnancy at 31 years of age. We, therefore, conclude that YST is a curable disease, and that fertility-preservation surgery and subsequent immediate combination chemotherapy is the treatment of choice. PMID- 23351424 TI - Osteoblastoma in the region of the hip. AB - Osteoblastoma occurring in the region of the hip is very rare, and vague symptoms with uncharacteristic radiographic features often lead to misdiagnosis. Because of radiographic and histological similarities, it must be carefully distinguished from osteoid osteoma, aneurysmal bone cyst, giant cell tumor, and osteosarcoma. Computed tomography is the preferred imaging modality as it is able to detect the nidus and images will not exhibit the flare phenomenon caused by surrounding inflammation seen with magnetic resonance imaging. For hip joint lesions in weight-bearing areas, intralesional curettage may achieve satisfactory outcomes as compared with wide resection. We herein report two cases of osteoblastoma in the hip region in which diagnosis was delayed that were successfully treated with curettage and followed by high-speed burring. PMID- 23351425 TI - Immunological monitoring to prevent and treat sepsis. AB - The clinical, human and economic burden associated with sepsis is huge. Initiatives such as the Surviving Sepsis Campaign aim to effectively reduce risk of death from severe sepsis and septic shock. Nonetheless, although substantial benefits raised from the implementation of this campaign have been obtained, much work remains if we are to realise the full potential promised by this strategy. A deeper understanding of the processes leading to sepsis is necessary before we can design an effective suite of interventions. Dysregulation of the immune response to infection is acknowledged to contribute to the pathogenesis of the disease. Production of both proinflammatory and immunosuppressive cytokines is observed from the very first hours following diagnosis. In addition, hypogammaglobulinemia is often present in patients with septic shock. Moreover, levels of IgG, IgM and IgA at diagnosis correlate directly with survival. In turn, nonsurvivors have lower levels of C4 (a protein of the complement system) than the survivors. Natural killer cell counts and function also seem to have an important role in this disease. HLA-DR in the surface of monocytes and counts of CD4+CD25+ T-regulatory cells in blood could also be useful biomarkers for sepsis. At the genomic level, repression of networks corresponding to major histocompatibility complex antigen presentation is observed in septic shock. In consequence, cumulative evidence supports the potential role of immunological monitoring to guide measures to prevent or treat sepsis in a personalised and timely manner (early antibiotic administration, immunoglobulin replacement, immunomodulation). In conclusion, although diffuse and limited, current available information supports the development of large comprehensive studies aimed to urgently evaluate immunological monitoring as a tool to prevent sepsis, guide its treatment and, as a consequence, diminish the morbidity and mortality associated with this severe condition. PMID- 23351426 TI - The effect of adverse information and positive promotion on women's preferences for prescribed contraceptive products. AB - Recent rapid growth in the range of contraceptive products has given women more choice, but also adds complexity to the resultant decision of which product to choose. This paper uses a discrete choice experiment (DCE) to investigate the effect of adverse information and positive promotion on women's stated preferences for prescribed contraceptive products. In November 2007, 527 Australian women aged 18-49 years were recruited from an online panel. Each was randomly allocated to one of three information conditions. The control group only received basic information on contraceptive products. One treatment group also received adverse information on the risks of the combined oral pill. The other group received basic information and promotional material on the vaginal ring, newly introduced into Australia and on the transdermal patch, which is unavailable in Australia. Respondents completed 32 choice sets with 3 product options where each option was described by a product label: either combined pill, minipill, injection, implant, hormonal IUD, hormonal vaginal ring, hormonal transdermal patch or copper IUD; and by the attributes: effect on acne, effect on weight, frequency of administration, contraceptive effectiveness, doctor's recommendation, effect on periods and cost. Women's choices were analysed using a generalized multinomial logit model (G-MNL) and model estimates were used to predict product shares for each information condition. The predictions indicated that adverse information did not affect women's preferences for products relative to only receiving basic information. The promotional material increased women's preferences for the transdermal patch. Women in all groups had a low preference for the vaginal ring which was not improved by promotion. The findings highlight the need for researchers to pay attention to setting the context when conducting DCEs as this can significantly affect results. PMID- 23351427 TI - Comparison of hypertonic saline versus normal saline on cytokine profile during CABG. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: Blood contact with artificial surfaces of the extracorporeal circuit and ischemia-reperfusion injury in CABG with CPB, may lead to a systemic inflammatory response. Hypertonic saline have been recently investigated as a fluid in order to decrease inflammatory response and cytokines generation in patients undergo cardiac operations. Our purpose is to study the prophylactic effect of HS 5% infusion versus NS on serum IL-6 as an inflammatory & IL-10 as an anti-inflammatory biomarker in CABG patients. METHODS: The present study is a randomized double-blinded clinical trial. 40 patients undergoing CABG were randomized to receive HS 5% or NS before operation. Blood samples were obtained after receiving HS or NS, just before operation, 24 and 48 hours post-operatively. Plasma levels of IL-6 and IL-10 were measured by ELISA. RESULTS AND MAJOR CONCLUSION: Patients received HS had lower levels of IL-6 and higher level of IL-10 compared with NS group, however these differences were not statistically significant. Results of this study suggest that pre-treatment with small volume hypertonic saline 5% may have beneficial effects on inflammatory response following CABG operation. PMID- 23351428 TI - Ozone oxidation of antidepressants in wastewater -Treatment evaluation and characterization of new by-products by LC-QToFMS. AB - BACKGROUND: The fate of 14 antidepressants along with their respective N desmethyl metabolites and the anticonvulsive drug carbamazepine was examined in a primary sewage treatment plant (STP) and following advanced treatments with ozone (O3). The concentrations of each pharmaceutical compound were determined in raw sewage, effluent and sewage sludge samples by LC-MS/MS analysis. The occurrence of antidepressant by-products formed in treated effluent after ozonation was also investigated. RESULTS: Current primary treatments using physical and chemical processes removed little of the compounds (mean removal efficiency: 19%). Experimental sorption coefficients (Kd) of each studied compounds were also calculated. Sorption of venlafaxine, desmethylvenlafaxine, and carbamazepine on sludge was assumed to be negligible (log Kd <= 2), but higher sorption behavior can be expected for sertraline (log Kd >= 4). Ozonation treatment with O3 (5 mg/L) led to a satisfactory mean removal efficiency of 88% of the compounds. Screening of the final ozone-treated effluent samples by high resolution-mass spectrometry (LC-QqToFMS) did confirm the presence of related N-oxide by products. CONCLUSION: Effluent ozonation led to higher mean removal efficiencies than current primary treatment, and therefore represented a promising strategy for the elimination of antidepressants in urban wastewaters. However, the use of O3 produced by-products with unknown toxicity. PMID- 23351429 TI - Health effects of exposure to nano-TiO2: a meta-analysis of experimental studies. AB - The paper is aimed to investigate the toxicity of nano-TiO2 and its potential harmful impact on human health using meta-analysis of in vitro and short-time animal studies. Data were retrieved according to included and excluded criteria from 1994 to 2011. The combined toxic effects of nano-TiO2 were calculated by the different endpoints by cell and animal models. From analysis of the experimental studies, more than 50% showed positive statistical significance except the apoptosis group, and the cytotoxicity was in a dose-dependent but was not clear in size-dependent manner. Nano-TiO2 was detained in several important organs including the liver, spleen, kidney, and brain after entering the blood through different exposure routes, but the coefficient of the target organs was altered slightly from animal models. It is possible that nano-TiO2 can induce cell damage related to exposure size and dose. Further studies will be needed to demonstrate that nanoparticles have toxic effects on human body, especially in epidemiological studies. PMID- 23351430 TI - Developing a patient and family-centred approach for measuring the quality of injury care: a study protocol. AB - BACKGROUND: Quality indicators (QI) are used in health care to measure quality of service and performance improvement. Health care professionals and organizations caring for patients with injuries need information regarding the quality of care provided and the outcomes experienced in order to target improvement efforts. However, very little is known about the quality of injury care provided to individual patients and populations and even less about patients' perspectives on quality of care. The absence of QIs that incorporate patient or family preferences, needs or values has been identified as an important gap in the science and practice of injury quality improvement. The primary objective of this research protocol is to develop and evaluate the first set of patient and family centred QIs of injury care for critically injured patients METHODS/DESIGN: This mixed methods study is comprised of three Sub-Studies. Sub-Study A will utilize focus group methodology to describe the preferences, needs and values of critically injured patients and their family members regarding the quality of health care delivered. Qualitative content analysis of the transcripts will begin after the first completed focus group and will draw on grounded theory using a process of open, axial and selective coding. A panel of stakeholders will be assembled during Sub-Study B to review the themes identified from the focus groups and develop a catalogue of potential patient and family-centred QIs of injury care using the RAND/UCLA Appropriateness Method (RAM). The QIs developed by the stakeholder panel will be pilot tested in Sub-Study C using surveys of patients and their family members to determine construct validity, intra-rater reliability and clinical sensibility. DISCUSSION: Measuring the quality of injury care is but a first step towards improving patient outcomes. This research will develop the first set of patient and family-centred QIs of injury care. To improve patient care, we need accessible, reliable indicators of quality that are important to patients, and that can then be used to establish quality of care benchmarks, to flag potential problems or successes, follow trends over time and identify disparities across organizations, communities, populations and regions. PMID- 23351431 TI - Ozonation of iodide-containing waters: selective oxidation of iodide to iodate with simultaneous minimization of bromate and I-THMs. AB - The presence of iodinated disinfection by-products (I-DBPs) in drinking water poses a potential health concern since it has been shown that I-DBPs are generally more genotoxic and cytotoxic than their chlorinated and brominated analogs. I-DBPs are formed during oxidation/disinfection of iodide-containing waters by reaction of the transient hypoiodous acid (HOI) with natural organic matter (NOM). In this study, we demonstrate that ozone pre-treatment selectively oxidizes iodide to iodate and avoids the formation of I-DBPs. Iodate is non-toxic and is therefore a desired sink of iodine in drinking water. Complete conversion of iodide to iodate while minimizing the bromate formation to below the guideline value of 10 MUg L-1 was achieved for a wide range of ozone doses in five raw waters with DOC and bromide concentrations of 1.1-20 mg L-1 and 170-940 MUg L-1, respectively. Lowering the pH effectively further reduced bromate formation but had no impact on the extent of iodate and bromoform formation (the main trihalomethane (THM) formed during ozonation). Experiments carried out with pre chlorinated/post-clarified samples already containing I-DBPs, showed that ozonation effectively oxidized I-THMs. Therefore, in iodide-containing waters, in which I-DBPs can be produced upon chlorination or especially chloramination, a pre-ozonation step to oxidize iodide to iodate is an efficient process to mitigate I-DBP formation. PMID- 23351432 TI - Electrochemical incineration of omeprazole in neutral aqueous medium using a platinum or boron-doped diamond anode: degradation kinetics and oxidation products. AB - The electrochemical incineration of omeprazole, a widely prescribed gastrointestinal drug which is detected in natural waters, has been studied in a phosphate buffer of pH 7.0 by anodic oxidation with electrogenerated H(2)O(2) (AO H(2)O(2)) operating at constant current density (j). The experiments were carried out in a cell equipped with either a Pt or a boron-doped diamond (BDD) anode and an air-diffusion cathode to continuously produce H(2)O(2). In these systems, organics are mainly oxidized by hydroxyl radicals formed at the Pt or BDD surface from water oxidation. A partial total organic carbon (TOC) abatement close to 78% for omeprazole was achieved by AO-H(2)O(2) with a BDD anode after consumption of 18 Ah L(-1) at 100 mA cm(-2), whereas the alternative use of Pt did not allow mineralizing the drug. However, the drug was totally removed using both anodes, although it decayed more rapidly using BDD. In this latter system, increasing j accelerated the degradation process, but lowering the mineralization current efficiency. Greater drug content also enhanced the degradation rate with higher mineralization degree and current efficiency. The kinetics for omeprazole decay always followed a pseudo-first-order reaction and its rate constant increased with increasing j and with decreasing its concentration. Seven heteroaromatic intermediates and four hydroxylated derivatives were detected by LC-MS, while nine short-linear carboxylic acids were identified and quantified by ion exclusion HPLC. These acids were largely accumulated using Pt and rapidly removed using BDD, thus explaining the partial mineralization of omeprazole achieved by AO-H(2)O(2) with the latter anode. The release of inorganic ions such as NO(3)( ), NH(4)(+) and SO(4)(2-) was followed by ionic chromatography. A plausible reaction sequence for omeprazole mineralization involving all intermediates detected is proposed. PMID- 23351433 TI - Optimization of an integrated electrodisinfection/electrocoagulation process with Al bipolar electrodes for urban wastewater reclamation. AB - In this work, a novel integrated electrochemical process for urban wastewater regeneration is described. The electrochemical cell consists in a Boron Doped Diamond (BDD) or a Dimensionally Stable Anode (DSA) as anode, a Stainless Steel (SS) as cathode and a perforated aluminum plate, which behaves as bipolar electrode, between anode and cathode. Thus, in this cell, it is possible to carry out, at the same time, two different electrochemical processes: electrodisinfection (ED) and electrocoagulation (EC). The treatment of urban wastewater with different anodes and different operating conditions is studied. First of all, in order to check the process performance, experiments with synthetic wastewaters were carried out, showing that it is possible to achieve a 100% of turbidity removal by the electrodissolution of the bipolar electrode. Next, the effect of the current density and the anode material are studied during the ED-EC process of actual effluents. Results show that it is possible to remove Escherichia coli and turbidity simultaneously of an actual effluent from a WasteWater Treatment Facility (WWTF). The use of BDD anodes allows to remove the E. coli completely at an applied electric charge of 0.0077 A h dm(-3) when working with a current density of 6.65 A m(-2). On the other hand, with DSA anodes, the current density necessary to achieve the total removal of E. coli is higher (11.12 A m(-2)) than that required with BDD anodes. Finally, the influence of cell flow path and flow rate have been studied. Results show that the performance of the process strongly depends on the characteristics of the initial effluent (E. coli concentration and Cl(-)/NH(4)(+) initial ratio) and that a cell configuration cathode (inlet)-anode (outlet) and a higher flow rate enhance the removal of the turbidity from the treated effluent. PMID- 23351434 TI - Variability of chlorination by-product occurrence in water of indoor and outdoor swimming pools. AB - Swimming is one of the most popular aquatic activities. Just like natural water, public pool water may contain microbiological and chemical contaminants. The purpose of this study was to study the presence of chemical contaminants in swimming pools, in particular the presence of disinfection by-products (DBPs) such as trihalomethanes (THMs), haloacetic acids (HAAs) and inorganic chloramines (CAMi). Fifty-four outdoor and indoor swimming pools were investigated over a period of one year (monthly or bi-weekly sampling, according to the type of pool) for the occurrence of DBPs. The results showed that DBP levels in swimming pools were greater than DBP levels found in drinking water, especially for HAAs. Measured concentrations of THMs (97.9 vs 63.7 MUg/L in average) and HAAs (807.6 vs 412.9 MUg/L in average) were higher in outdoor pools, whereas measured concentrations of CAMi (0.1 vs 0.8 mg/L in average) were higher in indoor pools. Moreover, outdoor pools with heated water contained more DBPs than unheated pools. Finally, there was significant variability in tTHM, HAA9 and CAMi levels in pools supplied by the same municipal drinking water network, suggesting that individual pool characteristics (number of swimmers) and management strategies play a major role in DBP formation. PMID- 23351435 TI - An efficient piecewise linear model for predicting activity of caspase-3 inhibitors. AB - BACKGROUND AND PURPOSE OF THE STUDY: Multimodal distribution of descriptors makes it more difficult to fit a single global model to model the entire data set in quantitative structure activity relationship (QSAR) studies. METHODS: The linear (Multiple linear regression; MLR), non-linear (Artificial neural network; ANN), and an approach based on "Extended Classifier System in Function approximation" (XCSF) were applied herein to model the biological activity of 658 caspase-3 inhibitors. RESULTS: Various kinds of molecular descriptors were calculated to represent the molecular structures of the compounds. The original data set was partitioned into the training and test sets by the K-means classification method. Prediction error on the test data set indicated that the XCSF as a local model estimates caspase-3 inhibition activity, better than the global models such as MLR and ANN. The atom-centered fragment type CR2X2, electronegativity, polarizability, and atomic radius and also the lipophilicity of the molecule, were the main independent factors contributing to the caspase-3 inhibition activity. CONCLUSIONS: The results of this study may be exploited for further design of novel caspase-3 inhibitors. PMID- 23351436 TI - [Aspirin for preventing the recurrence of venous thromboembolism]. PMID- 23351437 TI - The major role of toxicology societies in global collaborations - a call to action. PMID- 23351438 TI - Schizophrenia and potentially preventable hospitalizations in the United States: a retrospective cross-sectional study. AB - BACKGROUND: Persons with schizophrenia may face barriers to high quality primary care due to communication difficulties, cognitive impairment, lack of social support, and fragmentation of healthcare delivery services. As a result, this group may be at high risk for ambulatory care sensitive (ACS) hospitalizations, defined as hospitalizations potentially preventable by timely primary care. The goal of this study was to determine if schizophrenia is associated with overall, acute, and chronic ACS hospitalizations in the United States (US). METHODS: We conducted a retrospective cross-sectional study. Hospitalization data for the US were obtained from the Nationwide Inpatient Sample for years 2003-2008. We examined 15,275,337 medical and surgical discharges for adults aged 18-64, 182,423 of which had a secondary diagnosis of schizophrenia. ACS hospitalizations were measured using the Agency for Healthcare Research and Quality's Prevention Quality Indicators (PQIs). We developed logistic regression models to obtain nationally-weighted odds ratios (OR) for ACS hospitalizations, comparing those with and without a secondary diagnosis of schizophrenia after adjusting for patient, hospitalization, and hospital characteristics. RESULTS: Schizophrenia was associated with increased odds of hospitalization for acute ACS conditions (OR = 1.34; 95% CI: 1.31, 1.38), as well as for chronic ACS conditions characterized by short-term exacerbations. Schizophrenia was associated with decreased odds of hospitalization for diabetes mellitus long-term complications and diabetes-related lower extremity amputation, conditions characterized by long term deterioration. CONCLUSIONS: Additional research is needed to determine which individual and health systems factors contribute to the increased odds of hospitalization for acute PQIs in schizophrenia. PMID- 23351439 TI - Healthy behaviours and abdominal adiposity in adolescents from southern Italy. AB - OBJECTIVE: The present study aimed to evaluate the prevalence of meeting health recommendations on diet and physical activity (having breakfast, eating fruit and vegetables, consumption of milk/yoghurt, performing moderate-to-vigorous physical activity, limiting television watching) and to assess junk snack food consumption in adolescents from southern Italy. The association between healthy behaviours and abdominal adiposity was also examined. DESIGN: In a cross-sectional protocol, anthropometric data were measured by trained operators while other data were collected through a structured interview. SETTING: Three high schools in Naples, Italy. SUBJECTS: A sample of 478 students, aged 14-17 years, was studied. RESULTS: The proportion of adolescents who met each of the health recommendations varied: 55.4% had breakfast on >=6 d/week; 2.9% ate >=5 servings of fruit and vegetables/d; 1.9% had >=3 servings of milk/yoghurt daily; 13.6% performed moderate-to-vigorous physical activity for >=60 min/d; and 46.3% watched television for <2 h/d. More than 65% of adolescents consumed >=1 serving of junk snack foods/d. Only 5% fulfilled at least three recommendations. Healthy habits tended to correlate with each other. As the number of health recommendations met decreased, the percentage of adolescents with high abdominal adiposity (waist-to height ratio >=0.5) increased. The trend was not significant when the proportion of overweight/obese adolescents was considered. Logistic regression analysis indicated that male gender and watching television for >=2 h/d were independently associated with a higher waist-to-height ratio. CONCLUSIONS: Most adolescents failed to meet the five health recommendations considered. Male gender and excessive television watching were associated with abdominal adiposity. PMID- 23351440 TI - Anticancer activity of Pupalia lappacea on chronic myeloid leukemia K562 cells. AB - BACKGROUND: Cancer is one of the most prominent human diseases which has enthused scientific and commercial interest in the discovery of newer anticancer agents from natural sources. Here we demonstrated the anticancer activity of ethanolic extract of aerial parts of Pupalia lappacea (L) Juss (Amaranthaceae) (EAPL) on Chronic Myeloid Leukemia K562 cells. METHODS: Antiproliferative activity of EAPL was determined by MTT assay using carvacrol as a positive control. Induction of apoptosis was studied by annexin V, mitochondrial membrane potential, caspase activation and cell cycle analysis using flow cytometer and modulation in protein levels of p53, PCNA, Bax and Bcl2 ratio, cytochrome c and cleavage of PARP were studied by Western blot analysis. The standardization of the extract was performed through reverse phase-HPLC using Rutin as biomarker. RESULTS: The results showed dose dependent decrease in growth of K562 cells with an IC50 of 40 +/- 0.01 MUg/ml by EAPL. Induction of apoptosis by EAPL was dose dependent with the activation of p53, inhibition of PCNA, decrease in Bcl2/Bax ratio, decrease in the mitochondrial membrane potential resulting in release of cytochrome c, activation of multicaspase and cleavage of PARP. Further HPLC standardization of EAPL showed presence 0.024% of Rutin. CONCLUSION: Present study significantly demonstrates anticancer activity of EAPL on Chronic Myeloid Leukemia (K562) cells which can lead to potential therapeutic agent in treating cancer. Rutin, a known anti cancer compound is being reported and quantified for the first time from EAPL. PMID- 23351441 TI - [Science in Mexico]. PMID- 23351442 TI - [Efficacy of clinical evaluation in diagnosing injury zone in open globe ocular trauma]. AB - BACKGROUND: Risk of retinal damage in open globe eye injuries increases as the zone (location of the wound vertex) is more rearward. The value of clinical exploration to assess this variable is unknown. OBJECTIVE: To establish the efficacy of clinical exploration as a diagnostic test to identify the injury zone in open globe ocular trauma. METHODS: Assessment of patients with open globe ocular trauma, preoperative clinical assessment of injury zone and surgical description of the wound were carried out. The proportion and 95% confidence intervals (CI) of eyes whose zone changed during surgical repair were established, and the efficacy of clinical evaluation to diagnose zone was estimated. Features of eyes with and without zone change were compared using chi(2) test. RESULTS: 89 eyes, mean age 27.1 years. Clinically, the identified zone was I in 36 eyes (40.4%), II in 38 (31.5%) and III in 25 (28.1%); the identified zone during surgery was I in 36 eyes (40.4%), II in 43 (48.3%) and III in 10 (11.2%). Zone changed in 30 eyes (34%, 95% C.I. 24 to 44). Specificity (96%), positive predictive value (93%) and positive likelihood ratio (13.9) were high only for zone II. No feature was associated with zone change. CONCLUSIONS: Clinical exploration was not efficient enough to identify injury zone in open globe trauma and has low prognostic value. It is not necessary to define the injury zone at first contact; it is enough identifying properly the agent, visual function and pupil reflexes for an efficient assessment. PMID- 23351443 TI - [Economic analysis of dalteparin use in knee surgery at Instituto Mexicano del Seguro Social]. AB - BACKGROUND: Knee surgery is a risk factor for thromboembolic disease. Prophylaxis reduces the risk of this condition. METHODS: Economic and health consequences of drugs preventing and treating thromboembolic disease in patients undergoing knee surgery from the institutional perspective (time horizon: 1 year) were estimated. The measures of effectiveness were: reduction in the number of cases (per 1,000 patients) of deep vein thrombosis, pulmonary embolism, hospital admissions and deaths. Transition probabilities were estimated by meta-analysis. The alternatives were: warfarin (reference), dalteparin, enoxaparin, nadroparin, unfractionated heparin + warfarin, and non-prophylaxis. Data on resources use and costs corresponds to the Instituto Mexicano del Seguro Social (IMSS). Acceptability curves were constructed. RESULTS: No prophylaxis implied three times higher cost ($18,835.10 versus $5,967.10) and less effectiveness in comparison with warfarin. The incremental cost-effectiveness ratios for enoxaparin were $3, $13, $17 and $3 per each additional case of deep vein thrombosis, pulmonary embolism, death and hospital admission avoided. Results of nadroparin and unfractionated heparin were inferior to warfarin (59.1% and 72.9% more costly and less effective in three measures of effectiveness, respectively). Dalteparin showed higher health outcomes and lower cost compared with warfarin ( 20.6%). Dalteparin had a higher probability of being cost-effective than enoxaparin. DISCUSSION: thromboprophylaxis is a clinically and economically favorable alternative. The identification of a pharmacoeconomic profile of alternatives to perform it becomes relevant given the increasing pressure on institutional budgets. CONCLUSIONS: Dalteparin would be a cost-saving alternative in thromboprophylaxis of patients undergoing knee surgery at IMSS. PMID- 23351444 TI - [Profiles of cell proliferation and apoptosis in the mouse epithelial regeneration model K6b-E6/E7]. AB - BACKGROUND: Mammals have limited epithelial regeneration capacity. The K6b-E6/E7 mice model has been described as useful for the study of epithelial regeneration. The objective of this study is to compare the expression of E6/E7 oncogenes with those of cell proliferation and apoptosis during epithelization. The hypothesis of this study is that alterations in cell proliferation and apoptosis in K6b E6/E7 mice will only occur during epithelization. METHODS: Deep 2 mm punches were performed in the middle of transgenic and control mice's ears. A biopsy was collected from the epithelization zone 72 hours and 2 weeks post-injury. Assays for cell proliferation and apoptosis were carried out by immunohistochemistry and TUNEL techniques, respectively. RT-PCR in situ was performed to compare E6/E7 expressions in the areas studied. RESULTS: Transgenic strain K6b-E6/E7 presented more proliferative cells and less apoptotic cells in epithelizated zones. This effect was limited to suprabasal stratum only, and correlates with E6/E7 oncogenes expression. Two weeks post-injury, cell proliferation and apoptosis were similar in both samples as the E6/E7 expression went down. CONCLUSION: K6b E6/E7 mouse model is useful for epithelial regeneration. Its mechanisms should be considered for the treatment of deep wounds. PMID- 23351445 TI - [Distant heart procurement for transplantation]. AB - BACKGROUND: The low availability of organ donors is a serious hindrance to heart transplantation. Long-distance organ procurement has been accepted as an option despite longer ischemic time for the heart. METHODS: Long-distance procurement from outside Mexico City in adult patients with terminal heart failure submitted to orthotopic heart transplantation between February 1st 2011, and January 31st 2012, was assessed. Ischemic time, distance from Mexico City, and perioperative and short-time mortality were determined. RESULTS: There were 14 orthotopic heart transplants during the analyzed period. In 12 cases long-distance heart procurement was required. Mean age of recipients was 42.7 years (range between 17 and 61 years). Seven patients were male and five female. Mean ischemic time was 228.58 minutes. The longest distance of procurement for land and air travel was 2,319 km; and the lowest, 22.5 km. Perioperative mortality was 8.33% (one patient), and there were 2 short-term deaths due to non-cardiac complications. In this series we included a case of heart-kidney transplantation from same donor. CONCLUSION: At our hospital, long-distance procurement for heart transplantation is a useful procedure with good results. PMID- 23351446 TI - [Totally implantable central venous access devices in patients with cancer. Experience at a private oncology center]. AB - BACKGROUND: Use of totally implantable central venous access ports in cancer patients is a common practice for chemotherapy not excluding early and late morbidity. OBJECTIVE: To report the experience using these devices in a private cancer center. METHODS: A consecutive series of 156 cases of patients using these devices placed by the same surgical team to enhance chemotherapy. They were evaluated over a period of 44 months. Prevalence of early and late complications and days-risk for patient infection was determined. RESULTS: In 140 cases (89.8%) patients underwent placement of totally implantable devices by surgical cut down through the external jugular vein. One case was done (0.6%) through the internal jugular, and another one (0.6%) through the cephalic vein (0.6%). In the remaining 13 cases (8.4%) devices were placed by percutaneous puncture of the subclavian vein. In one case it was impossible to place it by any of the two access ways (0.6%). The prevalence of early complications was 3.22% and of late complications 1.93%. The average days-risk for the development of infection was 473.8/patient. One case had fracture of the catheter during follow up. There was no mortality. DISCUSSION: Overall complication rate was 5.15%, similar to that reported by reference centers, without infection during follow-up. Access through the external jugular vein facilitates correct positioning of the catheter and has fewer complications. CONCLUSIONS: The combination of a trained surgical team and careful monitoring reduces morbidity and prevents infections. Access through the external jugular is recommended for its accessibility and low morbidity. PMID- 23351447 TI - [Direct cost of spinal cord injuries]. AB - BACKGROUND: High prevalence and high costs in the treatment of spine injuries make a cost study necessary. The objective of this paper is to analyze, from the economic point of view, the behavior of traumatic and non-traumatic spinal pathologies in relation to hospital stay. METHODS: Analysis of economic cost per hospital stay (January 2000 to May 2010). RESULTS: 4,173 cases studied, 45% women and 55% men, predominantly elderly and a mean age of 48.9, standard deviation 16.8 years, with a notable increase in hospital expenses in prevalence and peak months: January, February and April; and a decrease in July, October and December. Total expenses for hospital stay were estimated as $85,565,288.00. Traumatic entities consumed $40,404,477.00, and degenerative $21,866,815.00. The months of highest spending were: April, $11,072,683.00, December, $8,423,773.00 and February $8,154,152.00; whereas July showed the lowest spending: $4,874,261.00. Inflation up to July 2011 remained at 3.55% on average, down 2.98 percentage points from 2008 figures. DISCUSSION: there is a clear increase in spending connected with spine condition treatment at hospitals, in particular those resulting from traumatic events. The definition of risk groups for preventive measures is also reflected in the spending records. Spending on hospital treatment of spinal conditions of the elderly reflects an increment in degenerative conditions. CONCLUSION: It is necessary to plan a timely resource distribution by month and year in order to achieve a better and more efficient scheme for health services. The epidemiological basis for the reorientation of the current models is now clear. PMID- 23351448 TI - [Initial experience in laparoscopic retroperitoneal lymphadenectomy for the management of nonseminomatous testicular cancer]. AB - BACKGROUND: Germ cell tumors of the testis represent 1% of all cancers in males. The mean age of occurrence is between 15 and 35 years. Early diagnosis and accuracy of staging are factors that have an impact in survival. According with stage I SO in nonseminoma tumors, there are three management options. Choice among them is based on the risk of recurrence, their morbidity and informed consent of the patient. The objective of this paper is to present the first results of retroperitoneal laparoscopic lymphadenectomy (RLL) in testicular germ cell nonseminoma tumors stage I S-0 at the Oncology Unit of Hospital Juarez de Mexico. METHODS: Retrospective study of the data base of patients diagnosed with nonseminomatous testicular cancer Stage I, S-0 and subject to retroperitoneal laparoscopic lymphadenectomy in the period between May 2010 to December 2011. RESULTS: Ten patients underwent transperitoneal retroperitoneal laparoscopic lymphadenectomy with modified limits, ipsilateral to the affected testicle, 70% were stage I-A, showing a nodal count of 15.3 nodes. None suffered from metastases. The followup mean for all patients was 9.6 months. One patient suffered retroperitoneal relapse off lymphadenectomy's reach 10 months after the original surgery. CONCLUSION: Retroperitoneal laparoscopic lymphadenectomy is a safe procedure with reasonable morbidity, hospital stay and nodal count. It requires a surgeon expert in laparoscopic techniques. PMID- 23351449 TI - [Hypothyroidism incidence after multimodal treatment for laryngeal cancer]. AB - BACKGROUND: Hypothyroidism following total laryngectomy or radiotherapy treatment for laryngeal cancer is not a rare event, especially in advanced stages. There are no reports on the incidence of hypothyroidism in patients who received chemotherapy and radiotherapy. The objective of this study is to determine the incidence of thyroid dysfunction in a group of patients with laryngeal cancer who underwent surgery as sole treatment, total laryngectomy or radiotherapy alone, and patients with combined treatment: surgery plus radiotherapy, concomitant chemoradiation therapy and chemoradiation therapy plus salvage surgery. METHODS: A prospective study of patients diagnosed with laryngeal cancer whose serum TSH and T4 levels were evaluated in a serial fashion. RESULTS: 70 patients with laryngeal cancer were studied; the average age at diagnosis was 70.2 years. Male patients were more affected, with a men-women ratio of 3.6:1. Glottic localization was the most frequent (44%). 64% of tumors were locally advanced carcinomas and 51% received multimodal treatment. 45 patients (63%) were diagnosed with hypothyroidism; 49% of the patients with subclinical hypothyroidism, and 51% with clinical hypothyroidism. CONCLUSIONS: Hypothyroidism is a complication following treatment for laryngeal cancer. It is recommended to evaluate the thyroid function periodically for timely detection. PMID- 23351450 TI - [Forestier disease. Case report and literature review]. AB - BACKGROUND: Forestier disease is a systemic disorder characterized by ossification of the anterior spinal longitudinal ligament (ALL) in at least three adjacent vertebrae, and diffuse spinal enthesopathy. Indication for surgical treatment is rare and limited to cases of related myelopathy, fracture or significant dysphagia. Few cases of surgical treatment are reported in the medical literature. Surgical treatment depends on the particular symptoms or complications, and usually involves osteophytectomy through the standard anterior approach. Surgery may bring about complications, such as pharyngeal paralysis, thrombosis, infections and respiratory obstruction. CLINICAL CASE: 79-year old male with dysphagia of 10 years of evolution, and hoarseness and respiratory distress since 8 years ago. Screening studies showed a diffuse calcification of anterior longitudinal ligament along with large cervical osteophytes. Forestier disease and secondary dysphagia were diagnosed. Surgical treatment consisted of resection of bone exostoses in C4 and C5 vertebral bodies. Six months after surgery, the patient reported improvement of esophageal and respiratory symptoms without evidence of recurrence on imaging studies. CONCLUSIONS: Data on Forestier disease's epidemiological nature and impact on life quality in Mexico is unknown. An increase in its occurrence is projected as the Mexican population ages. An observational study is required to identify the characteristics of this disease in Mexico. PMID- 23351451 TI - [Arthritis: an unusual and anticipatory clinical presentation of pediatric acute lymphoblastic leukemia. A case report]. AB - BACKGROUND: Acute lymphoblastic leukemia initially shows osteoarticular manifestations. However, it is rare that it shows juvenile idiopathic arthritis (JIA) symptoms. CLINICAL CASE: A child with acute lymphoblastic leukemia initially misdiagnosed with malignant neoplasia and septic arthritis, and later on with juvenile idiopathic arthritis. The child had persistent articular pain and swelling despite treatment. Six months later, a full blood count revealed leukopenia and neutropenia with lymphocytosis. A bone marrow aspirate confirmed pre-B acute lymphoblastic leukemia with hypodyploidia. CONCLUSION: This case initially showed typical signs of arthritis, and a diagnosis of acute lymphoblastic leukemia was ruled out, since the those clinical features and hematologic alterations characterizing this hematologic neoplasia. PMID- 23351452 TI - [Superior vena cava replacement with autologous pericardial conduit in redo cardiac surgery]. AB - BACKGROUND: Iatrogenic lesions needing repair can occur during redo cardiac surgery. Lacerations of the superior vena cava in redo cardiac surgery have been underreported. There is still debate around what prosthesis is best to replace the superior vena cava. A case of superior vena cava replacement for iatrogenic injury in a case of redo mitral valve surgery is reported. Use of fresh autologous pericardium to create a total conduit restoring the continuity of the superior vena cava is described. CLINICAL CASE: 54-year-old female with previous cardiac surgery undergoing prosthetic mitral valve replacement. During the course of the procedure, a major laceration in the superior vena cava was detected and successfully repaired by interposing a total conduit of fresh autologous pericardium. CONCLUSIONS: Use of autologous pericardium in order to make a total conduit for the superior vena cava reconstruction can be recommended because no long-term anticoagulation is required, and there is no additional economical cost and virtually no risk of infection. PMID- 23351453 TI - [Necrotizing fasciitis caused by cutaneous mucormycosis. A case report]. AB - BACKGROUND: Mucormycosis are opportunistic infections with high morbidity and mortality caused by fungi of the class Zygomycetes, they mainly affect diabetic and immunocompromised patients. In up to 20% of all cases the main infection is localized in the skin, with a great number of them presenting in healthy patients that have suffered from severe trauma or burns. Zygomycetes tend to invade arteries, which leads to thrombosis and generates wide necrotic areas; this favors the progress of the infection and invasion of deep tissues. Up to 24% of primary cutaneous mucormycosis can be complicated with necrotizing fasciitis. CLINICAL CASE: We present the case of a 52 year-old male that received the clinical diagnosis of necrotizing fasciitis. The patient received wide spectrum antibiotics and was submitted to extensive debridement of the wound bed; transoperative biopsy revealed the presence of zygomycetes in the tissues and the diagnosis of primary cutaneous zygomycosis was made. Antifungal treatment with amphotericin B was initiated and two weeks later autologous skin grafts were applied over the wounds. CONCLUSION: A high index of suspicion is needed to diagnose cutaneous zygomycosis, therefore it should always be considered amongst the differentials of necrotic wounds that do not respond to standard treatment. The rapid evolution of the disease remarks the importance of biopsying the wound bed early and treating aggressively. PMID- 23351454 TI - [Left lobe mesenchymal hamartoma of liver. Uncommon location]. AB - BACKGROUND: Mesenchymal hamartoma of the liver is a rare benign liver tumor in children, usually arising from the right liver lobe and represents about 5 to 6% of all primary hepatic tumors. Complete surgical resection of the tumor is curative. CLINICAL CASE: A 30 months old male presented with epigastrium abdominal pain and a palpable mass over a period of two days with no other symptom. The mass was excised completely. Postoperatively the patient recovered with an uneventful course and was discharge 13 days following surgery. All microscopic findings were consistent with the diagnosis of mesenchymal hamartoma of the liver. CONCLUSIONS: Approximately 75% of mesenchymal hamartoma of the liver occur in the right lobe of the liver. Several diagnostic considerations should be elucidated to differentiate these type of tumors in the left lobe from other benign liver tumors. Sometimes a multidisciplinary approach is necessary to complete a successful complete surgical excision. Our case exemplifies a rare entity in a rare location, an adequate treatment in a third level reference hospital setting. PMID- 23351455 TI - [Targeted epigenetic therapy of cancer. Achievements and perspectives]. AB - In this review, we provide an overview of the physiological and pathophysiological epigenetic changes of normal cells and cancer cells, and emphasize the achievements and the perspectives of cancer epigenetic therapy. Cancer epigenetic alterations correspond foremost to hypermethylation of tumor suppressor genes promotors, global DNA hypomethylation, and overexpression and activity of histone deacetylases. The purpose of epigenetic therapy is to revert the epigenetic alterations in cancer cells and obtain the "normal epigenome" restoration. Epigenetic targets in cancer therapy have focused on HDACs and DNMTs inhibition. The azacitidine and the decitabine, the vorinostat and the romidepsin were approved by US-FDA for treatment of myelodysplastic syndrome, and cutaneous T-cell lymphoma, respectively. Epigenetic and epigenomic changes in single or multiple genes have showed potential impact in cancer as early detection, prognosis and predictive marks. The epigenetic revolution has arrived for biology. The significant progress in epigenetic studies have allowed us, to understand new looks in the physiology and pathophysiology of embryonic development, cancer and other chronic diseases. Specific molecular epigenetic alterations in different cancer types, give us new strategies to design improved cancer therapy. The challenge for epigenetic investigators is design more specific epidrugs with lesser side effects. PMID- 23351456 TI - [Thromboprophylaxis in the perioperative: implications for technical regional anesthetic]. AB - BACKGROUND: Thromboprophylaxis in surgical patients requires specific measures to implement regional anesthesia techniques. In this regard the current clinical practice guidelines of anesthesiology summarizes the recommendations of the review of current evidence. OBJECTIVE: We must recognize the general guidelines for thromboprophylaxis and impact modifiers of coagulation for the Surgical Team to implement the actions for each specific patient. DISCUSSION: The most feared event by anesthesiologists is the spinal hematoma, but given its rarity there is a prospective randomized study, nor is there currently a laboratory model. Therefore the consensus established clinical practice recommendations for making a decision to anesthesia / analgesia epidural or spinal or peripheral nerve and the time of catheter removal in a patient receiving coagulation modifiers should be based on a individual analysis, weighing the small but definite risk of neuraxial hematoma with the benefits of regional anesthesia for a specific patient. CONCLUSION: the coagulation status should be evaluated and optimized at the time of placement of a needle anesthesia or continue either epidural, spinal or peripheral nerve blockade to continue prophylaxis as a priority without minimizing the risk of serious complications such as spinal bleeding. PMID- 23351457 TI - Meta-analysis of plaque composition by intravascular ultrasound and its relation to distal embolization after percutaneous coronary intervention. AB - Controversies exist regarding the association between plaque composition and distal embolization phenomenon after percutaneous coronary intervention (PCI). We evaluated the effect of plaque characteristics on embolization after PCI by grayscale and virtual histology-intravascular ultrasound (IVUS). We searched PubMed, Ovid MEDLINE, and Cochrane databases for IVUS studies evaluating the coronary plaque characteristics in no reflow, distal embolization, and periprocedural myocardial infarction after PCI. Sixteen studies were included, totaling 1,697 patients who underwent PCI (292 patients with embolization and 1,405 patients without embolization). At the minimum lumen sites, the external elastic membrane (weighted mean difference 2.38 mm(2), 95% confidence interval [CI] 1.02 to 3.74) and the plaque and media cross-sectional areas (weighted mean difference 2.44 mm(2), 95% CI 1.44 to 3.45) were significantly greater in the embolization group than in the no embolization group. Pooled analysis showed that the absolute necrotic core volume (standardized mean difference 0.49, 95% CI 0.13 to 0.85), absolute (standardized mean difference 0.73, 95% CI 0.14 to 1.31) and relative (standardized mean difference 1.02, 95% CI 0.72 to 1.31) necrotic core areas at the minimum lumen sites were significantly greater in the embolization group than in the no embolization group, but the other plaque components were similar in the 2 groups. In conclusion, the necrotic core component derived from virtual histology-IVUS and the morphologic characteristics of plaque derived from grayscale IVUS are closely related to the distal embolization phenomenon after PCI. PMID- 23351458 TI - Optical coherence tomographic observations of polytetrafluoroethylene-covered sirolimus-eluting coronary arterial stent. AB - The aim of this study was to evaluate neointimal coverage obtained using a new method of polytetrafluoroethylene-covered stent (PCS) implantation combined with underlying longer sirolimus-eluting stent (SES) implantation using optical coherence tomography. Nine patients were enrolled in this study, including patients with coronary artery perforations, original coronary aneurysms, and acquired coronary aneurysms after drug-eluting stent implantation. All patients were first treated with long SES implantation and then with focal PCS implantation. Postprocedural and follow-up angiographic and optical coherence tomographic examinations were performed in all patients, and intravascular ultrasound was performed in 5 patients. All patients were asymptomatic during follow-up, without recurrent angina. There was no stent-edge or stent-segment binary restenosis. Values of late loss for proximal SES segments, PCS segments, and distal SES segments were similar (0.09, 0.07, and 0.04 mm, respectively, p = 0.8113). The mean neointimal thickness of PCS was less than that of proximal and distal SES. However, no malapposed cross sections or uncovered cross sections were found in PCS segments compared with SES segments (p = 0.0011). In conclusion, the combination of PCS and underlying longer SES implantation can offer better angiographic follow-up results. High-resolution optical coherence tomography provided convincing proof of full neointimal coverage of PCS. This new method of combined PCS and SES implantation may be a better choice compared with direct PCS implantation in certain clinical settings. PMID- 23351459 TI - Usefulness of biventricular volume as a predictor of mortality in patients with diabetes mellitus (from the Diabetes Heart Study). AB - Patients with type 2 diabetes mellitus are at increased risk for cardiovascular disease (CVD) and mortality. Beyond traditional CVD risk factors, novel measures reflecting additional aspects of disease pathophysiology, such as biventricular volume (BiVV), may be useful for risk stratification. The aim of this study was to examine the relationship between BiVV and risk for mortality in European Americans with type 2 diabetes mellitus from the Diabetes Heart Study (DHS). BiVV was calculated from 771 noncontrast computed tomographic scans performed to image coronary artery calcified plaque. Relationships between BiVV and traditional CVD risk factors were examined. Cox proportional-hazards regression was performed to determine risk for mortality (all-cause and CVD mortality) associated with increasing BiVV. Area under the curve analysis was used to assess BiVV utility in risk prediction models. During 8.4 +/- 2.4 years of follow-up, 23% of the patients died. In unadjusted analyses, BiVV was significantly associated with increasing body mass index, height, coronary artery calcified plaque, history of hypertension, and previous myocardial infarction (p <0.0001 to 0.012). BiVV was significantly associated with all-cause (hazard ratio 2.45, 95% confidence interval 1.06 to 5.67, p = 0.036) and CVD (hazard ratio 4.36, 95% confidence interval 1.36 to 14.03, p = 0.014) mortality in models adjusted for other known CVD risk factors. Area under the curve increased from 0.76 to 0.78 (p = 0.04) and from 0.74 to 0.77 (p = 0.02) for all-cause and CVD mortality with the inclusion of BiVV. In conclusion, in the absence of echocardiography or other noninvasive imaging modalities to assess ventricular volumes, or when such methods are contraindicated, BiVV from computed tomography may be considered a tool for the stratification of high-risk patients, such as those with type 2 diabetes mellitus. PMID- 23351460 TI - Association between bilirubin and mode of death in severe systolic heart failure. AB - The bilirubin level has been associated with worse outcomes, but it has not been studied as a predictor for the mode of death in patients with systolic heart failure. The Prospective Randomized Amlodipine Evaluation Study (PRAISE) cohort (including New York Heart Association class IIIB-IV patients with left ventricular ejection fraction <30%, n = 1,135) was analyzed, divided by bilirubin level: <=0.6 mg/dl, group 1; >0.6 to 1.2 mg/dl, group 2; and >1.2 mg/dl, group 3. Multivariate Cox proportional hazards models were used to determine the association of bilirubin with the risk of sudden or pump failure death. Total bilirubin was entered as a base 2 log-transformed variable (log2 bilirubin), indicating doubling of the bilirubin level corresponding to each increase in variable value. The higher bilirubin groups had a lower ejection fraction (range 19% to 21%), sodium (range 138 to 139 mmol/L), and systolic blood pressure (range 111 to 120 mm Hg), a greater heart rate (range 79 to 81 beats/min), and greater diuretic dosages (range 86 to 110 furosemide-equivalent total daily dose in mg). The overall survival rates declined with increasing bilirubin (24.3, 31.3, and 44.3 deaths per 100 person-years, respectively, for groups 1, 2, and 3). Although a positive relation was seen between log2 bilirubin and both pump failure risk and sudden death risk, the relation in multivariate modeling was significant only for pump failure mortality (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82, p = 0.0004), not for sudden death mortality (hazard ratio 1.21, 95% confidence interval 0.98 to 1.49, p = 0.08). In conclusion, an increasing bilirubin level was significantly associated with the risk of pump failure death but not for sudden death in patients with severe systolic heart failure. PMID- 23351461 TI - Usefulness of albuminuria as a prognostic indicator in patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. AB - Albuminuria is an established risk factor for mortality and cardiovascular events in the general population. Albuminuria might be a marker of the various pathophysiologic changes, such as diffuse vascular injury and systemic inflammation, that arise in patients with chronic heart failure (CHF). However, the relation between albuminuria and CHF has not yet been fully elucidated. Therefore, the purpose of the present study was to assess the prevalence and prognostic significance of albuminuria in patients with CHF secondary to ischemic or idiopathic dilated cardiomyopathy. Of the 712 patients with CHF, 311 had normoalbuminuria, 304 had microalbuminuria, and 97 had macroalbuminuria. The patients with albuminuria had more cardiovascular co-morbidity and worse renal function than those with normoalbuminuria. A total of 152 cardiac events occurred during the follow-up period. Kaplan-Meier analysis demonstrated that patients with albuminuria had a greater incidence of cardiac events than those without albuminuria. Furthermore, albuminuria was significantly associated with an increased risk of cardiac events, even after adjustment for other prognostic variables. In conclusion, albuminuria is a powerful and independent predictor of adverse prognosis in patients with CHF and could be useful for risk stratification of patients with CHF. PMID- 23351462 TI - Diagnostic accuracy retrospectively of electrocardiographic findings and cancer history for tamponade in patients determined to have pericardial effusion by transthoracic echocardiogram. AB - Unexpected pericardial effusions are often found by frontline providers who perform computed tomography. To study the hypothesis that electrocardiographic findings and whether cancer is known or suspected importantly change the likelihood of tamponade for such providers, all unique patients with moderate or large pericardial effusions determined by transthoracic echocardiography during a 6-year period were retrospectively identified. Electrocardiograms were evaluated by blinded investigators for electrical alternans (total and QRS), low voltage (limb leads only, precordial leads only, and both), and tachycardia (>100 QRS complexes/min). Medical records were reviewed to determine whether cancer was known or suspected and whether tamponade was diagnosed. Tamponade was present in 66 patients (27% of 241) with moderate or large pericardial effusions. No tachycardia lowered the odds of tamponade the most (likelihood ratio 0.4, 95% confidence interval 0.3 to 0.6) but by a degree less than any single diagnostic element increased it when present. The combined presence of all 3 electrocardiographic findings and cancer increased the odds of tamponade 63-fold (likelihood ratio 63, 95% confidence interval 33 to 150), whereas their combined absence decreased the odds only fivefold (likelihood ratio 0.2, 95% confidence interval 0.2 to 0.3). In conclusion, electrocardiography findings and cancer rule in tamponade better than they rule it out. Combining these diagnostic elements improves their discriminatory power but not sufficiently enough to rule out tamponade in patients with moderate or large pericardial effusions. PMID- 23351463 TI - Comparison of stent length reported by the stent's manufacturer to that determined by quantitative coronary angiography at the time of implantation versus that determined by coronary computed tomographic angiography at a later time. AB - The aim of this study was to assess whether coronary computed tomographic angiography (CCTA) would allow accurate length measurements that may help select optimal stent length. In 19 patients who underwent stent implantation and CCTA, the lengths of 30 implanted stents were assessed independently using quantitative coronary angiography (QCA) at the time of implantation and CCTA during follow-up. Measurements on CCTA and QCA were compared with the actual lengths of the implanted stents. The mean actual stent length was 17.3 +/- 6.3 mm; the mean length of the stents measured using CCTA was 17.25 +/- 5.54 mm, and the mean length of the stents measured using QCA was 15.92 +/- 5.86 mm. There was a stronger positive correlation between measurements on CCTA versus actual stent lengths (R = 0.99, p = 0.0001) than between measurements on QCA versus actual stent lengths (R = 0.82, p = 0.0001) (p <0.0001 for the difference between correlation coefficients). In conclusion, the length measurements obtained with CCTA correlate better with an anatomic gold standard (actual stent lengths) than those obtained using QCA. PMID- 23351464 TI - Infarct artery distribution and clinical outcomes in occluded artery trial subjects presenting with non-ST-segment elevation myocardial infarction (from the long-term follow-up of Occluded Artery Trial [OAT]). AB - We hypothesized that the insensitivity of the electrocardiogram in identifying acute circumflex occlusion would result in differences in the distribution of the infarct-related artery (IRA) between patients with non-ST-segment elevation myocardial infarction (NSTEMI) and STEMI enrolled in the Occluded Artery Trial. We also sought to evaluate the effect of percutaneous coronary intervention to the IRA on the clinical outcomes for patients with NSTEMI. Overall, those with NSTEMI constituted 13% (n = 283) of the trial population. The circumflex IRA was overrepresented in the NSTEMI group compared to the STEMI group (42.5 vs 11.2%; p <0.0001). The 7-year clinical outcomes for the patients with NSTEMI randomized to percutaneous coronary intervention and optimal medical therapy versus optimal medical therapy alone were similar for the primary composite of death, myocardial infarction, and class IV congestive heart failure (22.3% vs 20.2%, hazard ratio 1.20, 99% confidence interval 0.60 to 2.40; p = 0.51) and the individual end points of death (13.8% vs 17.0%, hazard ratio 0.82, 99% confidence interval 0.37 to 1.84; p = 0.53), myocardial infarction (6.1 vs 5.1%, hazard ratio 1.11, 99% confidence interval 0.28 to 4.41; p = 0.84), and class IV congestive heart failure (6.7% vs 6.0%, hazard ratio 1.50, 99% confidence interval 0.37 to 6.02; p = 0.45). No interaction was seen between the electrocardiographically determined myocardial infarction type and treatment effect (p = NS). In conclusion, the occluded circumflex IRA is overrepresented in the NSTEMI population. Consistent with the overall trial results, stable patients with NSTEMI and a totally occluded IRA did not benefit from randomization to percutaneous coronary intervention. PMID- 23351465 TI - Comparison of hemodynamic performance of self-expandable CoreValve versus balloon expandable Edwards SAPIEN aortic valves inserted by catheter for aortic stenosis. AB - Transcatheter aortic valve implantation with the self-expandable CoreValve (CV) and the balloon-expandable Edwards SAPIEN (ES) bioprostheses has been widely used for the treatment of severe aortic stenosis. However, a direct comparison of the hemodynamic results associated with these 2 prostheses is lacking. The aim of the present study was to compare the hemodynamic performance of both bioprostheses. A total of 41 patients who underwent transcatheter aortic valve implantation with the CV prosthesis were matched 1:1 for prosthesis size (26 mm), aortic annulus size, left ventricular ejection fraction, body surface area, and body mass index with patients who underwent transcatheter aortic valve implantation with the ES prosthesis. Doppler-echocardiographic data were prospectively collected before the intervention and at hospital discharge, and all examinations were sent to, and analyzed in, a central echocardiography core laboratory. The mean transprosthetic residual gradient was lower (p = 0.024) in the CV group (7.9 +/- 3.1 mm Hg) than in the ES group (9.7 +/- 3.8 mm Hg). The effective orifice area tended to be greater in the CV group (1.58 +/- 0.31 cm(2) vs 1.49 +/- 0.24 cm(2), p = 0.10). The incidence of severe prosthesis-patient mismatch was, however, similar between the 2 groups (effective orifice area indexed to the body surface area <=0.65 cm(2)/m(2); CV 9.8%, ES 9.8%, p = 1.0). The incidence of paravalvular aortic regurgitation was greater with the CV (grade 1 or more in 85.4%, grade 2 or more in 39%) than with the ES (grade 1 or more in 58.5%, grade 2 or more in 22%; p = 0.001). The number and extent of paravalvular leaks were greater in the CV group (p <0.01 for both comparisons). In conclusion, transcatheter aortic valve implantation with the CV prosthesis was associated with a lower residual gradient but a greater rate of paravalvular aortic regurgitation compared to the ES prosthesis. The potential clinical consequences of the differences in hemodynamic performance between these transcatheter heart valves needs to be addressed in future studies. PMID- 23351467 TI - [Introduction. Pulmonary hypertension]. PMID- 23351468 TI - [Diagnostic and prognostic evaluation in patients with pulmonary hypertension]. AB - Pulmonary hypertension (PH) is a hemodynamic disorder that occurs in a series of distinct diseases and is defined by the presence of a mean pulmonary artery pressure of >= 25 mm Hg. Clinically, this disorder is classified in five groups. Of these, group I, or pulmonary arterial hypertension (PAH), although infrequent, deserves special attention due to the specific therapeutic implications involved. Based on clinical suspicion and/or the results of echocardiogram, the diagnosis of this entity is established by following a strict protocol that should include right-sided cardiac catheterization. PH is a severe, progressive disease whose prognosis mainly depends on the degree of right ventricular involvement. Once the diagnosis has been confirmed, severity must be evaluated to initiate the most appropriate treatment for the patient's status. To do this, several clinical, biological, and echocardiographic-hemodynamic parameters and indicators of exercise capacity can be used. PMID- 23351466 TI - What are those cilia doing in the neural tube? AB - Primary cilia are present on almost all vertebrate cells, and they have diverse functions in distinct tissues. Cilia are important for sensation in multiple capacities in contexts as different as the retina, kidney, and inner ear. In addition to these roles, cilia play a critical part in various developmental processes. Of particular importance is the development of the neural tube, where cilia are essential for the transduction of the Sonic Hedgehog (Shh) signaling pathway that specifies neuronal cell fates. This relationship is well established and is the most recognizable function for cilia in the neural tube, but it may be part of a larger picture. Here, we discuss the links between cilia and Shh signaling, as well as suggesting additional roles for cilia, and mechanisms for their placement, in the neural tube. PMID- 23351469 TI - [Role of echocardiography in suspected pulmonary hypertension]. AB - Echocardiography is the non-invasive method of choice for the study of patients with suspected pulmonary hypertension. This technique allows systolic pulmonary artery pressure to be estimated and can also provide additional information on the cause and effects of the disease. To estimate systolic pulmonary pressure, equivalent to right ventricular systolic pressure, maximal flow velocity of tricuspid regurgitation and right atrial pressure--estimated on the basis of the degree of inferior vena cava dilation--can be employed. Other parameters that should be evaluated are those related to right cavity size and right ventricular function. Unlike the left ventricle, the anatomy and geometry of the right ventricle is complex, hampering calculation of its systolic function. Consequently, over the years, various indirect methods have been developed to estimate right systolic function, the most commonly used being tricuspid annular plane systolic excursion (TAPSE) and the Tei index. New echocardiographic methods such as study of myocardial deformation (strain) and three-dimensional echocardiography may soon provide data suggesting poor clinical course in the short and medium term. Consequently, accurate determination and characterization of these data are essential. PMID- 23351470 TI - [Hemodynamic study: indications for right- and left-sided catheterization in the diagnosis and follow-up of pulmonary hypertension]. AB - Pulmonary artery hypertension (PAH) is a category of pulmonary hypertension consisting of mean pulmonary artery pressure greater than 25 mmHg at rest, with normal pulmonary capillary occlusion pressure (less than 15 mmHg) and pulmonary vascular resistance greater than 3 Wood units. The diagnosis of PAH is made through the exclusion of other disorders, including pulmonary, thromboembolic, left ventricular and valvular heart disease. All patients with PAH suspected on the basis of non-invasive tests should undergo right-sided catheterization before treatment is started, with measurement of pulmonary artery pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance. Pulmonary vasoreactivity and cardiac output should also be measured. To test pulmonary vasoreactivity, inhaled nitric oxide and intravenous adenosine or epoprosterenol are used. A reduction of 10 mmHg in mean pulmonary arterial pressure or achieving a mean pulmonary artery pressure of less than 40 mmHg, with no change or an increase in cardiac output, is considered a positive response. These criteria are met by only 10% of patients with PAH undergoing this test. Patients with a positive response will probably also show a sustained response to calcium channel blockers. This test should not be used in patients with PAH secondary to left cardiac disease, pulmonary disease or pulmonary embolism. PMID- 23351471 TI - [The cardiopulmonary exercise test in the management of patients with pulmonary hypertension]. AB - The main symptom of patients with pulmonary hypertension (PH) is exercise intolerance. The gold standard for evaluation of exercise capacity is the incremental cardio-pulmonary exercise test (ICPET) on a bicycle ergometer. Exercise tolerance in patients with PH is mainly determined by the capacity to increase cardiac output to meet metabolic demands, which depends on right ventricular function. Therefore, right ventricular dysfunction is the main factor limiting exercise tolerance in PH. Patients with PH also show hypoxemia during exercise and hyperventilation is also common, both at rest and during exercise, which can be attributed to greater chemosensitivity. The present review analyzes the physiological mechanisms determining exercise tolerance, exercise response in patients with PH, the variables of greatest interest in the study of this disorder, the similarities and differences between ICPET and other, simpler tests such as the 6-minute walk test, and the prognostic value of exercise testing in these patients. Evaluation of exercise tolerance is an essential element in the clinical assessment of patients with PH. Consequently, detailed knowledge of the information provided by exercise testing and its limitation is of undoubted interest in the clinical management of this complex disease. PMID- 23351472 TI - [Biological markers. Utility in the management of patients with pulmonary hypertension]. AB - A biological marker can be defined as any substance that can be objectively measured and evaluated as an indicator of a normal biological process, a pathogenic process or pharmacological responses to a therapeutic intervention. In pulmonary hypertension (PH), in addition to routine markers (hemodynamic and functional), there are a growing number of biomarkers that allow an increasingly comprehensive approach to knowledge of susceptibility to this disease and to diagnosis, prognosis and treatment response. These markers can be both constitutive (genetic) and disease-related (related to right ventricular failure, such as BMP/NT-proBNP, endothelial dysfunction, such as endothelin-1, or inflammation, such as certain cytokines and chemokines). Novel insights in genomics and proteomics may allow major advances in this field. PMID- 23351473 TI - [Tadalafil: novel aspects of phosphodiesterase-5 inhibition in the treatment of pulmonary hypertension]. AB - Tadalafil, which was commercialized in 2009, is a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, and may be a safe and effective therapeutic alternative for patients with class II and III pulmonary hypertension (PH) in the World Health Organization's classification--as stated in the Clinical Practice Guidelines for the Diagnosis and Treatment of PH of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)--providing benefits in exercise tolerance, delaying clinical deterioration and improving quality of life. Given the greater half-life of this drug, allowing a single oral dose of 40 mg per day, tadalafil could improve therapeutic compliance--thus facilitating treatment adherence--among patients with PH. PMID- 23351474 TI - High surface area Au-SBA-15 and Au-MCM-41 materials synthesis: tryptophan amino acid mediated confinement of gold nanostructures within the mesoporous silica pore walls. AB - Advantages of confining the gold nanostructures formation within the mesoporous silica pore walls during its silica condensation and consequent improvement in the textural properties such as specific surface area, pore volume, pore diameter have been demonstrated, while retaining gold nanostructures within the silica walls. This has been achieved by tryptophan mediated confinement of gold nanoparticles formation within the condensing silica framework, to obtain Au-SBA 15 (SSA 1247 m(2)/g, V(t)~1.37 cm(3)/g) and Au-MCM-41 (SSA 1287 m(2)/g, V(t)~1.1 cm(3)/g), mesoporous silica materials having the combination of very high surface area from the porous support as well as gold nanoparticles infiltrated silica walls. Choice of tryptophan for this purpose is that it has an indole group, which was known to reduce gold ions to form gold nanoparticles and its amine and carboxylic acid groups, catalyze the hydrolysis of silica precursors in a wide range of pH. These properties have been utilized in restricting the gold nanostructures formation inside the condensing silica phase without affecting the self assembly between the silica precursors and the triblock copolymer (for SBA 15) or cetyltrimethylammonium bromide template (for MCM-41). The polytryptophan and the gold nanostructures, which were encapsulated within the silica framework and upon removal of the template by calcination resulting in the formation mesoporous materials wherein the silica walls become microporous due to the removal of occluded polytryptophan and the resulting microchannels contain very small gold nanostructures. Hence, the resulting materials have very high surface area, high pore volume and narrow pore size distribution as compared to their parent SBA-15, MCM-41 and SBA-15, MCM-41 post functionalized with gold nanoparticles inside the pores. PMID- 23351475 TI - Self-assembly of resins and asphaltenes facilitates asphaltene dissolution by an organic acid. AB - Asphaltene precipitation occurs in petroleum fluids under certain unfavorable conditions, but can be controlled by tuning composition. Aromatic solvents in large quantities can prevent precipitation entirely and can dissolve already precipitated asphaltenes. Some polymeric surfactants can dissolve asphaltenes when added at much lower concentrations than required by aromatic solvents. Other dispersants can truncate asphaltene precipitation at the sub-micron length scale, creating stable colloidal asphaltene dispersants. One particular asphaltene dispersant, dodecylbenzene sulfonic acid (DBSA), can do both, namely: (1) stabilize asphaltene colloids and (2) dissolve asphaltenes to the molecular scale. Acid-base interactions are responsible for the efficiency of DBSA in dissolving asphaltenes compared to aromatic solvents. However, many details remain to be quantified regarding the action of DBSA on asphaltenes, including the effect of petroleum fluid composition. For instance, resins, naturally amphiphilic components of petroleum fluids, can associate with asphaltenes, but it is unknown whether they cooperate or compete with DBSA. Similarly, the presence of metals is known to hinder asphaltene dissolution by DBSA, but its effect on colloidal asphaltene stabilization has yet to be considered. We introduce the concepts of cooperativity and competition between petroleum fluid components and DBSA in stabilizing and dissolving asphaltenes. Notably, we find that resins cooperatively interact with DBSA in dissolving asphaltenes. We use UV vis spectroscopy to investigate the interactions responsible for the phase transitions between unstable suspensions, stable suspensions, and molecular solutions of asphaltenes. PMID- 23351476 TI - Comparing the effects of fluoxetine and imipramine on total cholesterol, triglyceride, and weight in patients with major depression. AB - BACKGROUND: There are some reports on the effects of antidepressants on metabolic syndrome. However, our search in the previously published literature showed a lack of information on the comparison of the effects of different classes of antidepressants on lipid profile. Therefore, this study was aimed to compare the effects of fluoxetine and imipramine on serum total cholesterol (TC) and triglyceride (TG) as well as body weight (BW) in patients with major depressive disorder. METHODS: Fifty one patients, 18 to 70 years of age, with major depressive disorder complied with the criteria of this preliminary, open label clinical trial. Subjects received either imipramine (75-200 mg/day) or fluoxetine (20-40 mg/day) for 8 weeks. Total cholesterol and TG levels, as well as BW were compared at baseline with those at weeks 4 and 8. Data was analyzed by SPSS software version 16.0. RESULTS: In the fluoxetine group, TC levels decreased from 165.71 mg/dL to 156.71 mg/dL at week 4 (P = 0.07), and to 143.94 mg/dL at week 8 (P = 0.16); TG levels decreased from 129.35 mg/dL to 115.88 mg/dL at week 4 (P <0.001), and to 110.41 mg/dL at week 8 (P = 0.56). In the imipramine group, TC levels increased from 169.10 mg/dL to 178.69 mg/dL at week 4 (P = 0.07), and to 208.69 mg/dL at week 8 (P < 0.001) while TG levels increased from 111.73 mg/dL to 128.83 mg/dL at week 4 (P = 0.005), and to 160.90 mg/dL at week 8 (P < 0.001). BW was significantly increased in the imipramine group at weeks 4 and 8. In the fluoxetine group, BW was non-significantly decreased from 75.69 +/- 7.97 Kg (baseline) to 75.67 +/- 8.01 Kg at week 4 (P = 0.88), and to 75.22 +/- 8.67 Kg at week 8 (P = 0.20), while in the imipramine group, BW had significant increases from 72.53 +/- 8.55 Kg (baseline) to 73.95 +/- 8.61 mg/dL at week 4 (P < 0.001), and to 75.13 +/- 8.34 mg/dL at week 8 (P < 0.001).Repeated measures ANOVA showed significant effects on both TC and TG levels as well as on BW in all patients receiving imipramine. However, in patients on fluoxetine, repeated measures ANOVA showed significant effects of this medication only on TC levels in males. CONCLUSIONS: Monitoring TC and TG and BW is recommended before starting imipramine in depressed patients with increased risk for cardiovascular disease. Fluoxetine may be the preferred agent in those with high or borderline high lipid levels. PMID- 23351477 TI - Transnasal endoscopic approach with powered instrumentation for treating squamous papilloma in the nasopharyngeal surface of the soft palate. AB - OBJECTIVE: To demonstrate a safe and effective method for complete resection of squamous papilloma in the nasopharyngeal surface of the soft palate. This technique was used on a patient in whom the papilloma had twice recurred following uvulopalatopharyngoplasty. METHODS: Case report and review of the relevant literature. RESULTS: The patient reported in this paper had recurrent squamous papilloma in the nasopharyngeal surface of the soft palate following uvulopalatopharyngoplasty. He also suffered from nasal regurgitation when drinking water. This lesion, which was difficult to access, was successfully treated via a transnasal endoscopic approach using powered instrumentation. CONCLUSION: This case report highlights a novel approach for the complete removal of a recurrent papilloma in a relatively inaccessible location. Compared with a transoral approach such as uvulopalatopharyngoplasty, the transnasal endoscopic approach using powered instrumentation could provide a safer, faster, easier and less invasive means of treating squamous papilloma in the nasopharyngeal surface of the soft palate, especially for a lesion that recurs following a transoral approach. PMID- 23351478 TI - Management of vascular lesions by electrical fulguration (by continuous flow of electric current at 210-220 V with 50-Hz A/C cycle): a new technique. PMID- 23351479 TI - Presentation of intramuscular myxoma as an unusual neck lump. AB - Intramuscular myxoma (IM) has a distinct diagnostic identity among soft tissue myxomas. IMs have an approximate incidence of 1 per million of the population per year, with a female-to-male ratio of 14:3. The age range for presentation is 40 to 70 years, and the thigh is affected most frequently. IMs most commonly affect larger muscle groups, making the head and neck a rare site. To the authors' knowledge, there is 1 previous report of an IM presenting in the sternocleidomastoid muscle. In addition, IMs usually present as slow-growing asymptomatic swellings. Although abnormal gag reflexes have been reported in cases of glossopharyngeal schwannoma and neurofibroma in patients with neurofibromatosis-1, a gag reflex has not been reported previously as a complication of IM in the head and neck. A case of IM in the left sternocleidomastoid muscle, presenting with an intense gag reflex on palpation, in a 70-year-old woman is presented. PMID- 23351480 TI - Laser versus ultrasound on bone density recuperation after distraction osteogenesis-a cone-beam computer tomographic analysis. AB - PURPOSE: To assess the effects of low-level laser versus ultrasound irradiation on bone mineral density after distraction osteogenesis using cone-beam computed tomographic analysis in an experimental study. MATERIALS AND METHODS: Distraction osteogenesis was performed with rapid maxillary expansion devices (Hyrax-Morelli, Sorocaba-Sao Paulo-Brazil). After a 2-day latency period, the distraction devices were activated for 10 days at a rate of 1 mm/day. Four groups of 6 animals were distributed as follows: 1) control, 2) laser irradiation on the right side, 3) ultrasound irradiation on the right side, and 4) laser irradiation on the right side and ultrasound on the left side. Cone-beam computed tomography was used to determine bone mineral density by measuring the recovery (percentage). Analysis of variance and the Tukey test (P = .05) were used for statistical analyses. RESULTS: The influences of low-intensity laser and ultrasound irradiation on bone mineral density were statistically significant. The analyses showed greater bone mineral density recuperation in the mandibular side with the ultrasound application. CONCLUSIONS: The results of this study suggest an acceleration of bone mineral density after laser and ultrasound irradiation. Ultrasound irradiation showed the greatest effects and the laser power positively influenced the recuperation of the bone density on the side opposite its application, causing a cross reaction or even exacerbating the inherent action of ultrasound irradiation. PMID- 23351481 TI - Bone marrow carcinosis in head and neck carcinoma in a young adult. AB - Bone marrow carcinosis has been reported as a consequence of several solid tumors. However, in relation to head and neck squamous cell carcinoma, it is an indication of the rarity of the disease that only 2 reported cases exist in the literature. A 36-year-old male patient was admitted with the diagnosis of squamous cell carcinoma on the floor of the mouth. After the exclusion of distant metastatic disease, tumor surgery was performed. After a regular postoperative course over 3 days, the patient complained of progressive pain in the lower back. Extensive workup included position-emission tomography, which detected an enhancement of the bone marrow. Bone marrow biopsy elucidated advanced bone marrow carcinosis. Palliative chemotherapy was recommended, but the patient deteriorated rapidly and died from septic multiorgan failure within 6 weeks after surgery. Thus, bone marrow carcinosis must be considered in patients with head and neck tumor and osseous pain. PMID- 23351482 TI - Characterization of mandibular fractures incurred from battle injuries in Iraq and Afghanistan from 2001-2010. AB - PURPOSE: The mandible is the most commonly fractured bone in the craniomaxillofacial skeleton among military casualties. The purpose of this study was to characterize the nature and severity of mandibular fractures incurred by US military personnel during combat. MATERIALS AND METHODS: We queried the Joint Theater Trauma Registry from October 2001 to April 2011 using all pertinent International Classification of Diseases, Ninth Revision codes to identify fractures of the mandible. Fractures were then classified based on type and location. Chart reviews were performed on the subset of patients who were treated at San Antonio Military Medical Center to further classify the anatomic pattern and treatment of these fractures. RESULTS: We identified 391 patients with mandibular fractures, of whom 45 were transferred to San Antonio Military Medical Center. Open fractures were seen in 75% of patients. Two or more fractures of the mandible were seen in 51% of patients. Comminuted fractures were present in 84%, and 31% had segmental losses. Eighty-six percent of fractures were operative; two thirds of patients required a single surgical procedure, whereas the remaining one-third required multiple procedures. Forty-six percent of patients had pan facial fractures. CONCLUSIONS: Mandibular fractures as a result of combat blast injuries were characterized by a high incidence of open, comminuted, multiple fractures. Associated facial fractures were common. PMID- 23351483 TI - Preparation of water-soluble nanographite and its application in water-based cutting fluid. AB - Water-soluble nanographite was prepared by in situ emulsion polymerization using methacrylate as polymeric monomer. The dispersion stability and dispersion state of graphite particles were evaluated by UV-visible spectrophotometry and scanning electron microscopy, respectively. The water-soluble nanographite was then added into the water-based cutting fluid as lubricant additive. The lubrication performance of water-based cutting fluid with the nanographite additive was studied on four-ball friction tester and surface tensiometer. Results indicate that the modification method of in situ emulsion polymerization realizes the uniform and stabilized dispersion of nanographite in aqueous environment. The optimal polymerization condition is 70 degrees C (polymerization temperature) and 5 h (polymerization time). The addition of nanographite decreases the friction coefficient and wear scar diameter by 44% and 49%. Meanwhile, the maximum non seizure load (PB) increases from 784 to 883 N, and the value of surface tension (32.76 * 10-3 N/m) is at low level. Nanographite additive improves apparently the lubrication performance of water-based cutting fluid. PMID- 23351485 TI - The University of Michigan Dioxin Exposure Study: estimating residential soil and house dust exposures to young children. AB - The University of Michigan Dioxin Exposure Study provides extensive data on elevated residential soil and house dust concentrations of polychlorinated dioxins and dibenzofurans (PCDD/Fs) and adult body burdens among residents near a chemical manufacturing plant in Midland, Michigan. Recent reports found no significant contribution of residential soil/dust concentrations to serum lipid PCDD/Fs in adults. Although child body burdens were not studied by the University of Michigan, internal dose modeling that incorporates recent findings on demonstrated shorter elimination half life of PCDD/Fs in children (1-2 year half life in children vs. ~7 years in older adults) can be applied to assess this important issue. The model examines children (ages 0-7 years) with background dietary intake and exposure to residential soils at selected concentrations (10, 100 and 1000 pg/g 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents, TEQ) using the congener patterns observed in Midland. Model predictions assuming 50th percentile TEQ uptake from soil/dust-related dermal and ingestion exposures indicate no measurable changes in serum lipid TEQ concentrations up to 1000 pg/g in soil/dust. Assuming 95th percentile uptake, the model shows no measurable serum lipid TEQ change up to 100 pg/g in soil/dust, but serum lipid TEQ levels rose ~2 pg/g at 1000 pg/g in soil/dust. Since the vast majority of soil/dust data were below 100 pg/g, Michigan children exposed to such soil/dust TEQ concentrations are not reasonably expected to exhibit measurable changes in serum lipid TEQ concentrations when compared to typical background dietary exposures. With adequate data, this approach can be applied to evaluate child dose and risk for other persistent chemicals. PMID- 23351484 TI - Induced in-source fragmentation pattern of certain novel (1Z,2E)-N (aryl)propanehydrazonoyl chlorides by electrospray mass spectrometry (ESI-MS/MS). AB - BACKGROUND: Collision induced dissociation (CID) in the triple quadrupole mass spectrometer system (QQQ) typically yields more abundant fragment ions than those produced with resonance excitation in the presence of helium gas in the ion trap mass spectrometer system (IT). Detailed product ion spectra can be obtained from one stage MS2 scan using the QQQ. In contrast, generating the same number of fragment ions in the ion trap requires multiple stages of fragmentation (MSn) using CID via in-trap resonance excitation with the associated time penalties and drop in sensitivity. RESULTS: The use of in-source fragmentation with electrospray ionization (ESI) followed by product ion scan (MS2) in a triple quadrupole mass spectrometer system, was demonstrated. This process enhances the qualitative power of tandem mass spectrometry to simulate the MS3 of ion trap for a comprehensive study of fragmentation mechanisms. A five pharmacologically significant (1Z, 2E)-N-arylpropanehydrazonoyl chlorides (3a-e) were chosen as model compounds for this study. In this work, detailed fragmentation pathways were elucidated by further dissociation of each fragment ion in the ion spectrum, essentially, by incorporating fragmentor voltage induced dissociation (in-source fragmentation) and isolation of fragments in a quadrupole cell Q1. Subsequently, CID occurs in cell, Q2, and fragment ions are analyzed in Q3 operated in product ion mode this process can be referred to as pseudo-MS3 scan mode. CONCLUSIONS: This approach allowed unambiguous assignment of all fragment ions using tandem mass spectrometer and provided adequate sensitivity and selectivity. It is beneficial for structure determination of unknown trace components. The data presented in this paper provide useful information on the effect of different substituents on the ionization/fragmentation processes and can be used in the characterization of this important class of compounds. PMID- 23351486 TI - Hormones, sterols, and fecal indicator bacteria in groundwater, soil, and subsurface drainage following a high single application of municipal biosolids to a field. AB - A land application of dewatered municipal biosolids (DMB) was conducted on an agricultural field in fall 2008 at a rate of 22Mg dry weight (dw) ha(-1). Pre- and post- application, hormone, sterol and fecal indicator bacteria concentrations were measured in tile drainage water, groundwater (2, 4, 6m depth), surface soil cores, and DMB aggregates incorporated in the soil (~0.2m depth) for a period of roughly 1year post-application. Hormones and sterols were detected up to 1year post-application in soil and in DMB aggregates. Hormone (androsterone, desogestrel, estrone) contamination was detected briefly in tile water samples (22d and ~2months post-app), at lowngL(-1) concentrations (2-34ngL( 1)). Hormones were not detected in groundwater. Sterols were detected in tile water throughout the study period post-application, and multiple fecal sterol ratios suggested biosolids as the source. Coprostanol concentrations in tile water peaked at >1000ngL(-1) (22d post-app) and were still >100ngL(-1) at 6months post-application. Fecal indicator bacteria were detected throughout the study period in tile water, groundwater (?2m depth), soil and DMB aggregate samples. These bacteria were strongly linearly related to coprostanol in tile water (R(2)>0.92, p<0.05). The limited transport of hormones and sterols to tile drainage networks may be attributed to a combination of the hydrophobicity of these compounds and limited macroporosity of the field soil. This transitory contamination from hormones and sterols is unlikely to result in any significant pulse exposure risk in subsurface drainage and groundwater. PMID- 23351487 TI - Effects of IMODTM and AngiparsTM on mouse D-galactose-induced model of aging. AB - The aim of this study was to evaluate the effects of two registered herbal drugs called IMOD and Angipars on mouse model. Aging was induced by D-galactose (500 mg/kg) administered to animals for 6 weeks through drinking water. Male BALB/c mice were randomly divided into 5 groups receiving D-galactose (D-galactose, 500 mg/kg) for 6 weeks; positive control (D-galactose [500 mg/kg] for 6 weeks + Vitamin E [200 mg/kg/day] intraperitoneally for 4 weeks); IMOD (D-galactose [500 mg/kg] for 6 weeks + IMOD [20 mg/kg/day] intraperitoneally for 4 weeks), Angipars (D-galactose [500 mg/kg] for 6 weeks + Angipars [2.1 mg/kg/day] by gavage for 4 weeks); and the fifth group that was sham and not given D-galactose. At the end of treatment, pro-inflammatory markers including tumor necrosis factor-alpha (TNF alpha), interlukine-1beta (IL-beta), interlukine-6 (IL-6), Nuclear Factor-kappaB (NF-kappab), total antioxidant power (TAP), lipid peroxides (LPO) and male sex hormones i.e. testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were measured in the blood.Results showed that D-Galactose induces a significant oxidative stress and proinflammatory cascade of aging while both IMOD and Angipars recovered all of them. Interestingly, IMOD and Angipars were better than Vitamin E in improving male sex hormones in aged mice. This effect is so important and should be considered as an advantage although it cannot be explained with current knowledge. The conclusion is that IMOD and Angipars have marked anti-aging effect on D-galactose-induced model of aging. PMID- 23351488 TI - Preliminary study of ventilation with 4 ml/kg tidal volume in acute respiratory distress syndrome: feasibility and effects on cyclic recruitment - derecruitment and hyperinflation. AB - INTRODUCTION: Cyclic recruitment-derecruitment and overdistension contribute to ventilator-induced lung injury. Tidal volume (Vt) may influence both, cyclic recruitment-derecruitment and overdistension. The goal of this study was to determine if decreasing Vt from 6 to 4 ml/kg reduces cyclic recruitment derecruitment and hyperinflation, and if it is possible to avoid severe hypercapnia. METHODS: Patients with pulmonary acute respiratory distress syndrome (ARDS) were included in a crossover study with two Vt levels: 6 and 4 ml/kg. The protocol had two parts: one bedside and other at the CT room. To avoid severe hypercapnia in the 4 ml/kg arm, we replaced the heat and moisture exchange filter by a heated humidifier, and respiratory rate was increased to keep minute ventilation constant. Data on lung mechanics and gas exchange were taken at baseline and after 30 minutes at each Vt (bedside). Thereafter, a dynamic CT (4 images/sec for 8 sec) was taken at each Vt at a fixed transverse region between the middle and lower third of the lungs. Afterward, CT images were analyzed and cyclic recruitment-derecruitment was determined as non-aerated tissue variation between inspiration and expiration, and hyperinflation as maximal hyperinflated tissue at end-inspiration, expressed as % of lung tissue weight. RESULTS: We analyzed 10 patients. Decreasing Vt from 6 to 4 ml/kg consistently decreased cyclic recruitment-derecruitment from 3.6 (2.5 to 5.7) % to 2.9 (0.9 to 4.7) % (P <0.01) and end-inspiratory hyperinflation from 0.7 (0.3 to 2.2) to 0.6 (0.2 to 1.7) % (P = 0.01). No patient developed severe respiratory acidosis or severe hypercapnia when decreasing Vt to 4 ml/kg (pH 7.29 (7.21 to 7.46); PaCO2 48 (26 to 51) mmHg). CONCLUSIONS: Decreasing Vt from 6 to 4 ml/kg reduces cyclic recruitment-derecruitment and hyperinflation. Severe respiratory acidosis may be effectively prevented by decreasing instrumental dead space and by increasing respiratory rate. PMID- 23351489 TI - Methyloligella halotolerans gen. nov., sp. nov. and Methyloligella solikamskensis sp. nov., two non-pigmented halotolerant obligately methylotrophic bacteria isolated from the Ural saline environments. AB - Two newly isolated halotolerant obligately methylotrophic bacteria (strains C2(T) and SK12(T)) with the serine pathway of C1 assimilation are described. The isolates are strictly aerobic, Gram negative, asporogenous, non-motile rods, forming rosettes, multiplying by binary fission. Mesophilic and neutrophilic, accumulate intracellularly compatible solute ectoine and poly-beta hydroxybutyrate. The novel strains are able to grow at 0 up to 16% NaCl (w/v), optimally at 3-5% NaCl. The major cellular fatty acids are C18:1omega7c and C19:0cyc and the prevailing quinone is Q-10. The predominant phospholipids are phosphatidylcholine, phosphatidylglycerol, phosphatidyldimethylethanolamine and phosphatidylethanolamine. Assimilate NH4(+) by glutamate dehydrogenase and via the glutamate cycle (glutamine synthetase and glutamate synthase). The DNA G+C contents of strains C2(T) and SK12(T) are 60.9 and 60.5 mol% (Tm), respectively. 16S rRNA gene sequence similarity between the two new isolates are 99% but below 94% with other members of the Alphaproteobacteria thus indicating that they can be assigned to a novel genus Methyloligella. Rather low level of DNA-DNA relatedness (53%) between the strains C2(T) and SK12(T) indicates that they represent two separate species of the new genus, for which the names Methyloligella halotolerans gen. nov., sp. nov. and Methyloligella solikamskensis sp. nov. are proposed. The type strain of Methyloligella halotolerans is C2(T) (=VKM B-2706(T)=CCUG 61687(T)=DSM 25045(T)) and the type strain of Methyloligella solikamskensis is SK12(T) (=VKM B-2707(T)=CCUG 61697(T)=DSM 25212(T)). PMID- 23351490 TI - Photobacterium marinum sp. nov., a marine bacterium isolated from a sediment sample from Palk Bay, India. AB - The novel, cream colored, Gram-staining-negative, rod-shaped, motile bacteria, designated strains AK15(T) and AK18, were isolated from sediment samples collected from Palk Bay, India. Both strains were positive for arginine dihydrolase, lysine decarboxylase, oxidase, nitrate reduction and methyl red test. The major fatty acids were C16:0, C18:1 omega7c, C16:1 omega7c and/or C16:1 omega6c and/or iso-C15:0 2-OH (summed feature 3). Polar lipids content of strains AK15(T) and AK18 were found to bephosphatidylethanolamine (PE), two unidentified phospholipids (PL1 and PL2) and three unidentified lipids (L1-L3). The 16S rRNA gene sequence analysis indicated strains AK15(T) and AK18 as the members of the genus Photobacterium and closely related to the type strain Photobacterium jeanii with pair-wise sequence similarity of 96.7%. DNA-DNA hybridization between strain AK15(T) and AK18 showed a relatedness of 87%. Based on data from the current polyphasic study, strains AK15(T) and AK18 are proposed as novel species of the genus Photobacterium, for which the name Photobacterium marinum sp. nov. is proposed. The type strain of Photobacterium marinum is AK15(T) (=MTCC 11066(T)=DSM 25368(T)). PMID- 23351491 TI - Retention of the rural allied health workforce in New South Wales: a comparison of public and private practitioners. AB - BACKGROUND: Policy initiatives to improve retention of the rural health workforce have relied primarily on evidence for rural doctors, most of whom practice under a private business model. Much of the literature for rural allied health (AH) workforce focuses on the public sector. The AH professions are diverse, with mixed public, private or combined practice settings. This study explores sector differences in factors affecting retention of rural AH professionals. METHODS: This study compared respondents from the 2008 Rural Allied Health Workforce (RAHW) survey recruiting all AH professionals in rural New South Wales. Comparisons between public (n = 833) and private (n = 756) groups were undertaken using Chi square analysis to measure association for demographics, job satisfaction and intention to leave. The final section of the RAHW survey comprised 33 questions relating to retention. A factor analysis was conducted for each cohort. Factor reliability was assessed and retained factors were included in a binary logistic regression analysis for each cohort predicting intention to leave. RESULTS: Six factors were identified: professional isolation, participation in community, clinical demand, taking time away from work, resources and 'specialist generalist' work. Factors differed slightly between groups. A seventh factor (management) was present only in the public cohort. Gender was not a significant predictor of intention to leave. Age group was the strongest predictor of intention to leave with younger and older groups being significantly more likely to leave than middle aged.In univariate logistic analysis (after adjusting for age group), the ability to get away from work did not predict intention to leave in either group. In multivariate analysis, high clinical demand predicted intention to leave in both the public (OR = 1.40, 95% CI = 1.08, 1.83) and private (OR = 1.61, 95% CI = 1.15, 2.25) cohorts. Professional isolation (OR = 1.39. 95% CI = 1.11, 1.75) and Participation in community (OR = 1.57, 95% CI = 1.13, 2.19) also contributed to the model in the public cohort. CONCLUSIONS: This paper demonstrates differences between those working in public versus private sectors and suggests that effectiveness of policy initiatives may be improved through better targeting. PMID- 23351492 TI - The distribution and possible role of ERK8 in mouse oocyte meiotic maturation and early embryo cleavage. AB - It is well known that extracellular signal-regulated kinase 8 (ERK8) plays pivotal roles in various mitotic events. But its physiological roles in oocyte meiotic maturation remain unclear. In this study, we found that although no specific ERK8 signal was detected in oocyte at the germinal vesicle stage, ERK8 began to migrate to the periphery of chromosomes shortly after germinal vesicle breakdown. At prometaphase I, metaphase I (MI), anaphase I, telophase I, and metaphase II (MII) stages, ERK8 was stably detected at the spindles. By taxol treatment, we clarified that the ERK8 signal was stained on the spindle fibers as well as microtubule asters in MI and MII oocytes. In fertilized eggs, the ERK8 signal was not observed in the two pronuclei stages. At prometaphase, metaphase, and anaphase of the first mitosis, ERK8 was detected on the mitotic spindle. ERK8 knock down by antibody microinjection and specific siRNA caused abnormal spindles, failed chromosome congression, and decreased first polar body extrusion. Taken together, our results suggest that ERK8 plays an important role in spindle organization during mouse oocyte meiotic maturation and early embryo cleavage. PMID- 23351493 TI - Structured self monitoring of blood glucose in Iranian people with type 2 diabetes; A cost consequence analysis. AB - BACKGROUND: Self-Monitoring of Blood Glucose (SMBG) is considered as a key factor in management of people with diabetes which is a growing and cost demanding health problem. The purpose of this study was to investigate the effect of comprehensive patient management using structured SMBG on metabolic control as well as its cost consequence analysis. METHODS: Sixty subjects were recruited in an observational study for a period of 6 months. They were provided with the ACCU CHEK 360 degrees View tool to fill in the values of the 7-point blood glucose profiles in three consecutive days during the study on a monthly basis. Changes in metabolic control were assessed by HbA1c and lipid profile measurement at the beginning and at the end of the study. In addition, cost consequence analysis was done considering different level of health care professionals with or without insurance coverage. The Average Cost Effectiveness Ratio (ACER) as well as Cost saving analysis were calculated and compared. RESULTS: The analysis showed significant reduction in HbA1c during the 6-month period in all subjects (P = 0.000). Furthermore, a positive effect was observed on lipid profile. The cost of endocrinologist's visit in private sector was estimated to be 265.76 USD while this figure was149.15 USD for general practitioner in public sector with insurance coverage. Total complications and mortality cost saving was 154.8 USD. The lowest ACER was calculated for intervention with general practitioner in public sector with insurance coverage. CONCLUSION: Structured SMBG results in significant improvement of glycemic status. Moreover, it is more cost saving in public sector with insurance coverage. It seems that general practitioner visits with insurance coverage is the most affordable option for people with type 2 diabetes. PMID- 23351494 TI - Pediatric ovarian torsion: case series and review of the literature. AB - BACKGROUND: Ovarian torsion in children is an uncommon cause of acute abdominal pain but mandates early surgical management to prevent further adnexal damage. The clinical presentation mimics other pathologies, such as appendicitis. We sought to more completely characterize ovarian torsion with respect to pain and ancillary studies, such as urinalysis. METHODS: We performed a retrospective review of hospital charts of all patients aged 0-18 years with a diagnosis of ovarian torsion at the Children's Hospital at London Health Sciences Centre, in London, Ont., from 1993 to 2008. RESULTS: We analyzed 13 charts of patients aged 7 months to 18 years. Most patients presented with peripheral leukocytosis, vomiting and right lower quadrant pain that did not radiate or migrate. On urinalysis, about half the patients demonstrated pyuria without bacteruria. Pelvic ultrasound revealed an ovarian cyst on the same side of the pain in 11 of 13 patients. Most were found to have a hemorrhagic cyst or ovary and underwent salpingo-oophorectomy or cystectomy within 48 hours of presentation. CONCLUSION: Ovarian torsion should be considered in any female child with acute onset lower abdominal pain accompanied by vomiting. Pain can be characterized as constant or colicky, but unlike with appendicitis, does not typically migrate. Sterile pyuria is found in a substantial proportion of cases. Ultrasound is the most useful initial diagnostic modality, but the absence of flow on Doppler imaging is not always present. Conservative management with detorsion and oophoropexy is recommended. PMID- 23351496 TI - Survey of terminology used for the intraoperative direction of C-arm fluoroscopy. AB - BACKGROUND: Orthopedic surgeons depend on the intraoperative use of fluoroscopy to facilitate procedures across all subspecialties. The versatility of the C-arm fluoroscope allows acquisition of nearly any radiographic view. This versatility, however, creates the opportunity for difficulty in communication between surgeon and radiation technologist. Poor communication leads to delays, frustration and increased exposure to ionizing radiation. There is currently no standard terminology employed by surgeons and technologists with regards to direction of the fluoroscope. METHODS: The investigation consisted of a web-based survey in 2 parts. Part 1 was administered to the membership of the Canadian Orthopedic Association, part 2 to the membership of the Canadian Association of Medical Radiation Technologists. The survey consisted of open-ended or multiple-choice questions examining experience with the C-arm fluoroscope and the terminology preferred by both orthopedic surgeons and radiation technologists. RESULTS: The survey revealed tremendous inconsistency in language used by orthopedic surgeons and radiation technologists. It also revealed that many radiation technologists were inexperienced in operating the fluoroscope. CONCLUSION: Adoption of a common language has been demonstrated to increase efficiency in performing defined tasks with the fluoroscope. We offer a potential system to facilitate communication based on current terminology used among Canadian orthopedic surgeons and radiation technologists. PMID- 23351495 TI - Transforaminal epidural steroid injections prevent the need for surgery in patients with sciatica secondary to lumbar disc herniation: a retrospective case series. AB - BACKGROUND: The median orthopedic surgery wait time in Canada is 33.7 weeks, thus alternative treatments for pathologies such as lumbar disc herniations (LDH) are needed. We sought to determine whether transforaminal epidural steroid injections (TFESIs) alleviate or merely delay the need for surgery. METHODS: We retrospectively reviewed the charts of patients with LDH who received TFESIs between September 2006 and July 2008. Patient demographics, level and side of pathology, workers' compensation status, levels injected, treatment outcome and time from referral to treatment were evaluated. The primary outcome measure was the need for versus the avoidance of surgery. RESULTS: We included 91 patients in our analysis. Time from family physician referral to injection was 123 (standard deviation [SD] 88) days; no significant differences in wait times were found between TFESI patients and those requiring surgery. In all, 51 patients (22 women, 29 men) with a mean age of 45.8 (SD 10.2) years avoided surgery following TFESI, whereas 40 patients (16 women, 24 mean) with a mean age of 43.1 (SD 12.0) years proceeded to surgery within 189 (SD 125) days postinjection. In all, 15 patients received multiple injections, and of these, 9 did not require surgical intervention. Age, sex and level/side of pathology did not influence the treatment outcome. Workers' compensation status influenced outcome significantly; these patients demonstrated less benefit from TFESI. CONCLUSION: Transforaminal epidural steroid injections are an important treatment tool, preventing the need for surgery in 56% of patients with LDH. PMID- 23351497 TI - Surgical waste audit of 5 total knee arthroplasties. AB - BACKGROUND: Operating rooms (ORs) are estimated to generate up to one-third of hospital waste. At the London Health Sciences Centre, prosthetics and implants represent 17% of the institution's ecological footprint. To investigate waste production associated with total knee arthroplasties (TKAs), we performed a surgical waste audit to gauge the environmental impact of this procedure and generate strategies to improve waste management. METHODS: We conducted a waste audit of 5 primary TKAs performed by a single surgeon in February 2010. Waste was categorized into 6 streams: regular solid waste, recyclable plastics, biohazard waste, laundered linens, sharps and blue sterile wrap. Volume and weight of each stream was quantified. We used Canadian Joint Replacement Registry data (2008 2009) to estimate annual weight and volume totals of waste from all TKAs performed in Canada. RESULTS: The average surgical waste (excluding laundered linens) per TKA was 13.3 kg, of which 8.6 kg (64.5%) was normal solid waste, 2.5 kg (19.2%) was biohazard waste, 1.6 kg (12.1%) was blue sterile wrap, 0.3 kg (2.2%) was recyclables and 0.3 kg (2.2%) was sharps. Plastic wrappers, disposable surgical linens and personal protective equipment contributed considerably to total waste. We estimated that landfill waste from all 47 429 TKAs performed in Canada in 2008-2009 was 407 889 kg by weight and 15 272 m3 by volume. CONCLUSION: Total knee arthroplasties produce substantial amounts of surgical waste. Environmentally friendly surgical products and waste management strategies may allow ORs to reduce the negative impacts of waste production without compromising patient care. LEVEL OF EVIDENCE: Level IV, case series. PMID- 23351498 TI - Reducing elective general surgery cancellations at a Canadian hospital. AB - BACKGROUND: In Canadian hospitals, which are typically financed by global annual budgets, overuse of operating rooms is a financial risk that is frequently managed by cancelling elective surgical procedures. It is uncertain how different scheduling rules affect the rate of elective surgery cancellations. METHODS: We used discrete event simulation modelling to represent perioperative processes at a hospital in Toronto, Canada. We tested the effects of the following 3 scenarios on the number of surgical cancellations: scheduling surgeons' operating days based on their patients' average length of stay in hospital, sequencing surgical procedures by average duration and variance, and increasing the number of postsurgical ward beds. RESULTS: The number of elective cancellations was reduced by scheduling surgeons whose patients had shorter average lengths of stay in hospital earlier in the week, sequencing shorter surgeries and those with less variance in duration earlier in the day, and by adding up to 2 additional beds to the postsurgical ward. CONCLUSION: Discrete event simulation modelling can be used to develop strategies for improving efficiency in operating rooms. PMID- 23351499 TI - Off-pump anteroapical aneurysm plication following left ventricular postinfarction aneurysm: effect on cardiac function, clinical status and survival. AB - BACKGROUND: In patients with coronary disease and aneurysm, ventricular reconstruction with revascularization is a surgical option. Details of patient selection and optimal surgical technique are still debated. We report our results with off-pump aneurysm plication after ventricular aneurysm with relative wall thinning. METHODS: We retrospectively reviewed the records of 248 patients who had an operation for postinfarction left ventricular aneurysm. Reconstruction was accomplished by off-pump anteroapical aneurysm plication. The following variables were recorded: preoperative clinical, angiographic and echocardiographic findings and operative procedures. Outcomes were early mortality, long-term survival and poor 5-year result, defined as the need for transplantation or repeated hospitalization for congestive heart failure. Risk factors were pinpointed using the t test and survival curves. Independent risk factors were identified using Cox regression methods. RESULTS: Hospital mortality was low (2.0%). Mean follow up was 5.8 (standard deviation [SD] 3.8) years. Actuarial survival at 1 and 5 years was 94% and 84%. Among the 232 survivors, 200 were in functional class I or II, and the average increase in ejection fraction was 14.0% (SD 3.1%). As determined by multivariable analysis, factors predicting poor outcome were advanced age, ejection fraction less than 0.35, conicity index less than 1, end systolic volume index greater than 80 mL/m2, advanced New York Heart Association functional class and congestive heart failure. CONCLUSION: Using wall thinning as a criterion for patient selection, the technique of off-pump anteroapical aneurysm plication can be performed with low operative mortality and provides good symptomatic relief and long-term survival. PMID- 23351500 TI - Outcome 1 year after digestive surgery in malnourished, elderly patients, with an emphasis on quality of life analysis. AB - BACKGROUND: Quality of life data after digestive surgery in malnourished, elderly patients are rarely reported. What can we expect as 1-year outcomes in these high risk patients after digestive surgery? METHODS: We conducted a prospective observational study in a digestive surgery department in a tertiary, nonacademic hospital in Mulhouse, France. Malnourished, older patients (according to the Nutritional Risk Index) undergoing digestive surgery between November 2007 and December 2008 were included and followed up for 1 year. Quality of life was measured by the European Organization for Research and Treatment of Cancer QLQ C30 questionnaire at the end of the study period. RESULTS: We included 37 patients with a median age of 76 (range 66-86) years in our study. The mean global health status and quality of life score in 17 of 24 living patients 1 year after surgery was 68.6 (standard deviation [SD] 12.4), and no difference with the score of a reference population 70.8 (SD 22.1) was observed (p = 0.68). In hospital mortality was 11% and morbidity was 70%. CONCLUSION: The present study suggests that despite high postoperative mortality and morbidity, an acceptable quality of life can be achieved in malnourished, elderly survivors of digestive surgery. PMID- 23351501 TI - Quality indicators for sentinel lymph node biopsy: is there room for improvement? AB - BACKGROUND: Eleven quality indicators (QI) for sentinel lymph node biopsy (SLNB) were previously developed through a consensus-based approach, yet still need to be incorporated into clinical practice. We sought to evaluate the applicability and clinical relevance for surgeons. METHODS: Breast cancer patients undergoing SLNB between 2004 and 2008 at Mount Sinai Hospital, Toronto, were evaluated. Clinical and pathological data were obtained from an institutional database. Information on axillary recurrences was obtained through a retrospective chart review. Adherence to standardized protocols was evaluated in each case. RESULTS: All 11 QIs were measurable in 300 patients. The identification rate was 100%. More than 1 SLN was identified in 78.6% of patients. The SLNB was performed simultaneously with primary surgery in 96.7% of patients; 61 SLNs harboured metastasis. Of these patients, 80.3% underwent completion lymphadenectomy. Cases complied with protocols for radiocolloid injection and pathologic SLN evaluation/reporting. No ineligible patients underwent SLNB. Of patients with a complete 5-year follow-up (n = 42), only 1 had axillary recurrence. CONCLUSION: Applying QIs for SLNB was feasible, but modifications were necessary to develop a more practical approach to quality assessment. Of the 11 suggested QIs, those that encompass protocols (nuclear medicine and pathology) should be reclassified as prerequisites, as they are independent of the technical aspect of SLNB performance. The remaining 8 QIs encompass surgery per se and should be measured routinely by surgeons. Furthermore, concise and clinically relevant target rates are necessary for these QIs to be established as widely recognized control standards. PMID- 23351502 TI - Randomized trial of the effect of intravenous paracetamol on inflammatory biomarkers and outcome in febrile critically ill adults. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: The febrile reaction is a complex response involving immunologic and other physiologic systems. Antipyretics are commonly used in critically ill patients with fever. We investigated the inflammatory responses following application of antipyretic therapy in febrile critically ill patients with Systemic Inflammatory Response Syndrome (SIRS). PATIENTS AND METHODS: In a prospective, randomized controlled study, critically ill patients with fever (T >= 38.3 degrees C), SIRS diagnosed within 24 hours of Intensive Care Unit (ICU) admission and Acute Physiology and Chronic Health Evaluation II (APACHE II) score >=10 were randomized into two groups. Upon appearance of fever, one group received intravenous paracetamol 650 mg every 6 hours for 10 days and other group received no treatment unless temperature reached 40 degrees C. Body temperature, Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sepsis-related Organ Failure Assessment (SOFA) scores, length of ICU stay, ICU mortality and infectious complications were recorded. Levels of Interleukin-1 alpha (IL-1alpha), IL-6, IL-10, Tumour Necrosis Factor alpha (TNFalpha) and High-Sensitive C-Reactive Protein (HS-CRP) were assessed at baseline and 2, 6 and 24 hours after intervention. RESULTS AND DISCUSSION: During a period of 15-month screening, 20 patients met the criteria and randomized to the control or paracetamol group. Body temperature decreased significantly in the paracetamol group (p = 0.004) and control group (p = 0.001) after 24 hours, but there was no significant difference between two groups at this time point (p = 0.649). Levels of IL-6 and IL-10 decreased significantly (p = 0.025 and p = 0.047, respectively) in the paracetamol group at 24 hours but this was not of statistical significance in control group. No patterns over time in each group or differences across two groups were found for HS-CRP, TNFalpha, and IL-1alpha (p > 0.05). There were no differences regarding ICU length of stay, mortality and infectious complications between both groups. CONCLUSION: These results suggest that antipyretic therapy may not be indicated in all ICU patients. Allowing fever to take its natural course does not appear to have detrimental effects on critically ill patients with SIRS and may avoid unnecessary expenses. PMID- 23351503 TI - Phytochemical screening and evaluation of cardioprotective activity of ethanolic extract of Ocimum basilicum L. (basil) against isoproterenol induced myocardial infarction in rats. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: The objectives of the present study were phytochemical screening and study of the effects of ethanolic extract of aerial parts of Ocimum basilicum (basil) on cardiac functions and histopathological changes in isoproterenol-induced myocardial infarction (MI). METHODS: The leaves of the plant were extracted with ethanol by maceration and subjected to colorimetry to determine flavonoids and phenolic compounds. High-performance TLC analysis and subsequent CAMAG's TLC scanning were performed to quantify rosmarinic acid content. Wistar rats were assigned to 6 groups of normal control, sham, isoproterenol, and treatment with 10, 20, and 40 mg/kg of the extract two times per day concurrent with MI induction. A subcutaneous injection of isoproterenol (100 mg/kg/day) for 2 consecutive days was used to induce MI. RESULTS: Phytochemical screening indicated the presence of phenolic compounds (5.36%) and flavonoids (1.86%). Rosmarinic acid was the principal phenolic compound with a 15.74% existence. The ST-segment elevation induced by isoproterenol was significantly suppressed by all doses of the extract. A severe myocardial necrosis and fibrosis with a sharp reduction in left ventricular contractility and a marked increase in left ventricular end-diastolic pressure were seen in the isoproterenol group, all of which were significantly improved by the extract treatment. In addition to in-vitro antioxidant activity, the extract significantly suppressed the elevation of malondialdehyde levels both in the serum and the myocardium. CONCLUSION: The results of the study demonstrate that Ocimum basilicum strongly protected the myocardium against isoproterenol-induced infarction and suggest that the cardioprotective effects could be related to antioxidative activities. PMID- 23351504 TI - lesion development in a new intestinal loop model indicates the involvement of a shared Clostridium perfringens virulence factor in haemorrhagic enteritis in calves. AB - Clostridium perfringens-associated enterotoxaemia is a fatal disease in fast growing suckler and veal calves. An intestinal loop model was developed to study the pathogenesis of the disease. Loops were injected with stationary and logarithmic C. perfringens cultures with or without, a milk protein-based commercial milk replacer for calves. Isolates tested were from cases of bovine enterotoxaemia and from calves without signs of enterotoxaemia, in addition to netB-positive and -negative isolates from poultry, a type C isolate from piglets and the human isolate JIR325. All isolates induced necrohaemorrhagic lesions in combination with milk replacer, while all control loops (i.e. medium plus milk replacer) remained histologically normal. In addition, time-course experiments were conducted using an isolate from an outbreak of bovine enterotoxaemia. Histological examination showed that the earliest lesion was congestion of the capillaries, starting within 30 min of inoculation. Haemorrhage and mucosal necrosis began at the tips of the villi 3-4 h after bacterial inoculation. These lesions are similar to those observed in natural cases of bovine enterotoxaemia. Therefore, in this model, necrohaemorrhagic lesions can be induced by C. perfringens isolates from diverse origins, suggesting that the lesions may be caused by one or more virulence factors that are shared by these isolates. PMID- 23351505 TI - Dermatophytosis caused by Trichophyton spp. in a Tenerife Lizard (Gallotia galloti): an immunohistochemical study. AB - Reports of dermatophytosis in reptiles are rare. This report describes the microscopical and immunohistochemical findings in a case of dermatophytosis caused by Trichophyton spp. in a 2-year-old Tenerife lizard (Gallotia galloti) with ulcerative and pustular skin lesions. Microscopically, the lesions were characterized by superficial epidermal pustules containing heterophils with numerous fungal hyphae that stained by periodic acid-Schiff and Grocott's stain. Fungal culture was not performed, but a panel of polyclonal antibodies specific for different fungal genera was applied to tissue sections. These immunohistochemical studies demonstrated reactivity of the hyphae only with antiserum specific for Trichophyton spp. PMID- 23351506 TI - Characterization of rare mammary tumours appearing on the neck of RIII/Sa mice infected with mouse mammary tumour virus. AB - RIII/Sa and C3H mice harbour milk-borne mouse mammary tumour virus (MMTV) and develop mammary tumours at a high incidence. These mammary tumours usually arise ventrally and/or on the sides of the animals. In the present study, some mice of both strains were observed to have tumours in the dorsal neck area. Histological analysis of the tumours indicated their similarity to mammary tumours induced by MMTV oncogenesis. The neck tumours were found by thin-section electron microscopy to contain both type A and type B particles that are hallmarks of MMTV infection. In addition, the neck tumour DNA possessed insertion mutations of Wnt-1 and Fgf-3 proto-oncogenes, the activation of which play important roles in the development of mouse mammary tumours. These neck tumours appear to be mammary tumours that arise in the context of in-situ mammary tissue, similar to rare 'ectopic' human breast cancers that arise in the axillary region and other sites remote from the breast. PMID- 23351507 TI - Starting the clock: defining nonoperative management of blunt splenic injury by time. AB - BACKGROUND: There is no consensus when the designation of nonoperative management (NOM) for splenic injury (BSI) should start. We evaluated NOM success rates based on different time points after admission. METHODS: The National Trauma Data Bank was evaluated for BSI for the year 2008. Observations were evaluated by facility, the time to splenectomy, and the volume of BSI admissions. RESULTS: Of 15,732 BSIs identified, the overall splenectomy salvage rate was 81%. After the 5th hour, the NOM success rate was 95%. Multivariable analysis revealed that higher BSI grades, level 2 centers and community hospitals, and age >=55 were associated with failed NOM. CONCLUSIONS: The grade of injury is an important predictor for failure of NOM. If a 5% failure rate is to be considered a benchmark, then the 5 hour time point after admission should be used for the calculation of NOM success rates. PMID- 23351508 TI - Abdominal wall reconstruction: a case series of ventral hernia repair using the component separation technique with biologic mesh. AB - BACKGROUND: Sixty-eight consecutive patients from October 2008 until February 2012 were selected for this retrospective review. METHODS: A midline fascial closure with component separation was completed using biologic mesh onlay in all cases. Recurrence rates of the hernias, complication rates, patient satisfaction, and time to return to work/normal activities were investigated. RESULTS: The recurrence rate was 1.5% (n = 65) with ongoing follow-ups (mean = 20 months). The average age was 57 years, and the average body mass index was 36 kg/m(2) (range 22 to 60). The average hernia defect was 20 cm (range 12 to 26) transversely. Wound infection and/or breakdown occurred in 32%, and seroma formation occurred in 9% of patients. Patient satisfaction was 3.63 of 4. The average time to return to work/normal activities was 16 weeks (range 1 to 76 weeks). CONCLUSIONS: Large complex ventral hernias can be reliably repaired using the component separation technique. The short-term recurrence rate is significantly reduced in this case series using a biologic mesh onlay. PMID- 23351509 TI - Changing paradigms in minimally invasive surgery training. AB - BACKGROUND: Realizing the trends toward minimally invasive procedures, the Accreditation Council for Graduate Medical Education (ACGME) increased the requirements for laparoscopic procedures effective 2007 to 2008. Our purpose was to analyze the trend of laparoscopic versus open cases. METHODS: We analyzed national ACGME general surgery operative log program data for basic and advanced open and laparoscopic procedures performed by graduating surgical residents between academic years 1996 to 1997 and 2009 to 2010. RESULTS: From 1997 to 2010, the average number of procedures performed by graduating residents increased for appendectomies (36.5 to 59.3), cholecystectomies (90.9 to 112), hernia repairs (58.9 to 67.4), and colectomies (40.1 to 60.2). These increases have been accompanied by decreases in the percentage of open procedures for appendectomies (84% to 30%), cholecystectomies (24% to 9%), hernia repairs (90% to 70%), and colectomies (97% to 71%), which have resulted primarily from a decrease in open procedures (basic) or an increase in laparoscopic procedures (advanced). CONCLUSIONS: The rising number of laparoscopic procedures performed by surgical residents is associated with a drastic decrease in the number of basic open procedures. Although the number of open procedures is sufficient to meet ACGME requirements for now, this is an area of concern for the adequacy of training in the future. PMID- 23351510 TI - Neoadjuvant therapy for rectal cancer decreases the number of lymph nodes harvested in operative specimens. AB - BACKGROUND: We evaluated the effect of neoadjuvant therapy (NAT) on lymph node harvest in rectal cancer patients undergoing anatomic resection with curative intent. METHODS: A prospectively maintained database was retrospectively queried for rectal cancer cases from 1990 to 2010. Demographic data, NAT, and lymph node yield were analyzed. Nonanatomic resections were excluded. RESULTS: Five hundred two cases were identified; the mean age was 68 years (range 34-89), and 56% were men. One hundred fifty-one (30%) patients received NAT. Overall, the lymph node yield was diminished in proctectomy specimens after NAT (mean = 9, median = 7) compared with specimens without therapy (mean = 13, median = 10, P = .001). Age was not a significant factor in the lymph node yield (P = .213 and .329). Among patients treated with NAT, younger patients had a significantly lower lymph node yield (P < .0001). CONCLUSIONS: A decreased lymph node yield in proctectomy specimens from patients treated with NAT is consistent with prior studies. Younger patients had a greater reduction in lymph node harvest after NAT compared with senior patients. PMID- 23351511 TI - Early-phase technetium-99m sestamibi scintigraphy can improve preoperative localization in primary hyperparathyroidism. AB - BACKGROUND: In hyperparathyroidism, dual-phase technetium-99m sestamibi scintigraphy is important for parathyroid adenoma localization. We hypothesized that reviewing early-phase scans can increase localization in patients with primary hyperparathyroidism (PHPT). METHODS: We reviewed our prospectively maintained database for patients with sestamibi scans before parathyroidectomy for PHPT from 2001 to 2011. Early-phase scans were read and compared with the location of the gland(s) removed at operation. RESULTS: Of 902 patients identified, radiologists read 693 scans as positive. Of 209 negative scans, 141 (67%) were positive in the early phase; 135 (96%) correctly identified the side of the adenoma. Using radiologist reads, 35% of patients with negative scans and 41% of patients with falsely localized glands required bilateral exploration compared with 5% of patients with correctly localized glands. CONCLUSIONS: A review of early scans in patients with negative imaging increases accurate adenoma localization and allows for minimally invasive operations in more patients. PMID- 23351512 TI - [National Forum III for Pneumonologists in Training. Training through participation]. PMID- 23351513 TI - [Smoking in COPD]. AB - Smoking is a recurrent, chronic addictive disease that causes multiple diseases and is the main known cause of avoidable morbidity and mortality, constituting a major public health problem. In developed countries, smoking is the main single cause of premature preventable morbidity and mortality. Tobacco combustion releases more than 4,000 toxic substances and more than 50 substances with demonstrated carcinogenic effects; smoking is a risk factor for six of the eight main causes of death worldwide. The treatment of smoking is both effective and cost-effective. Any therapeutic intervention performed by health professions for smoking will have beneficial results. If such interventions are adapted to the individual characteristics of each patient, their efficacy and efficiency will be much greater. All treatments are safe, with generally mild adverse effects that rarely lead to treatment withdrawal. Patients with COPD show higher nicotine dependence and seem to have greater difficulty in quitting smoking. Nevertheless, smoking cessation should be a priority in these patients, as it constitutes the only measure able to halt progression of the disease. PMID- 23351514 TI - [Tuberculosis]. AB - Tuberculosis (TB) continues to be an important public health problem. Currently, 2,100 million people--one third of the world population--are infected by Mycobacterium tuberculosis, with an estimated annual rate of 9.4 million new cases, and 440,000 cases of multidrug-resistant (MDR) TB in 2008; furthermore, cases of extensively-resistant (XDR) TB have been detected in 57 countries. While TB cases are constantly declining in industrialized countries, the rates and mortality due to this infection in developing countries remain alarming and will continue to be so in the future. Although the priorities in these countries are at present simpler, methods allowing rapid diagnosis of TB and of resistant strains will obviously contribute to better control of the disease. Nucleic acid amplification techniques allow M. tuberculosis detection in clinical samples in a few hours, while liquid media cultures may yield positive results in only 2 to 4 weeks, half the time that is usually required for growth in conventional solid media, which also allows more rapid determination of drug susceptibilities. Similarly, based on molecular biology, several approaches may rapidly identify gene mutations associated with resistance to antituberculosis drugs in clinical samples. Finally, the main obstacle to treatment adherence among patients--its length--could be minimized in the future if the new combinations of drugs currently under investigation, and some promising new vaccines, confirm similar rates of efficacy to those used at present. PMID- 23351515 TI - [idiopathic interstitial pneumonia]. AB - Idiopathic interstitial pneumonias (IIPs) are a diagnostic challenge for pneumologists, radiologists and pathologists alike. The classification of IPPs is currently controversial. Pulmonary function testing is an essential component in order to establish a diagnosis and is required to guide prognosis and follow-up and monitor treatment outcome. High-resolution computed tomography is also essential for the diagnosis of IPPs and may also provide data on disease activity and prognosis. PMID- 23351516 TI - [Introduction]. PMID- 23351517 TI - [Incisions and routes of surgical access]. AB - The correct choice of the incision to the chest is essential for surgical success and a favorable postoperative course. The route of access to the thorax must be adapted both to the disease and to the thoracic surgeon's experience, striking a balance between aggressiveness and the safety of the technique. This article describes the characteristics of surgical incisions, including classical thoracotomy, sternotomy and its variants, thoracoscopy and minimally-invasive surgery. The distinct techniques used to explore mediastinal lymphatic areas, including video-assisted mediastinal lymphadenectomy and transcervical extended mediastinal lymphadenectomy, are also described. PMID- 23351518 TI - [Surgical complications of pulmonary resection]. AB - We review incidence, etiology, diagnosis, prevention and treatment of the following complications of pulmonary resection: prolonged air leak, subcutaneous emphysema, residual pleural spaces, early bronchial stump dehiscence, bleeding, pleural empyema, bronchopleural fistula, esophagopleural fistula, chylothorax, cardiac herniation, pulmonary torsion, postpneumonectomy syndrome, nerve injuries and tumor embolism. PMID- 23351519 TI - [Mediastinitis]. AB - Mediastinitis is defined as acute or chronic inflammation of the mediastinal structures and generally has a low incidence. The most frequent acute cause is sternotomy following cardiac revascularization surgery with both internal mammary arteries, with an incidence of 0.4% to 5% and a mortality of 16.5% to 47%. The most frequent vector is Staphylococcus aureus. Esophageal perforation, usually iatrogenic, is the second most frequent cause of acute mediastinitis, produced by common oropharyngeal flora, with a mortality rate of 20% to 60%, depending on the time of diagnosis. The third most frequent cause is descending necrotizing mediastinitis, the origin being an odontogenous focus in 60% and beta-hemolytic streptococcus the causative agent in 71.5% of cases. The most accurate diagnostic imaging technique is computed tomography. Treatment is almost always surgical and survival depends on its early performance. The worst postsurgical prognostic factor is septic shock. PMID- 23351520 TI - [Diseases of the diaphragm]. AB - The diaphragm is the main muscle involved in ventilation and is supplied exclusively by the phrenic nerves. Congenital defects of the diaphragm muscle or phrenic nerve injury cause diaphragmatic paralysis-eventration. Prognosis and treatment depend on whether involvement is unilateral or bilateral and on the patient's previous clinical status. In addition, the diaphragm is an anatomical barrier between the thoracic and abdominal cavities and is traversed by the esophagus and important vascular and nerve structures. Abnormal dilation of the natural orifices of the diaphragm or loss of its continuity can cause abdominal structures to pass into the chest cavity, an occurrence known as diaphragmatic hernias. According to their etiology, hernias are divided into congenital, acquired and traumatic. Clinical manifestations, prognosis and treatment depend mainly on hernia size and age at diagnosis. Like any muscle, the diaphragm can develop benign or malignant primary tumors. However, diaphragm involvement due to tumors arising in adjacent organs is much more common. The prognosis is good in benign primary tumors and poor in both primary and secondary malignant tumors. This article reviews the main anatomical and physiological characteristics of the diaphragm, routes of surgical access and the most frequent diseases affecting this structure. PMID- 23351521 TI - The mitotic spindle protein SPAG5/Astrin connects to the Usher protein network postmitotically. AB - BACKGROUND: Mutations in the gene for Usher syndrome 2A (USH2A) are causative for non-syndromic retinitis pigmentosa and Usher syndrome, a condition that is the most common cause of combined deaf-blindness. To gain insight into the molecular pathology underlying USH2A-associated retinal degeneration, we aimed to identify interacting proteins of USH2A isoform B (USH2AisoB) in the retina. RESULTS: We identified the centrosomal and microtubule-associated protein sperm associated antigen (SPAG)5 in the retina. SPAG5 was also found to interact with another previously described USH2AisoB interaction partner: the centrosomal ninein-like protein NINLisoB. Using In situ hybridization, we found that Spag5 was widely expressed during murine embryonic development, with prominent signals in the eye, cochlea, brain, kidney and liver. SPAG5 expression in adult human tissues was detected by quantitative PCR, which identified expression in the retina, brain, intestine, kidney and testis. In the retina, Spag5, Ush2aisoB and NinlisoB were present at several subcellular structures of photoreceptor cells, and colocalized at the basal bodies. CONCLUSIONS: Based on these results and on the suggested roles for USH proteins in vesicle transport and providing structural support to both the inner ear and the retina, we hypothesize that SPAG5, USH2AisoB and NINLisoB may function together in microtubule-based cytoplasmic trafficking of proteins that are essential for cilium formation, maintenance and/or function. PMID- 23351523 TI - Comment on "An update on toxicology of aluminum phosphide". PMID- 23351522 TI - Sustaining remission of psychotic depression: rationale, design and methodology of STOP-PD II. AB - BACKGROUND: Psychotic depression (PD) is a severe disabling disorder with considerable morbidity and mortality. Electroconvulsive therapy and pharmacotherapy are each efficacious in the treatment of PD. Expert guidelines recommend the combination of antidepressant and antipsychotic medications in the acute pharmacologic treatment of PD. However, little is known about the continuation treatment of PD. Of particular concern, it is not known whether antipsychotic medication needs to be continued once an episode of PD responds to pharmacotherapy. This issue has profound clinical importance. On the one hand, the unnecessary continuation of antipsychotic medication exposes a patient to adverse effects, such as weight gain and metabolic disturbance. On the other hand, premature discontinuation of antipsychotic medication has the potential risk of early relapse of a severe disorder. METHODS/DESIGN: The primary goal of this multicenter randomized placebo-controlled trial is to assess the risks and benefits of continuing antipsychotic medication in persons with PD once the episode of depression has responded to treatment with an antidepressant and an antipsychotic. Secondary goals are to examine age and genetic polymorphisms as predictors or moderators of treatment variability, potentially leading to more personalized treatment of PD. Individuals aged 18-85 years with unipolar psychotic depression receive up to 12 weeks of open-label treatment with sertraline and olanzapine. Participants who achieve remission of psychosis and remission/near-remission of depressive symptoms continue with 8 weeks of open label treatment to ensure stability of remission. Participants with stability of remission are then randomized to 36 weeks of double-blind treatment with either sertraline and olanzapine or sertraline and placebo. Relapse is the primary outcome. Metabolic changes are a secondary outcome. DISCUSSION: This trial will provide clinicians with much-needed evidence to guide the continuation and maintenance treatment of one of the most disabling and lethal of psychiatric disorders. PMID- 23351524 TI - Brief assessment for suicidal ideation in OEF/OIF veterans with positive depression screens. AB - OBJECTIVES: We describe processes, rates, and patient and system correlates of brief structured assessments (BSAs) for suicidal ideation among Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans with positive depression screens. METHODS: Electronic Veterans Affairs (VA) medical record and Department of Defense data were used to identify individual-level and BSA-process variables for 1662 OEF/OIF veterans at three VA Medical Centers. RESULTS: Overall, 1349/1662 (81%) veterans received BSAs for suicidal ideation within 1 month of depression screening; 94% of BSAs were conducted within 1 day. Stratified analyses revealed significant intersite differences in veteran demographics, instruments used, clinical setting and staff performing assessments, and correlates of assessment completion. At two sites, men were more likely to be assessed than women [odds ratio (OR)=2.15 (95% confidence interval {CI}=1.06-4.38) and 3.14 (CI=1.27-7.76)]. In a combined model adjusted for intrasite correlation, assessment was less likely during months 8-12 and 13-18 of the study period [OR=0.39 (CI=0.28-0.54) and OR=0.48 (95% CI=0.35-0.68), respectively] and more likely to occur among veterans receiving depression or posttraumatic stress disorder diagnoses on the day of depression screening [OR=1.83 (CI=1.36-2.46) and OR=1.50 (CI=1.13-1.98), respectively]. CONCLUSIONS: Most veterans with positive depression screens receive timely BSAs for suicidal ideation. Processes used for brief assessment for suicidal ideation vary substantially across VA settings. PMID- 23351525 TI - Change in behavioral functional capacity is associated with preexisting cognitive function rather than with cognitive decline in patients 1 year after cardiac surgery. AB - OBJECTIVE: The objective was to examine whether preexisting cognitive function rather than cognitive decline associated with intraoperative procedures may predict change in behavioral functional capacity in patients 1 year after cardiac surgery. METHOD: Forty-five patients completed a cognitive evaluation, including the Trail Making Test part B (TMT-B) for attention and psychomotor speed, the Memory with 10-s interference for working memory, the Digit Span test for short term memory and the Instrumental Activities of Daily Living (IADLs) questionnaire for behavioral functional capacity, before surgery and 1 year after cardiac surgery. RESULTS: Sixteen patients (36%) exhibited cognitive decline after cardiac surgery. Preoperative scores on TMT-B significantly predicted change in behavioral functional capacity as measured by IADLs (beta = 0.371, P < .05), whereas the postoperative cognitive decline and intraoperative variables were unrelated to residualized change scores in IADLs (all Ps > .08). CONCLUSIONS: Preexisting cognitive dysfunctions as assessed by TMT-B can be a marker of preoperative brain dysfunction, which, in turn, in addition to brain damage caused by cardiac surgery procedures, may further predispose patients to poor behavioral functional capacity and outcome 1 year after surgery. Impaired cognitive functions before surgery should be considered when evaluating the effects of cardiac surgery procedures on long-term behavioral functional status of patients. PMID- 23351526 TI - Antipsychotic prophylaxis in surgical patients modestly decreases delirium incidence--but not duration--in high-incidence samples: a meta-analysis. AB - OBJECTIVE: The objective was to examine whether prophylactic treatment with antipsychotics can decrease the incidence and severity of postsurgical delirium. METHOD: A meta-analysis of existing trials comparing delirium incidence between patients given prophylactic antipsychotic and placebo was performed. Secondary outcomes were total hospital days, total days of delirium and severity. Pooled odds ratios (ORs) and mean differences were calculated using a random-effects model. RESULTS: Five randomized placebo-controlled trials comprising a total of 1491 patients were included. In the pooled analysis, prophylactic antipsychotic administration showed a reduction in delirium incidence (OR: 0.42; 95% confidence interval (CI): 0.24, 0.74). Among the studies reporting other outcomes, patients receiving antipsychotics prophylactically showed no differences in total hospital days (0.1; 95% CI: -0.73, 0.94), days of delirium (-1.17; 95% CI: -5.22, 2.88) or delirium severity (-1.02; 95% CI: -6.81, 4.76). CONCLUSIONS: Prophylactic antipsychotic treatment in surgical patients modestly decreases the incidence of delirium, but not the length of hospital stay, duration of delirium or its severity. Given the modest protective effect of antipsychotics and their potential adverse reactions, there is insufficient evidence to support its universal use as a preventive agent, though potential benefit may be seen in populations at high risk of developing delirium. PMID- 23351527 TI - Prevalence of depression among outpatients visiting a general internal medicine polyclinic in rural Japan. AB - OBJECTIVE: In Europe and the US, primary care has been anticipated in identifying untreated depression. Findings show a high prevalence of depression in such settings. However, the prevalence of depression in an internal medicine clinic in a rural area of Japan, which has a role in primary care, is unclear. METHOD: The prevalence of depression and comorbid psychiatric disorders among outpatients of an internal medicine clinic in a rural general hospital was measured by a structured interview using the Mini International Neuropsychiatric Interview. Outpatients were recruited consecutively and stratified by Patient Health Questionnaire-9 (PHQ-9) scores. Among 598 outpatients, we interviewed 75 randomly selected patients and 29 whose results of the PHQ-9 were positive. We estimated prevalence of depressive episode using age, sex, physical findings by internal medical doctors and PHQ-9 scores as covariates. RESULTS: The estimated prevalence of major and minor depressive episodes were 7.4% [95% confidence interval (CI): 3.4%-11.4%] and 6.8% (95% CI: 2.6%-10.9%), respectively. Among major depressed patients, 71.4% had current suicidal ideation. CONCLUSION: Given the high rate of depression and suicidality, identification of depression and collaboration between internal medical doctors in a rural area of Japan and mental health professionals are needed. PMID- 23351528 TI - Lingual thyroid: diagnosis using a hybrid of single photon emission computed tomography and standard computed tomography. AB - AIM: To present a rare case of lingual thyroid detected using a hybrid of single photon emission computed tomography and standard computed tomography in a young woman with hypothyroidism. MATERIALS AND METHODS: A 29-year-old woman was screened for autoimmune thyroid disorders in early pregnancy, and found to have subclinical hypothyroidism. No thyroid tissue was found in the anterior neck upon ultrasonography, raising suspicions of an ectopic thyroid. The patient was treated with levothyroxine throughout the remainder of her pregnancy, and developed postpartum thyroiditis requiring an increase in levothyroxine dosage. Whole-body scintigraphy and zoomed static head and neck scintigraphy were performed. Abnormal 99mTc-pertechnetate uptake was observed in the oral region, whereas no uptake was found in the usual thyroid location. Hybrid imaging using single photon emission computed tomography and standard computed tomography was performed to improve three-dimensional representation of the area of increased activity. RESULTS: The latter imaging modality detected ectopic thyroid tissue in the tongue. CONCLUSION: Whole body 99mTc-pertechnetate scintigraphy and a hybrid of single photon emission computed tomography and standard computed tomography are effective imaging modalities for the investigation of ectopic thyroid tissue. The latter modality is particularly recommended, as it allows more precise spatial visualisation of increased isotope uptake activity in the head and neck. PMID- 23351529 TI - Isolation and characterization of exopolysaccharide with immunomodulatory activity from fermentation broth of Morchella conica. AB - BACKGROUND AND THE PURPOSE OF THIS STUDY: Mushroom polysaccharides have traditionally been used for the prevention and treatment of a multitude of disorders like infectious illnesses, cancers and various autoimmune diseases. In vitro and in vivo studies suggest that certain polysaccharides affect immune system function. Morchella conica (M. conica) is a species of rare edible mushroom whose multiple medicinal functions have been proven. Thus, the objective of this study is to isolate and characterize of exopolysaccharide from submerged mycelial culture of M. conica, and to evaluate its immunomodulatory activity. METHODS: A water-soluble Morchella conica Polysaccharides (MCP) were extracted and isolated from the fermentation broth of M. conica through a combination of DEAE-cellulose and Sephacryl S-300 HR chromatograph. NMR and IR spectroscopy has played a developing role in identification of polysaccharide with different structure and composition from fungal and plant sources, as well as complex glycosaminoglycans of animal origin. Thus, NMR and IR spectroscopy were used to analyze the chemical structure and composition of the isolated polysaccharide. Moreover, the polysaccharide was tested for its immunomodulatory activity at different concentrations using in vitro model. RESULTS: The results showed that MCP may significantly modulate nitric oxide production in macrophages, and promote splenocytes proliferation. Analysis from HPLC, infrared spectra and nuclear magnetic resonance spectroscopy showed that MCP was a homogeneous mannan with an average molecular weight of approximately 81.2 kDa. The glycosidic bond links is ->6)-alpha-D-Man p-(1->. CONCLUSION: The results suggested that the extracted MCP may modulate nitric oxide production in macrophages and promote splenocytes proliferation, and it may act as a potent immunomodulatory agent. PMID- 23351530 TI - Effect of patient Age on surgical outcomes for Graves' disease: a case-control study of 100 consecutive patients at a high volume thyroid surgical center. AB - OBJECTIVE: To compare outcomes between children (<18 yrs) and adults undergoing total thyroidectomy for Graves' disease (GD) at a high volume, multidisciplinary thyroid center. SUMMARY OF BACKGROUND DATA: Reported complication rates for children undergoing surgery for Graves' disease are worse than for adults. METHODS: 100 consecutive patients (32 children; 68 adults) who underwent total thyroidectomy for Graves' disease (GD) by a high-volume endocrine surgery team from were compared. RESULTS: The mean patient age was 9.7 yrs (range 3.4-17.9 yrs) in children versus 44.9 yrs (range 18.4-84.2 yrs) in adults. Operative times were longer in children (2.18 +/- 0.08 hrs) than in adults (1.66 +/- 0.03 hrs) (p = 0.003). Pediatric thyroid specimens averaged 38.6.0 +/- 8.9 gm (range: 9-293 gm) and adult thyroid specimens averaged 48.0 +/- 6.4 gm (range: 6.6-203 gm) (p = 0.34). Thyroid to body weight ratios were greater in children (0.94 +/- 0.11 gm/kg) than adults (0.67 +/- 0.8 gm/kg) (p = 0.05). In all patients, the hyperthyroid state resolved after surgery. There was no operative mortality, recurrence, or permanent hypoparathyroidism. Transient post-operative hypocalcemia requiring calcium infusion was greater in children than adults (6/32 vs. 1/68; p = 0.004). Transient recurrent laryngeal nerve dysfunction occurred in two children and in no adults (p = 0.32). Postoperative hematoma occurred in two adults and in no children (p = 0.46). The length of stay was longer for children (1.41 +/- 0.12 days) than for adults (1.03 +/-0.03 days) (p = 0.004). CONCLUSION: Surgical management of GD is technically more challenging in children as evidenced by longer operative times. Whereas temporary hypocalcemia occurs more commonly in children than adults, the risks of major complications including disease recurrence, permanent hypoparathyroidism, recurrent laryngeal nerve injury, or neck hematoma were indistinguishable. These data suggest that excellent and equivalent outcomes can be achieved for GD surgery in children and adults when care is rendered by a high volume, endocrine surgery team. PMID- 23351531 TI - New and future resuscitation fluids for trauma patients using hemoglobin and hypertonic saline. AB - Hemoglobin-based oxygen carriers (HBOC) and hypertonic saline solutions (HSS) are used for resuscitation of trauma patients with hemorrhagic shock. In this review, the clinical application, dosing, administration, and side effects of these solutions are discussed. Although HBOC and HSS are not ideal resuscitation fluids, until rapidly thawed universal donor frozen blood and blood component therapy becomes widely available in North America, these fluids should to be considered immediately after injury and throughout the spectrum of care for patients with hemorrhagic shock, until blood and blood components become available. PMID- 23351532 TI - Trauma and aggressive homeostasis management. AB - Homeostasis refers to the capacity of the human body to maintain a stable constant state by means of continuous dynamic equilibrium adjustments controlled by a medley of interconnected regulatory mechanisms. Patients who sustain tissue injury, such as trauma or surgery, undergo a well-understood reproducible metabolic and neuroendocrine stress response. This review discusses 3 issues that concern homeostasis in the acute care of trauma patients directly related to the stress response: hyperglycemia, lactic acidosis, and hypothermia. There is significant reason to question the "conventional wisdom" relating to current approaches to restoring homeostasis in critically ill and trauma patients. PMID- 23351533 TI - Nonsurgical techniques to control massive bleeding. AB - Significant advancements in nonsurgical and surgical approaches to control bleeding in severely injured patients have also improved the treatment of critical trauma-related coagulopathy. Nonsurgical procedures such as angiographic embolization are progressively considered to terminate arterial bleeding from pelvic fractures. The disturbance of coagulation may aggravate bleeding and hamper surgical procedures. The administration of coagulation factors and factor concentrates may be useful for correcting systemic coagulopathy and reducing the need for fresh frozen plasma, platelet, and red blood cell transfusions, which are associated with various adverse outcomes. In this review, nonsurgical management of critical trauma bleeding is discussed. PMID- 23351534 TI - Point of care devices for assessing bleeding and coagulation in the trauma patient. AB - Severe trauma is associated with bleeding, coagulopathy, and transfusion of blood and blood products, all contributing to higher rates of morbidity and mortality. The aim of this review is to focus on point-of-care devices to monitor coagulation in trauma. Close monitoring of bleeding and coagulation as well as platelet function in trauma patients allows goal-directed transfusion and an optimization of the patient's coagulation, reduces the exposure to blood products, reduces costs, and probably improves clinical outcome. Noninvasive hemoglobin measurements are not to be used in trauma patients due to a lack in specificity and sensitivity. PMID- 23351535 TI - Advances in the management of the critically injured patient in the operating room. AB - Care of trauma patients continues to improve through better understanding of optimal timing of operating room (OR) interventions, improved monitoring for patients with head injury and hemodynamic compromise, optimization of volume status, and use of appropriate vasoactive agents. Investigation of the pathophysiology of trauma patients as they progress to the chronic phase continues to advance interventions in the ICU and the OR. This article is an evidence-based update of anesthetic considerations for these patients, including management of intracranial pressure, cardiac monitoring, management of the damage control abdomen, fluid and hemodynamic management, and control of coagulopathies. PMID- 23351536 TI - Resuscitation in a multiple casualty event. AB - A major weakness in the emergency medical response to multiple casualty events continues to be the resuscitation component, which should consist of the systematic application of basic, advanced, and prolonged life support and definitive care within 24 hours. There have been major advances in emergency medical care over the last decade, including the feasibility of point-of-care ultrasound to aid in rapid assessment of injuries in the field, damage control resuscitation, and resuscitative surgery protocols, delivered by small trauma/resuscitation teams equipped with regional anesthesia capability for rapid deployment. Widespread adoption of these best practices may improve the delivery of resuscitative care in future multiple casualty events. PMID- 23351537 TI - Anesthesia in an austere setting: lessons learned from the haiti relief operation. AB - The practice of medicine to care for injured patients after an earthquake can challenge physicians. The great need requires an open mind to develop anesthetic plans around locally available resources. A focus on monitored anesthetic care and regional anesthesia is frequently practiced and beneficial to patients. Anesthesiologists will serve as leaders to organize perioperative surgical services and provide input into the ethical triage of patients. The physicians should be mentally and physically prepared to enter into service in this disorganized zone of service to provide care. PMID- 23351538 TI - Anesthesia department preparedness for a multiple-casualty incident: lessons learned from the Fukushima earthquake and the Japanese nuclear power disaster. AB - In the Great East Japan Earthquake, which occurred on March 11, 2011, many lives were lost in the accompanying giant tsunami. Fukushima prefecture was widely contaminated with radioactive substances emitted by the accident at the nuclear power plant. Only a few trauma and emergency patients were brought to our hospital by ambulance, and an unexpectedly small number of emergency surgeries performed. There were patients with radiation-induced sickness and injury, but no cases of severe exposure requiring surgery or intensive care. As a logistic support hospital, we should prepare for and simulate these cases to respond to any such future occurrence. PMID- 23351539 TI - Trauma in the elderly: considerations for anesthetic management. AB - The volume of geriatric trauma patients is expected to increase significantly in coming years. Recognition of severe injuries may be delayed because they are less likely to mount classic symptoms of hemodynamic instability. Head injuries of any severity may place geriatric patients at increased risk of mortality, but there are currently no geriatric-specific treatment recommendations that differ from usual adult guidelines. Our understanding of best practices in geriatric trauma and anesthesia care continues to expand, as it does in all other areas of medicine. PMID- 23351540 TI - Management and outcomes of trauma during pregnancy. AB - Approximately 1% to 4% of pregnant women are evaluated in emergency/delivery room because of traumatic injury, yet there are few educational strategies targeted toward prevention/management of maternal trauma. Use of illicit drugs and alcohol, domestic abuse, and depression contribute to maternal trauma; thus a high index of suspicion should be maintained when treating injured young women. Treating the mother appropriately is beneficial for both the mother and the fetus. Fetal viability should be assessed after maternal stabilization. Pregnancy related morbidity occurs in approximately 25% of cases and may include placental abruption, uterine rupture, preterm delivery, and the need for cesarean delivery. PMID- 23351541 TI - Use of video-assisted intubation devices in the management of patients with trauma. AB - Patients with trauma may have airways that are difficult to manage. Patients with blunt trauma are at increased risk of unrecognized cervical spine injury, especially patients with head trauma. Manual in-line stabilization reduces cervical motion and should be applied whenever a cervical collar is removed. All airway interventions cause some degree of cervical spine motion. Flexible fiberoptic intubation causes the least cervical motion of all intubation approaches, and rigid video laryngoscopy provides a good laryngeal view and eases intubation difficulty. In emergency medicine departments, video laryngoscopy use is growing and observational data suggest an improved success rate compared with direct laryngoscopy. PMID- 23351542 TI - Training in trauma management: the role of simulation-based medical education. AB - Simulation-based medical education (SBME) offers a safe and "mistake-forgiving" environment to teach and train medical professionals. The diverse range of medical-simulation modalities enables trainees to acquire and practice an array of tasks and skills. SBME offers the field of trauma training multiple opportunities to enhance the effectiveness of the education provided in this challenging domain. Further research is needed to better learn the role of simulation-based learning in trauma management and education. PMID- 23351543 TI - Pitfalls of hemodynamic monitoring in patients with trauma. AB - This article provides an update for the anesthesiology community on the mechanisms and limitations of common modalities used to assess the early hemodynamic status in patients with trauma. Figures are provided to illustrate important concepts through the use of computer simulation and real-world examples. This article is of value to anesthesiologists whose practice includes management of hemorrhagic shock. PMID- 23351544 TI - Foreword. PMID- 23351545 TI - Postmarketing pharmaceutical product pitfalls in trauma care. PMID- 23351546 TI - Experimental and quantum chemical studies of a novel synthetic prenylated chalcone. AB - BACKGROUND: Chalcones are ubiquitous natural compounds with a wide variety of reported biological activities, including antitumoral, antiviral and antimicrobial effects. Furthermore, chalcones are being studied for its potential use in organic electroluminescent devices; therefore the description of their spectroscopic properties is important to elucidate the structure of these molecules. One of the main techniques available for structure elucidation is the use of Nuclear Magnetic Resonance Spectroscopy (NMR). Accordingly, the prediction of the NMR spectra in this kind of molecules is necessary to gather information about the influence of substituents on their spectra. RESULTS: A novel substituted chalcone has been synthetized. In order to identify the functional groups present in the new synthesized compound and confirm its chemical structure, experimental and theoretical 1H-NMR and 13C-NMR spectra were analyzed. The theoretical molecular structure and NMR spectra were calculated at both the Hartree-Fock and Density Functional (meta: TPSS; hybrid: B3LYP and PBE1PBE; hybrid meta GGA: M05-2X and M06-2X) levels of theory in combination with a 6 311++G(d,p) basis set. The structural parameters showed that the best method for geometry optimization was DFT:M06-2X/6-311++G(d,p), whereas the calculated bond angles and bond distances match experimental values of similar chalcone derivatives. The NMR calculations were carried out using the Gauge-Independent Atomic Orbital (GIAO) formalism in a DFT:M06-2X/6-311++G(d,p) optimized geometry. CONCLUSION: Considering all HF and DFT methods with GIAO calculations, TPSS and PBE1PBE were the most accurate methods used for calculation of 1H-NMR and 13C-NMR chemical shifts, which was almost similar to the B3LYP functional, followed in order by HF, M05-2X and M06-2X methods. All calculations were done using the Gaussian 09 software package. Theoretical calculations can be used to predict and confirm the structure of substituted chalcones with good correlation with the experimental data. PMID- 23351547 TI - Clinicopathologic significance of miR-10b expression in gastric carcinoma. AB - We have investigated microRNA (miRNA) expression profiles of gastric cancer and the clinicopathologic significance of miR-10b expression in gastric carcinoma. miRCURY LNA Arrays (v.16.0; Exiqon, Vedbaek, Denmark) were used to screen miRNAs in 17 gastric cancers. Reverse transcriptase polymerase chain reaction was performed to determine the expression of miR-10b in 56 gastric tumors. Expression of miR-10b in 436 paraffin-embedded cancer tissues was also investigated. In gastric cancer, 49 miRNAs were overexpressed by 2.0-fold or greater, and 39 miRNAs were down-regulated by 1.5-fold or greater, whereas miR-10b was up regulated by 2.98-fold. miR-10b was highly expressed in gastric cancer and correlated with size of tumor, Lauren classification, depth of invasion, lymph node and distant metastasis, TNM stage, and prognosis. In stages I, II, and III, the 5-year survival rate of patients with high levels of miR-10b expression was significantly lower than that in patients with low levels of expression. In stage IV, the expression level of miR-10b did not correlate with the 5-year survival rate. miR-10b may play an important role in progression and prognosis of gastric cancer. PMID- 23351548 TI - Umbelliprenin is cytotoxic against QU-DB large cell lung cancer cell line but anti-proliferative against A549 adenocarcinoma cells. AB - BACKGROUND: Umbelliprenin is a natural compound, belonging to the class of sesquiterpene coumarins. Recently, umbelliprenin has attracted the researchers' attention for its antitumor activities against skin tumors. Its effect on lung cancer is largely unknown. The aim of our study was to investigate the effects of this natural compound, which is expected to have low adverse effects, on lung cancer. METHODS: The QU-DB large cell and A549 adenocarcinoma lung cancer cell lines were treated with umbelliprenin. IC50 values were estimated using methyl thiazolely diphenyl-tetrazolium bromide (MTT) assay, in which a decrease in MTT reduction can occur as a result of cell death or cell proliferation inhibition. To quantify the rate of cell death at IC50 values, flow cytometry using Annexin V FITC (for apoptotic cells), and propidium iodide (for necrotic cells) dyes were employed. RESULTS: Data from three independent MTT experiments in triplicate revealed that IC50 values for QU-DB and A549 were 47 +/- 5.3 MUM and 52 +/- 1.97 MUM, respectively. Annexin V/PI staining demonstrated that umbelliprenin treatment at IC50 induced 50% cell death in QU-DB cells, but produced no significant death in A549 cells until increasing the umbelliprenin concentration to IC80. The pattern of cell death was predominantly apoptosis in both cell lines. When peripheral blood mononuclear cells were treated with 50 MUM and less concentrations of umbelliprenin, no suppressive effect was observed. CONCLUSIONS: We found cytotoxic/anti-proliferative effects of umbelliprenin against two different types of lung cancer cell lines. PMID- 23351549 TI - Characterizing biobank organizations in the U.S.: results from a national survey. AB - BACKGROUND: Effective translational biomedical research hinges on the operation of 'biobanks,' repositories that assemble, store, and manage collections of human specimens and related data. Some are established intentionally to address particular research needs; many, however, have arisen opportunistically, in a variety of settings and with a variety of expectations regarding their functions and longevity. Despite their rising prominence, little is known about how biobanks are organized and function beyond simple classification systems (government, academia, industry). METHODS: In 2012, we conducted the first national survey of biobanks in the U.S., collecting information on their origins, specimen collections, organizational structures, and market contexts and sustainability. From a list of 636 biobanks assembled through a multi-faceted search strategy, representatives from 456 U.S. biobanks were successfully recruited for a 30-minute online survey (72% response rate). Both closed and open ended responses were analyzed using descriptive statistics. RESULTS: While nearly two-thirds of biobanks were established within the last decade, 17% have been in existence for over 20 years. Fifty-three percent listed research on a particular disease as the most important reason for establishment; 29% listed research generally. Other reasons included response to a grant or gift, and intent to centralize, integrate, or harmonize existing research structures. Biobank collections are extraordinarily diverse in number and types of specimens and in sources (often multiple) from which they are obtained, including from individuals, clinics or hospitals, public health programs, and research studies. Forty-four percent of biobanks store pediatric specimens, and 36% include postmortem specimens. Most biobanks are affiliated in one or multiple ways with other entities: 88% are part of at least one or more larger organizations (67% of these are academic, 23% hospitals, 13% research institutes). The majority of biobanks seem to fill a particular 'niche' within a larger organization or research area; a minority are concerned about competition for services, although many are worried about underutilization of specimens and long-term funding. CONCLUSIONS: Effective utilization of biobank collections and effective policies to govern their use will require understanding of the immense diversity found in organizational features, including the very different history and primary goals that many biobanks have. PMID- 23351550 TI - Emergent CT findings of impending cardiac arrest: a report of 4 cases. PMID- 23351551 TI - Blood glucose may be an alternative to cholesterol in CVD risk prediction charts. AB - BACKGROUND: Established risk models for the prediction of cardiovascular disease (CVD) include blood pressure, smoking and cholesterol parameters. The use of total cholesterol for CVD risk prediction has been questioned, particularly for primary prevention. We evaluated whether glucose could be used instead of total cholesterol for prediction of fatal CVD using data with long follow-up. METHODS: We followed-up 6,095 men and women aged >=16 years who participated 1977-79 in a community based health study and were anonymously linked with the Swiss National Cohort until the end of 2008. During follow-up, 727 participants died of CVD. Based on the ESC SCORE methodology (Weibull regression), we used age, sex, blood pressure, smoking, and fasting glucose or total cholesterol. The mean Brier score (BS), area under the receiver-operating characteristic curve (AUC) and integrated discrimination improvement (IDI) were used for model comparison. We validated our models internally using cross-validation and externally using another data set. RESULTS: In our models, the p-value of total cholesterol was 0.046, that of glucose was p < 0.001. The model with glucose had a slightly better predictive capacity (BS: 2216x10-5 vs. 2232x10-5; AUC: 0.9181 vs. 0.9169, IDI: 0.009 with p value 0.026) and could well discriminate the overall risk of persons with high and low concentrations. The external validation confirmed these findings. CONCLUSIONS: Our study suggests that instead of total cholesterol glucose can be used in models predicting overall CVD mortality risk. PMID- 23351553 TI - Canadian physicians need better CMA representation. PMID- 23351552 TI - A high-content, live-cell, and real-time approach to the quantitation of ligand induced beta-Arrestin2 and Class A/Class B GPCR mobilization. AB - We report the development of a method to analyze receptor and beta-arrestin2 mobilization between Class A and B GPCRs via time-resolved fluorescent microscopy coupled with semiautomated high-content multiparametric analysis. Using transiently expressed, tagged beta2-adrenergic receptor (beta2-AR) or parathyroid hormone receptor type 1 (PTH1R), we quantified trafficking of the receptors along with the mobilization and colocalization of coexpressed tagged beta-arrestin2. This classification system allows for exclusion of cells with nonoptimal characteristics and calculation of multiple morphological and spatial parameters including receptor endosome formation, beta-arrestin mobilization, colocalization, areas, and shape. Stimulated Class A and B receptors demonstrate dramatically different patterns with regard to beta-arrestin interactions. The method provides high kinetic resolution measurement of receptor translocation, which allows for the identification of the fleeting beta-arrestin interaction found with beta2-AR agonist stimulation, in contrast to stronger mobilization and receptor colocalization with agonist stimulation of the PTH1R. Though especially appropriate for receptor kinetic studies, this method is generalizable to any dual fluorescence probe system in which quantification of object formation and movement is desired. These methodologies allow for quantitative, unbiased measurement of microscopy data and are further enhanced by providing real-time kinetics. PMID- 23351555 TI - Biological effects of bariatric surgery on obesity-related comorbidities. AB - The prevalence of obesity has increased so rapidly over the last few decades that it is now considered a global epidemic. Obesity, defined as a body mass index (BMI) of 30 or more, is associated with several comorbid conditions that decrease life expectancy and increase health care costs. Diet therapies have been reported to be ineffective in the long-term treatment of obesity, and guidelines for the surgical therapy of morbid obesity (BMI >= 40 or BMI >= 35 in the presence of substantial comorbidities) have since been established. Considering the number of bariatric surgical procedures has dramatically increased since these guidelines were established, we review the types of bariatric surgical procedures and their impact on diabetes, sleep apnea, dyslipidemia and hypertension - 4 major obesity related comorbidities. PMID- 23351556 TI - Systematic review of complications after intramedullary fixation for displaced midshaft clavicle fractures. AB - BACKGROUND: The number of displaced midshaft clavicle fractures treated surgically is increasing, and open reduction and intramedullary fixation is an emerging surgical treatment option. The study quality and scientific levels of published evidence in which possible complications of this treatment are presented vary greatly. METHODS: We performed systematic computer-based searches of EMBASE and PubMed/MEDLINE. Studies included for review reported complications after intramedullary fixation alone or in comparison to either treatment with plate fixation and/or nonoperative treatment. The Level of Evidence rating and Quality Assessment Tool were used to assess the methodological quality of the studies. Included studies were ranked according to their levels of evidence. RESULTS: Six articles were eligible for inclusion and final quality assessment; 3 studies were graded the highest level of evidence. Major complications like bone healing problems and deep infections requiring implant removal were reported at a rate no higher than 7%. Reported rates for minor complications, such as wound infection and implant irritation that could be resolved without further surgery, were as high as 31%. CONCLUSION: The noted rates for major complications requiring additional surgery were low, but implant-related problems that require additional surgery might present with high prevalence. Owing to routine implant removal, treatment with intramedullary fixation often requires an additional surgical procedure. PMID- 23351557 TI - Is there an association between implementation of a medical team training program and surgical mortality? PMID- 23351558 TI - Efficacy of 'Itrifal Saghir', a combination of three medicinal plants in the treatment of obesity; A randomized controlled trial. AB - BACKGROUND: Herbal combination of Itrifal Saghir (triphala) has been widely used in traditional medicine. And brings health benefits such as antioxidant effect and scavenger of hydroxyl radicals and nitric oxide radicals activity and substantiated in traditional medicine a anti-obesity. MATERIAL AND METHOD: In this study we aimed to assess the efficacy of this herbal medicinal on reduction of weight and body mass index (BMI) of simple obese subjects in comparison with placebo. Obese subjects aged between 16 and 60 years were selected for 12-week, double-blind, randomized, placebo-controlled trial using a parallel design. Subjects were randomly assigned to take 5 grams of either the Itrifal Saghir (n = 31) or placebo (n = 31), 2 times daily for 12 weeks. Measures of body weight, BMI, waist circumference (WC), hip circumference (HC), were assessed at baseline and once every four weeks during the 12 week treatment period. The safety was evaluated by means of measuring the liver and kidney function. Homeostasis model of insulin resistance (HOMA-IR) was calculated as [fasting insulin (MUU/mL) * fasting glucose (mmol/L)/22.5]. RESULTS: Compared to placebo group, in treatment group the mean difference of effective weight loss was 4.82Kg (CI95% 3.52 - 6.11, rho < 0.001), the mean of decrease in waist circumference was 4.01 cm (CI 95% 2.13 - 5.90, rho < 0.001), and the mean decrease in hip circumference was 3. 21 cm (CI 95% 1.96 - 4.45, rho < 0.001) in treated subjects. No adverse effects or significant changes in liver and kidney function tests were observed in both placebo and treated groups. CONCLUSIONS: Itrifal Saghir appears to produce a positive effect on weight loss in obese subjects. PMID- 23351559 TI - A survey of poison control centers worldwide. AB - To stem the rising incidence of toxic exposure as well as the associated morbidity and mortality, the past century has seen the establishment and evolution of poison control centers (PCCs) worldwide. Depending on the location, PCCs vary in terms of staffing model, services offered, and funding sources. In this article, we discuss a survey of poison control centers worldwide. PMID- 23351560 TI - Malignant insulinoma misdiagnosed and treated as epilepsy. AB - Pancreatic neuroendocrine tumors (PNET) are extremely rare, and although insulinomas are the commonest, less than 10% of insulinomas are malignant. Most patients with insulinomas present neuroglycopenic symptoms. Because of the rarity of the condition, we report the case of a 56-year-old man with malignant insulinoma, which was misdiagnosed as epilepsy. Timely diagnosis of this disease is of paramount importance to prevent neurologic sequelae of hypoglycemia. Insulinomas should be regarded from the beginning as potentially malignant, although the majority of malignant insulinomas progresses slowly. PMID- 23351561 TI - Desensitization of allergy to human insulin and its analogs by administering insulin aspart and insulin glargine. AB - Insulin allergy is a rare clinical situation. We report a 51-year-old patient with type 2 diabetes who required multiple daily insulin injections. The patient developed allergy to human regular insulin and insulin analogs (insulin aspart and insulin glargine), which was resolved by subcutaneous insulin desensitization. PMID- 23351562 TI - Association of the G-250A promoter polymorphism in the hepatic lipase gene with the risk of type 2 diabetes mellitus. AB - OBJECTIVE: Variants in hepatic lipase (HL) gene which is a lipolytic enzyme involved in the metabolism of plasma lipoprotein and regulating lipid and lipoprotein metabolism are potential candidate genes for type 2 diabetes. Association of the polymorphisms in the promoter region of the HL gene (LIPC) to the plasma HDL-C concentration has been investigated. In this study, we investigated whether the G-250A polymorphism of LIPC is associated with type 2 diabetes in Chinese Han population. SUBJECTS AND METHODS: A total of 130 patients with type 2 diabetes and 133 healthy subjects as control were randomly selected from January 2008 to January 2011 in endocrine wards of Zhengzhou People's Hospital. The G-250A polymorphisms were studied by polymerase chain reaction and restriction fragment length polymorphism. A logistic regression analysis was performed to determine the association between the rare allele and type 2 diabetes mellitus. RESULTS: The frequency of the -250A allele was 0.297 in the T2DM group and 0.388 in the control group (P<0.05), with the difference remaining significant. CONCLUSIONS: Patients who are carrying of the -250A allele in the promoter of the LIPC gene are susceptible to type 2 diabetes mellitus in Chinese Han population. PMID- 23351563 TI - Mammalian Clusterin associated protein 1 is an evolutionarily conserved protein required for ciliogenesis. AB - BACKGROUND: Clusterin associated protein 1 (CLUAP1) was initially characterized as a protein that interacts with clusterin, and whose gene is frequently upregulated in colon cancer. Although the consequences of these observations remain unclear, research of CLUAP1 homologs in C. elegans and zebrafish indicates that it is needed for cilia assembly and maintenance in these models. To begin evaluating whether Cluap1 has an evolutionarily conserved role in cilia in mammalian systems and to explore the association of Cluap1 with disease pathogenesis and developmental abnormalities, we generated Cluap1 mutant mice. METHODS: Cluap1 mutant embryos were generated and examined for gross morphological and anatomical defects using light microscopy. Reverse transcription PCR, beta-galactosidase staining assays, and immunofluorescence analysis were used to determine the expression of the gene and localization of the protein in vivo and in cultured cell lines. We also used immunofluorescence analysis and qRT-PCR to examine defects in the Sonic hedgehog signaling pathway in mutant embryos. RESULTS: Cluap1 mutant embryos die in mid-gestation, indicating that it is necessary for proper development. Mutant phenotypes include a failure of embryonic turning, an enlarged pericardial sac, and defects in neural tube development. Consistent with the diverse phenotypes, Cluap1 is widely expressed. Furthermore, the Cluap1 protein localizes to primary cilia, and mutant embryos were found to lack cilia at embryonic day 9.5. The phenotypes observed in Cluap1 mutant mice are indicative of defects in Sonic hedgehog signaling. This was confirmed by analyzing hedgehog signaling activity in Cluap1 mutants, which revealed that the pathway is repressed. CONCLUSIONS: These data indicate that the function of Cluap1 is evolutionarily conserved with regard to ciliogenesis. Further, the results implicate mammalian Cluap1 as a key regulator of hedgehog signaling and as an intraflagellar transport B complex protein. Future studies on mammalian Cluap1 utilizing this mouse model may provide insights into the role for Cluap1 in intraflagellar transport and the association with colon cancer and cystic kidney disorders. PMID- 23351564 TI - Assessing the effectiveness and cost-effectiveness of audit and feedback on physician's prescribing indicators: study protocol of a randomized controlled trial with economic evaluation. AB - BACKGROUND: Physician prescribing is the most frequent medical intervention with a highest impact on healthcare costs and outcomes. Therefore improving and promoting rational drug use is a great interest. We aimed to assess the effectiveness and cost-effectiveness of two forms of conducting prescribing audit and feedback interventions and a printed educational material intervention in improving physician prescribing. METHOD/DESIGN: A four-arm randomized trial with economic evaluation will be conducted in Tehran. Three interventions (routine feedback, revised feedback, and printed educational material) and a no intervention control arm will be compared. Physicians working in outpatient practices are randomly allocated to one of the four arms using stratified randomized sampling. The interventions are developed based on a review of literature, physician interviews, current experiences in Iran and with theoretical insights from the Theory of Planned Behavior. Effects of the interventions on improving antibiotics and corticosteroids prescribing will be assessed in regression analyses. Cost data will be assessed from a health care provider's perspective and incremental cost-effectiveness ratios will be calculated. DISCUSSION: This study will determine the effectiveness and cost effectiveness of three interventions and allow us to determine the most effective interventions in improving prescribing pattern. If the interventions are cost effective, they will likely be applied nationwide. TRIAL REGISTRATION: Iranian Registry of Clinical Trials Registration Number: IRCT201106086740N1Pharmaceutical Sciences Research Center of TUMS Ethics Committee Registration Number: 90-02-27 07. PMID- 23351565 TI - Potential role of membrane-bound COMT gene polymorphisms in female depression vulnerability. AB - BACKGROUND: Several polymorphic variants within the catechol-O-methyltransferase (COMT) gene locus have been associated with a number of diverse psychiatric phenotypes including affective disorders. COMT enzyme participates in metabolic pathways involving brain catecholamines, as well as steroid hormones such as estrogens. Given the suggested mood enhancing role of estrogens and the higher prevalence of depression in women, we set out to investigate the potential impact of functional COMT genetic variants on depression and anxiety symptoms in a homogeneous female community sample. METHODS: We genotyped three common polymorphisms within the COMT gene in a rural female population isolate (n=391) interviewed for the presence of lifetime major depression episodes and generalized anxiety disorder. Furthermore, well validated self-rated questionnaires were administered evaluating state depressive symptoms and neuroticism personality trait. Single-marker and haplotype association analyses were performed. RESULTS: Two highly correlated markers located in the membrane bound (MB) COMT promoter region (rs2020917, rs737865) were significantly associated with both self-rated and clinician-rated depressive symptomatology. We did not detect any robust association with generalized anxiety disorder or neuroticism. Exploratory haplotype analysis examining the two promoter markers in combination with the extensively studied val 158met polymorphism (rs4680) did not provide any further support for the contribution of this variant in depressive mood. LIMITATIONS: The relative small sample size should be considered a limitation of this study. CONCLUSIONS: Our results provide promising evidence that MB-COMT specific genetic variation may represent an as yet unrecognized genetic factor that influences predisposition to depression amongst females. PMID- 23351566 TI - Bridging the gap for ethnic minority adult outpatients with depression and anxiety disorders by culturally adapted treatments. AB - BACKGROUND: Culturally adapted guideline driven depression and anxiety treatments have been developed for ethnic minority patients in Western countries to boost effectiveness for these growing and vulnerable groups. The aims of this study are to systematically review the empirical literature of outcomes associated with culturally adapted guideline driven depression and anxiety interventions, to describe the cultural adaptation and to identify the contribution of the cultural adaptation and approach as such. METHOD: Comprehensive search of the major bibliographical databases (Cochrane Central Register of Controlled Trials, Pubmed; Psychinfo) for randomized controlled trials. RESULTS: Nine eligible studies were identified and all were conducted in the USA. The pooled random standardized differences in means of the culturally adapted depression and anxiety treatment on clinical outcome was 1.06 (CI 95% 0.51-1.62, P=0.00). Two studies demonstrated effectiveness of the population specific cultural adaptation per se. All studies incorporated a focus on cultural values and beliefs as a cultural adaptation. LIMITATION: We only identified a small number of USA studies so generalisation of the findings to other western countries can be discussed. CONCLUSION: Culturally adapted guideline driven depression and anxiety treatment was effective for USA minority patients from different cultural backgrounds. There is some evidence for the effectiveness of the population specific cultural adaptation as such. PMID- 23351567 TI - Relationship between area-level socioeconomic characteristics and outdoor NO2 concentrations in rural and urban areas of northern Spain. AB - BACKGROUND: Socioeconomic variables are associated with mortality and morbidity in a variety of diseases at both the individual and neighborhood level. Investigating whether low socioeconomic status populations are exposed to higher air pollution has been an important objective for the scientific community during the last decade. The goal of this study was to analyze the associations between outdoor nitrogen dioxide (NO2) concentrations in an area of Asturias (Spain) and two socioeconomic indexes-one based on occupation and the other on educational level at the census-tract level. METHODS: A map of NO2 concentration was obtained from a land-use regression model. To obtain a census-tract average value, NO2 was estimated at the centroids of all 50 * 50 grids within a census tract. Standard socioeconomic variables were used from the Census of Population and Housing 2001. We analyzed the association between NO2 concentration and socioeconomic indicators for the entire area and stratified for more urban and more rural areas. RESULTS: A positive linear relationship was found between the levels of education and NO2 exposure in the urban area and the overall study area, but no association was found in the rural area. A positive association between socioeconomic index based upon occupation and NO2 concentration was found in urban areas; however, this association was reversed in the rural and overall study areas. CONCLUSIONS: The strength and direction of the association between socioeconomic status and NO2 concentration depended on the socioeconomic indicator used and the characteristics of the study area (urban, rural). More research is needed with different scenarios to clarify the uncertain relationship among socioeconomic indexes, particularly in non-urban areas, where little has been documented on this topic. PMID- 23351568 TI - Design and characterization of diclofenac diethylamine transdermal patch using silicone and acrylic adhesives combination. AB - BACKGROUND AND PURPOSE OF THE STUDY: The objective of the study was to develop and characterize Diclofenac Diethylamine (DDEA) transdermal patch using Silicone and acrylic adhesives combination. METHODS: Modified solvent evaporation method was employed for casting of film over Fluoropolymer coated polyester release liner. Initial studies included solubilization of drug in the polymers using solubilizers. The formulations with combination of adhesives were attempted to combine the desirable features of both the adhesives. The effect of the permeation enhancers on the drug permeation were studied using pig ear skin. All the optimized patches were subjected to adhesion, dissolution and stability studies. A 7-day skin irritancy test on albino rabbits and an in vivo anti inflammatory study on wistar rats by carrageenan induced paw edema method were also performed. RESULTS: The results indicated the high percent drug permeation (% CDP-23.582) and low solubility nature (1%) of Silicone adhesive and high solubility (20%) and low% CDP (10.72%) of acrylic adhesive. The combination of adhesives showed desirable characteristics for DDEA permeation with adequate % CDP and sufficient solubility. Release profiles were found to be dependent on proportion of polymer and type of permeation enhancer. The anti-inflammatory study revealed the sustaining effect and high percentage inhibition of edema of C4/OLA (99.68%). The acute skin irritancy studies advocated the non-irritant nature of the adhesives used. CONCLUSION: It was concluded that an ideal of combination of adhesives would serve as the best choice, for fabrication of DDEA patches, for sustained effect of DDEA with better enhancement in permeation characteristics and robustness. PMID- 23351569 TI - Focused cardiac ultrasound training: how much is enough? AB - BACKGROUND: Focused transthoracic echocardiography (F-TTE) is an important tool to assess hemodynamically unstable patients in the Emergency Department. Although its scope has been defined by the American College of Emergency Physicians, more research is needed to define an optimal F-TTE training program, including assessment of proficiency. OBJECTIVE: The goal of this study was to determine the effectiveness of current standards in post-residency training to reach proficiency in F-TTE. METHODS: Fourteen staff Emergency Physicians were enrolled in a standardized teaching curriculum specifically designed to meet the 2008 American College of Emergency Physicians' guidelines for general ultrasound training applied to echocardiography. This training program consisted of 6 h of didactics and 6 h of scanning training, followed by independent scanning over a 5 month period. Acquisition of echocardiographic knowledge was assessed by an online pre- and post-test. At the conclusion of the study, a hands-on skills test assessed the trainees' ability to perform and interpret F-TTE. RESULTS: Ninety percent of trainees passed the written post-test. Two views, the parasternal long and short axis, were easily obtainable, regardless of the level of training or the number of ultrasounds completed. Other views were more difficult to master, but strong trends toward increased competency were evident after 10 h of mixed didactic and scanning training and > 45 ultrasounds. CONCLUSIONS: A short, 12-h didactic training in F-TTE provided proficiency in image interpretation and in obtaining adequate images from the parasternal window. More extensive training is needed to master the apical and subcostal windows in a timely manner. PMID- 23351570 TI - Army flight medic performance of paramedic level procedures: indicated vs. performed. AB - BACKGROUND: There is great disparity in the education, experience, and staffing requirements for civilian and Army aeromedical transports (AMT). OBJECTIVE: This study sought to determine if medical skills beyond the standard training for Army flight medics were indicated and being performed on Army AMT missions. As a secondary measure, the percentage of indicated interventions performed by basic Emergency Medical Technician (EMT-B) and paramedic (EMT-P) flight medics were compared. METHODS: This was a retrospective review of Army AMT charts including patients transported by an EMT-B-staffed unit in Iraq and an EMT-P-staffed unit in Afghanistan from July 2008 to June 2009. Charts were reviewed independently by two Emergency Medicine board-certified Army flight surgeons. RESULTS: Of 984 interventions found to be indicated on the 406 charts that met inclusion criteria, 36% were rated as EMT-P level. Seventeen percent were indicated but not performed. EMT-Bs failed to perform indicated procedures 35% of the time vs. 3% in the EMT-P group (p < 0.001). For paramedic-level procedures, EMT-Bs failed to make 76% of appropriate interventions, compared to <1% in the EMT-P group (p < 0.001). CONCLUSIONS: There seems to be a substantial number of procedures beyond the scope of standard Army flight medic training being required for Army AMT missions. It seems that when advance interventions are indicated, those trained to the EMT-P level perform them significantly more often than those trained to Army standard. CONCLUSIONS: Based on the findings of this study, the authors suggest the Army consider adopting the standards required for civilian AMT. PMID- 23351571 TI - Sixteen-year-old athlete with chest pain and shortness of breath due to pulmonary emboli. AB - BACKGROUND: Pulmonary embolism (PE) is a life-threatening condition that is extremely uncommon in the healthy pediatric population. OBJECTIVE: Because pediatric PE is rarely on the Emergency Physician's differential diagnosis, with this case we hope to increase the clinical suspicion for PE in children who present to the Emergency Department (ED). CASE REPORT: This is a case of bilateral pulmonary embolism in a 16-year-old basketball player whose only risk factor is oral contraceptive medication. Initial vital signs demonstrated a temperature of 37.1 degrees C (98.8 degrees F), blood pressure 124/74 mm Hg, heart rate 74 beats/min, respiratory rate 16 breaths/min, and oxygen saturation 100% on room air. Subsequent vital signs, physical examination, chest radiograph, electrocardiogram, and laboratory assessments were all within normal limits. Using clinician gestalt in combination with the patient's Wells score of 0, a D dimer was obtained and returned at 1916 ng/mL. The computed tomography scan with PE protocol detected a total of seven pulmonary emboli bilaterally. The patient was anticoagulated with Lovenox (Sanofi US, Bridgewater, NJ) in the ED and admitted to the pediatric intensive care unit. Complete thrombophilia work-up was negative. The patient was discharged with Lovenox and was transitioned to warfarin. CONCLUSIONS: Emergency Physicians may be inclined to discharge a pediatric patient at low pre-test probability for PE with outpatient follow-up if the work-up is non-contributory. But the current adult PE clinical criteria are not as sensitive or specific in the pediatric population. This case demonstrates that the clinician's gestalt should play a major role in combination with the Wells score and PERC (pulmonary embolism rule-out criteria) rule to exclude PE until clinical decision rules specific for the pediatric population are established. PMID- 23351572 TI - Videolaryngoscopy with glidescope reduces cervical spine movement in patients with unsecured cervical spine. AB - BACKGROUND: Unconscious patients with severe trauma often require urgent endotracheal intubation. In trauma victims with possible cervical spine injury, any movement of the head and neck should be avoided. STUDY OBJECTIVES: We investigated the effect of GlideScope videolaryngoscopy on cervical spine movement compared with conventional laryngoscopy in anesthetized patients with unsecured cervical spines. METHODS: Sixty patients scheduled for elective surgery with general anesthesia and without anticipated airway problems were enrolled in the study after ethics committee approval and written informed consent. Intubation was performed with videolaryngoscopy (GlideScope((r)), Verathon Inc., Bothell, WA) or conventional laryngoscopy (MacIntosh). Using video motion analysis with a lateral view, the maximum extension angle alpha was measured with reference to anatomical points (baseline and line drawn from processus mastoideus to os frontale [glabella]). Values were analyzed using Mann Whitney U-tests. RESULTS: The deviation of alpha was a median 11.8 degrees in the videolaryngoscope group and 14.3 degrees in the conventional group (p = 0.045), with a maximum of 19.2 degrees (videolaryngoscopy) vs. 29.3 degrees (conventional). Intubation by physicians with some experience in videolaryngoscopy was associated with a reduced angle deviation (alpha = 10.3 degrees ) compared to inexperienced physicians (12.8 degrees , p = 0.019). Intubation time was a median 24 s (min/max 12/75 s) in the MacIntosh group and 53 s (min/max 28/210 s) in the GlideScope group. In 3 patients randomized to the conventional group in whom conventional intubation failed, intubation could be successfully performed using videolaryngoscopy. CONCLUSION: GlideScope videolaryngoscopy reduces movements of the cervical spine in patients with unsecured cervical spines and therefore might reduce the risk of secondary damage during emergency intubation of patients with cervical spine trauma. PMID- 23351573 TI - Tetanus after home piercing. PMID- 23351574 TI - Google Internet searches on residency applicants do not facilitate the ranking process. AB - BACKGROUND: Information used by program directors (PDs) to evaluate and rank residency applicants is largely limited to the Electronic Residency Application Service and the interview day. The Internet represents a potential source of additional data on applicants. Recent surveys reveal that up to 90% of United States (US) companies are already using the Internet to post jobs and to screen candidates. However, its use in residency applicant evaluation is not well studied. OBJECTIVE: We hypothesize that the Internet, through the use of a Google search, will provide useful information to PDs in ranking applicants. METHODS: This prospective observational study was completed by six Accreditation Council for Graduate Medical Education-accredited Emergency Medicine residency programs. After the interview process, programs formed their rank order list in their usual fashion. Then participating programs performed a Google search on applicants from their list. A standardized search was used and information reviewed was limited to the first two Google pages. The main outcome measure was change in an applicant's status on the rank order list. Change in status was based on the judgment of the individual program's PD. RESULTS: A total of 547 applicants were reviewed. The time for review of information was 4,386 min total and a mean of 7.2 min per resident. Position on the rank order list was changed for three applicants; two moved up on the list and one moved down. Four programs made no changes. No applicants were removed. CONCLUSIONS: The Internet, through the use of a Google search, did not appear to provide useful information in a time effective manner to PDs in ranking applicants. PMID- 23351575 TI - The influence of microbial physiology on biocatalyst activity and efficiency in the terminal hydroxylation of n-octane using Escherichia coli expressing the alkane hydroxylase, CYP153A6. AB - BACKGROUND: Biocatalyst improvement through molecular and recombinant means should be complemented with efficient process design to facilitate process feasibility and improve process economics. This study focused on understanding the bioprocess limitations to identify factors that impact the expression of the terminal hydroxylase CYP153A6 and also influence the biocatalytic transformation of n-octane to 1-octanol using resting whole cells of recombinant E. coli expressing the CYP153A6 operon which includes the ferredoxin (Fdx) and the ferredoxin reductase (FdR). RESULTS: Specific hydroxylation activity decreased with increasing protein expression showing that the concentration of active biocatalyst is not the sole determinant of optimum process efficiency. Process physiological conditions including the medium composition, temperature, glucose metabolism and product toxicity were investigated. A fed-batch system with intermittent glucose feeding was necessary to ease overflow metabolism and improve process efficiency while the introduction of a product sink (BEHP) was required to alleviate octanol toxicity. Resting cells cultivated on complex LB and glucose-based defined medium with similar CYP level (0.20 MUmol gDCW-1) showed different biocatalyst activity and efficiency in the hydroxylation of octane over a period of 120 h. This was influenced by differing glucose uptake rate which is directly coupled to cofactor regeneration and cell energy in whole cell biocatalysis. The maximum activity and biocatalyst efficiency achieved presents a significant improvement in the use of CYP153A6 for alkane activation. This biocatalyst system shows potential to improve productivity if substrate transfer limitation across the cell membrane and enzyme stability can be addressed especially at higher temperature. CONCLUSION: This study emphasises that the overall process efficiency is primarily dependent on the interaction between the whole cell biocatalyst and bioprocess conditions. PMID- 23351576 TI - From the editor: selling the benefit of drug therapy. PMID- 23351577 TI - Achieving adherence to lipid-lowering regimens. PMID- 23351578 TI - Wax-matrix extended-release niacin vs inositol hexanicotinate: a comparison of wax-matrix, extended-release niacin to inositol hexanicotinate "no-flush" niacin in persons with mild to moderate dyslipidemia. AB - BACKGROUND: Nicotinic acid (NA), long used for the treatment of dyslipidemia, has shown problems with undesirable side effects and safety issues. Wax-matrix, extended-release niacin (WMER) and inositol hexanicotinate (IHN) have both been formulated to increase patient tolerability. Several trials of WMER demonstrated good efficacy in improving dyslipidemia; however, there are few scientific data on the use of IHN. OBJECTIVE: This study was designed to compare the efficacy and tolerability of WMER and IHN to each other and placebo to help clinicians make an informed choice of NA agents. METHODS: This was a 6-week blinded, placebo controlled trial comparing 1500 mg/d of WMER with 1500 mg/d IHN. Subjects with mild-to-moderate dyslipidemia (low-density lipoprotein = 130-190/dL) were randomized, after a 4-week diet lead-in period, to three parallel study arms (40 subjects/arm). Diet, pill compliance, and side effects were monitored as well as lipid and blood chemistry profiles (baseline, 6 weeks). A dose-reduction protocol was included for subjects who did not tolerate the 1500-mg dose of NA. A pharmacokinetic substudy was conducted on subjects from the WMER (n = 5) and IHN (n = 5) groups. RESULTS: WMER demonstrated significant improvements in total cholesterol = -11%, low-density lipoprotein = -18%, high-density lipoprotein = +12%, and non-high-density lipoprotein = -15% (P < .001), whereas IHN and placebo showed no significant improvement in lipids. All groups had good medication compliance and treatment tolerance with only one dropout in the WMER group as the result of flushing. Blood chemistries showed small (24%-27%) mean increases in hepatic transaminases; six subjects completed the study at reduced dosage protocol with good lipid results. Pharmacokinetics demonstrated an intermediate release and absorption rate for WMER over 6 hours and IHN showed no evidence of bioavailability. CONCLUSION: WMER demonstrated good tolerance and efficacy and extended-release kinetics. IHN was well tolerated but was no better than placebo in lipid improvement and showed no evidence of bioavailability. PMID- 23351579 TI - High-density lipoprotein levels are strongly associated with the recovery rate of insulin sensitivity during the acute phase of myocardial infarction: a study by euglycemic hyperinsulinemic clamp. AB - BACKGROUND: The decrease of insulin sensitivity (IS) during myocardial infarction (MI) is strongly associated with increased morbidity and mortality. Recent data suggest that in individuals under stable conditions, high-density lipoprotein (HDL) may improve IS. To date, the role of HDL in the modulation of IS in acute metabolic stress conditions such as MI remains unknown. OBJECTIVE: To explore the association between plasma HDL-C and the change in IS during the acute phase of MI. METHODS: Consecutive nondiabetic patients with ST-segment elevation MI (n = 22) underwent direct measurement of IS through the euglycemic hyperinsulinemic clamp on the first morning and on the fifth day after onset of MI. Patients were grouped according to HDL-C levels at admission above and below the median value (35 mg/dL). RESULTS: At admission, there was no significant difference in baseline IS index, clinical, anthropometric, or treatment characteristics between low and high HDL groups. Between admission and fifth day, there was a decrease of 8% in IS index in the low HDL group and an 11% increase in the high HDL group (P = .001 for intragroup and P = .012 for intergroup difference). This difference remained significant after we controlled for the sex, age, waist circumference, triglycerides, baseline IS index, and statin dose during hospitalization. CONCLUSION: This is the first study to provide evidence that plasma levels of HDL C are strongly associated with the recovery rate of IS during the acute phase of MI. PMID- 23351580 TI - Interrelationships between the concentration and size of the largest high-density lipoprotein subfraction and apolipoprotein C-I in infants at birth and follow-up at 2-3 months of age and their parents. AB - BACKGROUND: Lipoprotein subfractions in infants may predict the risk of cardiovascular disease factors in children. OBJECTIVE: To examine the relationships between lipid and nonlipid factors and lipoprotein subfractions in infants at birth and follow-up (FU) and in their parents. METHODS: Prospective study in a community-based hospital of 103 families ascertained through a pregnant mother at 36 weeks gestation or older. Of 103 infants studied at birth, 85 were sampled at FU at 2-3 months of age, along with 76 fathers. Lipids, lipoproteins, and their subclasses were determined by nuclear magnetic resonance spectroscopy. Correlations of lipid-related parameters were calculated using Spearman rank correlations. RESULTS: Female gender in infants and use of formula only were the only nonlipid variables associated with lipoprotein subfractions. LDL parameters were significantly correlated between infants at birth and FU. The largest high-density lipoprotein subfraction, H5C, was the only lipid variable significantly associated between mothers and infants at birth. Paternal low density lipoprotein size was significantly correlated with that of infants at FU but not at birth. In each of the four groups, markedly inverse interrelationships were found between H5C and small LDL particles. At birth and at FU, apoC-I was strongly related with H5C but not TG. Conversely, apoC-I in the parents was strongly related with TG but not H5C. CONCLUSION: Significant relationships were found between lipoprotein subfractions within infants at birth and FU and their parents. ApoC-I and H5C levels very early in life may affect the development of dyslipidemia and obesity in childhood. PMID- 23351581 TI - Apolipoproteins A-I, B, and C-III in young adult Cherokee with metabolic syndrome with or without type 2 diabetes. AB - BACKGROUND: Because type 2 diabetes (T2D) is a coronary artery disease risk equivalent, it is important to identify difference in risk markers between cases with T2D and the metabolic syndrome (MetS) compared with those with MetS alone. We evaluated apolipoproteins as possible distinguishing markers in the Oklahoma Cherokee. OBJECTIVE: To assess apolipoproteins (apo) A-I, B, and C-III in young adult Cherokee who have the metabolic syndrome (MetS), as defined by the National Cholesterol Education Program (NCEP), either with or without T2D. METHODS: A cross-sectional comparison of young adult Oklahoma Cherokee, ages 18 to 40 years, was conducted to assess differences in the apolipoproteins caused by the presence or absence of T2D among those with MetS, after we adjusted for age and gender. RESULTS: ApoA-I (P = .0222) and high-density lipoprotein cholesterol (HDL-C; P = .0364) were lower, and apoB (P = .0106) and the apoB to A-I ratio (P < .0001) were greater in participants with the MetS and T2D than in those with MetS but without T2D. However, cholesterol, triglyceride, low-density lipoprotein cholesterol, non-HDL-C, total apoC-III, non-HDL apoC-III and the bimodal lipoprotein distribution of apoC-III (apoC-III ratio) were not significantly different between the two groups. CONCLUSION: ApoA-I and HDL-C are lower and apoB and the apoB:A-I ratio are greater in those with MetS and T2D than in those who have the MetS but without T2D, suggesting that the presence of diabetes adversely influences plasma apoA-I and apoB levels. However, apoC-III and non-HDL apoC-III are unchanged by the addition of diabetes suggesting that the increased levels associated with MetS may precede T2D. PMID- 23351582 TI - Compliance with the Adult Treatment Panel III guidelines for hyperlipidemia in a resident-run ambulatory clinic: a retrospective data analysis. AB - BACKGROUND: One in every six adults (16.3% of the U.S. adult population) has high total cholesterol levels, and they are at double the risk of heart disease compared with people with optimal levels. OBJECTIVE: To evaluate compliance of internal medicine residents with the latest National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines in treating patients with hyperlipidemia. DESIGN: Retrospective observational study. SETTING: Ambulatory Clinic, Saint Vincent Hospital, Worcester, Massachusetts. PATIENTS: Patients with a diagnosis of hyperlipidemia who attended the clinic during a 1 ear period, from December 2009 to November 2010. MEASUREMENTS: A review of medical records was conducted to evaluate residents' compliance with the NCEP-ATP III guidelines for LDL cholesterol and non-HDL cholesterol management. RESULTS: Seven hundred seventy charts were reviewed. Only 212 (27.5%) met the inclusion criteria. Analysis of data revealed better compliance with drug therapy (44%-77%) and therapeutic lifestyle changes (44%-83%) when compared with follow-up recommendations (22%-31%). An increase in compliance also was noted in all areas of intervention when patients had an abnormal lipid profile. LIMITATIONS: Compliance was assessed on the basis of electronic medical record documentation alone and hence we may be underestimating compliance with therapeutic lifestyle changes and follow-up recommendations. CONCLUSION: Compliance among internal medicine residents in the diagnosis, treatment and follow-up of patients with hyperlipidemia according to NCEP-ATP III guidelines was suboptimal and needs improvement. PMID- 23351583 TI - Postprandial lipemia is not increased in patients with previous unprovoked venous thromboembolism. AB - BACKGROUND: Patients with arterial cardiovascular disease have increased postprandial lipemia, and plasma levels of postprandial remnants are related to the progression of atherosclerosis. Studies have shown that patients with unprovoked venous thromboembolism have increased risk of arterial cardiovascular disease. OBJECTIVE: To investigate whether patients with a history of unprovoked venous thromboembolism have increased postprandial lipemia. METHODS: A population based case-control study was performed in 20 patients with a history of unprovoked venous thromboembolism and 20 age- and gender-matched healthy controls. Participants were subjected to a standard fat tolerance test (1 g/kilo body weight) with subsequent blood sampling every second hour for 8 hours. Lipids were measured by traditional methods and lipoprotein subclasses by proton nuclear magnetic resonance. RESULTS: Fasting lipids and lipoprotein subclasses did not differ between groups. The postprandial lipemia, assessed by the incremental area under the triglyceride curve, was not different in venous thromboembolism patients and healthy controls (5.0 +/- 3.6 mmol/L*h vs 5.3 +/- 4.4 mmol/L*h, P = .81). Similarly, the distribution and size of the lipoprotein subclasses obtained 4 hours postprandially did not differ between groups. CONCLUSION: Patients with a history of unprovoked venous thromboembolism had similar lipoprotein subclasses size, distribution, and postprandial lipemia as healthy controls. Our findings indicate that postprandial lipemia is not a link between unprovoked venous thromboembolism and arterial cardiovascular disease. PMID- 23351584 TI - Common variation in cholesteryl ester transfer protein: relationship of first major adverse cardiovascular events with the apolipoprotein B/apolipoprotein A-I ratio and the total cholesterol/high-density lipoprotein cholesterol ratio. AB - BACKGROUND: The preference of the apolipoprotein (apo) B/apoA-I ratio over the total cholesterol/HDL cholesterol (TC/HDL-C) ratio in cardiovascular risk prediction is disputed. Cholesteryl ester transfer protein (CETP) is instrumental in lipoprotein remodelling and affects the cholesterol content in pro- and antiatherogenic lipoproteins relative to their major apolipoproteins. We tested the influence of common CETP variations on the strength of associations of a first major adverse cardiovascular event (MACE) with the apoB/apoA-I ratio compared with the TC/HDL-C ratio. METHODS: A prospective case-cohort study was performed (PREVEND cohort; no previous cardiovascular disease and no use of lipid lowering drugs initially). Fasting serum TC/HDL-C, apoB/apoA-I, triglycerides, and common CETP variations (TaqIB [rs708272] and -629C>A [rs1800775] polymorphisms) were measured at baseline. The composite end point was incident MACE. RESULTS: A total of 532 of 6780 subjects experienced a first MACE during 10.8 years follow-up. The age- and sex-adjusted hazard ratio was 1.31 (95 % confidence interval 1.23-1.41) for the apoB/apoA-I ratio and 1.22 (95% confidence interval 1.26-1.39) for the TC/HDL-C ratio (both P < .001). These relationships were essentially similar within each TaqIB and -629C>A CETP genotype group. No interactions of the apoB/apoA-I ratio and the TC/HDL-C ratio with the TaqIB and the -629C>A CETP variations on incident MACE were observed (P > .20 for all). CONCLUSION: The relationship of first MACE with the TC/HDL-C and the apoB/apoA-I ratio is not to an important extent dependent on common CETP variations. CETP variations are unlikely to affect the strength of the relationship of first MACE with the apoB/apoA-I ratio compared with the TC/HDL-C ratio. PMID- 23351586 TI - A novel mutation in the ABCA1 gene causing an atypical phenotype of Tangier disease. AB - Tangier disease is a rare autosomal-recessive disorder caused by mutation in the ATP binding cassette transporter 1 (ABCA1) gene. Typically, Tangier disease manifests with symptoms and signs resulting from the deposition of cholesteryl esters in nonadipose tissues; chiefly, in peripheral nerves leading to neuropathy and in reticulo-endothelial organs, such as liver, spleen, lymph nodes, and tonsils, causing their enlargement and discoloration. An association with early cardiovascular disease can be variable. We describe a patient with a unique phenotype of Tangier disease from a novel splice site mutation in the ABCA1 gene that is associated with a central nervous system presentation resembling multiple sclerosis, and the presence of premature atherosclerosis. PMID- 23351587 TI - A prop to explain LDL particles. PMID- 23351588 TI - Evaluation of the incidence and risk factors for development of fenofibrate associated nephrotoxicity. PMID- 23351585 TI - Genetic determinants of cardiometabolic risk: a proposed model for phenotype association and interaction. AB - This review provides a translational and unifying summary of metabolic syndrome genetics and highlights evidence that genetic studies are starting to unravel and untangle origins of the complex and challenging cluster of disease phenotypes. The associated genes effectively express in the brain, liver, kidney, arterial endothelium, adipocytes, myocytes, and beta cells. Progression of syndrome traits has been associated with ectopic lipid accumulation in the arterial wall, visceral adipocytes, myocytes, and liver. Thus, it follows that the genetics of dyslipidemia, obesity, and nonalcoholic fatty liver disease are central in triggering progression of the syndrome to overt expression of disease traits and have become a key focus of interest for early detection and for designing prevention and treatments. To support the "birds' eye view" approach, we provide a road-map depicting commonality and interrelationships between the traits and their genetic and environmental determinants based on known risk factors, metabolic pathways, pharmacologic targets, treatment responses, gene networks, pleiotropy, and association with circadian rhythm. Although only a small portion of the known heritability is accounted for and there is insufficient support for clinical application of gene-based prediction models, there is direction and encouraging progress in a rapidly moving field that is beginning to show clinical relevance. PMID- 23351589 TI - Inflammatory cast of the tympanic membrane after acute otitis media. AB - OBJECTIVE: To describe a relatively unknown clinical entity - inflammatory cast of the tympanic membrane after acute otitis media - and its simple out-patient treatment. STUDY DESIGN: Retrospective review of case series. SETTING: Subspecialty practice at a tertiary hospital. PATIENTS: Seven patients diagnosed previously with acute otitis media with perforation or otitis externa, and with persistent ear discomfort. METHODS: Retrospective chart review. RESULTS: The patients presented with weeks to months of persistent hearing loss after acute otitis media with perforation or acute otitis externa. Visits to their primary care physicians had been uninformative. After comparison of the affected and unaffected tympanic membranes, a thin, hard cast was identified and removed from the affected tympanic membrane. Improvement in hearing was documented in the three patients who underwent audiometric testing; the remainder had subjective improvement without audiometric evaluation. CONCLUSION: Otolaryngologists should be aware of the possibility of an inflammatory cast of the tympanic membrane following acute otitis media with perforation or otitis externa, and should carefully compare the unaffected and affected ears in such cases. Treatment - removal of the rigid cast - is both simple and effective. PMID- 23351590 TI - Effect of a single dose of escitalopram on serotonin concentration in the non human and human primate brain. AB - Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for treatment of psychiatric disorders. The exact mechanism underlying the clinical effects of SSRIs remains unclear, although increased synaptic serotonin concentrations have been hypothesized to be an initial step. [11C]AZ10419369 is a novel 5-HT(1B) receptor selective radioligand, which is sensitive to changes in endogenous serotonin concentrations. To assess whether a single dose of the SSRI escitalopram affects endogenous serotonin concentrations in serotonergic projection areas and in the raphe nuclei (RN), three cynomolgus monkeys and nine human subjects underwent PET examinations with [11C]AZ10419369 at baseline conditions and after escitalopram administration. In monkeys, the binding potential (BP(ND)) was significantly lower post dose compared to baseline in dorsolateral prefrontal cortex, occipital cortex, thalamus, midbrain and RN (p < 0.05). In humans, the BP(ND) tended to decrease in RN post dose (p = 0.08). In all serotonergic projection areas, the BP(ND) was conversely higher post dose compared to baseline. The increase was significant in a combined region of all projection areas (p = 0.01) and in occipital and temporal cortex (p < 0.05). SSRIs are generally assumed to elevate endogenous serotonin concentrations in projection areas, evoking the antidepressant effect. In the present study, a single, clinically relevant, dose of escitalopram was found to decrease serotonin concentrations in serotonergic projection areas in humans. Hypothetically, desensitization of inhibitory serotonergic autoreceptors will cause the serotonin concentration in projection areas to increase over time with chronic administration. Thus, the findings in the present study might aid in understanding the mechanism of SSRIs' delayed onset of clinical effect. PMID- 23351591 TI - Fetal asphyctic preconditioning modulates the acute cytokine response thereby protecting against perinatal asphyxia in neonatal rats. AB - BACKGROUND: Perinatal asphyxia (PA) is a major cause of brain damage and neurodevelopmental impairment in infants. Recent investigations have shown that experimental sublethal fetal asphyxia (FA preconditioning) protects against a subsequent more severe asphyctic insult at birth. The molecular mechanisms of this protection have, however, not been elucidated. Evidence implicates that inflammatory cytokines play a protective role in the induction of ischemic tolerance in the adult brain. Accordingly, we hypothesize that FA preconditioning leads to changes in the fetal cytokine response, thereby protecting the newborn against a subsequent asphyctic insult. METHODS: In rats, FA preconditioning was induced at embryonic day 17 by clamping the uterine vasculature for 30 min. At term birth, global PA was induced by placing the uterine horns, containing the pups, in a saline bath for 19 min. We assessed, at different time points after FA and PA, mRNA and protein expression of several cytokines and related receptor mRNA levels in total hemispheres of fetal and neonatal brains. Additionally, we measured pSTAT3/STAT3 levels to investigate cellular responses to these cytokines. RESULTS: Prenatally, FA induced acute downregulation in IL-1beta, TNF alpha and IL-10 mRNA levels. At 96 h post FA, IL-6 mRNA and IL-10 protein expression were increased in FA brains compared with controls. Two hours after birth, all proinflammatory cytokines and pSTAT3/STAT3 levels decreased in pups that experienced FA and/or PA. Interestingly, IL-10 and IL-6 mRNA levels increased after PA. When pups were FA preconditioned, however, IL-10 and IL-6 mRNA levels were comparable to those in controls. CONCLUSIONS: FA leads to prenatal changes in the neuroinflammatory response. This modulation of the cytokine response probably results in the protective inflammatory phenotype seen when combining FA and PA and may have significant implications for preventing post-asphyctic perinatal encephalopathy. PMID- 23351592 TI - GC-MS analysis of insecticidal essential oil of flowering aerial parts of Saussurea nivea Turcz. AB - BACKGROUND: Several species from Saussurea have been used in the traditional medicine, such as S. lappa, S. involucrate, and S. obvallata. There is no report on medicinal use of S. nivea. The aim of this research was to determine chemical composition and insecticidal activity of the essential oil of S. nivea Turcz (Asteraceae) aerial parts against maize weevils (Sitophilus zeamais Motschulsky) for the first time. RESULTS: Essential oil of S. nivea flowering aerial parts was obtained by hydrodistillation and analyzed by gas chromatography-mass spectrometry (GC-MS). A total of 43 components of the essential oil of S. nivea were identified. The principal compounds in the essential oil were (+)-limonene (15.46%), caryophyllene oxide (7.62%), linalool (7.20%), alpha-pinene (6.43%), beta-pinene (5.66%) and spathulenol (5.02%) followed by beta-eudesmoll (4.64%) and eudesma-4,11-dien-2-ol (3.76%). The essential oil of S. nivea exhibited strong contact toxicity against S. zeamais with an LD50 value of 10.56 MUg/adult. The essential oil also possessed fumigant toxicity against S. zeamais with an LC50 value of 8.89 mg/L. CONCLUSION: The study indicates that the essential oil of S. nivea flowering aerial parts has a potential for development into a natural insecticide/fumigant for control of insects in stored grains. PMID- 23351593 TI - Informed consent in the era of biobanks. AB - Biorepositories collecting human specimens and health information have proliferated in recent years. Efforts to set a range of policies related to biorepositories, including those related to procedures for obtaining informed consent and recontacting participants, have been hindered by a paucity of data on the diverse forms biorepositories take and the variety of institutional settings where they are established. A recent survey demonstrates in detail, for the first time, the diversity of biorepositories in the USA. SEE RESEARCH ARTICLE: http://genomemedicine.com/content/5/1/3. PMID- 23351594 TI - Tubby is required for trafficking G protein-coupled receptors to neuronal cilia. AB - BACKGROUND: Tubby is the founding member of the tubby-like family of proteins. The naturally occurring tubby mutation in mice causes retinitis pigmentosa, hearing loss and obesity. Tubby has been proposed to function as an accessory factor in ciliary trafficking. We directly examined a role for tubby in ciliary trafficking in vivo. METHODS: We used immunofluoresence labeling to examine the subcellular localization of rhodopsin, somatostatin receptor 3 (SSTR3) and melanin concentrating hormone receptor 1 (MCHR1), all of which are G protein coupled receptors (GPCR), in the retina and brain of wild type (WT) and tubby mutant mice. RESULTS: In tubby mouse retina, rhodopsin is not fully transported across the connecting cilia to the outer segments with ensuing photoreceptor degeneration. In the tubby mouse brain, SSTR3 and MCHR1 fail to localize at the neuronal primary cilia in regions where these receptors play critical roles in neural signaling. The tubby mutant does not manifest a generalized defect in ciliogenesis or protein trafficking. CONCLUSIONS: Tubby plays a critical role in trafficking select GPCRs to the cilia. This role is reminiscent of tubby-like proteins 1 and 3, which have been proposed to facilitate trafficking of rhodopsin and select GPCRs in photoreceptors and the developing neural tube, respectively. Thus tubby-like proteins may be generally involved in transciliary trafficking of GPCRs. PMID- 23351595 TI - The effect of Cinnamaldehyde on mucositis and salivary antioxidant capacity in gamma-irradiated rats (a preliminary study). AB - BACKGROUND AND PURPOSE OF THE STUDY: The aim of this study was to investigate the effect of cinnamaldehyde on mucositis and salivary total antioxidant capacity in gamma-irradiated rats. METHODS: The study was conducted on 28 male Wistar rats, 7 11 weeks of age and 160 +/- 20 g body weight, divided into four groups of seven rats each. The first group receiving normal saline (S), the second group receiving saline and gamma radiation (SR), the third group receiving 50 mg/kg cinnamaldehyde 98% (C), and the fourth group receiving 50 mg/kg cinnamaldehyde 98% and gamma radiation (CR). SR and CR groups were exposed to 15 Gy gamma irradiation for 7 min and 39 s. Rats were intraperitoneally injected each day during the 10-day period of the experiment, and their tongues and lips were examined to assess the incidence and severity of mucositis. The saliva samples were taken from the animals three times on day zero, six, and ten. RESULTS: The mean mucositis incidence appeared to be delayed in the CR than the SR group (P = 0.024), and the severity was significantly higher in the SR compared to the CR group;the difference was statistically significant on the second day (P = 0.027). In the evaluation of salivary antioxidant capacity, salivary antioxidant concentration was significantly higher in the C than the S, SR, and CR groups on the tenth day of the experiment (p <0.05). CONCLUSION: The clinical effects in the CR group seem to be due to antioxidant, anti-bacterial and anti-inflammatory effects of cinnamaldehyde; this conclusion, however, requires further investigations. Delayed antioxidant effect in the CR group was evident in ip cinnamaldehyde injection, the exact mechanism is not clear. PMID- 23351596 TI - Evaluation of the safety and efficacy of warfarin in Taiwanese patients. AB - OBJECTIVE: The safety and efficacy of warfarin therapeutic range in Asians remain to be ascertained. Physicians in Taiwan consider Asians are more likely to have bleeding complications rather than thromboembolic events from warfarin. The aim of this study was to determine if the proper INR range for patients in Taiwan is different. METHODS: A retrospective study was conducted with 161 patients on warfarin therapy for more than 24 consecutive months during March 1, 2006 to Sepember 30, 2008. Total follow-up time was 3,504 patient-months. The incidence rates of thromboembolic and bleeding events for INR categories were calculated. RESULTS: The overall incidence rates of INR ranges of < 1.5, 1.5 - 1.9, 2.0 - 2.4, 2.5 - 2.9, 3.0 - 3.4, and >= 3.5 were 8.1, 5.6, 2.0, 7.6, 33.3, and 121.2 per 1,000 patientmonths, respectively. The overall incidence rate at INR of > 3 is higher than that at INR of < 2 or 2 - 3 (p < 0.001), with the lowest incidence rate at INR between 2.0 and 2.4. When INR was maintained at a level < 2, patients taking warfarin for secondary prevention had a significantly higher event rate compared to the primary prevention group (p < 0.05). Age greater than 73 years was a risk factor for thromboembolic events before and after covariate adjustment. CONCLUSION: An INR range of 2 - 2.4 appeared to be associated with lower complications and better clinical outcomes in Taiwanese patients treated with warfarin. Lowering the intensity of anticoagulant therapy further does not decrease the number of events. PMID- 23351597 TI - Relative bioavailability of levodropropizine 60 mg capsule and syrup formulations in healthy male Korean volunteers: a singledose, randomized-sequence, open-label, two-way crossover study. AB - BACKGROUND: Levodropropizine is an oral non-opioid anti-tussive drug used in treatment of cough. A new generic 60 mg capsule formulation of levodropropizine has recently been developed. OBJECTIVES: The aim of this study was to assess the pharmacokinetics and bioequivalence of the test (capsule) formulation and reference (syrup) formulation of levodropropizine (60 mg) in healthy, fasted, male Korean volunteers. METHODS: This was a single-dose, randomized sequence, open-label, 2-period crossover study conducted in healthy male Korean volunteers in the fasted state at Kyung Hee University Medical Center (Seoul, Republic of Korea). A single oral dose of the test or reference formulation was followed by a 1-week washout period, after which subjects received the alternative formulation. Blood samples were collected at 0 (predose), 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after study drug administration. Plasma concentration of levodropropizine was determined using a validated liquid chromatography tandem mass spectrometry (LCMS/ MS) method. The formulations were considered bioequivalent if the 90% CIs for C(max), AUC(0-12h) and AUC(0-infinity) were within the predetermined bioequivalence range (80 - 125%, according to the guidelines of the Korea Food and Drug Administration (Korea FDA)). Tolerability was evaluated throughout the study based on vital sign measurements, laboratory analysis (blood biochemistry, hematology, hepatic function and urinalysis) and subject interviews concerning adverse events (AEs). RESULTS: A total of 36 male Korean subjects (mean (SD) age, 23.9 (2.4) years (range 19 - 30 years); height, 176.2 (6.1) cm (range 161 - 190 cm); weight, 69.8 (9.1) kg (range 54.0 - 92.2 kg); body mass index, 22.4 (2.1) kg/m2 (range 19.1 - 28.3 kg/m2)) was enrolled and completed the study. The mean values for C(max), t(max), AUC(0-12h), and AUC(0-infinity) with the test formulation of levodropropizine were 331.51 ng/ml, 0.60 hours, 784.32 ng*h/ml, and 825.82 ng*h/ml, respectively; for the reference formulation, the values were 332.81 ng/ml, 0.44 hours, 726.46 ng*h/ml, and 769.46 ng*h/ ml, respectively. The 90% CIs for the logtransformed ratios of C(max) (92.74 - 111.24), AUC(0-12h) (104.31 - 113.67) and AUC(0-infinity) (103.87 - 113.57) were within the predetermined range for the assumption of bioequivalence. No serious adverse events were reported. CONCLUSIONS: This single-dose (60 mg) study found that the test (capsule) and reference (syrup) formulations of levodropropizine met the regulatory criterion for assuming bioequivalence in these healthy, fasted, male Korean subjects. Both formulations were well tolerated in the population studied. Korea FDA registration number: BED-1784. PMID- 23351598 TI - Monitoring of adverse drug reactions associated with antihypertensive medicines at a university teaching hospital in New Delhi. AB - AIM: To monitor the adverse drug reactions (ADRs) caused by antihypertensive medicines prescribed in a university teaching hospital. METHODS: The present work was an open, non-comparative, observational study conducted on hypertensive patients attending the Medicine OPD of Majeedia Hospital, Jamia Hamdard, New Delhi, India by conducting patient interviews and recording the data on ADR monitoring form as recommended by Central Drugs Standard Control Organization (CDSCO), Government of India. RESULTS: A total of 21 adverse drug reactions were observed in 192 hypertensive patients. Incidence of adverse drug reactions was found to be higher in patients more than 40 years in age, and females experienced more ADRs (n = 14, 7.29%) than males, 7 (3.64%). Combination therapy was associated with more number of adverse drug reactions (66.7%) as against monotherapy (33.3%). Calcium channel blockers were found to be the most frequently associated drugs with adverse drug reactions (n = 7), followed by diuretics (n = 5), and beta-blockers (n = 4). Among individual drugs, amlodipine was found to be the commonest drug associated with adverse drug reactions (n = 7), followed by torasemide (n = 3). Adverse drug reactions associated with central nervous system were found to be the most frequent (42.8%) followed by musculo-skeletal complaints (23.8%) and gastro-intestinal disorders (14.3%). CONCLUSIONS: The present pharmacovigilance study represents the adverse drug reaction profile of the antihypertensive medicines prescribed in our university teaching hospital. The above findings would be useful for physicians in rational prescribing. Calcium channel blockers were found to be the most frequently associated drugs with adverse drug reactions. PMID- 23351599 TI - Longitudinal linear growth and final height is impaired in childhood acute lymphoblastic leukemia survivors after treatment without cranial irradiation. AB - OBJECTIVE: To evaluate long-term growth and final height (FH) in survivors of childhood acute lymphoblastic leukemia (ALL) who were treated without cranial radiation therapy and underwent evaluation of growth hormone (GH) status at the end of treatment. STUDY DESIGN: Data on longitudinal growth (collected at the start of treatment, end of treatment, and 1 year thereafter) and FH of 67 adult survivors of childhood ALL who had been treated according to European Organisation for Research and Treatment of Cancer 58831/2 protocols with chemotherapy as the only treatment modality were reviewed retrospectively. Height data were expressed as SDS for national references. The relative role of sex, age at diagnosis, intensity of chemotherapeutic regimen, and GH status at the end of treatment as contributing factors were analyzed. RESULTS: A modest but significant loss in FH (change in SDS [DeltaSDS] = -0.59 +/- 0.86; P < .001) was found. Two-thirds of the height deficit observed from diagnosis until FH occurred during treatment. The height deficit was more severe in the male patients (P = .036). The DeltaSDS for height from diagnosis to FH was not correlated with age at diagnosis or intensity of treatment. No correlation was found between the results of the GH stimulation test and DeltaSDS for height from diagnosis or the end of treatment to FH. CONCLUSION: Adult survivors of childhood ALL treated with chemotherapeutic regimens of moderate intensity without cranial radiation therapy exhibit a modest loss in SDS for height at FH irrespective of GH status at the cessation of treatment. PMID- 23351600 TI - Patent ductus arteriosus, low platelets, cyclooxygenase inhibitors, and intraventricular hemorrhage in very low birth weight preterm infants. AB - OBJECTIVE: To assess the risk for intraventricular hemorrhage (IVH) in very low birth weight preterm infants with patent ductus arteriosus (PDA) and low platelet count with treatment with cyclooxygenase (COX) inhibitors. STUDY DESIGN: Diagnosis and treatment of PDA, as well as risk factors for IVH, were assessed using prospectively collected data of all infants born at a gestational age <32 weeks and with a birth weight <= 1500 g at Innsbruck University Hospital (January 2003-December 2009). Infants with severe thrombocytopenia (<50 * 10(9)/L) were excluded from analysis. RESULTS: Sixty-five (20%) of the 325 infants had IVH, and 149 (45.9%) of the 325 were treated with COX inhibitors. Treatment of PDA with COX inhibitors was not an independent risk predictor for IVH in preterm infants with platelets >= 100 * 10(9)/L. However, COX inhibitors amplified the risk of bleeding in the presence of moderately decreased platelets (50-99 * 10(9)/L) on days of life 2-7. Multivariable OR for IVH were 0.89 [95% CI 0.43-1.87] for patients with platelets >= 100 * 10(9)/L and treatment with COX inhibitors, 3.40 [95% CI 1.13-10.29] for those with moderately decreased platelets without treatment, and 53.3 [95% CI 5.9-484] for patients with both moderately decreased platelets and COX inhibitor treatment compared with those with platelets >= 100 * 10(9)/L and no treatment (reference group) (P < .001). CONCLUSION: In very low birth weight infants with moderate thrombocytopenia treatment with COX inhibitors increased the risk for intracerebral bleeding. Any benefits of this therapy should be carefully balanced against this potential hazard. PMID- 23351601 TI - Relationships between maternal ethnicity, gestational age, birth weight, weight gain, and severe retinopathy of prematurity. AB - OBJECTIVE: To develop an algorithm that allows advanced identification of infants requiring treatment for retinopathy of prematurity (ROP). STUDY DESIGN: A retrospective observational study was performed at 2 tertiary neonatal units serving a multiethnic population in the UK, using data on 929 infants eligible for ROP screening. The relationships between study variables and the risk of developing ROP requiring treatment were analyzed using multiple logistic regression. RESULTS: After applying exclusion criteria, data from 589 infants were analyzed; of these, 57 required laser treatment. The proportion of treated infants was 5.9% of those born to black mothers, 9.39% of those born to white mothers, and 12.8% of those born to Asian mothers (P = .047). Multiple logistic regression showed that gestational age, birth weight, maternal ethnicity, and early weight gain were predictors for the development of ROP requiring treatment, with maternal ethnicity having greater predictive power compared with early weight gain. We developed an algorithm for predicting the development of ROP requiring treatment with sensitivity, specificity, and positive and negative predictive values of 100%, 65.7%, 23.8%, and 100%, respectively. CONCLUSION: Gestational age, birth weight, early weight gain, and maternal ethnicity are important predictors for the development of ROP requiring treatment. In a multiethnic population, an algorithm to predict development of ROP requiring treatment should include maternal ethnicity. If confirmed through prospective studies, this algorithm could reduce the number of opthalmologic examinations performed for ROP screening. PMID- 23351602 TI - Association of tic disorders with poor academic performance in central Spain: a population-based study. AB - OBJECTIVE: To analyze the association between tic disorders and poor academic performance in school-aged children. STUDY DESIGN: This was a cross-sectional, observational study conducted in a randomly selected sample of mainstream school aged children (aged 6-16 years). The sampling frame included different types of schools and educational levels. Children with poor academic performance (eg, repeating a grade, special needs), and tic disorders (defined based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision criteria) were identified. Children with and without tics and children with and without poor academic performance were compared in terms of clinical features (ie, medical history and neurologic and psychiatric comorbidities), school, and environmental characteristics. Logistic regression analyses were performed using school performance (dependent variable) and tic disorders (independent variable), after adjusting for confounding variables. RESULTS: The study cohort comprised 1867 children (mean age, 10.9 + 2.9 years; 1007 males [53.9%]). Tics were present in 162 children (8.6%), and poor academic performance was noted in 223 (11.9%). Overall poor academic performance was associated with age (OR, 1.71; P < .0001), television viewing (OR, 5.33; P = .04), attention deficit hyperactivity disorder (OR, 1.38; P < .0001), and family history of school dysfunction (OR, 2.43; P = .02) and was negatively associated with higher IQ score (OR, 0.90; P < .0001) and tic disorders (OR, 0.29; P = .01). CONCLUSION: After adjusting for other covariates, the presence of tic disorders was not associated with poor academic performance in our cohort. Early academic support and modification of environmental characteristics are needed for children at higher risk for school dysfunction, to enhance academic performance. PMID- 23351603 TI - Population based case-control study of serious non-fatal motorcycle crashes. AB - BACKGROUND: Motorcycle sales, registration and use are increasing in many countries. The epidemiological literature on risk factors for motorcycle injury is becoming outdated, due to changes in rider demography, licensing regulations, traffic mix and density, road environments, and motorcycle designs and technologies. Further, the potential contribution of road infrastructure and travel speed has not yet been examined. METHODS/DESIGN: A population based case control study together with a nested case-crossover study is planned. Cases will be motorcycle riders who are injured but not killed in a motorcycle crash on a public road within 150 km radius of Melbourne, Australia, and admitted to one of the study hospitals. Controls will be motorcycle riders who ride through the crash site on the same type of day (weekday or weekend) within an hour of the crash time. Data on rider, bike, and trip characteristics will be collected from the participants by questionnaire. Data on crash site characteristics will be collected in a structured site inspection, and travel speed for the cases will be estimated from these data. Travel speed for the controls will be measured prior to recruitment with a radar traffic detection device as they ride through the crash site. Control sites for the case-crossover study will be selected 1 km upstream from the crash site and matched on either intersection status or road curvature (either straight or cornered). If the initial site selected does not match the case site on these characteristics, then the closest matching site on the case route will be selected. Conditional multivariate logistic regression models will be used to compare risk between the matched case and control riders and to examine associations between road infrastructure and road environment characteristics and crash occurrence. Interactions between type of site and speed will be tested to determine if site type is an effect modifier of the relationship between speed and crash risk. The relationship between rider factors and travel speed generally will be assessed by multivariate regression methods. DISCUSSION: In the context of the changing motorcycling environment, this study will provide evidence on contemporary risk factors for serious non-fatal motorcycle crashes. PMID- 23351604 TI - Metformin loaded non-ionic surfactant vesicles: optimization of formulation, effect of process variables and characterization. AB - BACKGROUND: Metformin an oral hypoglycemic has been widely used as a fist line of treatment of Type II Diabetes but in a very high dose 2-3 times a day and moreover suffers from a number of side effects like lactic acidosis, gastric discomfort, chest pain, allergic reactions being some of them. The present work was conducted with the aim of sustaining the release of metformin so as to decrease its side effects and also reduce its dosing frequency using a novel delivery system niosomes (non-ionic surfactant vesicles). Non-ionic surfactant vesicles of different surfactants were prepared using thin film hydration technique and were investigated for morphology, entrapment, in-vitro release, TEM (transmission electron microscopy) and physical stability. Optimized formulation was further studied for the effect of Surfactant concentration, DCP (Dicetyl phosphate), Surfactant: cholesterol ratio and volume of hydration. The release studies data was subjected to release kinetics models. RESULTS: The prepared vesicles were uniform and spherical in size. Optimized formulation MN3 entrapped the drug with 84.50+/-0.184 efficiency in the vesicles of the size 487.60+/-2.646 and showed the most sustained release of 73.89+/-0.126. Also it was resulted that 100 molar concentration of cholesterol and surfactant, Presence of DCP, equimolar ratio of span 60: cholesterol and 15 ml of volume of hydration were found to be optimum for miosome preparation. CONCLUSIONS: The present work concluded metformin loaded niosomes to be effective in sustaining the drug release leading to decreased side effects and increased patient compliance. PMID- 23351605 TI - The role of high mobility group box chromosomal protein 1 expression in the differential diagnosis of hepatic actinomycosis: a case report. AB - INTRODUCTION: Primary hepatic actinomycosis is a rare disease, but is important in the differential diagnosis of hepatoma in endemic areas. As high mobility group box chromosomal protein 1 plays an important role in the pathogenesis of both acute and chronic inflammatory conditions, we postulate that high mobility group box chromosomal protein 1 may have a possible pathogenic role in hepatic actinomycosis. To the best of our knowledge, our report is the first to detect an association between highly elevated high mobility group box chromosomal protein 1 expression and hepatic actinomycosis. CASE PRESENTATION: A 67-year-old Chinese man was admitted to our hospital with a three-month history of epigastric pain, anorexia, and subjective weight loss. Ultrasonography and computed tomography of the patient's abdomen confirmed a hypodense mass measuring seven cm in diameter in the left lateral segment of his liver. A hepatic tumor was suspected and surgical resection was scheduled. Histopathologic examination revealed that the overall features of the hepatic tissues were consistent with hepatic actinomycosis. Whole blood and hepatic tissue samples of the patient, of patients who had hepatocellular carcinoma and of healthy donors were collected. Serum high mobility group box chromosomal protein 1 concentration in actinomycosis was 8.5ng/mL, which was higher than the hepatocellular carcinoma level of 5.2ng/mL and the normal level of 100 nM) significantly decreased for Senegal (from 86 nM (59%) to 39 nM (25%)), Mali (from 84 nM (50%) to 51 nM (31%)), Ivory Coast (from 75 nM (59%) to 29 nM (16%)) and Cameroon (from 181 nM (75%) to 51 nM (37%)). Both analyses (molecular and in vitro susceptibility) were performed for the 2004-2011 period, after the four countries had officially discontinued CQ and showed an accelerated decline of the resistant isolates for the four countries. Meanwhile, CQ use among children significantly deceased in this region (fixed effects slope = -0.3, p < 10-3). CONCLUSIONS: An increase in CQ susceptibility following official withdrawal of the drug was observed in travellers returning from West and Central African countries. The same trends were observed for molecular and in vitro analysis between 2004-2011 and they correlated to the decrease of the drug pressure. PMID- 23351611 TI - Pulmonary arteriovenous malformations presenting as difficult-to-control asthma: a case report. AB - INTRODUCTION: Although pulmonary arteriovenous malformations are relatively rare disorders, they are an important part of the differential diagnosis of common pulmonary problems, such as hypoxemia, dyspnea on exertion and pulmonary nodules. CASE PRESENTATION: An 11-year-old Croatian boy of Mediterranean origin with a history of asthma since childhood was admitted to our hospital for evaluation of difficult-to-control asthma during the previous six months. A chest X-ray showed a homogeneous soft tissue mass in the lingual area. Computed tomography angiography of the thorax showed two pulmonary arteriovenous malformations, one on each side of the lungs. Diagnosis of hereditary hemorrhagic telangiectasia was made clinically by Curacao criteria. Genetic analysis revealed a mutation in the endoglin gene. The patient was treated with embolotherapy with good clinical outcome. CONCLUSION: We present a case of pulmonary arteriovenous malformations masquerading as refractory asthma. PMID- 23351613 TI - Biosimilars; a unique opportunity for Iran national health sector and national pharmaceutical industry. PMID- 23351612 TI - Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function. AB - Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug (APD) treatment. Most APDs are potent antagonists or partial agonists of dopamine (DA) D2 receptors; atypical APDs also have multiple serotonergic activities. DA and serotonin regulate many neurodevelopmental processes. Thus, early life APD treatment can, potentially, perturb these processes, causing long-term behavioural and neurobiological sequelae. We treated adolescent, male rats with olanzapine (Ola) on post-natal days 28-49, under dosing conditions that approximate those employed therapeutically in humans. As adults, they exhibited enhanced conditioned place preference for amphetamine, as compared to vehicle-treated rats. In the nucleus accumbens core, DA D1 receptor binding was reduced, D2 binding was increased and DA release evoked by electrical stimulation of the ventral tegmental area was reduced. Thus, adolescent Ola treatment enduringly alters a key behavioural response to rewarding stimuli and modifies DAergic neurotransmission in the nucleus accumbens. The persistence of these changes suggests that even limited periods of early life Ola treatment may induce enduring changes in other reward related behaviours and in behavioural and neurobiological responses to therapeutic and illicit psychotropic drugs. These results underscore the importance of improved understanding of the enduring sequelae of paediatric APD treatment as a basis for weighing the benefits and risks of adolescent APD therapy, especially prophylactic treatment in high-risk, asymptomatic patients. PMID- 23351614 TI - Aortic and coronary calcifications in Takayasu arteritis. AB - OBJECTIVES: Atherosclerosis is well recognized in Takayasu arteritis (TAK) and the associated plaques tend to be more common in areas of arteritis. We now report arterial wall calcification in a large group of TAK patients and controls. We hypothesized that the degree of coronary artery calcification would point to a systemic effect of inflammation while that in the thoracic aorta more of local inflammation. METHODS: A total of 47 patients with TAK, 43 patients with SLE and 70 healthy controls (HC) were studied. The presence of coronary artery and thoracic aorta calcifications (ToAC) was investigated by multi-detector computed tomography (MDCT). Atherosclerotic plaques in the carotid arteries were screened using B mode ultrasound. RESULTS: The frequency of coronary artery calcification was significantly increased among patients with SLE as compared to the healthy controls while the increase in TAK did not reach statistical significance. There were more TAK patients with ToAC among the TAK as compared to the SLE patients [21/47 (45%) vs 10/43 (23%), P = 0.033]. In addition, a circumferential type of calcification, vs a punctuate or linear type, was the more common type in 67% of patients with TAK whereas only the linear or punctuate type was seen in SLE patients and HC. SLE and TAK patients were found to have increased risk for carotid artery plaques. Among TAK patients, coronary artery calcification, ToAC and carotid artery plaques tend to be at sites of primary vasculitic involvement. CONCLUSIONS: There is increased atherosclerosis in TAK and SLE. Vessel wall inflammation seems to be also important in the atherosclerosis associated with TAK. PMID- 23351616 TI - Intestinal mast cells and eosinophils in relation to Strongyloides ratti adult expulsion from the small and large intestines of rats. AB - Mucosal mast cells (MMC) play a crucial role in the expulsion of Strongyloides ratti adults from the small intestine of mice. We reported the large intestinal parasitism of S. ratti in rats, and there has been no report on MMC in the large intestine of the natural host. We studied kinetics of MMC, together with eosinophils, in the upper and lower small intestines, caecum and colon of infected rats. Two distinct phases of mastocytosis were revealed: one in the upper small intestine triggered by stimulation of 'ordinary' adults, and the other in the colon stimulated by 'immune-resistant' adults that started parasitizing the colon around 19 days post-infection. In all 4 intestinal sites, the MMC peaks were observed 5-7 days after the number of adult worms became the maximum and the height of MMC peaks appeared to be dependent on the number of parasitic adults, suggesting an important role played by worms themselves in the MMC buildup. PMID- 23351615 TI - The effect of physical activity and motivation on function in ankylosing spondylitis: a cohort study. AB - OBJECTIVES: Exercise is reported to improve function for people with ankylosing spondylitis (AS) but it is not clear if this effect is causal or if patients with milder disease find it easier to exercise. This study examines the effect of exercise and motivation to exercise on function, while controlling for disease severity. METHODS: Participants who were members of an existing AS cohort were asked about physical activity, motivation to exercise, function, and disease severity. Path analysis on STATA was used to examine the correlation between factors associated with function at time of exercise and with function after 3 months of follow-up. RESULTS: The response rate to the questionnaire was 88% (326/371). Improvement in function was greatest for people with higher physical activity levels and those who were more motivated to exercise-this was especially the case for patients with the most severe disease activity. The effect of motivation to exercise not only had a direct effect on function, but also an indirect effect of improving activity levels thereby improving both current and future function. People with high intrinsic motivation (driven by pleasure) had the greatest benefit to activity and function. CONCLUSIONS: Exercise does improve function, especially for those with severe disease. In addition, motivation alone improves function as much as exercising itself. Therefore, interventions targeting motivation to exercise would have as much effect on improving function as interventions offering exercise opportunities. In addition, any intervention that both improves motivation and increases opportunities to exercise would have a 2-fold influence on function. PMID- 23351617 TI - Withholding or continuing beta-blocker treatment before dipyridamole myocardial perfusion imaging for the diagnosis of coronary artery disease? A randomized clinical trial. AB - BACKGROUND: Although it has been shown that acute beta-blocker administration may reduce the presence or severity of myocardial perfusion defects with dipyridamole stress, little information is available about the potential effect of chronic beta-blocker treatment on the sensitivity of dipyridamole myocardial perfusion imaging (DMPI). METHODS: As a randomized clinical trial, one hundred twenty patients (103 male and 17 female) with angiographically confirmed CAD who were on long-term beta blocker therapy (>=3 months) enrolled in a randomized clinical trial study. The patients were allocated into two groups: Group A (n=60) in whom the beta-blocker agent was discontinued for 72h before DMPI and Group B (n=60) without discontinuation of beta-blockers prior to DMPI. RESULTS: No significant difference was noted between the groups concerning age, sex, type of the injected radiotracer and number of involved coronary vessels. The mean rank of total perfusion scores for whole myocardium (irrespective of reversibility or irreversibility) in group B was not significantly different from that of group A, (65.75 vs. 55.25, P=0.096). Regarding the only irreversible perfusion defects, the mean rank of perfusion score in group B was higher than that of group A for whole myocardium (72 vs. 49, P=0.0001); however, no difference was noted between two groups for only reversible perfusion defects (61.0 vs. 60.0, P=0.898). The overall sensitivity of DMPI for the diagnosis of CAD in group A (91.7%) was not statistically different from group B (90%). CONCLUSION: Beta-blocker withholding before DMPI did not generally affect the sensitivity of the test for the diagnostic purposes in our study. Thus, beta-blocker withdrawal for just the purpose of diagnostic imaging is not mandatory particularly when medication discontinuation may cause the patients to face increased risk of heart events. PMID- 23351619 TI - Diet quality: hidden benefits emerging in a calorie-focused era. PMID- 23351618 TI - NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: integrated analysis of two phase III, randomized, controlled trials. AB - BACKGROUND: HIV-associated distal sensory polyneuropathy (HIV-DSP) is the most frequently reported neurologic complication associated with HIV infection. NGX 4010 is a capsaicin 8% dermal patch with demonstrated efficacy in the treatment of HIV-DSP. Data from two phase III, double-blind studies were integrated to further analyze the efficacy and safety of NGX-4010 and explore the effect of demographic and baseline factors on NGX-4010 treatment in HIV-DSP. METHODS: Data from two similarly designed studies in which patients with HIV-DSP received NGX 4010 or a low-concentration control patch (capsaicin 0.04% w/w) for 30 or 60 minutes were integrated. Efficacy assessments included the mean percent change from baseline in Numeric Pain Rating Scale (NPRS) scores to Weeks 2-12. Safety and tolerability assessments included adverse events (AEs) and pain during and after treatment. RESULTS: Patients (n = 239) treated with NGX-4010 for 30 minutes demonstrated significantly (p = 0.0026) greater pain relief compared with controls (n = 100); the mean percent change in NPRS scores from baseline to Weeks 2-12 was -27.0% versus -15.7%, respectively. Patients who received a 60-minute application of NGX-4010 (n = 243) showed comparable pain reductions (-27.5%) to patients treated for 30 minutes, but this was not statistically superior to controls (n = 115). NGX-4010 was effective regardless of gender, baseline pain score, duration of HIV-DSP, or use of concomitant neuropathic pain medication, although NGX-4010 efficacy was greater in patients not receiving concomitant neuropathic pain medications. NGX-4010 was well tolerated; the most common AEs were application-site pain and erythema, and most AEs were mild to moderate. The transient increase in pain associated with NGX-4010 treatment decreased the day after treatment and returned to baseline by Day 2. CONCLUSIONS: A single 30 minute application of NGX-4010 provides significant pain relief for at least 12 weeks in patients with HIV-DSP and is well tolerated. TRIAL REGISTRATION: C107 = NCT00064623; C119 = NCT00321672. PMID- 23351620 TI - Strengthen our competence, address health disparities. PMID- 23351621 TI - 2012 Journal reader survey results. PMID- 23351622 TI - Authors' response. PMID- 23351623 TI - Dietary intervention in non-alcoholic fatty liver disease. PMID- 23351624 TI - Prediabetes: a prevalent and treatable, but often unrecognized, clinical condition. PMID- 23351626 TI - Does compliance with nutrition guidelines lead to healthy aging? A quality-of life approach. AB - OBJECTIVES: We aimed to estimate, in a large French cohort of middle-aged adults derived from the Supplementation en Vitamines et Mineraux Antioxydants trial, the association of compliance with the guidelines of the French Nutrition and Health Program (PNNS) assessed at inclusion and change in health-related quality of life (HRQoL) over 12 years. A secondary objective was to identify the relative contribution of diet and physical activity to long-term change in HRQoL. DESIGN/SUBJECTS: Subjects were Supplementation en Vitamines et Mineraux Antioxydants trial participants aged 45 to 60 years at inclusion in the cohort. MAIN OUTCOME MEASURES: Compliance with nutrition guidelines (diet and physical activity) was assessed by the PNNS Guideline Score (maximum 15 points) at inclusion. HRQoL was measured by the Medical Outcomes Survey Short Form 36 (SF 36) at 1 year (initial measurement) and 13 years (final measurement) after inclusion. The primary end point was change in the SF-36 physical component summary (PCS) and mental component summary (MCS) scores over 12 years. RESULTS: In total, 3,005 subjects (mean age 51.4 +/- 4.3 years) completed the SF-36 at the initial and final measurement. The mean PNNS Guideline Score was 7.8 +/- 1.9 and the mean PCS and MCS was 52.2 +/- 6.4 and 50.3 +/- 7.0, respectively, at the initial measurement and 48.0 +/- 9.6 and 51.2 +/- 8.7 at the final measurement. Better compliance with nutritional guidelines was associated with better initial and final HRQoL but not associated with change in HRQoL. Compliance with dietary guidelines was associated with positive change in PCS score but not associated with initial PCS score. In contrast, compliance with dietary guidelines was related to positive initial MCS score but not related to change in MCS score. Compliance with physical activity guidelines was related to initial PCS and MCS scores but not related to change in PCS and MCS scores. CONCLUSIONS: Following physical activity guidelines may be associated with better concomitant HRQoL and following dietary guidelines with better future physical HRQoL. PMID- 23351625 TI - The relationships between sugar-sweetened beverage intake and cardiometabolic markers in young children. AB - BACKGROUND: The consumption of sugar-sweetened beverages has been implicated as a major contributor to the development of obesity and cardiometabolic disease. OBJECTIVE: To evaluate the relationships between sugar-sweetened beverage intake and cardiometabolic markers in young children. DESIGN: A cross-sectional analysis of the National Health and Nutrition Examination Survey data collected by the National Center for Health Statistics. PARTICIPANTS: A total of 4,880 individuals aged 3 to 11 years from nationally representative samples of US children participating in the National Health and Nutrition Examination Survey during 1999 2004 were studied. MAIN OUTCOME MEASURES: Concentrations of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, and C-reactive protein as well as waist circumference and body mass index percentile for age-sex. STATISTICAL ANALYSES PERFORMED: Multivariate linear regression analyses were performed to determine independent associations between each outcome variable and the number of serving equivalents of sugar-sweetened beverages consumed after adjusting for age, sex, race, poverty status, physical activity, and energy intake. RESULTS: Increased sugar-sweetened beverage intake was independently associated with increased C-reactive protein concentrations (P=0.003), increased waist circumference (P=0.04), and decreased high-density lipoprotein cholesterol concentrations (P<0.001). Subgroup analyses demonstrated differences in the association of sugar-sweetened beverage intake with metabolic markers and anthropometric measurements among age ranges, sex, and racial/ethnic groups. CONCLUSIONS: In this cross-sectional analysis of children's dietary data, sugar-sweetened beverage intake was independently associated with alterations in lipid profiles, increased markers of inflammation, and increased waist circumference in children. Prospective studies are needed, but awareness of these trends is essential in combating the growing metabolic and cardiovascular disease burden in the pediatric population. PMID- 23351627 TI - Single-larger-portion-size and dual-column nutrition labeling may help consumers make more healthful food choices. AB - BACKGROUND: The Food and Drug Administration is considering changes to the Nutrition Facts label to help consumers make more healthful choices. OBJECTIVE: To examine the effects of modifications to the Nutrition Facts label on foods that can be listed as having 1 or 2 servings per container, but are reasonably consumed at a single eating occasion. DESIGN: Participants were randomly assigned to study conditions that varied on label format, product, and nutrition profile. Data were collected via an online consumer panel. PARTICIPANTS/SETTING: Adults aged 18 years and older were recruited from Synovate's online household panel. Data were collected during August 2011. A total of 32,897 invitations were sent for a final sample of 9,493 interviews. INTERVENTION: Participants were randomly assigned to one of 10 label formats classified into three groups: listing 2 servings per container with a single column, listing 2 servings per container with a dual column, and listing a single serving per container. Within these groups there were versions that enlarged the font size for "calories," removed "calories from fat," and changed the wording for serving size declaration. MAIN OUTCOME MEASURES: The single product task measured product healthfulness, the amount of calories and various nutrients per serving and per container, and label perceptions. The product comparison task measured ability to identify the healthier product and the product with fewer calories per container and per serving. STATISTICAL ANALYSES PERFORMED: Analysis of covariance models with Tukey Kramer tests were used. Covariates included general label use, age, sex, level of education, and race/ethnicity. RESULTS: Single-serving and dual-column formats performed better and scored higher on most outcome measures. CONCLUSIONS: For products that contain 2 servings but are customarily consumed at a single eating occasion, using a single-serving or dual-column labeling approach may help consumers make healthier food choices. PMID- 23351628 TI - Middle school student and parent perceptions of government-sponsored free school breakfast and consumption: a qualitative inquiry in an urban setting. AB - Universal free access to school breakfast is available in large urban schools, but participation rates are less than half of what they are at lunch. The purpose of this qualitative study was to understand the discrepancy between access and participation in school breakfast in a low-income, urban school district. Youth (n=23) and parents (n=22) were recruited from three middle schools where >= 50% of students were eligible for free or reduced-price meals. Parent focus groups (n=2) and student focus groups (n=4) were conducted in the fall/winter of 2009/2010. Content analysis was conducted to code transcripts and a constant comparative technique was used to identify emergent themes. Findings were validated using triangulation methods. The following themes emerged from the student and parent perceptions: sociocultural beliefs, physical availability, economic accessibility, social stigma, and consumption practices. There was agreement between students and parents across most themes, except consumption practices. Students were commonly purchasing food and beverages on the way to school, which was in conflict with parent rules. Parents desired access to copies of the school menus to be more involved in breakfast decisions with their child and students desired input into menu planning and taste testing to overcome school meal quality concerns. Future research aiming to improve participation in the breakfast program should examine the impact of student involvement in school menu planning and environmental modifications to reduce the social stigma associated with the program. PMID- 23351629 TI - Dietary adherence and mealtime behaviors in young children with type 1 diabetes on intensive insulin therapy. AB - Diet is an important component of diabetes treatment and integral to successful management. While intensive insulin therapy can allow patients to eat more freely, it is not known how the rapid uptake of intensive therapy in young children with type 1 diabetes has impacted their diet and if diet and healthful eating in young children correlates with mealtime behaviors and glycemic control. This study examined diet, mealtime behaviors, and glucose control in a sample of 39 young children on intensive therapy. This was a one-sample, cross-sectional study. Children had a mean age of 5.1 +/- 1.1 years. Children's 3-day diet diaries were assessed using a deviation scale (measure of adherence) and a healthy eating index. Mealtime behaviors were assessed using the Behavioral Pediatric Feeding Assessment Scale. Children's glucose control was measured using continuous glucose monitoring. Children's mean carbohydrate intake was 72% +/- 24% of the recommended levels based on their age, sex, size, and activity level, and children exceeded national guidelines for percentage of calories from fat and saturated fat. A more healthful diet correlated with fewer child mealtime behavior problems, but better dietary adherence correlated with more parent mealtime behavior problems. Even in the context of intensive management, diet can be problematic for young children with type 1 diabetes. Parent-reported problems with mealtime behaviors seem to correlate with healthy eating and dietary adherence. PMID- 23351630 TI - Risk factors for predicting hypoglycemia in patients receiving concomitant parenteral nutrition and insulin therapy. AB - The occurrence of hypoglycemia in patients receiving parenteral nutrition (PN) is low, yet its consequences can be detrimental. Treatment of hyperglycemia with insulin to achieve optimal blood glucose control is challenging and potentially associated with increased risk of the development of hypoglycemia. The objective of this study was to determine the association of patient characteristics on the risk of hypoglycemia among patients receiving concomitant PN and insulin therapy. This retrospective cohort study was conducted from January 1, 2008, to December 31, 2011, and included 1,657 patients who received PN. There was a significant decrease in the occurrence of hypoglycemia observed over time: 9.1% (43 of 475) in 2008, 6.4% (30 of 468) in 2009, 5.8% (20 of 347) in 2010, and 3.5% (13 of 367) in 2011 (P=0.013). Patients in whom hypoglycemia developed had a significantly longer duration on PN (18.0 vs 8.1 days, P<0.0001) as well as more days requiring insulin in the PN (16.1 vs 2.7 days, P<0.0001). The strongest predictors of hypoglycemia were: receiving PN in the ICU (OR 1.86, 95% CI 1.16 to 3.01), history of diabetes (OR 2.10, 95% CI 1.26 to 3.51), days on PN (OR 0.93, 95% CI 0.91 to 0.95), and an insulin drip (OR 3.14, 95% CI 1.81 to 5.42). With the identification of patient factors that contribute to an increase in hypoglycemia, existing protocols can be modified to treat hyperglycemia and prevent hypoglycemia. PMID- 23351631 TI - Reducing calories and added sugars by improving children's beverage choices. AB - Because childhood obesity is such a threat to the physical, mental, and social health of youth, there is a great need to identify effective strategies to reduce its prevalence. The objective of this study was to estimate the mean calories from added sugars that are saved by switching sugar-sweetened beverages (including soda, fruit-flavored drinks, and sport drinks) and flavored milks consumed to unflavored low-fat milk (<1% fat) at meals and water between meals. Simulation analyses used 24-hour dietary recall data from the third School Nutrition Dietary Assessment Study (n=2,314), a 2005 national cross-sectional study of schools and students participating in the National School Lunch Program, to estimate changes in mean calories from added sugars both at and away from school. Overall, these changes translated to a mean of 205 calories or a 10% savings in energy intake across all students (8% among children in elementary school and 11% in middle and high schools). Eighty percent of the daily savings were attributed to beverages consumed away from school, with results consistent across school level, sex, race/ethnicity, and weight status. Children's consumption of sugar-sweetened beverages at home contributed the greatest share of empty calories from added sugars. Such findings indicate that parental education should focus on the importance of reducing or eliminating sugar sweetened beverages served at home. This conclusion has implications for improving children's food and beverage environments for food and nutrition educators and practitioners, other health care professionals, policy makers, researchers, and parents. PMID- 23351632 TI - Mediterranean diet, healthy eating index 2005, and cognitive function in middle aged and older Puerto Rican adults. AB - Adherence to a Mediterranean diet has recently been shown to protect against cognitive decline and dementia. It remains unclear, however, whether such protection extends to different ethnic groups and middle-aged individuals and how it might compare with adherence to the US Department of Agriculture's 2005 Dietary Guidelines for Americans (measured with Healthy Eating Index 2005 [HEI 2005]). This study examined associations between diet quality, as assessed by the Mediterranean diet and HEI 2005, and cognitive performance in a sample of 1,269 Puerto Rican adults aged 45 to 75 years and living in the Greater Boston area of Massachusetts. Dietary intake was assessed with a food frequency questionnaire specifically designed for and validated with this population. Adherence to the Mediterranean diet was assessed with a 0- to 9-point scale, and the HEI 2005 score was calculated with a maximum score of 100. Cognitive performance was measured with a battery of seven tests and the Mini Mental State Examination was used for global cognitive function. Greater adherence to the Mediterranean diet was associated with higher Mini Mental State Examination score (P trend=0.012) and lower likelihood (odds ratio=0.87 for each additional point; 95% CI 0.80 to 0.94; P<0.001) of cognitive impairment, after adjustment for confounders. Similarly, individuals with higher HEI 2005 score had higher Mini Mental State Examination score (P trend=0.011) and lower odds of cognitive impairment (odds ratio=0.86 for each 10 points; 95% CI 0.74 to 0.99; P=0.033). In conclusion, high adherence to either the Mediterranean diet or the diet recommended by the US Department of Agriculture 2005 Dietary Guidelines for Americans can protect cognitive function in middle-aged and older adults. PMID- 23351634 TI - Position of the academy of nutrition and dietetics: total diet approach to healthy eating. AB - It is the position of the Academy of Nutrition and Dietetics that the total diet or overall pattern of food eaten is the most important focus of healthy eating. All foods can fit within this pattern if consumed in moderation with appropriate portion size and combined with physical activity. The Academy strives to communicate healthy eating messages that emphasize a balance of food and beverages within energy needs, rather than any one food or meal. Public policies and dietary patterns that support the total diet approach include the 2010 Dietary Guidelines for Americans, DASH (Dietary Approaches to Stop Hypertension) Diet, MyPlate, Let's Move, Nutrition Facts labels, Healthy People 2020, and the Dietary Reference Intakes. In contrast to the total diet approach, classification of specific foods as good or bad is overly simplistic and can foster unhealthy eating behaviors. Alternative approaches are necessary in some situations. Eating practices are dynamic and influenced by many factors, including taste and food preferences, weight concerns, physiology, time and convenience, environment, abundance of foods, economics, media/marketing, perceived product safety, culture, and attitudes/beliefs. To increase the effectiveness of nutrition education in promoting sensible food choices, skilled food and nutrition practitioners utilize appropriate behavioral theory and evidence-based strategies. Focusing on variety, moderation, and proportionality in the context of a healthy lifestyle, rather than targeting specific nutrients or foods, can help reduce consumer confusion and prevent unnecessary reliance on supplements. Proactive, empowering, and practical messages that emphasize the total diet approach promote positive lifestyle changes. PMID- 23351633 TI - Dose-dependent consumption of farmed Atlantic salmon (Salmo salar) increases plasma phospholipid n-3 fatty acids differentially. AB - Enhanced n-3 fatty acid intake benefits cardiovascular disease (CVD) risk reduction. Increasing consumption at a population level may be better addressed by diet than through supplementation. However, limited data are available on the effect of the dose response to fish intake on plasma levels of n-3 fatty acids. To compare the effects of different doses of farmed Atlantic salmon on plasma phospholipid fatty acid proportions and CVD risk biomarkers (eg, glucose, insulin, homeostasis model of assessment-insulin resistance, high-sensitivity C reactive protein, and interleukin-6) in healthy subjects we performed a randomized three-period crossover-designed trial (4-week treatment, 4- to 8-week washout) to compare the effects of twice per week consumption of farmed Atlantic salmon at doses of 90, 180, and 270 g in 19 apparently healthy men and women (mean age 40 to 65 years) and a body mass index between 25 and 34.9. All study visits were conducted at the US Department of Agriculture Agricultural Research Service Grand Forks Human Nutrition Research Center. Eicosapentaenoic acid and total n-3 concentrations were increased (P<0.05) by all treatments in a dose response manner, with total n-3 of 8.03% +/- 0.26% and 9.21% +/- 0.26% for 180- and 270-g doses, respectively. Linoleic acid did not change in response to treatment, whereas arachidonic acid (P<0.05) and total n-6 fatty acids decreased dose dependently (<0.0001). The addition of farmed Atlantic salmon to the diet twice per week for 4 weeks at portions of 180 g and 270 g modifies phospholipid fatty acid proportions of n-3 and n-6 in a level associated with decreased risk for CVD. PMID- 23351635 TI - 2012 Lenna Frances Cooper Memorial Lecture: "When nothing is sure, all things are possible". PMID- 23351636 TI - Networking groups: advancing nutrition and dietetics through practice, culture, and geography. PMID- 23351637 TI - What is green coffee extract? PMID- 23351638 TI - Immunohistochemical studies of angiogenin in the skin of patients with amyotrophic lateral sclerosis. AB - Angiogenin (ANG) is a member of the ribonuclease superfamily which is implicated in angiogenesis. ANG maintains normal vasculature and thereby protects motor neurons from various stress conditions. It is suggested that ANG may play a role in pathomechanism of amyotrophic lateral sclerosis (ALS). However, there have been no studies of ANG in ALS skin. We made a quantitative immunohistochemical study of the expression of ANG in the skin from 20 patients with sporadic ALS, 20 patients with other neurologic or muscular disorders (control group A), and 20 patients without neurologic or muscular disorders (control group B). The nuclei of the epidermal cells showed a weak ANG immunoreactivity in ALS patients. These findings became more marked as ALS progressed. The optical density for ANG immunoreactivity of the nucleus in the epidermal cells in ALS patients was significantly lower (p<0.001) than in control groups A and B. There was a significant negative relationship (r=-0.82, p<0.001) between the optical density for ANG immunoreactivity of the nucleus and duration of illness in ALS patients. These data suggest that changes of ANG in ALS skin are related to the disease process and that metabolic alterations of ANG may take place in the skin of ALS patients. PMID- 23351639 TI - Increased levels of interleukins 8 and 10 as findings of canine inflammatory mammary cancer. AB - Inflammatory mammary cancer (IMC) is a distinct form of mammary cancer that affects dogs and women [in humans, IMC is known as inflammatory breast cancer (IBC)], and is characterized by a sudden onset and an aggressive clinical course. Spontaneous canine IMC shares epidemiologic, histopathological and clinical characteristics with the disease in humans and has been proposed as the best spontaneous animal model for studying IBC, although several aspects remain unstudied. Interleukins (ILs) play an important role in cancer as potential modulators of angiogenesis, leukocyte infiltration and tumor growth. The aims of the present study were to assess serum and tumor levels of several ILs (IL 1alpha, IL-1beta, IL-6, IL-8 and IL-10) by enzyme-immunoassay in dogs bearing benign and malignant mammary tumors, including dogs with IMC, for a better understanding of this disease. Forty-eight dogs were prospectively included. Animals consisted of 7 healthy Beagles used as donors for normal mammary glands (NMG) and serum controls (SCs), 10 dogs with hyperplasias and benign mammary tumors (HBMT), 24 with non-inflammatory malignant mammary tumors (non-IMC MMT) and 7 dogs with clinical and pathological IMC. IL-8 (serum) and IL-10 (serum and tissue homogenate) levels were higher in the dogs with IMC compared with the non IMC MMT group. ILs were increased with tumor malignancy as follows: in tumor homogenates IL-6 levels were higher in malignant tumors (IMC and non-IMC MMT) versus HBMT and versus NMG and tumor IL-8 was increased in malignant tumors versus NMG; in serum, IL-1alpha and IL-8 levels were higher in the malignant groups respect to HBMT and SCs; interestingly, IL-10 was elevated only in the serum of IMC animals. To the best of our knowledge, this is the first report that analyzes ILs in IMC and IL-10 in canine mammary tumors. Our results indicate a role for IL-6, IL-8 and IL-10 in canine mammary malignancy and specific differences in ILs content in IMC versus non-IMC MMT that could have future diagnostic and therapeutic implications, to be confirmed in a larger series of IMC cases. These results help to support the validity of the IMC canine model for the study of human IBC and provide insight into this uncommon malignancy in dogs. PMID- 23351640 TI - Immunogenomic analysis of insect bite hypersensitivity in a model horse population. AB - Equine insect bite hypersensitivity (IBH) is a seasonal IgE-mediated dermatosis caused by bites of insects of the genus Culicoides. A familial predisposition for the disease has been shown but, except for the MHC, the genes involved have not been identified so far. An immunogenomic analysis of IBH was performed in a model population of Old Kladruby horses, all living in the same environment. Clinical signs of IBH were used as phenotypic manifestation of IBH. Furthermore, total serum IgE levels were determined in the sera of these horses and used as an independent phenotypic marker for the immunogenetic analysis. Single nucleotide polymorphisms (SNPs) in candidate immunity-related genes were used for association analyses. Genotypes composed of two to five genes encoding interferon gamma -IFNG, transforming growth factor beta 1 -TGFB1, Janus kinase 2 -JAK2, thymic stromal lymphopoietin -TSLP, and involucrin -IVL were associated with IBH, indicating a role of the genes in the pathogenesis of IBH. These findings were supported by analysis of gene expression in skin biopsies of 15 affected and 15 unaffected horses. Two markers associated with IBH, IFNG and TGFB1, showed differences in mRNA expression in skin biopsies from IBH-affected and non affected horses (p<0.05). Expression of the gene coding for the CD14 receptor molecule -CD14 was different in skin biopsies at p<0.06. When total IgE levels were treated as binary traits, genotypes of IGHE, ELA-DRA, and IL10/b were associated with this trait. When treated as a continuous trait, total IgE levels were associated with genes IGHE, FCER1A, IL4, IL4R, IL10, IL1RA, and JAK2. This first report on non-MHC genes associated with IBH in horses is thus supported by differences in expression of genes known to play a role in allergy and immunity. PMID- 23351641 TI - Systemic administration of lipopolysaccharide in laying hens stimulates antimicrobial properties of egg white against Staphylococcus aureus. AB - The natural protective system of eggs relies on egg yolk immunoglobulins and on antimicrobial proteins/peptides mainly concentrated in the egg white. There is much evidence concerning the specific stimulation of immunoglobulins by antigens but to date, the influence of the hen milieu on the regulation of the egg innate molecular immunity has not been established. To explore the hypothesis of modulation in egg antimicrobial molecules, laying hens were immune-challenged with intravenous injections of Salmonella enterica Enteritidis lipopolysaccharide (LPS) at 24 h intervals. Eggs of the control and LPS groups were collected over a period of 21 days following the first LPS injection and the egg white activities against Staphylococcus aureus and Escherichia coli were assessed. The increase in egg white anti-S. aureus activity reached 20.9% and 23.4% (p<0.05) respectively on days 5 and 6 after the first LPS injection. Anti-E. coli activity increased moderately only on days 9 and 15 after the LPS treatment. To explore the origin of these increased antimicrobial activities, we analyzed the lysozyme and proteases inhibiting (anti-trypsin and anti-chymotrypsin) activities and the pH variations of egg whites. We recorded no significant variations between the two experimental groups for these potential modulating factors. Finally, using RT qPCR we studied the expression of several genes coding for antimicrobial proteins and peptides involved in the immune response in the infundibulum and the magnum, Out of the 11 genes, only TLR4 in the magnum and ovocalyxin-36 in infundibulum were over-expressed respectively 24h and 8 days after the first LPS injection. The other candidate genes showed similar or down regulated expression in the LPS group as compared to the control especially during the first 24h. Our results suggest that the hen enhances the albumen antimicrobial activity of its eggs when exposed to immune stimulations or infections. This could be an attempt to preventively reinforce the protection of the embryo with nonspecific antimicrobial agents in addition to the specific antibodies exported to the egg. The origin of this stimulation of egg molecular immunity remains to be characterized amongst the numerous novel egg proteins recently identified. PMID- 23351642 TI - Hydrocortisone inhibits IFN-gamma production in equine, ovine, and bovine PBMCs. AB - Hydrocortisone is widely accepted as an anti-inflammatory agent and there are many products available containing hydrocortisone as an active ingredient. Surprisingly, there is little data available specifically on the immunological effects of hydrocortisone in large animals. Glucocorticoids are well characterized for their ability to repress inflammation via a wide variety of mechanisms including suppression of cytokine production. In this study the effects of hydrocortisone on IFN-gamma production by equine, bovine, and ovine PBMCs were assessed using flow cytometric or ELISpot analysis. Hydrocortisone suppressed mitogen-driven IFN-gamma production by PBMCs from all three species of animals, confirming that this agent mediates anti-inflammatory effects in large animals. Although the results from this study were expected based on the precedence set in murine and human systems, it is important to understand the effects of administration of a compound or product in the species of interest as species-specific indications are not always available. PMID- 23351643 TI - Fabrication of docetaxel surfaced Fe3O4 magnetite nanoparticles and their cytotoxicity on 4 T1 breast cancer cells. AB - BACKGROUND: In the recent years, there is an increasing attention to the using of Fe3O4 magnetite nanoparticles (MNPs) as drug delivery systems. Application of this nanoparticles could profit advantages of nanomedicine to enhance biological activity of pharmaceutical ingredients. METHODS: Fe3O4 MNPs were synthesised by a chemical method and characterized by transmission electron microscopy and energy dispersive spectroscopy techniques. In the next step, docetaxel-coated Fe3O4 MNPs were prepared, using percipitation method. The surface chemistry of docetaxel coated Fe3O4 MNPs as well as their thermal decomposition characteristics were examined using fourier transform infrared spectroscopy and thermogravimetric analyzer equipment, respectively. The cytotoxicity assay was conducted on 4 T1 breast cancer carsinoma by MTT assay to evaluate the possible in vitro antiproliferative effects of docetaxel-coated Fe3O4 MNPs. RESULTS: During precipitation process, docetaxel molecules were precipitated on the surface of Fe3O4 MNPs by the ratio of 3:100 w/w which indicates that each milligram of coated Fe3O4 MNPs averagely contained 30 MUg pure docetaxel compound. Docetaxel showed aniproliferative effects against mentioned cell line. The higestest concentartion of docetaxel (80 MUg/ml) caused about 80% cell death. However, the results demostarted that much lower amounts of docetaxel will be needed in combination of Fe3O4 MNPs to produce the potent antiproliferative effect compared to docetaxel alone. Dose response cytotoxicity assay of docetaxel-coated Fe3O4 MNPs against 4 T1 breast cancer cells showed that lower amount of docetaxel (0.6 MUg/ml) can exhibit higher cytotoxic effect against this cancer cell line (90% cell death). PMID- 23351644 TI - First national survival data for colorectal cancer among Saudis between 1994 and 2004: what's next? AB - BACKGROUND: Colorectal cancer (CRC) is the second most common malignancy in the Saudi population. This study aimed to review CRC data from the Saudi Cancer Registry (SCR) in order to evaluate the prognostic factors for CRC survival in Saudi patients. METHODS: This study was a retrospective censored overall survival (OS) analysis of CRC data for the period 1994-2004 obtained from the SCR. Data were collected from all 13 administrative regions of the Kingdom of Saudi Arabia (KSA) by the SCR in collaboration with the National Information Center of the Ministry of Interior. The Kaplan-Meier method was used to calculate the cumulative survival rate, which was then stratified by gender and by period (1994 1999 versus 2000-2004). The clinico-pathological variables that might affect CRC survival were analyzed by Cox regression analysis. RESULTS: Between 1994 and 2004, 549 CRC cases were diagnosed (363 [66.1%] in males and 186 [33.9%] in females). The OS for CRC during this period was 44.6% (44.7% for 1994-1999 and 44.3% for 2000-2004 [p=0.7]). There was a significant (p=0.003) discrepancy of 9.6% between the male five-year OS (41.0%) and the female five-year OS (50.6%). The five-year OS was 63.3% for patients with localized disease, 50.2% for those with regional disease, and 14.7% for patients with metastases. By Cox regression analysis, age and extent were significant prognostic factors of survival in patients with colon cancer; the risk was higher in patients with distant metastasis (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.17-5.45; p=0.01). In patients with rectal cancer, the risk was lower in males (HR, 0.66; CI, 0.45-0.98; p=0.04), but higher in patients with unknown tumor extent (HR, 3.70; 95% CI, 1.66-8.24; p=0.01). CONCLUSIONS: The five-year OS for 1994-2004 was 44.6% for patients with CRC. More so, five-year OS based on CRC stage was generally lower than the typically reported survival rates. The establishment of a national screening program and increased access to specialized medical faculties may be necessary to improve CRC survival in the KSA. PMID- 23351645 TI - [We cannot wait with fingers crossed]. PMID- 23351646 TI - Predictors and outcomes of restenosis following tibial artery endovascular interventions for critical limb ischemia. AB - OBJECTIVE: Restenosis following tibial artery endovascular interventions (TAEIs) is thought to be benign but is not well characterized. This study examines the consequences and predictors of recurrent stenosis of TAEIs for critical limb ischemia. METHODS: All TAEIs for critical limb ischemia performed between 2004 and 2010 were retrospectively reviewed. Restenosis was detected by noninvasive imaging and angiography when indicated. Restenoses were identified and the limb outcomes recorded. Tibial reinterventions were performed only for persistent, worsening, or recurrent tissue loss or rest pain with evidence of recurrence on duplex ultrasound or hemodynamic imaging. The chi test and logistic regression were applied as indicated. One-year patency rates were calculated using the Kaplan-Meier method. RESULTS: A total of 235 limbs in 210 patients were treated for critical limb ischemia (70% tissue loss, 30% rest pain). Tissue loss included gangrene (49%) and ulcers (51%), and involved the forefoot (80%), the heel (14%), or both (6%). Seventy-eight percent of limbs had Trans-Atlantic InterSociety Consensus C/D lesions, with mean preoperative runoff score of 12. Interventions were isolated tibial (45%) or multilevel (55%) (including tibial). Mean postoperative runoff score improved to 6.6, but restenosis occurred in 96 limbs (41%) at a mean of 4 months. The 1-year primary patency was 59% with a mean follow-up of 9 months. Restenosis presented with a persistent wound (32%), worsened wound (42%), rest pain (16%), or no symptoms (10%). A repeat TAEI was performed in 42 (44%), major amputation in 26 (27%), open bypass in 20 (21%), and observation in eight (8%). The overall amputation rate was 13%, but limb loss was significantly higher in patients with restenosis (n = 26 [27%]) than in patients with no restenosis (n = 5 [4%]; P < .001). Patients with restenosis and tissue loss were more likely to have presented with gangrene (63% vs 38%; P = .0003) but had comparable wound distribution (P = NS). There was a trend toward a higher restenosis rate in patients with renal insufficiency (odds ratio, 5.57; P = .08), but this was unaffected by diabetes, statin therapy, or smoking (P = NS). The rate of repeat intervention after the first reintervention was 36%, with an 87% overall limb salvage rate. CONCLUSIONS: TAEIs can be used successfully to treat patients with critical limb ischemia with acceptable limb salvage rates. Special attention should be given to patients with extensive tissue loss or gangrene because they are at risk for early restenosis and subsequent limb loss. Strict wound and hemodynamic surveillance, wound care, and timely reinterventions are crucial to achieve successful outcomes in this patient population. Amputation or alternative revascularization options, when feasible, should be considered in patients with restenosis and tissue loss given the high rate of limb loss with tibial reinterventions. PMID- 23351647 TI - Role of hemodynamic forces in the ex vivo arterialization of human saphenous veins. AB - BACKGROUND: Human saphenous vein grafts are one of the salvage bypass conduits when endovascular procedures are not feasible or fail. Understanding the remodeling process that venous grafts undergo during exposure to arterial conditions is crucial to improve their patency, which is often compromised by intimal hyperplasia. The precise role of hemodynamic forces such as shear stress and arterial pressure in this remodeling is not fully characterized. The aim of this study was to determine the involvement of arterial shear stress and pressure on vein wall remodeling and to unravel the underlying molecular mechanisms. METHODS: An ex vivo vein support system was modified for chronic (up to 1 week), pulsatile perfusion of human saphenous veins under controlled conditions that permitted the separate control of arterial shear stress and different arterial pressure (7 mm Hg or 70 mm Hg). RESULTS: Veins perfused for 7 days under high pressure (70 mm Hg) underwent significant development of a neointima compared with veins exposed to low pressure (7 mm Hg). These structural changes were associated with altered expression of several molecular markers. Exposure to an arterial shear stress under low pressure increased the expression of matrix metalloproteinase (MMP)-2 and MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 at the transcript, protein, and activity levels. This increase was enhanced by high pressure, which also increased TIMP-2 protein expression despite decreased levels of the cognate transcript. In contrast, the expression of plasminogen activator inhibitor-1 increased with shear stress but was not modified by pressure. Levels of the venous marker Eph-B4 were decreased under arterial shear stress, and levels of the arterial marker Ephrin-B2 were downregulated under high-pressure conditions. CONCLUSIONS: This model is a valuable tool to identify the role of hemodynamic forces and to decipher the molecular mechanisms leading to failure of human saphenous vein grafts. Under ex vivo conditions, arterial perfusion is sufficient to activate the remodeling of human veins, a change that is associated with the loss of specific vein markers. Elevation of pressure generates intimal hyperplasia, even though veins do not acquire arterial markers. CLINICAL RELEVANCE: The pathological remodeling of the venous wall, which leads to stenosis and ultimately graft failure, is the main limiting factor of human saphenous vein graft bypass. This remodeling is due to the hemodynamic adaptation of the vein to the arterial environment and cannot be prevented by conventional therapy. To develop a more targeted therapy, a better understanding of the molecular mechanisms involved in intimal hyperplasia is essential, which requires the development of ex vivo models of chronic perfusion of human veins. PMID- 23351648 TI - Laparoscopic inferior mesenteric-gonadal vein bypass for the treatment of nutcracker syndrome. AB - Nutcracker syndrome is a rare entity caused by extrinsic compression on the left renal vein (LRV) crossing between the superior mesenteric artery and the aorta. This article reports the treatment of two cases of nutcracker syndrome using laparoscopic inferior mesenteric-gonadal vein bypass, knowing that this treatment option would avoid renal reperfusion injury and LRV hypertension. In addition, it is easier to operate compared with laparoscopic splenorenal venous bypass and laparoscopic transposition of LRV into the inferior vena cava. PMID- 23351649 TI - Ruptured mycotic infrapopliteal aneurysm. AB - Mycotic aneurysms involving infrapopliteal arteries are rare. Ruptured infrapopliteal aneurysms are particularly uncommon and represent a surgical or endovascular emergency. We describe a case of 51-year-old male who presented with a 12-cm ruptured aneurysm of the tibioperoneal trunk 5 years after an episode of bacterial endocarditis. Our surgical approach included using extremity exsanguination and tourniquet to control hemorrhage during aneurysm ligation, followed by successful arterial reconstruction. Review of the English literature suggests that this is the largest ruptured infrapopliteal aneurysm reported. PMID- 23351651 TI - Within-patient emergence of the influenza A(H1N1)pdm09 HA1 222G variant and clear association with severe disease, Norway. AB - The association between a particular mutation in the HA1 subunit of the influenza virus haemagglutinin, D222G, and severe and fatal disease in cases of influenza A(H1N1)pdm09 in Norway during the 2009 pandemic was investigated using pyrosequencing. The prevalence of the variant among fatal cases was 8/26 and among severe non-fatal cases 5/52. No D222G mutations were found among the 381 mild cases. This difference could not be attributed to sampling differences, such as body location of sampling, or duration of illness. In cases with mutant virus where clinical specimens from different days of illness were available, transition from wild-type to mutant virus was commonly observed (4/5), indicating that the mutant virus emerged sporadically in individual patients. In patients with paired samples from both the upper and lower respiratory tract (n=8), the same viral genotypes were detected in both locations. In most of the D222G cases (11/13), the mutant virus was found as a quasispecies. PMID- 23351652 TI - Molecular epidemiological typing within the European Gonococcal Antimicrobial Resistance Surveillance Programme reveals predominance of a multidrug-resistant clone. AB - Treatment of gonorrhoea is threatened by antimicrobial resistance, and decreased susceptibility and resistance to recommended therapies is emerging in Europe. Current associations between resistance and molecular type remain poorly understood. Gonococcal isolates (n=1,066) collected for the 2009 and 2010 European Gonococcal Antimicrobial Surveillance Programme were typed by Neisseria gonorrhoeae multi-antigen sequence typing (NG-MAST). A total of 406 sequence types (STs) were identified, 125 of which occurred in >=two isolates. Seven major genogroups of closely related STs (varying by <=1% at just one of the two target loci) were defined. Genogroup 1407 (G1407), observed in 20/21 countries and predominant in 13/21 countries, accounted for 23% of all isolates and was associated with decreased susceptibility to cefixime and resistance to ciprofloxacin and raised minimum inhibitory concentrations for ceftriaxone and azithromycin. Genogroup 225 (G225), associated with ciprofloxacin resistance, was observed in 10% of isolates from 19/21 countries. None of the other genogroups were associated with antimicrobial resistance. The predominance of a multidrug resistant clone (G1407) in Europe is worrying given the recent reports of recommended third generation cephalosporins failing to treat infections with this clone. Identifying associations between ST and antimicrobial resistance aids the understanding of the dissemination of resistant clones within a population and could facilitate development of targeted intervention strategies. PMID- 23351653 TI - A snapshot of genetic lineages of Mycobacterium tuberculosis in Ireland over a two-year period, 2010 and 2011. AB - Mycobacterial interspersed repetitive-unit-variable-number tandem repeat typing alone was used to investigate the genetic lineages among 361 Mycobacterium tuberculosis strains circulating in Ireland over a two-year period, 2010 and 2011. The majority of isolates, 63% (229/361), belonged to lineage 4 (Euro American), while lineages 1 (Indo-Oceanic), 2 (East-Asian) and 3 (East-African Indian) represented 12% of isolates each (42/361, 45/361, and 45/361, respectively). Sub-lineages Beijing (lineage 2), East-African-Indian (lineage 1) and Delhi/central-Asian (lineage 3) predominated among foreign-born cases, while a higher proportion of Euro-American lineages were identified among cases born in Ireland. Eighteen molecular clusters involving 63 tuberculosis (TB) cases were identified across four sub-lineages of lineage 4. While the mean cluster size was 3.5 TB cases, the largest cluster (involving 12 Irish-born cases) was identified in the Latin American-Mediterranean sub-lineage. Clustering of isolates was higher among Irish-born TB cases (47 of 63 clustered cases), whereas only one cluster (3/63) involved solely foreign-born individuals. Four multidrug-resistant cases identified during this period represented lineages 2 and 4. This study provides the first insight into the structure of the M. tuberculosis population in Ireland. PMID- 23351654 TI - Imported diphyllobothriasis in Switzerland: molecular methods to define a clinical case of Diphyllobothrium infection as Diphyllobothrium dendriticum, August 2010. AB - Following a first clinical case of infection by Diphyllobothrium dendriticum in Switzerland in 2006, we report a second case in the country. The species was identified by molecular methods. In the Swiss, French and Italian subalpine regions, human diphyllobothriasis has seen a comeback since the late 1980's, and Diphyllobothrium latum is usually considered the causative agent of the disease. In addition, several locally acquired and imported clinical infections due to allochthonous Diphyllobothrium species have been documented in the last years. Due to the colonisation potential of these parasites and their probably underestimated presence in the human population, there is a need for discriminating them at the medical laboratory level. Because the morphological characters are very similar among the different taxa, a correct identification requires the use of molecular methods. Molecular identification would improve diagnosis and help monitor the distribution of Diphyllobothrium species in Europe. PMID- 23351655 TI - Molecular-based surveillance of campylobacteriosis in New Zealand--from source attribution to genomic epidemiology. AB - Molecular-based surveillance of campylobacteriosis in New Zealand contributed to the implementation of interventions that led to a 50% reduction in notified and hospitalised cases of the country's most important zoonosis. From a pre intervention high of 384 per 100,000 population in 2006, incidence dropped by 50% in 2008; a reduction that has been sustained since. This article illustrates many aspects of the successful use of molecular-based surveillance, including the distinction between control-focused and strategy-focused surveillance and advances in source attribution. We discuss how microbial genetic data can enhance the understanding of epidemiological explanatory and response variables and thereby enrich the epidemiological analysis. Sequence data can be fitted to evolutionary and epidemiological models to gain new insights into pathogen evolution, the nature of associations between strains of pathogens and host species, and aspects of between-host transmission. With the advent of newer sequencing technologies and the availability of rapid, high-coverage genome sequence data, such techniques may be extended and refined within the emerging discipline of genomic epidemiology. The aim of this article is to summarise the experience gained in New Zealand with molecular-based surveillance of campylobacteriosis and to discuss how this experience could be used to further advance the use of molecular tools in surveillance. PMID- 23351656 TI - ECDC starts pilot phase for collection of molecular typing data. PMID- 23351660 TI - Cofactor engineering through heterologous expression of an NADH oxidase and its impact on metabolic flux redistribution in Klebsiella pneumoniae. AB - BACKGROUND: Acetoin is an important bio-based platform chemical. However, it is usually existed as a minor byproduct of 2,3-butanediol fermentation in bacteria. RESULTS: The present study reports introducing an exogenous NAD+ regeneration sysytem into a 2,3-butanediol producing strain Klebsiella pneumoniae to increse the accumulation of acetoin. Batch fermentation suggested that heterologous expression of the NADH oxidase in K. pneumoniae resulted in large decreases in the intracellular NADH concentration (1.4 fold) and NADH/NAD+ ratio (2.0 fold). Metabolic flux analysis revealed that fluxes to acetoin and acetic acid were enhanced, whereas, production of lactic acid and ethanol were decreased, with the accumualation of 2,3-butanediol nearly unaltered. By fed-batch culture of the recombinant, the highest reported acetoin production level (25.9 g/L) by Klebsiella species was obtained. CONCLUSIONS: The present study indicates that microbial production of acetoin could be improved by decreasing the intracellular NADH/NAD+ ratio in K. pneumoniae. It demonstrated that the cofactor engineering method, which is by manipulating the level of intracellular cofactors to redirect cellular metabolism, could be employed to achieve a high efficiency of producing the NAD+-dependent microbial metabolite. PMID- 23351661 TI - Variability in the intensity of nematode larvae from gastrointestinal tissues of a natural herbivore. AB - The migration of infective nematode larvae into the tissues of their hosts has been proposed as a mechanism of reducing larval mortality and increase parasite lifetime reproductive success. Given that individual hosts differ in the level of exposure, strength of immune response and physiological conditions we may expect the number of larvae in tissue to vary both between and within hosts. We used 2 gastrointestinal nematode species common in the European rabbit (Oryctolagus cuniculus) and examined how the number of larvae in the tissue changed with the immune response, parasite intensity-dependent constraints in the lumen and seasonal weather factors, in rabbits of different age, sex and breeding status. For both nematode species, larvae from the gastrointestinal tissue exhibited strong seasonal and host age-related patterns with fewer larvae recovered in summer compared to winter and more in adults than in juveniles. The number of larvae of the 2 nematodes was positively associated with intensity of parasite infection in the lumen and antibody responses while it was negatively related with air temperature and rainfall. Host sex, reproductive status and co-infection with the second parasite species contributed to increase variability between hosts. We concluded that heterogeneities in host conditions are a significant cause of variability of larval abundance in the gastrointestinal tissues. These findings can have important consequences for the dynamics of nematode infections and how parasite's life-history strategies adjust to host changes. PMID- 23351662 TI - Incidence of deep vein thrombosis in the first month after kidney transplantation in Korean versus Caucasian populations. PMID- 23351659 TI - Photoreceptor sensory cilia and ciliopathies: focus on CEP290, RPGR and their interacting proteins. AB - Ciliopathies encompass a broad array of clinical findings associated with genetic defects in biogenesis and/or function of the primary cilium, a ubiquitous organelle involved in the transduction of diverse biological signals. Degeneration or dysfunction of retinal photoreceptors is frequently observed in diverse ciliopathies. The sensory cilium in a photoreceptor elaborates into unique outer segment discs that provide extensive surface area for maximal photon capture and efficient visual transduction. The daily renewal of approximately 10% of outer segments requires a precise control of ciliary transport. Here, we review the ciliopathies with associated retinal degeneration, describe the distinctive structure of the photoreceptor cilium, and discuss mouse models that allow investigations into molecular mechanisms of cilia biogenesis and defects. We have specifically focused on two ciliary proteins - CEP290 and RPGR - that underlie photoreceptor degeneration and syndromic ciliopathies. Mouse models of CEP290 and RPGR disease, and of their multiple interacting partners, have helped unravel new functional insights into cell type-specific phenotypic defects in distinct ciliary proteins. Elucidation of multifaceted ciliary functions and associated protein complexes will require concerted efforts to assimilate diverse datasets from in vivo and in vitro studies. We therefore discuss a possible framework for investigating genetic networks associated with photoreceptor cilia biogenesis and pathology. PMID- 23351663 TI - The infrequent removal of retrievable IVC filters. PMID- 23351664 TI - Estimated glomerular filtration rate is associated with major bleeding complications but not thromboembolic events, in anticoagulated patients taking warfarin. AB - BACKGROUND: Decreased glomerular filtration rate is an established risk factor for bleeding but there are limited data on its association with bleeding risk in well-controlled anticoagulated patients taking warfarin. OBJECTIVES: The aim was to investigate the relationship between glomerular filtration rate, major bleeding and thromboembolic complications in patients with tight anticoagulation control. PATIENTS/METHODS: A cohort study of patients from a Swedish quality register for anticoagulation, including all the registered patients that received anticoagulation during 2008 in the anticoagulation center of Skane University Hospital, Malmo. Key outcome measures were major bleeding and arterial or venous thrombosis during 2008. A total of 3536 patients (2875 treatment years) were included. RESULTS: Total rates of 2.6 (2.0-3.2) bleeding events and 1.8 (1.3-2.3) thrombotic events per 100 treatment years were recorded (75 bleeding and 51 thromboembolic events). Data on estimated glomerular filtration rate were available in 3349 patients. Mean time in therapeutic range (international normalized ratio 2.0-3.0) was 74.5% (n=2894). Major bleeding events were significantly related to age and percentage of time with international normalized ratio >3.0 (P<0.001). Glomerular filtration rate levels <30 ml/min/1.73 m(2) were particularly associated with high risk of bleeding, especially in elderly patients. No correlation between glomerular filtration rate and thromboembolic events was seen. CONCLUSIONS: With good anticoagulation control as measured by time in therapeutic range, patients had a relatively low risk for major bleeding if their renal function is normal. Despite good anticoagulation control, severely impaired kidney function is associated with a very high yearly risk of major bleeding events. PMID- 23351665 TI - Evaluation of automated immunoassays in the diagnosis of heparin induced thrombocytopenia. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) is caused by platelet activating antibodies that recognize platelet factor 4/heparin (PF4/hep) complexes. The in vitro demonstration of PF4/hep antibodies using functional and immunological methods is essential for optimal management of patients suspected to have HIT. Since functional assays are technically challenging and limited to specialized laboratories, antigen-binding assays are commonly used in routine laboratories. STUDY DESIGN: Blood samples from 448 consecutive patients in whom HIT was suspected were investigated using a latex agglutination test HemosIL(r) HIT-Ab(PF4-H) (HemosIL-Ab), two chemiluminescence tests HemosIL AcuStar HIT Ab(PF4-H) (HemosIL AcuStar-Ab) and AcuStar HIT-IgG(PF4-H) (HemosIL AcuStar-IgG), an in-house PF4/hep IgG enzyme immunoassay (EIA) and the heparin induced platelet aggregation (HIPA) test. RESULTS: Antibodies against PF4/hep were detectable in 44 out of 119 samples using HemosIL-Ab among which 20 samples were also reactive in the HIPA; and in 122, 64 and 108 out of 448 sera using HemosIL AcuStar-Ab, HemosIL AcuStar-IgG and in-house PF4/hep IgG-EIA, respectively, among which 52 sera were also reactive in the HIPA. All assays had high sensitivities of >95% for platelet activating antibodies; however, they differed in their specificities. The highest specificity and positive predictive value was observed by HemosIL AcuStar-IgG (96% and 78%, respectively). CONCLUSION: Automated immunoassays are useful in the laboratory investigations of HIT and present a potential improvement toward standardization of laboratory investigations of HIT. The high positive predictive capability may justify treating the patient with alternative anticoagulants without waiting for the results of a functional assay. PMID- 23351666 TI - General Practitioners' coronary risk estimates, decisions to start lipid-lowering treatment, gender and length of clinical experience: their interactions in primary prevention. AB - AIM: We investigated whether the risk estimates of General Practitioners (GPs) and their treatment decisions mutually influence each other and whether factors not related to the patient's risk, such as the gender and length in clinical practice, interact. BACKGROUND: The quantitative assessment of the absolute risk of developing coronary heart disease (CHD) and the decision to start treatment with lipid-lowering drugs are crucial tasks in the primary prevention of CHD. METHODS: Nine clinical vignettes, four rated high-risk and five rated low-risk according to the Framingham equation, were mailed to three groups of 90 randomly selected GPs in Stockholm. One group (R) was asked to estimate the risk of CHD within 10 years on a visual analogue scale. A second group (R1D) was asked to estimate the risk and to specify whether they would recommend a pharmacological lipid-lowering treatment. A third group (D) only to indicate whether they would recommend treatment. RESULTS: Response rate ranged from 42.2% to 45.6%. The median risk estimates were higher in the R group than in the R1D group (difference not statistically significant). R1D group showed higher proportions of correct decisions to start treatment compared with the R group (86.2% versus 77.5%, P50.19). More correct decisions were made by female doctors (OR 1.77, 95% CI 1.19-2.61, P50.004) and by less experienced doctors (OR 0.97, 95% CI 0.95 0.99, P50.016). CONCLUSIONS: The task of making CHD risk estimates and the task of making decisions whether to start lipid-lowering treatment do not seem to influence each other. The gender of physicians and the length of clinical experience seem to affect treatment decisions. Female GPs and less experienced GPs are more likely to make correct decisions. However, the relatively low response rate to the questionnaires may limit the generalizability of these results. PMID- 23351667 TI - Analysis of whole genome sequences of 16 strains of rubella virus from the United States, 1961-2009. AB - Rubella virus is the causative agent of rubella, a mild rash illness, and a potent teratogenic agent when contracted by a pregnant woman. Global rubella control programs target the reduction and elimination of congenital rubella syndrome. Phylogenetic analysis of partial sequences of rubella viruses has contributed to virus surveillance efforts and played an important role in demonstrating that indigenous rubella viruses have been eliminated in the United States. Sixteen wild-type rubella viruses were chosen for whole genome sequencing. All 16 viruses were collected in the United States from 1961 to 2009 and are from 8 of the 13 known rubella genotypes. Phylogenetic analysis of 30 whole genome sequences produced a maximum likelihood tree giving high bootstrap values for all genotypes except provisional genotype 1a. Comparison of the 16 new complete sequences and 14 previously sequenced wild-type viruses found regions with clusters of variable amino acids. The 5' 250 nucleotides of the genome are more conserved than any other part of the genome. Genotype specific deletions in the untranslated region between the non-structural and structural open reading frames were observed for genotypes 2B and genotype 1G. No evidence was seen for recombination events among the 30 viruses. The analysis presented here is consistent with previous reports on the genetic characterization of rubella virus genomes. Conserved and variable regions were identified and additional evidence for genotype specific nucleotide deletions in the intergenic region was found. Phylogenetic analysis confirmed genotype groupings originally based on structural protein coding region sequences, which provides support for the WHO nomenclature for genetic characterization of wild-type rubella viruses. PMID- 23351668 TI - Incidence of genital warts in adolescents and their association with cervical intraepithelial lesions. AB - OBJECTIVES: To estimate the incidence of genital warts in adolescents and analyze their relationship with the development of cervical squamous intraepithelial lesions (SIL). STUDY DESIGN: From 1993 to 2006 we followed 846 adolescents in the gynecology clinic of a public hospital in Rio de Janeiro. They were sexually active, had a normal smear test and no genital warts upon recruitment and completed two years of follow-up. Data were analyzed using EPI-INFO software. The research was approved by the hospital Ethics Committee. RESULTS: The mean age at recruitment was 15.8 +/- 1.4 years and at first intercourse was 14.7 +/- 1.6. Sixty-three (7.4%) adolescents presented condylomata, 5.6% (48/846) during the first year of sexual activity and 1.8% (15/846) during the second year. Within two years, 20.5% (174/846) of the patients had an abnormal smear test. Seventy percent (44/63) of the patients with genital warts developed a SIL. The association between warts and SIL showed a RR=4.2(3.3-5.3). CONCLUSIONS: The incidence of condylomata was one third of the incidence of SIL and was higher during the first than in the second year of sexual activity. Adolescents with genital warts had a fourfold increase in risk of SIL and therefore should be carefully followed up. PMID- 23351669 TI - Mild hydronephrosis after uncomplicated hysterectomy. AB - OBJECTIVE: To explore differences in the incidence of hydronephrosis following different hysterectomy methods for benign gynecological disease. STUDY DESIGN: Retrospective chart review of ultrasound findings on all patients undergoing simple hysterectomy for benign gynecological pathology between July 2004 and September 2008. Elective renal ultrasonography was performed pre-operatively and within 3 days after hysterectomy as part of the routine follow-up in our hospital. RESULTS: Of 385 eligible patients, six were excluded because of pre existing hydronephrosis or suspected intra-operative ureteral injury. In the resulting group of 379 patients, abdominal (33.3%), vaginal (11.8%) or laparoscopic hysterectomy (54.9%) was performed. The last group included total laparoscopic hysterectomy (TLH, 20.3%), laparoscopic supracervical hysterectomy (LASH, 19.3%), and laparoscopically assisted vaginal hysterectomy (LAVH, 15.3%). Overall, 56.7% of patients showed mild hydronephrosis (5-15 mm pelvicalyceal dilatation) after surgery. Mostly, it occurred unilaterally. The incidence varied according to the type of procedure, the highest being documented following vaginal hysterectomy (64.4%) and the lowest after LASH (46.6%), but this did not reach statistical significance. CONCLUSION: Mild hydronephrosis is a frequent finding after uncomplicated hysterectomy for benign pathology in otherwise asymptomatic patients. Although not statistically significant, there may be variability of mild hydronephrosis depending on the hysterectomy method. PMID- 23351671 TI - The type of GnRH analogue used during controlled ovarian stimulation influences early embryo developmental kinetics: a time-lapse study. AB - OBJECTIVE: To explore if the GnRH analogue used for controlled ovarian stimulation (COS) and the ovulation triggering factor (GnRH agonist + hCG triggering versus GnRH antagonist + GnRH agonist triggering) affect embryo development and kinetics. STUDY DESIGN: In a retrospective cohort study in the Instituto Valenciano de Infertilidad (IVI) Alicante and the Instituto Universitario-IVI Valencia, Spain, 2817 embryos deriving from 400 couples undergoing oocyte donation were analysed. After controlled ovarian stimulation and IVF/intracytoplamic sperm injection, the timing of embryonic cleavages was assessed by a video time-lapse system. The results were analysed using Student's t test for comparison of timings (hours) and Chi-squared test for comparison of proportions. A p-value < 0.05 was considered to be statistically significant. RESULTS: Embryos from cycles co-treated with GnRH antagonist + GnRH agonist (n = 2101) cleaved faster than embryos deriving from patients co-treated with GnRH agonist + hCG (n = 716): these differences were significant at the first stages of development but they disappeared as long as the embryo developed. Assessing embryo quality in terms of morphokinetic characteristics, we did not find significant differences between the two groups. CONCLUSION(S): By adopting a time lapse video system, we can suggest that the type of protocol used for controlled ovarian stimulation influences embryo kinetics of development but these variations are not reflected in embryo quality. PMID- 23351670 TI - Increased levels of oxidative stress markers in the peritoneal fluid of women with endometriosis. AB - OBJECTIVE: To evaluate 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-isoprostane levels in the peritoneal fluid (PF) of women with endometriosis. STUDY DESIGN: One hundred and ten women with laparoscopically and histopathologically confirmed endometriosis and, as reference groups, 119 patients with simple serous (n=78) and dermoid (n=41) ovarian cysts were studied. Peritoneal fluid 8-OHdG and 8 isoprostane concentrations were evaluated by enzyme-linked immunosorbent assays. RESULTS: 8-OHdG and 8-isoprostane levels in peritoneal fluid were significantly higher in patients with endometriosis compared with the reference groups. Higher PF 8-OHdG and 8-isoprostane concentrations were observed in patients with advanced stages of endometriosis. A statistically significant positive correlation was found between 8-OHdG and 8-isoprostane levels in peritoneal fluid. CONCLUSION: Endometriosis induces greater oxidative stress and frequent DNA mutations in peritoneal fluid than nonendometriotic ovarian cysts. The most severe oxidative stress occurs in the peritoneal cavity of women with more advanced stages of the disease. PMID- 23351672 TI - Perspective on lead toxicity, a comparison between the United States and Iran. AB - Lead is a pervasive toxin that has been implicated in human poisonings throughout history. Exposure mitigation strategies in the United States and worldwide have led to a decline in symptomatic poisonings and population blood lead levels; however, lead remains a major health hazard. In this article, we review the history of lead toxicity, clinical manifestations ranging from subclinical and subtle features to life-threatening complications, and the subsequent public health interventions in the US. In addition, we explore common routes of lead exposure and the unique differences between the US and Iran. Although the US has made significant strides with regard to this public health issue, lead poisoning in both countries continues to be a health hazard in the adult and pediatric populations. It is also critical to consider natural disasters and reconstruction efforts as potential sources of lead contamination. In conclusion, we make recommendations that both the US and Iranian authorities can implement to eradicate lead as a public health hazard. PMID- 23351673 TI - Effects of tight versus non tight control of metabolic acidosis on early renal function after kidney transplantation. AB - BACKGROUND: Recently, several studies have been conducted to determine the optimal strategy for intra-operative fluid replacement therapy in renal transplantation surgery. Since infusion of sodium bicarbonate as a buffer seems to be safer than other buffer compounds (lactate, gluconate, acetate)that indirectly convert into it within the liver, We hypothesized tight control of metabolic acidosis by infusion of sodium bicarbonate may improve early post operative renal function in renal transplant recipients. METHODS: 120 patients were randomly divided into two equal groups. In group A, bicarbonate was infused intra-operatively according to Base Excess (BE) measurements to achieve the normal values of BE (-5 to +5 mEq/L). In group B, infusion of bicarbonate was allowed only in case of severe metabolic acidosis (BE <= -15 mEq/L or bicarbonate <= 10 mEq/L or PH <= 7.15). Minute ventilation was adjusted to keep PaCO2 within the normal range. Primary end-point was sampling of serum creatinine level in first, second, third and seventh post-operative days for statistical comparison between groups. Secondary objectives were comparison of cumulative urine volumes in the first 24 h of post-operative period and serum BUN levels which were obtained in first, second, third and seventh post-operative days. RESULTS: In group A, all of consecutive serum creatinine levels were significantly lower in comparison with group B. With regard to secondary outcomes, no significant difference between groups was observed. CONCLUSION: Intra-operative tight control of metabolic acidosis by infusion of Sodium Bicarbonate in renal transplant recipients may improve early post-operative renal function. PMID- 23351674 TI - Impact of a mass media campaign on bed net use in Cameroon. AB - BACKGROUND: In 2011, Cameroon and its health partners distributed over eight million free long-lasting insecticide treated nets (LLINs) in an effort to reduce the significant morbidity and mortality burden of malaria in the country. A national communications campaign was launched in July 2011 to ensure that as the nets were delivered, they would be used consistently to close a net use gap: only 51.6% of adults and 63.4% of their children in households with at least one net were sleeping under nets before the distribution. Even in households with at least one net for every two people, over 35% of adults were not sleeping under a net. Malaria No More (MNM) adapted its signature NightWatch communications programme to fit within the coordinated "KO Palu" (Knock Out Malaria) national campaign. This study evaluates the impact of KO Palu NightWatch activities (that is, the subset of KO Palu-branded communications that were funded by MNM's NightWatch program) on bed net use. METHODS: Using national survey data collected at baseline (in March/April 2011, before the national LLIN distribution and KO Palu NightWatch launch) and post-intervention (March/April 2012), this study evaluates the impact of exposure to KO Palu NightWatch activities on last-night net use by Cameroonian adults and their children under five. First, a plausible case for causality was established by comparing net use in 2011 and 2012 and measuring exposure to KO Palu NightWatch; next, a propensity score matching (PSM) model was used to estimate the impact of exposure on net use by simulating a randomized control trial; finally, the model was tested for sensitivity to unmeasured factors. RESULTS: The PSM model estimated that among Cameroonians with at least one net in their household, exposure to KO Palu NightWatch activities was associated with a 6.6 percentage point increase in last-night net use among respondents (65.7% vs 59.1%, p < 0.05) and a 12.0 percentage point increase in last-night net use among respondents' children under five (79.6% vs 67.6%, p < 0.025). Sensitivity analysis suggests only a very small risk of bias from omitted factors influencing exposure and net use. CONCLUSIONS: Extrapolating the results of the PSM model to the population of Cameroonians with access to at least one mosquito net, this analysis estimates that approximately 298,000 adults and over 221,000 of their children under five slept under a bed net because of the knowledge, motivation, and/or timely reminder provided by KO Palu NightWatch activities. The programme cost less than $0.16 per adult reached, and less than $1.62 per additional person protected by a net. The results suggest a strong role for mass media communication interventions in support of investments in malaria control commodities such as LLINs. PMID- 23351675 TI - Synthesis and biological evaluation of propargyl acetate derivatives as anti mycobacterial agents. AB - BACKGROUND: The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) has intensified efforts to discover novel drugs for tuberculosis (TB) treatment. Targeting the persistent state of Mtb, a condition in which Mtb is resistant to conventional drug therapies, is of particular interest. METHODS: This study is focused on propargyl acetate derivatives. Eight molecules were designed based on propargyl alcohols and different acid anhydrides. RESULTS: All the synthesized compounds and commercially available ones were evaluated for anti-tuberculosis activity. CONCLUSIONS: Inhibitors against Mtb have been identified and characterized for further development into potential novel anti-tubercular drugs. PMID- 23351676 TI - Synthesis and antibacterial activity of novel levofloxacin derivatives containing a substituted thienylethyl moiety. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: Piperazinyl quinolones such as ciprofloxacin, ofloxacin and levofloxacin are an important group of quinolone antimicrobials which are widely used in the treatment of various infectious diseases. In the present study, we synthesized a new series of levofloxacin derivatives and evaluated their antibacterial activities. METHODS: The N substituted analogs of levofloxacin 6a-j were prepared by nucleophilic reaction of N-desmethyl levofloxacin 11 with thienylethyl bromide derivatives 8 or 9. All target compounds were tested using conventional agar dilution method in comparison to levofloxacin and N-desmethyl levofloxacin and their MIC values were determined against a panel of Gram-positive and Gram-negative bacteria. RESULTS: All compounds showed significant antibacterial activities against Gram-positive bacteria (MIC = 0.04-6.25 MUg/mL); however, the activity against Gram-negative bacteria was lower (MIC = 1.56-100 MUg/mL). As is evident from the data, oxime derivatives 6e, 6h and 6i are superior in inhibiting the growth of Gram-positive bacteria (MIC = 0.04-0.19 MUg/mL), and their activities were found to be 5-25 times better than N-desmethyl levofloxacin 11 and equal or better than levofloxacin 4. CONCLUSION: We have designed and synthesized novel quinolone derivatives bearing functionalized thienylethyl moiety on the piperazine ring of levofloxacin. The results of antibacterial screening against Gram-positive and Gram-negative bacteria revealed that the introduction of functionalized thienylethyl moiety on the piperazine ring of levofloxacin can improve the activity against Gram-positive bacteria. Gram-positive bacteria are responsible for a wide range of infectious diseases, and rising resistance in this group is causing increasing concern. Thus, this study introduces structural features of levofloxacin scaffold for development of new candidates in the field of anti-Gram positive chemotherapy. PMID- 23351677 TI - Emergency preparedness for people with disabilities: guide and checklist. PMID- 23351678 TI - The authors respond. PMID- 23351679 TI - Lack of adherence to the laser dosage recommendations from the World Association for Laser Therapy in Achilles study. PMID- 23351680 TI - Extended preoperative chemotherapy, extent of liver resection and blood transfusion are predictive factors of liver failure following resection of colorectal liver metastasis. AB - AIM: The aim of this study was to determine the incidence and prognostic factors of postoperative liver failure in patients submitted to liver resection for colorectal metastases. METHOD: Patients with CLM who underwent hepatectomy from 1998 to 2009 were included in retrospective analysis. Postoperative liver failure was defined using either the 50-50 criteria or the peak of serum bilirubin level above 7 mg/dL independently. RESULTS: Two hundred and nine (209) procedures were performed in 170 patients. 120 surgeries were preceded by chemotherapy within six months. The overall morbidity rate was 53.1% and 90-day mortality was 2.3%. Postoperative liver failure occurred in 10% of all procedures, accounting for a mortality rate of 9.5% among this group of patients. In multivariate analysis, extent of liver resection, need of blood transfusion and more than eight preoperative chemotherapy cycles were independent prognostic factors of postoperative liver insufficiency. This complication was not related with the chemotherapy regimen used. CONCLUSION: We conclude that postoperative liver failure has a relatively low incidence (10%) after CLM resection, but a remarkable impact on postoperative mortality rate. The amount of liver resected, the need of blood transfusion and extended preoperative chemotherapy are independent predictors of its occurrence and this knowledge can be used to prevent postoperative liver failure in a multidisciplinary approach. PMID- 23351681 TI - Outcomes of isolated limb perfusion in the treatment of extremity soft tissue sarcoma: a systematic review. AB - BACKGROUND: Isolated limb perfusion (ILP) may provide a limb salvage option for locally advanced soft tissue sarcoma (STS) not amenable to local resection. METHODS: A systematic review was performed for studies reporting outcome of ILP for locally advanced STS performed after 1980 in patients aged >= 12 years old. The main endpoints were tumour response and limb salvage rates. Complication and recurrence rates were secondary endpoints. RESULTS: Eighteen studies were included, providing outcomes for 1030 patients. Tumour necrosis factor-alpha with melphalan was the commonest chemotherapy regime. When reported, 22% of cases achieved a complete tumour response (216/964, 15 studies) with an overall response rate of 72% (660/911, 15 studies). At median follow-up times ranging between 11 and 125 months, the limb salvage rate was 81% in patients who otherwise would have been subjected to amputation. However, 27% of patients suffered local recurrence and 40% suffered distant failure. ILP was associated with severe locoregional reactions in 4% (22/603) of patients. Amputation due to complications within 30 days was necessary in 1.2% of cases (7/586, nine studies). There was insufficient evidence to determine the effect of ILP on survival. CONCLUSION: ILP induces a high tumour response rate, leads to a high limb salvage rate but is associated with a high recurrence rate. It provides a limb salvage alternative to amputation when local control is necessary. PMID- 23351682 TI - [medecine/sciences 2013: new goals, new challenges]. PMID- 23351683 TI - [Innate immunity and reprogramming, help between Nobel prize]. PMID- 23351684 TI - [Interleukin 22 may represent a new therapeutic tool towards thymic regeneration in vivo]. PMID- 23351685 TI - [Towards bisphenols without hormonal effects]. PMID- 23351686 TI - [Dendritic spines and local protein synthesis contribute to Down and fragile X syndromes]. PMID- 23351687 TI - [H19 gene controls placental development through a miRNA]. PMID- 23351688 TI - [Towards a universal vaccine against flu?]. PMID- 23351689 TI - [Mutations in NMNAT1 cause Leber congenital amaurosis with severe macular and optic atrophy]. PMID- 23351690 TI - [The mTOR pathway: a new target for treating cognitive deficits of schizophrenia?]. PMID- 23351691 TI - [Opioid receptors associated with portal vein regulate a gut-brain neural circuitry limiting food intake]. PMID- 23351692 TI - [Structure and mode of injection of the oncoprotein CagA of Helicobacter pylori]. PMID- 23351693 TI - [Resistance of chronic lymphocytic leukemia cells in apoptosis: key role of stromal cells in maintaining the redox potential of CLL cells]. PMID- 23351694 TI - [Rabies]. AB - Rabies virus, a neurotropic lyssavirus responsible for unavoidable fatal encephalitis, is transmitted by saliva of infected animals through bite, scratch or licking of broken skin or a mucous membrane. Infection can be prevented by timely prevention (wash for several minutes, antisepsis and vaccination completed by antirabies immunoglobulins [Ig] according to the severity of exposure). The 55,000 human deaths estimated annually worldwide result mainly from uncontrolled canine rabies in enzootic countries (particularly in Africa and in Asia), attributable to a lack of resources or interest for this disease. Bat rabies, henceforth first cause of human's rabies in many countries in America, affects a very small number of individuals but seems more difficult to control. Shortened vaccine protocols, rationalized use of Ig and development of products of substitution should enhance access of exposed patients to prevention. Finally, research on the biological cycle, the pathogeny and on escape of virus-induced mechanisms from the immune system should continue to pave the way for presently unknown treatments of clinical rabies. PMID- 23351695 TI - [The Janus face of monoclonal antibodies in oncology: passive immunity and vaccination]. AB - Monoclonal antibodies used in oncology exert direct anti-tumor action leading to cancer cell death. This is due to a variety of mechanisms, ranging from the induction of apoptosis to the recruitment of effector cells from the innate immunity. However, antibodies can also induce long-lasting anti-tumor effects thanks to the induction of an adaptive immunity where CD4(+) and CD8(+) T cells play a central role. Different preclinical experimental models, strengthened by a few clinical observations, have shown that, far from being involved only in passive immunotherapy, monoclonal antibodies used in oncology are also endowed with a "vaccine" effect, inducing immune memory, likely responsible for the long lasting clinical responses that have been sometimes observed. This capacity of triggering/re-installing tumor immune surveillance could be also reinforced by the use, possibly in combination, of antibodies antagonizing molecules such as CTLA-4 or PD-1 that play a key role in the inhibition of the anti-tumor immune responses. Finally, this novel paradigm of therapeutic anti-tumor antibodies as inducers of anti-tumor adaptive immune responses with long-term memory should lead us to re-examine how antibody treatment, chemotherapy, radiotherapy, and biological response modifiers are combined, in particular both in terms of timing and doses. PMID- 23351696 TI - [Recombinant proteins or monoclonal antibodies: comparative properties and interest in systemic lupus erythematosus]. AB - The emergence of biologic therapies, such as monoclonal antibodies or recombinant fusion proteins, have revolutionized the management of autoimmune disorders, in particular rheumatoid arthritis. These biologic agents have been engineered to deplete key cellular populations or to block cytokines or molecules involved in the activation and/or the differentiation of immune cells, such as T cells or B cells. In systemic lupus erythematosus (SLE), a monoclonal antibody directed against the B-cell activating factor of the TNF family (BAFF or BLyS), belimumab, has demonstrated its efficacy in large, randomized and placebo-controlled studies, whereas rituximab, a monoclonal antibody directed against the CD20 expressed by B cells, failed to achieve his primary endpoint in renal and non renal SLE. Studies on the safety and the efficacy of monoclonal antibodies or recombinant fusion proteins directed against other key molecules involved in the pathogenesis of SLE are ongoing. PMID- 23351697 TI - [The Drosophila midgut as a model to study adult stem cells]. AB - Constant renewal of cells occurs in most tissues throughout the adult lifetime and is insured by the activity of resident stem cells. Recent work has demonstrated the presence of adult stem cells in the Drosophila intestine and consequently, the Drosophila intestine has become a powerful model to understand adult stem cells in vivo. In this review, we summarize our current understanding of the mechanisms controlling cell fate decisions of the intestinal stem cells with a particular focus on the role of the Notch pathway in this process. We also summarize what is known about proliferation control of the intestinal stem cells, which is crucial to maintain tissue homeostasis during normal and environmentally stressful conditions. PMID- 23351698 TI - [Cancers of the upper aerodigestive tract associated with human papillomavirus]. AB - Carcinomas of the aerodigestive tract are most often secondary to alcohol and tobacco intoxication. However, it is shown that the oncogenic human papillomavirus (HPV) have an increasing role in the carcinogenesis of these cancers. Patients with HPV+ carcinoma are generally younger and not alcohol and tobacco users. These carcinomas are mainly localized in the oropharynx and in particular at the tonsil. HPV is found in 40 to 90 % of the cancers in the oropharynx, depending on the country. These HPV+ carcinomas have a better prognosis with better radio or chemosensitivity. To date, no change of treatment is recommended, however, several trials are underway. Preventive vaccination of boys is a real public health issue, especially since it is recommended in some countries. Moreover, a better understanding of the tumor microenvironment will ultimately offer therapeutic vaccination. PMID- 23351699 TI - [Anthropology of medical research in developing countries: a Senegalese experience]. AB - Medical research is an essential tool of biomedicine that raises many social and ethical questions especially in resource-poor countries where the number of clinical trials has increased significantly over the past two decades. This article presents the way anthropology of medical research critically examines medical research in non-western countries without questioning its strategic importance for advances in scientific knowledge and in public health improvement. This article draws on observations conducted in Senegal in 2007 during a vaccine trial against meningitis and discusses, more broadly, medical research in non western-countries related to: the presence and management of medical research sites, the impact of medical research benefits on its representations and the questions raised by blood-stealing rumours regarding medical research practice itself. PMID- 23351700 TI - [Structural anthropology of bird flu: about Un monde grippe by Frederic Keck]. PMID- 23351701 TI - [Myriad's proprietary mutation database]. PMID- 23351702 TI - [Exosomes are carriers for immunostimulatory viral RNA]. PMID- 23351703 TI - [Antagonists of PAR1: towards a new antiviral strategy against flu]. PMID- 23351704 TI - Hypomorphic MGAT5 polymorphisms promote multiple sclerosis cooperatively with MGAT1 and interleukin-2 and 7 receptor variants. AB - Deficiency of the Golgi N-glycan branching enzyme Mgat5 in mice promotes T cell hyperactivity, endocytosis of CTLA-4 and autoimmunity, including a spontaneous multiple sclerosis (MS)-like disease. Multiple genetic and environmental MS risk factors lower N-glycan branching in T cells. These include variants in interleukin-2 receptor-alpha (IL2RA), interleukin-7 receptor-alpha (IL7RA), and MGAT1, a Golgi branching enzyme upstream of MGAT5, as well as vitamin D3 deficiency and Golgi substrate metabolism. Here we describe linked intronic variants of MGAT5 that are associated with reduced N-glycan branching, CTLA-4 surface expression and MS (p=5.79*10(-9), n=7,741), the latter additive with the MGAT1, IL2RA and IL7RA MS risk variants (p=1.76*10(-9), OR=0.67-1.83, n=3,518). PMID- 23351705 TI - IgM to S-nitrosylated protein is found intrathecally in relapsing-remitting multiple sclerosis. AB - This study has established the presence of IgM against S-nitrosylated proteins in cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients using S nitrosocysteine epitope (anti-SNOcys) as previously shown in serum. Anti-SNOcys IgM increased significantly in CSF during relapsing-remitting MS compared to milder neurological conditions. Evidence from albumin, IgG and IgM suggest that the production of anti-SNOcys IgM is intrathecal rather than the result of ingress from serum. Two correlations during relapse: between CSF level of anti SNOcys IgM and time elapsed since relapse onset; and between CSF and serum anti SNOcys IgM levels, suggest that this antibody may have potential as a biomarker. PMID- 23351707 TI - Determination of the role of calcium on instability of neurotoxic metabolite of ecstasy by HPTLC-mass. AB - BACKGROUND: Ecstasy is one of the popular illicit drugs in the world and its usage has been recently increased in Iran. This compound can destroy the serotonergic neurons and produces cognitive and psychopathology diseases. 3,4 dihydroxymethamphetamine (HHMA) which is the main metabolite of this compound, seems to be responsible for this effect. However, no consensus has been reached among the researchers about its role. This disagreement between the researches may be due to failure in determination of HHMA as free form in physiological fluids. In this study, the stability of this crucial metabolite of ecstasy was examined in different mediums. METHODS: The stability of HHMA was studied in the perfusion medium and water at 100 and 10 ng/mL concentrations. Moreover, the effect of temperature (0-25 degrees C), pH (3-10), calcium chloride (0-150 g/L) and ethylenediaminetetraacetic acid (EDTA) on the stability of HHMA was also examined. RESULTS: Our result suggested that the free form of HHMA could be degraded in the perfusion medium. The rate of this degradation has direct proportion to temperature (at 25 degrees C = 0.037 min-1 and at 0 degrees C = 0.002 min-1). Calcium chloride and sodium bicarbonate are two responsible components in this instability. Moreover, the alkaline pHs and increasing the shaking time can accelerate this effect. Although, while degradation was prevented at pH=3, EDTA could only reduce this rate about 30%. CONCLUSIONS: Calcium cation can act as an accelerator of HHMA degradation. Therefore, the perfusion medium should not contain Ca2+ and the pH of medium is better to be adjusted at acidic range. Since, the internal cellular source of calcium is endoplasmic reticulum system, it can be assumed that, this cation may change HHMA and dopamine to reactive compounds that can bind covalently to the cysteinyl group of biological compounds and damage cellular components. PMID- 23351706 TI - Multiple essential roles for primary cilia in heart development. AB - BACKGROUND: The primary cilium is a microtubule-based, plasma membrane ensheathed protrusion projecting from the basal bodies of almost all cell types in the mammalian body. In the past several years a plethora of papers has indicated a crucial role for primary cilia in the development of a wide variety of organs. We have investigated heart development in cobblestone, a hypomorphic allele of the gene encoding the intraflagellar transport protein Ift88, and uncovered a number of the most common congenital heart defects seen in newborn humans. METHODS: We generated serial sections of mutant cobblestone and wild type embryos in the region encompassing the heart and the cardiac outflow tract. The sections were further processed to generate three-dimensional reconstructions of these structures, and immunofluorescence confocal microscopy, transmission electron microscopy, and in situ hybridization were used to examine signal transduction pathways in the relevant areas. Whole mount in situ hybridization was also employed for certain developmental markers. RESULTS: In addition to an enlarged pericardium and failure of both ventricular and atrial septum formation, the cobblestone mutants displayed manifold defects in outflow tract formation, including persistent truncus arteriosus, an overriding aorta, and abnormal transformation of the aortic arches. To discern the basis of these anomalies we examined both the maintenance of primary cilia as well as endogenous and migratory embryonic cell populations that contribute to the outflow tract and atrioventricular septa. The colonization of the embryonic heart by cardiac neural crest occurred normally in the cobblestone mutant, as did the expression of Sonic hedgehog. However, with the loss of primary cilia in the mutant hearts, there was a loss of both downstream Sonic hedgehog signaling and of Islet 1 expression in the second heart field, a derivative of the pharyngeal mesoderm. In addition, defects were recorded in development of atrial laterality and ventricular myocardiogenesis. Finally, we observed a reduction in expression of Bmp4 in the outflow tract, and complete loss of expression of both Bmp2 and Bmp4 in the atrioventricular endocardial cushions. Loss of BMP2/4 signaling may result in the observed proliferative defect in the endocardial cushions, which give rise to both the atrioventricular septa as well as to the septation of the outflow tract. CONCLUSIONS: Taken together, our results potentially identify a novel link between Sonic hedgehog signaling at the primary cilium and BMP-dependent effects upon cardiogenesis. Our data further point to a potential linkage of atrioventricular septal defects, the most common congenital heart defects, to genes of the transport machinery or basal body of the cilia. PMID- 23351708 TI - A cross-sectional survey on knowledge and perceptions of health risks associated with arsenic and mercury contamination from artisanal gold mining in Tanzania. AB - BACKGROUND: An estimated 0.5 to 1.5 million informal miners, of whom 30-50% are women, rely on artisanal mining for their livelihood in Tanzania. Mercury, used in the processing gold ore, and arsenic, which is a constituent of some ores, are common occupational exposures that frequently result in widespread environmental contamination. Frequently, the mining activities are conducted haphazardly without regard for environmental, occupational, or community exposure. The primary objective of this study was to assess community risk knowledge and perception of potential mercury and arsenic toxicity and/or exposure from artisanal gold mining in Rwamagasa in northwestern Tanzania. METHODS: A cross sectional survey of respondents in five sub-villages in the Rwamagasa Village located in Geita District in northwestern Tanzania near Lake Victoria was conducted. This area has a history of artisanal gold mining and many of the population continue to work as miners. Using a clustered random selection approach for recruitment, a total of 160 individuals over 18 years of age completed a structured interview. RESULTS: The interviews revealed wide variations in knowledge and risk perceptions concerning mercury and arsenic exposure, with 40.6% (n=65) and 89.4% (n=143) not aware of the health effects of mercury and arsenic exposure respectively. Males were significantly more knowledgeable (n=59, 36.9%) than females (n=36, 22.5%) with regard to mercury (x2=3.99, p<0.05). An individual's occupation category was associated with level of knowledge (x2=22.82, p=<0.001). Individuals involved in mining (n=63, 73.2%) were more knowledgeable about the negative health effects of mercury than individuals in other occupations. Of the few individuals (n=17, 10.6%) who knew about arsenic toxicity, the majority (n=10, 58.8%) were miners. CONCLUSIONS: The knowledge of individuals living in Rwamagasa, Tanzania, an area with a history of artisanal gold mining, varied widely with regard to the health hazards of mercury and arsenic. In these communities there was limited awareness of the threats to health associated with exposure to mercury and arsenic. This lack of knowledge, combined with minimal environmental monitoring and controlled waste management practices, highlights the need for health education, surveillance, and policy changes. PMID- 23351710 TI - A hypothesis on the origin and evolution of tubulin. AB - Tubulin, the protein subunit of microtubules (MTs), is an alpha/beta heterodimer. In this chapter, a hypothesis on the evolution of the tubulin molecule is proposed, based in part on recent reports on the structures and functions of different forms of tubulin and its relatives. The concentration is on three main areas. 1) Evolution of the vertebrate beta-tubulin isotypes. In addition to providing a clear idea about the relationships among these isotypes, recent data suggest that tubulin may have functions that do not involve being in a MT, namely, that it can function as an isolated alpha/beta dimer or as a non-MT polymer. 2) Examination of the entire tubulin superfamily, which includes not only tubulins alpha, beta, gamma, delta, epsilon, eta, and others but also a variety of prokaryotic proteins. The hypothesis is presented that the common ancestor of all these proteins formed a filamentous curving polymer that used the energy of GTP hydrolysis to apply force to nucleic acids and/or membranes and that this common ancestor may have been coeval with the first cells. A variety of chaperones, motors and MT-associated proteins may have coevolved with tubulin and their histories illuminate that of tubulin. The branched, highly negatively charged C-terminal domain present on alpha- and beta-tubulin appears to be a relatively recent addition to tubulin. 3) The hypothesis is presented that the C terminal domain may have been of prebiotic origin and that it gradually developed into a protein serving particular metabolic functions whose gene eventually became fused with those of alpha- and beta-tubulin. Finally, some experiments are proposed that could illuminate the probability of these hypotheses. PMID- 23351711 TI - Dynamin: expanding its scope to the cytoskeleton. AB - The large GTPase dynamin is well known for its actions on budded cellular membranes to generate vesicles, most often, clathrin-coated endocytic vesicles. The scope of cellular processes in which dynamin-mediated vesicle formation occurs, has expanded to include secretory vesicle formation at the Golgi, from other endosomes and nonclathrin structures, such as caveolae, as well as membrane remodeling during exocytosis and vesicle fusion. An intriguing new facet of dynamin's sphere of influence is the cytoskeleton. Cytoskeletal filament networks maintain cell shape, provide cell movement, execute cell division and orchestrate vesicle trafficking. Recent evidence supports the hypothesis that dynamin influences actin filaments and microtubules via mechanisms that are independent of its membrane-remodeling activities. This chapter discusses this emerging evidence and considers possible mechanisms of action. PMID- 23351709 TI - Molecular insights into intracellular RNA localization. AB - Localization of mRNAs to specific destinations within a cell or an embryo is important for local control of protein synthesis. mRNA localization is well known to function in very large and polarized cells such as neurons, and to facilitate embryonic patterning during early development. However, recent genome-wide studies have revealed that mRNA localization is more widely utilized than previously thought to control gene expression. Not only can transcripts be localized asymmetrically within the cytoplasm, they are often also localized to symmetrically distributed organelles. Recent genetic, cytological, and biochemical studies have begun to provide molecular insight into how cells select RNAs for transport, move them to specific destinations, and control their translation. This chapter will summarize recent insights into the mechanisms and function of RNA localization with a specific emphasis on molecular insights into each step in the mRNA localization process. PMID- 23351713 TI - Cytoskeletal proteins: shaping progression of hepatitis C virus-induced liver disease. AB - Hepatitis C virus (HCV) infection, which results in chronic hepatitis C (CHC) in most patients (70-85%), is a major cause of liver disease and remains a major therapeutic challenge. The mechanisms determining liver damage and the key factors that lead to a high rate of CHC remain imperfectly understood. The precise role of cytoskeletal (CS) proteins in HCV infection remains to be determined. Some studies including our recent study have demonstrated that changes occur in the expression of CS proteins in HCV-infected hepatocytes. A variety of host proteins interact with HCV proteins. Association between CS and HCV proteins may have implications in future design of CS protein-targeted therapy for the treatment for HCV infection. This chapter will focus on the interaction between host CS and viral proteins to signify the importance of this event in HCV entry, replication and transportation. PMID- 23351714 TI - Integrins and small GTPases as modulators of phagocytosis. AB - Phagocytosis is the mechanism whereby cells engulf large particles. This process has long been recognized as a critical component of the innate immune response, which constitutes the organism's defense against microorganisms. In addition, phagocytic internalization of apoptotic cells or cell fragments plays important roles in tissue homeostasis and remodeling. Phagocytosis requires target interactions with receptors on the plasma membrane of the phagocytic cell. Integrins have been identified as important mediators of particle clearance, in addition to their well-established roles in cell adhesion, migration and mechanotransduction. Indeed, these ubiquitously expressed proteins impart phagocytic capacity to epithelial, endothelial and mesenchymal cell types. The importance of integrins in particle internalization is emphasized by the ability of microbial and viral pathogens to exploit their signaling pathways to invade host cells, and by the wide variety of disorders that arise from abnormalities in integrin-dependent phagocytic uptake. PMID- 23351715 TI - Investigation of the ZNF804A gene polymorphism with genetic risk for bipolar disorder in attention deficit hyperactivity disorder. AB - BACKGROUND: Genome-wide association studies (GWAS) have been conducted on many psychiatric disorders. Evidence from large GWAS indicates that the single nucleotide polymorphism (SNP) rs1344706 in the zinc-finger protein 804A gene (ZNF804A) is associated with psychotic disorders including bipolar disorder and schizophrenia. One study also found significant association between rs1344706 and the executive control network of attention. In this study we examine the role of the rs1344706 polymorphism that previously showed association with BD and is known to alter expression of the gene in two clinical family-based ADHD samples from the UK and Taiwan. FINDINGS: To investigate the association between rs1344706 and ADHD, two family samples of ADHD probands from the United Kingdom (n = 180) and Taiwan (n = 212) were genotyped using TaqMan SNP genotyping assays and analysed using within-family transmission disequilibrium test. No significant associations were found between rs1344706 polymorphism and ADHD in either of the samples from Taiwan (P = 0.91) and UK (P = 0.41). Even combining the two datasets together the A allele of rs1344706 SNP was still not significantly over transmitted to affected probands (P = 0.50). Furthermore, there was no evidence of association with the specific symptoms subgroups of inattention or hyperactivity-impulsivity. CONCLUSIONS: In this study we used family-based ADHD data in the UK and Taiwanese population to test for an association between rs1344706 SNP in the ZNF804A gene and ADHD. Results showed no significant association of rs1344706 with ADHD in UK and Taiwanese samples. PMID- 23351712 TI - Beta-barrel scaffold of fluorescent proteins: folding, stability and role in chromophore formation. AB - This review focuses on the current view of the interaction between the beta barrel scaffold of fluorescent proteins and their unique chromophore located in the internal helix. The chromophore originates from the polypeptide chain and its properties are influenced by the surrounding protein matrix of the beta-barrel. On the other hand, it appears that a chromophore tightens the beta-barrel scaffold and plays a crucial role in its stability. Furthermore, the presence of a mature chromophore causes hysteresis of protein unfolding and refolding. We survey studies measuring protein unfolding and refolding using traditional methods as well as new approaches, such as mechanical unfolding and reassembly of truncated fluorescent proteins. We also analyze models of fluorescent protein unfolding and refolding obtained through different approaches, and compare the results of protein folding in vitro to co-translational folding of a newly synthesized polypeptide chain. PMID- 23351716 TI - The role of clusterin on pancreatic beta cell regeneration after exendin-4 treatment in neonatal streptozotocin administrated rats. AB - We investigated the effects of exendin-4 (Ex4) treatment on expression of clusterin and beta cell regeneration in the endocrine pancreas in neonatal streptozotocin (nSTZ) diabetic rats. Three groups were used: (1) n2-STZ group; on the second day after birth 100mg/kg STZ was given i.p. to two groups of newborn rats, (2) n2-STZ+Ex4 group; 3MUg/kg/day Ex4 was given for 5 days starting on the third day, and (3) control group. In situ hybridization for mRNAs of insulin and clusterin, double immunostaining for insulin/clusterin and insulin/BrdU were carried out. Immunostaining for insulin, glucagon, somatostatin, clusterin, synaptophysin and pdx-1 was performed. In the n2-STZ+Ex4 group, BrdU/insulin and insulin/clusterin immunopositive cells were significantly increased in the islets of Langerhans in comparison to the other groups. The areas occupied by the insulin mRNA and peptide positive cells and also pdx-1 immunopositive cells were decreased in the n2-STZ diabetic group compared with the other groups. The clusterin mRNA and protein positive cells, and also the glucagon and somatostatin cells, were significantly increased in the islets of the n2-STZ and the n2 STZ+Ex4 groups compared with the control group. The results show that Ex4 treatment induces new beta cell clusters via up-regulation of clusterin, which might be effective on beta-cell proliferation and neogenesis. PMID- 23351717 TI - Signal amplification in immunohistochemistry: loose-jointed deformable heteropolymeric HRP conjugates vs. linear polymer backbone HRP conjugates. AB - Improvements in reagents and protocols for immunohistochemistry have led to increased sensitivity of detection systems. A significant level of signal amplification was achieved by the chain-polymer conjugate technology utilizing enzyme-labeled inert "backbone" molecule of dextran (Dako). However, the relatively large size of the dextran molecule in aqueous phase appears to create spatial hindrance compromising the penetrative ability of the detection reagent. Novel AmpliStainTM detection systems (SDT GmbH, Baesweiler, Germany) seem to overcome these constraints offering a more compact and deformable conjugate design that facilitates agile penetration through the narrowest diffusion pathways in tissue sections. Here, we compared the level of signal amplification achievable with AmpliStainTM-HRP (SDT) and EnVisionTM+-HRP (Dako). Our results show that the AmpliStainTM-HRP systems allow higher dilutions of primary antibodies in both immunohistochemistry and ELISA. Compared with EnVisionTM+, anti-mouse AmpliStainTM enables at least three times more sensitive detection of mouse antibodies, whereas anti-rabbit AmpliStainTM is ten times more sensitive than anti-rabbit EnVisionTM+. PMID- 23351718 TI - Helminth egg excretion with regard to age, gender and management practices on UK Thoroughbred studs. AB - Few studies have described the combined effect of age, gender, management and control programmes on helminth prevalence and egg shedding in grazing equines. Here, fecal samples collected from 1221 Thoroughbred horses, residing at 22 studs in the UK, were analysed. The distribution of strongyle eggs amongst individuals in relation to age, gender and management practices was investigated. Fecal worm egg counts (FWECs), described as the number of eggs per gramme (epg) of feces, were determined using a modification of the salt flotation method. The FWEC prevalence (mean%) of strongyles, Parascaris equorum, tapeworm spp. and Strongyloides westeri was 56, 9, 4 and 8%, respectively. Strongyle, P. equorum, tapeworm spp. and S. westeri infections were detected on 22 (100%), 11 (50%), 9 (41%) and 8 (36%) of studs, respectively. Within all age and gender categories, strongyle FWECs were highly over-dispersed (arithmetic mean = 95 epg, aggregation parameter k=0.111) amongst horses. Animal age, last anthelmintic type administered and management practices (for example, group rotation on grazing) most strongly influenced strongyle prevalence and level of egg shedding (P < 0.05). Overall, 11% of equines (range: 234-2565 epg) were responsible for excreting 80% of the strongyle eggs detected on FWEC analysis. The results confirm that the judicious application of targeted treatments has potential to control equine strongyle populations by protecting individual horses from high burdens, whilst promoting refugia for anthelmintic susceptible genotypes. PMID- 23351719 TI - High number of CD56(bright) NK-cells and persistently low CD4+ T-cells in a hemophiliac HIV/HCV co-infected patient without opportunistic infections. AB - BACKGROUND: Both the human immunodeficiency virus (HIV) and hepatitis C virus (HCV), either alone or as coinfections, persist in their hosts by destroying and/or escaping immune defenses, with high morbidity as consequence. In some cases, however, a balance between infection and immunity is reached, leading to prolonged asymptomatic periods. We report a case of such an indolent co infection, which could be explained by the development of a peculiar subset of Natural Killer (NK) cells. RESULTS: Persistently high peripheral levels of CD56+ NK cells were observed in a peculiar hemophiliac HIV/HCV co-infected patient with low CD4 counts, almost undetectable HIV viral load and no opportunistic infections. Thorough analysis of NK-subsets allowed to identify a marked increase in the CD56bright/dim cell ratio and low numbers of CD16+/CD56- cells. These cells have high levels of natural cytotoxicity receptors but low NCR2 and CD69, and lack both CD57 and CD25 expression. The degranulation potential of NK-cells which correlates with target cytolysis was atypically mainly performed by CD56bright NK-cells, whereas no production of interferon gamma (IFN-gamma) was observed following NK activation by K562 cells. CONCLUSIONS: These data suggest that the expansion and lytic capacity of the CD56bright NK subset may be involved in the protection of this " rare " HIV/HCV co-infected hemophiliac A patient from opportunistic infections and virus-related cancers despite very low CD4+ cell counts. PMID- 23351720 TI - In vitro alpha-glucosidase inhibitory activity of phenolic constituents from aerial parts of Polygonum hyrcanicum. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: The early stage of diabetes mellitus type 2 is associated with postprandial hyperglycemia. Hyperglycemia is believed to increase the production of free radicals and reactive oxygen species, leading to oxidative tissue damage. In an effort of identifying herbal drugs which may become useful in the prevention or mitigation of diabetes, biochemical activities of Polygonum hyrcanicum and its constituents were studied. METHODS: Hexane, ethylacetate and methanol extracts of P. hyrcanicum were tested for alpha glucosidase inhibitory, antioxidant and radical scavenging properties. Active constituents were isolated and identified from the methanolic extract in an activity guided approach. RESULTS: A methanolic extract from flowering aerial parts of the plant showed notable alpha-glucosidase inhibitory activity (IC50 = 15 MUg/ml). Thirteen phenolic compounds involving a cinnamoylphenethyl amide, two flavans, and ten flavonols and flavonol 3-O-glycosides were subsequently isolated from the extract. All constituents showed inhibitory activities while compounds 3, 8 and 11 (IC50 = 0.3, 1.0, and 0.6 MUM, respectively) were the most potent ones. The methanol extract also showed antioxidant activities in DPPH (IC50 = 76 MUg/ml) and FRAP assays (1.4 mmol ferrous ion equivalent/g extract). A total phenol content of 130 mg/g of the extract was determined by Folin-Ciocalteu reagent. CONCLUSION: This study shows that P. hyrcanicum contains phenolic compounds with in vitro activity that can be useful in the context of preventing or mitigating cellular damages linked to diabetic conditions. PMID- 23351721 TI - Association between use of beta-blockers and prostate cancer-specific survival: a cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. AB - BACKGROUND: We recently reported reduced prostate cancer (PCa)-specific mortality for beta-blocker users among patients receiving androgen-deprivation therapy in a health survey cohort including 655 PCa patients. Information on clinical characteristics was limited. OBJECTIVE: To assess the association between beta blockers and PCa-specific mortality in a cohort of 3561 prostate cancer patients with high-risk or metastatic disease, and to address potential confounding from the use of statins or acetylsalicylic acid (ASA). DESIGN, SETTING, AND PARTICIPANTS: Clinical information from all men reported to the Cancer Registry of Norway with a PCa diagnosis between 2004 and 2009 (n=24 571) was coupled with information on filled prescriptions between 2004 and 2011 from the Norwegian Prescription Database. Exclusion criteria were low- or intermediate-risk disease; planned radiotherapy or radical prostatectomy; initiation of beta-blocker, ASA, or statin use after diagnosis where applicable; missing information on baseline Gleason score, prostate-specific antigen level, T stage or performance status; and missing follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox proportional hazards modelling and competing risk regression modelling were used to analyse the effects of beta-blocker use on all-cause and PCa-specific mortality, respectively. Differences between beta-blocker users and nonusers regarding baseline clinical characteristics were assessed by the Wilcoxon-Mann Whitney U test, Pearson chi-square test, and Student t test. RESULTS AND LIMITATIONS: Median follow-up was 39 mo. beta-Blocker use was associated with reduced PCa mortality (adjusted subhazard ratio: 0.79; 95% confidence interval [CI], 0.68-0.91; p value: 0.001). The observed reduction in PCa mortality was independent of the use of statins or ASA. We observed no association with all cause mortality (adjusted hazard ratio: 0.92; 95% CI, 0.83-1.02). The main limitations of the study were the observational study design and short follow-up. CONCLUSIONS: beta-Blocker use was associated with reduced PCa-specific mortality in patients with high-risk or metastatic disease at the time of diagnosis. Our findings need validation from further observational studies. PMID- 23351723 TI - Application of spectroscopy in herbal metabolomics. PMID- 23351722 TI - Deep venous thrombosis and atypical antipsychotics: three cases report. AB - BACKGROUND: Deep venous Thrombosis is a serious, possible life threatening event which is often ignored in psychiatric Settings. PURPOSE: In this paper three cases of deep venous Thrombosis (DVT) following the use of olanzapine and risperidone are presented. METHODS: The data of Three patients was collected from hospital records. RESULTS: The patients were in good general physical health and had no personal or familial history of DVT. The patients were not overweight (BMI < 25) but they suffered from DVT after initiating risperidone and olanzapine. CONCLUSION: Risk of DVT exists in patients under treatment with atypical antipsychotics in spite of no pre existing risk factor. PMID- 23351724 TI - Adolescents' risk perceptions on mobile phones and their base stations, their trust to authorities and incivility in using mobile phones: a cross-sectional survey on 2240 high school students in Izmir, Turkey. AB - BACKGROUND: Use of mobile phones has rapidly risen among adolescents despite a lack of scientific certainty on their health risks. Risk perception is an important determinant of behavior, and studies on adolescents' risk perceptions of mobile phones or base stations are very scarce. This study aims to evaluate high school students' risk perceptions on mobile phones and base stations, their trust to authorities, their opinions regarding incivility while using mobile phones and to assess associated factors. METHODS: For this cross-sectional study, 2530 students were chosen with stratified cluster sampling among 20,493 high school students studying in Bornova district of Izmir, Turkey, among whom 2240 (88.5%) participated. Risk perceptions and opinions were questioned with a 5 point Likert scale for 24 statements grouped under four dimensions. The mean responses to the four dimensions were categorized as <3.5 (low) and >=3.5 (high) and the determinants were analyzed with logistic regression. RESULTS: Mean risk perception scores for the mobile phone, base station, trust to authority and incivility dimensions were 3.69 +/- 0.89, 4.34 +/- 0.78, 3.77 +/- 0.93, 3.16 +/- 0.93 and the prevalence of high risk perception was 65.1%, 86.7%, 66.2%, 39.7%, respectively. In the mobile phone dimension; students attending industrial technical high school had lower risk perceptions while female students, lower mothers' education groups and students not using mobile phones (OR = 2.82, 95% CI = 1.80-4.40) had higher risk perceptions. In the base station dimension girls had higher risk perceptions (OR = 1.68, 95% CI = 1.20-2.37). Girls and students attending industrial technical high school had significantly lower risk perception however 11-12th grade group perceived the risk higher (OR = 1.45 95% CI = 1.15-1.84) in the trust to authority dimension. For the incivility dimension, female students (OR = 1.44, 95% CI = 1.14-1.82), illiterate/only literate mothers (OR = 1.79, 95% CI = 1.04-2.75) and students not using mobile phones (OR = 2.50, 95% CI = 1.62-3.87) perceived higher risk. CONCLUSIONS: Understanding the effects of these determinants might aid in developing more effective educational interventions to specific subgroups on this topic. As debates on the health consequences of electromagnetic fields continue, it would be cautious to approach this issue with a preventive perspective. Efforts should be made to equalize the varying level of knowledge and to ensure that students are informed accurately. PMID- 23351725 TI - Chronic effects of exposure to a pharmaceutical mixture and municipal wastewater in zebrafish. AB - Pharmaceuticals and personal care products (PPCPs) are discharged in municipal wastewater. Effects in aquatic organisms exposed to individual pharmaceuticals in the laboratory have raised concerns regarding the environmental impacts of PPCPs, yet environmental exposures are always to complex mixtures. In this study, adult zebrafish (Danio rerio) showed significantly decreased embryo production after a 6 week exposure to a pharmaceutical mixture (MIX; 0.5 and 10MUgL(-1)) of acetaminophen, carbamazepine, gemfibrozil and venlafaxine and to diluted wastewater effluent (WWE; 5% and 25%). Atretic oocytes and altered ovarian histology were significantly increased in female zebrafish exposed to both concentrations of MIX or WWE, which indicates a direct effect on oocyte development that may account for reduced embryo production. Apoptosis within the thecal and granulosa cell layers was identified in female zebrafish with atresia. Exposures to MIX or WWE at both concentrations severely altered kidney proximal tubule morphology, but no histological impacts on other organs were observed. Exposure of embryos to MIX or WWE at the high concentration significantly increased the incidence of developmental abnormalities. Embryo mortality was elevated with exposure to the high concentration of MIX. These studies indicate that chronic exposure of fish to pharmaceutical mixtures and wastewater impacts reproduction and induces histopathological changes, similar to what we have previously seen with single compound exposures. These data suggest that fish populations exposed to pharmaceuticals discharged in wastewater are at risk of negative impacts to reproductive capacity and health. PMID- 23351726 TI - Cost-effectiveness of adding-on new antiepileptic drugs to conventional regimens in controlling intractable seizures in children. AB - BACKGROUND AND PURPOSE OF THE STUDY: Intractable seizures are a subgroup of epileptic disorders challenging the physicians' skills to become controlled. Showing resistance towards common pharmacotherapy, they demand newer antiepileptic drugs acquired at higher costs. 0.06% of children around the world are estimated to suffer from epilepsy and its consequences. The aim of the present study has been to evaluate the cost-effectiveness of these drugs in the treatment of intractable seizures in children. METHODS: Clinical and cost data were collected from medical and cost records preserved at a neurologist office and a referral pharmacy respectively. Based on the new AED which are accessible in Iran, regimens were categorized into eight groups. The first group consisting of conventional AEDs was considered as comparator and the effectiveness of other groups was compared with it. Incremental Cost-effectiveness Ratio (ICER) of adding-on each new antiepileptic drug was calculated in terms of Rials per consequence (Rls/consq) and compared with each other. Furthermore ICER of the regimens was compared with the GDP per capita (Gross Domestic Product) of the year (2010). RESULTS: the ICER of the adding-on regimens range from negative values for Gabapentin, Levetiracetam and Zonisamide to low values for Lamotrigine (~ 6.4 million Rials/consequence [mil Rls/consq]) and Oxcarbazepine (~7.7 mil Rls/consq) and followed by high values for Topiramate (~21 mil Rls/consq) and Vigabatrin (~43.7 mil Rls/consq) considering the three months of remaining on regimen. By increasing the limit of remaining time to six months, the previously mentioned regimens persist on negative values. However Oxcarbazepine (~28.7 mil Rls/consq) and Lamotrigine (~13.8 mil Rls/consq) show a steep increase. Topiramate (~23.6 mil Rls/consq) displays a less change. Opposite to other regimens, the ICER value of Vigabatrin (~17.26 mil Rls/consq) has shown an important increase. MAJOR CONCLUSIONS: Adding-on new antiepileptics to conventional regimens are cost-effective and justified considering the GDP per capita. PMID- 23351727 TI - "Pelvic: deferred"-have nongynecologists been right all along? PMID- 23351728 TI - The incidence of heterotopic ossification in hip arthroscopy. AB - PURPOSE: The purpose of this study was to assess the incidence of heterotopic ossification (HO) after hip arthroscopy. METHODS: Between July 2010 and July 2011, 83 patients underwent hip arthroscopy for various etiologies. We prospectively reviewed 50 consecutive hip arthroscopy procedures (31 male and 19 female patients; mean age, 36.7 years) with a mean follow-up of 29.56 weeks (range, 9 to 62 weeks) to assess the incidence of HO and its effect on function and clinical outcome. Preoperative and postoperative evaluation included general assessment by visual analog scoring, modified Harris Hip Score, Hip Outcome Score, and preoperative and postoperative radiographs. Heterotopic bone formation was assessed on radiographs at a minimum of 9 weeks from surgery with the Brooker classification. RESULTS: Of the patients, 22 (44%) had radiographic evidence of postoperative HO (15 male patients): 13 (26%) had Brooker stage 1, 5 (10%) had Brooker stage 2, and 4 (8%) had Brooker stage 3. HO appeared as early as 9 weeks after surgery. No significant difference was found in demographic data, surgery related data, or clinical and functional scores between patients with HO and patients without HO. No factor was found to significantly affect the incidence of HO after logistic regression. No distinct clinical manifestation was associated with the presence of HO. CONCLUSIONS: This study shows that the incidence of HO after hip arthroscopy may be underestimated. We could not find a contributing factor to the formation of HO. Although in most cases the presence of HO will have minimal or no clinical and functional significance, it should be sought at a minimum of 9 weeks postoperatively. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23351729 TI - Reliability of a new standardized measurement technique for reverse Hill-Sachs lesions in posterior shoulder dislocations. AB - PURPOSE: The purpose of this study was to determine whether standardized measurements are more reliable than mere estimation in determining the extent of the defect in reverse Hill-Sachs lesions. METHODS: Twelve patients with 13 reverse Hill-Sachs lesions and available computed tomographic scans were included in this study. Based on the computed tomographic scans, estimation and measurement of the defect size in reverse Hill-Sachs lesions using a novel standardized method were carried out twice by 6 observers (3 experts and 3 residents), with an interval of 3 months between observations. To assess and compare the reliability of the estimation of the defect size and the measurement of the defect size, intraclass correlation coefficients were computed. RESULTS: Estimation of the defect size showed a low interobserver reliability of 0.61 (95% confidence interval [CI], 0.38 to 0.83) and 0.47 (95% CI, 0.24 to 0.74) and a moderate intraobserver reliability of 0.71 (95% CI, 0.51 to 0.89). The estimations of the different observers showed statistically significant differences (P < .001). The standardized measurements reached high interobserver reliability (at least >=0.81) and excellent intraobserver reliability (at least >=0.88). Residents provided less reliable estimations compared with experts; however, they obtained similarly high reliability when applying the standardized measurements. CONCLUSIONS: The mere estimation of the size of reverse Hill-Sachs lesions showed poor reliability, raising the concern for potential overestimation or underestimation in clinical practice. Standardized measurements, which showed good reliability, should be used whenever analyzing the size of a reverse Hill Sachs defect. LEVEL OF EVIDENCE: Level IV, diagnostic case series. PMID- 23351730 TI - Does cast immobilization contribute to posterior stability after posterior cruciate ligament reconstruction? AB - PURPOSE: The purpose of this study was to confirm the contribution of long leg cast immobilization to posterior stability after reconstruction of isolated posterior cruciate ligament (PCL) injuries. METHODS: Of 84 patients who underwent arthroscopic PCL reconstruction between November 2006 and December 2009, 44 patients were randomly assigned to 2 groups and analyzed prospectively. For 22 patients (the cast group), long leg cast immobilization was applied until postoperative week 5 and then a 0 degrees locking brace was worn until week 12. Full weight bearing was allowed immediately after operation. For the other 22 patients (the brace group), only a 0 degrees locking brace was applied until postoperative week 12 without cast immobilization. Range of motion (ROM), clinical scores, Telos device (Telos, Marburg, Germany) posterior stress radiographic assessment results and International Knee Documentation Committee (IKDC) grades of both groups were analyzed preoperatively and at postoperative years 1 and 2. RESULTS: The mean preoperative side-to-side difference on Telos posterior stress radiographs was 11.3 +/- 2.5 mm in the cast group and 12.7 +/- 2.1 mm in the brace group, revealing no differences between the 2 groups (P = .743), but postoperatively the mean difference measured 2.5 +/- 1.9 mm and 4.8 +/ 2.4 mm, respectively, showing a significantly smaller difference in the cast group (P = .004); the improvement was 8.8 mm and 7.9 mm, respectively, and was statistically significant (P = .021). Preoperative IKDC grades were not different between the 2 groups (P > .05), but 2 years postoperatively, the cast group showed a significantly better distribution of grades (P = .012). The mean ROM, Lysholm scores, IKDC subjective scores, and Tegner scores 2 years postoperatively were not significantly different between the 2 groups (P > .05). CONCLUSIONS: The patients immobilized with long leg casts until 5 weeks after PCL reconstruction showed significantly better results in Telos posterior stress radiographs and distribution of IKDC grades 2 years postoperatively and did not show limited ROM when compared with the patients who wore braces only. However, IKDC subjective scores were not found to be different between the 2 groups. LEVEL OF EVIDENCE: Level I, prospective randomized comparative study. PMID- 23351731 TI - Therapeutic rescue of misfolded/mistrafficked mutants: automation-friendly high throughput assays for identification of pharmacoperone drugs of GPCRs. AB - Mutations cause protein folding defects that result in cellular misrouting of otherwise functional proteins. Such mutations are responsible for a wide range of disease states, especially among G-protein coupled receptors. Drugs which serve as chemical templates and promote the proper folding of these proteins are valuable therapeutic molecules since they return functional proteins to the proper site of action. Small molecules have been identified that are able to function as pharmacological chaperones or "pharmacoperones" and stabilize the correct conformations of their target proteins with high specificity. Most of these are also agonists or antagonists of the proteins of interest, complicating potential therapeutic use. This is due, in part, to the fact that the majority of these were discovered during high-throughput screening campaigns using assays designed to detect agonists and antagonists, rather than compounds which improve the trafficking of misrouted mutants. The assays described in this report are designed specifically to identify compounds which result in the reactivation and correct trafficking of misfolded gonadotropin releasing hormone receptor and vasopressin type 2 receptor mutants, rather than those which act as agonists directly. The system reported is a generalizable approach amenable to use in automated (robotic) high-throughput screening efforts and can be used to identify compounds which affect protein conformation without necessarily acting as direct agonists or antagonists. PMID- 23351733 TI - Single-molecule imaging technique to study the dynamic regulation of GPCR function at the plasma membrane. AB - The lateral diffusion of a G-protein-coupled receptor (GPCR) in the plasma membrane determines its interaction capabilities with downstream signaling molecules and critically modulates its function. Mechanisms that control GPCR mobility, like compartmentalization, enable a cell to fine-tune its response through local changes in the rate, duration, and extent of signaling. These processes are known to be highly dynamic and tightly regulated in time and space, usually not completely synchronized in time. Therefore, bulk studies such as protein biochemistry or conventional confocal microscopy will only yield information on the average properties of the interactions and are compromised by poor time resolution. Single-particle tracking (SPT) in living cells is a key approach to directly monitor the function of a GPCR within its natural environment and to obtain unprecedented detailed information about receptor mobility, binding kinetics, aggregation states, and domain formation. This review provides a detailed description on how to perform single GPCR tracking experiments. PMID- 23351732 TI - Trafficking of the follitropin receptor. AB - The follitropin or follicle-stimulating hormone receptor (FSHR) belongs to a highly conserved subfamily of the G protein-coupled receptor (GPCR) superfamily and is mainly expressed in specific cells in the gonads. As any other GPCR, the newly synthesized FSHR has to be correctly folded and processed in order to traffic to the cell surface plasma membrane and interact with its cognate ligand. In this chapter, we describe in detail the conditions and procedures used to study outward trafficking of the FSHR from the endoplasmic reticulum to the plasma membrane. We also describe some methods to analyze phosphorylation, beta arrestin recruitment, internalization, and recycling of this particular receptor, which have proved useful in our hands for dissecting its downward trafficking and fate following agonist stimulation. PMID- 23351734 TI - GPCR oligomerization and receptor trafficking. AB - The effects of oligomerization of G protein-coupled receptors (GPCRs) upon their trafficking around the cell are considerable, and this raises the potential of significant impact upon the use of existing pharmacological agents and the development of new ones. Herein, we describe a number of different techniques that can be used to study receptor dimerization/oligomerization and trafficking, beginning with a cellular system which allows the expression of two GPCRs simultaneously, one under inducible control. Subsequently, we describe means to visualize and monitor the movement of GPCRs within the cell, detect oligomerization by both resonance energy transfer and more traditional biochemical approaches, and to measure the internalization of GPCRs as part of the process of receptor regulation. PMID- 23351735 TI - beta-Arrestins and G protein-coupled receptor trafficking. AB - Arrestins are adaptor proteins that function to regulate G protein-coupled receptor (GPCR) signaling and trafficking. There are four mammalian members of the arrestin family, two visual and two nonvisual. The visual arrestins (arrestin 1 and arrestin-4) are localized in rod and cone cells, respectively, and function to quench phototransduction by inhibiting receptor/G protein coupling. The nonvisual arrestins (beta-arrestin1 and beta-arrestin2, a.k.a. arrestin-2 and arrestin-3) are ubiquitously expressed and function to inhibit GPCR/G protein coupling and promote GPCR trafficking and arrestin-mediated signaling. Arrestin mediated endocytosis of GPCRs requires the coordinated interaction of beta arrestins with clathrin, adaptor protein 2, and phosphoinositides such as PIP(2)/PIP(3). These interactions are facilitated by a conformational change in beta-arrestin that is thought to occur upon binding to a phosphorylated activated GPCR. In this chapter, we provide an overview of the reagents and techniques used to study beta-arrestin-mediated receptor trafficking. PMID- 23351736 TI - Tracking cell surface mobility of GPCRs using alpha-bungarotoxin-linked fluorophores. AB - GABA(B) receptors are G-protein-coupled receptors (GPCRs) that are activated by GABA, the principal inhibitory neurotransmitter in the central nervous system. Cell surface mobility of GABA(B) receptors is a key determinant of the efficacy of slow and prolonged synaptic inhibition initiated by GABA. Therefore, experimentally monitoring receptor mobility and how this can be regulated is of primary importance for understanding the roles of GABA(B) receptors in the brain, and how they may be therapeutically exploited. Unusually for a GPCR, heterodimerization between the R1 and R2 subunits is required for the cell surface expression and signaling by prototypical GABA(B) receptors. Here, we describe a minimal epitope-tagging method, based on the incorporation of an alpha bungarotoxin binding site (BBS) into the GABA(B) receptor, to study receptor internalization in live cells using a range of imaging approaches. We demonstrate how this technique can be adapted by modifying the BBS to monitor the simultaneous movement of both R1 and R2 subunits, revealing that GABA(B) receptors are internalized as heteromers. PMID- 23351737 TI - Regulatory mechanism of G protein-coupled receptor trafficking to the plasma membrane: a role for mRNA localization. AB - Trafficking and localization of G protein-coupled receptors (GPCRs) to the plasma membrane and its retention in the agonist-naive state are critically important for signaling by these receptors. Agonist-induced desensitization of activated GPCRs and their removal from the cell surface have been studied and reviewed extensively. However, less attention has been given to the regulatory mechanisms and different steps that control the trafficking of newly synthesized receptors to the plasma membrane. It is generally believed that the mRNAs encoding GPCRs are targeted to the endoplasmic reticulum by a cotranslational, signal-sequence recognition particle-dependent pathway that results in protein translation and translocation to the plasma membrane. In this chapter, we discuss the importance of cis-targeting elements and trans-recognition factors in GPCR mRNA translational silencing, trafficking, and localization within the cell and its importance in receptor trafficking to the plasma membrane. Knockdown of the critical trans-recognition factors (RNA-binding proteins) resulted in translation of GPCR mRNAs in the perinuclear region and the receptors failed to traffic to the plasma membrane. Thus, a new paradigm is emerging in GPCR trafficking that suggests a fundamental role for mRNA partitioning to specific cytoplasmic regions for efficient plasma membrane localization of the receptors. PMID- 23351738 TI - Dissecting trafficking and signaling of atypical chemokine receptors. AB - Atypical chemokine receptors are a distinct subset of chemokine receptors able to modulate immune responses by acting as chemokine decoy/scavengers or transporters. Intracellular trafficking properties sustained by Galphai independent signaling have emerged as a major determinant of their biological properties, which support continuous uptake, transport, and/or concentration, of the ligands. Here, we are providing methods to study both trafficking and signaling of this class of chemokine receptors focusing on the atypical chemokine receptor D6 that degrades inflammatory CC chemokines. PMID- 23351739 TI - Systematic and quantitative analysis of G protein-coupled receptor trafficking motifs. AB - Plasma membrane expression of G protein-coupled receptors (GPCRs) is a dynamic process balancing anterograde and retrograde trafficking. Multiple interrelated cellular processes determine the final level of cell surface expression, including endoplasmic reticulum (ER) export/retention, receptor internalization, recycling, and degradation. These processes are highly regulated to achieve specific localization to subcellular domains (e.g., dendrites or basolateral membranes) and to affect receptor signaling. Analysis of potential ER trafficking motifs within GPCRs requires careful consideration of intracellular dynamics, such as protein folding, ER export and retention, and glycosylation. This chapter presents an approach and methods for qualitative and quantitative assessment of these processes to aid in accurate identification of GPCR trafficking motifs, utilizing the analysis of a hydrophobic extracellular trafficking motif in alpha2C adrenergic receptors as a model system. PMID- 23351740 TI - Identification of endoplasmic reticulum export motifs for G protein-coupled receptors. AB - Coat protein complex II (COPII) vesicle-mediated protein export from the endoplasmic reticulum (ER) can be controlled by linear, independent motifs embedded within the cargo. ER export motifs directly interact with selective components of COPII vesicles and enhance cargo recruitment onto COPII vesicles. Moreover, ER export motifs are able to confer their transport abilities to other proteins. We have recently identified a novel ER export motif for alpha(2B) adrenergic receptor (alpha(2B)-AR). This motif selectively interacts with Sec24C/D isoforms of COPII vesicles and facilitates alpha(2B)-AR export from the ER as well as transport to the cell surface. This motif can also mediate CD8 glycoprotein transport. These studies indicate that ER export of nascent G protein-coupled receptors (GPCRs) may be directed by specific codes that mediate receptor interaction with the ER-derived COPII vesicles. In this chapter, I discuss experimental approaches to identify ER export motifs for GPCRs by using alpha(2B)-AR as a model. PMID- 23351741 TI - Amino acid residues of G-protein-coupled receptors critical for endoplasmic reticulum export and trafficking. AB - Analysis of the structural features of rhodopsin-type G-protein-coupled receptors (GPCRs) revealed the existence of an additional alpha-helix, termed helix 8, in the C-terminal tail. Furthermore, these GPCRs were determined to possess several conserved residues in their transmembrane domains. The functional deficiencies of receptors in which these domains or residues have been mutated have not been examined in living cells due to their accumulation in the endoplasmic reticulum (ER), although the ligand affinities of these receptors have been tested in membrane preparations. Recent studies have demonstrated that ER-accumulated receptors are effectively exported from ER using membrane permeable ligands as pharmacological chaperones. Here, we identified several residues of the platelet activating factor receptor and leukotriene B(4) type-II receptor that are crucial for export from ER. Moreover, we used their specific ligands as pharmacological chaperones to traffic ER-accumulated GPCRs to the cell surface in order to examine the functional deficiencies of each mutant receptor. Here, we introduce the novel technique of site-specific N-terminal labeling of cell surface proteins in living cells with Sortase-A, a transpeptidase isolated from Staphylococcus aureus, to evaluate the trafficking of receptors after agonist stimulation. PMID- 23351743 TI - Hetero-oligomerization and specificity changes of G protein-coupled purinergic receptors: novel insight into diversification of signal transduction. AB - The formation of homo- and hetero-oligomers between various G protein-coupled receptors (GPCRs) has been demonstrated over the past decade. In most cases, GPCR heterodimerization increases the diversity of intracellular signaling. GPCR-type purinergic receptors (adenosine and P2Y receptors) are actively reported to form hetero-oligomers with each other, with GPCRs belonging to the same group (type 1, rhodopsin-like), and even with GPCRs from another group. This chapter describes common strategies to identify dimerization of purinergic receptors (coimmunoprecipitation, bioluminescence resonance energy transfer (BRET), and immunoelectron microscopy) and to assess the alteration of their pharmacology (ligand binding, intracellular cAMP, and intracellular Ca(2+) assays). We have reported dimerization of purinergic receptors using these strategies in transfected human embryonic kidney 293T cells and native brain tissue. Our data suggest that homo- and hetero-oligomerization between purinergic receptors exert unique pharmacology in this receptor group. According to these discoveries, heterodimerization is likely to be employed for the "fine-tuning" of purinergic receptor signaling. PMID- 23351742 TI - G-protein-coupled heteromers: regulation in disease. AB - Over the past decade, an increasing number of studies have shown that G-protein coupled receptors including opioid and cannabinoid receptors associate to form heteromers. Moreover, G-protein-coupled receptor heteromerization leads to the modulation of the binding, signaling, and trafficking properties of individual receptors. Although very little information is available about the physiological role of receptor heteromers, some studies have shown that the levels of some heteromers are upregulated in disease states such as preeclamptic pregnancy, schizophrenia, Parkinson's, ethanol-induced liver fibrosis, and development of tolerance to morphine. The recent generation of antibodies that selectively recognize distinct heteromers and, of peptides that selectively disrupt them, have started to elucidate the contribution of heteromers to the disease state. Here, we describe the methods for the generation of heteromer-selective antibodies and elucidation of their levels and localization under normal and pathological conditions. PMID- 23351744 TI - Bimolecular fluorescence complementation analysis of G protein-coupled receptor dimerization in living cells. AB - Emerging evidence indicates that G protein-coupled receptor (GPCR) signaling is mediated by receptor-receptor interactions at multiple levels. Thus, understanding the biochemistry and pharmacology of those receptor complexes is an important part of delineating the fundamental processes associated with GPCR mediated signaling in human disease. A variety of experimental approaches have been used to explore these complexes, including bimolecular fluorescence complementation (BiFC) and multicolor BiFC (mBiFC). BiFC approaches have recently been used to explore the composition, cellular localization, and drug modulation of GPCR complexes. The basic methods for applying BiFC and mBiFC to study GPCRs in living cells are the subject of the present chapter. PMID- 23351745 TI - G protein-coupled receptor heterodimerization in the brain. AB - G protein-coupled receptors (GPCRs) play critical roles in cellular processes and signaling and have been shown to form heteromers with diverge biochemical and/or pharmacological activities that are different from those of the corresponding monomers or homomers. However, despite extensive experimental results supporting the formation of GPCR heteromers in heterologous systems, the existence of such receptor heterocomplexes in the brain remains largely unknown, mostly because of the lack of appropriate methodology. Herein, we describe the in situ proximity ligation assay procedure underlining its high selectivity and sensitivity to image GPCR heteromers with confocal microscopy in brain sections. We describe here how the assay is performed and discuss advantages and disadvantages of this method compared with other available techniques. PMID- 23351746 TI - Experimental strategies for studying G protein-coupled receptor homo- and heteromerization with radioligand binding and signal transduction methods. AB - Before the molecular biology era, functional experiments on isolated organs and radioligand binding and biochemical experiments on animal tissues were widely used to characterize G protein-coupled receptors (GPCRs). The introduction of recombinant cell lines expressing a single GPCR type has been a big step forward for studying both drug-receptor interactions and signal transduction. Before the introduction of the concept of receptor oligomerization, all data generated were attributed to the interaction of drugs with receptor monomers. Now, considerable data must be reinterpreted in light of receptor homo- and heteromerization. In this chapter, we will review some of the methods used to study radioligand binding and signal transduction modifications induced by GPCR homo- and heteromerization. PMID- 23351747 TI - Analysis of GPCR dimerization using acceptor photobleaching resonance energy transfer techniques. AB - The ability of GPCRs to assemble into multimeric complexes is one of the most recently studied and discussed topics for many reasons, including the possibility that GPCR assemblies show a distinct pharmacological profile offering an innovative avenue for the drug synthesis. In addition, the possible differential coupling of monomeric versus multimeric GPCRs to G proteins and other downstream partners, as well as the signaling, the regulation through desensitization and internalization, and the subcellular localization can well represent additional factors that contribute to GPCR-mediated physiopathological states. The standard biochemical techniques used to identify GPCR interactions, such as coimmunoprecipitation, have obvious limitations owing to the use of nonphysiological buffers and detergents that disrupt the natural cell environment and biological interactions and preclude the analysis of subcellular localization and compartmentalization. In the past decade, new biophysical proximity assays based on the resonance energy transfer (RET) between two chromophores allow the study of dimerization in intact living cells, thus proving more information on GPCR physiological roles. In this chapter, we detail the application of two RET techniques based on fluorescence (FRET) and bioluminescence (BRET) to the study of GPCR dimerization and describe the results that can be obtained. PMID- 23351748 TI - Techniques for the discovery of GPCR-associated protein complexes. AB - Biosynthesis and function of G protein-coupled receptors (GPCR) are accompanied by multiple GPCR-associated protein complexes. Despite considerable sequence diversity, all GPCRs are assumed to share a common 7-transmembrane-spanning architecture giving rise to an extracellular, intracellular, and transmembrane interface for the interaction with protein partners recognizing either linear or structural receptor epitopes. Different purification techniques have been developed in the past to identify GPCR-associated proteins other than classically known interacting proteins like heterotrimeric G proteins and beta-arrestins. These techniques use either entire receptors or receptor subdomains as baits. We are presenting here two proteomic approaches developed in our laboratory to purify protein complexes interacting either with receptor subdomains from cell or tissue lysates or with entire receptors from intact cells. PMID- 23351750 TI - Modern methods to investigate the oligomerization of glycoprotein hormone receptors (TSHR, LHR, FSHR). AB - As for other GPCRs, the oligomerization of glycoprotein hormone receptors (GPHRs) appears as critical event for receptor function. By means of modern techniques based on the BRET or FRET principle, GPHR oligomerization has been reported to explain several physiological and pathological conditions. In particular, the presence of oligomers was demonstrated not only in in vitro heterologous systems but also in in vivo tissues, and GPHR homodimerization appears associated with strong negative cooperativity, thus suggesting that one hormone molecule may be sufficient for receptor dimer stimulation. In addition, oligomerization has been reported to occur early during the posttranslational maturation process and to be involved in the dominant negative effect exerted by loss-of-function TSH receptor (TSHR) mutants, that are prevalently retained inside the cell, on the surface expression of wild-type receptors. This molecular mechanism thus explains the dominant inheritance of certain forms of TSH resistance. Here, we provide the description of the methods used in the original BRET, FRET, and HTRF-RET experiments. PMID- 23351749 TI - Expression, purification, and analysis of G-protein-coupled receptor kinases. AB - G-protein-coupled receptor (GPCR) kinases (GRKs) were first identified based on their ability to specifically phosphorylate activated GPCRs. Although many soluble substrates have since been identified, the chief physiological role of GRKs still remains the uncoupling of GPCRs from heterotrimeric G-proteins by promoting beta-arrestin binding through the phosphorylation of the receptor. It is expected that GRKs recognize activated GPCRs through a docking site that not only recognizes the active conformation of the transmembrane domain of the receptor but also stabilizes a more catalytically competent state of the kinase domain. Many of the recent gains in understanding GRK-receptor interactions have been gleaned through biochemical and structural analysis of recombinantly expressed GRKs. Described herein are current techniques and procedures being used to express, purify, and assay GRKs in both in vitro and living cells. PMID- 23351751 TI - Methods in Enzymology. G protein coupled receptors trafficking and oligomerization. Preface. PMID- 23351753 TI - From small things, quantum leaps. PMID- 23351752 TI - Primary cilia utilize glycoprotein-dependent adhesion mechanisms to stabilize long-lasting cilia-cilia contacts. AB - BACKGROUND: The central tenet of cilia function is sensing and transmitting information. The capacity to directly contact extracellular surfaces would empower primary cilia to probe the environment for information about the nature and location of nearby surfaces. It has been well established that flagella and other motile cilia perform diverse cellular functions through adhesion. We hypothesized that mammalian primary cilia also interact with the extracellular environment through direct physical contact. METHODS: We identified cilia in rod photoreceptors and cholangiocytes in fixed mouse tissues and examined the structures that these cilia contact in vivo. We then utilized an MDCK cell culture model to characterize the nature of the contacts we observed. RESULTS: In retina and liver tissue, we observed that cilia from nearby cells touch one another. Using MDCK cells, we found compelling evidence that these contacts are stable adhesions that form bridges between two cells, or networks between many cells. We examined the nature and duration of the cilia-cilia contacts and discovered primary cilia movements that facilitate cilia-cilia encounters. Stable adhesions form as the area of contact expands from a single point to a stretch of tightly bound, adjacent cilia membranes. The cilia-cilia contacts persisted for hours and were resistant to several harsh treatments such as proteases and DTT. Unlike many other cell adhesion mechanisms, calcium was not required for the formation or maintenance of cilia adhesion. However, swainsonine, which blocks maturation of N-linked glycoproteins, reduced contact formation. We propose that cellular control of adhesion maintenance is active because cilia adhesion did not prevent cell division; rather, contacts dissolved during mitosis as cilia were resorbed. CONCLUSIONS: The demonstration that mammalian primary cilia formed prolonged, direct, physical contacts supports a novel paradigm: that mammalian primary cilia detect features of the extracellular space, not just as passive antennae, but also through direct physical contact. We present a model for the cycle of glycoprotein-dependent contact formation, maintenance, and termination, and discuss the implications for potential physiological functions of cilia-cilia contacts. PMID- 23351754 TI - Third molar uncertainty. PMID- 23351755 TI - Infected facial tissue fillers. PMID- 23351756 TI - Lessons from Penn State. PMID- 23351757 TI - Infected facial tissue fillers. PMID- 23351758 TI - Radiographic assessment of changes in articular tubercle after Dautrey's procedure. AB - PURPOSE: The aim of this retrospective study was to evaluate the increase in height and change in position of neo-articular tubercle in cases treated by Dautrey's procedure. METHOD: 10 cases of Tempromandibular joint (TMJ) disorders satisfying the inclusion criteria were included in this study, out of which 8 had bilateral chronic recurrent dislocations (CRD) and remaining 2 were suffering from bilateral symptomatic TMJ subluxations. Clinical and radiographic finding were recorded. Bilateral Dautrey's procedure was done under general anaesthesia (GA). Post operative clinical findings and radiographic parameters were compared. RESULTS: Data analysis showed mean age in this study group was 40.9 years. Out of 10 patients 7 were females and 3 males.The procedure resulted in statically significant stable decrease in mouth opening after 12 months. In radiological evaluation using orthopantomograph (OPG), average increase in articular tubercle height was 3.65 mm on right side and 3.52 mm on left side. The mean anterior shift of articular tubercle lowest point was 4.56 mm on right side and 4.51 mm on left side which were statically highly significant. CONCLUSION: Dautrey's procedure is simple, effective procedure to prevent anterior excursion of condyles. In this study it was found that down fractured zygomatic arch significantly increases the articular tubercle height and relocates the lowest point anteriorly thereby preventing excessive anterior excursion of condyles. PMID- 23351759 TI - Alveolar distraction osteogenesis for dental implant rehabilitation following fibular reconstruction: a case series. AB - OBJECTIVE: Alveolar distraction osteogenesis (ADO), a novel bone augmentation technique, is gaining acceptance in restoring the vertical bone discrepancy between the transplanted graft and the residual alveolar bone after mandibular reconstruction. This case series presents the outcomes of ADO in fibula reconstructed mandibles rehabilitated with dental implants, with an emphasis on clinical indications, surgical protocol, clinical outcomes, histologic evidence, and complications. MATERIALS AND METHODS: Five patients underwent fibula distraction procedures after undergoing mandibular reconstruction with a vascularized fibula bone graft. The indication for the application of ADO was for the correction of the vertical discrepancy between the top of the reconstructed fibula and the adjacent alveolar crest to achieve adequate vertical bone height before implant placement. RESULTS: The mean vertical bone height achieved was 13.58 mm. Twenty-two dental implants were placed in 5 patients. All patients were rehabilitated with implant-supported prostheses. Bone biopsies showed the distracted area was filled with newly formed, bony trabeculae between the transported fibula and the basal segments. The most common complication was transient infection around the distractor rod. CONCLUSIONS: ADO can be performed on fibula-reconstructed mandibles to achieve the restoration of alveolar height, which then can be rehabilitated with dental implant-supported prostheses. The procedure has a minor risk of infection associated with the distractor rod, which does not compromise the bone regeneration from distraction. Patients with mandibles reconstructed with fibulas can attain dental implant rehabilitation with ADO, achieving good esthetic and occlusal outcomes. PMID- 23351760 TI - Do angulated implants increase the amount of bone loss around implants in the anterior maxilla? AB - PURPOSE: The aim of this study was to evaluate the relation between angulated implants and the bone loss around implants in the anterior maxilla. MATERIALS AND METHODS: The subjects studied had a missing tooth in the anterior maxilla and a bone deficiency that required restoration with an angulated dental implant. After mounting the casts on the articulator, the amount of direction was measured with a facebow by calculating the difference between the mean buccopalatal angulation of the 2 adjacent natural teeth and the buccopalatal angulation of the implant abutment to the occlusal plane. Radiography was performed in each patient immediately after loading and repeated a minimum of 36 months after loading. RESULTS: Fifty-eight subjects who received delayed-loading angulated implants were studied. The results showed that the mean implant angulation was 15.2 degrees and the mean bone resorption was 0.87 mm. Analysis of the data showed a significant correlation between implant follow-up time and bone loss. No correlation was seen between the implant angulation and bone loss. An assessment of predictive factors showed a relation between the implant type and bone loss. The follow-up time had a significant effect on bone loss. The implant angulation did not change bone resorption on the mesial and distal surfaces of the implants. CONCLUSIONS: The angulation of implants was not associated with an increased risk for bone loss, and angulated implants may be a satisfactory alternative to vertical implants to avoid grafting procedures. The type of implant may be an important factor that affects bone resorption, although follow-up time was the strongest predictive factor. PMID- 23351761 TI - The 7-hole angle plate for mandibular angle fractures. AB - PURPOSE: To evaluate the 7-hole angle plate for open reduction, internal fixation of mandibular angle fractures when the Champy technique is inadequate and more rigid or semirigid fixation is beneficial and to provide rational indications for the choice of the 7-hole angle plate. PATIENTS AND METHODS: Retrospective evaluation of 10 patients selected at Parkland Memorial Hospital over a 2-year period when the 7-hole angle plate stabilized their angle fracture. Patients were evaluated for postoperative complications including pain, malocclusion, and infection. RESULTS: All 10 patients had sufficient follow-up for inclusion in this retrospective study. Correct placement of the 7-hole angle plate, easily accomplished with adequate assistance, produced no reportable postoperative complications. CONCLUSION: The 7-hole angle plate is a good first option when more rigid or semirigid fixation is required, and the best fallback when the Champy technique is ineffective. PMID- 23351762 TI - Comparative finite element analysis of the biomechanical stability of 2.0 fixation plates in atrophic mandibular fractures. AB - PURPOSE: The objective of the present study was to conduct a computational, laboratory-based comparison of the biomechanical stability of 2.0 fixation locking plates with different profiles in Class III atrophic mandibular fractures using 3-dimensional finite element analysis. MATERIALS AND METHODS: Three dimensional finite element models simulating Class III atrophic mandibular fractures were constructed. The models were divided into 4 groups according to plate thickness (1.0, 1.5, 2.0, and 2.5 mm). Fractures were simulated in left mandibular bodies, and 3 locking screws were used on each side of each fracture for fixation. Bite forces of approximately 63 N were simulated in the incisor and molar regions of the mandibles in finite element models. RESULTS: The level of compressive strain on the bone around the screw was within the physiological limit. No significant difference was observed in the displacement of bone segments in the fracture region. Von Mises stress was higher during simulated bites in the molar region for plates with thicknesses of 1.0 mm. Plate tension values were below the level required for permanent deformation or fracture in all models. The 2.5-mm-thick plate presented better biomechanical performance than all other plates. The 2.0-mm-thick plate also showed satisfactory results and adequate safety limits. CONCLUSION: Large-profile (2.0-mm-thick) locking plates showed better biomechanical performance than did 1.0- and 1.5-mm-thick plates and can be considered an alternative reconstruction plate for the treatment of Class III atrophic mandibular fractures. PMID- 23351763 TI - Accuracy of predicting the duration of a surgical operation. AB - PURPOSE: The ability to predict how long a particular operation will take is important for maintaining operating room efficiency. The purpose of this study was to determine how accurate oral and maxillofacial surgeons (OMSs) can be in making this determination. MATERIALS AND METHODS: Three experienced OMSs predicted their operating times for various operations; these predictions were compared with the actual times. The cases were then grouped into those with accurate predictions and those with overestimated and underestimated times, and the operative reports were reviewed for possible operation trends or other contributing factors. RESULTS: In the 100 cases analyzed, the surgeons correctly estimated operating times 26% of the time, overestimated 42% of the time, and underestimated 32% of the time. In the 42 overestimated times, 10 cases involved multiple tooth extractions or removal of impacted third molars, and 8 cases involved orthognathic surgery. In the 32 underestimated cases, 7 involved orthognathic surgery and 8 involved the open reduction of fractures. The 26 accurately estimated cases involved 7 cases of multiple tooth extractions or impacted third molar removal and 5 cases of arthroscopic temporomandibular joint lysis and lavage. CONCLUSIONS: Although operating times need to be used for scheduling purposes, they can be highly unpredictable. Surgeons need to constantly analyze their predictions for confounding factors in order to improve their accuracy. PMID- 23351764 TI - Custom-made implant for maxillofacial defects using rapid prototype models. PMID- 23351765 TI - Navigation-assisted Le Fort I osteotomy with midpalatal split to treat compressive pathologies of the craniovertebral junction. AB - This report describes the management of the case of an 11-year-old girl with serious compressive pathology of the craniocervical junction using a navigation guided Le Fort I level maxillotomy and midline split. In this pediatric case, image guidance significantly enhanced intraoperative orientation and helped to determine the correct location of the horizontal osteotomy lines at the Le Fort I level. PMID- 23351766 TI - Use of superiorly based vertical rectus abdominis myocutaneous flap for the correction of costal osteomyelitis at the pectoralis major myocutaneous flap donor site. PMID- 23351767 TI - Maxillary reconstruction with bone transport distraction and implants after partial maxillectomy. AB - Maxillary and mandibular bone defects can result from injury, congenital defect, or accident, or as a consequence of surgical procedures when treating pathology or defects affecting jaw bones. The glandular odontogenic cyst is an infrequent type of odontogenic cyst that can leave a bony defect after being treated by aggressive surgical means. First described in 1987 by Padayachee and Van Wyk, it is a potentially aggressive entity, having a predisposition to recur when treated conservatively, with only 111 cases having been reported hitherto. Most reports emphasize its clinical, radiographic, and histologic features, including a few considerations on rehabilitation for these patients. The aim of this article is to present the case of a 24-year-old male patient who, in 2001, was diagnosed with a glandular odontogenic cyst and to focus on the surgical approach and rehabilitation scheme. We performed an anterior partial maxillectomy. The osseous defect was treated using bone transport distraction. Dental and occlusal rehabilitation was achieved with titanium implants over transported bone and an implant-supported overdenture. A 9-year follow-up shows no evidence of recurrence of the pathology, adequate shape and amount of bone, functional occlusal and dental rehabilitation, and patient's satisfaction. PMID- 23351768 TI - Marginal mandibulectomy for lower gingival carcinoma with a cheek-splitting transbuccal approach and reconstruction by buccal fat pad flap: a case report. PMID- 23351769 TI - Long-term results of implants immediately placed into extraction sockets grafted with beta-tricalcium phosphate: a retrospective study. AB - PURPOSE: The aim of this 10 year retrospective study was to evaluate the crestal bone loss around immediate implant placed in tricalcium phosphate (TCP) grafted extraction sockets MATERIALS AND METHODS: Data were collected from files of 58 patients (33 females, 25 males, average age 54.78 years) undergoing immediate implant placement into fresh extraction socket with or without the use of TCP (Cerasorb, Curasan AG, Kleinostheim, Germany) grafting. After implant placement, horizontal gaps larger than 1.5 mm between the implant surface and the bony plate were grafted with TCP without the use of a membrane, while smaller gaps were not grafted. Two hundred fifty-four implants were inserted: 79 were placed immediately with the use of beta-TCP as grafting material (group A), 175 were placed in healed extraction sites, with 61 implants placed with the use of beta TCP graft material (group B), and 114 implants were placed without any grafting material (group C). Bone loss recordings were performed using periapical radiography. Measurements were performed from the neck of the implant to level of the surrounding bone in the vertical dimension. RESULTS: No implant was lost during the follow-up period. Statistical analysis showed no correlation between implant placement timing (delayed or immediate), the use of bone graft, and extent of bone loss. CONCLUSION: The use of TCP (Cerasorb) as a grafting material during immediate implant placement allowed no bone loss in 72.1% of the implants, which was very similar to the nongrafted cases for which implants were placed in favorable conditions. PMID- 23351770 TI - Biomechanical evaluation of undersized drilling on implant biomechanical stability at early implantation times. AB - PURPOSE: The present study evaluated the effect of different drilling dimensions (undersized, regular, and oversized) in the insertion and removal torques of dental implants in a beagle dog model. METHODS: Six beagle dogs were acquired and subjected to bilateral surgeries in the radii 1 and 3 weeks before euthanasia. During surgery, 3 implants, 4 mm in diameter by 10 mm in length, were placed in bone sites drilled to 3.2 mm, 3.5 mm, and 3.8 mm in final diameter. The insertion and removal torque was recorded for all samples. Statistical analysis was performed by paired t tests for repeated measures and by t tests assuming unequal variances (all at the 95% level of significance). RESULTS: Overall, the insertion torque and removal torque levels obtained were inversely proportional to the drilling dimension, with a significant difference detected between the 3.2 mm and 3.5 mm relative to the 3.8 mm groups (P < 0.03). Although insertion torque removal torque paired observations was statistically maintained for the 3.5 mm and 3.8 mm groups, a significant decrease in removal torque values relative to insertion torque levels was observed for the 3.2 mm group. A different pattern of healing and interfacial remodeling was observed for the different groups. CONCLUSIONS: Different drilling dimensions resulted in variations in insertion torque values (primary stability) and stability maintenance over the first weeks of bone healing. PMID- 23351771 TI - Hyposalivation: the roles of radioactive iodine and stapes surgery. AB - PURPOSE: The aim of this study is to call attention to the role that radioactive iodine ((131)I) and stapes surgery may play in causing hyposalivation. MATERIALS AND METHODS: The manner in which (131)I and stapes surgery can cause salivary damage was reviewed. A case report is presented to illustrate the involved pathophysiology. RESULTS: The case report clearly shows the significant injury to the parotid glands caused by the (131)I. However, subjective symptoms of oral dryness only developed after injury to the chorda tympani nerve (CTN) during stapes surgery. CONCLUSIONS: The loss of function of both parotid glands after (131)I therapy for thyroid cancer was initially compensated by the secretions of the more radiation-resistant submandibular and sublingual salivary glands (SMSG/SLSG). Damage to the CTN's secretory fibers in one SMSG/SLSG complex led to subjective oral dryness by accentuating an existing objective hyposalivation. PMID- 23351772 TI - Long-term clinical outcome analysis of poly-methyl-methacrylate cranioplasty for large skull defects. AB - PURPOSE: The goal of secondary cranioplasty is permanent cerebral protection in an esthetically acceptable fashion. Reconstruction of cranial defects can be performed with several different materials. Alloplastic materials, such as preformed methyl-methacrylate (PMMA) cranioplasties, are an alternative frequently used at our institution. This retrospective analysis was designed to review the outcomes of PMMA cranioplasty for skull defect reconstruction. MATERIALS AND METHODS: Seventy consecutive patients who had 78 PMMA cranioplasties placed from 2003 through 2010 were identified. Mechanism of injury, location of cranioplasty, type of original repair, postoperative complications, and follow-up time were reviewed. RESULTS: Of the 70 patients, 6 patients had failure and removal of their original PMMA cranioplasty and reinsertion of another, and 2 patients had failure and removal of 2 cranioplasties with replacement of a third, creating a total of 78 PMMA cranioplasties placed. The predominant mechanism of injury was trauma (64%). The most frequent postoperative complication was infection (13%). With the exception of the 2 patients with implant exposure, no patients reported an unacceptable cosmetic result. An overall complication rate of 24% was seen. CONCLUSIONS: The results of previous studies have shown that infection and complication rates of cranioplasties accomplished with bone cement are substantially higher, that titanium-based implants may obscure follow-up imaging for tumor patients, and that the outcomes regarding hydroxyapatite-based ceramics, although similar to PMMA, are associated with a much higher cost. PMMA remains a cost-effective and proven method to repair cranial defects that fulfills the goals of cranial reconstruction for skull defects. PMID- 23351773 TI - Guide for a bone-cutting line in intraoral vertical ramus osteotomy using an elastic thread connected to two sigmoid retractors. PMID- 23351774 TI - Endoscopically assisted intraoral modified Le Fort II type midfacial advancement using piezoelectric surgery and an intraoperative RED system. AB - PURPOSE: The Le Fort II midfacial advancement appears to be an effective surgical method for the treatment of severe midfacial-nose hypoplasia with a skeletal class III malocclusion, which is usually combined with syndromic midfacial anomalies. However, the conventional surgical method requires the coronal approach, including a coronal incision, together with other surgical approaches, such as an intraoral incision. Therefore, surgeons often hesitate to propose this type of osteotomy, even for patients who develop severe nonsyndromic midfacial nose hypoplasia. This report presents a new surgical approach for performing a safe Le Fort II osteotomy for nasomaxillary, midfacial corrective advancement via a solely intraoral approach. MATERIALS AND METHODS: Surgery was performed with endoscopically assisted piezoelectric surgery. The osteotomized nasomaxillary Le Fort II segment was successfully protracted without aggressive down-fracture procedures with the sole intraoperative use of a rigid external distraction (RED) system, followed by internal rigid fixation, and the subsequent removal of the RED system. Seven patients (all patients were nonsyndromic, but 2 had cleft lip and palate, and an average age of 19.9 years) were included in this study. RESULTS: The degrees of midfacial advancement at the base of nasal bone (the top edge of the modified Le Fort II segment) that was osteotomized and at maxillary point A was 8.3 mm (range 5.8 mm to 10.5mm) and 8.5 mm (range 5.9 mm to 9.8 mm), respectively. CONCLUSION: This new method less invasively facilitates safe, secure, and ideal nasomaxillary midfacial protraction to yield a satisfactory resultant facial profile and favorable occlusion in patients with severe midfacial-nose hypoplasia and skeletal class III malocclusions. PMID- 23351775 TI - Serial ultrasound findings associated with early liver transplantation after Kasai portoenterostomy in biliary atresia. AB - AIM: To investigate the ultrasound findings associated with early liver transplantation (LT) after Kasai portoenterostomy (Kasai) in children with biliary atresia (BA). MATERIALS AND METHODS: Children with BA (n = 30) who underwent Kasai were classified into early LT group (n = 17, LT within 1 year after Kasai) and Kasai alone group (n = 13, alive with their native livers). Serial ultrasound (baseline and follow-up before LT or post-Kasai 1 year) images were reviewed to investigate significant ultrasound findings related to early LT using both univariate and multivariate models. Images were reviewed focusing on the hepatic artery diameter, portal vein diameter, and signs of portal hypertension. RESULTS: The hepatic artery diameters in the early LT group were significantly larger than those in the Kasai alone group both at baseline (p = 0.007) and follow-up ultrasound (p < 0.001). The portal vein diameters on follow up ultrasound were smaller in the early LT group than the Kasai alone group (p < 0.001). On multivariate analysis, baseline hepatic artery diameter (hazard ratio, 20.4; 95% confidence interval, 3.7-110.6; p < 0.001) and the presence of splenomegaly at follow-up ultrasound (17.7; 2.6-121.8; p = 0.004) were significant predictors associated with early LT. The optimal cut-off value of the baseline hepatic artery diameter was 1.9 mm (82% sensitivity and 77% specificity). CONCLUSION: Enlarged hepatic artery at baseline ultrasound and the presence of splenomegaly at follow-up ultrasound were associated with early LT after Kasai in children with BA. PMID- 23351776 TI - Post-processing applications in thoracic computed tomography. AB - The rapid evolution of multidetector computed tomography (MDCT) and the introduction of dual-energy CT (DECT) have been paralleled by an unprecedented advancement in post-processing techniques. This has provided complementary methods of two- and three-dimensional visualization of the airways and lung parenchyma, many of which are easily available and not too time-consuming. In addition, advanced imaging has paved the way for methods of quantification of disease that may have a role to play in monitoring chronic obstructive pulmonary disease (COPD) and interstitial lung disease. Computer-aided detection also continues to be explored in lung cancer and pulmonary embolism detection. However, many of these techniques have not yet found widespread adoption in clinical practice. In this article, we review the imaging techniques (used in both single-energy and DECT) that can benefit from post-processing, describe the various post-processing tools available, and consider their clinical application with specific reference to COPD, diffuse lung disease, lung cancer, and pulmonary embolism. PMID- 23351777 TI - Nocardiosis in solid-organ transplant recipients: spectrum of imaging findings. AB - Nocardiosis is an infrequent but severe infection that primarily affects the lung and thence is able to produce disseminated disease. Prompt diagnosis of pulmonary and disseminated nocardiosis is of utmost importance in solid-organ transplant recipients to reduce mortality. Knowledge of the different radiological manifestations in the appropriate clinical setting is key to successful management of these patients. The aim of this review is to describe the radiological features of nocardiosis in immunosuppressed patients, particularly in solid-organ transplant recipients. PMID- 23351778 TI - Differences among array, fast array, and high-definition scan modes in bone mineral density measurement at dual-energy x-ray absorptiometry on a phantom. PMID- 23351779 TI - Determinants in adolescence for adult sickness absence in women and men: a 26 year follow-up of a prospective population based cohort (Northern Swedish cohort). AB - BACKGROUND: To date little is known regarding how factors measured in adolescence predict sickness absence in adulthood, and whether different patterns of factors exist for women and men that could contribute to an explanation of adult gender differences in sickness absence. METHODS: All pupils in the last year of compulsory school in the municipality of Lulea with complete information from surveys (questionnaires) in 1981 and 1983 (compulsory and upper-secondary schooling; 16 and 18 years of age, N=719) were followed with register data on medically certified sickness absence (1993-2007). Generalised linear models were applied to calculate Risk Ratios with 95% Confidence Intervals (CI) comparing annual mean numbers of sickness absence spells in exposed versus unexposed groups. RESULTS: In the multivariate model, the following factors were found to be predictive of future sickness absence in women: participating in an upper secondary school program in 1983 dominated by women (> 60%): 1.41 (95% CI 1.00 - 1.97); sometimes sickness absence from school in 1981: 1.60 (95% CI 1.18 - 2.17) and low parental socioeconomic status in 1981: 2.20 (95% CI 1.44 - 3.38). In men, low school grades in 1981: 4.36 (95% CI 2.06 - 9.22) and fathers not in gainful employment in 1981: 2.36 (95% CI 1.53 - 3.66) were predictive. CONCLUSION: The findings suggest that sickness absence in adulthood is predicted by factors measured in adolescence. These predictors may differ for women and men. For women, early life absence and social environmental factors, for men low achievements at school and lack of employment of their father seem to be predictive. PMID- 23351780 TI - Large scale screening of commonly used Iranian traditional medicinal plants against urease activity. AB - BACKGROUND AND PURPOSE OF THE STUDY: H. pylori infection is an important etiologic impetus usually leading to gastric disease and urease enzyme is the most crucial role is to protect the bacteria in the acidic environment of the stomach. Then urease inhibitors would increase sensitivity of the bacteria in acidic medium. METHODS: 137 Iranian traditional medicinal plants were examined against Jack bean urease activity by Berthelot reaction. Each herb was extracted using 50% aqueous methanol. The more effective extracts were further tested and their IC50 values were determined. RESULTS: 37 plants out of the 137 crude extracts revealed strong urease inhibitory activity (more than 70% inhibition against urease activity at 10 mg/ml concentration). Nine of the whole studied plants crude extracts were found as the most effective with IC50 values less than 500 MUg/ml including; Rheum ribes, Sambucus ebulus, Pistachia lentiscus, Myrtus communis, Areca catechu, Citrus aurantifolia, Myristica fragrans, Cinnamomum zeylanicum and Nicotiana tabacum. CONCLUSIONS: The most potent urease inhibitory was observed for Sambucus ebulus and Rheum ribes extracts with IC50 values of 57 and 92 MUg/ml, respectively. PMID- 23351781 TI - Carbohydrate co-ingestion with protein does not further augment post-prandial muscle protein accretion in older men. AB - BACKGROUND: A blunted muscle protein synthetic response to protein ingestion may contribute to the age related loss of muscle tissue. We hypothesized that the greater endogenous insulin release following co-ingestion of carbohydrate facilitates post-prandial muscle protein accretion after ingesting a meal-like bolus of protein in older males. METHODS: Twenty-four healthy older men (75+/-1 y) were randomly assigned to ingest 20 g intrinsically L-[1-13C] phenylalanine labeled casein protein with (PRO-CHO) or without (PRO) 40 g carbohydrate. Ingestion of specifically produced intrinsically L-[1-13C] phenylalanine labeled protein allowed us to assess post-prandial incorporation of dietary protein derived amino acids into muscle protein. Blood samples were collected at regular intervals, with muscle biopsies being obtained prior to and 2 and 6 h after protein ingestion. RESULTS: Plasma glucose and insulin concentrations showed a greater increase in PRO-CHO compared with PRO (P<0.001). Muscle protein-bound L [1-13C] phenylalanine enrichments tended to increase to a greater extent in PRO CHO compared with PRO during the first 2 h after protein ingestion (0.0072+/ 0.0013 vs 0.0046+/-0.010 MPE, respectively; P=0.13). However, 6 h after protein ingestion, differences in muscle protein-bound L-[1-13C] phenylalanine enrichments were no longer observed between experiments (0.0213+/-0.0024 vs 0.0185+/-0.0010 MPE, respectively; P=0.30). CONCLUSIONS: This study shows that carbohydrate ingestion may accelerate, but does not further augment post-prandial incorporation of dietary protein derived amino acids into muscle protein in healthy elderly men. PMID- 23351782 TI - Optimization of the in vitro oxidative biotransformation of glimepiride as a model substrate for cytochrome p450 using factorial design. AB - BACKGROUND AND PURPOSE OF THE STUDY: Glimepiride (GLM) was chosen as a model substrate in order to determine the kinetic parameters for in vitro metabolism via human liver micrososmes (HLM). We aimed to optimize the turnover of the substrate by the test system in relation to incubation time and HLM concentration in such a way that it was linearly dependent on time and less than 20% of the substrate was consumed which utilized the lowest amount of the HLM. Further we aimed to report Km and Vmax values for GLM. METHODS: Linearity of enzyme reactions in microsomal incubations was assessed by monitoring the effect of incubation time (from 5 to 60 min) and HLM concentration (from 0.2 to 0.75 mg/ml) on metabolite formation of GLM. The ideal conditions for turnover of GLM were justified using 3x3 factorial design. F value was calculated to confirm the omission of insignificant terms from the full-model to derive a reduced- model polynomial equation. The regression equation was used to develop a contour plot that showed turnover rate within the limits of this design. The optimized reaction velocity data was extrapolated to carry out the kinetic studies in vitro to generate a saturation curve for the determination of Km and Vmax values. RESULTS: The reaction was found to be linear with respect to both incubation time between 24 and 50 min and HLM concentration between 0.3 to 0.65 mg/ml. The Km and Vmax values obtained by nonlinear least squares regression method was found to be 28.9 +/- 2.97 MUMole and 0.559 +/- 0.017 MUMole respectively. Lineweaver-Burk plot was also used to estimate Km and Vmax which yield value of 29.411 +/- 1.25 MUMole and 0.571 +/- 0.020 MUMole/min/mg protein respectively. MAJOR CONCLUSION: The statistical approach successfully allows for the optimization of reaction time course experiments. The results obtained with linear as well as the nonlinear transformation were found to be in close agreement with each other which shows the best precision for estimates of Km and Vmax. PMID- 23351784 TI - Enhanced antibacterial activity of roxithromycin loaded pegylated poly lactide-co glycolide nanoparticles. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: The purpose of this study was to prepare pegylated poly lactide-co-glycolide (PEG-PLGA) nanoparticles (NPs) loaded with roxithromycin (RXN) with appropriate physicochemical properties and antibacterial activity. Roxithromycin, a semi-synthetic derivative of erythromycin, is more stable than erythromycin under acidic conditions and exhibits improved clinical effects. METHODS: RXN was loaded in pegylated PLGA NPs in different drug;polymer ratios by solvent evaporation technique and characterized for their size and size distribution, surface charge, surface morphology, drug loading, in vitro drug release profile, and in vitro antibacterial effects on S. aureus, B. subtilis, and S. epidermidis. RESULTS AND CONCLUSION: NPs were spherical with a relatively mono-dispersed size distribution. The particle size of nanoparticles ranged from 150 to 200 nm. NPs with entrapment efficiency of up to 80.0+/-6.5% and drug loading of up to 13.0+/-1.0% were prepared. In vitro release study showed an early burst release of about 50.03+/-0.99% at 6.5 h and then a slow and steady release of RXN was observed after the burst release. In vitro antibacterial effects determined that the minimal inhibitory concentration (MIC) of RXN loaded PEG-PLGA NPs were 9 times lower on S. aureus, 4.5 times lower on B. subtilis, and 4.5 times lower on S. epidermidis compared to RXN solution. In conclusion it was shown that polymeric NPs enhanced the antibacterial efficacy of RXN substantially. PMID- 23351783 TI - Enhanced cognitive function and antidepressant-like effects after krill oil supplementation in rats. AB - BACKGROUND: The purpose of the study was to evaluate the effects of krill oil (KO) on cognition and depression-like behaviour in rats. METHODS: Cognition was assessed using the Aversive Light Stimulus Avoidance Test (ALSAT). The Unavoidable Aversive Light Stimulus (UALST) and the Forced Swimming Test (FST) were used to evaluate the antidepressant-like effects of KO. Imipramine (IMIP) was used as the antidepressant reference substance. RESULTS: After 7 weeks of KO intake, both males and females treated with KO were significantly better in discriminating between the active and the inactive levers in the ALSAT from day 1 of training (p<0.01). Both KO and IMIP prevented resignation/depression on the third day in the UALST. Similarly, a shorter immobility time was observed for the KO and IMIP groups compared to the control in the FST (p<0.001). These data support a robust antidepressant-like potential and beneficial cognitive effect of KO. Changes in expression of synaptic plasticity-related genes in the prefrontal cortex and hippocampus were also investigated. mRNA for brain-derived neurotrophic factor (Bdnf) was specifically upregulated in the hippocampus of female rats receiving 7 weeks of KO supplementation (p=0.04) and a similar trend was observed in males (p=0.08). Males also exhibited an increase in prefrontal cortex expression of Arc mRNA, a key protein in long-term synaptic plasticity (p=0.05). IMIP induced clear effects on several plasticity related genes including Bdnf and Arc. CONCLUSIONS: These results indicate that active components (eicosapentaenoic acid, docosahexaenoic acid and astaxanthin) in KO facilitate learning processes and provide antidepressant-like effects. Our findings also suggest that KO might work through different physiological mechanisms than IMIP. PMID- 23351785 TI - "Clinical pharmacognosy"- A new interesting era of pharmacy in the third millennium. PMID- 23351786 TI - MeCP2 modulates gene expression pathways in astrocytes. AB - BACKGROUND: Mutations in MECP2 encoding methyl-CpG-binding protein 2 (MeCP2) cause the X-linked neurodevelopmental disorder Rett syndrome. Rett syndrome patients exhibit neurological symptoms that include irregular breathing, impaired mobility, stereotypic hand movements, and loss of speech. MeCP2 protein epigenetically modulates gene expression through genome-wide binding to methylated CpG dinucleotides. While neurons have the highest level of MeCP2 expression, astrocytes and other cell types also express detectable levels of MeCP2. Recent studies suggest that astrocytes likely control the progression of Rett syndrome. Thus, the object of these studies was to identify gene targets that are affected by loss of MeCP2 binding in astrocytes. METHODS: To identify gene targets of MeCP2 in astrocytes, combined approaches of expression microarray and chromatin immunoprecipitation of MeCP2 followed by sequencing (ChIP-seq) were compared between wild-type and MeCP2-deficient astrocytes. MeCP2 gene targets were compared with genes in the top 10% of MeCP2 binding levels in gene windows either within 2 kb upstream of the transcription start site, or the 'gene body' that extended from transcription start to end site, or 2 kb downstream of the transcription end site. RESULTS: A total of 118 gene transcripts surpassed the highly significant threshold (P < 0.005, fold change > 1.2) in expression microarray analysis from triplicate cultures. The top 10% of genes with the highest levels of MeCP2 binding were identified in two independent ChIP-seq experiments. Together this integrated, genome-wide screen for MeCP2 target genes provided an overlapping list of 19 high-confidence MeCP2-responsive gene transcripts in astrocytes. Validation of candidate target gene transcripts by RT PCR revealed that expression of Apoc2, Cdon, Csrp and Nrep were consistently responsive to MeCP2 deficiency in astrocytes. CONCLUSIONS: The first MeCP2 ChIP seq and gene expression microarray analysis in astrocytes reveals a set of potential MeCP2 target genes that may contribute to normal astrocyte signaling, cell division and neuronal support functions, the loss of which may contribute to the Rett syndrome phenotype. PMID- 23351787 TI - Specific organized substrates of ventricular fibrillation: comparison of 320 slice CT heart images in non-ischemic ventricular fibrillation subjects with non ischemic sustained and non-sustained ventricular tachycardia subjects. AB - PURPOSE: If specific organized substrates of ventricular-fibrillation (VF) are identified, they may provide important-information for prevention of sudden cardiac-death. To identify specific organized substrates of VF, we compared 320 slice CT heart images in non-ischemic VF subjects with non-ischemic sustained and non-sustained ventricular-tachycardia (VT) subjects. MATERIALS AND METHODS: Retrospective analysis of a total of 103 subjects who had VF (17 subjects; age, 59 +/- 16 years), sustained VT (20 subjects; 62 +/- 19 years), or non-sustained VT (66 subjects; 60 +/- 15 years) underwent 320-slice CT (Aquilion one). RESULTS: After excluding 26 ischemic subjects with >50% stenosis in any coronary arteries on CT, myocardial infarction, or coronary vasospastic angina, a total of 77 non ischemic subjects (12 VF subjects; age, 58 +/- 18 years), (13 sustained VT subjects; 55 +/- 20 years) or (52 non-sustained VT subjects; 58 +/- 15 years) were analyzed. On CT, myocardial abnormal-late-enhancement was significantly more frequent in the VF group (75%, all myocardial abnormal-late-enhancement in left ventricle) than in the sustained VT group (31%) and the non-sustained VT group (35%) (both P<0.01). Myocardial fatty change was significantly more frequent in the sustained VT group (54%) than in the VF group (17%) and the non-sustained VT group (12%) (both P<0.01). Final diagnoses of the non-ischemic VF and sustained groups included four subjects in each case with normal cardiac structure on transthoracic echocardiogram; the former included two subjects who had abnormal late-enhancement on CT without specific ECG findings. CONCLUSIONS: Myocardial abnormal-late-enhancement and fatty change on CT may be substrates of VF or sustained VT in non-ischemic subjects. 320-slice CT can evaluate both coronary arteries and myocardium. PMID- 23351788 TI - T-cell co-stimulation by CD28-CD80/86 and its negative regulator CTLA-4 strongly influence accelerated atherosclerosis development. AB - OBJECTIVE: T-cells are central to the immune response responsible for native atherosclerosis. The objective of this study is to investigate T-cell contribution to post-interventional accelerated atherosclerosis development, as well as the role of the CD28-CD80/86 co-stimulatory and Cytotoxic T-Lymphocyte Antigen (CTLA)-4 co-inhibitory pathways controlling T-cell activation status in this process. METHODS AND RESULTS: The role of T-cells and the CD28-CD80/86 co stimulatory and CTLA-4 co-inhibitory pathways were investigated in a femoral artery cuff mouse model for post-interventional remodeling, with notable intravascular CTLA-4+ T-cell infiltration. Reduced intimal lesions developed in CD4(-/-) and CD80(-/-)CD86(-/-) mice compared to normal C57Bl/6J controls. Systemic abatacept-treatment, a soluble CTLA-4Ig fusion protein that prevents CD28-CD80/86 co-stimulatory T-cell activation, prevented intimal thickening by 58.5% (p=0.029). Next, hypercholesterolemic ApoE3*Leiden mice received abatacept treatment which reduced accelerated atherosclerosis development by 78.1% (p=0.040) and prevented CD4 T-cell activation, indicated by reduced splenic fractions of activated KLRG1+, PD1+, CD69+ and CTLA-4+ T-cells. This correlated with reduced plasma interferon-gamma and elevated interleukin-10 levels. The role of CTLA-4 was confirmed using CTLA-4 blocking antibodies, which strongly increased vascular lesion size by 66.7% (p=0.008), compared to isotype-treated controls. CONCLUSIONS: T-cell CD28-CD80/86 co-stimulation is vital for post interventional accelerated atherosclerosis development and is regulated by CTLA-4 co-inhibition, indicating promising clinical potential for prevention of post interventional remodeling by abatacept. PMID- 23351789 TI - Expansion of the red cell distribution width and evolving iron deficiency as predictors of poor outcome in chronic heart failure. AB - BACKGROUND: An elevated red cell distribution width (RDW) and iron deficiency (ID) at baseline predict enhanced mortality in chronic heart failure (CHF), but little is known about the prognostic implications of their temporal trends. We sought to determine the survival implications of temporal changes in RDW and evolving ID in patients with CHF. METHODS: The relation between red cell indices on first consultation and over time with mortality in 274 stable patients with systolic CHF was analysed. The combination of a rising RDW with a falling mean cell volume (MCV) over time defined evolving ID. RESULTS: Over a median 12 month period, 51% and 23% of patients had a rise in RDW and evolving ID, respectively. After a median follow-up of 27 months, 60 (22%) patients died. A rising RDW predicted enhanced all-cause mortality (unadjusted HR for 1% per week rise 9.27, 95% CI 3.58 to 24.00, P<0.0001) independently and incrementally to baseline RDW, with an absolute increase >0.02% per week optimally predictive. Evolving ID also related to higher rates of mortality (HR 2.78, 95% CI 1.64 to 4.73, P<0.001) and was prognostically worse than a rising RDW alone (P<0.005). Patients with evolving ID who maintained their Hb levels over time had a 2-fold greater risk of death than those whose Hb levels declined without evolving ID. CONCLUSIONS: An expanding RDW and evolving iron deficiency over time predict an amplified risk of death in CHF and should be utilised for risk stratification and/or therapeutically targeted to potentially improve outcomes. PMID- 23351790 TI - Sex-related differences in peri- and post-ablation clinical data for patients with atrial flutter. AB - Sex-related differences were not reported for the atrial flutter (AF). The purpose of the study was to look for the influence of gender on indications, clinical data and long-term results of AFl ablation. METHODS: 985 patients, [227 females (23%)] were referred for radiofrequency AFl ablation. Clinical history, echocardiography were collected. Patients were followed from 3 months to 10 years. RESULTS: Age of women and men was similar (65.5 +/- 12 vs 64 +/- 11.5 years). Underlying heart disease (HD) was as frequent in women as men (77.5 vs 77%), but women had more congenital HD (10 vs 2%;p<0.001), valvular HD (18 vs 10%;p<0.002), hypertensive HD (24 vs 18%;p<0.05), and less chronic lung disease (5 vs 10%;p<0.01), and ischemic HD (5 vs 20%;p<0.001). Atrial fibrillation (AF) history was more frequent in women (36 vs 27%;p<0.001). AFl-related tachycardiomyopathy (4.5 vs 8%;p<0.03) was more frequent, but 1/1 AFl (10 vs 6%;p=NS) as frequent. Failure of ablation (16 vs 10%;p<0.01), ablation-related major complications (3.5 vs 0.9%;p<0.005) were more frequent in women. After 3 +/ 3 years, AFl recurrences were as frequent in women and men (10 vs 14%), AF occurrence more frequent in women (34 vs 19.5%; p<0.001). After excluding patients with previous AF, AF risk remained higher in women (19 vs 12%; p<0.004). CONCLUSIONS: In patients admitted for ablation, AFL was less common in women than in men, despite similar age and similarly prevalent HD. More than men, women had frequent AF history, a higher risk of failure of ablation and AFl ablation related major complications and a higher risk of AF after ablation. PMID- 23351791 TI - The relationship of waist circumference distribution to blood pressure levels among children and adolescents in Shandong, China. AB - BACKGROUND: Several studies have documented a positive association between waist circumference (WC) and risk factors for chronic disease in children and adolescents. The present study examined the relationship of WC distribution to BP levels and prevalence of relatively high BP among children and adolescents in Shandong, China. METHODS: A total of 6895 students (3442 boys and 3453 girls) aged 7-17 years participated in this study. Height, weight, WC and BP of all subjects were measured; body mass index (BMI) and waist-to-height ratio (WHtR) were calculated from their height, weight and WC. Relatively high BP status was defined as systolic blood pressure (SBP) and/or diastolic blood pressure (DBP)>= 95th percentile for age and gender. RESULTS: SBP and DBP were positively correlated with WC, WHtR and BMI in both boys and girls. The strongest correlation observed for BP was with WC. Z-scores of BP and the prevalence of relatively high BP increased with WC percentiles, this trend being especially obvious in the upper percentiles of WC. The prevalence of relatively high BP increased from 9.21% (boys) and 11.76% (girls) in the <5th WC percentile group to 58.99% (boys) and 40.34% (girls) in the >= 95th WC percentile group, an increase of 5.4- and 2.4-times. CONCLUSION: Children and adolescents with elevated WC might have an increased risk of hypertension. These findings emphasize the importance of the prevention of overweight and obesity in order to prevent future related problems such as hypertension in children and adolescents. PMID- 23351792 TI - First experience of a bioresorbable vascular scaffold implantation in left main stenosis. PMID- 23351794 TI - Talking orders--opening dialogue about gun control. PMID- 23351795 TI - Neglected tropical diseases: progress and priorities. PMID- 23351793 TI - Trafficking in and to the primary cilium. AB - Polarized vesicle trafficking is mediated by small GTPase proteins, such as Rabs and Arls/Arfs. These proteins have essential roles in maintaining normal cellular function, in part, through regulating intracellular trafficking. Moreover, these families of proteins have recently been implicated in the formation and function of the primary cilium. The primary cilium, which is found on almost every cell type in vertebrates, is an organelle that protrudes from the surface of the cell and functions as a signaling center. Interestingly, it has recently been linked to a variety of human diseases, collectively referred to as ciliopathies. The primary cilium has an exceptionally high density of receptors on its membrane that are important for sensing and transducing extracellular stimuli. Moreover, the primary cilium serves as a separate cellular compartment from the cytosol, providing for unique spatial and temporal regulation of signaling molecules to initiate downstream events. Thus, functional primary cilia are essential for normal signal transduction. Rabs and Arls/Arfs play critical roles in early cilia formation but are also needed for maintenance of ciliary function through their coordination with intraflagellar transport (IFT), a specialized trafficking system in primary cilia. IFT in cilia is pivotal for the proper movement of proteins into and out of this highly regulated organelle. In this review article, we explore the involvement of polarized vesicular trafficking in cilia formation and function, and discuss how defects in these processes could subsequently lead to the abnormalities observed in ciliopathies. PMID- 23351796 TI - Thank you Michael, welcome David: a new era for NICE. PMID- 23351797 TI - Is Option B+ the best choice? PMID- 23351798 TI - Capturing covert consciousness. PMID- 23351801 TI - Thomas LaVeist: framing the debate on health disparities. PMID- 23351802 TI - Reanalysis of "Bedside detection of awareness in the vegetative state: a cohort study". PMID- 23351803 TI - Reanalysis of "Bedside detection of awareness in the vegetative state: a cohort study" - Authors' reply. PMID- 23351804 TI - Violence against public health workers during armed conflicts. PMID- 23351805 TI - Redeeming diagnosis in psychiatry: timing versus specificity. PMID- 23351806 TI - Haematemesis, haemoptysis, or both? PMID- 23351807 TI - Patients in China face crisis. PMID- 23351808 TI - Deep reflection needed on China's medical-help-seeking culture. PMID- 23351809 TI - World Leprosy Day: where does Iran stand? PMID- 23351810 TI - A review on delayed toxic effects of sulfur mustard in Iranian veterans. AB - Iranian soldiers were attacked with chemical bombs, rockets and artillery shells 387 times during the 8-years war by Iraq (1980-1988). More than 1,000 tons of sulfur mustard gas was used in the battlefields by the Iraqis against Iranian people. A high rate of morbidities occurred as the result of these attacks. This study aimed to evaluate the delayed toxic effects of sulfur mustard gas on Iranian victims. During a systematic search, a total of 193 (109 more relevant to the main aim) articles on sulfur mustard gas were reviewed using known international and national databases. No special evaluation was conducted on the quality of the articles and their publication in accredited journals was considered sufficient. High rate of morbidities as the result of chemical attacks by sulfur mustard among Iranian people occurred. Iranian researchers found a numerous late complications among the victims which we be listed as wide range of respiratory, ocular, dermatological, psychological, hematological, immunological, gastrointestinal and endocrine complications, all influenced the quality of life of exposed victims. The mortality rate due to this agent was 3%. Although, mortality rate induced by sulfur mustard among Iranian people was low, variety and chronicity of toxic effects and complications of this chemical agent were dramatic. PMID- 23351811 TI - Effects of Neospora caninum infection on brain microvascular endothelial cells bioenergetics. AB - BACKGROUND: The brain is the most commonly affected organ during Neospora caninum infection but the mechanisms utilized by this protozoan parasite for traversal of the blood-brain barrier (BBB) are not yet understood. Herein, we investigate the cellular pathogenicity of N. caninum infection on bioenergetics of human brain microvascular endothelial cells (HBMECs), a fundamental component of the BBB. METHODS: We tracked the growth kinetics of N. caninum in HBMECs. Focusing on cell bioenergetics, oxygen consumption rate (OCR) was determined using Clark electrode system and mitochondrial membrane potential (DeltaPsim) was evaluated using DePsipher staining by fluorescence microscopy in the presence and absence of infection. RESULTS: HBMECs provided a receptive environment for parasite proliferation. N. caninum tachyzoites were able to invade and replicate within HBMECs without significantly altering cell proliferation rate, as measured with the MTT assay, up to 24 hr post infection (pi). The oxygen consumption rate (OCR) was significantly inhibited (p < 0.001) by 10 mM glucose [from -2.26+/-0.23 to 0.6+/-0.21 nmol 106 cell min-1 and from -0.29+/-0.09 to -0.16+/-0.1 nmol 106 cell min-1 for uninfected HBMECs and free N. Caninum tachyzoites, respectively]. After normalization for DNA content the basal OCR did not differ between two host cell types: HBMECs and K562. The OCR of HBMECs was significantly elevated 24 hr pi in the absence of substrate, in 10 mM glucose and in the presence of a tetramethyl-p phenylenediamine (TMPD)/ascorbate redox shuttle. Although quantitatively similar results were observed for uninfected K562 cells, there was no effect on their OCR 24 hr pi with N. caninum under any of the above substrate conditions. 6mM azide abolished OCR in all situations. Mitochondrial staining with DePsipher indicated no change in their membrane potential (Deltapsim) up to 24 hr pi. CONCLUSIONS: N. caninum is able to grow in HBMECs without markedly disrupting their normal proliferation or mitochondrial integrity. However, it is associated with an increase in infected cell respiration. Whether this increase reflects numeric addition of the parasites own respiration or results from an additional energy demand upon the host cell remains to be elucidated. PMID- 23351812 TI - Rationale and design of the Investigation of the Management of Pericarditis (IMPI) trial: a 2 * 2 factorial randomized double-blind multicenter trial of adjunctive prednisolone and Mycobacterium w immunotherapy in tuberculous pericarditis. AB - BACKGROUND: In spite of antituberculosis chemotherapy, tuberculous (TB) pericarditis causes death or disability in nearly half of those affected. Attenuation of the inflammatory response in TB pericarditis may improve outcome by reducing cardiac tamponade and pericardial constriction, but there is uncertainty as to whether adjunctive immunomodulation with corticosteroids and Mycobacterium w (M. w) can safely reduce mortality and morbidity. OBJECTIVES: The primary objective of the IMPI Trial is to assess the effectiveness and safety of prednisolone and M. w immunotherapy in reducing the composite outcome of death, constriction, or cardiac tamponade requiring pericardial drainage in 1,400 patients with TB pericardial effusion. DESIGN: The IMPI trial is a multicenter international randomized double-blind placebo-controlled 2 * 2 factorial study. Eligible patients are randomly assigned to receive oral prednisolone or placebo for 6 weeks and M. w injection or placebo for 3 months. Patients are followed up at weeks 2, 4, and 6 and months 3 and 6 during the intervention period and 6 monthly thereafter for up to 4 years. The primary outcome is the first occurrence of death, pericardial constriction, or cardiac tamponade requiring pericardiocentesis. The secondary outcome is safety of immunomodulatory treatment measured by effect on opportunistic infections (eg, herpes zoster) and malignancy (eg, Kaposi sarcoma) and impact on measures of immunosuppression and the incidence of immune reconstitution disease. CONCLUSIONS: IMPI is the largest trial yet conducted comparing adjunctive immunotherapy in pericarditis. Its results will define the role of adjunctive corticosteroids and M. w immunotherapy in patients with TB pericardial effusion. PMID- 23351813 TI - Partial oral treatment of endocarditis. AB - BACKGROUND: Guidelines for the treatment of left-sided infective endocarditis (IE) recommend 4 to 6 weeks of intravenous antibiotics. Conversion from intravenous to oral antibiotics in clinically stabilized patients could reduce the side effects associated with intravenous treatment and shorten the length of hospital stay. Evidence supporting partial oral therapy as an alternative to the routinely recommended continued parenteral therapy is scarce, although observational data suggest that this strategy may be safe and effective. STUDY DESIGN: This is a noninferiority, multicenter, prospective, randomized, open label study of partial oral treatment with antibiotics compared with full parenteral treatment in left-sided IE. Stable patients (n = 400) with streptococci, staphylococci, or enterococci infecting the mitral valve or the aortic valve will be included. After a minimum of 10 days of parenteral treatment, stable patients are randomized to oral therapy or unchanged parenteral therapy. Recommendations for oral treatment have been developed based on minimum inhibitory concentrations and pharmacokinetic calculations. Patients will be followed up for 6 months after completion of antibiotic therapy. The primary end point is a composition of all-cause mortality, unplanned cardiac surgery, embolic events, and relapse of positive blood cultures with the primary pathogen. CONCLUSION: The Partial Oral Treatment of Endocarditis study tests the hypothesis that partial oral antibiotic treatment is as efficient and safe as parenteral therapy in left-sided IE. The trial is justified by a review of the literature, by pharmacokinetic calculations, and by our own experience. PMID- 23351814 TI - Enhancing the efficacy of delivering reperfusion therapy: a European and North American experience with ST-segment elevation myocardial infarction networks. AB - Advances in technique and adjunctive medication have improved outcome of ST segment elevation myocardial infarction (STEMI) patients. However, the timely delivery and administration of reperfusion strategies to all eligible patients remain challenging. Currently, up to one-third of eligible STEMI patients in industrialized countries worldwide receive no specific reperfusion treatment, a problem that is rectified by the development and implementation of STEMI networks, as also recommended by the latest European Society of Cardiology and American College of Cardiology/American Heart Association guidelines. Indeed, over the last 5 years, published figures demonstrate that STEMI networks increase the percentage of patients treated by any reperfusion strategy, and the percentage of patients receiving treatment within the recommended time frames has also improved, thereby reducing in-hospital and long-term mortality to very low levels. This manuscript demonstrates how STEMI networks can be adapted to local needs and circumstances against pre-existing barriers and despite the heterogeneity in local situations, patient's characteristics, treatment delays, and distances for transfer. Modern and efficacious networks must be prepared to offer both primary percutaneous coronary intervention and thrombolytic therapy, preferably prehospital, as long as primary percutaneous coronary intervention cannot be guaranteed to all individuals within the recommended timeline. PMID- 23351815 TI - Percutaneous recanalization of chronic total occlusions: wherein lies the body of proof? AB - Although interventional technology and skills have markedly advanced, percutaneous coronary intervention (PCI) for coronary chronic total occlusion (CTO) lesions remains challenging. Indeed, CTO PCI is technically complex, carries the potential for a relatively high likelihood of failure and acute complications, and requires specifically skilled operators and a demanding use of resources. In addition, controversy persists surrounding appropriate indications for attempting CTO revascularization. Finally, there is a wide uncertainty on the actual benefits achieved with successful CTO recanalization. A growing number of studies have reported procedural results and/or assessed functional effects and long-term clinical outcomes of CTO PCI. We therefore sought to review and critically appraise the evidence base for procedural outcomes and potential clinical benefits of CTO PCI. PMID- 23351816 TI - Anemia and mortality in acute coronary syndromes: a systematic review and meta analysis. AB - BACKGROUND: Anemia is a common comorbidity among patients with acute coronary syndromes (ACS) and may adversely affect cardiovascular outcomes in these patients. We conducted a systematic review and meta-analysis to examine the association between anemia and mortality among patients with ACS. METHODS: We systematically searched MEDLINE to identify cohort studies and secondary analyses of randomized controlled trials examining the association between anemia and all cause mortality among patients with ACS. Data were aggregated at 4 follow-up times (inhospital, 30 days, 1 year, and maximal available follow-up) using random effects meta-analysis models. RESULTS: Twenty-seven studies met the inclusion criteria, involving 233,144 patients. Anemia was present in 44,519 (19.1%) of these patients. Anemic patients were generally older and had a higher prevalence of comorbidities including diabetes mellitus, congestive heart failure, cerebrovascular disease, and history of major bleeding. Anemia was associated with an increased risk of crude all-cause mortality (relative risk 2.08, 95% CI 1.70-2.55) and reinfarction (relative risk 1.25, 95% CI 1.02-1.53) at maximal available follow-up. When adjusted risk ratios from individual studies' multivariable regression analyses were pooled, the magnitude of the associated mortality risk was attenuated but remained significant at maximal follow-up (hazard ratio 1.49, 95% CI 1.23-1.81). Clinically and statistically significant increases in mortality were observed as early as at 30 days post-ACS and persisted at 1 year. CONCLUSIONS: Anemia in patients with ACS is independently associated with a significantly increased risk of early and late mortality. PMID- 23351817 TI - Head-to-head comparison of prospectively triggered vs retrospectively gated coronary computed tomography angiography: Meta-analysis of diagnostic accuracy, image quality, and radiation dose. AB - BACKGROUND: In coronary computed tomography (CT) angiography (CTA) prospective electrocardiography triggering requires less radiation dose than retrospective electrocardiography gating but provides less cardiac phases for interpretation. This meta-analysis presents a concise and comprehensive head-to-head comparison of image quality, diagnostic accuracy, and radiation dose of prospectively triggered coronary CTA vs retrospectively gated CTA in patients with suspected or known coronary artery disease (CAD). METHODS: In patients with CAD and without tachyarrhythmia, eligible studies (selected from 4 databases) compared prospectively triggered vs retrospectively gated CTA (performed with >=64-slice CT or dual-source CT) in 2 groups having approximately similar patient characteristics, scored CTA image quality, and/or assessed how accurately CTA diagnoses >=50% coronary stenoses compared with catheter angiography and reported the radiation dose. The data were meta-analyzed by random-effects models, with CIs provided in the text. RESULTS: Among 3,330 patients from 20 included studies, 91.3% of CTAs (segments: 97.8%) had diagnostic quality with prospective triggering and 93.3% of CTAs (segments: 98.4%) with retrospective gating (P > .05). Among 664 patients from 5 studies, the pooled sensitivity/specificity of diagnostic CTAs was 98.7%/91.3% (segment level: 91.3%/97.7%) with prospective triggering and 96.9%/95.8% (segment level: 93.1%/97.6%) with retrospective gating (P > .05). The pooled effective dose was 3.5 mSv with prospective triggering and thus, by a factor of 3.5, lower than the pooled effective dose of retrospective gating, which was 12.3 mSv (P < .01). CONCLUSIONS: In patients with CAD and without tachyarrhythmia, prospectively triggered coronary CTA provides image quality and diagnostic accuracy comparable with retrospectively gated CTA, but at a much lower radiation dose. PMID- 23351818 TI - Inflammation in young adulthood is associated with myocardial infarction later in life. AB - BACKGROUND: There is evidence that atherosclerosis begins in childhood. There is also evidence that inflammatory markers measured in middle and old age predict risks of cardiovascular disease. In this report, we test whether an inflammatory marker measured in young adult men is associated with risk of myocardial infarction in middle age. METHODS: During Swedish national conscription tests from 1969 through 1978, the erythrocyte sedimentation rate, as a measure of inflammation, was measured in 433,577 young Swedish men. The cohort was observed for subsequent myocardial infarction events through December 2009. RESULTS: During an average follow-up time of 35 years, a total of 8,081 first-time myocardial infarctions occurred within the cohort. After adjustments for potential confounders and known risk factors for myocardial infarction, men with an elevated erythrocyte sedimentation rate (>=15 mm/h) had a 1.7 times increased risk of myocardial infarction during follow-up (95% CI 1.4-2.1) compared with men with an erythrocyte sedimentation rate of 1 mm/h. This relationship was dose dependent for each unit increase in erythrocyte sedimentation rate (P for trend < .001). CONCLUSIONS: In this cohort of young Swedish men, the erythrocyte sedimentation rate was associated with risk of myocardial infarction 35 years later after control of the available data on other coronary risk factors. These data add important relevant information to the existing evidence that atherosclerosis begins in childhood. PMID- 23351819 TI - Marijuana use and long-term mortality among survivors of acute myocardial infarction. AB - BACKGROUND: Smoking marijuana has been reported to increase risk of myocardial infarction (MI) immediately after use, but less is known about the long-term impact of marijuana use among patients with established coronary disease. METHODS: The Determinants of MI Onset Study is a multicenter inception cohort study of myocardial infarction (MI) patients enrolled in 1989 to 1996 and followed up for mortality using the National Death Index. In an initial analysis of 1,935 MI survivors followed up for a median of 3.8 years, we found an increased mortality rate among marijuana users. The current article includes 3,886 Determinants of MI Onset Study patients followed up for up to 18 years. We used Cox proportional hazards models to calculate the hazard ratio and 95% CI for the association between marijuana use and mortality and a propensity score matched analysis to further control confounding. RESULTS: Over up to 18 years of follow-up, 519 patients died, including 22 of the 109 reporting marijuana use in the year before their MI. There was no statistically significant association between marijuana use and mortality. Compared with nonusers, the mortality rate was 29% higher (95% CI 0.81-2.05, P = .28) among those reporting any marijuana use. CONCLUSIONS: Habitual marijuana use among patients presenting with acute MI was associated with an apparent increased mortality rate over the following 18 years that did not reach nominal statistical significance. Larger studies with repeated measures of marijuana use are needed to definitively establish whether there are adverse cardiovascular consequences of smoking marijuana among patients with established coronary heart disease. PMID- 23351820 TI - Spaced administration of PA32540 and clopidogrel results in greater platelet inhibition than synchronous administration of enteric-coated aspirin and enteric coated omeprazole and clopidogrel. AB - BACKGROUND: A common regimen for patients requiring dual-antiplatelet therapy who are at risk for gastrointestinal complications is the synchronous administration of enteric-coated (EC) aspirin, a proton pump inhibitor, and clopidogrel, although proton pump inhibitors have the potential for pharmacodynamic interaction with clopidogrel. Spaced administration of a clopidogrel and a single tablet formulation of aspirin and immediate-release omeprazole (PA32540) was considered as an alternative that might reduce this potential pharmacodynamic interaction. METHODS AND RESULTS: A randomized, open-label, crossover study was conducted in healthy subjects (n = 30). Two 7-day treatments were separated by 14 day washout periods: (a) PA32540 + clopidogrel (300 mg loading/75 mg maintenance) 10 hours later and (b) synchronous dosing of clopidogrel + EC aspirin (81 mg) + EC omeprazole (40 mg). The primary end point was the inhibition of platelet aggregation (20 MUM adenosine diphosphate, maximal extent) after 7 days. CYP2C19 and ABCB1 genotypes were determined. Inhibition of platelet aggregation was greater with spaced PA32540 + clopidogrel therapy vs synchronous clopidogrel + EC aspirin + EC omeprazole therapy (P = .004). There was no difference in day 7 arachidonic acid-induced aggregation. The effect of spacing on pharmacodynamics was independent of genotype. CONCLUSIONS: PA32540 and clopidogrel spaced 10 hours apart had greater antiplatelet effects than did synchronously administered EC aspirin (81 mg), clopidogrel (75 mg), and EC omeprazole in healthy volunteers. These finding are directly relevant to the treatment for patients with high gastrointestinal risk who require dual-antiplatelet therapy and gastroprotection. PMID- 23351821 TI - Trends in outcome after transfemoral transcatheter aortic valve implantation. AB - BACKGROUND: Transfemoral transcatheter aortic valve implantation (TF-TAVI) is a viable and safe treatment strategy for patients with symptomatic severe aortic stenosis and high operative risk and has been introduced as such in the recently updated European guidelines on the management of valvular heart disease.Our aim was to assess trends in outcome after TF-TAVI. METHODS: Propensity score-matched analysis of a multicenter registry of consecutive patients undergoing TF-TAVI subdivided into 3 tertiles based on enrollment date was performed. Three tertiles of 214 propensity score-matched patients were compared. RESULTS: With mounting experience and moving from the initial to the last cohort, procedural contrast volume and radiation time decreased. Over time, there were less major vascular complications (15% vs 7.9%, P = .023), life-threatening bleedings (17.8% vs 7.9%, P = .003), and major bleedings (22.4% vs 12.1%, P = .007). Major vascular complications and life-threatening bleedings caused by closure device failure decreased significantly (9.2% vs 3.1% [P = .01] and 5.7% vs 1 % [P = .01], respectively). The combined safety end point dropped from 31.3% in tertile (T) (T1) to 17.8% in T3 (P < .001). By multivariable analysis, the last cohort as compared with the initial cohort was associated with significant reductions in 30 day mortality (odds ratio [OR] 0.35, 95% CI 0.12-0.96), stage 3 AKI (OR 0.12, 95% CI 0.29-0.93), and the combined safety end point (OR 0.52, 95% CI 0.29-0.93). One year survival improved significantly (T1 79% vs T3 86%, P = .016). CONCLUSIONS: Over time, TAVI is performed with significant reductions in major vascular complications, life-threatening bleedings, and the combined clinical safety end point and improved 1-year survival. PMID- 23351822 TI - Clinical characteristics, response to exercise training, and outcomes in patients with heart failure and chronic obstructive pulmonary disease: findings from Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF ACTION). AB - BACKGROUND: The aim of this study was to investigate the clinical characteristics, exercise training response, beta-blocker selectivity, and outcomes in patients with heart failure (HF) and chronic obstructive pulmonary disease (COPD). METHODS: We performed an analysis of HF-ACTION, which randomized 2,331 patients with HF having an ejection fraction of <=35% to usual care with or without aerobic exercise training. We examined clinical characteristics and outcomes (mortality/hospitalization, mortality, cardiovascular [CV] mortality/CV hospitalization, and CV mortality/HF hospitalization) by physician-reported COPD status using adjusted Cox models and explored an interaction with exercise training. The interaction between beta-blocker cardioselectivity and outcomes was investigated. RESULTS: Of patients with COPD status documented (n = 2311), 11% (n = 249) had COPD. Patients with COPD were older, had more comorbidities, and had lower use of beta-blockers compared with those without COPD. At baseline, patients with COPD had lower peak oxygen consumption and higher V(E)/V(CO)(2) slope. During a median follow-up of 2.5 years, COPD was associated with increased mortality/hospitalization, mortality, and CV mortality/HF hospitalization. After multivariable adjustment, the risk of CV mortality/HF hospitalization remained increased (hazard ratio [HR] 1.46, 95% CI 1.14-1.87), whereas mortality/hospitalization (HR 1.15, 95% CI 0.96-1.37) and mortality (HR 1.33, 95% CI 0.99-1.76) were not significantly increased. There was no interaction between COPD and exercise training on outcomes or between COPD and beta-blocker selectivity on mortality/hospitalization (all P > .1). CONCLUSIONS: Chronic obstructive pulmonary disease in patients with HF was associated with older age, more comorbidities, reduced exercise capacity, and increased CV mortality/HF hospitalization, but not a differential response to exercise training. beta Blocker selectivity was not associated with differences in outcome for patients with vs without COPD. PMID- 23351823 TI - Clinical and echocardiographic correlations of exercise-induced pulmonary hypertension in systemic sclerosis: a multicenter study. AB - BACKGROUND: Patients with systemic sclerosis (SSc) are at risk for developing pulmonary hypertension, which is associated with a poor prognosis. Exercise Doppler echocardiography enables the identification of exercise-induced increase in pulmonary artery systolic pressure (PASP) and may provide a thorough noninvasive hemodynamic evaluation. AIM: The aim of this study was to evaluate the clinical and echocardiographic determinants of exercise-induced increase in PASP in a large population of patients with SSc. METHODS: We selected 164 patients with SSc (age 58 +/- 13 years, 91% female) with normal resting PASP (<40 mm Hg) who underwent a comprehensive 2-dimensional and Doppler echocardiography and graded bicycle semisupine exercise Doppler echocardiography. Pulmonary artery systolic pressure, cardiac output, and pulmonary vascular resistance (PVR) were estimated noninvasively. Cutoff values of PASP >=50 mm Hg and PVR >=3.0 Wood Units at peak exercise were considered a significant exercise-induced increase in PASP and PVR, respectively. RESULTS: Sixty-nine (42%) patients showed a significant exercise-induced increase in PASP. Among them, peak PVR >=3 Wood Units was present only in 11% of patients, about 5% of the total population. Univariate analysis showed that age, presence of interstitial lung disease, and both right and left diastolic dysfunction are predictors of peak PASP >=50 mm Hg, but none of these parameters predict elevated peak PVR. CONCLUSIONS: Exercise induced increase in PASP occurs in almost one-half of patients with SSc with normal resting PASP. Peak exercise PASP is affected by age, interstitial lung disease, and right and left ventricular diastolic dysfunction and, only in 5% of the patients, is associated with an increase in PVR during exercise, suggesting heterogeneity of the mechanisms underlying exercise-induced pulmonary hypertension in SSc. PMID- 23351824 TI - Plasma n-3 polyunsaturated fatty acids in chronic heart failure in the GISSI Heart Failure Trial: relation with fish intake, circulating biomarkers, and mortality. AB - Treatment with long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) can improve clinical outcomes in patients with heart failure (HF). Circulating levels of n-3 PUFA, an objective estimation of exposure, have never been measured in a large cohort of patients with HF. METHODS: We measured n-3 PUFA in plasma phospholipids at baseline and after 3 months in 1,203 patients with chronic HF enrolled in the GISSI-Heart Failure trial and randomized to n-3 PUFA 1 g/daily or placebo. N-3 PUFA levels were related to clinical characteristics, pharmacologic treatments, dietary habits, circulating biomarkers, and mortality. RESULTS: Baseline n-3 PUFA (5.1 +/- 1.8 mol%) was associated with dietary fish intake, with an average difference of 43% between patients with the lowest and highest consumptions (P < .0001). Baseline eicosapentaenoic acid (EPA) but not docosahexaenoic acid (DHA) was inversely related to C-reactive protein, pentraxin-3, adiponectin, natriuretic peptide, and troponin levels. Three-month treatment with n-3 PUFA raised their levels by 43%, independently of dietary fish consumption; increases in EPA levels were associated with decreased pentraxin-3. Low baseline levels of EPA but not DHA were no longer related to higher mortality after the addition of circulating biomarkers to multivariable models. CONCLUSION: Before supplementation, circulating n-3 PUFA levels in patients with chronic HF mainly depend on dietary fish consumption and are inversely related to inflammatory markers and disease severity. Three-month treatment with n-3 PUFA markedly enriched circulating EPA and DHA, independently of fish intake, and lowered pentraxin-3. Low EPA levels are inversely related to total mortality in patients with chronic HF. PMID- 23351825 TI - Clinical profile and prognostic value of low systolic blood pressure in patients hospitalized for heart failure with reduced ejection fraction: insights from the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial. AB - BACKGROUND: Systolic blood pressure (SBP) is related to the pathophysiologic development and progression of heart failure (HF) and is inversely associated with adverse outcomes during hospitalization for HF (HHF). The prognostic value of SBP after initiating inhospital therapy and the mode of death and etiology of cardiovascular readmissions based on SBP have not been well characterized in HHF. METHODS: A post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 hours of admission for worsening HF with an ejection fraction (EF) <=40% and an SBP >=90 mm Hg, for a median follow-up of 9.9 months. Systolic blood pressure was measured at baseline, daily during hospitalization, and at discharge/day 7. Patients were divided into the following quartiles by SBP at baseline: <=105, 106 to 119, 120 to 130, and >=131 mm Hg. Outcomes were all-cause mortality (ACM) and the composite of cardiovascular mortality or HHF (CVM + HHF). The associations between baseline, discharge, and inhospital change in SBP and ACM and CVM + HHF were assessed using multivariable Cox proportional hazards regression models adjusted for known covariates. RESULTS: Median (25th, 75th) SBP at baseline was 120 (105, 130) mm Hg and ranged from 82 to 202 mm Hg. Patients with a lower SBP were younger and more likely to be male; had a higher prevalence of prior revascularization and ventricular arrhythmias; had a lower EF, worse renal function, higher natriuretic peptide concentrations, and wider QRS durations; and were more likely to require intravenous inotropes during hospitalization. Lower SBP was associated with increased mortality, driven by HF and sudden cardiac death, and cardiovascular hospitalization, primarily caused by HHF. After adjusting for potential confounders, SBP was inversely associated with risk of the coprimary end points both at baseline (ACM: hazard ratio [HR]/10-mm Hg decrease 1.15, 95% CI1.08-1.22; CVM + HHF: HR 1.09/10-mm Hg decrease, 95% CI 1.04-1.14) and at the time of discharge/day 7 (ACM: HR 1.15/10-mm Hg decrease, 95% CI 1.08-1.22; CVM + HHF: HR 1.07/10-mm Hg decrease, 95% CI 1.02-1.13), but the association with inhospital SBP change was not significant. CONCLUSION: Systolic blood pressure is an independent clinical predictor of morbidity and mortality after initial therapy during HHF with reduced EF. PMID- 23351826 TI - Aborted myocardial infarction after primary percutaneous coronary intervention: magnetic resonance imaging insights from the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. AB - BACKGROUND: Aborted myocardial infarction (AbMI) in patients with ST-elevation MI defined by ST resolution with less than 2-fold elevation in biomarkers has been previously reported. We examined the association among AbMI, other metrics of infarct size, and left ventricular (LV) function defined by cardiac magnetic resonance (CMR). METHODS: A total of 5745 patients with ST-elevation MI enrolled in the APEX-AMI trial, and 73 who were part of the CMR substudy within 3 to 5 days of randomization were evaluated. Core laboratories analyzed electrocardiograms, angiograms, and CMR images. RESULTS: Aborted MI (peak creatine kinase/creatine kinase MB <2* upper limit of normal) with typical evolutionary electrocardiogram changes was observed in 11% (437/3938) overall and in 19% (14/73) of patients within the CMR study. Patients with AbMI were older (62 vs 60 years, P = .003) and tended to achieve complete STE-resolution post percutaneous coronary intervention (>=70% resolution: 64% vs 32%; P = .076) compared with patients with MI. Cardiac magnetic resonance revealed that patients with AbMI had a smaller infarct size (4.7% vs 14.9% LV, P < .001), less "no reflow" (0.9% vs 1.7% LV, P = .017), enhanced LV function (ejection fraction 54.4% vs 46.5%, P = .064), smaller LV end-systolic volumes (46.5 mL vs 67.2 mL, P = .009), and less transmurality (21.4% vs 50.9% with at least 1 segment with >75% wall thickness, P = .046) when compared with patients with MI. CONCLUSIONS: Patients with AbMI had smaller subendocardial infarcts with enhanced LV size and function. Cardiac magnetic resonance provides corroborative evidence of AbMI and insights into its pathophysiology, specifically rapid successful reperfusion leading to limitation of the "wavefront" of infarct to the subendocardium. PMID- 23351827 TI - Targeted anti-inflammatory systemic therapy for restenosis: the Biorest Liposomal Alendronate with Stenting sTudy (BLAST)-a double blind, randomized clinical trial. AB - BACKGROUND: Activation of systemic innate immunity is critical in the chain of events leading to restenosis. LABR-312 is a novel compound that transiently modulates circulating monocytes, reducing accumulation of these cells at vascular injury sites and around stent struts. The purpose of the study was to examine the safety and efficacy of a single intravenous bolus of LABR-312 in reducing restenosis in patients treated for coronary narrowing. Patient response was examined in light of differential inflammatory states as evidenced by baseline circulating monocyte levels, diabetes mellitus, and acute coronary syndrome. METHODS: BLAST is a Phase II prospective, randomized, multicenter, double-blind, placebo-controlled trial that assessed the safety and efficacy of LABR-312. Patients were randomized to receive LABR-312 at 2 dose levels or placebo as an intravenous infusion during percutaneous coronary intervention and bare metal stent implantation. The primary end point was mean angiographic in-stent late loss at 6 months. RESULTS: Patients (N = 225) were enrolled at 12 centers. There were no safety concerns associated with the study drug. For the overall cohort, there were no differences between the groups in the primary efficacy end point (in-stent late loss of 0.86 +/- 0.60 mm, 0.83 +/- 0.57 mm, and 0.81 +/- 0.68 mm for the placebo, low-dose, and high-dose group, respectively; P = not significant for all comparisons). In the prespecified subgroups of patients with a baseline proinflammatory state, patients with diabetes mellitus, and patients with high baseline monocyte count, there was a significant treatment effect. CONCLUSIONS: Intravenous administration of LABR-312 to patients undergoing percutaneous coronary intervention is safe and effectively modulates monocyte behavior. The average late loss did not differ between the treatment and placebo groups. However, in the inflammatory patient group with baseline monocyte count higher than the median value, there was a significant reduction in late loss with LABR 312. PMID- 23351828 TI - Safety and efficacy of everolimus- versus sirolimus-eluting stents: a systematic review and meta-analysis of 11 randomized trials. AB - BACKGROUND: While EES have proven superior to paclitaxel-eluting stents, it remains uncertain whether EES improve clinical outcomes compared to SES, which are the most efficacious among the first-generation drug-eluting stents. We performed a meta-analysis of randomized trials comparing the efficacy and safety of everolimus-eluting stents (EES) versus sirolimus-eluting stents (SES) in patients undergoing percutaneous coronary intervention. METHODS: From online and offline search until December 2011, we identified 11 randomized trials (total 12,869 patients). The primary endpoint was major adverse cardiac events. RESULTS: The risk of major adverse cardiac events did not differ significantly between the patients treated with EES versus SES [OR, 0.90 (95% CI, 0.77-1.04); P = .162]. However, we found a significant reduction in the risk of repeat revascularization in the EES arm [OR, 0.85 (95% CI, 0.71-1.00); P = .047]. There were no significant differences regarding the risk of cardiac death [OR, 0.97 (95% CI, 0.74-1.27); P = .834], or myocardial infarction [OR, 0.95 (95% CI, 0.75-1.20), P = .656]. The risk of definite or probable stent thrombosis tended to be lower [OR, 0.68 (95% CI, 0.45-1.02); P = .065], while definite ST was significantly lower [OR, 0.44 (95% CI, 0.25-0.80); P = .007] with EES. CONCLUSIONS: In a large systematic overview of comparative trials involving percutaneous revascularization with drug-eluting stents, treatment with EES significantly reduced the risk of repeat revascularization and definite ST compared to SES. We found no significant differences in the risk of cardiac death or myocardial infarction. PMID- 23351829 TI - Reply to Letter to the Editor regarding "Incidence and predictors of acute kidney injury after transcatheter aortic valve replacement". PMID- 23351830 TI - Regarding "Incidence and predictors of acute kidney injury after transcatheter aortic valve replacement". PMID- 23351831 TI - The Motivation and Pleasure Scale-Self-Report (MAP-SR): reliability and validity of a self-report measure of negative symptoms. AB - The Clinical Assessment Interview for Negative Symptoms (CAINS) is an empirically developed interview measure of negative symptoms. Building on prior work, this study examined the reliability and validity of a self-report measure based on the CAINS-the Motivation and Pleasure Scale-Self-Report (MAP-SR)-that assesses the motivation and pleasure domain of negative symptoms. Thirty-seven participants with schizophrenia or schizoaffective disorder completed the 18-item MAP-SR, the CAINS, and other measures of functional outcome. Item analyses revealed three items that performed poorly. The revised 15-item MAP-SR demonstrated good internal consistency and convergent validity with the clinician-rated Motivation and Pleasure scale of the CAINS, as well as good discriminant validity, with little association with psychotic symptoms or depression/anxiety. MAP-SR scores were related to social anhedonia, social closeness, and clinician-rated social functioning. The MAP-SR is a promising self-report measure of severity of negative symptoms. PMID- 23351832 TI - Social functioning in first contact mania: clinical and neurocognitive correlates. AB - PURPOSE: To study social functioning, and its relationship with clinical and neurocognitive variables, in patients having their first treatment contact for a manic episode. METHODS: A total of 55 first contact mania patients, 34 with a first manic episode (FM) and 21 with previously untreated manic episodes (PM), and 110 healthy control subjects matched for age, sex and education to the patient group, completed the Social Functioning Scale (SFS), a self-reported assessment of social functioning. The patients also completed a broad neuropsychological test battery. RESULTS: Both patient groups scored significantly lower on self-rated social functioning compared to healthy controls, with PM patients reporting significantly lower functioning than FM patients. There were no significant correlations between clinical symptoms and social functioning. On a trend level, a reduced SFS score was associated with more cannabis use, higher levels of depression and more depressive episodes as well as an earlier age at onset. There was no significant association between social function and neurocognition. CONCLUSIONS: Social dysfunction was present in patients with BD at first treatment contact-the main predictors of which being the severity of clinical symptoms. PMID- 23351833 TI - Anomalous subjective experiences in schizophrenia, bipolar disorder, and unipolar depression. AB - BACKGROUND: The purpose of the present study was to compare anomalous subjective experiences in patients with schizophrenia, bipolar disorder, and unipolar depression, in order to elucidate differences in subjective experiences and examine their potential clinical correlates in schizophrenia and mood disorders. METHODS: The subjective experiences of 78 outpatients with schizophrenia (n=32), bipolar disorder (n=24) and unipolar depression (n=22), and 32 healthy controls were comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). RESULTS: The FCQ total score was significantly higher in the schizophrenia and depression groups than in the healthy control group. There were no significant differences in the FCQ total or subscale scores among the schizophrenia, unipolar depression, and bipolar disorder groups. In the schizophrenia group, the Positive and Negative Syndrome Scale negative factor score was a significant negative predictor of the severity of subjective experiences assessed by the FCQ total score. Disruption of subjective experiences in patients with unipolar depression was associated with greater severity of depressive symptoms and younger age. In the bipolar disorder group, women reported more disruptions in subjective experience. CONCLUSIONS: Anomalous subjective experiences measured by the FCQ are not specific to schizophrenia, and the severity of these experiences in unipolar depression is substantially high. The finding of a dissimilar pattern of predictors of subjective experiences across different diagnostic groups suggests the complexity and variety of factors contributing to anomalous subjective experiences in schizophrenia and mood disorders. PMID- 23351834 TI - [Idiopathic pulmonary fibrosis and sleep disorders]. AB - Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease. Despite progress made in understanding the pathophysiological mechanisms behind the development of the disease, its prognosis is poor. For this reason, any measure to improve the quality of life for these patients should be preferred. Some authors are interested in sleep disorders, and possible impact on quality of life. Patients with IPF have lowered scores of quality of life compared to those found in general population, with some correlation with the scores of sleep quality. There is a hyperfragmentation with many arousals and desaturation events. Some authors also report an apnea-hypopnea index higher in these patients, but these data are not found in all the studies. Correcting these obstructive phenomena may have a beneficial effect on survival, which would make systematic the sleep assessment in these patients. Finally, the relationship between IPF, gastroesophageal reflux and sleep apnea syndrome remains unclear. PMID- 23351835 TI - Adipose tissue arachidonic acid content is associated with the expression of 5 lipoxygenase in atherosclerotic plaques. AB - BACKGROUND: The content of arachidonic acid in adipose tissue is positively associated with the risk of myocardial infarction, whereas the content of eicosapentaenoic acid in adipose tissue has been reported to be negatively associated with the risk of myocardial infarction. Both arachidonic acid and eicosapentaenoic acid are substrates for the synthesis of pro-inflammatory leukotrienes and leukotrienes derived from eicosapentaenoic acid are generally much less potent. In this study we hypothesized that a high content of arachidonic acid in adipose tissue would reflect a high formation of arachidonic acid derived leukotrienes and a high expression of 5-lipoxygenase in atherosclerotic plaques. Likewise, we hypothesized that a high content of eicosapentaenoic acid in adipose tissue would reflect a low formation of arachidonic acid derived leukotrienes and a low expression of 5-lipoxygenase in plaques. METHODS: In a cross sectional study we included 45 consecutive subjects undergoing femoral thrombendarterectomy. The expression of 5-lipoxygenase in plaques was assessed by a semi-automated image analysis computer programme after immunohistochemical staining with mono-clonal 5-lipoxygenase antibodies. Leukotriene B4 and cysteinyl leukotriene formation from stimulated femoral artery plaques was quantified using ELISA methods. The fatty acid content of adipose tissue biopsies from the thigh was analyzed using gas chromatography. Associations between variables were assessed by Pearson correlations and were further explored in a multivariable linear regression model adjusting for potential confounders. RESULTS: A high content of arachidonic acid in adipose tissue was associated with a higher expression of 5-lipoxygenase in plaques (r = 0.32, p = 0.03), but no significant associations with leukotriene B4 (r = 0.22, p = 0.14) and cysteinyl leukotriene (r = -0.11, p = 0.46) formation was seen. No significant associations were found between the content of eicosapentaenoic acid in adipose tissue and 5-lipoxygenase expression or leukotriene formation in plaque. CONCLUSIONS: Adipose tissue arachidonic acid contents correlated positively with the expression of 5-lipoxygenase in plaques. This association might represent a causal link between adipose tissue arachidonic acid and the risk of myocardial infarction but confirmatory studies are needed. PMID- 23351837 TI - Methamphetamin abuse a new concern in Iran. PMID- 23351836 TI - Evaluation of an internet-based aftercare program to improve vocational reintegration after inpatient medical rehabilitation: study protocol for a cluster-randomized controlled trial. AB - BACKGROUND: Mental disorders are the main reasons for rising proportions of premature pension in most high-income countries. Although inpatient medical rehabilitation has increasingly targeted work-related stress, there is still a lack of studies on the transfer of work-specific interventions into work contexts. Therefore, we plan to evaluate an online aftercare program aiming to improve vocational reintegration after medical rehabilitation. METHODS: Vocationally strained patients (n = 800) aged between 18 and 59 years with private internet access are recruited in psychosomatic, orthopedic and cardiovascular rehabilitation clinics in Germany. During inpatient rehabilitation, participants in stress management group training are cluster randomized to the intervention or control group. The intervention group (n = 400) is offered an internet-based aftercare with weekly writing tasks and therapeutic feedback, a patient forum, a self-test and relaxation exercises. The control group (n = 400) obtains regular e-mail reminders with links to publicly accessible information about stress management and coping. Assessments are conducted at the beginning of inpatient rehabilitation, the end of inpatient rehabilitation, the end of aftercare, and 9 months later. The primary outcome is a risk score for premature pension, measured by a screening questionnaire at follow-up. Secondary outcome measures include level of vocational stress, physical and mental health, and work capacity at follow-up. DISCUSSION: We expect the intervention group to stabilize the improvements achieved during inpatient rehabilitation concerning stress management and coping, resulting in an improved vocational reintegration. The study protocol demonstrates the features of internet-based aftercare in rehabilitation. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register (ISRCTN:ISRCTN33957202). PMID- 23351838 TI - The impact of the Cyprus comprehensive smoking ban on air quality and economic business of hospitality venues. AB - BACKGROUND: Several countries, including Cyprus, have passed smoke-free legislations in recent years. The goal of this study was to assess the indoor levels of particulate matter in hospitality venues in Cyprus before and after the implementation of the law on 1/1/2010, evaluate the role of enforcement, and examine the legislation's effect on revenue and employment. METHODS: Several hospitality venues (n = 35) were sampled between April 2007 and January 2008, and 21 of those were re-sampled after the introduction of the smoking ban, between March and May 2010. Data on enforcement was provided by the Cyprus Police whereas data on revenue and employment within the hospitality industry of Cyprus were obtained from the Cyprus Statistical Service; comparisons were made between the corresponding figures before and after the implementation of the law. RESULTS: The median level of PM2.5 associated with secondhand smoking was 161 MUg/m3 pre ban and dropped to 3 MUg/m3 post-ban (98% decrease, p < 0.0001). Furthermore, in the year following the ban, the hotel turnover rate increased by 4.1% and the restaurant revenue by 6.4%; employment increased that same year by 7.2% and 1.0%, respectively. CONCLUSION: Smoke free legislations, when enforced, are highly effective in improving the air quality and reducing the levels of indoor PM2.5. Strict enforcement plays a key role in the successful implementation of smoking bans. Even in nations with high smoking prevalence comprehensive smoking laws can be effectively implemented and have no negative effect on accommodation, food, and beverage services. PMID- 23351839 TI - Isolated brainstem cysticercosis: a review. AB - OBJECTIVE: Review of patients with isolated brainstem cysticercus to outline the features of this form of neurocysticercosis. METHODS: MEDLINE and manual search of patients with isolated brainstem cysticercus. Abstracted data included: demographic profile, clinical manifestations, neuroimaging findings, evolutive stage of parasites neurocysticercosis, therapy, and follow-up. RESULTS: Twenty nine patients were reviewed. Of these, 22 (76%) came from India. Mean age was 31 years, and 72% were men. Parasites were located in midbrain (16 patients), pons (12 patients), and medulla (one patient). All but three lesions were less than 10 mm in diameter and most were at or near the midline. Most common clinical forms of presentation were isolated paresis of the third cranial nerve, internuclear ophthalmoplegia, and crossed brainstem syndromes. Neuroimaging studies showed colloidal cysticercus in 24 patients, vesicular cysts in four, and a calcification in one. Fourteen patients received cysticidal drugs, eight were treated with steroids alone, and three received no therapy at all. The remaining four patients underwent surgical resection of the lesion. Twenty-seven patients recovered completely and the remaining two were left with mild sequelae. Control neuroimaging studies showed complete or partial resolution of the lesion in the 18 patients in whom they were performed. CONCLUSIONS: Isolated brainstem cysticercosis is rare. Clinical and neuroimaging findings on admission allowed a correct differentiation of this condition from other space-occupying lesions of the brainstem (tuberculomas, abscesses, gliomas) in most patients. The prognosis is benign provided the patients receive prompt therapy. PMID- 23351840 TI - Differentiation of pure vasogenic edema and tumor-infiltrated edema in patients with peritumoral edema by analyzing the relationship of axial and radial diffusivities on 3.0T MRI. AB - OBJECT: The purpose of this study was to analyze the relationship of axial diffusivity (AD) and radial diffusivity (RD) in peritumoral edema of high grade glioma, metastasis, and meningioma, and to differentiate tumor-infiltrated edema from pure vasogenic edema. MATERIALS AND METHODS: Twenty patients with high-grade glioma and 16 with meningioma or metastatic tumor were enrolled in our study. All cases were confirmed by histopathological study. Diffusion tensor imaging (DTI) was performed in all patients. Peritumoral edema of high-grade glioma was considered tumor-infiltrated edema, and edema of meningioma or metastasis was considered pure vasogenic edema. Fractional anisotropy (FA), mean diffusivity (MD), AD, RD, regression coefficient of RD to AD (RCRD-AD), and tumor infiltration index (TII) in tumor-infiltrated edema and pure vasogenic edema were analyzed and compared. Receiver operating characteristic (ROC) curve analysis was conducted to demonstrate their differential effectiveness. RESULTS: RCRD-AD in tumor-infiltrated edema (0.724+/-0.125) was significantly higher than that in pure vasogenic edema (0.571+/-0.111) (P=0.001). FA of tumor-infiltrated edema (0.175+/-0.025) was significantly lower than that of pure vasogenic edema (0.203+/-0.035) (P=0.007). Other parameters showed no significant difference between the 2 types of edema. ROC curve analysis showed RCRD-AD was the most effective parameter in distinguishing tumor-infiltrated edema from pure vasogenic edema. Using a threshold of 0.6, a sensitivity of 0.85 and specificity of 0.69 can be achieved with RCRD-AD. CONCLUSION: Analysis of the AD and RD relationship may reflect differences in diffusion characteristics of edema surrounding high grade glioma and meningioma or metastasis, and may be helpful in detecting peritumoral infiltration in high-grade glioma. PMID- 23351841 TI - Assessment of the vaccine industry in Iran in context of accession to WTO: a survey study. AB - BACKGROUND: The vaccine industry is one of the most important health-related industries. It can be affected by accession to the World Trade Organization (WTO) because of probable dramatic changes in the business environment. Iran has already initiated accession negotiations. PURPOSE OF THE STUDY: In this paper, we investigate the position of, challenges to, and opportunities for vaccine manufacturing in Iran with regard to accession to the WTO. METHODS: This is a qualitative and cross sectional study. To collect information, we designed a questionnaire and interviewed some of the vaccine industry's key opinion leaders in Iran. Before the interviews were conducted, the questionnaires were sent to these individuals by email. RESULTS: According to the interviewees, the country's main challenges with regard to accession to the WTO are the lack of firm internal intellectual property (IP) rules, not being recognized as pre-qualified by the World Health Organization (WHO), the use of old equipment, and a lack of cooperation with global vaccine companies. MAJOR CONCLUSIONS: Iran's local vaccine industry, with a long history and international reputation that could be used as an advantage, is faced with several challenges, such as problems with keeping up with Current Good Manufacturing Practice (cGMP), a lack of adequate and meaningful investment in research and development (R&D), and limitations on private sector participation in the production of vaccines.Gradual privatization of the industry, improved international relations, utilization of the R&D power of small hi-tech companies, consistent education of human resources, and modernization of infrastructures and equipment are among the suggested solutions. PMID- 23351842 TI - The effect of Camellia Sinensis (green tea) mouthwash on plaque-induced gingivitis: a single-blinded randomized controlled clinical trial. AB - Background and the purpose of the StudyComplementary medicine received high attention during last decades. We aimed to assess the efficacy of Green tea mouthwash on plaque-induced gingivitis as the most common form of periodontal disease. METHODS AND MATERIALS: We designed a single blinded placebo controlled clinical trial. High school female students with chronic generalized plaque induced gingivitis were distributed to receive either 5 ml of Green tea 5% two times/day or normal saline with the same dosage. Gingival index (Sillness & Loe), plaque index (Sillness & Loe) and bleeding index (Barnett) were recorded at baseline and five consecutive weeks. Comparisons were made by a general linear model, repeated measure ANOVA and a Bonferroni test applied for multiple comparisons. RESULTS: Twenty five students were recruited in each arm of the study. A significant improvement was observed in all periodontal indices during the study (P < 0.001). Two groups were contrasted by changing patterns of alteration of indices (P < 0.05). Although total amount of improvement was higher in mouthwash group, the differences did not reach a statistically significant level (P > 0.05, observed power for GI: 0.09, PI: 0.11 and BI: 0.07). CONCLUSION: Green tea mouthwash may be a safe and feasible adjunct treatment for inflammatory periodontal diseases. A future larger scale study is warranted for better evaluating the effect of green tea. PMID- 23351843 TI - Cilia develop long-lasting contacts, with other cilia. PMID- 23351844 TI - Evaluation of organ-specific peripheral doses after 2-dimensional, 3-dimensional and hybrid intensity modulated radiation therapy for breast cancer based on Monte Carlo and convolution/superposition algorithms: implications for secondary cancer risk assessment. AB - BACKGROUND AND PURPOSE: To make a comprehensive evaluation of organ-specific out of-field doses using Monte Carlo (MC) simulations for different breast cancer irradiation techniques and to compare results with a commercial treatment planning system (TPS). MATERIALS AND METHODS: Three breast radiotherapy techniques using 6MV tangential photon beams were compared: (a) 2DRT (open rectangular fields), (b) 3DCRT (conformal wedged fields), and (c) hybrid IMRT (open conformal+modulated fields). Over 35 organs were contoured in a whole-body CT scan and organ-specific dose distributions were determined with MC and the TPS. RESULTS: Large differences in out-of-field doses were observed between MC and TPS calculations, even for organs close to the target volume such as the heart, the lungs and the contralateral breast (up to 70% difference). MC simulations showed that a large fraction of the out-of-field dose comes from the out-of-field head scatter fluence (>40%) which is not adequately modeled by the TPS. Based on MC simulations, the 3DCRT technique using external wedges yielded significantly higher doses (up to a factor 4-5 in the pelvis) than the 2DRT and the hybrid IMRT techniques which yielded similar out-of-field doses. CONCLUSIONS: In sharp contrast to popular belief, the IMRT technique investigated here does not increase the out-of-field dose compared to conventional techniques and may offer the most optimal plan. The 3DCRT technique with external wedges yields the largest out-of-field doses. For accurate out-of-field dose assessment, a commercial TPS should not be used, even for organs near the target volume (contralateral breast, lungs, heart). PMID- 23351846 TI - Infiltrating lobular breast cancer: truly a separate entity! Consequences for radiation therapy. AB - Infiltrating lobular cancer is known for its diffuse growth pattern and difficult radiological visualization. Based on this review, infiltrating lobular cancer patients do not have a higher local recurrence risk after breast conserving therapy. Lobular histology should also be considered as a separate prognostic factor in favour of referral for radiotherapy after mastectomy. PMID- 23351845 TI - Enhanced radioresponse with a novel recombinant human endostatin protein via tumor vasculature remodeling: experimental and clinical evidence. AB - PURPOSE: This study aimed to examine the effect of the novel recombinant human endostatin (rh-Endo) protein on tumor vasculature, and to explore and evaluate the optimal scheduling of rh-Endo and radiotherapy (RT). METHODS: Tumor-perfusion parameters and hypoxia were monitored after rh-Endo treatment in 10 non-small cell lung-cancer (NSCLC) patients. Eight-week female C57BL/6J mice were randomized to receive rh-Endo or control (saline) once daily for 12 days when Lewis lung carcinoma (LLC) reached approximately 100-150 mm(3). On planned days, tumors were measured for cell apoptosis, microvessel density, pericytes, blood vessel morphology, and tumor hypoxia. The tumor response under different combinations of rh-Endo and RT schedules was evaluated. RESULTS: Tumor hypoxia was significantly reduced 5 days after rh-Endo in NSCLC patients, and a similar result was found in the LLC mouse model. The anti-tumor effect was markedly enhanced when RT was administered within the remodeling period compared to any other treatment schedule. rh-Endo treatment remodeled the tumor vasculature after 5 days by reducing microvessel density and increasing pericytic coverage of the vessel endothelium. CONCLUSION: This study demonstrated decreased hypoxia in animals and patients upon rh-Endo treatment, which also enhanced the radioresponse within the vasculature-remodeling period. The optimal clinical combination of rh-Endo and RT warrants further investigation. PMID- 23351847 TI - Temperature changes among organophosphate poisoned patients, Tehran- Iran. AB - BACKGROUND: Acute poisoning with organophosphorus compounds (OPs) is a major global clinical problem in the developing countries. There have been many animal studies and few human surveys on the effects of organophosphorus pesticide (OP) poisoning on thermoregulation. The aim of this prospective study was to document the pattern of tympanic temperature changes among OP poisoned patients throughout the length of their hospital stay. METHODS: 60 patients with diagnose of organophosphate poisoning were included in this study. Questioner was filled out by trained nurses including demographic, clinical and paraclinical data. Tympanic temperature and Pulse rate data of the cases were collected on five- occasions after admission. RESULTS: There were 41 (68.3%) male and 19 (31.7%) female, with a mean age of 34.4 +/-19.4 years (range 13-89 years). Forty five patients had intentional poisoning for suicidal attempt. At the time of entry, the mean tympanic temperature, pulse rate, respiratory rate and blood pressure (systolic and diastolic) of the OP poisoned patients were respectively 37.1+/-0.6 degrees C (36.0- 39.5), 91+/-18 (55-145), 18+/-5.6 (8-44), 116+/-20 mm Hg (70-170) and 75+/ 11.6 mm Hg (40-110). 41.7% of the cases had serum butyryl cholinesterase activities (BChE) >= 50% normal (>=1600 mU/ml). Our patients had normal temperature at the time entry (mean = 37.1). Tympanic temperature decreasing below 36 degrees C was not detected among the patients during the study period. A rise in mean tympanic temperature was found after atropine administration. CONCLUSION: Our study showed hypothermia was not considerable factor among organophosphate poisoned patients, although more studies with similar situations in tropical countries are needed. PMID- 23351848 TI - The functional anatomy of suggested limb paralysis. AB - Suggestions of limb paralysis in highly hypnotically suggestible subjects have been employed to successfully model conversion disorders, revealing similar patterns of brain activation associated with attempted movement of the affected limb. However, previous studies differ with regard to the executive regions involved during involuntary inhibition of the affected limb. This difference may have arisen as previous studies did not control for differences in hypnosis depth between conditions and/or include subjective measures to explore the experience of suggested paralysis. In the current study we employed functional magnetic resonance imaging (fMRI) to examine the functional anatomy of left and right upper limb movements in eight healthy subjects selected for high hypnotic suggestibility during (i) hypnosis (NORMAL) and (ii) attempted movement following additional left upper limb paralysis suggestions (PARALYSIS). Contrast of left upper limb motor function during NORMAL relative to PARALYSIS conditions revealed greater activation of contralateral M1/S1 and ipsilateral cerebellum, consistent with the engagement of these regions in the completion of movements. By contrast, two significant observations were noted in PARALYSIS relative to NORMAL conditions. In conjunction with reports of attempts to move the paralysed limb, greater supplementary motor area (SMA) activation was observed, a finding consistent with the role of SMA in motor intention and planning. The anterior cingulate cortex (ACC, BA 24) was also significantly more active in PARALYSIS relative to NORMAL conditions - suggesting that ACC (BA 24) may be implicated in involuntary, as well as voluntary inhibition of prepotent motor responses. PMID- 23351849 TI - Fundamental deficits of auditory perception in Wernicke's aphasia. AB - OBJECTIVE: This work investigates the nature of the comprehension impairment in Wernicke's aphasia (WA), by examining the relationship between deficits in auditory processing of fundamental, non-verbal acoustic stimuli and auditory comprehension. WA, a condition resulting in severely disrupted auditory comprehension, primarily occurs following a cerebrovascular accident (CVA) to the left temporo-parietal cortex. Whilst damage to posterior superior temporal areas is associated with auditory linguistic comprehension impairments, functional imaging indicates that these areas may not be specific to speech processing but part of a network for generic auditory analysis. METHODS: We examined analysis of basic acoustic stimuli in WA participants (n = 10) using auditory stimuli reflective of theories of cortical auditory processing and of speech cues. Auditory spectral, temporal and spectro-temporal analysis was assessed using pure tone frequency discrimination, frequency modulation (FM) detection and the detection of dynamic modulation (DM) in "moving ripple" stimuli. All tasks used criterion-free, adaptive measures of threshold to ensure reliable results at the individual level. RESULTS: Participants with WA showed normal frequency discrimination but significant impairments in FM and DM detection, relative to age- and hearing-matched controls at the group level (n = 10). At the individual level, there was considerable variation in performance, and thresholds for both FM and DM detection correlated significantly with auditory comprehension abilities in the WA participants. CONCLUSION: These results demonstrate the co occurrence of a deficit in fundamental auditory processing of temporal and spectro-temporal non-verbal stimuli in WA, which may have a causal contribution to the auditory language comprehension impairment. Results are discussed in the context of traditional neuropsychology and current models of cortical auditory processing. PMID- 23351850 TI - Competent and compassionate care for the sickest of children. PMID- 23351851 TI - Why not a slow code? PMID- 23351852 TI - Can a minor refuse assent for emergency care? PMID- 23351853 TI - Pediatric end-of-life decisions when abuse is suspected. PMID- 23351854 TI - Teaching trainees to perform procedures on critically ill children: ethical concerns and emerging solutions. PMID- 23351855 TI - The AMA code of medical ethics' opinion on confidential services for children and adolescents. PMID- 23351856 TI - Titration of medication and the management of suffering at the end of life. PMID- 23351857 TI - Off-label use of therapeutic hypothermia for infants with hypoxic-ischemic encephalopathy. PMID- 23351858 TI - Minors' refusal of life-saving therapies. PMID- 23351859 TI - Legal and ethical policies regarding research involving critically ill children. PMID- 23351860 TI - Ethical issues in pediatric emergency medicine's preparation for and response to disasters. PMID- 23351861 TI - Adolescents' right to consent to reproductive medical care: balancing respect for families with public health goals. PMID- 23351862 TI - Bone regeneration strategies: current trends but what the future holds? PMID- 23351863 TI - Treatment of cartilage lesions: what works and why? AB - Cartilage injuries have a high incidence and a high impact on society. In an attempt to fulfill patients' expectations and successfully treat this pathology, various techniques have been developed over the years. Treatments proposed for cartilage lesions are described with their rationale and indications, ranging from conservative measures to surgical approaches, reparative or regenerative. Among the numerous and heterogeneous procedures proposed over time to treat cartilage defects none has clearly proven to lead to a hyaline articular surface nor to offer better clinical results. Regenerative procedures have been introduced as ambitious techniques that aim to overcome the limitations of the more traditional reparative approaches and restore the articular surface with a hyaline-like tissue; improvement in tissue engineering with new scaffolds as well as new regenerative options involving growth factors or MSCs are currently being investigated as promising solutions to further improve the treatment of cartilage lesions. However, the current literature findings are not conclusive. Randomized controlled trials are necessary to evaluate new regenerative approaches, to show clearly advantages and disadvantages with respect to the more traditional procedures, besides their potential, limits, and indications to improve the treatment of patients affected by chondral and osteochondral lesions. Since clear and commonly accepted treatment algorithms are not available in the literature, the massively increasing number of controversial results may be confusing for the orthopaedic surgeon who has to choose the proper management of patients with cartilage lesions. Thus, the results obtained through the study of the authors' 20 years' experience in cartilage treatment were analyzed to give some indications on the potential and limits of different treatment approaches available in clinical practice. PMID- 23351864 TI - Fresh osteochondral allograft is a suitable alternative for wide cartilage defect in the knee. AB - INTRODUCTION: There are several surgical options to restore a wide osteochondral defect in the knee. Fresh osteochondral allografts are usually considered a poor alternative due to their difficulties in surgical application. The aim of this work is first to present our experience including the surgical technique and the functional results of patients receiving fresh osteochondral allograft to restore major knee lesions, then, to compare our results with other results presented in literature. METHODS: Between 2006 and 2011, we treated 11 patients with osteochondral lesion of the knee (Outerbridge IV degrees ). The average lesion size was 10.3 cm(2) (range 3-20 cm(2)). The average age was 34 years (range 18 66). Patients were followed from 12 to 55 months (average of 26.5) through clinical examination, X-ray film and MRI every 3 months for the first year, then every 6 months. RESULTS: The treatment was successful in 10 patients showing pain regression and mean IKDC subjective score improvements from 27.3 to 58.7. The IKDC objective score also improved of at least one class for each patient except the who failed. The radiographs show good osteointegration in all cases but one. CONCLUSIONS: Fresh allograft is an effective therapy for osteochondral defects repair because it allows functional recovery in a considerable number of patients. This technique obtains better results in lesion smaller than 8 cm(2). However larger lesion show good results. LEVEL OF EVIDENCE: Therapeutic study, Level IV. PMID- 23351865 TI - Indications and limits of meniscal allografts. AB - Meniscal allograft transplantation has emerged as a useful treatment for carefully selected patients. The aim of this review of meniscal allograft transplantation is to put this procedure into a clinical perspective. Since there still is a lack of consensus on how the success of meniscal transplantation should be evaluated it is difficult to compare study outcomes. Nevertheless, almost all studies report an increase in patient satisfaction and improvement in pain and function. Clinical and functional outcome is improved in the majority of patients. Progression of cartilage degeneration according to MRI and radiological criteria was halted in a number of patients, indicating a chondroprotective effect. Joint space narrowing is only significantly progressive at long-term follow-up. On magnetic resonance imaging, shrinkage is seen after some years, but more in lyophilized allografts. Second-look arthroscopy usually shows good healing to the capsule. Overall, the clinical results of this type of surgery are encouraging and long-lasting in a well selected patient population who suffered a total meniscectomy. Meniscal allografting appears to becoming the golden standard therapy for these type of patients. PMID- 23351866 TI - Application of scaffolds for bone regeneration strategies: current trends and future directions. AB - Scaffolds are extensively used in surgery to replace missing bone and to achieve bony union and fusion. An ideal scaffold should not only maintain, induce, and restore biological functions where cells, extracellular matrix, and growth factors are needed, but also have the right properties with respect to degradation, cell binding, cellular uptake, non-immunogenicity, mechanical strength, and flexibility. Here we examine both the basic science behind the development of scaffolds and comprehensively and systematically review the clinical applications. PMID- 23351867 TI - Repair of osteochondral defects in joints--how to achieve success. AB - Osteochondral defects in the knee are difficult to repair because intrinsic healing of cartilage is poor and gradual progression to "early-onset" osteoarthritis leads to severe pain and disability. Of all methods tested to achieve regeneration of hyaline cartilage and long-lasting repair, autologous chondrocyte transplantation (ACI-C and MACI) has been the most successful with 80% of good results and graft survival in this unit in a very large series over 10 years. The repair mechanism is unclear but our work shows that the criteria for success are: young patient age, no previous operative procedures on the defect, no obesity, no smoking, defect on femoral condyles or trochlea and no pre existing degenerative joint changes. Future research is aimed at non transplantation, single-stage procedures aided by use of new scaffolds and growth factors and the extension of such techniques into arthritic joints. PMID- 23351868 TI - Clinical applications of growth factors in bone injuries: experience with BMPs. AB - The management of open fractures and delayed or non unions continue to be complicated by high rates of treatment failure and significant patient disability and dissatisfaction. The use of bone morphogenetic proteins (BMPs) in the treatment of these injuries has been assessed by several authors. BMPs induce the process of bone healing by recruiting bone-forming cells to the area of lesion. The use of BMP currently has two FDA-approved indications: treatment of open tibial fractures treated with intramedullary fixation and treatment of tibia long bone non-union. Despite this limited target, off-label BMP use continues to push the spectrum for new applications. This review describes the current evidence for the use of BMPs in open fractures and non-unions. PMID- 23351869 TI - Autograft versus BMPs for the treatment of non-unions: what is the evidence? AB - Autograft is considered the gold standard in non-union treatment. However, it is associated with significant morbidity and limited biological activity. The introduction of bone morphogenetic proteins (BMPs) has added a valuable tool to the surgeon's possibilities. The initial expectations of the effectiveness of BMPs were high, but over the years the union rate of BMPs was shown to be comparable with autograft. In this overview, both treatment modalities are compared. The off-label use of BMPs, the combination of BMPs and autograft, and the economic perspective of BMP use are summarized. In their current formulation, BMPs are an effective alternative for autograft in selected cases. The beneficial effect outweighs the economic costs. Widening of the indication to other long bone non-unions and new formulations are expected in the nearby future. PMID- 23351870 TI - Treatment of non-unions with bone defects: which option and why? AB - Bone defects associated with non-unions occur as a result of the initial insult or as a consequence of bone excision following non-union development. Historically management of this clinical scenario consisted mainly of amputation, which provided a short recovery period but a significant loss of limb function. Today treatment has evolved and multiple options are available for reconstruction of the bone defect. Broadly these are: bone shortening with lengthening later or bone transport and 'docking' (distraction osteogenesis based techniques); the use of vascularised and non-vascularised bone grafts; bone substitutes; stem cells; growth factors; scaffolds and gene therapy. PMID- 23351871 TI - Cellular therapies for the treatment of non-union: the past, present and future. AB - Non-union fracture is a pathological condition having some impairment of the cellular part of the repair: a reduction of MSC and of the osteoblastic activation. Non union is therefore a good indication for cell-based therapies using stem cells. We described the rational of this treatment and described the technique of autologous bone marrow concentrate implantation that was until now used. With the development of stem cell research and regenerative medicine, we believed that therapy based on cytotherapy has great potential. In this review, clinical applications of cytotherapy are summarized and analyzed. Current problems and future challenges are discussed. PMID- 23351872 TI - Genetic predisposition to non-union: evidence today. AB - Atrophic non-union represents a complex clinical condition and research is ongoing in an effort to elucidate its pathophysiology and to offer new and more efficient treatment modalities. Differences seen in fracture healing responses and final outcome may be attributed among other factors to biological variations between patients resulting in a "disturbed" signalling pathway and an "inert or deficient local biology with reduced potentials for bone regeneration". The genetic contribution with or without the interaction of other exogenous factors in cases of impaired fracture healing, is yet to be elucidated. However, preliminary animal and human studies demonstrate the molecular basis of fracture non-unions and correlate genetic variants of the molecules regulating fracture healing and their expression patterns with impaired bone healing and fracture non union. Further research is needed to clarify the genetic component and its role and interaction with other risk factors that may result in increased susceptibility of a patient to develop this complication. PMID- 23351873 TI - Teriparatide in the treatment of non-unions: scientific and clinical evidences. AB - INTRODUCTION: Each fracture has a failing risk which can lead to a non-union. Among the non-invasive strategies proposed to improve bone healing, also in non union, the use of teriparatide, a drug for the treatment of the osteoporosis, has increasing supporting data. EXPERIMENTAL DATA: Many studies mainly on rats, but also on primates, demonstrate the positive effect on fracture healing of teriparatide, both in physiological and pathological conditions, with a more rapid evolution of the reparative callus. CLINICAL DATA: A double blinded randomized controlled study on wrist fractures demonstrated a positive effect, in term of healing speed, of teriparatide at the dose of 20 MUg/day, but not at the higher dose of 40 MUg/day. A prospectic randomized study on pelvic fractures showed a faster healing in teriparatide treated patients. The use of teriparatide in non-unions is reported as effective in numerous case report. The effect of teriparatide seems very useful in the non-unions consequent to an atypical femoral fracture after long-term administration of bisphosphonates. CONCLUSIONS: A conceivable positive effect of teriparatide on fracture healing is well documented on animals, and very likely on humans, however further studies are needed to confirm these hopeful hypotheses. PMID- 23351874 TI - Clinical strategies at the docking site of distraction osteogenesis: are open procedures superior to the simple compression of Ilizarov? AB - This retrospective review reports on forty-five tibial non-unions who underwent docking site treatment for non-union using closed versus open and endoscopic strategies. In this cohort of patients, all but twelve were infected non-unions. Sixteen patients initially treated with single compression were compared to twenty-three patients treated with open revision of the docking site, and six endoscopic procedures. In the single compression group, an average of 6.4 cm of bone was resected and index lengthening was 2.01. In the open revision group, a mean of 9.4 cm was resected and the index lengthening was 1.72. In the endoscopic group, an average of 8.6 cm of bone was resected and index lengthening was 1.71. Consolidation at the docking site occurred in 41 cases out of 45 following the first procedure. There was no statistical difference between the three groups. Conclusive evidence of superiority of one modality of treatment over the other cannot be drawn from our data. The simple compression procedure requires less invasive surgery and is probably less demanding and more cost-effective in short transports, although the two cases of failure due to recurrence of sepsis were observed after this procedure. Further studies are desirable to investigate the effectiveness of open docking site grating procedures. PMID- 23351875 TI - Monotherapy vs. polytherapy in the treatment of forearm non-unions and bone defects. AB - OBJECTIVE: To determinate the efficacy of "polytherapy", a surgical technique that utilize all the components of the diamond concept (mesenchymal stem cells, bone morphogenetic proteins and scaffold) versus a "monotherapy", a surgical technique that utilize only one component of the diamond conceptin the treatment of severe forearm non-unions. METHODS: We studied a database of 52 patients with 52 forearm non-unions; we classified the patients with the NUSS SCORE and we divided the patients in two group according to the treatment received. So we distinguished a group of patients treated according to the principles of "monotherapy" (33 patients) and a group of patients treated according to the principles of "polytherapy" (19 patients). The minimum follow up was 12 months. RESULTS: In the monotherapy group 21/33 non-unions (63.64%) went on to develop a radiographic and clinical healing within a period of 12 months, the calculated DASH SCORE showed a mean value of 55.15 points. In the polytherapy group 17/19 (89.47%) nonunions went on to develop clinical and radiographic healing within 12 months, and the average DASH score showed a mean value of 45.47 points. CONCLUSION: The polytherapy technique with the use of recombinant morphogenetic proteins, autologous MSCs and scaffold in the same surgical time appears to be an effective treatment for patients with severe forearm non-unions. PMID- 23351876 TI - Vascularized bone grafts for the management of skeletal defects in orthopaedic trauma and reconstructive surgery. AB - Bone loss from trauma, neoplasia, reconstructive surgery and congenital defects remains a major health problem. The long-term clinical goal is to reconstruct bony tissue in an anatomically functional three-dimensional morphology. In the extremities, bone grafts are used for the treatment of non-unions and necrotic lesions, for skeletal structural support and for the reconstruction of defects resulting from trauma, tumor excision, osteomyelitis, congenital pseudarthrosis, or radiation necrosis. In all cases their use is successful provided that the host bed has adequate vascularization. In cases of decreased blood supply, a vascularized bone graft should be applied. The intrinsic blood supply of the vascularized bone grafts leads to higher success rates and to acceleration of the repair process in the reconstruction of defects and necrotic lesions of the skeleton. PMID- 23351877 TI - Subtrochanteric fracture non-unions with implant failure managed with the "Diamond" concept. AB - BACKGROUND: Subtrochanteric femoral non-unions in the setting of failed metalwork pose a challenging clinical problem. This study assessed the clinical outcome of patients treated according to the principles of the "Diamond" concept. METHODS: Between 2007 and 2011 all patients presented with a subtrochanteric atrophic aseptic non-union in the setting of metalwork failure (broken cephalomedullary reconstruction nail), and treated in a single tertiary referral unit were included to this study. The hypertrophic and the non-unions of pathologic fractures were excluded. The revision strategy was based on the "Diamond concept"; optimisation of the mechanical and the biological environment (implantation of growth factor (rhBMP-7), scaffold (RIA bone graft from contralateral femur) and concentrated mesenchymal stem cells (MSCs) harvested from the iliac crest). The minimum follow up was 26 months (16-48). RESULTS: Fourteen patients met the inclusion criteria. A specific sequence of metalwork failure was noted with initial breakage of the distal locking screws followed by nail breakage at the lag screw level. The intraoperative examination of the removed nails revealed no gross structural damage indicative of inappropriate drilling at the time of the initial intramedullary nailing. Varus mal-alignment was present in the majority of the cases, with an average of 5.2 degrees (0-11). The average time to distal locking screw failure was 4.4 months (2-8.5) and nail failure was 6.5 months (4-10). The time to union after the revision surgery was 6.8 months (5-12). Complications included two deaths in elderly patients (due to unrelated causes), one pulmonary embolism, one myocardial infarction, one below the knee deep vein thrombosis and one blade plate failure that required further revision with double plating and grafting. CONCLUSION: Varus mal-alignment must be avoided in the initial stabilisation of subtrochanteric fractures. Distal locking screw failure is predictive of future fracture non-union and nail breakage. In the absence of sepsis, a single stage procedure based on the "Diamond concept" that simultaneously optimizes the mechanical and biological environment is a successful method for managing complex subtrochanteric atrophic non-unions with failed metalwork. PMID- 23351878 TI - Management of shoulder periprosthetic fractures: our institutional experience and review of the literature. AB - Fractures of the humerus in patients with total shoulder replacement are rare and difficult to treat. The treatment of periprosthetic humeral fractures depends on the location of the fracture in relation to the humeral stem and the stability of the stem/bone interface. We wished to determine the treatment outcomes in a series of patients managed in our institution with periprosthetic humeral fractures. We also carried out a review of the literature. Over a 5 year period, out of 10 patients, 7 were available at the final follow up with a mean age of 72 years (range 68-75). A fall from standing height was the most common mechanism of injury. All patients were found to have stable prosthesis in situ and were treated with angular stable plates and cerclage wiring. The mean time from the total shoulder replacement to injury (fracture) was 11.2 months (range 8-21). All fractures united without complications at a mean time of 5.1 months (range 4-6). The literature review revealed a limited number of publications reporting on the management of approximately 40 patients. The outcome noted in these patients is also presented. PMID- 23351879 TI - Use of bone graft substitutes in the management of tibial plateau fractures. AB - The current available evidence for the use of bone graft substitutes in the management of subchondral bone defects associated with tibial plateau fractures as to their efficiency and safety has been collected following a literature review of the Ovid MEDLINE (1948-Present) and EMBASE (1980-Present). Nineteen studies were analysed reporting on 672 patients (674 fractures), with a mean age of 50.35 years (range 15-89), and a gender ratio of 3/2 males/females. The graft substitutes evaluated in the included studies were calcium phosphate cement, hydroxyapatite granules, calcium sulphate, bioactive glass, tricalcium phosphate, demineralised bone matrix, allografts, and xenograft. Fracture healing was uneventful in over 90% of the cases over a variant period of time. Besides two studies reporting on injectable calcium phosphate cement excellent incorporation was reported within 6 to 36 months post-surgery. No correlation was made by any of the authors between poor incorporation/resorption and adverse functional or radiological outcome. Secondary collapse of the knee joint surface >= 2 mm was reported in 8.6% in the biological substitutes (allograft, DBM, and xenograft), 5.4% in the hydroxyapatite, 3.7% in the calcium phosphate cement, and 11.1% in the calcium sulphate cases. The recorded incidence of primary surgical site and donor site infection (3.6%) was not statistically significant different, however donor site-related pain was reported up to 12 months following autologous iliac bone graft (AIBG) harvest. Shorter total operative time, greater tolerance of early weight bearing, improved early functional outcomes within the first year post-surgery was also recorded in the studies reporting on the use of injectable calcium phosphate cement (Norian SRS). Despite a lack of good quality randomised control trials, there is arguably sufficient evidence supporting the use of bone graft substitutes at the clinical setting of depressed plateau fractures. PMID- 23351880 TI - Echocardiographic integrated backscatter for detecting progression and regression of aortic valve calcifications in rats. AB - BACKGROUND: Calcification is an independent predictor of mortality in calcific aortic valve disease (CAVD). The aim of this study was to evaluate the use of non invasive, non-ionizing echocardiographic calibrated integrated backscatter (cIB) for monitoring progression and subsequent regression of aortic valvular calcifications in a rat model of reversible renal failure with CAVD, compared to histology. METHODS: 28 male Wistar rats were prospectively followed during 21 weeks. Group 1 (N=14) was fed with a 0.5% adenine diet for 9 weeks to induce renal failure and CAVD. Group 2 (N=14) received a standard diet. At week 9, six animals of each group were killed. The remaining animals of group 1 (N=8) and group 2 (N=8) were kept on a standard diet for an additional 12 weeks. cIB of the aortic valve was calculated at baseline, 9 and 21 weeks, followed by measurement of the calcified area (Ca Area) on histology. RESULTS: At week 9, cIB values and Ca Area of the aortic valve were significantly increased in the adenine-fed rats compared to baseline and controls. After 12 weeks of adenine diet cessation, cIB values and Ca Area of group 1 decreased compared to week 9, while there was no longer a significant difference compared to age-matched controls of group 2. CONCLUSIONS: cIB is a non-invasive tool allowing quantitative monitoring of CAVD progression and regression in a rat model of reversible renal failure, as validated by comparison with histology. This technique might become useful for assessing CAVD during targeted therapy. PMID- 23351881 TI - Dynamic enhancement of drug product labels to support drug safety, efficacy, and effectiveness. AB - Out-of-date or incomplete drug product labeling information may increase the risk of otherwise preventable adverse drug events. In recognition of these concerns, the United States Federal Drug Administration (FDA) requires drug product labels to include specific information. Unfortunately, several studies have found that drug product labeling fails to keep current with the scientific literature. We present a novel approach to addressing this issue. The primary goal of this novel approach is to better meet the information needs of persons who consult the drug product label for information on a drug's efficacy, effectiveness, and safety. Using FDA product label regulations as a guide, the approach links drug claims present in drug information sources available on the Semantic Web with specific product label sections. Here we report on pilot work that establishes the baseline performance characteristics of a proof-of-concept system implementing the novel approach. Claims from three drug information sources were linked to the Clinical Studies, Drug Interactions, and Clinical Pharmacology sections of the labels for drug products that contain one of 29 psychotropic drugs. The resulting Linked Data set maps 409 efficacy/effectiveness study results, 784 drug-drug interactions, and 112 metabolic pathway assertions derived from three clinically oriented drug information sources (ClinicalTrials.gov, the National Drug File - Reference Terminology, and the Drug Interaction Knowledge Base) to the sections of 1,102 product labels. Proof-of-concept web pages were created for all 1,102 drug product labels that demonstrate one possible approach to presenting information that dynamically enhances drug product labeling. We found that approximately one in five efficacy/effectiveness claims were relevant to the Clinical Studies section of a psychotropic drug product, with most relevant claims providing new information. We also identified several cases where all of the drug-drug interaction claims linked to the Drug Interactions section for a drug were potentially novel. The baseline performance characteristics of the proof-of-concept will enable further technical and user-centered research on robust methods for scaling the approach to the many thousands of product labels currently on the market. PMID- 23351882 TI - Quantification of left-to-right shunt through patent ductus arteriosus by colour Doppler in children admitted for a device closure. PMID- 23351883 TI - Identification and characterization of microRNAs in the pancreatic fluke Eurytrema pancreaticum. AB - BACKGROUND: Eurytrema pancreaticum is one of the most common flukes, which mainly infects ruminants globally and infects human beings accidentally; causing eurytremiasis that has high veterinary and economic importance. MicroRNAs (miRNAs) are small non-coding RNAs and are now considered as a key mechanism of gene regulation at the post-transcription level. METHODS: We investigated the global miRNA expression profile of E. pancreaticum adults using next-generation sequencing technology combined with real-time quantitative PCR. RESULTS: By using the genome of the closely-related species Schistosoma japonicum as reference, we obtained 27 miRNA candidates out of 16.45 million raw sequencing reads, with 13 of them found as known miRNAs in S. japonicum and/or S. mansoni, and the remaining 14 miRNAs were considered as novel. Five out of the 13 known miRNAs coming from one family named as sja-miR-2, including family members from miR-2a to miR-2e. Targets of 19 miRNAs were successfully predicated out of the 17401 mRNA and EST non-redundant sequences of S. japonicum. It was found that a significant high number of targets were related to "chch domain-containing protein mitochondrial precursor" (n = 29), "small subunit ribosomal protein s30e" (n = 21), and "insulin-induced gene 1 protein" (n = 9). Besides, "egg protein cp3842" (n = 2), "fumarate hydratase" (n = 2), "ubiquitin-conjugating enzyme" (n = 2), and "sperm-associated antigen 6" (n = 1) were also found as targets of the miRNAs of E. pancreaticum. CONCLUSIONS: The present study represents the first global characterization of E. pancreaticum miRNAs, which provides novel resources for a better understanding of the parasite, which, in turn, has implications for the effective control of the disease it causes. PMID- 23351885 TI - AMPK and the endocrine control of energy metabolism. PMID- 23351884 TI - Dramatic early event in chronic allograft nephropathy: increased but not decreased expression of MMP-9 gene. AB - OBJECTIVE: The infiltration of mononuclear cells and replication and migration of smooth muscle cells (SMCs) from media into the intima in the vascular wall are the cardinal pathological changes in the early stage of chronic allograft nephropathy (CAN). But the mechanism is unclear. Therefore we investigated the role of matrix metalloproteinase 9 (MMP-9) and its interaction with TGF-beta1, tubulointerstitial mononuclear cells infiltration and migration of SMCs in the early stage of CAN. METHODS: Kidneys of Fisher (F334) rats were orthotopically transplanted into bilaterally nephrectomized Lewis (LEW) recipients. To suppress an initial episode of acute rejection, rats were briefly treated with cyclosporine A (1.5 mg/kg/day) for the first 10 days. Animals were harvested at 12 weeks after transplantation for histological, immunohistochemistry and molecular biological analysis. RESULTS: The expression of MMP-9 was up-regulated in interstitium and vascular wall in the early stage of CAN, where there were interstitial mononuclear cells infiltration and SMCs migration and proliferation. Moreover the expression of MMP-9 were positively correlated with the degree of interstitial mononuclear cells infiltration, the quantity of SMCs in arteriolar wall, and also the increased TFG-beta1 expression in the tubulointerstitium and arteriolar wall. CONCLUSIONS: MMP-9 may play an important role in the mechanism of pathological changes during the earlier period of CAN. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1582313332832700. PMID- 23351886 TI - Milestones in the history of research on cardiac energy metabolism. AB - The present study summarizes the history of research on cardiac metabolism from antiquity till the 21st century. It describes important landmarks regarding the discovery of oxygen and of the 3 steps of cellular respiration, as well as major research on cardiac energy metabolism. For this purpose, we conducted a thorough search of original manuscripts, books, and contemporary reviews published in PubMed. The first views and concepts about the heart's function appear in Greek philosophic manuscripts of 2500 years ago. According to Aristotle, the heart is responsible for heat production, which is essential for life. The understanding of cardiac metabolism awaited new discoveries. The discovery of oxygen during the 18th century, along with the idea of energy conservation, or what is now known as one of the first versions of the first law of thermodynamics, played an important role in initiating the study of energy metabolism in general and heart metabolism later. The discovery of glycolysis, of the Krebs cycle, and of adenosine triphosphate offered a better understanding of cellular respiration, necessary for later research. Indeed, many researchers dedicated their studies to energy metabolism, but Richard John Bing, the renowned German research cardiologist, is the one who guided the exploration of cardiac metabolism, and he is therefore considered to be the father of cardiac energy metabolism. Since then, encouraging new research has been taking place, offering important clinical applications for heart patients. PMID- 23351887 TI - Biology not culture explains dissociation in posttraumatic stress disorder. PMID- 23351888 TI - Toward a neuroanatomy of obsessive-compulsive disorder revisited. PMID- 23351889 TI - Have no fear: the neural basis of anxiolytic drug action in generalized social phobia. PMID- 23351890 TI - The efficacy of magnesium sulfate loading on microalbuminuria following SIRS: One step forward in dosing. AB - BACKGROUNDS: Magnesium has been known for its antioxidative and antiinflammatory properties in many studies. In this study two dosing regimens of magnesium were compared with a placebo control group in order to investigate safety and efficacy of high doses of intravenous magnesium sulfate infusion on critically ill trauma patients. Inflammatory and oxidative factors were measured in this trial. METHODS: 45 trauma patients with systemic inflammatory response syndromes (SIRS) were randomly assigned into 2 treatment and one placebo groups. The high dose group received 15 g MgSO4, low dose group received 7.5 g of MgSO4 over 4 hour infusion, and placebo group received saline alone. The initial and post magnesium sulfate injections levels of tumor necrosis factor alpha (TNF-alpha), total antioxidant power and lipid peroxidation were measured after 6, 18 and 36 hours. The pre-infusion along with 6 and 36 hour level of microalbuminuria were also determined. RESULTS: Repeated measurements illustrated that there was no significant difference in TNF-alpha, total antioxidant power and lipid peroxidation levels among groups during the period of analysis. The microalbuminuria at 36 hour post infusion of high dose group was lower than that of control group (p = 0.024). Patient's mortality (28 day) was similar among all treatment groups. Both magnesium infusion groups tolerated the drug without experiencing any complications. CONCLUSION: No evidence for antioxidative and antiinflammatory effects of magnesium in traumatic SIRS positive patients was found. Magnesium in high doses may be recommended for traumatic patients with SIRS status to prevent microalbuminuria. PMID- 23351891 TI - Inhibition of HIV and HSV infection by vaginal lactobacilli in vitro and in vivo. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: The cervico-vaginal mucosa which is populated with microflora (mostly includes lactobacilli) is the portal of entry for sexually transmitted pathogens. METHODS: The in vitro anti-viral effect of vaginal and non-vaginal lactobacillus was evaluated using single cycle HIV-1 replication and HSV-2 plaque reduction assays. The XTT proliferation assay was used to monitor the cellular toxicity. The in vivo anti-HSV-1 activity was evaluated in BALB/c mouse model by monitoring skin lesion and immune response development. RESULTS AND MAJOR CONCLUSION: DMEM culture supernatant of L. Gasseri and L. fermentum (PH 7.3) did not show toxic effect but inhibited 50% of HIV replication at 12 and 31% concentrations, respectively. Co-culture of L. gasseri (1000 CFU/ target cell) showed mild cytotoxicity but inhibited 68% of HIV replication. The supernatant of L. crispatus inhibited 50% of HSV replication at 4% and also co-culture of L. gasseri, L. rhamnosus and L. crispatus revokes almost all of the HSV multiplication. Culture supernatants of L. gasseri and L. crispatus had significant virucidal effect against the HIV and HSV and inhibited HSV infection in a stage before viral entry to the target cells. Alive L. gasseri cells showed high potential for inhibiting HSV-1 infection in vivo condition. Current data indicates that lactobacilli supernatant encompasses components with neutralizing activity against HIV and HSV and it would be a determinant factor for viral diseases transmission and promising lead for anti-viral probiotic design. PMID- 23351892 TI - Accountability in rationing. PMID- 23351893 TI - Surgery for placebo effect? PMID- 23351894 TI - Patient self-rationing, a health system problem. PMID- 23351895 TI - Is understaffing a unit a form of rationing care? PMID- 23351896 TI - The Family Medicine Accelerated Track model: producing more family doctors faster. PMID- 23351898 TI - The inconclusive evidence on CT screening for lung cancer. PMID- 23351899 TI - Cancer gene sequencing: ethical challenges and promises. PMID- 23351900 TI - The constitutionality of the Affordable Care Act: an update. PMID- 23351901 TI - National Quality Forum guidelines for comparing outcomes and resource use. PMID- 23351902 TI - Improving health outcomes and promoting stewardship of resources: ABIM Foundation's Choosing Wisely campaign. PMID- 23351903 TI - Power, politics, and health spending priorities. PMID- 23351904 TI - God panels and the history of hemodialysis in America: a cautionary tale. PMID- 23351905 TI - A single-payer system would reduce U.S. health care costs. PMID- 23351906 TI - Assessment of health-related quality of life in Turkish patients with facial prostheses. AB - BACKGROUND: Facial prostheses are intended to provide a non-operative rehabilitation for patients with acquired facial defects. By improving aesthetics and quality of life (QOL), this treatment involves reintegration of the patient into family and social life. The aim of this study was to evaluate the perception of QOL in adult patients with facial prostheses and to compare this perception with that of a control group. METHODS: The study participants consisted of 72 patients, who were divided into three equal-sized groups according to the type of prosthesis (OP- orbital prosthesis, AP- auricular prosthesis, NP - nasal prosthesis) and 24 healthy control participants without any congenital or acquired deformity of face or body. Clinical and socio-demographic data were gathered from each person's medical chart. Participants completed the Turkish version of the World Health Organization Quality of Life Instrument, Short Form (WHOQOL-BREF). Descriptive statistics, independent sample t-tests, Pearson's chi square test, ANOVA, ANCOVA, and Pearson correlation were used to analyse the data. RESULTS: Compared with the control participants, patients with NP scored lower on the all domains of QOL and all three patient groups had lower scores on overall QOL and its domains of physical and environmental health. Patients with OP reported significantly lower physical health scores than those with AP, while patients with NP reported significantly lower overall QOL and psychological health scores than those with AP. Female patients had lower environmental domain scores than did male patients. The patient's age and income correlated with social relationships QOL, while the patient's income and the age of facial prosthesis were correlated with environmental QOL. CONCLUSION: Patients with facial prostheses had lower scores in overall QOL, physical and environmental health domains than the control participants. Socio-demographic and clinical characteristics such as age, gender, income, localization of the defect, and age of facial prosthesis were associated with patients' QOL. These findings may provide valuable information about the specific health needs of these patients that may affect their well-being. Further studies are needed to confirm these results. Use of the WHOQOL-BREF may provide valuable information for determining patients' needs and priorities as well as for planning and developing comprehensive prosthetic rehabilitation programs. PMID- 23351907 TI - Chitosan and chitosan chlorhydrate based various approaches for enhancement of dissolution rate of carvedilol. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: Carvedilol nonselective beta adrenoreceptor blocker, chemically (+/-)-1-(Carbazol-4-yloxy)-3-[[2-(o methoxypHenoxy) ethyl] amino]-2-propanol, slightly soluble in ethyl ether; and practically insoluble in water, gastric fluid (simulated, TS, pH 1.1), and intestinal fluid (simulated, TS without pancreatin, pH 7.5) Compounds with aqueous solubility less than 1% W/V often represents dissolution rate limited absorption. There is need to enhance the dissolution rate of carvedilol. The objective of our present investigation was to compare chitosan and chitosan chlorhydrate based various approaches for enhancement of dissolution rate of carvedilol. METHODS: The different formulations were prepared by different methods like solvent change approach to prepare hydrosols, solvent evaporation technique to form solid dispersions and cogrind mixtures. The prepared formulations were characterized in terms of saturation solubility, drug content, infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X ray diffraction (PXRD), electron microscopy, in vitro dissolution studies and stability studies. RESULTS: The practical yield in case of hydrosols was ranged from 59.76 to 92.32%. The drug content was found to uniform among the different batches of hydrosols, cogrind mixture and solid dispersions ranged from 98.24 to 99.89%. There was significant improvement in dissolution rate of carvedilol with chitosan chlorhdyrate as compare to chitosan and explanation to this behavior was found in the differences in the wetting, solubilities and swelling capacity of the chitosan and chitosan salts, chitosan chlorhydrate rapidly wet and dissolve upon its incorporation into the dissolution medium, whereas the chitosan base, less water soluble, would take more time to dissolve. CONCLUSION: This technique is scalable and valuable in manufacturing process in future for enhancement of dissolution of poorly water soluble drugs. PMID- 23351908 TI - Recurrent spinal epidural hematoma: case report. AB - We report the case of a man of 65 who, at 20 and 37 days from surgery of C6 corpectomy, experienced two epidural hematomas at C7-D1. We assume that the pathogenic cause of this rare disease was an overlap between three main factors: the surgical aggression of the internal anterior epidural venous plexus; a possible increase of intra-thoracic pressure due to chronic obstructive pulmonary disease; and double antiplatelet drug therapy. PMID- 23351909 TI - Seymour fractures: retrospective analysis and therapeutic considerations. AB - PURPOSE: To analyze the management of Seymour fractures (juxta-epiphyseal fractures of the terminal phalanx of the finger in conjunction with flexion deformity at the fracture site, laceration of the nail bed, and frequently ungual subluxation) and to determine clinical and radiographic results following operative or conservative treatment. METHODS: Clinical and radiological results of 24 skeletally immature patients (7 girls and 17 boys; mean age, 8.5 y) with Seymour fractures were evaluated. Assessment after a mean follow-up of 10 years (range, 1-18 y) included the range of motion, the modified Kapandji index, growth disturbance of the effected digit and nail, pain according to the visual analog scale, and patients' satisfaction. RESULTS: Nine patients received nonoperative treatment. Operative management included debridement, open reduction, and fixation in 9. Owing to instability, an additional K-wire passing across the distal interphalangeal joint was used in 5. In 1 patient, the nail was removed. All surgically treated patients received a splint and perioperative cephalosporin. Twenty-three patients out of 24 gained full motion (mean, 80 degrees ; range, 65 degrees -90 degrees ). The average modified Kapandji index was 5.0 for extension and 4.8 for flexion. Long-term minor growth disturbance of the distal phalanx (seen on radiographs at high amplification only) and nail were noted in 5 patients, and solitary nail dystrophies were observed in 6 patients. Nine of the 11 nail growth irregularities were not a relevant cosmetic problem for the patients. Patients' satisfaction assessment revealed a good clinical outcome. There was neither flexion deformity nor infection in our collective. At the 1-year follow-up examination, the average visual analog score was 0.6 (range, 0-2). CONCLUSIONS: According to the literature, the Seymour fracture is an often underestimated injury, and open cases are prone to infection. Evaluation of the outcome in our collective demonstrated good results with the treatment approaches described. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 23351910 TI - Arthroscopically assisted repair of triangular fibrocartilage complex foveal tears. AB - PURPOSE: To give a detailed clinical outcome analysis of a consecutive series of patients treated arthroscopically for traumatic triangular fibrocartilage complex (TFCC) foveal tears. METHODS: This study was a consecutive case series of 11 patients who underwent arthroscopically assisted repair for traumatic TFCC foveal lesions. The mean age at the time of surgery was 27 years. The mean follow-up was 30 months (range, 20-51 mo). All patients underwent arthroscopy-assisted foveal reattachment of the TFCC by means of a transosseous outside-in technique. The primary outcome measure was a self-administered upper limb disability questionnaire (Hand20 questionnaire) at the final follow-up. The Hand20 scores range from 0 to 100, with high scores indicating severe disability. Secondary outcome measures included pain, grip strength, range of motion, distal radioulnar joint (DRUJ) instability, and the Mayo Modified Wrist Score. We assessed postoperative complications for all patients. RESULTS: The mean preoperative Hand20 score was 29; it decreased significantly to 6 at final follow-up. Pain completely resolved in 7 patients, whereas mild pain during activity persisted in 4 patients. Grip strength improved significantly after surgery, from 84% to 98% of the unaffected side. Nine patients had no DRUJ instability and 2 had mild DRUJ instability at final follow-up. The Mayo Modified Wrist Score at final follow-up was 94 points; results were excellent in 7 patients, good in 3, and fair in 1. Skin irritation at the ulnar neck caused by the suture thread was recognized as a postoperative complication in 3 patients. CONCLUSIONS: Transosseous arthroscopic repair for traumatic TFCC foveal tear can restore stability to the DRUJ and provide satisfactory subjective and objective results without serious complications after more than 20 months' follow-up. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 23351911 TI - Denervation of the lateral humeral epicondyle for treatment of chronic lateral epicondylitis. AB - PURPOSE: Chronic lateral epicondylitis remains a treatment challenge. Traditional surgical treatments for lateral epicondylitis involve variations of the classic Nirschl lateral release. Anatomic studies reveal that the posterior branch or branches of the posterior cutaneous nerve of the forearm consistently innervate the lateral humeral epicondyle. We undertook the present study to determine the effectiveness of denervation of the lateral humeral epicondyle in treating chronic lateral epicondylitis. METHODS: An institutional review board-approved prospective study included 30 elbows in 26 patients. Inclusion criteria included failure to respond to nonoperative treatment for more than 6 months and improvement in grip strength and in visual analog pain scale after diagnostic nerve block of the posterior branches of the posterior cutaneous nerve of the forearm proximal to the lateral humeral epicondyle. We excluded patients who had undergone previous surgery for lateral epicondylitis. Outcome measures included visual analog pain scale and grip strength testing. Denervation surgery involved identification and transection of the posterior cutaneous nerve of the forearm branches with implantation into the triceps. The presence of radial tunnel syndrome was noted but did not affect inclusion criteria; if it was present, we did not correct it surgically. We used no postoperative splinting and permitted immediate return to activities of daily living. RESULTS: At a mean of 28 months of follow-up, the average visual analog scale score decreased from 7.9 to 1.9. Average grip strength with the elbow extended improved from 13 to 24 kg. A total of 80% of patients had good or excellent results, as defined by an improvement of 5 or more points on the visual analog scale for pain. CONCLUSIONS: Denervation of the lateral epicondyle was effective in relieving pain in 80% of patients with chronic lateral epicondylitis who had a positive response to a local anesthetic block of the posterior branches of the posterior cutaneous nerve of the forearm. Radial nerve compression syndromes must be evaluated as a confounding source of symptoms and may require additional treatment in patients who fail to improve with denervation alone. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 23351912 TI - Measurement scales in clinical research of the upper extremity, part 1: general principles, measures of general health, pain, and patient satisfaction. AB - Measurement is a fundamental cornerstone in all aspects of scientific discovery, including clinical research. To be useful, measurement instruments must meet several key criteria, the most important of which are satisfactory reliability, validity, and responsiveness. Part 1 of this article reviews the general concepts of measurement instruments and describes the measurement of general health, pain, and patient satisfaction. PMID- 23351914 TI - "Off-label" use of orthopedic implants in the wrist. PMID- 23351913 TI - Measurement scales in clinical research of the upper extremity, part 2: outcome measures in studies of the hand/wrist and shoulder/elbow. AB - Part 1 of this article outlined the basic characteristics of useful clinical measurement instruments and described scales used to measure general health, pain, and patient satisfaction. Part 2 describes the features of some of the scales most commonly used in clinical research in the hand, wrist, elbow, and shoulder. PMID- 23351915 TI - In reply. PMID- 23351917 TI - Pulmonary valve cyst mimicking pulmonary artery neoplasia: a case report. AB - Cardiac valve cysts are rare beyond infancy. The tricuspid and mitral valve are the most common sites, with few reported cases of pulmonary valve cysts in the literature. This case illustrates a pulmonary valve cyst mimicking a tumour in a child 13 years after cardiac surgery. Although these lesions are extremely rare, they could be considered in the differential diagnosis in patients presenting with valvular mass lesions. PMID- 23351916 TI - Differences in osteogenic and apoptotic genes between osteoporotic and osteoarthritic patients. AB - BACKGROUND: Osteoporosis is a metabolic disorder characterized by a reduction in bone mass and deterioration in the microarchitectural structure of the bone, leading to a higher risk for spontaneous and fragility fractures.The main aim was to study the differences between human bone from osteoporotic and osteoarthritic patients about gene expression (osteogenesis and apoptosis), bone mineral density, microstructural and biomechanic parameters. METHODS: We analyzed data from 12 subjects: 6 with osteoporotic hip fracture (OP) and 6 with hip osteoarthritis (OA), as the control group. All subjects underwent medical history, analytical determinations, densitometry, histomorphometric and biochemical study. The expression of 86 genes of osteogenesis and 86 genes of apoptosis was studied in pool of bone samples from patients with OP and OA by PCR array. RESULTS: We observed that most of the genes of apoptosis and osteogenesis show a decrease in gene expression in the osteoporotic group in comparison with the osteoarthritic group. The histomorphometric study shows a lower bone quality in the group of patients with hip fractures compared to the osteoarthritic group. CONCLUSIONS: The bone tissue of osteoporotic fracture patients is more fragile than the bone of OA patients. Our results showed an osteoporotic bone with a lower capacities for differentiation and osteoblastic activity as well as a lower rate of apoptosis than osteoarthritic bone. These results are related with structural and biochemical parameters. PMID- 23351918 TI - [Hypertension, coronary heart disease and stroke: should the blood pressure J curve be a concern?]. AB - The paradoxical increase in cardiovascular events in patients with treatment induced low blood pressure (BP), particularly in hypertensives with pre-existing coronary artery disease, especially those with critically low diastolic BP, which conflicts with data from epidemiologic observational studies, is referred to as a J-curve. It was first described over 30 years ago and is still the subject of considerable controversy. Recent large clinical outcomes trials (INVEST, TNT, ONTARGET, PROVE IT-TIMI 22, SMART) and meta-analyses strongly support its existence for systolic and diastolic BP. The diastolic J-curve is commonly more pronounced. In contrast to cardiovascular complications related to coronary artery disease, no J-curve phenomenon was noted for stroke in most of these studies. This is explained by differences in cerebral and coronary autoregulation and because coronary perfusion occurs only during diastole. On the basis of this review, we suggest a cautious, individualized approach to treatment, particularly in hypertensive patients with coronary heart disease or high risk for impaired coronary blood flow. In these patients we advise against treatment that lowers systolic BP below 120-125 mmHg and, particularly, diastolic BP below 70-75 mmHg. PMID- 23351919 TI - [A rare cause of pericardial disease]. AB - Among cardiovascular diseases, pericardial disease has specific characteristics. Its etiology, diagnosis and medical management are not as well understood as in coronary and valvular heart disease. In most cases, its cause is benign, although the proportion decreases with more severe clinical presentation. The authors present the case of a 35-year-old man with no relevant past medical history, who went to the emergency department with what appeared to be an idiopathic case of acute pericarditis. However, over the following five months, there was an unfavorable evolution to constrictive pericarditis, requiring pericardiectomy. The final diagnosis was only made following surgery - a rare case of a primary pericardial tumor, a mesothelioma. PMID- 23351920 TI - Long-term effect of bosentan in pulmonary hypertension associated with complex congenital heart disease. AB - BACKGROUND: Bosentan is recommended for symptomatic patients with Eisenmenger syndrome due to simple congenital lesions such as atrial and ventricular septal defects (VSD). However, its long-term efficacy and safety in patients with pulmonary arterial hypertension (PAH) associated with complex congenital heart disease (CHD) is unknown. OBJECTIVES: We examined the short- and long-term effects and safety profile of bosentan in patients with PAH and complex CHD. METHODS: We followed 14 patients with PAH and complex CHD for a mean of four years. Demographic parameters, exercise capacity assessed by the six-minute walking test (6MWT) and oxygen saturation were assessed at baseline, six months and at follow-up. RESULTS: Mean age was 37.1 +/- 11.7 years; 90% were in WHO class III or IV. The most common diagnosis was pulmonary atresia with VSD (35.7%), followed by truncus arteriosus (28.6%), patent ductus arteriosus (21.4%) and transposition of the great arteries (14.3%). After six months of treatment, six-minute walking distance (6MWD) increased from 371.9 to 428.4 m (p=0.005) and functional class was improved (p=0.005). After four years, one patient discontinued bosentan due to side effects and four patients were started on sildenafil, after a mean 38 months of bosentan treatment. Mean 6MWD for patients on bosentan monotherapy (n=8) was 440.1 +/- 103.8 m, whereas for patients on bosentan-sildenafil combination therapy (n=4) it was 428.8 +/- 96.9 m, after four years of therapy. Two patients died during follow-up. CONCLUSIONS: Bosentan was safe and was associated with improved exercise capacity in patients with PAH and complex CHD. This improvement was sustained for up to four years and the safety profile was similar to simple CHD patients. PMID- 23351921 TI - Novel mutation in the KCNH2 gene associated with long QT syndrome. PMID- 23351922 TI - Solitary fibrous tumors of the soft tissues: imaging features with histopathologic correlations. AB - PURPOSE: To describe the imaging features of soft tissue solitary fibrous tumors, with histopathological correlations and clinical outcome. MATERIAL AND METHODS: Twenty-seven patients with histologically proven SFTs were retrospectively evaluated. Imaging studies included six radiographs, five U/S studies, eighteen CT scans, fourteen MRI exams, and one angiography. RESULTS: On CT scans, two lesions were isodense and five were mildly hypodense compared to muscle while 11 lesions appeared heterogeneous-mixed of iso and hypodense areas. Heterogeneous enhancement was depicted in 13 lesions and four lesions enhanced homogeneously. Six lesions were partially calcified. On T1W MR images, seven lesions were isointense and one was slightly hyperintense relative to adjacent muscles while five lesions appeared heterogeneous-mixed of iso and hypointense areas. T2W images showed high SI in two cases and heterogeneous-mixed in seven cases. Enhancement was heterogeneous in six and homogeneous in four lesions. Patchy unenhanced areas (on CT and T1W MR images) along with patchy areas of low to markedly high SI on T2W images were depicted in 19 lesions. The enhanced portions correlated to areas of increased vascularity and cellularity. The four clinically more aggressive lesions could not be predicted on imaging. CONCLUSION: Typical soft tissue SFTs are deep masses made of isodense and isointense areas relative to adjacent muscles mixed with hypodense and hypointense areas on unenhanced CT and MR T1W respectively. Variable enhancement patterns and mixed to high signal intensities on MRT2W are attributed to tumor's cellularity, vascularity, collagen distribution and/or degeneration. Heterogeneity of SFTs affects imaging features on MRI and CT modalities. The biological behavior of soft tissue SFTs can not be predicted based solely either on histopathologic or imaging evaluation. PMID- 23351923 TI - Evaluation of the effectiveness of a semi-finished occlusal appliance--a randomized, controlled clinical trial. AB - INTRODUCTION: Painful temporomandibular disorders (TMDs) are usually treated with physiotherapy, self-exercises, medication-based therapy and splint therapy. For splint therapy different types of splints are available. Therefore this randomized controlled study compared the effectiveness of a semi-finished occlusal appliance (SB) with a laboratory-made occlusal appliance (SS) in myofascial pain patients. METHOD: The trial subjects allocated to the experimental groups with the (SB) occlusal appliance and those provided with a laboratory-made occlusal appliance (SS) did, in addition, receive conservative treatment (self-exercises, drug-based and manual therapy). The control group was given conservative therapy (CO) only. Overall, a total of 63 patients participated in the study with each group consisting of 21 subjects. RESULTS: When the first follow-up examination took place (14 days after splint insertion) mouth opening within the SB group was significantly enlarged. When the second examination was conducted (2.5 months after splint insertion) mouth opening was significantly enlarged in both splint groups when compared with the initial value. In the control group, no significant enlargement of mouth opening was detected. At no point there was a significant reduction in the number of pressure sensitive areas of the TMJ. On palpation of the masticatory muscles however, a significant reduction in the number of pressure-sensitive areas could be observed within the CO group and the SS group after 2.5 months. When comparing pain reduction (muscle/joint pain) and mouth opening, no significant differences could be detected between the treatments. CONCLUSION: The results suggest that TMD should be treated conservatively. In cases of restricted mouth opening, the additional use of occlusal appliances can eliminate the patient's discomfort more quickly. In this context, the tested, semi-finished occlusal appliance appears to offer an immediately available, temporary alternative to laboratory-made splints. PMID- 23351925 TI - 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. AB - Many developments have occurred since the publication of the widely-used 2009 Canadian Cardiovascular Society (CCS) Dyslipidemia guidelines. Here, we present an updated version of the guidelines, incorporating new recommendations based on recent findings and harmonizing CCS guidelines with those from other Societies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used, per present standards of the CCS. The total cardiovascular disease Framingham Risk Score (FRS), modified for a family history of premature coronary disease, is recommended for risk assessment. Low-density lipoprotein cholesterol remains the primary target of therapy. However, non-high density lipoprotein cholesterol has been added to apolipoprotein B as an alternate target. There is an increased emphasis on treatment of higher risk patients, including those with chronic kidney disease and high risk hypertension. The primary panel has recommended a judicious use of secondary testing for subjects in whom the need for statin therapy is unclear. Expanded information on health behaviours is presented and is the backbone of risk reduction in all subjects. Finally, a systematic approach to statin intolerance is advocated to maximize appropriate use of lipid-lowering therapy. This document presents the recommendations and principal conclusions of this process. Along with associated Supplementary Material that can be accessed online, this document will be part of a program of knowledge translation. The goal is to increase the appropriate use of evidence-based cardiovascular disease event risk assessment in the management of dyslipidemia as a fundamental means of reducing global risk in the Canadian population. PMID- 23351926 TI - Canadian Cardiovascular Society guidelines on the use of cardiac resynchronization therapy: evidence and patient selection. AB - Recent landmark trials provided the impetus to update the recommendations for cardiac resynchronization therapy (CRT). This article provides guidance on the prescription of CRT within the confines of published data. A future article will explore the implementation of these guidelines. These guidelines are intended to serve as a framework for the prescription of CRT within the Canadian health care system and beyond. They were developed through a critical evaluation of the existing literature, and expert consensus. The panel unanimously adopted each recommendation. The 8 recommendations relate to ensuring the adequacy of medical therapy before the initiation of CRT, the use of symptom severity to select candidates for CRT, differing recommendations based on the presence or absence of sinus rhythm, the presence of left bundle branch block vs other conduction patterns, and QRS duration. The use of CRT in the setting of chronic right ventricular pacing, left ventricular lead placement, and the routine assessment of dyssynchrony to guide the prescription of CRT are also included. The strength of evidence was weighed, taking full consideration of any risks of bias, as well as any imprecision, inconsistency, and indirectness of the available data. The strength of each recommendation and the quality of evidence were adjudicated. Trade-offs between desirable and undesirable consequences of alternative management strategies were considered, as were values, preferences, and resource availability. These guidelines were externally reviewed by experts, modified based on those reviews, and will be updated as new knowledge is acquired. PMID- 23351924 TI - Cilia, Wnt signaling, and the cytoskeleton. AB - Primary cilia have recently been highlighted as key regulators in development and disease. This review focuses on current work demonstrating the broad role of cilia-related proteins in developmental signaling systems. Of particular consideration is the importance of the basal body region, located at the base of the cilium, in its role as a focal point for many signaling pathways and as a microtubule organizing center. As the cilium is effectively a microtubular extension of the cytoskeleton, investigating connections between the cilium and the cytoskeleton provides greater insight into signaling and cell function. Of the many signaling pathways associated with primary cilia, the most extensively studied in association with the cytoskeleton and cytoskeletal rearrangements are both canonical and non-canonical Wnt pathways. One of the key concepts currently emerging is a possible additional role for the traditionally 'cilia-related' proteins in other aspects of cellular processes. In many cases, disruption of such processes manifests at the level of the cilium. While the involvement of cilia and cilia-related proteins in signaling pathways is currently being unraveled, there is a growing body of evidence to support the notion that ciliary proteins are required not only for regulation of Wnt signaling, but also as downstream effectors of Wnt signaling. This review summarizes recent advances in our understanding of the involvement of cilia and basal body proteins in Wnt signaling pathways. PMID- 23351927 TI - A flea and tick collar containing 10% imidacloprid and 4.5% flumethrin prevents flea transmission of Bartonella henselae in cats. AB - BACKGROUND: Bartonella henselae is transmitted amongst cats by Ctenocephalides felis and is associated with multiple clinical syndromes in cats and people. In a previous study, monthly spot-on administration of 10% imidacloprid/1% moxidectin was shown to block transmission of B. henselae amongst cats experimentally exposed to infected C. felis. The purpose of this study was to determine whether application of a flea and tick collar containing 10% imidacloprid and 4.5% flumethrin would lessen C. felis transmission of B. henselae amongst cats for 8 months. METHODS: Specific pathogen free cats (n = 19) were housed in three adjoining enclosures that were separated by mesh to allow C. felis to pass among groups but prevent cats in different enclosures from contacting one another. One group of 4 cats was inoculated intravenously with B. henselae and after infection was confirmed in all cats based on positive PCR assay results, the cats were housed in the middle enclosure. The B. henselae infected cat group was flanked by a group of 8 cats that had the collar placed and maintained for the duration of the study and a group of 7 cats that were not treated. Ctenocephalides felis (50 males and 50 females) raised in an insectary were placed on each of the 4 cats in the B. henselae infected group monthly for 7 applications and then every 2 weeks for 4 applications starting the day the collar was applied. Blood was collected from all cats weekly for Bartonella spp. PCR, serology and culture. RESULTS: While side-effects associated with the collars were not noted, persistent fever necessitating enrofloxacin therapy occurred in two of the untreated cats. While B. henselae infection was ultimately confirmed in 4 of 7 of the untreated cats, none of the cats with collars became infected (P = 0.026). CONCLUSIONS: In this study design, use of a collar containing 10% imidacloprid and 4.5% flumethrin was well tolerated and prevented C. felis transmission of B. henselae amongst cats for 8 months. PMID- 23351928 TI - Dielectric effect on electric fields in the vicinity of the metal-vacuum dielectric junction. AB - The dielectric effect was theoretically investigated in order to describe the electric field in the vicinity of a junction of a metal, dielectric, and vacuum. The assumption of two-dimensional symmetry of the junction leads to a simple analytic form and to a systematic numerical calculation for the field. The electric field obtained for the triple junction was found to be enhanced or reduced according to a certain criterion determined by the contact angles and dielectric constant. Further numerical calculations of the dielectric effect show that an electric field can experience a larger enhancement or reduction for a quadruple junction than that achieved for the triple junction. It was also found that even though it changes slowly in comparison with the shape effect, the dielectric effect was noticeably large over the entire range of the shape change. PMID- 23351929 TI - Increasing the risk of spontaneous abortion and major malformations in newborns following use of serotonin reuptake inhibitors during pregnancy: A systematic review and updated meta-analysis. AB - Selective serotonin reuptake inhibitors (SSRIs) are the most frequently used antidepressants during pregnancy. There are conflicting results about their influence on pregnancy outcomes. The goal of this study was to update our previous meta-analysis about pregnancy outcomes following exposure to SSRIs. For this purpose, all relevant databases were searched from 1990 to March 2012 for studies investigating the pregnancy outcomes following exposure to any therapeutic dosage of any SSRI (fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine) during pregnancy. Types of outcome investigated were spontaneous abortion, major malformations, cardiovascular malformations, and minor malformations. A total of 25 studies met our criteria and were included in the meta-analysis. The odds ratio (OD) values are 1.87 (95% CI: 1.5 to 2.33, P< 0.0001) for spontaneous abortion, 1.272 (95% CI: 1.098 to 1.474, P = 0.0014) for major malformations, 1.192 (95% CI: 0.39 to 3.644, P= 0.7578) for cardiovascular malformations, and 1.36 (95% CI: 0.61 to 3.04, P= 0.4498) for minor malformations. The results demonstrated that SSRIs increase the risk of spontaneous abortion and major malformations during pregnancy while they don't increase the risk of cardiovascular malformations and minor malformations. Our previous meta-analysis only showed an increase in the risk of spontaneous abortion following the use of SSRIs during pregnancy. This might be due to increase in the number of studies included or addition of two new SSRIs (citalopram and escitalopram). The message to researchers is to try considering SSRIs individually during pregnancy to reduce heterogeneity, although all are aware of inevitable limitations to study on pregnant mothers. PMID- 23351930 TI - [Evolution of the concept of apathy: the need for a multifactorial approach in schizophrenia]. AB - BACKGROUND: Schizophrenia is a chronic and severe mental illness that affects over 1% of the population, characterized by multiple symptom dimensions. One of this class of symptoms, "negative symptoms", have received more attention over the last few years. Negative symptoms, including among others blunted affect, withdrawal or apathy, are particularly important for recovery and are associated with negative functional outcomes, such as inability to get an employment and conduct normal daily living activities. While positive symptoms are usually treated by antipsychotic drugs, negative symptoms are usually persistent, which indicates the need for better treatment. The aim of this article is to highlight recent scientific progress on apathy and to explore current multidimensional approaches of this concept in schizophrenia. Apathy is a symptom frequently encountered in schizophrenia and in many neurological disorders. Therefore, it can be regarded as a transnosographic symptom. LITERATURE FINDINGS: A long time considered as a loss of motivation (psychological concept hard to define), recent descriptive and etiological models have proposed to consider apathy as a multidimensional phenomenon. Marin et al., have proposed a model of apathy in reference to the motivation concept. Marin et al.'s apathy model is composed of three dimensions: firstly, cognitive dimension, secondly, sensory-motor dimension and thirdly, affective dimension. These authors propose to differentiate "apathy syndrome" from "apathy symptom". "Apathy syndrome" resulting from a lack of motivation whereas "apathy symptom" results from cognitive and/or emotional/affective disorders. In addition, Marin et al. propose that apathy syndrome corresponds to the "lack of motivation" not attributable to diminished level of consciousness, cognitive impairment or emotional distress. Following this proposal, Levy and Dubois propose to define apathy as a quantitative reduction of self-generated, voluntary and purposeful behaviors. It is therefore observable and can be quantified. Levy and Dubois have proposed an apathy model considering: firstly, apathy as a syndrome related to reduction in goal-directed behaviors; secondly, anatomically, apathy can be secondary to dysfunctions or lesions of the prefrontal cortex. Since the prefrontal cortex is functionally and anatomically heterogeneous, subtypes of apathy occur in diseases affecting the basal ganglia, because these diseases disrupt associative and limbic pathways from/to the prefrontal cortex; thirdly, from a pathophysiological point of view, apathy may be explained by the impact of lesions or dysfunctions of the basal ganglia, because these lesions or dysfunctions lead to a loss of temporal and spatial focalization, both of which result in a diminished extraction of the relevant signal within the frontal cortex, thereby inhibiting the capacity of the frontal cortex to select, initiate, maintain and shift programs of action. PMID- 23351931 TI - [Injunction to care. Results of a study carried out in the regions of Alsace and Lorraine]. AB - INTRODUCTION: The act of June 17, 1998 created a new form of compulsory treatment: the injunction to care. This is a legal measure intended to fight against recidivism of offenders and sex offenders through medical measures. The only therapies that have demonstrated partial efficacy are cognitive behavioural therapy and treatment with anti-hormone. In France, psychodynamic therapies are paramount in the treatment of perpetrators of sexual violence, although such treatments have not demonstrated effectiveness in reducing sexual recidivism. Very few studies are available regarding the implementation of court-ordered treatment in France. The recent report by the General Inspectorate of Social Affairs (IGAS) in 2011 confirms the absence of medical statistics on the implementation of court-ordered care. OBJECTIVE: We conducted a study on the procedure of the injunction to care in the regions of Alsace and Lorraine. The aim of the study is to develop an inventory coordinator for practitioners (number, type of exercise) and the profile of patients undergoing the injunction of care (type of offense convicted for, psychiatric comorbidity identified for example). METHODS: We first identified the practicing coordinator doctors by contacting the High Courts in the geographic area studied. We then sent out a questionnaire by post to coordinator doctors to profile their patients on care injunctions. RESULTS: We identified 16 practicing coordinator doctors in two study areas: 13 are state hospital doctors and three are private practice. Of the 16 doctors contacted, six returned the completed questionnaires (38% of the sample). This allows characterizing a sample of 50 patients on care injunctions. The majority of convicted crimes are of a sexual nature (92% of cases). This is mostly for crimes or sexual offenses involving minors aged under 15 (83% of cases). Psychiatric comorbidity is the most frequently identified paedophile primary (38%) followed by mental retardation (14%), dissocial personality disorder (6%) and a borderline personality, and emotional liability (6%). Other comorbidities are divided between paranoid schizophrenia, chronic alcoholism, or other personality disorder. The follow-up is monitored by a physician in 82% of cases, while it is provided by a psychologist in 18% of cases. The management consists of a simple psychotherapy in 66% of cases. Pharmacological treatment is most often prescribed with antipsychotics (26% of cases), followed by anti depressants (4%) and the anti-hormone (4%). CONCLUSION: Our study confirms that the majority of patients on care injunctions are sexual offenders involving minors under the age of 15. The most implemented treatment is a simple psychotherapy. The pharmacological option is infrequent and generally involves the use of inappropriate treatment (neuroleptics). Suppressive libido treatment (antidepressants and anti hormone) remains an exception in France. PMID- 23351932 TI - [Prodromes of schizophrenia: consensus or confusion?]. AB - LITERATURE FINDINGS: Prospective studies of subjects at high genetic risk of psychosis (at least one first relative with schizophrenia) and retrospective studies of patients at the end of the first episode of delusion or hallucination have identified various subjective and objective symptoms which emerged months or years before the diagnostic of schizophrenia. The objective symptoms presently designed as prodromes are either transient or of infradiagnostic intensity. The objective signs have been used to define an ultrahigh risk (UHR) state, and have been operationalized by psychometric instruments, which also include criteria for genetic risk (schizotypal dimensions) and alteration of social functioning. The main instruments are the Comprehensive Assessment of At-risk Mental States (CAARMS) and the SIPS (Structured Interview for Prodromal Symptoms). The subjective symptoms, which consist exclusively in inner experiences, have been named basic symptoms, and are operationalized by the Bonn Scale for the Assessment of Basic Symptoms (BSABS) and the Schizophrenia Proneness Instrument (SPI-A, Adult version). Prospective studies of selected individuals with a psychiatric help demand have shown that signs of endogenicity (schizotypal traits), and severity (high symptomatic scores and poor functioning), are of major value to predict conversion. In contrast, the positive predictive value of isolated prodromal symptoms is rather poor (much less than the 80% required for clinical validation). DISCUSSION: This suggests that the population of subjects with prodromes is structured by two latent subgroups: those who express transient psychotic manifestations (which are quite frequent in the general population), and those with an active psychotic process, who are progressively evolving towards the categorical diagnostic of schizophrenia. However, results obtained by between groups comparison of mean psychometric variables are unable to distinguish between these two populations at baseline. Because of this, introduction of the risk of psychosis category in the DSM-V has been bitterly criticized. In accordance, therapeutic prevention assays using antipsychotics, antidepressants, or cognitive therapy have provided inconsistent results. Only the administration of omega-3 polyunsaturated fatty acids has produced a long term efficient effect. PMID- 23351933 TI - [French validation of the Anger Rumination Scale]. AB - BACKGROUND: The aim of this study was to propose a French version of the Anger Rumination Scale (ARS). The main contribution of this scale is to evaluate cognitive responses involved in rumination experience related to anger. The rumination experience is assessed through four scales: angry afterthoughts, thoughts of revenge, angry memories and understanding of causes. Because anger rumination is related to anger experience, it is usually understood to be a dysfunctional or unconstructive behavior. However, because the rumination involves cognitive activity, it can be assimilated as a cognitive strategy to cope with a negative event in a specific context. The ARS seems to be useful in understanding the rumination effects both on anger experience as well as on aggressive behaviors. METHOD: The original scale was translated following scientific recommendations for cultural adaptation of questionnaires. Six hundred and seventeen voluntary undergraduate students were asked to complete the ARS French version. Among these 617 students: 305 completed the French ARS version twice over a 1-month period to test the reliability of the French version; 361 filled out both the French ARS version and the STAXI-II; 342 filled out both the French ARS version and the Aggression Questionnaire (AQ). The Total Sample was randomly split into two groups. An exploratory factor analysis (EFA) was conducted with group I's data. The confirmatory factor analysis (CFA) was conducted with group II's data. RESULTS: The EFA revealed a four factors solution close to the original version. The CFA confirmed a good model fit for the original four factors solution (chi(2)146: 302.14 CFI: 0.96 RMSEA: 0.058). A one factor model was tested, but was not retained. The ARS's internal consistency coefficients replicated those of the literature: alpha coefficients ranged from 0.60 to 0.86, and test-retest correlation coefficients ranged from 0.65 to 0.70. External validity indices conformed to previous studies, both for gender differences and for relationship with STAXI-II and AQ. CONCLUSION: Results of the present study support the validity and the reliability of the French version of the ARS. This validation provides a multifactorial scale for assessing anger rumination. This scale could be used, for example, to explore processes leading to aggressive behavior in several contexts in which overt behavior is prohibited or detrimental to performance. PMID- 23351934 TI - [The Gulf War Syndrome twenty years on]. AB - INTRODUCTION: After Operation Desert Storm which took place in Iraq from August 1990 to July 1991 involving a coalition of 35 countries and a 700,000 strong contingent of mainly American men, some associations of war veterans, the media and researchers described a new diagnostic entity: the Gulf War Syndrome (GWS). LITERATURE FINDINGS: GWS seems to be a new disorder which associates a litany of functional symptoms integrating the musculoskeletal, digestive, tegumentary and neurosensory systems. The symptoms presented do not allow a syndrome already known to be considered and the aetiology of the clinical picture remains unexplained, an increasing cause for concern resulting from the extent of the phenomenon and its media coverage. It quickly appears that there is no consensus amongst the scientific community concerning a nosographic description of GWS: where can all these functional complaints arise from? Different aetiopathogenic hypotheses have been studied by the American administration who is attempting to incriminate exposure to multiple risks such as vaccines and their adjuvants, organophosphorous compounds, pyridostigmine (given to the troops for the preventive treatment of the former), impoverished uranium, and the toxic emanations from oil well fires. But despite extremely in-depth scientific investigations, 10 years after the end of the war, no objective marker of physical suffering has been retained to account for the disorders presented. It would appear that the former soldiers are in even better objective health than the civil population whereas their subjective level of health remains low. Within this symptomatic population, some authors have begun to notice that the psychological disorders appear and persist associating: asthenia, fatigability, mood decline, sleep disorders, cognitive disorders and post-traumatic stress disorder (PTSD). Within the nosological framework, does GWS cause functional disorders or somatisation? Finally, 20 years after the end of the fighting, only PTSD has been causally attributed to military deployment. CLINICAL FINDINGS: Certain functional symptoms of GWS occur during the latent phase of a future reexperiencing syndrome, latent phase which is the locus of nonspecific symptoms. The psychotraumatised subject does not express himself spontaneously and waits to be invited to do so: if the social context does not allow this expression, the suffering can remain lodged in a few parts of the body. How can the inexpressible part of the trauma be recounted, particularly if the social context does not allow it? For civil society, calling into question "the somatic word" of veterans is difficult: why were they sent to face these hardships? What could we learn from these soldiers we do not wish to listen to: the horror of the war, the aggressive impulse of men, and the confrontation with death? Another obstacle to this reflection is the reference to stress as a prevalent aetiopathogenic model of the psychological trauma. A model like this, considering that PTSD is a normal reaction to an abnormal situation, finally discredits the subject and society and disempowers them by freezing them in a passive status of victim. DISCUSSION: However, as GWS affects approximately a quarter of subjects deployed, it is not very likely that all these symptoms are caused by a psychotraumatic reaction. Many veterans suffering from GWS have themselves rejected the diagnosis of PTSD, arguing that they do not suffer repetition nightmares. What the veterans rightly tell us here is that the notions of stress and trauma cannot strictly be superimposed. A subject may have been intensely stressed without ever establishing traumatic flashbacks and likewise; a psychological trauma can be experienced without stress and without fear but in a moment of terror. This clarification is in line with the first criterion of the DSM-IV-TR which necessarily integrates the objective and subjective dimensions as determinants of PTSD. Yet, scientific studies relating to GWS are struggling to establish opposition or continuity links between the objective external exposure (smoke from petrol wells, impoverished uranium, biological agents, chemicals) and the share of inner emotion albeit reactive and characterised by a subjective stress. There were no lack of stress factors for the troops deployed: repeated alerts of chemical attacks, hostility of the environment with its sandstorms and venomous animals, climatic conditions making long hours of backup and static observation difficult, collecting bodies, lack of knowledge of the precise geography of their movements and uncertainty of the duration of the conflict. The military anti nuclear-bacteriological-chemical uniform admittedly provided protective confinement, shutting out the hostile world from which the threat would come but, at the same time, this isolation increases the fear of a hypothetical risk whilst the internal perceptions are increased and can open the way to future somatisations. In a context like this, the somatic manifestations of anxiety (palpitations, sweating, paresthesia...) are willingly associated with somatised functional disorders to which can also be assigned over-interpretations of bodily feelings according to a hypochondriacal mechanism. The selective attention to somatic perceptions in the absence of mentalisations, the request for reassurance reiterated and the excessive use of the treatment system will be diagnostic indices of these symptoms caused by the stress. Rather than toxic exposure to such and such a substance, the non-specific syndrome called "Gulf War Syndrome" is the result of exposure to the eponymous operational theatre. But if the psychological and psychosomatic suffering occurring in veterans is immutable throughout history, the expression of these difficulties has specificities according to the past cultural, political and scientific context. In the example of GWS, the diffusion of the fear of a pathology resulting from chemical weapons has promoted this phenomenon. In the end, biochemical and biological weapons have not been used on a large scale but the mediatisation of this possibility has led to a deleterious... To spare the bother of a group psychological reflection, the scientific and political authorities chose to investigate the implication of environmental factors in the genesis of the disorder. At individual as well as social level, rather than accept a psychogenic origin, a common defence mechanism is to assign the suffering to an external cause. With the perspective of preventing the risk of diffusion of other unexplained syndromes, which could occur following future armed conflicts, new epidemiological diagnostic models must be defined. The media also has considerable responsibility for the diffusion of epidemic psychological reactions but at the same time, they can inform the population about certain individual or group psychopathological mechanisms. CONCLUSION: The GWS exists: it is not an "imaginary illness" but a serious public health issue which has led to tens of thousands of complaints and swallowed up millions of dollars. To reply to human suffering, a new nosographic entity can spread through society taking the epidemic expression of a somatised disorder via identification, imitation and suggestion mechanisms. This possibility questions not only mental health but also the sociology and politics. It is necessary to inform the leaders and the general population of the possibility of this type of mass reaction, which can take the shape of a highly contagious complex functional syndrome. PMID- 23351935 TI - [The cost of schizophrenia: a literature review]. AB - INTRODUCTION: Schizophrenia represents a major burden for patients, their families, healthcare systems and societies. The objective of this literature review is to document the economic burden of schizophrenia. METHOD: The literature search was performed using the MEDLINE-PUBMED database and the following keywords: schizophrenia and cost, burden of disease, qaly or price. The grey literature search was performed using several databases (e.g. Banque de Donnees en Sante Publique) and the Google Scholar((r)) web search engine. The studies that met the following criteria were included: published since 1998, written in English or French, studied OECD countries and presented costs data that were given in monetary terms. The costs data identified in the literature were classified into the following five main categories: cost for healthcare system, cost for social and medico-social system (medico-social system is a French specificity), cost for prison and legal systems, cost of informal care given by family, and cost associated with productivity losses. To improve comparability, costs were reported as a percentage of health care expenditures and as a per-ten-thousand of GDP (gross domestic product). RESULTS: Among the 201 articles identified as potentially relevant to the topic, nine were included in the literature review. Schizophrenia health care costs ranged from four (Ireland) to 140000 of GDP (Spain). Hospital care was the main health care cost driver but ranged from 19 (USA) to 92% (Belgium) demonstrating a great variability in treatment patterns. The costs for social and medico-social system ranged from 1.3 (Korea) to 13.80000 of GDP (USA) and the costs of informal caregivers ranged from 1.2 (Australia) to 12.70000 of GDP (Spain). The productivity losses associated with unemployment ranged from 6.2 (Australia) to 21.30000 of GDP (USA). The productivity losses associated with premature mortality ranged from less than 0.01 (Canada) to 3.850000 (Ireland). Among others factors, such as targeted population, the choice of valuation method between "Friction costs" and "Human Capital" could account for the heterogeneity of estimates. DISCUSSION: Median health care costs of schizophrenia represented 1.1% of total national health care expenditures. Productivity losses associated with morbidity constituted the major cost burden of schizophrenia. Valuation method, costs items, target populations and prevalence rates differed widely from study to study. Furthermore, the burden attributable to loss of quality of life was not estimated in the studies. CONCLUSION: Cost-of-illness studies of schizophrenia provide information about its burden on society. The external validity of such studies however is poor and justifies country-specific data collection. PMID- 23351936 TI - Report of methamphetamine use and cardiomyopathy in three patients. AB - BACKGROUND: Methamphetamine (meth) is a stimulant used illegally around the world, including in Iran. Cardiomyopathy and cardiac failure may occur following chronic meth use and may cause the patients referred to the emergency department. CASE REPORTS: A 28-year old man and two women, ages 29 and 31-year-old, with a history of meth use, were admitted to the emergency department with severe dyspnea at rest. Each had sinus tachycardia with tachypnea and an echocardiogram that showed severe systolic dysfunction consistent with heart failure. Additional evaluation in the hospital revealed cardiomyopathy with no other etiology other than the meth use. CONCLUSION: There are several reports that show an increase in frequency of meth use, suggesting that cardiomyopathy and acute heart failure may be a new medical concern. PMID- 23351937 TI - A comparison of the mechanical properties of a modified silorane based dental composite with those of commercially available composite material. AB - OBJECTIVES: The aim of this study was to compare the mechanical properties of the nano-hydroxyapatite incorporated silorane composite material with the commercially available dental composites. METHODS: Filtek Silorane resin composite was incorporated with 5% and 10% nano-hydroxyapatite crystals and then mechanically tested in comparison along with the commercially available Filtek Silorane and Filtek Supreme XT after 1, 14, 30 and 90 days period. RESULTS: The mechanical tests revealed that the modified silorane based dental composite had a significant increase in the mechanical properties than the commercially available Filtek Silorane and Filtek Supreme XT. SIGNIFICANCE: The collected data suggests that nano-hydroxyapatite crystals modified silorane may provide the clinicians with a better composite materials having a longer life especially in the posterior restorations where the masticatory forces are very much high. PMID- 23351938 TI - On choosing the "perfect" doctor. PMID- 23351939 TI - National resident matching program violations. PMID- 23351940 TI - Personality testing in resident selection. PMID- 23351941 TI - Legacy admissions in medical school. PMID- 23351942 TI - 2011 winning essay: is anything wrong here? state university's scholarship case. PMID- 23351943 TI - 2011 runner-up essay: the purpose of a medical school. PMID- 23351944 TI - 2011 runner-up essay: "social engineering" versus "medical patriotism": what flexner can teach us about solving the primary care crisis. PMID- 23351945 TI - 2011 runner-up essay: incentives for medical school students to practice primary care through the lens of John Rawls. PMID- 23351946 TI - 2011 runner-up essay: stuffing mouths with gold: equitable solutions to the primary care physician shortage. PMID- 23351947 TI - Becoming a doctor in Europe: objective selection systems. PMID- 23351948 TI - Expectations of gender in medical education. PMID- 23351949 TI - Assessing noncognitive attributes: the primary care orientation scale. PMID- 23351950 TI - Bias in assessment of noncognitive attributes. PMID- 23351951 TI - Affirmative action and medical school admissions. PMID- 23351952 TI - The National Resident Matching Program all-in policy: potential consequences and ethical questions. PMID- 23351953 TI - Honesty and fairness in the residency match. PMID- 23351954 TI - Selecting medical students, then and now. PMID- 23351955 TI - Standardizing and Improving the Content of the Dean's Letter. PMID- 23351956 TI - Measurement of lower limb volume: agreement between the vertically oriented perometer and a tape measure method. AB - OBJECTIVE: To investigate the agreement between lower limb volume measurements for the vertically oriented perometer and a tape measure method. DESIGN: Between methods agreement and test-retest reliability study. SETTING: University setting. PARTICIPANTS: Thirty university staff and students were recruited using convenience sampling with no participant drop-outs. INTERVENTIONS: All participants' dominant lower limb volumes were measured using the vertically oriented perometer and a tape measure method. MAIN OUTCOME MEASURES: The Bland Altman difference plot was reported for determining the bias between the two methods and its 95% confidence interval. Test-retest reliability and the measurement error for the perometer method were determined using the ICC(2,1) model and within-subject standard deviation (sw) respectively. RESULTS: There was a lack of agreement between the tape measure and perometer method. The Bland Altman difference plot showed that the tape measure method overestimated limb volume by 157ml compared to the perometer method. A 95% confidence interval of 834ml to 519ml was observed. The test-retest reliability of the perometer method was ICC(2,1)=0.99. The measurement error of the perometer method was clinically acceptable (sw=121ml). CONCLUSIONS: There was a lack of agreement between the two methods investigated. Therefore the perometer and tape measure methods are not interchangeable. It is recommended that future validity and reliability studies for the vertically oriented perometer are conducted on clinical populations. PMID- 23351957 TI - Antifertility activity of methanolic bark extract of Aegle marmelos (l.) in male wistar rats. AB - BACKGROUND: Aegle marmelos leaf, seed and fruit from earlier studies is known to affect male fertility in reversible manner. However they had delayed onset and recovery was found to be prolonged. The present study was undertaken with an aim to evaluate the effect of Aegle marmelos bark extract on rats as the extract is found to be a rich source of marmin and fagarine known for reducing male fertility. Three different concentration of methanolic bark extracts of Aegle marmelos (L.) were evaluated for male antifertility activity on albino wistar rats. Methanolic bark extract of Aegle marmelos at the dose of 200, 400, and 600 mg/Kg b.w was administered orally for 60 days. Treatments were stopped thereafter and animals were sacrificed after a recovery period of 30 days. Control animal were administered vehicle (0.5% CMC for 60 days). Lonidamine was used as standard drug to compare the effect of extract. RESULTS: Methanolic extract causes a dose & duration dependent infertility via reducing reproductive organ weight and serum testosterone levels. Sperm analysis results showed reduction in sperm density, motility, viability and sperm acrosomal integrity without interfering libido and vital organ body weight. Histopathological studies of testes revealed exfoliation of elongated spermatids, nuclear chromatin condensation, degeneration and prominent spaces detected within the germinal epithelium signifying testicular cytotoxicity and necrosis. Time dependent complete infertility was observed in all dose levels. Animals after the withdrawal from treatment, for 30 days showed restoration of the morphological as well as physiological parameters in extract treated rats. Methanolic extract showed lipid lowering activity compared to control, suggestive good candidature of this plant for further studies. CONCLUSIONS: Our studies suggested Aegle marmelos barks methanolic extract as strong candidate for male contraceptive via its ability to produce complete inhibition of pregnancy, rapid restoration of fertility after withdrawal from treatment and its lipid correcting ability proving further beneficial effects. PMID- 23351958 TI - Tibia shaft fractures: costly burden of nonunions. AB - BACKGROUND: Tibia shaft fractures (TSF) are common for men and women and cause substantial morbidity, healthcare use, and costs. The impact of nonunions on healthcare use and costs is poorly described. Our goal was to investigate patient characteristics and healthcare use and costs associated with TSF in patients with and without nonunion. METHODS: We retrospectively analyzed medical claims in large U.S. managed care claims databases (Thomson Reuters MarketScan(r), 16 million lives). We studied patients >= 18 years old with a TSF diagnosis (ICD-9 codes: 823.20, 823.22, 823.30, 823.32) in 2006 with continuous pharmaceutical and medical benefit enrollment 1 year prior and 2 years post-fracture. Nonunion was defined by ICD-9 code 733.82 (after the TSF date). RESULTS: Among the 853 patients with TSF, 99 (12%) had nonunion. Patients with nonunion had more comorbidities (30 vs. 21, pre-fracture) and were more likely to have their TSF open (87% vs. 70%) than those without nonunion. Patients with nonunion were more likely to have additional fractures during the 2-year follow-up (of lower limb [88.9% vs. 69.5%, P < 0.001], spine or trunk [16.2% vs. 7.2%, P = 0.002], and skull [5.1% vs. 1.3%, P = 0.008]) than those without nonunion. Nonunion patients were more likely to use various types of surgical care, inpatient care (tibia and non-tibia related: 65% vs. 40%, P < 0.001) and outpatient physical therapy (tibia related: 60% vs. 42%, P < 0.001) than those without nonunion. All categories of care (except emergency room costs) were more expensive in nonunion patients than in those without nonunion: median total care cost $25,556 vs. $11,686, P < 0.001. Nonunion patients were much more likely to be prescribed pain medications (99% vs. 92%, P = 0.009), especially strong opioids (90% vs. 76.4%, P = 0.002) and had longer length of opioid therapy (5.4 months vs. 2.8 months, P < 0.001) than patients without nonunion. Tibia fracture patterns in men differed from those in women. CONCLUSIONS: Nonunions in TSF's are associated with substantial healthcare resource use, common use of strong opioids, and high per-patient costs. Open fractures are associated with higher likelihood of nonunion than closed ones. Effective screening of nonunion risk may decrease this morbidity and subsequent healthcare resource use and costs. PMID- 23351959 TI - Pharmacokinetics, tissue distribution and excretion study of resveratrol and its prodrug 3,5,4'-tri-O-acetylresveratrol in rats. AB - 3,5,4'-Tri-O-acetylresveratrol (TARES) synthesized by acetylating three hydroxyl groups of resveratrol (RES) is a prodrug of RES. The aim of this study was to investigate and compare the pharmacokinetics, tissue distribution and excretion of TARES and RES in rats following a single intragastric gavage (i.g.) administration. After RES is transformed into TARES, its pharmacokinetic properties are improved, such as the t1/2 has been prolonged and the AUC has been enhanced. And TARES follows linear plasma pharmacokinetics across the investigated dosage range in rats (77.5-310 mg/kg). The major distribution tissues of TARES or RES in rats were liver, spleen, heart and lung. TARES can increase the content of RES in lung significantly. There was no long-term accumulation of RES in rat tissues. Whether we administrated to rats of equimolar TARES or RES, total recoveries of RES in urine and feces within 36 h were low (0.99% or 0.07% in urine and 1.69% or 0.15% in feces). PMID- 23351960 TI - Neuroprotective effects of inhaled lavender oil on scopolamine-induced dementia via anti-oxidative activities in rats. AB - Lavender is used in traditional medicines in Asia, Europe, ancient Greece and Rome, and was mentioned in the Bible and in ancient Jewish texts. Also, lavender is reported to be an effective medical plant in treating inflammation, depression, stress and headache. The present study was undertaken in order to investigate the antioxidant and antiapoptotic activities of the lavender essential oils from Lavandula angustifolia ssp. angustifolia Mill. and Lavandula hybrida Rev. using superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) specific activities, total content of reduced glutathione (GSH), malondialdehyde (MDA) level (lipid peroxidation) and DNA fragmentation assays in male Wistar rats subjected to scopolamine-induced dementia rat model. In scopolamine-treated rats, lavender essential oils showed potent antioxidant and antiapoptotic activities. Subacute exposures (daily, for 7 continuous days) to lavender oils significantly increased antioxidant enzyme activities (SOD, GPX and CAT), total content of reduced GSH and reduced lipid peroxidation (MDA level) in rat temporal lobe homogenates, suggesting antioxidant potential. Also, DNA cleavage patterns were absent in the lavender groups, suggesting antiapoptotic activity. Taken together, our results suggest that antioxidant and antiapoptotic activities of the lavender essential oils are the major mechanisms for their potent neuroprotective effects against scopolamine-induced oxidative stress in the rat brain. PMID- 23351961 TI - Inhibitory effects of curcumin on gastric cancer cells: a proteomic study of molecular targets. AB - Curcumin, a natural anticancer agent, has been shown to inhibit cell growth in a number of tumor cell lines and animal models. We examined the inhibition of curcumin on cell viability and its induction of apoptosis using different gastric cancer cell lines (BGC-823, MKN-45 and SCG-7901). 3-(4,5-dimethyl-thiazol-2-yl)-2 5-diphenyltetrazolium-bromide (MTT) assay showed that curcumin inhibited cell growth in a dose- (1, 5, 10 and 30 MUM) and time- (24, 48, 72 and 96 h) dependent manner; analysis of Annexin V binding showed that curcumin induced apoptosis at the dose of 10 and 30 MUM when the cells were treated for 24 and 48 h. As cancers are caused by dysregulation of various proteins, we investigated target proteins associated with curcumin by two-dimensional gel electrophoresis (2-DE) and MALDI TOF-TOF mass spectrometer. BGC-823 cells were treated with 30 MUM curcumin for 24 h and total protein was extracted for the 2-DE. In the first dimension of the 2 DE, protein samples (800 MUg) were applied to immobilized pH gradient (IPG) strips (24 cm, pH 3-10, NL) and the isoelectric focusing (IEF) was performed using a step-wise voltage ramp; the second dimension was performed using 12.5% SDS-PAGE gel at 1 W constant power per gel. In total, 75 proteins showed significant changes over 1.5-fold in curcumin-treated cells compared to control cells (Student's t-test, p<0.05). Among them, 33 proteins were upregulated and 42 proteins downregulated by curcumin as determined by spot densitometry. 52 proteins with significant mascot scores were identified and implicated in cancer development and progression. Their biological function included cell proliferation, cycle and apoptosis (20%), metabolism (16%), nucleic acid processing (15%), cytoskeleton organization and movement (11%), signal transduction (11%), protein folding, proteolysis and translation (20%), and immune response (2%). Furthermore, protein-protein interacting analysis demonstrated the interaction networks affected by curcumin in gastric cancer cells. These data provide some clues for explaining the anticancer mechanisms of curcumin and explore more potent molecular targets of the drug expected to be helpful for the development of new drugs. PMID- 23351962 TI - Protective effects of oral crocin against intracerebroventricular streptozotocin induced spatial memory deficit and oxidative stress in rats. AB - Intracerebroventricular (ICV) streptozotocin (STZ) has been shown to cause cognitive impairment, associated with free radical generation. In this study, we evaluated the effects of crocin on cognitive performance in ICV STZ-lesioned rats (3 mg/kg bilaterally, on day 1 and 3). Crocin (100 mg/kg, p.o.) was administered for 21 consecutive days, starting 1h prior to the first dose of STZ. Cognitive performance was assessed using Morris water maze task while the parameters of oxidative stress assessed, were malondialdehyde (MDA) and total thiol levels besides glutathione peroxidase (GPx) activity. STZ-lesioned rats showed a severe deficit in memory associated with elevated MDA levels, reduced GPx activity and total thiol content. Crocin treatment improved cognitive performance and resulted in a significant reduction in MDA levels and elevation in total thiol content and GPx activity. This study demonstrates that crocin may have beneficial effects in the treatment of neurodegenerative disorders such as Alzheimer's disease. PMID- 23351963 TI - Functional expression of a proton-coupled organic cation (H+/OC) antiporter in human brain capillary endothelial cell line hCMEC/D3, a human blood-brain barrier model. AB - BACKGROUND: Knowledge of the molecular basis and transport function of the human blood-brain barrier (BBB) is important for not only understanding human cerebral physiology, but also development of new central nervous system (CNS)-acting drugs. However, few studies have been done using human brain capillary endothelial cells, because human brain materials are difficult to obtain. The purpose of this study is to clarify the functional expression of a proton-coupled organic cation (H+/OC) antiporter in human brain capillary endothelial cell line hCMEC/D3, which has been recently developed as an in vitro human BBB model. METHODS: Diphenhydramine, [3H]pyrilamine and oxycodone were used as cationic drugs that proved to be H+/OC antiporter substrates. The in vitro uptake experiments by hCMEC/D3 cells were carried out under several conditions. RESULTS: Diphenhydramine and [3H]pyrilamine were both transported into hCMEC/D3 cells in a time- and concentration-dependent manner with Km values of 59 MUM and 19 MUM, respectively. Each inhibited uptake of the other in a competitive manner, suggesting that a common mechanism is involved in their transport. The diphenhydramine uptake was significantly inhibited by amantadine and quinidine, but not tetraethylammonium and 1-methyl-4-phenylpyridinium (substrates for well known organic cation transporters). The uptake was inhibited by metabolic inhibitors, but was insensitive to extracellular sodium and membrane potential. Further, the uptake was increased by extracellular alkalization and intracellular acidification. These transport properties are completely consistent with those of previously characterized H+/OC antiporter in rat BBB. CONCLUSIONS: The present results suggest that H+/OC antiporter is functionally expressed in hCMEC/D3 cells. PMID- 23351964 TI - Positive effect of septimebTM on mortality rate in severe sepsis: a novel non antibiotic strategy. AB - BACKGROUND: Septimeb is a new herbal-derived remedy, recently approved for its potential immunomodulatory effects. Regarding the key role of immune system in the pathogenesis of severe sepsis and lack of any standard treatment for improving survival of these patients; we evaluated the effect of Septimeb -as an adjutant to standard treatment-on inflammatory biomarkers and mortality rates in patients with severe sepsis. METHODS: In this multicenter, randomized, single blind trial, we assigned patients with severe sepsis and Acute Physiology and Chronic Health Evaluation (APACHE II) score of more than 20 to receive standard treatment of severe sepsis (control group) or standard treatment plus Septimeb. This group was treated with Septimeb for 14 days then followed up for another14 days. APACHE score, Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score (SAPS) were calculated daily. Blood samples were analyzed for interleukin 2 tumor necrosis factor-alpha, total antioxidant power, platelet growth factor and matrix metalloproteinase 2. RESULTS: A total of 29 patients underwent randomization (13 in control group and 16 in Septimeb group). There was significant difference between the Septimeb and control group in the 14 days mortality rate (18.8% vs. 53.85 respectively, P=0.048). Compared to control group, Septimeb was significantly effective in improving SAPS (P= 0.029), SOFA (P=0.003) and APACHE II (P=0.008) scores. Inflammatory biomarkers didn't change significantly between the two groups (P>0.05). CONCLUSION: Septimeb reduces mortality rates among patients with severe sepsis and it could be added as a safe adjutant to standard treatment of sepsis. PMID- 23351965 TI - Analysis of ependymal ciliary beat pattern and beat frequency using high speed imaging: comparison with the photomultiplier and photodiode methods. AB - BACKGROUND: The aim of this study was to compare beat frequency measurements of ependymal cilia made by digital high speed imaging to those obtained using the photomultiplier and modified photodiode techniques. Using high speed video analysis the relationship of the power and recover strokes was also determined. METHODS: Ciliated strips of ependyma attached to slices from the brain of Wistar rats were incubated at 30 degrees C and observed using a *50 water immersion lens. Ciliary beat frequency was measured using each of the three techniques: the high speed video, photodiode and photomultiplier. Readings were repeated after 30 minutes incubation at 37 degrees C. Ependymal cilia were observed in slow motion and the precise movement of cilia during the recovery stroke relative to the path travelled during the power stroke was measured. RESULTS: The mean (95% confidence intervals) beat frequencies determined by the high speed video, photomultiplier and photodiode at 30 degrees C were 27.7 (26.6 to 28.8), 25.5 (24.4 to 26.6) and 20.8 (20.4 to 21.3) Hz, respectively. The mean (95% confidence intervals) beat frequencies determined by the high speed video, photomultiplier and photodiode at 37 degrees C were 36.4 (34 to 39.5), 38.4 (36.8 to 39.9) and 18.8 (16.9 to 20.5) Hz. The inter and intra observer reliability for measurement of ciliary beat frequency was 3.8% and 1%, respectively. Ependymal cilia were observed to move in a planar fashion during the power and recovery strokes with a maximum deviation to the right of the midline of 12.1(11.8 to 13.0) degrees during the power stroke and 12.6(11.6 to 13.6) degrees to the left of the midline during the recovery stroke. CONCLUSION: The photodiode technique greatly underestimates ciliary beat frequency and should not be used to measure ependymal ciliary beat frequency at the temperatures studied. Ciliary beat frequency from the high speed video and photomultiplier techniques cannot be used interchangeably. Ependymal cilia had minimal deviation to the right side during their power stroke and to the left during the recovery stroke. PMID- 23351967 TI - Academic affiliated training centers in humanitarian health, Part I: program characteristics and professionalization preferences of centers in North America. AB - The collaborative London based non-governmental organization network ELRHA (Enhancing Learning and Research for Humanitarian Assistance) supports partnerships between higher education institutions and humanitarian organizations worldwide with the objective to enhance the professionalization of the humanitarian sector. While coordination and control of the humanitarian sector has plagued the response to every major crisis, concerns highlighted by the 2010 Haitian earthquake response further catalyzed and accelerated the need to ensure competency-based professionalization of the humanitarian health care work force. The Harvard Humanitarian Initiative sponsored an independent survey of established academically affiliated training centers in North America that train humanitarian health care workers to determine their individual training center characteristics and preferences in the potential professionalization process. The survey revealed that a common thread of profession-specific skills and core humanitarian competencies were being offered in both residential and online programs with additional programs offering opportunities for field simulation experiences and more advanced degree programs. This study supports the potential for the development of like-minded academic affiliated and competency-based humanitarian health programs to organize themselves under ELRHA's regional "consultation hubs" worldwide that can assist and advocate for improved education and training opportunities in less served developing countries. PMID- 23351966 TI - Genetic determinants of voluntary exercise. AB - Variation in voluntary exercise behavior is an important determinant of long-term human health. Increased physical activity is used as a preventative measure or therapeutic intervention for disease, and a sedentary lifestyle has generally been viewed as unhealthy. Predisposition to engage in voluntary activity is heritable and induces protective metabolic changes, but its complex genetic/genomic architecture has only recently begun to emerge. We first present a brief historical perspective and summary of the known benefits of voluntary exercise. Second, we describe human and mouse model studies using genomic and transcriptomic approaches to reveal the genetic architecture of exercise. Third, we discuss the merging of genomic information and physiological observations, revealing systems and networks that lead to a more complete mechanistic understanding of how exercise protects against disease pathogenesis. Finally, we explore potential regulation of physical activity through epigenetic mechanisms, including those that persist across multiple generations. PMID- 23351968 TI - Radiologists are still changing the way health care is being delivered. PMID- 23351969 TI - A literature review of findings in physical elder abuse. AB - PURPOSE: To review the medical literature for reports on the types of physical injuries in elder abuse with the aim of eliciting patterns that will aid its detection. MATERIALS AND METHODS: The databases of PubMed, CINAHL, EMBASE, and TRIP were searched from 1975 to March 2012 for articles that contained the following phrases: "physical elder abuse," "older adult abuse," "elder mistreatment," "geriatric abuse," "geriatric trauma," and "nonaccidental geriatric injury." Distribution and description of injuries in physical elder abuse from case-control studies, cross-sectional studies, case series, and case reports as seen at autopsy, in hospital emergency departments, or in medicolegal reports were tabulated and summarized. RESULTS: A review of 9 articles from a total of 574 articles screened yielded 839 injuries. The anatomic distribution in these was as follows: upper extremity, 43.98%; maxillofacial, dental, and neck, 22.88%; skull and brain, 12.28%; lower extremity, 10.61%; and torso, 10.25%. CONCLUSION: Two-thirds of injuries that occur in elder abuse are to the upper extremity and maxillofacial region. The social context in which the injuries takes place remains crucial to accurate identification of abuse. This includes a culture of violence in the family; a demented, debilitated, or depressed and socially isolated victim; and a perpetrator profile of mental illness, alcohol or drug abuse, or emotional and/or financial dependence on the victim. PMID- 23351970 TI - Case of the month #180: Atypical thalamic and mesencephalic neurocytoma--a rare neoplasm in children. PMID- 23351971 TI - Case of the month #181: Iatrogenic colon perforation during epicardial pacing wire placement. PMID- 23351973 TI - Special issue: ESCCAP - Toxocara 2012. Introduction. PMID- 23351974 TI - In vitro ovicidal and larvicidal activity of the essential oil of Artemisia lancea against Haemonchus contortus (Strongylida). AB - Prolonged use of chemical anthelmintics has been found to result in anthelmintic resistance and environmental issues, thereby limiting the application of these drugs in domestic animals and prompting interest in the study of plant extracts as alternative sources thereof. The aim of this study was to evaluate the in vitro effect of the essential oil (EO) of Artemisia lancea against the parasitic nematode Haemonchus contortus using egg hatch assay, larval development assay, and larval migration inhibition assay. The EO yield of extraction was 0.63% (w/w), and the major constituents were 1,8-cineole (34.56%) and camphor (16.65%). In the egg hatch assay, an inhibition greater than 99% was observed with the EO at 10 mg mL(-1) and the LC50 was 1.82 mg mL(-1). 1,8-Cineole demonstrated moderate ovicidal activity with a LC50 of 4.64 mg mL(-1), whereas camphor did not show enough activity to have its LC50 determined. In the larval development assay, the EO, 1,8-cineole, and camphor inhibited 93.6%, 65.2%, and 57% of larval development at 10 mg mL(-1) and exhibited dose-dependent responses with LC50 values of 1.66, 5.07, and 7.80 mg mL(-1), respectively. In the migration inhibition assay, the EO and 1,8-cineole at best inhibited 77% and 60.3% of larval migration at 10 mg mL(-1), respectively. Camphor showed low inhibition capacity, and its efficacy was not dose dependent. The results indicate that the in vitro anthelmintic activity of the EO of A. lancea may be associated with the additive action of the two major constituents, as well as other more minor terpenoid components. PMID- 23351972 TI - Toxocara canis: molecular basis of immune recognition and evasion. AB - Toxocara canis has extraordinary abilities to survive for many years in the tissues of diverse vertebrate species, as well as to develop to maturity in the intestinal tract of its definitive canid host. Human disease is caused by larval stages invading musculature, brain and the eye, and immune mechanisms appear to be ineffective at eliminating the infection. Survival of T. canis larvae can be attributed to two molecular strategies evolved by the parasite. Firstly, it releases quantities of 'excretory-secretory' products which include lectins, mucins and enzymes that interact with and modulate host immunity. For example, one lectin (CTL-1) is very similar to mammalian lectins, required for tissue inflammation, suggesting that T. canis may interfere with leucocyte extravasation into infected sites. The second strategy is the elaboration of a specialised mucin-rich surface coat; this is loosely attached to the parasite epicuticle in a fashion that permits rapid escape when host antibodies and cells adhere, resulting in an inflammatory reaction around a newly vacated focus. The mucins have been characterised as bearing multiple glycan side-chains, consisting of a blood-group-like trisaccharide with one or two O-methylation modifications. Both the lectins and these trisaccharides are targeted by host antibodies, with anti lectin antibodies showing particular diagnostic promise. Antibodies to the mono methylated trisaccharide appear to be T. canis-specific, as this epitope is not found in the closely related Toxocara cati, but all other antigenic determinants are very similar between the two species. This distinction may be important in designing new and more accurate diagnostic tests. Further tools to control toxocariasis could also arise from understanding the molecular cues and steps involved in larval development. In vitro-cultivated larvae express high levels of four mRNAs that are translationally silenced, as the proteins they encode are not detectable in cultured larvae. However, these appear to be produced once the parasite has entered the mammalian host, as they are recognised by specific antibodies in infected patients. Elucidating the function of these genes, or analysing if micro-RNA translational silencing suppresses production of the proteins, may point towards new drug targets for tissue-phase parasites in humans. PMID- 23351975 TI - Understanding the role of dogs (Canis lupus familiaris) in the transmission dynamics of Trypanosoma cruzi genotypes in Colombia. AB - The dog (Canis lupus familiaris) is the most important domestic reservoir of Chagas disease, a zoonosis that affects more than 10 million people in Latin America. Trypanosoma cruzi, the etiologic agent of the disease, displays remarkable genetic variability, as indicated by its six genotypes (TcI-TcVI). A pilot study was conducted to establish the prevalence of T. cruzi among the canine population by analyzing 80 dogs. We report the identification of the TcI, TcII, TcIV and TcVI genotypes as single infections. TcI/TcII and TcI/TcIV presented as mixed infections and included the presence of Trypanosoma angel. The implications of this distribution are herein discussed. Based on the molecular epidemiology findings, this study suggests a plausible role for canine synanthropism in the transmission of T. cruzi. PMID- 23351976 TI - Different mutations of the human c-mpl gene indicate distinct haematopoietic diseases. AB - The human c-mpl gene (MPL) plays an important role in the development of megakaryocytes and platelets as well as the self-renewal of haematopoietic stem cells. However, numerous MPL mutations have been identified in haematopoietic diseases. These mutations alter the normal regulatory mechanisms and lead to autonomous activation or signalling deficiencies. In this review, we summarise 59 different MPL mutations and classify these mutations into four different groups according to the associated diseases and mutation rates. Using this classification, we clearly distinguish four diverse types of MPL mutations and obtain a deep understand of their clinical significance. This will prove to be useful for both disease diagnosis and the design of individual therapy regimens based on the type of MPL mutations. PMID- 23351977 TI - Membrane stabilization as a mechanism of the anti-inflammatory activity of methanol extract of garden egg (Solanum aethiopicum). AB - BACKGROUND: Some observations and reports show that people with high consumption of Solanum aethiopicum (African garden egg) have relief in arthritic pains and swelling. We aimed at assessing the effect of methanol extract of Solanum aethiopicum in experimentally induced inflammation using leukocyte mobilization and vascular permeability tests in rats and human red blood cell (HRBC) membrane stabilization as studies. METHODS: Twenty five (25) adult Wistar rats of either sex (120 g - 200 g) divided into five groups of five rats each were used for each of the animal models. Groups 2, 3 and 4 were administered varied doses of the extract (100, 200 and 400 mg/kg), while groups 1 (vehicle control) and 5 (treatment control) received normal saline and indomethacin (50 mg/kg) respectively. Vascular permeability was induced by the intra-peritoneal injection of 1 ml of acetic acid and monitored using 0.5 ml intravenous injection of 1% Evans blue solution. Leukocyte mobilization was induced by the intra-peritoneal injection of 0.5 ml of 3% agar suspension in normal saline. Heat and hypotonicity induced heamolysis of HRBC membrane was used to assess membrane stabilization. RESULTS: The methanol extracts of garden egg significantly and dose dependently reduced (p<=0.05) the acetic acid induced vascular permeability and agar induced leukocyte mobilization in rats. The percentage inhibitions of induced vascular permeability were 21 +/- 3.39, 25 +/-1.92 and 60 +/- 3.81 for the 100, 200 and 400 mg/kg of the extract while the inhibitions of the agar induced leucocyte migration were 23 +/- 2.17, 26 +/- 1.58 and 32 +/- 1.58 for the 100, 200 and 400 mg/kg of the extract respectively. The extract also, at doses of 100, 200, 400, 600 and 800 MUg/ml significantly inhibited heat induced lysis of the human red cell membrane with values of 66.46 +/- 2.89, 65.14 +/- 4.58, 46.53 +/- 2.52, 61.88 +/- 4.51and 86.67 +/- 3.06 respectively. CONCLUSIONS: These results show that methanol extract of Solanum aethiopicum has anti-inflammatory properties and can reduce inflammatory injury and tissue damage. PMID- 23351979 TI - Current opinion on nanotoxicology. AB - Nanotechnology is one of the premiere technologies available today, having expanded both as field of scientific study and in the public consciousness. Despite this growth, the drawbacks, limitations and potential safety hazards associated with the incorporation of nanotechnology into existing industries are still being learned. The noticeable point is that there is no enough data available yet to analyze global use of nanotechnology from a meta-perspective. Three challenges can be defined in light of nanotoxicology. One, materials that might prove to be significantly toxic must be identified. Two, a system for the categorization of NP materials must be codified and made available to toxicologists. Third, a better understanding of nanoparticles biological interactions must be obtained, in order to make the best use of the first two goals. For all three, it must be remembered that research standards need to be developed for the gathering of data on the nanoscale, as that level is where the NPs and the patient's biosystems will be interacting.As requiring toxicologists to become nanotechnology experts would not be feasible, to properly incorporate the care of nanotoxicity into the existing medical framework, a range of experts across multiple fields of study must work in close synchronization. The focus needs to be on mechanism-driven research to ensure a solid scientific foundation for the assessment of NP and their role in healthcare. PMID- 23351980 TI - Viral Encephalopathy and Retinopathy in groupers (Epinephelus spp.) in southern Italy: a threat for wild endangered species? AB - BACKGROUND: Betanodaviruses are the causative agents of Viral Encephalopathy and Retinopathy (VER). To date, more than 50 species have proved to be susceptible and among them, those found in genus Epinephelus are highly represented. Clinical disease outbreaks are generally characterized by typical nervous signs and significant mortalities mainly associated with aquaculture activities, although some concerns for the impact of this infection in wild fish have been raised. In this study, the authors present the first documented report describing an outbreak of VER in wild species in the Mediterranean basin. CASE PRESENTATION: In late summer--early winter 2011 (September-December), significant mortalities affecting wild Dusky grouper (Epinephelus marginatus), Golden grouper (Epinephelus costae) and European sea bass (Dicentrarchus labrax) were reported in the municipality of Santa Maria di Leuca (Northern Ionian Sea, Italy). The affected fish showed an abnormal swimming behavior and swollen abdomens. During this epizootic, five moribund fish showing clear neurological signs were captured and underwent laboratory investigations. Analytical results confirmed the diagnosis of VER in all the specimens. Genetic characterization classified all betanodavirus isolates as belonging to the RGNNV genotype, revealing a close genetic relationship with viral sequences obtained from diseased farmed fish reared in the same area in previous years. CONCLUSION: The close relationship of the viral sequences between the isolates collected in wild affected fish and those isolated during clinical disease outbreaks in farmed fish in the same area in previous years suggests a persistent circulation of betanodaviruses and transmission between wild and farmed stocks. Further investigations are necessary to assess the risk of viral transmission between wild and farmed fish populations, particularly in marine protected areas where endangered species are present. PMID- 23351978 TI - Single-row vs. double-row arthroscopic rotator cuff repair: clinical and 3 Tesla MR arthrography results. AB - BACKGROUND: Arthroscopic rotator cuff repair has become popular in the last few years because it avoids large skin incisions and deltoid detachment and dysfunction. Earlier arthroscopic single-row (SR) repair methods achieved only partial restoration of the original footprint of the tendons of the rotator cuff, while double-row (DR) repair methods presented many biomechanical advantages and higher rates of tendon-to-bone healing. However, DR repair failed to demonstrate better clinical results than SR repair in clinical trials. MR imaging at 3 Tesla, especially with intra-articular contrast medium (MRA), showed a better diagnostic performance than 1.5 Tesla in the musculoskeletal setting. The objective of this study was to retrospectively evaluate the clinical and 3 Tesla MRA results in two groups of patients operated on for a medium-sized full-thickness rotator cuff tear with two different techniques. METHODS: The first group consisted of 20 patients operated on with the SR technique; the second group consisted of 20 patients operated on with the DR technique. All patients were evaluated at a minimum of 3 years after surgery. The primary end point was the re-tear rate at 3 Tesla MRA. The secondary end points were the Constant-Murley Scale (CMS), the Simple Shoulder Test (SST) scores, surgical time and implant expense. RESULTS: The mean follow-up was 40 months in the SR group and 38.9 months in the DR group. The mean postoperative CMS was 70 in the SR group and 68 in the DR group. The mean SST score was 9.4 in the SR group and 10.1 in the DR group. The re-tear rate was 60% in the SR group and 25% in the DR group. Leakage of the contrast medium was observed in all patients. CONCLUSIONS: To the best of our knowledge, this is the first report on 3 Tesla MRA in the evaluation of two different techniques of rotator cuff repair. DR repair resulted in a statistically significant lower re tear rate, with longer surgical time and higher implant expense, despite no difference in clinical outcomes. We think that leakage of the contrast medium is due to an incomplete tendon-to-bone sealing, which is not a re-tear. This phenomenon could have important medicolegal implications. Level of evidence III. Treatment study: Case-control study. PMID- 23351981 TI - Statistical optimization of a novel excipient (CMEC) based gastro retentive floating tablets of propranolol HCl and it's in vivo buoyancy characterization in healthy human volunteers. AB - The objective of the present investigation is to formulate gastro retentive floating drug delivery systems (GRFDDS) of propranolol HCl by central composite design and to study the effect of formulation variables on floating lag time, D1hr (% drug release at 1 hr) and t90 (time required to release 90% of the drug). 3 factor central composite design was employed for the development of GRFDDS containing novel semi synthetic polymer carboxymethyl ethyl cellulose (CMEC) as a release retarding polymer. CMEC, sodium bicarbonate and Povidone concentrations were included as independent variables. The tablets were prepared by direct compression method and were evaluated for in vitro buoyancy and dissolution studies. From the polynomial model fitting statistical analysis, it was confirmed that the response floating lag time and D1hr is suggested to quadratic model and t90 is suggested to linear model. All the statistical formulations followed first order rate kinetics with non-Fickian diffusion mechanism. The desirability function was used to optimize the response variables, each having a different target, and the observed responses were highly agreed with experimental values. Statistically optimized formulation was characterized by FTIR and DSC studies and found no interactions between drug and polymer. The results demonstrate the feasibility of the model in the development of GRFDDS containing a propranolol HCl. Statistically optimized formulation was evaluated for in vivo buoyancy studies in healthy humans for both fed and fasted states. From the results, it was concluded that gastric residence time of the floating tablets were enhanced at fed stage but not in fasted state. PMID- 23351982 TI - 1,5-Diphenylpent-3-en-1-ynes and methyl naphthalene carboxylates from Lawsonia inermis and their anti-inflammatory activity. AB - Lawsonia inermis (Lythraceae) known as henna is one of the most popular and ancient plants used in cosmetics and hair dying. It is cultivated for its leaves but other parts such as seeds, flowers, stem bark and roots are also used in traditional medicine for millennia. Henna tattoo paste also proved to be beneficial for wound healing and in several skin diseases suggesting potent anti inflammatory activity. To evaluate henna anti-inflammatory activity, 31 compounds, including three 1,5-diphenylpent-3-en-1-yne derivatives, lawsochylin A C and three methyl naphthalene carboxylates, lawsonaphthoate A-C, were isolated from the stems and leaves of henna utilizing a bioassay-guided fractionation. The structures of the compounds were elucidated by spectroscopic data. Two compounds, lawsochylin A and lawsonaphthoate A showed potent anti-inflammatory activity by inhibition of superoxide anion generation (IC(50)=1.80 and 1.90 MUg/ml) and elastase release (IC(50)=1.58 and 3.17 MUg/ml) of human neutrophils in response to fMLP or cytochalasin B. Moreover, the known compounds, luteolin, apigenin, 4S 4-hydroxy-alpha-tetralone, and 2-butoxysuccinic acid, also showed potent inhibition of superoxide anion generation (IC(50)=0.75-1.78 MUg/ml) and elastase release (IC(50)=1.62-3.61 MUg/ml). PMID- 23351983 TI - Brief report: adolescent adjustment in affluent communities: the role of motivational climate and goal orientation. AB - Researchers now recognize that affluent youth experience tremendous achievement pressures, yet contributing factors or outcomes are rarely explored. Using a sample of affluent adolescents, the present study investigates the mediating role of goal orientation (GO) on relations between school motivational climate (MC) and adolescent adjustment. Adolescents from four high schools completed measures of MC (i.e., Performance and Mastery), GO (i.e., Ego and Task), and adjustment (i.e., depressive symptoms, anxiety, and life satisfaction). Performance climates were associated with more adjustment problems while Mastery climates were associated with fewer adjustment problems. Adolescents with higher Ego orientation reported more depressive and anxiety symptoms, while adolescents with higher Task orientation indicated fewer depressive symptoms and greater life satisfaction. Adolescent Task orientation mediated the relations between Mastery climate and two adjustment outcomes (i.e., depressive symptoms and life satisfaction). Results suggest the importance of non-competitive achievement oriented values and collaborative school contexts in adolescent adjustment. PMID- 23351984 TI - Cilia - the prodigal organelle. PMID- 23351985 TI - Epidemiology of congenital neutropenia. AB - Epidemiologic investigations of congenital neutropenia aim to determine several important indicators related to the disease, such as incidence at birth, prevalence, and outcome in the population, including the rate of severe infections, leukemia, and survival. Genetic diagnosis is an important criterion for classifying patients and reliably determining the epidemiologic indicators. Patient registries were developed in the 1990s. The prevalence today is probably more than 10 cases per million inhabitants. The rate of infection and leukemia risk can now be calculated. Risk factors for leukemia seem to depend on both the genetic background and cumulative dose of granulocyte colony stimulating factor. PMID- 23351987 TI - Genetics and pathophysiology of severe congenital neutropenia syndromes unrelated to neutrophil elastase. AB - Considerable progress has been made in recent years in understanding of the genetic basis for congenital neutropenia syndromes. With the advent of high throughput genomic analyzing technologies, the underlying genetic causes of other congenital neutropenia syndromes are expected to be resolved in the near future. This knowledge will provide the foundation for genotype-phenotype correlations for infection susceptibility, response to therapy, and risk of malignant transformation, enabling optimal care for individual patients depending on their molecular pathophysiology. It is hoped that these investigations will enable the development of tailored molecular therapies to specifically correct the aberrant signaling cascades. PMID- 23351988 TI - Granulocyte colony-stimulating factor receptor signaling: implications for G-CSF responses and leukemic progression in severe congenital neutropenia. AB - Following activation by their cognate ligands, cytokine receptors undergo intracellular routing toward lysosomes, where they are degraded. This review focuses on the signaling function of the G-CSFR in relation to the dynamics of endosomal routing of the G-CSFR. Mechanisms involving receptor lysine ubiquitination and redox-controlled phosphatase activities are discussed. Specific attention is paid to the consequences of G-CSFR mutations, acquired in patients with severe congenital neutropenias who receive G-CSF therapy, particularly in the context of leukemic transformation, a major clinical complication of the disease. PMID- 23351986 TI - ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. AB - The 2 main forms of hereditary neutropenia are cyclic (CN) and severe congenital (SCN) neutropenia. CN is an autosomal dominant disorder in which neutrophil counts fluctuate with 21-day periodicity. SCN consists of static neutropenia, with promyelocytic maturation arrest in the bone marrow. Unlike CN, SCN displays frequent acquisition of somatic mutations in the gene CSF3R. CN is caused by heterozygous mutations in the gene ELANE, encoding neutrophil elastase. SCN is genetically heterogeneous but is most frequently associated with ELANE mutations. We discuss how the mutations provide clues into the pathogenesis of neutropenia and describe current hypotheses for its molecular mechanisms. PMID- 23351989 TI - Defective G-CSFR signaling pathways in congenital neutropenia. AB - Several signaling systems downstream of G-CSFR have been identified that are defective or hyperactivated in myeloid cells of patients with congenital neutropenia: severely reduced expression of myeloid-specific transcription factors LEF-1 and C/EBPalpha, severely reduced expression and functions of HCLS1 protein, severely reduced expression of neutrophil elastase protein, dramatic compensatory up-regulation of the NAMPT/NAD(+)/SIRT pathway leading to continuous activation of emergency granulopoiesis via the transcription factor C/EBPbeta, and hyperactivation of STAT5 protein by tyrosine phosphorylation. PMID- 23351991 TI - Leukocyte adhesion deficiencies. AB - During inflammation, leukocytes play a key role in maintaining tissue homeostasis through elimination of pathogens and removal of damaged tissue. Leukocytes migrate to the site of inflammation by crawling over and through the blood vessel wall, into the tissue. Leukocyte adhesion deficiencies (ie, LAD-I, -II, and LAD I/variant, the latter also known as LAD-III) are caused by defects in the adhesion of leukocytes to the vessel wall, resulting in severe recurrent nonpussing infections and neutrophilia, often preceded by delayed separation of the umbilical cord. Although dependent on the genetic defect, hematopoietic stem cell transplantation is often the only curative treatment. PMID- 23351990 TI - Chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) is a paradigm for nonlymphoid primary immune defects, and has guided elucidation of oxygen metabolism in the phagocyte, vasculature, and brain. It has been in the forefront of the development of antimicrobial prophylaxis before the advent of advanced HIV and before its routine use in neutropenia. It has been an attractive target for gene therapy and bone marrow transplantation for nonmalignant diseases. Therefore, CGD is worthy of attention for its historical interest and because it is a disease for which expert management is imperative. PMID- 23351992 TI - Clinical and molecular pathophysiology of Shwachman-Diamond syndrome: an update. AB - Shwachman-Diamond syndrome (SDS) is an inherited neutropenia syndrome associated with a significant risk of aplastic anemia and malignant transformation. Multiple additional organ systems, including the pancreas, liver, and skeletal and central nervous systems, are affected. Mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene are present in most patients. There is growing evidence that SBDS functions in ribosomal biogenesis and other cellular processes. This article summarizes the clinical phenotype of SDS, diagnostic and treatment approaches, and novel advances in our understanding of the molecular pathophysiology of this disease. PMID- 23351994 TI - Preface. Neutropenia. PMID- 23351993 TI - Animal models of human granulocyte diseases. AB - In vivo animal models have proven very useful to the understanding of basic biologic pathways of the immune system, a prerequisite for the development of innovate therapies. This article addresses currently available models for defined human monogenetic defects of neutrophil granulocytes, including murine, zebrafish, and larger mammalian species. Strengths and weaknesses of each system are summarized, and clinical investigators may thus be inspired to develop further lines of research to improve diagnosis and therapy by use of the appropriate animal model system. PMID- 23351996 TI - Neglect and failures of human security in humanitarian settings: challenges and recommendations. AB - The lack of attention to basic safety and security standards by the humanitarian community is endemic. The tragic bombing and loss of life of the United Nations Assistance Mission in Iraq in 2003 is but one of many unfortunate examples; these incidents are increasing in number. Tools for establishing an organizational security framework are readily available. Capacity to implement this framework requires understanding the culture of safety and security and individual and organizational leadership. This report outlines the essential steps and components necessary to meet this requirement. PMID- 23351995 TI - Association of reduced glyoxalase 1 activity and painful peripheral diabetic neuropathy in type 1 and 2 diabetes mellitus patients. AB - AIMS: The present study was undertaken to investigate the relationship between glyoxalase 1 (Glo1) enzyme activity and painful diabetic neuropathy (DN) in patients with diabetes mellitus. METHODS: Glo1 activity and biochemical markers were determined in blood samples from 108 patients with type 1 diabetes, 109 patients with type 2 diabetes, and 132 individuals without diabetes as a control. Painful and painless peripheral DN was assessed and multivariate regression analysis was used to determine independent association of Glo1 activity with occurrence of painful DN. RESULTS: In patients with type 1 and type 2 diabetes mellitus and painful DN compared to patients with painless DN, Glo1 activity was significantly reduced by 12 and 14%, respectively. The increase in Glo1 activity was significantly associated with reduced occurrence of painful DN after adjusting for confounders by multivariate analysis. CONCLUSIONS: Our results demonstrate for the first time that Glo1 activity is lower in patients with both types of diabetes mellitus who were diagnosed with painful DN. These data support the hypothesis that Glo1 activity modulates the phenotype of DN and warrant further investigation into the role of Glo1 in DN. PMID- 23351997 TI - Systematic review of randomized controlled trials of new anticoagulants for venous thromboembolism prophylaxis in major orthopedic surgeries, compared with enoxaparin. AB - BACKGROUND: In the past 10 years, new anticoagulants (NACs) have been studied for venous thromboembolism (VTE) prophylaxis. OBJECTIVE: To evaluate the risk/benefit profile of NACs versus enoxaparin for VTE prophylaxis in major orthopedic surgery. METHODS: A systematic review of double-blind randomized phase III studies was performed. The search strategy was run from 2000 to 2011 in the main medical electronic databases in any language. Independent extraction of articles was performed by 2 authors using predefined data fields, including study quality indicators. RESULTS: Fifteen published clinical trials evaluating fondaparinux, rivaroxaban, dabigatran, and apixaban were included. Primary efficacy (any deep vein thrombosis [DVT], nonfatal pulmonary embolism, or all-cause mortality) favored fondaparinux (relative risk [RR] 0.50; 95% CI, 0.39, 0.63) and rivaroxaban (RR, 0.50; 95% CI, 0.34, 0.73) over enoxaparin, although significant heterogeneity was observed in both series. The primary efficacy of dabigatran at 220 mg, apixaban, and bemiparin were similar, with RRs of 1.02 (95% CI, 0.86, 1.20), 0.63 (95% CI, 0.39, 1.01), and 0.87 (95% CI, 0.65, 1.17), respectively. The primary efficacy of dabigatran at 150 mg (RR, 1.20; 95% CI, 1.03, 1.41), was inferior to enoxaparin. The incidence of proximal DVT favored apixaban (RR, 0.45; 95% CI, 0.27, 0.75) only. Rivaroxaban (RR, 0.45; 95% CI, 0.27, 0,77) and apixaban (RR, 0.38; 95% CI, 0.16, 0.90) produced significantly lower frequencies of symptomatic DVT. The incidence of major VTE favored rivaroxaban (RR, 0.44; 95% CI, 0.25, 0.81), only. Bleeding risk was similar for all NACs, except fondaparinux (RR, 1.27; 95% CI, 1.04, 1.55), which exhibited a significantly higher any-bleeding risk compared with enoxaparin, and apixaban (RR, 0.88; 95% CI, 0.79, 0.99), which was associated with a reduced risk of any bleeding. Alanine amino transferase was significantly lower with 220 mg of dabigatran, (RR, 0.67; 95% CI, 0.79, 0.99) than with enoxaparin. CONCLUSIONS: NACs can be considered alternatives to conventional thromboprophylaxis regimens in patients undergoing elective major orthopedic surgery, depending on clinical characteristics and cost-effectiveness. The knowledge of some differences concerning efficacy or safety profile, pointed out in this systematic review, along with the respective limitations, may be useful in clinical practice. PMID- 23351998 TI - Radiocephalic fistula: review and update. AB - Since initially described in 1966, radiocephalic fistula or Brescia-Cimino fistula is one of the most commonly performed fistulas in the world of arteriovenous access. The indications for insertion include, but are not limited to, hemodialysis. Although this is a frequently performed procedure, the primary and secondary patency rates and predictors of failure are not well defined. The review of this topic is difficult because of the diversity in reporting and the absence of consensus between series. Following the current published recommendations by the Society of Vascular Surgery regarding standardization of terminology to facilitate meaningful comparison between the diversity of published data, this review is an attempt to summarize and highlight the relevant information with regard to primary patency, secondary patency, and predictors of failure of radiocephalic fistula using the available English literature. PMID- 23351999 TI - Worsening of preoperative foot ischemia after occlusion of polytetrafluoroethylene femorotibial grafts: a comparison with saphenous vein grafts. AB - BACKGROUND: The aim of this study was to determine the hemodynamic and clinical changes after occlusion of polytetrafluoroethylene (PTFE) femorotibial grafts. METHODS: Twenty-seven patients were randomly selected from all patients who underwent femorotibial bypass grafting in our department. In 10 patients, the reversed autologous saphenous vein was used as graft, and in 17 patients a PTFE prosthesis was used. Out of the latter 17 patients, 10 began long-term aspirin therapy and 7 began oral anticoagulation with warfarin. RESULTS: Nine out of the 10 patients with occluded PTFE grafts and who received only aspirin therapy had a critical ischemia after occlusion of the graft, and 4 underwent major amputation. Among the 10 patients with occluded autologous vein bypass, critical ischemia was present in only 4 patients, and only 2 required some form of surgical therapy with no case of major amputation. CONCLUSIONS: After occlusion of a PTFE femorotibial graft, there is a condition of critical ischemia that is less common after occlusion of a vein graft. Oral anticoagulation seems to prevent these negative changes. PMID- 23352001 TI - The frontiers of organ transplantation: "Oh, the places we'll go". PMID- 23352000 TI - Circulating sICAM-1 and sE-Selectin as biomarker of infection and prognosis in patients with systemic inflammatory response syndrome. AB - BACKGROUND: Vascular endothelium activation is a key pathogenic step in systemic inflammatory response syndrome (SIRS) that can be triggered by both microbial and sterile proinflammatory stimuli. The relevance of soluble adhesion molecules as clinical biomarkers to discriminate between infectious and non-infectious SIRS, and the individual patient prognosis, has not been established. METHODS: We prospectively measured by sandwich ELISA, serum levels of soluble E-Selectin (sE Selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble intercellular adhesion molecule-2 (sICAM-2) at ICU admission and at days 3, 7, 14 and 28 in patients with sepsis and at days 3 and 7 in patients with non-infectious SIRS. RESULTS: At ICU admission, sE-Selectin, sVCAM-1 and sICAM-1 in patients with infectious SIRS were significantly higher than those found in patients with non-infectious SIRS. ROC analysis revealed that the AUC for infection identification was best for sICAM-1 (0.900+/-0.041; 95% CI 0.819-0.981; p<0.0001). Moreover, multivariate analysis showed that 4 variables were significantly and independently associated with mortality at 28 days: male gender (OR 15.90; 95% CI, 2.54-99.32), MODS score (OR 5.60; 95% CI, 1.67-18.74), circulating sE-Selectin levels (OR 4.81; 95% CI, 1.34-17.19) and sVCAM-1 concentrations (OR 4.80; 95% CI, 1.34-17.14). CONCLUSIONS: Patients with SIRS secondary to infectious or non-infectious etiology show distinctive patterns of disturbance in serum soluble adhesion molecules. Serum ICAM-1 is a reliable biomarker for classifying patients with infectious SIRS from those with non-infectious SIRS. In addition, soluble E Selectin is a prognostic biomarker with higher levels in patients with SIRS and fatal outcome. PMID- 23352002 TI - Assessing the motives of living, non-related donors. PMID- 23352003 TI - Should a nonadherent adolescent receive a second kidney? PMID- 23352004 TI - Family physicians' role in discussing organ donation with patients and the public. PMID- 23352005 TI - Online ethics-education modules and ethics forums of the American Society of Transplant Surgeons. PMID- 23352007 TI - Living-donor grafts for patients with hepatocellular carcinoma. PMID- 23352008 TI - Severe brain injury and organ solicitation: a call for temperance. PMID- 23352009 TI - Sham surgery. PMID- 23352010 TI - Reproductive tissue transplants defy legal and ethical categorization. PMID- 23352011 TI - Contemporary debates over the acceptability of kidneys for donation. PMID- 23352012 TI - Rationing livers: the persistence of geographic inequity in organ allocation. PMID- 23352013 TI - Implications of the Affordable Care Act for kidney transplantation. PMID- 23352014 TI - The veneer of altruism. PMID- 23352015 TI - The ethics of organ transplantation: a brief history. PMID- 23352016 TI - Liver transplantation: the illusion of choice. PMID- 23352017 TI - The limits of altruism: selecting living donors. PMID- 23352019 TI - Are advanced practice psychiatric mental health nurses prepared to deliver integrated care? PMID- 23352020 TI - Psychiatric elopement: using evidence to examine causative factors and preventative measures. AB - BACKGROUND: Elopement is a problem in the inpatient mental health community. Elopement can have serious and long term effects for the patients and staff. OBJECTIVE: The purposes of this paper are to present a review of the literature regarding elopement and to provide recommendation for practice. DESIGN: Using several databases, a search of the existing literature was conducted. RESULTS: Elopement occurs due to a number of factors, including: psychosocial issues, staff-patient interaction, the patient's attitude toward hospitalization, and their mental illness. CONCLUSION: It is important to understand why patients seek to elope from treatment facilities to prevent further occurrences. PMID- 23352021 TI - Mental health issues of women deployed to Iraq and Afghanistan. AB - The number of women serving in the military and deployed to active-duty is unprecedented in the history of the United States. When women became a permanent sector of the U.S. Armed Services in 1948, their involvement was restricted to comprise only 2% of the military population; today women constitute approximately 14.5% of the 1.4 million active component and 18% of the 850,000 reserve component. Yet, little attention has been paid to the mental health needs of women military members. This review article highlights the history of women in the military and then focuses on the impact of combat exposure and injuries, military sexual trauma, alcohol use, and family separations which are associated with PTSD, depression, suicide, difficulty with reintegration, and homelessness. PMID- 23352022 TI - Counseling and exercise intervention for smoking reduction in patients with schizophrenia: a feasibility study. AB - Smoking cessation is possible for individuals with schizophrenia but the relapse rate is high. It is necessary to develop more flexible approaches to help these patients. The aim of this study was to examine the feasibility of an intervention approach that integrates counseling and exercise for participants with schizophrenia or schizoaffective disorder. A single group prospective design was used in this study. A sample of inpatients with schizophrenia or schizoaffective disorder participated in a program called "oxygen group", a program combining five sessions of smoking reduction counseling and three sessions of moderate intensity exercise over an 8-week period. Tobacco consumption, motivation, carbon monoxide level, anxiety and depression, smoking self-efficacy, nicotine dependence and waist circumference were measured pre- and post-intervention. Participants reported their satisfaction with the study characteristics after completion of the intervention. Smoking consumption and CO level were assessed at 6-week post-intervention follow-up. Twelve individuals (mean age 45.7+/ 10.8years) were recruited. Participant attendance was 81.3%. There were no dropouts. Significant decreases were found for tobacco consumption (P=.04) and CO rate (P=.003) at the end of the intervention and were maintained at 6-week follow up. Compared to baseline levels, there were no changes in depression and anxiety. Smoking cessation motivation increased significantly. This intervention appears feasible and acceptable to patients with schizophrenia and there were promising findings regarding smoking reduction. Larger trials to test the intervention are warranted. PMID- 23352023 TI - Comparison of psychosocial determinants in inpatients with first-episode and chronic schizophrenia in china. AB - This study aimed at comparing psychosocial factors in inpatients with first episode and chronic schizophrenia in China. A sample of 197 first-episode schizophrenia inpatients was compared with 392 chronic schizophrenics using Positive and Negative Syndrome Scale, Social Support Rating Scale and Childhood Traumatic Questionnaire. Our findings showed that chronic schizophrenic patients had significant higher negative symptoms but lower on positive symptoms. They were also less likely to receive social support. Our results provide understanding on the existing differences between first-episode and chronic schizophrenia. Therefore, comprehensive nursing interventions are needed to facilitate social support and medication adherence in order to prevent relapses. PMID- 23352024 TI - Self-management among Chinese people with schizophrenia and their caregivers: a qualitative study. AB - This study explores the practice of self-management in Chinese people with schizophrenia and their caregivers. Twenty-one patients and 14 caregivers were interviewed. Four themes were identified, reflecting the practice of self management from both the patients' and caregivers' perspective: managing medication, monitoring and dealing with symptoms, maintaining social relations, and seeking health information and maintaining medical appointments. In general, self-management practices among Chinese people with schizophrenia were not optimal. This study highlights the importance of developing and implementing family-based self-management programs for Chinese people with schizophrenia and their family in order to enhance their self-management abilities and improve care outcomes. PMID- 23352025 TI - A pilot study on effects of a group program using recreational therapy to improve interpersonal relationships for undergraduate nursing students. PMID- 23352026 TI - ISPN DNP Task Force Statement on the DNP. PMID- 23352027 TI - Social media in healthcare: educational policy implications. PMID- 23352028 TI - Treatment outcomes in REM sleep behavior disorder. AB - OBJECTIVE: REM sleep behavior disorder (RBD) is usually characterized by potentially injurious dream enactment behaviors (DEB). RBD treatment aims to reduce DEBs and prevent injury, but outcomes require further elucidation. We surveyed RBD patients to describe longitudinal treatment outcomes with melatonin and clonazepam. METHODS: We surveyed and reviewed records of consecutive RBD patients seen at Mayo Clinic between 2008-2010 to describe RBD-related injury frequency-severity as well as RBD visual analog scale (VAS) ratings, medication dosage, and side effects. Statistical analyses were performed with appropriate non-parametric matched pairs tests before and after treatment, and with comparative group analyses for continuous and categorical variables between treatment groups. The primary outcome variables were RBD VAS ratings and injury frequency. RESULTS: Forty-five (84.9%) of 53 respondent surveys were analyzed. Mean age was 65.8 years and 35 (77.8%) patients were men. Neurodegenerative disorders were seen in 24 (53%) patients and 25 (56%) received antidepressants. Twenty-five patients received melatonin, 18 received clonazepam, and two received both as initial treatment. Before treatment, 27 patients (60%) reported an RBD associated injury. Median dosages were melatonin 6 mg and clonazepam 0.5 mg. RBD VAS ratings were significantly improved following both treatments (p(m) = 0.0001, p(c) = 0.0005). Melatonin-treated patients reported significantly reduced injuries (p(m) = 0.001, p(c) = 0.06) and fewer adverse effects (p = 0.07). Mean durations of treatment were no different between groups (for clonazepam 53.9 +/- 29.5 months, and for melatonin 27.4 +/- 24 months, p = 0.13) and there were no differences in treatment retention, with 28% of melatonin and 22% of clonazepam treated patients discontinuing treatment (p = 0.43). CONCLUSIONS: Melatonin and clonazepam were each reported to reduce RBD behaviors and injuries and appeared comparably effective in our naturalistic practice experience. Melatonin-treated patients reported less frequent adverse effects than those treated with clonazepam. More effective treatments that would eliminate injury potential and evidence-based treatment outcomes from prospective clinical trials for RBD are needed. PMID- 23352029 TI - Sleep loss as risk factor for neurologic disorders: a review. AB - Sleep loss refers to sleep of shorter duration than the average baseline need of seven to eight hours per night. Sleep loss and sleep deprivation have severe effects on human health. In this article, we review the main aspects of sleep loss, taking into account its effects on the central nervous system. The neurocognitive and behavioral effects of sleep loss are well known. However, there is an increasing amount of research pointing to sleep deprivation as a risk factor for neurologic diseases, namely stroke, multiple sclerosis, Alzheimer's disease, headache, epilepsy, pain, and somnambulism. Conversely, sleep loss has been reported to be a potential protective factor against Parkinson's disease. The pathophysiology involved in this relationship is multiple, comprising immune, neuroendocrine, autonomic, and vascular mechanisms. It is extremely important to identify the individuals at risk, since recognition and adequate treatment of their sleep problems may reduce the risk of certain neurologic disorders. PMID- 23352031 TI - First case report of intrathecal panitumumab for treatment of meningeal carcinomatousis in an EGFR mutant lung adenocarcinoma patient. PMID- 23352030 TI - Work-related burn injuries in Ontario, Canada: A follow-up 10-year retrospective study. AB - Work-related burn injuries contribute to a quarter of all burns in the USA. In 2009, the provincial Workplace Safety and Insurance Board reported 64,824 work related injuries that resulted in time lost, 1188 injuries (2%) were a result of burns. There were two previous studies performed at a regional burn centre (1984 1990 and 1998-2000) that examined incidence and characteristics of work-related burns. There was no significant change between these two groups. The purpose of this study was to identify the recent pattern of work-related burns from 2001 to 2010 and to compare it to the previous studies. During the study period, 1427 patients were admitted for an acute injury to the regional burn centre. Of these, 330 were due to a work-related incident (23%). The mean age of patients was 40.5+/-11.9 years, 95% were male. The mean total body surface area burn was 11.9+/-16.2%. The most common mechanism of injury was flame (32.7%) followed by electrical (27%) and scald (19.7%), inhalation injury was present in 4.8% of patients and the mortality was 1.8%. Our study shows a significant decrease in the incidence in work-related burns treated at the regional burn centre (23.1% vs. 28.2% vs. 30.2%, p<0.01), flame burns have now become the leading cause of injury, there was a significant reduction in inhalation injury (4.8% vs. 23% vs. 14.8%, p<0.00001), and mortality over time (1.8% vs. 4% vs. 6.7% p=0.02). These findings strongly suggest a change in the cause of work-related burns, improvement in burn care, and that prevention strategies may have been more effective. PMID- 23352032 TI - Diagnostic value of CEA and CYFRA 21-1 tumor markers in primary lung cancer. AB - Lung cancer is sometimes difficult to differentiate from benign lung diseases expressing nodular shadow in imaging study. We assessed the diagnostic value of two commonly used tumor markers in distinguishing primary lung cancer from benign lung disease. The serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) were retrospectively analyzed in 655 lung cancer patients and 237 patients with benign lung disease. The standard cut-off levels of 3.2 ng/mL CEA and 3.5 ng/mL CYFRA 21-1 and twice these respective levels (6.4 ng/mL and 7.0 ng/mL) were used. CEA and CYFRA 21-1 levels were elevated in 32% and 11% of benign lung disease patients, respectively. CEA sensitivity and specificity for lung cancer diagnosis was 69% and 68% respectively, while that for CYFRA 21-1 was 43% and 89%, respectively. Thus, the combined value for the specificity of the two tumor markers was greater than either alone. Patients were grouped depending on their hospital status, and prevalence rates were determined. The prevalence rate of lung cancer in admitted patients was 51%, the prevalence rate of lung cancer in outpatients was 12%, and the prevalence rate of lung cancer identified during health check-ups was 0.1%. Positive predictive values (PPVs) were calculated using Bayes' theorem, and varied with the serum tumor marker and prevalence rate: PPVs of CEA [prevalence rate] were 69.2% [51%], 22.7% [12%], and 0.22% [0.1%], while PPVs of CYFRA 21-1 were 80.3% [51%], 34.8% [12%], and 0.39% [0.1%]. However, PPVs for lung cancer diagnosis at a prevalence rate of 51% were 87.3% or higher when the patient exhibited positive CEA and CYFRA 21-1, or CEA or CYFRA 21-1 levels twice the standard cut-off. Our results indicate that CEA and CYFRA 21-1 are reliable serum tumor markers for the diagnosis of lung cancer in addition to CT scans when combined or used individually at twice the standard cut-off level in high prevalence rate groups. The prevalence rate should therefore be taken into account when these serum tumor markers are used as diagnostic tools for lung cancer. PMID- 23352033 TI - Reliability of EGFR and KRAS mutation analysis on fine-needle aspiration washing in non-small cell lung cancer. AB - INTRODUCTION: Molecular profiling of advanced non-small cell lung cancer (NSCLC) has become essential for predicting customized medical treatment decision. In light of recent advances in non-invasive diagnostic procedures in NSCLC, we aimed to demonstrate the reliability of assessing molecular tests for epidermal growth factor receptor (EGFR) and KRAS genes on cytological samples by comparing the molecular profile obtained on cells from scraped smears with that on paired needle washing in a series of NSCLC cases. METHODS: Thirty-two cytological specimens obtained by fine-needle aspiration biopsy procedures from primary or metastatic lesions of NSCLCs were Giemsa stained for a rapid on-site evaluation and, in case of an adequate sampling, the cellular material obtained from needle washing was collected into a saline solution. Scraped smears and needle washings were tested for EGFR and KRAS by polymerase chain reaction followed by direct sequencing. RESULTS: The concordance between EGFR and KRAS mutational status in 29 paired scraped smears and needle washing was 100%, with 7 paired samples showing the same EGFR mutation (4 L858R mutation, 2 E746_A750 deletion and 1 A767_V769 duplication) and 8 paired samples showing the same KRAS mutations (4 G12D, 1 G12A, 1 G12V and 2 G12C). Three scraped smears, uninformative for poor DNA quality, resulted EGFR mutated on paired needle washings. CONCLUSIONS: Needle washing obtained in the course of NSCLC non-invasive fine needle diagnostic procedures allows reliable mutation testing and can be regarded as an additional important source of biological material for molecular profiling of advanced NSCLC. PMID- 23352034 TI - Accuracy of sentinel node biopsy in the staging of non-small cell lung carcinomas: systematic review and meta-analysis of the literature. AB - BACKGROUND: Not all patients with non-small cell lung carcinoma (NSCLC) have mediastinal lymph node involvement and development of less invasive methods for evaluating mediastinal lymph nodes is important. Sentinel node biopsy has been used for NSCLC since 1999 to decrease the need for mediastinal lymph node dissection. In this review, we searched the literature in this regard and reported the results in a meta-analysis format. METHODS: Medline, SCOPUS, and ISI web of knowledge were searched using: "(lung AND sentinel)" with no date or language limit. Any study with more than 5 patients and enough information to calculate detection rate and sensitivity was included. RESULTS: Overall 47 and 43 studies (including subgroups) had the criteria for detection rate and sensitivity pooling respectively. Pooled detection rate was 80.6% [76.8-84%] and pooled sensitivity was 87% [83-90%]. Using radiotracers or both radiotracers and dyes had higher detection rate and sensitivity compared to dye alone. Among studies using radiotracers, highest detection rate was in intra-operative peri-tumoral injection group and highest sensitivity was in peri-tumoral pre-operative injection group. Emerging methods of sentinel node surgery including magnetic materials, fluorescent dyes, CT contrast agents, and carbon nano-particles had promising results. CONCLUSIONS: Sentinel node mapping using radiotracers is a feasible technique for mediastinal lymph node staging of N0 NSCLC patients. Alternative methods of sentinel node mapping are promising and warrant further studies. PMID- 23352035 TI - Pharmacokinetics of combined gene therapy expressing constitutive human GM-CSF and hyperthermia-regulated human IL-12. AB - BACKGROUND: An adenovirus that expresses both interleukin (IL)-12 and granulocyte macrophage colony-stimulating-factor (GM-CSF) has been proven to be very effective in treating several tumors, but causes serious normal tissue toxicities. METHODS: In this study, a novel adenoviral vector was constructed by placing the human GM-CSF gene under the control of the CMV-IE promoter and human IL-12 gene under the control of heat shock protein 70B gene promoter. Both hGM CSF and hIL-12 expressions in virus-infected tumor cells were analyzed in vitro and in vivo when underlying single or multiple rounds of hyperthermia. RESULTS: We observed constitutive high expression of human GM-CSF and heat-induced expression of human IL-12 after a single round of hyperthermia post viral infection. The heat-induced hIL-12 expression exhibited a pulse-like pattern with a peak at 24 hrs followed by a decline 48 hrs post heat stress. Repeated heat treatment was more effective in inducing hIL-12 expression than a one-time heat treatment. Interestedly, we also observed that constitutive expression of hGM-CSF could be stimulated by heat stress in tested tumor cells. CONCLUSION: Our study provided a novel strategy for combined gene therapy that allows constitutive expression of a non-toxic gene such as GM-CSF and heat-induced expression of a toxic gene such as IL-12. In addition, our study also showed that hyperthermia can be used to trigger gene expression in temporal and special manner. PMID- 23352036 TI - Menopause and lead body burden among US women aged 45-55, NHANES 1999-2010. AB - BACKGROUND: Environmental factors in menopause have received limited attention. Lead is a known reproductive toxicant associated with delayed puberty in girls that may also affect menopause. METHODS: The odds of menopause among US women aged 45-55 were estimated in the National Health and Nutrition Examination Survey, 1999-2010, in relation to quartiles of blood lead. Women still menstruating (n=2158) were compared to women with natural menopause (n=1063). Logistic regression models included age, race/ethnicity, current hormone use, poverty, smoking and where available, bone density or bone alkaline phosphatase. RESULTS: Lead levels (ug/dL) were higher in menopausal women, geometric mean (standard error)=1.71 (0.04) vs. 1.23 (0.02). Adjusted odds of menopause and 95% confidence intervals for lead quartiles (lowest quartile referent) were 1.7 (1.0 2.8), 2.1 (1.2-3.6), and 4.2 (2.5-7.0) respectively. Results adjusting for bone markers were generally similar but had less precision. CONCLUSIONS: Blood lead was associated with natural menopause in US women even after adjustment for bone turnover. This raises concern that lead exposure, even at low levels, may shorten women's reproductive lifespan. PMID- 23352037 TI - Drying of a plasmid containing formulation: chitosan as a protecting agent. AB - BACKGROUND: Along with research on development of more efficient gene delivery systems, it is necessary to search on stabilization processes to extend their active life span. Chitosan is a nontoxic, biocompatible and available gene delivery carrier. The aim of this study was to assess the ability of this polymer to preserve transfection efficiency during spray-drying and a modified freeze drying process in the presence of commonly used excipients. METHODS: Molecular weight of chitosan was reduced by a chemical reaction and achieved low molecular weight chitosan (LMWC) was complexed with pDNA. Obtained nanocomplex suspensions were diluted by solutions of lactose and leucine, and these formulations were spray dried or freeze dried using a modified technique. Size, polydispersity index, zeta potential, intensity of supercoiled DNA band on gel electrophoresis, and transfection efficiency of reconstituted nanocomplexes were compared with freshly prepared ones. RESULTS AND CONCLUSION: Size distribution profiles of both freeze dried, and 13 out of 16 spray-dried nanocomplexes remained identical to freshly prepared ones. LMWC protected up to 100% of supercoiled structure of pDNA in both processes, although DNA degradation was higher in spray-drying of the nanocomplexes prepared with low N/P ratios. Both techniques preserved transfection efficiency similarly even in lower N/P ratios, where supercoiled DNA content of spray dried formulations was lower than freeze-dried ones. Leucine did not show a significant effect on properties of the processed nanocomplexes. It can be concluded that LMWC can protect DNA structure and transfection efficiency in both processes even in the presence of leucine. PMID- 23352038 TI - The effect of platelet rich plasma on angiogenesis in ischemic flaps in VEGFR2 luc mice. AB - To improve skin flap healing, one promising strategy in reconstructive surgery might be to optimize platelet rich plasma (PRP) bioactivity and the ischemia altered expression of genes. We studied both the effect of PRP on ischemic flaps, and whether in vivo bioluminescence imaging (BLI) is a suitable method for the longitudinal monitoring of angiogenesis in surgical wounds. Axial murine skin flaps were created in four experimental groups. In vivo measurements of VEGFR2 expression levels were made every other day until the 14th day. The local VEGF level and microvessel density were quantified on the 14th day via ELISA and immunohistochemistry, and flap survival rates were measured. We demonstrated that PRP and induced ischemia have a beneficial influence on angiogenesis and flap healing. Combining the two resulted in a significantly robust increase in angiogenesis and flap survival rate that was corroborated by bioluminescence imaging of VEGFR2 activity. This study shows that angiogenic effects of PRP may be potentialized by the stimulus of induced ischemia during free flap harvesting, and thus the two procedures appear to have a synergistic effect on flap healing. This study further demonstrates that BLI of modulated genes in reconstructive surgery is a valuable model for longitudinal in vivo evaluation of angiogenesis. PMID- 23352039 TI - Surface engineering of cardiovascular stent with endothelial cell selectivity for in vivo re-endothelialisation. AB - The in vivo endothelialisation of materials provides a promising strategy for the rapid re-endothelialisation of a cardiovascular implantation. Although many studies have focused on improving the rapid endothelialisation through the immobilisation of bioactive molecules, it should be noted that the endothelial cells (ECs) will compete with other cell types in vivo. Thus, the efforts to partially enhance the EC growth without considering the cell competition might be misleading and meaningless in vivo. In this study, we demonstrated that the competitive growth of human umbilical vein endothelial cells (HUVECs) over human aortic smooth muscle cells (HASMCs) could be increased through the synergic action of the nonspecific resistance to phosphorylcholine and the specific recognition of the REDV peptide. Further in vivo data indicate that the competitive ability of ECs over SMCs, instead of the number of ECs, is a significantly more important criterion for the development of a pure endothelial layer in vivo and thus the attainment of a better anti-restenosis effect. Consequently, the surface tailoring of a stent to obtain high endothelial cell selectivity is likely an effective design criterion for in situ endothelialisation and a possible future solution for the problem of in-stent restenosis. PMID- 23352040 TI - Dual modes of antitumor action of an amphiphilic peptide A(9)K. AB - Following our recent report of attractive antibacterial properties of a designed amphiphilic peptide, A(9)K, we have investigated its antitumor activities by examining the modes of its action against different mammalian cell types. The peptide strongly inhibited the growth of cancerous HeLa cells and human promyelocytic leukemia HL60 cells whilst remaining benign to the host cells, including Cos 7 cells, mouse fibroblast NIH3T3 cells and human red blood cells. Images from SEM and fluorescence microscopy showed that A(9)K penetrated HeLa cell membranes and disrupted membrane structures, a feature broadly similar to that observed from its bactericidal actions. Further interactions of A(9)K with inner cellular membranes caused mitochondrial dysfunction associated with the F actin reorganization and the decreased transcription of bcl-2 and c-myc genes, resulting in HeLa cell apoptosis in a mitochondria-induced apoptosis pathway. Thus A(9)K has high selectivity against cancerous cells and kills them by dual modes of action: membrane disruption and cell apoptosis. In addition, the peptide does not induce non-specific immunological effects and is not degraded by proteases. These features are crucial for developing their applications in future research. PMID- 23352041 TI - In vitro antitumor activity of methotrexate via pH-sensitive chitosan nanoparticles. AB - Nanoparticles with pH-sensitive behavior may enhance the success of chemotherapy in many cancers by efficient intracellular drug delivery. Here, we investigated the effect of a bioactive surfactant with pH-sensitive properties on the antitumor activity and intracellular behavior of methotrexate-loaded chitosan nanoparticles (MTX-CS-NPs). NPs were prepared using a modified ionotropic complexation process, in which was included the surfactant derived from N(alpha),N(epsilon)-dioctanoyl lysine with an inorganic lithium counterion. The pH-sensitive behavior of NPs allowed accelerated release of MTX in an acidic medium, as well as membrane-lytic pH-dependent activity, which facilitated the cytosolic delivery of endocytosed materials. Moreover, our results clearly proved that MTX-CS-NPs were more active against the tumor HeLa and MCF-7 cell lines than the free drug. The feasibilty of using NPs to target acidic tumor extracellular pH was also shown, as cytotoxicity against cancer cells was greater in a mildly acidic environment. Finally, the combined physicochemical and pH-sensitive properties of NPs generally allowed the entrapped drug to induce greater cell cycle arrest and apoptotic effects. Therefore, our overall results suggest that pH-sensitive MTX-CS-NPs could be potentially useful as a carrier system for tumor and intracellular drug delivery in cancer therapy. PMID- 23352042 TI - The potential of apolipoprotein E4 to act as a substrate for primary cultures of hippocampal neurons. AB - The E4 isoform of apolipoprotein (apoE4) is known to be a major risk factor for Alzheimer's Disease (AD). Previous in vitro studies have shown apoE4 to have a negative effect on neuronal outgrowth when incubated with lipids. The effect of apoE4 itself on the development of neurons from the central nervous system (CNS), however, has not been well characterized. Consequently, apoE4 alone has not been pursued as a substrate for neuronal cultures. In this study, the effect of surface-bound apoE4 on developmental features of rat hippocampal neurons was examined. We show that apoE4 substrates elicit significantly enhanced values in all developmental features at day 2 of culture when compared to laminin (LN) substrates, which is the current substrate-of-choice for neuronal cultures. Interestingly, the adhesion of hippocampal neurons was found to be significantly lower on LN substrates than on glass substrates, but the axon lengths on both substrates were similar. In addition, this study demonstrates that the adhesion- and growth-enhancing effects of apoE4 substrates are not mediated by heparan sulfate proteoglycans (HSPGs), proteins that have been indicated to function as receptors or co-receptors for apoE4. In the absence of lipids, apoE4 appears to use an unknown pathway for up-regulating neuronal adhesion and neurite outgrowth. Our results indicate that apoE4 is better than LN as a substrate for primary cultures of CNS neurons and should be considered in the design of tissue engineered CNS. PMID- 23352043 TI - A molecular dynamics simulation study on the effect of lipid substitution on polyethylenimine mediated siRNA complexation. AB - Polycations have been explored as non-viral carriers for effective delivery of small interfering RNA (siRNA). Modifying polycations such as polyethylenimine (PEI) with lipid substitution was found to improve the siRNA delivery efficiency of polycationic carriers. However, the role of such lipid modification is not clear and remains to be probed at the atomistic level. In this work, we elucidate the role of lipid modification through a series of all-atom molecular dynamics simulations on siRNA complexation mediated by a native PEI and four analogous obtained by different lipid modifications. The lipid modification does not affect PEI's capability of neutralizing the siRNA charge, neither does it affect the polyion bridging which plays an important role in siRNA complexation. Significant linkages among the lipid modified PEIs via association of lipid side-groups are observed and this results in more stable and compact PEI/siRNA polyplexes. The lipid associations between short lipids form and break frequently while the lipid associations between long lipids are more stable. For PEIs modified with short lipids, increasing the lipid substitution level results in more compact and stable siRNA structure. For PEIs modified with long lipids, increasing the lipid substitution does not change the amount of PEI linkage via lipid association, and has a reverse effect on compacting siRNA structure due to increased steric hindrance brought by the lipid association on individual PEIs. The simulation results generally correlate well with experimental data and suggest a framework of designing and systematic evaluation of polycation-based siRNA carriers using molecular dynamics simulations. PMID- 23352044 TI - Engineering ear-shaped cartilage using electrospun fibrous membranes of gelatin/polycaprolactone. AB - Tissue engineering approach continuously requires for emerging strategies to improve the efficacy in repairing and regeneration of tissue defects. Previously, we developed a sandwich model strategy for cartilage engineering, using the combination of acellular cartilage sheets (ACSs) and chondrocytes. However, the process for the preparation of ACSs is complicated, and it is also difficult to obtain large ACSs. The aim of this study was to engineer cartilage with precise three-dimensional (3-D) structures by applying electrospun fibrous membranes of gelatin/polycaprolactone (GT/PCL). We first prepared the electrospun GT/PCL membranes into rounded shape, and then seeded chondrocytes in the sandwich model. After in vitro and in vivo cultivation, the newly formed cartilage-like tissues were harvested. Macroscopic observations and histological analysis confirmed that the engineering of cartilage using the electrospun GT/PCL membranes was feasible. An ear-shaped cartilage was then constructed in the sandwich model, with the help of an ear-shaped titanium alloy mold. After 2 weeks of culture in vitro and 6 weeks of subcutaneous incubation in vivo, the ear-shaped cartilage largely maintained their original shape, with a shape similarity up to 91.41% of the titanium mold. In addition, the engineered cartilage showed good elasticity and impressive mechanical strength. These results demonstrated that the engineering of 3-D cartilage in a sandwich model using electrospun fibrous membranes was a facile and effective approach, which has the potential to be applied for the engineering of other tissues with complicated 3-D structures. PMID- 23352045 TI - Utility of an optically-based, micromechanical system for printing collagen fibers. AB - Collagen's success as the principal structural element in load-bearing, connective tissue has motivated the development of numerous engineering approaches designed to recapitulate native fibril morphology and strength. It has been shown recently that collagen fibers can be drawn from monomeric solution through a fiber forming buffer (FFB), followed by numerous additional treatments in a complex serial process. However, internal fibril alignment, packing and resultant mechanical behavior of the fibers have not been optimized and remain inferior to native tissue. Further, no system has been developed which permits simultaneous application of molecular crowding, measurement of applied load, and direct observation of polymerization dynamics during fiber printing. The ability to perform well-controlled investigations early in the process of fiber formation, which vary single input parameters (i.e. collagen concentration, crowding agent concentration, draw rate, flow rate, temperature, pH, etc.) should substantially improve fiber morphology and strength. We have thus designed, built, and tested a versatile, in situ, optically-based, micromechanical assay and fiber printing system which permits the correlation of parameter changes with mechanical properties of fibers immediately after deposition into an FFB. We demonstrate the sensitivity of the assay by detecting changes in the fiber mechanics in response to draw rate, collagen type, small changes in the molecular crowding agent concentration and to variations in pH. In addition we found the ability to observe fiber polymerization dynamics leads to intriguing new insights into collagen assembly behavior. PMID- 23352047 TI - Para-suicidal amnestic behavior associated with chronic zolpidem use: implications for patient safety. PMID- 23352046 TI - General medical conditions are associated with delay to treatment in patients with bipolar disorder. AB - BACKGROUND: Bipolar disorder (BPD) is associated with worse physical health. Indeed patients with BPD more frequently suffer from medical conditions such as cardiovascular illness, hypertension, diabetes, hypothyroidism, respiratory disease, liver disease, peptic ulcer, and arthritis. Since some clinical characteristics have been associated with worse course and outcome of BPD, it is possible that they might also bring to an increased medical burden in patients with BPD. The aim of the present report is to assess the prevalence of medical conditions in patients with BPD, and to determine the clinical variables associated with the presence of a medical condition. METHODS: Charts of patients with BPD I and II were reviewed: socio-demographic and clinical information were collected. Medical conditions were classified by the ICD-10 and grouped according to the Cumulative Illness Rating Scales in: cardiac, vascular, hematopoietic, respiratory, ear/nose/throat, upper and lower gastrointestinal, hepatic, renal, genitourinary, musculoskeletal, neurologic, endocrine/metabolic. The associations between the presence of medical conditions and demographic/clinical variables of BPD were then analyzed. RESULTS: Charts of 309 patients were included in the study. 170 (55%) patients had at least one medical condition. The most common were endocrine/metabolic disease (23%), and vascular disease (21%). Having a medical condition was associated with longer duration of untreated illness and female gender. CONCLUSIONS: Patients with BPD have high rates of medical conditions, especially hypertension and metabolic disorders. A longer duration of untreated illness is associated with having a medical condition, probably due to the long-lasting adoption on unhealthy lifestyles not counterbalanced by treatment and psychoeducation. PMID- 23352048 TI - The development of a patient-centered program based on the relaxation response: the Relaxation Response Resiliency Program (3RP). AB - BACKGROUND: Chronic daily stress has significant physical, emotional, and financial implications; levels of stress are increasing in the US. Dr. Benson highlighted how the mind and body function together in one's experience of the stress response and proposed the existence of the relaxation response (RR). OBJECTIVE: The current paper describes the foundation and development of an 8 session multimodal treatment program for coping with chronic stress: the Relaxation Response Resiliency Program (3RP). METHODS: We review the past decades of RR research, outline the development of the 3RP treatment, and provide an overview of the program's theory and content. RESULTS: Extensive research and clinical work have examined how eliciting the RR may combat stress through down regulation of the sympathetic nervous system. Related to this work are the multidimensional constructs of resiliency and allostatic load. The 3RP is based on principles from the fields of stress management, cognitive-behavioral therapy, and positive psychology, and has three core target areas: (1) elicitation of the RR; (2) stress appraisal and coping; and (3) growth enhancement. An 8-week patient-centered treatment program has been developed, with the purpose of assisting patients with a variety of psychological and medical issues to better cope with chronic stress. CONCLUSIONS: Mastery of the RR is theorized to maximize one's ability to benefit from multimodal mind body strategies. The goal of the 3RP is to enhance individuals' adaptive responses to chronic stress through increasing awareness and decreasing the physiological, emotional, cognitive, and behavioral effects of the stress response, while simultaneously promoting the effects of being in the RR. PMID- 23352049 TI - Face transplantation: psychological outcomes at three-year follow-up. AB - BACKGROUND: The advent of face transplantation has raised both ethical and psychological issues. Mortality of 18 existing face transplant recipients is 11.1% (2/18) through 2011. OBJECTIVE: Psychological outcomes are as important in face transplantation as is restoring the face physically. Little quantitative information has been published this area. METHODS: Data was systematically collected over 3 years with a face transplant recipient, including appearance self-rating, body image, mood changes, pain rating, perception of teasing, quality of life, self-esteem, and social reintegration. We identified a significant gap in rating instruments for use in the field, so we developed the Perception of Teasing-FACES, Facial Anxiety Scale-State, and the Cleveland Clinic FACES score, analogous to the model for end-stage liver disease (MELD) score for prioritizing patients for a face transplant registry. RESULTS: Appearance self rating rose from 3/10 prior to transplantation to 7/10 now. Anxiety about body image and the Facial Anxiety score were halved by the end of the third year. Beck Depression Inventory fell from 16 (prior to transplant) to 8. Chronic daily pain was 6-7/10 prior to transplant and 0/10 by day 50. Perception of Teasing-FACES scores fell from 25 to 9 by the end of year 3. Quality of life improved on the Social Environment Domain of the psychological adjustment to illness scale-self rated (PAIS-SR), where the score dropped from 15 to 1 by the end of year 3, indicating marked improvement in social reintegration. CONCLUSIONS: Standardized data collection may help quantify psychological outcomes with facial transplantation to determine whether the risks of immunosuppression over time are offset by improved quality of life for recipients. PMID- 23352050 TI - Looking at the roots of psychosomatic medicine: Adolf Meyer. AB - BACKGROUND: Adolf Meyer, the first Professor of Psychiatry at Johns Hopkins, and Chief of the Phipps Clinic, brought a bevy of new ideas to clinical practice and to medical education. He used the word "psychobiology," which helped to establish psychosomatic medicine and formed the basis for Engel's "biopsychosocial" concept. OBJECTIVE: This paper aims to review the contributions of Adolf Meyer, who proposed that in studying patients, it was impossible to consider the mind and body separately. RESULTS: Adolf Meyer, through his insight and tenacity, promoted the integration of psychiatry and medicine in medical education and practice. CONCLUSION: By taking a closer look at the role of Meyer's work in relation to today's psychosomatic medicine, current challenges do not appear to be dramatically different from the issues faced a century ago. PMID- 23352051 TI - Delirious mania associated with Bardet-Biedl syndrome, an inherited ciliopathy. PMID- 23352052 TI - Reflection on design and testing of pancreatic alpha-amylase inhibitors: an in silico comparison between rat and rabbit enzyme models. AB - BACKGROUND: Inhibitors of pancreatic alpha-amylase are potential drugs to treat diabetes and obesity. In order to find compounds that would be effective amylase inhibitors, in vitro and in vivo models are usually used. The accuracy of models is limited, but these tools are nonetheless valuable. In vitro models could be used in large screenings involving thousands of chemicals that are tested to find potential lead compounds. In vivo models are still used as preliminary mean of testing compounds behavior in the whole organism. In the case of alpha-amylase inhibitors, both rats and rabbits could be chosen as in vivo models. The question was which animal could present more accuracy with regard to its pancreatic alpha amylase. RESULTS: As there is no crystal structure of these enzymes, a molecular modeling study was done in order to compare the rabbit and rat enzymes with the human one. The overall result is that rabbit enzyme could probably be a better choice in this regard, but in the case of large ligands, which could make putative interactions with the -4 subsite of pancreatic alpha-amylase, interpretation of results should be made cautiously. CONCLUSION: Molecular modeling tools could be used to choose the most suitable model enzyme that would help to identify new enzyme inhibitors. In the case of alpha-amylase, three dimensional structures of animal enzymes show differences with the human one which should be taken into account when testing potential new drugs. PMID- 23352053 TI - Preoperative transfusion in patients with sickle-cell disease. PMID- 23352054 TI - The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial. AB - BACKGROUND: No consensus exists on whether preoperative blood transfusions are beneficial in patients with sickle-cell disease. We assessed whether perioperative complication rates would be altered by preoperative transfusion. METHODS: We did a multicentre, randomised trial. Eligible patients were aged at least 1 year, had haemoglobin SS or Sbeta(0)thalassaemia sickle-cell-disease subtypes, and were scheduled for low-risk or medium-risk operations. Patients were randomly assigned no transfusion or transfusion no more than 10 days before surgery. The primary outcome was the proportion of clinically important complications between randomisation and 30 days after surgery. Analysis was by intention to treat. FINDINGS: 67 (96%) of 70 enrolled patients-33 no preoperative transfusion and 34 preoperative transfusion-were assessed. 65 (97%) of 67 patients had the haemoglobin SS subtype and 54 (81%) were scheduled to undergo medium-risk surgery. 13 (39%) of 33 patients in the no-preoperative-transfusion group had clinically important complications, compared with five (15%) in the preoperative-transfusion group (p=0.023). Of these, 10 (30%) and one (3%), respectively, had serious adverse events. The unadjusted odds ratio of clinically important complications was 3.8 (95% CI 1.2-12.2, p=0.027). 10 (91%) of 11 serious adverse events were acute chest syndrome (nine in the no-preoperative transfusion group and one in the preoperative-transfusion group). Duration of hospital stay and readmission rates did not differ between study groups. INTERPRETATION: Preoperative transfusion was associated with decreased perioperative complications in patients with sickle-cell disease in this trial. This approach could, therefore, be beneficial for patients with the haemoglobin SS subtype who are scheduled to undergo low-risk and medium-risk surgeries. FUNDING: NHS Blood and Transplant. PMID- 23352055 TI - The transition zone: an essential functional compartment of cilia. AB - Recent studies of the primary cilium have begun to provide further insights into ciliary ultrastructure, with an emerging picture of complex compartmentalization and molecular components that combine in functional modules. Many proteins that are mutated in ciliopathies are localized to the transition zone, a compartment of the proximal region of the cilium. The loss of these components can disrupt ciliary functions such as the control of protein entry and exit from the cilium, the possible trafficking of essential ciliary components, and the regulation of signaling cascades and control of the cell cycle. The discovery of functional modules within the primary cilium may help in understanding the variable phenotypes and pleiotropy in ciliopathies. PMID- 23352056 TI - Magnetic resonance scanning vs axillary radiography in the assessment of glenoid version for osteoarthritis. AB - BACKGROUND: Osteoarthritic shoulders are mainly associated with glenoid retroversion. Total shoulder arthroplasty with the glenoid component implanted in retroversion predisposes to loosening of the glenoid prosthesis. Correction of glenoid retroversion through anterior eccentric reaming, before glenoid component implantation, is performed to restore normal joint biomechanics. Accurate preoperative assessment is required to ascertain the degree of retroversion and calculate the degree of reaming. MATERIALS AND METHODS: We assessed the utility of magnetic resonance imaging (MRI) for the assessment of glenoid version in glenohumeral osteoarthritis compared with standard plain axillary radiography (AXR). Two independent observers reviewed both types of imaging in 48 primary osteoarthritic shoulders on 2 separate occasions. RESULTS: The mean glenoid version measured was -14.3 degrees on MRI and -21.6 degrees on AXR (mean difference, -7.36 degrees ; P < .001). Intraobserver and interobserver reliability coefficients were 0.96 and 0.9, respectively, for MRI and 0.8 and 0.71, respectively, for AXR. Glenoid retroversion was greater in 73% of AXR. CONCLUSION: We demonstrated that MRI is more reproducible in the assessment of glenoid version in osteoarthritis and provides excellent intraobserver and interobserver reliability. MRI is useful for preoperative osseous imaging for total shoulder arthroplasty because it offers a more precise method of determining glenoid version compared with x-ray imaging in addition to the standard assessment of rotator cuff integrity. PMID- 23352057 TI - Utility and complications of long-stem humeral components in revision shoulder arthroplasty. AB - BACKGROUND: Currently, there is little information on the benefits and problems associated with long-stem humeral components in shoulder arthroplasty. This study examined the frequency of use, indications, complications, and security of fixation using a long-stem humeral component in revision shoulder arthroplasty. MATERIALS AND METHODS: Eighty revision shoulder arthroplasties were monitored clinically for at least 2 years or until repeat revision surgery. The primary indications for use of an intermediate or long stem were proximal bone loss in 40, nonunion in 14, a malpositioned previous stem with bone loss in 10, an acute intraoperative fracture in 7, an acute preoperative periprosthetic fracture in 5, diaphyseal bone loss in 2, and a box-shaped osteotomy to remove a well-fixed stem in 2. Clinical follow-up was an average of 5.9 years, and radiographic follow-up was an average of 4.7 years. RESULTS: Intraoperative complications included fracture removing the previous stem in 5, a cortical perforation in 6, and cement extrusion in 7. Late complications included fracture nonunion in 5, deep infection in 2, and component loosening in 1. One component met criteria to be considered radiographically "at risk" for clinical loosening. CONCLUSIONS: Long stem humeral components are useful to obtain secure fixation in healthy bone in revision shoulder arthroplasty in patients with proximal bone loss, diaphyseal fracture, or a previously malpositioned stem. Complications are frequent, and caution should be taken to avoid intraoperative fractures, distal cortical perforation, or cement extrusion. These components are at low risk for loosening. PMID- 23352058 TI - Glenoid fracture after Bristow-Latarjet shoulder stabilization: a case report and review of the literature. PMID- 23352059 TI - Analysis of complaints in a rural emergency medical service system. AB - INTRODUCTION: The health care industry is increasingly focused on customer service, one aspect of which is dealing with customer complaints. The purpose of this study was to assess the prevalence and nature of complaints against prehospital providers in a rural Emergency Medical Services (EMS) system. METHODS: This retrospective study of logged complaints utilized data from May 28, 1999 through September 26, 2008. All complaints were investigated by a single trained staff member of the regional EMS office. He interviewed witnesses, and reviewed statements and other documentation related to the complaints. Each complaint was classified into one of four categories: (1) operational; (2) clinical; (3) educational; or (4) customer service. In addition, each complaint was examined to determine if the grievance was founded. The study was conducted in a seven-county region of western Pennsylvania with a population of 639,641 and more than 3,000 EMS providers. RESULTS: There were 110 complaints over a nine year period (approximately 12 per year). Forty were considered unfounded complaints (43%) and 49 persons (45%) had made more than a single complaint. No EMS provider had an EMS certification suspended or revoked based on a clinically related complaint. The data revealed a substantial number of complaints for which insufficient information was available to allow a conclusion based on reasonable certainty or the degree of certainty expected of a reasonable person evaluating the facts. CONCLUSION: One hundred ten complaints were logged for the study EMS program. No complaints violated treatment protocols. Forty complaints were unfounded. There were 49 "repeat" complaints against providers who had previously had complaints made against them. PMID- 23352060 TI - Self-reported changes in the professional singing voice after surgical intervention treatment for breast cancer: a survey pilot study of female professional singers. AB - BACKGROUND: The effects of breast cancer surgical treatment on the professional singing voice are unknown. OBJECTIVE: The purpose of this study was to discover whether there are self-perceived changes in the quality and/or process of singing experienced by professional female singers who have undergone surgical intervention for the treatment of diagnosed breast cancer-including any changes perceived from the use of radiation, chemotherapy, and other drug treatments related to those surgeries. METHODS: A voluntary subject pool comprised female professional singers who have undergone surgery for breast cancer was recruited from professional singing networks. Participants underwent evaluation through an anonymous online survey, psychometrically vetted for content and instrument reliability/validity before administration. RESULTS: Valid participants (N=56) responded to 45 questions regarding surgical procedures, related therapies, and self-perceived vocal effects. Analysis of results produced a preliminary description of types of voice change, duration of changes, and qualitative self perceptions. CONCLUSIONS: This initial report reveals that there are self perceived singing voice changes experienced by professional singers treated for breast cancer. However, additional research is needed to determine the degree of vocal impact perceived to be attributable to individual surgical interventions and related therapies. PMID- 23352061 TI - Quantifying component parts of indirect and direct voice therapy related to different voice disorders. AB - Voice therapy changes how people use and care for their voices. Speech-language pathologists (SLPs) have a multitude of choices from which to modify patient's vocal behaviors. Six SLPs performed 1461 voice therapy sessions and quantified the percentage of time spent in eight component parts of indirect and four component parts of direct voice therapy across five common voice disorders. Voice therapy data collection forms were prospectively completed immediately following each therapy visit. The SLPs were free to choose the component parts of voice therapy best suited for their respective patients. Results showed that direct voice therapy represented more than 75% of the treatment time across all voice therapy sessions. In the components of direct voice therapy, there was no statistical difference between percentages of time spent in resonant voice and flow phonation across all voice disorders. However, a significant difference was found for the time spent addressing transfer to conversational speech for muscle tension dysphonia, lesions, and scar than for vocal immobility and atrophy. Interestingly, while SLPs used a more common approach to direct voice therapy across voice disorders, they tended to vary the use of indirect components of therapy across voice disorders with certain components being addressed in greater length for specific voice disorders. Collectively, these results indicate that although SLPs may individualize their approach to indirect voice therapy, when it comes to direct voice therapy, SLPs have a common approach to voice therapy regardless of voice disorder. PMID- 23352062 TI - Coping with unfamiliarity in medicine. PMID- 23352063 TI - Language barriers in the emergency room. PMID- 23352064 TI - Fibromyalgia confounds allopathic habits of mind. PMID- 23352065 TI - "Don't you have any American doctors?": international medical graduates and patient prejudice. PMID- 23352066 TI - American Medical Association Code of Medical Ethics' opinion on cultural sensitivity and ethnic disparities in care. PMID- 23352067 TI - I am not myself: understanding illness as unhomelike being-in-the-world. PMID- 23352068 TI - Integrating immigrants into the U.S. health system. PMID- 23352069 TI - Citizenship requirements for Medicaid coverage. PMID- 23352071 TI - The fallacy and dangers of dichotomizing cultural differences: the truth about medical truth telling in China. PMID- 23352070 TI - "A little more than kin, and less than kind": U.S. immigration policy on international medical graduates. PMID- 23352072 TI - "Sickness is a place": the foreign culture of illness. PMID- 23352074 TI - Analysis of the spectrum and antibiotic resistance of uropathogens in vitro: results based on a retrospective study from a tertiary hospital. AB - BACKGROUND: Antibiotic resistance of uropathogens in urinary tract infections (UTIs) is increasing worldwide. This study aimed to compare the spectrum and antimicrobial resistance of uropathogens in community-acquired UTIs (CAUTIs) and nosocomial-acquired UTIs (NAUTIs) at a tertiary hospital in China. METHODS: Retrospective analysis of uropathogens from UTI patients was performed at Zhong Da Hospital. RESULTS: A total of 1129 strains was isolated from 653 community acquired and 476 nosocomial-acquired infections. Escherichia coli was the most common uropathogen, accounting for 55.9% of the CAUTIs and 27.1% of the NAUTIs. Among the CAUTIs, Escherichia coli was followed in prevalence by Enterococcus spp (12.9%) and Proteus mirabilis (3.7%). Among the NAUTIs, Escherichia coli was followed by Enterococcus spp (15.3%) and Klebsiella pneumoniae (6.9%). The proportion of fungi in the NAUTIs (23.7%) was higher than that in the CAUTIs (3.1%) (P < .05). Extended-spectrum beta-lactamase-producing strains of E coli accounted for 70.6% of the NAUTIs and 47.3% of the CAUTIs. Carbapenems, amikacin, and nitrofurantoin were active agents against E coli. The resistance rates of E coli to cephalosporins, ampicillin, ampicillin/sulbactam, quinolones, and gentamicin were higher in the NAUTIs than in the CAUTIs (P < .05). CONCLUSION: The distribution of species was different between CAUTIs and NAUTIs. Higher antibiotic resistance rates were observed in the NAUTIs than in the CAUTIs. PMID- 23352075 TI - Measles in health-care settings. AB - Despite the availability of an effective and safe vaccine for almost half a century, measles is re-emerging in several developed countries because of the insufficient vaccination coverage among specific subpopulations, the emerging anti-vaccination movement, and the increasing movement of humans across borders. In this context, health-care settings play a critical role in the transmission of infection and generation of numerous cases. Health-care-associated outbreaks may be associated with severe morbidity and mortality among specific groups of patients, disruption of health-care services, and considerable costs. Misdiagnosis or delayed diagnosis of a measles case and inadequate implementation of infection control measures are common in almost all events of nosocomial spread. Measles vaccination of health-care workers is an effective means of prevention of nosocomial measles outbreaks. Eliminating measles by 2010 has not been accomplished. Stronger recommendations and higher vaccination coverage against measles in health-care workers could contribute to eliminate measles in the general population. PMID- 23352077 TI - Promise of rapalogues versus mTOR kinase inhibitors in subset specific breast cancer: old targets new hope. AB - The PI3K-AKT-mTOR network has been the major focus of attention for cancer researchers (both in the clinic and the laboratory) in the last decade. An incomplete knowledge of the molecular biology of this complex network has seen an expansion of first generation allosteric mTOR inhibitors, rapalogues, but also biomarker studies designed to identify the best responders of these agents. Currently, research in this pathway has focused on the dual nature of mTOR that is integrated by mTOR-RAPTOR complex (mTORC1) and mTOR-RICTOR complex (mTORC2). These two complexes are regulated by different upstream proteins and also regulated by multiple different compensatory feedback loops. The related advantage of feedback regulation of signaling systems is that it allows diversification in signal response. This deeper understanding has facilitated the development of a novel second generation of inhibitors that are able to affect both mTORC1 and mTORC2, and their downstream effectors, through inhibition of their catalytic activity (ATP competitive inhibitors, attacking the kinase domain of this protein) than binding to the FKBP12 regulatory proteins as for rapalogues. This article reviews the newest insight in the signaling network of the mTOR pathway, preclinical/clinical status of mTOR inhibitors (including second generation of kinase inhibitors) and then focuses on the development of a new wave of research related to combination therapies in subset specific breast tumors. PMID- 23352076 TI - The effect of improved compliance with hygiene guidelines on transmission of Staphylococcus aureus to newborn infants: the Swedish Hygiene Intervention and Transmission of S aureus study. AB - BACKGROUND: Newborn infants are often colonized with Staphylococcus aureus originating from health care workers (HCWs). We therefore use colonization with S aureus of newborn infants to determine the effect of an improved compliance with hygiene guidelines on bacterial transmission. METHODS: Compliance with hygiene guidelines was monitored prior to (baseline) and after (follow-up) a multimodal hygiene intervention in 4 departments of obstetrics and gynecology. spa typing was used to elucidate transmission routes of S aureus collected from newborn infants, mothers, fathers, staff members, and environment. RESULTS: The compliance with hygiene guidelines increased significantly from baseline to follow-up. The transmission of S aureus from HCWs to infants was however not affected. Fathers had the highest colonization rates. Persistent carriage was indicated in 18% of the HCWs. The most commonly isolated spa type was t084, which was not detected in a previous study from the same geographic area. CONCLUSION: It is possible to substantially improve the compliance with hygiene guidelines, by using multimodal hygiene intervention. The improved compliance did not decrease the transmission of S aureus from sources outside the own family to newborn infants. Furthermore, we show the establishment of a new spa type (t084), which now is very common in our region. PMID- 23352078 TI - Comparative morphology and genealogical delimitation of cryptic species of sympatric isolates of Sphaeroforma (Ichthyosporea, Opisthokonta). AB - Of the ancient clades of unicellular relatives of the multicellular animals, ichthyosporea are among the easiest to collect, cultivate, and analyze at the population level. Once identified, species can be correlated with their animal hosts and geographical ranges. However, the spherical stages common to many ichthyosporea provide little basis for morphological species identification. This study of the genus Sphaeroforma is the first to apply patterns of genetic discontinuity to delimit species among any of the unicellular 'holozoa.' Sequences of three loci from 148 sympatric isolates, along with type cultures, provided concordant support for new species "Sphaeroforma nootkatensis" and "Sphaeroforma gastrica," and for formally describing 'Pseudoperkinsus tapetis,' as "Sphaeroforma tapetis". We document light and electron microscopic characters that distinguish the genus but not its species. "S. tapetis" sometimes had brief amoeboid or plasmodial motile stages and endospore release through pores. Unlike closely related Creolimax, Sphaeroforma lacked a central vacuole but had multiple peripheral nucleoli. Like distantly related eccrinales, Sphaeroforma cell walls had pores and a calyx. Analyses of allele frequencies in "S. tapetis" indicated geographical differentiation but no host specificity. Accurate molecular identification of species will increase the feasibility and reliability of further studies of Sphaeroforma in its natural habit. PMID- 23352079 TI - Corals from the Persian/Arabian Gulf as models for thermotolerant reef-builders: prevalence of clade C3 Symbiodinium, host fluorescence and ex situ temperature tolerance. AB - Corals in the Arabian/Persian Gulf endure summer temperatures of up to 36 degrees C, making them ideal subjects to study the mechanisms underlying thermal tolerance. Unexpectedly, we found the "generalist" Symbiodinium clade C3 to be the prevalent symbiont among seven coral species from Abu Dhabi (UAE) waters. Moreover, C3 represented the only dominant symbiont type in Porites spp. from this region. The "thermotolerant" symbionts D1a and C15 were not encountered, indicating that the association with these symbionts cannot be the sole reason for the heat tolerance of Gulf corals. The association of Porites lobata with specific symbiont types (C3 vs. C15) in samples from habitats with very different temperature regimes (Abu Dhabi vs. Fiji) remained unaffected by laboratory culture. During temperature stress experiments specimens from both locations strongly downregulated green fluorescent protein (GFP)-like pigments. However, the Abu Dhabi samples were less prone to bleaching and showed lower mortality. PMID- 23352080 TI - Complication of a columellar strut in an edentulous patient. AB - The cartilaginous columellar strut is a well established, commonly used graft in rhinoplasty which provides support and stability to the nasal base. The risk of such a graft is related to grafts designs, whereby the posterior aspect can cause clicking with movement across the anterior nasal spine. We present an additional unusual complication of ill-fitting maxillary dentures in an edentulous patient, previously not reported in the literature. This unique complication should alert facial plastic surgeons to use additional caution when sculpting columellar grafts in edentulous patients in order to avoid potential post-operative complications in this specific patient population. PMID- 23352081 TI - Evaluation of the effects of the use of platelet-rich plasma (PRP) on alveolar bone repair following extraction of impacted third molars: prospective study. AB - Platelet-rich plasma (PRP) is rich in growth factors, target-specific polypeptides that play a role in cell proliferation and differentiation and can thus encourage wound repair. This study sought to assess the effects of PRP on new bone formation in a sample of 25 patients with clinical indications for extraction of all four impacted third molars with similar orientation, depth, and root morphology. Immediately after extraction, sockets on one side received PRP, whereas those on the other side (control) did not. Patients underwent 6 months of clinical and radiographic follow-up. Periapical radiographs were scanned and bone repair was assessed by image histogram analysis. The radiographic densities of the extraction sockets were compared to the densities of the distal surfaces of the adjacent teeth, with the difference between both serving to distinguish the PRP and control sides. Results showed that healing of PRP-treated sockets was significantly different from that of control sockets at 1-, 3-, and 6-month follow-up, in mandibular and maxillary sockets alike. The results of this sample suggest that PRP provides a safe and effective means of speeding alveolar bone repair. PMID- 23352082 TI - Risk assessment of parents' concerns at 18 months in preventive child health care predicted child abuse and neglect. AB - OBJECTIVE: As child maltreatment has a major impact, prevention and early detection of parenting problems are of great importance. We have developed a structured interview which uses parents' concerns for a joint needs assessment by parents and a child health care nurse, followed by a professional judgment on the risk level of future parenting and developmental problems: the Structured Problem Analysis of Raising Kids (SPARK). Previous results have shown that the risk assessment of the SPARK is associated with risk factors for child maltreatment. This study reports the predictive value of the SPARK for reports on high impact parenting problems and child abuse and neglect. METHOD: Cross-sectional study with a 1.5-year follow-up based on 1,850 18-month old children, living in Zeeland, a province of the Netherlands. Data on the SPARK were obtained in the period of June 2007 to March 2008. Outcomes of the SPARK were in October 2009 compared to reports of the Advice and Reporting Centers for Child Abuse and Neglect (ARCAN) and Youth Care Agency (YCA). Univariate and multivariate logistic regression analysis was done using the risk assessment, parents' concerns, the perceived need for support and known risk factors as predictors. RESULTS: The overall risk assessment of the SPARK is the strongest predictor for reports to ARCAN and YCA in the 1.5 years after completing the SPARK (odds ratio of high versus low risk: 16.3 [95% confidence interval: 5.2-50.8]. Controlling for the risk assessment, only the sum of known risk factors and an unemployed father remained as significant predictors. The reported groups differ significantly from the children without a report with regard to family characteristics, but not with regard to child characteristics. CONCLUSIONS: A structured assessment of the concerns and care needs of toddlers' parents by a child health care nurse is a valuable predictor of reports on child abuse and neglect and serious parenting problems in toddlers. PRACTICAL IMPLICATIONS: Systematically exploring and evaluating parental concerns with an instrument like the SPARK can contribute to the early recognition of families at risk for major child rearing problems. PMID- 23352083 TI - Does child abuse and neglect explain the overrepresentation of Aboriginal and Torres Strait Islander young people in youth detention? Findings from a birth cohort study. AB - OBJECTIVE: Determine whether a history of family social disadvantage and/or child abuse and neglect explain the overrepresentation of Indigenous Australian young people in youth detention. METHODS: Maternal survey data from the Mater University Study of Pregnancy was linked with child abuse and neglect and youth justice data from the Queensland Department of Families, Youth and Community Care. RESULTS: Indigenous Australian children were 1.81 times more likely to be notified to child protection authorities for maltreatment and 1.77 times more likely to have that maltreatment substantiated. Indigenous Australian young people were 3.07 times more likely to have a youth justice history. When adjusted for social disadvantage, the odds of the Indigenous Australian youth having had involvement with the youth justice authorities remained 2.51 times that of their non-Indigenous peers. When adjusted for substantiated maltreatment, the odds of the Indigenous Australian youth having had involvement with the youth justice authorities remained 2.83 times that of their non-Indigenous peers. When adjusted for both social disadvantage and substantiated maltreatment, the odds of the Indigenous Australian youth having had involvement with the youth justice authorities remained 2.48 times that of their non-Indigenous peers. CONCLUSIONS: The overrepresentation of Australian Aboriginal and Torres Strait Islander young people in the youth justice system, including Youth Detention, is only partly explained by their greater social disadvantage and by their greater experience of substantiated maltreatment, either separately or combined. PMID- 23352084 TI - On-field investigation and process modelling of end-of-life vehicles treatment in the context of Italian craft-type authorized treatment facilities. AB - The present article analyses the current situation of End-of-Life-of-Vehicles (ELVs) management in Europe, with particular attention on Italian condition. Similarly to other European countries, metal recycling is the main activity of the whole system, but such situation is evolving due to the 2000/53/EC Directive, which sets out targets for Reuse, Recycling and Recovery of ELVs. Due to the relevance of the ELVs problem, in 2008 Italian Ministry of Environment subscribed a framework agreement with competent stakeholders as carmakers, dismantlers, shredders. The main result is an industrial plan to promote (amongst other objectives) technological progress for residual waste (Automotive Shredder Residue-ASR) treatment. According with Italian Trial 2006 analysis about ELVs, Reuse and Recycling rate is currently estimated to be about 81%. At the present time, dismantling plants constitute the first collection points for ELVs; for this reason, during 2009 an investigation has been done over a number of ten Authorized Treatment Facilities (ATFs) operating in Italy. The first step of the analysis was aimed to find out major practices and methods through observations of ATFs activities and interviews to operators. Furthermore, the depollution and dismantling treatments of about 70 different ELVs have been observed and timed in detail over a period of three months. The results included the identification of most relevant critical issues in ELVs treatment, such as distortions between scrapping activities and Directive's regulation, and the assessment of the time and of the resources needed to perform each operation. In the second step of the survey, a process simulation model has been built on the basis of such data. The model was aimed to include the real variability and all the uncertainties that are typical of dismantling activities; it is intended as a tool for process layout planning and for its management. Some control parameters have been introduced; these are able to dynamically modify process path depending on ELVs queues and priorities. The model can also be used for the economic assessments of single operations or of the whole treatment activity. PMID- 23352085 TI - Echocardiography for assessment of mechanical dyssynchrony in children: the search must go on. PMID- 23352086 TI - Authors' reply. PMID- 23352088 TI - Graduate education programs for diagnostic imaging professionals. PMID- 23352089 TI - Vascular education at the scientific sessions: a review and a preview. PMID- 23352090 TI - Iron status and its determinants in a nationally representative sample of pregnant women. AB - Iron-deficiency anemia is associated with adverse neonatal health outcomes. Iron status and its determinants were assessed in a representative sample of Belgian pregnant women. Blood samples were collected and a questionnaire was completed face-to-face. Hemoglobin (Hb) and mean cell volume were measured using a Beckman Coulter Hematology Analyzer and serum ferritin (SF) and transferrin receptor (sTfr) concentrations by immunoassay. In total, 55 obstetric clinics and 1,311 pregnant women were included. Approximately 40% of third-trimester and 6% of first-trimester women had SF levels less than 15 MUg/L. Approximately 21% of third-trimester and 4% of first-trimester women had anemia (Hb <110 g/L). Of the third-trimester women, 23% were iron-deficient nonanemic (SF <15 MUg/L and Hb >=110 g/L), 16% had iron-deficiency anemia (SF <15 MUg/L and Hb <110 g/L), and approximately 7% had tissue iron deficiency (sTfr >8.5 mg/L). The median body iron stores were 8.1 mg/kg among first-trimester women, but only 3.6 mg/kg among third-trimester women. SF levels were significantly positively associated with age and education level, and were higher among nulliparous women and lower among North-African women. sTfr concentrations were significantly negatively associated with age and were lower among smokers, nulliparous women, and women who planned their pregnancy. Despite the fact that two thirds of Belgian pregnant women took iron-containing supplements, iron deficiency and iron-deficiency anemia were frequent in third-trimester women. The World Health Organization regards this as a moderate public health problem. National iron supplementation guidelines are needed in Belgium to optimize iron status during pregnancy. PMID- 23352091 TI - [Hyperandrogenism in a postmenopausal woman]. PMID- 23352092 TI - Design, implementation and application of distributed order PI control. AB - In this paper, a series of distributed order PI controller design methods are derived and applied to the robust control of wheeled service robots, which can tolerate more structural and parametric uncertainties than the corresponding fractional order PI control. A practical discrete incremental distributed order PI control strategy is proposed basing on the discretization method and the frequency criterions, which can be commonly used in many fields of fractional order system, control and signal processing. Besides, an auto-tuning strategy and the genetic algorithm are applied to the distributed order PI control as well. A number of experimental results are provided to show the advantages and distinguished features of the discussed methods in fairways. PMID- 23352093 TI - Mismatch between heart failure patients in clinical trials and the real world. AB - BACKGROUND: Evidence-based medicine urges physicians to translate results from clinical trials to their patients. This, however, can only work, if real world patients are represented in clinical trials. METHODS: We searched the literature on chronic heart failure (1950-2/2011) for studies designed to detect effects on mortality (mortality studies, MS) and exercise training studies (ETS) as the leading non-pharmaceutical/non-surgical treatment option in order to compare their characteristics with European (Euro Heart Survey on Heart Failure, EHSHF) and North American (Framingham Heart Study, FHS) epidemiological studies. RESULTS: After an extensive literature search, we identified 207 ETS and 59 MS. Subjects enrolled in ETS were younger (ETS: 62.5 +/- 6.6; MS: 63.9 +/- 4.6; EHSHF: 71.0 +/- 3.5; FHS: 78.0 years), more often male (ETS: 80.9%; MS: 77.3%; EHSHF: 53.0%; FHS: 49.6%; p<0.001), and had substantially less comorbidities such as diabetes mellitus (ETS: 13.6%; MS: 22.5%; EHSHF: 27.0%; FHS: 25.3%; p<0.001), or hypertension (ETS: 26.3%; MS: 39.1%; EHSHF: 53.0%; FHS: 46.9%; p<0.001). Angiotensin converting enzyme-inhibitors, beta-blockers, and angiotensin-receptor blockers were more commonly used in ETS than in EHSHF (all p<0.001). Only 16 (10.6%) ETS and 20 (62.5%) MS reported ethnic background. CONCLUSION: Heart failure patients in exercise training studies and mortality studies do not represent real world patients. In order to extrapolate data to the general population future exercise training studies as well as mortality studies need to include representative patients. Otherwise, knowledge gained can only be translated to a minority of our patients. PMID- 23352094 TI - [New section in Radiologia: article from a resident]. PMID- 23352095 TI - Early vascular healing with rapid breakdown biodegradable polymer sirolimus eluting versus durable polymer everolimus-eluting stents assessed by optical coherence tomography. AB - BACKGROUND: Differences in early arterial healing patterns after stent implantation between biodegradable and durable polymer based new generation drug eluting stents are not well understood. The aim of this study was to compare the healing patterns of a novel rapid breakdown (<=8 weeks) biodegradable polymer sirolimus-eluting stent (BP-SES) with a durable polymer everolimus-eluting stent (EES) using intravascular optical coherence tomography (OCT) at 4 months. METHODS: A total of 20 patients were randomly assigned to stenting with BP-SES (n=11) or EES (n=9). Overall intravascular imaging was available for 15 (75%) patients. The primary endpoint was the difference in rate of uncovered struts between BP-SES and EES. To account for strut-level clustering, the results in both treatment groups were compared using a generalized linear mixed model approach. RESULTS: Regarding the primary endpoint, BP-SES as compared to EES showed similar rates of uncovered struts (37 [6.8%] versus 167 [17.5%], odds ratio (OR) 0.45 (95% CI 0.09-2.24), p=0.33). There were no malapposed struts in BP-SES group and 14 malapposed struts in EES group (p=0.97). No difference in percent neointimal volume (14.1+/-8.2% vs. 11.4+/-6.4%, p=0.56) was observed. CONCLUSIONS: Although rapid-breakdown BP-SES as compared to EES showed signs of improved early tissue coverage, after adjustment for strut-level clustering these differences were not statistically significant. No differences in ability to suppress neointimal hyperplasia after stent implantation between 2 stents were observed. PMID- 23352096 TI - Sperm vacuoles are not modified by freezing--thawing procedures. AB - Since the development of the motile sperm organellar morphology examination (MSOME) in 2001 for observing the cephalic vacuoles at high magnification, no study as yet assessed the effect of cryopreservation on these vacuoles, although sperm freezing-thawing procedures are known to affect sperm quality. Examination of the vacuoles before and after freezing-thawing would indicate whether the same normality criteria can be applied for frozen as for fresh spermatozoa when performing intracytoplasmic morphologically selected sperm injection. In 27 sperm samples from fertile men, analysis of conventional sperm parameters (motility, vitality, percentage of normal forms) and a morphological analysis at high magnification (*6000) using image analysis software was performed before freezing and after thawing. Whereas there were expected decreases in motility (P<0.0001), vitality (P<0.001) and percentage of normal forms (P<0.05) after cryopreservation, there was no evidence for any difference in any vacuolar criteria (relative vacuole area, total vacuole area, vacuole area in the anterior, median and basal parts of the head, percentage of spermatozoa with a vacuole area <=6.5% and percentage of spermatozoa with a vacuole area >13%). Freezing-thawing procedures have no effect on human sperm vacuoles. PMID- 23352097 TI - Polarization microscopy and rescue ICSI. AB - A fraction of standard IVF cycles is afflicted by total fertilization failure. For several years, attempts have been made to develop strategies for rescuing these cycles in order to reduce the physical, psychological and economic burden imposed by an assisted reproduction technology treatment. Rescue ICSI is the approach by which failed fertilized oocytes can be microinjected on day 1 post insemination with the aim of achieving fertilization and thereby preventing cycle cancellation. In a study presented in this issue, Moon and colleagues perfected the rescue ICSI methodology by adopting polarized light microscopy as a tool to identify and treat only failed fertilized oocytes not penetrated by spermatozoa. In their experience, this approach generates a higher rate of normal fertilization. However, doubts concerning the safety of using failed fertilized, and therefore in-vitro aged, oocytes and the factual efficacy of rescue ICSI remain. PMID- 23352098 TI - Evaluation of the degree of satisfaction in oocyte donors using sustained-release FSH corifollitropin alpha. AB - Ovarian stimulation treatment is recognized as placing a physical and psychological burden on patients and oocyte donors. The introduction of sustained follicle stimulants will reduce the number of injections and may improve the overall patient experience. This study aimed to evaluate the degree of satisfaction in oocyte donors undergoing treatment with corifollitropin alpha, a synthetic recombinant rFSH which replaces daily FSH injections for the first week of ovarian stimulation. The results showed no significant differences in clinical parameters between the two protocols (recombinant FSH versus corifollitropin alpha). Implantation rates for the corifollitropin alpha and daily FSH protocol groups were 39.1% and 38.4%, respectively, while ongoing pregnancy rates were 45.9% and 44.4%. There were no statistical between-group differences in the responses to the questionnaires. However, donors treated with corifollitropin alpha who had undergone a previous cycle with daily FSH reported greater satisfaction with the corifollitropin alpha protocol. In conclusion, no significant differences were found in any analysed parameters between treatments. However, when donors who had undergone both treatments chose which treatment they preferred, the results clearly showed a positive trend towards choosing corifollitropin alpha, confirming that this protocol may reduce treatment burden and increase donor compliance. PMID- 23352099 TI - Exogenous administration of recombinant human FSH does not improve germ cell survival in human prepubertal xenografts. AB - In a previous study, meiotic activity was observed in human intratesticular xenografts from peripubertal patients. However, full spermatogenesis could not be established. The present study aimed to evaluate whether the administration of recombinant human FSH could improve the spermatogonial survival and the establishment of full spermatogenesis in intratesticular human xenografts. Human testicular tissue was obtained from six boys (aged 2.5-12.5years). The testicular biopsy was fragmented and one fragment of 1.5-3.0mm(3) was transplanted to the testis of immunodeficient nude mice. Transplanted mice were assigned to different experimental groups to enable evaluation of the effects of FSH administration and freezing. The structural integrity of the seminiferous tubules, the spermatogonial survival and the presence of differentiated cells were evaluated by histology and immunohistochemistry. Freezing or administration of FSH did not influence tubule integrity and germ cell survival in human xenografts. Meiotic germ cells were observed in the xenografts. More tubules containing only Sertoli cells were observed in frozen-thawed grafts, and more tubules with meiotic cells were present in fresh grafts. There was no clear influence of FSH treatment on meiotic differentiation. Administration of FSH did not improve the establishment of full spermatogenesis after intratesticular tissue grafting. PMID- 23352100 TI - Spindle examination in unfertilized eggs using the polarization microscope can assist rescue ICSI. AB - Rescue ICSI can induce a high rate of 3 pronuclei (PN) formation from double insemination in eggs already fertilized by IVF but lacking signs of normal pronuclear formation. This study was performed to determine whether the number of 3PN embryos could be reduced by using the polarization microscope for rescue intracytoplasmic sperm injection (ICSI). As a study group, after conventional insemination, 81 unfertilized mature oocytes from 11 couples were checked for the number of spindles using the polarization microscope. One spindle (82.7%) or two spindles (17.3%) were observed in this group. Rescue ICSI was only performed on the unfertilized oocytes showing one spindle. In the control group, 87 mature oocytes which lacked visualization of any fertilization signs were selected for rescue ICSI and none of them underwent observation of the spindle. After rescue ICSI, the normal fertilization rate in the study group was significantly higher than in the control (68.7% versus 43.7%; P=0.0032). The rate of 3PN or 4PN embryos was significantly decreased in the study group with one spindle compared with the group without observation of the spindle (4.5% versus 26.4%; P=0.0004). PMID- 23352101 TI - Anti-Mullerian hormone as a predictor of pregnancy following IVF. AB - This single-centre retrospective observational study was performed at a university IVF centre. The aim was to examine the predictive power of AMH concentrations for clinical pregnancy rate (CPR) and establish a cut-off concentration of AMH below which no pregnancies were achieved. Data from 820 women with one treatment cycle each were analysed. There was a significant difference in CPR (24.4% and 40.0%; P<0.01) between the lowest and highest quartiles of AMH. This study failed to establish a cut-off concentration of AMH below which there were no clinical pregnancies as several pregnancies were achieved despite an AMH less than 1pmol/l. Log AMH showed a strong positive correlation with number of oocytes retrieved (r=0.522; P<0.001). Log AMH and overall CPR were weakly correlated (r=0.112, P<0.001), but this was not maintained when controlled for the number of oocytes. Age was a stronger independent predictor of CPR than AMH. In conclusion, although an excellent marker of ovarian response, AMH is only a weak predictor of clinical pregnancy. With AMH below the third percentile, CPR was 15%. However AMH is very useful for patient counselling and assessment when used in conjunction with age. PMID- 23352102 TI - Fertility in cancer patients after cryopreservation of one ovary. AB - This questionnaire study describes the fertility and ovarian function in 143 adult female cancer survivors with only one ovary due to cryopreservation of the other. The women were asked about their ovarian function (as defined by the presence of a spontaneous menstrual cycle), pregnancies and their outcome. The mean follow-up time was 58months after cryopreservation (range 24-129months). The risk of premature ovarian failure was high in the group of patients with leukaemia (13/15; 87%) but low in the breast cancer group (5/54; 9%). Fifty-seven women had actively tried to become pregnant after end of treatment; of these, 41 women obtained a total of 68 pregnancies resulting in 45 live births and five ongoing pregnancies, 15 spontaneous abortions, one ectopic pregnancy and two elective abortions. In the remaining 86 women without a pregnancy wish, there had been five elective abortions. Ninety-three per cent of the pregnancies were after natural conception and only four cases were a result of fertility treatment. The overall risk of premature ovarian failure was low (22%). Patients who retain their ovarian function after treatment of a malignant disease have a good chance of becoming pregnant. PMID- 23352103 TI - Psoriasis induced by anti-tumour necrosis factor therapy in patients with inflammatory bowel disease. PMID- 23352104 TI - Effect of intensive granulocyte and monocyte adsorptive apheresis in patients with ulcerative colitis positive for cytomegalovirus. AB - BACKGROUND AND AIM: Cytomegalovirus (CMV) exacerbates ulcerative colitis (UC) refractory to immunosuppressive therapies. The conditions under which CMV reactivation occurs in patients with UC, however, is unclear. In addition, the diagnostic and treatment strategies for UC positive for CMV have not been established. Granulocyte and monocyte adsorptive apheresis (GMAA) is natural biological therapy for UC in which the granulocytes/macrophages producing inflammatory cytokines are removed. We investigated the rate of colonic CMV reactivation and the efficacy of GMAA in active UC patients positive for CMV without concomitant corticosteroid (CS) therapy. METHODS: Fifty-one active UC patients without concomitant CS therapy were enrolled. Colonic CMV reactivation was examined by real-time polymerase chain reaction (PCR) using biopsy specimen and/or histological examination. All patients were treated with intensive GMAA (twice per week). Rates of clinical remission and mucosal healing were compared between UC patients positive and negative for CMV. RESULTS: Of 51 patients, 15 (29.4%) were diagnosed as CMV positive. The clinical remission rates following intensive GMAA did not differ between UC patients positive and negative for CMV (73.3% vs 69.4%, p=0.781). Proportion of patients achieving mucosal healing was also similar between these two groups. CMV-DNA became negative in all UC patients positive for CMV who achieved clinical remission 1 week after completion of intensive GMAA. CONCLUSIONS: Intestinal inflammation might trigger CMV reactivation in a subpopulation of active UC patients without CS treatment. GMAA could be a promising option for active UC positive for CMV. PMID- 23352105 TI - Genetic variation in codons 167, 198 and 200 of the beta-tubulin gene in whipworms (Trichuris spp.) from a range of domestic animals and wildlife. AB - A recurrent problem in the control of whipworm (Trichuris spp.) infections in many animal species and man is the relatively low efficacy of treatment with a single application of benzimidazoles (BZs). The presence of single nucleotide polymorphisms (SNPs) in codons 167, 198 and 200 in the beta-tubulin gene has been associated with BZ anthelmintic resistance in intestinal nematodes of veterinary importance. We hypothesized that the low susceptibility to BZ could be related to a natural tolerance or induced resistance caused by BZ-resistant associated SNPs. The aim of the present study was therefore to investigate the presence of these SNPs in the beta-tubulin gene of Trichuris spp. obtained from a range of animals. DNA was extracted from a total of 121 Trichuris spp. adult whipworm specimens obtained from 6 different host species. The number of worms from each host was pig: 31, deer: 21, sheep: 18, mouse: 17, dog: 19 and Arabian camels: 14. A pooled sample of Trichuris eggs from 3 moose was also used. In order to amplify the beta tubulin fragments which covered codons 167, 198 and 200 of the gene, degenerate primers were designed. The sequences obtained were used to design species specific primers and used to amplify a ~476 bp fragment of the beta-tubulin gene. The PCR products were sequenced, analysed and evaluated. We did not identify SNPs in codons 167, 198 or 200 that led to amino acid substitutions in any of the studied Trichuris spp., but genetic variation expected to be related to species differences was observed. The cluster analysis showed close evolutionary relationship between Trichuris spp. from ruminants and between mouse and dog whereas the pig-derived worms, T. suis, clustered with T. trichiura obtained from Genbank. PMID- 23352106 TI - Acaricidal activity of extracts from Adonis coerulea Maxim. against Psoroptes cuniculi in vitro and in vivo. AB - The acaricidal activity of Adonis coerulea extracts was investigated against Psoroptes cuniculi. The aqueous, methanol, acetic ether and petroleum ether extracts all showed marked acaricidal activity in vitro. Especially, the acetic ether extract possessed strong toxicity against mites in vitro with LT50 values 0.743 h, 2.730 h, 5.919 h and 22.536 h at concentrations of 500, 250, 125 and 62.5 mg/ml, respectively. At the same time, the acetic ether extract showed the best effectiveness topically to infested rabbits in vivo. After three times treatment, at the day 20, rabbits treated with A. coerulea extract were observed only small scabs or secretions in ear canal, but no mites. These findings suggested that as a potential insecticide, A. coerulea should be studied further to develop active components or a new acaricidal drug. PMID- 23352107 TI - Resistance of Fasciola hepatica against Triclabendazole in cattle in Cajamarca (Peru): a clinical trial and an in vivo efficacy test in sheep. AB - Fasciolosis caused by Fasciola hepatica, is the most prevalent parasitic disease in dairy cattle from the northern region of Cajamarca, Peru. The control of this parasite is based on the use of Triclabendazole (TCBZ), a drug that has been used for more than fifteen years in this area. Recent studies, however, have reported a lack of clinical efficacy after treating dairy cattle. This research was aimed to determine the efficacy of TCBZ in a clinical trial. Eleven dairy cows all positive to F. hepatica identified by presence of eggs in feces, were treated with TCBZ (Fasinex((r)) 10%) at 12 mg/kg body weight. Fourteen and thirty days after treatment, the animals were analyzed for F. hepatica eggs in their feces by the fecal egg count reduction test. The results found show an overall efficacy of 31.05% and 13. 63% (14 and 30 days post treatment, respectively). Furthermore, an in vivo efficacy test was conducted in sheep with metacercariae obtained from eggs isolated from a cow clinically resistant to TCBZ. Eleven sheep divided in two groups, a control group with no treatment (n=5) and a treated group (n=6) were all infected with two hundred metacercariae. One hundred and six days after infection all the animals demonstrated F. hepatica eggs in their feces, confirming the presence of adult parasites in their livers. The animals were then treated with TCBZ (Fasinex((r)) 10%) at 10mg/kg body weight. Fifteen days later, the animals were sacrificed and the number of F. hepatica in their livers counted. The results of this experiment showed an efficacy of the flukicide of 25.2% confirming the resistance to TCBZ of the F. hepatica isolated from dairy cattle in Cajamarca, Peru. PMID- 23352108 TI - Prevalence of Babesia microti-like infection in red foxes (Vulpes vulpes) from Portugal. AB - The prevalence of piroplasm (order Piroplasmida) infection was assessed in blood and bone marrow samples from 91 red foxes (Vulpes vulpes) from northern, central and southern Portugal by means of molecular methods. PCR for the 18S rRNA gene of Babesia spp. followed by sequencing revealed 63 foxes positive for the Babesia microti-like piroplasm (syn. Theileria annae) (69.2%; 95% confidence interval [CI]: 58.7-78.5%) and one fox positive for Babesia canis (1.1%; 95% CI: 0.0 6.0%). Positivity to the B. microti-like piroplasm or B. canis in 43 blood samples (83.7%) was significantly higher (p<0.001) than in 43 paired bone marrow samples (20.9%). There were no statistically significant differences in the prevalence of infection between genders (p=0.219) or age groups (<2 years vs. >= 2 years) (p=1.0). This is the first report of the B. microti-like piroplasm in foxes from Portugal as well as the first report on detection by PCR and genotyping of B. canis in a red fox worldwide. A natural cycle of the B. microti like piroplasm is suggested in red fox populations based on the high prevalence of the protozoan. Red foxes might be a reservoir of the B. microti-like piroplasm and a source of infection to dogs. PMID- 23352109 TI - Philosophy matters in brain matters. AB - PURPOSE: Although most neuroscientists and physicians would argue against Cartesian dualism, Descartes's version of the psyche/soma divide, which has been controversial since he proposed it in the seventeenth century, continues to haunt contemporary neurological diagnoses through terms such as functional, organic, and psychogenic. Drawing on my own experiences as a person with medically unexplained seizures, I ask what this language actually means if all human experience has an organic basis. METHODS: Close reading of a textbook chapter on psychogenic seizures. RESULTS: I expose the author's unreflective embrace of psyche and soma as distinct entities, his inherent bias against illnesses labeled psychogenic, and the implicit sexism of his position. I further argue that even when a patient's symptoms are not alleviated, heightened self-consciousness and narrative framing can strengthen his or her sense of agency and have therapeutic benefits. CONCLUSION: The ethical treatment of patients requires a respect for their stories. PMID- 23352111 TI - Retargeting of regulatory T cells to surface-inducible autoantigen La/SS-B. AB - The nuclear autoantigen La can be detected on the surface of dying cells. Here we present an assay which enables us to show that La protein is not limited to the surface of dying cells but will be released upon stress-induced cell death. As released La protein tightly binds to the surface of neighboring intact cells we asked the question whether or not La protein could serve as a stress-inducible target e.g. for redirecting of regulatory T cells (Tregs) into damaged tissues to downregulate an immune response. In order to provide first proof of concept we developed a novel fully humanized single-chain bispecific antibody (bsAb) which on the one hand is directed to the La antigen and on the other hand to the CD3 complex of T cells. A cross-linkage of Tregs with La-decorated target cells mediated by this bsAb resulted indeed in the activation of the Tregs in a target dependent manner. Moreover, such bsAb activated Tregs displayed a potent suppressive capacity and negatively influenced proliferation, expansion and cytokine production of autologous CD4(+) and CD8(+) Teff cells. PMID- 23352112 TI - Prognosis of intracerebral hemorrhage after conservative treatment. AB - BACKGROUND: The aim of this population-based study was to determine the short term prognosis of patients treated conservatively for spontaneous intracerebral hemorrhage (ICH), a disease with a high rate of mortality. METHODS: During a 39 month period beginning in October 2007, 594 patients (mean age 72 +/- 12 years; 52% female; median National Institutes of Health Stroke Scale [NIHSS] score 9) with spontaneous ICH were enrolled in this prospective, population-based study. RESULTS: Of 594 patients, 74 (12%) died during hospitalization (10.3 +/- 7 days). Adjusted logistic regression analyses revealed that the in-hospital mortality rate was significantly associated with age >80 years (odds ratio [OR] 3.1; 95% confidence interval [CI] 1.3-7.5; P = .01), NIHSS score >15 (OR 3.3; 95% CI 1.4 9.7; P = .007), unconsciousness at admission (OR 5.3; 95% CI 2.0-13.6; P = .001), and cerebral edema detected by cranial computed tomography at admission (OR 14.7; 95% CI 6.2-34.6; P < .001). At hospital discharge, 329 patients (63%) agreed to participate in the inquiry. At 3 months of follow-up, 55 (18%) of 309 patients died. The 3-month mortality rate correlated significantly with age >80 years (OR 3.5; 95% CI 1.4-8.7; P = .008), previous stroke (OR 4.1; 95% CI 1.6-10.3; P = .002), unconsciousness at admission (OR 5.7; 95% CI 2.4-13.9; P = .001), pneumonia suffered during hospitalization (OR 3.3; 95% CI 1.2-9.6; P = .02), and cerebral edema (OR 5.7; 95% CI 2.3-13.8; P < .001). CONCLUSIONS: Our study may help clinicians estimate the short-term prognosis of patients treated conservatively for ICH. PMID- 23352110 TI - SBIRT for adolescent drug and alcohol use: current status and future directions. AB - Adolescence is a period of rapid biological, psychological, and social development in the human life cycle. Drug and alcohol misuse during this critical period poses substantial problems for individual and public health, yet is highly prevalent in the United States and elsewhere. The screening, brief interventions, and referral to treatment (SBIRT) model may be well-suited for identifying and intervening with adolescents who are at-risk of developing substance use disorders and those adolescents whose substance use puts them at risk for injury or illness. This article reviews the literature on SBIRT for adolescent populations, focusing on findings from randomized controlled trials. The limited evidence suggests that brief interventions may be effective with adolescents, but a number of gaps in the literature were identified. Considerations for implementing SBIRT with adolescent populations are discussed. Randomized trials are needed that have adequate statistical power, employ longer-term follow-ups, and test the effectiveness of SBIRT for adolescents in various service delivery settings. PMID- 23352113 TI - Incidence rate of cerebrovascular diseases in northern Japan determined from the Iwate Stroke Registry with an inventory survey system. AB - BACKGROUND: Long-term stroke registries in large populations often fail to maintain accuracy. This study presents an inventory survey system for stroke registries and the incidence rate of cerebrovascular diseases in a region with the highest stroke mortality rate in Japan. METHODS: Using the data of the stroke registry determined with the inventory survey from 2004 to 2008 in northern Iwate Prefecture, with a population of 235,280 (111,584 men and 123,696 women), the age specific annual incidence rates, the age-adjusted annual incidence rates, and the ratio of incidence rate relative to mortality rate of the cerebrovascular diseases were investigated. RESULTS: A total of 3415 cases (1714 men and 1701 women) were registered and analyzed in this study. The age-adjusted incidence rates by the 1985 model population of Japan and by the world standard population (range 35-64 years) were 100.4 and 89.4 per 100,000 population in men and 49.8 and 29.7 in women for cerebral infarction; 53.6 and 77.2 in men and 34.2 and 39.5 in women for intracerebral hemorrhage; 12.9 and 23.3 in men and 21.1 and 34.6 in women for subarachnoid hemorrhage; and 166.9 and 189.8 in men and 105.0 and 103.7 in women for all subtypes. The ratios of incidence rate relative to mortality rate were 1.66 for all stroke subtypes, 1.69 for cerebral infarction, 1.76 for intracerebral hemorrhage, and 1.31 for subarachnoid hemorrhage. CONCLUSIONS: High incidence rates of cerebrovascular diseases were revealed in the stroke registry with a good inventory survey in northern Iwate Prefecture, Japan. PMID- 23352114 TI - Aphasia predicts unfavorable outcome in mild ischemic stroke patients and prompts thrombolytic treatment. AB - BACKGROUND: Patients with an acute ischemic stroke rated as mild, and for this reason not submitted to thrombolysis, have an unfavorable outcome in a non negligible proportion. Whether selective presentation features help identify those at risk of bad outcome, and whether it could be recommended to treat only patients with such features, is poorly elucidated. We report our experience based on retrospective evaluation of a consecutive series of patients scoring 6 or less on baseline National Institutes of Health Stroke Scale (NIHSS), some of whom received thrombolysis. METHODS: From the prospective Careggi Hospital Stroke Registry, Florence, Italy, we selected a series of patients who fulfilled the following criteria: (1) screening for treatment within 3 hours of symptom onset; (2) mild symptoms, defined as a score of 6 or less on NIHSS, with or without rapid improvement; (3) no other reason for exclusion from thrombolysis; (4) no previous disability; and (5) admission to the stroke unit. We choose a modified Rankin scale score of less than 2 to define a good 3-month functional outcome. We studied as potential outcome predictors: age, baseline NIHSS score, isolated aphasia, motor impairment with or without aphasia, thrombolysis, previous stroke or transient ischemic attack, and interactions between each of these factors and thrombolysis. RESULTS: Between February 2004 and June 2011, 128 patients fulfilled the selection criteria: 47 (36.7%) received tissue plasminogen activator, 81 (63.3%) did not. At 3 months, of the 81 patients not receiving tissue plasminogen activator, 14 (17.3%) had an unfavorable outcome, compared with 6 (12.8%) among the 47 treated. Hemorrhagic complications or death occurred in neither group. Adjusting for major confounders and for thrombolysis, the presence of aphasia on early assessment proved the only independent predictor of worse outcome. NIHSS score variation showed no effect. CONCLUSIONS: Aphasia is an early marker of unfavorable outcome in mild ischemic stroke patients. In these patients thrombolysis should be considered beyond the NIHSS scoring. PMID- 23352115 TI - Working memory deficits and related disinhibition of the cAMP/PKA/CREB are alleviated by prefrontal alpha4beta2*-nAChRs stimulation in aged mice. AB - The present study investigates in aged mice the working memory (WM) enhancing potential of the selective alpha4beta2* nicotinic receptor agonist S 38232 as compared with the cholinesterase inhibitor donepezil, and their effect on cAMP response element binding protein (CREB) phosphorylation (pCREB) as a marker of neuronal activity. We first showed that aged mice exhibit a WM deficit and an increase of pCREB in the prelimbic cortex (PL) as compared with young mice, whereas no modification appears in the CA1. Further, we showed that systemic administration of S 38232 restored WM in aged mice and alleviated PL CREB overphosphorylation. Donepezil alleviated age-related memory deficits, however, by increasing pCREB in the CA1, while pCREB in PL remained unaffected. Finally, whereas neuronal inhibition by lidocaine infusion in the PL appeared deleterious in young mice, the infusion of Rp-cAMPS (a compound known to inhibit CREB phosphorylation) or S 38232 rescued WM in aged animals. Thus, by targeting the alpha4beta2*-nicotinic receptor of the PL, S 38232 alleviates PL CREB overphosphorylation and restores WM in aged mice, which opens new pharmacologic perspectives of therapeutic strategy. PMID- 23352116 TI - Mutational analysis of FBXO7 gene in Parkinson's disease in a Taiwanese population. AB - Mutations in the FBXO7 gene cause an autosomal-recessive early-onset parkinsonism with pyramidal tract signs. Its role in typical Parkinson's disease (PD) without pyramidal features is unclear. We assayed FBXO7 gene in 900 participants comprising 448 PD patients and 452 age- and sex-matched control subjects from Taiwan. The entire FBXO7 coding region and intron-exon boundaries were sequenced. We identified 2 novel missense substitutions, p.Ile87Thr and p.Asp328Arg, in a single heterozygous state in 2 early-onset PD patients individually (1.1% early onset PD). These 2 variants were not observed in control subjects with a total of 904 normal alleles. Additionally, we also found 1 noncoding variant, exon 1 IVS 329C>T, modestly associated with PD. The frequency of the CT/TT genotype was higher in PD patients compared with control subjects (odds ratio, 1.43; 95% confidence interval, 1.02-2.01; p = 0.04). The clinical phenotypes of genetic variant carriers are similar to that seen in idiopathic PD. We conclude that FBXO7 gene contributes little to typical PD in our population. Further studies in other ethnic cohorts will be important to address its potential pathophysiological role in PD. PMID- 23352117 TI - [Brachytherapy in France: past, present and what future?]. PMID- 23352118 TI - Intracellular delivery and antitumor effects of pH-sensitive liposomes based on zwitterionic oligopeptide lipids. AB - pH-sensitive liposomes (HHG2C(18)-L and PEGHG2C(18)-L) based on zwitterionic oligopeptide lipids as anticancer drug carriers were developed and evaluated for effective intracellular delivery and enhanced antitumor activity. The amino acid based lipids, 1,5-dioctadecyl-l-glutamyl 2-histidyl-hexahydrobenzoic acid (HHG2C(18)) and 1,5-distearyl N-(N-alpha-(4-mPEG2000) butanedione)-histidyl-l glutamate (PEGHG2C(18)), were synthesized, which have the multistage pH-response to tumor microenvironmental pH (pH(e), pH 6.0-7.0) and endosomal/lysosomal pH (pH(i), pH 4.0-6.0) successively. HHG2C(18)-L contains HHG2C(18), while PEGHG2C(18)-L includes HHG2C(18) and PEGHG2C(18). Both of them displayed the capability of charge conversion to the surrounding pH. The zeta potentials of HHG2C(18)-L and PEGHG2C(18)-L were negative at pH 7.4, whereas positive at pH 6.5 and more positive at lower pH. Coumarin 6-loaded HHG2C(18)-L (C6/HHG2C(18)-L) and PEGHG2C(18)-L (C6/PEGHG2C(18)-L) showed higher tumor cellular uptake due to electrostatic absorptive endocytosis at pH(e) (pH 6.5), produced proton sponge effect for endo-lysosomal escape, and accumulated to the mitochondria based on stronger positive charge by the hydrolysis of a pH-sensitive linker at pH(i) (pH 5.5 and pH 4.5). Furthermore, temsirolimus (CCI-779)-loaded HHG2C(18)-L (CCI 779/HHG2C(18)-L) and PEGHG2C(18)-L (CCI-779/PEGHG2C(18)-L) had significantly higher antiproliferative and apoptosis inducing effects toward the human renal carcinoma (A498) cells at pH 6.5 relative to that at pH 7.4. The half maximal inhibitory concentration (IC50) of CCI-779/HHG2C(18)-L and CCI-779/PEGHG2C(18)-L were about 3 MUg/mL and 5 MUg/mL at pH 6.5, 1.67-fold and 1.60-fold improved relative to that at pH 7.4, respectively. The total apoptotic ratio of CCI 779/HHG2C(18)-L and CCI-779/PEGHG2C(18)-L increased from 9.90% and 7.78% at pH 7.4 to 19.53% and 12.10% at pH 6.5, respectively. In vivo, CCI-779/PEGHG2C(18)-L after intravenous administration presented remarkably higher bioavailability and blood persistence compared with unPEGylated CCI-779/HHG2C(18)-L, and had the strongest antitumor efficacy against xenograft renal cancer (Renca) tumor models. Accordingly, the results provide the feasibility of using pH-sensitive zwitterionic oligopeptide lipids to extend the applications of liposomes to efficient anticancer drug delivery in cancer therapy. PMID- 23352119 TI - Mesoporous silica-encapsulated gold nanoparticles as artificial enzymes for self activated cascade catalysis. AB - A significant challenge in chemistry is to create synthetic structures that mimic the complexity and function of natural systems. Here, a self-activated, enzyme mimetic catalytic cascade has been realized by utilizing expanded mesoporous silica-encapsulated gold nanoparticles (EMSN-AuNPs) as both glucose oxidase- and peroxidase-like artificial enzymes. Specifically, EMSN helps the formation of a high degree of very small and well-dispersed AuNPs, which exhibit an extraordinarily stability and dual enzyme-like activities. Inspired by these unique and attractive properties, we further piece them together into a self organized artificial cascade reaction, which is usually completed by the oxidase peroxidase coupled enzyme system. Our finding may pave the way to use matrix as the structural component for the design and development of biomimetic catalysts and to apply enzyme mimics for realizing higher functions. PMID- 23352120 TI - A long-acting formulation of a polypeptide drug exenatide in treatment of diabetes using an injectable block copolymer hydrogel. AB - This study is aimed to develop a long-acting injectable formulation in treatment of type II diabetes. A glucoregulatory polypeptide, exenatide (EXT), was chosen as the model drug, and an aqueous block copolymer system with a sol-gel transition upon the increase of temperature was selected as the delivery matrix of EXT. The thermoreversible hydrogel composed of poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers was found to slower the degradation of the polypeptide to a large extent. However, the initial formulation in this study exhibited a significant drug burst effect, which is a common problem to load a hydrophilic small or medium-size polypeptide into a hydrogel. Zinc acetate was then introduced to slow down the EXT release by formation of insoluble Zn-EXT complexes in the thermogel matrix. Yet an incomplete release became another crucial problem, which is also common for peptide and protein delivery. The synergistic effect of three excipients (zinc acetate, PEG, and sucrose) under an appropriate condition overcame these two problems simultaneously, and the sustained release of drug lasted for 1 week. In vivo experiments via mice oral glucose tolerance tests demonstrated an improved glucose tolerance for 1 week after a single subcutaneous injection of the optimal EXT formulation. As a result, a formulation of antidiabetic drugs was set up, and meanwhile a strategy using synergistic excipients to adjust release profiles of peptides from hydrogels was put forward. PMID- 23352121 TI - Campaign to counter a deteriorating consumer market: Philip Morris's Project Sunrise. AB - OBJECTIVES: From 1997 to 2000, Philip Morris implemented Project Sunrise. This paper discusses the impact of this project on national and Philip Morris's cigarette unit sales, public opinion about smoking and secondhand tobacco smoke, and national prevalence trends for tobacco use. STUDY DESIGN: A qualitative archival content analysis of Project Sunrise from 1997 to 2000, and a descriptive statistical analysis of cigarette unit sales and operating profits, acceptability of smoking and secondhand tobacco smoke, and national prevalence trends for tobacco use from 1996 to 2006. METHODS: Qualitative data sources related to Project Sunrise found on WebCat, Pubmed.com, LexisNexis Academic and Philip Morris's website, and archived tobacco industry documents were analysed using NVivo Version 9.0. A descriptive statistical analysis of cigarette unit sales, public opinion about smoking and secondhand tobacco smoke, and national prevalence trends for tobacco use was undertaken. RESULTS: Project Sunrise was a high-level strategic corporate plan to maintain profits that included four possible scenarios resulting in seven interwoven strategies. However, national prevalence rates for tobacco use declined, sales of national and Philip Morris cigarettes declined, operating profits remained at substantially lower levels after 2000 from 2001 to 2006, and a large majority of Americans agreed that there were significant health dangers associated with smoking and secondhand tobacco smoke. CONCLUSION: The impact of Project Sunrise, including countering the anti tobacco movement, was less than successful in the USA. PMID- 23352122 TI - Tobacco control in Vietnam. AB - OBJECTIVES: To investigate the use of tobacco in Vietnam. STUDY DESIGN: Review study. METHODS: Data were collected through a review of tobacco-related literature in Vietnam. Grey literature and web content from agencies such as the World Health Organization and the US Centers for Disease Control and Prevention were consulted. RESULTS: Tobacco smoking is still common in Vietnam, although numerous policies have been issued and implemented over the last two decades. Based on the most recent data (2010), the prevalence of smoking among adults aged >15 years was 23.8%, with a higher percentage among males (47.4%) than females (1.4%). The prevalence of smoking among students aged 13-15 was 3.8% (2007), with a similar gender pattern. The prevalence of exposure to secondhand smoke is of concern, with 73.1% and 55.9% of adults reporting exposure to secondhand smoke at home and at work or other places, respectively. Of the adult respondents, 55.5% believed that smoking may cause lung cancer, stroke and heart disease. Most students (93.4%) and adults (91.6%) had seen anti-smoking media messages. Of the students, 56.4% had seen pro-cigarette advertisements on billboards, 36.9% had seen pro-cigarette advertisements in newspapers or magazines, and 8.2% had been offered free cigarettes by tobacco company representatives. The price of cigarettes decreased by approximately 5% between 1995 and 2006, whereas gross domestic product per capita increased by more than 150%. On average, smokers smoked 13.5 cigarettes per day, and spent US$86 on cigarettes per year. Despite such high levels of tobacco exposure in Vietnam, the total tax on cigarettes remains at 45% of the retail price. Furthermore, only 29.7% of smokers had been advised to quit by a healthcare provider in the past 12 months. CONCLUSION: Strong enforcement and evidence-based regulations which rounded on MPOWER are needed to help protect current smokers and non-smokers from the devastating effects of tobacco. PMID- 23352123 TI - Optimization of the basal medium for improving production and secretion of taxanes from suspension cell culture of Taxus baccata L. AB - BACKGROUND AND PURPOSE OF THE STUDY: Taxol is one of the most effective anticancer drugs that isolated from Taxus sp. due to the slow growth of Taxus trees and low concentration of Taxol in the tissues, the biotechnological approaches especially plant cell culture have been considered to produce Taxol in commercial scale. METHODS: We investigated the effects of basal medium type used in culture media on production of Taxol and other taxane compounds from cell suspension culture of T. baccata L. Briefly, five commonly basal media including Gamborg, Murashige and Skoog, Woody Plant, Schenk and Hildebrandt, and Driver and Kuniyuki medium were used for preparing separate suspension culture media. The intra- and extra-cellular yields of taxanes were analyzed by using HPLC after 21 days period of culturing. RESULTS: The yields of taxanes were significantly different for the cultures prepared by different basal media. Moreover, the effects of basal medium on the yield of products differed for varius taxane compounds. Maximum yields of Baccatin III (10.03 mgl-1) and 10-deacetyl baccatin III (4.2 mgl-1) were achieved from the DKW basal media, but the yield of Taxol was maximum (16.58 mgl-1) in the WPM basal media. Furthermore, the secretion of taxanes from the cells into medium was also considerably affected by the type of basal medium. The maximum extra-cellular yield of Taxol (7.81 mgl-1), Baccatin III (5.0 mgl-1), and 10-deacetyl baccatin III (1.45 mgl-1) were also obtained by using DKW basal medium that were significantly higher than those obtained from other culture media. PMID- 23352124 TI - Handedness and dominant side of symptoms in Parkinson's disease. AB - BACKGROUND AND OBJECTIVE: To investigate the association between handedness and the side of symptom dominance in Parkinson's disease (PD). PATIENTS AND METHODS: One hundred and forty-six PD patients with symmetric symptoms (92 males and 54 females), aged 64.3 +/- 9.1 years old, from a series of 247 PD patients were assessed for handedness and clinical features. The severity of PD was scored by unified Parkinson's disease rating scale (UPDRS) and Hoehn-Yahr staging on the "ON" state. RESULTS: Of 134 right-handed patients (91.8%), 83 (61.7%) had an initial onset on the right side (P=0.008), while of 12 left-handed patients (8.2%), 9 (75.0%) had an initial onset on the left side (P=0.013). Out of right handed patients, 103 (76.9%) had the right-side dominance of PD symptoms (P<0.001). Among the left-handed subjects, 7 patients (58.3%) had left-sided and 5 patients (41.7%) had right-sided symptom dominance (P=0.564). In general, dominant side of symptoms was in accordance with handedness (P=0.008). In right handed patients, rest tremor was the most common initial symptom (P<0.001), while rest tremor and rigidity-bradykinesia were initial symptoms in left-handed patients (P=0.366). CONCLUSIONS: PD symptoms emerge more often on the dominant hand-side, and the dominant side of symptoms is in accordance with handedness. PMID- 23352125 TI - [Consumption of energy drinks with alcohol, hazardous mixture]. PMID- 23352127 TI - Cost of reproduction. Changes in metabolism and endosulfan lethality caused by reproductive behavior in Hyalella curvispina (Crustacea: Amphipoda). AB - Biocides are periodically applied in agricultural activities, reaching aquatic systems and acting upon the biota. Amphipods are widely used in toxicity tests because of their sensitivity to a wide range of pollutants. In this work, we report the differential lethality of a widely used pesticide, endosulfan, on the amphipod Hyalella curvispina at two life stages and in three different adult groups, males and females separated by sex and both sexes grouped together. In addition, oxygen consumption of adult groups was determined as a way to estimate the role of behavioral activities and exposure to endosulfan in metabolism shifts. There were no differences between the LC(50) of juveniles and the adults when they were separated by sex (p>0.05). Nevertheless, the LC(50) of adults without sexual differentiation was significantly lower than the LC(50) of juveniles and adults separated by sex (p<0.05). The oxygen consumption rate was higher when adults were grouped without sexual differentiation in the control group. The exposure to low concentrations of endosulfan causes an increase in oxygen consumption in all the treatments. The sexual behavior increased the metabolism and the sensitivity to endosulfan. In future evaluations, adults grouped without sexual differentiation, which were the most sensitive group, should be included in order to mimic the environmental conditions. Using only juveniles or adults separated by sex in toxicity tests may inaccurately estimate the lethality of biocides, especially in species with constant reproductive activities. PMID- 23352126 TI - LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. AB - The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ~20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, as selectively inducing apoptosis in LKB1-deficient NSCLC cells. Therapeutic trials in Kras-dependent mouse models of NSCLC revealed that tumors with Kras and Lkb1 mutations, but not those with Kras and p53 mutations, showed selective response to phenformin as a single agent, resulting in prolonged survival. This study suggests phenformin as a cancer metabolism-based therapeutic to selectively target LKB1-deficient tumors. PMID- 23352128 TI - Characterization of polycyclic aromatic hydrocarbons in concurrently monitored surface seawater and sediment along Dalian coast after oil spill. AB - Polycyclic aromatic hydrocarbons (PAHs) were measured in concurrently sampled surface seawater and sediment collected at 20 sites around Dalian, China 50 days after an oil spill accident. The concentrations of total PAHs ranged from 15 to 160 ng L(-1) in seawater, and from 64 to 2100 ng g(-1) dry weight in surface sediment. The spatial trends of PAHs in seawater, but not in sediment, showed a significant negative correlation with the distance from the oil spill site, indicating a strong source of PAHs from oil spill place to the surrounding seawater. The similar profiles for PAH composition in both crude oil and seawater could indicate that oil spill caused PAHs concentration in seawater, but not in sediment. Analysis of water-sediment exchange of PAHs showed that the direction of the net flux of PAHs was from sediment to seawater for most priority PAHs, and from water to sediment for a few HWM-PAHs. PMID- 23352129 TI - Oxidative and genotoxic effects of 900 MHz electromagnetic fields in the earthworm Eisenia fetida. AB - Accumulating evidence suggests that exposure to radiofrequency electromagnetic field (RF-EMF) can have various biological effects. In this study the oxidative and genotoxic effects were investigated in earthworms Eisenia fetida exposed in vivo to RF-EMF at the mobile phone frequency (900 MHz). Earthworms were exposed to the homogeneous RF-EMF at field levels of 10, 23, 41 and 120 V m(-1) for a period of 2h using a Gigahertz Transversal Electromagnetic (GTEM) cell. At the field level of 23 V m(-1) the effect of longer exposure (4h) and field modulation (80% AM 1 kHz sinusoidal) was investigated as well. All exposure treatments induced significant genotoxic effect in earthworms coelomocytes detected by the Comet assay, demonstrating DNA damaging capacity of 900 MHz electromagnetic radiation. Field modulation additionally increased the genotoxic effect. Moreover, our results indicated the induction of antioxidant stress response in terms of enhanced catalase and glutathione reductase activity as a result of the RF-EMF exposure, and demonstrated the generation of lipid and protein oxidative damage. Antioxidant responses and the potential of RF-EMF to induce damage to lipids, proteins and DNA differed depending on the field level applied, modulation of the field and duration of E. fetida exposure to 900 MHz electromagnetic radiation. Nature of detected DNA lesions and oxidative stress as the mechanism of action for the induction of DNA damage are discussed. PMID- 23352130 TI - Induction of liver GST transcriptions by tert-butylhydroquinone reduced microcystin-LR accumulation in Nile tilapia (Oreochromis niloticus). AB - The cyanobacterial toxin, MC-LR, is predominantly presented during toxic cyanobacterial blooms and is consumed by phytoplanktivorous fish and zooplanktivorous fish directly. Detoxification of MC-LR in liver was believed to begin with conjugate formation with GSH, catalyzed by GSTs. MC-LR GSH conjugates display increased solubility and are subjected to accelerated biliary excretion. In this study, we showed that the mRNA transcriptions of GSTA, GPX and UCP2 were increased within 8h following MC-LR exposure in isolated hepatocytes of Nile tilapia, confirming the roles of phase II enzymes, especially GSTs, in MC-LR detoxification in tilapia. The widely used food-additive, synthetic antioxidant, tert-butylhydroquinone (tBHQ) has been shown to induce phase II enzymes including GSTs, via the antioxidant responsive elements (ARE) locate in the regulatory regions of these genes. Our results also showed that the transcription of various GSTs, including GSTA, GSTR2 and GSTT were significantly induced by tBHQ in Nile tilapia. In consistence, fish fed on tBHQ-containing diet (0.01 percent tBHQ) showed significantly reduced MC-LR accumulation in liver tissues 48 h after an oral administration of a single dose of 250 MUg MC-LR/kg body weight (bwt). The findings in this research suggested that tBHQ could reduce MC-LR accumulations in liver, likely through the induction of phase II metabolizing enzymes such as GSTs. Subacute effects of tBHQ and its potential applications in fishery need to be further investigated. PMID- 23352131 TI - Nucleosome remodelers in double-strand break repair. AB - ATP-dependent nucleosome remodelers use ATP hydrolysis to shift, evict and exchange histone dimers or octamers and have well-established roles in transcription. Earlier work has suggested a role for nucleosome remodelers such as INO80 in double-strand break (DSB) repair. This review will begin with an update on recent studies that explore how remodelers are recruited to DSBs. We then examine their impact on various steps of repair, focusing on resection and the formation of the Rad51-ssDNA nucleofilament. Finally, we will explore new studies that implicate remodelers in the physical movement of chromatin in response to damage. PMID- 23352132 TI - As personal genomes join big data will privacy and access shrink? PMID- 23352133 TI - Bringing protein engineering and natural product biosynthesis together. AB - In this issue of Chemistry & Biology, Zhang and colleagues developed a yeast cell surface display strategy to effectively evolve the substrate specificity of DhbE, one of the adenylation domains of the bacillibactin synthetase complex. The method yields DbhE variants that have dramatically altered substrate specifities toward unnatural aryl substrates. PMID- 23352134 TI - Small molecule disruption of B. subtilis biofilms by targeting the amyloid matrix. AB - Small molecule inhibitors of amyloid aggregation have potential as treatment for a variety of conditions. In this issue of Chemistry & Biology, Romero and colleagues use amyloid-dependent B. subtilis biofilm formation to screen for amyloid inhibitors, identifying compounds that not only inhibit B. subtilis biofilm formation but also ones that disrupt preformed biofilms. PMID- 23352135 TI - Investigating cellular structures at the nanoscale with organic fluorophores. AB - Super-resolution fluorescence imaging can provide insights into cellular structure and organization with a spatial resolution approaching virtually electron microscopy. Among all the different super-resolution methods single molecule-based localization microscopy could play an exceptional role in the future because it can provide quantitative information, for example, the absolute number of biomolecules interacting in space and time. Here, small organic fluorophores are a decisive factor because they exhibit high fluorescence quantum yields and photostabilities, thus enabling their localization with nanometer precision. Besides past progress, problems with high-density and specific labeling, especially in living cells, and the lack of suited standards and long term continuous imaging methods with minimal photodamage render the exploitation of the full potential of the method currently challenging. PMID- 23352137 TI - Cloning, heterologous expression, and characterization of the gene cluster required for gougerotin biosynthesis. AB - Gougerotin, a peptidyl nucleoside antibiotic, possesses antitumor, antiviral, antibacterial, antimycoplasma, anthelmintic, and acaricidal activities. Here, we report the cloning of a complete gougerotin biosynthetic gene cluster from Streptomyces graminearus and heterologous production of gougerotin in Streptomyces coelicolor. Sequence analysis of a 28.7 kb DNA fragment indicated that the cluster consists of 25 open reading frames (ORFs). Gene disruption and genetic complementation experiments revealed that 15 of the 25 ORFs are required for gougerotin biosynthesis. A gougerotin biosynthetic pathway was proposed based on the analyses of bioinformatics and intermediates accumulated in selected gene inactivation mutants. These studies substantially promoted our understanding of gougerotin biosynthesis and provide "building blocks" for combinatorial biosynthesis using genes encoding different enzymes in nucleoside antibiotics. PMID- 23352136 TI - HTS by NMR of combinatorial libraries: a fragment-based approach to ligand discovery. AB - Fragment-based ligand design (FBLD) approaches have become more widely used in drug discovery projects from both academia and industry, and are even often preferred to traditional high-throughput screening (HTS) of large collection of compounds (>10(5)). A key advantage of FBLD approaches is that these often rely on robust biophysical methods such as NMR spectroscopy for detection of ligand binding, hence are less prone to artifacts that too often plague the results from HTS campaigns. In this article, we introduce a screening strategy that takes advantage of both the robustness of protein NMR spectroscopy as the detection method, and the basic principles of combinatorial chemistry to enable the screening of large libraries of fragments (>10(5) compounds) preassembled on a common backbone. We used the method to identify compounds that target protein protein interactions. PMID- 23352138 TI - Elucidation of the biosynthetic gene cluster and the post-PKS modification mechanism for fostriecin in Streptomyces pulveraceus. AB - Fostriecin is a unique phosphate monoester antibiotic that was isolated from Streptomyces pulveraceus as a protein phosphatase 2A (PP2A) and PP4A selective inhibitor. However, its biosynthetic mechanism remains to be elucidated. In this study, a 73 kb gene cluster encoding a six modular Type I polyketide synthases (PKS) and seven tailoring enzymes was identified by cosmid sequencing from the producer. The functions of two tailoring enzymes were characterized by gene disruption and an in vitro enzyme activity assay. Remarkably, the isolation of three malonylated fostriecin analogs from post-PKS gene knockout mutants indicated malonylated-polyketide formation could be a normal biosynthetic process in the formation of the unsaturated six-membered lactone in fostriecin. Based on this study, a comprehensive post-PKS modification mechanism for fostriecin biosynthesis was proposed. PMID- 23352140 TI - Structural properties of model phosphatidylcholine flippases. AB - Lipid translocation from one lipid bilayer leaflet to the other, termed flip flop, is required for the distribution of newly synthesized phospholipids during membrane biogenesis. However, a dedicated biogenic lipid flippase has not yet been identified. Here, we show that the efficiency by which model transmembrane peptides facilitate flip of reporter lipids with different headgroups critically depends on their content of helix-destabilizing residues, the charge state of polar flanking residues, and the composition of the host membrane. In particular, increased backbone dynamics of the transmembrane helix relates to its increased ability to flip lipids with phosphatidylcholine and phosphatidylserine headgroups, whereas a more rigid helix favors phosphatidylethanolamine flip. Further, the transmembrane domains of many SNARE protein subtypes share essential features with the dynamic model peptides. Indeed, recombinant SNAREs possess significant lipid flippase activity. PMID- 23352139 TI - A small molecule inhibitor of the BLM helicase modulates chromosome stability in human cells. AB - The Bloom's syndrome protein, BLM, is a member of the conserved RecQ helicase family. Although cell lines lacking BLM exist, these exhibit progressive genomic instability that makes distinguishing primary from secondary effects of BLM loss problematic. In order to be able to acutely disable BLM function in cells, we undertook a high throughput screen of a chemical compound library for small molecule inhibitors of BLM. We present ML216, a potent inhibitor of the DNA unwinding activity of BLM. ML216 shows cell-based activity and can induce sister chromatid exchanges, enhance the toxicity of aphidicolin, and exert antiproliferative activity in cells expressing BLM, but not those lacking BLM. These data indicate that ML216 shows strong selectivity for BLM in cultured cells. We discuss the potential utility of such a BLM-targeting compound as an anticancer agent. PMID- 23352141 TI - A bacterial source for mollusk pyrone polyketides. AB - In the oceans, secondary metabolites often protect otherwise poorly defended invertebrates, such as shell-less mollusks, from predation. The origins of these metabolites are largely unknown, but many of them are thought to be made by symbiotic bacteria. In contrast, mollusks with thick shells and toxic venoms are thought to lack these secondary metabolites because of reduced defensive needs. Here, we show that heavily defended cone snails also occasionally contain abundant secondary metabolites, gamma-pyrones known as nocapyrones, which are synthesized by symbiotic bacteria. The bacteria, Nocardiopsis alba CR167, are related to widespread actinomycetes that we propose to be casual symbionts of invertebrates on land and in the sea. The natural roles of nocapyrones are unknown, but they are active in neurological assays, revealing that mollusks with external shells are an overlooked source of secondary metabolite diversity. PMID- 23352142 TI - Effector kinase coupling enables high-throughput screens for direct HIV-1 Nef antagonists with antiretroviral activity. AB - HIV-1 Nef, a critical AIDS progression factor, represents an important target protein for antiretroviral drug discovery. Because Nef lacks intrinsic enzymatic activity, we developed an assay that couples Nef to the activation of Hck, a Src family member and Nef effector protein. Using this assay, we screened a large, diverse chemical library and identified small molecules that block Nef-dependent Hck activity with low micromolar potency. Of these, a diphenylpyrazolo compound demonstrated submicromolar potency in HIV-1 replication assays against a broad range of primary Nef variants. This compound binds directly to Nef via a pocket formed by the Nef dimerization interface and disrupts Nef dimerization in cells. Coupling of nonenzymatic viral accessory factors to host cell effector proteins amenable to high-throughput screening may represent a general strategy for the discovery of new antimicrobial agents. PMID- 23352143 TI - Engineering the substrate specificity of the DhbE adenylation domain by yeast cell surface display. AB - The adenylation (A) domains of nonribosomal peptide synthetases (NRPSs) activate aryl acids or amino acids to launch their transfer through the NRPS assembly line for the biosynthesis of many medicinally important natural products. In order to expand the substrate pool of NRPSs, we developed a method based on yeast cell surface display to engineer the substrate specificities of the A-domains. We acquired A-domain mutants of DhbE that have 11- and 6-fold increases in k(cat)/K(m) with nonnative substrates 3-hydroxybenzoic acid and 2-aminobenzoic acid, respectively and corresponding 3- and 33-fold decreases in k(cat)/K(m) values with the native substrate 2,3-dihydroxybenzoic acid, resulting in a dramatic switch in substrate specificity of up to 200-fold. Our study demonstrates that yeast display can be used as a high throughput selection platform to reprogram the "nonribosomal code" of A-domains. PMID- 23352144 TI - Biofilm inhibitors that target amyloid proteins. AB - Bacteria establish stable communities, known as biofilms, that are resistant to antimicrobials. Biofilm robustness is due to the presence of an extracellular matrix, which for several species-among them Bacillus subtilis-includes amyloid like protein fibers. In this work, we show that B. subtilis biofilms can be a simple and reliable tool for screening of molecules with antiamyloid activity. We identified two molecules, AA-861 and parthenolide, which efficiently inhibited biofilms by preventing the formation of amyloid-like fibers. Parthenolide also disrupted pre-established biofilms. These molecules also impeded the formation of biofilms of other bacterial species that secrete amyloid proteins, such as Bacillus cereus and Escherichia coli. Furthermore, the identified molecules decreased the conversion of the yeast protein New1 to the prion state in a heterologous host, indicating the broad range of activity of the molecules. PMID- 23352145 TI - Heterologous expression and engineering studies of labyrinthopeptins, class III lantibiotics from Actinomadura namibiensis. AB - Labyrinthopeptins are class III lantibiotics produced by the actinomycete Actinomadura namibiensis. The most characteristic structural feature is the posttranslationally installed triamino triacid labionin with a quaternary alpha carbon. In addition to the unique structure, labyrinthopeptin A2 possess remarkable antiviral and antiallodynic biological activities. To harness the substrate tolerance of the biosynthetic machinery, we developed an efficient system for the generation of labyrinthopeptin analogs. Streptomyces lividans was used as a heterologous host since the natural producer Actinomadura namibiensis remained genetically intractable. Generation of a library of 39 mutants allowed identification of variable and invariable regions in the labyrinthopeptin structures. Additional data on the flexibility of the biosynthetic machinery were provided by in vitro experiments. This study is detailed investigation on the potential to generate analogs of class III lantibiotics by genetic engineering. PMID- 23352147 TI - Preparation and characterization of anti-algal sustained-release granules and their inhibitory effects on algae. AB - The objectives of this work were to prepare and characterize an anti-algal sustained-release granule, then study its mode of action on Microcystis aeruginosa. The anti-algal sustained-release granule was prepared with artemisinin using alginate-chitosan microcapsule technology and characterized by a high performance liquid chromatography with an evaporative light-scattering detector, Fourier transform infrared spectral analysis, and a scanning electron microscope. The optimum preparation (in %, w/v) using the orthogonal method was: 2.5 sodium alginate; 0.25 chloride; 0.6 artemisinin; 2 calcium chloride; and 1.5 mL of the cross-linking agent, glutaraldehyde. These artemisinin sustained release granules had a high encapsulation efficiency (up to 68%) and good release properties (release time of more than 40 d). Artemisinin sustained-release granules released cumulatively in a solution containing M. aeruginosa, and the stress on algae increased gradually within 30 d. Artemisinin sustained-release granules decreased the content of the soluble protein, Chlorophyll a in 30 d, increased the superoxide dismutase activity of M. aeruginosa, but exerted no effect on the soluble sugar content. Compared to direct dosing of artemisinin, algae can be inhibited longer and more effectively by the artemisinin sustained release granules. The results of our research can aid in the development of new anti-algal sustained-release granules and lead to further study of their application in the field. PMID- 23352146 TI - Identification of widespread adenosine nucleotide binding in Mycobacterium tuberculosis. AB - Computational prediction of protein function is frequently error-prone and incomplete. In Mycobacterium tuberculosis (Mtb), ~25% of all genes have no predicted function and are annotated as hypothetical proteins, severely limiting our understanding of Mtb pathogenicity. Here, we utilize a high-throughput quantitative activity-based protein profiling (ABPP) platform to probe, annotate, and validate ATP-binding proteins in Mtb. We experimentally validate prior in silico predictions of >240 proteins and identify 72 hypothetical proteins as ATP binders. ATP interacts with proteins with diverse and unrelated sequences, providing an expanded view of adenosine nucleotide binding in Mtb. Several hypothetical ATP binders are essential or taxonomically limited, suggesting specialized functions in mycobacterial physiology and pathogenicity. PMID- 23352148 TI - Copper complexing properties of exudates and metabolites of macroalgae from the Aegean Sea. AB - Macroalgae are a significant source of extracellular organic material in the coastal areas of the Mediterranean, including organic ligands which serve as modulators of metal complexing capacity. This paper examines the release of copper-complexing ligands by 24 macroalgal species, including chlorophyta, rhodophyta, ochrophyta as well as Posidonia oceanica, common throughout the Mediterranean. Metabolites isolated from the algae Dictyota dichotoma and Pterocladiella capillacea were examined for the first time regarding their Cu complexing properties. The concentration of ligands (LT) and the copper-binding strength (logKapp) of exudates and metabolites were determined by electrochemical methods. All algal species released ligands giving LT concentrations ranging from 109 to 744 nM in unfiltered samples. An increase in the concentration of ligands up to 15 times in comparison to the blank was observed after 48 h of culturing macroalgae in artificial seawater. The binding strength (log Kapp) varied among species from 7.0 to 8.6, except for the metabolites for which it was lower (log Kapp=6). Most of the ligands released were in the dissolved phase, with the contribution of particulate and/or colloidal organic matter (up to 46% of total ligands) appearing to be important only in specific macroalgal species. PMID- 23352149 TI - Distal biceps and triceps ruptures. AB - Biceps and triceps tendon ruptures are rather uncommon injuries and are most commonly diagnosed clinically. Magnetic resonance imaging can help the clinician to differentiate an incomplete tear and define any degeneration of the tendon. Surgical anatomical repair is typically performed in acute complete ruptures whereas nonoperative treatment can be used for partial ruptures, as well as for patients unfit for surgery. Single incision techniques are associated with a higher rate of nerve injuries, while double incision repairs have a higher prevalence of heterotopic ossification. Although various fixation methods have been applied including bone tunnels, interference screws, suture anchors, cortical button fixation, the current evidence does not support the superiority of one method over the other. A well-planned postoperative rehabilitation programme is essential for a good final outcome. As better fixation devices are being used, more aggressive rehabilitation programmes have been applied. Epidemiology, clinical evaluation, diagnosis, surgical and conservative management of these injuries are presented in this review along with the authors' preferred technique for the anatomical repair of acute complete ruptures. PMID- 23352150 TI - Technical considerations in microsurgical treatment of paediatric hand injuries. AB - Microsurgical techniques are vital for the treatment of many aspects of trauma in the child, both in initial management and later reconstructive surgery. The basic principles of microsurgery pertain to all patients, but there are nuances of technique and of the psycho-social and peri-operative aspects of treatment which are particularly important in the child. It is these distinctions that are examined in this paper. PMID- 23352151 TI - Clinical and translational aspects of hypothermia in major trauma patients: from pathophysiology to prevention, prognosis and potential preservation. AB - The human body strives at maintaining homeostasis within fairly tight regulated mechanisms that control vital regulators such as core body temperature, mechanisms of metabolism and endocrine function. While a wide range of medical conditions can influence thermoregulation the most common source of temperature loss in trauma patients includes: exposure (environmental, as well as cavitary), the administration of i.v. fluids, and anaesthesia/loss of shivering mechanisms, and blood loss per se. Loss of temperature can be classified either according to the aetiology (i.e. accidental/spontaneous versus trauma/haemorrhage-induced temperature loss), or according to an unintended, accidental induction in contrast to a medically intended therapeutic hypothermia. Hypothermia occurs infrequently (prevalence<10% of all injured), but more often (30-50%) in the severely injured. Hypothermia usually come together with and may aggravate acidosis and coagulopathy (the "lethal triad of trauma"), which again may be associated with a high mortality. However, recent studies disagree in the independent predictive role of hypothermia and mortality. Prevention of hypothermia is imperative through all phases of trauma care and must be an interest among all team members. Hypothermia in the trauma setting has attracted focus in the past from a pathophysiological, preventive and prognostic perspective; yet recent focus has shifted towards the potential for using hypothermia for pre-emptive and cellular protective purposes. This paper gives a brief update on some of the clinically relevant aspects of hypothermia in the injured patient. PMID- 23352152 TI - Microsurgical reconstruction of soft-tissue defects in digits. AB - Injuries that cause soft tissue defects could threaten the function and viability of the involved digit. Reconstruction of such defects can be challenging and requires careful consideration in restoring both the aesthetic and functional deficit. The purpose of this review is to describe appropriate reconstructive technique using various free tissue transfers. According to the location and the size of a defect, a proper reconstructive option is indicated. Owing to the specialized mechano-sensory property of its volar soft tissue, fingertip injury, when significant defects exist, are reconstructed using specialized free flaps with appropriate histological and functional similarities. Composite tissue including bone may be required in selected cases. Additional procedures, such as secondary skin graft or division of the flap, should be done after several weeks of the first operation. Refinements and improvements in free tissue transfer allow an expanse of reconstructive options for soft tissue defect in the digit. PMID- 23352153 TI - Approach to radial nerve palsy caused by humerus shaft fracture: is primary exploration necessary? AB - INTRODUCTION: While recommendations for early exploration and nerve repair in cases of open fractures of the humeral shaft associated with radial nerve palsy are clear, the therapeutic algorithm for the management of closed humeral shaft fractures complicated by radial nerve palsy is still uncertain. The purpose of this study was to determine whether patients with complete sensory and motor radial nerve palsy following a closed fracture of the humeral shaft should be surgically explored. PATIENTS AND METHODS: Twenty-five patients with closed humeral shaft fractures complicated by complete radial nerve palsy were retrospectively reviewed during a 12-year period. Surgical intervention was indicated if functional recovery of the radial nerve was not present after 16 weeks of expectant management. RESULTS: Surgical exploration was performed in 12 patients (48%) after a mean period of expectant management of 16.8 weeks (range: 16-18 weeks). In 2 of them (10%) total nerve transection was found. In the rest 10 patients underwent surgical exploration the radial nerve was found to be macroscopically intact. All intact nerves were fully recovered after a mean time of 21.6 weeks (range: 20-24 weeks) post-injury. In 13 patients (52%) in whom surgical exploration was not performed the mean time to full nerve recovery was 12 weeks (range: 7-14 weeks) post-injury. CONCLUSIONS: We proposed immediate exploration of the radial nerve in case of open fractures of the humeral shaft, irreducible fractures or unacceptable reduction, associated vascular injuries, radial nerve palsy after manipulation or intractable neurogenic pain. Due to high rate of spontaneous recovery of the radial nerve after closed humeral shaft fractures we recommend 16-18 weeks of expectant management followed by surgical intervention. PMID- 23352154 TI - How useful is carcinoembryonic antigen in detecting colorectal malignancy? PMID- 23352155 TI - Rare inherited variation in autism: beginning to see the forest and a few trees. AB - In this issue of Neuron, two papers (Lim et al., 2013; Yu et al., 2013) use whole exome sequencing (WES) to elucidate the contribution of inherited variation to the risk for autism by leveraging the increased penetrance of homozygous and compound heterozygous rare variants in autosomes and hemizygous rare variants in the X chromosome of males. Together, they expand our knowledge about the genetic architecture of ASD, verify previously identified genes, and identify novel mutations that will guide the discovery of the critical biological processes disrupted in autism. PMID- 23352156 TI - Fragile X syndrome therapeutics: translation, meet translational medicine. AB - Fragile X syndrome, a common cause of intellectual disability and autism, is thought to occur due to abnormal regulation of neuronal protein synthesis. A study by Osterweil et al. (2013), in this issue, demonstrates that the HMG-CoA reductase inhibitor lovastatin can normalize protein synthesis and also reduce audiogenic seizures in Fmr1 knockout mice. PMID- 23352157 TI - Common principles of voltage-dependent gating for Hv and Kv channels. AB - Voltage-activated proton (Hv1) channels are relatives of classical voltage activated cation channels. In this issue of Neuron, Hong et al. (2013) and Qiu et al. (2013) investigate the functional mechanisms of Hv1 gating and uncover key relationships with Kv channels. PMID- 23352158 TI - Volitional control of cortical oscillations and synchrony. AB - Oscillatory activity in motor cortex has been observed in many experimental contexts, leading to various hypotheses about its possible behavioral function. In this issue of Neuron, Engelhard et al. (2013) report that oscillations can be volitionally controlled, opening new directions to explore their function and underlying mechanisms. PMID- 23352159 TI - Vulnerable neural systems and the borderland of brain aging and neurodegeneration. AB - Brain aging is characterized by considerable heterogeneity, including varying degrees of dysfunction in specific brain systems, notably a medial temporal lobe memory system and a frontostriatal executive system. These same systems are also affected by neurodegenerative diseases. Recent work using techniques for presymptomatic detection of disease in cognitively normal older people has shown that some of the late life alterations in cognition, neural structure, and function attributed to aging probably reflect early neurodegeneration. However, it has become clear that these same brain systems are also vulnerable to aging in the absence of even subtle disease. Thus, fundamental systemic limitations appear to confer vulnerability of these neural systems to a variety of insults, including those recognized as typical disease and those that are attributed to age. By focusing on the fundamental causes of neural system vulnerability, the prevention or treatment of a wide range of late-life neural dysfunction might be possible. PMID- 23352161 TI - Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. AB - Many neuropsychiatric symptoms of fragile X syndrome (FXS) are believed to be a consequence of altered regulation of protein synthesis at synapses. We discovered that lovastatin, a drug that is widely prescribed for the treatment of high cholesterol, can correct excess hippocampal protein synthesis in the mouse model of FXS and can prevent one of the robust functional consequences of increased protein synthesis in FXS, epileptogenesis. These data suggest that lovastatin is potentially disease modifying and could be a viable prophylactic treatment for epileptogenesis in FXS. PMID- 23352160 TI - Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. AB - To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (<= 5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD. PMID- 23352162 TI - Risk-responsive orbitofrontal neurons track acquired salience. AB - Decision making is impacted by uncertainty and risk (i.e., variance). Activity in the orbitofrontal cortex, an area implicated in decision making, covaries with these quantities. However, this activity could reflect the heightened salience of situations in which multiple outcomes-reward and reward omission-are expected. To resolve these accounts, rats were trained to respond to cues predicting 100%, 67%, 33%, or 0% reward. Consistent with prior reports, some orbitofrontal neurons fired differently in anticipation of uncertain (33% and 67%) versus certain (100% and 0%) reward. However, over 90% of these neurons also fired differently prior to 100% versus 0% reward (or baseline) or prior to 33% versus 67% reward. These responses are inconsistent with risk but fit well with the representation of acquired salience linked to the sum of cue-outcome and cue-no-outcome associative strengths. These results expand our understanding of how the orbitofrontal cortex might regulate learning and behavior. PMID- 23352164 TI - Voltage-sensing domain of voltage-gated proton channel Hv1 shares mechanism of block with pore domains. AB - Voltage-gated sodium, potassium, and calcium channels are made of a pore domain (PD) controlled by four voltage-sensing domains (VSDs). The PD contains the ion permeation pathway and the activation gate located on the intracellular side of the membrane. A large number of small molecules are known to inhibit the PD by acting as open channel blockers. The voltage-gated proton channel Hv1 is made of two VSDs and lacks the PD. The location of the activation gate in the VSD is unknown and open channel blockers for VSDs have not yet been identified. Here, we describe a class of small molecules which act as open channel blockers on the Hv1 VSD and find that a highly conserved phenylalanine in the charge transfer center of the VSD plays a key role in blocker binding. We then use one of the blockers to show that Hv1 contains two intracellular and allosterically coupled gates. PMID- 23352163 TI - Using whole-exome sequencing to identify inherited causes of autism. AB - Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs. PMID- 23352165 TI - Subunit interactions during cooperative opening of voltage-gated proton channels. AB - Voltage-gated proton (Hv1) channels are dimers, where each subunit has a separate permeation pathway. However, opening of the two pathways is highly cooperative. It is unclear how Hv1 channels open their permeation pathways, because Hv1 channels lack a classic pore domain. Using voltage-clamp fluorometry, we here detect two conformational changes reported by a fluorophore attached to the voltage sensor S4 in Hv1 channels. The first is voltage dependent and precedes channel opening, with properties consistent with reporting on independent S4 charge movements in the two subunits. The second is less voltage dependent and closely correlates with channel opening. Mutations that reduce dimerization or alter the intersubunit interface affect both the second conformational change and channel opening. These observations suggest that, following an initial S4 charge movement in the two subunits, there is a second, cooperative conformational change, involving interactions between subunits, that opens both pathways in Hv1 channels. PMID- 23352166 TI - Multiple interactions control synaptic layer specificity in the Drosophila visual system. AB - How neurons form synapses within specific layers remains poorly understood. In the Drosophila medulla, neurons target to discrete layers in a precise fashion. Here we demonstrate that the targeting of L3 neurons to a specific layer occurs in two steps. Initially, L3 growth cones project to a common domain in the outer medulla, overlapping with the growth cones of other neurons destined for a different layer through the redundant functions of N-Cadherin (CadN) and Semaphorin-1a (Sema-1a). CadN mediates adhesion within the domain and Sema-1a mediates repulsion through Plexin A (PlexA) expressed in an adjacent region. Subsequently, L3 growth cones segregate from the domain into their target layer in part through Sema-1a/PlexA-dependent remodeling. Together, our results and recent studies argue that the early medulla is organized into common domains, comprising processes bound for different layers, and that discrete layers later emerge through successive interactions between processes within domains and developing layers. PMID- 23352167 TI - Neurexin regulates visual function via mediating retinoid transport to promote rhodopsin maturation. AB - Neurexins are cell adhesion molecules involved in synapse formation and synaptic regulation. Mutations in the neurexin genes are linked to a number of neurodevelopmental disorders such as autism. Here, we show that the Drosophila homolog of alpha-Neurexin is critical for fly visual function. Lack of Neurexin leads to significantly impaired visual function due to reduced rhodopsin levels. We show that the decreased chromophore levels cause deficits in rhodopsin maturation and that Neurexin is required for retinoid transport. Using yeast two hybrid screening, we identify that Neurexin interacts with apolipoprotein I (ApoL I), a product generated by cleavage of retinoid- and fatty acid-binding glycoprotein (RFABG) that functions in retinoid transport. Finally, we demonstrate that Neurexin is essential for the apolipoproteins level. Our results reveal a role for Neurexin in mediating retinoid transport and subsequent rhodopsin maturation and suggest that Neurexin regulates lipoprotein function. PMID- 23352168 TI - Synaptic vesicles position complexin to block spontaneous fusion. AB - Synapses continually replenish their synaptic vesicle (SV) pools while suppressing spontaneous fusion events, thus maintaining a high dynamic range in response to physiological stimuli. The presynaptic protein complexin can both promote and inhibit fusion through interactions between its alpha-helical domain and the SNARE complex. In addition, complexin's C-terminal half is required for the inhibition of spontaneous fusion in worm, fly, and mouse, although the molecular mechanism remains unexplained. We show here that complexin's C-terminal domain binds lipids through a novel protein motif, permitting complexin to inhibit spontaneous exocytosis in vivo by targeting complexin to SVs. We propose that the SV pool serves as a platform to sequester and position complexin where it can intercept the rapidly assembling SNAREs and control the rate of spontaneous fusion. PMID- 23352169 TI - Social deprivation enhances VTA synaptic plasticity and drug-induced contextual learning. AB - Drug addiction is driven, in part, by powerful drug-related memories. Deficits in social life, particularly during adolescence, increase addiction vulnerability. Social isolation in rodents has been used extensively to model the effects of deficient social experience, yet its impact on learning and memory processes underlying addiction remains elusive. Here, we show that social isolation of rats during a critical period of adolescence (postnatal days 21-42) enhances long-term potentiation of NMDA receptor (NMDAR)-mediated glutamatergic transmission in the ventral tegmental area (VTA). This enhancement, which is caused by an increase in metabotropic glutamate receptor-dependent Ca(2+) signaling, cannot be reversed by subsequent resocialization. Notably, memories of amphetamine- and ethanol-paired contextual stimuli are acquired faster and, once acquired, amphetamine-associated contextual memory is more resistant to extinction in socially isolated rats. We propose that NMDAR plasticity in the VTA may represent a neural substrate by which early life deficits in social experience increase addiction vulnerability. PMID- 23352171 TI - Inducing gamma oscillations and precise spike synchrony by operant conditioning via brain-machine interface. AB - Neural oscillations in the low-gamma range (30-50 Hz) have been implicated in neuronal synchrony, computation, behavior, and cognition. Abnormal low-gamma activity, hypothesized to reflect impaired synchronization, has been evidenced in several brain disorders. Thus, understanding the relations between gamma oscillations, neuronal synchrony and behavior is a major research challenge. We used a brain-machine interface (BMI) to train monkeys to specifically increase low-gamma power in selected sites of motor cortex to move a cursor and obtain a reward. The monkeys learned to robustly generate oscillatory gamma waves, which were accompanied by a dramatic increase of spiking synchrony of highly precise spatiotemporal patterns. The findings link volitional control of LFP oscillations, neuronal synchrony, and the behavioral outcome. Subjects' ability to directly modulate specific patterns of neuronal synchrony provides a powerful approach for understanding neuronal processing in relation to behavior and for the use of BMIs in a clinical setting. PMID- 23352170 TI - New modules are added to vibrissal premotor circuitry with the emergence of exploratory whisking. AB - Rodents begin to use bilaterally coordinated, rhythmic sweeping of their vibrissae ("whisking") for environmental exploration around 2 weeks after birth. Whether (and how) the vibrissal control circuitry changes after birth is unknown, and the relevant premotor circuitry remains poorly characterized. Using a modified rabies virus transsynaptic tracing strategy, we labeled neurons synapsing directly onto vibrissa facial motor neurons (vFMNs). Sources of potential excitatory, inhibitory, and modulatory vFMN premotor neurons, and differences between the premotor circuitry for vFMNs innervating intrinsic versus extrinsic vibrissal muscles were systematically characterized. The emergence of whisking is accompanied by the addition of new sets of bilateral excitatory inputs to vFMNs from neurons in the lateral paragigantocellularis (LPGi). Furthermore, descending axons from the motor cortex directly innervate LPGi premotor neurons. Thus, neural modules that are well suited to facilitate the bilateral coordination and cortical control of whisking are added to the premotor circuitry in parallel with the emergence of this exploratory behavior. PMID- 23352172 TI - Inhibition of cell death of bone marrow-derived macrophages infected with Ehrlichia muris. AB - Ehrlichia muris is a Gram-negative obligate intracellular bacterium belonging to the family Anaplasmataceae. It preferentially replicates inside macrophages by utilizing nutrients and processes of the host cell. In the present article, we studied the effects of E. muris infection on cell death of bone marrow-derived macrophages (BMDMs). Primary BMDMs were used for accessing E. muris-induced cell death, pro-inflammatory cytokine production and Western blot analysis. Human embryonic kidney cell line 293T (HEK293T) was used to access nuclear factor kappaB (NF-kappaB) activity. BMDMs infected with E. muris showed significant inhibition of cell death when compared to uninfected cells. E. muris infection resulted in IkappaBalpha degradation, thus activation of NF-kappaB. In NF-kappaB reporter gene assay, the HEK293T cells infected with E. muris exhibited robust NF kappaB-dependent luciferase activity in a bacterial dose-dependent manner. Furthermore, E. muris-induced inhibition of BMDMs cell death was abolished in the presence of MG132, a proteasome inhibitor that blocks NF-kappaB activation. Taken together, the results suggest that E. muris infection of BMDMs may have an inhibitory effect on cell death via a mechanism dependent on NF-kappaB activation. PMID- 23352173 TI - First report of Amblyomma helvolum (Acari: Ixodidae) from the Taiwan stink snake, Elaphe carinata (Reptilia: Colubridae), collected in southern Taiwan. AB - A Taiwan stink snake (Elaphe carinata) was captured in shrubbery at a fruit farm in southern Taiwan, and 3 female ticks (2 flat, one fully engorged) observed on this snake were collected and identified as Amblyomma helvolum, the first record of this host association in mainland Taiwan. The key morphological characters of female A. helvolum were photographed using a stereomicroscope. This first report of A. helvolum feeding on a reptilian host in Taiwan includes the first color illustrations of adult A. helvolum ever published. The increased international trade in wild reptiles may contribute to accidental transportation of ticks into Taiwan. The host range and vector capacity of A. helvolum for various tick-borne pathogens need to be further clarified. PMID- 23352174 TI - Short-term preoperative supplementation of an immunoenriched diet does not improve clinical outcome in well-nourished patients undergoing abdominal cancer surgery. AB - OBJECTIVE: A recent study suggested that the anti-inflammatory effect of immunonutrition starts after only two d. We therefore investigated the effect of an immunoenriched oral diet administered for three d preoperatively. METHODS: In this prospective, randomized, double-blind, placebo-controlled study, well nourished patients (Nutrition Risk Screening 2002 <3) with gastrointestinal cancer who were scheduled for major elective abdominal cancer surgery were randomly assigned to either 750 mL of an immunoenriched formula (IEF group) or 750 mL of an isocaloric, isonitrogenous placebo diet (Con group) for 3 consecutive d preoperatively. RESULTS: A total of 108 patients (IEF group: n = 55; Con group: n = 53) were randomized. The two groups were comparable for all baseline and surgical characteristics. The overall mortality was 2.8% and not significantly different between the two groups (IEF group: 3.6% vs. Con group: 1.9%, P = 1.00). Intention-to-treat analysis showed no difference for the incidence of postoperative overall (IEF group: 29% vs. Con group: 30%; P = 1.00) and infectious (IEF group: 15% vs. Con group: 17%; P = 0.79) complications. Length of hospital stay was 12 +/- 4.9 d in the IEF group and 11.6 +/- 5.3 d in the Con group (P = 0.68). CONCLUSIONS: Preoperative oral supplementation with an immunoenriched diet for 3 d preoperatively did not improve postoperative outcome compared with the placebo in well-nourished patients with elective gastrointestinal cancer surgery. PMID- 23352175 TI - Iron deficiency is associated with increased risk for cardiovascular disease and all-cause mortality in the elderly living in long-term care facilities. AB - OBJECTIVE: The association between serum iron status, cardiovascular disease (CVD), and all-cause mortality remains controversial in the elderly. In the present study, we aim to determine the relevance of serum iron level on the incidences of CVD and all-cause mortality in an elderly population. METHODS: A baseline cohort of 336 participants, aged >=65 y, was recruited from eight long term care facilities between 2002 and 2003. The degree of iron deficiency was defined based on the serum iron level (mild: 40 mg/dL <=serum iron <60 mg/dL; severe: serum iron <40 mg/dL). Cox proportional hazard regression analyses were adopted to evaluate the relative risks (RRs) of CVD and all-cause death. Taiwan's Department of Health provided the mortality data. RESULTS: There were 210 deaths during a 5-y follow-up period, 62 of which were due to CVD. The prevalence of iron deficiency among the subjects was 50.3%. Age, sex, body mass index, waist circumference, mean arterial pressure, performance status, lifestyle factors, blood glucose, hemoglobin, lipid, albumin, and high sensitivity C-reactive protein levels were adjusted to compare the RRs of the subjects. The RRs (95% confidence interval) of CVD and all-cause mortality among mildly iron-deficient subjects were 1.08 (0.51-2.29) and 1.63 (1.14-2.31), respectively, and 2.77 (1.28 5.99) and 1.96 (1.26-3.04), respectively, among severely iron-deficient subjects. The severity of iron deficiency was positively associated with CVD and all-cause mortality. CONCLUSIONS: These results suggest that iron deficiency is independently associated with CVD and all-cause mortality in elderly Taiwanese living in long-term care facilities. PMID- 23352176 TI - Wheat germ oil: a potential facilitator to improve lutein bioavailability in mice. AB - OBJECTIVE: The aim of this study is to determine the effect of wheat germ oil (WGO) compared with groundnut oil (GNO) and mixed micelles (control) on lutein bioavailability and bioactivity in mice. The choice of carrier lipid is critical to achieve an enhanced bioavailability of lutein. METHODS: Mice were intubated with single and repeated doses (2 wk) of lutein solubilized in WGO, GNO, or control mixed micelles to study lutein bioavailability, as well as changes in the lipase activity, antioxidant enzymes, lipid peroxidation, and fatty-acid profile. RESULTS: Single-dose (nmol/8 h/mL) and repeated-dose (MUg/dL) studies revealed that plasma lutein levels were higher (P > 0.05) in the WGO (88.4 +/- 6, 3.2 +/- 1) and GNO (23.36 +/- 4, 4.7 +/- 0.5) groups than in the control (12.4 +/- 1, 2.6 +/- 0.6) group. Liver and eye lutein levels in WGO (41% and 53%, respectively) and GNO (6% and 41%, respectively) groups also were found to be higher than the control group. However, the dietary lutein response in plasma and tissues was more pronounced in the WGO group than the GNO group. The decrease in plasma malondialdehyde (MDA) levels in the WGO (41%) and GNO (26.4%) groups compared with the control group indicates the higher bioavailability and bioactivity of absorbed lutein. CONCLUSION: The increased lutein bioavailability in the WGO group compared with the other two groups may be attributed to the polar lipids and intestinal lipase activity found in this study. The results imply a new insight into the application of WGO for improving lutein bioavailability. PMID- 23352177 TI - High-fat diets rich in omega-3 or omega-6 polyunsaturated fatty acids have distinct effects on lipid profiles and lipid peroxidation in mice selected for either high body weight or leanness. AB - OBJECTIVE: The aim of the study is to determine the response of muscle lipid peroxidation and the fatty-acid profile of three groups of mice-high body weight (DU6) obesity-prone mice, high treadmill performance (DUhTP) lean mice, and unselected control mice (DUK) fed high-fat diets (HFDs) rich in omega-3 or omega 6 polyunsaturated fatty acids (PUFA). METHODS: The isocaloric HFDs were enriched with either omega-3 PUFA (27% fish oil, omega-3 HFD) or omega-6 PUFA (27% sunflower oil, omega-6 HFD), and the control group was fed standard chow (7.2% fat). Statistical calculations were done with procedure GLM of SAS. RESULTS: As expected, the omega-3 and omega-6 PUFA-rich HFDs showed significant effects on fatty-acid concentrations of skeletal muscle in all three lines of mice compared with the standard chow. The investigations of muscle lipid peroxidation revealed that the omega-3 PUFA-rich HFD caused the highest lipid peroxidation values in muscle of lean DUhTP mice and unselected control DUK mice. However, lower lipid peroxidation levels were observed in the obesity-prone DU6 mice. In contrast, the omega-6 PUFA-rich HFD did not influence lipid peroxidation in muscle of any of the different lines of mice. The present study suggests that a higher overall antioxidant capacity in the muscle tissue of obesity-prone DU6 mice may lead to lower levels of reactive oxygen species formation by omega-3 PUFA-rich HFDs in comparison with lean DUhTP mice. CONCLUSION: These studies raise the possibility that obesity per se may be protective against oxidative damage when high omega-3 PUFA diets are used. PMID- 23352178 TI - Effects of cigarette smoking on priapism induced by quetiapine: a case report. AB - Priapism is defined as an unwanted, prolonged, and painful erection which is unrelated to sexual stimulation. Some case studies suggest that priapism is an adverse effect of antipsychotic medications. In our case study a 30 year-old Iranian male with schizophrenia was experiencing recurrent priapism associated with quetiapine use. There are three interesting facts about this case: Firstly, the patient suffered priapism after even low dose consumption of quetiapine. Secondly, this case had experienced priapism with risperidone, olanzapine, and even clozapine in the past, suggesting a possible pharmacodynamic interaction of antipsychotics and inner biological traits in this particular case. Thirdly, priapism induced by low dose quetiapine was resolved after cigarette smoking. PMID- 23352179 TI - Symmetry of trunk and femoro-pelvic movement responses to single leg loading tests in asymptomatic females. AB - Single leg loading tests are used clinically to examine balance and loading strategies in individuals with lower limb pain. Interpretation of these tests is through pain responses and comparisons with the asymptomatic leg. The purpose of this study was to examine normal differences in trunk and pelvic movement between legs during the single leg stand, single leg squat, hip hitch and hip drop tests, and to compare observational and quantitative assessments of trunk movement during the single leg squat test. Thirty-one asymptomatic females (age = 21.7 +/- 3.1 years) performed each test in a random sequence and quantitative analysis of coronal plane trunk lean (magnitude and direction), and femoro-pelvic angle was conducted using photographic image analysis. Within- and between-side minimal significant differences (MD) for femoro-pelvic angle were defined for each test. All tests had excellent within-side reliability (intra-class correlation coefficients (ICC) = 0.87-0.97, standard error of measurement (SEM) = 0.6-1.2 degrees ). The between-side MD for femoro-pelvic angle was 6.3, 6.5, 9.7, and 6.7 degrees for the single leg stand, single leg squat, hip hitch and hip drop tests respectively. The magnitude of trunk lean was small, increased with test complexity and was not consistent in relation to the stance leg. Excellent agreement (87-93%) for the direction of trunk movement between observers, and between observational and quantitative analysis (80-96%) was established for the single leg squat test. The patterns of trunk motion, and thresholds for significant difference in femoro-pelvic angle established in this study, will assist the interpretation of single leg loading tests in individuals with lower limb pain disorders. PMID- 23352180 TI - The effectiveness of Long's manipulation on patients with chronic mechanical neck pain: a randomized controlled trial. AB - Long's manipulation (LM) is a representative Chinese manipulation approach incorporating both spinal manipulation and traditional Chinese massage (TCM) techniques. This randomized controlled trial (RCT) aimed to compare the immediate and short-term relative effectiveness of LM to TCM on patients with chronic neck pain. Patients were randomly assigned to either LM group or TCM group. LM group was treated with Long's manipulation, while the TCM group received TCM therapy. Patients attended 8 sessions of treatment (one session every three days). Outcome measures included neck disability (Northwick Park Neck Pain Questionnaire; NPQ), pain intensity (Numeric Pain Rating Scale; NPRS), patient perceived satisfaction of care (PPS) (11-point scale), craniovertebral angle (CV angle) and cervical range of motion (ROM). A blinded assessor performed assessment at baseline, immediate after treatment and 3 months post treatment. LM group achieved significantly greater improvement than TCM group in pain intensity (p < 0.001), neck disability (p = 0.049) and satisfaction (p < 0.001) up to 3-month follow-up. There was no significant difference in improvements in CV angle and most of cervical ROM between groups (p = 0.169 ~ 0.888) with an exception of flexion at 3 month follow-up (p = 0.005). This study shows that LM could produce better effects than TCM in relieving pain and improving disability in the management of patients with chronic mechanical neck pain. PMID- 23352181 TI - The use of Biobrane(r) as a delivery method for cultured epithelial autograft in burn patients. AB - BACKGROUND: Cultured epithelial autografts (CEA) are well described in the literature and are advantageous when dealing with major burns. There have been many methods of CEA application described, however they all have their own difficulties. Here we describe a novel technique of culturing the keratinocytes in Biobrane((r)). METHODS: Skin samples were taken from three patients and cultured into pre-confluent keratinocytes. These were seeded in Biobrane((r)) and applied directly to the patients' wounds. RESULTS: Three patients had Biobrane((r)) with seeded keratinocytes applied. The Biobrane was applied to both donor and burn wound sites, with healing times being similar to the keratinocyte sheets. CONCLUSION: The experience of the authors shows that using Biobrane((r)) seeded with keratinocytes was easier to handle and quicker to produce than confluent sheets of keratinocytes, with no perceived disadvantages to the patients. PMID- 23352182 TI - Age-related degenerative functional, radiographic, and histological changes of the shoulder in nonhuman primates. AB - BACKGROUND: Nonhuman primates have similar shoulder anatomy and physiology compared to humans, and may represent a previously underutilized model for shoulder research. This study sought to identify naturally occurring bony and muscular degeneration in the shoulder of nonhuman primates and to assess relationships between structural and functional aspects of the shoulder and measures of physical function of the animals. We hypothesized that age-related degenerative changes in the shoulders of nonhuman primates would resemble those observed in aging humans. METHODS: Middle-aged (n = 5; ages 9.4-11.8 years) and elderly (n = 6; ages 19.8-26.4 years) female vervet monkeys were studied for changes in mobility and shoulder function, and radiographic and histologic signs of age-related degeneration. RESULTS: Four out of 6 (4/6) elderly animals had degenerative changes of the glenoid compared to 0/5 of the middle-aged animals (P = .005). Elderly animals had glenoid retroversion, decreased joint space, walked slower, and spent less time climbing and hanging than middle-aged vervets (P < .05). Physical mobility and shoulder function correlated with glenoid version angle (P < .05). Supraspinatus muscles of elderly animals were less dense (P = .001), had decreased fiber cross-sectional area (P < .001), but similar amounts of nuclear material (P = .085). Degenerative rotator cuff tears were not observed in any of the eleven animals. DISCUSSION AND CONCLUSION: The vervet monkey naturally undergoes age-related functional, radiographic and histological changes of the shoulder, and may qualify as an animal model for selected translational research of shoulder osteoarthritis. PMID- 23352183 TI - Optimal shoulder immobilization postures following surgical repair of rotator cuff tears: a simulation analysis. AB - BACKGROUND: There is a high incidence of retear following surgical repair of rotator cuff tears. Postoperative shoulder immobilization is commonly prescribed to protect the repair; but there is no consensus on the best immobilization postures. METHODS: A generic musculoskeletal model of the shoulder was used to simulate postoperative immobilization of full thickness rotator cuff tears involving the supraspinatus only and the supraspinatus concomitantly with the infraspinatus or subscapularis. Optimal immobilization postures, which simultaneously minimized the stresses in the repaired tendons and the angle of humerus elevation, were obtained. RESULTS: For isolated supraspinatus tears, elevation of the humerus in planes close to the scapular plane was suggested. When the infraspinatus was also involved, planes posterior to the scapular plane were suggested; while, if the subscapularis was also involved, planes anterior to the scapular plane and internal rotation were suggested. The required thoracohumeral elevation angles ranged from 58 degrees to 109 degrees , depending on the tear length and the muscles involved. The optimal postures reduced the stresses in the repaired tendons by between 29% and 90%. CONCLUSION: Prescription of immobilization posture for a patient should be based on the conditions of the tear repaired. Appropriate choice of immobilization posture will reduce the stress in the repair, and as such has the potential to reduce retear rates. PMID- 23352184 TI - Myotendinous lengthening of the elbow flexor muscles to improve active motion in patients with elbow spasticity following brain injury. AB - BACKGROUND: The objective of this study was to evaluate the outcomes of a novel technique of fractional myotendinous lengthening of the elbow flexors in patients with volitional motor control and spastic elbow flexion deformities after brain injury. METHODS: A retrospective review of 42 consecutive patients with spastic elbow flexion deformities and upper motor neuron (UMN) syndrome was performed. Each patient had volitional motor control but limited elbow extension and underwent myotendinous lengthening of the elbow flexor muscles. Outcome measures included pre and post-operative active and passive arc of motion, Modified Ashworth Scale (MAS) of spasticity, and complications. RESULTS: There were 26 men and 16 women. The etiologies of UMN syndrome were stroke (30 patients), traumatic brain injury (11 patients), and cerebral palsy (1 patient). Average duration between injury and surgery was 6.6 years. At an average follow-up of 14 months, improvements were noted in active extension (42 degrees to 20 degrees ; P < .001). In addition, active arc of motion increased from 77 degrees (range of motion [ROM]: 42 degrees to 119 degrees ) to 113 degrees (ROM: 20 degrees to 133 degrees ) (P < .001) and passive arc of motion increased from 103 degrees (ROM: 24 degrees -127 degrees ) to 131 degrees (ROM: 8 degrees -139 degrees ) (P < .001). Significant improvement in MAS was also noted after surgery (2.7 to 1.9; P < .001). Superficial wound dehiscence occurred in 2 patients and was successfully treated nonoperatively. CONCLUSION: In patients with spastic elbow flexion deformities and active motor control, fractional myotendinous lengthening of the elbow flexors safely improves active extension and the overall arc of motion while affording immediate postoperative elbow motion. LEVEL OF EVIDENCE: Level IV, Case Series, Treatment Study. PMID- 23352185 TI - How to assess scapular dyskinesis precisely: 3-dimensional wing computer tomography--a new diagnostic modality. AB - BACKGROUND: Aberrations in scapular motion are believed to be associated with the presence of shoulder or elbow pathologies. There are many methods to evaluate scapular kinematics, but they have certain limitations. Nevertheless, it is believed that appropriate rehabilitation for each type of scapular dyskinesis is important. METHODS: Eighty-nine athletes were videotaped and seven blinded observers categorized scapular dyskinesis into 4 types, which was followed by 3 dimensional (3D) wing computer tomography (CT). Four blinded examiners evaluated 5 angles [upward rotation (UR), internal rotation (IR), anterior tilting (AT), superior translation (ST), and protraction (PRO)] on the 3D wing CT. Inter-rater reliability (IRR) was calculated for both the methods. CT scan measurements were compared with the 4 observational types to establish the validity. RESULTS: The IRR with observational assessment of scapular dyskinesis into 4 types was good, 0.780. The 3D wing CT analysis had a very high IRR, 0.972. There was a statistically significant correlation between observational assessment and 3D wing CT analysis. The UR angle, ST angle in type 3 scapular dyskinesis, and AT angle in type 1 scapular dyskinesis were increased as compared with those in the other types of scapular dyskinesis. All these measurements were made in the resting position of the scapula. CONCLUSION: The 3D wing CT analysis allows precise quantification of a position associated with scapular dyskinesis. Therefore, 3D wing CT can be considered as an alternative method for assessing scapular dyskinesis. PMID- 23352186 TI - Risk factors in idiopathic adhesive capsulitis: a case control study. AB - BACKGROUND: The etiology of idiopathic adhesive capsulitis (IAC) of the shoulder is poorly understood. In this case control study, we examine potential risk factors for the development of IAC. METHODS: Consecutive patients who presented to the senior author with IAC between 2000 and 2009 were included retrospectively in this case control study. Complete data were available for 87 patients. An age- and sex-matched group of 176 patients who presented to the same practice during the same time period with non-shoulder related orthopedic complaints were recruited as the control group. Health records and patient-completed questionnaires were utilized to identify comorbidities and other risk factors. RESULTS: Bivariate analyses demonstrated that diabetes, hypothyroidism, a lower body weight, a lower body mass index (BMI), and a positive family history of IAC were all risk factors for IAC. Diabetes, BMI, and positive family history of IAC remained independent variables with multivariate logistic regression analyses. There was a trend towards increased incidence of Dupuytren's disease in those with IAC, but this was not statistically significant. With regard to racial predilection, being born in the British Isles or having parents/grandparents born in the British Isles were risk factors for IAC. CONCLUSION: We confirm diabetes as an independent predictor of IAC. In addition, we identify a possible racial predilection for the development of IAC. Future research is needed to confirm whether a specific genetic component or environmental factors is responsible. PMID- 23352187 TI - Clinical effectiveness of bee venom acupuncture and physiotherapy in the treatment of adhesive capsulitis: a randomized controlled trial. AB - BACKGROUND: Bee venom acupuncture (BVA) has been used in the treatment of adhesive capsulitis (AC) in the clinical field. This study aimed to investigate whether the addition of BVA to physiotherapy (PT) would be more effective in the management of AC, and whether BVA would have a dose-dependent effect. MATERIALS AND METHODS: Sixty-eight patients diagnosed with AC were recruited into 3 groups; BV 1 (1:10,000 BVA plus PT), BV 2 (1:30,000 BVA plus PT), and group 3 (normal saline (NS) injection, as a control, plus PT). PT was composed of 15 minutes of transcutaneous electrical nerve stimulation (TENS), transcutaneous infrared thermotherapy (TDP), and manual PT. Treatments were given in 16 sessions within 2 months. Shoulder pain and disability index (SPADI), pain visual analogue scale (VAS), and 3) active/passive range of motion (ROM) were measured before treatment and at 2, 4, 8, and 12 weeks after the treatment. RESULTS: All 3 groups showed statistically significant improvements in SPADI, pain VAS scores, and active/passive ROM. The BV 1 group showed significantly better outcomes in SPADI at 8 and 12 weeks, in pain VAS (at rest) at 8 weeks, and in pain VAS (during exercise) at 12 weeks than the NS group. No significant differences were found in active/passive ROM among all the groups. CONCLUSION: BVA in combination with PT can be more effective in improving pain and function than PT alone in AC. However, the effectiveness of BVA was not shown in a dose-dependent manner. PMID- 23352188 TI - Adiponectin receptor as a key player in healthy longevity and obesity-related diseases. AB - Adiponectin is a fat-derived hormone whose reduction plays central roles in obesity-linked diseases including insulin resistance/type 2 diabetes and atherosclerosis. The cloning of Adiponectin receptors AdipoR1 and AdipoR2 has stimulated adiponectin research, revealing pivotal roles for AdipoRs in pleiotropic adiponectin actions, as well as some postreceptor signaling mechanisms. Adiponectin signaling has thus become one of the major research fields in metabolism and clinical medicine. Studies on AdipoRs will further our understanding of the role of adiponectin in obesity-linked diseases and shortened life span and may guide the design of antidiabetic and antiaging drugs with AdipoR as a target. PMID- 23352189 TI - Regulation of decidualization in human endometrial stromal cells through exchange protein directly activated by cyclic AMP (Epac). AB - INTRODUCTION: Human endometrial stromal cells (ESCs) undergo differentiation during the decidualization process. Decidualization is characterized by their enhanced production of IGF binding protein-1 (IGFBP-1), prolactin (PRL), and the forkhead transcriptional factor FOXO1, and transformation into more rounded cells, during the secretory phase of the menstrual cycle and subsequent pregnancy. Protein kinase A (PKA)-mediated cAMP signaling is crucial for this process. The present study was undertaken to examine the involvement of a mediator of cAMP signaling, exchange protein directly activated by cAMP (Epac), in decidualization of cultured ESCs. RESULTS: Treatment of ESCs with the Epac selective cAMP analog 8-CPT-2-OMe-cAMP (CPT) had no effect on IGFBP-1, PRL, and FOXO1 mRNA expression. However, CPT potentiated IGFBP-1 and PRL expression stimulated by the PKA-selective cAMP analog N(6)-Phe-cAMP (Phe) and activated Rap1, a downstream regulator of Epac signaling. Knock-down of Epac1, Epac2, or Rap1 significantly inhibited the Phe- or Phe/CPT-induced increase in IGFBP-1 and PRL expression, as well as Rap1 activation. Furthermore, CPT enhanced IGFBP-1 and PRL expression and the morphological differentiation induced by ovarian steroids, whereas Epac1, Epac2, or Rap1 knock-down suppressed these events. CONCLUSION: These data provide evidence for the involvement of the Epac/Rap1 signaling pathway in cAMP-mediated decidualization of human ESCs. PMID- 23352190 TI - The effects of cyclic AMP, sex steroids and global hypomethylation on the expression of genes controlling the activity of the renin-angiotensin system in placental cell lines. AB - The placental renin-angiotensin system (RAS) is involved in placentation. We have shown that prorenin mRNA (REN) is expressed in a first trimester trophoblast cell line (HTR-8/SVneo) but not in a choriocarcinoma cell line (BeWo). We attempted to stimulate RAS expression in these cells by cAMP, 5'-aza-2'-deoxycytidine (AZA; an inhibitor of methylation), cAMP and AZA combined, and the sex steroids medroxyprogesterone acetate (MPA) and estradiol-17beta (E(2)) with and without cAMP. RAS mRNAs were measured by qPCR and prorenin concentration in supernatants measured by an ELISA. In HTR-8/SVneo cells, all treatments increased REN expression compared to controls and cAMP + AZA combined was more effective than either treatment alone. Prorenin levels in supernatants were similarly upregulated. In HTR-8/SVneo cells, angiotensinogen (AGT) mRNA expression was increased by MPA + E(2) either with or without cAMP. AGT expression was also significantly increased by AZA. BeWo cells did not express REN or prorenin and it was not inducible with any treatment. AGT expression was significantly increased with AZA, the combination of cAMP + AZA, and MPA + E(2) + cAMP treatments. Since cAMP, AZA, cAMP and AZA combined, or MPA and E(2) with and without cAMP in HTR 8/SVneo cells, a cell line most similar in its RAS expression to the in vivo placenta, these factors may affect placental RAS activity. Surprisingly, these treatments also induced AGT expression in BeWo cells. Whether they are involved in regulating AGT in choriocarcinomas in vivo remains to be determined. PMID- 23352191 TI - Placental expression of osteopontin(OPN) in monochorionic twins with discordant growth. AB - Shallow invasion could result in pathological processes of placenta leading to fetal growth restriction (FGR) in singletons and twins. Osteopontin (OPN) plays an important role in trophoblast invasion. So our study aims to investigate the expression level of OPN in placenta of discordant monochorionic (MC) twins. OPN expression was compared in the placental samples of 10 discordant MC twins and 12 concordant MC twins. OPN levels were evaluated using quantitative Real-time PCR and western blot. Our results showed that OPN expression at mRNA and protein level was significantly decreased in placenta (p < 0.05) of small fetuses in discordant MC twins. The expression level of OPN transcript strongly correlated with the territory of placenta. PMID- 23352192 TI - Involvement of the NLRP3 inflammasome in the modulation of an LPS-induced inflammatory response during morphine tolerance. AB - BACKGROUND: Morphine is widely used for its analgesic effects. In addition to its high potential for addiction and tolerance, morphine also induces immunosuppression. Inflammasomes, NLRP3 being the most characterized, is a platform for activation of pro-inflammatory cytokines, particularly IL-1beta. We have explored the effects of lipopolysaccharide (LPS) during morphine tolerance on expression of the NLRP3 inflammasome and related inflammatory genes. METHODS: Morphine-pellet administration was used to induce morphine tolerance in F344 rats. Control rats were given a placebo. On day 5, the animals received either saline or 250 MUg/kg LPS. LPS-induced protein expression of TNF-alpha, IL-1beta, and IL- 6 was examined in the spleen of rats with and without morphine tolerance. A PCR array was used to examine LPS-induced expression of 84 inflammasome-related genes with and without morphine tolerance. RESULTS: LPS-induced IL-1beta and TNF alpha protein expression was significantly lower in the spleen of the morphine tolerant animals than in the placebo-control animals. In response to LPS, expression of 27 genes, including NLRP3, TNF-alpha, IL-1beta, and IL-6, was significantly increased, and expression of 3 genes was significantly decreased in both the morphine-tolerant and placebo-control groups compared to the saline treated animals. However, there was only a 2.7-fold increase in NLRP3 expression in response to LPS in the morphine-tolerant rats compared to a 4.5-fold increase in the placebo-control animals. CONCLUSION: Our data indicate that, in the morphine-tolerant state, LPS-induced expression of NLRP3 is suppressed and cytokine/chemokine expression is inhibited, which may be one of the mechanisms involved in morphine-induced immunosuppression. PMID- 23352193 TI - Progression of intermediate age-related macular degeneration with proliferation and inner retinal migration of hyperreflective foci. AB - PURPOSE: Drusen and migrating retinal pigment epithelium have been associated with hyperreflective foci (HF) detected by spectral-domain optical coherence tomography (SD-OCT). This study sought to quantify the change in intraretinal HF distribution and its correlation with age-related macular degeneration (AMD) disease progression. DESIGN: Prospective observational study from the multicenter Age-Related Eye Disease Study 2 (AREDS2) Ancillary SD-OCT Study. PARTICIPANTS: Patients (n=299) with 1 enrolled eye with intermediate AMD and baseline SD-OCT, followed by SD-OCT imaging at 1-year and 2-year visits. METHODS: The number and location of HF were scored in SD-OCT scans of all 299 eyes. The change in transverse (horizontal) and axial (vertical) distribution of HF in the macula were evaluated with pairwise signed-rank tests. Two-year inner retinal HF migration was determined by the change in HF-weighted axial distribution (AxD) score calculated for each eye. The correlation of HF with SD-OCT features of AMD progression was evaluated with logistic regression analysis. MAIN OUTCOME MEASURES: The mean change in number of HF, transverse and axial distribution of HF in the macula, and AxD per eye. RESULTS: In 299 study eyes, the 2-year increase in the number of HF (P<0.001) and the AxD (P<0.001) per eye represented longitudinal proliferation and shift to inner retinal layers, respectively. Eyes with geographic atrophy (GA) at 2 years were correlated with the presence of baseline HF (P<0.001; odds ratio [OR], 4.72; 95% confidence interval [CI], 2.43 9.80), greater number of baseline HF (P<0.001; OR, 1.61 per HF; 95% CI, 1.32 2.00), and greater baseline AxD (P<0.001; OR, 1.58 per AxD point; 95% CI, 1.29 1.95). CONCLUSIONS: Proliferation and inner retinal migration of SD-OCT HF occurred during follow-up in eyes with intermediate AMD. These characteristics were associated with greater incidence of GA at year 2; therefore, SD-OCT HF proliferation and migration may serve as biomarkers for AMD progression. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23352194 TI - The 10-year incidence and risk factors of retinal vein occlusion: the Beijing eye study. AB - OBJECTIVE: To assess the 10-year incidence of retinal vein occlusions (RVOs) and associated factors in adult Chinese subjects. DESIGN: Population-based, longitudinal study. PARTICIPANTS: The Beijing Eye Study, which included 4439 subjects (age: 40+ years) in 2001, was repeated in 2011 with 2695 subjects participating (66.4% of the survivors). METHODS: The study participants underwent a detailed ophthalmic examination. Fundus photographs were examined for the new development of RVOs, differentiated into branch RVOs (BRVOs) and central RVOs (CRVOs). MAIN OUTCOME MEASURES: Incidence of RVOs. RESULTS: Incident RVOs were detected in 51 eyes (49 subjects) with an incidence of 1.9 +/- 0.1 per 100 persons and 1.0 +/- 0.1 per 100 eyes. Incidence of BRVO was 1.6 +/- 0.1 per 100 subjects (43 subjects [88% of patients with RVO]; 44 eyes), and incidence of CRVO was 0.3 +/- 0.1 per 100 persons. Of 61 patients with an RVO in 2001 and 25 subjects reexamined in 2011, at least 4 subjects (7%) developed a second RVO. Incident BRVOs were located more often in the superior temporal quadrant and inferior temporal quadrant (32% and 34%, respectively) than in the superior nasal quadrant and inferior nasal quadrant (21% and 14%, respectively). In 35 eyes (80% of the BRVO eyes), the BRVO was located at an arteriovenous crossing. At the crossing sites, arterioles were found superficial to venules in 28 eyes (64% of the BRVO eyes). Macular edema was detected in 18 (37%) of all RVO eyes, including 13 (30%) of BRVO eyes. In multivariate logistic analysis, incident RVOs were associated with higher systolic blood pressure (P = 0.01; odds ratio [OR], 1.04), hypertension (P = 0.03; OR, 4.62), lower cognitive function score (P = 0.007; OR, 0.88), blood concentration of cholesterol >= 5.72 mmol/L (P = 0.007; OR, 3.29), and status after cerebral infarction/hemorrhage (P = 0.02; OR, 1.19). Incident RVOs were not significantly related to the intake of aspirin (P=0.37). CONCLUSIONS: The 10-year incidence of RVOs in Greater Beijing (1.9 +/- 0.1 per 100 persons) was similar to that in other studies on Caucasian populations. The 10-year incidence of RVOs was related to the known risk factors of arterial hypertension, hypercholesterolemia, and status after cerebral infarction/hemorrhage, as well as with a lower cognitive function score. Incident BRVO was approximately 6 times more frequent than incident CRVO. Macular edema was detected in approximately 30% of BRVO eyes. PMID- 23352195 TI - The impact of an electronic health record transition on a glaucoma subspecialty practice. AB - PURPOSE: To assess the impact of an electronic health record (EHR) on patient experience, physician behavior, and clinic workflow in a glaucoma subspecialty clinic. DESIGN: Case-control (before/after) study. PARTICIPANTS: One hundred thirty-one adult patients seeking treatment at a glaucoma subspecialty practice for a nonprocedural office visit who consented to direct observation and 273 patients whose progress through the clinic stations was timed. METHODS: Three time points relative to the EHR transition were evaluated: a 2-week period before the transition, a 2-week period at 2 weeks after the transition, and a 2-week period at 6 months after the transition. At each of these time points, detailed timing of physician actions during the doctor-patient encounter were measured, a survey of patient attitudes regarding their visit and the method of documentation was conducted, and time spent by patients in each of the major aspects of the visit (screening/testing, physician, waiting) was recorded. MAIN OUTCOME MEASURES: Time spent by physicians on the clinical examination, computer, paper records, or multitasking; patient experience of their clinic visit; and time spent by patients at various clinic stations. RESULTS: Two weeks after the transition, physicians spent more time with patients overall compared with baseline (8.4 vs. 11.6 minutes), reviewing paper records (0.2 vs. 0.6 minutes), and on computer-related tasks (2.3 vs. 4.2 minutes). At 6 months after EHR transition, physicians also spent more time compared with baseline on the clinical examination (5.1 vs. 6.4 minutes). There was a relative decrease in the percentage of patient time spent waiting to see the physician, although patients' perceptions of their visit and the EHR remained largely unchanged. Annual clinic volumes also were unaffected by the new EHR. CONCLUSIONS: There were changes in the physician-patient encounter that manifested within 2 weeks of EHR transition and then stabilized, suggesting that although an EHR transition is not without consequences, these can be measured early. Some of these findings, such as increased time dedicated to the clinical examination and the lack of change in patient perception after the switch, were unexpected. This study supports the contention that EHR implementation can be accomplished in an ophthalmology practice without compromising the efficiency of or patient satisfaction with the clinical encounter. PMID- 23352197 TI - Use of corneal power-specific constants to improve the accuracy of the SRK/T formula. AB - PURPOSE: To evaluate the effect of average corneal power (K) and axial length (AL) in a data-adjusted A-constant for improving the refractive outcome in the Sanders-Retzlaff-Kraff (SRK)/T formula. DESIGN: Retrospective, consecutive, case series. PARTICIPANTS: A total of 637 patients (637 eyes) who underwent uncomplicated phacoemulsification with implantation of the Acrysof IQ (IQ; Alcon, Fort Worth, TX; 314 eyes) or Akreos AO (AO; Bausch & Lomb, Rochester, NY; 323 eyes) intraocular lens (IOL) by a single surgeon. METHODS: The correlation among the K, AL, and predicted refractive error in the SRK/T formula was analyzed. Patients were divided into 2 subgroups, the first to calculate the different data adjusted A-constants based on the K and the second to compare the median absolute error (MedAE) based on different A-constants with the traditional A-constant in the SRK/T formula. MAIN OUTCOME MEASURES: The data-adjusted A-constant and the MedAE (diopters [D]). RESULTS: The data-adjusted A-constant showed a decreasing trend as K increased. The data-adjusted A-constant was 119.04 in the IQ group and 118.27 in the AO group. The calculated A-constant was 119.33 in the IQ group and 118.57 in the AO group when the cornea was flatter than 43.0 D and 43.2 D, respectively. The A-constant was 118.71 in the IQ group and 117.96 in the AO group when the cornea was steeper than or equal to 44.7 D and 45.0 D, respectively. The MedAE decreased from 0.29 D to 0.23 D in the IQ group (P = 0.001) and from 0.44 D to 0.38 D in the AO group (P < 0.001) when different A constants were used. The MedAE further decreased from 0.36 D to 0.24 D in the IQ group (P = 0.005) and from 0.58 D to 0.37 D in the AO group (P < 0.001) when subjects with K 1.00 D or more above or 1.00 D below the most accurate K in each group were compared. CONCLUSIONS: For a steep cornea, the calculated A-constant was smaller than that of the entire K, but for a flat cornea, a larger A-constant was calculated. Using different A-constants based on the K improved the refraction outcomes relying on the SRK/T formula. PMID- 23352196 TI - Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. AB - OBJECTIVE: To evaluate the 12-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly and on an as-needed (PRN) basis in treatment-naive patients with subfoveal neovascular age-related macular degeneration (wet AMD). DESIGN: A 24-month, phase III, randomized, multicenter, double-masked, dose-response study. PARTICIPANTS: Patients aged >= 50 years with subfoveal wet AMD. METHODS: Patients (n = 1098) were randomized to receive ranibizumab 0.5 mg or 2.0 mg intravitreal injections administered monthly or on a PRN basis after 3 monthly loading doses. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean change from baseline in best-corrected visual acuity (BCVA) at month 12. Key secondary end points included the mean number of ranibizumab injections, the mean change from baseline in central foveal thickness (CFT) over time, and the proportion of patients who gained >= 15 letters of BCVA. Unless otherwise specified, end point analyses were performed using the last observation-carried-forward method to impute missing data. RESULTS: At month 12, the mean change from baseline in BCVA for the 4 groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained >= 15 letters from baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1%, and 33.0%, respectively. The mean change from baseline in CFT at month 12 in the 4 groups was -172.0 MUm, -161.2 MUm, -163.3 MUm, and -172.4 MUm, respectively. The mean number of injections was 7.7 and 6.9 for the 0.5-mg PRN and 2.0-mg PRN groups, respectively. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and comparable between groups. CONCLUSIONS: At month 12, the ranibizumab 2.0 mg monthly group did not meet the prespecified superiority comparison and the ranibizumab 0.5 mg and 2.0 mg PRN groups did not meet the prespecified noninferiority (NI) comparison. However, all treatment groups demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes, with the PRN groups requiring approximately 4 fewer injections (6.9-7.7) than the monthly groups (11.2-11.3). No new safety events were observed despite a 4-fold dose escalation in the study. The pHase III, double-masked, multicenter, randomized, Active treatment controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) study confirmed that ranibizumab 0.5 mg dosed monthly provides optimum results in patients with wet AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23352198 TI - Spectral-domain optical coherence tomographic assessment of Schlemm's canal in Chinese subjects with primary open-angle glaucoma. AB - PURPOSE: To evaluate in vivo features of Schlemm's canal (SC) in patients with primary open-angle glaucoma (POAG) with spectral-domain optical coherence tomography (SD-OCT) and to investigate the relationship of SC size with intraocular pressure (IOP) and glaucoma severity. DESIGN: Prospective, comparative study. PARTICIPANTS: Fifty Chinese patients with newly diagnosed POAG who had not undergone surgery and 50 normal Chinese subjects from a population based, cross-sectional study in Shanghai. METHODS: All participants underwent SD OCT. The diameter and area of SC were examined in the temporal and nasal sections and measured with customized software. MAIN OUTCOME MEASURES: Patient demographics, repeatability and reproducibility assessed with the coefficient of variation (CV) and the intraclass correlation coefficient (ICC), SC parameters and their correlation with IOP, and the mean deviation (MD) of the visual field were analyzed. RESULTS: The percentage of sections in which SC was observable was similar between eyes with POAG and normal eyes, and ranged from 78% to 86%. For intraobserver repeatability, the CV and ICC values were 7.9% and 0.97 for diameter, and 13.8% and 0.83 for area, respectively. For interobserver repeatability, the CV and ICC values were 13.6% and 0.89 for diameter, and 13.4% and 0.80 for area, respectively. Significant differences between the 2 groups were found for the average SC area (11332 +/- 2015 MUm(2) vs. 13991 +/- 1357 MUm(2); P<0.001), but not for the SC diameter (40.2 +/- 7.1 MUm vs. 45.2 +/- 4.0 MUm; P = 0.195). In addition, the mean IOP values correlated well only with the SC area (rho = -0.674, P<0.001), not with the SC diameter (rho = -0.103, P = 248). No significant correlations were found between the MD values and the SC parameters. CONCLUSIONS: Eyes with POAG have a decreased SC area compared with normal eyes. A correlation between the SC area and the IOP also was observed. However, the degree of glaucoma damage was not consistently associated with the SC area. Spectral-domain OCT could be used for investigating SC changes in patients with glaucoma. PMID- 23352200 TI - Antiepileptic drugs during pregnancy and cognitive outcomes. PMID- 23352201 TI - Effects of intraarticular treatment with stanozolol on synovial membrane and cartilage in an ovine model of osteoarthritis. AB - Aim of the study was to verify the clinical and morphological effects of intra articular stanozolol or placebo treatment, lasting 3 and 9 months, in sheep in which a femoro-tibial osteo-arthritis (OA) were surgically induced (medial bilateral meniscectomy). Twenty healthy sheep divided into four groups and two control animals group, after surgical medial bilateral meniscectomy, were weekly injected in femoral-tibial joint (FTJ) with stanozolol or placebo. Lameness evaluation was performed and synovial fluid was collected from all sheep at each treatment time. Necropsies were performed after 3 or 9 month as described in experimental design. Gross pathologies were described and specimen tissues collected from femoro-tibial articular joints were processed for routine histological examination. The gross anatomy of the FTJ was well-preserved in stanozolol-treated sheep; this also applied to the histological features of articular cartilage. Joint aseptic inflammation and fibrosis were observed in placebo-treated sheep, associated with a different degree of severity of condylar and tibial plate cartilage degeneration. Stanozolol intra-articular treatment reduces osteophytes formation and subchondral bone reaction and promotes articular cartilage regeneration. PMID- 23352199 TI - Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. AB - BACKGROUND: Many women of childbearing potential take antiepileptic drugs, but the cognitive effects of fetal exposure are uncertain. We aimed to assess effects of commonly used antiepileptic drugs on cognitive outcomes in children up to 6 years of age. METHODS: In this prospective, observational, assessor-masked, multicentre study, we enrolled pregnant women with epilepsy on antiepileptic drug monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and February, 2004, at 25 epilepsy centres in the UK and the USA. Our primary outcome was intelligence quotient (IQ) at 6 years of age (age-6 IQ) in all children, assessed with linear regression adjusted for maternal IQ, antiepileptic drug type, standardised dose, gestational birth age, and use of periconceptional folate. We also assessed multiple cognitive domains and compared findings with outcomes at younger ages. This study is registered with ClinicalTrials.gov, number NCT00021866. FINDINGS: We included 305 mothers and 311 children (six twin pairs) in the primary analysis. 224 children completed 6 years of follow-up (6-year-completer sample). Multivariate analysis of all children showed that age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94 101) than to carbamazepine (105, 102-108; p=0.0015), lamotrigine (108, 105-110; p=0.0003), or phenytoin (108, 104-112; p=0.0006). Children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiepileptic drugs and on non-verbal and executive functions compared with lamotrigine (but not carbamazepine or phenytoin). High doses of valproate were negatively associated with IQ (r=-0.56, p<0.0001), verbal ability (r=-0.40, p=0.0045), non-verbal ability (r=-0.42, p=0.0028), memory (r=-0.30, p=0.0434), and executive function (r=-0.42, p=0.0004), but other antiepileptic drugs were not. Age-6 IQ correlated with IQs at younger ages, and IQ improved with age for infants exposed to any antiepileptic drug. Compared with a normative sample (173 [93%] of 187 children), right-handedness was less frequent in children in our study overall (185 [86%] of 215; p=0.0404) and in the lamotrigine (59 [83%] of 71; p=0.0287) and valproate (38 [79%] of 40; p=0.0089) groups. Verbal abilities were worse than non-verbal abilities in children in our study overall and in the lamotrigine and valproate groups. Mean IQs were higher in children exposed to periconceptional folate (108, 95% CI 106-111) than they were in unexposed children (101, 98-104; p=0.0009). INTERPRETATION: Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age. Reduced right-handedness and verbal (vs non verbal) abilities might be attributable to changes in cerebral lateralisation induced by exposure to antiepileptic drugs. The positive association of periconceptional folate with IQ is consistent with other recent studies. PMID- 23352203 TI - Tumor on the great toe of the left foot. Eccrine syringofibroadenoma. PMID- 23352202 TI - Large-scale brain networks in affective and social neuroscience: towards an integrative functional architecture of the brain. AB - Understanding how a human brain creates a human mind ultimately depends on mapping psychological categories and concepts to physical measurements of neural response. Although it has long been assumed that emotional, social, and cognitive phenomena are realized in the operations of separate brain regions or brain networks, we demonstrate that it is possible to understand the body of neuroimaging evidence using a framework that relies on domain general, distributed structure-function mappings. We review current research in affective and social neuroscience and argue that the emerging science of large-scale intrinsic brain networks provides a coherent framework for a domain-general functional architecture of the human brain. PMID- 23352205 TI - Treatment complexity in cystic fibrosis: trends over time and associations with site-specific outcomes. AB - BACKGROUND: Patients with cystic fibrosis (CF) have increasing treatment complexity and high treatment burden. We describe trends in treatment complexity and evaluate its relationship with health outcomes. METHODS: Using Epidemiologic Study of Cystic Fibrosis (ESCF) data, we developed a treatment complexity score (TCS) from 37 chronic therapies and assessed change by age group (6-13, 14-17, and 18+ years) over a three year period. Differences in average site TCS were evaluated by quartiles based on FEV1, BMI, or Treatment Burden score on the Cystic Fibrosis Questionnaire-Revised (CFQ-R). RESULTS: TCS scores were calculated for 7252 individual patients (42% child, 16% adolescent, 43% adult) across 153 sites. In 2003, mean TCS was 11.1 for children, 11.8 for adolescents, and 12.1 for adults. In all 3 age groups, TCS increased over 3 years; the increase in TCS from 2003-2005 for children was 1.25 (95% CI 1.16-1.34), for adolescents 0.77 (0.62-0.93), and for adults 1.20 (1.08-1.31) (all P<0.001 for trend over time). At the site level, there were no significant differences in mean TCS based on FEV1 quartile. Mean TCS was higher in the highest BMI z-score quartile. Across all 3 versions of the CFQ-R, mean TCS was lower at sites in the highest quartiles (lowest burden) for CFQ-R treatment burden scores. CONCLUSION: Treatment complexity was highest among adults with CF, although over 3 years, we observed a significant increase in treatment complexity in all age groups. Such increases in treatment complexity pose a challenge to patient self-management and adherence. Future research is needed to understand the associations between treatment complexity and subsequent health outcomes to reduce treatment burden and improve disease management. PMID- 23352206 TI - The fellowship in family planning. PMID- 23352204 TI - Renin inhibition and AT(1)R blockade improve metabolic signaling, oxidant stress and myocardial tissue remodeling. AB - OBJECTIVE: Strategies that block angiotensin II actions on its angiotensin type 1 receptor or inhibit actions of aldosterone have been shown to reduce myocardial hypertrophy and interstitial fibrosis in states of insulin resistance. Thereby, we sought to determine if combination of direct renin inhibition with angiotensin type 1 receptor blockade in vivo, through greater reductions in systolic blood pressure (SBP) and aldosterone would attenuate left ventricular hypertrophy and interstitial fibrosis to a greater extent than either intervention alone. MATERIALS/METHODS: We utilized the transgenic Ren2 rat which manifests increased tissue expression of murine renin which, in turn, results in increased renin angiotensin system activity, aldosterone secretion and insulin resistance. Ren2 rats were treated with aliskiren, valsartan, the combination (aliskiren+valsartan), or vehicle for 21 days. RESULTS: Compared to Sprague Dawley controls, Ren2 rats displayed increased systolic blood pressure, elevated serum aldosterone levels, cardiac tissue hypertrophy, interstitial fibrosis and ultrastructural remodeling. These biochemical and functional alterations were accompanied by increases in the NADPH oxidase subunit Nox2 and 3-nitrotyrosine content along with increases in mammalian target of rapamycin and reductions in protein kinase B phosphorylation. Combination therapy contributed to greater reductions in systolic blood pressure and serum aldosterone but did not result in greater improvement in metabolic signaling or markers of oxidative stress, fibrosis or hypertrophy beyond either intervention alone. CONCLUSIONS: Thereby, our data suggest that the greater impact of combination therapy on reductions in aldosterone does not translate into greater reductions in myocardial fibrosis or hypertrophy in this transgenic model of tissue renin overexpression. PMID- 23352207 TI - alpha-Synuclein coaggregation in familial amyotrophic lateral sclerosis with SOD1 gene mutation. AB - Immunohistochemical studies were performed on postmortem brain and spinal cord from a patient with familial amyotrophic lateral sclerosis characterized by a C111Y mutation in the Cu/Zn superoxide dismutase gene. Clinically, the patient presented with classical amyotrophic lateral sclerosis and died of respiratory failure at age 53 years without ventilator dependence, 4 years after the onset. Pathologically, loss of motor neurons was more extensive than upper motor neurons. Lower motor neurons developed massive intracellular cytoplasmic neuronal inclusions, which were immunoreactive for Cu/Zn superoxide dismutase and phosphorylated alpha-synuclein, often colocalized. The inclusions were TAR DNA binding protein 43 negative. The clinicopathologic significance of coaggregation of alpha-synuclein and Cu/Zn superoxide dismutase protein, a novel finding in neurodegenerative disorders, needs further investigation. PMID- 23352208 TI - Anaplastic lymphoma kinase-positive large B-cell lymphoma: a case report with particular immunophenotypic features. AB - Anaplastic lymphoma kinase-positive large B-cell lymphoma is a rare and aggressive B-cell lymphoma mostly associated with t(2:17) involving the clathrin gene at 17q23 and the anaplastic lymphoma kinase gene at 2p23. The characteristic immunophenotype includes a granular cytoplasmic anaplastic lymphoma kinase expression, CD20 negativity and the presence of plasma cell markers (CD138, VS38c, and CD38). We report a case with aberrant immunophenotype (CD138-, VS38c-, CD38+/-) and discuss the utility of other immunohistochemical markers in establishing a terminal B-cell differentiation. PMID- 23352209 TI - Atypical lipomatous tumor mimicking giant fibrovascular polyp of the esophagus: report of a case and a critical review of literature. AB - An 81-year-old man presented to the emergency department with a mass protruding from his mouth after an episode of emesis. A computed tomography scan showed a hypodense, polypoid structure with a fatty component. The long polyp was attached by a narrow stalk to the cervical esophagus. A 14.0-cm slender mass resembling a giant fibrovascular polyp (GFP) of the esophagus was resected. The microscopic, immunohistochemical, and molecular findings were, however, those of an atypical lipomatous tumor (ALT). Atypical lipomatous tumor of the esophagus is a rare, low grade malignant neoplasm, with a potential for local recurrence and, in most instances, presents as a large intraluminal polyp mimicking a GFP. Cases reported in the literature as primary myxoid liposarcomas of the esophagus are in all likelihood examples of ALT with myxoid change. A recent case reported as a GFP with karyotypic abnormalities on comparative genomic hybridization is also most likely to be an ALT mimicking a GFP. Pathologists need to be aware of the pitfalls in the diagnosis of ALT of the esophagus and should carefully evaluate the adipocytic component of these lesions. PMID- 23352210 TI - PIK3CA-AKT pathway mutations in micropapillary breast carcinoma. AB - Micropapillary carcinoma of the breast is associated with increased rates of lymph node metastasis and lymphovascular invasion. While activating point mutations in PIK3CA (encoding phosphatidylinositol-3-kinase catalytic subunit) or AKT1 are found in 25% to 30% of invasive ductal carcinomas, the mutational profile of invasive micropapillary carcinomas has not been characterized in detail. Micropapillary carcinomas, concurrent metastatic and precursor breast lesions from 19 patients were identified. Lesional tissue was punched from paraffin-tissue blocks, and genomic DNA was extracted and screened for a large panel of known hotspot mutations using multiplex polymerase chain reaction and mass-spectroscopy analysis (643 mutations in 53 genes). Hotspot point mutations were identified in 35% (7/20) of micropapillary breast carcinomas, including PIK3CA exons 7, 9 and 20 hotspots, as well as the AKT1 plekstrin homology domain mutation (E17K); mutations in TP53 and KRAS were each found in a single patient. In 6 patients, micropapillary and non-micropapillary components of the same tumor were separately tested, yielding concordant results in five; one had a wild type micropapillary component, but a PIK3CA mutation in the invasive ductal component. Concurrent lymph node metastases were mostly wild type (2/8 mutant). Accompanying ductal carcinoma in situ had point mutations in 45% (5/11), mostly concordant with invasive carcinoma; however, mutational status of other breast proliferative lesions was generally discordant with accompanying carcinoma. The rate of PIK3CA mutations in this series of micropapillary carcinomas is similar to invasive ductal carcinomas; however, there may be an enrichment of AKT1 mutations (10%). The non-micropapillary components and precursor lesions occasionally had different mutations. PMID- 23352211 TI - [Cardiovascular risk in human immunodeficiency virus-infected patients in Spain. Author's reply]. PMID- 23352212 TI - [An analysis of adherence to the "Recommendations for the treatment of human immunodeficiency virus-infected adults" in a penitentiary in Barcelona]. AB - AIM: To analyze the adherence to the "Guidelines for the treatment of HIV infected adults" among HIV-infected prison inmates. METHODS: A cross-sectional study was conducted in 2010 in the Quatre Camins Prison (Barcelona, Spain). Epidemiological, clinical and therapeutic variables were collected. We verified whether antiretroviral therapy (ART) met the Guidelines and analyzed the variables associated with compliance using bivariate and multivariate analysis. RESULTS: There were a total of 202 HIV infected prison inmates, 83.2% of whom were on ART. An undetectable viral load (VL) was observed in 80.4% of treated patients. The large majority (86.1%) met the guidelines, and 42.9% of non compliance to guidelines was because the patients refused ART. More undetectable VL (P=.001; ORA: 4,30, 95%CI: 1,85 to 10.0) was found in those patients following the guidelines. CONCLUSION: Compliance with the guidelines is high, and is significantly associated with undetectable VL. We suggest evaluating the quality of prescriptions periodically, and to correct them if needed. PMID- 23352213 TI - Chronic colonization of Inquilinus limosus in a patient with cystic fibrosis: first report in Spain. PMID- 23352214 TI - Effect of chicory seed extract on glucose tolerance test (GTT) and metabolic profile in early and late stage diabetic rats. AB - BACKGROUND AND PURPOSE OF THE STUDY: The goal was to evaluate and compare the effects of aqueous extract of the seeds of chicory, Cichorium intybus L., on glucose tolerance test (GTT) and blood biochemical indices of experimentally induced hyperglycemic rats. METHODS: Late stage and early stage of Type 2 diabetes mellitus (T2DM) were induced in rats by streptozotocin (STZ) and a combination of STZ and niacinamide (NIA/STZ), respectively. Within each group, one subgroup received daily i. p. injections of chicory extract (125 mg/kg body weight, for 28 days). Body weight and fasting blood sugar (FBS) were measured weekly. Blood was analyzed for glycosylated hemoglobin (HbA1c) and sera for alanine aminotransferase (ALT), aspartate aminotransferase (AST), nitric oxide (NO), triacylglycerol (TG), total cholesterol (TC), total protein, and insulin on days 10 and 28 after treatment. Intraperitoneal glucose tolerance test (IPGTT) along with insulin determination was performed on a different set of rats in which the chicory-treated groups received the extract for 10 days. RESULTS: During 4 weeks of treatment, chicory prevented body-weight loss and decreased FBS. ALT activities and levels of TG, TC and HbA1c decreased, and concentration of NO increased in the chicory treated groups (p < 0.05). Unlike late-stage diabetes, fasting serum insulin concentrations were higher and GTT pattern approximated to normal in chicory-treated early-stage diabetic rats. CONCLUSIONS: Chicory appeared to have short-term (about 2 hours, as far as GTT is concerned) and long-term (28 days, in this study) effects on diabetes. Chicory may be useful as a natural dietary supplement for slowing down the pace of diabetes progress, and delaying the development of its complications. PMID- 23352216 TI - The CD70-CD27 axis, a new brake in the T helper 17 cell response. AB - The CD70-CD27 interaction is known to positively regulate T cell expansion and effector function by providing costimulatory signals. In this issue of Immunity, Coquet et al. (2013) show an unexpected T-helper-17-cell-specific negative regulation mediated by CD70-CD27 interaction. PMID- 23352217 TI - Sterol-izing innate immunity. AB - In this issue of Immunity, studies by Blanc et al. (2013) and Liu et al. (2013) reveal how interferon induction of cholesterol-25-hydroxylase mediates innate immunity against multiple diverse viruses. PMID- 23352218 TI - Inflammation makes T cells sensitive. AB - Inflammatory cytokines shape CD8(+) T cell responses. In this issue of Immunity, Richer et al. (2013) and Raue et al. (2013) demonstrate that inflammatory cytokines dynamically fine-tune antigen sensitivity of CD8(+) T cells to potently detect and better eliminate infected cells. PMID- 23352219 TI - What mAbs tell us about shapes: multiple roads lead to Rome. AB - In this issue of Immunity, Liao et al. (2013) utilize monoclonal antibodies isolated from RV144 vaccinees to gain key insights into the structural vulnerabilities of the V1-V2 loops of HIV gp120 protein and how they might be associated with vaccine efficacy. PMID- 23352220 TI - Whole-body anatomy of human T cells. AB - Knowledge of the regional tissue distribution of T cell subsets is a prerequisite for understanding protective immunity and the pathophysiology of T cell-mediated diseases. In this issue of Immunity, Sathaliyawala et al. (2012) present a comprehensive human tissue T cell analysis. PMID- 23352222 TI - Seizures following hippocampal kindling induce QT interval prolongation and increased susceptibility to arrhythmias in rats. AB - The prolonged seizures of status epilepticus produce chronic arrhythmogenic changes in cardiac function. This study was designed to determine if repeated, self-limiting seizures administered to kindled rats induce similar cardiac dysfunction. Multiple seizures administered to rats following hippocampal kindling resulted in cardiac QT interval prolongation and increased susceptibility to experimental arrhythmias. These data suggest that multiple, self-limiting seizures of intractable epilepsy may have cardiac effects that can contribute to sudden unexpected death in epilepsy (SUDEP). PMID- 23352223 TI - Preventing COPD exacerbations with macrolides: a review and budget impact analysis. AB - Long-term treatment with macrolides has recently been shown to reduce COPD exacerbations in doses lower than bactericidal doses. This article aims to critically review the international literature relating to the long-term effectiveness and safety of macrolides and to estimate the budget impact of preventing exacerbations with azithromycin in Belgium. Controlled clinical studies focusing on the prevention of COPD exacerbations with long-term macrolide treatment were identified in PubMed, EMBASE, Controlled Trials Registry of the Cochrane Library, and Social Science and Citation Index. The budget impact of preventing exacerbations with azithromycin in Belgium over a one-year period was calculated as the difference between the additional expenditure of annual treatment with azithromycin and the savings in hospital expenditure arising from fewer COPD exacerbations in patients with GOLD stages II-IV. Prevalence and resource use data were derived from the literature and unit cost data from Belgian sources. The literature review suggests that long-term treatment of COPD patients with azithromycin, erythromycin or clarithromycin is effective and safe, and reduces exacerbations and related hospitalizations. However, uncertainty remains about the specific patient population that is most likely to benefit from long-term macrolide treatment, the optimal dose and duration of macrolide treatment, and the potential impact of long-term macrolide treatment on resistance. The budget impact analysis demonstrated that annual hospital savings of ?950 million resulting from fewer exacerbations outweighed additional expenditure on azithromycin of ?595 million, implying that the prevention of COPD exacerbations with azithromycin is a cost saving strategy in Belgium. PMID- 23352221 TI - Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. AB - Interleukin-2 (IL-2) is a pleiotropic cytokine produced after antigen activation that plays pivotal roles in the immune response. Discovered as a T cell growth factor, IL-2 additionally promotes CD8(+) T cell and natural killer cell cytolytic activity and modulates T cell differentiation programs in response to antigen, promoting naive CD4(+) T cell differentiation into T helper 1 (Th1) and T helper 2 (Th2) cells while inhibiting T helper 17 (Th17) and T follicular helper (Tfh) cell differentiation. Moreover, IL-2 is essential for the development and maintenance of T regulatory cells and for activation-induced cell death, thereby mediating tolerance and limiting inappropriate immune reactions. In this review, we focus on the molecular mechanisms and complex cellular actions of IL-2, its cooperative and opposing effects with other cytokines, and how both promoting and blocking the actions of IL-2 are being utilized in clinical medicine. PMID- 23352224 TI - Comparison of changes in lung function measured by plethymography and IOS after bronchoprovocation. AB - AIM: Lung function tests are essential for the diagnosis and management of bronchial asthma. Impulse oscillation (IOS) system is an alternative way to measure lung mechanics for some patients. We investigated the relative sensitivities of IOS, body plethysmography and spirometry in detecting allergen- and methacholine-induced bronchoconstriction. METHOD: Twenty-two subjects had single allergen inhalation and 8 subjects had 3 methacholine challenges. The tests were stopped when FEV1 fell by 20%. Lung function was measured using IOS (R5, R20, R5-R20, X5, AX, fres), plethysmography (sRaw, sGaw, FRC, lung volumes) and spirometry (FEV1, FVC, PEF, FEF50%) during inhalation challenges, and expressed as percent change from pre-challenge baseline. RESULTS: All subjects were non-smoking adults with mild allergic asthma. Following allergen challenges, the most sensitive IOS index was R5-R20 and the most sensitive plethysmography and spirometry measurements were sRaw, sGaw and FEF50%. Following methacholine challenge the most sensitive IOS index was AX, the most sensitive plethysmography measurement was sRaw. Overall, IOS (R5-R20, AX, X5Hz) proved to be more sensitive than plethysmography and spirometry measurements following allergen-induced and methacholine-induced bronchoconstriction. CONCLUSION: Our result shows that IOS is more sensitive than other lung function tests following allergen and methacholine challenge. In addition, IOS can act as an alternative measurement technique of airway resistance and obstruction in patients where manoeuvres involved in plethysmography and spirometry prove difficult to perform. PMID- 23352225 TI - Bronchiolitis in young female smokers. AB - BACKGROUND: Smoking is a growing concern among young women. However, the pulmonary effects of smoking in young female smokers in their 20's are unknown. OBJECTIVE: The purpose of this study was to determine whether young female smokers demonstrate smoking-related lung abnormalities such as bronchiolitis in their 20's. METHODS: We recruited young females (20-30 yr) from Izmir, Turkey; 29 smokers and 31 lifetime non-smokers. They were all asymptomatic. All subjects performed complete lung function measurements and underwent thoracic computed tomography (CT) scanning at suspended full inspiration using a Toshiba "Aquilion" multi-slice CT scanner. The CT images were analyzed using custom software (Emphylx-J) and published equations to calculate total lung volume, mean lung density, lung mass, and the extent of emphysema. CT images were also read semi quantitatively for respiratory bronchiolitis and emphysema by 2 experienced chest radiologists. When there was substantial difference in scoring, a 3rd (independent) radiologist read the CT scans. Plasma biomarkers of smoking were also measured in these subjects. RESULTS: Although none of the subjects demonstrated emphysema on CT images, 41% of smokers (compared with only 15% of non-smokers) had evidence for respiratory bronchiolitis (with a score of 2 or more; p = 0.0301). There was a significant relationship between pack-years of smoking and the severity of respiratory bronchiolitis in smokers. Plasma interleukin (IL)-6 levels were also higher in smokers than in non-smokers (p = 0.028). Quantitative analysis for emphysema or airways disease on CT scans did not reveal any significant differences in the two groups with the exception of lung mass, which was higher in the smokers than in non-smokers. Lung function was similar between the two groups. CONCLUSION AND CLINICAL RELEVANCE: Young female smokers in their 20's and 30's demonstrate CT changes consistent with respiratory bronchiolitis and elevated plasma IL-6 levels. They also have "heavier" lungs compared with lifetime non-smokers. These data indicate that pathologic changes of smoking occur early in young female smokers in the absence of demonstrable airflow limitation or symptoms. Public health efforts to curb smoking in young women are clearly needed to reduce the burden of smoking related lung disease in women. PMID- 23352226 TI - A randomised trial of fluticasone furoate/vilanterol (50/25 MUg; 100/25 MUg) on lung function in COPD. AB - BACKGROUND: Fluticasone furoate (FF)/vilanterol (VI) is a novel once-daily inhaled corticosteroid/long-acting beta2-agonist combination therapy for COPD. We aimed to assess the efficacy and safety of two strengths of FF/VI (100/25 MUg; 50/25 MUg) vs. individual components (FF 100 MUg, VI 25 MUg) and placebo over 24 weeks. METHODS: Multicentre, randomised, placebo-controlled, double-blind, parallel-group study of patients (N = 1030) with moderate-to-severe COPD. All medication was administered once daily in the morning. Co-primary efficacy endpoints were: (1) weighted mean (wm) FEV1 (0-4 h post-dose on day 168) to assess acute lung function effects; and (2) trough FEV1 (23-24 h post-dose on day 169) to assess long-lasting effects. Symptom-related outcomes were analysed and adverse events (AEs) assessed. RESULTS: Main findings were: (1) the combination of FF/VI at a strength of 100/25 MUg significantly (p < 0.001) improved wm FEV1 (173 ml) and trough FEV1 (115 ml) vs. placebo. Similar effects were observed with FF/VI 50/25 MUg; (2) no significant difference was seen between FF/VI 100/25 MUg and VI 25 MUg for trough FEV1 (48 ml, p = 0.082), while an effect was observed between FF/VI 100/25 MUg and FF 100 MUg for wm FEV1 (120 ml, p < 0.001); (3) VI 25 MUg over 24 weeks improved lung function vs. placebo significantly for wm FEV1 (103 ml, p < 0.001) and trough FEV1 (67 ml, p = 0.017); and (4) no safety signal was observed. CONCLUSIONS: In subjects with moderate-to-severe COPD, FF/VI 100/25 MUg provides rapid and significant sustained bronchodilation at 24 weeks. Lung function is improved to a similar extent with FF/VI 50/25 MUg and to a somewhat lesser extent with VI 25 MUg. All treatments were well tolerated. GSK study number: HZC112206. ClinicalTrials.gov: NCT01053988. PMID- 23352228 TI - When we test, do we stress? Impact of the testing environment on cortisol secretion and memory performance in older adults. AB - CONTEXT: The majority of studies find that older adults have worse memory performance than young adults. However, contextual features in the testing environment may be perceived as stressful by older adults, increasing their stress hormone levels. Given the evidence that older adults are highly sensitive to the effects of stress hormones (cortisol) on memory performance, it is postulated that a stressful testing environment in older adults can lead to an acute stress response and to memory impairments. OBJECTIVE: The current study compared salivary cortisol levels and memory performance in young and older adults tested in environments manipulated to be stressful (unfavourable condition) or not stressful (favourable condition) for each age group. METHODS: 28 young adults and 32 older adults were tested in two testing conditions: (1) a condition favouring young adults (constructed to be less stressful for young adults), and (2) a condition favouring older adults (constructed to be less stressful for older adults). The main outcome measure was salivary cortisol levels. Additionally, immediate and delayed memory performances were assessed during each condition. RESULTS: In older adults only, we found significantly high cortisol levels and low memory performance in the condition favouring young adults. In contrast, cortisol levels were lower and memory performance was better when older adults were tested in conditions favouring them. There was no effect of testing condition in young adults. CONCLUSIONS: The results demonstrate that older adults' memory performance is highly sensitive to the testing environment. These findings have important implications for both research and clinical settings in which older adults are tested for memory performance. PMID- 23352227 TI - mTOR, linking metabolism and immunity. AB - mTOR is an evolutionarily conserved serine/threonine kinase that plays a critical role in cell growth and metabolism by sensing different environmental cues. There is a growing appreciation of mTOR in immunology for its role in integrating diverse signals from the immune microenvironment and coordinating the functions of immune cells and their metabolism. In CD8 T cells, mTOR has shown to influence cellular commitment to effector versus memory programming; in CD4 T cells, mTOR integrates environmental cues that instruct effector cell differentiation. In this review, we summarize and discuss recent advances in the field, with a focus on the mechanisms through which mTOR regulates cellular and humoral immunity. Further understanding will enable the manipulation of mTOR signaling to direct the biological functions of immune cells, which holds great potential for improving immune therapies and vaccination against infections and cancer. PMID- 23352229 TI - Does intranasal oxytocin promote prosocial behavior to an excluded fellow player? A randomized-controlled trial with Cyberball. AB - The neuropeptide oxytocin has been shown to stimulate prosocial behavior. However, recent studies indicate that adverse early caregiving experiences may moderate the positive effects of oxytocin. In this double blind randomized controlled trial we investigated the effects of oxytocin on prosocial behavior during a virtual ball-tossing game called Cyberball. We examined the influence of oxytocin on prosocial helping behavior toward a socially excluded person who was known to the participant, taking into account early caregiving experiences and the emotional facial expression of the excluded person as potential moderators. Participants were 54 women who received a nasal spray containing either 16IU of oxytocin or a placebo and had reported how often their mother used love withdrawal as a disciplinary strategy involving withholding love and affection after a failure or misbehavior. We found that participants compensated for other players' ostracism by throwing the ball more often toward the excluded player. Oxytocin administration further increased the number of ball throws toward the excluded person, but only in individuals who experienced low levels of maternal love withdrawal. The facial expression of the excluded person did not affect prosocial helping behavior and did not moderate the effects of oxytocin. Our findings indicate that the positive effects of oxytocin on prosocial behavior toward a victim of social exclusion are limited to individuals with supportive family backgrounds. PMID- 23352230 TI - Analysis and regulation of amoeboid-like cell motility using synthetic Ca(2+) sensitive proteins. AB - Several recent reports have demonstrated how engineered proteins can control cell motility, an important functional module for ultimately programming cells as therapeutics. We have reported two engineered proteins that regulate the blebbing cell morphology using chimeras of RhoA, a protein that regulates cytoskeletal tension. Here, we show that engineered switching of blebbing can be used to regulate cell motility. First, the analysis of morphology and motility characteristics showed that blebbing cells wobbled, or shifted, faster and less linearly than cells with a wild type morphology. Second, activating engineered protein switches that regulate cell morphology led to predictable changes in motility characteristics. Last, exogenous stimuli such as blue light, acetylcholine and VEGF-A were used to show that groups of proteins could cooperatively increase cell motility in vitro. This work demonstrates that control of RhoA can program the motility patterns of living cells and has implications in studying the relationship between cell morphology and motility. PMID- 23352231 TI - The effects of dehydration, moderate alcohol consumption, and rehydration on cognitive functions. AB - This study investigated the impact of mild-moderate dehydration on alcohol induced deteriorations in cognitive functions. Sixteen healthy males participated in a single-blind, placebo-controlled cross-over design study involving 4 experimental trials (separated by >=7 d). In each trial, participants were dehydrated by 2.5% body mass through exercise. After 1 h recovery in a thermo neutral environment (22 +/- 2 degrees C, 60-70% relative humidity) 4 tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were administered to the participants (test 1). In two of the trials, participants were provided with water equivalent to either 50% or 150% body mass loss and given salt (NaCl) capsules (50 mmol/L). A set volume of alcohol or placebo was then consumed in each trial, incorporating the conditions: dehydration-placebo (DP), dehydration-alcohol (DA), partial rehydration-alcohol (PA), and full rehydration-alcohol (FA). The same 4 CANTAB tasks were then re-administered (test 2). Subjective ratings of mood and estimates of alcohol intoxication and driving impairment were also recorded in each trial. Alcohol consumption caused deterioration on 3 of the 4 CANTAB measures (viz., choice reaction time, executive function and response inhibition). This reduction in performance was exacerbated when participants were dehydrated compared to trials where full rehydration occurred. Subjective ratings of impairment and intoxication were not significantly different between any of the trials where alcohol was consumed; however ratings for alcohol trials were significantly higher than in the placebo trial. These findings suggest that rehydration after exercise that causes fluid loss can attenuate alcohol-related deterioration of cognitive functions. This may pose implications for post match fluid replacement if a moderate amount of alcohol is also consumed. PMID- 23352232 TI - Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. AB - Dendritic cells (DCs) are crucial for mounting allergic airway inflammation, but it is unclear which subset of DCs performs this task. By using CD64 and MAR-1 staining, we reliably separated CD11b(+) monocyte-derived DCs (moDCs) from conventional DCs (cDCs) and studied antigen uptake, migration, and presentation assays of lung and lymph node (LN) DCs in response to inhaled house dust mite (HDM). Mainly CD11b(+) cDCs but not CD103(+) cDCs induced T helper 2 (Th2) cell immunity in HDM-specific T cells in vitro and asthma in vivo. Studies in Flt3l(-/ ) mice, lacking all cDCs, revealed that moDCs were also sufficient to induce Th2 cell-mediated immunity but only when high-dose HDM was given. The main function of moDCs was the production of proinflammatory chemokines and allergen presentation in the lung during challenge. Thus, we have identified migratory CD11b(+) cDCs as the principal subset inducing Th2 cell-mediated immunity in the LN, whereas moDCs orchestrate allergic inflammation in the lung. PMID- 23352233 TI - CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. AB - Gene regulation by cytokine-activated transcription factors of the signal transducer and activator of transcription (STAT) family requires serine phosphorylation within the transactivation domain (TAD). STAT1 and STAT3 TAD phosphorylation occurs upon promoter binding by an unknown kinase. Here, we show that the cyclin-dependent kinase 8 (CDK8) module of the Mediator complex phosphorylated regulatory sites within the TADs of STAT1, STAT3, and STAT5, including S727 within the STAT1 TAD in the interferon (IFN) signaling pathway. We also observed a CDK8 requirement for IFN-gamma-inducible antiviral responses. Microarray analyses revealed that CDK8-mediated STAT1 phosphorylation positively or negatively regulated over 40% of IFN-gamma-responsive genes, and RNA polymerase II occupancy correlated with gene expression changes. This divergent regulation occurred despite similar CDK8 occupancy at both S727 phosphorylation dependent and -independent genes. These data identify CDK8 as a key regulator of STAT1 and antiviral responses and suggest a general role for CDK8 in STAT mediated transcription. As such, CDK8 represents a promising target for therapeutic manipulation of cytokine responses. PMID- 23352235 TI - Human inflammatory dendritic cells induce Th17 cell differentiation. AB - Dendritic cells (DCs) are critical regulators of immune responses. Under noninflammatory conditions, several human DC subsets have been identified. Little is known, however, about the human DC compartment under inflammatory conditions. Here, we characterize a DC population found in human inflammatory fluids that displayed a phenotype distinct from macrophages from the same fluids and from steady-state lymphoid organ and blood DCs. Transcriptome analysis showed that they correspond to a distinct DC subset and share gene signatures with in vitro monocyte-derived DCs. Moreover, human inflammatory DCs, but not inflammatory macrophages, stimulated autologous memory CD4(+) T cells to produce interleukin 17 and induce T helper 17 (Th17) cell differentiation from naive CD4(+) T cells through the selective secretion of Th17 cell-polarizing cytokines. We conclude that inflammatory DCs represent a distinct human DC subset and propose that they are derived from monocytes and are involved in the induction and maintenance of Th17 cell responses. PMID- 23352234 TI - Peripheral prepositioning and local CXCL9 chemokine-mediated guidance orchestrate rapid memory CD8+ T cell responses in the lymph node. AB - After an infection, the immune system generates long-lived memory lymphocytes whose increased frequency and altered state of differentiation enhance host defense against reinfection. Recently, the spatial distribution of memory cells was found to contribute to their protective function. Effector memory CD8+ T cells reside in peripheral tissue sites of initial pathogen encounter, in apparent anticipation of reinfection. Here we show that within lymph nodes (LNs), memory CD8+ T cells were concentrated near peripheral entry portals of lymph borne pathogens, promoting rapid engagement of infected sentinel macrophages. A feed-forward CXCL9-dependent circuit provided additional chemotactic cues that further increase local memory cell density. Memory CD8+ T cells also produced effector responses to local cytokine triggers, but their dynamic behavior differed from that seen after antigen recognition. These data reveal the distinct localization and dynamic behavior of naive versus memory T cells within LNs and how these differences contribute to host defense. PMID- 23352236 TI - Focused parathyroidectomy with intraoperative parathyroid hormone monitoring in patients with lithium-associated primary hyperparathyroidism. AB - BACKGROUND: Lithium-associated hyperparathyroidism has been attributed to multigland hyperplasia requiring bilateral exploration and subtotal parathyroidectomy. Recent studies suggest that some patients may have single gland disease and be eligible for minimally invasive parathyroidectomy. METHODS: We performed a retrospective review of a prospective, single institution parathyroid database of 1,010 patients who underwent parathyroidectomy between December 1999 and October 2010. RESULTS: Nineteen patients with a history of lithium therapy and sporadic hyperparathyroidism were identified. Median age was 50 years (16-68); median duration of therapy was 19 years (1-37); 11 (58%) were on active therapy with lithium for multiple reasons. Preoperative median serum calcium was 10.9 mg/dL (10.0-12.3), median parathyroid hormone was 111 pg/mL (60 186). A total of 18 patients underwent preoperative imaging. Of 12 patients with single-site localization, 6 (50%) underwent a minimally invasive parathyroidectomy, 2 (17%) underwent unilateral explorations, 1 (8%) underwent bilateral exploration, and 3 (25%) had concomitant thyroidectomies. Six patients did not localize and underwent bilateral exploration for multigland disease. One patient without preoperative imaging had single-gland disease. In all operations surgeons used intraoperative parathyroid hormone (IOPTH) monitoring and met intraoperative criteria. Median IOPTH decrease was 74% (54-86) in single-gland disease and 85% (76-95) in multigland disease. Median abnormal gland weight was 590 mg (134-6,750) in single-gland disease and 296 mg (145-2,170) in multigland disease. All patients were normocalcemic at a median follow-up of 19 months (2 118). CONCLUSION: Of 19 patients with lithium exposure, 6 (32%) had multigland disease. However, of the 13 (68%) patients with single gland disease, all 12 who had preoperative imaging had single-site localization. If localization suggests single gland disease, minimally invasive parathyroidectomy with IOPTH monitoring can be successfully performed. PMID- 23352237 TI - Commentary on: The benefits of international rotations to resource-limited settings for U.S. surgery residents. PMID- 23352238 TI - A phase II study of bevacizumab and everolimus as treatment for refractory metastatic renal cell carcinoma. AB - BACKGROUND: Agents that inhibit the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways in metastatic renal cell carcinoma (mRCC) prolong progression-free survival (PFS), but durable complete responses are rare. Combinations of these cytostatic therapies have great potential to improve efficacy and to escape tumoral resistance mechanisms, but supra-additive toxicity is a valid concern. We investigated whether horizontal blockade with the combination of bevacizumab, a monoclonal antibody to VEGF-A, and of everolimus, an oral mTOR inhibitor, improved PFS in patients with clear cell mRCC who had received prior VEGF blockade. METHODS: In this phase II investigator-initiated study, 10 of 30 planned patients were enrolled. Bevacizumab 10 mg/kg was administered intravenously every 14 days. Everolimus was orally dosed at 10 mg daily. The patients were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. RESULTS: The median age was 55 years. The majority of patients were white men with an Eastern Cooperative Oncology Group performance status of 1 (80%) and intermediate risk disease by Memorial Sloan Kettering Cancer Center criteria (70%). All the patients had received 1 prior VEGF inhibitor. The median PFS in the 10 evaluable patients was 5.1 months, which was less than the expected historical control of bevacizumab monotherapy at 6 months. The median overall survival was 21 months. The best response was a partial response in 1 patient and stable disease in 9. Forty percent of the patients were discontinued from the study due to toxicity. CONCLUSIONS: In our experience, the combination of bevacizumab and everolimus was toxic. The efficacy achieved did not support its combined use over sequential administration. Ongoing randomized studies will definitively evaluate the combination's efficacy and tolerability. PMID- 23352239 TI - Benzene, coumarin and quinolinone derivatives from roots of Citrus hystrix. AB - Two coumarins, hystrixarin (1) and (+)-hopeyhopin (2); a benzenoid derivative, hystroxene-I (3) and a quinolinone alkaloid, hystrolinone (4), along with 33 known compounds were isolated from the crude acetone extract of the roots of Citrus hystrix. Their structures were determined by analysis of 1D and 2D NMR spectroscopic data. The antioxidant, anti-HIV and antibacterial activities of the isolated compounds were also evaluated. PMID- 23352240 TI - Celebrating 15 years of new connections. PMID- 23352242 TI - The utility of paradoxical components in biological circuits. AB - A recurring theme in biological circuits is the existence of components that are antagonistically bifunctional, in the sense that they simultaneously have two opposing effects on the same target or biological process. Examples include bifunctional enzymes that carry out two opposing reactions such as phosphorylating and dephosphorylating the same target, regulators that activate and also repress a gene in circuits called incoherent feedforward loops, and cytokines that signal immune cells to both proliferate and die. Such components are termed "paradoxical", and in this review we discuss how they can provide useful features to cell circuits that are otherwise difficult to achieve. In particular, we summarize how paradoxical components can provide robustness, generate temporal pulses, and provide fold-change detection, in which circuits respond to relative rather than absolute changes in signals. PMID- 23352241 TI - Design principles of regulatory networks: searching for the molecular algorithms of the cell. AB - A challenge in biology is to understand how complex molecular networks in the cell execute sophisticated regulatory functions. Here we explore the idea that there are common and general principles that link network structures to biological functions, principles that constrain the design solutions that evolution can converge upon for accomplishing a given cellular task. We describe approaches for classifying networks based on abstract architectures and functions, rather than on the specific molecular components of the networks. For any common regulatory task, can we define the space of all possible molecular solutions? Such inverse approaches might ultimately allow the assembly of a design table of core molecular algorithms that could serve as a guide for building synthetic networks and modulating disease networks. PMID- 23352244 TI - Switches, switches, every where, in any drop we drink. AB - In this issue, Broussard et al. (2013) report genetic switches that regulate cell fate selection; a recombinase attachment site is embedded within a repressor coding sequence, such that integration truncates a proteolysis domain, stabilizing the repressor and setting the switch. PMID- 23352245 TI - Comprehensive mapping of DNA damage: from static genetic maps to condition specific maps. AB - DNA damage can dramatically affect the cell; thus, cells developed multiple pathways to detect and repair such damage. In this issue, Guenole et al. (2013) systematically map genetic interactions in different DNA damage conditions, uncovering specific repair pathways. PMID- 23352243 TI - From systems to structure: bridging networks and mechanism. AB - There is a wide gap between the generation of large-scale biological data sets and more-detailed, structural and mechanistic studies. However, recent studies that explicitly combine data from systems and structural biological approaches are having a profound effect on our ability to predict how mutations and small molecules affect atomic-level mechanisms, disrupt systems-level networks, and ultimately lead to changes in organismal fitness. In fact, we argue that a shared framework for analysis of nonadditive genetic and thermodynamic responses to perturbations will accelerate the integration of reductionist and global approaches. A stronger bridge between these two areas will allow for a deeper and more-complete understanding of complex biological phenomenon and ultimately provide needed breakthroughs in biomedical research. PMID- 23352246 TI - Baseline laboratory test abnormalities are common in early arthritis but rarely contraindicate methotrexate: study of three cohorts (ESPOIR, VErA, and Brittany). AB - OBJECTIVE: To evaluate the prevalence of baseline abnormalities in standard laboratory tests in patients with early arthritis and their impact on selection of disease-modifying antirheumatic drugs according to American College of Rheumatology (ACR) recommendations and/or of nonsteroidal anti-inflammatory drugs. METHODS: In three cohorts of patients with early arthritis (the ESPOIR, VErA, and Brittany cohorts), we evaluated the prevalence of anemia (hemoglobin <1 3 g/dL in men and 12 g/dL in women), leukopenia (<3500 per mm(3)), thrombocytopenia (<150000 per mm(3)), renal dysfunction (mild, creatinine clearance [CrCl]=60-89.9 mL/min; moderate, CrCl=30-59.9 mL/min; or severe, CrCl<30 mL/min), liver cytolysis (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]>N or>2N), and systemic inflammation (erythrocyte sedimentation rate [ESR]>20 and C-reactive protein [CRP]>6). RESULTS: We evaluated 1393 patients (1018 women and 375 men). Anemia was present in 363/1366 (26.5%) patients, leukopenia in 18/1372 (1.3%), and thrombocytopenia in 13/1371 (0.9%). ESR elevation was seen in 50.4% of patients and CRP elevation in 62.7%. The level of AST was above normal in 4% and of ALT in 10% of patients. No patient had severe renal dysfunction, 5.6% had moderate renal dysfunction, and 42.6% had mild renal dysfunction. Among the 1094 patients who had undergone all the tests, only 18 (1.64%, 95% confidence interval, 1-2.64) had a formal contraindication to methotrexate therapy according to ACR recommendations (4 had leukopenia, 12 had high ALT levels, and 2 had high ALT and AST levels). CONCLUSION: Patients with recent-onset arthritis often have anemia, mild or moderate renal dysfunction, and abnormal liver function. However, fewer than 2% have laboratory test abnormalities contraindicating methotrexate therapy. PMID- 23352247 TI - Factors associated with adherence to pharmaceutical treatment for rheumatoid arthritis patients: a systematic review. AB - OBJECTIVES: To identify factors associated with adherence to medication for rheumatoid arthritis or undifferentiated inflammatory arthritis using a systematic literature search. METHODS: PubMed, PsycINFO, EMbase and CINAHL databases were systematically searched from inception to February 2011. Articles were included if they addressed medication adherence, used a reproducible definition, determinants and its statistical relationship. Methodological quality was assessed using a quality assessment list for observational studies derived from recommendations from Sanderson et al. (2007) [12]. Resulting factors were interpreted using the Health Belief Model (HBM). RESULTS: 18 out of 1479 identified studies fulfilled the inclusion criteria. 64 factors were identified and grouped according to the HBM into demographic and psychosocial characteristics, cues to action and perceived benefits versus perceived barriers. The belief that the medication is necessary and DMARD use prior to the use of anti-TNF had strong evidence for a positive association with adherence. There is limited evidence for positive associations between adherence and race other than White, general cognition, satisfactory contact with the healthcare provider and the provision of adequate information from the healthcare provider. There is limited evidence for negative associations between adherence and having HMO insurance, weekly costs of TNF-I, having a busy lifestyle, receiving contradictory information or delivery of information in an insensitive manner by the rheumatologist. 18 factors were unrelated to adherence. CONCLUSIONS: The strongest relation with adherence is found to be prior use of DMARDs before using anti-TNF and beliefs about the necessity of the medication. Because the last one is modifiable, this provides hope to improve adherence. PMID- 23352248 TI - Cardiovascular thromboembolic events associated with febuxostat: investigation of cases from the FDA adverse event reporting system database. AB - OBJECTIVE: Uloric (Febuxostat) has been linked with cardiovascular thromboembolic events in gout patients. However, no post-marketing data analysis has investigated these drug-associated adverse event reports. The study objective was to identify febuxostat-associated cardiovascular thromboembolic event reports in the US using the Food and Drug Administration adverse event reporting system (AERS) database. METHODS: Reports listing uloric and febuxostat as the suspect drug and cardiovascular thromboembolic events (combined in a single term based on adverse event reports of myocardial infarction, stroke, among others) as the adverse event were extracted from the drug's approval date through the fourth quarter of 2011. Bayesian statistics within the neural network architecture was implemented to identify potential signals of febuxostat-associated cardiovascular thromboembolic events. A potential signal for the drug-adverse event combination reports is generated when the lower limit of the 95% two-sided confidence interval of the information component (IC), denoted by IC025 is greater than zero. RESULTS: Twenty-one combination reports of febuxostat-associated cardiovascular thromboembolic events were identified in gout patients in the US. The mean age of combination cases was 64 years. Potential signals (IC025 = 4.09) was generated for combination reports of febuxostat-associated cardiovascular thromboembolic events. CONCLUSION: AERS indicated potential signals of febuxostat associated cardiovascular thromboembolic events. AERS is not capable of establishing the causal link and detecting the true frequency of an adverse event associated with a drug. The positive IC value found in this study merits continued surveillance and assessment of cardiovascular thromboembolic events associated with Febuxostat. PMID- 23352249 TI - Lactulose breath test to assess oro-cecal transit delay and estimate esophageal dysmotility in scleroderma patients. AB - OBJECTIVES: To assess the correlation between delayed oro-cecal transit time (OCTT) and esophageal motility abnormalities in a cohort of systemic sclerosis (SSc) patients. METHODS: We prospectively enrolled 50 consecutive SSc patients and 60 healthy volunteers (HVs) as controls. Both groups underwent glucose breath test (GBT) to exclude small intestine bacterial overgrowth, lactulose hydrogen, and octanoic acid breath tests (LHBT and OBT) to measure OCTT and gastric emptying (GE), respectively, and manometry to assess esophageal motility. RESULTS: Thirty-one (63%) SSc patients presented ineffective esophageal motility (IEM) compared with 3 HVs (5%; P<0.01), 37 (74%) had an abnormal OCTT compared with 4 HVs (7%; P <0.01), and 16 (32%) had an altered GE compared with 4 HVs (7%; P <0.01). The median OCTT and gastric t1/2 were longer in SSc than in HVs (165 min vs. 101 min and 125 min vs. 78 min, respectively; P <0.01). A delayed GE was present in 12/37 (32%), whereas IEM in 27/37 (73%) SSc patients with prolonged OCTT. The prevalence of IEM increased in parallel with the prolongation of OCTT (31% when OCTT<150 min, 73% when OCTT>=150 min, and up to 85% when OCTT>180 min, P<0.01). CONCLUSIONS: Abnormalities of both esophageal and small intestine motility are frequent in SSc patients and esophageal motility is altered in most cases with small bowel involvement. Delayed GE plays a limited role in prolonging OCTT. LHBT is a non-invasive, cheap, well-tolerated diagnostic tool that may be useful to estimate intestinal involvement and also to estimate a higher risk of esophageal hypomotility in SSc patients. PMID- 23352250 TI - Progressive bilateral lipoma arborescens of the knee complicated by juvenile spondyloarthropathy: a case report and review of the literature. AB - OBJECTIVES: To report an unusual case of lipoma aborescens (LA) presented in a patient with treatment-responsive juvenile spondyloarthropathy (JSPA) and to summarize the clinical manifestations, therapy and prognosis of LA by literature review. METHODS: We report an atypical case of a 17-year-old patient with an initial presentation of juvenile spondyloarthropathy, whose inflammatory condition was improved successfully by traditional anti-rheumatic drugs and an anti-TNF alpha agent but developed progressive swelling of bilateral knees. Lipoma arborescens were diagnosed in each knee by synovial biopsy obtained by arthroscopic surgery. Fifty-one cases of LA have been reported and are reviewed in detail. RESULTS: Clinically, LA could present as monoarthritis or oligoarthritis. The lateral compartment of the knee is the most common site of involvement. Several cases were reported as a comorbidity of inflammatory diseases, but were not improved by anti-inflammatory therapy. Most patients were diagnosed by classic MRI and biopsy findings. The lesions can be managed by open or arthroscopic surgery, but a minority of the cases may have reoccurrence in the same or opposite joint. CONCLUSIONS: LA is a very rare lesion of the synovial and bursal tissue with an unknown etiology. It is considered to be a benign proliferation of the synovial fat associated with trauma, degenerative or inflammatory conditions. LA should be considered as a secondary or comorbid condition in inflammatory arthropathies if other joints respond well to intensive therapy and one or more do not. PMID- 23352251 TI - Intra-articular steroid injection for temporomandibular joint arthritis in juvenile idiopathic arthritis: A systematic review on efficacy and safety. AB - OBJECTIVE: To determine the current level of evidence for the use of intra articular corticosteroid injections (IACI) against temporomandibular joint (TMJ) arthritis in patients with juvenile idiopathic arthritis (JIA) with a particular focus on clinical and radiological improvements and safety profile. METHODS: A comprehensive electronic search strategy was performed in all major medical databases in February 2012. Studies were selected independently by two reviewers in accordance with a pre-specified protocol and a risk of bias assessment for all included studies. RESULTS: Ninety-four unique citations were identified of which seven remained after the inclusion criteria were applied and all of these were assessed to have a high risk of bias. The current limited level of evidence suggests potential beneficial properties of IACI in patients with TMJ arthritis related symptoms and/or MRI-verified signs of TMJ inflammation. Currently, no scientific evidence substantiates the effect of IACI in terms of (I) improving maximal mouth opening capacity significantly, (II) reducing radiological disease progression, (III) normalising/improving mandibular growth, and (IV) increasing efficacy upon repeated injections. CONCLUSION: The current level of evidence allows only very limited conclusions on the effect of IACI therapy in patients with TMJ arthritis. Knowledge on the long-term impact of IACI on mandibular growth is not available. Future studies designed in accordance with evidence based standards are needed to allow a more general conclusion on efficacy and safety of this treatment modality in patients with TMJ arthritis. PMID- 23352252 TI - Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases. AB - OBJECTIVES: To systematically review literature about the structure and function of nucleotide-binding oligomerization domain containing 2 (NOD2) and its disease association. METHODS: The English literature was searched using keywords "NOD2" and "disease". Relevant original and review articles were reviewed. RESULTS: NOD2 is an intracellular protein and shares similar molecular structure with NOD1, pyrin, and cryopyrin. There are more than 100 NOD2 gene mutations, some of which have been linked to diseases such as Crohn disease, Blau syndrome, and NOD2 associated autoinflammatory disease (NAID). The NOD2 variants located in the leucine-rich repeat (LRR) region are susceptible to Crohn disease, and the variants in the nucleotide-binding domain (NBD) and in between the NBD and LRR are associated with Blau syndrome and NAID, respectively. No disease association with the gene variants has been found in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis/psoriatic arthritis, adult sarcoidosis, granulomatous polyangiitis, or multiple sclerosis. The potential association of the NOD2 variants with graft-versus-host-disease remains controversial. NOD2 functions mainly through RICK or RIP2 to activate p38 mitogen activated protein kinases and NF-kappaB, resulting in inflammatory response, and enhanced autophagic activity. Biologic therapy may be beneficial for NOD2 associated diseases, and new drug development may be realized based upon the signaling pathways. CONCLUSIONS: NOD2 gene mutations are associated with several diseases, and some of the mutations are of diagnostic value in Blau disease and NAID. To understand the NOD2 function, disease association, and its pathogenesis is important given the ever increasing clinical significance of NOD2. PMID- 23352253 TI - Childhood obesity case statement. AB - OBJECTIVE: The goal of this publication is to raise awareness of the impact of childhood obesity on the musculoskeletal health of children and its potential long-term implications. METHODS: Relevant articles dealing with musculoskeletal disorders either caused by or worsened by childhood obesity were reviewed through a Pub Med search. Efforts to recognize and combat the childhood obesity epidemic were also identified through Internet search engines. This case statement was then reviewed by the members of the pediatric specialty group of the US Bone and Joint Initiative, which represents an extensive number of organizations dealing with musculoskeletal health. RESULTS: Multiple musculoskeletal disorders are clearly caused by or worsened by childhood obesity. The review of the literature clearly demonstrates the increased frequency and severity of many childhood musculoskeletal disorders. Concerns about the long-term implications of these childhood onset disorders such as pain and degenerative changes into adulthood are clearly recognized by all the member organizations of the US Bone and Joint Initiative. CONCLUSIONS: It is imperative to recognize the long-term implications of musculoskeletal disorders caused by or worsened by childhood obesity. It is also important to recognize that the ability to exercise comfortably is a key factor to developing a healthy lifestyle and maintaining a healthy body weight. Efforts to develop reasonable and acceptable programs to increase physical activity by all facets of society should be supported. Further research into the long-term implications of childhood musculoskeletal disorders related to childhood obesity is necessary. PMID- 23352254 TI - Anti-glomerular basement membrane antibody disease treated with rituximab: A case based review. AB - OBJECTIVES: To report the successful use of rituximab in a patient with anti- glomerular basement membrane (GBM) antibody disease and to review the literature regarding rituximab use in anti-GBM mediated disease. METHODS: We report a case of anti-GBM antibody disease with both anti-GBM antibodies and anti myeloperoxidase (MPO) specific p-ANCA, who developed thrombotic thrombocytopenic purpura (TTP) on high dose prednisone, plasmapheresis, and cyclophosphamide therapy. The patient was then treated with rituximab. We analyzed the clinical features of five additional patients of anti-GBM disease treated with rituximab identified through a systematic literature review. RESULTS: Our patient was 68 year-old female who presented with acute renal failure. Renal biopsy showed crescentic glomerulonephritis with linear deposits of IgG antibody along the glomerular basement membrane. Treatment was initiated with high dose prednisone, plasmapheresis and oral cyclophosphamide, with subsequent development of leukopenia and TTP and discontinuance of cyclophosphamide. Treatment with rituximab was initiated with clinical improvement of her hematological parameters but not her renal function. Among the five previously reported cases of anti-GBM disease treated with rituximab, three received brief course of IV cyclophosphamide prior to use of rituximab. Except one patient, all recovered renal function and remained dialysis independent. The anti-GBM antibody level remained undetected in all patients. CONCLUSIONS: Combination of prednisone, plasmapheresis, and rituximab can be an effective therapy in patients with an anti-GBM antibody disease complicated with TTP. PMID- 23352255 TI - Clinimetric methods in Sjogren's syndrome. AB - OBJECTIVE: Clinimetric tools are useful in both clinical practice and research of Sjogren's syndrome. These instruments assist in the establishment of diagnosis and in the evaluation of disease status. We reviewed the available methods used to monitor sicca signs and symptoms, fatigue, quality of life as well as activity/chronicity in SS. METHODS: PubMed and MEDLINE database were searched for the keywords "keratoconjunctivitis sicca diagnosis," "dry eye and dry mouth assessment," "sialometry," "sialochemistry," "Sjogren's syndrome outcomes," "Sjogren's syndrome activity," "Sjogren's syndrome damage," "fatigue scales in Sjogren's syndrome," and "Sjogren's syndrome quality of life." All relevant articles and pertinent secondary references were reviewed. RESULTS: As there is a moderate correlation between sicca symptoms and signs, the assessment of both is crucial. Most of the tests focus on oral and ocular dryness (vital dye staining, tear quantification, tear composition, sialometry, sialochemistry, etc.) and may not be disease specific. Symptoms such as dryness and fatigue have been evaluated with different instruments, being the PROFAD and ESSPRI disease-specific tools. Standardized measures for activity (SSDAI, SCAI, and ESSDAI) and chronicity (SSDDI and SSDI) indexes are currently used, however these methods still present limitations such as low external validity and cross-validation. CONCLUSION: The heterogeneous nature of the disease and its slow progression, challenge the evaluation of these patients. The use of composite measures might increase our ability to diagnose and evaluate disease activity and cumulative irreversible organ injury in this disease. However the distinction among oral and ocular activity vs. damage is still a matter of research. PMID- 23352256 TI - 25 years of Current Opinion in Cell Biology. PMID- 23352257 TI - Development of a validated HPLC method for the simultaneous determination of flavonoids in Cuscuta chinensis Lam. by ultra-violet detection. AB - BACKGROUND: Cuscuta species known as dodder, have been used in traditional medicine of eastern and southern Asian countries as liver and kidney tonic. Flavonoids are considered as the main biologically active constituents in Cuscuta plants especially in C. chinensis Lam. OBJECTIVE: In the present study, a fast, simple and reliable method for the simultaneous determination and quantization of C. chinensis flavonols including hyperoside, rutin, isorhamnetin and kaempferol has been developed. MATERIALS AND METHODS: The chromatographic separation was carried out on a reversed phase ACE 5 C18 with eluting at a flow rate of 1 ml/min using a gradient with O-phosphoric acid 0.25% : acetonitrile for 42 min. UV spectra were collected across the range of 200-900 nm, extracting 360 nm for the chromatograms. The method was validated according to linearity, selectivity, precision, recovery, LOD and LOQ. RESULTS: The method was selective for determination of rutin, hyperoside, isorhamnetin and kampferol. The calibration graphs of flavonols were linear with r2 > 0.999. RSDs% of intra- and inter-day precisions were found 1.3&3.4 for rutin, 1.5&2.8 for hyperoside, 1.3&3.3 for isorhamnetin and 1.7 & 2.9 for kaempferol which were satisfactory. LODs and LOQs were calculated as 1.73 & 8.19 for rutin, 0.09 & 4.19 for hyperoside, 2.09 & 6.3 for isorhamnetin and 0.18 & 0.56 for kaempferol. The recovery averages of above mentioned flavonols were 90.3%, 97.4%, 98.7% and 90.0%, respectively. CONCLUSION: The simplicity of the method makes it highly valuable for quality control of C. chinensis according to quantization of flavonols. PMID- 23352258 TI - Genetic basis of Y-linked hearing impairment. AB - A single Mendelian trait has been mapped to the human Y chromosome: Y-linked hearing impairment. The molecular basis of this disorder is unknown. Here, we report the detailed characterization of the DFNY1 Y chromosome and its comparison with a closely related Y chromosome from an unaffected branch of the family. The DFNY1 chromosome carries a complex rearrangement, including duplication of several noncontiguous segments of the Y chromosome and insertion of ~160 kb of DNA from chromosome 1, in the pericentric region of Yp. This segment of chromosome 1 is derived entirely from within a known hearing impairment locus, DFNA49. We suggest that a third copy of one or more genes from the shared segment of chromosome 1 might be responsible for the hearing-loss phenotype. PMID- 23352260 TI - [Staphylococcus aureus nasal colonization in medical students: importance in nosocomial transmission]. AB - BACKGROUND: Staphylococcus aureus is the main pathogen causing nosocomial infections. Health professionals, including medical students, could be a source of transmission. The aims of the study were to determine the rate of nasal carriage of S.aureus susceptible and resistant to methicillin (MRSA) and evaluate the knowledge and adherence that students had about hand hygiene. METHODS: The study included medical students attached to the Hospital Universitario 12 de Octubre (Madrid, Spain). We collected samples from both nasal vestibules, and the antimicrobial susceptibility was determined on all isolates. Data collection was performed using a self-administered questionnaire that included risk factors for colonization, hygiene habits and knowledge of hand hygiene protocols. RESULTS: Of the 140 students included, 55 (39.3%) were colonized by S.aureus, and 3 (2,1%) by MRSA. The exposure to antibiotics in the last 3 months was lower in colonized students (12.3% vs. 25.9%, P=.03). Self-assessment showed that 56.4% of students almost never washed their hands before to attending to the first patient, and only 38.6% always washed after examining patients. More than a third (35.7%) ignored the hand hygiene protocol, and 38.6% had not received specific formation. CONCLUSIONS: Medical students should be included in hospital infection control programs. Hand hygiene training should be given to students before they begin their practices in the hospital. PMID- 23352259 TI - Mutations in DNA2 link progressive myopathy to mitochondrial DNA instability. AB - Syndromes associated with multiple mtDNA deletions are due to different molecular defects that can result in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia (PEO) to multisystemic disorders of variable severity. The autosomal-dominant form of PEO is genetically heterogeneous. Recently, causative mutations have been reported in several nuclear genes that encode proteins of the mtDNA replisome machinery (POLG, POLG2, and C10orf2) or that are involved in pathways for the synthesis of deoxyribonuclotides (ANT1 and RRM2B). Despite these findings, putative mutations remain unknown in half of the subjects with PEO. We report the identification, by exome sequencing, of mutations in DNA2 in adult-onset individuals with a form of mitochondrial myopathy featuring instability of muscle mtDNA. DNA2 encodes a helicase/nuclease family member that is most likely involved in mtDNA replication, as well as in the long-patch base-excision repair (LP-BER) pathway. In vitro biochemical analysis of purified mutant proteins revealed a severe impairment of nuclease, helicase, and ATPase activities. These results implicate human DNA2 and the LP-BER pathway in the pathogenesis of adult-onset disorders of mtDNA maintenance. PMID- 23352261 TI - [Eradication of a nosocomial outbreak of multidrug-resistant Acinetobacter baumannii infections after adjusting nursing workloads and reinforcing specific precautions]. AB - INTRODUCTION: During 2009, an outbreak of multidrug-resistant Acinetobacter baumannii (MDR A. baumannii) infections was detected in a 27-bed intensive care unit, resulting in 25 cases being infected. METHODS: A matched case-control study was conducted to identify risk factors for infection. The colonization pressure, or the proportion of other patients colonized by MDR A. baumannii, was estimated. TISS-28 and Omega scores of each patient were calculated to evaluate nursing work requirements. Conditional logistic regression analyses were carried out. RESULTS: Breakdowns in hand washing and glove use were observed. Infected patients (cases) were more likely than paired controls to have had longer exposure to invasive devices and antimicrobial treatment. The independent risk factors identified by the multivariate analysis were, mechanical ventilation [odds ratio (OR)=1.03; 95% confidence interval (CI), 1.01-1.05; P=.01], and exposure to an infected or colonized patient [OR=1.7; 95%CI, 1.1-2.6; P=.02). A combined infection control strategy was implemented, including strict compliance with isolation precautions, grouping of patients, reinforcing cleaning and disinfection of surfaces, and a decrease in work load. Subsequently, a sharp reduction in the incidence MDR A. baumannii infections was shown. Therapeutic activity scores were significantly higher for cases than for controls. CONCLUSION: The results suggest patient-to patient transmission of MDR A. baumannii. Reinforcement of specific procedures and work load adjustment were essential to eradicate this outbreak. PMID- 23352262 TI - Comparison of adverse outcomes after contemporary percutaneous coronary intervention in women versus men with acute coronary syndrome. AB - Previous studies have shown a relation between female gender and adverse outcomes after percutaneous coronary intervention (PCI). The aim of this study was to determine whether there are differences in correlates between genders for these long-term adverse outcomes in patients with acute coronary syndromes. Gender differences were evaluated in the clinical outcomes of 6,929 consecutive patients with acute coronary syndromes from a large, contemporary PCI registry. Rates of major adverse cardiovascular events, defined as all-cause mortality, myocardial infarction, and target lesion revascularization at 1-year follow-up, are reported. Independent correlates of adverse outcomes were identified using multivariate proportional-hazards regression analysis. Women were older (p <0.001); had a higher prevalence of diabetes mellitus (p <0.001), systemic hypertension (p <0.001), chronic renal insufficiency (p = 0.02), peripheral arterial disease (p <0.001), and congestive heart failure (p <0.001); had lower body surface areas (p <0.001); and had higher body mass indexes (p <0.001). Acute coronary syndrome presentation in women tended to be unstable angina pectoris with Canadian Cardiovascular Society class III and IV symptoms, whereas men had more acute myocardial infarctions. At 1 year, the unadjusted rates of all-cause mortality (10.7% vs 7.5%, p <0.001) and major adverse cardiovascular events (16.4% vs 12.7%, p <0.001) were higher in women. There was a stark difference between the genders in independent correlates of mortality and major adverse cardiovascular events at 1 year. Moreover, the traditional correlates did not have the same impact in women as in men. In conclusion, although there are differences in clinical outcomes after PCI for women compared with men, there are different correlates for these adverse outcomes. These gender-based differences should be taken into account when women undergo contemporary PCI. PMID- 23352263 TI - What we counted. PMID- 23352264 TI - Comparison of two-dimensional versus real-time three-dimensional transesophageal echocardiography for evaluation of patent foramen ovale morphology. AB - The aim of this study was to elucidate patent foramen ovale (PFO) morphology and the change of PFO size using real-time 3-dimensional (3D) transesophageal echocardiography (TEE). PFO is a 3D structure, and its shape changes during the cardiac cycle. Therefore, it may be difficult to estimate accurate PFO morphology using 2-dimensional (2D) TEE. The study included 50 patients with PFO who underwent 2D and 3D TEE. PFO heights (PHs) at entrance, mid, and exit were measured by 2D and 3D TEE. Systolic and diastolic areas were also measured by 3D TEE. PH by 3D TEE was larger than that by 2D TEE (entrance 0.32 +/- 0.18 vs 0.21 +/- 0.15 cm, p <0.001; mid 0.25 +/- 0.14 vs 0.15 +/- 0.11 cm, p <0.001; exit 0.19 +/- 0.11 vs 0.11 +/- 0.08 cm, p <0.001). Systolic area was greater than diastolic area at each location (entrance 0.19 +/- 0.17 vs 0.11 +/- 0.11 cm(2), p = 0.001; mid 0.13 +/- 0.11 vs 0.08 +/- 0.06 cm(2), p = 0.001; exit 0.09 +/- 0.09 vs 0.06 +/- 0.05 cm(2), p = 0.01). Additionally, entrance area was greater than exit area in systole and diastole (systole 0.19 +/- 0.17 vs 0.09 +/- 0.09 cm(2), p <0.001; diastole 0.11 +/- 0.11 vs 0.06 +/- 0.05 cm(2), p = 0.001). There were good correlations between PH by 3D TEE and PFO area (entrance r = 0.68, mid r = 0.71, exit r = 0.78) but weak correlations between PH by 2D TEE and PFO area (entrance r = 0.62, mid r = 0.50, exit r = 0.51). In conclusion, real-time 3D TEE could provide detailed and unique information on PFO morphology. PMID- 23352265 TI - Association of serum uric acid and cardiovascular disease in healthy adults. AB - Studies in different populations with high risk for cardiovascular disease (CVD) have shown an association between serum uric acid (SUA) and CVD. However, only a few studies have demonstrated such an association in healthy populations. The aim of this study was to investigate the association between SUA and CVD in a cohort of men and women without diabetes or CVD. A retrospective study was conducted, with a mean 4.8-year follow-up. The outcome was the occurrence of a cardiovascular event, defined as the diagnosis of ischemic heart disease, acute coronary syndrome, acute myocardial infarction, or ischemic stroke. Mean SUA levels were 6.2 +/- 1.1 mg/dl for men (n = 6,580) and 4.4 +/- 1.1 mg/dl for women (n = 2,559). For women, the rate of CVD occurrence was 11.6% for the highest quartile of SUA level, compared with 5.0% to 6.5% for the lower 3 quartiles. For men, the rate of CVD occurrence was 14.0% for the highest quartile of SUA level, compared with 10.8% for the lowest quartile. The hazard ratio for CVD, adjusted for age, serum creatinine level, body mass index, systolic blood pressure, low density lipoprotein cholesterol level, triglyceride level, plasma fasting glucose, physical activity, cardiovascular family history, use of diuretics, and current smoking, was 1.24 (95% confidence interval 1.08 to 1.41) for women and 1.06 (95% confidence interval 1.00 to 1.13) for men (p for interaction = 0.04). In conclusion, the strong association of SUA levels with CVD in women, compared with the much lesser degree in men, highlights the necessity of stratifying by gender in investigations of cardiovascular risk factors and supports exploration of SUA as a marker of CVD risk in healthy populations. PMID- 23352266 TI - Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus. AB - Recent reports indicate that statins are associated with an increased risk for new-onset diabetes mellitus (DM) compared with placebo and that this relation is dose dependent. The aim of this study was to perform a comprehensive network meta analysis of randomized controlled trials (RCTs) investigating the impact of different types and doses of statins on new-onset DM. RCTs comparing different types and doses of statins with placebo were searched for using the MEDLINE, Embase, and Cochrane databases. A search of RCTs pertinent to this meta-analysis covering the period from November 1994 to October 2012 was conducted by 2 independent investigators using the MEDLINE, Cochrane, Google Scholar, and Embase databases as well as abstracts and presentations from major cardiovascular meetings. Seventeen RCTs reporting the incidence of new-onset DM during statin treatment and including a total of 113,394 patients were identified. The RCTs compared either a statin versus placebo or high-dose versus moderate-dose statin therapy. Among different statins, pravastatin 40 mg/day was associated with the lowest risk for new-onset DM compared with placebo (odds ratio 1.07, 95% credible interval 0.86 to 1.30). Conversely, rosuvastatin 20 mg/day was numerically associated with 25% increased risk for DM compared with placebo (odds ratio 1.25, 95% credible interval 0.82 to 1.90). The impact on DM appeared to be intermediate with atorvastatin 80 mg/day compared with placebo (odds ratio 1.15, 95% credible interval 0.90 to 1.50). These findings were replicated at moderate doses. In conclusion, different types and doses of statins show different potential to increase the incidence of DM. PMID- 23352267 TI - Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity. AB - The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity. PMID- 23352268 TI - A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines acting as antimycobacterial agents. AB - A series of fourteen dispiropyrrolidines were synthesized using [3+2] cycloaddition reactions and were screened for their antimycobacterial activity against Mycobacterium tuberculosis H(37)Rv in HTS (High Throughput Screen). Most of the compounds showed moderate to good activity with MIC of less than 20 MUM. Compound 4'-(4-bromophenyl)-1'-methyldispiro[acenaphthylene-1,2'-pyrrolidine 3',2"-indane]-2,1"(1H)-dione (4c) was found to be the most active with MIC of 12.50 MUM. PMID- 23352269 TI - Synthesis and enzymatic incorporation of alpha-L-threofuranosyl adenine triphosphate (tATP). AB - Threose nucleic acid (TNA) is an artificial genetic polymer in which the natural ribose sugar found in RNA has been replaced with an unnatural threose sugar. TNA can be synthesized enzymatically using Therminator DNA polymerase to copy DNA templates into TNA. Here, we expand the substrate repertoire of Therminator DNA polymerase to include threofuranosyl adenine 3'-triphsophate (tATP). We chemically synthesized tATP by two different methods from the 2'-O-acetyl derivative. Enzyme-mediated polymerization reveals that tATP functions as an efficient substrate for Therminator DNA polymerase, indicating that tATP can replace the diaminopurine analogue (tDTP) in TNA transcription reactions. PMID- 23352270 TI - Increasing glucose load while maintaining normoglycemia does not evoke neuronal damage in prolonged critically ill rabbits. AB - BACKGROUND & AIMS: Preventing severe hyperglycemia with insulin reduced the neuropathological alterations in frontal cortex during critical illness. We investigated the impact of increasing glucose load under normoglycemia on neurons and glial cells. METHODS: Hyperinflammatory critically ill rabbits were randomized to fasting or combined parenteral nutrition containing progressively increasing amounts of glucose (low, intermediate, high) within the physiological range but with a similar amount of amino acids and lipids. In all groups, normoglycemia was maintained with insulin. On day 7, we studied the neuropathological alterations in frontal cortex neurons, astrocytes and microglia, and MnSOD as marker of oxidative stress. RESULTS: The percentage of damaged neurons was comparable among all critically ill and healthy rabbits. Critical illness induced an overall 1.8-fold increase in astrocyte density and activation status, largely irrespective of the nutritional intake. The percentage of microglia activation in critically ill rabbits was comparable with that in healthy rabbits, irrespective of glucose load. Likewise, MnSOD expression was comparable in critically ill and healthy rabbits without any clear impact of the nutritional interventions. CONCLUSIONS: During prolonged critical illness, increasing intravenous glucose infusion while strictly maintaining normoglycemia appeared safe for neuronal integrity and did not substantially affect glial cells in frontal cortex. PMID- 23352272 TI - Gill histopathological and oxidative stress evaluation in native fish captured in Portuguese northwestern rivers. AB - The Northwestern Portuguese region is densely populated and highly industrialized, suffering from high anthropogenic pressure. To assess the biological effect of the several pollutants that are constantly released to the water, a biomarker-based biomonitoring is a promising approach that may provide early-warning signals of pollutants exposure. Fish gill is the first target of pollutants action, thus histopathological and biochemical changes may constitute potential biomarkers. To evaluate this hypothesis, three native fish species (barbel-Luciobarbus bocagei, chub-Squalius carolitertii and nase Pseudochondrostoma sp.) were sampled in Northwestern Portuguese rivers, the gill histopathological changes were qualitative and quantitatively analyzed and the lipid peroxidation and glutathione-S-transferase activity were determined. A multivariate statistical analysis was performed to establish correlations between these biological responses, environmental variables and ecological status. The quantitative evaluation of the main histopathological changes and oxidative stress responses emphasize the differences, among species, in the responses to the presence of contaminants in water. Discriminant canonical analysis showed that filament epithelium proliferation, necrosis and GST activity were the main contributors to discriminate the ecological status classification. In addition, the results showed that a wide range of environmental factors are influencing fish physiology. In conclusion, the gill biological responses, although not reflecting specific contaminants, can be used as biomarkers of ecosystems perturbation. PMID- 23352271 TI - Prolonged breast-feeding is an independent risk factor for postmenopausal osteoporosis. AB - OBJECTIVES: This study investigated the effects of parity and age at first pregnancy and breast-feeding, as well as duration of BF for total and per child on postmenopausal osteoporosis. STUDY DESIGN: The study was conducted among 542 cases who were divided based on the presence or absence of osteoporosis. Patients were separated according to their first pregnancy and breast-feeding age as before or after 27 years. Osteoporosis was defined as a T score of -2.5 or lower. MAIN OUTCOME MEASURES: Parity, age at first pregnancy and breast-feeding, breast feeding period for total and average duration per child according to a questionnaire were assessed. RESULTS: Osteoporosis group had significantly lower parity compared to non-osteoporosis group. The age at first pregnancy and breast feeding<27 age were significantly more frequent in osteoporosis group. They also had prolonged breast-feeding period. Women who had a breast-feeding period per child>1 year under age 27 was higher in osteoporosis group. In multivariate analysis, women who breast-fed>1 year per child had the highest risk for osteoporosis (odds ratio: 12.92; 95% confidence interval, 3.1-52.6) and osteoporosis risk for women who breast-fed>1 year per child under age 27 was 7.1. Increased parity was associated with a significant protective effect for osteoporosis. CONCLUSIONS: Extended breast-feeding period per child>1 year is the highest risk factor for osteoporosis independent of first breast-feeding age. However, high parity has a protective effect. PMID- 23352274 TI - The influence of inequality on the standard of living: worldwide anthropometric evidence from the 19th and 20th centuries. AB - We provide empirical evidence on the existence of the Pigou-Dalton principle. The latter indicates that aggregate welfare is - ceteris paribus - maximized when incomes of all individuals are equalized (and therefore marginal utility from income is as well). Using anthropometric panel data on 101 countries during the 19th and 20th centuries, we determine that there is a systematic negative and concave relationship between height inequality and average height. The robustness of this relationship is tested by means of several robustness checks, including two instrument variable regressions. These findings help to elucidate the impact of economic inequality on welfare. PMID- 23352273 TI - Inhibiting connexin channels protects against cryopreservation-induced cell death in human blood vessels. AB - OBJECTIVES: Cryopreserved blood vessels are being increasingly employed in vascular reconstruction procedures but freezing/thawing is associated with significant cell death that may lead to graft failure. Vascular cells express connexin proteins that form gap junction channels and hemichannels. Gap junction channels directly connect the cytoplasm of adjacent cells and may facilitate the passage of cell death messengers leading to bystander cell death. Two hemichannels form a gap junction channel but these channels are also present as free non-connected hemichannels. Hemichannels are normally closed but may open under stressful conditions and thereby promote cell death. We here investigated whether blocking gap junctions and hemichannels could prevent cell death after cryopreservation. MATERIALS AND METHODS: Inclusion of Gap27, a connexin channel inhibitory peptide, during cryopreservation and thawing of human saphenous veins and femoral arteries was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assays and histological examination. RESULTS: We report that Gap27 significantly reduces cell death in human femoral arteries and saphenous veins when present during cryopreservation/thawing. In particular, smooth muscle cell death was reduced by 73% in arteries and 71% in veins, while endothelial cell death was reduced by 32% in arteries and 51% in veins. CONCLUSIONS: We conclude that inhibiting connexin channels during cryopreservation strongly promotes vascular cell viability. PMID- 23352275 TI - Dorsal/ventral parcellation of the amygdala: relevance to impulsivity and aggression. AB - Investigations into the specific association of amygdala volume, a critical aspect of the fronto-limbic emotional circuitry, and aggression have produced results broadly consistent with the 'larger is more powerful' doctrine. However, recent reports suggest that the ventral and dorsal aspects of the amygdala play functionally specific roles, respectively, in the activation and control of behavior. Therefore, parceling amygdala volume into dorsal and ventral components might prove productive in testing hypotheses regarding volumetric association to aggression, and impulsivity, a related aspect of self-control. We sought to test this hypothesis in a group of 41 psychiatric patients who received standard magnetic resonance imaging and a psychometric protocol including aggression and impulsivity measures. Whole amygdala volumes were not associated with aggression or impulsivity, but significant correlations were found when dorsal/ventral amygdalae were analyzed separately. Specifically, left and right ventral amygdala volume was positively associated with motor impulsivity, and left dorsal amygdala was negatively associated with aggression. Results are discussed in terms of an activation and control model of brain-behavior relations. Potential relevance to the continuum of amygdala hyper- to hypo-activation and aggression is discussed. PMID- 23352276 TI - Decreased fMRI activity in the hippocampus of patients with schizophrenia compared to healthy control participants, tested on a wayfinding task in a virtual town. AB - Intact episodic memory requires the ability to make associations between the contextual features of an event, referred to as contextual binding. Binding processes combine different contextual elements into a complete memory representation. It has been proposed that binding errors during the encoding process are responsible for the episodic memory impairments reported in schizophrenia. Since the hippocampus is critical for contextual binding and episodic memory, it was hypothesized that patients with schizophrenia would show a deficit in information processing in the hippocampus, measured with functional magnetic resonance imaging (fMRI). In the current experiment, 21 patients with schizophrenia and 22 healthy control participants were scanned while being tested on navigating in a virtual town (i.e. find the grocery store from the school), a task that was shown to be critically dependent on the hippocampus. Between-group comparisons revealed significantly less activation among patients relative to controls in the left middle frontal gyrus, and right and left hippocampi. We propose that the context and the content are not appropriately linked, therefore affecting the formation of a cognitive map representation in the patient group and eliciting a contextual binding deficit. PMID- 23352277 TI - Altered resting-state functional connectivity of the dentate nucleus in Parkinson's disease. AB - We used functional magnetic resonance imaging (fMRI) to measure functional connectivity of the dentate nucleus (DN) between patients with Parkinson's disease (PD) and normal controls who were studied in a resting state. Images were acquired in 18 PD patients and in age- and sex-matched normal controls. Connectivity of the bilateral DN was calculated and compared between patients and controls, connectivity of the bilateral DN within the cerebellum was compared between rigidity and bradykinesia-dominant patients (PD(AR)) and tremor-dominant patients (PD(T)), and correlation analysis was performed between the connectivity strength and behavioral measures within the cerebellum. Some regions in the cerebellum showed enhanced connectivity with the bilateral DN in PD patients, and decreased connectivity of the DN with the bilateral cerebellar posterior lobe was observed in PD(T) as compared to PD(AR). A set of regions consistent with the default mode network showed disrupted connectivity with the DN. Decreased connectivity between the inferior parietal lobule and the DN was also observed in PD patients. Additional analyses did not show any significant correlations between functional connectivity within the cerebellum and Unified Parkinson's Disease Rating Scale-III scores. Our findings suggest that connectivity of the DN in the resting state is disrupted in PD, and there may be a compensatory cerebellar connectivity mechanism in the resting state in PD. Further study of the cerebellum may clarify the pathophysiology of PD. PMID- 23352278 TI - Pediatric dermatology inpatient consultations: a retrospective study of 427 cases. AB - BACKGROUND: Limited reviews of inpatient pediatric dermatology (PD) exist in the current medical literature. OBJECTIVE: We sought to profile the inpatient PD consultations at a large tertiary care children's hospital. METHODS: We reviewed the electronic medical records of 427 consecutive PD consultations over a 52 month period from January 2006 to April 2010. The age, gender, diagnosis, requesting service, number of skin biopsies performed, and reason for admission to the hospital were recorded. RESULTS: Patients ranged in age from newborn to 17 years old: 18% were 6 weeks to 11 months of age. General pediatrics was the service that most frequently consulted PD (44% of consultations). The most common diagnostic categories included infectious diseases, graft-versus-host disease, dermatitis, vascular anomalies, and drug eruptions. The most common diagnoses when hospitalization was primarily for skin-related disease were infections and vascular anomalies. Admission for skin disease associated with a systemic illness was most frequently for infections and drug eruptions. LIMITATIONS: The retrospective nature of the study, its reliance on electronic medical records, and occurrence at a tertiary care children's hospital are potential limitations. CONCLUSIONS: Information obtained from this study may be used to: (1) tailor teaching to relevant diagnoses for health care providers and trainees who care for children in a hospital setting, (2) inform clinicians about the array of conditions on which PD consultants provide input, and (3) understand the impact PD consultations have in a pediatric tertiary care center. PMID- 23352279 TI - Skin tape stripping and cheek swab method for a detection of filaggrin. PMID- 23352280 TI - Unfolded protein response in keratinocytes: impact on normal and abnormal keratinization. AB - The unfolded protein response (UPR) is a signaling pathway from the endoplasmic reticulum (ER) to the nucleus that protects cells from stress caused by misfolded or unfolded proteins. As such, ER stress is an ongoing challenge for all cells, given the central biologic importance of secretion as part of normal physiologic functions. Mild UPR is activated by mild ER stress, which occurs under normal conditions. Abnormal UPR is activated by severe ER stress, which occurs under pathological conditions. Abnormal UPR activation is associated with a number of diseases, including diabetes mellitus and Alzheimer's disease. Within skin tissues, keratinocytes in the epidermis are especially dependent upon a mild UPR for normal differentiation in the course of their differentiation into secretory cells in the uppermost granular layers. Association between abnormal UPR activation and hereditary keratoses, including Darier's disease, keratosis linearis with ichthyosis congenita and keratoderma syndrome, erythrokeratoderma variabilis, and ichthyosis follicularis with atrichia and photophobia syndrome, have been elucidated recently. This review describes the UPR in normal and abnormal keratinization and discusses the regulation of abnormal UPR activation by chemical chaperones as a potential treatment for one of the hereditary keratoses. PMID- 23352281 TI - Confocal laser endomicroscopy for in vivo diagnosis of Barrett's oesophagus and associated neoplasia: a pilot study conducted in a single Italian centre. AB - BACKGROUND: Diagnosis and management of Barrett's oesophagus are controversial. Technical improvements in real-time recognition of intestinal metaplasia and neoplastic foci provide the chance for more effective target biopsies. Confocal laser endomicroscopy allows to analyze living cells during endoscopy. AIMS: To assess the diagnostic accuracy, inter- and intra-observer variability of endomicroscopy for detecting in vivo neoplasia (dysplasia and/or early neoplasia) in Barrett's oesophagus. METHODS: Prospective pilot study. Patients referred for known Barrett's oesophagus were screened. Endomicroscopy was carried out in a circular fashion, every 1-2 cm, on the whole columnar-lined distal oesophagus. Visible lesions, when present, were analyzed first. Targeted biopsies were taken. Confocal images were classified according to confocal Barrett classification. Endomicroscopic and histological findings were compared. RESULTS: Forty-eight out of 50 screened patients underwent endomicroscopy. Visible lesions were observed in 3 patients. In a per-biopsy analysis, Barrett's-oesophagus-associated neoplasia could be predicted with an accuracy of 98.1%. The agreement between endomicroscopic and histological results was substantial (kappa=0.76). CONCLUSIONS: This study suggests that endomicroscopy can provide in vivo diagnosis of Barrett's oesophagus-associated neoplasia. Because it allows for the study of larger surface areas of the mucosa, endomicroscopy may lead to significant improvements in the in vivo screening and surveillance of Barrett's oesophagus. PMID- 23352282 TI - Dhat syndrome: a systematic review. AB - BACKGROUND: Dhat syndrome is a widely recognized clinical condition often seen on the Indian subcontinent that is characterized by a preoccupation with semen loss in urine and other symptoms such as fatigue or depressed mood. Although it has been considered to be a culture-bound syndrome, it may also be regarded as a distinct manifestation of depression or another medical illness. OBJECTIVE: The purpose of this paper was to carry out a systematic review on Dhat syndrome. METHODS: A review of the literature published up until February 2012 was conducted using the key words [Dhat syndrome] or [semen-loss anxiety] or [semen loss syndrome]. We included only original studies. REVIEW: The majority of studies reported patients from the Indian subcontinent. There was a high degree of heterogeneity among the studies. Dhat was a common condition in young people from certain cultures and origins. Depressive and anxiety symptoms were common, including fatigue, sleepiness, and sexual dysfunction. Good clinical engagement, social support, and sexual education were useful in some cases. Given the high rate of comorbid depressive symptoms, antidepressant has been used. DISCUSSION: In an increasingly globalized world, clinicians must be able to properly diagnose and treat patients from other cultures, who may report symptoms that are influenced by their beliefs, culture, or place of origin. Dhat may be a common manifestation of a depressive or anxiety disorder in certain cultures. Further research is needed to improve our understanding of this condition, to clarify its nosologic status, and to offer appropriate treatment to affected individuals. PMID- 23352284 TI - Access site complications and puncture site pain following transradial coronary procedures: a correlational study. AB - BACKGROUND: Transradial coronary angiography (CA) and percutaneous coronary intervention (PCI) are gaining worldwide popularity due to the low incidence of major vascular complications and early mobilization of patients post procedures. Although post transradial access site complications are generally considered as minor in nature, they are not being routinely recorded in clinical settings. OBJECTIVES: To evaluate the incidence of access site complications and level of puncture site pain experienced by patients undergoing transradial coronary procedures and to examine factors associated with access site complications occurrence and puncture site pain severity. METHODS: A cross-sectional correlational study of 85 Chinese speaking adult patients scheduled for elective transradial CA and or PCI. Ecchymosis, bleeding, hematoma and radial artery occlusion (RAO) were assessed through observation, palpation and plethysmographic signal of pulse oximetry after coronary procedures. Puncture site pain was assessed with a 100mm Visual Analogue Scale. Factors that were related to access site complications and puncture site pain were obtained from medical records. RESULTS: Ecchymosis was the most commonly reported transradial access site complication in this study. Paired t-test showed that the level of puncture site pain at 24 h was significantly (p<0.001) lower than that at 3 h after the procedure. Stepwise multivariable regression showed that female gender and shorter sheath time were found to be significantly associated with bleeding during gradual deflation of compression device. Only longer sheath time was significantly associated with RAO. Female gender and larger volume of compression air were associated with the presence of ecchymosis and puncture site pain at 3 h after procedure, respectively. CONCLUSIONS: The study findings suggest that common access site complications post transradial coronary procedures among Chinese population are relatively minor in nature. Individual puncture site pain assessment during the period of hemostasis is important. Nurses should pay more attention to factors such as female gender, sheath time and volume of compression that are more likely to be associated with transradial access site complications and puncture site pain. PMID- 23352283 TI - Normocalcemic hyperparathyroidism and treatment resistant depression. PMID- 23352285 TI - ASPMN backs pain champion: Russell Portenoy. PMID- 23352286 TI - The effect of Halofuginone in the amelioration of radiation induced-lung fibrosis. AB - The lung is one of the most sensitive organs to ionizing radiation, and damage to normal lung tissue remains a major dose limiting factor for patients receiving radiation to the thorax. Radiation induced lung injury (RILI) which is also named as "radiation pneumonpathy" is a continuous process and regarded as the result of an abnormal healing response. It has been shown that transforming growth factor beta-1 (TGF-beta1) plays an integral role in the radiation induced lung fibrosis formation by promoting the chemoattraction of fibroblasts and their conversion to myofibroblasts. Halofuginone is a, low molecular weight plant derived alkaloid, isolated from the Dichroa febrifuga plant that exhibits antifibrotic activity and inhibition of type I collagen synthesis. Halofuginone has been shown to protect against radiation induced soft tissue fibrosis by virtue of inhibiting various members of TFG-beta signaling pathway. By the light of these findings, we hypothesize that Halofuginone may be able to ameliorate the radiation induced lung fibrosis. PMID- 23352287 TI - Can interventional ablation be applied to the treatment of arterial aneurysm? AB - Interventional therapy is commonly applied to the treatment of arterial aneurysm. Thermal ablation features rapid and minimal invasive treatment. A hypothesis of combining these two techniques was proposed to treat arterial aneurysm. An antenna is delivered with a catheter into the aneurysm sac and heated with microwave or RF, and hence induces instant coagulation and thrombosis of blood flow in the aneurysm sac so that the treatment motivation is achieved. The initiation of this hypothesis is to overcome the disadvantages of biological/mechanical mismatch between the interventional devices and the arteries in the interventional therapy, also utilize the advantages of rapid treatment and minimal invasion in the thermal ablation procedure. PMID- 23352288 TI - Detection of DNA mutations based on analysis of multiple wavelength excitation/emission fluorescence kinetics curves in real-time PCR. AB - The key method for therapies of various cancer types could be the molecular targeted therapy, based on individual gene profile for each patient. One of the main procedures used for genetic testing is the real-time polymerase chain reaction (real-time PCR). Physical principle behind real-time PCR procedure is the fluorescence. Fluorescence labeled probes (primers) is attached to quenchers. Upon reaction of polymerization, quenchers are removed, and the fluorescence emission intensity increases in time. Emission spectra shape and its maximum position can differ if the fluorophore was present in different microenvironment. That property is widely exploited in fluorescence spectroscopy and chromatography. This paper, for the first time, describes utilization of full spectroscopic potential of multichannel excitation/emission filter sets in real time PCR device. Instead of monitoring fluorescence intensity in time for a single fluorescence emission channel, the ratio values of three different kinetics curves were calculated and analyzed by applying k-means clustering and dendrogram analysis. Obtained results have shown that described analytical improvement provides identification of nine different groups of mutations if the commercial QIAGEN(r) EGFR PCR Kit was used. Method can be applied to any kit, capable to simultaneously detect several different mutations. PMID- 23352289 TI - Application of the sleep disturbance scale for children (SDSC) in preschool age. AB - BACKGROUND: The Sleep Disturbance Scale for Children (SDSC) was originally validated on a sample of healthy children aged 6-16 years, investigating the occurrence of sleep disorders during the previous 6 months. AIMS: The aim of this new study was to assess the psychometric properties of the SDSC in an Italian population of preschool children. METHODS: The SDSC was distributed to the primary caregivers of children recruited via nurseries. Letters describing the study design and requesting the co-operation of the caregivers (parents) and co signed by the investigators and by the head teacher were distributed with the questionnaire and collected by the teachers. Reliability analysis for evaluating internal consistency and item-total correlation coefficients, and factor analysis were performed. RESULTS: During a 12-months study period, 601 questionnaires from healthy preschool age children (range 3-6 years) were collected. SDSC in preschool children showed a good level of internal consistency (Cronbach's alpha: 0.83) and six factors were derived from the factor analysis by using the principal component method of extraction and rotated with the varimax method: Parasomnias, Difficulty in initiating and maintaining sleep, Sleep disordered breathing, Disorders of excessive somnolence, Sleep hyperhydrosis and Non restorative Sleep. CONCLUSIONS: The statistical analysis, the internal consistency and the factor analysis support the use of SDSC as an evaluation tool even at preschool age. A different factorial structure from the original SDSC was found due to a different prevalence of the sleep disturbances in younger children, but with similar cut-off total SDSC score. PMID- 23352290 TI - Atypical Sturge-Weber syndrome requires confirmation. PMID- 23352291 TI - [Thyroid in the elderly (Part 1)]. AB - Aging is associated with changes in thyroid function at several levels of regulation. Thyroid hormones levels are usually within the lower part of normal values reported in the general population. Two changes in aging are of clinical importance: a shift in the distribution of TSH levels, the 97.5th percentile of the TSH distribution being within 6 MUUI/ml after 70 years and within 7.5 MUUI/ml in subjects older than 80 instead of 4.5 MUU/ml in the general population, and an increased prevalence of thyroid nodularity, requiring reliable and non-invasive methods of investigation in older people. Lastly, aging may be associated with comorbidities, high risk of drug interactions and under nutrition, which may make difficult the interpretation of laboratory data and in some cases induce iatrogenic thyroid diseases. Considering the high prevalence of the thyroid diseases in older patients and a better understanding of the physiopathological hormonal variations with the ageing, it seemed useful to propose a review to help the clinician in the care of these situations. PMID- 23352292 TI - Natural gums as sustained release carriers: development of gastroretentive drug delivery system of ziprasidone HCl. AB - BACKGROUND: Objective of this study is to show the potential use of natural gums in the development of drug delivery systems. Therefore in this work gastro retentive tablet formulations of ziprasidone HCl were developed using simplex lattice design considering concentration of okra gum, locust bean gum and HPMC K4M as independent variables. A response surface plot and multiple regression equations were used to evaluate the effect of independent variables on hardness, flag time, floating time and drug release for 1 h, 2 h, and 8 h and for 24 h. A checkpoint batch was also prepared by considering the constraints and desirability of optimized formulation to improve its in vitro performance. Significance of result was analyzed using ANOVA and p < 0.05 was considered statistically significant. RESULTS: Formulation chiefly contains locust bean gum found to be favorable for hardness and floatability but combined effect of three variables was responsible for the sustained release of drug. The in vitro drug release data of check point batch (F8) was found to be sustained well compared to the most satisfactory formulation (F7) of 7 runs. The 'n' value was found to be between 0.5 and 1 suggesting that release of drug follows anomalous (non-fickian) diffusion mechanism indicating both diffusion and erosion mechanism from these natural gums. Predicted results were almost similar to the observed experimental values indicating the accuracy of the design. In vivo floatability test indicated non adherence to the gastric mucosa and tablets remain buoyant for more than 24 h. CONCLUSIONS: Study showed these eco-friendly natural gums can be considered as promising SR polymers. PMID- 23352293 TI - Response to Plainis. PMID- 23352294 TI - Role of flexible bronchoscopic cryotechnology in diagnosing endobronchial masses. AB - BACKGROUND: Endobronchial masses obstruct the central airway, and cryotechnology is reportedly a feasible means of managing such masses. However, few reports have explored the role of cryotechnology in diagnosing endobronchial masses. METHODS: All endobronchial masses were sampled for pathologic diagnosis by forceps biopsy and cryotechnology, performed during flexible bronchoscopy. The diagnostic accuracy of forceps biopsy and that of cryotherapy were compared by the chi(2) test, and the obtained specimen sizes were compared by the t test. RESULTS: Between 2007 and 2011, 75 patients with a median age of 64 years (interquartile range [IQR], 49-76; 48 men; 27 women; and 52 smokers [69.3%]) were diagnosed with endobronchial masses. The sites of these masses included the trachea (n = 17), left main bronchus (n = 16), right main bronchus (n = 11), right upper lobe bronchus (n = 11), right intermediate bronchus (n = 8), right lower lobe bronchus (n = 4), left upper lobe bronchus (n = 3), left lower lobe bronchus (n = 3), and right middle lobe bronchus (n = 2). Fifty-nine lesions were malignant, and 16 were benign. Lung squamous cell carcinoma (n = 23) was the leading cause of malignancy, and endobronchial tuberculosis (n = 9) was the most common benign disease. The diagnostic accuracy of cryotechnology was significantly higher than that of forceps biopsy (100% vs 69.3%, p < 0.0001). The specimen size obtained by cryotechnology was also significantly larger than that obtained by forceps biopsy (13.8 +/- vs 1.9 +/- 0.6 mm, p < 0.0001). CONCLUSIONS: The current study supports the view that cryotechnology is a good tool for diagnosing endobronchial masses. Cryotechnology also provides a better diagnostic specimen and has greater diagnostic accuracy than traditional forceps biopsy. PMID- 23352295 TI - Factors influencing hospital length of stay after robotic totally endoscopic coronary artery bypass grafting. AB - BACKGROUND: Robotic totally endoscopic coronary artery bypass grafting (TECAB) is an evolving minimally invasive technology with the potential to reduce hospital length of stay (LOS). Little is known about the factors that influence LOS after this procedure. The aim of this study is to define the preoperative, intraoperative, and postoperative variables that predict LOS after TECAB. METHODS: From 2001 to 2011, 541 patients, aged 60 years (range, 26 to 90 years), 394 (72.8%) male, 147 (27.1%) female, underwent TECAB using the daVinci telemanipulation system at one European and one American institution. Three hundred forty-six (63.9%) single-, 171 (31.6%) double-, 23 (4.2%) triple-, and 1 (0.2%) quadruple-vessel TECABs were carried out with an overall LOS of 6 days (range, 2 to 54 days) and 30-day mortality of 0.9% (5 of 541); 44.5% of patients (241 of 541) were hybrid intent-to-treat candidates. RESULTS: The following variables showed significant positive correlation with LOS: age, r = 0.188 (p < 0.001); Society of Thoracic Surgeons risk score, r = 0.263 (p < 0.001); EuroSCORE, r = 0.191 (p < 0.001); creatinine, r = 0.135 (p = 0.002); and operative time, r = 0.216 (p < 0.001). Other factors that had significant influence on LOS were hemodialysis (p = 0.037), cerebrovascular disease (p = 0.002), learning curve case (p < 0.001), intraoperative surgical problem (p < 0.001), conversion or on-table revision (p < 0.001), revision for bleeding (p < 0.001), postoperative stroke (p < 0.001), intraaortic balloon pump (p < 0.001), hemodialysis (p < 0.001), and atrial fibrillation (p < 0.001). By multivariate analysis, learning curve case, conversion or on-table revision, and revision for bleeding were independent predictors for prolonged LOS (defined as LOS > 6 days). CONCLUSIONS: Multiple variables affect LOS after TECAB. Older patients, patients on hemodialysis, patients with cerebrovascular disease, and those with higher general risk scores should expect prolonged LOS. Intraoperative surgical difficulties and conversion to open coronary artery bypass grafting also lead to extended LOS. Postoperative events that are known to prolong LOS in open coronary artery bypass grafting also prolong LOS after TECAB. PMID- 23352296 TI - Bilateral internal thoracic artery harvest and deep sternal wound infection in diabetic patients. AB - BACKGROUND: Coronary artery bypass graft surgery is superior to percutaneous intervention in diabetic patients with multivessel disease. The use of bilateral internal thoracic arteries (BITA) may provide better long-term graft patency, but the risk of postoperative deep sternal wound infection has limited its use in diabetic patients. However, studies have reported conflicting results, and require systematic evaluation. METHODS: MEDLINE, EMBASE, World of Science, and the Cochrane library were searched for randomized controlled trials and observational studies comparing the incidence of deep sternal wound infection in diabetic patients undergoing either left internal thoracic artery (LITA) or BITA harvest. We used random effect models to compare risk ratios within groups. RESULTS: One randomized controlled trial and 10 observational studies (126,235 diabetic patients: 122,465 LITA, 3,770 BITA) met inclusion criteria. Deep sternal wound infection occurred in 3.1% and 1.6% for the BITA and LITA cohorts, respectively. The risk ratio for deep sternal wound infection development was 1.71 (1.37 to 2.14) for BITA compared with LITA. Patients who underwent skeletonized BITA harvest had a similar risk of deep sternal wound infection compared with LITA (0.9 [0.42 to 2.09]), although pedicled harvest demonstrated increased risk (1.77 [1.4 to 2.23]). Early mortality was comparable in the LITA cohort (2.5%) and the BITA cohort (2.3%; p = 0.8). CONCLUSIONS: The risk of deep sternal wound infection can be minimized in diabetic patients undergoing coronary artery bypass graft surgery by performing ITA harvested in a skeletonized manner with meticulous attention to preserving sternal blood flow. Pedicled harvest is to be discouraged when utilizing both ITA owing to a significant increase in the risk of postoperative deep sternal wound infection. PMID- 23352297 TI - Specimen processing techniques for endobronchial ultrasound-guided transbronchial needle aspiration. AB - BACKGROUND: Endobronchial ultrasound is used for sampling thoracic pathologic processes. Histologic examination may provide added diagnostic yield to cytologic preparations owing to superior assessment of architecture and immunohistochemistry. It remains unclear whether specific specimen processing technique impacts diagnostic yield. We hypothesized that diagnostic yield using histologic analysis of core needle biopsies is higher than cytologic preparations alone. METHODS: We evaluated 177 consecutive patients with mediastinal abnormalities. An interventional pulmonologist or thoracic surgeon performed endobronchial ultrasound. We compared diagnostic yields of two specimen processing techniques, fixed slides (cytology) and formalin-fixed core samples (histology). Results were categorized as malignant, benign (infectious, inflammatory), normal nodal tissue, or inadequate sampling (nondiagnostic). Malignancy, a defined benign process, and normal lymph node were considered diagnostic. RESULTS: The diagnostic yield for benign processes was higher by histologic examination (n = 37) than in cytologic preparations (n = 22; p = 0.0064). The diagnostic yield was comparable in malignancy (p = 0.7530). The combination of both techniques provided a higher overall diagnostic rate: 84% (n = 148) by histology, 82% (n = 146) by cytology, and 89% (n = 158) using both. Using two techniques revealed discordance in 23% (n = 40), demonstrating that the use of one technique alone would have resulted in missed diagnoses. CONCLUSIONS: Adding histologic analysis of tissue cores obtained by endobronchial ultrasound offers higher diagnostic accuracy than only cytologic preparation of needle aspirates. Histologic and cytologic methods offer comparable diagnostic rates for malignancy. However, diagnostic yield for benign conditions is higher using histologic examination. Together, histology and cytology provide fewer missed diagnoses than either individually. When using endobronchial ultrasound, it is ideal to routinely use both needle aspirate cytology and core biopsy histology. PMID- 23352298 TI - Local allocation of lung donors results in transplanting lungs in lower priority transplant recipients. AB - BACKGROUND: Under the current lung allocation system, if organs are accepted for a candidate within the local donor service area (DSA), they are never offered to candidates at the broader regional level who are potentially more severely ill, even if the nonlocal candidate has a higher lung allocation score (LAS). The purpose of this study was to determine the frequency with which organs were allocated to a local lung recipient while a blood group-matched and size-matched candidate with a higher LAS existed in the same region. METHODS: United Network for Organ Sharing (UNOS) provided deidentified patient-level data. The study population included all locally allocated organs for double-lung transplants (DLTs) performed in 2009 in the United States (n=580). All occurrences of an ABO blood group-matched, height-matched (+/-10 cm), double-lung candidate in the same region, with a higher LAS than the local candidate who actually received the organs, were calculated; these occurrences were termed events. RESULTS: In 2009, 3,454 events occurred when a local DLT recipient candidate received a DLT while a DLT candidate in the same region had a higher LAS. With a mean of 5.96 events per transplant, this impacted 480 (82.8%) of the 580 DLTs. Further, 555 (16.1%) of these events involved 1 (or more) of the 185 regional candidates who ultimately did not receive transplants and died while on the waiting list. CONCLUSIONS: This analysis suggests that the locally based lung allocation system results in a high frequency of events whereby an organ is allocated to a lower-priority candidate while an appropriately matched higher priority candidate exists regionally. PMID- 23352299 TI - [Greenlight((r)) photoselective vaporisation for benign prostatic hyperplasia: a systematic review]. AB - INTRODUCTION: Transurethral resection of the prostate (TURP) is the most common surgical procedure in urology and remains the gold standard treatment of complicated benign prostatic hyperplasia or refractory to medical treatment. Routinely used since the 2000s, prostate photoselective vaporization (PVP) with Greenlight((r)) laser has been developed to improve the safety of hemostasis in elderly patients and/or with high surgical risk. The purpose of this study was to review the results of PVP from the international literature. MATERIAL AND METHODS: [corrected] A systematic review of the literature on the research base Pubmed (http://www.ncbi.nlm.nih.gov/) was performed using the keywords benign prostatic hyperplasia; greenlight; photovaporisation; Laser; IPSS score; endoscopicsurgery; morbidity; complication. Prospective and retrospective studies in English and French were selected from its first use in 1998. Finally, we looked for studies that reported at least one of the following items: surgical technique; operative data; complications; anatomical and functional results and/or direct comparison between PVP and TURP. RESULTS: Regardless the PVP technique used to treat adenoma and identify the limits of the prostatic capsule, some parameters are well defined (sweepspeed, angle and distance of the fiber with the tissue) but others are still debated (number of joules per volume, when do we have to stop the PVP) and are reported in a heterogeneous manner due to the different generators. Versus TURP, PVP would offer the same functional results in the medium term but with a lower risk of per- and postoperative bleeding. The study of the risk of erectile dysfunction (ED) after PVP is made difficult due to the heterogeneity of DE assessment and study populations. However, PVP does not seem associated with an increased risk of ED versus TURP. The lack of histological material should lead to preoperative individual screening of prostate. The economy generated by PVP regarding the decrease in average length of stay has been clearly identified in Australia, Canada, Switzerland and USA. Studies will be published soon on French economic model. CONCLUSION: PVP with Greenlight((r)) laser appears to be a safe and effective technique. With the new generator XPS, the PVP technique reaches maturity. Its development will certainly lead to a long-term evaluation with high levels of evidence based. PMID- 23352300 TI - [Metabolic syndrome and insulin resistance in patients with prostate cancer treated with androgen deprivation hormone]. AB - INTRODUCTION AND OBJECTIVES: Androgen suppression in prostate cancer is responsible for many side effects. Many studies, mostly retrospective, have found an association between androgen deprivation and increased cardiovascular morbidity. If the cardiovascular impact was chosen, an etiological explanation would be the occurrence of metabolic disorders, particularly insulin resistance. The objective of our work was to conduct a review of the literature assessing the impact of androgen deprivation on the onset of insulin resistance, the metabolic syndrome and changes in key markers of insulin resistance. MATERIALS AND METHODS: A systematic review of literature from the Pubmed database search was performed using the following keywords: androgen deprivation therapy, metabolic syndrome, insulin resistance, hyperglycemia, cardiovascular diseases, cardiovascular risk, abdominal obesity. RESULTS: Twelve studies were included, bringing into focus a 55% prevalence of metabolic syndrome in patients treated for more than 12 months, an increase in fat mass and decreased lean body mass, an increase in abdominal subcutaneous fat and in visceral adiposity. The insulin was increased in four studies (25 to 60% three months dice). The increased insulin resistance was assessed by the Homeostasis Model Assessment (HOMA) was postponed three times (12% in two prospective cohort studies of type). The increase in triglycerides (20 to 40% at 12 months) and total cholesterol (7 to 11%) was observed in five studies, and increased LDL cholesterol and HDL in three studies (9 to 22%). CONCLUSION: All studies of this analysis appeared to converge towards the development of insulin resistance and metabolic disorders, however, no prospective cohort study of good methodological quality were identified. It would be necessary to conduct a prospective multicenter study in order to have a causal quality. PMID- 23352301 TI - [Update on FGFR3 mutation and multiple regional epigenetic silencing (MRES) phenotype in urothelial carcinogenesis]. AB - FGFR3 mutation leads to a constitutive activation of the receptor 3 to Fibroblast Growth Factor. This mutation is early in urothelial carcinogenesis and is strongly associated to low grade papillary tumors. Multiple regional epigenetic silencing (MRES) phenotype corresponds to the transcriptional inactivation of chromosomal regions in muscle invasive bladder cancer, and is strongly associated to the molecular signature of carcinoma in situ. These alterations could be targeted by new specific therapies. PMID- 23352302 TI - [Perioperative outcomes and mid-term results of radiofrequency ablation and partial nephrectomy in indications of renal tumor treatment and imperative nephron-sparing procedure]. AB - OBJECTIVE: To compare morbidity, oncological and functional outcomes of percutaneous radiofrequency ablation (RFA) and partial nephrectomy in indications of renal tumor treatment with imperative nephron-sparing procedure. PATIENTS AND METHODS: Between January 2005 and December 2010, 50 consecutive patients were referred in our center for NP or RFA for a renal tumor with either a renal function impairment defined as estimated glomerular filtration (eGFR) less than 60 mL/min/1.73 m(2), and/or solitary kidney and/or bilateral tumors. Perioperative outcomes were compared. RESULTS: Thirty-six PN and 14 RFA were performed. RFA patients were older (79.2 vs. 62.5 years old), had a higher ASA score (3 vs. 2), a lower RENAL score (6 vs. 7.5) and a lower rate of tumor on solitary kidney or bilateral tumors (P=0.009). Overall complications (29.4% vs. 6.3%), transfusions (20.6% vs. 0) and longer hospital stay (9 vs. 3 days) were more likely to occur in the NP group. During a median follow-up of 22 months (4.3 53.7), eGFR decrease was similar between the two groups (P=0.34). On multivariate analysis, PN was associated with an increased occurrence of overall complications (OR=14.09, P=0.02) but with a similar eGFR decrease. No patient died. CONCLUSION: For patients with an indication of treatment of renal tumor and imperative nephron-sparing procedure, RFA seems to provide low morbidity and comparable functional outcomes as partial nephrectomy. Our limited follow-up does not permit to conclude on oncologic data. PMID- 23352303 TI - [Pathological features of radiofrequency ablation (RFA) renal scar CT-imaging in a swine model]. AB - PURPOSE: To analyze the changes in vicinal kidney parenchyma after percutaneous RFA. MATERIALS AND METHODS: [corrected] Twenty-four CT-guided RFA procedures were performed on six pigs using 2 cm LeVeen coaxial needles. We studied volume, morphology, cavitation and enhancement of the ablation zones (AZ) before and after the procedure on contrast-injected CT-scans. The kidneys were removed four weeks later and studied in the path lab. RESULTS: All the procedures were successfully completed. Four weeks later, the CT-scans showed AZ that were either clearly circumscribed or with unclear borders, heterogenous areas associating necrosis and infarct tissue and mesenchyma showing a process of apoptosis around the edges. A treatment considered as incomplete on the CT-scan (presenting as an enhancement) was always associated with necrosis on the histology slides, although the necrotic areas behaved in various different ways on the CT-scan after injection of contrast medium: an enhancement of more than 10 HU did not mean that no necrotic tissue was present. CONCLUSION: RFA causes heterogenous tissue changes, associating necrotic and ischemic zones and an apoptotic reaction. The mechanisms of these changes and their therapeutic significance should be studied. CT-scans performed immediately after RFA procedure and one month later are not predictive of the efficacy of the treatment because an enhancement of the AZ does not mean that it is not necrotic. The value of a CT scan performed one month after the procedure is debatable, because the tissue remodeling that occurs in the kidneys is not definitive at this time-point. PMID- 23352304 TI - [Long-term outcome of renal transplantation: impact of surgical complications on graft survival]. AB - OBJECTIVE: To determine the incidence of surgical complications of renal transplantation at one institution, relate this to donor and recipient factors and to long-term graft survival. PATIENTS AND METHODS: A consecutive series of 145 renal transplants were audited, and a database of donor and recipient characteristics created for risk-factor analysis. An unstented Barry-Sarramon anastomosis was the most used method of ureteric reimplantation. Lich-Gregoir anastomosis was used in 28.9% of cases. The mean follow-up time was 14.4 +/- 6.23 years. RESULTS: There were 67 surgical complications including ten vascular, 39 urological and 18 parietal complications. Among urological complications, 13 were urinary leaks, four distal ureteric necrosis, 13 symptomatic ureteric reflux, six primary ureteric obstructions, and one ureteric stone at some time after transplantation. The overall incidence of urological complications was 26.2%. There was no association with recipient or donor age, cold ischaemic times before organ reimplantation, dialysis duration before transplantation, operating times, or ureteric stenting. Overall surgical complications had a significant pejorative impact on graft survival (Hazard Ratio [HR]=1.805; P=0.32), but as we studied them separately, we highlighted that in fact only vascular complications had an impact on long-term graft survival (HR=17.442, P<5E-10). There was no association between urological (P=0.566) or parietal (P=0.797) complications and long-term graft outcome. CONCLUSION: The onset of a urological or a parietal complication had no impact in this series on long-term graft survival. Vascular complications dramatically increase the rate of graft loss. PMID- 23352305 TI - [Does PCA3 score and prostatic MRI help selection of patients scheduled for initial prostatic biopsy?]. AB - INTRODUCTION: Determinate if the adjunction of PCA3 score and/or prostatic MRI can improve the selection of the patients who have an indication of first prostate biopsy. PATIENTS AND METHODS: Multiparametric prostatic MRI and PCA3 score were made before biopsy to men scheduled for initial prostate biopsy for abnormal digital rectal examination and/or PSA superior to 4 ng/mL. T2-weighted imaging, diffusion-weighted imaging and dynamic contrast-enhanced imaging looked for suspect target classified on a scale of four. It was a prospective, single centre study. The diagnostic accuracy of PCA3 score and MRI was to evaluate in comparison with biopsy results. RESULTS: Sixty-eight patients were included, median PSA was 5.2 ng/mL (3.2-28). Negative predictive value (NPV) of MRI score 0, 1 and 2 were respectively 80%, 43% and 69%. Positive predictive value (PPV) of MRI score 3 and 4 were 50% and 81%. The PCA3 cutoff with best accuracy was 21 (Se: 0.91; Sp: 0.50). Only one patient with positive biopsy (0.5mm of Gleason score 3+3) had negative MRI and PCA3 inferior to 21. CONCLUSION: MRI and PCA3 score in association allowed, in this study, to consider reduction of unnecessary initial biopsy without ignoring potential aggressive tumor. PMID- 23352307 TI - [Photovaporisation of the prostate using KTP laser in patients on antithrombotics. About a restrospective study of 120 cases]. AB - Antithrombotic (AT) medications are more and more prescribed, so complicating the surgery of benign prostatic hyperplasia (BPH). KTP laser is an alternative to the transurethral resection of the prostate thanks to its haemostatic properties. OBJECTIVES: To study the functional outcomes and complications of KTP 80W laser treatment in patients taking AT, comparing with patients without AT (nAT). PATIENTS AND METHODS: A single-center retrospective study has been conducted in the department of Urology of Nice Teaching Hospital, in patients with uncomplicated symptomatic BPH, treated with the KTP 80W laser treatment, between November 2005 and October 2009. The cohort was divided into two matched groups AT/nAT. In the AT group patients, treatment with aspirin and vitamin K antagonist (VKA) were maintained, whereas clopidogrel was discontinued. The urinary flowmetry, measurement of residual urine, International Prostate Symptom Score (IPSS) and question 8 of the IPSS score were analyzed. The duration of intervention, the amount of laser energy delivered, duration of catheterization and postoperative hospitalization, and the rate of blood transfusion have been evaluated. Clavien classification was used to characterize the postoperative complications. RESULTS: A total of 120 patients were included in two groups (50 AT/70 nAT), with a median follow-up of 24 months. The two study groups were comparable except for age which was significantly higher in patients on AT (P=0.001). The average duration of operation, of catheterization and hospital stay were significantly longer in patients receiving AT. Seven complications were reported in the AT group versus three complications in the nAT. No significant difference was reported on the evaluation of voiding parameters and IPSS score. CONCLUSION: Photovaporisation of the prostate using KTP 80W laser treatment provided functional outcomes comparable in patients on AT and untreated patients, with minimal risk of complication. PMID- 23352306 TI - [Salvage radiotherapy outcomes for biochemical recurrence following radical prostatectomy among the African-Caribbean population of Guadeloupe]. AB - OBJECTIVES: To make the first analysis of the salvage radiotherapy outcomes for biochemical recurrence of prostate cancer after radical prostatectomy in African descendant people, witch has no healthcare access difficulties: the French West Indies African-Caribbean people of Guadeloupe. PATIENTS AND METHOD: Ninety successive patients, with biological failure after radical prostatectomies were treated in the University Hospital of Pointe-a-Pitre with salvage radiotherapy between April 2003 and December 2008. The retrospective study analysed the biochemical disease free survival (bDFs) after irradiation with Kaplan-Meier method, and the independent predictors of bDFs using the Cox model, with P<0.05. The treatment failure was defined for PSA superior or equal to nadir +0.1 ng/mL. RESULTS: The median dose was 64 Gy. At the median follow-up of 24.63 months, 35 (38.9%) patients had biochemical recurrence. The median bDFs was 55.3 months, the bDFs probabilities at months 12, 24, 36 and 48 were 8.1%, 70.3%, 61.9% and 56.1%. Multivariate analysis determined that the independents predictors of treatment failure were the seminals vesicles invasion (P=0.0094, Hazard ratio=2.63 CI 95%: [1.28-5.55]), the PSA velocity superior or equal to 0.75 ng/mL per year (P=0.0002, Hazard ratio=3.88 CI95%: [1.86-7.75]) and the pre-irradiation PSA level superior or equal to 1.5 ng/mL (P=0.0093, Hazard ratio=2.89 CI95%: [1.30 6.45]). CONCLUSION: Salvage radiotherapy for African descendent people with no healthcare difficulty access was an efficient treatment for the biochemical recurrence and had the same outcomes than others Caucasian people. PMID- 23352308 TI - [Is there an outcome difference between posterior urethral valves diagnosed prenatally and postnatally at the time of antenatal screening?]. AB - PURPOSE: Posterior urethral valves (PUV) diagnosed during childhood have classically been associated with a better outcome than antenatally diagnosed PUV. The aim of our study was to compare long-term outcome of these two patients' groups. MATERIAL AND METHODS: We retrospectively reviewed the medical records of boys with PUV managed between 1990 and 2010. Patient demographics, clinical background, radiographic data (including prenatal ultrasonography data when available), renal and bladder functional outcomes, surgical procedures and urinary tract infections (UTI) were abstracted. Impaired renal function (IRF) was defined as glomerular filtration rate less than 90 mL/min/1.73 m(2) at last follow-up. RESULTS: We identified 69 patients with confirmed PUV. Thirty-eight were diagnosed prenatally (group 1) at 30.5 weeks of gestation and 31 had a delayed diagnosis (group 2) at a median age of 6.31 years. At diagnosis, 20 patients in group 1 had renal insufficiency versus two in group 2 (P<0.05). At the end of mean follow-up of 7.2 +/- 0.5 years, in group 1, 26.3% developed IRF versus 6.3% in group 2 (mean follow-up 2.3 years). Mean age at last follow-up was 7.3 years in group 1 versus 8.3 in group 2 (P>0.05). In group 1, 27% had voiding dysfunction versus 30% in group 2 (NS). In group 1, 35% had UTI during follow-up versus 10% (P=0.01). CONCLUSION: During the follow-up, the patients with delayed diagnosis VUP have developed fewer complications related to the initial obstruction than the population who was detected antenatally and managed from the early hours of life. However, the rate of IRF and voiding disorders in our study, associated with the data of the literature, highlights the potential persistence and worsening of these conditions. That is why, whatever the age at diagnosis, VUP patients require a close monitoring. PMID- 23352309 TI - [Bladder neck traumatic rupture in children]. AB - Transverse rupture of the bladder neck injury is rare in children. We report a new case in a 10-month boy with urinary peritonitis. Diagnosis was intraoperative. Surgical treatment in emergency with urethrovesical anastomosis protected by a perivesical drain and a large-bore urinary catheter was performed without urogenital complication. PMID- 23352310 TI - Evidence-based practice. PMID- 23352311 TI - Reduction of platelet cytosolic phospholipase A2 activity by atorvastatin and simvastatin: biochemical regulatory mechanisms. AB - Statins have demonstrated effects beyond reducing cholesterol level that may contribute to their clinical benefit, including effects on platelet biochemistry and function. OBJECTIVES: To explore and compare the antiplatelet effect of two lipophilic statins (atorvastatin and simvastatin) and one hydrophilic statin (pravastatin) concerning: a) collagen-induced platelet aggregation and thromboxane A2 (TXA2) synthesis; b) the additive effect of statins on TXA2 synthesis in platelets treated with a submaximally effective concentration of aspirin and c) the biochemical mechanisms involved. METHODS AND RESULTS: Washed human platelets were incubated with statins (1-20MUM), and stimulated with collagen (1MUg/ml) or arachidonic acid (AA) (200MUM) and TXB2 was quantified by ELISA. Incubation with simvastatin or atorvastatin reduced (36.2% and 31.0%, respectively) collagen-induced TXB2 synthesis (p<0.05) and platelet aggregation (p<0.001), whereas pravastatin had no effects. Simultaneous incubation with a submaximally effective concentration of aspirin (1MUM) and atorvastatin or simvastatin significantly increased the inhibition of TXB2 synthesis by aspirin by 4.4- and 4.1-fold, respectively. Statins did not affect AA-induced TXB2 synthesis, excluding an effect on COX-1/TXA2 synthase activities. Atorvastatin and simvastatin concentration-dependently inhibited the collagen-induced increase in cytosolic calcium and the kinetics of cPLA2 phosphorylation. Lipophilic statins reduced phosphorylation of both ERK1/2 and p38 MAPK, which regulate cPLA2 phosphorylation and calcium movement. CONCLUSION: We report for the first time a direct downregulation by atorvastatin and simvastatin of platelet cPLA2 activity through effects on calcium and MAPK, which reduce collagen-induced TXA2 synthesis. These mechanisms might contribute to their beneficial effects, even in aspirin-treated patients. PMID- 23352312 TI - Dermatitis linearis: vesicating dermatosis caused by paederus species (coleoptera: staphylinidae). Case series and review. AB - OBJECTIVE: Outbreaks of dermatitis linearis have been documented worldwide. We present a case series of dermatitis linearis from Latin America to highlight the importance of this clinical entity. Clinical, historical, epidemiological, and pathological aspects of the condition are discussed, and a concise current approach to the management and treatment of this morbidity is presented. METHODS: We present a series of 4 selected cases reflecting the clinical spectrum exhibited in dermatitis linearis by Paederus along with a review of the literature. RESULTS: In this review we demonstrate the need for awareness of dermatitis linearis as a clinical entity that must be considered in the broad list of differential diagnosis embracing vesicating linear lesions. CONCLUSIONS: Capture of the insect, epidemiologic features, and a high clinical suspicion can aid in making the correct diagnosis. Primary prevention through public awareness, decreased use of artificial lighting, and mosquito nets can limit the extent and severity of outbreaks. PMID- 23352313 TI - Two successive necrotic lesions secondary to presumed loxosceles envenomation. AB - Brown recluse spider (Loxosceles reclusa) envenomations with subsequent necrotic skin lesions occur infrequently, and systemic loxoscelism is rarer still. We report a case of 2 successive developing necrotic lesions, each on adjacent medial aspects of the legs, secondary to presumed Loxosceles envenomation. A 31 year-old man with no significant past medical history presented to the emergency department with 2, large, necrotic lesions, 1 on each medial thigh. They had progressed over the course of 1 month from small blisters to large necrotic lesions with eschar. He underwent surgical debridement without skin grafting with no further complications. Bites from recluse spiders that progress to necrosis usually present as single lesions. The differential diagnoses for a necrotic skin lesion is large. The presence of more than 1 lesion argues against Loxosceles envenomation; however, in the absence of underlying infection, systemic diseases, immunodeficiency, or malignancy, the diagnosis must be considered if the case presents in an endemic area. Brown recluse spiders rarely bite multiple times, thus confounding the diagnosis of an already nonspecific clinical finding. PMID- 23352314 TI - Expression of alpha 1,6-fucosyltransferase 8 in hepatitis B virus-related hepatocellular carcinoma influences tumour progression. AB - BACKGROUND: Alpha 1,6-fucosyltransferase 8 expression was demonstrated to be enhanced during hepatocarcinogenesis. AIMS: Our study aimed to find out the clinical significance and biological function of alpha 1,6-fucosyltransferase 8 in hepatitis B virus-related hepatocellular carcinoma. METHODS: Alpha 1,6 fucosyltransferase 8 expression levels were determined in 52 pairs of tissues to compare its expression between tumour tissues [with/without portal vein tumour thrombus] and adjacent noncancerous liver tissues. Relationship between alpha 1,6 fucosyltransferase 8 expression and clinical indicators was also investigated. An alpha 1,6-fucosyltransferase 8-knockdown (by RNAi) cell line MHCC97-H/siFUT8 was established to reveal functional impact of alpha 1,6-fucosyltransferase 8 on cell growth, migration and invasion in hepatocellular carcinoma, respectively using Cell Counting Kit-8, wound healing migration assay, transwell assay and gelatin zymography. RESULTS: We observed a higher alpha 1,6-fucosyltransferase 8 expression level in tumour tissues than adjacent noncancerous liver tissues. In portal vein tumour thrombus group, alpha 1,6-fucosyltransferase 8 protein expressed more in portal vein tumour thrombus tissues than that in adjacent noncancerous liver tissues. The expression level in tumour tissues was highly correlated with tumour size and presence of satellite nodules (P<0.05). Furthermore, alpha 1,6-fucosyltransferase 8-knockdown suppressed the tumour proliferation, migration and invasion of MHCC97-H cells. CONCLUSION: These findings suggest that alpha 1,6-fucosyltransferase 8 expression might be a good indicator of poor prognosis in hepatocellular carcinoma. High alpha 1,6 fucosyltransferase 8 expression may play an important role in hepatitis B virus related hepatocellular carcinoma progression. PMID- 23352315 TI - Rendezvous procedure for the treatment of bile leaks and injury following segmental hepatectomy. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography is a minimally invasive procedure used for the evaluation and management of biliary injuries. At times, ERCP fails and percutaneous modalities may be required. Rendezvous procedures are combined endoscopic and percutaneous techniques that have been used to restore anatomic continuity and biliary drainage in cases where retrograde and/or transhepatic access alone has failed either due to anatomic variation or traumatic injury with biloma formation. AIMS: To assess if the Rendezvous technique plays a role in establishing biliary continuity in patients with a bile leak after segmental hepatectomy. METHODS: We herby present a series of 3 patients who had complex bile leaks after segmental liver resection and underwent a combined percutaneous and endoscopic Rendezvous procedure to establish biliary continuity. RESULTS: This technique was successful in restoring biliary continuity and avoiding hepaticojejunostomy in 2 of the 3 patients. CONCLUSION: The Rendezvous technique may play a role in establishing biliary continuity in patients with biliary leak secondary to hepatic surgery. PMID- 23352316 TI - Blockade of ventral midbrain NMDA receptors enhances brain stimulation reward: a preferential role for GluN2A subunits. AB - Ventral midbrain (VM) neurons that project to limbic structures play a role in reward and incentive motivation. It has been suggested that a reward-related signal is transmitted when the firing rate of VM dopamine neurons shifts from a tonic to a phasic mode. Since glutamate is necessary for this transduction process, it is likely to play a role in reward signaling. This study was aimed at determining the effect of VM N-Methyl-D-Aspartate (NMDA) receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer an electrical stimulation in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and after bilateral VM injections of the following NMDA receptor antagonists: R-CPP, 3-(R-2-Carboxypiperazin-4-yl)-propyl-1 phosphonic acid, (0, 20.6, 41.2 and 82.5 pmol/0.5 MUl/side), PPPA, (2R,4S)-4-(3-Phosphonopropyl)-2 piperidinecarboxylic acid, (0, 0.825 and 1.65 nmol/0.5 MUl/side) orRo04-5595, 1 [2-(4-Chlorophenyl)ethyl]-1,2,3,4-tetrqahydro-6-methoxy-2-methyl-7-isoquinolinol hydrochloride (0, 0.825, 1.65 nmol/0.5 MUl/side). R-CPP and PPPA produced a dose and time dependent decrease in reward threshold, an effect that was, at some doses and times after the injection, accompanied by an increase in maximum responses. These effects were not observed with Ro04-5595 over the range of doses tested. While previous studies suggest a role for glutamate in reward signaling, the present results show that VM glutamate exerts a tonic inhibition on the reward-relevant pathway. The selectivity of Ro04-5595 for NMDA receptors composed of GluN2B subunits and the higher affinity of R-CPP and PPPA for GluN2A suggest that the inhibition is mediated by receptors composed of GluN2A subunits. PMID- 23352317 TI - beta-endorphin degradation and the individual reactivity to traumatic stress. AB - Reactivity to traumatic stress varies between individuals and only a minority of those exposed to trauma develops stress-induced psychopathologies. Currently extensive effort is made to unravel the specific mechanisms predisposing to vulnerability vs. resilience to stress. We investigated in rats the role of beta endorphin metabolism in vulnerability to acute traumatic stress. Responders (showing extreme anxiety; n=7) and resilient non-responders (not differing from the non-stressed individuals; n=8) to traumatic foot-shock stress were compared for their blood levels of stress hormones as well as brain levels and activity of two opioid-degrading enzymes. beta-endorphin is a substrate to insulin degrading enzyme, which also degrades insulin. Therefore, the effects of insulin application on behavioral and hormonal responses and on beta-endorphin degradation were tested. Pre- and post-stress levels of serum corticosterone, and post-stress plasma beta-endorphin concentration differentiated between the responders and the non-responders. In brain, responders showed enhanced degradation rates of beta-endorphin, assessed by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS), in hippocampal and amygdalar slices as compared to non-responders. Application of insulin to the amygdala, prior to exposure to traumatic stress, reduced post-stress anxiety and serum corticosterone levels only in the responders. In parallel, amygdalar beta-endorphin degradation rate was also reduced by insulin. These results suggest that slowing down beta endorphin degradation rate may constitute an integral part of the normal stress response, upon a failure of which an extreme anxiety develops. Modulation of opioid degradation may thus present a potential novel target for interference with extreme anxiety. PMID- 23352318 TI - Suicide attempts and psychological risk factors in patients with bipolar and unipolar affective disorder. AB - Suicide is an important clinical problem in psychiatric patients. The highest risk of suicide attempts is noted in affective disorders. The aim of the study was looking for suicide risk factors among personality dimensions and value system in patients with diagnosis of unipolar and bipolar affective disorder (n=189 patients, n=101 controls). To establish the diagnosis, we used SCID (Structured clinical interview for diagnostic and statistical manual of mental disorders, fourth edition) questionnaire, TCI (Temperament and Character Inventory) questionnaire and Value Survey--to assess the personality. The main limitations of the study are number of participants, lack of data about stressful life events and treatment with lithium. Novelty seeking and harm avoidance dimensions constituted suicide attempt risk factors in the group of patients with affective disorders. Protective role of cooperativeness was discovered. Patients with and without suicide attempt in lifetime history varied in self-esteem position in Value Survey. PMID- 23352319 TI - Toxicity and cosmesis following partial breast irradiation consisting of 40 Gy in 10 daily fractions. AB - PURPOSE: To assess the toxicity and cosmetic results in breast cancer patients undergoing adjuvant partial breast irradiation (PBI) to a total dose of 40 Gy in 10 daily fractions (4 Gy/fraction). METHODS AND MATERIALS: Patients affected by early-stage breast cancer were enrolled in this phase II trial. Patients had to be 60 years old and treated with breast conservative surgery for early stage (pT1 T2 pN0-N1a) invasive ductal carcinoma. RESULTS: 77 patients were enrolled. Median follow-up was 18 months. The proposed schedule was well tolerated. One patient reported Grade 3 pain at the site of irradiation. Four (5%) patients experience Grade 2 erythema. Late Grade 2 and 1 fibrosis was observed in 3 (4%) and 14 (18%) patients, respectively. Cosmesis was judged "good/excellent" and "poor" in 75 (97%) and in 2 (3%) patients, respectively. CONCLUSIONS: 40 Gy in 10 daily fractions, 4 Gy/fraction, is a well tolerated regimen to deliver PBI. PMID- 23352320 TI - [Integrating information about imaging biomarkers into structured radiology reports]. AB - Imaging biomarkers describe objective characteristics that are related to normal biological processes, diseases, or the response to treatment. They enable radiologists to incorporate into their reports data about structure, function, and tissue components. With the aim of taking maximum advantage of the quantification of medical images, we present a procedure to integrate imaging biomarkers into radiological reports, bringing the new paradigm of personal medicine closer to radiological workflow. In this manner, the results of quantification can complement traditional radiological diagnosis, improving accuracy and the evaluation of the efficacy of treatments. A more personalized, standardized, structured radiological report should include quantitative analyses to complement conventional qualitative reporting in selected cases. PMID- 23352321 TI - Preface to the special issue entitled "The future of translational epilepsy research". PMID- 23352322 TI - C9orf72 G4C2 repeat expansions in Alzheimer's disease and mild cognitive impairment. AB - C9orf72 G4C2 repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Its role in Alzheimer's disease (AD) is less clear. We assessed the prevalence of G4C2 pathogenic repeat expansions in Flanders-Belgian patients with clinical AD or mild cognitive impairment (MCI). In addition, we studied the effect of non-pathogenic G4C2 repeat length variability on susceptibility to AD, and on AD cerebrospinal fluid (CSF) biomarker levels. A pathogenic repeat expansion was identified in 5 of 1217 AD patients (frequency <1%). No pathogenic expansions were observed in patients with MCI (n = 200) or control individuals (n = 1119). Nonpathogenic repeat length variability was not associated with AD, risk of conversion to AD in MCI individuals, or CSF biomarker levels. We conclude that pathogenic C9orf72 G4C2 repeat expansions can be detected in clinical AD patients and could act as a contributor to AD pathogenesis. Non-pathogenic repeat length variability did not affect risk of AD or MCI, nor AD biomarker levels in CSF, indicating that C9orf72 is not a direct AD risk factor. PMID- 23352323 TI - Examination of muscularity and body fat depictions in magazines that target heterosexual and gay men. AB - Previous content analyses of magazine images have typically examined within genres but failed to include comparisons between publications intended for various populations. The purpose of this study was to examine depictions of muscularity and thinness of male images in several widely distributed magazines that target male audiences from a variety of genres. Twenty-three magazine titles with the highest circulation rates that targeted heterosexual men, gay men, and general audiences were selected for image analyses. We found that magazines that target gay male audiences depicted images of men who were thinner in comparison to magazines targeting heterosexual men. Both gay and heterosexual magazines depicted male images with greater muscularity than magazines intended for general audiences. Differences in male image depictions in magazines may contribute to the promotion of an unattainable body ideal in some subgroups of gay culture. PMID- 23352324 TI - Testing the Tripartite Influence Model of body image and eating disturbance among Hungarian adolescents. AB - We tested the Tripartite Influence Model of body image and eating disturbance on two separate samples of Hungarian boys (n=145) and girls (n=225), aged 10-16 years. Our results supported the model among Hungarian adolescents; however we found notable gender differences. The associations were stronger in girls compared to boys; moreover, internalization and body dissatisfaction mediated the relationship between appearance-related sociocultural influences and self-esteem only in girls. BMI and weight perception were also involved in the model, and we could present evidence that the sociocultural influence and the weight perception predict independently body dissatisfaction. Our data are in line with previous results; however, further exploration of gender, age, and culture-related differences in the pattern of associations may contribute to the refinement of intervention programs. PMID- 23352325 TI - Immunohistochemical expression of heat shock protein 70 in vitiligo. AB - Heat shock proteins (HSPs) are proteins that are expressed under variety of stresses including pathologic conditions. How stresses affect vitiligo is not fully understood and little is known about the role of HSPs generally and Hsp70 specifically in vitiligo. The current study investigated the expression of Hsp70 in vitiliginous (32) and normal skin (10) by immunohistochemistry together with correlating this expression with the clinicopathologic parameters in the studied vitiligo group. Hsp70 was expressed in the cytoplasm of epidermis in all normal skin compared with its localization to the cytoplasm in 35.5% and to the nuclei in 64.5% of epidermis in vitiligo lesions. Intense (P < .001) and diffuse (P < .001) expression of Hsp70 was in favor of vitiligo skin compared with normal skin. Nuclear form of Hsp70 tended to be expressed in progressive forms of the disease. The percentage of Hsp70 expression tended to be decreased with the duration of the disease. From the present study, up-regulation of HSP 70, in the form of its intense and diffuse expression, may be blamed in pathogenesis of vitiligo. Nuclear localization of HSP 70 may be more important than its presence or absence, beside it may be related to progression of the disease. PMID- 23352326 TI - Postradiofrequency ablation inflammatory pseudotumor associated with pulmonary venoocclusive disease: case report and review of the literature. AB - Radiofrequency ablation of pulmonary veins is a common therapeutic intervention for atrial fibrillation. Pulmonary vein stenosis and venoocclusive disease are recognized complications, but the spectrum of pathologies postablation have not been previously reviewed. A recent case at our hospital showed a left hilar soft tissue mass in association with superior pulmonary vein stenosis in a patient 4 years postablation. On resection, this proved to be an inflammatory pseudotumor composed of myofibroblasts in an organizing pneumonia-type pattern with adjacent dendriform ossifications. Pulmonary venoocclusive change was a prominent feature. Literature on the histopathology of postradiofrequency ablation complications is limited. The severity of vascular pathology appears to increase with the postablation interval. Although pulmonary vascular changes are the most common late finding, fibroinflammatory changes including pulmonary pseudotumor formation, attributable to thermal injury, should be considered in the differential diagnosis of these cases. PMID- 23352327 TI - The analytic network process for the pharmaceutical sector: Multi criteria decision making to select the suitable method for the preparation of nanoparticles. AB - BACKGROUND: This paper presents the methodology for assessing and selecting the most appropriate procedure for the preparation of nanoparticles by implementing the analytical network process. The commonly utilized nanoparticle preparation methods are Polymer Precipitation, Interfacial polymer deposition, Complex Coacervation, Cross linking, Emulsion solvent diffusion, Homogenization and Polymerization method. There are numerous parameters to be considered in groundwork of nanoparticles that departs the conclusion manufacturer in bias. One has to address a number of components in alignment to determine and choose the optimum conclusion choices, because an unsuitable conclusion could lead to the eventual merchandise having to be formulated and developed again. For this cause in this paper, we study selecting the most appropriate procedure for the preparation of nanoparticles utilizing one of the multi criteria-decision making techniques, Analytic Network Process. METHODOLOGY: The main goal was determined. The criteria and sub-criteria that affect the main goal were determined. The alternatives for the problem were determined. The interactions between criteria, sub-criteria, and alternatives respect to the main goal were determined. The super matrixes according to the network were assembled and then weighted super matrix and limit super matrix were then constructed. The values of this limit matrix are the desired priorities of the elements with respect to the goal. The alterative with the highest priority was finally chosen as the best alternative. RESULTS: The emulsion solvent diffusion technique (M-5) has the highest value (0.434379) among the alternative methods that are applicable to the preparation of the nanoparticles. The second highest is Polymer Precipitation (M-1) with a value of 0.178798, and the lowest value or last choice is Cross Linking (M-4) with a value of only 0.024516. The alternative with the highest priority would achieve the goal, i.e., the best method for the preparation of the nanoparticles. CONCLUSION: The alternative M5 emulsion solvent diffusion technique, scoring 0.434379 was the one with largest main concern amidst all the other alternatives and thereby judged to be the most apt procedure for the preparation of nanoparticles. PMID- 23352328 TI - Phenotype variation in Treacher Collins Syndrome: from missense to splice site mutations. PMID- 23352329 TI - A comparison of non-toxin vaccine adjuvants for their ability to enhance the immunogenicity of nasally-administered anthrax recombinant protective antigen. AB - Development of nasal immunization for human use is hindered by the lack of acceptable adjuvants. Although CT is an effective adjuvant, its toxicity will likely prevent its use in nasal vaccines. This study compared non-toxin adjuvants to CT for their ability to induce protective antibody responses with nasal immunization. C3H/HeN and C57BL/6 mice were immunized with rPA formulated with the following adjuvants: CT, IL-1alpha, LPS, CpG, Pam3CSK4, 3M-019, resiquimod/R848 or c48/80. Serum and nasal wash cytokine concentrations were monitored 6h post-vaccination as biomarkers for acute activation of the innate immune system. Not all of the adjuvants induced significant changes in innate serum or nasal wash cytokines, but when changes were observed, the cytokine signatures were unique for each adjuvant. All adjuvants except Pam3CSK4 induced significantly increased anti-rPA serum IgG titers in both strains of mice, while only IL-1alpha, c48/80 and CpG enhanced mucosal anti-rPA IgA. Pam3CSK4 was the only adjuvant unable to enhance the induction of serum LeTx-neutralizing antibodies in C3H/HeN mice while c48/80 was the only adjuvant to induce increased serum LeTx-neutralizing antibodies in C57BL/6 mice. Only CT enhanced total serum IgE in C3H/HeN mice while IL-1alpha enhanced total serum IgE in C57BL/6 mice. The adjuvant influenced antigen-specific serum IgG subclass and T cell cytokine profiles, but these responses did not correlate with the induction of LeTx neutralizing activity. Our results demonstrate the induction of diverse innate and adaptive immune responses by non-toxin nasal vaccine adjuvants that lead to protective humoral immunity comparable to CT and that these responses may be influenced by the host strain. PMID- 23352330 TI - Efficacy of a divalent and a multivalent water-in-oil formulated vaccine against a highly virulent strain of Flavobacterium psychrophilum after intramuscular challenge of rainbow trout (Oncorhynchus mykiss). AB - Flavobacterium psychrophilum is a well-known pathogen causing significant problems in aquaculture worldwide. In recent years an increasing number of disease outbreaks caused by F. psychrophilum has been reported on juvenile and post smolts of rainbow trout (Oncorhynchus mykiss) in Norway. The current study was performed to assess the efficacy of two autogenous water-in-oil formulated vaccines containing whole cell antigens of F. psychrophilum to induce protective immunity against challenge. The vaccines were formulated either as multivalent (FLAVO AVM6) or divalent (FLAVO IPN) and administered by the intraperitoneal route. Intramuscular challenge with a field strain of F. psychrophilum was carried out 552 day degrees post vaccination, at a time when the FLAVO AVM6 and FLAVO IPN vaccinated groups had significantly higher antibody responses compared to the negative control. Results from the challenge study showed that the multivalent and the divalent vaccines had capacity to induce significant protection, with RPS60>87% and RPSend>77.5% for both vaccines. The high level of protection seen in the vaccinated groups was also reflected in the reduced ulceration rates observed at the injection site. Combining our results demonstrate that vaccination with FLAVO AVM6 and FLAVO IPN induces responses capable of protecting rainbow trout against infections with F. psychrophilum. PMID- 23352332 TI - The social life of drugs. PMID- 23352331 TI - The molecular adjuvant mC3d enhances the immunogenicity of FimA from type I fimbriae of Salmonella enterica serovar Enteritidis. AB - BACKGROUND: The fimbriae of Salmonella enterica serovar Enteritidis are used for colonization and invasion into host cells, and have drawn considerable interest because fimbriae can serve as potential immunogens against many pathogenic bacteria that colonize on epithelial surfaces. The purpose of the study is to use a molecular adjuvant, C3d, to enhance the immunogenicity of FimA proteins against Salmonella enterica serovar Enteritidis. METHODS: FimA of type I fimbriae from Salmonella enteritidis and FimA with one copy of mC3d, two copies of mC3d2 and three copies of mC3d3 were cloned into the expression vector pCold-TF. Soluble fusion proteins of FimA with different copy of mC3d were induced by IPTG and expressed into Escherichia coli BL21 (DE3). Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) showed that the recombinant proteins from pCold-TF fimA, TF-fimA-mC3d, TF-fimA-mC3d2, TF-fimA-mC3d3 were 70 kDa, 100 kDa, 130 kDa and 160 kDa, respectively. The fusion protein was recognized by rabbit anti fimbriae polyclonal antibodies, and then visualized by goat anti-rabbit polyclonal antibodies with a chrome appearance by enzyme-subtract interaction. The recombinant proteins were purified by Ni-TED (tris-carboxymethyl ethylene diamine), immobilized metal ion affinity chromatography (IMAC). Balb/c mice were subcutaneously immunized with the purified proteins and the immune response was monitored by an enzyme-linked immunosorbent assay (ELISA) for FimA-specific antibody. The immunized mice were challenged with a 10-fold LD50 dose (i.e., 100 CFU) of Salmonella enterica serovar Enteritidis standard strain (SD-2) 1 week after the second immunization. RESULTS: The immunized mice with the fusion proteins FimA-mC3d2 and FimA-mC3d3 had increased levels of ELISA titer of antibody that were 2 and 4 logs, respectively, more immunogenic than the TF-FimA protein alone. The challenge results showed that immune protection rate in the mice immunized with 10 MUg of FimA, FimA-mC3d2, and FimA-mC3d3 were 50%, 75% and 100%, respectively. CONCLUSION: We conclude that mC3d can be expressed in a prokaryotic vector and enhance the immune response of the recombinant protein. FimA-mC3d3 is potentially a subunit vaccine against S. enterica serovar Enteritidis infection. PMID- 23352333 TI - Japan's hiropon panic: resident non-Japanese and the 1950s meth crisis. AB - BACKGROUND: This qualitative historical policy analysis explores Japan's early postwar market for hiropon (methamphetamine/meth) and the impact of its anti hiropon campaigns. The paper traces the origins of medical methamphetamine production in prewar Japan; known at that time by its former brand-name, 'Philopon' (pronounced hiropon), and argues that the anti-meth 'shock-horror' campaigns of the 1950s were exacerbated by long-simmering animosity toward non Japanese residents - especially Koreans and Taiwanese. METHODS: Through an analysis of both English- and Japanese-language source materials, the paper explores the gritty, frightening themes of Japan's 1950s-era anti-meth propaganda campaigns and the parallel effort by police to arrest, prosecute, and deport members of the resident Korean and Taiwanese communities. RESULTS: The author demonstrates that by incorporating a wider variety of contemporary Japanese language sources such as news reports and anti-drug propaganda materials about the postwar hiropon trade, we may more fully appreciate the historic, underlying social tensions behind the swift and targeted public response. CONCLUSION: The author concludes that Japan's postwar federal and municipal governments, together with police and media agencies, cultivated a sensational 'drug panic' designed both to dissuade citizens from using hiropon and to fuel a concerted police campaign against non-Japanese involved in the meth trade. PMID- 23352334 TI - Opposite social gradient for alcohol use and misuse among French adolescents. AB - BACKGROUND: This study investigates the association of the family occupational category (F-OC) with adolescent alcohol use and its potential variation according to the frequency of use. METHODS: A national survey representative of adolescents aged 17 living in continental France conducted in 2005 (n = 29,393). Three outcomes were considered: overall use describes the drinking status (lifetime abstinence, use before the month prior the survey, use in the month prior the survey) without considering the frequency of use; last month use and binge drinking detail the frequency of use (1-5 uses, 6-9, 10-19 and 20+ uses) and of binge drinking (0, 1-2, 3-5, 6+ episodes of 5+ glasses in a single occasion) of the previous month users. F-OC was described in 7 categories based on the highest occupational category of the parents (from managers/professionals to unemployed). Analysis used generalised logistic regressions, controlling for gender, F-OC, parental separation, autonomy, other substance use, being out of school and sociability. RESULTS: There was a double gradient: adolescents from high F-OC families were more often experimenters and drinkers during the previous month whereas those of low F-OC families were more often binge drinkers. Adolescents from farmers' families were the most at risk for frequent use and binge drinking in the last month. Interactions tests show that the effect of F-OC was not significantly related to gender. CONCLUSIONS: Except for gender, adolescents' patterns of use reflect those observed in the adult population. Mechanisms that favour and hinder progression in alcohol use should be studied in various socioeconomic groups. PMID- 23352335 TI - 'It's just a social thing': drug use, friendship and borderwork among marginalized young people. AB - This article joins a growing chorus of researchers who doubt the utility of the concept of peer pressure for explaining young people's initiation to and use of drugs. Drawing on interview data with 45 patrons of a youth drop-in centre in Ottawa, Canada, we argue that drug use is more intricately woven into friendship affective relationships of trust and intimacy, belonging and sharing - rather than simply part of the unidirectional pressures some young people put on others to fit in to a subculture. Marginalized young people's narratives show that drugs and alcohol furnish them with a relatively inexpensive pastime to share with friends, introducing opportunities for intimacy that are otherwise difficult to attain at the individualistic and isolating margins of neoliberal cities. We demonstrate how young drug users draw boundaries between acceptable and unacceptable relationships to drugs and alcohol, articulating an important sense of belonging to a superior group of drug users. Through this 'borderwork', they solidify the bonds they share with the people with whom they smoke cannabis and drink alcohol. PMID- 23352336 TI - The contractual governance of drug users in treatment. AB - One of the challenges for drug treatment services is how to engage drug users effectively. This commentary examines one particular strategy for enhancing engagement that appears to have spread quite rapidly in recent years: the use of contract-like written agreements between treatment service providers and users. The development of the contractual governance of drug users in treatment is located in the wider context of emerging social control strategies and practices. In particular, insights are drawn from the socio-legal literature which has begun to examine these new control practices in diverse domains. The commentary also reports on the findings of a national survey of all 149 local authority areas in England that was designed to provide a preliminary mapping of the extent of contractual governance in treatment settings (response rate=62%). In spite of the fact that the use of contracts between drug services and service users does not feature in the national drug policy framework, our survey strongly indicates that it is a widespread practice. Although these agreements can take on many different forms, typically they set out the responsibilities and requirements placed on users and, somewhat less frequently, what the service commits to providing for them. This novel practice of contractual governance may be viewed as having considerable potential but it also raises important issues concerning justice and rights. We conclude by arguing that this is an important area of emerging practice which raises significant theoretical and policy questions and the need for further research. PMID- 23352337 TI - Metallophilic macrophages of the rodent thymus. AB - For a very long time, we studied the metallophilic macrophages of the rodent thymus and in this review our results on morphological, histochemical, enzymehistochemical, immunohistochemical, ultrastructural and functional features of these cells, as well as the molecular regulation of their development, will be presented. Furthermore, the differences between species will also be discussed and the comparisons with similar/related cell types (metallophilic macrophages in the marginal sinus of the spleen, subcapsular sinus of the lymph nodes and germinal centers of secondary lymphoid follicles) will be made. Metallophilic macrophages are strategically positioned in the thymic cortico-medullary zone and are very likely to be involved in: (i) the metabolism, synthesis and production of bioactive lipids, most likely arachidonic acid metabolites, based on their histochemical and enzymehistochemical features, and (ii) the process of negative selection that occurs in the thymus, based on their ultrastructural features and their reactivity after the application of toxic or immunosuppressive/immunomodulatory agents. Taken together, their phenotypic and functional features strongly suggest that metallophilic macrophages play a significant role in the thymic physiology. PMID- 23352338 TI - Adenotonsillectomy for sleep-disordered breathing in a predominantly obese pediatric population. AB - OBJECTIVES: To determine the efficacy of adenotonsillectomy (T&A) in the treatment of pediatric sleep-disordered breathing, and to determine the natural history in untreated children. METHODS: The charts of children aged 1-12 who underwent polysomnography (PSG) between 1/2006 and 6/2009 were reviewed to identify children with positive studies. Children not treated by T&A were recruited and matched by age, time since initial PSG, and apnea-hypopnea index (AHI) to children who underwent T&A. All participants were evaluated by a clinical assessment score (CAS-15), follow-up PSG, and the Child Behavior Checklist (CBCL). RESULTS: Sixteen matched pairs completed the study. Ten (63%) T&A patients were overweight or obese compared with 14 (88%) untreated patients. There was a greater median improvement in AHI in the surgical group compared to the nonsurgical group (10.3 vs. 6.5, p=0.044). Although the T&A children were more likely to have a follow-up AHI<5 (81% vs. 69%) and <1 (44% vs. 25%), these results were not significant. The T&A group had significantly lower mean (SD) scores on the CAS-15 [8.9(6.1) vs. 29.4(16.2), p<0.001] and the CBCL total problem score [43.9(8.7) vs. 58.9(13.0), p<0.001]. Younger age at presentation (rho=-0.76, p<0.001), initial AHI (0.87, p<0.001), and initial AI (0.63, p=0.05) were correlated with change in AHI among T&A subjects. CONCLUSIONS: T&A was more effective in reducing AHI than no surgery. Median AHI improved in the nonsurgical group, and 4/16 (25%) untreated patients were cured (AHI<1). PMID- 23352339 TI - Vitreomacular traction as a consequence of posterior hyaloidal contraction after transpupillary thermotherapy. AB - PURPOSE: To describe the pathogenesis, clinical characteristics, management, and outcomes of patients in whom vitreomacular traction evolved pursuant to treatment of choroidal melanoma with transpupillary thermotherapy. DESIGN: Retrospective, uncontrolled, observational, interventional case series. METHODS: Vitreomacular traction with macular distortion, macular edema, and vision loss developed in 6 eyes of 6 patients after successful transpupillary thermotherapy for choroidal melanoma. Clinical examination, fluorescein angiography, fundus photography, and spectral-domain optical coherence tomography were performed. Symptomatic patients underwent pars plana vitrectomy (PPV). Primary outcome measures include visual acuity and resolution of macular distortion by clinical examination, spectral domain optical coherence tomography, or both. RESULTS: In all 6 patients, the malignant lesions were treated successfully. The posterior hyaloid was attached in all eyes before transpupillary thermotherapy. All eyes demonstrated focal hyaloidal contraction and vitreomacular traction between the transpupillary thermotherapy scar and the macula. Mean time from transpupillary thermotherapy to PPV for treatment of vitreomacular traction was 23 +/- 18 months. Mean length of follow-up was 11 months. Mean logarithm of the minimal angle of resolution visual acuity before transpupillary thermotherapy was 0.23 +/- 0.38. Mean visual acuity after transpupillary thermotherapy was 0.53 +/- 0.42. Mean visual acuity before membrane peel was 0.65 +/- 0.34. Mean visual acuity after membrane peel was 0.44 +/- 0.21. All patients undergoing PPV showed visual improvement. CONCLUSIONS: Hyaloidal contraction can occur after transpupillary thermotherapy and is a reversible cause of vision loss. The mechanism of vision loss resulting from hyaloidal contraction is flat vitreomacular traction. PPV and membrane peeling are effective in improving macular anatomic features and visual function. PMID- 23352340 TI - Comparison of clinical characteristics between Korean and Western normal-tension glaucoma patients. AB - PURPOSE: To detect potential differences in the phenotypes between Western normal tension glaucoma (NTG) and Korean NTG. DESIGN: A retrospective, cross-sectional study. METHODS: One hundred eighty-four NTG eyes of 71 patients of the Jules Stein Eye Institute, University of California, Los Angeles, and 113 patients of the Seoul National University Hospital, Seoul, Korea, were studied after reviewing medical charts retrospectively. All eligible patients from both institutions who were evaluated between July 2007 and June 2008 were included. The groups were matched for stage of glaucoma severity based on the visual field mean deviation value. All patients underwent a complete ophthalmic examination, Humphrey perimetry, Heidelberg Retina Tomography, Stratus optical coherence tomography, and pachymetry. Structural and functional parameters between the 2 groups were compared. RESULTS: There were no statistically significant differences in the baseline intraocular pressure, disc area, frequency of disc hemorrhage, or peripapillary atrophy (P > .05). Cup-shape measure (by Heidelberg Retina Tomography), average RNFL thickness (by Stratus optical coherence tomography), and central corneal thickness were significantly different (P < .002). The eyes of Korean NTG patients showed higher values for cup-shape measure, higher average RNFL thicknesses, and thinner central corneal thicknesses than Western NTG patients. The difference was significant (P < .001) while controlling for age, sex, disc area, mean deviation, pattern standard deviation, and spherical equivalent with multivariate analysis. CONCLUSIONS: Korean NTG patients showed steeper cup shapes, thicker RNFL thickness, and thinner central corneal thickness compared with Western NTG patients with similar amounts of visual field loss. This result may help clinicians understand the clinical characteristics of NTG patients and points to the heterogeneous character of the glaucomas. PMID- 23352341 TI - High-resolution imaging of retinal nerve fiber bundles in glaucoma using adaptive optics scanning laser ophthalmoscopy. AB - PURPOSE: To detect pathologic changes in retinal nerve fiber bundles in glaucomatous eyes seen on images obtained by adaptive optics (AO) scanning laser ophthalmoscopy (AO SLO). DESIGN: Prospective cross-sectional study. METHODS: Twenty-eight eyes of 28 patients with open-angle glaucoma and 21 normal eyes of 21 volunteer subjects underwent a full ophthalmologic examination, visual field testing using a Humphrey Field Analyzer, fundus photography, red-free SLO imaging, spectral-domain optical coherence tomography, and imaging with an original prototype AO SLO system. RESULTS: The AO SLO images showed many hyperreflective bundles suggesting nerve fiber bundles. In glaucomatous eyes, the nerve fiber bundles were narrower than in normal eyes, and the nerve fiber layer thickness was correlated with the nerve fiber bundle widths on AO SLO (P < .001). In the nerve fiber layer defect area on fundus photography, the nerve fiber bundles on AO SLO were narrower compared with those in normal eyes (P < .001). At 60 degrees on the inferior temporal side of the optic disc, the nerve fiber bundle width was significantly lower, even in areas without nerve fiber layer defect, in eyes with glaucomatous eyes compared with normal eyes (P = .026). The mean deviations of each cluster in visual field testing were correlated with the corresponding nerve fiber bundle widths (P = .017). CONCLUSIONS: AO SLO images showed reduced nerve fiber bundle widths both in clinically normal and abnormal areas of glaucomatous eyes, and these abnormalities were associated with visual field defects, suggesting that AO SLO may be useful for detecting early nerve fiber bundle abnormalities associated with loss of visual function. PMID- 23352342 TI - Vernal keratoconjunctivitis-like disease in adults. AB - PURPOSE: To identify clinical, demographic, immunologic, and health-related quality-of-life data from a cohort of vernal keratoconjunctivitis (VKC) patients with the onset of the disease after puberty (VKC-like disease). DESIGN: Retrospective, observational case series. METHODS: Forty-nine patients with late onset VKC-like disease from among 600 consecutive VKC patients. History of disease, test results for allergen sensitivity, signs and symptoms, impact of disease on work productivity, health-related quality of life, and treatment satisfaction were assessed. In addition, multiplex bead analysis for Th1/Th2 cytokines were carried out in tear samples from 20 VKC patients (10 adults and 10 children) and from 10 normal subjects. RESULTS: A family history of allergy was positive in only 28% and positive prick test results were present in 55% of the 49 VKC-like adult patients. Based on typical signs and symptoms, 48% were affected by the limbal form, 33% were affected by the tarsal form, and 19% were affected by the mixed form. Corneal ulcer complicated the disease in only 2 adult patients. Although the disease was not considered a limiting factor for work, productivity was reduced by 26% and social activities were reduced by 31% during active flare-ups. No significant differences were found in tear cytokine pattern production between VKC in children and VKC in adults. CONCLUSIONS: A late onset VKC-like disease can appear in young adults with signs and symptoms similar to those in pediatric disease, but with less corneal involvement. PMID- 23352343 TI - Angiographic and optical coherence tomography characteristics of recent myopic choroidal neovascularization. AB - PURPOSE: To analyze the contribution of fluorescein angiography (FA) and spectral domain optical coherence tomography (SD OCT) to the diagnosis of recent choroidal neovascularization (CNV) associated with high myopia. DESIGN: Retrospective, observational case series. METHODS: Ninety eyes of 73 highly myopic patients (refractive error >=-6 diopters) with CNV in 1 or both eyes were included. Epidemiologic features, refractive error, fundus examination, fluorescein angiography, and SD OCT findings at onset of CNV were analyzed. RESULTS: Mean age at onset of CNV was 54.4 +/- 14 years. CNV was bilateral in 17 of 73 cases. Mean refractive error was -13.9 +/- 5.2 diopters. Myopic CNV was associated more frequently with patchy or geographic atrophy (P = .019). CNV was associated with exudative features on fluorescein angiography in 82% of cases (64/78), and on SD OCT in 48.6% of cases (36/74). There was no agreement about signs of active CNV between these 2 imaging methods (kappa = 25.7 +/- 10%; P = .0044). CNV area was significantly smaller in younger patients (<55 years) than in older patients (0.57 mm(2) vs 1.21 mm(2), respectively; P = .023). CONCLUSIONS: Exudative features of myopic CNV are more obvious on FA than on SD OCT, suggesting that fluorescein angiography should be performed when new-onset myopic CNV is suspected. Myopic CNV occurring in older patients (>=55 years) is larger than those seen in younger patients and resembles CNV associated with age-related macular degeneration. This suggests an overlap between myopic CNV in older patients and age-related macular degeneration. PMID- 23352344 TI - Retroprosthetic membrane and risk of sterile keratolysis in patients with type I Boston Keratoprosthesis. AB - PURPOSE: To evaluate whether retro-backplate retroprosthetic membrane is correlated with risk of melt in patients with a type I Boston Keratoprosthesis (KPro). DESIGN: Retrospective, observational case series. METHODS: Study of 50 eyes of 47 patients with type I Boston KPro and postoperative anterior segment optical coherence tomography (AS OCT) imaging performed at the University of Illinois at Chicago. Main outcome measures were presence of retro-backplate membrane and development of melt requiring explantation. For eyes with melt, membrane thickness was measured using the AS OCT images obtained at the last visit before melt occurred. For eyes without melt, the last available AS OCT images were used for measurement. RESULTS: AS OCT evidence of a retro-backplate membrane was observed in 100% of eyes that melted and in 34.1% of eyes that did not (P = .0034; risk ratio, 2.9; 95% confidence interval, 1.9 to 4.4). Retro backplate membrane thickness in the melt group was 278 MUm versus 193 MUm in the nonmelt group (P = .025). CONCLUSIONS: The retro-backplate portion of a retroprosthetic membrane is to be differentiated from the retro-optic portion seen at the slit lamp. The retro-backplate membrane as shown by AS OCT imaging is correlated with an increased risk of sterile keratolysis, possibly because of impedance of nutritional support from the aqueous humor. Further studies are needed to better standardize the AS OCT measurements of retro-backplate membranes as well as to identify early interventions to prevent progression of thin membranes once identified on AS OCT. PMID- 23352345 TI - Comparison of two biochemical methods for identifying Corynebacterium pseudotuberculosis isolated from sheep and goats. AB - The biochemical pattern of Cowan and Steel (BPCS) was compared with a commercial biochemical strip for the identification of Corynebacterium pseudotuberculosis isolated from small ruminants. On 16S rRNA gene sequencing, 40/78 coryneform isolates from the lymph nodes of sheep and goats with lesions resembling caseous lymphadenitis were identified as C. pseudotuberculosis. The sensitivities of the BPCS and the commercial biochemical strip relative to 16S rRNA sequencing were 80% and 85%, and their specificities were 92.1% and 94.7%, respectively; the level of agreement between the BPCS and the commercial biochemical strip was high (kappa=0.82). Likelihood ratios for positive and negative results were 10.0 and 0.22 for the BPCS, and 16.0 and 0.16 for the commercial biochemical strip, respectively. These results indicate that the BPCS and the commercial biochemical strip are both useful for identifying C. pseudotuberculosis in veterinary microbiology laboratories. PMID- 23352346 TI - Analysis of [11C]methyl-candesartan kinetics in the rat kidney for the assessment of angiotensin II type 1 receptor density in vivo with PET. AB - INTRODUCTION: Angiotensin II type 1 (AT(1)) receptors play a key role in the regulation of renal and cardiovascular functions and have been implicated in the pathogenesis of many diseases. The aim of this study was to assess binding of the novel radioligand [(11)C]methyl-candesartan to AT(1) receptors in the rat kidney in vivo with PET. METHODS: Dynamic PET images were acquired for 60 min at baseline, with coinjection of candesartan (5 mg/kg), and after injection of PD123,319 (5 mg/kg). Volumes of distribution (R(C)?V(T)) were estimated with a two-compartment model, by Logan analysis, and by taking the tissue-to-plasma activity ratio at 50-60 min post-injection. RESULTS: The two-compartment model did not describe the kinetics at baseline adequately and the baseline scans were too short to obtain accurate estimates of R(C)?V(T) with the Logan approach. Based on the tissue-to-plasma ratios, roughly one-third of V(T) at baseline could be attributed to AT(1) receptor binding. There were no indications of AT(2) receptor binding in the rat kidney. CONCLUSION: It may be possible to detect changes in AT(1) receptor density in the rat kidney in vivo with [(11)C]methyl candesartan and PET. Imaging AT(1) receptors with PET may provide valuable information on the role of these receptors in the pathogenesis of diseases such as hypertension, diabetic nephropathy, ventricular remodeling, and heart failure. PMID- 23352347 TI - [Evolution of food supply (apart from school catering) between 2004/2005 and 2009/2010 in middle- and high-schools of Aquitaine, France]. AB - BACKGROUND: The aim of this study was to assess the evolution of food supply (apart from school catering) between school years 2004/2005 and 2009/2010, in middle- and high-schools from the Aquitaine region (southwest France), in order to evaluate the impact of actions conducted within the framework and the program Nutrition, Prevention and Health of children and adolescents in Aquitaine (southwest France). METHODS: Two surveys were carried out among all middle- and high-schools of the Aquitaine region in 2004/2005 (n=536) and 2009/2010 (n=539) within the framework of a regional multidisciplinary public health program "Nutrition, prevention and health of children and teenagers in Aquitaine". For both 2004/2005 and 2009/2010, data were collected using the same questionnaire and dealt with school characteristics and modalities of food supply (apart from school catering). RESULTS: Response rate was 84.1% in 2004/2005 and 79.6% in 2009/2010. The proportion of schools offering food to pupils (apart from school catering) significantly decreased in 5 years (from 80.1% to 50.1%, P<0.001). Between 2004/2005 and 2009/2010, we observed a stabilization in the proportion of schools offering free food (from 19.7 to 17%, P=0.3), a significant decrease of those selling food (from 62.8 to 37.1, P<0.001), offering vending machines (from 43.5 to 7.2, P<0.001) and a significant increase of those offering water supply (from 8.2 to 44%, P<0.001). The composition of each modality of food supply (apart from school catering) has also been improved: less sweet and fat food, more bread and fruits. CONCLUSION: This study shows an overall improvement of food supply apart from school catering (food sale, free food and vending machines) in middle- and high-schools from the Aquitaine region (southwest France) between 2004/2005 and 2009/2010. This improvement is related to the proportion of schools offering food (quantitative improvement), as well as to the composition of food supply (qualitative improvement). These results show an improvement of food supply (apart from school catering), suggesting that actions implemented in the framework of the program "Nutrition, prevention and health of children and adolescents in Aquitaine" may have led to these improvements. PMID- 23352348 TI - Surgical management of dural arteriovenous fistulas of the transverse-sigmoid sinus in 42 patients. AB - A retrospective study was performed to analyse a prospectively collected database from a single surgeon (M.K.M.) of transverse-sigmoid sinus dural arteriovenous fistulas (DAVF) between 1991 and August 2011. During the study period, 144 patients with 160 DAVF were managed. Sixty-five of the DAVF were located in the transverse-sigmoid sinus and 42 were treated with surgery, or embolisation and surgery. All patients who underwent surgery were symptomatic with retrograde cortical venous drainage. The average follow-up period was 18months (range, 2 82months). Total elimination of the DAVF was achieved in all instances, including two patients (5%) who required further surgery after postoperative cerebral angiography showed that some venous drainage had persisted after the first operation. There was no new permanent neurological deficit or mortality attributable to surgery. Our institutional experience shows that in selected patients with transverse-sigmoid sinus DAVF, the involved sinus can be surgically resected with a high success rate and it is as safe as many alternative options. We suggest that this definitive treatment option should be offered to patients, and the outcome should be compared to other treatment modalities. PMID- 23352349 TI - A 19-year-old male with cerebellar ataxia and cognitive impairment following glandular fever. AB - A 19-year-old male, who was previously functionally independent, presented with cerebellar ataxia and cognitive impairment following glandular fever. This case highlights the importance of considering an Epstein-Barr virus aetiology in children or young adults with acute cerebellar ataxia. PMID- 23352350 TI - Hemorrhagic epidermoid cyst in a patient with generalized tonic clonic seizure. AB - Epidermoid cysts account for approximately 1% of all intracranial tumors. Hemorrhage into an epidermoid cyst is extremely rare, and has only been reported a few times. To our knowledge, there are no reports of a hemorrhagic epidermoid cyst presenting with a first generalized tonic clonic seizure. We present a 68 year old female with an epidermoid cyst with intracystic hemorrhage who presented with a first time generalized tonic clonic seizure. When complicated with hemorrhage, the diagnosis of an epidermoid cyst is challenging and there is a potential for misdiagnosis. PMID- 23352351 TI - Prevalence, clinical features and treatment outcomes of patients with myasthenia gravis positive for antibodies to muscle-specific kinase in Thailand. AB - A small but variable subgroup of patients with myasthenia gravis (MG) who have antibodies to muscle-specific kinase (MuSKAb-MG) can present with distinct phenotypes and are often treatment-resistant. The prevalence, clinical phenotypes and outcomes of treatment of patients with MuSKAb-MG in Thailand were determined. Eight (16.3%) of the 49 patients with generalized MG who were negative for acetylcholine receptor antibodies (AChRAb) were positive for muscle-specific kinase antibodies. Most patients had predominant oculobulbar features and respiratory failure occurred in three. At follow up, three out of the seven patients who underwent thymectomy were in complete stable remission and four had improved and were on reduced immunosuppression medication, suggesting a possible benefit of thymectomy. PMID- 23352352 TI - Long-term survival of patients with glioblastoma multiforme (GBM). AB - Long-term survival is an often used, yet poorly defined, concept in the study of glioblastoma multiforme (GBM). This study suggests a method to define a time point for long-term survival in patients with GBM. Data for this study were obtained from the Surveillance, Epidemiology and End-Results database, which was limited to the most recent data using the period approach. Relative survival measures were used and modelled using piecewise constant hazards to describe the survival profile of long-term survivors of GBM. For patients with GBM, the first quarter of the second year (5th quarter) post-diagnosis is considered to be the peak incidence of mortality with an excess hazard ratio of 7.58 (95% confidence interval=6.54, 8.78) and the risk of death due to GBM decreases to half of its rate at 2.5 years post-diagnosis. The 2.5-year cumulative relative survival (CRS) for all patients is approximately 8%, with a CRS of approximately 2% at 10 years. Using the definition of long-term survival suggested here, the results indicate that long-term survivors are patients who survive at least 2.5 years post diagnosis. The most likely time period for patients with GBM to die is the 5th quarter post-diagnosis. PMID- 23352353 TI - Fuzzy logic model to describe anesthetic effect and muscular influence on EEG Cerebral State Index. AB - The well-known Cerebral State Index (CSI) quantifies depth of anesthesia and is traditionally modeled with Hill equation and propofol effect-site concentration (Ce). This work brings out two novelties: introduction of electromyogram (EMG) and use of fuzzy logic models with ANFIS optimized parameters. The data were collected from dogs (n=27) during routine surgery considering two propofol administration protocols: constant infusion (G1, n=14) and bolus (G2, n=13). The median modeling error of the fuzzy logic model with Ce and EMG was lower or similar than that of the Hill with Ce (p=0.012-G1, p=0.522-G2). Furthermore, there was no significant performance impact due to model structure alteration (p=0.288-G1, p=0.330-G2) and EMG introduction increased or maintained the performance (p=0.036-G1, p=0.798-G2). Therefore, the new model can achieve higher performance than Hill model, mostly due to EMG information and not due to changes in the model structure. In conclusion, the fuzzy models adequately describe CSI data with advantages over traditional Hill models. PMID- 23352354 TI - Determinants of specificity in two-component signal transduction. AB - Maintaining the faithful flow of information through signal transduction pathways is critical to the survival and proliferation of organisms. This problem is particularly challenging as many signaling proteins are part of large, paralogous families that are highly similar at the sequence and structural levels, increasing the risk of unwanted cross-talk. To detect environmental signals and process information, bacteria rely heavily on two-component signaling systems comprised of sensor histidine kinases and their cognate response regulators. Although most species encode dozens of these signaling pathways, there is relatively little cross-talk, indicating that individual pathways are well insulated and highly specific. Here, we review the molecular mechanisms that enforce this specificity. Further, we highlight recent studies that have revealed how these mechanisms evolve to accommodate the introduction of new pathways by gene duplication. PMID- 23352355 TI - Apathy and weight loss in nursing home residents: longitudinal study. AB - OBJECTIVES: Determine which behavioral syndromes of dementia are independently related to weight loss. DESIGN: Longitudinal study using four subsequent quarterly Minimum Data Set (MDS) 2.0 assessments. Characteristics obtained in one period were related to weight loss observed in the next period. SETTING: Eight nursing homes in the Netherlands. PARTICIPANTS: The initial population was 2031 nursing home residents with four quarterly MDS assessments within a period of 15 months. We selected 1850 subjects who were at least 65 years old at the time of the first assessment and who were not comatose. MEASUREMENTS: Information about the presence of four behavioral syndromes (depression, apathy, agitation, and rejection of care), demographic data, cognition status, body mass index (BMI), and time that residents were involved in activities were obtained from MDS 2.0. RESULTS: Bivariate correlation showed that weight loss at follow-up assessments was related to all baseline behavioral syndromes, degree of cognitive impairment, body mass index, and time that residents were involved in activities. Multivariable binary logistic regression with these factors showed that the only behavioral syndrome that was independently related to subsequent weight loss was apathy. In multivariable analysis, the degree of cognitive impairment and BMI were also independently related to weight loss. CONCLUSION: These results suggest that of all behavioral factors we have assessed, apathy had the strongest association with weight loss in nursing home residents even when adjusted for the degree of cognitive impairment. PMID- 23352356 TI - Reducing antipsychotic use in long term care residents: addressing psychological and spiritual needs of residents with dementia is crucial. PMID- 23352357 TI - Foot claudication with plantar flexion as a result of dorsalis pedis artery impingement in an Irish dancer. AB - Dorsalis pedis artery impingement is an extremely rare cause of foot claudication, with a single case reported in the literature. In this report, we describe the case of a 17-year-old female Irish dancer who presented with intermittent bilateral foot pain and discoloration during active plantar flexion. PMID- 23352358 TI - Regional quality groups in the Society for Vascular Surgery(r) Vascular Quality Initiative. AB - The Society for Vascular Surgery Vascular Quality Initiative (SVS VQI) is designed to improve the quality, safety, effectiveness, and cost of vascular health care. The SVS VQI is uniquely organized as a distributed network of regional quality improvement groups across the United States. The regional approach allows for the involvement of a variety of health care professionals, the pooling of available resources and expertise, and serves as a motivating factor for each participating institution. Regional quality group sizes, administrative structure, and meeting logistics vary according to geography and regional needs. This review describes the process of forming, growing, and maintaining a regional quality improvement group of the SVS VQI. PMID- 23352359 TI - Retrograde ascending Stanford B aortic dissection complicating a routine infrarenal endovascular aortic reconstruction. AB - Retrograde ascending aortic dissections usually complicate endovascular reconstructions of Stanford B dissections. Although rare, with an incidence of 1.3% to 6.8%, they are catastrophic, with a high mortality rate of up to 42%. The exact mechanism is not known, but all indications point to a mechanical interaction between the tips of the proximal bare stent and a fragile aortic wall. Practically all reported cases involve dissections of the thoracic aorta. We report a patient with an asymptomatic retrograde ascending aortic dissection that originated at the level of a damaged suprarenal stent during capture tip retrieval during a routine endovascular aneurysm repair to treat an infrarenal aortic aneurysm. PMID- 23352360 TI - Secondary interventions after elective thoracic endovascular aortic repair for degenerative aneurysms. AB - OBJECTIVE: We assessed the incidence and outcomes of graft-related secondary interventions (ie, open conversion or proximal or distal extensions) after elective thoracic endovascular aortic repair (TEVAR) for aneurysmal disease. METHODS: An institutional review of TEVAR for descending thoracic aortic aneurysms (DTAAs), between 2000 and 2011, was performed. Only elective TEVAR for DTAA using commercially available endografts was selected. Emergent cases, nonaneurysmal aortic pathology (ie, transection, pseudoaneurysm, dissection), and cases that used physician-modified devices were excluded. The incidence of unplanned graft-related secondary interventions was examined and outcomes were analyzed. RESULTS: During the study period, 83 patients underwent elective TEVAR for DTAA that met the inclusion criteria. Subsequent graft-related secondary interventions were required in eight patients (10%). The mean interval to the secondary intervention was 31.8 months. Endoleak was the most common indication. Patients who required secondary interventions were significantly younger (mean age, 58 +/- 12 vs 69 +/- 11 years; P < .05). Operative mortality (<30 day) was zero, with one aneurysm-related late death occurring at 2 years after the secondary intervention. Factors that predisposed the need for secondary interventions were fusiform morphology of the aneurysm (P = .05) and extent of graft coverage in the proximal landing zone <3 cm (P < .05). Size of the aneurysm treated and the type of device used were not significant factors leading to secondary intervention. CONCLUSIONS: Intermediate and long-term results of elective TEVAR for DTAA demonstrate good durability, with acceptable rates of graft-related secondary interventions. Age, fusiform aneurysm morphology, and extent of proximal landing zones <3 cm were significant factors that led to subsequent secondary interventions. PMID- 23352361 TI - Early quantitative evaluation of indocyanine green angiography in patients with critical limb ischemia. AB - OBJECTIVE: Patients requiring lower extremity revascularization are increasingly complex. Traditional means of evaluating perfusion before and after revascularization are often limited by the presence of medial calcinosis, open wounds, prior toe or forefoot amputations, and infection. We evaluated the initial application of indocyanine green angiography (ICGA) to patients with severe lower extremity ischemia to develop quantitative, reproducible parameters to assess perfusion. METHODS: ICGA uses a charge-coupled device camera, a laser, and intravenous contrast to visually assess skin surface perfusion. From January 2011 to April 2012, we performed ICGA within 5 days of 31 revascularization procedures in patients with Rutherford class 5 and 6 ischemia. We also compared ICGA before and after revascularization in a subset of 13 patients. We evaluated multiple, quantitative parameters to assess perfusion. RESULTS: Twenty-four patients underwent ICGA associated with 31 revascularization procedures (26 endovascular, four open, one hybrid) for 26 lower limb wounds; 92% were diabetic and 20% were dialysis-dependent. In 50% of these patients, it was not possible to measure ankle-brachial indexes due to medial calcinosis. Paired analysis of ingress (increase in pixel strength [PxS]), ingress rate (slope of increase in PxS), curve integral (area under the curve in PxS over time), end intensity (PxS at end of study), egress (decrease in PxS from maximum), and egress rate (slope of decrease in PxS) increased significantly (P < .05) after revascularization. CONCLUSIONS: ICGA provides rapid visual and quantitative information about regional foot perfusion. We believe this is the first report describing quantification of foot perfusion before and after lower extremity revascularization for severe limb ischemia. Further study is warranted to help define the utility of this intriguing new technology to assess perfusion, response to revascularization, and potentially, to predict likelihood of wound healing. PMID- 23352362 TI - Surgical management of a neuroendocrine tumor of the inferior vena cava. AB - Neuroendocrine tumors occurring outside of the gastrointestinal tract or lungs are very few, and to find a primary neuroendocrine tumor of the infrahepatic inferior vena cava (IVC) is extremely rare. We present a case of a patient with a large, 7 * 4 cm neuroendocrine tumor of the IVC, where the IVC and renal veins were completely extirpated and not reconstructed. As a result, the liver was anastomosed to the intrapericardial IVC, and the patient relied on collateral drainage. After an initial postoperative period of anasarca and weight gain, she ultimately recovered fully with no evidence of recurrence in the IVC. PMID- 23352363 TI - Comparative effectiveness study of self-directed walking exercise, lower extremity revascularization, and functional decline in peripheral artery disease. AB - OBJECTIVE: Among individuals with peripheral artery disease (PAD), we compared annual change in 6-minute walk performance between participants who neither underwent lower extremity revascularization nor walked for exercise (group 1, reference), those who walked regularly for exercise (group 2), and those who underwent lower extremity revascularization (group 3). METHODS: Participants were recruited from Chicago-area vascular laboratories and followed annually. Change in 6-minute walk was calculated beginning at the study visit preceding lower extremity revascularization or exercise behavior and continuing for 1 additional year after the therapy was reported. Results are adjusted for age, sex, race, comorbidities, and other confounders. RESULTS: Of 348 PAD participants, 43 underwent revascularization during median follow-up of 84 months. Adjusted annual declines in 6-minute walk were -96.6 feet/year for group 1, -49.9 feet/year for group 2, and -32.6 feet/year for group 3 (P < .001). Forty-one percent of revascularizations were not associated with ankle-brachial index (ABI) improvement. When group 3 was limited to participants with ABI improvement >=0.15 after revascularization, annual adjusted changes in 6-minute walk were -97.7 feet/year for group 1, -46.5 feet/year for group 2, and +68.1 feet/year for group 3 (P < .001). When group 3 was limited to participants without ABI improvement >=0.15 after revascularization, annual adjusted changes in 6-minute walk were 99.2 feet/year for group 1, -48.0 feet/year for group 2, and -61.7 feet/year for group 3 (P < .001). CONCLUSIONS: A large proportion of PAD participants did not have ABI improvement of at least 0.15 at follow-up study visit after revascularization. The benefits of lower extremity revascularization in patients with PAD appear closely tied to improvements in the ABI after revascularization. PMID- 23352364 TI - Ultrasound is a critical adjunct in the diagnosis and treatment of popliteal entrapment syndrome. AB - This article describes our approach and evidence-based evaluation of popliteal entrapment syndrome. Included is a technical description of our use of preoperative intravascular ultrasound for diagnosis and operative planning in combination with our utilization of intraoperative duplex ultrasound. This evidence-based, methodical approach enables not only the correct diagnosis of the type of popliteal entrapment, but more importantly, identifies irreparable injury to the popliteal artery that would necessitate operative arterial reconstruction prior to surgery. PMID- 23352365 TI - Difference in operative time according to stone location for endoscopic management of ureteral and renal stones. AB - OBJECTIVE: To study the difference in operative time for endoscopic management of ureteral and renal stones according to the stone location. MATERIALS AND METHODS: We hypothesized that these cases are not equivalent in terms of the surgeon's work as measured by the operating time, and we assessed whether significant variations exist within the umbrella of the Common Procedural Terminology code 52353: "ureterorenoscopic lithotripsy." We retrospectively reviewed the records of all patients undergoing unilateral ureteroscopic laser lithotripsy or retrograde intrarenal surgery under the care of 1 fellowship-trained endourologist from 2008 to 2010. The patients who underwent simultaneous additional endoscopic procedures, including bilateral ureteropyeloscopy, were excluded. The demographics, stone size and location, presence of a previously placed stent, and operative time were assessed and compared. The cohorts were designated according to the stone location--ureteral or renal. RESULTS: Of the total 213 ureteroscopic laser lithotripsy and retrograde intrarenal surgery cases reviewed, 115 were ureteral stones and 98 were renal stones. The renal stones required a significantly increased mean operative time (112 minutes) than did the ureteral stones (70 minutes; P <.001). The renal stone size was significantly larger (11.3 vs 7.7 mm, P <.001), and these cases had a greater preoperative stent rate (55% vs 37%, P = .014). CONCLUSION: Despite bundling within a single Current Procedural Terminology code, endoscopic management of renal stones and ureteral stones were markedly different, with a significant increase in the operative time for renal stones. The renal stone size was significantly larger, as expected. Current Procedural Terminology differentiation should be considered to appreciate the difference between ureteral and renal ureterorenoscopic lithotripsy in terms of resource requirements. PMID- 23352366 TI - Editorial comment. PMID- 23352367 TI - Congenital Megaprepuce: surgical approach. AB - OBJECTIVE: To describe surgical procedure and results of Congenital Megaprepuce (CMP) that consists in phimosis and megaprepuce; glans and corpora trapped into pre-pubic fat; incomplete micturition with typical "ballooning" aspect. METHODS: Genitoplasty with penoscrotal separation (GPS) was performed at Pediatric Surgery Department of Hospital Nord - Marseille, between July and December 2010, in 5 uncircumcised children with CMP, by the same surgeon. Transversal incision at the ventral penoscrotal junction was used, with shaft bipartition and Buck's ventral fascia exposition. The inner layer of prepuce was resected while the outer layer was preserved for coverture of the penile shaft. The dorsal foreskin was medially and longitudinally incised to obtain adequate length of the dorsal shaft. The first middle dorsal suture was made using PDS 6.0 and completed in ventral direction with interrupted stitches. The urinary catheter was placed and hydrocolloid duoderm dressing used. Perioperative prophylactic antibiotic was given and pain control achieved with paracetamol and codeine. RESULTS: All patients presented urinary troubles before surgery. Skin penile coverage was complete in all patients with cosmetically and functionally satisfying results; no complication was observed at 12 months mean follow-up. CONCLUSION: CMP is a specific entity of "inconsistent penis." Surgical treatment should be discussed at diagnosis, resolving micturition troubles. GPS is a simple and reproducible procedure by experienced surgeons. Excellent cosmetic and functional results are obtained at mean follow-up, even if long-term results are required. GPS can be useful in other malformations of the penile shaft. PMID- 23352368 TI - Endoscopic forceps for ureteroscopy: a comparative in vitro analysis. AB - OBJECTIVE: To evaluate the functional characteristics of different ureteroscopic graspers. METHODS: The Captura (2.8F, Cook Medical, Bloomington, IN), Platinum (3.0F, Bard Urological, Covington, GA), TriClaw (2.4F, UroGyn Medical, Inc., Valapraiso, IN), Graspit (2.6F, Boston Scientific, Natick, MA), and Boston Scientific Tricep (2.4F, 3.0F, and 3.0F non-retracting) graspers were tested. Opening dynamics were evaluated using high-resolution images. Grip strength was determined by measuring the maximum tensional force applied while grasping stone models attached to an inline load cell. Safety profile was evaluated by the maximum force required to perforate aluminum foil. Impact on ureteroscope deflection was assessed by measurement of maximum deflection (baseline = 247 degrees ) and bending radius after advancing each grasper through a flexible ureteroscope working channel. The Tukey test for inequality assuming unequal variance with Bonferroni adjustment was used to compare grip strength and perforation forces. RESULTS: The Tricep (2.4F, 3.0F NR, and 3.0F) and Captura graspers required the least distance (7.9-8.1 mm) to attain a grasping width of 5 mm. When compared across all stone models, the TriClaw and Graspit had greater grip strengths than all other devices. The Captura (1.92 +/- 0.43 N) and Tricep 2.4F (1.72 +/- 0.88 N) required the greatest forces to perforate aluminum foil. Ureteroscope deflection was least impacted by the Tricep 2.4F (213 degrees , 1.35 cm radius), Graspit (207 degrees , 1.35 cm radius), TriClaw (206 degrees , 1.3 cm radius), and all graspers could be deployed and operated at maximum deflection. CONCLUSION: There are significant differences in opening dynamics, grip strength, perforation forces, and ureteroscope deflection among ureteroscopic graspers that may predict clinical performance capabilities. PMID- 23352370 TI - Phosphorylation status of Fas-associated death domain protein is associated with biochemical recurrence after radical prostatectomy. AB - OBJECTIVE: To assess whether the phosphorylated Fas-associated death domain protein (FADD) at 194 serine (p-FADD) is valuable as a marker of biochemical recurrence in hormone-naive patients who had undergone radical prostatectomy. MATERIALS AND METHODS: We used radical prostatectomy specimens from 106 patients. None of the patients had received neoadjuvant or adjuvant therapy. The percentage of positive p-FADD cells (nuclear staining) was immunohistochemically evaluated. The correlation between FADD phosphorylation and the clinicopathologic parameters was assessed. The correlation between the biochemical recurrence-free rate and the p-FADD expression level was analyzed using the Kaplan-Meier method. RESULTS: Overall, 39 patients developed biochemical recurrence. We investigated the expression of p-FADD in 106 patients with prostate cancer using immunohistochemistry. We compared our findings with the clinicopathologic parameters, including the follow-up data. Patients with a greater positive p-FADD rate had a significantly lower biochemical recurrence rate than those with a lower positive p-FADD rate (P < .001). A significant inverse correlation was found between the positive p-FADD rate and the Gleason score. CONCLUSION: A low expression of p-FADD could be a predictor of biochemical recurrence in hormone naive patients who have undergone radical prostatectomy. PMID- 23352371 TI - Editorial comment. PMID- 23352372 TI - Using preoperative albumin levels as a surrogate marker for outcomes after radical cystectomy for bladder cancer. AB - OBJECTIVE: To evaluate preoperative albumin levels as a marker for comparing survival outcomes after cystectomy in patients with bladder cancer. MATERIALS AND METHODS: We performed a retrospective record review using our bladder cancer database of 238 patients from 2004 to 2011. Of these, we included 187 patients with sufficient data for analysis, aged 35 years or older, who survived to undergo cystectomy. Serum albumin levels were routinely checked the day before cystectomy. Overall survival and cancer-specific survival by albumin levels were compared using Kaplan-Meier and Cox proportional hazards regression models. Complication rates between albumin groups were compared by a 2-sample test of proportions. RESULTS: Thirty-one patients (16.5%) were in the low-albumin cohort (defined as albumin <3.5 g/dL), and 156 patients had albumin levels within normal reference ranges. Multivariable analysis showed overall survival at 3 years was 41% and 56% (adjusted hazard ratio, 1.76; P = .04) and cancer-specific survival was 57% and 72% (hazard ratio, 1.57; P = .22) in the low- and normal-albumin groups, respectively. Overall complication rates were significantly higher in the cohort with low albumin than in those with normal albumin (87% vs 65%; P = .014). CONCLUSION: Our single-institution retrospective study demonstrates that patients with low preoperative albumin levels had an increased overall mortality and cancer-specific mortality risk than those with normal albumin levels. Albumin may therefore be a reflection of disease state as well as nutritional status. PMID- 23352373 TI - In vitro examination of effects of hyperprolactinemia and hypoprolactinemia on seminal vesicle contractions. AB - OBJECTIVE: To investigate the contractile characteristics of the seminal vesicles in rats, in which hyperprolactinemia and hypoprolactinemia was induced by prolactin and bromocriptine administration. MATERIALS AND METHODS: A total of 24 Wistar albino rats were randomly divided into 3 groups: control group, hyperprolactinemia group, and hypoprolactinemia group. The rats in the control group were administered 0.1 mL saline subcutaneously for 21 days. The rats in group 2 received prolactin 51 MUg/kg subcutaneously for 21 days. The rats in the third group received intraperitoneal bromocriptine mesylate at a dose of 66 MUg/kg. All the rats were decapitated at 21 days. The seminal vesicles were removed using a microsurgical technique, and the tissue sections were prepared (0.5 * 0.2 cm). These sections were suspended in the organ bath. Subsequently, contractions were induced using 10 MUmol acetylcholine or 100 mmol potassium chloride. RESULTS: The amplitude values induced by potassium chloride in the prolactin group were significantly greater than those in the bromocriptine group or control group. Similarly, the amplitude values induced by acetylcholine were also significantly greater in the prolactin group than in the other 2 groups. CONCLUSION: Experimental hyperprolactinemia results in an increase in the smooth muscle contraction and tonus of the seminal vesicles. The alterations in the smooth muscle tonus in the seminal vesicles and genitourinary tract might be involved in the etiology of infertility occurring in hyperprolactinemia. PMID- 23352374 TI - Staging paratesticular rhabdomyosarcoma in the "as low as reasonably achievable" age: the case for PET-CT. AB - Rhabdomyosarcoma accounts for 40% of paratesticular malignancies and 5% of testicular and paratesticular malignancies in children and adolescents. The Children's Oncology Group currently recommends computed tomography (CT) or magnetic resonance imaging for staging of paratesticular rhabdomyosarcoma in children. The present case illustrates a 9-year-old boy with paratesticular rhabdomyosarcoma who had negative findings on a staging CT scan and a subsequent positron emission tomography-CT scan demonstrating retroperitoneal lymph node metastasis. In the era of "as low as reasonably achievable" imaging, positron emission tomography-CT should be considered first-line imaging for staging to improve the sensitivity and specificity of staging for paratesticular rhabdomyosarcoma. PMID- 23352375 TI - Combined use of liposuction and arthroscopic shaver in lower-limb fasciocutaneous flap contouring. AB - The goals of reconstruction in the foot and ankle should be to restore ambulation and enable the patient to use normal footwear. In these wounds, free fasciocutaneous flaps provide pliable protection and gliding of tendons. There can however be problems with contour and bulk. We describe the combined use of liposuction and arthroscopic shaving to achieve effective flap contouring in a single session. We performed the technique in 10 free fasciocutaneous flaps in nine patients. The average interval between the initial reconstructive procedure and flap debulking was 7 months. Complications included two cases of flap superficial epidermal loss and one haematoma. At an average of 8.6 months follow up, five patients reported that they were very satisfied with the procedure, three were satisfied and one was dissatisfied. Seven of the nine patients were using their original covered footwear at the time of follow-up. In conclusion, the combined use of liposuction and arthroscopic shaving is simple and effective in the contouring of fasciocutaneous flaps leading to good patient satisfaction and enabling the use of normal footwear. PMID- 23352376 TI - [Cardiac tamponade following sternal puncture. Usefulness of ultrasound focussed assessment with sonography for trauma]. AB - One of the aims of the medical profession is to be able to detect complications in patients during diagnostic tests and treatments. The early diagnosis of these complications can prevent a fatal outcome. The diagnosis is often based on clinical symptoms and supported by complementary tests. Diagnostic tests have been developed in the last few years that are rapid and easy to use, as well as being cost effective and minimally invasive. Focussed assessment with sonography for trauma ultrasound (echo-FAST) was introduced in the 1990s in the field of resuscitation as a test for the rapid detection of intra-abdominal and pericardial fluid in multiple injury patients, but its uses in other cases not involving trauma still raise doubts and controversy. A case is presented of a patient subjected to a sternal puncture for a bone marrow aspirate, who had a complication of a secondary cardiac tamponade, which was diagnosed early using echo-FAST. PMID- 23352377 TI - Protein-nucleic interactions: 'I have a cunning plan...'. PMID- 23352378 TI - Attenuated adiposopathy in perivascular adipose tissue compared with subcutaneous human adipose tissue. AB - BACKGROUND: We hypothesized that human perivascular and subcutaneous adipose tissues hold distinct phenotypic signatures. We also evaluated the impact of clinical parameters on the adipose phenotype. Our overall goal is to understand the determinants of adipose biology so that this tissue can be manipulated therapeutically to lessen peripheral vascular disease. METHODS: Perivascular and subcutaneous adipose tissues were collected from patients undergoing lower extremity amputation (n = 27) and protein assayed for proinflammatory mediators (ie, interleukin 6, interleukin 8, leptin, tumor necrosis factor alpha, monocyte chemoattractant protein-1, and resistin), atheroprotective adiponectin, and the fibrinolysis inhibitor plasminogen activator inhibitor-1. RESULTS: Leptin (2.7 fold, P = .015), TNF-alpha (2.2-fold, P = .013), MCP-1 (1.5-fold, P = .047), and adiponectin (1.8-fold, P = .004) were more abundant in subcutaneous vs perivascular adipose tissue. Age positively correlated with perivascular adipose tissue PAI-1 expression (beta = .64, P = .042), and hyperlipidemia negatively correlated with perivascular adiponectin (beta = -1.18, P = .039). CONCLUSIONS: Human perivascular and subcutaneous adipose tissues hold distinct phenotypic signatures. In amputation patients, the subcutaneous adipose tissue proinflammatory phenotype was relatively attenuated in perivascular adipose tissue. PMID- 23352379 TI - Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis: a 54-week randomized trial. AB - BACKGROUND: Treatment with oral antihyperglycemic agents has not been well characterized in patients with type 2 diabetes and end-stage renal disease (ESRD). The efficacy and safety of sitagliptin and glipizide monotherapy in patients with type 2 diabetes and ESRD on dialysis therapy were assessed in this study. STUDY DESIGN: 54-week, randomized, double-blind, parallel-arm study. SETTING & PARTICIPANTS: From 31 clinical sites in 12 countries, 129 patients 30 years or older with type 2 diabetes and ESRD who were on dialysis therapy and had a hemoglobin A1c (HbA1c) level of 7%-9% were randomly assigned 1:1 to treatment. INTERVENTION: Monotherapy with sitagliptin, 25 mg daily or glipizide (initiated with 2.5 mg daily and titrated up to a potential maximum dose of 10 mg twice daily or down to avoid hypoglycemia). OUTCOMES: Primary end points were 54-week change in HbA1c level from baseline and tolerability with sitagliptin. A secondary end point was the comparison of sitagliptin versus glipizide on the incidence of symptomatic hypoglycemia. RESULTS: Of 129 patients randomly assigned, 64 were in the sitagliptin group (mean baseline age, 61 years; HbA1c, 7.9%) and 65 were in the glipizide group (mean baseline age, 59 years; HbA1c, 7.8%). After 54 weeks, the least squares mean change from baseline in HbA1c level was -0.72% (95% CI, -0.95% to -0.48%) with sitagliptin and -0.87% (95% CI, -1.11% to -0.63%) with glipizide, for a difference of 0.15% (95% CI, -0.18% to 0.49%). The incidences of symptomatic hypoglycemia and severe hypoglycemia were 6.3% versus 10.8% (between-group difference, -4.8% [95% CI, -15.7% to 5.6%]) and 0% versus 7.7% (between-group difference, -7.8% [95% CI, -17.1% to -1.9%]) in the sitagliptin and glipizide groups, respectively. Higher incidences (ie, 95% CI around between-treatment difference excluded 0) of cellulitis and headache were found with sitagliptin compared to glipizide (6.3% vs 0%, respectively, for both). LIMITATIONS: Small sample size limits between-group comparisons. CONCLUSIONS: Treatment with sitagliptin or glipizide monotherapy was effective and well tolerated over 54 weeks in patients with type 2 diabetes and ESRD who were receiving dialysis. PMID- 23352380 TI - Associations of health literacy with dialysis adherence and health resource utilization in patients receiving maintenance hemodialysis. AB - BACKGROUND: Although limited health literacy is common in hemodialysis patients, its effects on clinical outcomes are not well understood. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 260 maintenance hemodialysis patients enrolled in a randomized clinical trial of symptom management strategies from January 2009 through April 2011. PREDICTOR: Limited health literacy. OUTCOMES: Dialysis adherence (missed and abbreviated treatments) and health resource utilization (emergency department visits and end-stage renal disease [ESRD]-related hospitalizations). MEASUREMENTS: We assessed health literacy using the Rapid Estimate of Adult Literacy in Medicine (REALM) and used negative binomial regression to analyze the independent associations of limited health literacy with dialysis adherence and health resource utilization over 12-24 months. RESULTS: 41 of 260 (16%) patients showed limited health literacy (REALM score, <=60). There were 1,152 missed treatments, 5,127 abbreviated treatments, 552 emergency department visits, and 463 ESRD-related hospitalizations. Limited health literacy was associated independently with an increased incidence of missed dialysis treatments (missed, 0.6% vs 0.3%; adjusted incidence rate ratio [IRR], 2.14; 95% CI, 1.10-4.17), emergency department visits (annual visits, 1.7 vs 1.0; adjusted IRR, 1.37; 95% CI, 1.01-1.86), and hospitalizations related to ESRD (annual hospitalizations, 0.9 vs 0.5; adjusted IRR, 1.55; 95% CI, 1.03 2.34). LIMITATIONS: Generalizability and potential for residual confounding. CONCLUSIONS: Patients receiving maintenance hemodialysis who have limited health literacy are more likely to miss dialysis treatments, use emergency care, and be hospitalized related to their kidney disease. These findings have important clinical practice and cost implications. PMID- 23352381 TI - Endothelial keratoplasty without Descemet's stripping in congenital hereditary endothelial dystrophy. AB - PURPOSE: To compare outcomes of non-Descemet's stripping endothelial keratoplasty (nDSEK) with Descemet's stripping endothelial keratoplasty (DSEK) for the surgical management of congenital hereditary endothelial dystrophy (CHED). METHODS: Patients with CHED who were treated with DSEK or nDSEK were analyzed and compared with respect to graft adhesion, graft clarity, visual acuity, refraction, and complications. RESULTS: A total of 6 patients were included in the series. Of these, 3 (mean age, 5.6 +/- 1.52 years; 1 male) underwent DSEK and 3 (mean age, 5.6 +/- 0.57 years; 2 males) nDSEK. Preoperative best-corrected visual acuity of patients who underwent DSEK was 1.3 logMAR units compared with 1.13 logMAR units for nDSEK patients. There were no intraoperative complications. During the early postoperative period, 1 patient who had n DSEK had lenticule detachment and was successfully managed by repeat air injection. The average time for resolution of graft edema was 30 days. The postoperative best-corrected visual acuity was 0.13 +/- 0 .10 in DSEK patients and 0.13 +/- 0 .10 in nDSEK patients (P = 1). Mean refraction was comparable in both groups of patients. CONCLUSIONS: The outcomes of nDSEK were similar to DSEK in CHED in this small series. The specific advantage of nDSEK is the decreased surgical time and intraocular tissue manipulation. PMID- 23352382 TI - Functional magnetic resonance imaging of horizontal rectus muscles in esotropia. AB - PURPOSE: Monkey neurophysiology suggests that changes in neural drive rather than extraocular muscle structure underlie sensory-induced strabismus. If this is true, then extraocular muscle structure should be normal. We used magnetic resonance imaging to measure horizontal rectus muscle size and contractility to determine whether muscle structure is a factor in human concomitant esotropia. METHODS: High-resolution, quasicoronal plane magnetic resonance imaging was performed in target-controlled central gaze, abduction, and adduction in 13 orthotropic controls (mean age, 38 +/- 19 years) and 12 adults (mean age, 52 +/- 16 years) who had concomitant esotropia averaging 28(Delta) +/- 18(Delta) at distance. Thyroid ophthalmopathy was excluded. Horizontal rectus muscle cross sections were determined in 6 contiguous, 2-mm-thick midorbital image planes. Contractility was computed in each plane as the difference in cross section from contraction to relaxation. RESULTS: Medial rectus muscle cross sections in multiple planes averaged up to 39% larger in esotropic patients than in controls (P < 0.005), whereas lateral rectus muscle cross sections in esotropia were up to 28% larger but only significantly larger in one plane (P < 0.02). Medial rectus contractility was increased by up to 60% in esotropic patients (P < 0.005), whereas lateral rectus contractility in esotropia was slightly but not significantly supernormal. CONCLUSIONS: Medial rectus muscle size is supernormal and lateral rectus muscle size is not subnormal in concomitant esotropia. This finding indicates that human concomitant esotropia is associated with peripheral muscular abnormality. PMID- 23352383 TI - Improved sensory status and quality-of-life measures in adult patients after strabismus surgery. AB - PURPOSE: To evaluate the change in sensory status and quality-of-life measures in adults with long-standing childhood-onset constant strabismus. METHODS: Consecutive patients with childhood-onset, long-term constant strabismus were enrolled. Sensory status was examined with Bagolini striated glasses test and Worth 4-dot test. Stereopsis was tested with the Lang and TNO stereopsis tests. Quality of life was studied with 2 different questionnaires (Short Form Health Survey [SF-36] and the Amblyopia and Strabismus Questionnaire [A&SQ]), which patients completed before and 3 months after strabismus surgery. RESULTS: A total of 20 patients (age range, 18-63 years) were included, 10 of whom were esotropic and 10 of whom were exotropic. Of these, 13 obtained a satisfactory postoperative alignment and demonstrated an increase of sensory status with Bagolini striated glasses. Six patients who demonstrated suppression preoperatively achieved fusion and stereopsis postoperatively. The mean score in all domains of the A&SQ improved significantly, particularly with regard to social contact and cosmesis (P = 0.00067), distance estimation (P = 0.000312), and visual disorientation (P = 0.004777). Similarly, the mean score in 7 of 8 areas in the SF-36 improved significantly, particularly with regard to physical function (P = 0.000564), general health (P = 0.002296), vitality (P = 0.002891), social function (P = 0.004234), and mental health (P = 0.000334). The overall mean score of both questionnaires improved in all patients with a satisfactory postoperative alignment and increase of sensory status. CONCLUSIONS: Surgical treatment of strabismus in adults with long-standing childhood-onset constant strabismus can result in patients feeling that their quality of life has improved and can restore binocular sensory function. PMID- 23352384 TI - Targeting treatable disease--not just risk factors--in pediatric vision screening. PMID- 23352385 TI - New insights into amblyopia: binocular therapy and noninvasive brain stimulation. AB - The current approach to the treatment of amblyopia is problematic for a number of reasons. First, it promotes recovery of monocular vision but because it is not designed to promote binocularity, its binocular outcomes often are disappointing. Second, compliance is poor and variable. Third, the effectiveness of the treatment is thought to decrease with increasing age. We discuss 2 new approaches aimed at recovering visual function in adults with amblyopia. The first is a binocular approach to amblyopia treatment that is showing promise in initial clinical studies. The second is still in development and involves the use of well established noninvasive brain stimulation techniques to temporarily alter the balance of excitation and inhibition in the visual cortex. PMID- 23352386 TI - [Clinical impact of introducing ventilation with high flow oxygen in the treatment of bronchiolitis in a paediatric ward]. AB - OBJECTIVE: To analyse the safety and efficacy of high-flow oxygen therapy for treatment of moderate to severe bronchiolitis in children admitted to the paediatric hospital wards. METHODS: A prospective observational study was conducted on children < 18 months of age with bronchiolitis admitted to the paediatric ward of a tertiary-care teaching hospital during the 2011-12 respiratory season. Children were treated with a high-flow ventilation system (Fisher & Paykel). Clinical and cardio-respiratory parameters were evaluated every hour for the duration of therapy. RESULTS: A total of 25 patients, with a median age of 2 months (range: 0.6-11 months) were included. Respiratory syncytial virus (RSV) was positive in 75% of cases. Indications for high-flow therapy included: progressive respiratory distress (Wood-Downes >= 8) (88%), apnoea (8%) and desaturation (4%). Median duration of therapy was 4 days (range: 3-7 days), with a median of 9 days in hospital (range: 8-12 days). High flow therapy was associated with a significant decrease in cardio-respiratory parameters, heart rate, respiratory rate, which resulted in a significant improvement of the Wood-Downes Score (from 10+/-1.21 to 3+/-0.77, P=.001). No adverse effects were observed. Five patients (20%) were admitted to the Paediatric Intensive Care Unit (PICU), which represents an 80% reduction of PICU admissions compared with historic data of previous years. CONCLUSIONS: High-flow ventilation therapy achieved a significant improvement in heart rate, respiratory rate, and scale of severity in patients with bronchiolitis. This novel therapeutic strategy allows safe management of bronchiolitis patients in the regular ward, reducing admissions to the PICU. PMID- 23352387 TI - [Acro-osteolysis in a 4 year-old patient: clinical features of Hajdu-Cheney syndrome]. PMID- 23352388 TI - A common mode of recognition for methylated CpG. AB - Much is known about vertebrate DNA methylation, however it is not known how methylated CpG within particular sequences is recognized. Two recent structures of C2H2 zinc finger (ZnF) proteins in complex with methylated DNA reveal a common recognition mode for 5-methylcytosine (5mC) that involves a 5mC-Arg-G triad. In the two ZnF proteins, an arginine that precedes the first Zn-binding histidine (RH motif) can interact with a 5mCpG or TpG dinucleotide. Among a family of >300 human Kruppel-associated box (KRAB) domain containing ZnF proteins examined, two thirds contained at least one ZnF that included an RH motif. We propose that the RH-ZnF motifs provide specificity for 5mCpG, whereas the neighboring Zn fingers recognize the surrounding DNA sequence context. PMID- 23352389 TI - Risk factors for developing mineral bone disease in phenylketonuric patients. AB - There is a compromised bone mass in phenylketonuria patients compared with normal population, but the mechanisms responsible are still a matter of investigation. In addition, tetrahydrobiopterin therapy is a new option for a significant proportion of these patients and the prevalence of mineral bone disease (MBD) in these patients is unknown. We conducted a cross-sectional observational study including 43 phenylketonuric patients. Bone densitometry, nutritional assessment, physical activity questionnaire, biochemical parameters, and molecular study were performed in all patients. Patients were stratified by phenotype, age and type of treatment. The MBD prevalence in phenylketonuria was 14%. Osteopenic and osteoporotic (n=6 patients) had an average daily natural protein intake significantly lower than the remaining (n=37) patients with PKU (14.33 +/- 8.95 g vs 21.25 +/- 20.85 g). Besides, a lower body mass index was found. There were no statistical differences in physical activity level, calcium, phosphorus and fat intake, and in phenylalanine, vitamin D, paratohormone, docosahexaenoic and eicosapentaenoic acid blood levels. Mutational spectrum was found in up to 30 different PAH genotypes and no relationship was established among genotype and development of MBD. None of the twelve phenylketonuric patients treated with tetrahydrobiopterin (27.9%), for an average of 7.1 years, developed MBD. Natural protein intake and blood levels of eicosapentaenoic acid were significantly higher while calcium intake was lower in these patients. This study shows that the decrease in natural protein intake can play an important role in MBD development in phenylketonuric patients. Therapy with tetrahydrobiopterin allows a more relaxed protein diet, which is associated with better bone mass. PMID- 23352390 TI - Fifth INTERMACS annual report: risk factor analysis from more than 6,000 mechanical circulatory support patients. AB - The 5th annual report of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) summarizes and analyzes the first 6 years of patient and data collection. The current analysis includes more than 6000 patients and updated risk factors for continuous flow pumps. Among continuous flow pumps, actuarial survival is 80% at 1 year and 70% at 2 years. Quality of life indicators are generally favorable and adverse event burden will likely influence patient selections of advanced heart failure therapies. PMID- 23352391 TI - The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: executive summary. PMID- 23352392 TI - Impact of long term left ventricular assist device therapy on donor allocation in cardiac transplantation. AB - BACKGROUND: Left Ventricular Assist Devices (LVAD) are increasingly used as a bridge to transplant (BTT) for patients with advanced congestive heart failure (CHF) and are assigned United Network for Organ Sharing (UNOS) high priority status (1B or 1A). METHODS: The purpose of our study was asses the effect of organ allocation in the era of continuous flow pumps. A retrospective chart review was performed of all patients transplanted between 1/2001-1/2011 at Columbia University Medical Center. RESULTS: Seven hundred twenty six adult heart transplantations were performed. Two hundred seventy four BTT patients were implanted with LVAD; of which 227 patients were transplanted. Sixty three patients were transplanted as UNOS-1B, while 164 were transplanted as UNOS-1A (72%). Of these 164 patients, 65 were transplanted during their 30-day 1A period (43%) and 96 after upgrading to UNOS-1A for device complication (56%). For 452 non-device patients 139 (31%) were transplanted as UNOS-1A, 233 as UNOS-1B (52%), and 80 as UNOS-2 (17%). The percentage of patients bridged with LVAD increased from 19% in 2001 to 64% in 2010 while the number transplanted during their 30 day 1A grace period declined from 57% in 2005 to 16% in 2011; i.e. 84% of BTT patients in 2011 needed more than 30 days 1A time to be transplanted. Most LVAD patients are now transplanted while suffering device complication. There was no difference in post transplant survival between LVAD patients transplanted as UNOS 1B, 1A grace period or for a device complication CONCLUSIONS: As wait time for cardiac transplantation increased the percentage of patients being bridged to transplant with an LVAD has increased with the majority of them transplanted in the setting of device complication. PMID- 23352393 TI - Cognitive outcomes in pediatric heart transplant recipients bridged to transplantation with ventricular assist devices. AB - BACKGROUND: Ventricular assist devices (VADs) have been associated with high rates of neurologic injury in pediatric patients during the period of support, but the delayed consequences of this type of injury have not been described in the literature. METHODS: In this study we assess cognitive outcomes with indices of general intellectual functioning, including working memory, processing speed, perceptual reasoning and verbal comprehension, for pediatric heart transplant recipients who required VAD support as a bridge to transplant (n = 9). We present an aggregate of these VAD patients combined with heart transplant recipients who did not require mechanical circulatory support (n = 11), and compare the performance of all transplant patients (n = 20) to typically developing, healthy comparators (n = 12). We also present a post hoc analysis of those transplant recipients with significant medical morbidity in the first year of life, referred to as the "high-risk" transplant group (n = 5), and compare them with the "low risk" transplant group (n = 15) and the typically developing comparators (n = 12). RESULTS: The mean performance of the VAD patients was in the average range for each of the examined indices of cognitive functioning. A total of 11% of the VAD patients performed in the impaired range and 78% performed in the average range, with 11% in the superior range on measures of general intellectual functioning. The typically developing participants performed significantly better than the aggregated transplant recipients on all indices except verbal comprehension. Lower cognitive performance in the combined transplant group appears to be associated with medical morbidity in the first year of life. CONCLUSIONS: Despite significant neurologic risk factors, this cohort of pediatric patients who were bridged to transplant with VAD demonstrated resiliency in terms of cognitive outcomes. In this heterogeneous population, it is likely that multiple factors contributed to the cognitive outcomes. As VAD use becomes more common in pediatric patients, a prospective evaluation of cognitive outcomes is warranted. PMID- 23352394 TI - The biomarker plasma galectin-3 in advanced heart failure and survival with mechanical circulatory support devices. AB - BACKGROUND: During screening of heart transplantation (HTx) candidates supported by ventricular assist devices (VADs) for plasma biomarkers we found that galectin 3 (Gal-3) was increased pre-operatively in patients who later died during VAD support. Therefore, we analyzed the predictive value of plasma Gal-3 in the context of other potential clinical risk factors for death on device (DOD) in a cohort of 175 VAD patients. METHODS: We analyzed numerous clinical factors and plasma Gal-3 levels of 175 VAD patients before device implantation. Eighty VAD patients were successfully bridged to HTx (BTT, 45.7%), 80 (45.7%) died on VAD, 2 recovered on device (BTR, 1.1%) and 13 (7.4%) were still on device. Uni- and multivariate analyses were performed to assess the importance of Gal-3 with respect to other clinical factors. Myocardial gene expression of Gal-3 was investigated in apex samples by RT-PCR (n = 30) and Western blotting (n = 45). RESULTS: Plasma Gal-3 levels were higher in VAD patients than in controls (16.6 +/- 9.3 vs 9.5 +/- 3.9 ng/ml, p < 0.0001). Cox regression showed several clinical factors and type of VAD as independent outcome predictors, but Gal-3 was not among them. Using the regression equation we grouped patients according to their factor constellation for prediction of survival on VAD. We propose a calculation method for VAD survival prediction. Gal-3 mRNA and protein were detectable in failing myocardium, but did not correlate with its plasma concentration. CONCLUSIONS: Galectin-3 levels are associated with severe heart failure but do not provide sufficient discrimination for prediction of outcomes after VAD implantation. Importantly, we were unable to confirm myocardial tissue as a primary source for the observed plasma elevations of Gal-3. PMID- 23352395 TI - Preponderance and implications of etiologic misclassification in advanced heart failure: a clinical-pathologic investigation. PMID- 23352396 TI - Reliability of surface electromyographic recordings during walking in individuals with knee osteoarthritis. AB - To determine test-retest reliability of a surface electromyographic protocol designed to measure knee joint muscle activation during walking in individuals with knee osteoarthritis (OA). Twenty-one individuals with moderate medial compartment knee OA completed two gait data collections separated by approximately 1month. Using a standardized protocol, surface electromyograms from rectus femoris plus lateral and medial sites for the gastrocnemii, vastii and hamstring muscles were recorded during walking. After full-wave rectification and low pass filtering, time and amplitude normalized (percent of maximum) waveforms were calculated. Principal component analysis (PP-scores) and co-contraction indices (CCI) were calculated from the waveforms. Intraclass correlation coefficients (ICC2,k) were calculated for PP-scores and CCI's. No differences in walking speed, knee muscle strength and symptoms were found between visits (p>0.05). The majority of PP-scores (17 of 21) and two of four CCIs demonstrated ICC2,k values greater than 0.81. Remaining PP-scores and CCIs had ICC2,k values between 0.61 and 0.80. The results support that reliable EMG characteristics can be captured from a moderate knee OA patient population using a standardized protocol. PMID- 23352397 TI - Platelet-rich plasma in tendon models: a systematic review of basic science literature. AB - PURPOSE: To perform a systematic review of the basic science literature on the use of platelet-rich plasma (PRP) in tendon models. METHODS: We searched the PubMed/Medline and Embase databases in June 2012 using the following parameters: ((tenocytes OR tendon OR tendinitis OR tendinosis OR tendinopathy) AND (platelet rich plasma OR PRP OR autologous conditioned plasma OR ACP)). The inclusion criteria for full-text review were in vivo and in vitro studies examining the effects of PRP on tendons and/or tenocytes. Clinical studies were excluded. Only studies published in peer-reviewed journals that compared PRP directly with a control were included. Data were extracted based on a predefined data sheet, which included information on PRP preparation, study methods, and results. Studies were analyzed for trends, comparing and contrasting the reported effects of PRP. RESULTS: The search yielded 31 articles for inclusion in our review. Of the studies, 22 (71%) reported platelet concentrations in the PRP; 6 (19%) reported cytology. Eight in vivo studies found decreased tendon repair time, increased fiber organization, or both with PRP treatment. Eight in vitro studies reported that PRP treatment increased cell proliferation; 7 reported an increase in growth factor expression. Three in vivo studies found increased vascularity, and 4 found increased tensile strength with PRP treatment. CONCLUSIONS: In the basic science studies evaluated, it appears that PRP confers several potential effects on tendon models compared with a control. However, the literature is inconsistent with regard to reporting the methods of preparation of PRP and in reporting platelet concentrations and cytology. CLINICAL RELEVANCE: Establishing proof of concept for PRP may lead to further high-quality clinical studies in which the appropriate indications can be defined. PMID- 23352398 TI - Evaluation of ploidy level and endoreduplication in carnation (Dianthus spp.). AB - Carnation (Dianthus caryophyllus L.) is one of the fifth most important ornamental species worldwide. Many desirable plant characteristics, such as big size, adaptation under stress, and intra or interspecific hybridization capability, are dependent on plant ploidy level. We optimized a quick flow cytometry method for DNA content determination in wild and cultivated carnation samples that allowed a systematic evaluation of ploidy levels in Dianthus species. The DNA content of different carnation cultivars and wild Dianthus species was determined using internal reference standards. The precise characterization of ploidy, endoreduplication and C-value of D. caryophyllus 'Master' makes it a suitable standard cultivar for ploidy level determination in other carnation cultivars. Mixoploidy was rigorously characterized in different regions of several organs from D. caryophyllus 'Master', which combined with a detailed morphological description suggested some distinctive developmental traits of this species. Both the number of endoreduplication cycles and the proportion of endopolyploid cells were highly variable in the petals among the cultivars studied, differently to the values found in leaves. Our results suggest a positive correlation between ploidy, cell size and petal size in cultivated carnation, which should be considered in breeding programs aimed to obtain new varieties with large flowers. PMID- 23352399 TI - Light energy management in micropropagated plants of Castanea sativa, effects of photoinhibition. AB - The limited development of photoprotective mechanisms, specifically heat dissipation capacity, found in micropropagated plants may be the result of low xanthophyll cycle pigment content and reduced de-epoxidation capacity making them highly susceptible to photodamage. The effects of gradual or sudden increase of light on Castanea sativa in vitro cultured and during their ex vitro transference was evaluated. The results were compared with those determined in nursery-grown plants. In vitro plants responded poorly to gradual increase in irradiance, exhibiting a low electron transport rate (ETR) agreeing with low non photochemical quenching (NPQ) and a limited de-epoxidation capacity, not synthesizing detectable amounts of zeaxanthin (Z). Regarding a sudden increase in light (photoinhibition treatment, PhT); post-PhT as in vitro as well nursery plants showed a significant decrease in their maximal efficiency of PSII (F(v)/F(m)), but in vitro the decrease was very drastic (around 0.2) different from that observed in nursery (around 0.69). In vitro, NPQ was mainly determined by the slow relaxing component, NPQ(s) (80.8%), concomitant with a pronounced decrease of D1 protein post-PhT, and a lack of de-epoxidation capacity. During ex vitro transfer, PhT lead to death of some plants, specifically during root induction. The photoprotective mechanisms were activated over time in ex vitro conditions, indicating that micropropagated Castanea sativa display a potential for light acclimation, adjusting their photosynthetic apparatus to the ambient growth irradiance. Understanding the mechanisms that micropropagated plants deployed and how they face high light intensity events, will allow us to search for strategies to improve performance to possible light fluctuations that normally occur in ex vitro conditions during plant acclimation. PMID- 23352400 TI - Optimizing virus-induced gene silencing efficiency with Cymbidium mosaic virus in Phalaenopsis flower. AB - Virus-induced gene silencing (VIGS) is a good way to study floral gene functions of orchids, especially those with a long life cycle. To explore the applicability and improve viral silencing efficiency for application of Cymbidium mosaic virus (CymMV)-induced gene silencing, we examined several variables, including the optimal length of the DNA fragment, the effect of developmental maturation status of inflorescence, and suitable inoculation sites. A CymMV-based VIGS system can be used with orchids to silence genes including PeUFGT3, PeMADS5 and PeMADS6 and induce prominent phenotypes with silencing efficiency up to 95.8% reduction. The DNA fragment size used for silencing can be as small as 78-85 bp and still reach 61.5-95.8% reduction. The effect of cDNA location as a target in VIGS varies among genes because of non-target gene influence when using the 5' terminus of the coding region of both PeMADS5 and PeMADS6. Use of VIGS to knock down a B class MADS-box gene (PeMADS6) in orchids with different maturation status of inflorescence allowed for observing discernable knockdown phenotypes in flowers. Furthermore, silencing effects with Agro-infiltration did not differ with both leaf and inflorescence injections, but injection in the leaf saved time and produced less damage to plants. We propose an optimized approach for VIGS using CymMV as a silencing vector for floral functional genomics in Phalaenopsis orchid with Agro-infiltration: (1) DNA fragment length about 80 bp, (2) a more mature status of inflorescence and (3) leaf injection. PMID- 23352401 TI - Native arbuscular mycorrhizal fungi isolated from a saline habitat improved maize antioxidant systems and plant tolerance to salinity. AB - High soil salinity is a serious problem for crop production because most of the cultivated plants are salt sensitive, which is also the case for the globally important crop plant maize. Salinity stress leads to secondary oxidative stress in plants and a correlation between antioxidant capacity and salt tolerance has been demonstrated in several plant species. The plant antioxidant capacity may be enhanced by arbuscular mycorrhizal fungi (AMF) and it has been proposed that AM symbiosis is more effective with native than with collection AMF species. Thus, we investigated whether native AMF isolated from a dry and saline environment can help maize plants to overcome salt stress better than AMF from a culture collection and whether protection against oxidative stress is involved in such an effect. Maize plants inoculated with three native AMF showed higher efficiency of photosystem II and stomatal conductance, which surely decreased photorespiration and ROS production. Indeed, the accumulation of hydrogen peroxide, the oxidative damage to lipids and the membrane electrolyte leakage in these AM plants were significantly lower than in non-mycorrhizal plants or in plants inoculated with the collection AMF. The activation of antioxidant enzymes such as superoxide dismutase or catalase also accounted for these effects. PMID- 23352402 TI - Proteomic and histological analyses of endosperm development in Cyclamen persicum as a basis for optimization of somatic embryogenesis. AB - The endosperm plays an important role for the development of zygotic embryos, while somatic embryos lack a seed coat and endosperm and often show physiological disorders. This study aims at elucidating the cellular and physiological processes within the endosperm of the ornamental species Cyclamen persicum Mill. Histological analyses were performed from 0 to 11 weeks after pollination (WAP). At 3WAP, a syncytium was clearly visible with a globular zygotic embryo. From 4WAP, cellularization of the endosperm, at 5WAP a small torpedo shaped embryo, and from 7WAP cell expansion was observed. By 11WAP the endosperm appeared fully differentiated. Total soluble proteins were extracted from the endosperm at 4, 5, 7, 9 and 11WAP and resolved using two dimensional isoelectric focussing/sodium dodecyl sulphate-polyacrylamide gel electrophoresis (2D IEF/SDS-PAGE). A shift from high-molecular-mass proteins to low-molecular-mass proteins during endosperm development was observed. A total of 1137proteinspots/gel were detected in the three protein fractions extracted at 7, 9 and 11WAP. Mass spectrometry analysis of the 48 predominant protein spots in endosperm at 7, 9 and 11WAP resulted in the identification of 62 proteins, ten of which were described for the first time in Cyclamen. Additionally, 186 proteins were identified using the C. persicum embryo proteome reference map. Proteins involved in abscisic acid signalling and oxidative stress responsive proteins were found to be important for seed development in Cyclamen. The new insights into endosperm physiology including storage compounds are discussed. PMID- 23352403 TI - Gasotransmitters are emerging as new guard cell signaling molecules and regulators of leaf gas exchange. AB - Specialized guard cells modulate plant gas exchange through the regulation of stomatal aperture. The size of the stomatal pore is a direct function of the volume of the guard cells. The transport of solutes across channels in plasma membrane is a crucial process in the maintenance of guard cell water status. The fine tuned regulation of that transport requires an integrated convergence of multiple endogenous and exogenous signals perceived at both the cellular and the whole plant level. Gasotransmitters are novel signaling molecules with key functions in guard cell physiology. Three gasotransmitters, nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H(2)S) are involved in guard cell regulatory processes. These molecules are endogenously produced by plant cells and are part of the guard cells responses to drought stress conditions through ABA-dependent pathways. In this review, we summarize the current knowledge of gasotransmitters as versatile molecules interacting with different components of guard cell signaling network and propose them as players in new paradigms to study ABA-independent guard cell responses to water deficit. PMID- 23352404 TI - The response of Hordeum spontaneum desert ecotype to drought and excessive light intensity is characterized by induction of O2 dependent photochemical activity and anthocyanin accumulation. AB - The goal of the current research was to study the role of anthocyanin accumulation, O(2)-related photochemical processes and non-photochemical quenching (NPQ) in the response of desert and Mediterranean plants to drought and excessive light. Plants of Hordeum spontaneum were collected from Mediterranean and desert environments and were subjected to terminal drought for 25 days and then measured for PSII yield at 2 and 21% O(2), NPQ, net carbon assimilation, stomatal conductance, leaf relative water content (LRWC), anthocyanin concentration and leaf absorbance. Under terminal drought, LRWC, carbon assimilation and stomatal conductance decreased similarly and significantly in both the Mediterranean and the desert ecotypes. Anthocyanin accumulated more in the desert ecotype than in the Mediterranean ecotype. NPQ increased more in the Mediterranean ecotype as compared with the desert ecotype. PSII yield decreased significantly in the Mediterranean ecotype under drought and was much lower than in the desert ecotype under drought. The relatively high PSII yield under drought in the desert ecotype was O(2) dependent. The response of the H. spontaneum ecotype from a desert environment to drought stress was characterized by anthocyanin accumulation and induction of O(2) dependent photochemical activity, while the response of the Mediterranean ecotype was based on a higher induction of NPQ. PMID- 23352405 TI - Iron excess affects rice photosynthesis through stomatal and non-stomatal limitations. AB - Iron toxicity is the most important stressor of rice in many lowland environments worldwide. Rice cultivars differ widely in their ability to tolerate excess iron. A physiological evaluation of iron toxicity in rice was performed using non invasive photosynthesis, photorespiration and chlorophyll a fluorescence imaging measurements and chlorophyll content determination by SPAD. Four rice cultivars (BR IRGA 409; BR IRGA 412; BRA 041171 and BRA 041152) from the Brazilian breeding programs were used. Fe(2+) was supplied in the nutrient solution as Fe-EDTA (0.019, 4, 7 and 9 mM). Increases in shoot iron content due to Fe(2+) treatments led to changes in most of the non-invasive physiological variables assessed. The reduction in rice photosynthesis can be attributed to stomatal limitations at moderate Fe(2+) doses (4mM) and both stomatal and non-stomatal limitations at higher doses. Photorespiration was an important sink for electrons in rice cultivars under iron excess. A decreased chlorophyll content and limited photochemical ability to cope with light excess were characteristic of the more sensitive and iron accumulator cultivars (BRA 041171 and BRA 041152). Chlorophyll fluorescence imaging revealed a spatial heterogeneity of photosynthesis under excessive iron concentrations. The results showed the usefulness of non-invasive physiological measurements to assess differences among cultivars. The contributions toward understanding the rice photosynthetic response to toxic levels of iron in the nutrient solution are also discussed. PMID- 23352406 TI - Disruption of ROOT PHOTOTROPISM2 gene does not affect phototropin-mediated stomatal opening. AB - Phototropins (phot1 and phot2), blue light-receptor protein kinases in plants, mediate stomatal opening by activating the plasma membrane H(+)-ATPase in guard cells, but the signaling from phototropins to the H(+)-ATPase remains unknown. A recent study concluded that ROOT PHOTOTROPISM2 (RPT2) is involved in the primary step of this process. However, this conclusion is based solely on the determination of stomatal apertures in the epidermis. We investigated the role of RPT2 in blue light-dependent stomatal opening in more detail. We generated double mutants of rpt2 and phototropins (phot1 or phot2) in the Col ecotype background and obtained the typical phenotypes of rpt2 mutants, including the impairment in phototropism. In contrast, neither blue light-dependent H(+) pumping nor blue light-dependent H(+)-ATPase activation in guard cells was affected in the rpt2 mutants of rpt2, phot1 rpt2, and phot2 rpt2. Stomata in these rpt2 mutants opened widely by blue light in both epidermal peels and intact leaves, and no difference in the responses was found between the wild type and the mutants. From these results, we concluded that RPT2 gene disruption does not affect blue light dependent stomatal opening. PMID- 23352407 TI - Nuclease released by Verticillium dahliae is a signal for non-host resistance. AB - A DNase released from the fungal pathogen of bean, Fusarium solani f. sp. phaseoli (Fsph), was previously shown to signal the activation of total disease resistance and activate pathogenesis-related (PR) genes in pea. Data in the current study which used the pea-endocarp model to research non-host resistance, indicated that DNase released by Verticillium dahliae (Vd), pathogenic on potato also has non-host resistance-inducing capabilities in peas. Other strains of Vd that release DNase are pathogenic on other plant species. DNase catalytic activity was also released from representative genera of other pathogenic fungi. Purified VdDNase induced pisatin and pea gene DRR49 (PR-10 gene) in pea endocarp tissue. VdDNase reduced the in vitro growth of Vd but completely inhibited that of F. solani f. sp. pisi (Fspi) and a Colletotrichum pathogen of potato. VdDNase (2 units) applied to pea endocarp tissue both broke resistance to Fsph and increased resistance to Fspi. Pea DNA damage generated both by the VdDNase enzyme and the intact Vd spores indicated that the host DNA alteration is a component of the non-host resistance response (innate immunity). These data support the previously reported inductive potential of fungal DNase and further implicate fungal DNases as signals in activating non-host resistance responses. PMID- 23352408 TI - Identification and characterization of novel and conserved microRNAs in radish (Raphanus sativus L.) using high-throughput sequencing. AB - MicroRNAs (miRNAs) are endogenous, non-coding, small RNAs that play significant regulatory roles in plant growth, development, and biotic and abiotic stress responses. To date, a great number of conserved and species-specific miRNAs have been identified in many important plant species such as Arabidopsis, rice and poplar. However, little is known about identification of miRNAs and their target genes in radish (Raphanus sativus L.). In the present study, a small RNA library from radish root was constructed and sequenced using the high-throughput Solexa sequencing. Through sequence alignment and secondary structure prediction, a total of 545 conserved miRNA families as well as 15 novel (with their miRNA* strand) and 64 potentially novel miRNAs were identified. Quantitative real-time PCR (qRT-PCR) analysis confirmed that both conserved and novel miRNAs were expressed in radish, and some of them were preferentially expressed in certain tissues. A total of 196 potential target genes were predicted for 42 novel radish miRNAs. Gene ontology (GO) analysis showed that most of the targets were involved in plant growth, development, metabolism and stress responses. This study represents a first large-scale identification and characterization of radish miRNAs and their potential target genes. These results could lead to the further identification of radish miRNAs and enhance our understanding of radish miRNA regulatory mechanisms in diverse biological and metabolic processes. PMID- 23352409 TI - Tricin biosynthesis during growth of wheat under different abiotic stresses. AB - In plants, O-methylation is mediated by an enzyme family of O-methyltransferases (OMTs) that transfer the methyl groups from the methyl donor, S-adenosyl-L methionine (AdoMet) to suitable phenolic acceptor molecules. In a previous study [1], a flavonoid OMT (TaOMT2) was isolated and characterized from wheat (Triticum aestivum L.) leaves. Its novel gene product catalyzes three sequential O methylations of the flavone tricetin (5,7,3',4',5'-pentahydroxyflavone) to its 3' monomethyl-(selgin)->3',5'-dimethyl-(tricin)->3',4',5'-trimethyl (TMT) ether derivatives, with tricin being the major product of the reaction. In this report, the biological significance of tricetin methylation was investigated by measuring the OMT activity, its expression level, and the accumulation of its major product (tricin) at different stages of development of wheat plants exposed to different abiotic stresses such as cold, salt and drought. The results showed that tricin accumulates mostly in wheat inflorescences under normal conditions compared to leaves and other developmental stages. Tricin accumulation was associated with increased TaOMT2 expression level and its enzyme activity, suggesting a possible de novo synthesis of the enzyme at this important developmental stage. This phenomenon may be attributed to the putative role of tricin in protecting seeds against biotic and abiotic stresses. The functions of tricin during growth and development of wheat and the importance of tricetin methylation during abiotic stresses are discussed. PMID- 23352410 TI - Identification of heat-sensitive QTL derived from common wild rice (Oryza rufipogon Griff.). AB - Understanding the responses of rice plants to heat-stress is a challenging, yet crucial, endeavor. A set of introgression lines was previously developed using an advanced backcrossing strategy that involved the elite indica cultivar Teqing as the recipient and an accession of common wild rice (Oryza rufipongon Griff.) as the donor. In this study, we evaluated the responses of 90 of these previously developed introgression lines to heat stress. Five quantitative trait loci (QTLs) related to heat response were detected. The phenotypic variances explained by these QTLs ranged from 6.83% to 14.63%, and O. rufipogon-derived alleles at one locus reduced sensitivity to heat. A heat-sensitive introgression line, YIL106, was identified and characterized. Genotypic analysis demonstrated that YIL106 contained four introgressed segments derived from O. rufipongon and two QTLs (qHTS1-1 and qHTS3) related to heat response. Physiological tests, including measurements of chlorophyll content, electrolyte leakage, malondialdehyde content, and soluble sugar content, were consistent with the heat sensitivity observed in YIL106. Ultrastructural analysis of YIL106 mesophyll cells showed that they were severely damaged following heat stress. This suggests that modification of the cell membrane system is a primary response to heat stress in plants. Identification and characterization of the heat-sensitive line YIL106 may facilitate the isolation of genes associated with the response of rice plants to heat stress. PMID- 23352411 TI - Designed transcriptional regulators for trait development. AB - Development is largely controlled by proteins that regulate gene expression at the level of transcription. These regulatory proteins, the genes that control them, and the genes that they control, are organized in a hierarchical structure of complex interactions. Altering the expression of genes encoding regulatory proteins controlling critical nodes in this hierarchy has potential for dramatic phenotypic modification. Constitutive over-expression of genes encoding regulatory proteins in transgenic plants has resulted in agronomically interesting phenotypes along with developmental abnormalities. For trait development, the magnitude and timing of expression of genes encoding key regulatory proteins will need to be precisely controlled and targeted to specific cells and tissues at certain developmental timepoints. Such control is made possible by designed transcriptional regulators which are fusions of engineered DNA binding proteins and activator or repressor domains. Expression of genes encoding such designed transcriptional regulators enable the selective modulation of endogenous gene expression. Genes encoding proteins controlling regulatory networks are prime targets for up- or down-regulation via such designed transcriptional regulators. PMID- 23352412 TI - Water stress induces a differential and spatially distributed nitro-oxidative stress response in roots and leaves of Lotus japonicus. AB - Water stress is one of the most severe problems for plant growth and productivity. Using the legume Lotus japonicus exposed to water stress, a comparative analysis of key components in metabolism of reactive nitrogen and oxygen species (RNS and ROS, respectively) were made. After water stress treatment plants accumulated proline 23 and 10-fold in roots and leaves respectively, compared with well-watered plants. Significant changes in metabolism of RNS and ROS were observed, with an increase in both protein tyrosine nitration and lipid peroxidation, which indicate that water stress induces a nitro-oxidative stress. In roots, .NO content was increased and S nitrosoglutathione reductase activity was reduced by 23%, wherein a specific protein nitration pattern was observed. As part of this response, activity of NADPH-generating dehydrogenases was also affected in roots resulting in an increase of the NADPH/NADP(+) ratio. Our results suggest that in comparison with leaves, roots are significantly affected by water stress inducing an increase in proline and NO content which could highlight multiple functions for these metabolites in water stress adaptation, recovery and signaling. Thus, it is proposed that water stress generates a spatial distribution of nitro-oxidative stress with the oxidative stress component being higher in leaves whereas the nitrosative stress component is higher in roots. PMID- 23352413 TI - [Primary care and maternal and infant mortality in Latin American countries]. AB - INTRODUCTION: Family physicians, as leaders of primary healthcare teams, have demonstrated to be cost-effective in reducing infant mortality in developed nations, but their effect in developing nations is yet unknown. METHODS: A descriptive study was conducted in 11 Latin American countries to observe their health indicators, and the possible association of the presence and actions of their family physicians regarding achieving a reduction in maternal and infant mortality. National scientific associations of family and community medicine in the region provided information for each country; a centralized statistical analysis was made. RESULTS: There was a wide variation between the different countries, as regards their socio-demographic characteristics, inequalities, public investment in primary care, the proportion of family physicians within the medical profession, healthcare indicators, those relating to the level of development, and to the resources assigned to healthcare in each country. Maternal mortality was not associated to the presence and actions of family physicians in each country (R(2): 0.003) nor together with other medical specialties (R(2): 0.07); in contrast, infant mortality was associated with the presence and actions of family physicians (R(2): 0.37; 95% CI 0.04-0.95; P<0.05). CONCLUSION: The presence and actions of family physicians in primary healthcare in Latin America was associated to a reduction of infant mortality, with the Millenium challenges contributing to this reduction. PMID- 23352414 TI - [Fable of the mousetrap in the farmyard: the ups and some downs of the young and proud specialist in family and community medicine]. PMID- 23352415 TI - A changed pattern of insulin use following the introduction of basal analog insulin treatment in primary care. AB - AIMS: We analyzed the impact of the removal of administrative restrictions on basal analog insulin prescribing by primary care physicians in the year 2008 in a large HMO. METHODS: This cross-sectional database study of patients with diabetes study was conducted in Maccabi Healthcare Services, the second largest HMO in Israel, insuring 1.9 million members countrywide. The research population included men over 40 and women over the age of 45 from MHS diabetes registry during the time period 1.1.2002-31.12.2009. RESULTS: After removal of basal analog insulin prescription restrictions, more primary care physicians initiated treatment with basal analog insulin than with other types of insulin and did so with fewer referrals for specialty diabetes consultation. No growth in the relative number of patients commencing insulin use was observed, nor did we find an earlier initiation of insulin. CONCLUSION: In the first year following the relaxation of prescribing restrictions on the use of basal analog insulin we observed an increase in its use amongst patients previously treated with other types of insulin. The administrative changes did not result in an overall increase in the use of insulin in the study population. PMID- 23352417 TI - Changes in income inequality and the health of immigrants. AB - Research suggests that income inequality is inversely associated with health. This association has been documented in studies that utilize variation in income inequality across countries or across time from a single country. The primary criticism of these approaches is their inability to account for potential confounders that are associated with income inequality. This paper uses variation in individual experiences of income inequality among immigrants within the United States (U.S.) to evaluate whether individuals who moved from countries with greater income inequality than the U.S. have better health than those who migrated from countries with less income in equality than the U.S. Utilizing individual-level (March Current Population Survey) and country-level data (the United Nations Human Development Reports), we show that among immigrants who have resided in the U.S. between 6 and 20 years, self-reported health is more favorable for the immigrants in the former category (i.e., greater income inequality) than those in the latter (i.e., lower income inequality). Results also show that self-reported health is better among immigrants from more developed countries and those who have more years of education, are male, and are married. PMID- 23352416 TI - Englerin A stimulates PKCtheta to inhibit insulin signaling and to simultaneously activate HSF1: pharmacologically induced synthetic lethality. AB - The natural product englerin A (EA) binds to and activates protein kinase C-theta (PKCtheta). EA-dependent activation of PKCtheta induces an insulin-resistant phenotype, limiting the access of tumor cells to glucose. At the same time, EA causes PKCtheta-mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence. By promoting glucose addiction, while simultaneously starving cells of glucose, EA proves to be synthetically lethal to highly glycolytic tumors. PMID- 23352418 TI - Postoperative surveillance for non-small cell lung cancer resected with curative intent: developing a patient-centered approach. AB - Local recurrence or the development of metachronous cancer after surgical therapy for early-stage non-small cell lung cancer (NSCLC) is not uncommon, and these conditions are often amenable to curative therapy. Predictors of recurrence based on surgical, patient, and pathologic factors are well known. A literature search was performed for articles regarding identification or treatment with curative intent of early local recurrence or metachronous cancer after resection of NSCLC. A patient-centered algorithm for surveillance after resection can be developed based on both risk of recurrence and potential benefit from further treatment to optimize individual follow-up algorithms. PMID- 23352419 TI - Lung injury and acute respiratory distress syndrome after cardiac surgery. AB - As many as 20% of patients undergoing cardiac surgery will have acute respiratory distress syndrome during the perioperative period, with a mortality as high as 80%. If patients at risk can be identified, preventative measures can be taken and may improve outcomes. Care for patients with acute respiratory distress syndrome is supportive, with low tidal volume ventilation being the mainstay of therapy. Careful fluid management, minimization of blood product transfusion, appropriate nutrition, and early physical rehabilitation may improve outcomes. In cases of refractory hypoxemia, rescue therapies such as recruitment maneuvers, high-frequency oscillatory ventilation, and extracorporeal membrane oxygenation may preserve life. PMID- 23352421 TI - Interrelationships of nutrition, metabolic hormones and resumption of ovulation in multiparous suckled beef cows on subtropical pastures. AB - The effect of nutrition before and after calving on metabolic status and the resumption of ovulation postpartum was examined in multiparous sucked beef cows on subtropical pastures. At 6-7 months of gestation, Droughtmaster cows were randomly assigned on body weight (BW) and stage of gestation to two groups that received either standard subtropical pasture (SP, n = 7, 543 +/- 12 kg BW) or improved pasture (IP, n = 7, 564 +/- 12 kg BW). The two nutritional treatments were maintained after calving. Starting at 1 week after calving, cows were monitored for BW and body condition score (BCS, biweekly) and for circulating concentrations of insulin, glucose, IGF-1, GH and leptin (weekly). Ovarian follicular status was monitored weekly by trans-rectal ultrasonography. Fecal samples were obtained at 3-week intervals to ascertain percentage crude protein (%CP) and dry matter digestibility (DMD) of pastures. Crude protein and DMD were greater (P < 0.05) for cows on IP during the first 9 weeks after calving after which there were no differences between nutritional treatments. Cows on IP were heavier (P < 0.05) and had a greater (P < 0.01) BCS than cows on SP at 1 week after calving (585 +/- 9 kg and 3.7 +/- 0.2 BCS and 528 +/- 21 kg and 2.3 +/- 0.2 BCS, respectively). Cows on SP showed a gradual increase in BW and there were no differences in BW after approximately 7 weeks postpartum whilst BCS remained less for cows on SP. Plasma concentrations of insulin, glucose, IGF-1 and leptin were all greater (P < 0.01) for cows on IP compared with cows on SP, whilst GH did not differ. The diameter of the largest follicle did not differ between cows on IP and SP throughout the postpartum period. However, 7 of 7 cows on IP resumed ovulations between 12 and 15 weeks postpartum whilst only 1 of 7 cows on SP had resumed ovulation during the study. It is concluded from the findings that exposure of cows to IP and SP before and after calving resulted in two groups of cows with different metabolic homeostasis and that the greater circulating concentrations of insulin, glucose, IGF-1 and leptin promoted the earlier resumption of ovulation for cows on IP. PMID- 23352420 TI - Do reports of sleep disturbance relate to coronary and aortic calcification in healthy middle-aged women?: Study of women's health across the nation. AB - BACKGROUND: Poor sleep may be associated with the cardiovascular disease (CVD) morbidity and mortality. It is less clear if poor sleep is associated with subclinical CVD. We evaluated cross-sectional associations between self-reported sleep disturbance and duration and calcification in the coronary arteries (CAC) and aorta (AC) in healthy mid-life women. METHODS: 512 black and white women enrolled in the SWAN Heart Study, underwent a computed tomography protocol for measurement of CAC and AC and completed questionnaires about their sleep. Linear and partial proportional logit regression analyses adjusted for site, race, age, body mass index, and the Framingham risk score (model 1). Additional covariates of education, perceived health, hypnotic medication and alcohol use were evaluated (model 2), plus depressive symptoms (model 3). RESULTS: AC was related to higher levels of trouble falling asleep, waking earlier than planned, overall poor sleep quality, and cough/snoring and shorter sleep duration in linear regression analyses (model 1). Adjustments for additional covariates showed that poor sleep quality and waking earlier than planned remained associated with higher AC (models 2 and 3). CAC was unrelated to sleep characteristics. CONCLUSIONS: Poor sleep quality is related to AC in middle-aged women. Sleep quality should routinely be assessed in mid-life women. PMID- 23352422 TI - Egg related parameters affecting fertility and hatchability in the Italian bantam breed Mericanel della Brianza. AB - Local chicken breeds are a vital reservoir of gene resources and their conservation has a technical role related to the future development of the productive system, as well as a social-cultural role. The aim of this study was to evaluate the effects of egg weight, egg storage period and egg weight loss on hatchability of fertile eggs in the Italian bantam breed Mericanel della Brianza. Fourteen females and eight males were kept in floor pens and divided in 8 families (1M:1 or 2F) during the reproductive season (March-June). Birds received a photoperiod of 14L:10D and were fed ad libitum. Egg production and egg weight were recorded daily. Eggs were divided in 4 weight groups: EW1 =< 33 g, EW2 = 33 36 g, EW3 = 36-39 g and EW4 =>= 39 g. Eggs were stored at 18 degrees C and classified in 3 egg storage groups: ES1 = 0-4, ES2 = 5-9 and ES3 = 10-15 days. Egg weight loss was recorded and distributed in 5 different classes: EWL1 =< 10%, EWL2 = 10-15%, EWL3 = 16-20%, EWL4 = 21-25%, EWL5 => 25%. Fertility, embryo mortality and hatchability were recorded. The mean values during the reproductive season were 82% fertility and 50% hatchability of fertile eggs. The best combination of fertility and hatchability values were recorded in EW2 and lower fertility was recorded in EW1 (P < 0.05). Hatchability decreased under 50% after 10 day storage period before incubation and the best hatchability was recorded in EWL1. The present results contribute to the knowledge on reproductive parameters necessary to improve the reproductive efficiency of this Italian breed within a conservation plan. PMID- 23352423 TI - Vertebral artery dissection in rheumatoid arthritis with cervical spine disease. AB - A 59-year-old woman with long-standing active rheumatoid arthritis presented with posterior circulation ischemic stroke after vertebral dissection. She had severe multilevel degenerative changes of her cervical spine. She did not have classic stroke risk factors nor evidence of atherosclerotic disease or other systemic diseases. The most likely mechanism appears to be injury of the artery wall by an osteophyte, causing dissection that resulted in thrombosis and subsequent embolic strokes. PMID- 23352424 TI - Not all PBC is the same! PMID- 23352425 TI - [Generalized lichen nitidus]. PMID- 23352426 TI - Contrast volume use in manual vs automated contrast injection systems for diagnostic coronary angiography and percutaneous coronary interventions. AB - BACKGROUND: Contrast-induced nephropathy (CIN) is an important cause of iatrogenic morbidity and mortality. The amount of contrast delivered has a major effect on CIN and is operator-dependent. A few studies suggested that the use of automated contrast injection systems is associated with reduced contrast volume. It is unknown whether this is true when smaller amounts of contrast are used and how this is affected by training. METHODS: Volume of contrast media was measured in 1358 consecutive patients undergoing diagnostic catheterization and percutaneous coronary intervention (PCI) from January 31 to May 31, 2011. Patients were allocated to manual stopcock-manifold contrast injection (1052 patients) or automated contrast injection (306 patients). RESULTS: No significant difference in contrast volume use was found between manual and automated contrast injection systems, respectively: diagnostic catheterization, 72 +/- 40 mL vs 96 +/- 63 mL (P = 0.08); diagnostic catheterization with left ventricular angiography, 98 +/- 40 mL vs 95 +/- 35 mL (P = 0.51); PCI, 206 +/- 82 mL vs 205 +/- 90 mL (P = 0.84); diagnostic catheterization and PCI, 264 +/- 83 mL vs 253 +/ 93 mL (P = 0.51). No significant difference in CIN incidence, according to contrast injection systems, was found among patients receiving PCI (manual 9.8% vs automated 7.4%, P = 0.43). Using smaller sized catheters during diagnostic procedures was associated with injection of smaller amounts of contrast (P < 0.0001). CONCLUSIONS: The use of automated contrast injection for diagnostic catheterization and PCI is not associated with reduced contrast volume as compared with manual injection. The use of smaller calibre catheters might reduce contrast volume. PMID- 23352427 TI - Reply to Mirrakhimov and Mirrakhimov--nonalcoholic fatty liver disease and cardiovascular risk in obese children and adolescents. PMID- 23352428 TI - Intraoperative imaging with a 3D C-arm system after zygomatico-orbital complex fracture reduction. AB - PURPOSE: During the repair of zygomatico-orbital complex (ZMC) fractures, the lateral orbital wall and/or the orbital floor is often reduced by merely reducing the zygoma. Intraoperative 3D imaging can help surgeons decide whether the orbit must be reconstructed as well. The purpose of this study was therefore to assess the usefulness of intraoperative 3D C-arm imaging in evaluating the adequacy of fracture reduction. METHODS: A total of 21 patients with unilateral ZMC fractures were enrolled in this retrospective study. Four fractures were treated with a closed reduction technique. Seventeen fractures were repaired with open reduction and internal fixation of the zygomaticomaxillary buttress area. Intraoperative 3D C-arm imaging was performed in all cases. All patients underwent postoperative computed tomography and a clinical examination no earlier than 5 months after the procedure. RESULTS: After reduction of the ZMC fractures, intraoperative 3D scans showed inadequate repair of the orbital floor in 2 patients and inadequate repair of the lateral orbit in 1 patient. Zygoma and zygomatic arch fracture reduction had to be corrected in 1 further case. The other 17 patients did not need an additional procedure. Postoperative imaging showed that no patient required a secondary operation. No postoperative diplopia or enophthalmos developed in any patient. CONCLUSIONS: Intraoperative 3D C-arm imaging appears to be an effective tool for evaluating ZMC fracture reduction. It helps avoid additional procedures and thus helps reduce morbidity. In addition, there appears to be no need for postoperative imaging. PMID- 23352429 TI - A phase 2 open-label safety and immunogenicity study of a meningococcal B bivalent rLP2086 vaccine in healthy adults. AB - BACKGROUND: Neisseria meningitidis serogroup B (MnB) is a leading cause of bacterial meningitis and septicemia in adolescents and young adults. No currently licensed and available vaccine has been shown to provide broad protection against endemic MnB disease. A bivalent rLP2086 vaccine based on two factor H-binding proteins (fHBPs) has been developed to provide broad protection against MnB disease-causing strains. METHODS: This study assessed the safety and immunogenicity of the final formulation of a bivalent rLP2086 vaccine in 60 healthy adults (18-40 years of age) receiving 120 MUg doses at 0, 1, and 6 months. Safety was assessed by collecting solicited reactogenicity data and participant-reporting of adverse events. Immunogenicity was evaluated by human serum bactericidal assay (hSBA) against 5 MnB strains expressing distinct fHBP variants and fHBP-specific immunoglobulin G titre. RESULTS: After each immunisation, local reactions such as pain at the injection site and erythema were generally mild or moderate. The most common vaccine-related adverse event was upper respiratory tract infection, which was reported by two participants. Seroprotection (hSBA titres >= 1:4) was achieved in 94.3% of participants against a MnB strain expressing the vaccine-homologous fHBP variant A05 and 70.0%-94.7% against MnB strains expressing the heterologous fHBP variants B02, A22, B44, and B24. Seroconversion rates (>= 4-fold rise in hSBA titres) ranged from 70.0% to 94.7% across the five MnB test strains following the 3-dose vaccination regimen. Immunogenicity responses tended to increase upon subsequent vaccine doses. CONCLUSIONS: Bivalent rLP2086 is a promising vaccine candidate for broad protection against MnB disease-causing strains. PMID- 23352430 TI - Identification of early replicating fragile sites that contribute to genome instability. AB - DNA double-strand breaks (DSBs) in B lymphocytes arise stochastically during replication or as a result of targeted DNA damage by activation-induced cytidine deaminase (AID). Here we identify recurrent, early replicating, and AID independent DNA lesions, termed early replication fragile sites (ERFSs), by genome-wide localization of DNA repair proteins in B cells subjected to replication stress. ERFSs colocalize with highly expressed gene clusters and are enriched for repetitive elements and CpG dinucleotides. Although distinct from late-replicating common fragile sites (CFS), the stability of ERFSs and CFSs is similarly dependent on the replication-stress response kinase ATR. ERFSs break spontaneously during replication, but their fragility is increased by hydroxyurea, ATR inhibition, or deregulated c-Myc expression. Moreover, greater than 50% of recurrent amplifications/deletions in human diffuse large B cell lymphoma map to ERFSs. In summary, we have identified a source of spontaneous DNA lesions that drives instability at preferred genomic sites. PMID- 23352431 TI - Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. AB - Long noncoding RNAs (lncRNAs) are often expressed in a development-specific manner, yet little is known about their roles in lineage commitment. Here, we identified Braveheart (Bvht), a heart-associated lncRNA in mouse. Using multiple embryonic stem cell (ESC) differentiation strategies, we show that Bvht is required for progression of nascent mesoderm toward a cardiac fate. We find that Bvht is necessary for activation of a core cardiovascular gene network and functions upstream of mesoderm posterior 1 (MesP1), a master regulator of a common multipotent cardiovascular progenitor. We also show that Bvht interacts with SUZ12, a component of polycomb-repressive complex 2 (PRC2), during cardiomyocyte differentiation, suggesting that Bvht mediates epigenetic regulation of cardiac commitment. Finally, we demonstrate a role for Bvht in maintaining cardiac fate in neonatal cardiomyocytes. Together, our work provides evidence for a long noncoding RNA with critical roles in the establishment of the cardiovascular lineage during mammalian development. PMID- 23352432 TI - [Nurse perception of care in homes for the elderly in Barcelona: analysis using a grounded theory approach]. AB - OBJECTIVE: To identify nurse perception of care in homes for the elderly in the city of Barcelona. METHOD: We performed a qualitative study that included in depth interviews, participant observations and discussion groups with registered nurses at two care homes for the elderly. Data were collected from June to October 2008 and in May in 2009, and analysed using grounded theory methodology. RESULTS: Twelve registered nurses and 10 student nurses participated in the study. Nurses reported feelings of happiness and affection, increased sensitivity in human values, and personal growth, despite work-related obstacles. CONCLUSIONS: Although care of the elderly is undervalued by society and by nurses working in other health fields, nurses in residential homes for the elderly perceive their work as authentic nursing care. PMID- 23352433 TI - [Validity of the Connor-Davidson resilience scale (10 items) in a population of elderly]. AB - AIMS: To examine the psychometric properties of the Spanish version of the CD RISC 10-items in a sample of the elderly population of Cuenca, Spain; and to assess if the Spanish version preserves the same factorial structure as the original one. METHODS: A cross sectional study was conducted in five health centres in the province of Cuenca. The study included a random sample of 500 people aged 60-75 years who lived within the community. MEASUREMENTS: The sociodemographic variables, CD-RISC-10 (resilience), PSS (perceived stress), SF 12v2, Pfeiffer Short Portable Mental Status questionnaire, GDS (geriatric depression), and MOS (social support), were all used to gather data. The number of factors underlying the CD-RISC 10 items was analysed using exploratory factor analysis. Furthermore, this factor structure was tested by confirmatory factor analysis. RESULTS: A single underlying factor was found in the CD-RISC 10 items. The factor structure was tested using confirmatory factor analysis and it was found that a single factor model showed acceptable goodness of fit values for both men and women. Convergent validity was performed to test whether the mean scores of the variables were significantly associated with resilience. The Cronbach's alpha coefficient for the CD-RISC 10 items scale was 0.81. The overall scores of the Spanish version of the CD-RISC-10 items correlated directly with MOS and the physical and mental components of SF-12, and inversely with the PSS and GDS. CONCLUSIONS: The Spanish version of the CD-RISC-10 showed good psychometric properties. Thus, it can be used as a valid and reliable instrument to measure resilience in the non-institutionalized older population. PMID- 23352434 TI - Hepatitis A virus cellular receptor 1/kidney injury molecule-1 is a susceptibility gene for clear cell renal cell carcinoma and hepatitis A virus cellular receptor/kidney injury molecule-1 ectodomain shedding a predictive biomarker of tumour progression. AB - AIM OF THE STUDY: To correlate hepatitis A virus cellular receptor (HAVCR)/kidney injury molecule-1 (KIM-1) expression in clear cell renal cell carcinoma (ccRCC) tumours with patient outcome and study the consequences of HAVCR/KIM-1 ectodomain shedding. METHODS: HAVCR/KIM-1 expression in ccRCC, oncocytomes, papillary carcinomas and unaffected tissue counterparts was evaluated. Minimal change disease and pre-clamping normal and ccRCC tissue biopsies were included. Tissue microarrays from 98 ccRCC tumours were analysed. Tumour registry data and patient outcome were retrospectivelly collected. Deletions in HAVCR/KIM-1 ectodomain and lentiviral infection of 786-O cells with HAVCR/KIM-1 mutated constructs to determine their subcellular distribution and invasive capacity were performed. RESULTS: HAVCR/KIM-1 was expressed in ccRCC, papillary tumours and in tubule cells of adjacent and distal unaffected counterparts of ccRCC tumours. The latest was not related to ischemic or tumour-related paracrine effects since pre clamping normal biopsies were positive for HAVCR/KIM-1 and unaffected counterparts of papillary tumours were negative. HAVCR/KIM-1 analyses in patients and the invasive capacity of HAVCR/KIM-1 shedding mutants in cell lines demonstrated that: (i) relative low HAVCR/KIM-1 membrane levels correlate with activated shedding in ccRCC patients and mutant cell lines; (ii) augmented shedding directly correlates with higher invasiveness and tumour malignancy. CONCLUDING STATEMENTS: Constitutive expression of HAVCR/KIM-1 in kidney might constitute a susceptibility trait for ccRCC tumour development. Enhanced HAVCR/KIM-1 ectodomain shedding promotes invasive phenotype in vitro and more aggressive tumours in vivo. PMID- 23352435 TI - Incidence and survival of neuroendocrine tumours in the Netherlands according to histological grade: experience of two decades of cancer registry. AB - PURPOSE: Epidemiological studies on neuroendocrine tumours (NETs) generally show a major increase in incidence. To investigate this increase, epidemiological data from the Netherlands were evaluated according to histological grade. METHODS: All 47,800 patients with NET (diagnosed 1990-2010) from the population-based Netherlands Cancer Registry were stratified according to the latest World Health Organization (WHO) classification for the digestive system: well-differentiated NET grade 1 and 2 (G1NET and G2NET), and poorly differentiated (grade 3) neuroendocrine carcinoma, subdivided into large cell (G3-LCNEC) and small cell (G3-SCNEC). RESULTS: The age-standardised incidence rate (excluding G3-SCNEC) increased from 2.1/100,000 in 1990 to 4.9/100,000 in 2010. The incidence of G1NET increased from 2.0 to 3.0; there was a large increase in G2NET from 0.01 in 1990 to 0.2 in 2010, and of the G3-LCNEC from 0.01 to 1.8, respectively. In G3-SCNEC incidence in men decreased from 21.3 to 10.1, whereas in women it increased from 4.5 to 7.7. The 5-year survival improved in G1NET, particularly for metastatic disease, from 30% in 1990-2000 to 47% in 2001-2010. CONCLUSION: The increasing incidence of NET (without G3-SCNEC) was mainly due to the increase of G3-LCNEC. This increase is related to improved diagnostic procedures and to shifting in pathology from other entities (such as undifferentiated carcinoma) to NET. Improved survival was seen in all sites and stages, especially in patients with metastatic G1NET. Because of its influence on incidence and survival, we recommend to present epidemiological studies on NET according to histological classification. PMID- 23352436 TI - Radical treatment of non-small cell lung cancer during the last 5 years. AB - The management of non-small cell lung cancer (NSCLC) has continued to improve over the last 5 years due to advances in surgery, radiological staging, combined modality therapies and advances in radiation technology. We have an updated staging classification (7th Edition American Joint Committee on Cancer staging) and now in 2011, a new histology classification introducing the concepts of adenocarcinoma in situ and minimally invasive adenocarcinoma. This classification has profound surgical implications as the role of limited resection is reconsidered for early stage lesions. Surgery is curative in early stage disease. The role of surgery in locally advanced NSCLC remains controversial. The principal aim is a complete resection as this will determine long-term prognosis. Intraoperative staging of lung cancer is extremely important to determine the extent of resection according to the tumour and nodal status. Systematic nodal dissection is generally advocated to obtain accurate intraoperative staging and to help decide on adjuvant therapy. Radiotherapy currently plays a major role in the management of lung cancer as most patients are not surgical candidates due to disease stage, fitness and co-morbidities. In the last 5 years we have seen continuing optimisation of chemo-radiotherapy combinations and technological advances including the development of image guided radiotherapy (IGRT), stereotactic ablative body radiotherapy (SABR) and intensity modulated radiotherapy (IMRT). Quality of life evaluation is becoming increasingly important and should be considered when deciding on a specific treatment, especially in a multimodality setting. PMID- 23352437 TI - A novel human anti-syndecan-1 antibody inhibits vascular maturation and tumour growth in melanoma. AB - INTRODUCTION: Syndecan-1 is a cell membrane protein that, after its shedding by heparanase enzymes, is accumulated in the extracellular matrix of some tumours, e.g. myeloma and lung carcinoma, where it modulates several key processes of tumourigenesis such as cancer cell proliferation and apoptosis, angiogenesis and metastasis. Few studies have focused on syndecan-1 in malignant melanoma, a tumour for which new therapeutic targets are desperately needed. We aimed to investigate the role of syndecan-1 in melanoma and to evaluate the potential therapeutic efficacy of a novel fully human anti-syndecan-1 recombinant antibody in this deadly disease. METHODS: The OC-46F2 recombinant antibody was generated by selecting a human antibody phage display library on human melanoma cells and by its expression in mammalian cells. The specific antigen recognised by the antibody was identified by mass spectrometry. Murine models of human melanoma and ovarian carcinoma were used in the pre-clinical in vivo experiments. RESULTS: The fully human antibody OC-46F2, specific for the extracellular domain of syndecan 1, inhibited vascular maturation and tumour growth in an experimental human melanoma model. The therapeutic efficacy of this antibody was also demonstrated in an experimental ovarian carcinoma model. A co-distribution of syndecan-1 with vascular endothelial growth factor receptor 2 (VEGFR2) observed in the intratumour melanoma microenvironment was absent in the tumours from mice treated with OC-46F2 scFv. CONCLUSION: These findings highlight the role of syndecan-1 as a potential therapeutic target in melanoma and ovarian carcinoma and provide a new tool able to block vessel maturation, one of the mechanisms that underpin the angiogenic process essential for solid tumour growth. PMID- 23352438 TI - An in vivo hypoxia metagene identifies the novel hypoxia inducible factor target gene SLCO1B3. AB - A hypoxia-associated gene signature (metagene) was previously derived via in vivo data-mining. In this study, we aimed to investigate whether this approach could identify novel hypoxia regulated genes. From an initial list of nine genes, three were selected for further study (BCAR1, IGF2BP2 and SLCO1B3). Ten cell lines were exposed to hypoxia and interrogated for the expression of the three genes. All three genes were hypoxia inducible in at least one of the 10 cell lines with SLCO1B3 induced in seven. SLCO1B3 was studied further using chromatin immunoprecipitation and luciferase assays to investigate hypoxia inducible factor (HIF) dependent transcription. Two functional HIF response elements were identified within intron 1 of the gene. The functional importance of SLCO1B3 was studied by gene knockdown experiments followed by cell growth assays, flow cytometry and Western blotting. SLCO1B3 knockdown reduced cell size and 3 dimensional spheroid volume, which was associated with decreased activation of the mammalian target of rapamycin (mTOR) pathway. Finally, Oncomine analysis revealed that head and neck and colorectal tumours had higher levels of SLCO1B3 compared to normal tissue. Thus, the knowledge based approach for deriving gene signatures can identify novel biologically relevant genes. PMID- 23352440 TI - Long term improved quality of life by a 2-week group physical and educational intervention shortly after breast cancer chemotherapy completion. Results of the 'Programme of Accompanying women after breast Cancer treatment completion in Thermal resorts' (PACThe) randomised clinical trial of 251 patients. AB - BACKGROUND: Quality of life (QoL) after breast cancer is nowadays a major challenge. Complementary interventions are necessary because of frequent depression symptoms after treatment and also to favour return to activity. Besides, radio-chemotherapy has side-effects like weight gain and fatigue. Several strategies including group behavioural-educational interventions, physical training and/or dietary education, have been tested to answer these difficulties with moderate success in the long run. METHODS: Two hundred and fifty-one non-metastatic patients were accrued after chemotherapy in a prospective randomised multicenter trial between 2008 and 2010, testing a 2-week intervention in SPA centres. Intervention comprised group physical training, dietary education and physiotherapy. Selected patients were in complete remission. QoL was evaluated with SF36 questionnaire, anxiety and depression with the hospital anxiety and depression (HAD) one. Anthropometric measures and QoL evaluations were obtained before randomisation and every 6 months during 3 years. RESULTS: Two hundred and twenty patients were evaluable at 1 year. Intervention increased SF36 score by 9.5 points (p=0.000006), 4.6 (p=0.032) and 6.2 (p=0.028) respectively at 6, 12 and 24 months. Effect size (ES) was 0.63 [0.37; 0.90], 0.29 [0.03; 0.55] and 0.41 [0.04; 0.78]. Anxiety score was shortly minored by intervention (6-month ES=-0.24 [-0.42; -0.05]) and depression score more durably: ES=-0.45 [-0.72; -0.18], -0.34 [-061; -0.08], and -0.26 [-0.63; 0.11] at 6, 12 and 24 months. CONCLUSION: This 2-week group intervention seemed to durably influence QoL of breast cancer patients treated by chemotherapy. Differences, smaller at 12 months than at six, suggest that a second but shorter intervention could help maintain the 6-month benefits. PMID- 23352439 TI - Role of chemotherapy for advanced/recurrent gastric cancer: an individual-patient data meta-analysis. AB - We conducted an individual-patient-data meta-analysis of the efficacy of chemotherapy on overall survival (OS) and progression-free survival (PFS) in advanced/recurrent gastric cancer (AGC). Our primary research question was whether the experimental arms of the trials included in the meta-analysis showed a benefit as compared with their corresponding control arms. MEDLINE (up to 2010), Cochrane Central Register of Controlled Trials, National Institutes of Health (NIH) trial registry and proceedings of major oncologic and gastrointestinal cancer meetings were searched. Randomised controlled trials for AGC closed to patient accrual before the end of 2006 were eligible. As of December 2010, individual patient data were available from 22 trials (4245 patients, representing 47% of the targeted data) of 55 eligible trials. The overall comparison of experimental arms with the corresponding control arms showed statistically significant differences in terms of both OS and PFS. Hazard ratio was 0.88 (95% confidence interval 0.82-0.94, P<0.0001) for OS and 0.81 (0.76-0.88, P<0.0001) for PFS. The results of the sub-analysis of adding a given chemotherapeutic agent to any chemotherapy confirm the results of the overall analysis, with a hazard reduction of 11% for OS (P<0.01) and 26% for PFS (P<0.0001). This meta-analysis of individual patient data shows that the additions of experimental chemotherapeutic agents to pre-existing control or standard regimens have produced a modest improvement in OS and PFS. Median survival remained below 1 year for all investigated chemotherapy regimens and none emerged as a clear standard. PMID- 23352441 TI - Reactive oxygen species H2O2 and *OH, but not O2*(-) promote oridonin-induced phagocytosis of apoptotic cells by human histocytic lymphoma U937 cells. AB - We reported previously that phagocytosis of apoptotic cells by U937 cells was enhanced by the treatment with oridonin that showed high activity to induce the generation of reactive oxygen species (ROS) in many cells. ROS, important signaling molecules, are involved in the immune defenses, cell repair and proliferation. In this study, oridonin caused modest amount of ROS generation in U937 cells, with hydrogen peroxide (H2O2) and hydroxyl free radical (OH) as the major types. Meanwhile, H2O2 and OH were positive regulators involved in oridonin enhanced engulfment of apoptotic cells through down-regulating mitochondrial membrane potential (MMP) and inducing autophagy. The ROS-mediated phagocytosis was independent of cellular adenosine triphosphate (ATP) levels. H2O2 and OH generation also activated phosphatidylinositol 3-kinases-Akt (PI3K-Akt) and phospholipase C gamma-protein kinase C(PLC gamma)-Ras-Raf-ERK signaling pathways, which were essential for oridonin-induced engulfment of apoptotic cells. Phagocytosis, the loss of MMP, autophagy and the activated signaling pathways were all suppressed by ROS scavenger N-acetyl-l-cysteine (NAC), H2O2 scavenger catalase or OH scavenger glutathione (GSH). However, superoxide anion (O2-) and its scavenger superoxide dismutase (SOD) did not significantly affect these oridonin-induced biological processes. PMID- 23352442 TI - Echinocystic acid, a metabolite of lancemaside A, inhibits TNBS-induced colitis in mice. AB - The rhizome of Codonopsis lanceolata (CL, family Campanulaceae), of which the main constituent is lancemaside A, has been used for cough and bronchitis in traditional Chinese medicine. To evaluate anti-colitic effect of CL, we examined anti-inflammatory effect of CL extracts, lancemaside A and its metabolites in lipopolysaccharide (LPS)-stimulated peritoneal macrophages and 2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced colitic mice. Among CL extracts, CL BuOH extract inhibited LPS-induced IL-1beta, IL-6 and TNF-alpha expression, as well as NF-kappaB activation most potently. CL BuOH extract also inhibited colon shortening and myeloperoxidase activity in TNBS-induced colitic mice. Among lancemaside A, a main constituent of CL BuOH extract, and its metabolites (lancemaside X, echinocystic acid-3-O-beta-d-glucopyranoside and echinocystic acid), echinocystic acid inhibited the expression of the pro-inflammatory cytokines, IL-1beta, IL-6, and TNF-alpha, as well as the phosphorylation of IKKbeta and p65 in LPS-stimulated peritoneal macrophages most potently. Echinocystic acid also potently inhibited the binding of LPS to TLR4 on peritoneal macrophages. Lancemaside A and its metabolite, echinocystic acid, inhibited TNBS-induced colonic inflammation, including colon shortening, increased myeloperoxidase activity and pro-inflammatory cytokine expression, and NF-kappaB activation in mice. The anti-colitic effect of echinocystic acid was superior to that of lancemaside A. Based on these findings, orally administered lancemaside A may be metabolized to echinocystic acid, which may express anti colitic effect by inhibiting the binding of LPS to TLR4 on the macrophages. PMID- 23352444 TI - Tissue senescence and periodontal disease--a reciprocal association? PMID- 23352443 TI - Suppression of LPS-induced inflammatory responses by gossypol in RAW 264.7 cells and mouse models. AB - Gossypol, a yellowish polyphenolic compound originally from cotton plant, has been known to exert a potential for anti-cancer, anti-inflammatory and other important therapeutic activities. The purpose of this investigation was to determine the protection of gossypol on inflammation in Lipopolysaccharide (LPS) stimulated RAW 264.7 cells and LPS induced in vivo lung injury model. The effects of gossypol on pro-inflammatory cytokines and signaling pathways were evaluated by enzyme-linked immunosorbent assay and Western blot. The results showed that gossypol significantly inhibited the production of LPS-induced TNF-alpha, IL-6 and IL-1beta both in vitro and vivo. Furthermore, gossypol blocked the phosphorylation of IkappaBalpha protein, p65, p38, c-Junterminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in LPS stimulated RAW 264.7 cells. From the in vivo study, it was observed that gossypol attenuated lung histopathologic changes in mouse models. The present data suggest that gossypol suppresses the inflammation in vitro and vivo, and may be a potential therapeutic candidate for the treatment of inflammatory disorders. PMID- 23352445 TI - An evolutionary perspective of mammal salivary peptide families: cystatins, histatins, statherin and PRPs. AB - Saliva's role in the oral cavity, such as lubrication, protection of tissues and antimicrobial action is a reflex of its composition, among which are several peptide families like statherin, histatins, proline rich proteins (PRPs) and some members of the cystatin family. These peptides present different evolutionary pathways being in the case of histatin, statherin and PRP families restricted to few millions and comprising few species when compared with cystatins, where duplication occurred at more than 650 mya. Though the recognized relevance of phylogenetic approaches to disclose relationships among different species, information on the salivary proteins that allow the association between peptide families-related structure and function in the oral cavity is scarce. In the present study, the four major salivary peptides classes are reviewed considering the few known phylogenetic studies focusing on their evolution among mammals. New perspectives and challenges for future and multidisciplinary experimental works are drawn. PMID- 23352446 TI - Dental caries and chemical analyses in reconstruction of diet, health and hygienic behaviour in the Middle Euphrates valley (Syria). AB - OBJECTIVES: The aim of this study was to use two methods, biological and chemical, to examine changes in diet and health in individuals from the Middle Euphrates valley (Syria). We determined the frequency distribution of dental caries. Chemical analyses were concerned with the presence of elements such as strontium, barium, calcium and stable carbon isotopes ((13)C/(14)C). We chose three consecutive periods: Late Roman (2nd-4th century AD), Islamic (600-1200 AD) and Modern Islamic (1850-1950 AD). MATERIALS AND METHODS: We analysed the dental remains of 145 individuals, with a total of 2530 teeth. We used visual research (magnifying glass/sharp dental probe) and radiography. The frequencies of caries were calculated on the basis of the proportional correction factor of Erdal and Duyar. We chose 39 permanent second molars for chemical analyses. RESULTS: The frequency of carious lesions was similar in all three periods (6-8%). In the Modern Islamic and Islamic periods, occlusal surfaces were infected with caries most often, while the cemento-enamel junction (CEJ) and approximal surfaces were affected to a lesser degree. However, in the Late Roman period, the CEJ and approximal surfaces showed caries most frequently, in contrast to occlusal surfaces, which seldom showed signs of caries. Chemical analyses showed lower Sr/Ca ratios and Observed Ratio index values for the Modern Islamic and higher values for the Islamic and Late Roman periods. Mean stable isotope (delta(13)C) analyses demonstrated that the Modern Islamic period was strongly divergent from the other periods. DISCUSSION: These data suggest a similar socio-economic status during the Late Roman and Islamic periods. The diet of the population living in the Late Roman and Islamic periods contained a larger number of products containing strontium than calcium. In the modern population these proportions have been reversed. PMID- 23352447 TI - The clinical spectrum of frontotemporal dementia: a case of rapidly progressive dementia. PMID- 23352448 TI - Emergency stroke care in Spain's "stroke Belt". PMID- 23352449 TI - Eyelid reanimation with gold weight implant and tendon sling suspension: evaluation of excursion and velocity using the FACIAL CLIMA system. AB - OBJECTIVE: This study aims to analyse the efficacy of static techniques, namely gold weight implant and tendon sling, in the reanimation of the paralytic eyelid. Upper eyelid rehabilitation in terms of excursion and blinking velocity is performed using the automatic motion capture system, FACIAL CLIMA. METHODS: Seventy-four patients underwent a total of 101 procedures including 58 upper eyelid gold weight implants and 43 lower eyelid tendon suspension with 27 patients undergoing both procedures. The presence of lagophtalmos, eye dryness, corneal ulcer, epiphora and lower lid ptosis/ectropion was assessed preoperatively. The Wilcoxon signed-rank test was used to compare preoperative versus postoperative measurements of upper eyelid excursion and blinking velocity determined with FACIAL CLIMA. Significance was set at p <0.05. RESULTS: FACIAL CLIMA revealed significant improvement of eyelid excursion and velocity of blinking (p < 0.001). Eye dryness improved in 49 patients (90.7%) and corneal ulcer resolved without any further treatment in 12 (85.7%) of those with a gold weight inserted. Implant extrusion was observed in 8.6% of the cases. Of the patients with lower lid tendon suspension, correction of ptosis/ectropion and epiphora was achieved in 93.9% and 91.9% of cases, respectively. In eight patients (18.6%), further surgery was needed to adjust tendon tension. CONCLUSIONS: The paralytic upper and lower eyelid can be successfully managed with gold weight implant and tendon suspension. The FACIAL CLIMA system is a reliable method to quantify upper eyelid excursion and blinking velocity and to detect the exact position of the lower eyelid. PMID- 23352450 TI - A chimeric vascularised groin lymph node flap and DIEP flap for the management of lymphoedema secondary to breast cancer. PMID- 23352451 TI - Virions proteins of an RSIV-type megalocytivirus from spotted knifejaw Oplegnathus punctatus (SKIV-ZJ07). AB - Megalocytiviruses have three main genotypes, which are represented by ISKNV, RSIV, and TRBIV. To date, the virion-associated proteins of RSIV and TRBIV are still unknown. The spotted knifejaw iridovirus (SKIV) is a newly characterized RSIV-type megalocytivirus. In this study, the virion-associated proteins of SKIV were identified by systemic one-dimensional gel electrophoresis-based proteomic approaches. A total of 49 viral proteins and 33 cellular proteins were associated with the SKIV virions by LC MS/MS, including 18 highly abundant structural proteins that were detected by MALDI TOF/TOF-MS. One highly abundant structural protein of interest was identified as the virus-inducible stress protein (VISP) and further characterized as an envelope protein. However, knockdown of mVISP by siRNA method showed no effect in virion production. The current study is the first to present detailed information on the virion-associated proteins of an RSIV-type megalocytivirus and to identify a novel cellular envelope protein of this virus. PMID- 23352452 TI - Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling. AB - Raf kinases are essential for normal Ras-Raf-MEK-ERK pathway signaling, and activating mutations in components of this pathway are associated with a variety of human cancers, as well as the related developmental disorders Noonan, LEOPARD, and cardiofaciocutaneous syndromes. Although the Raf kinases are known to dimerize during normal and disease-associated Raf signaling, the functional significance of Raf dimerization has not been fully elucidated. Here, using mutational analysis and a peptide inhibitor, we show that dimerization is required for normal Ras-dependent Raf activation and for the biological function of disease-associated Raf mutants with moderate, low, or impaired kinase activity. However, dimerization is not needed for the function of B-Raf mutants with high catalytic activity, such as V600E-B-Raf. Importantly, we find that a dimer interface peptide can effectively block Raf dimerization and inhibit Raf signaling when dimerization is required for Raf function, thus identifying the Raf dimer interface as a therapeutic target. PMID- 23352454 TI - Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. AB - O-linked N-acetylglucosamine (O-GlcNAc) transferase (Ogt) activity is essential for embryonic stem cell (ESC) viability and mouse development. Ogt is present both in the cytoplasm and the nucleus of different cell types and catalyzes serine and threonine glycosylation. We have characterized the biochemical features of nuclear Ogt and identified the ten-eleven translocation (TET) proteins Tet1 and Tet2 as stable partners of Ogt in the nucleus of ESCs. We show at a genome-wide level that Ogt preferentially associates with Tet1 to genes promoters in close proximity of CpG-rich transcription start sites. These regions are characterized by low levels of DNA modification, suggesting a link between Tet1 and Ogt activities in regulating CpG island methylation. Finally, we show that Tet1 is required for binding of Ogt to chromatin affecting Tet1 activity. Taken together, our data characterize how O-GlcNAcylation is recruited to chromatin and interacts with the activity of 5-methylcytosine hydroxylases. PMID- 23352453 TI - A core chromatin remodeling factor instructs global chromatin signaling through multivalent reading of nucleosome codes. AB - ATP-dependent NuRD repressor complexes involve combinatorial assembly of its subunits. However, the mechanism of gene transcription by MTA1/NuRD remains enigmatic. Here we report that MTA1 methylation by G9a methytransferase and demethylation by LSD1 determines the nucleosome remodeling and transcriptional outcome. Contrary to the current static repressor model of the NuRD complex, we discovered that MTA1 association with nucleosomes and corepressor/coactivator complexes is dynamic. While methylated MTA1 is required for the NuRD repressor complex, demethylated MTA1 recognizes the bivalent histone H3K4-AcK9 mark and recruits coactivator NURF-trithorax remodeling complex in a signaling-dependent manner. MTA1's lysine 532 methylation represents a molecular switch as methylated and demethylated MTA1 nucleate NuRD or NURF complexes with opposite functions in a cyclical manner. In addition, MTA1 possesses an inherent histone amplifier activity with an instructive role in impacting the epigenetic landscape, providing a new perspective to the molecular governance of dual coregulator functions of a master coregulator. PMID- 23352455 TI - Nutritional status and disease severity in patients with chronic obstructive pulmonary disease (COPD). AB - The purpose of this study was to identify the relationship between nutritional status and the severity of the disease in patients with COPD in South Korea. This study used pretest data from a larger intervention study. Data were collected from March to October 2010, and 251 patients diagnosed with COPD from five hospitals in South Korea were included in the analysis. All participants were interviewed face-to-face. Actual dietary intake was measured by a 24-h dietary recall, and the body mass index (BMI), obstruction of the airway (FEV1% predicted), degree of dyspnea (modified Medical Research Council: MMRC), and exercise capacity (6min walking distance: 6MWD) (BODE) index was calculated to estimate the severity of the condition. Lower BODE index scores indicate lower risk of mortality. The data were analyzed by descriptive statistics, a chi(2) test, t-tests, analysis of variance (ANOVA), Pearson correlation, and hierarchical multiple regression using SPSS 18.0. The mean age of the participants was 66.83 years and 92.4% of the participants were men. The mean total energy intake was 1431.65kcal, and the mean BODE index score was 2.89. Total energy intake significantly explained additional variance in BODE, BMI, the severity of the perceived dyspnea, and the length of 6min walk after controlling for age, duration after diagnosed with COPD, and physical activities. The findings of this study emphasized the importance of calorie intake in the disease severity among COPD patients. Further research on the effects of nutritional intervention on the health outcomes of patients with COPD is warranted. PMID- 23352456 TI - Archives of Gerontology and Geriatrics. Editorial. PMID- 23352458 TI - Is the HCV pipeline heading in the right direction? PMID- 23352459 TI - [Subvalvular aortic stenosis associated with 8p23 deletion]. AB - We report the case of a 35-year-old man admitted due to heart failure, who had had moderate cognitive deficit, craniofacial dysmorphism, epilepsy, panic attacks and congenital heart disease (subvalvular aortic stenosis) associated with chronic atrial fibrillation since childhood. In view of his facial dysmorphism and clinical presentation, karyotype analysis was performed and revealed a de novo interstitial deletion in chromosome 8 in the region p23.1-p23.2. This is a rare chromosomal anomaly (about 50 descriptions in the literature), whose most common manifestations include heart defects, cognitive retardation and behavioral disturbances. In this paper we present the first case with associated subvalvular aortic stenosis and review the literature on this chromosomal abnormality. PMID- 23352460 TI - Expression and role of Toll-like receptors on human umbilical cord mesenchymal stromal cells. AB - BACKGROUND AIMS: Toll-like receptors (TLRs) play an important role in innate and adaptive immunity by recognizing pathogen-associated molecular patterns (PAMPs). METHODS: In the present study, we investigated the expression and role of TLRs on human umbilical cord mesenchymal stromal cells (UC-MSCs). The proliferation, differentiation and immunoregulatory activity of UC-MSCs primed with or without TLR ligands were determined. RESULTS: At the RNA level, the expression of TLR2, 4, 6 and 9 was relatively higher than that of other TLRs. However, TLR3 and TLR4 expression were relatively higher at the protein level. UC-MSCs expressed functional TLRs by nuclear factor-kappaB activation and cytokine expression assay. Poly-inosinic acid:cytidylic acid [Poly(I:C)] stimulation inhibited the proliferation of UC-MSCs, but the ligand of other TLRs had no significant effect. Poly(I:C) stimulation enhanced the adipogenic differentiation capability of UC MSCs, but lipopolysaccharide inhibited the adipogenic differentiation. Poly(I:C) and CpG-oligonucleotide promoted the immunosuppressive potentiality of UC-MSCs, accompanied with the phosphorylation of interferon regulatory factor 3 (IRF3) and increased expression of indoleamine 2,3-dioxygenase and interferon beta, whereas activation of other TLR ligands (synthetic analog fibroblast-stimulating lipopeptide-1 and lipopolysaccharide) failed to affect the immunoregulatory activity of UC-MSCs. CONCLUSIONS: Taken together, our data demonstrated that TLR activation influenced the function of UC-MSCs, which might have important implications in future efforts to explore the clinical potentials of UC-MSCs. PMID- 23352461 TI - Therapeutic angiogenesis of three-dimensionally cultured adipose-derived stem cells in rat infarcted hearts. AB - BACKGROUND AIMS: To successfully treat myocardial infarction (MI), blood must be resupplied to the ischemic myocardium by inducing angiogenesis. Many studies report enhanced angiogenesis using stem cells; however, the therapeutic efficacy of cell transplant remains low because transplanted cells may not survive, be retained at the site of transplant, or develop into vascular tissue. In this study, we assessed the therapeutic potential of three-dimensional cell masses (3DCM) composed of human adipose-derived stem cells (hASC) in a rat MI model. METHODS: For formation of 3DCM, hASC were cultured on a substrate with immobilized fibroblast growth factor 2. The morphology and phenotypes of 3DCM were analyzed 1 day after culture. The cells (hASC and 3DCM, 5 * 10(5) cells) were injected into ischemic regions after ligation of the left coronary artery (n = 6 in each group). Cell retention ratio, therapeutic efficacy and vascularization were evaluated 4 weeks after transplant. RESULTS: A spheroid-type 3DCM, which included vascular cells (CD34(+)/CD31(+)/KDR(+)/alpha-SMA(+)) with high production of human vascular endothelial growth factor, was obtained. Infarct size and cardiomyocyte apoptosis were reduced in the 3DCM-injected group compared with the hASC-injected group. The retention ratio of hASC was 14-fold higher in the 3DCM-injected group. Many transplanted cells differentiated into endothelial and smooth muscle cells and formed vascular networks incorporated into host vessels. CONCLUSIONS: Transplant of 3DCM may be useful for angiogenic cell therapy to treat MI. PMID- 23352463 TI - The peculiar biology of mouse mesenchymal stromal cells--oxygen is the key. AB - Because of the ability to manipulate their genome, mice are the experimental tool of choice for many areas of scientific investigation. Moreover, established experimental mouse models of human disease are widely available and offer a valuable resource to obtain proof-of-concept for many cell-based therapies. Nevertheless, efforts to establish reliable methods to isolate mesenchymal stromal cells (MSCs) from mouse bone marrow have been elusive. Indeed, a variety of physical and genetic approaches have been described to fractionate MSCs from other cell lineages in bone marrow, but few have achieved high yields or purity while maintaining the genomic integrity of the cells. We provide a historic overview of published procedures dedicated to the isolation of mouse MSCs from bone marrow and compact bone. We also review current findings indicating that growth-restrictive conditions imposed by atmospheric oxygen promotes immortalization of mouse MSCs and how expansion in a low-oxygen environment enhances cell yields and maintains genomic stability. Finally, we provide basic recommendations for isolating primary mouse MSCs and discuss potential pitfalls associated with these isolation methods. PMID- 23352462 TI - Differential gene expression profile of first-generation and second-generation rapamycin-resistant allogeneic T cells. AB - BACKGROUND AIMS: We completed a phase II clinical trial evaluating rapamycin resistant allogeneic T cells (T-rapa) and now have evaluated a T-rapa product manufactured in 6 days (T-rapa(6)) rather than 12 days (T-Rapa(12)). METHODS: Using gene expression microarrays, we addressed our hypothesis that the two products would express a similar phenotype. The products had similar phenotypes using conventional comparison methods of cytokine secretion and surface markers. RESULTS: Unsupervised analysis of 34,340 genes revealed that T-rapa(6) and T rapa(12) products clustered together, distinct from culture input CD4(+) T cells. Statistical analysis of T-rapa(6) products revealed differential expression of 19.3% of genes (n = 6641) compared with input CD4(+) cells; similarly, 17.8% of genes (n = 6147) were differentially expressed between T-rapa(12) products and input CD4(+) cells. Compared with input CD4(+) cells, T-rapa(6) and T-rapa(12) products were similar in terms of up-regulation of major gene families (cell cycle, stress response, glucose catabolism, DNA metabolism) and down-regulation (inflammatory response, immune response, apoptosis, transcriptional regulation). However, when directly compared, T-rapa(6) and T-rapa(12) products showed differential expression of 5.8% of genes (n = 1994; T-rapa(6) vs. T-rapa(12)). CONCLUSIONS: Second-generation T-rapa(6) cells possess a similar yet distinct gene expression profile relative to first-generation T-rapa(12) cells and may mediate differential effects after adoptive transfer. PMID- 23352464 TI - Average cell viability levels of human dental pulp stem cells: an accurate combinatorial index for quality control in tissue engineering. AB - BACKGROUND AIMS: One of the most important issues in tissue engineering (TE) is the search for a suitable stem cell reservoir with optimal cell viability levels for the development of new tissues relevant for therapeutic needs. The aim of this study was to evaluate the cell viability levels of 10 sequential cell passages of human dental pulp stem cells (hDPSC) to determine their potential for TE techniques. METHODS: To assess the average cell viability levels of hDPSC, four cell viability assays were used in a combinatorial approach: trypan blue exclusion test, water-soluble tetrazolium 1 assay, live/dead assay and electron probe x-ray microanalysis. RESULTS: The results showed that cell viability as determined by trypan blue staining and live/dead assays was greater than 85%, with a significant decrease at the second passage (P < 0.05) and a significant increase at the ninth passage (P < 0.05). Electron probe x-ray microanalysis showed that the highest cell viability corresponded to the ninth passage, with the lowest K/Na values found at the third passage. No statistical differences were found among the different passages for the water-soluble tetrazolium 1 assay (P = 0.219). CONCLUSIONS: Assessment of average cell viability levels showed that the highest viability of hDPSC was reached after nine passages, suggesting that this passage would be the most adequate for use in TE protocols. PMID- 23352466 TI - Herbo-probiotic therapy in cardioprotection: a new way of nature to nurture. PMID- 23352465 TI - C16 peptide shown to prevent leukocyte infiltration and alleviate detrimental inflammation in acute allergic encephalomyelitis model. AB - Integrins are important adhesion receptors for leukocytes binding to endothelial cellular adhesion molecules. Previous studies have suggested that blocking relevant integrins might prevent leukocyte infiltration and suppress clinical and pathological features of neuroinflammatory disease. Experimental autoimmune encephalomyelitis (EAE), a rodent model of Multiple sclerosis (MS), is characterized by chronic inflammatory disorder of the central nervous system in which circulating leukocytes enter the brain and spinal cord leading to inflammation, myelin damage and subsequent paralysis. To prove this hypothesis and explore a promising application for MS treatment, the effects of C16, an alphanubeta3 integrin-binding peptide, were tested in vitro and in vivo by transendothelial assay, electron microscopy observation, multiple histological and immunohistochemical staining. The results showed C16 inhibited transendothelial migration of the C8166-CD4 lymphoblast cells, and alleviated extensive spinal cord and brain infiltration of leukocytes and macrophages in the EAE model. Furthermore, a significant amelioration of astrogliosis and a dramatic decrease in demyelination and axonal loss were observed in C16 treated animals. The attenuating inflammatory progression may improve the regional environment and trigger further neuroprotective effects on myelin and axons, all this suggests that C16 peptide may be a promising therapeutic agent for multiple sclerosis. PMID- 23352468 TI - The peer review process and JSES procedures. PMID- 23352467 TI - Antioxidant activity of melatonin in diabetes in relation to the regulation and levels of plasma Cu, Zn, Fe, Mn, and Se in Zucker diabetic fatty rats. AB - OBJECTIVE: To study the antioxidant activity of melatonin in diabetes in relation to the regulation and levels of plasma copper (Cu), zinc (Zn), iron (Fe), manganese (Mn), and selenium (Se) in Zucker diabetic fatty (ZDF) and lean (ZL) rats. METHODS: At 6 wk of age, both ZDF (n = 30) and ZL (n = 30) animals were subdivided into three groups: control (C) (n = 10), vehicle (V) (n = 10), and melatonin-treated (M) (10 mg/kg/d; n = 10) rats for a 6-wk period. At the end of treatment period, plasma mineral levels were measured by flame (Cu, Zn, and Fe), electrothermal (Mn), and hydride generation (Se) atomic absorption spectrometry. RESULTS: ZDF rats had significantly higher Cu, Fe, and Mn plasma levels than did ZL rats (P < 0.05). No significant differences were found between control and vehicle groups (P > 0.05). Melatonin treatment did not influence plasma levels of these antioxidant minerals (Cu, Zn, Fe, and Mn) in ZDF groups (M-ZDF versus C-ZDF group) and ZL (M-ZL versus C-ZL group) rats with the exception of Zn, whose mean plasma level was lower in the M-ZL versus C-ZL group. However, plasma Se levels increased significantly (P < 0.05) after melatonin supplementation in both groups (M-ZDF and M-ZL). CONCLUSION: The higher mean plasma Cu, Fe, and Mn levels in the ZDF group are related to the enhanced oxidative stress in diabetes and obesity. Melatonin administration significantly enhanced plasma Se levels in both groups (M-ZDF and M-ZL). This is the first study to report that melatonin treatment increases plasma Se levels. PMID- 23352469 TI - Collateral ligament injury in the displaced radial head and neck fracture: correlation with fracture morphology and management strategy to the torn ulnar collateral ligament. AB - BACKGROUND: The purpose of our study was to correlate the morphology of displaced radial head and neck (DRHN) fractures with associated ligament injuries and evaluate the outcomes of management of the torn ulnar collateral ligament (UCL). METHODS: Twenty-nine surgically treated patients presenting with a DRHN fracture were classified using the Charalambous classification by 3-dimensional computed tomography. Accordingly, the collateral ligament and overlying muscle injuries and bony contusions were investigated with magnetic resonance imaging. The valgus stress test was performed intraoperatively on 20 patients with magnetic resonance confirmed complete UCL rupture. If there was no firm end point, the UCL was repaired (group B). The others were treated conservatively (group A). The Minnesota Elbow Performance Score and Disabilities of the Arm, Shoulder and Hand scores were used to measure patient outcome. RESULTS: There was a trend toward a higher incidence of complete UCL rupture in Charalambous type 3D and 4D fractures (P = .110) and complete lateral UCL rupture in Charalambous type 1D and 2D fractures (P = .126), although this was not statistically significant. Rupture of the overlying muscles was more common in group B than in group A (P < .05). Functional outcome between the 2 groups was not significantly different. CONCLUSIONS: DRHN fracture is always a complex fracture accompanied by collateral ligament injuries. Type 3D and 4D tended to have a higher association with UCL rupture compared with type 1D and 2D, types commonly associated with lateral UCL rupture. The magnetic resonance imaging-confirmed torn UCL could be managed conservatively if there was a firm end point on valgus stress test. PMID- 23352470 TI - Surgical release of elbow stiffness after internal fixation of intercondylar fracture of the distal humerus. AB - BACKGROUND: Loss of motion is common after intercondylar fracture of the distal humerus despite proper management. The purpose of the current study was to report the results of contracture release for stiffness that developed after open reduction and internal fixation (ORIF) of distal humeral intercondylar fractures. METHODS: Twenty-four consecutive patients with a stiff elbow after ORIF of intercondylar fractures (20 AO type C2 and 4 type C3 fractures) were managed with contracture release at a median of 13 months. The surgical indication was total arc of motion of less than 100 degrees despite physical therapy for more than 6 months. Plates and screws for ORIF were removed concomitantly in 16 patients. Each patient was evaluated by final arc of motion and Mayo Elbow Performance Score (MEPS). RESULTS: The main lesions causing stiffness were heterotopic ossification or excessive callus in 13 patients and capsular fibrosis in 11. The mean total range of motion (ROM) was improved from 60.2 degrees preoperatively to 104.8 degrees postoperatively. At the final follow-up, 17 of the 24 elbows (71.8%) obtained a total ROM of more than 100 degrees . The mean MEPS improved from 69 points preoperatively to 87 points at the final follow-up (P < .05). Refracture occurred during ROM exercise in 4 patients who had undergone concomitant implant removal during the contracture release. CONCLUSION: Surgical release of a stiff elbow that develops after ORIF of intercondylar fractures can result in satisfactory restoration of ROM in most patients. However, potential risk of refracture after release should be considered when implants are concomitantly removed. PMID- 23352471 TI - Open arthrolysis and prosthetic replacement of the radial head for elbow stiffness associated with rotation limitation. AB - BACKGROUND: Limited forearm rotation is a frequent combined disorder in elbow stiffness. If the radial head cannot be saved during open arthrolysis, prosthetic replacement might be considered because it enhances stability and allows early motion. METHODS: In this study we retrospectively analyzed the outcome of 8 patients (7 men, 1 woman) who underwent open arthrolysis and simultaneous prosthetic replacement after resection of the radial head to restore elbow range of motion and forearm rotation. Patients were a mean age of 31.7 years (range, 22 40 years). RESULTS: Postoperatively, the mean (range) active range of motion improved from 29.4 degrees (0 degrees -70 degrees ) to 113.1 degrees (80 degrees -135 degrees ), mean (range) supination increased from 38.8 degrees (0 degrees -80 degrees ) to 77.5 degrees (50 degrees -90 degrees ), and mean (range) pronation improved from 18.8 degrees (0 degrees -80 degrees ) to 68.8 degrees (50 degrees -80 degrees ). The Mayo Elbow Performance Score improved from a mean (range) of 57.5 (50-70) to 92.5 (85-100) points. No elbow valgus instability was detected over a mean duration of 26 months of follow-up. The implant was considered stable in all patients. CONCLUSIONS: Open arthrolysis and prosthetic replacement of the radial head are effective in treating elbow stiffness with associated rotation limitation after resection of the radial head. PMID- 23352472 TI - Intermediate-term outcomes for floating elbow and floating elbow variant injuries. AB - BACKGROUND: There are limited outcome studies describing floating elbow injuries. The purpose of this report is to describe patient outcomes after floating elbow injury using the American Shoulder and Elbow Surgeons (ASES) elbow assessment form. MATERIALS AND METHODS: From 1994 to 2004, 19 patients were retrospectively identified at 3 Level I trauma centers and returned for follow-up evaluation after treatment of their floating elbow injury. Patient outcomes were assessed based on physical examination and the ASES elbow form. RESULTS: The 19 patients were evaluated at a mean of 6.7 years (range, 2.3-13.4 years) after treatment of their floating elbow injuries. The mean ASES elbow score was 89 (range, 13-99), and the mean visual analog scale satisfaction with elbow surgery was 8.7 (range, 7-10). Fifteen of 19 patients reported continued pain in the elbow. Patient age, arm dominance, type of humeral fixation, type of forearm fixation, open fracture, multiple surgeries, and fracture pattern were not significantly associated with outcomes. Nerve injury was associated with lower ASES elbow scores (P = .03). There was also a significant correlation between the ASES elbow score and follow up time, indicating that patients with a longer duration of follow-up had better subjective outcomes (Spearman coefficient = 0.55; P = .02). CONCLUSION: Floating elbow fractures represent high-energy trauma and have significant associated injuries. Nerve injury is correlated with lower subjective outcomes. Patients continue to improve for several years with acceptable mid-term results. PMID- 23352473 TI - Complications and re-operations after Bristow-Latarjet shoulder stabilization: a systematic review. AB - BACKGROUND: Various methods of bony stabilization, including modifications of Bristow and Latarjet procedures, are considered gold-standard treatment for recurrent anterior shoulder instability but are associated with unique complications and risk of reoperation. The purpose of this study was to identify the prevalence of these complications. We hypothesized that the Bristow-Latarjet procedure would be a successful technique for treatment of shoulder instability but associated with a risk of recurrent postoperative instability, reoperation, and other complications. METHODS: A systematic review of multiple medical databases included studies reporting outcomes with complication and reoperation rates following original or modified versions of the Bristow or Latarjet shoulder stabilization surgeries. RESULTS: Forty-five studies were analyzed (1,904 shoulders) (all Level IV evidence). Most subjects were male (82%). The dominant shoulder was the operative shoulder in 64% of cases. Mean subject age was 25.8 years. Mean clinical follow-up was 6.8 years. Ninety percent of surgeries were done open; 9.3% were all-arthroscopic. Total complication rate was 30%. Recurrent anterior dislocation and subluxation rates were 2.9% and 5.8%, respectively. When reported, most dislocations occurred within the first year postoperatively (73%). Nearly 7% of patients required an unplanned reoperation following surgery. CONCLUSION: Osseous stabilization shoulder surgery using original or modified Bristow and Latarjet procedures has a 30% complication rate. Rates of recurrent dislocation and reoperation were 2.9% and 7%, respectively. Mild loss of external rotation is common. Reoperation rates were lower following all-arthroscopic techniques. There was a greater loss of postoperative external rotation with all arthroscopic surgery. PMID- 23352474 TI - Isolated contralateral glossopharyngeal and vagal nerve palsy after arthroscopic rotator cuff surgery: a case report. PMID- 23352475 TI - Regarding "Long-term follow-up of cases of rotator cuff tear treated conservatively". PMID- 23352476 TI - Regarding "The superior capsule of the shoulder joint complements the insertion of the rotator cuff". PMID- 23352477 TI - Reply to: "The superior capsule of the shoulder joint complements the insertion of the rotator cuff". PMID- 23352478 TI - Regarding "A systematic review and comprehensive classification of pectoralis major tears". PMID- 23352479 TI - Lesser occipital nerve neurotmesis following shoulder arthroscopy. PMID- 23352480 TI - Partial distal humeral resurfacing of a trochlear defect after elbow fracture dislocation. PMID- 23352481 TI - Design, synthesis and structure-activity relationship of novel tricyclic benzimidazolone derivatives as potent 18 kDa translocator protein (TSPO) ligands. AB - The 18 kDa translocator protein (TSPO) was identified as a discrete receptor for diazepam (1). Since TSPO in the central nervous system (CNS) is believed to regulate neurosteroids biosynthesis, selective TSPO ligands are expected to be useful in the treatment of psychiatric disorders. We synthesized three novel tricyclic benzimidazolone derivatives, and selected the dihydroimidazoquinolinone derivative 27 as a lead TSPO ligand. Study of the structure-activity relationship (SAR) of dihydroimidazoquinolinone derivatives revealed compounds with potent affinity for TSPO (subnanomolar K(i) values), but poor metabolic stability. The optimization of these compounds led to compound 48 with potent affinity for TSPO and good in vitro PK profile. PMID- 23352482 TI - Synthesis of 5,7-disubstituted-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amines as microtubule inhibitors. AB - Compounds 1-4 were previously reported as potent antimitotic and antitumor agents with Pgp modulatory effects. Compounds 5-18 have been synthesized in an attempt to optimize the various activities of 1-4. Compounds 5-10 explored the influence of methoxy substitutions on the 7-benzyl moiety in 1, while 11-18 investigated the influence of incorporation of a sulfur linker at C5 compared to 1-3. Compounds 5-10 demonstrated potent single-digit micromolar tumor cell cytotoxicity, Pgp modulation and microtubule inhibition. Compound 7 of this series was the most potent and showed GI(50) values in the nanomolar range against several human tumor cell lines in the standard NCI preclinical in vitro screen. Antitumor activity and Pgp modulatory effects were found to decrease for the 5-phenylthio compounds 11-14 compared to their 5-phenylethyl analogs 2-4 and the standard compound Taxol. Incorporation of methoxy substitutions on the 7 benzyl moiety improved antitumor activity for the 5-phenylthio compounds 16 and 17. Compounds 16 and 17 demonstrated single to two-digit micromolar inhibition of tumor cells. PMID- 23352483 TI - New PAH derivatives functionalized by cyclic nitrone framework: synthetic design, anti-proliferative activity and interaction with DNA. AB - Novel approach to functionalized polycyclic aromatic hydrocarbons (PAHs) is presented. Incorporation of cyclic nitrone framework into the structure of PAHs was studied with respect to their anti-proliferative activities and interaction with double stranded DNA. Theoretical docking studies and UV titration methods were used for preliminary evaluation of binding of new PAH derivatives to DNA structure. PMID- 23352484 TI - Comparative performance of commercial and laboratory enzymatic complexes from submerged or solid-state fermentation in lignocellulosic biomass hydrolysis. AB - The aim of this study was to compare the hydrolysis performances of four lignocellulolytic complexes from commercial or laboratory origin and produced either by solid-state fermentation or by submerged fermentation. To evaluate their potential, saccharification tests were performed on cellulose, as model substrate, and wheat bran, as lignocellulosic substrate, using either the same filter paper unit or the same amount of protein to introduce these enzymatic complexes. A great difference was observed for the laboratory enzymatic complex produced by solid-state fermentation, which has shown a greater efficiency of cellobiohydrolase on cellulose and better conversion capacity on wheat bran, probably due to the presence of side activities. This comparison has proved that solid-state fermentation could be a promising technology to overcome the biomass recalcitrance and lower the cost of conversion step. PMID- 23352485 TI - Don't forget how severe varicella can be--complications of varicella in children in a defined Polish population. AB - BACKGROUND: This study aimed to analyze the causes of hospitalization in children with varicella, based on a defined Polish population. METHODS: This was a retrospective analysis of causes of hospitalization in children under 18 years of age with varicella, treated on the Infectious Diseases Ward of the Children's Hospital in Poznan, Poland from January 2007 to June 2012. The ward serves almost the entire child population of the Greater Poland region (10% of the Polish population - almost 600,000 children). The analysis was based on hospital records. Patients were identified using the International Classification of Diseases Tenth Revision (ICD-10) codes. The case definition consisted of physical evidence of varicella. RESULTS: A total of 224 children were hospitalized for varicella complications. The median age of admitted patients was 37.5 months (range 6 days to 17 years). Rates of hospitalization decreased with age. The highest rates were among children during their first year. Ninety-two percent of children were healthy prior to hospitalization (no chronic diseases). The most common complications were respiratory tract infections (26%), followed by skin infections (21%) and neurological symptoms (18%). Twenty-five patients (11%) had more than one complication. The most common coexisting conditions were dehydration and otitis media. CONCLUSIONS: The results presented here serve to remind us that varicella may to lead to severe complications in unvaccinated children and adolescents, and demonstrate the benefits of varicella vaccination. Most children hospitalized with varicella were immunologically healthy. Meningitis was more common in older children (>6 years of age). Streptococcus pyogenes was the most commonly identified bacterial pathogen. PMID- 23352487 TI - Routine preprocedural transesophageal echocardiography might not be necessary for stroke prevention evaluation in AF patients on anticoagulation therapy. AB - BACKGROUND: Preprocedural transesophageal echocardiography (TEE) is used to reduce the stroke during atrial fibrillation (AF) ablation. This study evaluated whether routine preprocedural TEE in addition to multidetector computed tomography (MDCT) is necessary to prevent periprocedural stroke in AF ablation. METHODS: Each patient underwent MDCT and TEE (group 1, n=247) or MDCT alone (group 2, n=103) for the initial evaluation before AF ablation. In group 2, TEE was performed only in patients who had left atrial (LA) thrombus or blood stasis in MDCT. RESULTS: There was no difference in sex, CHADS2 score, or LA dimension between the two groups. In group 1, a thrombus was detected in 12 (5%) and 6 (2%) patients by the MDCT and TEE, respectively. All (100%) patients, who were revealed to have thrombus in TEE, also had a thrombus in MDCT. In group 2, 3 (3%) patients exhibited LA thrombus in MDCT, among whom thrombus was observed in only one patient (1%) in TEE. AF ablation was not performed in patients with thrombus. While one patient had a periprocedural stroke in group 1, no patient had in group 2 (P=0.52). CONCLUSION: The overall periprocedural stroke rate was low (0.3%) in AF patients on anticoagulation therapy. The preprocedural MDCT detected all patients with the LA thrombus. In AF patients with low CHADS2 score, optimal anticoagulation and relatively preserved left ventricular ejection fraction, routine preprocedural TEE in addition to the MDCT might not be necessary to decrease the periprocedural stroke rate. PMID- 23352486 TI - Primary pulmonary sarcomatoid carcinomas. AB - OBJECTIVE: To describe the characteristics and the result of surgical treatment in a series of patients with primary pulmonary sarcomatoid carcinoma (PSC). METHODOLOGY: A descriptive study of 11 patients with primary PSC who were treated by the Thoracic Surgery Department at the Hospital Universitario 12 de Octubre in Madrid (Spain) between 2005 and 2009. We analyzed age, gender, histologic type, pathological stage, type of surgery and survival (in months). RESULTS: Ten patients were male and 11 were smokers; mean age of was 55. The pathologic stages were: 4 stage IIA, 3 stage IIB, 2 stage IB and 2 stage IA. The most frequent histologic type was pleomorphic carcinoma, which was found in 5 cases. Complete resection was performed in 10 cases, and 7 received adjuvant therapy. Seven are disease-free after a mean follow-up period of 49 months. CONCLUSIONS: Complete surgery in the initial stages of primary PSC can improve survival. PMID- 23352488 TI - Rapid bedside identification of high-risk population in heart failure with reduced ejection fraction by acoustic cardiography. AB - BACKGROUND: Low left ventricular ejection fraction (LVEF) and the presence of restrictive LV filling pattern are poor prognosticators in heart failure patients with reduced EF (HFREF). We sought to investigate whether acoustic cardiography can identify these high-risk HFREF subgroups. METHODS: A total of 127 HFREF patients (EF<50%) were enrolled into our study. All patients underwent acoustic cardiographic and echocardiographic examinations. Acoustic cardiographic parameters included S3 score (probability that the third heart sound exists), electromechanical activation time (EMAT, interval from Q wave to the first heart sound; %EMAT is the proportion of cardiac cycle that EMAT occupies), and systolic dysfunction index (SDI, a derived variable from the combination of %EMAT, S3 score, QRS duration and QR interval). Receiver operating characteristic curves were used to determine diagnostic utility of acoustic cardiography. RESULTS: SDI discriminated (area under curve [AUC], 0.79; 95% confidence interval [CI], 0.71 0.87) patients with severely impaired EF (EF <= 35%) from those with moderately impaired EF (35% 5 that yielded 87% sensitivity and 60% specificity. An S3 score>4 identified patients with restrictive LV filling pattern with 0.76 AUC (95% CI, 0.67-0.84), 81% sensitivity and 55% specificity. CONCLUSIONS: SDI and S3 score obtained by acoustic cardiography identified HFREF patients with severely impaired systolic and diastolic function, respectively. This simple, bedside technology may be used as a screening tool to identify the sickest HFREF patients for more intensive therapy. PMID- 23352489 TI - Roles of miR-1-1 and miR-181c in ventricular septal defects. AB - BACKGROUND: MicroRNAs (miRNAs) are endogenous noncoding RNAs of approximately 22 nucleotides in length that mediate post-transcriptional gene silencing by annealing to sequences in the 3'-untranslated region of target mRNAs. METHODS: In this study, we analyzed 25 candidate miRNAs selected based on microarray data for cardiac tissue from individuals with congenital heart defects (CHDs) and from healthy control tissue. RESULTS: This study identified specific changes in the miR-1-1 and miR-181c levels in human cardiac samples from individuals with ventricular septal defects (VSDs) relative to the levels in healthy control tissue. Increased levels of GJA1 and SOX9 were associated with the decreased expression of miR-1-1 in VSD patients, and increased miR-181c expression was correlated with downregulated BMPR2 levels. In addition, the results revealed that miR-1-1 and miR-181c directly regulate the expression of these predicted targets. CONCLUSIONS: miR-1-1 and miR-181c are associated with the pathogenesis of VSDs. PMID- 23352490 TI - Effects of nitrate dosing on methanogenic activity in a sulfide-producing sewer biofilm reactor. AB - Nitrate dosing is widely used by water industry to control hydrogen sulfide production in sewers. This study assessed the impact of nitrate addition on methane generation by sewer biofilms using a lab-scale rising main sewer reactor. It was found that methanogenesis could coexist with denitrification and sulfate reduction in sewers dosed with nitrate. However, methane production was substantially reduced by nitrate addition. Methanogenic rates remained below 10% of its baseline level, with 30 mg-N/L of nitrate dosing for each pump event. By calculating the substrate penetration depth in biofilms, it is suggested that methanogenesis may persist in deeper biofilms due to the limited penetration of nitrate and sulfate, and better penetration of soluble organic substrates. The control of methane and sulfide production was found to be determined by the nitrate penetration depth in biofilms and nitrate presence time in sewers, respectively. The presence of nitrous oxide after nitrate addition was transient, with a negligible discharge of nitrous oxide from the sewer reactor due to its further reduction by denitrifiers after nitrate depletion. PMID- 23352491 TI - The first case of pulmonary disease caused by Mycobacterium septicum in China. AB - Mycobacterium septicum is a rapidly growing Mycobacterium (RGM) that rarely causes pulmonary disease globally. We describe a case of M. septicum pulmonary disease, which to our knowledge is the first reported in China. The isolates were identified as M. septicum and were susceptible in vitro to amikacin, ciprofloxacin, ofloxacin, levofloxacin, kanamycin, and sulfamethoxazole. PMID- 23352492 TI - Genetic analysis of Bordetella pertussis in Ontario, Canada reveals one predominant clone. AB - OBJECTIVE: To characterize Bordetella pertussis isolates in Ontario, Canada in order to understand the clonal diversity of strains present in this province. METHODS: A total of 521 isolates from the period 1998-2006 were analyzed by serotyping, pulsed-field gel electrophoresis (PFGE), and DNA sequencing of their virulence factors of pertactin, fimbriae 3, pertussis toxin subunit 1, and pertussis toxin gene promoter. Characteristics of the Ontario isolates were compared to those described for isolates from Europe and Australia. RESULTS: A single predominant clone was identified in Ontario, Canada, represented by 83.5% of the 521 isolates analyzed. This clone was characterized by the genotype fim3B, prn2, ptxS1A, and ptxP3 (sequence type (ST)-1), and 72.9% of this clone displayed three closely related PFGE profiles of BpSR11, BpSR5, and BpSR12. Pertussis isolates in Europe with these PFGE profiles and virulence factor genotype are reported as common. The Australian epidemic clone was previously reported to have the genotype prn2 and ptxP3. CONCLUSION: The finding of one predominant B. pertussis clone in Ontario, Canada, with characteristics identical to strains involved in epidemics in Europe and Australia, suggests a potential link of this strain to the resurgence of pertussis in this province. PMID- 23352493 TI - Thymosin alpha-1-transformed Bifidobacterium promotes T cell proliferation and maturation in mice by oral administration. AB - Thymosin alpha-1 (Talpha1) has been used as an immune potentiator for treatment of immune deficiency diseases by injection administration. However, injection is inconvenient and may cause many side effects. In order to improve the administration convenience of Talpha1, a human Talpha1 gene transformed Bifidobacterium longum (BL-Talpha1) was prepared and its effects on mice immunity by oral administration were investigated. The Balb/c mice were treated with BL Talpha1, which was pre-induced with 0.2% l-arabinose, every other day for 2 weeks. The B. longum transformed with empty vector (BL-0) was used as the negative control, and normal saline (NS, 0.9% saline) was used as the blank control. The results shown that (1) the CD3(+)CD4(+) and CD3(+)CD8(+) T-cells in blood, spleen and thymus, and the CD4(+)CD8(+) cells in thymus and spleen of BL Talpha1 group were all significantly increased than that of negative control BL-0 group respectively; (2) the interferon-gamma (IFN-gamma) and interleukin-12 (IL 12) in serum of BL-Talpha1 group were significantly increased. No significant differences were found in the levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-4 (IL-4) between BL-Talpha1 group and BL-0 group; (3) thymic hyperplasia and lymphadenectasis were observed in BL-Talpha1 group after three month treatment. In conclusion, the Talpha1-transformed B. longum promotes thymus and lymph nodes growth, stimulates T cell proliferation and maturation, and enhances cellular immunity through Th1 pathway by oral administration. PMID- 23352494 TI - The quality of parent/child relationships in adolescence is associated with poor adult psychosocial adjustment. AB - This study used data gathered over the course of a New Zealand longitudinal study (N = 924) to examine the relationships between measures of parental bonding and attachment in adolescence (age 15-16) and later personal adjustment (major depression; anxiety disorder; suicidal behaviour; illicit drug abuse/dependence; crime) assessed up to the age of 30. Key findings included: 1) There were significant (p < 0.05) and pervasive associations between all measures of attachment and bonding and later outcomes. 2) Structural equation modelling showed that all measures of bonding and attachment loaded on a common factor reflecting the quality of parent/child relationships in adolescence. 3) After adjustment for covariates there were modest relationships (beta = 0.16-0.17) between the quality of parent/child relationships in adolescence factor and later adjustment. The study findings suggest that the quality of parent/child relationships in adolescence is modestly related to later psychosocial functioning in adulthood. PMID- 23352495 TI - Dysglycemia, brain volume and vascular lesions on MRI in a memory clinic population. AB - OBJECTIVE: It is unclear, if the association between abnormalities in glucose metabolism (dysglycemia) and impaired cognitive functioning is primarily driven by degenerative or vascular brain damage. We therefore examined the relation between dysglycemia and brain volume and vascular lesions on MRI in a memory clinic population. METHODS: The relations between markers of glycemia (HbA1c and fasting glucose levels) and normalized brain volume, medial temporal lobe atrophy and vascular lesions (white matter hyperintensities, lacunes) were assessed in 274 consecutive patients attending a memory clinic, using linear regression analyses. RESULTS: Clinical diagnoses were subjective complaints (n=117), mild cognitive impairment (n=62), Alzheimer's disease (n=61) and other type of dementia (n=34). Twenty patients had a history of diabetes. Across the whole study population there was no relation between HbA1c or fasting glucose and the brain MRI measurements, after adjustments for age, sex and diagnostic group. Secondary analyses after stratification by diabetes status, diagnosis and median age (67 years) did not change the results. CONCLUSION: In this memory clinic population, dysglycemia was not associated with either brain volume or vascular lesions. Apparently, dysglycemia is not associated with a specific class of brain pathology in patients with cognitive complaints. PMID- 23352496 TI - Potential of incretin-based therapies for non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is becoming an epidemic, paralleling the increased prevalence of obesity and diabetes, which are risk factors. In this review, we present the current pre-clinical evidence showing that GLP-1 analogues and DPP4 inhibitors can improve hepatic steatosis. Although some of the effects could be due to overall improvement in metabolic parameters, there are data to support improvements independent of weight loss, as well as direct effects on the hepatocyte in vitro. Multiple hepatocyte signal transduction pathways appear to be activated by GLP-1 and its analogues, with both AMP-activated protein kinase and Akt proposed to be key players in improving hepatic steatosis. However, it is controversial as to whether the pancreatic-type GLP-1 receptor is present or responsible for conferring the GLP-1 signal in the hepatocyte. In total, the data support the need for more rigorous prospective clinical trials to further investigate the potential of incretin therapies for treatment of NAFLD. PMID- 23352497 TI - The role of high-resolution endoscopy and narrow-band imaging in the evaluation of upper GI neoplasia in familial adenomatous polyposis. AB - BACKGROUND: The Spigelman classification stratifies cancer risk in familial adenomatous polyposis (FAP) patients with duodenal adenomatosis. High-resolution endoscopy (HRE) and narrow-band imaging (NBI) may identify lesions at high risk. OBJECTIVE: To compare HRE and NBI for the detection of duodenal and gastric polyps and to characterize duodenal adenomas harboring advanced histology with HRE and NBI. DESIGN: Prospective, nonrandomized, comparative study. Retrospective image evaluation study. SETTING: Tertiary-care center. PATIENTS: Thirty-seven FAP patients undergoing surveillance upper endoscopies. INTERVENTION: HRE endoscopy was followed by NBI. The number of gastric polyps and Spigelman staging were compared. Duodenal polyp images were systematically reviewed in a learning and validation phase. MAIN OUTCOME MEASUREMENTS: Number of gastric and duodenal polyps detected by HRE and NBI and prevalence of specific endoscopic features in duodenal adenomas with advanced histology. RESULTS: NBI did not identify additional gastric polyps but detected more duodenal adenomas in 16 examinations, resulting in upgrades of the Spigelman stage in 2 cases (4.4%). Pictures of 168 duodenal adenomas (44% advanced histology) were assessed. In the learning phase, 3 endoscopic features were associated with advanced histology: white color, enlarged villi, and size >=1 cm. Only size >=1 cm was confirmed in the validation phase (odds ratio 3.0; 95% confidence interval, 1.2-7.4). LIMITATIONS: Nonrandomized study, scant number of high-grade dysplasia adenomas. CONCLUSION: Inspection with NBI did not lead to a clinically relevant upgrade in the Spigelman classification and did not improve the detection of gastric polyps in comparison with HRE. The only endoscopic feature that predicted advanced histology of a duodenal adenoma was size >=1 cm. PMID- 23352498 TI - Novel technique for submucosal tunneling and endoscopic resection of submucosal tumors (with video). PMID- 23352499 TI - Radiotherapy capacity in European countries: an analysis of the Directory of Radiotherapy Centres (DIRAC) database. AB - Radiotherapy is used for cure or palliation in around half of patients with cancer. We analysed data on radiotherapy equipment in 33 European countries registered in the Directory of Radiotherapy Centres (DIRAC) database, managed by the International Atomic Energy Agency. As of July, 2012, Europe had 1286 active radiotherapy centres. The average number of teletherapy machines per radiotherapy centre ranged from 1.2 to 7.0 in different countries. Nordic countries, the UK, the Netherlands, and Slovenia all have large centres with four to ten teletherapy machines. Most western and southern European countries have several small centres with one or two machines, with few larger centres. The fragmentation in radiotherapy services that prevails in many European countries might affect the economic burden of radiotherapy and its quality. Eastern and southeastern European countries need to expand and modernise their radiotherapy equipment. PMID- 23352500 TI - Predictability of corneal flap thickness in laser in situ keratomileusis using a 200 kHz femtosecond laser. AB - PURPOSE: To compare the intended versus the resultant thickness of laser in situ keratomileusis (LASIK) flaps created with a new femtosecond laser and to report the 3-month postoperative refractive outcomes. SETTING: Wellington Eye Clinic, Dublin, Ireland. DESIGN: Retrospective consecutive case series. METHODS: A consecutive series of eyes having LASIK flaps created using a Wavelight FS200 femtosecond laser were included in this analysis. Eyes with preoperative spherical equivalent (SE) myopic refractive errors up to -12.00 diopters (D), hyperopic refractive errors up to +5.50 D, and astigmatism up to 6.00 D received primary LASIK. Outcomes included postoperative flap thickness and 3-month postoperative refraction. RESULTS: Outcomes in 431 eyes of 258 patients having LASIK with femtosecond flap creation were assessed. With an intended flap thickness of 120 MUm, the mean post-LASIK flap thickness was 120.23 MUm +/- 13.94 (SD). In 349 of 813 eyes, EX500 optical pachymetry measurements were compared with Scheimpflug pachymetry readings. The mean corneal thickness was 553.52 +/- 29.81 MUm with optical pachymetry and 553.39 +/- 29.12 MUm with the Pentacam rotating Scheimpflug camera. In 162 eyes, the flap thickness was measured with optical coherence tomography; the mean was 121.94 +/- 10.52 MUm. Achieved flap dimensions were as intended. CONCLUSIONS: This study provides evidence of the predictability and lower variability of LASIK flaps created using the femtosecond laser. Consecutive patients having LASIK had good, predictable, and stable outcomes at the 3-month mark. PMID- 23352501 TI - Liver X receptor alpha mediated genistein induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1) in Hep G2 cells. AB - Cytosolic sulfotransferases are one of the major families of phase II drug metabolizing enzymes. Sulfotransferase-catalyzed sulfonation regulates hormone activities, metabolizes drugs, detoxifies xenobiotics, and bioactivates carcinogens. Human dehydroepiandrosterone sulfotransferase (hSULT2A1) plays important biological roles by sulfating endogenous hydroxysteroids and exogenous xenobiotics. Genistein, mainly existing in soy food products, is a naturally occurring phytoestrogen with both chemopreventive and chemotherapeutic potential. Our previous studies have shown that genistein significantly induces hSULT2A1 in Hep G2 and Caco-2 cells. In this study, we investigated the roles of liver X receptor (LXRalpha) in the genistein induction of hSULT2A1. LXRs have been shown to induce expression of mouse Sult2a9 and hSULT2A1 gene. Our results demonstrate that LXRalpha mediates the genistein induction of hSULT2A1, supported by Western blot analysis results, hSULT2A1 promoter driven luciferase reporter gene assay results, and mRNA interference results. Chromatin immunoprecipitation (ChIP) assay results demonstrate that genistein increase the recruitment of hLXRalpha binding to the hSULT2A1 promoter. These results suggest that hLXRalpha plays an important role in the hSULT2A1 gene regulation. The biological functions of phytoestrogens may partially relate to their induction activity toward hydroxysteroid SULT. PMID- 23352503 TI - Inhibitory effects of epi-sesamin on HMGB1-induced vascular barrier disruptive responses in vitro and in vivo. AB - Nuclear DNA-binding protein high mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions, such as sepsis and septic shock. Epi-sesamin (ESM), an important component of Asarum sieboldii roots, is known to exhibit anti-allergic, anti-nociceptive, and anti-fungal effects. However, little is known of its effects on HMGB1-mediated inflammatory responses. Here, we investigated this issue by monitoring the effects of ESM on lipopolysaccharide (LPS) or cecal ligation and the puncture (CLP)-mediated release of HMGB1, and on modulation of HMGB1-mediated inflammatory responses. ESM potently inhibited HMGB1 release, down-regulated HMGB1-dependent inflammatory responses in human endothelial cells, and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ESM resulted in reduced CLP-induced release of HMGB1 and sepsis-related mortality. Of particular interest, ESM inhibition of HMGB1-mediated anti inflammatory activity was more potent than that by sesamin (SM), likely due to differences between their three-dimensional structures. These results indicate that ESM could be a candidate therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway. PMID- 23352502 TI - Global protein phosphorylation dynamics during deoxynivalenol-induced ribotoxic stress response in the macrophage. AB - Deoxynivalenol (DON), a trichothecene mycotoxin produced by Fusarium that commonly contaminates food, is capable of activating mononuclear phagocytes of the innate immune system via a process termed the ribotoxic stress response (RSR). To encapture global signaling events mediating RSR, we quantified the early temporal (<=30min) phosphoproteome changes that occurred in RAW 264.7 murine macrophage during exposure to a toxicologically relevant concentration of DON (250ng/mL). Large-scale phosphoproteomic analysis employing stable isotope labeling of amino acids in cell culture (SILAC) in conjunction with titanium dioxide chromatography revealed that DON significantly upregulated or downregulated phosphorylation of 188 proteins at both known and yet-to-be functionally characterized phosphosites. DON-induced RSR is extremely complex and goes far beyond its prior known capacity to inhibit translation and activate MAPKs. Transcriptional regulation was the main target during early DON-induced RSR, covering over 20% of the altered phosphoproteins as indicated by Gene Ontology annotation and including transcription factors/cofactors and epigenetic modulators. Other biological processes impacted included cell cycle, RNA processing, translation, ribosome biogenesis, monocyte differentiation and cytoskeleton organization. Some of these processes could be mediated by signaling networks involving MAPK-, NFkappaB-, AKT- and AMPK-linked pathways. Fuzzy c-means clustering revealed that DON-regulated phosphosites could be discretely classified with regard to the kinetics of phosphorylation/dephosphorylation. The cellular response networks identified provide a template for further exploration of the mechanisms of trichothecenemycotoxins and other ribotoxins, and ultimately, could contribute to improved mechanism-based human health risk assessment. PMID- 23352504 TI - Inhibition of AKT enhances mitotic cell apoptosis induced by arsenic trioxide. AB - Accumulated evidence has revealed a tight link between arsenic trioxide (ATO) induced apoptosis and mitotic arrest in cancer cells. AKT, a serine/threonine kinase frequently over-activated in diverse tumors, plays critical roles in stimulating cell cycle progression, abrogating cell cycle checkpoints, suppressing apoptosis, and regulating mitotic spindle assembly. Inhibition of AKT may therefore enhance ATO cytotoxicity and thus its clinical utility. We show that AKT was activated by ATO in HeLa-S3 cells. Inhibition of AKT by inhibitors of the phosphatidyl inositol 3-kinase/AKT pathway significantly enhanced cell sensitivity to ATO by elevating mitotic cell apoptosis. Ectopic expression of the constitutively active AKT1 had no effect on ATO-induced spindle abnormalities but reduced kinetochore localization of BUBR1 and MAD2 and accelerated mitosis exit, prevented mitotic cell apoptosis, and enhanced the formation of micro- or multi nuclei in ATO-treated cells. These results indicate that AKT1 activation may prevent apoptosis of ATO-arrested mitotic cells by attenuating the function of the spindle checkpoint and therefore allowing the formation of micro- or multi nuclei in surviving daughter cells. In addition, AKT1 activation upregulated the expression of aurora kinase B (AURKB) and survivin, and depletion of AURKB or survivin reversed the resistance of AKT1-activated cells to ATO-induced apoptosis. Thus, AKT1 activation suppresses ATO-induced mitotic cell apoptosis, despite the presence of numerous spindle abnormalities, probably by upregulating AURKB and survivin and attenuating spindle checkpoint function. Inhibition of AKT therefore effectively sensitizes cancer cells to ATO by enhancing mitotic cell apoptosis. PMID- 23352505 TI - A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity. AB - Drug-induced liver injury (DILI) is the major cause for liver failure and post marketing drug withdrawals. Due to species-specific differences in hepatocellular function, animal experiments to assess potential liabilities of drug candidates can predict hepatotoxicity in humans only to a certain extent. In addition to animal experimentation, primary hepatocytes from rat or human are widely used for pre-clinical safety assessment. However, as many toxic responses in vivo are mediated by a complex interplay among different cell types and often require chronic drug exposures, the predictive performance of hepatocytes is very limited. Here, we established and characterized human and rat in vitro three dimensional (3D) liver co-culture systems containing primary parenchymal and non parenchymal hepatic cells. Our data demonstrate that cells cultured on a 3D scaffold have a preserved composition of hepatocytes, stellate, Kupffer and endothelial cells and maintain liver function for up to 3months, as measured by the production of albumin, fibrinogen, transferrin and urea. Additionally, 3D liver co-cultures maintain cytochrome P450 inducibility, form bile canaliculi like structures and respond to inflammatory stimuli. Upon incubation with selected hepatotoxicants including drugs which have been shown to induce idiosyncratic toxicity, we demonstrated that this model better detected in vivo drug-induced toxicity, including species-specific drug effects, when compared to monolayer hepatocyte cultures. In conclusion, our results underline the importance of more complex and long lasting in vitro cell culture models that contain all liver cell types and allow repeated drug-treatments for detection of in vivo-relevant adverse drug effects. PMID- 23352506 TI - Protective effect of sanguinarine against acetic acid-induced ulcerative colitis in mice. AB - The quaternary ammonium salt, sanguinarine (SANG), is of great practical and research interest because of its pronounced, widespread physiological effects, which promote anti-microbial and anti-inflammatory responses in experimental animals. Although SANG is originally shown to possess anti-inflammatory properties and it has been used to treat various inflammatory diseases, its effects on ulcerative colitis have not been previously explored. The aim of the present study is to evaluate the effect of SANG on acetic acid-induced ulcerative colitis in mice. Experimental animals received SANG (1, 5 and 10 mg/kg, p.o.) and sulfasalazine (500 mg/kg, p.o.) for seven consecutive days after induction of colitis by intra-rectal acetic acid (5% v/v) administration. The colonic mucosal injury was assessed by clinical, macroscopic, biochemical and histopathological examinations. SANG treatment significantly decreased mortality rate, body weight loss, disease activity index (DAI), wet colon weight, macroscopic and histological score when compared to acetic acid-induced controls. In addition, administration of SANG effectively inhibited p65 NF-kappaB protein expression and MPO activity accumulation. The levels of TNF-alpha and IL-6 in the serum and colon tissue of mice with experimental colitis were decreased by SANG in a concentration-dependent manner in response to p65 NF-kappaB. The possible mechanism of protection on experimental colitis was that SANG could be through attenuating early steps of inflammation as well as decreasing the expression of NF-kappaB and subsequent pro-inflammatory cytokines production. PMID- 23352507 TI - 5-AIQ inhibits H2O2-induced apoptosis through reactive oxygen species scavenging and Akt/GSK-3beta signaling pathway in H9c2 cardiomyocytes. AB - Poly(adenosine 5'-diphosphate ribose) polymerase (PARP) is a nuclear enzyme activated by DNA strand breaks and plays an important role in the tissue injury associated with ischemia and reperfusion. The aim of the present study was to investigate the protective effect of 5-aminoisoquinolinone (5-AIQ), a PARP inhibitor, against oxidative stress-induced apoptosis in H9c2 cardiomyocytes. 5 AIQ pretreatment significantly protected against H2O2-induced cell death, as determined by the XTT assay, cell counting, terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay, and Western blot analysis of apoptosis related proteins such as caspase-3, Bax, and Bcl-2. Upregulation of antioxidant enzymes such as manganese superoxide dismutase and catalase accompanied the protective effect of 5-AIQ on H2O2-induced cell death. Our data also showed that 5-AIQ pretreatment protected H9c2 cells from H2O2-induced apoptosis by triggering activation of Akt and glycogen synthase kinase-3beta (GSK-3beta), and that the protective effect of 5-AIQ was diminished by the PI3K inhibitor LY294002 at a concentration that effectively abolished 5-AIQ-induced Akt and GSK-3beta activation. In addition, inhibiting the Akt/GSK-3beta pathway by LY294002 significantly attenuated the 5-AIQ-mediated decrease in cleaved caspase-3 and Bax activation and H9c2 cell apoptosis induction. Taken together, these results demonstrate that 5-AIQ prevents H2O2-induced apoptosis in H9c2 cells by reducing intracellular reactive oxygen species production, regulating apoptosis-related proteins, and activating the Akt/GSK-3beta pathway. PMID- 23352508 TI - Autophagy regulates chlorpyrifos-induced apoptosis in SH-SY5Y cells. AB - Recent studies have shown that up-regulation of autophagy may be a tractable therapeutic intervention for clearing disease-causing proteins, including alpha synuclein, ubiquitin, and other misfolded or aggregated proteins in pesticide induced neurodegeneration. In a previous study, we reported that chlorpyrifos (CPF)-induced mitochondria-dependent apoptosis is mediated through reactive oxygen species in SH-SY5Y cells. In this study, we explored a novel pharmacotherapeutic approach to prevent CPF neurotoxicity involving the regulation of autophagy. We investigated the modulation of CPF-induced apoptosis according to autophagy regulation. We found that CPF induced apoptosis in SH-SY5Y cells, as demonstrated by the activation of caspase-3 and nuclear condensation. In addition, we observed that cells treated with CPF underwent autophagic cell death by monitoring the expression of LC3-II and p62. Pretreatment with the autophagy inducer rapamycin significantly enhanced the cell viability of CPF exposed cells, and the enhancement of cell viability was partially due to alleviation of CPF-induced apoptosis via a decrease in levels of cleaved caspase 3. Specifically, rapamycin pretreatment decreased Bax and increased Bcl-2 expression in mitochondria. In addition, rapamycin significantly decreased cytochrome c release in from mitochondria into the cytosol. However, pretreatment of cells with the autophagy inhibitor, 3-methyladenine (3MA), remarkably increased CPF toxicity in these cells; this with correlated with increased expression of Bax and decreased expression of Bcl-2 in mitochondria. Our results suggest that CPF-induced cytotoxicity is modified by autophagy regulation and that rapamycin protects against CPF-induced apoptosis by enhancing autophagy. Pharmacologic induction of autophagy by rapamycin may be a useful treatment strategy in neurodegenerative disorders. PMID- 23352509 TI - Pharmacological properties and predicted binding mode of arylmethylene quinuclidine-like derivatives at the alpha3beta4 nicotinic acetylcholine receptor (nAChR). AB - We have carried out a pharmacological evaluation of arylmethylene quinuclidine derivatives interactions with human alpha3beta4 nAChRs subtype, using cell-based receptor binding, calcium-influx, electrophysiological patch-clamp assays and molecular modeling techniques. We have found that the compounds bind competitively to the alpha3beta4 receptor with micromolar affinities and some of the compounds behave as non-competitive antagonists (compounds 1, 2 and 3), displaying submicromolar IC(50) values. These evidences suggest a mixed mode of action for these compounds, having interactions at the orthosteric site and more pronounced interactions at an allosteric site to block agonist effects. One of the compounds, 1-benzyl-3-(diphenylmethylene)-1-azoniabicyclo[2.2.2]octane chloride (compound 3), exhibited poorly reversible use-dependent block of alpha3beta4 channels. We also found that removal of a phenyl group from compound 1 confers a partial agonism to the derived analog (compound 6). Introducing a hydrogen-bond acceptor into the 3-benzylidene quinuclidine derivative (compound 7) increases agonism potency at the alpha3beta4 receptor subtype. Docking into the orthosteric binding site of a alpha3beta4 protein structure derived by comparative modeling accurately predicted the experimentally-observed trend in binding affinity. Results supported the notion that binding requires a hydrogen bond formation between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the conserved Trp-149. PMID- 23352511 TI - New imidazo[1,2-a]pyridines carrying active pharmacophores: synthesis and anticonvulsant studies. AB - Five new series of imidazo[1,2-a]pyridines carrying biologically active pyrazoline (4a-e), cyanopyridone (5a, b), cyanopyridine (6a-f), 2-aminopyrimidine (7a-f) and pyrimidine-2-thione (8a-d) systems were designed and synthesized as prominent anticonvulsant agents. The target compounds were screened for their in vivo anticonvulsant activity following maximal electroshock (MES) and subcutaneous pentylene tetrazole (scPTZ) methods at a small test dose of 10 mg/kg. Further, Rotarod toxicity method was used to study the toxicity profile of selected compounds. Compounds 4b, 5a, 5b, 6a, 7e and 8d possessing 4-fluorophenyl substituent at 2nd position of imidazo[1,2-a]pyridine ring displayed potent anticonvulsant activity without displaying any toxicity. Enhanced activity profile was observed for new compounds in PTZ method over MES method. PMID- 23352510 TI - Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): kinase profiling guided optimization of a 1,2,3-benzotriazole lead. AB - A series of amino-pyrimidines was developed based upon an initial kinase cross screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation. PMID- 23352512 TI - Comparative properties of Abeta1-42, Abeta11-42, and [Pyr11]Abeta11-42 generated from O-acyl isopeptides. AB - The use of water-soluble O-acyl isopeptides enabled us to investigate the biochemical properties of Abeta11-42 species, by preparing highly concentrated stock solutions after a pretreatment. Abeta11-42 and [Pyr(11)]Abeta11-42 showed comparable aggregation capability and cytotoxicity, suggesting that the pyroglutamate modification at Glu(11) does not have a crucial role in these events. However, given that Abeta11-42 is converted to [Pyr(11)]Abeta11-42 by a glutamyl cyclase in vivo, the potential aggregative and cytotoxic nature of [Pyr(11)]Abeta11-42 that was observed in the present study provides valuable insights into the pathological functions of pyroglutamate-modified Abeta species in Alzheimer's disease. PMID- 23352513 TI - Side effects of corticosteroid injections: what's new? AB - The risk of sepsis with a hip or knee implant does not seem to be increased by prior joint injections, as long as the injection and surgery are separated by at least two months. Calcifications have been reported after intradiscal injection in the coccygeal region for coccydynia. Complete rest for 24 hours after injection of triamcinolone hexacetonide into the knee had no effect on systemic diffusion of the product. Patients infected by HIV who are treated with ritonavir are at much greater risk for Cushing syndrome after epidural injection. Problems with menstruation after corticosteroid injection seem to be related to a transient decrease in estradiol levels, without alterations in FSH and LH levels. The risk of central serous chorioretinopathy and acute necrosis of the retina after injection is not known, even by ophthalmologists. Transient dysphonia occurs in 12% of patients receiving corticosteroid injections. The impressive Tachon's syndrome seems to be the venous counterpart to Nicolau's syndrome for arteries. Injections into C1-C2 should be abandoned because of the neurological risks. Since serious neurological events after foraminal injections could be the result of an overly fast injection into the arterialized radicular veins rather than in the arteries, only slow injections with products having a low risk of embolism or vascular complications should be allowed. Dexamethasone-based preparations seem to contain no particles or crystals, and have not induced any neurological accidents in various animal models, even after direct administration into vertebral or carotid arteries. PMID- 23352514 TI - Performance of the American College of Rheumatology/European League Against Rheumatism 2010 criteria for the diagnosis of rheumatoid arthritis in Chinese patients. AB - OBJECTIVES: To evaluate the ability of American College of Rheumatology (ACR) 2010 classification criteria to diagnose rheumatoid arthritis (RA) compared to the widely used ACR 1987 criteria in Chinese patients. METHODS: Four hundred and four patients suffering from arthritis were included in the study. Two hundred and twenty-one of them were classified as RA patients and 183 had alternative diagnoses. The patients were further subdivided into three groups according to their disease duration of within one year, one to two years or more than two years. The diagnostic value of ACR/EULAR 2010 criteria for RA was evaluated by comparing the sensitivity and specificity with those of ACR 1987 criteria in these patients. RESULTS: The sensitivity and specificity of ACR/EULAR 2010 criteria for diagnosing RA were 95% and 92.9%, respectively. In contrast, the sensitivity and specificity of ACR 1987 criteria were 81.4% and 92.9%, respectively. The efficacy of ACR/EULAR 2010 criteria was superior to the ACR 1987 criteria by comparing their area under the curves (AUC) (0.940, 95% CI [0.912, 0.967] vs. 0.872, 95% CI [0.835, 0.909]). The recognition accuracy of ACR/EULAR 2010 criteria was higher than that of ACR 1987 criteria (94.5% vs. 86.6%, P<0.05). Inter-rater analysis showed that agreement of the two criteria was substantial (Kappa=0.744, P<0.001). For patients with disease duration within one year, one to two years and over two years, the sensitivities of ACR 1987 criteria were 69.2%, 81.3% and 89.9%, while the specificities were 94.4%, 90.6% and 92%, respectively. The corresponding sensitivities of ACR/EULAR 2010 criteria in these patients were 91%, 93.8% and 98.2%, while the corresponding specificities were 94.4%, 96.6% and 89.3%, respectively. The advantage of ACR/EULAR 2010 criteria over 1987 criteria in higher sensitivity was remarkable particularly in patients with disease duration within one year (P<0.001). CONCLUSIONS: The ACR/EULAR 2010 criteria is more accurate in RA diagnosis compared to the ACR 1987 criteria by elevating the sensitivity while preserving the specificity, especially in patients with disease duration within one year. The ACR/EULAR 2010 criteria may serve as new diagnostic tools in daily clinical practice. PMID- 23352515 TI - Estrogens, osteoarthritis and inflammation. AB - Estrogens participate in several biological processes through different molecular mechanisms. Their final actions consist of a combination of both direct and indirect effects on different organ and tissues. Estrogen may have pro- and anti inflammatory properties depending on the situation and the involved tissue. In general, acute loss of estrogens increases the levels of reactive oxygen species and activates nuclear factor-kappaB and pro-inflammatory cytokine production, indicating their predominant anti-inflammatory properties. Furthermore, pro inflammatory cytokine expression has been shown to be attenuated by estrogen replacement. Osteoarthritis and cardiovascular disease are two of the more prevalent diseases once menopause is established, which has suggested the link between estrogens and both processes. In addition, deletion of estrogen receptors in female mice results in cartilage damage, osteophytosis and changes in the subchondral bone of the joints suggesting that estrogens have a protective role on the maintenance of joint homeostasis. Furthermore, in spite of the negative effect of estrogen replacement reported in 2002 by the Women's Health Initiative study, several works published afterwards have explored the potential protective effect of estrogen supplementation in animal models and have postulated that these actions may justify a beneficial role of estrogens in different diseases where inflammation is the major feature. In this review, we will analyze the effects of estrogens on certain pathological situations such as osteoarthritis, some autoimmune diseases and coronary heart disease, especially in postmenopausal women. PMID- 23352517 TI - Influence of two types of organic matter on interaction of CeO2 nanoparticles with plants in hydroponic culture. AB - An important aspect in risk assessment of nanoparticles (NPs) is to understand their environmental interactions. We used hydroponic plant cultures to study nanoparticle-plant-root interaction and translocation and exposed wheat and pumpkin to suspensions of uncoated CeO2-NP for 8d (primary particle size 17-100 nm, 100 mg L(-1)) in the absence and presence of fulvic acid (FA) and gum arabic (GA) as representatives of different types of natural organic matter. The behavior of CeO2-NPs in the hydroponic solution was monitored regarding agglomeration, sedimentation, particle size distribution, surface charge, amounts of root association, and translocation into shoots. NP-dispersions were stable over 8d in the presence of FA or GA, but with growing plants, changes in pH, particle agglomeration rate, and hydrodynamic diameter were observed. None of the plants exhibited reduced growth or any toxic response during the experiment. We found that CeO2-NPs translocated into pumpkin shoots, whereas this did not occur in wheat plants. The presence of FA and GA affected the amount of CeO2 associated with roots (pure>FA>GA) but did not affect the translocation factor. Additionally, we could confirm via TEM and SEM that CeO2-NPs adhered strongly to root surfaces of both plant species. PMID- 23352518 TI - Microcalorimetric studies of the effect of cerium (SH) on isolated rice mitochondria fed by pyruvate. AB - Mitochondria were isolated from the hybrid rice Xiangzaoxian 31, then the effects of low and high concentrations of Ce (SH) on metabolism of mitochondria fed by pyruvate were investigated respectively, by microcalorimetry and oxygen electrode method The thermogenic curve of mitochondria without Ce (SH) could be divided into three parts: activity recovery phase, stationary phase and decline phase. And the thermokinetic parameters have been calculated through the metabolic thermogenic curves. With addition of different concentrations of Ce (SH), the results demonstrated that low levels of cerium ion stimulated the metabolic activity of energized mitochondria and the inhibition was discovered with high concentrations of Ce (SH). At the same time, it is shown that the effect in respiration correspond to the effect on mitochondrial metabolism on addition of different concentrations of Ce (SH). Moreover, the addition of low and high concentrations of Ce (SH) had no obvious effect on the total heat output (Q). The concentration-dependent effect of Ce (SH) on metabolism of mitochondria is similar to plant growth response to rare earth elements (Hormesis effect). PMID- 23352519 TI - Comments on "Ozonation of a mixture of estrogens and progestins in aqueous solution: interpretation of experimental results by computational methods" by Ekaterina V. Rokhina, Nagarjuna S. Vattikonda, Candice Johnson, Rominder P.S. Suri [Chemosphere 89 (11) (2012) 1323-1329]. PMID- 23352520 TI - Effect of redox potential and pH status on degradation and adsorption behavior of tylosin in dairy lagoon sediment suspension. AB - Veterinary antibiotics are the most heavily used pharmaceuticals in intensive animal farming operation. Their presence in the environment through application of manure and lagoon water as fertilizer in agricultural fields has generated a growing concern in recent years due to potential threat to the ecosystem and the risk they pose to human and animal health. Among the antibiotics, tylosin, a macrolide class of antibiotics, has been widely used for disease prevention and growth promotion in swine, cattle/dairy, and poultry production. To understand degradation and sorption behavior of tylosin A, a laboratory microcosm incubation study was conducted on dairy lagoon sediments suspension under different pH (5.5, 7.0, 8.5) and redox potentials (Eh at -100 mV, 0 mV, +250 mV, +350 mV). Sorption and degradation of tylosin was strongly influenced by sediment pH and redox conditions. Under acidic (pH 5.5) and reduced (Eh -100 mV) condition, tylosin persisted in the solution phase of dairy lagoon sediment suspension much longer with resident time of 77 d. Under oxidized (Eh +350 mV) condition, microbial degradation was much greater causing 68-75% of tylosin loss from the solution at pH 5.5 and 32-75% at pH 7.0 during the 20 d incubation. At pH 8.5, abiotic transformation of tylosin A into unknown degradates rather than sediment adsorption and microbial degradation was the major mechanism controlling tylosin disappearance from the solution regardless of the status of redox potentials. Overall, the results suggested that under reduced condition with low pH, tylosin will be persisted in the lagoon effluents and residue of tylosin may enter agricultural fields through the application of lagoon slurry as fertilizer. PMID- 23352521 TI - Evaluation of the gas stripping technique for calculation of Henry's law constants using the initial slope method for 1,2,4,5-tetrachlorobenzene, pentachlorobenzene, and hexachlorobenzene. AB - Henry's law constant (HLC) is an important factor used in environmental risk assessment and fate and transport models to describe mass transfer of chemical between water and air. HLCs and structure-property relationships were assessed for 1,2,4,5-tetrachlorobenzene (TeCB), pentachlorobenzene (PeCB), and hexachlorobenzene (HCB). HLCs were determined using the volatilization rate (kv) of sparged chemical at 25 degrees C. Despite the assumption that kv should be constant throughout the stripping duration, results indicated that kv decreased over time according to three separate slope regions. Results of ANCOVA indicate that kv is statistically different in the third slope region, which leads to the conclusion that use of the entire stripping data set would lead to biased HLCs. This decrease in kv may be attributed to desorption from sparger surfaces, which has not been considered widely in the literature. Statistical analysis was possible because of the robustness of the current experimental procedure which included numerous replications (15 total spargers) and extensive data points available to discern key slope changes. HLCs determined using the gas stripping technique were 57, 33, and 30 Pa m(3) mol(-1) for 1,2,4,5-TeCB, PeCB, and HCB, respectively. In comparison to literature values, current TeCB and HCB HLCs were within wide reference ranges spanning approximately an order of magnitude for each chemical. PeCB HLC of the current study was two times lower than the lowest reference data. PMID- 23352522 TI - Mosquito allergy. PMID- 23352523 TI - Management of hereditary angioedema in 2012: scientific and pharmacoeconomic perspectives. PMID- 23352524 TI - Asthma medication adherence: the role of God and other health locus of control factors. AB - BACKGROUND: Medication adherence is an important determinant of disease outcomes, yet medication use on average tends to be low among patients with chronic conditions, including asthma. Although several predictors of non-adherence have been assessed, more research is needed on patients' beliefs about God and how these relate to medication use. OBJECTIVE: To examine the relationship between perceptions about "God's" role in health and other locus of control factors with inhaled corticosteroid (ICS) adherence among asthma patients. METHODS: Participants were from a clinical trial to improve ICS adherence and were 5-56 years old, had a diagnosis of asthma, and were receiving ICS medication. Baseline adherence was estimated from electronic prescription and pharmacy fill records. Patients were considered to be adherent if ICS use was >=80% of prescribed. A baseline survey with the Multidimensional Health Locus of Control scale was used to assess five sources (God, doctors, other people, chance, and internal). RESULTS: Medication adherence was low (36%). Patients' who had a stronger belief that God determined asthma control were less likely to be adherent (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.70-0.96). This relationship was stronger among African American (OR 0.68, 95% CI0.47-0.99) compared to white patients (OR 0.89, 95% CI 0.75-1.04), and among adults (OR 0.81, 95% CI 0.69 0.96) compared to children (OR 0.84, 95% CI 0.58-1.22). CONCLUSION: Patients' belief in God's control of health appears to be a factor in asthma controller use, and therefore should be considered in physician-patient discussions concerning course of treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00459368. PMID- 23352525 TI - Association between latitude and allergic diseases: a longitudinal study from childhood to middle-age. AB - BACKGROUND: Worldwide variations in allergy prevalence suggest that geographic factors may contribute to asthma. Ecologic studies have suggested that latitude, a marker of UV-B exposure and allergen exposures, may be related to clinical allergies. OBJECTIVE: To examine the relationship between latitude or UV-B based on self-reported geolocation and allergic sensitization and disease prevalence in Australia. METHODS: The Tasmanian Longitudinal Health Study is a population-based study of respiratory disease spanning childhood to adulthood. The most recent follow-up included a postal survey of 5,729 participants and a clinical substudy of 1,396 participants. Participants' residential addresses were coded for latitude and linked with the UV-B data from satellite-based observations of atmospheric ozone. Multivariable logistic regression analyses were performed to estimate the associations between latitude or UV-B and allergic diseases. RESULTS: Most northerly latitude, that is, latitude closest to the Equator, and high current UV-B exposure were associated with increased odds of hay fever, food allergy, and skin sensitization to house dust mites and molds. More northerly latitude and higher UV-B exposure were associated with increased odds of current asthma among atopic individuals contrasting with a reduced odds of current asthma among nonatopic individuals. CONCLUSION: This is the first study, to our knowledge, to demonstrate a differential effect of atopic status on the relationship between latitude and current asthma. Our study demonstrates in a genetically and culturally similar group of individuals that geographic factors may a play role in the development of allergic disease. PMID- 23352526 TI - Adverse reactions during drug challenges: a single US institution's experience. AB - BACKGROUND: Drug challenge is a useful tool when diagnostic testing lacks predictive value for a questionable history of drug allergy. Placebo-controlled drug challenge studies demonstrate that a significant number of patients report purely subjective symptoms to placebo. OBJECTIVE: To evaluate the safety and rate of adverse effects when performing drug challenges and to identify predictive factors for occurrences of subjective symptoms during drug challenges. METHODS: We performed a 6-year, retrospective medical record review of patients who underwent drug challenges by members of the Allergy and Immunology Division after consultation deemed drug challenges to be appropriate. Statistical analysis was performed to compare the proportion of patients with subjective symptoms based on certain factors, including sex, age, number of listed drug allergies, interval from historical drug reaction to the drug challenge, and types of historical reaction. RESULTS: A total of 114 patients underwent 123 drug challenges. Only 1 patient was deemed to have a true positive drug challenge result. Twenty patients reported subjective symptoms during graded challenge, all of which were not deemed a positive challenge. There was a significantly higher proportion of patients who reported subjective symptoms in females, those with a higher number of listed drug allergies, and those whose historical reactions were primarily subjective in nature. CONCLUSION: Drug challenges are safe procedures in appropriately selected patients. A number of patients report subjective symptoms during drug challenges. Identifying patients at high risk for subjective symptoms may assist in determining whether placebo-controlled drug challenges should be performed. PMID- 23352527 TI - Characterization of aspirin allergies in patients with coronary artery disease. AB - BACKGROUND: Aspirin prevents coronary thrombosis and is used extensively in cardiovascular prophylaxis. However, patients with a prior history of an aspirin "reaction" are routinely denied this medication. OBJECTIVE: To characterize the clinical presentation of a cohort of patients with coronary artery disease (CAD) and aspirin reactions. METHODS: Between 2009 and 2012, using a retrospective computer analysis, information was collected on all patients within a county-wide health care system presenting with CAD and a prior history of aspirin reactions. RESULTS: Of 9,565 patients with CAD, a prior history of aspirin reactions was recorded in 142 patients. Of these 142 patients, 30 (21%) had histories compatible with cutaneous and/or respiratory reactions. The other patients described adverse effects to aspirin, mostly gastrointestinal intolerance and bleeding. Aspirin-induced anaphylaxis was recorded in patients but may have been misdiagnosed, describing instead respiratory hypersensitivity reactions. Of the 142 patients, only 34 (24%) were receiving daily cardiovascular prophylaxis with aspirin. Of 108 patients not receiving aspirin, 25 (17.6%) were prescribed clopidogrel. CONCLUSION: Histories of aspirin reactions in patients with CAD are uncommon, occurring in only 1.5% of our study population. The 21% of patients with histories compatible with aspirin hypersensitivities can be challenged and, if the results are positive, successfully desensitized. Moreover, almost all patients with gastric intolerance to aspirin can be treated with aspirin and a proton pump inhibitor. However, both approaches, which result in restoration of cardiovascular prophylaxis, were seriously underused in our study population. PMID- 23352528 TI - Anaphylaxis in a tertiary adult allergy clinic: a retrospective review of 516 patients. AB - BACKGROUND: Anaphylaxis is a life-threatening acute allergic reaction that can occur at any age. OBJECTIVE: To determine the frequency, triggering factors, and clinical features of anaphylaxis among adult patients who were referred to a tertiary health care facility. METHODS: A retrospective medical chart review was performed including all patients referred to the outpatient clinic of the adult allergy department in our university hospital between January 1, 2008 and December 30, 2011 to determine cases involving anaphylaxis. RESULTS: A total of 516 (2.11%) patients among 24,443 admissions were diagnosed with anaphylaxis. Although the second highest frequency of anaphylaxis cases took place in 2008, a gradual rise in the frequency was determined from 2009 to 2011. Drugs (90.7%) were the most frequent cause, followed by Hymenoptera stings (5.4%), foods (1.6%), latex (0.4%), and exercise (0.2%) respectively. The clinical manifestations during anaphylaxis reported by patients were cutaneous (n = 292, 56.6%), respiratory (n = 253, 49%), cardiovascular (n = 212, 41%), neuropsychiatric (n = 60, 11.6%), and gastrointestinal (n = 52, 10.1%), respectively. Approximately one fifth of the patients received epinephrine, whereas 43% of patients did not receive epinephrine during their treatment in the emergency room. An epinephrine auto-injector was prescribed to 42 patients (8.1%). CONCLUSION: In this study, the second pattern of National Institute of Allergy and Infectious Disease (NIAID) and the Food Allergy and Anaphylaxis Network (FAAN) diagnostic criteria for anaphylaxis predominated among adult patients. Drugs were the leading triggering factor, followed by Hymenoptera stings, foods, latex, and exercise, respectively. Atopy, asthma, and allergic rhinitis were rarely detected. PMID- 23352529 TI - Glycogen synthase kinase 3 in chronic rhinosinusitis: two faces of a single enzyme in one disease. AB - BACKGROUND: The origin and pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) remain unclear. Glycogen synthase kinase 3 (GSK-3) is a unique multitasking kinase involved in the regulation of inflammation and apoptosis and is an important messenger in the downstream signaling of interleukin 6. OBJECTIVE: To analyze the possible role of GSK-3 in the pathogenesis of CRSwNP. METHODS: We examined tissue samples of nasal polyps and the inferior turbinate of patients with CRSwNP and the inferior turbinate of individuals without chronic sinusitis (healthy mucosa). Expression levels of GSK-3 and its inactivated form phosphorylated GSK-3 (pGSK-3) were analyzed using DNA microarray, protein array, Western hybridization, and immunohistochemical analysis. RESULTS: We found increased expression of GSK-3 in both the nasal polyps and the inferior turbinate of patients with CRSwNP compared with those with healthy mucosa (P < .01). We did not observe a difference between nasal polyps and the inferior turbinate of patients with CRSwNP, but a highly significant increase in the phosphorylation rate of GSK-3 was detected in the tissue of nasal polyps compared with the turbinates of patients with CRSwNP (P < .01). CONCLUSION: GSK-3 may play a crucial role in the inflammatory process in CRSwNP. Nasal polyps originate mainly in the mucosa of the middle meatus of the nose and rarely occur in the region of the inferior turbinate. The inhibition of GSK-3 by phosphorylation in nasal polyps, in contrast to the inferior turbinate, is a possible explanation for the different behavior of the mucosa of the middle meatus and the inferior turbinate. PMID- 23352530 TI - Effect of mite allergen immunotherapy on the altered phenotype of dendritic cells in allergic asthmatic children. AB - BACKGROUND: Allergic asthma is a T(H)2 inflammatory disease. Dendritic cells (DCs) play key roles in the T(H)1/T(H)2 balance. Allergen specific immunotherapy (SIT) has the potential to modify the course of allergy because the ratio of T(H)1 to T(H)2 cytokines produced is increased after SIT. OBJECTIVE: To determine how SIT affects DCs in children and to define novel parameters of this treatment. METHODS: We investigated the changes of phenotypic and functional variations of monocyte-derived DCs from allergic asthmatic children undergoing complete mite SIT. Peripheral blood monocytes from SIT allergic asthmatic children, allergic asthmatic controls, and healthy controls were cultured with granulocyte macrophage colony-stimulating factor and interleukin 4 and then stimulated with Dermatophagoides pteronyssinus (Der p) allergen or lipopolysaccharide (LPS). The expressions of surface molecules on monocyte-derived DCs were assessed by flow cytometry. Cytokine production by cultured monocyte-derived DCs was determined by enzyme-linked immunosorbent assay. RESULTS: After LPS stimulation, monocyte derived DCs of the allergic asthmatic group had a higher CD86 and lower HLA-DR expression than the healthy controls. In SIT patients, the expression was similar to that of the healthy controls. After Der p stimulation monocyte-derived DCs of the allergic asthmatic patients displayed lower Toll-like receptor 4 (TLR4), whereas again in SIT patients the expression was similar to that of healthy controls. CONCLUSION: These findings indicate that SIT normalizes the expression of CD86, HLA-DR, and TLR4 on DCs. Moreover, CD86, HLA-DR, and TLR4 may be useful parameters for monitoring SIT. Decreased TLR4 expression in allergic asthmatic patients might be compensated by TLR4 agonists, with the potential of amplifying the effects of SIT. PMID- 23352531 TI - Long-term efficacy of fixed-dose omalizumab for patients with severe chronic spontaneous urticaria. AB - BACKGROUND: Treatment of chronic urticaria is challenging because many patients are refractory to or experience adverse effects with conventional therapy. Recently, short-term efficacy of omalizumab has been demonstrated. OBJECTIVE: To determine both the short- and long-term efficacy of omalizumab in the treatment of chronic urticaria. METHODS: Sixteen patients with severe chronic spontaneous urticaria at our center received omalizumab, 150 mg every 2 to 4 weeks, between 2010 and 2011. Disease severity was measured by urticaria activity scores before the first injection, during treatment, and at most recent follow-up, ranging from 9 to 24 months. Duration of therapy was determined individually for each patient. In this retrospective analysis, outcome measures include number of treatments required to induce remission and long-term remission sustainability. RESULTS: Ten patients had remission of urticaria after their first injection (62%). Four patients required 2 to 6 treatments to achieve remission. Two patients discontinued treatment after 2 injections. Of the 14 patients who initially benefited (88%), 4 remain in remission more than 9 months after their last treatments. Seven patients continue to achieve remission with maintenance omalizumab, dosed at intervals appropriate for individual remission duration. Three patients became refractory and discontinued treatment (19%). CONCLUSION: Omalizumab is an effective treatment for inducing and maintaining long-term remission for patients with severe chronic urticaria. Onset of remission is rapid, although duration is variable, with some patients requiring maintenance treatment. Large-scale randomized trials are necessary to confirm our findings that support the long-term efficacy of anti-IgE therapy for the treatment of this disease. PMID- 23352532 TI - A case of DRESS syndrome induced by the antituberculosis drugs, prothionamide, and para-aminosalycilic acid. PMID- 23352533 TI - Persistent papilloma and polyoma virus infection in common variable immunodeficiency with progressive multifocal leukoencephalopathy. PMID- 23352534 TI - Mannose-binding lectin deficiency in a patient with multiple opportunistic infections, strongyloidiasis, and spindle cell tumor. PMID- 23352535 TI - Wheat-dependent exercise-induced anaphylaxis in elderly patients. PMID- 23352536 TI - Success with immunomodulatory therapies in the treatment of recalcitrant chronic urticaria. PMID- 23352537 TI - Glucoamylase is a potential allergen in products expressed in Neurospora crassa. PMID- 23352538 TI - Hypogammaglobulinemia treated with infusion therapy associated with cortisol deficiency. PMID- 23352539 TI - Author response. Anaphylaxis in the community setting: determining risk factors for admission--the role of asthma. PMID- 23352540 TI - Anaphylaxis in the community setting: determining risk factors for admission--the role of asthma. PMID- 23352541 TI - Should exhaled nitric oxide be part of routine asthma management? PMID- 23352542 TI - Author response. Should exhaled nitric oxide be part of routine asthma management? PMID- 23352543 TI - Allergen of the month--European beech. PMID- 23352545 TI - Cellular responses in the Malpighian tubules of Scaptotrigona postica (Latreille, 1807) exposed to low doses of fipronil and boric acid. AB - Studies of sub-lethal effects of pesticide residues on stingless bees are scarce and morphological analysis of organs would add information to toxicological analysis in order to clarify the continuous exposure of Scaptotrigona postica to insecticides. The aim of this study was to evaluate the morphology and histochemistry of the Malpighian tubules (excretory organ) of S. postica exposed to fipronil or boric acid to detect cellular responses that indicate toxicity or adaptative mechanisms to stress induced by exposure of worker bees to low doses of these chemical compounds. Newly emerged bees were submitted to toxicological bioassays and morphological analyses by optical microscopy and Transmission Electron Microscopy, as well as histochemical methods, were performed to detect proteins and glycoconjugates. Additionally, immunohistochemical detection of DNA fragmentation and HSP70 (70-kDa Heat shock protein) were performed to detect cell death and stress response, respectively. Statistical analysis, for the bioassays conducted with ingestion of contaminated diet with boric acid at 0.75% (w/w) or with fipronil at 0.1MUg/kg of food, showed that the survival of bees that ingested the contaminated diets were significantly different to the survival rate presented by the control group (P<0.0001). Although some characteristics indicative of initiation of cell death were observed, the cells remained metabolically active in the processes of excretion and inactivation of chemical compounds. The data from this study reinforce the importance of research on sublethal effects of low doses of pesticides on bees in an attempt to assess a possible realistic dose and evaluate the risk assessment of stingless bee S. postica foraging in the vicinity of cultivated fields and/or in green urban areas. PMID- 23352544 TI - Atlanto-axial rotatory subluxations in postmortem CT: radiologists be aware of a common pitfall. AB - The aim of the present study was to determine the frequency of atlanto-axial rotatory subluxations (AARS) in multi detector computed tomography (MDCT) performed on human corpses for forensic purposes and to investigate whether these are a physiological postmortem finding or indicate a trauma to the neck region. 80 forensic cases examined with MDCT from November 2003 to March 2007 were included in the study. The study was approved by the regional ethics committee. For each case volumes were rendered and investigated with reference to suspected AARS and any other anomalies of the head and neck region. The rotation of the head as well as in the atlanto-axial joint were measured and occurring AARS were judged according Fielding's classification. The finding of AARS was correlated to case criteria such as postmortem head rotation, sex, age, cause of death, time since death and further autopsy results. Statistical analysis was performed using Fisher's exact test, Wilcoxon's rank sums test and Chi-square test with Pearson approximation. 70% (n=56) of the cases included in the study presented with an AARS. A strong correlation (P<.0001) between suspected AARS and postmortem head rotation was found. Two cases presented with an atlanto-axial rotation greater than the head rotation. One showed an undiscovered lateral dislocation of the atlas, and one an unfused atlas-ring. There was no correlation to any further investigated case criteria. Ipsilateral AARS with head rotation alone does not indicate trauma to the neck. PmCT can substantially support forensic examinations of the skeleton, especially in body regions, which are elaborate to access at autopsy, such as the cervical spine. Isolated AARS (Fielding type I) on pmCT is usually a normal finding associated with ipsilateral head rotation. PMID- 23352546 TI - Radial nerve injury associated with application of a hinged elbow external fixator: a report of 2 cases. PMID- 23352547 TI - Reverse shoulder arthroplasty glenoid fixation: is there a benefit in using four instead of two screws? AB - BACKGROUND: To allow osseous integration to occur and thus provide long-term stability, initial glenoid baseplate fixation must be sufficiently rigid. A major contributing factor to initial rigid fixation is baseplate screw fixation. Current baseplate designs use a 4-screw fixation construct. However, recent literature suggests adequate fixation can be achieved with fewer than 4 screws. The purpose of the present study was to determine whether a 4-screw construct provides more baseplate stability than a 2-screw construct. METHODS: A flat backed glenoid baseplate with 4 screw hole options was implanted into 6 matched pairs of cadaver scapulas using standard surgical technique. Within each pair, 2 screws or 4 screws were implanted in a randomized fashion. A glenosphere was attached allowing cyclic loading in an inferior-to-superior direction and in an anterior-to-posterior direction. Baseplate motion was measured using 4 linear voltage displacement transducers evenly spaced around the glenosphere. RESULTS: There was no statistical difference in the average peak central displacements between fixation with 2 or 4 screws (P = .338). Statistical increases in average peak central displacement with increasing load (P < .001) and with repetitive loading (P < .002) were found. CONCLUSION: This study demonstrates no statistical difference in baseplate motion between 2-screw and 4-screw constructs. Therefore, using fewer screws could potentially lead to a reduction in operative time, cost, and risk, with no significant negative effect on overall implant baseplate motion. PMID- 23352548 TI - Supraspinatus atrophy as a predictor of rotator cuff tear size: an MRI study utilizing the tangent sign. AB - HYPOTHESIS: We hypothesize that the degree of supraspinatus atrophy, as assessed with the tangent sign will significantly correlate with increasing rotator cuff tear size. METHODS: A retrospective review was performed assessing presence of muscle atrophy using the tangent sign, fatty atrophy based on Goutallier classification, and size of rotator cuff tear in 34 patients. A correlation analysis was performed. RESULTS: All agreement measures among both evaluators were statistically significant (P < .05). Agreement among the 2 physicians for the tangent sign was consider almost perfect k = 87.2 (95%CI = 51.7, 87.2). Weighted kappa agreement using the Goutallier sign was 75.1 (95%CI = 58.7, 91.4), suggesting substantial agreement. The relationship between the positive tangent sign and coded tear grade was very good with a correlation of R = .84 and R = .87, respectively, showing a strong correlation between the presence of a tangent sign and a larger rotator cuff tear. A strong relationship was also found when comparing the tangent sign to a Goutallier's classification of 2 or greater with a correlation of R = .92 and R = .94 for the 2 physicians. The lowest correlation was found between the Goutallier sign and tear grade from both physicians. All of these findings were statistically significant (P < .05). CONCLUSION: The tangent sign shows good interobserver reliability and is easily performed to measure rotator cuff atrophy and a positive tangent sign shows an excellent correlation with the size of the rotator cuff tear and may be predictive of the ability of the cuff to be primarily repaired. PMID- 23352549 TI - Single incision power optimizing cost-effective (SPOC) distal biceps repair. AB - BACKGROUND: The purpose of this study was to review the results of a single anterior incision distal biceps tendon repair that reattaches the tendon to its posterior anatomic insertion site. We hypothesize this repair maximizes the supination torque of the biceps muscle throughout the full arc of forearm rotation. METHODS: A consecutive series of patients with distal biceps tears were treated using a technique that reattaches the distal biceps tendon to the posterior radial surface similar to a 2-incision repair, which optimizes the biceps moment arm in all forearm positions including maximum supination. This method of distal biceps reattachment has been utilized in our practice since December 2008 on 40 distal biceps tendon repairs. Biodex testing was used to quantify the peak supination torque, the supination work, and the power of supination at each degree of forearm rotation and included on patients with a minimum clinical follow up of 12 months. Range of motion was also recorded. RESULTS: Thirty patients met the inclusion criteria. Three patients, 2 of whom were lost to follow-up and 1 with bilateral repairs, were not included in this study. Seventeen of the remaining 27 patients completed strength testing using a Biodex Isokinetic Testing machine. Supination strength averaged 91% and 91% of the uninjured side at 60 and 120 deg/sec, respectively. Twenty-five (93%) patients reported no pain and had returned to work or normal activities. CONCLUSION: A single anterior incision distal biceps tendon repair that maximizes supination torque throughout full forearm rotation has been utilized. No specialized anchors or equipment are required. LEVEL OF EVIDENCE: Level IV, Case Series, Treatment Study. PMID- 23352550 TI - Ultrasound changes after rotator cuff repair: is supraspinatus tendon thickness related to pain? AB - BACKGROUND: Little is known about the morphology of healing rotator cuffs after surgical repair. This investigation aimed to determine whether there are changes in tendon thickness, subacromial bursa, anatomical footprint, tendon vascularity, and capsular thickness after rotator cuff repair, and whether supraspinatus tendon thickness correlates with pain. METHODS: Fifty-seven patients completed a validated pain questionnaire. Using a standardized protocol, their shoulders were scanned by the same ultrasonographer at 1 week, 6 weeks, 3 months, and 6 months postarthroscopic repair by a single surgeon. The contralateral shoulders, if uninjured, were also scanned. RESULTS: Of 57 patients, 4 re-tore their tendons at 6 weeks and 4 retore at 3 months. Sixteen of the remaining 49 patients had intact contralateral supraspinatus tendons. The repaired supraspinatus tendon thickness remained unchanged throughout the 6 months. Compared to week 1, at 6 months, bursal thickness decreased from 1.9 (0.7) mm to 0.7 (0.5) mm (P < .001); anatomical footprint increased from 7.0 (2.0) mm to 9.3 (1.5) mm; tendon vascularity decreased from mild to none (P < .001); posterior capsule thickness decreased from 2.3 (0.8) mm to 1.3 (0.6) mm (P < .001). Frequency and severity of pain and shoulder stiffness decreased (P < .001). There was no correlation between tendon thickness and pain. CONCLUSION: After rotator cuff repair, there was an immediate increase in subacromial bursa thickness, tendon vascularity, and posterior glenohumeral capsular thickness. These normalized after 6 months. Tendon thickness was unchanged while footprint contact was comparable with the contralateral tendons. There was no correlation between tendon thickness and pain. PMID- 23352551 TI - Folic acid and cancer--where are we today? PMID- 23352553 TI - Application of the Teager-Kaiser energy operator in bearing fault diagnosis. AB - Condition monitoring of rotating machines is important in the prevention of failures. As most machine malfunctions are related to bearing failures, several bearing diagnosis techniques have been developed. Some of them feature the bearing vibration signal with statistical measures and others extract the bearing fault characteristic frequency from the AM component of the vibration signal. In this paper, we propose to transform the vibration signal to the Teager-Kaiser domain and feature it with statistical and energy-based measures. A bearing database with normal and faulty bearings is used. The diagnosis is performed with two classifiers: a neural network classifier and a LS-SVM classifier. Experiments show that the Teager domain features outperform those based on the temporal or AM signal. PMID- 23352554 TI - A 21 marker insertion deletion polymorphism panel to study biogeographic ancestry. AB - Insertion/deletion polymorphisms have recently received increased interest in the forensic genetics community. This class of markers combines the advantageous genetic properties of single nucleotide polymorphisms (i.e., low mutation rate, genetic stability, and short amplicon size) with the technical advantage of short tandem repeat markers (simple detection by fluorescence-labelled PCR and capillary electrophoresis). For a large number of indel markers significant differences in allele frequencies between the major populations have been reported, making this class of markers suitable for the analysis of biogeographic ancestry. We have developed a multiplex PCR assay designed to establish the biogeographic ancestry of forensic DNA samples based on insertion/deletion polymorphisms. A panel of 21 short indels with allele frequency differences between three major population groups (European, African and Asian) was selected to be incorporated into a single-tube multiplex PCR assay. The assay is highly sensitive, requiring less than 0.5 ng of genomic DNA for successful typing. Due to the short fragment lengths below 200 bp, the assay is ideally suited for the typing of challenging forensic genetic case work samples. A population genetic study has been performed proving the performance of the assay in inferring the ancestral population of individuals. The chosen 21 markers are sufficient to distinguish between three major global population groups. Furthermore, the assay design leaves room for an extension in order to cover additional population groups. PMID- 23352552 TI - Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals. AB - BACKGROUND: Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification. METHODS: In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data on cancer incidence. We obtained individual participant datasets that included 49,621 participants in all 13 such trials (ten trials of folic acid for prevention of cardiovascular disease [n=46,969] and three trials in patients with colorectal adenoma [n=2652]). All these trials were evenly randomised. The main outcome was incident cancer (ignoring non-melanoma skin cancer) during the scheduled treatment period (among participants who were still free of cancer). We compared those allocated folic acid with those allocated placebo, and used log rank analyses to calculate the cancer incidence rate ratio (RR). FINDINGS: During a weighted average scheduled treatment duration of 5.2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57.3 nmol/L for the folic acid groups vs 13.5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1.06, 95% CI 0.99-1.13, p=0.10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0.23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0.13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site. INTERPRETATION: Folic acid supplementation does not substantially increase or decrease incidence of site specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials. FUNDING: British Heart Foundation, Medical Research Council, Cancer Research UK, Food Standards Agency. PMID- 23352556 TI - Thoracic surgery interventions in patients with chronic bronchial aspiration after laparoscopic gastric banding. PMID- 23352555 TI - Predictors of death in Malaysian HIV-infected patients on anti-retroviral therapy. AB - OBJECTIVE: To determine the predictors of death in Malaysian HIV-infected patients undergoing antiretroviral therapy (ART). METHODS: Data from 845 HIV infected patients aged >= 20 years on ART in a large teaching hospital in Malaysia from 1989 to 2009 were analyzed using Kaplan-Meier and Cox regression analyses. RESULTS: 72.7% of the patients survived. Multivariate Cox regression showed that significant predictors of death were age >= 50 years (HR 1.76; 95% CI 1.18-2.64), secondary education (HR 3.57; 95% CI 1.12-11.37), tertiary education (HR 3.57; 95% CI 1.09-11.70), being unemployed (HR 1.49; 95% CI 1.07-2.09), AIDS on initial presentation (HR 5.75; 95% CI 3.29-10.07), single-drug ART (HR 1.84; 95% CI 1.27, 2.66), double-drug ART (HR 1.63; 95% CI 1.19-2.25) and inability to achieve viral load <= 50 copies/ml (HR 10.22; 95% CI 7.26-14.37). CONCLUSION: Every effort needs to be made to ensure that all HIV patients have access to triple drug ART, to lower viral load to <= 50 copies/ml and to treat HIV patients before they progress to AIDS as these are significant modifiable predictors of death in Malaysian HIV patients. PMID- 23352557 TI - The way to a woman's heart is through her stomach. PMID- 23352561 TI - Dental arch restoration using tooth macrowear patterns with application to Rudapithecus hungaricus, from the late Miocene of Rudabanya, Hungary. AB - Dental arch reconstructions present as much of a challenge in paleoanthropology as in orthodontics and maxillo-facial surgery. Dentists and dental technicians know that it is very difficult to find the precise physiological crown positions that will yield individually correct occlusal kinematics in living individuals, and this difficulty is compounded by damage and deformation in fossil specimens. Typically, dental arch reconstructions of fossils are not validated, although a functionally correct reconstruction is of undoubted importance for accurate morphological descriptions and comparative studies of fossil dentitions. Here we describe a new method for functional dental arch reconstruction derived from detailed wear facet mapping (Occlusal Fingerprint Analysis, OFA) and dental technical approaches. OFA was used to restore the entire dental arches of the most complete late Miocene fossil great ape dentition, that of Rudapithecus hungaricus, from Rudabanya in Hungary. Dental stone casts of the maxillary and mandibular dentition were repositioned in a dental articulator. The correct alignment of the tooth crowns was monitored by physically and virtually testing the tooth contacts during occlusal movements. The characteristic distribution pattern of the individual macrowear facets strongly constrains the antagonistic crown relationships in the Rudabanya specimen. We propose that the method used to reconstruct the functional dental arches of R. hungaricus, derived from kinematic evidence encoded in macrowear patterns, can be used as a reliable foundation for dental and facial restorations in fossils, and for individual occlusal crown morphology and dental arch reconstructions in modern dentistry and prosthetics. PMID- 23352562 TI - Re-examination of the dates of large blade technology in China: a comparison of Shuidonggou Locality 1 and Locality 2. AB - The presence and age of large blade technology at the Shuidonggou site is a pivotal issue in discussions of the spread of blade technology in East Eurasia. Madsen and colleagues' influential work uses the dates (24,000-29,000 rcy BP [radiocarbon years before present]) they obtained from Shuidonggou Locality 2 to estimate the age of blade technology in this region, and suggested a very late arrival of Levallois-like blade technology from the north. This paper re-examines the evidence for the age of blade technology at Shuidonggou by comparing the lithic assemblages from the new excavations at Locality 2 with those from Locality 1. Several important points are demonstrated: (1) the lithic industry of cultural layers 1 through 4 at Locality 2 is not based on large blades, so reported dates from these layers cannot be an indicator of the age of large blade technology; (2) comparing Locality 1 and 2, the age of large blade technology appears to be around 34,000-38,000 calendar years BP (before present) in this region, suggesting a relatively rapid technology dispersal from the west and/or north; (3) the so-called 'Shuidonggou lower cultural layer' at Locality 1 includes both large blade and simple flake industries. PMID- 23352563 TI - [A long survival after the treatment of a squamous cell carcinoma of the gallbladder]. AB - We report the case of a long survival after the treatment of a squamous cell carcinoma of the gallbladder. The patient is a 58-year-old man, who was treated by cholecystectomy, followed by postoperative radiotherapy of the tumour bed at a dose of 45Gy, combined with 5-fluoro-uracil chemotherapy. After 18 years, the patient is alive in complete remission. The end point of this work was to study the clinical and therapeutic characteristics of squamous cell carcinoma of the gallbladder and its prognosis through this case and a review of literature. PMID- 23352564 TI - [Isis((r)) trapeziometacarpal prosthesis in basal thumb osteoarthritis: 30 months follow-up in 30 cases]. AB - OBJECTIVES: The goal of our work was to evaluate the results of the Isis((r)) trapeziometacarpal prosthesis. METHODS: Our retrospective study included 26 patients, 30 prosthesis. The mean follow-up was 30 months. Preoperatively, the pain was 8.1 out of 10, the QuickDASH was 68.5 and the average Kapandji score was 7.8. The Dell's stage was 2.3. The prosthesis used was hybrid: the trapezial cup was cemented in 90% of cases, and the metacarpal stem was cementless. RESULTS: Eighty-seven percent of patients were satisfied or very satisfied. At last follow up, the pain was 3.4 out of 10, the QuickDASH was 37.8, and the average Kapandji score 9.1. The range of motion in flexion-extension and abduction-adduction were respectively 30.5 degrees and 31.7+/-11 degrees . The strength of the key-pinch, pulp-pinch and grasp averaged 75% of the contralateral side. On radiologic review, the rate of radiolucent lines was 20%, and the loosening or non osteointegration rate 10%. No dislocation was noted. One surgical revision was necessary for symptomatic metacarpal non-osteointegration. The survival rate of the prosthesis was 93% at 42 months. DISCUSSION: Clinical results are good. However, the rate of abnormal radiographic images (30%) at 30 months follow-up must incite caution. Although these prosthetic loosenings seem to be less symptomatic, a longer follow-up is necessary to assess the sustainability of clinical results and the future of these periprosthetic radiolucent lines. This led us to change our practice to using noncemented prostheses from now on. PMID- 23352565 TI - Surgical discectomy for lumbar disc herniation: surgical techniques. AB - Discectomy for lumbar discal herniation is the most commonly performed spinal surgery. The basic principle of the various techniques is to relieve the nerve root compression induced by the herniation. Initially, the approach was a unilateral posterior 5-cm incision: the multifidus was detached from the vertebra, giving access through an interlaminar space in case of posterolateral herniation; an alternative paraspinal approach was used for extraforaminal herniation. Over the past 30 years, many technical improvements have decreased operative trauma by reducing incision size, thereby reducing postoperative pain and hospital stay and time off work, while improving clinical outcome. Magnification and illumination systems by microscope and endoscope have been introduced to enable minimally invasive techniques. Several comparative studies have analyzed the clinical results of these various techniques. Although the methodology of most of these studies is debatable, all approaches seem to provide clinical outcomes of similar quality. At all events, minimally invasive techniques reduce hospital stay. While technical proficiency is essential, the final result depends on strict compliance with a prerequisite for surgical indication: close correlation between clinical symptoms and radiological findings. It is essential to discuss the risk/benefit ratio and explain the pros and cons of the recommended technique to the patient. PMID- 23352566 TI - Acute and old ruptures of the extensor apparatus of the knee in adults (excluding knee replacement). AB - Rupture of the extensor apparatus of the knee in adults is infrequent and dominated by patellar fracture, which in our experience is six times as frequent as quadriceps or patellar tendon tear. Patellar fracture poses few diagnostic problems and treatment is now well codified. Tension-band osteosynthesis is generally used, involving two longitudinal K-wires and wire in a figure-of-eight pattern looped over the anterior patella; sometimes, for more complex fractures, cerclage wiring is added to the tension band. Non-union is rare and generally well tolerated. Quadriceps tendon tear mainly affects patients over 40 years of age, in a context of systemic disease. Diagnosis is easily suggested by inability to actively extend the knee, but is unfortunately still often overlooked in emergency. In most cases, early surgical management is needed to reinsert the tendon at the proximal pole of the patella by bone suture. For chronic lesions, it is often necessary to lengthen the quadriceps tendon by V-Y plasty or the Codivilla technique. Patellar tendon tear, on the other hand, typically occurs in patients under 40 years of age, often involved in sports. Diagnosis is again clinically straightforward, but again may be missed in emergency, especially in case of incomplete tear. Surgery is mandatory in all cases. The procedure depends on the type of lesion: either end-to-end suture or transosseous reinsertion. In most cases repair is protected by tendon augmentation. Old lesions often require tendon graft or a tendon-bone-tendon-bone graft taken from the opposite side. PMID- 23352567 TI - Patterns and determinants of surgical management of screen detected breast cancer in the South-East Netherlands. AB - INTRODUCTION: Patients with screen detected breast cancer tend to have small, non palpable tumours with favourable characteristics for breast conserving surgery (BCS). The aims of this study were to analyse patterns in surgical management in patients with screen detected breast cancer and to determine factors predictive of the need for a re-operation after BCS (re-excision or secondary mastectomy). METHODS: Patient data were retrieved from the population based Eindhoven Cancer Registry, which covers 14 hospitals in de south of the Netherlands. Data of patients aged 50-74 years, diagnosed with operable, invasive, non-metastasised, T1 or T2 tumours in the period from 1999 to 2005 were linked to the patients recorded by the Dutch Breast Screening Organisation to identify the screen detected cancers. RESULTS: A total of 5657 patients were diagnosed with early stage invasive breast cancer. In 2822 of the 5657 patients (50%) breast cancer was detected by screening. Eighty percent of the screen-detected breast cancers was smaller than 2 cm. Of all 2822 patients with screen-detected cancer 82% underwent primary BCS. From 1999 until 2006 the percentage of re-excisions after this primary BCS decreased from 14% to 8% and the percentage of secondary mastectomies decreased from 23% to 8%. Primary BCS rates ranged from 64% to 93% between the 14 hospitals. Multivariable analyses showed that tumour size >2 cm, lobular histology, axillary nodal tumour involvement and poor differentiation of the tumour were associated with a statistically significant increase in the risk of re-operation after BCS. CONCLUSION: The need for a second operation after breast conserving surgery in patients with screen-detected breast cancer has decreased significantly in the southern Netherlands since 1999. However, considerable variation in surgical approach and re-operation rate between hospitals was observed. PMID- 23352568 TI - Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. AB - BACKGROUND: Trastuzumab is associated with improvements in overall survival (OS) among patients with HER2-positive metastatic breast cancer (MBC); however disease course and patterns of care in individual patients are highly variable. METHODS: 113 HER2-positive patients diagnosed with MBC from 1999 to 2005 who received trastuzumab-based therapy were retrospectively identified to allow for a minimum of 5 years of follow-up time. Median OS and median duration of therapy were determined using Kaplan-Meier methodology and group comparisons were based on the log-rank test. Hazard ratios (HR) were obtained using a Cox proportional hazards model. RESULTS: Median OS was 3.5 years (95% CI 3.0-4.4) from time of initiation of first therapy in the metastatic setting. On univariate analysis, central nervous system (CNS) disease at first recurrence was associated with a shorter OS compared with liver and/or lung metastases or other sites (CNS: 1.9 years CI 0.1 5.9, liver/lung: 3.2 years CI 2.5-4.2, other: 4.6 years CI 2.7-8.0; p = 0.05), however, this was not predictive of survival outcome in multivariate analysis. CNS metastases developed in 62 (55%) patients by the time of death or last follow up. Median duration of therapy was similar up to 6 lines of treatment, and ranged from 5.2 months to 7.2 months. CONCLUSIONS: The natural history of HER2-positive MBC has evolved with trastuzumab-based therapy with median OS now exceeding 3 years. CNS disease is a major problem with continued risk of CNS progression over time. Patients demonstrate clinical benefit to multiple lines of HER2-directed therapy. PMID- 23352569 TI - Decomposing developmental differences in probabilistic feedback learning: a combined performance and heart-rate analysis. AB - Learning on the basis of outcome feedback shows pronounced developmental changes, however, much is still unknown about its underlying processes. In the current study, we aimed at decomposing how value updating, feedback monitoring and executing behavioral control contribute to children's probabilistic feedback learning. Children (ages 8-9), young adolescents (ages 11-13) and young adults (ages 18-24), performed two probabilistic feedback tasks: one required building a value representation on the basis of feedback (noninformed task), while in the other value representations were explicitly presented (informed task). Heart-rate was recorded to augment performance measures of feedback processing. We observed substantial developmental differences in heart-rate responses toward feedback in the noninformed task. Adult's heart-rate slowed more to negative compared to positive feedback relative to the children and young adolescents. In contrast, in the informed task all age groups showed larger heart-rate slowing toward negative compared to positive feedback. These results indicate that children are not impaired in monitoring probabilistic feedback per se, but have a specific deficit in building a task-appropriate value representation on the basis of probabilistic feedback. PMID- 23352570 TI - High cardiac vagal control protects against future depressive symptoms under conditions of high social support. AB - High cardiac vagal control (as measured by respiratory sinus arrhythmia; RSA) is associated with lower depression. Recent theories argue that people's responsiveness to social resources is a key mechanism in this association. This argument implies two hypotheses: first, high RSA should be related to decreased depressive symptoms only when social resources (social support) are available; second, utilization of available social resources (social engagement) should serve as a mechanism for the positive effects of RSA. To test these hypotheses, we measured RSA in 131 adults. Participants reported their social support, social engagement, and depressive symptoms. Six months later, they again reported their depressive symptoms. Participants with higher RSA reported fewer depressive symptoms six months later, but only under conditions of high social support. The interaction between RSA and social support in predicting depressive symptoms was fully mediated by social engagement. These findings provide crucial support for the idea that cardiac vagal control contributes to decreased depressive symptoms via social processes. Implications for biological sensitivity to context and differential susceptibility theories as well as for the prevention and treatment of depression are discussed. PMID- 23352571 TI - The reconstructive microsurgery ladder in orthopaedics. AB - Since the advent of the operating microscope by Julius Jacobson in 1960, reconstructive microsurgery has become an integral part of extremity reconstruction and orthopaedics. During World War I, with the influx of severe extremity trauma Harold Gillies introduced the concept of the reconstructive ladder for wound closure. The concept of the reconstructive ladder goes from simple to complex means of attaining wound closure. Over the last half century microsurgery has continued to evolve and progress. We now have a microsurgical reconstructive ladder. The microsurgical reconstruction ladder is based upon the early work on revascularization and replantation extending through the procedures that are described in this article. PMID- 23352572 TI - Study on cheliceral sensilla of the brown dog tick Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae) involved in taste perception of phagostimulants. AB - Phagostimulants are chemical compounds that stimulate feeding. Some tick species are known to have pores in their inner cheliceral digits, called pit sensillum (ps), which are involved in taste perception. This study investigated the existence of ps in chelicerae of Rhipicephalus sanguineus ticks by scanning electron microscopy (SEM) and their involvement in the perception of phagostimulatory substances, such as the salts potassium chloride and sodium chloride (KCl and NaCl), sugars (glucose, sucrose and fructose), purines (guanine and hypoxanthine), the nucleotide adenosine triphosphate (ATP) and the tripeptide reduced glutathione (GSH), as well as their combinations at different concentrations. By means of scanning electron microscopy, a ps was observed at the expected location. Using a single-sensillum recording technique, strong activity by R. sanguineus cheliceral sensilla in response to glucose, ATP, GSH and high concentrations of salts was recorded. The responses to ATP and to KCl at 1M were multicellular, while the responses to the other stimulant compounds were monocellular. Glucose and GSH stimulated different neurons. The taste response of R. sanguineus chelicerae seemed to be selective, given that substances that were not expected to participate in this tick's biology were not perceived. PMID- 23352573 TI - Induction of apoptosis in non-small cell lung cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPA/siRNA complex nanoparticles. AB - Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer caused human death. In this work, we selected oncogene mouse double minute 2 (MDM2) as a therapeutic target for NSCLC treatment and proposed that sufficient MDM2 knockdown could inhibit tumor growth via induction of cell cycle arrest and cancer cell apoptosis. On this regard, a new pH-responsive diblock copolymer of poly(methacryloyloxy ethyl phosphorylcholine)-block-poly(diisopropanolamine ethyl methacrylate) (PMPC-b-PDPA)/siRNA-MDM2 complex nanoparticle with minimized surface charge and suitable particle size was designed and developed for siRNA MDM2 delivery in vitro and in vivo. The experimental results showed that the nanoparticles were spherical with particle size around 50 nm. MDM2 knockdown in p53 mutant NSCLC H2009 cells induced significant cell cycle arrest, apoptosis and growth inhibition through upregulation of p21 and activation of caspase-3. Furthermore, the growth of H2009 xenograft tumor in nude mice was inhibited via repeated injection of PMPC-b-PDPA/siRNA-MDM2 complex nanoparticles. These results suggested that PMPC-b-PDPA/siRNA complex nanoparticles targeting a unique set of oncogenes could be developed into a new therapeutic approach for NSCLC treatment. PMID- 23352574 TI - Development and application of tools for Monte Carlo based simulations in a particle beam radiotherapy facility. AB - The integration of Monte Carlo (MC) transport codes into a particle therapy facility could be more easily achieved thanks to dedicated software tools. MC approach has been applied to several purposes at CNAO (Centro Nazionale di Adroterapia Oncologica), such as database generation for the treatment planning system, quality assurance calculations and biologically related simulations. In this paper we describe another application of the MC code and its tools by analyzing the impact of the dose delivery and range uncertainties on patient dose distributions. PMID- 23352576 TI - Infliximab induces a dysregulated tissue-homing profile on human T-lymphocytes in vitro: a novel mechanism for paradoxical inflammation? PMID- 23352577 TI - Laparoscopic ileocolic resection for perforated Crohn's disease in pregnancy. PMID- 23352578 TI - Hyperglycaemia and beta-cell antibodies: is it always pre-type 1 diabetes? AB - We describe 10-year-old girl with mild incidental hyperglycaemia, impaired glucose tolerance and GADA positivity. Family history for mild hyperglycaemia and GADA fluctuation alerted us to a possible MODY diagnosis which was confirmed by detection of GCK mutation c.626C>T; p.T209M. Weak or transient beta-cell autoimmunity should not preclude genetic testing for MODY when the clinical features are suggestive. PMID- 23352579 TI - Brief report: Use of the Mini-Cog as a screening tool for cognitive impairment in diabetes in primary care. AB - The Mini-Cog was shown to be a brief, acceptable and practical cognitive screen for older people with diabetes when administered by a primary care nurse. It could be integrated easily into the annual diabetes review and help to identify those who may benefit from extra help with their management. PMID- 23352575 TI - The maternal to zygotic transition in mammals. AB - Prior to activation of the embryonic genome, the initiating events of mammalian development are under maternal control and include fertilization, the block to polyspermy and processing sperm DNA. Following gamete union, the transcriptionally inert sperm DNA is repackaged into the male pronucleus which fuses with the female pronucleus to form a 1-cell zygote. Embryonic transcription begins during the maternal to zygotic transfer of control in directing development. This transition occurs at species-specific times after one or several rounds of blastomere cleavage and is essential for normal development. However, even after activation of the embryonic genome, successful development relies on stored maternal components without which embryos fail to progress beyond initial cell divisions. Better understanding of the molecular basis of maternal to zygotic transition including fertilization, the activation of the embryonic genome and cleavage-stage development will provide insight into early human development that should translate into clinical applications for regenerative medicine and assisted reproductive technologies. PMID- 23352581 TI - Blinded assessment of operative performance after fundamentals of laparoscopic surgery in gynecology training. AB - STUDY OBJECTIVE: To determine the pass rate for the Fundamentals of Laparoscopic Surgery (FLS) examination among senior gynecology residents and fellows and to find whether there is an association between FLS scores and previous laparoscopic experience as well as laparoscopic intraoperative (OR) skills assessment. DESIGN: Prospective cohort study (Canadian Task Force classification II-2). SETTING: Three gynecology residency training programs. PARTICIPANTS: Third- and fourth year gynecology residents and urogynecology fellows. INTERVENTIONS: All participants participated in the FLS curriculum, written and manual skills examination, and completed a survey reporting baseline characteristics and opinions. Fourth-year residents and fellows underwent unblinded and blinded pre- and post-FLS OR assessments. Objective OR assessments of fourth-year residents after FLS were compared with those of fourth-year resident controls who were not FLS trained. MEASUREMENTS AND MAIN RESULTS: Twenty-nine participants were included. The overall pass rate was 76%. The pass rate for third- and fourth-year residents and fellows were 62%, 85%, and 100%, respectively. A trend toward improvement in OR assessments was observed for fourth-year residents and fellows for pre-FLS curriculum compared with post-FLS testing, and FLS-trained fourth year residents compared with fourth-year resident controls; however, this did not reach statistical significance. Self-report of laparoscopic case load experience of >20 cases was the only baseline factor significantly associated with passing the FLS examination (p = .03). CONCLUSION: The FLS pass rate for senior residents and fellows was 76%, with higher pass rates associated with increasing levels of training and laparoscopic case experience. PMID- 23352580 TI - Prospective evaluation of the incidence of uterine vascular malformations developing after abortion or delivery. AB - STUDY OBJECTIVE: To describe the incidence of uterine vascular malformations (UVMs) including uterine arteriovenous malformations (AVMs) in patients after abortion or delivery and in outpatients. DESIGN: Prospective study (Canadian Task Force classification II-3). SETTING: Fukushima Red Cross Hospital. PATIENTS: Six patients with a UVM including 1 with an AVM. INTERVENTIONS: Clinical screening of patients using transvaginal color Doppler ultrasonography between April 2010 and March 2012. MEASUREMENTS AND MAIN RESULTS: The incidence of UVM developing after abortion or delivery or in outpatients was prospectively evaluated using transvaginal color Doppler ultrasonography. From 959 patients, we identified 6 (0.63%) with UVMs, including 1 (0.10%) with a uterine AVM. Specifically, we detected UVMs in 4 of 77 patients (5.2%) after abortion, 1 of 458 patients (0.22%) after delivery, and 1 of 424 outpatients (0.24%). Four patients after abortion and 1 after delivery reported mild symptoms, which were treated conservatively; however, the outpatient had a severe uterine AVM, which was confirmed via 3-dimensional computed tomography angiography. CONCLUSION: The incidence of UVMs was relatively higher, in particular in the patients after abortion, and was significantly higher than that in postpartum or outpatient groups. Therefore, it is important to consider the possibility of UVMs in any patient with episodes of unexplained uterine bleeding and to perform follow-up analysis using color Doppler ultrasonography. Such an approach will facilitate accurate diagnosis and lead to appropriate clinical management to prevent unnecessary dangerous repeat curettage, which might induce profuse uterine bleeding. PMID- 23352582 TI - Tension-free vaginal tape-O and -Secur for the treatment of stress urinary incontinence: a thirty-six-month follow-up single-blind, double-arm, randomized study. AB - OBJECTIVE: To compare the efficacy of the inside-out tension-free vaginal tape obturator (TVT-O) device versus the single-incision TVT-Secur device 36 months after the procedure. METHODS: A single-blind, randomized, parallel-group study on 154 patients with stress urinary incontinence (77 treated with TVT-O and 77 with the TVT-Secur hammock approach). The primary endpoint was the objective cure rate 36 months after the procedure evaluated with the challenge stress test. Secondary endpoints were subjective cure rate (evaluated with bladder diary, quality-of life questionnaires, and patient-reported outcome tools) and intraoperative and postoperative complications. The primary endpoint was evaluated with a noninferiority study design. RESULTS: Sixty-six patients in the TVT-O group and 64 in the TVT-Secur group concluded the study. Thirty-six months after the procedure, 57/66 patients (86.4%) in the TVT-O and 50/64 (78.1%) in the TVT-Secur groups were objectively cured (noninferiority unilateral u test: p < .05). No differences were observed in the subjective cure and complication rates. CONCLUSIONS: TVT-Secur seems not to be inferior to TVT-O in the surgical treatment of stress urinary incontinence and causes less postoperative pain. The possibility of severe blood loss cannot be ruled out when TVT-Secur is used. PMID- 23352583 TI - Origin and diversification of a metabolic cycle in oligomer world. AB - Based on the oligomer-world hypothesis we propose an abstract model where the molecular recognition among oligomers is described in the shape space. The origin of life in the oligomer world is regarded as the establishment of a metabolic cycle in a primitive cell. The cycle is sustained by the molecular recognition. If an original cell acquires the ability of the replication of oligomers, the relationship among oligomers changes due to the poor fidelity of the replication. This change leads to the diversification of metabolic cycles. The selection among diverse cycles is the basis of the evolution. The evolvability is one of the essential characters of life. We demonstrate the origin and diversification of the metabolic cycle by the computer simulation of our model. Such a simulation is expected to be the simplified demonstration of what actually occurred in the primordial soup. Our model describes an analog era preceding the digital era based on the genetic code. PMID- 23352584 TI - Are suppression and deterrence mechanisms enough? Examining the "pulling levers" drug market intervention strategy in Peoria, Illinois, USA. AB - BACKGROUND: Police agencies across the globe enforce laws that prohibit drug transportation, distribution, and use with varying degrees of effectiveness. Within the United States, law enforcement strategies that rely on partnerships between criminal justice officials, neighbourhood residents, and social service providers (i.e., collaborative implementation) have shown considerable promise for reducing crime and disorder associated with open-air drug markets. The current study examines a comprehensive police enforcement strategy conducted in Peoria, Illinois (USA) designed to reduce patterns of crime and violence associated with an open-air drug market in a specific neighbourhood. METHODS: Change in neighbourhood crime was assessed using Autoregressive Integrated Moving Average (ARIMA) interrupted time series analysis. Further, target area residents were surveyed to gauge their awareness of the police intervention as well as perceived changes in local crime patterns. RESULTS: Analyses indicate that the intervention did not produce significant changes in neighbourhood crime offense rates between pre- and post-intervention periods. In addition, the majority of surveyed residents within the target area did not demonstrate an awareness of the intervention nor did they report perceived changes in local crime patterns. CONCLUSIONS: Study findings suggest that police-led approaches in the absence of high levels of community awareness and involvement may have less capacity to generate crime-control when focusing on open-air drug markets. We propose that police agencies adopting this strategy invest considerable resources toward achieving community awareness and participation in order to increase the potential for attaining significant and substantive programmatic impact. PMID- 23352585 TI - Removal of pharmaceuticals from wastewater by biological processes, hydrodynamic cavitation and UV treatment. AB - To augment the removal of pharmaceuticals different conventional and alternative wastewater treatment processes and their combinations were investigated. We tested the efficiency of (1) two distinct laboratory scale biological processes: suspended activated sludge and attached-growth biomass, (2) a combined hydrodynamic cavitation-hydrogen peroxide process and (3) UV treatment. Five pharmaceuticals were chosen including ibuprofen, naproxen, ketoprofen, carbamazepine and diclofenac, and an active metabolite of the lipid regulating agent clofibric acid. Biological treatment efficiency was evaluated using lab scale suspended activated sludge and moving bed biofilm flow-through reactors, which were operated under identical conditions in respect to hydraulic retention time, working volume, concentration of added pharmaceuticals and synthetic wastewater composition. The suspended activated sludge process showed poor and inconsistent removal of clofibric acid, carbamazepine and diclofenac, while ibuprofen, naproxen and ketoprofen yielded over 74% removal. Moving bed biofilm reactors were filled with two different types of carriers i.e. Kaldnes K1 and Mutag BioChipTM and resulted in higher removal efficiencies for ibuprofen and diclofenac. Augmentation and consistency in the removal of diclofenac were observed in reactors using Mutag BioChipTM carriers (85%+/-10%) compared to reactors using Kaldnes carriers and suspended activated sludge (74%+/-22% and 48%+/-19%, respectively). To enhance the removal of pharmaceuticals hydrodynamic cavitation with hydrogen peroxide process was evaluated and optimal conditions for removal were established regarding the duration of cavitation, amount of added hydrogen peroxide and initial pressure, all of which influence the efficiency of the process. Optimal parameters resulted in removal efficiencies between 3-70%. Coupling the attached-growth biomass biological treatment, hydrodynamic cavitation/hydrogen peroxide process and UV treatment resulted in removal efficiencies of >90% for clofibric acid and >98% for carbamazepine and diclofenac, while the remaining compounds were reduced to levels below the LOD. For ibuprofen, naproxen, ketoprofen and diclofenac the highest contribution to overall removal was attributed to biological treatment, for clofibric acid UV treatment was the most efficient, while for carbamazepine hydrodynamic cavitation/hydrogen peroxide process and UV treatment were equally efficient. PMID- 23352586 TI - Sonochemical effectiveness factor (e(US)) in the reactors for wastewater treatment by sono-Fenton oxidation: novel considerations. AB - A comprehensive algorithm was recently proposed for calculation of the sonochemical effectiveness factor and wastewater treatment modeling. The presented approach implies that ultrasound is an auxiliary source of free radicals in Fenton type reactions; introduction of ultrasound represents an enhancement of pollutant degradation rates. The sonochemical effectiveness factor was introduced in kinetic models as the eUS factor (Grcic et al., 2012 [1]). As a substantial follow-up, this study presents novel considerations. The eUS factor was modeled as a function of employed frequency, actual cavitation-related power intensity of ultrasound and a portion of the cavitationally active zone, i.e. dimensionless active volume. The effect of temperature was disregarded in the present model considerations. Cavitationally active zone in reactors was determined based on the erosion of aluminum foil, resulting in cone-shaped space arising from transducer. In the present study, sonochemical treatment of industrial wastewater containing HCOONa as organic pollutant was performed using different equipment: ultrasonic baths (UB1, UB2 and UB3), cylindrical reactor with homogenizer (HCR) and three-frequency hexagonal cell, i.e. ultrasonic pilot reactor prototype (PP). Explored frequency range was from 20 to 120 kHz. Homogeneous and heterogeneous Fenton-type sonochemical processes, US/Fe(II)(FeSO4,aq.)/H2O2 and US/Fe(II)(steel-plate)/H2O2, respectively, applied to industrial wastewater were investigated in terms of mineralization kinetics. Newly modeled eUS factor was introduced in corresponding kinetic models and the overall model was validated. Kinetic parameters of Fenton process were treated as independent of ultrasound, since eUS factor consists of cavitation-related phenomena responsible for the mineralization rate enhancement. In average, a 21% increase of mineralization efficiency was achieved using a single frequency, while more than 70% increase can be achieved by combining 20, 68 and 120 kHz in PP. PMID- 23352587 TI - Use of birth weight threshold for macrosomia to identify fetuses at risk of shoulder dystocia among Chinese populations. AB - OBJECTIVE: To assess the incidence of macrosomia and the influence of birth weight on shoulder dystocia risk among a cohort of Chinese women. METHODS: A retrospective analysis was conducted of 80953 singleton deliveries recorded at the Prince of Wales Hospital, Hong Kong, between 1995 and 2009. The incidences of macrosomia (birth weight >= 4000 g) and shoulder dystocia were assessed by birth weight; risk factors for shoulder dystocia were examined by multiple logistic regression analysis. RESULTS: The incidence of macrosomia was 3.4%. The overall incidence of shoulder dystocia was 0.3%; however, the incidence rose with increasing birth weight. The odds ratio (OR) for a birth weight of 4000-4199 g was 22.40, while the OR for a birth weight of 4200 g or above was 76.10. Other independent risk factors for shoulder dystocia included instrumental delivery (OR 12.11), short stature (OR 2.16), maternal diabetes mellitus (OR 1.78), and obesity (OR 1.58). CONCLUSION: Although the overall incidences of macrosomia and shoulder dystocia were low, the risk of shoulder dystocia was strongly linked to increasing birth weight. International guidelines for elective cesarean delivery in suspected cases of macrosomia may not, therefore, apply to Chinese women. PMID- 23352588 TI - IFPA Gabor Than Award lecture: molecular control of placental growth: the emerging role of microRNAs. AB - Fetal growth is dependent on appropriate growth and function of the placenta. This is modulated by a variety of factors, including maternal growth factors that exert their actions by binding to specific receptors on trophoblast to promote activation of signaling events. Kinases and phosphatases within trophoblast act in concert to regulate growth factor actions and recent studies have begun to elucidate a role for microRNAs (miRs) in regulating the levels of these proteins in the placenta. This review will discuss growth factor signaling in the placenta and describe the emerging role of miRs in regulating placental development. PMID- 23352589 TI - Partial seizures during ACTH therapy in a cryptogenic West syndrome patient. AB - BACKGROUND: Partial seizures often develop during the clinical course of infantile spasms. Herein, we report a boy with cryptogenic West syndrome, who developed partial seizures that we suspected were induced by the ACTH therapy. SUBJECT: The patient developed cryptogenic West syndrome at six months of age and ACTH therapy was started. On the tenth day of treatment, he developed frequent partial seizures, characterized by being motionless during the seizure with eye deviation to the right. The partial seizures stopped after the ACTH was discontinued, although oral carbamazepine was commenced at the same time. Thus, a definitive role for carbamazepine in the treatment of the partial seizures was unclear as the timing of the seizure cessation also corresponded to the discontinuation of the ACTH therapy. We suspected that the partial seizures were induced by the ACTH therapy for the following reasons: (1) seizures appeared only during ACTH therapy, (2) no new epileptic focus was revealed by EEG, MRI, or (99m)TcECD SPECT, and (3) the seizures were different from the epileptic spasms. CONCLUSION: Our results suggest that ACTH might induce partial seizures in West syndrome. Further studies are required to confirm this phenomenon. PMID- 23352590 TI - The influence of 5-lipoxygenase on Alzheimer's disease-related tau pathology: in vivo and in vitro evidence. AB - BACKGROUND: Intracellular deposition of tau protein is a hallmark lesion of Alzheimer's disease. Although it is known this event is secondary to excessive tau phosphorylation, the mechanisms involved remain unknown. We previously reported that the enzyme 5-Lipoxygenase (5LO) acts as a modulator of Abeta peptides formation in vivo, and here we investigate its influence on tau protein. METHODS: Tg2576 mice overexpressing neuronal 5LO were generated and its contribution to endogenous tau levels and metabolism investigated. RESULTS: Although no differences were noted in the levels of total tau for both groups, compared with controls, Tg2576 mice overexpressing 5LO had a significant increase in the phosphorylation state of tau at S396 and S396/S404, as recognized by the antibodies PHF-13 and PHF-1, respectively. By contrast, no phosphorylation changes were observed in other tau epitopes. This increase was associated with a significant elevation in cyclin dependent kinase-5 but not other kinases that have been involved in tau phosphorylation. Additionally, mice overexpressing 5LO had biochemical evidence of altered synaptic integrity because they manifested a reduction in PSD-95, synaptophysin and MAP2. CONCLUSIONS: This study demonstrates a new role for 5LO in regulating endogenous tau metabolism in the central nervous system and supports the hypothesis that its pharmacologic inhibition could be beneficial for Alzheimer's disease-related tau neuropathology. PMID- 23352591 TI - Logistic models--an odd(s) kind of regression. AB - The logistic regression model bears some similarity to the multivariable linear regression with which we are familiar. However, the differences are great enough to warrant a discussion of the need for and interpretation of logistic regression. PMID- 23352592 TI - Budesonide MMX and mesalamine to induce remission in patients with ulcerative colitis. PMID- 23352593 TI - Antioxidants for chronic pancreatitis: reasons for disappointing results despite sound principles. PMID- 23352594 TI - John Gaetano Forte, PhD. PMID- 23352595 TI - Double vision. Hepatic foregut duplication cyst and concurrent acute gangrenous cholecystitis. PMID- 23352596 TI - The self-reported density of truck traffic on residential streets and the impact on asthma, hay fever and eczema in young adolescents. AB - BACKGROUND: Conflicting results have been reported, mostly in developed countries, on the relationship between exposure to traffic and allergic diseases. This study aims to examine the impact of truck traffic on asthma, rhinitis and eczema in early adolescence in Skopje, the capital of the Republic of Macedonia, as a developing country with a lower middle rate of high truck traffic exposure and low prevalence rates of allergic diseases. METHODS: Self-reported data was used, obtained through the International Study of Asthma and Allergies in Childhood Phase 3 written questionnaires, from 3026 adolescents aged 13-14 years from Skopje. Truck traffic density on the street of residence on weekdays was correlated to current and ever-diagnosed asthma, rhinitis and eczema by odds ratios (OR, 95% CI) in binary logistic regression, with and without adjustments for potential confounding factors separately and for their joint effect. RESULTS: A positive association of truck traffic density appeared to be limited to current dry night cough (aOR: 1.63; 1.07-2.47; aOR: 2.17; 1.40-3.35; and aOR: 2.33; 1.43 3.79 for truck traffic seldom, frequently through the day, and almost the whole day, respectively) with an exposure-response relationship and to current wheeze only for truck traffic almost the whole day (aOR: 1.87; 1.02-3.42). CONCLUSION: The findings suggest an aggravating effect of truck traffic on current asthma symptoms, but not on asthma, allergic rhinitis and eczema diagnoses. It seems that it probably has an impact as a direct respiratory irritant in early adolescence. PMID- 23352597 TI - Tau protein levels in children do not increase during severe asthma attack induced hypoxic conditions. PMID- 23352598 TI - Sexually dimorphic myofilament function and cardiac troponin I phosphospecies distribution in hypertrophic cardiomyopathy mice. AB - The pathological progression of hypertrophic cardiomyopathy (HCM) is sexually dimorphic such that male HCM mice develop phenotypic indicators of cardiac disease well before female HCM mice. Here, we hypothesized that alterations in myofilament function underlies, in part, this sex dimorphism in HCM disease development. Firstly, 10-12month female HCM (harboring a mutant [R403Q] myosin heavy chain) mice presented with proportionately larger hearts than male HCM mice. Next, we determined Ca(2+)-sensitive tension development in demembranated cardiac trabeculae excised from 10-12month female and male HCM mice. Whereas HCM did not impact Ca(2+)-sensitive tension development in male trabeculae, female HCM trabeculae were more sensitive to Ca(2+) than wild-type (WT) counterparts and both WT and HCM males. We hypothesized that the underlying cause of this sex difference in Ca(2+)-sensitive tension development was due to changes in Ca(2+) handling and sarcomeric proteins, including expression of SR Ca(2+) ATPase (2a) (SERCA2a), beta-myosin heavy chain (beta-MyHC) and post-translational modifications of myofilament proteins. Female HCM hearts showed an elevation of SERCA2a and beta-MyHC protein whereas male HCM hearts showed a similar elevation of beta-MyHC protein but a reduced level of cardiac troponin T (cTnT) phosphorylation. We also measured the distribution of cardiac troponin I (cTnI) phosphospecies using phosphate-affinity SDS-PAGE. The distribution of cTnI phosphospecies depended on sex and HCM. In conclusion, female and male HCM mice display sex dimorphic myofilament function that is accompanied by a sex- and HCM dependent distribution of sarcomeric proteins and cTnI phosphospecies. PMID- 23352599 TI - Specific binding of DNA to aggregated forms of Alzheimer's disease amyloid peptides. AB - Anomalous protein aggregation is closely associated to age-related mental illness. Extraneuronal plaques, mainly composed of aggregated amyloid peptides, are considered as hallmarks of Alzheimer's disease. According to the amyloid cascade hypothesis, this disease starts as a consequence of an abnormal processing of the amyloid precursor protein resulting in an excess of amyloid peptides. Nuclear localization of amyloid peptide aggregates together with amyloid-DNA interaction, have been repeatedly reported. In this paper we have used surface plasmon resonance and electron microscopy to study the structure and behavior of different peptides and proteins, including beta-lactoglobulin, bovine serum albumin, myoglobin, histone, casein and the amyloid-beta peptides related to Alzheimer's disease Abeta25-35 and Abeta1-40. The main purpose of this study is to investigate whether proneness to DNA interaction is a general property displayed by aggregated forms of proteins, or it is an interaction specifically related to the aggregated forms of those particular proteins and peptides related to neurodegenerative diseases. Our results reveal that those aggregates formed by amyloid peptides show a particular proneness to interact with DNA. They are the only aggregated structures capable of binding DNA, and show more affinity for DNA than for other polyanions like heparin and polyglutamic acid, therefore strengthening the hypothesis that amyloid peptides may, by means of interaction with nuclear DNA, contribute to the onset of Alzheimer's disease. PMID- 23352600 TI - Hemophilia clinical gene therapy: brief review. AB - Genetic correction of hemophilia A and B was long considered amenable to the available gene transfer technologies. This assumption has come to fruition with the recent results of a phase I/II trial for hemophilia B. Here we review the clinical application of gene therapy for the hemophilia's as a paradigm of the evolution of gene transfer science and technology. This review is not intended as comprehensive but rather to highlight current clinical developments of gene therapy for the hemophilias. PMID- 23352601 TI - Reply by authors. PMID- 23352602 TI - Radiolabeling of the cannabinoid receptor agonist AZD1940 with carbon-11 and PET microdosing in non-human primate. AB - INTRODUCTION: N-(2-tert-butyl-1-((4,4-difluorocyclohexyl)methyl)-1H benzo[d]imidazol-5-yl)ethanesulfonamide (AZD1940) is a candidate drug for treatment of neuropathic pain. As part of the preclinical evaluation of AZD1940, a microdosing study with positron emission tomography (PET) was conducted to assess brain exposure. METHODS: AZD1940 was radiolabeled with carbon-11 in the benzimidazole moiety. The radioactive precursor, lithium [(11)C]pivalate was obtained via (11)C-carboxylation of tert-butyl lithium. The target compound, [(11)C]AZD1940, was in turn obtained by the microwave assisted reaction between lithium [(11)C]pivalate and the o-phenylene diamine analog of AZD1940 (N-(3-amino 4-((4,4-difluorocyclohexyl)methylamino)phenyl)ethanesulfonamide) in neat phosphorous oxychloride. A brain PET measurement was performed in cynomolgus monkey. RESULTS: The overall radiochemical yield of final formulated radiochemically pure (>99%) [(11)C]AZD1940 was 0.4% (uncorrected for decay) and the specific radioactivity was 13GBq/MUmol at time of administration (58min after end of bombardment). After intravenous injection to cynomolgus monkey, the maximum concentration of radioactivity detected in the brain region of interest was 0.7% of the total injected radioactivity. The regional distribution of radioactivity within brain was homogenous. CONCLUSIONS: AZD1940 was radiolabelled with carbon-11 and its brain exposure, assessed using PET, was relatively low in comparison to peripheral organ exposure. PMID- 23352603 TI - A comparison of Re-188-MN-16ET-lipiodol and transcatheter arterial chemoembolization in the treatment of hepatoma: an animal study. AB - INTRODUCTION: In patients with unresectable HCC, transcatheter arterial chemoembolization (TACE) is a widely used treatment. Recently, as an alternative treatment modality for HCC, transcatheter arterial embolization with radioisotopes has been investigated. In this study, we compared the therapeutic efficacy of an intra-hepatic arterial injection of Re-188-MN-16ET-lipiodol and the TACE method in rats with liver tumors. METHODS: Twelve male rats bearing hepatic tumors were divided into three groups to evaluate the efficacy of treatment (four in each group). Group 1 received an intra-hepatic arterial injection of 0.2mCi of Re-188-MN-16ET-lipiodol; group 2 received epirubicin (0.5mg/kg) and 0.1ml of lipiodol emulsion; group 3 received 0.1ml of normal saline and served as the control group. Tumor size was measured by liver sonography before injection, at two weeks, four weeks and eight weeks after injection. Survival time was calculated from the day of treatment to 56days after treatment by the life-table method. The response to treatment and the survival time in each group were evaluated and compared. RESULTS: All rats treated with Re 188 MN-16ET-lipiodol showed good response to the therapy. Their tumor size decreased and all rats survived over eight weeks. All rats treated with epirubicin plus lipiodol survived over 8weeks; however, two rats (50%) showed increased tumor size in the 8th week. As for the control group (rats treated with normal saline), all rats survived less than 37days with continuous tumor growth. CONCLUSION: Results showed that Re-188-MN-16ET-lipiodol can be a potential therapeutic pharmaceutical for the treatment of liver tumors. PMID- 23352604 TI - Efficacy and safety of bevacizumab-based combination regimens in patients with previously untreated metastatic colorectal cancer: final results from a randomised phase II study of bevacizumab plus 5-fluorouracil, leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC ACCORD 13/0503 study). AB - BACKGROUND: The combination of bevacizumab and bolus 5-fluorouracil, leucovorin and irinotecan is highly effective in patients with metastatic colorectal cancer (mCRC). This randomised, multicenter, non-comparative phase II trial assessed the efficacy and safety of bevacizumab plus oral capecitabine plus irinotecan (XELIRI) or infusional 5-fluorouracil, leucovorin plus irinotecan (FOLFIRI) as first-line therapy for patients with mCRC. PATIENTS AND METHODS: Patients received bevacizumab 7.5mg/kg on day 1 plus XELIRI (irinotecan 200mg/m(2) on day 1 and oral capecitabine 1,000 mg/m(2) bid on days 1-14) every 3 weeks or bevacizumab 5mg/kg on day 1 plus FOLFIRI (5-fluorouracil 400mg/m(2) on day 1 plus 2,400 mg/m(2) as a 46-h infusion, leucovorin 400mg/m(2) on day 1, and irinotecan 180 mg/m(2) on day 1) every 2 weeks. Patients aged >= 65 years received a lower dose of capecitabine (800 mg/m(2) twice daily). The primary endpoint was 6-month progression-free survival (PFS) rate. RESULTS: A total of 145 patients were enrolled (bevacizumab-XELIRI, n=72; bevacizumab-FOLFIRI, n=73). The 6-month PFS rate was 82% (95% confidence intervals (CI) 71-90%) in the bevacizumab-XELIRI arm and 85% (95% CI 75-92%) in the bevacizumab-FOLFIRI arm. In both the bevacizumab XELIRI and bevacizumab-FOLFIRI arms, median PFS and overall survival (OS) were 9 and 23 months, respectively. The most frequent toxicities were grade 3/4 neutropenia (bevacizumab-XELIRI 18%; bevacizumab-FOLFIRI 26%) and grade 3 diarrhoea (12% and 5%, respectively). CONCLUSIONS: This randomised non comparative study demonstrates that bevacizumab-XELIRI and bevacizumab-FOLFIRI are effective regimens for the first-line treatment of patients with mCRC with manageable toxicity profiles. PMID- 23352605 TI - Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. AB - The prospects for using autologous induced pluripotent stem cells (iPSCs) in cell replacement therapy have been tempered by evidence that undifferentiated, syngeneic mouse iPSCs are immunogenic upon transplantation. However, the immunogenicity of more therapeutically relevant differentiated cells remains unexplored. Here, we differentiated mouse iPSCs into embryoid bodies (EBs) or representative cell types spanning the three embryonic germ layers and assessed their immunogenicity in vitro and after their transplantation into syngeneic recipients. We found no evidence of increased T cell proliferation in vitro, rejection of syngeneic iPSC-derived EBs/tissue-specific cells (TSCs) after transplantation, or an antigen-specific secondary immune response. Thus, differentiated cells derived from syngeneic iPSCs do not appear to be rejected after transplantation. We also found little evidence of an immune response to undifferentiated, syngeneic iPSCs. Our data support the idea that differentiated cells generated from autologous iPSCs could be applied for cell replacement therapy without eliciting immune rejection. PMID- 23352607 TI - Acceptance of hospital nurses toward sensor-based medication systems: a questionnaire survey. AB - BACKGROUND: Sensor-based technologies offer numerous benefits in hospital environments as they can be used (1) to improve efficiency defined processes and (2) to monitor their conduction in order to prevent errors. However, the impact of these technologies on the stakeholders involved such as professional ward nurses is largely unexplored. The early assessment of technology acceptance and user resistance is crucial to anticipate potential conflicts and to improve future implementation success. OBJECTIVES: To understand the attitudes and intentions of usage of professional ward nurses toward sensor-based medication systems based on an adjusted extended technology acceptance model (TAM2) in a pre implementation stage. DESIGN: A scenario-based research design was used in a nation-wide empirical study. SETTINGS: Nurses of Australian associations/unions evaluated a scenario of a sensor-based medication support system. PARTICIPANTS: A randomly selected sample of 579 professional ward nurses participated in this study. METHODS: Data were collected using an online questionnaire and explored using hierarchical regression analysis. RESULTS: The majority of nurses intend to use the system but 25% - not voluntarily. 8% reject the system entirely. In assessing the nurses' perceived usefulness, image, demonstrability, qualitative and quantitative overload as well as personal innovativeness were found to have a significant impact. Qualitative and quantitative overload also have a significant negative effect on personal innovativeness. Regarding the nurses' usage intention, we identified a significant negative influence of subjective norm, moderated by experience and a positive effect of perceived usefulness on intention to use the system. Image, qualitative and quantitative overload as well as personal innovativeness are significantly influenced by age. CONCLUSIONS: Our findings support a successful implementation of medication support systems in hospitals by stating acceptance drivers and barriers. Nurses' adoption is promoted once a high degree of perceived usefulness is achieved by result demonstrability, a positive image of the technology and a high degree of personal innovativeness. Image and innovativeness are moderated by age, showing that an increase in age leads to an increase in user resistance toward the perceived usefulness of the envisioned medication support systems. Future studies should investigate these barriers in further stages of implementation to extend understanding of sensor-based medication system acceptance. PMID- 23352606 TI - Divergent regulation of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor by hypoxia and female sex steroids in human endometrial stromal cells. AB - OBJECTIVE: To investigate whether hypoxia or the female sex steroids exert direct effects on angiopoietin-1 (ANGPT1), ANGPT2, and vascular endothelial growth factor (VEGF) in human endometrial stromal cells (ESCs) to clarify the regulatory function of these local angiogenic factors in the endometrium. STUDY DESIGN: Human endometrial tissues were obtained from 18 patients aged 34-47 years undergoing hysterectomy for benign reasons. ESCs were cultured under hypoxic condition or treated with 17beta-estradiol (E) and/or medroxyprogesterone acetate (MPA). The mRNA levels and production of ANGPT1, ANGPT2, and VEGF were assessed by real-time RT-PCR and ELISA, respectively. Analysis of hypoxia-inducible factor 1alpha (HIF-1alpha) and estrogen receptor alpha (ERalpha) protein levels were evaluated by Western blot analysis. RESULT(S): Hypoxia reduced the mRNA expression and protein production of ANGPT-1 in ESCs, whereas those of ANGPT2 were unaffected, resulting in an increase of the ANGPT2/ANGPT1 ratio. Hypoxia induced mRNA expression and protein production of VEGF. E simultaneously induced VEGF production and suppressed ANGPT1 production, resulting in an increase of the ANGPT2/ANGPT1 ratio. MPA or E+MPA reduced ANGPT2 production and sustained the levels of ANGPT1, resulting in a decrease of the ANGPT2/ANGPT1 ratio. With regard to the interaction of E and hypoxia, E did not affect the regulation of angiogenic factors, HIF-1alpha, and ERalpha under hypoxic conditions. CONCLUSIONS: Hypoxia and female sex hormones independently regulate the ANGPT2/ANGPT1 ratio and VEGF expression in human ESCs. These results may indicate a potential mechanism for hypoxia or female sex steroids influencing angiogenesis in the human endometrium. PMID- 23352608 TI - Discharge within 24 to 72 hours of colorectal surgery is associated with low readmission rates when using Enhanced Recovery Pathways. AB - BACKGROUND: Enhanced Recovery Pathways (ERPs) have demonstrated reduced hospital length of stay and improved outcomes after colorectal surgery. Concerns exist about increases in readmission rates. Laparoscopic colorectal surgery with an ERP can permit earlier discharge without compromising safety or increasing readmission rates. STUDY DESIGN: A review of a prospective database was performed for major elective colorectal procedures by a single surgeon. All patients followed a standardized ERP and discharge criteria. Patients were categorized by approach and day of discharge (DoD) of <= 1, <= 2, <= 3, <= 7, and >7 days. Main outcomes measures were length of stay and 30-day readmission rates in each group. RESULTS: Eight hundred and six cases (609 laparoscopic, 197 open) were identified during a 64-month period. Mean age was similar for the laparoscopic (59.1 years) and open (58.3 years) groups. Mean overall DoD was at 5 days (+/- 4.8 days); by approach, the mean laparoscopic DoD was at 3.9 days and open DoD was at 8.4 days. Twenty-nine percent were discharged within 48 hours (38% laparoscopic and 8% open) and 50% were discharged within 72 hours (62% laparoscopic and 19% open). Only 8.9% of all patients (n = 72) were readmitted (7.2% laparoscopic, 14.2% open). The cumulative readmission rate for laparoscopic patients in early DoD groups postoperative days 1, 2, and 3 were 0.2%, 1.6%, and 3.4%, respectively. CONCLUSIONS: Combining laparoscopy with an ERP optimizes patient care in colorectal surgery. The combination permits early discharge; 38% were discharged within 2 days and 62% within 3 days of surgery, with low readmission rates. These results support that early DoD is possible without compromising patient safety or increasing readmission rates. This might be a marker for low readmission rate, and suggests that readmission rate alone might not be an adequate marker of quality. PMID- 23352610 TI - The Polycystic Ovary Syndrome and recent human evolution. AB - The Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder characterised both by reproductive and metabolic disturbance, and is the most common cause globally of ovarian infertility. It is also a familial polygenic condition, linked genetically to both Type 2 diabetes and the metabolic syndrome. The striking evolutionary paradox of this prominent genetically-based condition, which impairs fertility, is that not only should it have diminished in prevalence, but it should have done so rapidly - unless there has been some form of balancing selection. The emerging discipline of evolutionary medicine can provide important insights into the causes and patterns of occurrence of common diseases such as PCOS. In this paper we review the impacts of PCOS on infertility, fecundability and lifetime reproductive success and then critically appraise published hypotheses about the evolutionary origins of PCOS and related conditions. PMID- 23352609 TI - Manipulating Y receptor subtype activation of short neuropeptide Y analogs by introducing carbaboranes. AB - Short selective neuropeptide Y (NPY) analogs are highly attractive because of their facile synthesis. Based on the reduced-size NPY analog [Pro(30), Nle(31), Bpa(32), Leu(34)]NPY 28-36 position 32 was identified as a key position to alter the preferential activation pattern of the human neuropeptide Y receptors (hYRs). By replacing benzoylphenylalanine (Bpa) by a biphenylalanine (Bip) the photostability was first improved while the biological activity was maintained. SAR-studies showed that both aromatic rings have a high influence on the preferential hYR subtype activation. Interestingly, replacement of Bpa(32) by a strongly hydrophobic moiety changed the hYR subtype preference of the analog. Whereas the parent compound is able to activate the human neuropeptide Y1 receptor (hY1R) subtype, the introduction of an N(epsilon)-ortho-carbaboranyl propionic acid modified lysine resulted in a loss of activity at the hY1R but in an increased activity at both the hY2R and the hY4R. However, subsequent receptor internalization studies with this novel analog revealed that receptor internalization can neither be triggered at the hY2R nor at the hY4R suggesting a biased ligand. Surprisingly, investigations by (1)H NMR spectroscopy revealed structural changes in the side chains of residues Pro(30) and Leu(34) which nicely correlates with the shift from hY1R/hY4R to hY2R/hY4R activation preference. Thus, position 32 has been identified to switch the bioactive conformation and subsequently influences receptor subtype activation behavior. PMID- 23352611 TI - Response of the authors on: comments on "Effect of different labor forces on fetal skull molding" by Pu et al., Med. Eng. Phys. 33 (2011) 620-625. PMID- 23352612 TI - Is there any information on micro-structure in microwave tomography of bone tissue? AB - In this work, two-dimensional simulations of the microwave dielectric properties of models with ellipses and realistic models of trabecular bone tissue are performed. In these simulations, finite difference time domain methodology has been applied to simulate two-phase structures containing inclusions. The results presented here show that the micro-structure is an important factor in the effective dielectric properties of trabecular bone. We consider the feasibility of using the dielectric behaviour of bone tissue to be an indicator of bone health. The frequency used was 950 MHz. It was found that the dielectric properties can be used as an estimate of the degree of anisotropy of the micro structure of the trabecular tissue. Conductivity appears to be the most sensitive parameter in this respect. Models with ellipse shaped-inclusions are also tested to study their application to modelling bone tissue. Models with ellipses that had an aspect ratio of a/b=1.5 showed relatively good agreement when compared with realistic models of bone tissue. According to the results presented here, the anisotropy of trabecular bone must be accounted for when measuring its dielectric properties using microwave imaging. PMID- 23352613 TI - Reconfiguration of the upper extremity relative to the pushrim affects load distribution during wheelchair propulsion. AB - OBJECTIVE: Repetitive loading during manual wheelchair propulsion (WCP) is associated with overuse injury to the upper extremity (UE). The aim of this study was to determine how RF redirection and load distribution are affected by changes upper extremity kinematic modifications associated with modifications in seat positions during a WCP task. The aim of this study was to determine how RF redirection and load distribution are affected by upper extremity kinematic changes associated with seat position adjustment during a WCP task. DESIGN: Dynamic simulations using an experiment-based multi-link inverse dynamics model were used to generate solutions for redistributing UE mechanical load in different seating positions without decrements in WCP task performance. METHODS: Experimental RF and kinematic data were collected for one subject propelling at a self-selected speed and used as input into the model. Shoulder/axle distance, wrist angular position, and RF direction were systematically modified to simulate how the mechanical demand imposed on the upper extremity (elbow and shoulder net joint moments (NJMs) and net joint forces) may vary. RESULTS: Load distribution depended on UE orientation relative to the wheel. At peak force, lower shoulder/axle distances and more anterior wrist positions on the pushrim allowed for more extended elbow positions and reduced total NJM load. INTERPRETATION: Simulation results incorporating subject-specific data may provide mechanically based information to guide clinical interventions that aim to maintain WCP performance and redistribute load by modifying RF direction, seat configuration and hand/rim interaction. PMID- 23352614 TI - PTK6 promotes degradation of c-Cbl through PTK6-mediated phosphorylation. AB - PTK6 (also known as Brk) is an intracellular tyrosine kinase which induces proliferation, anti-apoptosis, migration, and anchorage-independent growth. Herein we report that PTK6 phosphorylates and down-regulates E3 ubiquitin ligase c-Cbl. Tyr(700), Tyr(731), and Tyr(774) residues in the C-terminal domain of c Cbl are major phosphorylation sites targeted by PTK6. The phosphorylated c-Cbl is subjected to auto-ubiquitination and degraded through the ubiquitin-proteasome pathway. These results provide evidence for a novel mechanism demonstrating the oncogenic potential of PTK6 through degradation of c-Cbl, which is an E3 ligase important in down-regulation of oncoproteins. PMID- 23352615 TI - Estrogen represses CXCR7 gene expression by inhibiting the recruitment of NFkappaB transcription factor at the CXCR7 promoter in breast cancer cells. AB - Although many studies reported mechanisms involved in the positive regulation of estrogens (E2) target genes, very little is known concerning the repressive effect of E2. In this study, we explored the molecular mechanisms by which E2 regulates CXCR7 expression in breast cancer cells. Our results show that E2 mediated down-regulation of CXCR7 occurs at the transcriptional level as demonstrated using actinomycin D and requires estrogen receptor alpha (ERalpha). In addition, CXCR7 is a primary ERalpha-target gene because the effect of E2 does not require the synthesis of an intermediary protein as revealed by the translational inhibitor cycloheximide treatment. Using an inhibitor of the NFkappaB pathway and chromatin immunoprecipitation assays, we demonstrated that NFkappaB is necessary for the high expression of CXCR7 gene and is recruited to the proximal promoter of the CXCR7 gene. Interestingly, the chromatin immunoprecipitation analyses also showed that E2-treatment significantly prevented the recruitment of NFkappaB to the promoter. Altogether, our results demonstrate that E2, through ERalpha, directly down-regulates CXCR7 expression by interfering with NFkappaB transcription factor at the promoter level. PMID- 23352616 TI - Caveolin-1 interacts with protein phosphatase 5 and modulates its activity in prostate cancer cells. AB - Caveolin-1 is highly expressed in prostate cancer cells, and is implicated in disease progression. Here, we identified protein phosphatase 5 (PP5) as a novel cellular binding partner of caveolin-1 using a pull-down approach in combination with mass spectrometry-based proteomic analyses. In situ proximity ligation assays demonstrated co-localization and physical interaction of caveolin-1 and PP5 in the cytoplasm of PC-3 human prostate cancer cells. Using yeast two-hybrid analysis, we found that caveolin-1 interacted with the catalytic domain of PP5. We also found that PP5 activity was elevated about 1.7-fold in the presence of 2 MUM caveolin-1, and that the scaffolding domain of caveolin-1 is required for this activation. Our results suggest that caveolin-1 is a novel physiological activator of PP5. PMID- 23352617 TI - Simultaneous tracking of 3D actin and microtubule strains in individual MLO-Y4 osteocytes under oscillatory flow. AB - Osteocytes in vivo experience complex fluid shear flow patterns to activate mechanotransduction pathways. The actin and microtubule (MT) cytoskeletons have been shown to play an important role in the osteocyte's biochemical response to fluid shear loading. The dynamic nature of physiologically relevant fluid flow profiles (i.e., 1Hz oscillatory flow) impedes the ability to image and study both actin and MT cytoskeletons simultaneously in the same cell with high spatiotemporal resolution. To overcome these limitations, a multi-channel quasi 3D microscopy technique was developed to track the actin and MT networks simultaneously under steady and oscillatory flow. Cells displayed high intercellular variability and intracellular cytoskeletal variability in strain profiles. Shear Exz was the predominant strain in both steady and oscillatory flows in the form of viscoelastic creep and elastic oscillations, respectively. Dramatic differences were seen in oscillatory flow, however. The actin strains displayed an oscillatory strain profile more often than the MT networks in all the strains tested and had a higher peak-to-trough strain magnitude. Taken together, the actin networks are the more responsive cytoskeletal networks in osteocytes under oscillatory flow and may play a bigger role in mechanotransduction pathway activation and regulation. PMID- 23352618 TI - Intermittent use of an "anchor system" improves postural control in healthy older adults. AB - Haptic information, provided by a non-rigid tool (i.e., an "anchor system"), can reduce body sway in individuals who perform a standing postural task. However, it was not known whether or not continuous use of the anchor system would improve postural control after its removal. Additionally, it was unclear as to whether or not frequency of use of the anchor system is related to improved control in older adults. The present study evaluated the effect of the prolonged use of the anchor system on postural control in healthy older individuals, at different frequencies of use, while they performed a postural control task (semi-tandem position). Participants were divided into three groups according to the frequency of the anchor system's use (0%, 50%, and 100%). Pre-practice phase (without anchor) was followed by a practice phase (they used the anchor system at the predefined frequency), and a post-practice phase (immediate and late-without anchor). All three groups showed a persistent effect 15min after the end of the practice phase (immediate post-practice phase). However, only the 50% group showed a persistent effect in the late post-practice phase (24h after finishing the practice phase). Older adults can improve their postural control by practicing the standing postural task, and use of the anchor system limited to half of their practice time can provide additional improvement in their postural control. PMID- 23352619 TI - Rectovesical ligament and fusion defect of the uterus with or without obstructed hemivagina and ipsilateral renal agenesis. AB - OBJECTIVE: The rectovesical ligament is a peritoneal band in women with failure of fusion of the two Mullerian ducts. The aim was to evaluate existence of this abnormal structure in women with dysfused uterus and its possible relations to concomitant vaginal and renal anomalies. STUDY DESIGN: The study group comprised 47 women with uterine fusion defect (37 didelphic and 10 bicornuate uterus). They had undergone laparoscopy or laparotomy to visualize the pelvic cavity, and imaging for renal evaluation. The rectovesical ligament was present if inspection of the pelvic cavity revealed a broad peritoneal band between the two hemiuteri, attached anteriorly to the bladder and posteriorly to the sigmoid. Presence or absence of the ligament was reported, and concomitant renal and vaginal anomalies were evaluated. RESULTS: The rectovesical ligament was not visualized in 14 patients with didelphic or complete bicornuate uterus associated with unilateral renal agenesis: of these 13 had a previously treated obstructive longitudinal vaginal septum. A peritoneal band was found in 27 women with didelphic uterus with longitudinal vaginal septum with no obstruction and normal bilateral kidneys. Six women with bicornuate uterus had normal kidneys and an identified rectovesical ligament between the uterine hemicorpora, except for one with partial bicornuate uterus. CONCLUSION: The rectovesical ligament is not merely a consequence of the failed fusion of two Mullerian ducts, but its relation to uterine malformation with or without vaginal and renal anomalies indicates some share of this structure in the early development of the urogenital system. PMID- 23352620 TI - Current obstetric guidelines on thromboprophylaxis in the United Kingdom: evidence based medicine? AB - In the United Kingdom, the national guidance from Royal College of Obstetricians and Gynaecologists (RCOG) and National Institute for Health and Clinical Excellence (NICE) encourages the use of low molecular weight heparin thromboprophylaxis in high risk pregnancies. The recommendation, however, is based largely on expert opinion with almost no evidence from randomised controlled trials or meta-analyses. Here we examine the evidence for and against use of thromboprophylaxis and suggest that careful consideration is needed in implementing change in practice with follow-up of complications due to a real risk of unintended consequences. Therefore, large-scale and well-designed studies are urgently needed. We find that health economic assessments, which should be central to any major health policy change, appear entirely absent in this context. PMID- 23352621 TI - Electrophoretic and immunocytochemical analysis of Hsp72 and Hsp73 expression in heat-stressed mouse testis and epididymis. AB - OBJECTIVE: One of the most profound events in stressed cells is the synthesis of a highly conserved family of proteins, the 'heat shock proteins' (Hsp). The Hsp70 family is the most diverse, and includes constitutive as well as stress-inducible proteins with overlapping or unique functions in different cell compartments. Elucidation of Hsp70 expression during different stages of spermatogenesis and maturation of germ cells is of particular interest due to their high sensitivity to heat treatment. STUDY DESIGN: Expression of the main isoforms of the Hsp70 family (constitutive Hsp73 and stress-inducible Hsp72) was determined in normal and heat-stressed mouse testes and epididymis from sexually mature (60-day-old) mice during spermatogenesis and maturation of germ cells. Immunocytochemical analysis and one- and two-dimensional gel electrophoresis were used to separate mouse testicular and epididymal proteins from saline extracts, followed by Western blotting. RESULTS: Using a polyclonal anti-Hsp70 antibody that recognizes both isoforms, inducible Hsp72 expression, was demonstrated immunocytochemically only in heat-stressed tissues, while a high level of constitutive Hsp73 isoform expression was found in both normal and heat-stressed mouse male reproductive tissues. Morphological studies have shown that round and elongated spermatids in the testes, as well as all segments of the epididymis, are most sensitive to heat stress. In the epididymis, the reaction was localized in different cell compartments. CONCLUSION: In heat stress conditions, Hsp73 is mobilized to prevent apoptosis in the testes and epididymis, and assists Hsp72 in the repair of stress-altered protein conformations. PMID- 23352622 TI - IgA deficiency in wolves. AB - Low mean concentrations of serum immunoglobulin A (IgA) and an increased frequency of overt IgA deficiency (IgAD) in certain dog breeds raises the question whether it is a breeding-enriched phenomenon or a legacy from the dog's ancestor, the gray wolf (Canis lupus). The IgA concentration in 99 serum samples from 58 free-ranging and 13 captive Scandinavian wolves, was therefore measured by capture ELISA. The concentrations were markedly lower in the wolf serum samples than in the dog controls. Potential differences in the IgA molecule between dogs and wolves were addressed by sequencing the wolf IgA heavy chain constant region encoding gene (IGHA). Complete amino acid sequence homology was found. Detection of wolf and dog IgA was ascertained by showing identity using double immunodiffusion. We suggest that the vast majority of wolves, the ancestor of the dog, are IgA deficient. PMID- 23352624 TI - Molecular cloning, recombinant expression and characterization of GMCSF from the rhesus monkey, Macaca mulatta. AB - Recent studies have found that, in addition to hematopoiesis, granulocyte macrophage colony-stimulating factor (GMCSF) plays pivotal roles in multiple immune disorders. The gene encoding Macaca mulatta GMCSF (mmGMCSF) was cloned from stimulated peripheral blood mononuclear cells (PBMCs). Concanavalin A (Con A) and mismatched allogeneic antigen-stimulation significantly increased the production of mmGMCSF by monkey PBMCs. The gene encoding mature mmGMCSF was first expressed as a soluble fusion protein in Escherichia coli, and native mmGMCSF was further prepared by protease cleavage. The recombinant mmGMCSF induced antigen presenting dendritic cells from monkey PBMCs, suggesting a central role of mmGMCSF in the immune system of the rhesus monkey. Although the predicted mature mmGMCSF protein differs from human GMCSF (hGMCSF) at six amino acid residues, mmGMCSF showed a strong ability to support human TF-1 cell survival. Additional co-immunoprecipitation experiments revealed that mmGMCSF cross reacts with the hGMCSF receptor (hGMCSFR). In addition, the hGMCSF-neutralizing agents hGMCSFR-Fc and anti-hGMCSF antibody reduced the biological effects of mmGMCSF on TF-1 cells. These results suggest that recombinant mmGMCSF might be used for the in vitro evaluation of novel hGMCSF-neutralizing agents prior to the in vivo preclinical evaluation of these agents in the rhesus monkey model. PMID- 23352623 TI - Identification of TNF13b (BAFF) gene from grass carp (Ctenopharyngodon idella) and its immune response to bacteria and virus. AB - The TNF superfamily B cell activating factor (BAFF) is a central cytokine in several diseases. A BAFF gene has been cloned from grass carp (Ctenopharyngodon idella), analyzed its structure, and investigated its expression pattern in various tissues after Aeromonas hydrophila and Aquareovirus infection. The open reading frame of grass carp BAFF (gcBAFF) consists of 804 bases encoding 267 amino acids. Phylogenetic analysis shows the gcBAFF is most closely related to other teleost BAFFs with the highest similarity to zebrafish. RT-PCR analysis shows the gcBAFF transcript is expressed in a wide range of tissues with the highest expression in skin and spleen. Upon induction by A. hydrophila and Aquareovirus, its expression is significantly up-regulated in gill, liver, kidney, spleen and skin as compared to PBS injected fish. The association of increased BAFF expression after bacterial and viral infections suggests that it plays a potentially important role in immune system of fish. PMID- 23352625 TI - Phenotypic maturation of porcine NK- and T-cell subsets. AB - Detailed information concerning the development of the immune system in young pigs is still rudimental. In the present study, we analyzed changes in phenotype and absolute numbers of natural killer cells, gammadelta T cells, T helper cells, regulatory T cells and cytolytic T cells in the blood of pigs from birth to six months of age. For each lymphocyte subpopulation, a combination of lineage and differentiation markers was investigated by six-color flow cytometry. Major findings were: (i) absolute numbers of gammadelta T cells strongly increased from birth until 19-25 weeks of age, indicating an important role for these cells during adolescence; (ii) phenotype of T helper cells changed over time from CD8alpha(-)SLA-DR(-)CD27(+) towards CD8alpha(+)SLA-DR(+)CD27(-) but CD45RC(-) T helper cells were found immediately after birth, therefore questioning the role of this marker for the identification of T-helper memory cells; (iii) for cytolytic T cells, putative phenotypes for early effector (CD3(+)CD8alphabeta(+)perforin(+)CD27(dim)) and late effector or memory cells (CD3(+)CD8alphabeta(+)perforin(+)CD27(-)) could be identified. PMID- 23352626 TI - [Prevalence and risk factors of peripheral arterial disease in an outpatient screening campaign]. AB - BACKGROUND: Peripheral arterial disease (PAD) is an important predictor of cardiovascular disease with major medico-economic consequences. However, systematic screening of asymptomatic patients free from history of cardiovascular disease is debated. OBJECTIVE: Determining the prevalence, risk factors for PAD in a population of outpatients at intermediate or high-risk of cardiovascular disease, free from history of cardiovascular disease to assess the potential impact of PAD screening in such groups of patients. METHODS: Multicenter 1-day screening program of PAD conducted from 2008 to 2010 in a population defined by diabetes plus age greater than 50 years, positive active smoking status, or age greater than 70 years. PAD was defined as an ankle-brachial index (ABI) less than 0.9 measured as follows: lowest systolic ankle pressure divided by highest systolic arm pressure. RESULTS: Ten thousand six hundred and fourteen patients fulfilled study inclusion criteria: 16.7% (n = 1774) exhibited an ABI less than 0.9 and 3.8% (n = 407) an ABI less than 0.7. ABI greater than 1.3 was found in 7.7% of patients (n = 818). Age greater than 70 years, male gender, active smoking status, hypertension and diabetes (treated) were independent risk factors for PAD. CONCLUSION: Primary prevention outpatient screening of a population with intermediate or high cardiovascular risk can identify numerous patients with PAD. The medical impact in terms of cardiovascular mortality and morbidity of such a screening needs to be assessed. PMID- 23352627 TI - [Ultrasound-guided percutaneous insertion of implantable venous devices: a review of 102 patients]. AB - Techniques of insertion of implantable venous devices have been widely described. The use of ultrasound guidance is part of the good practice recommendations of the SOR 2008 but there are few data in the literature and recommendations are based only on expert agreement. To this end we conducted a prospective, single center study from January 2008 to August 2009 on percutaneous ultrasound-guided insertion of implantable devices. In addition to age, sex, the therapeutic indication and the site of implantation, we identified the operative time and number of venipunctures performed for each procedure. We then identified the infectious complications at three months and thromboembolic complications at 1 year and a half. Our study examined 102 consecutive patients. The mean age was 61.8 years (28-90); 71% of patients were men. For 101 patients, the internal jugular vein was punctured, the subclavian vein in one patient. In 86% of cases, the implantable venous device was inserted into the right vein. The average length of procedure was 30 minutes (18-60) for a single-vein puncture. Among the 102 patients, the overall morbidity was 7.8% with four infections (3.9%) and four thromboses (3.9%). There were no immediate perioperative complications (arterial puncture, hematoma, pneumothorax). In conclusion, percutaneous ultrasound-guided insertion of implantable venous devices in the internal jugular vein is a safe, minimally invasive technique which complies with the 2008 SOR recommendations by preventing the risk of venous thrombosis and avoiding repeated venous puncture. Less invasive than the open surgical approach, ultrasound-guided insertion is safer than puncture based solely on anatomical landmarks. In summary, this is a reliable, simple and easily reproducible technique which limits iatrogenic risks and improves patient comfort. PMID- 23352628 TI - Time trends and seasonal variations in the diagnosis of childhood acute lymphoblastic leukaemia in France. AB - BACKGROUND: Several studies have evidenced an increase in the incidence of childhood leukaemia since the 1970s but the variations since 2000 have received little attention. Seasonal variations in incidence have also been widely investigated, with however inconsistent conclusions. The present study aimed to investigate jointly the temporal trends and the seasonal variations in the month of diagnosis of childhood acute lymphoblastic leukaemia (ALL). METHODS: All the cases of ALL registered in the French National Registry of Childhood Haematological malignancies during 1990-2007 were included in the study. The overall temporal trend and seasonality of ALL were tested with Poisson regression models on 0-14-year-old ALL cases, and specifically on the B-cell precursor ALL (Bcp-ALL) cases. The analyses were also stratified by age groups and gender. RESULTS: Over 1990-2007, a significant time trend in risk of +0.48% (0.02-0.95%) per year for all ALL and +0.85% (0.33-1.37%) for Bcp-ALL was found. The increase was more marked for 7-14-year-old girls with a trend of +2.84% (1.34-4.36%) per year for Bcp-ALL. Seasonal variations were also evidenced for 1-6-year-old boys, with a standardised incidence ratio of 1.11 (1.04-1.18) for Bcp-ALL in April, August and December. CONCLUSION: The study showed an increase in childhood ALL risk over 1990-2007, which tended to be stronger for 7-14-year-old Bcp-ALL, particularly in girls (about one case per year, on average). However, although in accordance with the log-linear assumption, the increase in risk seemed less marked after 2001. The study also suggested seasonal variations in the month of diagnosis for 1-6-year-old boys. PMID- 23352629 TI - Association of metformin use with cancer incidence and mortality: a meta analysis. AB - PURPOSE: To assess the effect of metformin intake on cancer incidence and mortality. METHODS: Original articles in English published until June 15, 2012 were searched for in electronic databases (MEDLINE, ISI Web of Science and EMBASE databases) and relevant reviews were examined. Meta-analysis was applied to calculate the summary relative risk (SRR) and their 95% confidence intervals (95% CI). Sensitivity analysis was conducted to assess the robustness of the pooled estimator. The risk of publication bias was assessed by the Egger regression asymmetry test. RESULTS: According to the eligibility criteria, 37 studies comprising 1,535,636 participants, were selected in terms of intervention and data of cancer incidence or mortality. Among metformin users compared with non users, the SRR for overall-cancer incidence was 0.73 (95% CI, 0.64-0.83) and that for mortality was 0.82 (95% CI, 0.76-0.89). The risk reductions for liver, pancreatic, colorectal and breast cancer incidence were 78%, 46%, 23% and 6%, respectively. Also, metformin can reduce the mortality of liver cancer (SRR, 0.23; 95% CI, 0.09-0.60) and breast cancer (SRR, 0.63; 95% CI, 0.40-0.99). No statistically significant association between metformin and prostate cancer incidence was found. CONCLUSIONS: Metformin can reduce the incidence of overall cancer, liver cancer, pancreatic cancer, colorectal cancer and breast cancer as well as the mortality of overall cancer, liver cancer and breast cancer. No beneficial effect on prostate cancer incidence was found for meformin intake in the meta-analysis. PMID- 23352630 TI - Letter to the editor: Regarding "rectal versus axillary temperatures: is there a significant difference in infants less than 1 year of age?". PMID- 23352631 TI - Validation of the first treatment-specific questionnaire for the assessment of patient satisfaction with allergen-specific immunotherapy in allergic patients: the ESPIA questionnaire. AB - BACKGROUND: Satisfaction with treatment is a patient-reported outcome shown to be associated with the patient's health-related decisions and treatment-related behavior, thereby influencing the chances of successful treatment, and is especially relevant in long-term treatment, such as allergen-specific immunotherapy (AIT). OBJECTIVE: We sought to assess the psychometric properties of the Satisfaction Scale for Patients Receiving Allergen Immunotherapy (ESPIA) questionnaire so as to determine the satisfaction of patients receiving AIT treatment. METHODS: An observational, longitudinal, multicenter study was performed on patients with allergic rhinitis (AR) undergoing AIT treatment. Sociodemographic, clinical, and patient-centered health outcomes data were gathered at the study visits. Feasibility, reliability, validity, and sensitivity to change of the prevalidated version of the ESPIA questionnaire were assessed. RESULTS: Four hundred twenty-nine patients were included (52.2% women, 33.6 years of age, 54.5% of the cases with intermittent AR and 62.5% with moderate AR). Low levels of missing items and ceiling/floor effects were found for the overall score of the ESPIA questionnaire. The overall Cronbach alpha value and intraclass correlation coefficient were 0.90 and 0.92, respectively. The overall score for the ESPIA questionnaire was strongly associated with months receiving AIT, AR type and intensity, presence of conjunctivitis, self-perceived health status, effect of AR on daily life, and expectations about the AIT treatment. The pattern of correlations obtained with other patient-centered health outcomes was consistent with expectations. The ESPIA questionnaire also showed good sensitivity to change for improved health status. CONCLUSION: The ESPIA questionnaire to assess patient satisfaction with respect to AIT treatment presented satisfactory psychometric properties for its use in clinical practice. PMID- 23352632 TI - Advances in mechanisms of allergy and clinical immunology in 2012. AB - Manuscripts published in the "Mechanisms of allergy and clinical immunology" section of the Journal of Allergy and Clinical Immunology during 2012 enhanced our knowledge of the involvement of cytokines and other mediators in allergic disorders and described novel approaches for understanding mechanisms of allergic and immunologic diseases. Also published were articles focused on mechanisms of allergen-specific immunotherapy and the development of novel antiallergic treatments, as well as strategies to achieve tolerance to allergens. The highlights of these studies and their potential clinical implications are summarized in this review. PMID- 23352633 TI - In DOCK8 deficiency donor cell engraftment post-genoidentical hematopoietic stem cell transplantation is possible without conditioning. PMID- 23352634 TI - Initial description of pork-cat syndrome in the United States. PMID- 23352635 TI - Fast method for the resolution and determination of sex steroids in urine. AB - The main aim of the study was to develop a simple, fast, sensitive and inexpensive method for the separation and quantification of various steroid hormones in urine. Ultra high performance liquid chromatography was used to analyze estrone, estriol, 17-alpha-estradiol, 17-beta-estradiol, progesterone, pregnenolone, and testosterone. Three columns were chosen for the present study: two octadecyl columns and one octyl column. The best results of separation were obtained for the octadecyl columns. Complete separation of all sex steroids was impossible when methanol was used during the chromatographic studies. The most interesting and valuable result was obtained with regard to the complete separation of isomers. All seven steroids were successfully separated in 10min, next the time of single analysis was reduced to 5.5min with gradient elution. Linearity was evaluated over a range of concentrations of 0.08-12.11ngml(-1). The correlation coefficient ranged from 0.9987 to 0.9998. The LOD values were between 0.02 and 0.33ngml(-1) and LOQ ranged between 0.10 and 1.10ngml(-1). The developed method is suitable for routine analysis of these compounds in urine. PMID- 23352636 TI - A rapid ultra HPLC-MS/MS method for the quantitation and pharmacokinetic analysis of 3-deazaneplanocin A in mice. AB - 3-Deazaneplanocin A (DZNep) has been shown to have anti-cancer activity in numerous cancer types and its continued preclinical, and eventual clinical, drug development will require rapid and sensitive bioanalytical methods in order to quantitate this drug for pharmacokinetic analyses. The ultra HPLC with positive thermospray tandem mass spectrometric (LC-MS/MS) detection affords the most sensitive (limit of quantitation 5ng/mL) and rapid (3min run time) bioanalytical method to date for DZNep. Due to the polar nature of this drug and the internal standard (tubercidin), a hydrophilic-interaction column (HILIC) was used. The method was accurate, with less than 10% deviation from nominal values, as well as precise, where both within-day and between-day precisions were less than 15%. A liquid-liquid extraction procedure was able to recover ~90% of drug from a small volume (50MUL) of mouse plasma. This method was successfully applied to a pharmacokinetic study in mice intravenously injected with DZNep. PMID- 23352637 TI - Rituximab maintenance therapy until progression after rituximab and chemotherapy induction in patients with follicular lymphoma. AB - INTRODUCTION: The PRIMA (Primary Rituximab and Maintenance) study established 2 years of maintenance rituximab (MR) as a standard of care for follicular lymphoma (FL) patients who achieve an objective response after induction chemotherapy. A 17% improvement in progression-free survival (PFS) compared with those who did not receive MR was observed. However, the decision to stop MR after 2 years was arbitrary, and the PRIMA study reports only short-term follow-up of 3 years. Longer series on FL outcomes describe ubiquitous relapse and death following recurrence. The optimal duration of MR is under investigation. Herein, we report our experience with prolonged MR in FL. PATIENTS AND METHODS: In this retrospective analysis, the outcome of 25 consecutive, unselected, previously untreated patients with low-grade high tumor burden FL in need for treatment is described. All patients achieved a partial or complete response to induction immunochemotherapy and received ongoing MR therapy. RESULTS: With a median follow up of 5.0 years and 5.2 years mean duration of MR, there are no relapses. Five deaths have occurred, unrelated to lymphoma or therapy. Prolonged MR treatment has been well-tolerated. Hypogammaglobulinemia is the only observed adverse event, with only one patient requiring monthly intravenous gamma globulin infusions due to recurrent pneumonia. There has been no discontinuation of MR or refusal to remain on MR. CONCLUSION: These provocative long-term results suggest that continuous MR beyond 2 years is safe and may be associated with prolonged PFS in patients with FL who achieve an objective response after immunochemotherapy. PMID- 23352638 TI - Synthesis of novel 2-alkyl triazole-3-alkyl substituted quinoline derivatives and their cytotoxic activity. AB - The propargyl alcohol on reaction with alkylazides under Sharpless conditions through click chemistry concept gave exclusively 1,4-disubstituted triazoles 2. The compounds 2 were oxidized to aldehydes 3 followed by reaction with aniline resulted Schiff's bases 4. The compounds 4 was further reacted with various aldehydes having alpha-hydrogen using molecular iodine as a catalyst and obtained 2-alkyl triazole-3-alkyl substituted quinoline derivatives 5. All the final compounds were screened against four human cancer cell lines (THP-1, Colo205, U937 & HeLa) and promising compounds have been identified. PMID- 23352639 TI - Lidocaine-induced seizure during carotid endarterectomy. PMID- 23352640 TI - Similar outcomes in Asian and Western patients with diffuse large B-cell lymphoma treated with R-CHOP. AB - BACKGROUND: Little is known on racial differences in patients with diffuse large B-cell lymphoma (DLBCL). The aim of this retrospective study is to compare characteristics, prognostic factors and outcomes of Asian and Western patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). METHODS: Patient-level data was collected from 8 centers. All patients were diagnosed with DLBCL and treated with R-CHOP. Patients were divided into Asian and Western, according to the country of report. Comparisons and univariate/multivariate survival analyses were performed. RESULTS: 712 patients, 455 Asian and 257 Western patients were included. Westerners were more likely to present with elevated LDH (64% vs. 48%, p<0.01) and advanced stage (58% vs. 49%, p<0.01). After a median follow-up of 36 months, there was no difference in progression-free (PFS; p=0.33) or overall survival (OS; p=0.69). There were no PFS or OS differences between races when evaluating separately each age-adjusted International Prognostic Index category. In the multivariate analyses, performance status and stage were associated with PFS and OS in both races. CONCLUSIONS: There are no differences in prognostic factors, PFS and OS between Asian and Western patients with DLBCL treated with R-CHOP. PMID- 23352641 TI - Abducted by the illness: a qualitative study of traumatic stress in individuals with acute leukemia. AB - Symptoms of traumatic stress are common in acute leukemia. The goal of the present qualitative study was to understand this traumatic stress, as perceived by patients. Participants were 43 patients with acute leukemia in Toronto, Canada. Participants were asked in serial interviews about their experience of diagnosis and treatment. A total of 65 interviews were analyzed utilizing the grounded theory method. Our findings provide insight into the traumatic experience of the diagnosis and treatment, as well as the initial psychological response to this trauma. Patients coped by surrendering control to the medical team, in whom they felt great trust. Patients also expressed a strong preference for limited information, with a preference to avoid discussions about overall prognosis. These results may inform interventions to relieve traumatic stress in this high risk population. PMID- 23352642 TI - The oncoprotein HBXIP up-regulates Skp2 via activating transcription factor E2F1 to promote proliferation of breast cancer cells. AB - Hepatitis B X-interacting protein (HBXIP) is a novel oncoprotein. In this study, we found that the expression levels of HBXIP were positively associated with those of S-phase kinase-associated protein 2 (Skp2) in clinical breast cancer tissues and cell lines. Moreover, we found that HBXIP was able to stimulate the promoter of Skp2 through binding to the -640/-443 region in Skp2 promoter involving activating E2F transcription factor 1 (E2F1). Skp2 plays crucial roles in HBXIP-enhanced proliferation of breast cancer cells in vitro and in vivo. We conclude that HBXIP up-regulates Skp2 via activating E2F1 to promote proliferation of breast cancer cells. PMID- 23352643 TI - Snail2 promotes osteosarcoma cell motility through remodelling of the actin cytoskeleton and regulates tumor development. AB - The function of Snail2 in mesenchymal tumors is, to date unknown. Using knockdown and overexpression studies, we show that Snail2 regulates migration and invasion of osteosarcoma cells. Knockdown resulted in significantly decreased motility, remodelling of the actin cytoskeleton, and loss of cellular protrusions. Over expression increased motility, formation of actin-rich cellular protrusions, and altered expression of some non-canonical Wnt pathway components whilst decreasing expression of the adhesion molecule OB-cadherin. Unexpectedly, knockdown also resulted in significantly smaller tumors in an in vivo CAM assay. Therefore Snail2 may be a potential therapeutic target for clinical intervention of osteosarcoma. PMID- 23352644 TI - Deleted in breast cancer 1 (DBC1) deficiency results in apoptosis of breast cancer cells through impaired responses to UV-induced DNA damage. AB - DBC1 (deleted in breast cancer 1) participates in the regulation of cell survival and death in response to various stimuli. In particular, DBC1 promotes cell death upon DNA damage through inhibition of SIRT1 deacetylase. However, the SIRT1 independent functions of DBC1 in the regulation of DNA damage response are less well understood. Therefore, we analyzed the DNA damage response in Hs578T breast cancer cell line in which the DBC1-SIRT1 interaction is barely detectable. DBC1 siRNA transfected cells showed a failure in the DNA damage checkpoint and the accumulation of genomic damage following UV irradiation. In addition, DBC1 deficient cells exhibited less JNK activation. Finally, the interruptions of signaling in DBC1-depleted cells contributed to cell death in response to UV irradiation. Overall, these data suggest that DBC1 is essential for a fully efficient and effective response to UV irradiation. Therefore, DBC1 plays a critical role in maintaining genomic stability and cellular integrity following UV-induced genotoxic stress. PMID- 23352645 TI - MicroRNA-503 targets FGF2 and VEGFA and inhibits tumor angiogenesis and growth. AB - FGF2 and VEGFA are the two most potent angiogenic factors. Here we report that miR-503 can simultaneously down-regulate FGF2 and VEGFA. The expression of miR 503 is repressed in HCC cells and primary tumors due to a potential epigenetic mechanism. Overexpression of miR-503 reduced tumor angiogenesis in vitro and in vivo. We also found that miR-503 expression was down-regulated by hypoxia through HIF1alpha. These results identify a miRNA that targets both FGF2 and VEGFA in cancers, demonstrate the anti-angiogenesis role of miR-503 in tumorigenesis, and provide a novel mechanism for hypoxia-induced FGF2 and VEGFA through HIF1alpha mediated inhibition of miR-503. PMID- 23352647 TI - Metal-based methods for protein inactivation. AB - Metal complexes are efficient catalysts for protein inactivation. Because of their special reactivity, metal-based molecules can achieve results that are difficult, if not impossible to obtain with more traditional, organic-based inhibitors. This article summarizes the chemistry of hydrolytic and oxidative catalysts for protein inactivation. PMID- 23352646 TI - Mesenchymal and stem-like cell properties targeted in suppression of chronically induced breast cell carcinogenesis. AB - Stem-like cells and the epithelial-to-mesenchymal transition (EMT) program are postulated to play important roles in various stages of cancer development, but their roles in breast cell carcinogenesis and intervention remain to be clarified. We investigated stem-like cell- and EMT-associated properties and markers in breast epithelial cells chronically exposed to low-dose 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene in the presence and absence of the preventive agents green tea catechins and grape seed extract. Our results indicate that stem-like cell- and EMT-associated properties and markers should be seriously considered as new cancer-associated indicators for detecting breast cell carcinogenesis and as endpoints for intervention of carcinogenesis. PMID- 23352648 TI - Viscoelastic properties of the ferret brain measured in vivo at multiple frequencies by magnetic resonance elastography. AB - Characterization of the dynamic mechanical behavior of brain tissue is essential for understanding and simulating the mechanisms of traumatic brain injury (TBI). Changes in mechanical properties may also reflect changes in the brain due to aging or disease. In this study, we used magnetic resonance elastography (MRE) to measure the viscoelastic properties of ferret brain tissue in vivo. Three dimensional (3D) displacement fields were acquired during wave propagation in the brain induced by harmonic excitation of the skull at 400 Hz, 600 Hz and 800 Hz. Shear waves with wavelengths in the order of millimeters were clearly visible in the displacement field, in strain fields, and in the curl of displacement field (which contains no contributions from longitudinal waves). Viscoelastic parameters (storage and loss moduli) governing dynamic shear deformation were estimated in gray and white matter for these excitation frequencies. To characterize the reproducibility of measurements, two ferrets were studied on three different dates each. Estimated viscoelastic properties of white matter in the ferret brain were generally similar to those of gray matter and consistent between animals and scan dates. In both tissue types G' increased from approximately 3 kPa at 400 Hz to 7 kPa at 800 Hz and G" increased from approximately 1 kPa at 400 Hz to 2 kPa at 800 Hz. These measurements of shear wave propagation in the ferret brain can be used to both parameterize and validate finite element models of brain biomechanics. PMID- 23352649 TI - Variation of the ultrasonic response of a dental implant embedded in tricalcium silicate-based cement under cyclic loading. AB - The use of tricalcium silicate-based cement (TSBC) as bone substitute material for implant stabilization is promising. However, its mechanical behavior under fatigue loading in presence of a dental implant was not reported so far because of the difficulty of measuring TSBC properties around a dental implant in a nondestructive manner. The aim of this study is to investigate the evolution of the 10 MHz ultrasonic response of a dental implant embedded in TSBC versus fatigue time. Seven implants were embedded in TSBC following the same experimental protocol used in clinical situations. One implant was left without any mechanical solicitation after its insertion in TSBC. The ultrasonic response of all implants was measured during 24 h using a dedicated device deriving from previous studies. An indicator I based on the temporal variation of the signal amplitude was derived and its variation as a function of fatigue time was determined. The results show no significant variation of I as a function of time without mechanical solicitation, while the indicator significantly increases (p<10(-5), F=199.1) at an average rate of 2.2 h(-1) as a function of fatigue time. The increase of the indicator may be due to the degradation of the Biodentine-implant interface, which induces an increase of the impedance gap at the implant surface. The results are promising because they show the potentiality of ultrasonic methods to (i) investigate the material properties around a dental implant and (ii) optimize the conception of bone substitute materials in the context of dental implant surgery. PMID- 23352651 TI - Has anyone seen my executive function recently? PMID- 23352650 TI - Point-to-point ligand-receptor interactions across the subunit interface modulate the induction and stabilization of conformational states of alpha7 nAChR by benzylidene anabaseines. AB - The homomeric alpha7 nicotinic acetylcholine receptor is a well-studied therapeutic target, though its characteristically rapid desensitization complicates the development of drugs with specific agonist effects. Moreover, some experimental compounds such as GTS-21 (2,4diMeOBA), a derivative of the alpha7-selective partial agonist benzylidene anabaseine (BA), produce a prolonged residual desensitization (RD) in which the receptor remains non-activatable long after the drug has been removed from extracellular solution. In contrast, the desensitization caused by GTS-21's dihydroxy metabolite (2,4diOHBA) is relatively short-lived. RD is hypothetically due to stable binding of the ligand to the receptor in its desensitized state. We can attribute the reduction in RD to a single BA hydroxyl group on the 4' benzylidene position. Computational prediction derived from homology modeling showed the serine36 (S36) residue of alpha7 as a reasonable candidate for point-to-point interaction between BA compounds and the receptor. Through evaluating the activity of BA and simple derivatives on wild type and mutant alpha7 receptors, it was observed that the drug-receptor pairs which were capable of hydrogen bonding at residue 36 exhibited significantly less stable desensitization. Further experiments involving the type II positive allosteric modulator (PAM) PNU-120596 showed that the various BA compounds' preference to induce either a PAM-sensitive (D(s)) or PAM-insensitive (D(i)) desensitized state is concentration dependent and suggested that both states are destabilized by S36 H-bonding. These results indicate that the fine-tuning of agonists for specific interaction with S36 can facilitate the development of therapeutics with targeted effects on ion channel desensitization properties and conformational state stability. PMID- 23352652 TI - Injuries at the Iranian championship in indoor rock climbing. PMID- 23352653 TI - Neurobehavioural evidence for the involvement of the FMR1 gene in female carriers of fragile X syndrome. AB - For years, premutation-carriers of fragile X-syndrome (FXS) were assumed free from any deleterious phenotype. In this review, we discuss the current literature on neurocognitive, emotional and neuromotor profiles emerging in females with the fragile-X premutation, and discuss phenotypic profiles in male premutation carriers to gain insights into possible underlying mechanisms associated with FMR1 gene expression. We contend that this emerging phenotypic profile in females with the fragile-X premutation needs further investigation using experimentally driven tasks sensitive to neural networks especially vulnerable to FMR1 gene expression. Further investigation of developmental aspects of the female carrier profile is needed to determine the extent to which emotional, cognitive and neurobehavioural challenges indicate at-risk profiles for later degenerative decline, or rather a stable developmental phenotype. These future research avenues will provide critical new information which will enable identification of women at greatest risk for subtle age-dependent neurobehavioural changes well before the onset of more serious clinical consequences alongside the identification of biomarkers which may be useful in establishing the efficacy of future therapeutic interventions. PMID- 23352654 TI - TVT-O: a new gold standard surgical treatment of female stress urinary incontinence? PMID- 23352656 TI - Experts' opinion: Recommendations for retesting breast cancer metastases for HER2 and hormone receptor status. AB - The human epidermal growth factor receptor 2 (HER2) and hormone receptor status of recurrent breast cancer may change between the tumor and metastases from negative to positive and vice versa, potentially affecting the treatment regimen. Retesting of metastases may therefore be crucial to allow appropriate selection of patients for whom targeted therapy is indicated; however, retesting is not routinely performed. This article recommends that metastases be retested for HER2 and hormone receptor status and provides practical guidance on when and how to retest, as agreed by a panel of expert pathologists with extensive experience of HER2 and hormone receptor testing. PMID- 23352655 TI - Extremely high copy numbers and polymorphisms of the rDNA operon estimated from single cell analysis of oligotrich and peritrich ciliates. AB - The copy number and sequence variation of the ribosomal DNA (rDNA) operon are of functional significance in evolution and ecology of organisms. However, the relationship between copy number and sequence variation of rDNA in protists has been rarely studied. Here we quantified rDNA copy numbers of oligotrich and peritrich ciliate species using single-cell quantitative PCR. We also examined the rDNA sequence variation by using single-cell PCR, cloning, and sequencing of multiple clones. We found that the rDNA copy numbers per cell were extremely high and different among even congeners, with the highest record of about 310,000. There was substantial intraindividual haplotype diversity and nucleotide diversity for the rDNA markers, with sequence differences primarily characterized by single nucleotide polymorphisms. Haplotype and nucleotide diversity was positively correlated to the rDNA copy number. Our findings provide evidence that: (1) ciliates generally have much higher rDNA copy numbers than other protists and fungi, which could lead to overestimation of the relative abundance of ciliates in environmental samples when rDNA sequence-based methodologies are used; and that (2) the rDNA might not always evolve in a strictly concerted manner in ciliates, which may raise problems in rDNA-based inference of species richness and phylogeny. PMID- 23352657 TI - Physiological responses of the tropical tree Tibouchina pulchra Cogn under the influence of combustion of crude oil and natural gas at an oil refinery. AB - A refinery located on the slopes of a mountain range in the city of Cubatao (SE Brazil) is the main source of sulfur dioxide (SO(2)) in the region. For this reason, the refinery replaced a system in which energy was produced from crude oil combustion in boilers with a system of energy and vapor co-generation in a thermoelectric power plant fueled by natural gas. The aim of this study was to investigate the responses of Tibouchina pulchra to the fuel switching. Saplings planted in pots were distributed throughout monitoring sites around the polluting source (sites I, II, III and IV) and in a site (V) far from emissions. Changes on the plants responses occur along the three fuel switching phases. During the last phase, increased carbon assimilation (Asat) and decreased stomatal conductance (gs) were observed in plants growing in sites II and III; as a consequence, intrinsic water use efficiency (iWUE) increased. However, the increase in Asat did not promote growth increase suggesting that changes at the refinery did not result in better air quality, but only in a change in the main contaminants. PMID- 23352658 TI - [Case-cohort surveys]. AB - In this paper, we present the main tools for conception, implementation and analysis of case-cohort surveys. In particular, we describe the classical weighted estimators, the weighted approach recently suggested by Breslow et al. and the multiple imputation approach, an alternative to weighted analysis of case cohort data. Variance estimators are also described. We show how to obtain the subcohort size. Finally, we mention the functions and procedures available in R, SAS and Stata software and we illustrate their implementation using simulated subcohorts from the PRIME cohort. PMID- 23352660 TI - Voluntary resistance running induces increased hippocampal neurogenesis in rats comparable to load-free running. AB - Recently, we reported that voluntary resistance wheel running with a resistance of 30% of body weight (RWR), which produces shorter distances but higher work levels, enhances spatial memory associated with hippocampal brain-derived neurotrophic factor (BDNF) signaling compared to wheel running without a load (WR) [17]. We thus hypothesized that RWR promotes adult hippocampal neurogenesis (AHN) as a neuronal substrate underlying this memory improvement. Here we used 10 week-old male Wistar rats divided randomly into sedentary (Sed), WR, and RWR groups. All rats were injected intraperitoneally with the thymidine analogue 5 Bromo-2'-deoxuridine (BrdU) for 3 consecutive days before wheel running. We found that even when the average running distance decreased by about half, the average work levels significantly increased in the RWR group, which caused muscular adaptation (oxidative capacity) for fast-twitch plantaris muscle without causing any negative stress effects. Additionally, immunohistochemistry revealed that the total BrdU-positive cells and newborn mature cells (BrdU/NeuN double-positive) in the dentate gyrus increased in both the WR and RWR groups. These results provide new evidence that RWR has beneficial effects on AHN comparable to WR, even with short running distances. PMID- 23352659 TI - Environment and primary biliary cirrhosis: electrophilic drugs and the induction of AMA. AB - Environmental stimulation is a major factor in the initiation and perpetuation of autoimmune diseases. We have addressed this issue and focused on primary biliary cirrhosis (PBC), an autoimmune disease of the liver. Immunologically, PBC is distinguished by immune mediated destruction of the intra hepatic bile ducts and the presence of high titer antimitochondrial autoantibodies (AMA) directed against a highly specific epitope within the lipoic acid binding domain of the pyruvate dehydrogenase E2 subunit (PDC-E2). We submit that the uniqueness of AMA epitope specificity and the conformational changes of the PDC-E2 lipoyl domain during physiological acyl transfer could be the lynchpin to the etiology of PBC and postulate that chemical xenobiotics modification of the lipoyl domain of PDC E2 is sufficient to break self-tolerance, with subsequent production of AMA in patients with PBC. Indeed, using quantitative structure activity relationship (QSAR) analysis on a peptide-xenobiotic conjugate microarray platform, we have demonstrated that when the lipoyl domain of PDC-E2 was modified with specific synthetic small molecule lipoyl mimics, the ensuing structures displayed highly specific reactivity to PBC sera, at levels often higher than the native PDC-E2 molecule. Hereby, we discuss our recent QSAR analysis data on specific AMA reactivity against a focused panel of lipoic acid mimic in which the lipoyl di sulfide bond are modified. Furthermore, data on the immunological characterization of antigen and Ig isotype specificities against one such lipoic acid mimic; 6,8-bis(acetylthio)octanoic acid (SAc), when compared with rPDC-E2, strongly support a xenobiotic etiology in PBC. This observation is of particular significance in that approximately one third of patients who have taken excessive acetaminophen (APAP) developed AMA with same specificity as patients with PBC, suggesting that the lipoic domain are a target of APAP electrophilic metabolites such as NAPQI. We submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate loss of tolerance and lead to the development of PBC. PMID- 23352662 TI - Depletion of cognate charged transfer RNA causes translational frameshifting within the expanded CAG stretch in huntingtin. AB - Huntington disease (HD), a dominantly inherited neurodegenerative disorder caused by the expansion of a CAG-encoded polyglutamine (polyQ) repeat in huntingtin (Htt), displays a highly heterogeneous etiopathology and disease onset. Here, we show that the translation of expanded CAG repeats in mutant Htt exon 1 leads to a depletion of charged glutaminyl-transfer RNA (tRNA)(Gln-CUG) that pairs exclusively to the CAG codon. This results in translational frameshifting and the generation of various transframe-encoded species that differently modulate the conformational switch to nucleate fibrillization of the parental polyQ protein. Intriguingly, the frameshifting frequency varies strongly among different cell lines and is higher in cells with intrinsically lower concentrations of tRNA(Gln CUG). The concentration of tRNA(Gln-CUG) also differs among different brain areas in the mouse. We propose that translational frameshifting may act as a significant disease modifier that contributes to the cell-selective neurotoxicity and disease course heterogeneity of HD on both cellular and individual levels. PMID- 23352661 TI - RUNX1 is a key target in t(4;11) leukemias that contributes to gene activation through an AF4-MLL complex interaction. AB - The Mixed Lineage Leukemia (MLL) protein is an important epigenetic regulator required for the maintenance of gene activation during development. MLL chromosomal translocations produce novel fusion proteins that cause aggressive leukemias in humans. Individual MLL fusion proteins have distinct leukemic phenotypes even when expressed in the same cell type, but how this distinction is delineated on a molecular level is poorly understood. Here, we highlight a unique molecular mechanism whereby the RUNX1 gene is directly activated by MLL-AF4 and the RUNX1 protein interacts with the product of the reciprocal AF4-MLL translocation. These results support a mechanism of transformation whereby two oncogenic fusion proteins cooperate by activating a target gene and then modulating the function of its downstream product. PMID- 23352663 TI - Lgr5-expressing cells are sufficient and necessary for postnatal mammary gland organogenesis. AB - Mammary epithelial stem cells are vital to tissue expansion and remodeling during various phases of postnatal mammary development. Basal mammary epithelial cells are enriched in Wnt-responsive cells and can reconstitute cleared mammary fat pads upon transplantation into mice. Lgr5 is a Wnt-regulated target gene and was identified as a major stem cell marker in the small intestine, colon, stomach, and hair follicle, as well as in kidney nephrons. Here, we demonstrate the outstanding regenerative potential of a rare population of Lgr5-expressing (Lgr5(+)) mammary epithelial cells (MECs). We found that Lgr5(+) cells reside within the basal population, are superior to other basal cells in regenerating functional mammary glands (MGs), are exceptionally efficient in reconstituting MGs from single cells, and exhibit regenerative capacity in serial transplantations. Loss-of-function and depletion experiments of Lgr5(+) cells from transplanted MECs or from pubertal MGs revealed that these cells are not only sufficient but also necessary for postnatal mammary organogenesis. PMID- 23352664 TI - A fasting-responsive signaling pathway that extends life span in C. elegans. AB - Intermittent fasting is one of the most effective dietary restriction regimens that extend life span in C. elegans and mammals. Fasting-stimulus responses are key to the longevity response; however, the mechanisms that sense and transduce the fasting stimulus remain largely unknown. Through a comprehensive transcriptome analysis in C. elegans, we find that along with the FOXO transcription factor DAF-16, AP-1 (JUN-1/FOS-1) plays a central role in fasting induced transcriptional changes. KGB-1, one of the C. elegans JNKs, acts as an activator of AP-1 and is activated in response to fasting. KGB-1 and AP-1 are involved in intermittent fasting-induced longevity. Fasting-induced upregulation of the components of the SCF E3 ubiquitin ligase complex via AP-1 and DAF-16 enhances protein ubiquitination and reduces protein carbonylation. Our results thus identify a fasting-responsive KGB-1/AP-1 signaling pathway, which, together with DAF-16, causes transcriptional changes that mediate longevity, partly through regulating proteostasis. PMID- 23352665 TI - Rapid transcription fosters coordinate snail expression in the Drosophila embryo. AB - Transcription is commonly held to be a highly stochastic process, resulting in considerable heterogeneity of gene expression among the different cells in a population. Here, we employ quantitative in situ hybridization methods coupled with high-resolution imaging assays to measure the expression of snail, a developmental patterning gene necessary for coordinating the invagination of the mesoderm during gastrulation of the Drosophila embryo. Our measurements of steady state mRNAs suggest that there is very little variation in snail expression across the different cells that make up the mesoderm and that synthesis approaches the kinetic limits of Pol II processivity. We propose that rapid transcription kinetics and negative autoregulation are responsible for the remarkable homogeneity of snail expression and the coordination of mesoderm invagination. PMID- 23352666 TI - High-resolution enzymatic mapping of genomic 5-hydroxymethylcytosine in mouse embryonic stem cells. AB - We describe the use of a unique DNA-modification-dependent restriction endonuclease AbaSI coupled with sequencing (Aba-seq) to map high-resolution hydroxymethylome of mouse E14 embryonic stem cells. The specificity of AbaSI enables sensitive detection of 5-hydroxymethylcytosine (5hmC) at low-occupancy regions. Bioinformatic analysis suggests 5hmCs in genic regions closely follow the 5mC distribution. 5hmC is generally depleted in CpG islands and only enriched in a small set of repetitive elements. A regularly spaced and oscillating 5hmC pattern was observed at the binding sites of CTCF. 5hmC is enriched at the poised enhancers with the monomethylated histone H3 lysine 4 (H3K4me1) marks, but not at the active enhancers with the acetylated histone H3 lysine 27 (H3K27Ac) marks. Non-CG hydroxymethylation appears to be prevalent in the mitochondrial genome. We propose that some amounts of transiently stable 5hmCs may indicate a poised epigenetic state or demethylation intermediate, whereas others may suggest a locally accessible chromosomal environment for the TET enzymatic apparatus. PMID- 23352667 TI - Relapsing, remitting hypercortisolism in Cushing's disease due to intratumoral hemorrhages in pituitary microadenoma. AB - We report two patients with Cushing's disease (CD) from adrenocorticotropic hormone-secreting microadenomas in whom intralesional hemorrhage caused an episodic, remitting and relapsing pattern of hypercortisolism. To our knowledge this is the first report of patients in whom hemorrhage within a microadenoma caused cyclic CD. Both patients were treated successfully with transsphenoidal surgery. PMID- 23352669 TI - Neuroblastoma and tooth abnormalities: a common history? PMID- 23352668 TI - Selection for increased voluntary wheel-running affects behavior and brain monoamines in mice. AB - Selective-breeding of house mice for increased voluntary wheel-running has resulted in multiple physiological and behavioral changes. Characterizing these differences may lead to experimental models that can elucidate factors involved in human diseases and disorders associated with physical inactivity, or potentially treated by physical activity, such as diabetes, obesity, and depression. Herein, we present ethological data for adult males from a line of mice that has been selectively bred for high levels of voluntary wheel-running and from a non-selected control line, housed with or without wheels. Additionally, we present concentrations of central monoamines in limbic, striatal, and midbrain regions. We monitored wheel-running for 8 weeks, and observed home-cage behavior during the last 5 weeks of the study. Mice from the selected line accumulated more revolutions per day than controls due to increased speed and duration of running. Selected mice exhibited more active behaviors than controls, regardless of wheel access, and exhibited less inactivity and grooming than controls. Selective-breeding also influenced the longitudinal patterns of behavior. We found statistically significant differences in monoamine concentrations and associated metabolites in brain regions that influence exercise and motivational state. These results suggest underlying neurochemical differences between selected and control lines that may influence the observed differences in behavior. Our results bolster the argument that selected mice can provide a useful model of human psychological and physiological diseases and disorders. PMID- 23352670 TI - Intestinal dendritic cells: their role in intestinal inflammation, manipulation by the gut microbiota and differences between mice and men. AB - The intestinal immune system maintains a delicate balance between immunogenicity against invading pathogens and tolerance of the commensal microbiota and food antigens. Dendritic cells (DC) generate primary T-cell responses, and determine whether these responses are immunogenic or tolerogenic. The regulatory role of DC is of particular importance in the gut due to the high antigenic load. Intestinal DC act as sentinels, sampling potentially pathogenic antigens but also harmless antigens including the commensal microbiota. Following antigen acquisition, intestinal DC migrate to secondary lymphoid organs to activate naive T-cells. DC also imprint specific homing properties on T-cells that they stimulate; gut DC specifically induce gut-homing properties on T-cells upon activation, enabling T cell migration back to intestinal sites. Data regarding properties on gut DC in humans is scarce, although evidence now supports the role of DC as important players in intestinal immunity in humans. Here, we review the role of intestinal DC in shaping mucosal immune responses and directing tissue-specific T-cell responses, with a special focus on the importance of distinguishing DC subsets from macrophages at intestinal sites. We compare and contrast human DC with their murine counterparts, and discuss the ability of the gut microbiota to shape intestinal DC function, and how this may be dysregulated in inflammatory bowel disease (IBD). Lastly, we describe recent advances in the study of probiotics on intestinal DC function, including the use of soluble secreted bacterial products. PMID- 23352671 TI - Array-CGH revealed one of the smallest 16q21q22.1 microdeletions in a female patient with psychomotor retardation. AB - A 28-month-old girl with dysmorphic craniofacial features, microcephaly, hypotonia, psychomotor retardation, failure to thrive and gastrointestinal problems was referred for clinical evaluation. Array-CGH analysis revealed one of the smallest de novo microdeletions on chromosome 16q21q22.1, 2.03 Mb in size. Advanced molecular analysis contributes to more precise genotype-phenotype correlation and accurate definition of the breakpoints in the deleted/duplicated regions. PMID- 23352672 TI - Rehabilitation of hand burn injuries: current updates. AB - The improved short and long term survival rate of individuals with large burn injuries has made rehabilitation for optimal recovery of the patient increasingly important. Burn injury to the hands worsens the prospect of functional recovery and good quality of life in single events, especially when included in larger burns. The purpose of this paper is to present a narrative review of examination strategies used for children with burn injuries to the hands in the acute, intermediate and long term stages of rehabilitation, and apply these concepts to selected treatments, using a case that is representative of this complex patient population. The model of health described by the World Health Organisation provided the framework for the review, to structure the review in the domains of body structures and body functions, functional activities and participation in life roles. The lack of consensus in the burn literature regarding the most appropriate outcome measures and interventions necessitates futures research and long term outcome studies to identify, predict and prevent the difficulties patients may face over their lifespan. PMID- 23352673 TI - IV access in bleeding trauma patients: a performance review. AB - BACKGROUND: Exsanguinating haemorrhage is a leading cause of death in severely injured trauma patients. Management includes achieving haemostasis, replacing lost intravascular volume with fluids and blood, and treating coagulopathy. The provision of fluids and blood products is contingent on obtaining adequate vascular access to the patient's venous system. We sought to examine the nature and timing of achieving adequate intravenous (IV) access in trauma patients requiring uncrossmatched blood in the trauma bay. METHODS: We performed a retrospective chart review of all patients admitted to our trauma centre from 2005 to 2009 who were transfused uncrossmatched blood in the trauma bay. We examined the impact of IV access on prehospital times and time to first PRBC transfusion. RESULTS: Of 208 study patients, 168 (81%) received prehospital IV access, and the on-scene time for these patients was 5 min longer (16.1 vs 11.4, p<0.01). Time to achieving adequate IV access in those without any prehospital IVs occurred on average 21 min (6.6-30.5) after arrival to the trauma bay. A central venous catheter was placed in 92 (44%) of patients. Time to first blood transfusion correlated most strongly with time to achieving central venous access (Pearson correlation coefficient 0.94, p<0.001) as opposed to time to achieving adequate peripheral IV access (Pearson correlation coefficient 0.19, p=0.12). CONCLUSIONS: We found that most bleeding patients received a prehospital IV; however, we also found that obtaining prehospital IVs was associated with longer EMS on-scene times and longer prehospital times. Interestingly, we found that obtaining a prehospital IV was not associated with more rapid initiation of blood product transfusion. Obtaining optimal IV access and subsequent blood transfusion in severely injured patients continues to present a challenge. PMID- 23352674 TI - Toe-to-thumb reconstruction. AB - Multiple digital losses will result in crippled hand function and toe transfers are proven to provide replacement of prehensile function. Given that basic hand function requires three factors, viz. an ulnar component, a radial component and opposition, various toe transfers can accomplish thumb ray and ulnar digital defect restoration. Opponensplasty and interpositional suspension arthroplasty can provide circumduction to the thumb component required to perform prehensile functions. PMID- 23352675 TI - Management of acute acromioclavicular joint dislocation with a double-button fixation system. AB - INTRODUCTION: Numerous static and dynamic techniques have been described for the management of acute acromioclavicular (AC) joint dislocation. To date, no standard technique has been established and several complications have been described for each of these techniques. The purpose of the present study was to evaluate the functional and radiographic outcomes of acute AC joint reconstruction after a mini-open technique using the double-button fixation system. PATIENTS AND METHODS: Twelve patients with acute AC joint dislocation treated with the double-button fixation system by one surgeon were retrospectively reviewed. Functional assessment was performed by an independent reviewer using the DASH, Constant and the VAS scores. The coracoclavicular (CC) distance of the affected shoulder was assessed on a standard radiograph and compared with the contralateral normal one. RESULTS: Eight patients were operated on for grade III AC joint dislocation and 4 for grade IV. The mean age of the patients at the time of surgery was 27.5 years. The mean follow-up was 18.25 months (range: 12-30 months). At the most recent follow-up, the mean Constant score was 94.8 (range: 84-100) showing a significant increase compared with the mean pre-operative value of 34.4 (range: 25-52) (p<0.001). The mean DASH score was significantly decreased from 19.6 (range: 14-28) preoperatively to 0.25 (range: 0-3) at the last follow-up (p<0.001). The mean VAS score showed a significant decrease from 5.75 (range: 4-7) to 0.2 (range: 0-2) (p<0.001). The mean CC distance on the operated shoulder was found to have no significant difference from the CC distance on the contralateral normal side (10.5 vs. 10mm) (p>0.05). There was no evidence of AC joint osteoarthrosis, CC calcification or osteolysis of the distal clavicle or the coracoid process. CONCLUSIONS: The proposed mini-open technique provides adequate exposure of the base of the coracoid with minimal damage to the soft tissues surrounding the CC ligaments while ensures an excellent cosmetic result. We recommend this fast and relatively simple technique for all type IV injuries and for type III injuries in heavy manual workers and high-demand upper extremities athletes. PMID- 23352676 TI - A new classification to aid the selection of revascularization techniques in major degloving injuries of the upper limb. AB - Difficulties in management of major degloving injuries of the upper limb are compounded by their relative rarity and a lack of clarity in decision-making regarding surgical treatment strategies. Management options include salvaging the degloved segment through revascularization techniques such as direct arterial anastamosis or arterio-venous (AV) shunting, and reconstructing the unsalvageable degloving injury with microsurgical or non-microsurgical techniques. This article focuses on the use of revascularization techniques as a means to salvaging a major degloved segment. We propose a new classification to aid decision-making in strategies to salvage the degloved skin. This is based on assessment of the degloved segment regarding its suitability for revascularization, the choice of revascularization technique, and its anatomical expendability. Major degloving injuries involving the palm but not the digits is a strong indication for AV shunting in isolation (Group 1). Major degloving injuries that include the digits as well require both AV shunting and digital artery revascularization (Group 2). Major deglovings involving the dorsum of hand or forearm are only relative indications for AV shunting and traditional management with flap reconstruction or skin grafting is equally appropriate. This new classification and its application are discussed in a number of case examples. PMID- 23352677 TI - Obstetrical brachial plexus palsy: lessons in functional neuroanatomy. AB - Obstetrical branchial plexus paralysis is a serious and possibly disabling disorder. While thoroughly described as a clinical entity, much concerning its pathogenesis is still unknown. Basic science studies alongside with studies on functional neuroanatomy of peripheral and central nervous system and their interactions lead to deeper understanding of its pathology. Research concentrates on the consequences of branchial plexus traction to peripheral nerves and muscles function and viability and rehabilitation options. Changes obstetrical branchial plexus paralysis causes to central nervous systems organisation have been, to some extent, investigated. It seems that central nervous system is not "blind" after obstetrical branchial plexus paralysis but instead proceeds to remodelling so to adapt to new needs. Research indicates that both this entity and organism's response are much more complicated than previously believed. Current treatment options include microsurgery and palliative surgery but their improvement is possible by focusing on central nervous system. Current report discusses these topics and tries to reach useful conclusions. PMID- 23352678 TI - Clavicular reconstruction with free fibula flap: a report of four cases and review of the literature. AB - Midclavicular fracture is one of the most common injuries of the skeleton, representing 3-5% of all fractures and 45% of all shoulder injuries. The recurrent failure of clavicular fracture treatment, whether conservative or surgical, could give rise to multiple surgeries, ultimately leading to a painful nonunion. The aim of the article is to address the indications, surgical technique and results of clavicular reconstruction using vascularised fibular flaps based on 4 cases reports. PMID- 23352679 TI - Hemorrhagic risk of emergent endovascular treatment plus stenting in patients with acute ischemic stroke. AB - BACKGROUND: Several endovascular revascularization strategies have been described for the treatment of acute ischemic stroke (AIS). One of them is stenting when a very narrow stenosis with high reocclusion risk remains after recanalization. This study describes the risk of symptomatic intracerebral hemorrhage (SICH) after emergent stenting in patients with AIS treated with endovascular therapies. METHODS: Consecutive patients who underwent endovascular treatment over a 37 month period were retrospectively analyzed. Patients were classified in 2 groups: (1) patients in whom a stent was deployed; and (2) patients without stenting. Double antiplatelet treatment with aspirin and clopidogrel was administered at the time of stenting. SICH was defined as any hemorrhagic transformation with National Institutes of Health Stroke Scale (NIHSS) score worsening 4 points or more (European-Australasian Acute Stroke Study II criteria). RESULTS: A total of 143 patients were included (mean age: 66.1+/-11.7 years, median NIHSS score: 18). Acute phase stenting was performed in 24 subjects (16.8%): 4 intracranial (3 in basilar artery, 1 in middle cerebral artery) and 20 extracranial (internal carotid artery). SICH occurred in 11 patients, 5 of 24 (20.8%) in patients with stenting and in 3 of 119 (2.5%) without (P=.008). No differences were found with respect to baseline NIHSS score or intravenous tissue plasminogen activator administration. Acute phase stenting emerged as an independent predictor of SICH after adjustment for potential confounders and procedure duration: odds ratio 7.3 (confidence interval 1.4-36.8, P=.016). CONCLUSIONS: Our findings suggest that emergent stenting in endovascular treatment of AIS is associated with SICH. PMID- 23352680 TI - Examination timing and lesion patterns in diffusion-weighted magnetic resonance imaging of patients with classically defined transient ischemic attack. AB - BACKGROUND: This study investigated factors associated with the presence of acute ischemic lesions after transient ischemic attack (TIA), using diffusion-weighted imaging (DWI) data from a multicenter retrospective, observational study. METHODS: Of the 464 patients admitted to 13 stroke centers in Japan within 7 days after TIA onset, 458 patients underwent a DWI examination in this registry. Patients were divided into those with acute ischemic lesions and those without. We analyzed associations between DWI lesions and baseline characteristics, including age, sex, comorbidities, large artery atherosclerosis (LAA), type and duration of symptoms, the presence of multiple occurrences of TIA within 90 days before hospital visits (multiple TIAs) and the time from symptom onset to DWI examination (time-to-DWI). RESULTS: Among the 458 patients (291 men, 68.4+/-13.2 years old), 374 (81.7%) underwent a DWI examination within the initial 24 hours after the symptom onset. DWI lesions were found in 96 patients (21.0%), and divided into a single lesion (56 patients, 12.2%) or multiple lesions (40 patients, 8.7%). The presence of DWI lesions had an association with male sex (odds ratio [OR] 1.84; 95% confidence interval [CI] 1.07-3.29), time-to-DWI longer than 24 hours (OR 2.96; CI 1.57-5.52), and intracranial LAA (OR 1.99; CI 1.02-3.79). The presence of a single DWI lesion had an association with atrial fibrillation (OR 2.70; CI 1.41-5.03), and multiple DWI lesions did with time-to DWI longer than 24 hours (OR 6.20; CI 2.60-15.20), multiple TIAs (OR 3.04; CI 1.35-6.76), intracranial LAA (OR 3.63; CI 1.44-8.89), and extracranial LAA (OR 3.53; CI 1.08-10.78). CONCLUSIONS: Acute ischemic lesions on DWI were associated with time-to-DWI and LAA in patients with classically defined TIA. Additionally, we identified some differences in relating factors between patients with single and multiple DWI lesions. These results indicate that time-to-DWI and DWI lesion pattern may be important for the diagnosis and management of TIA. PMID- 23352681 TI - Predictors of functional outcome among stroke patients in Lima, Peru. AB - BACKGROUND: Because of the aging population in low- and middle-income countries, cerebrovascular disease is expected to remain a leading cause of death. Little has been published about stroke in Peru. We conducted a retrospective cohort study of hospitalized stroke patients at a referral center hospital in Lima, Peru to explore factors associated with functional outcome among stroke patients. METHODS: We identified 579 patients hospitalized for ischemic stroke or intracerebral hemorrhage stroke at the National Institute of Neurologic Sciences in Lima, Peru in 2008 and 2009. A favorable outcome was defined as a modified Rankin scale score of <= 2 at discharge. RESULTS: The mean age was 63.3 years; 75.6% had ischemic stroke; the average duration of stay was 17.3 days. At hospital discharge, 231 (39.9%) had a favorable outcome. The overall mortality rate was 5.2%. In multivariate models, the likelihood of having a favorable outcome decreased linearly with increasing age (P = .02) and increasing National Institutes of Health Stroke Scale (NIHSS) score (P = .02). Favorable outcome was also associated with male gender (relative risk [RR] 1.2; 95% confidence interval [CI] 1.0-1.5) and divorced status (RR 1.3; 95% CI 1.1-1.7). Patients on Salud Integral de Salud (SIS; public assistance-type insurance; RR 0.7; 95% CI 0.5-1.0) were also less likely to have a favorable outcome. CONCLUSIONS: Favorable outcome after stroke was independently associated with younger age, a lower NIHSS score, male gender, being divorced, and not being on SIS insurance. These findings suggest that additional study of worse functional outcomes in patients with SIS insurance be conducted and confirm the importance of risk adjustment for age, stroke severity (according to the NIHSS scale), and other socioeconomic factors in outcomes studies. Future studies should preferentially assess outcome at 30 days and 6 months to provide more reliable comparisons and allow additional study of Peruvian end-of-life decision-making and care. PMID- 23352682 TI - Charlson comorbidity index in ischemic stroke and intracerebral hemorrhage as predictor of mortality and functional outcome after 6 months. AB - BACKGROUND: The Charlson Comorbidity Index (CCI) is commonly used in outcome and mortality studies. Our aim was to investigate the association between CCI score and the functional outcome and mortality 6 months after ischemic stroke (IS) or intracerebral hemorrhage. METHODS: This was a prospective observational cohort of patients with spontaneous intracerebral hemorrhage and IS admitted to the stroke unit during 18 months. The modified Rankin scale (mRS) score was obtained for subjects 6 months after event. The CCI score was dichotomized (low comorbidity 0 or 1 versus high >= 2) for analysis. The mRS score was also dichotomized (good outcome, mRS score 0 or 1 versus poor outcome, mRS score >= 2). RESULTS: In all, 175 patients were enrolled in the study. Logistic regression showed that those with a high CCI score (>= 2) had 37.3% increased odds of having a poor outcome (>= 2) at 6 months and 68.4% greater odds of death at 6 months. CONCLUSIONS: Comorbid medical conditions independently influence outcome after IS or intracerebral hemorrhage. PMID- 23352683 TI - Residual shunt after patent foramen ovale closure: preliminary results from Italian patent foramen ovale survey. AB - BACKGROUND: Percutaneous patent foramen ovale (PFO) closure is accepted as treatment for cryptogenic ischemic stroke/transient ischemic attack in young subjects. However, a thorough evaluation of residual right-to-left shunt (rRLS) after PFO closure is needed. Our aims were to analyze the characteristics related to PFO diagnosis and closure, focusing on rRLS and clinical recurrences until 24 month follow-up. Data were extrapolated from the 12-month Italian PFO Survey. METHODS: In all, 1035 patients were included. PFO diagnosis and right-to-left shunt (RLS) were assessed by contrast-enhanced transesophageal and/or transthoracic echocardiography and/or transcranial Doppler. RESULTS: PFO diagnosis with RLS data were available in 894 of 1035 (86.4%) patients. rRLS was investigated in 49.6% (6 months), 27.1% (12 months), and 3.5% (24 months), and observed in 19.5% (6 months) and 18.2% (12 months) of subjects. Large permanent rRLS was observed in less than 3% of RLS-positive patients after 1 year. Eleven of 14 and 3 of 14 neurological recurrences were observed in 10 of 444 (2.25%) and 2 of 243 (0.8%) patients within the 6- and 12-month follow-up, respectively. Among these, no large rRLS was reported. There were no neurological events at 2 year follow-up. Forty of 444 subjects had non-neurological complications, mostly cardiac arrhythmias within the sixth month. CONCLUSIONS: PFO closure is a safe procedure. rRLS is not uncommon but large rRLS is rare. Clinical complications, mostly related to cardiac arrhythmias, are not unusual. Evaluation of the data of the whole survey is underway. PMID- 23352684 TI - Initial experience with upfront arterial and perfusion imaging among ischemic stroke patients presenting within the 4.5-hour time window. AB - BACKGROUND: Although perfusion imaging is being evaluated as a tool to select acute ischemic stroke patients who are most likely to benefit from reperfusion therapies beyond the standard time windows, there are limited data on the utility of perfusion imaging within the intravenous (IV) thrombolytic time window. METHODS: A new stroke imaging protocol was initiated at Emory University Hospital including computed tomographic angiography (CTA) and computed tomographic perfusion (CTP). All patients presenting within 4.5 hours from last known normal time with suspected stroke were prospectively identified. Impact of CTA and CTP on the clinical management was recorded prospectively by stroke team members. RESULTS: During the study period, 87 patients met eligibility criteria for the CTA/CTP protocol, of which 83 (95%) underwent this upfront comprehensive imaging protocol and 30 (34%) received IV thrombolytics. Overall, stroke team members reported that CTA and/or CTP aided their clinical management in 39 (47%) cases, including aiding in identification of a nonstroke diagnosis (n = 18), triage to the neurologic intensive care unit (n = 9), early triage to endovascular therapy (n = 4), and initiation of IV thrombolytic for low National Institutes of Health Stroke Scale score with large vessel occlusion (n = 3). Door to needle time <=60 minutes was achieved in only 18% of patients receiving IV thrombolysis during the study period, but had improved to 44% in the subsequent 6-month period. CONCLUSIONS: An upfront CTA/CTP protocol aided stroke team decision-making in nearly half of cases. Implementation of a CTA/CTP protocol was associated with a learning curve of 6 months before door to needle time <=60 minutes returned to similar rates as the pre-CTA/CTP protocol. PMID- 23352687 TI - Family conferences in stroke rehabilitation: a literature review. AB - BACKGROUND: Family conferences in hospital settings are acknowledged as being important and beneficial for enhancing communication between patients, family members, and the multidisciplinary team. They provide feedback on progress and therapeutic findings, and facilitate problem solving in cases of complex discharge planning. METHODS: A literature review was conducted, with 23 articles highlighting problem areas within current practice and discussing the merits of existing approaches. RESULTS: The articles suggest that stroke survivors and their families have additional education and support needs beyond what is already provided, and that intervention may be enhanced by being more proactive rather than reactive, preventing potentially avoidable crises or disputes. This review provides insight into the ideal methods for communicating and planning and identifies better uses of these opportunities. CONCLUSIONS: Much more can be done within the multidisciplinary team to ensure that the information needs of patients and families are catered for during their inpatient admission and on their return to the community. Additional research and trials of interventions by established rehabilitation services will allow for improved and more informed clinical practice (including cost effectiveness), enhanced knowledge of caregiver needs, and essentially more positive outcomes for rehabilitation patients and their families. Research may be able to develop best practice guidelines to ensure reduced caregiver stress and anxiety during admission and discharge. We require additional investigation of the effects of educational and emotional support provided in the hospital setting and as an outpatient on quality of life for caregivers and prevention of readmission to hospital or entrance into residential care for patients. PMID- 23352686 TI - Silent coronary artery disease in Japanese patients undergoing carotid artery stenting. AB - BACKGROUND: The aim of this retrospective study was to determine the prevalence of silent coronary artery disease (CAD) and the risk factors associated with concomitant CAD in Japanese patients undergoing carotid artery stenting (CAS). METHODS: The records of 112 consecutive patients (99 men and 13 women; mean age 70 +/- 8 years) who underwent elective CAS at our institution for extracranial carotid artery stenosis between January 2006 and January 2011 were reviewed retrospectively. During this period, preoperative CAD screening by coronary angiography was performed in all patients. Patients were diagnosed with CAD when >= 1 coronary arteries had stenosis >= 75% and were classified into 2 groups: (1) a group with CAD that was based on preoperative coronary angiography or a history of percutaneous coronary intervention (PCI) and/or coronary artery bypass grafting (CABG), and (2) a group without CAD that had no angiographically documented stenosis >= 75%. RESULTS: Sixteen (14.3%) patients had CAD that had already been treated by PCI and/or CABG. Silent CAD was detected in 39 (34.8%) of 112 patients. Taken together, 55 (49.1%) patients had clinically significant CAD. The patients with CAD were more likely to have diabetes mellitus (DM; P = .001), dyslipidemia (P = .013), and bilateral carotid disease (P = .033). Multivariate analysis revealed that DM (odds ratio 3.07; 95% confidence interval 1.25-7.53) and bilateral carotid stenosis (odds ratio 2.72; 95% confidence interval 1.10 6.75) were independent variables associated with concomitant CAD. CONCLUSIONS: Perioperative CAD screening revealed that silent CAD was frequently diagnosed in Japanese patients scheduled for CAS, particularly in those with DM and/or bilateral carotid stenosis. PMID- 23352685 TI - Resistive training improves insulin sensitivity after stroke. AB - BACKGROUND: Insulin resistance is highly prevalent after stroke, contributing to comorbid cardiovascular conditions that are the leading cause of death in the stroke population. This study determined the effects of unilateral resistive training (RT) of both the paretic and nonparetic legs on insulin sensitivity in stroke survivors. METHODS: We studied 10 participants (mean age 65 +/- 2 years; mean body mass index 27 +/- 4 kg/m2) with hemiparetic gait after remote (>6 months) ischemic stroke. All subjects underwent 1-repetition maximum (1-RM) strength testing, 9 had an oral glucose tolerance test (OGTT), and 7 completed a 2-hour hyperglycemic clamp (with glucose elevation targeted at 98 mg/dL above baseline fasting level) before and after 12 weeks (3*/week) of progressive, high repetition, high-intensity RT. Body composition was assessed by dual-energy x-ray absorbtiometry in all participants. RESULTS: Leg press and leg extension 1-RM increased in the paretic leg by 22% (P < .05) and 45% (P < .01), respectively. Fasting insulin decreased 23% (P < .05), with no change in fasting glucose. The 16% reduction in OGTT insulin area under the curve (AUC) across training was not statistically significant (P = .18). There was also no change in glucose AUC. First-phase insulin response during the hyperglycemic clamp (0-10 minutes) decreased 24% (P < .05), and second-phase insulin response (10-120 minutes) decreased 26% (P < .01). Insulin sensitivity increased by 31% after RT according to clamp calculations (P < .05). CONCLUSIONS: These findings provide the first preliminary evidence that RT may reduce hyperinsulinemia and improve insulin sensitivity after disabling stroke. PMID- 23352688 TI - Rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation for the secondary prevention of stroke: a subgroup analysis of J ROCKET AF. AB - BACKGROUND: The overall analysis of the rivaroxaban versus warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial revealed that rivaroxaban was not inferior to warfarin with respect to the primary safety outcome. In addition, there was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban compared with warfarin. METHODS: In this subanalysis of the J-ROCKET AF trial, we investigated the consistency of safety and efficacy profile of rivaroxaban versus warfarin among the subgroups of patients with previous stroke, transient ischemic attack, or non-central nervous system systemic embolism (secondary prevention group) and those without (primary prevention group). RESULTS: Patients in the secondary prevention group were 63.6% of the overall population of J-ROCKET AF. In the secondary prevention group, the rate of the principal safety outcome (% per year) was 17.02 in rivaroxaban treated patients and 18.26 in warfarin-treated patients (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.70-1.29), while the rate of the primary efficacy endpoint was 1.66 in rivaroxaban-treated patients and 3.25 in warfarin-treated patients (HR 0.51; 95% CI 0.23-1.14). There were no significant interactions in the principal safety and the primary efficacy endpoints of rivaroxaban compared to warfarin between the primary and secondary prevention groups (P=.090 and .776 for both interactions, respectively). CONCLUSIONS: The safety and efficacy profile of rivaroxaban compared with warfarin was consistent among patients in the primary prevention group and those in the secondary prevention group. PMID- 23352689 TI - Stroke subtypes and comorbidity among ischemic stroke patients in Brasilia and Cuenca: a Brazilian-Spanish cross-cultural study. AB - BACKGROUND: With the increase in life expectancy worldwide, changes in stroke subtypes and burden of stroke population are expected in both developing and developed countries. Prevalence of stroke subtypes and comorbidity in ischemic stroke patients was assessed in Brasilia, Brazil, and Cuenca, Spain. METHODS: This was an international (Brazilian-Spanish) cross-sectional study. Stroke subtypes were assessed by means of Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. Modified Rankin scale was used to measure functional recovery and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) was used to assess comorbidity. RESULTS: A total of 500 patients (mean age 66.2 +/- 16.4 years; 48% female; 48.2% Spanish) were included in the study. Spanish patients were significantly older than Brazilian ones (76.4 +/- 11.2 versus 56.7 +/- 14.6 years; P < .0001). Prevalence of ischemic cardiopathy (20.3% versus 6.2%) and atrial fibrillation (25.7% versus 6.6%) was significantly higher in Spanish stroke patients, whereas they less frequently used tobacco (28.3% versus 52.9%); P less than .0001. Prevalence of stroke subtypes in Spanish and Brazilian stroke patients was: stroke of undetermined etiology (58.1% versus 32.4%), cardioembolism (24.5% versus 11.6%), lacunar infarct (11.6% versus 25.5%), atherothrombotic (3.7% versus 19.7%), and other causes (2.1% versus 10.8%); P less than .0001. The Spanish sample had a significantly higher frequency of comorbidities. The CIRS-G total score and CIRS-G mean number of affected organs significantly increased with age, and correlated with the level of functional dependence as measured by Rankin scale (rS = 0.50; P = .0005). CONCLUSION: Spanish stroke people had a higher frequency of comorbid conditions, atrial fibrillation, and cardioembolism and these facts were associated with age. Atherothrombotic and lacunar strokes were more common in the younger Brazilian stroke population. PMID- 23352690 TI - Menopause, atherosclerosis, and coronary artery disease. AB - Women have coronary heart disease (CHD) later than men. This review describes studies of CHD risk factors or outcomes based on studies of premenopausal women followed through the menopause transition, and prospective cohort studies of younger or older women with CHD risk markers or disease outcomes in the context of their menopause history. Major early reports from both types of studies are included in order to put more recent work in context. Most attention has been paid to the Healthy Women Study (HWS), Study of Women's Health across the Nation (SWAN), the Nurses' Health Study (NHS), and the Rancho Bernardo Study (RBS) because they continue to produce recent publications designed to distinguish the effect of age from the effect of menopause. Understanding these differences has important implications for women's cardiovascular health, but remains incomplete. Transition studies have relatively short (<10 years) follow-up and exclude women with surgical menopause. Cohort studies suggest that women with oophorectomy are at greater risk for CHD than intact women, pointing to a greater risk from testosterone deficiency than from estradiol levels. PMID- 23352691 TI - Nitrate therapy and nitrate tolerance in patients with coronary artery disease. AB - Despite the continuous development of newer drugs, the therapy of coronary artery disease remains challenging. Organic nitrates are among the oldest drugs, but they still remain a widely used adjuvant in the treatment of symptomatic coronary artery disease. While their efficacy in relieving angina pectoris symptoms in acute settings and in preventing angina before physical or emotional stress is undisputed, the chronic use of nitrates has been associated with potentially important side effects such as tolerance and endothelial dysfunction. The identification of the mitochondrial aldehyde dehydrogenase as the enzyme responsible for the bioactivation of nitroglycerin has allowed the formulation of a complex but plausible hypothesis regarding the mechanism of action and the development of the side effects associated with nitrate therapy. Further, the discovery of important differences among nitrates suggests that these drugs should not be considered as a homogeneous class. Finally, the identification of nonhemodynamic properties of nitrates, and newer insight on the mechanism of nitrate tolerance, have led us to question the prognostic impact of these drugs. PMID- 23352694 TI - Dung beetles use the Milky Way for orientation. AB - When the moon is absent from the night sky, stars remain as celestial visual cues. Nonetheless, only birds, seals, and humans are known to use stars for orientation. African ball-rolling dung beetles exploit the sun, the moon, and the celestial polarization pattern to move along straight paths, away from the intense competition at the dung pile. Even on clear moonless nights, many beetles still manage to orientate along straight paths. This led us to hypothesize that dung beetles exploit the starry sky for orientation, a feat that has, to our knowledge, never been demonstrated in an insect. Here, we show that dung beetles transport their dung balls along straight paths under a starlit sky but lose this ability under overcast conditions. In a planetarium, the beetles orientate equally well when rolling under a full starlit sky as when only the Milky Way is present. The use of this bidirectional celestial cue for orientation has been proposed for vertebrates, spiders, and insects, but never proven. This finding represents the first convincing demonstration for the use of the starry sky for orientation in insects and provides the first documented use of the Milky Way for orientation in the animal kingdom. PMID- 23352692 TI - Flaviviruses: braking the entering. AB - Flaviviruses are small spherical virus particles covered by a dense icosahedral array of envelope (E) proteins that mediate virus attachment to cells and the fusion of viral and cellular membranes. Our understanding of the mechanism by which flavivirus E proteins orchestrate entry into cells has been advanced by studies of E structure and arrangement on the virion at different steps of the virus entry/membrane fusion process. When combined with an increasingly clear (albeit still incomplete) view of the cell biology of virus entry, these advances suggest new antiviral strategies. Indeed, inhibitors that target cellular and viral processes involved in entry show promise as powerful tools to study this critical step of the viral lifecycle, and with luck, may ultimately lead to therapeutic advances. PMID- 23352693 TI - Effect of selective decontamination on antimicrobial resistance in intensive care units: a systematic review and meta-analysis. AB - BACKGROUND: Many meta-analyses have shown reductions in infection rates and mortality associated with the use of selective digestive decontamination (SDD) or selective oropharyngeal decontamination (SOD) in intensive care units (ICUs). These interventions have not been widely implemented because of concerns that their use could lead to the development of antimicrobial resistance in pathogens. We aimed to assess the effect of SDD and SOD on antimicrobial resistance rates in patients in ICUs. METHODS: We did a systematic review of the effect of SDD and SOD on the rates of colonisation or infection with antimicrobial-resistant pathogens in patients who were critically ill. We searched for studies using Medline, Embase, and Cochrane databases, with no limits by language, date of publication, study design, or study quality. We included all studies of selective decontamination that involved prophylactic application of topical non-absorbable antimicrobials to the stomach or oropharynx of patients in ICUs, with or without additional systemic antimicrobials. We excluded studies of interventions that used only antiseptic or biocide agents such as chlorhexidine, unless antimicrobials were also included in the regimen. We used the Mantel-Haenszel model with random effects to calculate pooled odds ratios. FINDINGS: We analysed 64 unique studies of SDD and SOD in ICUs, of which 47 were randomised controlled trials and 35 included data for the detection of antimicrobial resistance. When comparing data for patients in intervention groups (those who received SDD or SOD) versus data for those in control groups (who received no intervention), we identified no difference in the prevalence of colonisation or infection with Gram positive antimicrobial-resistant pathogens of interest, including meticillin resistant Staphylococcus aureus (odds ratio 1.46, 95% CI 0.90-2.37) and vancomycin-resistant enterococci (0.63, 0.39-1.02). Among Gram-negative bacilli, we detected no difference in aminoglycoside-resistance (0.73, 0.51-1.05) or fluoroquinolone-resistance (0.52, 0.16-1.68), but we did detect a reduction in polymyxin-resistant Gram-negative bacilli (0.58, 0.46-0.72) and third-generation cephalosporin-resistant Gram-negative bacilli (0.33, 0.20-0.52) in recipients of selective decontamination compared with those who received no intervention. INTERPRETATION: We detected no relation between the use of SDD or SOD and the development of antimicrobial-resistance in pathogens in patients in the ICU, suggesting that the perceived risk of long-term harm related to selective decontamination cannot be justified by available data. However, our study indicates that the effect of decontamination on ICU-level antimicrobial resistance rates is understudied. We recommend that future research includes a non-crossover, cluster randomised controlled trial to assess long-term ICU-level changes in resistance rates. FUNDING: None. PMID- 23352695 TI - Drosophila tracks carbon dioxide in flight. AB - Carbon dioxide (CO(2)) elicits an attractive host-seeking response from mosquitos yet is innately aversive to Drosophila melanogaster despite being a plentiful byproduct of attractive fermenting food sources. Prior studies used walking flies exclusively, yet adults track distant food sources on the wing. Here we show that a fly tethered within a magnetic field allowing free rotation about the yaw axis actively seeks a narrow CO(2) plume during flight. Genetic disruption of the canonical CO(2)-sensing olfactory neurons does not alter in-flight attraction to CO(2); however, antennal ablation and genetic disruption of the Ir64a acid sensor do. Surprisingly, mutation of the obligate olfactory coreceptor (Orco) does not abolish CO(2) aversion during walking yet eliminates CO(2) tracking in flight. The biogenic amine octopamine regulates critical physiological processes during flight, and blocking synaptic output from octopamine neurons inverts the valence assigned to CO(2) and elicits an aversive response in flight. Combined, our results suggest that a novel Orco-mediated olfactory pathway that gains sensitivity to CO(2) in flight via changes in octopamine levels, along with Ir64a, quickly switches the valence of a key environmental stimulus in a behavioral-state-dependent manner. PMID- 23352696 TI - DNA quality control by a lesion sensor pocket of the xeroderma pigmentosum group D helicase subunit of TFIIH. AB - BACKGROUND: Nucleotide excision repair is a versatile DNA repair reaction that removes bulky adducts generated by environmental mutagens such as the UV spectrum of sunlight or chemical carcinogens. Current multistep models of this excision repair pathway accommodate its broad substrate repertoire but fail to explain the stringent selectivity toward damaged nucleotides among excess native DNA. To understand the mechanism of bulky lesion recognition, we postulated that it is necessary to analyze the function of xeroderma pigmentosum group D (XPD) protein beyond its well-known role in the unwinding of double-stranded DNA. RESULTS: We engineered two new XPD mutants (Y192A and R196E), involving amino acid substitutions near its central protein pore, that confer defective DNA repair despite normal transcription. In situ fluorescence-based protein dynamics studies in living cells demonstrated that both new mutants were unable to recognize DNA damage and failed to form stable associations with lesion sites. However, when their biochemical properties were tested in the framework of an archaeal protein homolog, they both retained ATPase and DNA-unwinding activity. The outstanding difference versus the wild-type control was that their directional 5'-3' translocation along DNA was not stopped by a bulky lesion, and moreover, they were unable to build long-lived demarcation complexes at damaged sites. CONCLUSIONS: By uncoupling for the first time the unwinding and damage sensor activities of XPD, we describe an unprecedented genome quality control process whereby a recognition pocket near the central DNA helicase pore scans individual substrate strands to capture base adducts. PMID- 23352697 TI - High-resolution cine MRI with TGRAPPA for fast assessment of left ventricular function at 3 Tesla. AB - PURPOSE: To implement and evaluate the accuracy of multislice dual-breath hold cine MR for analysis of global systolic and diastolic left ventricular function at 3T. MATERIALS AND METHODS: 25 patients referred to cardiac MR underwent cine imaging at 3T (MAGNETOM Verio) using prospective triggered SSFP (TR 3.1 ms; TE 1.4 ms; FA 60 degrees ). Analysis of LV function was performed using a standard non-accelerated single-slice approach (STD) with multiple breath-holds and an accelerated multi-slice technique (TGRAPPA; R=4) encompassing the ventricles with 5 slices/breath-hold. Parameters of spatial and temporal resolution were kept identical (pixel: 1.9 * 2.5 mm(2); temporal resolution: 47 ms). Data of both acquisition techniques were analyzed by two readers using semiautomatic algorithms (syngoARGUS) with respect to EDV, ESV, EF, myocardial mass (MM), peak filling rate (PFR) and peak ejection rate (PER) including assessment of interobserver agreement. RESULTS: Volumetric results of the TGRAPPA approach did not show significant differences to the STD approach for left ventricular ejection fraction (62.3 +/- 10.6 vs. 61.0 +/- 8.4, P=0.2), end-diastolic volume (135.8 +/- 47.5 vs. 130.8 +/- 46.4, P=0.07), endsystolic volume (53.0 +/- 29.7 vs. 53.1 +/- 32.7, P=0.99) and myocardial mass (114.2 +/- 32.5 vs. 114.6+/-30.6, P=0.9). Moreover, a comparison of peak ejection rate (601.3 +/- 190.2 vs. 590.8 +/- 218.2, P=0.8) and peak filling rate (535.1+/-191.2 vs. 535.4 +/- 210.7, P=0.99) did not reveal significant differences between the two groups. Limits in interobserver agreement were low for all systolic and diastolic parameters in both groups (P >= 0.05). Total acquisition time for STD was 273 +/- 124 s and 34 +/- 5 s for TGRAPPA (P <= 0.001). Evaluation time for standard and multislice approach was equal (10.8 +/- 1.4 vs. 9.8 +/- 2.1 min; P=0.08). PMID- 23352698 TI - Anatomical differences in lower third molars visualized by 2D and 3D X-ray imaging: clinical outcomes after extraction. AB - The purpose of this study was to evaluate the relationship between third molars and the inferior alveolar canal using panoramic radiographs and cone beam computed tomography (CBCT) scans and to assess clinical outcomes after third molar removal retrospectively. The degree of superimposition, buccolingual position (buccal, central, and lingual) and physical relationship (separation, contact, and involved) were measured using CBCT scanning. Post-extraction complications were recorded. Based on radiographic evaluation, 45.9% of third molar roots were inside the inferior alveolar canal, 21.3% were in contact with the inferior alveolar canal, and 32.8% were separated from the canal. The frequency at which the mandibular canal was separated from the root apex was significantly higher when the canal was in the buccal position (80.0%) than in the central (20.0%) and lingual positions (0.0%). Although on panoramic radiographs all third molars were directly superimposed on the inferior alveolar canal, CBCT showed direct contact or canal involvement in 67.2% and separation of the canal from the root apex in 32.8%. Complications occurred in nine patients: eight had third molar root apices inside or in contact with the inferior alveolar canal. The prevalence of post-extraction complications correlated with the absence of cortication around the inferior alveolar canal. PMID- 23352699 TI - Intraoral extra-mucosal fixation of fractures in the atrophic edentulous mandible. AB - Atrophy of the mandible leads to a decrease in the bone mass, making it more vulnerable to fractures. A direct relationship has been demonstrated between the height of the bone in the area of the fracture and the incidence of postoperative complications of bone healing. Basic principles of fracture management in both edentulous and non edentulous patients are open reduction and internal fixation with osteosynthesis of the fracture to achieve restoration in terms of aesthetics and functionality. Several authors have discussed the advantages and disadvantages of the transoral and extraoral approaches. Between January 2007 and June 2011, 13 patients affected by bilateral fractures of atrophic mandibles were treated by extra-mucosal intraoral stabilization with satisfactory results. This approach reduces the risks of damage of the marginalis mandibulae nerve with low operation time, while avoiding unsightly scars. PMID- 23352700 TI - In situ application of polyelectrolytes in zinc oxide nanorod synthesis: understanding the effects on the structural and optical characteristics. AB - We report a facile and simple means of synthesizing a macroscopic array of ZnO nanorods with high feature densities using a modified hydrothermal approach that involves the in situ introduction of polyelectrolyte. The ZnO nanorod arrays with heights of 1.5 MUm and diameters of 350 nm were consistently reproducible and were bestowed with the advantage of in situ process tunability offered by employing polyethylenimine (PEI) as a surface modifying agent. The fabrication combines benefits from the hydrothermal approach in terms of process simplicity and flexibility and from the use polyelectrolyte that offers a better nanorod surface, quenched defect levels and enhancement of the UV band edge emission. Structural and elemental analysis of the PEI-modified and unmodified nanorods emphasize the fact that the intentional introduction of PEI results in a nanorod with better surface quality as evidenced by photoluminescence (PL) spectra. The tunability of the feature dimensions of the nanorods and an analysis of the bulk and surface (surface defect) responses to the PL point to significant promise of high density orthogonal nanorods in a number of optoelectronic applications. While the defects in the ZnO nanorods can point towards the application of ZnO nanorods in charge trap flash memory devices, highly crystalline, size tunable, high aspect ratio nanorods find applications as building components in solid state lighting. PMID- 23352701 TI - Template-assisted deposition of CTAB-functionalized gold nanoparticles with nanoscale resolution. AB - In this paper, we demonstrate the template-assisted deposition of cetyltrimethylammonium bromide (CTAB) stabilized gold nanorods at lithographically defined positions on a substrate. Overcoating of the nanoparticles with polystyrenesulfonate allows to switch the original nanoparticles positive surface charge to negative and to apply the template assisted deposition technique developed for citrate-capped gold nanoparticles also to CTAB stabilized nanoparticles. The successful, selective deposition of gold nanorods in trenches with widths down to 50 nm is demonstrated. Our results indicate the potential of this method for the fabrication of well controlled, reproducible plasmonic biosensing substrates, applicable to the vast palette of anisotropic nanoparticle shapes synthesized with CTAB as the templating agent. PMID- 23352702 TI - Poly(allyl methacrylate) functionalized hydroxyapatite nanocrystals via the combination of surface-initiated RAFT polymerization and thiol-ene protocol: a potential anticancer drug nanocarrier. AB - Hydroxyapatite nanocrystals (HAP NCs) were encapsulated by poly(allyl methacrylate) (PolyAMA) employing controlled surface-initiated reversible addition-fragmentation chain transfer (SI-RAFT) polymerization of allyl methacrylate to afford HAP-PolyAMA nanohybrids. The subsequent thiol-ene coupling of nanohybrids with 2-mercaptosuccinic acid resulted HAP-Poly(AMA-COOH) possessing multicarboxyl group. The formation of the nanohybrids was confirmed by FT-IR and EDS analyses. The TGA and FE-SEM investigation were further suggested the grafting of PolyAMA onto HAP NCs. The utility of the HAP-PolyAMA nanohybrid as drug carrier was also explored. The pendant carboxyl groups on the external layers of nanohybrids were conjugated with anticancer drug cisplatin to afford HAP-Poly(AMA-COOH)/Pt complex. The formation of the complex was confirmed by FT IR, XPS, and FE-SEM. In vitro evaluation of the synthesized complex as nanomedicine revealed its potential chemotherapeutic efficacy against cancer cell lines. PMID- 23352703 TI - Salinomycin induces apoptosis and senescence in breast cancer: upregulation of p21, downregulation of survivin and histone H3 and H4 hyperacetylation. AB - BACKGROUND: In the present study, we investigated the effect of Salinomycin on the survival of three human breast cancer cell lines MCF-7, T47D and MDA-MB-231 grown in adherent culture conditions. METHODS: Cell viability was measured by Cell Titer-Glo and Trypan blue exclusion assay. Apoptosis was determined by caspase 3/7 activation, PARP cleavage and Annexin V staining. Cell cycle distribution was assessed by propidium iodide flow cytometry. Senescence was confirmed by measuring the senescence-associated beta-galactosidase activity. Changes in protein expression and histone hyperacetylation was determined by western blot and confirmed by immunofluorescence assay. RESULTS: Salinomycin was able to inhibit the growth of the three cell lines in time- and concentration dependent manners. We showed that depending on the concentrations used, Salinomycin elicits different effects on the MDA-MB-231 cells. High concentrations of Salinomycin induced a G2 arrest, downregulation of survivin and triggered apoptosis. Interestingly, treatment with low concentrations of Salinomycin induced a transient G1 arrest at earlier time point and G2 arrest at later point and senescence associated with enlarged cellmorphology, upregulation of p21 protein, increase in histone H3 and H4 hyperacetylation and expression of SA-beta-Gal activity. Furthermore, we found that Salinomycin was able to potentiate the killing of the MCF-7 and MDA-MB-231 cells, by the chemotherapeutic agents, 4-Hydroxytamoxifen and frondo side A, respectively. CONCLUSION: Our data are the first to link senescence and histone modifications to Salinomycin. SIGNIFICANCE: This study provides a new insight to better understand the mechanism of action of Salinomycin, at least in breast cancer cells. PMID- 23352704 TI - Equine preantral follicles obtained via the Biopsy Pick-Up method: histological evaluation and validation of a mechanical isolation technique. AB - The aims of this study in mares were to: (1) compare preantral follicle parameters between in vitro Biopsy Pick-Up (BPU) and scalpel blade collection methods and between histological and mechanical isolation processing (experiment 1); (2) histologically evaluate preantral follicles (experiment 2); and (3) compare histological analysis with a previously established mechanical isolation technique using a tissue chopper (experiment 3) for ovarian cortical fragments obtained in vivo using a BPU instrument. In experiment 1, preantral follicles were analyzed (N = 220; 90% primordial and 10% primary). Proportions of primordial and primary follicles did not differ (P > 0.05) between tissue collection (BPU vs. scalpel blade dissection) or processing (mechanical isolation vs. histology) methods. Follicle viability and morphology rates were similar (P > 0.05) between tissue collection methods, but mechanical isolation produced more (P < 0.05) morphologically normal follicles than histology. For experiment 2, preantral follicles (N = 332) were analyzed and primordial and transitional (combined) follicles and oocytes were 36.3 +/- 0.3 and 26.1 +/- 0.3 MUm in diameter, respectively, and primary follicles and oocytes averaged 42.9 +/- 1.8 and 31.8 +/- 2.1 MUm. For experiment 3 (188 preantral follicles), within the same animals, the proportion of primordial versus primary follicles was higher (P < 0.03) for histological analysis (98%) compared to tissue chopper analysis (94%), and number of follicles per mg of tissue was not affected (P > 0.05) by processing methods. In conclusion, most parameters evaluated for preantral follicles were similar between histological and tissue chopper processing techniques; hence, mechanical isolation efficiently dissociated equine preantral follicles from the ovarian cortex. Therefore, the tissue chopper could be used to isolate large numbers of morphologically normal equine preantral follicles for cryopreservation and/or in vitro culture. PMID- 23352705 TI - [A case of gyrate atrophy]. PMID- 23352706 TI - [Sclerochoroidal calcifications]. PMID- 23352707 TI - [Kyrieleis arteritis: report of two cases and literature review]. AB - We report the cases of two patients presenting with unilateral Kyrieleis arteritis complicating severe posterior uveitis, one secondary to toxoplasmosis and the other in the context of Behcet's disease. The treatment response was favorable with complete visual recovery in both cases. Kyrieleis arteritis has been described since 1933, but its pathogenesis is still unknown. However, it appears to be more of a periarteritis than an actual arteritis. It is classically associated with posterior uveitis without a direct correlation with disease severity. PMID- 23352708 TI - [Evaluation of a new intraocular lens platform: centration and rotational stability]. AB - PURPOSE: To assess the rotational stability and centration of a single-piece hydrophilic acrylic intraocular lens (IOL) during the first postoperative year. SETTING: Clinique Beausoleil, 117, avenue de Lodeve, 34070 Montpellier, France. DESIGN: Retrospective case series. METHOD: The POD AY 26% monofocal aspheric yellow intraocular lens is designed to facilitate its intraoperative orientation within the capsular bag. This study consists of a retrospective analysis of 117 consecutive eyes implanted with this IOL to determine its postoperative stability. Data collected include ocular biometry, patient history, IOL power, pre- and postoperative visual acuity and refraction, and slit lamp photos after one and three weeks, and 3 and 12 months. RESULTS: Mean postoperative visual acuity was 0.95 after 3 months and remained stable after 1 year. The refraction was also stable over time, although a slight effect related to corneal healing could be observed (0.1D). The mean absolute rotation of the implant was 2.5 +/- 2.6 degrees . The position of the center of the implant relative to the pupillary center expressed as a vector was 0.01 mm at 70 degrees . CONCLUSION: This new IOL design is as stable as a C-Loop IOL but provides much better maneuverability during implantation. It provides physiologic centration and good rotational stability over 1 year. It would be a perfect platform for a toric optic. PMID- 23352709 TI - [Optic nerve schwannoma]. AB - OBJECTIVE: To report the occurrence of an orbital schwannoma probably arising from the optic nerve sheath. PATIENT AND METHOD: Clinical case report. RESULTS: A 65-year-old patient presented with a painless, progressive right proptosis over five years. Magnetic resonance imaging revealed an intraconal mass, radiographically consistent with a cavernous hemangioma. Surgical resection was performed and pathology disclosed a schwannoma affecting the optic nerve. The optic nerve, which does not contain Schwann cells, is exceptionally rarely affected by Schwannomas, which may arise from a few sympathetic nerve fibers or from a few ectopic cells, not normally present within the optic nerve. CONCLUSION: The radiologic appearance of the very rare optic nerve Schwannoma may be confused with a cavernous hemangioma, a more common tumor in this location. PMID- 23352710 TI - The single nucleotide polymorphism (SNP) of the estrogen receptor-beta gene, rs1256049, is associated with knee osteoarthritis in Korean population. AB - BACKGROUND: Estrogens affect articular cartilage metabolism via estrogen receptors (ER) in chondrocytes and are believed to play an important role in the pathophysiology of osteoarthritis (OA). The aim of this study is to determine whether the single nucleotide polymorphism (SNP) of the estrogen receptor-beta (ER-beta) is associated with an increased susceptibility to knee OA. METHODS: The possible influence of the SNP of the ER-beta was investigated in 286 OA patients and 294 healthy subjects as controls. A polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) assay and a PCR-single strand conformation polymorphism (SSCP) assay were used to identify the Rsa polymorphism genotype among healthy controls and OA patients, respectively. RESULTS: For rs1256049 (Rsa), frequencies of genotypes GG, GA, and AA were 49.0% (144/294), 43.5% (128/294), and 7.5% (22/294) in healthy controls, and 35.3% (101/286), 45.5% (130/286), and 19.2% (55/286) in OA patients. Frequencies of alleles G and A among healthy controls were 70.7% (416/588) and 29.3% (172/588); whereas those among OA patients were 58.0% (332/572) and 42.0% (240/572). Statistically significant differences in allele and genotype frequencies of rs1256049 were observed between OA patients and controls (P<0.0001). In particular, the risk of OA was significantly increased in carriers with the rs1256049A allele and rs1256049 AA homozygotes. CONCLUSIONS: These results suggest a close association of rs1256049 ER-beta polymorphisms with susceptibility to OA in the Korean population. CLINICAL RELEVANCE: The rs1256049 polymorphism of the estrogen receptor-beta gene can potentially be used to identify genetically high-risk subgroup of osteoarthritis in advance and to understand pathogenesis of osteoarthritis. PMID- 23352712 TI - Wormian bones in a general paediatric population. AB - Wormian bones are small bones that are often found within the sutures and fontanelles of the skull. When a child presents an unexplained fracture or fracture(s), osteogenesis imperfecta is usually suggested when an "abnormally high number" of fractures are seen. PURPOSE: To assess the frequency, number, and topography of wormian bones in a "normal" paediatric population. MATERIALS AND METHODS: In a population aged from 0 to 3 years, we retrospectively analysed 605 CT brain scans carried out for a range of indications, excluding cases in which there was a suspicion of constitutional bone disease. RESULTS: In our population, wormian bones were found in 53% of children (n=320): 43% of the children had between one and three (n=260), 10% had four or more (n=60), and 6% had five or more (n=40). There was no significant relationship between the number of wormian bones and the various indications that had led to the CT scan being carried out. Wormian bones in the lambdoid suture were found in by far the greatest numbers. CONCLUSION: Wormian bones are common and can sometimes be numerous without necessarily pointing to osteogenesis imperfecta, since 10% of the children in our study had at least four. PMID- 23352711 TI - Association between long-term quadriceps weakness and early walking muscle co contraction after total knee arthroplasty. AB - INTRODUCTION: Quadriceps weakness is one of the primary post-operative impairments that persist long term for patients after total knee arthroplasty (TKA). We hypothesized that early gait muscle recruitment patterns of the quadriceps and hamstrings with diminished knee performance at 3months after surgery would be related to long-term quadriceps strength at 1year after TKA. METHODS: Twenty-one subjects who underwent primary unilateral TKA and 14 age matched healthy controls were analyzed. At 3months after TKA, the maximum voluntary isometric contraction of the quadriceps and a comprehensive gait analysis were performed. Quadriceps strength was assessed again at 1year after surgery. RESULTS: Quadriceps muscle recruitment of the operated limb was greater than the non-operated limb during the loading response of gait (p=0.03), but there were no significant differences in hamstring recruitment or co-contraction between limbs (p>0.05). There were significant differences in quadriceps muscle recruitment during gait between the non-operated limbs of the TKA group and the healthy control group (p<0.05). The TKA group showed a significant inverse relationship between one year quadriceps strength and co-contraction (r=-0.543) and hamstring muscle recruitment (r=-0.480) during loading response at 3months after TKA. CONCLUSIONS: The results revealed a reverse relationship where stronger patients tended to demonstrate lower quadriceps recruitment at 3months post-surgery that was not observed in the healthy peer group. The altered neuromuscular patterns of the quadriceps and hamstrings during gait may influence chronic quadriceps strength in individuals after TKA. LEVEL OF EVIDENCE: III. PMID- 23352714 TI - Image analysis is driving a renaissance in growth measurement. AB - The domain of machine vision, in which digital images are acquired automatically in a highly structured environment for the purpose of computationally measuring features in the scene, is applicable to the measurement of plant growth. This article reviews the quickly growing collection of reports in which digital image processing has been used to measure plant growth, with emphasis on the methodology and adaptations required for high-throughput studies of populations. PMID- 23352713 TI - Steric analysis of epoxyalcohol and trihydroxy derivatives of 9-hydroperoxy linoleic acid from hematin and enzymatic synthesis. AB - We characterize the allylic epoxyalcohols and their trihydroxy hydrolysis products generated from 9R- and 9S-hydroperoxy-octadecenoic acid (HPODE) under non-enzymatic conditions, reaction with hematin and subsequent acid hydrolysis, and enzymatic conditions, incubation with Beta vulgaris containing a hydroperoxide isomerase and epoxide hydrolase. The products were resolved by HPLC and the regio and stereo-chemistry of the transformations were determined through a combination of (1)H NMR and GC-MS analysis of dimethoxypropane derivatives. Four trihydroxy isomers were identified upon mild acid hydrolysis of 9S,10S-trans epoxy-11E-13S-hydroxyoctadecenoate: 9S,10R,13S, 9S,12R,13S, 9S,10S,13S and 9S,12S,13S-trihydroxy-octadecenoic acids, in the ratio 40:26:22:12. We also identified a prominent delta-ketol rearrangement product from the hydrolysis as mainly the 9-hydroxy-10E-13-oxo isomer. Short incubation (5 min) of 9R- and 9S HPODE with B. vulgaris extract yielded the 9R- and 9S-hydroxy-10E-12R,13S-cis epoxy products respectively. Longer incubation (60 min) gave one specific hydrolysis product via epoxide hydrolase, the 9R/S,12S,13S trihydroxyoctadecenoate. These studies provide a practical approach for the isolation and characterization of allylic epoxy alcohol and trihydroxy products using a combination of HPLC, GC-MS and (1)H NMR. PMID- 23352715 TI - Microsurgical clipping of previously coiled intracranial aneurysms. AB - OBJECTIVE: Endovascular coiling techniques for the treatment of intracranial aneurysms have rapidly developed as an alternative option to surgical clipping. A distinct problem after endovascular coiling is the management of a residual aneurysm neck due to incomplete filling, compaction of coils or regrowth of the aneurysm. Treatment options in this situation include surgical clipping, re coiling, stent implantation or observation. METHODS: From June 2006 to August 2011, 15 patients underwent surgical clipping of residual or recurrent aneurysms after previous endovascular treatment. The mean age of the patients was 50.6 years (range, 27-85 years). The mean interval between coiling and clipping was 76.5 weeks (range, 0-288 weeks). RESULTS: Thirteen patients revealed a regrowth of coiled aneurysms, and in 5 patients compaction of coils was present. Coil extrusion was observed in 9 patients intraoperatively. In case of coil obstruction at the aneurysmal neck during surgery, coils were partially or completely removed. In all cases complete occlusion of the aneurysms was surgically achieved. CONCLUSION: Coiled aneuryms with incomplete occlusion, coil compaction or regrowth of the aneurysmal neck can be successfully treated with microsurgical clipping. Coil extrusion was more often observed intraoperatively than expected. Complete occlusion of the aneurysm can be performed safely, even if loops of coils protrude into the aneurysmal neck. In these cases intraoperative removal of the coils enables secure closure of the aneurysm with a surgical clip. PMID- 23352716 TI - Stable Huh-7 cell lines expressing non-structural proteins of genotype 1a of hepatitis C virus. AB - Hepatitis C virus (HCV) infection has infected approximately 3% of the world population. HCV genotype 1a is distributed throughout the world, and along with genotype 1b, is relatively resistant to current standards of therapy compared to other HCV genotypes. The present study was designed to produce stable Huh-7 cell lines expressing non-structural proteins of HCV genotype la, representing an in vitro system to facilitate the development of new antiviral drugs against chronic HCV infection. The non-structural genes of HCV genotype 1a were amplified and cloned in a mammalian expression vector pCR 3.1/FIagTag. Huh-7 cells were transfected with one of two expression plasmids, the first containing the NS2, NS3, and NS4a cassette, and second containing the NS5a and NS5b genes. Stable cell lines were produced under the selection of gentamycin (G418). mRNA and protein expression analysis was performed by RT-PCR and Western blotting. The RT PCR and Western blot results confirmed the stable expression of each of the gene products. Stable Huh-7 cell lines with HCV la non-structural proteins may be helpful for evaluating the role of HCV proteins in molecular pathogenesis, and could facilitate the development of new therapeutic drugs. PMID- 23352718 TI - Severe complications of strabismus surgery. AB - PURPOSE: To determine the type, incidence, and clinical outcomes of severe complications from strabismus surgery in the United Kingdom. METHODS: Cases were identified prospectively through a national surveillance unit between September 1, 2008, and August 31, 2010. Questionnaire data were requested at the time of the complication recognition and at 6 months' follow-up. Outcome was graded I to V, with a poor or very poor outcome meaning either loss of corrected visual acuity or primary position double vision. RESULTS: A total of 60 completed reports of adverse events and complications were received during the study period. During the same time approximately 24,000 strabismus surgeries were performed in the United Kingdom, yielding an overall incidence of 1 in 400 operations (95% binomial confidence, 1 per 333-500 operations). The most common reported complication was perforation of the globe (19 [0.08%]), followed by a suspected slipped muscle (16 [0.067%]), severe infection (14 [0.06%]), scleritis (6 [0.02%]), and lost muscle (5 [0.02%]). Overall, complications were reported in adults and children in equal numbers; however, scleritis was significantly more common in adults. A poor or very poor clinical outcome was recorded as 1 operation per 2,400. CONCLUSIONS: This study provides an assessment of the overall risks associated with strabismus surgery in the United Kingdom. Complications with the potential for a poor outcome are relatively common, but the final clinical outcome is good in the majority of cases. PMID- 23352717 TI - [The Spanish Society of Pediatric Infectious Diseases Guidelines for the diagnosis and treatment of congenital toxoplasmosis]. AB - Congenital toxoplasmosis is the result of transplacental fetal infection by Toxoplasma gondii after the primary maternal infection. The severity of the disease depends on the gestational age at transmission. First trimester infections are more severe, but less frequent, than third trimester infections. Acute maternal infection is diagnosed by seroconversion or by the detection of IgM antibodies and a low IgG avidity test. In these cases, spiramycin should be initiated to prevent transmission to the fetus. For identification of fetal infection, polymerase chain reaction (PCR) testing of amniotic fluid after 18 weeks gestation should be performed. If fetal infection is confirmed, the mothers should be treated with pyrimethamine, sulfadiazine and folinic acid. Most infants infected in utero are born with no obvious signs of toxoplasmosis, but up to 80% developed learning and visual disabilities later in life. Neonatal diagnosis with IgM/IgA antibodies or blood/cerebrospinal fluid PCR may be difficult because false-negative results frequently occur. In these cases diagnosis is possible by demonstrating a rise in IgG titers during follow-up or by the detection of antibodies beyond one year of age. Early treatment with pyrimethamine and sulfadiazine may improve the ophthalmologic and neurological outcome. Congenital toxoplasmosis is a preventable disease. Pre-pregnancy screening and appropriate counseling regarding prevention measures in seronegative women may prevent fetal infection. PMID- 23352719 TI - Incidence of cataract development by 6 months' corrected age in the Early Treatment for Retinopathy of Prematurity study. AB - PURPOSE: To report the incidence of cataract development by 6 months' corrected age in preterm children who participated in the Early Treatment for Retinopathy of Prematurity study. METHODS: Infants who developed prethreshold retinopathy of prematurity (ROP) in one or both eyes and were determined by the RM-ROP2 model to have a high risk of poor structural outcome without treatment were randomized to receive early treatment (ET), defined as laser photocoagulation at high-risk prethreshold ROP, or to be conventionally managed (CM), receiving treatment only if threshold ROP developed. Data on eyes developing a cataract by 6 months' corrected age were analyzed. RESULTS: Of 401 randomized infants, 366 survived patients were followed, and 8 eyes of 7 patients (1.9%) developed cataracts by 6 months' corrected age. Among these patients, mean birth weight was 754 g, and mean gestational age was 25.7 weeks. Mean gestational age at treatment was 36.3 weeks for ET patients and 39.5 weeks for CM patients. Three ET eyes and 5 CM eyes developed a cataract. Of the CM eyes, 3 with and 2 without laser treatment developed a cataract. All 6 treated eyes had plus disease when treated. Three eyes had ROP in zone 1, whereas the other 3 had ROP in zone 2. All eyes were treated using a diode laser. CONCLUSIONS: By 6 months' corrected age, a small number of both ET and CM eyes developed cataracts following diode laser treatment for retinopathy of prematurity. Absence of obvious intraoperative complications does not preclude subsequent cataract development, which can occur without laser treatment. PMID- 23352720 TI - Rectus muscle resection in Graves' ophthalmopathy. AB - BACKGROUND: In the treatment of Graves' ophthalmopathy, rectus muscle resections generally are avoided because of the concern of reaggravating inflammation and creating excessive extraocular muscle restriction. In patients with large-angle strabismus and in patients with residual strabismus after maximal recession surgery, however, rectus muscle resection may be considered. We report a series of 8 patients with Graves' ophthalmopathy who underwent rectus muscle resections. METHODS: The records of 270 patients with Graves' ophthalmopathy who had undergone strabismus surgery were retrospectively reviewed. Data from subjects who had undergone rectus muscle resections were collected, including age at surgery, duration of disease, duration of diplopia, previous eye or strabismus surgeries, history of radioactive iodine or corticosteroid treatment, current thyroid medications, current use of corticosteroids, tobacco use, and signs and symptoms used to diagnose Graves' ophthalmopathy. RESULTS: Eight patients (5 females) were identified (mean age, 51.1 +/- 17.6 years). Preoperatively, 4 patients had a horizontal deviation and 4 patients had both horizontal and vertical deviations in primary gaze. Mean preoperative horizontal deviation was 27.9(Delta) +/- 15.2(Delta) and mean vertical deviation was 6.3(Delta) +/- 5.4(Delta). At final follow-up examination, 7 patients were orthotropic in primary gaze; 1 patient had a larger deviation from slippage as the result of a broken suture within the first postoperative week. None of the patients were overcorrected or developed atypical inflammation. CONCLUSIONS: In this series, patients with Graves' ophthalmology were successfully treated with the use of rectus muscle resections as part of the surgical plan. Careful ocular motility assessment and patient selection is critical if this option is contemplated. PMID- 23352721 TI - A comparison of ocular alignment success of hang-back versus conventional bilateral lateral rectus muscle recession for true divergence excess intermittent exotropia. AB - PURPOSE: To assess whether hang-back or conventional bilateral lateral rectus muscle recessions were more successful in achieving a satisfactory postoperative ocular alignment in patients with true divergence excess intermittent exotropia. METHODS: The medical records of consecutive patients with true divergence excess intermittent exotropia who underwent bilateral lateral rectus muscle recession using hang-back or conventional techniques were retrospectively analyzed. All surgeries were performed by a single surgeon using the same standard table of surgical dosage. We compared the preoperative characteristics and motor surgical outcomes between the two groups. Success was defined as alignment within 10(Delta) of intermittent exotropias at distance and near. Any amount of postoperative esotropia was considered a failure. RESULTS: A total of 42 patients were included: 13 in the hang-back group and 29 in the conventional group. The mean age at surgery, mean preoperative deviation at near and distance, mean amount of lateral rectus muscle recession, and mean follow-up duration were not statistically significantly different between groups. At the most recent follow up, the conventional group had a significantly greater success rate (<=10(Delta) of intermittent exotropia) than the hang-back group (83% vs 31%, P = 0.0009). There was no statistically significant difference in the mean amount of lateral rectus recession between patients with successful and unsuccessful surgical outcomes in both groups. CONCLUSIONS: Within the limitations of this study, conventional bilateral lateral rectus recessions were more effective than hang back recessions in achieving a successful postoperative alignment in patients with true divergence excess intermittent exotropia. PMID- 23352722 TI - Pigmented choroidal nevus in a child with oculocutaneous albinism. AB - We report the case of an 8-year-old white girl with albinism and a flat pigmented choroidal lesion in the left eye measuring 0.5 mm in diameter. There was no subretinal fluid, lipofuscin, or drusen. The patient later displayed 10 lightly pigmented cutaneous nevi on her upper chest, left arm, and right leg at 8 months' follow-up. The choroidal nevus showed minimal change over 2 years. PMID- 23352723 TI - Reply: To PMID 23084378. PMID- 23352724 TI - Limitations of the study "Cost-effectiveness of tick-borne encephalitis vaccination in Slovenian adults". PMID- 23352725 TI - Arsenic levels in drinking water and mortality of liver cancer in Taiwan. AB - The carcinogenic effect of arsenic is well documented, but epidemiologic data on liver cancer were limited. To evaluate the dose-response relationship between arsenic in drinking water and mortality of liver cancer, we conducted a study in 138 villages in the southwest coast area of Taiwan. We assessed arsenic levels in drinking water using data from a survey conducted by the government and reviewed death certificates from 1971 to 1990 to identify liver cancer cases. Using village as the unit, we conducted multi-variate regression analyses and then performed post hoc analyses to validate the findings. During the 20-year period, 802 male and 301 female mortality cases of liver cancer were identified. After adjusting for age, arsenic levels above 0.64 mg/L were associated with an increase in the liver cancer mortality in both genders, but no significant effect was observed for lower exposure categories. Post hoc analyses and a review of literature supported these findings. We concluded that exposures to high arsenic levels in drinking water are associated with the occurrence of liver cancer, but such an effect is not prominent at exposure levels lower than 0.64 mg/L. PMID- 23352726 TI - The effect of tobacco and marijuana use on dental health status in Nevada adolescents: a trend analysis. AB - PURPOSE: Tobacco use is the leading cause of preventable death worldwide. If current trends persist, tobacco will kill more than 8 million people worldwide by 2030 and 1 billion by the end of the century. The purpose of this study was to determine trends in tobacco/marijuana use in Nevada adolescents and their effect on dental health status. Relative comparative data were compared with nationally reported data. METHODS: Retrospective data in this cohort study was from an ongoing statewide, school-based, dental health screening initiative that was conducted across 8 years (2002-2010) in public/private middle/high schools in Nevada. A total of 66,941 dental health screenings of adolescents between ages 13 18 were conducted. Self-reported data were collected on tobacco/marijuana use. Descriptive statistics and trends were reported. Means (SE) were computed for caries prevalence and severity. Effect size was reported on dental caries and use of tobacco/marijuana. RESULTS: Overall, percentage prevalence of tobacco use was approximately the same as the national average; however, there were significantly higher rates of marijuana use (12.0% vs. 3.3%). Prevalence and severity of dental caries was significantly higher in those who used tobacco/marijuana than those who did not across all variables and across all 8 years controlling for gender, race/ethnicity, where they lived, and exposure to secondhand smoke. CONCLUSIONS: Tobacco use negatively affected dental health status with marijuana having the largest negative effect. The findings from this study identified the need for tobacco/marijuana prevention services targeting adolescents residing in the geographic areas most at risk. PMID- 23352727 TI - Use of a social networking web site for recruiting Canadian youth for medical research. AB - PURPOSE: The use of advertising on Facebook for medical research is not widely utilized, and we sought to describe the effectiveness of this tool in medical research recruitment. METHODS: A survey study was designed to evaluate the prevalence of post-traumatic stress disorder (PTSD) in Canadian youth who were affected by violence. Participants were recruited from an advertisement on Facebook that targeted Canadian users aged 15 to 24 years and linked them to an online survey. This secondary analysis is a descriptive study of the effectiveness of the Facebook campaign. RESULTS: Over the course of the study, the advertisement was displayed 17.5 million times resulting in 3,440 clicks on the link to the survey (.020%). The overall cost worked out to $15.35 per final subject, totaling $1351.17. CONCLUSION: Facebook advertising is a cost-effective method of recruiting youth from a wide population. There are many potential uses for social networking in medical research. PMID- 23352729 TI - Effect of foot and hand massage in post-cesarean section pain control: a randomized control trial. AB - One of the problems for mothers in the post-cesarean section period is pain, which disturbs the early relationship between mothers and newborns; timely pain management prevents the side effects of pain, facilitates the recovery of patient, reduces the costs of treatment by minimizing or eliminating the mother's distress, and increases mother-infant interactions. The aim of this study was to determine the effect of hand and foot massage on post-cesarean section pain. This study is a randomized and controlled trial which was performed in Mustafa Khomeini Hospital, Elam, Iran, April 1 to July 30, 2011; it was carried out on 80 pregnant women who had an elective cesarean section and met inclusion criteria for study. The visual analog scale was used to determine the pain intensity before, immediately, and 90 minutes after conducting 5 minutes of foot and hand massage. Vital signs were measured and recorded. The pain intensity was found to be reduced after intervention compared with the intensity before the intervention (p < .001). Also, there was a significant difference between groups in terms of the pain intensity and requests for analgesic (p < .001). According to these findings, the foot and hand massage can be considered as a complementary method to reduce the pain of cesarean section effectively and to decrease the amount of medications and their side effects. PMID- 23352730 TI - The Ghanaian surgical nurse and postoperative pain management: a clinical ethnographic insight. AB - Nurses form an indispensable part of the clinical team that manages postoperative pain (POP). Within a particular clinical context, nurses perceive and respond to pain based on specific factors. This study aimed at illuminating the perceptions and responses of Ghanaian surgical nurses regarding their patients' POP. It also identified the factors that influenced nurses' pain responses. A focused ethnography was used, and data were collected through individual interviews. Sampling was performed purposively to include junior, senior, day, and night nurses who cared for surgical patients. Concurrent data analysis was performed and data were saturated with 12 individual interviews. The findings indicated that nurses perceived POP as an individual phenomenon, and nurses responded to patients' pain by administering analgesics and by using nonpharmacologic measures. Factors that influenced the nurses' response were individual factors, such as commitment, discretion, fear of addiction, and organizational factors, such as organizational laxity and challenges of teamwork. The study recommended that nurses should be educated, supported, and encouraged to ensure pain relief after surgery and that they should see pain relief as a priority postoperative care to avert the negative repercussions of poorly managed POP. PMID- 23352728 TI - Beyond pattern recognition: NOD-like receptors in dendritic cells. AB - Innate instruction of adaptive immunity was proposed more than 20 years ago as a mechanism by which long-lived lymphocyte responses are targeted to appropriate antigens. At the time Charles Janeway proposed this theory, most of the innate immune receptors were unknown, and the pivotal role of the dendritic cell in instructing T cell priming was debated. There is now overwhelming evidence that the innate and adaptive branches of the immune system must interact to generate immunity. Much of this work has focused on families of innate immune receptors called pattern recognition receptors (PRRs) on dendritic cells, which translate these inflammatory triggers into productive T cell responses. Nevertheless, we are only beginning to understand how these defence molecules shape the generation of immunity. We review the varied roles of one class of PRRs, the NOD-like receptors (NLRs), in immune responses and propose a new model in which adaptive immunity requires coordinated PRR activation within the dendritic cell. PMID- 23352731 TI - Management of vascular malformations of the parotid area. AB - OBJECTIVES: To describe our experience in the management of vascular malformations of the parotid area. MATERIALS AND METHODS: This was a retrospective study. Among 614 parotidectomy performed between 1998 and 2008 at our institution, 10 cases (1.6%) of vascular malformations have been identified. Clinical features and management of these patients were analyzed. RESULTS: Clinical presentation was usually related to that of a benign, slow-growing and asymptomatic tumor. There was a marked female predominance (90%). In any case, the diagnosis of vascular malformation could be obtained with certainty preoperatively. Surgical excision was performed most often referred to diagnosis. Sixty percent of vascular malformations were located in the superficial lobe of the parotid gland. On the histological we found a classic look with benign vascular proliferation of endothelial cells in the walls. The vessel lumen was either the head of a congestion or thrombosis or calcification (phleboliths). CONCLUSION: Vascular malformations of the parotid gland, rare disease, are mainly venous. The terminology is based on clinical data, scalable, histological and hemodynamic as classified by the International Society of Study of Vascular Anomaly (ISSVA). Despite advances in imaging including MRI they remain difficult to diagnose. The treatment of reference is surgical excision. PMID- 23352732 TI - Radiofrequency tonsillotomy versus bipolar scissors tonsillectomy for the treatment of OSAS in children: a prospective study. AB - INTRODUCTION: Tonsillotomy is an effective treatment for the management of obstructive sleep apnoea syndrome (OSAS) in children with tonsillar hypertrophy and appears to be associated with less pain and postoperative morbidity. OBJECTIVE: To compare postoperative morbidity and short-term and intermediate term efficacy of radiofrequency tonsillotomy (TT) and bipolar scissors tonsillectomy (TE) in children. PATIENTS AND METHODS: Children with OSAS due to tonsillar hypertrophy were included in a prospective, non-randomized study between February 4, 2008 and March 20, 2010. Exclusion criteria were recurrent tonsillitis (>= 3 episodes per year), clotting disorders and age less than 2 years. Postoperative complications, efficacy on OSAS, and operating times were evaluated. Pain was evaluated by the Postoperative Pain Measure for Parents score on D0, D1, D7 and D30. RESULTS: One hundred and ninety-three children were included: 105 in the TE group (age: 4.75 +/- 2.37 years) and 88 in the TT group (age: 4.88 +/- 2.6 years). The pain score was significantly lower in the TT group than in the TE group during the first postoperative week (P<0.05). A significant difference was observed for the secondary postoperative bleeding rate (1 after TT versus 8 after TE). No significant difference was observed between the two techniques in terms of the efficacy on OSAS. At 1 year, the tonsil regrowth rate in the TT group was 4.5%. CONCLUSION: Radiofrequency tonsillotomy is a safe technique for the treatment of obstructive tonsillar hypertrophy in children with good results on OSAS and a reduction of postoperative pain. PMID- 23352733 TI - Outcomes of fertility-sparing surgery for women of reproductive age with FIGO stage IC epithelial ovarian cancer. AB - OBJECTIVE: To report the clinical outcomes of patients with FIGO stage IC epithelial ovarian cancer (EOC) treated by fertility-sparing surgery (FSS). METHODS: A retrospective review was conducted of 18 women who underwent FSS at Niigata University Hospital, Japan, between December 15, 1986, and December 31, 2010. RESULTS: Tumors were mucinous (n=9), clear cell (n=4), endometrioid (n=3), and serous (n=2). Median follow-up was 78.0 months (range, 9.3-181.3 months). Five patients (27.8%) developed tumor recurrence at 7.4-19.2 months after initial surgery. The sites of recurrence were peritoneal lymph nodes (n=2), contralateral ovary (n=1), contralateral ovary and peritoneal cavity (n=1), and brain (n=1). In all, 7 full-term singleton pregnancies were recorded among 5 of the 10 women who attempted to conceive after FSS. CONCLUSION: Favorable reproductive outcomes were observed following FSS, suggesting that this procedure may be a valid treatment option for women with FIGO stage IC EOC who wish to conceive. PMID- 23352734 TI - Effect of 2 referral intervals on diagnostic discordance between cytology and histology at a colposcopy clinic. AB - OBJECTIVE: To determine the effect of the time interval between cervical cytology screening and histology at treatment on grade of cervical disease. METHODS: In a retrospective cross-sectional study at a colposcopy clinic in Soweto, Johannesburg, South Africa, data were compared from women with cytologic abnormalities referred for colposcopy between April 2003 and June 2010 to determine whether early (<= 180 days) or late (> 180 days) referral had an impact on dysplasia grade. RESULTS: In the early and late referral groups, there were 213 (13.43%) and 201 (14.63%) women, respectively, with upgrading of cervical dysplasia (P=0.35), and 1373 (86.57%) and 1173 (85.37%) women, respectively, with downgrading or no change (P=0.35). Risk factors for upgrading were HIV infection (odds ratio [OR], 1.63; P<0.001) and condom use (OR, 1.30; P=0.02). Four cases (0.68%) of invasion among women with low-grade squamous intraepithelial lesion (LSIL) and 50 cases (2.11%) among women with high-grade SIL (HSIL) were not detected by cytology. Risk factors for invasive disease on histology were age (OR, 1.09 per year; P<0.001), parity (OR, 1.32 per pregnancy; P<0.001), and HSIL on cytology (OR, 3.17; P=0.03). CONCLUSION: There was no difference in the up- or downgrading of cervical dysplasia between the 2 referral groups. PMID- 23352735 TI - A retrospective review of abdominal wall endometriosis in Shanghai, China. AB - OBJECTIVE: To quantify the demographic characteristics, symptoms, and outcomes of women with abdominal wall endometriosis (AWE) in order to identify the optimal treatment and prevention techniques for AWE in the Chinese population. METHODS: In a retrospective study, women diagnosed with AWE at the Gynecology Hospital of Fudan University, Shanghai, China, between January 2003 and December 2011 were identified from the hospital's medical records. Data on patient age, previous surgeries, symptoms, asymptomatic time interval, duration of complaints, mass location, size, tenderness, diagnosis, treatment, and recurrence were analyzed. RESULTS: During the study period, 229 women were diagnosed with AWE, and histopathologic confirmation was obtained for 227 women (mean age, 31.7+/-3.8 years). Each of these patients had undergone previous surgery, and 14 had undergone resection for AWE. The primary symptoms were pain, either cyclical (65.2%) or noncyclical (27.3%), and presence of a mass (84.1%; mean diameter, 2.9+/-1.3 cm). The mean time interval between previous surgery and onset of symptoms was 2.3+/-2.2 years. For all patients, the abdominal mass was surgically excised. The postoperative recurrence rate was 1.5%. CONCLUSION: Complete resection is the primary treatment for AWE. A combination of surgical re-excision and postoperative adjuvant medical therapy is recommended for patients with recurrent AWE. PMID- 23352737 TI - Effects of cannabinoids and endocannabinoid hydrolysis inhibition on pentylenetetrazole-induced seizure and electroencephalographic activity in rats. AB - Cannabinoids and drugs that increase endocannabinoid levels inhibit neuronal excitability and restrain epileptic seizures through CB1 receptor activation. Nevertheless, the results have not been entirely consistent, since pro-convulsant effects have also been reported. The present study aimed to further investigate the effects of cannabinoid-related compounds on seizures induced by pentylenetetrazole (PTZ) in rats. Video-EEG recordings were used to determine both electrographic and behavioral thresholds to ictal activity. The animals received injections of WIN-55,212-2 (0.3-3 mg/kg, non-selective) or ACEA (1-4 mg/kg, CB1-selective), two synthetic cannabinoids, or URB-597 (0.3-3 mg/kg), an anandamide-hydrolysis inhibitor (FAAH enzyme inhibitor), followed by PTZ. Both WIN-55,212-2 (1 mg/kg) and ACEA (1-4 mg/kg) reduced the threshold for myoclonic seizures and enhanced epileptiform EEG activity, typical pro-convulsive effects. On the contrary, URB-597 (1 mg/kg) had an anti-convulsive effect, as it increased the threshold for the occurrence of minimal seizures and reduced EEG epileptiform activity. None of the drugs tested altered the tonic-clonic maximal seizure threshold. These data suggest that the effects of CB1 signaling upon seizure activity may depend on how this receptor is activated. Contrary to direct agonists, drugs that increase anandamide levels seem to promote an optimal tonus and represent a promising strategy for treating myoclonic seizures. PMID- 23352738 TI - 15q13.3 microdeletions in a prospectively recruited cohort of patients with idiopathic generalized epilepsy in Bulgaria. AB - PURPOSE: The chromosome 15q13.3 region is a genomic rearrangement hotspot linked to idiopathic generalized epilepsies (IGEs) and such rearrangements remain the strongest risk factor for IGE known to date. Increasing evidence suggests that genetic variations can be highly population-specific. Therefore, we aimed to assess the frequency of 15q13.3 microdeletions in IGE patients from Bulgaria. METHODS: A cohort of 100 patients with various IGE syndromes was screened for large deletions/duplications by MLPA. All deletions and duplications were confirmed by array CGH analysis as previously described. RESULTS: In 100 prospectively recruited Bulgarian patients with IGE, we found one case with a microdeletion, which amounted to 1% frequency for this copy number variant. CONCLUSION: We confirm the frequency of 1% for the 15q13.3 microdeletion in a prospectively recruited cohort of Bulgarian epilepsy patients, demonstrating that this variation represents a significant risk factor for IGE for various populations and that it is retrospectively detected frequency is not due to selection bias. PMID- 23352736 TI - New insights into the archaeal diversity of a hypersaline microbial mat obtained by a metagenomic approach. AB - A metagenomic approach was carried out in order to study the genetic pool of a hypersaline microbial mat, paying more attention to the archaeal community and, specifically, to the putatively methanogenic members. The main aim of the work was to expand the knowledge of a likely ecologically important archaeal lineage, candidate division MSBL1, which is probably involved in methanogenesis at very high salinities. The results obtained in this study were in accordance with our previous report on the bacterial diversity encountered by using a number of molecular techniques, but remarkable differences were found in the archaeal diversity retrieval by each of the procedures used (metagenomics and 16S rRNA based methods). The lack of synteny for most of the metagenomic fragments with known genomes, together with the low degree of similarity of the annotated open reading frames (ORFs) with the sequences in the databases, reflected the high degree of novelty in the mat community studied. Linking the sequenced clones with representatives of division MSBL1 was not possible because of the lack of additional information concerning this archaeal group in the public gene repositories. However, given the high abundance of representatives of this division in the 16S rRNA clone libraries and the low identity of the archaeal clones with known genomes, it was hypothesized that some of them could arise from MSBL1 genomes. In addition, other prokaryotic groups known to be relevant in organic matter mineralization at high salinities were detected. PMID- 23352739 TI - Angelman syndrome caused by deletion: a genotype-phenotype correlation determined by breakpoint. AB - OBJECTIVES: Deletion of the chromosome 15q11-q13, the most common genetic mechanism associated with Angelman syndrome (AS), is highly associated with a severe phenotype. However, deletion is not a genetically homogeneous group as it is composed by two main groups: Class I with breakpoints at BP1 (proximal) and BP3 (distal) and Class II present breakpoints at BP2 (proximal) and BP3 (distal). In this study, we aimed to evaluate the impact of the breakpoint on the electroclinical profile. METHODS: We evaluated 16 patients with AS caused by 15q11-13 deletion (6 were Class I; 10 were Class II). We characterized epilepsy features by clinical history obtained from parents and caretakers with a pre standard questionnaire. These data were corroborated by medical records, contact with previous physicians, and video-EEG monitoring. Suggestive EEG patterns for AS were classified according to the classical description of Boyd et al. (1988). RESULTS: AS patients with BP1-BP3 deletion had significantly more daily and disabling seizures than AS patients with BP1-BP2 deletion. They also presented a significant higher frequency of status epilepticus and epilepsy aggravated by fever. Need for polytherapy was significantly more frequent in BP1-BP3 patients. EEG features were similar in both groups. CONCLUSION: This study shows a significant correlation between the two deletion classes and AS clinical, but not the electrographic phenotype. Epilepsy is more severe and refractory to treatment in patients with larger deletions. Deletion is not a homogeneous group and knowledge on the breakpoint may have a clinical implication and represent an important factor in parental counseling. PMID- 23352741 TI - Increased EphA/ephrinA expression in hippocampus of pilocarpine treated mouse. AB - PURPOSE: EphA family receptor tyrosine kinases and their ephrinA ligands are involved in patterning axonal connections during brain development. Although it has been evidenced that these molecules continue to play a key role in synaptic reorganization and plasticity in normal and injured adult brains, their effect still remains unclear during epileptogenesis. Temporal lobe epilepsy (TLE) is the most common form of adult focal epilepsy and often associates with sclerosis of the hippocampus and mossy fiber sprouting (MFS). The purpose of this study is to evaluate the relationship between EphA/ephrinA molecules and epileptogenesis after status epilepticus (SE). METHOD: A mouse model of chronic temporal lobe epilepsy was prepared by intraperitoneal administration of pilocarpine. EphAs/ephrinAs expression levels of the mouse hippocampus areas were detected at different time points after SE by PCR, in situ hybridization and immunohistochemistry. Mossy fiber sprouting was estimated by Neo-Timm staining. RESULT: EphAs/ephrinAs were widely distributed in the hippocampus area. EphA10 and ephrinA4 were increased significantly following epileptogenesis, and mossy fiber sprouting appeared after SE. CONCLUSION: The up-regulation of EphA/ephrinA expression after SE suggests that they are involved in the pilocarpine-induced epileptogenesis. PMID- 23352740 TI - Assessing hippocampal functional reserve in temporal lobe epilepsy: a multi-voxel pattern analysis of fMRI data. AB - Assessing the functional reserve of key memory structures in the medial temporal lobes (MTL) of pre-surgical patients with intractable temporal lobe epilepsy (TLE) remains a challenge. Conventional functional MRI (fMRI) memory paradigms have yet to fully convince of their ability to confidently assess the risk of a post-surgical amnesia. An alternative fMRI analysis method, multi-voxel pattern analysis (MVPA), focuses on the patterns of activity across voxels in specific brain regions that are associated with individual memory traces. This method makes it possible to investigate whether the hippocampus and related structures contralateral to any proposed surgery are capable of laying down and representing specific memories. Here we used MVPA-fMRI to assess the functional integrity of the hippocampi and MTL in patients with long-standing medically refractory TLE associated with unilateral hippocampal sclerosis (HS). Patients were exposed to movie clips of everyday events prior to scanning, which they subsequently recalled during high-resolution fMRI. MTL structures were delineated and pattern classifiers were trained to learn the patterns of brain activity across voxels associated with each memory. Predictable patterns of activity across voxels associated with specific memories could be detected in MTL structures, including the hippocampus, on the side contralateral to the HS, indicating their functional viability. By contrast, no discernible memory representations were apparent in the sclerotic hippocampus, but adjacent MTL regions contained detectable information about the memories. These findings suggest that MVPA in fMRI memory studies of TLE can indicate hippocampal functional reserve and may be useful to predict the effects of hippocampal resection in individual patients. PMID- 23352742 TI - Monoamines and glycogen levels in cerebral cortices of fast and slow methionine sulfoximine-inbred mice. AB - The experimental model of seizures which depends upon methionine sulfoximine (MSO) simulates the most striking form of human epilepsy. MSO generates epileptiform seizures in a large variety of animals, increases brain glycogen content and induces brain monoamines modifications. We selected two inbred lines of mice based upon their latency toward MSO-dependent seizures, named as MSO-Fast (sensitive), having short latency toward MSO, and MSO-Slow (resistant) with a long latency. We determined 13 monoamines and glycogen contents in brain cortices of the MSO-Fast and slow lines in order to determine the relationships with MSO dependent seizures. The present data show that using these MSO-Fast and MSO-Slow inbred lines it could be demonstrated that: (1) in basal conditions the neurotransmitter 5-HT is significantly higher in MSO-Fast mice than in MSO-Slow ones; (2) MSO in both lines induced a significant increase in brain content of DOPAC (3,4-dihydroxyphenylacetic acid), HVA (homovanillic acid), MHPG (3-methoxy 4-hydroxyphenylglycol), and 5-HT (serotonin); a significant decrease in MSO-Slow mice in brain content of NME (normetepinephrine), and 5-HIAA (5 hydroxyindoleacetic acid) and the variation of other monoamines were not significant; (3) the brain glycogen content is significantly higher in MSO-Fast mice than in MSO-Slow ones, both in basal conditions and after MSO administration. From our data, we propose that brain glycogen content may constitute a defense against epileptic attack, as glycogen may be degraded down to glucose-6-phosphate that can be used to either postpone the epileptic attack or to provide neurons with energy when they needed it. Brain glycogen might therefore be considered as a molecule that can contribute to struggle seizures, at least in MSO-dependent seizure. The 5-HT content may constitute a defense against MSO-dependent epilepsy. PMID- 23352743 TI - Mutations in PRRT2 result in familial infantile seizures with heterogeneous phenotypes including febrile convulsions and probable SUDEP. AB - Mutations of PRRT2, which encodes proline-rich transmembrane protein 2, are associated with heterogeneous phenotypes including benign familial infantile seizures (BFIS) and/or familial paroxysmal kinesigenic dystonia (PKD). Here, we performed mutation screening of PRRT2 in six Italian families with BFIS/PKD phenotypes. The mutation, c.649dupC (p.Arg217ProfsX8), was found in two families with BFIS phenotype. In a third BFIS family, a missense mutation, c.718C/T (R240X), was identified. All these mutations co-segregated with the disease and were not observed in 100 controls of matched ancestry. In one BFIS family that carried the c.649dupC mutation, one affected member developed afebrile focal seizures and died at age of 14 years of probable sudden unexpected death in epilepsy, while his brother also had simple febrile convulsions (FC) and performed poorly on complex psychomotor functioning. In another family carrying the c.718C/T mutation, two of three affected members also had simple FC. This study enlarges the clinical spectrum related to PPRT2 mutations and underscores the complexity of the phenotypic consequences of mutations in this gene. PMID- 23352744 TI - Rebelliousness in patients suffering from schizophrenia-spectrum disorders--a possible predictor of attitudes towards medication. AB - The inclusive trait of rebelliousness has a proven role both in development and in the understanding of non-psychotic psychopathologies. The present study focused on evaluating rebelliousness levels and their possible correlation with the attitude towards medication among patients suffering from schizophrenia spectrum disorders. Patient suffering from schizophrenia-spectrum disorders (n=75) and non-psychotic disorders (n=53) underwent a thorough clinical evaluation. The attitude towards medication was evaluated using the Drug Attitude Inventory (DAI-10), and levels of rebelliousness via the validated rebelliousness scale. Rebelliousness was also assessed in an additional control group (n=64). A significant negative correlation between levels of rebelliousness and the attitude towards medication was found uniquely in the schizophrenia group (r= 0.434, p<0.001). In a regression model rebelliousness levels were found to be the strongest predictor of the attitude towards medication ((beta=-0.434, p<0.01)) compared with other demographic variables such as drug abuse (beta=-0.256, p<0.05) and involuntary treatment (beta=0.236, p<0.05). The intriguing correlation between rebelliousness and drug attitude (as an indicator of adherence) should be further studied in additional longitudinal prospective studies. PMID- 23352745 TI - The "thorough QT study": a valid paradigm to test new algorithms for QT interval measurements? PMID- 23352746 TI - Individual and combined effects of rhynchophylline and ketamine on proliferation, NMDAR1 and GluA2/3 protein expression in PC12 cells. AB - Rhynchophylline is an active component of the Uncaria species, which is a member of the Rubiaceae family. Our studies show that the downregulation of N-methyl-d aspartate (NMDA) receptor subunit GluN2B expression in the nucleus accumbens, amygdala, medial prefrontal cortex, and hippocampal CA1 area by rhynchophylline is beneficial for the treatment of psychological dependence on amphetamines. The individual and combined effects of rhynchophylline and ketamine on proliferation and GluN1 and GluA2/3 protein expression in PC12 cells were investigated. PC12 cells were differentiated into neuron-like cells by treatment with nerve growth factor (50 ng/mL). After treatment for 48 h, differentiated PC12 cell proliferation and GluN1 and GluA2/3 protein expression were analyzed. The viability of PC12 cells was reduced by ketamine at doses of 0.50, 1.00, 1.50, and 2.00 mmol/L, with the viability of cells treated with 1.50 and 2.00 mmol/L of ketamine significantly lower than that of the control cells. However, PC12 cells treated with rhynchophylline showed no toxicity at doses of 0.25, 0.50, 0.75, or 1.00 mmol/L. While GluA2/3 protein expression was upregulated by ketamine, it was not influenced by rhynchophylline. GluN1 protein expression was downregulated by rhynchophylline (1 mmol/L), while treatment with ketamine, either alone or with rhynchophylline, had no effect. These findings demonstrate that rhynchophylline suppresses GluA2/3 expression in ketamine-induced PC12 cells and downregulates GluN1 expression. Ketamine's lack of effect on GluN1 expression offers a partial explanation for ketamine addiction and the anti-addictive properties of rhynchophylline. PMID- 23352747 TI - Triterpenoids of Chrysosplenium carnosum. AB - A phytochemical study of the ethanolic extract of Chrysosplenium carnosum Hook. f. et Thoms. led to the isolation of two new oleanane-type triterpenoids, 6beta hydroxy-3-oxoolean-12-en-27-oic acid (1) and 3beta, 21alpha-dihydroxyolean-12-en 27-oic acid (2), along with fourteen known compounds (3-16), all of which were isolated from this plant for the first time. The structures of these compounds were established on the basis of spectroscopic methods. Compounds 1-4 were evaluated for their in vitro anti-tumor activities on B16F10, SP2/0 and Hep-G2 cells lines. Compounds 1, 3 and 4 exhibited strong inhibitory activity against B16F10 and SP2/0 cells' growth, compared with moderate cytotoxic activity against Hep-G2 cells. However, compound 2 showed to be inactive against these tumor cells. PMID- 23352748 TI - Rhododendron tomentosum (Ledum palustre). A review of traditional use based on current research. AB - Rhododendron tomentosum Harmaja (previously: Ledum palustre) is a fragrant evergreen shrub found in peaty soils in northern Europe, Asia and North America, commonly referred to as wild rosemary, marsh tea, marsh rosemary or northern Labrador tea. At least since the eighteenth century it has been used in ethnomedicine for the treatment of various ailments, such as rheumatism, cough, cold and insect bites, as well as a repellent. The essential oil of wild rosemary with the rich polyphenolic fraction possesses analgesic, anti-inflammatory, antimicrobial, antiviral, antifungal and insecticidal potential, demonstrated by in vivo and in vitro studies. In addition, recent scientific research reported the promising antidiabetic, antioxidant and anticancer properties. This review summarizes the information concerning taxonomy, botany, ecology, chemical composition, biological activities, toxicology and traditional and contemporary application of Rhododendron tomentosum plants. PMID- 23352749 TI - Immunogenicity and safety of an enterovirus 71 vaccine in healthy Chinese children and infants: a randomised, double-blind, placebo-controlled phase 2 clinical trial. AB - BACKGROUND: Enterovirus 71 (EV71) outbreaks are a socioeconomic burden, especially in the western Pacific region. Results of phase 1 clinical trials suggest an EV71 vaccine has a clinically acceptable safety profile and immunogenicity. We aimed to assess the best possible dose and formulation, immunogenicity, and safety profile of this EV71 vaccine in healthy Chinese children. METHODS: This randomised, double-blind, placebo-controlled, phase 2 trial was undertaken at one site in Donghai County, Jiangsu Province, China. Eligible participants were healthy boys or girls aged 6-36 months. Participants were randomly assigned (1:1:1:1:1) to receive either 160 U, 320 U, or 640 U alum adjuvant EV71 vaccine, 640 U adjuvant-free EV71 vaccine, or a placebo (containing alum adjuvant only), according to a blocked randomisation list generated by SAS 9.1. Participants and investigators were masked to the assignment. The primary endpoint was anti-EV71 neutralising antibody geometric mean titres (GMTs) at day 56, analysed according to protocol. The study is registered with ClinicalTrials.gov, number NCT01399853. FINDINGS: We randomly assigned 1200 participants, 240 (120 aged 6-11 months [infants] and 120 aged 12-36 months [children]) of whom were assigned to each dose. 1106 participants completed the study and were included in the according-to-protocol analysis. The main reasons for dropout were withdrawal of consent and refusal to donate a blood sample. Infants who received the 640 U adjuvant vaccine had the highest GMTs on day 56 (742.2 [95% CI 577.3-954.3]), followed by those who received the 320 U formulation (497.9 [383.1-647.0]). For children, those who received the 320 U formulation had the highest GMTs on day 56 (1383.2 [1037.3-1844.5]). Participants who received the vaccine had significantly higher GMTs than did who received placebo (p<0.0001). For the subgroup of participants who were seronegative at baseline, both infants and children who received the 640 U adjuvant vaccine had the highest GMTs on day 56 (522.8 [403.9-676.6] in infants and 708.4 [524.1 957.6] in children), followed by those who received the 320 U adjuvant vaccine (358.2 [280.5-457.5] in infants and 498.0 [383.4-646.9] in children). 549 (45.8%) of 1200 participants (95 CI 42.9-48.6%) reported at least one injection-site or systemic adverse reaction, but the incidence of adverse reactions did not differ significantly between groups (p=0.36). The 640 U alum-adjuvant vaccine group had a significantly higher incidence of induration than did the 640 U adjuvant-free group (p=0.001). INTERPRETATION: Taking immunogenicity, safety, and production capacity into account, the 320 U alum-adjuvant formulation of the EV71 vaccine is probably the best possible formulation for phase 3 trials. FUNDING: The National Science and Technology Major Project (2011ZX10004-902) of the Chinese Ministry of Science and Technology, China's 12-5 National Major Infectious Disease Program (2012ZX10002-001), and Beijing Vigoo Biological. PMID- 23352750 TI - A tipping point for change: saving millions of additional lives in 2013 and beyond. PMID- 23352752 TI - The effect of an ambulance diversion ban on emergency department length of stay and ambulance turnaround time. AB - STUDY OBJECTIVE: Massachusetts became the first state in the nation to ban ambulance diversion in 2009. It was feared that the diversion ban would lead to increased emergency department (ED) crowding and ambulance turnaround time. We seek to characterize the effect of a statewide ambulance diversion ban on ED length of stay and ambulance turnaround time at Boston-area EDs. METHODS: We conducted a retrospective, pre-post observational analysis of 9 Boston-area hospital EDs before and after the ban. We used ED length of stay as a proxy for ED crowding. We compared hospitals individually and in aggregate to determine any changes in ED length of stay for admitted and discharged patients, ED volume, and turnaround time. RESULTS: No ED experienced an increase in ED length of stay for admitted or discharged patients or ambulance turnaround time despite an increase in volume for several EDs. There was an overall 3.6% increase in ED volume in our sample, a 10.4-minute decrease in length of stay for admitted patients, and a 2.2 minute decrease in turnaround time. When we compared high- and low-diverting EDs separately, neither saw an increase in length of stay, and both saw a decrease in turnaround time. CONCLUSION: After the first statewide ambulance diversion ban, there was no increase in ED length of stay or ambulance turnaround time at 9 Boston-area EDs. Several hospitals actually experienced improvements in these outcome measures. Our results suggest that the ban did not worsen ED crowding or ambulance availability at Boston-area hospitals. PMID- 23352751 TI - FDG PET/CT findings in rare sarcomas. AB - The role of FDG PET/CT in management of soft tissue and bone sarcomas has been described in many studies up-to-date. However, contribution of PET/CT to diagnosis and treatment in some types of sarcomas that are seen with low incidence has not been identified properly yet. Clear cell sarcoma, synovial sarcoma of chest and myxoid lyposarcoma are rare types of sarcomas. We aimed to describe the FDG uptake patterns of these rare tumors and find out the role of FDG PET/CT in management of disease. PMID- 23352753 TI - Polyamino geranic derivatives as new chemosensitizers to combat antibiotic resistant gram-negative bacteria. AB - Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate reagent (BOP) serves as an efficient and versatile coupling reagent for the design and synthesis of new polyamino geranic acid derivatives in moderate to good chemical yields varying from 47% to 83%. These compounds induced a significant decrease of antibiotic resistance in two Gram-negative bacterial MDR strains. Our data suggested that their mechanism of action is closely associated with the inhibition of the efflux pumps. PMID- 23352754 TI - o-Benzenedisulfonimido-sulfonamides are potent inhibitors of the tumor-associated carbonic anhydrase isoforms CA IX and CA XII. AB - By using phthalimido-substituted aromatic sufonamides as lead molecules, a series of new sulfonamides incorporating ortho-benzenedisulfonimide moieties have been synthesized and tested against the human (h) cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isozymes hCA I and hCA II and the transmembrane, tumor-associated isozymes hCA IX and hCA XII. All these compounds showed Ki values lower than 100nM and many of them showed better Kis than the reference compound acetazolamide, a clinically used sulfonamide. The tumor-associated isozymes were better inhibited than the cytosolic ones. A molecular docking within the active site of some CA isoforms, such as hCA I, explained these findings, as the benzenedisulfonimide moiety makes favorable interactions (hydrogen bonds) with amino acid residues involved in binding of inhibitors, such as Gln92, His67, and His64. PMID- 23352755 TI - Mechanistic studies of the inactivation of tyrosinase by resorcinol. AB - The inactivation of tyrosinase by resorcinol (1,3-dihydroxybenzene) and seventeen simple derivatives has been investigated using combined spectrophotometry and oximetry together with hplc/ms examination of the oxidation products. The results are consistent with a Quintox mechanism, analogous to that proposed for catechol inactivation of tyrosinase, in which the resorcinol substrate is oxidised via the monooxygenase route leading to a hydroxy intermediate that undergoes deprotonation and results in irreversible elimination of Cu(0) from the active site. Hplc/ms evidence for formation of the resorcinol monooxygenase product (3 hydroxy-ortho-quinone) is presented and the relationship between the ring position of simple resorcinol substituents (H, Me, F, Cl) and tyrosinase inactivation is rationalised. PMID- 23352756 TI - Nebulosides A-B, novel triterpene saponins from under-ground parts of Gypsophila arrostii Guss. var. nebulosa. AB - A bioassay-guided phytochemical analysis of the triterpene saponins from under ground parts of Gypsophila arrostii var. nebulosa allowed the isolation of two triterpene saponins; nebuloside A, B based on gypsogenin and quillaic acid aglycone. Two new oleanane type triterpenoid saponins (nebuloside A, B) and three known saponins (1-3) were isolated from the root bark of Gypsophila arrostii var. nebulosa. The structures of the two new compounds were elucidated as 3-O-beta-D galactopyranosyl-(1->2)-[beta-D-xylopyranosyl-(1->3)]-beta-D-glucuronopyranosyl quillaic acid 28-O-beta-D-glucopyranosyl-(1->3)-[beta-D-xylopyranosyl-(1->3)-beta D-xylopyranosyl-(1->4)]-alpha-L-rhamnopyranosyl-(1->2)-beta-D-fucopyranosyl ester (nebuloside A) and 3-O-beta-D-xylopyranosyl-(1->3)-[beta-D-galactopyranosyl(1->3) beta-D-galactopyranosyl-(1->2)]-beta-D-glucuronopyranosyl gypsogenin 28-O-beta-D glucopyranosyl-(1->3)-[beta-D-xylopyranosyl-(1->3)-beta-D-xylopyranosyl-(1->4)] alpha-L-rhamnopyranosyl-(1->2)-beta-D-fucopyranosyl ester (nebuloside B), on the basis of extensive spectral analysis and chemical evidence. Nebuloside A and B showed toxicity enhancing properties on saporin a type-I RIP without causing toxicity by themselves at 15 MUg/mL. PMID- 23352757 TI - Functional connectivity of the frontoparietal network predicts cognitive modulation of pain. AB - The experience of pain can be significantly influenced by expectancy (predictive cues). This ability to modulate pain has the potential to affect therapeutic analgesia substantially and constitutes a foundation for nonpharmacological pain relief. In this study, we investigated (1) brain regions involved in visual cue modulation of pain during anticipation of pain, pain administration, and pain rating; and (2) the association between pretest resting state functional connectivity and the magnitude of cue effects on pain ratings. We found that after cue conditioning, visual cues can significantly modulate subjective pain ratings. Functional magnetic resonance imaging results suggested that brain regions pertaining to the frontoparietal network (prefrontal and parietal cortex) and a pain/emotion modulatory region (rostral anterior cingulate cortex) are involved in cue modulation during both pain anticipation and administration stage. Most interestingly, we found that pretest resting state functional connectivity between the frontoparietal network (as identified by independent component analysis) and the rostral anterior cingulate cortex/medial prefrontal cortex was positively associated with cue effects on pain rating changes. We believe that these findings will shed new light on our understanding of variable cue/expectancy effects across individuals and how the intrinsic connectivity of the brain may influence expectancy-induced modulation of pain. PMID- 23352758 TI - The importance of context: when relative relief renders pain pleasant. AB - Context can influence the experience of any event. For instance, the thought that "it could be worse" can improve feelings towards a present misfortune. In this study we measured hedonic feelings, skin conductance, and brain activation patterns in 16 healthy volunteers who experienced moderate pain in two different contexts. In the "relative relief context," moderate pain represented the best outcome, since the alternative outcome was intense pain. However, in the control context, moderate pain represented the worst outcome and elicited negative hedonic feelings. The context manipulation resulted in a "hedonic flip," such that moderate pain elicited positive hedonics in the relative relief context. Somewhat surprisingly, moderate pain was even rated as pleasant in this context, despite being reported as painful in the control context. This "hedonic flip" was corroborated by physiological and functional neuroimaging data. When moderate pain was perceived as pleasant, skin conductance and activity in insula and dorsal anterior cingulate were significantly attenuated relative to the control moderate stimulus. "Pleasant pain" also increased activity in reward and valuation circuitry, including the medial orbitofrontal and ventromedial prefrontal cortices. Furthermore, the change in outcome hedonics correlated with activity in the periacqueductal grey (PAG) of the descending pain modulatory system (DPMS). The context manipulation also significantly increased functional connectivity between reward circuitry and the PAG, consistent with a functional change of the DPMS due to the altered motivational state. The findings of this study point to a role for brainstem and reward circuitry in a context-induced "hedonic flip" of pain. PMID- 23352759 TI - Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain in a rat model. AB - Bone cancer pain has a strong impact on the quality of life of patients, but is difficult to treat. Better understanding of the pathogenic mechanisms underlying bone cancer pain will likely lead to the development of more effective treatments. In the present study, we investigated whether inhibition of KCNQ/M channels contributed to the hyperexcitability of primary sensory neurons and to the pathogenesis of bone cancer pain. By using a rat model of bone cancer pain based on intratibial injection of MRMT-1 tumour cells, we documented a prominent decrease in expression of KCNQ2 and KCNQ3 proteins and a reduction of M-current density in small-sized dorsal root ganglia (DRG) neurons, which were associated with enhanced excitability of these DRG neurons and the hyperalgesic behaviours in bone cancer rats. Coincidently, we found that inhibition of KCNQ/M channels with XE-991 caused a robust increase in the excitability of small-sized DRG neurons and produced an obvious mechanical allodynia in normal rats. On the contrary, activation of the KCNQ/M channels with retigabine not only inhibited the hyperexcitability of these small DRG neurons, but also alleviated mechanical allodynia and thermal hyperalgesia in bone cancer rats, and all of these effects of retigabine could be blocked by KCNQ/M-channel antagonist XE-991. These results suggest that repression of KCNQ/M channels leads to the hyperexcitability of primary sensory neurons, which in turn causes bone cancer pain. Thus, suppression of KCNQ/M channels in primary DRG neurons plays a crucial role in the development of bone cancer pain. PMID- 23352760 TI - Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age? AB - Morphine is widely used to treat severe pain in neonatal intensive care unit patients. Animal studies suggest adverse long-term side effects of neonatal morphine, but a follow-up study of 5-year-old children who participated in a morphine-placebo controlled trial as newborns found no such effects on the child's general functioning. This study indicated that morphine may negatively affect response inhibition, a domain of executive functions. Therefore, we performed a second follow-up study in the same population at the age of 8 to 9 years, focused on the child's general functioning in terms of intelligence, visual motor integration, and behavior and on executive functions. Children in the morphine group showed significantly less externalizing problems according to the parents but more internalizing behavior according to the teachers, but only after adjustment for intelligence quotient (IQ), potential confounders using a propensity score, and additional open-label morphine. Morphine-treated children showed significantly fewer problems with executive functions in daily life as rated by parents for the subscales inhibition and organization of materials and for planning/organizing as rated by the teachers. After adjustment for IQ and the propensity score, executive functioning as rated by the parents remained statistically significantly better in the morphine-treated group. The influence of the additional morphine given was not of a significant influence for any of the outcome variables. Overall, the present study demonstrates that continuous morphine infusion of 10 MUg/kg/h during the neonatal period does not harm general functioning and may even have a positive influence on executive functions at 8 to 9 years. PMID- 23352761 TI - I can't stop looking at them: interactive effects of body mass index and weight dissatisfaction on attention towards body shape photographs. AB - Although attentional biases toward body-related information contribute to the etiology and maintenance of body dissatisfaction (BD) and eating disorders (EDs), attentional disengagement in women with BD and EDs is not clear. The present study investigated the association between weight dissatisfaction and attentional disengagement from body-related pictures and the possible moderating effect of body mass index (BMI) on this relation. Two hundred and four undergraduate women engaged in an experiment using a pictorial spatial cueing paradigm including fat/thin bodies and neutral household photos. Partial correlations and simple slopes regression analyses were conducted with attentional disengagement index scores of each category of cues. Findings suggested that independent of BMI, weight dissatisfaction was directly associated with attentional disengagement from both fat and thin pictures. In addition, among women with low and medium BMIs, the more they were dissatisfied with their bodyweight, the more difficulty they had disengaging their attention from fat body pictures. PMID- 23352762 TI - Out-of-hours MRI provision in the UK and models of service delivery. AB - AIM: To examine current out-of-hours magnetic resonance imaging (MRI) provision through a snapshot survey of National Health Service (NHS) trusts and to assay how radiographer staffing cover was provided for out-of-hours services. MATERIALS AND METHODS: A snapshot postal survey was mailed to heads of service of all 234 trusts in England and Wales. A literature search on the models of service delivery and correlation with the authors' internal MRI rota, which has provided a full on-call service for 20 years was undertaken. RESULTS: The response rate was 45.7% (107 of 234); 14% of responders provided full access to MRI 24 h a day; 63% provided extended weekday service, typically to 20.00 h; and 81% provided a weekend daytime service. The radiographers running the service were typically from the core MRI team. Approximately one-third (29.9%) of trusts provided training in basic brain and spine MRI to non-core MRI team members, but they typically did not participate in out-of-hours provision. CONCLUSION: There is currently a paucity of information on the provision of out-of-hours MRI in the NHS. However, there is increasing pressure to provide complex imaging out of hours, and in the future, trauma centres may be required to provide MRI to assess spinal injury. The authors describe a system to provide access to MRI at no additional cost to the organization based on 20 years of experience. A minority of surveyed acute NHS trusts have full out-of-hours access to MRI. Demand for MRI provision out of core hours is likely to increase. PMID- 23352763 TI - Homogeneous high attenuation renal cysts and solid masses--differentiation with single phase dual energy computed tomography. AB - AIM: To assess the feasibility of using single-phase dual-energy computed tomography (DECT) to differentiate between homogeneous high attenuation renal cysts and solid renal masses. MATERIALS AND METHODS: Twenty-nine pathologically proven solid renal masses in 29 patients and 14 high attenuation renal cysts from 11 patients were evaluated retrospectively. Two readers independently measured CT values from each lesion using both unenhanced single-energy phase and nephrographic dual-energy phase scans. Enhancement was defined as the attenuation difference between average-weighted 120 kV images and unenhanced images. Diagnostic sensitivity, specificity and accuracy based on enhancement, D-value (CT: 80 kV-140 kV) and DE-ratio (CT: 80/140 kV) were compared by the receiver operator characteristic (ROC) curves. RESULTS: Using 17.6 HU as the cutoff value for enhancement, resulted in a sensitivity, specificity and accuracy of 96.6%, 100% and 97.7%, respectively. Corresponding values were 100%, 92.9% and 97.7% using a D-value cutoff of 15.6 HU, and 100%, 85.7% and 95.3% using a DE-ratio cutoff of 1.3. There were no significant differences in the AUCs obtained from the ROC curves for enhancement, D-value or DE-ratio. The mean effective radiation dose was 6.04 mSv with biphasic scanning compared with 2.91 mSv for single dual energy nephrographic phase scanning. CONCLUSION: Single-phase dual-energy CT is able to differentiate high attenuation renal cysts and solid renal masses with high sensitivity, specificity and accuracy, based on either D-value or DE-ratio. Omitting unenhanced scanning reduces the radiation dose by more than 50%. PMID- 23352764 TI - Understanding the principles in management of Wilms' tumour: can imaging assist in patient selection? AB - The management of Wilms' tumour has evolved through thorough systematic research, predominantly lead by two groups: the Wilms' Tumour Study Committee of the International Society of Paediatric Oncology (SIOP) and National Wilms' Tumor Study Group (NWTSG) of North America. These two groups differ in their approach: SIOP advocates initial chemotherapy of 4-6 weeks followed by surgery, whereas the NWTSG advocates upfront surgery, with certain exceptions. This review briefly discusses the principles, and pros and cons of each approach. Both the treatment approaches have equivalent outcomes (in the form of event-free survival and overall survival), when compared stage-wise. With this knowledge, modern imaging can be used for individualizing treatment in anticipation of minimizing complications. The review identifies critical imaging features and discusses the reliability of imaging based on current reports in the literature. PMID- 23352765 TI - Factors related to postoperative pain among patients who underwent radiofrequency ablation of hepatocellular carcinoma. AB - AIM: To evaluate the incidence and associated factors of postoperative intense pain and haemodynamic changes during radiofrequency ablation of hepatocellular carcinoma. MATERIALS AND METHODS: A total of 123 consecutive hepatocellular carcinoma patients who underwent radiofrequency ablation were prospectively recruited. Patient factors, tumour characteristics, procedural factors, intraoperative haemodynamic changes, complications, postoperative events, laboratory values before and after ablation, and postoperative pain were evaluated. Postoperative pain was scored using a visual analogue scale after the procedure. RESULTS: The mean age of the patients was 65.6 +/- 9.6 years. In multiple logistic regression analysis, patients who underwent general anaesthesia [odds ratio (95% CI): 2.68 (1.23-5.81); p = 0.013] and had more postoperative nausea and vomiting episodes [3.10 (1.11-8.63); p = 0.036] were associated with intense pain. These findings remain robust after propensity score matching. For mean difference values between before and after RFA, higher in change in aspartate transaminase (p = 0.026), alanine transaminase (p = 0.016) and white blood cell count (p = 0.015), and lower in change in haemoglobin (p = 0.009) were also correlated with intense pain. There was no significant difference in haemodynamic changes between the general anaesthesia and local anaesthesia group during ablation. CONCLUSION: General anaesthesia, postoperative nausea and vomiting, and laboratory factors were associated with postoperative intense pain in patients who underwent radiofrequency ablation. Counselling and modification of analgesics should be considered in patients with related factors for intense pain. PMID- 23352766 TI - Development of a phantom for dose distribution verification in Stereotactic Radiosurgery. AB - A geometric acrylic phantom was designed and built for dose distribution verification in Stereotactic Radiosurgery. Acrylic objects representing the tumor tissue, (target volume (TV)), and the organ at risk (OAR), the brainstem, were inserted inside this phantom. The TV is represented by two semi-spheres of acrylic with a diameter of 13.0 mm, both having a central cavity for accommodation of a TLD-100 detector and a small radiochromic Gafchromic EBT film. The OAR is represented by the two parts of a 38.0 mm length acrylic cylinder with a diameter 18.0 mm and cavities along the cylinder central axis able to accommodate 5 TLD - 100 detectors and another of EBT film between the two cylinder parts. This experimental setup was submitted to a radiosurgical treatment, after which the TL dosimeters were evaluated and their responses were compared with the planned dose values. The radiochromic EBT films showed the dose distributions. The linear accelerator used was a Varian 2300 C/D, generating a 6 MV photon beam. The investigated phantom system was able to check the accuracy of dose delivery to predetermined points and the dose distribution due to stereotactic radiosurgery treatments and proved to be a good tool for quality control in these situations. PMID- 23352767 TI - Kinematics of treadmill locomotion in mice raised in hypergravity. AB - The study compared the motor performance of adult C57Bl/6J mice previously exposed to a 2G gravity environment during different periods of their development. 12 mice were housed in a large diameter centrifuge from the conception to Postnatal day 10 (P10). Another group of 10 mice was centrifuged form P10 to P30, and a third group of 9 mice was centrifuged from conception to P30. Their gait parameters, and kinematics of joint excursions were compared with 11 control mice, at the age of 2 months using a video-radiographic apparatus connected to a motorized treadmill. The mice that returned to Earth gravity level at the age of P10 showed a motor pattern similar to control mice. At variance the two groups that were centrifuged from P10 to P30 showed a different motor pattern with smaller and faster strides to walk at the same velocity as controls. On the other hand all the centrifuged mice showed significant postural changes, particularly with a more extended ankle joint, but the mice centrifuged during the whole experimental period differed even more. Our results showed that the exposure to hypergravity before P10 sufficed to modify the posture, suggesting that postural control starts before the onset of locomotion, whereas the gravity constraint perceived between P10 and P30 conditioned the tuning of quadruped locomotion with long term consequences. These results support the existence of a critical period in the acquisition of locomotion in mice. PMID- 23352769 TI - An ERcentric view of Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta and the accumulation of intracellular inclusions containing alpha-synuclein (alphaSyn). Growing evidence from studies in human PD brain, in addition to genetic and toxicological models, indicates that endoplasmic reticulum (ER) stress is a common feature of the disease and contributes to neurodegeneration. Recent reports place ER dysfunction as an early component of PD pathogenesis, and in this article we review the impact of ER stress in PD models and discuss the multiple mechanisms underlying the perturbation of secretory pathway function. Possible therapeutic strategies to mitigate ER stress in the context of PD are also discussed. PMID- 23352768 TI - Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase. AB - Inhibitors of neuronal nitric oxide synthase have been proposed as therapeutics for the treatment of different types of neurological disorders. On the basis of a cis-3,4-pyrrolidine scaffold, a series of trans-cyclopropyl- and methyl containing nNOS inhibitors have been synthesized. The insertion of a rigid electron-withdrawing cyclopropyl ring decreases the basicity of the adjacent amino group, which resulted in decreased inhibitory activity of these inhibitors compared to the parent compound. Nonetheless, three of them exhibited double digit nanomolar inhibition with high nNOS selectivity on the basis of in vitro enzyme assays. Crystal structures of nNOS and eNOS with these inhibitors bound provide a basis for detailed structure-activity relationship (SAR) studies. The conclusions from these studies will be used as a guide in the future development of selective NOS inhibitors. PMID- 23352770 TI - Acceptance, cognitive restructuring, and distraction as coping strategies for acute pain. AB - Little is known about treatment mechanisms underlying acceptance strategies. Acceptance is a strategy that is expected to increase pain tolerance more than distraction, while distraction should lead to lower pain intensity. The effect of cognitive restructuring on experimental pain has not yet been investigated. The present study aimed to explore differential short-term effects of acceptance, distraction, and cognitive restructuring on pain tolerance and intensity. Pain was induced in a sample of 109 female students using a thermode. We conducted analyses of covariance with instruction as the independent variable and posttest scores on pain variables as dependent variables, covarying for pretest scores. In addition, adherence to instructions and credibility of instructions were included as covariates. Acceptance led to a higher increase in pain tolerance than did cognitive restructuring of pain-related thoughts. No differences were detected between either acceptance and distraction or distraction and cognitive restructuring with respect to pain tolerance. Distraction led to lower pain intensity compared to acceptance. Cognitive restructuring did not differ from either acceptance or distraction with respect to pain intensity. As a short-term strategy, cognitive restructuring was not as useful as acceptance in increasing pain tolerance. Further studies should evaluate the preconditions under which different strategies are most effective. PERSPECTIVE: This study demonstrated that acceptance was superior to cognitive restructuring in increasing tolerance for experimentally induced pain, but was inferior to distraction with respect to decreasing pain intensity. Knowledge about the types of strategies that are useful in targeting diverse pain-related outcome measures is important for efforts to refine the treatment of chronic pain. PMID- 23352771 TI - Barriers to care for rural people living with HIV: a review of domestic research and health care models. AB - Historically, the availability of heath care in rural areas has been sparse, and specialized care for people living with HIV (PLWH) has been especially problematic. Rural patients are faced with substantially greater barriers to care than their urban counterparts. A systematic review of empirical studies was conducted concerning barriers to care among patients infected with HIV in rural areas of the United States. This systematic review yielded 15 viable articles for analysis. Among the 27 barriers identified, the most commonly discussed were transportation needs, provider discrimination and stigma, confidentiality concerns, and affordability and lack of financial resources. Barriers to care must be addressed in conjunction with one another in order to alleviate their impacts. Key health care models addressing these concerns are highlighted and used to address the state of the field and provide suggestions for future research. PMID- 23352772 TI - Patient-specific predictors of image noise in coronary CT angiography. AB - BACKGROUND: Coronary computed tomography (CT) angiography can be associated with high radiation exposure. Reduction of tube voltage from 120 kV to 100 kV can reduce the dose by up to 40%, but it also increases image noise. OBJECTIVE: We aimed to find a patient-specific predictor of image noise to determine the use of reduced tube voltage. METHODS: Contrast-enhanced coronary dual-source CT angiography data sets [prospectively electrocardiogram (ECG)-triggered axial and retrospectively ECG-gated spiral acquisition, rotation of 280 milliseconds, 2 * 128 * 0.6 mm collimation, 100 kV, 320 mAs] of 165 patients (age, 54 +/- 13 years) for the detection of coronary artery stenoses were analyzed. Image noise was measured in the aortic root. Influence of body weight, height, body mass index, thoracic cross sectional area, as well as the area of the thoracic solid tissue were analyzed. RESULTS: Mean image noise in the aorta was 35.1 +/- 8.9 HU. Mean dose length product was 207 +/- 184 cm . cGy with an average effective dose of 2.9 +/- 2.6 mSv. The patient cohort was divided into tertiles according to image noise. Numerous parameters, including BMI and body weight, were significantly different between the highest and lowest tertiles. In multivariable regression analysis, the area of the thoracic solid tissue was the only independent predictor of image noise (P < 0.0001). CONCLUSIONS: The area of the thoracic solid tissue at the level of the aortic root predicts image noise and may hence be used for the decision to reduce tube voltage from 120 kV to 100 kV. PMID- 23352773 TI - Characterization of the bending strength of craniofacial sutures. AB - The complex, thin and irregular bones of the human craniofacial skeleton (CFS) are connected together through bony articulations and connective tissues. These articulations are known as sutures and are commonly divided into two groups, facial and cranial sutures, based on their location in the CFS. CFS sutures can exhibit highly variable degrees of interdigitation and complexity and are believed to play a role in accommodating the mechanical demands of the skull. This study aimed to evaluate the mechanical behavior of CFS bone samples with and without sutures and to determine the effect of sutural interdigitations on mechanical strength. Sagittal, coronal, frontozygomatic and zygomaticotemporal sutures along with adjacent bone samples not containing sutures were excised from six fresh-frozen cadaveric heads. The interdigitation of the sutures was quantified through MUCT based analysis. Three-point bending to failure was performed on a total of 29 samples. The bending strength of bone samples without sutures demonstrated a non-significant increase of 14% as compared to samples containing sutures (P=0.2). The bending strength of bones containing sutures was positively correlated to the sutural interdigitation index (R=0.701, P=0.002). The higher interdigitation indices found in human cranial vs. facial sutures may be present to resist bending loads as a functional requirement in protecting the brain. PMID- 23352774 TI - Multivariate injury risk criteria and injury probability scores for fractures to the distal radius. AB - The purpose of this study was to develop a multivariate distal radius injury risk prediction model that incorporates dynamic loading variables in multiple directions, and interpret the distal radius failure data in order to establish injury probability thresholds. Repeated impacts with increasing intensity were applied to the distal third of eight human cadaveric radius specimens (mean (SD) age=61.9 (9.7)) until injury occurred. Crack (non-propagating damage) and fracture (specimen separated into at least two fragments) injury events were recorded. Best subsets analysis was performed to find the best multivariate injury risk model. Force-only risk models were also determined for comparison. Cumulative distribution functions were developed from the parameters of a Weibull analysis and the forces and risk scores (i.e., values calculated from the injury risk models) from 10% to 90% probability were calculated. According to the adjusted R(2), variance inflation factor and p-values, the model that best predicted the crack event included medial/lateral impulse, Fz load rate, impact velocity and the natural logarithm of Fz (Adj. R(2)=0.698), while the best predictive model of the fracture event included medial/lateral impulse, impact velocity and peak Fz (Adj. R(2)=0.845). The multivariate models predicted injury risk better than both the Fz-only crack (Adj. R(2)=0.551) and fracture (Adj. R(2)=0.293) models. Risk scores of 0.5 and 0.6 corresponded to 10% failure probability for the crack and fracture events, respectively. The inclusion of medial/lateral impulse and impact velocity in both crack and fracture models, and Fz load rate in the crack model, underscores the dynamic nature of these events. This study presents a method capable of developing a set of distal radius fracture prediction models that can be used in the assessment and development of distal radius injury prevention interventions. PMID- 23352775 TI - Psychometric properties of the Childhood Trauma Questionnaire-Short Form (CTQ-SF) in Korean patients with schizophrenia. AB - OBJECTIVE: Despite increasing interest in the relationship between childhood trauma and psychosis, measures used to assess early trauma have not had their psychometric properties extensively tested among individuals with serious mental illness. This study investigated the reliability and validity of one of the most widely-used self-reports of early adversity, the Childhood Trauma Questionnaire, Short Form (CTQ), among patients with schizophrenia. METHODS: The CTQ was administered to 100 patients (52 inpatients and 48 outpatients) diagnosed with schizophrenia in three training hospitals. Internal consistency, four-week test retest reliability and validity were calculated. Participants also completed the Trauma Antecedents Questionnaire (TAQ), the Impact of Events Scale-Revised (IES R), and the Dissociative Experiences Scale-Taxon (DES-T). RESULTS: Our analysis indicated high test-retest reliability (Spearman rho=0.75) and internal consistency (Cronbach alpha=0.89). Concurrent validity was confirmed as each type of childhood trauma was significantly correlated with the corresponding subscales of the TAQ. In addition, the CTQ was positively related to post-traumatic stress symptoms and pathological dissociation, demonstrating the convergent validity of the scale. CONCLUSION: The CTQ is a reliable and valid self-report measure for assessing childhood trauma in both inpatients and outpatients with schizophrenia. PMID- 23352776 TI - A randomized controlled trial of olanzapine improving memory deficits in Han Chinese patients with first-episode schizophrenia. AB - Olanzapine is an atypical antipsychotic for the treatment of schizophrenia, in which memory impairment is a core deficit. The methods of positive and negative syndrome scale (PANSS), Wechsler memory scale-4th edition (WMS-IV) and event related potential (ERP) were used to study the effects of olanzapine on the cognitive function in the first-episode schizophrenic patients. We performed multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trial to study the cognitive functioning in Han Chinese first-episode schizophrenic patients in a 12-week treatment regime with olanzapine (129 cases) or placebo (132 cases). The results showed that (1) the patients with first episode schizophrenia showed significant deficits in the long-term memory, short term memory, immediate memory and memory quotient by WMS-IV assessment, and decreases the total scores, positive symptoms, negative symptoms and general psychopathology by PANSS assessment; (2) olanzapine could significantly improve the PANSS scores including total scores, positive symptoms, negative symptoms and general psychopathology in the first-episode schizophrenic patients; (3) olanzapine could significantly improve the short-term memory, immediate memory and memory quotient in the first-episode schizophrenic patients; and (3) although the latencies of P(2), N(2) and P(3) were significantly prolonged, P(2) and P(3) amplitudes were decreased and the latencies of N(1) did not change, olanzapine did not influence any P(300) items in the first-episode schizophrenic patients. The data suggested that that olanzapine could improve cognitive process, such as memorizing and extraction of the information although there were many changes of cognitive functions in Han Chinese first-episode schizophrenic patients. PMID- 23352777 TI - Inhibition of caudal fin regeneration in Corydoras aeneus by lithium chloride. AB - In the present study we examined the effects of lithium chloride on the Corydoras aeneus caudal fin regeneration. After caudal fin amputation, the fish were exposed 3h daily to 35 mM lithium chloride for 9 days. The effects of lithium chloride treatment were evaluated by analyzing the caudal fin structure at 3, 6 and 9 days after amputation. Comparison of normal and LiCl treated fish clearly shows that regeneration of amputated caudal fins was inhibited or delayed after lithium treatment. By the third day after amputation (dpa) either no epidermal cap or blastema ever formed or the epidermal cap had an abnormal morphology in lithium treated fish. By the 3 and 6 dpa no lepidotrichial matrix deposition was observed in the lithium treated fish compared to control fish. Unlike the control fish that completely regenerate their caudal fins after 9 dpa and have fully mineralized lepidotrichia, lithium treated fish have small blastema. In some treated fish, small amounts of new lepidotrichial matrix were observed at this time, in some fin rays. Ultrastructural observations have shown differences between control and lithium treated fish. Thus, in the lithium treated fish we observed expanded intercellular spaces between epidermal cells and many apoptotic cells. Results of this study suggest the use of this model in elucidating the molecular mechanisms that are responsible for regeneration of complex structures such as fish fins. PMID- 23352778 TI - Resolution of left bundle branch block-induced cardiomyopathy by cardiac resynchronization therapy. AB - OBJECTIVES: The study sought to describe a specific syndrome characterized by isolated left bundle branch block (LBBB) and a history of progressive left ventricular (LV) dysfunction, successfully treated by cardiac resynchronization therapy (CRT). BACKGROUND: Isolated LBBB in animals causes cardiac remodeling due to mechanical dyssynchrony, reversible by biventricular stimulation. However, the existence of LBBB-induced cardiomyopathy in humans remains uncertain. METHODS: Between 2007 and 2010, 375 candidates for CRT were screened and retrospectively included in this study if they met all criteria of a pre-defined syndrome, including: 1) history of typical LBBB for >5 years; 2) LV ejection fraction (EF) >50%; 3) decrease in LVEF to <40% and development of heart failure (HF) to NYHA functional class II to IV over several years; 4) major mechanical dyssynchrony; 5) no known etiology of cardiomyopathy; and 6) super-response to CRT with LVEF >45% and decrease in NYHA functional class at 1 year. RESULTS: The syndrome was identified in 6 patients (1.6%), 50.5 years of age on average at the time of LBBB diagnosis. HF developed over a mean of 11.6 years. At the time of referral, Doppler echocardiograms showed major mechanical dyssynchrony at left atrioventricular, interventricular, and left intraventricular levels. During CRT, NYHA functional class decreased, LV dimensions normalized and mechanical dyssynchrony was nearly resolved in all patients, and mean LVEF increased from 31 +/- 12% to 56 +/- 8% (p = 0.027). CONCLUSIONS: These observations support the existence of a specific LBBB-induced cardiomyopathy resolved by CRT. Its prevalence, time course, and risk factors need to be prospectively studied. PMID- 23352779 TI - Intravascular ultrasound and fractional flow reserve in assessment of the intermediate coronary stenosis: what you see is not what you get. PMID- 23352780 TI - Steroid therapy effectively delays Duchenne's cardiomyopathy. PMID- 23352781 TI - All-cause mortality and cardiovascular outcomes with prophylactic steroid therapy in Duchenne muscular dystrophy. AB - OBJECTIVES: This study sought to determine the impact of steroid therapy on cardiomyopathy and mortality in patients with Duchenne muscular dystrophy (DMD). BACKGROUND: DMD is a debilitating X-linked disease that afflicts as many as 1 in 3,500 boys. Although steroids slow musculoskeletal impairment, the effects on cardiac function and mortality remain unknown. METHODS: We conducted a cohort study on patients with DMD treated with renin-angiotensin-aldosterone system antagonists with or without steroid therapy. RESULTS: Eighty-six patients, 9.1 +/ 3.5 years of age, were followed for 11.3 +/- 4.1 years. Seven of 63 patients (11%) receiving steroid therapy died compared with 10 of 23 (43%) not receiving steroid therapy (p = 0.0010). Overall survival rates at 5, 10, and 15 years of follow-up were 100%, 98.0%, and 78.6%, respectively, for patients receiving steroid therapy versus 100%, 72.1%, and 27.9%, respectively, for patients not receiving steroid therapy (log-rank p = 0.0005). In multivariate propensity adjusted analyses, steroid use was associated with a 76% lower mortality rate (hazard ratio: 0.24; 95% confidence interval: 0.07 to 0.91; p = 0.0351). The mortality reduction was driven by fewer heart failure-related deaths (0% vs. 22%, p = 0.0010). In multivariate analyses, steroids were associated with a 62% lower rate of new-onset cardiomyopathy (hazard ratio: 0.38; 95% confidence interval: 0.16 to 0.90; p = 0.0270). Annual rates of decline in left ventricular ejection fraction (-0.43% vs. -1.09%, p = 0.0101) and shortening fraction (-0.32% vs. 0.65%, p = 0.0025) were less steep in steroid-treated patients. Consistently, the increase in left ventricular end-diastolic dimension was of lesser magnitude (+0.47 vs. +0.92 mm per year, p = 0.0105). CONCLUSIONS: In patients with DMD, steroid therapy is associated with a substantial reduction in all-cause mortality and new-onset and progressive cardiomyopathy. PMID- 23352783 TI - Overview of the 2011 Food and Drug Administration Circulatory System Devices Panel of the Medical Devices Advisory Committee Meeting on the CardioMEMS Champion Heart Failure Monitoring System. AB - The CardioMEMS Champion Heart Failure Monitoring System (CardioMEMS, Atlanta, Georgia) is a permanently implantable pressure measurement system designed to wirelessly measure and monitor pulmonary artery (PA) pressure and heart rate in heart failure (HF) patients to guide ambulatory HF management and to reduce HF hospital stays. On December 8, 2011, the Food and Drug Administration (FDA) Circulatory System Device Panel reviewed the CardioMEMS Champion HF Monitoring System premarket approval (PMA) application. The majority of Panel members agreed that that the discussed monitoring system is safe for use in the indicated patient population. However, new information reported by the FDA with regard to preferential support in management of patients in the treatment group raised concerns among the Panel members with regard to potential bias in analyzing the efficacy of the device itself. Additionally, Panel members raised concerns with regard to the efficacy of the device in certain patient subpopulations. Hence, most Panel members decided that there was not reasonable assurance that the discussed monitoring system is effective. This summary aims to describe the discussions and recommendations made during this meeting. PMID- 23352784 TI - When cardiac function dangles on a thread of conduction: dyssynchronopathy in patients with left bundle branch block. PMID- 23352782 TI - Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis. AB - OBJECTIVES: This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD. BACKGROUND: Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. METHODS: We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects. RESULTS: We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele. CONCLUSIONS: The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype. PMID- 23352785 TI - Allogeneic cardiospheres safely boost cardiac function and attenuate adverse remodeling after myocardial infarction in immunologically mismatched rat strains. AB - OBJECTIVES: We sought to characterize the immunologic profile of allogeneic cardiospheres, which are 3-dimensional, self-assembling, cardiac-derived microtissues, and to evaluate their safety and efficacy in repairing ischemic heart tissue. BACKGROUND: Intramyocardial injection of autologous cardiospheres ameliorates remodeling and improves global function in infarcted myocardium. It is as yet unknown whether allogeneic cardiospheres are similarly effective without eliciting deleterious immune reactions. METHODS: We expanded cardiospheres from male Wistar Kyoto rat hearts and injected them surgically in the peri-infarct zone of Wistar Kyoto (syngeneic group, n = 28) and Brown Norway female rats (allogeneic group, n = 29). Female rats from both strains (n = 37) injected with normal saline served as controls. RESULTS: In vitro, cardiospheres expressed a low immunogenic profile and inhibited proliferation of alloreactive T cells. In vivo, cell engraftment was similar in the syngeneic and allogeneic groups 1 week and 3 weeks after transplantation. Reductions in scar size and scar collagen content and increases in viable mass in the risk region were accompanied by improvements in left ventricular function and attenuation of left ventricle remodeling that were sustained during 6 months of follow up. Transplantation of allogeneic cardiospheres increased tissue expression of the regenerative growth factors vascular endothelial growth factor, hepatocyte growth factor, and insulin like growth factor-1, stimulating angiogenesis. Syngeneic and allogeneic cardiospheres attenuated the inflammatory response observed histologically in the peri-infarct region. CONCLUSIONS: Allogeneic cardiospheres increase viable myocardium, decrease scar, improve function, and attenuate adverse remodeling in the infarcted rat heart, without deleterious immunological sequelae. These observations lay the groundwork for developing cardiospheres as a novel off-the shelf microtissue product for myocardial regeneration. PMID- 23352786 TI - FIRST: Fractional Flow Reserve and Intravascular Ultrasound Relationship Study. AB - OBJECTIVES: FIRST (Fractional Flow Reserve and Intravascular Ultrasound Relationship Study) aimed to determine the optimal minimum lumen area (MLA) by intravascular ultrasound (IVUS) that correlates with fractional flow reserve (FFR) and to assess the correlation between virtual histology IVUS and FFR for intermediate coronary lesions. BACKGROUND: FFR is considered the gold standard for assessing intermediate coronary lesions. Measurements of <=0.8 are considered clinically significant and indicative of physiological ischemia. METHODS: FIRST is a multicenter, prospective, international registry of patients with intermediate coronary lesions, defined as 40% to 80% stenosis by angiography. In total, 350 patients (367 lesions) were enrolled at 10 U.S. and European sites. Patients were followed through hospital discharge. RESULTS: Overall, an MLA <3.07 mm(2) (64.0% sensitivity, 64.9% specificity, area under curve [AUC] = 0.65) was the best threshold value for identifying FFR <0.8. The accuracy improved when reference vessel-specific analyses were performed. An MLA <2.4 mm(2) (AUC = 0.66) was best for reference vessel diameters <3.0 mm, an MLA <2.7 mm(2) (AUC = 0.71) for reference vessel diameters of 3.0 to 3.5 mm, and an MLA <3.6 mm(2) (AUC = 0.68) for reference vessel diameters >3.5 mm. FFR correlated with plaque burden (r = -0.220, p < 0.001) but not with other plaque morphology. CONCLUSIONS: Anatomic measurements by IVUS show a moderate correlation with the FFR values. The optimal cutoff for an MLA to FFR <0.8 is vessel dependent. Plaque morphology characteristics do not correlate with FFR. The utility of IVUS MLA as an alternative to FFR to guide intervention in intermediate lesions may be limited in accuracy and should be tested clinically. (Fractional Flow Reserve and Intravascular Ultrasound Relationship Study [FIRST]; NCT01153555). PMID- 23352787 TI - Anterior table remodeling after treatment for Pott's puffy tumor. AB - We report a case of near-complete remodeling of the anterior table of the frontal sinus after treatment for an erosive Pott's Puffy Tumor. A 61-year-old male presented with progressive swelling of his left forehead. Examination showed a doughy left forehead mass, and a sinus CT showed a lateral left frontal sinus mucocele with complete anterior table erosion. Frontal trephination with marsupialization of the mucocele was performed, and at 8 month follow-up, the patient had no visible defect and only minimally palpable bony defect. The anterior table had remodeled with no additional intervention resulting in a cosmetic outcome imperceptible from the patient's baseline. PMID- 23352788 TI - The peripartum management of a patient with glutaric aciduria type 1. AB - The management of cesarean delivery for a parturient with placenta previa at 36 weeks' gestation and glutaric aciduria type 1 is presented. The management goal was to prevent encephalopathic crisis by ensuring adequate caloric intake with dextrose infusion and to provide carnitine supplementation and adequate anesthesia. PMID- 23352790 TI - The bHLH transcription factor Ascl1a is essential for the specification of the intestinal secretory cells and mediates Notch signaling in the zebrafish intestine. AB - Notch signaling has a fundamental role in stem cell maintenance and in cell fate choice in the intestine of different species. Canonically, Notch signaling represses the expression of transcription factors of the achaete-scute like (ASCL) or atonal related protein (ARP) families. Identifying the ARP/ASCL genes expressed in the gastrointestinal tract is essential to build the regulatory cascade controlling the differentiation of gastrointestinal progenitors into the different intestinal cell types. The expression of the ARP/ASCL factors was analyzed in zebrafish to identify, among all the ARP/ASCL factors found in the zebrafish genome, those expressed in the gastrointestinal tract. ascl1a was found to be the earliest factor detected in the intestine. Loss-of-function analyses using the pia/ascl1a mutant, revealed that ascl1a is crucial for the differentiation of all secretory cells. Furthermore, we identify a battery of transcription factors expressed during secretory cell differentiation and downstream of ascl1a. Finally, we show that the repression of secretory cell fate by Notch signaling is mediated by the inhibition of ascl1a expression. In conclusion, this work identifies Ascl1a as a key regulator of the secretory cell lineage in the zebrafish intestine, playing the same role as Atoh1 in the mouse intestine. This highlights the diversity in the ARP/ASCL family members acting as cell fate determinants downstream from Notch signaling. PMID- 23352789 TI - BMP and TGF-beta pathway mediators are critical upstream regulators of Wnt signaling during midbrain dopamine differentiation in human pluripotent stem cells. AB - Although many laboratories currently use small molecule inhibitors of the BMP (Dorsomorphin/DM) and TGF-beta (SB431542/SB) signaling pathways in protocols to generate midbrain dopamine (mDA) neurons from hES and hiPS cells, until now, these substances have not been thought to play a role in the mDA differentiation process. We report here that the transient inhibition of constitutive BMP (pSMADs 1, 5, 8) signaling, either alone or in combination with TGF-beta inhibition (pSMADs 2, 3), is critically important in the upstream regulation of Wnt1-Lmx1a signaling in mDA progenitors. We postulate that the mechanism via which DM or DM/SB mediates these effects involves the up-regulation in SMAD-interacting protein 1 (SIP1), which results in greater repression of the Wnt antagonist, secreted frizzled related protein 1 (Sfrp1) in stem cells. Accordingly, knockdown of SIP1 reverses the inductive effects of DM/SB on mDA differentiation while Sfrp1 knockdown/inhibition mimics DM/SB. The rise in Wnt1-Lmx1a levels in SMAD inhibited cultures is, however, accompanied by a reciprocal down-regulation in SHH-Foxa2 levels leading to the generation of few TH+ neurons that co-express Foxa2. If however, exogenous SHH/FGF8 is added along with SMAD inhibitors, equilibrium in these two important pathways is achieved such that authentic (Lmx1a+Foxa2+TH+) mDA neuron differentiation is promoted while alternate cell fates are suppressed in stem cell cultures. These data indicate that activators/inhibitors of BMP and TGF-beta signaling play a critical upstream regulatory role in the mDA differentiation process in human pluripotent stem cells. PMID- 23352791 TI - Regulation of G-protein signaling via Gnas is required to regulate proximal tubular growth in the Xenopus pronephros. AB - In the kidney, proximal tubules are very important for the reabsorption of water, ions and organic solutes from the primary urine. They are composed of highly specialized epithelial cells that are characterized by an elaborate apical brush border to increase transport efficiency. Using the pronephric kidney of Xenopus laevis we discovered that the G-protein modulator cholera toxin resulted in a dramatic reduction of the proximal tubular size. This phenotype was accompanied by changes in the cytoarchitecture characterized by ectopic expression of the distal tubular marker 4A6 and an impairment of yolk platelet degradation. In addition, cholera toxin caused edema formation. However, this phenotype was not due to kidney defects, but rather due to impaired vasculature development. Based on experiments with antisense morpholino oligomers as well as pharmacological agonists and antagonists, we could show that the complex phenotype of cholera toxin in the pronephric kidney was caused by the hyperactivation of a single G protein alpha subunit, Gnas. This-in turn-caused elevated cAMP levels, triggered a Rapgef4-dependent signaling cassette and perturbed exo- and endocytosis. This perturbation of the secretory pathway by Ctx was not only observed in Xenopus embryos. Also, in a human proximal tubular cell line, cholera toxin or a Rapgef4 specific agonist increased uptake and decreased secretion of FITC-labeled Albumin. Based on these data we propose that the Gnas/cAMP/Rapgef4 pathway regulates the signals inducing the proliferation of proximal tubules to acquire their final organ size. PMID- 23352792 TI - Molecular analysis of SMN1, SMN2, NAIP, GTF2H2, and H4F5 genes in 157 Chinese patients with spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is a common and lethal autosomal recessive neurodegenerative disorder, which is caused by mutations of the survival motor neuron 1 (SMN1) gene. Additionally, the phenotype is modified by several genes nearby SMN1 in the 5q13 region. In this study, we analyzed mutations in SMN1 and quantified the modifying genes, including SMN2, NAIP, GTF2H2, and H4F5 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), multiplex ligation-dependent probe amplification (MLPA), TA cloning, allele specific long-range PCR, and Sanger sequencing in 157 SMA patients. Most SMA patients (94.90%) possessed a homozygous SMN1 deletion, while 10 patients demonstrated only the absence of exon 7, but the presence of exon 8. Two missense mutations (c.689 C>T and c.844 C>T) were identified in 2 patients who both carried a single copy of SMN1. We found inverse correlations between SMN2, the NAIP copy number, and the clinical severity of the disease. Furthermore, 7 severe type I patients possessed large-scale deletions, including SMN1, NAIP, and GTF2H2. We conclude that SMN1 gene conversion, SMN1 subtle mutations, SMN2 copy number, and the extent of deletion in the 5q13 region should all be considered in the genotype-phenotype analysis of SMA. PMID- 23352793 TI - Rapid screening of 12 common mutations in Turkish GSD 1a patients using electronic DNA microarray. AB - Glycogen storage disease type Ia (GSD Ia) is an autosomal recessive disorder caused by mutations in the G6PC gene encoding glucose-6-phosphatase (G6Pase), a key enzyme for the maintenance of glucose homeostasis. Molecular analysis is a reliable and accurate way of diagnosing GSD Ia without to need for invasive liver biopsies for enzyme tests. In some ethnic groups and geographic regions, allelic homogeneity was detected in GSD Ia. In the present study, the most common 12 mutations in the world were searched by microelectronic array technology, a new method, in 27 Turkish patients diagnosed for GSD Ia and the relation between detected mutations and clinical and laboratory findings was investigated. Mutations causing the disease were detected in 45 (83.3%) of 54 alleles screened in the cases with GSD Ia. Allelic frequency of mutations (p.R83C, p.G270V, p.G188R, p.W77R) looked for were found as 68.5%, 7.4%, 3.7%, and 3.7%, respectively. p.G188R mutation was detected for the first time in a patient of Turkish origin. Eight (p.R170Q, p.Q347X, c.79delC, c.380_381insTA, p.D38V, p.W63X, c.648G>T, c.979_981delTTC) of 12 mutations looked for were coincided in none of the patients. The patient with homozygous p.W77R mutation seemed to present milder clinical and laboratory findings, compared to other patients. In conclusion, we suggest that microarray technology, which allows rapid analysis of frequently detected mutations and has considerably lower costs than other methods, can be successfully used in diagnosis of GSD Ia in populations with allelic homogeneity, such as patients of Turkish origin, instead of screening the whole gene. PMID- 23352794 TI - Germline mosaicism in Rubinstein-Taybi syndrome. AB - Rubinstein-Taybi syndrome is an autosomal dominant disorder with multiple congenital anomalies and genetic heterogeneity. Clinical manifestations include mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and characteristic facial features. Mutations in the gene encoding the transcriptional coactivator CREB-binding protein (CREBBP; OMIM 600140) on chromosome 16p13, account for about 50% to 70% of patients. Most of CREBBP mutations are de novo and the rate of recurrence in a family is low. Families with several affected children are extremely rare. We report here a Moroccan family with two children with RSTS and apparently unaffected parents. The molecular studies showed a heterozygous mutation c.4361T>A (p.Leu1454His) in exon 26 of the CREBBP gene in the two affected siblings. Neither the parents, nor the healthy brother, carry this mutation in hematologic cells. The mutation was also absent in buccal epithelial cells of both parents. We discuss the hypothesis of germinal mosaicism. This concept is very important because it complicates genetic counseling of this family who has a risk of recurrence of the mutation in subsequent pregnancies. PMID- 23352795 TI - Association of TGF-beta1 -509 C/T, 29 C/T and 788 C/T gene polymorphisms with chronic periodontitis: a case-control study. AB - The aim of this study was to investigate the possible association between TGF beta1 -509 C/T (rs1800469), 29 C/T (Prol10Leu, rs1800470) and 788 C/T (Thr263Ile, rs1800472) gene polymorphisms and chronic periodontitis (CP) in a sample of Iranian population. This case-control study was conducted on 100 CP patients and 100 healthy unrelated, age-, sex-, and ethnicity-matched. Genotyping was performed by tetra amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) technique. Our findings showed that there was a significant difference between the groups regarding TGF-beta1 29 C/T (rs1800470) polymorphism (chi2=23.23, P<0.0001). The CT and TT genotypes increased the risk of CP in comparison with the CC genotype (OR=4.42, 95% CI=2.16-9.06, P<0.001 and OR=5.84, 95% CI=2.32-14.71, P<0.001, respectively). The T allele increased the risk of CP (OR=2.50, 95% CI=1.66-3.74, P<0.001) in comparison with C allele. No significant association was found among the groups regarding -509 C/T and 788 C/T variants of TGF-beta1 gene. This study shows that TGF-beta1 29 C/T polymorphism, but not -509 C/T and 788 C/T polymorphisms, may contribute to the development of CP in a sample of Iranian population. Further studies with larger sample sizes and different ethnicities are needed to validate our findings. PMID- 23352796 TI - Proportion of bony cochlear nerve canal anomalies in unilateral sensorineural hearing loss in children. AB - OBJECTIVE: The aim of this study was to characterize the various bony anomalies of the inner ear in patients with unilateral sensorineural hearing loss using high-resolution temporal bone computed tomography and establish the relationship between hearing and the diameter of the bony cochlear nerve canal. METHODS: We performed a retrospective review of 51 patients (mean age 11 years, range 0-20 years, 27 boys, 24 girls) who were diagnosed with unilateral sensorineural hearing loss with an audiogram. Coronal and axial diameter of the inner ear structures, including the internal auditory canal, bony cochlear nerve canal, and each turn of the cochlea and semicircular canals, were measured with high resolution temporal bone computed tomography. The mean values (+/- 2 standard deviations) were calculated and compared between sensorineural hearing loss and normal ears, and between narrow bony cochlear nerve canal and normal bony cochlear nerve canal ears. Bony cochlear nerve canal atresia/stenosis was defined as a value less than 1.4mm in axial images. RESULTS: The diameter of the bony cochlear nerve canal was significantly smaller in sensorineural hearing loss ears than in normal ears (p<.05). Associated inner ear anomalies, such as IAC stenosis (24%), cochlear hypoplasia (7-17%), and narrow semicircular canal bony island (8%) were only observed in the narrow bony cochlear nerve canal group. This group also showed statistically significant, severe to profound hearing loss compared to the normal bony cochlear nerve canal group (p<.05, R(2)=12.8%). CONCLUSIONS: Most (57%) of the unilateral sensorineural hearing loss ears had bony cochlear nerve canal stenosis/atresia and this group showed associated inner ear anomalies. When the diameter of the bony cochlear nerve canal was less than 1.4mm, pure tone audio averages were more than 70 dB HL in most ears. PMID- 23352797 TI - Congenital parotid ectopia in accessory maxilla and facial cleft anomalies: three cases report. AB - To further document the clinical features of accessory maxilla with three additional cases report. Clinical and radiological features of three cases of accessory maxilla were presented. Related literature was summarized for comparison. Ectopic parotid gland, facial cleft and accessory maxilla are three concomitant malformations in this condition. The tooth-bearing accessory maxillary duplication derives from the abnormal growth of the zygoma or zygomatic arch. Facial cleft, parotid ectopia and tooth-bearing accessory maxilla may constitute a rare congenital syndrome. PMID- 23352798 TI - An exploration of women's reasons for termination timing in the setting of fetal abnormalities. AB - BACKGROUND: Over 3% of pregnancies are complicated by a fetal abnormality, of which, approximately 80% are terminated. Despite early screening options, women often present at the cusp of legal limits for termination. STUDY DESIGN: A qualitative study was conducted with women terminating pregnancies for fetal abnormalities. Semi-structured interviews explored reasons for termination timing. Analysis utilized latent content and constant comparative methods. RESULTS: Of 30 participants between 13+4 and 23+5 weeks gestation, their median age was 35 years, 73.3% were white, 70% were religiously affiliated, and 60% had children. The median time from abnormality identification until termination was 16.5 days (range 2-73). The major themes for termination timing included (1) an abrupt shift in "low-risk" pregnancy perception; (2) challenging medical interactions; (3) an emotional decision-making process; and (4) termination access barriers. CONCLUSIONS: Timing of termination for fetal abnormalities is attributable to multiple issues. Future research should identify optimal prenatal counseling strategies, address systemic barriers, and identify patient decision making resources. PMID- 23352799 TI - Prescription requirements and over-the-counter access to oral contraceptives: a global review. AB - BACKGROUND: Since the prescription requirement for oral contraceptives (OCs) can act as a barrier for some women, over-the-counter (OTC) access may improve uptake and continuation. The goal of this study was to ascertain the prescription requirements and informal OTC availability of OCs worldwide. STUDY DESIGN: From April 2011 to September 2012, we researched official documentation and conducted an online survey with government officials and pharmaceutical and reproductive health specialists on OC availability in countries worldwide. Results were compiled in a database and entered into a map for analysis of regional patterns. RESULTS: Data were obtained for 147 countries. OCs were informally available without prescription in 38% of countries, legally available without prescription (no screening by a health professional required) in 24% of countries, legally available without prescription (screening required) in 8% of countries and available only by prescription in 31% of countries. Notable regional patterns in OC prescription requirements emerged. CONCLUSIONS: OCs are available without prescription in the majority of countries. Country experiences with OTC provision may provide evidence about the safety and effectiveness of OTC provision as a strategy to improve access to effective family planning. PMID- 23352800 TI - Comparison of serum and cervical mucus hormone levels during hormone-free interval of 24/4 vs. 21/7 combined oral contraceptives. AB - BACKGROUND: This study analyzes levels of progesterone, estradiol, norethindrone (NET) and ethinyl estradiol (EE) in serum and levels of NET in cervical mucus on the last day of the hormone-free interval (HFI) in users of 24/4 [norethindrone acetate (NETA)/EE-24] vs. 21/7 (NETA/EE-21) regimens. STUDY DESIGN: This was a randomized controlled, crossover, equivalency trial. Subjects were randomized to receive NETA/EE-24 or NETA/EE-21 for 2 months and then switched between study drugs. Blood and cervical mucus samples were obtained on Days 12-16 and on the last day of the HFI. RESULTS: From April 2010 to November 2011, 32 subjects were enrolled with 18 subjects completing all study visits. There were no statistically significant differences in either day 12-16 (p=.54) or last hormone free day (p=.33) cervical mucus NET concentrations between the regimens. On the last day of the HFI, median serum progesterone levels did not differ significantly; however, users of NETA/EE-24 had higher levels of serum NET (p<.001) and users of NETA/EE-21 had higher levels of serum estradiol (p=.01). CONCLUSION: This data supports the fact that inhibition of the pituitary-ovarian axis occurs during oral contraceptive use and during the HFI. We demonstrated that a reduced HFI of 4 days resulted in better suppression of the ovarian hormone production, thereby reducing the risk of ovulation and potential contraceptive failure. PMID- 23352801 TI - Same-day cervical preparation with misoprostol prior to second trimester D&E: a case series. AB - BACKGROUND: Traditionally, overnight cervical preparation with osmotic dilators has been used for second trimester dilation and evacuation (D&E) procedures. Misoprostol offers an alternative treatment that could shorten cervical preparation time. STUDY DESIGN: This study reports on a case series of patients who received only buccal or vaginal misoprostol for cervical preparation on the same day as the D&E procedure. Data were collected from charts of women undergoing second trimester D&E at an outpatient women's health clinic. Eligible cases included procedures performed between January 2001 and December 2010 at 17 0/7 to 23 0/7 weeks of gestation. RESULTS: Chart review identified 1177 cases of D&E during the study period. After deletion of 96 multiple-day cases using laminaria, 1081 misoprostol-only cases remained for analysis. Two of the cases were not able to be completed in the same day (0.2%). Ninety-eight percent of cases were 17-20 weeks of gestation. The average time from either vaginal or buccal placement of the first misoprostol dose to procedure completion was 4.9 h (SD+/-1.7 h). The average procedure length was 13.0 min (SD+/-10.2 min). Complications were reported in 21 of 1079 same-day procedures (2%) and included resuction (n=4), hemorrhage (n=5), cervical laceration (n=4), endometritis (n=5), pulmonary embolus (n=1), disseminated intravascular coagulation (n=1) and perforation (n=1). CONCLUSION: Same-day cervical preparation with misoprostol for second trimester D&E is both safe and effective. With the continuing shortage of D&E providers, the resulting increase in travel distance to obtain the procedure, mandatory waiting periods and the capability of having the procedure completed in a single day may increase patient access, reduce cost and improve patient satisfaction. PMID- 23352802 TI - A chitosan-modified graphene nanogel for noninvasive controlled drug release. AB - A near infrared (NIR) triggered drug delivery platform based on the chitosan modified chemically reduced graphene oxide (CRGO) incorporated into a thermosensitive nanogel (CGN) was developed. CGN exhibited an NIR-induced thermal effect similar to that of CRGO, reversible thermo-responsive characteristics at 37-42 degrees C and high doxorubicin hydrochloride (DOX) loading capacity (48 wt%). The DOX loaded CGN (DOX-CGN) released DOX faster at 42 degrees C than at 37 degrees C. The fluorescence images revealed DOX expression in the cytoplasm of cancer cells when incubated with DOX-CGN at 37 degrees C but in the nucleus at 42 degrees C. Upon irradiation with NIR light (808 nm), a rapid, repetitive DOX release from the DOX-CGN was observed. Furthermore, the cancer cells incubated with DOX-CGN and irradiated with NIR light displayed significantly greater cytotoxicity than without irradiation owing to NIR-triggered increase in temperature leading to nuclear DOX release. These results demonstrate CGN's promising application for on-demand drug release by NIR light. FROM THE CLINICAL EDITOR: These investigators report the successful development of a novel near infrared triggered drug delivery platform based on chitosan-modified chemically reduced graphene oxide (CRGO) incorporated into a thermosensitive nanogel (CGN). PMID- 23352803 TI - Phase separation in equiatomic AlCoCrFeNi high-entropy alloy. AB - The microstructure of the as-cast AlCoCrFeNi high entropy alloy has been investigated by transmission electron microscopy and atom probe tomography. The alloy shows a very pronounced microstructure with clearly distinguishable dendrites and interdendrites. In both regions a separation into an Al-Ni rich matrix and Cr-Fe-rich precipitates can be observed. Moreover, fluctuations of single elements within the Cr-Fe rich phase have been singled out by three dimensional atom probe measurements. The results of investigations are discussed in terms of spinodal decomposition of the alloying elements inside the Cr-Fe-rich precipitates. PMID- 23352804 TI - Interactive visualization of APT data at full fidelity. AB - Understanding the impact of noise and incomplete data is a critical need for using atom probe tomography effectively. Although many tools and techniques have been developed to address this problem, visualization of the raw data remains an important part of this process. In this paper, we present two contributions to the visualization of data acquired through atom probe tomography. First, we describe the application of a rendering technique, ray-cast spherical impostors, that enables the interactive rendering of large numbers (as large as 10 million plus) of pixel perfect, lit spheres representing individual atoms. This technique is made possible by the use of a consumer-level graphics processing unit (GPU), and it yields an order of magnitude improvement both in render quality and speed over techniques previously used to render spherical glyphs in this domain. Second, we present an interactive tool that allows the user to mask, filter, and colorize the data in real time to help them understand and visualize a precise subset and properties of the raw data. We demonstrate the effectiveness of our tool through benchmarks and an example that shows how the ability to interactively render large numbers of spheres, combined with the use of filters and masks, leads to improved understanding of the three-dimensional (3D) and incomplete nature of atom probe data. This improvement arises from the ability of lit spheres to more effectively show the 3D position and the local spatial distribution of individual atoms than what is possible with point or isosurface renderings. The techniques described in this paper serve to introduce new rendering and interaction techniques that have only recently become practical as well as new ways of interactively exploring the raw data. PMID- 23352805 TI - Quantitative methods for the APT analysis of thermally aged RPV steels. AB - Atom Probe Tomography (APT) is extensively used for the analysis of RPV steels. However, many different analysis methods and cluster search parameters are used, making comparisons between different datasets difficult. Suitable d(max) and N(min) parameters for the maximum separation method are investigated. In a randomised distribution of solute there is a finite probability that a group of more than N(min) solute ions exists within the d(max) distance. The same is true for experimental datasets from samples which have been thermally aged or irradiated, however these background clusters are not the result of ageing, they are purely statistically random co-incidences. A method is presented for identifying such "background" statistical clusters in real APT data sets, based upon their size and composition, which allows for improved sensitivity to small clusters. PMID- 23352806 TI - Sleep and biomarkers in the English Longitudinal Study of Ageing: associations with C-reactive protein, fibrinogen, dehydroepiandrosterone sulfate and hemoglobin. AB - Sleep duration and quality are associated with adverse physical health outcomes. The mechanisms are not well understood, and little is known about associations with biomarkers in older population cohorts. This study assessed cross-sectional associations between self-reported sleep measures and biomarkers in a representative sample of British people aged 50 years and above. Participants were 6465 men and women aged 50-99 years from the English Longitudinal Study of Ageing (ELSA). Associations of sleep duration and sleep disturbance with C reactive protein (CRP), fibrinogen, dehydroepiandrosterone sulfate (DHEAS) and hemoglobin were analyzed, adjusting for age, wealth, body mass index (BMI), smoking, physical activity, limiting long-standing illness and depressive symptoms. In men, long sleep duration (OR: 1.50, 1.05-2.14) and greater sleep disturbance (OR: 1.29, C.I. 1.05-1.59) were associated with raised CRP levels, while long sleep was also related to raised plasma fibrinogen (P=0.001). DHEAS levels were lower among men reporting more sleep disturbances (P=0.016), but were not related to sleep duration. Sleep duration (P=0.015) and sleep disturbance (P=0.039) were associated with lower hemoglobin levels, and anemia was more prevalent among men with disturbed sleep (OR: 1.73, C.I. 1.13-2.65). In women more disturbed sleep was associated with greater likelihood of anemia (OR: 1.59, C.I. 1.02-2.46), but there was no relationship between sleep disturbance or duration with other biomarkers. This study suggests that self-reported sleep duration and disturbance are related to biological risk factors in community dwelling older adults, with different associations being present in men and women. A better understanding of these relationships using longitudinal cohort studies will broaden our understanding of the mechanisms relating sleep indices and ill health in advancing age. PMID- 23352807 TI - The risk for bacterial endocarditis in cirrhotic patients: a population-based 3 year follow-up study. AB - BACKGROUND: We noted only rare reports of cirrhotic patients with bacterial endocarditis (BE). There is insufficient data on the risk of BE in liver cirrhosis. This is the first national population-based study evaluating the risk of BE in cirrhotic patients. METHODS: We used the National Health Insurance Database, which is derived from the Taiwan National Health Insurance Program. The study cohort comprised 40803 patients with cirrhosis and the comparison cohort consisted of 40841 randomly selected subjects with a similar age and sex distribution. RESULTS: Of the total 81644 patients, 192 (0.24%) experienced BE during the 3-year follow-up period, 121 patients from the study cohort (0.30% of the cirrhotic patients) and 71 patients from the comparison group (0.17% of non cirrhotic patients) (p<0.001). After adjusting for patient age, sex, and comorbid disorders, the Cox regression analysis showed that cirrhotic patients had a high risk of BE compared to non-cirrhotic patients during the 3-year follow-up period (hazard ratio 2.04, 95% confidence interval 1.61-2.44, p<0.001). CONCLUSION: We conclude that liver cirrhosis is a risk factor for the occurrence of BE. PMID- 23352808 TI - Genetically encoded Ca(2+) indicators: properties and evaluation. AB - Genetically encoded calcium ion (Ca(2+)) indicators have become very useful and widely used tools for Ca(2+) imaging, not only in cellular models, but also in living organisms. However, the in vivo and in situ characterization of these indicators is tedious and time consuming, and it does not provide information regarding the suitability of an indicator for particular experimental environments. Thus, initial in vitro evaluation of these tools is typically performed to determine their properties. In this review, we examined the properties of dynamic range, affinity, selectivity, and kinetics for Ca(2+) indicators. Commonly used strategies for evaluating these properties are presented. This article is part of a Special Issue entitled: 12th European Symposium on Calcium. PMID- 23352809 TI - Orbital aspects following monobloc advancement in syndromic craniosynostosis. AB - The monobloc advancement with distraction is a treatment modality for syndromic craniosynostosis, to correct exorbitism, upper airway compromise and malocclusion. In this report orbital volume and movements of (peri-)orbital structures and globes of seven patients following monobloc distraction are evaluated. In preoperative and postoperative CT-scans orbital volume was assessed and a 3D coordinate system with eleven landmarks was used to measure the movements of orbital structures and globes and to measure the change of exorbitism. Correlation between orbital volume, movements of the orbital structures and change in exorbitism was studied. The orbital volume increased by 49.9% (left) and 50.4% (right). The average anterior movement of the bone was 13.6 mm (left) and 13.9 mm (right). The mean anterior movement of the left globe was 5.8 mm and of the right globe 5.3 mm. The ratio of globe/bone movement was 0.4. Exorbitism decreased with 7.8 mm (left) and 8.1 mm (right). Differences between left and right for orbital volume, for movements and for the decrease in exorbitism were not significant. Volume enlargement and decrease in exorbitism were correlated (p <= 0.05). Following monobloc advancement orbital volume increases, (peri-)orbital structures and the globe move forward and exorbitism diminishes. PMID- 23352811 TI - In vivo epigenomic profiling of germ cells reveals germ cell molecular signatures. AB - The limited number of in vivo germ cells poses an impediment to genome-wide studies. Here, we applied a small-scale chromatin immunoprecipitation sequencing (ChIP-seq) method on purified mouse fetal germ cells to generate genome-wide maps of four histone modifications (H3K4me3, H3K27me3, H3K27ac, and H2BK20ac). Comparison of active chromatin state between somatic, embryonic stem, and germ cells revealed promoters and enhancers needed for stem cell maintenance and germ cell development. We found the nuclear receptor Nr5a2 motif to be enriched at a subset of germ cell cis-regulatory regions, and our results implicate Nr5a2 in germ cell biology. Interestingly, in germ cells, the H3K27me3 histone modification occurs more frequently at regions that are enriched for retrotransposons and MHC genes, indicating that these loci are specifically silenced in germ cells. Together, our study provides genome-wide histone modification maps of in vivo germ cells and reveals the molecular chromatin signatures of germ cells. PMID- 23352810 TI - Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. AB - Tet enzymes (Tet1/2/3) convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in various embryonic and adult tissues. Mice mutant for either Tet1 or Tet2 are viable, raising the question of whether these enzymes have overlapping roles in development. Here we have generated Tet1 and Tet2 double-knockout (DKO) embryonic stem cells (ESCs) and mice. DKO ESCs remained pluripotent but were depleted of 5hmC and caused developmental defects in chimeric embryos. While a fraction of double-mutant embryos exhibited midgestation abnormalities with perinatal lethality, viable and overtly normal Tet1/Tet2-deficient mice were also obtained. DKO mice had reduced 5hmC and increased 5mC levels and abnormal methylation at various imprinted loci. Nevertheless, animals of both sexes were fertile, with females having smaller ovaries and reduced fertility. Our data show that loss of both enzymes is compatible with development but promotes hypermethylation and compromises imprinting. The data also suggest a significant contribution of Tet3 to hydroxylation of 5mC during development. PMID- 23352812 TI - A tilting embryo culture system increases the number of high-grade human blastocysts with high implantation competence. AB - Human embryos normally experience mechanical stimuli during development in vivo. To apply appropriate stimuli to embryos, this study group developed a tilting embryo culture system (TECS) and investigated whether it could improve the grade of fresh human embryos compared with a control static culture system. A total of 450 retrieved oocytes from 32 IVF or intracytoplasmic sperm injection cycles of 32 women were cultured for 5-6 days. Oocytes were divided randomly into TECS and control groups and then were inseminated in vitro. All embryos were evaluated at days 3 and 5 using standard grading criteria for embryo quality. The rates of fertilization per mature oocyte and high-grade cleavage-stage embryo formation in the TECS group were similar to those in the control group. The rates of blastocyst formation and of blastocysts graded 3BB or higher at day 5 were significantly higher in the TECS group than those in the control group: 45.3% (67/148) versus 32.1% (51/159) (P=0.018) and 29.1% (43/148) versus 17.6% (28/159) (P=0.018), respectively. The TECS group produced more high-grade blastocysts than the control group. Embryo movement or mechanical stimulation during embryo culture may be beneficial for human embryonic development. PMID- 23352813 TI - Morphological systems of human embryo assessment and clinical evidence. AB - Success rates with IVF have improved remarkably since the procedure was first established for clinical use with the first successful birth in 1978. The main goals today are to perform single-embryo transfer in order to prevent multiple pregnancies and achieve higher overall pregnancy rates. However, the ability to identify the most viable embryo in a cohort remains a challenge despite the numerous scoring systems currently in use. Clinicians still depend on developmental rate and morphological assessment using light microscopy as the first-line approach for embryo selection. Active research in the field involves developing non-invasive methods for scoring embryos and ranking them according to their ability to implant and give rise to a healthy birth. Current attention is particularly being focused on time-lapse evaluation. Available data from preliminary studies indicate that these systems are safe;prospective data now need to be collected to determine whether these methods do improve implantation rates. This review gives brief consideration to the use of morphological evaluations in assisted reproduction treatment, discusses the types of embryo scoring,digital imaging and biometric approaches currently in use and comments on future developments for embryo evaluation. PMID- 23352814 TI - Exploring the oVEMP montage. PMID- 23352815 TI - Differential effects of optic media opacities on mfERGs and mfVEPs. AB - OBJECTIVE: To assess different effects of image degradation that could result from optic media opacities on multifocal retinal (mfERG) and cortical responses (mfVEP). METHODS: Monocular flash-mfERGs and pattern-reversal mfVEPs were recorded. MfERG-P1 amplitudes and implicit times and mfVEP root-mean-square values (RMS) and delays were compared for different filter conditions (none, 8% luminance, 50% luminance, 50% luminance plus blur) in a total of ten participants with normal vision. RESULTS: Reducing stimulus luminance down to 50% and 8% reduced mfERG amplitudes to 86% and 42%, respectively, with no significant effect on mfVEP amplitude. Implicit times were increased for mfERGs by 0.9 ms and 6.0 ms, respectively, and for mfVEPs by 1.0 ms and 6.3 ms, respectively. For '50% luminance plus blur' mfERG amplitudes were significantly reduced centrally and enhanced peripherally and delayed by 1.3 ms. MfVEPs were reduced close to noise level independent of eccentricity. CONCLUSIONS: Degradation of the retinal image is a potential source of discrepancies between mfERGs and mfVEPs. Image blur suppresses the mfVEP at all locations and changes mfERG topography, resulting in a selective loss of central responses. SIGNIFICANCE: Considering optic media opacities is of importance for the correct interpretation of mfERG and mfVEP recordings, particularly in elderly patients. PMID- 23352816 TI - Primary percutaneous coronary intervention in patients with acute myocardial infarction, resuscitated cardiac arrest, and cardiogenic shock: the role of primary multivessel revascularization. AB - OBJECTIVES: This study sought to assess the impact of multivessel (MV) primary percutaneous coronary intervention (PCI) on clinical outcomes in patients with ST segment elevation myocardial infarction (STEMI) presenting with cardiogenic shock (CS) and resuscitated cardiac arrest (CA). BACKGROUND: The safety and efficacy of MV primary PCI in patients with STEMI and refractory CS is unknown. METHODS: We conducted a multicenter prospective observational study of consecutive STEMI patients presenting to 5 French centers. Patients were classified as having single-vessel (SVD) or multivessel (MVD) coronary disease, and underwent culprit only or MV primary PCI. Baseline characteristics and 6-month survival were compared. RESULTS: Among 11,530 STEMI patients, 266 had resuscitated CA and CS. Patients with SVD (36.5%) had increased 6-month survival compared to those with MVD (29.6% vs. 42.3%, p = 0.032). Baseline characteristics were similar in those with MVD undergoing culprit-only (60.9%) or MV (39.1%) primary PCI. However, 6 month survival was significantly greater in patients who underwent MV PCI (43.9% vs. 20.4%, p = 0.0017). This survival advantage was mediated by a reduction in the composite of recurrent CA and death due to shock (p = 0.024) in MV PCI patients. In those with MVD, culprit artery PCI success (hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.41 to 0.96, p = 0.030) and MV primary PCI (HR: 0.57; 95% CI: 0.38 to 0.84, p = 0.005) were associated with increased 6-month survival. CONCLUSIONS: The results of this study suggest that in STEMI patients with MVD presenting with CS and CA, MV primary PCI may improve clinical outcome. Randomized trials are required to verify these results. PMID- 23352817 TI - Angiographic success and procedural complications in patients undergoing percutaneous coronary chronic total occlusion interventions: a weighted meta analysis of 18,061 patients from 65 studies. AB - OBJECTIVES: This study sought to perform a weighted meta-analysis of the complication risk during chronic total occlusion (CTO) percutaneous coronary intervention (PCI). BACKGROUND: The safety profile of CTO PCI has received limited study. METHODS: We conducted a meta-analysis of 65 studies published between 2000 and 2011 reporting procedural complications of CTO PCI. Data on the frequency of death, emergent coronary artery bypass graft surgery, stroke, myocardial infarction, perforation, tamponade, stent thrombosis, major vascular or bleeding events, contrast nephropathy, and radiation skin injury were collected. RESULTS: A total of 65 studies with 18,061 patients and 18,941 target CTO vessels were included. Pooled estimates of outcomes were as follows: angiographic success 77% (95% confidence interval [CI]: 74.3% to 79.6%); death 0.2% (95% CI: 0.1% to 0.3%); emergent coronary artery bypass graft surgery 0.1% (95% CI: 0.0% to 0.2%); stroke <0.01% (95% CI: 0.0% to 0.1%); myocardial infarction 2.5% (95% CI: 1.9% to 3.0%); Q-wave myocardial infarction 0.2% (95% CI: 0.1% to 0.3%); coronary perforation 2.9% (95% CI: 2.2% to 3.6%); tamponade 0.3% (95% CI: 0.2% to 0.5%); and contrast nephropathy 3.8% (95% CI: 2.4% to 5.3%). Compared with successful procedures, unsuccessful procedures had higher rates of death (0.42% vs. 1.54%, p < 0.0001), perforation (3.65% vs. 10.70%, p < 0.0001), and tamponade (0% vs. 1.65%, p < 0.0001). Among 886 lesions treated with the retrograde approach, success rate was 79.8% with no deaths and low rates of emergent coronary artery bypass graft surgery (0.17%) and tamponade (1.2%). CONCLUSIONS: CTO PCI carries low risk for procedural complications despite high success rates. PMID- 23352818 TI - ST-segment elevation myocardial infarction, cardiac arrest, and cardiogenic shock: an interventional triumvirate of opportunity. PMID- 23352819 TI - The safety and outcomes of chronic total occlusion interventions. PMID- 23352820 TI - Same-day discharge compared with overnight hospitalization after uncomplicated percutaneous coronary intervention: a systematic review and meta-analysis. AB - OBJECTIVES: This study sought to evaluate outcomes of same-day discharge (SDD) following percutaneous coronary intervention (PCI) versus overnight hospitalization (ON). BACKGROUND: Although there are data on the safety and feasibility of SDD after PCI, ON continues to be prevalent. METHODS: The Cochrane search strategy was used to search the PubMed database, EMBASE, and the Cochrane Library for relevant literature. Thirteen studies (5 randomized and 8 observational) of SDD after uncomplicated PCI versus ON met inclusion criteria. Data were pooled using a random effects model, and reported as odds ratios (OR) with their 95% confidence intervals (CI). The primary outcomes were incidence of total complications, major adverse cardiovascular events (MACE), and rehospitalization within 30 days after PCI. RESULTS: A total of 13 studies, involving 111,830 patients were pooled. There was significant variation in the definition of outcomes across studies. For total complications, the strategy of SDD compared with ON after PCI had an estimated OR of 1.20 (95% CI: 0.82 to 1.74) in randomized and 0.67 (95% CI: 0.27 to 1.66) in observational studies. Similar results were found for MACE (randomized, OR: 0.99, 95% CI: 0.45 to 2.18; observational, OR: 0.59, 95% CI: 0.06 to 5.57) and rehospitalizations (randomized, OR: 1.10, 95% CI: 0.70 to 1.74; observational, OR: 0.62, 95% CI: 0.10 to 3.98) at 30 days post PCI. CONCLUSIONS: There is considerable heterogeneity across published studies comparing SDD with ON. This, coupled with the low event rate and wide corresponding CIs, suggest that an adequately powered multicenter randomized trial comparing SDD with ON would require a very large sample size (>17,000). Until such a trial is completed, SDD after uncomplicated PCI seems a reasonable approach in selected patients. PMID- 23352821 TI - Same-day discharge after percutaneous coronary intervention: are we ready? PMID- 23352822 TI - From conditioned hypoglycemia to obesity: following the data. AB - While a graduate student in the late 1960s I trained rats to lower their blood glucose in response to an arbitrary cue, a phenomenon called conditioned hypoglycemia. Over many years as my colleagues and I attempted to understand the underlying physiology of conditioned insulin secretion and conditioned hypoglycemia, it became clear that there were many implications that were highly important, including the entry of insulin into the brain, the existence of insulin receptors in certain brain areas, neural reflexes that project to insulin secreting B-cells in the pancreas, the entrainment of those reflexes to improve the efficiency of meal-taking, and the possibility of adiposity signals from the body to the brain that influence behavior and metabolism. This article summarizes how we tackled each of these areas of research. PMID- 23352823 TI - Dependence of simulated positron emitter yields in ion beam cancer therapy on modeling nuclear fragmentation. AB - In ion beam cancer therapy, range verification in patients using positron emission tomography (PET) requires the comparison of measured with simulated positron emitter yields. We found that (1) changes in modeling nuclear interactions strongly affected the positron emitter yields and that (2) Monte Carlo simulations with SHIELD-HIT10Areasonably matched the most abundant PET isotopes (11)C and (15)O. We observed an ion-energy (i.e., depth) dependence of the agreement between SHIELD-HIT10Aand measurement. Improved modeling requires more accurate measurements of cross-section values. PMID- 23352824 TI - Electron scattering cross sections from anthracene over a broad energy range (0.00001-10,000 eV). AB - We report a computational investigation of electron scattering by anthracene (C14H10) in the gas phase. Integral and differential cross sections have been calculated by employing two distinct ab-initio quantum scattering methods: the symmetry adapted-single centre expansion method (ePOLYSCAT) and a screening corrected form of the independent atom model (IAM-SCAR) at low and high energies, respectively. After a detailed evaluation of the current results, we present a complete set of integral scattering cross sections from 0.00001 to 10,000 eV. PMID- 23352825 TI - Anisotropy and charge effect in collisions of ions with biomolecules. AB - Charge transfer dynamics induced by collision of carbon ions with biological targets has been investigated theoretically by means of ab-initio quantum chemistry molecular methods. The series of pyrimidine nucleobases, thymine, uracil and 5-halouracil with similar skeleton and different substituents have been considered. The charge effect between C(6+) and C(4+) carbon ions is analyzed as well as the anisotropy of the electron exchange process. PMID- 23352826 TI - Convenient identification of desulfoglucosinolates on the basis of mass spectra obtained during liquid chromatography-diode array-electrospray ionisation mass spectrometry analysis: method verification for sprouts of different Brassicaceae species extracts. AB - Over the past decade, glucosinolates (GLs) present in different tissues of Brassicaceae and their breakdown products, especially isothiocyanates formed after myrosinase catalyzed hydrolysis, have been regarded as not only environment friendly biopesticides for controlling soilborne pathogens, but most importantly as promising anticarcinogenic compounds. For these reasons, the identification and quantitative determination of the content of individual glucosinolates in plant material is of great interest. Among the different analytical approaches available today for determining GLs in brassica plant samples, HPLC analysis of their desulfo derivatives (DS-GLs) according to ISO 9167-1, 1992, method is the most widely used. However, the notorious lack of commercially available standards limits its usefulness. To overcome these limitations, liquid chromatography electrospray ionisation-mass spectrometry was investigated as a potential method for the identification of DS-GLs. The characteristic pattern of fragmentation either in positive or negative ionisation was established based on mass spectra of 11 DS-GL standards, then proposed for additional over 30 most common desulfated GLs. The applicability of MS detection of DS-GLs was verified for real plant samples, the extracts of 14 kinds of brassica sprouts. The results indicated that this methodology combines a convenient identification of DS-GLs with the well established analytical procedure preferred by many researchers. Thus, incorporation of MS detection into popular ISO method seems to result in an improved and more reliable approach to GLs determination. PMID- 23352827 TI - Influence of cimetidine and its metabolites on Cisplatin--investigation of adduct formation by means of electrochemistry/liquid chromatography/electrospray mass spectrometry. AB - Cimetidine has been studied as an additive in cancer chemotherapy. It is claimed to reduce the side effects of Cisplatin. This study focuses on possible interactions between Cisplatin and cimetidine on the molecular level. Due to the fact that cimetidine is metabolized in the liver, interactions between its metabolites and Cisplatin are also investigated. By means of LC/ESI-MS, Cisplatin cimetidine adducts were detected. In a second step, the metabolism of cimetidine was simulated by electrochemical oxidation. These results were compared with microsomal incubations of cimetidine using rat and human liver cell microsomes. Because the two methods showed a correlation, the electrochemical approach was further used to investigate Cisplatin's interactions with metabolites of cimetidine. However, notable interactions that might take place in the human body could neither be observed for pure cimetidine nor for its metabolites. Finally, the impact of cimetidine on Cisplatin-protein interactions were studied using the model protein beta-lactoglobulin A. In the presence of cimetidine, the affinity of Cisplatin towards the model protein appears to be increased. PMID- 23352829 TI - Peak sweeping and gating using thermal gradient gas chromatography. AB - When axial temperature gradients are applied in gas chromatography (GC), i.e., "thermal gradient GC" (TGGC), the temperature changes both in time and position, T(t,L), along the column, allowing unique control of the movement and elution of sample components. One method of performing TGGC involves introducing a sample into a column with a preset decreasing temperature gradient along its length, waiting for a short time until the sample separates along the gradient, and then raising the temperature to sweep all of the compounds out of the column and into the detector (i.e., "peak sweeping"). This method of operation is demonstrated here using a simple laboratory apparatus based on simultaneous resistive heating and convective cooling. An experimental comparison between isothermal GC (ITGC), temperature programmed GC (TPGC) and TGGC shows that TGGC is essentially equivalent in performance to TPGC operation when using the same column length (peak capacity production rate of 106, 381 and 469 min(-1), respectively); however, narrower peaks and higher signal-to-noise are achieved in TGGC. Furthermore, TGGC helps to minimize band broadening and peak tailing that arise from column adsorption and less than perfect sample injection. The low thermal mass of the TGGC system allows rapid column heating (4000 degrees C/min) and cooling (3500 degrees C/min) for selective separation (i.e., "peak gating") of compounds in a mixture without sacrificing the resolution of earlier or later eluting compounds. PMID- 23352828 TI - The use of ultra-high pressure liquid chromatography with tandem mass spectrometric detection in the analysis of agrochemical residues and mycotoxins in food - challenges and applications. AB - In the field of food contaminant analysis, the most significant development of recent years has been the integration of ultra-high pressure liquid chromatography (UHPLC), coupled to tandem quadrupole mass spectrometry (MS/MS), into analytical applications. In this review, we describe the emergence of UHPLC through technological advances. The implications of this new chromatographic technology for MS detection are discussed, as well as some of the remaining challenges in exploiting it for chemical residue applications. Finally, a comprehensive overview of published applications of UHPLC-MS in food contaminant analysis is presented, with a particular focus on veterinary drug residues. PMID- 23352830 TI - Reversed-phase ion-pair ultra-high-performance-liquid chromatography-mass spectrometry for fingerprinting low-molecular-weight heparins. AB - Heparin is a complex mixture of sulfated linear carbohydrate polymers. It is widely used as an antithrombotic drug, though it has been shown to have a myriad of additional biological activities. Heparin is often partially depolymerized in order to decrease the average molecular weight, as it has been shown that low molecular weight heparins (LMWH) possess more desirable pharmacokinetic and pharmacodynamic properties than unfractionated heparin (UFH). Due to the prevalence of LMWHs in the market and the emerging availability of generic LMWH products, it is important that analytical methods be developed to ensure the drug quality. This work explores the use of tributylamine (TrBA), dibutylamine (DBA), and pentylamine (PTA) as ion-pairing reagents in conjunction with acetonitrile and methanol modified mobile phases for reversed-phase ion-pairing ultraperformance liquid chromatography coupled to mass spectrometry (RPIP-UPLC MS) for fingerprint analysis of LMWH preparations. RPIP-UPLC-MS fingerprints are presented and compared for tinzaparinand enoxaparin. PMID- 23352831 TI - Decreased regional homogeneity in lingual gyrus, increased regional homogeneity in cuneus and correlations with panic symptom severity of first-episode, medication-naive and late-onset panic disorder patients. AB - This study was designed to explore regional homogeneity (ReHo), an indicator of the synchronization of brain function, in first-episode, medication-naive and late-onset patients with panic disorder (PD). Participants comprised 30 patients and 21 healthy controls who underwent with 3-Tesla magnetic resonance imaging (MRI) scanning and ReHo functional MRI analysis. All participants were studied with clinical rating scales to assess the severity of PD symptoms. ReHo values were obtained using the REST toolbox (resting-state functional MRI data analysis toolbox). Differences in demographic data and ReHo values between the two groups were evaluated with the independent two-sample t-test function of the Statistical Package for the Social Sciences and REST. There were significant differences in clinical ratings between the two groups. No demographic differences were noted. We found decreased ReHo in the left lingual gyrus and increased ReHo in the right cuneus cortex of patients compared with controls. ReHo values of patients were negatively correlated with PD ratings in the right cuneus. ReHo differences found in the left lingual gyrus and the right cuneus might suggest sensory and inhibitory dysfunction in first-episode, medication-naive, late-onset patients with PD. PMID- 23352832 TI - Intercellular Ca(2+) wave propagation in human retinal pigment epithelium cells induced by mechanical stimulation. AB - Ca(2+) signaling is vitally important in cellular physiological processes and various drugs also affect Ca(2+) signaling. Thus, knowledge of Ca(2+) dynamics is important toward understanding cell biology, as well as the development of drug testing assays. ARPE-19 cells are widely used for modeling human retinal pigment epithelium functions and drug-testing, but intercellular communication has not been assessed in these cells. In this study, we investigated intercellular Ca(2+) communication induced by mechanical stimulation in ARPE-19 cells. An intercellular Ca(2+) wave was induced in ARPE-19 monolayer by point mechanical stimulation of a single cell. Dynamic changes of intracellular Ca(2+) concentration ([Ca(2+)](i)) in the monolayer were tracked with fluorescence microscopy imaging using Ca(2+)-sensitive fluorescent dye fura-2 in presence and absence of extracellular Ca(2+), after depletion of intracellular Ca(2+) stores with thapsigargin, and after application of gap junction blocker alpha glycyrrhetinic acid and P2-receptor blocker suramin. Normalized fluorescence values, reflecting amplitude of [Ca(2+)](i) increase, and percentage of responsive cells were calculated to quantitatively characterize Ca(2+) wave propagation. Mechanical stimulation of a single cell within a confluent monolayer of ARPE-19 cells initiated an increase in [Ca(2+)](i), which propagated to neighboring cells in a wave-like manner. Ca(2+) wave propagated to up to 14 cell tiers in control conditions. The absence of extracellular Ca(2+) reduced [Ca(2+)](i) increase in the cells close to the site of mechanical stimulation, whereas the depletion of intracellular Ca(2+) stores with thapsigargin blocked the wave spreading to distant cells. The gap junction blocker alpha glycyrrhetinic acid reduced [Ca(2+)](i) increase in the cell tiers close to the site of mechanical stimulation, indicating involvement of gap junctions in Ca(2+) wave propagation. The P2-receptor blocker suramin reduced the percentage of responsive cells participating in Ca(2+) wave spreading beyond the fourth cell tier, showing the necessity of P2-receptors for Ca(2+) wave propagation. In disconnected, i.e., subconfluent, ARPE-19 cell clusters Ca(2+) wave spreading was considerably less efficient compared to that in confluent ARPE-19 monolayer at the same distances. ARPE-19 cells showed repeatable and robust Ca(2+) dynamics after mechanical stimulus. The ARPE-19 cells exhibited two different mechanisms of Ca(2+) wave propagation dependent on the cell location: in the cells close to the site of mechanical stimulation the Ca(2+) wave propagated mainly through gap junctions and required Ca(2+) from both intracellular Ca(2+) stores and extracellular media, while farther away the propagation was more dependent on the purinergic receptors and did not require extracellular Ca(2+). The proposed method could provide a tool to assess the drug-induced changes in intercellular communication in in vitro assays in human retinal pigment epithelial cells. PMID- 23352833 TI - Autocrine CCL2, CXCL4, CXCL9 and CXCL10 signal in retinal endothelial cells and are enhanced in diabetic retinopathy. AB - This study aimed at examining the presence and role of chemokines (angiogenic CCL2/MCP-1 and angiostatic CXCL4/PF-4, CXCL9/Mig, CXCL10/IP-10) in proliferative diabetic retinopathy (PDR). Regulated chemokine production in human retinal microvascular cells (HRMEC) and chemokine levels in vitreous samples from 40 PDR and 29 non-diabetic patients were analyzed. MCP-1, PF-4, Mig, IP-10 and VEGF levels in vitreous fluid from PDR patients were significantly higher than in controls. Except for IP-10, cytokine levels were significantly higher in PDR with active neovascularization and PDR without traction retinal detachment (TRD) than those in inactive PDR, PDR with TRD and control subjects. Exploratory regression analysis identified associations between higher levels of IP-10 and inactive PDR and PDR with TRD. VEGF levels correlated positively with MCP-1 and IP-10. Significant positive correlations were observed between MCP-1 and IP-10 levels. In line with these clinical findings Western blot analysis revealed increased PF 4 expression in diabetic rat retinas. HRMEC produced MCP-1, Mig and IP-10 after stimulation with IFN-gamma, IL-1beta or lipopolysaccharide. IFN-gamma synergistically enhanced Mig and IP-10 production in response to IL-1beta or lipopolysaccharide. MCP-1 was produced by HRMEC in response to VEGF treatment and activated HRMEC via the ERK and Akt/PKB pathway. On the other hand, phosphorylation of ERK induced by VEGF and MCP-1 was inhibited by PF-4, Mig and IP-10. In accordance with inhibition of angiogenic signal transduction pathways, PF-4 inhibited in vitro migration of HRMEC. Thus, regulatory roles for chemokines in PDR were demonstrated. In particular, IP-10 might be associated with the resolution of active PDR and the development of TRD. PMID- 23352834 TI - Sensitizing capacity and allergenicity of enzymatically cross-linked sodium caseinate in comparison to sodium caseinate in a mouse model for cow's milk allergy. AB - A transglutaminase cross-linked caseinate was designed for use in dairy products to increase the viscosity of food matrices. The difference in structure of cross linked caseinate might have implications for the risk of developing cow's milk allergy. The sensitizing capacity and the allergenicity (the potency to induce an allergic effector response) of cross-linked sodium caseinate was investigated using a mouse model for cow's milk allergy. Mice were orally sensitized with cross-linked caseinate or caseinate using cholera toxin as adjuvant. Anaphylactic shock reactions, change in body temperature, acute allergic skin response, caseinate-, cross-linked caseinate-IgE and mMCP-1 concentrations were determined after challenge with cross-linked caseinate or caseinate. Sensitization with cross-linked caseinate did not result in anaphylactic shock symptoms, drop in body temperature or release of serum mMCP-1. A tendency toward decreased casein specific IgE levels was observed. The allergenicity did not differ between both products. These results indicate that in already caseinate-sensitized mice, cross linked caseinate did not provoke more pronounced allergenic reactions compared to sodium caseinate. On top of that, reduced sensitization to cross-linked caseinate was observed. Cross-linked caseinate might therefore be an interesting new dietary concept for humans at risk for food allergy although more mechanistic studies and clinical trials are needed for validation. PMID- 23352835 TI - Subcellular fractionation enhances proteome coverage of pancreatic duct cells. AB - OBJECTIVES: Subcellular fractionation of whole cell lysates offers a means of simplifying protein mixtures, potentially permitting greater depth of proteomic analysis. Here we compare proteins identified from pancreatic duct cells (PaDC) following organelle enrichment to those identified from PaDC whole cell lysates to determine if the additional procedures of subcellular fractionation increase proteome coverage. METHODS: We used differential centrifugation to enrich for nuclear, mitochondrial, membrane, and cytosolic proteins. We then compared - via mass spectrometry-based analysis - the number of proteins identified from these four fractions with four biological replicates of PaDC whole cell lysates. RESULTS: We identified similar numbers of proteins among all samples investigated. In total, 1658 non-redundant proteins were identified in the replicate samples, while 2196 were identified in the subcellular fractionation samples, corresponding to a 30% increase. Additionally, we noted that each organelle fraction was in fact enriched with proteins specific to the targeted organelle. CONCLUSIONS: Subcellular fractionation of PaDC resulted in greater proteome coverage compared to PaDC whole cell lysate analysis. Although more labor intensive and time consuming, subcellular fractionation provides greater proteome coverage, and enriches for compartmentalized sub-populations of proteins. Application of this subcellular fractionation strategy allows for a greater depth of proteomic analysis and thus a better understanding of the cellular mechanisms of pancreatic disease. PMID- 23352837 TI - Position-specific scoring matrix and hidden Markov model complement each other for the prediction of conopeptide superfamilies. AB - Classified into 16 superfamilies, conopeptides are the main component of cone snail venoms that attract growing interest in pharmacology and drug discovery. The conventional approach to assigning a conopeptide to a superfamily is based on a consensus signal peptide of the precursor sequence. While this information is available at the genomic or transcriptomic levels, it is not present in amino acid sequences of mature bioactives generated by proteomic studies. As the number of conopeptide sequences is increasing exponentially with the improvement in sequencing techniques, there is a growing need for automating superfamily elucidation. To face this challenge we have defined distinct models of the signal sequence, propeptide region and mature peptides for each of the superfamilies containing more than 5 members (14 out of 16). These models rely on two robust techniques namely, Position-Specific Scoring Matrices (PSSM, also named generalized profiles) and hidden Markov models (HMM). A total of 50 PSSMs and 47 HMM profiles were generated. We confirm that propeptide and mature regions can be used to efficiently classify conopeptides lacking a signal sequence. Furthermore, the combination of all three-region models demonstrated improvement in the classification rates and results emphasise how PSSM and HMM approaches complement each other for superfamily determination. The 97 models were validated and offer a straightforward method applicable to large sequence datasets. PMID- 23352838 TI - Polyproline tetramer organizing peptides in fetal bovine serum acetylcholinesterase. AB - Acetylcholinesterase (AChE) in the serum of fetal cow is a tetramer. The related enzyme, butyrylcholinesterase (BChE), in the sera of humans and horse requires polyproline peptides for assembly into tetramers. Our goal was to determine whether soluble tetrameric AChE includes tetramer organizing peptides in its structure. Fetal bovine serum AChE was denatured by boiling to release non covalently bound peptides. Bulk protein was separated from peptides by filtration and by high performance liquid chromatography. Peptide mass and amino acid sequence of the released peptides were determined by MALDI-TOF-TOF and LTQ Orbitrap mass spectrometry. Twenty polyproline peptides, divided into 5 families, were identified. The longest peptide contained 25 consecutive prolines and no other amino acid. Other polyproline peptides included one non-proline amino acid, for example serine at the C-terminus of 20 prolines. A search of the mammalian proteome database suggested that this assortment of polyproline peptides originated from at least 5 different precursor proteins, none of which were the ColQ or PRiMA of membrane-anchored AChE. To date, AChE and BChE are the only proteins known that include polyproline tetramer organizing peptides in their tetrameric structure. PMID- 23352840 TI - A novel bottom-up approach to bounding low-dose human cancer risks from chemical exposures. AB - We propose a novel bottom-up approach to the bounding of low-dose human cancer risks from chemical exposures that does not rely at all upon high-dose data for human or animal cancers. This approach can thus be used to provide an independent "reality check" on low-dose risk estimates derived with dose-response models that are fit to high-dose cancer data. The approach (1) is consistent with the "additivity to background" concept, (2) yields central and upper-bound risk estimates that are linear at all doses, and (3) requires only information regarding background risk, background (endogenous) exposure, and the additional exogenous exposure of interest in order to be implemented. After describing the details of this bottom-up approach, we illustrate its application using formaldehyde as an example. Results indicate that recent top-down risk extrapolations from occupational cohort mortality data for workers exposed to formaldehyde are overly conservative by substantial margins. PMID- 23352839 TI - FlgM proteins from different bacteria exhibit different structural characteristics. AB - Intrinsically disordered proteins (IDPs) are a unique class of proteins that do not require a stable structure for function. The importance of IDPs in many biological processes has been established but there remain unanswered questions about their evolution and conservation of their disordered state within a protein family. Our group has been studying the structural similarities among orthologous FlgM proteins, a model class of IDPs. We have previously shown that the FlgM protein from the thermophile Aquifex aeolicus has more structure at A. aeolicus' physiological temperature (85 degrees C) than is observed for the Salmonella typhimurium FlgM, suggesting that the disordered nature of FlgM varies among organisms and is not universally conserved. In this work, we extend these studies to the FlgM proteins from Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, and Bacillus subtilis. We demonstrate that the B. subtilis, E. coli, and S. typhimurium FlgMs exist in a premolten globule-like conformation, though the B. subtilis FlgM is in a more compacted conformation than the other two. The P. aeruginosa and P. mirabilis FlgM proteins exist in a currently unknown conformation that is not either coil-like or premolten globule-like. The P. aeruginosa FlgM appears to contain more weak intramolecular contacts given its more compacted state than the P. mirabilis FlgM. These results provide experimental evidence that members of the same protein family can exhibit different degrees of disorder, though understanding how different disordered states evolve in the same protein family will require more study. PMID- 23352836 TI - Intrinsically disordered regions of p53 family are highly diversified in evolution. AB - Proteins of the p53 family are expressed in vertebrates and in some invertebrate species. The main function of these proteins is to control and regulate cell cycle in response to various cellular signals, and therefore to control the organism's development. The regulatory functions of the p53 family members originate mostly from their highly-conserved and well-structured DNA-binding domains. Many human diseases (including various types of cancer) are related to the missense mutations within this domain. The ordered DNA-binding domains of the p53 family members are surrounded by functionally important intrinsically disordered regions. In this study, substitution rates and propensities in different regions of p53 were analyzed. The analyses revealed that the ordered DNA-binding domain is conserved, whereas disordered regions are characterized by high sequence diversity. This diversity was reflected both in the number of substitutions and in the types of substitutions to which each amino acid was prone. These results support the existence of a positive correlation between protein intrinsic disorder and sequence divergence during the evolutionary process. This higher sequence divergence provides strong support for the existence of disordered regions in p53 in vivo for if they were structured, they would evolve at similar rates as the rest of the protein. PMID- 23352842 TI - In vitro and in vivo inoculation of four endophytic bacteria on Lycopersicon esculentum. AB - Four bacteria selected on the basis of their capability of fixing atmospheric nitrogen, stimulating plant-growth, and protecting the host plant from pathogens Azospirillum brasilense, Gluconacetobacter diazotrophicus, Herbaspirillum seropedicae, Burkholderia ambifaria - were inoculated on tomato seeds either singularly, in couple and in a four bacteria mixer. Aim of this research was to evaluate: (1) effect of single and mixed cultures on the inoculated plant - plant growth, dry weight, root length and surface, number of leaves, among others; (2) colonization and interactions of the bacteria inside the host plant; (3) localization inside the host of single bacterial strains marked with the gusA reporter gene. The results obtained indicate that all selected microbial strains have colonized Lycopersicon esculentum but in a different way, depending on the single species. A. brasilense, G. diazotrophicus inoculated in vitro singularly and together were the best plant colonizers. In vivo essays, instead, B. ambifaria and the four-bacteria mixer gave the best results. It was possible to localize both A. brasilense and H. seropedicae inside the plant by the gusA reporter gene. The bacterial strains occur along the root axis from the apical zone until to the basal stem, on the shoot from the base up to the leaves. The four bacteria actively colonize tomato seeds and establish an endophytic community inside the plant. This review gives new information about colonization processes, in particular how bacteria interact with plants and whether they are likely to establish themselves in the plant environment after field application as biofertilizers or biocontrol agents. PMID- 23352841 TI - A novel four-color fluorescence in situ hybridization assay for the detection of TMPRSS2 and ERG rearrangements in prostate cancer. AB - Since the identification of the TMPRSS2-ERG rearrangement as the most common fusion event in prostate cancer, various methods have been developed to detect this rearrangement and to study its prognostic significance. We report a novel four-color fluorescence in situ hybridization (FISH) assay that detects not only the typical TMPRSS2-ERG fusion but also alternative rearrangements of the TMPRSS2 or ERG gene. We validated this assay on fresh, frozen, or formalin-fixed paraffin embedded prostate cancer specimens, including cell lines, primary prostate cancer tissues, xenograft tissues derived from metastatic prostate cancer, and metastatic tissues from castration-resistant prostate cancer (CRPC) patients. When compared with either reverse transcription-polymerase chain reaction or the Gen-Probe method as the technical reference, analysis using the four-color FISH assay demonstrated an analytical sensitivity of 94.5% (95% confidence interval [CI] 0.80-0.99) and specificity of 100% (95% CI 0.89-1.00) for detecting the TMPRSS2-ERG fusion. The TMPRSS2-ERG fusion was detected in 41% and 43% of primary prostate cancer (n = 59) and CRPC tumors (n = 82), respectively. Rearrangements other than the typical TMPRSS2-ERG fusion were confirmed by karyotype analysis and found in 7% of primary cancer and 13% of CRPC tumors. Successful karyotype analyses are reported for the first time on four of the xenograft samples, complementing the FISH results. Analysis using the four-color FISH assay provides sensitive detection of TMPRSS2 and ERG gene rearrangements in prostate cancer. PMID- 23352843 TI - Perfluorocarbon-loaded lipid nanocapsules as oxygen sensors for tumor tissue pO2 assessment. AB - The assessment of tumor oxygenation is a crucial factor in cancer therapy and may be carried out using fluorine MRI once fluorine probes have been distributed within the tumor. However, the deposit of those highly fluorinated compounds often jeopardizes anatomical image quality and requires emulsification of the probes. Due to the high density and the high lipophilicity of perfluorocarbons, nanoemulsion of these molecules usually requires high-energy processes. In the present work, we discuss the synthesis and the physico-chemical characterization of perfluorocarbon nanocapsules using a low-energy phase-inversion process. The nanocapsules were tested on a mouse tumor brain model to assess oxygenation. PMID- 23352844 TI - Mechanism underlying the effect of combined therapy using glucosamine and low dose cyclosporine A on the development of atopic dermatitis-like skin lesions in NC/Nga mice. AB - Combination therapy is often used in the treatment of atopic dermatitis (AD) to improve clinical efficacy or to spare the dose of each drug. Cyclosporine A (CsA) is a calcineurin inhibitor that was developed for the treatment of AD. Glucosamine (Glu) is a potent immunosuppressant that inhibits Th2-mediated immunity. We previously reported that Glu has an ameliorative effect on the development of the pathology in NC/Nga mice. The aims of our study were to investigate the therapeutic efficacy of combination of Glu and low-dose CsA in dermatophagoides farina (Df)-induced AD-like skin lesions in NC/Nga mice and to determine the underlying therapeutic mechanisms. The Df-induced NC/Nga mice with a clinical score of 7 were used for treatment with Glu (500mg/kg) alone, low-dose CsA (2, 5, and 10mg/kg) or in combination. The clinical scores were reduced significantly by the combination treatment with Glu and low-dose CsA. The suppression of dermatitis by combined therapy was accompanied by decrease in the plasma level of IgE and in the splenic level of IL-4, IL-5, IL-13, TARC and eotaxin. Histological analysis of the skin also revealed that combination treatment significantly reduced the inflammatory cellular infiltrate, including mast cells and eosinophils. Particularly, immunological evaluation reveals an increase of CD4(+)CD25(+) Treg cells in the combined treatment. The induction of TSLP, which leads to systemic Th2 response, was reduced in the skin on combination treatment. The protein expression of filaggrin and involucrin was recovered by combination treatment in the skin lesions, whereas the protein expression of keratin-10 and keratin-14 decreased in the combination treatment. Collectively, our findings suggest that combination treatment of Glu and low-dose CsA leads to the therapeutic effects in Df-induced AD-like skin lesion in NC/Nga mice through inhibition of IgE, inflammatory cellular infiltrate, and recovery of skin barrier function via a mechanism that may inhibition of Th2-mediated immune responses, in part, increment of CD4(+)CD25(+) Treg cells. These results suggest that this combined immunosuppressive treatment may provide important implications for the design of therapeutic strategies aimed at AD treatment. PMID- 23352845 TI - Cytotoxic cholesta-1,4-dien-3-one derivatives from soft coral Nephthea sp. AB - Five new steroids, (12beta, 22R)-12-acetoxy-22-hydroxy-cholesta-1,4-dien-3-one (1), (12beta, 22R)-12-hydroxy-22-acetoxy-cholesta-1, 4-dien-3-one (2), (12beta, 22R)-12, 22-diacetoxy-cholesta-1, 4-dien-3-one (3), (22R)-18, 22-diacetoxy cholesta-1, 4-dien-3-one (4), (20R, 22R)-20-hydroxy-22-acetoxy-cholesta-1, 4-dien 3-one (5), and one known steroid astrogorgol N (6), were isolated from soft coral Nephthea sp. Their structures were established by spectroscopic analysis (1D, 2D NMR, HRMS) and comparisons of their spectral data with those of related steroids. The absolute configuration at C-22 of 1 was determined to be R by Mosher's analysis. All isolated compounds exhibited cytotoxic activity against HeLa cells with IC50 values ranged from 7.51+/-0.22 to 18.72+/-0.78MUg/mL. PMID- 23352846 TI - Great saphenous vein harvesting for venous outflow reconstruction in living donor liver transplantation - a minimally invasive refinement of the conventional procedure. AB - BACKGROUND: With the popularization of living donor liver transplantation (LDLT), it has been discovered that adequate venous outflow from the transplanted liver is crucial for proper graft function. Recently, the harvesting of the LDLT recipient's autologous great saphenous vein (GSV) has been increasingly adopted as a solution to the shortage of cadaveric vascular grafts. Minimally invasive GSV harvesting for coronary artery bypass grafting was shown to improve the cosmetic result and reduce leg wound pain and other complications. For immunosuppressed patients such as LDLT recipients, these benefits could be especially valuable. MATERIALS AND METHODS: From April to August 2012, eleven LDLT recipients underwent either minimally invasive or short-incision harvesting of GSV. The patient profiles, operative and postoperative information regarding operation time, estimated blood loss, harvested GSV graft length, serum tacrolimus (FK506) levels and postoperative complications were recorded prospectively. RESULTS: The only wound complication was a subcutaneous hematoma, in our fourth patient. The mean operation time and the mean estimated blood loss were 33.9 min and 7.3 ml respectively. The mean incision length divided by the mean vein graft length was 31.6%. Two patients had poorly controlled diabetes mellitus. The mean serum FK506 level during the first postoperative week was 6.4 ng/ml (therapeutic range 5-10 ng/ml according to our protocol). No patient had surgical site infection in this series. CONCLUSIONS: GSV harvesting from LDLT recipients for hepatic venous outflow reconstruction is feasible without the need for expensive endoscopic systems, and an adequate length of vein can be obtained through a single 3 cm incision. PMID- 23352847 TI - Can pre-operative computed tomography predict the need for a thoracic approach for removal of retrosternal goitre? AB - A best evidence topic was written according to a structured protocol. The question addressed was whether in patients with retrosternal goitre the need for a thoracic approach can be predicted using pre-operative CT. A total of 381 papers were identified using the reported search protocol of which 7 represented the best evidence to answer the clinical question. The authors, journal, date, country of publication, patient group studied, study type, relevant outcomes and results are tabulated. The evidence on this subject is poor, none of the studies were randomised, only one used controls (historical) and all studies were retrospective. Despite these limitations, CT represents the gold-standard imaging modality in the pre-operative evaluation of patients with retrosternal goitre. CT is essential to define the extent and position of a retrosternal goitre. The literature suggests that CT is the single most valuable pre-operative investigation predicting whether a sternotomy or lateral thoracotomy will be necessary for removal of the retrosternal goitre. Although pre-operative CT does not have the precision to predict whether a thoracic approach is required in all cases, the presence of certain radiological features such as extension of the goitre below the aortic arch or into the posterior mediastinum, a dumbbell shape and a thoracic component that is wider than the thoracic inlet are all associated with the need for a thoracic approach. In some cases a pre-operative CT will not only determine that a thoracic approach is mandatory but it will also guide the surgeon upon the type of thoracic approach. PMID- 23352849 TI - Gender differences in detecting unanticipated stimuli: an ERP study. AB - The aim of the present study was to investigate the gender differences during an emotional anticipation task. Sixteen females and sixteen males participated in the experiment. Event-related potentials (ERPs) were measured in a modified cue target paradigm and were recorded following stimuli that differed in two dimensions: (1) predictable vs. unpredictable pictures and (2) negative vs. neutral pictures. Cue-induced ERP results demonstrated that females had enhanced positive component (P2) compared to males. Moreover, results showed that during the unpredictable condition, females displayed larger P2 amplitudes in negative and neutral anticipation than males. This study demonstrates that females have greater sensitivity to the unanticipated stimuli, which may contribute to evolution. PMID- 23352848 TI - Locally-generated acetaldehyde is involved in ethanol-mediated LTP inhibition in the hippocampus. AB - Consistent with the ability of severe alcohol intoxication to impair memory, high concentrations of ethanol (60mM) acutely inhibit long-term potentiation (LTP) in the CA1 region of rat hippocampal slices. To account for this, we hypothesized that local metabolism to acetaldehyde may contribute to the effects of high ethanol on synaptic function. However, sodium azide, a catalase inhibitor, and allyl sulfide, an inhibitor of cytochrome P450 2E1 (CYP2E1), failed to overcome LTP inhibition by 60mM ethanol. In contrast, LTP was successfully induced in the presence of ethanol plus 4-methylpyrazole (4MP), an inhibitor of alcohol dehydrogenase, suggesting that local metabolism via alcohol dehydrogenase contributes to synaptic effects. Furthermore, exogenously administered acetaldehyde overcame the effects of 4MP on LTP inhibition mediated by ethanol. These observations indicate that acetaldehyde generated by local metabolism within the hippocampus participates in the synaptic dysfunction associated with severe alcohol intoxication. PMID- 23352850 TI - Identification of a NEP1-35 recognizing peptide that neutralizes CNS myelin inhibition using phage display library. AB - Nogo-A has been identified as an inhibitory molecule to neurite outgrowth after injury in adult mammalian central nervous system (CNS). The C-terminal fragment of Nogo-A, Nogo-66, inhibits axonal regrowth through NgR1 signaling. Residues 1 32 of Nogo-66 cover two regions that contribute most affinity of Nogo-66 to NgR1. It is unclear whether blocking the two regions with specific small ligands could neutralize the inhibition of Nogo-66. Therefore in this study we explored two phage display peptide libraries to screen small peptides that might bind Nogo-66. NEP1-35 containing 1-33 residues of Nogo-66 was taken as the target for panning. We found that phage-borne peptides with stronger affinity to NEP1-35 contained a relatively conserved motif, RRXXXXXXXRRX. Afterwards one identified peptide, NH(2)-RRQTLSHQMRRP-COOH was synthesized and tested in neurite outgrowth assay, in which this small molecule showed moderate ability to neutralize CNS myelin inhibition in vitro. Our results demonstrated that short peptides could act as adaptors to Nogo-66 and neutralize CNS myelin inhibition in vitro. Additionally, the results also suggested that phage display could help to discover novel small molecules with high affinity to CNS regrowth inhibitors, which might be able to promote CNS regeneration with fewer side effects since they could block only the corresponding regions of inhibitors. PMID- 23352851 TI - The impulsivity behavior is correlated with prefrontal cortex gray matter volume reduction in heroin-dependent individuals. AB - PURPOSE: Chronic exposure to heroin induced cerebral structural abnormalities may underlie heroin-related behaviors. The aim of this study was to: (1) identify cerebral structural abnormalities in heroin-dependent individuals (HDIs) by an automated and unbiased morphometric technique. (2) Define the correlation between these cerebral structural abnormalities and the impulsivity characteristic in HDIs. METHODS: 24 HDIs and 24 control subjects were completed with (1) high resolution structural magnetic resonance imaging scanning and analysis of gray matter volume using voxel-based morphometry implemented in Statistical Parametric Mapping and (2) a Chinese translation Barratt Impulsiveness Scale-11 questionnaire survey. Differences in regional gray matter volume were tested using an analysis of covariance model, co-varying for global gray matter and age. Statistical maps were set at p<0.05, corrected for multiple comparisons. The abnormal brain regions were correlated with the duration of heroin use and impulsivity scores. RESULTS: After adjusting for effects of age and total gray matter volume, cortical gray matter volume in the bilateral medial prefrontal cortex, bilateral dorsal lateral prefrontal cortex, and right fusiform cortex were significantly reduced in HDIs. Moreover, the gray matter volume in prefrontal cortex that showed group differences was negatively correlated with the duration of heroin use and negatively correlated with the impulsivity characteristic in HDIs. CONCLUSION: These findings reveal the prefrontal cortex was impaired in HDIs, meanwhile, indicate the changes in gray matter volume are relating to the duration of heroin use and the impulsivity characteristic of the HDIs. PMID- 23352852 TI - Acute cocaine increases phosphorylation of CaMKII and GluA1 in the dorsolateral striatum of drug naive rats, but not cocaine-experienced rats. AB - Transport of GluA1-containing AMPA glutamate receptors to synapses in the nucleus accumbens, a process that involves phosphorylation of key serine residues by CaMKII, is associated with the reinstatement of cocaine-seeking behavior. A growing body of evidence indicates that the dorsal striatum contributes to aspects of cocaine addiction. However, the potential role of CaMKII-mediated phosphorylation of GluA1 subunits in the dorsolateral (DL) striatum during cocaine reinstatement has not been examined. In this study, rats were trained to self-administer cocaine and were partnered with saline-yoked rats that received injections of saline. Following extinction, each pair of rats received either a systemic priming injection of cocaine (10mg/kg, i.p.) or saline. As expected, cocaine-experienced rats displayed robust reinstatement of cocaine seeking in response to a challenge injection, whereas yoked saline controls did not. The DL striatum was dissected immediately following the reinstatement test session. Results from Western blotting experiments showed increased pGluA1-ser831 and pCaMKII-thr286 in the DL striatum of saline-yoked rats given an acute injection of cocaine. This effect was absent in cocaine-experienced rats that received a saline injection, and no changes were observed following a priming injection of cocaine in cocaine-experienced rats. These results indicate that acute exposure to cocaine in drug naive rats increased CaMKII-mediated phosphorylation of GluA1 containing AMPA receptors in the DL striatum, an effect that was not observed during cocaine priming-induced reinstatement of drug seeking. It is possible; therefore, that increased phosphorylation of CaMKII and GluA1 following acute cocaine is a compensatory mechanism in the DL striatum. PMID- 23352853 TI - Production and characterization of chimeric anti-HLA monoclonal antibodies targeting public epitopes as tools for standardizations of the anti-HLA antibody detection. AB - Two chimeric monoclonal antibodies (MoAbs) were designed with variable parts of the mouse antibodies W6/32 and F3.3, and the human constant parts C-gamma1 and C kappa. These chimeric MoAbs are specific for HLA-class I and HLA-class II public epitopes, respectively. The anti-class I MoAb recognizes all HLA-class I tested so far, and the anti-class II MoAb recognize all HLA-DR, DP, and only DQ antigens of the DQ2 subgroup. These Moabs were used as positive controls in routine tests for the detection of IgG anti-HLA antibodies in the sera of patients (Luminex, flow cytometry, and complement-dependent lymphocytotoxicity assay: CD-LCT). In tests with the LABScreen MIX assay, serial dilutions of the two MoAbs have allowed to determine the thresholds of detection by the Boltzmann sigmoidal regression. The thresholds of detection in mean of fluorescence intensity (MFI) were 926 and 866 for the anti-class I MoAb and the anti-class II MoAb, respectively. The thresholds defined as mean+3SD of MFI values obtained with 30 negative control sera were 411 and 251 for the anti-class I beads and the anti class II beads, respectively. For the daily validation of the anti-HLA IgG antibodies screening by LABScreen MIX we decided to use the positive control MoAbs at three concentrations (5, 50, and 500ng/ml) and we measured the repeatability (<10%) and reproducibility (<16%) of the method. Used as positive controls in tests with the LABScreen Single Antigen kit, the two MoAbs allowed to estimate daily the quality of beads coated with HLA antigens. The two anti HLA MoAbs were also used as positive control in the cross-match assay by flow cytometry or CD-LCT. In total these two chimeric anti-HLA-MoAbs, which have no equivalent so far, are valuable positive controls for the daily validations of most techniques used for the detection of anti-HLA antibodies according to the good practice guidelines for laboratories. PMID- 23352855 TI - Radiofrequency ablation for liver metastasis from gastrointestinal stromal tumor. AB - PURPOSE: To evaluate the feasibility, safety, and clinical outcomes of radiofrequency (RF) ablation for the treatment of liver metastases from gastrointestinal stromal tumor (GIST). MATERIALS AND METHODS: Seven consecutive patients with 21 GIST liver metastases received RF ablation under computed tomographic (CT) fluoroscopic guidance. Liver metastases were solitary in two patients and multiple in five patients, with a mean maximum tumor diameter of 2.2 cm+/-1.1 (range, 1.2-4.2 cm). In addition to feasibility and safety, local tumor progression and overall and GIST-related survival associated with RF ablation were assessed. RESULTS: All liver metastases were treated in 12 RF sessions, after which contrast-enhanced CT showed disappearance of tumor enhancement. No RF procedure-related complications occurred. Local tumor progression developed in one tumor (4.8%) during the mean follow-up period of 30.6 months+/-27.5 (range, 5.9-76.4 mo). New liver metastasis in untreated liver and lung metastasis developed in one patient each. One patient died of subarachnoid hemorrhage 5.9 months after RF ablation, but no GIST-related deaths occurred. The respective overall and GIST-related survival rates were 85.7% (95% confidence interval, 33.6%-97.8%) and 100% at 1, 3, and 5 years. CONCLUSIONS: RF ablation is a feasible, safe, and useful therapeutic option for the treatment for GIST liver metastases. PMID- 23352854 TI - Adenylylation of mycobacterial Glnk (PII) protein is induced by nitrogen limitation. AB - PII proteins are pivotal regulators of nitrogen metabolism in most prokaryotes, controlling the activities of many targets, including nitrogen assimilation enzymes, two component regulatory systems and ammonium transport proteins. Escherichia coli contains two PII-like proteins, PII (product of glnB) and GlnK, both of which are uridylylated under nitrogen limitation at a conserved Tyrosine 51 residue by GlnD (a uridylyl transferase). PII-uridylylation in E. coli controls glutamine synthetase (GS) adenylylation by GlnE and mediates the NtrB/C transcriptomic response. Mycobacteria contain only one PII protein (GlnK) which in environmental Actinomycetales is adenylylated by GlnD under nitrogen limitation. However in mycobacteria, neither the type of GlnK (PII) covalent modification nor its precise role under nitrogen limitation is known. In this study, we used LC-Tandem MS to analyse the modification state of mycobacterial GlnK (PII), and demonstrate that during nitrogen limitation GlnK from both non pathogenic Mycobacterium smegmatis and pathogenic Mycobacterium tuberculosis is adenylylated at the Tyrosine-51 residue; we also show that GlnD is the adenylyl transferase enzyme responsible. Further analysis shows that in contrast to E. coli, GlnK (PII) adenylylation in M. tuberculosis does not regulate GS adenylylation, nor does it mediate the transcriptomic response to nitrogen limitation. PMID- 23352856 TI - Evaluation of a multimodality MR/US coregistration system for investigation of hepatic metastases from colorectal cancer. AB - PURPOSE: To evaluate a magnetic resonance (MR)/ultrasound (US) coregistration system with US used in follow-up diagnostic studies of lesions originally identified by MR imaging. MATERIALS AND METHODS: A single-center prospective study enrolled 21 consecutive patients (age, 64.0 y+/-7.5; eight men [age, 63.0 y+/-7.1] and 13 women [age, 65.0 y+/-7.3]) evaluated for potential surgical resection of liver metastases. Each patient underwent same-day MR examination and two US examinations: one regular and one with the MR/US coregistration system. Target lesions were identified on MR imaging, and US was used in follow-up diagnostic studies of lesions originally identified by MR imaging. During US, two outcome measures (target localization success and target localization time) were collected. Ratios of lesions found per patient were compared with a paired Wilcoxon test, and a Student t test was used to compare target localization time. RESULTS: Ratios of lesions found per patient with the coregistered system (93.7%) and conventional US (73.3%) were statistically different (P =.003). Lesions found by the coregistration system but not conventional US were statistically smaller than those found by both systems (6.1 mm+/-4.0 vs 15.6 mm+/-9.8; P<.0006). There was no statistical difference in target localization time for detection of lesions found by coregistered (100 s+/-89) and conventional US (108 s+/-86; P = .78). CONCLUSIONS: The MR/US coregistration system increases the number of lesions detected with US versus standard US alone. This may prove beneficial in surgical and nonsurgical management of patients with focal liver lesions. PMID- 23352857 TI - Improved dissolution rate and oral bioavailability of lovastatin in red yeast rice products. AB - Lovastatin, categorized as a class II compound according to the Biopharmaceutics Classification System, is mainly responsible for the blood cholesterol lowering effect of red yeast rice (RYR). The aim of this study was to compare the dissolution rate, physical state, and oral bioavailability of lovastatin in three RYR products (LipoCol Forte, Cholestin, or Xuezhikang) to those of two lovastatin tablets (Mevacor or Lovasta). The results showed that the dissolution rate of lovastatin in various dissolution media in the registered RYR products was faster and higher than that of lovastatin in lovastatin tablets. Powder X-ray diffraction and differential scanning calorimetry patterns showed that the crystallinity of lovastatin was reduced in RYR products. In human studies, the AUC and Cmax values for both lovastatin and its active metabolite, lovastatin acid, were significantly higher in volunteers receiving LipoCol Forte capsules or powder than in those receiving lovastatin tablets or powder. In addition, shorter and less variable Tmax values were observed in volunteers taking LipoCol Forte than in those taking lovastatin tablets. These findings suggest that the oral bioavailability of lovastatin is significantly improved in RYR products as a result of a higher dissolution rate and reduced crystallinity. PMID- 23352858 TI - A thermosensitive morphine-containing hydrogel for the treatment of large-scale skin wounds. AB - PURPOSE: Topically applied opioids are an option to induce efficient analgesia in patients with severe skin wounds. For ongoing pain reduction, the vehicle should provide sustained drug release in order to increase the intervals during the regular wound dressing changes. In addition, the formulation should not impair wound healing. Hydrogels provide a moist wound environment, which is known to facilitate the healing process. METHODS AND RESULTS: Investigating poloxamer hydrogels as a carrier system for morphine in terms of release behavior and (per )cutaneous absorption, poloxamer 407 25wt.% hydrogel sustained morphine release up to 24h. The drug release rate decreased with increasing concentration of the gel forming triblock copolymer. Poloxamer 407 25wt.% hydrogel retarded morphine uptake into reconstructed human skin and percutaneous drug absorption compared to a hydroxyethyl cellulose reference gel. CONCLUSIONS: The results of our in vitro study indicate that the thermosensitive poloxamer 407 25wt.% hydrogel is an appropriate carrier system for the topical application of morphine with regard to sustained drug release and ongoing analgesia. PMID- 23352859 TI - Gas-phase synthesis of solid state DNA nanoparticles stabilized by l-leucine. AB - Aerosol flow reactor is used to generate solid-state nanoparticles in a one-step process that is based on drying of aerosol droplets in continuous flow. We investigated the applicability of aerosol flow reactor method to prepare solid state DNA nanoparticles. Precursor solutions of plasmid DNA with or without complexing agent (polyethylenimine), coating material (l-leucine) and mannitol (bulking material) were dispersed to nanosized droplets and instantly dried in laminar heat flow. Particle morphology, integrity and stability were studied by scanning electron microscopy. The stability of DNA was studied by gel electrophoresis. Plasmid DNA as such degraded in the aerosol flow process. Complexing agent protected DNA from degradation and coating material enabled production of dispersed, non-aggregated, nanoparticles. The resulting nanoparticles were spherical and their mean diameter ranged from 65 to 125nm. The nanoparticles were structurally stable at room temperature and their DNA content was about 10%. We present herein the proof of principle for the production of dispersed solid state nanoparticles with relevant size and intact plasmid DNA. PMID- 23352860 TI - Atypical presentation of a wandering spleen in niemann-pick disease. PMID- 23352861 TI - Emergency physician coverage of in-hospital codes. PMID- 23352862 TI - Perceived roles of Emergency Department physicians regarding anticipatory guidance on firearm safety. AB - BACKGROUND: Several professional medical societies advocate for firearm safety counseling with patients. Little is known about Emergency Physicians' practices and perceptions of firearm safety counseling. OBJECTIVE: To assess Emergency Physicians' beliefs regarding firearm control and their confidence in counseling patients on firearm safety. METHODS: A national random sample (n = 500) of the members of the American College of Emergency Physicians was sent a valid and reliable questionnaire on firearm safety counseling. RESULTS: Of the 278 (56.8%) responding physicians, those who were non-white and those who were not members of the National Rifle Association (NRA) perceived firearm violence to be more of a problem than white physicians and those who were members of the NRA. The majority did not believe that patients would view them as a good source of information on firearm safety (63.3%) or that patients would accept them providing anticipatory firearm safety guidance (56.5%). The majority of the Emergency Department physicians did not believe firearm safety counseling would impact firearm-related homicides (75.2%) or suicides (70%). CONCLUSIONS: The vast majority of Emergency Physicians had never been formally trained regarding firearm safety counseling, did not believe patients would see them as credible sources, and did not believe that anticipatory guidance on firearm safety would have any impact. These data may help inform Emergency Medicine residency programs on the training needs of residents regarding anticipatory guidance on firearm safety. PMID- 23352863 TI - Images in emergency medicine: sonographic evaluation of hepatic hydatid cyst. PMID- 23352864 TI - The prevalence of quality issues and adverse outcomes among 72-hour return admissions in the emergency department. AB - BACKGROUND: Records of patients discharged from the Emergency Department (ED) who return within 72 h and are admitted are often reviewed for potential quality issues. OBJECTIVES: We explored 72-h return admissions and determined the prevalence and predictors for substandard management on the initial visit or any adverse outcome. METHODS: Retrospective review of quality assurance data from 72 h return admissions in three hospitals from 2006-2010 was performed. Any substandard quality on the first visit or change in outcome on the return admission was considered "low quality." Multivariate logistic regression was used to assess the relationship between cases judged as low quality vs. not low quality. RESULTS: Of 741,132 ED visits across 5 years, 3682 (0.5%) were 72-h return admissions. Of those, 192 (5%) were low quality. In 158 (4%) and 8 (0.2%) there were moderate and severe deviations from care standards, respectively. Similarly, in 53 (1%) and 14 (0.4%) there were moderate and severe changes in outcome. In adjusted analysis, there were higher rates of low-quality 72-h return admissions in ambulance arrivals (odds ratio [OR] 1.5, 95% confidence interval (CI) 1.1-2.1); and lower rates in Medicaid patients (OR 0.3, 95% CI 0.2-0.7). There were higher rates in low-quality 72-h return admissions in hospital 1 (OR 3.6, 95% CI 2.2-6.1) and hospital 3 (OR 3.2, 95% CI 2.0-4.7) compared to hospital 2. CONCLUSIONS: Poor care on the initial visit or any poor outcome upon returning in 72-h return admissions is relatively rare in the ED. Reporting 72-h return admissions without chart review may not be a good way to measure clinical quality. PMID- 23352865 TI - Subacute infrarenal aortic occlusion. PMID- 23352866 TI - Emergency diagnosis of subarachnoid hemorrhage: an evidence-based debate. AB - BACKGROUND: The diagnosis of subarachnoid hemorrhage is of paramount concern in patients presenting to the Emergency Department (ED) with acute headache. Computed tomography followed by lumbar puncture is a time-honored practice, but recent technologic advances in magnetic resonance imaging with magnetic resonance angiography and computed tomography with computed tomography angiography can present alternatives for clinicians and patients. OBJECTIVE: The aim of this article was to compare diagnostic strategies for ED patients in whom subarachnoid hemorrhage is suspected. METHODS: We analyze and discuss current protocols, in addition to summarizing the advantages and disadvantages of each method. RESULTS: Through our residency's journal club, we organized an evidence-based debate that pitted proponents of the three subarachnoid hemorrhage diagnostic strategies against one another. Proponents of each strategy described its advantages and disadvantages. Briefly, computed tomography/lumbar puncture is time honored and effective, but is limited by complications and indeterminate lumbar puncture results. Magnetic resonance imaging with magnetic resonance angiography might be more effective in late presentations and can visualize aneurysms, yet has limited availability. Computed tomography with computed tomography angiography offers rapid diagnosis and is considered the most sensitive for diagnosing aneurysms, but has the highest radiation exposure. CONCLUSIONS: Each of the three strategies used to diagnose subarachnoid hemorrhage has advantages and disadvantages with which clinicians should be familiar. Patient factors (e.g., age, body habitus, and risk factors), presentation factors (e.g., time from headache onset and severity of presentation), and institutional factors (availability of magnetic resonance imaging with magnetic resonance angiography) can influence the choice of protocol. PMID- 23352867 TI - Upregulation of chicken TLR4, TLR15 and MyD88 in heterophils and monocyte-derived macrophages stimulated with Eimeria tenella in vitro. AB - Coccidiosis, caused by Eimeria parasites, is a major parasitic disease responsible for great economic losses in the poultry industry. Toll-like receptor (TLR) family is one of the most important innate immune receptors, which involved in pathogen detection by initiating host responses, and it plays important roles in the reduction and clearance of pathogens. Very little information is available about the roles of chicken TLRs (ChTLRs) during Eimeria tenella infection. In the current study, mRNA expression of ChTLRs and associated signal adaptors in heterophils and monocyte-derived macrophages stimulated with E. tenella in vitro were measured by real-time quantitative polymerase chain reaction. The results showed that ChTLR4 and ChTLR15 expression were increased significantly in heterophils and monocyte-derived macrophages following live E. tenella sporozoites stimulation. The heat-killed E. tenella sporozoites stimulated higher expression of ChTLRs and signal adaptors than live sporozoites, the expression of ChTLR4, ChTLR15 and MyD88 in heterophils and monocyte-derived macrophages stimulated with heat-killed E. tenella sporozoites were up-regulated significantly than unstimulated cells. The results suggest that ChTLR4 and ChTLR15 are involved in response to E. tenella infection, and may operate in a MyD88-dependent manner for host defense. PMID- 23352868 TI - Effect of reactive bed mineralogy on arsenic retention and permeability of synthetic arsenic-containing acid mine drainage. AB - Successive alkalinity producing systems (SAPSs) are widely used for treating acid mine drainage (AMD) and alleviating clogging commonly occurring in limestone systems due to an amorphous ferric precipitate. In this study, iron dust, bone char, micrite and their admixtures were used to treat arsenic-containing AMD. A particular interest was devoted to arsenic removal performance, mineralogical constraints on arsenic retention ability and permeability variation during column experiment for 140 days. The results showed that the sequence of the arsenic removal capacity was as follows: bone char > micrite > iron dust. The combination of 20% v/v iron dust and 80% v/v bone char/micrite columns can achieve better hydraulic conductivity and phosphorus-retention capacity than single micrite and bone char columns. The addition of iron dust created reductive environment and resulted in the transformation of coating material from colloidal phase to secondary mineral phase, such as green rust and phosphoerrite, which obviously ameliorates hydraulic conductivity of systems. The sequential extraction experiments indicated that the stable fractions of arsenic in columns were enhanced with help of iron dust compared to single bone char and micrite columns. A combination of iron dust and micrite/bone char represented a potential SAPS for treating As-containing AMD. PMID- 23352869 TI - Localization and reactivity of a hydrophobic solute in lecithin and caseinate stabilized solid lipid nanoparticles and nanoemulsions. AB - The distribution and reactivity of the lipophilic spin probe 4-phenyl-2,2,5,5 tetramethyl-3-imidazoline-1-oxyl nitroxide (PTMIO) in tetradecane (C14)- and eicosane (C20)-in-water emulsions and solid lipid nanoparticles (SLN) respectively, were investigated by electron paramagnetic resonance (EPR) spectroscopy. The lipid phase (10 wt% C14 or C20) was emulsified into either caseinate solutions (1 wt%) or lecithin+bile salt dispersions (2.4 wt%+0.6 wt%) at 70-75 degrees C. In C14 emulsions stabilized with lecithin+bile salt, three populations of PTMIO were observed: a population in the lipid phase (~60%, a(N)~13.9 G), an aqueous phase population (~20%, a(N)~15.4 G) with high mobility, and an immobilized surface layer population (~20%, a(N)~14.2 G) with low mobility. However, in C14 emulsions stabilized by caseinate, only two distinct populations of PTMIO were seen: a lipid phase population (~70%, a(N)~13.8 G) and an aqueous phase population (~30%, a(N)~15.5 G) with high mobility. In C20 SLN stabilized with either lecithin+bile salt or caseinate, PTMIO was excluded from the lipid phase. In lecithin+bile salt-stabilized C20 SLN, the majority of the probe (~77%) was in the interfacial layer. For both surfactant systems the rate of PTMIO reduction by aqueous iron/ascorbate was greater for C20 SLN than C14 emulsions. Lecithin affects the properties of emulsions and SLN as delivery systems by providing a distinct environment for small molecules. PMID- 23352870 TI - Tensiometric determination of Gibbs surface excess and micelle point: a critical revisit. AB - Amphiphile adsorption at the air/water interface lowers the surface tension (gamma) of the solution. After a critical surfactant concentration (C), gamma becomes constant (with a break in the gamma-logC plot), which is considered the critical micelle concentration (CMC). At very low amphiphile concentration, gamma decreases slowly, forming a plateau, then decreases sharply and often nonlinearly by a co-operative adsorption process till the second plateau is reached at CMC. To get the Gibbs surface excess (Gamma) of the amphiphile relative to water, a polynomial equation of appropriate degree needs to be used, since the drop in gamma progresses with continuous changing slope, which maximizes at CMC and becomes zero afterward. Recent research has evidenced that a complete saturated Gibbs monolayer may not always form at CMC; there may be formation of multilayer of micelles below the Gibbs monolayer, which cannot be assessed by ST measurements. A method like neutron reflectometry (NR) can evaluate the Gamma beyond CMC. A procedure for determining Gamma(max) from tensiometric results is herein proposed. Amphiphiles do sometimes show a linear decline in gamma with logC followed by a break with a plateau at CMC. There, a single slope leading to a single surface excess quantity is obtained for the Gibbs equation at all concentrations up to CMC. Possible reasons for such results are given. Current conflicting ideas and criticisms on the issue of Gibbs equation and determination of Gamma and Gamma(max) have been addressed. PMID- 23352871 TI - New catanionic surfactants with ionic liquid properties. AB - A systematic study of the physico-chemical properties of a series of new catanionic surfactants with ionic liquid properties is reported. Importantly, by avoiding environmentally unfriendly halide and imidazolium based moieties highly tunable surfactant ionic liquids have been prepared. PMID- 23352872 TI - Influence of acrylic superplasticizer and cellulose-ether on the kinetics of tricalcium silicate hydration reaction. AB - This paper reports on the analysis of the hydration kinetics of a tricalcium silicate paste cured in presence of polymers industrially used in the extrusion process of mortars. In particular, we investigated the effect of a rheology modifying additive (a methyl hydroxy ethyl cellulose) and a superplasticizer (a polyacrylic polymer). These polymers have been added to tricalcium silicate paste, both separately and together, to understand their distinct influence on the tricalcium silicate hydration and their possible synergies. The kinetic curves have been monitored from 10 to 40 degrees C by means of Differential Scanning Calorimetry and fitted using the generalized Boundary Nucleation and Growth Model combined to a diffusion-limited model, to extract: induction times, reaction rates, activation energies and diffusion coefficients. As a main result, this paper contributes to the advancement of the knowledge in the field of the extrusion process of cementitious materials, providing a thermodynamic support to the empirical evaluations of the additives performances. PMID- 23352873 TI - Driving force for the hydration of the swelling clays: case of montmorillonites saturated with alkaline-earth cations. AB - Important structural modifications occur in swelling clays upon water adsorption. The multi-scale evolution of the swelling clay structure is usually evidenced by various experimental techniques. However, the driving force behind such phenomena is still not thoroughly understood. It appears strongly dependent on the nature of the interlayer cation. In the case of montmorillonites saturated with alkaline cations, it was inferred that the compensating cation or the layer surface could control the hydration process and thus the opening of the interlayer space, depending on the nature of the interlayer cation. In the present study, emphasis is put on the impact of divalent alkaline-earth cations compensating the layer charge in montmorillonites. Since no experimental technique offers the possibility of directly determining the hydration contributions related to interlayer cations and layer surfaces, an approach based on the combination of electrostatic calculations and immersion data is developed here, as already validated in the case of montmorillonites saturated by alkaline cations. This methodology allows to estimate the hydration energy for divalent interlayer cations and therefore to shed a new light on the driving force for hydration process occurring in montmorillonites saturated with alkaline-earth cations. Firstly, the surface energy values obtained from the electrostatic calculations based on the Electronegativity Equalization Method vary from 450 mJ m(-2) for Mg montmorillonite to 1100 mJ m(-2) for Ba-montmorillonite. Secondly, considering both the hydration energy for cations and layer surfaces, the driving force for the hydration of alkaline-earth saturated montmorillonites can be attributed to the interlayer cation in the case of Mg-, Ca-, Sr-montmorillonites and to the interlayer surface in the case of Ba-montmorillonites. These results explain the differences in behaviour upon water adsorption as a function of the nature of the interlayer cation, thereby allowing the macroscopic swelling trends to be better understood. The knowledge of hydration processes occurring in homoionic montmorillonites saturated with both the alkaline and the alkaline-earth cations may be of great importance to explain the behaviour of natural clay samples where mixtures of the two types of interlayer cation are present and also provides valuable information on the cation exchange occurring in the swelling clays. PMID- 23352874 TI - The role of tomato products and lycopene in the prevention of gastric cancer: a meta-analysis of epidemiologic studies. AB - BACKGROUND: Gastric cancer is the second most common cause of death from cancer worldwide. Epidemiologic studies have examined the possible association between tomato products consumption and gastric cancer, but the relationship between tomato products and the risk of gastric cancer is controversial. We performed a meta-analysis of cohort and case-control studies to analyze this association. METHODS: We systematically searched MEDLINE and EMBASE and contacted authors to identify potential studies published from January 1966 to June 2012. We pooled the relative risks from individual studies using a random-effects model and performed heterogeneity and publication bias analyses. RESULTS: Twenty-one studies were eligible for our inclusion criteria, in a pooled analysis of all studies, consumption of large amounts of tomato products (in a comparison of the highest and lowest consumption groups) reduced the risk for gastric cancer (odds ratio, 0.73; 95% confidence interval, 0.60-0.90). The pooled OR of lycopene consumption and serum lycopene was 0.88 (95% CI=0.67-1.16) and 0.79 (95% CI=0.59 1.07), respectively. CONCLUSIONS: Consumption of large amounts of tomato products is associated with a reduced risk of gastric cancer. However, because of potential confounding factors and exposure misclassification, further studies are required to establish these findings. PMID- 23352875 TI - A review of scalp blockade for cranial surgery. AB - Neural blockade of the scalp may be used as an adjunct to general anesthesia or serve as the principal anesthetic for both intracranial and extracranial procedures. Effective scalp blockade typically requires anesthetizing multiple peripheral nerves; blockade of one or more of these is often used to diagnose and treat conditions such as chronic headache. Improved anatomic knowledge has refined the use of scalp blockade so that directed neural blockade is achieved. The vascularity of the scalp, proximity of arteries supplying the cerebral circulation, use of large volumes of local anesthetic, and presence of intracranial devices or bony defects require attention. The impact of perioperative scalp blockade on acute and chronic pain may offer insight into the benefits of perioperative neural blockade generally. PMID- 23352876 TI - Allelic variations of the vitamin D receptor (VDR) gene are associated with increased risk of coronary artery disease in type 2 diabetics: the DIABHYCAR prospective study. AB - AIM: Vitamin D deficiency is associated with coronary artery disease (CAD), and the actions of vitamin D are mediated by binding to a specific nuclear vitamin D receptor (VDR). This study investigated the associations of VDR gene variants with CAD in two cohorts of type 2 diabetes patients. METHODS: A cohort of 3137 subjects from the prospective DIABHYCAR study (CAD incidence: 14.8%; follow-up: 4.4 +/- 1.3 years) and an independent, hospital-based population of 713 subjects, 32.3% of whom had CAD, were assessed. Three SNPs in the VDR gene were genotyped: rs1544410 (BsmI); rs7975232 (ApaI); and rs731236 (TaqI). RESULTS: In the DIABHYCAR cohort, an association was observed between the A allele of BsmI and incident cases of CAD (HR: 1.16, 95% CI: 1.05-1.29; P = 0.002). Associations were also observed between BsmI (P = 0.01) and TaqI (P = 0.04) alleles and baseline cases of CAD. The AAC haplotype (BsmI/ApaI/TaqI) was significantly associated with an increased CAD prevalence at the end of the study compared with the GCT haplotype (OR: 1.12, 95% CI: 1.02-1.28; P = 0.04). In a cross-sectional study of the independent hospital-based cohort, associations of ApaI (P = 0.009) and TaqI (P = 0.03) alleles with CAD were observed, with similar haplotype results (OR: 1.33, 95% CI: 1.03-1.73; P = 0.03). CONCLUSION: The haplotype comprising the minor allele of BsmI, major allele of ApaI and minor allele of TaqI of VDR (AAC) was associated with an increased risk of CAD in type 2 diabetes patients. This effect was independent of the effects of other known cardiovascular risk factors. PMID- 23352877 TI - Retrograde systemic to pulmonary shunt simulating a pulmonary embolism. PMID- 23352878 TI - Pedunculated insulinoma on the anterior border of the head of the pancreas: an unusual location to be aware of. PMID- 23352879 TI - CT-guided biopsies in lung infections in patients with haematological malignancies. AB - CT-guided transparietal lung biopsy in imaging makes it possible to find the pathogenic agent in half of all fungal infections and most bacterial infections (sensitivity=55%, specificity=100%). Performance is decreased in consolidations (50% of infections) compared to masses. Complications, pneumothorax, alveolar bleeding and hemoptysis are generally benign and rarely (<5%) require specific treatment. On the other hand, the diagnostic performance increases significantly with the calibre of 18G co-axial systems compared to 20G. The risk is not related to the number of samples or platelet levels. PMID- 23352880 TI - Synonymous codon usage pattern analysis of Hepatitis D virus. AB - Hepatitis D virus (HDV) is the smallest animal infecting RNA virus with unique features distinguishing it from other Hepatitis viruses. Codon usage variation is considered as an indicator of the forces shaping genome evolution. RSCU (relative synonymous codon usage) values, nucleotide contents, ENC (effective number of codons) values, aromaticity and hydrophobicity of 28 HDV sequences were calculated and compared. RSCU values revealed that most of the codons ended with G or C. A comparative analysis of codon usage between HDV and human cells indicated that the synonymous codon usage pattern of HDV is a mixture of coincidence and antagonism to that of host cell. Finally the characteristics of the synonymous codon usage patterns, ENC plot and the correlation analysis revealed that the most important determinant of the codon usage pattern for HDV is mutational pressure and positive selection force might have some influence in sequence diversity. Comparison of ENC values and GC frequencies at 3rd codon position (GC3s) between HDV and other Hepatitis viruses indicated that HDV comprise a distinct entity. PMID- 23352881 TI - Infection and propagation of Crimean-Congo hemorrhagic fever virus in embryonated chicken eggs. AB - The embryonated chicken egg (ECE) provides a convenient, space-saving incubator for the cultivation of many kinds of animal viruses where the egg can be easily observed for viral replication throughout the development of the chicken embryo. Within the family Bunyaviridae, the embryonated egg has been used as a host system for many viruses such as Rift Valley fever virus and Akabane virus. The current study was conducted to determine the cultivation of Crimean-Congo hemorrhagic fever virus (CCHFV) in ECE. Four-day-old eggs were infected with CCHFV via the yolk sac route and harvested embryonic tissues and amino-allantoic fluid (AAF) that were used for virus passage and viral RNA (vRNA) detection. Quantification of vRNA copies was performed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our study indicated that CCHFV caused the death of the embryonated egg in a dose-dependent manner and the 50% egg infectious dose (EID50) was determined to be 6.47*10(5) copies/egg. CCHFV replicated and passaged well in the egg and high viral loads were detected both in embryonic tissue (10(9-10) copies/g) and AAF (10(7-9) copies/ml) of the embryonated egg. Thus, ECE could be used for viral cultivation and preservation, and as a potential host infection model for the study of the pathogenesis of CCHFV. PMID- 23352882 TI - Transient high level mammalian reovirus replication in a bat epithelial cell line occurs without cytopathic effect. AB - Mammalian reoviruses exhibit a large host range and infected cells are generally killed; however, most studies examined only a few cell types and host species, and are probably not representative of all possible interactions between virus and host cell. Many questions thus remain concerning the nature of cellular factors that affect viral replication and cell death. In the present work, it was observed that replication of the classical mammalian reovirus serotype 3 Dearing in a bat epithelial cell line, Tb1.Lu, does not result in cell lysis and is rapidly reduced to very low levels. Prior uncoating of virions by chymotrypsin treatment, to generate infectious subviral particles, increased the initial level of infection but without any significant effect on further viral replication or cell survival. Infected cells remain resistant to virus reinfection and secrete an antiviral factor, most likely interferon, that is protective against the unrelated encephalomyocarditis virus. Although, the transformed status of a cell is believed to promote reovirus replication and viral "oncolysis", resistant Tb1.Lu cells exhibit a classical phenotype of transformed cells by forming colonies in semisolid soft agar medium. Further transduction of Tb.Lu cells with a constitutively active Ras oncogene does not seem to affect cell growth or reovirus effect on these cells. Infected Tb1.Lu cells can produce low-level of infectious virus for a long time without any apparent effect, although these cells are resistant to reinfection. The results suggest that Tb1.Lu cells can mount an unusual antiviral response. Specific properties of bat cells may thus be in part responsible for the ability of the animals to act as reservoirs for viruses in general and for novel reoviruses in particular. Their peculiar resistance to cell lysis also makes Tb1.Lu cells an attractive model to study the cellular and viral factors that determine the ability of reovirus to replicate and destroy infected cells. PMID- 23352883 TI - [Dyskeratosis congenita: an update]. AB - Dyskeratosis congenita is a rare inherited bone marrow failure characterized by excessively short telomeres in highly proliferative tissues. These abnormalities are due to disturbance of the telomere maintenance machinery. The clinical presentation is characterized by skin pigmentation, nail dystrophy, and mucosal leukoplakia. All these mucocutaneous features are rare in childhood: they usually appear between 5 and 10 years of age. In young children, the initial presentation can associate bone marrow failure and neurological or ocular problems: Hoyeraal Hreidarsson and Revesz syndromes, respectively. Clinical progression of the disease can lead to aplastic anemia (86% of all patients) and to pulmonary or hepatic complications. These patients also have an increased risk of cancer. Diagnosis is often suspected on bone marrow failure with no clinical or biological abnormalities compatible with Fanconi anemia diagnosis. The telomere length study can be helpful for diagnosis in case of aplastic anemia in children before studying gene mutations. Until now, 6 genes (DKC1, TERT, TERC, NOLA2, NOLA3, TINF2) have been identified in dyskeratosis congenita. Transmission of the disease can be autosomal recessive, autosomal dominant, or X-linked. In half of the cases, the genetic abnormality is unknown. Treatment of DC has to be adapted to each patient, from symptomatic or androgenic treatment to hematopoietic stem cell transplantation. PMID- 23352884 TI - Impact of preoperative radiotherapy on head and neck free flap reconstruction: a report on 429 cases. AB - BACKGROUND: The primary objective of this study was to evaluate the impact of preoperative radiotherapy on the outcomes of head and neck microvascular reconstruction. The secondary objective was to assess the specific effects of irradiation doses (IDs) >=60 Gy on the outcomes of head and neck microvascular reconstruction. METHODS: All patients who underwent head and neck free-flap reconstruction in our institution between 2000 and 2010 were included in this retrospective study. A total of 429 patients were enrolled including 136 patients previously irradiated on the head and neck. The impact of preoperative radiotherapy on free-flap success, local and general complications, postoperative mortality, time of decannulation, duration of enteral nutrition and length of stay was assessed in univariate and multivariate analyses. RESULTS: In multivariate analysis, preoperative radiotherapy (irrespective of ID) was a significant risk factor for fistula formation (p = 0.003) and wound infection (p = 0.005). Previous neck irradiation at doses >=60 Gy was associated with an increased risk of free-flap failure (p = 0.04), overall local complications (p = 0.05), haematoma (p = 0.04) and longer duration of enteral nutrition (p = 0.006) and hospital stay (p = 0.004). CONCLUSIONS: Preoperative radiotherapy, particularly for ID >= 60 Gy, is one of the main determinants of the outcomes of head and neck microvascular reconstruction. PMID- 23352885 TI - Nasal asymmetry in unilateral cleft lip and palate. AB - OBJECTIVES: Comparison of nasal asymmetry between unilateral cleft lip and palate (UCLP) patients with and without nasal correction at primary repair. Assessment of the value of Symnose as a routine research tool. PARTICIPANTS: 75 ten-year-old UCLP patients who underwent primary lip repair by one of two techniques: classical Millard with primary nasal correction (n = 30) or modified Millard without nasal correction (n = 45). Control group of ten-year-old school children (n = 45). METHODS: Nasal asymmetry of participants was measured from facial photographs taken in two views: frontal and basal. The Symnose computer program was used to calculate asymmetry for three parameters: front perimeter (FP), base perimeter (BP) and nostrils (N). Total asymmetry was also calculated. Each image was traced on three separate occasions and a mean of the three measurements was calculated. RESULTS: BP, N and total asymmetry were significantly greater in UCLP patients without nasal correction compared to both controls and patients with correction (BP = 12.73% v 4.90% v 6.75%, N = 47.73% v 15.83% v 30.75%, total = 81.87% v 46.43% v 54.68%, p <= 0.001). FP asymmetry was significantly greater in controls than all UCLP patients (22.87% v. 18.18% and 15.07%, p = 0.001 and p = 0.008). BP measurements have a higher degree of repeatability than FP and N (Coefficient of repeatability = 5.99, 17.02 and 16.47, respectively). CONCLUSIONS: Primary nasal correction produces greater nasal symmetry during childhood from the basal view. Symnose is a simple method of objectively measuring asymmetry in UCLP, however improvements are required before it can be considered a useful research tool. PMID- 23352886 TI - Guidelines for the excision of cutaneous squamous cell cancers in the United Kingdom: the best cut is the deepest. AB - Surgical excision remains the gold standard for the management of cutaneous squamous cell cancers (SCC) and national guidelines for operative radial margins predict 95% oncological clearance with a margin of 4 mm for low-risk and 6 mm for high-risk tumours. We retrospectively analysed all cutaneous SCC excisions performed across 4 regional Plastic surgical units in England over a consecutive 24-month period and collected data on tumour characteristics, operative and histological margins and completeness of excision. We identified 633 eligible SCC excisions of which 265 (42%) were over 2 cm in diameter with 37 recurrent tumours (5.8%). The mean radial operative margin was 6.5 mm across all tumours and 8.4 mm for tumours greater than 2 cm. The mean histological tumour diameter was 21 mm. The overall incomplete excision rate was 7.6% (7.9% for tumours >2 cm). Ninety four percent (45/48) of incomplete excisions involved the deep margin and only 3 out of 633 excisions (0.47%) were incomplete at a radial margin only. No differences were observed in tumour size or excision margin between incompletely and completely excised tumours. Incomplete excisions were most common on the ear, nose and cheek. In summary our analysis demonstrates that despite adherence to recommended surgical margins for cutaneous SCCs the incomplete excision rate remains higher than expected. We believe that this is because most incomplete excisions are incomplete at the deep margin and question the utility of performing increasingly wide excisions, and, the generalisability of the evidence upon which recommendations for radial margins are based. PMID- 23352887 TI - Abnormal resting-state cerebellar-cerebral functional connectivity in treatment resistant depression and treatment sensitive depression. AB - BACKGROUND: Previous studies have commonly shown that patients with treatment resistant depression (TRD) and treatment-sensitive depression (TSD) demonstrate a different cerebellar activity. No study has yet explored resting-state cerebellar cerebral functional connectivity (FC) in these two groups. Here, seed-based FC approach was employed to test the hypothesis that patients with TRD and TSD had a different cerebellar-cerebral FC. The identified FC might be used to differentiate TRD from TSD. METHODS: Twenty-three patients with TRD, 22 patients with TSD, and 19 healthy subjects (HS) matched with age, gender, and education level participated in the scans. Seed-based connectivity analyses were performed by using cerebellar seeds. RESULTS: Relative to HS, both patient groups showed significantly decreased cerebellar-cerebral FC with the prefrontal cortex (PFC) (superior, middle, and inferior frontal gyrus) and default mode network (DMN) [superior, middle, and inferior temporal gyrus, precuneus (PCu), and inferior parietal lobule (IPL)], and increased FC with visual recognition network (lingual gyrus, middle occipital gyrus, and fusiform) and parahippocampal gyrus. However, the TRD group exhibited a more decreased FC than the TSD group, mainly in connected regions within DMN [PCu, angular gyrus (AG) and IPL]. Further receiver operating characteristic curves (ROC) analyses showed that cerebellar-DMN couplings could be applied as markers to differentiate the two subtypes with relatively high sensitivity and specificity. CONCLUSIONS: Both patient groups demonstrate similar pattern of abnormal cerebellar-cerebral FC. Decreased FC between the cerebellum and regions within DMN might be used to separate the two patient groups. PMID- 23352888 TI - VP8*P[8] lineages of group A rotaviruses circulating over 20 years in Brazil: proposal of six different sub-lineages for P[8]-3 clade. AB - Group A rotaviruses (RVA) is the most important cause of severe gastroenteritis among children worldwide. Vaccination is considered the best alternative among public health measures to reduce and prevent the global burden caused by RVA infections. RotarixTM, a monovalent vaccine based on a human strain with a G1P[8] 1 specificity, was introduced in the National Brazilian Immunization Programs (NIP) in March, 2006. RVA P[8] is the most prevalent P genotype worldwide and four distinct phylogenetic lineages: P[8]-1, -2, -3, and -4 have been described. In the current study phylogenetic analysis of the VP8(*) gene of 135 RVA P[8] Brazilian strains, in combination with G1, G3, G5 or G9 VP7 genotype, collected from 1986 to 2011 were carried out for a better understanding of the evolution of this viral genotype in Brazil. Lineages P[8]-1, P[8]-2, and P[8]-3 were observed circulating in Brazil. In 2001 these three P[8] lineages co-circulated simultaneously and this is the first report in South America to date. Considering the P[8] lineage and the G genotype, all G3 strains were related to lineage P[8] 3, whereas the G9 strains were related to P[8]-2 and P[8]-3 and G1 and G5 were related to P[8]-1, P[8]-2, and P[8]-3. In addition, the phylogenetic analysis based on estimate of genetic distances between P[8]-3 strains and the definition of a 1.5% cutoff value (with relevant statistical support) it was possible to propose a new classification for the P[8]-3 lineage into six different sub lineages: P[8]-3.1 to P[8]-3.6. These findings reinforce the notion of the existence of constraints within specific RVA strains populations. The results obtained in this study reinforce the importance of a continuous RVA surveillance of circulating strains in order to predict the possible variants that will circulate in a country, assess the effects of vaccination on RVA circulating strains, and ultimately help in the design, challenges, and prospects of RVA vaccines. PMID- 23352889 TI - Characterization of Meq proteins from field isolates of Marek's disease virus in Japan. AB - Serotype 1 strains of Marek's disease virus (MDV-1) cause malignant lymphomas in chickens (Marek's disease; MD). Although MD has been controlled by vaccination, field isolates of MDV-1 have tended to increase in virulence and cause MD even in vaccinated chickens. Meq, a putative MDV-1 oncoprotein, resembles the Jun/Fos family of basic leucine zipper (bZIP) transcription factors and can regulate the expression of viral and cellular genes as a homodimer or as a heterodimer with a variety of bZIP family proteins. Sequencing analysis of some of the viral genes of various MDV-1 strains revealed a distinct diversity of and point mutations in Meq, which may contribute to changes in the transcriptional activities of Meq and, consequently, to increases in MDV-1 oncogenicity. However, few reports have characterized MDV-1 strains isolated in Japan. In this study, we established the amino acid sequences of MDV-1 field isolates from Japan in order to determine whether they display a distinct diversity of and point mutations in Meq. In addition, we analyzed the transactivation activities of the Meq proteins in order to evaluate whether the observed mutations affect their functions. Japanese MDV-1 isolates displayed the distinct mutations in basic region 2 (BR2) and proline rich repeats (PRRs) of the Meq proteins as well as some unique mutations. Reporter assays revealed that the amino acid substitutions in BR2 and the PRRs affected the Meq transactivation activity. These results suggest that the distinct mutations are also present in the Meq proteins of MDV-1 isolates from Japan and affect their transactivation activities. PMID- 23352890 TI - Rapid blood meal scoring in anthropophilic Aedes albopictus and application of PCR blocking to avoid pseudogenes. AB - Blood meal analysis (BMA) is a useful tool for epidemiologists and vector ecologists to assess which vector species are critical to disease transmission. In most current BMA assays vertebrate primers amplify DNA from a blood meal, commonly an abundant mitochondrial (mtDNA) locus, which is then sequenced and compared to known sequences in GenBank to identify its source. This technique, however, is time consuming and costly as each individual sample must be sequenced for species identification and mixed blood meals cloned prior to sequencing. Further, we found that several standard BMA vertebrate primers match sequences of the mtDNA of the Asian tiger mosquito, Aedes albopictus, making their use for blood meal identification in this species impossible. Because of the importance of Ae. albopictus as a vector of dengue and chikungunya viruses to humans, we designed a rapid assay that allows easy identification of human blood meals as well as mixed meals between human and nonhuman mammals. The assay consists of a nested PCR targeting the cytochrome b (cytb) mtDNA locus with a blocking primer in the internal PCR. The blocking primer has a 3' inverted dT modification that when used with the Stoffel Taq fragment prevents amplification of nuclear cytochrome b pseudogenes in humans and allows for the continued use of cytb in BMA studies, as it is one of the most species-rich loci in GenBank. We used our assay to examine 164 blooded specimens of Ae. albopictus from suburban coastal New Jersey and found 62% had obtained blood from humans with 7.6% mixes between human and another mammal species. We also confirmed the efficiency of our assay by comparing it with standard BMA primers on a subset of 62 blooded Ae. albopictus. While this assay was designed for use in Ae. albopictus, it will have broader application in other anthropophilic mosquitoes. PMID- 23352891 TI - Two genetically-related multidrug-resistant Mycobacterium tuberculosis strains induce divergent outcomes of infection in two human macrophage models. AB - Mycobacterium tuberculosis has a considerable degree of genetic variability resulting in different epidemiology and disease outcomes. We evaluated the pathogen-host cell interaction of two genetically closely-related multidrug resistant M. tuberculosis strains of the Haarlem family, namely the strain M, responsible for an extensive multidrug-resistant tuberculosis outbreak, and its kin strain 410 which caused a single case in two decades. Intracellular growth and cytokine responses were evaluated in human monocyte-derived macrophages and dU937 macrophage-like cells. In monocyte-derived macrophages, strain M grew more slowly and induced lower levels of TNF-alpha and IL-10 than 410, contrasting with previous studies with other strains, where a direct correlation was observed between increased intracellular growth and epidemiological success. On the other hand, in dU937 cells, no difference in growth was observed between both strains, and strain M induced significantly higher TNF-alpha levels than strain 410. We found that both cell models differed critically in the expression of receptors for M. tuberculosis entry, which might explain the different infection outcomes. Our results in monocyte-derived macrophages suggest that strain M relies on a modest replication rate and cytokine induction, keeping a state of quiescence and remaining rather unnoticed by the host. Collectively, our results underscore the impact of M. tuberculosis intra-species variations on the outcome of host cell infection and show that results can differ depending on the in vitro infection model. PMID- 23352892 TI - Costs and benefits of employment transportation for low-wage workers: an assessment of job access public transportation services. AB - This paper focuses on an evaluation of public transportation-based employment transportation (ET) services to transport low-wage workers to jobs in the US. We make an attempt to capture a more comprehensive range of intended and unintended outcomes of ET services than those traditionally considered in the case of public transportation services. Using primary data from 23 locations across the country, we present a framework to evaluate how transportation improvements, in interaction with labor markets, can affect users' short-run economic welfare, users' long-run human capital accumulation and non-users' short-run economic welfare. These services were partially funded by a specialized program - the Job Access and Reverse Commute (JARC) program - which was consolidated into larger transit funding programs by recent legislation. In the sites examined, we found that low wage users benefited from self-reported increased access to jobs, improvements in earnings potential, as well as from savings in transport cost and time. Simulations show the potential of users to accrue long-term worklife benefits. At the same time, users may have accrued changes in leisure time as a result of transitioning from unemployment to employment, and generated a range of societal impacts on three classes of non-users: the general tax-paying public, the general commuting public in the service operating area and other low-wage workers in local labor markets. PMID- 23352894 TI - Leukocyte cell-derived chemotaxin 2 is a zinc-binding protein. AB - Leukocyte cell-derived chemotaxin 2 (LECT2) is a secreted hepatic protein that has been associated with several physiological activities. LECT2 belongs to the peptidase M23 family, suggesting that it is a zinc-binding protein. To test this possibility, electrospray ionization mass spectrometry and X-ray absorption fine structure analysis were performed. Results of these experiments indicated that recombinant mouse LECT2 produced by an animal cell line contains a zinc atom. Furthermore, the recombinant LECT2 was found to be self-oligomerized by disulfide bonds in vitro, but this was suppressed by addition of zinc. These results indicated that zinc stabilizes the LECT2 structure. PMID- 23352893 TI - Induction of base excision repair enzymes NTH1 and APE1 in rat spleen following aniline exposure. AB - Mechanisms by which aniline exposure elicits splenotoxicity, especially a tumorigenic response, are not well-understood. Earlier, we have shown that aniline exposure leads to oxidative DNA damage and up-regulation of OGG1 and NEIL1/2 DNA glycosylases in rat spleen. However, the contribution of endonuclease III homolog 1 (NTH1) and apurinic/apyrimidinic endonuclease 1 (APE1) in the repair of aniline-induced oxidative DNA damage in the spleen is not known. This study was, therefore, focused on examining whether NTH1 and APE1 contribute to the repair of oxidative DNA lesions in the spleen, in an experimental condition preceding tumorigenesis. To achieve this, male SD rats were subchronically exposed to aniline (0.5 mmol/kg/day via drinking water for 30 days), while controls received drinking water only. By quantitating the cleavage products, the activities of NTH1 and APE1 were assayed using substrates containing thymine glycol (Tg) and tetrahydrofuran, respectively. Aniline treatment led to significant increases in NTH1- and APE1-mediated BER activity in the nuclear extracts of spleen of aniline-treated rats compared to the controls. NTH1 and APE1 mRNA expression in the spleen showed 2.9- and 3.2-fold increases, respectively, in aniline-treated rats compared to the controls. Likewise, Western blot analysis showed that protein expression of NTH1 and APE1 in the nuclear extracts of spleen from aniline-treated rats was 1.9- and 2.7-fold higher than the controls, respectively. Immunohistochemistry indicated that aniline treatment also led to stronger immunoreactivity for both NTH1 and APE1 in the spleens, confined to the red pulp areas. These results, thus, show that aniline exposure is associated with induction of NTH1 and APE1 in the spleen. The increased repair activity of NTH1 and APE1 could be an important mechanism for the removal of oxidative DNA lesions. These findings thus identify a novel mechanism through which NTH1 and APE1 may regulate the repair of oxidative DNA damage in aniline induced splenic toxicity. PMID- 23352895 TI - Identification of microRNAs from Plutella xylostella larvae associated with parasitization by Diadegma semiclausum. AB - MicroRNAs (miRNAs) as small non-coding RNAs play important roles in many biological processes such as development, cell signaling and immune response. Small RNA deep sequencing technology provided an opportunity for a thorough survey of miRNAs in a global key pest Plutella xylostella as well as comparative analysis of miRNA expression profile of the insect in association with parasitization by Diadegma semiclausum. Combining the deep sequencing data and bioinformatics, 235 miRNAs were identified from P. xylostella. Differential expression of host cellular miRNAs in response to parasitism was examined by making small RNA libraries from parasitized and naive second instar larvae of P. xylostella. Bantam, miR-276*, miR-10, miR-31 and miR-184 were detected as five most abundant miRNAs in both libraries and 96 miRNAs were identified that were differentially expressed after parasitization. Bantam*, miR-184 and miR-281* were significantly down-regulated and two miRNAs miR-279b and miR-2944b* were highly induced in parasitized larvae. Interestingly, high copy numbers and differential expression of several miRNA passenger strands (miRNA*) suggest their potential roles in host-parasitoid interaction. In conclusion, expression profiling of miRNAs provided insights into their possible involvement in insect immune response to parasitism and offer an important resource for further studies. PMID- 23352896 TI - Evaluating the potential nonthermal microwave effects of microwave-assisted proteolytic reactions. AB - Microwave-assisted proteolytic digestion methods have evolved into a highly effective approach and serve as an alternative to conventional overnight digestion. This approach typically exploits the unique microwave properties to facilitate the digestion of proteins into their peptides within minutes. Conventional digestion is carried out at 37 degrees C while microwave-assisted digestion requires much higher and sometimes inconsistent temperatures. Thus, this study aims to investigate whether the faster reaction rate is due to the microwave quantum effect or the thermal effect. Quantitative mass spectrometry was used to conduct kinetic analysis of tryptic digestion for several proteins by microwave and conventional heating. The percentages of digestion products relative to internal standards showed no significant difference between microwave and conventional heating conditions at the same digestion temperature. The optimum temperature for tryptic digestion was determined to be 50 degrees C. Furthermore, this study compares the digestion completeness indicators of several proteins under microwave and conventional heating. Again, the values obtained from microwave and conventional heating were similar given identical temperatures. The overall results prove that a nonthermal effect does not exist in microwave-assisted tryptic digestion. Therefore, conventional heating at high temperatures (50 degrees C) can be also used to accelerate digestion reactions. PMID- 23352897 TI - Unravelling the complex venom landscapes of lethal Australian funnel-web spiders (Hexathelidae: Atracinae) using LC-MALDI-TOF mass spectrometry. AB - Spider venoms represent vast sources of bioactive molecules whose diversity remains largely unknown. Indeed, only a small subset of species have been studied out of the ~43,000 extant spider species. The present study investigated inter- and intra-species venom complexity in 18 samples collected from a variety of lethal Australian funnel-web spiders (Mygalomorphae: Hexathelidae: Atracinae) using C4 reversed-phase separation coupled to offline MALDI-TOF mass spectrometry (LC-MALDI-TOF MS). An in-depth investigation focusing on four atracine venoms (male Illawarra wisharti, male and female Hadronyche cerberea, and female Hadronyche infensa Toowoomba) revealed, on average, ~800 peptides in female venoms while male venoms contained ~400 peptides, distributed across most HPLC fractions. This is significantly higher than previous estimates of peptide expression in mygalomorph venoms. These venoms also showed distinct intersexual as well as intra- and inter-species variation in peptide masses. Construction of both 3D and 2D contour plots revealed that peptide mass distributions in all 18 venoms were centered around the 3200-5400m/z range and to a lesser extent the 6600-8200m/z range, consistent with previously described hexatoxins. These findings highlight the extensive diversity of peptide toxins in Australian funnel web spider venoms that that can be exploited as novel therapeutic and biopesticide lead molecules. BIOLOGICAL SIGNIFICANCE: In the present study we describe the complexity of 18 venoms from lethal Australian funnel-web spiders using LC-MALDI-TOF MS. The study includes an in-depth investigation, focusing on four venoms, that revealed the presence of ~800 peptides in female venoms and ~400 peptides in male venoms. This is significantly higher than previous estimates of peptide expression in spider venoms. By constructing both 3D and 2D contour plots we were also able to reveal the distinct intersexual as well as intra- and inter-species variation in venom peptide masses. We show that peptide mass distributions in all 18 venoms were centered around the 3200-5400 m/z range and to a lesser extent the 6600-8200 m/z range, consistent with the small number of previously described hexatoxins from these spiders. These findings highlight the extensive diversity of peptide toxins in Australian funnel-web spider venoms that that can be exploited as novel therapeutic and biopesticide lead molecules. The present study has greatly expanded our understanding of peptide variety and complexity in these lethal mygalomorph spiders. Specifically it highlights both the utility of LC-MALDI-TOF in spider taxonomy and the massive combinatorial peptide libraries that spider venoms offer the pharmaceutical and agrochemical industry. PMID- 23352898 TI - Commentary to 'Prevalence and risk factors for renal scars in children with febrile UTI and/or VUR: a cross-sectional observational study of 565 consecutive patients'. PMID- 23352899 TI - Cellular adaptive response of distal renal tubular cells to high-oxalate environment highlights surface alpha-enolase as the enhancer of calcium oxalate monohydrate crystal adhesion. AB - Hyperoxaluria is one of etiologic factors of calcium oxalate kidney stone disease. However, response of renal tubular cells to high-oxalate environment remained largely unknown. We applied a gel-based proteomics approach to characterize changes in cellular proteome of MDCK cells induced by 10mM sodium oxalate. A total of 14 proteins were detected as differentially expressed proteins. The oxalate-induced up-regulation of alpha-enolase in whole cell lysate was confirmed by 2-D Western blot analysis. Interaction network analysis revealed that cellular adaptive response under high-oxalate condition involved stress response, energy production, metabolism and transcriptional regulation. Down regulation of RhoA, which was predicted to be associated with the identified proteins, was confirmed by immunoblotting. In addition, the up-regulation of alpha-enolase on apical surface of renal tubular epithelial cells was also confirmed by immunoblotting of the isolated apical membranes and immunofluorescence study. Interestingly, blockage of alpha-enolase expressed on the cell surface by antibody neutralization significantly reduced the number of calcium oxalate monohydrate (COM) crystals adhered on the cells. These results strongly suggest that surface alpha-enolase plays an important role as the enhancer of COM crystal binding. The increase of alpha-enolase expressed on the cell surface may aggravate kidney stone formation in patients with hyperoxaluria. PMID- 23352900 TI - Multiple congenital malformations in a dicephalic spur-thighed tortoise (Testudo graeca ibera). AB - A 22-day-old dicephalic spur-thighed tortoise (Testudo graeca ibera) died following a history of lethargy, anorexia and absence of defecation. The two heads were anatomically similar with independent reaction to external stimuli. The carapace showed doubled first and extra second vertebral scutes. Radiography and transplastronal ultrasonography, performed when the animal was alive, revealed two symmetrical stomachs and two asynchronous hearts. These findings were confirmed by necropsy examination. Oesophagus, liver, gallbladder and trachea were also duplicated. Other malformations included pyloric valve atresia of the left stomach, focal stenosis of the transverse colon and liver hypoplasia. Dicephalism rarely occurs in Testudinidae and its pathogenesis, still unclear, is discussed. PMID- 23352901 TI - Improving molecular discrimination of Nosema apis and Nosema ceranae. AB - Nosema apis and Nosema ceranae are the causative agents of nosemosis, a contagious honeybee disease that weakens bee colonies. The species are discriminated through several PCR-based methods including a multiplex PCR recommended by the World Organization for Animal Health (OIE). In this study, the OIE protocol was compared to two other PCR protocols using different PCR kits with the same primer pairs as described in OIE. The results showed that the three PCR protocols have similar sensitivity but only the kit dedicated to multiplex PCR could detect small quantities of one Nosema species when greater quantities of the other were also present. However, singleplex PCR methods are currently the most sensitive methods for discerning each species. These results have important implications for epidemiology and the understanding of the disease. PMID- 23352902 TI - Molecular differentiation of Nosema apis and Nosema ceranae based on species specific sequence differences in a protein coding gene. AB - Nosema apis and Nosema ceranae are two microsporidian pathogens of the European honey bee, Apis mellifera. There is evidence that N. ceranae is more virulent than N. apis subject to environmental factors like climate. This makes N. ceranae one of the suspects in the increasing colony losses recently observed in many regions of the world. Correct differentiation between N. apis and N. ceranae is important and best accomplished by molecular methods. So far only protocols based on species-specific sequence differences in the 16S rRNA gene are available. However, recent studies indicated that these methods may lead to confusing results due to polymorphisms in and recombination between the multi-copy 16S rRNA genes. To solve this problem and to provide a reliable molecular tool for the differentiation between the two bee pathogenic microsporidia we here present and evaluate a duplex-PCR protocol based on species-specific sequence differences in the highly conserved gene coding for the DNA-dependent RNA polymerase II largest subunit. A total of 102 honey bee samples were analyzed by the novel PCR protocol and the results were compared with the results of the originally published PCR RFLP analysis and two recently published differentiation protocols, based on 16S rRNA sequence differences. Although the novel PCR protocol proved to be as reliable as the 16S rRNA gene based PCR-RFLP it was superior to simple 16S rRNA based PCR protocols which tended to overestimate the rate of N. ceranae infections. Therefore, we propose that species-specific sequence differences of highly conserved protein coding genes should become the preferred molecular tool for differentiation of Nosema spp. PMID- 23352903 TI - Interaction of aqueous Se(IV)/Se(VI) with FeSe/FeSe2: implication to Se redox process. AB - Since reductive precipitation is considered as the most effective way to immobilize (79)Se, interaction of aqueous Se(IV)/Se(VI) with Fe(II)-bearing minerals has received extensive attention. In contrast to the thermodynamic calculations, as well as the prevalence of iron selenide phases observed in soil, sediments and ore deposits, most laboratory experiments have found that Se(0) was the reaction product. In this study, the interaction of Se(IV)/Se(VI) with FeSe/FeSe2 were investigated. The results demonstrate that FeSe and FeSe2 can be oxidized to Se(0) by Se(IV) with relatively fast kinetics, while reaction between Se(VI) and FeSe/FeSe2 only occurs under limited conditions (i.e. in the presence of high ferrous content and higher pH) with much slower kinetics, and there is no evident reaction in most case. Therefore, reduction of Se(IV) by Fe(II)-bearing minerals, in particular by natural occurring minerals, is envisioned to produce Se(0) at the early stage of experiments, rather than FeSe or FeSe2. Due to the formation of bulk Se(0) and its low solubility, the Fe-Se-O-H2O system will maintain redox disequilibrium in laboratory time-scale. This study also reveals that iron selenides, like iron sulfides, have strong reactivity toward Fe(3+). The findings in this study give insight into possible controls on Se redox process. PMID- 23352904 TI - Trace metal and metalloid contamination levels in soils and in two native plant species of a former industrial site: evaluation of the phytostabilization potential. AB - This study aimed at identifying the extent and type of contamination of a former lead smelting site in the area of Marseille, France, dating from the industrial revolution, and to evaluate environmental hazards and opportunities for phytoremediation, a promising sustainable technology. Amongst the native plants growing in this semiarid shrub ecosystem, two perennials Globularia alypum L. and Rosmarinus officinalis L. were selected. Twenty-one soil/plant couples were collected and seventeen additional soil samples were added to better characterize the soil pollution of the area. A multi-contamination by Pb, As, Sb, Zn, Cu was demonstrated, with huge variations within the contamination levels. The soils highest concentrations were encountered along the horizontal chimney and on the slag heaps area. However, both sites differed from each other. The former was characterized by the highest Pb, As and Sb concentrations that could reach 130, 7.0 and 9.0gkg(-1) respectively, the latter, by high Cu, Fe, Mn, S concentrations, even if it was also heavily contaminated by Pb and Zn. G. alypum and R. officinalis were shown to be metal-tolerant and to accumulate trace metals and As. Due to the low bioconcentration and translocation factors determined, both species may not be used for phytoextraction, but seem to be good candidates for phytostabilization. PMID- 23352905 TI - Defluoridation of drinking water using adsorption processes. AB - Excessive intake of fluoride (F), mainly through drinking water, is a serious health hazard affecting humans worldwide. There are several methods used for the defluoridation of drinking water, of which adsorption processes are generally considered attractive because of their effectiveness, convenience, ease of operation, simplicity of design, and for economic and environmental reasons. In this paper, we present a comprehensive and a critical literature review on various adsorbents used for defluoridation, their relative effectiveness, mechanisms and thermodynamics of adsorption, and suggestions are made on choice of adsorbents for various circumstances. Effects of pH, temperature, kinetics and co-existing anions on F adsorption are also reviewed. Because the adsorption is very weak in extremely low or high pHs, depending on the adsorbent, acids or alkalis are used to desorb F and regenerate the adsorbents. However, adsorption capacity generally decreases with repeated use of the regenerated adsorbent. Future research needs to explore highly efficient, low cost adsorbents that can be easily regenerated for reuse over several cycles of operations without significant loss of adsorptive capacity and which have good hydraulic conductivity to prevent filter clogging during the fixed-bed treatment process. PMID- 23352906 TI - Bioleaching mechanism of heavy metals in the mixture of contaminated soil and slag by using indigenous Penicillium chrysogenum strain F1. AB - The ability and bioleaching mechanism of heavy metals by Penicillium chrysogenum in soils contaminated with smelting slag were examined in this study. Batch experiments were performed to investigate the growth kinetics of P. chrysogenum, organic acids production and to compare the removal efficiencies of heavy metals between bioleaching with P. chrysogenum and chemical organic acids. The results showed that the bioleaching had higher removals than chemical leaching, and the removal percentages of Cd, Cu, Pb, Zn, Mn and Cr reached up to 74%, 59%, 24%, 55%, 57% and 25%, respectively. Removal efficiencies of heavy metals (15.41 mg/50 mL) by bioleaching were higher than chemical leaching with 0.5% of citric acid (15.15 mg/50 mL), oxalic acid (8.46 mg/50 mL), malic acid (11.35 mg/50 mL) and succinic acid (10.85 mg/50 mL). The results of transmission electron microscope (TEM) showed that no damage was obviously observed on the surface of the living cell except for thinner cell wall, discontinuous plasma membrane, compartmentalized lumen and concentrated cytoplasm during bioleaching process. The activity of extracellular glucose oxidase (GOD) produced by P. chrysogenum is influenced severely by the multi-heavy metal ions. The result implied that P. chrysogenum can be used to remove heavy metals from polluted soil and smeltery slag. PMID- 23352907 TI - Changes in cytokinin form and concentration in developing kernels correspond with variation in yield among field-grown barley cultivars. AB - The aim of the present study was to determine if relationships between cytokinin (CK) profiles and corresponding enzymatic regulation were consistent with differences in kernel yield among commercial barley (Hordeum vulgare L.) cultivars, differing in parameters relating to productivity and grown under agronomically-relevant field conditions. Quantification of the CKs at six distinct stages of kernel development by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) revealed a significant increase in CKs, especially trans-zeatin (tZ), during the stage when grain filling occurs, with a greater CK concentration observed in the cultivar with the greatest number of kernels per spike, which was also the highest yielding cultivar. High levels of the cis-zeatin (cZ) CK form were observed at the first developmental stage, indicating a possible role in early embryo development and viability. Cytokinin oxidase (CKX; EC 1.5.99.12) activity was evaluated at each stage through a colorimetric assay, as the enzyme provides a primary mechanism for the irreversible degradation and, thus, regulation of CKs. However, no peaks in CKX activity were observed and no differences were detected at the particular stages examined. Isopentenyl transferase (IPT) gene expression was also examined and suggests that biosynthesis contributes to regulation of CK concentrations in developing barley kernels. PMID- 23352908 TI - Ultrasonic gene and drug delivery using eLiposomes. AB - eLiposomes are liposomes encapsulating emulsions and therapeutics for targeted delivery. By applying ultrasound to eLiposomes, emulsion droplets can transform from liquid to gas and rupture the lipid bilayer of the eLiposome to release a drug or plasmid. In this study, perfluoropentane (PFC5) emulsions were encapsulated inside folated eLiposomes carrying a model drug (calcein) or a model GFP plasmid to examine the effects of a folate ligand, PFC5 emulsion and various ultrasonic acoustic parameters in drug delivery and gene transfection into HeLa cells. Confocal microscopy was used to quantify drug delivery and the level of plasmid transfection into HeLa cells. The results showed that drug delivery or transfection was minimal without incorporation of internal PFC5 emulsions and folate ligand on the eLiposome surface. It was also shown that application of ultrasound greatly enhanced the drug delivery and plasmid transfection. Delivery of these therapeutics appears to be to the cytosol, indicating that the expansion of the emulsion droplets disrupted both the eLiposomes and the endosomes. PMID- 23352909 TI - Poly(styrene oxide)-poly(ethylene oxide) block copolymers: From "classical" chemotherapeutic nanocarriers to active cell-response inducers. AB - Two poly(styrene oxide)-poly(ethylene oxide) (PSO-PEO) triblock copolymers with different chain lengths were analyzed as potential chemotherapeutic nanocarriers, and their ability to inhibit the P-glycoprotein (P-gp) efflux pump in a multidrug resistant (MDR) cell line were measured in order to establish possible cell responses induced by the presence of the copolymer molecules. Thus, EO33SO14EO33 and EO38SO10EO38 polymeric micelles were tested regarding doxorubicin (DOXO) entrapment efficiency (solubilization test), physical stability (DLS), cytocompatibility (fibroblasts), release profiles at various pHs (in vitro tests), as well as P-gp inhibition and evasion and cytotoxicity of the DOXO loaded micelles in an ovarian MDR NCI-ADR/RES cell line and in DOXO-sensitive MCF 7 cells. EO33SO14EO33 and EO38SO10EO38 formed spherical micelles (~13nm) at lower concentration than other copolymers under clinical evaluation (e.g. Pluronic(r)), exhibited 0.2% to 1.8% loading capacity, enhancing more than 60 times drug apparent solubility, and retained the cargo for long time. The copolymer unimers inhibited P-gp ATPase activity in a similar way as Pluronic P85, favoring DOXO accumulation in the resistant cell line, but not in the sensitive cell line. DOXO loaded in the micelles accumulated more slowly inside the cells, but caused greater cytotoxicity than free drug solutions in the NCI-ADR-RES cell line, which overexpressed P-gp. Hence, PSO-PEO block copolymers offer interesting features as new biological response modifiers to be used in the design of efficient nanocarriers for cancer chemotherapy. PMID- 23352910 TI - Cell penetrating peptide tethered bi-ligand liposomes for delivery to brain in vivo: Biodistribution and transfection. AB - Targeted nano-particulate systems hold extraordinary potential for delivery of therapeutics across blood brain barrier (BBB). In this work, we investigated the potential of novel bi-ligand (transferrin-poly-l-arginine) liposomal vector for delivery of desired gene to brain, in vivo. The in vivo evaluation of the delivery vectors is essential for clinical translation. We followed an innovative approach of combining transferrin receptor targeting with enhanced cell penetration to design liposomal vectors for improving the transport of molecules into brain. The biodistribution profile of 1, 1'-dioctadecyl-3,3,3',3' tetramethyl-indocarbocyanine iodide(DiR)-labeled liposomes was evaluated in adult rats after single intravenous injection at dose of 15.2MUmoles of phospholipids/kg body weight. We demonstrated that bi-ligand liposomes accumulated in rat brain at significantly (p<0.05) higher concentrations as compared to the single-ligand (transferrin) or plain liposomes. In addition, the bi-ligand liposomes resulted in increased expression of beta-galactosidase(beta gal) plasmid in rat brain tissue in comparison to the single-ligand liposomes. Histological examination of the transfected tissues did not show any signs of tissue necrosis or inflammation. Hemolysis assay further authenticated the biocompatibility of bi-ligand liposomes in blood up to 600 nmoles of phospholipids/1.4*10(7) erythrocytes. The findings of this study provide important and detailed information regarding the distribution of bi-ligand liposomes in vivo and accentuate their ability to demonstrate improved brain penetration and transfection potential over single-ligand liposomes. PMID- 23352911 TI - Encapsulation of Nod1 and Nod2 receptor ligands into poly(lactic acid) nanoparticles potentiates their immune properties. AB - Most successful vaccines are able to induce persistent antibody responses that can last a lifetime. Emerging evidences indicate that activation of immune cells through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) or Nod-like receptors (NLRs) may be critical mechanisms. Among PRRs, the use of TLR ligands as adjuvants is already largely described whereas the use of NLRs ligands remains largely unexplored. As activation of intracytoplasmic NLRs is able to induce proinflammatory molecules, the added value of encapsulation of Nod1 and Nod2 receptor ligands into Poly(Lactic Acid) (PLA) biodegradable nanocarriers to modulate their immune properties on human dendritic cells (DCs) maturation has been evaluated. Their ability to induce systemic immune responses in mice was also measured and compared to free ligands and the Alum adjuvant. Nod ligands encapsulated into PLA NPs were efficiently taken up by DCs and subsequently induced a strong up-regulation of maturation markers and the enhancement of proinflammatory cytokine secretion by DCs. Furthermore, co injection of encapsulated Nod-ligands with PLA particles carrying Gag p24 HIV-1 antigen allowed a 100 fold increase in antibody responses in comparison to Alum. These results suggest that encapsulation of Nod ligands into PLA-NPs could be an effective way to improve vaccine efficiency. PMID- 23352912 TI - The insulin-mimetic effect of Morin: a promising molecule in diabetes treatment. AB - BACKGROUND: Type-2 diabetes is a worldwidely diffuse disease characterized by insulin resistance that arises from alterations of receptor and/or post-receptor events of insulin signalling. Studies performed with PTP1B-deficent mice demonstrated that PTP1B is the main negative regulator of insulin signalling. Inhibition or down regulation of this enzyme causes enhanced insulin sensitivity. Hence this enzyme represents the most attractive target for development of innovative anti-diabetic drugs. METHODS: Selection of new PTP1B inhibitors among an in house library of polyphenolic compounds was carried out screening their activity. The inhibition mechanism of Morin was determined by kinetic analyses. The cellular action of Morin was assayed on HepG2 cells. Analyses of the insulin signalling pathways was carried out by Western blot methods, glycogen synthesis was estimated by measuring the incorporation of [(3)H]-glucose, gluconeogenesis rate was assayed by measuring the glucose release in the cell medium. Cell growth was estimated by cell count. Docking analysis was conducted with SwissDock program. RESULTS: We demonstrated that Morin: i) is a non-competitive inhibitor of PTP1B displaying a Ki in the MUM range; ii) increases the phosphorylation of the insulin receptor and Akt; iii) inhibits gluconeogenesis and enhances glycogen synthesis. Morin does not enhance cell growth. CONCLUSIONS: We have identified Morin as a new small molecular non-competitive inhibitor of PTP1B, which behaves as an activator and sensitizer of the insulin receptor stimulating the metabolic pathways only. GENERAL SIGNIFICANCE: Our study suggests that Morin is a useful lead for development of new low Mr compounds potentially active as antidiabetic drugs. PMID- 23352913 TI - An evidence-based patient-centered method makes the biopsychosocial model scientific. AB - OBJECTIVE: To review the scientific status of the biopsychosocial (BPS) model and to propose a way to improve it. DISCUSSION: Engel's BPS model added patients' psychological and social health concerns to the highly successful biomedical model. He proposed that the BPS model could make medicine more scientific, but its use in education, clinical care, and, especially, research remains minimal. Many aver correctly that the present model cannot be defined in a consistent way for the individual patient, making it untestable and non-scientific. This stems from not obtaining relevant BPS data systematically, where one interviewer obtains the same information another would. Recent research by two of the authors has produced similar patient-centered interviewing methods that are repeatable and elicit just the relevant patient information needed to define the model at each visit. We propose that the field adopt these evidence-based methods as the standard for identifying the BPS model. CONCLUSION: Identifying a scientific BPS model in each patient with an agreed-upon, evidence-based patient-centered interviewing method can produce a quantum leap ahead in both research and teaching. PRACTICE IMPLICATIONS: A scientific BPS model can give us more confidence in being humanistic. In research, we can conduct more rigorous studies to inform better practices. PMID- 23352914 TI - Fractures of the capitellum concomitant with avulsion fractures of the triceps tendon. AB - We present 2 cases of a capitellum fracture with concomitant triceps avulsion fracture. Common radiologic features of these injuries include a comminuted fracture of the capitellum with extension to the lateral portion of the trochlea, absence of posterior lateral condyle comminution, and a triceps avulsion fragment that is avulsed in a posterolateral direction. PMID- 23352915 TI - Hepatic, testicular and spermatozoa antioxidant status in rats chronically treated with Garcinia kolaseed. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Garcinia kola seed is commonly used in African Traditional Medicine as a remedy for liver disorders, hepatitis, bronchitis, throat infections as well as an aphrodisiac and fertility enhancing substance. Owing to the abundance of complex mixture of phenolic compounds in Garcinia kola seed, there is a growing safety concern on its long-term use in folklore medicine. The present study evaluated the hepatic, testicular and spermatozoa antioxidant status in rats chronically treated with Garcinia kolaseed. MATERIALS AND METHODS: Adult male Wistar rats were randomly assigned to four groups of 10 rats each and were orally administered with Garcinia kola at 0, 250, 500 and 1000mg/kg for 6consecutive weeks. Clinical observations, serum biochemistry, oxidative stress biomarkers, spermatozoa parameters and histopathological examination of the organs were assessed to monitor treatment-related adverse effects inrats. RESULTS: Long-term treatment of Garcinia kola had no adverse effect on the spermatozoa characteristics but significantly elevated testosterone concentration when compared to the control group. Improvement of antioxidant systems was accompanied by a significant decrease in malondialdehyde level in the liver, testes and spermatozoa of Garcinia kola-treated rats. Histological observation revealed that chronic administration of Garcinia kola had no effect on the liver and testes at all doses when compared with control. CONCLUSION: Garcinia kola seed boosts the antioxidant status and exhibits no adverse effect on the liver, testes and spermatozoa after a long-term oral exposure inrats. PMID- 23352916 TI - Lung metastases treated with image-guided stereotactic body radiation therapy. AB - AIMS: To evaluate outcomes after treatment with image-guided stereotactic body radiation therapy (SBRT) using daily online cone beam computed tomography for malignancies metastatic to the lung. MATERIALS AND METHODS: Forty-seven lung metastases in 32 patients were treated with volumetrically guided SBRT. The median age was 62 years (21-87). Primaries included colorectal (n = 10), sarcoma (n = 4), head and neck (n = 4), melanoma (n = 3), bladder (n = 2), non-small cell lung cancer (n = 2), renal cell (n = 2), thymoma (n = 2), thyroid (n = 1), endometrial (n = 1) and oesophageal (n = 1). The number of lung metastases per patient ranged from one to three (68% single lesions). SBRT was prescribed to the edge of the target volume to a median dose of 60 Gy (48-65 Gy) in a median of four fractions (four to 10). Most lesions were treated using 12 Gy fractions (92%) to 48 or 60 Gy. RESULTS: The median follow-up was 27.6 months (7.6-57.1 months). The 1, 2 and 3 year actuarial local control rates for all treated lesions were 97, 92 and 85%, respectively. Two patients with colorectal primaries (four lesions in total) had local failure. The median overall survival was 40 months. The 1, 2 and 3 year overall survival from the time of SBRT completion was 83, 76 and 63%, respectively. There were no grade 4 or 5 toxicities. Grade 3 toxicities (one instance of each) included pneumonitis, dyspnoea, cough, rib fracture and pain. CONCLUSION: SBRT with daily online cone beam computed tomography for lung metastases achieved excellent local tumour control with low toxicity and encouraging 2 and 3 year survival. PMID- 23352917 TI - Hyperthermic intraperitoneal chemotherapy with carboplatin for optimally cytoreduced, recurrent, platinum-sensitive ovarian carcinoma: a pilot study. AB - OBJECTIVE: We aimed to evaluate the feasibility and tolerability of hyperthermic intraperitoneal carboplatin (HIPEC-carboplatin) following secondary cytoreduction for recurrent, platinum-sensitive ovarian cancer. METHODS: In a single institution prospective, pilot study, ten patients underwent secondary cytoreductive surgery followed by HIPEC-carboplatin at 1000 mg/m(2). Consolidation (6 cycles) was with platinum-based regimens. Adverse and quality of life were measured throughout treatment. RESULTS: Twelve patients were enrolled of which 2 were excluded (one each for extra-abdominal disease indentified before surgery and suboptimal cytoreduction). All 10 remaining patients received prescribed HIPEC-carboplatin. There were no intra-operative complications or AEs attributable to HIPEC-therapy. Grade 1/2 nausea was the most common post operative toxicity (6/10 patients). Two patients had grade 4 post-operative neutropenia and thrombocytopenia but only one experienced transient treatment delay. The median hospital stay was 5.5 days. 69/70 (98%) of planned chemotherapy doses were ultimately delivered with 1 patient electively forgoing her final treatment. At a median (range) follow-up of 16 (6-23) months, three patients have recurred at 8, 14, and 16 months from surgery. The median disease-free and overall survivals have not been reached. Fact-O scores were significantly lower following surgery (126 vs. 108, p<.01), but improved by completion of therapy (108 vs. 113, p=0.27). CONCLUSIONS: HIPEC-carboplatin at 1000 mg/m(2) following optimal cytoreduction for ovarian cancer is feasible. Surgical complications were not observed, and post-operative AEs were largely within expected ranges. Consolidation using standard platinum-based regimens was feasible following HIPEC carboplatin, and preliminary survival data suggests efficacy. Further investigation of HIPEC-carboplatin in the setting of debulkable cancer recurrence is warranted. PMID- 23352918 TI - PCM/TD-DFT analysis of 1-bromo-2,3-dichlorobenzene--a combined study of experimental (FT-IR and FT-Raman) and theoretical calculations. AB - This study represents an integral approach towards understanding the electronic and structural aspects of 1-bromo-2,3-dichlorobenzene (BDCB). The experimental spectral bands were structurally assigned with the theoretical calculation, and the thermodynamic properties of the studied compound were obtained from the theoretically calculated frequencies. The relationship between the structure and absorption spectrum and effects of solvents have been discussed. It turns that the hybrid PBE1PBE functional with 6-311+G(d,p) basis provide reliable lambda(max) when solvent effects are included in the model. The NBO analysis reveals that the studied compound presents a structural characteristic of electron-transfer within the compound. The frontier molecular orbitals (HOMO LUMO) are responsible for the electron polarization and electron-transfer properties. The reactivity sites are identified by mapping the electron density into electrostatic potential surface (MESP). Besides, (13)C and (1)H have been calculated using the gauge-invariant atomic orbital (GIAO) method. The thermodynamic properties at different temperatures were calculated, revealing the correlations between standard heat capacity, standard entropy, standard enthalpy changes and temperatures. Furthermore, the studied compound can be used as a good nonlinear optical material due to the higher value of first hyper polarizability (5.7 times greater than that of urea (0.37289*10(-30) esu)). Finally, it is worth to mentioning that solvent induces a considerable red shift of the absorption maximum going from the gas phase, and a slight blue shift of the transition S(0) >S(1) going from less polar to more polar solvents. PMID- 23352919 TI - Naphthalene based colorimetric sensor for bioactive anions: experimental and DFT study. AB - A simple anion selective colorimetric sensor L has been designed by combining 2 hydroxy-1-naphthaldehyde with 2-aminothiophenol. Sensor L portrayed a necked-eye detectable color change from light green to red upon addition of AcO(-), F(-) and H(2)PO(4)(-) anions in CH(3)CN, where as no significant color change was observed upon addition of other anions such as Cl(-), Br(-), I(-) and HSO(4)(-). Sensor L showed selectivity towards AcO(-) under competitive environment, with a detection limit (3sigma/S) down to 1.1*10(-7) M. In addition, the anion sensing ability of L was explored in mixed H(2)O/CH(3)CN (v/v) medium. Further, the nature of interactions between the sensor L and AcO(-) was investigated by (1)H NMR and the probable structure of the L-AcO(-) complex was predicted by B3LYP/6-31G(d,p) method. PMID- 23352920 TI - Development and validation of sensitive spectrophotometric method for determination of two antiepileptics in pharmaceutical formulations. AB - Rapid, sensitive and validated spectrophotometric methods for the determination of two antiepileptics (gabapentin (GAB) and pregabalin (PRG)) in pure forms and in pharmaceutical formulations was developed. The method is based on the formation of charge transfer complex between drug and the chromogenic reagents quinalizarin (Quinz) and alizarin red S (ARS) producing charge transfer complexes in methanolic medium which showed an absorption maximum at 571 and 528 nm for GAB and 572 and 538 nm for PRG using Quinz and ARS, respectively. The optimization of the reaction conditions such as the type of solvent, reagent concentration and reaction time were investigated. Beer's law is obeyed in the concentration ranges 0.4-8.0 and 0.5-10 MUg mL(-1) for GAB and PRG using Quinz and ARS, respectively. The molar absorptivity, Sandell sensitivity, detection and quantification limits are also calculated. The correlation coefficients were >=0.9992 with a relative standard deviation (RSD%) of <=1.76. The methods are successfully applied to the determination of GAB and PRG in pharmaceutical formulations and the validity assesses by applying the standard addition technique, which compared with those obtained using the reported methods. PMID- 23352921 TI - Highly sensitive luminescent sensor for cyanide ion detection in aqueous solution based on PEG-coated ZnS nanoparticles. AB - Using polyethylene glycol (PEG) coated ZnS nanoparticles (NPs), a novel and highly sensitive luminescent sensor for cyanide ion detection in aqueous solution has been presented. ZnS NPs have been used to develop efficient luminescence sensor which exhibits high reproducibility and stability with the lowest limit of detection of 1.29*10(-6) mol L(-1). The observed limit of detection of the fabricated sensor is ~6 times lower than maximum value of cyanide permitted by United States Environmental Protection Agency for drinking water (7.69*10(-6) mol L(-1)). The interfering studies show that the developed sensor possesses good selectivity for cyanide ion even in presence of other coexisting ions. Importantly, to the best of our knowledge, this is the first report which demonstrates the utilization of PEG- coated ZnS NPs for efficient luminescence sensor for cyanide ion detection in aqueous solution. This work demonstrates that rapidly synthesized ZnS NPs can be used to fabricate efficient luminescence sensor for cyanide ion detection. PMID- 23352922 TI - Synthesis, experimental, theoretical characterization and biological activities of 4-ethyl-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-thione. AB - This work presents the characterization of 4-ethyl-5-(2-hydroxyphenyl)-2H-1,2,4 triazole-3(4H)-thione (III) by quantum chemical calculations and spectral techniques. The molecular geometry, vibrational frequencies and gauge including atomic orbital (GIAO) (1)H and (13)C NMR chemical shift values of III in the ground state have been calculated using the density functional method (B3LYP) with the 6-31G(d) basis set. The calculated results show that the optimized geometry can well reproduce the crystal structure, and the theoretical vibrational frequencies and chemical shift values show good agreement with experimental values. To determine conformational flexibility, the molecular energy profile of the title compound was obtained by DFT calculations with respect to the selected torsion angle, which was varied from -180 degrees to +180 degrees in steps of 10 degrees . The energetic behavior of III in solvent media was examined using the B3LYP method with the 6-31G(d) basis set by applying the Onsager and the polarizable continuum model (PCM). The predicted nonlinear optical properties of III are greater than ones of urea. In addition, DFT calculations of molecular electrostatic potentials and frontier molecular orbitals of III were carried out at the B3LYP/6-31G(d) level of theory. The title compound was screened for antibacterial, antifungal and antioxidant activities. PMID- 23352923 TI - Not all stressors are equal: early social enrichment favors resilience to social but not physical stress in male mice. AB - Early experiences profoundly affect the adult coping response to stress and, consequently, adult vulnerability to psychopathologies triggered by stressing conditions, such as major depression. Though studies in animal models have demonstrated that individuals reared in different conditions are differently vulnerable to a stressor of a specific quality, no information is available as to whether such vulnerability differs when facing stressors of different qualities. To this purpose, we reared C57BL/6 male mice either in standard laboratory rearing condition (SN) or in Communal Nest (CN) condition, the latter consisting of a single nest where three mothers keep their pups together and share care giving behavior until weaning. We scored the amount of interactions with the mother and with peers and found that CN is a form of social enrichment because both these components are significantly increased. At adulthood, we exposed SN and CN mice, for 4 weeks, to either a physical (forced swim) or a social stress (social instability). Immediately before, at week 1 and at week 4 of the stress procedure, corticosterone levels and the hedonic profile were measured. The results show that CN mice are more resilient to social stress than SN mice since they displayed no anhedonia and lower corticosterone levels. By contrast, both experimental groups were similarly vulnerable to physical stress. Overall, our results show that, in male mice, the adult vulnerability to stress changes according to the quality of the stressor, as a function of early experiences. In addition, the stressor to which CN mice are resilient is qualitatively similar to the stimuli they have experienced early on, both concerning the social domain. PMID- 23352924 TI - Clinical spectrum of hypophosphatasia diagnosed in adults. AB - The presentation of hypophosphatasia (HPP) diagnosed in adults demonstrates a wide range of clinical manifestations, many of which are nonspecific. We sought to assess clinical characteristics of adult HPP by evaluation of Mayo Clinic Rochester adults diagnosed with HPP from 1976 through 2008. Subjects were identified by diagnostic code or medical records. Inclusion criteria were age >=18 years at diagnosis; low serum alkaline phosphatase (AP) without bisphosphonate therapy; and one additional element: elevated pyridoxal 5' phosphate (PLP) or urine phosphoethanolamine (PEA), evidence of osteomalacia, or family history. We were unable to distinguish manifesting carriers from silent unaffected carriers due to lack of a prospective standardized clinical evaluation and the absence of genetic testing. HPP was diagnosed in 22 unrelated adults (median age 49 years; 68% women). Most patients (68%) were symptomatic at presentation with features including musculoskeletal pain (41%) or incident fracture (18%). A history of fracture was present in 54%: hip/femoral neck (23%), feet (23%, all women), wrist (18%), and spine (9%, all men). Nine patients (36%) had multiple fractures while 4 (all women) had subtrochanteric femur fractures. Radiographic chondrocalcinosis (27%) and documented pyrophosphate arthropathy (14%) were only observed in women. Median minimum serum AP was 43% below the lower normal limit. Urine PEA was elevated in 15/16 patients (94%). PLP median was 68 MUg/L (normal, 5-50 MUg/L) and all (n=8) were above normal. Symptomatic subjects had more fractures and chondrocalcinosis, lower median minimum AP and PLP and higher median PEA levels. Clinical features more common in fracture patients included symptoms at presentation, history of childhood rickets, dental abnormalities, lower median minimum AP and PLP, and higher median urine PEA. Four subjects had iliac crest bone biopsies, with 2/4 specimens consistent with osteomalacia. These results suggest that adult HPP demonstrates a wide spectrum of clinical manifestations including musculoskeletal pain, fractures, chondrocalcinosis and dental anomalies with some overlap in laboratory characteristics in relationship to disease severity. In addition to genetic and environmental factors, gender may influence the clinical expression of HPP. PMID- 23352925 TI - Therapeutic impact of low amplitude high frequency whole body vibrations on the osteogenesis imperfecta mouse bone. AB - Osteogenesis imperfecta (OI) is characterized by extremely brittle bone. Currently, bisphosphonate drugs allow a decrease of fracture by inhibiting bone resorption and increasing bone mass but with possible long term side effects. Whole body mechanical vibrations (WBV) treatment may offer a promising route to stimulate bone formation in OI patients as it has exhibited health benefits on both muscle and bone mass in human and animal models. The present study has investigated the effects of WBV (45Hz, 0.3g, 15minutes/days, 5days/week) in young OI (oim) and wild type female mice from 3 to 8weeks of age. Vibration therapy resulted in a significant increase in the cortical bone area and cortical thickness in the femur and tibia diaphysis of both vibrated oim and wild type mice compared to sham controls. Trabecular bone was not affected by vibration in the wild type mice; vibrated oim mice, however, exhibited significantly higher trabecular bone volume fraction in the proximal tibia. Femoral stiffness and yield load in three point bending were greater in the vibrated wild type mice than in sham controls, most likely attributed to the increase in femur cortical cross sectional area observed in the MUCT morphology analyses. The vibrated oim mice showed a trend toward improved mechanical properties, but bending data had large standard deviations and there was no significant difference between vibrated and non-vibrated oim mice. No significant difference of the bone apposition was observed in the tibial metaphyseal trabecular bone for both the oim and wild type vibrated mice by histomorphometry analyses of calcein labels. At the mid diaphysis, the cortical bone apposition was not significantly influenced by the WBV treatment in both the endosteum and periosteum of the oim vibrated mice while a significant change is observed in the endosteum of the vibrated wild type mice. As only a weak impact in bone apposition between the vibrated and sham groups is observed in the histological sections, it is possible that WBV reduced bone resorption, resulting in a relative increase in cortical thickness. Whole body vibration appears as a potential effective and innocuous means for increasing bone formation and strength, which is particularly attractive for treating the growing skeleton of children suffering from brittle bone disease or low bone density pathologies without the long term disadvantages of current pharmacological therapies. PMID- 23352926 TI - RNA decay machines: the exosome. AB - The multisubunit RNA exosome complex is a major ribonuclease of eukaryotic cells that participates in the processing, quality control and degradation of virtually all classes of RNA in Eukaryota. All this is achieved by about a dozen proteins with only three ribonuclease activities between them. At first glance, the versatility of the pathways involving the exosome and the sheer multitude of its substrates are astounding. However, after fifteen years of research we have some understanding of how exosome activity is controlled and applied inside the cell. The catalytic properties of the eukaryotic exosome are fairly well described and attention is now drawn to how the interplay between these activities impacts cell physiology. Also, it has become evident that exosome function relies on many auxiliary factors, which are intensely studied themselves. In this way, the focus of exosome research is slowly leaving the test tube and moving back into the cell. The exosome also has an interesting evolutionary history, which is evident within the eukaryotic lineage but only fully appreciated when considering similar protein complexes found in Bacteria and Archaea. Thus, while we keep this review focused on the most comprehensively described yeast and human exosomes, we shall point out similarities or dissimilarities to prokaryotic complexes and proteins where appropriate. The article is divided into three parts. In Part One we describe how the exosome is built and how it manifests in cells of different organisms. In Part Two we detail the enzymatic properties of the exosome, especially recent data obtained for holocomplexes. Finally, Part Three presents an overview of the RNA metabolism pathways that involve the exosome. This article is part of a Special Issue entitled: RNA Decay mechanisms. PMID- 23352927 TI - Cooks training for Faith, Activity, and Nutrition project with AME churches in SC. AB - PURPOSE: This study describes the development and evaluation of a participatory training for cooks in African American churches. The 8-h training focused on providing healthy meals within the church food program. It enlisted cooks in hands-on "cooking with the chef" training and menu building exercises, and demonstrated development of flavor in foods through healthy ingredients. Cook ratings from pre- to post-training (possible range: 1-10) were evaluated with the Wilcoxon signed rank test. RESULTS: 114 cooks from 57 churches over the period from 7/21/07 to 3/21/11 participated in trainings. Self-rated cooking skill increased from pre- (6.5+/-SD) to post-training (7.9+/-SD), p=0.0001. Self-rated confidence in preparing meals also increased significantly (pre: 7.3+/-SD; post: 8.3+/-SD), p=0001. Qualitative feedback from the cooks' training has been positive. Two of the more frequently stated changes cooks report are using less salt and using more vegetables and fruits in menus. Lessons learned include: choosing the right church to host the training, teamwork as a key component, need for support system for church cooks, allocation of time for planning as well as shopping for healthy ingredients, and incorporation of flexibility into the training plan. PMID- 23352929 TI - Suppressive effects of Indigofera suffruticosa Mill extracts on lipopolysaccharide-induced inflammatory responses in murine RAW 264.7 macrophages. AB - Indigofera suffruticosa Mill is used as an herbal medicine for the treatment of inflammation. The aim of this study is to assess the anti-inflammatory potency of I. suffruticosa and its likely molecular mechanisms of action in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Both water and ethanolic extracts of I. suffruticosa significantly decreased LPS-induced nitric oxide (NO) as well as the expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha, and pro-interleukin-1beta. Moreover, LPS-induced inhibitory factor-kappaB-alpha phosphorylation, nuclear factor-kappaB (NF-kappaB) nuclear protein-DNA binding affinity, and NF-kappaB reporter gene activity were dramatically inhibited by I. suffruticosa extracts. Exogenous addition of I. suffruticosa significantly induced heme oxygenase-1 (HO-1) expression, and the presence of HO-1 small interfering RNA partly reversed the inhibitory effects of I. suffruticosa on LPS-induced NO production and iNOS expression. Furthermore, I. suffruticosa induced HO-1 expression may be through activation of the ERK/nuclear factor E2-related factor 2 pathway. Eight phenolic compounds were found in the I. suffruticosa extracts, but salicylic acid was the only one detected in the plasma of mice fed with I. suffruticosa extracts. In summary, I. suffruticosa have a strong anti-inflammatory property that diminishes pro-inflammatory mediator expressions by lessening LPS-induced NF-kappaB activation and inducing HO-1 expression in macrophages. PMID- 23352931 TI - Statement on matching language to the type of evidence used in describing outcomes data. PMID- 23352928 TI - Reelin signaling in development, maintenance, and plasticity of neural networks. AB - The developing brain is formed through an orchestrated pattern of neuronal migration, leading to the formation of heterogeneous functional regions in the adult. Several proteins and pathways have been identified as mediators of developmental neuronal migration and cell positioning. However, these pathways do not cease to be functionally relevant after the embryonic and early postnatal period; instead, they switch from guiding cells, to guiding synapses. The outcome of synaptic guidance determines the strength and plasticity of neuronal networks by creating a scalable functional architecture that is sculpted by cues from the internal and external environment. Reelin is a multifunctional signal that coordinates cortical and subcortical morphogenesis during development and regulates structural plasticity in adulthood and aging. Gain or loss of function in reelin or its receptors has the potential to influence synaptic strength and patterns of connectivity, with consequences for memory and cognition. The current review highlights similarities in the signaling cascades that modulate neuronal positioning during development, and synaptic plasticity in the adult, with a focus on reelin, a glycoprotein that is increasingly recognized for its dual role in the formation and maintenance of neural circuits. PMID- 23352933 TI - Gender comparisons of unhealthy weight-control behaviors among sixth-Graders. AB - OBJECTIVE: To examine gender differences in unhealthy weight-control behaviors (UWCB) and identify key psychosocial and demographic correlates of UWCB among sixth-graders. METHODS: A cross-sectional survey was completed by 146 boys and 153 girls at a middle school. Secondary data analyses included bivariate tests and multivariable logistic regression. RESULTS: Forty-seven percent of participants reported 1 or more UWCB, with no differences by gender (P = .75). Factors common to boys and girls included: lower global self-esteem; lower body esteem; and greater negative parental modeling among participants who engaged in UWCB compared to those who did not. However, multivariable models revealed gender differences. Among boys, body mass index, negative parental modeling, and global self-esteem retained statistically significant associations with UWCB after controlling for other variables in the model, whereas race and weight-related body-esteem remained significant for girls. CONCLUSIONS AND IMPLICATIONS: This research highlights the need for gender-specific UWCB prevention programs implemented in late childhood and early adolescence. PMID- 23352932 TI - Molecular origins of cofilin-linked changes in actin filament mechanics. AB - The actin regulatory protein cofilin plays a central role in actin assembly dynamics by severing filaments and increasing the concentration of ends from which subunits add and dissociate. Cofilin binding modifies the average structure and mechanical properties of actin filaments, thereby promoting fragmentation of partially decorated filaments at boundaries of bare and cofilin-decorated segments. Despite extensive evidence for cofilin-dependent changes in filament structure and mechanics, it is unclear how the two processes are linked at the molecular level. Here, we use molecular dynamics simulations and coarse-grained analyses to evaluate the molecular origins of the changes in filament compliance due to cofilin binding. Filament subunits with bound cofilin are less flat and maintain a significantly more open nucleotide cleft than bare filament subunits. Decorated filament segments are less twisted, thinner (considering only actin), and less connected than their bare counterparts, which lowers the filament bending persistence length and torsional stiffness. Using coarse-graining as an analysis method reveals that cofilin binding increases the average distance between the adjacent long-axis filament subunit, thereby weakening their interaction. In contrast, a fraction of lateral filament subunit contacts are closer and presumably stronger with cofilin binding. A cofilactin interface contact identified by cryo-electron microscopy is unstable during simulations carried out at 310K, suggesting that this particular interaction may be short lived at ambient temperatures. These results reveal the molecular origins of cofilin-dependent changes in actin filament mechanics that may promote filament severing. PMID- 23352934 TI - Re: letter to the editor on "Alemtuzumab induction in renal transplantation: a meta-analysis and systemic review". PMID- 23352935 TI - Systematic reviews of alemtuzumab in renal transplantation. PMID- 23352936 TI - The differential effects of acute vs. chronic stress and their combination on hippocampal parvalbumin and inducible heat shock protein 70 expression. AB - The hippocampus plays a central role in stress-related mood disorders. The effects of acute vs. chronic stress on the integrity of hippocampal circuitry in influencing the vulnerability to, or resiliency against, neuronal injury are poorly understood. Here we investigated whether acute vs. chronic psychosocial isolation stress or a combination of the two (chronic stress followed by acute stress) influences the expression of the interneuronal marker parvalbumin (PV) and the chaperone-inducible heat shock protein 70 (Hsp70i) in different subregions of the hippocampus. Low levels of the Ca(2+)-binding protein (PV) may increase the vulnerability to neuronal injury, and Hsp70i represents an indicator of intense excitation-induced neuronal stress. Adult male Wistar rats were exposed to 2h of immobilization (IM) or cold (4 degrees C) (acute stressors), 21d of social isolation (chronic stress), or a combination of both acute and chronic stress. Both chronic isolation and the combined stressors strongly decreased the PV-immunoreactive cells in the CA1, CA3 and dentate gyrus (DG) region of the hippocampus, while acute stress did not affect PV expression. The combination of acute and chronic stress induced a dramatic increase in Hsp70i expression in the DG, but Hsp70i expression was unaffected in acute and chronic stress alone. We also monitored serum corticosterone (CORT) levels as a neuroendocrine marker of the stress response. Acute stress increased CORT levels, while chronic isolation stress compromised hypothalamic-pituitary-adrenocortical (HPA) axis activity such that the normal stress response was impaired following subsequent acute stress. These results indicate that in contrast to acute stress, chronic isolation compromises the HPA axis and generates a considerable reduction in PV expression, representing a decrease in the calcium-buffering capacity and a putatively higher vulnerability of specific hippocampal interneurons to excitotoxic injury. The induction of Hsp70i expression in response to acute and chronic isolation reveals that neurons in the DG are particularly vulnerable to an acute stressor following a chronic perturbation of HPA activity. PMID- 23352937 TI - The vitamin D receptor in dopamine neurons; its presence in human substantia nigra and its ontogenesis in rat midbrain. AB - There is growing evidence that vitamin D is a neuroactive steroid capable of regulating multiple pathways important for both brain development and mature brain function. In particular, there is evidence from rodent models that prenatal vitamin D deficiency alters the development of dopaminergic pathways and this disruption is associated with altered behavior and neurochemistry in the adult brain. Although the presence of the vitamin D receptor (VDR) has been noted in the human substantia nigra, there is a lack of direct evidence showing that VDR is present in dopaminergic cells. Here we confirm that the VDR is present in the nucleus of tyrosine hydroxylase (TH)-positive neurons in both the human and rat substantia nigra, and it emerges early in development in the rat, between embryonic day 12 (E12) and E15. Consistent evidence based on immunohistochemistry, real-time PCR and western blot confirmed a pattern of increasing VDR expression in the rat midbrain until weaning. The nuclear expression of VDR in TH-positive neurons during critical periods of brain development suggests that alterations in early life vitamin D status may influence the orderly development of dopaminergic neurons. PMID- 23352938 TI - Notch-driven carcinogenesis: the merging of hepatocellular cancer and cholangiocarcinoma into a common molecular liver cancer subtype. PMID- 23352939 TI - Thermal and 31P-NMR studies to elucidate sumatriptan succinate entrapment behavior in phosphatidylcholine/cholesterol liposomes. Comparative 31P-NMR analysis on negatively and positively-charged liposomes. AB - In this paper, two techniques, differential scanning calorimetry (DSC) and phosphorus nuclear magnetic resonance ((31)P-NMR), have been used to characterize sumatriptan succinate-loaded charged liposomes. To complete the results obtained by DSC a hot stage microscopy (HSM) technique was used. Data concerning the drug entrapment efficiency were published in a previous paper. The differences in data concerning encapsulation into negatively and positively-charged vesicles, indicated an influence of drug in the structural conformation of lipids in the bilayer. Moreover, the inability to formulate chargeless vesicles contributed to the opinion that a physical formulation study might be relevant. Phosphatidylcholine and cholesterol were used as lipid film forming agents, whereas stearylamine (positive) and dicetylphosphate (negative) were added as charge-inducing agents. DSC studies demonstrated that phosphatidylcholine caused the disappearance of the melting peak (Tm) of sumatriptan succinate because a drug dissolution process occurs. In addition, thermograms showed interesting interactions between stearylamine and dicetylphosphate with sumatriptan succinate favoring drug entrapment into the liposomes. In the present work, (31)P-NMR technique demonstrated that the structural conformation of lipids in the membrane affected drug encapsulation into multilamellar (MLVs) and unilamellar (LUVs) vesicles. Bilayer structure in a liquid crystalline phase of the positively charged REV liposomes membrane has demonstrated a high structural stability and a better encapsulation efficacy for sumatriptan succinate than negatively-charged TLE and REV liposomes. Therefore, phosphatidylcholine interaction with sumatriptan succinate appears to be the cause of the inability to obtain neutral sumatriptan succinate liposomes. PMID- 23352940 TI - Non-hazardous anticancerous and antibacterial colloidal 'green' silver nanoparticles. AB - Poly(ethylene glycol) stabilized colloidal silver nanoparticles were prepared using the reductive potency of the aqueous extract of Thuja occidentalis leaves under ambient conditions. The nanoparticles were well dispersed within a narrow size spectrum (7-14 nm) and displayed characteristic surface plasmon resonance peak at around 420 nm and Bragg's reflection planes of fcc structure. MTT assay revealed the dose-dependent cytocompatibility and toxicity of the nanoparticles with the L929 normal cell line. On the other hand, the antiproliferative action of the nanoparticles was evaluated on HeLa cell (cancerous cells) line. Fluorescence and phase contrast microscopic imaging indicated the appearance of multinucleate stages with aggregation and nuclear membrane disruption of the HeLa cells post treatment with the nanoparticles. The interaction at the prokaryotic level was also assessed via differential antibacterial efficacy against Staphylococcus aureus (MTCC 3160) and Escherichia coli (MTCC 40). Under these perspectives, it is also necessary to observe the environmental impact of the prepared silver nanoparticles. Hence, the dose dependent toxicity of silver nanoparticles was evaluated upon the earthworm species Eisenia fetida. Neither the survival nor the reproduction was affected by the addition of silver nanoparticles up to 1000 ppm. Thus these 'green' silver nanoparticles have promising potential as future materials. PMID- 23352941 TI - Characteristics of amorphous complex formed between indomethacin and lidocaine hydrochloride. AB - Indomethacin (IM) easily forms an amorphous complex with lidocaine (LC) by heat treatment. To know the mechanism involved in the formation of this complex, we studied temperature-dependent phase changes in mixtures of IM and lidocaine hydrochloride (LH), in which the cationic form of LC forms a salt with Cl(-), in various molar ratios by using DSC and NMR. Although heating of the mixture of IM and LC (IM+LC), formed a eutectic mixture, that of IM and LH (IM+LH) did not, and IM in the IM+LH mixture was dissolved into fused LH. Cooling of the fused IM+LH showed the glass transition in all of the samples containing various amounts of IM, suggesting that fused IM+LH took a homogenous amorphous state (IM/LH) below its glass transition temperature, in contrast to the fused IM+LC, which formed the rubber state and/or glass state depending on the molar content of IM. The results of the NMR study showed that IM in IM/LH caused the electronic structure of LH to change in such a way as to become similar to that of LC, but this effect was limited. Hence, mode of interaction of LH with IM is different from that of LC with IM. PMID- 23352942 TI - Electrochemical characterization of redox polymer modified electrode developed for monitoring of adenine. AB - Electrochemical characterization of redox polymer for monitoring of adenine was described in this study using poly(vinylferrocenium) (PVF(+)) modified platinum (Pt) electrode. Scanning electron microscope (SEM) was used for the surface characterization. The electrochemical behaviors of polymer modified and adenine immobilized polymer modified electrodes were investigated by using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). In order to obtain more sensitive and improved electrochemical signals, analytical parameters such as the effects of polymeric film thickness, immobilization time of adenine, pH and adenine concentration were examined on the response of the polymer modified electrode. Alternating current (AC) impedance spectroscopy was used for the characterization of polymer modified and adenine immobilized polymer modified electrodes. The effect of possible interferents on the response of the electrode was examined. PMID- 23352943 TI - Interaction of two overlapped synthetic peptides from GB virus C with charged mono and bilayers. AB - The physical chemistry properties and interactions of E2 (125-139) and E2 (120 139) peptide sequences from GB virus C with model cell membranes were investigated by means of several biophysical techniques in order to gain better understanding of the effect of peptide length and lipid charge on membrane binding. The peptides, having one net negative charge at the pH of the assays, interacted with monolayers of all the phospholipids regardless of the charge but with more extent with the cationic DPTAP thus indicating that the interaction had both a hydrophobic and an electrostatic component as has been observed for other peptides of the same family. The peptides were able to leakage contents of liposomes and showed fluorescence energy transfer in vesicles depending on the vesicles lipid composition. On another hand, circular dichroism has shown that the peptides exist mainly as a mixture of disordered structure and beta-type conformations in aqueous solution but diminished its unstructured content, folding preferentially into alpha-helical conformation upon interaction with hydrophobic solvents or positively charged lipid surfaces. Altogether, results of this work indicate that the peptides interact at a surface level, penetrate into bilayers composed of fluid lipids and that conformational changes could be responsible for this effect. PMID- 23352944 TI - Morphology-directed synthesis of ZnO nanostructures and their antibacterial activity. AB - Zinc oxide (ZnO) nanostructures of various morphologies were produced in an aqueous system, with pyridine as a shape-directing agent. X-ray diffraction (XRD) and selected-area electron diffraction (SAED) revealed hexagonal wurtzite crystal structure. Variation in surface morphology was analyzed using transmission electron microscopy (TEM). Changes in surface morphology were attributed to the absence of steric stabilization in pyridine during synthesis process. Pyridine concentration affected morphology and optical properties. Fourier transform infrared spectroscopy (FTIR) confirmed the presence/absence of pyridine on the surface of ZnO nanostructures (ZnO-NSs). Optical measurements carried out using UV-visible spectrophotometer (UV-vis) and photoluminescence (PL) indicated the presence of defects. All the samples exhibited two PL peaks, at 350-370 nm and 560-624 nm. Variation in the intensities of PL peaks corresponded to the changes in the surface morphology from nanoparticles to rods and origin of deep-level defect luminescence is attributed to surface recombination. The toxicity of the nanostructures was tested on model Gram-negative and Gram-positive pathogens. Smaller nanorods were most toxic among the nanostructures tested. PMID- 23352945 TI - CDDP supramolecular micelles fabricated from adamantine terminated mPEG and beta cyclodextrin based seven-armed poly (L-glutamic acid)/CDDP complexes. AB - This research is aimed to develop a nano-sized supramolecular micelle delivery system of cis-dichlorodiammine platinum (II) (CDDP) in order to achieve the passive tumor targeting. Firstly, star-shaped poly (gamma-benzyl-L-glutamate) was synthesized by the ring-opening polymerization of gamma-benzyl-L-glutamate-N carboxyanhydride initiated with per-6-amino-beta-cyclodextrin. After removal of benzyl groups, beta-cyclodextrin based seven-armed poly (L-glutamic acid) (beta CD-7PLGA) was obtained. beta-CD-7PLGA/CDDP complexes were prepared by the complex reaction between the carboxylic groups of beta-CD-7PLGA and CDDP. Further inclusion of beta-CD-7PLGA/CDDP complexes with adamantine terminated mPEG (mPEG Ad) gave CDDP supramolecular micelles (mPEG-Ad@beta-CD-7PLGA/CDDP). The formation of mPEG-Ad@beta-CD-7PLGA/CDDP supramolecular micelles was confirmed by fluorescence spectrophotoscopy and particle size measurements. All the micelles showed spherical shape, and their sizes increased from 100 to 135 nm with the increase of PLGA arm molecular weight. mPEG-Ad@CD-7PLGA/CDDP micelles showed sustained drug release profiles over 50h in PBS. Compared with CDDP, mPEG-Ad@beta CD-7PLGA/CDDP supramolecular micelles showed essential decreased cytotoxicity to KB cells, suggesting their great potential as the delivery carriers of CDDP. PMID- 23352946 TI - Effects of surfactants on cell surface tension parameters and hydrophobicity of Pseudomonas putida 852 and Rhodococcus erythropolis 3586. AB - The interaction between bacteria and surfaces is central to many environmental, industrial and medical applications. Surfactants are commonly used in these applications and can potentially influence the bacterium/surface interaction. The effect of surfactants upon bacterial cell surface thermodynamic properties was examined using a combination of contact angle measurements and LW-AB surface free energy calculation. Two bacterial strains, hydrophilic Pseudomonas putida 852 and hydrophobic Rhodococcus erythropolis 3586, and two surfactant types, the anionic biosurfactant rhamnolipid and the non-ionic chemical surfactant tergitol, were examined. The study demonstrated that surfactant treatment could modify cell surface tension parameters including Lifshitz-van der Waals (gamma(LW)), electron donor (gamma(-)) and electron-acceptor (gamma(+)) and thereby the bacterial cell hydrophobicity, depending on the surfactant type and concentration and the bacterial surface characteristics. Rhamnolipid and tergitol were found to increase P. putida 852 hydrophobicity, but decrease the hydrophobicity of R. erythropolis 3586. The extent of change was dependent on surfactant concentration. Among the three surface tension parameters, gamma(-) was found to be the most important in predicting bacterial cell hydrophobicity. PMID- 23352947 TI - Antibacterial activity against Porphyromonas gingivalis and biological characteristics of antibacterial stainless steel. AB - To evaluate the possibility of an alternative to the traditional orthodontic stainless steel implants, the antibacterial activity against Porphyromonas gingivalis (P. gingivalis) and the related cytotoxicity of a type 304 Cu bearing antibacterial stainless steel were studied. The results indicated that the antibacterial stainless steel showed excellent antibacterial property against P. gingivalis, compared with the control steel (a purchased medical grade 304 stainless steel). Compared to the control steel, there were fewer bacteria on the surface of the antibacterial stainless steel, with significant difference in morphology. The cytotoxicities of the antibacterial stainless steel to both MG-63 and KB cells were all grade 1, the same as those of the control steel. There were no significant differences in the apoptosis rates on MG-63 and KB cells between the antibacterial stainless steel and the control steel. This study demonstrates that the antibacterial stainless steel is possible to reduce the incidence of implant-related infections and can be a more suitable material for the micro implant than the conventional stainless steel in orthodontic treatment. PMID- 23352948 TI - Biocompatibility of microbially reduced graphene oxide in primary mouse embryonic fibroblast cells. AB - Graphene nanosheet is a one-atom thick planar sheet of sp(2)-bonded carbon atoms, which are densely packed in a honeycomb crystal lattice, attracting tremendous attention from both fundamental research and industrial applications. The synthesis of graphene from graphene oxide (GO) using a biological method is one of the important topics in the areas of nanotechnology, because graphene-based nanomaterials have potential applications. A green, simple and non-toxic method for preparing graphene using biomass of Pseudomonas aeruginosa as the reducing reagent is proposed. The resulting microbially reduced graphene oxide (M-rGO) was characterized using a range of analytical techniques. UV-visible spectroscopy confirms the transition of graphene oxide to graphene. Fourier transform infrared spectroscopy (FT-IR) was used to study the changes in surface functionalities. X ray diffraction (XRD) and high resolution scanning electron microscopy (SEM) were used to investigate the crystalline nature and the morphologies of prepared graphene respectively. Furthermore, the biocompatibility of the M-rGO was investigated using primary mouse embryonic fibroblast (PMEF) cells. The present study suggests that the M-rGO has significant biocompatibility for PMEF cells, even at a high concentration of 100 MUg ml(-1). Therefore, the proposed safe and green method confers the M-rGO with a great potential for various biomedical applications. PMID- 23352949 TI - Release kinetics of 5-aminosalicylic acid from halloysite. AB - This paper investigates desorption of 5-aminosalicilyc acid (5-ASA) adsorbed onto halloysite (HL). Desorption isotherms were fitted according to kinetic laws obtained considering release of 5-ASA from HL as the phase of desorption of the previously adsorbed drug molecules both inside the nanotubes of HL as onto the surface of clay particles and/or in the inter-particle spaces of their aggregates. Desorption isotherms has been also fitted with other equations frequently used in drug release kinetics studies. The best fitting corresponded to the kinetic model proposed; in agreement with the results of adsorption. PMID- 23352950 TI - Choline acetate enhanced the catalytic performance of Candida rogusa lipase in AOT reverse micelles. AB - Choline acetate is an ionic liquid composed of a kosmotropic anion and a chaotropic cation. According to Hofmeister series, a kosmotropic anion and/or a chaotropic cation could stabilize an enzyme, thereby facilitating the retention of the catalytic activity of the enzyme. In this work, we first report the influence of choline acetate on the activity and stability of lipase in AOT/water/isooctane reverse micelles. The indicator reaction is the lipase catalyzed hydrolysis of 4-nitrophenyl butyrate. The results show that a low level of choline acetate does not affect the microstructure of the AOT reverse micelles, but the ionic liquid can improve the catalytic efficiency of lipase. Fluorescence spectra show that a high level of choline acetate has an impact on the conformation of lipase, so the activation is mainly due to the influence of choline acetate on the nucleophilicity of water. Infrared spectra demonstrate that choline acetate can form stronger hydrogen bonds with water surrounding lipase, and therefore enhance the nucleophilicity of the water, which makes it easier to attack the acyl enzyme intermediate, thereby increasing the activity of the lipase-catalyzed hydrolysis of the ester. A study on the stability of lipase in AOT reverse micelles indicates that the ionic liquid is able to maintain the activity of lipase to a certain extent. The effect of choline acetate is consistent with that predicted based on Hofmeister series. PMID- 23352951 TI - A549 lung cell line activity of biosynthesized silver nanoparticles using Albizia adianthifolia leaf. AB - Stable AgNPs were formed in vitro by reacting AgNO3 (aq) solution with the aqueous plant leaf extract. UV-vis revealed the surface plasmon resonance lambdamax at 448 nm and the absorbance steadily increased in intensity as a function of reaction time. Transmission electron microscope (TEM) and XRD studies were used to characterize the AgNPs; the size was 4-35 nm. Dynamic light scattering (DLS) was used as supporting evidence to determine hydrodynamic size and zeta potential recorded as 80.27 nm and -24.7 mV, respectively. FT-IR spectra suggest that AgNPs are capped with protein molecules and other water soluble phytocompounds such as saponins and glycosides which also behave as stabilizing agents; TEM images indicate a visible layer surrounding the AgNPs. Prominent absorption bands at 3380 and 1642 cm(-1) are assigned to alcohol and carbonyl groups, respectively. (1)H NMR of the neat aqueous plant extract indicates presence of a complex mixture of compounds; however the chemical shift at delta 6.0-8.0 and 1.0-4.0 ppm indicates the presence of few aromatic but abundant aliphatic compounds, respectively. Toxicity of AgNPs on lung cancer cells (A549) and normal healthy peripheral lymphocytes (PLs) at 10 MUg/ml and 50 MUg/ml was assessed using the MTT, ATP and lactate dehydrogenase assays. Viability data for A549 cells showed a 21% (10 MUg/ml) and 73% (50 MUg/ml) cell viability after 6h exposure to AgNPs compared to 117% (10 MUg/ml) and 109% (50 MUg/ml) cell viability of normal peripheral lymphocytes. Lactate dehydrogenase was only significantly altered at 50 MUg/ml AgNPs treated cells from 2.43+/-0.04 units to 0.77+/-0.04 units. PMID- 23352952 TI - Biosorption of Cd(II)/Pb(II) from aqueous solution by biosurfactant-producing bacteria: isotherm kinetic characteristic and mechanism studies. AB - The potentiality of biosurfactant-producing bacterium Pseudomonas sp. LKS06 to remove Cd(II) and Pb(II) ions from aqueous solution was investigated in this study. The maximum biosorption capacity of Pseudomonas sp. LKS06 biomass for Cd(II) and Pb(II) was found to be 27.5 and 77.8 mg g(-1), respectively, at the optimum pH of 6.0. The process can be better explained by Langmuir-Freundlich dual isotherm model (R(2)>0.981) while the kinetic data was best described by using the pseudo-second-order kinetic model (R(2)>0.999). Both metal ions were successfully recovered from the bacterial biomass using 0.1M HNO3 with 90% recovery and the biomass shows high stability in the experiment of regeneration. Scanning electron microscopic analysis demonstrates a conspicuous surface morphology change of the Cd(II)/Pb(II)-adsorbed biomass. The results of zeta potential measurement and Fourier transform infrared spectroscopy suggested the involvement of amine, carboxyl, phosphate and hydroxyl groups during the biosorption process. Based on the results, it can be concluded that the biomass of Pseudomonas sp. LKS06 can be evaluated as an alternative biosorbent to remove Cd(II) and Pb(II) ions from industrial wastewater. PMID- 23352953 TI - [Disease-modifying treatment for inflammatory rheumatism in sub-Saharan Africa: outcome at 6 months of 205 Senegalese patients with rheumatoid arthritis]. AB - RATIONALE: Few data are available on the treatment of rheumatoid arthritis (RA) in sub-Saharan Africa, where the diagnosis is often substantially delayed. Disease-modifying antirheumatic drugs (DMARDs) are more effective when started early. Biotherapies are not available. Given the socioeconomic constraints in sub Saharan Africa, treatments must be selected based on locally available resources. The objective of this study was to evaluate outcomes 6 months after initiation of conventional DMARDs in Senegalese patients with RA. METHODS: We retrospectively studied consecutive RA patients seen at the rheumatology outpatient clinic of the Le Dantec Teaching Hospital, Dakar, Senegal, from January 2005 through June 2009. All patients met the ACR criteria for RA. ACR and EULAR response criteria were evaluated 6 months after treatment initiation. RESULTS: The study included 205 patients. Corticosteroids were used in 205 patients, hydroxychloroquine in 190, methotrexate in 137, and sulfasalazine in 11. Combined corticosteroid, methotrexate, and hydroxychloroquine therapy was used in 122 patients and combined corticosteroid and hydroxychloroquine therapy in 63. DMARD treatment was interrupted for at least 5 days per month for 26% of the patients, either because the drugs were out of stock at the local pharmacies and/or because the patients could not afford to purchase them. During the first 6 months of treatment, patients had a mean of 4 clinic visits, and 48% of patients missed at least one scheduled visit. After 6 months, all clinical variables had improved significantly, except the swollen joint count. The ACR20, 50, and 70 response criteria were met in 50%, 31%, and 6.9% of patients, respectively. The EULAR response was good in 53.9% of patients, moderate in 12.7%, and poor in 23.1%. DMARD therapy failed in 10.3% of patients. Half the patients had their treatment modified during the 6-month study period. DMARD therapy was discontinued in 10 patients for the following reasons: plans to become pregnant, n = 5; pregnancy during treatment, n = 2; and tuberculosis, n = 3. CONCLUSION: In Senegal, the treatment of RA relies chiefly on variable combinations of methotrexate, hydroxychloroquine, and corticosteroids. The six-month outcomes are satisfactory. Biotherapy is required in 7% to 10% of patients, a rate that could be decreased by optimizing patient follow-up. The management of chronic inflammatory joint disease couple be improved despite the limited financial resources in sub-Saharan Africa with better physician training and the incorporation of osteoarticular diseases within a vast information and education program for the general population. PMID- 23352954 TI - Effects of high-resistance circuit training in an elderly population. AB - The aim of this study was to determine the efficacy of a program of high resistance circuit (HRC) training, and to compare the effects of HRC to traditional heavy strength (TS) training on strength, muscle size, body composition and measures of cardiovascular fitness in a healthy elderly population. Thirty-seven healthy men and women (61.6+/-5.3years) were randomly assigned to HRC (n=16), TS (n=14), or a control group (CG, n=7). Training consisted of weight lifting twice a week for 12weeks. Before and after the training, isokinetic peak torque in the upper and lower body, and body composition (dual X-ray absorptiometry) were determined. In addition, cardiovascular parameters were evaluated during an incremental treadmill test. Both HRC and TS groups showed significant increases in isokinetic strength (p<0.001), and the increase was significantly greater in the experimental groups than in CG (p<0.03). There were significant increases in lean mass (HRC, p<0.001; TS, p=0.025) and bone mineral density (HRC, p=0.025; TS, p=0.018) in the experimental groups. Only HRC showed a significant decrease in fat mass (p=0.011); this decrease was significantly greater in HRC than in CG (p=0.039). There were significant improvements in walking economy in the HRC group (p<0.049), although there were no statistical differences between groups. There were no changes in any variables in CG. Hence, HRC training was as effective as TS for improving isokinetic strength, bone mineral density and lean mass. Only HRC training elicited adaptations in the cardiovascular system and a decrease in fat mass. PMID- 23352955 TI - Phlebotomine sand flies (Diptera: Psychodidae: Phlebotominae) in urban rainforest fragments, Manaus -- Amazonas State, Brazil. AB - The non-flooded upland rainforest fragment in the Federal University of Amazonas Campus is considered one of the world's largest urban tropical woodland areas and Brazil's second largest one in an urban setting. It is located in the city of Manaus, State of Amazonas at 03 degrees 04' 34" S, 59 degrees 57' 30" W, in an area covering nearly 800 hectares. Forty-one (41) sand fly species belonging to genus Lutzomyia were found attaining a total of 4662 specimens collected. Lutzomyia umbratilis was the dominant species at all heights, followed by Lutzomyia anduzei and Lutzomyia claustrei. The fauna alpha diversity index showed to be 6.4, which is not much lower than that reported for areas of continuous forest in this Amazonian region. This data provides additional evidence on Phlebotomine sand flies found to transmit Leishmania and other trypanosomatids to humans and other animals circulating in this area. This is the first study being reported on sand flies collected in an urban rainforest fragment in Amazonia. PMID- 23352956 TI - Advances with the Chinese anthelminthic drug tribendimidine in clinical trials and laboratory investigations. AB - The anthelminthic drug tribendimidine has been approved by Chinese authorities for human use in 2004, and a first comprehensive review was published in Acta Tropica in 2005. Here, we summarise further advances made through additional clinical trials and laboratory investigations. Two phase IV trials have been conducted in the People's Republic of China, the first one enrolling 1292 adolescents and adults aged 15-70 years and the second one conducted with 899 children aged 4-14 years who were infected with one or multiple species of soil transmitted helminths. Oral tribendimidine (single 400mg enteric-coated tablet given to adolescents/adults and 200mg to children) showed high cure rates against Ascaris lumbricoides (90.1-95.0%) and moderate-to-high cure rates against hookworm (82.0-88.4%). Another trial done in school-aged children using a rigorous diagnostic approach found a cure rate against hookworm of 76.5%. A single oral dose of tribendimidine showed only low cure rates against Trichuris trichiura (23.9-36.8%) confirming previous results. Tribendimidine administered to children infected with Enterobius vermicularis (two doses of 200mg each on consecutive days) resulted in a high cure rate (97.1%). Importantly, a series of randomised, exploratory trials revealed that tribendimidine shows interesting activity against the liver flukes Opisthorchis viverrini and Clonorchis sinensis, the tapeworm Taenia spp. and the threadworm Strongyloides stercoralis with respective cure rates of 70.0%, 40.0%, 53.3% and 36.4%. Pharmacokinetic studies in healthy Chinese volunteers indicated that after oral administration of tribendimidine, no parent drug was detected in plasma, but its primary metabolite, p-(1-dimethylamino ethylimino) aniline (aminoamidine, deacylated amidantel) (dADT), was found in plasma. dADT is then further metabolised to acetylated dADT (AdADT). dADT exhibits activity against several species of hookworm and C. sinensis in experimental studies, similar to that of tribendimidine. First studies elucidating the mechanism of action suggested that tribendimidine is an L-type nicotinic acetylcholine receptor agonist. Additional experimental studies revealed that the anti-parasite spectrum of tribendimidine is very broad. Indeed, to date, activity has been documented against 20 different nematode, trematode and cestode species. Taken together, tribendimidine warrants further scientific inquiry, including more comprehensive toxicity appraisals, mechanism of action studies and clinical investigation as it holds promise as a broad spectrum anthelminthics. PMID- 23352957 TI - Is measurement of non-HDL cholesterol an effective way to identify the metabolic syndrome? AB - BACKGROUND AND AIMS: The metabolic syndrome (MetS) has been shown to predict coronary heart disease (CHD). Non-high-density lipoprotein cholesterol (non-HDL C) is also known to predict CHD, and recent evidence indicated non-HDL-C was able to predict MetS in adolescents. The study aim was to determine whether non-HDL-C serves as a useful metabolic marker for MetS in adults. METHODS AND RESULTS: Fasting non-HDL-C measurements were obtained in 366 non-diabetic adults not on lipid-lowering therapy. In addition to traditional non-HDL-C cut-points based on Adult Treatment Panel III guidelines, receiver-operating characteristic curve analysis was used to identify an optimal cut-point for predicting MetS. A secondary goal was to assess the relationship between non-HDL-C and insulin resistance, defined as the upper tertile of steady-state plasma glucose concentrations measured during the insulin suppression test. Prevalence of MetS was 40% among participants. Those with MetS had higher mean non-HDL-C (4.17 +/- 1.0 vs 3.70 +/- 0.85 mmol/L, p < 0.001), and the upper vs lower tertile of non HDL-C concentrations was associated with 1.8-fold increased odds of MetS (p < 0.05). Traditional non-HDL-C cut-points >= 4.14 and >= 4.92 mmol/L demonstrated respective sensitivities 46% and 24% (specificities 72% and 89%) for identifying MetS. The optimal non-HDL-C cut-point >= 4.45 mmol/L had sensitivity 39% (specificity 82%). Comparable results were observed when non-HDL-C was used to identify insulin resistance. CONCLUSION: While MetS was associated with increased non-HDL-C, an effective non-HDL-C threshold to predict MetS in adults was not identified. Dyslipidemic nuances may explain why non-HDL-C may be less useful as a metabolic marker for MetS and/or insulin resistance than for CHD. PMID- 23352958 TI - Flight behavior and pheromone changes associated to Nosema ceranae infection of honey bee workers (Apis mellifera) in field conditions. AB - Parasites are known to cause the loss of individuals in social insects. In honey bee colonies the disappearance of foragers is a common factor of the wide extended colony losses. The emergent parasite of the European honey bee Nosema ceranae has been found to reduce homing and orientation skills and alter metabolism of forager bees. N. ceranae-infected bees also show changes in Ethyl Oleate (EO) levels, which is so far the only primer pheromone identified in workers that is involved in foraging behavior. Thus, we hypothesized that N. ceranae (i) modifies flight activity of honey bees and (ii) induces EO changes that can alter foraging behavior of nestmates. We compared flight activity of infected bees and non-infected bees in small colonies using an electronic optic bee counter during 28 days. We measured EO levels by gas chromatography-mass spectrometry and spore-counts. Bee mortality was estimated at the end of the experiment. Infected bees showed precocious and a higher flight activity than healthy bees, which agreed with the more elevated EO titers of infected bees and reduced lifespan. Our results suggest that the higher EO levels of infected bees might delay the behavioral maturation of same age healthy bees, which might explain their lower level of activity. We propose that delayed behavioral maturation of healthy bees might be a protective response to infection, as healthy bees would be performing less risky tasks inside the hive, thus extending their lifespan. We also discuss the potential of increased flight activity of infected bees to reduce pathogen transmission inside the hive. Further research is needed to understand the consequences of host behavioral changes on pathogen transmission. This knowledge may contribute to enhance natural colony defense behaviors through beekeeping practices to reduce probability of colony losses. PMID- 23352959 TI - Prevalence and associated factors of stress in the Malaysian Police Force. AB - OBJECTIVE: This study aims to determine the prevalence of stress and the associated socio-demographic and work factors among police personnel in Metropolitan Kuala Lumpur, Malaysia. METHOD: A cross-sectional study was conducted in two randomly selected police districts in Kuala Lumpur from 2009 to 2011. A total of 579 police officers from 11 police stations and two headquarters participated in this study. The 21-item Depression, Anxiety and Stress questionnaire was used. Multinomial logistic regression analyses were carried out to examine the effect of socio-demographic and work factors on stress. RESULTS: The overall prevalence of stress was 38.8% (95% CI 34.2, 43.6) with 5.9% (3.9, 8.8), 14.9% (11.6, 18.8) and 18.0% (14.5, 22.2) for severe, moderate and mild stress, respectively. Inspectors were more likely to suffer from severe stress (aOR 10.68, 95% CI 3.51, 32.53) compared to junior officers. Those who complained that their salaries were not commensurate with their jobs were more likely to suffer from moderate levels of stress (aOR 2.73, 95% CI 1.43, 5.22) compared to those who were happy with their salaries. CONCLUSIONS: This study strengthens findings that police job is stressful. Special attention needs to be paid to Inspector-level ranks and the remuneration structure of police officers to address this issue. PMID- 23352960 TI - Low nocturnal ocular perfusion pressure as a risk factor for normal tension glaucoma. AB - OBJECTIVES: In the absence of raised intraocular pressure (IOP), haemodynamic parameters have been implicated in the development of normal tension glaucoma (NTG). The purpose of this study is to compare 24-hour IOP and haemodynamic parameters in NTG patients and non-glaucoma patients. METHODS: This is a cross sectional study involving 72 NTG patients from University of Malaya Medical Centre eye clinic glaucoma registry. The non-glaucoma patients were volunteers selected from eye clinic patients. All enrolled patients underwent 24-hour IOP and blood pressure monitoring via 2-hourly IOP and blood pressure (BP) measurements. All readings were taken in the sitting position during the diurnal period and in the supine position during the nocturnal period RESULTS: Comparison of the haemodynamic parameters, the nocturnal mean systolic BP, nocturnal mean diastolic BP and nocturnal mean arterial pressure (MAP) were significantly lower in the NTG group. The systemic ocular perfusion pressures (OPP), diastolic OPP and mean OPP taken at night were also significantly lower in the NTG group. The differences between the groups were still manifest after controlling for age and presence of hypertension. CONCLUSION: Our findings show that the nocturnal supine blood pressure parameters (systolic, diastolic and mean) and OPP were significantly lower in the NTG group compared to normals. This may reflect defective autoregulatory mechanisms in NTG patients. PMID- 23352962 TI - Expression, function and cooperating partners of protease-activated receptor type 3 in vascular endothelial cells and B lymphocytes studied with specific monoclonal antibody. AB - Receptor-specific antibodies can both prevent ligand-receptor interaction and initiate receptor signaling. Previously we generated monoclonal antibody 8E8 (mAb 8E8) against protease-activated receptor type 3 (PAR3) which inhibited proliferation of B cell hybridoma. Here we used mAb 8E8 and PAR1-specific polyclonal antibody to reveal the functions and cooperating partners of PAR3 in endothelial cells and in B lymphocytes. MAb 8E8 or PAR1 agonist peptide stimulated IL-6 and IL-8 production and VCAM-1 expression in HPMEC-ST1.6R cells. PAR1 antibody stimulated only VCAM-1 expression, while ICAM-1 expression was stimulated with mAB 8E8 or PAR3 peptide. MAb 8E8 stimulated weak mitogenic response, while PAR1 antibody inhibited it in normal but not in malignant B lymphocytes. Sandwich ELISA assay demonstrated the interaction of PAR3 with PAR1 in malignant cell lines and with IgM in normal B lymphocytes. It is concluded that PAR3 cooperates with PAR1 to mediate the effect of thrombin on cytokine production and VCAM-1 expression in endothelial cells and on cell proliferation in malignant B cells. ICAM-1 expression in endothelial cells requires PAR3 without PAR1. The inhibitory effect of thrombin in normal B lymphocytes is mediated by PAR1 alone, while mitogenic and pro-survival signaling in B lymphocytes is provided through PAR3 in cooperation with BCR. PMID- 23352961 TI - Granzyme H induces cell death primarily via a Bcl-2-sensitive mitochondrial cell death pathway that does not require direct Bid activation. AB - Natural killer and T cell-mediated cytotoxicity is important for the elimination of viruses and transformed cells. The granule lytic pathway utilizes perforin and granzymes to induce cell death, while receptor-mediated lytic pathways rely on molecules such as FasL. Pro-apoptotic activities of Granzyme B (GrB) and Fas are well-established, and many of their cellular targets have been identified. However, humans express additional related granzymes - GrA, GrM, GrK, and GrH. Neither the cytotoxic potential of GrH, nor the mechanism by which GrH may induce target cell death is currently understood. We proposed that GrH would have pro apoptotic activity that would be distinct from that of GrB and FasL, which could be relevant when Fas/FasL or GrB activity or death pathways were impaired. Our results, using a purified recombinant form of GrH, revealed that GrH induced cell death via a Bcl-2-sensitive mitochondrial pathway without direct processing of Bid. Additionally, neither the apoptosome nor caspase-3 was essential to the induction of GrH-mediated cell death. However, GrH did directly process DFF45, potentially leading to DNA damage. Our findings support the idea that multiple, non-redundant death pathways may be initiated by cytotoxic cells to counteract various immune evasion strategies. PMID- 23352963 TI - CO2 homeostasis is maintained in conscious humans by regulation of tidal volume, but not of respiratory rhythm. AB - Automatic regulation of tidal volume (VT) maintains CO2 homeostasis when spontaneous respiratory rhythm is replaced with a cortically triggered rhythm. We examined whether automatic regulation of respiratory frequency (fR) could maintain CO2 homeostasis at rest if the VT is cortically designated in experiments performed in 21 conscious humans. First, volitionally controlled fR at levels lower than baseline resulted in a larger VT, maintaining end-tidal CO2 fraction constant at eupneic levels. However, when fR was volitionally controlled at levels higher than baseline, end-tidal CO2 fraction decreased unexpectedly. Next, when the VT was volitionally constrained but fr was freely chosen, end tidal CO2 fraction decreased. The present study revealed some limitations in the control of CO2 homeostasis by automatic regulation of fR, probably because respiratory rhythm is susceptible to non-metabolic factors. This study also showed the importance of automatic regulation of VT in maintaining CO2 homeostasis at rest. Nevertheless, automatic regulation of VT was incomplete when fR was volitionally imposed at high levels. PMID- 23352964 TI - Evidence of different G-quadruplex DNA binding with biogenic polyamines probed by electrospray ionization-quadrupole time of flight mass spectrometry, circular dichroism and atomic force microscopy. AB - The binding properties of five G-quadruplex oligonucleotides (humtel24, k-ras32, c-myc22, c-kit1 and c-kit2) with polyamines have been investigated by electrospray ionization-quadrupole time of flight mass spectrometry, circular dichroism, melting temperature, atomic force microscopy (AFM) and molecular simulation. The MS results demonstrated that the polyamines and G-quadruplex DNA can form complexes with high affinity, and one molecule of G-quadruplex DNA can combine several molecules (1-5) of polyamines. The binding affinities of the polyamines to DNA were in the order of spermine > spermidine > putrescine. After binding with polyamines, the conformations of the G-quadruplex DNA were significantly changed, and spermine can induce the configurations of k-ras32 and c-kit1 to deviate from their G-quadruplex structures at high concentrations. In the presence of K(+), the conformations of G-quadruplex DNA were stabilized, while polyamines can also induced alterations of their configurations. Melting temperature experiments suggested that the Tm of the DNA-polyamine complexes obviously increased both in the absence and presence of K(+). The AFM results indicated that polyamines can induce aggregation of G-quadruplex DNA. Above results illustrated that the polyamines bound with the phosphate backbone and the base-pairs of G-quadruplex structures. Combining with the molecular simulation, the binding mode of the G-quadruplex DNA and polyamines were discussed. The results obtained would be beneficial for understanding the biological and physiological functions of polyamines and provide useful information for development of antitumor drugs. PMID- 23352965 TI - Up-regulation of neutrophil activating protein in Helicobacter pylori under high salt stress: structural and phylogenetic comparison with bacterial iron-binding ferritins. AB - It is generally accepted that most gastrointestinal diseases are probably caused by the bacterial pathogen Helicobacter pylori (H. pylori). In this study we have focused on the comparison of protein expression profiles of H. pylori grown under normal and high-salt conditions by a proteomics approach. We have identified about 190 proteins whose expression levels changed after growth at high salt concentration. Among these proteins, neutrophil-activating protein (NapA) was found to be consistently up-regulated under osmotic stress brought by high salts. We have investigated the effect of high salt on secondary and tertiary structures of NapA by circular dichroism spectroscopy followed by analytical ultracentrifugation to monitor the change of quaternary structure of recombinant NapA with increasing salt concentration. The loss of iron-binding activity of NapA coupled with noticeable energetic variation in protein association of NapA as revealed by isothermal titration calorimetry was found under high salt condition. The phylogenetic tree analysis based on sequence comparison of 16 protein sequences encompassing NapA proteins and ferritin of H. pylori and other prokaryotic organisms pointed to the fact that all H. pylori NapA proteins of human origin are more homologous to NapA of Helicobacter genus than to other bacterial NapA. Based on computer modeling, NapA proteins from H. pylori of human isolates are found more similar to ferritin from H. pylori than to NapA from other species of bacteria. Taken together, these results suggested that divergent evolution of NapA and ferritin possessing dissimilar and diverse sequences follows a path distinct from that of convergent evolution of NapA and ferritin with similar dual functionality of iron-binding and ferroxidase activities. PMID- 23352966 TI - Supraorbital eyebrow craniotomy for removal of intraaxial frontal brain tumors: a technical note. AB - OBJECTIVE: To present the utility and selection criteria for the supraorbital (SO) craniotomy, an approach commonly used to remove extraaxial tumors such as meningiomas and craniopharyngiomas, to resect intraaxial frontal brain lesions. METHODS: All consecutive patients who underwent a SO craniotomy for an intraaxial lesion were retrospectively analyzed for lesion location, pathology, extent of resection, operative times, length of stay, and complications. RESULTS: During 28 months, 10 patients (mean age, 67.6 years; 7 women) underwent 11 SO procedures to resect intraaxial brain lesions. Pathologies included metastatic carcinoma (n = 7), glioma (n = 2), and radiation necrosis (n = 1). The mean distance of the shortest trajectory to the lesion was 2.4 mm. Gross total or near-total removal was achieved in 80% of the cases. Median length of hospital stay was 3 days (range, 2-6 days); it was 2 days for patients admitted electively for SO craniotomy. There were no new neurologic deficits, postoperative hematomas, or cerebrospinal fluid leaks. CONCLUSIONS: The SO "eyebrow" craniotomy is a safe and effective keyhole method to remove intraaxial frontal lobe lesions, particularly lesions of the frontal pole and orbitofrontal region, allowing for minimal disruption of normal brain parenchyma and promoting a rapid recovery and short hospital stay. Metastatic tumors and select gliomas in this area are most amenable to this approach. Deeper intraaxial tumors can also be effectively accessed via this route with excellent clinical outcomes. PMID- 23352967 TI - The complement system contributes to the pathology of experimental autoimmune encephalomyelitis by triggering demyelination and modifying the antigen-specific T and B cell response. AB - So far, studies of the human autoimmune disease multiple sclerosis (MS) have largely been hampered by the absence of a pathogenic B cell component in its animal model, experimental autoimmune encephalomyelitis (EAE). To overcome this shortcoming, we have previously introduced the myelin basic protein (MBP) proteolipid protein (PLP) MP4-induced EAE, which is B cell and autoantibody dependent. Here we show that MP4-immunized wild-type C57BL/6 mice displayed a significantly lower disease incidence when their complement system was transiently depleted by a single injection of cobra venom factor (CVF) prior to immunization. Considering the underlying pathomechanism, our data suggest that the complement system is crucial for MP4-specific antibodies to trigger CNS pathology. Demyelinated lesions in the CNS were colocalized with complement depositions. In addition, B cell deficient JHT mice reconstituted with MP4 reactive serum showed significantly attenuated clinical and histological EAE after depletion of complement by CVF. The complement system was also critically involved in the generation of the MP4-specific T and B cell response: in MP4 immunized wild-type mice treated with CVF the MP4-specific cytokine and antibody response was significantly attenuated compared to untreated wild-type mice. Taken together, we propose two independent mechanisms by which the complement system can contribute to the pathology of autoimmune encephalomyelitis. Our data corroborate the role of complement in triggering antibody-dependent demyelination and antigen-specific T cell immunity and also provide first evidence that the complement system can modify the antigen-specific B cell response in EAE and possibly MS. PMID- 23352968 TI - Increased Th17 response to myelin peptides in pediatric MS. AB - Studies of the underlying immune mechanisms of multiple sclerosis (MS) in children may shed light on the initial events of MS pathogenesis. We studied T cell responses to myelin peptides in 10 pediatric MS patients (PMS), 10 pediatric healthy controls (PHC), 10 adult MS patients (AMS) and 10 adult healthy controls (AHC). A significantly higher proportion of divided CD4+ T cell responses in response to myelin peptides by the CFSE assay in PMS compared to PHC at both concentrations of myelin peptide tested (t test, 95% CI, p=0.0067 for MP1; p=0.0086 for MP10), and between PMS and AMS (p=0.0012 at 1 MUg/mL of myelin peptides, p<0.0001 at 10 MUg/mL) was found. In addition, T cells with a central memory phenotype producing IL-17 were increased in PMS compared to PHC (p<0.05). IL-7 levels in culture supernatants were elevated in PMS compared to PHC and AMS (t test<0.01). PMID- 23352969 TI - Inhibition of CYP2E1 leads to decreased malondialdehyde-acetaldehyde adduct formation in VL-17A cells under chronic alcohol exposure. AB - AIM: Ethanol metabolism leads to the formation of acetaldehyde and malondialdehyde. Acetaldehyde and malondialdehyde can together form malondialdehyde-acetaldehyde (MAA) adducts. The role of alcohol dehydrogenase (ADH) and cytochrome P4502E1 (CYP2E1) in the formation of MAA-adducts in liver cells has been investigated. MAIN METHODS: Chronic ethanol treated VL-17A cells over-expressing ADH and CYP2E1 were pretreated with the specific CYP2E1 inhibitor - diallyl sulfide or ADH inhibitor - pyrazole or ADH and CYP2E1 inhibitor - 4 methyl pyrazole. Malondialdehyde, acetaldehyde or MAA-adduct formation was measured along with assays for viability, oxidative stress and apoptosis. KEY FINDINGS: Inhibition of CYP2E1 with 10 MUM diallyl sulfide or ADH with 2mM pyrazole or ADH and CYP2E1 with 5mM 4-methyl pyrazole led to decreased oxidative stress and toxicity in chronic ethanol (100 mM) treated VL-17A cells. In vitro incubation of VL-17A cell lysates with acetaldehyde and malondialdehyde generated through ethanol led to increased acetaldehyde (AA)-, malondialdehyde (MDA)-, and MAA-adduct formation. Specific inhibition of CYP2E1 or ADH and the combined inhibition of ADH and CYP2E1 greatly decreased the formation of the protein aldehyde adducts. Specific inhibition of CYP2E1 led to the greatest decrease in oxidative stress, toxicity and protein aldehyde adduct formation, implicating that CYP2E1 accelerates the formation of protein aldehyde adducts which can be an important mechanism for alcohol mediated liver injury. SIGNIFICANCE: CYP2E1 mediated metabolism of ethanol leads to increased AA-, MDA-, and MAA-adduct formation in liver cells which may aggravate liver injury. PMID- 23352970 TI - Investigation into mechanisms mediating the inhibitory effect of 1,4 benzodiazepines on mast cells by gene expression profiling. AB - AIMS: This study aims to identify by a molecular genetic approach potential targets in mast cells at which 1,4-benzodiazepines may cause their inhibitory effect on mast cell activity. MAIN METHODS: Gene expression analyses with microarray gene chip and/or quantitative PCR were performed using 1,4 benzodiazepine-treated human mast cell leukemia HMC-1.2 cells, promyelocytic leukemia HL-60 cells and human mast cells from healthy volunteers and patients with mast cell activation disease (MCAD). Pathway analysis was applied to search for enriched biological functions and canonical pathways within differentially regulated genes. KEY FINDINGS: Both neoplastic and normal human mast cells express several GABA(A) receptor subunits at the mRNA level. In mast cells from MCAD patients expression of some GABA(A) receptor subunits and expression of the translocator protein TSPO are increased compared with those from healthy controls. Expression of the protein tyrosine kinases Lyn, Fgr and Yes1 was increased in HMC-1.2 cells as compared with the ontogenetically related HL60 cells. Differences in gene regulation in HMC-1.2 cells after treatment with the 1,4-benzodiazepines clonazepam, flunitrazepam and 4-chlorodiazepam suggested that signaling and gene expression induced by clonazepam was similar to that of flunitrazepam but different from that of 4-chlorodiazepam. This conclusion is supported by the results of the pathway analysis. SIGNIFICANCE: A novel type of GABA(A) receptors on mast cells appears to be involved in the inhibition of mast cell activity by 1,4-benzodiazepines. These receptors seem to be composed without gamma subunits suggesting unique pharmacological properties. An action at Src kinases, or at TSPO located in the plasma membrane may also be involved. PMID- 23352972 TI - Inhibition by menthol and its related chemicals of compound action potentials in frog sciatic nerves. AB - AIMS: Transient receptor potential (TRP) vanilloid-1 (TRPV1) and melastatin-8 (TRPM8) channels play a role in transmitting sensory information in primary afferent neurons. TRPV1 agonists at high concentrations inhibit action potential conduction in the neurons and thus have a local anesthetic effect. The purpose of the present study was to know whether TRPM8 agonist menthol at high concentrations has a similar action and if so whether there is a structure activity relationship among menthol-related chemicals. MAIN METHODS: Compound action potentials (CAPs) were recorded from the frog sciatic nerve by using the air-gap method. KEY FINDINGS: (-)-Menthol and (+)-menthol concentration dependently reduced CAP peak amplitude with the IC(50) values of 1.1 and 0.93 mM, respectively. This (-)-menthol activity was resistant to non-selective TRP antagonist ruthenium red; TRPM8 agonist icilin did not affect CAPs, indicating no involvements of TRPM8 channels. p-Menthane, (+)-limonene and menthyl chloride at 7-10 mM minimally affected CAPs. On the other hand, (-)-menthone, (+)-menthone, ( )-carvone, (+)-carvone and (-)-carveol (in each of which chemicals OH or O group was added to p-menthane and limonene) and (+)-pulegone inhibited CAPs with extents similar to that of menthol. 1,8-Cineole and 1,4-cineole were less effective while thymol and carvacrol were more effective than menthol in inhibiting CAPs. SIGNIFICANCE: Menthol-related chemicals inhibited CAPs and were thus suggested to exhibit local anesthetic effects comparable to those of lidocaine and cocaine as reported previously for frog CAPs. This result may provide information to develop local anesthetics on the basis of the chemical structure of menthol. PMID- 23352971 TI - Varenicline and nicotine enhance GABAergic synaptic transmission in rat CA1 hippocampal and medial septum/diagonal band neurons. AB - AIMS: The FDA approved smoking cessation aid varenicline can effectively attenuate nicotine-stimulated dopamine release. Varenicline may also exert important actions on other transmitter systems that also influence nicotine reinforcement or contribute to the drug's cognitive and affective side effects. In this study, we determined if varenicline, like nicotine, can stimulate presynaptic GABA release. MAIN METHODS: Using whole-cell patch-clamp techniques, we measured GABA(A)R-mediated asynchronous, spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in acute brain slices from two brain regions important for learning and memory, the hippocampus and basal forebrain. KEY FINDINGS: Both varenicline (10 MUM) and nicotine (10 MUM) applications alone resulted in small but significant increases in amplitude, as well as robustly enhanced frequency of mIPSCs in hippocampal CA1 pyramidal neurons and medial septum/diagonal band (MS/DB) neurons. A unique subpopulation of MS/DB neurons showed decreases in frequency. In the presence of nicotine, varenicline effectively attenuated the expected enhancement of hippocampal mIPSC frequency like a competitive antagonist. However, in the MS/DB, varenicline only partially attenuated nicotine's effects. Reversing the order of drug application by adding nicotine to varenicline-exposed slices had little effect. SIGNIFICANCE: Varenicline, like nicotine, stimulates presynaptic GABA release, and also exerts a partial agonist action by attenuating nicotine-stimulated release in both the hippocampus and basal forebrain. These effects could potentially affect cognitive functions. PMID- 23352973 TI - Atrial stretch delays gastric emptying of liquids in awake rats. AB - AIMS: We previously reported that mechanical atrial stretch (AS) by balloon distention increased gastric tonus in anesthetized rats. The present study evaluated the effect of AS on the gastric emptying of a liquid test meal in awake rats and its underlying neural mechanisms. MAIN METHODS: Anesthetized male rats received a balloon catheter into the right atrium and a gastrostomy cannula. The next day, mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), and cardiac output (CO) were continuously monitored. After the first 20min of monitoring (basal interval), the balloon was either distended or not (control) with 30, 50, or 70MUl saline for 5min. Fifteen minutes later, the rats received the test meal (glucose solution with phenol red), and fractional gastric dye retention was determined 10, 20, or 30min later. KEY FINDINGS: Heart rate and CVP values were transiently increased by 50 or 70MUl AS but not 30MUl AS, whereas gastric emptying was slower after 30, 50, or 70MUl AS than after sham distention. Subdiaphragmatic vagotomy or splanchnicotomy+celiac ganglionectomy and capsaicin, ondansetron, hexamethonium, L-NAME, and glibenclamide treatment prevented the AS induced delay in gastric emptying, whereas atropine and guanethidine treatment failed to prevent it. SIGNIFICANCE: Atrial stretch inhibited the gastric emptying of liquid via non-adrenergic and non-cholinergic pathways that activate nitric oxide-K(+)ATP channels. PMID- 23352975 TI - Curcumin induces FasL-related apoptosis through p38 activation in human hepatocellular carcinoma Huh7 cells. AB - AIM: The aim of this study is to explore the underlying molecular mechanism of curcumin-induced apoptosis in human hepatocellular carcinoma (HCC) Huh7 cells. MAIN METHODS: Fas and FasL mRNA expression was analyzed by reverse transcription PCR. Western blot was applied to detect the protein expression of Bcl-2 family members, MAPK family members, c-Jun, c-Fos, ATF-2, caspase-3, PARP, TNF receptor family members and the respective ligands. Apoptotic cells were assayed with annexin V/PI double staining and flow cytometry. KEY FINDINGS: Curcumin treatment resulted in a fast and significant increase of Fas and Fas ligand (FasL) along with activation of caspase-3 and cleavage of PARP in Huh7 cells. Inhibition of caspase-3 activity by the specific inhibitor Z-DEVD-FMK rescued Huh7 cells from curcumin-induced apoptosis. Neutralization of FasL significantly protected the cells from curcumin-induced caspase-3 activation and apoptosis in a dose dependent manner. Moreover, p38 was rapidly activated in response to curcumin, and inactivation of p38 by pharmacologic inhibitor SB203580 dramatically suppressed curcumin-induced FasL expression and apoptosis. SIGNIFICANCE: Our results demonstrated that curcumin induces apoptosis through p38-denpendent up regulation of FasL in Huh7 cells. PMID- 23352976 TI - Polymorphisms in genes encoding aquaporins 4 and 5 and estrogen receptor alpha in patients with Meniere's disease and sudden sensorineural hearing loss. AB - AIMS: The etiologies of Meniere's disease and idiopathic sudden sensorineural hearing loss (SSNHL) remain unclear. The homeostasis of the water and blood circulation in the inner ear is essential for maintaining its hearing and equilibrium functions, and aquaporins and estrogen are involved in the fluid or ion balance in the inner ear. We investigated the associations between genetic polymorphisms in aquaporin 4 (AQP4, rs2075575), aquaporin 5 (AQP5, rs3736309), and estrogen receptor alpha (ERalpha1, rs2234693; ERalpha2, rs9340799) and susceptibility to Meniere's disease or SSNHL. MAIN METHODS: We compared 86 patients affected by Meniere's disease, 85 patients affected by SSNHL, and 2136 adults who were participants in a comprehensive longitudinal study of aging. KEY FINDINGS: With the AQP5 polymorphism, the odds ratio for Meniere's disease was 0.676 (95% confidence interval: 0.477-0.957) after adjustment for age and sex, when an additive genetic model was used. The AQP5 polymorphism entailed no significant risk of SSNHL and the polymorphisms of AQP4, ERalpha1, and ERalpha2 entailed no significant risk of Meniere's disease or SSNHL in the additive genetic model, regardless of adjustments for age and sex. SIGNIFICANCE: Our study suggests that the variant G allele of AQP5 polymorphism rs3736309 reduces the risk of Meniere's disease. PMID- 23352977 TI - Inhibition by capsaicin and its related vanilloids of compound action potentials in frog sciatic nerves. AB - AIMS: Although capsaicin not only activates transient receptor potential vanilloid-1 (TRPV1) channels but also inhibits nerve conduction, the latter action has not yet been fully examined. The purpose of the present study was to know whether various vanilloids have an inhibitory action similar to that of capsaicin and further to compare their actions with that of local anesthetic procaine. MAIN METHODS: Fast-conducting compound action potentials (CAPs) were recorded from frog sciatic nerve fibers by using the air-gap method. KEY FINDINGS: Capsaicin reversibly and concentration-dependently reduced the peak amplitude of the CAP. TRPV1 antagonist capsazepine did not affect the capsaicin activity, and powerful TRPV1 agonist resiniferatoxin had no effect on CAPs, indicating no involvement of TRPV1 channels. Capsaicin analogs and other various vanilloids also inhibited CAPs in a concentration-dependent manner. An efficacy sequence of these inhibitions was capsaicin=dihydrocapsaicin>capsiate>eugenol>guaiacol>=zingerone>=vanillin>vanilly amine. Vanillic acid had almost no effect on CAPs; olvanil and curcumin appeared to be effective less than capsaicin. Capsaicin and eugenol were, respectively, ten- and two-fold effective more than procaine in CAP inhibition, while each of guaiacol, zingerone and vanillin was five-fold effective less than procaine. SIGNIFICANCE: Various vanilloids exhibit CAP inhibition, the extent of which is determined by the property of the side chain bound to the vanillyl group, and some of them are more effective than procaine. These results may serve to unveil molecular mechanisms for capsaicin-induced conduction block and to develop antinociceptive drugs related to capsaicin. PMID- 23352974 TI - Hyperoxia and transforming growth factor beta1 signaling in the post-ischemic mouse heart. AB - AIMS: Following ischemic injury, myocardial healing and remodeling occur with characteristic myofibroblast trans-differentiation and scar formation. The current study tests the hypothesis that hyperoxia and nitric oxide (NO) regulate TGF-beta1 signaling in the post-ischemic myocardium. MAIN METHODS: C57BL/6 wild type (WT), endothelial and inducible nitric oxide synthase knockout (eNOS(-/-) and iNOS(-/-)) mice were subjected to 30-min left anterior descending coronary artery occlusion followed by reperfusion. Myocardial tissue oxygenation was monitored with electron paramagnetic resonance oximetry. Protein expressions of TGF-beta1, receptor-activated small mothers against decapentaplegic homolog (Smad), p21 and alpha-smooth muscle actin (alpha-SMA) were measured with enzyme linked immunosorbent assay (ELISA), Western immunoblotting, and immunohistochemical staining. KEY FINDINGS: There was a hyperoxic state in the post-ischemic myocardial tissue. Protein expressions of total and active TGF beta1, p-Smad2/3 over t-Smad2/3 ratio, p21, and alpha-SMA were significantly increased in WT mice compared to Sham control. Knockout of eNOS or iNOS further increased protein expression of these signals. The expression of alpha-SMA was more abundant in the infarct of eNOS(-/-) and iNOS(-/-) mice than WT mice. A protein band indicating nitration of TGF-beta type-II receptor (TGFbetaRII) was observed from WT heart. Carbogen (95% O2 plus 5% CO2) treatment increased the ratio of p-Smad2/t-Smad2, which was inhibited by 10006329 EUK (EUK134) and sodium nitroprusside (SNP). In conclusion, hyperoxia up-regulated and NO/ONOO(-) inhibited cardiac TGF-beta1 signaling and myofibroblast trans-differentiation. SIGNIFICANCE: These findings may provide new insights in myocardial infarct healing and repair. PMID- 23352978 TI - Sensitization of TRAIL-induced apoptosis in human hepatocellular carcinoma HepG2 cells by phytochemicals. AB - AIMS: The present study investigated and compared the potential chemosensitizing effect of indole-3-carbinol (I3C) and epigallocatechin-3-gallate (EGCG) on TRAIL induced apoptosis in human hepatocellular carcinoma (HCC) HepG2 cells as well as the possible mechanisms underlying these modulatory effects, particularly their effects on TRAIL death receptors (DR), Bcl-2 and c-FLIP proteins expression. MAIN METHODS: HepG2 cells were treated with different concentrations of TRAIL ranging from 3 to 400ng/ml for 24h. For studying the modulatory effects of the phytochemicals on TRAIL-induced apoptosis, I3C and EGCG were used at concentrations that inhibit only 5% of the cells which were found to be 110MUM and 70MUg/ml, respectively. KEY FINDINGS: It was found that 24h pre-treatment of HepG2 cells with either 110MUM I3C or 70MUg/ml EGCG significantly enhanced TRAIL cytotoxicity. EGCG induced more reduction in IC50 of TRAIL compared to I3C. Nevertheless, I3C was more efficient than EGCG in enhancing TRAIL cytotoxicity at higher concentrations of TRAIL. Both I3C and EGCG significantly increased caspase 3 activity, DNA fragmentation percentage, DR4 and DR5 protein expression as well as decreased Bcl-2 protein expression when compared to control groups. SIGNIFICANCE: Both I3C and EGCG chemosensitized HCC HepG2 cells to TRAIL-induced apoptosis. These modulatory effects were partially attributed to the up regulation of caspase-3 activity and DR4 and DR5 expression, as well as down regulation of Bcl-2 expression. Only EGCG was able to induce a significant decrease in c-FLIP expression level. PMID- 23352979 TI - Characteristics of Mexican American elders admitted to nursing facilities in the United States: data from the Hispanic Established Populations for Epidemiologic Studies of the Elderly (EPESE) study. AB - OBJECTIVES: The purpose of the current study was to describe the factors associated with Mexican American elders in the Southwestern United States who have spent time in a skilled nursing facility (SNF) compared with those who have not. DESIGN: Data were collected on the Mexican American elders who reported an SNF stay within 10 years of baseline. PARTICIPANTS: A probability sample of 3050 Mexican American elders from five Southwestern states followed from 1993 to 2005 were examined. MEASURES: Variables examined included sociodemographics, language of interview, disabilities with instrumental activities of daily living, activities of daily living, self-reported health, cognitive status, and depression. RESULTS: A total of 78 (3.9%) of 2020 subjects resided in SNFs. Using univariate analyses, older age, English-language interview, poorer cognitive status, and functional disabilities were independently associated with SNF admissions. Logistic regression analyses controlling for age revealed that SNF patients were older (OR = 1.08, P = .001), had an activities of daily living disability (OR = 4.94, P < .001), scored in the depressed range in the Geriatric Depression Scale (OR = 2.72, P = .001), and were more likely to interview in English (OR = 1.95, P = .042), when compared with community counterparts. CONCLUSIONS: Mexican American elders who resided in an SNF at some point in the previous 10 years were older, and were more likely to be functionally impaired. They also were more likely to prefer English as their primary language, indicating they were more likely to agree to an SNF stay than their Spanish speaking counterparts. PMID- 23352980 TI - PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells. AB - Radiotherapy plays a critical role in the treatment of non-small cell lung cancer (NSCLC). However, radioresistance is a major barrier against increasing the efficiency of radiotherapy for NSCLC. To understand the mechanisms underlying NSCLC radioresistance, we previously focused on the potential involvement of PIM1, PRAS40, FOXO3a, 14-3-3, and protein phosphatases. Among these proteins, PIM1 functioned as an oncogene and was found to act as a crucial mediator in radioresistant NSCLC cells. Therefore, we investigated the use of PIM1-specific inhibitors as novel therapeutic drugs to regulate radiosensitivity in NSCLC. After structure-based drug selection, SGI-1776, ETP-45299, and tryptanthrin were selected as candidates of PIM1 inhibitors that act as radiosensitizers. With irradiation, these drugs inhibited only PIM1 kinase activity without affecting PIM1 mRNA/protein levels or cellular localization. When PIM1 kinase activity was suppressed by these inhibitors, PRAS40 was not phosphorylated. Consequently, unphosphorylated PRAS40 did not form trimeric complexes with 14-3-3 and FOXO3a, leading to increased nuclear localization of FOXO3a. Nuclear FOXO3a promoted the expression of pro-apoptotic proteins such as Bim and FasL, resulting in a radiosensitizing effect on radioresistant NSCLC cells. Moreover, an in vivo xenograft mouse model confirmed this radiosensitizing effect induced by PIM1 inhibitors. In these model systems, tumor volume was significantly reduced by a combinational treatment with irradiation and PIM1 inhibitors compared to irradiation alone. Taken together, our findings provided evidence that PIM1 specific inhibitors, SGI-1776, ETP-45299, and tryptanthrin, can act as novel radiosensitizers to enhance the efficacy of radiotherapy by inhibiting irradiation-induced signaling pathway associated with radioresistance. PMID- 23352981 TI - Diabetes-induced loss of gastric ICC accompanied by up-regulation of natriuretic peptide signaling pathways in STZ-induced diabetic mice. AB - Our previous study demonstrated that natriuretic peptides (NPs) play an inhibitory role in regulation of gastric smooth muscle motility. However, it is not clear whether NPs are involved in diabetics-induced loss of gastric interstitial cell of Cajal (ICC). The present study was designed to investigate the relationship between diabetics-induced loss of gastric ICC and natriuretic peptide signaling pathway in streptozotocin (STZ)-induced diabetic mice. The results showed that the protein expression levels of c-Kit and membrane-bound stem cell factor (mSCF) in gastric smooth muscle layers were decreased in STZ induced diabetic mice. However, both mRNA and protein expression levels of natriuretic peptide receptor (NPR)-A, B and C were increased in the same place of the diabetic mice. The amplitude of spontaneous contraction in gastric antral smooth muscles was inhibited by C-type natriuretic peptide (CNP) dose-dependently and the inhibitory effect was potentiated in diabetic mice. Pretreatment of the cultured gastric smooth muscle cells (GSMCs) with different concentration of CNP can significantly decrease the mSCF expression level. 8-Bromoguanosine-3',5' cyclomo-nophosphate (8-Br-cGMP), a membrane permeable cGMP analog, mimicked the effect of CNP but not cANF (a specific NPR-C agonist). Methylthiazolyldiphenyl tetrazolium bromide (MTT) assay showed that high concentration of cANF (10(-6) mol/L) inhibited cell proliferation in cultured GSMCs. These findings suggest that up-regulation of NPs/NPR-A, B/cGMP and NPs/NPR-C signaling pathways may be involved in diabetes-induced loss of gastric ICC. PMID- 23352982 TI - Response surface modeling to predict fluid loss from beef strip loins and steaks injected with salt and phosphate with or without a dehydrated beef protein water binding adjunct. AB - This study was conducted using response surface methodology to predict fluid loss from injected beef strip steaks as influenced by levels of salt and sodium phosphates (SP) in the injection brine. Also, a beef-based dehydrated beef protein (DBP) water binding ingredient was evaluated. Paired U.S. select beef strip loins were quartered before being injected with 110% of initial weight with brines containing various concentrations of salt and SP (CON) or salt, SP and 5% DBP. Steaks were sliced, overwrapped and stored in the dark for 4d. Purge values ranged from 0.6% to 4.6% for CON and 0.3% to 2.1% for DBP. Fluid losses when accounting for the fluid lost from injection to slicing were as high as 6.8% for CON brines, but only 2.8% for DBP brines. The equations generated here and the DBP product could help producers achieve acceptable purge while reducing sodium use. PMID- 23352983 TI - [Mycoplasma pneumoniae: a cause of febrile hemolytic anemia in travelers]. AB - Mycoplasma pneumoniae can cause varied hematologic manifestations that are frequently associated with lower respiratory tract infections. Acute febrile hemolysis without respiratory symptoms is quite rare. We describe the case of a 25-year-old man, admitted for acute fever with hemolysis, after returning from Djibouti. M. pneumoniae infection was proved by serological testing. A favorable outcome followed macrolide treatment. PMID- 23352984 TI - G-protein-coupled receptor kinase interactor-1 serine 419 accelerates premature synapse formation in cortical neurons by interacting with Ca(2+)/calmodulin dependent protein kinase IIbeta. AB - In the present study, we investigated the mechanisms of brain derived neurotrophic factor (BDNF) in regulating cortical neuron premature synapse formation. KN-93, a specific inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), and G-protein-coupled receptor kinase interactor-1 (G1T1) siRNA were utilized, and the premature synapse formation of cortical neurons was detected under BDNF stimulation. Plasmids HA-GIT1, HA-GIT1 (DeltaSLD), HA-GIT1 (S419A) and Flag-CaMKIIbeta were constructed. The interaction between GIT1 and CaMKIIbeta, and their influence on the premature synapse formation of BDNF stimulated cortical neurons were examined. BDNF-stimulated cortical neurons were associated with increased premature synapse formation, the enhancement of phosphorylation for CaMKIIbeta, and the combination of GIT1 and p-CaMKII(thr286). G1T1 siRNA and KN-93 inhibited premature synapse formation in cortical neurons. The interaction between GIT1 and CaMKIIbeta required SLD domain and serine 419 in GIT1. BDNF-induced CaMKIIbeta phosphorylation and premature synapse formation were suppressed in GIT1 (S419A) transfected cortical neurons. By interacting with CaMKIIbeta, G1T1 (S419) were shown to participate in BDNF-induced premature synapse formation within cortical neurons. PMID- 23352985 TI - Evidence for the involvement of 5-HT1A receptor in the acute antidepressant-like effect of creatine in mice. AB - Creatine was previously shown to produce an antidepressant-like effect in the tail suspension test through a modulation of the dopaminergic system. In this study, the mechanisms underlying its antidepressant-like effect were further evaluated by investigating the involvement of the serotonergic system in its effect. The anti-immobility effect of creatine (1mg/kg) was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100mg/kg, i.p., for 4 consecutive days, an inhibitor of serotonin (5-HT) synthesis). Creatine (0.01 mg/kg, sub-effective dose) in combination with sub-effective doses of WAY100635 (0.1mg/kg, s.c., a 5-HT1A receptor antagonist), 8-OH-DPAT (0.1mg/kg, i.p., a 5-HT1A receptor agonist) or selective serotonin reuptake inhibitors fluoxetine (5mg/kg, p.o.), paroxetine (0.1mg/kg, p.o.), citalopram (0.1mg/kg, p.o.) and sertraline (3mg/kg, p.o.) reduced the immobility time in the tail suspension test as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an interaction with 5-HT1A receptors. Of note, the present results also indicate that creatine improves the effectiveness of the selective serotonin reuptake inhibitors, a finding that may have therapeutic implications for the treatment of depressive disorders. PMID- 23352986 TI - Differential regulation of drug transporter expression by all-trans retinoic acid in hepatoma HepaRG cells and human hepatocytes. AB - All-trans retinoic acid (atRA) is the active form of vitamin A, known to activate retinoid receptors, especially the heterodimer retinoid X receptor (RXR):retinoic acid receptor (RAR) that otherwise may play a role in regulation of some drug transporters. The present study was designed to characterize the nature of human hepatic transporters that may be targeted by atRA and the heterodimer RXR:RAR. Exposure of human hepatoma HepaRG cells and primary human hepatocytes to 5 MUM atRA down-regulated mRNA levels of various sinusoidal solute carrier (SLC) influx transporters, including organic anion transporting polypeptide (OATP) 2B1, OATP1B1, organic cation transporter (OCT) 1 and organic anion transporter (OAT) 2, and induced those of the canalicular breast cancer resistance protein (BCRP). The retinoid concomitantly reduced protein expression of OATP2B1 and OATP1B1 and activity of OATPs and OCT1 and induced BCRP protein expression in HepaRG cells. Some transporters such as OATP1B3 and the bile salt export pump (BSEP) were however down-regulated by atRA in primary human hepatocytes, but induced in HepaRG cells, thus pointing out discrepancies between these two liver cell models in terms of detoxifying protein regulation. atRA-mediated repressions of OATP2B1, OATP1B1, OAT2 and OCT1 mRNA expression were finally shown to be counteracted by knocking-down expression of RARalpha and RXRalpha through siRNA transfection in HepaRG cells. atRA thus differentially regulated human hepatic drug transporters, mainly in a RXR:RAR-dependent manner, therefore establishing retinoids and retinoid receptors as modulators of liver drug transporter expression. PMID- 23352987 TI - Framework for preventing preterm birth must include contraception. PMID- 23352988 TI - Reply: To PMID 23107077. PMID- 23352989 TI - Reply: To PMID 22999156. PMID- 23352990 TI - Involvement of MyD88 in zinc oxide nanoparticle-induced lung inflammation. AB - Zinc oxide nanoparticles (ZnONP) have great potential for medical applications. However, ZnONP is reported to induce acute lung inflammation, which limits its application in humans. We designed in vivo and in vitro studies to clarify ZnONP inflammation and its associated molecular signals. ZnONP with a single dose of 80 MUg/30 MUl was instilled into the tracheas of mice sacrificed at days 2, 7, 14, and 28 after instillation. Bronchoalveolar lavage fluid showed increased neutrophils and macrophages after treatment. Lung pathology showed a mixed inflammatory infiltrate of neutrophils, lymphocytes, and macrophages primarily in the bronchioles and peribronchiolar areas. Proinflammatory gene expression of TNF alpha, IL-6, CXCL1, and MCP-1 was increased at day 2 and decreased after 7 days. The lung pathology resolved at day 28, without fibrosis. It remains unclear whether this acute lung inflammation was caused by ZnONP themselves or Zn(2+) iron released from the nanoparticles. In vitro studies confirming the results of in vivo studies showed increased expression of proinflammatory genes in both MLE12 cells (mouse lung epithelial cells) and RAW264.7 cells (mouse macrophages) with either ZnONP or Zn(NO3)2 treatment; notably, increased levels of proinflammatory genes were obviously higher in cells treated with ZnONP than in cells treated with Zn(NO3)2 at the same molarity dose. TNF-alpha and MCP-1 were induced only in MLE12 cells. MyD88, an adaptor protein for most Toll-like receptors (TLR) signaling pathways, initiated the ZnONP or Zn(NO3)2-induced lung inflammation. Silencing MyD88 expression with siRNA significantly reduced ZnONP or Zn(NO3)2-induced proinflammatory gene expression in MLE12 and RAW264.7 cells. Single-dose exposure to ZnONP produced the short-term lung inflammation via a MyD88-dependent TLR pathway. These data suggest that although both ZnONP and zinc ion might participate in the inflammatory reactions, ZnONP more effectively induced MyD88-dependent proinflammatory cytokines than zinc ion in lung epithelial cells. PMID- 23352991 TI - Metastasis-associated protein, S100A4 mediates cardiac fibrosis potentially through the modulation of p53 in cardiac fibroblasts. AB - Metastasis-associated protein, S100A4 is suggested as a marker for fibrosis in several organs. It also modulates DNA binding of p53 and affects its function. However, the functional role of S100A4 in the myocardium has remained unclear. Therefore, we investigated the role of S100A4 and its relationship with p53 in cardiac fibrosis. In Dahl-rat hypertensive heart disease model, S100A4 was upregulated in the hypertrophic myocardium and further activated during transition to heart failure (HF). It was expressed in various cells including fibroblasts. In in vitro cardiac fibroblasts, the knockdown of S100A4 significantly suppressed both cell proliferation and collagen expressions. S100A4 co-localized and interacted with p53 in the nucleus. S100A4 knockdown increased the expression of p53-downstream genes, p21 and mdm2, and concomitant knockdown of p53 recovered cell proliferation and collagen expression. Transverse aortic constriction (TAC) was performed in S100A4 knockout (KO) mice, which showed a similar baseline-phenotype to wild type (WT) mice. Although there was no difference in hypertrophic response, KO mice showed reduced interstitial fibrosis, decreased myofibroblasts, and suppressed expressions of collagens and profibrotic cytokines in the left ventricle. Also, DNA microarray analysis showed that S100A4 knockout in vivo had a significant impact on expressions of p53 associated genes. These findings suggest that S100A4 modulates p53 function in fibroblasts and thereby mediates myocardial interstitial fibrosis through two distinct mechanisms; cell proliferation and collagen expression. Blockade of S100A4 may have therapeutic potential in cardiac hypertrophy and HF by attenuating cardiac fibrosis. PMID- 23352992 TI - Properties of electrospun pollock gelatin/poly(vinyl alcohol) and pollock gelatin/poly(lactic acid) fibers. AB - Pollock gelatin/poly(vinyl alcohol) (PVA) fibers were electrospun using deionized water as the solvent and pollock gelatin/poly(lactic acid) (PLA) fibers were electrospun using 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the solvent. The chemical, thermal, and thermal stability properties were examined for the electrospun samples. The electrospun PVA samples generally had thinner and more uniform fibers than the electrospun PLA samples. For the PVA samples, an increase in total solids content and PVA to gelatin ratio generally resulted in higher average fiber diameter values and wider diameter distributions. Pollock gelatin in both types of electrospun samples remained amorphous. The PVA in electrospun samples had comparable melting temperatures to that of neat PVA, whereas the PLA in electrospun samples had slightly lower melting temperatures than that of neat PLA. Also, the PLA in electrospun samples had crystallization temperatures approximately 30 degrees C lower than that in neat PLA. This was due to better alignment of PLA chains during electrospinning, which resulted in the chains being more readily crystallized at lower temperatures. In addition, the electrospun PVA samples completely dissolved in water at room temperature after soaking for one day, whereas the electrospun PLA samples remained intact even after soaking for three days. PMID- 23352993 TI - Synergistic effect of carbodiimide and dehydrothermal crosslinking on acellular dermal matrix. AB - Physicochemical properties are considered crucial for porcine acellular dermal matrix (PADM) scaffolds to maintain their native three dimensional structures and special functionalities in clinical applications. In this context, a combined technique of dehydrothermal treatment (DHT) and carbodiimide (EDC) crosslinking was applied to modify PADM scaffolds. Mechanical testing results suggested that crosslinking the scaffolds by DHT+EDC significantly improved the tensile strength of the scaffolds compared to that by either DHT or EDC crosslinking, but decreased the elongation at break slightly. And higher crosslink density and denaturation temperature were found in DHT+EDC group without any collapse in three-dimensional architecture, which may indicate the existence of synergistic effect between DHT and EDC crosslinking on PADM scaffolds. Moreover, PADM scaffolds for DHT+EDC group reflected a reduced degradation rate when they were exposed to bacterial collagenase. Meanwhile, the results obtained in the methyltetrazolium (MTT) study showed that no extra cytotoxicity was induced by DHT+EDC crosslinking on PADM scaffolds which was further confirmed by SEM images. In conclusion, the combined technique of dehydrothermal and carbodiimide treatment in this study has potential for promoting the physicochemical properties of PADM scaffolds for tissue engineering. PMID- 23352994 TI - To know or not to know, disclosure of a newborn carrier screening test result for cystic fibrosis. AB - PURPOSE: Most newborn screening (NBS) strategies for Cystic Fibrosis (CF) also identify carriers. However, it is unclear if parents want to be informed about their child's carrier status or not. METHODS: Focus group discussions with pregnant couples to explore their opinions about disclosure of a carrier result for CF of their newborn. RESULTS: All (n = 30) wanted to be informed when newborn screening would show their newborn being a CF-carrier. Their main reason was the implication of this knowledge for further family planning. Other family members could be informed and children within the family could be tested. Parents stated they have the right to know, but others also expressed that the choice of not being informed should be offered as well. CONCLUSION: Most parents want to be informed when NBS for CF reveals that their child is a CF-carrier, but the choice of not being informed should also be offered. PMID- 23352995 TI - Variability in ratings of trustworthiness across the menstrual cycle. AB - This study investigated how trusting behavior varies in naturally cycling women, as a function of sex and attractiveness of players in a trust game, at three distinct phases of the menstrual cycle. Women acted more cautiously in an investment game at the preovulatory phase, compared to the menstrual and the mid luteal phase. Reduced willingness to trust in strangers was particularly expressed toward male players at this time. The increase of estradiol levels from menses to the preovulatory phase was negatively correlated with trust in attractive male other players, whereas the increase of progesterone levels from menses to the mid-luteal phase was positively associated with trust in unattractive female other players. No particular contribution of a single hormone level could be identified for the generally reduced willingness to trust in strangers in the preovulatory phase. Thus, the results emphasize the impact of the menstrual cycle on interpersonal trust, although the exact mode of hormonal action needs to be further investigated. PMID- 23352996 TI - Osteocytes remove and replace perilacunar mineral during reproductive cycles. AB - Lactation is associated with an increased demand for calcium and is accompanied by a remarkable cycle of bone loss and recovery that helps to supply calcium and phosphorus for milk production. Bone loss is the result of increased bone resorption that is due, in part, to increased levels of PTHrP and decreased levels of estrogen. However, the regulation of bone turnover during this time is not fully understood. In the 1960s and 1970s many observations were made to suggest that osteocytes could resorb bone and increase the size of their lacunae. This concept became known as osteocytic osteolysis and studies suggested that it occurred in response to parathyroid hormone and/or an increased systemic demand for calcium. However, this concept fell out of favor in the late 1970s when it was established that osteoclasts were the principal bone-resorbing cells. Given that lactation is associated with increased PTHrP levels and negative calcium balance, we recently examined whether osteocytes contribute to bone loss during this time. Our findings suggest that osteocytes can remodel their perilacunar and pericanalicular matrix and that they participate in the liberation of skeletal calcium stores during reproductive cycles. These findings raise new questions about the role of osteocytes in coordinating bone and mineral metabolism during lactation as well as the recovery of bone mass after weaning. It is also interesting to consider whether osteocyte lacunar and canalicular remodeling contribute more broadly to the maintenance of skeletal and mineral homeostasis. PMID- 23352998 TI - Demographic and clinical manifestations of psychogenic non-epileptic seizures: the impact of co-existing epilepsy in patients or their family members. AB - PURPOSE: The aim of the current study was to clarify the impact of co-existing epileptic seizures (either in patients themselves or in their family members) on the demographic and clinical characteristics and manifestations of psychogenic non-epileptic seizures (PNES). METHODS: In this prospective study, all patients with a definite diagnosis of PNES were recruited at the epilepsy center at Shiraz University of Medical Sciences from September 2008 through May 2012. We subdivided the patients into three groups: those with PNES but without either epilepsy or a family history of epilepsy (group 1); those with PNES and concomitant epilepsy but without a family history of epilepsy (group 2); and those with PNES and a family history of epilepsy but without concomitant epilepsy (group 3). We studied the demographic and clinical findings and associated risk factors among these three groups. RESULTS: One hundred and eighty-eight patients had confirmed diagnosis of PNES at our center, of whom 32 patients (17%) had confirmed epilepsy. In total, 176 patients met our inclusion criteria and were studied: 103 patients in group 1, 19 patients in group 2, and 54 patients in group 3. Demographic characteristics, seizure characteristics, and semiology in these three groups of patients with PNES were similar. They reported similar associated factors for PNES. CONCLUSION: Epilepsy is relatively common among patients with PNES. The demographic and clinical characteristics of patients with PNES are similar in those with or without co-existing epilepsy (in themselves or among their family members). PMID- 23352997 TI - Early gamma oscillations during rapid auditory processing in children with a language-learning impairment: changes in neural mass activity after training. AB - Children with language-learning impairment (LLI) have consistently shown difficulty with tasks requiring precise, rapid auditory processing. Remediation based on neural plasticity assumes that the temporal precision of neural coding can be improved by intensive training protocols. Here, we examined the extent to which early oscillatory responses in auditory cortex change after audio-visual training, using combined source modeling and time-frequency analysis of the human electroencephalogram (EEG). Twenty-one elementary school students diagnosed with LLI underwent the intervention for an average of 32 days. Pre- and post-training assessments included standardized language/literacy tests and EEG recordings in response to fast-rate tone doublets. Twelve children with typical language development were also tested twice, with no intervention given. Behaviorally, improvements on measures of language were observed in the LLI group following completion of training. During the first EEG assessment, we found reduced amplitude and phase-locking of early (45-75 ms) oscillations in the gamma-band range (29-52 Hz), specifically in the LLI group, for the second stimulus of the tone doublet. Amplitude reduction for the second tone was no longer evident for the LLI children post-intervention, although these children still exhibited attenuated phase-locking. Our findings suggest that specific aspects of inefficient sensory cortical processing in LLI are ameliorated after training. PMID- 23352999 TI - A model-based approach to understanding school status of students with epilepsy. AB - This study constitutes a preliminary test of a theoretical model proposed by Sexson and Madan-Swain to explain the school status of students with epilepsy. Sixty-six classroom teachers participated in the study, as did 74 of their students with epilepsy. Three predictor variables-teachers' attitude towards persons with epilepsy, teachers' training in instructing students with epilepsy, and students' seizure frequency-were examined. Consistent with the model, the three variables collectively predicted attendance (F = 54.48, p<.001, R2 = 0.70), reading (F = 21.40, p<.001, R2 = .48), math (F = 12.61, p<.001, R2 = 0.35), writing (F = 12.61, p<.001, R2 = 0.35), and special education usage (chi2 = 30.96, p<.001). Moreover, both seizure frequency and teachers' attitude, but not teachers' training, uniquely predicted some outcome variables. Limitations and potential advantages of the model are discussed. PMID- 23353000 TI - Neonatal immune challenge exacerbates seizure-induced hippocampus-dependent memory impairment in adult rats. AB - Our aim was to examine whether neonatal lipopolysaccharide (LPS) exposure is associated with changes in microglia and whether these alternations could influence later seizure-induced neurobehavioral outcomes. Male pups were first injected intraperitoneally with either LPS or saline on postnatal day 3 (P3) and postnatal day 5 (P5). Immunohistochemical analysis showed that LPS-treated animals exhibited increased microglia activation that persisted into adolescence. At P45, seizures were induced in rats by intraperitoneal injection of kainic acid (KA). Rats treated with LPS neonatally showed significantly greater proinflammatory responses and performed significantly worse in the Y-maze, Morris water maze, and inhibitory avoidance tasks after KA insult. Treatment with minocycline at the time of neonatal LPS exposure to block LPS-induced microglia alternation attenuated the exaggerated neuroinflammatory responses and alleviated memory impairment associated with the KA insult. Our findings suggest that neonatal immune activation can predispose the brain to exacerbated behavioral deficits following seizures in adulthood, possibly by priming microglia. PMID- 23353001 TI - Activation of an immune response in Litopenaeus vannamei by oral immunization with phagocytosis activating protein (PAP) DNA. AB - The phagocytosis activating protein (PAP) gene has been reported to stimulate the phagocytic activity of shrimp hemocytes and to protect shrimp from several pathogens. In this study oral administration of the chitosan-PAP gene to shrimp was investigated for its ability to induce immunity. The PAP gene was cooperated into a phMGFP plasmid, named PAP-phMGFP. Chitosan-PAP-phMGFP nanoparticles were formed by mixing a low molecular weight chitosan (50 kDa) and a high molecular weight chitosan (150 kDa) with various ratios of PAP-phMGFP. The optimal ratio of chitosan PAP-phMGFP nanoparticles was first determined by transfection into Chinese Hamster Ovary (CHO) cells before being used for oral immunization in shrimp. The chitosan-PAP-phMGFP nanoparticles at a ratio of 2:1 with the low molecular weight chitosan were optimum for transfecting the CHO cells. The shrimp were then fed with 25, 50, 100 and 150 MUg/shrimp/day of chitosan-PAP-phMGFP (2:1) nanoparticles then challenged by the white spot syndrome virus (WSSV). Shrimp fed with 50 MUg of chitosan-PAP-phMGFP nanoparticles per day for 7 consecutive days, produced the highest relative percent survival (RPS) (94.45 +/- 9.86%). The presence of PAP-phMGFP was detected in every shrimp tissue including the hemolymph, lymphoid organ, heart, hepatopancreas, intestine and muscle. The folds increase of the PAP gene expression increased significantly together with an increase of the phagocytic activity in the immunized shrimp. The stability of the PAP-phMGFP in the immunized shrimp hemolymph was detected by determination of the expression of the GFP at various days after immunization ceased. GFP expression was detected until the 15th day but not at the 30th day after immunization ceased. A quantitative analysis of the WSSV copies in shrimp heart tissue was significantly reduced in the immunized shrimp. In addition, chitosan PAP-phMGFP nanoparticles protected shrimp against WSSV, Yellow head virus (YHV) and Vibrio harveyi with RPS values of 83.34 +/- 7.86%, 55.56 +/- 15.72% and 53.91 +/- 5.52%, respectively. This study therefore confirms the role of the PAP gene in shrimp immunity and may lead to the development of a way to prevent microbial diseases of shrimp at an industrial level by appropriate feeding of a chitosan/DNA complex. PMID- 23353002 TI - Cost analysis of anterior-posterior circumferential fusion and transforaminal lumbar interbody fusion. AB - BACKGROUND CONTEXT: Although lumbar interbody fusion has long been a common procedure in the practice of spine surgery, focus on the technological development has produced the relatively new procedure of transforaminal lumbar interbody fusion (TLIF). This procedure is often available to surgeons as an alternative to anterior-posterior circumferential fusion (AP fusion), and both procedures have been demonstrated to be clinically equivalent at up to 5 years after surgery. In the context of clinical equipoise, it is unknown which procedure is more economically advantageous. PURPOSE: To compare the hospital costs, charges, and payments received for surgical treatment with either AP fusion or TLIF. Future directions for health economic research with respect to spine surgery are also considered and discussed. STUDY DESIGN: This is an institutional review board-approved, single-institution retrospective chart review and cost analysis. PATIENT SAMPLE: Our study included patients undergoing either single-level AP fusion or single-level TLIF between 2006 and 2008. All patients were older than 18 years at the time of surgery; the decision of which procedure was performed was entirely at the discretion of the attending surgeon. OUTCOME MEASURES: Hospital costs, charges, and payments received for the treatment of each patient. METHODS: We performed a retrospective review of the medical and financial records of patients undergoing either AP fusion (n=179) or TLIF (n=90) on one operative level between 2006 and 2008. Medical records were evaluated for a history of spine surgery, operative time, estimated blood loss, and length of stay, whereas financial records were reviewed for the hospital costs, charges, and payments received as recorded by the hospital accounting data. Operative materials and service charges were also isolated and compared separately. This study was departmentally sponsored; there were no interest associated biases for any of the authors involved. RESULTS: AP fusion patients had a longer operative time than TLIF patients, with a mean time of 246.5 versus 202.7 minutes (p<.01). Conversely, TLIF patients had a higher estimated blood loss during surgery (469.8 cm(3)) than AP fusion patients (311.2 cm(3)) (p<.01). The mean hospital cost for AP fusion was $25,165, whereas for TLIF was $23,390 (p=.04). The mean hospital charges and payments received for AP fusion were 1.07 (p=.05) and 1.35 (p<.01) times those received for TLIF, respectively. Therefore, mean hospital charges and payments received for TLIF were 0.93 and 0.76 times those received for AP fusion, respectively. CONCLUSIONS: Our study demonstrates that a single-level AP fusion results in longer operative time, lower blood loss during surgery, higher hospital costs, higher hospital charges, and greater payments received than a single-level TLIF. Although the decision on how best to treat a patient lies solely at the judgment of the attending surgeon, this comparative cost information may be pertinent in cases of clinical equivalence. This study also calls attention to various shortcomings that are found in present spine surgery cost-effectiveness research, as there is an ongoing need for increased standards of quality in the area of health economics research. PMID- 23353003 TI - Papain-induced in vitro disc degeneration model for the study of injectable nucleus pulposus therapy. AB - BACKGROUND CONTEXT: Proteolytic enzyme digestion of the intervertebral disc (IVD) offers a method to simulate a condition of disc degeneration for the study of cell-scaffold constructs in the degenerated disc. PURPOSE: To characterize an in vitro disc degeneration model (DDM) of different severities of glycosaminoglycans (GAG) and water loss by using papain, and to determine the initial response of the human mesenchymal stem cells (MSCs) introduced into this DDM. STUDY DESIGN: Disc degeneration model of a bovine disc explant with an end plate was induced by the injection of papain at various concentrations. Labeled MSCs were later introduced in this model. METHODS: Phosphate-buffered saline (PBS control) or papain in various concentrations (3, 15, 30, 60, and 150 U/mL) were injected into the bovine caudal IVD explants. Ten days after the injection, GAG content of the discs was evaluated by dimethylmethylene blue assay and cell viability was determined by live/dead staining together with confocal microscopy. Overall matrix composition was evaluated by histology, and water content was visualized by magnetic resonance imaging. Compressive and torsional stiffness of the DDM were also recorded. In the second part, MSCs were labeled with a fluorescence cell membrane tracker and injected into the nucleus of the DDM or a PBS control. Mesenchymal stem cell viability and distribution were evaluated by confocal microscopy. RESULTS: A large drop of GAG and water content of the bovine disc were obtained by injecting >30 U/mL papain. Magnetic resonance imaging showed Grade II, III, and IV disc degeneration by injecting 30, 60, and 150 U/mL papain. A cavity in the center of the disc could facilitate later injection of the nucleus pulposus tissue engineering construct while retaining an intact annulus fibrosus. The remaining disc cell viability was not affected. Mesenchymal stem cells injected into the protease-treated DDM disc showed significantly higher cell viability than when injected into the PBS-injected control disc. CONCLUSIONS: By varying the concentration of papain for injection, an increasing amount of GAG and water loss could be induced to simulate the different severities of disc degeneration. MSC suspension introduced into the disc has a very low short-term survival. However, it should be clear that this bovine IVD DDM does not reflect a clinical situation but offers exciting possibilities to test novel tissue engineering protocols. PMID- 23353005 TI - [Assessment of surgical teleconsultations in a developing country: two years of experience in Djibouti]. AB - OBJECTIVE: Our objective was to assess the influence of teleconsultations on patient management and clinical outcomes in a developing country. MATERIALS AND METHODS: All the surgical teleconsultations by a single surgeon (orthopedist) between November 2009 and November 2011 were recorded. RESULTS: Neurosurgery and pediatric orthopedics were the two most important specialities most often concerned, accounting for 67% of the 157 teleconsultations for 138 patients. The teleconsultations resolved the diagnostic uncertainties in 29 of 37 cases (78%). Advice from the expert modified management in 69% cases. Clinical outcomes were good or very good in 86% of the treated patients. CONCLUSIONS: This study establishes the feasibility and usefulness of surgical teleconsultations in Djibouti. PMID- 23353006 TI - SNP discovery and High Resolution Melting Analysis from massive transcriptome sequencing in the California red abalone Haliotis rufescens. AB - The California red abalone, Haliotis rufescens that belongs to the Haliotidae family, is the largest species of abalone in the world that has sustained the major fishery and aquaculture production in the USA and Mexico. This native mollusk has not been evaluated or assigned a conservation category even though in the last few decades it was heavily exploited until it disappeared in some areas along the California coast. In Chile, the red abalone was introduced in the 1970s from California wild abalone stocks for the purposes of aquaculture. Considering the number of years that the red abalone has been cultivated in Chile crucial genetic information is scarce and critical issues remain unresolved. This study reports and validates novel single nucleotide polymorphisms (SNP) markers for the red abalone H. rufescens using cDNA pyrosequencing. A total of 622 high quality SNPs were identified in 146 sequences with an estimated frequency of 1 SNP each 1000bp. Forty-five SNPs markers with functional information for gene ontology were selected. Of these, 8 were polymorphic among the individuals screened: Heat shock protein 70 (HSP70), vitellogenin (VTG), lysin, alginate lyase enzyme (AL), Glucose-regulated protein 94 (GRP94), fructose-bisphosphate aldolase (FBA), sulfatase 1A precursor (S1AP) and ornithine decarboxylase antizyme (ODC). Two additional sequences were also identified with polymorphisms but no similarities with known proteins were achieved. To validate the putative SNP markers, High Resolution Melting Analysis (HRMA) was conducted in a wild and hatchery-bred population. Additionally, SNP cross-amplifications were tested in two further native abalone species, Haliotis fulgens and Haliotis corrugata. This study provides novel candidate genes that could be used to evaluate loss of genetic diversity due to hatchery selection or inbreeding effects. PMID- 23353004 TI - Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products. AB - Extracts from medicinal plants, many of which have been used for centuries, are increasingly tested in models of hepatotoxicity. One of the most popular models to evaluate the hepatoprotective potential of natural products is acetaminophen (APAP)-induced liver injury, although other hepatotoxicity models such as carbon tetrachloride, thioacetamide, ethanol and endotoxin are occasionally used. APAP overdose is a clinically relevant model of drug-induced liver injury. Critical mechanisms and signaling pathways, which trigger necrotic cell death and sterile inflammation, are discussed. Although there is increasing understanding of the pathophysiology of APAP-induced liver injury, the mechanism is complex and prone to misinterpretation, especially when unknown chemicals such as plant extracts are tested. This review discusses the fundamental aspects that need to be considered when using this model, such as selection of the animal species or in vitro system, timing and dose-responses of signaling events, metabolic activation and protein adduct formation, the role of lipid peroxidation and apoptotic versus necrotic cell death, and the impact of the ensuing sterile inflammatory response. The goal is to enable researchers to select the appropriate model and experimental conditions for testing of natural products that will yield clinically relevant results and allow valid interpretations of the pharmacological mechanisms. PMID- 23353007 TI - Design of label-free, homogeneous biosensing platform based on plasmonic coupling and surface-enhanced Raman scattering using unmodified gold nanoparticles. AB - Surface-enhanced Raman scattering (SERS) has emerged as a promising spectroscopic technique for biosensing. However, to design a SERS-based biosensor, almost all currently used methods involve the time-consuming and complicated modification of the metallic nanoparticles with the Raman active dye and biorecognition element, which restricts their widespread applications. Herein, we report a label-free, homogeneous and easy-to-operate biosensing platform for the rapid, simple and sensitive SERS detection by using the unmodified gold nanoparticles (Au NPs). This strategy utilizes the difference in adsorption property of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) on citrate-coated Au NPs. In the presence of dsDNA, the aggregation of Au NPs takes place after adding salt solution because the dsDNA cannot adsorb on the Au NPs to protect them from salt induced aggregation. Such aggregation gives rise to the plasmonic coupling of adjacent metallic NPs and turns on the enhancement of the Raman scattering, displaying a strong SERS signal. In contrast, the ssDNA can adsorb on the Au NPs surface through strong electrostatic attraction and protect them from salt induced aggregation, showing a weak SERS signal. This approach is not only straightforward and simple in design but also rapid and convenient in operation. The feasibility and universality of the design have been demonstrated successfully by the detection of DNA and Hg(2+), and the assay possesses the superior signal-to-background ratio as high as ~30 and excellent selectivity. The method can be extended to detect various analytes, such as other metal ions, proteins and small molecules by using the oligonucleotides that can selectively bind the analytes. PMID- 23353008 TI - A capacitive biosensor for ultra-trace level urea determination based on nano sized urea-imprinted polymer receptors coated on graphite electrode surface. AB - A novel urea biosensor based on capacitive detection was developed using nano sized molecularly imprinted polymers (nano-MIP). The sensitive layer was created by casting a thin layer of poly (vinyl chloride) (PVC)/nano-MIP composite on a graphite electrode surface. Cyclic voltammetry and impedance spectroscopy were used to monitor the electrode surface modification. The insulating properties of the layer were studied in the presence of K3Fe(CN)6/K4Fe(CN)6 redox couple by AC impedance measurements. The proposed capacitive sensor exhibited good selectivity for urea, compared to the chemicals with high resemblance to urea. The repeatability of the senor was found to be satisfactory. Very wide dynamic linear range (1*10(-11)-1*10(-4)M) as well as an ultra-trace detection limit equal to 5 picomolar was obtained for the sensor. The relevant experiments indicated satisfactory repeatability and reproducibility for the developed sensor. The results from sample analysis confirmed the applicability of the MIP-based sensor to quantitative analysis of urea in real samples. PMID- 23353010 TI - VEGF -634G>C polymorphism and diabetic retinopathy risk: a meta-analysis. AB - BACKGROUND: Vascular endothelial growth factor (VEGF), a multifunctional cytokine that promotes angiogenesis and is a potent mediator of microvascular permeability, which is critical for the development of diabetic retinopathy (DR). It has demonstrated that VEGF -634G>C (rs2010963) polymorphism alters the transcriptional activity of the gene. However, studies on the association between VEGF -634G>C polymorphism and DR in type 2 diabetes have reported conflicting results. Thus, the aim of the present study was to investigate whether VEGF 634G>C polymorphism is associated with the risk of DR in type 2 diabetes. METHODS: A systematic search of electronic databases (PubMed, Embase and Web of Science) and reference lists of relevant articles was carried out until September 15, 2012. The pooled odds ratios (ORs) and their corresponding 95% confidence interval (CI) were calculated by a fixed effect model. RESULTS: A total of 1525 DR cases and 1422 diabetic without retinopathy (DWR) controls in 9 independent studies were included in the meta-analysis. A significant relationship between VEGF -634G>C polymorphism and DR was found in an allelic genetic model (OR: 1.13, 95% CI: 1.01 to 1.25, P=0.03) and a recessive genetic model (OR: 1.26, 95% CI: 1.02 to 1.55, P=0.03). CONCLUSION: Our research confirmed the association between the VEGF -634G>C polymorphism and DR in subjects with type 2 diabetes. Well designed studies with larger sample size and more ethnic groups are required to further validate the results. PMID- 23353009 TI - Comparative study on aptamers as recognition elements for antibiotics in a label free all-polymer biosensor. AB - We present an all-polymer electrochemical microfluidic biosensor using Topas((r)) as substrate and a conductive polymer bilayer as electrode material. The conductive bilayer consists of tosylate doped poly(3,4-ethylenedioxythiophene) (PEDOT:TsO) and the hydroxymethyl derivative PEDOT-OH:TsO, which was covalently functionalized with two aptamer probes with affinity to ampicillin or kanamycin A, respectively. Using electrochemical impedance spectroscopy (EIS) we were able to detect ampicillin in a concentration range from 100pM to 1MUM and kanamycin A from 10nM to 1mM. The obtained EIS spectra were fitted with an equivalent circuit model successfully explaining the impedance signal. Real samples from regular ultra-high temperature treated low-fat milk spiked with ampicillin were successfully tested to assess the functionality of the sensor with real samples. In conclusion, we have demonstrated the applicability of the newly developed platform for real time, label-free and selective impedimetric detection of commonly used antibiotics. Additionally it was possible to detect ampicillin in a milk sample at a concentration below the allowed maximum residue limit (MRL) in the European Union. PMID- 23353011 TI - DISC1-related signaling pathways in adult neurogenesis of the hippocampus. AB - Disrupted-in-schizophrenia 1 (DISC1) is a multifunctional scaffold protein which plays an important role in neurogenesis and neural development in the adult brain, especially in the dentate gyrus (DG) of the hippocampus. Accumulated research has unveiled the role of DISC1 in several aspects of neural development and neurogenesis, such as neuronal maturation, proliferation, migration, positioning, differentiation, dendritic growth, axonal outgrowth, and synaptic plasticity. Studies on the function of this protein have explored multiple facets, including variants and missense mutants in genetics, proteins interactivity and signaling pathways in molecular biology, and pathogenesis and treatment targets of major mental illness, and more. In this review, we present several signaling pathways discussed in recent research, such as the AKT signaling pathway, GABA signaling pathway, GSK3beta signaling pathway, Wnt signaling pathway, and NMDA-R signaling pathway. DISC1 interacts, directly or indirectly, with these signaling pathways and they co-regulate the process of adult neurogenesis in the hippocampus. PMID- 23353012 TI - Feasibility of spray drying bacteriophages into respirable powders to combat pulmonary bacterial infections. AB - The use of bacterial viruses for antibacterial treatment (bacteriophage therapy) is currently being reevaluated. In this study, we analyze the potential of processing bacteriophages in a dry powder formulation, using a laboratory spray dryer. The phages were dried in the presence of lactose, trehalose or dextran 35, serving as an excipient to give the resulting powder the necessary bulk mass and offer protection to the delicate phage structure. Out of the three excipients tested, trehalose was found to be the most efficient in protecting the phages from temperature and shear stress throughout the spray drying process. A low inlet air temperature and atomizing force appeared to be the best parameter conditions for phage survival. Pseudomonas podovirus LUZ19 was remarkably stable, suffering less than 1 logarithmic unit reduction in phage titer. The phage titer of Staphyloccus phage Romulus-containing powders, a member of the Myoviridae family, showed more than 2.5 logarithmic units reduction. On the other hand, Romulus-containing powders showed more favorable characteristics for pulmonary delivery, with a high percentage of dry powder particles in the pulmonary deposition fraction (1-5 MUm particle diameter). Even though the parameters were not optimized for spray drying all phages, it was demonstrated that spray drying phages with this industrial relevant and scalable set up was possible. The resulting powders had desirable size ranges for pulmonary delivery of phages with dry powder inhalers (DPIs). PMID- 23353013 TI - Homogeneous duplex polymerase chain reaction assay using switchable lanthanide fluorescence probes. AB - We have developed a duplex polymerase chain reaction (PCR) assay based on switchable lanthanide chelate complementation probes. In the complementation probe technology, two nonfluorescent oligonucleotide probes, one labeled with a lanthanide ion carrier chelate and another with a light absorbing antenna ligand, form a fluorescent complex by self-assembly of the reporter molecules when the two probes are hybridized in adjacent positions to the target DNA. Here we report the synthesis of a new terbium(III) (Tb(III)) ion carrier chelate and a new light absorbing antenna ligand for Tb(III) and the development of a duplex Chlamydia trachomatis (Ct) PCR assay. For the detection of Ct in urine samples, a specific sequence in Ct cryptic plasmid was amplified and detected using europium(III) (Eu(III)) complementation probes. An internal amplification control was amplified in each reaction and detected using Tb(III) complementation probes to verify the Ct negative results. Ct bacteria were concentrated from urine samples with a rapid and simple centrifugation-based sample preparation method. Good diagnostic accuracy (99-100%) was achieved, and also Ct positive reactions yielded a very high Eu(III) signal-to-background ratio (maximum of 244). High performance of the complementation probes is advantageous when sample may contain impurities after a simple sample preparation. PMID- 23353014 TI - Comparison of Botrytis cinerea populations isolated from two open-field cultivated host plants. AB - The necrotrophic fungus Botrytis cinerea is reported to infect more than 220 host plants worldwide. In phylogenetical-taxonomical terms, the pathogen is considered a complex of two cryptic species, group I and group II. We sampled populations of B. cinerea on sympatric strawberry and raspberry cultivars in the North-East of Hungary for three years during flowering and the harvest period. Four hundred and ninety group II B. cinerea isolates were analyzed for the current study. Three different data sets were generated: (i) PCR-RFLP patterns of the ADP-ATP translocase and nitrate reductase genes, (ii) MSB1 minisatellite sequence data, and (iii) the fragment sizes of five microsatellite loci. The structures of the different populations were similar as indicated by Nei's gene diversity and haplotype diversity. The F statistics (Fst, Gst), and the gene flow indicated ongoing differentiation within sympatric populations. The population genetic parameters were influenced by polymorphisms within the three data sets as assessed using Bayesian algorithms. Data Mining analysis pointed towards the five microsatellite loci as the most defining markers to study differentiation in the 490 isolates. The results suggest the occurrence of host-specific, sympatric divergence of generalist phytoparasites in perennial hosts. PMID- 23353015 TI - Molecular cloning and characterization of acyl-CoA binding protein (ACBP) gene from shrimp Penaeus monodon exposed to salinity stress. AB - Acyl-CoA binding protein (ACBP), a protein present ubiquitously in wide range of organisms play significant role in transport of acyl groups for macromolecular biosynthesis involved in various functional and regulatory processes. In crustaceans, ACBP has functional role in growth, reproduction and temperature tolerance. In the present study, two suppression subtractive hybridization (SSH) cDNA libraries were performed using gut tissues of shrimp Penaeus monodon exposed to low (3 ppt) and high (55 ppt) salinity stress conditions. SSH library resulted in identification of differentially expressed genes that belonged to various functional classes such as the nucleic acid regulation and replication, defence proteins, allergen protein, signal transduction pathways, apoptosis, energy and metabolism, cell cycle regulation and hypothetical proteins. ACBP was identified as one of the differentially expressed gene in both the SSH libraries of shrimp P. monodon subjected to low and high salinity stress. The full-length cDNA of P. monodon ACBP gene was isolated and the sequence revealed 273 bp open reading frame encoding 90 amino acids with molecular mass of 10 kDa and pI 6.8. The ORF showed presence of four phosphorylation sites, with absence of signal peptide sequence and glycosylation sites. The deduced amino acid sequence of ACBP exhibited high sequence identity (92%) with ACBP class of protein identified from Fenneropenaeus chinensis. Real time PCR analysis of shrimps subjected to 3 ppt salinity conditions after 2 weeks revealed an increase in expression of ACBP transcripts, in the gut (28.08-folds), gills (11.71-folds) and in the muscle tissues (1.70-folds). Whereas, shrimps exposed to 55 ppt salinity conditions after 2 weeks exhibited increased ACBP transcript levels in the gut (11.95 folds), gills (1.052-folds) and muscle tissues (7.35-folds). The significant increase in expression levels of ACBP in various tissues of shrimps suggests a functional role of this gene in salinity stress tolerance and adaptation. PMID- 23353016 TI - Shotgun proteomics of coelomic fluid from the purple sea urchin, Strongylocentrotus purpuratus. AB - The purple sea urchin has a complex immune system that is likely mediated by gene expression in coelomocytes (blood cells). A broad array of potential immune receptors and immune response proteins has been deduced from their gene models. Here we use shotgun mass spectrometry to describe 307 proteins with possible immune function in sea urchins including proteins involved in the complement pathway and numerous SRCRs. The relative abundance of dual oxidase 1, ceruloplasmin, ferritin and transferrin suggests the production of reactive oxygen species in coelomocytes and the sequestration of iron. Proteins such as selectin, cadherin, talin, galectin, amassin and the Von Willebrand factor may be involved in generating a strong clotting reaction. Cell signaling proteins include a guanine nucleotide binding protein, the Rho GDP dissociation factor, calcium storage molecules and a variety of lipoproteins. However, based on this dataset, the expression of TLRs, NLRs and fibrinogen domain containing proteins in coelomic fluid and coelomocytes could not be verified. PMID- 23353017 TI - The evolution of complexity in social organization-A model using dominance subordinate behavior in two social wasp species. AB - Dominance and subordinate behaviors are important ingredients in the social organizations of group living animals. Behavioral observations on the two eusocial species Ropalidia marginata and Ropalidia cyathiformis suggest varying complexities in their social systems. The queen of R. cyathiformis is an aggressive individual who usually holds the top position in the dominance hierarchy although she does not necessarily show the maximum number of acts of dominance, while the R. marginata queen rarely shows aggression and usually does not hold the top position in the dominance hierarchy of her colony. In R. marginata, more workers are involved in dominance-subordinate interactions as compared to R. cyathiformis. These differences are reflected in the distribution of dominance-subordinate interactions among the hierarchically ranked individuals in both the species. The percentage of dominance interactions decreases gradually with hierarchical ranks in R. marginata while in R. cyathiformis it first increases and then decreases. We use an agent-based model to investigate the underlying mechanism that could give rise to the observed patterns for both the species. The model assumes, besides some non-interacting individuals, the interaction probabilities of the agents depend on their pre-differentiated winning abilities. Our simulations show that if the queen takes up a strategy of being involved in a moderate number of dominance interactions, one could get the pattern similar to R. cyathiformis, while taking up the strategy of very low interactions by the queen could lead to the pattern of R. marginata. We infer that both the species follow a common interaction pattern, while the differences in their social organization are due to the slight changes in queen as well as worker strategies. These changes in strategies are expected to accompany the evolution of more complex societies from simpler ones. PMID- 23353018 TI - Models of compensatory molecular evolution: effects of back mutation. AB - Compensatory mutations are individually deleterious but appropriate combinations of mutants are harmless. For several models of compensatory molecular evolution, we consider the effects of back mutation. It is shown that the effects of back mutation on the rate of compensatory molecular evolution are weak. Further we estimate the values of selection parameter of deleterious single mutants for the models of compensatory molecular evolution both with and without back mutation using sequence data of folded RNA molecules and compare them with the previous results. PMID- 23353019 TI - The plasma membrane proteome of maize roots grown under low and high iron conditions. AB - Iron (Fe) homeostasis is essential for life and has been intensively investigated for dicots, while our knowledge for species in the Poaceae is fragmentary. This study presents the first proteome analysis (LC-MS/MS) of plasma membranes isolated from roots of 18-day old maize (Zea mays L.). Plants were grown under low and high Fe conditions in hydroponic culture. In total, 227 proteins were identified in control plants, whereas 204 proteins were identified in Fe deficient plants and 251 proteins in plants grown under high Fe conditions. Proteins were sorted by functional classes, and most of the identified proteins were classified as signaling proteins. A significant number of PM-bound redox proteins could be identified including quinone reductases, heme and copper containing proteins. Most of these components were constitutive, and others could hint at an involvement of redox signaling and redox homeostasis by change in abundance. Energy metabolism and translation seem to be crucial in Fe homeostasis. The response to Fe deficiency includes proteins involved in development, whereas membrane remodeling and assembly and/or repair of Fe-S clusters is discussed for Fe toxicity. The general stress response appears to involve proteins related to oxidative stress, growth regulation, an increased rigidity and synthesis of cell walls and adaption of nutrient uptake and/or translocation. This article is part of a Special Issue entitled: Plant Proteomics in Europe. PMID- 23353020 TI - 2D gels still have a niche in proteomics. AB - With the rapid advance of MS-based proteomics one might think that 2D gel-based proteomics is dead. This is far from the truth. Current research has shown that there are still a number of places in the field of protein and molecular biology where 2D gels still play a leading role. The aim of this review is to highlight some of these applications. Examples from our own research as well as from other published works are used to illustrate the 2D gel driven research in the areas of: 1) de novo sequencing and protein identification from organisms with no or incomplete genome sequences available; 2) alternative detection methods for modification specific proteomics; 3) identification of protein isoforms and modified proteins. With an example of the glycoprotein TIMP-1 protein we illustrate the unique properties of 2D gels for the separation and characterisation of multiply modified proteins. We also show that careful analysis of experimental and theoretical protein mass and pI can lead to the identification of unanticipated protein variants modified by for example proteolytic cleavage. Together this shows that there is an important niche for 2D gel-based proteomics, which compliments traditional LC-MS techniques for specific protein research purposes. PMID- 23353021 TI - Discussion: 'Comparison of cervical cancer screening strategies,' by Cox et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. PMID- 23353022 TI - First-trimester detection of fetal anomalies in pregestational diabetes using nuchal translucency, ductus venosus Doppler, and maternal glycosylated hemoglobin. AB - OBJECTIVE: The frequency of fetal anomalies in women with pregestational diabetes correlates with their glycemic control. This study aimed to assess the predictive performance of first-trimester fetal nuchal translucency (NT), ductus venosus (DV) Doppler, and hemoglobin A1c (HbA1c) to predict fetal anomalies in women with pregestational diabetes. STUDY DESIGN: This was a prospective observational study of patients undergoing first-trimester NT with DV Doppler. Screening performance was tested for first-trimester parameters to detect fetal anomalies. RESULTS: Of 293 patients, 17 had fetal anomalies (11 cardiac, 7 major, 3 multisystem). All anomalous fetuses were suspected prenatally. One had NT >95th centile, 2 had reversed DV a-wave, and 13 had HbA1c >7.0%. The HbA1c was the primary determinant of anomalies (r(2), 0.15; P < .001) and >8.35% was the optimal cutoff for prediction of anomalies with an area under the curve of 0.72 (95% confidence interval, 0.57-0.88). Therefore, first-trimester prediction of anomalies was best in women with increased NT or HbA1c >8.3% (sensitivity 70.6%, specificity 77.4%, positive predictive value 16.2%, negative predictive value 97.7%, P < .001). CONCLUSION: In women with pregestational diabetes and poor glycemic control, an increased NT increases risks for major fetal anomalies. Second-trimester follow up is required to achieve accurate prenatal diagnosis. PMID- 23353024 TI - Term delivery following tuboovarian abscess after in vitro fertilization and embryo transfer. AB - A tuboovarian abscess (TOA) during pregnancy following oocyte retrieval is extremely rare. We report a rare case of pregnancy complicated by the development of a TOA following in vitro fertilization-embryo transfer that was treated successfully with laparoscopy. We also review all similar cases reported in the English-language literature. PMID- 23353025 TI - A novel analytical method for evolutionary graph theory problems. AB - Evolutionary graph theory studies the evolutionary dynamics of populations structured on graphs. A central problem is determining the probability that a small number of mutants overtake a population. Currently, Monte Carlo simulations are used for estimating such fixation probabilities on general directed graphs, since no good analytical methods exist. In this paper, we introduce a novel deterministic framework for computing fixation probabilities for strongly connected, directed, weighted evolutionary graphs under neutral drift. We show how this framework can also be used to calculate the expected number of mutants at a given time step (even if we relax the assumption that the graph is strongly connected), how it can extend to other related models (e.g. voter model), how our framework can provide non-trivial bounds for fixation probability in the case of an advantageous mutant, and how it can be used to find a non-trivial lower bound on the mean time to fixation. We provide various experimental results determining fixation probabilities and expected number of mutants on different graphs. Among these, we show that our method consistently outperforms Monte Carlo simulations in speed by several orders of magnitude. Finally we show how our approach can provide insight into synaptic competition in neurology. PMID- 23353026 TI - Oxidative stress involvement in manganese-induced alpha-synuclein oligomerization in organotypic brain slice cultures. AB - Overexposure to manganese (Mn) has been known to induce neuronal damage. However, little is known of the role that reactive oxygen species (ROS) play in protein aggregation resulting from Mn exposure. The current study investigated whether oxidative stress is involved in manganese-induced alpha-synuclein oligomerization in organotypic brain slices. After application of Mn (0-400MUM) for 24h, there was a dose-dependent increase in average percentage of propidium iodide positive (PI(+)) nuclei in slices and levels of lactate dehydrogenase (LDH) in the culture medium. Moreover, the treatment with Mn resulted in a dose-dependent increase in neurocyte apoptosis, ROS level, and decrease in superoxide dismutase (SOD) activity. Mn also caused oxidative damage in cell lipid and protein. At the same time, the exposure of Mn leaded to significantly increase in the expression of alpha-synuclein mRNA and protein. Alpha-synuclein oligomerization occurred in Mn treated slices, especially on membrane-bound form. It indicated that alpha synuclein oligomers were more likely to combination cell membranes and resulting in membrane damage. Mn-induced neurocyte damage and alpha-synuclein oligomerization were also partially alleviated by the pretreatment with GSH and aggravated by H2O2 pretreatment. The findings revealed Mn might exert its neurotoxic effects by oxidative stress-mediated alpha-synuclein oligomerization in organotypic brain slices. PMID- 23353027 TI - In vitro toxicological characterisation of the S-containing arsenic metabolites thio-dimethylarsinic acid and dimethylarsinic glutathione. AB - Inorganic arsenic is a well-documented, exposure relevant human carcinogen. A promising starting point to further understand the mechanisms behind inorganic arsenic carcinogenicity might be a formation of reactive, highly toxic metabolites during human arsenic metabolism. This study characterises the toxicity of recently identified S-containing arsenic metabolites in cultured human A549 lung adenocarcinoma epithelium cells. In direct comparison to arsenite, thio-dimethylarsinic acid (thio-DMA(V)) and dimethylarsinic glutathione (DMAG) exerted a 5- to 20-fold stronger cytotoxicity and showed a 2- to 20-fold higher cellular bioavailability, respectively. All three arsenicals disturbed cell cycle progression at cytotoxic concentrations, but failed to increase the level of reactive oxygen and nitrogen species (RONS) in healthy A549 cells. However, a strong disturbance of the oxidative defense system was observed after incubation with absolutely sub-cytotoxic, pico- to nanomolar concentrations of arsenite and thio-DMA(V), respectively. Thus, both GSH and GSSG levels were significantly decreased by up to 40%. Accordingly, RONS levels of oxidatively (H2O2) stressed cells were strongly increased by the arsenicals. Since in vivo RONS are permanently endogenously and exogenously produced, this boost of the existing oxidative stress by arsenite and thio-DMA(V) might contribute to the process of inorganic arsenic induced carcinogenicity. PMID- 23353023 TI - Down syndrome maternal serum marker screening after 18 weeks of gestation: a countrywide study. AB - OBJECTIVE: The objective of the study was to evaluate the efficacy of maternal serum markers in detecting Down syndrome after 18 weeks of gestation in women who book late for maternity care in a large national retrospective study. STUDY DESIGN: During the period 2007-2012, 27,648 women, regardless of maternal age (17.4% were 35 years old and over), were included in a late Down syndrome screening program (18(+0) to 35(+6) weeks) using the maternal serum markers alpha fetoprotein and human chorionic gonadotrophin-beta. Samples were assayed in a single laboratory. A dataset of median markers previously established in our laboratory was used for risk calculation. The control group consisted of 27,648 women (14(+0) to 17(+6) weeks) randomly selected from the routine database. RESULTS: When the later screening group was compared with the standard second trimester control group, the median multiples of medians (1.01 vs 0.98 for alpha fetoprotein, 1.03 vs 0.98 for human chorionic gonadotrophin-beta), median risks (1 of 2414 vs 1 of 2720), false-positive rates (11.1% vs 11.6%), and trisomy 21 detection rates (83.3% vs 85.7%) did not differ significantly. CONCLUSION: Late Down syndrome maternal serum screening is feasible with a good sensitivity/specificity compromise throughout gestation and is of clinical value in late-booking women. PMID- 23353028 TI - [Plasmodium knowlesi: an emerging species in humans?]. AB - Plasmodium knowlesi is typically found in macaques and has recently been recognized as the fifth Plasmodium species to cause malaria in humans. Several cases of P. knowlesi malaria have been reported in people in Southeast Asia. Most cases are simple but approximately one in 10 patients develops complications. The morphology of P. knowlesi parasites in human infections closely resembles that of Plasmodium malariae or Plasmodium falciparum, so a molecular method is the optimum diagnostic procedure. The treatment of choice for uncomplicated P. knowlesi malaria is oral chloroquine, whereas severe infection should be treated with intravenous quinine. PMID- 23353029 TI - Daytime sleepiness affects prefrontal regulation of food intake. AB - The recent epidemic of obesity corresponds closely with the decline in the average number of hours of sleep obtained nightly. While growing research suggests that sleep loss may affect hormonal and other physiological systems related to food intake, no studies have yet explored the role that sleepiness may play in reducing prefrontal inhibitory control over food intake. Because evidence suggests that women may be more prone to obesity and eating disorders, as well as more likely to suffer from sleep problems, we examined the relation between general daytime sleepiness, brain responses to food stimuli, and self-reported overeating separately for men and women. Thirty-eight healthy adults (16 women; 22 men) aged 18 to 45 underwent functional magnetic resonance imaging (fMRI) while viewing pictures of high- and low-calorie foods. Subjects completed the Epworth Sleepiness Scale (ESS) and provided a rating to the query "how often do you eat more than you intend to." Contrast images comparing brain activation derived from the high- versus low-calorie conditions were correlated voxel-wise with scores from the ESS in a second-level regression model, the output of which was used to predict self-reported overeating. As hypothesized, daytime sleepiness correlated with reduced activation in the ventromedial prefrontal cortex during perception of high- versus low-calorie food images. Moreover, activation within this cluster predicted overeating, but only for women. Findings suggest that normal fluctuations in sleepiness may be sufficient to affect brain regions important for regulating food intake, but that these effects may differ between men and women. PMID- 23353031 TI - Traveling waves and trial averaging: the nature of single-trial and averaged brain responses in large-scale cortical signals. AB - Analyzing single trial brain activity remains a challenging problem in the neurosciences. We gain purchase on this problem by focusing on globally synchronous fields in within-trial evoked brain activity, rather than on localized peaks in the trial-averaged evoked response (ER). We analyzed data from three measurement modalities, each with different spatial resolutions: magnetoencephalogram (MEG), electroencephalogram (EEG) and electrocorticogram (ECoG). We first characterized the ER in terms of summation of phase and amplitude components over trials. Both contributed to the ER, as expected, but the ER topography was dominated by the phase component. This means the observed topography of cross-trial phase will not necessarily reflect the phase topography within trials. To assess the organization of within-trial phase, traveling wave (TW) components were quantified by computing the phase gradient. TWs were intermittent but ubiquitous in the within-trial evoked brain activity. At most task-relevant times and frequencies, the within-trial phase topography was described better by a TW than by the trial-average of phase. The trial-average of the TW components also reproduced the topography of the ER; we suggest that the ER topography arises, in large part, as an average over TW behaviors. These findings were consistent across the three measurement modalities. We conclude that, while phase is critical to understanding the topography of event-related activity, the preliminary step of collating cortical signals across trials can obscure the TW components in brain activity and lead to an underestimation of the coherent motion of cortical fields. PMID- 23353030 TI - A quantitative magnetic resonance histology atlas of postnatal rat brain development with regional estimates of growth and variability. AB - There has been growing interest in the role of postnatal brain development in the etiology of several neurologic diseases. The rat has long been recognized as a powerful model system for studying neuropathology and the safety of pharmacologic treatments. However, the complex spatiotemporal changes that occur during rat neurodevelopment remain to be elucidated. This work establishes the first magnetic resonance histology (MRH) atlas of the developing rat brain, with an emphasis on quantitation. The atlas comprises five specimens at each of nine time points, imaged with eight distinct MR contrasts and segmented into 26 developmentally defined brain regions. The atlas was used to establish a timeline of morphometric changes and variability throughout neurodevelopment and represents a quantitative database of rat neurodevelopment for characterizing rat models of human neurologic disease. PMID- 23353032 TI - Phosphoproteome analysis reveals an important role for glycogen synthase kinase-3 in perfluorododecanoic acid-induced rat liver toxicity. AB - Perfluorododecanoic acid (PFDoA) is a member of the perfluoroalkyl acid (PFAA) family and has broad applications and a wide distribution in the environment. Here, we used TiO(2)-based phosphopeptide enrichment coupled with LC-MS/MS analysis to identify phosphopeptides in rat livers that were influenced by PFDoA treatment. We identified a total of 1443 unique phosphopeptides from among 769 phosphoproteins identified in normal and PFDoA-treated rat livers, 849 unique phosphorylation sites were also identified. Of these sites, 143 were considered to be novel phosphorylation sites. Many phosphoproteins were found to be associated with hepatic injuries and diseases, such as hepatotoxicity, regeneration, fatty liver, neoplasms and carcinoma. Furthermore, 25 of the identified phosphoproteins were found to be related to glycogen synthase kinase-3 (GSK3), either directly or indirectly. Western blot and qPCR results suggested that chronic PFDoA exposure inhibited insulin signal pathways and that inhibition of GSK3 might contribute to the observed increases of lipid levels in the liver. PMID- 23353033 TI - Protective and worsening peripheral nociceptin/orphanin FQ receptor-mediated effect in a rat model of experimental colitis. AB - Nociceptin/orphanin FQ (N/OFQ) and nociceptin orphanin peptide (NOP) receptors represent an endogenous system modulating gastrointestinal functions and inflammation. We investigated the peripheral effect of N/OFQ and of UFP-101, the NOP antagonist, in a model of colitis induced by TNBS (2,4,6 trinitrobenzenesulphonic acid; 60mg/kg). Male rats received two intraperitoneal injections per day of N/OFQ, UFP-101 or saline for 3 days after colitis induction. Four days after TNBS, animals were sacrificed and colonic histological damage, myeloperoxidase (MPO) activity and cytokine (IL-1beta and IL-10) levels were evaluated. N/OFQ plasmatic levels were assessed by radioimmunoassay. TNBS increased all the inflammatory variables considered. In colitic rats, N/OFQ (0.02 and 0.2nmol/kg) improved microscopic damage, MPO activity and decreased IL-1beta levels in comparison with TNBS group, whereas at the highest dose (20nmol/kg) the peptide worsened colitis. UFP-101 at the dose of 1nmol/kg, without pharmacological activity, antagonised the protective effect of N/OFQ (0.2nmol/kg) on colitis, but at a dose level of 3 and 10nmol/kg worsened inflammation, revealing the endogenous N/OFQergic system protective role. N/OFQ plasmatic levels were not modified in TNBS-treated rats compared with controls, whereas they were reduced in rats treated with the doses of UFP-101 aggravating colitis. In conclusion, peripheral low doses of N/OFQ have a beneficial effect on colonic inflammation in rats. In contrast, N/OFQ at a dose 100-1000-fold higher than those that protect worsens colitis, probably through different mechanisms. The peripheral N/OFQergic system can represent a new field of investigation in some intestinal inflammatory conditions. PMID- 23353034 TI - Structure-property relationships of energetic nitrogen-rich salts composed of triaminoguanidinium or ammonium cation and tetrazole-based anions. AB - Density functional theory and volume-based thermodynamics calculations have been performed to study the crystal densities, heats of formation (HOFs), energetic properties, and thermodynamics of formation for a series of ionic salts composed of triaminoguanidinium or ammonium cations and tetrazole-based anions. Substitution with --NF2, --CH2NF2, --CF2NF2, or --C(NO2)2NF2 groups increased the densities of the salts. The densities of the tetrazole-based salts are affected not only by different substituents but also by different cations. The --CN or - N3 groups are effective substituents for increasing the HOFs of the salts. The triaminoguanidinium cation is more effective than the ammonium cation for increasing the HOF of the tetrazole-based salts. Substitution with --NO2, --NF2, or --C(NO2)2NF2 groups enhances the explosive properties of the salts. The thermodynamics of formation of the salts reveal that all of the tetrazole-based salts with the triaminoguanidinium or ammonium cation could be synthesized using the proposed reactions. Our calculated methods provide a straightforward and inexpensive route for screening a large number of potentially energetic ionic salts. PMID- 23353036 TI - Role of therapeutic hypothermia in improving outcome after traumatic brain injury: a systematic review. AB - This systematic review delineates the effect of primary therapeutic hypothermia (PTH) (initiated on presentation of the patient) on both mortality and neurological outcome in patients with traumatic brain injury. The safety profile of the therapy is also assessed. A systematic search of the following databases was performed: MEDLINE, EMBASE, Zetoc database of conference proceedings, the Cochrane Database of Systematic Reviews, and the clinicaltrials.gov website, up to July 28, 2011. Relevant journals were hand-searched for further articles and reference lists were checked against the retrieved results for additional resources. The retrieved results were filtered for randomized controlled trials in English where systemic hypothermia was applied for >= 12 h in the treatment arm and outcome was assessed at a minimum of 3 months. Randomized controlled trials were assessed for quality of evidence using the GRADE system. Eighteen randomized controlled trials (1851 patients) were identified. The overall relative risk of mortality with PTH when compared with controls was 0.84 [95% confidence interval (CI)=0.72-0.98] and of poor neurological outcome was 0.81 (95% CI=0.73-0.89). However, when only high-quality trials were analysed, the relative risks were 1.28 (95% CI=0.89-1.83) and 1.07 (95% CI=0.92-1.24), respectively. Hypothermia was associated with cerebrovascular disturbances on rewarming and possibly with pneumonia in adult patients. Given the quality of the data currently available, no benefit of PTH on mortality or neurological morbidity could be identified. The therapy should therefore only be used within the confines of well-designed clinical trials. PMID- 23353035 TI - Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery. AB - BACKGROUND: Understanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6-24 months undergoing craniofacial reconstruction surgery. METHODS: Cohorts of six infants were enrolled sequentially to one of the three escalating loading dose-continuous i.v. infusion (CIVI) regimens: 25 mg kg(-1), 10 mg kg(-1) h(-1); 50 mg kg(-1), 20 mg kg(-1) h(-1); 100 mg kg(-1), 40 mg kg(-1) h(-1). Plasma EACA concentrations were determined using a validated high performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs. RESULTS: Population PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min(-1) (3.6 ml kg(-1) min(-1)), inter compartmental clearance of 42.4 ml min(-1) (4.8 ml min(-1) kg(-1)), central volume of distribution of 1.27 litre (0.14 litre kg(-1)), and peripheral volume of distribution of 2.53 litre (0.29 litre kg(-1)). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively. CONCLUSIONS: EACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg(-1) followed by a CIVI of 40 mg kg(-1) h( 1) is appropriate to maintain target plasma EACA concentrations in children aged 6-24 months undergoing these procedures. PMID- 23353037 TI - Life cycle assessment of biohydrogen and biomethane production and utilisation as a vehicle fuel. AB - Environmental burdens for the production and utilisation of biomethane vehicle fuel or a biohydrogen/biomethane blend produced from food waste or wheat feed, based on data from two different laboratory experiments, have been compared. For food waste treated by batch processes the two stage system gave high hydrogen yields (84.2l H2kg(-1) VS added) but a lower overall energy output than the single stage system. Reduction in environmental burdens compared with diesel was achieved, supported by the diversion of waste from landfill. For wheat feed, the semi continuously fed two stage process gave low hydrogen yields (7.5l H2kg(-1) VS added) but higher overall energy output. The process delivers reduction in fossil fuel burdens, and improvements in process efficiencies will lead to reduction in CO2 burdens compared with diesel. The study highlights the importance of understanding and optimising biofuel production parameters according to the feedstock utilised. PMID- 23353038 TI - Enhanced growth and lipid accumulation by a new Ettlia texensis isolate under optimized photoheterotrophic condition. AB - A green microalgae, named as Ettlia texensis was obtained from local freshwater in Turkey. The effects of autotrophic, photoheterotrophic and heterotrophic cultivations on biomass and lipid production were studied. Searching the preferences of the carbon and nitrogen source revealed that this strain could grow photoheterotrophically well with glucose and yeast extract. In the optimized medium, the highest biomass productivity and total lipid content achieved were 0.97 g/L d and 26% of dry weight basis, respectively. Moreover, the major fatty acid methyl esters were C16:0; C18:1; C18:2 and C18:3. In a scale-up attempt, productions were accomplished in a 3 L stirred tank bioreactor. The final biomass and lipid productivities obtained in bioreactor with 250 rpm agitation rate were 0.92 g/L d and 322 mg/L d, respectively. The biochemical compositions were monitored simultaneously by the FTIR spectroscopy during the production in bioreactor. E. texensis could be potent candidate for commercial production in the bioreactor photoheterotrophically. PMID- 23353039 TI - Influence of nitrogen sources on biomass productivity of microalgae Scenedesmus bijugatus. AB - The influence of different nitrogen source of varying concentrations on biomass production of green algae Scenedesmus was investigated. The result revealed that there was a significant difference among nitrogen sources in promoting algal biomass growth at lower concentrations of 5 and 10 mM. Nitrate was found to be a preferred form of nitrogen source and potassium (0.32 g/L) and sodium nitrates (0.28 g/L) performed better for biomass growth of Scenedesmus. Among the ammonical forms, urea (0.25 g/L) resulted in almost equal biomass as nitrates, making it an economical substitute for nitrogen source in large scale culturing of algae being commercially available. PMID- 23353040 TI - Thermo-chemical pre-treatment to solubilize and improve anaerobic biodegradability of press mud. AB - Different pre-treatment severities by thermo-alkaline conditions (100 degrees C, Ca(OH)2) on press mud were evaluated for different pre-treatment time and lime loading. COD solubilization and the methane yield enhancement were assessed. The biochemical methane potential was determined in batch assays under mesophilic conditions (37+/-1 degrees C). The best pre-treatment resulted in a surplus of 72% of methane yield, adding 10g Ca(OH)2 100g(-1)TS(-1) for 1h. Pre-treatment also increased the COD solubilization, but the optimal severity for COD solubilization as determined by response surface methodology did not ensure the highest methane production. Inhibitory effects on anaerobic digestion were noticed when the severity was increased. These results demonstrate the relevance of thermo-alkaline pre-treatment severity in terms of both lime loading and pre treatment time to obtain optimal anaerobic biodegradability of lignocellulosic biomass from press mud. PMID- 23353041 TI - Ecological advantages of partial migration as a conditional strategy. AB - Partial migration is a widespread phenomenon characterized by migrant and resident forms from the same population. In phenotypically plastic taxa with indeterminate growth, resident and migrant ecophenotypes can differ in size and life history traits in ways expected to maximize fitness in the different habitats they exploit. Studies of partial migration in different taxa have advocated either density-dependence or environmental stochasticity as explanations for partial migration. We used a demographic approach for a virtual Brook Trout population to demonstrate the ecological consequences of partial migration under interacting density dependence and environmental stochasticity. The maintenance of partial migration as a conditional strategy in species/populations where resident and migrant forms exhibit life history asymmetries provides ecological advantages. We show that density-dependent migration is expected to increase population fitness under constant environmental conditions or low environmental variation, but decreases population fitness under high environmental variation. These conditions favor intermediate levels of migration as an advantageous tactic. However, there are threshold rates of return migration below which partial migration is no longer a viable tactic. Our modeling approach also allowed the exploration of the distribution of the population by life stage and habitat in response to the strength of density dependence, costs of migration, and return rates, and demonstrated the importance of the conservation of ecophenotypes in partially migratory populations. PMID- 23353042 TI - Primary pericardial mesothelioma in a 19-year-old presenting as pericarditis. AB - Primary pericardial mesothelioma is a rare clinical entity. The association between asbestos and pericardial mesothelioma has not been well established, partly due to the small number of reported patients. Treatment options are limited for this very aggressive cancer. Surgical resection in the form of pericardiectomy can be curative, but owing to the frequently late presentation, surgical intervention is usually palliative. Chemotherapy and radiotherapy have overall poor results. We present the case of a 19-year-old man who initially had symptoms of pericarditis. He died 1 year after initial presentation. PMID- 23353043 TI - HMGB1 release by urothelial carcinoma cells in response to Bacillus Calmette Guerin functions as a paracrine factor to potentiate the direct cellular effects of Bacillus Calmette-Guerin. AB - PURPOSE: Prior study demonstrated that HMGB1 release by urothelial carcinoma cells in response to bacillus Calmette-Guerin is required for an in vivo antitumor effect. We evaluated the direct effects of HMGB1 on the in vitro response of urothelial carcinoma cells to bacillus Calmette-Guerin. MATERIALS AND METHODS: Two human urothelial carcinoma cell lines were used to study the effect of exogenous HMGB1 alone and combined with bacillus Calmette-Guerin on the tumor cell response to bacillus Calmette-Guerin. Antibody mediated blockade of receptors for HMGB1 or HMGB1 protein was used to determine the contribution of paracrine HMGB1 release to bacillus Calmette-Guerin biological effects. Response end points evaluated included the activation of intracellular signaling pathways, gene transactivation and cytotoxicity. RESULTS: Urothelial carcinoma cells expressed the receptor for HMGB1 signaling. Antibody blockade of the RAGE receptor confirmed the dependence of signaling in response to HMGB1 on RAGE function. Exogenous HMGB1 activated cell signaling pathways for NFkappaB, NRF2 and CEBP. Quantitative reverse transcriptase-polymerase chain reaction on a panel of bacillus Calmette-Guerin responsive genes revealed peak expression resulting from the combination of bacillus Calmette-Guerin and HMGB1. Blockade of paracrine HMGB1 released in response to bacillus Calmette-Guerin using HMGB1 and/or RAGE receptor blocking antibodies showed a significant decrease in gene expression relative to that of bacillus Calmette-Guerin alone. HMGB1 potentiated the cytotoxic effects of bacillus Calmette-Guerin. CONCLUSIONS: HMGB1 released by urothelial carcinoma cells after bacillus Calmette-Guerin treatment functions as a paracrine factor to potentiate the urothelial carcinoma cell response to bacillus Calmette-Guerin. This paracrine activity likely contributes to the dependence of an in vivo tumor response on HMGB1 release. PMID- 23353044 TI - Association of microvascular and capillary-lymphatic invasion with outcome in patients with renal cell carcinoma. AB - PURPOSE: We evaluated the association of microvascular and capillary-lymphatic invasion with patient outcome after nephrectomy for renal cell carcinoma. MATERIALS AND METHODS: We identified 1,433 patients surgically treated for sporadic, unilateral renal cell carcinoma between 2001 and 2008. All specimens were reviewed by a single uropathologist for microvascular and capillary lymphatic invasion. Associations with time to metastasis and death from renal cell carcinoma were evaluated using Cox proportional hazards models, controlling for established clinicopathological prognostic variables. RESULTS: Microvascular invasion and capillary-lymphatic invasion were identified in 119 (11%) and 17 (2%) of the 1,103 patients with clear cell, 5 (2%) and 1 (less than 1%) of the 219 with papillary, and 1 (1%) and 0 of the 86 with chromophobe renal cell carcinoma, respectively. Median followup in survivors was 6.4 years (range 0 to 11). In clear cell renal cell carcinoma cases microvascular invasion was univariately associated with an increased risk of metastasis and cancer specific death (HR 3.5 and 3.0, respectively, each p <0.001). However, on multivariate analysis these associations were no longer statistically significant (HR 1.2, p = 0.4 and HR 1.3, p = 0.1, respectively). Capillary-lymphatic invasion remained significantly associated with an increased risk of metastasis and death on univariate analysis (HR 15.9 and 11.6) and on multivariate analysis (HR 3.2 and HR 3.1, respectively, each p <0.001). CONCLUSIONS: Microvascular invasion is associated with an increased risk of metastasis and cancer death in patients with clear cell renal cell carcinoma, although this did not remain significant after controlling for established prognostic variables. Capillary-lymphatic invasion appears to be independently associated with metastasis and cancer death even after controlling for known prognostic risk factors. However, given its rarity, this feature may prove to be of limited clinical significance. PMID- 23353045 TI - Co-cultures provide a new tool to probe communication between adult sensory neurons and urothelium. AB - PURPOSE: Recent evidence suggests that the urothelium functions as a sensory transducer of chemical, mechanical or thermal stimuli and signals to nerve terminals and other cells in the bladder wall. The cellular and molecular basis of neuro-urothelial communication is not easily studied in the intact bladder. This led us to establish a method of co-culturing dorsal root ganglion sensory neurons and bladder urothelial cells. MATERIALS AND METHODS: Sensory neurons and urothelial cells obtained from dorsal root ganglia and bladders dissected from adult female Sprague-Dawley(r) rats were isolated by enzyme treatment and mechanical dissociation. They were plated together or separately on collagen coated substrate and cultured in keratinocyte medium for 48 to 72 hours. Retrograde tracer labeling was performed to identify bladder afferents used for functional testing. RESULTS: Neurite growth and complexity in neurons co-cultured with urothelial cells was increased relative to that in neuronal monocultures. The growth promoting effect of urothelial cells was reduced by the tyrosine kinase inhibitor K252a but upstream inhibition of nerve growth factor signaling with TrkA-Fc had no effect. Fura-2 calcium imaging of urothelial cells showed responses to adenosine triphosphate (100 MUM) and activation of TRPV4 (4alpha PDD, 10 MUM) but not TRPV1 (capsaicin, 1 MUM), TRPV3 (farnesyl pyrophosphate, 1 MUM) or TRPA1 (mustard oil, 100 MUM). In contrast, co-cultured neurons were activated by all agonists except farnesyl pyrophosphate. CONCLUSIONS: Co culturing provides a new methodology for investigating neuro-urothelial interactions in animal models of urological conditions. Results suggest that neuronal properties are maintained in the presence of urothelium and neurite growth is potentiated by a nerve growth factor independent mechanism. PMID- 23353046 TI - Incidence of abnormal imaging and recurrent pyelonephritis after first febrile urinary tract infection in children 2 to 24 months old. AB - PURPOSE: The AAP (American Academy of Pediatrics) no longer recommends voiding cystourethrogram in children 2 to 24 months old who present with a first urinary tract infection if renal-bladder ultrasound is normal. We identified factors associated with abnormal imaging and recurrent pyelonephritis in this population. MATERIALS AND METHODS: We retrospectively evaluated children diagnosed with a first episode of pyelonephritis at age 2 to 24 months using de-identified electronic medical record data from an institutional database. Data included age at first urinary tract infection, gender, race/ethnicity, need for hospitalization, intravenous antibiotic use, history of abnormal prenatal ultrasound, renal-bladder ultrasound and voiding cystourethrogram results, urinary tract infection recurrence and surgical intervention. Risk factors for abnormal imaging and urinary tract infection recurrence were analyzed by univariate logistic regression, the chi-square test and survival analysis. RESULTS: We identified 174 patients. Of the 154 renal-bladder ultrasounds performed 59 (38%) were abnormal. Abnormal prenatal ultrasound (p = 0.01) and the need for hospitalization (p = 0.02) predicted abnormal renal-bladder ultrasound. Of the 95 patients with normal renal-bladder ultrasound 84 underwent voiding cystourethrogram. Vesicoureteral reflux was more likely in patients who were white (p = 0.003), female (p = 0.02) and older (p = 0.04). Despite normal renal bladder ultrasound, 23 of 84 patients (24%) had dilating vesicoureteral reflux. Of the 95 patients with normal renal-bladder ultrasound 14 (15%) had recurrent pyelonephritis and 7 (7%) went on to surgical intervention. CONCLUSIONS: Despite normal renal-bladder ultrasound after a first pyelonephritis episode, a child may still have vesicoureteral reflux, recurrent pyelonephritis and the need for surgical intervention. If voiding cystourethrogram is deferred, parents should be counseled on these risks. PMID- 23353047 TI - Trifecta nerve complex: potential anatomical basis for microsurgical denervation of the spermatic cord for chronic orchialgia. AB - PURPOSE: We identified structural abnormalities in the spermatic cord nerves that may explain how microsurgical denervation of the spermatic cord provides pain relief in patients with chronic orchialgia. MATERIALS AND METHODS: We retrospectively reviewed a prospective database to compare spermatic cord biopsy specimens from 56 men treated with a total of 57 procedures for microsurgical denervation of the spermatic cord for chronic orchialgia vs a control group of men without pain treated with cord surgery, including varicocelectomy in 4 and radical orchiectomy in 6. Tissue biopsies were obtained from mapped regions of the spermatic cord in all cases. Biopsies stained with hematoxylin and eosin were examined by an independent pathologist. Three human cadaveric spermatic cords were dissected to confirm localization of the nerve distribution identified on pathological mapping. RESULTS: We identified a median of 25 small diameter (less than 1 mm) nerve fibers in the spermatic cord. Of the 57 procedures for orchialgia 48 (84%) showed wallerian degeneration in 1 or more of these nerves but only 2 of 10 controls (20%) had such degeneration (p = 0.0008). In decreasing order of nerve density the 3 primary sites (trifecta nerve complex) of these changes were the cremasteric muscle fibers (19 nerves per patient), perivasal tissues and vasal sheath (9 nerves per patient), and posterior cord lipomatous/perivessel tissues (3 nerves per patient). Cord nerve distribution mapped by the biopsies was confirmed by cadaveric dissection. CONCLUSIONS: In men with chronic orchialgia there appears to be wallerian degeneration in reproducible patterns in the spermatic cord nerve fibers. Transection of these nerves may explain the effect of the denervation procedure. PMID- 23353048 TI - A nephrolithometric nomogram to predict treatment success of percutaneous nephrolithotomy. AB - PURPOSE: Imaging is routinely done preoperatively and postoperatively to assess patients treated with percutaneous nephrolithotomy. We developed a nomogram for percutaneous nephrolithotomy success. MATERIALS AND METHODS: From November 2007 to December 2009 the CROES (Clinical Research Office of the Endourological Society) collected data on consecutive patients at 96 centers globally. Patients were evaluated for stone-free status using plain x-ray of the kidneys, ureters and bladder. Treatment success was defined as no visible stones or residual fragments less than 4 mm. Multivariate regression was used to model the relationship between preoperative descriptors and the stone-free rate. Variables included case load, prior treatment, body mass index, staghorn stones, renal anomalies, and stone burden, location and count. Bootstrapping techniques were used to validate the model. Adjusted chi-square statistic values were used to rank the prognostic value of variables. A nomogram was developed using significant predictors from the model. We assessed the predictive accuracy of the nomogram using the ROC curve AUC. The nomogram was calibrated. RESULTS: Stone burden was the best predictor of the stone-free rate (chi-square = 30.27, p <0.001). Other factors associated with the stone-free rate were case volume (chi square = 35.75, p <0.001), prior stone treatment (chi-square = 14.55, p <0.012), staghorn stone (adjusted chi-square = 4.73, p <0.029), stone location (chi-square = 14.74, p <0.001) and stone count (chi-square = 4.78, p <0.004). A nephrolithometric nomogram was developed with predictive accuracy (AUC 0.76). CONCLUSIONS: The percutaneous nephrolithotomy stone-free rate can be predicted using preclinical data and radiological information. We present a nephrolithometric nomogram for percutaneous nephrolithotomy. PMID- 23353049 TI - How to avoid local side effects of bladder photodynamic therapy: impact of the fluence rate. AB - PURPOSE: We studied how to avoid irritative bladder symptoms after bladder photodynamic therapy, such as urgency, frequency and pain, which are associated with the inflammation and destruction of normal urothelium. MATERIALS AND METHODS: Rats bearing orthotopic bladder tumors were instilled with hexyl aminolevulinate and illuminated with red light at a high vs low (100 vs 15 mW/cm(2)) fluence rate. Cystectomy specimens 48 hours after treatment were subjected to anatomopathological examination. Inflammatory reaction and apoptosis were evaluated. In vivo photobleaching was assessed during illumination at each fluence rate. RESULTS: All superficial tumors were eradicated irrespective of light dose and fluence rate. High fluence rates induced necrosis with inflammatory reaction and absent normal urothelium. Low fluence rates did not provoke inflammation and resulted in apoptotic cell death with preserved urothelial integrity. This could be attributable to faster photobleaching of the photosensitizer in normal urothelium at low fluence rates. CONCLUSIONS: Bladder photodynamic therapy at a low fluence rate minimizes side effects without hampering therapeutic efficacy. PMID- 23353050 TI - Determination of binding points of methylene blue and cationic phenoxazine dyes on human butyrylcholinesterase. AB - In this study, the binding points of MethB and two structurally-related cationic phenoxazine dyes [meldola blue (MB) and nile blue (NB)] to human butyrylcholinesterase (BChE) were investigated by molecular docking and site directed mutagenesis. The comparative inhibitory effects of MethB, MB and NB on recombinant wild type BChE and six human BChE mutants were spectrophotometrically studied. Kinetic analyses yielded the following information: MethB and MB were found to cause nonlinear inhibition of all recombinant BChEs except Y332A, compatible with a multi-site binding model. On the other hand, MethB and MB caused linear mixed inhibition of Y332A mutant, compatible with a single binding mode. Comparing the inhibitory effects in aspect of Ki values with recombinant wild type BChE (Ki=0.042 MUM), MethB was found to be ~30, 80 and 270-fold less effective as an inhibitor of Y332A, F329A and T120F, respectively. NB caused nonlinear inhibition of all recombinant BChEs. The inhibitory effect of NB on Y332A mutant was ~370-fold lower, compared to recombinant wild type BChE (Ki=0.006 MUM). Considering both kinetic and molecular docking results together, it was concluded that threonine 120, phenylalanine 329 and tyrosine 332 are critical amino acids in binding of cationic phenoxazine/phenothiazine structured ligands to human BChE. PMID- 23353051 TI - Construction of new cloning, lacZ reporter and scarless-markerless suicide vectors for genetic studies in Aggregatibacter actinomycetemcomitans. AB - To elucidate the putative function of a gene, effective tools are required for genetic characterization that facilitate its inactivation, deletion or modification on the bacterial chromosome. In the present study, the nucleotide sequence of the Escherichia coli/Aggregatibacter actinomycetemcomitans shuttle vector pYGK was determined, allowing us to redesign and construct a new shuttle cloning vector, pJT4, and promoterless lacZ transcriptional/translational fusion plasmids, pJT3 and pJT5. Plasmids pJT4 and pJT5 contain the origin of replication necessary to maintain shuttle vector replication. In addition, a new suicide vector, pJT1, was constructed for the generation of scarless and markerless deletion mutations of genes in the oral pathogen A. actinomycetemcomitans. Plasmid pJT1 is a pUC-based suicide vector that is counter-selectable for sucrose sensitivity. This vector does not leave antibiotic markers or scars on the chromosome after gene deletion and thus provides the option to combine several mutations in the same genetic background. The effectiveness of pJT1 was demonstrated by the construction of A. actinomycetemcomitans isogenic qseB single deletion (DeltaqseB) mutant and lsrRK double deletion mutants (DeltalsrRK). These new vectors may offer alternatives for genetic studies in A. actinomycetemcomitans and other members of the HACEK (Haemophilus spp., A. actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) group of Gram-negative bacteria. PMID- 23353052 TI - The pJan25 vector series: an enhancement of the Gateway-compatible vector pGWB533 for broader promoter testing applications. AB - Agrobacterium-mediated transformation of plants has enhanced our ability to progress more rapidly in plant genetic engineering. Development of binary vectors for Agrobacterium has played a major role in advancing plant biology. Here, we report new features added to the Gateway-compatible vector pGWB533 for promoter testing with the reporter gene encoding beta-glucuronidase (GUS). The original vector contains the spectinomycin/streptomycin adenylyltransferase (aadA) gene for bacterial selection and the hygromycin phosphotransferase gene (hpt) for transformed plant selection. However, some bacterial strains used to transform plants, such as Agrobacterium rhizogenes strain K599, have elevated tolerance to spectinomycin and streptomycin, thus making bacterial selection of pGWB533 inefficient. Although pGWB533 confers chemical selection for transgenic plants using hygromycin resistance, the plasmid has no visual marker that enables visual selection of transformed plants or transgenic tissue. In this regard, adding a gene to constitutively express green fluorescent protein (eGFP) makes it easier to visually select the transformed tissue and trim out the non-transformed. In this report we describe a series of vectors, pJan25S (NCBI: KC416200), pJan25T (NCBI: KC416201) and pJan25X (NCBI: KC416202), that are enhancements of pGWB533 for promoter testing. All three vectors contain the gene encoding eGFP as a visual marker for transformed tissue. However, in pJan25S and pJan25T, eGFP is controlled by the rolD promoter for root-specific expression, while in pJan25X it is controlled by the CaMV35S promoter for constitutive expression in all plant tissues. Spectinomycin and streptomycin resistance remains in pJan25S for bacterial selection; however, pJan25T and pJan25X contain the gene encoding tetracycline resistance (tet) for bacterial selection. These changes resulted in enhanced vectors with better visual and chemical selection that should have broad application in promoter studies. PMID- 23353053 TI - 1,2,3,4,6 Penta-O-galloyl-beta-d-glucose, a bioactivity guided isolated compound from Mangifera indica inhibits 11beta-HSD-1 and ameliorates high fat diet-induced diabetes in C57BL/6 mice. AB - Methanolic leaf extract of Mangifera indica (MEMI) was subjected to bioactivity guided fractionation in order to identify the active antidiabetic constituent. 32 fractions were evaluated for possible 11beta-HSD-1 inhibition activity under in vitro conditions. The EA-7/8-9/10-4 fraction was evolved as a most potent fraction among all the fractions and it was identified as well known gallotannin compound 1,2,3,4,6 penta-O-galloyl-beta-d-glucose (PGG) by spectral analysis. Based on these results the PGG was further evaluated in ex vivo 11beta-HSD-1 inhibition assay and high fat diet (HFD)-induced diabetes in male C57BL/6 mice. Single dose (10, 25, 50 and 100mg/kg) of PGG and carbenoxolone (CBX) have dose dependently inhibited the 11beta-HSD-1 activity in liver and adipose tissue. Furthermore, HFD appraisal to male C57BL/6 mice caused severe hyperglycemia, hypertriglyceridemia, elevated levels of plasma corticosterone and insulin, increased liver and white adipose mass with increase in body weight was observed compare to normal control. Also, oral glucose tolerance was significantly impaired compare to normal control. Interestingly, post-treatment with PGG for 21 days had alleviated the HFD-induced biochemical alterations and improved oral glucose tolerance compare to HFD-control. In conclusion, the PGG isolated from MEMI inhibits 11beta-HSD-1 activity and ameliorates HFD-induced diabetes in male C57BL/6 mice. PMID- 23353054 TI - Hesperidin attenuates cisplatin-induced acute renal injury by decreasing oxidative stress, inflammation and DNA damage. AB - Nephrotoxicity is an important complication in cancer patients undergoing cisplatin therapy. Oxidative stress, inflammation and apoptosis/necrosis are the major patho-mechanisms of cisplatin induced nephrotoxicity. In the present study, hesperidin, a naturally-occurring bioflavonoid has been demonstrated to have protective effect on cisplatin-induced renal injury in rats. Cisplatin intoxication resulted in structural and functional renal impairment which was revealed by massive histopathological changes and elevated blood urea nitrogen and serum creatinine levels, respectively. Renal injury was associated with oxidative stress/lipid peroxidation as evident by increased reactive oxygen species (ROS) and malondialdehyde (MDA) formation with decreased levels of antioxidants such as reduced glutathione, vitamin C, catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase and glutathione-S transferase. Cisplatin administration also triggered inflammatory response in rat kidneys by inducing pro-inflammatory cytokine, TNF-alpha, with the increased expression of myeloperoxidase (MPO). Furthermore, cisplatin increased the activity of caspase-3 and DNA damage with decreased tissue nitric oxide levels. Hesperidin treatment significantly attenuated the cisplatin-induced oxidative stress/lipid peroxidation, inflammation (infiltration of leukocytes and pro inflammatory cytokine), apoptosis/necrosis (caspase-3 activity with DNA damage) as well as increased expression of nitric oxide in the kidney and improved renal function. Thus, our results suggest that hesperidin co-administration may serve as a novel and promising preventive strategy against cisplatin-induced nephrotoxicity. PMID- 23353055 TI - TRPM7 mediates breast cancer cell migration and invasion through the MAPK pathway. AB - Metastasis is an inherent feature of breast cancer and transient receptor potential (TRP) channels were found to be potentially implicated in this process. Particularly, TRPM7 may regulate cell motility. We therefore examined the expression of TRPM7 mRNA in the Oncomine database and found that TRPM7 is correlated to metastasis and invasive breast cancer. Silencing TRPM7 with RNA interference resulted in a significant decrease in migration and invasion capability of MDA-MB-435 breast cancer cells, and phosphorylation levels of Src and MAPK but not AKT. Our results suggest that TRPM7 regulates migration and invasion of metastatic breast cancer cells via MAPK pathway. PMID- 23353057 TI - Edelfosine lipid nanosystems overcome drug resistance in leukemic cell lines. AB - Although current therapies have improved leukemia survival rates, adverse drug effects and relapse are frequent. Encapsulation of edelfosine (ET) in lipid nanoparticles (LNs) improves its oral bioavailability and decreases its toxicity. Here we evaluated the efficacy of ET-LN in myeloid leukemia cell lines. Drug loaded LN were as effective as free ET in sensitive leukemia cell lines. Moreover, the encapsulated drug overcame the resistance of the K562 cell line to the drug. LN containing ET might be used as a promising drug delivery system in leukemia due to their capacity to overcome the in vivo pitfalls of the free drug and their efficacy in vitro in leukemia cell lines. PMID- 23353056 TI - Advances for studying clonal evolution in cancer. AB - The "clonal evolution" model of cancer emerged and "evolved" amid ongoing advances in technology, especially in recent years during which next generation sequencing instruments have provided ever higher resolution pictures of the genetic changes in cancer cells and heterogeneity in tumors. It has become increasingly clear that clonal evolution is not a single sequential process, but instead frequently involves simultaneous evolution of multiple subclones that co exist because they are of similar fitness or are spatially separated. Co evolution of subclones also occurs when they complement each other's survival advantages. Recent studies have also shown that clonal evolution is highly heterogeneous: different individual tumors of the same type may undergo very different paths of clonal evolution. New methodological advancements, including deep digital sequencing of a mixed tumor population, single cell sequencing, and the development of more sophisticated computational tools, will continue to shape and reshape the models of clonal evolution. In turn, these will provide both an improved framework for the understanding of cancer progression and a guide for treatment strategies aimed at the elimination of all, rather than just some, of the cancer cells within a patient. PMID- 23353058 TI - Occurrence of copper acclimation in the least killifish Heterandria formosa, and associated biochemical and physiological mechanisms. AB - We investigated the occurrence of copper acclimation in the least killifish, Heterandria formosa using both lethal and sublethal endpoints. We also investigated potential mechanisms underlying the observed acclimation. To assess the occurrence of acclimation, fish were exposed to either a background Cu level or to 15 MUg/L Cu for seven days and subsequently exposed to a lethal Cu level (150 MUg/L Cu). During the latter exposure, fish were monitored for survival till all fish had died, and (during the first 8h of this exposure) for changes in whole-body Na levels and lipid peroxidation (LPO). During the high-level Cu exposure, fish pre-exposed to copper had a significantly longer time-to-death than did the control fish. Similarly, neither whole-body Na nor LPO changed in the Cu-pre-exposed fish during the 8h of the exposure to 150 MUg/L Cu - while both decreased significantly in the control fish. Thus, acclimation was evident for both time-to-death and the sublethal endpoints. These results also indicate that Cu toxicity may involve both Na loss and LPO, and that Cu-acclimation may be brought about by prevention of these effects. Our follow-up study on potential mechanisms underlying this copper acclimation used a similar pre exposure/exposure design. Fish were subsampled at the end of the 7-day acclimation period - just before the commencement of high-level Cu exposure (T), after 4h of this Cu exposure (T), and again after 8h of this Cu exposure (T). Whole-body Cu accumulation, Na/K-ATPase activity, metallothionein levels, and catalase activity were quantified for these time points. While Cu levels were higher in the Cu-pre-exposed fish than in the control fish at T, net Cu accumulation was faster in the control fish than in the Cu-pre-exposed fish during the subsequent high-level Cu exposure. Consequently, changes in Cu accumulation dynamics may play a role in the resistance. Metallothionein induction may also play a role in the observed acclimation, as Cu-acclimated fish had a significantly higher metallothionein concentration compared to the control fish. There was no evidence of involvement of Na/K-ATPase in the acclimation, as the activity of this enzyme remained lower in the pre-exposed fish than in the control fish throughout both Cu exposure periods. There was limited evidence that a reduced loss of catalase activity plays a role in the acclimation; catalase activity did not differ after the pre-exposure period but was significantly higher in Cu-acclimated fish than in the control fish at T. PMID- 23353059 TI - "Equo ne credite, Teucri. Quidquid id est, timeo Danaos et dona ferentes". PMID- 23353060 TI - Different grading scales for spontaneous subarachnoid hemorrhage and health related quality evaluations. PMID- 23353061 TI - The prehistoric practice of trepanation. PMID- 23353062 TI - Are knowledge gaps an expected result of the current culture of neurosurgical resident training? PMID- 23353063 TI - A pioneer and visionary in neuroimaging technological advances. PMID- 23353064 TI - Endoscopic mesial temporal lobe epilepsy surgery. PMID- 23353065 TI - Minimally invasive, but not at the cost of maximally effective, in the surgical removal of brainstem cavernous malformations. PMID- 23353066 TI - Cervical carotid disease: carotid endarterectomy and stenting. PMID- 23353067 TI - Making three-dimensional Monson's sphere using virtual dental models. AB - OBJECTIVES: The Monson's sphere and curve of Wilson can be used as reference for prosthetic reconstructions or orthodontic treatments. This study aimed to generate and measure the three-dimensional (3-D) Monson's sphere and curve of Wilson using virtual dental models and custom software. METHODS: Mandibular dental casts from 79 young adults of Korean descent were scanned and rendered as virtual dental models using a 3-D digitizing scanner. 26 landmarks were digitized on the virtual dental models using a custom made software program. The Monson's sphere was estimated by fitting a sphere to the cusp tips using a least-squares method. Two curves of Wilson were generated by finding the intersecting circle between the Monson's sphere and two vertical planes orthogonal to a virtual occlusal plane. Non-parametric Mann-Whitney and Kruskal-Wallis tests were performed to test for difference between sex and in cusp number within tooth position. RESULTS: The mean radius of Monson's sphere was 110.89 +/- 25.75 mm. There were significant differences between males and females in all measurements taken (p<0.01), within 16.87-17.27 mm. Furthermore, morphological variation derived from variability in cusp number in the second premolar and second molar were not found to influence occlusal curvature (p>0.05). CONCLUSIONS: This study describes a best-fit algorithm for generating 3-D Monson's sphere using occlusal curves quantified from virtual dental models. The radius of Monson's sphere in Korean subjects was greater than the original four-inch value suggested by Monson. CLINICAL SIGNIFICANCE: The Monson's sphere and curve of Wilson can be used as a reference for prosthetic reconstruction and orthodontic treatment. The data found in this study may be applied to improve dental treatment results. PMID- 23353069 TI - Effects of extreme cooling methods on mechanical properties and shear bond strength of bilayered porcelain/3Y-TZP specimens. AB - OBJECTIVES: This study investigated the effect of extreme cooling methods on the flexural strength, reliability and shear bond strength of veneer porcelain for zirconia. METHODS: Vita VM9 porcelain was sintered on zirconia bar specimens and cooled by one of the following methods: inside a switched-off furnace (slow), at room temperature (normal) or immediately by compressed air (fast). Three-point flexural strength tests (FS) were performed on specimens with porcelain under tension (PT, n=30) and zirconia under tension (ZT, n=30). Shear bond strength tests (SBS, n=15) were performed on cylindrical blocks of porcelain, which were applied on zirconia plates. Data were submitted to one-way ANOVA and Tukey's post hoc tests (p<0.05). Weibull analysis was performed on the PT and ZT configurations. RESULTS: One-way ANOVA for the PT configuration was significant, and Tukey's test revealed that fast cooling leads to significantly higher values (p<0.01) than the other cooling methods. One-way ANOVA for the ZT configuration was not significant (p=0.06). Weibull analysis showed that normal cooling had slightly higher reliability for both the PT and ZT configurations. Statistical tests showed that slow cooling decreased the SBS value (p<0.01) and showed less adhesive fracture modes than the other cooling methods. CLINICAL SIGNIFICANCE: Slow cooling seems to affect the veneer resistance and adhesion to the zirconia core; however, the reliability of fast cooling was slightly lower than that of the other methods. PMID- 23353068 TI - Dental primer and adhesive containing a new antibacterial quaternary ammonium monomer dimethylaminododecyl methacrylate. AB - OBJECTIVES: The main reason for restoration failure is secondary caries caused by biofilm acids. Replacing the failed restorations accounts for 50-70% of all operative work. The objectives of this study were to incorporate a new quaternary ammonium monomer (dimethylaminododecyl methacrylate, DMADDM) and nanoparticles of silver (NAg) into a primer and an adhesive, and to investigate their effects on antibacterial and dentin bonding properties. METHODS: Scotchbond Multi-Purpose (SBMP) served as control. DMADDM was synthesized and incorporated with NAg into primer/adhesive. A dental plaque microcosm biofilm model with human saliva was used to investigate metabolic activity, colony-forming units (CFU), and lactic acid. Dentin shear bond strengths were measured. RESULTS: Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the new DMADDM were orders of magnitude lower than those of a previous quaternary ammonium dimethacrylate (QADM). Uncured primer with DMADDM had much larger inhibition zones than QADM (p<0.05). Cured primer/adhesive with DMADDM-NAg greatly reduced biofilm metabolic activity (p<0.05). Combining DMADDM with NAg in primer/adhesive resulted in less CFU than DMADDM alone (p<0.05). Lactic acid production by biofilms was reduced by 20-fold via DMADDM-NAg, compared to control. Incorporation of DMADDM and NAg into primer/adhesive did not adversely affect dentin bond strength. CONCLUSIONS: A new antibacterial monomer DMADDM was synthesized and incorporated into primer/adhesive for the first time. The bonding agents are promising to combat residual bacteria in tooth cavity and invading bacteria at tooth-restoration margins to inhibit caries. DMADDM and NAg are promising for use into a wide range of dental adhesive systems and restoratives. PMID- 23353071 TI - A multimarker phylogeography of crested newts (Triturus cristatus superspecies) reveals cryptic species. AB - The crested newt Triturus cristatus superspecies is composed of five recognized species. One of these, T. karelinii sensu lato, comprises three geographically structured mitochondrial DNA lineages: 'eastern', 'central' and 'western T. karelinii'. Genetic divergence among these lineages is comparable to that of recognized crested newt species, but morphologically they are indistinguishable. Here, we conduct a multimarker phylogeographical survey to explore the evolutionary independence of these mitochondrial DNA lineages and we include representatives of the other species to guide our interpretation of the results. All markers show distinct patterns when analyzed singly (as a phylogeny or haplotype network) and none of them sort haplotypes fully in line with species or mitochondrial DNA lineage. A multilocus approach (BAPS and *BEAST) on the other hand shows that not only the recognized species, but also the three mitochondrial DNA lineages represent discrete nuclear DNA gene pools. A mismatch is found in the northwest of Asiatic Turkey, where several populations identified as 'central T. karelinii' based on nuclear DNA possesses 'western T. karelinii' mitochondrial DNA. We invoke asymmetric mitochondrial DNA introgression to explain this pattern and support this with a historical biogeographical scenario. The three spatial groups in T. karelinii sensu lato should be regarded as distinct species. PMID- 23353070 TI - Self-perceived changes in oral health-related quality of life after receiving different types of conventional prosthetic treatments: a cohort follow-up study. AB - OBJECTIVES: To evaluate the changes in oral health-related quality of life (OHRQoL) reported by subjects treated with conventional prostheses. METHODS: A consecutive sample of 153 patients seeking prosthodontic rehabilitation was recruited. Socio-demographic and prosthetic-related factors (Eichner Index; number of occlusal, aesthetic, and lost units) were registered. Baseline impacts on OHRQoL were collected using the OHIP-14 questionnaire. One month after treatment, the participants answered whether the prostheses had generated better, equal, or poorer effects within the 14 items of a retrospective scale (Post OHIP). The study patients were compared with the reference population (P population; n=123) in terms of OHRQoL. Such P-population consisted of Spanish adults wearing conventional dental prostheses who were not seeking any dental treatment. The reliability and validity of the tests applied and the factor structure of the Post-OHIP were investigated. A Poisson regression model was calculated to predict what items would change favourably after treatment. RESULTS: Four prosthetic cohorts were established according to the types of rehabilitations performed: 1-FDPs: metal-ceramic fixed dental prostheses; 2-M RPDs: metal-based removable partial dentures; 3-ADs: acrylic partial dentures and 4-CDs: complete dentures. Both tests confirmed adequate psychometric properties. Most items of the Post-OHIP consistently loaded on a single factor. Patients requiring ADs or CDs reported significantly lower baseline OHRQoL than those needing M-RPDs or FDPs. Pain/discomfort was the only hampering issue subsequent to removable rehabilitation. M-RPDs are expected to provide the significantly highest therapeutic improvements. CONCLUSIONS: Patients perceived benefits in chewing ability, aesthetics and satisfaction with their mouth after receiving conventional dental prostheses. CLINICAL SIGNIFICANCE: Conventional prosthetic therapy enhances patients' overall well-being although it can cause discomfort and chewing dysfunction in more than 20% of subjects. Metal-based removable partial dentures are the most predictable in terms of patient satisfaction. The higher the clinical impairment felt by patients, the higher the increase in OHRQoL after rehabilitation. PMID- 23353073 TI - Deep metazoan phylogeny: when different genes tell different stories. AB - Molecular phylogenetic analyses have produced a plethora of controversial hypotheses regarding the patterns of diversification of non-bilaterian animals. To unravel the causes for the patterns of extreme inconsistencies at the base of the metazoan tree of life, we constructed a novel supermatrix containing 122 genes, enriched with non-bilaterian taxa. Comparative analyses of this supermatrix and its two non-overlapping multi-gene partitions (including ribosomal and non-ribosomal genes) revealed conflicting phylogenetic signals. We show that the levels of saturation and long branch attraction artifacts in the two partitions correlate with gene sampling. The ribosomal gene partition exhibits significantly lower saturation levels than the non-ribosomal one. Additional systematic errors derive from significant variations in amino acid substitution patterns among the metazoan lineages that violate the stationarity assumption of evolutionary models frequently used to reconstruct phylogenies. By modifying gene sampling and the taxonomic composition of the outgroup, we were able to construct three different yet well-supported phylogenies. These results show that the accuracy of phylogenetic inference may be substantially improved by selecting genes that evolve slowly across the Metazoa and applying more realistic substitution models. Additional sequence-independent genomic markers are also necessary to assess the validity of the phylogenetic hypotheses. PMID- 23353072 TI - Genetic introgression and hybridization in Antillean freshwater turtles (Trachemys) revealed by coalescent analyses of mitochondrial and cloned nuclear markers. AB - Determining whether a conflict between gene trees and species trees represents incomplete lineage sorting (ILS) or hybridization involving native and/or invasive species has implications for reconstructing evolutionary relationships and guiding conservation decisions. Among vertebrates, turtles represent an exceptional case for exploring these issues because of the propensity for even distantly related lineages to hybridize. In this study we investigate a group of freshwater turtles (Trachemys) from a part of its range (the Greater Antilles) where it is purported to have undergone reticulation events from both natural and anthropogenic processes. We sequenced mtDNA for 83 samples, sequenced three nuDNA markers for 45 samples, and cloned 29 polymorphic sequences, to identify species boundaries, hybridization, and intergrade zones for Antillean Trachemys and nearby mainland populations. Initial coalescent analyses of phased nuclear alleles (using (*)BEAST) recovered a Bayesian species tree that strongly conflicted with the mtDNA phylogeny and traditional taxonomy, and appeared to be confounded by hybridization. Therefore, we undertook exploratory phylogenetic analyses of mismatched alleles from the "coestimated" gene trees (Heled and Drummond, 2010) in order to identify potential hybrid origins. The geography, morphology, and sampling context of most samples with potential introgressed alleles suggest hybridization over ILS. We identify contact zones between different species on Jamaica (T. decussata * T. terrapen), on Hispaniola (T. decorata * T. stejnegeri), and in Central America (T. emolli * T. venusta). We are unable to determine whether the distribution of T. decussata on Jamaica is natural or the result of prehistoric introduction by Native Americans. This uncertainty means that the conservation status of the Jamaican T. decussata populations and contact zone with T. terrapen are unresolved. Human-mediated dispersal events were more conclusively implicated for the prehistoric translocation of T. stejnegeri between Puerto Rico and Hispaniola, as well as the more recent genetic pollution of native species by an invasive pet turtle native to the USA (T. scripta elegans). Finally, we test the impact of introgressed alleles using the multispecies coalescent in a Bayesian framework and show that studies that do not phase heterozygote sequences of hybrid individuals may recover the correct species tree, but overall support for clades that include hybrid individuals may be reduced. PMID- 23353074 TI - [Prevalence of Plasmodium falciparum during the rainy season (June-December) in the southeast district of Haiti]. AB - This malaria prevalence survey was conducted in Haiti from June through November 2010. The Plasmodium falciparum rate was assessed in 16 municipalities and villages of the southeast district, by examination of thick films from a randomly drawn population sample. The study included 2,126 people aged one to 90 years. P. falciparum was detected among 201 non-febrile subjects. This district, with a P. falciparum rate of 9.5%, is in a low endemic area for malaria. Nonetheless, the infection rates varied considerably from one area to another. Along the coast, the P. falciparum rate ranged from 0 to 34.5%, in four separate categories: four highly infected (mean P. falciparum rate = 21.4% and mean gametocyte rate = 15.3%), four moderately infected (mean P. falciparum rate = 6.1% and gametocyte rate = 5.9%), five slightly infected (mean P. falciparum rate = 3.3% and gametocyte rate = 1.1%) and one uninfected in the interior. No cases of infection were detected in two areas located at an altitude above 600 m. The trophozoite and gametocyte rates varied little as a function of age and thus indicated a low level of protection within the population. This study shows the persistence of endemic malaria at highly variable prevalence levels in this district of Haiti. The development of this region that could be highly desirable to tourists requires the establishment of an appropriate disease control program. PMID- 23353075 TI - Pharmaceutical care for patients undergoing s-1 plus Cisplatin therapy for unresectable recurrent gastric cancer. AB - We examined the adverse gastrointestinal events associated with tegafur/gimeracil/oteracil potassium (S-1) plus cisplatin therapy for unresectable recurrent gastric cancer and risk factors for discontinuing therapy due to adverse events. A total of 65 subjects who had received S-1 plus cisplatin therapy for gastric cancer at Ogaki Municipal Hospital were examined. We found that the risk factors for discontinuation of the therapy due to adverse events were serum albumin (Alb) level less than 3.5 g/dL (odds ratio [OR]: 321.14, P = .0015), creatinine clearance (CrCl) rate less than 78 mL/min (OR: 35.23, P = .0123), and performance status (PS) more than 1 (OR:12.62, P = .0243). Moreover, grade 3 or 4 nonhematological toxicities (including malaise and anorexia) were significantly higher in subjects with Alb less than 3.5 g/dL and CrCl less than 78 mL/min (P < .01). In conclusion, we should pay attention to the safety and continuity of S-1 plus cisplatin therapy in cases where the Alb level is <3.5 g/dL, CrCl level is <78 mL/min, and PS level is >1. Pharmacists should consider reducing the treatment dosage and providing nutritional support in such cases. PMID- 23353077 TI - Tamoxifen-loaded lecithin organogel (LO) for topical application: Development, optimization and characterization. AB - Lecithin organogels (LOs) are semi-solid systems with immobilized organic liquid phase in 3-D network of self-assembled gelators. This paper attempts to study the various attributes of LOs, starting from selection of materials, optimization of influential components to LO specific characterization. After screening of various components (type of gelators, organic and aqueous phase) and construction of phase diagrams, a D-optimal mixture design was employed for the systematic optimization of the LO composition. The response surface plots were constructed for various response variables, viz. viscosity, gel strength, spreadability and consistency index. The optimized LO composition was searched employing overlay plots. Subsequent validation of the optimization study employing check-point formulations, located using grid search, indicated high degree of prognostic ability of the experimental design. The optimized formulation was characterized for morphology, drug content, rheology, spreadability, pH, phase transition temperatures, and physical and chemical stability. The outcomes of the study were interesting showing high dependence of LO attributes on the type and amount of phospholipid, PoloxamerTM, auxillary gelators and organic solvent. The optimized LO was found to be quite stable, easily applicable and biocompatible. The findings of the study can be utilized for the development of LO systems of other drugs for the safer and effective topical delivery. PMID- 23353076 TI - Pax6 regulates Tbr1 and Tbr2 expressions in olfactory bulb mitral cells. AB - Tracking olfactory bulb mitral cell development with BrdU labeling, we find that mitral cells are generated from Pax6+ radial glial cells in the ventricular zone of the embryonic olfactory bulb. Unlike cortical projection neurons, postmitotic mitral cell precursors express both Tbr1 and Tbr2. Our tracking experiments revealed that down-regulation of Pax6 preceded up-regulation of Tbrs, and that Tbr1 emerged earlier than Tbr2. Using in utero electroporation, we also show that Pax6 negatively regulates the expression of Tbr1 and Tbr2 in postmitotic mitral cell precursors. Exogenous expression of Pax6 in embryonic olfactory bulb postmitotic precursors decreased the number of cells that progressed to a mitral cell fate. In contrast, exogenous expression of Pax6 resulted in an increase of GABAergic and/or dopaminergic interneurons. These results indicate that Pax6 is a regulator of fate determination of precursor cells. PMID- 23353079 TI - Population-based characteristics of fatal and hospital admissions for poisoning in Fiji: TRIP Project-11. AB - This study investigated the incidence and characteristics of poisoning fatalities and hospital admissions among indigenous Fijians and Indians in Viti Levu, Fiji. Individuals with a mechanism of injury classified as poisoning were identified using the Fiji injury surveillance in hospitals system, a population-based registry established for 12 months in Viti Levu, and analysed using population based denominators. The mean annual rates of fatalities and hospitalisations were 2.3 and 26.0 per 100 000, respectively. Over two-thirds of poisonings occurred among people of Indian ethnicity. Most intentional poisoning admissions occurred among women (58.3%) and in 15-29-year-old individuals (73.8%). Unintentional poisoning admission rates were highest among Indian boys aged 0-14 years. While over 75% of events occurred at home, the substances involved were not systematically identified. The findings indicate the need for a strategy that addresses the differing contexts across age group, gender and ethnicity, and a lead agency responsible for implementing and monitoring its effectiveness. PMID- 23353081 TI - History of scorpion antivenom: one Arizonan's view. AB - This paper was originally presented as the Elsevier Lecture in July, 2012 at the International Society on Toxinology/Venom Week combined meeting in Honolulu, Hawaii. In it, the author addresses the ancient history of venom and immunity, from the Silurian Era to the 1890s; the development of the first antivenoms; the impact of shifting political and economic pressures; the special case of Arizona; the relative stability of the 1960s through 1990s; the transition to regulatory compliance that took place at the time of the author's own research; and concluding thoughts regarding the instability of apparent success. PMID- 23353080 TI - Pluripotent stem cells and gene therapy. AB - Human pluripotent stem cells represent an accessible cell source for novel cell based clinical research and therapies. With the realization of induced pluripotent stem cells (iPSCs), it is possible to produce almost any desired cell type from any patient's cells. Current developments in gene modification methods have opened the possibility for creating genetically corrected human iPSCs for certain genetic diseases that could be used later in autologous transplantation. Promising preclinical studies have demonstrated correction of disease-causing mutations in a number of hematological, neuronal, and muscular disorders. This review aims to summarize these recent advances with a focus on iPSC generation techniques, as well as gene modification methods. We will then further discuss some of the main obstacles remaining to be overcome before successful application of human pluripotent stem cell-based therapy arrives in the clinic and what the future of stem cell research may look like. PMID- 23353082 TI - First- and second-generation quinolone antibacterial drugs interacting with zinc(II): structure and biological perspectives. AB - Interaction of equimolar quantities of ZnCl2 with the quinolone antibacterial drugs flumequine (Hflmq), oxolinic acid (Hoxo) or enrofloxacin (Herx) and the N,N'-donor heterocyclic ligands 1,10-phenanthroline (phen) or 2,2'-bipyridine (bipy) results in the formation of 1:1 drug to metal complexes with the general formula [Zn(quinolone)(N,N'-donor)Cl], while excess of the quinolone leads to 1:2 metal to drug [Zn(quinolone)2(N,N'-donor)] complexes. In all complexes, the deprotonated bidentate quinolonato ligands are coordinated to zinc ion through the pyridone oxygen and a carboxylato oxygen. The crystal structures of [Zn(oxo)(phen)Cl], [Zn(flmq)(phen)Cl] and [Zn(flmq)2(phen)] have been determined by X-ray crystallography. All complexes exhibit good binding propensity to human or bovine serum albumin protein showing relatively high binding constant values. Interaction of the complexes with calf-thymus (CT) DNA, studied by UV spectroscopy, has shown that they bind to CT DNA, while [Zn(flmq)(phen)Cl] and [Zn(flmq)2(phen)] complexes exhibit the highest binding constants to CT DNA. Competitive study with ethidium bromide (EB) has shown that all complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB. Intercalative binding mode is proposed for the interaction of the complexes with CT DNA and has also been verified by DNA solution viscosity measurements. DNA electrophoretic mobility experiments suggest that all complexes bind to linearized pDNA and supercoiled pDNA by intercalative manner resulting in catenanes formation as well as in double-stranded cleavage reflecting (or ending) in the formation of linear DNA. The complexes exhibit significant antimicrobial activity tested on five different microorganisms. PMID- 23353083 TI - Photoinduced ligand exchange and DNA binding of cis-[Ru(phpy)(phen)(CH3CN)2]+ with long wavelength visible light. AB - The complex cis-[Ru(phpy)(phen)(CH3CN)2](+) (phpy=2-phenylpyridine, phen=1,10 phenanthroline) was investigated as a potential photodynamic therapy (PDT) agent. This complex presents desirable photochemical characteristics including a low energy absorption tail extending into the PDT window (600-850nm) and photoinduced exchange of the CH3CN ligands, generating a species analogous to the chemotherapy drug cisplatin. Furthermore, photochemical reactivity can be controlled through selective irradiation into the Ru-phen singlet metal-to-ligand charge transfer ((1)MLCT) band (lambdairr=500 nm) of [Ru(phpy)(phen)(CH3CN)2](+) in the presence of excess t-butylammonium chloride (TBACl) resulting in efficient photoinduced production of [Ru(phpy)(phen)(CH3CN)Cl] (Phi=0.25). This lower energy irradiation resulted in greater quantum yield of photosubstitution when compared to direct irradiation into the Ru-phpy (1)MLCT peak (lambdairr=450 nm; Phi=0.08) in CH2Cl2. It was found that the lower quantum yield observed for irradiation into the Ru >phpy(-)(1)MLCT band results from significant orbital mixing of the phpy(-) ligand with the t2g-type filled set in the metal, giving this state significant ligand-centered character. Lastly, this complex produced a decrease in the mobility of linearized ds-DNA when irradiated with lambdairr>=420nm, indicative of covalent binding by the transition metal complex similar to that observed for cisplatin. No change in mobility was found for the same samples kept in the dark indicating, unlike cisplatin, DNA binding of cis-[Ru(phpy)(phen)(CH3CN)2](+) only occurs with the activation of light. These observations support the use of cis [Ru(phpy)(phen)(CH3CN)2](+) as a potential PDT agent by the photoinduced generation of a cisplatin analog. PMID- 23353084 TI - Regulation of the physiological effects of peroxidovanadium(V) complexes by the electronic nature of ligands. AB - Although the physiological effects of peroxidovanadium(V) complexes (pVs) have been extensively investigated both in vitro and in vivo with regard to their pharmacological activity, such as insulin-mimetic and antitumor activities, the relationship between the chemical and pharmacological properties of pVs is still unclear. Rational drug design with pVs depends on a full understanding of this relationship. Toward this end, the current report evaluates the physiological effects of 13 pVs were evaluated bound to a variety of ligand. Six of these ligands are tripodal tetradentate ligands, one is a linear tetradentate ligand, one boasts two pendant groups, three are tridentate ligands, and two are alkoxido bridging, dinucleating ligands. The cytotoxicities of these pVs could be classified into three groups: significantly toxic, moderately toxic, and non- or negligibly toxic. Further, IC50 values could be related with the LMCT transition energies of the peroxido group, particularly among complexes with similar ligands. This relation indicates that the electronic properties of the peroxido group affected the physiological activity of the pV complex. We also investigated the insulin-signaling intensity of each pV. Phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2, two major insulin-signaling proteins, was observed after treating cells with pV for 30 min. Phosphorylation was particularly remarkable for complexes that exhibited high cytotoxicity. The present results demonstrate that the toxicity and physiological effects of pVs can be controlled by selecting an appropriate ancillary ligand. These findings provide a guide for synthesis of new pVs that may be used as candidate therapeutic agents. PMID- 23353085 TI - Structure, antimicrobial activity, DNA- and albumin-binding of manganese(II) complexes with the quinolone antimicrobial agents oxolinic acid and enrofloxacin. AB - The reaction of MnCl2 with the quinolone antibacterial drug oxolinic acid (Hoxo) results to the formation of [KMn(oxo)3(MeOH)3]. Interaction of MnCl2 with the quinolone Hoxo or enrofloxacin (Herx) and the N,N'-donor heterocyclic ligand 1,10 phenanthroline (phen) results in the formation of metal complexes with the general formula [Mn(quinolonato)2(phen)]. The crystal structures of [KMn(oxo)3(MeOH)3] and [Mn(erx)2(phen)], exhibiting a 1D polymeric and a mononuclear structure, respectively, have been determined by X-ray crystallography. In these complexes, the deprotonated bidentate quinolonato ligands are coordinated to manganese(II) ion through the pyridone oxygen and a carboxylato oxygen. All complexes can act as potential antibacterial agents with [Mn(erx)2(phen)] exhibiting the most pronounced antimicrobial activity against five different microorganisms. Interaction of the complexes with calf-thymus DNA (CT DNA), studied by UV spectroscopy, has shown that they bind to CT DNA. Competitive study with ethidium bromide (EB) has shown that all complexes can displace the DNA-bound EB indicating their binding to DNA in strong competition with EB. Intercalative binding mode is proposed for the interaction of the complexes with CT DNA and has also been verified by DNA solution viscosity measurements and cyclic voltammetry. DNA electrophoretic mobility experiments suggest that [Mn(erx)2(phen)] binds strongly to supercoiled pDNA and to linearized pDNA possibly by an intercalative manner provoking double-stranded cleavage reflecting in a nuclease-like activity. The complexes exhibit good binding propensity to human or bovine serum albumin protein showing relatively high binding constant values. The binding constants of the complexes towards CT DNA and albumins have been compared to their corresponding zinc(II) and nickel(II) complexes. PMID- 23353087 TI - The solid angle subtended by a well-type detector and a cylindrical source. AB - A Monte Carlo approach, based on total variance reduction, was presented in order to evaluate the solid angle subtended between a well-type NaI detector and a cylindrical source within the well. The results obtained, in the form of the geometrical efficiency epsilong, were within 0.7% of those in the literature, for a point and a volumetric radioactive source within the well. The effect of self absorption on the geometrical efficiency was investigated for different gamma-ray energies emitted by the volumetric source, different source matrices and radii. Self-absorption is found to be particularly significant for gamma-ray energies below 300keV regardless the source matrix and radius. Furthermore, self absorption becomes significant, in the case of the larger radius volumetric source, for the gamma-ray energies up to 1MeV considered. Hence, the effect of self-absorption on the geometrical factor should be considered in the absolute quantification of radioactivity of volumetric sources. PMID- 23353086 TI - Medaka fish, Oryzias latipes, as a model for human obesity-related glomerulopathy. AB - Obesity, an ongoing significant public health problem, is a part of complex disease characterized as metabolic syndrome. Medaka and zebrafish are useful aquatic experimental animals widely used in the field of toxicology and environmental health sciences and as a human disease models. In medaka, simple feeding of a high fat diet (HFD) can induce body weight gain, excessive accumulation of visceral adipose tissue, hyperglycemia, hyperlipidemia, and steatohepatitis, which mimics human metabolic syndrome. In the present study, to explore the possibility that the adult medaka fed with HFD (HFD-medaka) can be used as an animal model for human metabolic syndrome-associated glomerular disease, including obesity-related glomerulopathy (ORG), we analyzed structural alterations and protein expression in the mesonephric kidney of HFD-medaka. We found that the histopathology was consistent with glomerulomegaly accompanied by the dilation of glomerular capillaries and proliferative expansion of the mesangium, a condition partially comparable to human ORG. Moreover, expressions of several kinds of kidney disease-related proteins (such as MYH9, SM22alpha) were significantly elevated. Thus, the HFD-medaka has a high potential as an animal model useful for exploring the mechanism underling human ORG. PMID- 23353088 TI - Application of polystyrene films for indoor radon dosimetry as SSNTD. AB - In this study, the sensitivities and calibration factors of polystyrene (PS) to (220)Rn and (222)Rn have been investigated. The sensitivity of compact disks (CD/DVD) as thick polycarbonates (PC) to (220)Rn and (222)Rn has been also obtained by applying a new etching condition. Five different brands of X-ray radiology and MRI films with polystyrene base and four brands of CD/DVDs have been studied to assess their applicability as a passive detector for indoor radon monitoring. The comparison between the sensitivities of PS samples, CD/DVDs (as thick PC) and Lexan PC to (222)Rn and (220)Rn shows an improved sensitivity of PS over conventional PC currently being used as solid state nuclear track detectors (SSNTD). The sensitivity of X-ray radiology PS films to (222)Rn and (220)Rn was found to be 8.77+/-0.591 and 0.028+/-0.006 (cm(-2)kBq(-1)d(-1)m(3)). The sensitivities of MRI PS films to Rn-222 and Rn-220 was found to be 12.2+/-1.25 and 0.360+/-0.090 (cm(-2)kBq(-1)d(-1)m(3)). The CD/DVD PC found to have a sensitivity of 0.178+/-0.013 and 0.0024+/-0.00013 (cm(-2)kBq(-1)d(-1)m(3)) to (222)Rn and (220)Rn respectively. PMID- 23353089 TI - Methodology for characterizing seeds under development for brachytherapy by means of radiochromic and photographic films. AB - The development of new medical devices possess a number of challenges, including designing, constructing, and assaying prototypes. In the case of new brachytherapy seeds, this is also true. In this paper, a methodology for rapid dosimetric characterization of (125)I brachytherapy seeds during the early stages of their development is introduced. The characterization methodology is based on the joint use of radiochromic and personal monitoring photographic films in order to determine the planar anisotropy due to the radiation field produced by the seed under development, by means of isodose curves. To evaluate and validate the process, isodose curves were obtained with both types of films after irradiation with a commercial (125)I brachytherapy seed. PMID- 23353090 TI - Field gamma dose-rate assessment in natural sedimentary contexts using LaBr3(Ce) and NaI(Tl) probes: a comparison between the "threshold" and "windows" techniques. AB - Results are presented for a series of replicate in situ gamma spectrometry measurements (n=20) made in natural sedimentary contexts using LaBr3(Ce) and NaI(Tl) probes. For both types of detectors, gamma dose rates were calculated using the "threshold" technique (Murray et al., 1978), and compared with results obtained previously by Arnold et al. (2012) using the "windows" technique (Aitken, 1985). Our results show that gamma dose rates obtained using these two techniques are consistent at 1sigma for a given probe, and that the threshold technique yields reproducible results for the LaBr3(Ce) and NaI(Tl) probes. In comparison with the energy windows approach, the threshold approach offers an improvement in the precision with which gamma dose rates can be determined using the LaBr3(Ce) probe. The potential of an alternative threshold approach (the "energy threshold" approach of Guerin and Mercier, 2011) was also tested for both probe types, and the resultant gamma dose rates were found to be in agreement with those obtained using the standard threshold and energy windows techniques. Our results provide new insights into methods and instrumentation used for assessing in situ gamma dose rates in Electron Spin Resonance (ESR) and Luminescence dating. We conclude that LaBr3(Ce) probes can reliably be used for portable gamma dosimetry in low level activity sedimentary environments (500 1500MUGy/a) when using the threshold approach, provided that their non-negligible internal background activities (equivalent to ~758MUGy/a for our probe) are accurately assessed and subtracted from gamma ray spectra measured in the field. Our results also suggest that there may be some minor merit in applying an internal background-subtraction procedure to NaI(Tl) gamma ray spectra when using the threshold technique, in spite of the lower intrinsic activities of NaI(Tl) detectors. PMID- 23353091 TI - An empirical formula to calculate the full energy peak efficiency of scintillation detectors. AB - This work provides an empirical formula to calculate the FEPE for different detectors using the effective solid angle ratio derived from experimental measurements. The full energy peak efficiency (FEPE) curves of the (2"(*)2") NaI(Tl) detector at different seven axial distances from the detector were depicted in a wide energy range from 59.53 to 1408keV using standard point sources. The distinction was based on the effects of the source energy and the source-to-detector distance. A good agreement was noticed between the measured and calculated efficiency values for the source-to-detector distances at 20, 25, 30, 35, 40, 45 and 50cm. PMID- 23353092 TI - Concerning the time dependence of the decay rate of 137Cs. AB - The decay rates of eight nuclides ((85)Kr, (90)Sr, (108)Ag, (133)Ba, (137)Cs, (152)Eu, (154)Eu, and (226)Ra) were monitored by the standards group at the Physikalisch-Technische Bundesanstalt (PTB), Braunschweig, Germany, over the time frame June 1999 to November 2008. We find that the PTB measurements of the decay rate of (137)Cs show no evidence of an annual oscillation, in agreement with the recent report by Bellotti et al. However, power spectrum analysis of PTB measurements of a (133)Ba standard, measured in the same detector system, does show such evidence. This result is consistent with our finding that different nuclides have different sensitivities to whatever external influences are responsible for the observed periodic variations. PMID- 23353093 TI - Enhanced biodegradation of wastewater with electron beam pretreatment. AB - The traditional biological aerobic treatment of domestic wastewater only reduces the pathogen load, biological oxygen demand (BOD), and chemical oxygen demand (COD) to some extent. Irradiation with electrons to 1kGy alone was found to be sufficient to eliminate all the pathogens, but no significant reduction in COD and BOD was observed. However, electron irradiation to 1kGy followed by the biological treatment resulted in more complete and faster reduction in the pathogen count, COD, and BOD than the biological treatment alone. PMID- 23353094 TI - Application of gamma ray scattering technique for non-destructive evaluation of voids in concrete. AB - This paper describes application of the gamma ray scattering technique for NDE of concrete voids. A novel nonlinear extrapolation method is employed to correct for self-absorption and multiple scattered intensities. The attenuation data obtained from transmission method is employed for reconstruction of scattered images and the results show a good agreement in size and position of the voids with good spatial resolution. Intercomparison of the results of scattering and transmission techniques shows a good agreement in the position of the voids. PMID- 23353095 TI - The effect of lipophilicity on the hepatobiliary properties of iminodiacetic acid derivatives in the conditions of hyperbilirubinemia. AB - The partition coefficients (log P) of theoretically possible alkyliodinated iminodiacetic acid (IDA) derivatives and commercial IDA derivatives were calculated using two computer programs: ChemSketch Log P and ChemOffice Ultra. Newly synthesized ligands (DIETHYLIODIDA and DIISOPROPYLIODIDA) with the highest calculated log P were labeled with technetium-99m. The biodistribution and the influence of bilirubin on their biokinetics were investigated in rats and compared to corresponding results for commercial (99m)Tc-BROMIDA. Log P of (99m)Tc-complexes of synthesized ligands were determined experimentally as well as the protein binding. In comparison to (99m)Tc-BROMIDA, (99m)Tc-DIETHYLIODIDA has: (a) better biliary excretion (2.76+/-0.15%ID/g versus 1.83+/-0.10%ID/g); (b) faster hepatic clearance (2.90+/-0.21%ID/g versus 7.47+/-0.70%ID/g) and decreased biliary excretion (for 14% versus 22%) in conditions of hyperbilirubinemia after 15min. It is proved that (99m)Tc-DIISOPROPYLIODIDA has a prolonged hepatic transit time and decreased biliary excretion. PMID- 23353097 TI - Transport of organic cationic drugs: effect of ion-pair formation with bile salts on the biliary excretion and pharmacokinetics. AB - More than 40% of clinically used drugs are organic cations (OCs), which are positively charged at a physiologic pH, and recent reports have established that these drugs are substrates of membrane transporters. The transport of OCs via membrane transporters may play important roles in gastrointestinal absorption, distribution to target sites, and biliary and/or renal elimination of various OC drugs. Almost 40 years ago, a molecular weight (Mw) threshold of 200 was reported to exist in rats for monoquaternary ammonium (mono QA) compounds to be substantially (e.g., >10% of iv dose) excreted to bile. It is well known that some OCs interact with appropriate endogenous organic anions in the body (e.g., bile salts) to form lipophilic ion-pair complexes. The ion-pair formation may influence the affinity or binding of OCs to membrane transporters that are relevant to biliary excretion. In that sense, the association of the ion-pair formation with the existence of the Mw threshold appears to be worthy of examination. It assumes the ion-pair formation of high Mw mono QA compounds (i.e., >200) in the presence of bile salts in the liver, followed by accelerated transport of the ion-pair complexes via relevant bile canalicular transporter(s). In this article, therefore, the transport of OC drugs will be reviewed with a special focus on the ion-pair formation hypothesis. Such information will deepen the understanding of the pharmacokinetics of OC drugs as well as the physiological roles of endogenous bile salts in the detoxification or phase II metabolism of high Mw QA drugs. PMID- 23353096 TI - Fabrication and characterization of multiscale electrospun scaffolds for cartilage regeneration. AB - Recently, scaffolds for tissue regeneration purposes have been observed to utilize nanoscale features in an effort to reap the cellular benefits of scaffold features resembling extracellular matrix (ECM) components. However, one complication surrounding electrospun nanofibers is limited cellular infiltration. One method to ameliorate this negative effect is by incorporating nanofibers into microfibrous scaffolds. This study shows that it is feasible to fabricate electrospun scaffolds containing two differently scaled fibers interspersed evenly throughout the entire construct as well as scaffolds containing fibers composed of two discrete materials, specifically fibrin and poly(epsilon caprolactone). In order to accomplish this, multiscale fibrous scaffolds of different compositions were generated using a dual extrusion electrospinning setup with a rotating mandrel. These scaffolds were then characterized for fiber diameter, porosity and pore size and seeded with human mesenchymal stem cells to assess the influence of scaffold architecture and composition on cellular responses as determined by cellularity, histology and glycosaminoglycan (GAG) content. Analysis revealed that nanofibers within a microfiber mesh function to maintain scaffold cellularity under serum-free conditions as well as aid the deposition of GAGs. This supports the hypothesis that scaffolds with constituents more closely resembling native ECM components may be beneficial for cartilage regeneration. PMID- 23353099 TI - Interaction between electrical modulation of the brain and pharmacotherapy to control pharmacoresistant epilepsy. AB - In spite of the high success rate of many surgical procedures for pharmacoresistant epilepsy, a substantial number of patients do not become seizure-free. Different strategies for electrical modulation of the brain such as Deep Brain Stimulation, Vagal Nerve Stimulation and Transcraneal Magnetic Stimulation have gained considerable interest in the last decade as alternative therapies for patients with medically refractory epilepsy. Research into the mechanism of action of the strategies for electrical modulation of the brain suggests a crucial role of different molecules and channels such as glutamate, gamma-aminobutyric acid, adenosine, brain-derived neurotrophic factor, calcium channels, sodium channels as well as extracellular potassium. Electrical modulation of the brain may reduce the overexpression of P-glycoprotein, a drug efflux transporter that reduces the absorption of antiepileptic drugs. Electrical modulation of the brain induces long-term effects associated with beneficial consequences on clinical symptoms observed during the postictal state. In addition, electrical modulation of the brain might also promote the neurogenesis in subjects with pharmacoresistant epilepsy in whom this process is decreased. Targeting the regulatory pathways in charge of the effects of electrical modulation of the brain is discussed as a means to improve its efficacy. Electrical modulation of the brain combined with pharmacotherapy may represent an innovative approach to avoid epileptogenesis, reduce seizure activity, induce beneficial effects during the postictal state, diminish the amount of antiepileptic drugs, and improve alertness, memory and mood in pharmacoresistant epilepsy. PMID- 23353100 TI - Wall-eyed bilateral inter nuclear ophthalmoplegia with vertical gaze palsy. PMID- 23353101 TI - Is it time to denominate hypopituitarism after snake bite? PMID- 23353098 TI - Manipulating the epigenome for the treatment of urological malignancies. AB - Urological malignancies (cancers of the prostate, bladder, kidney and testes) account for 15% of all human cancers and more than 500,000 deaths worldwide each year. This group of malignancies is spread across multiple generations, affecting the young (testicular) through middle and old-age (kidney, prostate and bladder). Like most human cancers, urological cancers are characterized by widespread epigenetic insult, causing changes in DNA hypermethylation and histone modifications leading to silencing of tumor suppressor genes and genomic instability. The inherent stability yet dynamic plasticity of the epigenome lends itself well to therapeutic manipulation. Epigenetic changes are amongst the earliest lesions to occur during carcinogenesis and are essentially reversible (unlike mutations). For this reason, much attention has been placed over the past two decades on deriving pharmacological compounds that can specifically target and reverse such epi-mutations, either halting cancer on its developmental trajectory or reverting fully formed cancers to a more clinically manageable state. This review discusses DNA methyltransferase and histone deacetylase inhibitors that have been extensively studied in preclinical models and clinical trials for advanced and metastatic urological cancers. PMID- 23353102 TI - Spectroscopic insights into the decreased efficiency of chlorosomes containing bacteriochlorophyll f. AB - Chlorosomes are light-harvesting antenna complexes that occur in green photosynthetic bacteria which have only been shown naturally to contain bacteriochlorophyll (BChl) c, d, or e as the principal light-harvesting pigments. BChl f has long been thought to be an obvious fourth member of the so-called Chlorobium chlorophylls, because it possesses a C-7 formyl group like BChl e and lacks a methyl group at C-20 like BChl d. In organisms that synthesize BChl c or e, the bchU gene product encodes the enzyme that methylates the C-20 position of these molecules. A bchU null mutant of the green sulfur bacterium Chlorobaculum limnaeum strain 1677(T), which normally synthesizes BChl e, has recently been generated via insertional inactivation, and it produces chlorosomes containing BChl f [Vogl et al., 2012]. In this study, chlorosomes containing BChl f and monomeric BChl f in pyridine were characterized using a variety of spectroscopic techniques, including fluorescence emission and excitation spectroscopy, fluorescence lifetime and quantum yield determinations, and circular dichroism. These spectroscopic measurements, as well as Gaussian simulation of the data, show that chlorosomes containing BChl f are less efficient in energy transfer than those with BChl e. This can primarily be attributed to the decreased spectral overlap between the oligomeric BChl f (energy donor) fluorescence emission and the BChl a (energy acceptor) absorption in the chlorosome baseplate. This study allows us to hypothesize that, if they exist in nature, BChl f containing organisms most likely live in rare high-light, anoxic conditions devoid of Chl a, d, or BChl e filtering. ABSTRACT REFERENCE: K. Vogl, M. Tank, G.S. Orf, R.E. Blankenship, D.A. Bryant, Bacteriochlorophyll f: properties of chlorosomes containing the "forbidden chlorophyll," Front. Microbiol. 3 (2012) 298. PMID- 23353103 TI - COMT and MTHFR polymorphisms interaction on cognition in schizophrenia: an exploratory study. AB - The investigation of the catechol-O-methyltransferase (COMT-[rs4680]) and methylenetetrahydrofolate reductase (MTHFR-[rs1801133]) polymorphisms' interaction might shed light into the pathogenetic mechanisms of the cognitive dysfunction in schizophrenia. In an exploratory study, we hypothesized that the MTHFR 677T allele which has been related to a hypoactive MTHFR enzyme would augment the unfavorable effects of COMT Val158 homozygosity which has been associated with COMT enzyme hyperfunction. 90 schizophrenia patients and 55 healthy volunteers were assessed on psychomotor speed, pattern and spatial recognition memory (SRM), spatial working memory (SWM), attentional flexibility and planning (Stockings of Cambridge-SOC). IQ scores in a random subgroup of patients were also measured. A significant COMT*MTHFR interaction on SWM (p=0.048) and planning (p=0.026) was revealed in both groups. Among COMT-Val/Val participants, MTHFR-C/C made more SWM errors (p=0.033) and solved fewer SOC problems (p=0.025) than MTHFR-T carriers. In patients, there was a significant COMT*MTHFR interaction on full scale IQ (p=0.035): among COMT-Met carriers, MTHFR T carriers performed significantly worse than MTHFR-C/C (p=0.021), which was driven by a COMT*MTHFR interaction involving performance IQ (p=0.047). In conclusion, COMT and MTHFR polymorphisms interacted on cognition, suggesting that the MTHFR enzyme activity might moderate the effects of the COMT enzyme. In contrast to our initial hypothesis, the MTHFR T-allele attenuated the cognitive effects of COMT Val homozygosity. In this preliminary study, we propose that dopaminergic and intracellular methylation mechanisms could interact on cognitive deficits in schizophrenia. PMID- 23353104 TI - Analysis of spontaneous regeneration of olfactory structures with emphasis on myelination and re-innervation of cortical areas. AB - Regeneration of the lateral olfactory tract (LOT) occurs spontaneously after transection in developing rats. In neonatally LOT-transected rats, we observed a newly formed myelinated tract near the rhinal sulcus. The aim of this study was to analyze the precise re-innervated cortical areas and to demonstrate ectopic LOT myelination in neonatally LOT-transected rats. Neonatal rats were subjected to unilateral LOT transection and simultaneous injection of a retrograde fluorescent tracer into the posterior olfactory cortex to evaluate the degree of transection. After 8 weeks, bilateral olfactory bulbs of the rats were subjected to multiple injections of an anterograde neuronal tracer to determine the extent of the regenerated fibers. In the completely LOT-transected rats, the regenerated fibers were distributed in the anterior olfactory cortices; the anterior olfactory nucleus, the olfactory tubercle, and the rostral part of the piriform cortex. Ectopic myelination of LOT was evident immediately below the rhinal sulcus in the completely and incompletely LOT-transected rats. We concluded that the regenerated bulbar fibers were confined to the regions of the anterior olfactory cortices and that ectopic myelination of the regenerated LOT occurred only at a specific site near the rhinal sulcus. PMID- 23353105 TI - Profiling neurotransmitter receptor expression in the Ambystoma mexicanum brain. AB - Ability to regenerate limbs and central nervous system (CNS) is unique to few vertebrates, most notably the axolotl (Ambystoma sp.). However, despite the fact the neurotransmitter receptors are involved in axonal regeneration, little is known regarding its expression profile. In this project, RT-PCR and qPCR were performed to gain insight into the neurotransmitter receptors present in Ambystoma. Its functional ability was studied by expressing axolotl receptors in Xenopus laevis oocytes by either injection of mRNA or by direct microtransplantation of brain membranes. Oocytes injected with axolotl mRNA expressed ionotropic receptors activated by GABA, aspartate+glycine and kainate, as well as metabotropic receptors activated by acetylcholine and glutamate. Interestingly, we did not see responses following the application of serotonin. Membranes from the axolotl brain were efficiently microtransplanted into Xenopus oocytes and two types of native GABA receptors that differed in the temporal course of their responses and affinities to GABA were observed. Results of this study are necessary for further characterization of axolotl neurotransmitter receptors and may be useful for guiding experiments aimed at understanding activity-dependant limb and CNS regeneration. PMID- 23353106 TI - Visual electrodiagnosis in glaucoma screening: a clinical study. AB - BACKGROUND: The aim of the present study was to investigate the value of pattern visual-evoked potentials (pVEP) and pattern electroretinograms (pERG) in early glaucoma diagnosis. MATERIALS AND METHODS: Thirty-eight eyes of 38 patients were included. Patients were classified into normal control (NC) and glaucoma patient (GP) groups. Patients underwent a detailed clinical ophthalmic examination and an electrodiagnostic examination using steady-state pVEP and pERG. Differences between groups in the amplitudes of the second harmonic of the pVEP and pERG responses to 480' (A480) and 48' (A48) check sizes and the ratio of the above amplitudes (A48/A480) were examined. RESULTS: Differences in the 48' and 480' pVEP between groups were not statistically significant. The pVEP A48/A480 ratio was significantly higher in NC than in GP. Differences in pERG between groups were statistically not significant for both 48' and 480' check sizes. In contrast, respective differences in pERG A48/A480 ratio were statistically significant. CONCLUSIONS: Steady-state pVEP and pERG A48/A480 ratio may be of value in glaucoma diagnosis. PMID- 23353108 TI - The importance of fall history in fracture risk assessment. PMID- 23353107 TI - Plasma membrane Ca(2+) ATPase Atp2b1a regulates bone mineralization in zebrafish. AB - The zebrafish transgenic lines provide a possibility to observe the development of tissues and organs in real time. Using the reporter line for the zebrafish plasma membrane Ca(2+) ATPase (SqET4), we detected its expression in the epithelium of pharyngeal teeth and analyzed its role in their calcification and that of cranial bones. atp2b1a's expression in the pharyngeal epithelium is faithfully recapitulated in the SqET4 transgenics by GFP expression. We showed by morpholino knockdown of Atp2b1a translations as well as chemical inhibition of Atp2b1a pump activity using carboxyeosin, that its activity is required to facilitate calcification of the developing pharyngeal teeth by the dental epithelium. Atp2b1a could be required during calcification of endochondral bones, where it acts at two levels: 1) by exporting Ca(2+) from ameloblasts, it provides raw material for calcifying the pharyngeal teeth by adjacent odontoblasts; and 2) by regulating terminal differentiation of pharyngeal epithelial cells, including ameloblasts required for tissue hyper-mineralization. atp2b1a's expression in the pharyngeal epithelium is regulated by the homeodomain transcription factor dlx2b. PMID- 23353109 TI - One thousand minimally invasive mitral valve operations: early outcomes, late outcomes, and echocardiographic follow-up. AB - OBJECTIVE: The present study assessed the clinical and echocardiographic outcomes for 1000 patients undergoing minimally invasive mitral valve surgery. METHODS: The Brigham Cardiac Valve database was reviewed. From August 1996 to November 2011, 1000 patients had undergone minimally invasive mitral valve surgery (median follow-up, 7 years). Data on the surgical approach, complications, reoperations, and late survival were tabulated. Late echocardiographic data on the recurrence of mitral regurgitation after mitral repair in myxomatous disease were also collected. Survival, freedom from reoperation and recurrent mitral regurgitation (grade >= 3+) were evaluated with life tables and Kaplan-Meier analyses. RESULTS: The mean patient age was 57 years. Of the 1000 patients, 41% were women. Myxomatous degenerative disease was the predominant pathologic entity (86%). A lower hemisternotomy was the predominant surgical approach (75%). Mitral repair was performed in 923 patients and replacement in 77. Eight operative deaths (0.8%) occurred. A total of 44 patients with failed mitral repairs underwent reoperation, with 1 mitral valve replaced again on the same operative day for atrioventricular groove disruption. Nine failed repairs were repaired again (9/44 [20%]). A total of 106 late deaths occurred. The overall survival at 15 years was 79% +/- 3%. Freedom from reoperation at 15 years was 90% +/- 3% for repairs and 100% for replacements. Late echocardiograms were acquired for 615 of 815 eligible mitral repair patients with myxomatous disease (75%). Freedom from recurrent mitral regurgitation (grade >= 3+) at 1, 5, and 10 years was 99% +/- 1%, 87% +/- 2%, and 69% +/- 4%, respectively. CONCLUSIONS: Minimally invasive mitral valve surgery is effective, with excellent late results. The durability of minimally invasive mitral valve repair compared favorably with conventional full sternotomy methods at late follow-up. PMID- 23353110 TI - Moderate altitude is not associated with adverse postoperative outcomes for patients undergoing bidirectional cavopulmonary anastomosis and Fontan operation: a comparative study among Denver, Edmonton, and Toronto. AB - OBJECTIVE: Outcomes of patients with single ventricle physiology undergoing cavopulmonary palliations depend on pulmonary vascular resistance (PVR) and have been suggested to be adversely affected by living at elevated altitude. We compared the pulmonary hemodynamic data in correlation with postoperative outcomes at the 3 centers of Denver, Edmonton, and Toronto at altitudes of 1604, 668, and 103 meters, respectively. METHODS: Hemodynamic data at pre-bidirectional cavopulmonary anastomosis (BCPA) and pre-Fontan catheterization between 1995 and 2007 were collected. Death from cardiac failure or heart transplantation in the same period was used to define palliation failure. RESULTS: There was no significant correlation between altitude (ranged from 1 to 2572 meters) and PVR, pulmonary artery pressure (PAP) or transpulmonary gradient (TPG) at pre-BCPA and pre-Fontan catheterization. BCPA failure occurred in 11 (9.2%) patients in Denver, 3 (2.9%) in Edmonton, and 34 (11.9%) in Toronto. Fontan failure occurred in 3 (6.1%) patients in Denver, 5 (7.2%) in Edmonton, and 11 (7.0%) in Toronto. There was no significant difference in BCPA and Fontan failure among the 3 centers. BCPA failure positively correlated with PVR and the presence of a right ventricle as the systemic ventricle. Fontan failure positively correlated with PAP and TPG. CONCLUSIONS: Moderate altitude is not associated with an increased PVR or adverse outcomes in patients with a functional single ventricle undergoing BCPA and the Fontan operation. The risk factors for palliation failure are higher PVR, PAP, and TPG and a systemic right ventricle, but not altitude. Our study reemphasizes the importance of cardiac catheterization assessments of pulmonary hemodynamics before BCPA and Fontan operations. PMID- 23353111 TI - Evaluation of mitochondrial function and metabolic reprogramming during tumor progression in a cell model of skin carcinogenesis. AB - Metabolic reprogramming from mitochondrial aerobic respiration to aerobic glycolysis is a hallmark of cancer. However, whether it is caused by a dysfunction in the oxidative phosphorylation pathway is still under debate. In this work, we have analyzed the bioenergetic cellular (BEC) index and the relative cell ability to grow in the presence of either galactose or glucose as sources of sugar (Gal/Glu index) of a system formed by four epidermal cell lines with increasing tumorigenic potentials, ranging from nontumorigenic to highly malignant. We find that the BEC index gradually decreases whereas the Gal/Glu index increases with tumorigenicity, indicating that a progressive metabolic adaptation to aerobic glycolysis occurs in tumor cells associated with malignancy. Interestingly, this metabolic adaptation does not appear to be caused by damaged respiration, since the expression and activity of components of the respiratory chain complexes were unchanged in the cell lines. Moreover, the corresponding mitochondrial ATP synthetic abilities of the cell lines were found similar. The production of reactive oxygen species was also measured. A shift in ROS generation was found when compared nontumorigenic with tumorigenic cell lines, the latter exhibiting about threefold higher ROS levels than nontumorigenic cells. This result indicates that oxidative stress is an early event during tumor progression. PMID- 23353113 TI - Self-perceived attractiveness, romantic desirability and self-esteem: a mating sociometer perspective. AB - Sociometer theory proposes that self-esteem is an adaptation which evolved to monitor and regulate interpersonal relationships. It is therefore sensitive to self-assessments in domains relevant to relational desirability. Positive relationships between self-perceived physical attractiveness and self-esteem found in previous studies may reflect the functioning of a mating sociometer, designed to monitor individuals' desirability as romantic or sexual partners. We thus predicted that these relationships should be mediated by self-perceptions of romantic desirability, or more specifically, individuals' confidence in their abilities to successfully establish and maintain romantic relationships. Two hundred and eighty seven young adults (98 male) completed an online measure of self-perceived attractiveness, together with measures of self-confidence in appearance and romantic relationships, body-esteem and global self-esteem. Linear regression analyses indicated that self-perceived attractiveness, self-confidence in appearance and body-esteem all significantly predicted self-esteem, and that in each case, the relationship was mediated by romantic self-confidence. Self perceived attractiveness predicted self-esteem significantly more strongly in females than in males. We discuss these results in relation to sociometer and parental investment theories, and explore limitations and future directions. PMID- 23353112 TI - Hypoxia-induced collagen crosslinking as a mechanism for enhancing mechanical properties of engineered articular cartilage. AB - OBJECTIVE: The focus of tissue engineering of neocartilage has traditionally been on enhancing extracellular matrix and thus biomechanical properties. Emphasis has been placed on the enhancement of collagen type and quantity, and, concomitantly, tensile properties. The objective of this study was to improve crosslinking of the collagen network by testing the hypothesis that hypoxia could promote pyridinoline (PYR) crosslinks and, thus, improve neocartilage's tensile properties. METHODS: Chondrocyte expression of lysyl oxidase (LOX), an enzyme responsible for the formation of collagen PYR crosslinks, was first assessed pre- and post- hypoxia application. Then, the mechanical properties of self-assembled neocartilage constructs were measured, after 4 weeks of culture, for groups exposed to 4% O2 at different initiation times and durations, i.e., during the 1st and 3rd weeks, 3rd and 4th weeks, 4th week only, continuously after cell seeding, or never. RESULTS: Results showed that LOX gene expression was upregulated ~20-fold in chondrocytes in response to hypoxia. Hypoxia applied during the 3rd and 4th weeks significantly increased PYR crosslinks without affecting collagen content. Excitingly, neocartilage tensile properties were increased ~2-fold. It should be noted that these properties exhibited a distinct temporal dependence to hypoxia exposure, since upregulation of these properties was due to hypoxia applied only during the 3rd and 4th weeks. CONCLUSION: These data elucidate the role of hypoxia-mediated upregulation of LOX and subsequent increases in PYR crosslinks in engineered cartilage. These results hold promise toward applying hypoxia at precise time points to promote tensile integrity and direct construct maturation. PMID- 23353115 TI - Phasic dopamine as a prediction error of intrinsic and extrinsic reinforcements driving both action acquisition and reward maximization: a simulated robotic study. AB - An important issue of recent neuroscientific research is to understand the functional role of the phasic release of dopamine in the striatum, and in particular its relation to reinforcement learning. The literature is split between two alternative hypotheses: one considers phasic dopamine as a reward prediction error similar to the computational TD-error, whose function is to guide an animal to maximize future rewards; the other holds that phasic dopamine is a sensory prediction error signal that lets the animal discover and acquire novel actions. In this paper we propose an original hypothesis that integrates these two contrasting positions: according to our view phasic dopamine represents a TD-like reinforcement prediction error learning signal determined by both unexpected changes in the environment (temporary, intrinsic reinforcements) and biological rewards (permanent, extrinsic reinforcements). Accordingly, dopamine plays the functional role of driving both the discovery and acquisition of novel actions and the maximization of future rewards. To validate our hypothesis we perform a series of experiments with a simulated robotic system that has to learn different skills in order to get rewards. We compare different versions of the system in which we vary the composition of the learning signal. The results show that only the system reinforced by both extrinsic and intrinsic reinforcements is able to reach high performance in sufficiently complex conditions. PMID- 23353116 TI - Bioelectrocatalytic O(2) reduction with a laccase-bearing poly(3-methylthiophene) film based on direct electron transfer from the polymer to laccase. AB - This communication reports on O2 reduction with a biocathode composed of poly(3 methylthiophene) (P3MT) and laccase based on direct electron transfer (DET). The biocathode was fabricated simply by adsorption of laccase on a P3MT film which was formed on a gold electrode by electrochemical polymerization. Properties of the biocathode were examined by measuring steady-state currents at an arbitrary potential in buffer solutions saturated with O2 or N2 at room temperature. Efficient O2 reduction was achieved with the biocathode, which was attributed to DET from the P3MT film to laccase. The biocathode gave the O2 reduction current density of -150MUA/cm(2) at +0.40V (vs. Ag/AgCl). The onset potential of O2 reduction was +0.64+/-0.01V (vs. Ag/AgCl) at pH4.5. The O2 reduction current became maximum in the pH range 4.0-5.0. This pH dependency of the O2 reduction current is corresponding to that of the activity of native laccase. In addition, the O2 reduction current increased markedly with increasing amount of the charge passed through in the formation of the P3MT film. PMID- 23353117 TI - Association of IL-12p70 and IL-6:IL-10 ratio with autism-related behaviors in 22q11.2 deletion syndrome: a preliminary report. AB - 22q11.2 deletion syndrome (22q11DS) is a genetic disorder that conveys a significant risk for the development of social behavior disorders, including autism and schizophrenia. Also known as DiGeorge syndrome, 22q11DS is the second most common genetic disorder and is characterized by an elevated risk for immune dysfunction, up to 77% of individuals have an identifiable immune deficiency. We hypothesize that this immune dysfunction could contribute to the elevated risk of impaired social behavior seen in 22q11DS. The current study begins to elucidate these immune deficits and link them with the behavioral alterations associated with the disorder. Serum concentrations of a series of cytokines were examined, using a multiplex immunoassay, in sixteen individuals with 22q11DS and screened for autism-related behavior using the Autism Diagnostic Interview-Revised (ADI R). This preliminary study examined correlations between specific immune proteins and each of the ADI-R algorithm scores (social, communication, and repetitive behavior). The inflammatory cytokine IL-1beta, as well as the ratio between the inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10, were correlated with social scores (r=0.851, p=0.004; r=0.580, p=0.018). In addition, the inflammatory cytokines interferon gamma and IL-12p70 were correlated with repetitive behaviors (r=0.795, p=0.033; r=0.774, p=0.002). Interestingly, IL-12 has been reported to be increased in autistic children. These data show a positive association between severity of autism-related behaviors and level of serum concentrations of inflammatory cytokines in individuals with 22q11DS, providing a basis for further inquiry. PMID- 23353118 TI - Allogeneic peripheral blood stem cell transplantation is a promising and safe choice for the treatment of refractory/relapsed acute myelogenous leukemia, even with a higher leukemia burden. AB - The prognosis of patients with refractory/relapsed acute myelogenous leukemia (rAML) is poor. Recent studies have shown that more transplant centers are choosing allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for recipients, even with a higher leukemia burden. The purpose of the present study is to evaluate the outcome of rAML patients undergoing allo-PBSCT and to determine whether the disease status can predict the post-transplantation survival. The outcome of 58 patients (median age, 34 years; range, 14 to 52) with rAML who underwent allo-PBSCT in our institution from January 2000 until September 2011 was retrospectively studied. Thirty-three patients had complete remission (CR) before PBSCT, whereas 25 patients had no remission. Donors were matched related (31 patients) and unrelated (27 patients). Reduced-intensity conditioning was used for 18 patients with rAML, and myeloablative conditioning was used for others. Sixty-six consecutive non-rAML patients (median age, 33 years; range, 15 to 51) who received an allo-PBSCT at the same period were used as a control. Full donor-type engraftment was achieved in all patients. After a median follow-up of 61 months, the 5-year overall survival of rAML patients was 54.21% +/- 7.06%, which was lower than non-rAML patients (71.82% +/- 6.4%, P = .0386). However, the 5-year event-free survival for rAML and non-rAML patients had no statistical significance (53.54% +/- 6.87% versus 62.07% +/- 6.78%, P = .2626). The 5-year overall survival between rAML patients who had CR and no remission before PBSCT was 56.06% +/- 9.2% and 51.85% +/- 10.83%, respectively (P = .6408). These data demonstrate that allo-PBSCT is a promising and safe choice for the treatment of rAML, and the results were partially due to the rapid tapering of immunosuppressants in the early stage after PBSCT and prophylactic donor lymphocyte infusion. Meanwhile, the patients who did not achieve CR before PBSCT could also benefit from allo-PBSCT. PMID- 23353120 TI - Two new derivatives of 2, 5-dihydroxyphenylacetic acid from the kernel of Entada phaseoloides. AB - Two new aromatic compounds, butyl 2,5-dihydroxyphenylacetate (1) and butyl 2-O beta-D-glucopyranosyloxy-5-dihydroxyphenylacetate (2), together with three known ones, methyl 2,5-dihydroxyphenylacetate (3), ethyl 2,5-dihydroxyphenylacetate (4) and 2-O-beta-D-glucopyranosyloxy-5-hydroxyphenylacetic acid (5), were isolated from the EtOH extract of the kernel of Entada phaseoloides. The structures of the new compounds were elucidated by MS and NMR experiments. Compounds 1, 3 and 4 displayed potent inhibitory activities against HIV-1 replication, with EC(50) values of 9.80 MUM, 11.70 MUM and 9.93 MUM, respectively. PMID- 23353119 TI - Partially mismatched transplantation and human leukocyte antigen donor-specific antibodies. AB - The presence of donor human leukocyte antigen (HLA)-specific antibodies (DSA) increases engraftment failure risk in partially HLA-mismatched, or HLA haploidentical, allogeneic marrow (alloBMT) transplantation. As pre-existing sensitization to HLA antigens is not well characterized among candidates for HLA haploidentical alloBMT, we retrospectively evaluated both the incidence and relative strength of DSA in this patient population. Based on correlations of solid-phase antibody assays on the Luminex (Luminex, Austin, TX) platform with actual crossmatch tests, DSA were characterized as weak for results that were consistent with negative flow cytometric crossmatch results or as moderate-to strong for results consistent with positive flow cytometric or cytotoxicity crossmatches. We evaluated 296 alloBMT candidates; 111 (37.5%) were female. DSA were detected in 43 (14.5%) candidates, mostly among female candidates (42.9% female versus 12.5% male). Moderate-to-strong DSA strength was more frequently encountered when directed against haploidentical donors as compared with mismatched unrelated donors. DSA were most commonly detected in female patients directed against their children. Because the presence of DSA has been considered prohibitive for HLA-mismatched alloBMT, we additionally report a desensitization methodology used to reduce DSA to negative or weak levels, ie, levels well below those detectable in a flow cytometric crossmatch. Nine patients without other available donors underwent desensitization. Eight who reduced their DSA to negative or weak levels proceeded to alloBMT and achieved full donor engraftment. These data support routine DSA evaluation in all patients considered for mismatched alloBMT; however, for patients with no other viable options, desensitization to weak or negative DSA levels may afford the opportunity for successful transplantation. PMID- 23353121 TI - Synthesis of thiophene and NO-curcuminoids for antiinflammatory and anti-cancer activities. AB - In search of better NSAIDs four novel nitric oxide donating derivatives of curcumin (compounds 9a-d), and four thiophene curcuminoids (compounds 10a-c, 11) have been synthesised. The cytotoxic effects of these compounds along with the lead compound curcumin (7) and their effect on the production of the reactive oxygen species nitric oxide and pro-inflammatory cytokines IL-1beta, TNF-alpha and chemokine CXCL-8 were evaluated using human monocytic THP-1 and colon adenocarcinoma CACO-2 cell lines. All of the nitric oxide donating curcuminoids 9a-d and the thiophene curcuminoids 10a-c and 11 were non-cytotoxic to THP-1 cells over a concentration range of 10-100 MUM and compared with curcumin compounds 10b and 10c, were more toxic. In CACO-2 cells, 10b and 11 appeared to be non-toxic at 10 to 50 MUM, whereas 10a and 10c were non-cytotoxic at 10 MUM only. These results clearly indicate that the introduction of a nitroxybutyl moiety to curcumin and replacement of phenyl rings with thiophene units reduces the cytotoxic effect of the parent curcumin, whereas a methyl substituted thiophene increases the cytotoxic effects. In THP-1 cells, drugs 10a and 11 significantly decreased IL-1-beta production at their non-cytotoxic concentrations, whereas, they did not decrease TNF-alpha production in CACO-2 cells. Compound 11 showed a significant decrease in CXCL-8 production. PMID- 23353122 TI - Synthesis and characterization of novel dendrons bearing amino-nitro-substituted azobenzene units and oligo(ethylene glycol) spacers: thermal, optical properties, Langmuir blodgett films and liquid-crystalline behaviour. AB - In this work, we report the synthesis and characterization of a novel series of first and second generation Frechet type dendrons bearing amino-nitro substituted azobenzene units and tetra(ethylene glycol) spacers. These compounds were fully characterized by FTIR, 1H and 13C-NMR spectroscopies, and their molecular weights were determined by MALDI-TOF-MS. The thermal properties of the obtained dendrons were studied by TGA and DSC and their optical properties by absorption spectroscopy in solution and cast film. Molecular calculations were performed in order to determine the optimized geometries of these molecules in different environments. Besides, Langmuir and Langmuir Blodgett films were prepared with the first generation dendrons that were shown to be amphiphilic. Finally, some of the dendrons showed a liquid crystalline behaviour, which was studied by light polarized microscopy as a function of the temperature in order to determine the transition temperatures and the structure of the mesophase. PMID- 23353123 TI - Oxygen radical absorbance capacity of different varieties of strawberry and the antioxidant stability in storage. AB - Total antioxidant capacity of different varieties of strawberry (Ningfeng, Ningyu, Zijin 4, Toyonoka, Benihope, Sweet Charlie) in different developmental stages (including green unripe stages, half red stages, and red ripe stages) was investigated by oxygen radical absorbance capacity (ORAC) assay. In addition, effects of the antioxidant properties of strawberry stored at 4 degrees C or -18 degrees C for a period of five months were studied. The results showed that antioxidant capacity of strawberry changed based on tested part, developmental stage, variety, and time of collection. Calyces had significantly higher ORAC values compared with fruits. Strawberry fruits had higher ORAC values during the green unripe stages than the half red stages and red ripe stages. Strawberries got higher ORAC values during short-time storage, and then decreased during long time storage. Samples stored at -18 degrees C exhibited higher antioxidant capacity than those stored at 4 degrees C, while vacuum treatment could further increase ORAC values. The results indicated the potential market role of strawberries as a functional food and could provide great value in preventing oxidation reaction in food processing and storage for the dietary industry. PMID- 23353124 TI - Original TDAE strategy using propargylic chloride: rapid access to 1,4-diarylbut 3-ynol derivatives. AB - We report herein the first synthesis of propargylic alcohols using an organic reducing agent. Diarylbutynol derivatives are formed in moderate to good yields under mild conditions from the reaction of 1-(3-chloroprop-1-ynyl)-4-nitrobenzene with various aromatic aldehydes using tetrakis(dimethylamino)ethylene (TDAE) as reductant. PMID- 23353125 TI - Fruit coloration and anthocyanin biosynthesis after bag removal in non-red and red apples (Malus * domestica Borkh.). AB - In the present study, evolution of apple color (L* and a/b), the accumulation of anthocyanins and the activity of the related enzymes, phenylalanine ammonia-lyase (PAL), chalcone isomerase (CHI), dihydroflavonol4-reductase (DFR) and UDP Glucose: flavonoid-3-O-galactosyl transferase (UFGT), were investigated in bagged non-red apple cultivars ('Granny Smith' and 'Golden Delicious') and red apple cultivars ('Starkrimon' and 'Pink Lady'). Young fruits were bagged 40-45 days after flowering (DAF), and fruits of 'Golden Delicious' and 'Starkrimon' were uncovered and exposed to light 120 DAF, while those of 'Granny Smith' and 'Pink Lady' were exposed for 160 DAF. Results showed that cyanidin 3-galactoside (cy3 gal) was the most abundant anthocyanin in both non-red and red cultivars. Level of anthocyanins was higher in 'Granny Smith' than in 'Golden Delicious', indicating that red color was easier to develop in green cultivar 'Granny Smith' than in yellow cultivar 'Golden Delicious' after bag removal. The cy3-gal accumulation of non-red cultivars tested was not significantly correlated with PAL, CHI and DFR activity, but was significantly correlated with UFGT activity. During the reddening of non-red apples, UFGT may be the more important factor in the anthocyanin biosynthesis. PMID- 23353126 TI - Synergism of antifungal activity between mitochondrial respiration inhibitors and kojic acid. AB - Co-application of certain types of compounds to conventional antimicrobial drugs can enhance the efficacy of the drugs through a process termed chemosensitization. We show that kojic acid (KA), a natural pyrone, is a potent chemosensitizing agent of complex III inhibitors disrupting the mitochondrial respiratory chain in fungi. Addition of KA greatly lowered the minimum inhibitory concentrations of complex III inhibitors tested against certain filamentous fungi. Efficacy of KA synergism in decreasing order was pyraclostrobin > kresoxim methyl > antimycin A. KA was also found to be a chemosensitizer of cells to hydrogen peroxide (H2O2), tested as a mimic of reactive oxygen species involved in host defense during infection, against several human fungal pathogens and Penicillium strains infecting crops. In comparison, KA-mediated chemosensitization to complex III inhibitors/H2O2 was undetectable in other types of fungi, including Aspergillus flavus, A. parasiticus, and P. griseofulvum, among others. Of note, KA was found to function as an antioxidant, but not as an antifungal chemosensitizer in yeasts. In summary, KA could serve as an antifungal chemosensitizer to complex III inhibitors or H2O2 against selected human pathogens or Penicillium species. KA-mediated chemosensitization to H2O2 seemed specific for filamentous fungi. Thus, results indicate strain- and/or drug specificity exist during KA chemosensitization. PMID- 23353127 TI - Extraction of antioxidant components from Bidens pilosa flowers and their uptake by human intestinal Caco-2 cells. AB - Bidens pilosa L. var. radiata (BPR, Asteraceae) is a commonly used folk medicine for treating various disorders such as diabetes, inflammation and hypertension. Recent studies to determine its chemical composition have revealed three di-O caffeoylquinic acids (DiCQAs) and three polyacetylene glucosides (PGAs) to be among the major bioactive markers. To obtain the major compounds of these two chemical classes, the ethyl acetate fraction (EM) obtained using liquid-liquid partition from the methanol extract resulted in a fraction with the highest total phenolic and total flavonoid contents and antioxidant activities in radical scavenging and ferric reducing power assays. To assess the bioavailability of EM, we examined the in vitro uptake using the Caco-2 human colonic cell line. The apparent permeability coefficient (Papp) for each of the compounds within PGAs measured in both apical (AP) to basolateral (BL) and BL to AP was found to preferentially appear BL to AP direction, indicated that a basolateral to apical efflux system was detected in the study. DiCQAs had a lower efflux ratio than those from PGAs (2.32-3.67 vs. 6.03-78.36). Thus, it strongly implies that most of the DiCQAs are better absorbed than the PGAs. PMID- 23353128 TI - An efficient microwave-assisted Suzuki reaction using a new pyridine pyrazole/Pd(II) species as catalyst in aqueous media. AB - A new pyridine-pyrazole N-N ligand has been conveniently synthesized and characterized by 1H-, 13C-NMR, IR spectroscopies, HRMS and X-ray single-crystal crystallography analyses. The ligand adds to palladium(II) under basic conditions to give high yields of an air-stable and water-soluble complex that was fully characterized by NMR and HRMS. The complex was investigated as a catalyst for the Suzuki reaction in aqueous media under microwave irradiation. The compound proved to be an effective catalyst. PMID- 23353129 TI - Neoadjuvant chemotherapy with weekly paclitaxel and carboplatin followed by chemoradiation in locally advanced cervical carcinoma: a pilot study. AB - OBJECTIVE: To evaluate role of dose dense neo-adjuvant chemotherapy (NACT) prior to standard concurrent chemo-radiation (CCRT) in locally advanced cervical cancer. METHODS: Between June 2010 and December 2011, 28 patients (median age - 51 years, range, 35 to 67 years) with locally advanced cervical cancer received NACT using paclitaxel (60 mg/m(2)) and carboplatin (AUC-2) weekly for 6 doses. After a mean interval of 15 days (range 7-23 days), the patients then received definitive radiation and concomitant weekly infusion of cisplatin (40 mg/m(2) for 6 doses). Response to concurrent chemo-radiation and toxicity were end points. RESULTS: Following NACT, 67.8% of patients responded; complete (CR) - 2(7.1%), Partial (PR) - 17 (60.7%), stable 7 (25.0%) and 2 patients (7.1%) progressed. 24 of 28 patients received CCRT; 23/24 achieved CR. 22 of 23 complete responders continue to be in CR at a median follow-up of 12 months (range, 7 to 24 months). Grade III/IV neutropenia was the main hematological toxicity seen in 28.5% and 29% of patients, respectively during NACT and CCRT. CONCLUSIONS: Neoadjuvant chemotherapy with dose dense weekly paclitaxel and carboplatin followed by standard CCRT is a feasible approach and is associated with a high response rate in locally advanced cervical cancer. PMID- 23353130 TI - Bladder function after modified posterior exenteration for primary gynecological cancer. AB - OBJECTIVE: Bladder dysfunction caused by autonomic nerve injury is a well recognized complication of pelvic surgery. Modified posterior exenteration with or without nerve preservation was performed in patients with primary ovarian, tubal, peritoneal, and endometrial cancer. The aim of this retrospective study was to evaluate the impact of this surgical technique on bladder function. METHODS: Among the 60 consecutive patients in whom modified posterior exenteration was performed, bilateral and unilateral nerve-sparing surgeries were performed in 43 (72%) and 15 (25%) patients, respectively. In the remaining 2 patients (3%), the pelvic autonomic nerves on both sides were sacrificed. Symptoms and bladder function after bilateral or unilateral nerve-sparing surgery were analyzed using standardized questionnaires before and 3 and 6 months after surgery. RESULTS: All patients with bilateral nerve-sparing surgery had sufficient micturition from the early postoperative period. Though 40% of the patients with unilateral nerve-sparing surgery had difficulty in spontaneous voiding and needed intermittent catheterization, voiding ability of them improved and no self-catheterization was required 3 months after surgery. The assessment of patient questionnaires suggested that bladder function was acceptable in both groups at 6 months. Patients with bilateral nerve-sacrificing surgery complained of neurogenic bladder requiring self-catheterization even 6 months after surgery. CONCLUSIONS: This preliminary study showed that preservation of bladder function after modified posterior exenteration was feasible with a nerve sparing approach and that standardized outcome measures could be used to monitor this. However, careful follow-up is required. Future larger studies are needed to investigate pelvic autonomic nerve function. PMID- 23353131 TI - Rapid, sensitive and simultaneous determination of ascorbic and uric acids in human plasma by ion-exclusion HPLC-UV. AB - OBJECTIVES: Ascorbic (AA) and uric (UA) acids act as antioxidants and are capable to react with biologically relevant oxidants. We aimed to developed a simple, rapid, sensitive, and accurate ion-exclusion HPLC-UV methodology for the simultaneously determination of AA and UA in human plasma. METHODS: Analytical pre-requisites, such as the use of heparin as an anticoagulant and meta phosphoric acid as a stabilizer were added for accurate and reliable measurements. Chromatographic separation was achieved by an isocratic elution on a HEMA-BIO 1000 SB analytical column using a phosphate buffer, pH 2.4, as a mobile phase. RESULTS: Results indicated an excellent linearity with correlation coefficients (r(2))>=0.999. The LOD of AA and UA was 1.02 and 1.42nmol/mL, respectively, while LOQ ranged from 0.306 to 0.426nmol/mL. A great repeatability for both antioxidants was found, where the CV (%) values for intra-day were lower than 1.8% and under 6.5% for the inter-day assay. The recovery of AA ranged from 92% to 96% and from 99% to 100% for UA. CONCLUSION: This validated method allows the determination of both antioxidants within 10min, and is well suited to routine measurements and/or high-throughput clinical analysis. The methodology was applied to assess the antioxidant status of a group of Azorean subjects. PMID- 23353132 TI - Direct total and free testosterone measurement by liquid chromatography tandem mass spectrometry across two different platforms. AB - OBJECTIVES: To develop and validate liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the direct measurement of total and free testosterone in patient samples on two different analytical systems. DESIGN AND METHODS: An API 4000 and 5000 triple quadropoles were used and compared; the former is reported to be 3-5 times less sensitive, as was used to set the quantitation limits. Free testosterone was separated from the protein-bound fraction by equilibrium dialysis followed by derivatization. Either free or total testosterone, and a deuterated internal standard (d3-testosterone) were extracted by liquid-liquid extraction. The validation results were compared to two different clinical laboratories. RESULTS: The use of d2-testosterone was found to be unacceptable for our method. The total testosterone LC-MS/MS methods on both systems were linear over a wide concentration range of 1.5-2000ng/dL. Free testosterone was measured directly using equilibrium dialysis coupled LC-MS/MS and linear over the concentration range of 2.5-2500pg/mL. Good correlation (total testosterone, R(2)=0.96; free testosterone, R(2)=0.98) was observed between our LC-MS/MS systems and comparator laboratory. However, differences in absolute values for both free and total testosterone measurements were observed while a comparison to a second published LC-MS/MS method showed excellent correlation. Free and total testosterone measurements correlated well with clinical observations. CONCLUSIONS: To our knowledge, this is the first published validation of free and total testosterone methods across two analytical systems of different analytical sensitivities. A less sensitive system does not sacrifice analytical or clinical sensitivity to directly measure free and total testosterone in patient samples. PMID- 23353133 TI - The bradykinesia assessment task: an automated method to measure forelimb speed in rodents. AB - Bradykinesia in upper extremities is associated with a wide variety of motor disorders; however, there are few tasks that assay forelimb movement speed in rodent models. This study describes the bradykinesia assessment task, a novel method to quantitatively measure forelimb speed in rats. Rats were trained to reach out through a narrow slot in the cage and rapidly press a lever twice within a predefined time window to receive a food reward. The task provides measurement of multiple parameters of forelimb function, including inter-press interval, number of presses per trial, and success rate. The bradykinesia assessment task represents a significant advancement in evaluating bradykinesia in rat models because it directly measures forelimb speed. The task is fully automated, so a single experimenter can test multiple animals simultaneously with typically in excess of 300 trials each per day, resulting in high statistical power. Several parameters of the task can be modified to adjust difficulty, which permits application to a broad spectrum of motor dysfunction models. Here we show that two distinct models of brain damage, ischemic lesions of primary motor cortex and hemorrhagic lesions of the dorsolateral striatum, cause impairment in all facets of performance measured by the task. The bradykinesia assessment task provides insight into bradykinesia and motor dysfunction in multiple disease models and may be useful in assessing therapies that aim to improve forelimb function following brain damage. PMID- 23353134 TI - Modeling the relationship between health and health care expenditures using a latent Markov model. AB - We investigate the dynamic relationship between several dimensions of health and health care expenditures for older individuals. Health data from the Longitudinal Aging Survey Amsterdam is combined with data on hospital and long term care use. We estimate a latent variable based jointly on observed health indicators and expenditures. Annual transition probabilities between states of the latent variable are estimated using a Markov model. States associated with good current health and low annual health care expenditures are not associated with lower cumulative health care expenditures over remaining lifetime. We conclude that, although the direct health care cost saving effect is limited, the considerable gain in healthy lifeyears can make investing in the improvement of health of the older population worthwhile. PMID- 23353135 TI - Determinants of famous name processing speed: age of acquisition versus semantic connectedness. AB - The age of acquisition (AoA) and the amount of biographical information known about celebrities have been independently shown to influence the processing of famous people. In this experiment, we investigated the facilitative contribution of both factors to famous name processing. Twenty-four mature adults participated in a familiarity judgement task, in which the names of famous people were grouped orthogonally by AoA and by the number of bits of biographical information known about them (number of facts known; NoFK). Age of acquisition was found to have a significant effect on both reaction time (RT) and accuracy of response, but NoFK did not. The RT data also revealed a significant AoA*NoFK interaction. The amount of information known about a celebrity played a facilitative role in the processing of late-acquired, but not early-acquired, celebrities. Once AoA is controlled, it would appear that the semantic system ceases to have a significant overall influence on the processing of famous people. The pre-eminence of AoA over semantic connectedness is considered in the light of current theories of AoA and how their influence might interact. PMID- 23353136 TI - Is intrinsic aerobic exercise capacity a determinant of COPD susceptibility? AB - Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality, which is most commonly associated with smoking or exposure to environmental pollutants. Unfortunately, there is an inadequate understanding of the molecular and physiological determinants governing one's susceptibility for developing COPD. Here, we describe a novel hypothesis: Individuals with intrinsically low aerobic exercise capacity are more likely to develop COPD after exposure to key risk factors. The hypothesis is based on observations that aerobic exercise capacity is tightly associated with mortality across many complex diseases. The premise is supported by recent studies demonstrating that smokers who exercise regularly are less likely to develop or be hospitalized for COPD. Herein, we describe the evolutionary and molecular basis for this hypothesis and how it is a natural extension of previous theories explaining COPD susceptibility. PMID- 23353137 TI - The analysis of efficacy for AutoPulseTM system in flying helicopter. AB - AIM OF THE STUDY: The helicopter emergency medical service (HEMS) was introduced in Japan in 2001, and some cardiopulmonary arrest (CPA) patients are transported using this service. However, it is difficult to maintain continuous and effective manual cardiopulmonary resuscitation (CPR) in flying helicopters. To overcome this problem, the AutoPulseTM system, automated mechanical CPR devices, was induced. We conducted a retrospective study to clarify the efficacy of AutoPulseTM on CPA patients in flying helicopters. METHODS: In total, 92 CPA patients were enrolled in this study. Of these, 43 CPA patients received manual CPR (between April 2004 and June 2008), and 49 patients received AutoPulseTM CPR (between July 2008 and March 2011). We compared the manual CPR group with the AutoPulseTM group using logistic regression analysis and examined the efficacy of AutoPulseTM in flying helicopters. RESULTS: Rates for return of spontaneous circulation (ROSC) and survival to hospital discharge were increased in the AutoPulseTM group compared to the manual CPR group (ROSC, 30.6% [15 patients] vs. 7.0% [3 patients]; survival to hospital discharge, 6.1% [3 patients] vs. 2.3% [1 patient]). In multivariate analysis, the factors associated with ROSC were the use of AutoPulseTM (odds ratio [OR], 7.22; P=0.005) and patients aged <=65 years (OR, 0.31; P=0.042). CONCLUSION: The present study demonstrates that the use of AutoPulseTM in flying helicopters was significantly effective for the ROSC in CPA patients. The use of automated chest compression devices such as AutoPulseTM might be recommended at least for CPA patients transported by helicopters. PMID- 23353139 TI - A new method for flow rate measurement in millimeter-scale pipes. AB - Combining the Capacitively Coupled Contactless Conductivity Detection (C4D) technique and the principle of cross correlation flow measurement, a new method for flow rate measurement in millimeter-scale pipes was proposed. The research work included two parts. First, a new five-electrode C4D sensor was developed. Second, with two conductivity signals obtained by the developed sensor, the flow rate measurement was implemented by using the principle of cross correlation flow measurement. The experimental results showed that the proposed flow rate measurement method was effective, the developed five-electrode C4D sensor was successful, and the measurement accuracy was satisfactory. In five millimeter scale pipes with different inner diameters of 0.5, 0.8, 1.8, 3.0 and 3.9 mm respectively, the maximum relative difference of the flow rate measurement between the reference flow rate and the measured flow rate was less than 5%. PMID- 23353138 TI - Breathing-controlled Electrical Stimulation (BreEStim) for management of neuropathic pain and spasticity. AB - Electrical stimulation (EStim) refers to the application of electrical current to muscles or nerves in order to achieve functional and therapeutic goals. It has been extensively used in various clinical settings. Based upon recent discoveries related to the systemic effects of voluntary breathing and intrinsic physiological interactions among systems during voluntary breathing, a new EStim protocol, Breathing-controlled Electrical Stimulation (BreEStim), has been developed to augment the effects of electrical stimulation. In BreEStim, a single pulse electrical stimulus is triggered and delivered to the target area when the airflow rate of an isolated voluntary inspiration reaches the threshold. BreEStim integrates intrinsic physiological interactions that are activated during voluntary breathing and has demonstrated excellent clinical efficacy. Two representative applications of BreEStim are reported with detailed protocols: management of post-stroke finger flexor spasticity and neuropathic pain in spinal cord injury. PMID- 23353140 TI - Fast classification of meat spoilage markers using nanostructured ZnO thin films and unsupervised feature learning. AB - This paper investigates a rapid and accurate detection system for spoilage in meat. We use unsupervised feature learning techniques (stacked restricted Boltzmann machines and auto-encoders) that consider only the transient response from undoped zinc oxide, manganese-doped zinc oxide, and fluorine-doped zinc oxide in order to classify three categories: the type of thin film that is used, the type of gas, and the approximate ppm-level of the gas. These models mainly offer the advantage that features are learned from data instead of being hand designed. We compare our results to a feature-based approach using samples with various ppm level of ethanol and trimethylamine (TMA) that are good markers for meat spoilage. The result is that deep networks give a better and faster classification than the feature-based approach, and we thus conclude that the fine-tuning of our deep models are more efficient for this kind of multi-label classification task. PMID- 23353141 TI - Temperature grid sensor for the measurement of spatial temperature distributions at object surfaces. AB - This paper presents results of the development and application of a new temperature grid sensor based on the wire-mesh sensor principle. The grid sensor consists of a matrix of 256 Pt1000 platinum chip resistors and an associated electronics that measures the grid resistances with a multiplexing scheme at high speed. The individual sensor elements can be spatially distributed on an object surface and measure transient temperature distributions in real time. The advantage compared with other temperature field measurement approaches such as infrared cameras is that the object under investigation can be thermally insulated and the radiation properties of the surface do not affect the measurement accuracy. The sensor principle is therefore suited for various industrial monitoring applications. Its applicability for surface temperature monitoring has been demonstrated through heating and mixing experiments in a vessel. PMID- 23353142 TI - Critical evaluation of acetylthiocholine iodide and acetylthiocholine chloride as substrates for amperometric biosensors based on acetylcholinesterase. AB - Numerous amperometric biosensors have been developed for the fast analysis of neurotoxic insecticides based on inhibition of cholinesterase (AChE). The analytical signal is quantified by the oxidation of the thiocholine that is produced enzymatically by the hydrolysis of the acetylthiocholine pseudosubstrate. The pseudosubstrate is a cation and it is associated with chloride or iodide as corresponding anion to form a salt. The iodide salt is cheaper, but it is electrochemically active and consequently more difficult to use in electrochemical analytical devices. We investigate the possibility of using acetylthiocholine iodide as pseudosubstrate for amperometric detection. Our investigation demonstrates that operational conditions for any amperometric biosensor that use acetylthiocholine iodide must be thoroughly optimized to avoid false analytical signals or a reduced sensitivity. The working overpotential determined for different screen-printed electrodes was: carbon-nanotubes (360 mV), platinum (560 mV), gold (370 mV, based on a catalytic effect of iodide) or cobalt phthalocyanine (110 mV, but with a significant reduced sensitivity in the presence of iodide anions). PMID- 23353143 TI - Automatic stem mapping by merging several terrestrial laser scans at the feature and decision levels. AB - Detailed up-to-date ground reference data have become increasingly important in quantitative forest inventories. Field reference data are conventionally collected at the sample plot level by means of manual measurements, which are both labor-intensive and time-consuming. In addition, the number of attributes collected from the tree stem is limited. More recently, terrestrial laser scanning (TLS), using both single-scan and multi-scan techniques, has proven to be a promising solution for efficient stem mapping at the plot level. In the single-scan method, the laser scanner is placed at the center of the plot, creating only one scan, and all trees are mapped from the single-scan point cloud. Consequently, the occlusion of stems increases as the range of the scanner increases, depending on the forest's attributes. In the conventional multi-scan method, several scans are made simultaneously inside and outside of the plot to collect point clouds representing all trees within the plot, and these scans are accurately co-registered by using artificial reference targets manually placed throughout the plot. The additional difficulty of applying the multi-scan method is due to the point-cloud registration of several scans not being fully automated yet. This paper proposes a multi-single-scan (MSS) method to map the sample plot. The method does not require artificial reference targets placed on the plot or point-level registration. The MSS method is based on the fully automated processing of each scan independently and on the merging of the stem positions automatically detected from multiple scans to accurately map the sample plot. The proposed MSS method was tested on five dense forest plots. The results show that the MSS method significantly improves the stem-detection accuracy compared with the single-scan approach and achieves a mapping accuracy similar to that achieved with the multi-scan method, without the need for the point-level registration. PMID- 23353144 TI - Exploring techniques for vision based human activity recognition: methods, systems, and evaluation. AB - With the wide applications of vision based intelligent systems, image and video analysis technologies have attracted the attention of researchers in the computer vision field. In image and video analysis, human activity recognition is an important research direction. By interpreting and understanding human activity, we can recognize and predict the occurrence of crimes and help the police or other agencies react immediately. In the past, a large number of papers have been published on human activity recognition in video and image sequences. In this paper, we provide a comprehensive survey of the recent development of the techniques, including methods, systems, and quantitative evaluation towards the performance of human activity recognition. PMID- 23353145 TI - [Scan time reduction with a small field-of-view quadruple inversion-recovery high resolution contrast-enhanced MRI for carotid atherosclerosis]. AB - OBJECTIVE: To reduce the acquisition time of carotid high-resolution contrast enhanced magnetic resonance imaging (CEMRI), we designed a small field-of-view (FOV) quadruple-inversion-recovery (SF-QIR) T1WI and evaluated the image quality. METHODS: Twenty-four subjects with carotid plaque were enrolled in our study. All the subjects were imaged using the same 3.0T MRI by SF-QIR and standard rectangular FOV QIR (SrF-QIR) with identical parameters except for the phase encoding step numbers and the RF excitation methods. Three independent readers qualitatively evaluated the differences between the two sequences in regard of the carotid outer wall border delineation, fibrous cap and lipid-rich necrotic core (LR-NC) border delineation, and diagnostic confidence. The quantitative measurements included maximal stenosis, wall area, LR-NC area, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). The inter-reader variability was assessed. RESULTS: The application of SF-QIR combined with orthogonal radio frequency excitation resulted in nearly half of the scan time with the SrF-QIR. Both qualitative and quantitative assessment by the readers revealed no significant differences between the two sequences except for SNR and CNR (Pgt;0.05). Since the mean loss of SNR with SF-QIR was 37.7%, SrF-QIR demonstrated a superior performance in SNR (P<0.001). CONCLUSION: The small FOV QIR sequence is effective in high-resolution CEMRI for evaluating carotid plaques and can effectively reduce the scan time and eliminate motion artifacts. PMID- 23353146 TI - [Real-time three-dimensional echocardiographic assessment of left ventricular diastolic dyssynchrony and dysfunction in hypertrophic cardiomyopathy]. AB - OBJECTIVE: To assess left ventricular (LV) regional diastolic function in patients with hypertrophic cardiomyopathy (HCM) using single-beat real-time three dimensional echocardiography (RT-3DE). METHODS: Sixty-nine patients with HCM (LV ejection fraction>=45%) and 50 normal control subjects underwent examinations by two-dimensional echocardiography (2DE) and RT-3DE. The parameters analyzed by RT 3DE included the end diastolic sphericity index (EDSI), diastolic dyssynchrony index (DDI), dispersion end diastole [DISPED, including late (DDI-late) and early (DDI-early) diastole, dispersion end diastole (DISPED-late), and dispersion early diastole (DISPED-early)]. The patients were divided into 3 groups with impaired relaxation (n=23), pseudonormal filling (n=37), and restrictive filling (n=9). RESULTS: DDI and DISPED increased with the severity of diastolic dysfunction. In end diastole, DDI-late and DISPED-late were abnormal in cases with severe diastolic dysfunction (7.95?2.75 and 26.76?17.19, respectively, P<0.0001) but normal in cases with mild diastolic dysfunction. In early diastole, DDI-early and DISPED-early both increased in cases of mild (8.57?2.24 and 25.44?6.31, respectively, P<0.0001) and moderate (9.56?4.66 and 35.42?14.19, respectively, P<0.0001) diastolic dysfunction. CONCLUSION: In patients with HCM, dyssynchrony in early diastole is more obvious than that in late diastole and shows also a stronger correlation with diastolic dysfunction. This preclinical lesion can be detected by single-beat RT-3DE. PMID- 23353147 TI - [Prokaryotic expression, purification and antigenicity identification of mouse VEGFR2 extracellular 1-4 IgG-like domains]. AB - OBJECTIVE: To obtain 1-4 IgG-like domains of mouse vascular endothelial growth factor receptor 2 (VEGFR2) fusion protein (mVEGFR2D1-4/GST) and identify its antiginicity and biological activity. METHODS: The gene of mVEGFR2D1-4 was amplified by RT-PCR from 14-days embryos of Balb/c mice. The PCR product was cloned into pET-42a prokaryotic expression vector to construct the recombinant plasmid pET-42a-mVEGFR2D1-4, which was transformed into E. coli BL21 (DE3) strain for mVEGFR2D1-4/GST expression. The fusion protein was identified by SDS-PAGE and Western blotting, and the antigenicity of the protein purified by affinity chromatography was characterized by ELISA. The VEGF blocking effect of the purified protein in human umbilical vein endothelial cells (HUVECs) were evaluated in in vitro cell cultures. RESULTS: The mVEGFR2D1-4 gene was obtained, which had an identical sequence to that retrieved in GenBank. The prokaryotic expression vector for mVEGFR2D1-4 was successfully constructed as confirmed by enzyme digestion and DNA sequencing. Both Western blotting and ELISA demonstrated the antigenicity of the purified mVEGFR2D1-4 fusion protein, which obviously blocked the effect of VEGF in promoting HUVEC proliferation in vitro. CONCLUSION: The mVEGFR2D1-4/GST fusion protein obtained shows a strong antigenicity and biological activity to facilitate further study of active anti-tumor immunotherapy targeting VEGFR2. PMID- 23353148 TI - [Effects of Pseudomonas quinolone signal on the virulence of Pseudomonas aeruginosa]. AB - OBJECTIVE: To investigate the effect of Pseudomonas quinolone signal (PQS) on the virulence of Pseudomonas aeruginosa. METHODS: Pseudomonas aeruginosa strain PAO1 was treated with PQS alone, PQS plus farnesol, or farnesol alone. The transcriptional levels of the regulator gene ExsA and virulence protein gene ExoS of type III secretion system were examined using quantitative real-time PCR, and spectrophotometry was employed to detect pyocyanin production in the bacteria. The adhesion and invasiveness of the treated PAO1 in cultured alveolar epithelial cells A549 were assessed on plate count agar, and their effects on the survival of a mouse model of peritonitis was compared. RESULTS: The increase or decrease of PQS did not affect the growth of PAO1. Compared with the untreated bacteria, PQS-treated PAO1 showed obviously increased transcription levels of ExsA and ExoS (P<0.01) and pyocyanin production, which was significantly lowered by farnesol (P<0.01). In A549 cell cultures, farnesol-treated PAO1 exhibited significantly lowered adhesion and invasiveness, while PQS-treated PAO1 caused a significantly decreased survival time of mice with peritonitis (P<0.01). Farnesol treatment did not obviously affected ExsA transcription (P>0.05) but caused a significant reduction in the transcriptional level of Exos (P<0.05) in PAO1. PQS showed no significant effect on the adhesion and invasiveness of PAO1 (P<0.05). CONCLUSION: PQS can maintain the adhesion and invasiveness of Pseudomonas aeruginosa, and in the hosts of the bacteria, PQS concentration is positively correlated with pyocyanin production and hence negatively with the survival time of the hosts. PMID- 23353149 TI - [Interferon-gamma enhances human gammadelta T cell-mediated osteosarcoma cell killing in vitro]. AB - OBJECTIVE: To investigate the cytotoxic effect of gammadelta T cells from osteosarcoma patients against interferon-gamma (IFN-gamma)-treated osteosarcoma cells in vitro. METHODS: Human gammadelta T cells were amplified by zoledronate from peripheral blood cells of osteosarcoma patients. The expression of Fas on the osteosarcoma cells were measured by flow cytometry and quantitative real-time PCR analysis before and after IFN-gamma treatment. The cytotoxicity of gammadelta T cells against osteosarcoma cells was evaluated with LDH assay. RESULTS: IFN gamma significantly enhanced the susceptibility of the osteosarcoma cell lines HOS and U2OS to the cytotoxicity of gammaDelta; T cells from osteosarcoma patients (P<0.01). IFN-gamma obviously up-regulated the expression of Fas in HOS and U2OS cells (P<0.01). Anti-FasL mAb failed to inhibit the cytotoxicity of gammadelta T cells in untreated osteosarcoma targets (P>0.05), but significantly impaired gammadelta T cell cytotoxicity in IFN-gamma pre-treated osteosarcoma targets (P<0.01). CONCLUSION: IFN-gamma can enhance the cytotoxic effect of human gammadelta T cells from osteosarcoma patients against osteosarcoma cells in vitro. PMID- 23353150 TI - [Calcineurin/NFAT signaling pathway mediates endothelin-1-induced pulmonary artery smooth muscle cell proliferation by regulating phosphodiesterase-5]. AB - OBJECTIVE: To examine whether calcineurin/NFAT signaling pathway mediates endothelin-1 (ET-1)-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) by regulating phosphodiesterase-5 (PDE5) and the effect of the selective calcineurin inhibitor cyclosporine A and PDE5 inhibitor sildenafil on ET-1 induced PASMC proliferation. METHODS: PASMCs were treated with ET-1 to stimulate their proliferation with or without prior treatment of the cells with CsA or sildenafil. Calcineurin activity in the cells was measured using a calcineurin activity assay kit, PDE5 expression examined using immunoblotting, and cGMP level detected using a cGMP direct immunoassay kit. PASMC proliferation following the treatments was determined using [(3)H]thymidine incorporation assay. RESULTS: ET 1 caused a 2.05-fold increase in the cellular calcineurin activity, a 1.80-fold increase in PDE5 expression, and a 3.20-fold increase in the DNA synthesis rate, and reduced the cGMP level by 67%. Pretreatment of the cells with Cyclosporine blocked the effects of ET-1, and PDE5 inhibition by sildenafil pretreatment also abolished ET-1-induced reduction of cGMP level in the cells. Both Cyclosporine and sildenafil suppressed ET-1-stimulated PASMC proliferation. CONCLUSION: Activation of calcineurin/NFAT signaling pathway mediates ET-1-induced PASMC proliferation by stimulating PDE5 expression, which further degrades cGMP. Both Cyclosporine and sildenafil can suppress ET-1-stimulated PASMC proliferation in vitro. PMID- 23353151 TI - [Effect of Biejiajian Pills on Wnt/beta-catenin signal pathway and DKK-1 and FrpHe gene expressions in hepatocellular carcinoma cells]. AB - OBJECTIVE: To investigate the effect of Biejiajian Pills on Wnt signal pathway and its inhibitory gene (DKK-1 and FrpHe) expressions and explore the mechanism underlying the action of Biejiajian Pills to suppress the invasiveness of hepatocellular carcinoma. METHODS: Twenty-four Wistar rats were randomized equally into 3 groups for gavage of normal saline and Biejiajian Pills at 20- and 10-fold clinical doses for 3 days. Blood samples were then collected from the rats, and the serum was separated and added in HepG2 cell cultures. After 48 h of culture, the cells were collected to determine the cellular content of beta catenin protein using flow cytometry and detect DKK-1 and FrpHe mRNA expressions using qRT-PCR. RESULTS: HepG2 cells cultured in the presence of sera from rats fed with Biejiajian Pills showed significantly lowered beta-catenin protein expression and obvious down-regulation of DKK-1 mRNA expression, and the effect was correlated with the doses of the drug administered. The expression of FrpHe mRNA showed no significant differences between the 3 groups. CONCLUSIONS: Biejiajian Pills can effectively inhibit the invasiveness and migration of hepatocellular carcinoma cells, which is closely related to decreased expressions of beta-catenin and DKK-1 to cause block of the Wnt/beta-catenin signal pathway. PMID- 23353152 TI - [Delayed-enhanced magnetic resonance imaging for assessing a minipig myocardial infarction model established by percutaneous balloon occlusion]. AB - OBJECTIVE: To assess a minipig model of acute myocardial infarction (AMI) established by percutaneous balloon occlusion using delayed-enhanced magnetic resonance imaging (DE-MRI). METHODS: A minipig model of AMI was established by placement of a 2.0 mm*15.0 mm percutaneous transluminal coronary angioplasty balloon in the middle left anterior descending artery (LAD) through a percutaneous femoral puncture in the right inguinal region. The left anterior descending coronary artery (LAD) was occluded for 90 min, followed by assessment of the infarct size and cardiac function with DE-MRI, and the results were confirmed by pathological examination. RESULTS: DE-MRI showed a mean infarcts size of 10.2?2.9 cm3 in the minipig models. Compared to the control group, the minipigs with AMI had significantly increased end-diastolic and end-systolic volumes (P<0.05) with a decreased stroke volume, ejection fraction and cardiac output (P<0.001). These DE-MRI values were matched with the microsphere values obtained from short-axis slices in pathological examination. CONCLUSION: We have established a feasible approach for evaluating minipig models of AMI as a platform for assessing the therapeutic effect of stem cell transplantation for AMI. PMID- 23353153 TI - [Accuracy of correlation function method for evaluating pulsed high intensity focused ultrasound]. AB - OBJECTIVE: To investigate the accuracy of ultrasound monitoring during pulsed high intensity focused ultrasound (PHIFU) treatment and improve the sensitivity of ultrasound monitoring of tissue necrosis caused by PHIFU treatment. METHODS: Bovine liver ex vivo was dot-exposed with HIFU at the therapeutic doses of 2000 J (group A) and 1440 J (group B). The two groups were further divided into groups A1 (power 100 W, duty cycle 100%, irradiate 20 s) A2 (power 100 W, duty cycle 50%, irradiate 40 s), A3 (power 100 W, duty cycle 40%, irradiate 50 s), B1 (power 120 W, duty cycle 100%, irradiate 12 s), B2 (power 100 W, duty cycle 50%, irradiate 24 s), and B3 (power 100 W, duty cycle 40%, irradiate 30 s). The gray scale changes in the ultrasonic images after the exposures were observed, and the correlation function of the image was calculated before and after the exposure. The accuracy of evaluations based on the correlation function and gray-scale changes was compared. RESULTS: The correct rate of gray scale-based evaluation of tissue necrosis caused by PHIFU was only 51%, while that by correlation function based evaluation reached 85%. CONCLUSION: Monitoring of tissue necrosis caused by PHIFU treatment can not rely solely on evaluation of gray-scale change of the ultrasound images, and the correlation function-based evaluation can be more accurate and sensitive for that purpose. PMID- 23353154 TI - [Small interfering RNA-mediated glucose-regulated protein 78 knockdown enhances chemosensitivity of breast cancer cells to cisplatin]. AB - OBJECTIVE: To investigate the effect of small interfering RNA-mediated glucose regulated protein 78 (GRP78) knockdown on the chemosensitivity of breast cancer cells to cisplatin. METHODS: Human breast cancer cell line MDA-MB-231 was exposed to different doses of cisplatin (0, 1, 2, 4, 8, and 16 umol/L), and the changes in cell viability were detected using MTT assay. PI/Annexin V staining was used to observe the apoptosis of the cells in response to transfection with a small interfering RNA targeting GRP78 (pSH1Si-GRP78). Western blotting was employed to detect GRP78 expression in pSH1Si- GRP78-transfected cells after exposure to 8 umol/L cisplatin for 24, 48 and 72 h. RESULTS: Exposure of the cells to 8 umol/L cisplatin for 24, 48 and 72 h resulted in a cell survival rate of 83.13%, 54.22% and 35.79%, respectively, but the cell apoptosis rate was only 10.8% at 24 h. Transfection of MDA-MB-231 cells with pSH1Si-GRP78 caused a cell apoptosis rate of 24.6%, which increased to 48.9% in cells with both pSH1Si-GRP78 transfection and cisplatin exposure. Cisplatin exposure caused an initial up-regulation followed then by a down-regulation of GRP78 expression in MDA-MB-231 cells, while pSH1Si-GRP78 transfection produced an obvious down-regulation of GRP78 expression. CONCLUSIONS: Inhibition of GRP78 expression increases the apoptosis and enhance cisplatin chemosensitivity of breast cancer cells in vitro, suggesting the value of GRP78 as a potential therapeutic target in the clinical treatment of breast cancer. PMID- 23353155 TI - [Construction of a capsular tissue-engineered ureteral stent seeded with autologous urothelial cells]. AB - OBJECTIVE: To investigate the feasibility of constructing a capsular poly L lactic acid (PLLA) ureteral stent seeded with autologous urothelial cells using tissue engineering methods. METHODS: The capsular ureteral stent was constructed by subcutaneously embedding PLLA ureteral stent in the back of beagles for 3 weeks to induce the formation of connective tissue on the surfaces. After decellularization of the stent, the expanded autologous urothelial cells were seeded on the stent. The surface structure and cell adhesion of the stent were observed using HE staining, scanning electron microscope (SEM) and immunocytochemical staining. MTT assay was used to evaluate urothelial cell proliferation on the capsular PLLA ureteral stent and on circumferential small intestinal submucosa graft. RESULTS: HE staining and VIII factor immunohistochemistry revealed numerous capillaries in the connective tissue encapsulating the stent without obvious local inflammatory response. The results of SEM and immunocytochemical staining showed that the capsule contained rich collagenic fibers forming three-dimensional structures, and the seeded autologous urothelial cells could adhere and well aligned on the surface. MTT assay showed normal growth of the cells on the stent as compared with the cells grown on circumferential small intestinal submucosa graft. CONCLUSION: The capsular PLLA ureteral stent allows adhesion and proliferation of autologous urothelial cells and shows a potential in applications of constructing tissue-engineered ureter. PMID- 23353156 TI - [Determination of pazufloxacin concentration in saliva, gingival crevicular fluid and serum of healthy adults using high-performance liquid chromatography]. AB - OBJECTIVE: To establish a rapid and sensitive high-performance liquid chromatography (HPLC) method for detecting pazufloxacin concentrations in the saliva, gingival crevicular fluid and serum of healthy adults. METHODS: Samples of saliva, gingival crevicular fluid and serum were obtained from healthy adults receiving intravenous infusion of pazufloxacin. The concentrations of pazufloxacin in the samples were quantified by HPLC equipped with a reversed phase column (Agilent Zorbax SB-C18 5 um, 250 mm*4.6 mm). The mobile phase for pazufloxacin was a mixture of acetonitrile and 0.5% phosphoric acid containing 1% triethylamine (155:850), and 20 ul of the resulting solution was injected into the HPLC system at a flow rate of 1.0 ml/min. The detection wavelength was set at 245 nm. The samples were first deproteinized by precipitation with methanol followed by supernatant drying; the residue was reconstituted with the mobile phase and centrifuged, and the supernatants were directly injected into the HPLC system. RESULTS: Pazufloxacin in the samples were totally separated without interference by any endogenous substances. The calibration curves showed a good linear regression (r>0.999). The detection limit was 10 ng/ml with within-day and between-day coefficients of variation performance all below 5% and recovery rates all above 91%. CONCLUSION: HPLC is both sensitive and selective for quantification of pazufloxacin in saliva, gingival crevicular fluid and serum. PMID- 23353157 TI - [Preparation of chicken red blood cells for calibration of flow cytometry]. AB - OBJECTIVE: To prepare stable chicken red blood cells for the calibration of flow cytometry. METHODS: The traditional isolation method of chicken red blood cells was modified by incorporating gelatin technique, Ca2+-free HBSS treatment and low speed centrifugation. The effect of fluorescence staining of the cells was improved by the addition of TritonX-100 to enhance the membrane permeability and Rnase enzymes to disintegrate RNA tiles. The modified method was compared with the traditional method for viability of the freshly isolated cells and the DNA content coefficient of variation (CV) of the fixed cells. RESULTS: Chicken red blood cells obtained by the modified method showed a significantly higher viability than those obtained by the traditional method [(98.5?3.5)% vs (93.5?2.7)%, P<0.05]. After glutaraldehyde fixation, the isolated cells with the modified method were stable during the 90-day preservation with a significantly lower CV than the cells obtained by the traditional method [(6.0?0.3)% to 6.2?0.4% vs (8.6?0.5)% to (13.1?1.4)%, P<0.01]. CONCLUSION: The chicken red blood cells isolated using the modified method can be applicable for calibration of flow cytometry. PMID- 23353158 TI - [Effect of intermittent versus continuous exercise on obesity and fatty liver in rats fed with high-fat diet]. AB - OBJECTIVE: To examine the effects of continuous and intermittent exercises on obesity and fatty liver in rats fed with high-fat diet. METHODS: Wistar rats were randomly assigned into routine diet (R) and high-fat diet (H) groups, and each group were subdivided into sedentary group (S), continuous exercise (CE) group, and intermittent exercise (IE) group (n=8). In the CE group, the rats were forced to swim continuously for 90 min once daily, and those in the IE group swam for 30 min for 3 times (at a 4-h interval) daily. Both the CE and IE groups exercised for 5 days a week for 8 consecutive weeks. After the experiment, the retroperitoneal, epididymal, and visceral white and brown adipose tissues, the liver, and the gastrocnemius muscle of the rats were weighed. The lipogenesis rate was determined by incorporation of (3)H(2)0 into saponified lipids, and the blood lipid profiles were analyzed. The body weight and food intake of the rats were recorded daily. RESULTS: IE appeared to be more efficient than CE in reducing the adverse effects of high-fat diet and sedentarism. Compared with CE, IE resulted in an improved lipid profile with reduced food intake, body weight gain, visceral and central adiposity, and fatty liver. The effect of high-fat diet and different exercises on weight gain, adiposity, fatty liver, and lipid profile in rats was associated to the manner of exercise, time of each session, age, gender, and length of observation period. CONCLUSION: Intermittent exercise is an important nonpharmacological strategy to control obesity and the related complications. PMID- 23353159 TI - [Functional enhancement of gap junction by valproate acid sodium in breast cancer cells and the mechanism]. AB - OBJECTIVE: To investigate the effect of valproate acid sodium (VPA) on gap junction intercellular communication in breast cancer Hs578T cells and explore the mechanism. METHODS: MTT assay was used to detect the cytotoxicity of VPA on Hs578T cells, and parachute assay was used to detect the effect of VPA on dye spread of the cells. Western blotting was employed to detect the expression changes of Cx43 total protein in VPA-treated Hs578T cells. The effect of VPA on the expression of Cx43 on the surface of Hs578T cells was examined with immunofluorescence assay. RESULTS: MTT assay showed no obvious cytotoxicity of VPA on Hs578T cells at the concentrations below 10 mmol/L. VPA below 5 mmol/L obviously increased the gap junction function in Hs578T cells (P<0.01), and significantly enhanced the expression of Cx43 total protein (P<0.01) and Cx43 expression on the surface of Hs578T cells (P<0.01). CONCLUSION: VPA can obviously increase the gap junction function in Hs578T cells possibly by enhancing Cx43 total protein expression and Cx43 protein expression on the surface of Hs578T cells. PMID- 23353160 TI - [Preoperative platelet-lymphocyte ratio is an independent prognostic factor for resectable colorectal cancer]. AB - OBJECTIVE: To evaluate the impact of preoperative platelet-lymphocyte ratio (PLR) on the prognosis in patients with operable colorectal cancer. METHODS: The clinical data of 140 patients with operable colorectal cancer were analyzed retrospectively. According to preoperative PLR, the patients were divided into low PLR group (PLR<250) and high PLR group (PLR>=250). The overall 5-year survival rates and the clinicopathological factors in the two groups were analyzed using univariate analysis and COX regression model. RESULTS: The patients with a high PLR had a significantly lower overall 5-year survival rate than those with a low PLR (71.4% vs 51.5%, P=0.045). Univariate analyses identified tumor location, the depth of tumor invasion, lymph nodes metastasis, TMN stage, and PLR as significant risk factors for reduced overall 5-year survival. In COX regression model, a high PLR was identified as an independent risk factor for poorer prognosis in patients with resectable colorectal cancer (RR: 2.213; 95%CI: 1.007-4.863, P=0.0048). CONCLUSION: Preoperative PLR can be a clinically significant factor for assessment of prognosis of resectable colorectal cancer. PMID- 23353161 TI - [Age-related changes in resting functional connectivity of the marginal division of the neostriatum in healthy adults]. AB - OBJECTIVE: To investigate the age-related changes in resting functional connectivity of the marginal division (MrD) of the neostriatum in healthy adults detected using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Forty-four healthy volunteers aged between 22 and 44 years (mean 30.36?6.31 years) and 20 elderly volunteers aged between 48-83 years (mean 61.4?10.25 years) underwent conventional MRI, 3D structural MRI and rs-fMRI. MrD was defined manually on the structural images for computation of the functional connectivity maps. The single group data were analyzed with independent sample t test, and the data of the two-group were examined by analysis of covariance with gender as the covariance. RESULTS: In the young volunteers, the brain regions of functional connectivity related with the MrD were located in bilateral middle cingulate gyri, putamen, thalamus and amygdala, as compared with the brain regions of the bilateral putamen, thalamus, amygdala, insular cortex, rolandic operculum and right supramarginal gyrus in the elderly volunteers. Compared with the young volunteers, the elderly volunteers showed decreased functional connectivity related with the MrD in the bilateral middle cingulate gyri, parahippocampal gyri and left hippocampus. CONCLUSION: An increased age is associated with alterations in the functional connectivity related with the MrD in healthy adults. PMID- 23353162 TI - [Protective effect of propofol and resveratrol pretreatment against hepatocyte apoptosis in rats with hepatic ischemia-reperfusion injury]. AB - OBJECTIVE: To observe the effect of resveratrol and propofol, used either alone or in combination, on hepatocyte apoptosis in rats with hepatic ischemia reperfusion injury (HIRI). METHODS: A total of 144 male SD rats were randomized into 8 equal groups, including a sham-operated group and 7 HIRI (established using Pringle method) groups with pretreatments with normal saline, Tween80, propofol (10 or 20 mg.kg(-1).h(-1)), or resveratrol (10 or 20 mg/kg), or both propofol and resveratrol 10 min before hepatic portal vein occlusion. At 1, 3 and 6 h after the reperfusion, 6 rats from each group were sacrificed for histopathological examination of the liver tissue, detection of hepatocyte apoptosis using TUNEL assay, and measurement of Bcl-2, Bax and caspase-3 protein expressions using immunohistochemistry. RESULTS: Compared with normal saline and Tween80, propofol and resveratrol at different doses used alone or in combination all significantly alleviated the hepatic pathologies, lowered the apoptosis index (P<0.05), increased Bcl-2 expression (P<0.05), and reduced Bax and caspase-3 expressions in the liver tissues following HIRI (P<0.05). Compared with low doses of propofol and resveratrol used alone, their combination showed more obvious protective effects against hepatocyte apoptosis (P<0.05), but at higher doses, propofol and resveratrol either alone or in combination produced similar effects. CONCLUSIONS: Propofol and resveratrol can suppress HIRI-induced hepatocyte apoptosis by up-regulating Bcl-2 and down-regulating Bax and caspase-3 expressions, and their combined use can reduce the effective doses of the drugs. PMID- 23353163 TI - [Effects of monocyte chemotactic protein-3 on ICAM-1, VCAM-1, TF, and TFPI expression and apoptosis in human umbilical vein endothelial cells]. AB - OBJECTIVE: To investigate the effect of monocyte chemotactic protein-3 (MCP-3) on the expressions of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), tissue factor (TF, and tissue factor pathway inhibitor (TFPI) and cell apoptosis in human umbilical vein endothelial cells (HUVECs). METHODS: Cultured HUVECs were treated with MCP-3 at the optimal concentration determined previously 1 h after treatments with or without MCP-3 antibody (20 ng/ml), PI3K inhibitor, or LY-294002 (5 mmol/ml). The expressions of ICAM-1, VCAM-1, TF and TFPI were analyzed using RT-PCR and Western blot after the treatments. MCP-3 mRNA and protein expressions were detected in HUVECs exposed to 50 ug/ml ox-LDL for 24 h. The cell apoptosis and caspase-3 protein production in HUVECs treated with MCP-3 or with MCP-3 plus CCR2 antagonist for 24 h and 48 h were evaluated by flow cytometry and Western blotting. RESULTS: At the optimal concentration of 0.3 ng/ml, MCP-3 treatment for 24 h caused significantly increased ICAM-1, VCAM-1, and TF expressions with lowered expression of TFPI in HUVECs (P<0.05), and such effects were significantly inhibited by the application of MCP-3 antibody, PI3K inhibitor, or LY-294002 (P<0.05). Ox-LDL exposure significantly increased the expression of MCP-3 in HUVECs (P<0.05). HUVECs showed a significantly increased apoptosis rate after treatment with MCP-3 or with MCP-3 plus CCR2 antagonist (P<0.05), and the apoptosis rate increased significantly as the treatment time prolonged (P<0.05); caspase-3 protein expression in the cells showed a similar pattern of alterations following the treatments. CONCLUSION: ox LDL can induce MCP-3 expression in HUVECs. MCP-3 induces apoptosis of HUVECs and significantly affects the cellular function partially through the PI3K signaling pathway. PMID- 23353164 TI - [Feasibility of carotid bifurcation angle measurement with oblique sagittal T(1) weighted black-blood magnetic resonance imaging]. AB - OBJECTIVE: To evaluate the feasibility by oblique sagittal T(1)-weighted (QIR FSE) black-blood sequence for measurement of the carotid bifurcation angle. METHODS: Twenty-three patients undergoing carotid magnetic resonance imaging (MRI) were divided in normal group and plaque group. Carotid bifurcation angle was measured by both 2D-TOF and oblique sagittal T(1)W (QIR-FSE) black-blood sequence, and the measurement was repeated after 3 months to evaluate the reproducibility. The measurement results using 2D-TOF and oblique sagittal T(1)W (QIR-FSE) black-blood sequence were compared to assess the consistency of the two sequences. Four different angles of each carotid artery were measured from different locations on oblique sagittal T(1)W. The ratio of the bilateral carotid bifurcation angle (Right/Left) was compared. RESULTS: Ten patients in each group were enrolled after excluding 3 patients. Strong correlations were found between the results of the first and the second measurements for both 2D-TOF and oblique sagittal T(1)W sequences. No significant difference was found between the two sequences in the ratio of bilateral carotid bifurcation angle (right/left), nor in the 4 angles from different locations. CONCLUSION: Oblique sagittal T(1) weighted (QIR-FSE) black-blood sequence can be used to measure the carotid bifurcation angle. PMID- 23353165 TI - [Expression of enhancer of zeste homolog 2 in esophageal squamous cell carcinoma and its prognostic value in postoperative patients]. AB - OBJECTIVE: To investigate the expression of enhancer of zeste homolog 2 (EZH2) in esophageal squamous cell carcinoma and its association with the prognosis of postoperative patients. METHODS: Surgical specimens were obtained from 102 patients with esophageal squamous cell carcinoma undergoing radical resection in our hospital from 1996 to 2006. Immunochemistry was employed to examine EZH2 protein expressions in the specimens, including 102 carcinoma tissue specimens, 30 adjacent tissue specimens and 30 normal esophageal tissue specimens. The expression levels of EZH2 were analyzed in relation to the clinicopathological parameters of the patients including gender, age, tumor differentiation, TNM, and lymph node metastasis. The postoperative patients were followed up to analyze the association of EZH2 expression with the clinical outcomes. RESULTS: The esophageal squamous cell carcinoma tissue showed a higher EZH2 expression than the adjacent and normal esophageal tissues. EZH2 expression was higher in poorly differentiated carcinoma than in well differentiated tissue, and also higher in cases with lymph node metastasis than those without; the expression was higher in TNM stage II/III patients than in stage I patients but lower than in stage IV patients. The patients with low EZH2 expression was found to have a longer survival time than those with high EZH2 expression (P<0.05). CONCLUSION: EZH2 plays an important role in the differentiation and metastasis of esophageal squamous cell carcinoma, and a high EZH2 expression is associated with a poor outcome in the the postoperative patients. PMID- 23353166 TI - [Effects of Jiaweisinisan on gastric mucosal ultrastructure and brain-gut axis in a rat model of chronic psychological stress]. AB - OBJECTIVE: To study the effect of Jiaweisinisan (JWSNS), a traditional Chinese herbal medicinal recipe, on gastric mucosal ultrastructure and brain-gut axis in rat models of chronic psychological stress and elucidate the mechanism of JWSNS for ameliorating stress-induced gastrointestinal dysfunction. METHODS: Sixty rats were randomly assigned into normal control group, model group, 3 JWSNS groups (high, moderate, and small doses), and omeprazole group (n=10). Rat models of chronic psychological stress were established by random stressful stimulations, and following the corresponding interventions, plasma adrenocorticotropic hormone (ACTH) and cortisol (CORT) levels were detected using radioimmunoassay, and the mRNA expressions of gastrin receptor in the gastric tissue (GASR) and vasoactive intestinal peptide II receptor (VIPR2) in the jejunal tissue were examined using RT-PCR. Transmission electron microscopy was employed to examine the ultrastructural changes in the gastric mucosa tissue cells of the glandular stomach area and alterations in the intercellular junctions. RESULTS: Electron microscopy revealed obvious damages in gastric mucosal epithelial cell organelles and nuclei in the model rats. These damages were ameliorated after treatments with JWSNS and omeprazole. Compared with the model group, the 3 JWSNS groups and omeprazole group all showed significantly lowered plasma ACTH and CORT levels, increased gastrin receptor mRNA expression and decreased jejunal VIPR2 mRNA expression (P<0.05 or 0.01). CONCLUSION: JWSNS can obviously ameliorate the pathologies of the gastric mucosa cells, regulate the state of brain-gut axis, and modulate the gastric gastrin receptor and jejunal VIPR2 mRNA expressions in rats with chronic psychological stress. PMID- 23353167 TI - [Glycometabolic state in hypertensive and normotensive patients: identifying candidates for oral glucose tolerance tests]. AB - OBJECTIVE: To characterize unknown glycometabolic state in patients with essential hypertension (EHT) and normotensive patients and determine which EHT patients are candidates for oral glucose tolerance tests (OGTTs). METHODS: This cross-sectional study consecutively recruited 895 EHT patients and 486 normotensive patients. The data including blood glucose, blood pressure, blood lipids, angiography profiles, and left ventricular parameters were collected. RESULTS: OGTTs performed in all patients revealed that the prevalence of abnormal glucose metabolism (AGM) was significantly higher in EHT patients than in normotensive patients at both baseline (P<0.001) and post-OGTT analysis (P<0.001). In total, 76.4% of the individuals with impaired glucose tolerance and 78.2% of individuals with newly diagnosed diabetes would have remained undetected if OGTTs had not been performed. Newly diagnosed AGM was significantly correlated with the presence and severity of coronary stenosis and left ventricular structure abnormalities and dysfunction. EHT patients with fasting glucose >=5.6 mmol/L, hypertension duration exceeding 10 years, coronary artery disease, high sensitivity C-reactive protein >3 mg/L, or high levels of apoB/apoA-1 ratio were at high risk of AGM. CONCLUSIONS: AGM is more common in patients with EHT than in normotensive patients, and OGTTs is a cost-effective strategy to detect AGM in EHT patients. PMID- 23353168 TI - [Diagnostic value of (18)F-FDG PET/CT for solitary nodular-type bronchoalveolar carcinoma]. AB - OBJECTIVE: To assess the value of (18)F-FDG PET/CT in the diagnosis of solitary nodular-type bronchoalveolar carcinoma (BAC). METHODS: The clinical and radiographic data were analyzed retrospectively in 30 patients with pathologically confirmed solitary nodular-type BAC who underwent (18)F-FDG PET/CT examinations between August, 2005 and December, 2006. The morphological and radioactive findings of the lesions were reviewed, and the maximum standard uptake values (SUVmax) were measured. The diagnostic accuracy of PET, PET/CT, and HRCT were analyzed. RESULTS: The (18)F-FDG SUV was markedly lower in BAC than in other well differentiated adenocarcinoma. In 19 of the BAC cases, PET showed a SUVmax of no less than 2.5, demonstrating positive changes. Of the total of 30 cases, 5 had ground glass opacity (GGO) changes, 3 exhibited mixed nodules with GGO changes around the lesions, and 22 cases presented with solid nodules. HRCT showed that BAC located often in the superior lobes of the bilateral lungs, mostly below the pleura in the surrounding lung field; the lesions were patchy or nodular with irregular shapes, showing lobulation in 22 cases, spiculation in 15 cases, pleural indentation in 21 cases, and vacuolar changes in 4 cases. The diagnostic accuracy of PET, PET/CT and HRCT for solitary nodular-type BAC was 36.67%, 93.33%, and 93.33%, respectively. CONCLUSION: The SUVmax of BAC provides only limited value for defining the nature of the lesions, but can serve as a general reference for assessing the disease activity. PET/CT, which allows both functional and imaging assessment, can be a valuable modality to reduce the misdiagnosis rate of BAC. PMID- 23353169 TI - [Correlation analysis between post-stroke constipation and brain injury]. AB - OBJECTIVE: To investigate the incidence of constipation after stroke and explore the relationship between post-stroke constipation and brain injury. METHODS: Using a self-designed questionnaire, we collected the general information of 723 inpatients from 10 hospitals in Guangzhou, including the general demographic information, related factors of brain injury, defecation and previous history. RESULTS: The total incidence of post-stroke constipation was 34.6% in these patients. The incidence of constipation was 31.0% in ischemic stroke patients, 44.8% in hemorrhagic stroke patients, and 47.4% in patients with cerebral hemorrhage and infarction, showing a significant difference between stroke types (chi(2)=12.369, P=0.002). In terms of stages following stroke, the incidence was 41.6% in the acute phase, 31.5% in the recovery phase, and 22.6% in the sequelae phase. In light of lesion locations, the incidence was significantly higher in patients with basal ganglia involvement than in those without (P<0.001). Logistic multivariate analyses showed that stroke type, post-stroke stage, lesion number and basal ganglia involvement were significantly associated with the incidence of constipation. CONCLUSION: Constipation often occurs in the acute stage following stroke (especially hemorrhagic stroke), and the incidence is higher in patients with basal ganglia involvement. PMID- 23353170 TI - [Regulation of mesenchymal stem cells derived from umbilical cord on natural killer cells-mediated cytotoxicity against dendritic cells]. AB - OBJECTIVE: To observe the effect of mesenchymal stem cells derived from umbilical cord (UC-MSCs) on natural killer (NK) cells-mediated cytotoxicity against dendritic cells (DCs) and explore the mechanism. METHODS: MSCs were isolated from human umbilical cord by collagen digestion and cultured in vitro. NK cells were separated from healthy human peripheral blood by magnetic bead sorting. Mononuclear cells from healthy human peripheral blood were cultured in the presence of granulocyte and macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) to obtain the immature DCs. The DCs were then co-cultured with UC-MSCs in the presence of tumor necrosis factor alpha (TNFalpha) for 2 days, and the expressions of CD11c and CD86 on DCs and IL-12 level in the culture medium was detected using flow cytometry and ELISA, respectively. The cytotoxicity of NK cells against DCs was analyzed by LDH-releasing assay, and the expressions of ligands for killer activator receptor (MICA/B and ULBP1-3) on the DCs were detected with flow cytometry. RESULTS: Compared with the cytokine induced DCs, the DCs induced by co-culture with UC-MSCs showed an identical CD11c expression but lowered CD86 expression and IL-12 secretion. The natural killer cells produced a stronger cytotoxicity against UC-MSCs-induced DCs than against cytokine-induced DCs. The UC-MSCs-induced DCs also showed increased expressions of MICA and MICB on the surface. CONCLUSION: UC-MSCs can enhance NK cells mediated cytotoxicity against DCs possibly by inhibiting DC maturation and up regulating the ligands for killer activator receptor on the surface of the DCs. PMID- 23353171 TI - [E-cadherin expression and CDH1 promoter methylation in sporadic and hereditary gastric cancer]. AB - OBJECTIVE: To evaluate the role of E-cadherin (E-cad) and CDH1 gene encoding E cad in the occurrence of sporadic or hereditary gastric cancer. METHODS: Nineteen normal gastric mucosal issue specimens, 19 specimens of hereditary gastric cancer (diagnosed according to ICG-HGC criteria), and 19 specimens of sporadic gastric cancer examined for E-cad expression and CDH1 promoter methylation using immunohistochemistry and methylation-specific PCR (MSP). RESULTS: The protein expression of E-cad were significantly reduced in both of the cancer tissues (P<0.001) compared with that in the normal gastric mucosal tissues, and showed no significant difference between the two cancers (P=0.84). CDH1 promoter hypermethylation was found in 10 out of the 19 hereditary gastric cancer tissues, a rate significantly higher than that in sporadic gastric cancer tissues (3/19, P<0.01). CONCLUSION: CDH1 promoter hypermethylation is probably an important factor contributing to reduced E-cad expression in sporadic gastric cancer but not in hereditary gastric cancer. PMID- 23353172 TI - [Expression of SOX2 in cervical intraepithelial neoplasia and cervical cancer and its clinical significance]. AB - OBJECTIVE: To investigate the expression of SOX2 in cervical intraepithelial neoplasia (CIN) and cervical cancer and explore its association with the clinical features. METHODS: SOX2 expressions were examined using immunohistochemical method in 10 normal cervical tissue specimens, 36 cervical intraepithelial neoplasia specimens (including 10 cases of grade I, 12 of grade II, and 14 grade III) and 40 cervical cancer specimens (including 21 cases of stage I and 19 of stage II). The correlation between the immunohistochemical results and the clinical features of the patients was analyzed. RESULTS: SOX2 expression was negative in normal cervical tissues, and was positive in 41.6% of CIN specimens (10.0% in CIN I, 41.7% in CIN II, and 64.3% in CIN III) in 82.5% of cervical cancer specimens (78.2% in stage I and 88.2% in stage II). The patients with cervical cancer had a significantly higher positivity rate of SOX2 than normal control group (P<0.05). The positivity rate of SOX2 increased with the evolution of cervical disease. SOX2 protein expression was significantly correlated with the histological grade and lymph node metastasis (P<0.05), but not with the age or clinical stage of the patients (P<0.05). CONCLUSION: SOX2 expression may serve as a useful indicator for evaluating metastasis and malignancy of cervical cancer. PMID- 23353173 TI - [Hybrid operation for acute left leg deep venous thrombosis secondary to left iliac vein compression syndrome: analysis of 36 cases]. AB - OBJECTIVE: To evaluate the surgical techniques for acute left deep venous thrombosis (LDVT) secondary to left iliac vein compression syndrome (IVCS). METHODS: Thirty-six patients with acute LDVT secondary to IVCS received inferior vena cava filter placement, and in 2 of the cases, stent implantation was canceled for acute episode of obsolete DVT. The remaining 34 patients underwent left femoral venotomy for iliofemoral thrombectomy with Fogarty catheter and distal femoral vein thrombus removal by sequential compression of the legs, followed by implantation of stent-graft (2 cases) or bare-metal stents (32 cases) in the left common iliac veins. With routine anticoagulation and thrombolytic treatments, the patients were regularly examined for postoperative blood flow in the affected limb. RESULTS: In 2 of the cases undergoing bare-metal stent implantation, the residue thrombi were squeezed into the stent by balloon, which was managed subsequently with local thrombolysis. One patient with bare-metal stent implantation received a secondary stenting for posterior stent displacement. Three patients had self-limited bleeding due to decreased serum FBG. Significant improvements were achieved at 3, 6, 30 and 180 days postoperatively in the circumferences of the affected limb (P<0.05) and in the levels of D-dimer (P=0.011), and FBG level showed no significant variations (F=1.163, P=0.345). The total rate of excellent outcomes was 83.3% (26/34) with a total effective rate of 91.2% (31/34) in these cases. CONCLUSIONS: Thrombectomy to revascularize the inflow tract and stent implantation to enlarge stenosed iliac veins are key issues in treatment of acute LDVT secondary to IVCS. PMID- 23353174 TI - [Expressions of microtubule-associated protein 2 and nestin in the development of human embryo and fetal tongue muscles]. AB - OBJECTIVE: To explore the role of microtubule-associated protein 2 (MAP-2) and nestin in the development of tongue muscles of human embryos and fetuses. METHODS: PV immunohistochemistry was used to detect the expressions of MAP-2 and nestin proteins in the tongue tissues of human embryos and fetuses at the second, third and fourth months of gestation. RESULTS: MAP-2 and nestin positivity was detected in the tongue muscles of human embryos at 2 to 4 months of gestation. In the embryos at the second month of gestation, no obvious MAP-2 positive cells were found in the tongue muscles; at 3 and 4 months, the number of MAP-2-positive cells in the tongue muscles was 24.14?8.28 and 15.86?3.89, with the expression intensity of 109.42?11.62 and 124.27?8.73, respectively. At 2, 3 and 4 months of gestation, the number of nestin-positive cells in the tongue muscles was 12.50?3.17, 19.00?7.63, and 22.80?6.91, with expression intensity of 119.99?24.02, 102.20?11.76, and 98.24?10.66, respectively. As the gestational age increased, the number of MAP-2-positive cell number continued to decline following a transient increase but the expression intensity kept increasing; nestin-positive cells increased continuously but the expression intensity kept decreasing in the embryonic or fetal tongue muscles. CONCLUSION: MAP-2 and nestin proteins are involved in the regulation of the development of tongue muscles in human embryos and fetuses. PMID- 23353175 TI - [Postoperative complications of microscopic versus Palomo varicocelectomy for varicocele in army personnel]. AB - OBJECTIVE: To evaluate the postoperative complications of microscopic and conventional Palomo varicocelectomy in the treatment of varicocele in army personnel. METHODS: A total of 260 army personnel with varicocele were randomized to receive microscopic varicocelectomy (group A, n=130) and conventional Palomo varicocelectomy (group B, n=130). The postoperative recurrence and complications (scrotal edema, testicular pain and testicular atrophy) were compared between the two groups. RESULTS: After 1 year of follow-up, the recurrence rates in groups A and B were statistically comparable (5.3% vs 3.8%, P>0.05). The incidences of testicular atrophy and scrotal edema were significantly lower in group A than in group B (0.7% vs 3.1%, P<0.05; 3.1% vs 14.6%, P<0.05), and the rate of testicular pain relief was significantly higher in group A (90.7% vs 67.7%, P<0.05). CONCLUSION: Microscopic varicocelectomy can be a good choice in the treatment of varicocele in army personnel. PMID- 23353176 TI - [Correlation between left ventricular mass index and NADPH oxidase p22phox in patients with non-valvular chronic heart failure]. AB - OBJECTIVE: To study the correlation between the expression levels of phagocytic NADPH oxidase p22phox subunit and left ventricular mass index (LVMI) in patients with non-valvular chronic heart failure and explore the role of oxidative stress caused by NADPH oxidase p22phox subunit in left ventricular remodeling. METHODS: Semi-quantitative RT-PCR was used to examine the expression levels of phagocytic NADPH oxidase p22phox in 59 patients with non-valvular chronic heart failure and 20 control subjects. All the subjects underwent ultrasonic cardiography to record their IVST, LVPWT, LVEDd, LVEDs, and EF. Based on the calculated LVMI, the patients were divided into heart failure without LV hypertrophy (LVH) group and heart failure with LVH group. RESULTS: The patients with heart failure showed significantly higher expression of phagocytic NADPH oxidase p22phox than the control subjects (0.91?0.37 vs 0.68?0.33, P=0.039), and the patients with LVH had significantly higher p22phox expression than those without LVH (1.58?0.20 vs 0.71?0.24, P=0.026). LVMI showed a positive correlation with the expression of p22phox in these patients (r=0.508, P<0.05). CONCLUSION: NADPH oxidase p22phox expression level is positively correlated with LVMI and can be indicative of the level of left ventricular remodeling in patients with non-valvular chronic heart failure. PMID- 23353177 TI - [Pharmaceutical screening of the effective fraction from Smilax for treatment of chronic pelvic inflammatory disease]. AB - OBJECTIVE: To determine the effective fraction of Smilax for treatment of chronic pelvic inflammatory disease (CPID) by pharmacodynamic screening as the basis for further development of sarsaparilla preparations. METHODS: The chemical fractions of Smilax were administered intragastrically in rat models of CPID induced by injecting phenol mucilage into the uterus to observe the therapeutic effects. The anti-inflammatory effects of different extract fractions from Smilax were tested in mice with xylene-induced ear edema and in rats with cotton-ball-induced granuloma. RESULTS: High-dose ethyl acetate extract of Smilax could obviously inhibit uterus inflammation in rats with CPID, showing also strong anti inflammatory effects against ear edema in mice and granuloma in rats (P<0.01). The moderate dose of ethyl acetate extract also obviously ameliorated the inflammation. Both the ethyl acetate extract fraction and the total extract fraction of Smilax showed anti-inflammatory effects, while the former produced strong effects while the latter has only weak actions. CONCLUSION: The ethyl acetate extract fraction of Smilax is the effective fraction to produce anti inflammatory and anti-CPID effects. PMID- 23353178 TI - [Relationship between changes of serum soluble Fas levels and delayed encephalopathy after acute carbon monoxide poisoning]. AB - OBJECTIVE: By explore the role of serum soluble Fas (sFas) in occurrence and progression of delayed encephalopathy after acute carbon monoxide poisoning (DEACMP). METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to detect serum sFas levels in 40 patients with DEACMP in acute stage and convalescent stage, with 36 healthy elderly subjects as the control group. RESULTS: Serum sFas levels of the patients with DEACMP in both the acute and convalescent stages showed no significant difference from those in the control group (P=0.737 and 0.137, respectively), nor was any significant difference found between the patients in acute and exacerbation stages (P=0.059). CONCLUSION: Serum sFas is not involved in the occurrence and progression of DEACMP. PMID- 23353179 TI - [Normothermic arch-first technique without extracorporeal circulation in total aortic arch replacement for acute Stanford type A dissection: analysis of 23 cases]. AB - OBJECTIVE: To assess the effect of normothermic arch-first technique without extracorporeal circulation in total aortic arch replacement for management of acute Stanford type A dissection. METHODS: The surgical data were reviewed for 23 patients (age range 32-58 years) with Stanford type A dissection undergoing total aortic arch replacement with the arch-first technique in our department between January, 2006 and November, 2011. During the surgery, a 4-branched prosthetic graft was connected with the inflow tube and femoral artery using the Y-type tube. The 3 aortic branches were disconnected and anastomosed to the respective branches of the graft, with continuous perfusion of the brain by femoral arterial return. After clamping of the ascending aorta, the graft was connected to the remaining arch before the common stem of the graft was anastomosed with the aortic root. RESULTS: The operations were successfully completed in all the 23 cases with a mean total bypass time of 187?60 min (117-254 min), mean ascending aorta clamping time of 35?8 min, and mean nasopharyngeal temperature of 22?2 celsius;. Death occurred in one case (4.3%) after the operation, and 2 (8.7%) patients experienced temporary neurological dysfunctions. The postoperative consciousness recovery time was 6-8 h in these cases. The shortest postoperative mechanical ventilation time was 18 h, and 11 (48%) patients were weaned from mechanical ventilation within 48 h postoperatively. The ICU stay ranged from 3 to 7 days in these cases. CONCLUSION: Normothermic arch-first technique without extracorporeal circulation can provide better brain protection and reduced the incidence of postoperative complications by shortening the time of circulation bypass and aortic clamping. PMID- 23353180 TI - [Huge primary teratoma in the preperitoneal space: a case report and literature review]. AB - Huge primary teratoma in the preperitoneal space is an extremely rare clinical entity and can be easily misdiagnosed as tumors of the intraperitoneal or pelvic origin. We report a case of primary huge mature teratoma in the preperitoneal space in a 74-year-old women, and reviews the clinical data and the diagnosis and treatment of this case. The patient underwent complete resection of the teratoma, which was the optimal treatment option. The patient was followed-up for 10 months and no signs of recurrence were found, suggesting a favorable prognosis. PMID- 23353181 TI - [Left cystic mature adrenal teratoma: a case report]. AB - OBJECTIVE: Adrenal teratoma is a rare germline tumor with a malignant potential. We present a case of left adrenal teratoma complicated by diabetes. The 64-year old female patient showed multiple cystic space-occupying masses in the left kidney in B-mode ultrasound examination, and plain and enhanced CT reported a 9.0 cm heterogeneous mass in the left adrenal gland. After effective control of blood glucose, the mass was surgically removed and sent for pathological examination. The mass consisted of multiple cysts containing lipid-like substance with a cyst wall thickness of 0.2-0.4 cm; bony structures were found on the sections of the mass with fat tissues on the mass surface. A final diagnosis of left cystic mature adrenal teratoma was made based on the clinical and pathological findings and literature review. The patient was followed up for 6 months and no local recurrence or metastasis was found. Mature adrenal teratoma can be easily diagnosed by ultrasound and CT examinations and should be distinguished from other tumors of an adrenal source. Early diagnosis and early surgical resection is key to the treatment, and a definite diagnosis can be made pathologically. Chemotherapy is necessary in inoperable cases or for such tumors with a malignant potential. The patients should be followed up for life time after the treatment. PMID- 23353182 TI - Rab35 is required for Wnt5a/Dvl2-induced Rac1 activation and cell migration in MCF-7 breast cancer cells. AB - The small GTPases regulate many major biological processes in both tumorigenesis and tumor progression such as cell survival, actin cytoskeleton organization, cell polarity and movement. Wnt5a, a non-canonical Wnt family member, is implicated in the activation of small GTPases in breast cancer. We previously demonstrated that Wnt5a signaling stimulates the migration of breast cancer cells MDA-MB-231 via activating RhoA. However, we found here that RhoA activation was not enhanced by Wnt5a in breast cancer cells MCF-7. The conflicting results prompted us to further probe novel small GTPases in response to Wnt5a and investigate the mechanisms whereby cell migration is regulated. We showed here that Wnt5a dose dependently activated Dvl2, Rab35 and Rac1 and subsequently promoted the migration of MCF-7 cells, which was, however, abolished by knocking down Wnt5a expression via small interfering RNA (siRNA) transfection. Dvl2 siRNA significantly decreased background and Wnt5a-induced Rab35/Rac1 activation and, consequently, cell migration. Rab35 short hairpin RNA (shRNA) remarkably inhibited background and Wnt5a-induced Rac1 activation and cell migration. Additionally, blockade of Rac1 activation with Rac1 siRNA suppressed background and Wnt5a-induced cell migration. Co-immunoprecipitation and immunofluorescence assays showed that Dvl2 bound to Rab35 in mammalian cells. Taken together, we demonstrated that Wnt5a promotes breast cancer cell migration via the Dvl2/Rab35/Rac1 signaling pathway. These findings implicate Wnt5a signaling in regulating small GTPases, which could be targeted for manipulating breast cancer cell migration. PMID- 23353183 TI - Crosstalk from survival to necrotic death coexists in DU-145 cells by curcumin treatment. AB - Curcumin as an anticancer agent was investigated in regards to its ability to regulate the switching of cancer cells from survival to necrotic cell death. At higher concentrations, curcumin induced ROS production leading to JNK and p38 phosphorylation in DU-145 prostate cancer cells. Of the MAP kinases, ERK or p38/JNK were phosphorylated earlier during curcumin treatment, and were responsible for curcumin-induced cell survival at early time of treatment with the help of phosphorylated Akt, while significant amounts of ROS production in later periods stimulated cell death with caspase degradation. In addition to autophagic signaling, necrosis was dominant with little apoptotic cell death. Caspase activation was completely prohibited by procaspase degradation, which contributed to curcumin-induced early necrosis. At the later incubation period (24h), cytotoxicity caused by curcumin peaked, at which time survival or proliferation signals, such as phosphorylated Akt and phosphorylated ERK, was almost completely diminished. Curcumin-induced ROS were shown to function, biphasically depending on the incubation period; facilitating survival, in the earlier incubation period, and necrotic death in the later. Based on all of these results, we concluded that curcumin contributes to a complex signaling network, affecting cell survival and necrotic cell death, which in turn could inhibit apoptotic cell death. PMID- 23353184 TI - Covert visuospatial attention orienting in a brain-computer interface for amyotrophic lateral sclerosis patients. AB - BACKGROUND: Brain-computer interfaces (BCIs) allow people to control devices by translating brain signals into commands. BCIs represent a concrete solution with regard to communication and motor control disabilities of patients with amyotrophic lateral sclerosis (ALS). Most of the BCIs rely on visual interfaces in which patients must move their eyes to achieve efficient BCI control. This fact represents a limitation of BCI use in ALS patients who are in the final stages of the disease. OBJECTIVE: We aimed to improve visual interfaces for ALS patients to control the movement of a cursor on a monitor by orienting their covert visuospatial attention (i.e., orienting without eye movements). METHODS: A total of 10 ALS patients with different levels of impairment used 2 new visual interfaces in an event-related potential (ERP)-based BCI. In the first interface, they were required to use exogenous visuospatial attention orienting (VAO), whereas in the second interface, they were required to use endogenous VAO. RESULTS: . ALS patients were able to use the 2 interfaces for controlling the ERP based BCI system in real time. Nevertheless, better target classification and information transfer rate were associated with the interface that was based on endogenous VAO. CONCLUSIONS: ALS patients can exploit their covert VAO to control a BCI that does not require eye movements. The implementation of endogenous VAO in the design of covert visuospatial attention-based interfaces seems to be suitable for designing more ergonomic and efficient BCIs for ALS patients with impaired eye movements. PMID- 23353185 TI - Quantifying arm nonuse in individuals poststroke. AB - BACKGROUND: Arm nonuse, defined as the difference between what the individual can do when constrained to use the paretic arm and what the individual does when given a free choice to use either arm, has not yet been quantified in individuals poststroke. OBJECTIVES: (1) To quantify nonuse poststroke and (2) to develop and test a novel, simple, objective, reliable, and valid instrument, the Bilateral Arm Reaching Test (BART), to quantify arm use and nonuse poststroke. METHODS: First, we quantify nonuse with the Quality of Movement (QOM) subscale of the Actual Amount of Use Test (AAUT) by subtracting the AAUT QOM score in the spontaneous use condition from the AAUT QOM score in a subsequent constrained use condition. Second, we quantify arm use and nonuse with BART by comparing reaching performance to visual targets projected over a 2D horizontal hemi-work space in a spontaneous-use condition (in which participants are free to use either arm at each trial) with reaching performance in a constrained-use condition. RESULTS: All participants (N = 24) with chronic stroke and with mild to moderate impairment exhibited nonuse with the AAUT QOM. Nonuse with BART had excellent test-retest reliability and good external validity. CONCLUSIONS: BART is the first instrument that can be used repeatedly and practically in the clinic to quantify the effects of neurorehabilitation on arm use and nonuse and in the laboratory for advancing theoretical knowledge about the recovery of arm use and the development of nonuse and "learned nonuse" after stroke. PMID- 23353547 TI - Toxicological evaluation of neem (Azadirachta indica) oil: acute and subacute toxicity. AB - Neem (Azadirachta indica), popularly known as traditional medicine is a native plant in India. Neem oil is a vegetable oil derived from seeds or fruits of the neem tree through pressing or solvent extraction, and largely used in popular medicine to have antifungal, antibacterial, antimalarial, antiparasitic, anti inflammatory, as well as immunemodulatory properties in different animal species. In the present study, acute and 28-day subacute toxicity tests were carried out. In the acute toxicity test, the LD50 values of neem oil were found to be 31.95g/kg. The subacute treatment with neem oil failed to change body weight gain, food and water consumption. Serum biochemistry analysis showed no significant differences in any of the parameters examined under the dose of 1600mg/kg/day. Histopathological exams showed that the target organs of neem oil were testicle, liver and kidneys up to the dose of 1600mg/kg/day. PMID- 23353548 TI - Effect of sweet grass (Hierochloe odorata) on the physico-chemical properties of liver cell membranes from rats intoxicated with ethanol. AB - Changes in the composition and physicochemical properties of liver cell membranes due to ethanol intoxication are due mainly to reactive oxygen species (ROS). The destructive action of free radicals can be neutralized by administration of antioxidants. The purpose of this study was to investigate the efficacy of sweet grass on the physicochemical and biochemical properties of the rat liver membrane altered by chronic ethanol intoxication. Qualitative and quantitative composition of phospholipids and proteins in the membrane were determined by HPLC. Ethanol increased phospholipid levels and altered the level of integral proteins as determined by decreased phenylalanine, cysteine and lysine. Ethanol significantly enhanced changes in the surface charge density of the liver cell membranes as determined by electrophoresis. Administration of sweet grass to rats intoxicated with ethanol significantly protects lipids and proteins against oxidative modifications. Therefore, sweet grass protects against some of the deleterious membrane changes associated with ethanol exposure. PMID- 23353549 TI - Metabolic engineering for enhanced fatty acids synthesis in Saccharomyces cerevisiae. AB - Microbial production of biofuel has attracted significant attention in recent years. The fatty acids are important precursors for the production of fuels and chemicals, and its biosynthesis is initiated by the conversion of acetyl-CoA to malonyl-CoA which requires acetyl-CoA as key substrate. Herein, the yeast Saccharomyces cerevisiae was proposed to be metabolically engineered for cytosol acetyl-CoA enhancement for fatty acid synthesis. By gene disruption strategy, idh1 and idh2 genes involved in citrate turnover in tricarboxylic acid cycle (TCA cycle) were disrupted and the citrate production level was increased to 4- and 5 times in mutant yeast strains. In order to convert accumulated citrate to cytosol acetyl-CoA, a heterologous ATP-citrate lyase (ACL) was overexpressed in yeast wild type and idh1,2 disrupted strains. The wild type strain expressing acl mainly accumulated saturated fatty acids: C14:0, C16:0 and C18:0 at levels about 20%, 14% and 27%, respectively. Additionally, the idh1,2 disrupted strains expressing acl mainly accumulated unsaturated fatty acids. Specifically in Deltaidh1 strain expressing acl, 80% increase in C16:1 and 60% increase in C18:1 was detected. In Deltaidh2 strain expressing acl, 60% increase in C16:1 and 45% increase in C18:1 was detected. In Deltaidh1/2 strain expressing acl, there was 92% increase in C16:1 and 77% increase in C18:1, respectively. The increased fatty acids from our study may well be potential substrates for the production of hydrocarbon molecules as potential biofuels. PMID- 23353551 TI - Evaluations of an in-house drug resistance method for HIV-1 drug resistance using ViroSeqTM 2.0 genotyping system as a gold standard. AB - An in-house method was evaluated for its efficiency to detect the HIV-1 drug resistance mutations. This method was compared with the ViroSeqTM Genotyping System 2.0 (Celera Diagnostics, US) a gold standard. Sixty-five stored plasma samples, previously tested for HIV-1 drug resistance using the ViroSeqTM method were used to evaluate the in-house method. Out of the sixty five plasma samples, sixty were HIV-1 positive clinical samples; four samples from the Virology Quality Assessment (VQA) program and one positive control from the ViroSeqTM kit were used in this study. The sequences generated by the ViroSeqTM and an in-house method showed 99.5+/-0.5% and 99.7+/-0.4% (mean+/-SD) nucleotide and amino acid identity, respectively. Out of 214 Stanford HIVdb listed HIV-1 drug resistance mutations in the protease and reverse transcriptase regions, concordance was observed in 203 (94.9%), partial discordance in 11 (5.1%) and complete discordance was absent. The in-house primers are broadly sensitive in genotyping multiple HIV-1 group M subtypes. The amplification sensitivity of the in-house method was 1000 copies/ml. The evaluation of the in-house method provides results comparable with that of ViroSeqTM method thus, making the in-house method suitable for HIV-1 drug resistance testing in the developing countries. PMID- 23353550 TI - Loss of ascl1a prevents secretory cell differentiation within the zebrafish intestinal epithelium resulting in a loss of distal intestinal motility. AB - The vertebrate intestinal epithelium is renewed continuously from stem cells at the base of the crypt in mammals or base of the fold in fish over the life of the organism. As stem cells divide, newly formed epithelial cells make an initial choice between a secretory or enterocyte fate. This choice has previously been demonstrated to involve Notch signaling as well as Atonal and Her transcription factors in both embryogenesis and adults. Here, we demonstrate that in contrast to the atoh1 in mammals, ascl1a is responsible for formation of secretory cells in zebrafish. ascl1a-/- embryos lack all intestinal epithelial secretory cells and instead differentiate into enterocytes. ascl1a-/- embryos also fail to induce intestinal epithelial expression of deltaD suggesting that ascl1a plays a role in initiation of Notch signaling. Inhibition of Notch signaling increases the number of ascl1a and deltaD expressing intestinal epithelial cells as well as the number of developing secretory cells during two specific time periods: between 30 and 34hpf and again between 64 and 74hpf. Loss of enteroendocrine products results in loss of anterograde motility in ascl1a-/- embryos. 5HT produced by enterochromaffin cells is critical in motility and secretion within the intestine. We find that addition of exogenous 5HT to ascl1a-/- embryos at near physiological levels (measured by differential pulse voltammetry) induce anterograde motility at similar levels to wild type velocity, distance, and frequency. Removal or doubling the concentration of 5HT in WT embryos does not significantly affect anterograde motility, suggesting that the loss of additional enteroendocrine products in ascl1a-/- embryos also contributes to intestinal motility. Thus, zebrafish intestinal epithelial cells appear to have a common secretory progenitor from which all subtypes form. Loss of enteroendocrine cells reveals the critical need for enteroendocrine products in maintenance of normal intestinal motility. PMID- 23353552 TI - Liquid egg white pasteurization using a centrifugal UV irradiator. AB - Studies are limited on UV nonthermal pasteurization of liquid egg white (LEW). The objective of this study was to inactivate Escherichia coli using a UV irradiator that centrifugally formed a thin film of LEW on the inside of a rotating cylinder. The LEW was inoculated with E. coli K12 to approximately 8 log cfu/ml and was processed at the following conditions: UV intensity 1.5 to 9.0 mW/cm2; cylinder rotational speed 450 to 750 RPM, cylinder inclination angle 15 degrees to 45 degrees , and flow rate 300 to 900 ml/min, and treatment time 1.1 to 3.2s. Appropriate dilutions of the samples were pourplated with tryptic soy agar (TSA). Sublethal injury was determined using TSA+4% NaCl. The regrowth of surviving E. coli during refrigerated storage for 28 days was investigated. The electrical energy of the UV process was also determined. The results demonstrated that UV processing of LEW at a dose of 29 mJ/cm2 at 10 degrees C reduced E. coli by 5 log cfu/ml. Inactivation significantly increased with increasing UV dose and decreasing flow rate. The results at cylinder inclination angles of 30 degrees and 45 degrees were similar and were significantly better than those at 15 degrees . The cylinder rotational speed had no significant effect on inactivation. The occurrence of sublethal injury was detected. Storage of UV processed LEW at 4 degrees and 10 degrees C for 21 days further reduced the population of E. coli to approximately 1 log cfu/ml where it remained for an additional 7 days. The UV energy applied to the LEW to obtain a 5 log reduction of E. coli was 3.9 J/ml. These results suggest that LEW may be efficiently pasteurized, albeit at low flow rates, using a nonthermal UV device that centrifugally forms a thin film. PMID- 23353553 TI - Pressure inactivation of Tulane virus, a candidate surrogate for human norovirus and its potential application in food industry. AB - Human norovirus (HuNoV) is the leading causative agent for foodborne disease. Currently, studies of HuNoV usually rely on surrogates such as murine norovirus (MNV) due to the lack of a suitable cell culture system and a small animal model for HuNoV. Tulane virus (TV), a monkey calicivirus, is a cultivable enteric calicivirus that not only recognizes the same receptors as HuNoV, but is also genetically closely related to HuNoV. In this study, we determined the pH stability of TV and MNV-1, as well as the effect of high hydrostatic pressure (HHP) on inactivating both viruses in aqueous media, blueberries and oysters. We demonstrated that both TV and MNV-1 were very stable under an acidic environment. They were more resistant to pressure at an acidic environment than at neutral pH. Pressure treatment of 600 MPa for 2 min at different temperatures (4, 21 and 35 degrees C) barely caused any reduction of TV, as well as MNV-1, on un-wetted (dry) blueberries. However, both TV and MNV-1 on blueberries were successfully inactivated by a pressure of <=400 MPa when blueberries were immersed in phosphate-buffered saline during HHP. Pressure inactivation of both TV and MNV-1 in blueberries and oysters increased as sample temperature decreased in the order of 4>21>35 degrees C. TV was more sensitive to pressure than MNV-1 for the three matrices tested, culture media, blueberries and oysters. This study provides important information on the use of TV as a surrogate for HuNoV study. Results obtained from this study lay a foundation for designing effective HHP treatments for inactivation of HuNoV in high-risk foods such as berries and oysters. PMID- 23353554 TI - Salmonella prevalence and characterization in a free-range pig processing plant: tracking in trucks, lairage, slaughter line and quartering. AB - New consumer tendencies are focused on products derived from systems which allow both a high animal welfare condition and a high food safety level. However, sometimes animal welfare regulations make the adoption of adequate bio-security measures difficult, representing a barrier for animal health and food safety. Thus the aim of this study was to determine the prevalence of Salmonella at different points of the pig slaughtering process (Trucks, Lairage, Slaughter line and Quartering, TLSQ) from pigs reared in free-range systems. From eight samplings a total of 126 Salmonella isolates out of 1160 different samples were recovered (10.86%). The highest percentage of isolates was detected at the points of pre-scalding (29/80, 36.25%), trucks (13/56, 23.21%), cecal contents (17/80, 21.25%), tonsils (14/80, 17.50%), ileocecal lymph nodes (13/80, 16.25%) and lairage (9/64, 14.06%). Furthermore, eighteen isolates were obtained from different environmental samples from slaughter line and quartering plant (knives and surface of tables) (5.63%) and three isolates at the quartering plant samples (ham, shoulder and loin) (3.75%). Fourteen different serotypes were isolated: Bredeney, Rissen, Derby, Typhimurium, Montevideo, Israel, Anatum, Emek, Monophasic Salmonella Typhimurium (mST), Choleraesuis, Durban, Kentucky, London and Sandiego. S. Typhimurium phage types U311, 193, 104b and UT were identified. Moreover, mST strain was phage typed as U311. From TLSQ1, TLSQ2 and TLSQ4, different strains of S. Derby, S. Rissen and S. Bredeney serotypes were isolated from pig and environmental samples, pointing to a potential cross contamination. Molecular typing (Pulsed-Field Gel Electrophoresis, PFGE) of these strains confirmed the cross contamination. In the remaining samplings, different serotypes were obtained in each sampled point of the chain, assuming that the isolated serotypes belonged to different epidemiological origins. Our results show the isolation of different serotypes of Salmonella spp. from both pigs and environmental samples, which constitutes a great risk for the contamination of pork from free-range pigs both prior and post slaughter. These data support the intensification of the cleaning and disinfection in the pre-slaughter environment (i.e. trucks, lairage), especially when a higher workload is present, as well as the inclusion of new strategies to decrease or eliminate the risk of Salmonella spp. infection or recontamination from the environment in pork from organic or eco-friendly systems. PMID- 23353555 TI - The release of dipicolinic acid--the rate-limiting step of Bacillus endospore inactivation during the high pressure thermal sterilization process. AB - High pressure combined with elevated temperatures can produce low acid, commercially sterile and shelf-stable foods. Depending on the temperature and pressure levels applied, bacterial endospores pass through different pathways, which can lead to a pressure-induced germination or inactivation. Regardless of the pathway, Bacillus endospores first release pyridine-2,6-dicarboxylic acid (DPA), which contributes to the low amount of free water in the spore core and is consequently responsible for the spore's high resistance against wet and dry heat. This is therefore the rate-limiting step in the high pressure sterilization process. To evaluate the impact of a broad pressure, temperature and time domain on the DPA release, Bacillus subtilis spores were pressure treated between 0.1 and 900 MPa at between 30 and 80 degrees C under isothermal isobaric conditions during dwell time. DPA quantification was assessed using HPLC, and samples were taken both immediately and 2 h after the pressure treatment. To obtain a release kinetic for some pressure-temperature conditions, samples were collected between 1s and 60 min after decompression. A multiresponse kinetic model was then used to derive a model covering all kinetic data. The isorate lines modeled for the DPA release in the chosen pressure-temperature landscape enabled the determination of three distinct zones. (I) For pressures <600 MPa and temperatures >50 degrees C, a 90% DPA release was achievable in less than 5 min and no difference in the amount of DPA was found immediately 2 h after pressurization. This may indicate irreversible damage to the inner spore membrane or membrane proteins. (II) Above 600 MPa the synergism between pressure and temperature diminished, and the treatment temperature alone dominated DPA release. (III) Pressures <600 MPa and temperatures <50 degrees C resulted in a retarded release of DPA, with strong increased differences in the amount of DPA released after 2 h, which implies a pressure-induced physiological like germination with cortex degradation, which continues after pressure release. Furthermore, at 600 MPa and 40 degrees C, a linear relationship was found for the DPA release rate constants ln(k(DPA)) between 1 and 30 min. PMID- 23353556 TI - Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis. AB - The functional contribution of myofibroblasts in fibrosis is not well understood. Using a new genetic mouse model to track and isolate myofibroblasts, we performed gene expression profiling followed by biological validation to identify HE4 (encoding human epididymis protein 4, also known as WAP 4-disulfide core domain-2 or Wfdc2) as the most upregulated gene in fibrosis-associated myofibroblasts. The HE4 gene encodes for a putative serine protease inhibitor that is upregulated in human and mouse fibrotic kidneys and is elevated in the serum of patients with kidney fibrosis. HE4 suppresses the activity of multiple proteases, including serine proteases and matrix metalloproteinases, and specifically inhibits their capacity to degrade type I collagen. In particular, we identified two serine proteases, Prss35 and Prss23, as HE4 targets with functional relevance in kidney fibrosis. Administration of HE4-neutralizing antibodies accelerated collagen I degradation and inhibited fibrosis in three different mouse models of renal disease. Collectively these studies suggest that HE4 is a potential biomarker of renal fibrosis and a new therapeutic target. PMID- 23353557 TI - Therapeutic uses of prostaglandin F(2alpha) analogues in ocular disease and novel synthetic strategies. AB - The pharmacological management of glaucoma and ocular hypertension has significantly changed over the last 18 years with the introduction of PGF2alpha analogues, more specifically latanoprost (6), travoprost (8), bimatoprost (10) and tafluprost (12). Prostanoids are currently the first-line medicines among ocular antihypertensive drugs in terms of efficacy, safety, patient compliance and medical economy. Their ability to effectively reduce intraocular pressure with once-per-day dosing, ocular tolerability comparable to timolol and general lack of systemic adverse effects have made them the mainstay of pharmacological therapy for glaucoma and ocular hypertension all over the world. The present review reports a novel, convergent and highly diastereoselective method for the synthesis of PGF2alpha analogues from the structurally advanced prostaglandin phenylsulfone (5Z)-(+)-15 and new omega-chain synthons. The biochemistry, clinical efficacy and side effects of four commercially available PGF2alpha analogues, currently used as first-line agents for reducing intraocular pressure in patients with glaucoma or ocular hypertension, are also discussed. PMID- 23353558 TI - Measurement of tactile allodynia in a murine model of bacterial prostatitis. AB - Uropathogenic Escherichia coli (UPEC) are pathogens that play an important role in urinary tract infections and bacterial prostatitis. We have recently shown that UPEC have an important role in the initiation of chronic pelvic pain, a feature of Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS). Infection of the prostate by clinically relevant UPEC can initiate and establish chronic pain through mechanisms that may involve tissue damage and the initiation of mechanisms of autoimmunity. A challenge to understanding the pathogenesis of UPEC in the prostate is the relative inaccessibility of the prostate gland to manipulation. We utilized a previously described intraurethral infection method to deliver a clinical strain of UPEC into male mice thereby establishing an ascending infection of the prostate. Here, we describe our protocols for standardizing the bacterial inoculum as well as the procedure for catheterizing anesthetized male mice for instillation of bacteria. CP/CPPS is primarily characterized by the presence of tactile allodynia. Behavior testing was based on the concept of cutaneous hyperalgesia resulting from referred visceral pain. An irritable focus in visceral tissues reduces cutaneous pain thresholds allowing for an exaggerated response to normally non-painful stimuli (allodynia). Application of normal force to the skin result in abnormal responses that tend to increase with the intensity of the underlying visceral pain. We describe methodology in NOD/ShiLtJ mice that utilize von Frey fibers to quantify tactile allodynia over time in response to a single infection with UPEC bacteria. PMID- 23353559 TI - Editor's Foreword. PMID- 23353560 TI - A comparison of the aims of public policy with women's views on declining fertility rates in post-Soviet Russia. AB - The article compares an analysis of Russian federal policy documents enacted to address the decline in population size (apparent since the collapse of the former Soviet Union), with interviews of women living in two provincial capitals, Pskov and Velikiye Novgorod. The analysis indicates that the values reflected in state policy documents regarding the definition of the problem, the stated goals of family policy and the methods designated to achieve those goals are not consistent with the views and understandings of women representative of those targeted by state family policy, on the nature of the problem, the goals that they think most important to achieve, and the most effective means to accomplish them. Policies to promote greater gender equality and to provide quality secondary education are perceived to be essential pre-conditions to reverse population declines. PMID- 23353561 TI - A rural-urban comparison of client-provider interactions in patent medicine shops in South west Nigeria. AB - The increasing prominence of patent medicine vendors (PMVs) in healthcare provision makes information about how they operate of interest. This study assessed consumers' behavior and PMVs' performance in the treatment of childhood illnesses in rural and urban communities in South West Nigeria. Non-participatory observations were carried out in 163 licensed patent medicine stores in Oyo State, Nigeria. Many PMV shops (70.6% rural and 61.9% urban; p = 0.141); stocked non proprietary drugs. Clients often requested for drugs by name (75.4% urban versus 62.2% rural; p = 0.002) and PMVs mostly sold drugs as requested without questions (65.3% urban 57.8% rural; p = 0.07). Inappropriate treatment practices and invasive procedures were observed more often in urban PMVs shops (p < 0.001). PMVs functioned mostly as sales persons supplying clients' drug requests. Strategies to improve PMV treatment practices should include caregiver education to be effective. PMID- 23353562 TI - Evaluation of a social cognitive theory-based yoga intervention to reduce anxiety. AB - Yoga is often viewed as a form of alternative and complementary medicine, as it strives to achieve equilibrium between the body and mind that aids healing. Studies have shown the beneficial role of yoga in anxiety reduction. The purpose of this study was to design and evaluate a 10-week social cognitive theory based yoga intervention to reduce anxiety. The yoga intervention utilized the constructs of behavioral capability, expectations, self-efficacy for yoga from social cognitive theory, and included asanas (postures), pranayama (breathing techniques), shava asana (relaxation), and dhyana (meditation). A one-between and one-within group, quasi-experimental design was utilized for evaluation. Scales measuring expectations from yoga, self-efficacy for yoga, and Speilberger's State Trait Anxiety Inventory, were administered before and after the intervention. Repeated measures analyses of variance (ANOVA) were performed to compare pre-test and post-test scores in the two groups. Yoga as an approach shows promising results for anxiety reduction. PMID- 23353563 TI - Why actions for early treatment of febrile illnesses in children are delayed by caregivers. AB - The study explored why actions for early treatment of febrile illnesses in children are delayed by caregivers of children less than five years in five Local Government Areas (LGAs) of southwestern Nigeria using four indicators: caregivers' perception of illness, notion of causation and seriousness, belief in efficacy of selected pathway, and the decision making process. Seven types of febrile illnesses (yellow fever, typhoid fever, ordinary fever/malaria, hot body fever, rain fever, cold fever, and headache fever) were identified and yellow fever was perceived as the most severe type (60.8%). Only 24.2% correctly identified an infected mosquito bite as the cause of ordinary fever/malaria. Use of leftover drugs at home (55.6%) was the main action taken and fathers were the main decisionmakers in all cases. Empowerment of women for improved knowledge on causation, severity, and importance of prompt action for a healthy outcome is recommended. PMID- 23353564 TI - Educating staff and volunteers at a therapeutic community for homeless persons with co-morbid disorders: support for therapeutic community curriculum. AB - In Autumn 2011, 12 participants at a newly-formed therapeutic community in western Canada completed 54 hours of Therapeutic Community Curriculum (TCC). Participants completed a shortened version of the Survey of Essential Elements Questionnaire (SEEQ) before and after the training (De Leon & Melnick, 1993b). A paired sample t-test of the SEEQ items revealed a moderate-strong effect size (Cohen's d = .68) and the positive effect of 11 items, at least 1 each from the 6 conceptual domains of the SEEQ. Following training, a focus group found that participants had a better understanding of TC theory and the concepts and believed training would help them in their roles in the community. However, some volunteers felt overwhelmed by the amount of detail covered during training and both staff and volunteers suggested that the experiential exercises could be enhanced. PMID- 23353565 TI - A group case study assignment: implementation of the Baby Friendly Hospital Initiative in a U.S. community hospital setting. AB - While evidence demonstrates that hospital practices impact breastfeeding duration and exclusivity and the Baby Friendly Hospital Initiative (BFHI) is considered the gold standard for evidence-based breastfeeding care in hospitals, there remain hospital policies and practices that interfere with breastfeeding success. The U.S. Surgeon General and others have called for an improvement in the breastfeeding content in university programs. In this group case study assignment, appropriate for both undergraduate and graduate programs, students are introduced to the BFHI, and learn best management approaches as they address the case study problems at the individual, organizational, and community levels. Students develop administrative, management, and policy development skills as they design a plan to achieve Baby Friendly designation. PMID- 23353568 TI - Late-onset neutropenia (LON) after low-dose rituximab treatment in living related kidney transplantation--single-center study. AB - We have performed more than 200 ABO-incompatible and HLA-incompatible transplantations, by using low-dose rituximab (Rit) as one of the B cell depleting strategies. It has been revealed that a significant number of such patients who receive rituximab treatment develop late-onset neutropenia (LON). To obtain insights into the mechanism underlying the development of LON, we evaluated the kinetics of various cytokines involved in B-cell and granulocyte homeostases. The subjects of this study could be categorized into five groups, as follows; group 1: Rit(+)LON(+), N=22; group 2: Rit(+)LON(-), N=30; group 3: Rit( )LON(+), N=15; group 4: Rit(-)LON(-), N=53; and group5: CKD5 patients (N=10). Serum levels of the cytokines were examined pre-RTx, 6months after RTx, 12months after RTx and 1.5years after RTx. We investigated the association between the serum levels of the B cell-related cytokines and the incidence of acute rejection. Serum levels of BAFF were significantly elevated in groups 1, 2 and 3; in particular, group 1 patients showed marked elevation of the serum BAFF at 6 and 12months after RTx. No correlations were observed between the serum BAFF and the incidence of acute rejection. Transplant recipients treated with low-dose Rit and presenting with LON showed a marked elevation of the serum BAFF levels. PMID- 23353569 TI - Binding sugars: from natural lectins to synthetic receptors and engineered neolectins. AB - The large diversity and complexity of glycan structures together with their crucial role in many biological or pathological processes require the development of new high-throughput techniques for analyses. Lectins are classically used for characterising, imaging or targeting glycoconjugates and, when printed on microarrays, they are very useful tools for profiling glycomes. Development of recombinant lectins gives access to reliable and reproducible material, while engineering of new binding sites on existing scaffolds allows tuning of specificity. From the accumulated knowledge on protein-carbohydrate interactions, it is now possible to use nucleotide and peptide (bio)synthesis for producing new carbohydrate-binding molecules. Such a biomimetic approach can also be addressed by boron chemistry and supra-molecular chemistry for the design of fully artificial glycosensors. PMID- 23353570 TI - The failure of animal models of neuroprotection in acute ischemic stroke to translate to clinical efficacy. AB - The discrepancy in results regarding neuroprotective agents in animal experiments compared to clinical trials is a major problem. While many neuroprotective agents have been proven effective in a variety of animal ischemic stroke models, none have been shown to work in phase III clinical trials. This review retrospectively summarizes the neuroprotectants selected for human randomized controlled trials (RCT) and explores the reasons behind the clinical translational failure of these agents. Here, we suggest that there are many factors (model selection, anesthetic choice, physiological monitoring, model success criteria, embolus property, reperfusion damage, infarction area, therapeutic time window, drug penetration, blood concentration, gender difference, and outcome evaluation) responsible for this phenomenon. Ultra-early treatment using a "home run" drug and multi-target therapy may be the most promising for future consideration. PMID- 23353572 TI - Lifelong companions: RNA helicases and their roles in RNA metabolism. AB - The life of an RNA molecule is complicated. Once a newly synthesized eukaryotic RNA has emerged from the RNA polymerase in the nucleus, it will be processed, spliced, and exported into cytoplasm. In prokaryotes, transcribed RNA is synthesized directly in the cytoplasm. RNA molecules that serve as mRNAs have to be kept devoid of local structures that are inhibitory for ribosome scanning and translation. Quite differently, structural and catalytic RNAs have to adopt a defined three-dimensional conformation to exert their biological function, and may assemble with other protein and/or RNA partners into complex functional units. Ultimately, RNA degradation by the so-called degradosome will end the RNA's life. PMID- 23353573 TI - DEAD box RNA helicase functions in cancer. AB - Members of the DEAD box family of RNA helicases are known to be involved in most cellular processes that require manipulation of RNA structure and, in many cases, exhibit other functions in addition to their established ATP-dependent RNA helicase activities. They thus play critical roles in cellular metabolism and in many cases have been implicated in cellular proliferation and/or neoplastic transformation. These proteins generally act as components of multi-protein complexes; therefore their precise role is likely to be influenced by their interacting partners and to be highly context-dependent. This may also provide an explanation for the sometimes conflicting reports suggesting that DEAD box proteins have both pro- and anti-proliferative roles in cancer. PMID- 23353571 TI - Helicase-mediated changes in RNA structure at the single-molecule level. AB - RNA helicases are a diverse group of RNA-dependent ATPases known to play a large number of biological roles inside the cell, such as RNA unwinding, remodeling, export and degradation. Understanding how helicases mediate changes in RNA structure is therefore of fundamental interest. The advent of single-molecule spectroscopic techniques has unveiled with unprecedented detail the interplay of RNA helicases with their substrates. In this review, we describe the characterization of helicase-RNA interactions by single-molecule approaches. State-of-the-art techniques are presented, followed by a discussion of recent advancements in this exciting field. PMID- 23353574 TI - Large-scale screening identifies a novel microRNA, miR-15a-3p, which induces apoptosis in human cancer cell lines. AB - MicroRNAs (miRNAs) have been found to be involved in cancer initiation, progression and metastasis and, as such, have been suggested as tools for cancer detection and therapy. In this work, a large-scale screening of the complete miRNA mimics library demonstrated that hsa-miR-15a-3p had a pro-apoptotic role in the following human cancer cells: HeLa, AsPc-1, MDA-MB-231, KB3, ME180, HCT-116 and A549. MiR-15a-3p is a novel member of the pro-apoptotic miRNA cluster, miR 15a/16, which was found to activate Caspase-3/7 and to cause viability loss in B/CMBA.Ov cells during preliminary screening. Subsequent microarrays and bioinformatics analyses identified the following four anti-apoptotic genes: bcl2l1, naip5, fgfr2 and mybl2 as possible targets for the mmu-miR-15a-3p in B/CMBA.Ov cells. Follow-up studies confirmed the pro-apoptotic role of hsa-miR 15a-3p in human cells by its ability to activate Caspase-3/7, to reduce cell viability and to inhibit the expression of bcl2l1 (bcl-xL) in HeLa and AsPc-1 cells. MiR-15-3p was also found to reduce viability in HEK293, MDA-MB-231, KB3, ME180, HCT-116 and A549 cell lines and, therefore, may be considered for apoptosis modulating therapies in cancers associated with high Bcl-xL expression (cervical, pancreatic, breast, lung and colorectal carcinomas). The capability of hsa-miR-15a-3p to induce apoptosis in these carcinomas may be dependent on the levels of Bcl-xL expression. The use of endogenous inhibitors of bcl-xL and other anti-apoptotic genes such as hsa-miR-15a-3p may provide improved options for apoptosis-modulating therapies in cancer treatment compared with the use of artificial antisense oligonucleotides. PMID- 23353575 TI - A high-throughput screen to identify enhancers of ADAR-mediated RNA-editing. AB - Adenosine to inosine deamination of RNA is widespread in metazoa. Inosines are recognized as guanosines and, therefore, this RNA-editing can influence the coding potential, localization and stability of RNAs. Therefore, RNA editing contributes to the diversification of the transcriptome in a flexible manner. The editing reaction is performed by adenosine deaminases that act on RNA (ADARs), which are essential for normal life and development in many organisms. Changes in editing levels are observed during development but also in neurological pathologies like schizophrenia, depression or tumors. Frequently, changes in editing levels are not reflected by changes in ADAR levels suggesting a regulation of enzyme activity. Until now, only a few factors are known that influence the activity of ADARs. Here we present a two-stage in vivo editing screen aimed to isolate enhancers of editing. A primary, high-throughput yeast screen is combined with a more accurate secondary screen in mammalian cells that uses a fluorescent read-out to detect minor differences in RNA-editing. The screen was successfully employed to identify DSS1/SHFM1, the RNA binding protein hnRNP A2/B1 and a 3' UTR as enhancers of editing. By varying intracellular DSS1/SHFM1 levels, we can modulate A to I editing by up to 30%. Proteomic analysis indicates an interaction of DSS1/SHFM1 and hnRNP A2/B1 suggesting that both factors may act by altering the cellular RNP landscape. An extension of this screen to cDNAs from different tissues or developmental stages may prove useful for the identification of additional enhancers of RNA-editing. PMID- 23353576 TI - Vimentin interacts with the 5'-untranslated region of mouse mu opioid receptor (MOR) and is required for post-transcriptional regulation. AB - The opioid receptors are among the most highly studied members of the superfamily of G-protein coupled receptors. Morphine and endogenous mu opioid peptides exert their pharmacological actions mainly through the mu opioid receptor (MOR). Expression of opioid receptor proteins is controlled by extensive transcriptional and post-transcriptional processing. Previously, the 5'-untranslated region (UTR) of the mouse MOR was found to be important for post-transcriptional regulation of the MOR gene in neuronal cells. Here, we demonstrate for the first time the role of vimentin as a post-transcriptional repressor in MOR gene regulation. To identify potential regulators of the mouse MOR gene, we performed affinity column chromatography using 5'-UTR-specific RNA oligonucleotides using neuroblastoma NS20Y cells. Chromatography was followed by two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. We identified an intermediate filament protein, vimentin, which bound specifically to the region between -175 and -150 (175-150) of the MOR 5'-UTR. Binding was confirmed by western blot analysis and RNA supershift assay. Furthermore, a cotransfection study demonstrated that the presence of vimentin resulted in reduced expression of the mouse MOR. Our data suggest that vimentin functions as a repressor of MOR translation, dependent on 175-150 of the MOR 5'-UTR. PMID- 23353579 TI - Hyperarousal, sleep scheduling, and time awake in bed as mediators of outcome in computerized cognitive-behavioral therapy (cCBT) for insomnia. AB - This study investigated the relationship between hyperarousal, sleep scheduling, and time awake in bed in a secondary data analysis. Participants were 89 adults with chronic insomnia previously involved in a randomized controlled trial of 5 weeks of computerized cognitive behavioral therapy (cCBT). At measurement periods, participants completed the Pre-Sleep Arousal Scale, 7 days of sleep diaries, and the Insomnia Severity Index. Measures were re-administered at a 4 week follow-up. Results showed that improvements in hyperarousal and time awake in bed partially mediated the impact of cCBT on sleep at follow-up but that improvements in sleep schedule consistency did not. Of these mediators, pre-sleep arousal is more significant in explaining change associated with cCBT for insomnia. PMID- 23353577 TI - CrcZ and CrcX regulate carbon source utilization in Pseudomonas syringae pathovar tomato strain DC3000. AB - Small non-coding RNAs (ncRNAs) are important components of many regulatory pathways in bacteria and play key roles in regulating factors important for virulence. Carbon catabolite repression control is modulated by small RNAs (crcZ or crcZ and crcY) in Pseudomonas aeruginosa and Pseudomonas putida. In this study, we demonstrate that expression of crcZ and crcX (formerly designated psr1 and psr2, respectively) is dependent upon RpoN together with the two-component system CbrAB, and is influenced by the carbon source present in the medium in the model plant pathogen Pseudomonas syringae pv tomato DC3000. The distribution of the members of the Crc ncRNA family was also determined by screening available genomic sequences of the Pseudomonads. Interestingly, variable numbers of the Crc family members exist in Pseudomonas genomes. The ncRNAs are comprised of three main subfamilies, named CrcZ, CrcX and CrcY. Most importantly the CrcX subfamily appears to be unique to all P. syringae strains sequenced to date. PMID- 23353580 TI - In situ-ATR-FTIR analysis on the uptake and release of streptomycin from polyelectrolyte complex layers. AB - In-situ ATR-FTIR spectroscopy and line shape analysis of the diagnostic spectral region was used to quantify the bound amount and release of the antibiotic streptomycin (STRP) at polyelectrolyte (PEL) multilayers (PEM) of poly(ethyleneimine) (PEI) and poly(acrylic acid) (PAA) or PEI and sodium alginate (ALG). Unlike common concepts based on the drug enrichment of the release medium, this analytical concept allowed to measure quantitatively the drug depletion in the delivery matrix. The measured kinetic in situ ATR-FTIR data were analysed by a modified Korsmeyer-Peppas equation based on two characteristic release parameters k and n. As main experimental parameters the number of PEL layers (adsorption steps) z and the STRP/PEL ratio were varied. For z=8 the STRP/PEL ratio showed the most significant influence on release kinetics, whereby for STRP/PEL=1:25 slowest (n=0.77) and lowest (k=21.4%) and for STRP/PEL=1:5 most rapid (n=0.30) and highest (k=58.6%) drug releases were found. PEM-PEI/ALG-8 (STRP/PEL=1:5) revealed slower release rates (n=0.58) and lower released STRP amounts (k=17.1%) compared to PEI/PAA. UV-VIS data on time dependent STRP enrichment of the release medium showed a similar trend compared to respective ATR-FTIR data on STRP depletion in PEM. Released amounts of around 1-2mg from the herein introduced PEM films could be determined. The introduced analytical concept will be used as screening tool for other drugs, drug eluting films and bone substituting materials. PMID- 23353578 TI - Changes in higher order structures of chromatin by RNP complexes. AB - More than four decades ago, it was shown that RNA stably associates with chromatin. These studies indicated that chromatin-associated RNAs (caRNA) might be involved in the organization of chromatin structure. However, it is only recently that pools of chromatin-associated RNAs were characterized and functional studies were initiated. In Drosophila cells, an RNP complex consisting of snoRNAs and Decondensation factor 31 (Df31) is stably tethered to chromatin, mediated by the RNA- and histone-binding activities of Df31. Biochemical and functional characterizations suggest a structural role of this complex in chromatin organization. The binding of the Df31-snoRNA complex to chromatin results in the opening and the maintenance of accessible higher order structures of chromatin. We suggest that different classes of chromatin-associated RNPs are required for the targeted opening of higher order structures of chromatin, enabling the activation of DNA-dependent processes such as transcription. PMID- 23353581 TI - Investigation of the influence of molecular topology on ligand binding. AB - Molecular topology class has previously been put forward as a new concept of describing compound quality and it has been shown that compared to general bioactive compounds, drugs is more similar to natural products and human metabolites in terms of molecular topology class distribution, in which they are enriched with compounds having only one ring system. To further understand how the molecular topology is influencing the drug discovery process, we have investigated the compound potency of different molecular topologies in published chemical patents. Our study shows that the potency for compounds having one ring system is higher compared to compounds that have more than one ring system. Compounds with one ring system are significantly less lipophilic and smaller compared to compounds with several ring systems. Further the influence of the molecular topology on ligand efficiency (LE), ligand lipophilic efficiency (LLE) and ligand-efficiency-dependent lipophilicity (LELP) was also analyzed and it was found that on average compounds with fewer ring systems and in particular compounds with only one ring system show consistently better LE, LLE and LELP. The results suggest that compounds with fewer ring systems and in particular compounds with only one ring system have good properties and that they might be useful starting point for drug discovery projects. PMID- 23353582 TI - In silico identification of novel inhibitors against Plasmodium falciparum dihydroorate dehydrogenase. AB - Plasmodium falciparum causes the most fatal form of malaria and accounts for over 1 million deaths annually, yet currently used drug therapies are compromised by resistance. The malaria parasite cannot salvage pyrimidines and relies on de novo biosynthesis for survival. The enzyme dihydrooratate dehydrogenase (DHODH), a mitochondrial flavoenzyme, catalyzes the rate-limiting step of this pathway and is therefore an attractive anti-malarial chemotherapeutic target. In an effort to design new and potential anti-malarials, structure-based pharmacophore mapping, molecular docking, binding energy calculations and binding affinity predictions were employed in a virtual screening strategy to design new and potent P. falciparum dihydrooratate dehydrogenase (PfDHODH) inhibitors. A structure-based pharmacophore model was generated which consist of important interactions as observed in co-crystal of PfDHODH enzyme. The developed model was used to retrieve molecules from ChemBridge database, a freely available commercial database. A total of 87 molecules mapped on the modeled pharmacophore from the database. The retrieved hits were further screened by docking simulation, binding energy calculations and biding affinity predictions using genetic optimization for ligand docking (GOLD) and MOE. Based on these results, finally 26 chemo-types molecules were predicted as new, potential and structurally diverse PfDHODH inhibitors. PMID- 23353583 TI - Toward rational design of organic dye sensitized solar cells (DSSCs): an application to the TA-St-CA dye. AB - A computer aided rational design has been performed on TA-St-CA dye sensitizer in order to improve the desirable properties for new organic dye sensitized solar cell (DSSC). A number of electron-donating (ED) and electron-withdrawing (EW) units based on Dewar's rules are substituted into the pi-conjugated oligo phenylenevinylene bridge of the reference TA-St-CA dye. The effects of these alternations on the molecular structures and the electron absorption spectra are calculated using time-dependant density functional theory (TDDFT). It is found that chemical modifications using electron donating (ED) substitutions exhibit advantages over the electron withdrawing (EW) substitutes to reduce the HOMO-LUMO energy gap as well as the electron distribution of the frontier orbitals of the new dyes. Dewar's rule is a useful guideline for rational design of new dye sensitizers with desired HOMO-LUMO gap. The impact on the optical spectra of new dyes are, however, less significant. PMID- 23353584 TI - Assessment of new anti-HER2 ligands using combined docking, QM/MM scoring and MD simulation. AB - In the development of new anti-cancer drugs to tackle the problem of resistance to current chemotherapeutic agents, a new series of anti-HER2 (human epidermal growth factor receptors 2) agents has been synthesized and investigated using different computational methods. Although non-selective, the most active inhibitor in the new series shows higher activity toward HER2 than EGFR. The induced fit docking protocol (IFD) is performed to find possible binding poses of the new inhibitors in the active site of the HER2 receptor. Molecular dynamic simulations of the inhibitor-protein complexes for the two most active compounds from the new series are carried out. Simulations stability is checked using different stability parameters. Different scoring functions are employed. PMID- 23353585 TI - ViewMotions Rainbow: a new method to illustrate molecular motions in proteins. AB - The biological functions of many enzymes are often coupled with significant conformational changes. The end states of these conformational changes can often be determined by X-ray crystallography. These X-ray structures are snapshots of the two extreme conformations in which the macromolecule exists, but the dynamic movements between the states are not easily visualized in a two-dimensional illustration. Here we have developed a new method to visualize macromolecular motions called a ViewMotions Rainbow diagram. These diagrams show the initial and final states overlaid along with approximately 30 intermediate structures calculated by linear interpolation of the backbone coordinates of the initial and final states. This group of structures is then spectrally colored from the initial structure in blue to the final structure in red. ViewMotions Rainbow diagrams provide the reader with a much easier way to understand the macromolecular motions using a single two-dimensional illustration. Since producing these diagrams requires a number of different software packages, we have setup the ViewMotions Web Server (http://viewmotions.bc.edu) to automatically generate these diagrams from two Protein Data Bank files or from the Database of Macromolecular Movements (http://molmovdb.org). PMID- 23353586 TI - Identification of potential bivalent inhibitors from natural compounds for acetylcholinesterase through in silico screening using multiple pharmacophores. AB - The symptomatic cure observed in the treatment of Alzheimer's disease (AD) by FDA approved drugs could possibly be due to their specificity against the active site of acetylcholinesterase (AChE) and not by targeting its pathogenicity. The AD pathogenicity involved in AChE protein is mainly due to amyloid beta peptide aggregation, which is triggered specifically by peripheral anionic site (PAS) of AChE. In the present study, a workflow has been developed for the identification and prioritization of potential compounds that could interact not only with the catalytic site but also with the PAS of AChE. To elucidate the essential structural elements of such inhibitors, pharmacophore models were constructed using PHASE, based on a set of fifteen best known AChE inhibitors. All these models on validation were further restricted to the best seven. These were transferred to PHASE database screening platform for screening 89,425 molecules deposited at the "ZINC natural product database". Novel lead molecules retrieved were subsequently subjected to molecular docking and ADME profiling. A set of 12 compounds were identified with high pharmacophore fit values and good predicted biological activity scores. These compounds not only showed higher affinity for catalytic residues, but also for Trp86 and Trp286, which are important, at PAS of AChE. The knowledge gained from this study, could lead to the discovery of potential AChE inhibitors that are highly specific for AD treatment as they are bivalent lead molecules endowed with dual binding ability for both catalytic site and PAS of AChE. PMID- 23353587 TI - Increase of riboflavin biosynthesis underlies enhancement of extracellular electron transfer of Shewanella in alkaline microbial fuel cells. AB - Electrolyte pH tremendously affects the electricity output of microbial fuel cells. However, its underlying molecular mechanism remains elusive, in particular for Shewanella oneidensis MR-1, one of the most widely adopted electrogenic microorganisms. Herein, we found that MFCs were able to deliver a significant (but different) electricity output in a wide range of pH (from 6 to 10), with the maximum at pH=9 (alkaline), which delivers ~1.5times' higher power output than that at pH=7 (neutral). Furthermore, cyclic voltammetry analysis showed an enhanced electrochemical activity of riboflavin (responsible for extracellular electron transfer of Shewanella) at alkaline pH. Strikingly, the concentration of riboflavin synthesized by Shewanella in MFCs at different pH showed a good correlation with the electricity output of MFCs. Thus, our results substantiated that the increase of riboflavin biosynthesis by Shewanella at the alkaline condition underlies the improvement of the electricity output in MFCs. PMID- 23353588 TI - Kinetic study of pentosan solubility during heating and reacting processes of steam treatment of green bamboo. AB - Green bamboo was hydrolyzed over a range of durations at different temperatures. A simple pseudo-homogeneous irreversible first order kinetic model was developed to describe pentosan solubility during steam treatment of green bamboo. To avoid the influence of soluble pentosan during heating process, kinetic parameters were effectively dissolved based on the data in the reacting process. Moreover, the pentosan solubility during heating process was also well modeled by numerical algorithm method. According to the origin of H factor, a modified parameter called steam treatment factor (f(P)) was proposed in this paper based on the determined kinetic constants. Finally, residual pentosan in whole process could be predicted properly based on the f(P) and the introducing of potential hydrolysis degree (h(d)). After using f(P) to combine reaction temperature and time into a single factor, comparative result showed that steam treatment is more effective for removing pentosan compared with hot water extraction. PMID- 23353589 TI - Epidural anesthesia followed by epidural analgesia produces less inflammatory response than spinal anesthesia followed by intravenous morphine analgesia in patients with total knee arthroplasty. AB - BACKGROUND: Anesthesia and inflammatory response have been studied in major abdominal and thoracic surgical procedures, but not in major orthopaedic reconstructive procedures such as total knee arthroplasty. Most studies have compared general anesthesia with epidural anesthesia, but none has compared epidural with spinal. MATERIAL/METHODS: In a prospective randomized study, 2 groups of patients scheduled for total knee arthroplasty for osteoarthritis were evaluated regarding the inflammatory response to 2 types of regional anesthesia. In 30 patients (Group A) with spinal anesthesia followed by intravenous morphine analgesia, and in 26 patients (Group B) with epidural anesthesia followed by epidural analgesia, the inflammatory response was assessed through the calculation of leucocyte concentration (WBC), C-reactive protein (CRP), monocyte chemotactic protein 1 (MCP-1), interleukins (IL-1, IL-6, IL-10, IL-18), TNF-a, and leucocyte activation molecules CD11b and CD62l, in 3 blood samples (immediately before induction to anesthesia, immediately after closure of the operative wound, and at 24 hours post-operatively). RESULTS: The MCP-1 values showed a statistically significant increase (p<0.02) in the group of patients with spinal anesthesia. Of the leucocyte activation molecules, a high statistically significant increase was noticed in the expression of CD11b on monocytes in the sample taken 24 hours post-operatively in the patients of group A. Similarly, CD62l expression on neutrophils showed a high statistically significant reduction in the sample taken 24 hours post-operatively in the group of patients with spinal anesthesia compared to the group of patients with epidural anesthesia. CONCLUSIONS: Our results show that epidural anesthesia followed by epidural analgesia produced less inflammatory response compared with spinal anesthesia followed by intravenous morphine analgesia in patients operated on with total knee arthroplasty, and that the most sensitive markers of those investigated were the CD11b and CD62l leucocyte activation molecules. PMID- 23353590 TI - beta-Caryophyllene causes regression of endometrial implants in a rat model of endometriosis without affecting fertility. AB - Many studies have shown that anti-inflammatory agents are effective in the treatment of endometriosis. beta-Caryophyllene exerted a potent anti-inflammatory effect in vivo. However, its effect on endometriosis has not been investigated. This study aims at investigating the effect of beta-caryophyllene on endometriosis and on fertility and reproduction in adult female rats. Autologous fragments of the endometrium were implantated in the peritoneal cavity in adult female rats. The growth of the endometriotic implants that developed after four weeks was recorded. Treatment started then with beta-caryophyllene (10 mg/kg or 30 mg/kg) or vehicle (control) for 21 days and the growth of the endometriotic implants was measured again. In fertility studies, female rats that received beta caryophyllene or vehicle were mated and reproductive functions were observed including number and viability of implants, number of corpora lutea, length of pregnancy and outcome of litter. beta-Caryophyllene (10 mg/kg) suppressed the growth of endometriotic implants by 52.5% compared with controls. Also beta caryophyllene produced apoptosis in luminal epithelim of the cyst as well as in endothelial cells of blood vessels. Ultrstructural studies revealed the presence of active mast cells and eosinophils in both control and beta-caryophyllene treated rat cysts. No statistically significant difference was observed in any studied parameter between control and beta-caryophyllene-treated groups in fertility study. Therapy with beta-caryophyllene may present a promising novel, non-toxic therapeutic option for patients with endometriosis. PMID- 23353591 TI - A novel compound DSC suppresses lipopolysaccharide-induced inflammatory responses by inhibition of Akt/NF-kappaB signalling in macrophages. AB - A novel compound [4-(2-acetoxy-3-((R)-3-(benzylthio)-1-methoxy-1-oxopropan-2 ylamino)-3-oxopropyl)-1,2-phenylene diacetate (DSC)], derived from Danshensu, exerted cytoprotective effects by anti-oxidative and anti-apoptotic activities in vitro. Herein, we reported the protective effects of DSC on lipopolysaccharide (LPS)-induced inflammatory responses in murine RAW264.7 macrophages and the underlying mechanisms. We showed that DSC concentration-dependently attenuated nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression with less cytotoxicity. Signal transduction studies indicated that DSC significantly inhibited LPS-induced phosphorylation of Akt, but not c-Jun N terminal kinase 1/2, p38, or extracellular signal-regulated kinase 1/2. Meanwhile, LPS-induced nuclear translocation of nuclear factor-kappaB (NF-kappaB) p65 was decreased by DSC. Furthermore, a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 significantly suppressed LPS-induced NF-kappaB p65 nuclear translocation, iNOS expression, and NO production, which was also mimicked by pretreatment with DSC. These results suggested that DSC attenuated LPS-induced inflammatory response in macrophages, at least in part, through suppression of PI3K/Akt signaling and NF-kappaB activation. PMID- 23353592 TI - Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro. AB - Macitentan is a new non-selective endothelin-1 receptor antagonist under development for the treatment of pulmonary arterial hypertension. Information on the potential for macitentan to influence the pharmacokinetics of concomitantly administered drugs by inhibition or induction of drug metabolising enzymes or drug transporters is sparse. We therefore studied the potential of macitentan to inhibit and induce critical targets of drug metabolism and drug distribution (transporters) in vitro. Induction was quantified at the mRNA level by real-time RT-PCR in LS180 cells and revealed that macitentan significantly induced mRNA expression of cytochrome P450 3A4 (CYP3A4), P-glycoprotein (P-gp, ABCB1), solute carrier of organic anions 1B1 (SLCO1B1), and uridinediphosphate glucuronosyltransferase 1A3 (UGT1A9). By means of a reporter gene assay our study establishes macitentan as a potent activator of pregnane X receptor (PXR). Inhibition of drug transporters was evaluated by using transporter over expressing cell lines and fluorescent specific substrates of the respective transporters and revealed that macitentan is an inhibitor of P-gp, breast cancer resistance protein (BCRP), SLCO1B1, and SLCO1B3. Using commercial kits macitentan was demonstrated to be a moderate inhibitor of CYP3A4 and CYP2C19. In conclusion our data provide a comprehensive analysis of the interaction profile of macitentan with drug metabolising and transporting enzymes in vitro. Although macitentan has a similar or higher potency for induction and inhibition of drug metabolising enzymes and transporters than bosentan, its low plasma concentrations and minimal accumulation in the liver suggest that it will be markedly less prone to drug-drug interactions than bosentan. PMID- 23353593 TI - Should antihistamines be re-considered as antiasthmatic drugs as adjuvants to anti-leukotrienes? AB - In spite of histamine mimicking the symptoms of allergic bronchoconstriction and severe anaphylaxis, histamine antagonists most probably represent no effective treatment for these conditions. Anti-leukotrienes proved effective for preventing attacks of allergic asthma. In vitro evidence supports a supra-additive effect of histamine H1 receptor antagonists and anti-leukotrienes in vitro, in asthma models utilizing human bronchi. The same seems to hold true for human allergen provocation tests in vivo. We conclude that combinations of second-generation antihistamines and anti-leukotrienes deserve a large-scale clinical trial for preventing and/or treating attacks of allergic asthma. If useful, these drugs could provide a cost-effective alternative to some recent antiasthmatics. Given that redundant mechanisms may be included in asthma pathophysiology, other combinations (including thromboxane or platelet activating factor antagonists) could also be considered. PMID- 23353594 TI - Prolonged analgesic effect of amitriptyline base on thermal hyperalgesia in an animal model of neuropathic pain. AB - The best analgesic drugs for neuropathic pain have a long duration of action, can be given via multiple routes, and can be used preemptively. We evaluated the antinociceptive effects and duration of action of subcutaneously injected amitriptyline base (AMT-Base) (in oil). A plantar test in a spinal nerve ligation (SNL) model of neuropathic pain in rats showed that typical amitriptyline HCl (AMT-HCl) (in saline) and AMT-Base had a significant dose-dependent antinociceptive effect: the antinociceptive duration of a single 100 MUmol/kg injection of AMT-HCl was 5 h and of AMT-Base was 24 h when given 7 days after a SNL, and of a single 200 MUmol/kg injection of AMT-Base was 39 days when given 1 h before and 4 days when given 7 days after a SNL. The post-ligation antinociceptive duration of AMT-Base was 4.8 times that of AMT-HCl, but the duration of preemptive (pre-ligation) AMT-Base treatment was 9.7 times that of AMT-Base. We can conclude that preemptive amitriptyline base provides long lasting antinociception for neuropathic pain experimentally. PMID- 23353595 TI - Corneal endothelial regeneration and tissue engineering. AB - Human corneal endothelial cells (HCECs) have a limited proliferative capacity. Descemet stripping with automated endothelial keratoplasty (DSAEK) has become the preferred method for the treatment of corneal endothelial deficiency, but it requires a donor cornea. To overcome the shortage of donor corneas, transplantation of cultured HCEC sheets has been attempted in experimental studies. This review summarizes current knowledge about the mechanisms of corneal endothelial wound healing and about tissue engineering for the corneal endothelium. We also discuss recent work on tissue engineering for DSAEK grafts using cultured HCECs and HCEC precursor cell isolation method (the sphere-forming assay). DSAEK grafts (HCEC sheets) were constructed by seeding cultured HCECs on human amniotic membrane, thin human corneal stroma, and collagen sheets. The pump function of the HCEC sheets thus obtained was approximately 75%-95% of that for human donor corneas. HCEC sheets were transplanted onto rabbit corneas after DSAEK. While the untransplanted control group displayed severe stromal edema, the transplanted group had clear corneas throughout the observation period. The sphere-forming assay using donor human corneal endothelium or cultured HCECs can achieved mass production of human corneal endothelial precursors. These findings indicate that cultured HCECs transplanted after DSAEK can perform effective corneal dehydration in vivo and suggest the feasibility of employing the transplantation of cultured HCECs to treat endothelial dysfunction. Additionally, corneal endothelial precursors may be an effective strategy for corneal endothelial regeneration. PMID- 23353596 TI - UCP1 mRNA does not produce heat. AB - Because of the possible role of brown adipose tissue and UCP1 in metabolic regulation, even in adult humans, there is presently considerable interest in quantifying, from in-vitro data, the thermogenic capacities of brown and brite/beige adipose tissues. An important issue is therefore to establish which parameters are the most adequate for this. A particularly important issue is the relevance of UCP1 mRNA levels as estimates of the degree of recruitment and of the thermogenic capacity resulting from differences in physiological conditions and from experimental manipulations. By solely following UCP1 mRNA levels in brown adipose tissue, the conclusion would be made that the tissue's highest activation occurs after only 6h in the cold and then successively decreases to being only some 50% elevated after 1month in the cold. However, measurement of total UCP1 protein levels per depot ("mouse") reveals that the maximal thermogenic capacity estimated in this way is reached first after 1month but represents an approx. 10-fold increase in thermogenic capacity. Since this in vitro measure correlates quantitatively and temporally with the acquisition of nonshivering thermogenesis, this must be considered the most physiologically relevant parameter. Similarly, observations that cold acclimation barely increases UCP1 mRNA levels in classical brown adipose tissue but leads to a 200 fold increase in UCP1 mRNA levels in brite/beige adipose tissue depots may overemphasise the physiological significance of these depots, as the high fold increases are due to very low initial levels, and the UCP1 mRNA levels reached are at least an order of magnitude lower than in brown adipose tissue; furthermore, based on total UCP1 protein amounts, the brite/beige depots attain only about 10% of the thermogenic capacity of the classical brown adipose tissue depots. Consequently, inadequate conclusions may be reached if UCP1 mRNA levels are used as a proxy for the metabolic significance of recruited versus non recruited brown adipose tissue and for estimating the metabolic significance of brown versus brite/beige adipose tissues. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease. PMID- 23353597 TI - Overexpression of PLIN5 in skeletal muscle promotes oxidative gene expression and intramyocellular lipid content without compromising insulin sensitivity. AB - AIMS/HYPOTHESIS: While lipid deposition in the skeletal muscle is considered to be involved in obesity-associated insulin resistance, neutral intramyocellular lipid (IMCL) accumulation per se does not necessarily induce insulin resistance. We previously demonstrated that overexpression of the lipid droplet coat protein perilipin 2 augments intramyocellular lipid content while improving insulin sensitivity. Another member of the perilipin family, perilipin 5 (PLIN5), is predominantly expressed in oxidative tissues like the skeletal muscle. Here we investigated the effects of PLIN5 overexpression - in comparison with the effects of PLIN2 - on skeletal muscle lipid levels, gene expression profiles and insulin sensitivity. METHODS: Gene electroporation was used to overexpress PLIN5 in tibialis anterior muscle of rats fed a high fat diet. Eight days after electroporation, insulin-mediated glucose uptake in the skeletal muscle was measured by means of a hyperinsulinemic euglycemic clamp. Electron microscopy, fluorescence microscopy and lipid extractions were performed to investigate IMCL accumulation. Gene expression profiles were obtained using microarrays. RESULTS: TAG storage and lipid droplet size increased upon PLIN5 overexpression. Despite the higher IMCL content, insulin sensitivity was not impaired and DAG and acylcarnitine levels were unaffected. In contrast to the effects of PLIN2 overexpression, microarray data analysis revealed a gene expression profile favoring FA oxidation and improved mitochondrial function. CONCLUSIONS/INTERPRETATION: Both PLIN2 and PLIN5 increase neutral IMCL content without impeding insulin-mediated glucose uptake. As opposed to the effects of PLIN2 overexpression, overexpression of PLIN5 in the skeletal muscle promoted expression of a cluster of genes under control of PPARalpha and PGC1alpha involved in FA catabolism and mitochondrial oxidation. PMID- 23353598 TI - Bone morphogenic proteins signaling in adipogenesis and energy homeostasis. AB - A great deal is known about the molecular mechanisms regulating terminal differentiation of pre-adipocytes into mature adipocytes. In contrast, the knowledge about pathways that trigger commitment of mesenchymal stem cells into the adipocyte lineage is fragmented. In recent years, the role of members of the bone morphogenic protein family in regulating the early steps of adipogenesis has been the focus of research. Findings based on these studies have also highlighted an unexpected role for some bone morphogenic protein in energy homeostasis via regulation of adipocyte development and function. This review summarizes the knowledge about bone morphogenic proteins and their role in adipocyte commitment and regulation of whole body energy homeostasis. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease. PMID- 23353599 TI - Automatic processing of political preferences in the human brain. AB - Individual political preferences as expressed, for instance, in votes or donations are fundamental to democratic societies. However, the relevance of deliberative processing for political preferences has been highly debated, putting automatic processes in the focus of attention. Based on this notion, the present study tested whether brain responses reflect participants' preferences for politicians and their associated political parties in the absence of explicit deliberation and attention. Participants were instructed to perform a demanding visual fixation task while their brain responses were measured using fMRI. Occasionally, task-irrelevant images of German politicians from two major competing parties were presented in the background while the distraction task was continued. Subsequent to scanning, participants' political preferences for these politicians and their affiliated parties were obtained. Brain responses in distinct brain areas predicted automatic political preferences at the different levels of abstraction: activation in the ventral striatum was positively correlated with preference ranks for unattended politicians, whereas participants' preferences for the affiliated political parties were reflected in activity in the insula and the cingulate cortex. Using an additional donation task, we showed that the automatic preference-related processing in the brain extended to real-world behavior that involved actual financial loss to participants. Together, these findings indicate that brain responses triggered by unattended and task-irrelevant political images reflect individual political preferences at different levels of abstraction. PMID- 23353600 TI - Cerebral microvascular network geometry changes in response to functional stimulation. AB - The cortical microvessels are organized in an intricate, hierarchical, three dimensional network. Superimposed on this anatomical complexity is the highly complicated signaling that drives the focal blood flow adjustments following a rise in the activity of surrounding neurons. The microvascular response to neuronal activation remains incompletely understood. We developed a custom two photon fluorescence microscopy acquisition and analysis to obtain 3D maps of neuronal activation-induced changes in the geometry of the microvascular network of the primary somatosensory cortex of anesthetized rats. An automated, model based tracking algorithm was employed to reconstruct the 3D microvascular topology and represent it as a graph. The changes in the geometry of this network were then tracked, over time, in the course of electrical stimulation of the contralateral forepaw. Both dilatory and constrictory responses were observed across the network. Early dilatory and late constrictory responses propagated from deeper to more superficial cortical layers while the response of the vertices that showed initial constriction followed by later dilation spread from cortical surface toward increasing cortical depths. Overall, larger caliber adjustments were observed deeper inside the cortex. This work yields the first characterization of the spatiotemporal pattern of geometric changes on the level of the cortical microvascular network as a whole and provides the basis for bottom-up modeling of the hemodynamically-weighted neuroimaging signals. PMID- 23353601 TI - A two-level multimodality imaging Bayesian network approach for classification of partial epilepsy: preliminary data. AB - BACKGROUND: Quantitative neuroimaging analyses have demonstrated gray and white matter abnormalities in group comparisons of different types of non-lesional partial epilepsy. It is unknown to what degree these type-specific patterns exist in individual patients and if they could be exploited for diagnostic purposes. In this study, a two-level multi-modality imaging Bayesian network approach is proposed that uses information about individual gray matter volume loss and white matter integrity to classify non-lesional temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) mesial-temporal sclerosis and frontal lobe epilepsy (FLE). METHODS: 25 controls, 19 TLE-MTS, 22 TLE-no and 14 FLE were studied on a 4T MRI and T1 weighted structural and DTI images acquired. Spatially normalized gray matter (GM) and fractional anisotropy (FA) abnormality maps (binary maps with voxels 1 SD below control mean) were calculated for each subject. At the first level, each group's abnormality maps were compared with those from all the other groups using Graphical-Model-based Morphometric Analysis (GAMMA). GAMMA uses a Bayesian network and a Markov random field based contextual clustering method to produce maps of voxels that provide the maximal distinction between two groups and calculates a probability distribution and a group assignment based on this information. The information was then combined in a second level Bayesian network and the probability of each subject to belong to one of the three epilepsy types calculated. RESULTS: The specificities of the two level Bayesian network to distinguish between the three patient groups were 0.87 for TLE-MTS and TLE-no and 0.86 for FLE, the corresponding sensitivities were 0.84 for TLE-MTS, 0.72 for TLE no and 0.64 for FLE. CONCLUSION: The two-level multi-modality Bayesian network approach was able to distinguish between the three epilepsy types with a reasonably high accuracy even though the majority of the images were completely normal on visual inspection. PMID- 23353602 TI - Classification of amyloid-positivity in controls: comparison of visual read and quantitative approaches. AB - An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Abeta) deposition. Use of amyloid PET for this purpose, requires a reproducible method for defining a cutoff that separates individuals with no significant Abeta deposition from those in which Abeta deposition has begun. We previously reported the iterative outlier approach (IO) for the analysis of Pittsburgh Compound-B (PiB) PET data. Developments in amyloid imaging since the initial report of IO have led us to re-examine the generalizability of this method. IO was developed using full-dynamic atrophy-corrected PiB PET data obtained from a group of control subjects with a fairly distinct separation between PiB-positive [PiB(+)] and PiB-negative [PiB(-)] subjects. METHODS: We tested the performance of IO using late-summed tissue ratio data with atrophy correction or with an automated template method without atrophy correction and tested the robustness of the method when applied to a cohort of older subjects in which separation between PiB(+) and PiB(-) subjects was not so distinct. RESULTS: The IO method did not perform consistently across analyses and performed particularly poorly when separation was less clear. We found that a sparse k-means (SKM) cluster analysis approach performed significantly better; performing more consistently across methods and subject cohorts. We also compared SKM to a consensus visual read approach and found very good correspondence. CONCLUSION: The visual read and SKM methods, applied together, may optimize the identification of early Abeta deposition. These methods have the potential to provide a standard approach to the detection of PiB-positivity that is generalizable across centers. PMID- 23353604 TI - Vitamin D status and food security in North-East Asia. AB - The functions of vitamin D are pleiotropic affecting all body organs and systems in some way. Its adequacy depends principally on sunshine for UV light to stimulate its synthesis in skin and on foods which contain it, either animal derived or obtained from fungi or mushrooms, with the UV-responsive substrates dehydrocholesterol for vitamin D-3 or ergosterol for vitamin D-2, respectively. Thus, vitamin D health is very environmentally dependent. With ecosytem degradation, whether by atmospheric pollution or food systems which do not derive UV irradiation, as with fish farming or mushroom processing, then this nutrient input into human biology may falter. Vitamin D deficiency is now common and widespread in North-East Asia as elsewhere. When discovered early in the 20th century it was linked to rickets in children and osteomalacia in adults and, for a generation or so, children were given fish, usually cod, liver oil to prevent bone disease. Now cod as a species and many edible fish are threatened. Over exposure to sun-light increases the risk of skin cancer. We may tackle this problem by vitamin D supplementation with an alternative to fish liver. But the demographic pressures of population size and ageing (when the skin is less UV responsive) make the clinical and public health decisions and strategies demanding. Vitamin D health has become indicative of food security whose usual indicator is food diversity; such diversity may allow lesser concentrations to be more effective in organ and system function, but we have little evidence to support this at present. PMID- 23353605 TI - Thailand nutrition in transition: situation and challenges of maternal and child nutrition. AB - Double burden of malnutrition (DBMN), the coexistence of under- and overnutrition in the same population, is an emerging public health concern in developing countries, including Thailand. This paper aims to review the maternal and child nutrition situation and trends as the country moved from a low-income to a middle income country, using data from large scale national surveys. Protein-energy malnutrition and micronutrient deficiencies predominantly affected mothers and children prior to the 1980s. The situation greatly improved during the 1980s- 1990s, with the implementation of multi-sectoral policies and programs focusing on poverty alleviation and primary health care. Economic development, improved access to health services and effective community-based nutrition programs contributed to these positive trends. However, the prevalence of low birth weight remained at 8- 10%, while stunting and underweight declined to about 10% by the 1990s, with small change thereafter. The prevalence of anemia among pregnant women and children decreased by half and vitamin A deficiency is no longer a public health problem. Iodine deficiency, especially during pregnancy is still a major concern. As the country progressed in terms of economic and social development, overnutrition among women and children affected all socio-economic levels. Changes in lifestyles, food access and eating patterns are observed both in urban and rural areas. Although efforts have been made to address these challenges, harmonized policy and strategic programs that address DBMN in the complex social and economic environment are urgently needed. Early life undernutrition should be considered along with measures to address obesity and chronic diseases in children. PMID- 23353603 TI - Linear transforms for Fourier data on the sphere: application to high angular resolution diffusion MRI of the brain. AB - This paper presents a novel family of linear transforms that can be applied to data collected from the surface of a 2-sphere in three-dimensional Fourier space. This family of transforms generalizes the previously-proposed Funk-Radon Transform (FRT), which was originally developed for estimating the orientations of white matter fibers in the central nervous system from diffusion magnetic resonance imaging data. The new family of transforms is characterized theoretically, and efficient numerical implementations of the transforms are presented for the case when the measured data is represented in a basis of spherical harmonics. After these general discussions, attention is focused on a particular new transform from this family that we name the Funk-Radon and Cosine Transform (FRACT). Based on theoretical arguments, it is expected that FRACT based analysis should yield significantly better orientation information (e.g., improved accuracy and higher angular resolution) than FRT-based analysis, while maintaining the strong characterizability and computational efficiency of the FRT. Simulations are used to confirm these theoretical characteristics, and the practical significance of the proposed approach is illustrated with real diffusion weighted MRI brain data. These experiments demonstrate that, in addition to having strong theoretical characteristics, the proposed approach can outperform existing state-of-the-art orientation estimation methods with respect to measures such as angular resolution and robustness to noise and modeling errors. PMID- 23353606 TI - Eating beef: cattle, methane and food production. AB - A number of prominent people have advocated eating less meat or becoming a vegetarian to reduce global warming, because cattle produce the greenhouse gas methane. This raises a number of questions including: what will happen to the grasslands that much of the world's cattle currently graze; how will alternate protein be produced, and what will the greenhouse consequences of that production be? It comes down to production systems. About 70 per cent of the world's agricultural land is grassland, and the only way to produce food from grasslands is to graze ruminants on it. If domesticated animals do not graze the grasslands, native or feral ruminants, which also produce methane, tend to move in. Feeding high quality grain to cattle is much less defensible. Replacing animal protein with plant proteins like soybeans necessitates more cropping land, water, fuel and chemicals being used. A more rational food system would raise cattle on grasslands but not feed them high quality grains. Instead more of the currently grown crop could be devoted to human consumption. PMID- 23353607 TI - Validation of a self-monitoring device for estimating 24-hour urinary salt excretion. AB - BACKGROUND: The purpose of this study was to investigate the relationship between salt intake and urinary salt excretion and to examine the validity of a self monitoring device for estimating 24-h urinary salt excretion from overnight urine samples. METHODS: Twelve young, healthy female volunteers consumed test meals from days 1 to 14 and estimated urinary salt excretion on days 2-15 by using a self-monitoring device. The salt content of the test meals was as follows: 10 g (days 1-5), 6 g (days 6-8), 13 g (days 9-11), 6 g (day 12), 13 g (day 13), and 6 g (day 14). RESULTS: The average 24-h urinary salt excretion (the ratio of urinary salt excretion to salt intake of the previous day) estimated from the overnight urine samples was as follows: 8.01+/-1.15 g (0.73+/-0.11) on days 2-6, 5.86+/-0.85 g (1.01+/-0.15) on days 7-9, 9.69+/-1.64 g (0.74+/-0.13) on days 10 12, 6.51+/-1.56 g (1.03+/-0.25) on day 13, 8.60+/-3.25 g (0.71+/-0.14) on day 14, and 6.28+/-1.31 (1.05+/-0.22) on day 15. Thus, the salt excretion/salt intake ratio was approximately 0.8 during the high-salt phase and 1.0 during the low salt phase. CONCLUSION: The estimation of 24-h urinary salt excretion from overnight urine samples by using a self-monitoring device is a reasonably valid method in this young and healthy female population for detecting daily changes in salt intake. PMID- 23353608 TI - The atherosclerotic risk profile is affected differently by fish flesh with a similar EPA and DHA content but different n-6/n-3 ratio. AB - The aim of this study was to evaluate the effect of consuming gilthead sea bream fillets, with different n-6/ n-3 ratios, on atherosclerotic biomarkers. Twenty healthy subjects were included in a randomised single-blinded cross-over trial. Participants were randomized into 2 groups, both of which received approximately 630 g per week of gilthead sea bream fed with either 100% fishmeal (FM) or partial replacement with plant proteins (PP) over two consecutive 10 week periods, respectively. Group A consumed firstly the FM fillets followed by the PP fillets, whereas the reverse order was adopted for group B. Group A reported a significant decrease of 29.3% (Delta = -26 mg/dL) in total cholesterol after the first phase of the intervention, before returning to baseline levels after the dietary intervention with fish fed with PP. Similarly, in group A, both LDL cholesterol and triglycerides decreased significantly by 21.6% (Delta = -19 mg/dL) and 11.7% (Delta = -10.7 mg/dL), respectively, before increasing again after the intervention. Improvements in the inflammatory cytokines, interleukin-6 and -8 were also noted. Moreover, whole blood viscosity appeared significantly improved in group A, as seen by a significant increase of 7.59% (Delta = +4.59 mPA) for erythrocyte filtration rate. In conclusion, similar EPA+DHA content with different n- 6/n-3 ratio fish flesh intake was shown to have varied affects on lipid, inflammatory and haemorheological parameters in a group of healthy subjects. PMID- 23353609 TI - Iodized salt supplementation and its effects on thyroid status amongst Orang Asli in Hulu Selangor, Malaysia. AB - BACKGROUND: This research was performed to determine the prevalence of iodine deficiency disorder (IDD) and the effects of iodized salt supplementation on thyroid status amongst Orang Asli in Hulu Selangor, Malaysia. METHODS: Study respondents were from three target groups, i.e. pre-school children (PSC), primary school-going children (SGC) and adult women. Each household was supplied with iodized salt fortified with iodate fortificant for a period of 12 months and the iodine levels in the salt ranged from 20 to 30 MUg/L. Samples collected before and after 6 and 12 months of introduction to iodized salt were urine from all groups, as well as serum samples from adult women. RESULTS: A total of 200 respondents were recruited; 58 (29.0%) PSC, 65 (32.5%) SGC and 77 (38.5%) adult women. The median urine-iodine concentration (mUIC) in all groups were of moderately low before the iodized salt intervention, but increased significantly in all study groups after 6 and 12 months of intervention. However, at the end of the study, there was an increase in severe iodine deficiency (mUIC <20 MUg/L) from 7.5% to 12% and about 9% of PSC and SGC respondents had mUIC level of more than 300 MUg/L while the adult women showed a significant increase in free triiodothyronine (fT3) levels. CONCLUSION: The study demonstrated that iodized salt supplementation was able to show an improvement in iodine level amongst Orang Asli. However, an increase in severe iodine deficiency and iodine excess indicated that the iodized salt programme needs to be carefully monitored. PMID- 23353610 TI - Oral carbohydrate loading with 18% carbohydrate beverage alleviates insulin resistance. AB - Preoperative 12.6% oral carbohydrate loading is an element of the Enhanced Recovery After Surgery (ERAS) protocol aimed at alleviating postoperative insulin resistance; however, in Japan, beverages with 18% carbohydrate content are generally used for preoperative carbohydrate loading. We investigated the effect of 18% carbohydrate loading on alleviating insulin resistance. Six healthy volunteers participated in this crossover-randomized study and were segregated into 2 groups: volunteers in the carbohydrate-loading group (group A) who fasted from after 9 pm and ingested 375 mL of a beverage containing 18% carbohydrate (ArginaidWaterTM; Nestle, Tokyo, Japan) between 9 pm and 12 pm, and 250 mL of the same liquid at 6:30 am. Volunteers in control group (group B) drank only water. At 8:30 am, a hyperinsulinemic normoglycemic clamp was initiated. Glucose infusion rate (GIR) and levels of ketone bodies and cytokines (IL-1beta, IL-6, and TNF-alpha) before clamping were evaluated. p<0.05 was considered statistically significant. Levels of blood glucose, insulin, and cytokines at the start of the clamp were similar in both the groups. The GIR in group A was significantly higher than that in group B (11.5+/-2.4 vs 6.2+/-2.2 mg/kg/min, p=0.005), while blood ketone body levels were significantly lower in group A (22+/-4 vs 124+/-119 MUmol/L, p=0.04). Preoperative 18% carbohydrate loading could prevent the decrease in insulin sensitivity and suppress catabolism in healthy volunteers. Thus, carbohydrate loading with a beverage with 18% carbohydrate content might contribute to improvements in perioperative management. PMID- 23353611 TI - A multicentre assessment of malnutrition, nutritional risk, and application of nutritional support among hospitalized patients in Guangzhou hospitals. AB - BACKGROUND: To assess nutritional status, the prevalence of nutritional risk, and nutritional support in hospitalized patients in Guangzhou, to determine gender or age associated differences in the prevalence of nutritional risk. METHODS: A total of 2550 patients admitted during April to December 2008 from six departments (Gastroenterology, Pulmonology, Neurology, Nephrology, General Surgery and Thoracic Surgery) of four teaching hospitals were screened using the Nutritional Risk Screening 2002 tool. RESULTS: Overall prevalence of undernutrition and nutritional risk was 17.8% and 41.5%, respectively. The department of Pulmonology had the highest prevalence of undernutrition (28.2%) and nutritional risk (55.9%). The prevalence of nutritional risk was significantly higher in patients >=70 years of age than patients <70 years (64.2% vs 32.6%, p<0.001). No gender difference in the prevalence of nutritional risk was observed in general. In total, 47.6% of "at risk" and 19.4% of "not at risk" patients received nutritional support. Parenteral nutrition accounted for 88.8% of the nutritional support. CONCLUSIONS: The present study documented the prevalence of nutritional risk defined by NRS2002 and inappropriate assignment of nutritional interventions in Guangzhou hospitals. PMID- 23353613 TI - Regional percent fat and bone mineral density in Korean adolescents: the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV-3), 2009. AB - The effects of total and regional (trunk, arm, and leg) percent fat on total and regional (arm, leg, rib, thoracic spine, lumbar spine, proximal femur, and pelvis) bone mineral density (BMD) in Korean adolescents were examined using the Fourth Korea National Health and Nutrition Examination Survey, 2009. Percent fat and BMD were measured by dual energy X-ray absorptiometry in a population-based sample of 710 Korean adolescents (365 boys and 345 girls), aged 10-19 years. After adjusting for age, height, weight, serum vitamin D, dietary calcium intake, and menarche for girls in complex sampling linear regression analysis, higher total and regional percent fat were associated with low total BMD and BMD in all regions in boys aged 13-16 years, while the associations were inconsistent for early and late adolescent boys. In girls, the inverse associations were more consistent for those aged 17-19 years than for younger girls. While most of total and regional percent fat were negatively associated with BMD of thoracic and lumbar spine and femur in boys, most of these relationships were not significant in girls. The negative association with total BMD was consistent for trunk percent fat but variable for arm and leg percent fat according to age subgroup and gender. In conclusion, the unfavorable effect of regional percent fat on all regional BMD is more consistent in boys aged 13-16 years and in girls aged 17-19 years, while the relationship appears to be gender and age subgroup-specific. PMID- 23353612 TI - Serum and dietary antioxidant status is associated with lower prevalence of the metabolic syndrome in a study in Shanghai, China. AB - OBJECTIVE: The aim of our study was to examine the association between the metabolic syndrome (MS) and serum antioxidant status. METHODS: A cross-sectional study was conducted with 221 cases and 329 controls aged 18 to 65 years. Weight, height, body mass index, waist circumference, blood pressure, fasting blood glucose and lipids, as well as serum superoxide dismutase, glutathione peroxidase, malondialdehide, vitamins A, E, beta-carotene and lycopene were examined. Intakes of antioxidants were also estimated. RESULTS: Mean serum superoxide dismutase activity, beta-carotene concentrations were significantly lower, malondialdehide was higher (p<0.05) in persons with the MS (after adjusting for age, sex) than those without. Superoxide dismutase, glutathione peroxidase, and beta- carotene also decreased significantly (p<0.05) with increased number of components of the MS. Low levels of serum superoxide dismutase activity and beta-carotene concentration appeared to be associated with the MS status. Moreover, dietary energy, carbohydrate, vitamin C, zinc and copper intake in the MS patients were lower, but fat intake were higher. Vitamins E, C and manganese intake decreased with the elevated number of the MS components. For zinc and manganese, a lower risk was observed for other quartile of intake compared with the first one. Inverse links between dietary fat, energy intake and serum antioxidant status were found in MS patients, meanwhile dietary vitamin C was positively related with serum antioxidant level. CONCLUSIONS: Serum antioxidant status was associated with a lower prevalence of the MS, and with lower dietary fat, energy intake and higher vitamin C intake. PMID- 23353614 TI - The association of weight status with cognitive impairment in the elderly population of a Shanghai suburb. AB - OBJECTIVE: A population-based survey was conducted to analyze the association of under-weight, blood pressure, glucose and lipid metabolism with cognitive impairment in people, 60 years and over, living in 2 towns of Shanghai. METHODS: Face-to-face interviews were carried out to collect relevant information with questionnaires. Anthropometric indices of height, weight, waist circumference (WC) and hip circumference were measured. Multivariable logistic regression analyses were performed to evaluate the association of weight status with cognitive impairment. RESULTS: Cognitive impairment were diagnosed in 198 (7.0%) of the 2 809 participants. Compared to the normal BMI category, the under-weight category was significantly associated with the risk of cognitive impairment (OR= 2.47, 95%CI: 1.46-5.23). Subjects with a high WC were 1.5 times (OR= 1.42, 95%CI: 1.10-2.67) more likely and subjects with a high WHR were 1.7 times (OR= 1.68, 95%CI: 1.05-2.84) more likely to be associated with cognitive impairment than the subjects in the reference group. This study demonstrates a significant interaction between hypertension, lipid disorder and WC or WHR on the risk of cognitive impairment in a rural population in Shanghai. CONCLUSIONS: Central obesity was significantly associated with the risk of cognitive impairment. A low BMI may be a risk factor for cognitive impairment. A significant interaction between hypertension, lipid disorder and WC or WHR on the risk of cognitive impairment in Shanghai rural population was found. PMID- 23353615 TI - Prevalence of inappropriate dietary supplement use among pregnant women in Japan. AB - We investigated the characteristics of dietary supplements and their use by 1,076 Japanese pregnant women, the majority of whom were in mid- to late pregnancy. The subjects completed a self-reported survey on their sociodemographic characteristics, supplement use, and attitudes towards diet. The overall prevalence of supplement use did not change before and after pregnancy (75%); however, daily use increased by approximately twofold with pregnancy (20.2% versus 37.2%). After the onset of pregnancy, supplements containing folic acid were taken for fetal health. Daily users were more likely to be older, have a greater awareness of the risk of neural tube defects (NTD), view supplement use as acceptable, have less diet anxiety, and have more advisers regarding diet. Respondents used supplements containing folic acid alone or with other ingredients. Folic acid intake is recommended to reduce the risk of NTD. However, supplement use began after pregnancy recognition, suggesting a lack of knowledge on the appropriate timing of folic acid use. Information about supplements was obtained mostly from newspapers, magazines, flyers, and stores. These results indicate that more accurate information regarding the optimal timing of folic acid intake and the safety of dietary supplements must be disseminated. PMID- 23353616 TI - Low body weight gain, low white blood cell count and high serum ferritin as markers of poor nutrition and increased risk for preterm delivery. AB - This study determined factors of preterm delivery in Taiwan. Healthy women (n=520, age 29.1+/-4.2 y) at 8-12 weeks of pregnancy were recruited from prenatal clinics. Background information, anthropometrics, biochemical parameters, and dietary intake, collected by 24 h-recall were obtained from the first, second, and third trimesters to delivery. Clinical outcomes of neonates were also collected. The results show that 53.7% of women were primiparous and that the incidence of preterm delivery was 6.2%. Body weight gains in the first trimester and throughout pregnancy were significantly lower in mothers with preterm delivery (preterm group) than in mothers with term delivery (term group, p<0.05). Maternal cholesterol intake, circulating white blood cell counts (WBC) and serum albumin were significantly lower and that serum magnesium and ferritin were significantly higher in the preterm group than in the term group. Maternal weight gain was positively correlated with caloric and nutrient intake (p<0.05). Neonatal birth weight was positively correlated with maternal weight gain and intakes of protein and phosphate during pregnancy; with intakes of calories, vitamin B-1 and B-2 in the first trimester; and with intakes of calcium, magnesium, iron and zinc, as well as circulating WBC in the third trimester. However, neonatal birth weight was negatively correlated with serum iron in the third trimester and with serum iron and ferritin at the time of delivery. In conclusion, maternal weight gain in early pregnancy and WBC, mineral intake and iron status in late pregnancy seem to be major factors affecting delivery and neonatal outcomes. PMID- 23353617 TI - The nutritional status of young children and feeding practices two years after the Wenchuan Earthquake in the worst-affected areas in China. AB - This study was carried out to investigate the nutritional status and feeding practices of young children in the worst-affected areas of China two years after the Wenchuan Earthquake. The sample consisted of 1,254 children 6-23 months of age living in four selected counties from the disaster-affected provinces of Sichuan, Shaanxi and Gansu. Length-for-age, weight-for-age, weight-for-length, and hemoglobin concentration were used to evaluate nutritional status. Interviews with selected children's caretakers collected basic demographic information, children's medical history, and child feeding practices. Stunting, underweight, and wasting prevalence rates in children 6-23 months of age were 10.8%, 4.9% and 2.8% respectively, and anemia prevalence was 52.2%. Only 12.3% of children had initiated breastfeeding within the first hour after birth. Overall, 90.9% of children had ever been breastfed, and 87% children 6-8 months of age had received solid, semi-solid or soft foods the day before the interview. The diets of 45% of children 6-23 months of age met the definition of minimum dietary diversity, and the diets of 39% of breastfed and 7.6% non- breastfed children 6-23 months of age met the criteria for minimum meal frequency. The results highlight that a substantial proportion of young children in the earthquake affected disaster areas continue to have various forms of malnutrition, with an especially high prevalence of anemia, and that most feeding practices are suboptimal. Further efforts should be made to enhance the nutritional status of these children. As part of this intervention, it may be necessary to improve child feeding practices. PMID- 23353618 TI - Associations between uterine fibroids and lifestyles including diet, physical activity and stress: a case-control study in China. AB - This study was conducted to investigate the associations between uterine fibroids and lifestyles including diet, physical activity and stress from October 2009 to April 2011 in China. This case-control study composed of 73 women with uterine fibroids and 210 women without fibroids. Uterine fibroid cases were confirmed by ultrasound diagnosis or hysterectomy surgery. Information on women's dietary habits, physical activity and stress status were collected with a validated self administered questionnaire. A logistic regression model was used to estimate the odds ratios (OR) after controlling for age, gravidity and parity. We found that vegetable and fruit intakes and occupational intensity played positive effects on uterine fibroids. For premenopausal women, vegetable and fruit intakes (OR = 0.5; 95% CI: 0.3, 0.9) and occupational intensity (OR = 0.2; 95% CI: 0.1, 0.6) significantly decreased the risk of fibroids; conversely, BMI significantly increased the risk (OR = 1.2; 95% CI: 1.0, 1.4). However, the associations for postmenopausal women were not significant. Our findings suggested protective roles for vegetable and fruit intakes and occupational intensity on uterine fibroids, and supported the hypothesis that high BMI only increased the risk of uterine fibroids in premenopausal women. PMID- 23353619 TI - Isoflavone consumption and risk of breast cancer: a dose-response meta-analysis of observational studies. AB - Epidemiologic studies that examine whether isoflavone consumption protects against breast cancer have yielded inconsistent results. The controversy focuses on the effects of the menopausal status and exposure dose of isoflavone. We aim to conduct a meta-analysis on the association between isoflavone intake and breast cancer risk by comprehensively assessing isoflavone exposure in the targeted populations. We searched PUBMED and EMBASE databases for case-control and cohort studies that assess the association between isoflavone intake and breast cancer risk. We extracted relative risks (RR) and odds ratios (OR) of different reported categories of isoflavone intake from each study. Fixed- or random-effects models were used to summarize dose-response data. Twenty-two studies were selected for the meta-analysis. Overall, the results showed that isoflavone reduced the breast cancer risk (a combined RR/OR of 0.68, 95% CI: 0.52 0.89) in Asian populations rather than Western populations (a combined RR/OR of 0.98, 95% CI: 0.87, 1.11) for the high-dose category. Further analysis showed that the intake of isoflavone in postmenopausal Asian women 0.46 (95% CI: 0.28 0.78) was better than premenopausal 0.63 (95% CI: 0.50-0.80) but similar in postmenopausal Western women 1.00 (95% CI: 0.98-1.02) and premenopausal 0.99 (95% CI: 0.87-1.12). Exposure to high isoflavone may be associated with a reduced breast cancer risk in Asian populations, especially in postmenopausal women. However, no significant difference in the studies of Western populations may be due to the low intake of isoflavone levels. PMID- 23353620 TI - The association of tea consumption with bladder cancer risk: a meta-analysis. AB - The association between tea consumption and bladder cancer has been confirmed in several animal studies, but one epidemiological study in 2001 showed no association between them. In order to provide an accurate assessment of this, we conducted a meta-analysis on tea consumption and bladder cancer risk. Studies were identified by a literature search in PubMed from January 1980 to March 2012 and the reference lists of relevant studies. Random effect models were used to calculate summary relative risk estimates (RR) and their corresponding 95% confidence intervals (CI) based on high contrast to low intake values. Twenty four publications (6 cohort studies and 18 case-control studies) based on consumption of overall tea, black tea, and green tea to bladder cancer risk were included in this analysis. For overall tea, the summary RR indicated no association between tea consumption and bladder cancer (RR= 1.09, 95%CI: 0.85 1.40). In subgroup analyses, we found a moderate increase of bladder cancer risk in smoking group (RR= 1.77, 95%CI: 1.04-3.01). In the black tea group, no statistically significant association was observed (RR= 0.84, 95%CI: 0.70-1.01). Interestingly, in the subgroup of sex, a protective effect was observed between tea consumption and bladder cancer risk in female (RR= 0.61, 95%CI: 0.38- 0.98). For green tea group, there was no relationship associated with bladder cancer risk (RR= 1.03, 95%CI: 0.82- 1.31). In conclusion, our data suggest that high overall tea intake in smokers increased the risk of bladder cancer, and high black tea intake in female may reduce the risk of bladder cancer. PMID- 23353621 TI - Changes in the sodium content of Australian ready meals between 2008 and 2011. AB - Australians consume substantially more sodium than recommended. Three quarters of dietary sodium derives from processed food and the growing ready meal category is a significant contributor. This study examined changes in sodium levels of Australian ready meal products between 2008 and 2011. Sodium data were systematically collected from all product labels in the same 5 stores each year. Mean sodium levels were calculated overall and compared between ready meal types, and by major brands. The levels of sodium in new, discontinued and established products were also compared. There were 107 ready meal products in 2008, 313 in 2009, 219 in 2010 and 265 in 2011. Overall mean sodium content was unchanged between 2008 and 2011 (279 vs 277 mg/100g). There were clear differences between sodium levels of different brands (222 vs 310 mg/100g in McCain Healthy Choice and McCain products respectively) and marked variation in similar products (240 mg/100g in one brand of frozen cottage pie product vs 425mg/100g in another). The mean sodium content of recently introduced products was lower than discontinued products (289 vs 309 mg/100g), with the sodium level of established products remaining stable. The absence of any overall reduction in sodium levels of Australian ready meal products is discouraging. The failure of voluntary industry efforts to reduce the saltiness of these foods suggests a regulated approach will be required to drive product reformulation. PMID- 23353622 TI - Nutrition education in Japanese medical schools: a follow-up survey. AB - A questionnaire survey was used to determine the status of nutrition education in Japanese medical schools in 2009. A similar survey was conducted in 2004, at which time nutritional education was determined to be inadequate in Japanese medical schools. The current questionnaire was sent to the directors of Centers for Medical Education of 80 medical schools, who represented all medical schools in Japan. Sixty-seven medical schools (83.8%) responded, of which 25 schools (37.3%) offered dedicated nutrition courses and 36 schools (53.7%) did not offer dedicated nutrition courses but offered something related to nutrition in other courses; six schools (9.0%) did not offer any nutrition education. Overall, 61 schools (91.0%) offered at least some nutritional topics in their undergraduate education. Nevertheless, only 11 schools (16.4%) seem to dedicate more than 5 hours to substantial nutrition education as judged by their syllabi. Although the mean length of the course was 11 hours, substantial nutrition education accounted for only 4.2 hours. Of the 25 medical schools that offered dedicated nutrition courses, seven schools offered the nutrition course as a stand-alone course and 18 schools offered it as an integrated course. In conclusion, the status of nutrition education in Japan has improved slightly but is still inadequate. PMID- 23353624 TI - Associations between serum bone-specific alkaline phosphatase activity, biochemical parameters, and functional polymorphisms of the tissue-nonspecific alkaline phosphatase gene in a Japanese population. AB - INTRODUCTION: We had demonstrated that single nucleotide polymorphism (787T>C) in the tissue-nonspecific ALP (TNSALP) gene was associated with the bone mineral density (BMD). BMD was the lowest among TNSALP 787T homozygotes (TT-type) and highest among TNSALP 787T>C homozygotes (CC-type) in postmenopausal women. In the present study, we investigated the effects of the TNSALP genotype on associations among serum bonespecific alkaline phosphatase (BAP), serum calcium, and phosphorus in healthy young Japanese subjects. METHODS: Young healthy adult subjects (n=193) were genotyped for the polymorphism, and we measured the levels of serum BAP, serum calcium, and phosphorus. Dietary nutrient intakes were calculated based on 3-day food records before the day of blood examinations. RESULTS: Grouped by the TNSALP genotype, a significant negative correlation between serum BAP and phosphorus was observed in 787T>C homozygotes (CC-type), but not in heterozygotes (TCtype), nor in 787T homozygotes (TT-type). CONCLUSIONS: In the present study, we revealed that the single nucleotide polymorphism 787T>C in the TNSALP gene had effects on the correlation between serum BAP and phosphorus in young adult subjects. These results suggest that variation in TNSALP may be an important determinant of phosphate metabolism. Our data may be useful for planning strategies to prevent osteoporosis. PMID- 23353623 TI - Insulin receptor substrate 1 (IRS1) variants confer risk of diabetes in the Boston Puerto Rican Health Study. AB - OBJECTIVE: Published data concerning associations between IRS1 variants and type 2 diabetes and related traits have been inconsistent. We examined the relationship between common variants in IRS1, type 2 diabetes, and related traits including insulin resistance, hyperglycemia and DNA damage in the Boston Puerto Rican Health Study. METHODS: We genotyped six common IRS1 variants in an adult Puerto Rican population (n=1132) and tested for association with risk of type 2 diabetes and related traits. RESULTS: SNPs rs934167 and rs1801123 showed significant association with fasting glucose concentrations (p = 0.005 and p = 0.016, respectively) and rs934167 showed significant association with plasma insulin levels (p = 0.005). Carriers of the rs934167 minor allele had significantly higher HOMA-IR and lower QUICKI (p = 0.001 and p = 0.001, respectively), and a 40% and 58% greater likelihood of being hyperglycaemic or hyperinsulinemic (OR = 1.40 and 1.58; p = 0.013 and 0.002, respectively). However, they exhibited only a marginally significant trend towards having type 2 diabetes (OR=1.27, p = 0.077). Furthermore, carriers of the haplotype C-T of the rs934167 and rs1801123 minor alleles showed consistent patterns of associations after correction for multiple testing. In addition, the G972R (rs1801278) minor allele was significantly associated with higher urinary 8-OHdG concentrations (p = 0.020) and plasma CRP levels (p = 0.035). CONCLUSIONS: Our results support IRS1 variants associated with type 2 diabetes risk in adult Puerto Ricans. Moreover, we report the novel finding that IRS1 variant G972R (rs1801278) may contribute to oxidative DNA damage and inflammation. PMID- 23353625 TI - Vitamin D in North-East Asian clinical nutrition practice. AB - Sound clinical nutrition practice is grounded in evidence and stimulated by research. Yet, there are unanswered questions about food-health relationships. Clinical nutrition involves the identification of nutritional disorders and the motivation to rectify them with all required care. Vitamin D health exemplifies the biomedical, societal and environmental dimensions of clinical nutrition, its science and practice. It depends most of all on access to sunshine and food and probably represents a paradigm in human health which is still at its beginning. Nevertheless, the problem of its deficiency is much more widespread and common than has been thought since it was first identified as a cause of rickets and osteomalacia. It is now known to spare no body organ or system. The problem in North-East Asia is comparable to much of the rest of the world, but the risk profile for it is exaggerated by atmospheric pollution, cultures with sun avoidance on account of skin colour and potentially mitigated by foodstuffs like fish, eggs, organ meats and mushrooms which can partially offset sunshine deficiency. Diagnosis requires a high index of suspicion and confirmation by biochemistry which may not be affordable. Therefore a close working relationship between public health and clinical nutritionist is essential. PMID- 23353627 TI - Non-invasive determination of the complete elastic moduli of spider silks. AB - Spider silks possess nature's most exceptional mechanical properties, with unrivalled extensibility and high tensile strength. Unfortunately, our understanding of silks is limited because the complete elastic response has never been measured-leaving a stark lack of essential fundamental information. Using non-invasive, non-destructive Brillouin light scattering, we obtain the entire stiffness tensors (revealing negative Poisson's ratios), refractive indices, and longitudinal and transverse sound velocities for major and minor ampullate spider silks: Argiope aurantia, Latrodectus hesperus, Nephila clavipes, Peucetia viridans. These results completely quantify the linear elastic response for all possible deformation modes, information unobtainable with traditional stress strain tests. For completeness, we apply the principles of Brillouin imaging to spatially map the elastic stiffnesses on a spider web without deforming or disrupting the web in a non-invasive, non-contact measurement, finding variation among discrete fibres, junctions and glue spots. Finally, we provide the stiffness changes that occur with supercontraction. PMID- 23353626 TI - MRI-detectable pH nanosensors incorporated into hydrogels for in vivo sensing of transplanted-cell viability. AB - Biocompatible nanomaterials and hydrogels have become an important tool for improving cell-based therapies by promoting cell survival and protecting cell transplants from immune rejection. Although their potential benefit has been widely evaluated, at present it is not possible to determine, in vivo, if and how long cells remain viable following their administration without the use of a reporter gene. Here, we report a pH-nanosensor-based magnetic resonance imaging (MRI) technique that can monitor cell death in vivo non-invasively. We demonstrate that specific MRI parameters that change on cell death of microencapsulated hepatocytes are associated with the measured bioluminescence imaging radiance. Moreover, the readout from this pH-sensitive nanosensor can be directly co-registered with high-resolution anatomical images. All of the components of these nanosensors are clinical grade and hence this approach should be a translatable and universal modification of hydrogels. PMID- 23353628 TI - Polymer multilayer tattooing for enhanced DNA vaccination. AB - DNA vaccines have many potential benefits but have failed to generate robust immune responses in humans. Recently, methods such as in vivo electroporation have demonstrated improved performance, but an optimal strategy for safe, reproducible, and pain-free DNA vaccination remains elusive. Here we report an approach for rapid implantation of vaccine-loaded polymer films carrying DNA, immune-stimulatory RNA, and biodegradable polycations into the immune-cell-rich epidermis, using microneedles coated with releasable polyelectrolyte multilayers. Films transferred into the skin following brief microneedle application promoted local transfection and controlled the persistence of DNA and adjuvants in the skin from days to weeks, with kinetics determined by the film composition. These 'multilayer tattoo' DNA vaccines induced immune responses against a model HIV antigen comparable to electroporation in mice, enhanced memory T-cell generation, and elicited 140-fold higher gene expression in non-human primate skin than intradermal DNA injection, indicating the potential of this strategy for enhancing DNA vaccination. PMID- 23353629 TI - Ultrafast spin transport as key to femtosecond demagnetization. AB - Irradiating a ferromagnet with a femtosecond laser pulse is known to induce an ultrafast demagnetization within a few hundred femtoseconds. Here we demonstrate that direct laser irradiation is in fact not essential for ultrafast demagnetization, and that electron cascades caused by hot electron currents accomplish it very efficiently. We optically excite a Au/Ni layered structure in which the 30 nm Au capping layer absorbs the incident laser pump pulse and subsequently use the X-ray magnetic circular dichroism technique to probe the femtosecond demagnetization of the adjacent 15 nm Ni layer. A demagnetization effect corresponding to the scenario in which the laser directly excites the Ni film is observed, but with a slight temporal delay. We explain this unexpected observation by means of the demagnetizing effect of a superdiffusive current of non-equilibrium, non-spin-polarized electrons generated in the Au layer. PMID- 23353630 TI - Nanostructured high-strength molybdenum alloys with unprecedented tensile ductility. AB - The high-temperature stability and mechanical properties of refractory molybdenum alloys are highly desirable for a wide range of critical applications. However, a long-standing problem for these alloys is that they suffer from low ductility and limited formability. Here we report a nanostructuring strategy that achieves Mo alloys with yield strength over 800 MPa and tensile elongation as large as ~ 40% at room temperature. The processing route involves a molecular-level liquid liquid mixing/doping technique that leads to an optimal microstructure of submicrometre grains with nanometric oxide particles uniformly distributed in the grain interior. Our approach can be readily adapted to large-scale industrial production of ductile Mo alloys that can be extensively processed and shaped at low temperatures. The architecture engineered into such multicomponent alloys offers a general pathway for manufacturing dispersion-strengthened materials with both high strength and ductility. PMID- 23353631 TI - Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in hypertensive patients treated with thiazide diuretics. AB - OBJECTIVE: Single-nucleotide polymorphisms (SNPs) in NEDD4L may influence the ability of the NEDD4L protein to reduce epithelial sodium channel expression. A variant in NEDD4L, rs4149601, was associated with antihypertensive response and cardiovascular outcomes during treatment with thiazide diuretics and beta blockers in a Swedish population. We sought to further evaluate associations between NEDD4L polymorphisms, blood pressure response and cardiovascular outcomes with thiazide diuretics and beta-blockers. METHODS: Four SNPs, rs4149601, rs292449, rs1008899 and rs75982813, were genotyped in 767 patients from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) clinical trial and association was assessed with blood pressure response to hydrochlorothiazide and atenolol. One SNP, rs4149601, was also genotyped in 1345 patients from the International Verapmil SR Trandolapril Study (INVEST), and association was examined with adverse cardiovascular outcomes relative to hydrochlorothiazide treatment. RESULTS: Significant associations or trends were found between rs4149601, rs292449, rs75982813 and rs1008899 and decreases in blood pressure in whites on hydrochlorothiazide, and a significant association was observed with increasing copies of the GC rs4149601-rs292449 haplotype and greater blood pressure response to hydrochlorothiazide in whites (P = 0.0006 and 0.006, SBP and DBP, respectively). Significant associations were also seen with rs4149601 and an increased risk for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide [P = 0.022, odds ratio (95% confidence interval) = 10.65 (1.18-96.25)]. CONCLUSION: NEDD4L rs4149601, rs292449 and rs75982813 may be predictors for blood pressure response to hydrochlorothiazide in whites, and NEDD4L rs4149601 may be a predictor for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide. PMID- 23353632 TI - Take the (RN)A-train: localization of mRNA to the endoplasmic reticulum. AB - Protein translocation into the endoplasmic reticulum (ER) generally requires targeting of mRNAs encoding secreted or membrane proteins to the ER membrane. The prevalent view is that these mRNAs are delivered co-translationally, using the signal recognition particle (SRP) pathway. Here, SRP delivers signal sequence containing proteins together with associated ribosomes and mRNA to the SRP receptor present on the ER surface. Recent studies demonstrate the presence of alternative pathways to recruit mRNAs to ER or to specific subdomains of the ER independent of SRP or translation. Such targeting of specific mRNAs to the ER subdomains allows the cell to sort proteins before translocation or to ensure co localization of ER and mRNAs at specific locations. Translation-independent association of mRNAs involves ER-linked RNA-binding proteins and represents an alternative pathway of mRNA delivery to the ER. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum. PMID- 23353633 TI - Movement retraining using real-time feedback of performance. AB - Any modification of movement - especially movement patterns that have been honed over a number of years - requires re-organization of the neuromuscular patterns responsible for governing the movement performance. This motor learning can be enhanced through a number of methods that are utilized in research and clinical settings alike. In general, verbal feedback of performance in real-time or knowledge of results following movement is commonly used clinically as a preliminary means of instilling motor learning. Depending on patient preference and learning style, visual feedback (e.g. through use of a mirror or different types of video) or proprioceptive guidance utilizing therapist touch, are used to supplement verbal instructions from the therapist. Indeed, a combination of these forms of feedback is commonplace in the clinical setting to facilitate motor learning and optimize outcomes. Laboratory-based, quantitative motion analysis has been a mainstay in research settings to provide accurate and objective analysis of a variety of movements in healthy and injured populations. While the actual mechanisms of capturing the movements may differ, all current motion analysis systems rely on the ability to track the movement of body segments and joints and to use established equations of motion to quantify key movement patterns. Due to limitations in acquisition and processing speed, analysis and description of the movements has traditionally occurred offline after completion of a given testing session. This paper will highlight a new supplement to standard motion analysis techniques that relies on the near instantaneous assessment and quantification of movement patterns and the display of specific movement characteristics to the patient during a movement analysis session. As a result, this novel technique can provide a new method of feedback delivery that has advantages over currently used feedback methods. PMID- 23353634 TI - Insights into the isomerization of xylose to xylulose and lyxose by a Lewis acid catalyst. AB - We present electronic structure calculations on the isomerization and epimerization of xylose to xylulose and lyxose, respectively, by a zeolite Sn-BEA model at the MP2 and B3LYP theory levels. Benchmarking calculations at the CCSD(T) theory level are also presented. We show that lyxose is formed from a stable intermediate in the xylose-xylulose isomerization pathway. In agreement with experimental observations, we predict that xylulose is thermodynamically and kinetically favoured over lyxose. We find that the slowest step for both reactions involves hydrogen transfer from the C2 to the C1 carbon of the carbohydrate molecule and we characterize it using natural population analysis. We conclude that the hydrogen transfer does not take place as a hydride ion but rather as concerted neutral hydrogen-electron transfer that involves different centres for the hydrogen and electron transfer. PMID- 23353635 TI - Preparation and structural characterization of cDHAP-cyclic form of dihydroxyacetone phosphate-revealing chair and skew conformations of 1,3,2 dioxaphosphorinane ring. AB - A cyclic form of dihydroxyacetone phosphate, cDHAP, was obtained by the acidic hydrolysis of its dimethyl acetal (MeO)(2)cDHAP, and was crystallized in the hydrate, cDHAP-H (gem-diol; 1,3,2-dioxaphosphinane-2,5,5-triol 2-oxide) and the ketone, cDHAP-K (2-hydroxy-1,3,2-dioxaphosphinan-5-one 2-oxide) forms. The synthesis, MS and NMR analyses, crystallization and solid state structures determined by X-ray crystallography are described. The equilibrium state between the hydrate and ketone was established, revealing ~86% of cDHAP-H in aqueous solution at room temperature. The striking structural feature of the ketone and hydrate forms of the same cyclic phosphate diester in the crystalline state is different conformations of the six-membered P/O/C/C/C/O 1,3,2-dioxaphosphorinane ring, namely chair (C) in cDHAP-H.H2O (9a-H) and skew (S) in cDHAP-K (9a-K). Apart from one previous report on the non-chair-puckered, disordered [(MeO)2cDHAP]- anion in the crystal of its ammonium salt (Slepokura, K. Carbohydr. Res. 2008, 343, 113-131), this is the unique example of the cyclic phosphate diester in skew conformation. Both 9a-H and 9a-K crystallize with the phosphate group protonated, which has been so far rarely observed in the cyclic phosphates. Deformation of the phosphate group and flattening of the chair puckered ring in 9a-H is typical of protonated P/O/C/C/C/O rings. However, the skew-puckered 9a-K shows different values of O-P-O angles versus the same lengths of P-O(endo) and P-O(exo) bonds. PMID- 23353636 TI - The effect of subsurface military detonations on vadose zone hydraulic conductivity, contaminant transport and aquifer recharge. AB - Live fire military training involves the detonation of explosive warheads on training ranges. The purpose of this experiment is to evaluate the hydrogeological changes to the vadose zone caused by military training with high explosive ammunition. In particular, this study investigates artillery ammunition which penetrates underground prior to exploding, either by design or by defective fuze mechanisms. A 105 mm artillery round was detonated 2.6 m underground, and hydraulic conductivity measurements were taken before and after the explosion. A total of 114 hydraulic conductivity measurements were obtained within a radius of 3m from the detonation point, at four different depths and at three different time periods separated by 18months. This data was used to produce a three dimensional numerical model of the soil affected by the exploding artillery round. This model was then used to investigate potential changes to aquifer recharge and contaminant transport caused by the detonating round. The results indicate that an exploding artillery round can strongly affect the hydraulic conductivity in the vadose zone, increasing it locally by over an order of magnitude. These variations, however, appear to cause relatively small changes to both local groundwater recharge and contaminant transport. PMID- 23353637 TI - Optimization of the adult zebrafish ECG method for assessment of drug-induced QTc prolongation. AB - INTRODUCTION: Recent studies have shown the utility of adult zebrafish ECG (electrocardiogram) in assessing drug-induced QTc prolongation. While the method has significant advantages over current ECG animal models including ethical issues, low compound requirement and expense, adoption of the method into drug discovery programs has been hampered by specific limitations. The limitations include the inability to determine the exact dose of test compound administered, and potential effects due to variables such as flow rate of oral perfusion and immobilization method. We describe a refined method for the reproducible recording of the adult zebrafish ECG and illustrate its application in investigating drug-induced QTc prolongation using the histamine receptor antagonist Terfenadine as a test drug. METHOD: We chose to perform parenteral administration of test drug instead of perfusion on the basis of mg per kg body weight of adult zebrafish. Acclimatization and immobilization methods were optimized to avoid ECG artifacts due to sudden environmental changes. We further modified the formula for QT correction and ensured reproducible recording of stable ECGs. Various concentrations of Terfenadine were used and the resultant proarrhythmic effects were analyzed as compared to the baseline and untreated controls. RESULTS: Normal, stable and reproducible ECGs were recorded in all zebrafish. Terfenadine at the rate of 0.1mg/kg body weight was found to be the NOAEL. We found an excellent correlation between known QTc effects in humans and those observed in adult zebrafish at all concentrations. All Terfenadine-induced proarrhythmic effects observed in zebrafish were dose and time dependent. DISCUSSION: We report a refined method for reproducible recording of stable zebrafish ECGs to facilitate its routine application in preclinical investigation of QTc-prolonging drugs with reliable estimation of NOAEL. Our study is of relevance to the development and use of alternate animal models in drug discovery. PMID- 23353639 TI - Targeting two-pore domain potassium channels - a promising strategy for treating T cell mediated autoimmunity. AB - Two-pore domain potassium channels, such as TASK, are essential players in the regulation of the resting membrane potential. A recent publication in Experimental Neurology revealed that the pharmacological blockade of the two-pore domain potassium channel TASK1 improved clinical disease severity, the number of cellular infiltrates, as well as the degree of demyelination in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. This effect was driven by a reduction in the generation of proinflammatory cytokines and proliferation of T lymphocytes. Thus, functional activity of T lymphocytes was identified to be TASK1 dependent suggesting that this class of potassium channels may represent an interesting target for treating T cell-driven autoimmunity directed against the central nervous system. PMID- 23353638 TI - Intranasal delivery of cell-penetrating anti-NF-kappaB peptides (Tat-NBD) alleviates infection-sensitized hypoxic-ischemic brain injury. AB - Perinatal infection aggravates neonatal hypoxic-ischemic (HI) brain injury and may interfere with therapeutic hypothermia. While the NF-kappaB signaling pathway has been implicated in microglia activation in infection-sensitized HI, the current therapeutic strategies rely on systemic intervention, which could impair neonatal immunity and increase the risk of severe infection. To devise a brain targeted anti-NF-kappaB strategy, we examined the effects of intranasal delivery of tat-NBD peptides in two animal models of neonatal infection-sensitized HI. Kinetic experiments showed that tat-NBD peptides entered the olfactory bulbs rapidly (10-30 min) and peaked in the cerebral cortex around 60 min after intranasal application in P7 rats. Further, intranasal delivery of 1.4 mg/kg tat NBD, which is only 7% of the intravenous dose in past studies, markedly attenuated NF-kappaB signaling, microglia activation, and brain damage triggered by HI with 4 or 72 h pre-exposure to the bacterial endotoxin lipopolysaccharide (LPS). In contrast, intranasal delivery of mutant tat-NBD peptides or systemic application of minocycline failed to block LPS-sensitized HI injury. Yet, intranasal delivery of up to 5.6 mg/kg tat-NBD peptides immediately after pure-HI insult showed little protection, likely due to its rapid clearance from the brain and inability to inhibit parenchymal plasminogen activators. Together, these results suggest a novel therapy of infection-sensitized HI brain injury in newborns. PMID- 23353640 TI - External validation of the fatty liver index for identifying nonalcoholic fatty liver disease in a population-based study. AB - BACKGROUND & AIMS: We aimed to validate the fatty liver index (FLI), an algorithm that is based on waist circumference, body mass index, and levels of triglyceride and gamma-glutamyltransferase. We calculated its ability to identify fatty liver disease from any cause or nonalcoholic fatty liver disease (NAFLD) in a large population of white elderly persons. METHODS: We collected ultrasonography and FLI data from participants of the Rotterdam Study from February 2009 to February 2012; 2652 subjects (mean age, 76.3 +/- 6.0 years) were interviewed and received a clinical examination that included abdominal ultrasound, analysis of blood samples during fasting, and anthropometric assessment. The ability of the FLI to detect (nonalcoholic) fatty liver was assessed by using area under the receiver operator characteristic (AUROC) curve analysis. RESULTS: FLI score was associated with NAFLD in multivariable analysis (odds ratio, 1.05; 95% confidence interval [CI], 1.04-1.05; P < .001). FLI identified patients with NAFLD with an AUROC curve of 0.813 (95% CI, 0.797-0.830) and those with fatty liver from any cause with an AUROC curve of 0.807 (95% CI, 0.792-0.823). CONCLUSIONS: The FLI (an algorithm that is based on waist circumference, body mass index, and levels of triglyceride and gamma-glutamyltransferase) accurately identifies NAFLD, confirmed via ultrasonography, in a large, white, elderly population. PMID- 23353641 TI - Association between reduced levels of alkaline phosphatase and survival times of patients with primary sclerosing cholangitis. AB - BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) has not been shown to stop progression of primary sclerosing cholangitis (PSC). However, patients with primary biliary cirrhosis treated with UDCA whose levels of alkaline phosphatase (ALP) decrease have longer survival times than patients whose levels do not decrease. We compared survival times between patients with PSC treated with UDCA or placebo, with and without decreased levels of ALP. METHODS: We collected data from patients enrolled in the Scandinavian PSC UDCA trial. Patients were randomly assigned to groups given UDCA (17-23 mg/kg/day, n = 97) or placebo (n = 101) from 1996-2001 and were followed until 2010. End points were death, liver transplantation, or cholangiocarcinoma. They were considered to be biochemical responders if they had serum levels of ALP that were normal or reduced by >=40% after 1 year in the trial (regardless of whether they received UDCA or placebo). Numbers of patients surviving until the study end point were compared by using the Kaplan-Meier method. RESULTS: There were no differences in survival at the end of the study between patients given UDCA or placebo (P = .774, log-rank); 26 patients in the UDCA group and 29 in the placebo group reached an end point. On the basis of ALP levels, there were 79 responders and 116 nonresponders overall. Of patients given UDCA, significantly more biochemical responders survived for 10 years than nonresponders (P = .03, log-rank). However, differences remained significant regardless of group assignment; overall, patients with reductions in ALP level survived longer than patients without reductions in ALP (P = .0001, log rank). CONCLUSIONS: There is no significant difference in long-term survival between patients with PSC given UDCA (17-23 mg/kg/day) or placebo for 5 years. However, patients who have reduced or normal levels of ALP have longer survival times, regardless of whether they receive UDCA or placebo. PMID- 23353642 TI - 18-Fluorodeoxyglucose positron emission tomography does not aid in diagnosis of pancreatic ductal adenocarcinoma. AB - BACKGROUND & AIMS: There are no accurate and reliable tools for diagnosis of early stage pancreatic ductal adenocarcinoma (PDA) or small metastatic lesions. It is also a challenge to differentiate PDA from focal mass-forming pancreatitis (FMP). There is controversy regarding the efficacy of 18-fluorodeoxyglucose positron-emission tomography (FDG-PET) in the diagnosis of PDA. We investigated whether FDG-PET provides information that, combined with data from other imaging techniques, can aid in decision making for patients with suspected PDA. METHODS: We performed a retrospective analysis of data collected from 232 consecutive patients with suspected PDA at Kobe University Hospital from January 2006 through June 2012. All patients underwent a diagnostic imaging protocol that included multidetector row computed tomography, superparamagnetic iron oxide-enhanced magnetic resonance imaging, and FDG-PET. Based on endoscopic ultrasonography, fine-needle aspiration biopsy, or endoscopic retrograde cholangiopancreatography analyses, 218 patients had PDA (89 underwent resection and 129 did not) and 14 patients had FMP (8 had focal mass-forming chronic pancreatitis and 6 had focal mass-forming autoimmune pancreatitis). RESULTS: FDG-PET detected 50% of stages 0 and I, 91.9% of stage II, 100% of stage III, and 96.8% of stage IV tumors. Detection was affected significantly by tumor size (P = .024) and T stage (P = .023) in resected tumors. Multidetector row computed tomography detected significantly more liver metastases than FDG-PET. Few para-aortic lymph node or peritoneal metastases were detected by FDG-PET. FDG-PET correctly identified 11 of the 14 patients with FMP (5 of 8 with focal mass-forming chronic pancreatitis and 6 of 6 with focal mass-forming autoimmune pancreatitis). CONCLUSIONS: FDG-PET is not effective in detecting early stage PDA and small metastases, or in differentiating PDA from FMP. Combining FDG-PET with current diagnostic techniques for PDA did not provide any decisive information, therefore it should not be included in this analysis. PMID- 23353643 TI - Computer-assisted communication in intensive care: a useful instrument for listening to patients. PMID- 23353644 TI - Crystal structure of Dioclea violacea lectin and a comparative study of vasorelaxant properties with Dioclea rostrata lectin. AB - Lectins from Diocleinae subtribe belong to the family of legume lectins and are characterized by high identity between their amino acids sequences. It has been shown that punctual differences in amino acid sequences, such as one single amino acid or an alternative conformation, represent changes in biological activities caused by these lectins. Therefore, a more detailed understanding of three dimensional structures of these proteins is essential for accurate analyzing the relationship between structure and function. In this study lectins purified from the seeds of Dioclea violacea (DVL) and Dioclea rostrata (DRL) were compared with regard to crystal structure and vasorelaxant properties. Differences in structure of lectins were found to be reflected in differences in vasorelaxant effects based on their high specificity and selectivity for cell glycans. Binding activity was related to the position of specific residues in the carbohydrate recognition domain (CRD). DVL complexed structure was solved by X-ray crystallography and was compared to native DVL and DRL. Therefore, DVL was co crystallized with X-Man, and a molecular modeling with X-Man complexed with DVL was done to compare the complexed and native forms adjusted fit. The relatively narrow and deep CRD in DVL promotes little interaction with carbohydrates; in contrast, the wider and shallower CRD in DRL favors interaction. This seems to explain differences in the level of relaxation induced by DVL (43%) and DRL (96%) in rat aortic rings. PMID- 23353646 TI - Has the gap been bridged yet? Young people in paediatric and adult rheumatology. PMID- 23353645 TI - Acetylcholine and antibodies against the acetylcholine receptor protect neurons and astrocytes against beta-amyloid toxicity. AB - Aggregated amyloid-beta causes pathological changes in mixed cultures of neurons and astrocytes such as sporadic cytoplasmic intracellular Ca(2+)-signalling, increase in reactive oxygen species production and cell death. Some of the toxic effects of amyloid-beta are mediated through the interaction of the peptide with alpha7-type nicotinic acetylcholine receptors at the cell surface. Here we demonstrated that affinity purified antibodies to synthetic fragment 173-193 of the alpha7-subunit of the nAChR are able to protect cells from amyloid-beta induced cell death. The antibodies had no effect on the amyloid-beta induced calcium signal in astrocytes. However, they significantly reduced amyloid-beta induced and NADPH oxidase mediated ROS production. Modulation of the NADPH oxidase activity by either the antibodies, the receptor agonist acetylcholine or the antagonist of the alpha7-type nicotinic acetylcholine receptors alpha bungarotoxin was vital in inhibiting both amyloid-beta induced ROS production, caspase 3 cleavage as well as cell death. The uncovered details of the mechanism underlying the action of antibodies to alpha7-type nicotinic acetylcholine receptors gives additional insight into the involvement of this receptor in Alzheimer's disease pathology and provides a new approach to anti-Alzheimer's disease vaccine design. PMID- 23353647 TI - Role of NOD1 polymorphism in susceptibility and clinical progression of rheumatoid arthritis. AB - OBJECTIVE: One of the disease hallmarks of RA is progressive cartilage and bone destruction in the joints. The exact mechanism underlying this disease process is largely unknown. Nod1, an intracellular pattern recognition receptor expressed by the innate immune system, has been previously shown to display anti-inflammatory effects in experimental arthritis. Furthermore, an insertion/deletion polymorphism in NOD1 has been demonstrated to modulate cytokine responses of immune cells. In this study, the effect of the insertion/deletion polymorphism in NOD1 on RA susceptibility and severity was assessed. METHODS: Ex vivo stimulation of primary immune cells and osteoclasts with microbial triggers was performed to measure cytokine responses and osteoclast-specific gene expression in relation to the NOD1 genotype. In total, 1047 RA patients from two centres were genotyped for the NOD1 polymorphism and compared with 431 healthy controls. Clinical scores of joint inflammation and destruction were correlated with the NOD1 genotype. RESULTS: Functional analysis revealed increased production of pro-inflammatory cytokines in cells from individuals bearing the NOD1 +32656 insertion allele. Furthermore, osteoclast bone resorption activity was elevated, as reflected by increased expression of the lysosomal protease cathepsin K. However, the insertion allele of the NOD1 +32656 polymorphism was not associated with either susceptibility to, or clinical parameters of, inflammation or bone destruction in RA patients. CONCLUSION: These findings demonstrate that the NOD1 polymorphism modulates pro-inflammatory cytokine responses induced through Toll-like receptor or Nod-like receptor ligands. Nevertheless, these effects of genetic variation in NOD1 appear to be redundant in RA susceptibility and severity. PMID- 23353648 TI - A fatal attraction: eosinophils and the heart. PMID- 23353649 TI - Engagement promotes abstinence in a web-based cessation intervention: cohort study. AB - BACKGROUND: Web-based smoking cessation interventions can have a public health impact because they are both effective in promoting cessation and can reach large numbers of smokers in a cost-efficient manner. Their potential impact, however, has not been realized. It is still unclear how such interventions promote cessation, who benefits most, and how to improve their population impact. OBJECTIVE: To examine the effectiveness of a highly promoted Web-based smoking cessation intervention to promote quit behavior over time, identify the most effective features, and understand who is most likely to use those features by using unweighted and weighted analyses to estimate the impact in the broader pool of registered site users. METHODS: A sample of 1033 new adult registrants was recruited from a Web-based smoking cessation intervention by using an automated study management system. Abstinence was assessed by self-report through a mixed mode follow-up (online survey with telephone follow-up for nonrespondents) at 1, 3, and 6 months. Software tracked respondents' online activity. Generalized estimating equations (GEE) were used to examine predictors of website utilization and how utilization promoted abstinence using unweighted and weighted data. RESULTS: The 7-day point prevalence abstinence rates at 6 months ranged from 20.68% to 11.13% in the responder and intent-to-treat samples, respectively. Predictors of abstinence in unweighted analyses included number of visits to the website as well as accessing specific interactive or engaging features. In weighted analyses, only number of visits was predictive of abstinence. Motivation to quit was a key predictor of website utilization, whereas negative partner support decreased the likelihood of increasing visits or accessing engaging features. CONCLUSIONS: Engagement is critical to promoting smoking cessation. The next generation of Web-based smoking cessation interventions needs to maximize the initial engagement of all new visitors and work to retain those smokers who proceed to register on the site. PMID- 23353651 TI - Quercetin negatively regulates TLR4 signaling induced by lipopolysaccharide through Tollip expression. AB - Polyphenolic compounds have been regarded as one of the most promising dietary agents for the prevention and treatment of inflammation-related chronic diseases; however, the anti-inflammatory activities of flavonoids, such as quercetin, are not completely characterized, and many features remain to be elucidated. In this study, we showed the molecular basis for the downregulation of TLR4 signal transduction by quercetin. Quercetin markedly elevated the expression of the Toll interacting protein, a negative regulator of TLR signaling. Lipopolysaccharide induced expression of cell surface molecules (CD80, CD86, and MHC class I/II) and production of pro-inflammatory cytokines (tumor necrosis factor-alpha, IL-1beta, IL-6, and IL-12p70) were inhibited by quercetin, and this action was prevented by Toll-interacting protein silencing. In addition, quercetin-treated macrophages inhibited lipopolysaccharide-induced activation of mitogen-activated protein kinases, such as extracellular signal-regulated kinase 1/2, p38, and c-Jun N terminal kinase, and the translocation of nuclear factor-kappaB and p65 through Toll-interacting protein. Treatment with quercetin resulted in a significant decrease in prostaglandin E2 and cyclooxygenase-2 levels as well as inducible nitric oxide synthase-mediated nitric oxide production induced by lipopolysaccharide. Taken together, these findings represent new insights into the understanding of negative regulatory mechanisms of the TLR4 signaling pathway and effective therapeutic intervention for the treatment of inflammatory disease. PMID- 23353652 TI - Both C1B domain and pseudosubstrate region are necessary for saturated fatty acid induced translocation of epsilonPKC to the plasma membrane: distinct role of intramolecular domains for different translocation. AB - It is well known that protein kinase C (PKC) shows different translocation depending on subtype and stimulation, contributing to the physiological importance of the enzyme. However, molecular mechanism causing the different translocation has been unknown. Therefore, using GFP-tagged mutant epsilonPKC, we attempted to identify the intramolecular domains required for saturated fatty acid-induced translocation of epsilonPKC to the plasma membrane, and compared with those necessary for unsaturated fatty acid-induced translocation to the Golgi complex. We found that, unlike in the case of unsaturated fatty-acid induced translocation, both C1B domain and pseudosubstrate region are necessary for the saturated fatty acid-induced translocation of epsilonPKC to the plasma membrane. The results suggest that different domains of PKC mediate distinct translocation depending on different stimulations, contributing to their subtype- and stimulation-specific functions. PMID- 23353653 TI - State of the science: use of biomarkers and imaging in diagnosis and management of Alzheimer disease. AB - Alzheimer disease (AD) is a significant health problem with increasing costs to patients, families, and society. Historically, AD has been diagnosed clinically in living patients using patient history and cognitive testing, approaches with limited sensitivity and specificity. Definitive diagnosis becomes possible only after the patient's death, when physical evidence of the disease process is found upon autopsy. By the time signs and symptoms are sufficient for clinical diagnosis, brain pathology is often quite advanced, limiting benefits of treatment. New techniques have been developed in recent years allowing clinicians to see evidence of the AD pathophysiological process in vivo, allowing more definitive diagnosis while the patient is still alive. In vivo methods able to identify AD in its earliest stages, before the development of the cognitive impairment that allows clinical diagnosis, could enable treatment to begin before pathology is advanced. In 2011, the U.S. NIH National Institute on Aging and the Alzheimer's Association issued new diagnostic guidelines for AD allowing use of biomarker and imaging techniques in addition to clinical criteria. This article describes these new techniques and discusses how they might be used in the diagnosis and management of AD. PMID- 23353654 TI - Postictal psychosis: implications for nursing. AB - Postictal psychosis (PIP) is a serious outcome of epilepsy, which may be preventable. Once the symptoms are identified, rapid diagnosis and treatment will prevent further deterioration in the patient's condition. The nurse plays a critical role in this process. The specific presentation of PIP, along with clarification of potential causes and strategies to prevent the occurrence of this complication, will be discussed. Through a case study format and emphasis on the role of the nurse, the specifics of case finding and rapid intervention will be described. PMID- 23353655 TI - Sonhafouonic acid, a new cytotoxic and antifungal hopene-triterpenoid from Zehneria scabra camerunensis. AB - A new hopene-type triterpenoid, namely sonhafouonic acid 1a was isolated from Zehneria scabra camerunensis, together with eight known compounds. The structure of 1a was established by extensive NMR and high resolution MS techniques and confirmed by single-crystal X-ray crystallographic analysis. Compound 1a exhibited inhibitory activity against mycelial growth of two peronosporomycete phytopathogens Pythium ultimum and Aphanomyces cochliodes and cytotoxicity towards brine shrimp larvae (Artemia salina) at 10 MUg/mL. PMID- 23353650 TI - A large-scale evaluation of computational protein function prediction. AB - Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally. If computational predictions are to be relied upon, it is crucial that the accuracy of these methods be high. Here we report the results from the first large-scale community-based critical assessment of protein function annotation (CAFA) experiment. Fifty-four methods representing the state of the art for protein function prediction were evaluated on a target set of 866 proteins from 11 organisms. Two findings stand out: (i) today's best protein function prediction algorithms substantially outperform widely used first generation methods, with large gains on all types of targets; and (ii) although the top methods perform well enough to guide experiments, there is considerable need for improvement of currently available tools. PMID- 23353656 TI - Pestaloficiols Q-S from the plant endophytic fungus Pestalotiopsis fici. AB - Two new isoprenylated chromone derivatives, pestaloficiols Q (1) and R (2), and one new benzofuran derivative, pestaloficiol S (3), along with three known metabolites, anofinic acid (4), siccayne (5), and pyrenophorol (6) were isolated from solid cultures of the plant endophytic fungus Pestalotiopsis fici. Their structures were elucidated primarily by NMR spectroscopy, and the absolute of the C-6 secondary alcohol in 1 was deduced on the basis of circular dichroism (CD) data. Compound 5 showed cytotoxic activity against the human cancer cell lines, HeLa and HT29, with IC50 values of 48.2 and 33.9MUM, respectively. PMID- 23353657 TI - Labdane diterpenoids and lignans from Calocedrus macrolepis. AB - Three new labdane diterpenoids, calomacrins A-C (1-3), and a new diaryl butyrolactone-type lignan, calomacrol A (8), as well as four known labdane diterpenoids and six known lignans, were isolated from the twigs and leaves of Calocedrus macrolepis. Structures of the new compounds were elucidated on the basis of their spectroscopic methods, including 1D and 2D NMR techniques. Compounds 3-14 were evaluated for cytotoxicity against HL-60, SMMC-7721, A-549, MCF-7, and SW480 cell lines. PMID- 23353658 TI - In vitro permeability analysis, pharmacokinetic and brain distribution study in mice of imperatorin, isoimperatorin and cnidilin in Radix Angelicae Dahuricae. AB - Coumarins are important constituents of Radix Angelicae Dahuricae, a well-known traditional Chinese medicine possess several known bioactivities with potentials in the treatment of central nervous system diseases. By using an HPLC-MS/MS method, we analyzed the in vivo plasma and brain pharmacokinetics of three ingredients of coumarins, including imperatorin, isoimperatorin and cnidilin in mice after oral administration of Dahuricae extract at doses of 800mg/kg. The biosamples were prepared using acetonitrile precipitation and the separation was achieved on an XDB-C18 column by gradient elution. The BBB permeability and P-gp mediated efflux were further examined in Madin Canine kidney cells transfected with full length cDNA for human multidrug resistance gene1 (MDCKII-MDR1). Our results demonstrate that the method has excellent and satisfactory selectivity, sensitivity, linearity, precision, and accuracy for simultaneous determination of imperatorin, isoimperatorin and cnidilin. The pharmacokinetics parameters were determined by using noncompartmental analyses, including the AUC(0-t) in plasma (1695.22, 1326.45 and 636.98mg*h/L), the AUC(0-t) in brain (1812.35, 2125.17 and 1145.83ng*h/g) as well as the T1/2 in plasma (0.66, 0.82, 0.97h) and brain (0.96, 1.1, 0.99h) for imperatorin, isoimperatorin and cnidilin, respectively, suggesting that the three coumarins could easily pass through the BBB in vivo. In the in vitro model we observed high permeability of imperatorin and isoimperatorin with the P-gp-mediated efflux ratios of 0.53 and 0.06, as well as medium permeability of cnidilin with 0.82. All data suggest that these three coumarins have high BBB permeability and have pharmacokinetic potentials for the treatment of central nervous system diseases. PMID- 23353659 TI - Phenolic glycosides from Curculigo orchioides Gaertn. AB - Five new chlorophenolic glucosides, curculigine E (1), curculigine F (2), curculigine G (3), curculigine H (5), curculigine I (6) and one new phenolic glycoside, orcinoside H (4), together with eight known phenolic glycosides (7-14) were isolated from the Curculigo orchioides Gaertn. Their structures were established by spectroscopic techniques (IR, UV, MS, 1D and 2D NMR). The isolated phenolic glycosides were evaluated for antiosteoporotic activity against MC3T3-E1 cell line using MTT assays. Compounds 1, 2, 3, and 5 showed moderate antiosteoporotic activity with the proliferation rate of 10.1-14.1%. PMID- 23353660 TI - Sleep and neurocognitive functioning in children with eczema. AB - Sleep disruption in childhood is associated with clearly defined deficits in neurocognition and behaviour. Childhood eczema is also a potent cause of sleep disruption though it is unknown whether it too results in neurocognitive deficits. To test this hypothesis, neurocognitive (WISC-IV), parental-reported sleep quality (Sleep Disturbance Scale of Children (SDSC)) and overnight polysomnographic (PSG) data were collected in 21 children with eczema and 20 healthy controls (age range 6-16 years). Children with eczema had worse sleep quality on both PSG (notably increased nocturnal wakefulness, a higher number of stage shifts and a longer latency to REM onset) and parental report. In addition, they demonstrated significant neurocognitive deficits (especially verbal comprehension, perceptual reasoning and to a lesser extent working memory) with a composite Full Scale IQ 16 points lower than controls. Parental reported sleep problems but not PSG parameters were correlated with reduced neurocognitive performance. However, hierarchical regression analyses revealed that eczema status was predictive while sleep fragmentation (parental or PSG) was not predictive of neurocognitive performance. As this is the first study to systematically examine neurocognitive functioning in children with eczema and given the finding of significant deficits it merits replication especially given the prevalence of the condition. The unanswered question is whether these cognitive deficits normalise with effective eczema treatment and if this is mediated by improvements in sleep architecture. PMID- 23353661 TI - Somatosensory P2 reflects resource allocation in a game task: assessment with an irrelevant probe technique using electrical probe stimuli to shoulders. AB - The present study investigated whether event-related brain potentials (ERPs) elicited by task irrelevant somatosensory stimuli to the shoulders reflect the amount of processing resources allocated to a game task. In the experiment, electrical stimuli were presented to the right (or left) shoulder with a high probability (80%) and to the other shoulder with a low probability (20%) while participants were performing a driving simulation game. The deviant low probability stimuli elicited somatosensory P2, and this P2 amplitude decreased when the task was difficult. The results show that the ERPs for somatosensory stimuli to the shoulders can reflect the amount of resources deployed even when the stimuli are ignored. This is a useful method for the evaluation of mental workloads in complex circumstances because it does not interfere with inputs of auditory or visual information or operations using the limbs. PMID- 23353662 TI - Controllable dual protein delivery through electrospun fibrous scaffolds with different hydrophilicities. AB - Tissue engineered scaffolds should actively participate not only in structural support but also in functional tissue regeneration. Thus, novel smart biomaterial scaffolds have been developed, which incorporate a variety of bioactive molecules to accelerate neo-tissue formation. The effective delivery of multiple bioactive molecules with distinct kinetics to target sites at an appropriate concentration and in a timely manner is desired to drive tissue development to completion. To achieve effective, controllable delivery of multiple factors, a dual protein delivery system has been developed by electrospinning poly(lactide-co-glycolide) (PLGA) with different hydrophilicities. Bovine serum albumin or myoglobin was incorporated into and released gradually from these electrospun fibrous PLGA scaffolds. All the scaffolds exhibited similar loading efficiencies of approximately 80% of the target proteins. The introduction of Pluronic F-127 (PF127) dramatically increased scaffold hydrophilicity, which affected the release kinetics of these proteins from the scaffolds. Furthermore, distinct protein release patterns were achieved when using dual protein-loaded scaffolds with different hydrophilicities when these scaffolds were fabricated by co electrospinning. This system may be useful as a method for delivering multiple bioactive vehicles for tissue engineering applications. PMID- 23353664 TI - Extending access to specialist services: the impact of an onsite helipad and analysis of the first 100 flights. AB - BACKGROUND: In November 2011, University Hospital Southampton (UHS), now a major trauma centre, opened its onsite helipad, allowing patients to be brought to the emergency department (ED) directly by air ambulance. Prior to this, helicopters were required to land at a local playing field and the patient had to be transferred by land ambulance. This study aims to investigate the impact this change in practice has had on the flow of patients to the ED. METHODS: The authors completed a retrospective case analysis of the first 100 patients brought directly to UHS by helicopter. Data were obtained from ED notes and helicopter provider databases. Analysis was conducted on the type of incident and appropriateness of referral. Incident locations were plotted geographically. RESULTS: 100 patients arrived at UHS ED by helicopter between 17 November 2011 and 31 March 2012. Of these, 79 were primary helicopter emergency medical service (HEMS) missions and 21 were secondary transfers from other hospitals. Of the HEMS patients, 38 were likely to have been transported to another hospital, had there not been an onsite helipad at UHS. 29 passed another suitable receiving hospital en route and therefore may have come to UHS for speciality services. CONCLUSIONS: The provision of an onsite, 24 h helipad facility at UHS has resulted in a significant number of patients being transported to the hospital by helicopter who might otherwise have attended an alternative hospital. PMID- 23353663 TI - Association of out-of-hospital advanced airway management with outcomes after traumatic brain injury and hemorrhagic shock in the ROC hypertonic saline trial. AB - OBJECTIVE: Prior studies suggest adverse associations between out-of-hospital advanced airway management (AAM) and patient outcomes after major trauma. This secondary analysis of data from the Resuscitation Outcomes Consortium Hypertonic Saline Trial evaluated associations between out-of-hospital AAM and outcomes in patients suffering isolated severe traumatic brain injury (TBI) or haemorrhagic shock. METHODS: This multicentre study included adults with severe TBI (GCS <=8) or haemorrhagic shock (SBP <=70 mm Hg, or (SBP 71-90 mm Hg and heart rate >=108 bpm)). We compared patients receiving out-of-hospital AAM with those receiving emergency department AAM. We evaluated the associations between airway strategy and patient outcomes (28-day mortality, and 6-month poor neurologic or functional outcome) and airway strategy, adjusting for confounders. Analysis was stratified by (1) patients with isolated severe TBI and (2) patients with haemorrhagic shock with or without severe TBI. RESULTS: Of 2135 patients, we studied 1116 TBI and 528 shock; excluding 491 who died in the field, did not receive AAM or had missing data. In the shock cohort, out-of-hospital AAM was associated with increased 28-day mortality (adjusted OR 5.14; 95% CI 2.42 to 10.90). In TBI, out of-hospital AAM showed a tendency towards increased 28-day mortality (adjusted OR 1.57; 95% CI 0.93 to 2.64) and 6-month poor functional outcome (1.63; 1.00 to 2.68), but these differences were not statistically significant. Out-of-hospital AAM was associated with poorer 6-month TBI neurologic outcome (1.80; 1.09 to 2.96). CONCLUSIONS: Out-of-hospital AAM was associated with increased mortality after haemorrhagic shock. The adverse association between out-of-hospital AAM and injury outcome is most pronounced in patients with haemorrhagic shock. PMID- 23353665 TI - Are physicians required during winch rescue missions in an Australian helicopter emergency medical service? AB - BACKGROUND: A helicopter emergency medical service (HEMS) capable of winching offers several advantages over standard rescue operations. Little is known about the benefit of physician winching in addition to a highly trained paramedic. OBJECTIVE: To analyse the mission profiles and interventions performed during rescues involving the winching of a physician in the Greater Sydney Area HEMS (GSA-HEMS). METHODS: All winch missions involving a physician from August 2009 to January 2012 were identified from the prospectively completed GSA-HEMS electronic database. A structured case sheet review for a predetermined list of demographic data and physician-only interventions (POIs) was conducted. RESULTS: We identified 130 missions involving the winching of a physician, of which 120 case sheets were available for analysis. The majority of patients were traumatically injured (90%) and male (85%) with a median age of 37 years. Seven patients were pronounced dead at the scene. A total of 63 POIs were performed on 48 patients. Administration of advanced analgesia was the most common POI making up 68.3% of interventions. Patients with abnormal RTSc(2) scores were more likely to receive a POI than those with normal RTSc(2) (84.8% vs 15.2%; p=0.03). The performance of a POI had no effect on median scene times (45 vs 43 min; p=0.51). CONCLUSIONS: Our high POI rate of 40% (48/120) coupled with long rescue times and the occasional severe injuries support the argument for winching Physicians. Not doing so would deny a significant proportion of patients time-critical interventions, advanced analgesia and procedural sedation. PMID- 23353666 TI - The impact of consultation on length of stay in tertiary care emergency departments. AB - BACKGROUND: Consultations in the emergency department (ED) are infrequently studied. This study quantifies the contribution of consultations to ED length of stay (LOS) and examines patient and consultation characteristics associated with prolonged ED LOS. METHODS: Prospective cohort study of a convenience sample of shifts by volunteering emergency physicians (EP) at two urban tertiary care Canadian EDs. EPs completed standardised forms on all patients for whom a consultation was requested. Medical chart reviews and secondary analyses of administrative databases were also performed. Factors associated with longer LOS were determined through linear regression modelling. RESULTS: 1180 patients received at least one consultation during study shifts and EPs completed data collection on 841 (71%) of these. Median patient age was 54 years, 53.3% were male, and 2.9% had documented dementia. Admitted patients receiving consultations had a longer overall LOS compared to discharged patients. Median time from triage to consultation request accounted for approximately 28% of the total median LOS in admitted patients compared to 46% for discharged patients. Consultation decision time accounted for 33% and 54% of the LOS for admitted and discharged patients, respectively. Linear regression modelling revealed that advanced age, longer latency between arrival and first consultation request, history of dementia and multiple consultations were significantly associated with longer LOS. Conversely, undergoing procedures while in the ED was associated with a shorter LOS. CONCLUSIONS: Consultation decision time contributes significantly to ED LOS. Further efforts are needed to validate these results in other ED settings and improve this aspect of ED throughput. PMID- 23353667 TI - The delivery of the new prehospital emergency medicine curriculum: reflections on a pilot programme in the UK. AB - INTRODUCTION: Pre-hospital Emergency Medicine is a subspecialty of Emergency Medicine and Anaesthesia in the UK, overseen by the Inter-collegiate Board for Training in Pre-hospital Emergency Medicine (IBTPHEM). Organisations delivering General Medical Council (GMC) approved programmes require clear educational governance frameworks to ensure high standards of training. This study outlines the experiences of an Emergency Medicine trainee during an Out of Programme Year with a regional Air Ambulance service in the UK. METHODS: Retrospective review of the clinical logbook for an Emergency Medicine trainee during a 12-month attachment with an Air Ambulance service in the UK. IBTPHEM assessment tools were completed to complement the clinical logbook. Clinical experience and the degree of clinical supervision were compared with the standards published by the IBTPHEM. RESULTS: Supervision rates were similar to those in other pilots (17.33%). Clinical workload was comparable with that reported in other organisations. More advanced procedures (eg, conscious sedation/prehospital anaesthetics) were completed than in IBTPHEM pilot programmes. The vast majority of curriculum elements detailed by the IBTPHEM were fulfilled. CONCLUSIONS: The experiences of an Emergency Medicine trainee in pilot programme at a regional Air Ambulance in the UK compared favourably with the results of formal pilots of the IBTPHEM programme conducted at other centres. The IBTPHEM assessment tools are appropriately designed and sufficient in number to ensure that fulfilment of the curriculum elements can be recorded and trainee development monitored. Areas for future developments in training and support, notably in curriculum areas regarding the management of obstetric prehospital emergencies, are suggested. PMID- 23353668 TI - Hypertrophic differentiation during chondrogenic differentiation of progenitor cells is stimulated by BMP-2 but suppressed by BMP-7. AB - OBJECTIVE: Bone morphogenic protein (BMP)-2 and BMP-7 are clinically approved and their recombinant proteins are used for bone tissue regenerative purposes and widely evaluated for cartilage regeneration. Previous comparison of the in vitro chondrogenic characteristics of BMP-2 vs BMP-7 did not address hypertrophic differentiation and characterizing their chondrogenic properties with a focus in on chondrocyte hypertrophy was topic of investigation in this study. DESIGN: Equimolar concentrations of BMP-2 or BMP-7 were added to chondrogenic differentiating ATDC5, human bone marrow stem cells or rabbit periosteal explants. Expression of Col2a1, Sox9, Acan, Col10a1, Runx2, ALP, Mmp13, Mef2c and Bapx1/Nkx3.2 was determined by reverse transcription-quantitative PCR (RT-qPCR) and immunoblotting. Glycosaminoglycan content, cell proliferation capacity and ALP activity were analysed by colourimetric analyses. Expression of Bapx1/Nkx3.2 and Sox9 was targeted by transfection of target specific siRNA duplexes. RESULTS: BMP-2 dose-dependently increased chondrocyte hypertrophy during chondrogenic differentiation of progenitor cells, whereas BMP-7 acted hypertrophy-suppressive and chondro-promotive. Both BMPs did not influence cell proliferation, but they did increase total glycosaminoglycan content. In a candidate approach Bapx1/Nkx3.2 was found to be involved in the BMP-7 mediated suppression of chondrocyte hypertrophy in ATDC5 cells. CONCLUSIONS: BMP-2 and BMP-7 display opposing actions on the chondrogenic outcome of differentiating progenitor cells: BMP-2 acts a specific inducer of chondrocyte hypertrophy, while BMP-7 appears to increase or maintain chondrogenic potential and prevent chondrocyte hypertrophy. Our results pave the way for an application-dependent differential use of BMP-2 or BMP-7. PMID- 23353669 TI - Parathyroid hormone [1-34] improves articular cartilage surface architecture and integration and subchondral bone reconstitution in osteochondral defects in vivo. AB - OBJECTIVE: The 1-34 amino acid segment of the parathyroid hormone (PTH [1-34]) mediates anabolic effects in chondrocytes and osteocytes. The aim of this study was to investigate whether systemic application of PTH [1-34] improves the repair of non-osteoarthritic, focal osteochondral defects in vivo. DESIGN: Standardized cylindrical osteochondral defects were bilaterally created in the femoral trochlea of rabbits (n = 8). Daily subcutaneous injections of 10 MUg PTH [1 34]/kg were given to the treatment group (n = 4) for 6 weeks, controls (n = 4) received saline. Articular cartilage repair was evaluated by macroscopic, biochemical, histological and immunohistochemical analyses. Reconstitution of the subchondral bone was assessed by micro-computed tomography. Effects of PTH [1-34] on synovial membrane, apoptosis, and expression of the PTH receptor (PTH1R) were determined. RESULTS: Systemic PTH [1-34] increased PTH1R expression on both, chondrocytes and osteocytes within the repair tissue. PTH [1-34] ameliorated the macro- and microscopic aspect of the cartilaginous repair tissue. It also enhanced the thickness of the subchondral bone plate and the microarchitecture of the subarticular spongiosa within the defects. No significant correlations were established between these coexistent processes. Apoptotic levels, synovial membrane, biochemical composition of the repair tissue, and type-I/II collagen immunoreactivity remained unaffected. CONCLUSIONS: PTH [1-34] emerges as a promising agent in the treatment of focal osteochondral defects as its systemic administration simultaneously stimulates articular cartilage and subchondral bone repair. Importantly, both time-dependent mechanisms of repair did not correlate significantly at this early time point and need to be followed over prolonged observation periods. PMID- 23353670 TI - Relationship between anisotropic diffusion properties and tissue morphology in porcine TMJ disc. AB - OBJECTIVE: To investigate the relationship between anisotropic solute diffusion properties and tissue morphology in porcine temporomandibular joint (TMJ) discs. DESIGN: TMJ discs from eleven pigs aged 6-8 months were divided into five regions: anterior, intermediate, posterior, lateral, and medial. The transport properties and tissue morphology were investigated in three orthogonal orientations: anteroposterior (AP), mediolateral (ML), and superoinferior (SI). The anisotropic diffusivity of fluorescein (332 Da) in the right discs was determined by the fluorescence recovery after photobleaching (FRAP) protocols. The tissue morphology in the left discs was quantified by scanning electron microscopy. RESULTS: The diffusivities of fluorescein in the TMJ disc were significantly anisotropic, except for the anterior region. In the medial, intermediate, and lateral regions, the diffusion along the fiber orientation (i.e., AP direction) was significantly faster than the diffusion in ML and SI directions. In the posterior region, the diffusion along the fiber orientation (i.e., ML direction) was significantly faster than the diffusion in AP and SI directions. The diffusion in the anterior region was mostly isotropic with the lowest degree of diffusion anisotropy, as well as collagen fiber alignment, likely due to the multi-directional fiber arrangement. The anterior region had the highest mean diffusivity [65.6 (49.3-81.8) MUm(2)/s] in the disc, likely due to its high water content. The overall average diffusivity of fluorescein across the TMJ disc was 57.0 (43.0-71.0) MUm(2)/s. CONCLUSIONS: The solute diffusion in porcine TMJ discs was strongly anisotropic and inhomogeneous, which associated with tissue structure (i.e., collagen fiber alignment) and composition (e.g., water content). PMID- 23353671 TI - Severe bacterial non-aids infections in HIV-positive persons: incidence rates and risk factors. AB - OBJECTIVES: This study aimed to determine incidence rates (IR) and identify risk factors for severe bacterial non-AIDS infections (SBnAI) requiring hospital admission. METHODS: Data from the prospective EuroSIDA cohort were utilized to determine IRs of first diagnosis of the following SBnAI requiring hospital admission: bacteremia, endocarditis, meningitis, peritonitis, pneumonia, osteitis, and pyolonephritis. Incidence rate-ratios (IRRs) and risk factors were assessed by Poisson regression. RESULTS: During 35,839 person-years of follow-up (PYFU), 275 patients were diagnosed with SBnAI (IR = 7.67 per 1000 PYFU, 95% confidence interval: 6.79-8.64). The most frequent infections were pneumonia (IR = 5.36, 4.63-6.17), bacteremia (IR = 1.14, 0.82-1.55), and pyelonephritis (IR = 0.67, 0.43-1.00). A strong risk factor for SBnAI was reduced estimated glomerular filtration rate [eGFR] (adjusted IRR = 5.07, 2.12-12.1 and IRR = 2.73, 1.63-4.56 for eGFR <= 60 and 60.1-90 compared to eGFR > 90, respectively). No current combined antiretroviral therapy (cART) compared with current cART use increased the risk of SBnAI (adjusted IRR = 2.96, 2.03-4.32). Other risk factors for SBnAI included current CD4+ count <350 cells/MUL, female gender, age, infection with HIV through IDU, prior AIDS diagnosis, and anaemia. CONCLUSIONS: Enhanced attention directed towards people with comorbidity is warranted to limit the burden of these infections. PMID- 23353672 TI - Nanorod-nanosheet hierarchically structured ZnO crystals on zinc foil as flexible photoanodes for dye-sensitized solar cells. AB - In this paper, ZnO nanorod-nanosheet hierarchical structures were fabricated using a facile method on zinc foil and used as flexible photoanodes in dye sensitized solar cells (DSCs). Compared to nanorods (NRs) obtained by the dissolution-precipitation method, the nanorod-nanosheet (NR-NS) hierarchical structures obtained by a second-step homogeneous precipitation improved the performance of DSCs by increasing photocurrent density significantly. As a result, the power conversion efficiency of the devices based on such a NR-NS hierarchical structure reached up to 2.4% under 100 mW cm(-2) illumination condition. This represents an enhancement by 108% as compared to DSCs based on NR assembled nanoflowers, for which the efficiency was 1.1%. The enhancement of the photocurrent was due mainly to the much larger specific surface area and resulting dye-loading amount. The electron transport properties in this structure were also investigated by means of electrochemical impedance spectroscopy (EIS). Furthermore, the formation mechanism of the NR-NS hierarchical structures are discussed. PMID- 23353673 TI - Arrays of single-walled carbon nanotubes with full surface coverage for high performance electronics. AB - Single-walled carbon nanotubes have exceptional electronic properties and have been proposed as a replacement for silicon in applications such as low-cost thin film transistors and high-performance logic devices. However, practical devices will require dense, aligned arrays of electronically pure nanotubes to optimize performance, maximize device packing density and provide sufficient drive current (or power output) for each transistor. Here, we show that aligned arrays of semiconducting carbon nanotubes can be assembled using the Langmuir-Schaefer method. The arrays have a semiconducting nanotube purity of 99% and can fully cover a surface with a nanotube density of more than 500 tubes/um. The nanotube pitch is self-limited by the diameter of the nanotube plus the van der Waals separation, and the intrinsic mobility of the nanotubes is preserved after array assembly. Transistors fabricated using this approach exhibit significant device performance characteristics with a drive current density of more than 120 uA um( 1), transconductance greater than 40 uS um(-1) and on/off ratios of ~1 * 10(3). PMID- 23353674 TI - Wear: One atom after the other. PMID- 23353675 TI - A subwavelength plasmonic metamolecule exhibiting magnetic-based optical Fano resonance. AB - The lack of symmetry between electric and magnetic charges, a fundamental consequence of the small value of the fine-structure constant, is directly related to the weakness of magnetic effects in optical materials. Properly tailored plasmonic nanoclusters have been proposed recently to induce artificial optical magnetism based on the principle that magnetic effects are indistinguishable from specific forms of spatial dispersion of permittivity at optical frequencies. In a different context, plasmonic Fano resonances have generated a great deal of interest, particularly for use in sensing applications that benefit from sharp spectral features and extreme field localization. In the absence of natural magnetism, optical Fano resonances have so far been based on purely electric effects. In this Letter, we demonstrate that a subwavelength plasmonic metamolecule consisting of four closely spaced gold nanoparticles supports a strong magnetic response coupled to a broad electric resonance. Small structural asymmetries in the assembled nanoring enable the interaction between electric and magnetic modes, leading to the first observation of a magnetic-based Fano scattering resonance at optical frequencies. Our findings are supported by excellent agreement with simulations and analytical calculations, and represent an important step towards the quest for artificial magnetism and negative refractive index metamaterials at optical frequencies. PMID- 23353676 TI - Plasmonics: The dark side of the ring. PMID- 23353677 TI - In-plane heterostructures of graphene and hexagonal boron nitride with controlled domain sizes. AB - Graphene and hexagonal boron nitride (h-BN) have similar crystal structures with a lattice constant difference of only 2%. However, graphene is a zero-bandgap semiconductor with remarkably high carrier mobility at room temperature, whereas an atomically thin layer of h-BN is a dielectric with a wide bandgap of ~5.9 eV. Accordingly, if precise two-dimensional domains of graphene and h-BN can be seamlessly stitched together, hybrid atomic layers with interesting electronic applications could be created. Here, we show that planar graphene/h-BN heterostructures can be formed by growing graphene in lithographically patterned h-BN atomic layers. Our approach can create periodic arrangements of domains with size ranging from tens of nanometres to millimetres. The resulting graphene/h-BN atomic layers can be peeled off the growth substrate and transferred to various platforms including flexible substrates. We also show that the technique can be used to fabricate two-dimensional devices, such as a split closed-loop resonator that works as a bandpass filter. PMID- 23353678 TI - Nanoscale wear as a stress-assisted chemical reaction. AB - Wear of sliding contacts leads to energy dissipation and device failure, resulting in massive economic and environmental costs. Typically, wear phenomena are described empirically, because physical and chemical interactions at sliding interfaces are not fully understood at any length scale. Fundamental insights from individual nanoscale contacts are crucial for understanding wear at larger length scales, and to enable reliable nanoscale devices, manufacturing and microscopy. Observable nanoscale wear mechanisms include fracture and plastic deformation, but recent experiments and models propose another mechanism: wear via atom-by-atom removal ('atomic attrition'), which can be modelled using stress assisted chemical reaction kinetics. Experimental evidence for this has so far been inferential. Here, we quantitatively measure the wear of silicon--a material relevant to small-scale devices--using in situ transmission electron microscopy. We resolve worn volumes as small as 25 +/- 5 nm(3), a factor of 10(3) lower than is achievable using alternative techniques. Wear of silicon against diamond is consistent with atomic attrition, and inconsistent with fracture or plastic deformation, as shown using direct imaging. The rate of atom removal depends exponentially on stress in the contact, as predicted by chemical rate kinetics. Measured activation parameters are consistent with an atom-by-atom process. These results, by direct observation, establish atomic attrition as the primary wear mechanism of silicon in vacuum at low loads. PMID- 23353679 TI - Worrisome solitary dark growing nodule on the vertex: challenge. Atypical cellular blue nevus. PMID- 23353680 TI - Mobile health (mHealth) approaches and lessons for increased performance and retention of community health workers in low- and middle-income countries: a review. AB - BACKGROUND: Mobile health (mHealth) describes the use of portable electronic devices with software applications to provide health services and manage patient information. With approximately 5 billion mobile phone users globally, opportunities for mobile technologies to play a formal role in health services, particularly in low- and middle-income countries, are increasingly being recognized. mHealth can also support the performance of health care workers by the dissemination of clinical updates, learning materials, and reminders, particularly in underserved rural locations in low- and middle-income countries where community health workers deliver integrated community case management to children sick with diarrhea, pneumonia, and malaria. OBJECTIVE: Our aim was to conduct a thematic review of how mHealth projects have approached the intersection of cellular technology and public health in low- and middle-income countries and identify the promising practices and experiences learned, as well as novel and innovative approaches of how mHealth can support community health workers. METHODS: In this review, 6 themes of mHealth initiatives were examined using information from peer-reviewed journals, websites, and key reports. Primary mHealth technologies reviewed included mobile phones, personal digital assistants (PDAs) and smartphones, patient monitoring devices, and mobile telemedicine devices. We examined how these tools could be used for education and awareness, data access, and for strengthening health information systems. We also considered how mHealth may support patient monitoring, clinical decision making, and tracking of drugs and supplies. Lessons from mHealth trials and studies were summarized, focusing on low- and middle-income countries and community health workers. RESULTS: The review revealed that there are very few formal outcome evaluations of mHealth in low-income countries. Although there is vast documentation of project process evaluations, there are few studies demonstrating an impact on clinical outcomes. There is also a lack of mHealth applications and services operating at scale in low- and middle-income countries. The most commonly documented use of mHealth was 1-way text-message and phone reminders to encourage follow-up appointments, healthy behaviors, and data gathering. Innovative mHealth applications for community health workers include the use of mobile phones as job aides, clinical decision support tools, and for data submission and instant feedback on performance. CONCLUSIONS: With partnerships forming between governments, technologists, non-governmental organizations, academia, and industry, there is great potential to improve health services delivery by using mHealth in low- and middle-income countries. As with many other health improvement projects, a key challenge is moving mHealth approaches from pilot projects to national scalable programs while properly engaging health workers and communities in the process. By harnessing the increasing presence of mobile phones among diverse populations, there is promising evidence to suggest that mHealth can be used to deliver increased and enhanced health care services to individuals and communities, while helping to strengthen health systems. PMID- 23353681 TI - Near infrared optical projection tomography for assessments of beta-cell mass distribution in diabetes research. AB - By adapting OPT to include the capability of imaging in the near infrared (NIR) spectrum, we here illustrate the possibility to image larger bodies of pancreatic tissue, such as the rat pancreas, and to increase the number of channels (cell types) that may be studied in a single specimen. We further describe the implementation of a number of computational tools that provide: 1/ accurate positioning of a specimen's (in our case the pancreas) centre of mass (COM) at the axis of rotation (AR); 2/ improved algorithms for post-alignment tuning which prevents geometric distortions during the tomographic reconstruction and 3/ a protocol for intensity equalization to increase signal to noise ratios in OPT based BCM determinations. In addition, we describe a sample holder that minimizes the risk for unintentional movements of the specimen during image acquisition. Together, these protocols enable assessments of BCM distribution and other features, to be performed throughout the volume of intact pancreata or other organs (e.g. in studies of islet transplantation), with a resolution down to the level of individual islets of Langerhans. PMID- 23353682 TI - Molecular characterization of anisakid nematode larvae from 13 species of fish from Western Australia. AB - This study characterized anisakid nematodes in estuarine and near-shore species of fish in southern Western Australia. A total of 108 fish representing 13 species were examined for anisakid larvae. For the molecular characterization of anisakid larvae (n=218), we used PCR-coupled mutation scanning-sequencing phylogenetic analyses of sequence variation in the internal transcribed spacers of nuclear ribosomal DNA. With the exception of Sillaginoides punctatus and Sillago schomburgkii, all the fish species examined (Aldrichetta forsteri, Arripis georgianus, Hyporhamphus regularis, Mugil cephalus, Platycephalus speculator, Pomatomus saltatrix, Pseudocaranx dentex, Pseudocaranx wrighti, Thysanophrys cirronatus, Trachurus novaezeelandiae and Upeneichthys lineatus) harboured at least one species of anisakid. Mutation scanning analysis identified 11 different genotypes of anisakid larvae. Phylogenetic analyses of the sequence data, employing reference sequence data for a wide range of anisakids (31 species) from public databases, revealed the presence of Anisakis pegreffii (n=3), Contracaecum multipapillatum (49), Contracaecum ogmorhini (1), Hysterothylacium larval type IV (82), Hysterothylacium larval type Vb (14), Hysterothylacium larval type VIII (3), Hysterothylacium larval type X (65), and Terranova type I (1) in the fish examined. The present study provides valuable information on the diversity of anisakids in southern Western Australia and also a basis for future investigations to assess the public health significance of these parasites. PMID- 23353683 TI - Polymer crowders and protein crowders act similarly on protein folding stability. AB - Recently a polymer crowder and two protein crowders were found to have opposite effects on the folding stability of chymotrypsin inhibitor 2 (CI2), suggesting that they interact differently with CI2. Here we propose that all the macromolecular crowders act similarly, with an entropic component favoring the folded state and an enthalpic component favoring the unfolded state. The net effect is destabilizing below a crossover temperature but stabilizing above it. This general trend is indeed observed in recent experiments and hints experimental temperature as a reason for the opposite crowding effects of the polymer and protein crowders. PMID- 23353684 TI - Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms. AB - alpha(2)-Macroglobulin (alpha(2)M) is an extracellular chaperone that inhibits amorphous and fibrillar protein aggregation. The reaction of alpha(2)M with proteases results in an 'activated' conformation, where the proteases become covalently-linked within the interior of a cage-like structure formed by alpha(2)M. This study investigates, the effect of activation on the ability of alpha(2)M to inhibit amyloid formation by Abeta(1-42) and I59T human lysozyme and shows that protease-activated alpha(2)M can act via two distinct mechanisms: (i) by trapping proteases that remain able to degrade polypeptide chains and (ii) by a chaperone action that prevents misfolded clients from continuing along the amyloid forming pathway. PMID- 23353685 TI - beta-Arrestin-1 directly interacts with Galphas and regulates its function. AB - beta-Arrestins function to mediate G protein-coupled receptor (GPCR) desensitization and internalization and to initiate G protein independent signaling of GPCRs. Elucidating how beta-arrestin and G protein signal pathways coordinate with each other is important to fully understand GPCR signaling. Here we report that beta-arrestin-1 directly interacts with Galpha(s). Purified beta arrestin-1 binds to Galpha(s) in a rapid association and dissociation manner. beta-Arrestin-1 promotes the binding and the release of GTPgammaS from Galpha(s) in vitro. beta-Arrestin-1 L33K mutant shows reduced interaction with Galpha(s) and has no detectable effects on Galpha(s) function. Our study thus reveals a direct crosstalk of beta-arrestin-1 with Galpha(s). PMID- 23353687 TI - 18F-FDG labeling of mesenchymal stem cells and multipotent adult progenitor cells for PET imaging: effects on ultrastructure and differentiation capacity. AB - Because of their extended differentiation capacity, stem cells have gained great interest in the field of regenerative medicine. For the development of therapeutic strategies, more knowledge on the in vivo fate of these cells has to be acquired. Therefore, stem cells can be labeled with radioactive tracer molecules such as (18)F-FDG, a positron-emitting glucose analog that is taken up and metabolically trapped by the cells. The aim of this study was to optimize the radioactive labeling of mesenchymal stem cells (MSCs) and multipotent adult progenitor cells (MAPCs) in vitro with (18)F-FDG and to investigate the potential radiotoxic effects of this labeling procedure with a range of techniques, including transmission electron microscopy (TEM). METHODS: Mouse MSCs and rat MAPCs were used for (18)F-FDG uptake kinetics and tracer retention studies. Cell metabolic activity, proliferation, differentiation and ultrastructural changes after labeling were evaluated using an Alamar Blue reagent, doubling time calculations and quantitative TEM, respectively. Additionally, mice were injected with MSCs and MAPCs prelabeled with (18)F-FDG, and stem cell biodistribution was investigated using small-animal PET. RESULTS: The optimal incubation period for (18)F-FDG uptake was 60 min. Significant early tracer washout was observed, with approximately 30%-40% of the tracer being retained inside the cells 3 h after labeling. Cell viability, proliferation, and differentiation capacity were not severely affected by (18)F-FDG labeling. No major changes at the ultrastructural level, considering mitochondrial length, lysosome size, the number of lysosomes, the number of vacuoles, and the average rough endoplasmic reticulum width, were observed with TEM. Small-animal PET experiments with radiolabeled MAPCs and MSCs injected intravenously in mice showed a predominant accumulation in the lungs and a substantial elution of (18)F-FDG from the cells. CONCLUSION: MSCs and MAPCs can be successfully labeled with (18)F-FDG for molecular imaging purposes. The main cellular properties are not rigorously affected. TEM confirmed that the cells' ultrastructural properties are not influenced by (18)F-FDG labeling. Small-animal PET studies confirmed the intracellular location of the tracer and the possibility of imaging injected prelabeled stem cell types in vivo. Therefore, direct labeling of MSCs and MAPCs with (18)F-FDG is a suitable technique to noninvasively assess cell delivery and early retention with PET. PMID- 23353689 TI - Fluorescence quenching of Rhodamine B base by two amines. AB - Fluorescence quenching of Rhodamine B base (RhB) in DMF solution has been studied at different concentrations of the amine Triethyl amine (TEA) and n-butyl amine (NBA) at room temperature. It has been observed that the fluorescence intensity of RhB decrease with increase in the concentration of the TEA and NBA. It has been observed that the quenching due to amines proceeds via dynamic quenching process. The rate constants for the quenching process have been calculated using Stern-Volmer equation. Time resolved fluorescence study and (1)H NMR spectral study have also been carried out and discussed. PMID- 23353688 TI - Synthesis and evaluation of 11C-LY2795050 as a kappa-opioid receptor antagonist radiotracer for PET imaging. AB - Kappa-opioid receptors (KOR) are believed to be involved in the pathophysiology of depression, anxiety disorders, drug abuse, and alcoholism. To date, only 1 tracer, the KOR agonist (11)C-GR103545, has been reported to be able to image KOR in primates. The goal of the present study was to synthesize the selective KOR antagonist (11)C-LY2795050 and evaluate its potential as a PET tracer to image KOR in vivo. METHODS: The in vitro binding affinity of LY2795050 was measured in radioligand competition binding assays. Ex vivo experiments were conducted using microdosing of the unlabeled ligand in Sprague-Dawley rats and in wild-type and KOR knockout mice, to assess the ligand's potential as a tracer candidate. Imaging experiments with (11)C-LY2795050 in monkeys were performed on the Focus 220 scanner with arterial blood input function measurement. Binding parameters were determined with kinetic modeling analysis. RESULTS: LY2795050 displays full antagonist activity and high binding affinity and selectivity for KOR. Microdosing studies in rodents and ex vivo analysis of tissue concentrations with liquid chromatography-tandem mass spectrometry identified LY2795050 as an appropriate tracer candidate able to provide specific binding signals in vivo. (11)C-LY2795050 was prepared in an average yield of 12% and greater than 99% radiochemical purity. In rhesus monkeys, (11)C-LY2795050 displayed a moderate rate of peripheral metabolism, with approximately 40% of parent compound remaining at 30 min after injection. In the brain, (11)C-LY2795050 displayed fast uptake kinetics (regional activity peak times of <20 min) and an uptake pattern consistent with the distribution of KOR in primates. Pretreatment with naloxone (1 mg/kg, intravenously) resulted in a uniform distribution of radioactivity. Further, specific binding of (11)C-LY2795050 was reduced by the selective KOR antagonist LY2456302 in a dose-dependent manner. CONCLUSION: (11)C-LY2795050 displayed favorable pharmacokinetic properties and binding profiles in vivo and therefore is a suitable ligand for imaging the KOR in primates. This newly developed KOR antagonist tracer has since been advanced to PET imaging of KOR in humans and constitutes the first successful KOR antagonist radiotracer. PMID- 23353690 TI - Experimental and theoretical investigation of optical nonlinearities in (nitrovinyl)-1H-pyrazole derivative. AB - This work reports on the optical nonlinearities of a newly synthesized pyrazole derivative, namely (E)-1-(4-chlorophenyl)-4-(2-nitrovinyl)-1H-pyrazole. The Z scan technique with femtosecond laser pulses was used to determine the two-photon absorption (2PA) cross-section spectrum, which presents a maximum of 67 GM at 690 nm. We have combined hyper-Rayleigh scattering (HRS) experiments and second-order Moller-Plesset perturbation theory (MP2) calculations to study the first hyperpolarizability (beta(HRS)). It was found that the MP2/6-311+G(d) model, taking into account solvent and dispersion effects, provides the beta(HRS) value of 40*10(-30) cm(5)/esu for the compound, in good agreement with the experimental result of 45+/-2*10(-30) cm(5)/esu. PMID- 23353691 TI - Synthesis, nucleation, growth, structural, spectral, thermal, linear and nonlinear optical studies of novel organic NLO crystal: 4-fluoro 4-nitrostilbene (FONS). AB - A novel organic nonlinear optical material 4-fluoro 4-nitrostilbene (FONS), with molecular formula (C(14)H(10)FNO(2)) has been synthesized. Using ethyl methyl ketone as solvent, the synthesized material has been repeatedly recrystallized to minimize the impurities and good optical quality single crystals were harvested by slow evaporation method. Single crystal X-ray diffraction analysis reveals that the grown FONS crystal belongs to monoclinic system with noncentrosymmetric space group "P2(1)". The powder X-ray diffraction pattern of FONS has been recorded. Functional groups of the title compound were confirmed by FTIR and the molecular structure was confirmed by (1)HNMR. The UV-vis-NIR absorption study reveals no absorption in the visible region and the cut-off wavelength was found to be at 408 nm. Optical band gap (E(g)) of the grown crystal was found to be 3.27 eV and also the optical constants were determined. Thermal behaviour of the FONS has been studied by TGA/DTA analyses. From the mass spectrum, the ratio of compound formation of FONS was analyzed. The NLO property has been confirmed by Kurtz and Perry powder SHG technique and the SHG efficiency of FONS (262 mV) crystal was found to be 12 times greater than that of KDP (21.7 mV). PMID- 23353692 TI - The synthesis and characterization of dinuclear ruthenium sensitizers and their applications in photocatalytic hydrogen production. AB - A dinuclear ruthenium(II) dye sensitizer, ([Ru(2)(bpy)(4)BL](ClO(4))(2)) referred as Compound 1, where bpy=2,2'-bipyridine, BL=2,2'-((1E,1'E)-(((E)-diazene-1,2 diyl-bis(2,1-phenylene))-bis(azanylylidene))-bis (methanylylidene)) diphenol (a bidentate bridging ligand), was designed, synthesized and characterized. The dye sensitizer was used on the photocatalytic water splitting for hydrogen (H(2)) production over TiO(2) (P25) under visible light (lambda>=400 nm) irradiation using triethanolamine (TEOA) as a sacrificial electron donor. The dye sensitized TiO(2) demonstrated a good stability and sufficient reproducibility for over 6 h. The photosensitization ability of the sensitizer was due to its conjugation system, large molecular area, TiO(2) linkage mode and the antenna effect. PMID- 23353693 TI - FT-IR spectroscopic analyses of 2-(2-furanylmethylene) propanedinitrile. AB - In the present work, a computational study for the optimized molecular structural parameters, thermo-chemical parameters, total dipole moment, HOMO-LUMO energy gap and a combined experimental and computational study for FT-IR spectra for 2-(2 furanylmethylene) propanedinitrile have been investigated using B3LYP utilizing 6 31G and 6-311G basis set. Our calculated results showed that the investigated compound possesses a dipole moment of 7.5D and HOMO-LUMO energy gap of 3.92eV using B3LYP/6-311G which indicates that our investigated compound is highly applicable for photovoltaic solar cell applications. PMID- 23353694 TI - Synthesis, characterization and electrical properties of peripherally tetra aldazine substituted novel metal free phthalocyanine and its zinc(II) and nickel(II) complexes. AB - The novel phthalonitrile containing azine segment and its corresponding tetra aldazine substituted metal free- and metallo-phthalocyanines (Zn(II) and Ni(II)) were synthesized and characterized by IR, (1)H NMR, Mass, UV-Vis spectroscopy and elemental analysis and addition to these techniques for substituted phthalonitrile (13)C NMR have been used. In addition, dc and ac electrical properties of the films of these novel phthalocyanines were investigated as a function of temperature (295-523 K) and frequency (40-10(5)Hz). Activation energy values of the films of the phthalocyanines were calculated from straight portions of the Arrhenius plot (lnsigma(dc)-1/T curves) as 0.70 eV, 0.93 eV and 0.91 eV for the films of metal free, nickel- and zinc-phthalocyanines, respectively. From impedance spectroscopy measurements, it is observed that bulk resistance decreases with increasing temperature indicating semiconductor property. PMID- 23353695 TI - Computational and spectroscopic studies of a new Schiff base 3-hydroxy-4 methoxybenzylidene(2-hydroxyphenyl)amine and molecular structure of its corresponding zwitterionic form. AB - Computational and spectroscopic properties of a novel Schiff base compound, 3 hydroxy-4-methoxybenzylidene(2-hydroxyphenyl)amine were studied. The crystal structures of the title compound and its corresponding zwitterionic form were analyzed by X-ray diffraction. The presence of N-H, C-O and C=N stretching vibrations in IR spectrum strongly suggest that the title compound has zwitterionic form in the solid state. Molecular geometry of the title compound in the ground state has been calculated using the density functional method (DFT) at B3LYP 6-31++G(d,p) basis set and was compared with the experimental data. The calculated results of the title compound show that the optimized geometry can well reproduce the crystal structure. The molecule shows absorption bands at 345 and 363 nm in EtOH. The shoulder-shaped bands at 415 nm can be assigned to n >pi(*) transitions. The absorption band is observed at 285 nm in EtOH corresponds to the pi->pi(*) transitions. PMID- 23353696 TI - From gestures to words: spontaneous verbal labeling of complex sequential hand movements reduces fMRI activation of the imitation-related regions. AB - The association of verbal labels with visuo-spatial patterns and sequences detectably alters neuronal activity in the brain in ways that have yet to be fully characterized. This study investigated the neural substrates involved in the effect of spontaneous verbal labeling on memorizing increasingly complex sequences of hand movements. We used functional magnetic resonance imaging (fMRI) to test our hypothesis that when verbal labels were employed, neuronal activity in imitation-related regions, such as the left inferior frontal gyrus (IFG), would be reduced, whereas without verbal labels, neuronal activation would increase. Sixteen healthy adults satisfactorily performed an immediate imitation task involving six levels of increasing complexity. After the fMRI experiment, participants reported at which complexity level they had formed verbal labels. Based on the self-report, we categorized the task blocks at each complexity level as either with verbal labeling (VL+) or without (VL-). Compared with VL+, the VL- condition activated the left IFG, bilateral middle frontal gyri, left precentral gyrus, and the right angular gyrus, whereas the opposite contrast revealed no significant brain activation. Verbal labeling seems to serve as an efficient heuristic that reduces the cost of cortical activation in the imitation-related regions. PMID- 23353697 TI - Assessments of injectable alginate particle-embedded fibrin hydrogels for soft tissue reconstruction. AB - Soft tissue reconstruction is often needed after massive traumatic damage or cancer removal. In this study, we developed a novel hybrid hydrogel system consisting of alginate particles and a fibrin matrix that could maintain tissue volume long term. Alginate particles were fabricated by mixing 5% alginate with a 20 mM calcium solution. Cells and these alginate particles were then embedded in fibrin (alginate-fibrin) hydrogels using a dual syringe mixer. Cell-hydrogel constructs were evaluated in terms of cell survival and proliferation in the constructs in vitro. The results indicated that cellular viability, spreading and proliferation in the alginate-fibrin hydrogels were significantly higher compared to constructs fabricated with fibrin or alginate only. In vivo explants showed that cells contained within fibrin-only hydrogels did not contribute to neo tissue formation, and the fibrin was fully degraded within a 12 week period. In the alginate-fibrin system, higher cellularity and vascular ingrowth were observed in vivo. This resulted in neo-tissue formation in the alginate-fibrin hydrogels. These results demonstrate that fibrin may enhance cell proliferation and accelerate the formation of extracellular matrix proteins in the alginate fibrin system, while the alginate particles could contribute to volume retention. This injectable hybrid system composed of degradable and non-degradable hydrogels may be a preferable approach to the repair of soft tissue defects. PMID- 23353698 TI - ABT-737 resistance in B-cells isolated from chronic lymphocytic leukemia patients and leukemia cell lines is overcome by the pleiotropic kinase inhibitor quercetin through Mcl-1 down-regulation. AB - Chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in adult population and despite numerous studies, it is considered an incurable disease. Since CLL is characterized by overexpression of pro-survival Bcl-2 family members, treatments with their antagonists, such as ABT-737, represent a promising new therapeutic strategy. ABT-737 is a BH3 mimetic agent which binds Bcl-2, Bcl-XL and Bcl-w with high affinity, while weakly interacts with Mcl-1 and Bfl-1. Previous studies demonstrated that quercetin, a flavonoid naturally present in food and beverages, was able to sensitize B-cells isolated from CLL patients to apoptosis when associated with death ligands or fludarabine, through a mechanism involving Mcl-1 down-regulation. Here, we report that the association between ABT-737 and quercetin synergistically induces apoptosis in B-cells and in five leukemic cell lines (Combination Index <1). Peripheral blood mononuclear cell from healthy donors were not affected by quercetin treatment. The molecular pathways triggered by quercetin have been investigated in HPB-ALL cells, characterized by the highest resistance to both ABT-737 and quercetin when applied as single molecules, but highly sensitivity to the co-treatment. In this cell line, quercetin down-regulated Mcl-1 through the inhibition of PI3K/Akt signaling pathway, leading to Mcl-1 instability. The same mechanism was confirmed in B-cells. These results may open new clinical perspectives based on a translational approach in CLL therapy. PMID- 23353699 TI - c-Src-dependent MAPKs/AP-1 activation is involved in TNF-alpha-induced matrix metalloproteinase-9 expression in rat heart-derived H9c2 cells. AB - TNF-alpha plays a critical mediator in the pathogenesis of chronic heart failure contributing to cardiac remodeling and peripheral vascular disturbances. The implication of TNF-alpha in inflammatory responses has been shown to be mediated through up-regulation of inflammatory genes, including matrix metalloproteinase-9 (MMP-9). However, the detailed mechanisms of TNF-alpha-induced MMP-9 expression are largely unclear in the heart cells. Here, we demonstrated that in rat embryonic-heart derived H9c2 cells, TNF-alpha could induce MMP-9 mRNA expression associated with an increase in the secretion of MMP-9, determined by real-time PCR, zymography, and promoter activity assays. TNF-alpha-mediated responses were attenuated by pretreatment with the inhibitor of c-Src (PP1), EGFR (AG1478), PDGFR (AG1296), PI3K (LY294002), Akt (SH-5), MEK1/2 (U0126), p38 MAPK (SB202190), JNK1/2 (SP600125), or AP-1 (Tanshinone IIA) and transfection with siRNA of c-Src, EGFR, PDGFR, p110, Akt, or c-Jun. TNF-alpha stimulated c-Src, PDGFR, and EGFR phosphorylation, which were reduced by PP1. In addition, TNF-alpha-stimulated Akt phosphorylation was inhibited by PP1, AG1478, AG1296, or LY294002. We further demonstrated that TNF-alpha markedly stimulated p38 MAPK, p42/p44 MAPK, and JNK1/2 phosphorylation via a c-Src/EGFR, PDGFR/PI3K/Akt pathway. Finally, we showed that, in H9c2 cells, TNF-alpha-stimulated AP-1 promoter activity, c-Jun mRNA expression, and c-Jun phosphorylation were attenuated by PP1, AG1478, AG1296, LY294002, SB202190, SP600125, or U0126. These results suggested that TNF alpha-induced MMP-9 expression is mediated through a c-Src/EGFR, PDGFR/PI3K/Akt/MAPKs/AP-1 cascade in H9c2 cells. Consequently, MMP-9 induction may contribute to cell migration and cardiovascular inflammation. PMID- 23353700 TI - Tamoxifen magnifies therapeutic impact of ceramide in human colorectal cancer cells independent of p53. AB - Poor prognosis in patients with later stage colorectal cancer (CRC) necessitates the search for new treatment strategies. Ceramide, because of its role in orchestrating death cascades in cancer cells, is a versatile alternative. Ceramide can be generated by exposure to chemotherapy or ionizing radiation, or it can be administered in the form of short-chain analogs (C6-ceramide). Because intracellular P-glycoprotein (P-gp) plays a role in catalyzing the conversion of ceramide to higher sphingolipids, we hypothesized that administration of P-gp antagonists with C6-ceramide would magnify cell death cascades. Human CRC cell lines were employed, HCT-15, HT-29, and LoVo. The addition of either tamoxifen, VX-710, verapamil, or cyclosporin A, antagonists of P-gp, enhanced C6-ceramide cytotoxicity in all cell lines. In depth studies with C6-ceramide and tamoxifen in LoVo cells showed the regimen induced PARP cleavage, caspase-dependent apoptosis, mitochondrial membrane permeabilization (MMP), and cell cycle arrest at G1 and G2. At the molecular level, the regimen, but not single agents, induced time-dependent upregulation of tumor suppressor protein p53; however, introduction of a p53 inhibitor staved neither MMP nor apoptosis. Nanoliposomal formulations of C6-ceramide and tamoxifen were also effective, yielding synergistic cell kill. We conclude that tamoxifen is a favorable adjuvant for enhancing C6-ceramide cytotoxicity in CRC, and demonstrates uniquely integrated effects. The high frequency of expression of P-gp in CRC presents an adventitious target for complementing ceramide-based therapies, a strategy that could hold promise for treatment of resistant disease. PMID- 23353701 TI - Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. AB - Transmethylation is an important reaction that transfers a methyl group in S adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity. PMID- 23353702 TI - NADPH P450 oxidoreductase: structure, function, and pathology of diseases. AB - Cytochrome P450 oxidoreductase (POR) is an enzyme that is essential for multiple metabolic processes, chiefly among them are reactions catalyzed by cytochrome P450 proteins for metabolism of steroid hormones, drugs and xenobiotics. Mutations in POR cause a complex set of disorders that often resemble defects in steroid metabolizing enzymes 17alpha-hydroxylase, 21-hydroxylase and aromatase. Since our initial reports of POR mutations in 2004, more than 200 different mutations and polymorphisms in POR gene have been identified. Several missense variations in POR have been tested for their effect on activities of multiple steroid and drug metabolizing P450 proteins. Mutations in POR may have variable effects on different P450 partner proteins depending on the location of the mutation. The POR mutations that disrupt the binding of co-factors have negative impact on all partner proteins, while mutations causing subtle structural changes may lead to altered interaction with specific partner proteins and the overall effect may be different for each partner. This review summarizes the recent discoveries related to mutations and polymorphisms in POR and discusses these mutations in the context of historical developments in the discovery and characterization of POR as an electron transfer protein. The review is focused on the structural, enzymatic and clinical implications of the mutations linked to newly identified disorders in humans, now categorized as POR deficiency. PMID- 23353704 TI - Appropriate excitation wavelength removes obfuscations from pyrene excimer kinetics and mechanism studies. AB - The experimental procedures of time-resolved laser photolysis studies of pyrene excimer formation in solution have been scrutinized and the appropriate modifications have been implemented. Contrary to the experimental methods applied in all related previous work, the selection of a suitable excitation wavelength (such that the corresponding pyrene absorbance is less than 0.5 absorbance units) utilized in our study results in simple homogeneous kinetics. Consequently, the rate parameters obtained and the mechanism proposed differ significantly from those published previously. The rate constant values of the unimolecular decay of the pyrene monomer, the unimolecular decay of the pyrene excimer, and the excimer formation in decane solution (eta = 0.860 mPa s) at 25 degrees C are (2.38 +/- 0.01) * 10(6) s(-1), (2.78 +/- 0.02) * 10(7) s(-1), and (3.11 +/- 0.06) * 10(9) M(-1) s(-1), respectively. The dissociation of the excimer to form a singlet excited state pyrene and a ground state pyrene was shown to be negligible. The energies of activation corresponding to the monomer and excimer unimolecular decays were found to be 2.51 +/- 0.07 and 25.7 +/- 0.7 kJ mol(-1), respectively. Also, our temperature resolved laser photolysis data revealed that the excimer formation has a negative energy of activation equal to -11.2 +/- 0.5 kJ mol(-1). This unique phenomenon may be attributed to steric effects in the collision of the reactants. The current findings are important for the correct data analysis and interpretation in many applications of the pyrene excimer. PMID- 23353705 TI - Tailgut cyst: A case report in a 9-month-old infant. AB - INTRODUCTION: Tailgut cysts or retrorectal cystic hamartomas are rare developmental anomalies that are believed to arise from the embryonic hindgut. PRESENTATION OF CASE: 9 months old male infant was presented with swelling in the right gluteal region. MRI lumbo-sacral spine showed well defined round to oval lesion which is brightly hypertense on T2W1 and hypotense on T1W1 posterior to sacrum and coccyx with no evidence of connection to the thecal sac indicating cyst. Complete excision of the cyst was done. Histopathology report shows cyst wall partially lined with stratified squamous epithelium and cyst wall shows spaces lined by cuboidal epithelium and nerve bundles with no evidence of malignancy suggestive of tailgut cyst. DISCUSSION: Tailgut cysts are rare congenital anomalies. Most commonly located in the retrorectal space. They are thought to be derived from the remnants of the embryonic hindgut. Age ranges from 4 to 73 years but an average presentation is at 35 years. Female to male ratio is 3:1. MRI is a good diagnostic tool for diagnosis of tailgut cyst. Complete surgical excision is the treatment of choice as this provides a definite diagnosis and prevents possible complications such as infection, fistula formation and malignant degeneration. CONCLUSION: The aim of presenting this case is its rarity. Complete surgical excision is the treatment of choice. Preoperative imaging with MRI is essential to plan the most appropriate surgical approach. PMID- 23353707 TI - Modular pharmacology: deciphering the interacting structural organization of the targeted networks. AB - Because multiple drugs act within the context of the regulatory networks in which drug targets and disease gene products function, module-designed studies are becoming increasingly important for revealing the relationships between drug actions and disease outcomes in network pharmacology. In this review we discuss how network-based analyses of modules' structures and new modules have contributed to the genesis of modular structure and how these studies have improved the global understanding of the interacting structural organization at a genomic level, so as to suggest a new paradigm for medical research and drug discovery. We develop a framework of Modular Pharmacology (MP) that deciphers a given-ordered modular design of diseases and optimizes modules in a pharmacological network to reverse the complex diseases. PMID- 23353706 TI - Intra-articular correction of extra-articular tibial deformities with total knee arthroplasty. AB - INTRODUCTION: Extra-articular leg deformities may occur in the femur or tibia from mal-unions from previous trauma or metabolic bone disease. Secondary osteoarthritis at the knee occurs due to loss of mechanical alignment of the limb. At surgery for total knee arthroplasty, mechanical alignment can be restored intra-articularly with appropriate bone cuts and soft tissue balancing. PRESENTATION OF CASE: We describe 2 case studies with extra-articular tibial deformities (9 degrees and 24 degrees varus deformity) which were corrected with a 1 stage procedure of total knee arthroplasty with intra-articular deformity correction. DISCUSSION: Patient selection, pre-operative considerations and surgical technique are discussed with reference to the literature. CONCLUSION: One stage intra-articular correction of extra-articular deformity is suitable for mild degrees of varus deformities (<30 degrees ). Staged corrective procedures with larger deformities in the tibia or femur can be performed with extra-articular osteotomies on top of intra-articular corrections. Consideration should be given to the use of computer navigation when conventional jigs cannot be applied to deformed bone. PMID- 23353708 TI - Clinical, laboratory, endoscopical and histological characteristics predict severe ulcerative colitis. AB - BACKGROUND/AIMS: Ulcerative colitis is a remitting and relapsing chronic inflammatory disorder of the colon with a mortality rate of 7% from acute severe UC. METHODOLOGY: A retrospective study of the correlation of clinical indicators, laboratory indicators, endoscopical features, and histological features with clinical severity of UC was conducted in 125 UC cases. RESULTS: Diarrhea, mucous and pus in the stool, fever, anemia, weight loss and tachycardia symptoms and the erythrocyte sedimentation rate, concentrations of C-reactive protein, amount of white blood cells and platelets, and positive occult blood test positively correlated with the severity of disease. Whereas, serum total protein, albumin, and hemoglobin levels negatively correlated with the severity of UC. The endoscopic observations of mucosa bleeding, granular mucosa, pseudopolyps, pouch lighter or disappeared, and luminal stenosis as well as the grade and extent of disease were significantly associated with the severity of UC. Histological grade and granular mucosa were significantly associated with the severity of UC. Failure of conservative treatment, severely low gastrointestinal bleeding, and the discovery of a suspicious cancer in the biopsy are the main indicators for colectomy. CONCLUSIONS: Significant reduction in serum total protein, albumin, and hemoglobin concentration is a relatively specific indicator of severe UC. PMID- 23353703 TI - Adipocytes: impact on tumor growth and potential sites for therapeutic intervention. AB - The prevalence of obesity has increased dramatically in recent decades, reaching epidemic proportions. It is becoming clear that obesity is associated not only with type 2 diabetes mellitus and cardiovascular disease, but also with multiple types of cancer. Obesity is characterized by impaired adipose tissue function, leading to adipocyte hypertrophy, inflammation, hypoxia and induced angiogenesis, extracellular matrix remodeling and fibrosis as well as additional stress responses. While epidemiological data indicate that obesity is a well-established risk factor for certain malignancies, the molecular mechanisms underlying the link between obesity and cancer are still poorly understood. Recent data implicates systemic and paracrine factors secreted from adipose tissue during the obese state, promoting cancer development and progression. Here, we focus on the obesity-associated adipose tissue remodeling that may not only lead to metabolic complications, but also to a permissive pro-tumorigenic environment. Particular attention is given to the local pro-tumorigenic effects derived from adipocytes that present an important part of the tumor microenvironment of at least some cancers, in an attempt to describe the nature of the major players of the adipocyte-cancer cell crosstalk that dictates to a large extent tumor progression. PMID- 23353710 TI - Clinically relevant cancer biomarkers and pharmacogenetic assays. AB - BACKGROUND: The number of pharmacogenetic assays available is continuously expanding as more molecularly targeted anticancer drugs are under clinical development. While the literature regarding drug-gene associations and therapeutic implications is often robust, reviews regarding clinical assay availability and profiling methodologies of commonly used cancer biomarkers are often lacking. OBJECTIVE: To concisely identify and describe cancer biomarkers and their respective pharmacogenetic assays currently available in clinical practice. DISCUSSION: Analysis of germ-line DNA mutations can often help to predict pharmacokinetic and pharmacodynamic responses, whereas somatic DNA mutations are particularly useful in predicting tumor response. Molecular profiling and pre-emptive identification of cancer biomarkers can help to predict disease prognosis as well as response to anticancer therapy. Dozens of pharmacogenetic assays, utilizing several common methodologies, are currently available in clinical practice. It is essential for clinicians to understand the molecular pathways for anticancer drugs, the therapeutic implications of mutations within these pathways, the clinical assay(s) available to test for pharmacogenetic differences, and the common profiling methodology employed. CONCLUSION: As research continues to unveil more drug-gene and disease-gene associations, it is critical that clinicians understand which pharmacogenetic assays are available to identify inter-individual differences that predict safety and efficacy of anticancer drugs as we move toward the concept of personalized medicine. PMID- 23353711 TI - Intravenous chemotherapy preparation errors: patient safety risks identified in a pan-Canadian exploratory study. AB - BACKGROUND: This exploratory study was launched following a critical chemotherapy medication incident to thoroughly and proactively examine the current processes for ordering, preparing, labeling, verifying, administering, and documenting ambulatory intravenous chemotherapy in Canada, and to identify factors that may contribute to preventable adverse drug events. METHODS: Field observations in six Canadian cancer centers to identify end-to-end processes in clinic, pharmacy, and treatment areas; analysis of processes to identify risks. RESULTS: Three types of previously locally unrecognized potential chemotherapy preparation errors in Canadian oncology pharmacies were uncovered, all of which are undetectable if they occur. Although the frequency of these errors is unknown, their impact is potentially catastrophic. INTERPRETATION: Dispensing errors in high-risk intravenous preparation have been studied in the past, but it is unlikely that these studies have detected these errors because of the inherent limitations of the detection methods used. Research on preparation errors using more sensitive methods is therefore urgently needed to establish the extent to which pharmacy preparation practices may be error-prone, and to allow reliable evaluation of the impact of mitigation strategies. Widespread practice changes in Canadian oncology pharmacies are necessary, and are currently underway. PMID- 23353709 TI - Levetiracetam has opposite effects on alcohol- and cocaine-related behaviors in C57BL/6J mice. AB - The antiepileptic drug levetiracetam (LEV) is a potential treatment for alcohol use disorders, yet few preclinical studies exist on its effects in animal models relevant to drug or alcohol abuse. We investigated the effects of LEV on locomotor stimulation following acute and repeated administration of alcohol or cocaine and on alcohol- and cocaine-mediated changes in responding for brain stimulation reward (BSR) in C57BL/6J mice. LEV alone (10.0-100.0 mg/kg intraperitoneally) had no significant effect on locomotor activity or intracranial self-stimulation. Pretreatment with LEV reduced acute locomotor stimulation by 2.0 g/kg alcohol, attenuated the development of locomotor sensitization to alcohol with repeated exposure, and produced a shift in the dose response curve for alcohol on BSR threshold without affecting maximum operant response rate (MAX). Conversely, LEV pretreatment enhanced both acute locomotor stimulation by 15 mg/kg cocaine and development of locomotor sensitization following repeated exposure and produced a leftward shift in the dose-response curve for cocaine on BSR threshold without affecting MAX. Electrophysiological recordings in vitro showed that LEV reduced excitatory currents in both ventral tegmental area (VTA) dopamine neurons and nucleus accumbens (NAc) medium spiny neurons, consistent with a presynaptic effect. The opposite effects of LEV pretreatment on alcohol- and cocaine-related behaviors may predict its clinical utility in the treatment of patients with alcohol, but not psychostimulant abuse disorders. PMID- 23353712 TI - A retrospective study of patients' out-of-pocket costs for granulocyte colony stimulating factors. AB - OBJECTIVE: With rising healthcare costs, there is an increasing concern with the burden of out-of-pocket costs on cancer patients. This study examined patients' out-of-pocket expenditures for granulocyte colony-stimulating factors, pegfilgrastim and filgrastim, which are given to cancer patients receiving myelosuppressive chemotherapy and have been shown to decrease the incidence of febrile neutropenia. METHODS: Adult patients who received chemotherapy and granulocyte colony-stimulating factors in the outpatient setting in the United States between January 2007 and June 2010 were evaluated using medical and pharmacy claims data from two healthcare data sources, the MarketScan((r)) Commercial and Medicare Supplemental Databases and the HealthCore Integrated Research Database(SM). The distribution of out-of-pocket costs for granulocyte colony-stimulating factors per patient and per administration was described for each quarter. Longitudinal analyses of out-of-pocket costs for granulocyte colony stimulating factors were also performed for patients with continuous health plan eligibility during each calendar year from 2007 to 2009. RESULTS: The pattern of out-of-pocket expenditures for pegfilgrastim and filgrastim was generally consistent between the databases and over time. On average, about 65%-75% of patients had zero quarterly out-of-pocket costs for granulocyte colony stimulating factors. Across the years, the mean quarterly out-of-pocket costs per patient were $100-$150 and $50-$80 for pegfilgrastim and filgrastim, respectively. The mean quarterly out-of-pocket costs for granulocyte colony stimulating factors per administration were $40-$70 and $8-$10, respectively. CONCLUSION: In this retrospective analysis of medical and pharmacy claims data, most patients who received chemotherapy and granulocyte colony-stimulating factors in 2007 to 2010 had incurred no quarterly out-of-pocket costs associated with G-CSF use. PMID- 23353713 TI - Syndrome of Inappropriate Antidiuretic Hormone after vinorelbine treatment. AB - BACKGROUND: Among oncologic patients, Syndrome of Inappropriate Antidiuretic Hormone is a common cause of hyponatremia, a prevalent electrolyte disorder. There are many causes for Syndrome of Inappropriate Antidiuretic Hormone, including chemotherapy medications. To date, only three cases associating vinorelbine and Syndrome of Inappropriate Antidiuretic Hormone have been published. CASE: A 47-year-old woman with stage IIIC serous ovarian adenocarcinoma developed life-threatening hyponatremia (124 mmol/L) after three cycles of vinorelbine. Assessment revealed Syndrome of Inappropriate Antidiuretic Hormone as the most likely culprit. Conservative managements including free fluid restriction normalized her sodium level and Syndrome of Inappropriate Antidiuretic Hormone resolved after vinorelbine discontinuation. CONCLUSION: Vinorelbine can cause Syndrome of Inappropriate Antidiuretic Hormone. It is important to monitor sodium concentration during vinorelbine treatment to avoid serious neurological complications of hyponatremia and to improve patient's quality of life. PMID- 23353714 TI - Panitumumab following disease progression on cetuximab in patients with metastatic colorectal cancer: a retrospective review. AB - Despite advances in treatment options for metastatic colorectal cancer over the past decade, the number of chemotherapy agents available remains limited. We report here a retrospective review of 11 patients who were treated with panitumumab following documented disease progression on cetuximab. Two patients demonstrated minor radiographic responses, albeit only for a short period of time. We conclude that the use of one epidermal growth factor receptor inhibitor following failure on the other may be of benefit to patients who would otherwise have no other treatment options. However, studies to help identify the subset of patients who might benefit from this strategy are needed. PMID- 23353715 TI - N-acetylcysteine protects against cadmium-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in testes. AB - Cadmium (Cd) is a reproductive toxicant that induces germ cell apoptosis in the testes. Previous studies have demonstrated that endoplasmic reticulum (ER) stress is involved in Cd-induced germ cell apoptosis. The aim of the present study was to investigate the effects of N-acetylcysteine (NAC), an antioxidant, on Cd induced ER stress and germ cell apoptosis in the testes. Male CD-1 mice were intraperitoneally injected with CdCl2 (2.0 mg kg(-1)). As expected, acute Cd exposure induced germ cell apoptosis in the testes, as determined by terminal dUTP nick-end labelling (TUNEL). However, the administration of NAC alleviated Cd induced germ cell apoptosis in the testes. Further analysis showed that NAC attenuated the Cd-induced upregulation of testicular glucose-regulated protein 78 (GRP78), an important ER molecular chaperone. Moreover, NAC inhibited the Cd induced phosphorylation of testicular eukaryotic translation initiation factor 2alpha (eIF2alpha), a downstream target of the double-stranded RNA-activated kinase-like ER kinase (PERK) pathway. In addition, NAC blocked the Cd-induced activation of testicular X binding protein (XBP)-1, indicating that NAC attenuates the Cd-induced ER stress and the unfolded protein response (UPR). Interestingly, NAC almost completely prevented the Cd-induced elevation of C/EBP homologous protein (CHOP) and phosphorylation of c-Jun N-terminal kinase (JNK), two components of the ER stress-mediated apoptotic pathway. In conclusion, NAC protects against Cd-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in the testes. PMID- 23353716 TI - Exploration of functional health, mental well-being and cross-sex hormone use in a sample of Thai male-to-female transgendered persons (kathoeys). AB - Transgender people sometimes use cross-sex hormones without medical supervision. The use of cross-sex hormones, as well as the functional health and mental well being, among male-to-female transgendered people ('kathoeys') in Chiang Mai, Thailand, was studied. Sixty kathoeys were interviewed regarding their use of cross-sex hormones and their family relationships. Individuals also completed the Life Orientation Test Revised (LOT-R) to assess dispositional optimism, the Social Functioning Questionnaire (SFQ) and the Short Form Health Survey 36 (SF 36). Three categories were established as follows: those who never cross-dress, those who sometimes cross-dress and those who always cross-dress in public. Of the 60 subjects, 44 had used hormones for prolonged periods (9.7+/-6.1 years). Their use was related to the permanence of cross-dressing but unrelated to functional health and mental well-being. Fifty percent of subjects had overdosed on commonly used oral contraceptives. Three people used injectable oestrogen in a higher-than-recommended dose. Self-acceptance was high or reasonably good (83%) compared to no acceptance (17%), and neither was related to the permanence of cross-dressing. Their acceptance by parents and siblings was also relatively high (85% and 89%, respectively). The permanence of cross-dressing had no effect on the scores of optimism, SF-36 scores and social functioning. Acceptance by oneself or one's parents did not seem to affect most aspects of functional health and mental well-being, but non-acceptance by siblings generated lower scores on the social functioning and general mental health subscales. Stressors tended to include physical rather than social factors. In conclusion, the unsupervised use of cross-sex hormones was common among kathoeys, and 50% of the sample had overdosed on them. Acceptance was relatively good, except by siblings. New strategies are needed for a more responsible use of cross-sex hormones. PMID- 23353717 TI - Serum prostate-specific antigen as a predictor of prostate volume and lower urinary tract symptoms in a community-based cohort: a large-scale Korean screening study. AB - The aim of this study is to assess the ability of serum prostate-specific antigen (PSA) to predict prostate volume (PV) and lower urinary tract symptoms (LUTS) represented by the international prostate symptom score (IPSS). From January 2001 to December 2011, data were collected from men who first enrolled in the Korean Prostate Health Council Screening Program. Patients with a serum PSA level of >10 ng ml(-1) or age <40 years were excluded. Accordingly, a total of 34 857 men were included in our study, and serum PSA, PV and the IPSS were estimated in all patients. Linear and age-adjusted multivariate logistic analyses were used to assess the potential association between PSA and PV or IPSS. The predictive value of PSA for estimating PV and IPSS was assessed based on the receiver operating characteristics-derived area under the curve (AUC). The mean PV was 29.9 ml, mean PSA level was 1.49 ng ml(-1) and mean IPSS was 15.4. A significant relationship was shown between PSA and PV, and the IPSS and PSA were also significantly correlated after adjusting by age. The AUCs of PSA for predicting PV >20 ml, >25 ml and >35 ml were 0.722, 0.728 and 0.779, respectively. The AUCs of PSA for predicting IPSS >7, >13 and >19 were 0.548, 0.536 and 0.537, respectively. Serum PSA was a strong predictor of PV in a community-based cohort in a large-scale screening study. Although PSA was also significantly correlated with IPSS, predictive values of PSA for IPSS above the cutoff levels were not excellent. Further investigations are required to elucidate the exact interactions between PSA and LUTS and between PSA and PV in prospective controlled studies. Such studies may suggest how PSA can be used to clinically predict PV and the IPSS. PMID- 23353718 TI - Falling sperm counts twenty years on: where are we now? PMID- 23353719 TI - miR-21, miR-221 and miR-222 expression and prostate cancer recurrence among obese and non-obese cases. AB - Recent evidence shows that certain microRNAs (miRNAs) play a role in both obesity and prostate cancer recurrence, but the association between the expression of these miRNAs and obesity in prostate cancer recurrence is unknown. In this study, we examined the effect of the interaction between obesity and miR-21, miR-221 or miR-222 expression on prostate cancer recurrence among 28 recurrent and 37 non recurrent prostate cancer cases. miRNA expression was determined using quantitative real-time polymerase chain reaction. Cox proportional hazard models adjusting for age at diagnosis, clinical stage and Gleason score were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for recurrence free survival. A significantly (P=0.014) higher proportion of recurrent cases (78.6%) than non-recurrent cases (48.6%) had a low expression of miR-21 and the difference was more prominent in obese than non-obese patients. Multivariate analysis showed that the expression of miR-21 was an independent risk factor for recurrence in obese (HR=6.15, 95% CI=1.04-36.48, P=0.045), but not in non-obese (HR=1.28, 95% CI=0.30-5.49, P=0.74) cases. A significant association with recurrence was not observed for the expression of miR-221 and miR-222. In summary, our findings show that miR-21 is associated with prostate cancer recurrence after radical prostatectomy and suggest that the differential expression of miR-21 is more prominent in obese than in non-obese cases. Future larger studies are warranted to confirm these initial findings and to elucidate the mechanisms involved. PMID- 23353720 TI - Tamsulosin alters levofloxacin pharmacokinetics in prostates derived from rats with acute bacterial prostatitis. AB - The combination of levofloxacin and alpha1 adrenergic antagonist treatment is the current preferred choice for both bacterial and non-bacterial prostatitis. The aim of this study is to explore the influence of alpha1 adrenergic antagonists on the pharmacokinetics of levofloxacin using rat models with acute bacterial prostatitis (ABP) induced by direct injection with Escherichia coli (ATCC25922). A total of 96 model rats were randomly assigned into two groups: the experimental group (treated with both tamsulosin and levofloxacin, n=48) and the control group (treated with levofloxacin and solvents, n=48). Six rats from each group were euthanized to collect blood, liver, kidney and prostate samples at the time points of 0.125, 0.25, 0.5, 1, 2, 4, 8 and 12 h after drug administration. The levofloxacin concentrations were detected by high performance liquid chromatography (HPLC), and the pharmacokinetic parameters were calculated using the 3p97 software program. There were no obvious differences (P>0.05) between the experimental and control groups in the major pharmacokinetic parameters of levofloxacin, including the halftime (t1/2), time to peak (tpeak), clearance rate (CL), maximum concentration (Cmax) and area under the curve (AUC0~12), in the plasma or in the hepatic and kidney tissues of the model rats. However, in the prostatic tissues, tamsulosin increased the Cmax, prolonged the t1/2 and decreased the CL of levofloxacin (P<0.05). These results indicate that tamsulosin may enhance the effect of levofloxacin in the treatment of bacterial prostatitis without changing the drug concentration in the liver and kidney. PMID- 23353721 TI - Corporoplasty with small soft axial prostheses (VIRILIS I(r)) and bovine pericardial graft (HYDRIX(r)) in Peyronie's disease. AB - The surgical techniques used by Austoni and Egydio in the treatment of Peyronie's disease are based on geometric principles. The aim of this paper is to report our multicentric experience and technical changes to Austoni's original technique, focusing on several tips and tricks to make this technique easy to perform, even by less experienced practitioners. We performed operations in three different Italian institutions. We implanted a small soft Virilis I(r) axial prostheses (O 7 Fr.), using a bovine pericardium collagen matrix patch (Hydrix(r)) to cover the defect in the tunica albuginea. Sixty patients with a mean age of 58 years (range 44-76 years) underwent surgery between September 2005 and January 2010. After surgery, mean lengthening of the shaft was 2 cm (range 1.2-2.3 cm) with complete correction of penile recurvatum. Thirty-nine patients resumed sexual activity 60 days later, 14 after 90 days and 7 after 120 days. The international index of erectile function (IIEF) score was 15.5 before surgery and it improved to 23 at 12 and 24 months after surgery. Furthermore, the visual analogue scale (VAS) showed good results in terms of the recovery of natural sexual intercourse (over 80% of couples) and of the original length and girth of the penis. The soft implant we used takes advantage of erection that occurs spontaneously, using the residual erection of the spared cavernous tissue. The method is easy to learn and reproducible, and the use of pericardium speeds up the operation, while also covering large defects of the tunica albuginea that result from complex recurvatum. PMID- 23353722 TI - Are sperm counts declining? Or did we just change our spectacles? PMID- 23353723 TI - Incidence rate of prostate cancer in men treated for erectile dysfunction with phosphodiesterase type 5 inhibitors: retrospective analysis. AB - The purpose of this study was to determine the incidence rate of prostate cancer among men with erectile dysfunction (ED) treated with phosphodiesterase type 5 inhibitors (PDE-5i) over a 7-year period vs. men with ED of the same age and with similar risk factors who were not treated with PDE-5i. In a retrospective review of electronic medical records and billing databases between the years 2000 and 2006, men with ED between the ages of 50 and 69 years and no history of prostate cancer prior to 2000 were identified. These individuals were divided into two groups: 2362 men who had treatment with PDE-5i, and 2612 men who did not have treatment. Demographic data in each group were compared. During the study period, 97 (4.1%) men with ED treated with PDE-5i were diagnosed with prostate cancer compared with 258 (9.9%) men with ED in the non-treated group (P<00001). A higher percentage of African Americans were treated with PDE-5i vs. those who were not (10.5% vs. 7.1%; P<0.0001). The PDE-5i group had lower documented diagnosis of elevated prostate-specific antigen (10.0% vs. 13.1%; P=0.0008) and higher percentage of benign prostatic hyperplasia (38.4% vs. 35.1%; P=0.0149). Men with ED treated with PDE-5i tended to have less chance (adjusted odds ratio: 0.4; 95% confidence intervals: 0.3-0.5; P<0.0001) of having prostate cancer. Our data suggest that men with ED treated with PDE-5i tended to have less of a chance of being diagnosed with prostate cancer. Further research is warranted. PMID- 23353725 TI - Functional relationships. PMID- 23353724 TI - The human and animal baby schema effect: correlates of individual differences. AB - We investigated the animal and human baby schema effect (BSE) in relation to gender, parental status, and individual features. In three, independent online surveys, conducted during three consecutive years, (Ntotal=1389), ratings of photographs of human and animal infants as well as of adults, sociodemographic variables (age, gender, parental status) and personality attributes (empathy, attachment, interpersonal closeness, narcissism, and need to belong) were assessed. We demonstrated that humans are sensitive to the baby schemata of both humans and animals and that both are weakly positively correlated. BSE is positively associated with female gender and (affective) empathy. Higher interpersonal closeness and need to belong were additionally connected specifically to the human BSE. In contrast, narcissism and insecure attachment were not related to the BSE, suggesting a robustness of this phenomenon to possible negative influences of these two personality attributes. PMID- 23353726 TI - What do humans learn in a double, temporal bisection task: absolute or relative stimulus durations? AB - The relative-coding hypothesis of temporal discrimination asserts that humans learn to respond to the relative duration of stimuli ("short" and "long"). The most frequently used procedure to test the hypothesis is the double bisection task. In one task, participants learn that red and green are the correct comparisons following 2s (short) and 5s (long) samples respectively. In another task, participants learn that triangle and circle are the correct comparisons following 3.5s (short) and 6.5s (long) samples, respectively. Later the samples of one task are tested with the comparisons of the other task, and vice versa. According to the hypothesis, participants will choose red following a 3.5s sample because that sample is short and red is the comparison that goes with short. Similarly, they will choose circle following 5s samples because that sample is long and circle goes with long. We replicated this procedure and improved it by introducing several sample durations during testing to obtain the whole psychometric function of each task. Results from Experiment 1 only partially corroborated the relative-coding hypothesis. Results from Experiment 2 did not corroborate the hypothesis. The combined data from Experiments 1 and 2 partially corroborate the hypothesis. Alternatively, we present an explanation of relative coding-like results that posits exclusively absolute coding of temporal stimuli. PMID- 23353727 TI - Insights into the insect salivary gland proteome: diet-associated changes in caterpillar labial salivary proteins. AB - The primary function of salivary glands is fluid and protein secretion during feeding. Compared to mammalian systems, little is known about salivary protein secretion processes and the effect of diet on the salivary proteome in insect models. Therefore, the effect of diet nutritional quality on caterpillar labial salivary gland proteins was investigated using an unbiased global proteomic approach by nanoLC/ESI/tandem MS. Caterpillars of the beet armyworm, Spodoptera exigua Hubner, were fed one of three diets: an artificial diet containing their self-selected protein to carbohydrate (p:c) ratio (22p:20c), an artificial diet containing a higher nutritional content but the same p:c ratio (33p:30c) or the plant Medicago truncatula Gaertn. As expected, most identified proteins were associated with secretory processes and not influenced by diet. However, some diet-specific differences were observed. Nutrient stress-associated proteins, such as peptidyl-propyl cis-trans isomerase and glucose-regulated protein94/endoplasmin, and glyceraldehyde 3-phosphate dehydrogenase were identified in the labial salivary glands of caterpillars fed nutritionally poor diets, suggesting a link between nutritional status and vesicular exocytosis. Heat shock proteins and proteins involved in endoplasmic reticulum-associated protein degradation were also abundant in the labial salivary glands of these caterpillars. In comparison, proteins associated with development, such as arylphorin, were found in labial salivary glands of caterpillars fed 33p:30c. These results suggest that caterpillars fed balanced or nutritionally-poor diets have accelerated secretion pathways compared to those fed a protein-rich diet. PMID- 23353728 TI - A 58-year-old man with a cough and fever. PMID- 23353729 TI - The control of cell adhesion on a PMMA polymer surface consisting of nanopillar arrays. AB - We investigated the effect of arrayed nanostructures on the cell adhesion rate by forming nanopillars on a PMMA polymer surface, and demonstrated cell patterning tools for the polymer surface without biological or chemical reagents. Nanopillar arrayed structures with various heights (0, 50, 100, 150, and 200nm with 50nm of pitch size and 60nm of diameter) were formed on a PMMA surface by using nano molding techniques with nanoporous AAO (anodic aluminum oxide) as a template. The nanopillar arrayed structures provide negative effects on the cell adhesion on the non-treated PMMA (moderate hydrophobic, >=80 degrees of contact angle), whereas slightly positive and no effects were shown by nanopillar structures on plasma (hydrophilic, <=20 degrees ) and silane-treated PMMA (moderate, 40-70 degrees ), respectively. The microstructure on the polymer surface showed a 20% positive effect on the cell adhesion rate. As a result, nano or micro patterning structures could control the cell adhesion rate (15-120%) and it enabled the formation of closed cell patterns on the PMMA surface without chemical or biological surface treatments. PMID- 23353730 TI - Improved properties of micronized genetically modified flax fibers. AB - The aim of this study was to investigate the effect of micronization on the compound content, crystalline structure and physicochemical properties of fiber from genetically modified (GM) flax. The GM flax was transformed with three bacterial (Ralstonia eutropha) genes coding for enzymes of polyhydroxybutyrate (PHB) synthesis and under the control of the vascular bundle promoter. The modification resulted in fibers containing the 3-hydroxybutyrate polymer bound to cellulose via hydrogen and ester bonds and antioxidant compounds (phenolic acids, vanillin, vitexin, etc.). The fibers appeared to have a significantly decreased particle size after 20h of ball-milling treatment. Micronized fibers showed reduced phenolic contents and antioxidant capacity compared to the results for untreated fibers. An increased level of PHB was also detected. Micronization introduces structural changes in fiber constituents (cellulose, hemicellulose, pectin, lignin, PHB) and micronized fibers exhibit more functional groups (hydroxyl, carboxyl) derived from those constituents. It is thus concluded that micronization treatments improve the functional properties of the fiber components. PMID- 23353731 TI - New oxidovanadium(IV) N-acylhydrazone complexes: promising antileishmanial and antitrypanosomal agents. AB - Searching for new promising metal-based hits against Trypanosoma cruzi and Leishmania parasites, two related oxidovanadium(IV) N-acylhydrazone complexes, [V(IV)O(LASSBio1064-2H)(H2O)], 1, and [V(IV)O(LASSBio1064-2H)(phen)].(H2O), 2, where LASSBio1064=(E)-N'-(2-hydroxybenzylidene-4-chlorobenzohydrazide and phen = 1,10-phenanthroline, were synthesized and characterized in the solid state and in solution by elemental analysis, conductimetric measurements and ESI-MS, FTIR, EPR and (51)V NMR spectroscopies and were evaluated on T. cruzi and Leishmania major. In addition, their unspecific cytotoxicity was tested against murine macrophages. Furthermore, to provide insight into the possible mechanism of its antiparasitic action, [VO(LASSbio1064-2H)(phen)].(H2O) was tested for its DNA interaction ability on plasmid DNA by atomic force microscopy (AFM) and on CT DNA by using DNA viscosity measurements and fluorescence spectroscopy. Both complexes were active in vitro against the epimastigote form of T. cruzi (Tulahuen 2 strain) showing IC50 values of the same order or significantly lower than that of the reference trypanosomicidal drug Nifurtimox. However, only the mixed-ligand oxidovanadium(IV) complex 2, which includes phen in its coordination sphere, showed activity on L. major promastigotes with a IC50 value of 22.1 +/- 0.6 MUM. The compounds show low toxicity on mammalian cells (IC50 > 100 MUM). DNA interaction studies showed that the mixed-ligand complex is able to interact with this biomolecule probably through an intercalative mode, pointing out at DNA as a potential target in the parasite. The results suggest that [V(IV)O(LASSBio1064 2H)(phen)].(H2O) may be a promising compound for further drug development stages. PMID- 23353732 TI - High antitumor activity of 5,7-dihalo-8-quinolinolato tin(IV) complexes. AB - Three tin(IV) complexes [Sn(ClQ)2Cl2] (1), [Sn(BrQ)2Cl2] (2) and [Sn(ClIQ)2Cl2] (3) were prepared (H-ClQ = 5,7-dichloro-8-hydroxylquinoline, H-BrQ = 5,7-dibromo 8-hydroxylquinoline, H-ClIQ = 5-chloro-7-iodo-8-hydroxylquinoline) and their in vitro cytotoxicities against BEL7404, SKOV-3, NCI-H460, HL-7702 cell lines were evaluated. The complexes showed high anti-proliferative activity toward the tested cell lines with IC50 values ranging from 20 nM to 5.11 MUM. Compared with 5,7-dihalo-8-quinolinol, most complexes exhibited significantly enhanced cytotoxicity (except 2 against SKOV-3 and NCI-H460). They also displayed some selective cytotoxicity favoring the tested tumor cells over the normal human liver HL-7702 cells. Compared with their quinolinol ligands, complexes 1-3 bind more strongly with DNA. Intercalation is the most probable binding mode for both the complexes and their quinolinol ligands. PMID- 23353733 TI - A flexible approach to 1,4-di-substituted 2-aminoimidazoles that inhibit and disperse biofilms and potentiate the effects of beta-lactams against multi-drug resistant bacteria. AB - The pyrrole-imidazole alkaloids are a 2-aminoimidazoles containing family of natural products that possess anti-biofilm activity. A library of 1,4-di substituted 2-aminoimidazole/triazoles (2-AITs) was synthesized, and its anti biofilm activity as well as oxacillin resensitization efficacy toward methicillin resistant Staphylococcus aureus (MRSA) was investigated. These 2-AITs were found to inhibit biofilm formation by MRSA with low micromolar IC50 values. Additionally, the most active compound acted synergistically with oxacillin against MRSA lowering the minimum inhibitory concentration (MIC) 4-fold. PMID- 23353734 TI - Synthesis and evaluation of oxime derivatives as modulators for amyloid beta induced mitochondrial dysfunction. AB - Starting from quinuclidinyl oxime 1 identified by preliminary screening, a series of azacycles-containing oxime derivatives was synthesized. Their mPTP blocking activities were evaluated by a JC-1 assay, measuring the change of mitochondrial membrane potential. The inhibitory activity of nine compounds against amyloid beta-induced mPTP opening was comparable or even superior to that of piracetam. Among them, 12d effectively maintained mitochondrial function and cell viabilities on the ATP assay, the MTT assay, and the ROS assay. In addition, it exhibited favorable in vitro stability and pharmacokinetic characteristics, which hold a promise for further development of AD therapeutics. PMID- 23353735 TI - Syntheses and anti-allergic activity of 2 ((bis(trimethylsilyl)methylthio/methylsulfonyl)methyl)-5-aryl-1,3,4-oxadiazoles. AB - A new class of sila-substituted 1,3,4-oxadiazoles was synthesized by a convenient synthetic method. Both silathio/silasulfonyl acetic acids were efficiently condensed with benzohydrazides in the presence of phosphorus oxychloride to give sila-substituted 1,3,4-oxadiazoles in high yields. The compounds displayed variable extent of anti-allergic activity on IgE/Ag-stimulated RBL-2H3 cells at 50 and 100 MUM concentrations. Compounds having sulfonyl moiety with bis(trimethylsilyl)-1,3,4-oxadiazoles (5a-c), exhibited better anti-allergic activities than those of compounds having sulphur moiety with bis(trimethylsilyl) 1,3,4-oxadiazoles (4a-c). PMID- 23353736 TI - Synthesis of derivatives of methyl rosmarinate and their inhibitory activities against matrix metalloproteinase-1 (MMP-1). AB - A series of MMP-1 inhibitors have been identified based upon a methyl rosmarinate scaffold using structure-based drug design methods. The best compound in the series showed an IC50 value of 0.4 MUM. A docking study was conducted for compound (S)-10n in order to investigate its binding interactions with MMP-1. The structure-activity relationships (SAR) were also briefly discussed. Useful SAR was established which provides important guidelines for the design of future generations of potent inhibitors against MMP-1. PMID- 23353737 TI - Anti-hepatitis B virus and anti-cancer activities of novel isoflavone analogs. AB - We have synthesized a series of novel isoflavone analogs and evaluated their anti HBV and anti-cancer activities in vitro. The bioassays showed that the majority of the resultant compounds exerted inhibitory effects on HBsAg and HBeAg levels, HBV DNA replication, as well as the growth of four human cancer cell lines to various extents, which supported the rationale of the design. In particular, compound 8f showed the highest activity against HBV infection and HBV-related liver cancer. Compound 7l (IC50 = 0.47 MUM) also exerted remarkable inhibitory effect on the growth lung cancer cell line A-549. PMID- 23353738 TI - Synthesis, cytotoxicity and antiplasmodial activity of novel ent-kaurane derivatives. AB - This paper reports on the syntheses and spectrometric characterisation of eleven novel ent-kaurane diterpenoids, including a complete set of (1)H, (13)C NMR and crystallographic data for two novel ent-kaurane diepoxides. Moreover, the antineoplastic cytotoxicity for kaurenoic acid and the majority of ent-kaurane derivatives were assessed in vitro against a panel of fourteen cancer cell lines, of which allylic alcohols were shown to be the most active compounds. The good in vitro antimalarial activity and the higher selectivity index values observed for some ent-kaurane epoxides against the chloroquine-resistant W2 clone of Plasmodium falciparum indicate that this class of natural products may provide new hits for the development of antimalarial drugs. PMID- 23353739 TI - Synthesis, surface tension properties and antibacterial activities of amphiphilic D-galactopyranose derivatives. AB - Several amphiphilic d-galactopyranose derivatives were synthesized in which the glycosidic moiety was separated from the hydrophobic alkyl chain (along 8 or 12 carbon atoms) by a spacer arm (butyl, butynyl or benzyl) in order to increase their surfactant properties and to obtain new antibacterial compounds. The surface tensions of the products were analyzed by Critical Micelle Concentration (CMC) and gammaCMC measurements and the antimicrobial activities were assayed against 10 bacterial species by Minimum Inhibitory Concentration (MIC) determination in liquid broth. The introduction of an aliphatic spacer arm increased the amphiphilic properties of the compounds and the CMC values were 40 500 times lower than their analogs without spacer arm. In the same manner, the spacer arms significantly increased the antibacterial power of the compounds. The products 4d and 4e exhibiting a C12 alkyl chain and an aliphatic spacer arm (butyl and butynyl) were the best surfactants (CMC = 0.023 and 0.032 mmol/L, respectively) and presented also the best antibacterial activities (MIC = 15.62 and 3.91 MUg/mL for Micrococcus luteus, respectively). But the antibacterial activity of the newly synthesized products seemed to depend more on the cell wall composition of the bacteria than only on the amphiphilic character of the compounds. PMID- 23353740 TI - Biotransformation of LASSBio-579 and pharmacological evaluation of p-hydroxylated metabolite a N-phenylpiperazine antipsychotic lead compound. AB - Using a combination of docking and molecular dynamics simulations, we predicted that p-hydroxylation by CYP1A2 would be the main metabolic pathway for the 1-[1 (4-chlorophenyl)-1H-4pyrazolylmethyl] phenylhexahydropiperazine, LASSBio-579 (3). As the result of a screening process with strains of filamentous fungi, Cunninghamella echinulata ATCC 9244 was chosen to scale up the preparation of the p-hydroxylated metabolite (4). About 30 min after i.p. administration of (3) to rats was identified as the p-hydroxylated metabolite, confirming our in silico previsions. Chemical synthesis of the metabolite was performed and allowed its pharmacological evaluation in binding assays revealing its high affinity for D2 and D4 receptors, indicating that this metabolite should participate to the antipsychotic effect of (3) in vivo. Furthermore, we report here that both (3) and its p-hydroxylated metabolite (4) have a much lower affinity than clozapine for two receptors involved in adverse reactions. Voltammetric assays were useful to understand the redox profile of (3). PMID- 23353741 TI - Synthesis and biological evaluation of some novel resveratrol amide derivatives as potential anti-tumor agents. AB - Three series of novel resveratrol amide derivatives (1a-q, 2a-h, 3a-l) were synthesized and evaluated for their biological activities. All compounds were characterized by (1)H NMR, (13)C NMR, MS and elemental analysis. Furthermore, compound 3e was also characterized by X-ray crystallography. All the compounds were evaluated for their anti-tumor activity against MCF-7, A549 and B16-F10 tumor cell lines as well as cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) inhibitory activity of murine macrophage RAW 264.7 cell line. Among them, compounds 1c, 1g and 3e displayed the most potent COX-2 inhibitory activity with the IC50 values of 1.02, 1.27 and 1.98 MUM, respectively. Molecular docking studies were performed to position compounds 1c and 3e into the active site of COX-2 to determine the probable binding modes. PMID- 23353742 TI - Design, synthesis and SAR of piperidyl-oxadiazoles as 11beta-hydroxysteroid dehydrogenase 1 inhibitors. AB - The potential roles of 11beta-HSD1 inhibitors in metabolic syndrome, T2D and obesity were well established and currently several classes of 11beta-HSD1 inhibitors have been developed as promising agents against metabolic diseases. To find potent compounds with good pharmacokinetics, we used the bioisosterism approach, and designed the compound 2 and 3 bearing an 1,2,4-oxadiazole ring to replace the amide group in compound 1. Guided by docking study, we then transformed compound 3 into a potent lead compound 4a by changing sulfonamide group to amide. To elaborate this series of piperidyl-oxadiazole derivatives as human 11beta-HSD1 inhibitors, we explored the structure-activity relationship of several parts of the lead compound. Based on their potency toward human 11beta HSD1 two compounds 4h and 4q were advanced to pharmacokinetic study. It was found that 4h and 4q are potent and selective human 11beta-HSD1 inhibitors with better pharmacokinetic properties than those of the original piperidine-3-carboxamide compound 1, and suitable for further in vivo preclinical study in primate model. PMID- 23353743 TI - Design and synthesis of novel 1,2,3-triazole-dithiocarbamate hybrids as potential anticancer agents. AB - A series of novel 1,2,3-triazole-dithiocarbamate hybrids were designed, synthesized and evaluated for anticancer activity against four selected human tumor cell lines (MGC-803, MCF-7, PC-3, EC-109). Majority of the synthesized compounds exhibited moderate to potent activity against MGC-803 and MCF-7. Among them, compounds 3a and 3c showed excellent broad spectrum anticancer activity with IC50 values ranging from 0.73 to 11.61 MUM and 0.49-12.45 MUM, respectively. Particularly, compound 3a was more potent than 5-fluorouracil against all tested human cancer cell lines. Flow cytometry analysis demonstrated that treatment of MGC-803 with 3c led to cell cycle arrest at G2/M phase accompanied by an increase in apoptotic cell death after 12 h. PMID- 23353744 TI - Design, synthesis and anticancer properties of 5-arylbenzoxepins as conformationally restricted isocombretastatin A-4 analogs. AB - A series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogs according to a convergent strategy using the coupling of N tosylhydrazones with aryl iodides under palladium catalysis. The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range. In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations. Docking studies demonstrated that benzoxepin 6b adopt an orientation similar to that of isoCA-4 at the colchicine binding site on beta tubulin. PMID- 23353745 TI - (E)-4-aryl-4-oxo-2-butenoic acid amides, chalcone-aroylacrylic acid chimeras: design, antiproliferative activity and inhibition of tubulin polymerization. AB - Antiproliferative activity of twenty-nine (E)-4-aryl-4-oxo-2-butenoic acid amides against three human tumor cell lines (HeLa, FemX, and K562) is reported. Compounds showed antiproliferative activity in one-digit micromolar to submicromolar concentrations. The most active derivatives toward all the cell lines tested bear alkyl substituents on the aroyl moiety of the molecules. Fourteen compounds showed tubulin assembly inhibition at concentrations <20 MUM. The most potent inhibitor of tubulin assembly was unsubstituted compound 1, with IC50 = 2.9 MUM. Compound 23 had an oral LD50in vivo of 45 mg/kg in mice. Cell cycle analysis on K562 cells showed that compounds 1, 2 and 23 caused accumulation of cells in the G2/M phase, but inhibition of microtubule polymerization is not the principal mode of action of the compounds. Nevertheless, they may be useful leads for the design of a new class of antitubulin agents. PMID- 23353746 TI - 2,3-Diarylpropenoic acids as selective non-steroidal inhibitors of type-5 17beta hydroxysteroid dehydrogenase (AKR1C3). AB - The aldo-keto reductase AKR1C3 is an important target for the development of new drugs. Selective inhibitors of this enzyme are needed because they should not inhibit other, structurally closely related AKR1C isoforms. A comprehensive series of 2,3-diarylpropenoic acids was synthesized and evaluated for the inhibition of AKR1C1-AKR1C3. We found that the 4-methylsulfonylphenyl substituent at position 2 of these acids is required to exhibit the selective inhibition of AKR1C3. The best results were obtained for the compounds that fulfill the above requirement and possess a 4-bromophenyl, 4-methylthiophenyl, 4-methylphenyl or 4 ethylphenyl substituent at position 3 of the substituted propenoic acids (i.e., acids 28, 29, 37, and 39, respectively). These compounds represent an important step toward the development of drug candidates for a treatment of the hormone dependent and hormone-independent forms of prostate and breast cancers. PMID- 23353747 TI - Cytotoxicity of lapachol, beta-lapachone and related synthetic 1,4 naphthoquinones against oesophageal cancer cells. AB - Naphthoquinones have been found to have a wide range of biological activities, including cytotoxicity to cancer cells. The secondary metabolites lapachol, alpha and beta-lapachone and a series of 25 related synthetic 1,4-naphthoquinones were screened against the oesophageal cancer cell line (WHCO1). Most of the compounds exhibited enhanced cytotoxicity (IC50 1.6-11.7 MUM) compared to the current drug of choice cisplatin (IC50 = 16.5 MUM). This study also established that the two new synthetic halogenated compounds 12a and 16a (IC50 = 3.0 and 7.3 MUM) and the previously reported compound 11a (IC50 = 3.9 MUM), were non-toxic to NIH3T3 normal fibroblast cells. Cell death of oesophageal cancer cells by processes involving PARP cleavage caused by 11a was shown to be associated with elevated c Jun levels, suggesting a role for this pathway in the mechanism of action of this cohort of naphthoquinone compounds. PMID- 23353748 TI - Design, synthesis and biological evaluation of novel hybrid compounds of imidazole scaffold-based 2-benzylbenzofuran as potent anticancer agents. AB - A series of novel hybrid compounds between 2-benzylbenzofuran and imidazole has been prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the existence of benzimidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl or 4-methoxyphenacyl group were vital for modulating cytotoxic activity. In particular, hybrid compounds 46 and 47 were found to be the most potent derivatives against 5 strains human tumor cell lines and more active than cisplatin (DDP), and exhibited cytotoxic activities selectively against breast carcinoma (MCF-7) and myeloid liver carcinoma (SMMC-7721), respectively. PMID- 23353749 TI - Synthesis of an MIF-1 analogue containing enantiopure (S)-alpha-trifluoromethyl proline and biological evaluation on nociception. AB - The synthesis and the effect of a novel MIF-1 analogue on nociception during acute pain in rat model are reported. The synthesis of this enantiopure trifluoromethyl group containing tripeptide was performed through a peptide coupling reaction between the HCl. Leu-Gly-NH2 and the (S)-alpha-Tfm-proline. The analgesic effect of the CF3-(MIF-1) 2 has been evaluated in vivo on rat model by paw pressure (PP) and hot plate (HP) tests and compared to the native peptide MIF 1. Highest analgesic effect was observed with CF3-(MIF-1) 2 only in PP test. In order to study the mechanisms of nociception induced by the studied peptides, the involvement of the opioid and the nitric oxideergic systems was investigated. The results are in favor of a participation of both system since pretreatment, 20 min before injection of the CF3-(MIF-1) 2, with the non-competitive antagonist of opiate receptors naloxone, the nitric oxide synthase (NOS) inhibitor l-N(G) nitroarginine ester (l-NAME) or the nitric oxide (NO) donor l-arginine (l-Arg) significantly decreased the pain perception in PP and HP tests. PMID- 23353750 TI - Oxo-heterocyclic fused naphthalimides as antitumor agents: synthesis and biological evaluation. AB - Three series of novel oxo-heterocyclic fused naphthalimide derivatives (8a-8f, 13a-13d, 17a-17d) were prepared. The newly-synthesized compounds, and their thio heterocyclic fused analogs (1a-1c, 2a-2d, 3a-3c) exhibited potent antiproliferative activity correlated well with their structure. Further research demonstrated that all the representative compounds 13a, 2a and 17a, 3a showed strong inhibition activity to topo II similarly with amonafide, and also potent topo I inhibition activity, which was seldom reported before for naphthalimide derivatives. Preliminary exploration proved their DNA sequence preference. In all, dual topo I/topo II inhibition and DNA sequence preference might contribute to enhancing tumor selectivity and overcoming drug resistance. PMID- 23353751 TI - Synthesis, characterization, cytotoxicity and antimicrobial studies on bis(N furfuryl-N-(2-phenylethyl)dithiocarbamato-S,S')zinc(II) and its nitrogen donor adducts. AB - [Zn(fpedtc)2] (1), [Zn(fpedtc)2(py)] (2), [Zn(fpedtc)2(1,10-phen)] (3) and [Zn(fpedtc)2(2,2'-bipy)] (4) (where fpedtc = N-furfuryl-N-(2 phenylethyl)dithiocarbamate, py = pyridine, 1,10-phen = 1,10-phenanthroline and 2,2'-bipy = 2,2'-bipyridine) were synthesized. Characterization of the complexes were achieved by IR and NMR ((1)H and (13)C) spectra and in addition, for 2 and 3, by X-ray crystallography. Single crystal X-ray structural analysis of 2 and 3 showed that complex 2 is almost half way between trigonal bipyramidal and square pyramidal and complex 3 has a distorted octahedral geometry. Zn-N distances in 2 is shorter than that found in a six coordinate complex 3 due to the change in coordination number. These complexes were also screened for in vitro antibacterial and antifungal activities and significant activities have been found. In vitro cytotoxic activity of all the synthesized complexes was evaluated on HeLa cell line. Complex 1 exhibits maximum inhibitory effect at a concentration of 40 MUg mL(-1) on HeLa cell line. PMID- 23353752 TI - Synthesis and biological evaluation of novel neuroprotective agents for paraquat induced apoptosis in human neuronal SH-SY5Y cells. AB - Three types of resveratrol analogues were designed, synthesized and evaluated in vitro against paraquat-induced apoptosis in SH-SY5Y cells. The results showed that some compounds, especially those containing an indene core, exhibit good activities. Analogue 3'a showed a potent neuroprotective effect at a low concentration (10 MUM). Further investigation showed that compound 3'a could attenuate paraquat-induced nuclear morphological changes, significantly decrease paraquat-induced ROS (reactive oxygen species) generation in SH-SY5Y cells and elevate the expression of SOD (Superoxide Dismutase) and GPx (glutathione peroxidase) in a dose-dependent manner. Furthermore, analogue 3'a could decrease Bax protein levels in a concentration-dependent manner and increase Bcl-2 protein expression, which was accompanied by increasing chances of cell survival. PMID- 23353753 TI - Novel agmatine dipeptide inhibitors against the West Nile virus NS2B/NS3 protease: a P3 and N-cap optimization study. AB - This communication describes the synthesis and inhibitory activities of thirty seven novel C-terminal agmatine dipeptides used as screening compounds to study the structure-activity relationship between active-site peptidomimetics and the West Nile virus (WNV) NS2B/NS3 serine protease. Our efforts lead to the discovery of a novel agmatine dipeptide inhibitor (compound 33, IC50 2.6 +/- 0.3 MUM) with improved inhibitory activity in comparison to the most potent inhibitor described in our recent report [IC50 4.7 +/- 1.2 MUM; Lim et al., Eur. J. Med. Chem. 46 (2011) 3130-3134]. In addition, our study cleared the contention surrounding the previous X-ray co-crystallization study and an enzyme inhibition report on the binding conformation adopted by active-site peptide aldehydes. Our data should provide valuable insights into the design of future peptidomimetic antivirals against WNV infections. PMID- 23353754 TI - Inhibition of enterovirus 71 infections and viral IRES activity by Fructus gardeniae and geniposide. AB - Fructus gardeniae has long been used by traditional Chinese medical practitioners for its anti-inflammatory, anti-oxidant, anti-tumor and anti-hyperlipidemic characteristics. Here we describe our finding that F. gardeniae greatly reduces anti-enterovirus 71 (EV71) activity, resulting in significant decreases in EV71 virus yields, EV71 infections, and internal ribosome entry site activity. We also found that geniposide, a primary F. gardeniae component, inhibited both EV71 replication and viral IRES activity. Our data suggest the presence of a mechanism that blocks viral protein translation. According to our findings, F. gardeniae and geniposide deserve a closer look as potential chemopreventive agents against EV71 infections. PMID- 23353755 TI - Synthesis, characterization and in vitro anticancer evaluation of novel 1,2,4 triazolin-3-one derivatives. AB - A series of novel 2-(4-chlorophenyl)-5-methyl-4-(2-amine/oxy-ethyl)-2,4-dihydro [1,2,4]triazol-3-one (5a-t) were synthesized and in vitro anticancerous action of the resulting compounds was studied against NCI-60 Human Tumor Cell Line at a single high dose (10(-5) M) concentration for primary cytotoxicity assay. Among the tested compounds (5a-e, 5g-h, 5k, 5p), the compound 5g (NSC: 761736/1) was further evaluated for five dose criteria at five different minimal concentrations against the full panel of 60 human tumor cell lines which exhibited activity against Leukemia (GI50: 1.10 MUM), Non-Small Cell Lung Cancer (GI50: 1.00 MUM), Renal Cancer (GI50: 1.00 MUM), Colon Cancer (GI50: 1.66 MUM), CNS Cancer (GI50: 1.36 MUM), Melanoma (GI50: 1.82 MUM), Ovarian Cancer (GI50: 1.64 MUM) and Breast Cancer (GI50: 1.69 MUM). PMID- 23353756 TI - Synthesis, pharmacological evaluation and QSAR modeling of mono-substituted 4 phenylpiperidines and 4-phenylpiperazines. AB - A series of mono-substituted 4-phenylpiperidines and -piperazines have been synthesized and their effects on the dopaminergic system tested in vivo. The structure activity relationship (SAR) revealed that the position and physicochemical character of the aromatic substituent proved to be critical for the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the brain of freely moving rats. In order to investigate how the structural properties of these compounds affect the response, a set of tabulated and calculated physicochemical descriptors were modeled against the in vivo effects using partial least square (PLS) regression. Furthermore, the binding affinities to the dopamine D2 (DA D2) receptor and monoamine oxidase A (MAO A) enzyme were determined for a chosen subset and QSAR models using the same descriptors as in the in vivo model were produced to investigate the mechanisms leading to the observed DOPAC response. These models, in combination with a strong correlation between the levels of striatal DOPAC and the affinities to DA D2 and MAO A, provides a comprehensive understanding of the biological response for compounds in this class. PMID- 23353757 TI - Coordination chemistry for antibacterial materials: a monolayer of a Cu(2+) 2,2' bipyridine complex grafted on a glass surface. AB - A propyltrimethoxysilane-modified 2,2'-bipyridine ligand is synthesized and its acetonitrile solutions are used to prepare monolayers of the molecule on glass surfaces. Absorption and X-ray photoelectron spectroscopy demonstrate that the modified glass surfaces bind Cu(2+) with a 1:1 ratio with respect to the 2,2' bipyridine moieties under the chosen preparative conditions, producing materials bearing 0.016 MUg cm(-2) of copper. Although in trace amounts, the bound Cu(2+) cations exert a significant microbicidal effect against Escherichia coli and Staphylococcus aureus. PMID- 23353758 TI - Prenatal inhibition of the tryptophan-kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus. AB - Glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) are important in early brain development, influencing cell proliferation and migration, neuritogenesis, axon guidance and synapse formation. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Rats were treated in late gestation with 3,4 dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]-benzene-sulphonamide (Ro61-8048), an inhibitor of kynurenine-3-monoxygenase which diverts kynurenine metabolism to kynurenic acid. Within 5h of drug administration, there was a significant decrease in GluN2A expression and increased GluN2B in the embryo brains, with changes in sonic hedgehog at 24h. When injected dams were allowed to litter normally, the brains of offspring were removed at postnatal day 21 (P21). Recordings of hippocampal field excitatory synaptic potentials (fEPSPs) showed that prenatal exposure to Ro61-8048 increased neuronal excitability and paired pulse facilitation. Long-term potentiation was also increased, with no change in long-term depression. At this time, levels of GluN2A, GluN2B and postsynaptic density protein PSD-95 were all increased. Among several neurodevelopmental proteins, the expression of sonic hedgehog was increased, but DISC1 and dependence receptors were unaffected, while raised levels of doublecortin and Proliferating Cell Nuclear Antigen (PCNA) suggested increased neurogenesis. The results reveal that inhibiting the kynurenine pathway in utero leads to molecular and functional synaptic changes in the embryos and offspring, indicating that the pathway is active during gestation and plays a significant role in the normal early development of the embryonic and neonatal nervous system. PMID- 23353759 TI - Malformations and mortality in the Asian Common Toad induced by exposure to pleurolophocercous cercariae (Trematoda: Cryptogonimidae). AB - Malformations and increased mortality due to infection by the digenetic trematode, Riberioa ondatrae have been reported for many species of amphibians. Severe malformations have also been reported in the Common Hourglass Tree Frog, Polypedates cruciger induced by pleurolophocercous cercariae in Sri Lanka in addition to the changes in the behaviour, development and survival of the host. We exposed pre-limb bud stage tadpoles (Gosner stages 25-26) of the Asian Common Toad, Duttaphrynus melanostictus to the same pleurolophocercous type cercariae under laboratory conditions. Molecular and morphological identification showed that these cercariae belonged Acanthostomum burminis infecting freshwater snakes as definitive hosts. These cercariae induced malformations (27.8%) and reduced survival to metamorphosis (53.8%). The magnitude of the effects increased with the dose of cercariae. Types of malformations were mainly axial, such as scoliosis and kyphosis. Severe limb malformations such as extra or missing limbs as reported for amphibians exposed to R. ondatrae were not observed in the D. melanostictus. Same authors reported a higher percentage of malformations previously when P. cruciger was exposed to the cercariae A. burminis compared to D. melanostictus. However, tadpoles of D. melanostictus, which are smaller compared to those of P. cruciger, experienced higher mortality than P. cruciger tadpoles. Trematode induced malformations and mortality in amphibians are highly variable and depend on multiple factors such as host species differences such as resistance to infection and tolerance, life-history characteristics such as size at metamorphosis and length of the metamorphosis period, and other factors such as size of the amphibian at the time of trematode exposure. PMID- 23353760 TI - Investigations of FT-IR, FT-Raman, FT-NMR spectra and quantum chemical computations of Esculetin molecule. AB - In this work, we report a combined experimental and theoretical study on molecular structure, vibrational spectra and electronic properties of Esculetin (ESC). The FT-IR, FT-Raman and FT-NMR spectra have been recorded and analyzed. The molecular geometry, harmonic vibrational frequencies, chemical shifts, HOMO, LUMO energies and molecular electrostatic potential map of ESC have been calculated by using Density Functional Theory (B3LYP) with 6-311G++(d,p), cc pVDZ, cc-pVQZ and cc-pVTZ basis sets. PMID- 23353761 TI - Development of a reliable analytical method for extraction spectrophotometric determination of ruthenium(III) from catalyst and fissium alloy using o methylphenyl thiourea as a chromogenic chelating ligand. AB - A simple and selective method is developed for the extraction spectrophotometric determination of ruthenium(III) using o-methylphenyl thiourea (OMPT) as a chromogenic chelating ligand. The basis of the proposed method is ruthenium(III) OMPT complex formation in aqueous hydrochloric acid media (3.0molL(-1)) after 5.0min heating on a boiling water bath and the complex formed is extracted into chloroform. The absorbance of green colored ruthenium(III)-OMPT complex is measured at 590nm against the reagent blank. Beer's law was obeyed up to 42.5MUgmL(-1) of ruthenium(III) and the optimum concentration range is 7.56 39.81MUgmL(-1) of ruthenium(III) as evaluated by Ringbom's plot. Molar absorptivity and Sandell's sensitivity of ruthenium(III)-OMPT complex in chloroform are 2.34*10(3)Lmol(-1) cm(-1) and 0.043MUgcm(-2) respectively. The composition of ruthenium(III):OMPT complex (1:2) was established from slope ratio method, mole ratio method and Job's continuous variation method. Complex was stable for more than 48h. The interfering effect of various foreign ions was studied and suitable masking agents are used wherever necessary to enhance the selectivity of the method. Proposed method is successfully applied for determination of ruthenium(III) from binary and ternary synthetic mixtures, synthetic mixtures corresponding to fissium alloy and ruthenium catalyst. Repetition of the method was checked by finding relative standard deviation (R.S.D) for 10 determinations which was 0.23%. A scheme for sequential separation of palladium(II), ruthenium(III), rhodium(III) and platinum(IV) has been developed. PMID- 23353762 TI - Synthesis, structure characterization and antimicrobial evaluation of 4 (substituted phenylazo)-3,5-diacetamido-1H-pyrazoles. AB - The present article deals with the synthesis, spectral characterization and antimicrobial activity of phenylazo dyes. All of the synthesized phenylazo dyes were characterized using ATR-FTIR, FT-Raman, (1)H NMR, (13)C NMR, elemental analysis and mass spectroscopic techniques. Solvent effects on the UV-Vis absorption spectra of these phenylazo dyes were studied. Acid and base effects on the visible absorption maxima of the phenylazo dyes were also reported. The structural and spectroscopic analysis of the molecules were carried out using Density Functional Theory (DFT) employing the standard 6-31G(d) basis set, and the optimized geometries and calculated vibrational frequencies were evaluated via comparison with experimental values. The antimicrobial activity of 4 (substituted phenylazo)-3,5-diacetamido-1H-pyrazoles was reported against bacteria, including B. cereus (RSKK 863), S. aureus (ATCC 259231), M. luteus (NRRL B-4375), E. coli (ATCC 11230) and the yeast C. albicans (ATCC 10239). PMID- 23353763 TI - A rhodamine based fluorescent probe for Hg2+ and its application to cellular imaging. AB - A new rhodamine-based fluorescent probe (Rh-F) for detection of Hg(2+) ions was synthesized, which could bind Hg(2+) in aqueous ethanol (7:3, v/v) at pH 7.0 with detectable change in color and fluorescence. The response is based on a ring opening reaction and formation of a 1:1 complex, while ring-opening process of spirolactam enables large fluorescent enhancement and colorimetric change upon the addition of Hg(2+). The response is reversible and linear in the range between 200nM and 1000nM, with a detection limit of 4.2nM. Selectivity and competition experiments with various other metal ion revealed that Rh-F possesses highly selective fluorescent response to Hg(2+). Furthermore, the probe was successfully applied to fluorescent imaging of Hg(2+) in L-929 cells confirm that Rh-F can be used as a fluorescent probe for monitoring Hg(2+) in living cells. PMID- 23353764 TI - Decellularization for whole organ bioengineering. AB - Organ transplantation in an orthotopic location is the current treatment for end stage organ failure. However, the need for transplantable organs far exceeds the number of available donor organs. As a result, new options, such as tissue engineering and regenerative medicine, have been explored to achieve functional organ replacement. Although there have been many advances in the laboratory leading to the reconstruction of tissue and organ structures in vitro, these efforts have fallen short of producing organs that contain intact vascular networks capable of nutrient and gas exchange and are suitable for transplantation. Recently, advances in whole organ decellularization techniques have enabled the fabrication of scaffolds for engineering new organs. These scaffolds, consisting of naturally-derived extracellular matrix (ECM), provide biological signals and maintain tissue microarchitecture, including intact vascular systems that could integrate into the recipient's circulatory system. The decellularization techniques have led to the development of scaffolds for multiple organs, including the heart, liver, lung and kidney. While the experimental studies involving the use of decellularized organ scaffolds are encouraging, the translation of whole organ engineering into the clinic is still distant. This paper reviews recently described techniques used to decellularize whole organs such as the heart, lung, liver and kidney and describes possible methods for using these matrices for whole organ engineering. PMID- 23353765 TI - Photosynthetic and antioxidant responses of Liquidambar formosana and Schima superba seedlings to sulfuric-rich and nitric-rich simulated acid rain. AB - To study whether differential responses occur in photosynthesis and antioxidant system for seedlings of Liquidambar formosana, an acid rain (AR)-sensitive tree species and Schima superba, an AR-tolerant tree species treated with three types of pH 3.0 simulated AR (SiAR) including sulfuric-rich (S-SiAR), nitric-rich (N SiAR), sulfate and nitrate mixed (SN-SiAR), we investigated the changes of leaf necrosis, chlorophyll content, soluble protein and proline content, photosynthesis and chlorophyll fluorescence characteristics, reactive oxygen species production, membrane lipid peroxidation, small molecular antioxidant content, antioxidant enzyme activities and related protein expressions. Our results showed that SiAR significantly caused leaf necrosis, inhibited photosynthesis, induced superoxide radical and hydrogen peroxide generation, aggravated membrane lipid peroxidation, changed antioxidant enzyme activities, modified related protein expressions such as Cu/Zn superoxide dismutase (SOD), l ascorbate peroxidase (APX, EC 1. 11. 1. 11), glutathione S transferase (GST, EC 2. 5. 1. 18) and Rubisco large subunit (RuBISCO LSU), altered non-protein thiols (NPT) and glutathione (GSH) content in leaves of L. formosana and S. superba. Taken together, we concluded that the damages caused by SiAR in L. formosana were more severe and suffered from more negative impacts than in S. superba. S-SiAR induced more serious damages for the plants than did SN-SiAR and N-SiAR. PMID- 23353766 TI - A novel salt-induced gene from sheepgrass, LcSAIN2, enhances salt tolerance in transgenic Arabidopsis. AB - Salt stress affects plant growth and development, and limits the productivity of crops. Sheepgrass can grow well under various environmental and soil conditions and is a good wild resource in Triticeae. Using 454 high throughout sequencing technique, a large number of salt stress responsive genes have been picked out from sheepgrass. In this study, a novel salt-induced gene and its promoter were cloned and the gene was designated as LcSAIN2 (Leymus chinensissalt-induced 2). Bioinformatics analysis predicted that LcSAIN2 has one transmembrane helix and is localized in nucleus. Experiments of subcellular localization in tobacco leaf cells also indicated that it was mainly localized in nucleus. Several stress responsive elements were found in the promoter region of the LcSAIN2 gene. The expression analysis confirmed that LcSAIN2 was induced by salinity, PEG, ABA, and cold stresses, especially by high salinity. Overexpression of LcSAIN2 in Arabidopsis enhanced salt tolerance of transgenic plants by accumulating osmolytes, such as soluble sugars and free proline, and improving the expression levels of some stress-responsive transcription factors and key genes. Our results suggest that LcSAIN2 might play an important positive modulation role in salt stress tolerance and be a candidate gene utilized for enhancing stress tolerance in wheat and other crops. PMID- 23353767 TI - Biofilms: survival of the wrinkliest. PMID- 23353769 TI - Extreme sweetness: protein glycosylation in archaea. AB - Although N-glycosylation was first reported in archaea almost 40 years ago, detailed insights into this process have become possible only recently, with the availability of complete genome sequences for almost 200 archaeal species and the development of appropriate molecular tools. As a result of these advances, recent efforts have not only succeeded in delineating the pathways involved in archaeal N-glycosylation, but also begun to reveal how such post-translational protein modification helps archaea to survive in some of the harshest environments on the planet. PMID- 23353770 TI - Erythemal dose rate under noon overcast skies. AB - The incidence of ultraviolet radiation (UVR) under noon overcast skies was investigated in an urban, tropical site. Overcast skies stimulate people to be outdoors more freely and carelessly than under a cloudless scenario, thereby representing a situation with UVR. 153 occurrences of noon overcast skies were reported for erythemal dose rates (EDR) of up to 0.395 W m(-2) (Extreme UV-Index) and average of 0.121 W m(-2) (Moderate UVI). Erythemal doses varied from 0.4 to 21.6 Standard Erythema Dose (SED) units and averaged 7.7 SED. 34% of the occurrences of Extreme UVI were events of radiation enhancement up to 19% above the summer peak value of 0.332 W m(-2). The elapsed time for such events ranged from 2 to 7 minutes and averaged 4.5 minutes. Cloud genera referring to EDR were predominantly Cu followed by As in summer, and Cu plus Sc and As in the other seasons. For events of radiation enhancement, cloud genera featured a reduction in the occurrence of Cu and an increase in the occurrence of As and Ac. PMID- 23353768 TI - Sticking together: building a biofilm the Bacillus subtilis way. AB - Biofilms are ubiquitous communities of tightly associated bacteria encased in an extracellular matrix. Bacillus subtilis has long served as a robust model organism to examine the molecular mechanisms of biofilm formation, and a number of studies have revealed that this process is regulated by several integrated pathways. In this Review, we focus on the molecular mechanisms that control B. subtilis biofilm assembly, and then briefly summarize the current state of knowledge regarding biofilm disassembly. We also discuss recent progress that has expanded our understanding of B. subtilis biofilm formation on plant roots, which are a natural habitat for this soil bacterium. PMID- 23353771 TI - Nrf2 is associated with the regulation of basal transcription activity of the BRCA1 gene. AB - BRCA1 is closely related to the pathogenesis of breast cancer. The activity of BRCA1 promoter is regulated by transcriptional factors. The transcription factor Nrf2 (Nuclear factor-erythroid-2p45-related factor 2) is a potent transcriptional activator and plays a central role in inducible expression of many cytoprotective genes. In this report, we found that over-expression of Nrf2 stimulated BRCA1 expression, knockdown of Nrf2 attenuated BRCA1 expression. Nrf2 also interacted with CBP and p300 to form an active transcription complex, which could bind to the ARE (antioxidant response element) site on the BRCA1 promoter and activate its transcription by inducing histone acetylation. Our finding could lead to a better understanding of the development of breast cancer. PMID- 23353772 TI - Changes in plasma methionine-enkephalin levels associated with a cluster headache episode. AB - Eighteen male cluster headache (CH) inpatients within a CH series participated in this research. Blood samples were drawn from patients at least 6-hour pain-free after the last acute CH episode and then shortly prior (SP), during, and soon after (SA) a new acute CH attack. Three healthy male, age-comparable drug-free volunteers served as controls; 5 samples were obtained from each of these individual over a 24-hour period. Individual patient's methionine-enkephalin (MET) plasma concentration showed significant changes, and in some subjects, dramatic changes, during the different phases of a single CH episode. Peptide levels followed a general pattern of higher plasma concentration SP to an acute CH attack, followed by decreased levels during the attack itself, and falling even further SA the acute episode. Consistently, 16 of the 18 patients tested showed pre-CH peptide levels significantly higher (arbitrarily the authors considered values 20% or more as "significant") than their own values obtained during the acute CH pain phase, with observed differences reaching 80% or more in 7 of these individuals. For about half of these patients, peptide concentration during the acute CH episode was significantly above the control's range (68.2 87.6 pg MET/mL; control's circulating MET concentration remaining essentially unchanged during a 24-hour period). MET levels were further decreased in essentially all of the post-CH samples, with values falling within (n = 6) or even further below than those in the control's range (n = 11). Neither age, time of CH occurrence, nor patient's use of a number of medications known for failing to influence plasma MET degradation kinetics seemed to significantly influence MET levels. These results might help in the biochemical characterization of the actual phases of a CH episode. Developing drugs modulating MET bioavailability could lead to novel antinociceptive agents useful for the treatment of CH's associated pain. PMID- 23353773 TI - Prevention by sulforaphane of diabetic cardiomyopathy is associated with up regulation of Nrf2 expression and transcription activation. AB - This study was to investigate whether sulforaphane (SFN) can prevent diabetic cardiomyopathy. Type 1 diabetes was induced in FVB mice by multiple intraperitoneal injections with low-dose streptozotocin. Hyperglycemic and age matched control mice were treated with or without SFN at 0.5mg/kg daily in five days of each week for 3 months and then kept until 6 months. At 3 and 6 months of diabetes, blood pressure and cardiac function were assessed. Cardiac fibrosis, inflammation, and oxidative damage were assessed by Western blot, real-time qPCR, and histopathological examination. SFN significantly prevented diabetes-induced high blood pressure and cardiac dysfunction at both 3 and 6 months, and also prevented diabetes-induced cardiac hypertrophy (increased the ratio of heart weight to tibia length and the expression of atrial natriuretic peptide mRNA and protein) and fibrosis (increased the accumulation of collagen and expression of connective tissue growth factor and tissue growth factor-beta). SFN also almost completely prevented diabetes-induced cardiac oxidative damage (increased accumulation of 3-nitrotyrosine and 4-hydroxynonenal) and inflammation (increased tumor necrotic factor-alpha and plasminogen activator inhibitor 1 expression). SFN up-regulated NFE2-related factor 2 (Nrf2) expression and transcription activity that was reflected by increased Nrf2 nuclear accumulation and phosphorylation as well as the mRNA and protein expression of Nrf2 downstream antioxidants. Furthermore, in cultured H9c2 cardiac cells silencing Nrf2 gene with its siRNA abolished the SFN's prevention of high glucose-induced fibrotic response. These results suggest that diabetes-induced cardiomyopathy can be prevented by SFN, which was associated with the up-regulated Nrf2 expression and transcription function. PMID- 23353774 TI - Growth hormone from striped catfish (Pangasianodon hypophthalmus): genomic organization, recombinant expression and biological activity. AB - Growth hormone is an essential polypeptide required for normal growth and development of vertebrates. In this report, striped catfish (Pangasianodon hypophthalmus) growth hormone gene and cDNA were isolated by reverse transcriptase-polymerase chain reaction. The striped catfish growth hormone (scGH) encoding gene contains 5 exons and 4 introns. The cDNA sequence of the scGH gene contains a 603bp open reading frame and encodes for a 200-aa protein consisting of a putative 22-aa signal peptide and the mature 178-aa protein. The recombinant histidine-tagged scGH protein which expressed in Escherichia coli as inclusion bodies was unfolded, refolded and purified to near-homogeneity by Ni(2+)-NTA chromatography. Analysis of the secondary structure content by CD spectroscopy showed that the alpha-helical content of the refolded scGH is 55%. Elucidation of the folding pathway of scGH by fluorescence spectroscopy showed that denaturation transition of scGH is coincident and cooperative, consistent with the two-state denaturation mechanism. The purified scGH was biologically active and exhibited growth-promoting activity in striped catfish, but not tilapia. PMID- 23353775 TI - Segmented K-mer and its application on similarity analysis of mitochondrial genome sequences. AB - K-mer-based approach has been widely used in similarity analyses so as to discover similarity/dissimilarity among different biological sequences. In this study, we have improved the traditional K-mer method, and introduce a segmented K mer approach (s-K-mer). After each primary sequence is divided into several segments, we simultaneously transform all these segments into corresponding K-mer based vectors. In this approach, it is vital how to determine the optimal combination of distance metric with the number of K and the number of segments, i.e., (K(*), s(*), and d(*)). Based on the cascaded feature vectors transformed from s(*) segmented sequences, we analyze 34 mammalian genome sequences using the proposed s-K-mer approach. Meanwhile, we compare the results of s-K-mer with those of traditional K-mer. The contrastive analysis results demonstrate that s-K mer approach outperforms the traditionally K-mer method on similarity analysis among different species. PMID- 23353776 TI - First report of HGD mutations in a Chinese with alkaptonuria. AB - Alkaptonuria (AKU) is one of the first prototypic inborn errors in metabolism and the first human disease found to be transmitted via Mendelian autosomal recessive inheritance. It is caused by HGD mutations, which leads to a deficiency in homogentisate 1,2-dioxygenase (HGD) activity. To date, several HGD mutations have been identified as the cause of the prototypic disease across different ethnic populations worldwide. However, in Asia, the HGD mutation is very rarely reported. For the Chinese population, no literature on HGD mutation screening is available to date. In this paper, we describe two novel HGD mutations in a Chinese AKU family, the splicing mutation of IVS7+1G>C, a donor splice site of exon 7, and a missense mutation of F329C in exon 12. The predicted new splicing site of the mutated exon 7 sequence demonstrated a 303bp extension after the mutation site. The F329C mutation most probably disturbed the stability of the conformation of the two loops critical to the Fe(2+) active site of the HGD enzyme. PMID- 23353777 TI - DCC (deleted in colorectal carcinoma) gene variants confer increased susceptibility to gallbladder cancer (Ref. No.: Gene-D-12-01446). AB - BACKGROUND AND AIM: GBC is a lethal and multifaceted disease. Deleted in colorectal carcinoma (DCC) is a well known tumor suppressor gene. Recently a small genome-wide association study (GWAS) identified DCC to be significantly associated with gallbladder cancer (GBC) susceptibility in a Japanese population sample. However, the study sample size was small and lacked independent replication. Therefore, the present study was carried out to replicate the association of two GWAS identified DCC SNPs (A>Grs4078288, C>Trs7504990) and two other SNPs (C>Grs2229080 and A>Grs714) previously associated with various cancers. METHODOLOGY: The study was accomplished in 406 GBC cases and 260 healthy control samples from North India. Genotyping was carried out by PCR-RFLP and Taqman genotyping assays. Statistical analysis was performed by using SPSS ver16 and functional prediction of these variants was carried out using Bioinformatics tools (FAST-SNP, F-SNP). RESULT: We did not observe association with GWAS identified SNPs of DCC but other SNPs showed significant association. In addition, a DCC haplotype Grs2229080-Ars4078288-Crs7504990-Ars714 conferred high risk of GBC in India. The haplotype associated risk was independent of gallstone, sex or tobacco usages which are well-known modifiers of GBC risk. Further analysis suggested DCC A>Grs714 as a major risk conferring SNP in the Indian population. CONCLUSION: This study re-affirms the role of plausible tumor suppressor DCC variants, in gallbladder carcinogenesis and the risk haplotype may be explored as a useful marker for GBC susceptibility. PMID- 23353778 TI - Development of a DNA-launched replicon as a vaccine for porcine reproductive and respiratory syndrome virus. AB - Though a modified live attenuated vaccine (MLV) is available against porcine reproductive and respiratory syndrome virus (PRRSV), its limitations in protective efficacy, safety and few others warrant the development of newer vaccines. In this study, we have constructed a propagation-defective DNA-launched PRRSV replicon as a vaccine candidate and evaluated its immunogenicity and protective efficacy in a group of pigs along with MLV vaccinated group. Our data showed that prior to the intranasal challenge with a homologous strain of PRRSV, only MLV vaccinated pigs developed antibody response measured by ELISA and none of the pigs in any group developed PRRSV neutralizing antibodies in serum. The MLV vaccinated group also showed high PRRSV-specific INF-gamma response, whereas the replicon-vaccinated pigs showed low but detectable INF-gamma response. After 14 days post challenge, all groups showed similar PRRSV-specific serum neutralizing titers and were positive for PRRSV-specific ELISA antibody. In addition, the replicon-vaccinated group showed a significant reduction in viremia in comparison to the control group. In conclusion, vaccination with the PRRSV DNA launched replicon decreased the viremia and viral load in bronchoalveolar lavage fluids of the PRRSV-challenged pigs and increased numbers of IFN-gamma producing cells. Thus, the vaccine is partially protective and is a potential vaccine candidate for future with further improvement. The possible means of improvement is the expression of immunostimulatory genes by the replicon. We demonstrated the feasibility of this approach by expression of a foreign gene encoding firefly luciferase after transfection of cultured cells with the replicon plasmid DNA. PMID- 23353779 TI - Evidence of genetic reassortment between Indian isolate of bluetongue virus serotype 21 (BTV-21) and bluetongue virus serotype 16 (BTV-16). AB - The genome of bluetongue virus (BTV) consists of 10 segments. Of these seg-2 encoded VP2 is the major serotype determining protein, and seg-6 encoded VP5 protein enhances the protective neutralizing activity of VP2 protein inducing higher serotype specific antibody titer than the VP2 alone. Out of the twenty-six BTV serotypes found worldwide, 22 were reported from different states of India. These include serotype 21 which was recently isolated from Andhra Pradesh, and was involved in a severe outbreak of bluetongue in Indian native sheep. BTV21 (KMNO-7) and BTV16 were circulating at the same time. This co-circulation, along with the fact that the virus genome is segmented, provides an opportunity for these two isolates of different serotypes to simultaneously infect the same animal, and even the same cell or a same vector with the potential for generation of reassortant viruses. This study was carried out to provide some insights into the outbreak. We carried out full length sequencing of genome seg-2 and seg-6 of Indian isolates VJW64 (BTV16) and KMNO-7 (BTV21). Detailed phylogenetic analysis revealed that genome seg-6 of Indian isolate KMNO-7 (BTV21) clusters with isolates of BTV16 showing maximum nucleotide similarity of 97.6% with TUR/2000/02 isolate of BTV16, which is much more than it shows with any isolate of BTV21. KMNO-7 (BTV21) significantly diverged from original strain of BTV21, and is a reassortant strain having acquired seg-6 from an isolate of BTV16. This study provides some useful insights into the epidemiology of the bluetongue disease, and undermines serotyping on genome seg-6 basis. PMID- 23353780 TI - Inhibition of MerTK increases chemosensitivity and decreases oncogenic potential in T-cell acute lymphoblastic leukemia. AB - Pediatric leukemia survival rates have improved dramatically over the past decades. However, current treatment protocols are still largely ineffective in cases of relapsed leukemia and are associated with a significant rate of chronic health conditions. Thus, there is a continued need for new therapeutic options. Here, we show that mer receptor tyrosine kinase (MerTK) was abnormally expressed in approximately one half of pediatric T-cell leukemia patient samples and T-cell acute lymphoblastic leukemia (T-ALL) cell lines. Stimulation of MerTK by the ligand Gas6 led to activation of the prosurvival proteins Erk 1/2 and Stat5, and MerTK-dependent activation of the STAT pathway in leukemia represents a novel finding. Furthermore, inhibition of MerTK expression increased the sensitivity of T-ALL cells to treatment with chemotherapeutic agents and decreased the oncogenic potential of the Jurkat T-ALL cell line in a methylcellulose colony-forming assay. Lastly, inhibition of MerTK expression significantly increased median survival in a xenograft mouse model of leukemia (30.5 days vs 60 days, P<0.0001). These results suggest that inhibition of MerTK is a promising therapeutic strategy for the treatment of leukemia and may allow for dose reduction of currently used chemotherapeutics resulting in decreased rates of therapy associated toxicities. PMID- 23353781 TI - Characterization of a novel high-density lipoprotein antioxidant capacity assay and its application to high-density lipoprotein fractions. AB - OBJECTIVES: High-density lipoprotein (HDL) inhibits low-density lipoprotein (LDL) oxidation therefore it is involved in the prevention of atherogenesis. HDL particles originating from different persons possess different antioxidant activities. Our aim was to establish a method for the measurement of HDL antioxidant capacity, which is suitable for testing the antioxidant activity of HDL samples in a wide range and produces data relevant to in vivo HDL-LDL interactions. Hemin was used as pro-oxidant since its role in the course of LDL oxidation and atherosclerosis is proven. METHODS: Hemin-induced and hydrogen peroxide catalyzed lipid peroxidation of LDL was performed in the presence and absence of HDL. The time interval required for reaching the maximum reaction velocity (DeltaT(Vmax)) was determined and HDL antioxidant capacity was expressed as the ratio of the DeltaT(Vmax) with and without HDL. HDL fractions (n=8) isolated by ultracentrifugation from healthy donors were analyzed and their antioxidant capacities were compared. RESULTS: In parallel with their increasing density, HDL fractions expressed increasing antioxidant capacity (106.12 194.12%). Within-run and within-laboratory CVs of the method were 1.72-1.87% and 4.09-4.93%, respectively. Alterations of hydrogen peroxide concentration in the range of 50-125 MUmol/L did not influence the assay results, while the elevation of hemin concentration (between 3 and 9 MUmol/L) resulted in decreased antioxidant capacity. The values for hemin degradation correlated well with conjugated diene formation. CONCLUSIONS: Hemin-induced LDL oxidation is a reliable assay system to test the antioxidant capacity of HDL and its subpopulations. PMID- 23353782 TI - Large improvement of photo-response of CuPc sensitized Bi(2)WO(6) with enhanced photocatalytic activity. AB - In order to harvest the solar energy more efficiently, a novel photocatalyst was designed by introducing an organic dye sensitizer, copper phthalocyanine (CuPc), into an inorganic semiconductor Bi(2)WO(6). This composite photocatalyst exhibited an improved photo-response in the whole visible spectrum and even the near infrared region. Under a red LED (lambda = 620 nm) irradiation, the CuPc/Bi(2)WO(6)/FTO electrode showed photocurrent response. The photo-degradation of RhB and phenol under simulated solar light demonstrated that the CuPc Bi(2)WO(6) composite exhibited much higher photocatalytic activity than bare Bi(2)WO(6). Moreover, the composite photocatalyst also showed photo-activity under a red LED (lambda = 620 nm) irradiation, further testifying the sensitization effect of CuPc. This study provides a new strategy to increase the utilization rate of solar energy substantially. PMID- 23353783 TI - In vitro osteogenic differentiation of human amniotic fluid-derived stem cells on a poly(lactide-co-glycolide) (PLGA)-bladder submucosa matrix (BSM) composite scaffold for bone tissue engineering. AB - Stem cells have become an important component of tissue regeneration, as they are able to differentiate into various cell types if guided appropriately. It is well known that cellular differentiation is greatly influenced by the surrounding microenvironment. We have developed a composite scaffold system using a collagen matrix derived from porcine bladder submucosa matrix (BSM) and poly(lactide-co glycolide) (PLGA). In this study, we investigated whether a composite scaffold composed of naturally derived matrix combined with synthetic polymers would provide a microenvironment to facilitate the induction of osteogenic differentiation. We first showed that human amniotic fluid-derived stem cells (hAFSCs) adhered to the composite scaffolds and proliferated over time. We also showed that the composite scaffolds facilitated the differentiation of hAFSCs into an osteogenic lineage. The expression of osteogenic genes, including RUNX2, osteopontin (OPN) and osteocalcin (OCN) was upregulated in cells cultured on the composite scaffolds incubated in the osteogenic medium compared with ones without. Increased alkaline phosphatase (ALP) activity and calcium content indicates that hAFSCs seeded on 3D porous BSM-PLGA composite scaffolds resulted in higher mineralization rates as the duration of induction increased. This was also evidenced by the mineralized matrix within the scaffolds. The composite scaffold system provides a proper microenvironment that can facilitate osteogenic differentiation of AFSCs. This scaffold system may be a good candidate material for bone tissue engineering. PMID- 23353784 TI - A comparative study of the interaction of Tamiflu and Oseltamivir carboxylate with bovine serum albumin. AB - Oseltamivir phosphate (Tamiflu) is a pro-drug that is metabolized to its active form (Oseltamivir carboxylate), after oral administration. OC inhibits influenza A and B neuraminidases in vitro and OP inhibits influenza virus infection and replication in vitro. Serum albumin is the most abundant of the proteins in the circulatory system of a wide variety of organisms and plays an important role in the transport and deposition of many drugs. The aim of this study was to examine the interaction of BSA with Tamiflu and Oseltamivir carboxylate in aqueous solution at physiological conditions, using a constant protein concentration and various drug contents. FTIR, UV-Vis spectroscopic methods were used to determine the drugs binding mode, the binding constant and the effects of drug complexation on protein secondary structure. Structural analysis showed that OP and OC bind BSA with overall binding constants of K(OP-BSA)=1.88 (+/-0.16)*10(4)M(-1) and K(OC-BSA)=5.7 (+/-0.09)*10(2)M(-1). Drug complexation alters protein conformation by major reduction of alpha-helix and random coil and increase of beta-sheet and turn structures that indicate a partial protein destabilization. The results suggest that BSA might act as carrier proteins for OP in delivering it to target molecules. PMID- 23353785 TI - Aberrant histone modifications in peripheral blood mononuclear cells from patients with Henoch-Schonlein purpura. AB - Henoch-Schonlein purpura (HSP), the most common type of leukocytoclastic vasculitis, is caused by T cell-mediated autoimmune reactions. In this study, we analyze histone modification patterns in peripheral blood mononuclear cells (PBMCs) of HSP patients, and investigate the expression levels of inflammatory cytokines (IFN-gamma, IL-2, IL-4, IL-6 and IL-13), transcription factors (T-bet, GATA-3 and TIM-1) and chemokines (CXCL4 and CXCL10) in HSP patients. Our results show that histone H3 acetylation and methylation are significantly enhanced in PBMCs from HSP patients. We also demonstrate specifically that marked increases in histone H3 acetylation and H3 lysine 4 trimethylation occur at the IL-4 loci in these patients. In addition, the expression levels of IL-4, IL-6, IL-13, GATA 3, TIM-1 and CXCL4 are also increased. These findings suggest that abnormal histone modifications are present in the PBMCs of patients with HSP, possibly contributing to the activation of pathological immune responses associated with HSP. PMID- 23353786 TI - Effects of dynamic disorder on exciton delocalization and photoinduced charge separation in DNA. AB - The nature of electronically excited states in DNA is analyzed in detail using a combination of quantum mechanical (QM) semiempirical calculations and molecular dynamics (MD). For this purpose, we consider homogeneous pi stacks extracted from the MD trajectory of a poly(A).poly(T) oligomer. The environment is accounted for within the QM/MM scheme. The effects of structural fluctuations on exciton delocalization and photoinduced charge separation are explored using the quantitative analysis of the electron density in the excited states. We distinguish the effects generated by the vibronic interactions within nucleobases and by the environment of the pi stack. While in ideal B-DNA stacks (A-T)n singlet excited states are spread over all intrastrand nucleobases, the average exciton length is ~0.75n, thermal fluctuations decrease considerably the extent of delocalization. The QM/MD model predicts that the excitons in (A-T)n stacks are spread over 3 bases (for n = 4 and 6, the average exciton length is found to be 2.6 +/- 0.3 and 2.8 +/- 0.3, respectively). We show that the main factor reducing the exciton length is the vibronic interactions within nucleobases whereas fluctuations of the pi stack environment play a relatively minor role. The oscillator strength of electronic transitions from the ground state to charge separated states Ak(+)Ak+/-1(-) and Tk(+)Tk+/-1(-) is found to be strong enough to populate directly these states by UV absorption at E = 5.0-5.3 eV. In contrast, the direct formation of interstrand charge transfer states Ai(+)Tj(-) is predicted to be unlikely. PMID- 23353787 TI - Structural basis for duplex RNA recognition and cleavage by Archaeoglobus fulgidus C3PO. AB - Oligomeric complexes of Trax and Translin proteins, known as C3POs, participate in several eukaryotic nucleic acid metabolism pathways, including RNA interference and tRNA processing. In RNA interference in humans and Drosophila, C3PO activates the RNA-induced silencing complex (RISC) by removing the passenger strand of the small interfering RNA precursor duplex, using nuclease activity present in Trax. How C3POs engage with nucleic acid substrates is unknown. Here we identify a single protein from Archaeoglobus fulgidus that assembles into an octamer highly similar to human C3PO. The structure in complex with duplex RNA reveals that the octamer entirely encapsulates a single 13-base-pair RNA duplex inside a large inner cavity. Trax-like-subunit catalytic sites target opposite strands of the duplex for cleavage separated by 7 base pairs. The structure provides insight into the mechanism of RNA recognition and cleavage by an archaeal C3PO-like complex. PMID- 23353788 TI - Chromatin signatures and retrotransposon profiling in mouse embryos reveal regulation of LINE-1 by RNA. AB - How a more plastic chromatin state is maintained and reversed during development is unknown. Heterochromatin-mediated silencing of repetitive elements occurs in differentiated cells. Here, we used repetitive elements, including retrotransposons, as model loci to address how and when heterochromatin forms during development. RNA sequencing throughout early mouse embryogenesis revealed that repetitive-element expression is dynamic and stage specific, with most repetitive elements becoming repressed before implantation. We show that LINE-1 and IAP retrotransposons become reactivated from both parental genomes after fertilization. Chromatin immunoprecipitation for H3K4me3 and H3K9me3 in 2- and 8 cell embryos indicates that their developmental silencing follows loss of activating marks rather than acquisition of conventional heterochromatic marks. Furthermore, short LINE-1 RNAs regulate LINE-1 transcription in vivo. Our data indicate that reprogramming after mammalian fertilization comprises a robust transcriptional activation of retrotransposons and that repetitive elements are initially regulated through RNA. PMID- 23353790 TI - Inspiring and celebrating women. PMID- 23353789 TI - An asymmetric SMC-kleisin bridge in prokaryotic condensin. AB - Eukaryotic structural maintenance of chromosomes (SMC)-kleisin complexes form large, ring-shaped assemblies that promote accurate chromosome segregation. Their asymmetric structural core comprises SMC heterodimers that associate with both ends of a kleisin subunit. However, prokaryotic condensin Smc-ScpAB is composed of symmetric Smc homodimers associated with the kleisin ScpA in a postulated symmetrical manner. Here, we demonstrate that Smc molecules have two distinct binding sites for ScpA. The N terminus of ScpA binds the Smc coiled coil, whereas the C terminus binds the Smc ATPase domain. We show that in Bacillus subtilis cells, an Smc dimer is bridged by a single ScpAB to generate asymmetric tripartite rings analogous to eukaryotic SMC complexes. We define a molecular mechanism that ensures asymmetric assembly, and we conclude that the basic architecture of SMC-kleisin rings evolved before the emergence of eukaryotes. PMID- 23353791 TI - Postoperative recovery with bispectral index versus anesthetic concentration guided protocols. AB - BACKGROUND: Use of the bispectral index (BIS) monitor has been suggested to decrease excessive anesthetic drug administration, leading to improved recovery from general anesthesia. The purpose of this substudy of the B-Unaware and BAG RECALL trials was to assess whether a BIS-based anesthetic protocol was superior to an end-tidal anesthetic concentration-based protocol in decreasing recovery time and postoperative complications. METHODS: Patients at high risk for awareness were randomized to either BIS-guided or end-tidal anesthetic concentration-guided general anesthesia in the original trials. Outcomes included time to postanesthesia care unit discharge readiness, time to achieve a postoperative Aldrete score of 9-10, intensive care unit length of stay, postoperative nausea and vomiting, and severe postoperative pain. Univariate Cox regression and chi-square tests were used for statistical analyses. RESULTS: The BIS cohort was not superior in time to postanesthesia care unit discharge readiness (hazard ratio, 1.0; 95% CI, 1.0-1.1; n = 2,949), time to achieve an Aldrete score of 9-10 (hazard ratio, 1.2; 95% CI, 1.0-1.4; n = 706), intensive care unit length of stay (hazard ratio, 1.0; 95% CI, 0.9-1.1; n = 2,074), incidence of postoperative nausea and vomiting (absolute risk reduction, -0.5%; 95% CI, -5.8 to 4.8%; n = 789), or incidence of severe postoperative pain (absolute risk reduction, 4.4%; 95% CI, -2.3 to 11.1%; n = 759). CONCLUSIONS: In patients at high risk for awareness, the BIS-guided protocol is not superior to an anesthetic concentration-guided protocol in time needed for postoperative recovery or in the incidences of common postoperative complications. PMID- 23353792 TI - Neuroprotective effects of dexmedetomidine against glutamate agonist-induced neuronal cell death are related to increased astrocyte brain-derived neurotrophic factor expression. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays a prominent role in neuroprotection against perinatal brain injury. Dexmedetomidine, a selective agonist of alpha2-adrenergic receptors, also provides neuroprotection against glutamate-induced damage. Because adrenergic receptor agonists can modulate BDNF expression, our goal was to examine whether dexmedetomidine's neuroprotective effects are mediated by BDNF modulation in mouse perinatal brain injury. METHODS: The protective effects against glutamate-induced injury of BDNF and dexmedetomidine alone or in combination with either a neutralizing BDNF antibody or an inhibitor of the extracellular signal-regulated kinase pathway (PD098059) were compared in perinatal ibotenate-induced cortical lesions (n = 10-20 pups/groups) and in mouse neuronal cultures (300 MUM of ibotenate for 6 h). The effect of dexmedetomidine on BDNF expression was examined in vivo and in vitro with cortical neuronal and astrocyte isolated cultures. RESULTS: Both BDNF and dexmedetomidine produced a significant neuroprotective effect in vivo and in vitro. Dexmedetomidine enhanced Bdnf4 and Bdnf5 transcription and BDNF protein cortical expression in vivo. Dexmedetomidine also enhanced Bdnf4 and Bdnf5 transcription and increased BDNF media concentration in isolated astrocyte cultures but not in neuronal cultures. Dexmedetomidine's protective effect was inhibited with BDNF antibody (mean lesion size +/- SD: 577 +/- 148 MUm vs. 1028 +/- 213 MUm, n = 14-20, P < 0.001) and PD098059 in vivo but not in isolated neuron cultures. Finally, PD098059 inhibited the increased release of BDNF induced by dexmedetomidine in astrocyte cultures. CONCLUSION: These results suggest that dexmedetomidine increased astrocyte expression of BDNF through an extracellular signal-regulated kinase-dependent pathway, inducing subsequent neuroprotective effects. PMID- 23353793 TI - Involvement of the Tyr kinase/JNK pathway in carbachol-induced bronchial smooth muscle contraction in the rat. AB - BACKGROUND: Tyrosine (Tyr) kinases and mitogen-activated protein kinases have been thought to participate in the contractile response in various smooth muscles. The aim of the current study was to investigate the involvement of the Tyr kinase pathway in the contraction of bronchial smooth muscle. METHODS: Ring preparations of bronchi isolated from rats were suspended in an organ bath. Isometric contraction of circular smooth muscle was measured. Immunoblotting was used to examine the phosphorylation of c-Jun N-terminal kinasess (JNKs) in bronchial smooth muscle. RESULTS: To examine the role of mitogen-activated protein kinase(s) in bronchial smooth muscle contraction, the effects of MPAK inhibitors were investigated in this study. The contraction induced by carbachol (CCh) was significantly inhibited by pretreatment with selective Tyr kinase inhibitors (genistein and ST638, n = 6, respectively), and a JNK inhibitor (SP600125, n = 6). The contractions induced by high K depolarization (n = 4), orthovanadate (a potent Tyr phosphatase inhibitor) and sodium fluoride (a G protein activator; NaF) were also significantly inhibited by selective Tyr kinase inhibitors and a JNK inhibitor (n = 4, respectively). However, the contraction induced by calyculin-A was not affected by SP600125. On the other hand, JNKs were phosphorylated by CCh (2.2 +/- 0,4 [mean+/-SEM] fold increase). The JNK phosphorylation induced by CCh was significantly inhibited by SP600125 (n = 4). CONCLUSION: These findings suggest that the Tyr kinase/JNK pathway may play a role in bronchial smooth muscle contraction. Strategies to inhibit JNK activation may represent a novel therapeutic approach for diseases involving airway obstruction, such as asthma and chronic obstructive pulmonary disease. PMID- 23353794 TI - Surgery results in exaggerated and persistent cognitive decline in a rat model of the Metabolic Syndrome. AB - BACKGROUND: Postoperative cognitive decline can be reproduced in animal models. In a well-validated rat model of the Metabolic Syndrome, we sought to investigate whether surgery induced a more severe and persistent form of cognitive decline similar to that noted in preliminary clinical studies. METHODS: In rats that had been selectively bred for low and high exercise endurance, the low capacity runners (LCR) exhibited features of Metabolic Syndrome (obesity, dyslipidemia, insulin resistance, and hypertension). Tibial fracture surgery was performed under isoflurane anesthesia in LCR and high capacity runner (HCR) rats and cognitive function was assessed postoperatively in a trace-fear conditioning paradigm and Morris Water Maze; non-operated rats were exposed to anesthesia and analgesia (sham). Group sizes were n = 6. RESULTS: On postoperative D7, LCR rats had shorter freezing times than postoperative HCR rats. Five months postoperatively, LCR rats had a flatter learning trajectory and took longer to locate the submerged platform than postoperative HCR rats; dwell-time in the target quadrant in a probe trial was shorter in the postoperative LCR compared to HCR rats. LCR and HCR sham rats did not differ in any test. CONCLUSION: Postoperatively, LCR rats diverged from HCR rats exhibiting a greater decline in memory, acutely, with persistent learning and memory decline, remotely; this could not be attributed to changes in locomotor or swimming performance. This Metabolic Syndrome animal model of surgery-induced cognitive decline corroborates, with high fidelity, preliminary findings of postoperative cognitive dysfunction in Metabolic Syndrome patients. PMID- 23353795 TI - Limb remote ischemic preconditioning for intestinal and pulmonary protection during elective open infrarenal abdominal aortic aneurysm repair: a randomized controlled trial. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) may confer the cytoprotection in critical organs. The authors hypothesized that limb RIPC would reduce intestinal and pulmonary injury in patients undergoing open infrarenal abdominal aortic aneurysm repair. METHODS: In this single-center, prospective, double blinded, randomized, parallel-controlled trial, 62 patients undergoing elective open infrarenal abdominal aortic aneurysm repair were randomly assigned in a 1:1 ratio by computerized block randomization to receive limb RIPC or conventional abdominal aortic aneurysm repair (control). Three cycles of 5-min ischemia/5-min reperfusion induced by a blood pressure cuff placed on the left upper arm served as RIPC stimulus. The primary endpoint was arterial-alveolar oxygen tension ratio. The secondary endpoints mainly included the intestinal injury markers (serum intestinal fatty acid-binding protein, endotoxin levels, and diamine oxidase activity), the markers of oxidative stress and systemic inflammatory response, and the scores of the severity of intestinal and pulmonary injury. RESULTS: In limb RIPC group, a/A ratio was significantly higher than that in control group at 8, 12, and 24 h after cross-clamp release (66 +/- 4 vs. 45 +/- 4, P = 0.003; 60 +/- 6 vs. 37 +/- 4, P = 0.002; and 60 +/- 5 vs. 47 +/- 6, P = 0.039, respectively). All biomarkers reflecting intestinal injury increased over time, and there was significant differences between limb RIPC and control group (P < 0.001). The severity of intestinal and pulmonary injury was decreased by limb RIPC (P = 0.014 and P = 0.001, respectively). CONCLUSIONS: Limb RIPC attenuates intestinal and pulmonary injury in patients undergoing elective open infrarenal abdominal aortic aneurysm repair without any potential risk. PMID- 23353797 TI - Anesthesiology: an art or a science? PMID- 23353798 TI - To be there. PMID- 23353796 TI - Effective volume of ropivacaine 0.75% through a catheter required for interscalene brachial plexus blockade. AB - BACKGROUND: Ultrasound guidance during peripheral nerve blocks has allowed for reduction in dose and volume of local anesthetic required to accomplish successful blockade using multiple injections through a needle. The authors undertook this study to determine the minimal effective volume required to accomplish successful interscalene brachial plexus block (ISB) through the catheter. METHODS: After obtaining institutional ethics committee approval and written informed consent, patients aged 18-75 yr and scheduled for arthroscopic shoulder surgery under ISB were enrolled. All patients using a step-up/step-down method and the starting dose of 15 ml of 0.75% ropivacaine received an ultrasound guided ISB catheter. The injection volume was increased or decreased by 1 ml in case of block failure or block success, respectively. RESULTS: The authors found that the proportion of patients with successful blockade increased sharply from approximately 57% at 6 ml to 100% by 7 ml, indicating that a small increase in volume of ropivacaine 0.75% markedly affects the success rate. A total of 12 ISB with injection volume less than 7 ml resulted in successful anesthesia within 30 min, yielding an ED95 of 7 ml (95% CI 6.8-7.2) ropivacaine 0.75%. For the group as a whole, the median (min-max) sensory block onset time was 5 (5-20) min, the median (min-max) motor blocks for the biceps and the deltoid muscles were 7.5 (5 15) min and 10 (5-15) min, respectively. The median (min-max) block duration was 8.9 (3-15) h. CONCLUSIONS: An injection of a minimum of 7 ml of ropivacaine 0.75% through the catheter is required for success rate and timely onset of surgical anesthesia with ISB. PMID- 23353800 TI - Taxonomic characterization, adaptation strategies and biotechnological potential of cryophilic yeasts from ice cores of Midre Lovenbreen glacier, Svalbard, Arctic. AB - Ten strains of cryophilic yeast were studied from glacier ice cores of Svalbard, Arctic. The ice melt samples contained about 3*10(3) - 1*10(4) colony forming unit (CFUs) per ml. Sequence analysis of the isolates, using D1/D2 domain identified five species of yeasts: Cryptococcus adeliensis (MLB-18 JX192655), Cryptococcus albidosimilis (MLB-19 JX192656), Cryptococcus saitoi (MLB-22 JX192659), Rhodosporidium lusitaniae (MLB-20 JX192657), and Rhodotorula mucilaginosa (MLB-27 JX192664). Effect of temperature on growth of these isolates was studied. The strains are able to grow at temperatures ranging between 1 and 20 degrees C. Screening of the cultures for amylase, cellulase, protease, lipase, urease and catalase activity were carried out indicating varying amounts of enzyme production at different temperatures. Characterization of lipase in strain Cryptococcus sp. MLB-24 was performed. Fatty acid methyl ester (FAME) analysis of the cultures grown at four different temperatures (1, 4, 15, and 20 degrees C) was also done. Decrease in temperature was reported to cause increase in concentration of unsaturated fatty acids. High amount of oleic acid accumulated with increase in temperature. These fatty acids possibly help the strains to survive in glacial ice core cold environment. The extracellular and intracellular filtrate of the cultures showed negative antifreeze protein (AFP) activity. The observations indicate that probably the isolates in the present undertaking adapt to low temperatures, by enzyme and PUFA secretion rather than by antifreeze protein secretion. PMID- 23353801 TI - Isothermal vitrification methodology development for non-cryogenic storage of archival human sera. AB - Biorepositories worldwide collect human serum samples and store them for future research. Currently, hundreds of biorepositories across the world store human serum samples in refrigerators, freezers, or liquid nitrogen without following any specific cryopreservation protocol. This method of storage is both expensive and potentially detrimental to the biospecimens. To decrease both cost of storage and the freeze/thaw stresses, we explored the feasibility of storing archival human serum samples at non-cryogenic temperatures using isothermal vitrification. When biospecimens are vitrified, biochemical reactions can be stopped, the specimen ceases to degrade, and macromolecules can be stabilized without requiring cryogenic storage. In this study, 0.2, 0.4, or 0.8M trehalose; 0, 0.005 or 0.01M dextran; and 0 or 10% (v/v) glycerol was added to human serum samples. The samples were either dried diffusively as sessile droplets or desiccated under vacuum after they are adsorbed onto glass microfiber filters. The glass transition temperatures (Tg) of the desiccated samples were measured by temperature-ramp Fourier Transform Infrared (FTIR) spectroscopy. Sera samples vitrified at 4+/-2 degrees C when 0.8M trehalose and 0.01M dextran were added and the samples were vacuum dried for two hours. Western immunoblotting showed that vitrified serum proteins were minimally degraded when stored for up to one month at 4 degrees C. About 80% of all proteins were recovered after storage at 4 degrees C on glass microfiber filters, and recovery did not decrease with storage time. These results demonstrated the feasibility of long-term storage of vitrified serum at hypothermic (and non-cryogenic) temperatures. PMID- 23353803 TI - Semi-ambulatory autologous peripheral blood SCT in 79 patients with multiple myeloma. PMID- 23353802 TI - Allogeneic matched-sibling hematopoietic cell transplantation for AML: comparable outcomes between Eastern Mediterranean (EMBMT) and European (EBMT) centers. AB - Allogeneic hematopoietic cell transplantation (HCT) activity significantly increased in the Eastern Mediterranean area over the past decade. However, comparative outcomes with longer established centers, especially European Blood and Marrow Transplantation (EBMT) centers, have not been reported. We compared outcomes of matched-sibling allogeneic HCT between East Mediterranean Blood and Marrow Transplantation (EMBMT) and EBMT centers for adult patients with AML in first CR using myeloablative conditioning. We matched 431 patients from EMBMT with 431 patients from EBMT centers according to patient, disease and transplant characteristics. EMBMT recipients and donors were more likely to be CMV seropositive. There were no significant differences in the incidence of acute or chronic GVHD, or the 3-year cumulative incidence of non-relapse mortality (NRM) and relapse incidence (RI) between the two groups (NRM: EMBMT=16% vs EBMT=11), (RI: EMBMT=13% vs EBMT=19%). Notably, the 3-year leukemia-free survival (LFS) and OS were similar between the groups (LFS: EMBMT=70+/-2% vs EBMT=69+/-3%), (OS: EMBMT=74+/-2% vs EBMT=73+/-2%). Despite differences in socioeconomics, health resources and transplant experience, matched-sibling allogeneic HCT outcomes in emerging centers in the EMBMT region appear similar to EBMT centers. PMID- 23353804 TI - Measurement of oral chronic GVHD: results from the Chronic GVHD Consortium. AB - Oral chronic GVHD (cGVHD) is a serious complication of alloSCT. Scales and instruments to measure oral cGVHD activity and severity have not been prospectively validated. The objective of this study was to describe the characteristics of oral cGVHD and determine the measures most sensitive to change. Patients enrolled in the cGVHD Consortium with oral involvement were included. Clinicians scored oral changes according to the National Institutes of Health (NIH) criteria, and patients completed symptom and quality-of-life measures at each visit. Both rated change on an eight-point scale. Of the 458 participants, 72% (n=331) had objective oral involvement at enrollment. Lichenoid change was the most common feature (n=293; 89%). At visits where oral change could be assessed, 50% of clinicians and 56% of patients reported improvement, with worsening reported in 4-5% for both the groups (weighted kappa=0.41). Multivariable regression modeling suggested that the measurement changes most predictive of perceived change by clinicians and patients were erythema and lichenoid, NIH severity and symptom scores. Oral cGVHD is common and associated with a range of signs and symptoms. Measurement of erythema and lichenoid changes and symptoms may adequately capture the activity of oral cGVHD in clinical trials but require prospective validation. PMID- 23353805 TI - Magnetic field triggered drug release from polymersomes for cancer therapeutics. AB - Local and temporal control of drug release has for long been a main focus in the development of novel drug carriers. Polymersomes, which can load both hydrophilic and hydrophobic species and, at the same time, be tailored to respond to a desired stimulus, have drawn much attention over the last decade. Here we describe polymersomes able to encapsulate up to 6% (w/w) of doxorubicin (DOX) together with 30% (w/w) of superparamagnetic iron oxide nanoparticles (USPIO; gamma-Fe2O3). Upon internalization in HeLa cells and when a high frequency AC magnetic field (14mT at 750kHz) was applied, the developed delivery system elicited an 18% increase in cell toxicity, associated with augmented DOX release kinetics. In order to ensure that the observed cytotoxicity arose from the increased doxorubicin release and not from a pure magnetic hyperthermia effect, polymersomes loaded with magnetic nanoparticles alone were also tested. In this case, no increased toxicity was observed. We hypothesize that the magnetic field is inducing a very local hyperthermia effect at the level of the polymersome membrane, increasing drug release. This approach opens new perspectives in the development of smart delivery systems able to release drug upon demand and therefore, improving treatment control. PMID- 23353806 TI - Multifunctional terpolymeric MRI contrast agent with superior signal enhancement in blood and tumor. AB - A new multifunctional terpolymeric system for simultaneous imaging and drug delivery has been recently developed in our laboratory. Herein we report the investigation of terpolymeric contrast agent for magnetic resonance imaging and doxorubicin (Dox) delivery. The polymer was synthesized by graft polymerization of methacrylic acid (MAA) and polysorbate 80 (PS 80) onto starch with multiple, chemically bound diethylenetriaminepenta acetic acid (DTPA) groups for gadolinium chelating. The terpolymer self-assembled to form nanoparticles upon addition of doxorubicin which binds with the PMAA chain. The physicochemical, biological and pharmacokinetic properties of the polymeric system were characterized and their contrast enhancement capability was evaluated in vitro and in vivo. The polymer was able to load gadolinium with high thermodynamic stability and exhibited low cytotoxicity. The Gd-loaded polymer (PolyGd), and Gd-Dox co-loaded nanoparticles (PolyGd-Dox) significantly enhanced MR signals, with ionic T1 relaxivities 3-5 times higher than those from Omniscan(r), a small molecule contrast agent. In vivo studies showed superior and prolonged contrast enhancement compared to Omniscan(r) at one fourth the equivalent dose, without adverse effects. The PolyGd and PolyGd-Dox accumulated in the tumor and painted the tumor boundaries clearly for at least 48h. The PolyGd also enhanced angiogram contrast with contrast to noise ratio values of up to 55-fold and a blood half-life time of 200min. Seven days after intravenous administration, only relatively small amounts of gadolinium could be detected in the major organs of the mice (supplementary materials). These results suggest that the new terpolymeric system is useful as a theranostic platform for contrast enhanced MR imaging of vasculature and tumor as well as Dox delivery. PMID- 23353808 TI - Silica-lipid hybrid (SLH) formulations enhance the oral bioavailability and efficacy of celecoxib: An in vivo evaluation. AB - This study is the first to demonstrate in canines the ability of silica-lipid hybrid (SLH) microparticles to enhance the bioavailability and efficacy of a poorly water-soluble drug after oral administration. Spray-dried SLH microparticles comprising Capmul MCM (mono-diglycerides of C8/C12 fatty acids) and silica nanoparticles (Aerosil(r) 380) were shown to significantly enhance the fasted state oral bioavailability of celecoxib (CEL) (6.5 fold, relative to an aqueous suspension and more than 2-fold higher relative to the fed state) after oral administration to beagle dogs. Comparable bioavailability was observed between the SLH microparticle formulation and a conventional Capmul lipid solution, however, plasma concentrations were observed to be higher (Cmax, 1.1+/ 0.06 vs. 0.8+/-0.03MUg/mL) (p<=0.05) with the SLH microparticle system. The enhanced bioavailability of CEL observed with the SLH microparticles was reflected in a subsequent efficacy study conducted in an adjuvant-induced arthritis model in the rat. Reduced clinical and histological severity was observed at a dose of 3mg/kg/day, with the progression of arthritic symptoms and tissue damage reduced to a similar degree to that of a higher dose administered at 5mg/kg/day and prepared in an aqueous suspension., The enhanced bioavailability and improved efficacy observed with the SLH microparticles were attributed to the maintenance of CEL in a solubilised form during digestion of the lipid vehicle. We hypothesise that the presence of silica in the formulation may have contributed to the prevention of drug precipitation in the intestinal lumen by providing an alternative binding site for CEL to adsorb to prior to re solubilisation and absorption. The study highlights the potential utility of novel SLH microparticle formulations as stable dry powders that possess the properties of a lipid-based formulation for the enhanced delivery and efficacy of poorly water-soluble drugs. PMID- 23353807 TI - Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension. AB - Current pharmacological interventions for pulmonary arterial hypertension (PAH) require continuous infusions, multiple inhalations, or oral administration of drugs that act on various pathways involved in the pathogenesis of PAH. However, invasive methods of administration, short duration of action, and lack of pulmonary selectivity result in noncompliance and poor patient outcomes. In this study, we tested the hypothesis that encapsulation of an investigational anti-PAH molecule fasudil (HA-1077), a Rho-kinase inhibitor, into liposomal vesicles results in prolonged vasodilation in distal pulmonary arterioles. Liposomes were prepared by hydration and extrusion method and fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient. Liposomes were then characterized for various physicochemical properties. Optimized formulations were tested for pulmonary absorption and their pharmacological efficacy in a monocrotaline (MCT) induced rat model of PAH. The entrapment efficiency of optimized liposomal fasudil formulations was between 68.1+/-0.8% and 73.6+/-2.3%, and the cumulative release at 37 degrees C was 98-99% over a period of 5 days. Compared to intravenous (IV) fasudil, a ~10 fold increase in the terminal plasma half-life was observed when liposomal fasudil was administered as aerosols. The t1/2 of IV fasudil was 0.39+/-0.12 h. and when given as liposomes via pulmonary route, the t1/2 extended to 4.71+/-0.72 h. One h after intratracheal instillation of liposomal fasudil, mean pulmonary arterial pressure (MPAP) was reduced by 37.6+/-5.7% and continued to decrease for about 3 h, suggesting that liposomal formulations produced pulmonary preferential vasodilation in MCT induced PAH rats. Overall, this study established the proof-of-principle that aerosolized liposomal fasudil is a feasible option for a non-invasive, controlled release and pulmonary preferential treatment of PAH. PMID- 23353809 TI - Troubleshooting carry-over of LC-MS/MS method for rifampicin, clarithromycin and metabolites in human plasma. AB - Clarithromycin and rifampicin are used for the treatment of Mycobacteria. Pharmacokinetic drug interaction is possibly due to the influence of the two drugs on the liver enzymes. Using a Hypurity Aquastar C18 column (50mm*2.1mm*5MUm) for liquid chromatography including a polar end-capped phase for the determination of clarithromycin, rifampicin and their metabolites together in plasma using LC-MS/MS resulted in a substantial carry-over. As a consequence, the throughput of the method is not assured. Using a step-by-step troubleshooting procedure, such carry-over was found originating from column memory effect. With the use of another type of C18 column, the carry-over is eliminated. Due to the absence of carry-over, the analytical concentration ranges are extended and are therefore more appropriate for the analysis of patient samples. The method was re-validated for linearity, reproducibility and dilution integrity. PMID- 23353810 TI - Development of ultrasound-assisted emulsification microextraction for determination of thiocynate ion in human urine and saliva samples. AB - Ultrasound-assisted emulsification microextraction (USAE-ME) procedure coupled with UV-vis spectrophotometric measurement has been developed for determination of thiocyanate ion (SCN(-)) in water and biological fluids samples. The method is based on protonation of SCN(-) ions in acidic medium and extraction of thiocyanic acid into fine droplets of chloroform as an extraction solvent contains rhodamine B (RhB). The RhB was protonated in presence of thiocynanic acid to form highly colored ion-pair complex of [thiocynate][RhBH(+)] in chloroform, which used for subsequent spectrophotometric determination of SCN(-) ions. Experimental parameters for both spectrophotometric reaction and USAE-ME procedure have been optimized. Under optimized conditions the calibration curve for SCN(-) showed good linearity in the range of 38.0-870.0ngmL(-1) (R(2)=0.9967). The limit of detection (S/N=3) and preconcentration factor were 5.0ngmL(-1) and 40, respectively. Relative standard deviation for determination of 200ngmL(-1) of SCN(-) was 2.8% (n=5). The proposed method has been successfully applied for determination of SCN(-) ion in tap water, mineral bottled water and human saliva and urine samples with an average recovery of 99.2%. PMID- 23353811 TI - Development of a sensitive and selective LC-MS/MS method for the determination of urea in human epithelial lining fluid. AB - A sensitive, selective, and quantitative method for the determination of urea has been developed and validated in human epithelial lining fluid (ELF; the supernatant from bronchoalveolar lavage). The method employs a simple derivatization of urea with camphanic chloride to improve the chromatographic retention and separation. The derivatization was performed after drying an aliquot of ELF (20MUL) without prior sample clean-up. Ultra High Performance Liquid Chromatography (UHPLC) on a HSS-T3 stationary phase column with 1.8MUm particle size was used for chromatographic separation coupled to tandem mass spectrometry. The method was validated over the concentration range of 8.78 103.78MUg/mL, however the dynamic range can be further lowered if needed. The results from assay validation show that the method is rugged, precise, accurate, and well-suited to support analysis of urea in ELF samples. In addition, the relatively small sample volume (20MUL) and a run time of 1.5min facilitate automation and allow for high-throughput analysis. This derivatization method was compared to a commercially available colorimetric assay kit, and it was used in a preclinical non-GLP mouse study where urea measurements were used as marker of bronchoalveolar lavage fluid dilution. PMID- 23353812 TI - Purification of recombinant EGFP by fusion with L2 (252-273) from ribosomal protein L2 using magnetic particles. AB - A basic polypeptide L2 (252-273) derived from Escherichia coli ribosomal protein L2 was used as a purification tag. In order to develop faster, less expensive methods for expression and purification of proteins, the L2 (252-273)-small ubiquitin like modifier (SUMO) fusion expression system was constructed. We comparatively analyzed the adsorption properties of the deleted protein of L2 (L2 (252-273)) on diatomite and superparamagnetic carboxymethyl chitosan nanoparticles. The time required to reach adsorption equilibrium of L2 (252-273) fusion protein on diatomite was shorter than that of L2 (252-273) fusion protein on magnetic particles. The maximum adsorption capacity of L2 (252-273) fusion protein on magnetic particles was about 5 times larger than that of L2 (252-273) fusion protein on diatomite. SUMO was introduced as a specific protease cleavage site between the target protein and the purification tags. The enhanced green fluorescent protein (EGFP) as a model protein was fused with the L2 (252-273) SUMO fusion protein and purified by a simple method which involves the electrostatic adsorption of L2 (252-273) fusion proteins on superparamagnetic carboxymethyl chitosan nanoparticles and the L2 (252-273)-SUMO fusion partner was removed based on the robust cleavage by the poly lysine tagged SUMO protease. The high purity of tag-free EGFP (>93%) was obtained. Our results preliminary proved that the system was an effective fusion expression system for the production of recombinant proteins in E. coli. PMID- 23353813 TI - Dinuclear mixed-valence Co(III)Co(II) complexes derived from a macrocyclic ligand: unique example of a Co(III)Co(II) complex showing catecholase activity. AB - The work in this paper presents the syntheses, characterization, catecholase activity, and electrospray ionization mass spectroscopic (ESI-MS positive) study of three mixed-valence dinuclear Co(III)Co(II) complexes of composition [Co(III)Co(II)L(N(3))(3)].CH(3)CN (1), [Co(III)Co(II)L(OCN)(3)].CH(3)CN (2), and [Co(III)Co(II)L(MU-CH(3)COO)(2)](ClO(4)) (3), derived from a tetraimino diphenolate macrocyclic ligand H(2)L, obtained on [2 + 2] condensation of 4-ethyl 2,6-diformylphenol and 2,2'-dimethyl-1,3-diaminopropane. While 1 and 2 are diphenoxo-bridged, 3 is a heterobridged bis(MU-phenoxo)bis(MU-acetate) system. Utilizing 3,5-di-tert-butyl catechol (3,5-DTBCH(2)) as the substrate, the catecholase activity of all the three complexes has been checked in methanol/acetonitrile/N,N-dimethyl formamide. While 2 and 3 are inactive, complex 1 shows catecholase activity with turnover numbers of 482.16 h(-1) and 45.38 h( 1) in acetonitrile and methanol, respectively. Electrospray ionization mass (ESI MS positive) spectra of complexes 1-3 have been recorded in acetonitrile solutions and the positive ions have been well characterized. The ESI-MS positive spectrum of complex 1 in the presence of 3,5-DTBCH(2) has also been recorded and, interestingly, two positive ions [Co(III)Co(II)L(N(3))(2)(3,5-DTBCH(-))H](+) and [Co(II)Co(II)L(MU-3,5-DTBCH(2-))Na](+) have been identified. PMID- 23353814 TI - In vitro evaluation of the interactions between human corneal endothelial cells and extracellular matrix proteins. AB - The corneal endothelium is the innermost cell layer of the cornea and rests on Descemet's membrane consisting of various extracellular matrix (ECM) proteins which can directly affect the cellular behaviors such as cell adhesion, proliferation, polarity, morphogenesis and function. The objective of this study was to investigate the interactions between the ECM environment and human corneal endothelial cells (HCECs), with the ultimate goal to improve cell proliferation and function in vitro. To evaluate the interaction of HCECs with ECM proteins, cells were seeded on ECM-coated tissue culture dishes, including collagen type I (COL I), collagen type IV (COL IV), fibronectin (FN), FNC coating mix (FNC) and laminin (LM). Cell adhesion and proliferation of HCECs on each substratum and expression of CEC markers were studied. The results showed that HCECs plated on the COL I, COL IV, FN and FNC-coated plates had enhanced cell adhesion initially; the number for COL I, COL IV, FN and FNC was significantly higher than the control (P < 0.05). In addition, cells grown on ECM protein-coated dishes showed more compact cellular morphology and CEC marker expression compared to cells seeded on uncoated dishes. Collectively, our results suggest that an adequate ECM protein combination can provide a long-term culture environment for HCECs for corneal endothelium transplantation. PMID- 23353815 TI - Involvement of the essential metal transporter Zip14 in hepatic Cd accumulation during inflammation. AB - Upregulation of Zip14 contributes to hepatic zinc (Zn) and non-transferrin-bound iron (Fe) uptake during infection and inflammation. We investigated whether this essential metal transporter is also involved in hepatic cadmium (Cd) uptake under these conditions. An injection of lipopolysaccharide (LPS), turpentine oil (Tur) and n-hexane (Hex) resulted in an decrease in plasma Zn and Fe concentrations to 25-50% and an increase in hepatic concentrations of both metals to 150-200% of control mice. LPS significantly increased plasma interleukin (IL)-6 levels more rapidly than Tur or Hex. Tur or Hex significantly increased hepatic Zip14 mRNA expression and decreased ferroportin 1 mRNA expression following continuous increase of IL-6 level. Hepatic Cd and Zn concentrations increased significantly after repeated injections of Cd in Tur- or Hex-treated mice fed a control diet. Treatment with Tur or Hex additionally increased hepatic Cd accumulation in Zn deficient mice, unlike in Fe-deficient mice. These results suggest that Zn transporters, such as Zip14, may be involved in hepatic Cd uptake during inflammation. PMID- 23353816 TI - Differential toxicity and gene expression in Caco-2 cells exposed to arsenic species. AB - Inorganic arsenic [As(V)+As(III)] and its metabolites, especially the trivalent forms [monomethylarsonous acid, MMA(III), and dimethylarsinous acid, DMA(III)], are considered the forms of arsenic with the highest degree of toxicity, linked to certain types of cancer and other pathologies. The gastrointestinal mucosa is exposed to these forms of arsenic, but it is not known what toxic effect these species may have on it. The aim of the present work was to evaluate the toxicity and some mechanisms of action of inorganic arsenic and its metabolites [monomethylarsonic acid, MMA(V), dimethylarsinic acid, DMA(V), MMA(III) and DMA(III)] in intestinal epithelial cells, using the Caco-2 human cell line as a model. The results show that the pentavalent forms do not produce toxic effects on the intestinal monolayer, but the trivalent species have a different degree of toxicity. As(III) induces death mainly by necrosis, whereas only apoptotic cells are detected after exposure to MMA(III), and for DMA(III) the percentages of apoptosis and necrosis are similar. The three forms produce reactive oxygen species, accompanied by a reduction in intracellular GSH and lipid peroxidation, the latter being especially notable in the dimethylated form. They also alter the enzyme activity of glutathione peroxidase and catalase and induce expression of stress proteins and metallothioneins. The results indicate that the trivalent forms of arsenic can affect cell viability of intestinal cells by mechanisms related to the induction of oxidative stress. Further studies are needed to evaluate how the effects observed in this study affect the structure and functionality of the intestinal epithelium. PMID- 23353817 TI - A novel microarray chemiluminescence method based on chromium oxide nanoparticles catalysis for indirect determination of the explosive triacetone triperoxide at the scene. AB - Chromium oxide (Cr(2)O(3)) nanoparticles were found to greatly enhance the chemiluminescence (CL) of the luminol-hydrogen peroxide (H(2)O(2)) system. A novel microarray CL method was originally developed for the detection of triacetone triperoxide (TATP). The novel CL method was based on the outstanding catalytic effect of a Cr(2)O(3) nanoparticle array on the CL reaction between lower concentrations of luminol and H(2)O(2), which come from hydrolysis of TATP vapor. The calibration curve of H(2)O(2) was linear over a range of 1.0 * 10(-8) to 3.0 * 10(-5) M with a detection limit of 1.6 * 10(-9) M (R(2) = 0.9992, n = 12). The CL method has the advantages of being sensitive, selective, simple, time saving, high-throughput, and shows good reproducibility. Therefore, these merits would make it easily popular. PMID- 23353818 TI - MicroRNA-296-5p increases proliferation in gastric cancer through repression of Caudal-related homeobox 1. AB - Caudal-related homeobox 1 (CDX1), an intestinal-specific transcription factor, has been reported to have vital roles in gastric intestinal metaplasia (IM). Although IM is a high-risk factor for gastric cancer (GC), the specific role of CDX1 in GC is largely unknown. In this study, we investigated the expression of CDX1 and its functional roles in GC, and its upstream regulatory mechanisms at the microRNA (miRNA) level were further explored. We found that CDX1 is lost in GC when compared with adjacent IM tissues. Gain-of-function studies showed that CDX1 significantly inhibited GC cell growth by inducing cell cycle arrest and apoptosis. Interestingly, we identified and verified an onco-mir, miR-296-5p, as a direct upstream regulator of CDX1. miR-296-5p overexpression significantly promoted GC cell growth and attenuated the CDX1-induced anti-growth effects by recurring cell cycle distribution and apoptotic status, whereas knockdown of miR 296-5p decreased GC cell growth. Furthermore, we found that the extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation and the subsequent downstream changes in protein levels related to cell cycle and apoptosis partly account for the miR-296-5p-CDX1-induced GC growth promotion. In addition, the detection of miR-296-5p and expression of CDX1 in primary GC tissues and adjacent IM tissues revealed that miR-296-5p is inversely correlated with CDX1, further supporting our in vitro results. Our results showed an anti-growth effect of CDX1 and identified its miRNA regulatory mechanism in GC. The identification of this novel miR-296-5p-CDX1-ERK1/2 axis sheds new light on the understanding of the process from IM to GC and may provide therapeutic targets for the treatment of GC. PMID- 23353820 TI - DNA: leukemia's secret weapon of bone mass destruction. AB - Interaction of tumour cells with their microenvironment impacts on all aspects of cancer, ranging from development through to treatment response. In this issue, Dvorak and colleagues(1) reveal a novel tumour/microenvironment relationship that may drive leukemia pathogenesis. Specifically, they find that leukemic cells secrete chromatin-complexed DNA that, in turn, triggers a variety of harmful effects, including cell death, in neighbouring stromal cells. Through this toxicity, DNA-mediated bone marrow destruction could promote disease progression by allowing leukemic cells to exit the bone marrow into the circulation. PMID- 23353819 TI - Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer. AB - MicroRNA-155 (miR-155) is frequently upregulated in various types of human cancer; however, its role in cancer angiogenesis remains unknown. Here, we demonstrate the role of miR-155 in angiogenesis through targeting von Hippel Lindau (VHL) tumour suppressor in breast cancer. Ectopic expression of miR-155 induced whereas knockdown of miR-155 inhibited human umbilical vein endothelial cell network formation, proliferation, invasion and migration. Furthermore, mammary fat pad xenotransplantation of ectopically expressed miR-155 resulted in extensive angiogenesis, proliferation, tumour necrosis and recruitment of pro inflammatory cells such as tumour-associated macrophages. Expression of VHL abrogated these miR-155 effects. Moreover, miR-155 expression inversely correlates with VHL expression level and is associated with late-stage, lymph node metastasis and poor prognosis, as well as triple-negative tumour in breast cancer. These findings indicate that miR-155 has a pivotal role in tumour angiogenesis by downregulation of VHL, and provide a basis for miR-155-expressing tumours to embody an aggressive malignant phenotype, and therefore miR-155 is an important therapeutic target in breast cancer. PMID- 23353821 TI - Cystathionase mediates senescence evasion in melanocytes and melanoma cells. AB - The development of malignant melanoma is a highly complex process, which is still poorly understood. A majority of human melanomas are found to express a few oncogenic proteins, such as mutant RAS and BRAF variants. However, these oncogenes are also found in nevi, and it is now a well-accepted fact that their expression alone leads to senescence. This renders the understanding of senescence escape mechanisms an important point to understand tumor development. Here, we approached the question of senescence evasion by expressing the transcription factor v-myc myelocytomatosis viral oncogene homolog (c-MYC), which is known to act synergistically with many oncogenes, in melanocytes. We observed that MYC drives the evasion of reactive-oxygen stress-induced melanocyte senescence, caused by activated receptor tyrosine kinase signaling. Conversely, MIZ1, the growth suppressing interaction partner of MYC, is involved in mediating melanocyte senescence. Both, MYC overexpression and Miz1 knockdown led to a strong reduction of endogenous reactive-oxygen species (ROS), DNA damage and senescence. We identified the cystathionase (CTH) gene product as mediator of the ROS-related MYC and MIZ1 effects. Blocking CTH enzymatic activity in MYC overexpressing and Miz1 knockdown cells increased intracellular stress and senescence. Importantly, pharmacological inhibition of CTH in human melanoma cells also reconstituted senescence in the majority of cell lines, and CTH knockdown reduced tumorigenic effects such as proliferation, H2O2 resistance and soft agar growth. Thus, we identified CTH as new MYC target gene with an important function in senescence evasion. PMID- 23353822 TI - Control of glutamine metabolism by the tumor suppressor Rb. AB - Retinoblastoma (Rb) protein is a tumor suppressor that is dysregulated in a majority of human cancers. Rb functions to inhibit cell cycle progression in part by directly disabling the E2F family of cell cycle-promoting transcription factors. Because the de novo synthesis of multiple glutamine-derived anabolic precursors is required for cell cycle progression, we hypothesized that Rb also may directly regulate proteins involved in glutamine metabolism. We examined glutamine metabolism in mouse embryonic fibroblasts (MEFs) isolated from mice that have triple knock-outs (TKO) of all three Rb family members (Rb-1, Rbl1 and Rbl2) and found that loss of global Rb function caused a marked increase in (13)C glutamine uptake and incorporation into glutamate and tricarboxylic acid cycle (TCA) intermediates in part via upregulated expression of the glutamine transporter ASCT2 and the activity of glutaminase 1 (GLS1). The Rb-controlled transcription factor E2F-3 altered glutamine uptake by direct regulation of ASCT2 mRNA and protein expression, and E2F-3 was observed to associate with the ASCT2 promoter. We next examined the functional consequences of the observed increase in glutamine uptake and utilization and found that glutamine exposure potently increased oxygen consumption, whereas glutamine deprivation selectively decreased ATP concentration in the Rb TKO MEFs but not the wild-type (WT) MEFs. In addition, TKO MEFs exhibited elevated production of glutathione from exogenous glutamine and had increased expression of gamma-glutamylcysteine ligase relative to WT MEFs. Importantly, this metabolic shift towards glutamine utilization was required for the proliferation of Rb TKO MEFs but not for the proliferation of the WT MEFs. Last, addition of the TCA cycle intermediate alpha-ketoglutarate to the Rb TKO MEFs reversed the inhibitory effects of glutamine deprivation on ATP, GSH levels and viability. Taken together, these studies demonstrate that the Rb/E2F cascade directly regulates a major energetic and anabolic pathway that is required for neoplastic growth. PMID- 23353823 TI - MicroRNAs and the genetic network in aging. AB - MicroRNAs (miRNAs) comprise a class of small RNAs important for the posttranscriptional regulation of numerous biological processes. Their combinatorial mode of function, in which an individual miRNA can target many genes and multiple miRNAs share targets, makes them especially suited for regulating processes and pathways at the "network" level. In particular, miRNAs have recently been implicated in aging, which is a complex process known to involve multiple pathways. Findings from genome-wide miRNA expression profiling studies highlight three themes in miRNA function during aging: many miRNAs are differentially expressed, many such miRNAs target known aging-associated pathways, and there are global trends in miRNA expression change over time. In addition, several miRNAs have emerged as potentially coordinating multiple pathways during aging. Elucidating the underlying network structure of genes and miRNAs involved in aging processes promises to advance our understanding of not only aging and associated pathogenesis but also how miRNAs can connect disparate pathways. PMID- 23353824 TI - Structural basis of the interaction of the breast cancer oncogene LMO4 with the tumour suppressor CtIP/RBBP8. AB - LIM-only protein 4 (LMO4) is strongly linked to the progression of breast cancer. Although the mechanisms underlying this phenomenon are not well understood, a role is emerging for LMO4 in regulation of the cell cycle. We determined the solution structure of LMO4 in complex with CtIP (C-terminal binding protein interacting protein)/RBBP8, a tumour suppressor protein that is involved in cell cycle progression, DNA repair and transcriptional regulation. Our data reveal that CtIP and the essential LMO cofactor LDB1 (LIM-domain binding protein 1) bind to the same face on LMO4 and cannot simultaneously bind to LMO4. We hypothesise that overexpression of LMO4 may disrupt some of the normal tumour suppressor activities of CtIP, thereby contributing to breast cancer progression. PMID- 23353825 TI - Brucella immunogenic BP26 forms a channel-like structure. AB - An outer membrane protein BP26/OMP28 of Brucella, BP26, is identified as a major immunodominant antigen and widely used as a diagnostic marker and for vaccination against Brucellosis. BP26 belongs to the family of proteins that contains a SIMPL (signaling molecule that associates with the mouse pelle-like kinase) domain, whose structure and function have been unknown. Here, we present the crystal structure of BP26 revealing that 16 BP26 molecules form a novel channel-like assembly as also shown by electron microscopy analysis. Eight BP26 molecules forming a ring structure contain a hole at the center of the octamer, and another octamer interacts with each other to form a channel having a large internal cavity. BP26 is found to be structurally similar to a bacteriophage protein involved in infection, implicating that BP26 might function during Brucella infection. In addition, the BP26 structure suggests that the protein functions as a multimeric channel-like form and provides a canonical model for the SIMPL domains. PMID- 23353827 TI - Domain swapping in the cytoplasmic domain of the Escherichia coli rhomboid protease. AB - Rhomboids are membrane-embedded serine proteases that cleave membrane protein substrates. Escherichia coli rhomboid GlpG (ecGlpG) consists of an N-terminal cytoplasmic domain and a membrane domain containing the active site. We determined the crystal structure of the soluble cytoplasmic domain of ecGlpG at 1.35A resolution and examined whether this domain affected the catalytic activity of the enzyme. The structure revealed that the ecGlpG cytoplasmic domain exists as a dimer with extensive domain swapping between the two monomers. Domain swapped dimers can be isolated from the full-length protein, suggesting that this is a physiologically relevant structure. An extensive steady-state kinetic analysis of the full-length ecGlpG and its membrane domain using soluble and transmembrane model protein substrates resulted in an unexpected conclusion: removal of the cytoplasmic domain does not alter the catalytic parameters for detergent-solubilized rhomboid for both substrates. PMID- 23353828 TI - Understanding protein-protein interactions using local structural features. AB - Protein-protein interactions (PPIs) play a relevant role among the different functions of a cell. Identifying the PPI network of a given organism (interactome) is useful to shed light on the key molecular mechanisms within a biological system. In this work, we show the role of structural features (loops and domains) to comprehend the molecular mechanisms of PPIs. A paradox in protein protein binding is to explain how the unbound proteins of a binary complex recognize each other among a large population within a cell and how they find their best docking interface in a short timescale. We use interacting and non interacting protein pairs to classify the structural features that sustain the binding (or non-binding) behavior. Our study indicates that not only the interacting region but also the rest of the protein surface are important for the interaction fate. The interpretation of this classification suggests that the balance between favoring and disfavoring structural features determines if a pair of proteins interacts or not. Our results are in agreement with previous works and support the funnel-like intermolecular energy landscape theory that explains PPIs. We have used these features to score the likelihood of the interaction between two proteins and to develop a method for the prediction of PPIs. We have tested our method on several sets with unbalanced ratios of interactions and non interactions to simulate real conditions, obtaining accuracies higher than 25% in the most unfavorable circumstances. PMID- 23353826 TI - beta-hairpin-mediated nucleation of polyglutamine amyloid formation. AB - The conformational preferences of polyglutamine (polyQ) sequences are of major interest because of their central importance in the expanded CAG repeat diseases that include Huntington's disease. Here, we explore the response of various biophysical parameters to the introduction of beta-hairpin motifs within polyQ sequences. These motifs (tryptophan zipper, disulfide, d-Pro-Gly, Coulombic attraction, l-Pro-Gly) enhance formation rates and stabilities of amyloid fibrils with degrees of effectiveness well correlated with their known abilities to enhance beta-hairpin formation in other peptides. These changes led to decreases in the critical nucleus for amyloid formation from a value of n=4 for a simple, unbroken Q23 sequence to approximate unitary n values for similar length polyQs containing beta-hairpin motifs. At the same time, the morphologies, secondary structures, and bioactivities of the resulting fibrils were essentially unchanged from simple polyQ aggregates. In particular, the signature pattern of solid-state NMR (13)C Gln resonances that appears to be unique to polyQ amyloid is replicated exactly in fibrils from a beta-hairpin polyQ. Importantly, while beta-hairpin motifs do produce enhancements in the equilibrium constant for nucleation in aggregation reactions, these Kn values remain quite low (~10(-)(10)) and there is no evidence for significant enhancement of beta-structure within the monomer ensemble. The results indicate an important role for beta-turns in the nucleation mechanism and structure of polyQ amyloid and have implications for the nature of the toxic species in expanded CAG repeat diseases. PMID- 23353831 TI - How did I get here? PMID- 23353829 TI - Allosteric inhibition of a zinc-sensing transcriptional repressor: insights into the arsenic repressor (ArsR) family. AB - The molecular basis of allosteric regulation remains a subject of intense interest. Staphylococcus aureus CzrA is a member of the ubiquitous arsenic repressor (ArsR) family of bacterial homodimeric metal-sensing proteins and has emerged as a model system for understanding allosteric regulation of operator DNA binding by transition metal ions. Using unnatural amino acid substitution and a standard linkage analysis, we show that a His97' NH(epsilon2)...O=C His67 quaternary structural hydrogen bond is an energetically significant contributor to the magnitude of the allosteric coupling free energy, ?Gc. A "cavity" introduced just beneath this hydrogen bond in V66A/L68V CzrA results in a significant reduction in regulation by Zn(II) despite adopting a wild-type global structure and Zn(II) binding and DNA binding affinities only minimally affected from wild type. The energetics of Zn(II) binding and heterotropic coupling free energies (?Hc, -T?Sc) of the double mutant are also radically altered and suggest that increased internal dynamics leads to poorer allosteric negative regulation in V66A/L68V CzrA. A statistical coupling analysis of 3000 ArsR proteins reveals a sector that links the DNA-binding determinants and the alpha5 Zn(II)-sensing sites through V66/L68 in CzrA. We propose that distinct regulatory sites uniquely characteristic of individual ArsR proteins result from evolution of distinct connectivities to this sector, each capable of driving the same biological outcome, transcriptional derepression. PMID- 23353832 TI - The pedicled reverse-flow lateral arm flap for coverage of complex traumatic elbow injuries. AB - PURPOSE: The pedicled reverse-flow lateral arm flap has been described primarily for the reconstruction of nontraumatic elbow wounds. We describe our experience using this flap in staged operations for soft tissue coverage after elbow trauma, including acute coverage of open fractures and salvage of infected hardware. METHODS: Review of patients who underwent staged pedicled reverse-flow lateral arm flap transfer for coverage of traumatic elbow defects. RESULTS: Three patients were identified; all underwent 2-stage repair with flap delay for coverage of traumatic elbow injuries. Each patient had stable wound coverage with this flap. The only complication was 5% distal flap necrosis in 1 patient. CONCLUSIONS: The pedicled reverse-flow lateral arm flap provides reliable soft tissue coverage of traumatic elbow defects with minimal donor-site morbidity. PMID- 23353830 TI - Structural and functional analysis of the C-terminal domain of Nup358/RanBP2. AB - The nuclear pore complex is the sole mediator of bidirectional transport between the nucleus and cytoplasm. Nup358 is a metazoan-specific nucleoporin that localizes to the cytoplasmic filaments and provides several binding sites for the mobile nucleocytoplasmic transport machinery. Here we present the crystal structure of the C-terminal domain (CTD) of Nup358 at 1.75A resolution. The structure reveals that the CTD adopts a cyclophilin-like fold with a non canonical active-site configuration. We determined biochemically that the CTD possesses weak peptidyl-prolyl isomerase activity and show that the active-site cavity mediates a weak association with the human immunodeficiency virus-1 capsid protein, supporting its role in viral infection. Overall, the surface is evolutionarily conserved, suggesting that the CTD serves as a protein-protein interaction platform. However, we demonstrate that the CTD is dispensable for nuclear envelope localization of Nup358, suggesting that the CTD does not interact with other nucleoporins. PMID- 23353833 TI - The use of fluorescent intrabodies to detect endogenous gankyrin in living cancer cells. AB - Expression of antibody fragments in mammalian cells (intrabodies) is used to probe the target protein or interfere with its biological function. We previously described the in vitro characterisation of a single-chain Fv (scFv) antibody fragment (F5) isolated from an intrabody library that binds to the oncoprotein gankyrin (GK) in solution. Here, we have isolated several other scFvs that interact with GK in the presence of F5 and tested whether they allow, when fused to fluorescent proteins, to detect by FRET endogenous GK in living cells. The binding of pairs of scFvs to GK was analysed by gel filtration and the ability of each scFv to mediate nuclear import/export of GK was determined. Binding between scFv-EGFP and RFP-labelled GK in living cells was detected by fluorescence lifetime imaging microscopy (FLIM). After co-transfection of two scFvs fused to EGFP and RFP, respectively, which form a tri-molecular complex with GK in vitro, FRET signal was measured. This system allowed us to observe that GK is monomeric and distributed throughout the cytoplasm and nucleus of several cancer cell lines. Our results show that pairs of fluorescently labelled intrabodies can be monitored by FLIM-FRET microscopy and that this technique allows the detection of lowly expressed endogenous proteins in single living cells. PMID- 23353834 TI - Critical role of TXNIP in oxidative stress, DNA damage and retinal pericyte apoptosis under high glucose: implications for diabetic retinopathy. AB - Diabetic retinopathy (DR) is characterized by early loss of retinal capillary pericytes and microvascular dysfunction. We recently showed that pro-oxidative stress and pro-apoptotic thioredoxin interacting protein (TXNIP) is significantly up-regulated in rat retinas in experimental diabetes and mediates inflammation and apoptosis. Therefore, we hypothesize here that TXNIP up-regulation in pericyte plays a causative role in oxidative stress and apoptosis under sustained high glucose exposure in culture. We maintained a rat retinal capillary pericyte cell line (TR-rPCT1) for 5 days under low glucose (LG, 5.5mM) or high glucose (HG, 25 mM) with or without anti-oxidant N-acetylcysteine (5mM, NAC), Azaseine (2 MUM, AzaS), an inhibitor of TXNIP, and TXNIP siRNA (siTXNIP3, 20 nM). The results show that HG increases TXNIP expression in TR-rPCT1, which correlates positively with ROS generation, protein S-nitrosylation, and pro-apoptotic caspase-3 activation. Furthermore, pericyte apoptosis is demonstrated by DNA fragmentation (alkaline comet assay) and a reduction in MTT survival assay. Treatment of TR rPCT1 with NAC or an inhibition of TXNIP by AzaS or siTXNIP3 each reduces HG induced ROS, caspase-3 activation and DNA damage demonstrating that TXNIP up regulation under chronic hyperglycemia is critically involved in cellular oxidative stress, DNA damage and retinal pericyte apoptosis. Thus, TXNIP represents a novel gene and drug target to prevent pericyte loss and progression of DR. PMID- 23353836 TI - Toxicology. PMID- 23353837 TI - The revival of Amaranth as a third-millennium food. AB - The article deals with the importance and advantages of the amaranth plant - a genus of herbs of the family Amarantaceae. Amaranth, highly nutritional pseudocereal and traditional american crop has good food potential value. Amaranth grain doesn't contain gluten. The high content of quality protein and unsaturated fatty acids is one of its advantages. It is also a carrier of a very valuable fibre and good source of squalene. PMID- 23353835 TI - Human Vgamma9Vdelta2-T cells efficiently kill influenza virus-infected lung alveolar epithelial cells. AB - gammadelta-T cells play an indispensable role in host defense against different viruses, including influenza A virus. However, whether these cells have cytotoxic activity against influenza virus-infected lung alveolar epithelial cells and subsequently contribute to virus clearance remains unknown. Using influenza virus infected A549 cells, human lung alveolar epithelial cells, we investigated the cytotoxic activity of aminobisphosphonate pamidronate (PAM)-expanded human Vgamma9Vdelta2-T cells and their underlying mechanisms. We found that PAM could selectively activate and expand human Vgamma9Vdelta2-T cells. PAM-expanded human Vgamma9Vdelta2-T cells efficiently killed influenza virus-infected lung alveolar epithelial cells and inhibited virus replication. The cytotoxic activity of PAM expanded Vgamma9Vdelta2-T cells was dependent on cell-to-cell contact and required NKG2D activation. Perforin-granzyme B, tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas-Fas ligand (FasL) pathways were involved in their cytotoxicity. Our study suggests that targeting gammadelta-T cells by PAM can potentially offer an alternative option for the treatment of influenza virus. PMID- 23353838 TI - Activation and detoxification metabolism of urban air pollutants 2 nitrobenzanthrone and carcinogenic 3-nitrobenzanthrone by rat and mouse hepatic microsomes. AB - OBJECTIVES: 2-Nitrobenzanthrone (2-NBA) has recently been detected in ambient air particulate matter. Its isomer 3-nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust. Understanding which enzymes are involved in metabolism of these toxicants is important in the assessment of individual susceptibility. Here, metabolism of 2-NBA and 3-NBA by rat and mouse hepatic microsomes containing cytochromes P450 (CYPs), their reductase (NADPH:CYP reductase), and NADH:cytochrome b5 reductase was investigated under anaerobic and aerobic conditions. In addition, using the same microsomal systems, 2-NBA and 3-NBA were evaluated to be enzymatically activated under anaerobic conditions to species generating 2-NBA- and 3-NBA-derived DNA adducts. METHODS: High performance liquid chromatography (HPLC) with ultraviolet (UV) detection was employed for the separation and characterization of 2-NBA and 3-NBA metabolites formed by hepatic microsomes of rats and mice under the anaerobic and aerobic conditions. Microsomal systems isolated from the liver of the control (untreated) rats and rats pretreated with Sudan I, beta naphthoflavone (beta-NF), phenobarbital (PB), ethanol and pregnenolon 16alpha carbonitrile (PCN), the inducers of cytochromes P450 (CYP) 1A1, 1A1/2, 2B, 2E1 and 3A, respectively, were used in this study. Microsomes of mouse models, a control mouse line (wild-type, WT) and Hepatic Cytochrome P450 Reductase Null (HRN) mice with deleted gene of NADPH:CYP reductase in the liver, thus absenting this enzyme in their livers, were also employed. To detect and quantify the 2-NBA and 3-NBA-derived DNA adducts, the 32P postlabeling technique was used. RESULTS: Both reductive metabolite of 3-NBA, 3-aminobenzanthrone (3-ABA), found to be formed predominantly under the anaerobic conditions, and two 3-NBA oxidative metabolites, whose structures have not yet been investigated, were formed by several microsomal systems used in the study. Whereas a 3-NBA reductive metabolite, 3-ABA, was found only in the microsomal systems of control rats, the rats treated with beta-NF and PB, and microsomes of WT and HRN mice, all hepatic microsomes tested in the study were capable of activating this carcinogen under the reductive conditions to form DNA adducts. A stability of a reactive intermediate of 3-NBA, N-hydroxy-3-aminobenzanthrone that is formed during 3-NBA reduction to 3-ABA, to form nitrenium (and/or carbenium) ions binding to DNA in individual microsomes as well as binding of these ions to proteins of these microsomes, might be the reasons explaining this phenomenon. In contrast to 3 NBA, its isomer 2-NBA was not metabolized by any of the used enzymatic systems both under the anaerobic and aerobic conditions. Likewise, no DNA adducts were detectable after reaction of 2-NBA in these systems with DNA. CONCLUSIONS: The results found in this study, the first report on the metabolism of 2-NBA and 3 NBA by rat and mouse hepatic microsomes demonstrate that 3-NBA, in contrast to 2 NBA, is reductively activated to form 3-NBA-derived DNA adducts by these enzymatic systems. NADPH:CYP reductase can be responsible for formation of these DNA adducts in rat livers, while NADH:cytochrome b5 reductase can contribute to this process in livers of HRN mice. PMID- 23353839 TI - Impact of histone deacetylase inhibitor valproic acid on the anticancer effect of etoposide on neuroblastoma cells. AB - OBJECTIVES: Etoposide (Vepesid, VP-16), an inhibitor of topoisomerase II, is a chemotherapeutic drug commonly used for treatment of different types of malignant diseases. By inhibiting the topoisomerase II enzyme activity in cancer cells, this drug leads to DNA damage and subsequently to cell death. In this study, we investigated the effect of this anticancer drug alone and in combination with a histone deacetylase (HDAC) inhibitor, valproic acid (VPA), on a human UKF-NB-4 neuroblastoma cell line. METHODS: The effects of etoposide and VPA on UKF-NB-4 cells were tested under the normoxic and also the hypoxic (1% O2) cultivation conditions. The cytotoxicity of etoposide and VPA to a UKF-NB-4 neuroblastoma cell line was evaluated with MTT assay. Apoptosis of the cells was analyzed by flow cytometry using an Annexin V and propidium iodide binding method. The effect of etoposide and VPA on the cell cycle distribution was determined by flow cytometric analysis using propidium iodide staining. RESULTS: The results of the study demonstrate that UKF-NB-4 neuroblastoma cells are sensitive both to etoposide and to VPA. They also indicate that the impact of VPA on cytotoxicity of etoposide in these tumor cells varies depending on the sequence of cultivation of the cells with the drugs. As a suitable sequence of cultivation, with a high rate of suppression of neuroblastoma cell growth was found the preincubation of the cells with etoposide, which was followed by their cultivation with VPA. In contrast, the reversed combination (preincubation of the cells with VPA before their treating with etoposide) did not give any increase in etoposide cytotoxicity. The effect of such combined treatment can be explained by measuring the cell cycle distribution, which shows that both etoposide and VPA change the cell cycle phase distribution. CONCLUSION: Etoposide and VPA were found as cycle phase specific drugs that are cytotoxic to human UKF-NB-4 neuroblastoma cells used either as single drugs or both together. However, whereas VPA might sensitize the cells to etoposide, inappropriate sequence of cultivation of the cells with VPA can decrease the etoposide cytotoxic efficacy. The results found here warrant further studies of combined treatment of neuroblastoma cells with etoposide with HDAC inhibitors and may help in the design of new protocols geared to the treatment of high risk neuroblastomas. PMID- 23353840 TI - Theoretical investigation of differences in nitroreduction of aristolochic acid I by cytochromes P450 1A1, 1A2 and 1B1. AB - OBJECTIVES: The herbal drug aristolochic acid (AA) derived from Aristolochia species has been shown to be the cause of aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN) and their urothelial malignancies. One of the common features of AAN and BEN is that not all individuals exposed to AA suffer from nephropathy and tumor development. One cause for these different responses may be individual differences in the activities of the enzymes catalyzing the biotransformation of AA. Thus, the identification of enzymes principally involved in the metabolism of AAI, the major toxic component of AA, and detailed knowledge of their catalytic specificities is of major importance. Human cytochrome P450 (CYP) 1A1 and 1A2 enzymes were found to be responsible for the AAI reductive activation to form AAI-DNA adducts, while its structurally related analogue, CYP1B1 is almost without such activity. However, knowledge of the differences in mechanistic details of CYP1A1-, 1A2-, and 1B1- mediated reduction is still lacking. Therefore, this feature is the aim of the present study. METHODS: Molecular modeling capable of evaluating interactions of AAI with the active site of human CYP1A1, 1A2 and 1B1 under the reductive conditions was used. In silico docking, employing soft-soft (flexible) docking procedure was used to study the interactions of AAI with the active sites of these human enzymes. RESULTS: The predicted binding free energies and distances between an AAI ligand and a heme cofactor are similar for all CYPs evaluated. AAI also binds to the active sites of CYP1A1, 1A2 and 1B1 in similar orientations. The carboxylic group of AAI is in the binding position situated directly above heme iron. This ligand orientation is in CYP1A1/1A2 further stabilized by two hydrogen bonds; one between an oxygen atom of the AAI nitro-group and the hydroxyl group of Ser122/Thr124; and the second bond between an oxygen atom of dioxolane ring of AAI and the hydroxyl group of Thr497/Thr498. For the CYP1B1:AAI complex, however, any hydrogen bonding of the nitro-group of AAI is prevented as Ser122/Thr124 residues are in CYP1B1 protein replaced by hydrophobic residue Ala133. CONCLUSION: The experimental observations indicate that CYP1B1 is more than 10* less efficient in reductive activation of AAI than CYP1A2. The docking simulation however predicts the binding pose and binding energy of AAI in the CYP1B1 pocket to be analogous to that found in CYP1A1/2. We believe that the hydroxyl group of S122/T124 residue, with its polar hydrogen placed close to the nitro group of the substrate (AAI), is mechanistically important, for example it could provide a proton required for the stepwise reduction process. The absence of a suitable proton donor in the AAI CYP1B1 binary complex could be the key difference, as the nitro group is in this complex surrounded only by the hydrophobic residues with potential hydrogen donors not closer than 5 A. PMID- 23353841 TI - Effects of cytochrome P450 inhibitors on peroxidase activity. AB - OBJECTIVES: Of several enzymes metabolizing xenobiotics, cytochrome P450 (CYP) and peroxidase enzymes seem to be most important. One of the major challenges in studies investigating metabolism of xenobiotics is to resolve which of these two groups of enzymes is predominant to metabolize individual xenobiotic compounds. Utilization of selective inhibitors of CYP and peroxidase enzymes might be a useful tool to identify the contribution of these enzymes to metabolism of xenobiotics in samples, where both types of enzymes are present. The aim of this study was to investigate specificities of several known CYP inhibitors to these enzymes; whether they inhibit only the CYP enzymes and do not inhibit peroxidases. METHODS: Since the oxidation of o-anisidine catalyzed by a model peroxidase used, horseradish peroxidase (HRP), is a two-substrate reaction, the inhibition potential of tested chemicals was studied with respect to both peroxidase substrates, o-anisidine and hydrogen peroxide. Initial velocities of o anisidine oxidation by HRP under various conditions were determined spectrophotometrically. RESULTS: The CYP inhibitors metyrapone, troleandomycine, disulfiram, sulfaphenazole, quinidine and 1-aminobenzotriazole do not inhibit o anisidine oxidation catalyzed by HRP. In contrast, ketoconazole, diethyldithiocarbamate, ellipticine, alpha-naphtoflavone, proadifen SKF525A, piperonylbutoxide, were found to inhibit not only the CYPs, but also the HRP mediated oxidation of o-anisidine. Interestingly, alpha-naphtoflavone inhibits oxidation of o-anisidine by HRP with respect to H2O2, but not with respect to o anisidine. Diethyldithiocarbamate is the most potent peroxidase inhibitor of o anisidine oxidation with Ki with respect to o-anisidine of 10 MUM and Ki with respect to H2O2 of 60 MUM, being even the better peroxidase inhibitor than the classical "peroxidase inhibitor" - propyl gallate (Ki with respect to o-anisidine of 60 MUM and Ki with respect to H2O2 of 750 MUM). CONCLUSIONS: The results of the present study demonstrate that 1-aminobenzotriazole, a potent inhibitor of various CYP enzymes, seems to be the best candidate suitable for utilization in studies evaluating participation of CYP enzymes in metabolism of xenobiotics in various complex biological materials containing both CYP and peroxidase enzymes. Moreover, precaution to prevent misinterpretation of results is necessary in cases when proadifen SKF525A, piperonylbutoxide, diethyldithiocarbamate, ketoconazole, alpha-naphtoflavone and ellipticine are used in similar studies (as CYP inhibitors in various complex biological materials containing both CYP and peroxidase enzymes), since these chemicals can except of CYP enzymes inhibit also peroxidase-mediated reactions. PMID- 23353842 TI - Mapping of interaction between cytochrome P450 2B4 and cytochrome b5: the first evidence of two mutual orientations. AB - OBJECTIVES: The cytochrome P450 (P450) and cytochrome b5 are membrane hemoproteins composing together with flavoprotein NADPH:P450 reductase a mixed function oxidase (MFO) system. The knowledge of the interaction between P450 and its redox partners within a MFO system is fundamental to understand P450 reaction mechanism, an electron transport from its redox partner and also detoxification of xenobiotics and/or metabolism of endogenous substrates with all positive or negative aspects for organisms. METHODS: The chemical cross-linking by soluble carbodiimide (EDC) in combination with the liquid chromatography coupled with high resolution mass spectrometry (LC-HRMS) has been employed to characterize the contact surface regions involved in the transient interaction between two catalytic domains of P450 2B4 and cytochrome b5. RESULTS: The cross-linking reaction was accomplished in an equimolar catalytic complex of P450 2B4:cytochrome b5 and the covalent hetero-dimers detected on SDS-PAGE electrophoresis were analyzed (after in gel trypsin digestion) using LC-HRMS to identify cross-linked amino-acid residues. The computed in silico models of P450 2B4:cytochrome b5 complex using amino-acids participating in cross-links (Asp134, Lys139, Glu424 and Glu439 located on a proximal surface of P450 2B4) suggest interpretation that two different types of cytochrome b5 orientations are present in the studied interaction within a MFO system: the first allowing potential cytochrome b5 electron donation to P450, the second one inducing cytochrome b5 modulation of P450 structural changes. CONCLUSIONS: The results demonstrated the capability of the used experimental approach to map the interaction between P450 and cytochrome b5 suggesting the formation of multi-meric structures within a MFO system as interpretation of the two observed mutual orientations. PMID- 23353844 TI - Toxicity hazard of organophosphate insecticide malathion identified by in vitro methods. AB - OBJECTIVES: Malathion is generally not classified as toxic. However, the toxicity seems to be species-dependent. Local and systemic toxicity data for birds are rare, but a decrease of wild bird densities in areas where malathion was applied was reported. Aim of the study was to extend knowledge on malathion toxicity on cellular and organ level and to evaluate embryotoxicity and genotoxicity for birds using the chick embryo model HET-CAM. METHODS: Skin and eye irritation was determined using reconstructed skin and eye cornea tissues and the chorioallantoic membrane of chick embryo to simulate conjunctiva. Cytotoxicity in 3T3 Balb/c fibroblast culture was determined to estimate acute systemic toxicity. Chick embryo model was further employed to evaluate acute embryotoxicity for birds (mortality and genotoxicity). Data were analysed by means of general linear models. RESULTS: Malathion is not a skin and eye irritant. Cytotoxicity in vitro test provided LD50 value of 616 mg/kg suggesting higher toxic potential than is generally published based on in vivo tests on laboratory rodents. Embryotoxicity studies revealed dose and age dependent mortality of chick embryos. Genotoxicity was identified by means of micronucleus test in erythroid cells isolated from chorioallantois vascular system of chick embryos. CONCLUSIONS: Using in vitro alternative toxicological methods, a higher toxic potential of malathion was demonstrated than is generally declared. An increased health and environmental hazard may occur in areas with intensive agricultural production. The environmental consequences of delayed effects and embryotoxicity for bird populations in areas exposed to organophosphate insecticides, such as malathion, are obvious. PMID- 23353843 TI - The influence of rosuvastatin on liver microsomal CYP2C6 in hereditary hypertriglyceridemic rat. AB - OBJECTIVES: The aim of this study was to investigate whether rosuvastatin affects expression and activity of rat CYP2C6. This cytochrome P450 is considered to be a counterpart of human CYP2C9, which metabolizes many drugs, including diclofenac, ibuprofen or warfarin. DESIGN: Male hereditary hypertriglyceridemic (HHTg) rats were fed standard laboratory diet (STD) or high cholesterol diet (HCD: STD + 1% of cholesterol w/w + 10% of lard fat w/w) for 21 days. A third group of rats were fed high a cholesterol diet with rosuvastatin added (0.03% w/w). Expression of CYP2C6 was measured in liver samples using real-time PCR (mRNA level) and Western blotting (protein level). Formation of diclofenac metabolites (typical enzyme activity of CYP2C6) was analyzed using HPLC with UV detection. RESULTS: Administration of rosuvastatin to HHTg rats resulted in significantly increased mRNA expression and enzyme activity in HCD-fed animals; changes of CYP2C6 protein were non-significant. These results suggest that CYP2C6 expression and activity are positively affected by rosuvastatin in hereditary hypertriglyceridemic rats after intake of HCD. CONCLUSION: The results presented open the possibility that in humans, rosuvastatin may affect the metabolism of many drugs by influencing expression and activity of CYP2C6 (counterpart of human CYP2C9). Further studies are needed to elucidate the effects of this statin on CYP2C9 in humans. PMID- 23353845 TI - Effect of four selected carrier solvents on embryonal stages of Danio rerio. AB - OBJECTIVES: The aim of this study was to determine the effects of 96 hour exposure to selected solvents on the embryonic stages of zebrafish (Danio rerio). We investigated mortality and various types of changes which appeared (oedema, tail and eye defects, weak pigmentation, and deformation of the body). Based on the results, values of NOEC and LOEC for embryos of D. rerio were determined. METHODS: Embryonal toxicity tests were conducted according to OECD guideline 212. Ethanol and methanol were tested at concentrations of 0.1, 0.5, 1, 1.5, 2%; acetone at concentrations of 0.1, 0.5, 1, 1.25, 1.5%; and dimethylsulfoxide at concentrations of 1, 1.5, 2, 2.5, 3%. RESULTS: The LOEC values of ethanol and methanol were detected in the 1% concentration. Statistically significant changes (oedema) were reported in 1% ethanol, and oedema, weak pigmentation and deformation of the body were observed in 1% methanol. After exposure to acetone, the most common occurrence of oedema was in the 0.5% concentration (LOEC = 0.5%). The solvent dimethylsulfoxide caused oedema and body deformation at the 2% concentration (LOEC = 2%). CONCLUSIONS: The NOEC concentrations of the individual solvents were as follows: ethanol and methanol, 0.5%; acetone, 0.1%; and dimethylsulfoxide, 1.5%. These concentrations of individual solvents were higher than the maximum recommended concentration for toxicity tests on fish. For this reason, it can be assumed that the concentration of solvent allowed by the norm does not affect the procedure or results of such tests. PMID- 23353846 TI - Comparison of the effects of four anaesthetics on haematological and blood biochemical profiles in pikeperch (Sander lucioperca L.). AB - OBJECTIVES: The objectives of the study were to compare the effects of Propiscin, 2-phenoxyethanol, clove oil and tricaine methane sulphonate (MS 222), anaesthetics frequently used in aquaculture. DESIGN: The haematological and biochemical blood profiles of pikeperch (Sander lucioperca L.) anesthetized with Propiscin (1.5 ml L-1), 2-phenoxyethanol (0.3 ml L-1), clove oil (33 mg L-1), MS 222 (150 mg L-1) and non-anesthetized control group were tested. Each tested group was divided into two subgroups, the first subgroup was sampled in anaesthesia 10 min after application of the anaesthetic and the second one live on 24h. RESULTS: The erythrocyte count and haematocrit was significantly decreased in 2-phenoxyethanol (24 h) compared with control group (CG). The mean corpuscular haemoglobin concentration was significantly increased in 2 phenoxyethanol (10 min), Propiscin (10 min and 24 h) compared to CG. The 2 phenoxyethanol (10 min and 24 h), MS 222 (24 h), clove oil (24 h), and Propiscin (10 min and 24 h) showed significantly lower leukocyte count compared with CG. The level of glucose was significantly (p<0.05) elevated with MS 222 (10 min) and clove oil (10 min) compared with CG. The 2-phenoxyethanol (10 min and 24 h), MS 222 (24 h), clove oil (24 h), and Propiscin (24 h) showed significantly lower (p<0.01) ammonia levels compared with CG. The triacylglycerols was significantly decreased (p<0.01) with Propiscin (10 min and 24 h), MS 222 (24 h), clove oil (24 h) and with 2-phenoxyethanol (24 h) compared with CG. After 24 hours MS 222 (24 h) and Propiscin (24 h) anaesthesia, fish showed significantly lower (p<0.01) concentration of inorganic phosphate compared with CG. CONCLUSIONS: On the basis of this experiment, it appears that clove oil was associated with the lowest effects in pikeperch and therefore would be recommended as an alternative to MS 222, while Propiscin and 2-phenoxyethanol are not suitable for manipulation with pikeperch in aquaculture. PMID- 23353847 TI - Acute toxicity of acetylsalicylic acid to juvenile and embryonic stages of Danio rerio. AB - OBJECTIVES: The aim of this study was to compare the acute toxicity of acetylsalicylic acid to embryonic and juvenile stages of aquarium fish - zebrafish (Danio rerio), oxidative stress parameters and detoxifying enzyme. METHODS: Tests were performed according to OECD No. 203 (Fish, acute toxicity test) and OECD No. 212 (Fish, short-term toxicity test on embryo and sac-fry stages) methodology. RESULTS: The results showed the mean acetylsalicylic acid LC50 value to be 567.7 mg/L in juvenile zebrafish. The acute toxicity of acetylsalicylic acid for zebrafish embryos was 274.6 mg/L. Statistically significantly higher activity of GST was found in concentrations 340, 380 and 420 mg/L of acetylsalicylic acid. TBARS, GPx and GST didn't show statistically significant activity in tested concentrations of acetylsalicylic acid. CONCLUSIONS: The results revealed a statistically significantly higher degree of sensitivity in the embryonic stages of zebrafish compared to its juveniles. Acetylsalicylic acid did not cause statistically significantly higher antioxidative defence in zebrafish. PMID- 23353848 TI - Combined exposure of carps (Cyprinus carpio L.) to cyanobacterial biomass and white spot disease. AB - OBJECTIVES: Under environmental conditions, fish can be exposed to multiple stressors including natural toxins and infectious agents at the same time. This study brings new knowledge on the effects of controlled exposure to multiple stressors in fish. The aim of this study was to test the hypothesis that influence of cyanobacterial biomass and an infection agent represented by the white spot disease can combine to enhance the effects on fish. METHODS: Common carps were divided into four groups, each with 40 specimens for 20 days: control group, cyanobacterial biomass exposed group, Ichthyophthirius multifiliis infected fish (Ich) and cyanobacterial biomass-exposed fish + Ichthyophthirius multifiliis-infected fish. During the experiment we evaluated the clinical signs, mortality, selected haematological parameters, immune parameters and toxin accumulation. RESULTS: There was no mortality in control fish and cyanobacterial biomass-exposed fish. One specimen died in Ichthyophthirius multifiliis-infected fish and the combined exposure resulted in the death of 13 specimens. The whole leukocyte counts (WBC) of the control group did not show any significant differences. Cyanobacteria alone caused a significant increase of the WBC on day 13 (p<=0.05) and on day 20 (p<=0.01). Also, I. multifiliis caused a significant elevation of WBC (p<=0.01) on day 20. Co-exposition resulted in WBC increased on day 13 and decrease on day 20, but the changes were not significant. It is evident from the differential leukocyte counts that while the increase of WBC in the group exposed to cyanobacteria was caused by elevation of lymphocytes, the increase in the group infected by I. multifiliis was due to the increase of myeloid cells. It well corresponds with the integral of chemiluminescence in the group infected by I. multifiliis, which is significantly elevated on day 20 in comparison with all other groups. CONCLUSIONS: We can confirm additive action of different agents on the immune system of fish. While single agents seemed to stimulate the immune response, the combination of both caused immunosuppression. PMID- 23353849 TI - Content of selected metals in muscle of cyprinid fish species from the Nitra River, Slovakia. AB - OBJECTIVES: This study presents a rate of bioaccumulation of some metal concentrations in the muscle of five common cyprinid fish species (gudgeon - Gobio gobio, Europen chub - Leuciscus cephalus, barbel - Barbus barbus, roach - Rutilus rutilus, and nase - Chondrostoma nasus). DESIGN: Besides, correlations among selected metals as well as standard length and total weight and order of metal accumulation in the fish muscle were determined. RESULTS: Recorded metal concentrations (mg/kg wet weight basis) ranged as follows: Fe 4.23-22.95, Mn 0.10 0.72, Zn 16.26-166.90, Cu 15.39-25.97, Ni 0.00-3.72, Pb 0.00-1.81, and Cd 0.00 0.11. CONCLUSIONS: The Slovak permissible limit for Cu (10.0 mg/kg), Ni (0.5 mg/kg), Pb (0.2 mg/kg) and Cd (0.05 mg/kg) defined in the Codex Alimentarius for safe human consumption exceeded in 100%, 12%, 6% and 10% of analyzed samples for Cu, Ni, Pb and Cd respectively. On an average, the order of metal concentrations in the fish muscle was: Zn>Cu>Fe>Mn>Ni>Pb>Cd. PMID- 23353850 TI - Effects of low-concentrations of simazine on early life stages of common carp (Cyprinus carpio L.). AB - OBJECTIVES: The aim of this study is to assess the toxicity of simazine in different developmental stages of common carp (Cyprinus carpio) on the basis of mortality, early ontogeny, occurrence of morphological anomalies, growth rate, and Fulton's condition factor during and at the conclusion of the test. DESIGN: The toxicity tests were performed on carp according to OECD 210 methodologies. The developmental stages of carp were exposed to simazine at four concentrations, 0.06, (reported concentration in Czech rivers), 60, 600, and 3000 ug/l for 36 days and compared to carp in a non-treated control group. RESULTS: Simazine in concentration 0.06 ug/l had no effect on early life stages of carp. Simazine in concentration 600 and 3000 ug/l caused decrease of mass and total length of carp. Fish exposed to three highest levels of simazine showed alteration of tubular system of caudal kidney. On the basis of histopatological changes the values of LOEC = 60 ug/l, NOEC = 0.06 ug/l for simazine were estimated. CONCLUSIONS: Chronic simazine exposure of early-life stages of common carp affected their growth rate, and histology. Some of the changes were observed only at higher exposures (600, 3000 ug/l), but change founded in caudal kidney was affected in fish exposed to the second lowest concentration tested (i.e., 60 ug/l), which is about 10 ug/l higher than reported in Colorado rivers in recent years. Concentrations of simazine in World rivers have been reported to generally vary in the range 0.0003-49.20 ug/l. PMID- 23353851 TI - Effect of beta-1.3/1.6-D-glucan derived from oyster mushroom Pleurotus ostreatus on biometrical, haematological, biochemical, and immunological indices in rainbow trout (Oncorhynchus mykiss). AB - OBJECTIVES: Effect of long-term oral administration of three different concentrations (0.5, 1.0, and 2.0%) of micronized beta-1.3/1.6-D-glucan derived from oyster mushroom (Pleurotus ostreatus, Hiratake) on biometrical, haematological, biochemical, and immunological indices of half-year-old rainbow trout (Oncorhynchus mykiss) was assessed in the study. DESIGN: Rainbow trout were feed commercial feed pellets containing beta-1.3/1.6-D-glucan in the concentrations of 0.5, 1.0, and 2.0% for 85 days. Biometrical indices consisted in total and standard length, body and liver weight, from which derived somatic parameters such as Fulton's condition factor and hepatosomatic index were calculated. Haematological parameters were evaluated according to unified methods for haematological examination in fish. Plasma biochemical profile was analysed using biochemical analyser Konelab 20i and Easy Lyte Analyzer. A phagocyte cells metabolic activity (induced chemiluminescence of phagocytes) was determined as an immunological parameter by a microplate luminometric method on Immunotech LM-01T. RESULTS: No clinical signs of behavioral, respiratory, or neurologic distress were observed in rainbow trout. Fish showed normal feeding behavior. As for biometric parameters, no significant changes in total and standard length, body weight, liver weight, as well as in condition factor and hepatosomatic index of experimental and control fish were found. In the course of the study, weight gains in rainbow trout were similar and continuous. Shifts in PCV (p<0.05), haemoglobin (p<0.05), and MCHC (p<0.01) were found within haematological indices. Plasma concentration of glucose, lactate, total protein, cholesterol, calcium, natrium, potassium (all p<0.05), albumins and chlorides (both p<0.01), as well as catalytic activities of ALT and AST (both p<0.05) were changed in the course of the study. A phagocyte cells metabolic activity (luminol-induced chemiluminescence) in rainbow trout was not altered by oyster mushroom beta 1.3/1.6-D-glucan administration. CONCLUSION: After long-term oral administration of three concentrations of micronized beta-1.3/1.6-D-glucan derived from oyster mushroom (Pleurotus ostreatus, Hiratake) shifts in haematological and biochemical profiling were found in half-year-old rainbow trout (O. mykiss) in environmental conditions of a commercial rainbow trout fishery. Biometrical indices were not found significantly altered. No specific effect of beta-glucan on immune system response of rainbow trout was found in the study. The use of beta-glucan in prosperous, clinically healthy aquaculture is still an issue, nevertheless, its use in breedings endangered by stress stimuli, infectious diseases or adverse environmental factors is indisputable. PMID- 23353852 TI - Comparison of the effect of platinum on producers in aquatic environment. AB - OBJECTIVES: An enhanced worldwide application of platinum group elements (PGE), in particular platinum, has been observed during recent decades. An increased concentration of PGE was determined in collected samples of great amount of aqueous ecosystems.The aim was to compare phytotoxic effect of platinum (PtCl4) by performing two different bioassays on green algae Pseudokirchneriella subcapitata and macrophyte duckweed, Lemna minor. MEDTHODS: The algal experiment (Pseudokichneriella subcapitata) followed OECD 201, the concentration row for PtCl4 was: 0.05; 0.01; 0.25; 0.5; 1 uM. The duckweed (Lemna minor) experiment was conducted according to OECD 221, employed PtCl4 concentrations were: 5; 10; 25; 50; 100 uM. Plants were cultivated as a microbiotest, using micro-volumes. RESULTS: The results of the algal test showed significant growth inhibition of the final biomass. The values of 72hEC5(u), 72hEC10(u), 72hEC20(u) counted on a basis of average specific growth rate (u) were 0.31 uM, 0.58 uM and 1.12 uM of PtCl4, respectively. The values, obtained on a basis of the area under the growth curves (A), were 0.04 uM (72hEC5(A)), 0.24 uM (72hEC10(A)) and 0.64 uM (72hEC20(A)). The experiment with duckweed showed 50% of growth inhibition and the values of 168hEC50(u) were 19.55 uM and 168hEC50(A) 13.63 uM of PtCl4. CONCLUSION: The fronds of duckweed showed strong adverse effect of platinum influence (chlorosis, necrosis). The algal test and the estimation of 72hEC5(A) appears to be the most sensitive. PMID- 23353853 TI - The effects of subchronic exposure to terbuthylazine on zebrafish. AB - OBJECTIVES: Terbuthylazine belongs to the group of symmetrical triazine herbicides used extensively in agriculture and non-agricultural sites, primarily to control broadleaf and some grassy weeds that have become ubiquitous contaminants of the environment. The aim of this study was to assess the impact of terbuthylazine in surface waters on fish under experimental conditions. The effects of subchronic exposure to terbuthylazine on fish growth and the development of histopathological changes in selected organs (gill, kidney, liver), and on the activity of some biochemical parameters - glutathione S transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx) and on the concentration of thiobarbituric acid reactive substances (TBARS) in Danio rerio were investigated during a 28 day toxicity test. METHODS: Juvenile growth tests were performed on Danio rerio according to OECD guideline No. 215. Fish at the age of 30 days were exposed for 28 days to a range of sublethal concentrations of terbuthylazine (0.55 - environmental concentration, 150, 400, 700 and 1000 MUg/L). RESULTS: There were no significant differences (p<0.05) between the specific growth rates (r) of the test groups and control group. Histopathological examination revealed pathological changes only in the liver in fish exposed to terbuthylazine at concentrations of 700 and 1000 MUg/L. Significant differences (p<0.05) in activities of biochemical markers were found in GST (400, 700 and 1000 MUg/L), GR (700 and 1000 MUg/L), significant differences (p<0.05) of TBARS concentration were found at 1000 MUg/L. CONCLUSIONS: Based on the results of growth rate, the histopathological examination of selected organs, and the results of biochemical parameters, it was found that the environmental concentration of terbuthylazine did not have any effects on juvenile D. rerio. The values of NOEC and LOEC for terbuthylazine for juvenile D. rerio were 150 MUg/L and 400 MUg/L. PMID- 23353854 TI - Influence of cyanobacteria on water activity and dry matter of muscles in the common carp (Cyprinus carpio L.) and rainbow trout (Oncorhynchus mykiss W.). AB - OBJECTIVES: Cyanobacteria are studied from the viewpoint of the issue of risks to water supply, agriculture and recreational activities for a long time. Cyanobacteria produce a wide range of substances which can be toxic and can influence the safety and quality of fish products. The aim of this study was to determine whether the diet with the content of cyanobacteria can affect the water activity and the dry matter of fish muscle and whether this diet can contribute significantly to the shelf life of fish muscles. METHODS: Common carp (Cyprinus carpio) and rainbow trout (Oncorhynchus mykiss) were used in this study. Both fish species were divided into two groups. The first group of fish was fed with feed with cyanobacteria (3% of dry matter), the second group with feed without cyanobacteria. The water activity and the dry matter were monitored immediately after sampling of the fish muscle on day 7, 14 and 21 (carp) or on day 10, 20 and 30 (rainbow trout) and seven days after every sampling and cold storage (6-8 degrees C). RESULTS: Feed with the content of cyanobacteria significantly decreased the water activity in muscles of both fish species on day 21 (in carp) and on day 30 (in rainbow trout). The dry matter of fish muscle significantly increased on day 7 and 21 (in carp) and on day 10 and 30, but decreased on day 20 (in rainbow trout). The cold storage significantly influenced the dry matter only. While the dry matter was increased in the common carp (7 days of cold storage after sampling on days 14 and 21), the dry matter decreased in the rainbow trout (7 days of cold storage after sampling on day 10). CONCLUSIONS: The decrease of water activity was found only after longer exposure in the both exposed fish species. The dry matter was influenced far greater and was mostly increased in the both exposed fish species. PMID- 23353855 TI - Oxidative stress parameters in early developmental stages of common carp (Cyprinus carpio L.) after subchronic exposure to terbuthylazine and metribuzin. AB - OBJECTIVES: This work assessed the subchronic effects of the triazine compounds terbuthylazine and metribuzin on embryo-larval stages of common carp (Cyprinus carpio L.) using biotransformation enzyme and selected oxidative stress parameters. DESIGN: Early developmental stages of fish, from embryo to larvae, were exposed to terbuthylazine at concentrations of 0.9, 160, 520, and 820 MUg/L, and metribuzin at concentrations of 0.9, 4, 14, and 32 mg/L for 30 days and compared to the non-treated control group. For assessment of free radical defence the activities of glutathione S-transferase (GST) and glutathione reductase (GR) were measured; the lipid peroxidation (TBARS) level was determined as a marker of free radical damage. RESULTS: Terbuthylazine had no significant effect (p>0.05) at any tested concentrations on GST activity. Terbuthylazine caused an increase (p<0.05) in GR activity at the concentration of 520 MUg/L. We found a non significant (p>0.05) effect of terbuthylazine exposure on TBARS level. In metribuzin treated groups, the activity of GST was increased (p<0.05) in all experimental groups, with the highest at the concentration of 32 mg/L. GR activity was increased in the 0.9, 4, and 14 mg/L groups and the TBARS levels were the highest in the 0.9 mg/L group. CONCLUSION: Our results suggest that terbuthylazine and metribuzin induced oxidative stress in embryo-larval stages of common carp. Increased activities of biotransformation enzymes or antioxidant defence enzymes were markers of free radical attack. There was low lipid peroxidation in early developed fish after triazine exposure. PMID- 23353856 TI - Effect of chronic exposure to prometryne on oxidative stress and antioxidant response in early life stages of common carp (Cyprinus carpio L.). AB - OBJECTIVES: The aim of the study was to investigate effects of the triazine herbicide prometryne on early life stages of common carp Cyprinus carpio as indicated by oxidative stress and antioxidant indices. DESIGN: Toxicity tests were performed according to OECD 210 methodologies. Common carp larvae and embryos exposed for 35 days to prometryne at three concentrations, 0.51 (reported concentration in Czech rivers), 80 (1% 96 h LC50), and 1200 (15% 96 h LC50) MUg/l, were compared to carp in a non-treated control group. Activity of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR), as well as levels of thiobarbituric acid reactive substances (TBARS) were assessed. RESULTS: Chronic exposure of early life stages of carp to prometryne showed no effect on growth and mortality rates. Levels of oxidative damage in fish test groups showed no significant differences from the controls. Glutathione reductase activity at exposure 0.51 MUg/l was significantly increase (p<0.01) compared with controls and other exposures. CONCLUSION: The chronic exposure to prometryne showed no influence on oxidative stress. Differences from control fish was observed in GR activity in exposure prometryne 0.51 MUg/l. PMID- 23353857 TI - Tacrine is implicated in oxidative stress in the laboratory guinea pig model. AB - OBJECTIVES: Tacrine was the first acetylcholinesterase inhibitor approved for the treatment of Alzheimer disease. The compound is not available for therapeutic purposes as it was withdrawn due to hepatotoxicity of its metabolites. The hepatotoxicity can be decreased by alternative ways of drug administration avoiding thus the first pass effect. The present study is aimed to investigate the influence of intramuscularly administrated tacrine on oxidative stress. METHODS: Laboratory guinea pigs were exposed to tacrine at doses of 0-800 MUg/kg. The animals were euthanized 1 and 24 hours after the exposure. Parameters such as ferric reducing antioxidant power (FRAP), thiobarbituric acid reactive substances (TBARS), carbonylated proteins, caspase 3 activity, superoxide dismutase activity and glutathione reductase activity were assessed in the frontal, temporal and occipital lobe, cerebellum, liver, spleen, heart, and kidney. Moreover, levels of glucose, total and HDL cholesterol forms, triglycerides, blood urea nitrogen, creatinine, total bilirubin, total protein, albumin and activities of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase were assessed in plasma samples. RESULTS: Activities of the enzymatic markers, level of carbonylated proteins in organs and levels of biochemical markers in plasma were only slightly influenced by tacrine. Dose dependent elevation of the FRAP value was recognized in the brain tissues and the liver. The TBARS value was increased in the kidney and heart 1 and 24 hours, respectively, after exposure. CONCLUSION: In the study, the effect of tacrine on markers of oxidative stress was proved. Possible positive effects of tacrine on the antioxidant defence in the brain tissue were discussed. PMID- 23353858 TI - Risk of single and combined exposure of birds to non-steroidal anti-inflammatory drugs and lead. AB - OBJECTIVES: Pharmaceuticals and heavy metals such as diclofenac and lead, respectively, have been identified as environmental contaminants toxic to birds and posing serious threats to declining populations of raptors worldwide. The aim of the present study was to test the hypothesis that a sublethal combination of non-steroidal anti-inflammatory drugs and lead induces more pronounced effects than single exposures in birds. METHODS: A total of 40 Japanese quails (Coturnix coturnix japonica) at the age of 2 months and average weight of 180g were on a random basis divided into four experimental groups of 10 specimens (i.e., control, diclofenac, lead, and lead+diclofenac exposures). Six lead shots in the total weight of 1.5 grams were inserted into the crop on day 0 of the experiment, while a total of 5 mg/kg of diclofenac administered intramuscularly were divided into treatments on days 0 and 5. Group responses were compared using haematology and biochemistry after 10 days. RESULTS: There was no mortality in control and both single and combined diclofenac and lead exposure groups, nor did the birds show any clinical signs of intoxication. Univariate analyses of blood parameters yielded a decrease in haematocrit in birds exposed to both substances when compared with the control, a lower haemoglobin level of the lead-exposed group, increased activity of aspartate aminotransferase in the NSAIDs-exposed group, increased activity of alkaline phosphatase in birds exposed to a combination of diclofenac and lead, and a higher phosphorus level in the lead-exposed group. The principal component analysis revealed no multivariate pattern of responses of blood parameters and did not allow separation of exposure groups from controls when the variables and samples were projected onto a two dimensional space. CONCLUSIONS: Results of the present study can enhance understanding of combination toxicity of veterinary drugs and heavy metals in birds, i.e. a scenario that has become environmentally relevant in recent decades. Fortunately, individual blood parameter effects prevailed and no joint mortal effects were recognised in Japanese quails exposed to a combination of sublethal doses of diclofenac and lead. PMID- 23353859 TI - Free-radical degradation of high-molar-mass hyaluronan induced by Weissberger's oxidative system: potential antioxidative effect of bucillamine. AB - OBJECTIVES: Hyaluronan (HA), one of the main components of extracellular matrix, is a glycosaminoglycan composed of repeating disaccharide units of N-acetyl-d glucosamine and d-glucuronic acid linked by beta-(1->4) and beta-(1->3) glycoside bonds. High-molar-mass HA was used as a model for studying its oxidative degradation. In the present paper protective effects of bucillamine against the free-radical degradation of HA were investigated. The HA fragments generated were characterized as well. METHODS: To induce free-radical-mediated degradation of high-molar-mass HA under aerobic conditions, we applied Weissberger's oxidative system, comprising biogenic compounds in relevant pathophysiological concentrations, i.e. 100 uM ascorbate plus 1 uM Cu(II). Time-dependent decreases of dynamic viscosity of the HA solutions were recorded by rotational viscometry. Electron donor behaviors of bucillamine were studied by a standard ABTS test method and a chemiluminescence (CL) assay. Ability of incorporation of generated bucillamine thiyl radicals into the biopolymer was verified by Fourier-transform infrared spectroscopy (FT-IR) and size exclusion chromatography with a multi angle light scattering photometer (SEC-MALS). RESULTS: Decrease of HA viscosity reflected HA degradation. The drug tested was applied in two arrangements: to prevent *OH radical generation (1) and ROO* type radicals propagation (2). Bucillamine, which acted as an efficient *H donor, is also a proper electron donor, as proved by ABTS and CL assays. FT-IR and SEC-MALS methods showed that the drug tested did not incorporate into the biopolymer chains. CONCLUSION: Bucillamine significantly protected high-molar-mass HA against free-radical degradation in vitro, and supposedly this positive action of the drug may be involved in its beneficial effect observed in clinical practice. PMID- 23353860 TI - Risk of combined exposure of birds to cyanobacterial biomass containing microcystins, acetylcholinesterase inhibitor and anticoagulant. AB - OBJECTIVES: The objective of this study was to examine the hypothesis that a combination of cyanobacterial biomass containing microcystins, acetylcholinesterase inhibitor and anticoagulant can enhance avian toxic effects produced by single exposures only. METHODS: A total of 48 two-month-old Japanese quails (Coturnix coturnix japonica) with average body weight of 160 g were randomly divided into 8 experimental groups of six birds and sex ratio of 1:1. Experimental groups of control Japanese quails (C) and birds exposed to single and combined sub-lethal doses of paraoxon (P), bromadiolone (B), and microcystins in cyanobacterial biomass (M) included: C, P, P+B, B, B+M, P+M, M, and P+B+M. During the 10-day exposure birds in the respective groups received biomass containing 61.62 ug microcystins daily (i.e. 26.54 ug MC-RR, 7.62 ug MC-YR and 27.39 ug MC-LR), two 250 MUg/kg doses of paraoxon, and two 500 mg/kg doses of bromadiolone. Group responses were compared using standard plasma biochemistry and antioxidant/oxidative stress parameters in tissues. RESULTS: While single and double combinations of toxicants induced responses in individual biochemical parameters measured and evaluated using univariate statistical analysis, those in the triple exposure were most extensive. The principal component analysis of antioxidant/oxidative stress parameters (glutathione reductase, lipid peroxidation, and ferric reducing antioxidant power) in tissues (liver, kidney, heart, brain, lungs, gonads, and pectoralis major muscle) clearly separated the triple group (P+B+M) from all single and double exposure groups and the control and indicated thus marked joint effects in the overall pattern of antioxidant/oxidative stress responses of this group. The separation was driven by the modification of the ferric reducing antioxidant power levels in heart and brain and the cardiac lipid peroxidation level, in particular. CONCLUSIONS: This experiment contributes to the understanding of the pathogenic mechanisms of combined sub-lethal exposure to natural toxins and agrochemicals and may be used for risk assessment of environmental pollution in birds. PMID- 23353861 TI - Avian high-dose toxicity of cyanobacterial biomass. AB - OBJECTIVES: Previous studies using oral administration of environmentally relevant doses of cyanobacterial biomass containing microcystins (MCs) induced only sub-lethal effects in experimental birds. Therefore, the objective of this study was to obtain data on avian high-dose toxicity of MCs and compute LD50, if possible, following the natural oral route of administration. DESIGN: Responses of birds to single high-dose exposure to MCs were evaluated in fourteen-day old Japanese quail males (Coturnix coturnix japonica) with average body weight of 50 g which were randomly divided into five groups. Birds from four experimental groups were administered 7.5 ml of cyanobacterial biomass suspension containing increasing MCs quantities of 2500, 5000, 10000, and 20000 ug/kg using oral gavage. Controls received an equal dose of drinking water instead of the test substance. Birds were observed for clinical signs of acute toxicity. Survivors were killed on day 5 to obtain body and liver weights. A five-grade semi quantitative system for histopathological liver damage scoring was used to compare cyanobacterial-biomass-exposed birds against controls. RESULTS: No mortality occurred during the period of five days post exposure in both control and MCs-exposed groups and this high-dose experiment failed to provide data to compute the LD50. Nevertheless, marked sub-lethal effects were recognised in the damage of liver that included dose-dependent changes in the body/liver ratios and morphological changes ranging from mild vacuolar dystrophy to focal liver necroses in the highest exposure group. Hepatic lesions were mainly observed in the pericentral area of the liver. CONCLUSIONS: Though maximum cyanobacterial biomass dose rates that could be administered to birds of the size were used in the present experiment and more pronounced hepatic lesions than after exposure to environmentally relevant doses were observed, birds would probably have survived unless killed for histopathology on day 5 of exposure. These results provide support to previously reported data on sub-lethal effects following exposure to cyanobacterial biomass containing MCs in birds and mortality occurring only in birds under combined action with other stressors. PMID- 23353862 TI - Stimulation of nitric oxide, cytokine and prostaglandin production by low molecular weight fractions of probiotic Lactobacillus casei lysate. AB - OBJECTIVES: Major medical indications of probiotic bacteria are conditions associated with the gastrointestinal tract. They exhibit not only the local but also systemic effects, the molecular mechanisms of which are poorly understood. We hypothesized that the action at remote sites of the body could be at least partially attributed to substances of the low molecular mass released from digested bacteria and able to cross the intestinal barrier. The aim of the study was the analysis of immunobiological properties of bacterial lysates and characterization of chemical constituents participating on this mode of action. METHODS: Lactobacillus casei probiotic strain DN-114001 was employed. Lysates were prepared by passing bacteria through a French press (1500 psi) followed by lyophilisation. The fractions were prepared by the microfiltration of the crude lysate using the 3-, 10-, 30-, 50-, and 100-kDa cutoff filters (Amicon(r) Ultra 0.5 ml, Millipore Corp.). This procedure completely removes biologically active bacterial macromolecules such as peptidoglycan (PGN), lipoteichoic acid (LTA) and lipopolysaccharide (LPS). Effects of microfiltrates on the in vitro production of nitric oxide (NO), cytokines, and prostaglandin E2 (PGE2) were investigated in rat peritoneal cells. RESULTS: The original crude lysate (<=10 ug/ml) activated the biosynthesis of NO, PGE2, and secretion of cytokines. The amount of the lysate needed for the preparation of microfiltered fractions exhibiting immunostimulatory effects was 10-fold higher (100 ug/ml). The molecules with the molecular mass <=3 kDa were responsible for approximately 45% and 83% of the NO- and PGE2-enhancing activities of the crude lysate, respectively. The microfiltered fractions of the lysate also enhanced secretion of interleukin-6 and tumor necrosis factor-alpha but not that of interleukin-10 and interferon gamma. CONCLUSION: The Lactobacillus casei probiotic strain DN-114001 contains low molecular mass (<=3 kDa) molecules possessing immunostimulatory properties. Their chemical nature remains to be identified. PMID- 23353863 TI - Impact of platinum on the soil invertebrate Folsomia candida. AB - OBJECTIVES: Regarding the environmental pollution, platinum group elements (PGE) are in the centre of interest of current research. These rare elements are used as effective substances in automotive catalysts to reduce pollution by emissions originating from fuel combustion. Due to their harmful potential, it is necessary to monitor their content and behaviour in different samples. Comprehensive studies on PGE behaviour and effects are still lacking. Their distribution in the food chain and data on bioaccumulation has not been described so far. METHODS: We focused on reproductive effects of platinum (PtCl4), in particular. Our study is based on a collembolan laboratory breed, test optimalization and validation according to the OECD 232 standards [CSN ISO 11267 - Soil quality - Inhibition of reproduction of Collembola (Folsomia candida) by soil pollutants]. The concentrations of PtCl4 tested were as follows: 5, 10, 25, 50 and 100 uM. The EC50 was determined after 28 days of testing. RESULTS: The results were evaluated using the inhibition of reproduction compared with controls. The EC50 was determined after the 28-day test. The value of 28dEC50 of the boric acid test was estimated at 120 mg/kg and the measured 28dEC50 of PtCl4 was 200.4 uM. CONCLUSION: The presented data can be considered as a step forward in the assessment of the potential risk of platinum in the terrestrial environment. However, more toxicity data for various species are needed to evaluate the environmental risk of platinum in soils. PMID- 23353864 TI - Appetite suppressants in pregnancy. AB - OBJECTIVES: Both, obesity as well as anorexia may be associated with infertility and other complications of pregnancy. Weight loss during pregnancy is therefore considered a risk factor. Weight loss and appetite suppressant are contraindicated during pregnancy, but the unintended exposure is probably not associated with higher risk. Our work was focused on trends in the appetite suppressants use in the Czech Republic and their embryotoxicity. METHODS: The pregnancies exposed to various appetite suppressants were followed prospectively in the years 1997-2012. The study group was compared to the comparison group which enrolled pregnant women exposed to non-teratogenic drugs. Drugs used as appetite suppressants were sibutramine and phentermine. RESULTS: Number of calls for this type of exposure was rare till 2005. Their number started to increase until 2009. Later, number of calls decreased because both drugs were withdrawn from the market. This finding reflects increasing tendency for the weight control in the group of fertile women in the Czech Republic. In our study, we did not reveal differences in pregnancy outcomes between study and comparison groups. CONCLUSIONS: However, we should be aware of the increasing food supplements exposure, that could be used as alternative to the appetite suppressants. Their potential risk results from the limited or completely absent control of their origin. Some of them have probably only placebo effect, but some of them could represent the risk. PMID- 23353865 TI - Melatonin influences antioxidant homeostasis and basal metabolism in the BALB/c mouse model. AB - OBJECTIVES: Melatonin is a hormone with strong antioxidant activity. It is biosynthesized in the pineal gland and serves in the biological signaling and control of the circadian rhythm. Though there is evidence of beneficial effects of melatonin, the substance was not investigated in greater details associated with specific regulation of oxidative stress in organs and tissues. DESIGN: The experiment is based on exposure of BALB/c mice to doses from 10 ug to 1mg of melatonin. Mice were euthanized after one and 24 hours, respectively. Biochemical markers in plasma, ferric reducing antioxidant power (FRAP), thiobarbituric acid reactive substances (TBARS) and activity of caspase-3 were examined in selected organs. RESULTS: We confirmed significant alteration in high-density lipoprotein and total cholesterols and glucose. After one day, levels of glucose and high density lipoprotein cholesterol were decreased, while total cholesterol increased in a dose dependent manner. FRAP values increased in spleen, liver, kidney, heart, and brain indicating a growing potential of low molecular weight antioxidants 24 hours after exposure. However, TBARS values indicating oxidative stress were elevated in heart, kidney, and liver. CONCLUSIONS: Despite the antioxidant properties of melatonin, its effect on the organism is more complicated. It influences not only the oxidative homeostasis but also the basal metabolism, as represented by, e.g., cholesterol and glucose. This substance could thus be used for therapeutical purposes such as amelioration of pathologies associated with generation of reactive species or some metabolic dysfunctions. PMID- 23353866 TI - Effects of novel quercetin derivatives on sarco/endoplasmic reticulum Ca2+-ATPase activity. AB - OBJECTIVES: We examined effect of novel quercetin derivatives on sarcoplasmic reticulum (SR) Ca-ATPase activity isolated from skeletal muscles and their potential to prevent injury of SERCA induced by peroxynitrite that is elevated in multiple pathological processes. METHODS: SR was isolated by ultracentrifugation, ATPase activity of SERCA was measured by NADH-coupled enzyme assay. Sulfhydryl and carbonyl groups content was determined to test oxidation of SERCA. Conformational changes in ATP and calcium binding site were assessed using specific fluorescent labels. RESULTS: Di(diacetylcafeoyl)-mono (monoacetylcafeoyl) quercetin (DACQ) restored and diquercetin significantly decreased activity of SERCA in the presence of peroxynitrite. Diquercetin significantly decreased SERCA activity in absence of peroxynitrite. All tested quercetin derivatives decreased thiol group content of SR and caused change in SERCA conformation. Significant decrease of protein carbonyls was observed in SERCA treated with di(diacetylcafeoyl)-mono-(monoacetylcafeoyl) quercetin in the presence of peroxynitrite. CONCLUSION: DACQ protected SERCA in SR against formation of carbonyls in vitro and protected activity of the pump against inhibition caused by peroxynitrite. However, none tested quercetin derivative did protect SERCA against conformational changes and sulfhydryl group oxidation. Diquercetin inhibited SERCA at relatively low concentrations in the presence of peroxynitrite. Diquercetin and DACQ may prove to be beneficial in treatment of cancer and inflammatory diseases, respectively. PMID- 23353868 TI - Stem cell therapies for liver failure and cirrhosis. PMID- 23353869 TI - Early infection events highlight the limited transmissibility of hepatitis C virus in vitro. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) poses a global health problem, with over 170 million chronically infected individuals at risk of developing progressive liver disease. The ability of a virus to spread within a host is a key determinant of its persistence and virulence. HCV can transmit in vitro by cell-free particle diffusion or via contact(s) between infected and naive hepatocytes. However, limited information is available on the relative efficiency of these routes, our aim is to develop physiologically relevant assays to quantify these processes. METHODS: We developed a single-cycle infection assay to measure HCV transmission rates. RESULTS: We compared HCV spread in proliferating and arrested cell systems and demonstrated a significant reduction in cell-to cell infection of arrested target cells. Comparison of cell-free and cell-to-cell virus spread demonstrated relatively poor transmission rates, with 10-50 infected producer cells required to infect a single naive target cell. We found HCV strain J6/JFH to be 10-fold more efficient at spreading via the cell-to-cell route than cell-free, whereas SA13/JFH and HK6/JFH strains showed comparable rates of infection via both routes. Importantly, the level of infectious virus released from cells did not predict the ability of a virus to spread in vitro, highlighting the importance of studying cell-associated viruses. CONCLUSIONS: These studies demonstrate the relatively poor infectivity of HCV and highlight differences between strains in their efficiency and preferred route of transmission that may inform future therapeutic strategies that target virus entry. PMID- 23353867 TI - Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis. AB - BACKGROUND & AIMS: Dysregulated glucose homeostasis and lipid accumulation characterize non-alcoholic fatty liver disease (NAFLD), but underlying mechanisms are obscure. We report here that Kruppel-like factor 6 (KLF6), a ubiquitous transcription factor that promotes adipocyte differentiation, also provokes the metabolic abnormalities of NAFLD by post-transcriptionally activating PPARalpha signaling. METHODS: Mice with either hepatocyte-specific depletion of KLF6 ('DeltaHepKlf6') or global KLF6 heterozygosity (Klf6+/-) were fed a high fat diet (HFD) or chow for 8 or 16 weeks. Glucose and insulin tolerance tests were performed to assess insulin sensitivity. Overexpression and knockdown of KLF6 in cultured cells enabled the elucidation of underlying mechanisms. In liver samples from a cohort of 28 NAFLD patients, the expression of KLF6-related target genes was quantified. RESULTS: Mice with global- or hepatocyte-depletion of KLF6 have reduced body fat content and improved glucose and insulin tolerance, and are protected from HFD-induced steatosis. In hepatocytes, KLF6 deficiency reduces PPARalpha-regulated genes (Trb3, Pepck) with diminished PPARalpha protein but no change in Pparalpha mRNA, which is explained by the discovery that KLF6 represses miRNA 10b, which leads to induction of PPARalpha. In NAFLD patients with advanced disease and inflammation, the expression of miRNA 10b is significantly downregulated, while PEPCK mRNA is upregulated; KLF6 mRNA expression also correlates with TRB3 as well as PEPCK gene expression. CONCLUSIONS: KLF6 increases PPARalpha activity, whereas KLF6 loss leads to PPARalpha repression and attenuation of lipid and glucose abnormalities associated with a high fat diet. The findings establish KLF6 as a novel regulator of hepatic glucose and lipid metabolism in fatty liver. PMID- 23353870 TI - Highly charged cyanine fluorophores for trafficking scaffold degradation. AB - Biodegradable scaffolds have been extensively used in the field of tissue engineering and regenerative medicine. However, noninvasive monitoring of in vivo scaffold degradation is still lacking. In order to develop a real-time trafficking technique, a series of meso-brominated near-infrared (NIR) fluorophores were synthesized and conjugated to biodegradable gelatin scaffolds. Since the pentamethine cyanine core is highly lipophilic, the side chain of each fluorophore was modified with either quaternary ammonium salts or sulfonate groups. The physicochemical properties such as lipophilicity and net charge of fluorophores played a key role in the fate of NIR-conjugated scaffolds in vivo after biodegradation. The positively charged fluorophore-conjugated scaffold fragments were found in salivary glands, lymph nodes, and most of the hepatobiliary excretion route. However, halogenated fluorophores intensively accumulated into lymph nodes and the liver. Interestingly, balanced-charged gelatin scaffolds were degraded into urine in a short period of time. These results demonstrate that the noninvasive optical imaging using NIR fluorophores can be useful for the translation of biodegradable scaffolds into the clinic. PMID- 23353872 TI - Stabilization of oxidovanadium(IV) by organic radicals. AB - o-Imino-p-R'-benzosemiquinone anion radical (L(R')(IS)(-)) complexes of oxidovanadium(IV) of type [(L(1)(R-))(VO(2+))(L(R')(IS)(-))] (R = H, R' = H, 1; R = H, R' = -CMe(3), 2; R = -CMe(3), R' = H, 3 and R = -CMe(3), R' = -CMe(3), 4) incorporating the redox-innocent tridentate NNO-donor L(1)(R-) ligands (L(1)(R)H = 2,4-di-R-6-{(2-(pyridin-2-yl)hydrazono)methyl}phenol) were isolated and substantiated by elemental analyses, IR, mass, NMR and UV-vis spectra including the single crystal X-ray structure determinations. The V-O(phenolato) (cis to the V=O) lengths spanning 1.905(3)-1.9355(15) A in 1-4 are consistent with the coordination to the [VO](2+) state. The V-O(IS) (trans to the V=O) lengths, 2.1505(17)-2.1869(15) A, in 1-4 are longer due to the trans influence of the V=O bond. The V-N(IS) lengths, 1.906(3)-1.924(2) A, in 1-4 are comparatively shorter due to the higher affinity of the paramagnetic [VO](2+) ion towards the L(R')(IS)(-) anion radicals. Density functional theory (DFT) calculations using B3LYP, B3PW91 and PBE1PBE functionals on 1 and 2 authenticated that the closed shell singlet (CSS) solutions (dianionic o-amido-p-R'-phenolates (L(R')(AP)(2-)) coordinated to VO(3+), Type I) of 1-4 are unstable with respect to the open shell singlet (OSS) perturbations. Broken symmetry, BS (1,1) M(s) = 0 (L(R')(IS)(-) coordinated to the VO(2+) ion, Type III) solutions of 1-4 are stable and reproduce the experimental bond parameters. Frozen glasses EPR spectra of [1 4](+) ions (e.g. g(||) = 1.948, g(?) = 1.978, A(||) = 184 (22 G), A(?) = 62(15 G) for [2](+)) and unrestricted DFT calculations on [1](+), [2](+), [1](-) and [2]( ) ions using doublet spin state elucidated that the reversible anodic waves at [0.15-0.31] V of 1-4 complexes are due to the oxidation of L(R')(IS)(-) generating [(L(1)(R-))(VO(2+))(L(R')(IQ))]+ complexes (L(R')(IQ) = o-imino-p-R' benzoquinone) coordinated to the [VO](2+) ion (Type V) while the irreversible cathodic waves at -[1.08-1.49] V are due to the formation of unstable [(L(1)(R ))(VO(2+))(L(R')(AP)(2-))](-) complexes (Type II). The second anodic waves at [0.76-0.89] V are assigned to a [VO](3+)-[VO](2+) couple affording diamagnetic [(L(1)(R-))(VO(3+))(L(R')(IQ))](2+), [1-4](2+) complexes (Type VI) which are identified by UV-vis spectra, DFT and time dependent (TD) DFT calculations. Spectro-electrochemical measurements and TD DFT calculations on 1 and 2 disclosed that lower energy electronic absorption bands of 1-4 are due to the LMCT and CSS OSS perturbation which disappear in [1-4](+) ions. [1-4](+) absorb at 600-650 nm due to d-d transitions and MLCT which are absent in VO(3+) complexes, [1-4](2+). PMID- 23353873 TI - An electrorotation technique for measuring the dielectric properties of cells with simultaneous use of negative quadrupolar dielectrophoresis and electrorotation. AB - This paper presents an effective electrorotation technique for measuring the dielectric properties of cells using a superposed electrical signal, which can simultaneously generate negative quadrupolar dielectrophoretic (nQDEP) force and electrorotational (ROT) torque. The proposed technique involves a three dimensional (3D) octode, which includes four electrodes arranged in a crisscross pattern on the top and bottom of a microchannel, respectively. A single cell was trapped in the center of the 3D octode by the nQDEP force and simultaneously rotated by the ROT torque. Using the proposed electrorotation technique, ROT spectra of human leukocyte subpopulations (T and B lymphocytes, granulocytes, and monocytes) and metastatic human breast (SkBr3) and lung (A549) cancer cell lines were accurately measured without any disturbance. Torque on the cells generated by the ROT signal was analyzed theoretically based on the single-shell dielectric model for the cells. Furthermore, the dielectric properties of the cells, such as area-specific membrane capacitance and cytoplasm conductivity, were extracted using the measured ROT spectra and the analyzed torque. PMID- 23353871 TI - Motor circuits help encode auditory memories of vocal models used to guide vocal learning. AB - Early auditory experience can leave a lasting imprint on brain and behavior. This lasting imprint is most notably manifested in culturally transmitted vocal behaviors, including speech and birdsong, where a vocal model heard early in postnatal life exerts a lifelong influence on the individual's vocal repertoire. Because auditory experience of the vocal model can precede accurate vocal imitation by months or even years, a longstanding idea is that a memory of the model is initially stored in auditory centers, and accessed by vocal motor circuits only later in development. This review considers recent evidence from studies in songbirds supporting the idea that vocal motor circuits also participate in the encoding of auditory experience of the vocal model. The encoding of auditory memories by vocal motor networks may represent an efficient strategy for vocal learning that generalizes to other vocal learning species, including humans. This article is part of a Special Issue entitled "Annual Reviews 2013". PMID- 23353874 TI - Nanoemulsion based gel for transdermal delivery of meloxicam: physico-chemical, mechanistic investigation. AB - AIMS: The aim of the present investigation was to develop a nanoemulsion (NE) gel formulation for the transdermal delivery of meloxicam (MLX) in order to ensure maximum controlled and sustained drug release capacity. MAIN METHODS: The MLX containing NE gel was prepared and characterized for particle size, zeta potential, pH, rheology, in vitro drug release, in vitro skin permeation, and in vitro hemolysis. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) of MLX-NE gel treated rat skin was performed to investigate the skin permeation mechanism of meloxicam from NE gel. Skin permeation potential of the developed gel formulation was assessed using confocal laser scanning microscopy (CLSM). The in vivo toxicity of MLX-NE gel was assessed by histopathological examination in rat. The rat paw edema test was performed to evaluate the anti-inflammatory activity of MLX-NE gel. KEY FINDINGS: Percutaneous absorption studies demonstrated a higher permeation of meloxicam from NE gel, than the drug solution. FTIR and DSC studies supported stratum corneum lipid extraction as a possible penetration enhancer mechanism for MLX-NE gel. CLSM studies confirmed the permeation of the NE gel formulation to the deeper layers of the skin (up to 130 MUm). MLX-NE gel turned out to be non-irritant, biocompatible, and provided maximum inhibition of paw edema in rats over 24 h in contrast to MLX solution. SIGNIFICANCE: The nanoemulsion gel formulation may hold promise as an effective alternative for the transdermal delivery of meloxicam. PMID- 23353875 TI - MiR-433 mediates ERRgamma-suppressed osteoblast differentiation via direct targeting to Runx2 mRNA in C3H10T1/2 cells. AB - AIMS: MicroRNAs (miRNA) are involved in various biological processes including cellular differentiation. However, the role of miR-433 in osteoblast differentiation remains poorly understood. The objective of this study was to investigate the effect of miR-433 on BMP2-induced osteoblast differentiation. MAIN METHODS: The expression of mature miR-433 in cells was detected by real-time PCR. RT-PCR or real-time PCR was used to confirm the expression of osteogenic genes. For the activation or inhibition of miR-433 expression, we used a precursor form of miR-433 or anti-miR-433. Functional activity of miR-433 and Runx2 was evaluated by promoter study. Osteoblast differentiation was evaluated by analyzing alkaline phosphatase (ALP) activity. KEY FINDING: ERRgamma increased miR-433 expression in the mesenchymal stem cell lineage C3H10T1/2. During the BMP2-induction of osteoblastic differentiation of C3H10T1/2, ERRgamma and miR433 expression decreased. In addition, during the osteoblastic differentiation, overexpression of ERRgamma or miR-433 inhibited the expression of osteogenic marker genes such as Runx2 and ALP. A computer-based prediction algorithm led to the identification of three miR-433 binding sites [S1 (114-145 bp), S2 (3735-3766 bp) and S3 (3828-3860 bp)] on the 3'-UTR of Runx2 mRNA. Furthermore, miR-433 directly targeted S1 and S2, and decreased the level of Runx2 transcript. In addition, miR-433 inhibited BMP2-induced 6*OSE-Luc activities. Anti-miR-433 recovered ERRgamma-suppressed Runx2 expression and ALP activity. SIGNIFICANCE: These results demonstrated that miR-433 suppressed BMP2-indcued osteoblast differentiation by decreasing the level of Runx2 transcript. PMID- 23353876 TI - Is basic research providing answers if adjuvant anti-estrogen treatment of breast cancer can induce cognitive impairment? AB - Adjuvant treatment of cancer by chemotherapy is associated with cognitive impairment in some cancer survivors. Breast cancer patients are frequently also receiving endocrine therapy with selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs) to suppress the growth of estradiol sensitive breast tumors. Estrogens are well-known, however, to target brain areas involved in the regulation of cognitive behavior. In this review clinical and basic preclinical research is reviewed on the actions of estradiol, SERMs and AIs on brain and cognitive functioning to see if endocrine therapy potentially induces cognitive impairment and in that respect may contribute to the detrimental effects of chemotherapy on cognitive performance in breast cancer patients. Although many clinical studies may be underpowered to detect changes in cognitive function, current basic and clinical reports suggest that there is little evidence that AIs may have a lasting detrimental effect on cognitive performance in breast cancer patients. The clinical data on SERMs are not conclusive, but some studies do suggest that tamoxifen administration may form a risk for cognitive functioning particularly in older women. An explanation may come from basic preclinical research which indicates that tamoxifen often acts agonistic in the absence of estradiol but antagonistic in the presence of endogenous estradiol. It could be hypothesized that the negative effects of tamoxifen in older women is related to the so-called window of opportunity for estrogen. Administration of SERMs beyond this so-called window of opportunity may not be effective or might even have detrimental effects similar to estradiol. PMID- 23353877 TI - Remediation of Cu(II), Ni(II), and Cr(III) ions from simulated wastewater by dendrimer/titania composites. AB - Generation 4 polyamidoamine (PAMAM) dendrimers with ethylenediamine cores (G4-OH) were immobilized on titania (TiO(2)) and examined as novel metal chelation materials. Characterization results indicate both the effective immobilization of dendrimers onto titania and retention of the dendrimer on titania following remediation. The effective remediation of Cu(II), Ni(II), and Cr(III), which are model pollutants commonly found in industrial electroplating wastewater, is demonstrated in this work. Important parameters that influence the efficiency of metal ion removal were investigated; e.g. solution pH, retention time, metal ion concentration, and composite material dosage. Metal ion removal was achieved over a wide metal concentration range within a 1 h equilibration time. Maximum metal ion removal was achieved at pH >=7 for both Cu(II) and Cr(III), and pH >=9 for Ni(II). Further, the dendrimer/titania composite materials were even more effective when metal ion mixtures were tested. Specifically, a dramatic increase was observed for Ni(II) chelation when in a mixture was compared to a pure nickel solution. These findings suggest new strategies for improving metal ion removal from industrial wastewater. PMID- 23353878 TI - Using EDDS and NTA for enhanced phytoextraction of Cd by water spinach. AB - A greenhouse experiment was used to test the applicability of [S,S] Ethylenediaminedisuccinic acid (EDDS) and nitrilotriacetic acid (NTA) at rates of 2.5 mmol kg(-1) and 5.0 mmol kg(-1), respectively, to increase the uptake of Cd by water spinach (Ipomoea aquatic Forsk) in soils with 2.5-30 mg Cd kg(-1). The addition of EDDS and NTA significantly increased water soluble Cd in soils. However, the Cd concentration in the root and shoot was higher in the NTA treatment than in the EDDS treatment. No instance of Cd hyperaccumulation was observed; however, the 5.0 mmol kg(-1) NTA treatment for soil with 30 mg Cd kg( 1) caused the Cd concentration to increase to 86 mg kg(-1), which is close to the critical concentration (100 mg kg(-1)) of a hyperaccumulator. The total Cd uptake in the treatments of EDDS and NTA for soils with 2.5, 5.0, and 10 mg Cd kg(-1) was acceptable, and was higher than the control. The level of 5.0 mmol kg(-1) EDDS was excessively high for enhanced phytoextraction in soils with 20 and 30 mg Cd kg(-1). Water spinach for Cd phytoextraction is a viable alternative to using herbaceous hyperaccumulators. PMID- 23353879 TI - Meeting world's most stringent Hg criterion: a pilot-study for the treatment of oil refinery wastewater using an ultrafiltration membrane process. AB - A membrane ultrafiltration (UF) technology was tested using an oil refinery's end of-pipe effluent to demonstrate the proof of concept, i.e. can the Great Lakes Initiative criterion of less than 1.3 ppt be consistently met at the pilot-scale, and to provide the data necessary for preliminary full-scale process design. This study presents the successful pilot test conducted with continuous but varying feed conditions over a protracted period. The UF membrane process consistently provided a constant permeate quality at all tested operating conditions, virtually independent of the feed water characteristics and the feed Hg concentration (0.5-22.7 ppt). The treatment target of less than 1.3 ppt of Hg was met and exceeded for all tested conditions during the pilot study. Turbidity measurements were <0.5 NTU (with a MDL of 0.5 NTU) 85% of the time and <0.16 NTU 95% of the time when analyzed on-line. The TMP values were below the specification of (negative) 7-12 psi at all tested conditions during the pilot study. Weekly maintenance cleans and monthly clean in place (CIP) events were very effective in consistently restoring the membrane permeability during the pilot-study. PMID- 23353880 TI - Impact on enzyme activity as a new quality index of wastewater. AB - The aim of this study was to define a new indicator for the quality of wastewaters that are released into the environment. A quality index is proposed for wastewater samples in terms of the inertness of wastewater samples toward enzyme activity. This involves taking advantage of the sensitivity of enzymes to pollutants that may be present in the waste samples. The effect of wastewater samples on the rate of a number of different enzyme-catalyzed reactions was measured, and the results for all the selected enzymes were analyzed in an integrated fashion (multi-enzymatic sensor). This approach enabled us to define an overall quality index, the "Impact on Enzyme Function" (IEF-index), which is composed of three indicators: i) the Synoptic parameter, related to the average effect of the waste sample on each component of the enzymatic sensor; ii) the Peak parameter, related to the maximum effect observed among all the effects exerted by the sample on the sensor components; and, iii) the Interference parameter, related to the number of sensor components that are affected less than a fixed threshold value. A number of water based samples including public potable tap water, fluids from urban sewage systems, wastewater disposal from leather, paper and dye industries were analyzed and the IEF-index was then determined. Although the IEF-index cannot discriminate between different types of wastewater samples, it could be a useful parameter in monitoring the improvement of the quality of a specific sample. However, by analyzing an adequate number of waste samples of the same type, even from different local contexts, the profile of the impact of each component of the multi-enzymatic sensor could be typical for specific types of waste. The IEF-index is proposed as a supplementary qualification score for wastewaters, in addition to the certification of the waste's conformity to legal requirements. PMID- 23353881 TI - Remediation to improve infiltration into compact soils. AB - Urban development usually involves soil compaction through converting large pervious land into developed land. This change typically increases runoff during runoff events and consequently may add to flooding and additional volume of runoff. The wash off of pollutants may also create numerous water quality and environmental problems for receiving waters. To alleviate this problem many municipalities are considering low impact development. One technique to reduce runoff in an urban area is to improve the soil infiltration. This study is specifically undertaken to investigate tilling and compost addition to improve infiltration rate, and to investigate measurement tools to assess the effectiveness of remediated soil. Soil remediation was performed at three sites in an urban area metropolitan area. Each site was divided into three plots: tilled, tilled with compost addition, and a control plot with no treatment. The infiltration effectiveness within each plot was assessed by measuring saturated hydraulic conductivity (K(sat)) using the modified Philip Dunne (MPD) infiltrometer during pre- and post-treatment. In addition, the use of soil bulk density and soil strength as surrogate parameters for K(sat) was investigated. Results showed that deep tillage was effective at reducing the level of soil strength. Soil strength was approximately half that of the control plot in the first six inches of soil. At two of the sites, tilling was also ineffective at improving the infiltration capacity of the soil. The geometric mean of K(sat) was 0.5-2.3 times that of the control plot, indicating little overall improvement. Compost addition was more effective than tilling by reducing the soil strength and compaction and increasing soil infiltration. The geometric mean of K(sat) on the compost plots was 2.7-5.7 times that of the control plot. No strong correlations were observed before remediation between either soil bulk density or soil strength and K(sat). Simulation results showed that the amount of runoff generated from a selection of design storms for treated soil was less than for untreated soil. The results presented in this study may be used as guidance for urban hydromodification and stormwater management plans. PMID- 23353882 TI - Evaluation of a coagulation/flocculation-lamellar clarifier and filtration-UV chlorination reactor for removing emerging contaminants at full-scale wastewater treatment plants in Spain. AB - The presence and elimination of 25 emerging contaminants in two full-scale Spanish wastewater treatment plants was studied. The tertiary treatment systems consisted of coagulation, flocculation lamellar settlement and filtration (pulsed bed sand filters) units, and disinfection was carried out by medium pressure UV light lamps and chlorination. Diclofenac and carbamazepine were found to be the emerging contaminants with the highest concentrations in secondary effluents. Photodegradable emerging contaminants (e.g. ketoprofen, triclosan and diclofenac) were removed by filtration-UV light radiation-chlorination whereas most hydrophobic compounds (e.g. galaxolide and tonalide) were eliminated by coagulation-flocculation followed by lamellar clarification, a unit in which a seasonal trend was observed. Overall mass removal efficiency was about 60%. 1-(8 Chlorocarbazolyl) acetic acid, an intermediate product of the photodegradation of diclofenac, was detected after filtration-UV-chlorination, but not after coagulation-flocculation and lamellar clarification. This study demonstrated potential for general applicability of two established tertiary treatment systems to eliminate emerging contaminants. PMID- 23353883 TI - Culture, intangibles and metrics in environmental management. AB - The demand for better representation of cultural considerations in environmental management is increasingly evident. As two cases in point, ecosystem service approaches increasingly include cultural services, and resource planners recognize indigenous constituents and the cultural knowledge they hold as key to good environmental management. Accordingly, collaborations between anthropologists, planners, decision makers and biodiversity experts about the subject of culture are increasingly common-but also commonly fraught. Those whose expertise is culture often engage in such collaborations because they worry a practitioner from 'elsewhere' will employ a 'measure of culture' that is poorly or naively conceived. Those from an economic or biophysical training must grapple with the intangible properties of culture as they intersect with economic, biological or other material measures. This paper seeks to assist those who engage in collaborations to characterize cultural benefits or impacts relevant to decision-making in three ways; by: (i) considering the likely mindset of would-be collaborators; (ii) providing examples of tested approaches that might enable innovation; and (iii) characterizing the kinds of obstacles that are in principle solvable through methodological alternatives. We accomplish these tasks in part by examining three cases wherein culture was a critical variable in environmental decision making: risk management in New Zealand associated with Maori concerns about genetically modified organisms; cultural services to assist marine planning in coastal British Columbia; and a decision-making process involving a local First Nation about water flows in a regulated river in western Canada. We examine how 'culture' came to be manifest in each case, drawing from ethnographic and cultural-models interviews and using subjective metrics (recommended by theories of judgment and decision making) to express cultural concerns. We conclude that the characterization of cultural benefits and impacts is least amenable to methodological solution when prevailing cultural worldviews contain elements fundamentally at odds with efforts to quantify benefits/impacts, but that even in such cases some improvements are achievable if decision-makers are flexible regarding processes for consultation with community members and how quantification is structured. PMID- 23353884 TI - Determination of background levels on water quality of groundwater bodies: a methodological proposal applied to a Mediterranean River basin (Guadalhorce River, Malaga, southern Spain). AB - Determine background levels are a key element in the further characterisation of groundwater bodies, according to Water Framework Directive 2000/60/EC and, more specifically, Groundwater Directive 2006/118/EC. In many cases, these levels present very high values for some parameters and types of groundwater, which is significant for their correct estimation as a prior step to establishing thresholds, assessing the status of water bodies and subsequently identifying contaminant patterns. The Guadalhorce River basin presents widely varying hydrogeological and hydrochemical conditions. Therefore, its background levels are the result of the many factors represented in the natural chemical composition of water bodies in this basin. The question of determining background levels under objective criteria is generally addressed as a statistical problem, arising from the many aspects involved in its calculation. In the present study, we outline the advantages of applying two statistical techniques applied specifically for this purpose: (1) the iterative 2sigma technique and (2) the distribution function, and examine whether the conclusions reached by these techniques are similar or whether they differ considerably. In addition, we identify the specific characteristics of each approach and the circumstances under which they should be used. PMID- 23353885 TI - 18F-FDG PET/CT-directed biopsy: does it offer incremental benefit? AB - PURPOSE: To study whether the metabolic information provided by a prior PET/computed tomography (CT) scan can add valuable information and an incremental benefit while performing image-guided biopsies. METHODS: Fluorine-18 fluorodeoxyglucose (F-FDG) PET/CT findings of 112 patients were available before biopsy and were considered for analysis. Biopsies were performed using standard techniques only after the needle tip was confirmed to be in the portion of the lesion corresponding to the hypermetabolic area seen on PET. This was achieved by visual coregistration and also by software registration algorithms that registered the intraprocedural CT images with the preselected PET/CT data. Only those biopsies for which a definitive histopathological diagnosis could be made were considered 'diagnostic'. Cases in which PET/CT added an incremental value were divided into three categories. RESULTS: A total of 112 patients (66 male and 46 female, age range 16-74 years) underwent a biopsy based on PET findings. The biopsy sites were as follows: lung, 54; lymph nodes, 27; bone, 12; and soft tissue masses/deposits, 19. Out of the 112 biopsies, an incremental benefit was seen overall in 53 patients (47.3%): in 40.7% (22/54) of patients who underwent lung biopsies, 44.4% (12/27) of those who underwent lymph node biopsies, 66.6% (8/12) of those who underwent bone biopsies and 57.8% (11/19) of those who underwent soft-tissue biopsies. Out of the cases that showed an incremental benefit, the highest number (30) belonged to the category in which the biopsy sample was obtained from the focal hypermetabolic portion of the apparently larger morphological lesion seen on CT. CONCLUSION: PET/CT data coregistered with intraprocedural CT images can guide needle placement in the viable portion of the lesion, thus increasing the chances of achieving a definitive diagnosis. This approach can offer a significant incremental benefit while performing image guided biopsies. PMID- 23353887 TI - A comparison of the diagnostic performance of half-time SPECT and multiplanar pelvic bone scan in patients with significant bladder artifacts. AB - OBJECTIVES: The objective of this study was to evaluate the diagnostic performance of half-time single-photon emission computed tomography (SPECT) in the interpretation of bone scans in patients with bladder artifacts in comparison with multiplanar imaging. We also investigated whether SPECT could reduce the radiation dose to nuclear medicine personnel and shorten the acquisition time. MATERIALS AND METHODS: Data from 29 patients with significant bladder artifacts were assessed by two nuclear medicine physicians. The presence or absence of pelvic bone lesions was individually interpreted with both techniques, multiplanar imaging and half-time SPECT, using a three-point pelvic score as follows: 0=definitely no lesion, 1=indeterminate, 2=definite positive lesion. A comparison of the diagnostic performances between the two techniques was made. The radiation dose to personnel and acquisition time were also investigated. RESULTS: Using half-time SPECT, the incidence of studies interpreted without interference from bladder artifacts (artifact-free image) was 100% on both patient-based and lesion-based analyses of 29 patients, whereas multiplanar imaging revealed incidences of 52 and 90% on patient-based and lesion-based analyses, respectively. Ninety percent of technologists and 58% of assistants received 1 uSv/case radiation dose while performing multiplanar imaging. Only 10% of technologists received 1 uSv/case and none of the assistants received a detectable radiation dose from SPECT. The SPECT technique could also reduce the examination time, particularly when positioning time was included. CONCLUSION: Half-time SPECT can significantly improve the diagnostic confidence of interpreting equivocal pelvic lesions in patients with bladder artifacts, compared with multiplanar imaging. This technique also provides lower radiation dose to nuclear medicine staff and requires shorter examination time. PMID- 23353886 TI - Utility of (18)F-FDG PET-CT in staging and restaging of patients with malignant salivary gland tumours: a single-institutional experience. AB - OBJECTIVE: The aim of this study was to evaluate the clinical utility of (18)F fluorodeoxyglucose ((18)F-FDG) positron emission tomography-computed tomography (PET-CT) in staging and restaging of patients with malignant primary salivary gland tumours. METHODS: Data pertaining to 30 patients (age: 43.8+/-16.8 years; male/female: 20/10) with histopathologically proven malignant primary salivary gland tumours who underwent 36 F-FDG PET-CTs were retrospectively analysed. Ten PET-CTs were performed for staging and 26 for restaging. The primary site was the parotid gland in 22 patients, the submandibular gland in seven and the minor salivary gland in one patient. (18)F-FDG PET-CT images were revaluated by two nuclear medicine physicians in consensus. Findings were grouped into local disease, nodal disease and distant metastasis. Results were compared with those of conventional imaging modalities [CIM (CT/ultrasound/bone scintigraphy)] when available (n=28). Clinical or imaging follow-up (minimum 6 months) data along with histopathological information (when available) were taken as the reference standard. RESULTS: Overall, 25 PET-CTs were positive and 11 were negative for disease. (18)F-FDG PET-CT showed local disease in 21 patients, nodal disease in 17 and distant metastasis in nine (lungs, four; liver, three; bones, four; and thyroid, one). Twenty-three PET-CTs were true positive, nine were true negative, two were false positive and two were false negative. The overall sensitivity of (18)F-FDG PET-CT was 92%, specificity was 82%, positive predictive value was 92%, negative predictive value was 82% and accuracy was 89%. No significant difference was seen in the accuracy of PET-CT between the staging and restaging groups (100 vs. 85%; P=0.468). In patients for whom comparable CIM data were available (n=28), PET-CT did not show any significant advantage over CIM (P=0.012) but was more specific (71 vs. 43%). CONCLUSION: (18)F-FDG PET-CT shows high accuracy in staging and restaging of patients with malignant primary salivary gland tumours. It is more specific than CIM for this purpose. PMID- 23353888 TI - Dose rates in nuclear medicine and the effectiveness of lead aprons: updating the department's knowledge on old and new procedures. AB - INTRODUCTION: Answers to common nuclear medicine radiation safety questions often involve the consideration of dose rates from injected patients and the inverse square law. For staff, lead aprons are available as an option, although they are not routinely used and their effectiveness varies depending on the isotope. New tests and procedures have been introduced at this hospital, including PET and Y microsphere implantation, which have required a review and investigation of their potential impact on staff doses. To answer these questions and to account for the recently introduced technologies and procedures, a study was conducted to measure and demonstrate the level of effectiveness of the department's lead aprons and to simulate patient dose rate measurements and estimations by obtaining measurements from water phantoms filled with these isotopes. MATERIALS AND METHODS: A calibrated survey meter was used to measure dose rates at varying distances from water phantoms filled with Tc, Ga, I, F and Y. Thermoluminescence dosimeters attached to an anthropomorphic phantom with a lead apron were used to assess the effectiveness of the lead aprons available within the department. An uncollimated detector from a gamma camera was used to observe the changes to the energy spectrum in the presence of the lead apron. RESULTS: The results from the dose rate measurements demonstrated an overestimation by the inverse square law at close distances. This overestimation can be in excess of four times the measurements made within this study. The use of a lead apron was shown to reduce doses by varying degrees depending on the isotope used. A 64.5% dose reduction was observed when shielding against Tc with diminishing effectiveness against the remaining isotopes. The results for Y suggest that using a lead apron could result in dose escalation at shallow depths. CONCLUSION: A table of conversion factors, independent of the isotope, was generated for the estimation of dose rates from injected patients at various distances. An isotope-specific conversion table was also generated. The effectiveness of the lead aprons within the department was also successfully measured and assessed and recommendations were passed on to staff regarding their use. PMID- 23353889 TI - TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. AB - TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine, an emerging dynamic epigenetic state of DNA that can influence transcription. Evidence has linked TET1 function to epigenetic repression complexes, yet mechanistic information, especially for the TET2 and TET3 proteins, remains limited. Here, we show a direct interaction of TET2 and TET3 with O-GlcNAc transferase (OGT). OGT does not appear to influence hmC activity, rather TET2 and TET3 promote OGT activity. TET2/3-OGT co-localize on chromatin at active promoters enriched for H3K4me3 and reduction of either TET2/3 or OGT activity results in a direct decrease in H3K4me3 and concomitant decreased transcription. Further, we show that Host Cell Factor 1 (HCF1), a component of the H3K4 methyltransferase SET1/COMPASS complex, is a specific GlcNAcylation target of TET2/3-OGT, and modification of HCF1 is important for the integrity of SET1/COMPASS. Additionally, we find both TET proteins and OGT activity promote binding of the SET1/COMPASS H3K4 methyltransferase, SETD1A, to chromatin. Finally, studies in Tet2 knockout mouse bone marrow tissue extend and support the data as decreases are observed of global GlcNAcylation and also of H3K4me3, notably at several key regulators of haematopoiesis. Together, our results unveil a step-wise model, involving TET-OGT interactions, promotion of GlcNAcylation, and influence on H3K4me3 via SET1/COMPASS, highlighting a novel means by which TETs may induce transcriptional activation. PMID- 23353891 TI - A low mortality rat model to assess delayed cerebral vasospasm after experimental subarachnoid hemorrhage. AB - OBJECTIVE: To characterize and establish a reproducible model that demonstrates delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) in rats, in order to identify the initiating events, pathophysiological changes and potential targets for treatment. METHODS: Twenty-eight male Sprague-Dawley rats (250 - 300 g) were arbitrarily assigned to one of two groups - SAH or saline control. Rat subarachnoid hemorrhage in the SAH group (n=15) was induced by double injection of autologous blood, 48 hr apart, into the cisterna magna. Similarly, normal saline (n=13) was injected into the cisterna magna of the saline control group. Rats were sacrificed on day five after the second blood injection and the brains were preserved for histological analysis. The degree of vasospasm was measured using sections of the basilar artery, by measuring the internal luminal cross sectional area using NIH Image-J software. The significance was tested using Tukey/Kramer's statistical analysis. RESULTS: After analysis of histological sections, basilar artery luminal cross sectional area were smaller in the SAH than in the saline group, consistent with cerebral vasospasm in the former group. In the SAH group, basilar artery internal area (.056 MUm +/- 3) were significantly smaller from vasospasm five days after the second blood injection (seven days after the initial blood injection), compared to the saline control group with internal area (.069 +/- 3; p=0.004). There were no mortalities from cerebral vasospasm. CONCLUSION: The rat double SAH model induces a mild, survivable, basilar artery vasospasm that can be used to study the pathophysiological mechanisms of cerebral vasospasm in a small animal model. A low and acceptable mortality rate is a significant criterion to be satisfied for an ideal SAH animal model so that the mechanisms of vasospasm can be elucidated. Further modifications of the model can be made to adjust for increased severity of vasospasm and neurological exams. PMID- 23353890 TI - Goliath family E3 ligases regulate the recycling endosome pathway via VAMP3 ubiquitylation. AB - Diverse cellular processes depend on endocytosis, intracellular vesicle trafficking, sorting and exocytosis, processes regulated post-transcriptionally by modifications such as phosphorylation and ubiquitylation. In addition to sorting to the lysosome, cargo is recycled to the plasma membrane via recycling endosomes. Here, we describe a role of the goliath gene family of protease associated (PA) domain E3 ligases in regulating recycling endosome trafficking. The two Drosophila members of this family--Goliath and Godzilla(CG10277)--are located on endosomes, and both ectopic expression and loss-of-function lead to the accumulation of Rab5-positive giant endosomes. Furthermore, the human homologue RNF167 exhibits similar behaviour. We show that the soluble N ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) protein VAMP3 is a target of these ubiquitin ligases, and that recycling endosome trafficking is abrogated in response to their activity. Furthermore, mutation of the Godzilla ubiquitylation target lysines on VAMP3 abrogates the formation of enlarged endosomes induced by either Godzilla or RNF167. Thus, Goliath ubiquitin ligases play a novel role in regulating recycling endosome trafficking via ubiquitylation of the VAMP3 SNARE protein. PMID- 23353892 TI - Optical imaging of retina in response to grating stimuli in cats. AB - We examined the intrinsic signals in response to grating stimuli in order to determine whether the light-evoked intrinsic signals of the retina are due to changes in the photoreceptor activities induced by the image projected on to the retina or are due to neural activities of the inner retina. The retinas of the left eye of 12 cats under general anesthesia were examined by a functional imaging fundus camera. Near infrared light was used to monitor the reflectance changes (RCs) of the retina. Vertical grating were used to stimulate the retina at 4 Hz. The spatial frequencies of the gratings were 0.05, 0.11, 0.22, 0.43, 0.86, 1.73, and 3.46 cycles/degree (cpd). Ten images were averaged and used to analyze the RCs to obtain the peak value (PV) of a two dimensional fast Fourier transfer of the RCs. The wavefront aberrations (WA) were measured with a compact wavefront aberrometer and the spatial modulation transfer function (MTF) of the eye was calculated. The retinal reflectance image had a grating pattern. The PV of the spatial sensitivity curve was highest at low spatial frequencies (0.05 and 0.11 cpd), and the sensitivity decreased steeply with an increase in the spatial frequency. RCs were not detectable at 3.46 cpd. The MTF decreased gradually with increases in the spatial frequencies and was 0.68 at 3.46 cpd. The reflectance pattern of the retinal intrinsic signal elicited by grating stimuli of different spatial frequencies was different from that of the MTF. This suggests that the intrinsic signal represents not only the response of the photoreceptors but also other neuronal or vascular changes in the retina. PMID- 23353893 TI - Long-term treatment with EXf, a peptide analog of Exendin-4, improves beta-cell function and survival in diabetic KKAy mice. AB - EXf is a C-terminally truncated fragment of Exendin-4 with two amino acid substitutions. Previous studies showed that EXf controls plasma glucose level acting as a glucagon-like peptide 1 (GLP-1) receptor agonist. The purpose of this study was to evaluate the effects of EXf on beta-cell function and survival in diabetic KKAy mice. EXf treatment significantly improved the glucose intolerance and reduced non-fasting and fasting plasma glucose levels, as well as plasma triglyceride levels in diabetic KKAy mice. In hyperglycemic clamp test, EXf treated mice displayed an increased glucose infusion rate and first-phase insulin secretion. Treatment with EXf also led to a significant restoration of islet morphology, an increase in Ki67 expression in beta-cells, and a reduction in the number of TUNEL positive beta-cells. In the pancreas, comparative transcription analysis showed up-regulation of Akt1. The up-regulation of phosphorylated Akt1 was confirmed by Western blot, and changes in the protein levels of members of the Akt1 pathway, such as PI3K, Bim, Bcl-2, Bax, Caspase-3, and Caspase-9, PDX-1, were observed as well. Therefore, EXf treatment could improve beta-cell function and survival in diabetic KKAy mice, likely as a result of islet morphology restoration, stimulation of beta-cell proliferation, and inhibition of beta-cell apoptosis. PMID- 23353894 TI - Near-infrared lipophilic fluorophores for tracing tissue growth. AB - Longitudinal monitoring of cell migration, division and differentiation is of paramount importance in cell-based medical treatment. However, currently available optical techniques for tracing cell growth and tissue development are limited in applications due to genetic modification, toxicity and inaccurate detection when utilizing the visible spectrum. We have developed lipophilic near infrared (NIR) fluorophores with high optical properties and a low background signal that allows longitudinal monitoring of cell proliferation and differentiation. Intracellular labeling efficacy was highly dependent on the physicochemical properties of fluorophores such as lipophilicity, charge, polar surface area and rotational bonds. Among the series of NIR cyanine fluorophores, ESNF 13 showed high solubility in aqueous buffer, high membrane penetration, low cytotoxicity and a long-term signal maintainability with a high signal intensity. This study will guide tissue engineers in designing long-term cell trafficking agents with better physicochemical and optical properties. PMID- 23353895 TI - Aqueous extract of unripe Rubus coreanus fruit attenuates atherosclerosis by improving blood lipid profile and inhibiting NF-kappaB activation via phase II gene expression. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Rubus coreanus has been used as a traditional herbal medicine for alleviation of inflammatory and vascular diseases in Asian countries. AIM OF THE STUDY: The anti-atherogenic effect of unripe Rubus coreanus fruit extract (URFE) and its underlying mechanism were analyzed in mice fed a high-fat diet (HFD) and in cell culture system. MATERIALS AND METHODS: Mouse was freely given HFD alone or supplemented with URFE for 14 weeks, followed by analysis of atherosclerotic lesions and serum lipid levels. For in vitro assay, macrophages were pretreated with URFE, followed by stimulation with lipopolysaccharide (LPS). Expression levels of inflammatory genes (TNF-alpha, IL 1beta, and iNOS) and phase II genes (heme oxygenase-1, glutamate cysteine lygase, and peroxiredoxine-1) as well as intracellular reactive oxygen species (ROS) level and NF-kappaB activation pathway were analyzed in cultured macrophages as well as mouse sera and aortic tissues. RESULTS: URFE supplementation reduced HFD induced atherosclerotic lesion formation which was correlated with decreased levels of lipids, lipid peroxides, and inflammatory mediators (TNF-alpha, IL 1beta, and nitric oxide) in sera as well as suppression of inflammatory gene in aortic tissues. In addition, pre-treatment of macrophages with URFE also suppressed LPS-induced NF-kappaB activation, ROS production, and inflammatory and phase II gene expressions. Inhibition of phase II enzyme and protein activities attenuated the suppressive effects URFE on ROS production, NF-kappaB activation, and inflammatory gene expression. CONCLUSION: These results suggest that URFE attenuates atherosclerosis by improving blood lipid profile and inhibiting NF kappaB activation via phase II antioxidant gene expression. PMID- 23353896 TI - Molecular mechanism of anti-inflammatory activity of Pluchea indica leaves in macrophages RAW 264.7 and its action in animal models ofinflammation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: PLUCHEA INDICA LESS.: (Asteraceae) is a Thai medicinal plant used in traditional medicine for the treatment of hemorrhoids, lumbago, leucorrhoea and inflammation. This study investigated the molecular mechanism of anti-inflammatory activity of Pluchea indica leaf extract in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and also determined its action in acute inflammation animal models. MATERIALS AND METHODS: The inhibitory effect of Pluchea indica leaf extract on LPS-induced nitric oxide (NO) production was evaluated by Griess reaction. Protein and mRNA expressions were determined by real time RT-PCR and Western blotting analysis, respectively. Inducible nitric oxide synthase (iNOS) promoter activity was evaluated by iNOS promoter based reporter gene assay. In vivo anti-inflammatory effect was examined in ethylphenylpropiolate (EPP)-induced ear edema and carrageenan-induced paw edema in rat models. RESULTS: Ethyl acetate fraction of ethanol extract of Pluchea indica leaves (EFPI) exhibited the potent inhibitory effect on NO production in LPS-induced macrophages and also inhibited PGE2 release. EFPI reduced iNOS mRNA and protein expression through suppressed iNOS promoter activity and nuclear translocation of subunit p65 of nuclear factor-kappaB, but did not inhibit phosphorylation of the mitogen-activated protein kinases (MAPKs). Moreover, EFPI possessed anti-inflammatory activities on acute phase of inflammation as seen in EPP-induced ear edema and carrageenan-induced paw edema inrats. CONCLUSIONS: These data support the pharmacological basis of Pluchea indica plant as a traditional herbal medicine for treatment of inflammation. PMID- 23353897 TI - Dillenia suffruticosa exhibited antioxidant and cytotoxic activity through induction of apoptosis and G2/M cell cycle arrest. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dillenia suffruticosa (Family: Dilleniaceae) locally known as Simpoh air has been reported to be used traditionally to treat cancerous growth. Therefore, the present study was attempted to investigate the antioxidant and cytotoxic properties of different parts (root, flower, fruit and leaf) of D. suffruticosa extracts. METHODS AND MATERIALS: In this study, direct solvent extraction (aqueous and methanol) from different parts of D. suffruticosa (root, flower, fruit and leaf) were carried out. Antioxidant activities of D. suffruticosa extract were determined by using DPPH, ABTS FRAP and beta-carotene bleaching assays. Cytotoxicity and cell cycle arrest of the active extract were determined using MTT assay and flow cytometer, respectively. Sequential solvent extraction (hexane, DCM, EtOAc, and MeOH) were also carried out in root of D. suffruticosa to further evaluate the antioxidant and cytotoxic activity of the different solvent extracts. RESULTS: Methanol (MeOH) root extract showed the highest TPC, antioxidant and cytotoxic activities (especially towards HeLa) compared to others (P<0.05). Based on the results, sequential solvent extraction (hexane, DCM, EtOAc and MeOH) was carried out in the roots of D. suffruticosa. MeOH extract exhibited the highest antioxidant activities among others and significantly correlated (P<0.05) with TPC, suggesting the important contribution of phenolic compounds to its antioxidant activity. On the other hand, the DCM and EtOAc exhibited higher cytotoxic activity to selected cancer cells (HeLa, MCF-7, MDA-MB-231, A549 and HT29) compared to others. In short, there is no established correlation between antioxidant and cytotoxic activities of D. suffruticosa extracts indicating that an agent with high antioxidant activities will not necessarily possesses good cytotoxic activities in return. Qualitative phytochemical screening of D. suffruticosa extracts suggested the presence of saponins, triterpenes, sterols, and polyphenolic compounds which are believed to contribute to the cytotoxic activities. CONCLUSION: It is suggested that the cytotoxicity of the active extracts in HeLa was due to the induction of apoptosis and cell cycle arrest at G2/M. PMID- 23353898 TI - Stem-bark of Terminalia arjuna attenuates human monocytic (THP-1) and aortic endothelial cell activation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Terminalia arjuna - stem bark extract is traditionally used as cardiotonic in Ayurvedic medicine. AIM OF THE STUDY: The present study was aimed to evaluate the molecular basis for cardioprotective potential of Terminalia arjuna (TA) stem bark, using cell cultures of human monocytic (THP-1) and human aortic endothelial cells (HAECs). MATERIALS AND METHODS: Inhibitory effect of alcoholic (TAAE) and aqueous (TAWE) extracts of TA stem bark was assessed on human 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lipoprotein lipase (LpL) and lipid peroxidation in rat (wistar) liver and heart homogenates. The patterns of H2O2 induced reactive oxygen species (ROS) generation were observed by confocal microscopy. The activities of antioxidant enzymes and reducing power of the cells were measured in a microplate reader. Gene transcripts of proinflammatory markers in THP-1 and HAECs were assayed by real time PCR and levels of inflammatory protein markers by ELISA or flow cytometry. Phytochemical analyses of TAAE and TAWE were done using liquid chromatography, coupled to mass spectrometry (LC-MS). RESULTS: TAAE and TAWE inhibited the lipid peroxidation and HMG-CoA reductase but had no effect on LpL. Both the extracts attenuated H2O2 mediated ROS generation in THP-1 cells by promoting catalase (CAT), glutathione peroxidase (GPx) activities, and by sustaining cellular reducing power. TAAE was highly effective in attenuating proinflammatory gene transcripts in THP-1 cells and HAECs, whereas the response to TAWE depended on the type of transcript and cell type. Both extracts decreased the levels of typical inflammatory marker proteins, viz. LPS induced tumor necrosis factor (TNF)-alpha secreted by THP-1 cells and TNF-alpha induced cell surface adhesion molecules on HAECs, namely vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Phytochemical analyses indicated the richness in phenolic compounds and terpenes of TAAE and TAWE, while revealing variability in their metabolite profile. CONCLUSION: Our study scientifically validates the antioxidative and antiinflammatory properties of Terminalia arjuna stem bark. The marked effects on cultured human monocytic and aortic endothelial cells (HAEC) provide the biochemical and molecular basis for therapeutic potential of TA-stem bark against cardiovascular diseases (CVD). PMID- 23353899 TI - Fundamentals of inertial focusing in microchannels. AB - Inertial microfluidics has been attracting considerable interest in recent years due to immensely promising applications in cell biology. Despite the intense attention, the primary focus has been on development of inertial microfluidic devices with less emphasis paid to elucidation of the inertial focusing mechanics. The incomplete understanding, and sometimes confusing experimental results that indicate a different number of focusing positions in square or rectangular microchannels under similar flow conditions, have led to poor guidelines and difficulties in design of inertial microfluidic systems. In this work, we describe and experimentally validate a two-stage model inertial focusing in microchannels. Our analysis and experimental results show that not only the well-accepted shear-induced and wall-induced lift forces act on particles within flow causing equilibration near microchannel sidewalls, but the rotation-induced lift force influences the position of these equilibria. In addition, for the first time, we experimentally measure lift coefficients, which previously could only be obtained from numerical simulations. More importantly, insights offered by our two-stage model of inertial focusing are broadly applicable to cross sectional geometries beyond rectangular. With elucidation of the equilibration mechanism, we envision better guidelines for the inertial microfluidics community, ultimately leading to improved performance and broader acceptance of the inertial microfluidic devices in a wide range of applications, from filtration to cell separations. PMID- 23353900 TI - Voltammetric discrimination of skatole and indole at disposable screen printed electrodes. AB - In this work, we study the electrochemical behaviour of skatole, one of the compounds responsible for the offensive smell in pork meat that is known as boar taint, at different metal and carbon electrodes. We then demonstrate for the first time that skatole and indole, the main electroactive interferent potentially present in real samples, can be discriminated and separately quantified using cheap and disposable screen printed electrodes (SPE). This implies significant progress compared to the colorimetric method reported by Mortensen in 1983. PMID- 23353902 TI - Gender-specific effects of fluoxetine on hippocampal glucocorticoid receptor phosphorylation and behavior in chronically stressed rats. AB - Chronic psychosocial isolation stress (CPSI) modulates glucocorticoid receptor (GR) functioning in Wistar male rat hippocampus (HIPPO) through alteration of nuclear GR phosphorylation and its upstream kinases signaling, which parallels animal depressive-like behavior. The current study investigated potential gender specificities regarding the effect of chronic therapy by an antidepressant fluoxetine (FLU) on GR signaling in HIPPO and depressive-like behavior in CPSI animals. FLU was administrated to female and male naive or CPSI rats for 21 days and GR protein, its phosphorylation status and upstream kinases, as well as GR and BDNF mRNA were followed in HIPPO together with animal serum corticosterone (CORT) and depressive-like behavior. The results showed that CPSI increased immobility in males versus hyperactivity in females and disrupted nuclear pGR232 Cdk5 pathway and JNK signaling in a gender-specific way. In contrast, in both genders CPSI increased the nuclear levels of GR and pGR246 but decreased CORT and mRNA levels of GR and BDNF. Concomitant FLU normalized the depressive-like behavior and altered the nuclear pGR232-Cdk5 signaling in a gender-specific manner. In both females and males, FLU reversed the nuclear levels of GR and pGR246 without affecting CORT and GR mRNA levels. In contrast, FLU exhibited gender-specific effect on BDNF mRNA in CPSI animals, by increasing it in females, but not in males. In spite of normalization the total nuclear GR level upon FLU treatment in both gender, down-regulation of GR mRNA is possibly maintained through prevalence of pGR232 isoform only in males. The gender-specific alterations of pGR232-Cdk5 signaling and BDNF gene expression in HIPPO and normalization of depressive-like behavior upon FLU treatment distinguishes this signaling pathway as potential future antidepressant target for gender-specific therapy of stress related mood disorders. PMID- 23353901 TI - Support for 5-HT2C receptor functional selectivity in vivo utilizing structurally diverse, selective 5-HT2C receptor ligands and the 2,5-dimethoxy-4 iodoamphetamine elicited head-twitch response model. AB - There are seemingly conflicting data in the literature regarding the role of serotonin (5-HT) 5-HT2C receptors in the mouse head-twitch response (HTR) elicited by the hallucinogenic 5-HT2A/2B/2C receptor agonist 2,5-dimethoxy-4 iodoamphetamine (DOI). Namely, both 5-HT2C receptor agonists and antagonists, regarding 5-HT2C receptor-mediated Gq-phospholipase C (PLC) signaling, reportedly attenuate the HTR response. The present experiments tested the hypothesis that both classes of 5-HT2C receptor compounds could attenuate the DOI-elicited-HTR in a single strain of mice, C57Bl/6J. The expected results were considered in accordance with ligand functional selectivity. Commercially-available 5-HT2C agonists (CP 809101, Ro 60-0175, WAY 161503, mCPP, and 1-methylpsilocin), novel 4 phenyl-2-N,N-dimethyl-aminotetralin (PAT)-type 5-HT2C agonists (with 5-HT2A/2B antagonist activity), and antagonists selective for 5-HT2A (M100907), 5-HT2C (SB 242084), and 5-HT2B/2C (SB-206553) receptors attenuated the DOI-elicited-HTR. In contrast, there were differential effects on locomotion across classes of compounds. The 5-HT2C agonists and M100907 decreased locomotion, SB-242084 increased locomotion, SB-206553 resulted in dose-dependent biphasic effects on locomotion, and the PATs did not alter locomotion. In vitro molecular pharmacology studies showed that 5-HT2C agonists potent for attenuating the DOI elicited-HTR also reduced the efficacy of DOI to activate mouse 5-HT2C receptor mediated PLC signaling in HEK cells. Although there were differences in affinities of a few compounds at mouse compared to human 5-HT2A or 5-HT2C receptors, all compounds tested retained their selectivity for either receptor, regardless of receptor species. Results indicate that 5-HT2C receptor agonists and antagonists attenuate the DOI-elicited-HTR in C57Bl/6J mice, and suggest that structurally diverse 5-HT2C ligands result in different 5-HT2C receptor signaling outcomes compared to DOI. PMID- 23353903 TI - Stop verbal abuse and lateral violence. PMID- 23353908 TI - "SWAM": Educating patients with HF. PMID- 23353910 TI - Looking beyond. PMID- 23353913 TI - Patient education series. Corneal abrasion. PMID- 23353914 TI - Cat scratch disease. PMID- 23353915 TI - Vietnam nurse project: teaching in Hanoi. PMID- 23353916 TI - Documenting the minutes at professional meetings. PMID- 23353917 TI - Maintaining urinary catheters: What does the evidence say? PMID- 23353918 TI - Lumbar epidural injections for low back pain. PMID- 23353919 TI - Improving change-of-shift report. PMID- 23353921 TI - Spider bite. PMID- 23353923 TI - Peering into the dynamics of social interactions: measuring play fighting in rats. AB - Play fighting in the rat involves attack and defense of the nape of the neck, which if contacted, is gently nuzzled with the snout. Because the movements of one animal are countered by the actions of its partner, play fighting is a complex, dynamic interaction. This dynamic complexity raises methodological problems about what to score for experimental studies. We present a scoring schema that is sensitive to the correlated nature of the actions performed. The frequency of play fighting can be measured by counting the number of playful nape attacks occurring per unit time. However, playful defense, as it can only occur in response to attack, is necessarily a contingent measure that is best measured as a percentage (#attacks defended/total # attacks X 100%). How a particular attack is defended against can involve one of several tactics, and these are contingent on defense having taken place; consequently, the type of defense is also best expressed contingently as a percentage. Two experiments illustrate how these measurements can be used to detect the effect of brain damage on play fighting even when there is no effect on overall playfulness. That is, the schema presented here is designed to detect and evaluate changes in the content of play following an experimental treatment. PMID- 23353925 TI - Nitric oxide synthase inhibitors protect against rotenone-induced, oxidative stress mediated parkinsonism in rats. AB - Rotenone is known to cause progressive dopaminergic neuronal loss in rodents, but it remains unclear how this mitochondrial complex-I inhibitor mediates neurodegeneration specific to substantia nigra pars compacta (SNpc). One of the proposed mechanisms is increased free radical generation owing to mitochondrial electron transport chain dysfunction following complex-I inhibition. The present study examined the role of nitric oxide (NO) and hydroxyl radicals (OH) in mediating rotenone-induced dopaminergic neurotoxicity. Indications of NO involvement are evidenced by inducible nitric oxide synthase (NOS) over expression, and increased NADPH-diaphorase staining in SNpc neurons 96h following rotenone administration. Treatment of these animals with specific neuronal NOS inhibitor, 7-nitroindazole (7-NI) and non-specific NOS inhibitor, N-omega-nitro-l argenine methyl ester (l-NAME) caused reversal of rotenone-induced striatal dopamine depletion, and attenuation of the neurotoxin-induced decrease in the number of tyrosine hydroxylase immunoreactive neurons in SNpc, as well as in apomorphine and amphetamine-induced unilateral rotations. Interestingly, the study also demonstrated the contribution of OH in mediating rotenone nigral toxicity since there appeared a significant generation of the reactive oxygen species in vivo 24h following rotenone administration, a copious loss of reduced and oxidized glutathione, and increased superoxide dismutase and catalase activities in the cytosolic fractions of the ipsilateral SNpc area on the 5th day. An OH scavenging capacity of 7-NI and l-NAME in a Fenton-like reaction, as well as complete reversal of the rotenone-induced increases in the antioxidant enzyme activities, and the loss in reduced and oxidized glutathione contents in the SNpc supported OH involvement in rotenone-induced dopaminergic neurotoxicity. While these results strongly suggest the contribution of both OH and NO, resulting in acute oxidative stress culminating in dopaminergic neurodegeneration caused by rotenone, the course of events indicated generation of OH as the primary event in the neurotoxic processes. PMID- 23353926 TI - Circuit modeling of the electrical impedance: I. Neuromuscular disease. AB - Multifrequency electrical impedance myography (MFEIM) in the 3-300 kHz range was applied to 68 subjects representing 19 different neuromuscular diseases, and the impedances analyzed using the 5-element circuit model. Depending on severity, the 'cellular' parameters r(2), r(3), 1/c(1) and 1/c(2) were found to be as much as 10- to 20-fold larger than for normal subjects (taking age and girth into account), but in almost every case the extracellular fluid parameter r(1) was at most only marginally affected. Strong correlations are found between r(2) and 1/c(1,) but in the case of ALS that breaks down when c(1) (representing the muscle fiber membrane capacitance) falls below half the normal value. Also, c(2) (tentatively associated with intracellular organelle membranes) was found to be the most sensitive to disease progress in ALS, about three times more so than the 50 kHz phase, already suggested for use in clinical drug testing. We conclude that following parameters obtained using the combined MFEIM/5-element circuit analysis scheme offer a reliable, non-invasive and objective way of characterizing muscle in neuromuscular disease or during clinical drug testing. PMID- 23353927 TI - An integrated microfluidic cell culture system for high-throughput perfusion three-dimensional cell culture-based assays: effect of cell culture model on the results of chemosensitivity assays. AB - Although microfluidic cell culture systems are versatile tools for cellular assays, their use has yet to set in motion an evolutionary shift away from conventional cell culture methods. This situation is mainly due to technical hurdles: the operational barriers to the end-users, the lack of compatible detection schemes capable of reading out the results of a microfluidic-based cellular assay, and the lack of fundamental data to bridge the gap between microfluidic and conventional cell culture models. To address these issues, we propose a high-throughput, perfusion, three-dimensional (3-D) microfluidic cell culture system encompassing 30 microbioreactors. This integrated system not only aims to provide a user-friendly cell culture tool for biologists to perform assays but also to enable them to obtain precise data. Its technical features include (i) integration of a heater chip based on transparent indium tin oxide glass, providing stable thermal conditions for cell culturing; (ii) a microscale 3-D culture sample loading scheme that is both efficient and precise; (iii) a non mechanical pneumatically driven multiplex medium perfusion mechanism; and (iv) a microplate reader-compatible waste medium collector array for the subsequent high throughput bioassays. In this study, we found that the 3-D culture sample loading method provided uniform sample loading [coefficient of variation (CV): 3.2%]. In addition, the multiplex medium perfusion mechanism led to reasonably uniform (CV: 3.6-6.9%) medium pumping rates in the 30 microchannels. Moreover, we used the proposed system to perform a successful cell culture-based chemosensitivity assay. To determine the effects of cell culture models on the cellular proliferation, and the results of chemosensitivity assays, we compared our data with that obtained using three conventional cell culture models. We found that the nature of the cell culture format could lead to different evaluation outcomes. Consequently, when establishing a cell culture model for in vitro cell based assays, it might be necessary to investigate the fundamental physiological variations of the cultured cells in different culture systems to avoid any misinterpretation of data. As a whole, we have developed an integrated microfluidic cell culture system that overcomes several technical hurdles commonly encountered in the practical application of microfluidic cell culture systems, and we have obtained fundamental information to reconcile differences found with data acquired using conventional methods. PMID- 23353924 TI - Circadian dysfunction may be a key component of the non-motor symptoms of Parkinson's disease: insights from a transgenic mouse model. AB - Sleep disorders are nearly ubiquitous among patients with Parkinson's disease (PD), and they manifest early in the disease process. While there are a number of possible mechanisms underlying these sleep disturbances, a primary dysfunction of the circadian system should be considered as a contributing factor. Our laboratory's behavioral phenotyping of a well-validated transgenic mouse model of PD reveals that the electrical activity of neurons within the master pacemaker of the circadian system, the suprachiasmatic nuclei (SCN), is already disrupted at the onset of motor symptoms, although the core features of the intrinsic molecular oscillations in the SCN remain functional. Our observations suggest that the fundamental circadian deficit in these mice lies in the signaling output from the SCN, which may be caused by known mechanisms in PD etiology: oxidative stress and mitochondrial disruption. Disruption of the circadian system is expected to have pervasive effects throughout the body and may itself lead to neurological and cardiovascular disorders. In fact, there is much overlap in the non-motor symptoms experienced by PD patients and in the consequences of circadian disruption. This raises the possibility that the sleep and circadian dysfunction experienced by PD patients may not merely be a subsidiary of the motor symptoms, but an integral part of the disease. Furthermore, we speculate that circadian dysfunction can even accelerate the pathology underlying PD. If these hypotheses are correct, more aggressive treatment of the circadian misalignment and sleep disruptions in PD patients early in the pathogenesis of the disease may be powerful positive modulators of disease progression and patient quality of life. PMID- 23353928 TI - NaYF4:Yb3+/Er3+ nanoparticle-based upconversion luminescence resonance energy transfer sensor for mercury(II) quantification. AB - Upconversion luminescence is an anti-Stokes' emission process by converting long wavelength near-infrared (NIR, 980 nm) irradiation into shorter wavelength visible light emission, which demonstrates many advantages including no autofluorescence, low damage to samples, no photobleaching, and high sensitivity. Based on the Rhodamine B thiolactone (RBT) functionalized NaYF(4):15%Yb(3+),5%Er(3+) (UCNPs@RBT) nanocomposites, an ultrasensitive, selective, and rapid upconversion luminescence resonance energy transfer (UC LRET) sensor has been developed for the detection of mercury ions (Hg(2+)) in water. Upconverting luminescence resonance energy transfer from the UCNPs to the RBT derivates occurs after the addition of Hg(2+) ions into the UCNPs@RBT colloidal solution. This UC-LRET recognition of Hg(2+) can be finished within 1 min and other cations have no influence on the detection of mercury ions. This newly developed sensor demonstrates high selectivity toward the mercury ions and enables ultrasensitive and rapid detection of mercury ions in water in the range of 5 nM to 10 MUM with a 3sigma limit of detection of 3.7 nM. This sensor can be used for a naked-eye detection of Hg(2+) ions via its green upconverting luminescence response under the infrared excitation (980 nm) with the merit of no autofluorescence interference and good photostability. In addition, by dipping the hydrogel of UCNPs@RBT nanocomposites onto the filter paper, a highly selective and convenient luminescent paper sensor for Hg(2+) ions was also developed. PMID- 23353929 TI - Longevity for free? Increased reproduction with limited trade-offs in Drosophila melanogaster selected for increased life span. AB - Selection for increased life span in Drosophila melanogaster has been shown to correlate with decreased early fecundity and increased fecundity later in life. This phenomenon has been ascribed to the existence of trade-offs in which limited resources can be invested in either somatic maintenance or reproduction. In our longevity selection lines, we did not find such a trade-off. Rather, we find that females have similar or higher fecundity throughout life compared to non-selected controls. To determine whether increased longevity affects responses in other traits, we looked at several stress resistance traits (chill coma recovery, heat knockdown, desiccation and starvation), geotactic behaviour, egg-to-adult viability, body size, developmental time as well as metabolic rate. Longevity selected flies were more starvation resistant. However, in females longevity and fecundity were not negatively correlated with the other traits assayed. Males from longevity selected lines were slower at recovering from a chill induced coma and resting metabolic rate increased with age, but did not correlate with life span. PMID- 23353930 TI - Mesocosm study on weathering characteristics of Iranian Heavy crude oil with and without dispersants. AB - The environmental fate of Iranian Heavy crude oil (IHC) with and without an added oil spill dispersant (OSD) has been studied using a 1000 kL capacity in situ mesocosm. Physical weathering and chemical composition changes of the oil were monitored for 77 days. Compound-specific effects of the OSD could be observed as changes over time in the content of the total petroleum hydrocarbon (TPH), unresolved complex mixture (UCM), alkanes, polycyclic aromatic hydrocarbons (PAHs), hopanes and steranes in the oil. As oil weathers, most hydrocarbons showed a rapid decreasing phase followed by a slowdown and stabilization. Recalcitrant biomarkers, however, showed a different trend. An increase in hydrocarbon contents in the form of UCM occurred after OSD treatment. The enhanced solubility of the low molecular weight PAHs by the OSD decreased the half-life of the alkylated PAHs in the OD. After 77 days of exposure at the sea surface, both the oils with and without the OSD exhibited moderate weathering. Most of the source diagnostic indices maintained their source information, and the weathering indices indicated that evaporation, dissolution, and dispersion were the major weathering processes. The mass balance of the weathered oil was calculated using laboratory and mesocosm data and the results demonstrate the importance of using a mesocosm for the production of environmentally realistic data. PMID- 23353931 TI - Removal of cations using ion-binding terpolymer involving 2-amino-6-nitro benzothiazole and thiosemicarbazide with formaldehyde by batch equilibrium technique. AB - 2-Amino-6-nitro-benzothiazole and thiosemicarbazide with formaldehyde (BTF) terpolymer was synthesized by the condensation polymerization technique. The elemental analysis and physico-chemical parameters of the terpolymer were measured. This chelation terpolymer was characterized by infrared, electronic and nuclear magnetic resonance ((1)H &(13)C NMR) spectral studies. The molecular weight of the terpolymer was determined by gel permeation chromatography (GPC). Surface analysis of the terpolymer was analyzed by scanning electron microscopy (SEM) and X-ray diffraction (XRD) method. The thermal stability of the terpolymer was analyzed by thermogravimetric analysis (TGA). The cation-exchange property of the terpolymer was determined by batch equilibrium method with the effect of pH, contact time and electrolytes. The reusability of the resin was also studied to estimate the effectiveness of the terpolymer resin. PMID- 23353932 TI - Relationships between PAHs and PCBs, and quantitative source apportionment of PAHs toxicity in sediments from Fenhe reservoir and watershed. AB - Sedimentary samples from 28 sites throughout the Fenhe reservoir and upstream watershed in China were measured, to study the relationships between PAHs and PCBs as well as perform quantitative source apportionment of toxicity. The distributions of ?16PAHs and ?123PCBs showed high correlation. The ?7C-PAHs (total concentrations of seven carcinogenic PAHs) varied from 87.7 to 2005.0ngg( 1)dw, and the ?6DL-PCBs (total concentrations of six dioxin-like PCB congeners) were n.d.-5.96ngg(-1)dw. Toxicity and biological risk were assessed using toxic equivalent quantity (TEQ) and sediment quality guideline quotient (SQGQ). The BaP played the dominant role for TEQPAH at most sites (37.17-89.40%), although the CHR showed the highest concentration level. PCB-81 contributed the highest TEQPCB. High correlations were observed between ?16PAHs and ?7C-PAHs, ?123PCBs and ?6DL-PCBs, ?7C-PAHs and ?6DL-PCBs as well as TEQPAH and TEQPCB. Furthermore, quantitative source apportionments for PAHs concentrations and TEQ were carried out, combining the positive matrix factorization (PMF) with the formula of TEQ. For most sites, the vehicular sources were the largest contributors to TEQPAH (46.58%), while coal combustion sources were the highest contributor for PAHs concentrations (43.31%). The relatively higher correlations between PCBs and contributions of coal combustion to PAHs might imply the similar distribution of industrial sources for PAHs and PCBs. PMID- 23353933 TI - Heavy metal retention in copper mine soil treated with mussel shells: batch and column experiments. AB - Batch and column experiments are used to study the effects of ground mussel shell amendment on the retention of heavy metals in acidic mine soil. The soil pH increases proportionally with the mussel shell concentration employed. Mussel shell amendment increases Cu, Cd, Ni and Zn retention in mine soil when compared with unamended soil. In fact, Cu retention was 6480MUmolkg(-1) (43% of the total added) when the maximum metal concentration (1570MUM) was added to the unamended soil, whereas retention reached 15,039MUmolkg(-1) (99.9% of the total Cu added) when soil was amended with 24gkg(-1) mussel shell; in the case of Cd, adsorption increases from 3257MUmolkg(-1) (15% of the total added) for the unamended soil, to 13,200MUmolkg(-1) (87% of the total added) for the shell-amended soil; Ni retention increased from 3767MUmolkg(-1) (25% of the total added) corresponding to unamended soil, to 11,854MUmolkg(-1) (77% of the total added) for the shell amended soil; and finally, Zn retention increased from 4684MUmolkg(-1) (31% of the total added), for unamended soil, to 14,952MUmolkg(-1) (98% of the total added) for shell-amended soil. The results of the constant flow transport experiments show that the addition of the 24gkg(-1) mussel shells can retain Cu, Cd, Ni and Zn within the first few centimetres of the column length, indicating the usefulness of ground mussel shells to drastically decrease the mobility and availability of these pollutants and to facilitate soil remediation. PMID- 23353934 TI - Multivariate evaluation and optimization of an activated-magnesium/co-solvent system for the reductive degradation of polycyclic aromatic hydrocarbons. AB - The present study evaluates the capability of an activated-magnesium metal and protic co-solvents to promote the reductive degradation of three different polycyclic aromatic hydrocarbons, specifically pyrene, benzo[k]fluoranthene and benzo[g,h,i]perylene. Multivariate analyses demonstrated that the kinetics of degradation was affected by several experimental factors such as magnesium loading, acid addition and solubility of the compounds. It was determined that an acid activator is needed for the degradation reaction to proceed and it is also noted that the use of a 1:1 ethanol/ethyl lactate co-solvent is ideal for the complete dissolution of all three compounds with concentrations varying from 200 to 275mgL(-1). The experimental results also indicate that, at room temperature conditions, only 0.05-0.1g of magnesium is required in order to achieve greater than 93% degradation efficiency after 24h of reaction. This methodology is attractive and may allow for the development of an economic and environmentally friendly field application for the remediation of other polycyclic aromatic hydrocarbons. PMID- 23353935 TI - Enantiomer-specific bioaccumulation and depuration of hexabromocyclododecanes in zebrafish (Danio Rerio). AB - The bioaccumulation and depuration of six hexabromocyclododecane enantiomers in zebrafish were investigated through dietary exposure. The bioaccumulation of (+/ )alpha-HBCD, (+/-)beta-HBCD and (+/-)gamma-HBCD was concentration dependent. The results from their concentration trends and assimilation efficiencies suggested that zebrafish selectively bioaccumulate the (+) alpha-enantiomer and (+) gamma enantiomer compared to their corresponding (-)-enantiomers. However, (+/-)beta HBCD did not show enantioselectivity in the process of bioaccumulation. The depuration of all six enantiomers in zebrafish followed first-order kinetics except (-)gamma-HBCD in low dose. These results showed that the bioaccumulation and depuration of HBCDs in zebrafish were enantiomer-selective. Each enantiomeric pair of HBCDs could display different biological process in organisms. PMID- 23353936 TI - Serum from hepatectomized rats induces the differentiation of adipose tissue mesenchymal stem cells into hepatocyte-like cells and upregulates the expression of hepatocyte growth factor and interleukin-6 in vitro. AB - Adipose tissue-derived mesenchymal stem cells (AT-MSCs) are an attractive alternative for clinical application due to their minimally invasive accessibility and availability in the body. However, the hepatic differentiation efficiency of AT-MSCs is insufficient for therapeutic application and the role of extrahepatic stem cells in liver regeneration remains poorly understood. This study was designed to investigate the effects of serum from rats subjected to 70% partial hepatectomy (PH) on the differentiation ability of rat AT-MSCs in vitro, and to explore the potential role of AT-MSCs in vivo following PH injury. Results showed that AT-MSCs treated with serum collected from rats 24 h after 70% PH differen-tiated into hepatocyte-like cells, resembled hepatocyte-like cells with round or polygonal shape, expressed alpha-fetoprotein, secreted albumin, synthesized urea and acquired cytochrome P450 type 3A4 enzyme activity, and upregulated the expression of interleukin (IL)-6 and hepatocyte growth factor (HGF) transiently in vitro, although the hepatic differentiation efficiency was extremely low. AT-MSC transplantation after 70% PH ameliorated liver injury and promoted liver regeneration, but did not increase the serum levels of IL-6 and HGF in vivo. This result suggests that the therapeutic effect of AT-MSCs in vivo after 24 h of 70% PH does not increase IL-6 and HGF expression. PMID- 23353938 TI - High-performance liquid chromatography using pressurized liquid extraction for the determination of seven tetracyclines in egg, fish and shrimp. AB - A simple and especially rapid method, pressurized liquid extraction, has been developed and applied to the quantitative determination of oxytetracycline, tetracycline, chlortetracycline, minocycline, methacycline, demeclocycline and doxycycline in egg, fish and shrimp. The procedure consisted of a trichloracetic acid/methanol extraction conducted at elevated temperature (60 degrees C) and pressure (65bar), without further clean-up, the extraction solution was concentrated and finally for high-performance liquid chromatography analysis. The limits of detection were 5.0-10.0MUg/kg and the limits of quantification were 10.0-15.0MUg/kg for tetracyclines in egg, fish and shrimp using UV detection. The analytical limits CCalpha and CCbeta were also calculated. The recoveries of tetracyclines spiked at levels of 15-300MUg/kg, averaged 75.6-103.5% with the relative standard deviation values less than 11%. The optimized procedure has been successfully applied to real samples in our laboratories. It demonstrated that the new method was robust and useful for monitoring and quantification of 7 tetracycline residues in food of animal origin. PMID- 23353939 TI - Identification and quantification of drug-albumin adducts in serum samples from a drug exposure study in mice. AB - The formation of drug-protein adducts following the bioactivation of drugs to reactive metabolites has been linked to adverse drug reactions (ADRs) and is a major complication in drug discovery and development. Identification and quantification of drug-protein adducts in vivo may lead to a better understanding of drug toxicity, but is challenging due to their low abundance in the complex biological samples. Human serum albumin (HSA) is a well-known target of reactive drug metabolites due to the free cysteine on position 34 and is often the first target to be investigated in covalent drug binding studies. Presented here is an optimized strategy for targeted analysis of low-level drug-albumin adducts in serum. This strategy is based on selective extraction of albumin from serum through affinity chromatography, efficient sample treatment and clean-up using gel filtration chromatography followed by tryptic digestion and LC-MS analysis. Quantification of the level of albumin modification was performed through a comparison of non-modified and drug-modified protein based on the relative peak area of the tryptic peptide containing the free cysteine residue. The analysis strategy was applied to serum samples resulting from a drug exposure experiment in mice, which was designed to study the effects of different acetaminophen (APAP) treatments on drug toxicity. APAP is bioactivated to N-acetyl-p benzoquinoneimine (NAPQI) in both humans and mice and is known to bind to cysteine 34 (cys34) of HSA. Analysis of the mouse serum samples revealed the presence of extremely low-level NAPQI-albumin adducts of approximately 0.2% of the total mouse serum albumin (MSA), regardless of the length of drug exposure. Due to the targeted nature of the strategy, the NAPQI-adduct formation on cys34 could be confirmed while adducts to the second free cysteine on position 579 of MSA were not detected. PMID- 23353937 TI - Multiple Nudix family proteins possess mRNA decapping activity. AB - RNA decapping is an important contributor to gene expression and is a critical determinant of mRNA decay. The recent demonstration that mammalian cells harbor at least two distinct decapping enzymes that preferentially modulate a subset of mRNAs raises the intriguing possibility of whether additional decapping enzymes exist. Because both known decapping proteins, Dcp2 and Nudt16, are members of the Nudix hydrolase family, we set out to determine whether other members of this family of proteins also contain intrinsic RNA decapping activity. Here we demonstrate that six additional mouse Nudix proteins--Nudt2, Nudt3, Nudt12, Nudt15, Nudt17, and Nudt19--have varying degrees of decapping activity in vitro on both monomethylated and unmethylated capped RNAs. The decapping products from Nudt17 and Nudt19 were analogous to Dcp2 and predominantly generated m7GDP, while cleavage by Nudt2, Nudt3, Nudt12, and Nudt15 was more pleiotropic and generated both m7GMP and m7GDP. Interestingly, all six Nudix proteins as well as both Dcp2 and Nudt16 could hydrolyze the cap of an unmethylated capped RNA, indicating that decapping enzymes may be less constrained for the presence of the methyl moiety. Investigation of Saccharomyces cerevisiae Nudix proteins revealed that the yeast homolog of Nudt3, Ddp1p, also possesses decapping activity in vitro. Moreover, the bacterial Nudix pyrophosphohydrolase RppH displayed RNA decapping activity and released m7GDP product comparable to Dcp2, indicating that decapping is an evolutionarily conserved activity that preceded mammalian cap formation. These findings demonstrate that multiple Nudix family hydrolases may function in mRNA decapping and mRNA stability. PMID- 23353940 TI - Determination of tissue distribution of potent antitumor agent ureidomustin (BO 1055) by HPLC and its pharmacokinetic application in rats. AB - Ureidomustin hydrochloride (BO-1055) was designed as a water-soluble nitrogen mustard, which exhibited potent anticancer activity and was selected as a candidate for preclinical studies. However, up to date, there is rarely an easy and economic method to quantize ureidomustin in the biological samples. The aim of this study is to develop a simple yet valid quantization method to tackle this challenge. Here we present a combined high-performance liquid chromatography with photodiode array (HPLC-PDA) method in quantizing the ureidomustin in the plasma and various organs of Sprague-Dawley rats. The method was validated in terms of precision, accuracy, and extraction recovery. Furthermore, the established method was applied to study pharmacokinetics of ureidomustin in the rat's plasma and verified via a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Calibration curves of the plasma and organ samples were falling at the range between 0.5-50MUg/mL and 0.1-50MUg/mL (r(2)>=0.999 and CV<=+/-15%), respectively. The limits of detection (LOD) were 0.1MUg/mL for plasma samples and 0.05MUg/mL for organ samples, while the detection limits of quantification (LOQ) were 0.5MUg/mL for plasma samples and 0.1MUg/mL for organ samples. The average recovery of ureidomustin was about 83%. These results demonstrated a linear pharmacokinetic pattern at dosages of 10 and 30mg/kg. The pharmacokinetic data revealed that ureidomustin was best fitted to a two-compartment model with a rapid distribution phase and a slow elimination phase. Besides, after a short intravenous administration time at the dose of 10mg/kg, ureidomustin was found to be quickly distributed to all organs in rats, accumulated mainly in the kidney, and only a limited amount was detected in the brain. PMID- 23353942 TI - Stop the noise and get to the point. PMID- 23353943 TI - Adverse drug events: are ICU patients at higher risk? PMID- 23353941 TI - Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. AB - OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Some recommendations were ungraded (UG). Recommendations were classified into three groups: 1) those directly targeting severe sepsis; 2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and 3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 hr of recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 hrs of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1C); initial fluid challenge in patients with sepsis induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients) (1C); fluid challenge technique continued as long as hemodynamic improvement, as based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure >= 65 mm Hg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO2/FIO2 ratio of <= 100 mm Hg in facilities that have experience with such practices (2C); head-of bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 hrs) for patients with early ARDS and a Pao2/Fio2 < 150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are > 180 mg/dL, targeting an upper blood glucose <= 180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hrs after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 hrs of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5 to 10 mins (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients. PMID- 23353944 TI - An aspirin a day keeps the acute respiratory distress syndrome away. PMID- 23353945 TI - Welcome to the fight: the cardiovascular ICU faces the challenge of delirium. PMID- 23353946 TI - Improving the efficiency of ICU admission decisions. PMID- 23353947 TI - Too much for too long-wrong targets, wrong timing? PMID- 23353948 TI - Challenges of heart rate variability research in the ICU. PMID- 23353949 TI - Predicting acute lung injury resolution: a role for chest CT? PMID- 23353950 TI - Perform bilateral vascular ultrasound before inserting a central line. PMID- 23353951 TI - Monitoring the brain to save the kidneys. PMID- 23353952 TI - Lung water-the pool of evidence deepens. PMID- 23353953 TI - Failure of noninvasive ventilation: one more chance? PMID- 23353954 TI - Prolonged infusion of carbapenems in critically ill patients: time to extend our practice. PMID- 23353955 TI - Of gifts, obligations, and political correctness: how may we speak of them? PMID- 23353956 TI - Are rapid response systems effective in reducing hospital mortality? PMID- 23353957 TI - Race to seal secretion leak past endotracheal tube cuff: back to the basics. PMID- 23353958 TI - Preventing ventilator-associated lung injury at the bedside. PMID- 23353959 TI - Spontaneous breathing in acute respiratory distress syndrome: friend and foe? PMID- 23353960 TI - The filamentous actin cytoskeleton organization and the endothelial cell barrier. PMID- 23353961 TI - Increased intracranial pressure: what to do about it and when? PMID- 23353962 TI - Preventing invasive candidiasis in high-risk critically ill patients: avoid antibiotics or give probiotics? PMID- 23353963 TI - Do not tell the children: toothbrushing does not make a difference (in your ventilator-associated pneumonia rates). PMID- 23353964 TI - Not all catheter-days are equal. PMID- 23353965 TI - The authors reply. PMID- 23353966 TI - Mild therapeutic hypothermia in cardiogenic shock syndrome. PMID- 23353967 TI - The authors reply. PMID- 23353968 TI - Severe community-acquired pneumonia: don't get rid of fluoroquinolone. PMID- 23353969 TI - The authors reply. PMID- 23353970 TI - Nasojejunal versus nasogastric nutritional support: ending a debate. PMID- 23353971 TI - Procalcitonin serum levels: only a useful variable or a must to start antibiotic therapy in the critically ill? PMID- 23353972 TI - The authors reply. PMID- 23353973 TI - Decrease in mean systemic filling pressure, increase in unstressed blood volume, or both? PMID- 23353974 TI - Treatment of four psychiatric emergencies in the ICU. PMID- 23353975 TI - The authors reply. PMID- 23353976 TI - Interhospital patient transfer infrastructure. PMID- 23353977 TI - Improving the incomplete infrastructure for interhospital patient transfer. PMID- 23353978 TI - The author replies. PMID- 23353979 TI - Measuring the success of rapid response systems. PMID- 23353980 TI - The author replies. PMID- 23353981 TI - Is an alternative method of cardiopulmonary resuscitation necessary in children because chest compressions are either too unreliably effective or have potentially fatal consequences, which make them contraindicated? PMID- 23353982 TI - The authors reply. PMID- 23353983 TI - Metabolic profile analysis of zebrafish embryos. AB - A growing goal in the field of metabolism is to determine the impact of genetics on different aspects of mitochondrial function. Understanding these relationships will help to understand the underlying etiology for a range of diseases linked with mitochondrial dysfunction, such as diabetes and obesity. Recent advances in instrumentation, has enabled the monitoring of distinct parameters of mitochondrial function in cell lines or tissue explants. Here we present a method for a rapid and sensitive analysis of mitochondrial function parameters in vivo during zebrafish embryonic development using the Seahorse bioscience XF 24 extracellular flux analyser. This protocol utilizes the Islet Capture microplates where a single embryo is placed in each well, allowing measurement of bioenergetics, including: (i) basal respiration; (ii) basal mitochondrial respiration (iii) mitochondrial respiration due to ATP turnover; (iv) mitochondrial uncoupled respiration or proton leak and (iv) maximum respiration. Using this approach embryonic zebrafish respiration parameters can be compared between wild type and genetically altered embryos (mutant, gene over-expression or gene knockdown) or those manipulated pharmacologically. It is anticipated that dissemination of this protocol will provide researchers with new tools to analyse the genetic basis of metabolic disorders in vivo in this relevant vertebrate animal model. PMID- 23353984 TI - Lysophosphatidic acid mediates the release of cytokines and chemokines by human fibroblasts treated with loxosceles spider venom. PMID- 23353985 TI - Nonlinear microscopy of eumelanin and pheomelanin with subcellular resolution. AB - Pump-probe microscopy nondestructively differentiates eumelanin and pheomelanin and can be used to quantify melanin distributions in thin biopsy slices. Here we have extended that work for imaging eumelanin and pheomelanin distributions on a subcellular scale, allowing elucidation of characteristics of different cell types. The results show that melanin heterogeneity, previously found to be characteristic of melanomas, persists on the subcellular scale. We have also found spectral changes associated with melanin located in melanophages that could potentially differentiate invasive pigmented melanocytes from melanophages without immunohistochemical staining. PMID- 23353986 TI - Keratin degradation by dermatophytes relies on cysteine dioxygenase and a sulfite efflux pump. AB - Millions of people suffer from superficial infections caused by dermatophytes. Intriguingly, these filamentous fungi exclusively infect keratin-rich host structures such as hair, nails, and skin. Keratin is a hard, compact protein, and its utilization by dermatophytes for growth has long been discussed as a major virulence attribute. Here, we provide strong support for the hypothesis that keratin degradation is facilitated by the secretion of the reducing agent sulfite, which can cleave keratin-stabilizing cystine bonds. We discovered that sulfite is produced by dermatophytes from environmental cysteine, which at elevated concentrations is toxic for microbes and humans. We found that sulfite formation from cysteine relies on the key enzyme cysteine dioxygenase Cdo1. Sulfite secretion is supported by the sulfite efflux pump Ssu1. Targeted mutagenesis proved that dermatophyte mutants in either Cdo1 or Ssu1 were highly growth-sensitive to cysteine, and mutants in Ssu1 were specifically sensitive to sulfite. Most notably, dermatophyte mutants in Cdo1 and Ssu1 were specifically growth-defective on hair and nails. As keratin is rich in cysteine, our identified mechanism of cysteine conversion and sulfite efflux supports both cysteine and sulfite tolerance per se and progression of keratin degradation. These in vitro findings have implications for dermatophyte infection pathogenesis. PMID- 23353988 TI - Serum gastrin-releasing peptide levels correlate with pruritus in patients with atopic dermatitis. PMID- 23353987 TI - Activation of TLR3 in keratinocytes increases expression of genes involved in formation of the epidermis, lipid accumulation, and epidermal organelles. AB - Injury to the skin, and the subsequent release of noncoding double-stranded RNA (dsRNA) from necrotic keratinocytes, has been identified as an endogenous activator of Toll-like receptor 3 (TLR3). As changes in keratinocyte growth and differentiation follow injury, we hypothesized that TLR3 might trigger some elements of the barrier repair program in keratinocytes. dsRNA was observed to induce TLR3-dependent increases in human keratinocyte mRNA abundance for ABCA12 (ATP-binding cassette, sub-family A, member 12), glucocerebrosidase, acid sphingomyelinase, and transglutaminase 1. Additionally, treatment with dsRNA resulted in increases in sphingomyelin and morphologic changes including increased epidermal lipid staining by Oil Red O and TLR3-dependent increases in lamellar bodies and keratohyalin granules. These observations show that dsRNA can stimulate some events in keratinocytes that are important for skin barrier repair and maintenance. PMID- 23353990 TI - The digital age of journals: the present and the possibilities. PMID- 23353989 TI - Vascular E-selectin expression correlates with CD8 lymphocyte infiltration and improved outcome in Merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-linked skin cancer. Although CD8 lymphocyte infiltration into the tumor is strongly correlated with improved survival, these cells are absent or sparse in most MCCs. We investigated whether specific mechanisms of T-cell migration may be commonly disrupted in MCC tumors with poor CD8 lymphocyte infiltration. Intratumoral vascular E-selectin, critical for T-cell entry into skin, was downregulated in the majority (52%) of MCCs (n=56), and its loss was associated with poor intratumoral CD8 lymphocyte infiltration (P<0.05; n=45). Importantly, survival was improved in MCC patients whose tumors had higher vascular E-selectin expression (P<0.05). Local nitric oxide (NO) production is one mechanism of E-selectin downregulation and it can be tracked by quantifying nitrotyrosine, a stable biomarker of NO-induced reactive nitrogen species (RNS). Indeed, increasing levels of nitrotyrosine within MCC tumors were associated with low E-selectin expression (P<0.05; n=45) and decreased CD8 lymphocyte infiltration (P<0.05, n=45). These data suggest that one mechanism of immune evasion in MCC may be restriction of T-cell entry into the tumor. Existing therapeutic agents that modulate E-selectin expression and/or RNS generation may restore T-cell entry and could potentially synergize with other immune-stimulating therapies. PMID- 23353991 TI - Peripheral refraction patterns out to large field angles. AB - PURPOSE: To investigate hyperopic shifts and the oblique (or 45-degree/135 degree) component of astigmatism at large angles in the horizontal visual field using the Hartmann-Shack technique. METHODS: The adult participants consisted of 6 hypermetropes, 13 emmetropes and 11 myopes. Measurements were made with a modified COAS-HD Hartmann-Shack aberrometer across +/- 60 degrees along the horizontal visual field in 5-degree steps. Eyes were dilated with 1% cyclopentolate. Peripheral refraction was estimated as mean spherical (or spherical equivalent) refraction, with/against the rule of astigmatism and oblique astigmatism components, and as horizontal and vertical refraction components based on 3-mm major diameter elliptical pupils. RESULTS: Thirty percent of eyes showed a pattern that was a combination of type IV and type I patterns of Rempt et al. (Rempt F, Hoogerheide J, Hoogenboom WP. Peripheral retinoscopy and the skiagram. Ophthalmologica 1971;162:1-10), which shows the characteristics of type IV (relative hypermetropia along the vertical meridian and relative myopia along the horizontal meridian) out to an angle of between 40 and 50 degrees before behaving like type I (both meridians show relative hypermetropia). We classified this pattern as type IV/I. Seven of 13 emmetropes had this pattern. As a group, there was no significant variation of the oblique component of astigmatism with angle, but about one-half of the eyes showed significant positive slopes (more positive or less negative values in the nasal field than in the temporal field) and one-fourth showed significant negative slopes. CONCLUSIONS: It is often considered that a pattern of relative peripheral hypermetropia predisposes to the development of myopia. In this context, the finding of a considerable portion of emmetropes with the IV/I pattern suggests that it is unlikely that refraction at visual field angles beyond 40 degrees from fixation contributes to myopia development. PMID- 23353993 TI - Letter to the editor: multicenter case-control study of the role of lens materials and care products on the development of corneal infiltrates. PMID- 23353994 TI - Authors' response. PMID- 23353997 TI - Optimization of lactulose synthesis from whey lactose by immobilized beta galactosidase and glucose isomerase. AB - In the present study, commercially available whey was used as a lactose source, and immobilized beta-galactosidase and glucose isomerase were used to synthesize lactulose from whey lactose in the absence of fructose. Optimal reaction conditions, such as lactose concentration, temperature, ionic strength of the buffer, and ratio of immobilized enzymes, were determined to improve lactulose synthesis using immobilized enzymes. Lactulose synthesis using immobilized enzymes improved markedly after optimizing the reaction conditions. When the lactulose synthesis was carried out at 53.5 degrees C using 20% (w/v) whey lactose, 12U/ml of immobilized beta-galactosidase and 60U/ml of immobilized glucose isomerase in 100mM sodium phosphate buffer at pH 7.5, the lactulose concentration and specific productivity were 7.68g/l and 0.32mg/Uh, respectively. Additionally, when the immobilized enzymes were reused for lactulose synthesis, their catalytic activity was 57.1% after 7 repeated uses. PMID- 23353996 TI - Silibinin inhibits TPA-induced cell migration and MMP-9 expression in thyroid and breast cancer cells. AB - Matrix metalloproteinases (MMPs) play an important role in cancer metastasis, cell migration and invasion. Herein, we investigated the effects of silibinin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell migration and MMP-9 expression in thyroid and breast cancer cells. Our results revealed that the levels of MMP-9 mRNA and protein expression were significantly increased by TPA but not MMP-2 in TPC-1 and MCF7 cells. To verify the regulatory mechanism of TPA induced MMP-9 expression, we treated TPC-1 and MCF7 cells with the MEK1/2 inhibitor, UO126, and TPA-induced MMP-9 expression was significantly decreased. We also found that TPA-induced cell migration and MMP-9 expression was significantly decreased by silibinin. In addition, TPA-induced phosphorylation of MEK and ERK was also inhibited by silibinin. Taken together, we suggest that silibinin suppresses TPA-induced cell migration and MMP-9 expression through the MEK/ERK-dependent pathway in thyroid and breast cancer cells. PMID- 23353998 TI - Computational analysis of associations between alternative splicing and histone modifications. AB - Pre-mRNA splicing is a complex process involving combinatorial effects of cis- and trans-elements. Here, we focused on histone modifications as typical trans regulatory elements and performed systematic analyses of associations between splicing patterns and histone modifications by using publicly available ChIP-Seq, mRNA-Seq, and exon-array data obtained in two human cell lines. We found that several types of histone modifications including H3K36me3 were associated with the inclusion or exclusion of alternative exons. Furthermore, we observed that the levels of H3K36me3 and H3K79me1 in the cell lines were well correlated with the differences in alternative splicing patterns between the cell lines. PMID- 23353999 TI - Characterization of nucleolin K88 acetylation defines a new pool of nucleolin colocalizing with pre-mRNA splicing factors. AB - Nucleolin is a multifunctional protein that carries several post-translational modifications. We characterized nucleolin acetylation and developed antibodies specific to nucleolin K88 acetylation. Using this antibody we show that nucleolin is acetylated in vivo and is not localized in the nucleoli, but instead is distributed throughout the nucleoplasm. Immunofluorescence studies indicate that acetylated nucleolin is co-localized with the splicing factor SC35 and partially with Y12. Acetylated nucleolin is expressed in all tested proliferating cell types. Our findings show that acetylation defines a new pool of nucleolin which support a role for nucleolin in the regulation of mRNA maturation and transcription by RNA polymerase II. PMID- 23354000 TI - Circuit modeling of the electrical impedance: II. Normal subjects and system reproducibility. AB - Part I of this series showed that the five-element circuit model accurately mimics impedances measured using multi-frequency electrical impedance myography (MFEIM), focusing on changes brought on by disease. This paper addresses two requirements which must be met if the method is to qualify for clinical use. First, the extracted parameters must be reproducible over long time periods such as those involved in the treatment of muscular disease, and second, differences amongst normal subjects should be attributable to known differences in the properties of healthy muscle. It applies the method to five muscle groups in 62 healthy subjects, closely following the procedure used earlier for the diseased subjects. Test-retest comparisons show that parameters are reproducible at levels from 6 to 16% (depending on the parameter) over time spans of up to 267 days, levels far below the changes occurring in serious disease. Also, variations with age, gender and muscle location are found to be consistent with established expectations for healthy muscle tissue. We conclude that the combination of MFEIM measurements and five-element circuit analysis genuinely reflects properties of muscle and is reliable enough to recommend its use in following neuromuscular disease. PMID- 23354001 TI - Target identification of small molecules based on chemical biology approaches. AB - Recently, a phenotypic approach-screens that assess the effects of compounds on cells, tissues, or whole organisms-has been reconsidered and reintroduced as a complementary strategy of a target-based approach for drug discovery. Although the finding of novel bioactive compounds from large chemical libraries has become routine, the identification of their molecular targets is still a time-consuming and difficult process, making this step rate-limiting in drug development. In the last decade, we and other researchers have amassed a large amount of phenotypic data through progress in omics research and advances in instrumentation. Accordingly, the profiling methodologies using these datasets expertly have emerged to identify and validate specific molecular targets of drug candidates, attaining some progress in current drug discovery (e.g., eribulin). In the case of a compound that shows an unprecedented phenotype likely by inhibiting a first in-class target, however, such phenotypic profiling is invalid. Under the circumstances, a photo-crosslinking affinity approach should be beneficial. In this review, we describe and summarize recent progress in both affinity-based (direct) and phenotypic profiling (indirect) approaches for chemical biology target identification. PMID- 23354003 TI - On the role of strong electron correlations in the surface properties and chemistry of uranium dioxide. AB - We report density functional calculations of the surface properties and chemistry of UO(2)(111) performed within the generalized gradient approximation corrected with an effective Hubbard parameter (GGA + U within Dudarev's formalism) to account for the strong on-site Coulomb repulsion between U 5f electrons. The variation of the properties of periodic slab models, with collinear ferromagnetic and antiferromagnetic arrangements of the uranium magnetic moments, was investigated while ramping up the effective Hubbard parameter from U(eff) = 0 eV, corresponding to standard density functional theory, up to U(eff) = 4 eV, the value that correctly reproduces the antiferromagnetic ground state of bulk UO(2). The chemical interactions of molecular water, dissociated water, dissociated oxygen and co-adsorbed molecular water and monatomic oxygen with the UO(2)(111) surface were also studied as functions of the U(eff) parameter. Calculations reveal that some of the key electronic and chemical properties controlling the surface reactivity are very sensitive to the value of this strong electron correlation parameter. PMID- 23354002 TI - Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice. AB - During systemic infection, inflammatory cytokines such as interleukin (IL)-6 are produced in excess in the brain of aged mice and induce severe behavioral deficits. However, no studies have examined how pro-inflammatory IL-6 trans signaling is involved in the exaggerated production of IL-6 in the aged brain, nor the extent to which IL-6 trans-signaling affects other markers of neuroinflammation, adhesion molecules, and behavior. Therefore, this study investigated in aged mice the presence of IL-6 signaling subunits in microglia; the central effects of soluble gp130 (sgp130)-a natural inhibitor of the IL-6 trans-signaling pathway-on IL-6 production in microglia; and the effects of sgp130 given intracerebroventricularly (ICV) on neuroinflammation and sickness behavior caused by i.p. injection of lipopolysaccharide (LPS). Here we show that microglia isolated from aged mice have higher expression of IL-6 receptor (IL-6R) compared to microglia from adults; and the level of mRNA for ADAM17, the enzyme responsible for shedding membrane-bound IL-6R in trans-signaling, is higher in the hippocampus of aged mice compared to adults. Additionally, we show in aged mice that peripheral LPS challenge elicits a hyperactive IL-6 response in microglia, and selective blockade of trans-signaling by ICV injection of sgp130 mitigates this. The sgp130-associated inhibition of IL-6 was paralleled by amelioration of exaggerated and protracted sickness behavior in aged mice. Taken together, the results show that microglia are important regulators of the IL-6 trans-signaling response in the aged brain and sgp130 exerts an anti-inflammatory effect by inhibiting the pro-inflammatory arm of IL-6 signaling. PMID- 23354004 TI - Sudden death syndrome in adult cows associated with Clostridium perfringens type E. AB - Clostridium perfringens type E is considered a rare toxinotype and an infrequent cause of enterotoxemia of lambs, calves, and rabbits. Until now, only cases of young animal of C. perfringens type E bovine enterotoxemia, characterized by hemorrhagic enteritis and sudden death, have been reported. The present report details the genotypic characterization of C. perfringens type E isolates obtained from intestinal samples of adult cattle during an outbreak of enterotoxemia in Argentina. The sequences of several housekeeping genes of these isolates were analyzed and compared with those obtained from calves in North America showing a clonal unique lineage. PMID- 23354005 TI - Development of antimicrobial synbiotics using potentially-probiotic faecal isolates of Lactobacillus fermentum and Bifidobacterium longum. AB - The aims of the present study were to investigate in vitro the antimicrobial activity of Lactobacillus fermentum and Bifidobacterium longum, isolated from faeces of healthy elderly individuals, against enterohaemorrhagic Escherichia coli (E. coli O157:H7) and enteropathogenic E. coli (E. coli O86), to determine the capability of the selected strains to tolerate acid and bile in vitro, to select suitable carbohydrates in order to enhance the growth and maximise antimicrobial activity of the putative probiotic organisms and examine the adhesion properties of the synbiotics. Antimicrobial activity of the putative probiotics and synbiotics was investigated by a microtitre method using cell-free culture supernatants (CFCS). Results of the antimicrobial assay showed that both putative probiotic strains produced compounds at pH 5 that lead to higher lag phases of both E. coli O157:H7 and E. coli O86. When half the quantity of cell free culture supernatants of both probiotic strains was used at pH 5, B. longum maintained the same antimicrobial effect against both strains of E. coli, whereas L. fermentum lead to a higher lag phase of E. coli O86 only. Neutralization of the culture supernatants with alkali reduced the antimicrobial effect with only cell-free supernatant of L. fermentum causing lower maximum growth rates of E. coli O157:H7 and E. coli O86. L. fermentum appeared to be acid tolerant whereas B. longum was more susceptible to acid and both isolates were bile tolerant. A short chain fructooligosaccharide (scFOS) and an isomalto-oligosaccharide (IMO) proved to be the most effective substrates, enhancing antimicrobial activity for L. fermentum and B. longum respectively. The adhesion of the synbiotic combinations showed that L. fermentum, exhibited higher percentage of adhesion when grown on glucose and as a synbiotic combination with scFOS whereas B. longum exhibited lowest percentage of adhesion when grown on both glucose and IMO. PMID- 23354006 TI - Leptin stimulates ovarian cancer cell growth and inhibits apoptosis by increasing cyclin D1 and Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways. AB - Obesity is known to be an important risk factor for many types of cancer, such as breast, prostate, liver and endometrial cancer. Recently, epidemiological studies have indicated that obesity correlates with an increased risk of developing ovarian cancer, the most lethal gynecological cancer in developed countries. Leptin is predominantly produced by adipocytes and acts as a growth factor and serum leptin levels positively correlate with the amount of body fat. In this study, we investigated the effects of leptin on the growth of ovarian cancer cells and the underlying mechanism(s) of action. Our results showed that leptin stimulated the growth of the OVCAR-3 ovarian cancer cell line using MTT assay and trypan blue exclusion. Using western blot analysis, we found that leptin enhanced the expression of cyclin D1 and Mcl-1, which are important regulators of cell proliferation and the inhibition of apoptosis. To investigate the signaling pathways that mediate the effects of leptin, cells were treated with leptin plus specific inhibitors of JAK2, PI3K/Akt and MEK/ERK1/2 and analysis of the phosphorylation state of proteins was carried out by western blot assays. We showed that the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways were involved in the growth-stimulating effect of leptin on ovarian cancer cell growth and the specific inhibitors of PI3K/Akt and MEK/ERK1/2 revealed that these two pathways interacted with each other. Our data demonstrate that leptin upregulates the expression of cyclin D1 and Mcl-1 to stimulate cell growth by activating the PI3K/Akt and MEK/ERK1/2 pathways in ovarian cancer. PMID- 23354007 TI - Treatment of internet addiction: a meta-analysis. AB - Internet addiction (IA) has become a widespread and problematic phenomenon. Little is known about the efficacy of treatment approaches for IA. Therefore, our objective was to perform an effect size analysis of psychological and pharmacological interventions for IA. We conducted a literature search using PsycINFO, PSYNDEX, MEDLINE, EMBASE, PQDT OPEN, WorldCat, Cochrane Clinical Trials Library, and manual searches. Our meta-analysis was based on 16 studies, covered a total of 670 participants, and used a random effects model. Special emphasis was given to the inclusion of studies from "non-western" countries. Effect size estimates suggest that psychological and pharmacological interventions were highly effective for improving IA (g=1.61), time spent online (g=0.94), depression (g=0.90) and anxiety (g=1.25) from pre- to post-treatment in the overall sample. Moderator analyses revealed that studies including individual treatments, a higher number of female participants, older patients, or a North American sample had larger effect sizes for some outcome variables. Most effect sizes were high, robust, unrelated to study quality or design, and maintained over follow-up. Due to a small number of included studies and methodological limitations the results of this meta-analysis should be regarded as preliminary. PMID- 23354009 TI - A straightforward method for stereospecific assignment of val and leu prochiral methyl groups by solid-state NMR: Scrambling in the [2-13C]Glucose labeling scheme. AB - The unambiguous stereospecific assignment of the prochiral methyl groups in Val and Leu plays an important role in the structural investigation of proteins by NMR. Here, we present a straightforward method for their stereospecific solid state NMR assignment based on [2-(13)C]Glucose ([2-(13)C]Glc) as the sole carbon source during protein expression. The approach is fundamentally based on the stereo-selective biosynthetic pathway of Val and Leu, and the co-presence of [2 (13)C]pyruvate produced mainly by glycolysis and [3-(13)C]/[1,3-(13)C]pyruvate most probably formed through scrambling in the pentose phosphate pathway. As a consequence, the isotope spin pairs (13)Cbeta-(13)Cgamma2 and (13)Calpha (13)Cgamma1 in Val, and (13)Cgamma-(13)Cdelta2 and (13)Cbeta-(13)Cdelta1 in Leu are obtained. The approach is successfully demonstrated with the stereospecific assignment of the methyl groups of Val and Leu of type 3 secretion system PrgI needles and microcrystalline ubiquitin. PMID- 23354008 TI - Efficacy and tolerability of advanced glycation end-products inhibitor in osteoarthritis: a randomized, double-blind, placebo-controlled study. AB - OBJECTIVES: Advanced glycation end-products (AGEs) play an important role in pathogenesis of osteoarthritis (OA). The objective of this study was to evaluate the efficacy and tolerability of AGEs inhibitor (benfotiamine [50 mg]+pyridoxamine [50 mg]+methylcobalamin [500 ug]; Vonder [Cosme Farma Laboratories Limited, Goa, India]) in OA patients. METHODS: A 24-week, double blind, randomized placebo-controlled study in primary OA patients (n=30 [F/M=26/4; mean age, 57.26+/-2.16 y]) meeting the classification criteria of American College of Rheumatology, was conducted. Inflammatory disease activity scores on the Western Ontario and McMaster University (WOMAC) Osteoarthritis Index, Lequesne Index, and Pain scores were analyzed. Biomarkers: serum nitrite, AGEs, thiobarbituric acid reactive substances, C-reactive protein, erythrocyte sedimentation rate, were also measured. Time taken to walk 20 m was also recorded. Patients were randomized to either AGEs inhibitor or placebo tablets as thrice-daily regimen. RESULTS: At 24 weeks, net decrease in pain score, -6.64+/ 2.71 versus -8.20+/-1.28, P=0.003; total WOMAC score, -5.88+/-0.84 versus -8.26+/ 1.24, P=0.013; Lequesne Index score, -0.60+/-0.06 versus -0.84+/-0.09, P=0.05; time taken for 20-m walk test, -5.0+/-1.39 versus -5.0+/-0.92 s, P=1.00, were observed in the placebo versus drug group, respectively. Net change in serum nitrite, -0.15+/-0.01 versus -0.79+/-0.12 umol/L, P<0.001; AGEs, -0.12+/-0.02 versus -0.99+/-0.09, arbitrary florescence units, P=0.001; thiobarbituric acid reactive substances, -0.69+/-0.12 versus -1.80+/-0.12 nmol/L, P<0.01; C-reactive protein, -0.12+/-0.35 versus -2.45+/-0.60 mg/L, P<0.01, were observed in the placebo versus drug group, respectively. DISCUSSION: This study shows the efficacy of an AGE inhibitor on decreasing pain and inflammation, and increasing daily activity and mobility in OA patients. PMID- 23354010 TI - The logic, experimental steps, and potential of heterologous natural product biosynthesis featuring the complex antibiotic erythromycin A produced through E. coli. AB - The heterologous production of complex natural products is an approach designed to address current limitations and future possibilities. It is particularly useful for those compounds which possess therapeutic value but cannot be sufficiently produced or would benefit from an improved form of production. The experimental procedures involved can be subdivided into three components: 1) genetic transfer; 2) heterologous reconstitution; and 3) product analysis. Each experimental component is under continual optimization to meet the challenges and anticipate the opportunities associated with this emerging approach. Heterologous biosynthesis begins with the identification of a genetic sequence responsible for a valuable natural product. Transferring this sequence to a heterologous host is complicated by the biosynthetic pathway complexity responsible for product formation. The antibiotic erythromycin A is a good example. Twenty genes (totaling >50 kb) are required for eventual biosynthesis. In addition, three of these genes encode megasynthases, multi-domain enzymes each ~300 kDa in size. This genetic material must be designed and transferred to E. coli for reconstituted biosynthesis. The use of PCR isolation, operon construction, multi cystronic plasmids, and electro-transformation will be described in transferring the erythromycin A genetic cluster to E. coli. Once transferred, the E. coli cell must support eventual biosynthesis. This process is also challenging given the substantial differences between E. coli and most original hosts responsible for complex natural product formation. The cell must provide necessary substrates to support biosynthesis and coordinately express the transferred genetic cluster to produce active enzymes. In the case of erythromycin A, the E. coli cell had to be engineered to provide the two precursors (propionyl-CoA and (2S)-methylmalonyl CoA) required for biosynthesis. In addition, gene sequence modifications, plasmid copy number, chaperonin co-expression, post-translational enzymatic modification, and process temperature were also required to allow final erythromycin A formation. Finally, successful production must be assessed. For the erythromycin A case, we will present two methods. The first is liquid chromatography-mass spectrometry (LC-MS) to confirm and quantify production. The bioactivity of erythromycin A will also be confirmed through use of a bioassay in which the antibiotic activity is tested against Bacillus subtilis. The assessment assays establish erythromycin A biosynthesis from E. coli and set the stage for future engineering efforts to improve or diversify production and for the production of new complex natural compounds using this approach. PMID- 23354011 TI - Sequential combination of azacitidine and lenalidomide in del(5q) higher-risk myelodysplastic syndromes or acute myeloid leukemia: a phase I study. PMID- 23354012 TI - Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1. AB - Multiple myeloma (MM) is a deadly hematopoietic malignancy characterized by proliferation of malignant plasma cells in the bone marrow (BM) and bone disease. Interactions between myeloma and BM cells facilitate tumor progression and resistance to therapies. CXCR4 and its ligand Stromal cell-derived factor-1 (SDF 1) have a primary role in this process and are associated with poor prognosis. The Notch pathway is active in myeloma cells, resulting in increased proliferation, resistance to apoptosis and osteolytic activity. We hypothesized that the CXCR4/SDF-1 axis mediates the effects of Notch signals in myeloma cells. Here we show that Notch positively controls CXCR4/SDF-1 expression and functions in myeloma cell lines, and that forced CXCR4 activation partially rescues tumor cells from the outcomes of Notch inhibition. Additionally, we provide evidences that Notch blocking in vivo significantly reduces BM infiltration by human myeloma cells in mouse xenografts. This is the first evidence that a Notch targeted approach effectively prevents MM cell migration, proliferation and resistance to apoptosis by reducing CXCR4 and SDF-1 levels. PMID- 23354013 TI - Efficient downregulation of ErbB-2 induces TACC1 upregulation in breast cancer cell lines. AB - The ErbB-2 gene, whose overexpression is observed in many types of tumors including breast cancer, plays an important role in carcinoma formation. Dysregulation of the human transforming acidic coiled-coil 1 (TACC1) and ErbB-2 genes is thought to be important in the development and progression of breast cancer. However, a putative interaction between ErbB-2 and TACC1 remains undetermined in breast cancer. After infecting BT474 cells with lentiviral mediated ErbB2-specific shRNA, we detected the expression of ErbB-2 and TACC1 by real-time PCR and western blotting. ErbB-2 mRNA expression was decreased in the Lenti-ShERBB2 infected cells, and western blotting indicated a concordant reduction in ErbB-2 protein. TACC1 expression at the mRNA and protein levels was significantly upregulated by ErbB-2 silencing in BT474 cells. CCK-8 assay indicated that the inhibition of ErbB-2 expression increased the sensitivity of BT474 cells to docetaxel treatment. These findings provide proof and the foundation for the molecular and biological relationships of ErbB-2 and TACC1 in breast cancer. PMID- 23354014 TI - Influence analysis for high-dimensional time series with an application to epileptic seizure onset zone detection. AB - Granger causality is a useful concept for studying causal relations in networks. However, numerical problems occur when applying the corresponding methodology to high-dimensional time series showing co-movement, e.g. EEG recordings or economic data. In order to deal with these shortcomings, we propose a novel method for the causal analysis of such multivariate time series based on Granger causality and factor models. We present the theoretical background, successfully assess our methodology with the help of simulated data and show a potential application in EEG analysis of epileptic seizures. PMID- 23354015 TI - Cerulein-induced chronic pancreatitis does not require intra-acinar activation of trypsinogen in mice. AB - BACKGROUND & AIMS: Premature activation of trypsinogen activation can cause pancreatic injury and has been associated with chronic pancreatitis (CP). Mice that lack intra-acinar activation of trypsinogen, such as trypsinogen-7-null (T( /-)) and cathepsin B-null (CB(-/-)) mice, have been used to study trypsin independent processes of CP development. We compared histologic features and inflammatory responses of pancreatic tissues from these mice with those from wild type mice after the development of CP. METHODS: CP was induced in wild-type, T(-/ ), and CB(-/-) mice by twice-weekly induction of acute pancreatitis for 10 weeks; acute pancreatitis was induced by hourly intraperitoneal injections of cerulein (50 MUg/kg * 6). Pancreatic samples were collected and evaluated by histologic and immunohistochemical analyses. Normal human pancreas samples, obtained from the islet transplant program at the University of Minnesota, were used as controls and CP samples were obtained from surgical resections. RESULTS: Compared with pancreatic tissues from wild-type mice, those from T(-/-) and CB(-/-) mice had similar levels of atrophy, histomorphologic features of CP, and chronic inflammation. All samples had comparable intra-acinar activation of nuclear factor (NF)-kappaB, a transcription factor that regulates the inflammatory response, immediately after injection of cerulein. Pancreatic tissue samples from patients with CP had increased activation of NF-kappaB (based on nuclear translocation of p65 in acinar cells) compared with controls. CONCLUSIONS: Induction of CP in mice by cerulein injection does not require intra-acinar activation of trypsinogen. Pancreatic acinar cells of patients with CP have increased levels of NF-kappaB activation compared with controls; regulation of the inflammatory response by this transcription factor might be involved in the pathogenesis of CP. PMID- 23354016 TI - Patients with celiac disease have a lower prevalence of non-insulin-dependent diabetes mellitus and metabolic syndrome. AB - BACKGROUND & AIMS: We investigated whether risk for non-insulin-dependent diabetes mellitus (NIDDM) and metabolic syndrome are affected by celiac disease. We examined the prevalence of NIDDM and metabolic syndrome among adults with celiac disease, compared with matched controls. METHODS: We assessed medical records of 840 patients with biopsy-proven celiac disease for diagnoses of NIDDM, hypertension, or hyperlipidemia; body mass index (BMI); lipid profile; and levels of glucose or glycosylated hemoglobin, to identify those with metabolic syndrome. Patients without celiac disease were matched for age, sex, and ethnicity (n = 840 controls). The prevalence of NIDDM and metabolic syndrome in the celiac disease cohort was compared with that of the controls and subjects included in the National Health and Nutrition Examination Survey. RESULTS: Twenty-six patients with celiac disease (3.1%) had NIDDM compared with 81 controls (9.6%) (P < .0001). Similarly, the prevalence of metabolic syndrome was significantly lower among patients with celiac disease than controls (3.5% vs 12.7%; P < .0001). The mean BMI of patients with celiac disease was significantly lower than that of controls (24.7 vs 27.5; P < .0001). However, celiac disease was still associated with a lower risk of NIDDM, after controlling for BMI. CONCLUSIONS: The prevalence of NIDDM and metabolic syndrome are lower among patients with celiac disease than in matched controls and the general population. These differences are not explained by differences in BMI. Studies are needed to determine the mechanisms by which celiac disease affects the risk for NIDDM and metabolic syndrome. PMID- 23354017 TI - Risk of cancer in cases of suspected lynch syndrome without germline mutation. AB - BACKGROUND & AIMS: Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS. METHODS: We studied a population-based cohort of 1705 consecutive patients, performing MSI tests and immunohistochemical analyses of MMR proteins. Patients were diagnosed with Lynch syndrome when they were found to have pathogenic germline mutations. Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylation, and no pathogenic mutation were considered to have LLS. The clinical characteristics of patients and the age- and sex-adjusted standardized incidence ratios (SIRs) of cancer in families were compared between groups. RESULTS: The incidence of CRC was significantly lower in families of patients with LLS than in families with confirmed cases of Lynch syndrome (SIR for Lynch syndrome, 6.04; 95% confidence interval [CI], 3.58-9.54; SIR for LLS, 2.12; 95% CI, 1.16-3.56; P < .001). However, the incidence of CRC was higher in families of patients with LLS than in families with sporadic CRC (SIR for sporadic CRC, 0.48; 95% CI, 0.27-0.79; P < .001). CONCLUSIONS: The risk of cancer in families with LLS is lower that of families with Lynch syndrome but higher than that of families with sporadic CRC. These results confirm the need for special screening and surveillance strategies for these patients and their relatives. PMID- 23354018 TI - Functions and imaging of mast cell and neural axis of the gut. AB - Close association between nerves and mast cells in the gut wall provides the microanatomic basis for functional interactions between these elements, supporting the hypothesis that a mast cell-nerve axis influences gut functions in health and disease. Advanced morphology and imaging techniques are now available to assess structural and functional relationships of the mast cell-nerve axis in human gut tissues. Morphologic techniques including co-labeling of mast cells and nerves serve to evaluate changes in their densities and anatomic proximity. Calcium (Ca(++)) and potentiometric dye imaging provide novel insights into functions such as mast cell-nerve signaling in the human gut tissues. Such imaging promises to reveal new ionic or molecular targets to normalize nerve sensitization induced by mast cell hyperactivity or mast cell sensitization by neurogenic inflammatory pathways. These targets include proteinase-activated receptor (PAR) 1 or histamine receptors. In patients, optical imaging in the gut in vivo has the potential to identify neural structures and inflammation in vivo. The latter has some risks and potential of sampling error with a single biopsy. Techniques that image nerve fibers in the retina without the need for contrast agents (optical coherence tomography and full-field optical coherence microscopy) may be applied to study submucous neural plexus. Moreover, the combination of submucosal dissection, use of a fluorescent marker, and endoscopic confocal microscopy provides detailed imaging of myenteric neurons and smooth muscle cells in the muscularis propria. Studies of motility and functional gastrointestinal disorders would be feasible without the need for full-thickness biopsy. PMID- 23354019 TI - Localized bioimpedance to assess muscle injury. AB - Injuries to lower limb muscles are common among football players. Localized bioimpedance analysis (BIA) utilizes electrical measurements to assess soft tissue hydration and cell membrane integrity non-invasively. This study reports the effects of the severity of muscle injury and recovery on BIA variables. We made serial tetra-polar, phase-sensitive 50 kHz localized BIA measurements of quadriceps, hamstring and calf muscles of three male football players before and after injury and during recovery until return-to-play, to determine changes in BIA variables (resistance (R), reactance (Xc) and phase angle (PA)) in different degrees of muscle injury. Compared to non-injury values, R, Xc and PA decreased with increasing muscle injury severity: grade III (23.1%, 45.1% and 27.6%), grade II (20.6%, 31.6% and 13.3%) and grade I (11.9%, 23.5% and 12.1%). These findings indicate that decreases in R reflect localized fluid accumulation, and reductions in Xc and PA highlight disruption of cellular membrane integrity and injury. Localized BIA measurements of muscle groups enable the practical detection of soft tissue injury and its severity. PMID- 23354020 TI - Inhibition mechanism exploration of quinoline derivatives as PDE10A inhibitors by in silico analysis. AB - As a potential target for the treatment of schizophrenia, the dual cAMP/cGMP hydrolyzing enzyme PDE10A has attracted a significant amount of attention. In the present work, the inhibition mechanism of 116 structurally diverse quinoline derivatives as PDE10A inhibitors was explored by 3D-QSAR, molecular docking and molecular dynamics (MD) simulations. The QSAR models based on the training set containing 88 molecules were established by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The resultant optimum CoMSIA model showed strong predictability with a Q(2) of 0.497, an R(ncv)(2) of 0.964 and an R(pre)(2) of 0.885. Furthermore, there was good consistency between the CoMSIA model, docking and MD results. Our findings are: (1) bulky substituents at the 8-position and ring D increase the biological activity. (2) The areas around the 14-position and ring D are the electrostatic and hydrophobic sensitive regions. (3) H-bonds, pi-pi stacking interactions and hydrophobic contacts are crucial in determining the binding affinity to PDE10A. (4) The six-membered heterocyclic group at ring D, especially a heterobenzene ring, containing the atom as an H-bond acceptor at the 18-position is essential to water-mediated H-bond networks and favorable in enhancing the inhibitory potency. These models and the derived information may help to provide better understanding of the interaction mechanism of PDE10A inhibitors and to facilitate lead optimization and novel inhibitors' design. PMID- 23354021 TI - Long-range PCR based sequencing of the highly homologous genes, SFTPA1 and SFTPA2. AB - In humans, Surfactant Protein A exists as two highly homologous genetic isoforms, SFTPA1 and SFTPA2. Mutations in these two genes are associated with idiopathic pulmonary fibrosis (IPF) and lung cancer. We have developed a Sanger DNA sequencing assay which utilizes long-range PCR to detect mutations in these two genes. PMID- 23354022 TI - Sensitivity of [Ru(phen)2dppz]2+ light switch emission to ionic strength, temperature, and DNA sequence and conformation. AB - The luminescence of DNA-bound [Ru(phen)(2)dppz](2+) is shown to be highly sensitive to environmental conditions such as ionic strength, temperature, and the sequence and secondary structure of the nucleic acid, although not to bulky DNA substituents in the major groove. Each enantiomer has two characteristic lifetimes with any polynucleotide and their relative amplitudes vary as a function of binding ratio. For [poly(dA-dT)](2) as a model sequence, the longer lifetime for Delta-[Ru(phen)(2)dppz](2+) has been assigned to canted intercalation of the complex and the shorter lifetime is ascribed to symmetric intercalation. At a fixed binding ratio, the longer lifetime amplitude increases with increasing ionic strength, without significant change in lifetimes. Increasing temperature has a similar effect, but also affects lifetimes. In general, emission is strongest with AT-rich polynucleotides and with higher-order secondary structures, with intensity increasing as single-stranded < duplex < triplex. However, sequence-context and secondary duplex structure also influence the photophysics since emission with [poly(dA)].[poly(dT)] is significantly higher than with [poly(dA-dT)](2) or [poly(rA)].[poly(rU)]. The strong influence of different environmental conditions on the emission of nucleic acid-bound [Ru(phen)(2)dppz](2+) reflects subtle heterogeneities that are inherent elements of DNA recognition by small molecules, amplified by large changes in photophysics caused by differential exposure of the dppz nitrogens to groove hydration. PMID- 23354023 TI - Phosphoregulation of the WAVE regulatory complex and signal integration. AB - The WAVE2 regulatory complex (WRC) induces actin polymerization by activating the actin nucleator Arp2/3. Polymerizing actin pushes against the cell membrane and induces dramatic edge protrusions. In order to properly control such changes in cell morphology and function, cells have evolved multiple methods to tightly regulate WRC and Arp2/3 activity in space and time. Of these mechanisms, phosphorylation plays a fundamental role in transmitting extracellular and intracellular signals to the WRC and the actin cytoskeleton. This review discusses the phosphorylation-based regulatory inputs into the WRC. Signaling pathways that respond to growth factors, chemokines, hormones, and extracellular matrix converge upon the WAVE and ABI components of the WRC. The Abl, Src, ERK, and PKA kinases promote complex activation through a WRC conformation change that permits interaction with the Arp2/3 complex and through WRC translocation to the cell edge. The neuron-specific CDK5 and constitutively active CK2 kinases inhibit WRC activation. These regulatory signals are integrated in space and time as they coalesce upon the WRC. The combination of WRC phosphorylation events and WRC activity is controlled by stimulus, cell type, and cell cycle-specific pathway activation and via pathway cross-inhibition and cross-activation. PMID- 23354025 TI - Nodular nongranulomatous vasculitis of the lung detected by 18F-FDG PET/CT. AB - We report a case of a nodular nongranulomatous vasculitis of the lung detected by (18)F-FDG PET/CT. A 51-year-old woman with fever of unknown origin underwent (18)F-FDG PET/CT, which showed multiple and bilateral pulmonary nodules at CT scan with increased radiopharmaceutical uptake in the largest one (20 mm in diameter). On the basis of the PET/CT findings, the patient was referred for excisional biopsy of the largest pulmonary nodules suspicious for neoplastic disease. Histological examination demonstrated the presence of an obliterative vasculitis with interstitial pulmonary perivascular inflammation. PMID- 23354024 TI - Propylisopropylacetic acid (PIA), a constitutional isomer of valproic acid, uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: a potential drug for bipolar disorder. AB - BACKGROUND: Mood stabilizers used for treating bipolar disorder (BD) selectively downregulate arachidonic acid (AA) turnover (deacylation-reacylation) in brain phospholipids, when given chronically to rats. In vitro studies suggest that one of these, valproic acid (VPA), which is teratogenic, reduces AA turnover by inhibiting the brain long-chain acyl-CoA synthetase (Acsl)4 mediated acylation of AA to AA-CoA. We tested whether non-teratogenic VPA analogues might also inhibit Acsl4 catalyzed acylation, and thus have a potential anti-BD action. METHODS: Rat Acsl4-flag protein was expressed in Escherichia coli, and the ability of three VPA analogues, propylisopropylacetic acid (PIA), propylisopropylacetamide (PID) and N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (MTMCD), and of sodium butyrate, to inhibit conversion of AA to AA-CoA by Acsl4 was quantified using Michaelis-Menten kinetics. RESULTS: Acsl4-mediated conversion of AA to AA-CoA in vitro was inhibited uncompetitively by PIA, with a Ki of 11.4mM compared to a published Ki of 25mM for VPA, while PID, MTMCD and sodium butyrate had no inhibitory effect. CONCLUSIONS: PIA's ability to inhibit conversion of AA to AA CoA by Acsl4 in vitro suggests that, like VPA, PIA may reduce AA turnover in brain phospholipids in unanesthetized rats, and if so, may be effective as a non teratogenic mood stabilizer in BD patients. PMID- 23354026 TI - The clinical value of dual-time point 18F-FDG PET/CT for differentiating extrahepatic cholangiocarcinoma from benign disease. AB - PURPOSE: The aim of this study was to assess the value of dual-time point PET/CT in the differentiation of extrahepatic cholangiocarcinoma from benign stricture and the added benefits of delayed PET/CT image. PATIENTS AND METHODS: Thirty-nine patients with suspected extrahepatic biliary malignancy based on conventional imaging studies such as ultrasonography, CT, and MRI between July 2008 and December 2010 were included. All patients underwent dual-time point PET/CT scans at 1 and 2 hours after radiotracer injection. From the site of suspected malignancy, the SUVmax for both time points (SUVmax1 and SUVmax2), the percent change in SUVmax between the 2 (Delta%SUVmax) and the ratio of SUVmax1, SUVmax2, Delta%SUVmax in comparison with average SUV of right hepatic lobe (T/L ratio1, T/L ratio2, and Delta%T/L ratio) were generated. Diagnostic performances using visual assessment and various SUVmax cutoff values were analyzed in the differential diagnosis of extrahepatic cholangiocarcinoma from benign disease. PET/CT results were correlated with histological results and radiological follow up for at least 6 months. RESULTS: Of 39 patients, the final diagnosis was cholangiocarcinoma in 34 and benign disease in 5. Between malignant and benign lesions, there were significant differences in SUVmax1 (5.43 +/- 4.66 vs 2.26 +/- 0.83, P = 0.003) and SUVmax2 (6.02 +/- 5.26 vs 2.26 +/- 0.76, P = 0.002). There was no significant difference in Delta%SUVmax, T/L ratio1, T/L ratio2, and Delta%T/L ratio. On receiver operator curve analysis, SUVmax1 with cutoff value of 2.5 demonstrated sensitivity of 97.6%, specificity of 60.0%, and accuracy of 92.3% and SUVmax2 with cutoff value of 3.1 demonstrated sensitivity of 88.2%, specificity of 100%, and accuracy of 89.7%. CONCLUSION: SUVmax from both early and delayed PET/CT scans are useful parameters in the differentiation of extrahepatic biliary malignancy from benign disease. However, there was no added benefit of delayed PET/CT in patients suspicious for extrahepatic cholangiocarcinoma. PMID- 23354027 TI - 18F-FDG imaging of the primary breast leiomyosarcoma and follow-up lung metastasis. AB - A 46-year-old woman presented with a large left breast mass. FDG PET/CT demonstrated a large left breast mass (SUV = 28). Preoperative biopsy showed malignant sarcoma. Modified radical mastectomy was performed. Immunohistochemical analysis using h-caldesmon and smooth muscle actin staining established the diagnosis of primary breast leiomyosarcoma. Despite intensive chemotherapy, 3 month follow-up PET/CT revealed a large lung metastasis suggesting aggressiveness and poor response to chemotherapy. Primary leiomyosarcoma of the breast is extremely rare and difficult to diagnose before excisional surgery because of the need for immunohistochemical staining to confirm the diagnosis. PMID- 23354028 TI - FDG PET/CT findings of solid pseudopapillary tumor of the pancreas with CT and MRI correlation. AB - PURPOSE: The aim of this study was to evaluate retrospectively (18)F-FDG PET/CT findings of solid pseudopapillary tumor of the pancreas (SPTP). PATIENTS AND METHODS: FDG PET/CT findings were reviewed in 8 patients with SPTP confirmed by pathology. Early PET/CT scans were performed 1 hour after FDG injection in all 8 patients. After an interval of 1 hour, delayed PET/CT scans were performed in 6 patients. All patients underwent enhanced CT and 4 patients underwent MRI. RESULTS: A total of 8 tumors were detected in all 8 patients. CT and MRI findings included encapsulation (n = 2), solid and cystic components (n = 4), focal calcification (n = 7), and weak enhancement during the arterial phase on enhanced CT or MRI and increasing enhancement during the portal venous phase (n = 8). All the tumors showed increased FDG uptake. The mean SUVmax of all tumors was 8.9, with a high variability of SUVmax among lesions ranging from 2.5 to 29.1. The tumors (n = 6) with high cellularity had stronger FDG uptake, whereas the tumors (n = 2) with low cellularity had relatively low FDG uptake. The tumors (n = 6) with pancreatic parenchymal, vascular, or perineural invasions had intense FDG uptake, whereas the tumors (n = 2) without invasions had slight-to-moderate FDG uptake. Two tumors with relatively high proliferative index had very strong FDG uptake, whereas those (n = 6) with low proliferative index or negative Ki-67 staining result had relatively lower FDG uptake. On delayed FDG PET/CT images, The SUVmax of SPTP increased in 4 patients and slightly decreased in 2 patients. CONCLUSIONS: CT or MRI demonstrated morphological features of SPTP and FDG PET/CT that reflected the histopathological composition of the tumors. FDG uptake of SPTP may be related to tumor cellularity, proliferative index, or histological malignancy. Familiarity with the morphological and functional imaging findings of SPTP may be helpful for correct diagnosis and appropriate treatment. PMID- 23354029 TI - Positron emission tomography revealed diffuse involvement of the lower legs and occult extracutaneous lesions in subcutaneous panniculitis-like T-cell lymphoma. AB - Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a very rare type of cutaneous lymphoma that localizes primarily in the subcutaneous adipose tissue without palpable involvement of the lymph nodes. Most often, it presents as multiple, painless, subcutaneous nodules on the extremities and trunk. In this study, we describe an unusual case of SPTCL that mimicked phlegmonous inflammation; PET/CT revealed massive diffuse involvement of the lower legs, low grade nodal active disease, and occult involvement of the intra-abdominal visceral fat. A repeat PET/CT study after CHOP chemotherapy revealed complete resolution of abnormal FDG uptake in the initially involved sites. PMID- 23354030 TI - 201Tl heart-liver radioactivity uptake ratio and prediction of decompensation in patients with cirrhosis. AB - PURPOSE: The present study aimed to determine the predictive value of the heart liver uptake ratio (H/L ratio) of rectally administered (201)Tl scintigraphy for hepatic decompensation, which was conducted in 107 patients with cirrhosis. METHODS: We retrospectively assessed the predictive value of a noninvasive parameter, H/L ratio, for decompensation during a median follow-up period of 45.4 months using follow-up data from 1996 through 2008 for 107 patients with compensated cirrhosis. Logistic regression analysis and odds ratio estimates were used to estimate independent value of the H/L ratio on the risk of decompensation with 95% confidence intervals. RESULTS: At first visit, all subjects were confirmed as patients with compensated cirrhosis, 39 by liver biopsy and 68 by standard laboratory and radiological criteria. At end of the evaluation time, 81 patients remained compensated, whereas 26 patients decompensated as evidenced by ascites in 23, hepatic encephalopathy in 8, and variceal bleeding in 1 patient. First-visit parameters except bilirubin level, alanine aminotransferase (ALT), and H/L ratio and last visit parameters except ALT and aspartate aminotransferase ALT ratio were significantly different between the 2 groups as ascertained by Wilcoxon rank sum test (P < 0.05). Among those parameters, we found that the last visit H/L ratio was a strongly reliable predictor of decompensation with an odds ratio estimates of 14.443, area under the receiver operating characteristic curve of 0.825, cutoff of 0.4, sensitivity of 73.1 %, and specificity of 71.6%. CONCLUSIONS: This evidence indicates that in patients with compensated cirrhosis, an increased H/L ratio at follow-up may be a useful predictive parameter showing a high risk of progression to a decompensated state. PMID- 23354031 TI - Acute 99mTc DMSA scan predicts dilating vesicoureteral reflux in young children with a first febrile urinary tract infection: a population-based cohort study. AB - OBJECTIVE: This study aimed to examine the ability of acute (99m)Tc DMSA scan for predicting dilating (grades III-V) vesicoureteral reflux (VUR) after a first febrile urinary tract infection in children aged 2 years or younger. PATIENTS AND METHODS: All children underwent ultrasonography (US), (99m)Tc DMSA scan, and voiding cystourethrography. Sensitivity, specificity, positive and negative predictive values, likelihood ratios, and receiver operating characteristic curves were performed to assess the diagnostic accuracy for predicting dilating VUR. Follow-up scan was performed at least 6 months after the acute infection to evaluate the presence of renal scarring (RS) or new scars. RESULTS: Of the 473 children analyzed (289 boys and 184 girls; median age, 5 months), 282 (59.6%) had abnormal acute (99m)Tc DMSA scan findings. There was VUR in 153 children (32.3%), whereas 95 (20.1%) had dilating VUR. The sensitivity and negative predictive value in predicting dilating VUR were 95.8% and 97.9%, respectively, for (99m)Tc DMSA and 97.9% and 98.6%, respectively, for combined US and (99m)Tc DMSA, whereas the positive and negative likelihood ratios were 1.90 and 0.08, respectively, for (99m)Tc DMSA and 1.57 and 0.06, respectively, for combined studies. On multivariate analysis, dilating VUR was a predictor for developing RS and new scars. CONCLUSIONS: Our results reveal the usefulness of acute (99m)Tc DMSA scan for predicting dilating VUR in children with a first febrile urinary tract infection. A voiding cystourethrography is indicated in only children with abnormalities found on a (99m)Tc DMSA and/or a US. The presence of dilating VUR predisposes to developing RS and new scars. PMID- 23354032 TI - Variance of SUVs for FDG-PET/CT is greater in clinical practice than under ideal study settings. AB - PURPOSE: Measurement variance affects the clinical effectiveness of PET-based measurement as a semiquantitative imaging biomarker for cancer response in individual patients and for planning clinical trials. In this study, we measured test-retest reproducibility of SUV measurements under clinical practice conditions and recorded recognized deviations from protocol compliance. METHODS: Instrument performance calibration, display, and analyses conformed to manufacture recommendations. Baseline clinical (18)F-FDG PET/CT examinations were performed and then repeated at 1 to 7 days. Intended scan initiation uptake period was to repeat the examinations at the same time for each study after injection of 12 mCi FDG tracer. Avidity of uptake was measured in 62 tumors in 21 patients as SUV for maximum voxel (SUV(max)) and for a mean of sampled tumor voxels (SUV(mean)). RESULTS: The range of SUV(max) and SUV(mean) was 1.07 to 21.47 and 0.91 to 14.69, respectively. Intraclass correlation coefficient between log of SUV(max) and log of SUV(mean) was 0.93 (95% confidence interval [CI], 0.88 0.95) and 0.92 (95% CI, 0.87-0.95), respectively.Correlation analysis failed to show an effect on uptake period variation on SUV measurements between the 2 examinations, suggesting additional sources of noise.The threshold criteria for relative difference from baseline for the 95% CI were +/- 49% or +/- 44% for SUV(max) or SUV(mean), respectively. CONCLUSIONS: Variance of SUV for FDG-PET/CT in current clinical practice in a single institution was greater than expected when compared with benchmarks reported under stringent efficacy study settings. Under comparable clinical practice conditions, interpretation of changes in tumor avidity in individuals and assumptions in planning clinical trials may be affected. PMID- 23354034 TI - Nephrogenic systemic fibrosis in a patient with renal failure demonstrating a "reverse superscan" on bone scintigraphy. AB - Nephrogenic systemic fibrosis (NSF) has been linked to utilization of gadolinium based contrast agents in patients with renal impairment. We present a 19-year-old female patient with end-stage renal failure presenting with joint pains and subcutaneous nodules. She had a prior gadolinium-enhanced magnetic resonance angiography when she was 14 years old. Clinical findings revealed firm subcutaneous nodules in both thighs. Whole-body bone scan demonstrates tracer uptake predominantly in the soft tissues and muscles of the extremities with minimal bony uptake. Incisional biopsy of the left thigh nodule revealed features of NSF with a total pathological score of 4, highly consistent with NSF. PMID- 23354033 TI - Effect of erythropoietin on bone marrow uptake of 18F-fluorocholine in prostate cancer: comparison with 18F-fluoride uptake. AB - The effect of erythropoietin stimulation on bone marrow uptake of FDG has been well documented. Similar metabolic activation of bone marrow with (18)F fluorocholine (FCH) has not been previously reported. FCH PET/CT was performed in a patient with biochemical recurrent prostate cancer who was receiving erythropoietin for hemochromatosis. Diffuse skeletal uptake of FCH was seen. (18)F-Fluoride PET/CT performed the following day demonstrates multiple abnormal focal bone metastases. Generalized skeletal uptake of FCH results in poor contrast between the metastases compared to noninvolved bone. The metabolic activation of bone marrow by erythropoietin could result in false-negative FCH results for detecting bone metastases. PMID- 23354035 TI - Feedback and rewards part III: commitment, goals, compensation, and job changes. AB - Formal and informal feedback is important to improve the performance, skill sets, commitment, accountability, and morale of the person being evaluated. Feedback can help people achieve their goals. Feedback is a basis for changes in compensation and other rewards. Formal reviews can also be the foundation for job changes. The latter includes promotions, lateral moves that are a better fit or will help the individual have new experiences or achieve new areas of proficiency, or finding opportunities to work outside the organization. PMID- 23354036 TI - Prognostic significance of FDG PET/CT on the follow-up of patients of differentiated thyroid carcinoma with negative I131 whole- body scan and elevated thyroglobulin levels. PMID- 23354037 TI - Klippel-Trenaunay syndrome (KTS) evaluated with bone and labeled RBC scintigraphy. AB - This is a case of a 4-year-old female child with gross left lower extremity deformity detected at birth, including a giant cutaneous hemangioma from flank to foot. She was found to have no other associated abnormalities and was diagnosed with Klippel-Trenaunay syndrome. This is a rare entity and literature regarding use of radionuclide imaging techniques to evaluate this is scarce. We present here bone and red cell scans performed to evaluate whether there was osseous involvement or only soft tissue disease, which showed classic signs of this condition. Patient photographs also show the syndrome's typical appearance. PMID- 23354038 TI - Elevated soft tissue activity in early but not delayed phase of bone scan in Klippel-Trenaunay syndrome. AB - Triple-phase bone scan is commonly used in the diagnosis of osteomyelitis. Elevated bone tracer activity in early but not delayed phase of the study favors cellulitis over osteomyelitis. We reported that Klippel-Trenaunay syndrome, a congenital disorder characterized by malformations of the capillary, venous, and lymphatic systems, can have images similar to cellulitis on triple-phase bone scan. PMID- 23354039 TI - Unusual case of emphysematous cystitis seen on FDG PET/CT. AB - Emphysematous cystitis is a rare condition requiring immediate aggressive medical attention. Here, we describe a very unusual case of emphysematous cystitis seen on FDG PET/CT. This finding was discovered in an 84-year-old man undergoing FDG PET/CT to monitor a known diagnosis of IgG4-related nodular sclerosis. Images revealed gas within the bladder wall and an anterior gas-filled bladder diverticulum. The patient subsequently developed sepsis with cultures revealing Escherichia coli. This case highlights the importance of recognizing this finding on varied imaging modalities, as life-threatening complications may arise from this condition. PMID- 23354040 TI - The scar sign: a useful finding on FDG PET/CT to distinguish sarcoidosis from other causes of lymphadenopathy. AB - Scar involvement is a rare but characteristic cutaneous manifestation of sarcoidosis. The concurrent presence of FDG-avid lymphadenopathy and scar involvement (the "scar sign") is a useful finding on FDG PET/CT to suggest sarcoidosis, especially when biopsy specimens are difficult to obtain. A 46-year old woman who presented with fever, cough, and weight loss was found to have mediastinal and hilar lymphadenopathy on chest radiography and CT scan. FDG PET/CT scan showed FDG-avid lower cervical, mediastinal, hilar, and inguinal lymphadenopathy. There was also increased FDG uptake along an old hysterectomy scar. Mediastinoscopy and nodal biopsy revealed noncaseating granulomas compatible with sarcoidosis. PMID- 23354041 TI - Incidental finding of the nutcracker phenomenon detected by 18F-FDG PET/CT. AB - A 46-year-old man was found to have an increased carcinoembryonic antigen level (25.7 MUg/L) during physical examination, and an (18)F-FDG PET/CT scan was subsequently performed. The PET image indicated abnormal radioactivity levels in the left kidney, and the coregistered CT revealed compression of the left renal vein between the aorta and superior mesenteric artery. An ultrasonography was then performed, which revealed that the ratio between the renal hilum and the aortomesenteric left renal vein was 3.2. Therefore, the nutcracker phenomenon was diagnosed. When abnormal radioactivity is found in the left kidney on PET/CT scanning, the nutcracker syndrome should be considered. PMID- 23354042 TI - Clostridium butyricum MIYAIRI 588 shows antitumor effects by enhancing the release of TRAIL from neutrophils through MMP-8. AB - Bacillus Calmette-Guerin (BCG) intravesical therapy against superficial bladder cancer is one of the most successful immunotherapies in cancer, though the precise mechanism has not been clarified. Recent studies have demonstrated urinary tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) levels to be higher in BCG-responsive patients than non-responders and shown that polymorphonuclear neutrophils (PMNs) migrating to the bladder after BCG instillation release large amounts of TRAIL. To establish a safer and more effective intravesical therapy than BCG, we examined whether other bacteria induced similar effects. We stimulated PMNs or peripheral blood mononuclear cells (PBMCs) with BCG or other bacteria, and then aliquots of the culture supernatants or cell lysates were assayed for TRAIL. We examined the signaling pathway regulating the release of TRAIL from PMNs and evaluated the antitumor effects of BCG or other bacteria in vitro and in vivo. We have found that Clostridium butyricum MIYAIRI 588 (CBM588) induces the release of endogenous TRAIL from PMNs as well as BCG. In addition, we have shown that matrix metalloproteinase 8 (MMP 8) is one of the key factors responsible for the release. Interestingly, TLR2/4 signaling pathway has been suggested to be important for the release of TRAIL by MMP-8. CBM588 has been proven to be as effective as BCG against cancer cells by inducing apoptosis in vivo as well as in vitro. Taken together, these results strongly suggest that CBM588 is promising for a safer and more effective therapy against bladder cancer. PMID- 23354043 TI - Materials science: Synthetic polymers with biological rigidity. PMID- 23354044 TI - H5N1 virus: Transmission studies resume for avian flu. PMID- 23354045 TI - Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. AB - Cellular reprogramming of somatic cells to patient-specific induced pluripotent stem cells (iPSCs) enables in vitro modelling of human genetic disorders for pathogenic investigations and therapeutic screens. However, using iPSC-derived cardiomyocytes (iPSC-CMs) to model an adult-onset heart disease remains challenging owing to the uncertainty regarding the ability of relatively immature iPSC-CMs to fully recapitulate adult disease phenotypes. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart disease characterized by pathological fatty infiltration and cardiomyocyte loss predominantly in the right ventricle, which is associated with life-threatening ventricular arrhythmias. Over 50% of affected individuals have desmosome gene mutations, most commonly in PKP2, encoding plakophilin-2 (ref. 9). The median age at presentation of ARVD/C is 26 years. We used previously published methods to generate iPSC lines from fibroblasts of two patients with ARVD/C and PKP2 mutations. Mutant PKP2 iPSC-CMs demonstrate abnormal plakoglobin nuclear translocation and decreased beta-catenin activity in cardiogenic conditions; yet, these abnormal features are insufficient to reproduce the pathological phenotypes of ARVD/C in standard cardiogenic conditions. Here we show that induction of adult-like metabolic energetics from an embryonic/glycolytic state and abnormal peroxisome proliferator-activated receptor gamma (PPAR-gamma) activation underlie the pathogenesis of ARVD/C. By co-activating normal PPAR-alpha-dependent metabolism and abnormal PPAR-gamma pathway in beating embryoid bodies (EBs) with defined media, we established an efficient ARVD/C in vitro model within 2 months. This model manifests exaggerated lipogenesis and apoptosis in mutant PKP2 iPSC CMs. iPSC-CMs with a homozygous PKP2 mutation also had calcium-handling deficits. Our study is the first to demonstrate that induction of adult-like metabolism has a critical role in establishing an adult-onset disease model using patient specific iPSCs. Using this model, we revealed crucial pathogenic insights that metabolic derangement in adult-like metabolic milieu underlies ARVD/C pathologies, enabling us to propose novel disease-modifying therapeutic strategies. PMID- 23354046 TI - Crystal structure of Prp8 reveals active site cavity of the spliceosome. AB - The active centre of the spliceosome consists of an intricate network formed by U5, U2 and U6 small nuclear RNAs, and a pre-messenger-RNA substrate. Prp8, a component of the U5 small nuclear ribonucleoprotein particle, crosslinks extensively with this RNA catalytic core. Here we present the crystal structure of yeast Prp8 (residues 885-2413) in complex with Aar2, a U5 small nuclear ribonucleoprotein particle assembly factor. The structure reveals tightly associated domains of Prp8 resembling a bacterial group II intron reverse transcriptase and a type II restriction endonuclease. Suppressors of splice-site mutations, and an intron branch-point crosslink, map to a large cavity formed by the reverse transcriptase thumb, and the endonuclease-like and RNaseH-like domains. This cavity is large enough to accommodate the catalytic core of group II intron RNA. The structure provides crucial insights into the architecture of the spliceosome active site, and reinforces the notion that nuclear pre-mRNA splicing and group II intron splicing have a common origin. PMID- 23354047 TI - Neuroscience: To go or not to go. PMID- 23354048 TI - Responsive biomimetic networks from polyisocyanopeptide hydrogels. AB - Mechanical responsiveness is essential to all biological systems down to the level of tissues and cells. The intra- and extracellular mechanics of such systems are governed by a series of proteins, such as microtubules, actin, intermediate filaments and collagen. As a general design motif, these proteins self-assemble into helical structures and superstructures that differ in diameter and persistence length to cover the full mechanical spectrum. Gels of cytoskeletal proteins display particular mechanical responses (stress stiffening) that until now have been absent in synthetic polymeric and low-molar-mass gels. Here we present synthetic gels that mimic in nearly all aspects gels prepared from intermediate filaments. They are prepared from polyisocyanopeptides grafted with oligo(ethylene glycol) side chains. These responsive polymers possess a stiff and helical architecture, and show a tunable thermal transition where the chains bundle together to generate transparent gels at extremely low concentrations. Using characterization techniques operating at different length scales (for example, macroscopic rheology, atomic force microscopy and molecular force spectroscopy) combined with an appropriate theoretical network model, we establish the hierarchical relationship between the bulk mechanical properties and the single-molecule parameters. Our results show that to develop artificial cytoskeletal or extracellular matrix mimics, the essential design parameters are not only the molecular stiffness, but also the extent of bundling. In contrast to the peptidic materials, our polyisocyanide polymers are readily modified, giving a starting point for functional biomimetic hydrogels with potentially a wide variety of applications, in particular in the biomedical field. PMID- 23354049 TI - In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. AB - The Wnt target gene Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5) marks actively dividing stem cells in Wnt-driven, self-renewing tissues such as small intestine and colon, stomach and hair follicles. A three dimensional culture system allows long-term clonal expansion of single Lgr5(+) stem cells into transplantable organoids (budding cysts) that retain many characteristics of the original epithelial architecture. A crucial component of the culture medium is the Wnt agonist RSPO1, the recently discovered ligand of LGR5. Here we show that Lgr5-lacZ is not expressed in healthy adult liver, however, small Lgr5-LacZ(+) cells appear near bile ducts upon damage, coinciding with robust activation of Wnt signalling. As shown by mouse lineage tracing using a new Lgr5-IRES-creERT2 knock-in allele, damage-induced Lgr5(+) cells generate hepatocytes and bile ducts in vivo. Single Lgr5(+) cells from damaged mouse liver can be clonally expanded as organoids in Rspo1-based culture medium over several months. Such clonal organoids can be induced to differentiate in vitro and to generate functional hepatocytes upon transplantation into Fah(-/-) mice. These findings indicate that previous observations concerning Lgr5(+) stem cells in actively self-renewing tissues can also be extended to damage-induced stem cells in a tissue with a low rate of spontaneous proliferation. PMID- 23354050 TI - The genomic signature of dog domestication reveals adaptation to a starch-rich diet. AB - The domestication of dogs was an important episode in the development of human civilization. The precise timing and location of this event is debated and little is known about the genetic changes that accompanied the transformation of ancient wolves into domestic dogs. Here we conduct whole-genome resequencing of dogs and wolves to identify 3.8 million genetic variants used to identify 36 genomic regions that probably represent targets for selection during dog domestication. Nineteen of these regions contain genes important in brain function, eight of which belong to nervous system development pathways and potentially underlie behavioural changes central to dog domestication. Ten genes with key roles in starch digestion and fat metabolism also show signals of selection. We identify candidate mutations in key genes and provide functional support for an increased starch digestion in dogs relative to wolves. Our results indicate that novel adaptations allowing the early ancestors of modern dogs to thrive on a diet rich in starch, relative to the carnivorous diet of wolves, constituted a crucial step in the early domestication of dogs. PMID- 23354051 TI - Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. AB - Insulin resistance is a fundamental pathogenic factor present in various metabolic disorders including obesity and type 2 diabetes. Although skeletal muscle accounts for 70-90% of insulin-stimulated glucose disposal, the mechanism underlying muscle insulin resistance is poorly understood. Here we show in mice that muscle-specific mitsugumin 53 (MG53; also called TRIM72) mediates the degradation of the insulin receptor and insulin receptor substrate 1 (IRS1), and when upregulated, causes metabolic syndrome featuring insulin resistance, obesity, hypertension and dyslipidaemia. MG53 expression is markedly elevated in models of insulin resistance, and MG53 overexpression suffices to trigger muscle insulin resistance and metabolic syndrome sequentially. Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. Mechanistically, MG53 acts as an E3 ligase targeting the insulin receptor and IRS1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. These findings define MG53 as a novel therapeutic target for treating metabolic disorders and associated cardiovascular complications. PMID- 23354052 TI - Towards practical, high-capacity, low-maintenance information storage in synthesized DNA. AB - Digital production, transmission and storage have revolutionized how we access and use information but have also made archiving an increasingly complex task that requires active, continuing maintenance of digital media. This challenge has focused some interest on DNA as an attractive target for information storage because of its capacity for high-density information encoding, longevity under easily achieved conditions and proven track record as an information bearer. Previous DNA-based information storage approaches have encoded only trivial amounts of information or were not amenable to scaling-up, and used no robust error-correction and lacked examination of their cost-efficiency for large-scale information archival. Here we describe a scalable method that can reliably store more information than has been handled before. We encoded computer files totalling 739 kilobytes of hard-disk storage and with an estimated Shannon information of 5.2 * 10(6) bits into a DNA code, synthesized this DNA, sequenced it and reconstructed the original files with 100% accuracy. Theoretical analysis indicates that our DNA-based storage scheme could be scaled far beyond current global information volumes and offers a realistic technology for large-scale, long-term and infrequently accessed digital archiving. In fact, current trends in technological advances are reducing DNA synthesis costs at a pace that should make our scheme cost-effective for sub-50-year archiving within a decade. PMID- 23354053 TI - Structural biology: Spliceosome's core exposed. PMID- 23354054 TI - Concurrent activation of striatal direct and indirect pathways during action initiation. AB - The basal ganglia are subcortical nuclei that control voluntary actions, and they are affected by a number of debilitating neurological disorders. The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum--the so-called direct and indirect pathways--have opposing effects on movement: activity of direct-pathway SPNs is thought to facilitate movement, whereas activity of indirect-pathway SPNs is presumed to inhibit movement. This model has been difficult to test owing to the lack of methods to selectively measure the activity of direct- and indirect-pathway SPNs in freely moving animals. Here we develop a novel in vivo method to specifically measure direct- and indirect-pathway SPN activity, using Cre-dependent viral expression of the genetically encoded calcium indicator (GECI) GCaMP3 in the dorsal striatum of D1 Cre (direct-pathway-specific) and A2A-Cre (indirect-pathway-specific) mice. Using fibre optics and time-correlated single-photon counting (TCSPC) in mice performing an operant task, we observed transient increases in neural activity in both direct- and indirect-pathway SPNs when animals initiated actions, but not when they were inactive. Concurrent activation of SPNs from both pathways in one hemisphere preceded the initiation of contraversive movements and predicted the occurrence of specific movements within 500 ms. These observations challenge the classical view of basal ganglia function and may have implications for understanding the origin of motor symptoms in basal ganglia disorders. PMID- 23354055 TI - Manufacturing and using piggy-back multibarrel electrodes for in vivo pharmacological manipulations of neural responses. AB - In vivo recordings from single neurons allow an investigator to examine the firing properties of neurons, for example in response to sensory stimuli. Neurons typically receive multiple excitatory and inhibitory afferent and/or efferent inputs that integrate with each other, and the ultimate measured response properties of the neuron are driven by the neural integrations of these inputs. To study information processing in neural systems, it is necessary to understand the various inputs to a neuron or neural system, and the specific properties of these inputs. A powerful and technically relatively simple method to assess the functional role of certain inputs that a given neuron is receiving is to dynamically and reversibly suppress or eliminate these inputs, and measure the changes in the neuron's output caused by this manipulation. This can be accomplished by pharmacologically altering the neuron's immediate environment with piggy-back multibarrel electrodes. These electrodes consist of a single barrel recording electrode and a multibarrel drug electrode that can carry up to 4 different synaptic agonists or antagonists. The pharmacological agents can be applied iontophoretically at desired times during the experiment, allowing for time-controlled delivery and reversible reconfiguration of synaptic inputs. As such, pharmacological manipulation of the microenvironment represents a powerful and unparalleled method to test specific hypotheses about neural circuit function. Here we describe how piggy-back electrodes are manufactured, and how they are used during in vivo experiments. The piggy-back system allows an investigator to combine a single barrel recording electrode of any arbitrary property (resistance, tip size, shape etc) with a multibarrel drug electrode. This is a major advantage over standard multi-electrodes, where all barrels have more or less similar shapes and properties. Multibarrel electrodes were first introduced over 40 years ago, and have undergone a number of design improvements until the piggy-back type was introduced in the 1980s. Here we present a set of important improvements in the laboratory production of piggy-back electrodes that allow for deep brain penetration in intact in vivo animal preparations due to a relatively thin electrode shaft that causes minimal damage. Furthermore these electrodes are characterized by low noise recordings, and have low resistance drug barrels for very effective iontophoresis of the desired pharmacological agents. PMID- 23354056 TI - Alignment as a consequence of expectation adaptation: syntactic priming is affected by the prime's prediction error given both prior and recent experience. AB - Speakers show a remarkable tendency to align their productions with their interlocutors'. Focusing on sentence production, we investigate the cognitive systems underlying such alignment (syntactic priming). Our guiding hypothesis is that syntactic priming is a consequence of a language processing system that is organized to achieve efficient communication in an ever-changing (subjectively non-stationary) environment. We build on recent work suggesting that comprehenders adapt to the statistics of the current environment. If such adaptation is rational or near-rational, the extent to which speakers adapt their expectations for a syntactic structure after processing a prime sentence should be sensitive to the prediction error experienced while processing the prime. This prediction is shared by certain error-based implicit learning accounts, but not by most other accounts of syntactic priming. In three studies, we test this prediction against data from conversational speech, speech during picture description, and written production during sentence completion. All three studies find stronger syntactic priming for primes associated with a larger prediction error (primes with higher syntactic surprisal). We find that the relevant prediction error is sensitive to both prior and recent experience within the experiment. Together with other findings, this supports accounts that attribute syntactic priming to expectation adaptation. PMID- 23354057 TI - Medial prefrontal cortex lesions impair decision-making on a rodent gambling task: reversal by D1 receptor antagonist administration. AB - Decision-making is a complex cognitive process that is impaired in a number of psychiatric disorders. In the laboratory, decision-making is frequently assessed using "gambling" tasks that are designed to simulate real-life decisions in terms of uncertainty, reward and punishment. Here, we investigate whether lesions of the medial prefrontal cortex (PFC) cause impairments in decision-making using a rodent gambling task (rGT). In this task, rats have to decide between 1 of 4 possible options: 2 options are considered "advantageous" and lead to greater net rewards (food pellets) than the other 2 "disadvantageous" options. Once rats attained stable levels of performance on the rGT they underwent sham or excitoxic lesions of the medial PFC and were allowed to recover for 1 week. Following recovery, rats were retrained for 5 days and then the effects of a dopamine D1 like receptor antagonist (SCH23390) or a D2-like receptor antagonist (haloperidol) on performance were assessed. Lesioned rats exhibited impaired decision-making: they made fewer advantageous choices and chose the most optimal choice less frequently than did sham-operated rats. Administration of SCH23390 (0.03 mg/kg), but not haloperidol (0.015-0.03 mg/kg) attenuated the lesion induced decision-making deficit. These results indicate that the medial PFC is important for decision-making and that excessive signaling at D1 receptors may contribute to decision-making impairments. PMID- 23354058 TI - Distribution and sequence of gonadotropin-inhibitory hormone and its potential role as a molecular link between feeding and reproductive systems in the Pekin duck (Anas platyrhynchos domestica). AB - The reproductive status of adult Pekin drakes is very sensitive to nutritional status. Thus, the purpose of this study was to increase our understanding of the neurobiology underlying the depressive effect of fasting on the secretion of reproductive hormones. It was hypothesized that this effect was mediated by gonadotropin-inhibitory hormone (GnIH). Networks of GnIH fibers were present throughout the diencephalon, and cell bodies were present primarily, in the hypothalamic paraventricular nucleus (PVN). The duck GnIH gene was cloned and sequenced and found to encode GnIH and two GnIH-related peptides (GnIH-RP1, GnIH RP2) which have a similar identity to those found in other avian species. Intracerebroventricular injection of GnIH, but not of GnIH-RP1, depressed plasma LH and stimulated feeding. Fasting for 48h depressed plasma LH and induced fos expression in about half the population of GnIH-ir neurons. These data suggest that GnIH neurons are mediators between feeding and reproductive systems in Pekin drakes. PMID- 23354059 TI - The eIF2alpha kinases: their structures and functions. AB - Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 (eIF2). Phosphorylation of eIF2alpha on serine 51 results in a severe decline in de novo protein synthesis and is an important strategy in the cell's armory against stressful insults including viral infection, the accumulation of misfolded proteins, and starvation. The phosphorylation of eIF2alpha is carried out by a family of four kinases, PERK (PKR-like ER kinase), PKR (protein kinase double stranded RNA-dependent), GCN2 (general control non-derepressible-2), and HRI (heme-regulated inhibitor). Each primarily responds to a distinct type of stress or stresses. Thus, while significant sequence similarity exists between the eIF2alpha kinases in their kinase domains, underlying their common role in phosphorylating eIF2alpha, additional unique features determine the regulation of these four proteins, that is, what signals activate them. This review will describe the structure of each eIF2alpha kinase and discuss how this is linked to their activation and function. In parallel to the general translational attenuation elicited by eIF2alpha kinase activation the translation of stress induced mRNAs, most notably activating transcription factor 4 (ATF4) is enhanced and these set in motion cascades of gene expression constituting the integrated stress response (ISR), which seek to remediate stress and restore homeostasis. Depending on the cellular context and concurrent signaling pathways active, however, translational attenuation can also facilitate apoptosis. Accordingly, the role of the kinases in determining cell fate will also be discussed. PMID- 23354061 TI - The translational factor eIF3f: the ambivalent eIF3 subunit. AB - The regulation of the protein synthesis has a crucial role in governing the eukaryotic cell growth. Subtle changes of proteins involved in the translation process may alter the rate of the protein synthesis and modify the cell fate by shifting the balance from normal status into a tumoral or apoptotic one. The largest eukaryotic initiation factor involved in translation regulation is eIF3. Amongst the 13 factors constituting eIF3, the f subunit finely regulates this balance in a cell-type-specific manner. Loss of this factor causes malignancy in several cells, and atrophy in normal muscle cells. The intracellular interacting partners which influence its physiological significance in both cancer and muscle cells are detailed in this review. By delineating the global interaction network of this factor and by clarifying its intracellular role, it becomes apparent that the f subunit represents a promising candidate molecule to use for biotherapeutic applications. PMID- 23354063 TI - From noncovalent to covalent bonds: a paradigm shift in target protein identification. AB - Phenotype-based screening has been recognized as an important research tool for the discovery of novel therapeutic agents. However, the subsequent identification (ID) of the target of bioactive small molecules has been a major bottleneck in the general application of phenotype-based screening to the drug discovery process. The outcome of conventional target ID methods is significantly influenced by the inherent binding affinity of bioactive small molecules, which can be easily affected by experimental buffer conditions and nonspecific interactions. To overcome these limitations in affinity-based target ID, there has been a community effort to develop new target ID methods. In this review, we focus on the paradigm shift in target ID from noncovalent to covalent bonds and the associated issues in target identification. PMID- 23354062 TI - Localization of epileptogenic zones in Lennox-Gastaut syndrome using frequency domain source imaging of intracranial electroencephalography: a preliminary investigation. AB - Although intracranial electroencephalography (iEEG) has been widely used to localize epileptogenic zones in epilepsy, visual inspection of iEEG recordings does not always result in a favorable surgical outcome, especially in secondary generalized epilepsy such as Lennox-Gastaut syndrome (LGS). Various computational iEEG analysis methods have recently been introduced to confirm the visual inspection results. Of these methods, high gamma oscillation in iEEG has attracted interest because a series of studies have reported a close relationship between epileptogenic zones and cortical areas with high gamma oscillation. Meanwhile, frequency domain source imaging of EEG and MEG oscillations has proven to be a useful auxiliary tool for identifying rough locations of epileptogenic zones. To the best of our knowledge, however, frequency domain source imaging of high gamma iEEG oscillations has not been studied. In this study, we investigated whether the iEEG-based frequency domain source imaging of high gamma oscillation (60-100 Hz) would be a useful supplementary tool for identifying epileptogenic zones in patients with secondary generalized epilepsy. The method was applied to three successfully operated on LGS patients, whose iEEG contained some ictal events with distinct high gamma oscillations before seizure onset. The resultant cortical source distributions were compared with surgical resection areas and with high gamma spectral power distributions on the intracranial sensor plane. While the results of the sensor-level analyses contained many spurious activities, the results of frequency domain source imaging coincided better with the surgical resection areas, suggesting that the frequency domain source imaging of iEEG high gamma oscillations might help enhance the accuracy of pre-surgical evaluations of patients with secondary generalized epilepsy. PMID- 23354060 TI - Regulation of microRNA biogenesis and turnover by animals and their viruses. AB - MicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes. PMID- 23354068 TI - Mitochondrial aldehyde dehydrogenase obliterates endoplasmic reticulum stress induced cardiac contractile dysfunction via correction of autophagy. AB - ER stress triggers myocardial contractile dysfunction while effective therapeutic regimen is still lacking. Mitochondrial aldehyde dehydrogenase (ALDH2), an essential mitochondrial enzyme governing mitochondrial and cardiac function, displays distinct beneficial effect on the heart. This study was designed to evaluate the effect of ALDH2 on ER stress-induced cardiac anomalies and the underlying mechanism involved with a special focus on autophagy. WT and ALDH2 transgenic mice were subjected to the ER stress inducer thapsigargin (1mg/kg, i.p., 48h). Echocardiographic, cardiomyocyte contractile and intracellular Ca(2+) properties as well as myocardial histology, autophagy and autophagy regulatory proteins were evaluated. ER stress led to compromised echocardiographic indices (elevated LVESD, reduced fractional shortening and cardiac output), cardiomyocyte contractile and intracellular Ca(2+) properties and cell survival, associated with upregulated autophagy, dampened phosphorylation of Akt and its downstream signal molecules TSC2 and mTOR, the effects of which were alleviated or mitigated by ALDH2. Thapsigargin promoted ER stress proteins Gadd153 and GRP78 without altering cardiomyocyte size and interstitial fibrosis, the effects of which were unaffected by ALDH2. Treatment with thapsigargin in vitro mimicked in vivo ER stress-induced cardiomyocyte contractile anomalies including depressed peak shortening and maximal velocity of shortening/relengthening as well as prolonged relengthening duration, the effect of which was abrogated by the autophagy inhibitor 3-methyladenine and the ALDH2 activator Alda-1. Interestingly, Alda-1 induced beneficial effect against ER stress was obliterated by autophagy inducer rapamycin, Akt inhibitor AktI and mTOR inhibitor RAD001. These data suggest a beneficial role of ALDH2 against ER stress-induced cardiac anomalies possibly through autophagy reduction. PMID- 23354069 TI - Impairment of the proteasome is crucial for glucose-induced lifespan reduction in the mev-1 mutant of Caenorhabditis elegans. AB - Hyperglycemia is a hallmark of diabetes that is associated with diabetic complications and a reduction of lifespan. Using the mev-1 mutant of the nematode Caenorhabditis elegans we here tried to identify molecular mechanisms underlying the lifespan reducing effects of glucose. The lowest glucose concentration tested (10mM) caused a significant lifespan reduction at 37 degrees C and was used to assess effects on mitochondrial efficiency, formation of protein carbonyls and levels of methylglyoxal, a precursor of advanced glycation end products (AGEs). RNA-interference (RNAi) served the identification of targets for glucose-induced damage. Levels of protein carbonyls and AGEs remained unaffected by 10mM glucose. Levels of reactive oxygen species inside mitochondria were increased but their scavenging by ascorbic acid did not influence lifespan reduction by glucose. Mitochondrial efficiency was reduced by glucose as concluded from a lowered P/O ratio. A reduced lifespan of mev-1 that was unaffected by the addition of glucose resulted from RNAi of key players of mitochondrial unfolded protein response. Besides increased accumulation of misfolded proteins, reduced proteasomal degradation caused the same phenotype as was evidenced by RNAi for UBQ-1 or UBA 1. Accumulation of functionally impaired proteins, e.g. in mitochondria, underlies the lifespan reducing effects of glucose. Our study provides evidence for a crucial importance of the proteostasis network for lifespan regulation which is impaired by glucose. PMID- 23354070 TI - Evidence for a new binding mode to GSK-3: allosteric regulation by the marine compound palinurin. AB - Glycogen synthase kinase 3beta (GSK-3beta) is widely recognised as a relevant player in the pathogenesis of several highly prevalent disorders such as Alzheimer's disease, mood disorders, diabetes and cancer. Therefore, this enzyme constitutes a highly attractive therapeutic target for the development of selective inhibitors as new promising drugs for the treatment of these pathologies. We describe here the isolation and biochemical characterization of the marine natural sesquiterpene palinurin as a GSK-3beta inhibitor. Experimental studies performed for characterizing the inhibitory mechanism indicate that GSK 3beta inhibition by palinurin cannot be competed out by ATP nor peptide substrate. Molecular modelling techniques have enabled us to propose an unconventional binding mode to GSK-3beta. Moreover, molecular dynamics simulations have identified an allosteric mechanism by which binding of palinurin leads to GSK-3beta inhibition. The inhibitory activities determined for a series of structurally related analogues support the proposed binding mode of palinurin, which is the first compound described to target this allosteric site. The results offer new opportunities for designing and developing selective inhibitors with novel mechanisms of action. PMID- 23354071 TI - A new cytotoxic quinolone alkaloid and a pentacyclic steroidal glycoside from the stem bark of Crataeva nurvala: study of anti-proliferative and apoptosis inducing property. AB - Chemical investigation of stem bark of Crataeva nurvala afforded 5,7-dimethoxy-3 phenyl-1-ethyl-1,4-dihydro-4-quinolone and a steroidal glycoside with unprecedented pentacyclic ring system named crataemine (1a) and crataenoside (2) respectively. The structures of the compounds were determined by spectroscopic analysis. A series of compounds with modification at position 1 of 1a (1a-1c) were prepared. All compounds were screened for cytotoxic activity against HeLa, PC-3 and MCF-7 cells. Only 1a and 2 showed potency against all three cells. Mechanism based study for activity of the compounds demonstrated that it could block the migration of more aggressive HeLa and PC-3 cells and prevent their colony formation ability as well. The compounds potentiated apoptosis in HeLa and PC-3 cells in a significant manner. PMID- 23354072 TI - Isolation and identification of beta-hematin inhibitors from Flacourtia indica as promising antiplasmodial agents. AB - An ethanolic extract (A001) of the leaves and twigs of Flacourtia indica (Burm.f.) Merr., was purified to give a new phenolic glycoside, 2-(2-benzoyl-beta D-glucopyranosyloxy)-7-(1alpha,2alpha,6alpha-trihydroxy-3-oxocyclohex-4-enoyl)-5 hydroxybenzyl alcohol (1) together with poliothrysoside (2), catechin-[5,6-e] 4beta-(3,4-dihydroxyphenyl)dihydro-2(3H)-pyranone (3), 2-(6-benzoyl-beta-D glucopyranosyloxy)-7-(1alpha,2alpha,6alpha-trihydroxy-3-oxocyclohex-4-enoyl)-5 hydroxybenzyl alcohol (4), chrysoeriol-7-O-beta-D-glucopyranoside (5), and mururin A (6). Compound 6 significantly inhibited the in vitro growth of both a chloroquine-sensitive (3D7) and a chloroquine-resistant (K1) strain of Plasmodium falciparum. It forms a complex with hematin and inhibits beta-hematin formation, suggesting that this compound act on a heme polymerization target. PMID- 23354073 TI - Cerebral blood flow studies in the diagnosis and management of intrauterine growth restriction. AB - PURPOSE OF REVIEW: To provide evidence that fetal brain vasodilatation can be related with postnatal cerebral structural and functional complications. RECENT FINDINGS: Most early-onset intrauterine growth restricted (IUGR) fetuses show signs of brain vasodilatation. As most of them are born prematurely, a high prevalence of short-term and long-term neurological complications is expected. However, the clinical significance of brain vasodilatation might be different. In the early stage of fetal deterioration, the risk of structural brain damage is low, but at advanced stages there is an increased risk of periventricular leukomalacia and intraventricular hemorrhage. The presence of brain vasodilatation in fetuses with an estimated fetal weight below the 10th centile but normal umbilical artery Doppler can be used to identify late-onset IUGR fetuses with latent placental insufficiency. These fetuses have an increased risk of abnormal neurological performance at birth and at 2 years of age. SUMMARY: Changes in cerebral brain blood perfusion in IUGR fetuses can be detected by Doppler ultrasound techniques. Despite its association with structural and functional neurological damage after birth, fetal brain vasodilatation is usually not considered in the decision to deliver, with the only exception of the 'return' to normal middle cerebral artery pulsatility index, which is highly associated with an increased risk for perinatal mortality. PMID- 23354074 TI - Discovering the cause of stillbirth. AB - PURPOSE OF REVIEW: Stillbirth remains a major problem worldwide, with disparities both between and within nations. Evaluation and classification is essential for development and evaluation of preventive strategies. RECENT FINDINGS: Recently, several organizations have developed standardized protocols for stillbirth evaluation on the basis of maternal history, foetal examination/autopsy and placental pathology. Evaluation is moving from a search for discrete causes to recognition of contributing factors. Comparison of classification guidelines identifies several with the potential for effective preservation of data and identification of causes or contributing factors for most stillbirths. Higher and lower income nations have differing rates, epidemiology and causes of stillbirths requiring different preventive strategies. SUMMARY: In lower income/higher risk groups, basic improvements in antenatal/obstetric care including targeted prevention/treatment of infections, induction after 41 weeks, skilled attendants at delivery and availability of emergency obstetric care can result in very significant risk reduction, whereas in higher income/lower risk groups, further research, more complex interventions and attention to societal risk factors such as obesity are required for further improvement. PMID- 23354075 TI - Environmental regulation of reproductive phase change in Agaricus bisporus by 1 octen-3-ol, temperature and CO2. AB - Reproductive phase change from vegetative mycelium to the initiation of fruiting in Agaricus bisporus is regulated in large part by the sensing of environmental conditions. A model is proposed in which three separate environmental factors exert control at different stages of the reproductive developmental process change. The eight carbon volatile 1-octen-3-ol controls the early differentiation from vegetative hyphae to multicellular knots; temperature reduction is essential for the later differentiation of primodia; and carbon dioxide level exerts quantitative control on the number of fruiting bodies developed. Analysis of transcriptomic changes during the reproductive phase change was carried out with initiation-specific microarrays, and the newly published A. bisporus genome was used to analyse the promoter regions of differentially regulated genes. Our studies have shown there to be both early and late initiation responses relating to sensing of eight carbon volatiles and temperature respectively. A subset of 45 genes was transcriptionally regulated during the reproductive phase change which exhibited a range of functions including cell structure, nitrogen and carbon metabolism, and sensing and signalling. Three gene clusters linking increased transcription with developmental stage were identified. Analysis of promoter regions revealed cluster-specific conserved motifs indicative of co-ordinated regulation of transcription. PMID- 23354076 TI - Ion channel complex disease in long QT syndrome. PMID- 23354077 TI - Imaging evaluation of implantation site of permanent direct His bundle pacing lead. PMID- 23354078 TI - Defibrillation success with high frequency electric fields is related to degree and location of conduction block. AB - BACKGROUND: We recently demonstrated that high frequency alternating current (HFAC) electric fields can reversibly block propagation in the heart by inducing an oscillating, elevated transmembrane potential (Vm) that maintains myocytes in a refractory state for the field duration and can terminate arrhythmias, including ventricular fibrillation (VF). OBJECTIVES: To quantify and characterize conduction block (CB) induced by HFAC fields and to determine whether the degree of CB can be used to predict defibrillation success. METHODS: Optical mapping was performed in adult guinea pig hearts (n = 14), and simulations were performed in an anatomically accurate rabbit ventricular model. HFAC fields (50-500 Hz) were applied to the ventricles. A novel power spectrum metric of CB-the loss of spectral power in the 1-30 Hz range, termed loss of conduction power (LCP)-was assessed during the HFAC field and compared with defibrillation success and VF vulnerability. RESULTS: LCP increased with field strength and decreased with frequency. Optical mapping experiments conducted on the epicardial surface showed that LCP and the size of CB regions were significantly correlated with VF initiation and termination. In simulations, subsurface myocardial LCP and CB sizes were more closely correlated with VF termination than surface values. Multilinear regression analysis of simulation results revealed that while CB on both the surface and the subsurface myocardium was predictive, subsurface myocardial CB was the better predictor of defibrillation success. CONCLUSIONS: HFAC fields induce a field-dependent state of CB, and defibrillation success is related to the degree and location of the CB. PMID- 23354079 TI - Smallest optical gap for quasi-one-dimensional iodo-bridged platinum compounds. AB - We synthesized a series of one-dimensional (1D) iodo-bridged platinum compounds with long alkyl chains on the counterions. In the compounds, the shortest Pt...Pt distance and the smallest band gap thus far reported were achieved. These compounds were found to be in a CDW state by using synchrotron X-ray diffraction measurements. PMID- 23354080 TI - AKT serine/threonine protein kinase modulates baicalin-triggered autophagy in human bladder cancer T24 cells. AB - Baicalin is one of the major compounds in the traditional Chinese medicinal herb from Scutellaria baicalensis Georgi. We investigated the molecular mechanisms of cell autophagy induced by baicalin in human bladder cancer T24 cells. Baicalin inhibited cell survival as shown by MTT assay and increased cell death by trypan blue exclusion assay in a concentration-dependent manner. Baicalin did not induce apoptotic cell death in T24 cells by TUNEL and caspase-3 activity assay. Baicalin induced the acidic vesicular organelle cell autophagy marker, manifested by acridine orange (AO) and monodansylcadaverine (MDC) staining and cleavage of microtubule-associated protein 1 light chain 3 (LC3). The protein expression levels of the Atg 5, Atg 7, Atg 12, Beclin-1 and LC3-II were upregulated in T24 cells after baicalin treatment. Inhibition of autophagy by 3-methyl-adenine (an inhibitor of class III phosphatidylinositol-3 kinase; 3-MA) reduced the cleavage of LC3 in T24 cells after baicalin treatment. Furthermore, protein expression levels of phospho-AKT (Ser473) and enzyme activity of AKT were downregulated in T24 cells after baicalin treatment. In conclusion, baicalin triggered cell autophagy through the AKT signaling pathway in T24 cells. PMID- 23354081 TI - Integrated photoacoustic ophthalmoscopy and spectral-domain optical coherence tomography. AB - Both the clinical diagnosis and fundamental investigation of major ocular diseases greatly benefit from various non-invasive ophthalmic imaging technologies. Existing retinal imaging modalities, such as fundus photography, confocal scanning laser ophthalmoscopy (cSLO), and optical coherence tomography (OCT), have significant contributions in monitoring disease onsets and progressions, and developing new therapeutic strategies. However, they predominantly rely on the back-reflected photons from the retina. As a consequence, the optical absorption properties of the retina, which are usually strongly associated with retinal pathophysiology status, are inaccessible by the traditional imaging technologies. Photoacoustic ophthalmoscopy (PAOM) is an emerging retinal imaging modality that permits the detection of the optical absorption contrasts in the eye with a high sensitivity. In PAOM nanosecond laser pulses are delivered through the pupil and scanned across the posterior eye to induce photoacoustic (PA) signals, which are detected by an unfocused ultrasonic transducer attached to the eyelid. Because of the strong optical absorption of hemoglobin and melanin, PAOM is capable of non-invasively imaging the retinal and choroidal vasculatures, and the retinal pigment epithelium (RPE) melanin at high contrasts. More importantly, based on the well-developed spectroscopic photoacoustic imaging, PAOM has the potential to map the hemoglobin oxygen saturation in retinal vessels, which can be critical in studying the physiology and pathology of several blinding diseases such as diabetic retinopathy and neovascular age-related macular degeneration. Moreover, being the only existing optical-absorption-based ophthalmic imaging modality, PAOM can be integrated with well-established clinical ophthalmic imaging techniques to achieve more comprehensive anatomic and functional evaluations of the eye based on multiple optical contrasts. In this work, we integrate PAOM and spectral-domain OCT (SD OCT) for simultaneously in vivo retinal imaging of rat, where both optical absorption and scattering properties of the retina are revealed. The system configuration, system alignment and imaging acquisition are presented. PMID- 23354082 TI - [Bone mineral metabolism that kidney controls]. AB - With progressive loss of kidney function, patients with chronic kidney disease develop multiple mineral metabolism abnormalities. Chronic kidney disease-mineral and bone disorder independently associated with cardiovascular disease and mortality. FGF23 which discovered in late years gave us new knowledge to elucidate these mechanisms. Further elucidation of FGF23-Klotho will help us to improve the understanding of pathogenesis of bone mineral metabolism abnormality. PMID- 23354083 TI - [Intercommunication between bone and central nervous system]. AB - The discovery that leptin regulates bone formation through the central nervous system shed light on a new regulatory system of bone metabolism, i.e., neuronal control. Of note, sympathetic nervous system and parasympathetic nervous system are intimately involved in bone remodeling separately and also in a coordinated manner. Moreover, orexigenic and anorexigenic peptides also regulate bone remodeling in various ways. PMID- 23354084 TI - [The relationship between bone and glucose/lipid metabolism]. AB - The fracture risks are increased in patients with lifestyle-related diseases such as diabetes mellitus and dyslipidemia. Bone has been recognized as an endocrine organ to regulate glucose and fat metabolism. Hyperglycemia, advanced glycation end products (AGEs) , and insulin signal are involved in diabetes-related bone disease. Previous studies suggest that hypercholesterolemia may increase the risk of fractures. Adipokines such as leptin and adiponectin derived from fat tissue, which are important regulators for glucose and lipid metabolism, regulate bone metabolism. On the other hand, it has been revealed that osteocalcin, which is secreted from bone tissue into the circulation, has a hormonal function in glucose and fat metabolism. PMID- 23354085 TI - [Bone metabolism and vascular calcification]. AB - Complication of osteopenia and vascular calcification are often observed among elderly, diabetes, or chronic kidney disease patients. It remains obscure whether these two conditions merely share common risk factors or they have clear cause result relationship. So called Moenckeberg type vascular calcification is classified into vascular ossification from the perspective of biomineralization mechanism. Vascular ossification has already begun before calcified deposition appears there. Thus, it is not simple to consider about its relationship with osteopenia. PMID- 23354086 TI - [Possible involvement of pituitary hormones in bone metabolism]. AB - Accumulating evidence clearly indicates both thyroid hormone and estrogen have a pivotal role in bone metabolism. Pituitary hormones, TSH and FSH, regulate circulating levels of thyroid hormone and estrogen, respectively. Recent works raise a possibility that either TSH or FSH also has its own direct effects on bone cells involved in bone resorption and formation. More recently, it is suggested that oxytocin and vasopressin are also involved in bone metabolism. However, several investigations of genetically manipulated model mice and clinical data from patients with certain diseases have provided inconsistent results. Thus, we need more data that answer the question whether or not each pituitary hormone is physiologically and pathophysiologically involved in controlling bone metabolism in human. PMID- 23354087 TI - [Parathyroid hormone : its anabolic action on bone]. AB - PTH actions on bone are exerted through multiple pathways from G-proteins coupled to a receptor PTH1R that is expressed on osteoblastic lineage cells. Physiological action of PTH may be through increased expression of RANKL, resulting in increased bone resorption and Ca( + + ) release from bone matrix by osteoclasts. Bone anabolic action of PTH by intermittent treatment is explained by ( I ) proliferation of osteogenic precursor cells, ( II ) differentiation of osteoblasts, ( III ) inhibition of apoptosis in osteoblastic cells, and ( IV ) inhibition of canonical Wnt inhibitor secretion from osteocytes. Two of these mechanisms ( II and III ) could be secondary to increased osteoclastogenesis after induction of RANKL in osteoblastic cells. Mechanisms involved in ( I ) might be controversial depending on cellular status including differentiation stages and cell density, and thus need to be clarified by further studies. PMID- 23354088 TI - [Sex steroid hormones and bone]. AB - Based on the progress of researches in bone biology field, it has been clarified that bone metabolism can be regulated by complex network between various tissues and organs. Among them, sex steroid hormones, including estrogen and androgen, are known as one of the players in bone metabolism. Sex steroid hormones play crucial roles for maintenance of bone tissue because bone mass can be decreased by deficiencies of sex steroid hormones. Also, sex steroid hormones replacement therapies, which have various adverse effects, can rescue bone loss and prevent fractures. This review introduces the direct and indirect regulatory mechanism of sex steroid hormones for bone metabolism. PMID- 23354089 TI - [Regulation of bone homeostasis by bone cells]. AB - Bone is constantly renewed by the balanced action of osteoblastic bone formation and osteoclastic bone resorption both of which mainly occur at the bone surface. This restructuring process called "bone remodeling" is important not only for normal bone mass and strength, but also for mineral homeostasis. Bone remodeling is stringently regulated by communication between bone component cells such as osteoclasts, osteoblasts and osteocytes. An imbalance of this process is often linked to various bone diseases. During bone remodeling, resorption by osteoclasts precedes bone formation by osteoblasts. Based on the osteocyte location within the bone matrix and the cellular morphology, it is proposed that osteocytes potentially contribute to the controls of bone remodeling. Thus, the elucidation of the regulatory mechanisms involved in bone remodeling is critical for a deeper understanding of the skeletal system in health and disease. PMID- 23354090 TI - [Glucocorticoid and bone metabolism and disease]. AB - Glucocorticoid (GC) is widely used to treat a variety of inflammatory and allergic diseases and about one million people in Japan are known to take oral GC. GC causes a number of significant side effects and among them osteoporosis and degenerative bone fracture are major complications of GC therapy. GC induces apoptosis of osteoblasts and osteocytes and prolongs lifespan of osteoclast, resulting in severe osteoporosis. However, few physicians are aware of the increased risk of fracture caused by GC. Recent multiple evidence strongly indicates that bisphosphonate is effective for treatment and prophylaxis of GC induced osteoporosis by improving both quantity and quality of bones, which results in reduction of the proportion of fractures. Recent findings regarding with anti-RANKL antibody and PTH (1-34) teriparatide for GC-induced osteoporosis will be also discussed. PMID- 23354091 TI - [Pulmonary diseases and bone]. AB - In the relationship between pulmonary diseases and bone, the systemic effects of pulmonary disease on bone metabolism, such as osteoporosis in COPD, have been recently investigated as well as abnormal bone metabolism induced by the therapy for lung diseases such as glucocorticoid-induced osteoporosis. However, the effective strategy for risk assessment, diagnosis and therapy of osteoporosis in lung diseases has not been established. Further studies including prospective intervention on bone metabolism in pulmonary diseases are warranted. PMID- 23354092 TI - [Gastrointestinal diseases and bone]. AB - Bone mineral density is decreased in inflammatory bowel diseases, which are intractable inflammation in the digestive tract. The causes of decreased bone mineral density are multifactorial including steroid use, insufficiency of nutritional intake, malabsorption in the gastrointestinal tract and activation of mucosal immune system. Insufficient levels of vitamins D and K are reported in patients with inflammatory bowel diseases and are also suggested to be involved in acceleration of intestinal inflammation. PMID- 23354093 TI - [Rheumatoid arthritis and bone -periarticular and systemic bone loss-]. AB - In rheumatoid arthritis (RA) , the osteoclast pathway is activated by an abnormal immune condition accompanied by chronic inflammation, resulting in periarticular osteoporosis and local bone destruction around joints. In addition, multiple factors including pharmacotherapies such as steroids, and reduced physical activity, lead to systemic osteoporosis. These conditions expose patients to increased fracture risk. In RA treatment, it is important to achieve suppression of fracture risk by controlling inflammation, which is associated with periarticular osteoporosis and bone destruction, using disease-modifying anti rheumatic drugs or biologic agents and by improving systemic osteoporosis using anti-osteoporotic agents. PMID- 23354094 TI - [Blood disease and bone]. AB - Certain types of hematological disorders show distinct bone lesions. Multiple myeloma and primary bone lymphoma develop in the bone marrow to often cause bone destruction. These tumors stimulate osteoclastogenesis and bone resorption by enhancing RANKL expression, and suppress bone formation by inhibiting osteoblast differentiation, leading to bone destruction with rapid loss of bone. Osteosclerotic lesions are manifested in POEMS syndrome and primary myelofibrosis. Hypercalcemia is often associated with aggressive types of adult T cell leukemia/lymphoma and multiple myeloma in advanced stages. PMID- 23354095 TI - [Bone health in patients with anorexia nervosa]. AB - Osteoporosis associated with anorexia nervosa (AN) is common, and tends to be severe, slow to recover from, and sometimes irreversible. The abnormal bone metabolism in severely emaciated AN patients involves both a reduction in bone formation and an increase in bone resorption. The annual change in lumbar bone mineral density (BMD) is significantly correlated with BMI at the entry. The critical BMI for a positive increase in BMD was 16.4+/-0.3 kg/m(2). Nutritional improvement with body weight gain is the most important goal of treatment for AN related osteoporosis since it increases both serum levels of insulin-like growth factor-I, a potent osteogenic factor, and estradiol, a powerful bone resorption inhibitor. However, it is difficult for AN patients to accept weight gain. About 50% of AN patients are insufficient of vitamin D and 43% show an increase in plasma undercalboxylated osteocalcin, indicating a deficiency state of the vitamin K(2). Vitamin D(3) or vitamin K(2) (menatetrenone) can prevent further bone loss in severely emaciated AN patients. Recently, bone strength has been evaluated by both BMD and bone quality. Plasma levels of homocysteine, a marker of degradation of bone quality, have significantly positive correlation with their ages of AN patients. We must evaluate bone density as well as bone quality in AN patients. PMID- 23354096 TI - Ontogeny of the adrenal gland in the spiny mouse, with particular reference to production of the steroids cortisol and dehydroepiandrosterone. AB - Synthesis of the androgen dehydroepiandrosterone (DHEA) by the fetal adrenal gland is important for placental estrogen production and may also be important for modulating the effects of glucocorticoids on the developing brain. The presence of cortisol in spiny mouse (Acomys cahirinus) blood led us to determine whether the adrenal gland of this precocial rodent also synthesized DHEA. Cytochrome P450 enzyme 17alpha-hydroxylase/17,20-lyase (P450c17), cytochrome-b5 (Cytb5), and 3beta-hydroxysteroid dehydrogenase (3betaHSD) were detected in the adrenal gland from 30 days gestation (term = 39 days), and DHEA, cortisol, and aldosterone were detected in fetal plasma from this time. Plasma DHEA concentrations increased 4-fold, whereas cortisol concentrations decreased from day 30 of gestation until the day of birth. Explant culture of fetal adrenal tissue showed that DHEA was produced from exogenous pregnenolone, and thus, the DHEA in the fetal circulation is likely to be of fetal origin. Clear zonation of the fetal adrenal cortex was evident by 38 days gestation when expression of Cytb5 was present throughout the cortex, and coexpression of P450c17 and Cytb5 occurred in the zona reticularis and fasciculata. 3betaHSD was expressed in the cortex from at least 30 days gestation and decreased as term approached, consistent with the fall of cortisol in late gestation in this species. These results show that the spiny mouse adrenal gland, like that of the human fetus, can synthesize and secrete DHEA from at least 30 days (relative gestation length, 30 days of a 39-day gestation, 0.76) of gestation, and DHEA may have important roles in placental biosynthesis of estrogens and in modulating the actions of glucocorticoids in the developing brain in this species. PMID- 23354097 TI - Phosphorylation of IGFBP-1 at discrete sites elicits variable effects on IGF-I receptor autophosphorylation. AB - We previously demonstrated that hypoxia and leucine deprivation cause hyperphosphorylation of IGF-binding protein-1 (IGFBP-1) at discrete sites that markedly enhanced IGF-I affinity and inhibited IGF-I-stimulated cell growth. In this study we investigated the functional role of these phosphorylation sites using mutagenesis. We created three IGFBP-1 mutants in which individual serine (S119/S169/S98) residues were substituted with alanine and S101A was recreated for comparison. The wild-type (WT) and mutant IGFBP-1 were expressed in Chinese hamster ovary cells and IGFBP-1 in cell media was isolated using isoelectric focusing-free-flow electrophoresis. BIACore analysis indicated that the changes in IGF-I affinity for S98A and S169A were moderate, whereas S119A greatly reduced the affinity of IGFBP-1 for IGF-I (100-fold, P < .0001). Similar results were obtained with S101A. The IGF-I affinity changes of the mutants were reflected in their ability to inhibit IGF-I-induced receptor autophosphorylation. Employing receptor-stimulation assay using IGF-IR-overexpressing P6 cells, we found that WT IGFBP-1 inhibited IGF-IRbeta autophosphorylation (~2-fold, P < .001), possibly attributable to sequestration of IGF-I. Relative to WT, S98A and S169A mutants did not inhibit receptor autophosphorylation. S119A, on the other hand, greatly stimulated the receptor (2.3-fold, P < .05). The data with S101A matched S119A. In summary, we show that phosphorylation at S98 and S169 resulted in milder changes in IGF-I action; nonetheless most dramatic inhibitory effects on the biological activity of IGF-I were due to IGFBP-1 phosphorylation at S119. Our results provide novel demonstration that IGFBP-1 phosphorylation at S119 can enhance affinity for IGF-I possibly through stabilization of the IGF-IGFBP-1 complex. These data also propose that the synergistic interaction of distinct phosphorylation sites may be important in eliciting more pronounced effects on IGF-I affinity that needs further investigation. PMID- 23354098 TI - Pulmonary GLP-1 receptor increases at birth and exogenous GLP-1 receptor agonists augmented surfactant-protein levels in litters from normal and nitrofen-treated pregnant rats. AB - The glucagon-like peptide-1 receptor (GLP-1R) is found in a variety of tissues outside of the pancreas. For example, GLP-1R is expressed in the lung, where it has been implicated in the regulation of the lipid fraction of surfactants, suggesting it fulfills an important role in lung function. Here, we show that GLP 1R expression is strongly up-regulated immediately after birth in neonatal rats, particular in male offspring. Moreover, administering long half-life GLP-1R agonists to the mother from gestational day 14 to birth (exendin-4 or liraglutide) increased surfactant protein (SP)-A and SP-B mRNA expression and the amount of SPs in the amniotic fluid at the end of pregnancy. These effects were similar or more potent to those induced by the glucocorticoid dexamethasone, which also increased GLP-1R expression in fetuses just before delivery. Lir increased fetal SP-A and GLP-1R expression in control rats and in a nitrofen induced model of lung hypoplasia. Moreover, lung size increased in controls after Lir administration, which also prevented the decrease in lung weight and the poor neonatal survival of the offspring from nitrofen-treated dams, effects that were not produced by dexamethasone. Taken together, our results demonstrate the importance of the GLP-1 system in regulating SP production and lung development. PMID- 23354100 TI - Consensus document on the radial approach in percutaneous cardiovascular interventions: position paper by the European Association of Percutaneous Cardiovascular Interventions and Working Groups on Acute Cardiac Care** and Thrombosis of the European Society of Cardiology. AB - Radial access use has been growing steadily but, despite encouraging results, still varies greatly among operators, hospitals, countries and continents. Twenty years from its introduction, it was felt that the time had come to develop a common evidence-based view on the technical, clinical and organisational implications of using the radial approach for coronary angiography and interventions. The European Association of Percutaneous Cardiovascular Interventions (EAPCI) has, therefore, appointed a core group of European and non European experts, including pioneers of radial angioplasty and operators with different practices in vascular access supported by experts nominated by the Working Groups on Acute Cardiac Care and Thrombosis of the European Society of Cardiology (ESC). Their goal was to define the role of the radial approach in modern interventional practice and give advice on technique, training needs, and optimal clinical indications. PMID- 23354099 TI - Hormonal contraception and HIV-1 infection: medroxyprogesterone acetate suppresses innate and adaptive immune mechanisms. AB - Recent observational studies indicate an association between the use of hormonal contraceptives and acquisition and transmission of HIV-1. The biological and immunological mechanisms underlying the observed association are unknown. Depot medroxyprogesterone acetate (DMPA) is a progestin-only injectable contraceptive that is commonly used in regions with high HIV-1 prevalence. Here we show that medroxyprogesterone acetate (MPA) suppresses the production of key regulators of cellular and humoral immunity involved in orchestrating the immune response to invading pathogens. MPA inhibited the production of interferon (IFN)-gamma, IL-2, IL-4, IL-6, IL-12, TNFalpha, macrophage inflammatory protein-1alpha (MIP-1alpha), and other cytokines and chemokines by peripheral blood cells and activated T cells and reduced the production of IFNalpha and TNFalpha by plasmacytoid dendritic cells in response to Toll-like receptor-7, -8, and -9 ligands. Women using DMPA displayed lower levels of IFNalpha in plasma and genital secretions compared with controls with no hormonal contraception. In addition, MPA prevented the down-regulation of HIV-1 coreceptors CXCR4 and CCR5 on the surface of T cells after activation and increased HIV-1 replication in activated peripheral blood mononuclear cell cultures. The presented results suggest that MPA suppresses both innate and adaptive arms of the immune system resulting in a reduction of host resistance to invading pathogens. PMID- 23354101 TI - Evaluation of methods for modeling transcription factor sequence specificity. AB - Genomic analyses often involve scanning for potential transcription factor (TF) binding sites using models of the sequence specificity of DNA binding proteins. Many approaches have been developed to model and learn a protein's DNA-binding specificity, but these methods have not been systematically compared. Here we applied 26 such approaches to in vitro protein binding microarray data for 66 mouse TFs belonging to various families. For nine TFs, we also scored the resulting motif models on in vivo data, and found that the best in vitro-derived motifs performed similarly to motifs derived from the in vivo data. Our results indicate that simple models based on mononucleotide position weight matrices trained by the best methods perform similarly to more complex models for most TFs examined, but fall short in specific cases (<10% of the TFs examined here). In addition, the best-performing motifs typically have relatively low information content, consistent with widespread degeneracy in eukaryotic TF sequence preferences. PMID- 23354102 TI - Single-base resolution methylomes of tomato fruit development reveal epigenome modifications associated with ripening. AB - Ripening of tomato fruits is triggered by the plant hormone ethylene, but its effect is restricted by an unknown developmental cue to mature fruits containing viable seeds. To determine whether this cue involves epigenetic remodeling, we expose tomatoes to the methyltransferase inhibitor 5-azacytidine and find that they ripen prematurely. We performed whole-genome bisulfite sequencing on fruit in four stages of development, from immature to ripe. We identified 52,095 differentially methylated regions (representing 1% of the genome) in the 90% of the genome covered by our analysis. Furthermore, binding sites for RIN, one of the main ripening transcription factors, are frequently localized in the demethylated regions of the promoters of numerous ripening genes, and binding occurs in concert with demethylation. Our data show that the epigenome is not static during development and may have been selected to ensure the fidelity of developmental processes such as ripening. Crop-improvement strategies could benefit by taking into account not only DNA sequence variation among plant lines, but also the information encoded in the epigenome. PMID- 23354103 TI - Draft genome sequence of chickpea (Cicer arietinum) provides a resource for trait improvement. AB - Chickpea (Cicer arietinum) is the second most widely grown legume crop after soybean, accounting for a substantial proportion of human dietary nitrogen intake and playing a crucial role in food security in developing countries. We report the ~738-Mb draft whole genome shotgun sequence of CDC Frontier, a kabuli chickpea variety, which contains an estimated 28,269 genes. Resequencing and analysis of 90 cultivated and wild genotypes from ten countries identifies targets of both breeding-associated genetic sweeps and breeding-associated balancing selection. Candidate genes for disease resistance and agronomic traits are highlighted, including traits that distinguish the two main market classes of cultivated chickpea--desi and kabuli. These data comprise a resource for chickpea improvement through molecular breeding and provide insights into both genome diversity and domestication. PMID- 23354104 TI - The AOSpine North America Geriatric Odontoid Fracture Mortality Study: a retrospective review of mortality outcomes for operative versus nonoperative treatment of 322 patients with long-term follow-up. AB - STUDY DESIGN: Retrospective, multicenter cohort study. OBJECTIVE: Assess for differences in short- and long-term mortality between operative and nonoperative treatment for elderly patients with type II odontoid fractures. SUMMARY OF BACKGROUND DATA: There is controversy regarding whether operative or nonoperative management is the best treatment for elderly patients with type II odontoid fractures. METHODS: This is a retrospective study of consecutive patients aged 65 years or older with type II odontoid fracture from 3 level I trauma centers from 2003-2009. Demographics, comorbidities, and treatment were abstracted from medical records. Mortality outcomes were obtained from medical records and a public database. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated. RESULTS: A total of 322 patients were included (mean age, 81.8 yr; range, 65.0-101.5 yr). Compared with patients treated nonoperatively (n = 157), patients treated operatively (n = 165) were slightly younger (80.4 vs. 83.2 yr, P = 0.0014), had a longer hospital (15.0 vs. 7.4 d, P < 0.001) and intensive care unit (1.5 vs. 1.1 d, P = 0.008) stay, and were more likely to receive a feeding tube (18% vs. 5%, P = 0.0003). Operative and nonoperative treatment groups had similar sex distribution (P = 0.94) and Charlson comorbidity index (P = 0.11). Within 30 days of presentation, 14% of patients died, and at maximal follow-up (average = 2.05 yr; range = 0 d-7.02 yr), 44% had died. On multivariate analysis, nonoperative treatment was associated with higher 30-day mortality (HR = 3.00, 95% CI = 1.51-5.94, P = 0.0017), after adjusting for age (HR = 1.10, 95% CI = 1.05-1.14; P < 0.0001), male sex (P = 0.69), and Charlson comorbidity index (P = 0.16). At maximal follow-up, there was a trend toward higher mortality associated with nonoperative treatment (HR = 1.35, 95% CI = 0.97-1.89, P = 0.079), after adjusting for age (HR = 1.07, 95% CI = 1.05-1.10; P < 0.0001), male sex (HR = 1.55, 95% CI = 1.10-2.16; P = 0.012), and Charlson comorbidity index (HR = 1.28, 95% CI = 1.16-1.40; P < 0.0001). CONCLUSION: Surgical treatment of type II odontoid fracture in this elderly population did not negatively impact survival, even after adjusting for age, sex, and comorbidities. The data suggest a significant 30-day survival advantage and a trend toward improved longer-term survival for operatively treated over nonoperatively treated patients. LEVEL OF EVIDENCE: 4. PMID- 23354105 TI - What is the incidence of dysphagia after posterior cervical surgery? AB - STUDY DESIGN: Prospective comparative study. OBJECTIVE: To determine whether dysphagia is a unique complication of anterior neck dissection or whether it occurs after any cervical surgery. SUMMARY OF BACKGROUND DATA: Dysphagia is a common complication after anterior cervical discectomy and fusion. However, current literature is scarce whether dysphagia occurs as a direct result of the anterior approach (dissection or instrumentation) or because of cervical spine surgery itself. METHODS: Patients undergoing posterior cervical surgery were prospectively evaluated for dysphagia up to 6 months after surgery. Patients were evaluated for dysphagia preoperatively, at 2 weeks and 6 weeks postoperatively using the dysphagia numeric rating scale. The data was compared with a previously published cohort of anterior cervical and lumbar surgical procedures from the same institution. Statistical significance was evaluated using the Fisher exact test. RESULTS: Eighty-five patients were included who underwent posterior cervical surgery. Baseline dysphagia was present in 11% (10/85) of patients. The incidence of new dysphagia was 10 of 85 (11%) at 2 weeks, 8 of 85 (8%) at 6 weeks, 13 of 85 (13%) at 12 weeks, and 5 of 85 (6%) at 24 weeks. The incidence of new dysphagia was significantly less than that of anterior cervical surgery at 2 weeks (posterior [P] 11% vs. anterior [A] 61.5%, P = 0.0001), 6 weeks (P 8% vs. A 44%, P = 0.0001), but not 12 weeks (P 13% vs. A 11%, P = 1). The incidence of dysphagia after posterior cervical surgery was significantly increased compared with that of lumbar surgery at 2 weeks (P 11% vs. lumbar surgery [L] 9%, P = 0.78), 6 weeks (P 8% vs. L 0%, P = 0.02), and 12 weeks (P 13% vs. L 0%, P = 0.007). At 12 weeks postoperatively, there was a statistically significant increase in postoperative neck pain (P = 0.008), tightness (P = 0.032), and peripheral pain/numbness (P = 0.032) in patients with dysphagia. CONCLUSION: Both anterior and posterior cervical surgery may result in long-term dysphagia in a small number of patients, perhaps due to loss of motion or postoperative pain. Surgeons should counsel their patients about possibility for dysphagia prior to all cervical spine surgery. PMID- 23354106 TI - Disparities in the outcomes of lumbar spinal stenosis surgery based on insurance status. AB - STUDY DESIGN: Retrospective cohort study using Thomson Reuter's MarketScan database. OBJECTIVE: To evaluate the extent to which Medicaid versus commercial insurance status affects outcomes after lumbar stenosis surgery. SUMMARY OF BACKGROUND DATA: The Affordable Care Act aims to expand health insurance and to help narrow existing health care disparities. Medicaid patients have previously been noted to be at an increased risk for impaired access to health care. Conversely, those with commercial insurance may be subject to overtreatment. We examine the surgical treatment of low back pain as an example that has raised significant public health concerns. METHODS: A total of 28,462 patients, ages 18 and older, were identified who had undergone laminectomy or fusion for spinal stenosis between 2000 and 2009. Patients were characterized by baseline demographic information, comorbidity burden, and type of insurance (Medicaid vs. commercial insurance). Multivariate analysis was performed comparing the relative effect of insurance status on reoperation rates, timing and type of reoperations, postoperative complications, and total postoperative health resource use. RESULTS: Medicaid patients had similar reoperation rates to commercially insured patients at 1 year (4.60% vs. 5.42%, P = .38); but had significantly lower reoperation rates at 2 (7.22% vs. 10.30%; adjusted odds ratio [aOR] = 0.661; 95% confidence interval [CI], 0.533-0.820; P = .0002) and more than 2 years (13.92% vs. 16.89%; aOR = 0.722; 95% CI, 0.612-0.851; P <.0001). Medicaid patients were particularly less likely to undergo fusion as a reoperation (aOR = 0.478; 95% CI, 0.377-0.606; P < 0001). Medicaid patients had greater health care resource utilization as measured by hospital days, outpatient services and medications prescribed; however, commercially insured patients had significantly higher overall health utilization costs at 1 and 2 years. CONCLUSION: There are insurance disparities that affect important surgical outcomes after initial surgery for spinal stenosis. Efforts for national health care reform should include explicit efforts to identify such system factors that will reduce current inequities in care. LEVEL OF EVIDENCE: 2. PMID- 23354107 TI - Role of environmental factors and history of low back pain in sciatica symptoms among Finnish adolescents. AB - STUDY DESIGN: Cross-sectional study in a subcohort of the 1986 Northern Finland Birth Cohort (n = 1987). OBJECTIVE: To investigate the role of environmental factors and LBP history in sciatica symptoms among Finnish young adults. SUMMARY OF BACKGROUND DATA: History of low back pain (LBP), smoking, and male sex are associated with sciatica in adult populations. The role of the environmental determinants of sciatica has not been evaluated in populations consisting of only adolescents. METHODS: Sciatic symptoms and environmental exposures were elicited by a mailed questionnaire and the associations were analyzed using multinomial logistic regression. RESULTS: Female sex was associated with severe sciatica at 18 years (OR, 3.9; 95% confidence interval (CI), 1.6-9.3). Both reported LBP at 16 years and LBP requiring consultation of a health care professional were associated with mild sciatica at 18 years (OR, 2.5; 95% CI, 1.3-4.9; and OR, 3.8; 95% CI, 1.2-11.9). In addition, LBP at 16 years requiring consultation of a health care professional was associated with severe sciatica at 18 years (OR, 5.0; 95% CI, 1.7-15.3). Smoking, obesity, physical workload, and level of physical activity were not associated with sciatica. CONCLUSION: Females reported sciatic pain more often than males. LBP at 16 years predicted sciatica at 18 years. LEVEL OF EVIDENCE: 2. PMID- 23354108 TI - Association between genetic determinants of peak height velocity during puberty and predisposition to adolescent idiopathic scoliosis. AB - STUDY DESIGN: An association study to comprehensively clarify variations of genetic determinants of peak height velocity (PHV) during puberty in adolescent idiopathic scoliosis (AIS). OBJECTIVE: To investigate whether the genetic determinants of timing and magnitude of PHV during puberty are associated with the susceptibility or curve progression of the female patients with AIS. SUMMARY OF BACKGROUND DATA: An involvement of abnormal pubertal growth pattern in the etiopathogenesis of AIS has been implicated in previous studies. However, there is no clear consensus on the anthropometric variations of stature or growth rate. The recent advance in the longitudinally identified genetic determinants of PHV offers new opportunities to facilitate analysis of the association of pubertal growth with the susceptibility or curve severity of AIS. METHODS: A gene-based association study was conducted using 9 single nucleotide polymorphisms (SNPs) in or near SOCS2, SF3B4/SV2A, C17orf67, CABLES1, DOT1L, CDK6, C6orf106, and LIN28B with confirmed association with PHV, peak growth age, or adult height. A total of 500 patients with AIS and 494 age-matched healthy controls were genotyped using the PCR-based Invader assay. Case-control study and case-only study were performed to define the contribution of the 9 SNPs to predisposition and curve severity of AIS. RESULTS: Strong associations between rs12459350 in DOT1L, rs4794665 in C17orf67, and susceptibility of AIS were found, with the PHV increasing allele G of rs12459350 and PHV/adult height increasing allele A of rs4794665 both being significant predisposition alleles of AIS (P = 0.001 for rs12459350, odds ratio = 1.16, 95% confidence interval = 1.06-1.27; P = 0.006 for rs4794665, odd ratio = 1.33, 95% confidence interval = 1.09-1.62). None of the genotyped SNPs was associated with curve severity in patients with AIS. CONCLUSION: Polymorphisms of the rs4794665 in C17orf67 and rs12459350 in DOT1L were associated with combined predisposition to AIS susceptibility and higher pubertal PHV, which strongly mirrored the anthropometric findings of taller pubertal stature and accelerated growth rate described in AIS. PMID- 23354109 TI - Spinal cavernous and capillary hemangiomas in adults. AB - STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: To evaluate the neurological outcomes after resection of intramedullary, intradural extramedullary, and extradural hemangiomas. SUMMARY OF BACKGROUND DATA: Spinal hemangiomas most commonly arise in the vertebral bodies and are typically asymptomatic. Uncommonly, hemangiomas may cause significant neurological deficits via extraosseous extension. Intramedullary hemangiomas may also occur and account for approximately 5% of all spinal cord lesions, with those located intradural extramedullary occurring rarely. Although retrospective studies have primarily examined the neurological outcome of intramedullary and vertebral hemangiomas, there is little literature comparing outcomes after surgical treatment of hemangiomas of varying location. METHODS: We performed a retrospective review of all patients treated for hemangiomas affecting the spinal cord at our institution between 1999 and 2012. Various patient, clinical, and tumor data were collected including patient demographics, neurological examinations, and procedure, clinic, and pathology notes. Imaging studies were evaluated to determine the extent of resection, presence of recurrence, and lesion volume. Functional status was defined using the Modified McCormick Scale (MMS). RESULTS: A total of 19 patients were evaluated, with our cohort consisting of 8 intramedullary, 5 intradural extramedullary, and 6 vertebral hemangiomas with extraosseous extension. Cavernous hemangiomas were most common (47.4%), followed by those of the capillary type. At long-term follow-up, 73.7% of patients had improved neurological outcome and 15.8% had worsened. However, only 50% of patients with intramedullary hemangiomas improved, compared with 80% and 100% for intradural extramedullary and vertebral hemangiomas, respectively. Also, those with intramedullary lesions more frequently had worse outcomes after surgery (25%) than those with intradural extramedullary (20%) and vertebral hemangiomas (0%). CONCLUSION: Although all patients typically present with a similar functional status, patients with intramedullary lesions are more unlikely to improve after surgical resection and derive less of a benefit compared with those with intradural extramedullary and vertebral hemangiomas. PMID- 23354110 TI - A novel method of cervical pedicle screw placement from C3 to C5 and its clinical applications. AB - STUDY DESIGN: Applied anatomical study and clinical application. OBJECTIVE: To design and optimize the method of cervical pedicle screw placement for cervical vertebrae C3-C5, and to test it in clinical applications. SUMMARY OF BACKGROUND DATA: Most of the anatomical studies on cervical pedicle screw placement previously published focused on the lower cervical vertebrae. Clinically, it is much more difficult to place C3, C4, and C5 screws than C6 and C7 screws; therefore, anatomical measurements of C3-C5 pedicles and design of an appropriate screw placement method are required. METHODS: A total of 20 cervical vertebrae specimens were prepared, and bilateral pedicle screws were manually inserted for C3-C5. The intersection of the horizontal line through the midpoint of the transverse process root and the vertical line through the mediolateral third of the superior articular process was used as the entry point. The screws were inserted along the axis of the pedicle, with the axis of the screw coinciding with that of the pedicle. The specimens were truncated along the horizontal or sagittal plane of the pedicle, and a variety of measurements were made to determine appropriate screw type and placement. Finally, this screw fixation technique was applied in clinical situations with the placement of 26 C3 screws, 26 C4 screws, and 38 C5 screws. RESULTS: Pedicular height was larger than pedicular width for the same segment of C3-C5, and pedicular width of the different segments did not significantly vary. The lengths of the screw channels for C3-C5 screw placement were similar. The transverse angles of C3-C5 segments displayed a decreasing trend, whereas the vertical angles did not. In all clinical cases, all screws were properly within the pedicles examined using postoperative computed tomography scan. Only 1 C3 screw penetrated the medial cortex and slightly entered the spinal canal, but no clinical symptoms occurred. CONCLUSION: The intersection of the horizontal line through the midpoint of the transverse process root and the vertical line through the mediolateral third of the superior articular process represents a superior frame of reference for the entry point for C3-C5 pedicle screw fixation. Clinically, we recommend the transverse angles to be 90 degrees for C3 and 80 degrees for C4 and C5, and the vertical angles to be 70 degrees for C3-C5. We found that screws with a diameter of 3.5 mm and length of 20 mm or 22 mm to be safe, objective, and reliable. PMID- 23354111 TI - Transforaminal lumbar interbody fusion with rhBMP-2 in spinal deformity, spondylolisthesis, and degenerative disease--part 2: BMP dosage-related complications and long-term outcomes in 509 patients. AB - STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: Without industry funding, the study evaluated short- and long-term complications related to off-label bone morphogenetic protein (BMP) used with transforaminal lumbar interbody fusion (TLIF) from a large consecutive series. Complications and results were analyzed by BMP dose, fusion length, and primary versus revision surgery. Based on the results, surgical technique and BMP dose recommendations were proposed. SUMMARY OF BACKGROUND DATA: Off-label use of BMP in TLIF, although common, has only been studied in small series and case reports using various techniques, cage types, and doses of BMP. Several of these studies have reported minimal complications. Others report problems related to BMP, which has led to questions regarding current widespread use of TLIF with BMP. METHOD: TLIF with rhBMP-2 was performed at 872 discs in 509 consecutive adults who underwent open posterior instrumented fusion and had minimum 2-year follow-up; diagnoses included degenerative disease (179), spondylolisthesis (207), deformity (123). Patient age averaged 61 years: 12% were smokers and 41% had revision surgery. TLIF was performed at 1.7 levels: single level: 229, 2 levels: 201, 3 levels: 74, 4 levels: 5. Local autograft was used for backfill around and behind each rectangular cage. Varying doses of interbody BMP were used at an average 7.3 mg per disc (range: 2-12 mg per disc). RESULTS: At 5 years average follow-up, 8 patients developed pseudoarthrosis at levels of TLIF (8 of 872 discs, 0.92%). Seroma (0.4%) and ectopic bone growth (0.6%) were too infrequent to be associated with a particular BMP dose. Deep infection was 2.6% overall (1.7% of the degenerative group). Symptomatic osteolysis or cage subsidence did not occur. Significant long-term improvement was noted in clinical and functional outcomes compared with preoperation. CONCLUSION: Five-year follow-up after TLIF with BMP, independent of industry, confirms effective arthrodesis in short and long fusions, both primary and revision. Most complications occurred in deformity patients. BMP-related complications (seroma, ectopic bone) were rare. LEVEL OF EVIDENCE: 3. PMID- 23354112 TI - The effect of age on cervical sagittal alignment: normative data on 100 asymptomatic subjects. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To determine age-related changes in cervical sagittal alignment using whole-spine standing radiographs in asymptomatic adults. SUMMARY OF BACKGROUND DATA: Modern surgical techniques have emphasized the importance of maintaining proper sagittal alignment. But there is a paucity of literature investigating age-related changes in cervical sagittal alignment. METHODS: One hundred healthy unoperated adults who were free of spinal problems obtained whole-spine standing radiographs. They consisted of 2 groups divided by age: those in their 20s and those older than 60 years. Each group had an equal ratio of males and females. Distances from C2 as well as C7 plumb lines to the following points were measured: thoracic and lumbar apex as well as the posterior superior corner of the S1 vertebral body. In addition, Cobb angles for C0-C2, C2-C7, thoracic kyphotic angle, lumbar lordotic angle, and T1 sagittal slope angles were measured. RESULTS: The distance between the C2 and C7 plumb lines did not vary with age. The thoracic apex shifted caudally from T6 in the younger group to T7 in the older group. The most common lumbar apex was L4 for both groups. The distance from C2, as well as C7 plumb lines to the posterior superior corner of the S1 vertebral body, as well as the thoracic apex increased significantly in the older group. On the contrary, the distance from the 2 plumb lines to the lumbar apex decreased in the older group. Also, C2-C7 angle increased and T1 sagittal slope angle decreased in the older group compared with the younger group. However, no difference was found for the other Cobb angles between the 2 groups. CONCLUSION: The distances between the plumb lines from C2 and C7 were maintained but C2-C7 sagittal angle increased with aging. PMID- 23354113 TI - Responding to neuromonitoring changes in 3-column posterior spinal osteotomies for rigid pediatric spinal deformities. AB - STUDY DESIGN: Retrospective review of prospectively collected data on the neuromonitoring changes recorded during a consecutive series of cord level 3 column posterior spinal osteotomies for the correction of rigid pediatric spinal deformities in children between 2005 and 2012. OBJECTIVE: To review the neuromonitoring changes observed during the performance of these procedures, to highlight the high-risk steps, and to describe actions taken to avert major neurological injury. SUMMARY OF BACKGROUND DATA: Significant motor evoked potentials (MEP) changes are common during the performance of spinal osteotomies in children. The real-time intraoperative information provided by MEPs can provide the necessary information to direct key surgical decisions. METHODS: The neuromonitoring changes occurring during the performance of 37 3-column, cord level, posterior spinal osteotomies in 28 patients were recorded. The procedures were divided, for comparative purposes, into 2 groups based on the presence or absence of alerts. A decrease in somatosensory evoked potentials and transcranial MEPs greater than 50% of baseline was considered an alert. Alerts were classified chronologically as type I: prior to decompression, type II: occurring during decompression and bone resection, type III: occurring after osteotomy closure. RESULTS: Somatosensory evoked potential alerts occurred in 3 patients, all of whom had significant MEP alerts. There were 2 type I, 15 type II, and 6 type III MEP alerts. Increasing blood pressure improved MEPs in all with the exception of 8 type II and 4 type III. The unresponsive 8 type II alerts were treated with osteotomy closure with the expectation that spinal shortening would decompress the spinal cord and improve spinal cord perfusion. The unresponsive 4 type III alerts all responded to reopening, manipulation, and subsequent reclosure of the osteotomy either with a cage or less correction. There were 5 immediate postoperative motor deficits. No patient had a permanent deficit. CONCLUSION: Changes unresponsive to increasing blood pressure occurring during decompression and bone resection (type II) responded well to osteotomy closure. Unresponsive changes during osteotomy closure (type III) were treated successfully with opening the osteotomy, cage adjustment, and less correction. PMID- 23354114 TI - Total atlanto-odontoid joint arthroplasty system: a novel motion preservation device for atlantoaxial instability after odontoidectomy. AB - STUDY DESIGN: An in vitro biomechanical study. OBJECTIVE: To determine the initial stability and function of a novel total atlanto-odontoid joint arthroplasty system (TAAS) in human cadaveric cervical spine models by comparing it with a conventional method. SUMMARY OF BACKGROUND DATA: Resection of the odontoid and anterior arch of the atlas results in atlantoaxial instability, which if left uncorrected may lead to severe neurological complications. Currently, such atlantoaxial instability is corrected by anterior and/or posterior atlantoaxial fusion. However, this results in considerable motion loss of the atlantoaxial complex. METHODS: Flexibility tests were conducted on 24 human cadaveric craniocervical specimens in the following sequence: (1) intact, (2) after dissection of the atlantoaxial ligaments and odontoidectomy, (3) after the TAAS implantation, and (4) after Harms rigid fixation. Rotational angles of the C1-C2 segment were measured to study the immediate stability and function of the TAAS implantation compared with the intact and Harms rigid fixation. RESULTS: Comparing the TAAS implantation to the intact state, the range of motion and neutral zone changed little in flexion, extension, and lateral bending but increased significantly in axial rotation (P < 0.001). Compared with Harms rigid fixation, the TAAS implantation significantly increased range of motion and neutral zone in all directions (P < 0.001). CONCLUSION: We have designed the TAAS for correcting atlantoaxial instability arising from C1-C2 anterior decompression procedures. The unique aspect of the TAAS is that it restores, to a great extent, the C1-C2 motion that is lost during current stabilization procedures. PMID- 23354115 TI - Comparison of teriparatide and bisphosphonate treatment to reduce pedicle screw loosening after lumbar spinal fusion surgery in postmenopausal women with osteoporosis from a bone quality perspective. AB - STUDY DESIGN: Prospective study. OBJECTIVE: To examine the efficacy of teriparatide or bisphosphonate treatment to reduce pedicle screw (PS) loosening after instrumented lumbar posterolateral fusion in postmenopausal women with osteoporosis. SUMMARY OF BACKGROUND DATA: Failure of fixation caused by loosening of PSs in osteoporosis is a problem in spinal surgery. Oral administration of bisphosphonate or intermittent injection of parathyroid hormone treatment increases bone mass and reduces the risk of osteoporotic vertebral fractures. Although these treatments may be factor in improving bone quality, a clinical study of the efficacy of bisphosphonate or parathyroid hormone for reducing PS loosening that addresses the quality of the bone marrow and pedicle cortex has not yet been reported. METHODS: Sixty-two women with osteoporosis diagnosed with degenerative spondylolisthesis were divided into 3 groups: a teriparatide group (daily subcutaneous injection of 20 MUg of teriparatide, n = 20), a bisphosphonate group (daily oral administration 2.5 mg of risedronate, n = 20), and a control group (without medication for osteoporosis, n = 22). All patients underwent decompression and 1- or 2-level instrumented posterolateral fusion with a local bone graft. Loosening of PSs and surgical outcome were evaluated radiographically, clinically, and by computed tomography 12 months after surgery. RESULTS: At 12-month follow-up, the incidence of PS loosening was 7% to 13% in the teriparatide group, 13% to 26% in the risedronate group, and 15% to 25% in the control group. The incidence of PS loosening in the teriparatide group was significantly lower than that in the risedronate or the control group (P < 0.05). In contrast, the extent of PS loosening in the risedronate group was not significantly different from that in the control group (P > 0.05). CONCLUSION: Our findings suggest that administration of teriparatide increased the quality of the lumbar spine bone marrow and pedicle cortex. PMID- 23354116 TI - Chaotropic agents in liquid chromatographic method development for the simultaneous analysis of levodopa, carbidopa, entacapone and their impurities. AB - The simultaneous pharmaceutical analysis of multi-component drugs represents a challenge due to a large total number of analytes present in the sample. These analytes are not only the active pharmaceutical ingredients, but also the impurities that might follow the active substances. The aim of this study was to develop an efficient reversed-phase LC method for the simultaneous analysis of antiparkinsonian drugs levodopa, carbidopa and entacapone along with their six related impurities. For the achievement of desirable separation, different acids with anions possessing different properties according to Hofmeister classification (ortho-phosphoric, trifluoroacetic and perchloric acid) were tested. Finally, in order to draw the unbiased conclusions when optimizing the analytical method, for the final tuning of the gradient program, Box-Behnken experimental design and Derringer's desirability function were used. The experiments were performed on Zorbax Extend C18, 150 mm * 4.6 mm, 5 MUm particle size column with the UV detection at 280 nm and mobile phase flow rate of 1 mL/min. The optimal mobile phase consisted of methanol and 20mM trifluoroacetic acid (pH 2.0 adjusted with NaOH), while their ratio is changed according to previously defined gradient program. The method was tested for selectivity, sensitivity, linearity, accuracy and precision, and proved to be suitable for routine qualitative and quantitative analysis of levodopa, carbidopa, entacapone and their impurities in their mixture. PMID- 23354117 TI - Osteochondral lesions of the talus: are there any differences between osteochondral and chondral types? AB - BACKGROUND: Among the types of osteochondral lesions of the talus (OLTs), the osteochondral and chondral types make up the majority of OLTs. There is a possibility that between these two types of lesions, the clinical outcomes and characteristics may differ. PURPOSE: This study was designed to compare the clinical outcomes, demographics, and characteristics of osteochondral- and chondral-type lesions of OLTs. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The authors retrospectively analyzed 298 ankles that underwent arthroscopic marrow-stimulating procedures for OLTs between 2001 and 2009 that had been arthroscopically determined as either chondral type (210 ankles) or osteochondral type (88 ankles). Clinical outcomes, demographics, and characteristics of the lesions were compared. RESULTS: The age distribution showed that the chondral type reached its peak in patients in their 50s, whereas the osteochondral type had a peak distribution for those in their 20s. The average duration of symptoms was greater in the chondral type (28.3 months; range, 7-240 months) than in the osteochondral type (14.4 months; range, 8-120 months) (P < .001). With regard to the characteristics of the lesions, differences only existed in the combined intra-articular lesions between the two types. Subchondral cysts (odds ratio [OR], 3.71; 95% CI, 1.61-8.55; P = .001) and soft tissue impingement (OR, 1.82; 95% CI, 1.10-3.03; P = .021) were more frequently present in the chondral type. The American Orthopaedic Foot and Ankle Society (AOFAS) and visual analog scale (VAS) for pain showed significant improvement from preoperative to postoperative scores in both groups. However, the preoperative and postoperative VAS and AOFAS scores did not differ significantly between the groups. CONCLUSION: Differences were found with age distribution, duration of symptoms, and combined intra-articular lesions between the osteochondral- and chondral-type lesions of OLTs. We achieved similar successful clinical outcomes in both types of lesions using arthroscopic marrow stimulating procedures, such as microfracture or abrasion arthroplasty. PMID- 23354119 TI - Rab GTPases are required for early orientation of the left-right axis in Xenopus. AB - The earliest steps of left-right (LR) patterning in Xenopus embryos are driven by biased intracellular transport that ensures a consistently asymmetric localization of maternal ion channels and pumps in the first 2-4 blastomeres. The subsequent differential net efflux of ions by these transporters generates a bioelectrical asymmetry; this LR voltage gradient redistributes small signaling molecules along the LR axis that later regulate transcription of the normally left-sided Nodal. This system thus amplifies single cell chirality into a true left-right asymmetry across multi-cellular fields. Studies using molecular genetic gain- and loss-of-function reagents have characterized many of the steps involved in this early pathway in Xenopus. Yet one key question remains: how is the chiral cytoskeletal architecture interpreted to localize ion transporters to the left or right side? Because Rab GTPases regulate nearly all aspects of membrane trafficking, we hypothesized that one or more Rab proteins were responsible for the directed, asymmetric shuttling of maternal ion channel or pump proteins. After performing a screen using dominant negative and wildtype (overexpressing) mRNAs for four different Rabs, we found that alterations in Rab11 expression randomize both asymmetric gene expression and organ situs. We also demonstrated that the asymmetric localization of two ion transporter subunits requires Rab11 function, and that Rab11 is closely associated with at least one of these subunits. Yet, importantly, we found that endogenous Rab11 mRNA and protein are expressed symmetrically in the early embryo. We conclude that Rab11-mediated transport is responsible for the movement of cargo within early blastomeres, and that Rab11 expression is required throughout the early embryo for proper LR patterning. PMID- 23354120 TI - Detection of suppressed maturation of the human COQ5 protein in the mitochondria following mitochondrial uncoupling by an antibody recognizing both precursor and mature forms of COQ5. AB - Yeast Coq5p is required for the biosynthesis of coenzyme Q6 (CoQ6), but its human homolog has not been studied. We purified soluble recombinant human COQ5 protein under native conditions and generated an antibody recognizing both precursor and mature forms of COQ5. Mitochondrial localization of the mature form in 143B cells was demonstrated with this antibody. Moreover, a chemical uncoupler in a dose that suppressed CoQ10 levels downregulated the mature form but augmented the precursor form of COQ5. The results that knockdown of the COQ5 gene reduced CoQ10 levels further indicated the critical role of COQ5 in the biosynthesis of CoQ10. PMID- 23354118 TI - Endothelial deletion of ADAM17 in mice results in defective remodeling of the semilunar valves and cardiac dysfunction in adults. AB - Global inactivation of the metalloproteinase ADAM17 during mouse development results in perinatal lethality and abnormalities of the heart, including late embryonic cardiomegaly and thickened semilunar and atrioventricular valves. These defects have been attributed in part to a lack of ADAM17-mediated processing of HB-EGF, as absence of soluble HB-EGF results in similar phenotypes. Because valvular mesenchymal cells are largely derived from cardiac endothelial cells, we generated mice with a floxed Adam17 allele and crossed these animals with Tie2 Cre transgenics to focus on the role of endothelial ADAM17 in valvulogenesis. We find that although hearts from late-stage embryos with ablation of endothelial ADAM17 appear normal, an increase in valve size and cell number is evident, but only in the semilunar cusps. Unlike Hbegf(-/-) valves, ADAM17-null semilunar valves do not differ from controls in acute cell proliferation at embryonic day 14.5 (E14.5), suggesting compensatory processing of HB-EGF. However, levels of the proteoglycan versican are significantly reduced in mutant hearts early in valve remodeling (E12.5). After birth, aortic valve cusps from mutants are not only hyperplastic but also show expansion of the glycosaminoglycan-rich component, with the majority of adults exhibiting aberrant compartmentalization of versican and increased deposition of collagen. The inability of mutant outflow valve precursors to transition into fully mature cusps is associated with decreased postnatal viability, progressive cardiomegaly, and systolic dysfunction. Together, our data indicate that ADAM17 is required in valvular endothelial cells for regulating cell content as well as extracellular matrix composition and organization in semilunar valve remodeling and homeostasis. PMID- 23354121 TI - Antioxidant activity by a synergy of redox-sensitive mitochondrial phospholipase A2 and uncoupling protein-2 in lung and spleen. AB - Mitochondrial uncoupling protein-2 (UCP2) has been suggested to participate in the attenuation of the reactive oxygen species production, but the mechanism of action and the physiological significance of UCP2 activity remain controversial. Here we tested the hypothesis that UCP2 provides feedback downregulation of oxidative stress in vivo via synergy with an H2O2-activated mitochondrial calcium independent phospholipase A2 (mt-iPLA2). Tert-butylhydroperoxide or H2O2 induced free fatty acid release from mitochondrial membranes as detected by gas chromatography/mass spectrometry, which was inhibited by r-bromoenol lactone (r BEL) but not by its stereoisomer s-BEL, suggesting participation of mt-iPLA2gamma isoform. Tert-butylhydroperoxide or H2O2 also induced increase in respiration and decrease in mitochondrial membrane potential in lung and spleen mitochondria from control but not UCP2-knockout mice. These data suggest that mt-iPLA2gamma dependent release of free fatty acids promotes UCP2-dependent uncoupling. Upon such uncoupling, mitochondrial superoxide formation decreased instantly also in the s-BEL presence, but not when mt-iPLA2 was blocked by R-BEL and not in mitochondria from UCP2-knockout mice. Mt-iPLA2gamma was alternatively activated by H2O2 produced probably in conjunction with the electron-transferring flavoprotein:ubiquinone oxidoreductase (ETFQOR), acting in fatty acid beta oxidation. Palmitoyl-d,l-carnitine addition to mouse lung mitochondria, respiring with succinate plus rotenone, caused a respiration increase that was sensitive to r-BEL and insensitive to s-BEL. We thus demonstrate for the first time that UCP2, functional due to fatty acids released by redox-activated mt-iPLA2gamma, suppresses mitochondrial superoxide production by its uncoupling action. In conclusion, H2O2-activated mt-iPLA2gamma and UCP2 act in concert to protect against oxidative stress. PMID- 23354122 TI - Non-muscle myosin IIA is involved in focal adhesion and actin remodelling controlling glucose-stimulated insulin secretion. AB - AIMS/HYPOTHESIS: Actin and focal adhesion (FA) remodelling are essential for glucose-stimulated insulin secretion (GSIS). Non-muscle myosin II (NM II) isoforms have been implicated in such remodelling in other cell types, and myosin light chain kinase (MLCK) and Rho-associated coiled-coil-containing kinase (ROCK) are upstream regulators of NM II, which is known to be involved in GSIS. The aim of this work was to elucidate the implication and regulation of NM IIA and IIB in beta cell actin and FA remodelling, granule trafficking and GSIS. METHODS: Inhibitors of MLCK, ROCK and NM II were used to study NM II activity, and knockdown of NM IIA and IIB to determine isoform specificity, using sorted primary rat beta cells. Insulin was measured by radioimmunoassay. Protein phosphorylation and subcellular distribution were determined by western blot and confocal immunofluorescence. Dynamic changes were monitored by live cell imaging and total internal reflection fluorescence microscopy using MIN6B1 cells. RESULTS: NM II and MLCK inhibition decreased GSIS, associated with shortening of peripheral actin stress fibres, and reduced numbers of FAs and insulin granules in close proximity to the basal membrane. By contrast, ROCK inhibition increased GSIS and caused disassembly of glucose-induced central actin stress fibres, resulting in large FAs without any effect on FA number. Only glucose-induced NM IIA reorganisation was blunted by MLCK inhibition. NM IIA knockdown decreased GSIS, levels of FA proteins and glucose-induced extracellular signal-regulated kinase 1/2 phosphorylation. CONCLUSIONS/INTERPRETATION: Our data indicate that MLCK-NM IIA may modulate translocation of secretory granules, resulting in enhanced insulin secretion through actin and FA remodelling, and regulation of FA protein levels. PMID- 23354123 TI - Revisiting the links between glycaemia, diabetes and cardiovascular disease. AB - Whilst the interplay between type 2 diabetes and cardiovascular disease (CVD) has been recognised for many years, recent analyses of existing studies have helped refine several aspects of this relationship with relevance to clinical practice. First, recent data demonstrate that fasting glucose is not linearly related to CVD risk in those without diabetes; rather, risk levels escalate (modestly at first) only beyond specific glucose thresholds. Consequently, glucose-based measures may not necessarily enhance CVD risk prediction in those without diabetes. Second, other data confirm that new-onset diabetes is not a post myocardial infarction 'risk equivalent' state and that, on average, several years of diabetes duration is needed to attain this level of risk. Third, meta-analyses and systemic reviews have confirmed that diabetes increases CVD risk by around twofold on average and this risk is subject to wide variation, being lowest in those newly diagnosed and highest in those with existing vascular disease, proteinuria or renal disease. Fourth, meta-analyses of major glucose-lowering trials suggest that, whilst glucose-lowering lessens vascular risk, risk reduction arising from statins and blood pressure-lowering is greater. Fifth, statins increase diabetes risk, albeit modestly, adding to the emerging concept that some agents that primarily target CVD risk may be diabetogenic, and vice versa. Finally, arising in part from the latter observation, as well as an understanding that CVD and diabetes risk overlap in some individuals but not others, the case for combined CVD/diabetes risk screening (generally using non fasting lipids and HbA1c), has gained strength. PMID- 23354124 TI - 14-3-3 proteins are essential signalling hubs for beta cell survival. AB - AIMS/HYPOTHESIS: Diabetes is characterised by pancreatic beta cell death and dysfunction, resulting from unbalanced pro-survival and pro-death signalling. The 14-3-3 proteins are molecular adaptors that integrate numerous signalling pathways, including the v-raf-leukaemia viral oncogene 1 (RAF1)/B cell leukaemia/lymphoma 2 (BCL-2)-associated agonist of cell death (BAD) pathway, which we have previously implicated in insulin-dependent beta cell survival. Nevertheless, the roles of 14-3-3 proteins in beta cell fate and function have not been investigated. METHODS: We examined the abundance, localisation, modulation and roles of 14-3-3 proteins using quantitative RT-PCR, immunoblot or imaging. MIN6 cells or mouse islets cells were manipulated with inhibitors, short interfering RNA (siRNA) or plasmids overexpressing 14-3-3. RESULTS: We first characterised the abundance and subcellular location of all seven 14-3-3 isoforms in mouse and human beta cells. Most isoforms were cytoplasmic, except 14-3 3sigma, which appeared to be nuclear. Analysis of 14-3-3 abundance under stress conditions revealed distinct modulation in mouse islets and MIN6 cells. Generalised 14-3-3 inhibition promoted apoptosis and dysfunction, and siRNA mediated knockdown revealed isoform-specific roles in caspase-3-dependent beta cell apoptosis, with a clear role for 14-3-3zeta. Overabundance of 14-3-3zeta sequestered BAD-BCL2-associated X protein (BAX) from mitochondria, attenuated Dp5 (also known as Hrk) and Puma (also known as Bbc3) induction, and increased survival in response to pro-inflammatory cytokines or thapsigargin. Anti apoptotic insulin treatment increased the sequestration of BAD/BAX by 14-3-3zeta. BAD mutants that were unable to bind 14-3-3zeta localised to mitochondria and induced apoptosis. CONCLUSIONS/INTERPRETATION: This first study of the 14-3-3 family in beta cells revealed specific regulation, localisation and anti apoptotic roles among the isoforms. Focus on 14-3-3zeta revealed its importance in preventing BAD-BAX mitochondrial localisation and protecting beta cells from multiple stresses. Thus, some 14-3-3 proteins are pro-survival signalling hubs. PMID- 23354125 TI - Molecular basis for the regulation of islet beta cell mass in mice: the role of E cadherin. AB - AIMS/HYPOTHESIS: In rodents and humans, the rate of beta cell proliferation declines rapidly after birth; formation of the islets of Langerhans begins perinatally and continues after birth. Here, we tested the hypothesis that increasing levels of E-cadherin during islet formation mediate the decline in beta cell proliferation rate by contributing to a reduction of nuclear beta catenin and D-cyclins. METHODS: We examined E-cadherin, nuclear beta-catenin, and D-cyclin levels, as well as cell proliferation during in vitro and in vivo formation of islet cell aggregates, using beta-TC6 cells and transgenic mice with green fluorescent protein (GFP)-labelled beta cells, respectively. We tested the role of E-cadherin using antisense-mediated reductions of E-cadherin in beta-TC6 cells, and mice segregating for a beta cell-specific E-cadherin knockout (Ecad [also known as Cdh1] betaKO). RESULTS: In vitro, pseudo-islets of beta-TC6 cells displayed increased E-cadherin but decreased nuclear beta-catenin and cyclin D2, and reduced rates of cell proliferation, compared with monolayers. Antisense knockdown of E-cadherin increased cell proliferation and levels of cyclins D1 and D2. After birth, beta cells showed increased levels of E-cadherin, but decreased levels of D-cyclin, whereas islets of Ecad betaKO mice showed increased levels of D-cyclins and nuclear beta-catenin, as well as increased beta cell proliferation. These islets were significantly larger than those of control mice and displayed reduced levels of connexin 36. These changes correlated with reduced insulin response to ambient glucose, both in vitro and in vivo. CONCLUSIONS/INTERPRETATION: The findings support our hypothesis by indicating an important role of E-cadherin in the control of beta cell mass and function. PMID- 23354126 TI - George S. Eisenbarth, 1947-2012. PMID- 23354127 TI - Diabetes, bilirubin and amputations: is there a link? AB - A study by Chan et al in this issue of Diabetologia (DOI: 10.1007/s00125-012-2818 4 ) reports that low plasma bilirubin levels are associated with an increased risk of amputation in patients with type 2 diabetes mellitus participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. These findings raise the interesting and clinically relevant hypothesis that bilirubin protects against risk of amputation in patients with type 2 diabetes. This commentary considers some of the limitations associated with research aiming to define any link between circulating bilirubin levels and vascular disease. Numerous confounding factors (several of which may be present in patients with type 2 diabetes) may explain why the literature regarding this potentially protective role of bilirubin remains controversial. PMID- 23354128 TI - Helping hands, healthy body? Oxytocin receptor gene and prosocial behavior interact to buffer the association between stress and physical health. AB - Providing help or support to others buffers the associations between stress and physical health. We examined the function of the neurohormone oxytocin as a biological mechanism for this stress-buffering phenomenon. Participants in a longitudinal study completed a measure of charitable behavior, and over the next two years provided assessments of stressful life events and physician-diagnosed physical ailments. Results indicated that charitable behavior buffered the associations between stressful events and new-onset ailments among individuals with the AA/AG genotypes of oxytocin receptor gene (OXTR) variant rs53576, but not among those with the GG genotype. These results suggest that oxytocin function may significantly affect health and may help explain the associations between prosocial behavior and health. More broadly, these findings are consistent with a role for the caregiving behavioral system in health and well being. PMID- 23354129 TI - Dynamic templating: a large area processing route for the assembly of periodic arrays of sub-micrometer and nanoscale structures. AB - A substrate-based templated assembly route has been devised which offers large area, high-throughput capabilities for the fabrication of periodic arrays of sub micrometer and nanometer-scale structures. The approach overcomes a significant technological barrier to the widespread use of substrate-based templated assembly by eliminating the need for periodic templates having nanoscale features. Instead, it relies upon the use of a dynamic template with dimensions that evolve in time from easily fabricated micrometer dimensions to those on the nanoscale as the assembly process proceeds. The dynamic template consists of a pedestal of a sacrificial material, typically antimony, upon which an ultrathin layer of a second material is deposited. When heated, antimony sublimation results in a continuous reduction in template size where the motion of the sublimation fronts direct the diffusion of atoms of the second material to a predetermined location. The route has broad applicability, having already produced periodic arrays of gold, silver, copper, platinum, nickel, cobalt, germanium and Au-Ag alloys on substrates as diverse as silicon, sapphire, silicon-carbide, graphene and glass. Requiring only modest levels of instrumentation, the process provides an enabling route for any reasonably equipped researcher to fabricate periodic arrays that would otherwise require advanced fabrication facilities. PMID- 23354130 TI - Substrate specificity studies of the cysteine peptidases falcipain-2 and falcipain-3 from Plasmodium falciparum and demonstration of their kininogenase activity. AB - We studied the substrate specificity requirements of recombinant cysteine peptidases from Plasmodium falciparum, falcipain-2 (FP-2) and falcipain-3 (FP-3), using fluorescence resonance energy transfer (FRET) peptides as substrates. Systematic modifications were introduced in the lead sequence Abz-KLRSSKQ-EDDnp (Abz=ortho-aminobenzoic acid; EDDnp=N-[2,4-dinitrophenyl]ethylenediamine) resulting in five series assayed to map S3-S'2 subsite specificity. Despite high sequence identity and structural similarity between FP-2 and FP-3, noteworthy differences in substrate specificity were observed. The S1 subsite of FP-2 preferentially accommodates peptides containing the positively charged residue Arg in P1, while FP-3 has a clear preference for the hydrophobic residue Leu in this position. The S2 subsite of FP-2 and FP-3 presents a strict specificity for hydrophobic residues, with Leu being the residue preferred by both enzymes. FP-2 did not show preference for the residues present at P3, while FP-3 hydrolysed the peptide Abz-ALRSSRQ-EDDnp, containing Ala at P3, with the highest catalytic efficiency of all series studied. FP-2 has high susceptibility for substrates containing hydrophobic residues in P'1, while FP-3 accommodates well peptides containing Arg in this position. The S'2 subsite of both enzymes demonstrated broad specificity. In addition, radioimmunoassay experiments indicated that kinins can be generated by FP-2 and FP-3 proteolysis of high molecular weight kininogen (HK). Both enzymes excised Met-Lys-bradykinin, Lys-bradykinin and bradykinin from the fluorogenic peptide Abz-MISLMKRPPGFSPFRSSRI-NH2, which corresponds to the Met(375) to Ile(393) sequence of HK. The capability of FP-2 and FP-3 to release kinins suggests the involvement of these enzymes in the modulation of malaria pathophysiology. PMID- 23354131 TI - Impact of chromosome ends on the biology and virulence of Plasmodium falciparum. AB - In recent years, many studies have focused on heterochromatin located at chromosome ends, which plays an important role in regulating gene expression in many organisms ranging from yeast to humans. Similarly, in the protozoan Plasmodium falciparum, which is the most virulent human malaria parasite, the heterochromatin present in telomeres and subtelomeric regions exerts a silencing effect on the virulence gene families located therein. Studies addressing P. falciparum chromosome ends have demonstrated that these regions participate in other functions, such as the formation of the T-loop structure, the replication of telomeric regions, the regulation of telomere length and the formation of telomeric heterochromatin. In addition, telomeres are involved in anchoring chromosome ends to the nuclear periphery, thereby playing an important role in nuclear architecture and gene expression regulation. Here, we review the current understanding of chromosome ends, the proteins that bind to these regions and their impact on the biology and virulence of P. falciparum. PMID- 23354133 TI - Probe-based confocal laser endomicroscopy of the urinary tract: the technique. AB - Probe-based confocal laser endomicroscopy (CLE) is an emerging optical imaging technology that enables real-time in vivo microscopy of mucosal surfaces during standard endoscopy. With applications currently in the respiratory and gastrointestinal tracts, CLE has also been explored in the urinary tract for bladder cancer diagnosis. Cellular morphology and tissue microarchitecture can be resolved with micron scale resolution in real time, in addition to dynamic imaging of the normal and pathological vasculature. The probe-based CLE system (Cellvizio, Mauna Kea Technologies, France) consists of a reusable fiberoptic imaging probe coupled to a 488 nm laser scanning unit. The imaging probe is inserted in the working channels of standard flexible and rigid endoscopes. An endoscope-based CLE system (Optiscan, Australia), in which the confocal endomicroscopy functionality is integrated onto the endoscope, is also used in the gastrointestinal tract. Given the larger scope diameter, however, application in the urinary tract is currently limited to ex vivo use. Confocal image acquisition is done through direct contact of the imaging probe with the target tissue and recorded as video sequences. As in the gastrointestinal tract, endomicroscopy of the urinary tract requires an exogenenous contrast agent-most commonly fluorescein, which can be administered intravenously or intravesically. Intravesical administration is a well-established method to introduce pharmacological agents locally with minimal systemic toxicity that is unique to the urinary tract. Fluorescein rapidly stains the extracellular matrix and has an established safety profile. Imaging probes of various diameters enable compatibility with different caliber endoscopes. To date, 1.4 and 2.6 mm probes have been evaluated with flexible and rigid cystoscopy. Recent availability of a < 1 mm imaging probe opens up the possibility of CLE in the upper urinary tract during ureteroscopy. Fluorescence cystoscopy (i.e. photodynamic diagnosis) and narrow band imaging are additional endoscope-based optical imaging modalities that can be combined with CLE to achieve multimodal imaging of the urinary tract. In the future, CLE may be coupled with molecular contrast agents such as fluorescently labeled peptides and antibodies for endoscopic imaging of disease processes with molecular specificity. PMID- 23354134 TI - Spiritual well-being: the fourth dimension of health. PMID- 23354132 TI - Phosphorylation of eIF2alpha attenuates statin-induced apoptosis by inhibiting the stabilization and translocation of p53 to the mitochondria. AB - Statins are effective cholesterol-lowering drugs that exert pleiotropic effects, including cytotoxicity to cancer cells. We previously reported that simvastatin triggered the mitochondrial apoptotic pathway in MethA fibrosarcoma cells, which was accompanied by the translocation of stabilized p53 to the mitochondria. In this study, we investigated whether statins induce the endoplasmic reticulum (ER) stress response and the mechanisms by which this response is linked to the stabilization of p53 and its translocation to the mitochondria. Statins induced typical ER stress-related proteins, such as BiP/78 kDa glucose-regulated protein (Grp78) and CCAAT/enhancer-binding protein homologous protein (CHOP), as well as the phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), eIF2alpha and JNK. The statin-induced phosphorylation of eIF2alpha and JNK was inhibited by supplementation with components of the mevalonate pathway, such as mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Salubrinal, an inhibitor of the dephosphorylation of eIF2alpha, suppressed the loss of mitochondrial membrane potential and the translocation of stabilized p53 and Bax to the mitochondria; however, SP600125, a JNK kinase inhibitor, did not exert this effect. Furthermore, the eIF2alpha knockdown sensitized cells to simvastatin-induced apoptosis and the overexpression of a non phosphorylatable eIF2alpha-mutant [serine 51(Ser51)/alanine] enhanced the stabilization of p53 and its translocation to the mitochondria in response to simvastatin treatment. Taken together, these data indicate that eIF2alpha phosphorylation in the context of the ER stress response plays a role in cell survival by counteracting the p53-mediated mitochondrial apoptosis in response to statins. PMID- 23354135 TI - Progress in health-related millennium development goals in the WHO South-East Asia Region. AB - Home to 25% of the world's population and bearing 30% of the Global disease burden, the South-East Asia Region [1] of the World Health Organization has an important role in the progress of global health. Three of the eight million development goal (MDG) goals that relate to health are MDG 4, 5, and 6. There is progress in all three goals within the countries of the region, although the progress varies across countries and even within countries. With concerted and accelerated efforts in some countries and certain specific areas, the region will achieve the targets of the three health MDGs. The key challenges are in sustainable scaling up of evidence-based interventions to improve maternal and child health and controlling communicable diseases. This will require continued focus and investments in strengthening health systems that provide individual and family centered comprehensive package of interventions with equitable reach and that which is provided free at the point of service delivery. Important lessons that have been learnt in implementing the MDG agenda in the past two decades will inform setting up of the post MDG global health agenda. This article provides a snap shot of progress thus far, key challenges and opportunities in WHO South East Asia Region and lays down the way forward for the global health agenda post 2015. PMID- 23354136 TI - Targeting rubella for elimination. AB - Rubella is an acute, usually mild viral disease. However, when rubella infection occurs just before conception or during the first 8-10 weeks of gestation, it causes multiple fetal defects in up to 90% of cases, known as Congenital Rubella Syndrome (CRS). It may result in fetal wastage, stillbirths and sensorineural hearing deficit up to 20 weeks of gestation. Rubella vaccine (RA 27/3) is highly effective and has resulted in elimination of rubella and CRS from the western hemisphere and several European countries. Review of several studies documents the duration of protection over 10-21 years following one dose of RA27/3 vaccination, and persistent seropositivity in over 95% cases. Studies in India show seronegativity to rubella among adolescent girls to vary from 10% to 36%. Although due to early age of infection resulting in protection in the reproductive age group, incidence of rubella in India is not very high. However, due to severity of CRS coupled with introduction of RCV in private sector and in some of the states which is likely to lead to sub-optimal coverage and resulting higher risk of rubella during pregnancy in the coming decades, it is imperative to adopt the goal of rubella elimination. As in order to control measles, the country has adopted strategy of delivering second dose of measles through measles campaigns covering children 9 months to 10 years of age in 14 states, it is recommended to synergize efforts for elimination of rubella with these campaigns by replacing measles vaccine by MR or MMR vaccine. Other states which are to give second dose of measles through routine immunization will also have to adopt campaign mode in order to eliminate rubella from the country over 10-20 years. Subsequently, measles vaccine can be replaced by MR or MMR vaccine in the national schedule. PMID- 23354137 TI - Landscaping biostatistics education in India. AB - Biostatistics plays an important role in measuring, understanding, and describing the overall health and well-being of a population. Biostatistics as a subject evolved from the application of statistics in various research aspects of biology, biomedical care, and public health. However, with a recent increase in number of health and pharmacy related research, the demand for trained biostatisticians is also increasing. The present paper is an attempt to undertake a situational analysis of biostatistics education in India. A systematic, predefined approach, with three parallel strategies was used to collect and assemble the data regarding training in biostatistics in India. Our study results show that there is paucity of programs providing specialized training in biostatistics in India. Only about 19 institutions in India are offering various courses in biostatistics/medical statistics/health statistics/biometry. It is important to look into the current capacity building initiatives in this domain. Some other means for giving importance to biostatistics could be by making it a separate branch/specialization in a majority of the institutions, particularly in medical colleges. PMID- 23354138 TI - Forecasting incidence of dengue in Rajasthan, using time series analyses. AB - AIM: To develop a prediction model for dengue fever/dengue haemorrhagic fever (DF/DHF) using time series data over the past decade in Rajasthan and to forecast monthly DF/DHF incidence for 2011. MATERIALS AND METHODS: Seasonal autoregressive integrated moving average (SARIMA) model was used for statistical modeling. RESULTS: During January 2001 to December 2010, the reported DF/DHF cases showed a cyclical pattern with seasonal variation. SARIMA (0,0,1) (0,1,1) 12 model had the lowest normalized Bayesian information criteria (BIC) of 9.426 and mean absolute percentage error (MAPE) of 263.361 and appeared to be the best model. The proportion of variance explained by the model was 54.3%. Adequacy of the model was established through Ljung-Box test (Q statistic 4.910 and P-value 0.996), which showed no significant correlation between residuals at different lag times. The forecast for the year 2011 showed a seasonal peak in the month of October with an estimated 546 cases. CONCLUSION: Application of SARIMA model may be useful for forecast of cases and impending outbreaks of DF/DHF and other infectious diseases, which exhibit seasonal pattern. PMID- 23354139 TI - Tobacco abuse among school going adolescents in a rural area of West Bengal, India. AB - Adolescents are vulnerable targets of tobacco industry with all consequences of usage. Studies reveal that tobacco abuse is rising in this age group in India. A cross sectional survey was carried out in two coeducational high schools of Anandanagar village of Singur block, Hooghly district, West Bengal among 276 students of VIII-IX standard to study the knowledge and abuse of tobacco and to find out influencing socio-demographic factors. Knowledge score was higher in females, students from nuclear families, and those with literate parents. Low prevalence of tobacco intake was obtained among the students, with 9.8% reported having ever used smokeless tobacco and 4.3% ever smoked. Tobacco intake was higher among those with a history of parental tobacco intake. Continued information education and communication (IEC) activities should be conducted by the school authorities, with involvement of nongovernment organizations (NGOs) and parents for primary prevention. PMID- 23354140 TI - Study on the availability of physical infrastructure and manpower facilities in sub-centers of Chittoor district of Andhra Pradesh. AB - The sub-centers (SCs) are under constant criticism for their inability to deliver quality services due to the nonavailability of adequate infrastructure, manpower and supply of drugs.A cross-sectional study was conducted in Chittoor District of Andhra Pradesh to assess the availability of physical infrastructure and manpower in the SCs. A total of 34 SCs were selected by multistage and stratified random sampling technique. The data was statistically analyzed by using Microsoft Excel. The deficiency in the availability of health workers male and female were found to be 67.7% and 27.5%, respectively. The residential facility for health workers was available only in 26.4% SCs. Only 20.6% of SCs had stethoscope and B.P apparatus. The physical infrastructure and manpower availability at the SCs needs considerable improvement as per the Indian Public Health Standard (IPHS). Facilities to conduct the normal delivery and 24-hours emergency referral services need to be addressed at the earliest. PMID- 23354141 TI - Ocular morbidity among children at a tertiary eye care hospital in Kolkata, West Bengal. AB - Eye diseases in childhood are important causes of medical consultation and it affects learning ability, adjustment in school and personality. To determine the pattern of ocular morbidity a cross-sectional observational study was conducted among 714 children, attending Ophthalmology department at a tertiary eye care center in Kolkata, West Bengal. All the children less than 15 years of age, attending in Unit II outpatient department were selected by complete enumeration method for duration of one year (January-December 2010). Distribution of association was analyzed by Chi-square test and difference between two proportions was calculated by z test for proportions. The common ocular morbidity were refractive errors (23.67%) followed by allergic conjunctivitis (17.23%), infection of the eye and adnexa (15.13%), ocular trauma (12.74%), and congenital eye diseases (13.59%). Majority of ocular morbidity is treatable and need early attention through eye screening cum intervention program beginning right from the childhood. PMID- 23354142 TI - Screening for thalassemia and other hemoglobinopathies in a tertiary care hospital of West Bengal: implications for population screening. AB - Hemoglobinopathies are common genetic disorders of hemoglobin, which can be prevented by population screening and offering genetic counseling. In absence of population-based screening for hemoglobinopathies, the hospital-based diagnosis register provide idea about the extent of problem in the community. The present study was undertaken to find out the burden of hemoglobinopathies and spectrum of this disorders among the population who were screened in the hospital-based screening program. A record-basedanalysis of subjects who underwent screening for hemoglobinopathies in Burdwan Medical College and Hospital over a period of 3 years and 4 months revealed that overall 29.3% of subjects were positive for hemoglobinopathies. Beta thalassemia heterozygous was the most commonhemoglobinopathy in this region closely followed by hemoglobin E heterozygous. In view of high prevalence of hemoglobinopathies in this region, a routine premarital screening program is needed for identification and prevention of high-risk marriages. PMID- 23354143 TI - A study on infant and young child feeding practices among mothers attending an urban health center in East Delhi. AB - A cross sectional study was conducted to study the diet pattern of children less than 2 years with regard to certain infant and young child feeding (IYCF) indicators. A total of 374 children less than 24 months of age coming to the immunization clinic were studied using a standard pretested and prevalidated questionnaire. Exclusive breastfeeding was followed by 57.1% of children under 6 months of age. Minimum dietary diversity, minimum meal frequency, and minimum acceptable diet were seen adequate in 32.6%, 48.6%, and 19.7% of children between 6 months and 2 years of age, respectively. PMID- 23354144 TI - Assessment of nutritional status by composite index for anthropometric failure: a study among slum children in Bankura, West Bengal. AB - A community-based cross-sectional study was conducted to find out the prevalence of composite index of anthropometric failure (CIAF) among 117 slum dwelling under five children in Bankura town, West Bengal and its relation with some common socio-economic factors. Among study population, the prevalence of underweight was 41.6%, whereas CIAF was 80.3%. CIAF gave a near complete estimation of undernutrition unlike underweight. Children who were unimmunized, with more number of siblings, living in a nuclear family, or with illiterate mothers were more likely to be undernourished. PMID- 23354145 TI - Evaluating quality of health services in health centres of Zanjan district of Iran. AB - To assess quality of health services in Zanjan health centres based on clients' expectations and perceptions. The study was conducted by using service quality (SERVQUAL) scale on a sample of 300 females, clients of health care centres in the district of Zanjan, selected by cluster sampling. The results indicated that there were negative quality gaps at five SERVQUAL dimensions. The most and least negative quality gap mean scores were in reliability dimension (-2.1) and tangible (-1.13) respectively. There was statistically significant difference between clients' perceptions and expectations mean scores at all of the five service quality dimensions (P<0.001). The negative quality gap level in health service dimensions can be used as a guideline for redistribution of resources and managerial attempts to reduce quality gaps and improvement of health care quality. PMID- 23354146 TI - Prevalence of metabolic syndrome among rural women in a primary health centre area in Tamil Nadu. AB - A study was conducted to estimate prevalence of metabolic syndrome among 150 rural women in the age group of 30-50 years in a primary health centre area in Tamil Nadu. Prevalence of metabolic syndrome was estimated using National Cholesterol Education program (NCEP), Third report Adult Treatment Panel ATP III criteria, and Modified NCEP ATP III criteria for Asian Indians. Prevalence of metabolic syndrome was found to be 30.7% based on NCEP, ATP-III Criteria. Based on the Modified NCEP, ATP-III Criteria, the prevalence was found to be 36%.The most commonly observed components of metabolic syndrome in this study was increased waist circumference (56.0%) followed by low HDL (45.3%), high triglyceride (37.3%), high blood pressure 29.3%, and fasting blood sugar 12.7%. Identifying the risk factors and treating patients with the metabolic syndrome is a public health challenge especially in the rural population. PMID- 23354147 TI - Nurses and Alzheimer's disease: a holistic perspective. PMID- 23354148 TI - Home-based rehabilitation enhances daily physical activity and motor skill in children who have undergone the Fontan procedure. AB - This randomized trial compared physical activity enhancing exercise prescription and education programs in 61 children (36 male) with single-ventricle physiology after Fontan. After Fontan, children are less active than recommended for optimal health. They are often geographically dispersed and unable to attend weekday programs. Participants, 5.9-11.7 years of age who were status 5.3 years post Fontan, received 12-month, parent-delivered home programs to enhance physical activity, motor skill, fitness, and activity attitudes. Daily moderate-to vigorous physical activity (MVPA) was measured at baseline and again at 6, 12, and 24 months. Secondary outcomes were gross motor skill, fitness, and activity attitudes. Gross motor skill (p = .01) was significantly greater at the end of the 2-year study period for both intervention groups combined. MVPA at 2 years was significantly greater (p = .03) than the predicted decrease with age. Spring season (85 +/- 25 min), male sex (69 +/- 21 min), greater baseline activity (0.3 +/- 0.1 min/baseline minute), and better gross motor skill (1.1 +/- 0.4 min/percentile) increased weekly MVPA in a multivariable repeated-measures regression model adjusted for intervention, maturation during the 2-year study, sex, season, and baseline activity. Benefits were not influenced by type of rehabilitation, compliance, or rural/urban location. Home-based, pediatric physical activity rehabilitation enhances physical activity, gross motor skill, exercise capacity, and physical fitness among preadolescent children after Fontan regardless of rural/urban location. Prescribed education and exercise programs are similarly effective for providing the important health benefits of daily physical activity. Enhanced gross motor skill is associated with increased MVPA despite exercise capacity limitations after Fontan. Rehabilitation attenuates the expected decrease in MVPA with age. PMID- 23354149 TI - Supracardiac total anomalous pulmonary venous connection with bilateral (right and left) vertical veins and bilateral obstruction. AB - This report describes a rare form of obstructed supracardiac total anomalous pulmonary venous connection with two vertical veins (right and left) draining the right- and the left-sided pulmonary veins respectively without formation of a common chamber and with bilateral obstruction. Surgery for these patients is technically challenging due to the absence of a common chamber, and the prognosis is worse than for patients with a common chamber. Also, it is important to be aware of this entity so that an accurate noninvasive preoperative diagnosis by echocardiography alone without invasive cardiac catheterization is possible. This facilitates emergency surgical repair without delay, which is crucial to improvement of the outcome. PMID- 23354150 TI - Periplasmic response upon disruption of transmembrane Cu transport in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa, an opportunistic pathogen, has two transmembrane Cu(+) transport ATPases, CopA1 and CopA2. Both proteins export cytoplasmic Cu(+) into the periplasm and mutation of either gene leads to attenuation of virulence. CopA1 is required for maintaining cytoplasmic copper levels, while CopA2 provides copper for cytochrome c oxidase assembly. We hypothesized that transported Cu(+) ions would be directed to their destination via specific periplasmic partners and disruption of transport should affect the periplasmic copper homeostasis. Supporting this, mutation of either ATPase gene led to large increments in periplasmic cuproprotein levels. Toward identifying the proteins participating in this cellular response the periplasmic metalloproteome was resolved in non denaturing bidimensional gel electrophoresis, followed by X-ray fluorescence visualization and identification by mass-spectrometry. A single spot containing the electron shuttle protein azurin was responsible for the observed increments in cuproprotein contents. In agreement, lack of either Cu(+)-ATPase induced an increase in azu transcription. This is associated with an increase in the expression of anr and rpoS oxidative stress response regulators, rather than cueR, a copper sensing regulator. We propose that azurin overexpression and accumulation in the periplasm is part of the cellular response to cytoplasmic oxidative stress in P. aeruginosa. PMID- 23354151 TI - Drug "supersaturation" states induced by polymeric micelles and liposomes: a mechanistic investigation into permeability enhancements. AB - The objective of this study was to investigate if the increase in apparent solubility induced by liposomalization or micellization of the poorly soluble drug hydrocortisone (HC) would lead to an enhancement of its permeability through biological membranes. For this purpose phosphatidylcholine liposome formulations as well as d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) micelle dispersions and polyvinylpyrrolidone (PVP) supersaturated solutions were prepared in order to increase the apparent solubility of HC. Both the apparent solubility of hydrocortisone (i.e. amount of drug entrapped plus non-entrapped in the carriers) as well as the concentration of molecularly dissolved drug (i.e. fraction non-entrapped into carriers, truly molecularly dissolved fraction) were characterized. Subsequently, the permeability of hydrocortisone was assessed for each type of formulation using the in vitro sheep nasal mucosa permeability assay. In all formulations where solubilizing agents are present, an enhanced flux of HC (compared to the pure drug powder suspension) is observed. The expected linear correlation between apparent solubilities and fluxes was not found, whereas, the concentrations of molecularly dissolved HC were found to be directly proportional to the respective fluxes. This is an experimental proof for the hypothesis that, of all the strategies to increase the apparent solubility of poorly soluble drugs, enhancement of the molecularly dissolved drug concentration (induction of true supersaturation) would lead to better permeation though membranes. PMID- 23354152 TI - Improved pharmaceutical stability of a boronphenylalanine mannitol formulation for boron neutron capture therapy. AB - Boron neutron capture therapy (BNCT) is a radiotherapy based cancer treatment requiring the availability of a low energy thermal neutron beam and a boron containing drug. These requirements limit BNCT availability with the latter pharmaceutical issue related to the extremely short shelf-life and clinical acceptability of the current fructose based L-boronphenylalanine (BPA) formulation. Resolution of the formulation issues would remove this factor and therefore the stability of an alternative mannitol BPA formulation has been investigated. A mannitol BPA solution formulation was prepared and either lyophilised or stored as a solution at varying temperatures. After suitable periods the formulation was analysed by HPLC for BPA and degradation products. Lyophilised and solution mannitol BPA formulations exhibited a temperature and time dependent loss of BPA with concomitant increases in degradation products. Autoclaving the solution induced and accelerated degradation. A solution or lyophilised mannitol BPA formulation has a shelf-life of between 1 and 4 years respectively, a marked improvement over the current fructose formulation. Due to temperature dependent degradation the formulation cannot be terminally sterilised by autoclaving. The enhanced stability of the mannitol formulation removes the requirement for extemporaneous aseptic preparation of BPA just prior to treatment and eliminates one of the issues complicating the delivery of BNCT. PMID- 23354153 TI - Novel multiple agents loaded PLGA nanoparticles for brain delivery via inner ear administration: in vitro and in vivo evaluation. AB - The aim of this study was to develop novel multiple agents loaded poly (D,L lactide-co-glycolide acid) (PLGA) nanoparticles (NPs) and evaluate their potential for brain delivery via inner ear administration. PLGA NPs loaded with salvianolic acid B (Sal B), tanshinone IIA (TS IIA) and panax notoginsenoside (PNS) were prepared by double emulsion/solvent evaporation method. It was observed that optimized NPs displayed satisfactory encapsulation efficiency and desired sustained-release characteristics. NPs following intratympanic administration (IT) in guinea pigs greatly improved drug distribution within the inner ear, cerebrospinal fluid (CSF) and brain tissues compared with intravenous administration (IV). Pharmacodynamic studies demonstrated that NPs following IT markedly inhibited oxidizing reactions and protected the brain from cerebral ischemia reperfusion (I/R) injury by upregulating superoxide dismutase (SOD) activity both in serum and brain tissues, simultaneously significantly reducing the levels of malondialdehyde (MDA) and nitric oxide synthase (NOS). Moreover intratympanic delivery did not cause injury of cochlear function by preliminary study on the toxicity. These findings suggested that PLGA NPs-based delivery system via inner ear administration was a promising candidate to brain delivery for the treatment of brain diseases. PMID- 23354154 TI - Colonic absorption of salmon calcitonin using tetradecyl maltoside (TDM) as a permeation enhancer. AB - Calcitonin is used as a second line treatment of postmenopausal osteoporosis, but widespread acceptance is somewhat limited by subcutaneous and intranasal routes of delivery. This study attempted to enable intestinal sCT absorption in rats using the mild surfactant, tetradecyl maltoside (TDM) as an intestinal permeation enhancer. Human Caco-2 and HT29-MTX-E12 mucus-covered intestinal epithelial monolayers were used for permeation studies. Rat in situ intestinal instillation studies were conducted to evaluate the absorption of sCT with and without 0.1 w/v% TDM in jejunum, ileum and colon. TDM significantly enhanced sCT permeation across intestinal epithelial monolayers, most likely due to combined paracellular and transcellular actions. In situ, TDM caused an increased absolute bioavailability of sCT in rat colon from 1.0% to 4.6%, whereas no enhancement increase was observed in ileal and jejunal instillations. Histological analysis suggested mild perturbation of colonic epithelia in segments instilled with sCT and TDM. These data suggest that the membrane composition of the colon is different to the small intestine and that it is more amenable to permeation enhancement. Thus, formulations designed to release payload in the colon could be advantageous for systemic delivery of poorly permeable molecules. PMID- 23354155 TI - [Retrospective study of viral causes of central nervous system infections in Tunisia (2003-2009)]. AB - OBJECTIVES: To determine the role of enteroviruses, Herpesviridae, West Nile virus and Sandfly Toscana virus in central nervous system (CNS) infections in Tunisia. METHODOLOGY: 847 cerebrospinal fluid (CSF) samples, 427 serum samples and 23 stool samples were collected from 1071 patients hospitalized for CNS viral infections from January 2003 through December 2009. All CSF samples were first tested by PCR to detect enteroviruses and Herpesviridae. In specific epidemic contexts in patients negative for these viruses, arbovirus infection was tested by ELISA. RESULTS: Virological testing was positive in 17.5% of cases. West Nile virus and enteroviruses accounted for 58% of them, enteroviruses 23.5%, Herpesviridae 8.5%, and Toscana virus 10%. West Nile virus infection was observed only in 2003, during an outbreak in coastal regions. Toscana virus circulated regularly throughout the study period. Enteroviruses were responsible for grouped cases of aseptic meningitis in both 2003 and 2005. Arboviruses and enteroviruses were detected mainly in summer and autumn. Herpesviridae were associated with sporadic cases of meningoencephalitis. CONCLUSION: This report on viral causes of CNS infections in Tunisia shows that West Nile virus and enteroviruses appear to circulate mainly during epidemics, while the circulation of Toscana virus seems continuous. Negative virus findings may be due, at least in part, to late sampling, inappropriate sample collection and transportation to the virology lab, or failure to test for the right virus. It is essential to promote collaboration between clinicians and biologists to maximize the likelihood of diagnosis. PMID- 23354156 TI - Stomata are less responsive to environmental stimuli in high background ozone in Dactylis glomerata and Ranunculus acris. AB - Two mesotrophic grassland species, Ranunculus acris and Dactylis glomerata were exposed to a range of ozone treatments (16.2-89.5 ppb 24 h mean) and two watering regimes under naturally fluctuating photosynthetically active radiation (PAR), vapour pressure deficit (VPD) and temperature. Stomatal conductance was measured throughout the experiments, and the combined data set (>1000 measurements) was analysed for effects of low and high ozone on responses to environmental stimuli. We show that when D. glomerata and R. acris were grown in 72.6-89.5 ppb ozone the stomata consistently lose the ability to respond, or have reduced response, to naturally fluctuating environmental conditions in comparison to their response in low ozone. The maximum stomatal conductance (g(max)) was also significantly higher in the high ozone treatment for D. glomerata. We discuss the hypotheses for the reduced sensitivity of stomatal closure to a changing environment and the associated implications for ozone flux modelling. PMID- 23354157 TI - Dietary exposure of Antarctic krill to p,p'-DDE: uptake kinetics and toxicological sensitivity in a key polar species. AB - This study evaluated the dietary uptake kinetics and sublethal toxicity of p,p' dichlorodiphenyl dichloroethylene (p,p'-DDE) in Antarctic krill. The uptake rate constant (characterised by the seawater volume stripped of contaminant sorbed to algae) of 200 +/- 0.32 mL g(-1) wet weight h(-1), average absorption efficiency of 86 +/- 13% and very low elimination rate constant of 5 * 10(-6) +/- 0.0031 h( 1) demonstrate the importance of feeding for p,p'-DDE bioaccumulation in Antarctic krill. Faecal egestion of unabsorbed p,p'-DDE of 8.1 +/- 2.7% indicates that this pathway contributes considerably to p,p'-DDE sinking fluxes. A median internal effective concentration (IEC50) of 15 mmol/kg lipid weight for complete immobility indicates baseline toxicity and that Antarctic krill exhibit comparable toxicological sensitivity as temperate species under similar 10 d exposure conditions. These findings support the critical body residue approach and provide insight to the role of Antarctic krill in the biogeochemical cycling of p,p'-DDE in the Southern Ocean. PMID- 23354158 TI - Sero-epidemiology of hepatitis B markers in the population of Tuscany, Central Italy, 20 years after the implementation of universal vaccination. AB - Italy was one of the first industrialized countries to introduce a program of universal vaccination against hepatitis B in 1991. Twenty years later we verified the impact of universal immunisation on the epidemiology of hepatitis B infection by analyzing the prevalence of specific viral markers (anti-HBs, anti-HBc and HBsAg). The ELISA tests were performed on residual blood samples collected by 0.05% of the resident population aged 1-50 years in Tuscany (Italy). About 63% of subjects aged < 30 years were anti-HBs positive compared to about 25% in older subjects, without differences between genders. About 22% of subjects over 40 years were anti-HBc-positive compared to 5% in the younger age groups. The number of HBsAg-positive subjects was almost 10 fold higher in the unvaccinated age groups than in the cohorts involved in the universal vaccination program. The results of our study show the persisting high anti-HBs reactivity in vaccinated cohorts, while HBV markers related to natural exposure or persistent infection remain remarkably higher in older age groups. This sero-epidemiological study supports with prevalence data the downward incidence trend of acute hepatitis B highlighted by epidemiological surveillance systems, and corroborates the forecast for elimination of hepatitis B in Italy in a few decades. PMID- 23354159 TI - Comparison of continuous breath test and gastric scintigraphy for the measurement of gastric emptying rate in healthy and dyspeptic individuals. AB - OBJECTIVE: To determine normative gastric emptying rates for the continuous breath test and to compare its findings with gastric scintigraphy in healthy volunteers and dyspeptic patients. METHODS: A standard 250 kcal meal double labeled with 1 mCi 99mTc colloid and 100 MUg nonradioactive 13C-octanoic acid was administered to 20 healthy individuals and 22 dyspeptic patients attending a tertiary medical center in 2009-2010. Gastric emptying rate was measured simultaneously with sequential gastric scintigraphy and the continuous breath test. The results of the healthy controls were used as a normative reference. The findings of the two tests were analyzed by linear regression and kappa statistics. In addition, the gastric half-emptying times (T 1/2) were compared by a kappa test for evaluating the agreement of normal/abnormal results in both methods. RESULTS: Background features were as follows: healthy individuals - 15 men/5 women, mean age 44.9 +/- 14 years and mean BMI 26.8 +/- 3.5; dyspeptic patients - 5 men/17 women, mean age 58.0 +/- 13 years and mean BMI 25.3 +/- 5.5. The upper limit of normal for gastric half-emptying time (T 1/2) was 140 min by the breath test. The linear correlation of T 1/2 between the methods was 0.64. The agreement of normal/abnormal T 1/2 between the methods was 0.65. CONCLUSION: The continuous breath test may be a suitable method for the evaluation of gastric emptying. A larger study is required to determine its feasibility as the standard of care in dyspeptic patients. PMID- 23354160 TI - Clinical significance of microRNA-93 downregulation in human colon cancer. AB - AIM: MicroRNA-93 (miR-93) has been shown to suppress proliferation and colony formation of colon cancer stem cells. The aim of this study was to examine the expression pattern and prognostic value of miR-93 in patients with colon cancer. MATERIALS AND METHODS: A quantitative real-time PCR analysis was carried out to detect the expression levels of miR-93 in 138 paired samples of tumoral and nontumoral colon tissues diagnosed with colon cancer. Associations of miR-93 expression with clinicopathological parameters and survival were also examined. RESULTS: miR-93 expression was significantly decreased in tumoral compared with nontumoral colon tissues (P<0.001). Low miR-93 expression was significantly correlated with advanced tumor stage (P=0.02), positive nodal metastasis (P=0.006), and positive distant metastases (P=0.01). In addition, Kaplan-Meier survival analysis by Cox regression showed that low miR-93 expression [hazard ratio (HR), 10.2; 95% confidence interval (CI), 1.9-42.8, P=0.003] was associated closely with poor overall survival in patients with colon cancer. Moreover, multivariate analysis showed that miR-93 decreased expression (HR, 4.3; 95% CI, 0.8-17.2, P=0.02), advanced tumor stage (HR, 3.1; 95% CI, 0.2-13.9, P=0.04), positive nodal metastasis (HR, 4.1; 95% CI, 0.7-16.8, P=0.02), and positive distant metastases (HR, 3.7; 95% CI, 0.5-14.1, P=0.03) were independent risk factors for overall survival in patients with colon cancer. CONCLUSION: Our data show for the first time that the downregulation of miR-93 was significantly correlated with unfavorable clinicopathologic features and short overall survival in patients with colon cancer, suggesting that decreased expression of miR-93 be used as a novel prognostic factor for this disease. PMID- 23354161 TI - A correlation of the endoscopic characteristics of colonic laterally spreading tumours with genetic alterations. AB - OBJECTIVES: Laterally spreading tumours (LSTs) are a heterogeneous group of adenomas that are emerging as important precursors of colorectal cancer and in which the risk for cancer is related to their endoscopically definable morphology. It is currently unclear whether different molecular alterations determine their morphologies. We aimed to assess this relationship in LSTs using strict morphological classifications. METHODS: We characterized 135 sessile adenomatous lesions (>= 20 mm) according to histopathology and the Paris classification. We investigated key molecular changes commonly found in colorectal neoplasms, namely mutation of KRAS, BRAF, APC and CTNNB1 and microsatellite instability, and determined their relationship with morphology. RESULTS: The Paris classification revealed a heterogeneous cohort comprising Is/IIa+Is (41.5%), IIa/IIb (53.3%) and IIc/IIa+IIc (5.2%) lesions. Histopathological analysis showed that 19 (14.1%) of these were sessile serrated adenomas. Here, we defined a group of 58 lesions that showed either Paris IIa or IIb morphology with no serrated histopathology. These 'classical LSTs' showed the following molecular characteristics: microsatellite instability 0/56 (0%), APC mutation 29/30 (96.7%), CTNNB1 mutation 2/55 (3.6%), KRAS mutation 24/55 (43.6%) and BRAF mutation 2/55 (3.6%). Separation of lesions according to surface morphology showed that KRAS mutations occurred much more frequently in granular (56.4%, 22/39) than in nongranular LSTs (12.5%, 1/16, P=0.004). CONCLUSION: The microsatellite instable pathway is not important in the development of LSTs, which are instead likely to develop along a divergent chromosomal instability pathway. We demonstrate the biological significance of endoscopic findings by showing that the morphological characteristics of LSTs are underpinned by distinctive molecular profiles. PMID- 23354162 TI - A case-control study of transjugular intrahepatic portosystemic stent shunts for patients admitted to intensive care following variceal bleeding. AB - INTRODUCTION: Variceal bleeding has a 6-week mortality of 20%. Recent evidence suggests that early covered transjugular intrahepatic portosystemic stent shunts (TIPSS) can improve outcomes following a variceal bleed in selected patients. We aim to assess the outcomes following the insertion of covered TIPSS in a real life intensive care setting. MATERIALS AND METHODS: This is a retrospective matched cohort study of all patients referred for TIPSS with variceal bleeding admitted to intensive care (2007-2009). Patients were matched with others admitted to intensive therapy unit following a variceal bleed but did not proceed to TIPSS. All TIPSS procedures were carried out using polytetrafluoroethylene covered stents. RESULTS: Thirty-eight patients [mean age 55.2 years; mean model for end-stage liver disease (MELD)=14.0; and median follow-up 458 days] were assessed. Nineteen underwent TIPSS and were well matched to the controls. All patients received terlipressin and antibiotics and 86% had active bleeding at endoscopy. Indication for TIPSS was salvage therapy (47%), rebleeding after day 5 (11%) and as secondary prophylaxis (42%). There was 34% all-cause inpatient mortality. The TIPSS group had lower mortality than the non-TIPSS group at 6 weeks (10.5 vs. 47.4%, P<0.05) that persisted at 1 year (21.1 vs. 52.6%, P<0.05). Multivariate analysis indicated MELD [HR 1.131, 95% confidence interval (CI) 1.018-1.257] and TIPSS (HR 0.301, 95% CI 0.091-0.995) as significant predictors of mortality (P<0.05). TIPSS was found to significantly reduce the incidence of failure to control bleeding and rebleeding (HR 0.120, 95% CI 0.015-0.978, P<0.05). CONCLUSION: Patients with recent severe variceal bleeding admitted to intensive care have significantly better outcomes following covered TIPSS insertion. These findings should be validated in randomized-controlled trials. PMID- 23354163 TI - Clinical and ultrasound evaluation of the response to tocilizumab treatment in patients with rheumatoid arthritis: a case series. AB - This case series evaluates the clinical and ultrasound response to tocilizumab treatment in patients with rheumatoid arthritis (RA). Six patients with active RA (DAS28 >= 3.2) for >=6 months, refractory to conventional DMARDs or anti-TNF agents, received tocilizumab 8 mg/kg every 4 weeks, as monotherapy or in combination with DMARDs, for 6 months. The following clinical parameters were assessed monthly: number of tender joints (28 and 44 joints), number of swollen joints (28 and 44 joints), DAS28-ESR, DAS28-CRP, VAS score, global health status, health assessment questionnaire, patient global assessment of disease activity, physician global assessment of disease activity, functional assessment of chronic illness therapy (FACIT), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). All patients also underwent a gray-scale ultrasonography (US) assessment with power Doppler evaluation at each visit. All clinical parameters improved during the study, versus baseline. This improvement was statistically significant for most parameters 2 months following tocilizumab initiation and was sustained to the end of the observation period. The number of tender joints (44 joint evaluation), the FACIT score, and ESR and CRP concentrations were significantly improved versus baseline values after the first month of tocilizumab treatment. The course of US evaluations mirrored that of clinical parameters; a faster and more evident response was observed for foot joints, with respect to hand joints. This case series suggested the rapid clinical benefit of tocilizumab. Ultrasound assessment showed that the onset of this effect was faster in the foot joints than in the hand joints. PMID- 23354164 TI - Comparison of ultrasound (US)-guided intra-articular injections by in-plain and out-of-plain on medial portal of the knee. AB - To compare the accuracy rates between ultrasound (US)-guided in-plain (IP), out of-plain (OOP) and blind knee intra-articular (IA) injection via the mid-medial portal. US-guided IA injection in the IP, OOP, and blind methods was performed on 126 knees with radiographically confirmed knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) without effusion. About 6 ml of a mixed material containing 1% lidocaine (1 mL) and triamcinolone 20 mg (1 mL) and nonionic contrast (4 mL) was injected into the IA space of the knee through the mid-medial portals. After an US-guided and blind IA injection into the knee joint, a radiographic image was taken to determine whether the injected material had reached the IA space or infiltrated into the soft tissue. US-guided IA injections in the IP (97%; P < 0.05) and OOP method (95%; P < 0.05) showed significantly higher accuracy rate than injections in the blind injection (78%). Both US-guided IA injection methods may be used to access the knee joint with high degree of accuracy. PMID- 23354165 TI - Magnetic resonance imaging versus musculoskeletal ultrasonography in detecting inflammatory arthropathy in systemic sclerosis patients with hand arthralgia. AB - The aim of the study was the detection of inflammatory arthropathy in patients with systemic sclerosis (SSc) with arthralgia using musculoskeletal ultrasonography (MSUS) and magnetic resonance imaging (MRI) and to compare between MRI versus MSUS detecting musculoskeletal abnormalities and find out its relation with other clinical and laboratory parameters. Sixteen SSc patients with hand arthralgia had a baseline MSUS for their hands. Six months later, patients had a second MSUS and MRI with gadolinium of their most symptomatic hand. Of the 16 patients examined by MSUS, it was found that on baseline and second examination, tenosynovitis was seen in 8 (50 %) and 7 (43.7%) patients and synovitis was seen in 4 (25%) and 5 (31%) patients, respectively, indicating persistence synovial inflammation, and erosion was seen in only 1 (6.3%) patient on baseline and second examination. Regarding MRI, 81.3% (13) patients had tenosynovitis, 87.5% (14) patients had synovitis, and 62.5% (10) patients had erosions. Applying the RAMRIS system (a semiquantitative MRI scoring system used in RA), the mean values for synovitis, bone marrow edema, and erosions fell within the range seen in RA. Systemic sclerosis patients with arthralgia that have no obvious clinical inflammatory arthritis were found to have persistent inflammatory erosive arthropathy in their hands and wrists using MSUS and MRI. While both MRI and MSUS are useful in characterizing synovial inflammation in SSc, MRI is clearly more sensitive than MSUS in this setting. Further studies on larger number of SSc patients with arthralgia and a control group consisting of SSc patients without arthralgia to better establish the clinical and radiological findings in SSc. PMID- 23354166 TI - Centrobin controls mother-daughter centriole asymmetry in Drosophila neuroblasts. AB - During interphase in Drosophila neuroblasts, the Centrobin (CNB)-positive daughter centriole retains pericentriolar material (PCM) and organizes an aster that is a key determinant of the orientation of cell division. Here we show that daughter centrioles depleted of CNB cannot fulfil this function whereas mother centrioles that carry ectopic CNB can. CNB co-precipitates with a set of centrosomal proteins that include gamma-TUB, ANA2, CNN, SAS-4, ASL, DGRIP71, POLO and SAS-6. Following chemical inhibition of POLO or removal of three POLO phosphorylation sites present in CNB, the interphase microtubule aster is lost. These results demonstrate that centriolar CNB localization is both necessary and sufficient to enable centrioles to retain PCM and organize the interphase aster in Drosophila neuroblasts. They also reveal an interphase function for POLO in this process that seems to have co-opted part of the protein network involved in mitotic centrosome maturation. PMID- 23354167 TI - GATA3 suppresses metastasis and modulates the tumour microenvironment by regulating microRNA-29b expression. AB - Despite advances in our understanding of breast cancer, patients with metastatic disease have poor prognoses. GATA3 is a transcription factor that specifies and maintains mammary luminal epithelial cell fate, and its expression is lost in breast cancer, correlating with a worse prognosis in human patients. Here, we show that GATA3 promotes differentiation, suppresses metastasis and alters the tumour microenvironment in breast cancer by inducing microRNA-29b (miR-29b) expression. Accordingly, miR-29b is enriched in luminal breast cancers and loss of miR-29b, even in GATA3-expressing cells, increases metastasis and promotes a mesenchymal phenotype. Mechanistically, miR-29b inhibits metastasis by targeting a network of pro-metastatic regulators involved in angiogenesis, collagen remodelling and proteolysis, including VEGFA, ANGPTL4, PDGF, LOX and MMP9, and targeting ITGA6, ITGB1 and TGFB, thereby indirectly affecting differentiation and epithelial plasticity. The discovery that a GATA3-miR-29b axis regulates the tumour microenvironment and inhibits metastasis opens up possibilities for therapeutic intervention in breast cancer. PMID- 23354169 TI - Combined ACL reconstruction and closing-wedge HTO for varus angulated ACL deficient knees. AB - PURPOSE: To report the medium-term clinical and radiographic outcomes of a group of patients who underwent anterior cruciate ligament (ACL) surgery combined with high tibial osteotomy (HTO) for varus-related early medial osteoarthritis (OA) and ACL deficiency knee. METHODS: Thirty-two patients underwent single-bundle over-the-top ACL reconstruction or revision surgery and a concomitant closing wedge lateral HTO. The mean age at surgery was 40.1 +/- 8.1 years. Evaluation at a mean of 6.5 +/- 2.7 years of follow-up consisted of subjective and objective IKDC, Tegner Activity Level, EQ-5D, VAS for pain and AP laxity assessment with KT 1000 arthrometer. Limb alignment and OA changes were evaluated on radiographs. RESULTS: All scores significantly improved from pre-operative status to final follow-up. KT-1000 evaluation showed a mean side-to-side difference of 2.2 +/- 1.0 mm. Two patients were considered as failures. The mean correction of the limb alignment was 5.6 degrees +/- 2.8 degrees . Posterior tibial slope decreased at a mean of 1.2 degrees +/- 0.9 degrees . At final follow-up, the mechanical axes crossed the medial-lateral length of tibial plateau at a mean of 56 +/- 23 %, with only 1 patient (3 %) presenting severe varus alignment. OA progression was recorded only on the medial compartment (p = 0.0230), with severe medial OA in 22 % of the patients. No patients underwent osteotomy revision, ACL revision, UKA or TKA. CONCLUSIONS: The described technique allowed patients with medial OA, varus alignment and chronic ACL deficiency to restore knee laxity, correct alignment and resume a recreational level of activity at 6.5 years of follow-up. PMID- 23354168 TI - Spatial regulation of VEGF receptor endocytosis in angiogenesis. AB - Activities as diverse as migration, proliferation and patterning occur simultaneously and in a coordinated fashion during tissue morphogenesis. In the growing vasculature, the formation of motile, invasive and filopodia-carrying endothelial sprouts is balanced with the stabilization of blood-transporting vessels. Here, we show that sprouting endothelial cells in the retina have high rates of VEGF uptake, VEGF receptor endocytosis and turnover. These internalization processes are opposed by atypical protein kinase C activity in more stable and mature vessels. aPKC phosphorylates Dab2, a clathrin-associated sorting protein that, together with the transmembrane protein ephrin-B2 and the cell polarity regulator PAR-3, enables VEGF receptor endocytosis and downstream signal transduction. Accordingly, VEGF receptor internalization and the angiogenic growth of vascular beds are defective in loss-of-function mice lacking key components of this regulatory pathway. Our work uncovers how vessel growth is dynamically controlled by local VEGF receptor endocytosis and the activity of cell polarity proteins. PMID- 23354170 TI - The effect of lateral opening wedge distal femoral osteotomy on medial knee opening: clinical and biomechanical factors. AB - PURPOSE: The case of a patient with knee valgus and instability due to combined ACL-MCL laxity who underwent lateral opening wedge distal femoral osteotomy (DFO) is presented. The symptoms of instability resolved following the surgery. It was unclear whether the increase in valgus stability was related only to a decrease in valgus moments during stance or also to a medial tensioning effect. We therefore performed a laboratory cadaveric study. The purpose of this study was to examine whether after MCL and ACL sectioning, lateral opening wedge DFO would result in decrease in medial opening under static conditions of valgus stress. METHODS: Medial knee opening under valgus load of 9.8 Nm was tested in 8 cadaveric specimens in scenarios of MCL and ACL sectioning and compared before and after performing lateral opening wedge DFO. RESULTS: When the superficial MCL was sectioned, medial knee opening in 30 degrees flexion decreased after lateral opening wedge DFO compared to medial opening before the osteotomy (i.e. from 6.5 +/- 0.5 degrees to 5.6 +/- 0.5 degrees , p = 0.01). When the superficial MCL, deep MCL, and ACL were all sectioned, medial knee opening in extension decreased after lateral opening wedge DFO compared to medial opening before the osteotomy but this was not significant (i.e. from 6.8 +/- 0.5 degrees to 6.1 +/- 0.5 degrees , p = n.s.). CONCLUSION: In superficial MCL-transected knees, medial laxity at 30 degrees of knee flexion decreased after lateral opening wedge DFO. However, the clinical relevance of the laxity decrease observed remains uncertain since the reduction was small in magnitude. PMID- 23354171 TI - Translation and validation of 'The Knee Society Clinical Rating System' into Spanish. AB - PURPOSE: The Knee Society Clinical Rating System (KSS) is a questionnaire evaluating knee function itself and the patient's ability to walk and climb stairs. The aim of our study is to present the validated translation of KSS into Spanish. METHODS: The validated method of translation-retrotranslation was used to translate KSS into Spanish. Three hundred and sixteen patients undergoing primary knee arthroplasty, before surgery and 6 months postoperative, completed the questionnaire (with an orthopedist's help). Psychometric properties of feasibility (percentage of no answers), validity and sensitivity to change (test's ability to detect change in patients' functional status over time) were assessed. In the second part of the study, the translated version of KSS was compared with two already validated questionnaires (SF-36 and WOMAC). RESULTS: During the translation process, item 3 (ROM) presented low appropriateness and null comprehensibility. The alternative writing proposed was 'for every 5 degrees , we sum up 1 point, as if 8 degrees were 1 point, to obtain the maximum scoring of 25 points you should bend more than 200 degrees '. Feasibility: the item 'malalignment' obtained 15 % of missing item at visit 1. The percentage of invalid items was high in both visits (60 and 47 %). VALIDITY: the coefficients of convergent correlation with WOMAC and SF-36 scales confirm the questionnaire's validity. Sensitivity to change: significant differences were found in all cases between the mean scores comparing both visits. CONCLUSION: The translated version 1.1 of KSS (final version) has shown to be feasible, valid and sensible to changes within the clinical practice of patients undergoing primary knees arthroplasty. PMID- 23354172 TI - Audiovisual perception of noise vocoded speech in dyslexic and non-dyslexic adults: the role of low-frequency visual modulations. AB - Visual speech inputs can enhance auditory speech information, particularly in noisy or degraded conditions. The natural statistics of audiovisual speech highlight the temporal correspondence between visual and auditory prosody, with lip, jaw, cheek and head movements conveying information about the speech envelope. Low-frequency spatial and temporal modulations in the 2-7 Hz range are of particular importance. Dyslexic individuals have specific problems in perceiving speech envelope cues. In the current study, we used an audiovisual noise-vocoded speech task to investigate the contribution of low-frequency visual information to intelligibility of 4-channel and 16-channel noise vocoded speech in participants with and without dyslexia. For the 4-channel speech, noise vocoding preserves amplitude information that is entirely congruent with dynamic visual information. All participants were significantly more accurate with 4 channel speech when visual information was present, even when this information was purely spatio-temporal (pixelated stimuli changing in luminance). Possible underlying mechanisms are discussed. PMID- 23354173 TI - Optical trapping of nanoparticles. AB - Optical trapping is a technique for immobilizing and manipulating small objects in a gentle way using light, and it has been widely applied in trapping and manipulating small biological particles. Ashkin and co-workers first demonstrated optical tweezers using a single focused beam. The single beam trap can be described accurately using the perturbative gradient force formulation in the case of small Rayleigh regime particles. In the perturbative regime, the optical power required for trapping a particle scales as the inverse fourth power of the particle size. High optical powers can damage dielectric particles and cause heating. For instance, trapped latex spheres of 109 nm in diameter were destroyed by a 15 mW beam in 25 sec, which has serious implications for biological matter. A self-induced back-action (SIBA) optical trapping was proposed to trap 50 nm polystyrene spheres in the non-perturbative regime. In a non-perturbative regime, even a small particle with little permittivity contrast to the background can influence significantly the ambient electromagnetic field and induce a large optical force. As a particle enters an illuminated aperture, light transmission increases dramatically because of dielectric loading. If the particle attempts to leave the aperture, decreased transmission causes a change in momentum outwards from the hole and, by Newton's Third Law, results in a force on the particle inwards into the hole, trapping the particle. The light transmission can be monitored; hence, the trap can become a sensor. The SIBA trapping technique can be further improved by using a double-nanohole structure. The double-nanohole structure has been shown to give a strong local field enhancement. Between the two sharp tips of the double-nanohole, a small particle can cause a large change in optical transmission, thereby inducing a large optical force. As a result, smaller nanoparticles can be trapped, such as 12 nm silicate spheres and 3.4 nm hydrodynamic radius bovine serum albumin proteins. In this work, the experimental configuration used for nanoparticle trapping is outlined. First, we detail the assembly of the trapping setup which is based on a Thorlabs Optical Tweezer Kit. Next, we explain the nanofabrication procedure of the double-nanohole in a metal film, the fabrication of the microfluidic chamber and the sample preparation. Finally, we detail the data acquisition procedure and provide typical results for trapping 20 nm polystyrene nanospheres. PMID- 23354174 TI - Analysis of calcium homeostasis in fresh lymphocytes from patients with sporadic Alzheimer's disease or mild cognitive impairment. AB - Alzheimer's disease (AD) is the most widespread, age-related neurodegenerative disorder. Its two subtypes are sporadic AD (SAD) of unknown etiology and genetically encoded familial AD (FAD). The onset of AD is often preceded by mild cognitive impairment (MCI). Calcium dynamics were found to be dysregulated in FAD models, but little is known about the features of calcium dynamics in SAD. To explore calcium homeostasis during the early stages of SAD, we investigated store operated calcium entry (SOCE) and inositol triphosphate receptor (IP3R)-mediated calcium release into the cytoplasm in unmodified B lymphocytes from MCI and SAD patients and compared them with non-demented subjects (NDS). Calcium levels in the endoplasmic reticulum and both the rising and falling SOCE slopes were very similar in all three groups. However, we found that SAD and MCI cells were more prone to IP3R activation than NDS cells, and increases in calcium levels in the cytoplasm were almost twice as frequent in SAD cells than in NDS cells. MCI cells and SAD cells exhibited an enhanced magnitude of calcium influx during SOCE. MCI cells but not SAD cells were characterized by higher basal cellular calcium levels than NDS cells. In summary, perturbed calcium homeostasis was observed in peripheral cells from MCI and SAD patients. Thus, lymphocytes obtained from MCI subjects may be promising in the early diagnosis of individuals who will eventually develop SAD. However, no conclusions are made regarding SAD due to the limited number patients. This article is part of a Special Issue entitled: 12th European Symposium on Calcium. PMID- 23354175 TI - Lipid fingerprints of intact viruses by MALDI-TOF/mass spectrometry. AB - A number of viruses contain lipid membranes, which are in close contact with capsid proteins and/or nucleic acids and have an important role in the viral infection process. In this study membrane lipids of intact viruses have been analysed by MALDI-TOF/MS with a novel methodology avoiding lipid extraction and separation steps. To validate the novel method, a wide screening of viral lipids has been performed analysing highly purified intact bacterial and archaeal viruses displaying different virion architectures. Lipid profiles reported here contain all lipids previously detected by mass spectrometry analyses of virus lipid extracts. Novel details on the membrane lipid composition of selected viruses have also been obtained. In addition we show that this technique allows the study of lipid distribution easily in subviral particles during virus fractionation. The possibility to reliably analyse minute amounts of intact viruses by mass spectrometry opens new perspectives in analytical and functional lipid studies on a wider range of viruses including pathogenic human ones, which are difficult to purify in large amounts. PMID- 23354176 TI - cis-9,trans-11 conjugated linoleic acid stimulates expression of angiopoietin like-4 in the placental extravillous trophoblast cells. AB - A number of studies have been carried out to examine the biological function of conjugated linoleic acid (CLA) and its potential health benefits. However, not much is known about how CLA isomers mediate their effect on angiogenesis and vascularization during early placentation. In this paper we demonstrate that cis 9,trans-11(c9,t11)-CLA stimulated the expression of angiopoietin like-4 (ANGPTL4) mRNA and protein accompanied by tube formation in first trimester placental trophoblast cells, HTR8/SVneo whereas the other CLA isomer, trans-10,cis-12 (t10,c12)-CLA had no such effects. c9,t11-CLA however did not stimulate expression of the most potent angiogenic factor, vascular endothelial growth factor (VEGF) in these cells. Silencing ANGPTL4 in these cells significantly reduced the stimulatory effect of c9,t11-CLA on tube formation, indicating the involvement of ANGPTL4. In addition, c9,t11-CLA increased the mRNA expression of several pro-angiogenic factors such as fatty acid binding protein-4 (FABP4), cyclooxygenase-2 (COX-2) and adipose differentiation-related protein (ADRP) in HTR8/SVneo cells. c9,t11-CLA also induced the uptake of docosahexaenoic acid, 22:6n-3 (DHA), a stimulator of tube formation in these cells. Triacsin C, an acylCoA synthetase inhibitor, attenuated c9,t11-CLA induced DHA uptake, tube formation and cellular proliferation in HTR8/SVneo cells. Our data suggest that the c9,t11-CLA isomer may regulate angiogenic processes during early placentation via increased expression of ANGPTL4 and other pro-angiogenic factors such as FABP4, COX-2 and ADRP with concomitant increase in the uptake of DHA in these cells. PMID- 23354177 TI - Fat lowers fat: purified phospholipids as emerging therapies for dyslipidemia. AB - Dyslipidemia is a major coronary heart disease (CHD) risk factor. In spite of the proven efficacy of statin drugs in reducing CHD burden, there is still much room for the discovery of novel therapeutic agents to address the considerable residual cardiovascular risk that remains after treatment with currently available medications. In particular, there is an urgent demand for drugs capable of boosting the concentration and/or function of high-density lipoprotein (HDL) and apolipoprotein A-I (apo A-I), thereby promoting reverse cholesterol transport. Phospholipids are naturally occurring fats that play indispensible role in human health via their structural, energy storage, signal transduction and metabolic functions. Supplementation with either purified or mixed preparations of bioactive phospholipids has been reported to ameliorate a range of nutritional and cardiovascular disorders. Moreover, several lines of evidence have supported the efficacy of dietary phospholipids in reducing serum and hepatic contents of cholesterol and triglycerides, while increasing HDL-C and apo A-I levels. These beneficial effects of phospholipids could be attributed to their ability in reducing intestinal cholesterol absorption, enhancing biliary cholesterol excretion and modulating the expression and activity of transcriptional factors and enzymes that are involved in lipoprotein metabolism. Given their extreme safety and biocompatibility, dietary supplementation with phospholipid preparations, in particular phosphatidylinositol, appears as a novel and effective strategy that could be used as an alternative or adjunctive therapy to the current medications. The present review outlines the in-vitro, in-vivo and clinical findings on the anti-dyslipidemic effects of three most abundant phospholipids in the human body and diet namely phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol. PMID- 23354178 TI - The GRS/GRC from the perspective of a graduate student and first time attendee. AB - The networking and collaborative opportunities afforded to the attendees of the Ocean and Human Health Gordon Research Seminar (GRS) and the Gordon Research Conference (GRC) are vast and great. The GRS/GRC, in particular, has the capability of facilitating interlaboratory and interdisciplinary collaborations. The following article highlights the benefits associated with attending the GRS/GRC as a graduate student and first time attendee. PMID- 23354180 TI - Dynamics of seawater bacterial communities in a shellfish hatchery. AB - Bacterial disease is a significant issue for larviculture of several species of shellfish, including oysters. One source of bacteria is the seawater used throughout the hatchery. In this study carried out at a commercial oyster hatchery in Tasmania, Australia, the diversity of the bacterial community and its relationship with larval production outcomes were studied over a 2-year period using terminal restriction fragment length polymorphism and tag-encoded pyrosequencing. The bacterial communities were very diverse, dominated by the Alphaproteobacteria, Gammaproteobacteria, Flavobacteria and Cyanobacteria. The communities were highly variable on scales of days, weeks and seasons. The difference between the intake seawater and treated clean seawater used in the hatchery was smaller than the observed temporal differences in the seawater throughout the year. No clear correlation was observed between production outcomes and the overall bacterial community structure. However, one group of Cyanobacterial sequences was more abundant when mass mortality events occurred than when healthy spat were produced although they were always present. PMID- 23354181 TI - The rise of pathogens: predation as a factor driving the evolution of human pathogens in the environment. AB - Bacteria in the environment must survive predation from bacteriophage, heterotrophic protists, and predatory bacteria. This selective pressure has resulted in the evolution of a variety of defense mechanisms, which can also function as virulence factors. Here we discuss the potential dual function of some of the mechanisms, which protect against heterotrophic protists, and how predation pressure leads to the evolution of pathogenicity. This is in accordance with the coincidental evolution hypothesis, which suggests that virulence factors arose as a response to other selective pressures, for example, predation rather than for virulence per se. In this review we discuss some of those environmental factors that may be associated with the rise of pathogens in the marine environment. In particular, we will discuss the role of heterotrophic protists in the evolution of virulence factors in marine bacteria. Finally, we will discuss the implications for expansion of current pathogens and emergence of new pathogens. PMID- 23354182 TI - Localization of SUMOylation factors and Osterix in odontoblast lineage cells during dentin formation and regeneration. AB - Small ubiquitin-related modifier (SUMO) conjugation (SUMOylation) is a post translational modification involved in various cellular processes including the regulation of transcription factors. In this study, to analyze the involvement of SUMOylation in odontoblast differentiation, we examined the immunohistochemical localization of SUMO-1, SUMO-2/3, and Osterix during rat tooth development. At the bud and cap stages, localization of SUMOs and Osterix was hardly detected in the dental mesenchyme. At the bell stage, odontoblasts just beginning dentin matrix secretion and preodontoblasts near these odontoblasts showed intense immunoreactivity for these molecules. However, after the root-formation stage, these immunoreactivities in the odontoblasts decreased in intensity. Next, to examine whether the SUMOylation participates in dentin regeneration, we evaluated the distribution of SUMOs and Osterix in the dental pulp after cavity preparation. In the coronal pulp chamber of an untreated rat molar, odontoblasts and pulp cells showed no immunoreactivity. At 4 days after cavity preparation, positive cells for SUMOs and Osterix appeared on the surface of the dentin beneath the cavity. Odontoblast-like cells forming reparative dentin were immunopositive for SUMOs and Osterix at 1 week, whereas these immunoreactivities disappeared after 8 weeks. Additionally, we further analyzed the capacity of SUMO 1 to bind Osterix by performing an immunoprecipitation assay using C2C12 cells, and showed that Osterix could undergo SUMOylation. These results suggest that SUMOylation might regulate the transcriptional activity of Osterix in odontoblast lineage cells, and thus play important roles in odontoblast differentiation and regeneration. PMID- 23354179 TI - Contrasting patterns of community assembly in the stratified water column of Great Salt Lake, Utah. AB - Phylogenetic examinations of communities sampled along geochemical gradients provide a framework for inferring the relative importance of niche-based ecological interactions (competition, environmental filtering) and neutral-based evolutionary interactions in structuring biodiversity. Great Salt Lake (GSL) in Utah exhibits strong spatial gradients due to both seasonal variation in freshwater input into the watershed and restricted fluid flow within North America's largest saline terminal lake ecosystem. Here, we examine the phylogenetic structure and composition of archaeal, bacterial, and eukaryal small subunit (SSU) rRNA genes sampled along a stratified water column (DWR3) in the south arm of GSL in order to infer the underlying mechanism of community assembly. Communities sampled from the DWR3 epilimnion were phylogenetically clustered (i.e., coexistence of close relatives due to environmental filtering) whereas those sampled from the DWR3 hypolimnion were phylogenetically overdispersed (i.e., coexistence of distant relatives due to competitive interactions), with minimal evidence for a role for neutral processes in structuring any assemblage. The shift from phylogenetically clustered to overdispersed assemblages was associated with an increase in salinity and a decrease in dissolved O2 (DO) concentration. Likewise, the phylogenetic diversity and phylogenetic similarity of assemblages was strongly associated with salinity or DO gradients. Thus, salinity and/or DO appeared to influence the mechanism of community assembly as well as the phylogenetic diversity and composition of communities. It is proposed that the observed patterns in the phylogenetic composition and structure of DWR3 assemblages are attributable to the meromictic nature of GSL, which prevents significant mixing between the epilimnion and the hypolimnion. This leads to strong physicochemical gradients at the halocline, which are capable of supporting a greater diversity. However, concomitant shifts in nutrient availability (e.g., DO) at and below the halocline drive competitive interactions leading to hypolimnion assemblages with minimal niche overlap. PMID- 23354184 TI - Post-transplantation lymphoproliferative disorders in renal vs. simultaneous renal-pancreas allograft recipients: a survey and analysis of data from the literature. AB - The epidemiology and other aspects of post-transplantation lymphoproliferative disorders (PTLD) are different in different transplant populations. In this study, we sought to determine the clinical, histopathological and various other features of PTLD in recipients of pancreas-renal allografts and to compare their data with renal-only transplant patients, based on the current available literature. We conducted a comprehensive search for the available data using the Pubmed and Google scholar search engines for reports of lymphoproliferative disorders after renal and simultaneous pancreas-renal (SPR) transplantations. A total of 229 recipients of renal and pancreas-renal allografts were included in the analysis. Localizations for SPR recipients were significantly higher than renal recipients in the pancreas (P <0.0001), skin (P = 0.035), liver (P = 0.043) and bone marrow (P = 0.022). Involvement of lymph nodes was more prevalent in renal recipients (P = 0.046). The occurrence of metastasis was more common among SPR recipients (P = 0.005). Hodgkin's and Hodgkin's-like PTLD were also more prevalent among SPR transplant patients (P <0.0001). Time to development of PTLD was significantly shorter among recipients of SPR (P <0.0001). In this study of international data, we found that PTLD in SPR transplant recipients have various characteristics in their site of involvement, disease presentation time and histopathological features. However, no difference in outcome was detected in these groups of PTLD patients. Future studies with larger study populations are needed for confirming and extending our study results. PMID- 23354185 TI - Focal and segmental glomerulosclerosis in renal allograft recipients: a clinico pathologic study of 37 cases. AB - Focal and segmental glomerulosclerosis (FSGS) in renal allografts may occur as a recurrence of primary FSGS, as a de novo phenomenon or as a complication of calcineurin inhibitor toxicity. There are very few studies in the literature describing the clinico-pathologic characteristics of FSGS in renal allografts. To the best of our knowledge, no such study exists from the Indian subcontinent. Thirty-seven cases showing FSGS, of 426 transplant biopsies performed over a 4 year period (2006-2009), were included in this study. The pre- and post transplant clinical data were noted. FSGS was classified as per the Columbia scheme. Appropriate statistical tests were applied. The age of the study patients ranged from 13 to 54 years, with a male preponderance. Thirty-five patients (94.6%) were diagnosed as FSGS more than 12 months after transplantation. All the patients presented with renal dysfunction (median serum creatinine 2.8 mg/dL) and detectable proteinuria at the time of diagnosis. Histologically, FSGS-NOS (70.3%) was observed as the most common subtype, followed by collapsing and perihilar varieties (13.5% each). Most of the biopsies (83.7%) showed grade-2 to -3 interstitial fibrosis and tubular atrophy. Follow-up data were available in 27 patients (73%), of whom 12 (44.4%) had graft loss with dialysis-dependent state at last follow-up. FSGS is one of the important causes of graft dysfunction, especially late in the post-transplantation period in cases of de novo FSGS. The long-term outcome of renal allografts developing this glomerular pathology is quite dismal, with a significant proportion of patients suffering graft loss. PMID- 23354183 TI - Adult immunization policies in advanced economies: vaccination recommendations, financing, and vaccination coverage. AB - OBJECTIVES: While many countries have robust child immunization programs and high child vaccination coverage, vaccination of adults has received less attention. The objective of this study was to describe the adult vaccination policies in developed countries. METHODS: From 2010 to 2011, we conducted a survey of 33 advanced economies as defined by the International Monetary Fund. The survey asked about national recommendations for adults for 16 vaccines or vaccine components, funding mechanisms for recommended adult vaccines, and the availability of adult vaccination coverage estimates. RESULTS: Thirty-one of 33 (93.9 %) advanced economies responded to the survey. Twelve of 31 (38.7 %) reported having a comprehensive adult immunization schedule. The total number of vaccines or vaccine components recommended for adults ranged from one to 15 with a median of 10. Seasonal influenza (n = 30), tetanus (n = 28), pneumococcal polysaccharide (n = 27), and hepatitis B (n = 27) were the most frequently recommended vaccines or components. CONCLUSIONS: Approximately two-thirds of survey respondents do not have a comprehensive adult vaccine schedule, and most do not measure vaccination coverage. We found that a funding mechanism is available for most recommended adult vaccines. PMID- 23354186 TI - Single-center experience on renal transplantation in primary focal and segmental glomerulosclerosis using hematopoietic stem cell transplantation in thymus, bone marrow, portal and peripheral circulation. AB - Recurrence of primary focal segmental glomerulosclerosis (FSGS) is an important cause of graft loss after renal transplantation (RTx). We report our experience in 34 patients with primary FSGS who underwent RTx between April 1999 and June 2009, using hematopoietic stem cell transplantation (HSCT). They belonged to four groups: group 1 (n = 12) received high-dose HSCT in periphery, thymus, bone marrow, and portal circulation with low-dose non-myeloablative conditioning; group 2 (n = 7) was modified with HSCT without marrow/thymic infusion; and group 3 (n = 3) received HSCT and proteasome inhibitor Bortezomib replacing conditioning. Group 4 (n = 12), were controls who opted for RTx under standard triple-drug immunosuppression. Patient/donor demographics were comparable in all. No recurrence was noted in group 1 with mean follow-up of 8.1 years, whereas 28.6% of group 2, 33.3% of group 3, and 36.4% of group 4 had recurrence over mean follow-up of 2.6, 1.1, and 6.5 years, respectively. Mean serum creatinine was 1.62, 1.69, 1.41, and 1.73 mg%, respectively. Rejections were noted in 41.7%, 28.6%, 0%, and 45.5% grafts, respectively. Groups 1 and 4 had 25% patient loss each, group 2 had 28.6% loss, and no loss was observed in group 3. Graft loss was noted in 33.3% in group 1, 14.3% in group 2, nil in group 3, and 16.7% in the last group. Recurrent FSGS was prevented in RTx with HSCT in thymic, marrow infusion under low-dose non-myeloablative conditioning compared to controls and Bortezomib group, thus suggesting potential role of central tolerance in FSGS. PMID- 23354187 TI - Rapid accelerated hemodialysis in children with end-stage renal disease: a randomized clinical trial. AB - In rapid accelerated hemodialysis (R-AHD), blood partially recirculates from the venous (outflow) to the arterial (inflow) line through a recirculation line (R) to selectively increase the filter blood flow rate (BFR). R-AHD PR uses two blood pump segments at the patient segment of the arterial line and at (R). To determine the effectiveness of R-AHD with regard to increasing anticoagulation and dialysis efficiency, we studied ten children with end-stage renal disease in two stages: stage 1 with 10 routine heparin R-AHD, then 10 half-dose heparin R AHD, then 145 routine heparin R-AHD sessions for 1 month and then routine heparin double needle hemodialysis (DNHD) for one month (control). In stage 2, we dialyzed the patients with 10 routine heparin-mixed AHD PR and DNHD sessions, then eight low-dose heparin R-AHD PR" sessions, then one of the children with 10 no-heparin R-AHD PR sessions and then 10 routine heparin DNHD sessions" (control). Signs of blood clotting and dialysis efficiency were monitored. Blood clots appeared in four out of 165 R-AHD 0 (one pump circuit) sessions but in none of the 28 R-AHD PR sessions. In stage 1, the mean urea reduction rate was 0.60, 0.60 and 0.70 for the R-AHD protocols, compared with 0.71 for the control (P >0.05). In stage 2, the arterial blood urea nitrogen was reduced by 0.66 +/- 0.15 after an R-AHD PR period, compared with 0.79 +/- 0.18 after a DNHD period (P = 0.059). In conclusion, R-AHD PR allowed successful low heparin and no heparin hemodialysis in children without increasing the patients' BFR. However, the technique did not increase the efficiency of dialysis. PMID- 23354188 TI - Ultrasound predictors of compensated liver cirrhosis in hemodialysis patients with hepatitis C. AB - Ultrasound examination was performed in 80 hemodialysis (HD) patients with chronic hepatitis C in order to determine the ultrasound predictors of compensated liver cirrhosis. The ultrasound score (US) was calculated from the morphological parameters (liver size, morphology, surface, echogenicity and spleen volume) and the hemodynamic parameters (portal vein diameter and portal vein mean flow velocity). The US ranged from 0 to 200, with a cut-off value of 66, for discrimination between absence and presence of liver cirrhosis. A logistic regression model with stepwise variable selection was used to determine predictors of the progression of liver disease. According to the calculated US, patients were divided into two groups. The first group consisted of 37 (46.3%) patients with US greater than 66, indicating the presence of compensated liver cirrhosis. The second group included 43 (53.7%) patients without liver cirrhosis, with US equal to or less than 66. The value of liver morphology was significantly higher, but the portal vein flow velocity was significantly lower in patients with compensated liver cirrhosis compared with those without cirrhosis. Furthermore, rounded liver surfaces and increased liver echogenicity were significantly more frequent in patients with compensated liver cirrhosis compared with the non-compensated group. Logistic regression model with stepwise discriminant analysis identified liver morphology, liver echogenicity and portal vein mean flow velocity as independent ultrasound predictors of compensated liver cirrhosis in HD patients with chronic hepatitis C. Ultrasound examination could be used for non-invasive diagnosis of compensated liver cirrhosis, with accurate estimation of the disease severity in HD patients with chronic hepatitis C. PMID- 23354189 TI - Mucocutaneous manifestations and nail changes in patients with end-stage renal disease on hemodialysis. AB - Mucocutaneous manifestations are common among patients on hemodialysis (HD). This study was undertaken to determine the prevalence of mucocutaneous manifestations in patients with end-stage renal disease (ESRD) who are on HD. In this cross sectional, descriptive and analytic study conducted in 2009, 100 patients on HD at the Five Azar Hospital in Gorgan city were randomly selected. All the patients underwent detailed examination by a dermatologist to look for lesions in the skin, hair, nail and mucous membranes; if felt necessary, biopsy was obtained from the lesions. The findings were statistically analyzed using SPSS-13 software. For evaluation of normality of distribution, Kolmogorov-Smirnov was used, for quantitative variables Mann-Whitney and T-test (abnormal distribution) were used and for qualitative variables, Chi-2 and Fisher were used. In this study, P-value less than 0.05 was considered significant. Fifty-one males and 49 females were enrolled. The mean age was 49 +/- 12 years. Diabetes was the most common cause of ESRD. In 95% of the patients, at least one mucocutaneous manifestation was present. Xerosis (78.3%) was the most common lesion, followed by pruritus (39.1%), lentigo (34.8%), skin discoloration (32.6%), leukonychia (32%) and thinning of the nail bed (24%). Xerosis, scaling, lentigo, folliculitis, idiopathic guttate hypopigmentation, leukonychia and half and half nail were associated with age. A significant relationship was seen between duration on dialysis and skin discoloration and leukonychia. Clubbing had a significant association with calcium-phosphorus product (Ca * P). There was a significant association between serum ferritin level and pruritus and tinea versicolor lesions. Our study shows that mucocutaneous manifestations are common among patients with ESRD. Identification of these manifestations and their association with causative factors are useful for preventing the lesions. PMID- 23354191 TI - Troponin-I is not falsely elevated in asymptomatic dialysis patients. AB - Dialysis patients with troponin-I levels above the cut-off value diagnostic for acute myocardial event (AME) are sometimes labeled as having "renal cause" of elevated troponin-I. Patients with troponin-I levels above 0.0 ng/mL, but below the cut-off level for an AME, are reported to have increased risk for coronary heart disease and mortality. Single pre-dialysis blood samples were taken from 150 asymptomatic dialysis patients (on hemo- or peritoneal dialysis) for troponin I, cardiac enzymes, C-reactive protein (CRP) and lipid parameters. Troponin-I was measured by a chemiluminescent microparticle immunoassay (CMIA), of which the cut off value for AME was set at >=0.4 ng/mL. Patients with troponin-I levels of 0.0 ng/mL, and those with levels between 0.1 and 0.3 ng/mL, were compared regarding their cardiovascular risk profile. None of the patients had troponin-I concentrations above the cut-off level diagnostic for an AME, with 85.3% of the patients having levels of 0.0 ng/mL. While there was no difference in the "traditional" risk factors such as age, body mass index, prevalence of diabetes mellitus, hypertension, total cholesterol and low-density lipoprotein cholesterol between patients with troponin-I levels of 0.1-0.3 ng/mL and those with levels of 0.0 ng/mL, CRP concentrations were higher in the former. In peritoneal dialysis patients, the weekly Kt/V was lower in the patients with troponin levels between 0.1 and 0.3 ng/mL. The findings should add strong support in settling the debate of whether or not in patients on dialysis, falsely elevated levels of troponin-I "commonly" occur. An increased level of CRP and lower Kt/V might add to the cardiovascular risk in patients with troponin-levels between 0.1 and 0.3 ng/mL. PMID- 23354190 TI - Relationship between serum leptin levels and bone mineral density and bone metabolic markers in patients on hemodialysis. AB - Leptin is the protein product of the obesity gene, which is produced in fat tissue. It was originally thought to be involved only in the regulation of food intake and energy balance. We aimed to investigate the relationship of serum leptin levels with bone mineral density (BMD) and biochemical markers of bone turnover in patients on hemodialysis (HD). This study included 72 patients (43 males and 29 females), whose mean age was 55.1 +/- 11.4 years, mean body mass index was 23.13 +/- 2.75 kg/m 2 and mean duration on HD was 5 +/- 3.4 years. The BMD values were calculated using dual-energy X-ray absorptiometry (DEXA) at the femoral neck and lumbar spine. Blood samples were taken for leptin, intact parathyroid hormone (I-PTH), bone alkaline phosphatase (BAP), calcium (Ca), phosphate (P) and albumin. The leptin levels were higher in females than in males (22.3 +/- 19.6 vs 20.8 +/- 23), but this difference was not significant. The serum leptin level had a strong positive correlation with Ca levels in the female patients (r = 0.659 and P = 0.01) and a negative correlation with albumin levels (r = -0.461 and P = 0.01). No correlation was found with age, BMI, duration on dialysis, BMD and serum levels of PTH, BAP and P for the entire patient group or either gender separately. The serum leptin level was significantly lower in females with PTH >300 pg/mL when compared with patients with PTH = 100-300 pg/mL (86 +/- 85 vs 47 +/- 48) (P = 0.011).Women with BAP <300 IU/L had significantly higher serum leptin than those with BAP 300-600 IU/L (P = 0.024). Women with Ca <8.5 mg/dL had significantly lower serum leptin levels compared with those with Ca levels of 8.5-10.5 mg/dL (P = 0.011). There was no significant difference between the two genders among variables such as age, BMI, duration on dialysis, serum leptin, I-PTH, Ca, P, BAP, albumin and BMD of the femoral neck and lumbar spine. PMID- 23354192 TI - Risk factors for renal scarring in children with primary vesicoureteral reflux disease. AB - To determine the incidence of renal scarring among patients with primary vesicoureteral reflux (VUR) and the possible risk factor(s), we studied 90 children (60 girls and 30 boys) with VUR followed in the Pediatric Nephrology Unit at the Ege University Hospital from 1998 to 2003. All the patients were assessed for VUR grade by voiding cystoureterography and for presence of renal scarring by (99 m) technetium dimercapto-succinic acid scintigraphy. All infants with VUR were given low-dose prophylactic antibiotics and followed-up until resolution of the reflux. Grade of reflux and number of urinary tract infection (UTI) episodes (>=3) were found to be statistically significant risk factors for renal scarring (P <0.05). However, gender, familial history and laterality of the disease were not found to be statistically significant risk factors (P >0.05). Similarly, there was no statistically significant difference of frequency of renal scarring among the different age groups (P >0.05). We conclude that recurrences of UTI and VUR severity are significant risk factors for renal scarring in children with VUR. Therefore, identification of VUR at an early age may offer the opportunity to prevent episodes of UTI and possible formation of renal scars that may result in end-stage renal failure. PMID- 23354193 TI - Effect of BMI and urinary pH on urolithiasis and its composition. AB - Urolithiasis is a common urological disease predominantly affecting males. The lifetime risk of urolithiasis varies from 1% to 5% in Asia, 5% to 9% in Europe, 10% to 15% in the USA and 20% to 25% in the middle-east; lowest prevalence is reported from Greenland and Japan. Such differences have been explained on the basis of race, diet and climate factors. Furthermore, changing socio-economic conditions have generated changes in the prevalence, incidence and distribution for age, sex and type of lithiasis in terms of both the site and the chemical as well as the physical composition of the calculi. The aim of our study was to determine the association between body mass index (BMI) and urine pH in patients with urolithiasis and the influence of body size, as reflected by the BMI, on the composition. The study was conducted in the Department of Biochemistry, Maharishi Markandeshwar Institute of Medical Sciences and Research, on urolithiatic patients. The data included patient's age, sex, BMI, urine pH, serum calcium, serum uric acid, serum creatinine and stone composition. Data from 100 patients, 70 men (70%) and 30 women (30%), were analyzed, with 28 patients having normal weight, 38 patients being overweight and 34 patients being obese. The mean age of the patients was 36.58 +/- 9.91 years in group I, 40.47 +/- 14.48 years in group II and 37.85 +/- 12.46 years in group III (P > 0.05). The stone composition was calcium oxalate (CaOx) in 66 patients, calcium phosphate (CaP) in 60 patients, uric acid (UA) in 38 patients, combined calcium oxalate and calcium phosphate in 28 patients and three stones in 10 patients. The urinary pH levels (mean +/- SD) were 7.78 +/- 1.49 in group I, 7.15 +/- 1.11 in group II and 6.29 +/- 1.14 in group III patients (P = 0.0001). Urine pH showed a stepwise decrease with increasing BMI (inverse correlation). Urine pH is inversely related to BMI among patients with urolithiasis, as is the occurrence of urate, calcium oxalate and calcium phosphate stones. Similarly, the serum creatinine increased as the BMI and number of stones increased among the study population. PMID- 23354194 TI - Assessing the intelligence of children with chronic kidney diseases. AB - To evaluate the level of intelligence in children with chronic kidney diseases (CKDs), 12 children with CKD stage 5 on regular hemodialysis, 12 children in the predialysis stage, and 12 as controls were assessed using the Wechsler Intelligence Scale for Children (WISC). Mean scores on the verbal, performance, and full scale IQ were significantly lower in the predialysis and dialysis children than in the healthy children, while the mean score on the arithmetic subtests was significantly lower in the predialysis children than in the dialysis group. In conclusion, a better understanding of the neurocognitive function in children with CKDs is a critical element to be ascertained early with proper assessment programs so as to design appropriate educational interventions for this handicapping illness. PMID- 23354195 TI - Deafness and blindness in a renal transplant recipient with cryptococcal meningitis. AB - Infections are a major determinant of outcome in kidney transplantation. Opportunistic pathogens are common in kidney recipients and several organs can be affected. Central nervous system infection in transplant recipients is a medical emergency. There is limited information in the literature concerning post transplantation cryptococcal infection. Deafness and blindness are not classic findings. We report a case of meningocerebral cryptococcosis complicated by deafness and blindness after kidney transplantation. Physicians need to consider the possibility of Cryptococcus neoformans when symptoms persist despite empiric antimicrobial therapy. PMID- 23354196 TI - A fatal case of prostatic abscess in a post-renal transplant recipient caused by Cladophialophora carrionii. AB - Fungal infection secondary to renal transplantation poses a significant threat to the life of the recipient with a high rate of morbidity and mortality. A high index of suspicion is necessary for early diagnosis of fungal infections in such patients. We herein report a fatal case of prostatic abscess in a post-renal transplant recipient. PMID- 23354197 TI - Cytomegalovirus disease in a renal transplant recipient: the importance of pre transplant screening of the donor and recipient. AB - A 16-year-old female patient who was born with a single kidney developed chronic kidney disease during her early childhood due to reflux nephropathy and recurrent urinary tract infection. She progressed to end-stage renal disease (ESRD) and was commenced on renal replacement therapy in the form of peritoneal dialysis in May 2011. Subsequently, she underwent living unrelated donor kidney transplantation in China. She was hospitalized soon after returning to Saudi Arabia for management of high-grade fever, shortness of breath, and deterioration of renal function, which was found to be due to cytomegalovirus (CMV) disease, proved by kidney biopsy and presence of high level of anti-CMV immunoglobulins. Allograft biopsy showed mature viral particles sized between 120 and 149 nm in the nuclei of the glomerular endothelial cells. The patient was treated with valgancyclovir and specific CMV immunoglobulin, as well as by reducing and even stopping the dose of tacrolimus and mycophenolate. Despite all these measures, her condition continued to deteriorate and she finally died. Our study emphasizes that unrelated renal transplantation, especially if unplanned and improperly prepared, is a very risky procedure that might transfer dangerous diseases and increase the morbidity and mortality of the patients. We strongly stress the need for mandatory and proper screening for CMV carrier status among donors as well as recipients prior to transplantation. Also, a recommendation is made to reject CMV positive donors. PMID- 23354198 TI - Florid diabetic complications in impaired glucose tolerance. AB - We report a 56-year-old gentleman who had a history of impaired fasting glucose 4 years earlier but spontaneously reverted to normoglycemia. He subsequently presented with impaired glucose tolerance and proteinuria. Detailed evaluation revealed florid complications of diabetes, including nodular glomerulosclerosis of the kidney. Such complications in pre-diabetes have rarely been reported. We need to search for them early to prevent further morbidity. PMID- 23354199 TI - Bladder hamartoma: a unique cause of urinary retention in a child with Goldenhar syndrome. AB - The bladder hamartoma is an extremely rare entity. We report on its presence in a 5-year-old boy with Goldenhar syndrome. Most probably, this is the first report of a bladder hamartoma presenting with obstruction of the bladder outlet resulting in urinary retention. The obstructive lesion was resected endoscopically. This proved to be curative for the lesion, since the follow-up voiding cysto-urethrogram revealed only a negligible post-void residual volume. Although urogenital anomalies have a well-known correlation with the Goldenhar syndrome, the existence of the bladder hamartoma found in association with this syndrome, according to the best of our knowledge, has not been previously reported in the world literature. With this report being only the 11 th described case of bladder hamartoma, we highlight on the management options for this exceptional histological finding. The incidence, screening, treatment decisions and important urogenital associations of the Goldenhar syndrome are also discussed. PMID- 23354200 TI - Acute renal failure in a patient with acute lymphoblastic leukemia: a rare cause. AB - A young adult was diagnosed to have acute lymphoblastic leukemia, T-cell immunophenotype and was initiated on chemotherapy. He presented with acute renal failure two days after the completion of his induction regimen. A renal biopsy showed features of necrotizing crescentic glomerulonephritis (GN). Serology for c anti-neutrophil cytoplasmic antibody (ANCA) was positive and a final diagnosis of ANCA-associated necrotizing crescentic GN was made. Aggressive immunosuppression could not be used due to the presence of nosocomial pneumonia and the patient expired 26 days after the renal biopsy diagnosis. We report for the first time the association of acute lymphoblastic leukemia with crescentic GN and, hence, expand the list of malignancy-related ANCA-positive GN. PMID- 23354201 TI - Emphysematous pyelonephritis in a non-diabetic patient with non-obstructed kidney: an unknown entity. AB - Emphysematous pyelonephritis (EPN) is an acute necrotizing infection with evidence of gas inside the kidney, perinephric space, and/or urinary collecting system. This condition is usually encountered in an obstructed urinary system of diabetics or immunocompromised patients and carries poor prognosis. The gold standard for early diagnosis is computed tomography (CT) of the abdomen. Percutaneous/surgical drainage and urgent or delayed nephrectomy are the available treatment options. We report one case of EPN, which was diagnosed in an immunocompetent non-diabetic man with a non-obstructed urinary system. PMID- 23354202 TI - Metastatic renal cell carcinoma of gall bladder. AB - Renal cell carcinoma (RCC) is well known for its propensity to metastasize to unusual sites. Metastasis to the gall bladder (GB) has been reported in the literature rarely. We herein report an interesting case of metastatic RCC, which presented with cholecystitis. Gall bladder is a rare site of metastasis of RCC. Polypoid lesions of the GB in patients who have a synchronous or a prior history of RCC should be considered as metastatic lesions. It needs to be differentiated from primary clear cell carcinoma of the GB with the help of immunohistochemistry. PMID- 23354203 TI - Acute tubular necrosis in a patient with paroxysmal nocturnal hemoglobinuria. AB - Acute renal failure (ARF) is a well-recognized complication of paroxysmal nocturnal hemoglobinuria (PNH). The predominant mechanism is intravascular hemolysis resulting in massive hemoglobinuria ARF. We report a case of acute tubular necrosis (ATN) developed in the absence of overwhelming evidence of intravascular hemolysis in a 21-year-old man with anemia, who was eventually diagnosed to have PNH. The patient presented with rapidly deteriorating renal functions in the background of iron deficiency anemia, which was attributed to reflux esophagitis. There was no clinical or laboratory evidence of intravascular hemolysis. Renal biopsy revealed ATN with deposition of hemosiderin in the proximal tubular epithelial cells. Diagnosis of PNH was confirmed with a positive Ham's test and flow cytometry. Our case emphasizes the need to consider ATN as a possible cause for ARF in patients suspected to have PNH even in the absence of overwhelming evidence of intravascular hemolysis. PMID- 23354204 TI - Long-term outcome of upper limb autogenous arteriovenous fistulas for hemodialysis access. AB - Provision of a reliable and durable vascular access for hemodialysis continues to be a challenge for clinicians. The aim of this study was to examine the outcome of upper limb autogenous arteriovenous fistula procedures for hemodialysis and factors influencing access survival. A retrospective review was carried out on 575 patients who underwent 842 consecutive vascular access procedures done over a period of ten-years. The overall primary failure rate was 5.5%, whereas the one- and five-year cumulative access survival rates were 70.0% and 52.1%, respectively. Diabetes mellitus status significantly influenced access survival (P = 0.022). Autogenous arteriovenous fistulas are reliable procedures with access sites often available in both the forearm and the arm. Patients with diabetes mellitus have significantly worse patency rates of upper limb autogenous arteriovenous fistulae. PMID- 23354205 TI - Buccal mucosal graft urethroplasty in long segment anterior urethral stricture - is it gold standard? AB - To assess the success of dorsal onlay buccal mucosal graft (BMG) urethroplasty in long segment anterior urethral stricture extending from external meatus to bulbar urethra). We studied 40 patients with long segment anterior urethral stricture, who underwent substitution urethroplasty using dorsal onlay BMG from January 2002 to December 2007. The patients were in the age range of 15-65 years (mean 35 years) in the LS group and 16-63 years (mean 34 years) in the non-lichen sclerosus (NLS) group. The cause of stricture was LS in 20 and NLS (inflammatory and idiopathic) in the other 20 patients. The mean stricture length was 14.5 cm (range 12-17 cm) in the LS group while it was 14.0 cm (range 12-16 cm) in the NLS group. The patients were evaluated with antegrade, retrograde urethrograms and sono-urethrograms and they were followed- up with uroflometery at three months for one year, then six- monthly for two years and then annually. The contrast studies were repeated at six-monthly intervals for one year and then annually for one year. Success was defined as normal voiding pattern without any intervention post-operatively. Median follow-up was 48 months (18-72 months) in the LS group, while it was 42 months (12-72 months) in the NLS group. Among the NLS group patients, three patients developed restricture on follow-up, while seven patients among the LS group developed restricture. We conclude that the high percentage of recurrence of strictures (35%) among the LS group renders BMG urethroplasty in long segment anterior urethral stricture an unacceptable solution, and it needs further study. PMID- 23354207 TI - Late latent syphilis in two hemodialysis units. PMID- 23354206 TI - Porphyria cutanea tarda in a hemodialysis patient with hepatitis C virus: efficacy of treatment with multiple phlebotomies and erythropoietin. PMID- 23354208 TI - Acute bacterial endopthalmitis following dialysis catheter-related sepsis. PMID- 23354209 TI - The impact of education on nutrition on the quality of life in patients on hemodialysis: a comparative study from teaching hospitals. PMID- 23354210 TI - The impact of thyroid dysfunction on renal function tests. PMID- 23354211 TI - Is amniotic membrane a suitable biomaterial for reconstruction of long ureteral defects? PMID- 23354212 TI - Profile and outcome of infantile nephrotic syndrome treated in a tertiary care center. PMID- 23354213 TI - APLA in post-partum renal cortical necrosis another skeleton in the closet. PMID- 23354214 TI - A novel case of persistent Bartters-like syndrome associated with gentamicin exposure. PMID- 23354215 TI - Nephropathic cystinosis in a developing country: the Egyptian experience. PMID- 23354216 TI - Living and cadaver donor transplant programs in the Maghreb. AB - In the Maghreb, organ failure constitutes a major public health problem, especially given the increasing number of patients with chronic renal failure and the high cost of care. In this study, we attempted to seek the recommendations, through a questionnaire, of various officials related to organ transplantation as well as leaders of ethics committees and religious groups in different countries of the Maghreb. The objective was to improve the rate of organ donation and transplantation. We received 36 replies (62%) within the prescribed time limit. In our survey, 83% of the respondents felt that living donor transplantation should be promoted initially, followed gradually by measures to increase cadaver donor transplantation to achieve a target of about 30 transplants with cadaver kidney donors per million inhabitants. To expand the donor pool, 83% of the respondents proposed to expand the family circle to include the spouse and in laws. To improve the cadaver donation activity, one should improve the organizational aspects to ensure at least 50 renal transplantations per year (100%) and provide material motivation to the treatment team proportional to the activity of organ donation and transplantation. Finally, 93% of the respondents suggested suitable moral motivation of the donors. PMID- 23354217 TI - Pediatric renal transplantation: Jordan's experience. AB - To evaluate our experience with pediatric renal transplantation at King Hussein Medical Center, the medical records of 71 pediatric patients who underwent a renal transplantation procedure between the years 2004 and 2010 or started follow up at our center within one week of transplantation done elsewhere were reviewed. Over the seven-year period, 71 children under the age of 14 years who received their first renal transplant were studied. About 56% (40) were males. The mean age was 9.44 +/- 2.86 years. Dysplastic kidney was the most common cause of end stage renal failure in our group, followed by glomerulonephritis. Mothers were the donors in 39.4% of the cases, followed by fathers. Twenty-three patients (32.4%) were transplanted preemptively. The overall one-year graft survival was 96%, three-year survival was 95%, and the five-year survival was 88%. Prednisone, tacrolimus, and mycophenolate mofetil formed the main-stay of immunosuppressive agents. We have developed a successful live donor program for renal transplantation in children at King Hussein Medical Center in Amman. Although our experience is still short, the graft survival is similar to that achieved in the developed world, especially with preemptive transplant. PMID- 23354218 TI - Ultrasound findings in urinary shistosomaisis infection in school children in the Gezira State Central Sudan. AB - To evaluate the ultrasound findings of urinary schistosomiasis in Quran school (Khalwas) children in Gezira State Sudan, we studied all the students from two schools. A total of 103 boys were tested for urinary schistosomiasis using the urine filtration method. Schistosoma haematobium (S. haematobium) eggs were counted. Ultrasound was performed for all the positive subjects. Seventy-three (71%) subjects were positive for S. haematobium. The mean age was 11.3 +/- 2.9 years. Sixty-six (90.4%) subjects showed urinary tract abnormalities. The findings revealed the following degrees of wall thickening: 53.0% mild, 18.2% moderate and 21.2% severe. Urinary bladder polyp(s) were noted in 43.3% (single) and 40.9% (multiple) of the subjects, and calcification of the bladder wall was observed in 7.6% subjects. Ureteric dilatation was noted in 38/73 (52.0%), while hydronephrosis was detected in 19/73 (26.3%). The vast majority of urinary tract schistomiasis lesions were in the urinary bladder. Ultrasound is a useful tool for identifying the morbidity of S. haematobium in endemic areas. PMID- 23354219 TI - Pattern of glomerular diseases in a tertiary care center in South India: a prospective study. AB - This prospective study was undertaken to evaluate the distribution and pattern of glomerular diseases from a clinico-pathological perspective in our hospital, which is a tertiary care center in Southern India. Seventy-five consecutive patients who underwent renal biopsy and were diagnosed to have glomerular disease over a two-year period were studied and followed-up for one year. Primary glomerular disorders were more common than secondary glomerular disorders. Minimal change disease was the most common primary glomerular disease and lupus was the most common secondary glomerular disorder. Other common primary glomerular disorders were IgA nephropathy (16%) and post-infectious glomerulonephritis (10.7%), while focal and segmental glomerulosclerosis accounted for only 5.3% of the cases. In one-third of the cases, the initial clinical diagnosis did not correlate with the final biopsy diagnosis, further emphasizing the importance of renal biopsy in glomerular disorders. PMID- 23354220 TI - Prevalence of renal disease in Nigerian children infected with the human immunodeficiency virus and on highly active anti-retroviral therapy. AB - Access to highly active anti-retroviral therapy (HAART) has improved the prognosis of Nigerian children infected with the human immunodeficiency virus (HIV); thus, more children are surviving. Long-term exposure to HAART is potentially nephrotoxic. We therefore aimed at assessing the prevalence of renal disease in Nigerian children infected with HIV, who are on HAART. In this cross sectional study, we studied children, aged ten months to 17 years, infected with HIV, attending the pediatric HIV clinics of the University of Benin Teaching Hospital. Demographic and clinical data were obtained by parental interview as well as from the medical records. Each child's urine was tested for albumin and microalbuminuria using multi test strips and mitral test strips, respectively. The serum creatinine level of each child was also estimated and used in calculating the glomerular filtration rate (GFR). Renal disease was defined as the presence of significant proteinuria of 1+ and above on dipstick or the presence of microalbuminuria of >=20 mg and/or GFR <60 mL/min/1.73 m 2 . Of the 99 children recruited, 60 were males and 39 were females. The mean age of the children was 6.6 +/- 3.5 years. All the children were on HAART and 85% had acquired the HIV infection by vertical transmission. The overall prevalence of renal disease was 16.2%. Microalbuminuria was seen in 11 children with renal disease (11.1%); 3 of them had significant proteinuria. GFR of less than 60 mL/min/1.73 m 2 was seen in five children (5.1%) with renal disease, but none had end-stage renal disease (GFR less than 15 mL/min/1.73 m 2 ). Renal disease was found to be significantly associated with advanced stage of HIV infection (P < 0.049). Our study showed that t he prevalence of renal disease in HAART-treated Nigerian children is high and majority of them are asymptomatic of renal disease, but in the advanced stages of HIV infection. PMID- 23354221 TI - Diagnostic yield of kidney biopsies performed in a suburban, satellite hospital. AB - Kidney biopsy is indicated to confirm the clinical diagnosis or to evaluate prognosis of a renal problem. It is a reliable and safe procedure, especially with real-time ultrasound guidance. This is a single-center, retrospective review of the biopsies performed in Hospital Tengku Ampuan Afzan, Pahang from 2000 to 2010. The demographic data, clinical parameters, and histological reports were extracted from clinic records and analyzed to determine the diagnostic adequacy of biopsy samples for both lupus and non-lupus patients. A total of 219 biopsies were performed throughout the period and only 74 were included in this review. Their mean age was 22.5 +/- 10.5 years. 59.5% of the biopsies were performed on female patients. Malays comprised 79.7% (n = 59) of them, followed by Chinese (18.9%, n=14) and Indian (1.4%, n=1). About one-third of the biopsies(n = 25) were performed on patients with lupus nephritis and two-thirds (n = 49) on non lupus nephritis patients. At the time of biopsy, their serum creatinine values were normal, serum albumin 28.4 +/- 10 g/L and total cholesterol 8.9 +/- 4.6 mmol/L (mean +/- SD). The urine dipstick was 3+ for both proteinuria and hematuria and daily protein excretion was 3.6 +/- 3.2 g. Sixty-seven specimens were considered adequate and only six (8%) were inadequate for histological interpretations. The mean number of glomeruli in the biopsy specimens was 16 +/- 9.9 (range: 0-47 glomeruli). In non-lupus patients, focal segmental glomerulosclerosis was the commonest histological diagnosis (n = 15, 30.6%), followed by minimal change disease (n = 13, 26.5%) and mesangial proliferative glomerulonephritis (n = 7, 14.3%). Membranous nephropathy was diagnosed in four (8.2%) and membranoproliferative glomerulonephritis in two (4.1%) specimens. Both post-infectious glomerulonephritis and advanced glomerulosclerosis were found in one specimen each. Among the lupus nephritis patients (n = 25), 88% of them were females (P <0.05) and lupus nephritis WHO class IV was the commonest variant (n = 12, 48%) followed by WHO class III (n = 7, 28%). Membranous glomerulopathy or lupus nephritis WHO class V was found in three (12%), and two (8%) had lupus nephritis WHO class II. Serum albumin, urinalysis findings, and daily urinary protein excretion were comparable for both lupus and non-lupus patients. In conclusion, renal biopsy in our center is adequate and sufficient for histological interpretations and management of patients with renal problems. PMID- 23354222 TI - Bond nature of active metal ions in SiO2-based electrochemical metallization memory cells. AB - Electrochemical metallization cells are candidates for the next-generation non volatile memory devices based on resistive switching. Despite the intensive studies in recent years a microscopic model of the processes in these nanoscale electrochemical systems is still missing and the physicochemical properties of the active metal ions have been rarely reported. We examined the bonding characteristics of Cu(z+) and Ag(+) ions in SiO(2)-based cells using soft X-ray absorption spectroscopy. Whereas the Ag/SiO(2) interfaces showed no chemical interaction of Ag ions, the Cu/SiO(2) showed clear signatures of partial oxidation into two ionic species of Cu(2+) and Cu(+). The analyses on the orbital hybridization strength evidently showed that the Cu(2+)-O(2-) bonds in SiO(2) are much weaker than the Cu(+)-O(2-) bonds, analogous to the case of bulk CuO and Cu(2)O. This suggests that the Cu(2+) ions should be more mobile and with a dominating role in the process of resistive switching. PMID- 23354224 TI - Improving the quality of science arising from the NTDB: we can do this! PMID- 23354225 TI - National Trauma Institute prospective evaluation of the ventilator bundle in trauma patients: does it really work? AB - BACKGROUND: Since its introduction by the Institute for Healthcare Improvement, the ventilator bundle (VB) has been credited with a reduction in ventilator associated pneumonia (VAP). The VB consists of stress ulcer prophylaxis, deep venous thrombosis prophylaxis, head-of-bed elevation, and daily sedation vacation with weaning assessment. While there is little compelling evidence that the VB is effective, it has been widely accepted. The Centers for Medical and Medicaid Services has suggested that VAP should be a "never event" and may reduce payment to providers. To provide evidence of its efficacy, the National Trauma Institute organized a prospective multi-institutional trial to evaluate the utility of the VB. METHODS: This prospective observational multi-institutional study included six Level I trauma centers. Entry criteria required at least 2 days of mechanical ventilation of trauma patients in an intensive care unit (ICU). Patients were followed up daily in the ICU until the development of VAP, ICU discharge, or death. Compliance for each VB component was recorded daily, along with patient risk factors and injury specifics. Primary outcomes were VAP and death. VB compliance was analyzed as a time-dependent covariate using Cox regression as it relates to outcomes. RESULTS: A total 630 patients were enrolled; 72% were male, predominately with blunt injury; and mean age, Injury Severity Score (ISS), and 24-hour Glasgow Coma Scale (GCS) score were 47, 24, and 8.7, respectively. VAP occurred in 36%; mortality was 15%. Logistic regression identified male sex and pulmonary contusion as independent predictors of VAP and age, ISS, and 24-hour Acute Physiology and Chronic Health Evaluation as independent predictors of death. Cox regression analysis demonstrated that the VB, as a time-dependent covariate, was not associated with VAP prevention. CONCLUSION: In trauma patients, VAP is independently associated with male sex and chest injury severity and not the VB. While quality improvement activities should continue efforts toward VAP prevention, the Institute for Healthcare Improvement VB is not the answer. Financial penalties for VAP and VB noncompliance are not warranted. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 23354226 TI - Hyperacute adrenal insufficiency after hemorrhagic shock exists and is associated with poor outcomes. AB - BACKGROUND: Adrenal insufficiency (AI) has been extensively described in sepsis but not in acute hemorrhage. We sought to determine the incidence of hyperacute AI (HAI) immediately after hemorrhage and its association with mortality. METHODS: Patients with acute traumatic hemorrhagic shock presenting to the R Adams Cowley Shock Trauma Center prospectively had serum cortisol levels collected on admission. Inclusion criteria were hypotension and active hemorrhage. Clinicians were blinded to results, and no patient received steroids in the acute phase. The primary outcome measure was death from hemorrhage within 24 hours of admission. RESULTS: Fifty-nine patients were enrolled during an 8 month period. Mean admission cortisol level was 18.3 +/- 8.9 MUg/dL. Acute mortality rate from hemorrhage was 27%. Overall mortality rate was 37%. Severe HAI (serum cortisol level <10 MUg/dL) was present in 10 patients (17%). Relative HAI (<25 MUg/dL) was present in 51 patients (86%). Those who died of acute hemorrhage had significantly lower mean cortisol levels (11.4 +/- 6.2 MUg/dL vs. 20.9 +/- 8.4 MUg/dL, p < 0.001) as did patients who ultimately died in the hospital (12.8 +/- 7.6 MUg/dL vs. 21.6 +/- 8.1 MUg/dL, p < 0.001). In multivariate analysis, cortisol levels were associated with mortality from acute hemorrhage, with an odds ratio of 1.17 (95% confidence interval, 1.02-1.35). Adjusted receiver operating characteristic analysis indicated that serum cortisol has a 91% accuracy in differentiating survivors of acute hemorrhage from nonsurvivors. CONCLUSION: This study is the first to report that AI occurs immediately after acute injury during hemorrhagic shock and is strongly associated with mortality. HAI may be a marker of depth of shock but is potentially rapidly modifiable as opposed to other markers, such as lactate or base deficit. Further work is needed to determine whether steroid administration can change outcome in selected patients. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. PMID- 23354227 TI - Cryopreserved deglycerolized blood is safe and achieves superior tissue oxygenation compared with refrigerated red blood cells: a prospective randomized pilot study. AB - BACKGROUND: During preservation, donated liquid red blood cells (RBCs) experience multiple functional and structural changes known as the storage lesion. Increased RBC age is associated with increased infection rates, organ failure, and mortality. METHODS: This prospective, randomized, double-blinded pilot study enrolled stable trauma patients who required RBC transfusion. Patients were randomly assigned to receive standard or cryopreserved RBCs. Continuous tissue oxygenation (StO2) monitoring was performed during the peritransfusion period. Hematocrit and thrombelastography before and after transfusion were evaluated. Patients were monitored for transfusion reactions and clinical outcomes. RESULTS: Fifty-seven patients were randomized, and groups were well matched for demographics and Injury Severity Score (ISS). No statistically significant differences were noted in hematocrit change, thrombelastography parameters, transfusion reactions, or clinical outcomes. StO2 was found to be higher in the cryopreserved group. CONCLUSION: Cryopreserved RBCs are equally safe and efficacious to refrigerated RBCs. This storage technique extends the life span of RBCs to 10 years, potentially preserving a precious resource and preventing the storage lesion. StO2 was superior in patients receiving cryopreserved RBCs. This finding has the potential to drive a paradigm shift in transfusion practices. LEVEL OF EVIDENCE: Therapeutic study, level II. PMID- 23354228 TI - TEG-guided resuscitation is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients. AB - BACKGROUND: For nearly a decade, our center performed thromboelastograms (TEGs) to analyze coagulation profiles, allowing rapid data-driven blood component therapy. After consensus recommendations for massive transfusion protocols (MTPs), we implemented an MTP in October 2009 with 1:1:1 ratio of blood (red blood cells [RBC]), plasma (fresh-frozen plasma [FFP]), and platelets. We hypothesized that TEG-directed resuscitation is equivalent to MTP resuscitation. METHODS: All patients receiving 6 units (U) or more of RBC in the first 24 hours for 21 months before and after MTP initiation in an urban Level I trauma center were examined. Demographics, mechanism of injury (MOI), Injury Severity Score (ISS), 24-hour volume of RBC, FFP, platelets, crystalloid, and 30-day mortality were compared, excluding patients with traumatic brain injuries. Variables were analyzed using Student's t-test and chi2 or Fisher's exact test. RESULTS: For the preMTP group, there were 165 patients. In the MTP group, there were 124 patients. There were no significant differences in ISS, age, or sex. PreMTP patients with 6U or more RBC had significantly more penetrating MOI (p = 0.017), whereas preMTP patients with 10U or more RBC had similar MOIs. All patients received less crystalloid after MTP adoption (p < 0.001). There was no difference in volume of blood products or mortality in patients receiving 6U or more RBC. Blunt trauma MTP patients who received 10U or more RBC received more FFP (p = 0.02), with no change in mortality. Penetrating trauma patients who received 10U or more RBC received a similar volume of FFP; however, mortality increased from 54.1% for MTP versus 33.3% preMTP (p = 0.04). CONCLUSION: TEG-directed resuscitation is equivalent to standardized MTP for patients receiving 6U or more RBC and for blunt MOI patients receiving 10U or more RBC. MTP therapy worsened mortality in penetrating MOI patients receiving 10U or more RBC, indicating a continued need for TEG-directed therapy. A 1:1:1 strategy may not be adequate in all patients. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 23354229 TI - Administration of fibrinogen concentrate in exsanguinating trauma patients is associated with improved survival at 6 hours but not at discharge. AB - BACKGROUND: Despite poor evidence and high costs, fibrinogen concentrate (FC) represents one of the most frequently used hemostatic agents in exsanguinating trauma. The aim was to assess whether the administration of FC in severely injured patients was associated with improved outcomes. METHODS: Patients documented in the Trauma Registry of the German Society for Trauma Surgery (primary admissions, Injury Severity Score [ISS] >=16) who had received FC during initial care between emergency department (ED) arrival and intensive care unit admission (FC+) were matched with patients who had not received FC (FC-). RESULTS: The matched-pairs analysis yielded two comparable cohorts (n = 294 in each group) with a mean ISS of 37.6 +/- 13.7 (FC+) and 37.1 +/- 13.3 (FC-) (p = 0.73); the mean age was 40 +/- 17 versus 40 +/- 16 (p = 0.72), respectively. Patients were predominantly male (71.1% in both groups, p = 1.0). On emergency department arrival, hypotension (systolic blood pressure, <=90 mm Hg) occurred in 51.4% (FC+) and 48.0% (FC-) (p = 0.41), and base excess was -7.4 +/- 5.3 mmol/L for FC+ and was -7.5 +/- 6.2 mmol/L for FC- (p = 0.96). Patients were administered 12.8 +/- 14.3 (FC+) versus 11.3 +/- 10.0 (FC-) packed red blood cell units (p = 0.20). Thromboembolism occurred in 6.8% (FC+) versus 3.4% (FC-) (p = 0.06), and multiple organ failure occurred in 61.2% versus 49.0% (p = 0.003), respectively. Whereas 6-hour mortality was 10.5% for FC+ versus 16.7% for FC- (p = 0.03), the mean time to death was 7.5 +/- 14.6 days versus 4.7 +/- 8.6 days (p = 0.006). The overall hospital mortality rate was 28.6% versus 25.5% (p = 0.40), respectively. CONCLUSION: This is the first study to investigate the effect of FC administration in bleeding trauma. In our large population of severely injured patients, the early use of FC was associated with a significantly lower 6-hour mortality and an increased time to death, but also an increased rate of multiple organ failure. A reduction of overall hospital mortality was not observed in patients receiving FC. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 23354230 TI - Redefining massive transfusion when every second counts. AB - BACKGROUND: The massive transfusion (MT) concept (>10-U packed red blood cells per 24 hours) is retrospective, arbitrary, and prone to survivor bias. Accounting for rate and timing is a more accurate conceptual framework. We redefined MT as a critical administration threshold (CAT) of 3 U/h, which is clinically pertinent and reflects hemorrhagic shock. The purpose of this study was to compare the traditional form of MT to a CAT definition in predicting mortality. METHODS: Patients receiving transfusion in the first 24 hours were included. Precise transfusion times for each unit, in minutes, were calculated from time of injury. MT and CAT were compared to determine risk of death. Univariate and multivariate analyses were used to examine inpatient mortality. RESULTS: A total of 169 patients(70%, >10 New Injury Severity Score [NISS]) were studied; 46% were CAT+; 22% met the MT criteria. With logistic regression, a CAT of 3 U/h (CAT+) was more predictive of death compared with 2, 4, 5, or 6 U/h. CAT was met once (CAT 1), twice (CAT 2) or more than 3 times (CAT 3) in 21%, 14%, and 11%, respectively. Increasing CAT was associated with increased mortality. CAT identified 75% of all deaths; MT only identified 33% and failed to identify 42% of CAT+ deaths. CAT (relative risk [RR] 3.58; 95% confidence interval [CI] 1.80-7.15) had a stronger association with mortality compared with MT(RR, 1.82; 95% confidence interval, 1.02-3.26). CONCLUSION: The traditional definition of MT is inadequate to reflect illness severity. Using CATs allows prospective identification of critically ill trauma patients and eliminates survivor bias. CAT may serve as an activation trigger for transfusion protocols, allowing early identification of patients with critical transfusion requirements. Clinical trials involving transfusion strategies should consider CAT as an instrument for evaluating outcomes. LEVEL OF EVIDENCE: Diagnostic/prognostic study, level II. PMID- 23354231 TI - Impact of inverse ratios on patients with exsanguinating vascular injuries: should more be the new paradigm? AB - BACKGROUND: Resuscitation strategies in patients with severe hemorrhage have evolved throughout the years. Optimal resuscitation ratios for civilian exsanguinating vascular injuries has not been determined. We hypothesize improved outcomes in patients with exsanguinating vascular injuries when an aggressive hemostatic resuscitation is used with an inverse ratio of fresh frozen plasma (FFP) to packed red blood cell (PRBC). METHODS: This is a 5-year retrospective analysis of vascular injuries requiring hemostatic resuscitation. Resuscitation groups by ratios of FFP/PRBC were inverse (>1:1), high (1-1:2), and low (<1:2). Patients with 10 or greater units of PRBC (massively transfused patients) were evaluated in each of the resuscitation groups. Demographics and complications throughout hospital length of stay and were compared between the resuscitation groups. Survivability Kaplan-Meier curves were generated at 6 hours and 5 days. RESULTS: A total of 258 patients with vascular injuries required component therapy resuscitation (low, n = 78; high, n = 156; inverse, n = 24). Massively transfused patients (n = 162, 62.7%) showed a significant Kaplan-Meier survivability difference at 6 hours (low, 65.0% vs. high, 75.0% vs. inverse, 100%, p = 0.024) and at 5 days (low, 52.5% vs. high, 62.0% vs. inverse, 100%, p = 0.008). Moreover, for massively transfused patients with extremity vascular injuries (n = 65, 39%), a relationship between resuscitation ratio and amputations was significant (low vs. high vs. inverse was 36.8% vs. 12.8% vs. 0%, respectively; p = 0.033). CONCLUSION: This is the first study that highlights the potential outcomes benefits of an inverse ratio of FFP-PRBC in patients with exsanguinating vascular injuries. Multi-institutional prospective analysis is needed to potentially elucidate the cytoprotective effect of FFP to validate these results. LEVEL OF EVIDENCE: Therapeutic study, level IV; diagnostic study, level III. PMID- 23354232 TI - Platelet mitochondrial membrane potential correlates with severity in patients with systemic inflammatory response syndrome. AB - BACKGROUND: The role of mitochondrial dysfunction has not been thoroughly clarified in the pathogenesis of critically ill patients. The objective of this study was to investigate mitochondrial membrane potential (DeltaPsim) and apoptosis in circulating platelets in patients with systemic inflammatory response syndrome (SIRS). METHODS: This prospective observational study was conducted from May 2011 to February 2012. Criteria for inclusion were adult patients with SIRS. We used mitochondrial indicator JC-1 in conjunction with flow cytometry to measure DeltaPsim and annexin V to evaluate apoptosis in peripheral blood platelets. DeltaPsim was expressed as the percentage of platelets with altered DeltaPsim. Severity of illness was assessed by SIRS score, Acute Physiology and Chronic Health Evaluation II score, and Sequential Organ Failure Assessment score. RESULTS: This study was composed of 36 patients who met the inclusion criteria and 12 healthy controls. Causes of SIRS were sepsis in 13, trauma in 13, and others in 10 patients. Platelet DeltaPsim depolarization was significantly enhanced in patients with SIRS versus that in controls (median [interquartile range], 10.6% [8.1-12.6%] vs. 7.1% [6.1-8.0%]; p < 0.001). The percentage of apoptotic platelets was significantly higher in patients with SIRS than in controls (8.7% [5.5-13.5%] vs. 5.4% [3.9-7.0%]; p = 0.006). Interestingly, DeltaPsim depolarization increased significantly with the increase in SIRS scores (p < 0.001). There was a significant correlation between DeltaPsim depolarization and severity of illness, as indicated by Acute Physiology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment score, and serum lactate levels (all, p < 0.05). CONCLUSION: We demonstrated that DeltaPsim depolarization and apoptosis were enhanced in circulating platelets in patients with SIRS. Our findings suggest that DeltaPsim depolarization may be associated with the progression of SIRS. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 23354233 TI - Applicability of an established management algorithm for colon injuries following blunt trauma. AB - BACKGROUND: Operative management at our institution for all colon injuries have followed a defined algorithm (ALG) based on risk factors originally identified for penetrating injuries. The purpose of this study was to evaluate the applicability of the ALG to blunt colon injuries. METHODS: Patients with blunt colon injuries during 13 years were identified. As per the ALG, nondestructive (ND) injuries are treated with primary repair. Patients with destructive wounds (serosal tear of >=50% colon circumference, mesenteric devascularization, and perforations) and concomitant risk factors (transfusion of >6 U packed red blood cells and/or presence of significant comorbidities) are diverted, while patients with no risk factors undergo resection plus anastomosis (RA). Outcomes included suture line failure (SLF), abscess, and mortality. Stratification analysis was performed to determine additional risk factors in the management of blunt colon injuries. RESULTS: A total 151 patients were identified: 76 with destructive injuries and 75 with ND injuries. Of those with destructive injuries, 44 (59%) underwent RA and 29 (39%) underwent diversion. All ND injuries underwent primary repair. Adherence to the ALG was 95%: three patients with destructive injuries underwent primary repair, and five patients with risk factors underwent RA. There were three SLFs (2%) (one involved deviation from the ALG) and eight abscesses (5%). Colon-related mortality was 2.1%. Stratification analysis based on mesenteric involvement, degree of shock, and need for abbreviated laparotomy failed to identify additional risk factors for SLF following RA for blunt colon injuries. CONCLUSION: Adherence to an ALG, originally defined for penetrating colon injuries, simplified the management of blunt colon injuries. ND injuries should be primarily repaired. For destructive wounds, management based on a defined ALG achieves an acceptably low morbidity and mortality rate. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III; therapeutic study, level IV. PMID- 23354234 TI - Chasing 100%: the use of hypertonic saline to improve early, primary fascial closure after damage control laparotomy. AB - BACKGROUND: Failure to achieve fascial closure after damage control laparotomy (DCL) is associated with increased morbidity and long-term disability. In addition, early closure is associated with reduces infectious, wound, and pulmonary complications. We hypothesized that hypertonic saline (HTS), which attenuates resuscitation-induced intestinal edema in animals, would improve early primary fascial closure (EPFC) rates. METHODS: This is a retrospective study of trauma patients undergoing DCL, from January 2010 to July 2011. Patients in the HTS group had 30 mL/h of 3% sodium chloride as maintenance fluids while the fascia was open. Patients in the cohort group had isotonic fluids (125 mL/h). The primary outcome, EPFC, was defined as primary fascial closure by postinjury day 7. RESULTS: Seventy-seven patients underwent DCL (23 received HTS and 54 received isotonic fluids). There were no differences in demographics, injury severity, or pre-intensive care unit vitals, laboratories, fluids, or transfusions. Median fluids in the first 24 hours were lower in the HTS group (3.9 vs. 7.8 L, p < 0.001). Times to fascial closure were shorter in those receiving HTS (34 vs. 49 hours, p < 0.001), as were the rates of closure at first take back (78% vs. 53%, p = 0.036). The primary outcome of EPFC was higher in the HTS group compared with standard fluids (100% vs. 76%, p = 0.010). At discharge, the HTS group had a 96% primary fascial closure rate compared with 80% with standard fluids. CONCLUSION: The use of 3% HTS as maintenance fluids after DCL was associated with 100% EPFC. HTS may be used as an adjunct to facilitate fascial closure in patients undergoing DCL. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 23354235 TI - Skin closure after trauma laparotomy in high-risk patients: opening opportunities for improvement. AB - BACKGROUND: Although many surgeons leave laparotomy incisions open after colon injury to prevent surgical site infection (SSI), other injured patient subsets are also at risk. We hypothesized that leaving trauma laparotomy skin incisions open in high-risk patients with any enteric injury or requiring damage control laparotomy (DCL) would not affect superficial SSI and fascial dehiscence rates. METHODS: Patients who underwent trauma laparotomy (2004-2008) at two Level I centers were reviewed. To ensure a high-risk sample, only patients with transmural enteric injuries or need for DCL surviving 5 days or more were included. SSIs were categorized by the CDC (Centers for Disease Control and Prevention) criteria and risk factors were analyzed by skin closure (open vs. any closure). Significant (p < 0.05) univariate variables were applied to two multivariate analyses examining superficial SSI and fascial dehiscence. RESULTS: Of 1,501 patients who underwent laparotomy, 503 met inclusion criteria. Patients were young (median, 28.0 years; range, 22.0-40.0 years) with penetrating (74%) or enteric (80%) injuries, and DCL (36%) and SSI (44%; superficial, 25%; deep, 3%; organ/space, 25%) were common. While no difference in superficial SSI after loose (n = 136) or complete skin closure (n = 224) was detected (p = 0.64), superficial SSIs were less common with open skin incisions (9.8%), despite multiple risk factors, than with any skin closure (31.1%, p < 0.001). Predictors of superficial SSIs and fascial dehiscence were each evaluated with multiple-variable logistic regression analysis. After adjusting for multiple potential confounding variables, any skin closure increased the risk of superficial SSIs approximately nine times (odds ratio, 8.6; p < 0.001) and fascial dehiscence six times (odds ratio, 5.7; p = 0.013). CONCLUSION: Management of skin incisions takes careful consideration like any other step of a laparotomy. Our results suggest that the decision to leave skin open is one simple method to improve outcomes in high-risk patients. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 23354236 TI - Serum creatine kinase levels are associated with extremity compartment syndrome. AB - BACKGROUND: Limb compartment syndrome (CS) is a difficult diagnosis. Accurate measurement of compartment pressure is user dependent, and there is no consensus on values to define CS. Given the prevalence of extremity CS, difficulty in timely diagnosis, and ramifications of a delay in diagnosis, a precise and reliable means for early diagnosis is needed. The purpose of our study was to determine if a threshold serum creatinine kinase (CK) level is associated with the development of CS. METHODS: All patients with isolated tibial/fibula fractures or extremity CS admitted to a three-hospital consortium from July 1, 2001, to June 30, 2011, were identified retrospectively using coded data. Age, basic metabolic panel, lactic acid, CK, and troponin I levels were abstracted. Univariate and multivariate regression analysis was undertaken using maximum and minimum values for each laboratory test to evaluate the association between the test and CS versus tibia/fibula fracture. RESULTS: Of the 97 patients in the study, 39 had CS. Tests most strongly associated with CS were maximum CK, minimum calcium, minimum blood urea nitrogen (BUN), maximum chloride, maximum lactate, and minimum HCO3. On univariate analysis, only maximum CK had adequate correlation with CS. Optimal cut points were maximum CK of greater than 4,000 U/L. Using the model CK level of greater than 4,000 U/L, chloride level of greater than 104 mg/dL, and BUN level of less than 10 mg/dL, 0 of 6 patients had CS when all three variables were absent. When one, two, or three variables were present, the percentage of patients with CS was 36%, 80%, and 100%, respectively. Using a cut point of two or more of these three variables being positive produced sensitivity, specificity, positive and negative prediction values, and total accuracy of 0.85, 0.87, 0.76, 0.92, and 0.86, respectively. CONCLUSION: CK level greater than 4,000 U/L is associated with CS. A model combining maximal CK level greater than 4,000 U/L, maximal chloride level greater than 104 mg/dL, and minimal BUN level less than 10 mg/dL has a 100% association with CS. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 23354237 TI - Early nonbronchoscopic bronchoalveolar lavage: predictor of ventilator-associated pneumonia? AB - BACKGROUND: Ventilator-associated pneumonia is a problem in trauma and emergency general surgery patients. Our hospital-acquired infection prevention committee approved the use of early nonbronchoscopic bronchoalveolar lavage (screening-BAL) in the surgical intensive care unit (SICU) to identify ventilated patients with bronchiolar bacteria before 48 hours. We reviewed the results of this quality improvement initiative. METHODS: All ventilated patients in the SICU (March 2011 to June 2012) underwent a screening-BAL 36 hours to 48 hours after intubation; quantitative culture results (>5 * 10(4) colony-forming unit per milliliter) were used to identify positive specimens. Clinical pneumonia was defined as clinical pulmonary infection score greater than 6 with a subsequent positive diagnostic BAL result. Sequential organ failure assessment scores were averaged for the first 48 hours in the SICU. Continuous and dichotomous data were compared, and a multivariate regression analysis was performed on the screening-BAL and pneumonia results. RESULTS: Screening-BALs were performed in 150 patients (99 trauma and 51 emergency general surgery patients), 72 of these specimens had positive findings. Fifty-three clinical pneumonias were diagnosed, and 45 (positive predictive value, 0.85) identified the same organism as the screening-BAL. Clinical pneumonia developed in eight patients with a negative screening-BAL (negative predictive value, 0.85). Antibiotic therapy at the time of the screening-BAL was associated with a negative screen (odds ratio, 0.44; p = 0.026). Pneumonia developed on median postintubation Day 4 (2-15 days) in patients with a positive screening-BAL results as compared with day 7.5 in the patients with a negative screening-BAL results (3.5-15 days; p = 0.007). Field intubation is an independent risk factor (odds ratio, 3.5; p = 0.004). CONCLUSION: Positive screening-BAL results in trauma and emergency general surgery patients are associated with the development of ventilator-associated pneumonia by the same organism and may play a role in identifying patients at risk for pneumonia. Further studies must be conducted to evaluate the role of screening-BAL in this patient population. LEVEL OF EVIDENCE: Diagnostic/prognostic study, level III. PMID- 23354238 TI - Which central venous catheters have the highest rate of catheter-associated deep venous thrombosis: a prospective analysis of 2,128 catheter days in the surgical intensive care unit. AB - BACKGROUND: Catheter-associated deep venous thromboses (CADVTs) are a common occurrence in the surgical intensive care unit (SICU), necessitating central venous catheter (CVC) removal and replacement. Previous studies evaluating risk factors for CADVT in SICU patients are limited, and most lack a true denominator of all CVC days. We sought to determine the true incidence of and risk factors for CADVT based on patient characteristics as well as CVC site, type, and duration of insertion. METHODS: The following data from all SICU patients in two urban Level I trauma centers were prospectively collected from 2009 to 2012: demographics, risk factors for DVT, CVC site/type/duration, and duplex results. Sites included the subclavian (SC), internal jugular (IJ), arm (for peripherally inserted central catheter [PICC] lines), and femoral. Types included multilumen (ML), introducer/hemodialysis (I/HD), and PICC. High-risk patients received weekly screening duplex examinations and a CADVT was defined as a DVT being detected on duplex with a CVC in place or within 7 days of removal. Rates of CADVT were normalized per 1,000 CVC days, and independent predictors of CADVT were determined using logistic regression. RESULTS: Data were complete for 184 patients, 354 CVCs, and 2,128 CVC days. Fifty-nine CADVTs were diagnosed in 28% of patients. Rates of CADVT were 9 per 1,000 catheter days for SC, 61 for IJ (p < 0.01 vs. SC), 27 for arm (p < 0.01), 36 for femoral (p < 0.01), 22 for ML, 57 for I/HD (p < 0.01 vs. ML), and 27 for PICC (p = 0.24). After adjusting for patient risk factors, predictors of CADVT included the IJ and arm sites (odds ratio, 6.0 and 3.0 compared with SC) and the I/HD type (odds ratio, 2.6 compared with ML, all p < 0.05). CONCLUSION: The IJ and arm sites and I/HD type are associated with increased CADVT. These data may be used to determine the optimal site and type of CVC for insertion. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. PMID- 23354239 TI - Acute care surgery: now that we have built it, will they come? AB - BACKGROUND: Concern over lack of resident interest caused by the nonoperative nature and compromised lifestyle associated with a career as a "trauma surgeon" has led to the emergence of a new acute care surgery (ACS) specialty. This study examined the opinions of current general surgical residents about training and careers in this new field. METHODS: A 36-item online anonymous survey regarding ACS was sent to the program directors of 55 randomly selected general surgery (GS) training programs for distribution to their categorical residents. The national sample consisted of 1,515 PGY 1 to 5 trainees. RESULTS: Response rate was 45%. More than 90% of residents had an appropriate understanding of the components of ACS as generally described (trauma, surgical critical care, and emergency GS). Nearly half (46%) of all respondents have considered ACS as a career. Overall, ACS ranked as the second most appealing career ahead of surgical critical care and trauma but behind GS. Most residents believed that ACS offers better or equivalent case complexity (88%), scope of practice (84%), case volume (75%), and level of reimbursement (69%) compared with GS alone. Respondents who answered ACS had a better scope of practice (61% vs. 36%), lifestyle as an attending surgeon (77% vs. 34%), or level of reimbursement (83% vs. 38%) compared with GS were twice as likely (p < 0.0001) to have considered ACS as a career. Overall, 40% of the residents believed that ACS offers a worse lifestyle in comparison with GS. CONCLUSION: These results suggest that there is notable interest in the emerging specialty of ACS. The level of resident interest in ACS as a fellowship and career may be increased by marketing those aspects of practice, which are viewed positively and addressing negative perceptions related to lifestyle. It may be appealing to add an elective GS component to certain ACS practice options. PMID- 23354240 TI - Resveratrol decreases inflammation in the brain of mice with mild traumatic brain injury. AB - BACKGROUND: Following a mild traumatic brain injury (TBI) event, the secondary brain injury that persists after the initial blow to the head consists of excitotoxicity, decreased cerebral glucose levels, oxidant injury, mitochondrial dysfunction, inflammation, and neuronal cell death. To date, there are no effective interventions used at decreasing secondary brain injury after mild TBI. METHODS: In this study, male mice were treated with either placebo or resveratrol (100 mg/kg) at 5 minutes and 12 hours after mild TBI. The mice were injured using the controlled cortical impact device. In this closed-head model, a midline incision was made to access the skull and the impactor tip was aligned on the sagittal suture midway between the bregma and lambda sutures. The mice were injured at a depth of 2.0 mm, velocity of 4 m/s, and a delay time of 100 milliseconds. At 72 hours following injury, the animals were intracardially perfused with 0.9% saline followed by 10% phosphate-buffered formalin. The whole brain was removed, sliced, and stained for microglial activation (Iba1). In addition, using the enzyme-linked immunosorbent assay, tissue levels of interleukin 6 (IL-6) and IL-12 were measured in the cerebral cortex and hippocampus. RESULTS: In this study, we found that in the placebo treatment group, there was a significant increase in Iba1 staining in the brain. The levels of microglial activation was reduced by resveratrol in the cerebral cortex (p < 0.001), corpus callosum (p < 0.001), and dentate gyrus (p < 0.005) brain regions after mild TBI. In addition to Iba1, resveratrol decreased the brain levels of IL 6 (p < 0.0001) and IL-12 (p < 0.004), which were observed in the hippocampus of the placebo group. In our model, no increase of IL-6 or IL-12 was observed in the cerebral cortex following TBI. CONCLUSION: Resveratrol given acutely after TBI results in a decrease in neuroinflammation. These results suggest that resveratrol may be beneficial in reducing secondary brain injury after experiencing a mild TBI. PMID- 23354241 TI - The effects of location and low-molecular-weight heparin administration on deep vein thrombosis outcomes in trauma patients. AB - BACKGROUND: Deep vein thrombosis (DVT) is common after trauma. Pulmonary embolism (PE) is a feared complication of DVT. Standard doses of low-molecular-weight heparin (LMWH) are commonly used to prevent and treat DVT and PE. There is variable bioavailability of LMWH with standard therapy. The traditional concept that below-knee DVT is associated with a lower risk of subsequent PE may result in less aggressive therapy. The purposes of this study were to assess the rates of PE in above-knee versus below-knee DVT and longitudinally evaluate outcomes of DVT treated with LMWH therapy. METHODS: This was a retrospective review of patients at a university Level I trauma center during the years 2005 through 2010. Patients diagnosed with lower-extremity DVT were included in this study. Patients were classified by location of lower-extremity DVT and type of LMWH therapy received. All high-risk trauma patients were evaluated with weekly duplex Doppler ultrasonography. All duplex studies were reviewed for DVT resolution or improvement. Symptomatic patients were evaluated with computed tomographic angiography to rule out PE. Demographics, total length of hospital stay, length of intensive care unit stay, and Injury Severity Score (ISS) were collected. RESULTS: Three-hundred eight trauma patients with lower-extremity DVT were included. More patients developed below-knee DVT (65.6%) compared with above-knee DVT (34.4%). Increased length of hospital stay, intensive care unit stay, and higher ISS were noted in patients with above-knee DVT. More patients had below knee DVT in the prophylactic dosing group. With LMWH therapy, three PEs occurred in patients in the prophylactic dosing group with below-knee DVT, and no PEs occurred in the therapeutic treatment group. The incidence of PE between patients with below-knee DVT compared with above-knee DVT overall was not different (3.3% and 4.7%, p = 0.59). To assess DVT outcomes, 157 of the 308 patients had serial duplex studies following diagnosis of lower-extremity DVT. The number of patients receiving either therapeutic or prophylactic LMWH was similar (51% and 49%). There was no difference in rates of resolution or improvement between LMWH dosing groups or location of DVT. CONCLUSION: In screened trauma patients, below-knee DVT is more common than above-knee DVT. There was no difference in the incidence of PE between groups. Standard prophylactic and therapeutic dosing of LMWH does not affect the rates of resolution or improvement of lower-extremity DVT. Rates of resolution and improvement of DVT is not dependent of location of lower extremity DVT. LEVEL OF EVIDENCE: Therapeutic study, level IV; epidemiologic study, level III. PMID- 23354242 TI - Recombinant tissue-type plasminogen activator-evoked hyperfibrinolysis is enhanced by acidosis and inhibited by hypothermia but still can be blocked by tranexamic acid. AB - BACKGROUND: Hypothermia and acidosis have been suggested as key initiators of trauma-induced coagulopathy, and severe bleeding caused by hyperfibrinolysis (HF) predicts mortality. We tested in vitro (1) whether clinically relevant grades of hypothermia, acidosis, and their combination impact on recombinant tissue-type plasminogen activator (r-tPA)-evoked HF and assessed (2) the efficacy of tranexamic acid (TA) in inhibiting fibrinolysis under such conditions. METHODS: To assess the effects of r-tPA-evoked HF, venous blood (3,000 MUL) from healthy volunteers was incubated with r-tPA (final concentration, 100 ng/mL) or saline (control) for 30 minutes at the final measurement temperature. Before thromboelastometric measurements, samples were acidified (addition of 40 MUL of 0.5 or 1N hydrochloric acid, respectively) to achieve a pH (alpha-stat) of approximately 7.1 or 6.9, respectively. To assess effects of hypothermia, tests were performed at blood/thromboelastometer temperatures of 33 degrees C and 37 degrees C, respectively. Coagulation was analyzed using rotational thromboelastometry (ROTEM), particularly assessing the Clot Lysis Index (CLI) after 45 minutes (CLI45) in extrinsically activated assays (EXTEM). RESULTS: Addition of r-tPA evoked fibrinolysis (CLI45: median, 64; 25th/75th percentile, 48/80) compared with saline controls (CLI45: median, 93; 25th/75th percentile, 91/96). Moderate acidosis (pH [mean +/- SD], 7.12 +/- 0.03) did not affect r-tPA induced fibrinolysis. However, severe acidosis (pH, 6.91 +/- 0.02) significantly aggravated r-tPA-induced fibrinolysis (CLI45: median, 49; 25th/75th percentile, 26/71; p = 0.0039) compared with fibrinolysis with normal pH and normothermia (median, 77; 25th/75th percentile, 65.5/83). In contrast, hypothermia (33 degrees C) at normal pH (median +/- SD, 7.37 +/- 0.02) markedly mitigated fibrinolysis (CLI45: median, 94; 25th/75th percentile, 88/96; p = 0.0156) compared with normothermia (CLI45: median, 64; 25th/75th percentile, 48/80). TA (final concentration, 0.33 mg/mL) abolished r-tPA-evoked fibrinolysis even during severe acidosis (CLI45: median, 92; 25th/75th percentile, 86.5/94; p = 0.0039). CONCLUSION: Severe acidosis significantly increases r-tPA-evoked fibrinolysis, whereas hypothermia markedly mitigates HF. The latter finding may imply that rapid rewarming of trauma patients might aggravate fibrinolysis. TA reliably abolished fibrinolysis also under these conditions, supporting its role in trauma induced coagulopathy. PMID- 23354243 TI - Inflammatory and apoptotic alterations in serum and injured tissue after experimental polytrauma in mice: distinct early response compared with single trauma or "double-hit" injury. AB - BACKGROUND: The exact alterations of the immune system after polytrauma leading to sepsis and multiple-organ failure are poorly understood. Thus, the early local and systemic inflammatory and apoptotic response was characterized in a new polytrauma model and compared with the alterations seen after single or combined injuries. METHODS: Anesthetized C57BL/6 mice were subjected to either blunt bilateral chest trauma (Tx), closed head injury, right femur fracture including contralateral soft tissue injury, or a combination of injuries (PTx). After 2 hours or 6 hours, animals were sacrificed, and the systemic as well as the local pulmonary immune response (bronchoalveolar lavage [BAL]/plasma cytokines, lung myeloperoxidase [MPO] activity, and alveolocapillary barrier dysfunction) were evaluated along with lung/brain apoptosis (lung caspase 3 Western blotting, immunohistochemistry, and polymorphonuclear leukocytes [PMN] Annexin V). RESULTS: Hemoglobin, PO2 saturation, and pH did not differ between the experimental groups. Local BAL cytokines/chemokines were significantly increased in almost all groups, which included Tx. There was no further enhancement of this local inflammatory response in the lungs in case of PTx. At 2 hours, all groups except sham and closed head injury alone revealed an increased activity of lung MPO. However, 6 hours after injury, lung MPO remained increased only in the PTx group. Increased BAL protein levels were found, reflecting enhanced lung leakage in all groups with Tx 6 hours after trauma. Only after PTx was neutrophil apoptosis significantly decreased, whereas lung caspase 3 and plasma interleukin 6/keratinocyte chemoattractant (KC) were substantially increased. CONCLUSION: The combination of different injuries leads to an earlier systemic inflammatory response when compared with the single insults. Interestingly, only after PTx but not after single or double hits was lung apoptosis increased, and PMN apoptosis was decreased along with a prolonged presence of neutrophils in the lungs, which may therefore represent a possible pathomechanism for lung injury after polytrauma. PMID- 23354244 TI - Proteasome inhibition prolongs survival during lethal hemorrhagic shock in rats. AB - BACKGROUND: Several lines of evidence suggest that proteasomes, the major nonlysosomal proteases in eukaryotes, are involved in the pathophysiology of various disease processes, including ischemia-reperfusion injury and trauma. Recently, we demonstrated that 26S proteasome activity is negatively regulated by adenosine triphosphate (ATP) and that proteasome activation during ischemia contributes to myocardial injury. The regulation of tissue proteasome activity by ATP and the potential of proteasomes as drug targets during hemorrhagic shock, however, are unknown. Thus, we evaluated the regulation of tissue proteasome peptidase activity and the effects of the proteasome inhibitor bortezomib in rat models of hemorrhagic shock. METHODS: Series 1 includes animals (n = 20) hemorrhaged to a mean arterial blood pressure of 30 mm Hg for up to 45 minutes. Series 2 includes animals hemorrhaged to a mean arterial blood pressure of 30 mm Hg for 30 minutes, followed by bortezomib (0.4 mg/kg) or vehicle administration (n =5 per group) and fluid resuscitation until 75 minutes. Series 3 includes animals that underwent 40% blood volume hemorrhage, followed by 2% blood volume hemorrhage every 15 minutes until death. Bortezomib (0.4 mg/kg) or vehicle were administered 15 minutes after the onset of hemorrhage (n = 6-7 per group). Vital signs were continuously monitored. The heart, lung, and pectoral muscle were analyzed for proteasome peptidase activities and levels of ATP, ubiquitin-protein conjugates, and cytokines (tumor necrosis factor alpha, interleukin 6, and interleukin 10). RESULTS: In Series 1, proteasome peptidase activities in tissue extracts increased proportional to the decrease in tissue ATP concentrations during hemorrhagic shock. Activation of proteasome peptidase activity with decreases of the ATP assay concentration was also detectable in normal tissue extracts. In Series 2, systemic administration of bortezomib inhibited tissue proteasome activities but did not affect the physiologic response. In Series 3, bortezomib inhibited tissue proteasome activities, increased endogenous ubiquitin protein conjugates, and prolonged survival time from treatment from 48.5 minutes in the control group to 85 minutes (p = 0.0012). Bortezomib treatment did not affect tissue cytokine levels. CONCLUSION: Proteasome activation contributes to the pathophysiology of severe hemorrhagic shock. Pharmacologic inhibition of the proteasome may provide a survival advantage during lethal hemorrhagic shock. PMID- 23354245 TI - Microvascular endothelial cell hyperpermeability induced by endogenous caspase 3 activator staurosporine. AB - BACKGROUND: Microvascular hyperpermeability following conditions such as hemorrhagic shock occurs mainly owing to disruption of the adherens junctional protein complex in endothelial cells. The objective of this study was to examine the action of staurosporine, a potent activator of endogenous caspase 3 on the adherens junction and the cellular pathway through which it causes possible endothelial cell barrier dysfunction. METHODS: Rat lung microvascular endothelial cell (RLMEC) permeability was measured by fluorescein isothiocyanate-albumin flux across the monolayer in a Transwell plate. Integrity of the endothelial cell adherens junctions was studied using immunofluorescence of beta-catenin and vascular endothelial-cadherin. Mitochondrial reactive oxygen species formation was determined by using dihydrorhodamine 123 and mitochondrial transmembrane potential by JC-1 fluorescent probe and flow cytometry. Caspase 3 enzyme activity was assayed fluorometrically. Cell death assay in RLMECs was performed using propidium iodide staining and analyzed by flow cytometry. RESULTS: Staurosporine (1 uM)-treated RLMEC monolayers showed significant increase in permeability, which was decreased by pretreatment with caspase 3 specific inhibitor, Z-DEVD-FMK (p < 0.05). Immunofluorescence studies showed staurosporine induced disruption of the adherens junction, which was reversed by Z-DEVD-FMK. Staurosporine treatment led to an increase in mitochondrial reactive oxygen species formation and a decrease in mitochondrial transmembrane potential. Furthermore, staurosporine induced a significant increase in caspase 3 activity (p < 0.05) but not cell death in RLMECs (p < 0.05). CONCLUSION: Staurosporine-induced disruption of the adherens junction and microvascular endothelial cell hyperpermeability is associated with the activation of mitochondrial "intrinsic" apoptotic signaling cascade but without causing endothelial cell death. Our results suggest that prevention of mitochondrial-mediated activation of caspase 3 has therapeutic potential against microvascular hyperpermeability. PMID- 23354246 TI - Protective effects of dexmedetomidine on blunt chest trauma-induced pulmonary contusion in rats. AB - BACKGROUND: Dexmedetomidine is a new and highly selective alpha2-adrenoreceptor agonist with potent anti-inflammatory capacity. This study explored the effects of dexmedetomidine on regulating hemodynamics, the plasma tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) levels, immunohistochemical localization of nuclear factor kappaB (NF-kappaB) from blunt chest trauma-induced pulmonary contusion in rats. METHODS: Fifty Sprague-Dawley rats were randomly assigned into five equal groups (n = 10) as follows: uninjured control group, uninjured plus dexmedetomidine group, injured group, injured plus dexmedetomidine group, injured plus dexmedetomidine plus yohimbine (IDY), an alpha2-adrenergic receptor antagonist, group. Dexmedetomidine was infused continuously through the left femoral vein cannula at the rate of 5.0 ug/kg per hour after blunt chest trauma 30 minutes in uninjured plus dexmedetomidine group, injured plus dexmedetomidine group, and IDY group. Animals in the IDY group received 0.2-mg/kg yohimbine immediately after the administration of dexmedetomidine. The right femoral artery was cannulated to monitor mean arterial pressure and heart rate and to draw blood samples. The plasma TNF-alpha and IL-1beta levels were measured using enzyme-linked immunosorbent assays. The lung tissue NF-kappaB expression was determined by immunohistochemistry. RESULTS: Bilateral blunt chest trauma produced progressive hypotension and a prolonged descent in heart rate. The plasma TNF-alpha and IL-1beta levels as well as the NF-kappaB activation of lung significantly increased after blunt chest trauma challenge alone. Dexmedetomidine not only significantly modified hemodynamics and relieved the infiltration of inflammatory cells into alveolar spaces but also inhibited the plasma TNF-alpha and IL-1beta production as well as the lung NF-kappaB activation (p < 0.05, respectively). Yohimbine treatment significantly reversed the effects of dexmedetomidine (p < 0.05). CONCLUSION: The administration of dexmedetomidine has beneficial effects on pulmonary contusion from blunt chest trauma in rats. The mechanisms were likely to inhibit the NF-kappaB activation via alpha2-adrenergic receptors and attenuate the proinflammatory cytokine responses. PMID- 23354247 TI - Systemic inflammation induced by a thoracic trauma alters the cellular composition of the early fracture callus. AB - BACKGROUND: We recently demonstrated that a blunt chest trauma, a strong inducer of the posttraumatic systemic inflammatory response and one of the most critical injuries in polytrauma patients, significantly delayed fracture healing in rats, possibly by the interaction of the systemic inflammation with early regeneration processes locally at the fracture site. The underlying cellular mechanisms, however, have as yet remained unknown. Therefore, the aim of this study was to analyze the cellular and morphologic composition of the early fracture callus after a blunt chest trauma. METHODS: Rats received an osteotomy of the right femur stabilized by an external fixator in combination with a blunt chest trauma or not. The animals were killed after 3, 7, and 35 days, and the fracture calli were analyzed histologically for new tissue formation, polymorphonuclear leucocytes, macrophages, osteoclasts, and the presence of the proinflammatory cytokine interleukin 6. RESULTS: The blunt chest trauma considerably increased the number of polymorphonuclear leucocytes in the callus by Day 3 compared with animals with isolated fractures. The number of macrophages was significantly reduced by the thoracic trauma at Days 3 and 7. The number of osteoclasts was not changed at any postoperative time point. After 3 days, the blunt chest trauma led to a significantly stronger interleukin 6 staining within the periosteal callus in zones of intramembranous ossification. During the time of cortical bridging at Day 35, the amount of newly formed bone was significantly decreased after blunt chest trauma. CONCLUSION: Our results suggest that the systemic posttraumatic inflammation induced by a thoracic trauma disturbed the inflammatory balance during the early healing stage by altering the recruitment of inflammatory cells and cytokine expression locally at the fracture site and thus impaired fracture healing. These findings provide new insights in the pathomechanisms of impaired fracture healing in patients experiencing severe trauma. PMID- 23354249 TI - Prognostic factors for failure of nonoperative management in adults with blunt splenic injury: a systematic review. AB - BACKGROUND: Contradictory findings are reported in the literature concerning prognostic factors for failure of nonoperative management (NOM) in the treatment of adults with blunt splenic injury. The objective of this systematic review was to identify prognostic factors for failure of NOM, with or without angiography and embolization. METHODS: MEDLINE, Embase, and the Cochrane Library databases were searched. Prospective or retrospective cohort studies addressing failure of nonoperative treatment, with and/or without angiography and embolization, of blunt abdominal injuries were included. Methodological quality of the studies was assessed. RESULTS: A total of 335 titles and abstracts were screened, of which 31 fulfilled the inclusion criteria. No randomized controlled trials were found. Ten articles were qualified as high-quality articles and used for data extraction (best-evidence synthesis). A total of 25 prognostic factors were investigated, of which 14 were statistically significant in one or more studies. Strong evidence exists that age of 40 years or above, Injury Severity Score (ISS) of 25 or greater, and splenic injury grade of 3 or greater are prognostic factors for failure of NOM. Moderate evidence was found for a splenic Abbreviated Injury Scale score of 3 or greater, trauma and ISS of less than 0.80, the presence of an intraparenchymal contrast blush, as well as transfusion of 1 unit of packed red blood cells or more. Limited evidence was found for large hemoperitoneum, lower Revised Trauma Score, lower Glasgow Coma Scale score, lower systolic blood pressure, male sex, the presence of traumatic brain injury, and splenic embolization as protective factor for failure of NOM. CONCLUSION: Awareness for failure of NOM is required in patients aged 40 years or older, in patients with an ISS of 25 or higher or those with splenic injury grade 3 or higher. The prognostic factors for failure that we identified should be confirmed in future prospective cohort studies or meta-analyses using individual patient data. LEVEL OF EVIDENCE: Systematic review, level III. PMID- 23354248 TI - Long-term preclinical evaluation of the intracorporeal use of advanced local hemostatics in a damage-control swine model of grade IV liver injury. AB - BACKGROUND: The purpose of this study was to evaluate the long-term efficacy and safety of kaolin- and chitosan-based hemostatic agents for hemorrhage control in a 14-day survival, damage-control swine model of Grade IV liver injury. METHODS: A total of 48 anesthetized pigs (40 kg) underwent a 35% total blood volume bleed, cooling to 34 degrees C and a standardized liver injury. The animals were randomized to standard gauze control (SG, n = 12), QuikClot Combat Gauze (QCCG, n = 12), Celox (CX, n = 12), or Celox Gauze (CXG, n = 12) packing. At 15 minutes, shed blood was calculated, followed by damage-control closure. At 48 hours, pack removal and definitive closure was performed. At 14-day sacrifice, the liver, kidney, heart, lung, and small bowel standard intra-abdominal organs were sampled for histopathological examination. RESULTS: Uncontrolled blood loss at 2 minutes demonstrated internal consistency of the injury. Blood loss at 15 minutes was significantly lower in the CX and QCCG arms (SG, 11.1 +/- 1.1 mL/kg; QCCG, 5.3 +/ 1.2 mL/kg; CX, 5.7 +/- 1.2 mL/kg; and CXG, 10.1 +/- 1.3 mL/kg; p = 0.002). Forty eight-hour survival was 50.0% for SG, 58.3% for QCCG, 83.3% for CX, and 41.7% for CXG (p = 0.161). Fourteen-day survival was 41.7% (5) for SG, 50.0% (6) for QCCG, 58.3% (7) for CX, and 41.7% (5) for CXG (p = 0.821). Four CX and two QCCG deaths were caused by bowel obstruction; one SG death was caused by sepsis; the remainder was caused by blood loss.Histopathology in one CX animal demonstrated eosinophilic material within a coronary vessel consistent with granule embolization. CONCLUSION: Celox and QuikClot Combat Gauze were effective hemostatic adjuncts to standard intracavitary damage-control packing. The hemostasis was durable, facilitating pack removal, and definitive closure at reoperation. There was however an increase in the development of intra-abdominal adhesions resulting in small bowel obstruction. The potential for distant embolization of granular agents warrants further investigation. PMID- 23354250 TI - Process improvement in trauma: compliance with recommended imaging evaluation in the diagnosis of high-grade renal injuries. AB - BACKGROUND: Appropriate imaging in renal trauma can avoid delayed recognition of collecting system injuries, allowing for prompt intervention and less morbidity. Current recommendations include obtaining abdominal and pelvic computed tomographic scans with intravenous contrast, followed by excretory images for high-grade injury or perinephric fluid. The purpose of this study was to evaluate compliance with this recommendation among adult Level I trauma centers in Utah. METHODS: A retrospective review was performed on all renal trauma patients evaluated at adult Level I trauma centers in Utah from January 2005 to January 2011. For all American Association for Surgery of Trauma grade 3 to 5 renal injuries, injury characteristics and outcomes were reviewed. We defined compliance as obtaining delayed images for grade 3 injuries with perinephric fluid or any grade 4 to 5 injuries. Descriptive statistics and univariate comparisons were calculated using statistical software. RESULTS: A total of 147 patients were identified with injuries of grade 3 or higher, but only 126 had available images for review at the time of the study. Of the 102 patients with a perinephric fluid collection or grade 4 to 5 injuries, delayed images were obtained in 74 (73%). In these patients, 14 (19%) had a collecting system injury. In the 28 patients without delayed images, 7 (25%) were later identified to have a collecting system injury. Of the 21 collecting system injuries, 7 (33%) had a delay in diagnosis because of lack of excretory images obtained on initial evaluation. CONCLUSION: Our findings support obtaining excretory images in patients with grade 4 to 5 injuries or those with a perinephric fluid collection. Poor compliance led to delayed diagnosis, with several patients requiring intervention for persistent urinary leak. We have implemented trauma imaging guidelines within Utah Level I trauma hospitals, which seek to minimize these diagnostic problems. LEVEL OF EVIDENCE: Epidemiologic study, level III; therapeutic study, level IV. PMID- 23354251 TI - Implementation of 24/7 intensivist presence in the SICU: effect on processes of care. AB - BACKGROUND: Staffing of attending intensivists 24 hours per day, 7 days per week (24/7) in the surgical intensive care unit (SICU) has unknown benefits. We hypothesized that 24/7 attending intensivist staffing in the SICU would improve outcomes and processes of care. METHODS: We retrospectively reviewed 26 months of admissions to our 20-bed SICU, comparing 13 months before and 13 months after addition of an in-house night intensivist to the existing day intensivist with a nighttime on-demand model. Primary outcomes were mortality, complications, SICU length of stay, and ventilator days. Secondary outcomes were use of intensivist directed ancillary testing and therapies, as well as physician billing (relative value units per full-time equivalent [RVU/FTE]). RESULTS: A total of 2,829 patients were included: 1,408 before and 1,421 after 24/7 staffing. Baseline characteristics, mortality, complications, ventilation days, ICU and hospital length of stay, and readmission rate were similar between groups (all p > 0.05). Use of blood products and imaging tests (computed tomographic scans) were significantly reduced. Total RVU increased, as did the RVU/FTE ratio. CONCLUSION: Implementation of 24/7 staffing did not improve SICU morbidity or mortality but was associated with decreased blood product use and fewer axial imaging studies. The RVU/FTE ratio was improved. Overall health care value may be decreased under this model. LEVEL OF EVIDENCE: Care management study, level IV. PMID- 23354253 TI - The value of lower-extremity duplex surveillance to detect deep vein thrombosis in trauma patients. AB - BACKGROUND: Venous duplex surveillance (VDS) is commonly used in trauma patients considered at risk for deep venous thrombosis. Economic evaluations have not addressed the quality of either the process of care or the outcomes achieved through the use of VDS. We sought to determine the value (quality/cost) of VDS in trauma patients stratified by risk for venous thromboembolism. METHODS: We reviewed records of all trauma patients from July 2006 to December 2010 who received weekly VDS examinations of the lower extremities. Prophylaxis and risk stratification were performed according to the American College of Chest Physicians recommendations. Patients were stratified by level of venous thromboembolism risk according to the results of a systematic review of the literature. The "value" of VDS was expressed as the number of clinically relevant findings divided by the cost (defined as the percent full-time equivalent of a certified vascular technologist performing VDS). RESULTS: A total of 2,169 patients met inclusion criteria and were stratified by deep venous thrombosis risk (218 moderate, 1,173 high, 778 highest). The quality of the process (the percent of sites adequately visualized per VDS) was not clinically different among risk groups. The quality of the outcome (number of clinically relevant findings) was significantly greater, and the work time required per finding was significantly lower in the highest-risk group (p < 0.001). The value of VDS was significantly greater in the highest-risk group compared with high or moderate risk groups (1,104 vs. 337 vs. 76 findings per percent full-time equivalent, respectively; p < 0.001). CONCLUSION: VDS has significantly greater value in the highest-risk group and is warranted in this group. It is of less value in the moderate risk trauma patient. Calculating the value of specific health care interventions can guide the allocation of limited resources. LEVEL OF EVIDENCE: Prognostic study, level II; value-based evaluation, level III. PMID- 23354252 TI - Improvements in pulmonary and general critical care reduces mortality following ventilator-associated pneumonia. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is the most common hospital acquired infection in the intensive care unit, with substantial subsequent mortality. The mortality following VAP declined in the 1980s and 1990s. Experts suggest that little progress has been made in the outcomes from VAP since several novel interventions have failed. We nonetheless hypothesized that mortality following VAP has continued to decrease owing to advances in pulmonary critical care. METHODS: We identified all adult patients with Centers for Disease Control and Prevention-defined, intensive care unit-acquired VAP between January 1, 1997, and December 31, 2008, from a prospectively collected database. RESULTS: A total of 793 cases of VAP occurred in the study period. Cases were divided into four periods (1997-1999, 2000-2002, 2003-2005, or 2006-2008) to compare outcomes over time. Acute Physiology and Chronic Health Evaluation II scores were stable, while mortality was significantly lower in Period 4 when compared with Periods 1 and 2 (p = 0.004 and 0.009, respectively). A logistic regression model predicting death (c statistic = 0.871) revealed age (odds ratio, 1.03; 95% confidence interval, 1.02-1.05), Acute Physiology and Chronic Health Evaluation II score (1.09, 1.05 1.14), white blood cell count (1.03, 1.00-1.06), transplant recipient (3.45, 1.40 8.53), transfusions (3.25, 1.37-7.68), and pulmonary disease (3.01, 1.67-5.45) were independent predictors of death, as was the presence of trauma (0.10, 0.06 0.18), chronic steroid therapy (0.39, 0.17-0.91), and patient length of stay (0.99, 0.98-0.99), with odds ratios less than 1.0. In addition, those patients treated in Period 1 (2.23, 1.16-4.29) or Period 2 (2.13, 1.12-4.06) had twice the risk of death following an episode of VAP when compared with those treated in the most recent period. CONCLUSION: We have shown that mortality following an episode of VAP continues to decrease over time and attribute this to advancements in pulmonary and general critical care rather than any specific interventions. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 23354254 TI - The clinical significance of isolated traumatic subarachnoid hemorrhage. AB - BACKGROUND: Mild traumatic brain injury is a clinical diagnosis predicated on a patient's neurologic status and encompasses a variety of pathologies on computed tomography. We wondered whether isolated traumatic subarachnoid hemorrhage (iSAH) without other intracranial pathologic diagnosis is a more benign form of minor head injury that does not warrant extensive (and expensive) observation and follow-up. METHODS: This is a retrospective review of patients identified prospectively via a trauma registry during a period of 7 years, who had the computed tomographic finding of iSAH on admission scan and a Glasgow Coma Scale (GCS) score of 13 or greater. RESULTS: There were 478 patients identified, with a mean age 61 years, and 223 were male. Median Injury Severity Score (ISS) was 10 (range, 9-48), and the distribution was 415, 54, and 12 for those with GCS score of 15, 14, and 13, respectively. In-hospital follow-up imaging in nine patients demonstrated increased pathologic findings, but subsequent imaging showed stable or decreasing blood, and none experienced a neurologic decline or underwent a neurosurgical procedure.Among those with no other injuries (ISS = 9, n = 118) patients spent a mean of 2.0 (95% confidence interval, 1.1-2.9) days in intensive care unit and 4.9 (95% confidence interval, 3.9-6.0) days in hospital. The likelihood of discharge home was significantly related to age (p < 0.0001), ISS (p < 0.01), and admission GCS (p < 0.01) (stepwise logistic regression), but not progression of SAH.At 6-week follow-up, one patient (0.2%) developed bilateral chronic subdurals requiring drainage, without neurologic sequela. CONCLUSION: In this largest reported series to date of iSAH in the setting of mild traumatic brain injury, the finding seems to be benign and can likely be managed without routine follow-up imaging or intensive care unit admission in the absence of other significant trauma. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III; therapeutic study, level IV. PMID- 23354255 TI - How much vertical displacement of the symphysis indicates instability after pelvic injury? AB - BACKGROUND: Measures of pubic symphyseal widening are used by at least two classification systems as determinants of injury grade. Recent work has challenged the commonly used parameter of 2.5 cm of pubic symphysis as an accurate marker of pelvic injury grade and has suggested a role of rotation in the flexion-extension plane as a determinant of pelvic stability. We investigated pelvic stability in the flexion-extension plane to determine a threshold of rotational displacement of the hemipelvis above which the potential for instability exists. METHODS: Cadaveric specimens were mounted onto a servohydraulic biaxial testing machine and subjected to a vertically directed flexion moment. Position of hemipelvis was recorded using a three-dimensional motion capture system and video recording. Displacement of the pubic symphysis and changes in length and position of the sacrospinous and sacrotuberous ligaments were recorded. Amount of force applied was measured and recorded. A yield point was determined as the first point at which the force plot exhibited a decrease in force and was correlated to the corresponding displacement. RESULTS: The mean vertical displacement of the pubic symphysis at the yield point was 16 mm (95% confidence interval, 11-22 mm). Mean sacrospinous ligament strain at yield point was 4% (range, 1.0-9.5%). CONCLUSION: Pelves with vertical rotational symphyseal displacement of less than 11 mm can reasonably be expected to have rotational stability in the flexion-extension plane. Those with displacement of greater than 22 mm can be expected to have lost some integrity regarding resistance to pelvic flexion. These values may allow clinicians to infer pelvic stability from amount of vertical symphyseal displacement. PMID- 23354256 TI - The impact of a standardized "spine damage-control" protocol for unstable thoracic and lumbar spine fractures in severely injured patients: a prospective cohort study. AB - BACKGROUND: In contrast to the established principles of "damage-control orthopedics" for temporary external fixation of long bone or pelvic fractures, the "ideal" timing and modality of fixation of unstable spine fractures in severely injured patients remains controversial. METHODS: A prospective cohort study was designed to evaluate the safety and efficacy of a standardized "spine damage-control" (SDC) protocol for the acute management of unstable thoracic and lumbar spine fractures in severely injured patients. A total of 112 consecutive patients with unstable thoracic or lumbar spine fractures and Injury Severity Score (ISS) of greater than 15 were prospectively enrolled in this study from October 1, 2008, to December 31, 2011. Acute posterior spinal fixation within 24 hours was performed in 42 patients (SDC group), and 70 patients underwent definitive operative spine fixation in a delayed fashion ("delayed surgery"[DS] group). Both cohorts were prospectively analyzed for baseline demographics, length of operative time, amount of intraoperative blood loss, total hospital length of stay, number of ventilator-dependent days, and incidence of early postoperative complications. RESULTS: The mean time to initial spine fixation was significantly decreased in the SDC group (8.9 [1.7] hours vs. 98.7 [22.4] hours, p < 0.01). The SDC cohort had a reduced mean length of operative time (2.4 [0.7] hours vs. 3.9 [1.3] hours), length of hospital stay (14.1 [2.9] days vs. 32.6 [7.8] days), and number of ventilator-dependent days (2.2 [1.5] days vs. 9.1 [2.4] days), compared with the DS group (p < 0.05). Furthermore, the complication rate was decreased in the SDC group with regard to wound complications (2.4% vs. 7.1%), urinary tract infections (4.8% vs. 21.4%), pulmonary complications (14.3% vs. 25.7%), and pressure sores (2.4% vs. 8.6%), compared with the DS cohort (p < 0.05). CONCLUSION: A standardized SDC protocol represents a safe and efficient treatment strategy for severely injured patients with associated unstable thoracic or lumbar fractures. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 23354257 TI - A contemporary analysis of the management of the mangled lower extremity. AB - BACKGROUND: The management of a mangled lower extremity is complex and requires consideration of a patient's injury pattern, medical history, social context, and preference. The Lower Extremity Assessment Project provides the highest level of evidence guiding management; however, the Lower Extremity Assessment Project cohort was recruited 15 years ago and was restricted to Level I trauma centers. Furthermore, as our ability to salvage limbs has improved, the decision to amputate in the early period following injury remains particularly challenging. Given these considerations, our primary objective was to characterize the contemporary management of the mangled lower extremity across a range of trauma centers and identify which patient and injury characteristics are associated with early amputation. METHODS: We used a retrospective cohort design and included adults in the National Trauma Databank (2007-2009) with a mangled lower extremity treated at Level I or II trauma centers. A mangle injury was defined as (1) a severe crush injury or (2) the combination of a severe fracture with selected severe injuries from at least two of three categories as follows: soft tissue, artery, or nerve. Logistic regression was used to evaluate the association of patient and injury characteristics with our primary outcome: amputation performed before the end of the first full calendar day following emergency department arrival (early amputation). RESULTS: A total of 1,354 patients were identified from 222 centers; 278 (21%) underwent amputation during their hospital course, with 124 (9%) undergoing early amputation. On multivariable analysis, only injury characteristic was associated with early amputation. The presence of severe head injury (Abbreviated Injury Scale [AIS] score >= 3), shock in the emergency department (systolic blood pressure < 90 mm Hg), limb injury type, and higher energy mechanism were independently associated with early amputation. CONCLUSION: Nearly half of all in-hospital amputations for mangled lower extremities are performed early. The decision to amputate early may not be guided by age, comorbidity level, or insurance status but rather by systemic and local injury characteristics. LEVEL OF EVIDENCE: Therapeutic study, level IV; prognostic/epidemiologic study, level IV. PMID- 23354258 TI - The management of degloving injury of lower extremities: technical refinement and classification. AB - BACKGROUND: Degloving injuries are severe and frequently underestimated lesions. Lower extremities are the most commonly affected limbs. This injury is associated with a high morbidity and mortality if mismanaged. The treatment of such patients still varies, clinical indicators for its prognosis are scarce, and some technical protocols are also controversial. METHODS: Between August 2002 and July 2011, 102 patients with skin avulsion of 129 lower extremities were treated with immediate full-thickness skin graft following a protocol of radical debridement. The full-thickness skin grafts were processed with sharp scalpels in situ. They were further secured with multiple sutures after repositioning to improve skin graft take. Outcomes were evaluated based on different patterns and age groups. RESULTS: Three patterns of injury, that is, a purely degloving injury (Pattern 1), a degloving injury with the involvement of deep soft tissues (Pattern 2), and a degloving injury with long-bone fractures (Pattern 3), were revealed. Among the three patterns, much higher primary healing rates were observed in Patterns 1 and 2. Younger patients in Pattern 3 achieved a higher primary healing rate than the old ones, whereas no differences of primary healing rate regarding different age groups were noted in Patterns 1 and 2. CONCLUSION: The degloving injuries of the lower extremities can be generally divided into three patterns. The preparation of full-thickness skin graft with scalpels is very simple and prompt. The management of degloving injury of the lower extremity with immediate full thickness skin grafting following the protocol of radical debridement is feasible. Age has little impact on the skin graft take except for severe cases (Pattern 3) in which old age is an indicator of unfavorable prognosis and special attention is required. LEVELS OF EVIDENCE: Prognostic study, level IV; therapeutic study, level V. PMID- 23354260 TI - Factors associated with patient exposure and environmental control during pediatric trauma resuscitation. AB - BACKGROUND: Exposure and environmental control are essential components of the advanced trauma life support primary survey, especially during the resuscitation of pediatric patients. Proper exposure aids in early recognition of injuries in patients unable to communicate their injuries, while warming techniques, such as the use of blankets, assist in maintaining normothermia. The purpose of this study was to identify factors associated with exposure compliance and duration during pediatric trauma resuscitation. METHODS: All pediatric trauma resuscitations over a 4-month period were reviewed for compliance and time to completion of clothing removal and warm blanket placement. Video review data were then linked with clinical data obtained from the trauma registry. Univariate and multivariate analyses were used to determine the associations of patient characteristics, injury mechanism, and clinical factors on exposure compliance and duration. RESULTS: Of 145 patients, 65 (52%) were never exposed. Lower exposure compliance was associated with increasing age (odds ratio, [OR], 0.90; 95% confidence interval [CI], 0.83-0.98), Glasgow Coma Scale (GCS) score of 14 or greater (OR, 0.16; 95% CI, 0.03-0.76), Injury Severity Score (ISS) of 15 or less (OR, 0.27; 95% CI, 0.09-0.82), and the absence of head injury (OR, 0.26; 95% CI, 0.08-0.87). Among those exposed, the duration of exposure was longer among children with GCS score of less than 14 (4.3 [1.6], p = 0.009), head injuries (3.33 [1.6], p = 0.04), and the need for intubation (8.4 [2.2], p < 0.001). In multivariate analyses, older age and ISS of 15 or less were associated with a decreased odds of exposure (p = 0.009, p = 0.04, respectively), while intubation was associated with increased exposure duration (p = 0.007). CONCLUSION: Despite the importance of exposure and environmental control during pediatric trauma resuscitation, compliance with these tasks was low, even among severely injured patients. Interventions are needed to promote the proper exposure of patients during the initial evaluation, while also limiting the duration of exposure during examinations and procedures in the trauma bay. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 23354259 TI - Predictors of mortality after emergent surgery for acute colonic diverticulitis: analysis of National Surgical Quality Improvement Project data. AB - BACKGROUND: The surgical treatment of acute colonic diverticulitis is associated with significant morbidity and mortality. However, patient and operative characteristics associated with mortality in this patient population are unclear. We hypothesize that demographic and perioperative variables can be used to predict postoperative mortality.The purpose of this study was to identify perioperative variables predictive of postoperative mortality after emergent surgery for acute diverticulitis. METHODS: Patients with diverticulitis undergoing colostomy and/or partial colectomy with or without primary anastomosis were retrieved from the American College of Surgeons National Surgical Quality Improvement Program database for years 2005 to 2008 inclusive. Only patients undergoing emergent surgery for acute diverticulitis were included. Univariate analyses were performed to compare demographic characteristics, preoperative laboratory values, comorbidities, and intraoperative variables. Variables with a significant (p < 0.10) difference between survivors and nonsurvivors were included in a stepwise logistic regression model to determine predictors of 30 day mortality. Concordance indices (c indices) for postoperative mortality were calculated using 2005 to 2008 data to determine predictive accuracy and validated on 2009 data. RESULTS: A total of 2,214 patients met inclusion criteria. Mean age was 61 years, and 50% of patients were male. Thirty-day mortality was 5.1%. Nine preoperative variables were significantly associated with postoperative mortality on multivariable analysis. The c index of this nine-variable model was 0.901. Renal dysfunction, hypoalbuminemia, American Society of Anesthesiologists class, and age were chosen to create a simpler model, with a c index of 0.886 for 2005 to 2008 data and 0.893 for 2009 data. CONCLUSION: Four readily available perioperative variables can be used to predict 30-day mortality after emergent surgery for acute diverticulitis. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 23354261 TI - A comparison of injuries, crashes, and outcomes for pediatric rear occupants in traffic motor vehicle collisions. AB - BACKGROUND: This study was initiated was initiated to describe pediatric rear occupant motor vehicle collision (MVC) injuries, including injury patterns and outcomes as well as characteristics associated with severe injury to the head and abdomen. METHODS: A retrospective cohort of severely injured (Injury Severity Score [ISS] > 12) pediatric (age <18 years) patients involved in a traffic MVC as a rear occupant and treated at one of two Ontario trauma centers (2001-2010) was studied was studied. Demographic, injury, crash and outcome data were obtained from the trauma registries. Data were statistically compared by two pediatric age groups: children (0-8 years; requiring a child or booster seat) versus adolescents (9-17 years; requiring a lap-shoulder belt). RESULTS: There were 36 children (34%) and 70 adolescents (66%) severely injured as rear occupants in MVCs. Despite similar ISS (p = 0.716) and mortality rates (p = 0.680) between age groups, there were significant differences in injury patterns and risk factors. Children were more likely to have severe head injuries (78% vs. 39%, p < 0.001) associated with a lack of an age-appropriate child restraints (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.1-10.8; p = 0.029), middle seating (OR, 6.2; 95% CI, 1.5-26.1; p = 0.013), and side-impact crashes (p = 0.007). Adolescents were more likely to have severe abdominal injuries (23% vs. 6%, p < 0.001) associated with the use of lap-shoulder belts (OR, 3.8; 95% CI, 1.1-13.3; p = 0.034), single-vehicle MVCs (p = 0.007), and vehicle extrications (p = 0.035). CONCLUSION: While safer than the front seat for children, additional study is needed on the restraint systems and the potential for injury to pediatric rear occupants in an MVC. Our data suggest that pediatric age groups differ in injuries, risk factors, and MVC impacts. Recommendations for improved protection of child occupants and preferred seating positions are required. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 23354262 TI - Traumatic cardiac arrest: should advanced life support be initiated? AB - BACKGROUND: Several studies recommend not initiating advanced life support in traumatic cardiac arrest (TCA), mainly owing to the poor prognosis in several series that have been published. This study aimed to analyze the survival of the TCA in our series and to determine which factors are more frequently associated with recovery of spontaneous circulation (ROSC) and complete neurologic recovery (CNR). METHODS: This is a cohort study (2006-2009) of treatment benefits. RESULTS: A total of 167 TCAs were analyzed. ROSC was obtained in 49.1%, and 6.6% achieved a CNR. Survival rate by age groups was 23.1% in children, 5.7% in adults, and 3.7% in the elderly (p < 0.05). There was no significant difference in ROSC according to which type of ambulance arrived first, but if the advanced ambulance first, 9.41% achieved a CNR, whereas only 3.7% if the basic ambulance first. We found significant differences between the response time and survival with a CNR (response time was 6.9 minutes for those who achieved a CNR and 9.2 minutes for those who died). Of the patients, 67.5% were in asystole, 25.9% in pulseless electrical activity (PEA), and 6.6% in VF. ROSC was achieved in 90.9% of VFs, 60.5% of PEAs, and 40.2% of those in asystole (p < 0.05), and CNR was achieved in 36.4% of VFs, 7% of PEAs, and 2.7% of those in asystole (p < 0.05). The mean (SD) quantity of fluid replacement was greater in ROSC (1,188.8 [786.7] mL of crystalloids and 487.7 [688.9] mL of colloids) than in those without ROSC (890.4 [622.4] mL of crystalloids and 184.2 [359.3] mL of colloids) (p < 0.05). CONCLUSION: In our series, 6.6% of the patients survived with a CNR. Our data allow us to state beyond any doubt that advanced life support should be initiated in TCA patients regardless of the initial rhythm, especially in children and those with VF or PEA as the initial rhythm and that a rapid response time and aggressive fluid replacement are the keys to the survival of these patients. LEVEL OF EVIDENCE: Therapeutic study, level IV; epidemiologic study, level III. PMID- 23354263 TI - Prognosis in moderate and severe traumatic brain injury: external validation of the IMPACT models and the role of extracranial injuries. AB - BACKGROUND: Several prognostic models to predict outcome in traumatic brain injury (TBI) have been developed, but few are externally validated. We aimed to validate the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) prognostic models in a recent unselected patient cohort and to assess the additional prognostic value of extracranial injury. METHODS: The Prospective Observational COhort Neurotrauma (POCON) registry contains 508 patients with moderate or severe TBI, who were admitted in 2008 and 2009 to five trauma centers in the Netherlands. We predicted the probability of mortality and unfavorable outcome at 6 months after injury with the IMPACT prognostic models. We studied discrimination (area under the curve [AUC]) and calibration. We added the extracranial component of the Injury Severity Score (ISS) to the models and calculated the increase in AUC. RESULTS: The IMPACT models had an adequate discrimination in the POCON registry, with AUCs in the external validation between 0.85 and 0.90 for mortality and between 0.82 and 0.87 for unfavorable outcome. Observed outcomes agreed well with predicted outcomes. Adding extracranial injury slightly improved predictions in the overall population (unfavorable outcome: AUC increase of 0.002, p = 0.02; mortality: AUC increase of 0.000, p = 0.37) but more clearly in patients with moderate TBI (unfavorable outcome: AUC increase of 0.008, p < 0.01, mortality: AUC increase of 0.012, p = 0.02) and patients with minor computed tomographic result abnormalities (unfavorable outcome: AUC increase of 0.013, p < 0.01; mortality: AUC increase of 0.001, p = 0.08). CONCLUSION: The IMPACT models performed well in a recent series of TBI patients. We found some additional impact of extracranial injury on outcome, specifically in patients with less severe TBI or minor computed tomographic result abnormalities. LEVEL OF EVIDENCE: Epidemiologic/prognostic study. PMID- 23354264 TI - The effect of age, severity, and mechanism of injury on risk of death from major trauma in Western Australia. AB - BACKGROUND: We examined the association between age, mechanism of injury, and Injury Severity Score (ISS) on mortality in major trauma. METHODS: We used 9 years of population-based linked major trauma (ISS >15) registry data for Western Australia (N = 4,411). These were categorized using the Sampalis classification of injury severity: survivable (ISS 16-24), probably survivable (ISS 25-49), and nonsurvivable (ISS 50+). Age was categorized as younger than 15 years, 15 to 64 years, and 65 years or older. Multivariable linear logistic regression analysis was used to examine the risk of death. RESULTS: Motor vehicle crashes (MVCs) were most prominent for those younger than 65 years, and falls dominated the 65 years and older group. The median ISS for the three age groups were 20, 25, and 24, respectively (p = 0.001). The proportion of deaths in the three groups were 7.2%, 11.5%, and 30.1%, respectively (p = 0.0001). Falls were the most common cause of death. The inflexion point, above which the risk of death increases exponentially, was age 47 years. For the potentially survivable ISS 25 to 49 group, the inflexion point was age 25 years. After adjusting for age and ISS, falls had the greatest risk for death (odds ratio, 1.62; 95% confidence interval, 1.21-2.18). A lower ISS had a disproportionate effect on the elderly. CONCLUSION: The risk for major trauma death increases as age increases, with the inflexion point at age 47 years. Those younger than 15 years have a significantly lower ISS. The elderly have an increased risk for death following falls. LEVEL OF EVIDENCE: Epidemiologic study, level II. PMID- 23354265 TI - Don't be a flamin' fool: effectiveness of an adult burn prevention media campaign in two regions in Queensland, Australia--an interventional study. AB - BACKGROUND: Major burn injuries cause devastating physical and psychosocial morbidity, combined with significant health care and community costs. The aim of this study was to evaluate the effectiveness of a targeted burn prevention message on burn safety knowledge and behavior. METHODS: An 11-year retrospective review of patients admitted to an adult tertiary burn center identified flammable liquid burn injuries in males older than 15 years as 23% of admissions and the most common preventable injury. Burn safety knowledge and experience were measured in a single-blinded, controlled, restricted (male, >15 years), interventional, (therapeutic) prevention study using a total of 2,053 computer assisted telephone interviews in an intervention region (IR) and control region. A two-week multimedia campaign with the theme "Don't Be a Flamin' Fool" was delivered in the IR. RESULTS: The preintervention survey revealed that 13% (218 of 1,637) reported having previously had a gasoline (petrol) burn. Following the intervention, there was a higher percentage of respondents in the IR that had seen or heard a burn prevention message in the previous 3 months (51% vs. 10%; p < 0.001) and perceived that gasoline was a danger when used to start a fire (97% vs. 91%; p = 0.001), that any volume of gasoline was unsafe (85% vs. 65%; p < 0.001), and that gasoline can explode (96% vs. 92%; p = 0.001). Awareness and memory reverted to preintervention levels at 12 months. Eighty-three percent of respondents (100 of 120) who had seen the "Flamin' Fool" campaign thought it was effective in getting its message across. CONCLUSION: This collaborative study found that a media prevention message had a significant impact on burn safety knowledge, which diminished over time. PMID- 23354266 TI - Inhalation of foreign bodies in children: experience of 22 years. AB - BACKGROUND: Foreign body (FB) inhalation into airways of the respiratory system is a life-threatening condition and can be fatal. The purpose of this survey was to evaluate the types and characteristics of inhaled foreign bodies, the age distribution of children, and the outcome. METHODS: We outlined a retrospective review of hospital data of patients between 1990 and 2012. FB inhalation occurring in children 0 year to 16 years was considered for inclusion. During the study period, 1,660 patients undergoing bronchoscopy with the diagnosis of FB were included. Deaths on arrival were excluded. RESULTS: Of the patients, 53% were male, and 47% were female (p > 0.05). The mean age was 6.2 years for girls and 4.7 years for boys. In 57% of all cases, the children were younger than 3 years. An FB was found within the respiratory tract of 1,565 patients. The FBs were always extracted by using rigid bronchoscopy. Hospitalization was always required owing to an institutional requirement. The origin of the FBs were within the two main groups of food and objects. Food FBs included seeds, nuts, beans, and fruit parts. FB objects included pins, toy parts, and metal pieces. FB and subsequent treatment revealed that morbidity was present; however, mortality was rare. CONCLUSION: Most of the inhaled FBs were found in the bronchial tree. Children younger than 3 years are more vulnerable. There seemed to be an association between the aspirated FBs and season, geographic locality, and sociocultural environment. The removal of choice is rigid bronchoscopy under general anesthesia. That most cases of FB in children occurs under the supervision of adults indicates that the incidence and severity of airway FB inhalation can be reduced by parental education and public awareness. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 23354267 TI - Advanced surgical skills for exposure in trauma: a new surgical skills cadaver course for surgery residents and fellows. AB - BACKGROUND: Surgical education is changing owing to workforce and economic demands. Simulation and other technical teaching methods are used to acquire skills transferable to the operating room. Operative management of traumatic injuries has declined, making it difficult to acquire and maintain competence. The ASSET course was developed by the Committee on Trauma's Surgical Skills Committee to fill a surgical skills need in resident and fellow education. Using a human cadaver, standardized rapid exposure of vital structures in the extremities, neck, thorax, abdomen, retroperitoneum, and pelvis is taught. METHODS: A retrospective analysis of 79 participants in four ASSET courses was performed. Operative experience data were collected, and self-efficacy questionnaires (SEQs) were administered before and after the course. Course evaluations and instructor evaluation data were analyzed. Student's and paired samples t tests as well as analysis of variance and Spearman rho correlation coefficient analysis were performed using alpha at p < 0.05. We hypothesized that the ASSET course would teach new surgical techniques and that learner self assessed ability would improve. RESULTS: Participants included 27 PGY-4, 20 PGY 5, 24 PGY-6 or PGY-7 and PGY-8 at other levels of training. Self-assessed confidence improved in all body regions (p < 0.001), with the greatest increase in upper extremity and chest. Pre- and post-SEQ scores correlated with trauma operative experience. Precourse SEQ scores differed by level of training. Instructor evaluations correlated with previous experience on a trauma service. Program evaluations averaged 4.73 on a 5-point scale, with gaining new knowledge rated at 4.8 and learning new techniques at 4.72. CONCLUSION: A standardized cadaver-based surgical exposures course offered to senior surgical residents adds new surgical skills and improves participant self-assessed ability to perform emergent surgical exposure of vital structures. PMID- 23354269 TI - Apples and oranges: looking forward to the next generation of combat casualty care statistics. PMID- 23354268 TI - Guidelines for alcohol screening in adolescent trauma patients: a report from the Pediatric Trauma Society Guidelines Committee. AB - BACKGROUND: Alcohol misuse is an important source of preventable injuries in the adolescent population. While alcohol screening and brief interventions are required at American College of Surgeons-accredited trauma centers, there is no standard screening method. To develop guidelines for testing, we reviewed available evidence regarding adolescent alcohol screening after injury, focusing on the questions of which populations require screening, which screening tools are most effective, and at which time point screening should be performed. METHODS: A comprehensive PubMed search for articles related to alcoholism, trauma, and screening resulted in 1,013 article abstracts for review. Eighty-five full-length articles were considered for inclusion. Articles were excluded based on study type, location (non-US), year of publication, and nonapplicability to the study questions. RESULTS: Twenty-six articles met full inclusion criteria. Results support universal screening for alcohol misuse in the adolescent trauma population. Although adolescents 14 years and older are more likely to test positive for alcohol misuse, studies suggest screening may need to start at 12 years or younger. Both survey and biochemical screens can identify at-risk adolescents, with the Alcohol Use Disorders Identification Test and the two question survey based on the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition criteria for alcohol-use disorders being the most sensitive surveys available. CONCLUSION: Injured adolescent trauma patients should be universally screened for alcohol misuse during their hospital visit. To maximize the number of at-risk adolescents targeted for interventions, screening should begin at minimum at 12 years. As no screen identifies all at-risk adolescents, a serial screening method using both biochemical tests and standardized questionnaires may increase screening efficacy. PMID- 23354270 TI - Vehicle factors and outcomes associated with hand-out-window motor vehicle collisions. AB - BACKGROUND: Patients can experience devastating injuries when an upper extremity travels out of a window during a motor vehicle collision. These injuries are typically very severe and may even result in loss of the affected limb. The purposes of this retrospective study were to determine the clinical fate of these extremities and analyze for common factors during the collisions. METHODS: A retrospective chart review of 20 patients between 2003 and 2010, evaluating the patient's age, arm involvement, number and types of surgeries, as well as the Mangled Extremity Severity Score (MESS) was conducted. In addition, patients were contacted to survey them about accident and vehicle factors and to complete the Quick Disabilities of the Arm, Shoulder, and Hand (quickDASH) survey. The data were then analyzed for common factors. RESULTS: The mean age of the 20 patients involved was 28.8 years. There were 11 men and 9 women. The mean MESS was 5.4. Two patients required amputation of some form. Fifteen patients were wearing a seatbelt at time of collision, four were not, and the restraint status of one patient is unknown. The closest extremity to the window was involved in 18 (90%) of 20 patients. Vehicle rollover was the most common mechanism of injury with 16 patients (80%) involved, while 4 patients (20%) were involved in head-on or side impact type collisions. The average quickDASH score was 24 (range, 5-91). CONCLUSION: The hand-out-of-the-window phenomenon during motor vehicle crashes results in very serious injury to the affected extremity. Most patients were involved in rollover accidents, and most were wearing a seatbelt. The arm closest to the window was nearly always involved. The mean MESS is high in these patients but did not necessarily correlate with amputation. LEVEL OF EVIDENCE: Therapeutic, level IV. PMID- 23354271 TI - Orthopedic medical instruments: from antiquity to modern times--a historical essay. PMID- 23354272 TI - NEXUS criteria compared to CT. PMID- 23354273 TI - ATV versus tree. PMID- 23354276 TI - Graphene-ferromagnet interfaces: hybridization, magnetization and charge transfer. AB - Electronic and magnetic properties of graphene-ferromagnet interfaces are investigated using first-principles electronic structure methods in which a single layer graphene is adsorbed on Ni(111) and Co(111) surfaces. Due to the symmetry matching and orbital overlap, the hybridization between graphene ppi and Ni (or Co) d(z(2)) states is very strong. This pd hybridization, which is both spin and k dependent, greatly affects the electronic and magnetic properties of the interface, resulting in a significantly reduced (by about 20% for Ni and 10% for Co) local magnetic moment of the top ferromagnetic layer at the interface and an induced spin polarization on the graphene layer. The calculated induced magnetic moment on the graphene layer agrees well with a recent experiment. In addition, a substantial charge transfer across the graphene-ferromagnet interfaces is observed. We also investigate the effects of thickness of the ferromagnet slab on the calculated electronic and magnetic properties of the interface. The strength of the pd hybridization and the thickness-dependent interfacial properties may be exploited to design structures with desirable magnetic and transport properties for spintronic applications. PMID- 23354275 TI - Identification of an H2-Kb or H2-Db restricted and glypican-3-derived cytotoxic T lymphocyte epitope peptide. AB - Glypican-3 (GPC3) is overexpressed in human hepatocellular carcinoma (HCC) but not expressed in normal tissues except for placenta and fetal liver and therefore is an ideal target for cancer immunotherapy. In this study, we identified an H2 Kb or H2-Db restricted and murine GPC3 (mGPC3)-derived cytotoxic T-lymphocyte (CTL) epitope peptide in C57BL/6 (B6) mice, which can be used in the design of preclinical studies of various therapies with GPC3-target immunotherapy in vivo. First, 11 types of 9- to 10-mer peptides predicted to bind with H2-Kb or H2-Db were selected from the mGPC3 amino acid sequence based on the binding score as calculated by the BIMAS software. We evaluated the peptide-binding affinity and confirmed that all peptides were able to bind to H2-Kb or H2-Db by in vitro cellular binding assay. Subsequently, a mixed peptide vaccine and single peptide vaccine were given to B6 mice to evaluate immunogenic potential of the 11 selected peptides. Using the splenocytes from peptide-vaccinated mice, interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) assays showed that mGPC3-1127-136 (AMFKNNYPSL) peptide was the most efficient for inducing CTLs among the 11 peptides. Next, we demonstrated that the mGPC3-1 peptide-specific CTL line could recognize mGPC3-expressing cancer cells, suggesting that mGPC3-1 peptide was an endogenously presented peptide. In conclusion, we identified mGPC3-1 as an H2-Kb or H2-Db restricted, mGPC3-derived CTL epitope peptide. PMID- 23354277 TI - Astroglial amino acid-based transmitter receptors. AB - Amino acids appear in prebiotic period being one of the first organic molecules on Earth. For neurobiologists, it is of importance that AAs are not only representing building blocks of life, but are also the essential part of metabolism and cellular signaling. In the mammalian brain, the most common excitatory and inhibitory transmitters acting upon cellular plasmalemmal receptors are the amino acid glutamate and its derivative gamma-aminobutyric acid, respectively. Other amino acids, i.e. aspartate, glycine, D-serine, and homocysteic acid, as well as the sulfonic acid taurine, are also active compounds involved in receptor-mediated brain signaling. Receptors for these amino acid based transmitters are either ion channels, also referred to as ionotropic receptors, or metabotropic, i.e. seven transmembrane domain G-protein coupled receptors. In this mini-review, we focus our interest on amino acid-based transmitter receptors on neuroglia, astrocytes in particular. PMID- 23354278 TI - Phylogenetic aspects of the sulfate assimilation genes from Thalassiosira pseudonana. AB - Diatoms are unicellular algae responsible for approximately 20 % of global carbon fixation. Their evolution by secondary endocytobiosis resulted in a complex cellular structure and metabolism compared to algae with primary plastids. In the last years the interest on unicellular algae increased. On the one hand assessments suggest that diatom-mediated export production can influence climate change through uptake and sequestration of atmospheric CO2. On the other hand diatoms are in focus because they are discussed as potential producer of biofuels. To follow the one or other idea it is necessary to investigate the diatoms biochemistry in order to understand the cellular regulatory mechanisms. The sulfur assimilation and methionine synthesis pathways provide S-containing amino acids for the synthesis of proteins and a range of metabolites such as dimethylsulfoniopropionate (DMSP) in order to provide basic metabolic precursors needed for the diatoms metabolism. To obtain an insight into the localization and organization of the sulfur metabolism pathways, the genome of Thalassiosira pseudonana-a model organism for diatom research-might help to understand the fundamental questions on adaptive responses of diatoms to dynamic environmental conditions such as nutrient availability in a broader context. PMID- 23354279 TI - Life's timekeeper. AB - Life's timekeeper is a 'free-running' intracellular oscillator synchronised across all cells. It runs throughout life splitting lifespan into equal length phases. During the maturational period it controls the overall rate of progression whereas in the post-maturational period it controls the overall rate of ageing. This includes the rate of senescence and hence time to death. As such life's timekeeper equates maturational and post-maturational time, hence explains the tight correlation between these time periods that has existed throughout mammalian evolution. Life's timekeeper is proposed to have played an important role in vertebrate evolution. A slower oscillatory frequency results in proportional life phase prolongation. This leads to increased body and brain size, together with extended lifespan. Higher brain centres, neocortex in mammals, are disproportionately enlarged. Hence behavioural capacity is increased. The extended post-maturational period ensures that there is enough time in order that the behavioural advantages can be fully manifest in the environment. A faster oscillatory frequency would result in proportional life phase reduction. This process however would lead to reduced behavioural capacity, and is hence unlikely to be positively selected. Therefore throughout evolution life's timekeeper has operated to extend lifespan. It has hence functioned to promote longevity as opposed to ageing. PMID- 23354280 TI - Mixed infection by Clostridium difficile in an in vitro model of the human gut. AB - OBJECTIVES: Clostridium difficile infection (CDI) is still a major clinical challenge. Previous studies have demonstrated multiple distinct C. difficile strains in the faeces of patients with CDI; yet whether true mixed CDI occurs in vivo is unclear. In this study we evaluated whether two distinct C. difficile strains could co-germinate and co-proliferate in an in vitro human gut model. METHODS: An in vitro triple-stage chemostat was used to study the responses of two PCR ribotype 001 C. difficile strains following exposure to ceftriaxone at concentrations observed in vivo (7 days). C. difficile viable counts (vegetative and spore forms), cytotoxin titres and indigenous microflora viable counts were monitored throughout the experiment. RESULTS: Both C. difficile strains germinated and proliferated following exposure to ceftriaxone. Cytotoxin production was detected in the gut model following C. difficile spore germination and proliferation. Ceftriaxone elicited reduced viable counts of Bifidobacterium spp. and elevated viable counts of Enterococcus spp. CONCLUSIONS: These data suggest that multiple C. difficile strains are able to proliferate concurrently in an in vitro model reflective of the human colon. Previous studies in the gut model have reflected clinical observations so clinicians should be mindful of the possibility that multiple C. difficile strains may infect patients. These observations augment recent human epidemiological studies in this area. PMID- 23354281 TI - Complete sequence of broad-host-range plasmid pNOR-2000 harbouring the metallo beta-lactamase gene blaVIM-2 from Pseudomonas aeruginosa. AB - OBJECTIVES: Metallo-beta-lactamases (MBLs) are increasingly reported not only in Enterobacteriaceae but also in Pseudomonas spp. These enzymes hydrolyse all beta lactams, including carbapenems, and are not inhibited by beta-lactamase inhibitors. The aim of this study was to fully characterize a plasmid bearing the blaVIM-2 MBL gene identified in a Pseudomonas aeruginosa isolate. METHODS: This plasmid was fully sequenced by high-density pyrosequencing and annotated using the GenDB version 2.0 annotation tool. The evaluation of the broad-host-range replication of the pNOR-2000 replication initiation gene was assessed using electro-transformation and conjugation assays and the distribution of this replicase gene was evaluated using an international collection of VIM-producing Pseudomonas spp. RESULTS: Analysis of the 21 880 bp sequence of pNOR-2000 revealed a truncated and non-functional transfer operon, in addition to novel genes encoding a serine protease and toxin/antitoxin addiction systems. This broad-host-range plasmid shares high gene synteny with part of the mobile genomic island pKLC102 identified in P. aeruginosa strain C. CONCLUSIONS: We report here the complete nucleotide sequence of plasmid pNOR-2000 from a P. aeruginosa clinical isolate harbouring the integron-located MBL gene blaVIM-2. PMID- 23354282 TI - Switching the third drug of antiretroviral therapy to maraviroc in aviraemic subjects: a pilot, prospective, randomized clinical trial. AB - OBJECTIVES: To evaluate the safety and efficacy of switching the third drug of antiretroviral treatment to maraviroc in aviraemic subjects infected with R5 HIV. PATIENTS AND METHODS: This is a pilot, prospective, randomized clinical trial (ClinicalTrials ID: NCT00966329). Eighty HIV-1-infected aviraemic adults on stable antiretroviral treatment for >=1 year and no antiretroviral drug resistance were screened for the presence of non-R5 HIV by triplicate proviral V3 population sequencing. From them, 30 subjects with R5 HIV-1 were randomized 1 : 1 to switch the non-nucleoside reverse transcriptase inhibitor or ritonavir-boosted protease inhibitor to maraviroc (n = 15) or to continue the same antiretroviral treatment (controls, n = 15). The principal endpoint was the proportion of subjects with HIV-1 RNA <50 copies/mL at week 48. Ultrasensitive proviral HIV-1 tropism testing (454 sequencing) was performed retrospectively at weeks 0, 4, 12, 24, 36 and 48. RESULTS: One subject in the maraviroc arm and one control had non R5 HIV in proviral DNA by retrospective 454 sequencing. The subject receiving maraviroc was the only individual to develop virological failure. However, plasma HIV at failure was R5. Switching to maraviroc was well tolerated and associated with small, but statistically significant, declines in total, high-density lipoprotein and low-density lipoprotein cholesterol. Median (IQR) triglyceride [1 (0.67-1.22) versus 1.6 (1.4-3.1) mmol/L, P = 0.003] and total cholesterol [4.3 (4.1-4.72) versus 5.4 (4-5.7) mmol/L, P = 0.059] values were lower in the maraviroc arm than in controls at week 48. CONCLUSIONS: In this pilot, prospective, randomized clinical trial, switching the third drug to maraviroc was safe, efficacious and improved lipid parameters. PMID- 23354283 TI - A three-way decomposition of a total effect into direct, indirect, and interactive effects. AB - Recent theory in causal inference has provided concepts for mediation analysis and effect decomposition that allow one to decompose a total effect into a direct and an indirect effect. Here, it is shown that what is often taken as an indirect effect can in fact be further decomposed into a "pure" indirect effect and a mediated interactive effect, thus yielding a three-way decomposition of a total effect (direct, indirect, and interactive). This three-way decomposition applies to difference scales and also to additive ratio scales and additive hazard scales. Assumptions needed for the identification of each of these three effects are discussed and simple formulae are given for each when regression models allowing for interaction are used. The three-way decomposition is illustrated by examples from genetic and perinatal epidemiology, and discussion is given to what is gained over the traditional two-way decomposition into a direct and an indirect effect. PMID- 23354284 TI - A text processing pipeline to extract recommendations from radiology reports. AB - Communication of follow-up recommendations when abnormalities are identified on imaging studies is prone to error. The absence of an automated system to identify and track radiology recommendations is an important barrier to ensuring timely follow-up of patients especially with non-acute incidental findings on imaging examinations. In this paper, we present a text processing pipeline to automatically identify clinically important recommendation sentences in radiology reports. Our extraction pipeline is based on natural language processing (NLP) and supervised text classification methods. To develop and test the pipeline, we created a corpus of 800 radiology reports double annotated for recommendation sentences by a radiologist and an internist. We ran several experiments to measure the impact of different feature types and the data imbalance between positive and negative recommendation sentences. Our fully statistical approach achieved the best f-score 0.758 in identifying the critical recommendation sentences in radiology reports. PMID- 23354285 TI - TIP47 plays a crucial role in the life cycle of hepatitis C virus. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) replication/morphogenesis takes place at the membranous web. Viral genome replication occurs in replicon complexes on the cytoplasmic face of the ER whereas HCV assembly is located on the surface of lipid droplets (LDs). This raises the question about targeting of de novo synthesized viral genomes from the replicon complex to LDs and cellular proteins involved in this process such as the LD-associated protein TIP47, also known as cytoplasmic sorting factor. METHODS: Viral replication was studied in HuH7.5 cells using the infectious HCV JHF1 culture system. Proteome analysis was performed by 2D gel electrophoresis and mass spectrometry. Expression of target genes was modulated by siRNA or lentiviral transduction. Confocal microscopy was performed for analysis of subcellular compartments. Protein/protein interactions were studied by co-immunoprecipitations, affinity chromatography, and yeast two hybrid screens. RESULTS: Proteome based analysis revealed that HCV replicating cells contain less TIP47 compared to control cells. However, expression analyses demonstrated an increased TIP47 expression in HCV replicating cells. TIP47 binds to RNA-loaded NS5A. Mapping of the binding domain revealed that NS5A binds to the N-terminal PAT domain of TIP47. Overexpression of TIP47 increases the amount of released viruses, while silencing of TIP47 decreases the amount of released infectious particles. Complete knockdown of TIP47 expression abolishes virus replication. CONCLUSIONS: TIP47 plays an essential role in the HCV life cycle. PMID- 23354286 TI - Response assessment methodologies in hepatocellular carcinoma: complexities in the era of local and systemic treatments. PMID- 23354288 TI - Functional outcomes following robotic prostatectomy using athermal, traction free risk-stratified grades of nerve sparing. AB - OBJECTIVE: To report our unique approach for individualizing robotic prostate cancer surgery by risk stratification and sub classification of the periprostatic space into 4 distinct compartments, and thus performing 4 precise different grades of nerve sparing based on neurosurgical principles and to present updated potency and continence outcomes data of patients undergoing robotic-assisted laparoscopic prostatectomy (RALP) using our risk-stratified approach based on layers of periprostatic fascial dissection. PATIENTS AND METHODS: (1) Between January 2005 and December 2010, 2,536 men underwent RALP by a single surgeon at our institution. (2) Included patients were those with >= 1-year follow-up and were preoperatively continent and potent, defined as having a SHIM questionnaire score of >21; thus, the final number of patient in the study cohort was 1,335. (3) Postoperative potency was defined as the ability to have successful intercourse (score of >= 4 on question 2 of the SHIM); continence was defined as the use of no pads per 24 h. RESULTS: (1) The potency and continence for NS grades 1, 2, 3, and 4 were found to be 90.6, 76.2, 60.5, and 57.1 % (P < 0.001) and 98, 93.2, 90.1, and 88.9 % (P < 0.001), respectively. (2) The overall PSM rates for patients with NS grades 1, 2, 3, and 4 were 10.5, 7, 5.8, and 4.8 %, respectively (P = 0.064). CONCLUSIONS: The study found a correlation between risk stratified grades of NS technique and continence and potency. Patients with lesser grades of NS had higher rates of potency and continence. PMID- 23354287 TI - A new structural paradigm in copper resistance in Streptococcus pneumoniae. AB - Copper resistance has emerged as an important virulence determinant of microbial pathogens. In Streptococcus pneumoniae, copper resistance is mediated by the copper-responsive repressor CopY, CupA and the copper-effluxing P(1B)-type ATPase CopA. We show here that CupA is a previously uncharacterized cell membrane anchored Cu(I) chaperone and that a Cu(I) binding-competent, membrane-localized CupA is obligatory for copper resistance. The crystal structures of the soluble domain of CupA and the N-terminal metal-binding domain (MBD) of CopA (CopA(MBD)) reveal isostructural cupredoxin-like folds that each harbor a binuclear Cu(I) cluster unprecedented in bacterial copper trafficking. NMR studies reveal unidirectional Cu(I) transfer from the low-affinity site on the soluble domain of CupA to the high-affinity site of CopA(MBD). However, copper binding by CopA(MBD) is not essential for cellular copper resistance, consistent with a primary role of CupA in cytoplasmic Cu(I) sequestration and/or direct delivery to the transmembrane site of CopA for cellular efflux. PMID- 23354290 TI - Isolation of normal and cancer-associated fibroblasts from fresh tissues by Fluorescence Activated Cell Sorting (FACS). AB - Cancer-associated fibroblasts (CAFs) are the most prominent cell type within the tumor stroma of many cancers, in particular breast carcinoma, and their prominent presence is often associated with poor prognosis. CAFs are an activated subpopulation of stromal fibroblasts, many of which express the myofibroblast marker alpha-SMA. CAFs originate from local tissue fibroblasts as well as from bone marrow-derived cells recruited into the developing tumor and adopt a CAF phenotype under the influence of the tumor microenvironment. CAFs were shown to facilitate tumor initiation, growth and progression through signaling that promotes tumor cell proliferation, angiogenesis, and invasion. We demonstrated that CAFs enhance tumor growth by mediating tumor-promoting inflammation, starting at the earliest pre-neoplastic stages. Despite increasing evidence of the key role CAFs play in facilitating tumor growth, studying CAFs has been an on going challenge due to the lack of CAF-specific markers and the vast heterogeneity of these cells, with many subtypes co-existing in the tumor microenvironment. Moreover, studying fibroblasts in vitro is hindered by the fact that their gene expression profile is often altered in tissue culture. To address this problem and to allow unbiased gene expression profiling of fibroblasts from fresh mouse and human tissues, we developed a method based on previous protocols for Fluorescence-Activated Cell Sorting (FACS). Our approach relies on utilizing PDGFRalpha as a surface marker to isolate fibroblasts from fresh mouse and human tissue. PDGFRalpha is abundantly expressed by both normal fibroblasts and CAFs. This method allows isolation of pure populations of normal fibroblasts and CAFs, including, but not restricted to alpha-SMA+ activated myofibroblasts. Isolated fibroblasts can then be used for characterization and comparison of the evolution of gene expression that occurs in CAFs during tumorigenesis. Indeed, we and others reported expression profiling of fibroblasts isolated by cell sorting. This protocol was successfully performed to isolate and profile highly enriched populations of fibroblasts from skin, mammary, pancreas and lung tissues. Moreover, our method also allows culturing of sorted cells, in order to perform functional experiments and to avoid contamination by tumor cells, which is often a big obstacle when trying to culture CAFs. PMID- 23354292 TI - Molecular ecology techniques reveal both spatial and temporal variations in the diversity of archaeal communities within the athalassohaline environment of Rambla Salada, Spain. AB - We have studied the distribution of the archaeal communities in Rambla Salada (Murcia, Spain) over three different seasons and observed the influence upon them of the environmental variables, salinity, pH, oxygen and temperature. Samples were collected from three representative sites in order to gain an insight into the archaeal population of the rambla as a whole. Denaturing gradient gel electrophoresis patterns and diversity indexes indicate that the diversity of the archaeal community in Rambla Salada changed mainly according to the season. We found no significant differences between the types of sample studied: watery sediments and soils. The upwelling zone showed most diversity in its archaeal community. The overall archaeal community was composed mainly of Halobacteriales and Thermoplasmatales, accounting for 72.6 and 12.1 % of the total, respectively. Haloarcula was the most abundant genus, being present at all three sites during all three seasons. Some few Crenarchaeota were always found, mainly at low salinity levels. Ordination canonical correspondence analysis demonstrated that salinity affected the structure of the community significantly, whilst pH, oxygen and temperature did so to a lesser extent. Most Halobacteriales correlated positively with salinity and pH, whilst Thermoplasmatales correlated negatively with both salinity and pH and positively with temperature and oxygen. The archaeal community with the highest diversity was sampled during June 2006, the season with the highest salt concentration. Catalyzed reporter deposition fluorescence in situ hybridization showed that the percentage of archaea in Rambla Salada compared to the total number of microorganisms (as measured by DAPI) ranged from 11.1 to 16.7 %. Our research group had isolated the most abundant taxon, Haloarcula, previously in Rambla Salada using classical culture techniques, but on this occasion, using culture-independent methods, we were also able to identify some phylotypes, Halorubrum, Methanolobus, Natronomonas, Halomicrobium, Halobacterium, Halosimplex, uncultured Thermoplasmatales and uncultured Crenarchaeota, that had remained undetected during our earlier studies in this habitat. PMID- 23354294 TI - Torsade de pointes. A rare cause of syncope in severe aortic stenosis. AB - The evaluation of syncope in severe aortic stenosis usually requires intense work up. Mechanical obstruction should not always be implicated as the underlying cause of syncope. Syncope at rest may be rarely associated with ventricular arrhythmias. We present a patient with severe aortic stenosis who experienced syncopal events due to torsade de pointes. PMID- 23354295 TI - Effect of peripheral vascular disease on kidney allograft outcomes: a study of U.S. Renal data system. AB - BACKGROUND: The U.S. Renal Data System was used to analyze renal allograft outcomes in patients with peripheral vascular disease (PVD) at the time of transplant listing. METHODS: We used an incident cohort of patients who underwent renal transplantation between June 2004 and September 2009. We defined PVD as symptomatic PVD at wait-listing. Comorbid conditions were diabetes mellitus, ischemic heart disease, cerebrovascular disease, hypertension, and smoking. Chi square test, Student's t test, and Cox regression were used for statistical associations. RESULTS: The mean graft survival was 55.3+/-0.40 months in patients with PVD versus 60.8+/-0.06 months in patients without PVD. There was an increased risk of graft failure with PVD (hazard ratio, 2.01; 95% confidence interval, 1.83-2.21; P=0.0001). After adjusting for other variables, PVD remained an independent risk factor for graft failure. Patients with PVD had lower death censored graft survival versus patients without PVD at 1 year (93.3% vs. 96.6%), 2 years (89.7% vs. 95%), and 3 years (87.2% vs. 93.7%). All-cause mortality was higher in PVD versus without PVD (6.2% vs. 3.0%). In African Americans, the mean allograft survival was 54.8+/-0.98, months with PVD versus 59.7+/-0.135 months without PVD (P=0.0001). In non-African Americans, the mean allograft survival was 55.4+/-0.44 months with PVD versus 61.1+/-0.069 months without PVD (P=0.0001). There were no differences in survival between African Americans with PVD and non African Americans with PVD. CONCLUSIONS: Patients with PVD have inferior allograft and patient survival versus those without PVD. Caution should be exercised when placing patients with symptomatic PVD or amputation on the wait list. PMID- 23354296 TI - Systematic comparison of four cell- and Luminex-based methods for assessment of complement-activating HLA antibodies. AB - BACKGROUND: Efforts to increase the specificity and sensitivity of human leukocyte antigen (HLA) antibody detection assays recently led to the establishment of two novel Luminex bead-based assays to detect complement activating antibodies by the assessment of complement products C1q or C4d. Here, we present a systematic comparison of the four methods, complement-dependent lymphocytotoxicity (CDC) and C1q-, C4d-, and IgG-Luminex, to assess or predict the complement-binding capability of HLA IgG antibodies. METHODS: Forty-five sera of highly immunized patients have been assessed by in-house modified C1q- and C4d Luminex assays and compared with standard CDC and IgG-Luminex. RESULTS: Antibody specificities assigned by the C1q- and C4d-Luminex assay revealed an excellent concordance of 94% and 97% for HLA class I and II, respectively. Complement fixing HLA class II antibodies were found less frequently among IgG antibodies compared with class I. Both C1q- and C4d-Luminex detected, on average, three times more specificities than CDC. Although we found a high correlation of mean fluorescence intensity values between C1q- and C4d-Luminex assays, IgG mean fluorescence intensity was not a suitable surrogate marker for the prediction of complement binding. CONCLUSIONS: C1q- and C4d-Luminex assays are characterized by an increased sensitivity and specificity compared with CDC, the current standard in detecting complement-fixing HLA antibodies. Pretransplantation risk assessment for transplantation but also posttransplantation monitoring are important applications for both assays to improve overall allograft survival. PMID- 23354291 TI - Community structures and distribution of anaerobic ammonium oxidizing and nirS encoding nitrite-reducing bacteria in surface sediments of the South China Sea. AB - Anaerobic ammonium oxidation (anammox) and denitrification are two important processes responsible for nitrogen loss; monitoring of microbial communities carrying out these two processes offers a unique opportunity to understand the microbial nitrogen cycle. The aim of the current study was to characterize community structures and distribution of anammox and nirS-encoding nitrite reducing bacteria in surface sediments of the northern South China Sea (SCS). The consistent phylogenetic results of three biomarkers of anammox bacteria, including 16S rRNA, hzo, and Scalindua-nirS genes, showed that Scalindua-like bacteria were the only anammox group presenting in surface sediments of the SCS. However, a relatively high micro-diversity was found within this group, including several SCS habitat-specific phylotypes, Candidatus "Scalindua zhenghei". Comparing to 16S rRNA gene, hzo and Scalindua-nirS genes provided a relatively higher resolution to elucidate anammox bacteria. For the nirS-encoding nitrite reducing bacteria, the detected nirS gene sequences were closely related to various marine nirS denitrifiers, especially those which originated from coastal and estuarine sediments with a much higher diversity than anammox bacteria. Anammox bacterial communities shifted along with the seawater depth, while nirS encoding nitrite-reducing bacteria did not. Although nirS-encoding nitrite reducing bacteria have a much higher abundance and diversity than anammox bacteria, they showed similar abundance variation patterns in research sites, suggesting the two microbial groups might be affected by the similar environmental factors. The significant correlations among the abundance of the two microbial groups with the molar ratio of NH4 (+) to (NO2 (-) + NO3 (-)), pH, and organic matters of sediments strongly supported this hypothesis. PMID- 23354297 TI - Health-related quality of life and long-term survival and graft failure in kidney transplantation: a 12-year follow-up study. AB - BACKGROUND: Although the prognosis of kidney transplantation is generally good, long-term survival varies substantially between patients. This study examined whether health-related quality of life (HRQOL) predicts long-term mortality in kidney transplantation after adjustment for known risk factors. METHODS: A cohort of 347 (46.77 +/- 13.96 years) kidney transplant recipients was followed up for 12 years after enrolment (1999-2001). Patients completed measures of HRQOL and medical records were reviewed to document clinical and cardiovascular risk factors and comorbidities at study entry (mean [SD], 8.57 [6.55] years after transplantation). The primary outcomes were ensuing all-cause mortality and all cause graft failure (a composite endpoint consisting of return to dialysis therapy, preemptive retransplantation, or death with function). Cox proportional hazards multivariate models were developed to identify predictors of long-term patient and graft survival. RESULTS: During the 12-year follow-up, 86 (24.8%) patients died, 64 (18.3%) died with a functioning graft, and 35 (11.1%) were placed back to dialysis. Physical QOL impairment increased the risk of mortality and graft failure during the follow-up period. The risk remained significant after adjusting for sociodemographic and clinical risk factors (adjusted hazard ratio, 1.89; 95% confidence interval, 1.09-2.95; P=0.022 and adjusted hazard ratio, 1.68; 95% confidence interval, 1.12-2.52; P=0.012 for patient and graft survival, respectively). Other significant risk factors were older age, time elapsed since transplantation, and Charlson comorbidity index. Risk of graft failure was also associated with glomerular filtration rate. CONCLUSIONS: Physical HRQOL predicts long-term mortality and graft failure independently of sociodemographic and clinical risk factors in renal transplant patients. Future research should identify the determinants of HRQOL and refine interventions to improve it. PMID- 23354298 TI - CYP3A5 gene variation influences cyclosporine A metabolite formation and renal cyclosporine disposition. AB - BACKGROUND: Higher concentrations of AM19 and AM1c9, secondary metabolites of cyclosporine A (CsA), have been associated with nephrotoxicity in organ transplant patients. The risk of renal toxicity may depend on the accumulation of CsA and its metabolites in the renal tissue. We evaluated the hypothesis that CYP3A5 genotype, and inferred enzyme expression, affects systemic CsA metabolite exposure and intrarenal CsA accumulation. METHODS: An oral dose of CsA was administered to 24 healthy volunteers who were selected based on their CYP3A5 genotype. CsA and its six main metabolites in whole blood and urine were measured by liquid chromatography-mass spectometry. In vitro incubations of CsA, AM1, AM9, and AM1c with recombinant CYP3A4 and CYP3A5 were performed to evaluate the formation pathways of AM19 and AM1c9. RESULTS: The mean CsA oral clearance was similar between CYP3A5 expressors and nonexpressors. However, compared with CYP3A5 nonexpressors, the average blood area under the concentration-time curve (AUC) for AM19 and AM1c9 was 47.4% and 51.3% higher in CYP3A5 expressors (P=0.040 and 0.011, respectively), corresponding to 30% higher AUCmetabolite/AUCCsA ratios for AM19 and AM1c9 in CYP3A5 expressors. The mean apparent urinary CsA clearance based on a 48-hr collection was 20.4% lower in CYP3A5 expressors compared with CYP3A5 nonexpressors (4.2+/-1.0 and 5.3+/-1.3 mL/min, respectively; P=0.037), which is suggestive of CYP3A5-dependent intrarenal CsA metabolism. CONCLUSIONS: At steady state, intrarenal accumulation of CsA and its secondary metabolites should depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to interpatient variability in the risk of CsA-induced nephrotoxicity. PMID- 23354293 TI - Broad diversity and newly cultured bacterial isolates from enrichment of pig feces on complex polysaccharides. AB - One of the fascinating functions of mammalian intestinal microbiota is fermentation of plant cell wall components. Eight-week continuous culture enrichments of pig feces with cellulose and xylan/pectin were used to isolate bacteria from this community. A total of 575 bacterial isolates were classified phylogenetically using 16S rRNA gene sequencing. Six phyla were represented in the bacterial isolates: Firmicutes (242), Bacteroidetes (185), Proteobacteria (65), Fusobacteria (55), Actinobacteria (23), and Synergistetes (5). The majority of the bacterial isolates had >= 97 % similarity to cultured bacteria with sequences in the RDP, but 179 isolates represent new species and/or genera. Within the Firmicutes isolates, most were classified in the families of Lachnospiraceae, Enterococcaceae, Staphylococcaceae, and Clostridiaceae I. The majority of the Bacteroidetes were most closely related to Bacteroides thetaiotaomicron, Bacteroides ovatus, and B. xylanisolvens. Many of the Firmicutes and Bacteroidetes isolates were identified as species that possess enzymes that ferment plant cell wall components, and the rest likely support these bacteria. The microbial communities that arose in these enrichment cultures had broad bacterial diversity. With over 30 % of the isolates not represented in culture, there are new opportunities to study genomic and metabolic capacities of these members of the complex intestinal microbiota. PMID- 23354299 TI - Sorafenib induces autophagy in human myeloid dendritic cells and prolongs survival of skin allografts. AB - BACKGROUND: Sorafenib, a multikinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma, has been reported inhibitory on the function of dendritic cells. This study was aimed to determine the effects of sorafenib on inducing autophagy and immunomodulatory activity and its implication on graft rejection. METHODS: Cell viability and surface antigens were examined by 7-amino-actinomycin D and flow cytometric analysis. Autophagy was characterized using light microscopy and transmission electron microscopy for morphology, Western blotting for LC3B-I lipidation and mammalian target of rapamycin signaling molecules, and immunofluorescence staining for endogenous LC3B, GFP-LC3 transfection, and acidic component vacuoles. Skin allograft in mice was used as an experimental transplantation rejection model. Soluble factors contained in culture medium and serum were measured by enzyme-linked immunosorbent assay. RESULTS: We found that sorafenib inhibited the viability of dendritic cells accompanied by morphologic changes characteristic of autophagy and immature differentiation. This autophagic effect induced by sorafenib was validated by LC3B-I lipidation and autophagosome accumulation. Sorafenib treatment was associated with the down-regulation of phosphorylated mammalian target of rapamycin and its downstream substrate p70S6K. We next performed skin graft model to testify the role of sorafenib-induced immature and autophagic dendritic cells. Intriguingly, sorafenib prolonged the survival of skin allograft without major toxicity. Blockade of autophagic flux by chloroquine partially diminished the protective effect of sorafenib, indicating an autophagy-related mechanism in vivo. CONCLUSION: This study suggests that sorafenib, in addition to being an anticancer agent, may have potential to be developed as a new category of immunosuppressant drugs acting via autophagy induction of dendritic cells. PMID- 23354300 TI - Monitoring for HHV-6 infection after renal transplantation: evaluation of risk factors for sustained viral replication. AB - BACKGROUND: Human herpesvirus-6 (HHV-6) is known to reactivate after renal transplantation and has been associated with several clinical manifestations. Risk factors for sustained viral replication, however, remain unclear. METHODS: Thirty consecutive kidney transplant patients were prospectively followed for HHV 6 replication between February 2007 and February 2008. Plasma samples for DNA detection were collected from the donor and the recipient before transplantation and from the recipient weekly for the first 2 months after transplantation and then every 2 weeks for 2 additional months. HHV-6 active infection was defined as detection of viral DNA in plasma, by polymerase chain reaction, in at least two consecutive samples over an interval of at least 1 week. RESULTS: Active viral infection was detected in 25% of the recipients before transplantation and 27% (8 of 30) of the patients after transplantation. The mean time to onset of viral replication was 28.1 days after transplantation and 7 of 8 (87.5%) were asymptomatic. Risk factors associated with active HHV-6 infection were receiving an organ from a living donor (P=0.028), recipients with IgM antibodies detected before transplantation (P=0.005), and pretransplantation recipient HHV-6 viral load more than 10,000 copies/mL plasma (P=0.034). CONCLUSIONS: Active HHV-6 infection occurs early after renal transplantation and is mostly asymptomatic. Donor or recipient infection may occur at the time of transplantation and are related to higher rates of posttransplantation infections. PMID- 23354301 TI - Early major neurologic complications after lung transplantation: incidence, risk factors, and outcome. AB - BACKGROUND: Early major neurologic complications after lung transplantation represent a major source of morbidity for patients and compromise their quality of life; however, the mechanisms underlying neurologic complications and their impact on outcomes in lung transplantation remain largely unknown. METHODS: Patients who received lung transplants at our institution between January 2004 and December 2010 were identified (n=759). Data on complications including occurrence, timing, management, and outcome were extracted from our transplant database and medical record review. Major neurologic complications were defined as those that were potentially life threatening, required urgent treatment/intubation, or required admission to the intensive care unit. RESULTS: Seventy (9.2%) patients experienced major neurologic complications within 2 weeks after lung transplantation. Most common complications were stroke (41%) and severe toxic/metabolic encephalopathy (37%). Multivariate analysis demonstrated that advanced age, history of coronary artery disease, prolonged use of cardiopulmonary bypass, and severe primary graft dysfunction increased the risk for death in patients with early major neurologic complications (P<0.05). There was a significant difference in survival between patients with neurologic complications and without (90-day mortality: 15% of patients who developed neurologic complications versus 4% of patients who did not; P=0.03; 5-year survival: 51.1% in patients who developed neurologic complication versus 62.1% in patients who did not; P<0.05). CONCLUSIONS: Early major neurologic complications after lung transplantation are common and carry substantial morbidity and mortality. Given the risk factors identified in this study, additional pretransplantation workup and intraoperative and postoperative monitoring for high-risk patients may help reduce the incidence of neurologic complications. PMID- 23354302 TI - Hepatic hemangiosarcoma: an absolute contraindication to liver transplantation- the European Liver Transplant Registry experience. AB - BACKGROUND: Liver transplantation (LT) is performed for hemangiosarcoma (HAS) despite disappointing results. METHODS: Retrospective study of 14 males and 8 females reported to the European Liver Transplant Registry. In view of the difficult differential diagnosis between HAS and hemangioendothelioma (HE), the study was deliberately restricted to the period 1986 to 2004 to allow comparison of clinical and biochemical behavior of HAS and HE liver recipients transplanted during the same time period. RESULTS: Clinical signs, symptoms, and biochemical parameters differed significantly. Pre-LT diagnosis of HAS was made in only 5 of 16 (31%) biopsied patients. HE (7 patients) and hepatocellular cancer (2 patients) were confounding diagnoses leading to LT. Extrahepatic disease was present at time of LT in 4 (19%) patients. Giant invalidating tumor (5 HAS, 1 with Budd-Chiari syndrome [BCS], and 10 supposed epithelioid hemangioendothelioma, 1 with BCS), acute BCS of unknown origin (2 patients), chronic liver failure (4 patients), and solitary hepatocellular cancer (1 patient) were the main indications for LT. Overall survival was 7.2+/-2.6 months; no patient survived after 23 months. Recurrence was diagnosed after 5.0+/-2.6 months. Seventeen (77.2%) patients died of tumor recurrence, and the remaining 5 patients died of early infections. CONCLUSIONS: HAS is an absolute contraindication to LT due to the poor outcome. When dealing with the difficult differential diagnosis between HAS and HE, futile LT can be avoided by taking into consideration their distinct clinical and biochemical behaviors as well as a 6-month wait-list observation period. This time period enables the evaluation of HAS disease progression without compromising prognosis of HE patients, thereby allowing to avoid organ wastage. PMID- 23354303 TI - Influence of extracellular pH on the cytotoxicity, cellular accumulation, and DNA interaction of novel pH-sensitive 2-aminoalcoholatoplatinum(II) complexes. AB - Extracellular acidity is a frequent pathophysiological condition of solid tumors offering possibilities for improving the tumor selectivity of molecular therapy. This might be accomplished by prodrugs with low systemic toxicity, attaining their full antitumor potency only under acidic conditions, such as bis(2 aminoalcoholato-kappa(2)N,O)platinum(II) complexes that are activated by protonation of alcoholato oxygen, resulting in cleavage of platinum-oxygen bonds. In this work, we examined whether the pH dependency of such compounds is reflected in differential biological activity in vitro. In particular, the pH dependence of cytotoxicity, cellular accumulation, DNA platination, GMP binding, effects on DNA secondary structure, cell cycle alterations, and induction of apoptosis was investigated. Enhanced cytotoxicity of five of these complexes in non-small-cell lung cancer (A549) and colon carcinoma (HT-29) cells at pH 6.0 in comparison with pH 7.4 was confirmed: 50 % growth inhibition concentrations ranged from 42 to 214 MUM in A549 cells and from 35 to 87 MUM in HT-29 cells at pH 7.4 and decreased at pH 6.0 to 11-50 and 7.3-25 MUM, respectively. The effects induced by all five pH-sensitive compounds involve increased 5'-GMP binding, cellular accumulation, and DNA platination as well as stronger effects on DNA secondary structure at pH 6.0 than at pH 7.4. As exemplified by treatment of A549 cells with a 2-amino-4-methyl-1-pentanolato complex, induction of apoptosis is enhanced at pH 6.5. These results confirm the increased reactivity and in vitro activity of these compounds under slightly acidic conditions, encouraging further evaluation of ring-closed aminoalcoholatoplatinum(II) derivatives in solid tumors in vivo. PMID- 23354304 TI - Deregulation of Wnt/beta-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors. AB - Carcinoid tumors are rare neuroendocrine tumors (NETs) that are increasing in incidence. Mutation and altered expression of Wnt/beta-catenin signaling components have been described in many tumors but have not been well-studied in NETs. Here, we observed accumulation of beta-catenin in the cytoplasm and/or nucleus in 25% of clinical NET tissues. By mutational analysis, the mutations of beta-catenin (I35S) and APC (E1317Q, T1493T) were identified in NET cells and the tissues. Expression of representative Wnt inhibitors was absent or markedly decreased in BON, a human pancreatic carcinoid cell line; treatment with 5-aza-2' deoxycytidine (5-aza-CdR) increased expression levels of the Wnt inhibitors. Methylation analyses demonstrated that CpG islands of SFRP-1 and Axin-2 were methylated, whereas the promoters of DKK-1, DKK-3 and WIF-1 were unmethylated in four NET cells. Aberrant methylation of SFRP-1 was particularly observed in most of clinical NET tissues. In addition, the repression of these unmethylated genes was associated with histone H3 lysine 9 dimethylation (H3K9me2) in BON cells. Together, 5-aza-CdR treatment inhibited cell proliferation and decreased the protein levels of H3K9me2 and G9a. Moreover, a novel G9a inhibitor, UNC0638, suppressed BON cell proliferation through inhibition of Wnt/beta-catenin pathway. Overexpression of the inhibitory genes, particularly SFRP-1 and WIF-1 in BON cells, resulted in suppression of anchorage-independent growth and inhibition of tumor growth in mice. Our findings suggest that aberrant Wnt/beta-catenin signaling, through either mutations or epigenetic silencing of Wnt antagonists, contributes to the pathogenesis and growth of NETs and have important clinical implications for the prognosis and treatment of NETs. PMID- 23354305 TI - Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau. AB - Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2 * 10(-5)) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners. PMID- 23354307 TI - Leptin-mediated regulation of MT1-MMP localization is KIF1B dependent and enhances gastric cancer cell invasion. AB - Leptin overexpression is closely correlated with gastric cancer (GC) invasion, but its exact effect and the underlying mechanism in tumorigenesis remain poorly understood. Membrane type 1-matrix metalloproteinase (MT1-MMP), a surface anchored 'master switch' proteinase, is overexpressed and plays crucial roles in tumor invasion. Here, we characterized the influence of leptin on the generation and surface localization of MT1-MMP in GC and elucidated its molecular mechanisms. Our results revealed that leptin promoted GC cell invasion in vitro by upregulating MT1-MMP expression. Furthermore, cell surface biotinylation assay and flow cytometry demonstrated that the surface expression of MT1-MMP was also enhanced by leptin, and knockdown of kinesin family member 1B (KIF1B, a microtubule plus end-directed monomeric motor protein) by small interference RNA inhibited this process. Notably, coimmunoprecipitation analysis indicated that leptin enhanced the interaction of MT1-MMP with KIF1B in a time-dependent manner, which consequently contributed to GC cell invasion. Moreover, leptin increased MT1-MMP or KIF1B expression by the protein kinase B (AKT) pathway and extracellular signal-regulated kinase 1/2 partially participated in this process. However, only AKT was implicated in the leptin-mediated membrane localization of MT1-MMP. Immunohistochemistry analysis revealed that leptin, MT1-MMP and KIF1B are overexpressed in GC tissues, and they positively correlated with clinical stage and lymph node metastasis. These observations indicate that this regulatory network exists in vivo. Taken together, our findings suggest that leptin is an effective intracellular stimulator of MT1-MMP and that leptin-enhanced cell surface localization of MT1-MMP is dependent on KIF1B, which consequently plays a critical role in GC invasion. PMID- 23354306 TI - CInQ-03, a novel allosteric MEK inhibitor, suppresses cancer growth in vitro and in vivo. AB - The mitogen-activated protein kinase kinase 1 and 2 signaling pathway is a major component of the RAS (Rat sarcoma)/RAF (Radpidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase kinase)/ERKs (Extracellular signal-regulated kinases) signaling axis that regulates tumorigenesis and cancer cell growth. MEK is frequently activated in various cancers that have mutations in the KRAS and BRAF oncogenes. Therefore, MEK has been suggested as a therapeutic target for inhibitor development against tumors that are dependent on the activating mutations in mitogen-activated protein kinase signaling. Herein, we report the discovery of three novel MEK inhibitors, herein referred to as CInQ-01, CInQ-03 and CInQ-06. All three inhibitors were highly effective in suppressing MEK1 and MEK2 in vitro kinase activity as well as anchorage-dependent and anchorage independent cell growth. The inhibitory activity was associated with markedly reduced phosphorylation of ERKs and ribosomal S6 kinases. Furthermore, administration of CInQ-03 inhibited colon cancer cell growth in an in vivo xenograft mouse model and showed no skin toxicity. Overall, these results suggest that these novel MEK inhibitors might be used for chemotherapy or prevention. PMID- 23354310 TI - The yin and yang of nitric oxide in cancer progression. AB - Nitric oxide (NO) is a short-lived, pleiotropic molecule that affects numerous critical functions in the body. Presently, there are markedly conflicting findings in the literature regarding NO and its role in carcinogenesis and tumor progression. NO has been shown to have dichotomous effects on cellular proliferation, apoptosis, migration, invasion, angiogenesis and many other important processes in cancer biology. It has been shown to be both pro- and antitumorigenic, depending on the concentration and the tumor microenvironment in question. NO is generated by three isoforms of NO synthase (NOS) that are widely expressed and sometimes upregulated in human tumors. Due to its vast array of physiological functions, it presents a huge challenge to researchers to discover its true potential in cancer biology and consequently, its use in anticancer therapies. In this study, we review the current knowledge in this area, with an emphasis placed on NO modulation as an anticancer therapy, focusing on NO donating drugs and NOS inhibitors. PMID- 23354308 TI - Degradation of NF-kappaB, p53 and other regulatory redox-sensitive proteins by thiol-conjugating and -nitrosylating drugs in human tumor cells. AB - The ionized cysteines present on the surfaces of many redox-sensitive proteins play functionally essential roles and are readily targeted by the reactive oxygen and reactive nitrogen species. Using disulfiram (DSF) and nitroaspirin (NCX4016) as the model compounds that mediate thiol-conjugating and nitrosylating reactions, respectively, we investigated the fate of p53, nuclear factor-kappaB (NF-kappaB) and other redox-responsive proteins following the exposure of human cancer cell lines to the drugs. Both drugs induced glutathionylation of bulk proteins in tumor cells and cell-free extracts. A prominent finding of this study was a time- and dose-dependent degradation of the redox-regulated proteins after brief treatments of tumor cells with DSF or NCX4016. DSF and copper-chelated DSF at concentrations of 50-200 uM induced the disappearance of wild-type p53, mutant p53, NF-kappaB subunit p50 and the ubiquitin-activating enzyme E1 (UBE1) in tumor cell lines. DSF also induced the glutathionylation of p53. The recombinant p53 protein modified by DSF was preferentially degraded by rabbit reticulocyte lysates. The proteasome inhibitor PS341 curtailed the DSF-induced degradation of p53 in HCT116 cells. Further, the NCX4016 induced a dose-dependent disappearance of the UBE1 and NF-kappaB p50 proteins in cell lines, besides a time-dependent degradation of aldehyde dehydrogenase in mouse liver after a single injection of 150 mg/kg. The loss of p53 and NF-kB proteins correlated with decreases in their specific binding to DNA. Our results demonstrate the hitherto unrecognized ability of the non-toxic thiolating and nitrosylating agents to degrade regulatory proteins and highlight the exploitable therapeutic benefits. PMID- 23354309 TI - Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells. AB - Our previous studies demonstrated that lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) closely interact in controlling growth of breast cancer cells. However, the underlying mechanisms are largely unknown. In this study, we showed that knockdown of LSD1 expression (LSD1-KD) by RNAi decreased mRNA levels of HDAC isozymes in triple-negative breast cancer (TNBC) cells. Small interfering RNA (siRNA)-mediated depletion of HDAC5 expression induced the most significant accumulation of H3K4me2, a specific substrate of LSD1. Combined treatment with LSD1 inhibitor, pargyline, and HDAC inhibitor, SAHA (Vorinostat), led to superior growth inhibition and apoptotic death in TNBC cells, but exhibited additive or antagonistic effect on growth inhibition in non-TNBC counterparts or non-tumorigenic breast cells. Additionally, LSD1-KD enhanced SAHA induced reexpression of a subset of aberrantly silenced genes, such as NR4A1, PCDH1, RGS16, BIK, and E-cadherin whose reexpression may be tumor suppressive. Genome-wide microarray study in MDA-MB-231 cells identified a group of tumor suppressor genes whose expression was induced by SAHA and significantly enhanced by LSD1-KD. We also showed that concurrent depletion of RGS16 by siRNA reduced overall cytotoxicity of SAHA and blocked the reexpression of E-cadherin, CDKN1C and ING1 in LSD1-deficient MDA-MB-231 cells. Furthermore, cotreatment with RGS16 siRNA reversed the downregulation of nuclear factor-kappaB expression induced by combined inhibition of LSD1 and HDACs, suggesting a crucial role of RGS16 in controlling key pathways of cell death in response to combination therapy. Taken together, these results provide novel mechanistic insight into the breast cancer subtype-dependent role of LSD1 in mediating HDAC activity and therapeutic efficacy of HDAC inhibitor. PMID- 23354311 TI - S-nitrosoglutathione reductase deficiency increases mutagenesis from alkylation in mouse liver. AB - In human hepatocellular carcinoma (HCC) and many other cancers, somatic point mutations are highly prevalent, yet the mechanisms critical in their generation remain poorly understood. S-nitrosoglutathione reductase (GSNOR), a key regulator of protein S-nitrosylation, is frequently deficient in human HCC. Targeted deletion of the GSNOR gene in mice can reduce the activity of the DNA repair protein O (6)-alkylguanine-DNA alkyltransferase (AGT) and promote both carcinogen induced and spontaneous HCC. In this study, we report that following exposure to the environmental carcinogen diethylnitrosamine, the mutation frequency of a transgenic reporter in the liver of GSNOR-deficient mice (GSNOR(-/-)) is significantly higher than that in wild-type control. In wild-type mice, diethylnitrosamine treatment does not significantly increase the frequency of the transition from G:C to A:T, a mutation deriving from diethylnitrosamine-induced O (6)-ethylguanines that are normally repaired by AGT. In contrast, the frequency of this transition from diethylnitrosamine is increased ~20 times in GSNOR(-/-) mice. GSNOR deficiency also significantly increases the frequency of the transversion from A:T to T:A, a mutation not affected by AGT. GSNOR deficiency in our experiments does not significantly affect either the frequencies of the other diethylnitrosamine-induced point mutations or hepatocyte proliferation. Thus, GSNOR deficiency, through both AGT-dependent and AGT-independent pathways, significantly raises the rates of specific types of DNA mutations. Our results demonstrate a critical role for GSNOR in maintaining genomic integrity in mice and support the hypothesis that GSNOR deficiency is an important cause of the widespread mutations in human HCC. PMID- 23354312 TI - Blockage of melatonin receptors impairs p53-mediated prevention of DNA damage accumulation. AB - Melatonin has been known to be a chemopreventive agent since its levels inversely correlate with the risk of developing cancer. We have recently shown that melatonin induces p38-dependent phosphorylation of both p53 and histone H2AX. This is associated with a p53-mediated increase in repair of both endogenous and chemotherapy-induced DNA damage. In addition, the inhibition of p38 activities impairs melatonin's capability to induce a p53-dependent DNA damage response and thus its ability to maintain genome integrity. Since melatonin-induced p53 phosphorylation requires an intact p38 phosphorylation cascade and p38 can be activated by G proteins, we supposed that melatonin's activities could be mediated by its G-protein-coupled membrane receptors, MT1 and MT2. Here, we show that the activation of the p53-dependent DNA damage response by melatonin is indeed mediated by MT1 and MT2. As a result, the absence of either receptor impairs melatonin's ability to reduce both cell proliferation and clonogenic potential of cancer cells. In addition, this causes an impairment of the p53 dependent DNA damage response. By providing molecular insight, our findings might have translational impact, suggesting the involvement of melatonin receptors in tumorigenesis. PMID- 23354313 TI - Design of a cluster-randomized controlled trial of a diabetes prevention program within African-American churches: The Fit Body and Soul study. AB - Evidence from varied community settings has shown that the Group Lifestyle Balance (GLB) Program and other adaptations of the Diabetes Prevention Program (DPP) intervention are effective in lowering diabetes risk. Most DPP data originated from studies of pre-diabetic whites, with only sparse evidence of the effect of DPP in African Americans (AAs) in community settings. This paper describes the design, methods, baseline characteristics and cost effective measures, of a single-blinded, cluster-randomized trial of a faith-based adaptation of the GLB program, Fit Body and Soul (FBAS). The major aims are to test efficacy and cost utility of FBAS in twenty AA churches. Randomization occurred at the church level and 604 AA overweight/obese (BMI>=25kg/m(2)) adults with fasting plasma glucose range from normal to pre-diabetic received either FBAS or a health-education comparison program. FBAS is a group-based, multi-level intervention delivered by trained church health advisors (health professionals from within the church), with the goal of >=7% weight loss, achieved through increasing physical activity, healthy eating and behavior modification. The primary outcome is weight change at 12weeks post intervention. Secondary outcomes include hemoglobin A1C, fasting plasma glucose, waist circumference, blood pressure, physical activity level, quality of life measures, and cost effectiveness. FBAS is the largest known cohort of AAs enrolled in a faith-based DPP translation. Reliance on health professionals from within the church for program implementation and the cost analysis are unique aspects of this trial. The design provides a model for faith-based DPPs and holds promise for program sustainability and widespread dissemination. PMID- 23354314 TI - [Whole body hyperthermia in pain therapy. A controlled trial on patients with fibromyalgia]. AB - BACKGROUND: The aim of this study was to evaluate whether mild water-filtered near infrared whole body hyperthermia in patients with fibromyalgia produces a benefit when applied as an addition to a standard multimodal rehabilitation. PATIENTS AND METHODS: In this study 67 patients at a German rehabilitation clinic were included and allocated to 3 study groups: the 2 intervention groups received additional mild water-filtered near infrared whole body hyperthermia once or twice a week over 3 weeks and the control group received only standard multimodal rehabilitation. Main outcome measure was pain intensity measured at baseline, discharge from the rehabilitation clinic and 6 months after discharge. RESULTS: Additional mild water-filtered near infrared whole body hyperthermia once a week proved to be significantly better than the second hyperthermia group and the control group with respect to pain reduction and affective sense of pain. Furthermore, hyperthermia once a week tended to result in better outcome regarding fibromyalgia-related quality of life and depression. CONCLUSION: There is evidence that mild water-filtered near infrared whole body hyperthermia is a reasonable complement to multimodal rehabilitation in the treatment of fibromyalgia. PMID- 23354315 TI - Improvement of functional recovery of transected peripheral nerve by means of artery grafts filled with diclofenac. AB - The objective was to assess the effect of topically administered diclofenac on peripheral nerve regeneration and functional recovery. Eighty male healthy white Wistar rats were divided into four experimental groups (n = 20), randomly: In transected group (TC), left sciatic nerve was transected and stumps were fixed in the adjacent muscle. In treatment group defect was bridged using an artery graft (AG/DICLO) filled with 10 MUL diclofenac (0.1 mg/kg). In artery graft group (AG), the graft was filled with phosphate-buffered saline alone. In sham-operated group (SHAM), sciatic nerve was exposed and manipulated. Each group was subdivided into four subgroups of five animals each and regenerated nerve fibers were studied 4, 8, 12 and 16 weeks after surgery. Behavioral testing, sciatic nerve functional study, gastrocnemius muscle mass and morphometric indices confirmed faster recovery of regenerated axons in AG/DICLO than AG group (p < 0.05). In immunohistochemistry, location of reactions to S-100 in AG/DICLO was clearly more positive than that in AG group. When loaded in an artery graft, diclofenac improved functional recovery and morphometric indices of sciatic nerve. Topical application of this readily available agent offers the benefit of cost savings as well as avoiding the complications associated with systemic administration. PMID- 23354316 TI - Intraoperative frozen section analysis of sentinel lymph nodes in breast carcinoma patients in a tertiary hospital in Pakistan. AB - Intraoperative evaluation of sentinel lymph nodes has become routine in many units that manage early breast carcinoma. The procedure is associated with minimal morbidity and can be cost effective, avoiding re operation and reducing hospital stay as an axillary clearance can be performed under the same anesthetic after a positive intraoperative diagnosis without awaiting conventional paraffin histology. In negative cases extensive axillary lymph node dissection and its associated side effects can be avoided altogether. With careful patient selection, the expertise of surgeons and pathologists can increase the sensitivity and specificity of the technique with a reduction in false negatives. A number of international studies have established the usefulness of intraoperative sentinel lymph node evaluation. However, no local study has assessed the accuracy of frozen section in evaluating sentinel lymph node biopsy. The purpose of our study was to compare the two techniques (frozen section versus conventional paraffin histology) of the sentinel lymph node examination and to present our local data highlighting its usefulness and pitfalls, comparing the results with those in published studies. From the results obtained, we strongly recommend intraoperative assessment of the sentinel lymph nodes in breast carcinoma patients; frozen section microscopy can be a reliable and accurate technique in the hands of an experienced histopathologist. PMID- 23354317 TI - Self-assembly of hierarchical star-like Co3O4 micro/nanostructures and their application in lithium ion batteries. AB - A novel hierarchical star-like Co(3)O(4) was successfully synthesized from self assembled hierarchical Co(OH)F precursors via a facile hydrothermal method and subsequent annealing in air. The morphological evolution process of the Co(OH)F precursors was investigated by examining the different reaction times during synthesis. First, hexagonal plates are formed, and then nanodiscs grow on the surface of the plates. Subsequently, dissolution and regrowth of Co(OH)F occur to form the star-like hierarchical structures. Co(3)O(4) obtained from thermal decomposition of the Co(OH)F precursor in air at 350 degrees C exhibited high reversible capacity as an anode material in lithium ion batteries. The specific charge capacity of 1036 mA h g(-1) was obtained in the first cycle at a current density of 50 mA g(-1), and after 100 cycles, the capacity retention was nearly 100%. When the current density was increased to 500 mA g(-1) and 2 A g(-1), the capacities were 995 and 641 mA h g(-1), respectively, after 100 cycles. In addition, a capacity of 460 mA h g(-1) was recorded at a current density of 10 A g(-1) in the rate capability test. The excellent electrochemical performance of the Co(3)O(4) electrodes can be attributed to the porous interconnected hierarchical nanostructures, which protect the small particles from agglomeration and buffer the volume change during the discharge-charge process. PMID- 23354318 TI - Improving care for inflammatory bowel disease patients infected with hepatitis B virus. PMID- 23354319 TI - The RANKL/RANK system as a therapeutic target for bone invasion by oral squamous cell carcinoma (Review). AB - Squamous cell carcinomas (SCCs) of the gingiva frequently invade the mandible or maxilla; this invasion is associated with a worse prognosis. The bone destruction associated with carcinomal invasion is mediated by osteoclasts rather than directly by the carcinoma. Therefore, if the cellular and molecular mechanisms by which oral SCC regulates bone invasion were known, it could inform the development of new therapeutic targets. Recently, dysregulation of the functional equilibrium in the receptor activator of NF-kappaB ligand (RANKL)/RANK/osteoprotegerin (OPG) triad has been shown to be responsible for osteolysis associated with the development of malignant tumors in bone sites. Furthermore, the administration of OPG or soluble RANK prevents bone metastasis by cancer cells. In this review, we discuss recent findings indicating that bone invasion by oral SCC is mediated via RANKL/RANK and may be successfully prevented by RANKL inhibition. PMID- 23354320 TI - Production of a chimeric allergen derived from the major allergen group 1 of house dust mite species in Nicotiana benthamiana. AB - Plants are widely accepted as a general platform for the large-scale production of recombinant proteins, which has been demonstrated by the successful expression of various exogenous proteins. Using plants as a bioreactor for mass production of target proteins for vaccines is thought to show the most potential. This study explores whether a chimeric allergen R8, derived from the major allergen group 1 of house dust mites species (Dermatophagoides farinae and Dermatophagoides pteronyssinus), is expressed in tobacco. The highly efficient and useful Tobacco mosaic virus RNA-based overexpression (TRBO) vector was used to investigate expression of the R8 molecule in tobacco by agroinfection. Presence of R8 was detected using SDS-PAGE and Western blotting. Purified allergens were characterized using IgE-binding activity assay and allergen-specific immunotherapy (ASIT) in murine asthmatic models. The recombinant R8 was successfully expressed in tobacco leaves. The pro-peptide was observed in the herbaceous leaf extracts. This protein exhibits properties similar to the parental allergen ProDer f 1 expressed in Escherichia coli or tobacco with respect to IgE immunoreactivity. R8 also rectifies imbalance of TH1/TH2 cells. An herbaceous plant expression system model allows mass production of R8, which might be used in the future for diagnosis of asthma or production of a candidate vaccine for allergen-specific immunotherapy of asthma. PMID- 23354321 TI - IL21 and IL21R polymorphisms and their interactive effects on serum IL-21 and IgE levels in patients with chronic hepatitis B virus infection. AB - Interleukin (IL)-21 may affect both T-cell and B-cell responses and was suggested to be involved in response to HBV infection. This study explored IL21rs907715 and rs2221903 and IL21R T-83C and rs3093301 polymorphisms and serum IL-21 and IgE levels in 395 patients with chronic HBV infection, 75 HBV infection resolvers and 174 healthy controls. IL21R T-83C was not polymorphic in the study populations. IL21 rs2221903 AG was less frequent in HBV patients than in resolvers (p<0.001, OR=0.364, 95% CI=0.211-0.629) or in controls (p=0.017, OR=0.589, 95% CI=0.381 0.911). IL21R rs3093301 TT was more frequent in HBV patients than in controls [p value after Bonferroni correction (pc)=0.022, OR=1.908, 95% CI=1.158-3.142] and more frequent in resolvers than in controls (pc=0.010, OR=2.965, 95% CI 1.375 6.392). The carriage of IL21 rs2221903 AG/IL21R rs3093301 CT+IL21 rs2221903 AG/IL21R rs3093301 TT was less frequent in patients than in resolvers (pc=0.007, OR=0.236, 95% CI=0.096-0.579) and more frequent in resolvers than in controls (pc=0.014, OR=4.354, 95% CI=1.660-11.420). IL21 rs2221903 was, by interaction with IL21R rs3093301, associated with serum IL-21 and IgE levels in HBV patients. It is suggested that IL21 rs2221903 and IL21R rs3093301 polymorphisms may, independently or interactively, affect the susceptibility to and/or persistence of HBV infection potentially through altering IL-21 and IgE production. PMID- 23354322 TI - Donor chimera model for tolerance induction in transplantation. AB - Tolerance induction is the basis of a successful transplantation with the goal being the re-establishment of homeostasis after transplantation. Non-autograft transplantation disrupts this maintenance drastically which would be avoided by administration of a novel procedure. At present, the blood group antigens and the genotypes of the donor and recipient are cross-matched before transplantation combined with a drug regimen that confers general immunosuppression. But the 'specific' unresponsiveness of the recipient to the donor organ, implied by 'tolerance', is not achieved in this process. This article introduces the 'donor chimera model' via the concept of the 'closed transplantation loop' approach for tolerance induction which seeks to limit the use of immunosuppressive therapy after transplantation. PMID- 23354323 TI - Study of the KIR gene profiles and analysis of the phylogenetic relationships of Rajbanshi population of West Bengal, India. AB - The natural killer (NK) cells have distinct receptors called killer cell immunoglobulin-like receptors (KIR) which are responsible for regulating NK cell responses to infections and malignancy. The extensive variations in the number and type of KIR genes can be used as a tool to understand the differentiation of populations and also for tracing genetic background. In this study, we have aimed to analyze the KIR gene polymorphism in the Rajbanshi population of West Bengal, India. To our knowledge this is the first report on the KIR gene polymorphism in the Rajbanshis, a population widely distributed in the Terai and Dooars region of West Bengal, India. Herein, we have studied the gene distribution of 14 KIR genes (KIR3DL1-3DL3, KIR 2DL1-2DL5, 2DS1-2DS5 and 3DS1) and two pseudogenes (KIR3DP1 and 2DP1). The gene frequencies and genotypic frequencies were calculated, based on which statistical analyses were performed. The presence of a considerable number of genotypic profiles suggests substantial diversity in the KIR gene pool of the Rajbanshis in the region studied. Apart from the framework genes (KIR2DL4, 3DL2, 3DL3 and 3DP1) present in all the individuals, the gene frequencies of other KIR genes varied between 0.84 and 0.15. Moreover the KIR polymorphisms of the Rajbanshis were also compared with that of available published data of the populations of other ethnicities. Though the Rajbanshi population showed a tendency to cluster with other Indian population based on KIR gene frequencies, the influence of Tibeto-Burman Lineage on their KIR genotypic profiles cannot be overlooked. Furthermore, evidences from previously published data on Y chromosome haplogroup diversity study on Rajbanshis support the view. Our results will not only help to understand the genetic background of the Rajbanshi population, but also in tracing the population migration events in the North-Eastern part of India and in illustrating the extensive genetic admixture amongst the different linguistic groups of the country and also in KIR-related disease researches. PMID- 23354324 TI - Stereoselective syntheses of racemic quercitols and bromoquercitols starting from cyclohexa-1,4-diene: gala-, epi-, muco-, and neo-quercitol. AB - The efficient synthesis of gala-, epi-, neo-, and muco-quercitols and some brominated quercitols starting from cyclohexa-1,4-diene is reported. Treatment of the dibromide, obtained by the addition of bromine to cyclohexa-1,4-diene, with m chloroperbenzoic acid (m-CPBA) yielded the dibromoepoxide, which was successfully converted to the desired dibromodiol by treatment with sulfuric acid. The resulting diol was reacted with 2,2-dimethoxypropane to give the dibromoketal. Hydrogen bromide elimination with NaOMe gave the key compound methoxyketal, rel (3aS,5R,7aS)-5-methoxy-2,2-dimethyl-3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxole. The second key compound, an isomeric methoxyketal, was prepared by ketalization of 4,5-dibromocyclohexane-1,2-diol with dimethoxypropane followed by the reaction with NaOMe. Deprotection of ketal functionality with sulfuric acid followed by acetylation with acetic anhydride in pyridine resulted in the formation of diacetate rel-(1S,2R,5R)-5-methoxycyclohex-3-ene-1,2-diyl diacetate. Epoxidation of the double bonds in isomeric methoxy diacetates and cis-hydroxylation followed by epoxide-opening and deprotection resulted in the formation of various quercitol derivatives. The inhibition activity of eleven quercitols, methoxyquercitols and bromoquercitols was tested against alpha-glycosidase. PMID- 23354325 TI - Aggregation of selected plant growth promoting Methylobacterium strains: role of cell surface components and hydrophobicity. AB - The bacterial cell surface plays a major role in the bacterial aggregation that in turn plays a positive role in affecting the bacterial dispersion and survival in soil and their ability to adhere to plant surfaces. Plant growth-promoting Methylobacterium strains, Methylobacterium goesingense CBMB5, Methylobacterium sp. CBMB12, Methylobacterium oryzae CBMB20, Methylobacterium fujisawaense CBMB37, M. oryzae CBMB110 and Methylobacterium suomiense CBMB120 were evaluated for aggregation efficiency. Aggregation occurred in all test strains under high C/N growth conditions, and the strain CBMB12 showed the highest aggregation of 53.4 % at 72 h. Disaggregation compound treatment studies revealed the role of protein protein interaction in Methylobacterium strains except CBMB110 and CBMB120 strains, where a possible carbohydrate-protein interaction is suspected. Surface layer protein extraction by LiCl followed by SDS-PAGE analysis showed the presence of proteins at molecular weights ranging from 41 to 49 kDa. Methylobacterium strains under aggregated conditions showed increased hydrophobicity compared to the cells under standard grown conditions. A relatively higher hydrophobicity of 50.1 % as evident by the adhesion with xylene was observed with strain CBMB12 under aggregated condition. This study reports the aggregation ability in plant growth-promoting Methylobacterium strains and the possible involvement of cellular components and hydrophobicity in this phenomenon. PMID- 23354326 TI - Characterization of burden on growth due to the nutritional state of media and pre-induced gene expression. AB - Studies have shown that the production of unnecessary proteins burdens the cellular growth mainly due to allocation of cellular resources to unnecessary protein synthesis, thereby limiting the resources available for growth. In the current study, we focus on the effect of pre-induction and nutritional status of the medium on the burden imposed on growth due to the synthesis of unnecessary protein. Escherichia coli cells with different history were grown in a glycerol media with and without IPTG to characterize the burden imposed due to the synthesis of beta-galactosidase. Effect of pre-induced lac operon on growth and beta-galactosidase expression on lactose milieu was also investigated. The study demonstrates that pre-induction has a strong influence on the extent of burden and is sustained in several generations. Further, the burden was much lower in a rich media relative to that observed in a minimal media. PMID- 23354327 TI - Virulence determinants and biofilm production among Trueperella pyogenes recovered from abscesses of captive forest musk deer. AB - Trueperella pyogenes (formerly Arcanobacterium) is commonly isolated from domesticated or wild ruminants as an opportunistic pathogen. To investigate the role of virulence determinants (VDs) and biofilm production in T. pyogenes isolates, a total of 36 T. pyogenes were collected from abscesses of forest musk deer in Miyaluo Farm (Sichuan Province, China). The prevalence of VDs and associations with clonal types, antibiotic resistance and biofilm production were analyzed by PCR and bioassay. Finally, T. pyogenes isolates were separated into three clonal types based on the DNA fingerprinting of BOX-PCR. Isolates with less VDs obtained from sick forest musk deer were mainly belonged to Type 1, and the isolates with robust VD repertoire obtained from dead forest musk deer were included in Type 3. Accordingly, resistant isolates exhibited significant lower virulence than susceptible ones. Majority of T. pyogenes isolates of this study were capable of producing a biofilm. However, no VDs presence and antibiotic resistance were statistically associated with biofilm production. In conclusion, the current study demonstrated that T. pyogenes was probably the primary pathogen of abscesses in the forest musk deer. Moreover, as an animal origin pathogen, the increasing resistance of T. pyogenes isolates could also associate with a decreased virulence. PMID- 23354328 TI - Erbin interacts with TARP gamma-2 for surface expression of AMPA receptors in cortical interneurons. AB - Inhibitory neurons control the firing of glutamatergic neurons and synchronize brain activity. However, little is known about mechanisms of excitatory synapse formation in inhibitory neurons. Here we demonstrate that Erbin is specifically expressed in cortical inhibitory neurons. It localizes at excitatory synapses and regulates AMPA receptor (AMPAR) surface expression. Erbin mutation reduced mEPSCs and AMPAR currents specifically in parvalbumin (PV)-positive interneurons but not in pyramidal neurons. We found that the AMPAR auxiliary protein TARP gamma-2 was specifically expressed in cortical interneurons. Erbin interacts with TARP gamma 2 and is crucial for its stability. Deletion of the gamma-2-interacting domain in Erbin attenuated surface AMPAR and excitatory transmission in PV-positive interneurons. Furthermore, we observed behavioral deficits in Erbin-null mice and in mice expressing an Erbin truncation mutant that is unable to interact with TARP gamma-2. These observations demonstrate a crucial function for Erbin in AMPAR surface expression in cortical PV-positive interneurons and may contribute to a better understanding of psychiatric disorders. PMID- 23354329 TI - Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids. AB - The prevalence of obesity has markedly increased over the past few decades. Exploration of how hunger and satiety signals influence the reward system can help us understand non-homeostatic feeding. Insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA remain unknown. We demonstrate that insulin, a circulating catabolic peptide that inhibits feeding, can induce long-term depression (LTD) of mouse excitatory synapses onto VTA dopamine neurons. This effect requires endocannabinoid-mediated presynaptic inhibition of glutamate release. Furthermore, after a sweetened high fat meal, which elevates endogenous insulin, insulin-induced LTD is occluded. Finally, insulin in the VTA reduces food anticipatory behavior in mice and conditioned place preference for food in rats. Taken together, these results suggest that insulin in the VTA suppresses excitatory synaptic transmission and reduces anticipatory activity and preference for food-related cues. PMID- 23354330 TI - Experience-dependent modification of a central amygdala fear circuit. AB - The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, the mechanism by which CeA contributes to the learning and expression of fear is unclear. We found that fear conditioning in mice induced robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of the CeA (CeL). This experience-dependent plasticity was cell specific, bidirectional and expressed presynaptically by inputs from the lateral amygdala. In particular, preventing synaptic potentiation onto somatostatin positive neurons impaired fear memory formation. Furthermore, activation of these neurons was necessary for fear memory recall and was sufficient to drive fear responses. Our findings support a model in which fear conditioning-induced synaptic modifications in CeL favor the activation of somatostatin-positive neurons, which inhibit CeL output, thereby disinhibiting the medial subdivision of CeA and releasing fear expression. PMID- 23354331 TI - Epigenetic control of female puberty. AB - The timing of puberty is controlled by many genes. The elements coordinating this process have not, however, been identified. Here we show that an epigenetic mechanism of transcriptional repression times the initiation of female puberty in rats. We identify silencers of the Polycomb group (PcG) as principal contributors to this mechanism and show that PcG proteins repress Kiss1, a puberty-activating gene. Hypothalamic expression of two key PcG genes, Eed and Cbx7, decreased and methylation of their promoters increased before puberty. Inhibiting DNA methylation blocked both events and resulted in pubertal failure. The pubertal increase in Kiss1 expression was accompanied by EED loss from the Kiss1 promoter and enrichment of histone H3 modifications associated with gene activation. Preventing the eviction of EED from the Kiss1 promoter disrupted pulsatile gonadotropin-releasing hormone release, delayed puberty and compromised fecundity. Our results identify epigenetic silencing as a mechanism underlying the neuroendocrine control of female puberty. PMID- 23354332 TI - Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging. AB - Aging has independently been associated with regional brain atrophy, reduced slow wave activity (SWA) during non-rapid eye movement (NREM) sleep and impaired long term retention of episodic memories. However, whether the interaction of these factors represents a neuropatholgical pathway associated with cognitive decline in later life remains unknown. We found that age-related medial prefrontal cortex (mPFC) gray-matter atrophy was associated with reduced NREM SWA in older adults, the extent to which statistically mediated the impairment of overnight sleep dependent memory retention. Moreover, this memory impairment was further associated with persistent hippocampal activation and reduced task-related hippocampal-prefrontal cortex functional connectivity, potentially representing impoverished hippocampal-neocortical memory transformation. Together, these data support a model in which age-related mPFC atrophy diminishes SWA, the functional consequence of which is impaired long-term memory. Such findings suggest that sleep disruption in the elderly, mediated by structural brain changes, represents a contributing factor to age-related cognitive decline in later life. PMID- 23354333 TI - Frequency-specific network connectivity increases underlie accurate spatiotemporal memory retrieval. AB - The medial temporal lobes, prefrontal cortex and parts of parietal cortex form the neural underpinnings of episodic memory, which includes remembering both where and when an event occurred. However, the manner in which these three regions interact during retrieval of spatial and temporal context remains untested. We employed simultaneous electrocorticographical recordings across multilobular regions in patients undergoing seizure monitoring while they retrieved spatial and temporal context associated with an episode, and we used phase synchronization as a measure of network connectivity. Successful memory retrieval was characterized by greater global connectivity compared with incorrect retrieval, with the medial temporal lobe acting as a hub for these interactions. Spatial versus temporal context retrieval resulted in prominent differences in both the spectral and temporal patterns of network interactions. These results emphasize dynamic network interactions as being central to episodic memory retrieval, providing insight into how multiple contexts underlying a single event can be recreated in the same network. PMID- 23354334 TI - Mephedrone (methylmethcathinone) in toxicology casework: a Northern Ireland perspective. AB - Mephedrone (4-methylmethcathinone) is the beta-keto analogue of 4 methylmethylamphetamine. Before its control in April 2010, it became popular as a legal high in the United Kingdom, displacing methylenedioxymethylamphetamine as the stimulant drug of choice. The drug has stimulant and psychoactive properties, and therefore has forensic significance in criminal and morbid toxicology. The purpose of this study was to survey casework involving the drug (impaired driving and sudden death). The cases were received in the laboratory for analysis between late 2009 and the end of 2010. Analysis of blood samples for mephedrone was conducted by liquid chromatography-mass spectrometry (LC-MS). Routine screening for alcohol and a range of other pharmaceuticals and drugs of abuse was conducted using a combination of enzyme-linked immunoassay, gas chromatography (GC) headspace, GC-MS and high-performance liquid chromatography with diode array detection. Mephedrone was detected in a total of 12 fatal cases. Most of these cases involved death by mechanical means; in two cases, death was attributed directly to mephedrone intoxication (blood concentrations of 2.1 and 1.94 mg/L). Mephedrone was detected in a total of 32 impaired driving cases. Blood concentrations ranged up to 0.74 mg/L (mean 0.21, median 0.10). The casework evidence in this study indicated that recreational use of the drug can produce to blood levels as high as 0.74 mg/L, although the most common value encountered is likely to lie between 0.2 and 0.3 mg/L. PMID- 23354335 TI - Choosing which practitioner sees the next patient in the preanesthesia evaluation clinic based on the relative speeds of the practitioner. AB - BACKGROUND: When a practitioner in a preanesthesia evaluation clinic is not evaluating a patient because no patient is waiting to be seen, the practitioner often has other responsibilities such as reviewing charts of patients. When practitioners differ in how quickly they complete evaluations, multiple scenarios can be created wherein the slowest practitioner would only evaluate patients when the number of patients waiting exceeds a threshold (e.g., at least 2 patients are waiting). METHODS: Review of operations research studies identified conditions for which such management of the queue can be beneficial (e.g., mean evaluation time of the fastest practitioner is less than half that of the slowest practitioner). These conditions were compared with the actual completion rates of certified registered nurse practitioners at a hospital's clinic. The 99.9% confidence intervals (CI) were calculated for ratios of mean evaluation times. RESULTS: The fastest practitioner was typically 1.23 times faster than the second fastest practitioner (CI 1.22-1.23) and 1.61 times faster than the slowest of three practitioners (1.59-1.61). These are significantly less than the 3 times and 2 times faster, respectively, that would be sufficiently large to warrant managing queue discipline. Practitioners with longer mean evaluation times had larger percentage utilizations of working time (Kendall taub = 0.56, P = 0.0001), inconsistent with preferential assignment of patients to the fastest practitioner(s) available. CONCLUSIONS: Practitioners' speeds in evaluating patients do not differ sufficiently for information systems to be used routinely to choose who evaluates the next patient (i.e., state-dependent assignment policy). Clinics aiming to reduce patient waiting should focus on reducing the overall mean evaluation time (e.g., by chart review ahead), appropriately scheduling patients, and having the right numbers of nursing assistants and practitioners. PMID- 23354336 TI - A comparison of two doses of mannitol on brain relaxation during supratentorial brain tumor craniotomy: a randomized trial. AB - BACKGROUND: Twenty percent mannitol is widely used to reduce brain bulk and facilitate the surgical approach in intracranial surgery. However, a dose response relationship has not yet been established. In this study, we compared the effects of 0.7 and 1.4 g.kg(-1) mannitol on brain relaxation during elective supratentorial brain tumor surgery. METHODS: In this prospective, randomized, double-blind study, we enrolled 80 patients undergoing supratentorial craniotomy for tumor resection. Patients were assigned to receive 0.7 g.kg(-1) (group L) or 1.4 g.kg(-1) (group H) of 20% mannitol at surgical incision. Brain relaxation was assessed immediately after opening of the dura on a scale ranging from 1 to 4 (1 = perfectly relaxed, 2 = satisfactorily relaxed, 3 = firm brain, 4 = bulging brain). RESULTS: There was no significant difference between the 2 groups regarding age, sex, body mass index, and brain tumor localization or size. In group L 52.5% of patients and in group H 77.5% of patients presented a midline shift (P = 0.03). The median scores of brain relaxation (interquantile range) were 2.0 (1.75-3) and 2.0 (1-3) (P = 0.16 for patients in group L and H, respectively). We then used a proportional odds model to adjust for this unbalanced distribution and to assess the group effect (low-dose versus high-dose mannitol) on brain relaxation scores. When adjusted for the presence of midline shift, the use of a higher dose of mannitol resulted in an odds ratio of 2.5 (P = 0.03). This indicates that, considering the effect of a midline shift, the odds of having a 1-level improvement in relaxation score in patients who received a higher dose of mannitol (group H) was 2.5 times as large as the odds for the low dose group. The odds ratio of 0.29 (P = 0.007) for the midline shift indicates that its occurrence was associated with a higher probability of a lower relaxation score, on average. CONCLUSION: In this study, we show that 1.4 g.kg( 1) of 20% mannitol results in equivalent brain relaxation scores as 0.7 g.kg(-1) in patients undergoing craniotomy for supratentorial brain tumor. When corrected for the presence of midline shift, this study reveals that patients in the high dose group had significantly more chances of obtaining a better relaxation score compared with the lower-dose group. PMID- 23354337 TI - A comparison of 4 airway devices on cervical spine alignment in cadaver models of global ligamentous instability at c1-2. AB - BACKGROUND: The effects of advanced airway management on cervical spine alignment in patients with upper cervical spine instability are uncertain. METHODS: To examine the potential for mechanical disruption during endotracheal intubation in cadavers with unstable cervical spines, we performed a prospective observational cohort study with 3 cadaver subjects. We created an unstable, type II odontoid fracture with global ligamentous instability at C1-2 in lightly embalmed cadavers, followed by repetitive intubations with 4 different airway devices (Airtraq laryngoscope, Lightwand, intubating laryngeal mask airway [LMA], and Macintosh laryngoscope) while manual in-line stabilization was applied. Motion analysis data were collected using an electromagnetic device to assess the degree of angular movement in 3 axes (flexion-extension, axial rotation, and lateral bending) during the intubation trials with each device. Intubation was performed by either an emergency medical technician or attending anesthesiologist. RESULTS: Overall, 153 intubations were recorded with the 4 devices. The Lightwand technique resulted in significantly less flexion-extension and axial rotation at C1-2 than with the intubating LMA (mean difference in flexion-extension 3.2 degrees [95% confidence interval {CI}, 0.9 degrees -5.5 degrees ], P = 0.003; mean difference in axial rotation 1.6 degrees [95% CI, 0.3 degrees -2.8 degrees ], P = 0.01) and Macintosh laryngoscope (mean difference in flexion-extension 3.1 degrees [95% CI, 0.8 degrees -5.4 degrees ], P = 0.005; mean difference in axial rotation 1.4 degrees [95% CI 0.1 degrees -2.6 degrees ], P = 0.03). CONCLUSIONS: In cadavers with instability at C1-2, the Lightwand technique produced less motion than the Macintosh and intubating LMA. PMID- 23354338 TI - The association of preoperative statin use and acute kidney injury after noncardiac surgery. AB - BACKGROUND: Our objective was to examine the association between preoperative statin therapy and the incidence of postoperative acute kidney injury (AKI) in patients undergoing elective noncardiac surgery. METHODS: We analyzed the electronic records of 57,246 patients who had elective noncardiac surgery at the Cleveland Clinic Main Campus between December 2004 and March 2010. Patients were divided into 2 groups depending on preoperative therapy with statin drugs. Our primary outcome was AKI, defined as "risk," "injury," or "failure" using the RIFLE (Risk, Injury, Failure, Loss, and End-stage Kidney) criteria. Secondary outcomes included postoperative dialysis and all-cause hospital mortality. Each statin user was matched to a nonuser based on propensity scores. The propensity scores were estimated using a multivariable logistic regression model, incorporating all available baseline potential confounders. After the propensity matching procedure, we performed final analyses for the primary and secondary outcomes. For the primary analysis, we used a univariable logistic regression model to estimate the odds ratio (OR) (and 95% confidence intervals) for AKI, postoperative dialysis, and hospital mortality between matched statin users and nonusers. RESULTS: Of the total group, 23,745 records were unusable because of missing data. Among the remaining 28,508 patients analyzed, the overall incidence of AKI was 6.1%. Three hundred sixty-one of 4805 statin users (7.5%) and 1377 of 23,703 nonusers (5.8%) experienced AKI. The incidence of postoperative dialysis was 0.05%. Six statin users (0.12%) and 8 nonusers (0.03%) required dialysis postoperatively. The incidence of hospital mortality was 0.62%. Mortality was observed for 47 patients (1.0%) and 130 patients (0.5%), respectively. Among 4172 matched pairs, the incidence (95% confidence interval) of AKI was 7.1% (6.2%, 8.1%) in the matched statin users and 8.0% (7.1%, 9.0%) in the nonusers, corresponding to an OR of 0.88 (0.75, 1.03), which was not statistically significant (P = 0.12, chi(2) test). The secondary outcomes were also not significantly different in matched statin users and nonusers. Postoperative dialysis was required for 0.10% (0.02%, 0.33%) and 0.12% (0.04%, 0.37%) of patients in the respective groups (OR = 0.80 [0.16, 3.70]; P = 0.74). Hospital mortality occurred in 1.0% (0.7%, 1.5%) and 1.3% (0.9%, 1.8%) of patients, respectively (OR = 0.76 [0.47, 1.20]; P = 0.18). CONCLUSIONS: Our data did not support the hypothesis that preoperative statin therapy in doses routinely used to treat hypercholesterolemia is associated with a change in the incidence of AKI, postoperative dialysis, or hospital mortality in patients undergoing noncardiac surgery. PMID- 23354339 TI - Characteristics of emergency pages using a computer-based anesthesiology paging system in children and adults undergoing procedures at a tertiary care medical center. AB - BACKGROUND: In our large academic supervisory practice, attending anesthesiologists concomitantly care for multiple patients. To manage communications within the procedural environment, we use a proprietary electronic computer-based anesthesiology visual paging system. This system can send an emergency page that instantly alerts the attending anesthesiologist and other available personnel that immediate help is needed. We analyzed the characteristics of intraoperative emergency pages in children and adults. METHODS: We identified all emergency page activations between January 1, 2005 and July 31, 2010 in our main operating rooms. Electronic medical records were reviewed for rates and characteristics of pages such as primary etiology, performed interventions, and outcomes. RESULTS: During the study period, 258,135 anesthetics were performed (n = 32,103 children, younger than 18 years) and 370 emergency pages (n = 309 adults, n = 61 children) were recorded (1.4 per 1000 cases; 95% confidence interval, 1.3-1.6). Infants had the highest rates (9.4 per 1000; 95% confidence interval, 5.7-14.4) of emergency page activations (P < 0.001 compared with each other age group). In adults, the most frequent causes were hemodynamic (55%), and in children respiratory and airway (60.7%) events. CONCLUSION: Emergency pages were rare in patients older than 2 years. Infants were more likely than children 1 to 2 years of age to have emergency page activation, despite both groups being cared for by pediatric fellowship trained anesthesiologists. PMID- 23354340 TI - Hippocampal insulin microinjection and in vivo microdialysis during spatial memory testing. AB - Glucose metabolism is a useful marker for local neural activity, forming the basis of methods such as 2-deoxyglucose and functional magnetic resonance imaging. However, use of such methods in animal models requires anesthesia and hence both alters the brain state and prevents behavioral measures. An alternative method is the use of in vivo microdialysis to take continuous measurement of brain extracellular fluid concentrations of glucose, lactate, and related metabolites in awake, unrestrained animals. This technique is especially useful when combined with tasks designed to rely on specific brain regions and/or acute pharmacological manipulation; for example, hippocampal measurements during a spatial working memory task (spontaneous alternation) show a dip in extracellular glucose and rise in lactate that are suggestive of enhanced glycolysis, and intrahippocampal insulin administration both improves memory and increases hippocampal glycolysis. Substances such as insulin can be delivered to the hippocampus via the same microdialysis probe used to measure metabolites. The use of spontaneous alternation as a measure of hippocampal function is designed to avoid any confound from stressful motivators (e.g. footshock), restraint, or rewards (e.g. food), all of which can alter both task performance and metabolism; this task also provides a measure of motor activity that permits control for nonspecific effects of treatment. Combined, these methods permit direct measurement of the neurochemical and metabolic variables regulating behavior. PMID- 23354341 TI - Cardiac MRI segmentation using mutual context information from left and right ventricle. AB - In this paper, we propose a graphcut method to segment the cardiac right ventricle (RV) and left ventricle (LV) by using context information from each other. Contextual information is very helpful in medical image segmentation because the relative arrangement of different organs is the same. In addition to the conventional log-likelihood penalty, we also include a "context penalty" that captures the geometric relationship between the RV and LV. Contextual information for the RV is obtained by learning its geometrical relationship with respect to the LV. Similarly, RV provides geometrical context information for LV segmentation. The smoothness cost is formulated as a function of the learned context which helps in accurate labeling of pixels. Experimental results on real patient datasets from the STACOM database show the efficacy of our method in accurately segmenting the LV and RV. We also conduct experiments on simulated datasets to investigate our method's robustness to noise and inaccurate segmentations. PMID- 23354343 TI - [Imaging diagnosis of locally advanced rectal cancer: tumor staging before and after preoperative chemoradiotherapy]. AB - Recently, treatment strategy of rectal cancer has changed dramatically. The application of total mesorectal excision (TME) and preoperative chemoradiation therapy (PCRT) has become standard procedure for locoregional and locally advanced rectal cancer, respectively. For the planning of patient-specific therapy, both functional and morphological radiologic evaluation as well as multidisciplinary approach is essential. In other words, the needs for more accurate T- and N-staging and assessment of circumferential resection margin, both before and after PCRT, are increasing rapidly. Although so far there is no consensus on the role of diagnostic imaging (endorectal ultrasound, CT, MRI) in the evaluation of rectal cancer patient, MRI with diffusion-weighted image is emerging as an essential imaging modality, especially in the assessment of tumor response and depiction of complete remission after PCRT. In this review, we intended to demonstrate the present diagnostic role of various imaging modalities in tumor assessment of locally advanced rectal cancer before and after PCRT, with the introduction of new emerging imaging tool. PMID- 23354342 TI - Clinical outcome of neurointerventional emergency treatment of extra- or intracranial tandem occlusions in acute major stroke: antegrade approach with wallstent and solitaire stent retriever. AB - BACKGROUND: Acute large cerebral artery occlusions respond poorly to systemic thrombolysis with recombinant tissue plasminogen activator (rTPA) alone. The value of stent retriever-based mechanical thrombectomy in patients with additional extracranial occlusion of the internal carotid artery (ICA), who require acute a priori extracranial stenting in order to reach the intracranial obstruction site, is not well known. We determined the outcome after emergency revascularization in acute stroke with tandem occlusions of the anterior circulation. METHODS: According to specific inclusion/exclusion criteria, eligible stroke patients with large artery occlusions underwent mechanical recanalization with the Solitaire stent retriever. In case of a tandem occlusion, we performed an acute stenting with the Wallstent before thrombectomy. From October 2009 to March 2011, 50 patients were treated according to this protocol; time frames, clinical data, recanalization rates, and midterm outcome were recorded. RESULTS: Forty-one patients had a large artery occlusion in the anterior circulation and nine in the posterior circulation. Mechanical recanalization was successful in 35/41 cases (85 %). Six of 41 patients (15 %) died in the acute phase. In 17/41 patients (42 %), thrombectomy was preceded by an emergency stenting in the extracranial portion of the internal carotid artery (ICA). National Institutes of Health Stroke Scale (NIHSS)/modified Rankin Scale (mRS) scores showed significant improvement in both the stenting group and the nonstenting group; there were no significant differences between the groups. At 90 days, 54 % of patients with emergency stenting had a good outcome. CONCLUSIONS: Acute extracranial stenting with the Wallstent combined with intracranial Solitaire-based thrombectomy is safe and may lead to an improvement in neurological outcome in patients with an otherwise poor prognosis under i.v. thrombolysis alone. PMID- 23354344 TI - Metabolomic study of a diagnostic model for the metabolites of stool fat. AB - BACKGROUND/AIMS: Metabolomics is a powerful tool for measuring low-molecular weight metabolites in an organism at a specified time under specific environmental conditions. The aim of this study was to determine the usefulness of metabolomics in identifying the metabolites in stool-fat-positive specimens, and to establish whether the results could be used to predict the long-term prognosis. METHODS: Fecal specimens were collected from 52 subjects with bowel habit change. The subjects were accessed using Rome III questionnaires and Bristol stool scale form, and followed after three years. The feces samples were centrifuged and the resulting extracts reconstituted for liquid chromatography/mass spectrometry analysis. The datasets were autoscaled, log transformed, and mean-centered in a column-wise fashion prior to principal components analysis and partial least-squares-discrimination analysis modeling. RESULTS: Fecal samples from 10 of the 52 patients gave a positive stool-fat result of 30-100 mm; those of the remaining 42 contained neither fatty acids nor neutral fats. The peak intensities of lithocholic acid (p=0.001), lysophosphatidyl ethanolamine (lysoPE) 16:0 (p=0.015), and lysoPE 18:1/0:0 (p=0.014) were correlated with the size of the fatty acid. Subjects with positive stool-fat result showed higher score in Bristol stool scale form than those with negative stool-fat result at initial (p=0.040) and after three years (p=0.012). CONCLUSIONS: The metabolomic assay of stool fatty acid revealed mainly lysoPEs and lithocholic acid. The size of the fatty acid was correlated with higher concentrations of lysoPEs and lithocholic acid in stool-fat-test-positive specimens and related to loose stool even after three years of follow-up period. PMID- 23354345 TI - Intussusception: as the cause of mechanical bowel obstruction in adults. AB - BACKGROUND/AIMS: Intussusception in adults is rarely seen and causes misdiagnosis due to its appearance with various clinical findings. The cause of intussusception in adults is frequently organic lesions. In this study, the underlying etiologic factors, diagnostic methods and alternative methods of treatment are discussed in the light of the literature. METHODS: In this study, a retrospective evaluation was performed on 47 cases with the diagnoses of intussusception, who were operated on for bowel obstruction between 1990-2011 in Department of Surgery of Necmettin Erbakan University Meram Medical Faculty. Data related to presentation, diagnosis, treatment and pathology were analyzed. RESULTS: Twenty-four of the patients (51%) were female, and 23 were male (49%). Mean age (year) was 49 (range: 23-78) in female group, and 50 (range: 17-72) in male group. All patients presented mechanical bowel obstruction findings and underwent operation. Intussusception was caused by benign and malignant tumors in 38 patients, and other reasons in 3 cases. No reason could be determined in the other 6 cases. Only small intestine resection was applied in 29 cases, and large intestine resection was also applied in 17 cases. Reduction and fixation surgery was performed in one patient. No postoperative mortality was observed. CONCLUSIONS: Adult intussusception remains a rare cause of abdominal pain. Diagnosis of intussusception in adults is still difficult. Main treatment was surgical in most cases. PMID- 23354346 TI - Comparison of clinical outcomes between endoscopic and radiologic placement of self-expandable metal stent in patients with malignant colorectal obstruction. AB - BACKGROUND/AIMS: This study compared the clinical outcomes between endoscopic and radiologic placement of self-expandable metal stent (SEMS) in patients with malignant colorectal obstruction. METHODS: In total, 111 patients were retrospectively enrolled in this study between January 2003 and June 2011 at Seoul National University Boramae Hospital. Technical and clinical success rates, complication rates, and stent patency were compared between using an endoscopic (n=73) or radiologic (n=38) method during the SEMS placement procedure. RESULTS: The technical success rate was higher in the endoscopic method than in the radiologic method (100% [73/73] vs. 92.1% [35/38], respectively; p=0.038). In addition, in 3 of the remaining 35 patients in the radiologic-method group, adjuvant endoscopic assistance was required. In the six patients (including the three aforementioned patients), the causes of technical failure were the inability to pass the guidewire into an obstructive lesion due to a tortuous, curved angulation of the sigmoid or descending colon (n=4), and a difficult approach to a lesion located at the descending or transverse colon (n=2). The clinical success rate, complication rate, and stent patency did not differ significantly between the two methods (p=0.424, 0.303, and 0.423, respectively). CONCLUSIONS: When the colorectal obstruction had a tortuous, curved angulation of the colon or was located at or proximal to the descending colon, the endoscopic method of SEMS placement appears to be more useful than the radiologic method. However, once SEMS placement was technically successful, the clinical success rate, complication rate, and stent patency did not differ with the method of insertion. PMID- 23354347 TI - [Efficacy of entecavir switching therapy in chronic hepatitis B patients with clevudine-induced myopathy]. AB - BACKGROUND/AIMS: Clevudine is a potent antiviral agent against HBV. However, long term clevudine therapy may cause myopathy. This study was carried out to identify the efficacy of entecavir switching therapy in chronic hepatitis B patients experiencing clevudine-induced myopathy. METHODS: One hundred forty six patients with chronic hepatitis B treated with 30 mg of clevudine per day for 73 weeks (range, 36-132 weeks) were enrolled. Among them, clevudine-induced myopathy occurred in 21 patients (14.4%) which was diagnosed if the patients had symptoms related to myopathy with concurrent CK and AST elevation. All the patients who were diagnosed as clevudine-induced myopathy stopped the therapy, and 17 patients (81%) were switched to entecavir 0.5 mg. RESULTS: The patients with clevudine induced myopathy were switched to entecavir 0.5 mg for median 68 weeks, and all of them showed disappearance of clinical myopathic symptoms and normalization of CK and AST level within median 2.2 months. Eight patients (47%) were HBeAg positive before entecavir treatment, and HBeAg seroconversion was achieved in 2 patients (25%). HBV DNA level was elevated in 3 patients (17.6%) at the time when the patients were diagnosed as myopathy, all of them achieved virological response with entecavir switching therapy. ALT level was elevated in 3 patients (17.6%) before entecavir treatment, all of them showed normalization of ALT level. During entecavir therapy, genotypic resistance to entecavir or virological breakthrough was not noted. CONCLUSIONS: In chronic hepatitis B patients experiencing clevudine-induced myopathy, switching to entecavir 0.5 mg per day showed a resolution of myopathy and adequate viral suppression. PMID- 23354348 TI - [A case of Crohn's disease having normal delivery after infliximab treatment during early pregnancy]. AB - Infliximab is a chimeric IgG1 monoclonal antibody to tumor necrosis factor (TNF) a used in the treatment of steroid refractory or dependent Crohn's disease (CD). Patients with active CD are more likely to experience stillbirth, preterm labor, or small for gestational aged babies. The safety of administering infliximab in pregnant patients is not well documented. A 25-year-old woman, who was diagnosed with small bowel CD three years ago, was admitted to our hospital due to the aggravation of abdominal pain. She had been treated with mesalazine, azathioprine and intermittent steroid for three years. After admission, she did not respond to steroid therapy, we decided to try infliximab. After the administration of infliximab, epigastric pain was relived and Crohn's disease activity index score decreased significantly. However after the fourth infusion of infliximab, the patient became aware that she was ten gestational weeks old pregnancy state After then, infliximab was stopped and maintained by mesalazine. The patient gave birth to a healthy baby via normal vaginal delivery without the recurrence of CD. This case suggests that infliximab administration is safe during the early period of pregnancy. Thus, we report this case with a review of literature. PMID- 23354349 TI - [A case of acute cholecystitis after colonoscopy]. AB - A 43-year-old man, who received total gastrectomy five years ago for advanced gastric cancer, underwent a screening colonoscopy and abdominal CT scan. Abdominal CT scan revealed no abnormal findings. Colonoscopy revealed polyps at the rectum, which were removed by polypectomy. The patient did not complain of abdominal pain or discomfort throughout the procedure. But, he developed right upper quadrant abdominal pain on the next day after colonoscopy. Abdominal CT scan revealed the distended gallbladder with mild wall thickening and suspicious sandy stones or sludge in the gallbladder. The patient underwent an open cholecystectomy. Pathology was compatible with acute cholecystitis. We should be aware of and consider cholecystitis in the differential diagnosis for patients with abdominal pain after colonoscopy. PMID- 23354350 TI - [Massive bleeding hemobilia occurred in patient with hepatocellular carcinoma]. AB - Massive bleeding hemobilia occurs rarely in patients with hepatocellular carcinoma (HCC) without any invasive procedure. Upper gastrointestinal bleeding in patient with cirrhosis and abdominal pain with progressive jaundice in patient with HCC were usually thought as variceal bleeding and HCC progression respectively. We experienced recently massive bleeding hemobilia in patient with HCC who was a 73-year old man and showed sudden abdominal pain, jaundice and hematochezia. He had alcoholic cirrhosis and history of variceal bleeding. One year ago, he was diagnosed as HCC and treated with transarterial chemoembolization periodically. Sudden right upper abdominal pain occurred then subsided with onset of hemotochezia. Computed tomography showed bile duct thrombosis spreading in the intrahepatic and extrahepatic ducts, while an ampulla of vater bleeding was observed during duodenoscopy. Hemobilia could be one of the causes of massive bleeding in patients with cirrhosis and HCC especially when they had sudden abdominal pain and abrupt elevation of bilirubin. PMID- 23354351 TI - Metastatic common bile duct cancer from pulmonary adenocarcinoma presenting as obstructive jaundice. AB - We report an extremely rare case of metastatic common bile duct cancer from pulmonary adenocarcinoma presenting as obstructive jaundice. The patient was a 76 year-old male, who presented with generalized weakness and right upper quadrant pain. Plain chest X-ray noted multiple small nodules in both lung fields. Abdominal computed tomography scan showed a stricture of the mid common bile duct along with ductal wall enhancement. Endoscopic retrograde cholangiography revealed a concentric, abrupt narrowing of the mid-common bile duct suggestive of primary bile duct cancer. However, pathology comfirmed metastatic common bile duct cancer arising from pulmonary adenocarcinoma with immunohistochemical study with thyroid transcriptional factor-1 (TTF-1). PMID- 23354352 TI - Absolute bioavailability studies of a new oral topotecan formulation in Chinese patients using UHPLC-MS/MS. AB - Xinze((r)) is a new capsule formulation of topotecan being made in China which is similar to Hycamtin((r)), the currently available oral formulation approved in 2007 for the treatment of relapsed small cell lung cancer (SCLC). As topotecan bioavailability and pharmacokinetic data for Chinese patients is limited, the aim of the study was to assess the absolute bioavailability and pharmacokinetics of Xinze((r)) in Chinese patients with SCLC treated intravenously (i.v.) with 1.5mg/m(2)/d topotecan (Hycamtin((r))) on day 1 and treated orally with 1.5mg/m(2)/d topotecan on day 2. An ultra high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the determination of total topotecan (lactone and carboxylate forms) and of topotecan in the lactone form in human plasma samples. The method was validated with respect to selectivity, extraction recovery, matrix effect, linearity, intra- and inter-day precision, accuracy, and stability. The quantification limits were 0.5ng/mL for total topotecan and 0.1ng/mL for topotecan in the lactone form. The mean absolute bioavailability of total topotecan and topotecan in the lactone form was 42.24+/-12.9% and 47.18+/-16.9%, respectively, values which illustrate good systemic exposure. The presented results demonstrated this method can be a sensitive and efficient tool for bioavailability studies of topotecan. PMID- 23354353 TI - [Eyelid hygiene for contact lens wearers with blepharitis. Comparative investigation of treatment with baby shampoo versus phospholipid solution]. AB - BACKGROUND: Blepharitis due to Meibom gland dysfunction (MGD) is presumed to be one of the main reasons for dry eye symptoms which occur in up to 50% of contact lens users. Thus, MGD presumably plays an important role in dry eye in contact lens wearers. In the present prospective, randomized and double blind trial the efficacy of two established treatment options for MGD and blepharitis was evaluated in symptomatic contact lens wearers. METHODS: In this prospective, randomized 2-centre trial 53 symptomatic contact lens wearers suffering from blepharitis were included. Patients were randomly selected for two treatment groups: group A performed lid margin hygiene using the commonly recommended mild baby shampoo (Bubchen Kinder Shampoo-extra augenmild, Bubchen Werk Ewald Hermes Pharmazeutische Fabrik GmbH, Soest, Germany) and group B performed lid margin hygiene using a phospholipid-liposome solution specially designed for lid hygiene (Blepha Cura, Optima, Moosburg/Wang, Germany), each for 4 weeks. Before as well as 4 weeks after initiation of this study the following tests were performed: standardized subjective assessment using the ocular surface disease index, non invasive break-up time (NIBUT) and objective evaluation of lid-parallel conjunctival folds (LIPCOF) and further lid margin criteria by double blinded evaluation of slit lamp photographs. RESULTS: Of the 53 symptomatic contact lens wearers suffering from blepharitis 21 (39,6%) were randomly selected for treatment group A and 32 (60.4%) for group B. In both treatment groups there was objective and subjective improvement of symptoms of dry eye in contact lens wearers. Interestingly, there was a significantly greater improvement, subjective as well as objective, in treatment group B which used the phospholipidliposome solution for lid margin hygiene compared to group A using baby shampoo. CONCLUSIONS: Although both therapies improved symptoms of dry eye due to blepharitis in symptomatic contact lens wearers, patients using phospholipid liposomal solution for lid margin hygiene demonstrated a significantly greater clinical benefit from the therapy. Thus, clinical practice recommending just baby shampoo for lid margin hygiene should be re-considered, as phospholipid-liposomal solution for lid margin hygiene appears to yield greater and faster clinical benefits for symptomatic contact lens wearers suffering from dry eye symptoms. PMID- 23354355 TI - [Prominent conjunctival tumor]. AB - The case of a 57-year-old woman with a rapidly growing unpigmented conjunctival tumor is presented. Despite the clinical appearance the histology surprisingly confirmed a malignant melanoma of the conjunctiva. Various phenotypes and the rareness of this disease complicate a clinical diagnosis. Therapeutically, a complete excision of the tumor including a safety margin, adjuvant topical chemotherapy and closely monitored follow-up are crucial. PMID- 23354354 TI - [Effect of resveratrol on the fundus oculi. An overview]. AB - Resveratrol is a polyphenol with various properties. Oncological studies have shown an excellent anti-carcinogenic effect. Due to many overlaps between tumor mediating signaling pathways and those which mediate neovascularization and proliferation in retinal diseases, this review intends to focus on studies about the application of resveratrol in diseases of the eye fundus in vitro and in vivo. Resveratrol has been well investigated in cell culture studies and animal models. Ophthalmological in vitro and in vivo investigations have shown a large variety of possible effects without toxic side effects and antiproliferative and immune modulatory effects in particular were observed. There is general consensus that the target protein of resveratrol is NF-kappaB. Clinical studies are needed to confirm these effects observed in cell culture and animal models. The exact mechanism of resveratrol remains unknown and seems to vary between cell types, tissues and the pathophysiological environment. PMID- 23354356 TI - [Are diurnal and nocturnal intraocular pressure measurements over 48 h justified?]. AB - PURPOSE: Diurnal intraocular pressure (IOP) measurements are recommended in cases of visual field deterioration in glaucoma patients. In this study the rationale of 24 h versus 48 h IOP measurements was investigated. PATIENTS AND METHODS: Mean IOP and maximum IOP values were obtained in 80 patients over a period of 48 h. The IOP measurements (Goldmann tonometry) of day 1 and 2 (taken every 4 h) were compared. To reduce interindividual and intraindividual differences of measurements the statistical calculation took a tolerance level of +/- 2 mmHg and +/- 1 mmHg into account. RESULTS: Maximum IOP measurements were found to differ between 37.5 % and 65.0% respectively for right eyes and 28.8 % and 47.5% respectively for left eyes depending on the measurement tolerance (+/-2 mmHg or +/-1 mmHg) between day 1 and day 2. Mean IOP values were found to differ by 25 % and 51.3 % respectively for right eyes and 26.3 % and 46.3% respectively for left eyes (+/- 2 or +/- 1 mmHg in) between day 1 and day 2. A time-related clustering of extreme deviations could not be found but the maximum values from all patients were found to be roughly equally distributed over daytime and nighttime hours. CONCLUSIONS: Both maximum IOP and mean IOP measurements were found to differ by at least +/- 2 or +/- 1 mmHg between day 1 and 2 at a significant percentage and the maximum values did not peak at a predictable time point during the 48 h. Therefore, 48 h IOP measurements appear to be more reliable than 24 h measurements. PMID- 23354357 TI - Probing hemoglobin confinement inside submicron silica tubes using synchrotron SAXS and electrochemical response. AB - The configuration of hemoglobin in solution and confined inside silica nanotubes has been studied using synchrotron small angle X-ray scattering and electrochemical activity. Confinement inside submicron tubes of silica aid in preventing protein aggregation, which is vividly observed for unconfined protein in solution. The radius of gyration (R g) and size polydispersity (p) of confined hemoglobin was found to be lower than that in solution. This was also recently demonstrated in case of confined hemoglobin inside layered polymer capsules. The confined hemoglobin displayed a higher thermal stability with R g and p showing negligible changes in the temperature range 25-75 degrees C. The differences in configuration between the confined and unconfined protein were reflected in their electrochemical activity. Reversible electrochemical response (from cyclic voltammograms) obtained in case of the confined hemoglobin, in contrary to the observance of only a cathodic response for the unconfined protein, gave direct indication of the differences between the residences of the electroactive heme center in a different orientation compared to that in solution state. The confined Hb showed loss of reversibility only at higher temperatures. The electron transfer coefficient (alpha) and electron transfer rate constant (k s) were also different, providing additional evidence regarding structural differences between the unconfined and confined states of hemoglobin. Thus, absence of any adverse effects due to confinement of proteins inside the inorganic matrices such as silica nanotubes opens up new prospects for utilizing inorganic matrices as protein "encapsulators", as well as sensors at varying temperatures. PMID- 23354358 TI - Perioperative blood pressure alterations after eversion and conventional carotid endarterectomy sustain in the midterm. AB - OBJECTIVE: Carotid endarterectomy (CEA) is associated with a profound effect on blood pressure. The aim of this study was to evaluate 24 h ambulatory blood pressure measurement (ABPM) after eversion (E-CEA) and conventional (C-CEA) endarterectomy including a midterm follow-up. METHODS: Seventy-one patients were included in this prospective study [E-CEA (37)/C-CEA (34)]. Daytime (8 a.m. to 10 p.m.) and nighttime (10 p.m. to 8 a.m.) ABPMs were analyzed perioperatively and at midterm after a median follow-up period of 9.5 months (interquartile range (IQR) 6.4-17.8) in the E-CEA group and 11.5 months (IQR 8.3-13.6) in the C-CEA group RESULTS: Patient demographics and preoperative antihypertensive regimens were similar in the two groups. Compared with baseline, ABPM decreased on postoperative day 1 in the C-CEA group (P < 0.01) but normalized by day three. By contrast, ABPM values were unchanged on day 1 in the E-CEA group but increased above baseline on day 3 (P < 0.01). E-CEA was associated with higher ABPM on day 1 (P < 0.001 daytime, P < 0.01 nighttime) and again on day 3 (P < 0.001 daytime, P < 0.01 nighttime). The use of vasodilators was more frequent in the E-CEA group, both in the recovery room (P = 0.007) and on the ward (P = 0.004). Midterm results showed no difference of average blood pressure values, but an increased maximal blood pressure (P = 0.01 daytime) and heart rate (HR) (P = 0.006 daytime) were reached in the E-CEA group and decreased HR (P = 0.01 nighttime) in the C CEA group. Compared with baseline [(E-CEA: median (IQR) 2 (1-3); C-CEA: median (IQR) 2 (1-3)], the number of antihypertensive medications at midterm was significantly higher in the E-CEA group [(median (IQR) 3 (2-3) vs. 2 (2-3), P = 0.002)]. In both groups, no adverse cardiovascular or cerebrovascular events during follow-up could be observed. CONCLUSION: Although the initial hypertensive effect of E-CEA diminishes during midterm follow-up, patients undergoing eversion endarterectomy keep needing more antihypertensive medications and are prone to develop higher maximal blood pressure. PMID- 23354359 TI - Outcome of functional end-to-end esophagojejunostomy in totally laparoscopic total gastrectomy. AB - PURPOSE: Totally laparoscopic total gastrectomy (TLTG) is unpopular because reconstruction is difficult. In fact, esophagojejunostomy is the most difficult surgical technique in TLTG. We adopted functional end-to-end anastomosis for esophagojejunostomy to simplify the procedure. The present study assesses the feasibility and surgical outcomes of TLTG with functional end-to-end esophagojejunostomy. METHODS: We assessed the intraoperative and postoperative outcomes of 65 consecutive patients who underwent TLTG with functional end-to-end esophagojejunostomy at Tonan Hospital between January 2006 and August 2011. RESULTS: The mean surgical duration was 271.5 +/- 64.7 min, and the mean blood loss was 85.2 +/- 143.2 g. One patient (1.5 %) was converted to open surgery, and two patients (3.1 %) required reoperation due to ileus because of an internal hernia and jejunojejunostomy leakage. No reoperation was associated with functional end-to-end esophagojejunostomy. The mean hospital stay was 21.4 +/- 13.5 days. Ten patients (15.4 %) developed postoperative complications, of which three (4.6 %) were anastomotic stenosis associated with functional end-to-end esophagojejunostomy. All of these were resolved by endoscopic dilation. CONCLUSION: Functional end-to-end esophagojejunostomy in TLTG is safe and feasible. PMID- 23354360 TI - Surgery of esophageal cancer. AB - BACKGROUND: Surgery is the only option for curative treatment in patients with esophageal carcinoma. Despite the debates related to the peri-operative therapy regime, a generally accepted consensus on surgical approach is not reached yet. The debate focuses mainly on pros and cons between radical transthoracic resection and the (limited) transhiatal resection in the last decade. METHODS: The PubMed database was searched for randomized trials, meta-analyses, and retrospective single-center studies. The search terms were "esophageal carcinoma," "esophageal junction carcinomas," "transhiatal," "transthoracic," "morbidity," "mortality," and "surgery." RESULTS: The radical transthoracic approach should be the standard of care for esophageal carcinoma since it does not go along with an increased risk of postoperative morbidity or mortality but reveals an improved survival. Patient-related co-morbidities are the most influencing factors for the postoperative outcome. For type II esophageal junction carcinoma, treatment options from transhiatal extended gastrectomy to esophagectomy with hemigastrectomy or esophagogastrectomy with colonic interposition are existing. In type III esophagogastric junction carcinomas, the transhiatal extended gastrectomy is the standard of care, and the minimally invasive approach should be performed in specialized centers. CONCLUSION: Based on current available study results, this expert review provides a decision support for the best surgical strategy depending on tumor localization and patients' characteristics. PMID- 23354361 TI - Isolation of cold-active, acidic endocellulase from Ladakh soil by functional metagenomics. AB - Mining of soil sample from cold desert of Ladakh by functional metagenomics led to the isolation of cold-adapted endocellulase (CEL8M) that hydrolyses carboxymethyl cellulose (CMC). Mature CEL8M, a 347-residue polypeptide with a molecular mass of 38.9 kDa showed similarity to beta-1,3-1,4 D-glucanase from Klebsiella sp. The enzyme contains the catalytic module of glycosyl hydrolase family 8 but does not possess a carbohydrate-binding domain. 3D structural model of the enzyme built by homology modeling showed an architecture of (alpha/alpha)6 barrel fold. The purified enzyme was found to be active against CMC, xylan, colloidal chitosan and lichenan but not active against avicel. Glucose was not among the initial hydrolysis products, indicating an endo mode of action. CEL8M displayed maximal activity at pH 4.5 and remained significantly active (~28 %) when the temperature decreased to 10 degrees C. Cold-active endocellulase CEL8M may find applications in textile industry at low temperature which can result in energy savings. PMID- 23354362 TI - Hierarchically assembled ZnO nanoparticles on high diffusion coefficient ZnO nanowire arrays for high efficiency dye-sensitized solar cells. AB - In this study, ZnO nanoparticles (ZnO NPs) were conformally covered on the surfaces of ZnO nanowires (ZnO NWs) with high diffusion coefficient (1.2 * 10(-2) cm(2) s(-1)) to make a composite photoanode. By using N719 to sensitize the composite photoanode, the conversion efficiency can reach 7.14%. PMID- 23354363 TI - Xiao Jin Wan, a traditional Chinese herbal formula, inhibits proliferation via arresting cell cycle progression at the G2/M phase and promoting apoptosis via activating the mitochondrial-dependent pathway in U-2OS human osteosarcoma cells. AB - Xiao Jin Wan (XJW) is a well-known traditional Chinese folk-medicine, which is commonly used for the treatment of various types of diseases including cancers. However, the mechanism of the anticancer activity of XJW against U-2OS human osteosarcoma cells, have not yet been reported. In the present study, we investigated the cellular effects of the XJW on the U-2OS human osteosarcoma cell line. Our results showed that XJW induced cell morphological changes, reduced cell viability in a dose- and time-dependent manner and arrested in the G2/M phase of the cell cycle suggesting that XJW inhibited the proliferation of U-2OS cells. Hoechst 33258 staining and Annexin V/propidium iodide double staining exhibited the typical nuclear features of apoptosis and increased the proportion of apoptotic Annexin V-positive cells in a dose-dependent manner, respectively. In addition, XJW treatment caused loss of plasma membrane asymmetry, collapse of mitochondrial membrane potential, activation of caspase-9 and caspase-3, and increase of the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2. Taken together, the results indicate that the U-2OS cell growth inhibitory activity of XJW was due to cell cycle arrested and mitochondrial-mediated apoptosis, which may partly explain the anticancer activity of Xiao Jin Wan. PMID- 23354364 TI - The association of preoperative breast magnetic resonance imaging and multiple breast surgeries among older women with early stage breast cancer. AB - To evaluate the association between preoperative breast magnetic resonance imaging (MRI) utilization and the rate of multiple surgeries, and to investigate the extent of any variation of rates of multiple surgeries among physicians. We identified patients with stage 0, I, or II breast cancer diagnosed between 2002 and 2007 in the Surveillance, Epidemiology, and End Results-Medicare database. Using diagnosis and procedure codes, we defined that the initial treatment episode had ended when a gap in surgery occurred at least 90 days after primary surgery. Surgical procedures of partial mastectomy or mastectomy during the initial treatment period were calculated to identify patients who received multiple surgeries. Multilevel logistic regression models were used to identify patient- and physician-level predictors of multiple surgeries. Of 45,453 women with early stage breast cancer who were treated by 2,595 surgeons during the study period, 9,462 patients (20.8 %) received multiple breast surgeries; of these patients, 8,318 (87.9 %) underwent one additional surgery, 988 (10.4 %) received two additional surgeries, and 156 (1.6 %) received three or more additional surgeries. Among 2,997 (6.6 % of the entire cohort) women who underwent preoperative breast MRI evaluation, 770 received multiple breast surgeries. After we adjusted for patient and tumor characteristics associated with multiple surgeries, we found that the rate of multiple surgeries was not significantly different between the two groups with or without preoperative breast MRI. Furthermore, the median odds ratio of 2.0, corresponding with the median value of the relative odds of receiving multiple surgeries between two randomly chosen physicians after controlling for other confounders, indicated a large individual surgeon effect. Substantial variation was observed in the rates of multiple surgeries in women aged 66 and older with early stage breast cancer. Evidence does not support that preoperative breast MRI reduces the incidence of multiple surgeries. PMID- 23354365 TI - Effects of adjuvant chemotherapy in HER2-positive or triple-negative pT1ab breast cancers: a multi-institutional retrospective study. AB - Previous studies have reported higher recurrence rates in T1a/b N0 breast cancers characterized by high-risk biology (HER2+ or triple-negative), but the benefits of adjuvant chemotherapy in these patients have not been established. This study was designed to determine whether recurrence risk is reduced with chemotherapy and to define a group of patients most appropriate for treatment based on retrospective data. We pooled cases from two multi-institutional databases spanning the period of 1996-2010. A propensity score model adjusted unbalanced confounders between the groups treated or untreated with adjuvant chemotherapy and, in case of HER2-positive disease, with trastuzumab. Competing risk analysis was utilized to study effects of chemotherapy on cancer recurrences in the matched populations. Among the 318 patients identified, 41 % received adjuvant chemotherapy and 54 % of HER2+ patients received it with trastuzumab. The cumulative risk of recurrence at 5 years was 7.3 %. Age less than 35 years and triple-negative status were the only significant prognostic factors. Overall, administration of chemotherapy was not associated with a significant decrease in the risk of recurrence (HR 0.93, p = 0.91). The rate of recurrence in HER2+ patients who received trastuzumab was lower but not statistically significant (HR 0.50, p = 0.63). Clinical characteristics are of limited prognostic value for stratifying risk of recurrence in very small, node-negative HER2+, or triple negative cancers. While limited by the small number of events, our analysis does not support the increasingly prevalent practice of administering adjuvant chemotherapy in this population without more accurate prognostic and predictive factors. PMID- 23354366 TI - The impact of a 1-week residential program on anxiety in adolescents with incontinence: a quasi-experimental study. AB - PURPOSE: To determine the effect of a 1-week residential program on anxiety in adolescents with bowel and/or bladder dysfunction. SUBJECTS AND SETTING: Participants were 89 adolescents (mean age = 14.56 years, range 11-18 years) attending a 1-week residential program for individuals with bowel and/or bladder dysfunction. The program is both educational and social in nature and is held at 1 of 3 rotating university campuses. METHODS: A quasi-experimental study design that included 3 administrations of the Multi-dimensional Anxiety Scale for Children (MASC) was employed for data collection. The MASC was administered immediately before the program, immediately after the program, and 2 to 4 months after conclusion of the program. INTERVENTION: The 1-week program includes structured and unstructured sessions facilitated by young adults with these conditions and/or WOC nurses. Topics are physiological and psychological in nature, focusing on strategies for home, school, and medical settings. There are also social activities designed to facilitate development of social relationships among peers. RESULTS: : A positive, statistically significant impact on total MASC scores was found (F1.679, 80.587 = 3.587; P = .404) as well as on the Social Anxiety scale (F2,96 = 5.299; P = .007) and its 2 subscales, Humiliation/Rejection Fears (F2,96 = 3.876; P = .024) and Performance Fears (F2,96 = 6.453; P = .002). CONCLUSIONS: This 1-week residential summer program was found to exert a positive impact on anxiety symptoms, particularly social anxiety, and benefits persisted for 2 to 4 months. This suggests the psychological benefits of even relatively brief experiences for individuals with bowel and/or bladder dysfunction. PMID- 23354367 TI - Biofilms in chronic wounds and the potential role of negative pressure wound therapy: an integrative review. AB - Biofilms are communities of microbes that exist in a variety of environments. The extracellular substances secreted by biofilms make them difficult to eradicate, giving the bacterial community in the biofilm a resistance advantage over freefloating (planktonic) microbes. Biofilms are particularly problematic in chronic wounds because of their resistance to conventional therapies and tendency to delay healing. Multimodal strategies to combat wound biofilms are necessary, including wound debridement, antimicrobial treatment, and continued disruption of biofilms. Negative pressure wound therapy with irrigation or instillation may lower the bacterial burden in chronic wounds and prevent the biofilm formation. This article provides an overview of biofilms and evolving strategies to counteract them. PMID- 23354368 TI - Does the diagnosis of breast or ovarian cancer trigger referral to genetic counseling? AB - OBJECTIVE: Kaiser Permanente Northern California is a large integrated health care delivery system in the United States that has guidelines for referring women with newly diagnosed BRCA1-and BRCA2-associated cancers for genetic counseling. This study assesses adherence to genetic counseling referral guidelines within this health system. METHODS: Chart review was performed to identify patients with cancer who met the following pathology-based Kaiser Permanente Northern California guidelines for referral for genetic counseling: invasive breast cancer, younger than age 40; nonmucinous epithelial ovarian, fallopian tube, or peritoneal cancer, younger than age 60; women with synchronous or metachronous primary cancers of the breast and ovaries; and male breast cancer. We assessed compliance with referral guidelines. An electronic notice was sent to the managing physician of patients with newly diagnosed cancer to assess the feasibility of this intervention. RESULTS: A total of 340 patients were identified with breast cancer at younger than age 40 or with ovarian, peritoneal, or tubal cancer between January and June, 2008. Upon chart review, 105 of these patients met pathology-based criteria for referral to genetic counseling, of whom 47 (45%) were referred within the 2-year study period. Of the 67 subjects with breast cancer, 40 subjects (60%) were referred. In contrast, only 7 (21%) of 33 patients with ovarian cancer were referred (P < 0.001). A pilot study was performed to test the feasibility of notifying managing oncologists with an electronic letter alerting them of eligibility for genetic referral of patients with new diagnosis (n = 21). In the 3 to 6 months after this notification, 12 of these 21 patients were referred for counseling including 5 of 7 patients with a diagnosis of ovarian cancer. CONCLUSION: There is a missed opportunity for referring patients to genetic counseling, especially among patients with ovarian cancer. A pilot study suggests that alerting treating physicians is a feasible strategy to increase appropriate referral. PMID- 23354369 TI - A population-based study of visual inspection with acetic acid (VIA) for cervical screening in rural Nigeria. AB - OBJECTIVE: Cervical cancer is the most common gynecological cancer in developing countries. Visual inspection with acetic acid (VIA) was introduced to screen for cervical premalignant lesions in developing countries owing to the inability of many countries to implement high-quality cytologic services. We sought to compare VIA performance among different health workers in Nigeria. METHODS: In a population-based project, 7 health workers who had been screening women with VIA for approximately 2 years at local government health centers in rural Nigeria were retrained in a 2-week program using the International Agency for Research on Cancer training manual. Women from a rural village who had never had cervical cancer screening were recruited into the study. Each woman had cervical cancer screening by VIA, liquid-based cytologic test, and oncogenic human papillomavirus (HPV) DNA test. RESULTS: Despite similar participant characteristics, across all age groups, providers had wide ranges of VIA results; 0% to 21% suspect cancer and 0% to 25% were VIA positive. Visual inspection with acetic acid was insensitive compared to a combination of cytologic and HPV tests. CONCLUSION: In our study, VIA was not reproducible, nor was it sensitive compared to cytologic and HPV tests. PMID- 23354370 TI - The prevalence of human papillomavirus in ovarian cancer: a systematic review. AB - OBJECTIVE: We performed a systematic review and a meta-analysis to estimate the prevalence of human papillomavirus (HPV) in ovarian cancer. METHODS: A comprehensive search of the Cochrane Library, MEDLINE, CANCERLIT, LILACS, Grey literature and EMBASE was performed for articles published from January 1990 to March 2012. The following MeSH (Medical Subject Headings) terms were searched: "ovarian tumor" or "ovarian cancers" and "HPV" or "human papillomavirus." Included were case-control and cross-sectional studies, prospective or retrospective, that evaluated clinical ovarian cancer and provided a clear description of the use of in situ hybridization, Southern blot hybridization, and polymerase chain reaction. The statistical analysis was performed using REVMAN 5.0. RESULTS: In total, 24 primary studies were included in this meta-analysis. Studies from 11 countries on 3 continents contained data on HPV and ovarian cancer, including 889 subjects. Overall, the HPV prevalence in patients with ovarian cancer was 17.5 (95% confidence interval [CI], 15.0%-20.0%). Human papillomavirus prevalence ranged from 4.0% (95% CI, 1.7%-6.3%) in Europe to 31.4% (95% CI, 26.9%-35.9%) in Asia. An aggregate of 4 case-control studies from Asia showed an odds ratio of 2.48 (95% CI, 0.64-9.57). CONCLUSIONS: We found a high prevalence of HPV-positive DNA in ovarian cancer cases, but the role of HPV in ovarian cancer remains inconclusive. Further studies are needed to control case to answer this question. PMID- 23354371 TI - Diabetes mellitus and ovarian cancer risk: a systematic review and meta-analysis of observational studies. AB - OBJECTIVE: The objective of this study was to evaluate the epidemiologic association between diabetes and risk of ovarian cancer. METHODS: We searched PubMed, EMBASE, and The Cochrane Library for observational studies on the association between diabetes and ovarian cancer. Cohort studies that reported relative risks (RRs) and case-control studies that showed odds ratios were included in the analysis. Summary RRs with 95% confidence intervals (CIs) were calculated with a random-effects model. RESULTS: A total of 19 studies from 18 articles (7 case-control studies and 11 cohort studies) met the inclusion criteria. Combining data from all studies, diabetes was associated with an increased risk of ovarian cancer, compared with no diabetes (summary RR of ovarian cancer incidence, 1.17; 95% CI, 1.02-1.33). In cohort and nested case control studies, patients with diabetes had statistically significant increased risk of ovarian cancer (RR, 1.16; 95% CI, 1.01-1.33), without significant heterogeneity (I = 27; P = 0.172). Among studies that control for age, body mass index, smoking, and alcohol, a prominent association between diabetes and ovarian cancer was found (RR, 1.55; 95% CI, 1.11-2.19). CONCLUSIONS: This study suggests that women with diabetes have a moderately increased risk of ovarian cancer. PMID- 23354372 TI - Exon 2 duplication of the MID1 gene in a patient with a mild phenotype of Opitz G/BBB syndrome. AB - The X-linked form of Opitz G/BBB syndrome is a congenital midline malformation syndrome caused by MID1 loss-of-function mutations, including point mutations and small-sized duplications, insertions, and deletions. Three patients with an Opitz G/BBB syndrome phenotype and relatively large duplications of part of the MID1 gene have been described up to date. Here we report a 2-months-old boy with a very mild phenotype including craniofacial dysmorphism, swallowing difficulties, and a normal psychomotor development. Molecular karyotyping revealed a 57-kb duplication involving exon 2 of the MID1 gene. The in-frame tandem duplication was confirmed by MID1 transcript analysis. This alteration results likely in a mutant MID1 protein which contains 32 duplicated amino acids in the first part of the coiled-coil domain. The mild phenotype of the patient with the microduplication suggests that MID1 mutations can be found in patients with hypertelorism with or without other clinical signs and MID1 alterations might be missed in individuals not fulfilling the minimal criteria for diagnosis of X linked Opitz G/BBB syndrome. This report further emphasizes the genotype-first approach in medical genetics in general and patients with unspecific clinical features in particular. PMID- 23354373 TI - Human health risk assessment of occupational and residential exposures to dechlorane plus in the manufacturing facility area in China and comparison with e waste recycling site. AB - A screening level human health risk assessment based on the worst-case scenario was conducted on the occupational and residential exposures to dechlorane plus (DP) in the manufacturing facility region and an electronic-waste (e-waste) recycling site in China, which are two of the most polluted areas of DP in the world. Total estimated exposure doses (EEDs) via dietary intake, dermal contact, and inhalation was approximately 0.01 mg kg(-1) d(-1) for people living in the manufacturing facility region. In comparison, total EEDs (approximate 0.03 MUg kg(-1), d(-1)) were 300-fold lower in people living near an e-waste recycling site in China. Chronic oral, dermal, and inhalation reference doses (RfDs) were estimated to be 5.0, 2.0, and 0.01 mg kg(-1)d (-1), respectively. The oral RfD was markedly greater than Mirex (2*10(-4) mg kg(-1) d(-1)) and decabromodiphenyl ether (BDE-209; 7*10(-3) mg kg(-1) d(-1)), which have been or might be replaced by DP as a flame retardant with less toxicity. Monte Carlo simulation was used to generate the probability densities and functions for the hazard index which was calculated from the EEDs and RfDs to assess the human health risk. The hazard index was three orders of magnitude lower than 1, suggesting that occupational and residential exposures were relatively safe in the manufacturing facility region and e-waste recycling site. PMID- 23354374 TI - Degradation of flumequine by the Fenton and photo-Fenton processes: evaluation of residual antimicrobial activity. AB - Flumequine is a broad-spectrum antimicrobial agent of the quinolone class, and it is widely used as a veterinary drug in food-producing animals. The presence of flumequine in the environment may contribute to the development of drug resistant bacterial strains. In this study, water samples fortified with flumequine (500 MUg L(-1)) were degraded using the Fenton and photo-Fenton processes. The maximum degradation efficiency for flumequine by the Fenton process was approximately 40% (0.5 mmol L(-1) Fe(II), 2.0 mmol L(-1) H(2)O(2) and 15 min). By applying UV radiation (photo-Fenton process), the efficiency reached more than 94% in 60 min when 0.25 mmol L(-1) Fe(II) and 10.0 mmol L(-1) H(2)O(2) were used. Under these conditions, the Fenton process was able to reduce the biological activity, whereas the photo-Fenton process eliminated almost all of the antimicrobial activity because it was not detected. Four byproducts with an m/z of 244, 238, 220 and 202 were identified by mass spectrometry, and a degradation pathway for flumequine was proposed. The byproducts were derived from decarboxylation and defluorination reactions and from modifications in the alkylamino chain of the fluoroquinolone. PMID- 23354375 TI - Bioremediation of diesel-polluted soil using biostimulation as post-treatment after oxidation with Fenton-like reagents: assays in a pilot plant. AB - The present study focuses on the remediation of diesel-polluted soil using modified Fenton treatment coupled with inorganic NPK fertilizer ("Fenton+NPK"). Studies were carried out in a pilot plant containing 1 m(3) of sandy soil contaminated with 20,000 mg kg(-1) of diesel, placed outdoors at a temperature ranging between 5 and 10 degrees C. Results showed that NPK-fertilizer as post treatment stimulated culturable degrading bacteria and enhanced dehydrogenase activity. Fenton+NPK treatment increased total petroleum hydrocarbon (TPH) removal efficacy. Natural attenuation removed 49% of TPH in the surface layer, 23% of TPH in the non-saturated layer and 4% of the TPH in the saturated layer, while the percentage removed of TPH after Fenton+NPK treatment was 58%, 57% and 32% respectively. The results from our study showed that, immediately after soil contamination, occurred a specialization and differentiation of the bacterial community, but after this initial modification, no significant changes of bacterial diversity was observed under natural attenuation conditions. In contrast, when the Fenton's reagent was applied a reduction of the bacterial biodiversity was observed. However, the post-biostimulation did enhance the degrading microbiota and stimulated their degrading biological activity. In conclusion, biostimulation, as a post-treatment step in chemical oxidation, is an effective solution to remediate hydrocarbon-polluted sites. PMID- 23354376 TI - Atmospheric mercury incorporation in soils of an area impacted by a chlor-alkali plant (Grenoble, France): contribution of canopy uptake. AB - This study focused on the fluxes of mercury (Hg) and mechanisms of incorporation into soils surrounding a chlor-alkali plant suspected to have emitted up to ~600 kg Hg year(-1) for decades into the atmosphere. Comparison of vertical Hg soil profiles with As, Cu, Ni and Zn (which were not emitted by the plant) support Hg enrichment in surface horizons due to atmospheric Hg inputs from the chlor-alkali plant. Based on chemical extractions and elemental correlations, Hg was found to be weakly leachable and bio-available for plants, and most probably strongly bound to organic matter. In contrast, other trace elements were probably associated with phyllosilicates, iron oxides or with primary minerals. Hg stocks in the surface horizon of a forested soil (1255 mg Hg m(-3)) were two-fold higher than in an agricultural soil (636 mg Hg m(-3)) at a similar distance to the plant. The difference was attributed to the interception of atmospheric Hg by the canopy (most likely gaseous elemental Hg and reactive gaseous Hg) and subsequent litterfall incorporation. Some differences in the ability to trap atmospheric Hg were observed between tree species. The characterization of the litter showed an increasing Hg concentration in the plant material proportional to their degradation stage. In agricultural soils, very low Hg concentrations found in corn leaves and grains suggested a limited uptake via both the foliar and root pathways. Thus, the short-term risk of Hg transfer to agricultural crops and higher levels of the trophic chain appeared limited. A possible risk which remains to be evaluated is the possible transfer of Hg-rich particles from the forest topsoil to downstream aquatic ecosystems during rain and snowmelt events. PMID- 23354377 TI - Sequential photo-bleaching to delineate single Schwann cells at the neuromuscular junction. AB - Sequential photo-bleaching provides a non-invasive way to label individual SCs at the NMJ. The NMJ is the largest synapse of the mammalian nervous system and has served as guiding model to study synaptic structure and function. In mouse NMJs motor axon terminals form pretzel-like contact sites with muscle fibers. The motor axon and its terminal are sheathed by SCs. Over the past decades, several transgenic mice have been generated to visualize motor neurons and SCs, for example Thy1-XFP and Plp-GFP mice, respectively. Along motor axons, myelinating axonal SCs are arranged in non-overlapping internodes, separated by nodes of Ranvier, to enable saltatory action potential propagation. In contrast, terminal SCs at the synapse are specialized glial cells, which monitor and promote neurotransmission, digest debris and guide regenerating axons. NMJs are tightly covered by up to half a dozen non-myelinating terminal SCs - these, however, cannot be individually resolved by light microscopy, as they are in direct membrane contact. Several approaches exist to individually visualize terminal SCs. None of these are flawless, though. For instance, dye filling, where single cells are impaled with a dye-filled microelectrode, requires destroying a labelled cell before filling a second one. This is not compatible with subsequent time-lapse recordings. Multi-spectral "Brainbow" labeling of SCs has been achieved by using combinatorial expression of fluorescent proteins. However, this technique requires combining several transgenes and is limited by the expression pattern of the promoters used. In the future, expression of "photo-switchable" proteins in SCs might be yet another alternative. Here we present sequential photo-bleaching, where single cells are bleached, and their image obtained by subtraction. We believe that this approach - due to its ease and versatility - represents a lasting addition to the neuroscientist's technology palette, especially as it can be used in vivo and transferred to others cell types, anatomical sites or species. In the following protocol, we detail the application of sequential bleaching and subsequent confocal time-lapse microscopy to terminal SCs in triangularis sterni muscle explants. This thin, superficial and easily dissected nerve-muscle preparation has proven useful for studies of NMJ development, physiology and pathology. Finally, we explain how the triangularis sterni muscle is prepared after fixation to perform correlated high-resolution confocal imaging, immunohistochemistry or ultrastructural examinations. PMID- 23354378 TI - Methods for analysis of citrinin in human blood and urine. AB - Citrinin (CIT), produced by several Penicillium, Aspergillus, and Monascus species, has been detected as contaminant in feeds, grains, and other food commodities. CIT can co-occur with ochratoxin A (OTA), a mycotoxin also known for its nephrotoxicity, and this raises concern regarding possible combined effects. But, in contrast to OTA, data on CIT contamination in foods for human consumption are scarce, and CIT biomonitoring has not been conducted so far due a lack of suitable methods for human specimen. Thus, it was the aim of the present study to develop sensitive methods for the analysis of CIT in human blood and urine to investigate human exposure. To this end, we assessed different methods of sample preparation and instrumental analysis for these matrices. Clean-up of blood plasma by protein precipitation followed by LC-MS/MS-based analysis allowed robust detection of CIT (LOD 0.07 ng/mL, LOQ 0.15 ng/mL). For urine, sample clean up by an immunoaffinity column (CitriTest((r))) proved to be clearly superior to SPE with RP(18) material for subsequent analysis by LC-MS/MS. For CIT and its metabolite dihydrocitrinone (HO-CIT), the LOD and LOQ determined by external calibration curves in matrix were 0.02 and 0.05 ng/mL for CIT, and those for HO CIT were 0.05 and 0.1 ng/mL urine. The newly developed method was applied in a small pilot study: CIT was present in all plasma samples from 8 German adults, at concentrations ranging from 0.11 to 0.26 ng/mL. The molar (nM) concentrations of CIT are similar to those measured for OTA in these samples as a result of dietary mycotoxin intake. CIT was detected in 8/10 urines (from 4 adults and 6 infants) in a range of 0.16-0.79 ng/mL, and HO-CIT was present in 5/10 samples at similar concentrations. Thus, CIT is excreted in urine as parent compound and also as metabolite. These first results in humans point to the need for further studies on CIT exposure. PMID- 23354379 TI - Focus on memory. PMID- 23354380 TI - Percept and the single neuron. PMID- 23354381 TI - The yin and yang of cortical layer 1. PMID- 23354382 TI - UP states rise from the depths. PMID- 23354383 TI - Scratching an itch. PMID- 23354384 TI - Memory and law: what can cognitive neuroscience contribute? AB - A recent decision in the United States by the New Jersey Supreme Court has led to improved jury instructions that incorporate psychological research showing that memory does not operate like a video recording. Here we consider how cognitive neuroscience could contribute to addressing memory in the courtroom. We discuss conditions in which neuroimaging can distinguish true and false memories in the laboratory and note reasons to be skeptical about its use in courtroom cases. We also discuss neuroscience research concerning false and imagined memories, misinformation effects and reconsolidation phenomena that may enhance understanding of why memory does not operate like a video recording. PMID- 23354385 TI - Epigenetics and persistent memory: implications for reconsolidation and silent extinction beyond the zero. AB - Targeting epigenetic mechanisms during initial learning or memory retrieval can lead to persistent memory. Retrieval induces plasticity that may result in reconsolidation of the original memory, in which critical molecular events are needed to stabilize the memory, or extinction, in which new learning during the retrieval trial creates an additional memory that reflects the changed environmental contingencies. A canonical feature of extinction is that the original response is temporarily suppressed, but returns under various conditions. These characteristics have defined whether a given manipulation alters extinction (when persistence does not occur) or reconsolidation (when persistence does occur). A problem arises with these behavioral definitions when considering the potential for persistent memory of extinction. Recent studies have found that epigenetic modulation of memory processes leads to surprisingly robust and persistent extinction. We discuss evidence from behavioral epigenetic approaches that forces a re-evaluation of widely used behavioral definitions of extinction and reconsolidation. PMID- 23354386 TI - Memory, navigation and theta rhythm in the hippocampal-entorhinal system. AB - Theories on the functions of the hippocampal system are based largely on two fundamental discoveries: the amnestic consequences of removing the hippocampus and associated structures in the famous patient H.M. and the observation that spiking activity of hippocampal neurons is associated with the spatial position of the rat. In the footsteps of these discoveries, many attempts were made to reconcile these seemingly disparate functions. Here we propose that mechanisms of memory and planning have evolved from mechanisms of navigation in the physical world and hypothesize that the neuronal algorithms underlying navigation in real and mental space are fundamentally the same. We review experimental data in support of this hypothesis and discuss how specific firing patterns and oscillatory dynamics in the entorhinal cortex and hippocampus can support both navigation and memory. PMID- 23354387 TI - Sleep-dependent memory triage: evolving generalization through selective processing. AB - The brain does not retain all the information it encodes in a day. Much is forgotten, and of those memories retained, their subsequent evolution can follow any of a number of pathways. Emerging data makes clear that sleep is a compelling candidate for performing many of these operations. But how does the sleeping brain know which information to preserve and which to forget? What should sleep do with that information it chooses to keep? For information that is retained, sleep can integrate it into existing memory networks, look for common patterns and distill overarching rules, or simply stabilize and strengthen the memory exactly as it was learned. We suggest such 'memory triage' lies at the heart of a sleep-dependent memory processing system that selects new information, in a discriminatory manner, and assimilates it into the brain's vast armamentarium of evolving knowledge, helping guide each organism through its own, unique life. PMID- 23354390 TI - From G-quartets to G-ribbon gel by concentration and sonication control. AB - Two guanosine analogues have been designed and synthesized by connecting one (1) or three adamantane branches (2). The compound containing a single adamantane branch formed G-quartets in acetonitrile solution, and was then transformed into a G-ribbon gel at concentrations higher than the critical gelation concentration. In contrast, the compound with three adamantane branches precipitated after a heating-cooling process. By means of circular dichroism and UV/visible spectra, NMR, SEM, and structural studies, the mechanism of the formation of the G quartets and G-ribbon gel, as well as the difference in the self-assembly modes of the two compounds, have been fully elucidated. Compound 1 firstly self assembled into G-quartets in solutions in the concentration range 5.0 * 10(-4) to 1.0 * 10(-2) M, and these G-quartets were transformed into a G-ribbon on further increasing the concentration. Gelation occurred when the G-ribbon self-assembled into a hexagonal columnar structure with the help of intermolecular hydrogen bonding and hydrophobic interactions. This gel was sensitive to sonication and underwent a morphology change from a columnar structure to a flower-like structure composed of flakes. In contrast, due to steric hindrance, compound 2 only assembled into a spherical structure based on hydrophobic interactions. PMID- 23354388 TI - Implications of memory modulation for post-traumatic stress and fear disorders. AB - Post-traumatic stress disorder, panic disorder and phobia manifest in ways that are consistent with an uncontrollable state of fear. Their development involves heredity, previous sensitizing experiences, association of aversive events with previous neutral stimuli, and inability to inhibit or extinguish fear after it is chronic and disabling. We highlight recent progress in fear learning and memory, differential susceptibility to disorders of fear, and how these findings are being applied to the understanding, treatment and possible prevention of fear disorders. Promising advances are being translated from basic science to the clinic, including approaches to distinguish risk versus resilience before trauma exposure, methods to interfere with fear development during memory consolidation after a trauma, and techniques to inhibit fear reconsolidation and to enhance extinction of chronic fear. It is hoped that this new knowledge will translate to more successful, neuroscientifically informed and rationally designed approaches to disorders of fear regulation. PMID- 23354389 TI - Human HDL containing a novel apoC-I isoform induces smooth muscle cell apoptosis. AB - AIMS: We discovered that some adults with coronary heart disease (CHD) have a high density lipoprotein (HDL) subclass which induces human aortic smooth muscle cell (ASMC) apoptosis in vitro. The purpose of this investigation was to determine what properties differentiate apoptotic and non-apoptotic HDL subclasses in adults with and without CHD. METHODS AND RESULTS: Density gradient ultracentrifugation was used to measure the particle density distribution and to isolate two HDL subclass fractions, HDL2 and HDL3, from 21 individuals, including 12 without CHD. The HDL fractions were incubated with ASMCs for 24 h; apoptosis was quantitated relative to C2-ceramide and tumour necrosis factor-alpha (TNF alpha). The observed effect of some HDL subclasses on apoptosis was ~6-fold greater than TNF-alpha and ~16-fold greater than the cell medium. We observed that apoptotic HDL was (i) predominately associated with the HDL2 subclass; (ii) almost exclusively found in individuals with a higher apoC-I serum level and a novel, higher molecular weight isoform of apoC-I; and (iii) more common in adults with CHD, the majority of whom had high (>60 mg/dL) HDL-C levels. CONCLUSIONS: Some HDL subclasses enriched in a novel isoform of apoC-I induce extensive ASMC apoptosis in vitro. Individuals with this apoptotic HDL phenotype generally have higher apoC-I and HDL-C levels consistent with an inhibitory effect of apoC-I on cholesteryl ester transfer protein activity. The association of this phenotype with processes that can promote plaque rupture may explain a source of CHD risk not accounted for by the classical risk factors. PMID- 23354391 TI - Safety evaluation of daidzein in laying hens: part II. Effects on calcium-related metabolism. AB - Daidzein, an estrogen-like product, has become increasingly popular as a dietary supplement, particularly for postpeak-estrus animals seeking a safe natural alternative to play a role of estrogen. However, there is little available safety data of it for raisers and consumers. A subchronic laying hensafety study has been conducted to examine if the high-dose daidzein could affect calcium-related metabolism (eggshell quality and bone mineralization). Seven hundred and sixty eight 56-week-old Hyline Brown were randomly assigned to 4 groups with 8 replicates of 24 birds each (192 laying hensper group) and 3weeks later fed diets supplemented with 0(control), 10, 50 and 100mg of daidzein/kg for 12week. Eggshell thickness, eggshell percentage, eggshell strength, eggshell Ca concentration was increased linearly with increasing dietary daidzein supplementation (P=0.001, P=0.007, P=0.002 and P=0.000, respectively). Serum Ca increased linearly with increasing dietarydaidzein supplementation (P=0.042), and serum P showed a significant quadratic response to dietarydaidzein supplementation (P=0.036). Bone ash and bone Ca were significantly influenced by dietarydaidzein supplementation (P<0.05). These findings indicate that daidzein hold no observed adverse effect on calcium metabolism, but also a safe and effective food additive for calcium metabolism in animals and humans. PMID- 23354392 TI - Prunin- and hesperetin glucoside-alkyl (C4-C18) esters interaction with Jurkat cells plasma membrane: consequences on membrane physical properties and antioxidant capacity. AB - Prunin (P)- and hesperetin glucoside (HG)-alkyl esters are lipid-soluble compounds with antimicrobial and antioxidant capacities in vitro. The effects of P- and HG-alkyl (C4-C18) esters (0.1-100MUM) on human leukemia T (Jurkat) cells viability and plasma membrane fluidity were evaluated. After 1h of exposure, cell viability was not affected in the range 0.1-10MUM. The decrease of cell viability found at 100MUM concentration depended on the length of the alkyl chain and reached a maximum with C6-C12 derivatives. At this concentration, cell hyperpolarization and shrinkage were also observed. Cell plasma membrane fluidity was not affected, regardless the depths of the membrane level evaluated, but mild changes in plasma membrane hydration were found. Esterification did not affect the antioxidant capacity of P and HG (0.1-10MUM) against 1mM H2O2. When exposed to 1mM AAPH, P-alkyl esters retained P antioxidant capacity, but HG-derivatives acted as pro-oxidants. Together, present experimental evidences suggest that short term exposures to 0.1-10MUM concentrations of P- and HG-alkyl (C4-C18) esters can be considered safe for cultured human cells, and further studies are required to investigate their long term effects, as well their safety for human consumption. PMID- 23354393 TI - Bioactive microconstituents and antioxidant properties of wild edible mushrooms from the island of Lesvos, Greece. AB - Crude composition, fatty acids, sterols, total phenolic content (TPC), individual polyphenols and terpenic acids were determined in five wild edible mushrooms species (Lactarius deliciosus, Lactarius sanguifluus, Lactarius semisanguifluus, Russula delica, Suillus bellinii) from Lesvos Island, Greece. In addition, the DPPH scavenging capacity, the ferric ion reducing power (FRAP) and the ferrous ion chelating activity of mushroom methanolic extracts were assessed. Among sterols, ergosterol predominated at concentrations 9.2-18.0mg/100g fw. Total phenolic content of mushroom extracts ranged from 6.0 to 20.8mg GAE/100g fw. Up to 19 simple polyphenols were determined in mushrooms extracts, the more abundant being p-OH-benzoic acid, p-OH-phenylacetic acid, o-coumaric acid, ferulic acid and chrysin. In addition, the triterpenic acids oleanolic and ursolic were detected for the first time in mushrooms. All species exerted antioxidant activity and ferrous ion chelating capacity. Principal component analysis revealed good correlations between TPC, DPPH and FRAP but not with metal chelating activity. It seems that mushrooms polyphenols exert antiradical and reducing activities, but they are not strong metal chelators, the observed chelating ability being probably due to other classes of compounds. To our knowledge, this is the first report on the bioactive microconstituents and antioxidant activity of wild Greek edible mushrooms. PMID- 23354394 TI - A 60day double-blind, placebo-controlled safety study involving Citrus aurantium (bitter orange) extract. AB - Bitter orange (Citrus aurantium) extract and its primary protoalkaloid p synephrine are widely consumed in dietary supplements for weight management and sports performance. p-Synephrine is also present in foods derived from a variety of Citrus species. Bitter orange extract is commonly used in combination with multiple herbal ingredients. Most clinical studies conducted on bitter orange extract alone have involved single doses. The purpose of this study was to assess the safety of bitter orange extract (approximately 49mg p-synephrine) alone or in combination with naringin and hesperidin twice daily given to 25 healthy subjects per group for 60days in a double-blinded, placebo-controlled protocol. No significant changes occurred in systolic or diastolic blood pressures, blood chemistries or blood cell counts in control or p-synephrine treated groups. Small, clinically insignificant differences in heart rates were observed between the p-synephrine plus naringin and hesperidin group and the p-synephrine alone as well as the placebo group. No adverse effects were reported in the three groups. Bitter orange extract and p-synephrine appear to be without adverse effects at a dose of up to 98mg daily for 60days based on the parameters measured. PMID- 23354395 TI - Amino acids as metabolic substrates during cardiac ischemia. AB - The heart is well known as a metabolic omnivore in that it is capable of consuming fatty acids, glucose, ketone bodies, pyruvate, lactate, amino acids and even its own constituent proteins, in order of decreasing preference. The energy from these substrates supports not only mechanical contraction, but also the various transmembrane pumps and transporters required for ionic homeostasis, electrical activity, metabolism and catabolism. Cardiac ischemia - for example, due to compromise of the coronary vasculature or end-stage heart failure - will alter both electrical and metabolic activity. While the effects of myocardial ischemia on electrical propagation and stability have been studied in depth, the effects of ischemia on metabolic substrate preference has not been fully appreciated: oxygen deprivation during ischemia will significantly alter the relative ability of the heart to utilize each of these substrates. Although changes in cardiac metabolism are understood to be an underlying component in almost all cardiac myopathies, the potential contribution of amino acids in maintaining cardiac electrical conductance and stability during ischemia is underappreciated. Despite clear evidence that amino acids exert cardioprotective effects in ischemia and other cardiac disorders, their role in the metabolism of the ischemic heart has yet to be fully elucidated. This review synthesizes the current literature of the metabolic contribution of amino acids during ischemia by analyzing relevant historical and recent research. PMID- 23354396 TI - Evaluation of healing wound and genotoxicity potentials from extracts hydroalcoholic of Plantago major and Siparuna guianensis. AB - Despite the large use of the Plantago major and Siparuna guianensis in traditional medicine, there are no studies demonstrating the effectiveness from extracts of these plants in the healing process by the present methodology. This study reported the effects and toxicity of the P. major and S. guianensis extracts in the wound healing compared with a commercial product used in Brazil by macroscopic and microscopic analysis. Following injury in cervical dorsal area of the mice, the extract from P. major and S. guianensis and ointment was applied after an injury in cervical dorsal area of the mice. Wound healing rates were calculated at 4, 9, 15 and 21 d after the wounding, and tissues were obtained on the ninth day for histological analysis. Moreover, mutagenic assay of extracts was performed. Mutagenicity studies carried out with plant extracts showed not mutagenic with or without metabolic activations. Reduction of the wound area occurred earlier in mice treated with P. major and control treatment. On the 15th day, the complete wound closure occurred in P. major-treated wounds. Throughout ointment and S. guianensis treatment it was not observed the wound closured. Microscopic analyses of the wound, on the ninth day, showed the more efficient formation of the neoepithelium and skin appendages in animals treated with S. guianensis and P. major, while ointment treatment presented no re epithelialization and absent skin appendages in wound. Thus, P. major extract showed good effects on wound healing processes rendering it a promising candidate for the treatment of wounds what also justified its traditional usage in wound treatment. PMID- 23354398 TI - Cross-talk between inflammation and angiotensin II: studies based on direct transfection of cardiomyocytes with AT1R and AT2R cDNA. AB - Ischemic myocardium exhibits inflammation, local angiotensin II (Ang II) generation and up-regulation of LOX-1, a lectin-like ox-LDL receptor. To define the inter-active roles of Ang II and inflammation in furthering tissue injury, cultured HL-1 cardiomyocytes were treated with Ang II. Ang II treatment up regulated the expression of Ang II type 1 (AT1R) and type 2 (AT2R) receptors as well as LOX-1. Ang II also activated p44/42MAPK, p38MAPK, c-Jun and NF-kappaB, and increased the expression of inflammation-related genes (interleukins-6, interleukins-10, tumor necrosis factor-alpha, intercellular adhesion molecule-1). To study how inflammation per se might affect expression of Ang II receptors and LOX-1, cultured, cardiomyocytes were treated with lipopolysaccharide (LPS). Like Ang II, LPS increased the expression of AT1R, AT2R and LOX-1. LPS also activated mitogen-acticated protein kinase (MAPKs), c-Jun and NF-kappaB, and pro inflammatory genes. The selective inhibitors of MAPKs, c-Jun and NF-kappaB each blocked the transcription of LOX-1 and pro-inflammatory genes in response to Ang II as well as LPS. These observations suggested a positive feedback between Ang II and inflammation. To delineate the role of AT1R and AT2R in LOX-1 expression, another set of cardiomyocytes were transfected with AT1R or AT2R cDNA. Forced over-expression of AT1R resulted in activation of MAPKs, c-Jun and NF-kappaB, up regulation of inflammatory genes and LOX-1; on the other hand forced AT2R over expression induced up-regulation of pro-apoptotic signals (pro-IL-1beta and IL 1beta), and decreased LOX-1 expression. These studies show that both Ang II and inflammation mediator LPS up-regulate AT1R, AT2R and LOX-1 expression. Up regulation of AT1R promotes inflammation and LOX-1 expression, whereas up regulation of AT2R promotes apoptosis signals and decreases LOX-1 expression. PMID- 23354397 TI - A chemoprotective fish oil/pectin diet enhances apoptosis via Bcl-2 promoter methylation in rat azoxymethane-induced carcinomas. AB - We have demonstrated that diets containing fish oil and pectin (FO/P) reduce colon tumor incidence relative to control (corn oil and cellulose [CO/C]) in part by inducing apoptosis of DNA-damaged colon cells. Relative to FO/P, CO/C promotes colonocyte expression of the antiapoptotic modulator, Bcl-2, and Bcl-2 promoter methylation is altered in colon cancer. To determine if FO/P, compared with CO/C, limits Bcl-2 expression by enhancing promoter methylation in colon tumors, we examined Bcl-2 promoter methylation, mRNA levels, colonocyte apoptosis and colon tumor incidence in azoxymethane (AOM)-injected rats. Rats were provided diets containing FO/P or CO/C, and were terminated 16 and 34 weeks after AOM injection. DNA isolated from paraformaldehyde-fixed colon tumors and uninvolved tissue was bisulfite modified and amplified by quantitative reverese transcriptase polymerase chain reaction to assess DNA methylation in Bcl-2 cytosine-guanosine islands. FO/P increased Bcl-2 promoter methylation (P = 0.009) in tumor tissues and colonocyte apoptosis (P = 0.020) relative to CO/C. An inverse correlation between Bcl-2 DNA methylation and Bcl-2 mRNA levels was observed in the tumors. We conclude that dietary FO/P promotes apoptosis in part by enhancing Bcl-2 promoter methylation. These Bcl-2 promoter methylation responses, measured in vivo, contribute to our understanding of the mechanisms involved in chemoprevention of colon cancer by diets containing FO/P. PMID- 23354400 TI - Differentially expressed genes and pathways induced by organophosphates in human neuroblastoma cells. AB - Organophosphates (OPs) are toxic chemicals commonly used as pesticides and herbicides. Some OPs are highly toxic to humans and have been used in warfare and terrorist attacks. In order to elucidate the molecular mechanisms of injury caused by OPs, the differentially expressed genes were analyzed in human SK-N-SH neuroblastoma cells induced by three OPs. The SK-N-SH cells were treated with one of the three OPs, chlorpyrifos, dichlorvos or methamidophos at LC20 (high-dose), the concentration causing 20% cell death, as well as 1/20 of LC20 (low-dose), a sub-lethal concentration with no detectable cell death, for 24 h. The genome-wide gene changes were identified by Agilent Microarray System, and analyzed by microarray analysis tools. The analysis revealed neuroblastoma cells treated with the high doses of all three OPs markedly activated cell apoptosis and inhibited cell growth and proliferation genes, which would most likely lead to the process of cell death. Interestingly, the analysis also revealed significant decrease in expressions of many genes in a specific spliceosome pathway in cells treated with the low doses of all three different OPs. The change of spliceosome pathway may represent an important mechanism of injury in neuronal cells exposed to low doses of various OPs. In addition to unraveling a potentially different form of OP pathogenesis, this finding could provide a new diagnostic marker in assessing OP associated injury in cells or tissues. In addition, these results could also contribute to the development of new prevention and/or therapeutic regimens against OP toxicity. PMID- 23354401 TI - Effects of low temperatures on proliferation-related signaling pathways in the hippocampus after traumatic brain injury. AB - To evaluate the influence of low temperatures on the proliferation of neural stem cells (NSCs) and the regulation of their signaling pathways after brain trauma, we examined changes in the expression levels of specific miRNAs and their target genes. We also evaluated NSC proliferation in the hippocampus after brain trauma under low-temperature conditions. We found that the expression profile of miRNAs in the hippocampus after trauma changed at both normal and low temperatures, and the expression of miR-34a decreased significantly lower in rats exposed to low temperatures. There was significant proliferation of endogenous NSCs in the hippocampus after brain trauma at both temperatures, but NSC proliferation was slower at low temperatures. In addition, the expression of Notch1 significantly increased in the hippocampus after brain trauma at both temperatures. However, at low temperatures, the degree of up-regulation of Notch signaling molecules was significantly lower. We conclude that low-temperature environments can inhibit the proliferation of endogenous NSCs in the hippocampus, possibly by alleviating the effects of miR-34a down-regulation and Notch signaling up-regulation induced by traumatic brain injury. PMID- 23354399 TI - Soluble epoxide hydrolase inhibition and peroxisome proliferator activated receptor gamma agonist improve vascular function and decrease renal injury in hypertensive obese rats. AB - Cardiometabolic syndrome occurs with obesity and consists of pathophysiological factors that increase the risk for cardiovascular events. Soluble epoxide hydrolase inhibition (sEHi) is a novel therapeutic approach that exerts renal and cardiovascular protection. Although sEHi as a therapeutic approach is promising, it could be more effective for the treatment of cardiometabolic syndrome when combined with peroxisome proliferator activated receptor gamma (PPARgamma) agonists. We hypothesized that the PPARgamma agonist, rosiglitazone in combination with a sEHi (tAUCB) will provide synergistic actions to decrease blood pressure, improve vascular function, decrease inflammation, and prevent renal damage in spontaneously hypertensive obese rats (SHROB). SHROB were treated with rosiglitazone, tAUCB or the combination of tAUCB and rosiglitazone for four weeks and compared with spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Blood pressure increased in SHROB (164 +/- 7 mmHg) and decreased 10 mmHg when treated with rosiglitazone, tAUCB, or tAUCB and rosiglitazone. Mesenteric artery dilation to the K(ATP) channel opener pinacidil was attenuated in SHROB (E(Max) = 77 +/- 7%), compared with WKY (E(Max) = 115 +/- 19) and SHR (E(Max) = 93 +/- 12%). Vasodilation to pinacidil was improved by rosiglitazone (E(Max) = 92 +/- 14%) but not tAUCB. Renal macrophage infiltration increased in SHROB and significantly decreased with rosiglitazone or tAUCB and rosiglitazone treatment. Albuminuria was increased in SHROB (90 +/- 20 mg/d) and was significantly decreased by the combination of tAUCB and rosiglitazone (37 +/- 9 mg/d). Glomerular injury in SHROB was also significantly decreased by tAUCB and rosiglitazone. These results indicate that even though sEHi or PPARgamma agonist have benefits when used individually, the combination is more beneficial for the multidisease features in cardiometabolic syndrome. PMID- 23354402 TI - Apigenin-induced apoptosis in A375 and A549 cells through selective action and dysfunction of mitochondria. AB - We isolated apigenin (5,7,4'-trihydroxy flavone) from ethanolic extract of Lycopodium clavatum (LC) used as a homeopathic mother tincture for treatment of various diseases. We assessed the anticancer potentials of the compound using human malignant melanoma cell line A375 and a lung carcinoma cell line A549 and focussed on its putative molecular mechanism of action on apoptosis induction. We examined the cytotoxicity of apigenin in both cancer cells and normal peripheral blood mononuclear cells (PBMC). A375 cells were more prone to apigenin-induced apoptosis, as compared with A549 cells after 24 h of treatment, while PBMC showed little or no cytotoxicity to apigenin. We also evaluated the effects of apigenin on interaction with DNA by comparative analysis of circular dichroism spectral data and melting temperature profiles (Tm) of calf thymus DNA (CT-DNA) treated with or without apigenin. Reactive oxygen species (ROS) accumulation in mitochondria, super-oxide dismutase and total thiol group (GSH) activities were also analyzed. The apoptotic process involved mitochondrial pathway associated with apigenin-DNA interaction, DNA fragmentation, ROS accumulation, cytochrome c (cyt c) release and mitochondrial transmembrane potential depolarization, Bax, caspase 3, 9, PARP, up-regulation, Bcl-2 down-regulation and down-regulation of cyt c in the mitochondrial fraction. Results of mitochondrial inner membrane swelling measurements, intracellular ADP/ATP ratio and ATPase activity showed that in A549 cells, apigenin did not appear to directly target the mitochondrial oxidative phosphorylation system but rather acted at an upstream step to activate the mitochondrial apoptotic pathway. However, apigenin could directly target and impair mitochondrial function in A375 cells by breaking down their oxidative phosphorylation system. Collectively, these results suggest that apigenin exhibits anticancer potential in A375 and A549 cells that may be mediated through DNA interaction, damage and mitochondrial dysfunction either by direct or indirect action on mitochondrial oxidative phosphorylation system. PMID- 23354403 TI - Evaluation of the pulmonary effects of short-term nose-only cigarette smoke exposure in mice. AB - Much is known about the chronic effects of cigarette smoke (CS) on lung function and inflammation and development of chronic obstructive pulmonary disease. However, the underlying pathophysiological mechanisms related to the short-term exposure to CS are not fully understood. Here, we assessed the effect of CS generated by nine consecutive cigarettes per day for four days in a nose-only exposure system on airway resistance measured using forced oscillation technique, lung inflammation and oxidative stress in BALB/c mice. Control mice were exposed to air. Mice exposed to CS showed a significant increase of neutrophils and lymphocytes numbers in bronchoalveolar lavage (BAL). The total protein and endothelin levels in BAL fluid were significantly augmented suggesting an increase of alveolar-capillary barrier permeability. Similarly, airway resistance was significantly increased in the CS group compared with controls. Furthermore, reactive oxygen species and lipid peroxidation levels in lung tissue were significantly increased. The antioxidant activities of reduced glutathione, glutathione S transferase and superoxide dismutase were all significantly increased following CS exposure, indicating that CS could trigger adaptive responses that counterbalance the potentially damaging activity of oxygen radicals induced by CS exposure. In conclusion, our data indicate that short-term nose-only exposure to CS causes lung inflammation and increase of airway resistance mediated at least partly through the oxidative stress. PMID- 23354404 TI - New method for isolation of both kidneys for studies of vascular reactivity in rats. AB - The isolated perfused rat kidney technique is one of the most widely used methods in renal research. It has proven useful to investigate biochemical, physiological, pharmacological and pathophysiological aspects of renal function, allowing variables to be changed in a controlled manner and eliminating systemic influences. This study was designed to test a new surgical procedure to isolate both kidneys for their utilization in this technique, mainly as a vascular preparation. The viability of the resulting preparations was compared with those obtained by the classical method, analyzing the responsiveness to the vasoconstrictor phenylephrine and to the endothelium-dependent vasodilator acetylcholine. Vascular reactivity was evaluated under normal conditions and in endothelium-denuded preparations. The dose response curves to phenylephrine and to acetylcholine were similar in the three experimental groups, regardless of the procedure used for kidney isolation, in both endothelium-intact and endothelium denuded preparations. We give a step-by-step description of the isolation method and key points for the success of the technique. In conclusion, the surgical procedure proposed in this paper reduces the number of animals required by half and hence reduces the cost of the experiments. This novel procedure is of special interest for acute experiments to test new vasoactive drugs and for analysis of the action mechanisms of these drugs. It could also be used in chronic studies or in genetically modified animals when different experimental protocols are performed on the left and right kidneys and to improve the accuracy of the results by analyzing cases in duplicate. PMID- 23354405 TI - Biomarkers assessing warm ischemic injury using an isolated porcine kidney hemoreperfusion model. AB - Prolonged warm ischemia (WI) occurring in marginal kidney donors together with reperfusion injury determines allograft survival, in which apoptosis and inflammation play crucial roles. There is no single valid biomarker, so far, to assess the degree of kidney donor injury. To define new biomarkers for detecting initial donor ischemic injury, caspase-3, caspase-7, apoptosis, inflammation, HSP70 and renal histological changes were examined in porcine kidneys subjected to 7- 15- 25- or 40-min WI, two-hour cold storage and six-hour hemoreperfusion. Caspase-3 activity was gradually increased by prolonged reperfusion, with a decrease trend against WI time. This result was verified by raised 17 kDa active caspase-3 in postreperfusion kidneys, with elevated 12 kDa active caspase-3 and lowered precursor at seven-minute WI. Active caspase-7 was also doubled by reperfusion with decreased precursor at seven-minute WI, but declined against prolonged WI. Apoptotic cells in tubular and interstitial areas were greatly increased by reperfusion at seven-minute WI, but decreased against prolonged WI. In addition, myeloperoxidase (MPO)+ cells were dramatically increased by reperfusion and presented as a bell-shape against WI time, while HSP70 was significantly increased at 7-min WI, but decreased at 40-min WI after reperfusion. In postreperfusion kidneys, tubular dilation and cell shedding were observed at 7- and 15-min WI, while tubular vacuolation and cell debris were found in tubular lumens at longer WI times. At 40-min WI, early nuclear pyknosis, tubular epithelia detachment and peri-tubular capillary dilation were detected. Furthermore, caspase-3, caspase-7, apoptosis, but not MPO+ cells or HSP70, were correlated with renal function. In conclusion, caspase-3, caspase-7 and apoptosis appear to be better biomarkers than MPO+ cells or HSP70 for assessing warm ischemic injury in donor kidneys. Hemoreperfusion activates caspase-3 and caspase 7, promotes apoptosis of damaged cells in kidneys only with limited WI, which might be beneficial to renal structural re-modeling and functional recovery. PMID- 23354406 TI - Increased Th1 immune response in SERPINB3 transgenic mice during acute liver failure. AB - Acute liver failure (ALF) is characterized by severe neurological complications, known as acute hepatic encephalopathy, where brain ammonia and inflammatory processes play a dominant role. In experimental models of acute liver failure SERPINB3 was found significantly increased in microglia, the intrinsic immune cells of the central nervous system. The aim of the present study was to investigate the extent of brain tissue damage and the inflammatory milieu in experimental acute liver failure using a SERPINB3-transgenic mouse model. C57BL/6J wild-type and transgenic mice were inoculated with acetaminophen or phosphate-buffered saline and sacrificed 20 h postinjection. Proliferation and apoptotic activity were analyzed in brain tissue by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique. The expression of cytokines was analysed in brain and liver tissue by real time polymerase chain reaction and in the corresponding serum samples using a Bio-Plex system. Acetaminophen induced a significantly lower body temperature and shorter survival in transgenic than in wild-type mice, despite liver function was similar in both groups. The brain of transgenic mice, expressing SERPINB3 positivity in microglia, showed increased glial cell number, associated to significant lower apoptotic death events, compared with wild-type mice. In mice injected with acetaminophen, remarkably higher values of cytokines mRNA were observed in the liver of both groups, with a trend toward higher values in transgenic animals. In brain tissue similar increase of tumor necrosis factor-alpha was detected in transgenic and wild-type mice, while IL-10 mRNA increased only in the wild-type group. A remarkable increase of circulating Th1 cytokines was detected in serum of transgenic mice, while in the wild-type group they remained rather unchanged. These figures were associated with lower levels of granulocyte macropage colony stimulating factor, despite similar increase of IL-10 values in both groups. In conclusion, in acute liver failure SERPINB3 determines an enhanced inflammatory background, mainly mediated by higher levels of Th1 proinflammatory cytokines. PMID- 23354407 TI - Rehabilitative exercise in a rat model of doxorubicin cardiotoxicity. AB - The use of exercise to minimize doxorubicin (DOX)-induced cardiotoxicity is gaining attention. However, very few clinically relevant reports exist investigating the effects of exercise performed during and following DOX treatments. The purpose of this study, therefore, was to examine the effects of voluntary wheel running during and following DOX treatment using two models of late-onset DOX cardiotoxicity in the rat. Female Sprague-Dawley rats received either DOX or saline injections using one of two separate treatment regimens. These regimens involved either daily or weekly DOX injections with cumulative doses for both protocols totaling 15 mg/kg. Daily DOX injections were 1 mg/kg and lasted for 15 consecutive days while weekly DOX injections were 2.5 mg/kg and lasted for six consecutive weeks with control animals receiving matched saline injection regimens. Immediately following the initial DOX/saline injection, animals were randomly housed in cages with voluntary running wheels or standard rat cages throughout DOX/saline treatments and continued until reaching 10 weeks. Cardiac function was then assessed using echocardiography and an isolated working heart model, and myosin heavy chain (MHC) isoform distribution was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. When compared wth controls, daily DOX treatment resulted in reduced running wheel distances at weeks 2-10 (P < 0.05), and weekly DOX treatment resulted in reduced running wheel distances at weeks 2, 6 and 10 (P < 0.05). Nonetheless, wheel running during and following daily and weekly DOX dosing protected against DOX-induced cardiotoxicity by preserving maximal mitral and aortic blood flow velocities, left ventricular developed pressure and MHC isoform expression. In conclusion, the overall reduced volume of activity during and following daily and weekly DOX treatments attenuated DOX-induced cardiac dysfunction suggesting that low-volume endurance training may be an effective rehabilitative approach in minimizing DOX cardiotoxicity in cancer patients. PMID- 23354409 TI - [Immunonutrition in intensive care medicine]. AB - The review presents the concept of immunonutrition in enteral and parenteral nutrition of the critically ill. The present indications for supplementing immune enhancing and anti-inflammatory substances are summarized and discussed in accordance with the recent literature and guidelines. PMID- 23354410 TI - High diving metabolism results in a short aerobic dive limit for Steller sea lions (Eumetopias jubatus). AB - The diving capacity of marine mammals is typically defined by the aerobic dive limit (ADL) which, in lieu of direct measurements, can be calculated (cADL) from total body oxygen stores (TBO) and diving metabolic rate (DMR). To estimate cADL, we measured blood oxygen stores, and combined this with diving oxygen consumption rates (VO2) recorded from 4 trained Steller sea lions diving in the open ocean to depths of 10 or 40 m. We also examined the effect of diving exercise on O2 stores by comparing blood O2 stores of our diving animals to non-diving individuals at an aquarium. Mass-specific blood volume of the non-diving individuals was higher in the winter than in summer, but there was no overall difference in blood O2 stores between the diving and non-diving groups. Estimated TBO (35.9 ml O2 kg( 1)) was slightly lower than previously reported for Steller sea lions and other Otariids. Calculated ADL was 3.0 min (based on an average DMR of 2.24 L O2 min( 1)) and was significantly shorter than the average 4.4 min dives our study animals performed when making single long dives-but was similar to the times recorded during diving bouts (a series of 4 dives followed by a recovery period on the surface), as well as the dive times of wild animals. Our study is the first to estimate cADL based on direct measures of VO2 and blood oxygen stores for an Otariid and indicates they have a much shorter ADL than previously thought. PMID- 23354412 TI - Preparation of 3D nanoporous copper-supported cuprous oxide for high-performance lithium ion battery anodes. AB - Three-dimensional (3D) nanoporous architectures can provide efficient and rapid pathways for Li-ion and electron transport as well as short solid-state diffusion lengths in lithium ion batteries (LIBs). In this work, 3D nanoporous copper supported cuprous oxide was successfully fabricated by low-cost selective etching of an electron-beam melted Cu(50)Al(50) alloy and subsequent in situ thermal oxidation. The architecture was used as an anode in lithium ion batteries. In the first cycle, the sample delivered an extremely high lithium storage capacity of about 2.35 mA h cm(-2). A high reversible capacity of 1.45 mA h cm(-2) was achieved after 120 cycles. This work develops a promising approach to building reliable 3D nanostructured electrodes for high-performance lithium ion batteries. PMID- 23354411 TI - Regulation of a truncated isoform of AMP-activated protein kinase alpha (AMPKalpha) in response to hypoxia in the muscle of Pacific oyster Crassostrea gigas. AB - AMP-activated protein kinase alpha (AMPKalpha) is a key regulator of energy balance in many model species during hypoxia. In a marine bivalve, the Pacific oyster Crassostrea gigas, we analyzed the protein content of adductor muscle in response to hypoxia during 6 h. In both smooth and striated muscles, the amount of full-length AMP-activated protein kinase alpha (AMPKalpha) remained unchanged during hypoxia. However, hypoxia induced a rapid and muscle-specific response concerning truncated isoforms of AMPKalpha. In the smooth muscle, a truncated isoform of AMPKalpha was increased from 1 to 6 h of hypoxia, and was linked with accumulation of AKT kinase, a key enzyme of the insulin signaling pathway which controls intracellular glucose metabolism. In this muscle, aerobic metabolism was maintained over the 6 h of hypoxia, as mitochondrial citrate synthase activity remained constant. In contrast, in striated muscle, hypoxia did not induce any significant modification of neither truncated AMPKalpha nor AKT protein content, and citrate synthase activity was altered after 6 h of hypoxia. Together, our results demonstrate that hypoxia response is specific to muscle type in Pacific oyster, and that truncated AMPKalpha and AKT proteins might be involved in maintaining aerobic metabolism in smooth muscle. Such regulation might occur in vivo during tidal intervals that cause up to 6 h of hypoxia. PMID- 23354413 TI - Rictor encounters RhoGDI2: the second pilot is taking a lead. AB - Rictor's role in cell migration has been first indicated in the original chemotaxis studies in Dictyostelium and more recent studies reported that rictor is required for migration of cancer cells. How rictor promotes cell migration remains poorly characterized. Based on our proteomics study we have identified a novel functional role of rictor in regulation of cell migration. Here, we discuss our recent finding that rictor by suppressing RhoGDI2 maintains activity of the Rac1/cdc42 GTPases and promotes cell migration. Our finding outlines a critical role of rictor in the regulation of RhoGDI2 activity. This study opens new avenues in the investigation of cancer metastasis by analyzing the rictor dependent post-translational modification of RhoGDI2. PMID- 23354414 TI - Influence of dietary nitrate supplementation on human skeletal muscle metabolism and force production during maximum voluntary contractions. AB - Dietary nitrate supplementation, which enhances nitric oxide (NO) bioavailability, has previously been shown to contribute to improved exercise performance by reducing both oxygen cost and energy expenditure. In contrast, previous studies have indicated that NO can lower force production in vitro. To examine the role of dietary nitrates in regulating force generation under normal physiological conditions, we undertook an extended nitrate supplementation regime and determined force output and energy cost with a repeated isometric maximum voluntary contraction (MVC) protocol. In a double-blind, randomized, crossover design, eight participants received 0.5 l/day of nitrate-rich (BR) or nitrate depleted (PL) beetroot juice for 15 days and completed an exercise protocol consisting of 50 MVCs at 2.5 h, 5 days and 15 days after the beginning of the supplementation period. No significant reduction in force output was determined for BR relative to PL for the peak contraction, the mean or the end force, and no significant time effect was found over the course of the supplementation period. There was a reduction in the mean PCr cost of exercise averaged over the BR supplementation trials, but this did not reach statistical significance for end exercise (BR 15.10 +/- 4.14 mM, PL 17.10 +/- 5.34 mM, P = 0.06) or the mean throughout the protocol (BR 15.96 +/- 4.14 mM, PL 17.79 +/- 4.51 mM, P = 0.06). However, a significant reduction in PCr cost per unit force output was found for BR at end exercise (P = 0.04). These results indicate that, under normal physiological conditions, increased NO bioavailability is not associated with a reduction of force-generating capability in human skeletal muscle and confirm that nitrate supplementation reduces the PCr cost of force production. PMID- 23354416 TI - Right ventricular systolic pressure measurements in combination with harvest of lung and immune tissue samples in mice. AB - The function of the right heart is to pump blood through the lungs, thus linking right heart physiology and pulmonary vascular physiology. Inflammation is a common modifier of heart and lung function, by elaborating cellular infiltration, production of cytokines and growth factors, and by initiating remodeling processes. Compared to the left ventricle, the right ventricle is a low-pressure pump that operates in a relatively narrow zone of pressure changes. Increased pulmonary artery pressures are associated with increased pressure in the lung vascular bed and pulmonary hypertension. Pulmonary hypertension is often associated with inflammatory lung diseases, for example chronic obstructive pulmonary disease, or autoimmune diseases. Because pulmonary hypertension confers a bad prognosis for quality of life and life expectancy, much research is directed towards understanding the mechanisms that might be targets for pharmaceutical intervention. The main challenge for the development of effective management tools for pulmonary hypertension remains the complexity of the simultaneous understanding of molecular and cellular changes in the right heart, the lungs and the immune system. Here, we present a procedural workflow for the rapid and precise measurement of pressure changes in the right heart of mice and the simultaneous harvest of samples from heart, lungs and immune tissues. The method is based on the direct catheterization of the right ventricle via the jugular vein in close-chested mice, first developed in the late 1990s as surrogate measure of pressures in the pulmonary artery. The organized team approach facilitates a very rapid right heart catheterization technique. This makes it possible to perform the measurements in mice that spontaneously breathe room air. The organization of the work-flow in distinct work-areas reduces time delay and opens the possibility to simultaneously perform physiology experiments and harvest immune, heart and lung tissues. The procedural workflow outlined here can be adapted for a wide variety of laboratory settings and study designs, from small, targeted experiments, to large drug screening assays. The simultaneous acquisition of cardiac physiology data that can be expanded to include echocardiography and harvest of heart, lung and immune tissues reduces the number of animals needed to obtain data that move the scientific knowledge basis forward. The procedural workflow presented here also provides an ideal basis for gaining knowledge of the networks that link immune, lung and heart function. The same principles outlined here can be adapted to study other or additional organs as needed. PMID- 23354417 TI - S100A9 promotes the proliferation and invasion of HepG2 hepatocellular carcinoma cells via the activation of the MAPK signaling pathway. AB - The S100A9 protein, a member of the S100 protein family, is often upregulated in various types of cancer, including hepatocellular carcinoma (HCC). S100A9 acts as a danger signal when secreted to the extracellular space and is thought to play an important role during tumorigenesis. Despite this fact, little is known about the effects of S100A9 in the tumor microenvironment on HCC. Therefore, in this study, we investigated the effects of exogenous S100A9 on the proliferation and invasion of HepG2 HCC cells, as well as the molecular mechanisms underlying these effects. Our results demonstrated that exogenous S100A9 promoted the proliferation, clone formation and invasion of HepG2 cells in vitro, as shown by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltrazolium bromide (MTT), clone formation and transwell invasion assays, respectively, and also promoted tumor growth in vivo by tumorigenicity assays in nude mice. Furthermore, S100A9 increased the phosphorylation of p38 and ERK1/2 mitogen-activated protein kinases (MAPKs) in HepG2 cells. When the phosphorylation of p38 was inhibited by SB203580 (a p38 inhibitor), the S100A9-induced cell invasion was reversed; when the phosphorylation of ERK1/2 was inhibited by PD98059 (an ERK1/2 inhibitor), the S100A9-induced cell proliferation was reversed. These data suggest that the S100A9-induced proliferation and invasion of HepG2 cells are partly mediated by the activation of the MAPK signaling pathway. PMID- 23354415 TI - The Rac1 hypervariable region in targeting and signaling: a tail of many stories. AB - Cellular signaling by small GTPases is critically dependent on proper spatio temporal orchestration of activation and output. In addition to their core G (guanine nucleotide binding)-domain, small GTPases comprise a hypervariable region (HVR) and a lipid anchor that are generally accepted to control subcellullar localization. The HVR encodes in many small GTPases a polybasic region (PBR) that permits charge-mediated association to the inner leaflet of the plasma membrane or to intracellular organelles. Over the past 15-20 years, evidence has accumulated for specific protein-protein interactions, mediated by the HVR, that control both targeting and signaling specificity of small GTPases. Using the RhoGTPase Rac1 as a paradigm we here review a series of protein partners that require the Rac1 HVR for association and that control various aspects of localized Rac1 signaling. Some of these proteins represent Rac1 activators, whereas others mediate Rac1 inactivation and degradation and yet others potentiate Rac1 downstream signaling. Finally, evidence is discussed which shows that the HVR of Rac1 also contributes to effector interactions, co operating with the N-terminal effector domain. The complexity of localized Rac1 signaling, reviewed here, is most likely exemplary for many other small GTPases as well, representing a challenge to identify and define similar mechanisms controlling the specific signaling induced by small GTPases. PMID- 23354418 TI - At-home environment, out-of-home environment, snacks and sweetened beverages intake in preadolescence, early and mid-adolescence: the interplay between environment and self-regulation. AB - Obesity-related behaviors, such as intake of snacks and sweetened beverages (SSB), are assumed to result from the interplay between environmental factors and adolescents' ability to self-regulate their eating behaviors. The empirical evidence supporting this assumption is missing. This study investigated the relationships between perceptions of at-home and out-of-home food environment (including SSB accessibility, parental, and peers' social pressure to reduce intake of SSB), nutrition self-regulatory strategies (controlling temptations and suppression), and SSB intake. In particular, we hypothesized that these associations would differ across the stages of preadolescence, early and mid adolescence. Self-reported data were collected from 2,764 adolescents (10-17 years old; 49 % girls) from 24 schools in the Netherlands, Poland, Portugal, and the United Kingdom. Path analysis indicated that direct associations between peers' social influence and SSB intake increased with age. Direct negative associations between at-home and out-of-home accessibility and SSB intake as well as direct positive associations between parental pressure and intake become significantly weaker with age. Accessibility was related negatively to self regulation, whereas higher social pressure was associated with higher self regulation. The effects of the environmental factors were mediated by self regulation. Quantitative and qualitative differences in self-regulation were observed across the stages of adolescence. The associations between the use of self-regulatory strategies and lower SSB intake become significantly stronger with age. In preadolescence, SSB intake was regulated by means of strategies that aimed at direct actions toward tempting food. In contrast, early and mid adolescents controlled their SSB intake by means of a combination of self regulatory strategies focusing on direct actions toward tempting food and strategies focusing on changing the psychological meaning of tempting food. PMID- 23354419 TI - A longitudinal study of the reciprocal effects of alcohol use and interpersonal violence among Australian young people. AB - The impact of alcohol-related violence on individuals and society continues to receive attention from both media and policy makers. However, the longitudinal relationship between alcohol consumption and violence is unclear, with findings from prospective studies producing mixed results. The current study utilized Australian data from the International Youth Development Study to examine longitudinal relationships between alcohol consumption and severe interpersonal violence across the developmental periods of early adolescence to late adolescence/emerging adulthood. The full sample comprised 849 adolescents (53.8 % female) who had been followed up over a 5 year period, from Grade 7 secondary school (age 13) until Grade 11 secondary school (age 17). Cross-lagged path analysis was used to examine reciprocal relationships between alcohol consumption and interpersonal violence; analyses controlled for a range of covariates considered to be common risk factors for both behaviors. Alcohol use during early and mid adolescence was found to predict violence 2 years later, whereas a bi directional relationship between adolescent heavy episodic drinking and violence was observed. Some of these relationships were not significant when covariates such as family conflict and affiliation with antisocial and drug using friends were included in the models. These findings suggest that risk processes begin in late childhood or very early adolescence; efforts to reduce one problem behavior are likely to reduce the other. Further, the role that social and family contexts have in influencing the relationships between alcohol use and interpersonal violence should be considered in future research to better inform preventive efforts. PMID- 23354420 TI - Teen motherhood and pregnancy prototypes: the role of social context in changing young African American mothers' risk images and contraceptive expectations. AB - Despite the declining rate of teen pregnancies in the United States, academic and public health experts have expressed concern over the still relatively high rate of rapid repeat pregnancies among adolescents, particularly among minority youth. Using a sample of over 300 African American female adolescents, the current study used insights from the prototype/willingness model of adolescent risk behavior to explore this risk. More specifically, it assessed the relationship between entry into unwed motherhood during mid-to-late adolescence and changes in prototypes of unmarried pregnant teens. Further, it explored the extent to which these changing prototypes accounted for young mothers' later contraceptive expectations. We tested the possibility that social images were affected not only by personal experience (the birth of a child) but also by the family and community context in which this experience took place. The findings show that the early entrance into teen motherhood was associated with a shift toward more favorable prototypes of unwed pregnant teens, but that this was only the case for young mothers in disadvantaged contexts. Given this, prototype changes helped to explain the link between teen motherhood and contraceptive expectations only for those in disadvantaged contexts. We discuss these findings in terms of their practical and theoretical implications. PMID- 23354421 TI - Racial/ethnic differences in serum sex steroid hormone concentrations in US adolescent males. AB - OBJECTIVE: Contrary to the hypothesis that the racial/ethnic disparity in prostate cancer has a hormonal basis, we did not observe a difference in serum testosterone concentration between non-Hispanic black and white men in the Third National Health and Nutrition Examination Survey (NHANES III), although non Hispanic black men had a higher estradiol level. Unexpectedly, Mexican-American men had the highest testosterone level. Next, we evaluated whether the same patterns are observed during adolescence, the time of prostate maturation. METHODS: We measured serum testosterone, estradiol, and sex hormone-binding globulin (SHBG) by immunoassay in 134 males aged 12-19 in NHANES III. Mean concentrations were compared by race/ethnicity adjusting for age, Tanner stage, percent body fat, waist, physical activity, tobacco smoke, and the other hormones. RESULTS: After multivariable adjustment, in the 12-15-year-old males, testosterone concentration was lower in non-Hispanic blacks than whites (p = 0.043), SHBG concentration did not significantly differ between the two groups. Mexican-Americans had the highest testosterone (versus non-Hispanic black: p = 0.002) and lowest SHBG (versus non-Hispanic white: p = 0.010; versus non-Hispanic black: p = 0.047) concentrations. Estradiol concentration was lower in non Hispanic blacks (p = 0.11) and Mexican-Americans (p = 0.033) compared with non Hispanic whites. After multivariable adjustment, in the 16-19-year-old males, testosterone, estradiol, and SHBG concentrations did not differ between non Hispanic blacks and whites. Mexican-Americans had the highest testosterone concentration (versus non-Hispanic white: p = 0.08), but did not differ from the other groups on estradiol and SHBG concentrations. In both age groups, these patterns were generally present, but less pronounced after adjusting for age and Tanner stage only. CONCLUSION: In adolescent males, non-Hispanic blacks did not have a higher testosterone concentration than non-Hispanic whites, and Mexican Americans had the highest testosterone concentration, patterns similar to adult males. PMID- 23354422 TI - Consumption of flaxseed, a rich source of lignans, is associated with reduced breast cancer risk. AB - PURPOSE: To investigate the association between intake of flaxseed-the richest source of dietary lignans (a class of phytoestrogens)-and breast cancer risk. METHODS: A food frequency questionnaire was used to measure the consumption of flaxseed and flax bread by 2,999 women with breast cancer and 3,370 healthy control women who participated in the Ontario Women's Diet and Health Study (2002 2003). Logistic regression was used to investigate associations between consumption of flaxseed and flax bread and breast cancer risk. Confounding by established and suspected breast cancer risk factors, as well as dietary factors, was assessed. RESULTS: Flaxseed or flax bread was consumed at least weekly by 21 % of control women. None of the 19 variables assessed were identified as confounders of the associations between flaxseed or flax bread and breast cancer risk. Consumption of flaxseed was associated with a significant reduction in breast cancer risk (odds ratio (OR) = 0.82, 95 % confidence interval (CI) 0.69 0.97), as was consumption of flax bread (OR = 0.77, 95 % CI 0.67-0.89). CONCLUSIONS: This Canadian study is, to our knowledge, the first to report on the association between flaxseed alone and breast cancer risk and has found that flaxseed intake is associated with a reduction in breast cancer risk. As dietary intake of flaxseed is modifiable, this finding may be of public health importance with respect to breast cancer prevention. PMID- 23354423 TI - Quantifying the health impacts of air pollution under a changing climate-a review of approaches and methodology. AB - Climate change has been predicted to affect future air quality, with inevitable consequences for health. Quantifying the health effects of air pollution under a changing climate is crucial to provide evidence for actions to safeguard future populations. In this paper, we review published methods for quantifying health impacts to identify optimal approaches and ways in which existing challenges facing this line of research can be addressed. Most studies have employed a simplified methodology, while only a few have reported sensitivity analyses to assess sources of uncertainty. The limited investigations that do exist suggest that examining the health risk estimates should particularly take into account the uncertainty associated with future air pollution emissions scenarios, concentration-response functions, and future population growth and age structures. Knowledge gaps identified for future research include future health impacts from extreme air pollution events, interactions between temperature and air pollution effects on public health under a changing climate, and how population adaptation and behavioural changes in a warmer climate may modify exposure to air pollution and health consequences. PMID- 23354424 TI - Incorporating neurophysiological concepts in mathematical thermoregulation models. AB - Skin blood flow (SBF) is a key player in human thermoregulation during mild thermal challenges. Various numerical models of SBF regulation exist. However, none explicitly incorporates the neurophysiology of thermal reception. This study tested a new SBF model that is in line with experimental data on thermal reception and the neurophysiological pathways involved in thermoregulatory SBF control. Additionally, a numerical thermoregulation model was used as a platform to test the function of the neurophysiological SBF model for skin temperature simulation. The prediction-error of the SBF-model was quantified by root-mean squared-residual (RMSR) between simulations and experimental measurement data. Measurement data consisted of SBF (abdomen, forearm, hand), core and skin temperature recordings of young males during three transient thermal challenges (1 development and 2 validation). Additionally, ThermoSEM, a thermoregulation model, was used to simulate body temperatures using the new neurophysiological SBF-model. The RMSR between simulated and measured mean skin temperature was used to validate the model. The neurophysiological model predicted SBF with an accuracy of RMSR < 0.27. Tskin simulation results were within 0.37 degrees C of the measured mean skin temperature. This study shows that (1) thermal reception and neurophysiological pathways involved in thermoregulatory SBF control can be captured in a mathematical model, and (2) human thermoregulation models can be equipped with SBF control functions that are based on neurophysiology without loss of performance. The neurophysiological approach in modelling thermoregulation is favourable over engineering approaches because it is more in line with the underlying physiology. PMID- 23354425 TI - Utilization of nitrate abolishes the "Custers effect" in Dekkera bruxellensis and determines a different pattern of fermentation products. AB - Nitrate is one of the most abundant nitrogen sources in nature. Several yeast species have been shown to be able to assimilate nitrate and nitrite, but the metabolic pathway has been studied in very few of them. Dekkera bruxellensis can use nitrate as sole nitrogen source and this metabolic characteristic can render D. bruxellensis able to overcome S. cerevisiae populations in industrial bioethanol fermentations. In order to better characterize how nitrate utilization affects carbon metabolism and the yields of the fermentation products, we investigated this trait in defined media under well-controlled aerobic and anaerobic conditions. Our experiments showed that in D. bruxellensis, utilization of nitrate determines a different pattern of fermentation products. Acetic acid, instead of ethanol, became in fact the main product of glucose metabolism under aerobic conditions. We have also demonstrated that under anaerobic conditions, nitrate assimilation abolishes the "Custers effect", in this way improving its fermentative metabolism. This can offer a new strategy, besides aeration, to sustain growth and ethanol production for the employment of this yeast in industrial processes. PMID- 23354427 TI - Palliative care on Twitter: who to follow to get started. AB - Palliative care on Twitter: who to follow to get started. PMID- 23354426 TI - Speaking truth to power: a challenge for the field of palliative care. PMID- 23354428 TI - Oral health perceptions of paediatric palliative care nursing staff. AB - Systematic oral care reduces oral complications among children in paediatric palliative care (PPC), yet little is known about the oral health perceptions of PPC nursing staff. This qualitative cross-sectional study used semi-structured interviews based on phenomenography to explore PPC nursing staff's perceptions of oral health and the relationship of oral care to comfort and quality of life. A purposive sample of nine nursing staff employed at a California PPC facility participated. Five themes emerged from the analysis of the interviews: signs of oral health, reasons for oral care, adaptation of oral care on a case-by-case basis, barriers to providing oral care, and facilitators of improving oral care. The perceived importance of oral health was the underlining similarity between the themes. A need for further research in the area of oral PPC is indicated. Collaboration with dental professionals may be needed to create oral PPC guidelines that fit the complex needs of children with life-limiting illnesses. PMID- 23354429 TI - External mirroring of inner chaos: blogging as experienced by the relatives of people with cancer. AB - BACKGROUND: Relatives of a person suffering from cancer risk being affected both physically and psychologically. Blogging has become increasingly popular as a forum for communicating experiences, but few studies have focused on what blogging about a relative's cancer journey means to the author. AIM: To illuminate relatives' experiences of blogging when a family member is in the end of-life phase of cancer. METHOD: Telephone interviews were conducted with 12 people about their experiences of blogging during and after their family member's illness. The data was analysed using qualitative content analysis. FINDINGS: Blogging facilitated everyday life, introduced the relatives to new friends with similar experiences, helped them in their grief process, and helped them to preserve memories. The negative aspects were being misunderstood and publicly criticised as well as the feeling of providing readers with 'reality show' entertainment. CONCLUSION: Blogging was seen as a complement to professional care that contributed to the prevention of ill health. PMID- 23354430 TI - Nurses' perceptions of caring for dying patients in an open critical care unit: a descriptive exploratory study. AB - BACKGROUND: Nurses in critical care areas play a vital part in providing end-of life care and recognise that an ideal death should be peaceful, dignified, and comfortable. However, environmental restrictions in critical care units can make a peaceful death unachievable and can have a profoundly negative impact on end-of life care. PURPOSE: To describe the provision of end-of-life care in an open high dependency unit. METHOD: A descriptive exploratory approach was used involving semi-structured interviews with a purposive sample of five registered nurses working in the high-dependency area at a major teaching hospital. The interviews were audiotaped and transcribed. Thematic analysis was used to code the data and identify themes. RESULTS: Three themes emerged from the data. The core theme was 'the nurse as protector'. The two other themes were 'conflict of care' and 'peace and quiet'. Within these themes, characteristics of an ideal death were identified and barriers to providing an ideal death were acknowledged. CONCLUSION: This study illustrates nurses' perceptions of caring for dying patients in an open critical care unit. This environment influences the development of the nursing role as protector and presents barriers to achieving an ideal death. PMID- 23354431 TI - Providing nutritional support for patients with cancer cachexia. AB - Malnutrition is the single most common secondary diagnosis for patients with advanced cancer, and can affect up to 85% of patients. Anorexia and weight loss affect up to 80% of patients and are responsible for death in up to 20% of cases. Cancer cachexia is a feature of advanced cancer characterised by anorexia and a progressive loss of body weight, reduced immune response, poor treatment response, and poor quality of life. Providing effective nutritional support for patients who experience cancer cachexia at the end of life is very challenging and requires a multidisciplinary team approach to consider the implications beyond the patient's dietary needs being met. Evidence suggests that health professionals have limited understanding of cachexia and are often at a loss as to how to manage patients who experience this severe form of weight loss. The purpose of this article is to examine the quality of life of patients with advanced cancer who experience cachexia. The article covers the aetiology and management of the condition as well as current treatment methods and management strategies. In particular, it emphasises the advantages of the Macmillan approach to weight and eating. This approach focuses on the social aspects of eating and weight gain, indicating the importance of considering the effects of malnutrition on both the patient and the carer. PMID- 23354432 TI - A profile of hospice-at-home physiotherapy for community-dwelling palliative care patients. AB - AIM: To profile a specialised palliative care physiotherapy service to community dwelling patients. DESIGN: Retrospective audit. SETTING: Milford Care Centre, Limerick, Ireland. PARTICIPANTS: Patients referred to hospice-at-home physiotherapy during September 2010-February 2011. OUTCOME MEASURE: Edmonton Functional Assessment Tool (EFAT-2). RESULTS: 165 patients were referred, of whom 90% had cancer. Nurses referred 120 (73%). Referrals appeared to be increased by the presence of physiotherapists in the nursing bases. No asssessment was conducted for 55 referrals (33%), mainly owing to clinical deterioration. The remaining 110 patients were assessed, with 47 (43%) being contacted within 2 days of referral (mean 4 days, standard deviation 4.2, range 0-21 days). Physical function ranged from 0-18 (median 7, mode 4) on the EFAT-2 scale. The most commonly used treatments were exercises and advice/education. CONCLUSION: Referrals to the at-home physiotherapy service are heavily dependent on nurses and their understanding of the physiotherapy role. Patients tended to be relatively high functioning and tolerated numerous interventions. PMID- 23354435 TI - Advanced visible-light-driven photocatalyst upon the incorporation of sulfonated graphene. AB - Zero bandgap and water soluble sulfonated graphene (SGE) has been introduced into an n-type semiconductor photocatalytic system to fabricate a Ag@AgBr/SGE composite photocatalyst. Due to its unique conduction and valence band dispersion and low Fermi level, SGE serves as an electron reservoir within the photocatalyst which enhances the charge carrier transfer and separation significantly. Furthermore, the stability and adsorptivity of Ag@AgBr/SGE are also improved owing to the sulfonic acid groups and conjugated sp(2) carbon network of SGE. The photocatalytic activity was found to be 11-fold higher than SGE-free Ag@AgBr upon the photodegradation of MO under visible light irradiation. This work provides a novel and in-depth perspective for understanding the graphene-involved photocatalytic mechanism and would stimulate the development of graphene-involved photocatalysts for the exploitation and utilization of solar energy. PMID- 23354437 TI - The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans. AB - Primary ciliary dyskinesia (PCD) is characterized by dysfunction of respiratory cilia and sperm flagella and random determination of visceral asymmetry. Here, we identify the DRC1 subunit of the nexin-dynein regulatory complex (N-DRC), an axonemal structure critical for the regulation of dynein motors, and show that mutations in the gene encoding DRC1, CCDC164, are involved in PCD pathogenesis. Loss-of-function mutations disrupting DRC1 result in severe defects in assembly of the N-DRC structure and defective ciliary movement in Chlamydomonas reinhardtii and humans. Our results highlight a role for N-DRC integrity in regulating ciliary beating and provide the first direct evidence that mutations in DRC genes cause human disease. PMID- 23354436 TI - Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. AB - Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ~1 in 2,200 (refs. 1,2). A specific genetic etiology can be identified in ~21% of cases, including mutations of TWIST1, which encodes a class II basic helix-loop-helix (bHLH) transcription factor, and causes Saethre-Chotzen syndrome, typically associated with coronal synostosis. Using exome sequencing, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis. The mutations predominantly occurred in individuals with coronal synostosis and accounted for 32% and 10% of subjects with bilateral and unilateral pathology, respectively. TCF12 encodes one of three class I E proteins that heterodimerize with class II bHLH proteins such as TWIST1. We show that TCF12 and TWIST1 act synergistically in a transactivation assay and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 have severe coronal synostosis. Hence, the dosage of TCF12-TWIST1 heterodimers is critical for normal coronal suture development. PMID- 23354438 TI - Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. AB - Aberrant Wnt signaling can drive cancer development. In many cancer types, the genetic basis of Wnt pathway activation remains incompletely understood. Here, we report recurrent somatic mutations of the Drosophila melanogaster tumor suppressor-related gene FAT1 in glioblastoma (20.5%), colorectal cancer (7.7%), and head and neck cancer (6.7%). FAT1 encodes a cadherin-like protein, which we found is able to potently suppress cancer cell growth in vitro and in vivo by binding beta-catenin and antagonizing its nuclear localization. Inactivation of FAT1 via mutation therefore promotes Wnt signaling and tumorigenesis and affects patient survival. Taken together, these data strongly point to FAT1 as a tumor suppressor gene driving loss of chromosome 4q35, a prevalent region of deletion in cancer. Loss of FAT1 function is a frequent event during oncogenesis. These findings address two outstanding issues in cancer biology: the basis of Wnt activation in non-colorectal tumors and the identity of a 4q35 tumor suppressor. PMID- 23354440 TI - Xerostomia after radiotherapy. What matters--mean total dose or dose to each parotid gland? AB - PURPOSE: Xerostomia is a debilitating side effect of radiotherapy in patients with head and neck cancer. We undertook a prospective study of the effect on xerostomia and outcomes of sparing one or both parotid glands during radiotherapy for patients with squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Patients with locally advanced squamous cell carcinoma of the head and neck received definitive (70 Gy in 2 Gy fractions) or adjuvant (60-66 Gy in 2 Gy fractions) curative-intent radiotherapy using helical tomotherapy with concurrent chemotherapy if appropriate. Group A received < 26 Gy to the left and right parotids and group B received < 26 Gy to either parotid. RESULTS: The study included 126 patients; 114 (55 in group A and 59 in group B) had follow-up data. There were no statistically significant differences between groups in disease stage. Xerostomia was significantly reduced in group A vs. group B (p = 0.0381). Patients in group A also had significantly less dysphagia. Relapse-free and overall survival were not compromised in group A: 2-year relapse-free survival was 86% vs. 72% in group B (p = 0.361); 2-year overall survival was 88% and 76%, respectively (p = 0.251). CONCLUSION: This analysis suggests that reducing radiotherapy doses to both parotid glands to < 26 Gy can reduce xerostomia and dysphagia significantly without compromising survival. Sparing both parotids while maintaining target volume coverage and clinical outcome should be the treatment goal and reporting radiotherapy doses delivered to the individual parotids should be standard practice. PMID- 23354439 TI - Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis. AB - The extracellular signal-related kinases 1 and 2 (ERK1/2) are key proteins mediating mitogen-activated protein kinase signaling downstream of RAS: phosphorylation of ERK1/2 leads to nuclear uptake and modulation of multiple targets. Here, we show that reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 (refs. 2,3,4,5,6,7), causes complex craniosynostosis (premature fusion of the cranial sutures) in humans and mice. Features of this newly recognized clinical disorder include multiple-suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay. Mice with functional Erf levels reduced to ~30% of normal exhibit postnatal multiple-suture synostosis; by contrast, embryonic calvarial development appears mildly delayed. Using chromatin immunoprecipitation in mouse embryonic fibroblasts and high-throughput sequencing, we find that ERF binds preferentially to elements away from promoters that contain RUNX or AP-1 motifs. This work identifies ERF as a novel regulator of osteogenic stimulation by RAS-ERK signaling, potentially by competing with activating ETS factors in multifactor transcriptional complexes. PMID- 23354441 TI - A 7-nitrobenz-2-oxa-1,3-diazole based highly sensitive and selective turn-on chemosensor for copper(II) ion with intracellular application without cytotoxicity. AB - A 7-nitrobenz-2-oxa-1,3-diazole (NBD) derived turn-on fluorescent probe (1) exhibits a reversible binding to Cu(2+) ion in presence of other metal ions, giving ~20 fold increase in fluorescence intensity. The apparent association constant (K(a)) for Cu(2+) was found to be 2.62 * 10(4) M(-1). The intracellular Cu(2+) imaging behaviour of chemosensor 1 on HeLa cells studied by fluorescence microscopy revealed that after incubation with 1 cells exhibited intensive fluorescence when exogenous Cu(2+) was introduced into the cell. Thus this probe features the ready availability, high sensitivity and selectivity towards Cu(2+) in MeCN-H(2)O (1:1, v/v) with cell imaging possibilities with no or negligible cytotoxicity. PMID- 23354442 TI - Proboscis lateralis. AB - INTRODUCTION: Proboscis lateralis is a rare congenitally acquired facial abnormality characterized by a soft-tissue tube- or trunk-like appendage projecting from the surface of the face, most frequently rooted in the medial canthal region. Proboscis lateralis is generally associated with a wide range of concomitant craniofacial anomalies, giving rise to multiple theories describing the embryological pathogenesis and various classification systems to account for the pathological associations. RESULTS/CONCLUSION: This paper provides a literature review of the rare manifestations of proboscis lateralis and represents a summary of current literature related to embryological pathogenesis, definitive diagnosis, and surgical management approaches. PMID- 23354443 TI - Spring-assisted posterior vault expansion in multisuture craniosynostosis. AB - PURPOSE: Patients with Apert and Crouzon syndromes and craniofrontonasal dysplasia need a vault expansion within the first year of life to treat or prevent the development of raised intracranial pressure. Many craniofacial units perform a conventional posterior vault expansion as initial surgery; an alternative to this technique is the spring-assisted posterior vault expansion. The purpose of this study was to demonstrate the efficacy of spring-assisted posterior vault expansion and to compare this technique with the conventional method. METHODS: A retrospective study was conducted among all consecutive patients who received a posterior vault expansion between 2006 and 2011. Patients treated with springs were compared with patients treated with the conventional technique for blood loss, duration of surgery, postoperative hospital admittance, increase in skull circumference and anterior-posterior length, and complications. RESULTS: Of the 31 included patients, 15 were treated with springs, and 16, with the conventional technique. Patients treated with springs had a significantly larger increase in skull circumference and anterior-posterior length, and not significant changes in blood loss compared with the conventional group. Complications in the conventional group were the following: minor dural tear in three patients, problematic wound healing in one patient, and insufficient expansion in one patient. Spring-related complications included skin perforation in two patients, a minor dural tear in two patients, and leakage of cerebrospinal fluid after an unnoticed dural tear during spring placement in one patient. CONCLUSION: Spring-assisted posterior vault expansion has some advantages over the conventional technique and is, therefore, the preferred technique in our center. PMID- 23354444 TI - Zymogram profiling of superoxide dismutase and catalase activities allows Saccharomyces and non-Saccharomyces species differentiation and correlates to their fermentation performance. AB - Aerobic organisms have devised several enzymatic and non-enzymatic antioxidant defenses to deal with reactive oxygen species (ROS) produced by cellular metabolism. To combat such stress, cells induce ROS scavenging enzymes such as catalase, peroxidase, superoxide dismutase (SOD) and glutathione reductase. In the present research, we have used a double staining technique of SOD and catalase enzymes in the same polyacrylamide gel to analyze the different antioxidant enzymatic activities and protein isoforms present in Saccharomyces and non-Saccharomyces yeast species. Moreover, we used a technique to differentially detect Sod1p and Sod2p on gel by immersion in NaCN, which specifically inhibits the Sod1p isoform. We observed unique SOD and catalase zymogram profiles for all the analyzed yeasts and we propose this technique as a new approach for Saccharomyces and non-Saccharomyces yeast strains differentiation. In addition, we observed functional correlations between SOD and catalase enzyme activities, accumulation of essential metabolites, such as glutathione and trehalose, and the fermentative performance of different yeasts strains with industrial relevance. PMID- 23354445 TI - Immobilization of nisin producer Lactococcus lactis strains to chitin with surface-displayed chitin-binding domain. AB - In this study, nisin producer Lactococcus lactis strains displaying cell surface chitin-binding domain (ChBD) and capable of immobilizing to chitin flakes were constructed. To obtain ChBD-based cell immobilization, Usp45 signal sequence with ChBD of chitinase A1 enzyme from Bacillus circulans was fused with different lengths of PrtP (153, 344, and 800 aa) or AcmA (242 aa) anchors derived from L. lactis. According to the whole cell ELISA analysis, ChBD was successfully expressed on the surface of L. lactis cells. Scanning electron microscope observations supported the conclusion of the binding analysis that L. lactis cells expressing the ChBD with long PrtP anchor (800 aa) did bind to chitin surfaces more efficiently than cells with the other ChBD anchors. The attained binding affinity of nisin producers for chitin flakes retained them in the fermentation during medium changes and enabled storage for sequential productions. Initial nisin production was stably maintained with many cycles. These results demonstrate that an efficient immobilization of L. lactis cells to chitin is possible for industrial scale repeated cycle or continuous nisin fermentation. PMID- 23354446 TI - Biological deterioration of alginate beads containing immobilized microalgae and bacteria during tertiary wastewater treatment. AB - Secondary treatment of municipal wastewater affects the mechanical stability of polymer Ca-alginate beads containing the microalgae Chlorella vulgaris that are jointly immobilized with Azospirillum brasilense as treating agents whose presence do not affect bead stability. Nine strains of potential alginate degrading bacteria were isolated from wastewater and identified, based on their nearly complete 16S rDNA sequence. Still, their population was relatively low. Attempts to enhance the strength of the beads, using different concentrations of alginate and CaCl2 or addition of either of three polymers (polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose), CaCO3, or SrCl2, failed. Beads lost their mechanical strength after 24 h of incubation but not the integrity of their shape for at least 96 h, a fact that sustained successful tertiary wastewater treatment for 48 h. In small bioreactors, removal of phosphorus was low under sterile conditions but high in unsterile wastewater. Alginate beads did not absorb PO4 (-3) in sterile wastewater, but in natural wastewater, they contained PO4 (-3). Consequently, PO4 (-3) content declined in the wastewater. A supplement of 10 % beads (w/v) was significantly more efficient in removing nutrients than 4 %, especially in a jointly immobilized treatment where >90 % of PO4 (-3) and >50 % ammonium were removed. Tertiary wastewater treatment in 25-L triangular, airlift, autotrophic bioreactors showed, as in small bioreactors, very similar nutrient removal patterns, decline in bead strength phenomena, and increase in total bacteria during the wastewater treatment only in the presence of the immobilized treatment agents. This study demonstrates that partial biological degradation of alginate beads occurred during tertiary wastewater treatment, but the beads survive long enough to permit efficient nutrient removal. PMID- 23354447 TI - Prevention of quorum-sensing-mediated biofilm development and virulence factors production in Vibrio spp. by curcumin. AB - The increasing occurrence of disease outbreaks caused by Vibrio spp. and the emergence of antibiotic resistance has led to a growing interest in finding alternative strategies to prevent vibriosis. Since the pathogenicity of vibrios is controlled in part by quorum-sensing (QS) system, interfering with this mechanism would prevent the pathogenicity of vibrios without developing resistance. Hence, a non-toxic phytochemical curcumin from Curcuma longa was assessed for its potential in reducing the production of QS-dependent virulence factors in Vibrio spp. The obtained results evidenced 88% reduction in bioluminescence of Vibrio harveyi by curcumin. Further, curcumin exhibited a significant inhibition in alginate, exopolysaccharides, motility, biofilm development and other virulence factors production in Vibrio parahaemolyticus, Vibrio vulnificus and V. harveyi. In in vivo analysis, curcumin enhanced the survival rate of Artemia nauplii up to 67% against V. harveyi infection by attenuating its QS-mediated virulence. PMID- 23354448 TI - Loop engineering of amadoriase II and mutational cooperativity. AB - Amadori compounds and their cross-linked products have been implicated in diabetic complications and some age-related diseases. Fructosyl amine oxidases (FAOXs) are a family of enzymes that can cleave the amadori compounds. However, the natural enzymes are only active on small substrates (fructosyl amino acids or dipeptides), which limits the therapeutic and diagnostic applications of these enzymes. In this study, amadoriase II, a member of the FAOX family from Aspergillus fumigatus was engineered to broaden its substrate range using a modified combinatorial active site saturation testing approach. The two loops at the entrance of the substrate channel were targeted. Saturation mutagenesis was carried out to search for hot-spot sites, followed by pairwise mutagenesis and subsequent combination of active mutations. Five sites on the loops were found to be critical for accessibility for two model bulky substrates, fructosyl adamantanamine and fructosyl-polylysine (3-13 lysines). Two best mutants (with three and five mutations, respectively) were obtained, with a specific activity toward the model substrates 20.6-fold and 16.8-fold that of the wild-type, respectively. Deconvolution experiments revealed the cooperativity of the mutations. PMID- 23354449 TI - Role of the pentose phosphate pathway and the Entner-Doudoroff pathway in glucose metabolism of Gluconobacter oxydans 621H. AB - Glucose catabolism by the obligatory aerobic acetic acid bacterium Gluconobacter oxydans 621H proceeds in two phases comprising rapid periplasmic oxidation of glucose to gluconate (phase I) and oxidation of gluconate to 2-ketogluconate or 5 ketogluconate (phase II). Only a small amount of glucose and part of the gluconate is taken up into the cells. To determine the roles of the pentose phosphate pathway (PPP) and the Entner-Doudoroff pathway (EDP) for intracellular glucose and gluconate catabolism, mutants defective in either the PPP (Deltagnd, Deltagnd zwf*) or the EDP (Deltaedd-eda) were characterized under defined conditions of pH 6 and 15 % dissolved oxygen. In the presence of yeast extract, neither of the two pathways was essential for growth with glucose. However, the PPP mutants showed a reduced growth rate in phase I and completely lacked growth in phase II. In contrast, the EDP mutant showed the same growth behavior as the reference strain. These results demonstrate that the PPP is of major importance for cytoplasmic glucose and gluconate catabolism, whereas the EDP is dispensable. Reasons for this difference are discussed. PMID- 23354450 TI - Efficient production of L-lactic acid by newly isolated thermophilic Bacillus coagulans WCP10-4 with high glucose tolerance. AB - A thermophilic Bacillus coagulans WCP10-4 with tolerance to high concentration of glucose was isolated from soil and used to produce optically pure L-lactic acid from glucose and starch. In batch fermentation at pH 6.0, 240 g/L of glucose was completely consumed giving 210 g/L of L-lactic acid with a yield of 95 % and a productivity of 3.5 g/L/h. In simultaneous saccharification and fermentation at 50 degrees C without sterilizing the medium, 200 g/L of corn starch was completely consumed producing 202.0 g/L of L-lactic acid. To the best of our knowledge, this strain shows the highest osmotic tolerance to glucose among the strains ever reported for lactic acid production. This is the first report of simultaneous saccharification and fermentation of starch for lactic acid production under a non-sterilized condition. PMID- 23354451 TI - Use of propidium monoazide and increased amplicon length reduce false-positive signals in quantitative PCR for bioburden analysis. AB - Rapid microbiological methods (RMMs) as an alternative to conventional cultivation-based bioburden analysis are receiving increasing attention although no single technology is currently able to satisfy the needs of the health care industry. Among the RMMs, quantitative PCR (qPCR) seems particularly suited. Its implementation is, however, hampered by false-positive signals originating from free DNA in PCR reagents or from dead cells in the samples to be analysed. In this study, we assessed the capability of propidium monoazide (PMA) to inactivate exogenous DNA in PCR reagents and thus to minimise its impact in bioburden analysis. PMA is a membrane-impermeant dye that intercalates into DNA and covalently binds to it upon photoactivation leading to strong inhibition of PCR amplification. PMA is currently used mainly for treatment of microbiological samples to exclude signals from membrane-compromised cells, but is also very useful for suppression of exogenous DNA signals. In addition to testing the effect of different PMA concentrations on non-template controls and target DNA, we demonstrate the effect of amplicon length on the exclusion of background amplification. Targeting a 1,108-bp 16S rRNA gene fragment using universal bacterial primers and PCR reagents treated with 5 MUM PMA resulted in complete suppression of signals from exogenous DNA within 50 cycles of amplification, while a limit of detection of 10 copies of Escherichia coli genomic DNA per PCR reaction was achieved. A combined PMA treatment of sample and PCR reagents furthermore improved the selective detection of live cells making this method appear a highly attractive RMM. PMID- 23354453 TI - Prevalence of xerophthalmia among malnourished children in rural Ethiopia. AB - To assess the prevalence of eye disease among malnourished children in a rural Ethiopian health center and evaluate correlations between xerophthalmia and grades of malnutrition. A retrospective, cross-sectional survey. An institution based cross-sectional prospective study was performed at Bushulo Health Center in rural south Ethiopia and included all children age 6 months to 14 years receiving care for malnourishment from June 1st to July 30th, 2008. Data collection involved a combination of interviews with caretakers, ocular examination by a pediatric ophthalmologist and anthropometric measurements. One hundred and seventy-three children (average age at examination 2.9 +/- 0.2 years) were treated for malnutrition (97 female, 76 male). One hundred and forty-nine patients had moderate malnutrition (86.03 %) and 24 had severe malnutrition (13.9 %). The following eye diseases were diagnosed--trachoma (12.1 %), blepharitis (13.3 %) and xerophthalmia (20.8 %). Severely malnourished children were more likely to suffer from xerophthalmia than moderately malnourished children (p < 0.0001). When comparing anthropometric measurements to the diagnosis of xerophthalmia, only weight percentile showed significance (p = 0.008). Xerophthalmia is a common global cause of pediatric blindness and is highly correlated with severe malnutrition. Continued efforts are necessary to improve nutrition and outcomes in these patients. PMID- 23354452 TI - MicroRNA 199b-5p delivery through stable nucleic acid lipid particles (SNALPs) in tumorigenic cell lines. AB - MicroRNA (miR)-199b-5p has been shown to regulate Hes-1, a downstream effector of the canonical Notch and noncanonical SHH pathways, whereby it impairs medulloblastoma (MB) cancer stem cells (CSCs) through a decrease in the CD133+/CD15+ cell population. Here, we have developed stable nucleic acid lipid particles (SNALPs) that encapsulate miR-199b-5p. The efficacy of the miR-199b-5p delivery by these SNALPs is demonstrated by significant impairment of Hes-1 levels and CSC markers in a range of different tumorigenic cell lines: colon (HT 29, CaCo-2, and SW480), breast (MDA-MB231T and MCF-7), prostate (PC-3), glioblastoma (U-87), and MB (Daoy, ONS-76, and UW-228). After treatment with SNALP miR-199b-5p, there is also impairment of cell proliferation and no signs of apoptosis, as measured by caspases 3/7 activity and annexin V fluorescence cell sorter analyses. These data strengthen the importance of such carriers for miRNA delivery, which show no cytotoxic effects and provide optimal uptake into cells. Thus, efficient target downregulation in different tumorigenic cell lines will be the basis for future preclinical studies. PMID- 23354454 TI - Optical coherence tomography of retinal astrocytic hamartomas in a 4-year-old boy affected by tuberous sclerosis. PMID- 23354456 TI - Antimycin A effect on the electron transport in chloroplasts of two Chlamydomonas reinhardtii strains. AB - The effects of antimycin A on the redox state of plastoquinone and on electron donation to photosystem I (PS I) were studied in sulfur-deprived Chlamydomonas reinhardtii cells of the strains cc406 and 137c. We found that this reagent suppresses cyclic electron flow around PS I in the cc406 strain, whereas this inhibitory effect was completely absent in the 137c strain. In the latter strain, antimycin A induced rapid reduction of plastoquinone in the dark and considerably enhanced the rate of electron donation to P700 (+) in the dark. Importantly, neither myxothiazol, an inhibitor of mitochondrial respiration, FCCP, a protonophore, nor propyl gallate, an inhibitor of the plastid terminal oxidase, induced such a strong effect like antimycin A. The results indicate that in the chloroplast of the 137c strain, antimycin A has a site of action outside of the machinery of cyclic electron flow. PMID- 23354457 TI - Pesticides and oncogenic modulation. AB - Pesticides constitute a diverse class of chemicals used for the protection of agricultural products. Several lines of evidence demonstrate that organochlorine and organophosphate pesticides can cause malignant transformation of cells in in vitro and in vivo models. In the current minireview a comprehensive summary of recent in vitro findings is presented along with data reported from human population studies, regarding the impact of pesticide exposure on activation or dysregulation of oncogenes and tumor suppressor genes. Substantial mechanistic work suggests that pesticides are capable of inducing mutations in oncogenes and increase their transcriptional expression in vitro, whereas human population studies indicate associations between pesticide exposure levels and mutation occurrence in cancer-related genes. Further work is required to fully explore the exact mechanisms by which pesticide exposure affects the integrity and normal function of oncogenes and tumor suppressor genes in human populations. PMID- 23354455 TI - Floral transition in maize infected with Sporisorium reilianum disrupts compatibility with this biotrophic fungal pathogen. AB - Sporisorium reilianum f. sp. zeae is an important biotrophic pathogen that causes head smut disease in maize. Head smut is not obvious until the tassels and ears emerge. S. reilianum has a very long life cycle that spans almost the entire developmental program of maize after the pathogen successfully invades the root. The aim of this study was to understand at a molecular level how this pathogen interacts with the host during its long life cycle, and how this interaction differs between susceptible and resistant varieties of maize after hyphal invasion. We investigated transcriptional changes in the resistant maize line Mo17 at four developmental stages using a maize 70mer-oligonucleotide microarray. We found that there was a lengthy compatible relationship between the pathogen and host until the early eighth-leaf stage. The resistance in Mo17 relied on the assignment of auxin and regulation of flavonoids in the early floral primordium during the early floral transition stage. We propose a model describing the putative mechanism of head smut resistance in Mo17 during floral transition. In the model, the synergistic regulations among auxin, flavonoids, and hyphal growth play a key role in maintaining compatibility with S. reilianum in the resistant maize line. PMID- 23354458 TI - Malondialdehyde and 4-hydroxynonenal adducts are not formed on cardiac ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) in diabetes. AB - Recently, we reported an elevated level of glucose-generated carbonyl adducts on cardiac ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2) in hearts of streptozotocin(STZ)-induced diabetic rats. We also showed these adduct impaired RyR2 and SERCA2 activities, and altered evoked Ca(2+) transients. What is less clear is if lipid-derived malondialdehyde (MDA) and 4 hydroxy-2-nonenal (4-HNE) also chemically react with and impair RyR2 and SERCA2 activities in diabetes? This study used western blot assays with adduct-specific antibodies and confocal microscopy to assess levels of MDA, 4-HNE, N (epsilon) carboxy(methyl)lysine (CML), pentosidine, and pyrraline adducts on RyR2 and SERCA2 and evoked intracellular transient Ca(2+) kinetics in myocytes from control, diabetic, and treated-diabetic rats. MDA and 4-HNE adducts were not detected on RyR2 and SERCA2 from either control or 8 weeks diabetic rats with altered evoked Ca(2+) transients. However, CML, pentosidine, and pyrraline adducts were elevated three- to five-fold (p < 0.05). Treating diabetic rats with pyridoxamine (a scavenger of reactive carbonyl species, RCS) or aminoguanidine (a mixed reactive oxygen species-RCS scavenger) reduced CML, pentosidine, and pyrraline adducts on RyR2 and SERCA2 and blunted SR Ca(2+) cycling changes. Treating diabetic rats with the superoxide dismutase mimetic tempol had no impact on MDA and 4-HNE adducts on RyR2 and SERCA2, and on SR Ca(2+) cycling. From these data we conclude that lipid-derived MDA and 4-HNE adducts are not formed on RyR2 and SERCA2 in this model of diabetes, and are therefore unlikely to be directly contributing to the SR Ca(2+) dysregulation. PMID- 23354459 TI - Surgical technique: Spike translation: a new modification in step-cut osteotomy for cubitus varus deformity. AB - BACKGROUND: Various methods of osteotomy have been proposed for the treatment of cubitus varus. We designed a modification of the step-cut osteotomy to achieve more correction of the deformity. We describe this new technique called spike translation step-cut osteotomy and report the clinical and radiographic outcomes (deformity correction, ROM, function, osteotomy healing, complications) in a series of patients treated for cubitus varus using this technique. DESCRIPTION OF TECHNIQUE: The technique involves a kind of closing-wedge osteotomy with a lateral spike to correct cubitus varus. To avoid lateral epicondyle prominence, the spike is translated medially and embedded in the proximal segment. METHODS: We treated 13 patients with cubitus varus using the new technique between 2005 and 2010. We compared preoperative and postoperative clinical and radiographic parameters (humerus-elbow-wrist angle, lateral prominence index, arc of elbow motion, DASH score) for all patients. Time to union was recorded. Postoperative evaluation was performed according to the modified criteria of Oppenheim et al. Minimum followup was 16 months (average, 27 months; range, 16-43 months). RESULTS: The average humerus-elbow-wrist angle improved from -26 degrees to 11 degrees . The mean lateral prominence index did not differ after correction of deformity compared with the normal side. By using our rehabilitation protocol, all patients regained preoperative arcs of elbow motion in a mean of 2.5 months (range, 1.50-3.50 months) postoperatively, and the mean union time was 1.65 months. According to the criteria of Oppenheim et al., there were 11 excellent and two good results. CONCLUSIONS: Our spike translation step-cut osteotomy with a larger contact surface of cancellous bone can be a reasonable alternative for correction of a cubitus varus deformity, with satisfactory deformity correction, reliable healing of osteotomy, and low complication rates. PMID- 23354460 TI - MRI predicts ALVAL and tissue damage in metal-on-metal hip arthroplasty. AB - BACKGROUND: Adverse local tissue reactions (ALTR) around metal-on-metal (MOM) hip arthroplasties are increasingly being recognized as a cause of failure. These reactions may be associated with intraoperative tissue damage and complication rates as high as 50% after revision. Although MRI can identify ALTR in MOM hips, it is unclear whether the MRI findings predict those at revision surgery. QUESTIONS/PURPOSES: We therefore (1) identified which MRI characteristics correlated with histologically confirmed ALTR (using the aseptic lymphocytic vasculitis-associated lesions [ALVAL] score) and intraoperative tissue damage and (2) developed a predictive model using modified MRI to detect ALVAL and quantify intraoperative tissue damage. METHODS: We retrospectively reviewed 68 patients with failed MOM hip arthroplasties who underwent preoperative MRI and subsequent revision surgery. Images were analyzed to determine synovial volume, osteolysis, and synovial thickness. The ALVAL score was used to grade tissue samples, thus identifying a subset of patients with ALTR. Intraoperative tissue damage was graded using a four-point scale. Random forest analysis determined the sensitivity and specificity of MRI characteristics in detecting ALVAL (score >= 5) and intraoperative tissue damage. RESULTS: Maximal synovial thicknesses and synovial volumes as determined on MRI correlated with the ALVAL score and were higher in cases of severe intraoperative tissue damage. Our MRI predictive model showed sensitivity and specificity of 94% and 87%, respectively, for detecting ALVAL and 90% and 86%, respectively, for quantifying intraoperative tissue damage. CONCLUSIONS: MRI is sensitive and specific in detecting ALVAL and tissue damage in patients with MOM hip implants. MRI can be used as a screening tool to guide surgeons toward timely revision surgery. PMID- 23354461 TI - Editorial: Research is a team sport: updated authorship guidelines for CORR. PMID- 23354462 TI - Impingement adversely affects 10-year survivorship after periacetabular osteotomy for DDH. AB - BACKGROUND: Although periacetabular osteotomy (PAO) for developmental dysplasia of the hip (DDH) provides conceptual advantages compared with other osteotomies and reportedly is associated with joint survivorship of 60% at 20 years, the beneficial effect of proper acetabular reorientation with concomitant arthrotomy and creation of femoral head-neck offset on 10-year hip survivorship remains unclear. QUESTIONS/PURPOSES: We asked the following questions: (1) Does the 10 year survivorship of the hip after PAO improve with proper acetabular reorientation and a spherical femoral head; (2) does the Merle d'Aubigne-Postel score improve; (3) can the progression of osteoarthritis (OA) be slowed; and (4) what factors predict conversion to THA, progression of OA, or a Merle d'Aubigne Postel score less than 15 points? METHODS: We retrospectively reviewed 147 patients who underwent 165 PAOs for DDH with two matched groups: Group I (proper reorientation and spherical femoral head) and Group II (improper reorientation and aspherical femoral head). We compared the Kaplan-Meier survivorship, Merle d'Aubigne-Postel scores, and progression of OA in both groups. A Cox regression analysis (end points: THA, OA progression, or Merle d'Aubigne-Postel score less than 15) was performed to detect factors predicting failure. The minimum followup was 10 years (median, 11 years; range, 10-14 years). RESULTS: An increased survivorship was found in Group I. The Merle d'Aubigne-Postel score did not differ. Progression of OA in Group I was slower than in Group II. Factors predicting failure included greater age, lower preoperative Merle d'Aubigne Postel score, and the presence of a Trendelenburg sign, aspherical head, OA, subluxation, postoperative acetabular retroversion, excessive acetabular anteversion, and undercoverage. CONCLUSIONS: Proper acetabular reorientation and the creation of a spherical femoral head improve long-term survivorship and decelerate OA progression in patients with DDH. PMID- 23354463 TI - A positive hip arthrogram may predict lower function in patients with primary hip arthroplasty. AB - BACKGROUND: A local anesthetic hip arthrogram is a simple test mainly used as an adjunct to define the origin of hip pain. Temporary pain relief (a positive response) following an injection may lead to a surgeon recommending hip surgery. However, it is unclear whether relief of pain corresponds to better postoperative pain relief or function. QUESTIONS/PURPOSES: We therefore compared the function in patients with a positive response to a local anesthetic hip arthrogram who underwent primary THA and patients with typical osteoarthritis presentation who underwent primary THA without a preoperative arthrogram. METHODS: We retrospectively reviewed 22 patients who had a positive response to a local anesthetic hip arthrogram who subsequently underwent primary hip arthroplasty and a control group of 74 patients who had typical osteoarthritis hip pain and subsequent primary hip arthroplasty without having a previous arthrogram. All patients completed the Oxford Hip Score, WOMACTM function short form, and the SF 12 preoperatively and at regular clinical followups. The minimum followups were 28 months (mean, 42 months; range, 28-72 months) for the study group and 33 months (mean, 52 months; range, 33-73 months) for the control group. RESULTS: Patients in the arthrogram group had lower mean functional scores: 30 versus 39 for the Oxford Hip Score, 39 versus 46 for the WOMACTM, and 36 versus 42 for the physical component of the SF-12. CONCLUSIONS: Preoperative use of a local anesthetic hip arthrogram remains an important tool to differentiate spinal disorders or confirm the hip as the cause of pain. However, patients who have a preoperative hip arthrogram to clarify symptoms may report a lower function score and pain relief than patients who do not. PMID- 23354464 TI - Total knee arthroplasty in the elderly: does age affect pain, function or complications? AB - BACKGROUND: TKA is one of the most commonly performed procedures in the elderly, yet whether age influences postoperative pain, function, and complication rates is not fully understood for this group. This is because the current literature has limited followup, small sample sizes, and no comparator group. QUESTIONS/PURPOSES: We therefore asked if increasing age adversely affects postoperative pain, Knee Society Scores((c)), and complication rates. METHODS: We retrospectively reviewed all 438 patients 80 years or older who underwent primary TKA between 1995 and 2005. We established a comparator group of 2754 patients younger than 80 years. We assessed pain, the Knee Society Score((c)) (KSS), and the Knee Society Function Score((c)) (KSFS). The number and type of complications were recorded and those graded 2 or more using the classification of Dindo et al. were analyzed. Minimum followup was 5 years (mean, 6 years; range, 5-15.5 years). RESULTS: We found no difference in pain scores at 3, 5, and 10 years between the two groups. The KSS was comparable between groups at Year 5, but the KSFS was lower in the octogenarians. Major complications rates were higher in the octogenarian group (19% versus 15%). CONCLUSIONS: When compared with younger patients, octogenarians can expect comparable pain relief and KSS but lower function and more complications. PMID- 23354465 TI - Osteonecrosis complicating developmental dysplasia of the hip compromises subsequent acetabular remodeling. AB - BACKGROUND: Osteonecrosis of the femoral head secondary to treatment of developmental dysplasia of the hip (DDH) affects acetabular remodeling but the magnitude of this effect is unclear. QUESTIONS/PURPOSES: Using four measures of acetabular development, we (1) determined whether acetabular remodeling differed in hips with and without osteonecrosis; and (2) determined the impact of severity of osteonecrosis contributing to acetabular remodeling. METHODS: We retrospectively reviewed 95 patients (118 hips) treated for DDH by closed or open reduction with or without femoral osteotomy between 1992 and 2006. We evaluated serial radiographs from the time when a stable reduction had been achieved. In 902 radiographs taken over 19 years, we measured the acetabular index and three other indices of hip development. Patients were followed for a mean of 8 years (range, 1-19 years). At last followup, 86 of the 118 hips (73%) had osteonecrosis according to the criteria by Bucholz and Ogden. RESULTS: The acetabular index improved with time in all hips but the magnitude of improvement was larger in hips without osteonecrosis. The adjusted mean acetabular index at 14 years was 17 degrees for hips with osteonecrosis (95% CI, 15 degrees -18 degrees ) and 10 degrees for hips without osteonecrosis (95% CI, 7 degrees -13 degrees ). The lateral centering ratio improved after reduction to a normal value less than 0.85 in both groups but the rate of change with 0.06 versus 0.05 was higher in hips with osteonecrosis. The superior centering ratio was worse at all times in hips with osteonecrosis with a mean difference of 0.04. If only radiographic changes of Grades II and greater were considered osteonecrosis, the mean adjusted acetabular index at 14 years was 17.7 degrees (15.6 degrees -19.7 degrees ) for hips with osteonecrosis and 12.4 degrees (10.3 degrees -14.4 degrees ) for hips without osteonecrosis. CONCLUSIONS: Although radiographic indices improved consistently with time in hips without osteonecrosis, hips with osteonecrosis had abnormal indices of acetabular remodeling throughout followup. Osteonecrosis of the femoral head inhibited acetabular remodeling. LEVEL OF EVIDENCE: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23354466 TI - Increased acetabular depth may influence physeal stability in slipped capital femoral epiphysis. AB - BACKGROUND: Multiple mechanical factors affecting the hip have been associated with the development of slipped capital femoral epiphysis (SCFE). Whether acetabular depth plays a role in the development of a SCFE has not been elucidated. QUESTIONS/PURPOSES: (1) What is the prevalence of a deep acetabulum in SCFE? (2) Is the presence of a deep acetabulum associated with physeal instability? (3) Is the presence of a deep acetabulum associated with the occurrence of a contralateral SCFE? METHODS: We retrospectively reviewed 232 patients (156 males) who presented with a unilateral SCFE. Fifty (22%) subsequently developed a contralateral SCFE. The involved and uninvolved sides were evaluated for the presence of a deep acetabulum (DA). Preoperative radiographic parameters, slip stability, development of a contralateral SCFE, and demographic factors were then compared between patients with and without DA. RESULTS: DA was present in 120 hips (52%) with a SCFE. DA was more common in females (55 of 76 [72%]) than males (65 of 156 [42%]). Patients with DA presented with a higher lateral center-edge angle (33 degrees versus 31 degrees ), slip angle (52 degrees versus 43 degrees ), and with a lower body mass index (28.1 versus 30.0 kg/m(2)). Increased acetabular depth was more common in patients with an unstable SCFE (29 of 41 [71%]) than those with a stable SCFE (91 of 191 [48%]). The presence of DA either on the affected side or the contralateral side did not predict a contralateral SCFE. CONCLUSIONS: Despite not predicting a contralateral SCFE, DA may influence physeal stability if a SCFE does develop. Therefore, the contralateral hip with DA should be closely monitored. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23354467 TI - Childhood obesity and musculoskeletal problems: editorial comment. PMID- 23354468 TI - The phenomenology and neurobiology of delusion formation during psychosis onset: Jaspers, Truman symptoms, and aberrant salience. AB - Following the publication of Karl Jaspers' General Psychopathology (1913), delusions have been characterized as being nonunderstandable in terms of the person's biography, motivations, and historical-cultural context. According to Jaspers, this loss of understandability is due to an underlying neurobiological process, which has interrupted the normal development of the individual's personality. Inheriting the 19th-century division between the natural- and human historical sciences, Jaspers emphasizes the psychological understanding of mental disorders as narrative-based, holistic, and contextual. By doing so, he embraces cultural, ethnic, and individual differences and anticipates a person-centered medicine. However, he also affirms the value of explanatory neurobiological approaches, especially in the research and diagnosis of delusions. The phenomenological approach leads to neurobiological hypotheses, which can be tested experimentally. The present article addresses these issues by illustrating Jaspers' fundamental contribution to current neurobiological research concerning the formation of delusions during early phases of psychosis. Specifically, we present delusional mood and Truman symptoms as core phenomenological features at the origin of psychosis onset, and we discuss their neurobiological substrate with the aberrant salience and dopamine dysregulation models. Jaspers and his successors' phenomenological approach suggests that delusion is formed through loss of context in its experiential-perceptual origins. This is consistent with the more recent neurobiological models. PMID- 23354470 TI - Fruiting and flushing phenology in Asian tropical and temperate forests: implications for primate ecology. AB - In order to understand the ecological adaptations of primates to survive in temperate forests, we need to know the general patterns of plant phenology in temperate and tropical forests. Comparative analyses have been employed to investigate general trends in the seasonality and abundance of fruit and young leaves in tropical and temperate forests. Previous studies have shown that (1) fruit fall biomass in temperate forest is lower than in tropical forest, (2) non fleshy species, in particular acorns, comprise the majority of the fruit biomass in temperate forest, (3) the duration of the fruiting season is shorter in temperate forest, and (4) the fruiting peak occurs in autumn in most temperate forests. Through our comparative analyses of the fruiting and flushing phenology between Asian temperate and tropical forests, we revealed that (1) fruiting is more annually periodic (the pattern in one year is similar to that seen in the next year) in temperate forest in terms of the number of fruiting species or trees, (2) there is no consistent difference in interannual variations in fruiting between temperate and tropical forests, although some oak-dominated temperate forests exhibit extremely large interannual variations in fruiting, (3) the timing of the flushing peak is predictable (in spring and early summer), and (4) the duration of the flushing season is shorter. The flushing season in temperate forests (17-28 % of that in tropical forests) was quite limited, even compared to the fruiting season (68 %). These results imply that temperate primates need to survive a long period of scarcity of young leaves and fruits, but the timing is predictable. Therefore, a dependence on low-quality foods, such as mature leaves, buds, bark, and lichens, would be indispensable for temperate primates. Due to the high predictability of the timing of fruiting and flushing in temperate forests, fat accumulation during the fruit-abundant period and fat metabolization during the subsequent fruit-scarce period can be an effective strategy to survive the lean period (winter). PMID- 23354469 TI - Experimental analysis of tablet properties for discrete element modeling of an active coating process. AB - Coating of solid dosage forms is an important unit operation in the pharmaceutical industry. In recent years, numerical simulations of drug manufacturing processes have been gaining interest as process analytical technology tools. The discrete element method (DEM) in particular is suitable to model tablet-coating processes. For the development of accurate simulations, information on the material properties of the tablets is required. In this study, the mechanical parameters Young's modulus, coefficient of restitution (CoR), and coefficients of friction (CoF) of gastrointestinal therapeutic systems (GITS) and of active-coated GITS were measured experimentally. The dynamic angle of repose of these tablets in a drum coater was investigated to revise the CoF. The resulting values were used as input data in DEM simulations to compare simulation and experiment. A mean value of Young's modulus of 31.9 MPa was determined by the uniaxial compression test. The CoR was found to be 0.78. For both tablet-steel and tablet-tablet friction, active-coated GITS showed a higher CoF compared with GITS. According to the values of the dynamic angle of repose, the CoF was adjusted to obtain consistent tablet motion in the simulation and in the experiment. On the basis of this experimental characterization, mechanical parameters are integrated into DEM simulation programs to perform numerical analysis of coating processes. PMID- 23354471 TI - FKBP10/FKBP65 expression in high-grade ovarian serous carcinoma and its association with patient outcome. AB - The frequent loss of chromosome 17 in epithelial ovarian carcinomas (EOC), particularly high-grade serous carcinomas (HGSC), has been attributed to the disruption of TP53 (at 17p13.1) and other chromosome 17 genes suspected to play a role in tumour suppressor pathways. In a transcriptome analysis of HGSC, we showed underexpression of a number of chromosome 17 genes, which included FKBP10 (at 17q21.1) and collagen I alpha 1 (COL1A1; at 17q21.33). FKBP10 codes for the immunophilin FKBP65 and is suspected to act as a chaperone for COL1A1. We have investigated FKBP10 (gene) and FKBP65 (protein) expression in HGSC samples and EOC cell lines that differ in their tumourigenic potential. COL1A1 expression was also investigated given the purported function of FKBP65. RT-PCR analysis verified underexpression of FKBP10 and COL1A1 in HGSCs (n=14) and six tumourigenic EOC cell lines, relative to normal ovarian surface epithelial cells and a non-tumourigenic EOC cell line. Immunohistochemistry analyses of 196 HGSC samples using tissue microarrays revealed variable staining intensities in the epithelial tumour component where only 7.8% and 1.0% of samples stained intensely for FKBP65 and COL1A1, respectively. Variable staining intensities were also observed for the stromal component where 23.6% and 24.1% stained intensely for FKBP65 and COL1A1, respectively. There was no significant correlation of staining intensity of either protein with disease stage. Staining of FKBP65 was clearly visible in normal epithelial cells of the ovarian surface and fallopian tube. There was a significant correlation between absence of FKBP65 staining in the epithelial cell component of the tumour and prolonged overall survival (p<0.001). Our results suggest that underexpression of FKBP65 protein is characteristic of HGSCs and that this expression profile may be linked to molecular pathways associated with an unfavourable outcome in cancer patients. PMID- 23354472 TI - Which hydrogen atom of toluene protonates PAH molecules in (+)-mode APPI MS analysis? AB - A previous study (Ahmed, A. et al., Anal. Chem. 84, 1146-1151( 2012) reported that toluene used as a solvent was the proton source for polyaromatic hydrocarbon compounds (PAHs) that were subjected to (+)-mode atmospheric-pressure photoionization. In the current study, the exact position of the hydrogen atom in the toluene molecule (either a methyl hydrogen or an aromatic ring hydrogen) involved in the formation of protonated PAH ions was investigated. Experimental analyses of benzene and anisole demonstrated that although the aromatic hydrogen atom of toluene did not contribute to the formation of protonated anthracene, it did contribute to the formation of protonated acridine. Thermochemical data and quantum mechanical calculations showed that the protonation of anthracene by an aromatic ring hydrogen atom of toluene is endothermic, while protonation by a methyl hydrogen atom is exothermic. However, protonation of acridine by either an aromatic ring hydrogen or a methyl hydrogen atom of toluene is exothermic. The different behavior of acridine and anthracene was attributed to differences in gas-phase basicity. It was concluded that both types of hydrogen in toluene can be used for protonation of PAH compounds, but a methyl hydrogen atom is preferred, especially for non-basic compounds. PMID- 23354475 TI - Sensing behavior of Al-rich AlN nanotube toward hydrogen cyanide. AB - In order to explore a sensor for detection of toxic hydrogen cyanide (HCN) molecules, interaction of pristine and defected Al-rich aluminum nitride nanotubes (AlNNT) with a HCN molecule has been investigated using density functional theory calculations in terms of energetic, geometric, and electronic properties. It has been found that unlike the pristine AlNNT, the Al-rich AlNNT can effectively interact with the HCN molecule so that its conductivity changes upon the exposure to this molecule. The adsorption energies of HCN on the pristine and defected AlNNTs have been calculated to be in the range of -0.16 to 0.62 eV and -1.75 to -2.21 eV, respectively. We believe that creating Al-rich defects may be a good strategy for improving the sensitivity of these tubes toward HCN molecules, which cannot be trapped and detected by the pristine AlNNT. PMID- 23354473 TI - Gas-phase reactivity of peptide thiyl (RS*), perthiyl (RSS*), and sulfinyl (RSO*) radical ions formed from atmospheric pressure ion/radical reactions. AB - In this study, we demonstrated the formation of gas-phase peptide perthiyl (RSS*) and thiyl (RS*) radical ions besides sulfinyl radical (RSO*) ions from atmospheric pressure (AP) ion/radical reactions of peptides containing inter chain disulfide bonds. The identity of perthiyl radical was verified from characteristic 65 Da (*SSH) loss in collision-induced dissociation (CID). This signature loss was further used to assess the purity of peptide perthiyl radical ions formed from AP ion/radical reactions. Ion/molecule reactions combined with CID were carried out to confirm the formation of thiyl radical. Transmission mode ion/molecule reactions in collision cell (q2) were developed as a fast means to estimate the population of peptide thiyl radical ions. The reactivity of peptide thiyl, perthiyl, and sulfinyl radical ions was evaluated based on ion/molecule reactions toward organic disulfides, allyl iodide, organic thiol, and oxygen, which followed in order of thiyl (RS*) > perthiyl (RSS*) > sulfinyl (RSO*). The gas-phase reactivity of these three types of sulfur-based radicals is consistent with literature reports from solution studies. PMID- 23354476 TI - Theoretical study on rate constants for the reactions of CF3CH 2NH 2 (TFEA) with the hydroxyl radical at 298 K and atmospheric pressure. AB - Theoretical investigations are carried out on reaction mechanism of the reactions of CF3CH2NH2 (TFEA) with the OH radical by means of ab initio and DFT methods. The electronic structure information on the potential energy surface for each reaction is obtained at MPWB1K/6-31+G(d,p) level and energetic information is further refined by calculating the energy of the species with a Gaussian-2 method, G2(MP2). The existence of transition states on the corresponding potential energy surface is ascertained by performing intrinsic reaction coordinate (IRC) calculation. Our calculation indicates that the H abstraction from -NH2 group is the dominant reaction channel because of lower energy barrier. The rate constants of the reaction calculated using canonical transition state theory (CTST) utilizing the ab initio data. The agreement between the theoretical and experimental rate constants is good at the measured temperature. From the comparison with CH3CH2NH2, it is shown that the fluorine substution decreases the reactivity of the C-H bond. PMID- 23354477 TI - The yin-yang of DNA damage response: roles in tumorigenesis and cellular senescence. AB - Senescent cells are relatively stable, lacking proliferation capacity yet retaining metabolic activity. In contrast, cancer cells are rather invasive and devastating, with uncontrolled proliferative capacity and resistance to cell death signals. Although tumorigenesis and cellular senescence are seemingly opposite pathological events, they are actually driven by a unified mechanism: DNA damage. Integrity of the DNA damage response (DDR) network can impose a tumorigenesis barrier by navigating abnormal cells to cellular senescence. Compromise of DDR, possibly due to the inactivation of DDR components, may prevent cellular senescence but at the expense of tumor formation. Here we provide an overview of the fundamental role of DDR in tumorigenesis and cellular senescence, under the light of the Yin-Yang concept of Chinese philosophy. Emphasis is placed on discussing DDR outcome in the light of in vivo models. This information is critical as it can help make better decisions for clinical treatments of cancer patients. PMID- 23354478 TI - Comparative in vivo assessment of some adverse bioeffects of equidimensional gold and silver nanoparticles and the attenuation of nanosilver's effects with a complex of innocuous bioprotectors. AB - Stable suspensions of nanogold (NG) and nanosilver (NS) with mean particle diameter 50 and 49 nm, respectively, were prepared by laser ablation of metals in water. To assess rat's pulmonary phagocytosis response to a single intratracheal instillation of these suspensions, we used optical, transmission electron, and semi-contact atomic force microscopy. NG and NS were also repeatedly injected intraperitoneally into rats at a dose of 10 mg/kg (0.5 mg per mL of deionized water) three times a week, up to 20 injections. A group of rats was thus injected with NS after oral administration of a "bioprotective complex" (BPC) comprised of pectin, multivitamins, some amino acids, calcium, selenium, and omega-3 PUFA. After the termination of the injections, many functional and biochemical indices and histopathological features of the spleen, kidneys and liver were evaluated for signs of toxicity, and accumulation of NG or NS in these organs was measured. From the same rats, we obtained cell suspensions of different tissues for performing the RAPD test. It was demonstrated that, although both nanometals were adversely bioactive in all respects considered in this study, NS was more noxious as compared with NG, and that the BPC tested by us attenuated both the toxicity and genotoxicity of NS. PMID- 23354479 TI - S-layer protein self-assembly. AB - Crystalline S(urface)-layers are the most commonly observed cell surface structures in prokaryotic organisms (bacteria and archaea). S-layers are highly porous protein meshworks with unit cell sizes in the range of 3 to 30 nm, and thicknesses of ~10 nm. One of the key features of S-layer proteins is their intrinsic capability to form self-assembled mono- or double layers in solution, and at interfaces. Basic research on S-layer proteins laid foundation to make use of the unique self-assembly properties of native and, in particular, genetically functionalized S-layer protein lattices, in a broad range of applications in the life and non-life sciences. This contribution briefly summarizes the knowledge about structure, genetics, chemistry, morphogenesis, and function of S-layer proteins and pays particular attention to the self-assembly in solution, and at differently functionalized solid supports. PMID- 23354480 TI - Melatonin may curtail the metabolic syndrome: studies on initial and fully established fructose-induced metabolic syndrome in rats. AB - To examine the effect of melatonin given to rats simultaneously with fructose on initial and fully developed metabolic syndrome, male Wistar rats had free access to chow and 5% or 10% fructose drinking solution for 8 weeks. As compared to controls, systolic blood pressure augmented significantly under both treatments whereas excessive body weight was seen in rats receiving the 10% fructose only. Rats drinking 5% fructose showed a greater tolerance to a glucose load while rats having access to a 10% fructose drinking solution exhibited the expected impaired glucose tolerance found in the metabolic syndrome. Circulating triglyceride and low density lipoproteins-cholesterol (LDL-c) concentration augmented significantly in rats showing a fully developed metabolic syndrome only, while high blood cholesterol levels were found at both stages examined. Melatonin (25 MUg/mL drinking solution) counteracted the changes in body weight and systolic blood pressure found in rats administered with fructose. Melatonin decreased the abnormal hyperglycemia seen after a glucose load in 10% fructose-treated rats but it did not modify the greater tolerance to glucose observed in animals drinking 5% fructose. Melatonin also counteracted the changes in plasma LDL-c, triglyceride and cholesterol levels and decreased plasma uric acid levels. The results underline a possible therapeutical role of melatonin in the metabolic syndrome, both at initial and established phases. PMID- 23354481 TI - Efficient Agrobacterium-Mediated Transformation of Hybrid Poplar Populus davidiana Dode x Populus bollena Lauche. AB - Poplar is a model organism for high in vitro regeneration in woody plants. We have chosen a hybrid poplar Populus davidiana Dode x Populus bollena Lauche. By optimizing the Murashige and Skoog medium with (0.3 mg/L) 6-benzylaminopurine and (0.08 mg/L) naphthaleneacetic acid, we have achieved the highest frequency (90%) for shoot regeneration from poplar leaves. It was also important to improve the transformation efficiency of poplar for genetic breeding and other applications. In this study, we found a significant improvement of the transformation frequency by controlling the leaf age. Transformation efficiency was enhanced by optimizing the Agrobacterium concentration (OD(600) = 0.8-1.0) and an infection time (20-30 min). According to transmission electron microscopy observations, there were more Agrobacterium invasions in the 30-day-old leaf explants than in 60-day-old and 90 day-old explants. Using the green fluorescent protein (GFP) marker, the expression of MD-GFP fusion proteins in the leaf, shoot, and root of hybrid poplar P. davidiana Dode x Populus. bollena Lauche was visualized for confirmation of transgene integration. Southern and Northern blot analysis also showed the integration of T-DNA into the genome and gene expression of transgenic plants. Our results suggest that younger leaves had higher transformation efficiency (~30%) than older leaves (10%). PMID- 23354482 TI - Regulation of Phosphatidylethanolamine Homeostasis—The Critical Role of CTP:Phosphoethanolamine Cytidylyltransferase (Pcyt2). AB - Phosphatidylethanolamine (PE) is the most abundant lipid on the protoplasmatic leaflet of cellular membranes. It has a pivotal role in cellular processes such as membrane fusion, cell cycle regulation, autophagy, and apoptosis. CTP:phosphoethanolamine cytidylyltransferase (Pcyt2) is the main regulatory enzyme in de novo biosynthesis of PE from ethanolamine and diacylglycerol by the CDP-ethanolamine Kennedy pathway. The following is a summary of the current state of knowledge on Pcyt2 and how splicing and isoform specific differences could lead to variations in functional properties in this family of enzymes. Results from the most recent studies on Pcyt2 transcriptional regulation, promoter function, autophagy, and cell growth regulation are highlighted. Recent data obtained from Pcyt2 knockout mouse models is also presented, demonstrating the essentiality of this gene in embryonic development as well as the major physiological consequences of deletion of one Pcyt2 allele. Those include development of symptoms of the metabolic syndrome such as elevated lipogenesis and lipoprotein secretion, hypertriglyceridemia, liver steatosis, obesity, and insulin resistance. The objective of this review is to elucidate the nature of Pcyt2 regulation by linking its catalytic function with the regulation of lipid and energy homeostasis. PMID- 23354483 TI - Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. AB - Two major populations of myeloid-derived suppressor cells (MDSCs), monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) regulate immune responses in cancer and other pathologic conditions. Under physiologic conditions, Ly6C(hi)Ly6G(-) inflammatory monocytes, which are the normal counterpart of M MDSCs, differentiate into macrophages and dendritic cells. PMN-MDSCs are the predominant group of MDSCs that accumulates in cancer. Here we show that a large proportion of M-MDSCs in tumor-bearing mice acquired phenotypic, morphological and functional features of PMN-MDSCs. Acquisition of this phenotype, but not the functional attributes of PMN-MDSCs, was mediated by transcriptional silencing of the retinoblastoma gene through epigenetic modifications mediated by histone deacetylase 2 (HDAC-2). These data demonstrate a new regulatory mechanism of myeloid cells in cancer. PMID- 23354484 TI - Plasma cells require autophagy for sustainable immunoglobulin production. AB - The role of autophagy in plasma cells is unknown. Here we found notable autophagic activity in both differentiating and long-lived plasma cells and investigated its function through the use of mice with conditional deficiency in the essential autophagic molecule Atg5 in B cells. Atg5(-/-) differentiating plasma cells had a larger endoplasmic reticulum (ER) and more ER stress signaling than did their wild-type counterparts, which led to higher expression of the transcriptional repressor Blimp-1 and immunoglobulins and more antibody secretion. The enhanced immunoglobulin synthesis was associated with less intracellular ATP and more death of mutant plasma cells, which identified an unsuspected autophagy-dependent cytoprotective trade-off between immunoglobulin synthesis and viability. In vivo, mice with conditional deficiency in Atg5 in B cells had defective antibody responses, complete selection in the bone marrow for plasma cells that escaped Atg5 deletion and fewer antigen-specific long-lived bone marrow plasma cells than did wild-type mice, despite having normal germinal center responses. Thus, autophagy is specifically required for plasma cell homeostasis and long-lived humoral immunity. PMID- 23354485 TI - Enhanced survival of lung tissue-resident memory CD8+ T cells during infection with influenza virus due to selective expression of IFITM3. AB - Infection with influenza virus results in the deposition of anti-influenza CD8(+) resident memory T cells (T(RM) cells) in the lung. As a consequence of their location in the lung mucosal tissue, these cells are exposed to cytopathic pathogens over the life of the organism and may themselves be susceptible to infection. Here we found that lung T(RM) cells selectively maintained expression of the interferon-induced transmembrane protein IFITM3, a protein that confers broad resistance to viral infection. Lung T(RM) cells that lacked IFITM3 expression were more susceptible to infection than were their normal counterparts and were selectively lost during a secondary bout of infection. Thus, lung T(RM) cells were programmed to retain IFITM3 expression, which facilitated their survival and protection from viral infection during subsequent exposures. PMID- 23354486 TI - [Anesthetist's briefing check. Tool to improve patient safety in the operating room]. AB - Adverse events are not unusual in a more and more complex anesthesiological environment. The main reasons for this are an increasing workload, economic pressure, growing expectations of patients and deficits in planning and communication. However, these incidents mostly do not refer to medical deficits but to flaws in non-technical skills (team organisation, task orientation, decision making and communication). The introduction of the WHO Safe Surgery Checklist depicted that a structural approach can improve the situation. However, it is still questionable if this measure is strong enough and recent publications revealed initial criticisms. Furthermore, remaining security gaps could be found even though the checklist was implemented in the anesthesiological practice of a big teaching hospital. Therefore, an additional checklist was developed to implement an anesthesia briefing in the daily routine. The main objective was to establish a security check before induction similar to the aeronautical pre flight check. Additionally, this measure should improve coordination of the anesthesiology team. Working through the checklist, doctors and nurses are guided to focus on conjoint patient care prior to induction of anesthesia. In a web based survey the general attitude of coworkers towards patient safety, as well as the acceptability of the new briefing check was scrutinised at two times: directly before implementation of the checklist and 1 year after. The results (84 % of medical and 97 % of healthcare staff answered the questionnaires) showed improvements with high relevance to parameters associated with awareness concerning safety issues and team coordination. In conclusion, it appears that patient safety can be significantly improved with little time effort of 3-5 min per patient. A prospective trial will be conducted to confirm the impact of this measure on improvements in patient safety. PMID- 23354487 TI - [Fatal incidents by crowd crush during mass events. (Un)preventable phenomenon?]. AB - BACKGROUND: Crowd crushes with dozens or even hundreds of casualties have occurred several times at the Hajj in Saudi Arabia and also in soccer stadiums in Western Europe. As fatal accidents after human stampedes during mass events occur very rarely and are usually accompanied by many years of criminal court proceedings in order to identify underlying responsible mechanisms and culprits, it is very difficult to draw conclusions and formulate precautions from an emergency medical point of view. METHODS: This study analyzed a fatal crowd crush which occurred on 4 December 1999 following the "Air & Style" snowboard contest with approximately 22,000 people attending in the Bergisel stadium in Innsbruck, Austria. Firstly, focused interviews were conducted with professional rescuers, police and physicians and secondly publicly available court records dealing with this incident in the district court of Innsbruck, Austria were analyzed. RESULTS: During the snowboard contest 87 emergency medical technicians, 6 emergency physicians, 1 leading emergency physician, 21 policemen and 140 security personnel were present. Following the accident additionally some 100 emergency medical technicians, 36 emergency medical service vehicles and 4 physician staffed emergency medical service vehicles responded to the scene. The deadly crowd crush resulting in 6 fatalities, 4 patients still in a vegetative state and 38 injured, was due to a severe crowd accumulation at one stadium exit, which was not recognized and dispersed in time. Construction of the exit in line with darkness, steep slope and slippery surface contributed adversely to this dangerous situation, although panic did not occur at any time. CONCLUSIONS: Unfortunately, there is no patent remedy to completely prevent fatal accidents by a crowd crush at mass events. If planning is initiated early, sufficient material and personnel reserves are kept in reserve and despite conflicting interests of the organizers, the host community, security, police and emergency medical services, a joint concept is designed and followed, the risk of a severe incident can be kept to a minimum. Each involved party including the spectators have to be aware of their responsibility in order to contribute to the success and safety of the mass event. A comprehensive and critical review of all facts and implementation of conclusions implies a time and financial burden but has a positive impact on the success and safety of mass events. PMID- 23354488 TI - [Take a position on changes in therapy aims and limiting therapy: Actio moralis practiced in intensive care medicine]. PMID- 23354489 TI - [Developmental abnormalities in children following surgery under general anesthesia: anesthesiological problem?]. PMID- 23354490 TI - Indium-catalyzed annulation of 3-aryl- and 3-heteroarylindoles with propargyl ethers: synthesis and photoluminescent properties of aryl- and heteroaryl[c]carbazoles. AB - Treatment of 3-aryl- and 3-heteroarylindoles with propargyl ethers under indium catalysis successfully provided aryl- and heteroaryl[c]carbazoles, which were found to be more efficient emitters compared with the corresponding [a]-analogs. PMID- 23354491 TI - Relationship between breast arterial calcifications detected on mammography and brachial artery intima-media thickness. AB - PURPOSE: Although breast arterial calcification (BAC) was shown to be related with coronary artery disease (CAD), hypertension (HT), diabetes mellitus (DM) and carotid intima-media thickness (C-IMT), but the association between BAC and brachial intima-media thickness (B-IMT) has not been evaluated yet. Our aim was to investigate whether associations existed between BAC and measure B-IMT and atherosclerosis (AS) by comparing these patients with healthy control subjects. METHODS: A Total of 75 patients were included in the study. Subjects with or without BAC were assigned into one of two groups and those with a BAC were graded. Main brachial artery IMT was measured. RESULTS: When the effect of age was partialled out statistically, we found a statistically significant difference in mean B-IMT between BAC (+) (0.54 +/- 0.09) and BAC (-) (0.45 +/- 0.08) groups (p = 0.001) after the groups were adjusted for age. CONCLUSIONS: In conclusion, even though the relationship between B-IMT and BAC was significant, like the relationship between C-IMT and BAC, significant age difference between BAC (+) and BAC (-) groups and no significant relationship between BAC and time after menopause, after adjustment for age, suggest a strong association between BAC and age rather than AS. This can be elucidated by pathological correlation studies in larger series of subjects. PMID- 23354492 TI - Fentanyl-induced cough during general anesthesia: a different perspective. PMID- 23354493 TI - The accuracy and inter-observer reliability of acetate templating in total hip arthroplasty. AB - AIM: The accuracy and inter-observer reliability (IOR) of acetate templating on hard copy X-rays in 33 primary total hip arthroplasties as measured by consultant and trainee surgeons was analyzed to find out how accurate are junior surgeons undertaking specialty training. METHODS: The study was questionnaire-based using a prospective cohort over a 4 weeks period. The Surgeon measurements of acetabular cup, femoral stem and femoral offset sizes were noted following acetate measurements and then compared with the final implant chosen during surgery. RESULTS: Prediction of sizing to within one size of the final match size was 75% accurate for cup and 91% accurate for femoral stem. Prediction of exact femoral offset sizes was 91% accurate. Templating showed strong IOR between senior consultant surgeon and junior trainee registrar within one size for cup (83%) and stem (100%) and for exact hip offset prediction (92%). CONCLUSION: We conclude that acetate templating on hard copy X-rays is beneficial to surgeons to gauge acetabular cup and femoral stem size to within one size range. This further helps in predicting nearly exact femoral offset size. PMID- 23354494 TI - Risk factors for surgical site infection following operative ankle fracture fixation. AB - BACKGROUND: Ankle fracture is a common injury and there is an increasingly greater emphasis on operative fixation. AIM: The purpose of the study was to determine the complication rate in this cohort of patients and, in doing so, determine risk factors which predispose to surgical site infection. METHODS: A prospective cohort study was performed at a tertiary referral trauma center examining risk factors for surgical site infection in operatively treated ankle fractures. RESULTS: Univariate and multivariate analysis was performed. Female gender and advancing age were determined to be the risk factors in univariate analysis. Drain usage and peri-operative pyrexia were found to be significant for infection in multivariate analysis. CONCLUSION: This study allows surgeons to identify those at increased risk of infection and counsel them appropriately. It also allows for a high level of vigilance with regard to soft tissue handling intra-operatively in this higher risk group. PMID- 23354495 TI - Transparency and accountability in mass media campaigns about organ donation: a response to Morgan and Feeley. AB - We respond to Morgan and Feeley's critique on our article "Mass Media in Organ Donation: Managing Conflicting Messages and Interests." We noted that Morgan and Feeley agree with the position that the primary aims of media campaigns are: "to educate the general public about organ donation process" and "help individuals make informed decisions" about organ donation. For those reasons, the educational messages in media campaigns should not be restricted to "information from pilot work or focus groups" but should include evidence-based facts resulting from a comprehensive literature research. We consider the controversial aspects about organ donation to be relevant, if not necessary, educational materials that must be disclosed in media campaigns to comply with the legal and moral requirements of informed consent. With that perspective in mind, we address the validity of Morgan and Feeley's claim that media campaigns have no need for informing the public about the controversial nature of death determination in organ donation. Scientific evidence has proven that the criteria for death determination are inconsistent with the Uniform Determination of Death Act and therefore potentially harmful to donors. The decision by campaign designers to use the statutory definition of death without disclosing the current controversies surrounding that definition does not contribute to improved informed decision making. We argue that if Morgan and Feeley accept the important role of media campaigns to enhance informed decision making, then critical controversies should be disclosed. In support of that premise, we will outline: (1) the wide-spread scientific challenges to brain death as a concept of death; (2) the influence of the donor registry and team-huddling on the medical care of potential donors; (3) the use of authorization rather than informed consent for donor registration; (4) the contemporary religious controversy; and (5) the effects of training desk clerks as organ requestors at the Department of Motor Vehicles offices. We conclude that organ donation is a medical procedure subject to all the ethical obligations that the medical profession must uphold including that of transparency and truthfulness. PMID- 23354496 TI - Heterologous expression and characterization of a glycoside hydrolase family 45 endo-beta-1,4-glucanase from a symbiotic protist of the lower termite, Reticulitermes speratus. AB - The termite symbiotic system is one of the efficient lignocellulose degradation systems. We tried to express and characterize a novel cellulolytic enzyme from this system. Here, we report the isolation of an endo-beta-1,4-glucanase gene homolog of glycoside hydrolase family 45 from a symbiotic protistan community of Reticulitermes speratus. Heterologous expression of this gene was performed using the expression system of Aspergillus oryzae. Analysis of enzymatic properties revealed 786 MUmol/min/mg protein in specific activity, a V max of 833.0 units/mg protein, and a K m value of 2.58 mg/ml with carboxymethyl cellulose as the substrate. Thin-layer chromatography analysis showed that RsSymEG2 produces cellobiose from cellodextrins larger than cellohexaose. This enzyme showed high specific activity like other endo-beta-1,4-glucanases from the symbiotic system of termites. It means that the termite symbiotic system is a good resource for highly active endo-beta-1,4-glucanases. PMID- 23354497 TI - Piper nigrum: micropropagation, antioxidative enzyme activities, and chromatographic fingerprint analysis for quality control. AB - A reliable in vitro regeneration system for the economical and medicinally important Piper nigrum L. has been established. Callus and shoot regeneration was encouraged from leaf portions on Murashige and Skoog (MS) medium augmented with varied concentrations of plant growth regulators. A higher callus production (90 %) was observed in explants incubated on MS medium incorporated with 1.0 mg L(-1) 6-benzyladenine (BA) along with 0.5 mg L(-1) gibberellic acid after 4 weeks of culture. Moreover, a callogenic response of 85 % was also recorded for 1.0 mg L( 1) BA in combination with 0.25 mg L(-1) alpha-naphthalene acetic acid (NAA) and 0.25 mg L(-1) 2,4-dichlorophenoxyacetic acid or 0.5 mg L(-1) indole butyric acid (IBA) along with 0.25 mg L(-1) NAA and indole acetic acid. Subsequent sub culturing of callus after 4 weeks of culture onto MS medium supplemented with 1.5 mg L(-1) thiodiazoran or 1.5 mg L(-1) IBA induced 100 % shoot response. Rooted plantlets were achieved on medium containing varied concentrations of auxins. The antioxidative enzyme activities [superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX)] revealed that significantly higher SOD was observed in regenerated plantlets than in other tissues. However, POD, CAT, and APX were higher in callus than in other tissues. A high-performance liquid chromatography (HPLC) fingerprint analysis protocol was established for quality control in different in vitro-regenerated tissues of P. nigrum L. During analysis, most of the common peaks represent the active principle "piperine." The chemical contents, especially piperine, showed variation from callus culture to whole plantlet regeneration. Based on the deviation in chromatographic peaks, the in vitro-regenerated plantlets exhibit a nearly similar piperine profile to acclimated plantlets. The in vitro regeneration system and HPLC fingerprint analysis established here brought a novel approach to the quality control of in vitro plantlets, producing metabolites of interest with substantial applications for the conservation of germplasm. PMID- 23354498 TI - Endopolysaccharides from Ganoderma resinaceum, Phlebia rufa, and Trametes versicolor affect differently the proliferation rate of HepG2 cells. AB - Fungi have been used for medicinal purposes for long time by Asian countries, being a putative source of powerful new phytopharmaceuticals such as polysaccharides. The aim of this study was to extract endopolysaccharides (IPS) from Ganoderma resinaceum, Phlebia rufa, and Trametes versicolor, grown under submerged culture, to compare crude IPS production, total carbohydrate, and protein yield, and to study the effect of these IPS on HepG2 cells proliferation rate. Total biomass produced by G. resinaceum, P. rufa, and T. versicolor was (in gram per liter) 3.32 +/- 0.80, 5.42 +/- 0.58, and 4.2 +/- 1.29 and the IPS yield (as the biomass percent) was 9.9 +/- 0.05, 29.0 +/- 6.3, and 9.1 +/- 3.1 %, respectively. Characterization of IPS has shown different proportion between total sugar and protein being, on average 6.04, 10.74, and 22.62, for G. resinaceum, T. versicolor, and P. rufa, respectively. The IPS effect, at 50, 100, and 200 MUg mL(-1) on HepG2 cell growth and viability was negligible for G. resinaceum and P. rufa but, in the case of T. versicolor, 200 MUg mL(-1) of IPS evoked 40 % reduction on cell growth. The results suggest that the intracellular polysaccharides from T. versicolor are a potential source for bioactive molecules with anti-proliferative properties. PMID- 23354499 TI - Heterotrophic nitrifying and oxygen tolerant denitrifying bacteria from greenwater system of coastal aquaculture. AB - In this work, herbivorous fish Mugil cephalus has been cultured to secrete protein rich green slime, which helps nitrifying and oxygen tolerant denitrifying bacteria to grow and colonize. Four strains representing Alcaligenaceae family have been isolated from greenwater system and characterized using biochemical test, fatty acid methyl ester (GC-FAME) analysis, 16S rRNA and functional gene approaches. They were tested for an ability to nitrify ammonia and nitrite aerobically. Two strains showed notable nitrification activity, when grown in a mineral salts medium containing ammonium sulfate and potassium nitrite. Functional gene analysis confirmed the presence of nitrous oxide reductase (nosZ) gene showing that they have an oxygen-tolerant denitrification system. It has been proposed that Alcaligenes faecalis strains heterotrophically nitrify ammonia into nitrite via formation of hydroxyl amine, which is oxidized to nitrous oxide using oxygen or nitrite as electron acceptor. These results provide a possible advantage of having nitrification and denitrification capabilities in the same organism, which plays an important role in biological wastewater system. PMID- 23354500 TI - Biodiesel residual glycerol metabolism by Klebsiella pneumoniae: pool of metabolites under anaerobiosis and oxygen limitation as a function of feeding rates. AB - The metabolism of residual glycerol from biodiesel synthesis by Klebsiella pneumoniae BLh-1 was investigated in this study. Batch and fed-batch cultivations were performed in bioreactors under anaerobic and oxygen limitation conditions. Results of batch cultivations showed that the main product was 1,3-propanediol (1,3-PD) in both conditions, although the higher yields and productivities (0.46 mol mol(-1) glycerol and 1.22 g L(-1) h(-1), respectively) were obtained under anaerobic condition. Large amounts of ethanol were also produced under batch anaerobic condition, peaking at 12.30 g L(-1). Batch cultivations under oxygen limitation were characterized by faster growth kinetics, with higher biomass production but lower conversions of glycerol into 1,3-PD, with yields and productivities of 0.33 mol mol(-1) glycerol and 0.99 g L(-1) h(-1), respectively. The fed-batch cultivations were carried out in order to investigate the effects of feeding of raw glycerol on cells. Fed-batch under anaerobiosis showed that 1,3 PD and ethanol concentrations increased with the feeding rate, with maximal productions of 26.12 and 19.2 g L(-1), respectively. The oxygen limitation conditions diverted the bacterium metabolism to an elevated lactic acid formation, reaching 59 g L(-1) in higher feeding rates of glycerol, but lowering the production of ethanol. PMID- 23354501 TI - Expression and large-scale production of human tissue plasminogen activator (t PA) in transgenic tobacco plants using different signal peptides. AB - An attempt was made to assess the expression level and targeting of a human protein entitled recombinant tissue plasminogen activator (rt-PA) through accumulation in three cellular compartments including the endoplasmic reticulum and cytosolic and apoplastic spaces in transgenic tobacco plants. In this context, three chimeric constructs pBI-SP-tPA, pBI-tPA-KDEL, and pBI-Ext-tPA were employed and transferred into the tobacco plants through a popular transformation based system called Agrobacterium tumefaciens. As an initial screening system, the incorporation of the rt-PA gene in the genomic DNA of tobacco transgenic plants and the possible existence of the rt-PA-specific transcript in the total RNAs of transgenic plant leaves were confirmed via PCR and reverse transcription (RT)-PCR, respectively. Southern blot analysis, in addition, was used to determine the copy number of the corresponding gene (i.e., t-PA) transformed into the each transgenic plant; one or more copies were detected regarding transformants derived from all three abovementioned constructs. According to the enzyme-linked immunosorbent assay, the mean values of t-PA expression were calculated as 0.50, 0.68, and 0.69 MUg/mg of the total soluble protein when a collection containing 30 transgenic plants transformed with pBI-SP-tPA, pBI-tPA KDEL, and pBI-Ext-tPA was taken into account, respectively. The zymography assay was lastly performed and concluded the expression of the properly folded rt-PA in this expression system. Our results, altogether, revealed that tobacco plants could be utilized as a bioreactor system for the large-scale production of enzymatically active t-PA and presumably other therapeutic recombinant proteins in large quantities. PMID- 23354502 TI - Expression of the acid protease gene from Saccharomycopsis fibuligera in the marine-derived Yarrowia lipolytica for both milk clotting and single cell protein production. AB - In this study, the native acid protease gene in Yarrowia lipolytica 22a-2 with high content of protein was disrupted, and the disruptant 3-13-10 obtained had very low acid protease activity. Then, the acid protease gene (AP1 gene) from Saccharomycopsis fibuligera A11 was actively expressed in the disruptant 3-13-10, and the transformant 43 carrying the AP1 gene had high specific acid protease activity (46.7 U/mg). The recombinant acid protease produced by the transformant 43 was found to be able to actively clot milk, and the transformant 43 still kept high content of protein. The hydrolysis products of kappa-casein under catalysis of the recombinant acid protease and the commercial calf rennet had the same molecular mass, suggesting that the recombinant acid protease and its producer can be used both in cheese manufacturing and as protein source in food industry. PMID- 23354503 TI - Overproduction of polygalacturonase by Penicillium griseoroseum recombinant strains and functional analysis by targeted disruption of the pgg2 gene. AB - Inactivation of the pgg2 gene, a polygalacturonase-encoding gene from Penicillium griseoroseum, reduced the total activity of polygalacturonase (PG) by 90 % in wild-type P. griseoroseum, which indicates that the pgg2 gene is the major gene responsible for PG production in this species. To increase PG production, the coding region of the pgg2 gene was cloned under the control of the glyceraldehyde 3-phosphate dehydrogenase (gpd) promoter and the terminator region of the tryptophan synthase (trpC) gene from Aspergillus nidulans (pAN52pgg2 vector). This vector was then used to transform P. griseoroseum. The transformed strains were characterized according to PG production using glucose, sucrose, or sugar cane juice as the carbon sources. The recombinant P. griseoroseum T146 strain contained an additional copy of the pgg2 gene, which resulted in a 12-fold increase in PG activity when compared with that detected in the supernatant of the control PG63 strain. The proteins secreted by the recombinant strain T146 showed a strong band at 38 kDa, which corresponds to the molecular weight of PG of the P. griseoroseum. The results demonstrate the significant biotechnological potential of recombinant P. griseoroseum T146 for use in PG production. PMID- 23354504 TI - A new trend on biosensor for neurotransmitter choline/acetylcholine--an overview. AB - Technology always has been an indispensible part in the development of biosensors. The performance of biosensors is being tremendously improved using new materials as transducer as well as binding material in their construction. The use of new materials allowed innovation on transduction technology in biosensor preparations. Because of the submicron dimensions of these sensors, simple and rapid analyses in vitro as well as in vivo are now possible. Portable instruments capable of analysing multiple components are becoming available, too. Sensors that provide excellent temporal and spatial resolution for in vivo monitoring such as for measurement of neurotransmitters have become prominent. The interest to improve the stability, sensitivity and selectivity of the sensors is paramount. This study tries to give an overview of the present status of the material-based biosensor design and new generation of choline/acetylcholine neurotransmitter biosensors. PMID- 23354505 TI - Case report of bilateral adrenal leiomyoma with review of literature. PMID- 23354507 TI - Correlation between sleep parameters, physical activity and quality of life in somnolent moderate to severe obstructive sleep apnea adult patients. AB - PURPOSE: Several symptoms are described in obstructive sleep apnea (OSA), including excessive daytime sleepiness, depressive mood and neurocognitive dysfunction. However, few studies examined the relationship between objective physical activity, quality of life and sleep parameters. The purpose of this study was to determine sleep parameters (evaluated by actigraphy and polysomnography) implied in the occurrence of impaired physical activity and reduced quality of life in somnolent moderate to severe OSA patients. METHODS: We reviewed retrospectively data of 75 somnolent moderate to severe (Apnea-Hypopnea Index > 20) OSA patients. Data of 5-days actigraphy and polysomnography were analysed. They all completed the Nottingham Health Profile questionnaire (NHP). Sleep parameters associated with physical activity and quality of life were assessed. RESULTS: Patients were mainly obese (mean BMI 36) and males (53 %). Controlling for age and BMI, physical activity, expressed as number of steps walked/day, is associated with OSA severity in REM sleep (p = 0.05). Subjective somnolence was not associated with reduced physical activity. Regarding quality of life, "sleep", "energy" and "emotional reactions" scored highest; and patients evaluated correctly their activity impairment through the "mobility" item of NHP questionnaire. CONCLUSIONS: Low level of physical activity is associated with increasing OSA severity in somnolent moderate to severe OSA patients but is not linked to subjective somnolence. These patients describe concomitantly a severely impaired quality of life in several domains, and the negative perception in the "mobility" domain is effectively related to an objective low level of physical activity. PMID- 23354508 TI - Sleep and beverage drinking among Thai college students. PMID- 23354509 TI - An electrocardiogram-based analysis evaluating sleep quality in patients with obstructive sleep apnea. AB - OBJECTIVE: The study compares polysomnography (PSG) and cardiopulmonary coupling (CPC) sleep quality variables in patients with (1) obstructive sleep apnea (OSA) and (2) successful and unsuccessful continuous positive airway pressure (CPAP) response. PATIENTS/METHODS: PSGs from 50 subjects (32 F/18 M; mean age 48.4 +/- 12.29 years; BMI 34.28 +/- 9.33) were evaluated. OSA patients were grouped by no (n = 16), mild (n = 13), and moderate to severe (n = 20) OSA (apnea-hypopnea index (AHI) <= 5, >5-15, >15 events/h, respectively). Outcome sleep quality variables were sleep stages in non-rapid eye movement, rapid eye movement sleep, and high (HFC), low (LFC), very low-frequency coupling (VLFC), and elevated LFC broad band (e-LFCBB). An AHI <= 5 events/h and HFC >= 50 % indicated a successful CPAP response. CPC analysis extracts heart rate variability and QRS amplitude change that corresponds to respiration. CPC-generated spectrograms represent sleep dynamics from calculated coherence product and cross-power of both time series datasets. RESULTS: T tests differentiated no and moderate to severe OSA groups by REM % (p = 0.003), HFC (p = 0.007), VLFC (p = 0.007), and LFC/HFC ratio (p = 0.038) variables. The successful CPAP therapy group (n = 16) had more HFC (p = 0.003), less LFC (p = 0.003), and e-LFCBB (p = 0.029) compared to the unsuccessful CPAP therapy group (n = 8). PSG sleep quality measures, except the higher arousal index (p = 0.038) in the unsuccessful CPAP group, did not differ between the successful and unsuccessful CPAP groups. HFC >= 50 % showed high sensitivity (77.8 %) and specificity (88.9 %) in identifying successful CPAP therapy. CONCLUSIONS: PSG and CPC measures differentiated no from moderate to severe OSA groups and HFC >= 50 % discriminated successful from unsuccessful CPAP therapy. The HFC >= 50 % cutoff showed clinical value in identifying sleep quality disturbance among CPAP users. PMID- 23354510 TI - Regular physical exercise: evidence for health benefits in OSA patients? PMID- 23354511 TI - Sleep-disordered breathing and daytime napping are associated with maternal hyperglycemia. AB - OBJECTIVES: Sleep disturbances in pregnancy may impair glucose mechanism. This study aimed to examine associations of sleep-disordered breathing, sleep, and nap duration with 1-h glucose challenge test (GCT) levels in pregnant women after controlling for known risk factors for gestational diabetes. METHODS: This is a case-control study of 104 pregnant women. All women underwent full polysomnography and a GCT and completed the multivariable apnea prediction and Pittsburgh Sleep Quality indexes. The primary outcome was maternal hyperglycemia measured by GCT. Bivariate and multivariable logistic regression analyses were performed. RESULTS: Over 13 % subjects reported habitual snoring in the first trimester. Only 9.3 % women with normoglycemia (GCT < 135) were habitual snorers, whereas 45.5 % women with hyperglycemia (GCT >= 135) had habitual snoring (p < 0.001). Sleep-disordered breathing symptoms (loud snoring, snorting/gasping, and apneas) (odds ratio (OR) 2.85; 95 % confidence interval (CI) 1.50-5.41; p = 0.001) and total nap duration (OR 1.48; 95 % CI 0.96-2.28; p = 0.08) were associated with hyperglycemia. After adjusting for confounders, sleep-disordered breathing symptoms (OR 3.37; 95 % CI 1.44-8.32; p = 0.005) and nap duration (OR 1.64; 95 % CI 1.00-2.681.02; p = 0.05) continued to be associated with hyperglycemia. However, the primary exposure measure, the apnea/hypopnea index in the first trimester was not significantly associated with hyperglycemia (OR 1.03; 95 % CI 0.83-1.28; p = 0.77). CONCLUSIONS: Sleep-disordered breathing symptoms and nap duration are associated with hyperglycemia. Sleep duration was not associated with hyperglycemia. Research is needed concerning whether women with sleep-disordered breathing and/or daytime napping are at risk for gestational diabetes. PMID- 23354512 TI - Automatic slice alignment method for cardiac magnetic resonance imaging. AB - OBJECTIVES: Automatic slice alignment is important for easier operation and shorter examination times in cardiac magnetic resonance imaging (MRI) examinations. We propose a new automatic slice alignment method for six cardiac planes (short-axis, vertical long-axis, horizontal long-axis, 4-chamber, 2 chamber, and 3-chamber views). MATERIALS AND METHODS: ECG-gated 2D steady-state free precession axial multislice images were acquired using a 1.5-T MRI scanner during a single breath-hold. The scanning time was set to <20 s in 23 volumes from 23 healthy volunteers. In this method, the positions of the mitral valve, cardiac apex, left ventricular outflow tract, tricuspid valve, anterior wall of the heart, and right ventricular corner are detected to determine the positions of six reference planes by combining knowledge-based recognition and image processing techniques. In order to evaluate the results of automatic slice alignment for the short-axis, 4-chamber, 2-chamber, and 3-chamber views, the angular and positional errors between the results obtained by our proposed method and by manual annotation were measured. RESULTS: The average angular errors for the short-axis, 4-chamber, 2-chamber, and 3-chamber views were 3.05 degrees , 4.52 degrees , 7.28 degrees , and 5.79 degrees , respectively. The average positional errors for the short-axis (base), short-axis (apex), 4-chamber, 2 chamber, and 3-chamber views were 6.61 degrees , 3.80 degrees , 1.55 degrees , 1.52 degrees , and 1.48 degrees , respectively. CONCLUSION: The experimental results showed that our proposed method can detect the cardiac planes quickly and accurately. Our method is therefore beneficial to both patients and operators. PMID- 23354513 TI - T2 relaxometry measurements in low spatial frequency brain regions differ between fast spin-echo and multiple-echo spin-echo sequences. AB - OBJECT: Dual-echo fast spin-echo (FSE) sequences are used in T2 relaxometry studies of neurological disorders because of shorter clinical scanning times and protocol simplicity. However, FSE sequences have possible spatial frequency dependent effects, and derived T2 values may include errors that depend on the spatial frequency characteristics of the brain region of interest. MATERIALS AND METHODS: Dual-echo FSE and multi-echo spin-echo (MESE) sequences were acquired in nine subjects. The T2 decay curves for FSE and MESE sequences were estimated and percent error maps were generated. T2 error values were obtained along each patient's corticospinal tract (CST). Whole-brain white matter (WM) and gray matter (GM) T2 error values were also obtained. The paired t test was performed to evaluate differences in T2 values in the CST between FSE and MESE sequences. RESULTS: Histograms of error values in CST and in whole-brain WM and GM structures revealed systematic errors in FSE sequences. Significant differences (P < 0.001) in CST T2 values were also observed between FSE and MESE sequences. CONCLUSION: Our findings indicate that T2 values derived from FSE sequences are prone to large errors, even in low spatial frequency regions such as the CST, when compared to MESE sequences. Future studies should be aware of this limitation of FSE sequences. PMID- 23354515 TI - Cardioprotection--time to take into account clinical complexity: the case of antiplatelet agents : editorial to "two classes of anti-platelet drugs reduce anatomical infarct size in monkey hearts" by Xi-Ming Yang et al. PMID- 23354514 TI - What patients think about E-health: patients' perspective on internet-based cognitive behavioral treatment for patients with rheumatoid arthritis and psoriasis. AB - In the past decade, the use of internet-based cognitive behavioral treatments (internet-based CBT) for a wide range of patients has grown intensively. Incorporating the patients' opinions and perspective into new health care innovations might improve the quality and applicability of these innovations, as high dropout rates and low attrition are the often-reported concerns in E-health research. Most studies to date have examined patient perspectives on specific internet-based interventions that patients had participated in, and not the views of the general public. The current paper explores the perspective of patients with rheumatoid arthritis and psoriasis on internet-based CBT for these patient groups. In total, 100 patients (55 % male) participated in a semi-structured telephone interview about internet-based CBT, including questions about possible advantages and disadvantages and the readiness to participate in this kind of treatment. Most patients (78 %) were prepared to participate in internet-based CBT. Patients endorsed the advantages (57 %) more often than the disadvantages (34 %). The ease of internet-based CBT and the time saved were especially appealing to patients. Main disadvantages according to patients are that not all patients will be reached due to computer illiteracy and the lack of face-to-face interaction with the therapist. The results suggest that, from the patients' perspective, internet-based CBT is a promising health care development. Further research into aspects such as therapist interaction and enhancing computer literacy might contribute to an effective way of E-health care delivery in the future. PMID- 23354517 TI - Downregulation of cell-free miR-198 as a diagnostic biomarker for lung adenocarcinoma-associated malignant pleural effusion. AB - Circulating cell-free microRNAs (miRNAs) are potential cancer biomarkers. The aim of this study was to identify miRNAs that are differentially expressed between benign pleural effusion (BPE) and lung adenocarcinoma-associated malignant pleural effusion (LA-MPE). The expression level of cell-free miRNA was investigated in 107 patients with pleural effusion. Microarrays were used to screen 160 miRNAs in a discovery set comprising 20 effusion samples (ten BPEs and ten LA-MPEs). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate the profiling results obtained for the discovery set and those obtained for a validation set comprising 42 BPEs and 45 LA-MPEs. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic performance of the identified miRNAs and other common tumor markers, such as carcinoembryonic antigen (CEA) and cytokeratin fragment (CYFRA) 21-1. Microarray profiling showed that miR-198 was significantly downregulated in LA-MPE compared with BPE (p = 0.002). The miRNA microarray analysis results were confirmed by qRT-PCR (p < 0.001) using the validation set. The AUCs for miR-198, CEA and CYFRA 21-1 in the validation set were 0.887, 0.898 and 0.836, respectively. The diagnostic performance of miR-198 was comparable with that of CEA, but better than that of CYFRA 21-1. The AUC for all three markers combined was 0.926 (95% confidence interval, 0.843-0.973) with a sensitivity of 89.2% and a specificity of 85.0%. The present study suggests that cell-free miR-198 from patients with pleural effusion might have diagnostic potential for differentiating LA-MPE from BPE. PMID- 23354518 TI - Cold pressor stress induces opposite effects on cardioceptive accuracy dependent on assessment paradigm. AB - Interoception depends on visceral afferent neurotraffic and central control processes. Physiological arousal and organ activation provide the biochemical and mechanical basis for visceral afferent neurotraffic. Perception of visceral symptoms occurs when attention is directed toward body sensations. Clinical studies suggest that stress contributes to the generation of visceral symptoms. However, during stress exposure attention is normally shifted away from bodily signals. Therefore, the net effects of stress on interoception remain unclear. We, therefore, investigated the impact of the cold pressor test or a control intervention (each n=21) on three established laboratory paradigms to assess cardioceptive accuracy (CA): for the Schandry-paradigm, participants were asked to count heartbeats, while during the Whitehead-tasks subjects were asked to rate whether a cardiac sensation appeared simultaneously with an auditory or visual stimulus. CA was increased by stress when attention was focused on visceral sensations (Schandry), while it decreased when attention was additionally directed toward external stimuli (visual Whitehead). Explanations for these results are offered in terms of internal versus external deployment of attention, as well as specific effects of the cold pressor on the cardiovascular system. PMID- 23354516 TI - Microarray analysis of gene expression in vestibular schwannomas reveals SPP1/MET signaling pathway and androgen receptor deregulation. AB - Vestibular schwannomas are benign neoplasms that arise from the vestibular nerve. The hallmark of these tumors is the biallelic inactivation of neurofibromin 2 (NF2). Transcriptomic alterations, such as the neuregulin 1 (Nrg1)/ErbB2 pathway, have been described in schwannomas. In this study, we performed a whole transcriptome analysis in 31 vestibular schwannomas and 9 control nerves in the Affymetrix Gene 1.0 ST platform, validated by quantitative real-time PCR (qRT PCR) using TaqMan low density arrays. We performed a mutational analysis of NF2 by PCR/denaturing high-performance liquid chromatography (dHPLC) and multiplex ligation-dependent probe amplification (MLPA), as well as a microsatellite marker analysis of the loss of heterozygosity (LOH) of chromosome 22q. The microarray analysis demonstrated that 1,516 genes were deregulated and 48 of the genes were validated by qRT-PCR. At least 2 genetic hits (allelic loss and/or gene mutation) in NF2 were found in 16 tumors, seven cases showed 1 hit and 8 tumors showed no NF2 alteration. MET and associated genes, such as integrin, alpha 4 (ITGA4)/B6, PLEXNB3/SEMA5 and caveolin-1 (CAV1) showed a clear deregulation in vestibular schwannomas. In addition, androgen receptor (AR) downregulation may denote a hormonal effect or cause in this tumor. Furthermore, the osteopontin gene (SPP1), which is involved in merlin protein degradation, was upregulated, which suggests that this mechanism may also exert a pivotal role in schwannoma merlin depletion. Finally, no major differences were observed among tumors of different size, histological type or NF2 status, which suggests that, at the mRNA level, all schwannomas, regardless of their molecular and clinical characteristics, may share common features that can be used in their treatment. PMID- 23354522 TI - [Ongoing "contract physicians" and other cooperation status quo and future prospects]. PMID- 23354523 TI - Assessing patterns of use of cardio-protective polypill component medicines in Australian women. AB - BACKGROUND: A low-cost 'polypill' could theoretically be one way of improving medication affordability and compliance for secondary prevention of cardiovascular and cerebrovascular disease. The polypill has also been proposed as a primary prevention strategy. Yet many of the issues surrounding the polypill are still being debated and the underlying assumptions have not been proven. In this paper, we step back from the complexities of the debate and report upon the utilization of polypill component medicines in two population cohorts of Australian women who were aged 56-61 years and 81-86 years in 2007. OBJECTIVES: The aims of this study were firstly, to describe the association between the women's characteristics (health, illness, behavioural, demographic, socioeconomic) and their use of statins and antihypertensive medicines for the treatment of heart disease, and secondly, to discuss possible health and economic benefits for women with these characteristics that may be expected to result from the introduction of a cardio-protective polypill. METHODS: Survey records from the Australian Longitudinal Study on Women's Health (ALSWH) were linked to 2007 Pharmaceutical Benefits Scheme (PBS) claims for 7,116 mid-aged women and 4,526 older-aged women. Associations between women's characteristics (self-reported in ALSWH surveys) and their use of statins and antihypertensive medicines (measured through PBS claims in 2007) were analysed using Chi-square and multivariate regression techniques. RESULTS: Between 2002 and 2007, the use of statins in combination with antihypertensives by mid- and older-aged Australian women increased. A moderate yet increasing proportion of mid-aged women were taking statins without antihypertensives, and a high proportion of older-aged women were using antihypertensives without statins. A high proportion of women who were prescribed both statins and antihypertensives were in lower socioeconomic groups and reported difficulty managing on their incomes. CONCLUSION: These results suggest that a polypill may provide an easy-to-take, cheaper alternative for Australian women already taking multiple cardiovascular disease medications, with particular benefits for older women and women in lower socioeconomic groups. Future research is needed to quantify the potential social and economic benefits of the polypill. PMID- 23354524 TI - Highly fluorescent peptide nanoribbon impregnated with Sn-porphyrin as a potent DNA sensor. AB - Highly fluorescent and thermo-stable peptide nanoribbons (PNRs) were fabricated by solvothermal self-assembly of a single peptide (D,D-diphenyl alanine peptides) with Sn-porphyrin (trans-dihydroxo[5,10,15,20-tetrakis(p-tolyl)porphyrinato] Sn(IV) (SnTTP(OH)2)). The structural characterization of the as-prepared nanoribbons was performed by transmitting electron microscopy (TEM), scanning electron microscopy (SEM) and atomic force microscopy (AFM), FT-IR and Raman spectroscopy, indicating that the lipophilic Sn-porphyrins are impregnated into the porous surface formed in the process of nanoribbon formation through intermolecular hydrogen bonding of the peptide main chains. Consequently the Sn porphyrin-impregnated peptide nanoribbons (Sn-porphyrin-PNRs) exhibited typical UV-visible absorption spectrum of the monomer porphyrin with a red shifted Q band, and their fluorescence quantum yield was observed to be enhanced compared to that of free Sn-porphyrin. Interestingly the fluorescence intensity and lifetimes of Sn-porphyrin-PNRs were selectively affected upon interaction with nucleotide base sequences of DNA while those of free Sn-porphyrins were not affected by binding with any of the DNA studied, indicating that DNA-induced changes in the fluorescence properties of Sn-porphyrin-PNRs are due to interaction between DNA and the PNR scaffold. These results imply that Sn porphyrin-PNR will be useful as a potent fluorescent protein analogue and as a biocompatible DNA sensor. PMID- 23354525 TI - Trichomonas vaginalis infection in men who submit self-collected penile swabs after internet recruitment. AB - BACKGROUND: Submission of self-collected penile samples collected at home could remove barriers that men face in getting tested for sexually transmitted infections (STIs). METHODS: From December 2006 to July 2012, sexually active men aged >=14 years were recruited by an educational internet program (http://www.iwantthekit.org) which offered free testing for Trichomonas vaginalis infection. Kits were ordered online and swabs were sent via US mail to the laboratory and tested by nucleic acid amplification tests. Demographics and sexual risk factors were accessed by questionnaires. Men called or were contacted to receive their results. Risk factors for trichomonas infection were determined by multivariate logistic regression RESULTS: Of 4398 men requesting kits, 1699 (38.6%) returned swabs by mail (55.4% returned in 2012). Forty-one percent of men were aged <25 years, 43% were black subjects and 45% were white. The overall prevalence for trichomonas in the 1699 men was 3.7%; the highest prevalence by age group was for men aged 40-49 years (5.2%) and, by year, 216 men screened in 2008 had the highest prevalence (12.5%). Risk factors for 919 men whose risk information was collected by questionnaire (prevalence 6.0%) indicated that 9.6% had a concurrent chlamydia infection. Significantly associated risks factors included: black race (adjusted OR 2.67), residence in Illinois (OR 12.02), age 30 39 years (OR 6.63) and age >40 years (OR 5.31). CONCLUSIONS: A fairly high prevalence of trichomonas and sexual risk factors were demonstrated from internet recruitment of men. This method of engaging men to get screened for trichomonas may augment screening in STI clinics. PMID- 23354526 TI - Posttraumatic intramedullary osteochondroma: report of a case. AB - We present a rare osteochondroma, which instead of being the usual exophytic growth outside bone, grew inward into the medullary cavity of distal femur in a patient with prior trauma to his knee. Except for its intramedullary location, the benign tumor had all the classic radiographic and pathologic features of typical osteochondroma. PMID- 23354527 TI - "Superior cleft sign" as a marker of rectus abdominus/adductor longus tear in patients with suspected sportsman's hernia. AB - OBJECTIVE: We describe a new imaging sign, the "superior cleft sign", identified at both symphysography and MRI, which should be used as a marker of rectus abdominis/adductor longus attachment tearing. MATERIALS AND METHODS: A study population of 25 patients presenting with clinically suspected sportsman's hernia, who had undergone both symphysography and MRI of the groin were included for study. In each case, images were reviewed to determine the presence of a superior cleft, secondary cleft, and or both abnormalities. RESULTS: Images of all patients complaining of groin crease discomfort similar to sportsman's hernia revealed the presence of a superior cleft at the rectus abdominis/adductor longus attachment. This "superior cleft sign" correlated with the side of symptoms in each case, and, in contrast to the previously described secondary cleft along the inferior margin of the inferior pubic ramus, occurred parallel to the inferior margin of the superior pubic ramus. CONCLUSIONS: The presence of the "superior cleft sign" should be sought in addition to the previously described secondary cleft sign in sportspeople presenting with exercise-related groin pain or pubalgia. It should specifically be sought in patients referred with suspected sportsman's hernia. PMID- 23354529 TI - Balloon dilation technology: let the truth be told. AB - Balloon dilation technology (BDT), also known as balloon sinuplasty, has been in clinical use since September, 2005. Prior to BDT, surgeons performed a procedure called FESS, or functional endoscopic sinus surgery, for patients with chronic sinusitis. As is true with any new technology or procedure in medicine, a debate often ensues between early adopters and mainstream practitioners. Over the past 7 years, much has been discussed, debated, and learned about BDT. What follows is a review of the origins of the BDT: the theory, technology, indications and applications; and a review of the pertinent outcomes literature. Independent of how one feels about BDT, the evidence strongly supports its safety, efficacy, and growing popularity among patients and physicians alike. PMID- 23354528 TI - Radiographic measurements of hip dysplasia at skeletal maturity--new reference intervals based on 2,038 19-year-old Norwegians. AB - OBJECTIVE: Normative references for radiographic measurements commonly used in the diagnosis of developmental dysplasia of the hip at skeletal maturity are incomplete. The present study therefore aimed to establish new gender-specific standards for measurements reflecting the acetabular morphology, namely Sharp's angle, the acetabular roof angle of Tonnis (AA) and the acetabular depth-width ratio (ADR), and measurements reflecting the position of the femoral head related to the acetabulum, namely the center-edge (CE) angle of Wiberg, the refined CE angle of Ogata, and the femoral head extrusion index (FHEI). The joint space width (JSW) is also reported. MATERIALS AND METHODS: The population-based 1989 Bergen Birth Cohort (n = 3,935) was invited at age 19 years to a follow-up during 2007-09, of which 2,038 (52 %) attended. A standardized antero-posterior radiograph was assessed. The normative references are presented as mean +/- standard deviation (SD) and 2.5-97.5 percentiles with 95 % confidence intervals. RESULTS: A total of 2,011 (841 males, 1,170 females, mean age 18.6 (SD 0.6)) radiographs were analyzed. Sharp's angle was 38.8 degrees +/- 3.5 degrees in males and 40.7 degrees +/- 3.5 degrees in females, with 97.5 percentiles of 46 degrees and 47 degrees , respectively. The CE angle was 32.1 degrees +/- 6.1 degrees in males and 31.0 degrees +/- 6.1 degrees in females, with 2.5 percentiles of 21 degrees and 20 degrees , respectively. The FHEI was 86.0 % +/- 6.3 % in males and 85.6 % +/- 6.6 % in females, with 2.5 percentiles of 74 degrees and 73 degrees , respectively. CONCLUSIONS: Updated gender-specific reference ranges for radiographic measurements commonly used for hip dysplasia at skeletal maturity are reported, similar to or slightly wider than those described in the literature. Statistically significant gender differences have been confirmed for most of the measurements. PMID- 23354530 TI - Nasal saline irrigations for the symptoms of acute and chronic rhinosinusitis. AB - The use of saline nasal irrigation (SNI) in the treatment of nasal and sinus disorders has its roots in the yoga tradition and homeopathic medicine. In recent years, SNI has been increasingly observed as concomitant therapy for acute (ARS) and chronic rhinosinusitis (CRS). Various devices are employed, such as nasal douches, neti pots or sprays. The saline solutions used vary in composition and concentration. This article gives a current overview of literature on the clinical efficacy of SNI in the treatment of ARS and CRS. It then answers frequent questions that arise in daily clinical routine (nasal spray vs. nasal irrigation, saline solution composition and concentration, possible risks for patients). SNI has been an established option in CRS treatment for many years. All large medical associations and the authors of systematic reviews consistently conclude that SNI is a useful addition for treating CRS symptoms. SNI use in ARS therapy, however, is controversial. The results of systematic reviews and medical associations' recommendations show the existing but limited efficacy of SNI in ARS. For clinical practice, nasal douches are recommended-whatever the form of rhinosinusitis-along with isotonic and hypertonic saline solutions in CRS (in ARS to a limited extent). To prevent infections, it is essential to clean the nasal douche thoroughly and use the proper salt concentration (2-3.5 %). Conclusive proof of the efficacy of SNI in the treatment of ARS is still pending. In CRS, SNI is one of the cornerstones of treatment. PMID- 23354532 TI - Caffeine increases liking and consumption of novel-flavored yogurt. AB - RATIONALE: Caffeine has been shown to increase preference for beverages with which it is paired; however, it is not known if caffeine alters liking for foods with which it is paired indirectly. OBJECTIVES: The purpose of the current experiment was to test the hypothesis that a caffeinated beverage paired with a novel-flavored yogurt will increase preference for that yogurt compared to one paired with placebo. We also tested the hypothesis that liking would increase more when caffeine was paired with high energy density yogurt. METHODS: Men and women (n = 62) were randomized to receive a beverage containing placebo (PLA) or caffeine (CAF) and to consume a low (LED) or high energy density (HED), novel flavored yogurt. Participants rated, ranked, and consumed seven novel-flavored yogurts and then had a target yogurt paired with either PLA or CAF over four consecutive days. RESULTS: In general, yogurt liking increased over time, the HED yogurt was liked more than the LED yogurt, and yogurt paired with caffeine was liked more than yogurt paired with placebo. Participants showed a significant increase in liking of LED yogurt paired with caffeine compared to those with LED yogurt paired with placebo. CONCLUSIONS: Caffeine administration may increase liking and consumption of novel-flavored foods, particularly if the food is not highly liked at baseline. This suggests that caffeine pairing may be a way to increase liking of LED foods, such as vegetables and fruit. PMID- 23354531 TI - Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in the rodent brain: revealed by multimodal MRI. AB - BACKGROUND: An effective NMDA antagonist imaging model may find key utility in advancing schizophrenia drug discovery research. We investigated effects of subchronic treatment with the NMDA antagonist memantine by using behavioural observation and multimodal MRI. METHODS: Pharmacological MRI (phMRI) was used to map the neuroanatomical binding sites of memantine after acute and subchronic treatment. Resting state fMRI (rs-fMRI) and diffusion MRI were used to study the changes in functional connectivity (FC) and ultra-structural tissue integrity before and after subchronic memantine treatment. Further corroborating behavioural evidences were documented. RESULTS: Dose-dependent phMRI activation was observed in the prelimbic cortex following acute doses of memantine. Subchronic treatment revealed significant effects in the hippocampus, cingulate, prelimbic and retrosplenial cortices. Decreases in FC amongst the hippocampal and frontal cortical structures (prelimbic, cingulate) were apparent through rs-fMRI investigation, indicating a loss of connectivity. Diffusion kurtosis MRI showed decreases in fractional anisotropy and mean diffusivity changes, suggesting ultra structural changes in the hippocampus and cingulate cortex. Limited behavioural assessment suggested that memantine induced behavioural effects comparable to other NMDA antagonists as measured by locomotor hyperactivity and that the effects could be reversed by antipsychotic drugs. CONCLUSION: Our findings substantiate the hypothesis that repeated NMDA receptor blockade with nonspecific, noncompetitive NMDA antagonists may lead to functional and ultra structural alterations, particularly in the hippocampus and cingulate cortex. These changes may underlie the behavioural effects. Furthermore, the present findings underscore the utility and the translational potential of multimodal MR imaging and acute/subchronic memantine model in the search for novel disease modifying treatments for schizophrenia. PMID- 23354533 TI - Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation. AB - RATIONALE: Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABAA receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence. OBJECTIVE: The present study used this approach to investigate the role of GABAA receptor subtypes in mediating dependence-like effects following benzodiazepine administration. METHODS: Squirrel monkeys (n = 6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1-10 mg/kg; nonselective GABAA receptor agonist), zolpidem (0.032-1.0 mg/kg; alpha1 subunit-containing GABAA subtype-preferring agonist), and HZ-166 (0.1-10 mg/kg; functionally selective alpha2 and alpha3 subunit containing GABAA receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem, and HZ-166 were assessed with flumazenil (0.1-3.2 mg/kg; nonselective GABAA receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with betaCCt and 3-PBC (0.1-3.2 mg/kg and 0.32-10 mg/kg, respectively; alpha1 subunit-containing GABAA receptor antagonists). RESULTS: Chlordiazepoxide, zolpidem, and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, betaCCT, and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both betaCCT and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem. CONCLUSIONS: These data raise the possibility that alpha1 subunit-containing GABAA receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine. PMID- 23354535 TI - Brahmi for the better? New findings challenging cognition and anti-anxiety effects of Brahmi (Bacopa monniera) in healthy adults. AB - RATIONALE: A number of studies have indicated positive effects of long-term administration (3 months) of Bacopa monniera (Brahmi) on various cognitive functions especially memory and anxiety. However, inconsistent results in literature may be linked to various methodological issues. OBJECTIVE: The present study aimed to test the chronic effects (12 weeks) of 450 mg of a B. monniera (Brahmi) extract on learning and memory, information processing and anxiety in healthy adult Indian population. METHODS: The study design was a randomised, double-blind, placebo-controlled parallel design. Participants comprised of 72 healthy urban adults, both men and women, in the age range of 35-60 years who were educated and English speaking with basic knowledge of computers from Bangalore. The outcome measures included verbal learning and memory, inspection time, attention and interference. State and trait anxiety were additional outcome variables. RESULTS: In the present study, there were no significant differences between the two groups on any of the cognitive measures. However, there was a trend for lower state anxiety in the B. monniera (Brahmi) group as compared to placebo group. CONCLUSIONS: The current study attempted to determine the chronic effects of single daily dose of 450 mg of Brahmi extract on cognitive performance and anxiety in healthy adults. The results of the current study are not in agreement with findings of some of the earlier studies which have found improvement both on cognitive parameters and a reduction of anxiety scores. PMID- 23354534 TI - Effects of the serotonergic agonist mCPP on male rats in the quinpirole sensitization model of obsessive-compulsive disorder (OCD). AB - RATIONALE: The serotonergic agonist, meta-chlorophenylpiperazine (mCPP), produces inconsistent effects on obsessive-compulsive disorder (OCD) symptoms, perhaps because clinical studies have not utilized a homogenous OCD subgroup of patients. OBJECTIVES: This study aimed to evaluate mCPP effects on functional components of compulsive checking, using the quinpirole sensitization rat model of OCD. METHODS: In study 1, the effects of mCPP were evaluated in quinpirole rats with compulsive checking. Two experimental groups were co-injected with quinpirole (0.125 mg/kg) and mCPP (0.625 or 1.25 mg/kg), while one control group was co injected with quinpirole (0.125 mg/kg) and saline and the other control group received co-injections of saline. In study 2, mCPP (0, 0.3125, 0.625, and 1.25 mg/kg) was administered repeatedly to naive rats and induction of compulsive checking evaluated. RESULTS: mCPP significantly attenuated quinpirole-induced compulsive checking behavior by reducing vigor of checking (indexed by frequency of checking and length of check) and increasing rest after a bout of checking (indexed by time to the next checking bout), but it did not affect focus on the task of checking (indexed by recurrence time of checking and number of stops before returning to check). In naive rats, mCPP did not induce compulsive behavior, but the highest dose reduced vigor of checking performance compared to saline controls. CONCLUSIONS: mCPP did not exacerbate or induce compulsive checking behavior. Instead, it ameliorated compulsive checking by reducing vigor of checking and increasing post-checking satiety, without affecting focus on checking. Ameliorative effects of mCPP may involve 5HT2A/2C receptors in substantia nigra pars reticulata that inhibit expression of motor vigor. PMID- 23354536 TI - Effects of repeated exposure to MDMA on 5HT1a autoreceptor function: behavioral and neurochemical responses to 8-OHDPAT. AB - A consistent effect of repeated exposure to 3,4 methylenedioxymethamphetamine (MDMA) is a decrease in the tissue levels of serotonin (5-HT). A variety of behavioural and neurochemical tests were conducted to determine whether the tissue deficits were accompanied by an increased sensitivity of the 5-HT1a autoreceptor. Tests were conducted 2 weeks following MDMA exposure (four injections of 10.0 mg/kg, IP, administered at 2-h intervals in a single day). The response to the 5-HT1a agonist, 8-OHDPAT (0.003-0.5 mg/kg, SC), was assessed using lower lip retraction (LLR), hypoactivity, and 5-hydroxytryptophan (5-HTP) accumulation following decarboxylase inhibition. The 8-OHDPAT produced a dose dependent increase in LLR and hypoactivity, but these effects were comparable for MDMA and saline pretreated groups. MDMA decreased tissue levels of 5-HT and the accumulation of 5-HTP, but these effects were not reflected in the changes in autoreceptor sensitivity. The data suggest that the decrease in tissue levels of 5-HT produced by MDMA is accompanied by a decrease in tryptophan hydroxylase activity but cannot be explained by supersensitivity of the 5-HT1a autoreceptor. PMID- 23354537 TI - Effects of time of feeding on psychostimulant reward, conditioned place preference, metabolic hormone levels, and nucleus accumbens biochemical measures in food-restricted rats. AB - RATIONALE: Chronic food restriction (FR) increases rewarding effects of abused drugs and persistence of a cocaine-conditioned place preference (CPP). When there is a single daily meal, circadian rhythms are correspondingly entrained, and pre- and postprandial periods are accompanied by different circulating levels of metabolic hormones that modulate brain dopamine function. OBJECTIVES: The present study assessed whether rewarding effects of d-amphetamine, cocaine, and persistence of cocaine-CPP differ between FR subjects tested in the pre- and postprandial periods. MATERIALS AND METHODS: Rats were stereotaxically implanted with intracerebral microinjection cannulae and an electrode in lateral hypothalamus. Rewarding effects of d-amphetamine and cocaine were assessed using electrical self-stimulation in rats tested 1-4 or 18-21 h after the daily meal. Nonimplanted subjects acquired a cocaine-CPP while ad libitum fed and then were switched to FR and tested for CPP at these same times. RESULTS: Rewarding effects of intranucleus accumbens (NAc) d-amphetamine, intraventricular cocaine, and persistence of cocaine-CPP did not differ between rats tested 18-21 h food deprived, when ghrelin and insulin levels were at peak and nadir, respectively, and those tested 1-4 h after feeding. Rats that expressed a persistent CPP had elevated levels of p-ERK1, GluA1, and p-Ser845-GluA1 in NAc core, and the latter correlated with CPP expression. CONCLUSIONS: Psychostimulant reward and persistence of CPP in FR rats are unaffected by time of testing relative to the daily meal. Further, NAc biochemical responses previously associated with enhanced drug responsiveness in FR rats are associated with persistent CPP expression. PMID- 23354538 TI - Discriminant and convergent validity of the anxiety construct in children with autism spectrum disorders. AB - Despite reports of high anxiety in children with autism spectrum disorders (ASD), there is controversy regarding differential diagnosis of ASD symptoms and anxiety symptoms. This study examined 88 children, aged 7-11 years, with ASD referred for concerns about anxiety. A multitrait-(social anxiety, separation anxiety, overall anxiety severity, and overall ASD severity), multimethod-(diagnostic interviews, parent-, and child-based measures) analysis was conducted. Results from structural equation modeling suggest statistical discrimination between anxiety and ASD severity and convergence among differing reports of two of the anxiety subdomains (separation anxiety and overall anxiety). These findings suggest that anxiety symptoms experienced by children with ASD are separate from ASD symptom severity and may instead reflect anxiety syndromes (e.g., separation anxiety) similar to those that occur in typically developing children. PMID- 23354539 TI - Quinazoline-2,4(1H, 3H)-diones inhibit the growth of multiple human tumor cell lines. AB - Quinazoline-2,4(1H, 3H)-diones exhibit a wealth of biological activities including antitumor proliferation. We established an improved method for the synthesis of quinazoline-2,4(1H, 3H)-dione derivatives with three points of molecular diversity. Data indicate that compounds 60 (average logGI50=-6.1), 65 (average logGI50=-6.13), 69 (average logGI50 = -6.44), 72 (average logGI50 = 6.39), and 86 (average logGI50 = -6.45) significantly inhibited the in vitro growth of 60 human tumor cell lines tested. Structure-activity relationship analyses indicate that chlorophenethylureido is the necessary substituent at the D3 diversity point (7-position of quinazoline-2,4(1H, 3H)-dione), in particular, o-chlorophenethylurea (69) achieved optimal activity. o- or m-Chlorophenethyl substitutions (69 and 72) at the D2 diversity point (3-position of quinazo line 2,4(1H, 3H)-dione) gave the most potent compounds. Methoxyl and 4-methylpiperazin 1-yl substitution at the D1 diversity point (6-position of quinazoline-2,4(1H, 3H)-dione skeleton) may yield better activity than other groups. The quinazoline 2,4(1H, 3H)-dione scaffold can be effectively replaced by 2H-benzo[b][1,4]thiazin 3(4H)-one. PMID- 23354540 TI - A rare cause of late-onset cerebellar ataxia: Erdheim-Chester disease. PMID- 23354541 TI - The influence of two lithium forms on the growth, L-ascorbic acid content and lithium accumulation in lettuce plants. AB - Lithium (Li) is a trace element that is essential in the human diet due to its importance for health and proper functioning of an organism. However, the biological activity of this metal in crop plants, which are the primary dietary sources of Li, is still poorly understood. The aim of the presented study was to comparatively analyse two Li chemical forms on the growth, as well as the L ascorbic acid content, the Li accumulation and translocation in butterhead lettuce (Lactuca sativa L. var. capitata) cv. Justyna. The plants were grown in a nutrient solution enriched with Li in the form of LiCl or LiOH at the following concentrations: 0, 2.5, 20, 50 or 100 mg Li dm(-3). The obtained results indicate that the presence of Li(+) ions in the root environment reduced the yield of edible parts of the lettuce if the Li concentration in a nutrient solution had reached 20 mg Li dm(-3). However, a yield reduction under these conditions was found to be significant only for LiOH. In plants exposed to 50 mg Li dm(-3), both shoot and root fresh weights (FW) significantly decreased, regardless of the supplied Li chemical form. On the other hand, under the lowest LiOH dose, a significant increase in the root FW was noted, suggesting beneficial effects of Li on the growth of lettuce plants. However, applied Li concentrations and forms did not affect the L-ascorbic acid content in the lettuce leaves. Regardless of which Li form was used, Li accumulated mainly in the root tissues. An exception was the higher concentration of this metal in the shoots than in the roots of plants supplied with 100 mg Li dm(-3) in LiCl, and there were almost the same Li concentrations in both examined organs of plants supplied with 100 mg Li dm(-3) in LiOH. The effectiveness of Li translocation from roots to shoots rose with increasing Li concentrations in the growth medium, and this suggests a relatively ready translocation of this metal throughout the plant. Moreover, these results suggest that Li toxicity in lettuce plants is related to a high accumulation of this element in the root and shoot tissues, causing a drastic reduction in the yield, in the presence either of LiCl or LiOH, but not affecting the L-ascorbic acid accumulation in the leaves. PMID- 23354542 TI - Age-related differences and relationships between elements in human amygdala and other limbic system or basal ganglia. AB - To elucidate the compositional changes of the amygdala with aging, the authors investigated age-related differences of elements in human amygdalae. In addition, the relationships between the amygdala and other brain regions were investigated from a viewpoint of elements. After ordinary dissections at Nara Medical University were finished, the amygdalae were removed from the cerebra of the subjects who consisted of 22 men and 23 women, ranging in age from 70 to 101 years. In addition, the hippocampus, dentate gyrus, mammillary body of the limbic system and the caudate nucleus, putamen, and globus pallidus of the basal ganglia were also removed from the identical cerebra. After the brain samples were incinerated with nitric acid and perchloric acid, the element contents were determined by inductively coupled plasma-atomic emission spectrometry. It was found that both the Ca and Mg contents increased significantly in the amygdalae with aging, but the other five element contents (P, S, Zn, Fe, and Na) did not change significantly in the amygdalae with aging. Regarding the relationships among elements, very significant or significant direct correlations were found among the Ca, P, and Mg contents in the amygdalae. To explore the relationships between the amygdala and either other limbic system or basal ganglia, the correlations between seven elements of the amygdala and hippocampus, dentate gyrus, or mammillary body, and between those of the amygdala and caudate nucleus, putamen, or globus pallidus which derived from the identical cerebra, were analyzed with Pearson's correlation. It was found that regarding the four elements of Ca, P, Mg, and Fe, a close relationship existed between the amygdala and hippocampus, globus pallidus, or mammillary body. PMID- 23354543 TI - The association between cytokines and intestinal mucosal immunity among broilers fed on diets supplemented with fluorine. AB - Fluorine (F) bioaccumulation has been reported in the organs and tissues of organisms, including intestine. The intestinal mucosa is very important to the immune development. Meanwhile, cytokines are present in the normal intestinal mucosal and play an important role in the immune function. Thus, changes of the cytokine contents are related to the state of intestinal mucosal immunity. In this study, we investigated the changes in contents of cytokines such as interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interferon gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) induced by dietary high F in the mucosa of different parts of intestines (duodenum, jejunum, and ileum) by enzyme-linked immunosorbent assay. A total of 280 one-day-old healthy avian broilers were randomly divided into four groups and fed on a corn-soybean basal diet as control diet (F 22.6 mg/kg) or the same basal diet supplemented with 400, 800, and 1,200 mg F/kg (high F groups I, II, and III) in the form of sodium fluoride for 42 days. The experimental data showed that the contents of IL 2, IL-4, IL-6, IFN-gamma, and TNF-alpha in the intestinal mucosa were significantly decreased in the high F groups II and III when compared with those of the control group from 14 to 42 days of age. It was concluded that dietary F in the range of 800-1,200 mg/kg significantly reduced the contents of aforementioned cytokines in the intestinal mucosa of broilers, which could impact the function of intestinal mucosal immunity through the pathways that decreased the lymphocyte population and/or lymphocyte activation. PMID- 23354544 TI - Selenium supplementation modulates zinc levels and antioxidant values in blood and tissues of diabetic rats fed zinc-deficient diet. AB - Diabetes mellitus is associated to a reduction of antioxidant defenses that leads to oxidative stress and complications in diabetic individuals. The present study was undertaken to investigate the effect of selenium on blood biochemical parameters, antioxidant enzyme activities, and tissue zinc levels in alloxan induced diabetic rats fed a zinc-deficient diet. The rats were divided into two groups; the first group was fed a zinc-sufficient diet, while the second group was fed a zinc-deficient diet. Half of each group was treated orally with 0.5 mg/kg sodium selenite. Tissue and blood samples were taken from all animals after 28 days of treatment. At the end of the experiment, the body weight gain and food intake of the zinc-deficient diabetic animals were lower than that of zinc adequate diabetic animals. Inadequate dietary zinc intake increased glucose, lipids, triglycerides, urea, and liver lipid peroxidation levels. In contrast, serum protein, reduced glutathione, plasma zinc and tissue levels were decreased. A zinc-deficient diet led also to an increase in serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and liver glutathione-S transferase and to a decrease in serum alkaline phosphatase activity and glutathione peroxidase. Selenium treatment ameliorated all the values approximately to their normal levels. In conclusion, selenium supplementation presumably acting as an antioxidant led to an improvement of insulin activity, significantly reducing the severity of zinc deficiency in diabetes. PMID- 23354545 TI - A prospective study of selenium concentration and risk of preeclampsia in pregnant Iranian women: a nested case-control study. AB - Preeclampsia remains a leading cause of maternal and perinatal mortality and morbidity worldwide; however, its specific etiology still remains obscure. Some studies implicate poor maternal selenium status predisposing the mother to preeclampsia. This study was designed to determine changes in plasma selenium levels in women having preeclampsia as compared with those with normal pregnancy. In a nested case-control study, 650 normal primigravida in their first 24-28 weeks participated in the study. After 3 months of follow-up of all subjects, blood selenium levels were measured in 38 women presenting consecutively with preeclampsia and in 38 women having a normal pregnancy by atomic absorption spectrophotometry. Birth outcomes were recorded, such as gestational age at delivery, height, weight, birth head circumflex and 1-min Apgar score. Preeclampsia affects about 5.84 % of pregnancies, and in our study, there were no significant differences in age, anthropometric indices, and family history of preeclampsia between the preeclamptic and control groups. The selenium concentrations in plasma in women with preeclampsia were significantly lower as compared with those in women with normal pregnancy (70.63 +/- 21.41 versus 82.03 +/- 15.54 MUg/L, p < 0.05). Being in the bottom tertile of selenium concentration (less than 62.2 MUg/L) was associated with greater risk of preeclampsia in pregnant women. The reduced selenium in the maternal circulations observed in the preeclamptic mothers support the hypothesis that insufficient selenium concentration may be a contributing factor to the pathophysiological mechanisms associated with preeclampsia, and optimizing the dietary selenium intake through supplementation could produce demonstrable clinical benefits. PMID- 23354547 TI - Depletion of JARID1B induces cellular senescence in human colorectal cancer. AB - The global incidence of colorectal cancer (CRC) is increasing. Although there are emerging epigenetic factors that contribute to the occurrence, development and metastasis of CRC, the biological significance of epigenetic molecular regulation in different subpopulations such as cancer stem cells remains to be elucidated. In this study, we investigated the functional roles of the H3K4 demethylase, jumonji, AT rich interactive domain 1B (JARID1B), an epigenetic factor required for the continuous cell growth of melanomas, in CRC. We found that CD44(+)/aldehyde dehydrogenase (ALDH)(+) slowly proliferating immature CRC stem cell populations expressed relatively low levels of JARID1B and the differentiation marker, CD20, as well as relatively high levels of the tumor suppressor, p16/INK4A. Of note, lentiviral-mediated continuous JARID1B depletion resulted in the loss of epithelial differentiation and suppressed CRC cell growth, which was associated with the induction of phosphorylation by the c-Jun N terminal kinase (Jnk/Sapk) and senescence-associated beta-galactosidase activity. Moreover, green fluorescent-labeled cell tracking indicated that JARID1B-positive CRC cells had greater tumorigenicity than JARID1B-negative CRC cells after their subcutaneous inoculation into immunodeficient mice, although JARID1B-negative CRC cells resumed normal growth after a month, suggesting that continuous JARID1B inhibition is necessary for tumor eradication. Thus, JARID1B plays a role in CRC maintenance. JARID1B may be a novel molecular target for therapy-resistant cancer cells by the induction of cellular senescence. PMID- 23354548 TI - Chickadees fail standardized operant tests for octave equivalence. AB - Octave equivalence occurs when an observer judges notes separated by a doubling in frequency perceptually similar. The octave appears to form the basis of pitch change in all human cultures and thus may be of biological origin. Previously, we developed a nonverbal operant conditioning test of octave generalization and transfer in humans. The results of this testing showed that humans with and without musical training perceive the octave relationship between pitches. Our goal in the current study was to determine whether black-capped chickadees, a North American songbird, perceive octave equivalence. We chose these chickadees because of their reliance on pitch in assessing conspecific vocalizations, our strong background knowledge on their pitch height perception (log-linear perception of frequency), and the phylogenetic disparity between them and humans. Compared to humans, songbirds are highly skilled at using pitch height perception to classify pitches into ranges, independent of the octave. Our results suggest that chickadees used that skill, rather than octave equivalence, to transfer the note-range discrimination from one octave to the next. In contrast, there is evidence that at least some mammals, including humans, do perceive octave equivalence. PMID- 23354549 TI - DNA damage promotes herpes simplex virus-1 protein expression in a neuroblastoma cell line. AB - Although the induction of the cellular DNA damage response by herpes simplex virus-1 (HSV-1) infection of epithelial cells in tissue culture promotes productive infection, there has been no experimental observation of the effect of the cellular DNA damage response on HSV-1 infection in vivo or in neuronal derived cell lines in tissue culture. Thus, it has been speculated that the lack of cellular DNA damage induction during infection of neurons may promote latency in these cells. This work examines the profile of HSV-1 promoter induction and protein expression, in the absence or presence of infection; using cellular DNA damage inducing topoisomerase inhibitors (Camptothecin and Etoposide) on a neuroblastoma cell line (C1300) in which HSV-1 infection fails to induce the DNA damage response. In the absence of infection, a plasmid expressing the immediate early ICP0 promoter was the most induced by the DNA damage drug treatments compared to the early (RR) and late (VP16) gene promoters. Similarly, drug treatment of C1300 cells infected with HSV-1 virus showed enhanced protein expression for ICP0, but not ICP4 and VP16 proteins. However, when the cells were infected with a HSV-1 virus defective in the immediate early gene trans-activator VP16 (in814) and treated with the DNA damaging drugs, there was enhanced expression of immediate early and late HSV-1 proteins. Although, viral infection of the neuroblastoma cell alone did not induce DNA damage, cellular DNA damage induced by drug treatments facilitated viral promoter induction and viral protein expression. This implicates a mechanism by which HSV-1 viral genes in a quiescent or latent state may become induced by cellular DNA damage in neuronal cells to facilitate productive infection. PMID- 23354550 TI - Global NeuroAIDS roundtable. AB - In May 2012, the Division of AIDS Research at the National Institute of Mental Health (NIMH) organized the "Global NeuroAIDS Roundtable" in conjunction with the 11th International Symposium on Neurovirology and the 2012 Conference on HIV in the Nervous System. The meeting was held in New York, NY, USA and brought together NIMH-funded investigators who are currently working on projects related to the neurological complications of AIDS (NeuroAIDS) in Africa, Asia, Eastern Europe, and Latin America in order to provide an opportunity to share their recent findings and discuss the challenges encountered within each country. The major goals of the roundtable were to evaluate HIV-associated neurocognitive impairment and determine if it may be directly attributable to distinct HIV subtypes or clades and to discuss the future priorities for global NeuroAIDS research. At the "Global NeuroAIDS Roundtable", presentations of preliminary research indicated that HIV-associated neurocognitive impairment is prevalent in all countries examined regardless of which HIV clade is present in the region. The only clear-cut difference between HIV-1 clades was in relation to subtypes A and D in Uganda. However, a key point that emerged from the discussions was that there is an urgent need to standardize neurocognitive assessment methodologies across the globe before definitive conclusions can be drawn regarding the relationship between HIV clade diversity and neuropathogenesis. Future research directions were also discussed at the roundtable with particular emphasis on the potential of viral and host factor molecular interactions to impact the pathophysiology of HIV-associated neurocognitive disorders (HAND) from a global perspective. PMID- 23354551 TI - Joint action and lethal levels of toluene, ethylbenzene, and xylene on midge (Chironomus plumosus) larvae. AB - Aquatic ecosystems are vulnerable to the exposure with petrochemicals such as toluene, ethylbenzene, and xylene (o-, m-, and p-xylene) (TEX) and their adverse effects. Considering the widespread use, occurrence, and high toxicity of TEX, the aim of this work was to investigate the differential toxicity of TEX against midge (Chironomus plumosus) larvae and reveal the joint action of binary and ternary mixtures of TEX using the predictive concentration addition model. More importantly, this research can afford the basic toxicity data and scientific reference for the establishment of water quality criteria or benchmark, water pollution control, and aquatic risk assessment. Single and joint toxic effects of TEX on C. plumosus larvae were investigated using a semi-static bioassay, and the type of joint effects of TEX was ascertained. In the single toxicant experiments, the toxicity of the three pollutants could be sequenced as ethylbenzene > xylene > toluene. Specifically, LC(50s) of T, E, and X after a 48-h exposure were 64.9, 37.8, and 42.0 mg/L, respectively. In the binary mixture experiments, the interaction between toluene and ethylbenzene, ethylbenzene and xylene, and toluene and xylene was largely in conformity with partial additive or additive effect as determined by isobologram representation and toxic unit models. In the ternary mixture experiments, the interaction was basically dependent on the use of additive index and mixture toxicity index methods. However, the antagonistic and synergistic actions were not significant. Thus, the tertiary mixture interaction could be regarded as additive action. The concentration addition model could successfully predict the joint action of TEX mixtures on C. plumosus larvae. Particularly, the additive action of TEX on C. plumosus larvae can be further recommended to evaluate water quality criteria of TEX. PMID- 23354555 TI - [Chronic pancreatitis]. PMID- 23354552 TI - Efficacy of oral palonosetron compared to intravenous palonosetron for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: a phase 3 trial. AB - BACKGROUND: Palonosetron (Aloxi((r)), Onicit((r))) is a pharmacologically unique 5-HT3 receptor antagonist (RA) approved as a single IV injection for the prevention of nausea and vomiting induced by chemotherapy (CINV) of either moderate or highly emetogenic potential (MEC and HEC, respectively). An oral palonosetron formulation has been developed and compared to the IV formulation. METHODS: In this multinational, multicenter, double-blind, double-dummy, dose ranging trial, 651 patients were randomly assigned to receive one of the following as a single dose prior to moderately emetogenic chemotherapy: oral palonosetron 0.25, 0.50, and 0.75 mg or IV palonosetron 0.25 mg. Patients were also randomized (1:1) to receive dexamethasone 8 mg IV or matched placebo on day 1. The primary endpoint was complete response (CR; no emesis, no rescue therapy) during the acute phase (0-24 h). RESULTS: Acute CR rates were 73.5, 76.3, 74.1, and 70.4 % for all patients receiving the palonosetron 0.25, 0.50, and 0.75 mg oral doses, and for IV palonosetron 0.25 mg, respectively; delayed CR (24-120 h) rates were 59.4, 62.5, 60.1, and 65.4 %, and overall CR (0-120 h) rates were 53.5, 58.8, 53.2, and 59.3 %, respectively. The addition of dexamethasone improved emetic control (acute CR rate) by at least 15 % for all groups except oral palonosetron 0.25 mg, where the acute CR improvement was approximately 7 %. Adverse events were similar in nature, incidence, and intensity for all oral and IV palonosetron groups, and were the expected adverse events for 5-HT3 RAs (primarily headache and constipation). CONCLUSION: Oral palonosetron has a similar efficacy and safety profile as IV palonosetron 0.25 mg and may be the preferred formulation in certain clinical situations. Among the tested oral treatments, a palonosetron 0.50-mg oral dose has been favored for the prevention of CINV in patients receiving moderately emetogenic chemotherapy due to a numerical gain in efficacy without a side effect disadvantage. PMID- 23354556 TI - [New guidelines on chronic pancreatitis : interdisciplinary treatment strategies]. AB - Chronic pancreatitis is a common disorder associated with significant morbidity and mortality. Interdisciplinary consensus guidelines have recently updated the definitions and diagnostic criteria for chronic pancreatitis and provide a critical assessment of therapeutic procedures. Diagnostic imaging relies on endoscopic ultrasound (EUS) as the most sensitive technique, whereas computed tomography (CT) and magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) remain a frequent preoperative requirement. Endoscopic retrograde cholangiopancreatography (ERCP) is now used mostly as a therapeutic procedure except for the differential diagnosis of autoimmune pancreatitis. Complications of chronic pancreatitis, such as pseudocysts, duct stricture and intractable pain can be treated with endoscopic interventions as well as open surgery. In the treatment of pseudocysts endoscopic drainage procedures now prevail while pain treatment has greater long-term effectiveness following surgical procedures. Currently, endocopic as well as surgical treatment of chronic pancreatitis require an ever increasing degree of technical and medical expertise and are provided increasingly more often by interdisciplinary centres. Surgical treatment is superior to interventional therapy regarding the outcome of pain control and duodenum-preserving pancreatic head resection is presently the surgical procedure of choice. PMID- 23354557 TI - [Surgical approach to chronic pancreatitis: draining and resection procedure]. AB - The major aims of surgical therapy in chronic pancreatitis (CP) are pain relief and good long-term quality of life with preservation of endocrine and exocrine organ function. The surgical approach is therefore focused on drainage of the congested pancreatic (and bile) duct as well as resection of fibrotic and calcified tissue. Draining procedures alone are adequate for drainage of pseudocysts (cystojejunostomy) and the pancreatic duct (Partington) if no inflammatory tumor is present in the organ. Most CP patients present with unclear head mass and subsequent duct dilation. In these patients the different modifications of duodenum-preserving pancreatic head resections (e.g. Beger, Bern) offer a preferable option. Partial duodenopancreatectomy is an alternative but may be difficult to perform due to inflammatory changes around the portal vein and venous collaterals. Segmental resection and V-shaped excision may be appropriate in special situations (segmental fibrosis, small duct disease) and are performed less frequently (approximately 5 %) in the entire surgical CP population. In cases of suspected CP-related malignancy, formal resections (partial, distal or total pancreaticoduodenectomy) must be the surgical procedures of choice and be performed according to oncological principles. PMID- 23354558 TI - [Isolated spleen injury after blunt abdominal trauma]. PMID- 23354559 TI - [Freiburg index of patient satisfaction: interdisciplinary validation of a new psychometric questionnaire to describe treatment-related patient satisfaction]. AB - BACKGROUND: The recently introduced Freiburg index of patient satisfaction (FIPS) is a new questionnaire to assess treatment-related patient satisfaction after surgery and interventional procedures. The questionnaire had first been tested psychometrically in a mixed population of urology patients. The current study describes the results of an interdisciplinary validation. In addition, an English version is presented. METHODS: The questionnaire was used in two cohorts of cardiology (n = 120) and surgical (n = 127) patients. The evaluation included a comprehensive methodological and statistical evaluation including validation in comparison to the ZUF-8 questionnaire. RESULTS: The psychometric evaluation showed good results. The analyzed samples showed no missing values or ceiling effects. Furthermore, a high reliability (Cronbach's alpha 0.82), unidimensionality, sufficient distribution of values and validity (high correlation to the ZUF-8, r = 0.65, p < 0.001) of the questionnaire could be confirmed. CONCLUSIONS: The FIPS constitutes an interdisciplinary validated questionnaire to evaluate treatment-related patient satisfaction which can be used to objectify and compare results from clinical studies and quality in patient care. Colleagues of English-speaking countries are invited to participate in the validation of the hereby presented English version. PMID- 23354560 TI - [Ex situ tracheobronchoplastic operations using the organ care system]. AB - First clinical experiences with the organ care system (OCS) in lung transplantation showed that this device allows perfusion and ventilation of the lungs under practically physiological conditions. Some pulmonary pathologies necessitate ex situ operations, e.g. to avoid pneumonectomy. The objective of this work was to investigate the feasibility of ex situ pulmonary surgery within the OCS.In the first procedure a large tracheobronchial leakage was covered with a pericardial patch. The procedure was authorized by the local committee of animal welfare. In the second surgery a replacement of the distal trachea using an aortic graft was performed after removal of the heart-lung segment from a pig from the slaughterhouse. The postoperative ventilation of both lungs was free of problems. The mean pressure of the pulmonary artery remained steady during the whole experiment. The setup to prevent lung edema was basically successful.Performing thoracic surgery with the OCS is feasible; however, this approach is reserved for very special indications. Further investigations to optimize technical details of the OCS setup for this purpose are necessary. PMID- 23354561 TI - [German trauma centers: level-dependent differences in polytrauma care regarding resources and diagnostic concepts]. AB - BACKGROUND: The aim was to survey the radiological diagnostics and type of primary radiological examination of polytraumatized patients treated in German hospitals at various levels in the three-tiered system. MATERIAL AND METHODS: A questionnaire was sent in October 2007 to every traumatology department registered in the DGU (German Society for Trauma Surgery) databank and forms returned by January 2008 were included in this study. RESULTS: A total of 273 (54.71 %) of forms were returned and were applicable to statistical analysis. In the three-tiered hospital system 35.9 % of returned questionnaires came from third-tier hospitals, 41.02 % from second-tier and 23.08 % from highest tier (maximum care) hospitals. With a higher hospital level of inpatient care more computed tomography (CT) scans were examined by a radiologist during 24 h daily (p = 0.0014) and CT scanners were located closer to the resuscitation room (p < 0.0001). We found significant differences in the ratios of primary whole-body CTs (WBCT) performed depending on the hospital level: third-tier hospitals 44 %, second tier hospitals 67 % and maximum care hospitals 84 % (p < 0.05). CONCLUSIONS: Standardized structures regarding radiological diagnostics of polytraumatized patients do not exist at either the same level of the three tiered hospital system or between levels of care of German hospitals.. PMID- 23354562 TI - [Advantages of Roux-en-Y reconstruction with jejunal pouch]. PMID- 23354563 TI - [Colon J-pouch versus coloplasty pouch after low anterior rectal resection: long term results]. PMID- 23354564 TI - Cause of death during long-term follow-up for superficial esophageal adenocarcinoma. AB - BACKGROUND: The purpose of this study was to evaluate long-term prognosis and cause of death in patients with superficial esophageal adenocarcinoma (SEAC) after surgery. PATIENTS AND METHODS: A total of 85 patients without adjuvant or neoadjuvant treatment underwent surgery for SEAC (pT1N0-1, M0) 1984-2011. Medical records and causes of death were reviewed, and 79 specimens (93 %) were reanalyzed for cancer penetration. Survival was calculated according to Kaplan Meier and comparisons of survival with log-rank test. Multivariate survival was analyzed with Cox proportional hazards model. RESULTS: Of 85 patients, 36 had transhiatal, 33 transthoracic en bloc, 6 minimally invasive en bloc, 5 vagal sparing esophageal resection and 5 endoscopic mucosal resections; 7 patients (8 %) had lymph node metastasis (LNM). Cancer penetration: 35 pT1a and 44 pT1b. Overall survival was 67 % at 5 years and 50 % at 10 years. Disease-specific survival was 82 % at 5 years and 78 % at 10 years. Recurrence-free survival was 80 % at 5 years. In a Cox multivariate model, poor overall survival was predicted only by LNM. Cumulative mortality during median follow-up of 5 years (0-25 years): 37 of 85 (44 %). Cause of death of these 37: SEAC recurrence for 15 (41 %), postoperative complications for 4 (11 %), another primary malignancy for 5 (14 %), non-cancer-related for 11 (30 %) and for 2 (5 %) cause unknown. Mortality after 5-year follow-up: 11 (30 %); 82 % of these deaths were unrelated to SEAC recurrence. CONCLUSIONS: With SEAC recurrence as the single most common cause of death, disease-specific 5-year survival was good. Overall and late (> 5-year) survival is affected by diseases related to aging. PMID- 23354565 TI - Effect of including cancer-specific variables on risk-adjusted hospital surgical quality comparisons. AB - BACKGROUND: Quality initiatives are increasingly focusing on the quality of oncologic surgery. However, there is concern that a lack of cancer-specific variables may make risk-adjusted hospital quality comparisons inadequate. Our objective was to assess whether hospital quality rankings for cancer surgery are influenced by the addition of cancer-specific variables to the risk-adjusted models. METHODS: Patients from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) and National Cancer Data Base (NCDB) who underwent colon or rectal resection for cancer were linked (2006-2008). Hierarchical models were developed predicting ACS NSQIP outcomes based on ACS NSQIP only vs a model using NSQIP and NCDB-derived cancer variables (e.g., stage and neoadjuvant therapy). Changes in hospital quality rankings were compared. RESULTS: A total of 11,405 patients underwent colon (n = 9,678, 146 hospitals) or rectal (n = 1,727, 135 hospitals) resection for cancer (2006-2008). Hospital level complication rates (and standard deviation) after colon surgery were 2.2 % (+/-2.7 %) for mortality and 17.2 % (+/-8.7 %) for serious morbidity. After rectal cancer resection, complication rates were 0.9 % (+/-3.8 %) for mortality and 22.3 % (+/-20.4 %) for serious morbidity. When cancer-specific variables were included in risk-adjustment, outlier agreement was very good (kappa >0.85), and hospital odds ratio correlations were nearly identical (R > 0.98) for all outcomes assessed. Median changes in hospital rankings with the addition of the cancer-specific variables ranged from 1 to 2 after colon resection to 2-4 after rectal resection. CONCLUSIONS: Addition of the available cancer-specific variables to risk-adjustment models did not affect hospital quality rankings for cancer surgery. Existing ACS NSQIP risk-adjustment variables appears to be sufficient for accurate comparisons of hospital quality. PMID- 23354566 TI - Prognostic significance of cyclin D1 polymorphisms on prostate-specific antigen recurrence after radical prostatectomy. AB - BACKGROUND: Cyclin D1 (CCND1) is an important cell-cycle regulator involved in carcinogenesis and progression of prostate cancer. We tested whether genetic variations within the CCND1 gene are related to clinical outcomes in prostate cancer patients receiving radical prostatectomy. METHODS: A total of 320 clinical localized prostate cancer patients who underwent radical prostatectomy in Taiwan were prospectively follow-up in this study. A total of 5 tagged single-nucleotide polymorphisms that captured the genetic variability across the CCND1 gene were genotyped, and the prognostic significance on prostate-specific antigen (PSA) recurrence was assessed using the Kaplan-Meier analysis and Cox regression model. RESULTS: We found a polymorphism, rs9344, and 2 haplotypes, GAGG and CTGG, consisting of rs667515, rs2450254, rs9344, and rs678653, were associated with PSA recurrence (P <= 0.033). After adjusting for other clinicopathologic predictors, including age, PSA levels, pathologic stage, Gleason score, and surgical margin, rs9344 and the haplotype CTGG remained significant (P <= 0.044). The model based on clinical variables plus CCND1 rs9344 or haplotype showed improvement over the model without genetic information, as indicated by >= 7.2 % net reclassification improvement (P <= 0.040), integrated discrimination index (P <= 0.041), and likelihood ratio test (P <= 0.028). CONCLUSION: Our data suggest that the CCND1 rs9344 and a specific haplotype CTGG may be prognostic factors for PSA recurrence after radical prostatectomy. PMID- 23354567 TI - A phase I trial of thermal sensitization using induced oxidative stress in the context of HIPEC. AB - BACKGROUND: Inducing oxidative stress under hyperthermic conditions significantly decreases tumor cell growth in a murine model of human colon cancer carcinomatosis. This phase I study examines the safety and pharmacokinetics of induced oxidative stress by the addition of hydrogen peroxide (H2O2) to the perfusate in patients undergoing cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced abdominal-only malignancies. METHODS: Patients with advanced colon or appendiceal malignancies underwent maximal cytoreduction followed by HIPEC with mitomycin C (MMC). In addition, H2O2 was added to the perfusate at three concentrations (n = 3/level, 0.05, 0.075, 0.1 %). A control group consisted of patients perfused with MMC alone (n = 3). Perfusate, serum MMC, and H2O2 levels were measured, as were tissue levels of MMC. RESULTS: Twelve patients were enrolled onto this trial. The median (range) peritoneal carcinomatosis index was 13 (3-20) requiring a median operative time of 6.3 (4 8.5) h. The median postoperative length of stay was 9 (5-34) days, with six patients requiring readmission within 30 days. Similar complications were observed at all three H2O2 levels, as well as in the control group. One patient required reexploration for a colon perforation (control group), and three patients developed enterocutaneous fistulas (0.075 % H2O2, 0.1 % H2O2 and control group). There were no operative mortalities. CONCLUSIONS: Hyperthermic intraperitoneal chemotherapy with induced oxidative stress after maximal cytoreduction is well tolerated. On the basis of the encouraging toxicity profile after cytoreduction and HIPEC with induced oxidative stress, a phase II trial to verify activity is indicated. PMID- 23354569 TI - Headaches in childhood and adolescence. PMID- 23354568 TI - Predictors of survival and recurrence in primary leiomyosarcoma. AB - BACKGROUND: Leiomyosarcoma is a soft tissue sarcoma whose outcome has historically been confounded by the inclusion of gastrointestinal stromal tumors. Thus, we sought to determine the factors that predict survival and recurrence in patients with primary leiomyosarcoma alone. METHODS: During 1982-2006, a total of 353 patients with primary resectable leiomyosarcoma were identified from a prospective database. Multivariate analysis was used to assess clinicopathologic factors for association with disease-specific survival (DSS). Competing risk survival analysis was used to determine factors predictive for local and distant recurrence. RESULTS: Of 353 patients, 170 (48 %) presented with extremity, 144 (41 %) with abdominal/retroperitoneal, and 39 (11 %) with truncal tumors. Median age was 57 (range, 18-88) years, and median follow-up was 50 (range, 1-270) months. Most tumors were high grade (75 %), deep (73 %), and completely resected (97 %); median size was 6.0 (range, 0.3-45) cm. Abdominal/retroperitoneal location was associated with worse long-term DSS compared to extremity or trunk (P = 0.005). However, by multivariate analysis, only high grade and size were significant independent predictors of DSS. Overall, 139 patients (39 %) had recurrence: 51 % of those with abdominal/retroperitoneal, 33 % of extremity, and 26 % of truncal disease. Significant independent predictors for local recurrence were size and margin, whereas predictors for distant recurrence were size and grade. Site was not an independent predictor of recurrence; however, late recurrence (>5 years) occurred in 9 % of abdominal/retroperitoneal and 4 % of extremity lesions. CONCLUSIONS: Grade and size are significant independent predictors of DSS and distant recurrence. Long-term follow-up in leiomyosarcoma is important, as late recurrence continues in 6-9 % patients. PMID- 23354570 TI - Development of a stable biosensor based on a SiO2 nanosheet-Nafion-modified glassy carbon electrode for sensitive detection of pesticides. AB - SiO(2) nanosheets (SNS) have been prepared by a chemical method using montmorillonite as raw material and were characterized by scanning electron microscopy and X-ray diffraction. SiO(2) nanosheet-Nafion nanocomposites with excellent conductivity, catalytic activity, and biocompatibility provided an extremely hydrophilic surface for biomolecule adhesion. Chitosan was used as a cross-linker to immobilize acetylcholinesterase (AChE), and Nafion was used as a protective membrane to efficiently improve the stability of the AChE biosensor. The AChE biosensor showed favorable affinity for acetylthiocholine chloride and catalyzed the hydrolysis of acetylthiocholine chloride with an apparent Michaelis Menten constant of 134 MUM to form thiocholine, which was then oxidized to produce a detectable and fast response. Based on the inhibition by pesticides of the enzymatic activity of AChE, detection of the amperometric response from thiocholine on the biosensor is a simple and effective way to biomonitor exposure to pesticides. Under optimum conditions, the biosensor detected methyl parathion, chlorpyrifos, and carbofuran at concentrations ranging from 1.0 * 10(-12) to 1 * 10(-10) M and from 1.0 * 10(-10) to 1 * 10(-8) M. The detection limits for methyl parathion, chlorpyrifos, and carbofuran were 5 * 10(-13) M. The biosensor developed exhibited good sensitivity, stability, reproducibility, and low cost, thus providing a new promising tool for analysis of enzyme inhibitors. PMID- 23354571 TI - A sensitive and specific ELISA for determining a residue marker of three quinoxaline antibiotics in swine liver. AB - Methyl-3-quinoxaline-2-carboxylic acid (MQCA) is a possible residue marker for three quinoxaline veterinary medicines (olaquindox, mequindox, and quinocetone). The wide application of mequindox/quinocetone or the illegal use of olaquindox leads to MQCA residue in animal's original food, thereby threatening the safety of human food. The indirect competitive enzyme-linked immunosorbent assay (IC ELISA) with a specific coating antigen and monoclonal antibody (MAB) was established and optimized for detecting MQCA in swine liver. Samples were acidified with 2 mol l(-1) hydrochloric acid, extracted with ethyl acetate-hexane isopropanol (8 + 1 + 1, v/v/v) and then detected by IC-ELISA. The logarithm correlation of standards to OD values ranged from 0.2 to 200 MUg l(-1), with IC(50) of 6.46 MUg l(-1). Negligible cross-reactivity happened to five quinoxaline antibiotics (olaquindox, mequindox, quinocetone, carbadox, and cyadox) and the metabolite of carbadox and cyadox (quinoxaline-2-carboxylic acid). When spiked with 1 to 100 MUg kg(-1) of MQCA, the recoveries ranged from 85.44 to 100.02 %, with the intra-assay coefficient of variation (CV) of 6.64 10.57 % and inter-assay CV of 7.29-10.88 %. The limit of detection for MQCA was 1.0 MUg kg(-1) in swine liver. Furthermore, incurred samples were detected by the IC-ELISA and then conformed by a reported LC/MS/MS method, it shown that there was good correlation between the two methods. All these results indicated that the IC-ELISA method is appropriate for surveillance MQCA residue in animal tissues. PMID- 23354572 TI - Effect-directed analysis of endocrine-disrupting compounds in multi-contaminated sediment: identification of novel ligands of estrogen and pregnane X receptors. AB - Effect-directed analysis (EDA)-based strategies have been increasingly used in order to identify the causative link between adverse (eco-)toxic effects and chemical contaminants. In this study, we report the development and use of an EDA approach to identify endocrine-disrupting chemicals (EDCs) in a multi contaminated river sediment. The battery of in vitro reporter cell-based bioassays, measuring estrogenic, (anti)androgenic, dioxin-like, and pregnane X receptor (PXR)-like activities, revealed multi-contamination profiles. To isolate active compounds of a wide polarity range, we established a multi-step fractionation procedure combining: (1) a primary fractionation step using normal phase-based solid-phase extraction (SPE), validated with a mixture of 12 non polar to polar standard EDCs; (2) a secondary fractionation using reversed-phase based high-performance liquid chromatography (RP-HPLC) calibrated with 33 standard EDCs; and (3) a purification step using a recombinant estrogen receptor (ER) affinity column. In vitro SPE and HPLC profiles revealed that ER and PXR activities were mainly due to polar to mid-polar compounds, while dioxin-like and anti-androgenic activities were in the less polar fractions. The overall procedure allowed final isolation and identification of new environmental PXR (e.g., di-iso-octylphthalate) and ER (e.g., 2,4-di-tert-butylphenol and 2,6-di tert-butyl-alpha-methoxy-p-cresol) ligands by using gas chromatography coupled with mass spectrometry with full-scan mode acquisition in mid-polar fractions. In vitro biological activity of these chemicals was further confirmed using commercial standards, with di-iso-octylphthalate identified for the first time as a potent hPXR environmental agonist. PMID- 23354573 TI - Effervescence-assisted carbon nanotubes dispersion for the micro-solid-phase extraction of triazine herbicides from environmental waters. AB - Extraction techniques are surface-dependent processes since their kinetic directly depends on the contact area between the sample and the extractant phase. The dispersion of the extractant (liquid or solid) increases this area improving the extraction efficiency. In this article, the dispersion of a nanostructured sorbent at the very low milligram level is achieved by effervescence thanks to the in situ generation of carbon dioxide. For this purpose, a special tablet containing the effervescence precursors (sodium carbonate as carbon dioxide source and sodium dihydrogen phosphate as proton donor) and the sorbent [multiwalled carbon nanotubes (MWCNTs)] is prepared. All the microextraction steps take place in a glass beaker containing 100 mL of the sample. After the extraction, the MWCNTs, enriched with the extracted analytes, are recovered by vacuum filtration. Methanol was selected to elute the retained analytes. The extraction mode is optimized and characterized using the determination of nine herbicides in water samples as model analytical problem. The absolute recoveries of the analytes were in the range 48-76 %, while relative recoveries were close to 100 % in all cases. These values permit the determination of these analytes at the low microgram per liter range with good precision (relative standard deviations lower than 9.3 %) using ultra performance liquid chromatography (UPLC) combined with ultraviolet detection (UV). PMID- 23354574 TI - Direct electrochemical detection of bisphenol A at PEDOT-modified glassy carbon electrodes. AB - The electrochemical behavior of bisphenol A (BPA) was studied on poly(3,4 ethylenedioxythiophene) (PEDOT)-modified glassy carbon electrodes by cyclic voltammetry. It was observed that BPA oxidation on PEDOT film produced a BPA polymer (pBPA) showing excellent redox activity with anodic and cathodic peaks at 0.15 and 0.01 V, respectively; the former being evaluated for BPA electrochemical sensing. The amount of deposited pBPA has been estimated by electrochemical and spectroscopic analysis by X-ray photoelectron spectroscopy. The effect of scan rate and pH on the oxidation of pBPA film has been studied. The oxidation current was found to vary linearly with BPA concentration in the range 90-410 MUM, and a detection limit of 55 MUM was evaluated. Results of BPA amperometric detection have also been collected by using a repetitive potential step program to give a linear response to BPA in the concentration range 40-410 MUM with a detection limit of 22 MUM and a sensitivity of 1.57 MUAMUM(-1) cm(-2). The developed sensor showed satisfactory reproducibility and anti-interference properties and was successfully applied to BPA determination in mineral water samples. PMID- 23354575 TI - Synchrotron FTIR microspectroscopy of Escherichia coli at single-cell scale under silver-induced stress conditions. AB - The present work was focused on elucidating biochemical changes in the model bacterium Escherichia coli exposed to ionic silver mediated stress, at a single cell scale. In order to achieve this, in situ synchrotron Fourier-transform infrared (sFTIR) microspectroscopy was performed, for the first time, on individual cells by attenuated total reflectance (ATR) combined with the use of zinc-selenide hemisphere for high spatial resolution. In a first part, the potential of the method was evaluated on bacteria subjected to a lethal 100 MUM AgNO(3) concentration for 2 h compared to untreated 100 % viable cells. Differences in cell composition were assessed for the C-H stretching and protein spectral regions, indicating that the inhibitory action was targeted against both fatty acids and proteins. Transmission electron microscopy (TEM) confirmed morphological damages of the cell ultrastructure. The relevance of ATR-sFTIR microspectroscopy for highlighting the heterogeneity in Ag(+)-mediated effects within a given bacterial population was also pointed out. In a second part, cells were exposed to sub-lethal Ag(+) concentrations (<10 MUM AgNO(3)) tested under "dynamic" growth mode: early addition vs. pulse in the mid-exponential phase, and compared to simultaneously batch-grown untreated bacteria or cells sampled just before the pulse, respectively. sFTIR microspectroscopy and TEM imaging were performed in close relation with growth kinetics characterization. No significant effect of the Ag(+) pulses was detected, in accordance with macrokinetics data. For early-treated cells, effects on fatty acid composition were shown, although no major alteration of protein secondary structure was noticed. These partial effects were consistent with TEM observations and growth kinetics. PMID- 23354576 TI - Miniaturised method for the quantitation of stabilisers in microtome cuts of polymer materials by HPLC with UV, MS or MS2 detection. AB - A method for quantitative depth profiling of polymer stabilisers in polypropylene materials is presented. Microtome cuts down to 10 MUm thickness were prepared and an amount of as low as 10 mg was used for subsequent analysis. The sample preparation procedure included dissolution in toluene, followed by precipitation of the polymer by addition of methanol or acetonitrile, and subsequent analysis of the solution by reversed phase HPLC coupled with UV, MS and MS(2) detection. A comparison of the different detection techniques is given and their particular advantages are discussed. Depending on the stabiliser type, the presented method with MS detection can quantify stabiliser concentrations down to 0.007 mg L(-1) (this corresponds to 0.0007 mg g(-1) in the polymer sample) with repeatabilities better than 5 % relative standard deviation (n = 3). This equals a quantitation of absolute stabiliser amounts at the 0.1-MUg level and concentrations down to 0.1 mg L(-1) in the corresponding polymer extracts. The developed method shows high sensitivity by the use of MS detection as well as good repeatabilities. Mainly due to the use of an appropriate internal standard, improved repeatability during sample extraction could be obtained. Furthermore, the applicability to real samples has been demonstrated. PMID- 23354577 TI - Molecular cartography in acute Chlamydia pneumoniae infections--a non-targeted metabolomics approach. AB - Infections with Chlamydia pneumoniae cause several respiratory diseases, such as community-acquired pneumonia, bronchitis or sinusitis. Here, we present an integrated non-targeted metabolomics analysis applying ultra-high-resolution mass spectrometry and ultra-performance liquid chromatography mass spectrometry to determine metabolite alterations in C. pneumoniae-infected HEp-2 cells. Most important permutations are elaborated using uni- and multivariate statistical analysis, logD retention time regression and mass defect-based network analysis. Classes of metabolites showing high variations upon infection are lipids, carbohydrates and amino acids. Moreover, we observed several non-annotated compounds as predominantly abundant after infection, which are promising biomarker candidates for drug-target and diagnostic research. PMID- 23354578 TI - Determination of fortified and endogenous folates in food-based Standard Reference Materials by liquid chromatography-tandem mass spectrometry. AB - The National Institute of Standards and Technology (NIST) is developing a wide variety of Standard Reference Materials (SRMs) to support measurements of vitamins and other nutrients in foods. Previously, NIST has provided SRMs with values assigned for the folate vitamer, folic acid (pteroylglutamic acid), which is fortified in several foods due to its role in prevention of neural tube defects. In order to expand the number of food-based SRMs with values assigned for folic acid, as well as additional endogenous folates, NIST has developed methods that include trienzyme digestion and isotope-dilution liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. Sample preparation was optimized for each individual food type, but all samples were analyzed under the same LC-MS/MS conditions. The application of these methods resulted in folic acid values for SRM 1849a Infant/Adult Nutritional Formula and SRM 3233 Fortified Breakfast Cereal of (2.33 +/- 0.06) MUg/g and (16.0 +/- 0.7) MUg/g, respectively. In addition, the endogenous folate vitamer 5-methlytetrahydrofolate (5-MTHF) was detected and quantified in SRM 1849a Infant/Adult Nutritional Formula, candidate SRM 1549a Whole Milk Powder, and candidate SRM 1845a Whole Egg Powder, resulting in values of (0.0839 +/- 0.0071) MUg/g, (0.211 +/- 0.014) MUg/g, and (0.838 +/- 0.044) MUg/g, respectively. SRM 1849a Infant/Adult Nutritional Formula is the first food-based NIST SRM to possess a reference value for 5-MTHF and the first certified reference material to have an assigned 5-MTHF value based on LC-MS/MS. The values obtained for folic acid and 5-MTHF by LC-MS/MS will be incorporated into the final value assignments for all these food-based SRMs. PMID- 23354579 TI - The use of mass defect plots for the identification of (novel) halogenated contaminants in the environment. AB - Mass defect is the difference between the nominal and exact mass of a chemical element or compound. An intrinsic property of polyhalogenated molecules is a uniquely negative mass defect, which readily distinguishes halogenated from non halogenated compounds in a complex mass spectrum and can be visualized by constructing a mass defect plot. This study demonstrates the utility of the mass defect plot as a powerful tool to screen gas-chromatography (ultra)high resolution mass spectrometry data for potentially toxic and bioaccumulative halogenated compounds in a Lake Ontario lake trout, an apex species in the Great Lakes environment. Our results indicate that the sample is contaminated with polychlorinated biphenyls, terphenyls, diphenylethers, as well as other chlorinated pesticides and flame retardants that are regulated and routinely analyzed by traditional target analyses. However, the mass defect plot also displays peaks which could be traced to the presence of as yet undiscovered contaminants. These include chlorinated polycyclic aromatic hydrocarbons as well as mixed halogenated analogues of the flame retardant Dechlorane 604. The identity of the latter class of compounds is supported by experiments with genuine standards. PMID- 23354580 TI - Time-resolved analysis of the emission of sidestream smoke (SSS) from cigarettes during smoking by photo ionisation/time-of-flight mass spectrometry (PI-TOFMS): towards a better description of environmental tobacco smoke. AB - In this study, the chemical composition of sidestream smoke (SSS) emissions of cigarettes are characterised using a laser-based single-photon ionisation time-of flight mass spectrometer. SSS is generated from various cigarette types (2R4F research cigarette; Burley, Oriental and Virginia single-tobacco-type cigarettes) smoked on a single-port smoking machine and collected using a so-called fishtail chimney device. Using this setup, a puff-resolved quantification of several SSS components was performed. Investigations of the dynamics of SSS emissions show that concentration profiles of various substances can be categorised into several groups, either depending on the occurrence of a puff or uninfluenced by the changes in the burning zone during puffing. The SSS emissions occurring directly after a puff strongly resemble the composition of mainstream smoke (MSS). In the smouldering phase, clear differences between MSS and SSS are observed. The changed chemical profiles of SSS and MSS might be also of importance on environmental tobacco smoke which is largely determined by SSS. Additionally, the chemical composition of the SSS is strongly affected by the tobacco type. Hence, the higher nitrogen content of Burley tobacco leads to the detection of increased amounts of nitrogen-containing substances in SSS. PMID- 23354581 TI - Partial enzymatic elimination and quantification of sarcosine from alanine using liquid chromatography-tandem mass spectrometry. AB - Since sarcosine and D,L-alanine co-elute on reversed-phase high-performance liquid chromatography (HPLC) columns and the tandem mass spectrometer cannot differentiate them due to equivalent parent and fragment ions, derivatization is often required for analysis of sarcosine in LC/MS systems. This study offers an alternative to derivatization by employing partial elimination of sarcosine by enzymatic oxidation. The decrease in apparent concentration from the traditionally merged sarcosine-alanine peak associated with the enzymatic elimination has been shown to be proportional to the total sarcosine present (R(2) = 0.9999), allowing for determinations of urinary sarcosine. Sarcosine oxidase was shown to eliminate only sarcosine in the presence of D,L-alanine, and was consequently used as the selective enzyme. This newly developed technique has a method detection limit of 1 MUg/L (parts per billion) with a linear range of 3 ppb-1 mg/L (parts per million) in urine matrices. The method was further validated through spiked recoveries of real urine samples, as well as the analysis of 35 real urine samples. The average recoveries for low, middle, and high sarcosine concentration spikes were 111.7, 90.8, and 90.1 %, respectively. In conclusion, this simple enzymatic approach coupled with HPLC/MS/MS is able to resolve sarcosine from D,L-alanine leading to underivatized quantification of sarcosine. PMID- 23354582 TI - Lateral-flow enzyme immunoconcentration for rapid detection of Listeria monocytogenes. AB - Lateral-flow enzyme immunochromatography coupled with an immunomagnetic step was developed for rapid detection of Listeria monocytogenes in food matrices. The target bacteria was first separated and concentrated by magnetic nanoparticles containing the enzyme and directly applied to the assay system to induce an antigen-antibody reaction without any additional steps. The color signals produced by an enzyme-substrate reaction at a specific site on the immunostrip were found to be directly proportional to the concentration of L. monocytogenes in the sample. The detection concept was demonstrated by performing an enzyme immunoassay on a microtiter well prior to applying it to the lateral-flow assay. Results of the chromatographic analysis yield a limit of detection of 95 and 97 +/- 19.5 CFU/mL in buffer solution and 2 % milk sample, respectively. In addition to the high sensitivity, it was also possible to shorten the separation and detection time to within 2 h. The system also showed no cross-reactivity with other bacteria (e.g., Escherichia coli O157:H7, Salmonella typhimurium, and Salmonella enteritidis). The analytical procedure developed will enable us to not only utilize the assay in the field where fast screening for pathogenic agents is required but also as a preventive measure to contain disease outbreak. PMID- 23354583 TI - Cloud point extraction of Delta9-tetrahydrocannabinol from cannabis resin. AB - A cloud point extraction coupled with high performance liquid chromatography (HPLC/UV) method was developed for the determination of Delta(9) tetrahydrocannabinol (THC) in micellar phase. The nonionic surfactant "Dowfax 20B102" was used to extract and pre-concentrate THC from cannabis resin, prior to its determination with a HPLC-UV system (diode array detector) with isocratic elution. The parameters and variables affecting the extraction were investigated. Under optimum conditions (1 wt.% Dowfax 20B102, 1 wt.% Na2SO4, T = 318 K, t = 30 min), this method yielded a quite satisfactory recovery rate (~81 %). The limit of detection was 0.04 MUg mL(-1), and the relative standard deviation was less than 2 %. Compared with conventional solid-liquid extraction, this new method avoids the use of volatile organic solvents, therefore is environmentally safer. PMID- 23354584 TI - Cyclin D1 G870A polymorphism and risk of colorectal cancer: a case control study. AB - The present study aimed to analyse the role of cyclin D1 A870G polymorphism in modulating the susceptibility to colorectal cancer (CRC) in the Kashmiri population. The genotype distribution of the cyclin D1 gene in 130 CRC cases in comparison with 160 healthy controls was investigated. No direct significant association between cyclin D1 genotypes and CRC was observed; however, the AG and AA genotypes were found to be associated with an increased risk of CRC compared to the GG genotype, with an almost 2-fold increase in OR. This study suggests that the cyclin D1 polymorphism is associated with an increased risk of CRC in the Kashmiri population. PMID- 23354585 TI - Effectiveness and safety of aliskiren and aliskiren hydrochlorothiazide (HCT) in a multiethnic, real-world setting. AB - INTRODUCTION: Numerous randomized clinical trials have demonstrated the efficacy and tolerability of aliskiren and aliskiren hydrochlorothiazide (aliskiren HCT) single-pill combination therapy in patients with hypertension. The objective of the present study was to evaluate the effectiveness and safety of aliskiren-based therapy under daily life conditions in a multiethnic population. METHODS: This observational, multicenter, noninterventional study, conducted at 420 centers in Asia and the Middle East, included adult patients with hypertension who received treatment with aliskiren or aliskiren HCT as single or add-on therapy for a planned treatment period of at least 26 weeks. The main effectiveness assessments included the proportion of patients achieving therapeutic blood pressure (BP) goal (defined as systolic BP [SBP]/diastolic BP [DBP]<140/90 mmHg, or <130/80 mmHg in patients with diabetes) and BP response, and change in mean sitting BP from baseline to study end. RESULTS: Of 4,826 patients (mean age 51.4 years, 65.9% male, 64.5% Asian, 41.5% diabetic) included in the study, 3,473 received aliskiren and 1,353 received aliskiren HCT. Almost half the study population (48.1%) received aliskiren or aliskiren HCT as add-on therapy. The therapeutic BP goal was achieved in 49.5% of patients treated with aliskiren and 48.3% of patients receiving aliskiren HCT; attainment of BP goal increased to more than 70% when a classic BP target of <140/90 mmHg was applied for all patients. Reductions in mean sitting SBP/DBP were significantly lower versus baseline for both aliskiren (24.1/12.2 mmHg) and aliskiren HCT (27.6/14.1 mmHg) and BP response rates were consistently achieved in more than 80% of all patients during the study. Aliskiren treatment was well tolerated with only a small proportion of patients experiencing adverse events (AEs; 2.1%) and serious AEs (0.3%). CONCLUSION: In this real-world, naturalistic setting, antihypertensive treatment with an aliskiren-based regimen was effective and well-tolerated in this multiethnic population with arterial hypertension. PMID- 23354586 TI - Novel mechanism of regulation of protein 4.1G binding properties through Ca2+/calmodulin-mediated structural changes. AB - Protein 4.1G (4.1G) is a widely expressed member of the protein 4.1 family of membrane skeletal proteins. We have previously reported that Ca(2+)-saturated calmodulin (Ca(2+)/CaM) modulates 4.1G interactions with transmembrane and membrane-associated proteins through binding to Four.one-ezrin-radixin-moesin (4.1G FERM) domain and N-terminal headpiece region (GHP). Here we identify a novel mechanism of Ca(2+)/CaM-mediated regulation of 4.1G interactions using a combination of small-angle X-ray scattering, nuclear magnetic resonance spectroscopy, and circular dichroism spectroscopy analyses. We document that GHP intrinsically disordered coiled structure switches to a stable compact structure upon binding of Ca(2+)/CaM. This dramatic conformational change of GHP inhibits in turn 4.1G FERM domain interactions due to steric hindrance. Based upon sequence homologies with the Ca(2+)/CaM-binding motif in protein 4.1R headpiece region, we establish that the 4.1G S(71)RGISRFIPPWLKKQKS peptide (pepG) mediates Ca(2+)/CaM binding. As observed for GHP, the random coiled structure of pepG changes to a relaxed globular shape upon complex formation with Ca(2+)/CaM. The resilient coiled structure of pepG, maintained even in the presence of trifluoroethanol, singles it out from any previously published CaM-binding peptide. Taken together, these results show that Ca(2+)/CaM binding to GHP, and more specifically to pepG, has profound effects on other functional domains of 4.1G. PMID- 23354587 TI - Survival and post-warming in vitro competence of human oocytes after high security closed system vitrification. AB - PURPOSE: To compare two vitrification methods and two warming methods for human oocyte vitrification using a high security closed device in terms of survival, fertilization and embryo development. METHODS: For vitrification, oocytes were (1) immediately placed in equilibration solution or (2) they were gradually exposed to the cryoprotectants. For warming, oocytes were placed (1) in a 25 MUl preheated (37 degrees C) thawing solution droplet that was put at room temperature for 1 min once the oocytes were inside or (2) in a 150 MUl droplet for 1 minute at 37 degrees C. RESULTS: Survival and preimplantation development were significantly lower when warming was performed in a small preheated droplet. There was no significant difference in survival and embryo development between the gradual or direct exposure to cryoprotectants. CONCLUSIONS: Using this high security closed vitrification device a 90 % survival rate can be achieved when the oocytes are immediately warmed in a large volume at 37 degrees C. PMID- 23354588 TI - Effects of reduced seminal enzymatic antioxidants on sperm DNA fragmentation and semen quality of Tunisian infertile men. AB - PURPOSE: To evaluate levels of sperm DNA fragmentation and enzymatic antioxidant status in seminal plasma of Tunisian fertile and infertile men in order to assess the effects of seminal oxidative stress on sperm DNA integrity and semen quality. METHODS: Semen samples from 100 infertile patients (40 oligoasthenoteratozoospermics, 31 teratozoospermics and 29 asthenozoospermics) and 50 fertile men (controls) were analyzed for DNA fragmentation by TUNEL assay and biochemical parameters. Seminal antioxidant activities (Superoxide dismutase, Glutathione peroxidase and Catalase) and malondialdehyde concentrations were measured spectrophotometrically. RESULTS: Sperm DNA fragmentation and malondialdehyde levels in infertile groups were more elevated than controls. Nevertheless, the activities of the antioxidant enzymes were significantly lower in abnormal groups compared to normozoospermics. Sperm DNA fragmentation was closely and positively correlated to malondialdehyde levels (r = 0.37, P = 0.008); meanwhile, reduced seminal antioxidant profile was negatively associated to sperm DNA fragmentation. Interestingly, we noted also that sperm DNA fragmentation was negatively correlated to sperm motility (r = -0.54, P < 0.001) and positively associated to the abnormal sperm morphology (r = 0.57, P = 0.002). CONCLUSIONS: This report revealed that increased sperm DNA fragmentation can be due to the impaired seminal enzymatic antioxidant profile and increased Lipid peroxidation. Our results sustain that the evaluation of sperm DNA fragmentation and seminal oxidative biomarkers in infertile men is recommended as a consistent prognostic tool for male infertility assessment. PMID- 23354589 TI - A novel cyclinE/cyclinA-CDK inhibitor targets p27(Kip1) degradation, cell cycle progression and cell survival: implications in cancer therapy. AB - p27(Kip1) (p27) binds and inhibits the cyclin E- or cyclin A-associated cyclin dependent kinases (CDKs)2 and other CDKs, and negatively regulates G1-G2 cell cycle progression. To develop specific CDK inhibitors, we have modeled the interaction between p27 and cyclin A-CDK2, and designed a novel compound that mimics p27 binding to cyclin A-CDK2. The chemically synthesized inhibitor exhibited high potency and selective inhibition towards cyclin E/cyclin A-CDK2 kinase in vitro but not other kinases. To facilitate permeability of the inhibitor, a cell penetrating peptide (CPP) was conjugated to the inhibitor to examine its effect in several cancer cell lines. The CPP-conjugated inhibitor significantly inhibited the proliferation of cancer cells. The treatment of the inhibitor resulted in the increased accumulation of p27 and p21(Cip1/Waf1) (p21) and hypo-phosphorylation of retinoblastoma protein (Rb). The degradation of p27, mediated through the phosphorylation of threonine-187 in p27, was also inhibited. Consequently, exposure of cells to the inhibitor caused cell cycle arrest and apoptosis. We conclude that specific cyclinE/cyclin A-CDK2 inhibitors can be developed based on the interaction between p27 and cyclin/CDK to block cell cycle progression to prevent tumor growth and survival. PMID- 23354590 TI - Viral therapy for pancreatic cancer: tackle the bad guys with poison. AB - Pancreatic cancer is one of the most devastating diseases with very poor prognosis. Only a small proportion is curable by surgical resection, whilst standard chemotherapy for patients with advanced disease has only modest effect with substantial toxicity. Therefore, there is an urgent need for the development of novel therapeutic approaches to improve the patient outcome. Recently the viral therapy is emerging as a novel effective therapeutic approach for cancer with the potential to selectively treat both primary tumor and metastatic lesions. This review provides an overview of the current status of viral treatment for pancreatic cancer, both in the laboratories and in clinical settings. PMID- 23354591 TI - Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression. AB - lncRNA H19 is essential for human tumor growth. However, little is known about whether H19 regulates bladder cancer metastasis. Here we found that H19 levels are remarkably increased in bladder cancer tissues, and upregulated H19 promotes bladder cancer cell migration in vitro and in vivo. H19 is associated with enhancer of zeste homolog 2 (EZH2), and that this association results in Wnt/beta catenin activation and subsequent downregulation of E-cadherin. A significant negative correlation is also observed between H19 levels and E-cad levels in vivo. These data suggest that upregulated H19 enhances bladder cancer metastasis by associating with EZH2 and inhibiting E-cad expression. PMID- 23354592 TI - Identification of an AKT-dependent signalling pathway that mediates tamoxifen dependent induction of the pro-metastatic protein anterior gradient-2. AB - The pro-metastatic protein anterior gradient-2 (AGR2) was previously demonstrated as a predictive factor of poor response to tamoxifen treatment. In this study we aimed to delineate the key signalling pathway that may contribute to regulation of AGR2 protein induction in order to identify novel targets to overcome tamoxifen resistance in tumour cells. Together, our data identify PDPK1-AKT as a pro-oncogenic signalling pathway that triggers AGR2 protein induction in response to tamoxifen and suggest that AKT inhibitors could be used as part of a therapeutic strategy to treat tamoxifen resistant, AGR2 over-expressing cancers. PMID- 23354593 TI - Investigating the stability of and relationships among global/local processing measures. AB - Global/local stimuli have been used to estimate global processing biases in individuals and groups, as well as in response to various manipulations. Throughout the literature, multiple different versions of global/local stimuli have been used, such as traditional hierarchical letters and numbers (i.e., Navon letters), abstract hierarchical shapes, and high- and low-spatial-frequency gratings and faces. However, currently it is unclear how reliable or stable performance is on these measures within individuals over time, and whether these seemingly different measures are tapping into the same underlying process. As such, the purpose of the present study was to examine the stability of individual performance on three distinct global/local measures over time and to examine the relationships among the measures. In two studies, we examined the reliability of the biases within, and the relationships among, standard Navon letters in a traditional interference task, hierarchical shapes in a forced choice task, and superimposed high- and low-pass spatial frequency faces in a forced choice task. In both studies, participants completed all three of the tasks, and then returned 7-10 days later to again complete the same tasks. The degree of global/local bias within an individual was found to be highly reliable in the hierarchical shape task and the spatial frequency face task, but less reliable in the traditional Navon letter task. Interestingly, in both studies we found that none of the three measures of global bias were related to each other. Therefore, while these measures do appear to be reliable over time, they may be tapping into distinct aspects of global/local processing. PMID- 23354594 TI - Comparing lexically guided perceptual learning in younger and older listeners. AB - Numerous studies have shown that younger adults engage in lexically guided perceptual learning in speech perception. Here, we investigated whether older listeners are also able to retune their phonetic category boundaries. More specifically, in this research we tried to answer two questions. First, do older adults show perceptual-learning effects of similar size to those of younger adults? Second, do differences in lexical behavior predict the strength of the perceptual-learning effect? An age group comparison revealed that older listeners do engage in lexically guided perceptual learning, but there were two age-related differences: Younger listeners had a stronger learning effect right after exposure than did older listeners, but the effect was more stable for older than for younger listeners. Moreover, a clear link was shown to exist between individuals' lexical-decision performance during exposure and the magnitude of their perceptual-learning effects. A subsequent analysis on the results of the older participants revealed that, even within the older participant group, with increasing age the perceptual retuning effect became smaller but also more stable, mirroring the age group comparison results. These results could not be explained by differences in hearing loss. The age effect may be accounted for by decreased flexibility in the adjustment of phoneme categories or by age-related changes in the dynamics of spoken-word recognition, with older adults being more affected by competition from similar-sounding lexical competitors, resulting in less lexical guidance for perceptual retuning. In conclusion, our results clearly show that the speech perception system remains flexible over the life span. PMID- 23354595 TI - Incidence of prostate, breast, lung and colorectal cancer following new consultation for musculoskeletal pain: a cohort study among UK primary care patients. AB - Musculoskeletal pain has been linked with subsequent cancer. The objective was to investigate associations between pain sites and specific cancers, and investigate the hypothesis that musculoskeletal pain is an early marker, rather than cause, of cancer. This was a cohort study in the General Practice Research Database. From a cohort of 46,656 people aged >=50 years with a recorded musculoskeletal problem in 1996 but not during the previous 2 years, patients with a new consultation for back, neck, shoulder or hip pain in 1996 were selected and compared with 39,253 persons who had had no musculoskeletal consultation between 1994 and 1996. Outcome was incidence of prostate, breast, lung and colorectal cancer up to 10 years after baseline consultation. Strongest associations with prostate cancer were in the first year of follow-up for males consulting initially with back (adjusted hazard ratio 5.42; 95% CI 3.31, 8.88), hip (6.08; 2.87, 12.85) or neck problems (3.46; 1.58, 7.58). These associations remained for back and neck problems over 10 years. Significant associations existed with breast cancer up to 5 years after consultation in females with hip problems, and with breast and lung cancer in the first year after presentation with back problems. Previously observed links between pain and cancer reflect specific associations between pain sites and certain cancers. One explanation is liability for bony metastases from primary sites, and that pain represents a potential early marker of cancer. However, older patients with uncomplicated musculoskeletal pain seen in clinical practice have a low absolute excess cancer risk. PMID- 23354596 TI - Detection of Cryptococcus gattii in selected urban parks of the Willamette Valley, Oregon. AB - Human and animal infections of the fungus Cryptococcus gattii have been recognized in Oregon since 2006. Transmission is primarily via airborne environmental spores and now thought to be locally acquired due to infection in non-migratory animals and humans with no travel history. Previous published efforts to detect C. gattii from tree swabs and soil samples in Oregon have been unsuccessful. This study was conducted to determine the presence of C. gattii in selected urban parks of Oregon cities within the Willamette Valley where both human and animal cases of C. gattii have been diagnosed. Urban parks were sampled due to spatial and temporal overlap of humans, companion animals and wildlife. Two of 64 parks had positive samples for C. gattii. One park had a positive tree and the other park, 60 miles away, had positive bark mulch samples from a walkway. Genotypic subtypes identified included C. gattii VGIIa and VGIIc, both considered highly virulent in murine host models. PMID- 23354598 TI - Effective serological and molecular screening of deceased tissue donors. AB - A comprehensive and effective screening programme is essential to support the banking of tissues from deceased donors. However, the overall quality of the samples obtained from deceased donors, quantity and condition, is often not ideal, and this may lead to problems in achieving accurate and reliable results. Additionally a significant percentage of referrals are still rejected upon receipt as unsuitable for screening. We are actively involved in improving the overall quality of deceased donor screening outcomes, and have specifically evaluated and validated both serological and molecular assays for this purpose, as well as developing a specific screening strategy to minimise the specificity issues associated with serological screening. Here we review the nature and effectiveness of the deceased donor screening programme implemented by National Health Service Blood and Transplant (NHSBT), the organisation with overall responsibility for the supply of tissue products within England. Deceased donor screening data, serological and molecular, from August 2007 until May 2012 have been collated and analysed. Of 10,225 samples referred for serology screening, 5.5 % were reported as reactive; of 2,862 samples referred for molecular screening, 0.1 % were reported as reactive/inhibitory. Overall 20 % of the serological and 100 % of the molecular screen reactivity was confirmed as reflecting true infection. The use of a sequential serology screening algorithm has resulted in a marked reduction of tissues lost unnecessarily due to non specific screen reactivity. The approach taken by NHSBT has resulted in the development of an effective and specific approach to the screening of deceased tissue donors. PMID- 23354597 TI - Validation of the BRCA1 antibody MS110 and the utility of BRCA1 as a patient selection biomarker in immunohistochemical analysis of breast and ovarian tumours. AB - BRCA1 protein measurement has previously been evaluated as a potential diagnostic marker without reaching a conclusive recommendation. In this study, we applied current best practice in antibody validation to further characterize MS110, a widely used antibody targeting BRCA1. Antibody specificity was investigated using different biochemical validation techniques. We found that BRCA1 could not be reliably detected using immunoprecipitation and Western blot in endogenously expressing cells. We used immunohistochemistry on formalin-fixed paraffin embedded cell pellets to establish compatibility with formalin-fixed paraffin embedded samples. We demonstrated that in transfected cells and cell lines with known genetic BRCA1 status, MS110 successfully detected BRCA1 giving the expected level of staining in immunohistochemistry. Following this, we investigated the use of BRCA1 protein measurement by immunohistochemistry in a cohort of triple negative breast and serous ovarian tumour samples to explore the use of BRCA1 protein measurement by immunohistochemistry for patient stratification. Using MS110 in repeated standardized experiments, on serial sections from a panel of patient samples, results demonstrated considerable run-to-run variability. We concluded that in formalin-fixed tissue samples, MS110 does detect BRCA1; however, using standard methodologies, BRCA1 expression levels in tissue samples is incompatible with the use of this protein as a statistically robust patient selection marker in immunohistochemistry. These results demonstrate the need for further development to deliver BRCA1 protein quantification by immunohistochemistry as a patient stratification marker. PMID- 23354599 TI - Immune effects of optimized DNA vaccine and protective effects in a MPTP model of Parkinson's disease. AB - It has been suggested that DNA vaccine plays a protective effect on degenerative diseases in the central nervous system (CNS), the Parkinson's disease (PD) included. In this study, we assessed the immune effects of optimized DNA vaccine (pVAX1-IL-4/SYN-B) in the C57BL/6 mice by ELISA, and immunohistochemistry. We also evaluated the neuroprotective effect of pVAX1-IL-4/SYN-B in MPTP model of Parkinson's disease, using behavioral methods, immunohistochemistry and western blot. We found that alphalpha-synuclein (alpha-syn) antibody significantly increased, IL-4 increased and IFN-r reduced in the serum of immunized C57BL/6 mice in optimized DNA vaccine group. The immune serum of mice specifically combined with the alpha-syn positive inclusion bodies in the brain of PD model mice. The preventive immunization with optimized DNA vaccine made the motor symptoms improved significantly, the apoptosis of tyrosine hydroxylase (TH) neuron and cyclooxygenase-2 (COX-2) expression significantly decreased in MPTP model mice. These results suggest that optimized DNA vaccine can make immunized mice produce high titers of specific alpha-syn antibody, mainly causing the humoral immune response; preventive immunization with optimized DNA vaccine can play neuroprotective and anti-inflammatory effects on mice suffering from the sub acute MPTP Parkinson's disease. PMID- 23354600 TI - Alzheimer's disease: amino acid levels and brain metabolic status. AB - To study brain free amino acids and their relation with dementia we measured, by high-performance liquid chromatography (HPLC), the concentration of eight free amino acids, amines and related compounds. We used temporal cortex (TC) samples obtained from 13 Alzheimer's disease (AD) patients and an equal number of age matched controls (AC). The patterns of free amino acids, amines and related compounds showed significant quantitative changes in AD conditions with respect to healthy ones. In Alzheimer patients, lower levels of GABA were found in the TC (-57 %). Amino acids glutamate (Glu), and aspartate (Asp) concentrations, also appeared significantly reduced in the TC of AD patients (Glu: -30 %; Asp: -40 %) when compared with controls. The significant gap between methionine (Met: -30 %) and cystathionine (Cysta: +60 %) levels in TC of AD people to controls, might suggest an under/over activity of the transmethylation and transsulphuration pathways, respectively. Glutamine (Gln) and Urea were an exception to this trend because their content was higher in AD patients than in controls. Albeit these compounds may have particular physiological roles, including the possible mediation of synaptic transmission, changes in amino acid levels and related compounds (detected in steady state) suggest a modified metabolic status in brains of AD patients that reveals a reduced function of synaptic transmission. Because several evidences show that patients might display quite different concentrations of neurotransmitters in brain areas, assessing metabolites in different and well-characterized AD stages should be investigated further. PMID- 23354601 TI - Plasma copeptin levels in Chinese patients with acute ischemic stroke: a preliminary study. AB - Copeptin is a stable by-product of arginine-vasopressin synthesis and reflects its secretion. The objective of the study was to evaluate the predictive value of copeptine on functional outcome at 90-day follow-up from stroke onset. We conducted a prospective, observational cohort study in the emergency department of two hospitals and enrolled 125 patients with acute ischemic stroke. Plasma copeptin concentrations, determined by a CT-proAVP-luminescence-immunoassay, were measured. There was a good correlation between levels of plasma copeptin and NIHSS score (r = 0.733, P < 0.01). In the 41 patients (32.8 %) with a poor functional outcome, copeptin levels were higher compared with those in patients with a favorable outcome (27.3; IQR, 14.9-34.8 pmol/L vs. 12.9; IQR, 9.4-21.6 pmol/L; P < 0.0001). Copeptin levels in 18 patients who died were more than two times greater as compared to patients who survived (32.4; IQR, 18.7-38.5 pmol/L vs. 15.1; IQR, 12.4-24.6 pmol/L; P < 0.0001). After adjusting for all other significant outcome predictors, copeptin level remained an independent predictor for poor functional outcome and mortality with an odds ratio of 3.12 (95 % CI 1.54-6.46), 3.16 (95 % CI 0.92-6.15), respectively. Our study suggests that copeptin levels are a useful tool to predict outcome and mortality 3 months after acute ischemic stroke and have a potential to assist clinicians. PMID- 23354602 TI - Evaluation of c-Fos immunoreactivity in the rat brainstem nuclei relevant in migraine pathogenesis after electrical stimulation of the trigeminal ganglion. AB - Migraine is a common neurological condition, causing high disability, but the pathomechanism of the disease is not yet fully understood. Activation of the trigeminovascular system could play a crucial role in the manifestation of the symptoms, but initial step of this activation remains unknown. Functional imaging studies have revealed that certain brainstem areas, referred to as migraine generators, are activated during a migraine attack, including the dorsal raphe, the periaqueductal gray, the locus coeruleus, and the nucleus raphe magnus. However, the studies performed to date have not demonstrated whether this activation is a trigger or a consequence of the migraine attack. With the aim of evaluating the functional relationship between activation of the trigeminal system and migraine generators, we examined the changes in c-Fos immunoreactivity in the above-mentioned nuclei after stimulation of the trigeminal ganglion, an animal model for trigeminovascular activation. The stimulation led to significant increases in the number of c-Fos immunoreactive cells in the nucleus raphe magnus and in the caudal part of the spinal trigeminal nucleus, 2 and 4 h after the stimulation. Activation of the trigeminal system failed to exhibit uniform activation of the brain stem nuclei related to migraine. Our results suggest that the activation of the trigeminal system in the rat by electrical stimulation of the trigeminal ganglion leads to the activation of the descending pain modulatory system, but not to the activation of "migraine generator" nuclei. Therefore, the activity pattern seen in functional studies may reflect a unique feature, exclusively present in migraine. PMID- 23354603 TI - Arithmetic knowledge in early semantic dementia. AB - The issue of whether arithmetic knowledge is invariably spared or impaired in semantic dementia is still under debate. The corpus of data mainly relies on single case-report descriptions. Relative to this issue, only one paper, by Julien et al. (Neuropsychologia 44(10): 2732-2744, 2008) explored in a systematic way arithmetic knowledge in an SD patient group. The present study is aimed to explore calculation in a group of eight patients affected by early semantic dementia (SD) using a neuropsychological battery devised to examine arithmetic knowledge (arithmetic signs recognition, arithmetic facts and written and mental calculation). These SD patients showed problems in recognition of arithmetic signs, difficulty in arithmetic facts and procedural errors in calculation. Still, the pattern of answers that the SD patients showed was not completely homogeneous and some individual variations were present. In contrast with most literature, the present study provides evidence for impairment of arithmetic knowledge in patients with early semantic dementia and contributes to the recent evidence that arithmetic knowledge cannot be considered an independent domain within the semantic system. PMID- 23354604 TI - Tempol reduces injury area in rat model of spinal cord contusion injury through suppression of iNOS and COX-2 expression. AB - The present study focused on the biologic effects of tempol on anti-inflammatory and nitric oxide generation in contusion spinal cord injury (SCI). The animal model of SCI was induced by dropping a 10-g rod (2.0 mm in diameter) at a height of 25 mm. Tempol was injected intraperitoneally a dose of 100 mg/kg at 15 min before SCI. Controls was injected with saline. The contused spinal segments were removed according to time courses, and the expression level of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was analyzed along with the size of irreversibly damaged region. After SCI, the relative amounts of COX-2 and iNOS mRNA were peaked at 8 h after post-injury, and then decreased up to 7 days post-injury, and normal level at 14 days. Expression of COX-2 protein was peaked at 8 h post-injury. With the tempol pre-treatment, the immunoreactivity of COX-2 and nitrotyrosine in paraffin-embedded tissue slices was profoundly decreased. The irreversibly damaged area of the spinal cord was peaked at 3 days after SCI. With tempol pre-treatment, the irreversibly damaged area shows a statistically significant decrease at 3 days after SCI. These evidences indicate that tempol pre-treatment reduces irreversibly damaged area on the contusion SCI in rat. The mechanisms of biologic reactions of tempol might be related to the decreased expressions of COX-2 and iNOS in spinal cord cells, neurons and glia. It is expected that the tempol effect on the SCI is not only antioxidant activity but also anti-inflammatory reaction. PMID- 23354605 TI - The 9-bp deletion in region V of mtDNA: a risk factor of hearing loss and encephalomyopathy in Caucasian populations? AB - A deletion of one of the two copies of the 9-bp tandem repeat sequence (CCCCCTCTA), in the small non-coding/untranslated segment located between the cytochrome oxidase II and lysine tRNA genes of mitochondrial DNA (mtDNA), has previously been used as a polymorphic anthropological marker (MIC9D) for people of Africa and Asia, but it has been rarely reported in Europe. 32 Sicilian patients with syndromic hearing loss, negative for mutations in GJB2 and GJB6 genes, were tested for mtDNA known point mutations associated with syndromic or non-syndromic hearing loss by RFLP and/or direct sequencing. We identified the presence of the MIC9D in homoplasmy in lymphocytes and muscle of three subjects with sensorineural hearing loss and encephalomyopathy, two of these also presented moderate mental retardation. This deletion was absent in 300 Caucasian controls. Although further studies are warranted, our results suggest that the MIC9D polymorphism could have a susceptibility role in Caucasus, such as Sicily population. PMID- 23354606 TI - Endovascular treatment of CCSVI in patients with multiple sclerosis: clinical outcome of 462 cases. AB - Although it is still debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients underwent endovascular treatment (ET) of CCSVI. The objective of the study is to evaluate the outcome and safety of ET in Italian MS patients. Italian MS centers that are part of the Italian MS Study Group were all invited to participate to this retrospective study. A structured questionnaire was used to collect detailed clinical data before and after the ET. Data from 462 patients were collected in 33 centers. ET consisted of balloon dilatation (93 % of cases) or stent application. The mean follow-up duration after ET was 31 weeks. Mean EDSS remained unchanged after ET (5.2 vs. 4.9), 144 relapses occurred in 98/462 cases (21 %), mainly in RR-MS patients. Fifteen severe adverse events were recorded in 3.2 % of cases. Given the risk of severe adverse events and the lack of objective beneficial effects, our findings confirm that at present ET should not be recommended to patients with MS. PMID- 23354607 TI - Dysgraphia due to anterior choroidal artery territory infarction: a case report. PMID- 23354608 TI - Rita Levi-Montalcini, one of the most prominent Italian personalities of the twentieth century. PMID- 23354609 TI - Protective effects of copper against aluminum toxicity on acetylcholinesterase and catecholamine contents of different regions of rat's brain. AB - The probable protective effects of copper on the acetylcholinesterase activity and the catecholamine levels in cerebellum, cortex and mid-brain of rat, which was intoxicated by aluminum, were studied during short and long terms. In this respect, male Wistar rats weighing 200-250 g were received daily intraperitoneal doses of aluminum, copper and also combined doses of both metals for 15 days (Al 10 mg kg(-1) BW and Cu 1 mg kg(-1) BW), 30 days (Al 5 mg kg(-1) BW and Cu 0.5 mg kg(-1) BW) and 60 days (Al 1 mg kg(-1) BW and Cu 0.1 mg kg(-1) BW), respectively. The results obtained from the short period of exposure (15 days) showed that aluminum produced significant (P < 0.05) decreases in the acetylcholinesterase activity by 24.14, 23.30 and 25.81 %. Similarly, the catecholamine levels were reduced by 10.69, 12.25 and 12.64 % in cerebellum, cortex and mid-brain, respectively. Treatment with copper increases both acetylcholinesterase activity and catecholamine contents of cerebellum, cortex and mid-brain. Simultaneous injection of copper and aluminum increased both acetylcholinesterase activity and catecholamine contents in all three parts of rat brain when compared to aluminum treated group. Same results were also observed following 30 and 60 days of exposures. In overall, it has been found that copper may have a protective-like ability to hinder aluminum toxicity in the brain. PMID- 23354610 TI - Monitoring the implementation of the State-Regional Council agreement 03/02/2005 as to the management of acute stroke events: a comparison of the Italian regional legislations. AB - Access to effective acute stroke services is a crucial factor to reduce stroke related death and disability, but is limited in different parts of Italy. Our study addresses this inequality across the Italian regions by examining the regional legislations issued to adopt and implement the State-Regional Council agreement 03/02/2005 as to the acute stroke management. All decrees and resolutions as to acute stroke were collected from each region and examined by the means of a check list including quantitative and qualitative characteristics, selected in accordance with the recommendations from the State-Regional Council document. Each completed check list was then sent to each regional reference person, who filled in the section on the implementation of the indications and compliance, with the collaboration of stroke specialists if necessary. The study was carried out from November 2009 to September 2010. The documents and information were collected from 19 regions. Our survey revealed disparities both in terms of number of decrees and resolutions and of topics covered by the regional legislations about stroke care. Most legislations lacked practical and economical details. This feedback from national and regional stroke regulations revealed a need of more concrete indications. Involvement of various stakeholders (legislators, consumers, providers) might possibly ensure that policies are actually adopted, implemented and maintained. Although considerable challenges are present to the development of standard and optimal stroke care more widely across Italian regions, the potential gains from such developments are substantial. PMID- 23354611 TI - Establishment of a biorepository for migraine research: the experience of Interinstitutional Multidisciplinary BioBank (BioBIM). AB - The development of Biobanks and recent advances in molecular biology have enhanced the possibility to accelerate translational research studies. The Interinstitutional Multidisciplinary BioBank (BioBIM) is organized in a large healthy donors collection and pathology-based biobanks with the aim to provide a service for development of interdisciplinary studies. A new pathology-based biobank has been organized to specifically collect biospecimen from patients affected by migraine, with the final goal to centralize data, collect blood, plasma, serum, DNA and RNA of patients with this disease. The BioBIM is fully equipped for the automation of sampling/processing, storage and tracking of biospecimens. Standard Operating Procedures have been developed for processing and storage phases as well as archive of clinical data. The availability of biospecimens and clinical data will constitute a resource for various research projects. PMID- 23354612 TI - Predictive toxicology and ecotoxicology within the ANTIOPES network. PMID- 23354614 TI - Biogeochemical behaviour and bioremediation of uranium in waters of abandoned mines. AB - The discharges of uranium and associated radionuclides as well as heavy metals and metalloids from waste and tailing dumps in abandoned uranium mining and processing sites pose contamination risks to surface and groundwater. Although many more are being planned for nuclear energy purposes, most of the abandoned uranium mines are a legacy of uranium production that fuelled arms race during the cold war of the last century. Since the end of cold war, there have been efforts to rehabilitate the mining sites, initially, using classical remediation techniques based on high chemical and civil engineering. Recently, bioremediation technology has been sought as alternatives to the classical approach due to reasons, which include: (a) high demand of sites requiring remediation; (b) the economic implication of running and maintaining the facilities due to high energy and work force demand; and (c) the pattern and characteristics of contaminant discharges in most of the former uranium mining and processing sites prevents the use of classical methods. This review discusses risks of uranium contamination from abandoned uranium mines from the biogeochemical point of view and the potential and limitation of uranium bioremediation technique as alternative to classical approach in abandoned uranium mining and processing sites. PMID- 23354616 TI - PCB contamination in soils of the Pearl River Delta, South China: levels, sources, and potential risks. AB - Polychlorinated biphenyls (PCBs) contamination in tropical and sub-tropical areas and the associated risks have attracted great concern. A total of 69 samples representing five distinct land types were collected to assess PCB concentrations in the Pearl River Delta (PRD), South China, including spatial distributions in soils of the area, the probable anthropogenic sources, and related potential risks. PCBs concentrations in soils of the PRD ranged from 0.3 to 202 ng g(-1). More severe PCBs contamination was presented in the western part than in the eastern part of the PRD region. The PCBs were dominated by low-chlorinated biphenyls; however, the proportion of higher-chlorinated biphenyls was elevated with the influence of industrial activities. Principal component analysis indicated that PCBs contamination in soils of the PRD region was mainly associated with 1#PCBs, while 2#PCB and e-waste emission in South China also accounted for it partly, especially to the industrial activity severely impacted areas. Toxic equivalent (TEQ) of the dioxin-like PCBs in the soils indicated that higher risk of PCB contamination was presented in the Dongjiang River Valley (55 ng TEQ kg(-1), on average) than in the Xijiang River Valley, and were mostly contributed by the congener of PCB126. PMID- 23354615 TI - Effects of mono-(2-ethylhexyl) phthalate (MEHP) on chicken germ cells cultured in vitro. AB - In recent decades, many toxicological tests based on in vivo or in vitro models, mainly from mammalian (rat-mouse) and fish species, were used to assess the risks raised by contact or ingestion of molecules of pharmaceutical, agricultural, or natural origin. But no, or few, in vitro tests using other non-mammalian models such as bird have been explored despite their advantages: the embryonic gonads of birds have a high plasticity of development sensitive to estrogen, and sperm production is nearly two times faster than in rodents. Hence, we have established an in vitro culture of germ cells and somatic cells from chicken post-natal testis, and we have evaluated the sensitivity against the endocrine disruptor compound mono-(2-ethylhexyl) phthalate (MEHP) in comparison to previous studies using rodent and human models. After 96 h of exposure in presence of 10 MUM MEHP, chicken seminiferous tubules cultures present a structural alteration, a reduction in cell proliferation and in germ cells population. Apoptosis of germ and somatic cells increases in presence of 1 MUM MEHP. Furthermore, MEHP does not affect inhibin B and lactate production by Sertoli cells. These results are in accordance with previous studies using rat, mice, or human culture of testicular cells and in similar range of exposures or even better sensitivity for some "end points" (biological parameters). In conclusion, the establishment of this postnatal testicular cells culture could be considered as an alternative method to in vivo experiments frequently used for evaluating the impact on the terrestrial wildlife species. This method could be also complementary to mammal model due to the limiting number of animals used and its elevated sensitivity. PMID- 23354617 TI - Application of GIS and modelling in health risk assessment for urban road mobility. AB - Transport is an essential sector in modern societies. It connects economic sectors and industries. Next to its contribution to economic development and social interconnection, it also causes adverse impacts on the environment and results in health hazards. Transport is a major source of ground air pollution, especially in urban areas, and therefore contributes to the health problems, such as cardiovascular and respiratory diseases, cancer and physical injuries. This paper presents the results of a health risk assessment that quantifies the mortality and the diseases associated with particulate matter pollution resulting from urban road transport in Haiphong City, Vietnam. The focus is on the integration of modelling and geographic information system approaches in the exposure analysis to increase the accuracy of the assessment and to produce timely and consistent assessment results. The modelling was done to estimate traffic conditions and concentrations of particulate matters based on geo referenced data. The study shows that health burdens due to particulate matter in Haiphong include 1,200 extra deaths for the situation in 2007. This figure can double by 2020 as the result of the fast economic development the city pursues. In addition, 51,000 extra hospital admissions and more than 850,000 restricted activity days are expected by 2020. PMID- 23354618 TI - Graphene-a promising material for removal of perchlorate (ClO4-) from water. AB - A batch adsorption process was applied to investigate the removal of perchlorate (ClO4 (-)) from water by graphene. In doing so, the thermodynamic adsorption isotherm and kinetic studies were also carried out. Graphene was prepared by a facile liquid-phase exfoliation. Graphene was characterized by Raman spectroscopy, Fourier-transform infrared spectroscopy, powder X-ray diffraction, scanning electron microscope, and zeta potential measurements. A systematic study of the adsorption process was performed by varying pH, ionic strength, and temperature. The adsorption efficiency of graphene was 99.2 %, suggesting that graphene is an excellent adsorbent for ClO4 (-) removal from water. The rate constants for all these kinetic models were calculated, and the results indicate that second-order kinetics model was well suitable to model the kinetic adsorption of ClO4 (-). Equilibrium data were well described by the typical Langmuir adsorption isotherm. The experimental results showed that graphene is an excellent perchlorate adsorbent with an adsorbent capacity of up to 0.024 mg/g at initial perchlorate concentration of 2 mg/L and temperature of 298 K. Thermodynamic studies revealed that the adsorption reaction was a spontaneous and endothermic process. Graphene removed the perchlorate present in the water and reduced it to a permissible level making it drinkable. PMID- 23354619 TI - Regeneration of spent TiO2 nanoparticles for Pb (II), Cu (II), and Zn (II) removal. AB - Spent sorbents in water treatment processes have potential risks to the environment if released without proper treatment. The aim of this work was to investigate the potential regeneration of commercially prepared nano-TiO2 (anatase) for the removal of Pb (II), Cu (II), and Zn (II) by pH 2 and ethylenediaminetetraacetic acid (EDTA) solutions. The percent of metal adsorption/desorption decreased with the increasing number of regeneration cycles, and the extent of decrease varied for each metal. Competitive effects were observed for the adsorption/desorption of different metals when the nano TiO2 was regenerated by EDTA solutions. Nano-TiO2 was able to treat simulated metal polluted water with greater than 94 % adsorption and greater than 92 % desorption after four cycles of regeneration using pH 2 solution. These results demonstrated that nano-TiO2 can be regenerated and reused using pH 2 solution compared to an EDTA solution for aquatic metal removal, which makes nanosorbents promising and economically and environmentally more attractive in the application of water purification. PMID- 23354620 TI - Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients. AB - BACKGROUND: Patients with primary biliary cirrhosis (PBC) exhibit a variety of clinical manifestations and patterns of disease progression. The aim of this study was to identify genetic determinants of PBC progression. METHODS: A total of 52 tag single nucleotide polymorphisms (SNPs) of 11 candidate genes involved in regulating bile acid synthesis were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, -high resolution melting curve analysis, or -direct DNA sequencing in 315 Japanese patients with PBC. RESULTS: In this study, four tag SNPs of CYP7A1 (rs1457043, rs8192870, rs3808607, and rs3824260), two tag SNPs of HNF4A (rs6017340 and 6031587), and one SNP of PPARGC1A (rs8192678) showed a significant association with PBC progression. In addition, a dual luciferase assay revealed that the polymorphism of rs3808607 in CYP7A1 altered the expression of CYP7A1 in HepG2. Specifically, the CYP7A1 promoter carrying the risk G allele for PBC progression induced higher expression of CYP7A1 under both the normal and cholestatic conditions in vitro as compared to another promoter carrying the non-risk T allele. CONCLUSION: These results suggested that the genetic variants of CYP7A1 and its transcriptional activators (HNF4A and PPARGC1A) may activate bile acid synthesis, resulting in the accumulation of bile acids in hepatocytes and eventually leading to the predisposition to PBC progression. Thus, the regulation of CYP7A1 expression may represent an attractive therapeutic target for cholestatic liver diseases including PBC. PMID- 23354621 TI - Clinical factors predictive of insufficient liver enhancement on the hepatocyte phase of Gd-EOB-DTPA-enhanced magnetic resonance imaging in patients with liver cirrhosis. AB - BACKGROUND: Estimating liver parenchymal enhancement prior to gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) imaging is crucial to accurate detection and characterization of focal hepatic lesions. We aimed to clarify the factors predictive of liver enhancement in a relatively large sample of patients. METHODS: Gd-EOB-DTPA enhanced MR images of 328 patients with liver cirrhosis (Child-Pugh class A in 223 patients, class B in 71 patients, and class C in 34 patients) were analyzed retrospectively. The liver parenchymal signal intensity (SI) was measured in pre contrast T1-weighted images and hepatocyte phase images. The relative enhancement (RE) was calculated: (hepatocyte phase SI-pre-contrast SI)/pre-contrast SI. We analyzed the correlation between hepatic function parameters and RE. RESULTS: RE of patients with Child-Pugh A cirrhosis was significantly higher than that of patients with Child-Pugh B or C cirrhosis (both P < 0.001). Among various clinical factors, platelet count, prothrombin activity, albumin, sodium, total bilirubin, aspartate aminotransferase, Model for End-stage Liver Disease (MELD) score, MELD-Na score, Child-Pugh score, and the presence of ascites were significantly correlated with RE. A multiple stepwise regression analysis revealed that MELD-Na, albumin, and the presence of ascites were the only factors that predicted liver parenchymal enhancement on hepatocyte-phase images. CONCLUSION: The degree of liver parenchymal enhancement after Gd-EOB-DTPA administration was correlated with liver function parameters. Gd-EOB-DTPA enhanced MR images require careful interpretation, particularly in patients with cirrhosis and clinical factors such as high MELD-Na score, hypoalbuminemia, or ascites. PMID- 23354622 TI - The role of allergy evaluation in children with eosinophilic esophagitis. AB - BACKGROUND: To our knowledge, in Asia, data on utility of allergy tests in management of eosinophilic esophagitis are lacking. The objective of our study was to determine the role of allergy evaluation in management of Saudi children with eosinophilic esophagitis. METHODS: Children diagnosed as having eosinophilic esophagitis during the period from 2009 to 2012 were referred to an allergist for allergy evaluation. The allergy evaluation consisted of total IgE level, radio allergosorbent assay, and skin prick test. Depending on the results of the allergy tests, a restricted or elemental diet was established. Swallowed fluticasone inhaler was prescribed to patients who rejected or failed to respond to the diet. Clinical, endoscopic, and histological evaluation was performed in 8 weeks to assess response. RESULTS: Eighteen children with eosinophilic esophagitis were included (13 males; mean age 5 years, range 1-11). Sensitization to foods was demonstrated in 14 patients: 4 with a positive test for a single food (28.5%), 1 for 2 food allergens (7%), and 9 for >=3 food allergens (64.5%). The most common food allergens were milk, soybean, wheat, egg, and nuts. Three young children out of the total 14 patients responded to elemental formula. Four of the 10 older children on the allergy testing guided-dietary restriction achieved partial remission and the remaining 6 did not respond. All 10 patients responded to a swallowed fluticasone inhaler. CONCLUSION: Although food sensitizations in Saudi children with eosinophilic esophagitis are common, the allergy tests had limited predictive value for the response to dietary elimination. PMID- 23354623 TI - WTAP regulates migration and invasion of cholangiocarcinoma cells. AB - BACKGROUND: Wilms' tumor 1-associating protein (WTAP) is a nuclear protein that has been associated with the regulation of proliferation and apoptosis. Although its dynamic expression and physiological functions in vascular cells have been reported, its expression and roles in cholangiocarcinoma cells are poorly characterized. METHODS: To examine the expression of WTAP in patient tissues, we performed immunohistochemistry. To examine motility of cholangiocarcinoma cells, we employed Boyden chamber, wound healing and Matrigel invasion assays, and a liver xenograft model. RESULTS: Immunohistochemistry in patient tissues showed WTAP overexpression in cholangiocarcinoma tissues and correlation of WTAP expression with metastasis of cholangiocarcinoma cells. Overexpression or knockdown of WTAP significantly increased or decreased the motility of cholangiocarcinoma cells. Moreover, WTAP overexpression or knockdown significantly increased or decreased tumorigenicity of cholangiocarcinoma cells in an orthotopic xenograft model. Furthermore, microarray study showed that WTAP induce the expressions of MMP7, MMP28, cathepsin H and Muc1. CONCLUSION: WTAP is overexpressed in cholangiocarcinoma and regulates motility of cholangiocarcinoma cells. PMID- 23354624 TI - Impact of anticancer treatment on recurrent obstruction in covered metallic stents for malignant biliary obstruction. AB - BACKGROUND: In patients with unresectable malignant biliary obstruction (MBO), anticancer treatment is often administered. The impact of anticancer treatment on recurrent biliary obstruction in covered self-expandable metallic stents (SEMS) has not been fully elucidated. METHODS: Data on 279 patients enrolled in a multicenter prospective cohort study of two different covered SEMS for distal MBO, WATCH study (141 partially covered WallFlex stents and 138 partially covered Wallstents) were retrospectively analyzed. The rates and causes of recurrent biliary obstruction (stent occlusion or migration) were compared between anticancer treatment group (n = 173) and best supportive care alone (BSC) group (n = 106). Cumulative time and prognostic factors for recurrent biliary obstruction were analyzed, using a proportional hazards model with death without recurrent biliary obstruction as a competing risk. RESULTS: The overall rate (43 vs. 25%, P = 0.002) and the cumulative incidence (16.1 vs. 8.2, 27.9 vs. 18.9 and 44.1 vs. 26.6% at 3, 6 and 12 months, P = 0.030 by Gray's test) of recurrent biliary obstruction were significantly higher in anticancer treatment group compared with BSC group. The multivariate analysis revealed anticancer treatment [subdistribution hazard ratio (SHR) 1.93, P = 0.007) as well as the use of a partially covered WallFlex stent (SHR 0.65, P = 0.049) as prognostic factors. CONCLUSIONS: Anticancer treatment was a risk factor for recurrent biliary obstruction in covered SEMS for distal MBO. The superiority of a partially covered WallFlex stent was again confirmed in this competing risk analysis; UMIN CTR: UMIN000002293. PMID- 23354625 TI - Management of dysfunctional covered self-expandable metallic stents in patients with malignant distal biliary obstruction. AB - BACKGROUND: Endoscopic placement of covered self-expandable metallic stents (CSEMSs) is effective for distal malignant biliary obstruction. However, management of dysfunctional CSEMSs has not been established. METHODS: Between March 1998 and July 2007, a total of 74 patients who underwent endoscopic re interventions for CSEMS dysfunction were analyzed. Second stent insertion (CSEMS or plastic stent) or mechanical cleaning of the occluded CSEMS was performed endoscopically. The period between second stent insertion and stent dysfunction or patient death (time to dysfunction; TTD) was calculated. The cleaned initial CSEMSs were analyzed as second stents. RESULTS: Dysfunction of the second stent occurred in 17 of 37 patients (45.9%) in the CSEMS group, 16 of 20 (80.0%) in the plastic stent group, and 13 of 17 (76.5%) in the cleaning group. The median TTD of each group was 176, 57, and 46 days, respectively. The cumulative TTD was significantly higher in the CSEMS group than in the plastic stent and cleaning groups (P = 0.08). From the multivariate analysis, sludge occlusion of the first CSEMS was identified as a significant risk factor for second stent dysfunction (HR, 2.51; 95% CI, 1.19-5.46), and placement of the second CSEMS significantly reduced the risk of dysfunction (HR, 0.39; 95% CI, 0.18-0.79). CONCLUSIONS: Insertion of a new CSEMS should be considered as the treatment of choice for the management of dysfunctional CSEMSs. PMID- 23354626 TI - Modulation of p38 MAPK signaling enhances dendritic cell activation of human CD4+ Th17 responses to ovarian tumor antigen. AB - The recent finding that Th17 infiltration of ovarian tumors positively predicts patient outcomes suggests that Th17 responses play a protective role in ovarian tumor immunity. This observation has led to the question of whether Th17 cells could be induced or expanded to therapeutic advantage by tumor vaccination. In this study, we show that treatment of ovarian tumor antigen-loaded, cytokine matured human dendritic cells (DC) with a combination of IL-15 and a p38 MAP kinase inhibitor offers potent synergy in antagonism of CD4(+) Treg induction and redirection toward CD4(+) Th17 responses that correlate with strong CD8(+) cytotoxic T lymphocyte (CTL) activation. Ovarian tumor antigen-specific CD4(+) T cells secrete high levels of IL-17 and show reduced expression of CTLA-4, PD-1, and Foxp3 following activation with IL-15/p38 inhibitor-treated DC. We further show that modulation of p38 MAPK signaling in DC is associated with reduced expression of B7-H1 (PD-L1), loss of indoleamine 2,3-dioxygenase activity, and increased phosphorylation of ERK 1/2 MAPK. These observations may allow the development of innovative DC vaccination strategies to boost Th17 immunity in ovarian cancer patients. PMID- 23354628 TI - [Internalized Stigma of Schizophrenia: Validation of the German Version of the Internalized Stigma of Mental Illness-Scale (ISMI)]. AB - OBJECTIVES: Schizophrenia is particularly associated with stigma. Especially internalized stigma, the inner subjective experience of stigma and its psychological effects resulting from applying negative stereotypes and stigmatising attitudes to oneself, is a barrier to recovery. The Internalized Stigma of Mental Illness-scale (ISMI) developed by Jennifer Boyd Ritsher and colleagues is a valid instrument for self-rated assessment of the subjective experience of stigma. The aim of the study was to examine the psychometric properties of the German Version of the ISMI among people with schizophrenia spectrum disorder. METHODS: The ISMI was translated into German. Reliability and validity of the instrument were tested and predictors of internalized stigma were explored. Data of 157 people were collected on the ISMI and demographic and clinical variables. Construct validity was tested by comparing results with already established constructs such as perceived devaluation and discrimination, depression, self-esteem, empowerment, control convictions and quality of life. RESULTS: The German Version of the ISMI showed good psychometric properties with high internal consistency, good test-retest reliability and good construct validity among people with schizophrenia spectrum disorder. About one third had a mean above the midpoint of the scale indicating a high level of internalized stigma. Internalized stigma was predicted by insufficient social network, level of education less than high school and inpatient or day clinic treatment compared to outpatient treatment. CONCLUSION: Results suggest that the German version of the ISMI is comparable to its original version. With the German version of the ISMI internalized stigma can be measured reliably and validly among people with schizophrenia spectrum disorder. Future studies may use the ISMI to record changes in internalized stigma pertinent to the achievement of therapeutic goals. PMID- 23354627 TI - Limiting assumptions in molecular modeling: electrostatics. AB - Molecular mechanics attempts to represent intermolecular interactions in terms of classical physics. Initial efforts assumed a point charge located at the atom center and coulombic interactions. It is been recognized over multiple decades that simply representing electrostatics with a charge on each atom failed to reproduce the electrostatic potential surrounding a molecule as estimated by quantum mechanics. Molecular orbitals are not spherically symmetrical, an implicit assumption of monopole electrostatics. This perspective reviews recent evidence that requires use of multipole electrostatics and polarizability in molecular modeling. PMID- 23354629 TI - Takotsubo cardiomyopathy in a male during a Euro 2012 football match. PMID- 23354630 TI - [Comparative performance of symptoms questionnaire, hydrogen test and genetic test for lactose intolerance]. AB - BACKGROUND: Genetically programmed adult-type hypolactasia affects 56% of Chilean population. Ideally, diagnosis should be confirmed. AIM: To compare diagnostic yield of genetic test, hydrogen (H2) expiratory test and a validated symptomatic structured survey (SS). MATERIAL AND METHODS: Patients submitted to H2 test answered a historic (anamnestic) and current SS (after the ingestion of 25 g of lactose). A blood sample was obtained for determination of genetic polymorphisms C/T_13910, C/G_13907 and G/A_22018 by polymerase chain reaction. The gold standard for diagnosis of lactose intolerance (LI) was the agreement of at least two of three tests. RESULTS: Sixty-one participants aged 39 +/- 12 years (21 males), were studied. Anamnestic SS was diagnostic of LI in all cases (score > 7), while current SS detected LI in 27/61 (46%). H2 test (an increase > 15 ppm after ingestion of 25 g of lactose) showed LI in 31/61 (51%). The locus C/G_13907 showed no polymorphism and locus G/A_22018 was in complete linkage disequilibrium with C/T_13910. Genotype C/C_13910, associated to hypolactasia, was present in 30/58 (52%). According to the gold-standard, 32/61 (52.5%) patients were diagnosed as LI. Sensitivity and specificity were, respectively, 79% and 69% for current SS, 93% and 93% for H2 test and 97% and 93% for the genetic test. The last two showed a positive likelihood ratio (LR) > 10 and a negative LR < 0.1, figures within the range considered clinically useful. CONCLUSIONS: Genotype C/C_13910 is responsible for hypolactasia in this population. Anamnestic report of symptoms after milk ingestion and symptoms after lactose ingestion, are not accurate enough. H2 and genetic tests are simple and similarly accurate to diagnose lactose intolerance in adults. PMID- 23354631 TI - [Decreased caspase 3 expression and cytotoxic T lymphocyte antigen-4 polymorphism in Chilean patients with type 1 diabetes]. AB - BACKGROUND: Several polymorphisms of the CTLA4 gene have been associated with autoimmune diseases. The activation of induced cell death is the major event and caspase 3 represents the main protein for the apoptotic machinery, especially in lymphocytes. AIM: To correlate CTLA4 polymorphisms with caspase 3 expression in peripheral blood mononuclear cells (PBMC) simulating in vitro the glucose effect. MATERIAL AND METHODS: CTLA4 polymorphisms were determined by restriction fragment length polymorphisms (RFLPs). PBMC from 21 patients with type 1 diabetes aged 8.5 +/- 4.3 years and 21 healthy subjects aged 18.3 +/- 1.8 years, were stimulated under normal (5 mM) and toxic (14 mM) glucose conditions to assess its effect on the expression and activity of caspase 3. Relative abundance of caspase 3 mRNA was measured by semi quantitative RT-PCR and its activity, by a colorimetric assay. RESULTS: When stimulated with 14 mM glucose, PBMC of G allele carriers with type 1 diabetes had significantly lower relative mRNA abundance of caspase 3 (median value = 0.12, range 0.01-0.70 AU) compared with non-carriers (median value = 0.81, range 0.06-1.09 AU). When the incubation was carried out with the lower glucose concentration, a similar profile of caspase 3 activity was observed in diabetic patients carrying G allele (median value = 0.57, range 0.13-1.20 AU) as compared with non-carriers (median value = 0.89, range 0.14-5.50 AU). No significant changes after stimulating with glucose, were observed in PBMCs of the control group. CONCLUSIONS: PBMC of recently diagnosed patients with T1D, carrying the G allele in + 49A/G polymorphisms of CTLA4, have a decreased expression and activity of caspase 3. PMID- 23354632 TI - [Positron emission tomography with fluorine-deoxyglucose in sarcomas and non sarcoma non-epithelial tumors]. AB - BACKGROUND: The usefulness of positron emission tomography (PET) with fluorine deoxyglucose (FDG) in sarcomas and non-sarcoma non-epithelial (NSNE) tumors is not clearly defined. AIM: To report a Chilean experience with NSNE tumors evaluated using PET with FDG. MATERIAL AND METHODS: Retrospective review of the database of a PET laboratory. Demographic data, indications and metabolic findings were compared with conventional imaging in 88 adults and children with diverse bone and soft tissue sarcomas as well as 24 gastrointestinal stromal tumors (GIST), 6 pleural malignant mesotheliomas in adults, and 9 medulloblastomas in children. RESULTS: FDG showed good concordance with conventional imaging in NSNE tumors. It was helpful for staging, restaging, follow-up after treatment and for the detection of new not previously suspected lesions. CONCLUSIONS: PET with FDG could have a prognostic role and help in patient management, mainly in musculoskeletal and high grade or less differentiated sarcomas. In GIST, it was a good tool for immunotherapy control. PMID- 23354633 TI - [Prevalence of peripheral neuropathy among primary care type 2 diabetic patients]. AB - BACKGROUND: Neuropathy is a common complication of diabetic patients. AIM: To determine the prevalence of diabetic peripheral neuropathy in Type 2 diabetic patients attended at a family medicine unit. MATERIAL AND METHODS: Cross sectional assessment of 348 type 2 diabetic patients aged 34-89 years (60% females) with a disease duration of 5 to 15 years. Peripheral neurological status was evaluated using The Michigan Neuropathy Screening Instrument, a tool that includes a self-assessment of symptoms and a physical examination. RESULTS: Diabetic neuropathy was found in 240 patients (69%). The prevalence in males and females was 72 and 67% respectively. The prevalence in patients with a disease duration of 5, 10 and 15 years, was 59, 69 and 77%, respectively. Fifty percent of patients with neuropathy complained of dry skin, 2% had ulcers, 43% had an abnormal perception of vibration and 29% had an abnormal monofilament test. CONCLUSIONS: The overall prevalence of peripheral neuropathy in this group of patients was 69% and was directly associated with the duration of the disease. PMID- 23354634 TI - [Lynch syndrome: selection of families by microsatellite instability and immunohistochemistry]. AB - BACKGROUND: Selection of patients with Lynch Syndrome (LS) for a genetic study involves the application of clinical criteria. To increase the rate of identification of mutations, the use of molecular studies as Microsatellite Instability (MSI) and Immunohistochemistry (IHC) in the tumor has been proposed. AIM: To demonstrate the usefulness of MSI and IHC in the detection of mutations in patients with LS. MATERIAL AND METHODS: From our Familial Colorectal Cancer Registry, families suspected of LS were selected according to Amsterdam or Bethesda clinical criteria. Screening of germline mutations of MLH1, MSH2 and MSH6 genes was performed. In addition, analysis of MSI and IHC were performed in colorectal tumors. RESULTS: A total of 35 families were studied (19 met Amsterdam and 16 met Bethesda criteria). Twenty one families harbored a germline alteration in MLH1, MSH2 or MSH6 (18 Amsterdam and 3 Bethesda). In these families, eighteen different alterations were found, 15 of which were mutations and 3 corresponded to variants of uncertain pathogenicity. On the other hand, 80% of the tumors showed positive microsatellite instability (27 MSI-high and 1 MSI-low), and immunohistochemical testing showed that 77% of tumors had the loss of a protein. Correlation between results of tumor molecular studies and the finding of germline nucleotide change showed that IHC and MSI predicted mutations in 81 and 100% of patients, respectively. CONCLUSIONS: MSI and IHC can efficiently select patients with a high probability of carrying a mutation in DNA repair genes. PMID- 23354635 TI - [Prevalence of alcohol consumption among medical students at the Universidad Catolica del Maule, Chile]. AB - BACKGROUND: Teenagers and university students are an especially vulnerable population towards unhealthy alcohol consumption. AIM: To assess the actual consumption of alcohol among medical students at the Universidad Catolica del Maule, Chile (UCM). MATERIAL AND METHODS: A cross sectional study of students who entered medical school between years 2004 and 2010.We applied CAGE questionnaire along with questions about frequency of alcohol consumption. RESULTS: From a universe of 317 students, 216 (age range 17-27 years, 54% females) answered the survey (68.8%), 64.2% admitted to consume alcohol and 6% had alcohol dependence. Seventy three percent of the alcohol drinkers were males. CONCLUSIONS: The prevalence of alcohol consumption in medical students of the UCM is significantly lower than the prevalence in students of another University surveyed in 2005 (74%) and it is similar to the national statistics. Alcohol consumption was higher in men that in women. PMID- 23354636 TI - [Multidimensional assessment of public health care services for adolescents in Chile]. AB - BACKGROUND: Adolescents are an especially vulnerable age group in terms of behavioral issues and require skilled teams in health centers. AIM: To assess the quality of health services provided to teenage users in Primary Health Care. MATERIAL AND METHODS: A study of multiple cases was carried out in two family health centers in Puente Alto, Chile. Health services delivered to adolescents were evaluated from the provider's perspective, through qualitative design of focus groups and interviews to the care teams at each centre. For technical quality, comparing electronic records of two tracer conditions (prenatal care and depression) with technical standards established by Delphi methodology and from teenage users perspective, through a survey of service satisfaction. RESULTS: In both centers, providers perceived a lack of training in adolescent care, a deficient preventive approach and a limited access to care. The technical evaluation showed an inappropriate recording of both tracer conditions. The instrument used to assess user satisfaction survey was reliable and showed that the best perceived issue was medical care and treatment, and the least perceived, was the access to the services. CONCLUSIONS: Professionals working in these health care facilities, feel unprepared to provide comprehensive approach to adolescents. The surveyed teenagers complained of limited access to care. Therefore this age group continues to be as a non-priority group for health care. PMID- 23354637 TI - [Validation of a questionnaire for psychosocial risk assessment in the workplace in Chile]. AB - BACKGROUND: The measurement of psychosocial risk among workers is becoming increasingly important. AIM: To adapt, validate and standardize a questionnaire to measure psychosocial risks in the workplace. MATERIAL AND METHODS: The Spanish version of the Copenhagen Psychosocial Questionnaire was adapted and evaluated. Its contents were first validated with a panel of experts. Afterwards a semantic adaptation of the questionnaires was carried out applying it to a pilot sample. Finally, it was applied to 1,557 workers (65% men). RESULTS: A preliminary questionnaire containing 97 questions was constructed. A good item-test correlation was found, the factorial structure was similar to the original questionnaire and it had a good internal consistency, convergent validity with the Goldberg Health Questionnaire and test-retest correlation. Ranges for the different dimensions and sub-dimensions of psychosocial risk were calculated by tertiles. CONCLUSIONS: The resulting questionnaire is useful for measuring psychosocial risk factors at work, with good psychometric properties. PMID- 23354638 TI - Cardiovascular fitness and cardiovascular risk factors among obese men and women aged 58 years and older, in Portugal. AB - BACKGROUND: A better physical fitness may have survival advantages in adults. AIM: To analyze the relationship between cardiorespiratory fitness and cardiovascular risk factors among obese subjects aged 58 years and older. MATERIAL AND METHODS: Cardiorespiratory fitness using the six-minute walk test, body composition by dual-energy x-ray absorptiometry and blood pressure were measured in a non-representative sample of 76 obese Portuguese subjects aged 58 to 87 years (55 women). Participants were stratified in tertiles of walking capacity according to the six-minute walk test. RESULTS: Six minutes walk test results were negatively correlated with percentage body fat (r = -0.28; p = 0.012) and systolic blood pressure (r = -0.23; p = 0.045). Participants located in the lowest tertile for the six minutes walk test had an odds ratio of 4.34 (95% confidence intervals: 1.02-18.43) for elevated blood pressure. CONCLUSIONS: A lower six minutes walk test result is associated with a higher risk for high blood pressure. PMID- 23354639 TI - [Limbic encephalitis with positive anti-N-methyl-D-aspartate antibodies. Report of one case]. AB - BACKGROUND: Limbic encephalitis is a subacute syndrome characterized by memory impairment, confusion, seizures, hypothalamic dysfunction and psychiatric symptoms. It has been associated to tumors located outside of the central nervous system. In 2007, anti-N-methyl-D-aspartate receptors (NMDAr) antibodies were found in serum and CSF of patients with this particular type of encephalitis. We report a 25-year-old female who, following upper respiratory tract symptoms, developed serious behavioral and consciousness impairment that progressed to coma. Cerebrospinal fluid (CSF) analysis showed a lymphocyte pleocytosis, the electroencephalogram was altered with a slow encephalopathic rhythm and a brain magnetic resonance imaging was normal. Infectious etiologies were ruled out. CSF and serum anti NMDA receptors antibodies were positive. PMID- 23354640 TI - [Menetrier disease. Report of one case]. AB - BACKGROUND: Menetrier disease is a rare disorder of the stomach, characterized by giant hypertrophic folds that usually involve the gastric body and fundus, associated to hypoalbuminemia due to serum protein loss across the gastric mucosa. We report a 55-years-old male presenting with abdominal pain, vomiting, weight loss and hypoalbuminemia. Diffuse hypertrophic gastric folds, elevated ulcerated sessile lesions and focal duodenal involvement were seen at endoscopy. Biopsies showed foveolar hyperplasia and glandular atrophy with cystic dilatation. A total gastrectomy was performed with a good outcome. PMID- 23354641 TI - Solid-pseudopapillary tumor of pancreas in a young woman: a case report and literature review. AB - Solid-pseudopapillary tumor of pancreas is a rare neoplasm which occurs pre dominantely in young females. This tumor generally is asymptomatic or minimally symptomatic and some imaging tests are useful for its diagnosis. We report a 17 years-old woman with dyspeptic symptoms submitted to an abdominal ultrasound (US), that revealed a hypoechogenic mass between the liver, right kidney and pancreas. Computer tomography (CT) scan showed a hypodense and heterogeneous mass on pancreas head. The patient underwent elective resection of the mass and the histopathology was consistent with a solid-pseudopapillary tumor of pancreas. Immunohistochemical positivity for NSE (neuron-specific enolase), progesterone receptor, alfa-1-antitrypsin, vimentin, AE1/AE3, and negativity for synaptophysin and chromogranin A confirmed the diagnosis. After four years of clinical follow up, the patient remains in a good general condition without signs of tumor recurrence. PMID- 23354642 TI - [Dupuytren disease]. AB - BACKGROUND: Dupuytren disease (DD) is a connective tissue disorder that consists in fibromatosis of the palmar and digital fascia (in form of nodules or flanges) that leads to the development of flexion contractures of the palm and fingers. The little and ring finger are particularly affected. The disease can limit hand function, reducing the quality of life. The disease can have a traumatic origin and is also associated with conditions such as diabetes mellitus, alcoholism, dyslipidemia, epilepsy and AIDS, among others. However, none of these conditions can fully explain the genesis of DD. A hereditary component is described in 40% of patients and is attributed to an autosomal dominant gene of variable penetrance, probably related to collagen synthesis. However there are also spontaneous and recessive inheritance cases. The diagnosis is clinical and based on physical examination. Treatment ranges from observation or use of injectable collagenase to the surgical option in cases with significant functional limitations. PMID- 23354643 TI - [Early evaluation of Alzheimer's disease: biomarkers and neuropsychological tests]. AB - BACKGROUND: Alzheimer disease is a neurodegenerative condition that affects cognitive, behavioral and global functioning of patients. Currently and due to the lack of conclusive biological testing, Alzheimer's disease diagnosis is based primarily on clinical criteria. Since its early diagnosis allows clinical interventions when neurological damage is relatively mild, the development of early detection tools has become a major topic of interest. In this article, we review the main neuro-biological and neuropsychological features of Alzheimer's disease, analyzing the use of biomarkers and neuropsychological testing for early detection. PMID- 23354644 TI - [Behaviors in public, private and university environments]. AB - BACKGROUND: In contemporary democracies, rules of conduct, in public places, are established by law and in private places, by morality. Between both, there is a middle area or interface given by community consensus. In the Community area, rules are consensual among its members. Institutions are an example of such situation. The University, as an institution, without contradicting the law, regulates and requires a behavior that is consistent with its purpose, beyond the private sphere, especially in the Schools of Medicine. We analyze what happens and the underlying purposes that represent the concept of University and Medicine. Special importance is given to ethical, social and cultural analyses. PMID- 23354645 TI - [First ten hematopoietic stem cell transplants performed in the adult public health service in Chile]. AB - BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an effective therapy for hematological diseases such as lymphoma and multiple myeloma. In 2004, the Cancer Unit of the Ministry of Health incorporated the HSCT to the National Cancer Program in Adults. Until 2008 we purchased services to private institutions while implementing the national center for HSCT of adults in the Hospital del Salvador. AIM: To report the first ten HSCT conducted in this center. MATERIAL AND METHODS: All cases were approved by a national commission for adult HSCT. The entire process was carried out based on evidence-based protocols. RESULTS: Six patients with Hodgkin lymphoma, three with multiple myeloma and one with a diffuse large B cell lymphoma were transplanted. Age range was 19 to 48 years and five patients were male. An average of 2.2 aphereses per patient was required. The CD 34 stem cell collection was 5.06 x 10(6) x Kg. The conditioning regimes were BEAM (carmustine, etoposide, cytosine arabinoside, melphalan) and melphalan 200 according to the underlying disease. Seventy percent of the patients developed mild to moderate mucositis and 50% had febrile neutropenia, with good response to treatment. In two cases there was an association with influenza. The engraftment of neutrophils and platelets was achieved on day +10 and +11 respectively. At follow-up until day +100, there was no morbidity or mortality. CONCLUSIONS: These results confirm the quality standard that this intervention has achieved in our institution. The Chilean National Center for HSCT on Adults should be established as a public core care, teaching and research facility. PMID- 23354646 TI - [The hidden curriculum in medical teaching]. AB - BACKGROUND: Medical education must ascribe to a curriculum but clinical teaching poses special difficulties that go beyond any programming attempt. Attitudes and skills learned during tutored clinical practice are called the "hidden curriculum". The figure and personal features of the teacher, his environment and the atmosphere that projects every particular medical school, are essential to shape the characteristics of the student. Paradoxically, it is almost impossible to measure the impact of this hidden curriculum. This article is a reflection on an issue that is acquiring special relevance in medical education. PMID- 23354647 TI - [William Osler (1849-1919): the man and his descriptions]. AB - BACKGROUND: William Osler was generally regarded as the greatest and most respected physician of his time. This paper describes Osler's life, his philosophy and views. He was an outstanding clinician who emphasized bedside teaching and observation. He possessed an extraordinary charm that inspired many others. As Professor of Medicine at four institutions in three countries, he was a great influence on medical education. He was a prolific writer, and his textbook became the most popular and widely read treatise on medicine in the world. He also was a medical historian, a classical scholar, and an avid bibliophile. He emphasized the value of hard work and ongoing education. His compassion and concern for patients and colleagues reflected his personality. We summarize Osler's descriptions, and some of his aphorisms. His wisdom is as relevant now, as it was in his time. Osler blended the art and science of Medicine perhaps better than anyone else, and remains a valuable role model for students and physicians more than ninety two years after his death. PMID- 23354648 TI - [Synantropic dangerous spiders from Chile]. PMID- 23354649 TI - [Reversible ageusia associated with clopidogrel use]. PMID- 23354650 TI - microRNA expression profiling and bioinformatic analysis of dengue virus-infected peripheral blood mononuclear cells. AB - Dengue virus (DENV) causes self-limiting dengue fever (DF), severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). It is generally considered that cytokine storm leads to the increased plasma leakage characteristic of DHF/DSS. In the present study, peripheral blood mononuclear cells (PBMCs) were isolated from blood samples of healthy volunteers and infected with DENV serotype 2 (DENV2). Culture supernatants of DENV2-infected and uninfected PBMCs were analyzed using a human cytokine array. Between a 6-12 h post-infection, levels of CCL5, IL-6 and IL-8 were markedly elevated, while those of TNF-alpha decreased. Total RNA isolated from these PBMCs was analyzed by human miRNA microarray to identify differentially expressed microRNAs (miRNAs). Quantitative reverse transcription polymerase chain reaction was used to validate 11 upregulated and 4 downregulated miRNAs. Sanger mibase, miRanda and TargetScan were used to identify 261 common predicted genes. Databases were used to identify homologous sequences on mRNAs of putative target genes that may be directly bound by the miRNAs identified. We found that cytokines and epigenetic regulators may be putative target genes of these miRNAs. Using ingenuity pathway analysis, we noted that canonical pathways, including biological regulation, may be modulated by these miRNAs. PMID- 23354651 TI - The p.L750V mutation in the NLRP7 gene is frequent in Mexican patients with recurrent molar pregnancies and is not associated with recurrent pregnancy loss. AB - OBJECTIVE: The aim of this study is to analyze NLRP7 mutation frequency in 20 Mexican patients with recurrent hydatidiform moles (RHMs). PATIENTS: Twenty patients with RHMs, 50 couples with recurrent pregnancy loss (RPL), and 100 controls were included in the study. Molecular analysis of the NLRP7 coding region was performed in patients with RHMs. Restriction enzyme digestion analysis and direct sequencing of the identified mutations were performed in controls and patients with RPL. RESULTS: Patients displayed between two and six moles, and 10 of them presented other forms of pregnancy loss. Twelve (60%) patients were homozygous for the missense mutation c.2248C > G (p.L750V), five (25%) patients were heterozygous for the p.L750V mutation and the c.1018 G > A (p.E340K) variant, and three (15%) patients were heterozygous for the c.1018 G > A (p.E340K) variant. Five (5%) control women and four women and one man (5%) with RPL were heterozygous for the p.L750V mutation and two (2%) patients with RPL were heterozygous for the p.E340K variant. CONCLUSIONS: A total of 60% of our RHM patients presented homozygous p.L750V mutations, 25% were compound heterozygotes for p.L750V mutation and the p.E340K variant, and 15% were heterozygous for p.E340K variant. Heterozygous p.L750V mutations were frequently observed in our population. Homozygous mutations were also present in patients with RHMs. Additional studies are needed to understand the role of the p.E340K variant in RHMs and RPL. PMID- 23354652 TI - The incidence and significance of multiple lesions in glioblastoma. AB - The location and distribution of glioblastoma (GBM) within the brain parenchyma plays an important role in surgical and radiation planning. Prior studies have reported incidences of multiple lesions at the time of diagnosis ranging from 0.5 to 20 %. Multiple lesions can be further categorized as multifocal (multiple areas involved, but with a clear path of spread from one lesion to another) or multicentric (multiple lesions, no clear path of spread). In this retrospective study, we reviewed our experience with GBM and found the incidence of multiple lesions at time of diagnosis was 35 %, much higher than previously suggested in the literature. Patients with single lesions had an improved overall survival when compared to patients with multiple lesions (18 vs. 10 months). Patients with multicentric lesions fared the worst, with average survival of 3 months. However, the difference between single and multiple lesions (multifocal or multicentric) was no longer significant when taking into consideration age, Karnofsky performance score (KPS) and extent of resection by multivariate analysis. Age, KPS, gross total resection, and MGMT status were independent predictors of outcome. Multiple lesions did not independently confer a worse outcome, but were associated with lower KPS scores and inability to perform gross total resection. These findings suggest that single, multiple and multicentric imaging exams represent a spectrum of presentations of a single disease. The rate of multiple lesions reported here may be the result of improved imaging technology, suggesting that incidence of multiple lesions will continue to increase as imaging technology advances. PMID- 23354653 TI - Disability, body image and sports/physical activity in adult survivors of childhood CNS tumors: population-based outcomes from a cohort study. AB - Childhood CNS tumor survivors risk health and functional impairments that threaten normal psychological development and self-perception. This study investigated the extent to which health and functional ability predict adult survivors' body image (BI) and self-confidence regarding sports and physical activity. The study cohort covered 708 eligible >= 18 year old CNS tumor survivors, and data from 528 (75 %) were analyzed. Disability was estimated using the Health Utilities IndexTM Mark2/3, a multidimensional self-report instrument. Physical self-confidence in terms of BI and sports/physical activity-related self confidence (SPAS) were assessed using the BI and the Sports/Athletics modules of a standardized self-report assessment scale. In adjusted regression models, global health and functional status (GHFS) predicted BI (B = 0.94, 95 % CI 0.69 1.19) and SPAS (B = 0.79, 95 % CI 0.55-1.04). Emotion and pain, and to a lesser degree cognition, speech and vision disability, were associated with poorer BI and SPAS. Gender, sub-diagnosis, and time since diagnosis influenced the relationship between health status and physical self-confidence outcomes. Females had poorer GHFS, BI and SPAS than males. Decreased health and functional ability following childhood CNS cancer intrudes on physical self-confidence, with females being at heightened risk for both disability and negative self-confidence. Identified disability and gender-related risk calls for a follow-up plan that integrates treatment of psychological sequelae in lifetime monitoring of childhood CNS tumor survivors to restore and protect self-image and self confidence, essential mental health correlates. An expanded plan should recognize the need for such services, optimizing life-long quality of survival for CNS tumor survivors. PMID- 23354654 TI - H3.3 G34R mutations in pediatric primitive neuroectodermal tumors of central nervous system (CNS-PNET) and pediatric glioblastomas: possible diagnostic and therapeutic implications? AB - Pediatric glioblastomas recently have been exon sequenced with evidence that approximately 30 % of cases harbour mutations of the histone H3.3 gene. Although studies to determinate their role in risk stratification are on-going, it remains to be determined whether H3.3 mutations could be found in other tumors such as pediatric primitive neuroectodermal tumors of the central nervous system (CNS PNETs) and whether the presence of H3.3 mutations in glioblastomas could be used as diagnostic tool in their differential diagnosis with CNS-PNETs. We performed a large mutational pyrosequencing-based screening on 123 pediatric glioblastomas and 33 CNS-PNET. The analysis revealed that 39/123 (31.7 %) glioblastomas carry H3.3 mutations. The K27M (AAG -> ATG, lysine -> methionine) mutation was found in 33 glioblastomas (26 %); the G34R (GGG -> AGG, glycine -> arginine) was observed in 6 glioblastomas (5.5 %). However, we also identified 4 of 33 cases (11 %) of CNS-PNETs harbouring a H3.3 G34R mutation. Multiplex ligation-dependent probe amplification analysis revealed PDGFR-alpha amplification and EGFR gain in two cases and N-Myc amplification in one case of H3.3 G34R mutated CNS-PNET. None of H3.3 mutated tumors presented a CDKN2A loss. In conclusion, because pediatric patients with glioblastoma and CNS-PNET are treated according to different therapeutic protocols, these findings may raise further concerns about the reliability of the histological diagnosis in the case of an undifferentiated brain tumor harbouring G34R H3.3 mutation. In this view, additional studies are needed to determine whether H3.3 G34 mutated CNS-PNET/glioblastomas may represent a defined tumor subtype. PMID- 23354656 TI - [Erythema scarlatiniforme desquamativum generalisatum]. AB - Erythema scarlatiniforme desquamativum generalisatum (Fereol-Besnier disease) is a rare skin disease characterized by generalized erythematous rash with subsequent desquamation. An 86-year-old woman presented with generalized erythema followed by an extensive, scarlatiniform peeling especially of the hands and feet. This generalized episode may be followed by erythema scarlatiniforme desquamativum localisatum recidivans, which is a recurring variant of the disease, localized to the hands and feet. PMID- 23354655 TI - Pharmacokinetics and efficacy of pemetrexed in patients with brain or leptomeningeal metastases. AB - Brain metastases (BM) and leptomeningeal metastases (LM) are devastating neurologic complications. Pemetrexed is a multi-targeted anti-folate agent approved for treatment of nonsquamous non-small cell lung cancer but has anti tumor activity in other solid tumors. We performed two trials using pemetrexed in patients with BM and LM to assess CSF penetration and anti-tumor activity. Patients were treated with intravenous pemetrexed at doses of 500 (n = 3), 750 (n = 3), 900 (n = 12) or 1,050 mg/m(2) (n = 3) every 3 weeks. Neuro-imaging was done every 6 weeks. Matched CSF and plasma samples were obtained serially from three patients with Ommaya reservoirs; the remaining patients had a single paired collection. Twenty-one patients (15 women and six men) with median age of 50 years and median KPS of 90 were treated. Primary tumors included breast (13), lung (4), colorectal (1), endometrial (1), esophageal (1) and pinealoblastoma (1). Nine patients had prior whole brain RT and median number of prior chemotherapies was two including prior methotrexate in four patients. Median pemetrexed doses administered was three (range 1-14). Responses included one partial response, ten stable disease and ten progressive disease. Median time to progression and survival was 2.7 and 7.3 months; PFS six was 22 %. No major toxicities were seen. Pemetrexed distributed from the plasma to the CSF within 1 4 h with the resulting CSF concentrations < 5 % of plasma. Pemetrexed was tolerated in solid tumor patients with CNS metastases. Limited anti-tumor activity was seen, which might have been due to low CSF concentrations, although some patients displayed prolonged benefit. PMID- 23354657 TI - [Topical hemoglobin promotes wound healing of patients with venous leg ulcers]. AB - BACKGROUND: Improvement of oxygenation is getting increasing attention as an important aspect in the modern wound care. The aim of such complementary wound care approaches is to improve and accelerate wound healing. PATIENTS AND METHODS: A solution comprising purified hemoglobin was added to the standard wound care procedure of patients with venous leg ulcers and compared to a second group without addition of the hemoglobin. In each group, 36 patients were included. The duration of treatment was 13 weeks. Primary end point was reduction of wound size or wound closing. RESULTS: In the group treated with the additional hemoglobin solution, an average of 53% of wound size reduction was obtained. No statistically significant reduction was observed in the second group. CONCLUSION: The addition of aemoglobin solution in the wound care procedure for venous leg ulcers showed a significant improvement of wound healing in comparison to a control group. PMID- 23354658 TI - Evaluation of right ventricular volume and ejection fraction by gated (18)F-FDG PET in patients with pulmonary hypertension: comparison with cardiac MRI and CT. AB - BACKGROUND: Right ventricular (RV) function is a powerful predictor of survival in patients with pulmonary hypertension (PH), but noninvasively assessing RV function remains a challenge. The aim of this study was to prospectively compare gated (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) myocardial imaging (gated PET), cardiac magnetic resonance (CMR), and cardiac computed tomography (CCT) for the assessment of RV volume and ejection fraction in patients with PH. METHODS: Twenty-three consecutive patients aged more than 16 years diagnosed with PH were included. All patients underwent gated PET, CMR, and CCT within 7 days. Right ventricular end-diastolic volume (RVEDV), right ventricular end-systolic volume (RVESV), and right ventricular ejection fraction (RVEF) were calculated by three imaging modalities. RV (18)F-FDG uptake was determined as RV-corrected standardized uptake value (SUV), and the ratio of RV to left ventricular (LV)-corrected SUV (Corrected SUV R/L). RESULTS: Gated PET showed a moderate correlation (r = 0.680, P < .001) for RVEDV, good correlation for RVESV (r = 0.757, P < .001) and RVEF (r = 0.788, P < .001) with CMR, and good correlation for RVEDV (r = 0.767, P < .001), RVESV (r = 0.837, P < .001), and RVEF (r = 0.730, P < .001) with CCT. Bland-Altman analysis revealed systematic underestimation of RVEDV and RVESV and overestimation of RVEF with gated PET compared with CMR and CCT. The correlation between RVESV (r = 0.863, P < .001), RVESV (r = 0.903, P < .001), and RVEF (r = 0.853, P < .001) of CMR and those of CCT was excellent; Bland-Altman analysis showed only a slight systematic variation between CMR and CCT. There were statistically significant negative correlations between RV-corrected SUV and RVEF-CMR (r = -0.543, P < .01), Corrected SUV R/L and RVEF-CMR (r = -0.521, P < .05), RV-corrected SUV and RVEF CCT (r = -0.429, P < .05), Corrected SUV R/L and RVEF-CCT (r = -0.580, P < .01), respectively. CONCLUSION: Gated PET had moderate-to-high correlation with CMR and CCT in the assessments of RV volume and ejection fraction. It is an available method for simultaneous assessing of RV function and myocardial glucose metabolism in patients with PH. PMID- 23354659 TI - Association between left ventricular mechanical dyssynchrony with myocardial perfusion and functional parameters in patients with left bundle branch block. AB - OBJECTIVE: To identify predictors of left ventricular mechanical dyssynchrony (LVMD) in patients with known left bundle branch block (LBBB) using gated single photon emission computed tomography (SPECT) phase analysis. METHODS: 81 patients (74% male, 70 +/- 10 years) with LBBB and suspected or known coronary artery disease underwent ECG-gated myocardial perfusion SPECT. LV perfusion and functional parameters were measured, and phase analysis was performed to quantify LV-dyssynchrony. RESULTS: 35/81 patients (42%) had prior myocardial infarction (MI), and the mean left ventricular ejection fraction (LVEF) was 49% +/- 16%. LVMD was present in 58/81 (72%) patients. The summed thickening score (STS) (P < .001; odds ratio 1.22) emerged as independent predictor for the presence of LVMD in a multivariate regression model. In addition, prior MI, low LVEF, summed stress score, summed rest score, summed motion score, and LAD rest extent were identified as predictors of LVMD in a univariate model. Clinical baseline characteristics, cardiac risk factors, and QRS duration (P = .051) had no influence on the presence of LVMD. CONCLUSION: In patients with LBBB, the occurrence of LVMD as assessed by gated SPECT phase analysis is mainly influenced by reduced myocardial contractility as expressed by the STS. Proper discrimination between LVMD arising from known electrical conduction delay as opposed to areas of MI causing reduced regional contractility seems to be mandatory for therapy planning in patients with LVMD. PMID- 23354660 TI - Thermoresponsive substrates used for the expansion of human mesenchymal stem cells and the preservation of immunophenotype. AB - The facile regeneration of undifferentiated human mesenchymal stem cells (hMSCs) from thermoresponsive surfaces facilitates the collection of stem cells avoiding the use of animal derived cell detachment agents commonly used in cell culture. This communication proposes a procedure to fabricate coatings from commercially available pNIPAm which is both affordable and a significant simplification on alternative approaches used elsewhere. Solvent casting was used to produce films in the micrometer range and successful cell adhesion and proliferation was highly dependent on the thickness of the coating produced with 1 MUm thick coatings supporting cells to confluence. 3T3 cell sheets and hMSCs were successfully detached from the cast coatings upon temperature reduction. Furthermore, results indicate that the hMSCs remained undifferentiated as the surface receptor profile of hMSCs was not altered when cells were detached in this manner. PMID- 23354661 TI - Top-down modulation of brain activity underlying intentional action and its relationship with awareness of intention: an ERP/Laplacian analysis. AB - Intentional actions are executed with the peculiar experience of "I decide to do that." It has been proposed that intentional actions involve a specific brain network involving the supplementary motor areas (SMAs). Here, we manipulated the internal representation participants attended to (intention vs. movement) in order to (1) examine the activity of SMAs and of the primary motor cortex (M1) during intentional action preparation and execution, and (2) investigate the temporal relationship between activity in these structures and intention awareness. Participants performed self-paced key presses. After each key press, participants were asked to report either the time they had the first intention to press the key (W-condition) or the time they actually started the movement (M condition). We then estimated surface Laplacians from brain electrical potentials recorded while participants were performing the task. Activity in SMAs was greater in the W-condition than in the M-condition more than 1 s before electromyographic (EMG) activation, suggesting that this region is indeed associated to the formation of conscious intention. Conversely, activity in primary motor cortex (M1) contralateral to the responding hand was larger in the M-condition than in the W-condition, revealing that this region is also modulated by top-down processes. In addition, waveforms time-locked to the W-judgement revealed that M1 as well as EMG activation preceded the time at which participants become aware of their intention by about 0.3 s. This observation argues against the possibility that the temporal delay between motor-related activation and intention awareness results from smearing artifacts. PMID- 23354662 TI - Monkeys would rather see and do: preference for agentic control in rhesus macaques. AB - Rhesus monkeys (Macaca mulatta) engaged in a series of computerized tasks modeled on billiards and arcade games in order to determine their degree of preference for scenarios in which food rewards were contingent on their actions, as opposed to those in which outcomes appeared externally caused. Throughout these tasks, subjects showed a consistent preference for "agentic control," a state in which goal-directed behavior is directly responsible for motivating outcomes. Other factors like the frequency and timing of reward deliveries were precisely controlled and did not explain observed preferences. PMID- 23354663 TI - The N3 is sensitive to odd-even congruency information in arithmetic fact retrieval. AB - This study investigated the behavioral and electrophysiological effects elicited by adults' simple addition verification when false answers agree or disagree with the odd-even status of the correct sum (parity congruency vs. parity incongruency), while they are near or far from correct (small vs. large splits). Event-related brain potentials were recorded from 18 students using a first answer-then-problem paradigm. The results showed that odd-even congruency had a significant effect on the N3 latency with a small, but not a large split. Specifically, odd-even congruent answers with a small split elicited an N3 with a longer latency. Analyses of RT similarly indicated a bigger parity-congruency effect with small-split answers compared with large-split answers. This pattern parallels the corresponding effects on N3 and confirms that the N3 is sensitive to odd-even information in arithmetic fact retrieval and that there are clear links between the event-related brain potential pattern and behavioral effects. PMID- 23354664 TI - The psychology of volition. AB - Volition can be studied from two perspectives. From the third-person view, volitional behaviour is internally generated, rather than being determined by the immediate environmental context, and is therefore, to some extent, unpredictable. Such behaviour is not unique to humans, since it is seen in many other species including invertebrates. From the first-person view, our experience of volitional behaviour includes a vivid sense of agency. We feel that, through our intentions, we can cause things to happen and we can choose between different actions. Our experience of agency is not direct. It depends on sub-personal inferences derived from prior expectations and sensations associated with movement. As a result, our experiences and intuitions about volition can be unreliable and uncertain. Nevertheless, our experience of agency is not a mere epiphenomenon. Anticipation of the regret we might feel after making the wrong choice can alter behaviour. Furthermore, the strong sense of responsibility, associated with agency, has a critical role in creating social cohesion and group benefits. We can only study the experience of agency in humans who can describe their experiences. The discussion of the experience of volition, that introspection and communication make possible, can change our experience of volitional actions. As a result, agency, regret and responsibility are cultural phenomena that are unique to humans. PMID- 23354665 TI - Reciprocal inhibition versus unloading response during stretch reflex in humans. AB - Rotation of an upper limb joint produces excitatory stretch reflex peaks M1 and M2 in the stretched muscles and simultaneous decrease in electromyographic (EMG) activity in the shortened muscles. The objective of this study was to examine whether the decreased activity in the antagonists (rINHIB) is purely from unloading of the spindles or receives active inhibition involving inhibitory interneurons. If rINHIB is due only to unloading, then the termination of rINHIB should vary with the duration of perturbation used to elicit stretch reflex, namely shorter stretches should result in shorter values of decreased periods of EMG. To examine this question, rectangular pulses, ranging in duration from 25 to 150 ms, were used to stretch wrist flexors or extensors with a torque motor. These rectangular pulses resulted in joint rotations which peaked at times (T(peak)) ranging from approximately 75-160 ms. As shown by previous authors, when the duration of rotation was shortened, the magnitude of M1 did not change, while the magnitude of M2 decreased. However, termination time of rINHIB in the shortened muscles did not change with change in T(peak), implying thereby that unloading of spindles of the antagonist muscles is not the only mechanism for the reduction in activity and that inhibitory reflex pathways most likely contribute. Possible sources of inhibition are discussed for the short- and long-latency inhibition. PMID- 23354666 TI - Perseveration effects in reaching and grasping rely on motor priming and not perception. AB - Perseveration effects in grasping were examined in two experiments. In both experiments, participants reached and grasped different versions of a novel object with their thumb and forefinger using either a horizontal or vertical pincer grasp. The dependent variable was the choice of grasp. In Experiment 1, trials were performed either with or without visual feedback. In Experiment 2, trials were performed either physically or using motor imagery. In both experiments, participants tended to perseverate in their choice of grip. Further, there was no evidence that either the availability of visual feedback during the preceding or current action modulated this effect; mode of responding was similarly inconsequential. The results were interpreted as evidence for a motor priming explanation of perseveration and against an account that relies on perceptual priming. PMID- 23354667 TI - Observers can reliably identify illusory flashes in the illusory flash paradigm. AB - In the illusory flash paradigm, a single flash may be experienced as two flashes when accompanied by two beeps or taps, and two flashes may be experienced as a single flash when accompanied by one beep or tap. The classic paradigm restricts responses to '1' and '2' (2-AFC), ignoring possible qualitative differences between real and illusory flashes and implicitly assuming that illusory flashes are indistinguishable from real flashes. We added a third response category 'different from that of either 1 or 2 flashes' (3-AFC). Eight naive and 6 experienced observers responded to 160 real and 160 illusory flash trials. Experienced observers were exposed to 1,200 trials before the experiment but without receiving feedback on their performance. The third response category was used for only 4 % of the real flash trials and for 44 % of the illusory flash trials. Experienced observers did so more often (78 %) than naive observers (18 %). This shows that observers can reliably identify illusory flashes and indicates that mere exposure to illusory flash trials (without feedback) is enough to detect and classify potential qualitative differences between real and illusory flashes. PMID- 23354669 TI - Automatic identification of wet and dry cough in pediatric patients with respiratory diseases. AB - Cough is the most common symptom of several respiratory diseases. It is a defense mechanism of the body to clear the respiratory tract from foreign materials inhaled accidentally or produced internally by infections. The identification of wet and dry cough is an important clinical finding, aiding in the differential diagnosis especially in children. Wet coughs are more likely to be associated with lower respiratory track bacterial infections. At present during a typical consultation session, the wet/dry decision is based on the subjective judgment of a physician. It is not available for the non-trained person, long term monitoring or in the assessment of treatment efficacy. In this paper we address these issues and develop an automated technology to classify cough into 'wet' and 'dry' categories. We propose novel features and a Logistic regression model (LRM) for the classification of coughs into wet/dry classes. The performance of the method was evaluated on a clinical database of pediatric coughs (C = 536) recorded using a bed-side non-contact microphone from N = 78 patients. Results of the automatic classification were compared against two expert human scorers. The sensitivity and specificity of the LRM in picking wet coughs were between 87 and 88% with 95% confidence interval on training/validation dataset (310 cough events from 60 patients) and 84 and 76% respectively on prospective dataset (117 cough events from 18 patients). The kappa agreement with two expert human scorers on prospective dataset was 0.51. These results indicate the potential of the method as a useful clinical tool for cough monitoring, especially at home settings. PMID- 23354668 TI - Bilateral deficits in fine motor control ability and manual dexterity in women with fibromyalgia syndrome. AB - The aim of the current study was to investigate fine motor control ability and manual dexterity women with fibromyalgia syndrome (FMS) without symptoms in the upper extremity compared to healthy women. Subtests of the Purdue Pegboard Test (one-hand, bilateral and assembly) and of the Jebsen-Taylor hand-function test (writing, turning cards, picking up small, light and large heavy objects, simulated feeding and stacking checkers) were evaluated bilaterally in 20 women with FMS (aged 35-55 years) without symptoms in the upper limb and 20 age- and hand dominance-matched healthy women. Differences between sides and groups were analysed with several analysis of variance (ANOVA). The ANOVA revealed significant differences between groups (P < 0.001) and sides (P = 0.007) for one hand pin placement subtest: women with FMS showed bilateral worse scores than controls. Patients also exhibited significantly lower scores in bilateral pin placement and assembly subtests when compared to healthy controls (P < 0.001). The ANOVA also revealed significant differences between groups for writing, turning over cards, picking up small objects, stacking checkers, picking up large light objects and picking up large heavy objects (all, P < 0.001): women with FMS needed more time for these subtests than healthy women with both hands. No difference for simulated feeding was found between groups. Our findings revealed bilateral deficits in fine motor control ability and manual dexterity in patients with FMS without symptoms in the upper extremity. These deficits are not related to the clinical features of the symptoms supporting an underlying central mechanism of altered motor control. PMID- 23354670 TI - Regional distribution of aerosol deposition in rat lungs using magnetic resonance imaging. AB - The toxic or therapeutic effect of an inhaled aerosol is highly dependent upon the site and extent of deposition in the lung. A novel MRI-based method was used to quantify the spatial distribution of particles in the rat lung. Rats were exposed to 0.95 MUm-diameter iron oxide particles in a controlled manner (N = 6) or to particle-free air (N = 6). Lungs were fixed in 3% glutaraldehyde by vascular perfusion, excised and imaged in a 3T scanner using a gradient-echo imaging protocol. The signal decay rate, R2*, was measured in each voxel of the entire left lung (1 mm thick slices). R2* was significantly higher in exposed animals (0.0065 +/- 0.0006 ms(-1)) than in controls (0.0050 +/- 0.0003 ms(-1), p < 0.001). A calibration curve between R2* and concentration of deposited particles (C(part)) was obtained by imaging gel samples with known particle concentrations. Regional deposition was assessed by comparing C(part) between the outer (C(part,peripheral)) and inner (C(part,central)) areas on each transaxial slice, and expressed as the c/p ratio. C(part,peripheral) (1.54 +/- 0.70 MUg/mL) was significantly higher than C(part,central) (1.00 +/- 0.39 MUg/mL, p<0.05), resulting in a c/p ratio of 0.65. This method may be used in future studies to quantify spatial distribution of deposited particles in healthy and diseased lungs. PMID- 23354671 TI - A novel domain of amino-Nogo-A protects HT22 cells exposed to oxygen glucose deprivation by inhibiting NADPH oxidase activity. AB - This study aimed to investigate the protective effect of the M9 region (residues 290-562) of amino-Nogo-A fused to the human immunodeficiency virus trans activator TAT in an in vitro model of ischemia-reperfusion induced by oxygen glucose deprivation (OGD) in HT22 hippocampal neurons, and to investigate the role of NADPH oxidase in this protection. Transduction of TAT-M9 was analyzed by immunofluorescence staining and western blot. The biologic activity of TAT-M9 was assessed by its effects against OGD-induced HT22 cell damage, compared with a mutant M9 fusion protein or vehicle. Cellular viability and lactate dehydrogenase (LDH) release were assessed. Neuronal apoptosis was evaluated by flow cytometry. The Bax/Bcl-2 ratio was determined by western blotting. Reactive oxygen species (ROS) levels and NADPH oxidase activity were also measured in the presence or absence of an inhibitor or activator of NADPH oxidase. Our results confirmed the delivery of the protein into HT22 cells by immunofluorescence and western blot. Addition of 0.4 MUmol/L TAT-M9 to the culture medium effectively improved neuronal cell viability and reduced LDH release induced by OGD. The fusion protein also protected HT22 cells from apoptosis, suppressed overexpression of Bax, and inhibited the reduction in Bcl-2 expression. Furthermore, TAT-M9, as well as apocynin, decreased NADPH oxidase activity and ROS content. The protective effects of the TAT-M9 were reversed by TBCA, an agonist of NADPH oxidase. In conclusion, TAT-M9 could be successfully transduced into HT22 cells, and protected HT22 cells against OGD damage by inhibiting NADPH oxidase-mediated oxidative stress. These findings suggest that the TAT-M9 protein may be an efficient therapeutic agent for neuroprotection. PMID- 23354672 TI - Independent risk factors for the co-colonization of vancomycin-resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus in the region most endemic for vancomycin-resistant Staphylococcus aureus isolation. AB - In the majority of cases of vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-resistant Enterococcus faecalis (VR E. faecalis) served as the vanA donor to S. aureus. Previous studies that evaluated the risk factors for co colonization with VRE and MRSA did not differentiate between VR E. faecalis and VR E. faecium. This study aimed to identify variables associated with VR E. faecalis and MRSA co-colonization. A retrospective case-control study from January 2008 to December 2009 was conducted at the Detroit Medical Center. Data were extracted from charts and pharmacy records. Unique patients co-colonized with VR E. faecalis and MRSA (defined as isolation of MRSA within 7 days of VR E. faecalis isolation) were compared with patients with VR E. faecalis who were not co-colonized with MRSA. A total of 546 patients with VR E. faecalis isolation were identified. 85 (15.6 %) VR E. faecalis patients were co-colonized with MRSA and 461 (84.4 %) VR E. faecalis patients were not co-colonized with MRSA. The mean age of the study cohort was 65.9 +/- 16.4 years, 424 (77.7 %) were African American, and 270 (49.5 %) were residing in long-term care institutions. Independent predictors of co-colonization of VR E. faecalis and MRSA were male gender, impaired consciousness, ICU stay prior to VR E. faecalis isolation, indwelling devices, and isolation of VR E. faecalis from wounds. MRSA was frequently isolated from the same culture specimen as VR E. faecalis (n = 39, 45.9 %), most commonly from wounds. This large study of patients with VR E. faecalis identified the severity of illness, indwelling devices, and chronic wounds as independent predictors of co-colonization with VR E. faecalis and MRSA. PMID- 23354673 TI - Healthcare-associated infections and the distribution of causative pathogens in patients with diabetes mellitus. AB - Diabetes mellitus (DM) is one of the most common diseases worldwide, and is a significant risk factor for healthcare-associated infections (HAIs). Our aim in this study was to compare the distributions of HAIs and the causative pathogens between diabetic and non-diabetic patients. In this study, 716 HAIs in 465 diabetic patients and 761 HAIs in 465 non-diabetic patients were evaluated. HAIs in patients with DM were most frequently urinary tract infections (UTIs) [266 infections (37.2 %)], followed by blood stream infections (BSIs) [161 infections (22.5 %)], surgical site infections (SSIs) [127 infections (17.7 %)], pneumonia [107 infections (14.9 %)] and any other infections [161 infections (22.5 %)]. The rates of UTIs, BSIs, SSIs, pneumonia and any other infections were similar between diabetic and non-diabetic patients. In terms of the causative pathogens, Staphylococcus aureus more frequently caused SSIs and Candida spp more frequently caused UTIs in diabetic patients compared with non-diabetic patients. We found no differences in the distribution of HAIs between patients without and with DM. However, S. aureus and Candida spp were more common causative pathogens of SSIs and URTIs, respectively, in diabetic patients than in non-diabetic patients. PMID- 23354674 TI - Respiratory tract infections during the 2011 Mycoplasma pneumoniae epidemic. AB - In 2011, Norway experienced a surge in community acquired Mycoplasma pneumoniae infections. Norway also has one of the highest rates of reported Bordetella pertussis infections, despite high vaccine coverage. We aimed to determine the prevalence of upper respiratory tract pathogens in patients attending primary care physicians for respiratory illness during the 2011 M. pneumoniae epidemic period. A retrospective analysis of data from 26,039 patients that have had nasopharyngeal swabs analysed by nucleic acid amplification testing (NAAT) for M. pneumoniae, C. pneumoniae and B. pertussis was performed. Subsets of samples were tested for additional pathogenic bacteria, including B. parapertussis and B. holmesii, as well as influenza virus. M. pneumoniae, C. pneumoniae and B. pertussis were detected in 2,484 (9.5 %), 261 (1.0 %) and 821 (3.2 %) patients, respectively. Co-infection of M. pneumoniae and B. pertussis was found in 50 (0.19 %) patients, C. pneumoniae and B. pertussis in 4 (0.02 %). Influenza virus was found in 899 (24.5 %) of 3,661 nasopharyngeal swabs. Co-infection of influenza virus and bacterial pathogens was common, although influenza virus co infection with B. pertussis occurred significantly more often than with C. pneumoniae and M. pneumoniae (20.4 % versus 2.9 % and 9.1 %, respectively; p<0.005). Testing for Bordetella species genes IS1001, IS1002 and recA showed that B. holmesii was most likely misdiagnosed as B. pertussis in 5.8 % of cases. The most prevalent respiratory tract pathogen in the general population in 2011 was M. pneumoniae. B. pertussis was also found frequently as was B. pertussis and influenza virus co-infections. PMID- 23354675 TI - Recent changes in bacteremia in patients with cancer: a systematic review of epidemiology and antibiotic resistance. AB - Bacteremia remains a major cause of life-threatening complication in patients with cancer. Significant changes in the spectrum of microorganisms isolated from blood culture have been reported in cancer patients over the past years. The aim of our systematic review was to inventory the recent trends in epidemiology and antibiotic resistance of microorganisms causing bacteremia in cancer patients. Data for this review was identified by searches of Medline, Scopus and Cochrane Library for indexed articles and abstracts published in English since 2008. The principal search terms were: "antimicrobial resistance", "bacteremia", "bacterial epidemiology", "bloodstream infection", "cancer patients", "carbapenem resistance", "Escherichia coli resistance", "extended-spectrum beta-lactamase producing E. coli", "febrile neutropenia", "fluoroquinolone resistance", "neutropenic cancer patient", "vancomycin-resistant Enterococcus", and "multidrug resistance". Boolean operators (NOT, AND, OR) were also used in succession to narrow and widen the search. Altogether, 27 articles were selected to be analyzed in the review. We found that Gram-negative bacteria were the most frequent pathogen isolated, particularly in studies with minimal use of antibiotic prophylaxis. Another important trend is the extensive emergence of antimicrobial resistant strains associated with increased risk of morbidity, mortality and cost. This increasing incidence of antibiotic resistance has been reported in Gram-negative bacteria as well as in Gram-positive bacteria. This exhaustive review, reporting the recent findings in epidemiology and antibiotic resistance of bacteremia in cancer patients, highlights the necessity of local continuous surveillance of bacteremia and stringent enforcement of antibiotic stewardship programs in cancer patients. PMID- 23354676 TI - Characteristics of Yersinia enterocolitica biotype 1A strains isolated from patients and asymptomatic carriers. AB - Yersinia enterocolitica biotype 1A strains are frequently isolated from the environment, foods, and animals, and also from humans with yersiniosis. There are controversial reports on the pathogenicity of biotype 1A strains. In this study, 811 fecal samples from asymptomatic humans from Switzerland were studied for the presence of Y. enterocolitica. Nine (1.1%) of the 811 samples were positive for Y. enterocolitica 1A. These strains were compared with 12 Y. enterocolitica 1A strains from Swiss patients with diarrhea isolated in the same year. Almost all (20/21) Y. enterocolitica 1A strains carried the ystB gene, seven strains carried the hreP gene, and none carried the ail, ystA, myfA, yadA, or virF genes. Most (17/21) Y. enterocolitica 1A strains belonged to two major clusters, A and B, by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Strains of cluster B were only isolated from humans with diarrhea; however, ystB and hreP genes were detected in strains from both clinical and non-clinical samples and from strains of clusters A and B. Using ribotyping, six restriction patterns among biotype 1A strains were obtained with HindIII enzyme. The most common ribotype (RT I) was found in strains isolated from humans with and without diarrhea. All biotype 1A strains had a unique NotI profile by pulsed-field gel electrophoresis (PFGE), showing a very high genetic diversity. In this study, Y. enterocolitica 1A strains from clinical and non clinical samples could not be clearly differentiated from each other. More research is needed in order to prove that biotype 1A strains are a primary cause for human yersiniosis and not only a secondary finding. PMID- 23354677 TI - DNA bacterial load in children with bacteremic pneumococcal community-acquired pneumonia. AB - This study was conducted to evaluate the association between pneumococcal DNA load and parapneumonic pleural effusion (PPE) in children with community-acquired pneumonia. Bacterial load was quantified and related to the presence of PPE with or without empyema in 72 otherwise healthy children aged <=5 years who were hospitalised because of radiographically confirmed CAP and showed a real-time polymerase chain reaction that was positive for Streptococcus pneumoniae. The proportion of children with a high bacterial load (i.e. >=265 DNA copies/mL) was larger among the subjects with PPE than those without it. Multivariate analysis showed that a high bacterial load was significantly associated with PPE (OR 8.65; 95% CI 1.10-67.8 vs a bacterial load of <125 copies/mL). Children with infection due to pneumococcal serotype 19A were at highest risk of developing PPE (OR 7.44; 95% CI 1.10-50.4 vs all other typeable serotypes). The patients with CAP due to pneumococcal serotypes that are not included in the 13-valent conjugate vaccine (PCV13) were more frequently affected by PPE than those with infections associated with serotypes included in the vaccine, except for serotype 19A. Bacterial loads of >=265 DNA copies/mL are significantly associated with PPE, and serotype 19A is significantly associated with a high bacterial load and the development of PPE. The mean bacterial load of the patients with empyema was higher than that of patients with simple PPE. Although further studies are required, it seems that serotypes not included in PCV13 can play a major role in causing a higher bacterial load and PPE. PMID- 23354678 TI - Comparison of seven commercial enzyme-linked immunosorbent assays for the detection of anti-diphtheria toxin antibodies. AB - Determination of immune status of patients to diphtheria toxin is based mainly on the results of commercially available ELISA kits. The aim of the present study was to compare the results obtained by ELISAs from seven different manufacturers: Mikrogen, Immunolab, Sekisui Virotech, NovaTec, Virion?Serion, IBL International and Euroimmun. All assays were performed according to the manufacturers' instructions. The concentrations of the anti-diphtheria toxin antibodies in 72 serum samples were calculated on the basis of curves constructed from standards supplied by manufacturers and the new reference material-International Standard for Diphtheria Antitoxin (10/262). The repeatability and reproducibility of all the ELISA kits tested were good. Number of sera with concentrations of the anti diphtheria toxin antibodies below the WHO-recommended level of protection (0.1 IU/ml) were dependent on the ELISA used: Mikrogen, 20/72 samples (27.7%); Immunolab, 11/72 samples (15.3%); Sekisui Virotech, 0/72 samples (0%); NovaTec 18/72 samples (25.0%); Serion 12/72 samples (16.7%); IBL International, 7/72 samples (9.7 %); and Euroimmun, 17/72 samples (23.6%). However, the results obtained in particular ELISAs, with the exception of Sekisui Virotech, were much more consistent when the concentrations of the anti-diphtheria toxin antibodies in 72 sera measured by using curves constructed from the International Standard 10/262. The data obtained clearly demonstrated that manufacturer-dependent differences between anti-diphtheria IgG ELISA kits exist. The differences in recommendations accepted by the individual manufacturers together with differences shown in our studies in sensitivity greatly affect the clinical interpretation of results. PMID- 23354679 TI - Immunohistochemical localization of two types of choline acetyltransferase in neurons and sensory cells of the octopus arm. AB - Cholinergic structures in the arm of the cephalopod Octopus vulgaris were studied by immunohistochemistry using specific antisera for two types (common and peripheral) of acetylcholine synthetic enzyme choline acetyltransferase (ChAT): antiserum raised against the rat common type ChAT (cChAT), which is cross reactive with molluscan cChAT, and antiserum raised against the rat peripheral type ChAT (pChAT), which has been used to delineate peripheral cholinergic structures in vertebrates, but not previously in invertebrates. Western blot analysis of octopus extracts revealed a single pChAT-positive band, suggesting that pChAT antiserum is cross-reactive with an octopus counterpart of rat pChAT. In immunohistochemistry, only neuronal structures of the octopus arm were stained by cChAT and pChAT antisera, although the pattern of distribution clearly differed between the two antisera. cChAT-positive varicose nerve fibers were observed in both the cerebrobrachial tract and neuropil of the axial nerve cord, while pChAT-positive varicose fibers were detected only in the neuropil of the axial nerve cord. After epitope retrieval, pChAT-positive neuronal cells and their processes became visible in all ganglia of the arm, including the axial and intramuscular nerve cords, and in ganglia of suckers. Moreover, pChAT-positive structures also became detectable in nerve fibers connecting the different ganglia, in smooth nerve fibers among muscle layers and dermal connective tissues, and in sensory cells of the suckers. These results suggest that the octopus arm has two types of cholinergic nerves: cChAT-positive nerves from brain ganglia and pChAT-positive nerves that are intrinsic to the arm. PMID- 23354680 TI - Clues from bariatric surgery: reversing insulin resistance to heal the heart. AB - Obesity is a state of metabolic dysregulation of the whole organism and a major contributing factor to the epidemic of insulin resistant diabetes. The nonpharmacologic treatment of obesity with bariatric surgery results in a dramatic and almost instantaneous reversal of insulin resistance. The present review collectively addresses the evidence for this phenomenon in the literature and discusses potential metabolic and neurohumoral mechanisms. We propose that nutrient restriction lowers the cell's defense mechanisms for nutrient overload in insulin responsive organs. PMID- 23354681 TI - Meat consumption, diabetes, and its complications. AB - Several prospective studies have reported that risk of type 2 diabetes (T2DM) is elevated in meat consumers, especially when processed meats are consumed. Elevated risks of coronary heart disease (CHD) and stroke in meat consumers have also been reported. In this overview, the evidence regarding meat consumption and the risk of diabetes, both type 1 diabetes (T1DM) and T2DM and their macro- and microvascular complications, is reviewed. For T2DM, we performed a new meta analysis including publications up to October 2012. For T1DM, only a few studies have reported increased risks for meat consumers or for high intake of saturated fatty acids and nitrates and nitrites. For T2DM, CHD, and stroke, the evidence is strongest. Per 100 g of total meat, the pooled relative risk (RR) for T2DM is 1.15 (95 % CI 1.07-1.24), for (unprocessed) red meat 1.13 (95 % CI 1.03-1.23), and for poultry 1.04 (95 % CI 0.99-1.33); per 50 g of processed meat, the pooled RR is 1.32 (95 % CI 1.19-1.48). Hence, the strongest association regarding T2DM is observed for processed (red) meat. A similar observation has been made for CHD. For stroke, however, a recent meta-analysis shows moderately elevated risks for meat consumers, for processed as well as for fresh meats. For the microvascular complications of diabetes, few prospective data were available, but suggestions for elevated risks can be derived from findings on hyperglycemia and hypertension. The results are discussed in the light of the typical nutrients and other compounds present in meat--that is, saturated and trans fatty acids, dietary cholesterol, protein and amino acids, heme-iron, sodium, nitrites and nitrosamines, and advanced glycation end products. In light of these findings, a diet moderate to low in red meat, unprocessed and lean, and prepared at moderate temperatures is probably the best choice from the public health point of view. PMID- 23354682 TI - Redefining meaningful age groups in the context of disease. AB - Age is an important factor when considering phenotypic changes in health and disease. Currently, the use of age information in medicine is somewhat simplistic, with ages commonly being grouped into a small number of crude ranges reflecting the major stages of development and aging, such as childhood or adolescence. Here, we investigate the possibility of redefining age groups using the recently developed Age-Phenome Knowledge-base (APK) that holds over 35,000 literature-derived entries describing relationships between age and phenotype. Clustering of APK data suggests 13 new, partially overlapping, age groups. The diseases that define these groups suggest that the proposed divisions are biologically meaningful. We further show that the number of different age ranges that should be considered depends on the type of disease being evaluated. This finding was further strengthened by similar results obtained from clinical blood measurement data. The grouping of diseases that share a similar pattern of disease-related reports directly mirrors, in some cases, medical knowledge of disease-age relationships. In other cases, our results may be used to generate new and reasonable hypotheses regarding links between diseases. PMID- 23354683 TI - Association of the K153R polymorphism in the myostatin gene and extreme longevity. AB - The myostatin (MSTN) gene is a candidate to influence extreme longevity owing to its role in modulating muscle mass and sarcopenia and especially in inhibiting the main nutrient-sensing pathway involved in longevity, i.e. mammalian target of rapamycin. We compared allele/genotype distributions of the exonic MSTN variants K153R (rs1805086), E164K (rs35781413), I225T and P198A, in Spanish centenarians (cases, n = 156; 132 women, age range 100-111 years) and younger adults (controls, n = 384; 167 women, age <50 years). No subject of either group carried a mutant allele of the E164K, I225T or P198A variation. The frequency of the variant R allele was significantly higher in centenarians (7.1%) than in controls (2.7%) (P = 0.001). The odds ratio of being a centenarian if the subject had the R allele was 3.48 (95% confidence interval 1.67-7.28, P = 0.001), compared to the control group, after adjusting for sex. The results were replicated in an Italian cohort (centenarians, n = 79 (40 women), age range 100-104 years; younger controls, n = 316 (155 women), age <50 years), where a higher frequency of the R allele in centenarians (7.6%) compared to controls (3.0%) (P = 0.004) was independently confirmed. Although more research is needed, the variant allele of the MSTN K153R polymorphism could be among the genetic contributors associated with exceptional longevity. PMID- 23354684 TI - Age-related changes in structure and extracellular matrix protein expression levels in rat tendons. AB - The musculoskeletal system (muscle-tendon-bone) demonstrates numerous age-related changes, with modifications in tendons the least well studied, although increased predisposition to tendinopathy and rupture have been reported. In order to gain insights into the basis of age-associated increase in tendon injuries, we compared Achilles and tibialis anterior tendons and myotendinous junctions (MTJs) from 3- to 5- and 22- to 25-month-old rats for underlying structure and composition. Significant decreases were observed by qRT-PCR for collagen I, III, and V mRNA expression in tendons of old rats, but immunostaining detected no apparent differences in collagen I and V expression on the protein level. Tendons of old compared with young rats had decreased mRNA expression levels of proteoglycan 4 (PRG4) and elastin (Eln), but no differences in the mRNA expression of connective tissue growth factor, TGF-beta 1, or stromal cell derived factor 1. For PRG4, immunostaining showed good correlation with qRT-PCR results. This is the first study to show reductions in PRG4 in tendons and MTJs of old rats. Decreased PRG4 expression in tendons could result in increased tendon stiffness and may be associated with decreased activity in the elderly. The diminished collagen mRNA expression in combination with decreased PRG4 and Eln mRNA expression may be associated with increased risk of tendon injury with aging. PMID- 23354686 TI - The Hippo size control pathway--ever expanding. AB - An important regulator of organ size and tumorigenesis is the Hippo pathway. Recent studies have unveiled increasing complexity in regulation of Hippo pathway activity at the level of the oncoprotein Yes-associated protein (YAP). The protein tyrosine phosphatase 14 (PTPN14, known as Pez in Drosophila) was identified as a protein that antagonizes the function of the key Hippo pathway protein YAP by promoting its cytoplasmic localization under high cell density conditions. In Drosophila, Pez was identified as a repressor of epithelial proliferation in vivo. Studies in mammalian cells showed that a family of G protein-coupled receptors, the protease-activated receptors, functioned as activators of YAP. These studies shed light on the intricate regulation of the Hippo pathway and also highlight the importance of investigating these newly discovered regulatory links in physiological and pathological settings to fully appreciate their importance. PMID- 23354685 TI - MiR-182 and miR-203 induce mesenchymal to epithelial transition and self sufficiency of growth signals via repressing SNAI2 in prostate cells. AB - MicroRNAs play critical roles in tumorigenesis and metastasis. Here, we report the dual functions of miR-182 and miR-203 in our previously described prostate cell model. MiR-182 and miR-203 were completely repressed during epithelial to mesenchymal transition (EMT) from prostate epithelial EP156T cells to the progeny mesenchymal nontransformed EPT1 cells. Re-expression of miR-182 or miR-203 in EPT1 cells and prostate cancer PC3 cells induced mesenchymal to epithelial transition (MET) features. Simultaneously, miR-182 and miR-203 provided EPT1 cells with the ability to self-sufficiency of growth signals, a well-recognized oncogenic feature. Gene expression profiling showed high overlap of the genes affected by miR-182 and miR-203. SNAI2 was identified as a common target of miR 182 and miR-203. Knock-down of SNAI2 in EPT1 cells phenocopied re-expression of either miR-182 or miR-203 regarding both MET and self-sufficiency of growth signals. Strikingly, considerable overlaps of changed genes were found between the re-expression of miR-182/203 and knock-down of SNAI2. Finally, P-cadherin was identified as a direct target of SNAI2. We conclude that miR-182 and miR-203 induce MET features and growth factor independent growth via repressing SNAI2 in prostate cells. Our findings shed new light on the roles of miR-182/203 in cancer related processes. PMID- 23354687 TI - Phosphoinositide 3-kinase gamma inhibits cardiac GSK-3 independently of Akt. AB - Activation of cardiac phosphoinositide 3-kinase alpha (PI3Kalpha) by growth factors, such as insulin, or activation of PI3Kgamma downstream of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors stimulates the activity of the kinase Akt, which phosphorylates and inhibits glycogen synthase kinase-3 (GSK-3). We found that PI3Kgamma inhibited GSK-3 independently of the insulin-PI3Kalpha-Akt axis. Although insulin treatment activated Akt in PI3Kgamma knockout mice, phosphorylation of GSK-3 was decreased compared to control mice. GSK-3 is activated when dephosphorylated by the protein phosphatase 2A (PP2A), which is activated when methylated by the PP2A methyltransferase PPMT-1. PI3Kgamma knockout mice showed increased activity of PPMT-1 and PP2A and enhanced nuclear export of the GSK-3 substrate NFATc3. GSK-3 inhibits cardiac hypertrophy, and the hearts of PI3Kgamma knockout mice were smaller compared to those of wild type mice. Cardiac overexpression of a catalytically inactive PI3Kgamma (PI3Kgamma(inact)) transgene in PI3Kgamma knockout mice reduced the activities of PPMT-1 and PP2A and increased phosphorylation of GSK-3. Furthermore, PI3Kgamma knockout mice expressing the PI3Kgamma(inact) transgene had larger hearts than wild-type or PI3Kgamma knockout mice. Our studies show that a kinase-independent function of PI3Kgamma could directly inhibit GSK-3 function by preventing the PP2A-PPMT-1 interaction and that this inhibition of GSK-3 was independent of Akt. PMID- 23354688 TI - Systems biology approach identifies the kinase Csnk1a1 as a regulator of the DNA damage response in embryonic stem cells. AB - In pluripotent stem cells, DNA damage triggers loss of pluripotency and apoptosis as a safeguard to exclude damaged DNA from the lineage. An intricate DNA damage response (DDR) signaling network ensures that the response is proportional to the severity of the damage. We combined an RNA interference screen targeting all kinases, phosphatases, and transcription factors with global transcriptomics and phosphoproteomics to map the DDR in mouse embryonic stem cells treated with the DNA cross-linker cisplatin. Networks derived from canonical pathways shared in all three data sets were implicated in DNA damage repair, cell cycle and survival, and differentiation. Experimental probing of these networks identified a mode of DNA damage-induced Wnt signaling that limited apoptosis. Silencing or deleting the p53 gene demonstrated that genotoxic stress elicited Wnt signaling in a p53-independent manner. Instead, this response occurred through reduced abundance of Csnk1a1 (CK1alpha), a kinase that inhibits beta-catenin. Together, our findings reveal a balance between p53-mediated elimination of stem cells (through loss of pluripotency and apoptosis) and Wnt signaling that attenuates this response to tune the outcome of the DDR. PMID- 23354689 TI - New posterior column reconstruction using titanium lamina mesh after total en bloc spondylectomy of spinal tumour. AB - PURPOSE: To investigate the usefulness of titanium lamina mesh for posterior column reconstruction after total en bloc spondylectomy in patients with spinal tumour and evaluate the radiographic outcomes of this method. METHOD: Eight patients who underwent total en bloc spondylectomy with posterior column reconstruction using titanium lamina mesh and bone graft to treat a spinal tumour were included in this study. The mean age at the time of surgery was 50.6 years (range, 16.5-70.9 years) and the mean follow-up duration was 50.2 months (range, 28.1-68.7 months). The pathological lesions were located from the T2 to L1 vertebrae. There were four patients in each primary and metastatic tumour group. For the posterior column reconstruction, titanium lamina mesh was used and bone graft was applied over the lamina mesh. Radiographic evaluation was used to investigate the displacement of lamina mesh and union of the grafted bone above lamina mesh. RESULTS: At the postoperative six month follow-up, a bony bridge on the titanium mesh between upper and lower adjacent lamina was observed in all cases, except for one with infection. On the last follow-up, there was no collapse or displacement of titanium lamina mesh, and there was no instability or malalignment of the spinal column. CONCLUSIONS: Posterior column reconstruction using titanium lamina mesh during total en bloc spondylectomy for spinal tumour was a useful surgical option that provided new lamina reconstruction for stability of spinal column and protection of the neural elements. PMID- 23354690 TI - Co-cultivated mesenchymal stem cells support chondrocytic differentiation of articular chondrocytes. AB - PURPOSE: This study investigated which of the reciprocal stimuli between articular chondrocytes (ACs) and mesenchymal stem cells (MSCs) played the more important role in enhancing cartilage matrix formation, and examined the relative importance of physical contact and soluble factors in the co-culture system. METHODS: Rat ACs and bone marrow MSCs with green fluorescent protein (GFP-BMSCs) were co-cultured in vitro with or without direct cell-cell contact at the ratio of 2:1. After co-culturing in direct cell-cell contact, ACs and GFP-BMSCs were separated by flow cytometry. The effects of different co-culture methods were analysed by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. RESULTS: SOX-9, COL2 and aggrecan mRNA levels and protein expression in ACs co-cultured with direct cell-cell contact were significantly higher than in ACs co-cultured without direct cell-cell contact; and similar results were found in GFP-BMSCs. After co-culture either with or without direct cell-cell contact, mRNA levels and protein expression of SOX-9, COL2 and aggrecan in GFP-BMSCs were significantly lower than in ACs in the equivalent co-culture systems. Though the expression of chondrocyte-specific proteins in GFP-BMSCs was enhanced, the protein expression was still much lower than in ACs cultured alone. CONCLUSIONS: Reciprocal interactions exist between ACs and BMSCs in co-culture. The stimulating and supporting effects of BMSCs on ACs were more important in enhancing cartilage-matrix formation than the reciprocal effect of ACs on BMSCs. Both soluble factors and direct physical contact occur in AC/BMSC co-cultures, with physical contact playing a predominant, or at least very important role. PMID- 23354691 TI - Comment on Krusche-Mandl et al.: Crossed pinning in paediatric supracondylar humerus fractures: a retrospective cohort analysis. PMID- 23354692 TI - In-vitro analysis of the effect of gentamicin and polyhexanide on bone tissue. AB - PURPOSE: Though anti-infectives have been used for a long time in surgical procedures, the effect on bone tissue has not been determined for most antibiotics and antiseptics. METHODS: In our in vitro study, 4x4x8 mm(3) blocks of rabbit cancellous bone tissue were incubated with Ringer's solution, gentamicin and Lavasorb((r)) each for time intervals of 15 minutes, 30 minutes, one hour, four hours and eight hours. Samples were examined double blinded through optical and electron microscopy. RESULTS: Tissue degeneration was observed in all samples. It was low in Ringer's solution. Samples with Lavasorb showed a moderate degeneration after 15 and 30 minutes, which was accelerated after one hour. Gentamicin led to a moderate degeneration of bone tissue after 15 and 30 minutes and to a more accelerated degeneration after one hour. The effect of gentamicin on bone tissue was more pronounced than the effect of Lavasorb. CONCLUSIONS: This investigation showed that local application of Lavasorb or gentamicin on bone tissue should be restricted to 30 minutes, while Lavasorb showed a better tissue tolerability. This finding could have clinical implications for the management of wounds with open osseous tissue and should be further investigated by in vivo studies. PMID- 23354693 TI - The impact of short term synaptic depression and stochastic vesicle dynamics on neuronal variability. AB - Neuronal variability plays a central role in neural coding and impacts the dynamics of neuronal networks. Unreliability of synaptic transmission is a major source of neural variability: synaptic neurotransmitter vesicles are released probabilistically in response to presynaptic action potentials and are recovered stochastically in time. The dynamics of this process of vesicle release and recovery interacts with variability in the arrival times of presynaptic spikes to shape the variability of the postsynaptic response. We use continuous time Markov chain methods to analyze a model of short term synaptic depression with stochastic vesicle dynamics coupled with three different models of presynaptic spiking: one model in which the timing of presynaptic action potentials are modeled as a Poisson process, one in which action potentials occur more regularly than a Poisson process (sub-Poisson) and one in which action potentials occur more irregularly (super-Poisson). We use this analysis to investigate how variability in a presynaptic spike train is transformed by short term depression and stochastic vesicle dynamics to determine the variability of the postsynaptic response. We find that sub-Poisson presynaptic spiking increases the average rate at which vesicles are released, that the number of vesicles released over a time window is more variable for smaller time windows than larger time windows and that fast presynaptic spiking gives rise to Poisson-like variability of the postsynaptic response even when presynaptic spike times are non-Poisson. Our results complement and extend previously reported theoretical results and provide possible explanations for some trends observed in recorded data. PMID- 23354694 TI - Double inhibition of NF-kappaB and XIAP via RNAi enhances the sensitivity of pancreatic cancer cells to gemcitabine. AB - The majority of patients with pancreatic cancer are resistant to gemcitabine. One of the mechanisms involved is the anti-apoptotic ability of these cells. The median lethal dose (LD50) of gemcitabine for PANC-1 cells was higher than that for Mia PaCa-2 cells and the former had higher nuclear factor-kappaB (NF-kappaB) and X-linked inhibitor of apoptosis protein (XIAP) levels. NF-kappaB contributes to the inhibition of apoptosis by the downregulation of downstream genes, such as XIAP and Bcl-2 and it confers chemoresistance. The two cell lines were infected with NF-kappaB p65 small interfering RNA (siRNA). p65 protein was effectively downregulated accompanied by the downregulation of XIAP protein. The combination treatment with gemcitabine and p65 siRNA increased the apoptotic rates in both cell lines; however, this was not sufficient. XIAP is involved in apoptosis to a greater extent compated to Bcl-2. XIAP may serve as another factor affecting the sufficiency of chemotherapy. XIAP siRNA was designed to knockdown XIAP. Mia PaCa 2 and PANC-1 cells were co-infected with XIAP siRNA and p65 siRNA. XIAP and p65 proteins were effectively downregulated and the gemcitabine-induced apoptotic rates were significantly increased. These results suggest that XIAP and NF-kappaB are two important factors conferring the chemoresistance of pancreatic cancer cells, and that their downregulation via RNAi effectively enhances the chemosensitivity of pancreatic cancer cells to gemcitabine. PMID- 23354695 TI - Environmental concentrations and bioaccumulations of cadmium and zinc in coastal watersheds along the Chinese Northern Bohai and Yellow Seas. AB - Cadmium (Cd) and zinc (Zn) in surface water, sediment, carp, and crab samples collected from upstream and downstream regions of coastal watersheds along the Chinese Northern Bohai and Yellow Seas were analyzed to provide a comprehensive understanding and assessment of their environmental concentrations and bioaccumulations. The results showed that downstream waters contaminated with Zn would have adverse effects on aquatic organisms. Although nearly all sediments were contaminated with Cd due to human activities, little potential existed for Cd toxicity in sediment-dwelling fauna. Concentrations of Cd and Zn in most water, sediment, carp, and crab were less than published values. The downstream carp and crabs had higher mean bioaccumulation factors and biota-sediment accumulation factors for Cd but lower mean biota-sediment accumulation factors for Zn than the upstream carp and crabs. Based on the relationships among Cd and Zn concentrations in water, sediment, and biota, the authors conclude that Cd and Zn in crabs primarily derived from sediment exposure. Although Cd and Zn in water and sediment originated from some of the same sources, the sources of Cd or Zn in water were likely different from those in sediment. PMID- 23354696 TI - Genetic tools to enhance the study of gene function and regulation in Staphylococcus aureus. AB - The bursa aurealis transposon has been used to create transposon insertion libraries of Bacillus anthracis and Staphylococcus aureus. To provide a set of genetic tools to enhance the utility of these libraries, we generated an allelic exchange system that allows for the replacement of the transposon with useful genetic markers and fluorescent reporter genes. These tools were tested in the Nebraska Transposon Mutant Library (NTML), containing defined transposon insertions in 1,952 nonessential S. aureus genes. First, we generated a plasmid that allows researchers to replace the genes encoding green fluorescent protein (GFP) and erythromycin resistance in the transposon with a noncoding DNA fragment, leaving a markerless mutation within the chromosome. Second, we produced allelic-exchange plasmids to replace the transposon with alternate antibiotic resistance cassettes encoding tetracycline, kanamycin, and spectinomycin resistance, allowing for the simultaneous selection of multiple chromosomal mutations. Third, we generated a series of fluorescent reporter constructs that, after allelic exchange, generate transcriptional reporters encoding codon-optimized enhanced cyan fluorescent protein (ECFP), enhanced yellow fluorescent protein (EYFP), DsRed.T3(DNT), and eqFP650, as well as superfolder green fluorescent protein (sGFP). Overall, combining the NTML with this allelic-exchange system provides an unparalleled resource for the study of S. aureus. PMID- 23354697 TI - High frequency of virulence factor genes tdh, trh, and tlh in Vibrio parahaemolyticus strains isolated from a pristine estuary. AB - Virulence factor genes encoding the thermostable direct hemolysin (tdh) and the thermostable direct hemolysin-related hemolysin (trh) are strongly correlated with virulence of the emergent human pathogen Vibrio parahaemolyticus. The gene encoding the thermolabile hemolysin (tlh) is also considered a signature molecular marker for the species. These genes are typically reported in very low percentages (1 to 2%) of nonclinical strains. V. parahaemolyticus strains were isolated from various niches within a pristine estuary (North Inlet, SC) and were screened for these genes using both newly designed PCR primers and more commonly used primers. DNA sequences of tdh and trh were recovered from 48% and 8.3%, respectively, of these North Inlet strains. The recovery of pathogenic V. parahaemolyticus strains in such high proportions from an estuarine ecosystem that is virtually free of anthropogenic influences indicates the potential for additional, perhaps environmental roles of the tdh and trh genes. PMID- 23354698 TI - Recent evolutionary radiation and host plant specialization in the Xylella fastidiosa subspecies native to the United States. AB - The bacterial pathogen, Xylella fastidiosa, infects many plant species in the Americas, making it a good model for investigating the genetics of host adaptation. We used multilocus sequence typing (MLST) to identify isolates of the native U.S. subsp. multiplex that were largely unaffected by intersubspecific homologous recombination (IHR) and to investigate how their evolutionary history influences plant host specialization. We identified 110 "non-IHR" isolates, 2 minimally recombinant "intermediate" ones (including the subspecific type), and 31 with extensive IHR. The non-IHR and intermediate isolates defined 23 sequence types (STs) which we used to identify 22 plant hosts (73% trees) characteristic of the subspecies. Except for almond, subsp. multiplex showed no host overlap with the introduced subspecies (subspecies fastidiosa and sandyi). MLST sequences revealed that subsp. multiplex underwent recent radiation (<25% of subspecies age) which included only limited intrasubspecific recombination (rho/theta = 0.02); only one isolated lineage (ST50 from ash) was older. A total of 20 of the STs grouped into three loose phylogenetic clusters distinguished by nonoverlapping hosts (excepting purple leaf plum): "almond," "peach," and "oak" types. These host differences were not geographical, since all three types also occurred in California. ST designation was a good indicator of host specialization. ST09, widespread in the southeastern United States, only infected oak species, and all peach isolates were ST10 (from California, Florida, and Georgia). Only ST23 had a broad host range. Hosts of related genotypes were sometimes related, but often host groupings crossed plant family or even order, suggesting that phylogenetically plastic features of hosts affect bacterial pathogenicity. PMID- 23354699 TI - Identification of homophenylalanine biosynthetic genes from the cyanobacterium Nostoc punctiforme PCC73102 and application to its microbial production by Escherichia coli. AB - L-Homophenylalanine (L-Hph) is a useful chiral building block for synthesis of several drugs, including angiotensin-converting enzyme inhibitors and the novel proteasome inhibitor carfilzomib. While the chemoenzymatic route of synthesis is fully developed, we investigated microbial production of L-Hph to explore the possibility of a more efficient and sustainable approach to L-Hph production. We hypothesized that L-Hph is synthesized from L-Phe via a mechanism homologous to 3 methyl-2-oxobutanoic acid conversion to 4-methyl-2-oxopentanoic acid during leucine biosynthesis. Based on bioinformatics analysis, we found three putative homophenylalanine biosynthesis genes, hphA (Npun_F2464), hphB (Npun_F2457), and hphCD (Npun_F2458), in the cyanobacterium Nostoc punctiforme PCC73102, located around the gene cluster responsible for anabaenopeptin biosynthesis. We constructed Escherichia coli strains harboring hphABCD-expressing plasmids and achieved the fermentative production of L-Hph from L-Phe. To our knowledge, this is the first identification of the genes responsible for homophenylalanine synthesis in any organism. Furthermore, to improve the low conversion efficiency of the initial strain, we optimized the expression of hphA, hphB, and hphCD, which increased the yield to ~630 mg/liter. The L-Hph biosynthesis and L-Leu biosynthesis genes from E. coli were also compared. This analysis revealed that HphB has comparatively relaxed substrate specificity and can perform the function of LeuB, but HphA and HphCD show tight substrate specificity and cannot complement the LeuA and LeuC/LeuD functions, and vice versa. Finally, the range of substrate tolerance of the L-Hph-producing strain was examined, which showed that m-fluorophenylalanine, o-fluorophenylalanine, and L-tyrosine were accepted as substrates and that the corresponding homoamino acids were generated. PMID- 23354700 TI - Thermostable alcohol dehydrogenase from Thermococcus kodakarensis KOD1 for enantioselective bioconversion of aromatic secondary alcohols. AB - A novel thermostable alcohol dehydrogenase (ADH) showing activity toward aromatic secondary alcohols was identified from the hyperthermophilic archaeon Thermococcus kodakarensis KOD1 (TkADH). The gene, tk0845, which encodes an aldo keto reductase, was heterologously expressed in Escherichia coli. The enzyme was found to be a monomer with a molecular mass of 31 kDa. It was highly thermostable with an optimal temperature of 90 degrees C and a half-life of 4.5 h at 95 degrees C. The apparent K(m) values for the cofactors NAD(P)(+) and NADPH were similar within a range of 66 to 127 MUM. TkADH preferred secondary alcohols and accepted various ketones and aldehydes as substrates. Interestingly, the enzyme could oxidize 1-phenylethanol and its derivatives having substituents at the meta and para positions with high enantioselectivity, yielding the corresponding (R) alcohols with optical purities of greater than 99.8% enantiomeric excess (ee). TkADH could also reduce 2,2,2-trifluoroacetophenone to (R)-2,2,2-trifluoro-1 phenylethanol with high enantioselectivity (>99.6% ee). Furthermore, the enzyme showed high resistance to organic solvents and was particularly highly active in the presence of H2O-20% 2-propanol and H2O-50% n-hexane or n-octane. This ADH is expected to be a useful tool for the production of aromatic chiral alcohols. PMID- 23354701 TI - Coinfection of Dermacentor silvarum olenev (acari: ixodidae) by Coxiella-Like, Arsenophonus-like, and Rickettsia-like symbionts. AB - We report that multiple symbionts coexist in Dermacentor silvarum. Based on 16S rRNA gene sequence analyses, we prove that Coxiella-like and Arsenophonus-like symbionts, with 95.6% and 96.7% sequence similarity to symbionts in the closest taxon, respectively, are novel. Moreover, we also provide evidence that the Coxiella-like symbiont appears to be the primary symbiont. PMID- 23354702 TI - Anaerobic sulfur metabolism coupled to dissimilatory iron reduction in the extremophile Acidithiobacillus ferrooxidans. AB - Gene transcription (microarrays) and protein levels (proteomics) were compared in cultures of the acidophilic chemolithotroph Acidithiobacillus ferrooxidans grown on elemental sulfur as the electron donor under aerobic and anaerobic conditions, using either molecular oxygen or ferric iron as the electron acceptor, respectively. No evidence supporting the role of either tetrathionate hydrolase or arsenic reductase in mediating the transfer of electrons to ferric iron (as suggested by previous studies) was obtained. In addition, no novel ferric iron reductase was identified. However, data suggested that sulfur was disproportionated under anaerobic conditions, forming hydrogen sulfide via sulfur reductase and sulfate via heterodisulfide reductase and ATP sulfurylase. Supporting physiological evidence for H2S production came from the observation that soluble Cu(2+) included in anaerobically incubated cultures was precipitated (seemingly as CuS). Since H(2)S reduces ferric iron to ferrous in acidic medium, its production under anaerobic conditions indicates that anaerobic iron reduction is mediated, at least in part, by an indirect mechanism. Evidence was obtained for an alternative model implicating the transfer of electrons from S(0) to Fe(3+) via a respiratory chain that includes a bc(1) complex and a cytochrome c. Central carbon pathways were upregulated under aerobic conditions, correlating with higher growth rates, while many Calvin-Benson-Bassham cycle components were upregulated during anaerobic growth, probably as a result of more limited access to carbon dioxide. These results are important for understanding the role of A. ferrooxidans in environmental biogeochemical metal cycling and in industrial bioleaching operations. PMID- 23354703 TI - Genome instability in Lactobacillus rhamnosus GG. AB - We describe here a comparative genome analysis of three dairy product isolates of Lactobacillus rhamnosus GG (LGG) and the ATCC 53103 reference strain to the published genome sequence of L. rhamnosus GG. The analysis showed that in two of three isolates, major DNA segments were missing from the genomic islands LGGISL1,2. The deleted DNA segments consist of 34 genes in one isolate and 84 genes in the other and are flanked by identical insertion elements. Among the missing genes are the spaCBA genes, which encode pilin subunits involved in adhesion to mucus and persistence of the strains in the human intestinal tract. Subsequent quantitative PCR analyses of six commercial probiotic products confirmed that two more products contain a heterogeneous population of L. rhamnosus GG variants, including genotypes with or without spaC. These results underline the relevance for quality assurance and control measures targeting genome stability in probiotic strains and justify research assessing the effect of genetic rearrangements in probiotics on the outcome of in vitro and in vivo efficacy studies. PMID- 23354704 TI - Photosynthetic Bradyrhizobium sp. strain ORS285 is capable of forming nitrogen fixing root nodules on soybeans (Glycine max). AB - The ability of photosynthetic Bradyrhizobium strains ORS285 and ORS278 to nodulate soybeans was investigated. While the nod gene-deficient ORS278 strain induced bumps only on soybean roots, the nod gene-containing ORS285 strain formed nitrogen-fixing nodules. However, symbiotic efficiencies differed drastically depending on both the soybean genotype used and the culture conditions tested. PMID- 23354705 TI - Frequent occurrence of extended-spectrum beta-lactamase- and transferable ampc beta-lactamase-producing Escherichia coli on domestic chicken meat in Sweden. AB - Forty-four percent of Swedish chicken meat fillets were contaminated with extended-spectrum or transferable AmpC beta-lactamase-producing Escherichia coli strains. Isolates from Swedish chicken meat and broilers were closely related to isolates from chicken meat imported into Sweden; these results indicate a common source of the contamination. PMID- 23354706 TI - Influence of therapeutic ceftiofur treatments of feedlot cattle on fecal and hide prevalences of commensal Escherichia coli resistant to expanded-spectrum cephalosporins, and molecular characterization of resistant isolates. AB - In the United States, the blaCMY-2 gene contained within incompatibility type A/C (IncA/C) plasmids is frequently identified in extended-spectrum-cephalosporin resistant (ESC(r)) Escherichia coli strains from both human and cattle sources. Concerns have been raised that therapeutic use of ceftiofur in cattle may increase the prevalence of ESC(r) E. coli. We report that herd ESC(r) E. coli fecal and hide prevalences throughout the residency of cattle at a feedlot, including during the period of greatest ceftiofur use at the feedlot, were either not significantly different (P >= 0.05) or significantly less (P < 0.05) than the respective prevalences at arrival. Longitudinal sampling of cattle treated with ceftiofur demonstrated that once the transient increase of ESC(r) E. coli shedding that follows ceftiofur injection abated, ceftiofur-injected cattle were no more likely than untreated members of the same herd to shed ESC(r) E. coli. Pulsed-field gel electrophoresis (PFGE) genotyping, antibiotic resistance phenotyping, screening for presence of the blaCMY-2 gene, and plasmid replicon typing were performed on 312 ESC(r) E. coli isolates obtained during six sampling periods spanning the 10-month residence of cattle at the feedlot. The identification of only 26 unique PFGE genotypes, 12 of which were isolated during multiple sampling periods, suggests that clonal expansion of feedlot-adapted blaCMY-2 E. coli strains contributed more to the persistence of blaCMY-2 than horizontal transfer of IncA/C plasmids between E. coli strains at this feedlot. We conclude that therapeutic use of ceftiofur at this cattle feedlot did not significantly increase the herd prevalence of ESC(r) E. coli. PMID- 23354707 TI - Genetic diversity of Cryptosporidium spp. within a remote population of Soay Sheep on St. Kilda Islands, Scotland. AB - This is the first report to characterize the genotypes and subtypes of Cryptosporidium species infecting a geographically isolated population of feral Soay sheep (Ovis aries) on Hirta, St. Kilda, Scotland, during two distinct periods: (i) prior to a population crash and (ii) as host numbers increased. Cryptosporidium DNA was extracted by freeze-thawing of immunomagnetically separated (IMS) bead-oocyst complexes, and species were identified following nested-PCR-restriction fragment length polymorphism (RFLP)/PCR sequencing at two Cryptosporidium 18S rRNA loci. Two hundred fifty-five samples were analyzed, and the prevalent Cryptosporidium species in single infections were identified as C. hominis (11.4% of all samples tested), C. parvum (9%), C. xiaoi (12.5%), and C. ubiquitum (6.7%). Cryptosporidium parvum was also present with other Cryptosporidium species in 27.1% of all samples tested. Cryptosporidium parvum- and C. hominis-positive isolates were genotyped using two nested-PCR assays that amplify the Cryptosporidium glycoprotein 60 gene (GP60). GP60 gene analysis showed the presence of two Cryptosporidium genotypes, namely, C. parvum IIaA19G1R1 and C. hominis IbA10G2. This study reveals a higher diversity of Cryptosporidium species/genotypes than was previously expected. We suggest reasons for the high diversity of Cryptosporidium parasites within this isolated population and discuss the implications for our understanding of cryptosporidiosis. PMID- 23354708 TI - Modulation of porcine beta-defensins 1 and 2 upon individual and combined Fusarium toxin exposure in a swine jejunal epithelial cell line. AB - Defensins are small antimicrobial peptides (AMPs) that play an important role in the innate immune system of mammals. Since the effect of mycotoxin contamination of food and feed on the secretion of intestinal AMPs is poorly understood, the aim of this study was to elucidate the individual and combined effects of four common Fusarium toxins, deoxynivalenol (DON), nivalenol (NIV), zearalenone (ZEA), and fumonisin B1 (FB1), on the mRNA expression, protein secretion, and corresponding antimicrobial effects of porcine beta-defensins 1 and 2 (pBD-1 and pBD-2) using a porcine jejunal epithelial cell line, IPEC-J2. In general, upregulation of pBD-1 and pBD-2 mRNA expression occurred following exposure to Fusarium toxins, individually and in mixtures (P < 0.05). However, no significant increase in secreted pBD-1 and pBD-2 protein levels was observed, as measured by enzyme-linked immunosorbent assay (ELISA). Supernatants from IPEC-J2 cells exposed to toxins, singly or in combination, however, possessed significantly less antimicrobial activity against Escherichia coli than untreated supernatants. When single toxins and two-toxin combinations were assessed, toxicity effects were shown to be nonadditive (including synergism, potentiation, and antagonism), suggesting interactive toxin effects when cells are exposed to mycotoxin combinations. The results show that Fusarium toxins, individually and in mixtures, activate distinct antimicrobial defense mechanisms possessing the potential to alter the intestinal microbiota through diminished antimicrobial effects. Moreover, by evaluating toxin mixtures, this improved understanding of toxin effects will enable more effective risk assessments for common mycotoxin combinations observed in contaminated food and feed. PMID- 23354709 TI - Symbiont-mediated protection against fungal pathogens in pea aphids: a role for pathogen specificity? AB - Here we show that a bacterial endosymbiont, Regiella insecticola, protects pea aphids (Acyrthosiphon pisum) from the aphid-specific fungal entomopathogen Zoophthora occidentalis but not from the generalist insect fungal pathogen Beauveria bassiana. This finding highlights the complex influence of fungi on the dynamics of this economically important agricultural pest. PMID- 23354710 TI - Microfluidic chip-based detection and intraspecies strain discrimination of Salmonella serovars derived from whole blood of septic mice. AB - Salmonella is a zoonotic pathogen that poses a considerable public health and economic burden in the United States and worldwide. Resultant human diseases range from enterocolitis to bacteremia to sepsis and are acutely dependent on the particular serovar of Salmonella enterica subsp. enterica, which comprises over 99% of human-pathogenic S. enterica isolates. Point-of-care methods for detection and strain discrimination of Salmonella serovars would thus have considerable benefit to medical, veterinary, and field applications that safeguard public health and reduce industry-associated losses. Here we describe a single, disposable microfluidic chip that supports isothermal amplification and sequence specific detection and discrimination of Salmonella serovars derived from whole blood of septic mice. The integrated microfluidic electrochemical DNA (IMED) chip consists of an amplification chamber that supports loop-mediated isothermal amplification (LAMP), a rapid, single-temperature amplification method as an alternative to PCR that offers advantages in terms of sensitivity, reaction speed, and amplicon yield. The amplification chamber is connected via a microchannel to a detection chamber containing a reagentless, multiplexed (here biplex) sensing array for sequence-specific electrochemical DNA (E-DNA) detection of the LAMP products. Validation of the IMED device was assessed by the detection and discrimination of S. enterica subsp. enterica serovars Typhimurium and Choleraesuis, the causative agents of enterocolitis and sepsis in humans, respectively. IMED chips conferred rapid (under 2 h) detection and discrimination of these strains at clinically relevant levels (<1,000 CFU/ml) from whole, unprocessed blood collected from septic animals. The IMED-based chip assay shows considerable promise as a rapid, inexpensive, and portable point-of-care diagnostic platform for the detection and strain-specific discrimination of microbial pathogens. PMID- 23354711 TI - Cytochrome P450 initiates degradation of cis-dichloroethene by Polaromonas sp. strain JS666. AB - Polaromonas sp. strain JS666 grows on cis-1,2-dichoroethene (cDCE) as the sole carbon and energy source under aerobic conditions, but the degradation mechanism and the enzymes involved are unknown. In this study, we established the complete pathway for cDCE degradation through heterologous gene expression, inhibition studies, enzyme assays, and analysis of intermediates. Several lines of evidence indicate that a cytochrome P450 monooxygenase catalyzes the initial step of cDCE degradation. Both the transient accumulation of dichloroacetaldehyde in cDCE degrading cultures and dichloroacetaldehyde dehydrogenase activities in cell extracts of JS666 support a pathway for degradation of cDCE through dichloroacetaldehyde. The mechanism minimizes the formation of cDCE epoxide. The molecular phylogeny of the cytochrome P450 gene and the organization of neighboring genes suggest that the cDCE degradation pathway recently evolved in a progenitor capable of degrading 1,2-dichloroethane either by the recruitment of the cytochrome P450 monooxygenase gene from an alkane catabolic pathway or by selection for variants of the P450 in a preexisting 1,2-dichloroethane catabolic pathway. The results presented here add yet another role to the broad array of productive reactions catalyzed by cytochrome P450 enzymes. PMID- 23354712 TI - Stochasticity in colonial growth dynamics of individual bacterial cells. AB - Conventional bacterial growth studies rely on large bacterial populations without considering the individual cells. Individual cells, however, can exhibit marked behavioral heterogeneity. Here, we present experimental observations on the colonial growth of 220 individual cells of Salmonella enterica serotype Typhimurium using time-lapse microscopy videos. We found a highly heterogeneous behavior. Some cells did not grow, showing filamentation or lysis before division. Cells that were able to grow and form microcolonies showed highly diverse growth dynamics. The quality of the videos allowed for counting the cells over time and estimating the kinetic parameters lag time (lambda) and maximum specific growth rate (MUmax) for each microcolony originating from a single cell. To interpret the observations, the variability of the kinetic parameters was characterized using appropriate probability distributions and introduced to a stochastic model that allows for taking into account heterogeneity using Monte Carlo simulation. The model provides stochastic growth curves demonstrating that growth of single cells or small microbial populations is a pool of events each one of which has its own probability to occur. Simulations of the model illustrated how the apparent variability in population growth gradually decreases with increasing initial population size (N(0)). For bacterial populations with N(0) of >100 cells, the variability is almost eliminated and the system seems to behave deterministically, even though the underlying law is stochastic. We also used the model to demonstrate the effect of the presence and extent of a nongrowing population fraction on the stochastic growth of bacterial populations. PMID- 23354713 TI - Identification of a cyclosporine-specific P450 hydroxylase gene through targeted cytochrome P450 complement (CYPome) disruption in Sebekia benihana. AB - It was previously proposed that regio-specific hydroxylation of an immunosuppressive cyclosporine (CsA) at the 4th N-methyl leucine is mediated by cytochrome P450 hydroxylase (CYP) in the rare actinomycete Sebekia benihana. This modification is thought to be the reason for the hair growth-promoting side effect without the immunosuppressive activity of CsA. Through S. benihana genome sequencing and in silico analysis, we identified the complete cytochrome P450 complement (CYPome) of S. benihana, including 21 CYPs and their electron transfer partners, consisting of 7 ferredoxins (FDs) and 4 ferredoxin reductases (FDRs). Using Escherichia coli conjugation-based S. benihana CYPome-targeted disruption, all of the identified CYP, FD, and FDR genes in S. benihana were individually inactivated. Among the 32 S. benihana exconjugant mutants tested, only a single S. benihana CYP mutant, DeltaCYP-sb21, failed to exhibit CsA hydroxylation activity. The hydroxylation was restored by CYP-sb21 gene complementation. Since all S. benihana FD and FDR disruption mutants maintained CsA hydroxylation activity, it can be concluded that CYP-sb21, a new member of the bacterial CYP107 family, is the only essential component of the in vivo regio-specific CsA hydroxylation process in S. benihana. Moreover, expression of an extra copy of the CYP-sb21 gene increased CsA hydroxylation in wild-type S. benihana and an NADPH-enriched Streptomyces coelicolor mutant, by 2-fold and 1.5-fold, respectively. These results show for the first time that regio-specific hydroxylation of CsA is carried out by a specific P450 hydroxylase present in S. benihana, and they set the stage for the biotechnological application of regio specific CsA hydroxylation through heterologous CYP-sb21 expression. PMID- 23354715 TI - Constitutive expression of the cytochrome P450 EthABCD monooxygenase system enables degradation of synthetic dialkyl ethers in Aquincola tertiaricarbonis L108. AB - In Rhodococcus ruber IFP 2001, Rhodococcus zopfii IFP 2005, and Gordonia sp. strain IFP 2009, the cytochrome P450 monooxygenase EthABCD catalyzes hydroxylation of methoxy and ethoxy residues in the fuel oxygenates methyl tert butyl ether (MTBE), ethyl tert-butyl ether (ETBE), and tert-amyl methyl ether (TAME). The expression of the IS3-type transposase-flanked eth genes is ETBE dependent and controlled by the regulator EthR (C. Malandain et al., FEMS Microbiol. Ecol. 72:289-296, 2010). In contrast, we demonstrated by reverse transcription-quantitative PCR (RT-qPCR) that the betaproteobacterium Aquincola tertiaricarbonis L108, which possesses the ethABCD genes but lacks ethR, constitutively expresses the P450 system at high levels even when growing on nonether substrates, such as glucose. The mutant strain A. tertiaricarbonis L10, which is unable to degrade dialkyl ethers, resulted from a transposition event mediated by a rolling-circle IS91-type element flanking the eth gene cluster in the wild-type strain L108. The constitutive expression of Eth monooxygenase is likely initiated by the housekeeping sigma factor sigma(70), as indicated by the presence in strain L108 of characteristic -10 and -35 binding sites upstream of ethA which are lacking in strain IFP 2001. This enables efficient degradation of diethyl ether, diisopropyl ether, MTBE, ETBE, TAME, and tert-amyl ethyl ether (TAEE) without any lag phase in strain L108. However, ethers with larger residues, n-hexyl methyl ether, tetrahydrofuran, and alkyl aryl ethers, were not attacked by the Eth system at significant rates in resting-cell experiments, indicating that the residue in the ether molecule which is not hydroxylated also contributes to the determination of substrate specificity. PMID- 23354714 TI - Homeostasis and catabolism of choline and glycine betaine: lessons from Pseudomonas aeruginosa. AB - Most sequenced bacteria possess mechanisms to import choline and glycine betaine (GB) into the cytoplasm. The primary role of choline in bacteria appears to be as the precursor to GB, and GB is thought to primarily act as a potent osmoprotectant. Choline and GB may play accessory roles in shaping microbial communities, based on their limited availability and ability to enhance survival under stress conditions. Choline and GB enrichment near eukaryotes suggests a role in the chemical relationships between these two kingdoms, and some of these interactions have been experimentally demonstrated. While many bacteria can convert choline to GB for osmoprotection, a variety of soil- and water-dwelling bacteria have catabolic pathways for the multistep conversion of choline, via GB, to glycine and can thereby use choline and GB as sole sources of carbon and nitrogen. In these choline catabolizers, the GB intermediate represents a metabolic decision point to determine whether GB is catabolized or stored as an osmo- and stress protectant. This minireview focuses on this decision point in Pseudomonas aeruginosa, which aerobically catabolizes choline and can use GB as an osmoprotectant and a nutrient source. P. aeruginosa is an experimentally tractable and ecologically relevant model to study the regulatory pathways controlling choline and GB homeostasis in choline-catabolizing bacteria. The study of P. aeruginosa associations with eukaryotes and other bacteria also makes this a powerful model to study the impact of choline and GB, and their associated regulatory and catabolic pathways, on host-microbe and microbe-microbe relationships. PMID- 23354717 TI - Development of a rapid, sensitive, and field-deployable razor ex BioDetection system and quantitative PCR assay for detection of Phymatotrichopsis omnivora using multiple gene targets. AB - A validated, multigene-based method using real-time quantitative PCR (qPCR) and the Razor Ex BioDetection system was developed for detection of Phymatotrichopsis omnivora. This soilborne fungus causes Phymatotrichopsis root rot of cotton, alfalfa, and other dicot crops in the southwestern United States and northern Mexico, leading to significant crop losses and limiting the range of crops that can be grown in soils where the fungus is established. It is on multiple lists of regulated organisms. Because P. omnivora is difficult to isolate, accurate and sensitive culture-independent diagnostic tools are needed to confirm infections by this fungus. Specific PCR primers and probes were designed based on P. omnivora nucleotide sequences of the genes encoding rRNA internal transcribed spacers, beta-tubulin, and the second-largest subunit of RNA polymerase II (RPB2). PCR products were cloned and sequenced to confirm their identity. All primer sets allowed early detection of P. omnivora in infected but asymptomatic plants. A modified rapid DNA purification method, which facilitates a quick (~30 min) on-site assay capability for P. omnivora detection, was developed. Combined use of three target genes increased the assay accuracy and broadened the range of detection. To our knowledge, this is the first report of a multigene-based, field deployable, rapid, and reliable identification method for a fungal plant pathogen and should serve as a model for the development of field-deployable assays of other phytopathogens. PMID- 23354716 TI - A hydrolase from Lactobacillus sakei moonlights as a transaminase. AB - Enzymatic transamination of amino acids yields alpha-keto acids and is the initial step for the production of volatile compounds that contribute to the sensory perception of fermented foods such as salami. Lactobacillus sakei is one of the lactic acid bacterial strains commonly used in starter cultures. Although the genome sequence of L. sakei 23K lacks genes encoding typical branched-chain amino acid transaminases, transamination activity and the formation of amino acid derived volatile metabolites could be demonstrated. A protein purified from L. sakei is held responsible for the transamination activity. By heterologous expression of the corresponding gene in Escherichia coli, we were able to characterize the transamination side activity of an enzyme annotated as a putative acylphosphatase (AcP). A transamination side activity of hen egg white lysozyme (HEWL) was also discovered. Both enzymes showed substrate specificity toward branched-chain and aromatic amino acids. AcP also accepted l-methionine. Activity was optimal at neutral pH for both enzymes, whereas AcP showed a significantly higher temperature optimum (55 degrees C) than that of HEWL (37 degrees C). Kinetic parameters revealed high affinity toward l-leucine for AcP (K(m) = 1.85 mM) and toward l-isoleucine for HEWL (K(m) = 3.79 mM). AcP seems to play a major role in the metabolism of amino acids in L. sakei. PMID- 23354718 TI - Direct assessment of metabolite utilization by Pseudomonas aeruginosa during growth on artificial sputum medium. AB - We grew Pseudomonas aeruginosa in LB and artificial sputum medium (ASM) (filtered and unfiltered) and quantified metabolite utilization and excretion by nuclear magnetic resonance (NMR) spectroscopy (metabolic footprinting or extracellular metabolomics). Utilization rates were similar between media, but there were differences in excretion-e.g., acetate was produced only in unfiltered ASM. PMID- 23354719 TI - Quantitative detection of viable Bifidobacterium bifidum BF-1 cells in human feces by using propidium monoazide and strain-specific primers. AB - We developed a PCR-based method to detect and quantify viable Bifidobacterium bifidum BF-1 cells in human feces. This method (PMA-qPCR) uses propidium monoazide (PMA) to distinguish viable from dead cells and quantitative PCR using a BF-1-specific primer set designed from the results of randomly amplified polymorphic DNA analysis. During long-term culture (10 days), the number of viable BF-1 cells detected by counting the number of CFU on modified MRS agar, by measuring the ATP contents converted to CFU, and by using PMA-qPCR decreased from about 10(10) to 10(6) cells/ml; in contrast, the total number of (viable and dead) BF-1 cells detected by counting 4',6-diamidino-2-phenylindolee (DAPI) stained cells and by using qPCR without PMA and reverse transcription-qPCR remained constant. The number of viable BF-1 cells in fecal samples detected by using PMA-qPCR was highly and significantly correlated with the number of viable BF-1 cells added to the fecal samples, within the range of 10(5.3) to 10(10.3) cells/g feces (wet weight) (r > 0.99, P < 0.001). After 12 healthy subjects ingested 10(10.3) to 10(11.0) CFU of BF-1 in a fermented milk product daily for 28 days, 10(4.5 +/- 1.5) (mean +/- standard deviation [SD]) BF-1 CFU/g was detected in fecal samples by using strain-specific selective agar; in contrast, 10(6.2 +/- 0.4) viable BF-1 cells/g were detected by using PMA-qPCR, and a total of 10(7.6 +/- 0.7) BF-1 cells/g were detected by using qPCR without PMA. Thus, the number of viable BF-1 cells detected by PMA-qPCR was about 50 times higher (P < 0.01) than that detected by the culture-dependent method. We conclude that strain-specific PMA-qPCR can be used to quickly and accurately evaluate viable BF 1 in feces. PMID- 23354720 TI - Glucose triggers ATP secretion from bacteria in a growth-phase-dependent manner. AB - ATP modulates immune cell functions, and ATP derived from gut commensal bacteria promotes the differentiation of T helper 17 (Th17) cells in the intestinal lamina propria. We recently reported that Enterococcus gallinarum, isolated from mice and humans, secretes ATP. We have since found and characterized several ATP secreting bacteria. Of the tested enterococci, Enterococcus mundtii secreted the greatest amount of ATP (>2 MUM/10(8) cells) after overnight culture. Glucose, not amino acids and vitamins, was essential for ATP secretion from E. mundtii. Analyses of energy-deprived cells demonstrated that glycolysis is the most important pathway for bacterial ATP secretion. Furthermore, exponential-phase E. mundtii and Enterococcus faecalis cells secrete ATP more efficiently than stationary-phase cells. Other bacteria, including Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus, also secrete ATP in exponential but not stationary phase. These results suggest that various gut bacteria, including commensals and pathogens, might secrete ATP at any growth phase and modulate immune cell function. PMID- 23354721 TI - Postinterventional pain and complications of sonographically guided interventions in the liver and pancreas. AB - PURPOSE: Sonographically guided interventions in abdominal organs are routine procedures with rare severe complications. However, potential patient discomfort or pain is frequently not addressed in the literature. MATERIALS AND METHODS: In a prospective 1-year study, the peri- and postinterventional pain of patients undergoing sonographically guided punctures of the liver and pancreas was analyzed. Data acquisition was done with a standardized questionnaire. This included three numeric rating scales (NRS) ranging from "0" to "10" to be answered at puncture and 1 hour and 4 hours later. Data concerning complications and administered analgesic medication was acquired from the patients' charts. RESULTS: 223/274 patients could be analyzed (83 %). 91 women (40.8 %) and 132 men (59.2 %) were included. The mean age was 56.0 yrs. Overall the average level of pain was 2.98 at puncture, 1.21 after 1 hour and 0.71 after 4 hours. In patients with diagnostic biopsies, the pain levels were 3.37(0 h)/1.33(1 h)/0.71(4 h) for liver parenchyma, 2.64(0 h)/0.95(1 h)/0.65(4 h) for focal liver lesions and 3.1(0 h)/1.9(1 h)/1.1(4 h) for pancreatic punctures. The pain levels at therapeutic interventions were 3.00(0 h)/2.00(1 h)/0.50(4 h). Female and younger (< 50 yrs) patients had statistically significantly more pain at puncture and 1 hour postintervention. Only minor complications occurred (0.9 %). CONCLUSION: Severe pain after sonographically guided interventions is rare. Most patients suffer only from mild pain postinterventionally. PMID- 23354722 TI - Structural plasticity of interneurons in the adult brain: role of PSA-NCAM and implications for psychiatric disorders. AB - Neuronal structural plasticity is known to have a major role in cognitive processes and in the response of the CNS to aversive experiences. This type of plasticity involves processes ranging from neurite outgrowth/retraction or dendritic spine remodeling, to the incorporation of new neurons to the established circuitry. However, the study of how these structural changes take place has been focused mainly on excitatory neurons, while little attention has been paid to interneurons. The exploration of these plastic phenomena in interneurons is very important, not only for our knowledge of CNS physiology, but also for understanding better the etiology of different psychiatric and neurological disorders in which alterations in the structure and connectivity of inhibitory networks have been described. Here we review recent work on the structural remodeling of interneurons in the adult brain, both in basal conditions and after chronic stress or sensory deprivation. We also describe studies from our laboratory and others on the putative mediators of this interneuronal structural plasticity, focusing on the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). This molecule is expressed by some interneurons in the adult CNS and, through its anti-adhesive and insulating properties, may participate in the remodeling of their structure. Finally, we review recent findings on the possible implication of PSA-NCAM on the remodeling of inhibitory neurons in certain psychiatric disorders and their treatments. PMID- 23354724 TI - [Neck mass]. PMID- 23354725 TI - [Results of stapedotomies performed under general anesthesia]. AB - INTRODUCTION: It is recommended that a stapedotomy be performed under local anaesthesia to enable intraoperative monitoring of hearing and vestibular function. In contrast, we prefer to carry out stapedotomies under general anesthesia. The aim of this study was to investigate whether this practice has an adverse effect on hearing results. PATIENTS AND METHODS: All stapedotomies performed in our department between May 2003 and February 2012 were included in the analysis. Revision surgery was excluded. All interventions were performed under general anesthesia with an endotracheal tube by the same surgeon using the same technique. Pure tone and speech audiometry, acoustic reflex testing and Schuller radiology were performed preoperatively. Follow-up examinations (pure tone and speech audiometry) took place 4-6 weeks following surgery. RESULTS: A total of 262 stapedotomies were carried out on 228 patients. Follow-up examinations could not be performed on six patients. Of the remaining 256 cases, closure of the air-bone gap to less than 10 dB was achieved in 220 patients (86%) and in 29 patients (11%) it was closed to less than 20 dB. Conductive hearing loss persisted in seven cases (3%). A mild sensorineural hearing loss with complete closure of the air-bone gap was experienced by two patients (0.8%). There was no instance of postoperative deafness. CONCLUSIONS: Performing stapedotomies under general rather than local anesthesia has no adverse effects on audiological results. PMID- 23354723 TI - Polysialic acid: versatile modification of NCAM, SynCAM 1 and neuropilin-2. AB - The glycan polysialic acid is well-known as a unique posttranslational modification of the neural cell adhesion molecule NCAM. Despite remarkable acceptor specificity, however, a few other proteins can be targets of polysialylation. Here, we recapitulate the biosynthesis of polysialic acid by the two polysialyltransferases ST8SIA2 and ST8SIA4 and highlight the increasing evidence that variation in the human ST8SIA2 gene is linked to schizophrenia and possibly other neuropsychiatric disorders. Moreover, we summarize the knowledge on the role of NCAM polysialylation in brain development gained by the analysis of NCAM- and polysialyltransferase-deficient mouse models. The last part of this review is focused on recent advances in identifying SynCAM 1 and neuropilin-2 as novel acceptors of polysialic acid in NG2 cells of the perinatal brain and in dendritic cells of the immune system, respectively. PMID- 23354726 TI - [Microlaryngoscopy and phonomicrosurgery]. AB - Microlaryngoscopy is a reliable technique and the most frequently applied method in laryngeal surgery. The design of new laryngoscopes and the application of video endoscopes may permit further improvements in laryngeal exposure, whilst minimizing the damage caused by their insertion. In contrast to this, the principle microsurgical procedures for improvement, restoration and preservation of the vocal function have remained almost unchanged. These techniques are oriented towards minimal excision of pathological tissue with maximal conservation of normal tissue, in particular the epithelium of the vocal folds and the lamina propria-the basic structures for vocal fold vibration. Phonomicrosurgy can only be justified on the basis of a proven improvement as evidenced by vocal function analysis. PMID- 23354727 TI - Osteoporosis in men: recent progress. AB - As osteoporosis in men has been recognized as an important clinical problem, new information is being accumulated on its scope, pathophysiology, evaluation, and treatment. Fracture risk calculators, such as FRAX, identify a large proportion of the older male population to be at heightened risk for fracture. The classification of osteoporosis into primary and secondary forms, while still useful, is affected by the fact that many men have multiple contributing factors to their fracture risk. The role of sex steroids is being better defined as other risk factors for fracture are delineated. As longevity continues to increase in men and until osteoporotic fracture is truly recognized as a potentially fatal disorder, many men will be undiagnosed and untreated. Two recent studies provide more evidence that treatments which decrease fracture risk in women do the same in men. With the publication of guidelines and increasing strength of evidence for treatment efficacy, it is hoped that more men will be evaluated and treated for this often neglected disorder. PMID- 23354729 TI - Characterization of placenta-specific microRNAs in fetal growth restriction pregnancy. AB - OBJECTIVE: The aim of this study was to characterize placenta-specific microRNAs in fetal growth restriction (FGR) pregnancy. METHOD: Placenta-specific miRNAs were identified by next-generation sequencing analysis. Subsequently, quantitative real-time reverse-transcription polymerase chain reaction was used to identify FGR placenta-specific miRNAs whose level of expression was significantly decreased in FGR placenta (n = 45) compared with uncomplicated placenta (n = 50). FGR pregnancy-associated, placenta-specific microRNAs were identified in maternal plasma after delivery at significantly decreased concentrations, and their circulating levels in maternal plasma was compared between FGR pregnancies (n = 10) and uncomplicated pregnancies (n = 10). RESULTS: Out of the ten placenta-specific microRNAs that we identified, seven placenta specific microRNAs (hsa-miR-518b, hsa-miR-1323, hsa-miR-516b, hsa-miR-515-5p, hsa miR-520h, hsa-miR-519d, and hsa-miR-526b) from the chromosome 19 microRNA cluster were identified as FGR placenta-specific microRNAs. Four FGR placenta-specific microRNAs (hsa-miR-518b, hsa-miR-1323, hsa-miR-520h, and hsa-miR-519d) were confirmed as FGR pregnancy-associated, placenta-specific miRNAs, but their circulating levels in maternal plasma showed no significant differences between FGR pregnancy and uncomplicated pregnancy. CONCLUSION: Our data suggest that reduced expression in placenta of certain FGR placenta-specific miRNAs is associated with FGR and that the discrepancy between expression in FGR placenta and their circulating levels in maternal plasma will be crucial to understanding how placenta-specific microRNAs are released into the maternal circulation. PMID- 23354728 TI - Investigational anti-hyperglycemic agents: the future of type 2 diabetes therapy? AB - As the pandemic of type 2 diabetes spreads globally, clinicians face many challenges in treating an increasingly diverse patient population varying in age, comorbidities, and socioeconomic status. Current therapies for type 2 diabetes are often unable to alter the natural course of the disease and provide durable glycemic control, and side effects in the context of individual patient characteristics often limit treatment choices. This often results in the progression to insulin use and complex regimens that are difficult to maintain. Therefore, a number of agents are being developed to better address the pathogenesis of type 2 diabetes and to overcome limitations of current therapies. The hope is to provide more options for glucose lowering and complication reduction with less risk for hypoglycemia and other adverse effects. These agents include newer incretin-based therapies and PPAR agonists, as well as new therapeutic classes such as sodium-coupled glucose cotransporter 2 inhibitors, free fatty acid receptor agonists, 11-beta-hydroxysteroid dehydrogenase type 1 inhibitors, glucokinase activators, and several others that may enter clinical use over the next decade. Herein we review these agents that are advancing through clinical trials and describe the rationale behind their use, mechanisms of action, and potential for glucose lowering, as well as what is known of their limitations. PMID- 23354730 TI - Predicting depression from illness severity in cardiovascular disease patients: self-efficacy beliefs, illness perception, and perceived social support as mediators. AB - BACKGROUND: Many studies have investigated the relationships between cardiovascular diseases and patients' depression; nevertheless, few is still known as regard the impact of illness severity on depression and whether psychosocial variables mediate this association. PURPOSE: The aim of this study is to investigate the putative mediating role of illness representations, self efficacy beliefs, and perceived social support on the relationship between illness severity and depression. METHODS: A total of 75 consecutive patients with cardiovascular disease (80 % men; mean age = 65.44, SD = 10.20) were enrolled in an Italian hospital. Illness severity was measured in terms of left ventricular ejection fraction, whereas psychological factors were assessed using self-report questionnaires. RESULTS: The relationship between left ventricular ejection fraction and depression was mediated by identity illness perception, self efficacy beliefs in managing cardiac risk factors, and perceived social support. CONCLUSION: The treatment of depression in cardiovascular disease patients may therefore benefit from a psychological intervention focused on patients' illness representations, self-efficacy beliefs, and their perceived social support. PMID- 23354732 TI - Reduction of connexin43 in human endothelial progenitor cells impairs the angiogenic potential. AB - Our previous work showed that arsenic trioxide down-regulated Cx43 and attenuated the angiogenic potential of human late endothelial progenitor cells (EPC). However, the relation between Cx43 and angiogenic activity of the EPC remained unclear. In the study, human late EPC were treated with siRNA specific to Cx43 (Cx43siRNA). The expression profiles as well as activity of the treated cells were examined. In parallel, the angiogenic potential of human EPC treated with Cx43siRNA was evaluated using murine hind limb ischemic model. The results showed that, in the EPC treated with Cx43siRNA, the activity of migration, proliferation, and angiogenic potential were attenuated, accompanied by reduction in vascular endothelial growth factor (VEGF) expression. In hind limb ischemia mice, EPC treated with Cx43siRNA lost the therapeutic angiogenic potential. VEGF supplementation partially recovered the activity impaired by Cx43 down regulation. In conclusion, reduced Cx43 expression per se in the EPC causes decreased expression of VEGF and impaired angiogenic potential of the cells. Prevention of Cx43 reduction is a potential target to maintain the angiogenic potential of the EPC. PMID- 23354733 TI - p55PIK-PI3K stimulates angiogenesis in colorectal cancer cell by activating NF kappaB pathway. AB - Vascular growth factor (VEGF) is an important mediator of angiogenesis. PI3K plays essential roles in angiogenesis; however, the mechanisms and specific functions of individual isoforms of PI3K members in tumor angiogenesis regulation are still not fully understood. In this study, we evaluate the role of p55PIK, a PI3K regulatory subunit encoded by PIK3R3 gene, in tumor angiogenesis. We reported that overexpression of p55PIK in cancer cells up-regulated HIF-1alpha expression and increased VEGF expression. Furthermore, overexpression of p55PIK increased tumor angiogenesis in vivo and in vitro. Moreover, data indicated enhanced HIF-1alpha expression by p55PIK-PI3K depended on its ability to activate NF-kB signaling pathways, especially to increase the phosphorylation of p65 subunits of NF-kappaB. Our study suggested that p55PIK-PI3K was essential in regulating cancer cell-mediated angiogenesis and contributed to tumor growth and that the p55PIK provides a potential and specific target for new anti angiogenesis drug development. PMID- 23354731 TI - Thriving within the host: Candida spp. interactions with phagocytic cells. AB - Certain Candida spp. (e.g. C. albicans, C. tropicalis, C. parapsilosis and C. glabrata) are not only well-adapted fungal commensals of humans, but are also able to cause superficial mucosal infections or even systemic disease. Professional phagocytes (neutrophils, macrophages and dendritic cells) constitute the first line of defence against Candida spp. Here, we review the interactions of phagocytes with pathogenic Candida spp., focusing on macrophages and neutrophils. We discuss the mechanisms involved in recognition, uptake and killing of these fungi. We go on to analyse the cellular responses of these yeasts towards phagocyte-imposed stresses, including metabolic flexibility, robust oxidative stress response and ability to cope with nitrosative stress. Finally, we address strategies that allow these opportunistic pathogens to thrive within the host, evading and escaping from the phagocyte attack. PMID- 23354734 TI - Recombination and synaptic adjustment in oocytes of mice heterozygous for a large paracentric inversion. AB - Homologous chromosome synapsis in inversion heterozygotes results in the formation of inversion loops. These loops might be transformed into straight, non homologously paired bivalents via synaptic adjustment. Synaptic adjustment was discovered 30 years ago; however, its relationship with recombination has remained unclear. We analysed this relationship in female mouse embryos heterozygous for large paracentric inversion In(1)1Rk using immunolocalisation of the synaptonemal complex (SYCP3) and mature recombination nodules (MLH1) proteins. The frequency of cells containing bivalents with inversion loops decreased from 69 % to 28 % during pachytene. If an MLH1 focus was present in the non-homologously paired inverted region of the straight bivalent, it was always located in the middle of the inversion. Most of the small, incompletely adjusted loops contained MLH1 foci near the points at which pairing partners were switched. This observation indicates that the degree of synaptic adjustment depended on the crossover position. Complete synaptic adjustment was only possible if a crossover (CO) was located exactly in the middle of the inversion. If a CO was located at any other site, this interrupted synaptic adjustment and resulted in inversion loops of different sizes with an MLH1 focus at or near the edge of the remaining loop. PMID- 23354735 TI - Fatherhood status and risk of prostate cancer: nationwide, population-based case control study. AB - Previous studies have shown a decreased risk of prostate cancer for childless men; however, the cause of the association remains to be elucidated. The aim of our study was to assess the risk of prostate cancer by fatherhood status, also considering potential confounding factors. In a case-control study in Prostate Cancer data Base Sweden 2.0, a nationwide, population-based cohort, data on number of children, marital status, education, comorbidity and tumor characteristics obtained through nationwide healthcare registers and demographic databases for 117,328 prostate cancer cases and 562,644 controls, matched on birth year and county of residence, were analyzed. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for prostate cancer overall and by risk category, adjusting for marital status and education. Childless men had a decreased risk of prostate cancer compared to fathers, OR = 0.83 (95% CI = 0.82-0.84), and risk was lower for low risk prostate cancer, OR = 0.74 (95% CI = 0.72-0.77), than for metastatic prostate cancer, OR = 0.93 (95% CI = 0.90-0.97). Adjustment for marital status and education attenuated the association in the low-risk category, adjusted OR = 0.87 (95% CI = 0.84-0.91), whereas OR for metastatic cancer remained virtually unchanged, adjusted OR = 0.92 (95% CI = 0.88-0.96). Our data indicate that the association between fatherhood status and prostate cancer to a large part is due to socioeconomic factors influencing healthcare-seeking behavior including testing of prostate-specific antigen levels. PMID- 23354736 TI - In vivo investigation of ceftiofur-loaded gelatin and PLGA microspheres in beagle dogs. AB - Drug delivery systems based on polymer microspheres have received considerable attention. Ceftiofur sodium and ceftiofur hydrochloride is widely used for the treatment of bacterial diseases in animals but the delivery in vivo has not been reported. In this paper, we report the synthesis of microspheres from gelatin and PLGA, two kinds of typical natural and artificial materials, for loading ceftiofur and the in vivo investigation of the pharmacokinetics in beagle dogs. By controlling the synthesis parameters, gelatin and PLGA microspheres with diameter between 5 and 35 microns were obtained. Assay procedures based on high performance liquid chromatography were evaluated and confirmed. The dogs were randomly divided into three groups, i.e., control group, gelatin group, and PLGA group and administrated via intravenous injection. Plasma concentrations of ceftiofur over time were measured and analyzed. Results indicate that the main kinetic parameters do not show significant difference for the gelatin group and control group, but the area under the curve, plasma half-life, apparent volume of distribution, and clearance ratio of PLGA group show significant difference from the gelatin group and the control group. The PLGA microspheres show a low area under the curve but long time release. PMID- 23354737 TI - In vivo biocompatibility of two PEG/PAA interpenetrating polymer networks as corneal inlays following deep stromal pocket implantation. AB - This study compared the effects of implanting two interpenetrating polymer networks (IPNs) into rabbit corneas. The first (Implant 1) was based on PEG diacrylate, the second (Implant 2) was based on PEG-diacrylamide. There were inserted into deep stromal pockets created using a manual surgical technique for either 3 or 6 months. The implanted corneas were compared with normal and sham operated corneas through slit lamp observation, anterior segment optical coherence tomography, in vivo confocal scanning and histological examination. Corneas with Implant 1 (based on PEG-diacrylate) developed diffuse haze, ulcers and opacities within 3 months, while corneas with Implant 2 (based on PEG diacrylamide) remained clear at 6 months. They also exhibited normal numbers of epithelial cell layers, without any immune cell infiltration, inflammation, oedema or neovascularisation at post-operative 6 month. Morphological studies showed transient epithelial layer thinning over the hydrogel inserted area and elevated keratocyte activity at 3 months; however, the epithelium thickness and keratocyte morphology were improved at 6 months. Implant 2 exhibited superior in vivo biocompatibility and higher optical clarity than Implant 1. PEG-diacrylamide based IPN hydrogel is therefore a potential candidate for corneal inlays to correct refractive error. PMID- 23354738 TI - Effects of two low-shrinkage composites on dental stem cells (viability, cell damaged or apoptosis and mesenchymal markers expression). AB - To investigate the effects of new two low-shrinkage composites SDR((r)) and Venus((r))Bulk Fill on the cell viability, cellular damage and expression of mesenchymal markers on dental stem cells. Specimens from two low-shrinkage composites were eluted with culture medium for 24 h. After 24 h of incubation, cytotoxicity of elutes were evaluated by MTT assay; apoptosis was determined using the DNA-specific fluorochrome Hoechst 33342 and the mesenchymal stem cells markers expression was analyzed by immunofluorescence staining. After 24 h of cell exposure to each extract media, dental stem cells expressed MSCs markers. The interaction among the material and cell line was not significantly correlated [F(1,60) = 2.251, P = 0.39], whereas statistically significant differences among cells lines were observed [F(1,60) = 9.157, P = 0.004], being dental pulp stem cells more resistant that periodontal ligament stem cells. Also, we did not find any significant effect between the tested materials [F(1,60) = 0.090, P = 0.765]. Furthermore, a very low proportion of exposed cells showed condensed or fragmented nuclei, typical of apoptotic cells at 24 h. The results suggest that SDR((r)) and Venus((r)) Bulk fill and should be considered when selecting an appropriate resin-based dental restorative material. PMID- 23354739 TI - Magnetoelastic vibrational biomaterials for real-time monitoring and modulation of the host response. AB - Magnetoelastic (ME) biomaterials are ferromagnetic materials that physically deform when exposed to a magnetic field. This work describes the real-time control and monitoring capabilities of ME biomaterials in wound healing. Studies were conducted to demonstrate the capacity of the materials to monitor changes in protein adsorption and matrix stiffness. In vitro experiments demonstrated that ME biomaterials can monitor cell adhesion and growth in real-time, and a long term in vivo study demonstrated their ability to monitor the host response (wound healing) to an implant and control local cell density and collagen matrix production at the soft tissue-implant interface. This approach represents a potentially self-aware and post-deployment activated biomaterial coating as a means to monitor an implant surface and provide an adjuvant therapy for implant fibrosis. PMID- 23354740 TI - [Validity of Recommendations for Secondary Prevention of Colon Cancer]. AB - BACKGROUND: Prevention programmes should only be recommended if they achieve what they promise to achieve. Therefore, we checked the variation and validity of recommendations for screening for colorectal cancer of nine organisations. METHODS: We analysed the information concerning recommended screening age, guaiac faecal occult blood test (gFOBT), faecal immunological test (FIT), faecal DNA test, sigmoidoscopy, colonoscopy, double-contrast examination/double-contrast barium enema, and virtual colonoscopy/CT colonography in the following three steps: 1) we gathered the references quoted by the nine organisations; 2) references were categorised according to mortality, incidence and sensitivity/specificity; 3) the validity of references that reported reduced mortality attributed to screening were evaluated. RESULTS: Evidence of occult faecal blood was the only screening method recommended by all nine organisations. Colonoscopy was recommended by seven organisations. Fifteen of the 33 references used endpoints other than mortality to justify screening. One publication was a meta-analysis. Eleven of 17 publications evaluated the gFOBT, three evaluated sigmoidoscopy, one FIT, one coloscopy, and one general diagnosis of the intestine. On average, two of nine validity criteria were completely fulfilled, five only partially, and two were not fulfilled. In two publications, none of the validity criteria were completely met. CONCLUSION: Analysis of screening for colorectal cancer revealed that nine organisations had different goals and different recommendations. Scrupulous and thorough evaluation of the scientific studies in relation to mortality, upon which these recommendations are based, revealed numerous shortcomings and therefore could not sufficiently substantiate the international recommendations for screening for colorectal cancer. It would be useful to establish a consensus about which data have to be collected to provide a reliable basis for health-care decisions. PMID- 23354742 TI - Deep remission in inflammatory bowel disease: looking beyond symptoms. AB - Inflammatory bowel diseases (IBD) are chronic and disabling conditions. Accumulating evidence indicates that we need to look beyond clinical symptoms as current therapeutic strategies have not modified the course of IBD. Therapeutic goals for IBD have evolved from a mere control of symptoms to mucosal healing (MH). Achieving deep remission (clinical remission, biomarker remission and MH) might be the only way to alter disease course in IBD patients. In Crohn's disease (CD), deep remission has been recently defined as Crohn's Disease Activity Index <150 and complete MH. In ulcerative colitis (UC), there is no proposed definition of deep remission. It could be defined as clinical and endoscopic remission in UC. These definitions remain to be validated in large prospective studies. In the near future, the concept of deep remission might include transmural healing in CD and histologic healing in UC. Advances in drug development have provided highly effective treatments for IBD, making deep remission a realistic goal. Whether IBD patients may benefit by experiencing a 'deep' remission beyond the control of clinical symptoms, which might ultimately impact on important outcomes such as the need for surgery and the development of disability, needs to be evaluated in future disease modification trials. PMID- 23354743 TI - Microtensile bond strength analysis of adhesive systems to Er:YAG and Er,Cr:YSGG laser-treated dentin. AB - The aim of this in vitro study was to evaluate the effect of different surface treatments (control, diamond bur, erbium-doped yttrium aluminum garnet (Er:YAG) laser, and erbium, chromium:yttrium-scandium-gallium-garnet (Er,Cr:YSGG) laser) on sound dentin surface morphology and on microtensile bond strength (MUTBS). Sixteen dentin fragments were randomly divided into four groups (n = 4), and different surface treatments were analyzed by scanning electron microscopy. Ninety-six third molars were randomly divided into eight groups (n = 12) according to type of surface treatment and adhesive system: G1 = Control + Clearfil SE Bond (SE); G2 = Control + Single Bond (SB); G3 = diamond bur (DB) + SE; G4 = DB + SB, G5 = Er:YAG laser (2.94 MUm, 60 mJ, 2 Hz, 0.12 W, 19.3 J/cm(2)) + SE; G6 = Er:YAG + SB, G7 = Er,Cr:YSGG laser (2.78 MUm, 50 mJ, 30 Hz, 1.5 W, 4.5 J/cm(2)) + SE; and G8 = Er,Cr:YSGG + SB. Composite blocks were bonded to the samples, and after 24-h storage in distilled/deionized water (37 degrees C), stick-shaped samples were obtained and submitted to MUTBS test. Bond strength values (in megapascal) were analyzed by two-way ANOVA and Tukey tests (alpha = 0.05). G1 (54.69 +/- 7.8 MPa) showed the highest mean, which was statistically significantly higher than all the other groups (p < 0.05). For all treatments, SE showed higher bond strength than SB, except only for Er,Cr:YSGG treatment, in which the systems did not differ statistically from each other. Based on the irradiation parameters considered in this study, it can be concluded that Er:YAG and Er,Cr:YSGG irradiation presented lower values than the control group; however, their association with self-etching adhesive does not have a significantly negative effect on sound dentin (MUTBS values of >20 MPa). PMID- 23354744 TI - Regulation, integrase-dependent excision, and horizontal transfer of genomic islands in Legionella pneumophila. AB - Legionella pneumophila is a Gram-negative freshwater agent which multiplies in specialized nutrient-rich vacuoles of amoebae. When replicating in human alveolar macrophages, Legionella can cause Legionnaires' disease. Recently, we identified a new type of conjugation/type IVA secretion system (T4ASS) in L. pneumophila Corby (named trb-tra). Analogous versions of trb-tra are localized on the genomic islands Trb-1 and Trb-2. Both can exist as an episomal circular form, and Trb-1 can be transferred horizontally to other Legionella strains by conjugation. In our current work, we discovered the importance of a site-specific integrase (Int 1, lpc2818) for the excision and conjugation process of Trb-1. Furthermore, we identified the genes lvrRABC (lpc2813 to lpc2816) to be involved in the regulation of Trb-1 excision. In addition, we demonstrated for the first time that a Legionella genomic island (LGI) of L. pneumophila Corby (LpcGI-2) encodes a functional type IV secretion system. The island can be transferred horizontally by conjugation and is integrated site specifically into the genome of the transconjugants. LpcGI-2 generates three different episomal forms. The predominant episomal form, form A, is generated integrase dependently (Lpc1833) and transferred by conjugation in a pilT-dependent manner. Therefore, the genomic islands Trb-1 and LpcGI-2 should be classified as integrative and conjugative elements (ICEs). Coculture studies of L. pneumophila wild-type and mutant strains revealed that the int-1 and lvrRABC genes (located on Trb-1) as well as lpc1833 and pilT (located on LpcGI-2) do not influence the in vivo fitness of L. pneumophila in Acanthamoeba castellanii. PMID- 23354745 TI - Two roles for aconitase in the regulation of tricarboxylic acid branch gene expression in Bacillus subtilis. AB - Previously, it was shown that an aconitase (citB) null mutation results in a vast overaccumulation of citrate in the culture fluid of growing Bacillus subtilis cells, a phenotype that causes secondary effects, including the hyperexpression of the citB promoter. B. subtilis aconitase is a bifunctional protein; to determine if either or both activities of aconitase were responsible for this phenotype, two strains producing different mutant forms of aconitase were constructed, one designed to be enzymatically inactive (C450S [citB2]) and the other designed to be defective in RNA binding (R741E [citB7]). The citB2 mutant was a glutamate auxotroph and accumulated citrate, while the citB7 mutant was a glutamate prototroph. Unexpectedly, the citB7 strain also accumulated citrate. Both mutant strains exhibited overexpression of the citB promoter and accumulated high levels of aconitase protein. These strains and the citB null mutant also exhibited increased levels of citrate synthase protein and enzyme activity in cell extracts, and the major citrate synthase (citZ) transcript was present at higher-than-normal levels in the citB null mutant, due at least in part to a >3 fold increase in the stability of the citZ transcript compared to the wild type. Purified B. subtilis aconitase bound to the citZ 5' leader RNA in vitro, but the mutant proteins did not. Together, these data suggest that wild-type aconitase binds to and destabilizes the citZ transcript in order to maintain proper cell homeostasis by preventing the overaccumulation of citrate. PMID- 23354746 TI - Activation of sarX by Rbf is required for biofilm formation and icaADBC expression in Staphylococcus aureus. AB - A major constituent of many Staphylococcus aureus biofilms is a polysaccharide known as the polysaccharide intercellular adhesin, or poly N-acetylglucosamine (PIA/PNAG). PIA/PNAG is synthesized by the 4 gene products of the icaADBC operon, which is negatively regulated by the divergently transcribed icaR gene. We previously reported the identification of a gene, rbf, involved in the positive transcriptional regulation of icaADBC transcription by repressing icaR in S. aureus strain 8325-4. However, we were unable to show binding of Rbf to DNA upstream of icaR or icaA, suggesting that Rbf may control expression of an unknown factor(s) that, in turn, regulates ica expression. Here we report that the unknown factor is SarX protein. Results from epistasis assays and genetic complementation analyses suggest that Rbf upregulates SarX, which then downregulates IcaR, thereby activating icaADBC. Electrophoretic mobility shift assays revealed that SarX protein bound to a sequence upstream of icaR within the icaA coding region. Cross-linking and immunoprecipitation experiments further suggested that Rbf binds to the sarX promoter in S. aureus. These results demonstrate that Rbf and SarX represent a regulatory cascade that promotes PIA dependent biofilm formation in S. aureus. PMID- 23354747 TI - A novel 3-sulfinopropionyl coenzyme A (3SP-CoA) desulfinase from Advenella mimigardefordensis strain DPN7T acting as a key enzyme during catabolism of 3,3' dithiodipropionic acid is a member of the acyl-CoA dehydrogenase superfamily. AB - 3-Sulfinopropionyl coenzyme A (3SP-CoA) desulfinase (AcdDPN7) is a new desulfinase that catalyzes the sulfur abstraction from 3SP-CoA in the betaproteobacterium Advenella mimigardefordensis strain DPN7(T). During investigation of a Tn5::mob-induced mutant defective in growth on 3,3' dithiodipropionate (DTDP) and also 3-sulfinopropionate (3SP), the transposon insertion was mapped to an open reading frame with the highest homology to an acyl-CoA dehydrogenase (Acd) from Burkholderia phenoliruptrix strain BR3459a (83% identical and 91% similar amino acids). An A. mimigardefordensis Deltaacd mutant was generated and verified the observed phenotype of the Tn5::mob-induced mutant. For enzymatic studies, AcdDPN7 was heterologously expressed in Escherichia coli BL21(DE3)/pLysS by using pET23a::acdDPN7. The purified protein is yellow and contains a noncovalently bound flavin adenine dinucleotide (FAD) cofactor, as verified by high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS) analyses. Size-exclusion chromatography revealed a native molecular mass of about 173 kDa, indicating a homotetrameric structure (theoretically 179 kDa), which is in accordance with other members of the acyl CoA dehydrogenase superfamily. In vitro assays unequivocally demonstrated that the purified enzyme converted 3SP-CoA into propionyl-CoA and sulfite (SO3(2-)). Kinetic studies of AcdDPN7 revealed a Vmax of 4.19 MUmol min(-1) mg(-1), an apparent Km of 0.013 mM, and a kcat/Km of 240.8 s(-1) mM(-1) for 3SP-CoA. However, AcdDPN7 is unable to perform a dehydrogenation, which is the usual reaction catalyzed by members of the acyl-CoA dehydrogenase superfamily. Comparison to other known desulfinases showed a comparably high catalytic efficiency of AcdDPN7 and indicated a novel reaction mechanism. Hence, AcdDPN7 encodes a new desulfinase based on an acyl-CoA dehydrogenase (EC 1.3.8.x) scaffold. Concomitantly, we identified the gene product that is responsible for the final desulfination step during catabolism of 3,3'-dithiodipropionate (DTDP), a sulfur-containing precursor substrate for biosynthesis of polythioesters. PMID- 23354749 TI - Enterotoxigenic Escherichia coli CS1 pilus: not one structure but several. PMID- 23354748 TI - AmrZ modulates Pseudomonas aeruginosa biofilm architecture by directly repressing transcription of the psl operon. AB - Pseudomonas aeruginosa strains recovered from chronic pulmonary infections in cystic fibrosis patients are frequently mucoid. Such strains express elevated levels of alginate but reduced levels of the aggregative polysaccharide Psl; however, the mechanistic basis for this regulation is not completely understood. Elevated pslA expression was observed in an amrZ null mutant and in strains expressing a DNA-binding-deficient AmrZ. AmrZ is a transcription factor that positively regulates twitching motility and alginate synthesis, two phenotypes involved in P. aeruginosa biofilm development. AmrZ bound directly to the pslA promoter in vitro, and molecular analyses indicate that AmrZ represses psl expression by binding to a site overlapping the promoter. Altered expression of amrZ in nonmucoid strains impacted biofilm structure and architecture, as structured microcolonies were observed with low AmrZ production and flat biofilms with amrZ overexpression. These biofilm phenotypes correlated with Psl levels, since we observed elevated Psl production in amrZ mutants and lower Psl production in amrZ-overexpressing strains. These observations support the hypothesis that AmrZ is a multifunctional regulator mediating transition of P. aeruginosa biofilm infections from colonizing to chronic biofilms through repression of the psl operon while activating the algD operon. PMID- 23354750 TI - Identification of the mutation responsible for the temperature-sensitive lipopolysaccharide O-antigen defect in the Pseudomonas aeruginosa cystic fibrosis isolate 2192. AB - Pseudomonas aeruginosa in the lungs of cystic fibrosis (CF) patients is characterized by a series of genotypic and phenotypic changes that reflect the transition from acute to chronic infection. These include the overproduction of the exopolysaccharide alginate and the loss of complete lipopolysaccharide (LPS). LPS is a major component of the Gram-negative outer membrane and is composed of lipid A, core oligosaccharide, and O antigen. In this report, we show that the LPS defect of the P. aeruginosa chronic infection isolate 2192 is temperature sensitive. When grown at 25 degrees C, 2192 expresses serotype O1 LPS with a moderate chain length and in reduced amounts relative to those of a wild-type serotype O1 laboratory strain (stO1). In contrast, 2192 expresses no LPS O antigen when grown at 37 degrees C. This is the first time that a temperature sensitive defect in O-antigen production has been reported. Using complementation analyses with a constructed wbpM deletion mutant of stO1, we demonstrate that the temperature-sensitive O-antigen production defect in 2192 is due to a mutation in wbpM, which encodes a UDP-4,6-GlcNAc dehydratase involved in O-antigen synthesis. The mutation, a deletion of a single amino acid (V636) from the extreme C terminus of WbpM, renders the protein less stable than its wild-type counterpart. This residue of WbpM, which is critical for stability and function, is located outside of the recognized domains of the protein and may provide insight into the structure-function relationship of this enzyme, which is found in all 20 serotypes of P. aeruginosa. We also identify a promoter of wbpM, map a transcriptional start site of wbpM, and show that mucoidy plays a role in the loss of expression of high-molecular-weight LPS in this CF isolate. PMID- 23354751 TI - The HtrA protease of Streptococcus pneumoniae controls density-dependent stimulation of the bacteriocin blp locus via disruption of pheromone secretion. AB - All fully sequenced strains of Streptococcus pneumoniae (pneumococcus) contain a version of the blp locus which is responsible for the regulation and secretion of a variable repertoire of pneumococcal bacteriocins called pneumocins and their associated immunity proteins. Pneumocins mediate intra- and interspecies competition in vitro and have been shown to provide a competitive advantage in vivo. Pneumocin production is stimulated by extracellular accumulation of the peptide pheromone, BlpC. Both BlpC and the functional pneumocins are secreted out of the cell via the Blp transporter, BlpAB. The conserved surface-expressed serine protease, HtrA, has been shown to limit activation of the locus and secretion of functional pneumocins. In this work, we demonstrate that htrA mutants stimulate the blp locus at lower cell density and to a greater extent than strains expressing wild-type HtrA. This effect is not due to direct proteolytic degradation of secreted pheromone by the protease, but instead is a result of HtrA-mediated disruption of peptide processing and secretion. Because pneumocins are secreted through the same transporter as the pheromone, this finding explains why pheromone supplementation cannot completely restore pneumocin inhibition to strains expressing high levels of HtrA despite restoration of blp transcriptional activity. HtrA restricts pneumocin production to high cell density by limiting the rate of accumulation of BlpC in the environment. Importantly, HtrA does not interfere with the ability of a strain to sense environmental pheromones, which is necessary for the induction of protective immunity in the face of pneumocin-secreting competitors. PMID- 23354752 TI - Biochemical properties of MutT2 proteins from Mycobacterium tuberculosis and M. smegmatis and their contrasting antimutator roles in Escherichia coli. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis, is at increased risk of accumulating damaged guanine nucleotides such as 8-oxo-dGTP and 8-oxo-GTP because of its residency in the oxidative environment of the host macrophages. By hydrolyzing the oxidized guanine nucleotides before their incorporation into nucleic acids, MutT proteins play a critical role in allowing organisms to avoid their deleterious effects. Mycobacteria possess several MutT proteins. Here, we purified recombinant M. tuberculosis MutT2 (MtuMutT2) and M. smegmatis MutT2 (MsmMutT2) proteins from M. tuberculosis (a slow grower) and M. smegmatis (fast growing model mycobacteria), respectively, for their biochemical characterization. Distinct from the Escherichia coli MutT, which hydrolyzes 8-oxo dGTP and 8-oxo-GTP, the mycobacterial proteins hydrolyze not only 8-oxo-dGTP and 8-oxo-GTP but also dCTP and 5-methyl-dCTP. Determination of kinetic parameters (Km and Vmax) revealed that while MtuMutT2 hydrolyzes dCTP nearly four times better than it does 8-oxo-dGTP, MsmMutT2 hydrolyzes them nearly equally. Also, MsmMutT2 is about 14 times more efficient than MtuMutT2 in its catalytic activity of hydrolyzing 8-oxo-dGTP. Consistent with these observations, MsmMutT2 but not MtuMutT2 rescues E. coli for MutT deficiency by decreasing both the mutation frequency and A-to-C mutations (a hallmark of MutT deficiency). We discuss these findings in the context of the physiological significance of MutT proteins. PMID- 23354753 TI - Streptococcus pneumoniae folate biosynthesis responds to environmental CO2 levels. AB - Although carbon dioxide (CO2) is known to be essential for Streptococcus pneumoniae growth, it is poorly understood how this respiratory tract pathogen adapts to the large changes in environmental CO2 levels it encounters during transmission, host colonization, and disease. To identify the molecular mechanisms that facilitate pneumococcal growth under CO2-poor conditions, we generated a random S. pneumoniae R6 mariner transposon mutant library representing mutations in 1,538 different genes and exposed it to CO2-poor ambient air. With Tn-seq, we found mutations in two genes that were involved in S. pneumoniae adaptation to changes in CO2 availability. The gene pca, encoding pneumococcal carbonic anhydrase (PCA), was absolutely essential for S. pneumoniae growth under CO2-poor conditions. PCA catalyzes the reversible hydration of endogenous CO2 to bicarbonate (HCO3(-)) and was previously demonstrated to facilitate HCO3(-)-dependent fatty acid biosynthesis. The gene folC that encodes the dihydrofolate/folylpolyglutamate synthase was required at the initial phase of bacterial growth under CO2-poor culture conditions. FolC compensated for the growth-phase-dependent decrease in S. pneumoniae intracellular long-chain (n > 3) polyglutamyl folate levels, which was most pronounced under CO2-poor growth conditions. In conclusion, S. pneumoniae adaptation to changes in CO2 availability involves the retention of endogenous CO2 and the preservation of intracellular long-chain polyglutamyl folate pools. PMID- 23354755 TI - Impact assessment of dredging to remove coal fly ash at the Tennessee Valley Authority Kingston Fossil plant using fathead minnow elutriate exposures. AB - On December 22, 2008, failure of an earthen containment structure resulted in the release of approximately 4.1 million m(3) of coal fly ash into the Emory River and the surrounding area from the Tennessee Valley Authority Kingston Fossil Plant near Kingston, Tennessee, USA. The purpose of the present study was to assess the potential of dredging activities performed to remove the fly ash from the river to result in increased risk to pelagic fish, with special consideration of mobilization of metals. Elutriates were created using two sources of fly ash by bubbling with air over 10 d. This elutriate preparation method was designed to represent worst-case conditions for oxidation, metal release, and dissolution. Larval and juvenile Pimephales promelas underwent 10-d exposures to these elutriates. Larval end points included survival and biomass, and juvenile end points included survival, length, biomass, liver somatic index, and bioaccumulation. No significant toxicity was observed. Bioaccumulation of metals in juveniles was found to be primarily attributable to metals associated with particles in the gut. Results suggest little potential for toxicity to related fish species due to fly ash removal dredging activities given the extreme conditions represented by the elutriates in the present study. PMID- 23354754 TI - GenR, an IclR-type regulator, activates and represses the transcription of gen genes involved in 3-hydroxybenzoate and gentisate catabolism in Corynebacterium glutamicum. AB - The genes required for 3-hydroxybenzoate and gentisate catabolism in Corynebacterium glutamicum are closely clustered in three operons. GenR, an IclR type regulator, can activate the transcription of genKH and genDFM operons in response to 3-hydroxybenzoate and gentisate, and it can repress its own expression. Footprinting analyses demonstrated that GenR bound to four sites with different affinities. Two GenR-binding sites (DFMn01 and DFMn02) were found to be located between positions --41 and --84 upstream of the --35 and --10 regions of the genDFM promoter, which was involved in positive regulation of genDFM transcription. The GenR binding site R-KHn01 (located between positions --47 and -16) overlapped the --35 region of the genKH promoter sequence and is involved in positive regulation of its transcription. The binding site R-KHn02, at which GenR binds to its own promoter, was found within a footprint extending from position - 44 to --67. It appeared to be involved in negative regulation of the activity of the genR promoter. A consensus motif with a 5-bp imperfect palindromic sequence [ATTCC-N(7(5))-GGAAT] was identified among all four GenR binding sites and found to be necessary to GenR regulation through site-directed mutagenesis. The results reveal a new regulatory function of the IclR family in the catabolism of aromatic compounds. PMID- 23354756 TI - The mitochondrial transport protein SLC25A43 affects drug efficacy and drug induced cell cycle arrest in breast cancer cell lines. AB - The mitochondria have been identified as key players of apoptosis, cell proliferation and cell cycle regulation. However, the role of mitochondria in breast cancer and treatment failure remains unclear. We have previously shown a common deletion of the gene SLC25A43 in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This gene is coding for a mitochondrial inner membrane transporter and, to date, little is known about the function of this protein. We have also found that low protein expression of SLC25A43 significantly correlates with a lower S phase fraction in HER2-positive breast cancer. The aim of this study was to investigate whether knockdown (KD) of SLC25A43 could have an effect on the cytotoxicity of different cytostatic drugs using MCF10A, MCF7 and BT-474 cells. Following siRNA-mediated KD of SLC25A43, one non-malignant and two breast cancer cell lines were exposed to the anthracycline epirubicin or the taxane paclitaxel. The HER2-positive breast cancer cells were also exposed to the targeted therapy trastuzumab and dual exposure to trastuzumab and paclitaxel. We found that KD of SLC25A43 resulted in a decreased cytotoxic effect of paclitaxel in the two cancer cell lines (P<0.05). Further analysis of cell cycle phase distribution showed that KD increased the paclitaxel-induced G2/M block in these two cell lines (P<0.05). KD of SLC25A43 also reduced the inhibitory effect of trastuzumab on cell proliferation in the HER2-positive cancer cell line BT-474 (P<0.05), and the drug-induced G0/G1 block (P<0.05). Moreover, SLC25A43 influenced the percentage of Ki-67-positive cells. Our findings demonstrate that the mitochondrial protein SLC25A43 affects drug efficacy and cell cycle regulation following drug exposure in breast cancer cell lines. PMID- 23354757 TI - Examining the "evolution of increased competitive ability" hypothesis in response to parasites and pathogens in the invasive paper wasp Polistes dominula. AB - Successful invaders often become established in new ranges by outcompeting native species. The "evolution of increased competitive ability" hypothesis predicts that invasive species are subjected to less predation and parasitization than sympatric native species, and thus can allocate resources from defence and immunity to growth and fecundity, thereby achieving higher fitness. In this study, we examined whether American invasive Polistes dominula paper wasps have reduced immunocompetence. To explore this scenario, we tested their susceptibility towards parasites and pathogens at both the individual (immune defence) and colony levels, i.e. hygienic behaviour (removal of diseased individuals by nestmates). First, we examined the response to the specific coevolved parasite Xenos vesparum (lost after invasion) in terms of individual host susceptibility and hygienic behaviour. Second, we explored the response against general pathogens by quantifying the bacterial clearance in individual wasps after a challenge with Escherichia coli and hygienic behaviour after a challenge with the fungus Beauveria bassiana. Our results show that American invasive P. dominula have a higher response against X. vesparum at the colony level, but at the individual level their susceptibility is not significantly different from conspecifics of the native range. On the other hand, invasive P. dominula display lower response after a challenge with general pathogens at both the individual and colony levels. While supporting the hypothesis of a reduction of immunocompetence towards general pathogens in invasive species, these findings also suggest that the response against coevolved parasites might follow different evolutionary pathways which are not always easily predictable. PMID- 23354758 TI - Optimal foraging, not biogenetic law, predicts spider orb web allometry. AB - The biogenetic law posits that the ontogeny of an organism recapitulates the pattern of evolutionary changes. Morphological evidence has offered some support for, but also considerable evidence against, the hypothesis. However, biogenetic law in behavior remains underexplored. As physical manifestation of behavior, spider webs offer an interesting model for the study of ontogenetic behavioral changes. In orb-weaving spiders, web symmetry often gets distorted through ontogeny, and these changes have been interpreted to reflect the biogenetic law. Here, we test the biogenetic law hypothesis against the alternative, the optimal foraging hypothesis, by studying the allometry in Leucauge venusta orb webs. These webs range in inclination from vertical through tilted to horizontal; biogenetic law predicts that allometry relates to ontogenetic stage, whereas optimal foraging predicts that allometry relates to gravity. Specifically, pronounced asymmetry should only be seen in vertical webs under optimal foraging theory. We show that, through ontogeny, vertical webs in L. venusta become more asymmetrical in contrast to tilted and horizontal webs. Biogenetic law thus cannot explain L. venusta web allometry, but our results instead support optimization of foraging area in response to spider size. PMID- 23354759 TI - Social learning of an associative foraging task in zebrafish. AB - The zebrafish (Danio rerio) is increasingly becoming an important model species for studies on the genetic and neural mechanisms controlling behaviour and cognition. Here, we utilized a conditioned place preference (CPP) paradigm to study social learning in zebrafish. We tested whether social interactions with conditioned demonstrators enhance the ability of focal naive individuals to learn an associative foraging task. We found that the presence of conditioned demonstrators improved focal fish foraging behaviour through the process of social transmission, whereas the presence of inexperienced demonstrators interfered with the learning of the control focal fish. Our results indicate that zebrafish use social learning for finding food and that this CPP paradigm is an efficient assay to study social learning and memory in zebrafish. PMID- 23354760 TI - Surgical pocket location for gluteal implants: a systematic review. AB - BACKGROUND: The safest pocket location for gluteal augmentation surgery using implants still is unknown. This study conducted a systematic review to derive evidence-based recommendations concerning the safest type of pocket location (sub muscular, subfascial, intramuscular, or intramuscular XYZ method) for silicone implants in terms of acute and long-term complication rates. METHODS: Articles from medline that met predetermined criteria were included in the study. The outcomes of interest included wound dehiscence, wound infection, seroma, hematoma, implant asymmetry, and capsular contracture. Pooling of statistical data was performed when possible. RESULTS: The authors reviewed 30 articles regarding five different types of pocket locations for gluteal implants described since 1969. The most common complications after gluteal augmentation surgery using implants are wound dehiscence (10.29%), seroma (2.49%), wound infection (1.12%), and hematoma (0.24%). Fulfilled expectations after surgery were assessed differently among studies and could not be compared. CONCLUSIONS: The pocket locations for gluteal augmentation surgery with implants that have the lowest complication rates are the following: intramuscular XZY method (13.18%), sub muscular (17.60%), intramuscular (18.05%), and subfascial (54.84%). LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23354762 TI - Muscle-splitting, subglandular, and partial submuscular augmentation mammoplasties: a 12-year retrospective analysis of 2026 primary cases. AB - BACKGROUND: Augmentation mammoplasty is a commonly performed procedure with a very high satisfaction rate. Various techniques have been described since the report of the first augmentation mammoplasty in 1963. Muscle-splitting augmentation mammoplasty, a technique first published in 2007, has been used by the author for primary and secondary augmentation mammoplasties and for mastopexy with augmentation. METHODS: A retrospective analysis of data prospectively collected using the Excel spreadsheet was performed. The patients were divided into three groups. The mammoplasty for group A used the subglandular pocket. In group B, the partial submuscular pocket was used for mammoplasties. Both of these groups had their mammoplasties performed between 1999 and 2005. Group C, the third group, included patients who had muscle-splitting mammoplasties between 2005 and 2011. RESULTS: Group A involved 793 patients who had their augmentation mammoplasties in the subglandular pocket. Of these 793 patients, 751 had the same size implants and were included in the analysis. The mean age of the patients in group A was 30.9+/-7.98 years (range 18-59 years), and their mean implant size was 317.5 cc+/-2.05 (range 200-555). In group A, 45.1% (n=339) of the patients were smokers, and 62.2% (n=467) had drains. The majority of the patients (78%) had an overnight stay in the clinic. Hematoma was seen in 2.7% (n=20) of the group A patients. Revision was performed for 6% (n=45). Periprosthetic infection was seen in 0.4% (n=3) and minor wound healing problems in 1.3% (n=10). Group B comprised 110 patients who had mammoplasties performed in partial submuscular pockets. All the patients had the same size implants. The mean age of the group B patients was 33+/-8.26 years (range 20-58 years), and their mean implant size was 300.6 cc+/-35.92 (range 205-395). Of these 110 patients, 51.8% (n=57) were smokers, and 94.5% (n=104) had drains. Hematoma was seen in 1.8% (n=2), and revision was performed for 7.3% (n=8) in the submuscular subgroup. Infection was seen in 3.6% (n=4) and minor wound healing problems in 4.5% (n=5). Group C consisted of 1,123 patients who had breast augmentation in the muscle-splitting biplane. Of these 1,123 patients, 914 had the same size implants. The mean age of the patients was 30.0+/-8.78 years (range 18-67 years), and their mean implant size was 338.2 cc+/-58.01 (range 170-655). In group C, 33.6% of the patients were smokers, and 8 % had drains. The majority of the patients (93.4%) were treated as day cases. Hematoma was seen in 0.7%, and 1.2% of the patients had revision surgery. Infection was seen in 1.6% (n=15) and minor wound healing in 4% (n=45). CONCLUSION: Muscle-splitting mammoplasty is a technique that can be performed as a day case without drains. The overall complications in the group were significantly lower than with the other two techniques performed by the author. LEVEL OF EVIDENCE IV: This journal requires that authors assign a 41 level of evidence to each article. For a full description of 42 these Evidence-Based Medicine ratings, please refer to the 43 Table of Contents or the online Instructions to Authors 44 http://www.springer.com/00266 . PMID- 23354761 TI - Silicone lymphadenopathy after breast augmentation: case reports, review of the literature, and current thoughts. AB - BACKGROUND: Silicone lymphadenopathy after implantation of silicone breast implants is a foreign body reaction due to the release or migration of silicone into the tissues surrounding the breast implant. METHODS: For the study, 14 cases of silicone lymphadenopathy were identified from the authors' files. Four patients had been implanted before 2000 and had various types of implants. The remaining 10 patients all were implanted between 2006 and 2009, and all had Poly Implant Prothese (PIP) implants. In addition to an analysis of the authors' own cases, a thorough bibliographic search was initiated to identify all reports of lymphadenopathy related to silicone breast implants. RESULTS: The implant age of the four patients implanted before 2000 was 12-34 years (mean, 17.25 years). The implant age of the 10 patients implanted after 2000 was 2-6 years (mean 3.45 years). The literature search identified 29 papers with case reports of silicone lymphadenopathy published between 1978 and 2012, with a total of 175 cases. Usable data were extracted from 164 of the 175 cases. Of these patients, 159 were implanted before (and including) the year 2000 and had a mean age of 11 years at presentation or explantation, and 5 of these patients were implanted after the year 2000 and had a mean age of 4.6 years at presentation or explantation . After inclusion of the authors' own cases, the mean age of the implants at presentation or explantation was 10.56 years in a total of 178 cases. Of these patients, 163 were implanted before (and including) the year 2000 and had a mean age of 11.16 years at presentation or explantation, and 15 of these patients were implanted after the year 2000 and had a mean age of 4.06 years at presentation or explantation. CONCLUSIONS: Current breast implant technology has minimized the release of silicone gel due to rupture or bleeding of silicone and its migration into the surrounding tissues, thus reducing the rate of silicone lymphadenopathy in the last 10 years. The PIP implant scandal highlights the fact that disregard for the implant manufacturing technologies and standards in favor of higher profits increased rupture rates and gel diffusion, leading to increased local complication rates. Silicone lymphadenopathy is a foreign body reaction that does not warrant treatment unless it is symptomatic or interferes with breast cancer detection. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23354763 TI - Laser lipolysis using a 924- and 975-nm laser diode in the lower extremities. AB - BACKGROUND: Laser technology provides the desired destruction of adipose tissue, hemostasis, and good skin retraction with a minimum of discomfort and a quick return to normal life for the patient. Here we present our experience with the use of laser-assisted liposuction (LAL) with a 924- and 975-nm laser diode and compare it with traditional liposuction alone. METHODS: A total of 430 patients were reviewed for this study. Three hundred thirty patients were treated with the 924- and 975-nm laser diode for laser lipolysis and 100 patients were treated with traditional liposuction of the anterior and inner thigh, the knee, the calf, and the trochanter. Patients were assessed by means of ultrasound. Pictures were taken and the degree of satisfaction was assessed. All complications were recorded. RESULTS: A total of 521 laser lipolysis procedures were performed at different areas: anterior thigh (86), inner thigh (122), trochanter (204), knee (67), and calf (42). The mean energy was area-dependent and evaluated in kJ: anterior thigh (15), inner thigh (14), trochanter (22), knee (5), and calf (4.5). The mean reduction of subcutaneous tissue with LAL in the anterior part of the thigh, the inner thigh, the calf, the knees, and the trochanter was 1.45, 1.9, 1.15, 1.2, and 3.6 cm, respectively. One hundred traditional liposuction procedures were performed for different areas: anterior thigh (27), inner thigh (38), trochanter (72), knee (21), and calf (12). The mean reduction of subcutaneous tissue in the anterior part of the thigh, the inner thigh, the calf, the knees, and the trochanter was 1.2, 1.6, 0.9, 0.6, and 3.2 cm, respectively. All patients who underwent LAL had superior satisfaction compared to those who had liposuction alone. CONCLUSION: Laser lipolysis with 924- and 975-nm diodes is adequate treatment for removal of adipose deposits and to obtain aesthetically good skin results, with a minimum of recovery time and high patient satisfaction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23354764 TI - Autologous fat transplantation: volumetric tools for estimation of volume survival. A systematic review. AB - Autologous fat transplantation has gained great recognition in aesthetic and reconstructive surgery. Two main aspects are of predominant importance for progress control after autologous fat transplantation to the breast: quantitative information about the rate of fat survival in terms of effective volume persistence and qualitative information about the breast tissue to exclude potential complications of autologous fat transplantation. There are several tools available for use in evaluating the rate of volume survival. They are extensively compared in this review. The anthropometric method, thermoplastic casts, and Archimedes' principle of water displacement are not up to date anymore because of major drawbacks, first and foremost being reduced reproducibility and exactness. They have been replaced by more exact and reproducible tools such as MRI volumetry or 3D body surface scans. For qualitative and quantitative progress control, MRI volumetry offers all the necessary information: evaluation of fat survival and diagnostically valuable imaging to exclude possible complications of autologous fat transplantation. For frequent follow-up, e.g., monthly volume analysis, repeated MRI exams would not be good for the patient and are not cost effective. In these cases, 3D surface imaging is a good tool and especially helpful in a private practice setting where fast data acquisition is needed. This tool also offers the possibility of simulating the results of autologous fat transplantation. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23354765 TI - Columella lengthening by a vascularized preauricular flap. AB - BACKGROUND: A short columella can result in significant cosmetic and functional deformities. Various techniques such as local flap transfer and composite grafts have been reported for columellar lengthening, but the overall results remain unsatisfactory. Transferring a local flap cannot provide new tissue for the columella, which limits its application. Composite grafting can provide new tissue volume, and the composite tissue from the preauricular region has an excellent color and texture match. However, the lack of a stable blood supply for the composite graft restricts its clinical application due to problems such as viability, dimensions, and atrophy. To overcome these limitations, the authors harvested a vascularized preauricular flap for columella lengthening. METHODS: Based on the superficial temporal vessels, the vascularized preauricular flap was harvested as a free flap and transferred to the columella region. The recipient vessels were angular vessels or facial vessels, and microsurgical anastomosis was performed between recipient vessels and the pedicle. The lateral femoral circumflex vessels were used as vascular grafts when the pedicle was not long enough. RESULTS: Eight patients who had short columellas were reconstructed with vascularized preauricular flaps. Six flaps were harvested in a reverse fashion, and the remaining two flaps were harvested in an anterograde direction. All the flaps survived well and showed a good color and texture match without hypertrophic scars. An average of 13.3 mm improvement in length was obtained for the eight patients. Two patients underwent a secondary debulking procedure to thin the flap. CONCLUSION: The free vascularized preauricular flap procedure is a reliable method for columellar lengthening and has wide clinical application. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23354766 TI - Trans-nipple double Z-plasty for benign periareolar disease with inverted nipple. AB - BACKGROUND: Various surgical procedures have been reported for correction of inverted nipples. The authors herein report a new procedure, "the trans-nipple double Z-plasty," for correction of inverted nipples combined with periareolar disease requiring excision. METHODS: From July 2010 to June 2012, 11 unilateral inverted nipples with other benign periareolar diseases were treated with this technique. A midline incision and 5-mm Z-incisions were designed on the nipple areola complex toward the direction of the combined breast disease. After removal of combined benign disease through the trans-nipple double Z-plasty incision, the defect was filled with surrounding breast tissue, and the inverted nipple was corrected. RESULTS: One case of partial necrosis improved with conservative treatment. No recurrence was reported during the follow-up period. Five patients each assessed the cosmetic result as excellent and good. CONCLUSION: The trans nipple double Z-plasty is an easy and useful technique for simultaneous management of periareolar disease with an inverted nipple. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23354767 TI - Breast reconstruction after mastectomy for gestational gigantomastia. AB - BACKGROUND: Gestational gigantomastia (GGM) is a rare complication of pregnancy. Management usually is initiated with bromocriptine. If this is unsuccessful, surgery may be required. The surgical management may be by breast reduction or by mastectomy and delayed reconstruction. CASE: A 24-year-old woman (G1P0) presented at 24 weeks gestation with massive hypertrophy of her breasts. A decision to operate was made by a multidisciplinary team. At 30 weeks gestation, bilateral mastectomies were performed, with removal of more than 8 kg per side. Reconstruction was started 10 months after delivery using tissue expanders followed by definitive implants. CONCLUSION: GGM can be successfully reconstructed. Knowledge of the treatment process and the expected outcomes can help clinicians inform their patients. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23354768 TI - Current management of microtia: a national survey. AB - BACKGROUND: Microtia reconstruction remains one of the most challenging procedures encountered by the reconstructive surgeon. A national report on the current management of microtia has never been presented before. The purpose of this project was to survey members of the American Society of Plastic Surgeons (ASPS) to identify their preferences and practices and report their opinions regarding issues related to microtia reconstruction. METHODS: An anonymous web based survey consisting of 19 questions was distributed to the members of the ASPS. Questions focused on the management of microtia. The study design was descriptive, using categorical data analysis. RESULTS: Thirty-eight percent of all respondents perform microtia reconstruction; 91 % learned the autogenous cartilage-based reconstruction technique, while only 16 % were exposed to alloplastic reconstruction. Seventy percent of all respondents learned autogenous cartilage-based ear reconstruction exclusively. Fifty percent of respondents who perform microtia reconstruction reported a steep learning curve. In the pediatric patient population, 49 % of microtia surgeons prefer performing the surgery when the patient is between 7 and 10 years of age, while 40 % of microtia surgeons prefer the patient to be 4-6 years of age. Fifty-nine percent of all respondents believe that in 15 years tissue engineering will represent the gold standard of microtia reconstruction. CONCLUSION: Staged microtia repair using autogenous cartilage remains the heavily favored method of microtia reconstruction among plastic surgeons. Moreover, there is a deficiency in training the newer surgical techniques, such as alloplastic and osseointegrated options. This study also highlights the continuing need to elucidate the optimal timing for microtia repair in the pediatric patient to mitigate the potential psychosocial morbidity well described in the literature. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23354771 TI - Prevalence of upper gastrointestinal symptoms and their influence on nutritional state and performance status in patients with different primary tumors receiving palliative care. AB - The aim of this study was to investigate the relationship between gastrointestinal symptoms, nutritional balance, and performance status in patients receiving palliative care for advanced cancers originating in different sites. We studied a total of 105 patients. Upper gastrointestinal symptoms, Eastern Cooperative Oncology Group Performance Status score (ECOG-PS), dietary intakes, anthropometric measures, and some serum proteins were determined. Unintentional weight loss, alterations in anthropometric measures, and highest number of symptoms were greater in patients with lung and stomach cancer. No differences were found in ECOG-PS according to cancer site. Patients with gastric or lung cancer have most evidence of protein-calorie malnutrition and a higher prevalence of upper gastrointestinal symptoms. The performance status is not affected by tumor site. Early nutritional support should be planned for all patients with cancer, especially for patients with gastric or lung cancer. PMID- 23354770 TI - Rapid vaccination using an acetalated dextran microparticulate subunit vaccine confers protection against triplicate challenge by bacillus anthracis. AB - PURPOSE: A rapid immune response is required to prevent death from Anthrax, caused by Bacillus anthracis. METHOD: We formulated a vaccine carrier comprised of acetalated dextran microparticles encapsulating recombinant protective antigen (rPA) and resiquimod (a toll-like receptor 7/8 agonist). RESULTS: We were able to protect against triplicate lethal challenge by vaccinating twice (Days 0, 7) and then aggressively challenging on Days 14, 21, 28. A significantly higher level of antibodies was generated by day 14 with the encapsulated group compared to the conventional rPA and alum group. Antibodies produced by the co-encapsulated group were only weakly-neutralizing in toxin neutralization; however, survival was not dependent on toxin neutralization, as all vaccine formulations survived all challenges except control groups. Post-mortem culture swabs taken from the hearts of vaccinated groups that did not produce significant neutralizing titers failed to grow B. anthracis. CONCLUSIONS: Results indicate that protective antibodies are not required for rapid protection; indeed, cytokine results indicate that T cell protection may play a role in protection from anthrax. We report the first instance of use of a particulate carrier to generate a rapid protective immunity against anthrax. PMID- 23354772 TI - First trimester maternal serum inhibin A concentrations in smokers. PMID- 23354775 TI - Liver-specific p38alpha deficiency causes reduced cell growth and cytokinesis failure during chronic biliary cirrhosis in mice. AB - p38alpha mitogen-activated protein kinases (MAPK) may be essential in the up regulation of proinflammatory cytokines and can be activated by transforming growth factor beta, tumor necrosis factor-alpha, interleukin-1beta, and oxidative stress. p38 MAPK activation results in hepatocyte growth arrest, whereas increased proliferation has been considered a hallmark of p38alpha-deficient cells. Our aim was to assess the role of p38alpha in the progression of biliary cirrhosis induced by chronic cholestasis as an experimental model of chronic inflammation associated with hepatocyte proliferation, apoptosis, oxidative stress, and fibrogenesis. Cholestasis was induced in wildtype and liver-specific p38alpha knockout mice by bile duct ligation and animals were sacrificed at 12 and 28 days. p38alpha knockout mice exhibited a 50% decrease in mean life-span after cholestasis induction. MK2 phosphorylation was markedly reduced in liver of p38alpha-deficient mice upon chronic cholestasis. Hepatocyte growth was reduced and hepatomegaly was absent in p38alpha-deficient mice during chronic cholestasis through down-regulation of both AKT and mammalian target of rapamycin. Cyclin D1 and cyclin B1 were up-regulated in liver of p38alpha-deficient mice upon chronic cholestasis, but unexpectedly proliferating cell nuclear antigen was down regulated at 12 days after cholestasis induction and the mitotic index was very high upon cholestasis in p38alpha-deficient mice. p38alpha-knockout hepatocytes exhibited cytokinesis failure evidenced by an enhanced binucleation rate. As chronic cholestasis evolved the binucleation rate decreased in wildtype animals, whereas it remained high in p38alpha-deficient mice. CONCLUSION: Our results highlight a key role of p38alpha in hepatocyte proliferation, in the development of hepatomegaly, and in survival during chronic inflammation such as biliary cirrhosis. PMID- 23354776 TI - Interspinous spacers for lumbar foraminal stenosis: formal trials are justified. AB - PURPOSE: To determine whether preliminary evidence supports X-STOP implants as an effective treatment for lumbar radiculopathy secondary to foraminal stenosis, and if larger formal trials are warranted. METHODS: Participants had a clinical diagnosis of lumbar radiculopathy supported by MRI findings of foraminal stenosis and relevant nerve root compression. Self-reported disability and pain were measured pre-operation, early and late post-operation using the widely used Oswestry Disablity Index (ODI) and the bodily pain scale of the Medical Outcomes Study 36-item Short Form Health Survey (SF-36BP). The statistical significance (paired samples t test; Wilcoxon signed ranks test), and clinical significance (Cohen's effect size; Standardised response means) of change scores was determined. RESULTS: Fifteen people had X-STOP implants. Data pre- early- and late post-operation were available for ten. Self-reported disability and pain improved substantially by the early post operative measurement. Mean change scores (ODI = 29; SF-36BP = -45), significant at the p < 0.05 but not significant at the p < 0.001, were very large and effect sizes exceeded notably criteria for large clinical improvements (>0.80). Improvements were maintained at 2-3 years. Both scales had floor and ceiling effects implying changes may be underestimated. There were no surgical complications. CONCLUSIONS: In this small study, X-STOP appeared safe and effective. It is less invasive than other established surgical procedures, but does not jeopardise other options in the event of failure. Large scale clinical trials are justified but floor and ceiling effects suggest that the ODI and SF-36 may not be the best choice of outcome measures for those studies. PMID- 23354777 TI - VEPTR: past experience and the future of VEPTR principles. AB - PURPOSE: This review summarizes the experience with the vertical expandable prosthetic titanium rib (VEPTR) device, which enables five new procedures to treat complex spine and chest wall abnormalities in pediatric patients, which cause thoracic insufficiency syndrome, the inability of the thorax to support normal respiration or lung growth. METHODS: The literature on VEPTR was reviewed and discussed by the author, the inventor of the VEPTR. RESULTS: The central VEPTR treatment principle is to correct volume depletion deformity of the thorax, and maintain the correction until skeletal maturity, at which time procedures such as spinal fusion can be considered. For individual cases of complex deformity, VEPTR strategies can differ remarkably. The goal of VEPTR surgery is to pursue the surgical strategy that provides the largest, most symmetrical, most functional thorax that can grow as normally as possible. Assessment of these results is difficult, since natural history of VEPTR-treated diseases are not clearly known and no current imaging test can measure thoracic insufficiency syndrome, but dynamic lung MRI have promise for the future in better defining this potentially lethal condition. CONCLUSION: VEPTR and its principles of use have become an important first step toward improving the quality of life and longevity of children with thoracic insufficiency syndrome, but much work remains to advance both its design and its use. PMID- 23354778 TI - Prediction of sagittal balance in patients with osteoporosis using spinopelvic parameters. AB - PURPOSE: Little data is available on the relationships between sagittal balance and spinopelvic parameters in osteoporosis. We analyzed sagittal spinopelvic parameters in osteoporotic patients. METHODS: In this prospective study, the patient and control groups comprised 124 osteoporotic patients and 40 controls. Average age was 72.4 +/- 6.8 in the osteoporosis group and 42.7 +/- 12.5 in the control group, which was significantly different (P < 0.001). Osteoporotic patients were allocated to two groups by sagittal vertical axis, namely, a sagittal balance group (n = 56) and a sagittal imbalance group (n = 68). All 164 study subjects underwent whole spine lateral radiography, which included hip joints. The radiographic parameters investigated were sacral slope, pelvic tilt, pelvic incidence, thoracic kyphosis, lumbar lordosis, and sagittal vertical axis. Statistical analysis was performed to identify significant differences between the two groups. RESULTS: Osteoporotic patients and controls were found to be significantly different in terms of sagittal vertical axis, sacral slope, pelvic tilt, lumbar lordosis, and thoracic kyphosis. However, no significant difference was observed between patients and controls in terms of pelvic incidence (P > 0.05). Significant differences were found between the balance and imbalance groups in terms of age, lumbar spine bone mineral density (LSBMD), femoral neck BMD (FNBMD), visual analogue scale (VAS) score, sacral slope, and pelvic incidence. Correlation analysis revealed significant relationships between sagittal parameters and osteoporosis. Stepwise logistic regression analysis revealed that FNBMD and pelvic incidence contributed significantly to sagittal balance. CONCLUSION: Sagittal spinopelvic parameters were found to be significantly different in patients and normal controls. Significant relationships were found between sagittal spinopelvic parameters in osteoporotic patients. In particular, low FNBMD and high pelvic incidence were significant parameters in determination of sagittal balance in osteoporotic patients. PMID- 23354780 TI - British spine surgery. PMID- 23354781 TI - Metastatic medullary carcinoma of thyroid presenting as a dural-based mass: case report and review of literature. AB - Dural metastasis from medullary thyroid carcinoma (MTC) is not well established in English literature. We present the case report of MTC with unusual clinical presentation as a dural-based mass in a 39-year-old male with no family history of multiple endocrine neoplasia syndrome. Magnetic resonance imaging showed an extra-axial dural-based mass in right frontal lobe with calvarium and soft tissue extension to the right superior orbit. Histopathology showed MTC with variegated morphology and various patterns. Thyroid mass and widespread metastases from medullary thyroid carcinoma were subsequently identified. PMID- 23354783 TI - Stem cell therapy: promising treatment in heart failure? AB - Cardiac repair through the use of regenerative medicine has been a considerable research focus over the last decade. Several stem cell types have been investigated over this timeframe as potential candidates to target post infarction heart failure. The progression of investigation through the rigors of clinical trial design has provided some answers as to the potential clinical utility of this therapy; although there are many questions that remain. This review will concentrate on the clinical trial results of stem cell therapy for cardiac repair since the turn of the century and discuss some of the points that need clarification before this form of therapy can be considered for widespread applicability. PMID- 23354785 TI - Differences between middle cerebral artery bifurcations with normal anatomy and those with aneurysms. AB - The objectives of this study were to elucidate the normal anatomy of middle cerebral artery (MCA) bifurcations and to analyze the differences in patients with MCA aneurysms. In the present study, 62 patients underwent three-dimensional magnetic resonance angiography, and no intracranial lesions were noted. The widths of M1 and the superior and inferior M2 branches, as well as their respective lateral angles, were measured. These values were used to calculate the daughter artery ratio (DA ratio; width of larger M2/width of smaller M2) and the lateral angle ratio (LA ratio; lateral angle between M1 and larger M2/lateral angle between M1 and smaller M2). The DA and LA ratios of 54 MCA aneurysm patients (34 with ruptured aneurysms, 20 with unruptured aneurysms) were also calculated, using three-dimensional digital subtraction angiography, and compared with the normal values. In normal patients, the widths of M1 and the branches of M2, the lateral angles, and the LA and DA ratios were not significantly different between the right and left sides. The bilateral superior and inferior lateral angles of normal MCAs were significantly wider than those of MCAs with aneurysms. The DA ratio was 1.5 +/- 0.4 in normal MCAs and 1.7 +/- 0.7 in MCAs with aneurysms; this difference was significant (p < 0.05). The LA ratio was 1.3 +/- 0.4 in normal MCAs and 2.1 +/- 1.4 in MCAs with aneurysms; these values were also significantly different (p < 0.01). Normal cerebral artery bifurcations show close to symmetric structure in the M2 branches and the lateral angles, whereas aneurysmal MCAs do not show this symmetry. PMID- 23354784 TI - Microglia: key elements in neural development, plasticity, and pathology. AB - A century after Cajal identified a "third element" of the nervous system, many issues have been clarified about the identity and function of one of its major components, the microglia. Here, we review recent findings by microgliologists, highlighting results from imaging studies that are helping provide new views of microglial behavior and function. In vivo imaging in the intact adult rodent CNS has revolutionized our understanding of microglial behaviors in situ and has raised speculation about their function in the uninjured adult brain. Imaging studies in ex vivo mammalian tissue preparations and in intact model organisms including zebrafish are providing insights into microglial behaviors during brain development. These data suggest that microglia play important developmental roles in synapse remodeling, developmental apoptosis, phagocytic clearance, and angiogenesis. Because microglia also contribute to pathology, including neurodevelopmental and neurobehavioral disorders, ischemic injury, and neuropathic pain, promising new results raise the possibility of leveraging microglia for therapeutic roles. Finally, exciting recent work is addressing unanswered questions regarding the nature of microglial-neuronal communication. While it is now apparent that microglia play diverse roles in neural development, behavior, and pathology, future research using neuroimaging techniques will be essential to more fully exploit these intriguing cellular targets for effective therapeutic intervention applied to a variety of conditions. PMID- 23354786 TI - Surgical management of thalamic gliomas: case selection, technical considerations, and review of literature. AB - This study aimed to identify (1) the thalamic gliomas suitable for surgical resection and (2) the appropriate surgical approach based on their location and the displacement of the posterior limb of the internal capsule (PLIC). A retrospective study over a 5-year period (from 2006 to 2010) was performed in 41 patients with thalamic gliomas. The mean age of these patients was 20.4 years (range, 2-65 years). Twenty (49 %) tumors were thalamic, 19 (46 %) were thalamopeduncular, and 2 (5 %) were bilateral. The PLIC, based on T2-weighted magnetic resonance axial sections, was displaced anterolaterally in 23 (56 %) cases and laterally in 6 (14 %) cases. It was involved by lesion in eight (20 %) cases and could not be identified in four (10 %) cases. Resection, favored in patients with well-defined, contrast-enhancing lesions, was performed in 34 (83 %) cases, while a biopsy was resorted to in 7 (17 %) cases. A gross total resection or near total resection (>90 %) could be achieved in 26 (63 %) cases. The middle temporal gyrus approach, used when the PLIC was displaced anterolaterally, was the commonly used approach (63.5 %). Common pathologies were pilocytic astrocytoma (58 %) in children and grade III/IV astrocytomas (86 %) in adults. Preoperative motor deficits improved in 64 % of the patients with pilocytic lesions as compared to 0 % in patients with grade III/IV lesions (P value, 0.001). Postoperatively, two patients (5 %) had marginal worsening of motor power, two patients developed visual field defects, and one patient developed a third nerve paresis. Radical resection of thalamic gliomas is a useful treatment modality in a select subset of patients and is the treatment of choice for pilocytic astrocytomas. Tailoring the surgical approach, depending on the relative position of the PLIC, has an important bearing on outcome. PMID- 23354787 TI - Paediatric community-acquired septic shock: results from the REPEM network study. AB - INTRODUCTION AND PURPOSE OF THE STUDY: With this study we aimed to describe a "true world" picture of severe paediatric 'community-acquired' septic shock and establish the feasibility of a future prospective trial on early goal-directed therapy in children. During a 6-month to 1-year retrospective screening period in 16 emergency departments (ED) in 12 different countries, all children with severe sepsis and signs of decreased perfusion were included. RESULTS: A 270,461 paediatric ED consultations were screened, and 176 cases were identified. Significant comorbidity was present in 35.8 % of these cases. Intensive care admission was deemed necessary in 65.7 %, mechanical ventilation in 25.9 % and vasoactive medications in 42.9 %. The median amount of fluid given in the first 6 h was 30 ml/kg. The overall mortality in this sample was 4.5 %. Only 1.2 % of the survivors showed a substantial decrease in Paediatric Overall Performance Category (POPC). 'Severe' outcome (death or a decrease >=2 in POPC) was significantly related (p < 0.01) to: any desaturation below 90 %, the amount of fluid given in the first 6 h, the need for and length of mechanical ventilation or vasoactive support, the use of dobutamine and a higher lactate or lower base excess but not to any variables of predisposition, infection or host response (as in the PIRO (Predisposition, Infection, Response, Organ dysfunction) concept). CONCLUSION: The outcome in our sample was very good. Many children received treatment early in their disease course, so avoiding subsequent intensive care. While certain variables predispose children to become septic and shocked, in our sample, only measures of organ dysfunction and concomitant treatment proved to be significantly related with outcome. We argue why future studies should rather be large multinational prospective observational trials and not necessarily randomised controlled trials. PMID- 23354788 TI - Extraintestinal manifestations in an infant with microvillus inclusion disease: complications or features of the disease? AB - Microvillus inclusion disease (MVID), a rare severe congenital enteropathy characterized by intracytoplasmic microvillous inclusions and variable brush border atrophy on intestinal epithelial cells histology, is associated with defective synthesis or abnormal function of the motor protein myosin Vb encoded by the MYO5B gene. Although MYO5B gene is expressed in all epithelial tissues, it is unclear so far whether organs other than intestine are affected in MVID patients. We report a case of an infant with MVID who presented liver dysfunction, hematuria, and Pneumocystis jiroveci pneumonia during the course of the disease. It is discussed whether extraintestinal manifestations in this patient are secondary consequences of MVID or might be features of the disease associated with altered MYO5B function. CONCLUSIONS: MVID is classically included in the differential diagnosis of congenital diarrhea of secretory type. Recent advances in our knowledge regarding the role of myosin Vb in the pathophysiology of MVID is expected to clarify the clinical spectrum of the disease and the possible primary involvement of organs other than intestine. PMID- 23354789 TI - Oral mucosal conditions in preschool children of low socioeconomic status: prevalence and determinant factors. AB - The aim of the present study was to determine the prevalence of oral mucosal conditions and associated factors among 541 preschoolers of low socioeconomic status. A cross-sectional study was carried out. Sociodemographic data and information on harmful oral habits were gathered with the use of a questionnaire. A clinical exam was performed for the determination of oral mucosal conditions, dental caries and level of oral hygiene. Data analysis involved statistical analysis, the Kruskal-Wallis test, Mann-Whitney test, chi-square test, Fisher's exact test and multivariate regression (p < 0.05, 95 % CI). The prevalence of oral mucosal conditions was 40.7 %. The most prevalent oral mucosal conditions were coated tongue (23.4 %), melanotic macules (14.4 %), oral ulcers (11.8 %), Fordyce's spots (8.1 %), angular cheilitis (3.0 %), geographic tongue (2.8 %), linea alba (1.5 %) and fistula (1.3 %). Children between 3 and 5 years of age had a greater chance of exhibiting coated tongue (OR, 2.55; 95 % CI, 1.6-4.1), melanotic macules (OR, 4.07; 95 % CI, 2.3-7.2) and Fordyce's spots (OR, 12.70; 95 % CI, 7.2-28.6). The female gender had a greater chance of exhibiting melanotic macules (OR, 2.23; 95 % CI, 1.3-1.8). Coated tongue was more prevalent among children from low-income families (OR, 2.35; 95 % CI, 1.3-4.3) and those with inadequate oral hygiene (OR, 4.65; 95 % CI, 2.9-7.4). Caries constituted a predictive factor for oral ulcers (OR, 2.15; 95 % CI, 1.2-3.9) and fistula (OR, 12.00; 95 % CI, 1.4-11.3). Bruxism (teeth clenching/grinding) was a predictive factor for angular cheilitis (OR, 5.55; 95 % CI, 1.9-16.3). The determinant factors for oral mucosal conditions were the female gender, age between 3 and 5 years, inadequate oral hygiene, low household income, residence in rural areas and presence of dental caries and bruxism. PMID- 23354790 TI - Activity-based costing for pathology examinations and comparison with the current pricing system in Turkey. AB - OBJECTIVE: To demonstrate the real cost data of the pathology examinations by using the activity-based costing method and to contribute to the financial planning of the departments, health managers and also the social security institution. MATERIAL AND METHOD: Forty-four examinations selected from the Healthcare Implementation Notification system list and performed at the Ankara University Faculty of Medicine Pathology Department during September 2010 were studied. The analysis and the real cost calculations were done according to the duration of the procedures. Calculated costs were compared with the Healthcare Implementation Notification system and Medicare price lists. RESULTS: The costs of the pathology tests listed within the same pricing levels in the Healthcare Implementation Notification system list showed great differences. The minimum and maximum costs in level 1, 2, 3, and 4 were 15,98-80,15 TL, 15,95-258,59 TL, 42,38 236,87 TL, and 124,42-406,76 TL, respectively. Medicare price levels were more consistent with the real costs of the examinations compared to the Healthcare Implementation Notification system price list. CONCLUSION: The prices of the pathology examination listed at different levels in the Healthcare Implementation Notification system lists do not cover the real costs of the work done. The principal parameters of Activity-Based Costing system are more suitable for making the most realistic cost categorization. Although the prices could differ between countries, the Medicare system categories are more realistic than the Healthcare Implementation Notification system. The Healthcare Implementation Notification system list needs to be revised in order to reflect the real costs of the pathology examinations. PMID- 23354791 TI - Hemophagocytic syndrome in patients with unexplained cytopenia: report of 15 cases. AB - OBJECTIVE: To investigate the frequency of hemophagocytic syndrome in a series of patients with otherwise unexplained cytopenia. MATERIAL AND METHOD: In this cross sectional, single-centre study, bone marrow specimens (n=288) were obtained from the patients with unexplained cytopenia. The diagnosis of hemophagocytic syndrome was made according to universally accepted criteria. Characteristics of the patients, as well as the clinical and laboratory findings were reported. RESULTS: Fifteen cases (5.2%) fulfilled the hemophagocytic syndrome criteria, including 8 males (53.3%) and 7 females (46.7%) with a mean age of 39.7+/-20.7 (range: 14-72) years at the time of diagnosis. The main clinical and laboratory findings were cytopenia (100%), fever (73.3%), hyperferritinemia (66.7%), elevated erythrocyte sedimentation rate (60%), hypertriglyceridemia (60%), organomegaly (53.3%), elevated liver enzymes (53.3%), lymphadenopathy (26.7%), neurological symptoms (20%), and skin rash (13.3%). Two patients (13.3%) died before a diagnosis was made. CONCLUSION: Our findings indicate that the hemophagocytic syndrome is not a rare pathologic condition in patients with otherwise unexplained cytopenia. Without treatment, the mortality rate may be high. PMID- 23354792 TI - Gastric histopathological findings and ghrelin expression in morbid obesity. AB - OBJECTIVE: The role of Ghrelin, also known as the appetite hormone, is not fully explained in the development of morbid obesity. Plasma Ghrelin level is low in obese and high in slim subjects. Ghrelin-expressing cells were investigated histopathologically in the stomach of morbid obese patients in this study. Tissue Ghrelin expression was also compared with various parameters such as the distribution of endocrine cells, age, gender, body mass index, preoperative plasma Ghrelin level and presence of accompanying diseases. MATERIAL AND METHOD: The study included 33 morbidly obese patients, and 8 non-obese control patients. Plasma Ghrelin levels were measured preoperatively. Sleeve gastrectomy resection materials of 33 cases were evaluated with histopathological and immunohistochemical (Ghrelin and Chromogranin-A) techniques. The results were statistically evaluated by nonparametric tests. RESULTS: Histopathological findings observed in sleeve gastrectomy resection materials were interstitial lymphocytic infiltration (63.6%), hyperplasia of lymphoid follicles in the lamina propria (60.7%) and microvesiculation / dilatation of parietal cells (57.6%). The number of Ghrelin immunopositive cells in the gastric mucosa in females was significantly higher compared to males (p=0,007). Additionally, the number of Ghrelin immunopositive cells was significantly higher at the fundus-proximal corpus compared to the distal corpus of the stomach (p=0.0001). No significant correlation was found between Ghrelin-chromogranin immunopositive endocrine cell distribution and preoperative plasma Ghrelin levels and endocrine cell hyperplasia. CONCLUSION: Our study confirms that Ghrelin producing cells are most dense in the proximal stomach. Increased number of Ghrelin expressing cells in the gastric mucosa in females compared to males suggests that gender may also be a factor in determining the method for treatment of morbid obesity. PMID- 23354793 TI - The prognostic value of tumor-stroma proportion in laryngeal squamous cell carcinoma. AB - OBJECTIVE: Tumor-stroma proportion of tumor has been presented as a prognostic factor in some types of adenocarcinomas, but there is no information about squamous cell carcinomas and laryngeal carcinomas. MATERIAL AND METHOD: Five digital images of the tumor sections were obtained from 85 laryngeal carcinomas. Proportion of epithelial tumor component and stroma were measured by a software tool, allowing the pathologists to mark 205.6 MUm2 blocks on areas as carcinomatous/stromal, by clicking at the image. Totally, 3.451 mm2 tumor areas have been marked to 16.785 small square blocks for each case. RESULTS: Median follow up was 48 months (range 3-194). The mean tumor-stroma proportion was 48.63+18.18. There was no difference for tumor-stroma proportion when tumor location, grade, stage and perinodal invasion were considered. Although the following results were statistically insignificant, the mean tumor-stroma proportion was the lowest (37.46+/-12.49) for subglottic carcinomas, and it was 52.41+/-37.47, 50.86+19.84 and 44.56+/-16.91 for supraglottic, transglottic and glottic cases. The tumor-stroma proportion was lowest in cases with perinodal invasion and the highest in cases without lymph node metastasis (44.72+/-20.23, 47.77+/-17.37, 50.05+/-17.34). Tumor-stroma proportion was higher in the basaloid subtype compared with the classical squamous cell carcinoma (53.76+/-14.70 and 48.63+/-18.38 respectively). The overall and disease-free survival analysis did not reveal significance for tumor-stroma proportion (p=0.08, p=0.38). Only pathological stage was an independent factor for overall survival (p=0.008). CONCLUSION: This is the first series investigating tumor-stroma proportion as a prognostic marker in laryngeal carcinomas proposing a new method, but the findings do not support tumor-stroma proportion as a prognostic marker. PMID- 23354794 TI - Immunohistochemical expression of p16 in pleomorphic salivary adenoma. AB - OBJECTIVE: This study aimed to characterize alteration in the immunohistochemical expression of p16 in normal tissue of the salivary gland surrounding pleomorphic adenoma, and the tumor cells of pleomorphic adenomas. MATERIAL AND METHOD: A selected series of 120 cases of pleomorphic adenomas were examined. RESULTS: The results showed that p16 expression in non tumor duct cells was strong positive nuclear staining in 98 (81.6%) cases out of 120, while there were 20 (16.6%) with moderate staining, and 2 (1.6%) with weak staining in the components of normal tissue of the salivary gland surrounding pleomorphic adenoma. p16 expression in pleomorphic adenomas showed 71 (59.1%) cases with moderate nuclear staining in the duct cells, 45 (37.5%) cases with nuclear weak staining, and 4 (3.3%) cases with negative staining. p16 nuclear staining in myxochondroid tissue was identified in 4 (3.3%) cases with strong staining, 65 (54.1%) cases had moderate staining, and 51 (42.5%) cases had weak staining. CONCLUSION: This study suggests alteration of p16 expression in pleomorphic adenomas. P16 might have a role in the development of pleomorphic adenoma. PMID- 23354795 TI - Histopathologic analysis of female genital tuberculosis: a fifteen-year retrospective study of 110 cases in eastern India. AB - OBJECTIVE: Tuberculosis remains a global health problem and is an important cause of morbidity and mortality. Female genital tuberculosis is rare in the western world, but relevant in developing countries like India. The aim of this study was to determine histologic findings of different parts of the female genital tract affected by tuberculosis and to correlate it with other features. MATERIAL AND METHOD: A total number of 110 cases of female genital tuberculosis from 92 patients were included over a period of 15 years. The age range of the patients was 17 to 45 years with a mean of 26.3. The diagnostic procedures used were curettage biopsy, hysterectomy, histologic examination, culture, Mycobacterium Tuberculosispolymerase chain reaction, laparoscopy, hysterosalpingography and ultrasonography. RESULTS: Patients with female genital tuberculosis presented with infertility (65-70%), pelvic/ abdominal pain (50-55%) and menstrual disturbances (20-25%). Female genital tuberculosis involved the vulva (2), vagina (1), cervix (5), endometrium (66), fallopian tube (24) and ovaries (12). Out of 66 endometrial tuberculosis cases, proliferative, secretory endometrium and atrophic endometrium were seen in 53, 9, and 4 cases, respectively. HIV co infection was found only in 5 cases and acid-fast bacilli in tissue sections were detected in 7 cases. CONCLUSION: Female genital tuberculosis is not uncommon in developing countries and is an important cause of infertility. Though the fallopian tube was the most common site in many studies, the endometrium was the commonest site in this study. PMID- 23354796 TI - Distribution of uterin cervical lesions and relation between age and parity rates in the Mardin province. AB - OBJECTIVE: The aim of this study is to evaluate the incidence and distribution of cervical lesions and compare characteristics such as parity and age of the women in Mardin province. MATERIAL AND METHOD: Pap smears were drawn from the women screened at Mardin Gynecology and Pediatric Diseases Hospital from 2008 to 2011. All cervicovaginal smears were conventional Pap smear samples evaluated according to the 2001 Bethesda system. RESULTS: There were 3.332 patients in total, whose smears showed no lesions in 3.125 patients. The mean age and number of parities of those patients were 37.34+/-11.25 and 4.78+/-3.28. There were 207 smears showing any lesions in cervix; ASC-US, ASC-H, LSIL, HSIL, AGC, squamous cell carcinoma and endocervical adenocarcinoma in 151 (72.94%); 16 (7.72%); 20 (9.66%); 8 (3.86%); 10 (4.83%); 1 (0.48%) and 1 (0.48%) patient, respectively. The mean age and the parities of the patients were 37.63+/-10.77 years and 4,74+/ 2,92. Although there was no difference between the control and lesion groups, the parity and the age of patients who had >=4 births in both the control and lesion groups were significantly higher than the patients with parities < 4 births (p=0.000). There was no difference within the cervical lesion group comparing the ASC-US group with the total of the other lesions. CONCLUSION: High parity was one of the risk factor for having a lesion in uterine cervix in this population. This study represents an initial attempt to reflect the prevalence and the distribution of cervical lesions and their relation with the parity rates in the eastern regions in Turkey. PMID- 23354797 TI - [A review on the impact of IUD in cervical cytology: Mardin Region Data]. AB - OBJECTIVE: The aim of the study was to provide an overview to infectious and reactive cytological effects of intrauterine devices, which are one of the most widely used methods of contraception, with the results we obtained in the Mardin region. MATERIAL AND METHOD: We evaluated together the pap smears of the 300 intrauterine device (+) and 300 intrauterine device (-) patients sent to the pathology department in the period of 2010-2011. Genital infection rates and frequency of reactive-dysplastic cellular changes were statistically compared between the groups together with the literature data. RESULTS: In the intrauterine device (+) group, 2 (+) and more severe inflammation was observed in 66.3% of cases. Bacterial vaginosis (26%), candida (12%) and trichomonas vaginalis (8%) were recorded as the most common infectious agents, followed by actinomyces (4%). Between the groups of intrauterine device (+) and (-), no significant difference was observed in terms of the incidence of squamous cell abnormalities, except ASC-US (p=0.02). In the intrauterine device (+) group, the presence of atypical glandular cells and reactive findings was significantly higher than the control group. After the removal of the intrauterine device, 61 cases that had control smears showed regression, with a rate of %75.4 (n=46). CONCLUSION: The local irritative and inflammatory effect of intrauterine devices basically causes reactive and regenerative changes mostly in glandular cells. Intrauterine devices disrupt the genital flora and significantly increase the frequency of genital infection by creating a foreign body reaction. PMID- 23354798 TI - Congenital mesoblastic nephroma: a rare pediatric neoplasm. AB - Congenital mesoblastic nephroma is a stromal neoplasm of infancy. It has been referred to as mesenchymal, cystic or leiomyomatous hamartoma. These tumors are centered around the hilus of the kidney. Mesoblastic nephromas need to be distinguished from other pediatric renal neoplasms as these lesions are treated by complete surgical excision without chemotherapy unless gross residual tumor remains. Here, we describe the gross and microscopic features of mesoblastic nephroma in a twenty-day old infant. PMID- 23354799 TI - Tubercular mastitis - a great masquerader. AB - Tubercular mastitis is a rare clinical entity as mammary gland tissue, like spleen and skeletal muscle, offers resistance to the survival and multiplication of the tubercle bacillus. Tuberculosis of the breast can mimic carcinoma, whereas in young patients it can be mistaken for a pyogenic breast abscess, thus labeled a "great masquerader" in recognition of its multifaceted presentation. Breast tuberculosis commonly affects women in the reproductive age group, between 21 and 30 years, and is rare in prepubescent females and elderly women. Fine needle aspiration cytology is very useful and it is a promising technique in expert hands. In tuberculosis-endemic countries, the finding of granuloma on fine needle aspiration cytology warrants empirical treatment for tuberculosis even in the absence of positive acid-fast bacilli and without culture results. We hereby report a case of tubercular mastitis in a post-menopausal seronegative female diagnosed on fine needle aspiration cytology with a positive acid-fast bacilli and a review of the recent literature. PMID- 23354800 TI - [Coexistence of multiple gastrointestinal stromal tumors and signet ring cell carcinoma of stomach in a patient with neurofibromatosis type-1: case report]. AB - Gastrointestinal stromal tumors are mesenchymal neoplasias which are derived from Cajal's interstitial cells. The most common site of involvement is the stomach. It may be multiple in patients with Neurofibromatosis Type-1, while the small intestine is the most common location. In this case report, we aimed to present a Neurofibromatosis Type-1 patient, showing coexistence of multiple gastrointestinal stromal tumors in the stomach and small intestine with a signet ring cell carcinoma in the stomach. A 74-year-old female patient with poor appetite, vomiting and stomach ache was admitted to the hospital. After detection of a tumoral lesion with an ulcerated surface in stomach during the upper gastrointestinal tract endoscopic examination, the patient underwent surgery. During the operation, multiple nodular lesions were observed in the serosal surfaces of the small intestine and stomach. Gastrectomy and partial small intestine resection specimens were evaluated and the patient was diagnosed as signet ring cell carcinoma in the stomach, and multiple gastrointestinal stromal tumors in the serosal surfaces of both the stomach and small intestine. Resection specimens of patients with GIST need to be evaluated carefully on macroscopic examination, considering the possible presence of a coexistent tumoral lesion. PMID- 23354801 TI - [Malignant rhabdoid tumor of the orbit]. AB - Malignant rhabdoid tumor is a rare and malignant tumor of childhood. Generally it originates from the kidney and central nervous system, but occasionally it may arise from the orbit. Differential diagnosis from other childhood soft tissue sarcomas should be done. We report here an 8-week-old female infant with malignant rhabdoid tumor of the orbit who was treated with chemotherapy and surgery. The 8 week-old girl was referred to our hospital with a history of right proptosis first noted at birth. Physical and laboratory evaluation of the patient was normal except for right proptosis. The mass was removed surgically. Histopathologic examination and immunohistochemical findings of the specimen were evaluated as malignant rhabdoid tumor. Chemotherapy was administered. While in clinical remission, she succumbed during a febrile episode. Malignant rhabdoid tumor can rarely originate from the orbit. Malignant rhabdoid tumor should be kept in mind in the differential diagnosis of orbital masses, and surgery, chemotherapy and local radiotherapy should be used as combined therapy due to the poor prognosis. PMID- 23354802 TI - Phyllodes tumor of the vulva: report of two cases. AB - Ectopic breast tissue can occur anywhere along the primitive embryonic milk line and can be the site of the same pathologic processes found in the normal breast. Phyllodes tumor is an extremely rare fibroepithelial neoplasm that occurs in ectopic breast tissue of the vulva. To date, only 8 cases of phyllodes tumor in the vulva have been reported in the literature. This paper presents two additional case of benign phyllodes tumor in the vulva. The first patient was a 43-year-old woman, presenting with a lesion on the left anterior mons pubis that had increased in size in the last three months. The second patient was a 50-year-old woman, presenting with a two-month history of a mass in the right labium majus. The patients underwent excisional biopsy. The histological examination of both specimens revealed a characteristic pattern of benign phyllodes tumor. In conclusion, the pathologists need to be aware that the lesion can occur in this location. Herein, the concepts about the histogenesis of phyllodes tumor in the vulva are discussed and a brief review of the previously reported cases is given. PMID- 23354803 TI - Intrauterine fetal loss associated with Candida glabrata chorioamnionitis: report of two cases. AB - Chorioamnionitis is most commonly the result of an ascending infection caused by bacteria found within the lower genital tract. Yeast infections causing chorioamnionitis are very uncommon. Candida glabrata is a yeast that is considered to be a commensal of the vagina but vaginitis and rarely upper genital tract infection have been described. We report two cases of fungal chorioamnionitis occurring in pregnancies with a history of in vitro fertilization and cervical cerclage, both resulting in fetal loss. The histological features in conjunction with the positive cultures enabled C. glabrata to be identified as the causative organism producing severe chorioamnionitis. C. glabrata was probably introduced into the cervix at the time of embryo transfer, and during stitching the cervix. To prevent unfavorable outcomes in pregnant women, we recommend that vaginal and in particular cervical swabs should be taken prior to cervical procedures and appropriate treatment should be provided. PMID- 23354804 TI - Actinomyces lymphadenitis: case report. AB - In this paper an unusual case of lymphadenopathy associated with Actinomyces infection is reported. In the literature, there are only two cases presented with histopathologic features. A forty-year-old male patient was admitted to the hospital with painless mass on the neck. Clinical examination revealed a firm mass on the right submandibular region. The patient had no malignancy history. A cystic mass radiologically compatible with abscess was detected adjacent to the submandibular gland. Sialadenitis and lymphadenitis were considered but the mass was refractory to the antibiotherapy. The mass and the right submandibular gland were excised. Histopathologic evaluation of the lymph node revealed characteristic sulfur granules of Actinomyces. PMID- 23354805 TI - Metachronous malignant mesothelioma and pulmonary adenocarcinoma. AB - The prevalence of multiple primary malignant neoplasms in a single patient is reported in a wide variation. The co-existence of malignant mesothelioma and pulmonary carcinoma is a rare entity. Herein, we reported a 60-year-old man who was a retired employee and heavy smoker. He had a suspicious history of asbestos exposure. He complained of chest pain and computerized tomography revealed a mass in the lower lobe of left lung. The patient underwent a left lower lobectomy and was diagnosed as pulmonary adenocarcinoma. During follow up two years after surgery, the patient complained of dyspnea and chest computerized tomography scan revealed right pleural effusion and diffuse pleural thickening. For the differential diagnosis, the patient underwent wedge biopsy from the right lower lobe and was diagnosed as epithelial diffuse malignant mesothelioma. The development of malignant pleural mesothelioma and lung carcinoma could be associated with asbestos exposure. However, a history of asbestos exposure is not required for the diagnosis. The influence of effective anticancer therapies that improve the survival rates and increase the population ages could be related to the occurrence of a second malignancy. PMID- 23354807 TI - Combination therapy of cilengitide with belotecan against experimental glioblastoma. AB - The prognosis of patients diagnosed with glioblastoma remains dismal in spite of the current concomitant chemoradiotherapy with temozolomide. In particular, the resistance to temozolomide appears to be the greatest obstacle to the treatment of glioblastoma. In the present study, we evaluated in vitro and in vivo the antitumor effects of combination therapy of cilengitide with belotecan, a camptothecin derivate, to treat experimental glioblastoma. The therapeutic effects of the drugs on the U87MG and U251MG human glioblastoma cell lines were assessed using in vitro cell viability and apoptosis assays. The combination treatment group with cilengitide and belotecan enhanced the cytotoxic effects to the glioblastoma cell lines and increased the apoptosis of the tumor cells compared to monotherapy with either drug alone in vitro. Nude mice with established U87MG glioblastoma were assigned to the following four groups: control, cilengitide, belotecan and combination treatment. The volume of tumors and length of survival were also measured. Animals in the combination therapy group demonstrated a significant reduction of tumor volume and an increase in survival (p < 0.05). Immunohistochemistry revealed a decrease in angiogenesis by cilengitide and an increase in apoptosis by cilengitide and belotecan in vivo. The combination therapy of cilengitide with belotecan presented more cytotoxic effects compared to the monotherapy of either drug in vitro and in vivo. This combination protocol may serve as an alternative treatment option for glioblastoma. PMID- 23354806 TI - Suicide gene therapy for hepatocellular carcinoma cells by survivin promoter driven expression of the herpes simplex virus thymidine kinase gene. AB - The aim of this study was to investigate the selective killing effect of the herpes simplex virus-thymidine kinase/ganciclovir (TK/GCV) suicide gene system controlled by the survivin promoter on hepatocellular carcinoma (HCC) cells in vitro. Recombinant plasmid vectors driven by the survivin promoter were constructed. HepG2 HCC and LO2 normal human liver cells were transfected with the recombinant plasmids, green fluorescent protein (GFP)/pSURV, TK/pSURV and TAT TK/pSURV. GFP expression was detected by fluoroscopy and flow cytometry (FCM). TK gene expression was detected using RT-PCR and western blot analysis. The selective killing effects after GCV application were evaluated by tetrazolium assay, FCM and western blot analysis. Statistical analysis was performed by ANOVA. After transfection with GFP/pSURV, TK/pSURV and TAT-TK/pSURV for 48 h, GFP expression was observed in the HepG2 cells, but not in the L02 cells and TK gene expression was evidently detected by RT-PCR and western blot analysis in the HepG2 cells. Three stably transfected cell lines (HepG2/pSURV, HepG2/TK/pSURV and HepG2/TAT-TK/pSURV) were successfully established. Compared with the HepG2/TK/pSURV group, a significant 'bystander effect' was observed in the HepG2/TAT-TK/pSURV group with the incorporation of unmodifed HepG2 cells at different ratios. Following transfection with TK/pSURV and TAT-TK/pSURV, the growth of HepG2 cells in the presence of GCV was markedly inhibited. This finding was further corroborated by FCM and immunoblot analysis revealed the repressed expression of proliferating cell nuclear antigen (PCNA). Our results showed that the plasmid vectors carrying the TK and TAT-TK fusion protein gene driven by the survivin promoter were successfully constructed and their specific expression in HepG2 cells provided the basis for the targeted gene therapy of HCC. PMID- 23354808 TI - Patient perspectives on type 2 diabetes and medicine use during Ramadan among Pakistanis in Denmark. AB - BACKGROUND: Type 2 diabetes is highly prevalent among people of Pakistani background. Studies show that adherence to medicines is complicated for people with type 2 diabetes in general. Also, studies indicate that many people with type 2 diabetes and Muslim background fast during the month of Ramadan without adequate counselling on how to adjust their medicines. OBJECTIVE: To explore patient perspectives on medicine use during Ramadan, reasons for fasting and experiences with counselling on medicine use during Ramadan among people of Pakistani background with type 2 diabetes and at least one other chronic condition. SETTING: Greater Copenhagen, Denmark. METHOD: The analysis is based on a study exploring lived experiences with counselling on medicines using semi structured interviews and medication reviews. The analysis presented here builds on the subset of patients with Pakistani background (six interviewers). RESULTS: All interviewees pointed out that Islam allows ill people to refrain from fasting during Ramadan. However, all had fasted during Ramadan despite being diagnosed with type 2 diabetes. While fasting, they adapted their use of medicines in different ways, e.g. by changing the time of intake or by skipping morning medicines. Fasting during Ramadan meant a feeling of improvement in well-being for all interviewees. Reasons for this improvement included physiological, social and religious aspects. Healthcare professionals were rarely included in the decision-making process on whether or not to fast. Instead, friends and relatives, especially those with type 2 diabetes, were considered important to the decision-making process. CONCLUSION: For people with Muslim background and a chronic condition, fasting during Ramadan may mean changes in medicine use that are not always discussed with healthcare professionals. Healthcare professionals should acknowledge that Muslim patients may find fasting during Ramadan beneficial to their well-being and therefore choose to fast despite the Islamic rule of exemption. This patient-centred approach to counselling on medicines may facilitate better medicine use and thus better clinical health outcomes among patients that choose to fast. PMID- 23354810 TI - Effect of itraconazole on the concentrations of tacrolimus and cyclosporine in the blood of patients receiving allogeneic hematopoietic stem cell transplants. AB - PURPOSE: The purpose of this study was to investigate the interactions of itraconazole (ITCZ) with orally administered calcineurin inhibitors (CNIs) in Japanese allogeneic hematopoietic stem cell transplant (HSCT) recipients. METHODS: Sixteen HSCT patients (8 patients each receiving tacrolimus or cyclosporine) were enrolled. An ITCZ oral solution was administered from day 30 after the initiation of ITCZ administration as a loading dose. Before the co administration of ITCZ and CNI and 1 week daily thereafter, whole blood ITCZ and CNI (tacrolimus or cyclosporine) concentrations were measured in samples taken just before (C0h) and 2 h (C2h) after CNI administration. RESULTS: The median dose-adjusted C0h values of tacrolimus and cyclosporine on day 7 after the start of ITCZ co-administration were 5.6- and 2.7-fold higher, respectively, than the corresponding values obtained before the initiation of ITCZ treatment. On day 7 after ITCZ treatment, the mean single dosages of tacrolimus and cyclosporine were reduced to 33.7 and 66.5 % of the dosages before ITCZ co-administration, respectively, to adjust the CNI target concentration. Although ITCZ co administration did not alter the dose-adjusted C0h values of tacrolimus in a patient with a CYP3A5 1/ 1 allele, it did change this value of tacrolimus in patients with CYP3A5 3 alleles. However, in patients receiving cyclosporine, no such tendency was observed. CONCLUSION: The magnitude of the interaction between orally administered tacrolimus and ITCZ was significantly greater than that between cyclosporine and ITCZ. Prospective analysis of the CYP3A5 polymorphism may be important to ensure safe and reliable immunosuppressive therapy with tacrolimus in patients treated with ITCZ. PMID- 23354809 TI - Population pharmacokinetics of piperacillin/tazobactam in neonates and young infants. AB - OBJECTIVES: To develop population pharmacokinetic (PK) models for piperacillin/tazobactam in neonates and infants of less than 2 months of age in order to determine the appropriate dosing regimen and provide a rational basis for the development of preliminary dosing guidelines suitable for this population. METHODS: A two-stage, open-label study was conducted in neonates and infants less than 2 months of age in the neonatal intensive care unit (NICU). A total of 207 piperacillin and 204 tazobactam concentration-time data sets from 71 patients were analyzed using a nonlinear mixed-effect modeling approach (NONMEM VII). PK models were developed for piperacillin and tazobactam. The final models were evaluated using both bootstrap and visual predictive checks. External model evaluations were made in 20 additional patients. RESULTS: For neonates and young infants less than 2 months of age, the median central clearance was 0.133 and 0.149 L/h/kg for piperacillin and tazobactam, respectively. Postmenstrual age (PMA) was identified as the most significant covariate on central clearance of piperacillin and tazobactam. However, the combination of current bodyweight (BW) and postnatal age proved to be superior to PMA alone. BW was the most important covariate for apparent central volume of distribution. Both internal and external evaluations supported the prediction of the final piperacillin and tazobactam PK models. The dosing strategy 44.44/5.56 mg/kg/dose piperacillin/tazobactam every 8 or 12 h evaluated in this study achieved the pharmacodynamic target (free piperacillin concentrations >4 mg/L for more than 50 % of the dosing interval) in about 67 % of infants. CONCLUSIONS: Population PK models accurately described the PK profiles of piperacillin/tazobactam in infants less than 2 months of age. The results indicated that higher doses or more frequent dosing regimens may be required for controlling infection in this population in NICU. PMID- 23354811 TI - 1H NMR spectra. Part 30(+): 1H chemical shifts in amides and the magnetic anisotropy, electric field and steric effects of the amide group. AB - The (1)H spectra of 37 amides in CDCl(3) solvent were analysed and the chemical shifts obtained. The molecular geometries and conformational analysis of these amides were considered in detail. The NMR spectral assignments are of interest, e.g. the assignments of the formamide NH(2) protons reverse in going from CDCl(3) to more polar solvents. The substituent chemical shifts of the amide group in both aliphatic and aromatic amides were analysed using an approach based on neural network data for near (<=3 bonds removed) protons and the electric field, magnetic anisotropy, steric and for aromatic systems pi effects of the amide group for more distant protons. The electric field is calculated from the partial atomic charges on the N.C?O atoms of the amide group. The magnetic anisotropy of the carbonyl group was reproduced with the asymmetric magnetic anisotropy acting at the midpoint of the carbonyl bond. The values of the anisotropies Deltachi(parl) and Deltachi(perp) were for the aliphatic amides 10.53 and -23.67 (*10(-6) A(3)/molecule) and for the aromatic amides 2.12 and -10.43 (*10(-6) A(3)/molecule). The nitrogen anisotropy was 7.62 (*10(-6) A(3)/molecule). These values are compared with previous literature values. The (1)H chemical shifts were calculated from the semi-empirical approach and also by gauge-independent atomic orbital calculations with the density functional theory method and B3LYP/6 31G(++) (d,p) basis set. The semi-empirical approach gave good agreement with root mean square error of 0.081 ppm for the data set of 280 entries. The gauge independent atomic orbital approach was generally acceptable, but significant errors (ca. 1 ppm) were found for the NH and CHO protons and also for some other protons. PMID- 23354813 TI - Computational approaches, databases and tools for in silico motif discovery. AB - Motifs are the biologically significant fragments of nucleotide or peptide sequences in a specific pattern. Motifs are categorized as structural motifs and sequence motifs. These are discovered by phylogenetic studies of similar genes across species. Structural motifs are formed by three dimensional arrangements of amino acids consisting of two or more alpha helices or beta strands whereas sequence motifs are formed by the nucleotide fragments appearing in the exons of a gene. The arrangement of residues in structural motifs may not be continuous while it is continuous in sequence motifs. Sequence motifs may encode to the structural motifs. The algorithms used for motif discovery are important part of the bio-computational studies. The purpose of motif discovery is to identify patterns in biopolymer (nucleotide or protein) sequences to understand the structure and function of the molecules and their evolutionary aspects. The main aim of this paper is to provide systematic compilation of a review on different approaches, databases and tools used in motif discovery. PMID- 23354812 TI - Perceived school safety is strongly associated with adolescent mental health problems. AB - School environment is an important determinant of psychosocial function and may also be related to mental health. We therefore investigated whether perceived school safety, a simple measure of this environment, is related to mental health problems. In a population-based sample of 11,130 secondary school students, we analysed the relationship of perceived school safety with mental health problems using multiple logistic regression analyses to adjust for potential confounders. Mental health problems were defined using the clinical cut-off of the self reported Strengths and Difficulties Questionnaire. School safety showed an exposure-response relationship with mental health problems after adjustment for confounders. Odds ratios increased from 2.48 ("sometimes unsafe") to 8.05 ("very often unsafe"). The association was strongest in girls and young and middle-aged adolescents. Irrespective of the causal background of this association, school safety deserves attention either as a risk factor or as an indicator of mental health problems. PMID- 23354814 TI - A computational prediction of structure and function of novel homologue of Arabidopsis thaliana Vps51/Vps67 subunit in Corchorus olitorius. AB - Vps mediated vesicular transport is important for transferring macromolecules trapped inside a vesicle. Although highly abundant, Vps shows tremendous sequence variation among diverse array of species. However, this difference in sequence, which seems to also translate into substantial functional variation, is hardly characterized in Corchorus spp. Here, our computational study investigates structural and functional features of one of the Vps subunit namely Vps51/Vps67 in C. olitorius. Broad scale structural characterization revealed novel information about the overall Vps structure and binding sites. Moreover, functional analyses indicate interaction partners which were unexplored to date. Since membrane trafficking is essentially associated with nutrient uptake and chemical de-toxification, characterization of the Vps subunit can well provide us with better insight into important agronomic traits such as stress response, immune response and phytoremediation capacity. PMID- 23354815 TI - Evaluation of biotransformed berberine derivatives as anti inflammatory drugs: an in silico study. AB - The anti inflammatory potential of the human and microbial biotransformed derivatives of berberine were determined by molecular docking. It was revealed that almost all derivatives formed as a result of biotransformation showed increase in phospholipase A(2) binding affinity compared to berberine. The newly introduced -OH group/groups establish stronger hydrogen bonding interactions and more number of van der Waals contacts with the protein. As phospholipase A(2) is a target of anti inflammatory drugs, it might be concluded that certain biotransformed derivatives of berberine could be better anti inflammatory agents compared to berberine. PMID- 23354816 TI - In silico exploration of novel phytoligands against probable drug target of Clostridium tetani. AB - Though tetanus is an old disease with well known medicines, its complications are still a serious issue worldwide. Tetanus is mainly due to a powerful neurotoxin, tetanolysin-O, produced by a Gram positive anaerobic bacterium, Clostridium tetani. The toxin has a thiol-activated cytolysin which causes lysis of human platelets, lysosomes and a variety of subcellular membranes. The existing therapy seems to have challenged as available vaccines are not so effective and the bacteria developed resistance to many drugs. Computer aided approach is a novel platform to screen drug targets and design potential inhibitors. The three dimensional structure of the toxin is essential for structure based drug design. But the structure of tetanolysin-O is not available in its native form. Moreover, the interaction and pharmacological activities of current drugs against tetanolysin-O is not clear. Hence, there is need for three dimensional model of the toxin. The model was generated by homology modeling using crystal structure of perfringolysin-O, chain-A (PDB ID: 1PFO) as the template. The modeled structure has 22.7% alpha helices, 27.51% beta sheets and 41.75% random coils. A thiol-activated cytolysin was predicted in the region of 105 to 1579, which acts as a functional domain of the toxin. The hypothetical model showed the backbone root mean square deviation (RMSD) value of 0.6 A and the model was validated by ProCheck. The Ramachandran plot of the model accounts for 92.3% residues in the most allowed region. The model was further refined by various tools and deposited to Protein Model Database (PMDB ID: PM0077550). The model was used as the drug target and the interaction of various lead molecules with protein was studied by molecular docking. We have selected phytoligands based on literatures and pharmacophoric studies. The efficiency of herbal compounds and chemical leads was compared. Our study concluded that herbal derivatives such as berberine (7, 8, 13, 13a-tetradehydro-9,10-dimethoxy-2,3 [methylenebis(oxy)] berbinium), curcumin ((1E,6E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), coumarin (2H-chromen-2-one), catechol (Benzene-1,2-diol) and diosphenol (2-hydroxy-3 methyl-6-propan-2-ylcyclohex-2-en-1-one) are the best inhibitors compared to known chemicals. Hence, these leads can be used as potential inhibitors against tetanolysin. PMID- 23354817 TI - Genetic ancestor of external antigens of pandemic influenza A/H1N1 virus. AB - The aim of the present investigation was to discover the genetic relationships of 2009 pandemic novel influenza A/H1N1 virus (NIV) external antigens Hemagglutinin (HA) and Neuraminidase (NA) with other influenza viruses by performing phylogenetic, comparative and statistical analyses. Phylogenetic trees of these two antigens show that the sequences of the NIV viruses are relatively homogeneous and these were derived from several viruses circulating in swine. The phylogenetic tree of HA shows that NIV had the closest relationship with North American pig lineages whereas NA had with European pig lineages. In both segments, NIVs had the closest genetic relationship with swine influenza virus lineages. It strongly suggests that pigs are the most possible animal reservoir. Comparative analysis shows that among clade A, NIVs had very low genetic divergence as well as high similarity and also suffered strong purifying selection whereas neighbor clade B shows moderate values when compared to those of clades C-F. It indicates that classical swine influenza viruses present in clade B might be an ancestor of NIVs external antigens. The process of re assortment occurred in classical swine influenza viruses. The mutation sites exclusively fixed in the NIV of swine and human along with vaccine strain provide an important suggestion for disease diagnosis and vaccine research. PMID- 23354818 TI - In silico analysis reveals the presence of a large number of Ankyrin repeat containing proteins in Ectocarpus siliculosus. AB - Proteins with Ankyrin repeat motifs (ANK) are found to be associated with diverse biological processes and molecular functions in most of the studied organisms. Several studies have been done on the ANK-motif containing proteins of various model species, but similar studies on their counterparts in brown algae are not available. In this study, we have identified a total of 1,372 ankyrin repeats in 339 proteins of the model brown algae Ectocarpus siliculosus and the consensus sequence of the ANK repeats was determined. The proteins were classified into eight different subfamilies depending on their structural diversity. The data provided in this study may provide useful basis for future reverse genetics analysis of the members of this family. PMID- 23354819 TI - Prot-Prop: J-tool to predict the subcellular location of proteins based on physiochemical characterization. AB - PROT-PROP is a computational tool to characterize 27 physicochemical properties of a protein along with its subcellular location (intra or extra) in a single window application. Other significant features of this software include calculation of numerical values for hydrophobicity, hydrophilicity; composition of small and large amino acids; net hydrophobic content in terms of low/high; and Navie's algorithm to calculate theoretical pI. PROT-PROP is an easy-to-install platform independent implementation of JAVA under a user-friendly interface. It is a standalone version as a virtual appliance and source code for platforms supporting Java 1.5.0 and higher versions, and downloadable from the web http://www.mzu.edu.in/schools/biotechnology.html . PROT-PROP can run under Windows and Macintosh Operating Systems. PROT-PROP is distributed with its source code so that it may be adapted or customized, if desired. PMID- 23354821 TI - Homology modeling and functional sites prediction of azoreductase enzyme from the cyanobacterium Nostoc sp. PCC7120. AB - Industrial dyes such as azodyes are potential environmental pollutants causing deleterious health hazards complications. These dyes are potentially degraded by azoreductase enzyme which is widely distributed in bacteria and also cyanobacteria. The azoreductase enzymes from cyanobacteria have not been explored in detail. Hence this enzyme from Nostoc sp. PCC 7120 has been addressed in detail in the present study considering to explore the physico-chemical properties, evolutionary relationships, functional sites and structural properties using various bioinformatics tools. Four conserved regions were obtained from the multiple sequence analysis. The multiple sequence alignment showed conserved regions at different stretches from 1-11, 40-57, 82-120 and 161 177 amino acid residues. These regions could be used for designing degenerate primers or probes for PCR-based amplification or hybridization-based detection of azoreductase sequences from different source organisms. Domain analysis and functional site prediction showed the presence of functional sites and domain such as flavodoxin like fold responsible for enzyme activity. 3D model was constructed and the best model was selected and validated. Superimposition of the final structure and the template showed variations in certain regions which might be involved in the accommodation of various dyes. Our results may be helpful for further investigations like docking studies as well as in vivo and in vitro conditions although these predictions still need to be studied. PMID- 23354820 TI - In silico investigation and structural characterization of virulent factor and a metallo peptidase present in Helicobacter pylori strain J99. AB - VacA is a high-molecular weight multimeric pore-forming protein encoded by the chromosomal gene vacA of Helicobacter pylori J99 strian. It plays a significant role in the development of gastric cancer in human by inducing the formation of vacuoles. Genomics and proteomics features of an organism have provided a plethora of potential drug targets. The crystal structure of VacA is not available in any structural database; hence a 3D structure is very essential for structural studies and discovery of potential inhibitors against proteins. In this study 3D structure of VacA is modelled a by using Bhageerath: an energy based web enabled computer software suite. According to our study VacA steriochemical validation shows 91.7% residues are in allowed region of Ramachandran plot. Further validation was done by WHAT CHECK to provide evidence that the distribution of the main chain bond lengths and omega bond angles were within limits with Z-score 1.0 and error values are negligible. The modelled protein was submitted to Protein Model Database and can be downloaded with PMDID PM0077963. Further we found that metallo peptidase "M3" cleaves VacA and helps in import mechanism in mitochondria. Structure of metallo peptidase is also not available in any structural database so we modelled and validated its structure. With the help of docking studies we blocked the active site of metallo peptidase by ligand LA3 and 294 with binding energy -5.9 and -5.2 KJ/mol respectively, thus prevented import mechanism of VacA in mitochondria. The inhibitors identified from our study were LA3 and 294 ligands. The investigation concluded that these drugs could be used as the potential inhibitors against the damage of stomach and duodenum, which ultimately reduces the likelihood of ulcer as well as gastric cancer. PMID- 23354822 TI - [Introduction to neurogenetics]. PMID- 23354823 TI - [Genetics of movement disorders]. AB - A number of genetic causes of movement disorders including Parkinson disease, dystonia, restless legs syndrome or essential tremor have been elucidated in recent years. This process was accelerated by novel technologies including genome wide association studies (GWAS) and next generation sequencing (NGS). Although monogenic forms are overall rare, they provide a unique opportunity to investigate mutation carriers who are still in the presymptomatic phase. As these subjects present individuals at risk to develop the disease, they have been included in longitudinal studies to unravel disease mechanisms and elucidate novel therapeutic targets. In addition, cell culture and animal studies have been performed to functionally characterize proteins mutated in different movement disorders to provide further insight into disturbed cellular pathways. In this article, we summarize known monogenic forms and the associated phenotype as well as genetic risk factors and review the function of relevant genes and proteins. PMID- 23354824 TI - Education as ehealth infrastructure: considerations in advancing a national agenda for ehealth. AB - This paper explores the role of education as infrastructure in large-scale ehealth strategies-in theory, in international practice and in one national case study. Education is often invisible in the documentation of ehealth infrastructure. Nevertheless a review of international practice shows that there is significant educational investment made in implementing national ehealth agendas. Disparate views about the role of education are implicit in the ehealth strategy literature, while there is a shortage of evidence-based accounts of ehealth education. In the case of Australia, the benefits and challenges of a broadly collaborative approach to ehealth education are highlighted through activities of various types occurring on many levels to support the implementation of a national ehealth system. This paper concludes that although evidence-based practice is a given in other areas of healthcare, and although there are many published evaluations of ehealth usability and acceptance in the health informatics literature, there is surprisingly little evidence about what works and doesn't work with regard to the ehealth education. PMID- 23354826 TI - The impact of utilization of early aneuploidy screening on amniocenteses available for training in obstetrics and fetal medicine. AB - OBJECTIVE: First-trimester aneuploidy screening has high detection rates and low false-positive rates. Their use as well as the implementation of non-invasive prenatal testing may affect specialty training in prenatal diagnosis procedures. STUDY DESIGN: Descriptive study of first-trimester aneuploidy screening and amniocentesis in an obstetric training program. Screening methods were tracked from their introduction in 2004 through 2011. The volume of amniocentesis procedures from 2000 to 2011 was evaluated. RESULTS: First-trimester screening tests increased from 283 to 1225 between 2005 and 2011, whereas genetic amniocenteses declined from 460 to 168 during the same period. The percent of older women who chose a first-trimester screen test rose from 12.7% to 44.2% CONCLUSION: First-trimester screening options reduce genetic amniocenteses available for training. Fetal medicine and general obstetrics training programs need to evaluate their clinical experience and determine whether simulation training methods are needed for education. PMID- 23354828 TI - Computer simulation of three-dimensional plaque formation and progression in the carotid artery. AB - Atherosclerosis is becoming the number one cause of death worldwide. In this study, three-dimensional computer model of plaque formation and development for human carotid artery is developed. The three-dimensional blood flow is described by the Navier-Stokes equation, together with the continuity equation. Mass transfer within the blood lumen and through the arterial wall is coupled with the blood flow and is modeled by a convection-diffusion equation. The low-density lipoproteins transports in lumen of the vessel and through the vessel tissue are coupled by Kedem-Katchalsky equations. The inflammatory process is modeled using three additional reaction-diffusion partial differential equations. Fluid structure interaction is used to estimate effective wall stress analysis. Plaque growth functions for volume progression are correlated with shear stress and effective wall stress distribution. We choose two specific patients from MRI study with significant plaque progression. Plaque volume progression using three time points for baseline, 3- and 12-month follow up is fitted. Our results for plaque localization correspond to low shear stress zone and we fitted parameters from our model using nonlinear least-square method. Determination of plaque location and composition, and computer simulation of progression in time for a specific patient shows a potential benefit for the prediction of disease progression. The proof of validity of three-dimensional computer modeling in the evaluation of atherosclerotic plaque burden may shift the clinical information of MRI from morphological assessment toward a functional tool. Understanding and prediction of the evolution of atherosclerotic plaques either into vulnerable or stable plaques are major tasks for the medical community. PMID- 23354827 TI - White matter integrity is reduced in bulimia nervosa. AB - OBJECTIVE: To investigate brain white matter (WM) functionality in bulimia nervosa (BN) in relation to anxiety. METHOD: Twenty-one control women (CW, mean age 27 +/- 7 years) and 20 BN women (mean age 25 +/- 5 years) underwent brain diffusion tensor imaging to measure fractional anisotropy (FA; an indication of WM axon integrity) and the apparent diffusion coefficient (ADC; reflecting WM cell damage). RESULTS: FA was decreased in BN in the bilateral corona radiata extending into the posterior limb of the internal capsule, the corpus callosum, the right sub-insular WM, and right fornix. In CW but not BN, trait anxiety correlated negatively with fornix, corpus callosum, and left corona radiata FA. ADC was increased in BN compared with CW in the bilateral corona radiata, corpus callosum, inferior fronto-occipital, and uncinate fasciculus. Alterations in BN WM functionality were not due to structural brain alterations. DISCUSSION: WM integrity is disturbed in BN, especially in the corona radiata, which has been associated with taste and brain reward processing. Whether this is a premorbid condition or an effect from the illness is yet uncertain. The relationships between WM FA and trait anxiety in CW but not BN may suggest that altered WM functionality contributes to high anxious traits in BN. PMID- 23354829 TI - Atypical multiple ileum metastases of renal cell carcinoma. PMID- 23354830 TI - Morphology of the atlas pedicle revisited: a morphometric CT-based study on 120 patients. AB - PURPOSE: To quantify the dimensions of the atlas pedicles and to analyze the relationship between extra medullary height (EMH) with intra medullary height (IMH) of the atlas pedicle. METHODS: The images of the patients who had CT scanning and three-dimensional (3D) reconstruction involving atlantoaxial complex between June 2011 and April 2012 and meet our inclusion criteria were studied retrospectively. After reformatting the original images, the EMH and IMH of the atlas pedicles were measured. RESULTS: Extra medullary height and IMH were, respectively, 4.83 +/- 1.13 and 1.29 +/- 1.10 mm for males and 3.75 +/- 0.93 and 0.60 +/- 0.83 mm for females, with statistical difference (P < 0.05). EMH and IMH had some correlation (correlation coefficient r = 0.804) but showed a large variability. Of 240 pedicles of 120 cases, 47.92% (115 pedicles) were >=1 mm; 12.08% (29 pedicles) were between 0 and 1 mm; and 40% (96 pedicles) were 0. CONCLUSION: The EMH and the IMH of the atlas pedicles were measured by using CT images of the atlas, providing anatomic parameters for surgery. They showed a certain correlation but with a high variability. C1 pedicle screw fixation was well performed when the medullary canal was >=1 mm, but the surgical procedure should be careful when it was between 0 and 1 mm, and avoided when there was no medullary canal in the atlas pedicle! So 3D CT reconstruction should be conducted to obtain data and establish individualized fixation strategy preoperatively. PMID- 23354831 TI - Cardiorenal syndrome and the role of ultrafiltration in heart failure. AB - Acute decompensated heart failure (ADHF) with associated volume overload is the most common cause of hospitalization in heart failure patients. When accompanied by worsening renal function, it is described as a cardiorenal syndrome and is a therapeutic challenge. Initial treatment commonly encompasses intravenous diuretics however, suboptimal results and high rehospitalization rates have led experts to search for alternative therapeutic strategies. Recent technological advances in extracorporeal therapies have made ultrafiltration a feasible option for treatment of hypervolemia in ADHF. Recent large randomized trials have compared the efficacy and safety of ultrafiltration with diuretics. Additionally, the benefits of novel pharmacologic approaches, including combining hypertonic saline with diuretics, have recently been studied. The aim of this review is to discuss the developments in both pharmacologic and extracorporeal methods for treating hypervolemia in ADHF and acute cardiorenal syndrome. PMID- 23354832 TI - A feasibility trial of postoperative adjuvant chemotherapy with S-1, an oral fluoropyrimidine, for elderly patients with non-small cell lung cancer: a report of the Lung Oncology Group in Kyushu (LOGIK) protocol 0901. AB - BACKGROUND: The present study was designed to determine whether adjuvant chemotherapy with S-1 after surgical resection is feasible in elderly patients with non-small cell lung cancer (NSCLC), using a multi-institutional trial. METHODS: From July 2009 to July 2011, 25 patients received the following regimen: 2 weeks of administration and 1 week of withdrawal of S-1 at 50-100 mg/body per day in an outpatient setting. The primary endpoint of this trial was the completion rate of eight cycles. RESULTS: The completion rate of eight cycles was 70.8 % [95 % confidence interval (CI) 52.7-89.0 %]. The perfect completion rate of eight cycles on schedule with full doses without delays was 50 % (95 % CI 30.0 70.0 %). The reasons for incomplete cycles were: patient refusal in four cases, anorexia in two cases and thrombocytopenia in one case. As a consequence of delays and/or dose reductions, the relative dose intensity of S-1 was 76.3 %. CONCLUSIONS: Adjuvant chemotherapy with S-1 at a reduced dose and schedule was therefore found to be a feasible treatment for elderly Japanese patients who had undergone surgical resection for NSCLC (UMIN Clinical Trials Registry number UMIN000002383). PMID- 23354833 TI - Predictive significance of mean apparent diffusion coefficient value for responsiveness of temozolomide-refractory malignant glioma to bevacizumab: preliminary report. AB - BACKGROUND: Recurrent glioblastoma after initial radiotherapy plus concomitant and adjuvant temozolomide is problematic. Here, patients with temozolomide refractory high-grade gliomas were treated with bevacizumab (BV) and evaluated using apparent diffusion coefficient (ADC) for response. METHODS: Nine post temozolomide recurrent or progressive high-grade glioma patients (seven with glioblastoma and two with anaplastic astrocytoma) were treated with BV monotherapy. Average age was 57 years (range, 22-78), median Karnofsky Performance Scale (KPS) was 70 (30-80) and median BV line number was 2 (2-5). Two had additional stereotactic radiotherapy within 6 months prior to BV. Magnetic resonance (MR) imaging after BV therapy was performed within 2 weeks with calculation of mean ADC (mADC) values of enhancing tumor contours. RESULTS: Post BV treatment MR imaging showed decreased tumor volumes in eight of nine cases (88.9 %). Partial response was obtained in four cases (44.4 %), four cases had stable disease, and one had progressive disease. Of 15 evaluable enhancing lesions, 11 shrank and four did not. Pretreatment mADC values were above 1100 (10(-6) mm(2)/s) in all responding tumors, while all non-responding lesions scored below 1100 (p = 0.001). mADC decreased after the first BV treatment in all lesions except one. KPS improved in four cases (44.4 %). Median progression-free survival and overall survival for those having all lesions with high mADC (>1100) were significantly longer than those with a low mADC (<1100) lesion (p = 0.018 and 0.046, respectively). CONCLUSIONS: Bevacizumab monotherapy is effective in patients with temozolomide-refractory recurrent gliomas and tumor mean ADC value can be a useful marker for prediction of BV response and survival. PMID- 23354834 TI - Microglial nodules in early multiple sclerosis white matter are associated with degenerating axons. AB - Microglial nodules in the normal-appearing white matter have been suggested as the earliest stage(s) of multiple sclerosis (MS) lesion formation. Such nodules are characterized by an absence of leukocyte infiltration, astrogliosis or demyelination, and may develop into active demyelinating MS lesions. Although the etiology of MS is still not known, inflammation and autoimmunity are considered to be the central components of this disease. Previous studies provide evidence that Wallerian degeneration, occurring as a consequence of structural damage in MS lesions, might be responsible for observed pathological abnormalities in connected normal-appearing white matter. As innate immune cells, microglia/macrophages are the first to react to even minor pathological changes in the CNS. Biopsy tissue from 27 MS patients and autopsy and biopsy tissue from 22 normal and pathological controls were analyzed to determine the incidence of microglial nodules. We assessed MS periplaque white matter tissue from early disease stages to determine whether microglial nodules are associated with altered axons. With immunohistochemical methods, the spatial relation of the two phenomena was visualized using HLA-DR antibody for MHC II expression by activated microglia/macrophages and by applying antibodies against damaged axons, i.e., SMI32 (non-phosphorylated neurofilaments) and amyloid precursor protein as well as neuropeptide Y receptor Y1, which marks axons undergoing Wallerian degeneration. Our data demonstrate that the occurrence of microglial nodules is not specific to MS and is associated with degenerating as well as damaged axons in early MS. In addition, we show that early MS microglial nodules exhibit both pro- and antiinflammatory phenotypes. PMID- 23354835 TI - Oligomers, fact or artefact? SDS-PAGE induces dimerization of beta-amyloid in human brain samples. AB - The formation of low-order oligomers of beta-amyloid (Abeta) within the brain is widely believed to be a central component of Alzheimer's disease (AD) pathogenesis. However, despite advances in high-throughput and high-resolution techniques such as xMAP and mass spectrometry (MS), investigations into these oligomeric species have remained reliant on low-resolution Western blots and enzyme-linked immunosorbent assays. The current investigation compared Abeta profiles within human cortical tissue using sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis (PAGE), xMAP and surface enhanced laser desorption/ionization time-of-flight MS and found that whilst there was significant correlation across the techniques regarding levels of monomeric Abeta, only SDS-PAGE was capable of detecting dimeric isoforms of Abeta. The addition of synthetic di-tyrosine cross-linked Abeta(1-40)Met(35)(O) to the AD tissue demonstrated that the MS methodology was capable of observing dimeric Abeta at femto-molar concentrations, with no noticeable effect on monomeric Abeta levels. Focus turned to the association between SDS-PAGE and levels of observable dimeric Abeta within the AD brain tissue. These investigations revealed that increased levels of dimeric Abeta were observed with increasing concentrations of SDS in the sample buffer. This finding was subsequently confirmed using synthetic Abeta(1-42) and suggests that SDS was inducing the formation of dimeric Abeta. The findings that SDS promotes Abeta dimerization have significant implications for the putative role of low-order oligomers in AD pathogenesis and draw into question the utility of oligomeric Abeta as a therapeutic target. PMID- 23354836 TI - Plant senescence and crop productivity. AB - Senescence is a developmental process which in annual crop plants overlaps with the reproductive phase. Senescence might reduce crop yield when it is induced prematurely under adverse environmental conditions. This review covers the role of senescence for the productivity of crop plants. With the aim to enhance productivity, a number of functional stay-green cultivars have been selected by conventional breeding, in particular of sorghum and maize. In many cases, a positive correlation between leaf area duration and yield has been observed, although in a number of other cases, stay-green cultivars do not display significant effects with regards to productivity. In several crops, the stay green phenotype is observed to be associated with a higher drought resistance and a better performance under low nitrogen conditions. Among the approaches used to achieve stay-green phenotypes in transgenic plants, the expression of the IPT gene under control of senescence-associated promoters has been the most successful. The promoters employed for senescence-regulated expression contain cis-elements for binding of WRKY transcription factors and factors controlled by abscisic acid. In most crops transformed with such constructs the stay-green character has led to increased biomass, but only in few cases to increased seed yield. A coincidence of drought stress resistance and stay-green trait is observed in many transgenic plants. PMID- 23354837 TI - Structural, kinetic and computational investigation of Vitis vinifera DHDPS reveals new insight into the mechanism of lysine-mediated allosteric inhibition. AB - Lysine is one of the most limiting amino acids in plants and its biosynthesis is carefully regulated through inhibition of the first committed step in the pathway catalyzed by dihydrodipicolinate synthase (DHDPS). This is mediated via a feedback mechanism involving the binding of lysine to the allosteric cleft of DHDPS. However, the precise allosteric mechanism is yet to be defined. We present a thorough enzyme kinetic and thermodynamic analysis of lysine inhibition of DHDPS from the common grapevine, Vitis vinifera (Vv). Our studies demonstrate that lysine binding is both tight (relative to bacterial DHDPS orthologs) and cooperative. The crystal structure of the enzyme bound to lysine (2.4 A) identifies the allosteric binding site and clearly shows a conformational change of several residues within the allosteric and active sites. Molecular dynamics simulations comparing the lysine-bound (PDB ID 4HNN) and lysine free (PDB ID 3TUU) structures show that Tyr132, a key catalytic site residue, undergoes significant rotational motion upon lysine binding. This suggests proton relay through the catalytic triad is attenuated in the presence of lysine. Our study reveals for the first time the structural mechanism for allosteric inhibition of DHDPS from the common grapevine. PMID- 23354838 TI - Clinical significance and functional studies of myeloid-derived suppressor cells in chronic hepatitis C patients. AB - PURPOSE: Myeloid-derived suppressor cells (MDSCs) are known to accumulate under some pathologic conditions and suppress immune system in a variety of ways. This study aims to evaluate the significance of MDSCs in chronic Hepatitis C (CHC) patients. METHODS: 14 CHC patients and healthy donors were enrolled and subject to antiviral therapy including Peg-INF-alpha and Ribavirin for 48 weeks. The peripheral blood mononuclear cells (PBMCs) were collected at different weeks post therapy and MDSC frequency was analyzed by flow cytometry. The correlation between MDSCs level with CHC disease parameters was analyzed by Spearman's rank test. The suppressive function of MDSCs from CHC patients and the underlying mechanism was further evaluated. RESULTS: A significant elevation of MDSCs was observed in the peripheral blood of treatment-naive CHC patients compared with healthy donors. The level of MDSCs in CHC patients correlated with plasma HCV-RNA (r = 0.7164, p = 0.0039), blood aminotransaminase (r = 0.6116, p = 0.021), and activated CD38(+) T cells (CD4(+): r = 0.6649, p = 0.0095; CD8(+): r = 0.6189, p = 0.0189). Initiation of clinical therapy reduced MDSC levels as early as 4 weeks, while it rebounded at week 12 post-therapy in patients. CHC-derived MDSCs could suppress T cell function in an arginase-1-dependent manner, that was distinct from the HCV core protein-generated MDSCs as previously reported. CONCLUSION: Our study reveals a significant correlation between MDSC levels with HCV disease progression, and their response to antiviral therapy. The arginase-1 dependent mechanism of MDSCs from CHC patients indicates that arginase-1 may be promising target for HCV immunotherapy. PMID- 23354839 TI - Tumor necrosis factor receptor-associated factor 1 influences KRN/I-Ag7 mouse arthritis autoantibody production. AB - PURPOSE: Recently, genomewide association analysis has revealed that the Tumor Necrosis Factor Receptor-associated factor 1-Complement 5 (TRAF1-C5) containing locus on chromosome 9 was associated with an increased risk for RA. Studies in model systems suggested that either gain- or loss-of-function TRAF1 mutations have immune effects that could plausibly lead to or exacerbate the arthritis phenotype. KRN/I-A(g7) (KxB/N) is a genetic mouse model of inflammatory arthritis. We aimed to assess the impact of TRAF1 deficiency on KRN/I-A(g7) mice. METHODS: We have bred KRN/I-A(g7) mice onto a TRAF1-deficient background and followed cohorts for the spontaneous appearance of arthritis. We have also transferred KxB/N serum to B6.I-A(g7) TRAF1KO recipients. In addition, systemic autoimmunity was induced through cGVH by injecting bm12 splenocytes into TRAF1KO recipient mice. RESULTS: TRAF1-deficient KRN/I-A(g7) mice spontaneously developed severe, progressive arthritis, comparable to that seen in TRAF1-intact KRN/I A(g7) mice. However, the anti-GPI antibody titer was significantly lower in the former group. Interestingly, the TRAF1KO mice that had background levels of anti GPI antibodies still showed severe arthritis, although with a brief delay compared to TRAF1 sufficient mice. In addition, TRAF1KO mice were fully susceptible to passive, serum transfer experiments. In another model of autoimmunity, TRAF1KO had no effect on cGVH autoantibodies production; nor was the response to an exogenous antigen impaired. CONCLUSION: The pathogenesis of spontaneous KRN/I-A(g7) arthritis can largely proceed by TRAF1-independent pathways. The production of anti-GPI autoantibody, but not other autoantibody or antibody responses, was markedly impaired by TRAF1 deficiency. The spontaneous arthritis model in KRN mice appears to be much less antibody dependent than previously believed. PMID- 23354840 TI - The DC-SIGNR 7/5 genotype is associated with high dendritic cell counts and their subsets in patients infected with HIV-1. AB - PURPOSE: The aim of this study was to assess peripheral blood dendritic cell (DC) frequencies and Dendritic Cell-specific intracellular adhesion molecule 3 grabbing non-integrin related (DC-SIGNR) genotyping in healthy individuals, injecting drug users and HIV-1 infected individuals and correlate with different clinical parameters from north India. METHODS: Blood from 30 seronegative healthy individuals, 30 injecting drug users, and 30 patients infected with HIV-1 from North India were collected. Peripheral blood DC frequencies were determined by flow cytometry and repeat region polymorphism in DC-SIGNR was performed by PCR. RESULTS: There was a significantly lower number of DCs and their subsets in patients infected with HIV-1 compared to injecting drug users and healthy individuals. A significant positive correlation of DCs and their subsets with CD4(+) T cells and negative correlation with HIV-1 viral load was found. A salient finding of this study was the association of the heterozygous 7/5 DC SIGNR genotypes with higher percentage of DCs and their subsets and higher CD4(+) T cell counts and lower viral load compared to the homozygous 7/7 DC-SIGNR genotypes in patients infected with HIV-1. CONCLUSIONS: This is the first study to assess the DC subsets and its association with DC-SIGNR polymorphism in injecting drug users and HIV-1 infected patients and suggests the protective role of 7/5 DC-SIGNR genotypes in HIV-1 infection. PMID- 23354841 TI - Macrophage migration inhibitory factor in head and neck squamous cell carcinoma: clinical and experimental studies. AB - PURPOSE: The present in vivo/in vitro study was undertaken in order to evaluate the importance of macrophage migration inhibitory factor (MIF) in the progression of head and neck squamous cell carcinoma (HNSCC). METHODS: Tumor tissue expression (MIF immunostaining) and plasma levels (ELISA) of MIF were determined in HNSCC patients and correlated with tumor recurrence and metastasis, and overall survival. Furthermore, the impact of MIF expression on cell proliferation and anticancer drug sensitivity was examined in murine squamous carcinoma cell line SCCVII after MIF knockdown (MIF-KD). RESULTS: As revealed by quantitative analysis of MIF immunostaining, tumor progression was accompanied by an increase in mean optical density (MOD) and labeling index (LI). Likewise, an elevation of MIF serum levels was noted in HNSCC patients (n = 66) versus healthy individuals (n = 16). Interestingly, comparison of laryngeal carcinoma patients on the basis of MIF tissue expression (high expression, LI >= 47, versus low expression, LI < 47) disclosed a significant difference between disease-free survival curves for local and nodal recurrence, and overall survival curve. In vitro, MIF knockdown in murine SCCVII cells resulted in reduced cell proliferation and a decrease in cell motility. In mice inoculated with SCCVII cells, MIF-KD tumors grew more slowly and also appeared more sensitive to chemotherapy. CONCLUSIONS: Both clinical observations and experimental data suggest that MIF plays a pivotal role in the progression of HNSCC. PMID- 23354842 TI - Vimentin as a poor prognostic factor for triple-negative breast cancer. AB - PURPOSE: Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, is a highly heterogeneous disease. Recent studies suggest that there are links between TNBC and the epithelial-mesenchymal transition (EMT). To identify prognostic biomarkers and novel therapeutic targets, vimentin, one of the most major factors associated with EMT was investigated in TNBC. MATERIALS AND METHODS: Sporadic invasive ductal carcinoma specimens were obtained from 659 Japanese patients, and 90 (14 %) cases were diagnosed as TNBC. The vimentin mRNA and protein expression levels were evaluated by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS: The mRNA expression of vimentin was significantly upregulated in the basal-type breast cancer cell line. Immunohistochemically, the vimentin expression was significantly higher (p = 0.0042) in TNBC compared with the other subtypes. Vimentin expression was associated with a younger age (p = 0.016), high nuclear grade (p = 0.023) and high Ki67 expression (p < 0.0001), and a poorer prognosis in terms of both the recurrence-free survival (RFS) (p = 0.0058) and overall survival (OS) (p = 0.013) in TNBC patients. A multivariate analysis showed that vimentin expression was an independent prognostic factor for the RFS (p = 0.043). Vimentin expression was also associated with a significantly shorter RFS (p = 0.021) and OS (p = 0.017) in patients with basal-like breast cancer (BLBC). CONCLUSIONS: The elevated expression of vimentin contributes to the aggressive phenotype and poor prognosis in TNBC. Vimentin expression might be useful as a biomarker for the prognosis of TNBC. PMID- 23354844 TI - NP-1250, an ABCG2 inhibitor, induces apoptotic cell death in mitoxantrone resistant breast carcinoma MCF7 cells via a caspase-independent pathway. AB - Chemoresistance is one of the main obstacles to successful cancer therapy and is frequently associated with multidrug resistance (MDR). One of the most studied mechanisms of MDR is the high expression of ATP-binding cassette (ABC) transporters. Here, we demonstrated that NP-1250, an ABCG2 inhibitor, induced apoptotic cell death in ABCG2-overexpressing multidrug-resistant MCF7/mitoxantrone-resistant (MX) human breast carcinoma cells via a caspase independent pathway. Incubation of MCF7/MX cells with NP-1250 significantly reduced cell viability, while NP-1250 had little effect on the viability of drug sensitive MCF7/wild-type cells. Although the target molecules of NP-1250 in cell death remain unknown, investigation of NP-1250 will aid in the elucidation of the molecular mechanism of drug resistance and NP-1250 may become a new therapy for MDR cancers. PMID- 23354843 TI - The migratory capacity of human trophoblastic BeWo cells: effects of aldosterone and the epithelial sodium channel. AB - Aldosterone is a key regulator of the epithelial sodium channel (ENaC) and stimulates protein methylation on the beta-subunit of the ENaC. We found that aldosterone (100 nM) promotes cellular migration in a wound-healing model in trophoblastic BeWo cells. Here, we tested if the positive influence of aldosterone on wound healing is related to methylation reactions. Cell migration and proliferation were measured in BeWo cells at 6 h, when mitosis is still scarce. Cell migration covered 12.4, 25.3, 19.6 and 45.1 % of the wound when cultivated under control, aldosterone (12 h), 8Br-cAMP and aldosterone plus 8Br cAMP, respectively. Amiloride blocked the effects of aldosterone alone or in the presence of 8Br-cAMP on wound healing. Wound healing decreased in aldosterone (plus 8Br-cAMP) coexposed with the methylation inhibitor 3-deaza-adenosine (3 DZA, 12.9 % reinvasion of the wound). There was an increase in wound healing in aldosterone-, 8Br-cAMP- and 3-DZA-treated cells in the presence of AdoMet, a methyl donor, compared to cells in the absence of AdoMet (27.3 and 12.9 % reinvasion of the wound, respectively). Cell proliferation assessed with the reagent MTT was not changed in any of these treatments, suggesting that cellular migration is the main factor for reinvasion of wound healing. Electrophysiological studies showed an increase in ENaC current in the presence of aldosterone. This effect was higher with 8Br-cAMP, and there was a decrease when 3-DZA was present. AdoMet treatment partially reversed this phenomenon. We suggest that aldosterone positively influences wound healing in BeWo cells, at least in part through methylation of the ENaC. PMID- 23354845 TI - The expression of p73 in the organum vasculosum of the lamina terminalis and choroid plexus of spontaneously hypertensive rats. AB - The p73 proteins are present in different kinds of cells of the central nervous system, such as the choroid plexus, circumventricular structures and neuroepithelium. It has been reported that spontaneously hypertensive rats show ventricular dilation, changes in cerebrospinal fluid proteins and variations in the circumventricular structures such as the organum vasculosum of the lamina terminalis and the choroid plexus, which are altered in ventricular dilation. The aim of the present work is to study p73 expression in the organum vasculosum of the lamina terminalis and the choroid plexus and its variations in high blood pressure. Brains from control Wistar-Kyoto rats and spontaneously hypertensive rats were used. The organum vasculosum of the lamina terminalis and the choroid plexus were processed by immunohistochemistry and western blot with anti-TAp73. We found weaker markings in the organum vasculosum of the lamina terminalis and stronger markings in the choroid plexus of the hypertensive than the control rats. Therefore, hypertension in the spontaneously hypertensive rats produces alterations in choroid plexus protein p73 expression that is similar to that described for other circumventricular organs, but it is different in the organum vasculosum of the lamina terminalis. We can conclude that the functional balance between p73, organum vasculosum of the lamina terminalis and choroid plexus, which is probably necessary to maintain the normal functioning of these structures, is altered by the hypertension found in these rats. PMID- 23354848 TI - Genotype-dependent cooperation of ionizing radiation with BRAF inhibition in BRAF V600E-mutated carcinomas. AB - BACKGROUND: A substantial proportion of solid tumors carry the BRAF V600E mutation, which causes activation of the MEK/MAPK pathway and is a poor prognostic indicator. Patients with locally advanced human cancers are often treated with external beam radiation therapy. Given the association of Raf overactivation with radioresistance, we hypothesized that, in BRAF V600E-mutated carcinomas, there would be combinatorial activity between radiation and PLX4720, a specific BRAF V600E-inhibitor. METHODS: Two BRAF V600E-mutated cancer cell lines and one BRAF-V600E wildtype (WT) cancer cell line were obtained. We performed cell viability assays and clonogenic assays using combinations of radiation and PLX4720. We assessed MEK and MAPK phosphorylation at different PLX4720 concentrations with western blotting, and cell cycle progression was evaluated by flow cytometry. RESULTS: Our results show combinatorial, additive activity between radiation and PLX4720 in BRAF V600E-mutated cell lines, but not in the BRAF WT line. In BRAF V600E-mutated cells, there was a PLX4720 concentration-dependent decrease in MEK and MAPK phosphorylation. In cells with BRAF V600E mutations, PLX4720 caused cell cycle arrest at G1, and, when combined with radiation, caused a combined G1 and G2 cell cycle arrest; this pattern of cell cycle effects was not seen in the BRAF WT cell line. CONCLUSIONS: These data suggest additive, combinatorial activity between radiation and PLX4720 in cancers carrying BRAF V600E mutations. Our data has potential for translation into the multimodality treatment of BRAF V600E-mutated cancers. PMID- 23354849 TI - A phase II study of cediranib (AZD 2171) in treatment naive patients with progressive unresectable recurrent or metastatic renal cell carcinoma. A trial of the PMH phase 2 consortium. AB - BACKGROUND: Inhibition of angiogenesis has emerged as an effective therapeutic strategy in metastatic renal cell cancer (mRCC). In this single arm phase 2 study, we evaluated the efficacy and tolerability of cediranib (AZD2171) a potent angiogenesis inhibitor in first line mRCC. METHODS: Eligible patients who had no prior systemic therapy received cediranib 45 mg orally once daily continuously. The primary endpoint was objective response rate (ORR). Secondary endpoints were clinical benefit rate (ORR plus stable disease (SD) >= 4 months), duration of response, progression free survival (PFS), median overall survival (OS), safety and tolerability. RESULTS: Between January 2006 and April 2008, 44 patients were accrued. The median age was 62 (range 44-83) and performance status was either 0 (22 patients) or 1 (22 patients). Of the 39 evaluable patients there were 15 (38 %) partial responses (95 % CI: 23-55 %); 18 stable disease (SD) for a clinical benefit rate of 33/39 = 85 % (95 % CI: 69-94 %) and 6 progressive disease. Median PFS was 8.9 months (95 % CI: 5.1-12.9); and median OS was 28.6 months (95 % CI: 18.2-37.3 months). The most frequent grade 3 or higher AEs included hypertension, fatigue, hand-foot syndrome and diarrhea. CONCLUSIONS: Cediranib demonstrated significant anti-tumour activity in first line, treatment-naive mRCC, with efficacy parameters comparable to the other approved agents (sunitinib and pazopanib) in this setting. The main toxicities were fatigue, diarrhea and hypertension. Based on these encouraging results, further evaluation of cediranib in mRCC at a more tolerable dose of 30 mg daily appears warranted. PMID- 23354850 TI - Accuracy of self-reported smoking status in first trimester aneuploidy screening. AB - OBJECTIVES: To review the accuracy of self-reporting of smoking status in our first trimester screening population and to assess the levels of pregnancy associated plasma protein-A (PAPP-A) and free-beta human chorionic gonadotropin (free-hCGbeta) in women who were classified for smoking status by serum cotinine concentrations and self-reporting. METHODS: Cotinine concentration was determined in the stored serum 696 self-reported smokers and 442 self-reported non-smokers. PAPP-A and free-hCGbeta multiples of the medians (MoMs) determined at screening were reverted to uncorrected for self-reported smoking status. RESULTS: A total of 21.7% of those self-reporting as non-smokers had increased serum cotinine concentrations (using a cut-off of 13.7 ng/mL), indicating a positive smoking status. This under-reporting meant that serum PAPP-A and free-hCGbeta MoMs were greater reduced in smokers classified by cotinine levels (17.2% and 9.7%) than in those classified by self-reporting (14.6% and 2.8%). Women who were classified as smokers at conception but had stopped at some time afterwards did not have significantly reduced marker MoMs to non-smokers. CONCLUSIONS: Self-reporting results in under-representation of smoking in our population, resulting in a significant bias and inflated screen-positive rates. PMID- 23354851 TI - [Fetal magnetic resonance imaging of thoracic and abdominal malformations]. AB - CLINICAL/METHODICAL ISSUE: Diagnosis and differential diagnosis of fetal thoracic and abdominal malformations. STANDARD RADIOLOGICAL METHODS: Ultrasound and magnetic resonance imaging (MRI). METHODICAL INNOVATIONS: In cases of suspected pathologies based on fetal ultrasound MRI can be used for more detailed examinations and can be of assistance in the differential diagnostic process. PERFORMANCE: Improved imaging of anatomical structures and of the composition of different tissues by the use of different MRI sequences. ACHIEVEMENTS: Fetal MRI has become a part of clinical routine in thoracic and abdominal malformations and is the basis for scientific research in this field. PRACTICAL RECOMMENDATIONS: In cases of thoracic or abdominal malformations fetal MRI provides important information additional to ultrasound to improve diagnostic accuracy, prognostic evaluation and surgical planning. PMID- 23354852 TI - A cross-sectional evaluation of correlates of HIV testing practices among men who have sex with men (MSM) in Mongolia. AB - This study analyzed patterns and associations of HIV testing including sexual practices, HIV related knowledge, and human rights contexts among MSM in Mongolia. 313 participants were accrued using respondent-driven sampling and administered a structured questionnaire. Descriptive statistics are presented with crude and adjusted-point estimates with confidence intervals (95 % CI); and logistic regression models were used to identify factors associated with HIV testing in the last 12 months. RDS-adjustment demonstrated that 48.9 % (95 % CI = 36.7-58.3) of MSM had an HIV test in the past 12 months. Logistic regression revealed that experience of a human rights violation, enacted (OR = 0.50, 95 % CI = 0.26-0.97) or perceived (OR = 0.56, 95 % CI = 0.26-0.97), was inversely associated with a recent HIV test. Higher level of education (OR = 1.84, 95 % CI = 1.14-2.99), knowledge that anal sex is highest risk for HIV infection (OR = 4.54, 95 % CI = 2.41-8.56), and having 5 or more male sexual partners (OR = 1.82, 95 % CI = 1.00-3.30), were positively associated with a recent HIV test. MSM in Mongolia are at high risk for HIV infection and coverage of HIV testing is suboptimal. Understanding the variable sexual risk practices and barriers to HIV testing are vital to designing effective and relevant HIV-status dependent HIV intervention services. PMID- 23354855 TI - Intussusception in the elderly. AB - We present the case of an 82-year-old Caucasian lady with a 16-day history of colicky lower abdominal pain and reduced appetite. When presenting to hospital she was haemodynamically stable with no fever. Examination revealed a soft but tender abdomen with normal bowel sounds. No masses or hernias were present. Per rectal examination revealed an empty rectum. Investigations showed raised inflammatory markers, white cell count 11.9 and C reactive protein 24, in addition to which she had dilated loops of small and large bowel on the abdominal radiograph. The patient underwent an emergency laparotomy where a mass in the descending colon was found to be intussuscepting into the proximal sigmoid colon for which a Hartmanns procedure was performed. Histopathology confirmed a Dukes B T3 N0 Mx adenocarcinoma. PMID- 23354859 TI - Thrombolysis in submassive pulmonary embolism, prudent or puerile? AB - Pulmonary embolism (PE) remains one of the leading causes of cardiovascular mortality. The safety and efficacy of thrombolytic therapy using tissue-type plasminogen activator (tPA) for acute PE in clinical practice remain unclear. We describe a case of life-threatening submassive PE causing extreme refractory hypoxaemia, where thrombolysis was successfully administered. Current consensus suggests that patients with features of hemodynamic instability as a result of an acute PE, that is, massive PE, should receive thrombolysis. Patients, not in shock however, but with evidence of right-ventricular (RV) dysfunction echocardiographically, that is, submassive PE may also benefit. Serum troponin and brain-type natriuretic peptide have been suggested as biomarkers of RV injury that may identify a subset of submassive PE patients who may particularly benefit from thrombolytic therapy. The clinical response of this patient to thrombolysis is important, as it may identify a subgroup of patients with submassive PE who warrant this intervention. PMID- 23354860 TI - Paediatric idiopathic intracranial hypertension. AB - Idiopathic intracranial hypertension (IIH) can occur in paediatric age with clinical characteristics that may differ from adult presentation. The authors present a case of an 11-year-old boy, presenting with severe holocranial headaches for the past 4 weeks. Best-corrected visual acuities (BCVA) were 20/200 bilaterally and the fundus examination showed marked bilateral optical disc and macular oedema. CT scan with contrast as well as MRI showed no space occupying lesions, normal permeability of the dural venous sinuses and a partially empty sella. Lumbar puncture revealed an opening pressure of 540 mm Hg, with clear cerebrospinal fluid, with normal biochemistry and cytology. The patient was treated medically and subsequently submitted to a ventriculoperitoneal shunting procedure. 3 months after surgery the symptoms got completely resolved and his BCVA were 20/20 bilaterally. PMID- 23354861 TI - A child with a long-standing, intensely itching subcutaneous nodule on a thigh: an uncommon (?) reaction to commonly used vaccines. AB - A 2-year-old girl presented with an intensely itching subcutaneous nodule on the front of a thigh. The nodule persisted for 10 months until it was excised. Subsequent investigation for malignancy and systemic disease showed no pathological findings. The diagnosis, persistent itching vaccination granuloma, was revealed by hazard almost 2 years after the onset of symptoms. Persistent itching subcutaneous nodules at the injection site for aluminium containing vaccines (mostly diphtheria-tetanus-pertussis combination vaccines for primary immunisation of infants) may appear with a long delay after the vaccination (months), cause prolonged itching (years) and are often associated with contact allergy to aluminium. The condition is poorly recognised in Health Care which may lead to prolonged symptoms and unnecessary investigations. PMID- 23354862 TI - Extrinsic colonic obstruction by congenital fibrous band in an infant. AB - The finding of a congenital fibrous band during laparotomy for intestinal obstruction is extremely rare. Preoperative diagnosis is challenging and no characteristic radiological findings have been described. We report the case of a premature baby in whom incomplete intestinal obstruction was due to a congenital band originating from the duodeno-jejunal flexure and extending across the ascending colon. PMID- 23354863 TI - Adenocarcinoma: not all that wheezes is asthma. PMID- 23354864 TI - Unforeseen renal pathological findings in a patient with type 2 cardiorenal syndrome who died after 4 years of continuous ambulatory peritoneal dialysis. AB - A man in his 30s with dilated cardiomyopathy was admitted to our hospital with heart failure exacerbation. Despite optimal medical treatment, his renal function progressively declined to end-stage renal failure. Type 2 cardiorenal syndrome (CRS) was diagnosed and continuous ambulatory peritoneal dialysis was started. He died of a brainstem infarction 4 years later. Postmortem renal pathology revealed no significant changes in the glomeruli except for shrinkage, normal arterioles and focal degeneration of the tubules with peritubular fibrosis. This suggests that renal replacement therapy can be withdrawn from some patients with type 2 CRS. PMID- 23354865 TI - Traumatic fibroma of tongue. PMID- 23354866 TI - Denervation of the ear and the 'folding flower' illusion. AB - Following acute denervation of the ear, I experienced altered cutaneous sensory perception analogous to that reported by patients after limb amputation. This suggests that any sudden, complete loss of somaesthetic sensation can result in cortical reorganisation reflecting lost peripheral input. Although the short time course of the phenomenon suggests an initial functional reorganisation, it does not preclude longer time course structural alterations at multiple levels of the nervous system. PMID- 23354867 TI - Reversible cerebral vasoconstriction syndrome and bilateral vertebral artery dissection presenting in a patient after cesarean section. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by sudden onset thunderclap headache and focal neurologic deficits. Once thought to be a rare syndrome, more advanced non-invasive imaging has led to an increase in RCVS diagnosis. Unilateral vertebral artery dissection has been described in fewer than 40% of cases of RCVS. Bilateral vertebral artery dissection has rarely been reported. We describe the case of a patient with RCVS and bilateral vertebral artery dissection presenting with an intramedullary infarct treated successfully with medical management and careful close follow-up. This rare coexistence should be recognized as the treatment differs. PMID- 23354869 TI - A closer look at associations between hospital leadership walkrounds and patient safety climate and risk reduction: a cross-sectional study. AB - Leadership walkrounds (WRs) are widely used in health care organizations to improve patient safety. This retrospective, cross-sectional study evaluated the association between WRs and caregiver assessments of patient safety climate and patient safety risk reduction across 49 hospitals in a nonprofit health care system. Linear regression analyses using units' participation in WRs were conducted. Survey results from 706 hospital units revealed that units with >= 60% of caregivers reporting exposure to at least 1 WR had a significantly higher safety climate, greater patient safety risk reduction, and a higher proportion of feedback on actions taken as a result of WRs compared with those units with <60% of caregivers reporting exposure to WRs. WR participation at the unit level reflects a frequency effect as a function of units with none/low, medium, and high leadership WR exposure. PMID- 23354868 TI - Tumor targeting of the IL-15 superagonist RLI by an anti-GD2 antibody strongly enhances its antitumor potency. AB - Immunocytokines (ICKs) targeting cytokines to the tumor environment using antibodies directed against a tumor-associated antigen often have a higher therapeutic index than the corresponding unconjugated cytokines. Various ICKs displaying significant antitumoral effects in several murine tumor models have already been developed, and some of them, in particular interleukin (IL)-2-based ICKs, are in Phase II clinical trials. Although sharing common biological activities with IL-2 in vitro, IL-15 is now considered as having a better potential in antitumor immunotherapeutical strategies and has been shown to be less toxic than IL-2 in preclinical studies. We previously developed the fusion protein RLI, linking a soluble form of human IL-15Ralpha-sushi+ domain to human IL-15. RLI showed better biological activities than IL-15 in vitro as well as higher antitumoral effects in vivo in murine and human cancer models. Here, we investigated, in the context of an ICK, the effect of associating RLI with an antibody targeting the GD2 ganglioside, a validated tumoral target expressed on many neurectodermal tumors. Anti-GD2-RLI fully retained the cytokine potential of RLI and the antibody effector functions (antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity). It displayed strong antitumor activities in two syngeneic cancer models in immunocompetent mice (subcutaneous EL4 and metastatic NXS2). Its therapeutic potency was higher than those of RLI and anti GD2 alone or in combination. We suggest that this is related to its bifunctional (cytokine and antibody) nature. PMID- 23354870 TI - Understanding and execution of discharge instructions. AB - Discharge from the acute care hospital is increasingly recognized as a time of heightened vulnerability for lapses in safety and quality. The capacity of patients to understand and execute discharge instructions is critical to promote effective self-care. This study explores factors that predict understanding and execution of discharge instructions in a sample of 237 recently discharged older adults. A study nurse conducted a postdischarge home visit to ascertain patient understanding and assess execution of instructions. Health literacy, cognition, and self-efficacy were important predictors of successful understanding and execution of instructions. Neither discharge diagnosis nor complexity of discharge instructions was found to be a significant predictor of these outcomes. Results indicate a need to implement reliable protocols that identify patients at risk for poor understanding and execution of hospital discharge instructions and provide customized approaches to meet them at their respective levels. PMID- 23354872 TI - Identifying preservation and restoration priority areas for desert fishes in an increasingly invaded world. AB - A commonly overlooked aspect of conservation planning assessments is that wildlife managers are increasingly focused on habitats that contain non-native species. We examine this management challenge in the Gila River basin (150,730 km(2)), and present a new planning strategy for fish conservation. By applying a hierarchical prioritization algorithm to >850,000 fish records in 27,181 sub watersheds we first identified high priority areas (PAs) termed "preservation PAs" with high native fish richness and low non-native richness; these represent traditional conservation targets. Second, we identified "restoration PAs" with high native fish richness that also contained high numbers of non-native species; these represent less traditional conservation targets. The top 10 % of preservation and restoration PAs contained common native species (e.g., Catostomus clarkii, desert sucker; Catostomus insignis, Sonora sucker) in addition to native species with limited distributions (i.e., Xyrauchen texanus, razorback sucker; Oncorhynchus gilae apache, Apache trout). The top preservation and restoration PAs overlapped by 42 %, indicating areas with high native fish richness range from minimally to highly invaded. Areas exclusively identified as restoration PAs also encompassed a greater percentage of native species ranges than would be expected by the random addition of an equivalent basin area. Restoration PAs identified an additional 19.0 and 26.6 % of the total ranges of two federally endangered species-Meda fulgida (spikedace) and Gila intermedia (Gila chub), respectively, compared to top preservation PAs alone-despite adding only 5.8 % of basin area. We contend that in addition to preservation PAs, restoration PAs are well suited for complementary management activities benefiting native fishes. PMID- 23354871 TI - Perioperative hypothermia in the pediatric population: a quality improvement project. AB - There are limited data in the pediatric population regarding the incidence of, risk factors for, and means to prevent perioperative hypothermia. The Institute for Healthcare Improvement Model for quality improvement (QI) methodology was used to bundle the most effective techniques to prevent hypothermia. A multidisciplinary QI team was assembled with the goal to decrease the incidence of perioperative hypothermia by 50%. The baseline incidence of hypothermia was determined and causes identified using a flowchart and a cause-and-effect diagram. Pareto charts were formed and opportunities to decrease the incidence of perioperative hypothermia were trialed. The baseline incidence of hypothermia was 8.9%. Implementation of a standardized temperature management bundle in the operating rooms decreased the incidence to 4.2%. The QI methodology was useful to bundle the most effective techniques to prevent hypothermia, resulting in standardized perioperative care and a sustained reduction in the incidence of perioperative hypothermia. PMID- 23354873 TI - Governance change and institutional adaptation: a case study from Harenna forest, ethiopia. AB - Many common pool resources have traditionally been managed through intricate local governance arrangements. Over time, such arrangements are confronted with manifold political, social, economic and ecological changes. However, the ways in which local governance arrangements react to such changes are poorly understood. Using the theoretical concept of institutional adaptation, we analyse the history of Harenna forest, Ethiopia, to examine processes of institutional change over the last 150 years. We find that the traditional institutions that governed Harenna's resources persisted, in essence, over time. However, these institutions were modified repeatedly to address changes caused by varying formal, supra regional governance regimes, the development of markets for forest products, increasing population pressure and changes in formal property rights. A key mechanism for adaptation was combining elements from both informal and formal institutions, which allowed traditional rules to persist in the guise of more formal arrangements. Our findings also highlight several constraints of institutional adaptation. For example, by abolishing fora for collective decision making, regime changes limited adaptive capacity. To conclude, we argue that such insights into traditional resource governance and its adaptability and dynamics over time are essential to develop sustainable approaches to participatory forest management for the future, both in Harenna and more generally. PMID- 23354874 TI - Autocrine role for Gas6 with Tyro3 and Axl in leiomyosarcomas. AB - Leiomyosarcoma (LMS) represent 15 % of adult sarcomas. The aim of this work was to identify novel altered pathways in LMS, which may be of therapeutic value for patients. Thirteen fresh frozen samples of soft tissue and visceral LMS were analyzed and compared with normal smooth muscle uterine tissue (NSM) for phosphoproteomic profile. Four proteins were found differentially expressed including Tyro3. The functional role of Tyro3 and its ligand Gas6 was investigated in two LMS cell lines, SK-LMS-1 and CNIO-AA. Four proteins and phosphoproteins were differentially expressed in LMS samples vs NSM: A loss of FAK Y397 phosphorylation was observed in all LMSs, while Tyro3, MSH2 and PKC theta were consistently overexpressed. Gas6, the major ligand of Tyro3, was expressed in 8 of the 13 LMS samples, and Gas6 expression highly correlated to Akt Y473 phosphorylation and to a lesser extent to Erk1/2 phosphorylation. SK-LMS 1 and CNIO-AA LMS expressed Tyro3, Axl and Gas6 at high level in CNIO-AA while at low levels in SK-LMS-1. Exposure of both cell lines to foretinib, a tyrosine kinase inhibitor of Met, Axl and Tyro3, reduced cell viability and induced caspase 3/7 activation. Transfection of CNIO-AA with small interfering RNA directed against Tyro3 and Axl genes induced a reduction of the expression of the specific proteins and, when combined, significantly reduced CNIO-AA cell viability. Leiomyosarcomas overexpress Tyro3. Gas6, a ligand of Tyro3, exerts an autocrine activities though Tyro3 and Axl in a subgroup of LMS. PMID- 23354876 TI - Executive function in eating disorders: the role of state anxiety. AB - OBJECTIVE: We examined the influence of depression and anxiety on executive function in individuals with a DSM-IV diagnosis of anorexia nervosa-restricting type, anorexia nervosa-binge-eating/purging type, bulimia nervosa, or eating disorder not otherwise specified. METHOD: We assessed 106 women after their inpatient treatment in an eating disorders program. All participants were nutritionally stable at the time of testing. RESULTS: Thirty percent of the total sample showed impaired performance on one or more tests of executive function. No differences in executive function were observed among diagnostic groups. Anxiety scores accounted for significant variance in performance for all groups. DISCUSSION: Executive function deficits were found in a minority of our sample, with significant variance in performance accounted for by self-reported anxiety. State anxiety appears to contribute to diminished executive function in women with eating disorders. PMID- 23354875 TI - Clinical meta-analyses of targeted therapies in adenocarcinoma. AB - Although the interpretation of the data reported in meta-analyses may hide several issues, it is undoubtable that this methodological approach may significantly contribute to implement the results of clinical trials, and represent a useful and practical tool for the evidence-based medicine process. Indeed, level-one recommendations should consider well-conducted meta-analyses as well as large and adequately powered randomized trials as the main contributors for the definition of guidelines for clinical practice. In addition, the role of meta-analyses for issues whereas conflicting data (and/or unpowered results) are provided, is well established. In the field of lung cancer, meta-analyses already participated to change the current standard, and are now facing the challenging issues of predictive biomarkers of prognosis and/or efficacy of targeted agents. With this aim, the meta-analytic approach helped in the recent years to implement the quantification of the magnitude of the benefit of targeted agents, and added new insights by interpreting the data coming from clinical trials by integrating them with biomarkers. The treatment-interaction analyses according to putative predictive factors of efficacy may clarify unknown issues and generate new hypotheses for future perspectives. The current review attempts to put in the context of the clinical data of targeted agents for lung cancer all the pros and cons of the meta-analytic process published to date, and critically analyze all the potential perspectives which this methodology may add for both current practice and forthcoming research. PMID- 23354878 TI - A case of unilateral fenestration of the external jugular vein, through which the cervical branch of the facial nerve passes. PMID- 23354877 TI - Sympathetic hyperactivity in chronic kidney disease: pathophysiology and (new) treatment options. AB - Abundant evidence shows that chronic kidney disease (CKD) is a disease state characterized by increased sympathetic activation. Kidney injury (ischemia) plays a central role in this pathogenesis. Sympathetic excitation is associated with an increased risk of cardiovascular morbidity and mortality. Several pharmacologic strategies are developed to decrease sympathetic activity. However, these medications have limitations. Percutaneous catheter-based renal denervation has the potential to become a new treatment option for CKD. This current report focuses on the effects of sympathetic hyperactivity in CKD, and gives an overview in experimental as well as clinical evidence for a central role of the kidneys in the pathophysiology of sympathetic hyperactivity. Moreover, the effect of pharmacologic treatment and the potential beneficial effect of renal denervation will be discussed. PMID- 23354879 TI - Structure elucidation of four prenylindole derivatives from Streptomyces sp. isolated from Ailuropoda melanoleuca feces. AB - Four new prenylindole derivatives, (R)-6-(2,3-dihydroxy-3-methylbutyl)indole (1), (R)-6-(2,3-dihydroxy-3-methylbutyl)indolin-2-one (2), and an unseparated mixture of (Z)-6-(4-hydroxy-3-methylbut-2-en-1-yl)indolin-2-one (3a) and (E)-6-(4-hydroxy 3-methylbut-2-en-1-yl)indolin-2-one (3b) with a ratio of 3 : 2, were isolated from the culture broth of a streptomycete isolated from Ailuropoda melanoleuca feces. Their structures were elucidated on the basis of 1D and 2D NMR spectroscopic techniques. The absolute configuration of 1 was determined by Mosher's method. PMID- 23354881 TI - The expression profile of microRNAs in wistar rats with lipopolysaccharide induced periventricular leukomalacia. AB - Over the recent decades, with numbers of premature infants being cured, clinical diseases on brain damage like periventricular leukomalacia (PVL) have become much more common. Meanwhile, since the discovery of first miRNA lin-4, an increasing number of important studies about this small RNA have been performed not only in the normal organ development but also in the pathogenic mechanism of diseases. However, throughout the past several years, there have been rare miRNA researches discussing the connection between the PVL and miRNA. In view of this situation, we constructed an animal model of PVL induced by lipopolysaccharide (LPS) and performed a miRNA microarray which was repeated three times to profile the expression of microRNAs (miRNAs) between two groups (PVL group versus control group). Then, miRNAs with notable fold changes (fold change >1.5) were found; some of them were further validated by real-time PCR. As a result, 104 differentially expressed miRNAs were identified using the microarray, including 64 upregulated and 40 downregulated miRNAs. Then, five miRNAs of them were selected, characterized by consistent trend in expression in all three microarrays. Among these five miRNAs (miRNA-451, miRNA-200b, miRNA-29a, miRNA-21, and miRNA-138), we subsequently selected miRNA-451 and miRNA-200b for real-time PCR because they possess the highest fold changes. Finally, the results of PCR are basically in accord with the microarray. We guess these new identified miRNAs may play an important role in the pathogenesis of PVL and may provide certain pathophysiological basis for the future research of related diseases in preterm infants. PMID- 23354880 TI - Galanin-like peptide (GALP) facilitates thermogenesis via synthesis of prostaglandin E2 by astrocytes in the periventricular zone of the third ventricle. AB - Administration of galanin-like peptide (GALP) leads to a decrease in both total food intake and body weight 24 h after injection, compared to controls. Moreover, GALP induces an increase in core body temperature. To elucidate the mechanism by which GALP exerts its effect on energy homeostasis, urethane-anesthetized rats were intracerebroventricularly injected with GALP or saline, after which oxygen consumption, heart rate, and body temperature were monitored for 4 h. In some cases, animals were also pretreated with the cyclooxygenase (COX) inhibitor, diclofenac, via intracerebroventricular (i.c.v.) or intravenous (i.v.) injection. c-Fos expression in the brain was also examined after injection of GALP, and the levels of COX and prostaglandin E(2) synthetase (PGES) mRNA in primary cultured astrocytes treated with GALP were analyzed by using qPCR. The i.c.v. injection of GALP caused biphasic thermogenesis, an effect which could be blocked by pretreatment with centrally (i.c.v.), but not peripherally (i.v.) administered diclofenac. c-Fos immunoreactivity was observed in astrocytes in the periventricular zone of the third ventricle. GALP treatment also increased COX-2 and cytosolic PGES, but not COX-1, microsomal PGES-1, or microsomal PGES-2 mRNA levels in cultured astrocytes. We, therefore, suggest that GALP elicits thermogenesis via a prostaglandin E(2)-mediated pathway in astrocytes of the central nervous system. PMID- 23354882 TI - Percutaneous computed tomography-guided resection of non-spinal osteoid osteomas in 54 patients and review of the literature. AB - BACKGROUND: Osteoid osteoma is a benign osteoblastic tumor with a nidus of <20 mm in maximum diameter. There are several treatment options, all of them aiming either to resect or to eliminate the nidus. PURPOSE: To report and to describe the benefits of treating non-spinal osteoid osteoma by percutaneous computed tomography-guided resection, according to our experience. STUDY DESIGN: Retrospective case series METHODS: Between 1992 and 2008, 54 patients with non spinal osteoid osteoma underwent primary treatment with percutaneous CT-guided resection. In all cases, the materials obtained were processed for pathology and microbiology. RESULTS: Fifty-four patients with a mean age of 22.7 years (range 10-47), of whom 46 were males (85.2 %) and 8 were females (14.8 %). The lesion size ranged between 5 and 15 mm with an average size of 6.9 mm. The resection was considered complete by the CT study in all 54 cases. Of all the specimens sent to pathology, the histological diagnosis was achieved in 41 (75.9 %). Cure was obtained in 50 patients (92.6 %) and the other four patients required a second surgery using the same technique, after which all of them achieved clinical and radiological improvement (100 %). CONCLUSION: Percutaneous computed tomography guided resection of non-spinal osteoid osteomas provides good results, similar to other surgical techniques, with the advantages of being a simple, mini invasive, safe and economic procedure without the need for specific materials. Level of evidence, IV. PMID- 23354883 TI - The value of resident presentations at scientific meetings. PMID- 23354884 TI - External auditory canal exostosis. PMID- 23354885 TI - Castleman disease of the neck: an uncommon location. PMID- 23354886 TI - Wegener granulomatosis. PMID- 23354887 TI - Bilateral mastoid subperiosteal abscesses in an infant. PMID- 23354888 TI - Large bilateral internal auditory meatus associated with bilateral superior semicircular canal dehiscence. AB - Superior semicircular canal dehiscence and an abnormally wide internal auditory meatus are clinical entities characterized by vestibular and cochlear symptoms. These symptoms are induced by hypersensitivity of labyrinthine receptors secondary to a bone defect of the otic capsule. We report the case of a 41-year old man with congenital right-sided hearing loss who presented with bilateral superior semicircular canal dehiscence that was associated with wide, bulbous internal auditory meatus and a loss of the bony wall separating the lateral end of the meatus from the cochlea. The patient was experiencing vestibular and cochlear symptoms in the right ear and disabling tinnitus in the left ear. However, he refused all treatment and was lost to follow-up. PMID- 23354889 TI - Nontuberculous mycobacterial otomastoiditis: a case report. AB - Nontuberculous mycobacterial otomastoiditis is rare and can be easily confused with various different forms of otitis media. We describe the case of a 50-year old woman who presented with left-sided chronic otitis media that had persisted for more than 1 year. It was not eradicated by standard antimicrobial therapy and surgical debridement. After appropriate antibiotic therapy for nontuberculous mycobacteria was added to the therapeutic regimen, the patient improved significantly and the lesion had healed by 6 months. Based on our experience with this case, we conclude that early bacterial culture and staining for acid-fast bacilli in ear drainage material or granulation tissue should be performed when standard antimicrobial therapy fails to eradicate chronic otitis media of an undetermined origin that is accompanied by granulation tissue over the external auditory canal or middle ear. Polymerase chain reaction testing is also effective for rapid diagnosis. Surgical debridement and removal of the foreign body can successfully treat nontuberculous mycobacterial otomastoiditis only when effective antimicrobial therapy is also administered. PMID- 23354890 TI - Pilomatricoma of the pinna. AB - A 4-year-old boy presented with a painless swelling over the right pinna of 4 months' duration. Histopathologic examination of the excised mass revealed features of pilomatricoma-a rare, benign skin neoplasm arising from hair follicle matrix cells. The unusual location of the lesion over the pinna, despite its frequent occurrence in the head and neck, prompted this article. We discuss the etiology, clinical presentation, and management of pilomatricoma of the auricular region. PMID- 23354892 TI - Ectopic thymus presenting as a retropharyngeal mass: surgical approach. AB - Cervical ectopic thymus is a rare cause of solid neck masses in children. Most children are asymptomatic, but some may present with a palpable neck mass, with or without compressive symptoms. Cervical ectopic thymus is often discovered incidentally and mistaken for an infection or neoplasm. We present the case of an infant with retropharyngeal ectopic thymus and describe our intraoral surgical approach. PMID- 23354891 TI - Primary mucosal melanoma arising from the eustachian tube with CTLA-4, IL-17A, IL 17C, and IL-17E upregulation. AB - Primary malignant melanoma arising from the eustachian tube is extremely rare. We report the case of a 63-year-old white man who presented with a 1-month history of left-sided hearing loss and aural fullness. Flexible fiberoptic laryngoscopy detected a blue-purple mass that appeared to arise from the left lateral nasopharynx. Computed tomography demonstrated an enhancing mass arising from an orifice of the left eustachian tube. The tumor was debulked endoscopically and was confirmed to have originated in the left eustachian tube. Histologically, the tumor was made up of heavily pigmented pleomorphic spindle cells with frequent mitoses. The tumor cells were immunohistochemically positive for S-100 protein, HMB-45, Melan-A, and PNL-2. The final diagnosis was a mucosal malignant melanoma. We also performed a nested polymerase chain reaction assay for several genes of interest, including CTLA-4, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F, PLZF, Foxp3, RORgammat, CD27, and CD70. These genes have been studied mainly in cutaneous melanomas, especially for the development of immunotherapy, but only very limited studies have been done on mucosal melanomas. Our investigation found upregulation of CTLA-4, IL-17A, IL-17C, and IL-17E. Based on our finding of CTLA 4 upregulation, it may be suggested that our patient might have had low antitumor immunity and that he might have benefited from CTLA-4 blockade. On the other hand, upregulation of IL-17A and IL-17E might reflect increased antitumor immunity, which could suggest that patients with a mucosal melanoma might benefit from immunomodulators associated with the effect of Th17. These genes also have great potential to help melanoma patients obtain tailored treatment, and they can be used as biomarkers for predicting prognosis. PMID- 23354893 TI - Parry-Romberg syndrome in an adult: report of a case. AB - Parry-Romberg syndrome is an uncommon degenerative disorder characterized by a slow and progressive atrophy of the subcutaneous tissue on one side of the face. Its etiology is unknown, and there is no cure. It is usually seen in children. Surgical reconstruction is often the best treatment option, and a wide variety of techniques have been employed. It is often difficult to diagnose Parry-Romberg syndrome because its signs and symptoms overlap with those of several other disorders. We describe a case of Parry-Romberg syndrome in a 42-year-old woman, whose age at onset was the unusual feature of this case. PMID- 23354894 TI - Complicated coexisting pyogenic and tuberculous otitis media affecting the temporozygomatic, infratemporal, and parotid areas: report of a rare entity. AB - We report an unusual case in which a 28-year-old woman presented with a long standing history of ear discharge, hearing loss, facial weakness with ipsilateral facial swelling and cellulitis, a postauricular fistula, and an abscess of the temporozygomatic, infratemporal, and parotid areas. The pus stained positive for bacteria and acid-fast bacilli, and culture was positive for Proteus vulgaris and mycobacteria. Based on these findings, a diagnosis of tuberculous otitis media with complications was made. Computed tomography showed extensive destruction of the tympanic and mastoid part of the temporal bone, as well as lytic lesions in the skull. The patient was placed on antituberculosis drug therapy. Although her facial nerve palsy and hearing loss persisted, she otherwise responded well and did not require surgery. PMID- 23354895 TI - Unilateral parotid agenesis associated with pleomorphic adenoma of ipsilateral accessory parotid gland. AB - Congenital agenesis of the parotid gland is rare, and its association with accessory parotid tissue is even rarer. We report an unusual case of unilateral agenesis of the left parotid gland associated with pleomorphic adenoma of the left accessory parotid gland. To best of our knowledge, this is only the second such published case in the literature. PMID- 23354896 TI - Acute dystonic reaction to general anesthesia with propofol and ondansetron: a graded response. AB - Propofol and ondansetron, alone and in combination, have been associated with acute dystonic reactions during recovery from anesthesia. We report the case of a 44-year-old woman who had undergone microlaryngoscopic fat injection to the vocal folds three times over a period of 10 months. Each procedure was performed by the same surgeon. On each occasion, the patient received an identical anesthetic that was administered by the same anesthetist. The anesthetic regimen included propofol and ondansetron. Following the first procedure, the patient experienced no reaction to these agents. However, she experienced a mild reaction after the second procedure and a severe acute dystonic reaction after the third. We believe this is the first report of a graded reaction to either propofol or ondansetron. PMID- 23354897 TI - Restoration of the efferent phase of the sneeze reflex after regression of an Arnold-Chiari malformation with compression of the medulla oblongata. AB - The precise location of the sneeze center in the human brain has not been definitively identified. The aim of this report is to contribute to the effort to detect its location. We report the case of a 13-year-old boy who presented to our outpatient clinic for evaluation of an inability to sneeze. In an attempt to trigger the afferent (nasal) phase of the sneeze reflex, we first applied a cotton swab and later a silver nitrate stick to the patient's nasal mucosa. Once that was accomplished, we observed that the patient could not complete the efferent (expiratory) phase of the sneeze reflex, and thus he did not sneeze. Cranial magnetic resonance imaging (MRI) revealed that his cerebellar tonsils extended approximately 10 mm inferiorly through the foramen magnum, which represented a type I Arnold-Chiari malformation. The tonsils were noted to have compressed the posterolateral portion of the medulla oblongata. At follow-up 21 months later, we noted that the patient was able to sneeze spontaneously as well as with nasal stimulation. Repeat MRI revealed that the Arnold-Chiari malformation had undergone a spontaneous partial regression, which resulted in relief of the compression of the medulla oblongata. We believe that the patient's earlier inability to sneeze might have been attributable to the compression of the medulla oblongata by the cerebellar tonsils and that the site of the compression might represent the location of his sneeze center. PMID- 23354898 TI - Hyperplastic epiglottis caused by chronic inflammation. PMID- 23354899 TI - Fungal sinusitis with a nasal septal perforation. PMID- 23354900 TI - Facial nerve sheath hematoma and paralysis after cochlear implant surgery. PMID- 23354901 TI - Intramuscular lipoma of the tongue masquerading as angioedema. AB - In most cases, the diagnostic evaluation of angioedema is challenging, as there are many possible etiologies. We report a case of an infiltrating lipoma of the tongue that masqueraded as angioedema. The patient, a 68-year-old man, presented with tongue swelling that had followed a waxing and waning course over a 6-month period. Physical examination showed a diffusely enlarged tongue with no discrete mass. A laboratory evaluation for angioedema was unremarkable. After the patient's condition did not respond to treatment with antihistamines and oral prednisone, a further workup was initiated. Magnetic resonance imaging of the neck and computed tomography of the oral cavity revealed only diffuse enlargement of the tongue. The patient underwent a tongue biopsy, which identified the cause of the swelling to be an infiltrating lipoma of the tongue. Clinicians should be aware that other causes of tongue swelling may mimic angioedema. PMID- 23354902 TI - Massive calcification in a pleomorphic adenoma: report of an unusual presentation. AB - We report a case of histology-proven pleomorphic adenoma of the parapharyngeal space in a 20-year-old man. This case was unusual in that a massive amount of dystrophic calcification was scattered throughout the tumor. The patient underwent successful surgical resection, and he exhibited no signs of recurrence during follow-up. Literature about such an unusual presentation is scarce. PMID- 23354903 TI - Malignant melanoma metastatic to the larynx: a case report. AB - Malignant melanoma of the larynx is a rare cancer that can appear as a primary tumor or as a metastasis from a cutaneous head and neck primary. To the best of our knowledge, only 60 cases of primary laryngeal melanoma have been reported in the world literature. Melanomas metastatic to the larynx are even more rare, as only 24 cases have been previously reported. Survival is poor, and recurrence is uncommon. We describe a new case of a malignant melanoma metastatic to the larynx, which represents the first such case in Iran. PMID- 23354904 TI - Purse-string approximation is superior to primary skin closure following stoma reversal: a systematic review and meta-analysis. AB - BACKGROUND: The incidence of surgical site infection (SSI) following stoma reversal can reach 40 %. A recent variation on primary linear closure (PLC) is purse-string approximation (PSA), where the skin is approximated via a purse string suture but not closed. The optimal technique remains to be determined. The objective of this review was to compare outcomes with PLC versus PSA for skin closure following stoma reversal. METHODS: A literature search of Embase and Medline was performed to identify studies comparing PLC with PSA published between 1966 and 2012. Reviews of each study were conducted and data extracted. Random-effects methods were used to combine data, and between-study heterogeneity was assessed. RESULTS: Six out of 47 identified studies met the inclusion criteria: 2 randomized controlled trials and 4 case controlled series. For the primary outcome of SSI rate, 233 patients in the PLC and 170 patients in the PSA group were available for comparison. PSA resulted in a reduced rate of SSI (2.4 % PSA vs. 29.6 % PLC; OR 0.083, 95 % CI = 0.03-0.21, p < 0.001). No differences were noted in length of hospital stay. Three studies assessed self-reported cosmetic results at a minimum of 7 months post-operatively. Patients who underwent PSA reported greater satisfaction with the cosmetic outcome (Standard mean difference = 0.47 on ten-point scale, 95 % CI 0.15-0.79, p = 0.005). CONCLUSIONS: Purse-string approximation of stoma wounds is associated with an 80 % reduction in SSI with no negative effect on length of hospital stay or long term cosmetic outcome. PMID- 23354905 TI - Ethics in prevention science involving genetic testing. AB - The Human Genome Project and rapid technological advances in genomics have begun to enrich prevention science's contributions to understanding the role of genetic factors in the etiology, onset and escalation of mental disorders, allowing for more precise descriptions of the interplay between genetic and non-genetic influences. Understanding of ethical challenges associated with the integration of genetic data into prevention science has not kept pace with the rapid increase in the collection and storage of genetic data and dissemination of research results. This article discusses ethical issues associated with (1) decisions to withhold or disclose personal genetic information to participants; (2) implications of recruitment and data collection methods that may reveal genetic information of family members; and the (3) nature and timing of informed consent. These issues are presented within the contexts of adult and pediatric research, longitudinal studies, and use of biobanks for storage of genetic materials. Recommendations for research ethics decision-making are provided. The article concludes with a section on justice and research burdens and the unique ethical responsibilities of prevention scientists to ensure the new genomic science protects the informational rights of participants, their families and communities. PMID- 23354906 TI - The teleomorph state of Candida deformans Langeron & Guerra and description of Yarrowia yakushimensis comb. nov. AB - Yarrowia lipolytica is the only known species in the teleomorph (i.e. sexual) genus Yarrowia and has its anamorph (i.e. asexual state) classified in the genus Candida Berkhout as Candida lipolytica. This species can be found readily in nature, has significant industrial value and is important to the food and medical fields. Candida deformans was first considered a variety of C. lipolytica and was later listed as a synonym of this species. More recent studies based on sequence variation in the nuclear rRNA gene sequences suggested C. deformans to be a separate species with no known teleomorph linked to it. In this study we show that C. deformans strains, obtained from South Africa, can mate with strains present in the CBS yeast collection and produce a Yarrowia teleomorph, described here as Yarrowia deformans. Strains of Candida yakushimensis nom. inval., a species also belonging to the Yarrowia phylogenetic clade, were also studied and described as a novel species of Yarrowia. PMID- 23354907 TI - Characterisation of caecal microbial diversity of lactating does and their offspring given diets with different neutral detergent soluble to insoluble fibre ratios. AB - The effect of neutral detergent soluble fibre (NDSF) to neutral detergent fibre (NDF) dietary ratio (0.29, LR and 0.43, HR) on the caecal ecosystem of lactating does and their offspring was studied. From the 17th day of lactation, each diet was given to four does, allowing for free access to their litters. Does were sampled at 17 and 28 days of lactation, and also two pups per litter at 17 (milk fed only), 28 (milk and solid fed) and 49 days of age. DGGE was used to study bacterial caecal biodiversity, and total bacterial concentration and relative proportions of Ruminococcus albus and Butyrivibrio fibrisolvens were quantified by real time PCR. In does, diet did not affect (P > 0.10) diversity indexes, total bacterial concentration or relative abundance of B. fibrisolvens, but at 28 days of lactation the proportion of R. albus was higher with LR (interaction Diet * Time, P = 0.037). Caecal communities of pups of 17 days were grouped by litter, but the influence of the mother was reduced at 28 days with solid feed intake, and at 49 days rabbits clustered by diet. Caecal biodiversity increased from 17 to 28 days, and was reduced at 49 days (Shannon index of 3.60, 3.71 and 3.57, respectively; P = 0.049). Total bacterial concentration and relative abundance of R. albus and B. fibrisolvens increased with solid feed intake from 17 to 28 days (P < 0.01), remaining unaffected thereafter. Access of pups to solid feed from 17 days of age modulates the development and composition of the caecal microbiota at weaning. PMID- 23354908 TI - Decreased levels of circulating CD4+CD25+Foxp3+ regulatory T cells in patients with primary antiphospholipid syndrome. AB - INTRODUCTION: CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cell dysfunction has been documented in various autoimmune disorders, but not in antiphospholipid syndrome (APS) so far. METHODS: In this cross-sectional study, we aim to investigate CD4(+)CD25(+)Foxp3(+) Treg cells, CD3(+)CD19(-) T cells and CD3(-)CD19(+) B cells in patients with primary APS and healthy controls. Cell subtypes were immunophenotyped using specific monoclonal antibodies (anti-CD3 CY5, anti-CD4 FITC, anti-CD25, anti-Foxp3, anti-CD19 PE) and flow cytometry. RESULTS: Twenty patients with APS and 20 age- and sex-matched controls were studied. The percentage of total lymphocytes, activated Th cells (CD4+CD25+), Treg cells and CD3(-)CD19(+) B cells were found significantly lower in APS patients as compared to controls (all p < 0.05). CONCLUSION: A dysfunction in CD4(+)CD25(+)Foxp3(+) Treg cells may represent one of the mechanisms leading to autoimmunity in APS patients. The decreased number of CD3(-)CD19(+) B cells of APS patients warrants further elucidation. PMID- 23354909 TI - Primary immunodeficiency diseases in different age groups: a report on 1,008 cases from a single Brazilian reference center. AB - Primary immunodeficiencies (PIDs) represent a large group of diseases that affect all age groups. Although PIDs have been recognized as rare diseases, there is epidemiological evidence suggesting that their real prevalence has been underestimated. We performed an evaluation of a series of 1,008 infants, children, adolescents and adults with well-defined PIDs from a single Brazilian center, regarding age at diagnosis, gender and PID category according to the International Union of Immunological Societies classification. Antibody deficiencies were the most common category in the whole series (61 %) for all age groups, with the exception of <2-year-old patients (only 15 %). In the >30-year old group, antibody deficiencies comprised 84 % of the diagnoses, mostly consisting of common variable immunodeficiency, IgA deficiency and IgM deficiency. Combined immunodeficiencies represented the most frequent category in <2-years-old patients. Most congenital defects of phagocytes were identified in patients <5 -years of age, as were the diseases of immune dysregulation, with the exception of APECED. DiGeorge syndrome and ataxia-telangiectasia were the most frequent entities in the category of well-defined syndromes, which were mostly identified in patients <10-years of age. Males represented three-quarters and two thirds of <2 -years-old and 2-5-years -old patients, respectively, whereas females predominated among the >30-year-old patients. Our data indicated that some PIDs were only detected at early ages, likely because affected patients do not survive long. In addition, our data pointed out that different strategies should be used to search for PIDs in infants and young children as compared to older patients. PMID- 23354910 TI - [Urodynamic testing of the lower urinary tract]. AB - Based on the measurement of simple physiological parameters urodynamic testing can reproduce clinical symptoms in a quantitative way, associates changes in physiological parameters to pathophysiological conditions and helps to establish a diagnosis in numerous lower urinary tract dysfunctions. Furthermore, urodynamic testing allows lower urinary tract dysfunctions to be classified as storage failure, voiding failure or combined storage and voiding failure. Therapeutic decision-making is based on this classification. PMID- 23354911 TI - [Long-term effects of osteopathic treatment of chronic prostatitis with chronic pelvic pain syndrome: a 5-year follow-up of a randomized controlled trial and considerations on the pathophysiological context]. AB - BACKGROUND: The etiology of chronic prostatitis chronic pelvic pain syndrome (CP/CPPS) is still unclear. As no pathological findings exist the diagnosis of CP/CPPS is essentially a diagnosis by exclusion and functional disorders, so called somatoform disorders play a more important role. Osteopathy treats functional disorders of the musculoskeletal system including all associated internal organs but little attention has so far been paid to this treatment method. Therefore, the 5-year follow-up period was intended to show that this is a sustainable form of therapy using exclusively manual and gentle techniques and simple treatment procedures resulting in manageable costs. MATERIALS AND METHODS: The aim of this study was to investigate whether sustainability of osteopathic treatment could be demonstrated even after 5 years. This was a randomized controlled study initially involving 5 treatment sessions, a follow-up without treatment after 6 weeks and further follow-up after 1.5 and 5 years. Of the 20 patients 19 in the test group participated in the 5-year follow-up. The control group were not asked because it would have been unacceptable to expect the patients to refrain from having treatment for as long as 5 years. The men were aged between 29 and 70 years. The patients were asked to complete the international prostate symptom score (IPSS), the National Institutes of Health chronic prostatitis symptom index (NIH-CPSI) and the quality of life (QOL) questionnaires once again and in particular to state whether they had received osteopathic treatment specifically for the prostate problem and how often they had been treated. RESULTS: The follow-up assessment of the symptoms of chronic prostatitis (NIH-CPSI) showed that they had further improved after 1.5 years (intragroup difference -1.8 points, 95 % confidence interval CI=-3.8 to 0.3) and also after 5 years (intragroup difference -1.3 points 95 % CI=-3.4 to 0.8). The urinary tract symptoms (IPSS) showed a statistically significant improvement (intergroup difference 8.9 points, 95 % CI=4.7-13.1, p<0.0005). At the second follow-up after 1.5 years there was a further improvement (intragroup difference 2.2 points, 95% CI=-3.9 to -0.4, p=0.02) which was found to remain constant after 5 years (intragroup difference 0.2 points). The quality of life (QOL) with respect to the symptoms showed a statistically significant improvement in comparing both groups during the study phase (intergroup difference chi 2: p<0.005). At follow-up after 5 years out of 19 patients 15 answered the question"how would you feel if the symptoms currently present would not change in the future?" with excellent or satisfactory and 11 patients would not have wanted further osteopathic treatment. Of the patients 8 reported that since the second follow-up (within 3.5 years) they had received osteopathic treatment one to eight times; however, this was partially more prophylactic than due to pain. CONCLUSIONS: Due to the sustainability of osteopathic treatment and the low amount of time involved, osteopathy should be taken seriously as a treatment for patients with CP/CPPS. Furthermore, due to the osteopathic treatment the patients learnt to alleviate or even eliminate their own symptoms in treating themselves. In order to help many other affected persons out of their dilemma it would be desirable if more urologists and internists would become acquainted with osteopathy in order to be able to offer this to patients at an early stage. Further studies with larger numbers of patients should be carried out to confirm these results. PMID- 23354912 TI - Scutellaria barbata D. Don induces G1/S arrest via modulation of p53 and Akt pathways in human colon carcinoma cells. AB - Cancer cells are characterized by an uncontrolled increase in cell proliferation. G1 to S transition is one of the two main checkpoints used by cells to control the cell cycle progress and cell proliferation. G1/S progression is highly regulated by multiple intracellular signaling transduction cascades including Akt and p53 pathways, which therefore becomes a promising target for the development of novel anticancer therapy. Scutellaria barbata D. Don (SB) is a major component in many Chinese medicine formulas that have long been used in China to clinically treat various cancers including colorectal cancer (CRC). Recently, we reported that the ethanol extract of SB (EESB) is able to induce cancer cell apoptosis via activation of the mitochondrion-dependent pathway and inhibit tumor angiogenesis through suppression of Hedgehog signaling. To further elucidate the precise mechanisms of its antitumor activity, in the present study we evaluated the effect of EESB on the proliferation of human colon carcinoma HT-29 cells and investigated the underlying molecular mechanism. We found that EESB could inhibit the proliferation of HT-29 cells through blocking the G1/S cell cycle progression. In addition, EESB treatment profoundly promoted antiproliferative p21 expression, but inhibited the expression of pro-proliferative PCNA, cyclin D1 and CDK4 in HT-29 cells. Moreover, the phosphorylation/activation of Akt was significantly suppressed by EESB treatment, whereas that of p53 was enhanced. These results suggest that EESB could effectively induce G1/S arrest in human colon carcinoma cells via modulation of multiple cell cycle-related signaling pathways. PMID- 23354913 TI - A cost effectiveness analysis of stepped care treatment for bulimia nervosa. AB - BACKGROUND: The cost effectiveness of various treatment strategies for bulimia nervosa (BN) is unknown. AIMS: To examine the cost effectiveness of stepped care treatment for BN. METHOD: Randomized trial conducted at four clinical centers with intensive measurement of direct medical costs and repeated measurement of subject quality of life and family/significant other time involvement. Two hundred ninety-three women who met DSM-IV criteria for BN received stepped care treatment or cognitive behavioral therapy. Cost effectiveness ratios were compared. RESULTS: The cost per abstinent subject was $12,146 for stepped care, and $20,317 for cognitive behavioral therapy. Quality of life ratings improved significantly with treatment, and family/significant other time burden diminished substantially. DISCUSSION: In this trial, stepped care for BN appeared cost effective in comparison to cognitive behavioral therapy. Treatment was associated with improved quality of life and diminished time costs of illness. PMID- 23354914 TI - Pituitary homeobox 2 (PITX2) protects renal cancer cell lines against doxorubicin toxicity by transcriptional activation of the multidrug transporter ABCB1. AB - The multidrug resistance (MDR) P-glycoprotein ABCB1 plays a major role in MDR of malignant cells and is regulated by various transcription factors, including Wnt/beta-catenin/TCF4. The transcription factor PITX2 (Pituitary homeobox-2) is essential for embryonic development. PITX2 operates by recruiting and interacting with beta-catenin to increase the expression of growth-regulating genes, such as cyclin D1/2 and c-Myc. The importance of PITX2 in malignancy is not yet known. Here we demonstrate that in the renal cancer cell lines ACHN and A498, the level of ABCB1 expression and function correlate with nuclear PITX2 localization and PITX2-luciferase reporter gene activity (A498 > ACHN). In A498 cells, doxorubicin toxicity is augmented by the ABCB1 inhibitor, PSC833. PITX2 overexpression increases ABCB1 expression and cell survival in ACHN cells. Silencing of PITX2 by siRNA downregulates ABCB1 and induces a greater chemotherapeutic response to doxorubicin in A498 cells, as determined by MTT cell viability and clonogenic survival assays. Two PITX2 binding sequences were identified in the ABCB1 promoter sequence. PITX2 binding was confirmed by chromatin immunoprecipitation. beta-Catenin is not required for PITX2 upregulation of ABCB1 because ABCB1 mRNA increased and doxorubicin toxicity decreased upon PITX2 overexpression in beta catenin(-/-) cells. The data show for the first time that ABCB1 is a target gene of PITX2 transcriptional activity, promoting MDR and cell survival of cancer cells. PMID- 23354915 TI - Nearly a third of abnormalities found after first-trimester screening are different than expected: 10-year experience from a single center. AB - OBJECTIVE: This study aimed to assess the efficacy of first-trimester aneuploidy screening in a single clinical setting. METHODS: Maternal age, nuchal translucency, and maternal serum levels of pregnancy-associated plasma protein A and free beta human chorionic gonadotrophin comprised first-trimester risk assessment for Down syndrome and trisomies 13/18. Means, screen positive rates, detection rates, and predictive values were calculated for Down syndrome and trisomies 13/18. RESULTS: Of the 23 329 first-trimester screenings, 6.3% were screen positive: 5.7% for Down syndrome only, 0.4% for trisomies 13/18 only, and 0.3% for Down syndrome and trisomies 13/18. An abnormal karyotype was present in 3.9% of screen positives for Down syndrome, 13.8% of screen positives for trisomies 13/18, and 45.9% of screen positives for both Down syndrome and trisomies 13/18. Of the 97 pregnancies found to have an abnormal karyotype, 29.9% had chromosome abnormalities other than trisomy 13, 18, or 21, with expected clinical outcomes ranging from likely benign to uniformly lethal. CONCLUSION: As expected, first-trimester screening is effective for detecting aneuploidy for chromosomes 13, 18, and 21; however, a significant number of chromosomally abnormal pregnancies initially identified by first-trimester screening have a different karyotype. With the possible exception of 47,XYY and 45,X, the dataset suggested that these different chromosome complements were likely to be randomly distributed. Nevertheless, prior to diagnostic testing, prospective parents should be counseled concerning the possibility of a chromosome abnormality other than the trisomies 13, 18, or 21. PMID- 23354916 TI - [Nanotechnology: a big revolution from the small world]. AB - Nanotechnology is a multidisciplinary field originating from the interaction of several different disciplines, such as engineering, physics, biology and chemistry. New materials and devices effectively interact with the body at molecular level, yielding a brand new range of highly selective and targeted applications designed to maximize the therapeutic efficiency while reducing the side effects. Liposomes, quantum dots, carbon nanotubes and superparamagnetic nanoparticles are among the most assessed nanotechnologies. Meanwhile, other futuristic platforms are paving the way toward a new scientific paradigm, able to deeply change the research path in the medical science. The growth of nanotechnology, driven by the dramatic advances in science and technology, clearly creates new opportunities for the development of the medical science and disease treatment in human health care. Despite the concerns and the on-going studies about their safety, nanotechnology clearly emerges as holding the promise of delivering one of the greatest breakthroughs in the history of medical science. PMID- 23354917 TI - Protein interactions, post-translational modifications and topologies in human cells. AB - The unique and remarkable physicochemical properties of protein surface topologies give rise to highly specific biomolecular interactions, which form the framework through which living systems are able to carry out their vast array of functions. Technological limitations undermine efforts to probe protein structures and interactions within unperturbed living systems on a large scale. Rapid chemical stabilization of proteins and protein complexes through chemical cross-linking offers the alluring possibility to study details of the protein structure to function relationships as they exist within living cells. Here we apply the latest technological advances in chemical cross-linking combined with mass spectrometry to study protein topologies and interactions from living human cells identifying a total of 368 cross-links. These include cross-links from all major cellular compartments including membrane, cytosolic and nuclear proteins. Intraprotein and interprotein cross-links were also observed for core histone proteins, including several cross-links containing post-translational modifications which are known histone marks conferring distinct epigenetic functions. Excitingly, these results demonstrate the applicability of cross linking to make direct topological measurements on post-translationally modified proteins. The results presented here provide new details on the structures of known multi-protein complexes as well as evidence for new protein-protein interactions. PMID- 23354918 TI - Management of hemangioma of the liver: surgical therapy or observation? AB - BACKGROUND: Elective surgery for liver hemangioma is controversial. We reviewed long-term outcomes following elective hepatectomy or observation only for symptomatic and asymptomatic liver hemangioma. METHODS: All patients (n = 307) with liver hemangioma referred to our hospital for surgical evaluation from January 1988 to December 2009 were identified, and imaging results, tumor characteristics, surgical indication, surgical mode, outcome of observation, clinical and/or postoperative outcome, and adverse events were retrospectively evaluated. RESULTS: Complete median follow-up for 246 patients was 124 months. Elective surgery was performed in 103 patients (symptomatic [n = 62] and asymptomatic [n = 41]). Postoperative morbidity occurred in 17 % of the patients and was significantly lower in asymptomatic patients (p = 0.002). No perioperative mortality was registered. Surgery relieved complaints in most (88 %) patients. In the observation group (n = 143), 56 % of patients had persistent or new onset of hemangioma-associated symptoms. Major hemangioma-related complications occurred in 12 patients (9 %) during the follow-up period, and 2 patients died after traumatic hemangioma rupture. Overall the rate of adverse events was by trend lower in the surgical group than in the observation group (35 versus 57 %; p = 0.08). CONCLUSIONS: The majority of patients with liver hemangioma can be safely managed by clinical observation. In a subset of patients, especially those with giant hemangioma and/or occurrence of symptoms, surgical treatment could be considered and is justified in high-volume centers. PMID- 23354919 TI - Utilization of a non-preserved cadaver to address deficiencies in technical skills during the third year of medical school: a cadaver model for teaching technical skills. AB - BACKGROUND: Emergency technical procedures performed by medical students have decreased in the last decade. An Emergency Surgical Skills Laboratory (ESSL) using a non-preserved cadaver was developed in response to address this deficiency. METHODS: A total of 232 students rotating through a 6-week surgery clerkship participated in the ESSL from 1 July 2008 to 1 July 2011. Two four-hour sessions using case-based trauma scenarios in the ESSL served as a model for procedural instruction. Skills taught included basic suturing, intubation, cricothyrotomy, chest tube placement, thoracentesis, venous access, central line, and radial arterial line placement. RESULTS: Students noted that technical proficiency in suturing was obtained during the ESSL sessions in comparison to the emergency department or operating room (p < 0.001) during the 6-week clerkship. During the 6-week rotation only 12 % of students participated in chest tube insertion, 5 % central venous line placement, and 14 % femoral vein blood draw. Finally, 90 % of respondents reported increased understanding and comfort in regard to trauma resuscitation following the ESSL. CONCLUSIONS: Technical procedural proficiency has become increasingly difficult to obtain in medical school due to multifactorial limitations. The ESSL provides an opportunity for developing technical skills needed for emergency situations not otherwise provided during the surgical clerkship. PMID- 23354920 TI - A higher glomerular filtration rate predicts low risk of developing chronic kidney disease in living kidney donors. AB - BACKGROUND: The risk of developing chronic kidney disease (CKD) among living kidney donors (LKDs) is seldom included in evaluations of patients' outcomes. Potential risk factors and new criteria for estimating the glomerular filtration rate (eGFR) indexed for body surface area (BSA) were investigated with a view to prevent the development of CKD in LKDs. METHODS: We conducted a retrospective study of LKDs from May 1983 to March 2011. The Mann-Whitney U test and chi(2) test were used to analyze the male versus female groups. Survival analysis was plotted as CKD-free survival and analyzed separately by different eGFR index classifications. The Cox regression model was used to identify potential risk factors for development of CKD. RESULTS: A total of 105 LKDs with a mean age of 46.3 +/- 12.5 years had a mean eGFR indexed for BSA of 88.9 +/- 21.5 ml/min per 1.73 m(2). After a mean duration of 5.4 +/- 4.9 years' follow-up, eGFR dropped to 61.4 +/- 16.4 ml/min per 1.73 m(2) (p = 0.002). Median CKD-free survival was only 5.7 years. The difference between eGFR >= 80 ml/min per 1.73 m(2) and <80 ml/min per 1.73 m(2) was not statistically significant (p = 0.980). Multivariate Cox regression analysis showed that higher eGFR at donation (HR = 0.952, p = 0.0199) could be a protective factor. The receiver operating characteristic (ROC) curve for initial eGFR with best sensitivity of 52.78 % and specificity of 81.40 % was obtained with a cutoff value of 90.2 ml/min per 1.73 m(2) for preoperative eGFR. An eGFR of 90 ml/min per 1.73 m(2) yielded a significant survival curve (p = 0.0199) after 21 years of follow-up. Further classifications of eGFR >90 ml/min per 1.73 m(2) into 90-99 ml/min per 1.73 m(2), 100-109 ml/min per 1.73 m(2), and >=110 ml/min per 1.73 m(2) were examined, but this survival curve was not statistically significant (p = 0.1247). CONCLUSIONS: Living kidney donors will develop CKD after a long duration of follow-up if there is insufficiently high eGFR at donation. An eGFR above 90 ml/min per 1.73 m(2) before donation is the only factor that predicts prevention of CKD. Larger studies with longer duration of follow-up are necessary to clarify the clinical outcome of this postoperative CKD group, especially for patients with eGFR between 80 and 90 ml/min per 1.73 m(2). PMID- 23354921 TI - Causes and costs of a decade of litigation following emergency appendectomy in England. AB - BACKGROUND: There has been recent interest in the delayed and nonoperative management of appendicitis. The present study assessed the causes and costs of litigation against surgeons following emergency appendectomy, with an emphasis on claims relating to preoperative management. MATERIALS AND METHODS: Data were obtained from the English NHS Litigation Authority for claims relevant to appendectomy between 2002 and 2011. Two authors independently extracted data and classified it against predetermined criteria. RESULTS: Successful litigation occurred in 66 % of closed cases (147/223) with a total payout of L8.1 million. There were 24 claims against organizational operating room delays (9 % of total) and 27 against delayed diagnosis (10 %), with respective success rates of 70 and 68 %. From 21 claims relating to damage to fertility, nine were due to either delayed diagnosis or organizational operating room delays. Misdiagnosis was the second most common cause for litigation (16 %), but it had the lowest likelihood of success (49 %). Faulty surgical technique was the most common reason for litigation (39 %), with a 70 % likelihood of success. Of eight claims related to fatality, one was due to unacceptable preoperative delay leading to preventable perforated appendicitis. The overall highest median payouts were for claims of damage to fertility (L52,384), operating list delays (L44,716), and delayed diagnosis (L42,292). CONCLUSIONS: There were significant medicolegal risks surrounding delays related to access to operating lists and diagnosis. Whereas future evidence regarding the safety of delayed appendectomy may provide scientific defense against these claims, the present study provides evidence of the current medicolegal risk to surgeons following delayed treatment of appendicitis. PMID- 23354922 TI - Liver resection for Bismuth type I and Type II hilar cholangiocarcinoma. AB - BACKGROUND: In patients with Bismuth type I and II hilar cholangiocarcinoma (HCCA), bile duct resection alone has been the conventional approach. However, many authors have reported that concomitant liver resection improved surgical outcomes. METHODS: Between January 2000 and January 2012, 52 patients underwent surgical resection for a Bismuth type I and II HCCA (type I: n = 22; type II: n = 30). Patients were classified into two groups: concomitant liver resection (n = 26) and bile duct resection alone (n = 26). RESULTS: Bile duct resection alone was performed in 26 patients. Concomitant liver resection was performed in 26 patients (right side hepatectomy [n = 13]; left-side hepatectomy [n = 6]; volume preserving liver resection [n = 7]). All liver resections included a caudate lobectomy. Patient and tumor characteristics did not differ between the two groups. Although concomitant liver resection required longer operating time (P < 0.001), it had a similar postoperative complication rate (P = 0.764), high curability (P = 0.010), and low local recurrence rate (P = 0.006). Concomitant liver resection showed better overall survival (P = 0.047). CONCLUSIONS: Concomitant liver resection should be considered in patients with Bismuth type I and II HCCA. PMID- 23354923 TI - Factors influencing the success of in vivo sentinel lymph node procedure in colon cancer patients: Swiss prospective, multicenter study sentinel lymph node procedure in colon cancer. AB - BACKGROUND: The sentinel lymph node (SLN) procedure has the potential to provide relevant improvement in nodal staging in colon cancer patients. However, there remains room for improvement for SLN identification and sensitivity. Therefore, the objective of the present investigation was to analyze factors influencing the success of the SLN procedure in colon cancer patients. METHODS: One hundred seventy-four consecutive colon cancer patients were prospectively enrolled in this multicenter study and underwent in vivo SLN procedure with isosulfan blue 1 % followed by open standard oncologic colon resection. Several patient-, tumor-, and procedure-related factors possibly influencing the SLN identification and sensitivity were analyzed. RESULTS: Sentinel lymph node identification rate and accuracy were 89.1 and 83.9 %, respectively. Successful identification of SLN was significantly associated with the intraoperative visualization of blue lymphatic vessels (p < 0.001) and with female gender (p = 0.024). True positive SLN results were significantly associated with higher numbers of SLN (p = 0.026) and with pN2 stage (p = 0.004). There was a trend toward better sensitivity in patients with lower body mass index (BMI) (p = 0.050). CONCLUSIONS: The success of the SLN procedure in colon cancer patients depends on both procedure-related factors (intraoperative visualization of blue lymphatic vessels, high number of SLN identified) and patient factors (gender, BMI). While patient factors can not be influenced, intraoperative visualization of blue lymphatics and identification of high numbers of SLN are key for a successful SLN procedure. PMID- 23354924 TI - Preoperative ultrasonography assessment of vocal cord movement during thyroid and parathyroid surgery. PMID- 23354925 TI - Comparing outcomes between side-to-side anastomosis and other anastomotic configurations after intestinal resection for patients with Crohn's disease: a meta-analysis. AB - BACKGROUND: Anastomotic configurations may be a predictor of postoperative recurrence for Crohn's disease. One previous meta-analysis showed side-to-side anastomosis was associated with fewer anastomotic leaks but did not reduce postoperative recurrence rates. After 2007, more articles that found distinct results were published. We aimed to update the meta-analysis comparing outcomes between side-to-side anastomosis and other anastomotic configurations after intestinal resection for patients with Crohn's disease. METHODS: A literature search that included PubMed, EMBASE, the Science Citation Index, and the Cochrane Library was conducted to identify studies up to May 2012. Trials comparing side to-side anastomosis with other anastomotic configurations for Crohn's disease were analyzed. Sensitivity analysis and heterogeneity assessment were also performed. RESULTS: Eleven trials compared side-to-side with other anastomotic configurations were included. Overall, results showed a significant reduction in the overall postoperative complications [n = 777; odds ratio (OR) = 0.60; P = 0.01], but side-to-side anastomosis did not reduce the anastomotic leak rate (n = 879; OR = 0.48; P = 0.07), complications other than anastomotic leak (n = 777; OR = 0.72; P = 0.13), endoscopic recurrence rates [hazard ratio (HR) = 0.73; P = 0.07], symptomatic recurrence rates (HR = 0.74; P = 0.20), and reoperation rates for recurrence (HR = 0.37; P = 0.06). Sensitivity analysis including two randomized controlled trials found no significant differences in short-term complications between the two groups. Sensitivity analysis including nine trials comparing only stapled side-to-side anastomosis with other anastomotic configurations showed stapled side-to-side anastomosis could reduce reoperation rates (HR = 0.38; P = 0.01). CONCLUSIONS: Side-to-side anastomosis did not reduce short-term complications and postoperative recurrence for Crohn's disease. Stapled side-to-side anastomosis may lead to fewer reoperations needed for recurrence. Further randomized, controlled trials should be conducted for confirmation of recurrent events. PMID- 23354926 TI - Optimal HbA1c cutoff for detecting diabetic retinopathy. AB - The associations between high glucose levels and diabetic retinopathy have been the basis for the diagnosis of diabetes. We aimed to provide updated data on the relationship between HbA1c and diabetic retinopathy, and to assess the diagnostic accuracy of the proposed HbA1c cutoff for detecting diabetic retinopathy. This cross-sectional study included 3,403 adults from the 2009 to 2010 Ansung Cohort Study. Retinopathy was assessed with single-field nonmydriatic fundus photography and graded according to the International Clinical Diabetic Retinopathy Disease Severity Scale. HbA1c was measured by standardized assay using high performance liquid chromatography. Based on deciles distribution, the prevalence of retinopathy was very low until the HbA1c range of 48-51 mmol/mol (6.5-6.8 %). The optimal HbA1c cutoff for detecting any diabetic retinopathy was 49 mmol/mol (6.6 %), moderate or severer retinopathy was 52 mmol/mol (6.9 %) from receiver operating characteristic curve analysis. The proposed HbA1c threshold of 48 mmol/mol (6.5 %) from American Diabetes Association produced comparable accuracy for identifying both any and moderate/severer retinopathy. This study confirmed that the proposed HbA1c threshold of 48 mmol/mol (6.5 %) allowed the proper detection of diabetic retinopathy. Our data support the judicious use of HbA1c for the diagnosis of diabetes and detecting diabetic retinopathy as well. PMID- 23354927 TI - Effect of weight loss on sympatho-vagal balance in subjects with grade-3 obesity: restrictive surgery versus hypocaloric diet. AB - Few and mostly uncontrolled studies indicate that weight loss improves heart rate variability (HRV) in grade-3 obesity. The aim of this study was to compare in grade-3 obesity surgery and hypocaloric diet on clinical and metabolic variables and on autonomic indices of HRV. Twenty-four subjects (body mass index, BMI 45.5 +/- 9.13 kg/m(2)) underwent surgery (n = 12, gastric banding, LAGB) or received hypocaloric diet (n = 12, 1,000-1,200 kg/day). Clinical [BMI, systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate] and metabolic variables [glucose, cholesterol, HDL- and LDL-cholesterol, triglycerides, AST and ALT transaminases] and 24-h Holter electrocardiographic-derived HRV parameters [R R interval, standard deviation of R-R intervals (SDNN); low/high-frequency (LF/HF) ratio, and QT interval] were measured at baseline and after 6 months. The two groups were identical at baseline. BMI (-7.5 +/- 3.57 kg/m(2), mean +/- SD), glucose (-24.1 +/- 26.77 mg/dL), SBP (-16.7 +/- 22.19 mmHg) and DBP (-6.2 +/- 8.56 mmHg) decreased in LAGB subjects (p < 0.05) and remained unchanged in controls. At 6 months, SDNN increased in LAGB subjects (+25.0 +/- 37.19 ms, p < 0.05) and LF/HF ratio diminished (2.9 +/- 1.84 vs. 4.9 +/- 2.78; p = 0.01), with no change in controls; LF (daytime) and HF (24 h and daytime) increased in LAGB subjects, with no change in controls. Decrease in BMI correlated with SBP and DBP decrease (p < 0.05), and DBP decrease correlated with HR decrease (p < 0.05) and QT shortening (p < 0.05). Weight loss is associated with improvement of glucose metabolism, of blood pressure, and with changes in time and frequency domain parameters of HRV; all these changes indicate recovery of a more physiological autonomic control, with increase in parasympathetic and reduction in sympathetic indices of HRV. PMID- 23354928 TI - Gene expression in self-repressing system with multiple gene copies. AB - We analyze a simple model of a self-repressing system with multiple gene copies. Protein molecules may bound to DNA promoters and block their own transcription. We derive analytical expressions for the variance of the number of protein molecules in the stationary state in the self-consistent mean-field approximation. We show that the Fano factor (the variance divided by the mean value) is bigger for the one-gene case than for two gene copies and the difference decreases to zero as frequencies of binding and unbinding increase to infinity. PMID- 23354929 TI - Transcriptional bursting diversifies the behaviour of a toggle switch: hybrid simulation of stochastic gene expression. AB - Hybrid models for gene expression combine stochastic and deterministic representations of the underlying biophysical mechanisms. According to one of the simplest hybrid formalisms, protein molecules are produced in randomly occurring bursts of a randomly distributed size while they are degraded deterministically. Here, we use this particular formalism to study two key regulatory motifs-the autoregulation loop and the toggle switch. The distribution of burst times is determined and used as a basis for the development of exact simulation algorithms for gene expression dynamics. For the autoregulation loop, the simulations are compared to an analytic solution of a master equation. Simulations of the toggle switch reveal a number of qualitatively distinct scenarios with implications for the modelling of cell-fate selection. PMID- 23354930 TI - Experimental and computational investigation of the role of stress fiber contractility in the resistance of osteoblasts to compression. AB - The mechanical behavior of the actin cytoskeleton has previously been investigated using both experimental and computational techniques. However, these investigations have not elucidated the role the cytoskeleton plays in the compression resistance of cells. The present study combines experimental compression techniques with active modeling of the cell's actin cytoskeleton. A modified atomic force microscope is used to perform whole cell compression of osteoblasts. Compression tests are also performed on cells following the inhibition of the cell actin cytoskeleton using cytochalasin-D. An active bio chemo-mechanical model is employed to predict the active remodeling of the actin cytoskeleton. The model incorporates the myosin driven contractility of stress fibers via a muscle-like constitutive law. The passive mechanical properties, in parallel with active stress fiber contractility parameters, are determined for osteoblasts. Simulations reveal that the computational framework is capable of predicting changes in cell morphology and increased resistance to cell compression due to the contractility of the actin cytoskeleton. It is demonstrated that osteoblasts are highly contractile and that significant changes to the cell and nucleus geometries occur when stress fiber contractility is removed. PMID- 23354931 TI - Topical herbal medicine combined with pharmacotherapy for psoriasis: a systematic review and meta-analysis. AB - This systematic review examines the current state of the evidence for the efficacy and safety of herbal medicines (HMs) used topically in conjunction with anti-psoriatic pharmacotherapy (APP) in the treatment of psoriasis. Searches were conducted in September 2012 of PubMed, EMBASE, Cochrane Library, two Chinese databases (China National Knowledge Infrastructure and Chinese Scientific Journals Full Text Database) and of article reference lists. We included randomized controlled trials published in English, Chinese or Japanese that investigated topical HM combined with APP used systemically and/or topically compared to pharmacotherapy alone. Studies employing phototherapy were excluded. Two authors conducted searches, extracted data on study characteristics and outcomes, and assessed Risk of Bias. Disagreements were resolved by discussion with a third author. Eight studies met the inclusion criteria. All used multi herb formulae, four in herbal baths, three in herbal ointments or creams, and one as herbal steam. The pooled data indicated a benefit for the add-on effect of herbal therapy to APP. Adding these topical HMs to conventional pharmacotherapy appeared to produce short-term additional clinical benefits. No serious adverse events were reported. Experimental studies suggest that some of the herbs possess anti-inflammatory, anti-pruritic, and/or anti-proliferative activities. However, these results need to be interpreted with caution due to methodological weaknesses and the lack of replicated studies. Studies that address the identified methodological deficiencies are required to further investigate the efficacy and safety of these HMs as adjunct therapies for psoriasis. PMID- 23354932 TI - Energy status and immune system alterations in Elliptio complanata after ingestion of cyanobacteria Anabaena flos-aquae. AB - Cyanobacteria have often been described as nutritionally poor for herbivorous organisms. To gain additional information on the potential impacts of invertebrates feeding on cyanobacteria, we fed Elliptio complanata mussels with two types of algae: Anabaena flos-aquae (cyanobacteria) and Pseudokirchneriella subcapitata (green algae). Physiological parameters were examined at the energy status, immune system and oxidative stress levels. Energy status was examined by following the rate of electron transport activity in mitochondria (a measure of cellular energy expense) and lipid/sugar stores in the visceral mass. The cyanobacteria were not actively producing toxins. Based on the digestive gland index, the mussels fed equally on either regime. However, the energy status in mussels fed A. flos-aquae revealed that the total sugar was lower in the digestive gland, whereas mitochondrial electron transport activity (MET), once corrected against the digestive gland somatic index, showed increased energy expenses. Acetylcholinesterase activity and lipid peroxidation (LPO) were also higher in mussels fed with A. flos-aquae compared with mussels fed with P. subcapitata. LPO was correlated by mitochondrial activity in both the digestive gland and gills, suggesting that oxidative stress resulted from metabolic respiration. Immunocompetence (phagocytic activity, natural killer cell-like activity, haemocyte count and viability) and humoral level of lysozyme were not affected in mussels by the algae or cyanobacteria regime. Moreover, the xenobiotic conjugating enzyme, glutathione S-transferase, hemoprotein oxidase and vitellogenin-like proteins were not affected in mussel organs via ingestion of A. flos-aquae. Our study suggests that ingestion of cyanobacteria leads to increased energy expenses, oxidative stress and increased acetylcholine turnover in mussels. PMID- 23354934 TI - The effect of thermal and ultrasonic treatment on amino acid composition, radical scavenging and reducing potential of hydrolysates obtained from simulated gastrointestinal digestion of cowpea proteins. AB - The effect of thermal and ultrasonic treatment of cowpea proteins (CP) on amino acid composition, radical scavenging and reducing potential of hydrolysates (CPH) obtained from in vitro simulated gastrointestinal digestion of CP was evaluated. Hydrolysis of native and treated CP with gastrointestinal pepsin and pancreatin yielded CPH that displayed antioxidant activities based on oxygen radical scavenging capacity (ORAC), ferric reducing antioxidant power (FRAP) and superoxide radical scavenging activity (SRSA). CPH derived from the treated CP yielded higher ORAC values than CPH from untreated proteins. However, lower significant FRAP and SRSA values were observed for these samples compared to untreated CPH (p < 0.05). Amino acid analysis indicated that CP processing decreased total sulphur-containing amino acids in the hydrolysates, particularly cysteine. The amount of cysteine appeared to be positively related to FRAP and SRSA values of CPH samples, but not ORAC. The results indicated that thermal and ultrasonic processing of CP can reduce the radical scavenging and reducing potential of the enzymatic hydrolysates possibly due to the decreased amounts of cysteine. Since the hydrolysates were generated with gastrointestinal enzymes, it is possible that the resulting compounds are produced to exert some health functions during normal consumption of cowpea. PMID- 23354935 TI - Effects of slow-releasing colistin microspheres on endotoxin-induced sepsis. AB - Lipopolysaccharide (LPS) is a major contributing factor to endotoxic shock. Colistin specifically binds to LPS. However, it has the disadvantages that adverse reactions are common and it has a short half-life. To overcome these disadvantages, we prepared slow-releasing colistin microspheres and examined the efficacy of these colistin microspheres in a mouse model of endotoxin-induced sepsis. We prepared the colistin microspheres using poly-lactic-co-glycolic acid. For acute toxicity investigations, mice were overdosed with colistin sulfate or colistin microspheres. The group administered with colistin microspheres was associated with less acute toxicity and fewer nephrotoxic changes on histopathological examination compared to the group administered with colistin sulfate alone. For pharmacokinetic analysis, mice were subcutaneously administered with colistin microspheres or colistin sulfate alone. The plasma concentration of colistin was higher in the colistin microspheres group than in the colistin sulfate group at 12 and 24 h after administration. Moreover, mice were intraperitoneally injected with LPS and then immediately subcutaneously administered with blank microspheres, colistin microspheres or colistin sulfate alone. The levels of endotoxin in the sera and cytokine in the spleens were then measured. A significant reduction in the serum endotoxin level in the colistin microspheres group was observed at 24 h. The reduced endotoxin levels in the sera were correlated with the lower cytokine levels in the spleens of mice treated with colistin microspheres. Our results suggest that the use of colistin microspheres may help to maintain a higher colistin concentration in blood, reduce the levels of endotoxin and cytokines in endotoxin-induced sepsis, and lead to decreased toxicity. PMID- 23354936 TI - A prospective comparison of nursing- and healthcare-associated pneumonia (NHCAP) with community-acquired pneumonia (CAP). AB - Nursing- and healthcare-associated pneumonia (NHCAP) has been proposed by the Japanese Respiratory Society as a new category of pneumonia considering the characteristics of the Japanese medical care environment. It is necessary to ascertain the epidemiology and clinical outcomes of NHCAP. A prospective study was conducted of patients with pneumonia who were hospitalized at our hospital from August 2011 to July 2012. We compared 192 cases of NHCAP with 114 cases of community-acquired pneumonia (CAP). Compared with CAP, NHCAP had a higher disease severity, higher 30-day mortality rate (10.9 vs. 3.5 %, P = 0.022), and longer length of hospital stay (median, 12 vs. 8 days, P < 0.001). Streptococcus pneumoniae was the most frequent causative pathogen in both NHCAP and CAP (33.9 vs. 34.8 %, P = 0.896). The incidence of atypical pathogens in NHCAP was low (1.7 %). Multidrug-resistant (MDR) pathogens were isolated more frequently in NHCAP than in CAP, but there was no significant difference (11.0 vs. 4.5 %, P = 0.135). Among 192 NHCAP patients, 122 (63.5 %) were aspiration pneumonia. Aspiration pneumonia was associated with poor outcomes and was considered a major characteristic of NHCAP. Our study suggested that many patients with NHCAP do not need broad-spectrum antibiotic therapy targeting MDR pathogens. Excess mortality in NHCAP patients is the result of patient backgrounds or disease severity rather than the presence of MDR pathogens. PMID- 23354937 TI - Systemic inflammatory response syndrome and prolonged hypoperfusion lesions in an infant with respiratory syncytial virus encephalopathy. AB - Respiratory syncytial virus (RSV) is a cause of neurological complications in infants. We report a rare case of RSV encephalopathy in an infant who presented with poor sucking and hypothermia at 17 days of age after suffering from rhinorrhea and a cough for several days. After hospitalization, the patient presented with stupor and hypotonia lasting for at least 24 h, and was intubated, sedated, and ventilated for treatment of pneumonia. These symptoms led to diagnosis of pediatric systemic inflammatory response syndrome (SIRS) caused by RSV infection. High-dose steroid therapy was combined with artificial ventilation because the initial ventilation therapy was ineffective. Interleukin (IL)-6 levels in spinal fluid were markedly increased upon admission, and serum IL-6 and IL-8 levels showed even greater elevation. The patient was diagnosed with RSV encephalopathy. On day 5, high signal intensity in the bilateral hippocampus was observed on diffusion-weighted magnetic resonance imaging (MRI). On day 14, the patient presented with delayed partial seizure and an electroencephalogram showed occasional unilateral spikes in the parietal area, but the hippocampal abnormality had improved to normal on MRI. (99m)Tc-labeled ethylcysteinate dimer single-photon emission computed tomography (SPECT) on day 18 showed hypoperfusion of the bilateral frontal and parietal regions and the unilateral temporal region. SPECT at 3 months after onset still showed hypoperfusion of the bilateral frontal region and unilateral temporal region, but hypoperfusion of the bilateral parietal region had improved. The patient has no neurological deficit at 6 months. These findings suggest that RSV encephalopathy with cytokine storm induces several symptoms and complications, including SIRS and prolonged brain hypoperfusion on SPECT. PMID- 23354938 TI - Assessment of the acaricidal activity of carvacrol, (E)-cinnamaldehyde, trans anethole, and linalool on larvae of Rhipicephalus microplus and Dermacentor nitens (Acari: Ixodidae). AB - The acaricidal activity of carvacrol, (E)-cinnamaldehyde, trans-anethole, and linalool was studied on Rhipicephalus microplus and Dermacentor nitens larvae. All the substances were tested at concentrations of 2.5, 5.0, 10.0, 15.0, and 20.0 MUl/ml, with 10 repetitions per treatment. The modified larval packet technique was employed in the tests and the mortality was evaluated after 24 h. In the groups treated with carvacrol, the lowest concentration (2.5 MUl/ml) was sufficient to cause 100% death of the R. microplus and D. nitens larvae. The same concentration of (E)-cinnamaldehyde resulted in death of approximately 99% of the larvae of both tick species and reached 100% at the other concentrations. For trans-anethole, mortality rates above 90% of the R. microplus and D. nitens larvae were only observed starting at the concentration of 15.0 MUl/ml and reached 100% at the highest concentration (20.0 MUl/ml). Finally, the mortality rates of the groups treated with linalool were low, only reaching 8.4 and 14.5% at the highest concentration (20.0 MUl/ml) for larvae of D. nitens and R. microplus, respectively. These results show that carvacrol, (E)-cinnamaldehyde, and trans-anethole have acaricidal activity, particularly carvacrol and (E) cinnamaldehyde, both of which resulted in high mortality rates for the larvae of these two tick species even at the lowest concentration. PMID- 23354939 TI - Egg viability studies on Clinostomum complanatum (Digenea: Clinostomidae) from two experimental animal model systems. AB - Viability of eggs is important for the successful completion of trematode life cycle, both in natural and laboratory conditions. The present study was designed to check the viability of eggs released by the digenetic trematode parasite Clinostomum complanatum transformed in experimentally infected chicken and rabbit eye. The incubation of the released eggs in distilled water at 28 +/- 1 degrees C led to the embryonation followed by hatching on tenth day to release miracidia. These can be used to infect the snails. We propose that these two in vivo model systems can be used as a source of viable eggs for further studies on developmental biology and life cycle where in law-protected animals are not to be used. To the best of our knowledge, in contrast to the previous attempts, this is the first successful study to report any experimental model to produce ovigerous adult worms capable of releasing viable eggs. PMID- 23354940 TI - The new national integrated strategy emphasizing infection sources control for schistosomiasis control in China has made remarkable achievements. AB - Schistosomiasis japonica remains one important public health concern that cause great loss of humans' health and social-economic development in the Peoples' Republic of China. At the end of 1990s and the beginning of 2000s, there were still about 0.8 million patients and nearly 85 million people living in the epidemic areas around China. We undertook full analysis of the epidemiological data of schistosomiasis taken from the report of schistosomiasis status in People's Republic of China from 1999 to 2010 for effectiveness assessment of China's new strategy for schistosomiasis control nationwide after its implementation since the beginning the 21st century. The schistosomiasis-endemic uncontrolled counties or towns decreased in number from 1,149 in 2002 to 643 in 2010 at a rate of 44%. The number of schistosomiasis patients decreased from nearly 800,000 to less than 326,000 in 2010 at a decrease rate of more than 50%. The number of acute schistosomiasis patients also decreased significantly, and only 43 cases were reported in 2010. The infection rates of cattle in the endemic uncontrolled provinces decreased greatly though the number of cattle and the actual snail habitat areas remained large with no obvious decline. The schistosome infection rates of human and cattle both decreased significantly by more than 64% and 75%. However, most of the uncontrolled schistosomiasis-endemic areas, schistosomiasis patients, and acute cases are generally located in the four provinces (Hunan, Hubei, Jiangxi, and Anhui) of the lake regions in the middle and lower reach of the Yangtze River, and the egg-positive rates in diagnosed human in endemic Hunan and Hubei remained higher than 10%. Therefore, the new strategy of schistosomiasis control via integrated measures emphasizing infection source control is scientific and successful around China, though it is essential to explore an effective and sustainable strategy for schistosomiasis control in the tough lake and marshland regions of China. The four provinces (Hunan, Hubei, Jiangxi, and Anhui) of the lake regions in China are the main battlefield of China's schistosomiasis control in the present and future. PMID- 23354941 TI - Isolation, cloning, and pathologic analysis of Trypanosoma evansi field isolates. AB - In recent years, the emergence of highly pathogenic Trypanosoma evansi strains in the Philippines has resulted in substantial losses in livestock production. In this study, we isolated T. evansi from infected-water buffaloes in the Philippines and analyzed their virulence using mice and cattle. A total of 10 strains of T. evansi were isolated. Evaluation of the virulence of each strain using mice depicted significant differences among the strains in the prepatent period, the level of parasitemia, and the survival time of the infected animals. In mice infected with the highly pathogenic T. evansi, signs of excessive inflammation such as marked splenomegaly and increase more than 6-fold in the number of leukocytes were observed at 8 days post-infection. To study the virulence of the parasite strains in cattle (which are the common T. evansi hosts in Philippines), cattle were infected with the T. evansi isolates that showed high and low virulence in mice. The rate of parasite growth and the length of the prepatent periods were found to be similar to those observed in mice for the respective strains. The cattle infected with the highly pathogenic strain developed anemia and a marked decrease in leukocyte counts. To determine the cause of the pathological changes, we analyzed the expression levels of inflammatory cytokines and observed up-regulation of tumor necrosis factor-alpha in anemic infected cattle. Our findings suggest that the epidemic of T. evansi in the Philippines is characterized by T. evansi strains with varying virulences from low to very high pathogenicity in cattle. PMID- 23354943 TI - Granzyme M cannot induce cell death via cleavage of mouse FADD. PMID- 23354942 TI - Prevalence and genetic diversity of Entamoeba species infecting macaques in southwest China. AB - Many colonies of macaques (Macaca fascicularis and Macaca mulatta) are maintained in China, especially in Guangxi and Guizhou. A total of 803 fresh stool samples infected with Entamoeba were obtained from three big colonies of macaques located in southwest China. The samples were examined for the presence of five Entamoeba species using PCR. Entamoeba nuttalli, Entamoeba dispar, Entamoeba coli, and Entamoeba chattoni infections were detected, but Entamoeba histolytica infection was not. This study is the first to report on the prevalence of E. nuttalli in wild macaques from China. Eighteen E. nuttalli isolates and five E. dispar isolates were obtained by culturing the samples in Tanabe-Chiba medium. The serine-rich protein (SRP), ribosomal RNA (rRNA), hexokinase (HXK), glucose-6 phosphate isomerase (GPI), and phosphoglucomutase (PGM) genes of E. nuttalli isolates were compared with other reported isolates. The results showed clear differences among the Chinese E. nuttalli isolates and other isolates based on the SRP gene sequences. However, HXK, GPI, and PGM genes of these strains were similar to those of other isolates. The rRNA genes of E. coli and E. chattoni were also amplified and analyzed from these samples. The results suggested that host species might be a more important factor than geographic location in amebic genetic diversity. PMID- 23354944 TI - Review article: risks of anemia and related management strategies: can perioperative blood management improve patient safety? AB - PURPOSE: Anemia in both acute and chronic conditions is associated with an increased risk of organ injury (brain, heart, kidney) and mortality. Thus, anemia is not "safe". Impairment of tissue oxygen delivery likely contributes as a central mechanism; however, the existing treatments for anemia (i.e., transfusion, erythropoiesis stimulating agents, blood substitutes) have not produced a demonstrable improvement in patient outcomes despite their efficacy to increase blood oxygen content. Indeed, transfusion of red blood cells (RBCs) has been attributed to increase mortality in non-bleeding patients. Thus, the pathophysiology of anemia-induced morbidity and mortality and its treatments are complex and incompletely understood. New knowledge continues to emerge regarding the cellular mechanisms that maintain oxygen homeostasis during anemia. Nevertheless, the application of this knowledge has not yet led to improvements in patient outcomes. As both anemia and transfusion are associated with increased mortality, utilization of multimodal patient blood management strategies may be effective in avoiding both of these predictors of adverse outcomes. We propose to review new strategies to avoid both anemia and transfusion with the goal of improving patient outcomes and safety. PRINCIPAL FINDINGS: We reviewed several approaches that utilize patient blood management to improve patient outcomes, including 1) characterization of biomarkers of anemia-induced tissue hypoxia to identify appropriate patient-specific treatment thresholds or hemoglobin (Hb) triggers; 2) development of adequately powered clinical trials that will help to define appropriate guidelines for the perioperative treatment of anemia and optimal Hb thresholds for transfusion of RBCs in specific patient populations; and 3) demonstration that an established blood conservation program (ONTraC) can reduce RBC transfusion and its associated adverse outcomes. CONCLUSIONS: Anemia is associated with increased morbidity and mortality. Ongoing initiatives to treat anemia and optimize patient blood management may improve patient outcomes. A broader application of these approaches may improve the overall safety of anesthesia and surgery for patients with anemia. PMID- 23354945 TI - Multiple treatment comparison analysis: If A is better than B, and B is better than C, is A better than C? PMID- 23354946 TI - Special problems for the elderly psychoanalyst in the psychoanalytic process. AB - The psychoanalytic process takes on a special ambience when the analyst is clearly elderly. The effects of this ambience on the the aging analyst's patients are discussed, and the sparse literature on the subject is reviewed. Clinical vignettes illustrate a number of these effects on the analytic process. Dealing with these special problems requires not only the analyst's awareness of their existence but a continual monitoring of the transference-countertransference in order to avoid a silent collusion of patient and analyst to pretend these problems do not exist. The dangerous consequences of being unaware of the situation, for both patient and analyst, are discussed. If the influence of the patient's perception of the analyst's aging is ignored, it may lead to destruction of the treatment either through massive acting out or by a hopeless stalemate with or without the development of an endless psychoanalysis. PMID- 23354947 TI - 3D fat-saturated T1 SPACE sequence for the diagnosis of cervical artery dissection. AB - INTRODUCTION: This study aims to demonstrate the added value of a 3D fat saturated (FS) T1 sampling perfection with application-optimised contrast using different flip angle evolutions (SPACE) sequence compared to 2D FS T1 spin echo (SE) for the diagnosis of cervical artery dissection. METHODS: Thirty-one patients were prospectively evaluated on a 1.5-T MR system for a clinical suspicion of acute or subacute cervical artery dissection with 3D T1 SPACE sequence. In 23 cases, the axial 2D FS T1 SE sequence was also used; only these cases were subsequently analysed. Two neuroradiologists independently and blindly assessed the 2D and 3D T1 sequences. The presence of recent dissection (defined as a T1 hyperintensity in the vessel wall) and the quality of fat suppression were assessed. The final diagnosis was established in consensus, after reviewing all the imaging and clinical data. RESULTS: Overall sensitivity and specificity were 0.929 and 1 for axial T1 SE, and 0.965 and 0.945 for T1 SPACE (P > 0.05), respectively. The two readers had excellent agreement for both sequences (k = 1 and 0.8175 for T1 SE and T1 SPACE, respectively; P > 0.05). The quality of the fat saturation was similar. Very good fat saturation was obtained in the upper neck. Multiplanar reconstructions were very useful in tortuous regions, such as the atlas loop of the vertebral artery or the carotid petrous entry. 3D T1 SPACE sequence has a shorter acquisition time (3 min 25 s versus 5 min 32 s for one T1 SE sequence) and a larger coverage area. CONCLUSION: 3D T1 SPACE sequence offers similar information with its 2D counterpart, in a shorter acquisition time and larger coverage area. PMID- 23354948 TI - Effects of EHD2 interference on migration of esophageal squamous cell carcinoma. AB - C-Terminal EH domain-containing protein 2 (EHD2) of the EHD family is associated with plasma membrane. We investigated the expression of EHD2 in human esophageal squamous cell carcinoma (ESCC) and the EHD2 expression to study the therapeutic effect of chemotherapy drugs. Western blot and immunohistochemistry were used to measure the expression of EHD2 protein in ESCC and adjacent normal tissue in 98 patients. EHD2 protein level was reduced in ESCC tissues in comparison with adjacent normal tissues. Under-expression of EHD2 increased the motility property of ESCC cell TE1 in vitro by wound-healing assays and transwell migration assays, and it was concurrent with the decreased expression of epithelial marker E cadherin. Under-expression of EHD2 in TE1 can cause resistance to cisplatin. Our results suggested that EHD2 low expression is involved in the pathogenesis of ESCC, and it might be a favorable independent poor prognostic parameter for ESCC. PMID- 23354949 TI - Knockdown of Dkk-3 decreases cancer cell migration and invasion independently of the Wnt pathways in oral squamous cell carcinoma-derived cells. AB - Oral squamous cell carcinoma (OSCC) is thought to arise as the result of cumulative genetic or epigenetic alterations in cancer-associated genes. We focused on the Dickkopf-3 (Dkk-3) gene as a candidate tumor suppressor in OSCC. Dkk-3 is a potential tumor suppressor, and its downregulation has been reported in various types of malignancies. However, our previous data demonstrated that the Dkk-3 protein was dominantly expressed in OSCC tissue, and its expression was correlated with a high incidence of metastasis and with poor prognosis. In order to explain this paradox, we performed functional analyses of the Dkk-3 gene in cancer cell lines. RT-PCR revealed that Dkk-3 mRNA expression was observed in OSCC-derived cell lines but not in gastrointestinal or colorectal adenocarcinoma derived cell lines. The siRNA for Dkk-3 was transfected into Dkk-3-expressing cells, and the changes in cell proliferation, invasion and migration were assessed. The knockdown of Dkk-3 mRNA by siRNA transfection did not affect cell proliferation, but it significantly decreased cell migration and invasion. To further investigate the precise mechanism that contributes to the potential oncogenic function of Dkk-3, the Wnt canonical pathway and non-canonical pathways were assessed. Western blotting demonstrated that the effect of Dkk-3 knockdown on cell migration or invasion was not caused by activation of the Wnt pathways. These data demonstrated that Dkk-3 expression in OSCC was different than that in adenocarcinomas. Dkk-3 may possess an oncogenic function that is independent of Wnt signaling. PMID- 23354951 TI - Alternative splicing of BRAF transcripts and characterization of C-terminally truncated B-Raf isoforms in colorectal cancer. AB - The BRAF proto-oncogene is mutated in a subset of human tumors, including colorectal cancer. A splicing variant lacking exons 14 and 15 (BRAF del E14/15) has been described recently. However, the frequency of the variant, the kinase activity of the protein isoform, its biological function, and which allele it is derived from remains unknown. BRAF mRNA from colorectal cancer cell lines and colonic epithelium was reversely transcribed, subcloned, and screened for alternative splicing. New transcript variants and allelic origin of alternatively spliced transcripts were analyzed by DNA sequencing. Kinase activity of the B-Raf isoforms was determined by Western blotting after transfections with expression constructs of the different BRAF variants. Four additional BRAF transcript variants resulting in C-terminal truncation of the gene product were found. Alternative splicing was found at frequencies from 4.7 to 16.7% in normal and neoplastic colorectal cells. Alternative transcripts were shown to be derived from both wild-type and V600E alleles. All nonconsensus B-Raf protein variants were found to be kinase-dead and failed to coactivate full-length B-Raf. In conclusion, we present a highly sensitive method for the detection of aberrantly spliced transcripts. Alternative splicing of exons 14, 15, 15b, 16b and 16c occurs in a considerable fraction of BRAF mRNA in normal colon and colorectal cancer cells and is independent of the V600E mutational status of the parental allele. Splicing of nonfunctional transcripts affects overall cellular B-Raf activity and might represent a mechanism to decrease sensitivity to growth signals. PMID- 23354952 TI - Comparison of three methods of cervical measurement in the first trimester: single-line, two-line, and tracing. AB - OBJECTIVES: To compare three methods of cervical length measurements using ultrasound in the first trimester: single-line, two-line, and tracing. METHODS: Images appropriate for cervical length measurements were obtained using transvaginal ultrasound between 11 + 0 and 13 + 6 weeks' gestation. The cervix was measured on stored images using three methods: a single straight line, two segments (two-line method), and by tracing the distance along the cervical canal. Results were compared for intraoperator repeatability and interoperator variability. The degree of the cervical curvature was measured. RESULTS: The mean cervical measurement using the single-line measurement was 32.8 (SD 4.4) mm. The mean cervical length was essentially the same using the two-line and tracing measurement: 34.4 (SD 4.7) mm and 34.5 (SD 4.7) mm, respectively. Both intra- and interoperator agreement was high. The degree of curvature of the cervical canal was variable, with a resultant variability in the difference between the single straight line measurement and the other two types of measurement. CONCLUSIONS: Using stored images, each of the measurement techniques is highly reproducible. Both the two-line and the tracing methods yield larger measurements than the single-line technique. Therefore, it appears that in select cases the straight line measurement significantly underestimates the actual cervical length. PMID- 23354950 TI - Binge eating disorder: the next generation of research. PMID- 23354953 TI - Genetic basis for recurrent vulvo-vaginal candidiasis. AB - Vulvovaginal candidiasis (VVC) is a frequent disease affecting more than 75% of all women at least once in their lifetime. Up to 8% of them suffer from recurrent VVC (RVVC) characterized by at least three episodes each year. Several risk factors, such as antibiotic use, diabetes, or pregnancy, are known, but the vast majority of women with RVVC develop the infection without having any risk factor, implying that a genetic component most likely plays an important role in the susceptibility to RVVC. This review summarizes the immunogenetic alterations that lead to an increased susceptibility to vaginal infections with Candida albicans. Different mutations and polymorphisms in innate immune genes alter the mucosal immune response against fungi and are likely to have an important role in susceptibility to RVVC. A better understanding of the genetic and immunological mechanisms leading to RVVC is important for both the understanding of the pathophysiology of the disease and the design of novel therapeutic strategies. PMID- 23354954 TI - Mixed vaginitis-more than coinfection and with therapeutic implications. AB - Mixed vaginitis is due to the simultaneous presence of at least two vaginal pathogens, both contributing to an abnormal vaginal milieu and, hence, symptoms and signs of vaginitis. In mixed vaginitis, both pathogens require specific therapy for complete eradication of concurrent manifestations. In coinfection, although two pathogens are identified, a potential pathogen may be present but may not be a cause of existing vaginal symptoms. Although data remain sparse, mixed vaginitis occurs rarely (<5 %). By contrast, pathogen coinfection occurs frequently in women with vaginitis. Approximately 20 %-30 % of women with bacterial vaginosis (BV) are coinfected with Candida species. Coexistence of BV pathogens and T. vaginalis is even more common, with coinfection rates of 60 %-80 %. Both coinfection and mixed vaginitis have significant clinical and therapeutic implications and are worthy of further investigation. PMID- 23354955 TI - Analogical reasoning in baboons (Papio papio): flexible reencoding of the source relation depending on the target relation. AB - Analogical reasoning is a cornerstone of human cognition, but the extent and limits of analogical reasoning in animals remains unclear. Recent studies have demonstrated that apes and monkeys can match relations with relations, suggesting that these species have the basic abilities for analogical reasoning. However, analogical reasoning in humans entails two additional cognitive processes that remain unexplored in animals. These include the ability to (1) flexibly reencode the relations instantiated by the source domain as a function of the relational properties of the target domain, and (2) to match relations across different stimulus dimensions. Using a two-dimensional relational matching-to-sample task, the present study demonstrates that these two abilities are in the scope of baboons, given appropriate training. These findings unveil the richness of the cognitive processes implicated during analogical reasoning in nonhuman primates and further reduce the apparent gap between animal and human cognition. PMID- 23354956 TI - Overt intracardiac shunt flow after arteriovenous graft placement. PMID- 23354957 TI - The learning curve in the use of trans-oral laser microsurgery for cancer treatment. PMID- 23354958 TI - Radiofrequency ablation of large renal angiomyolipoma: median-term follow-up. AB - PURPOSE: To study the feasibility of percutaneous radiofrequency ablation (RFA) of large angiomyolipomas (AMLs) using saline-cooled electrodes. MATERIALS AND METHODS: Institutional Review Board approval for the study was received. Four patients (all female, age range 33-67 years) with large AMLs (maximal axis 6.1 32.4 cm) not suitable for embolotherapy or surgery consented to a trial of RFA. Procedures were performed under computerized tomographic guidance using 14G saline-infused electrodes. Two ablations (diameter 4-7 cm) were undertaken in each patient. Variables studied were technical success, treatment safety, alteration of tumor consistency, tumor size, effect on renal function, and medium term freedom from haemorrhage. RESULTS: All four patients underwent successful RFA without any intraprocedural complications. There has been no haemorrhage, or new renal specific symptom, during a minimum 48-month period, and normal renal function has been normal. On follow-up radiological imaging, the tumors have become fattier with involution of the soft-tissue elements (soft tissue-to-total tumor ratio decreased mean [range] of 0.26 [0.14-0.48] to 0.17 [0.04-0.34] U; p = 0.04 [paired Student t test]). Further evidence of treatment effect was the development of a capsule around the ablation zone, but there was no change in overall tumor volume (mean [range] 1,120 [118-2,845] to 1150 [90-3,013] ml; p = 1 [paired Student t test]). CONCLUSION: RFA of large AMLs is technically feasible using saline-infused electrodes. The soft-tissue elements decreased in volume; the tumors become fattier; and there has been no renal haemorrhage during a 48 month period. PMID- 23354959 TI - Use of a thrombin-gelatin matrix for hemostasis after failed device closure of femoral arterial access. PMID- 23354960 TI - Hyaluronic acid gel injection to prevent thermal injury of adjacent gastrointestinal tract during percutaneous liver radiofrequency ablation. AB - This study evaluated the safety, feasibility, and clinical utility of hyaluronic acid gel injection to separate the gastrointestinal tract from the tumor during liver radiofrequency ablation (RFA). Eleven patients with liver tumors measuring 0.9-3.5 cm (mean +/- standard deviation, 2.1 +/- 0.8 cm) that were adjacent to the gastrointestinal tracts received RFA after the mixture of hyaluronic acid gel and contrast material (volume, 26.4 +/- 14.5 mL; range, 10-60 mL) was injected between the tumor and the gastrointestinal tract under computed tomographic fluoroscopic guidance. Each tumor was separated from the gastrointestinal tract by 1.0-1.5 cm (distance, 1.2 +/- 0.2 cm) after injection of hyaluronic acid gel, and subsequent RFA was performed without any complications in all patients. Although tumor enhancement disappeared in all patients, local tumor progression was found in a patient (9.1%, 1 of 11) during the follow-up of 5.5 +/- 3.2 months (range, 0.4-9.9 months). In conclusion, hyaluronic acid gel injection is a safe and useful technique to avoid thermal injury of the adjacent gastrointestinal tract during liver RFA. PMID- 23354961 TI - Safety of repeated yttrium-90 radioembolization. AB - PURPOSE: Repeated radioembolization (RE) treatments carry theoretically higher risk of radiation-induced hepatic injury because of the liver's cumulative memory of previous exposure. We performed a retrospective safety analysis on patients who underwent repeated RE. METHODS: From 2004 to 2011, a total of 247 patients were treated by RE. Eight patients (5 men, 3 women, age range 51-71 years) underwent repeated treatment of a targeted territory, all with resin microspheres (SIR-Spheres; Sirtex, Lane Cove, Australia). Adverse events were graded during a standardized follow-up. In addition, the correlation between the occurrence of RE induced liver disease (REILD) and multiple variables was investigated in univariate and multivariate analyses in all 247 patients who received RE. RESULTS: Two patients died shortly after the second treatment (at 84 and 107 days) with signs and symptoms of REILD. Both patients underwent whole liver treatment twice (cumulative doses 3.08 and 2.66 GBq). The other 6 patients demonstrated only minor toxicities after receiving cumulative doses ranging from 2.41 to 3.88 GBq. All patients experienced objective tumor responses. In the whole population, multifactorial analysis identified three risk factors associated with REILD: repeated RE (p = 0.036), baseline serum total bilirubin (p = 0.048), and baseline serum aspartate aminotransferase (p = 0.043). Repeated RE proved to be the only independent risk factor for REILD in multivariate analysis (odds ratio 9.6; p = 0.002). Additionally, the administered activity per target volume (in GBq/L) was found to be an independent risk factor for REILD, but only in whole liver treatments (p = 0.033). CONCLUSION: The risk of REILD appears to be elevated for repeated RE. Objective tumor responses were observed, but establishment of safety limits will require improvement in dosimetric measurement and prediction. PMID- 23354962 TI - The role of postintervention pullback pressure gradient in percutaneous transluminal angioplasty for central vein stenosis in dialysis patients. AB - PURPOSE: The severity of residual stenosis (RS) sometimes cannot be accurately measured by angiography during central vein intervention. This study evaluated the role of pullback pressure measurement during central vein stenosis (CVS) intervention. METHODS: A retrospective review enrolled 94 consecutive dialysis patients who underwent CVS interventions but not stenting procedures. Patients were classified into 2 groups by either angiography or pressure gradient (PG) criteria, respectively. Groups divided by angiographic result were successful group (RS <= 30 %) and acceptable group (50 % >= RS > 30 %), while groups divided by PG were low PG group (PG <= 5 mmHg) and high PG group (PG >5 mmHg). Baseline characteristics and 12-month patency rates between the groups were analyzed. RESULTS: The angiography results placed 63 patients in the successful group and 31 patients in the acceptable group. The patency rate at 12 month was not statistically different (P = 0.167). When the patients were reclassified by the postintervention pullback PG, the patency rate at 12 months was significant (P = 0.048). Further analysis in groups redivided by different combinations of RS and PG criteria identified significant differences in the group with both RS <= 30 % and PG <= 5 mmHg compared with those with either RS >30 % (P = 0.047) or PG >5 mmHg (P = 0.027). In addition, there was a significant difference between those with both RS <= 30 % and PG <= 5 mmHg compared with those with both RS >30 % and PG >5 mmHg (P = 0.027). CONCLUSION: Postintervention PG can better predict long term outcomes after angioplasty for CVS in nonstented dialysis patients than angiography. PMID- 23354963 TI - Below-the-knee interventions. PMID- 23354964 TI - Two cases of postmyomectomy pseudoaneurysm treated by transarterial embolization. AB - Pseudoaneurysm resulting from hysteroscopic myomectomy is a rare clinical situation, and interventional radiologists are not traditionally involved in the management. To our knowledge, endovascular treatment of a pseudoaneurysm resulting from hysteroscopic myomectomy has not yet been reported in the English language literature. Here, two such cases are reported, including one of a woman who later became pregnant. The case is unique because little is known about the influence of unilateral coil embolization of the uterine artery on fertility. PMID- 23354965 TI - Traumatic inferior gluteal artery pseudoaneurysm with compressive neuropathy managed with endovascular embolization and surgery. PMID- 23354966 TI - Fluoroscopically guided balloon dilation for postintubation tracheal stenosis. AB - PURPOSE: Little was known about the safety and long-term efficacy of fluoroscopically guided balloon dilation for postintubation tracheal stenosis. The purpose of this study was to evaluate the safety and long-term efficacy of fluoroscopically guided balloon dilation in patients with postintubation tracheal stenosis. METHODS: From February 2000 to November 2010, 14 patients underwent fluoroscopically guided balloon dilation for postintubation tracheal stenosis. Technical success, clinical success, and complications were evaluated. Patients were followed up for recurrent symptoms. RESULTS: In all patients, fluoroscopically guided balloon dilation was technically and clinically successful with no major complications. Following the initial procedure, six patients (43 %) remained asymptomatic during a follow-up period. Obstructive symptoms recurred in eight patients (57 %) within 6 months (mean, 1.7 months), who were treated with repeat balloon dilation (n = 4) and other therapies. Of the four patients who underwent repeat balloon dilation, three became asymptomatic. One patient became asymptomatic after a third balloon dilation. On long-term (mean, 74 months) follow-up, 71 % of patients experienced relief of symptoms following fluoroscopically guided balloon dilation. CONCLUSIONS: Fluoroscopically guided balloon dilation may be safe, is easy to perform, and resulted in effective treatment in patients with postintubation tracheal stenosis. PMID- 23354967 TI - French sizing of medical devices is not fit for purpose. AB - PURPOSE: The purpose of the study is to quantify the variation in the metric equivalent of French size in a range of medical devices, from various manufacturers, used in interventional radiology. METHODS: The labelling of a range of catheters, introducers, drains, balloons, stents, and endografts was examined. Products were chosen to achieve a broad range of French sizes from several manufacturers. To assess manufacturing accuracy, eight devices were selected for measurement using a laser micrometer. The external diameters of three specimens of each device were measured at centimeter intervals along the length of the device to ensure uniformity. RESULTS: A total of 200 labels of interventional radiology equipment were scrutinized. The results demonstrate a wide variation in the metric equivalent of French sizing. Labelled products can vary in diameter across the product range by up to 0.79 mm. The devices selected for measurement with the non-contact laser micrometer demonstrate acceptable manufacturing consistency. The external diameter differed by 0.05 mm on average. CONCLUSIONS: Our results demonstrate wide variation in the interpretation of the French scale by different manufacturers of medical devices. This has the potential to lead to problems using coaxial systems especially when the products are from different manufacturers. It is recommended that standard labelling should be employed by all manufacturers conveying specific details of the equipment. Given the wide variation in the interpretation of the French scale, our opinion is that this scale either needs to be abandoned or be strictly defined and followed. PMID- 23354968 TI - Large atrial thrombus at unusual site: masquerading atrial myxoma. PMID- 23354969 TI - APC-PCI complex levels for screening of AAA in patients with peripheral atherosclerosis. AB - To evaluate the use of activated protein C-protein C inhibitor (APC-PCI) complex levels for detection of abdominal aortic aneurysm (AAA) in patients with peripheral atherosclerotic disease (PAD). APC-PCI levels and aortic diameter evaluated in 511 PAD patients without previously known AAA followed-up concerning survival for 4.8(0.5) years. AAA was found in 13% of patients. Aortic diameter correlated (r = 0.138; p = 0.002) with APC-PCI levels which were higher (0.40[0.45] vs. 0.30[0.49] MUg/l; p = 0.004) in patients with AAA. This difference persisted in multivariate analysis (p = 0.029). A threshold value of APC-PCI >=0.15 MUg/L showed a specificity of 11%, a sensitivity of 97% and a negative predictive value of 96% for an AAA diagnosis. APC-PCI levels were higher in patients with AAA, and showed high sensitivity but low specificity for the diagnosis and can therefore not be considered as a screening tool in PAD patients. An AAA prevalence of 13% in patients with PAD indicates a need for AAA screening within this population. PMID- 23354970 TI - Systematic review of five feeding routes after pancreatoduodenectomy. AB - BACKGROUND: Current European guidelines recommend routine enteral feeding after pancreato-duodenectomy (PD), whereas American guidelines do not. The aim of this study was to determine the optimal feeding route after PD. METHODS: A systematic search was performed in PubMed, Embase and the Cochrane Library. Included were studies on feeding routes after PD that reported length of hospital stay (primary outcome). RESULTS: Of 442 articles screened, 15 studies with 3474 patients were included. Data on five feeding routes were extracted: oral diet (2210 patients), enteral nutrition via either a nasojejunal tube (NJT, 165), gastrojejunostomy tube (GJT, 52) or jejunostomy tube (JT, 623), and total parenteral nutrition (TPN, 424). Mean(s.d.) length of hospital stay was shortest in the oral diet and GJT groups (15(14) and 15(11) days respectively), followed by 19(12) days in the JT, 20(15) days in the TPN and 25(11) days in the NJT group. Normal oral intake was established most quickly in the oral diet group (mean 6(5) days), followed by 8(9) days in the NJT group. The incidence of delayed gastric emptying varied from 6 per cent (3 of 52 patients) in the GJT group to 23.2 per cent (43 of 185) in the JT group, but definitions varied widely. The overall morbidity rate ranged from 43.8 per cent (81 of 185) in the JT group to 75 per cent (24 of 32) in the GJT group. The overall mortality rate ranged from 1.8 per cent (3 of 165) in the NJT group to 5.4 per cent (23 of 424) in the TPN group. CONCLUSION: There is no evidence to support routine enteral or parenteral feeding after PD. An oral diet may be considered as the preferred routine feeding strategy after PD. PMID- 23354971 TI - Multimodality GPU-based computer-assisted diagnosis of breast cancer using ultrasound and digital mammography images. AB - PURPOSE: To improve the computer-aided diagnosis of breast lesions, by designing a pattern recognition system (PR-system) on commercial graphics processing unit (GPU) cards using parallel programming and textural information from multimodality imaging. MATERIAL AND METHODS: Patients with histologically verified breast lesions underwent both ultrasound (US) and digital mammography (DM), lesions were outlined on the images by an experienced radiologist, and textural features were calculated. The PR-system was designed to provide highest possible precision by programming in parallel the multiprocessors of the NVIDIA's GPU cards, GeForce 8800GT or 580GTX, and using the CUDA programming framework and C++. The PR-system was built around the probabilistic neural network classifier, and its performance was evaluated by a re-substitution method, for estimating the system's highest accuracy, and by the external cross-validation method, for assessing the PR-system's unbiased accuracy to new, "unseen" by the system, data. RESULTS: Classification accuracies for discriminating malignant from benign lesions were as follows: 85.5 % using US-features alone, 82.3 % employing DM features alone, and 93.5 % combining US and DM features. Mean accuracy to new "unseen" data for the combined US and DM features was 81 %. Those classification accuracies were about 10 % higher than accuracies achieved on a single CPU, using sequential programming methods, and 150-fold faster. CONCLUSION: The proposed PR system improves breast-lesion discrimination accuracy, it may be redesigned on site when new verified data are incorporated in its depository, and it may serve as a second opinion tool in a clinical environment. PMID- 23354973 TI - Heritability of boldness and aggressiveness in the zebrafish. AB - Behavioural traits that are consistent over time and in different contexts are often referred to as personality traits. These traits influence fitness because they play a major role in foraging, reproduction and survival, and so it is assumed that they have little or no additive genetic variance and, consequently, low heritability because, theoretically, they are under strong selection. Boldness and aggressiveness are two personality traits that have been shown to affect fitness. By crossing single males to multiple females, we estimated the heritability of boldness and aggressiveness in the zebrafish, Danio rerio. The additive genetic variance was statistically significant for both traits and the heritability estimates (95 % confidence intervals) for boldness and aggressiveness were 0.76 (0.49, 0.90) and 0.36 (0.10, 0.72) respectively. Furthermore, there were significant maternal effects accounting for 18 and 9 % of the proportion of phenotypic variance in boldness and aggressiveness respectively. This study shows that there is a significant level of genetic variation in this population that would allow these traits to evolve in response to selection. PMID- 23354974 TI - Novel quantitative trait loci for partial resistance to Phytophthora sojae in soybean PI 398841. AB - Phytophthora root and stem rot caused by Phytophthora sojae Kaufmann and Gerdemann is one of the most severe soybean [Glycine max (L.) Merr] diseases in the USA. Partial resistance is as effective in managing this disease as single gene (Rps gene)-mediated resistance and is more durable. The objective of this study was to identify quantitative trait loci (QTL) associated with partial resistance to P. sojae in PI 398841, which originated from South Korea. A population of 305 F7:8 recombinant inbred lines derived from a cross of OX20-8 * PI 398841 was used to evaluate partial resistance against P. sojae isolate C2S1 using a tray test. Composite interval mapping using a genome-wide logarithm of odd (LOD) threshold detected three QTL on chromosomes 1, 13, and 18, which individually explained 4-16 % of the phenotypic variance. Seven additional QTL, accounting for 2-3 % of phenotypic variance each, were identified using chromosome-wide LOD thresholds. Seven of the ten QTL for resistance to P. sojae were contributed by PI 398841. Seven QTL co-localized with known Rps genes and previously reported QTL for soil-borne root pathogens, isoflavone, and seed oil. Three QTL on chromosomes 3, 13, and 18 co-localized with known Rps genes, but PI 398841 did not exhibit an Rps gene-mediated resistance response following inoculation with 48 different isolates of P. sojae. PI 398841 is potentially a source of novel genes for improving soybean cultivars for partial resistance to P. sojae. PMID- 23354976 TI - Genetic determinants of mortality. Can findings from genome-wide association studies explain variation in human mortality? AB - Twin studies have estimated the heritability of longevity to be approximately 20 30 %. Genome-wide association studies (GWAS) have revealed a large number of determinants of morbidity, but so far, no new polymorphisms have been discovered to be associated with longevity per se in GWAS. We aim to determine whether the genetic architecture of mortality can be explained by single nucleotide polymorphisms (SNPs) associated with common traits and diseases related to mortality. By extensive quality control of published GWAS we created a genetic score from 707 common SNPs associated with 125 diseases or risk factors related with overall mortality. We prospectively studied the association of the genetic score with: (1) time-to-death; (2) incidence of the first of nine major diseases (coronary heart disease, stroke, heart failure, diabetes, dementia, lung, breast, colon and prostate cancers) in two population-based cohorts of Dutch and Swedish individuals (N = 15,039; age range 47-99 years). During a median follow-up of 6.3 years (max 22.2 years), we observed 4,318 deaths and 2,132 incident disease events. The genetic score was significantly associated with time-to-death [hazard ratio (HR) per added risk allele = 1.003, P value = 0.006; HR 4th vs. 1st quartile = 1.103]. The association between the genetic score and incidence of major diseases was stronger (HR per added risk allele = 1.004, P value = 0.002; HR 4th vs. 1st quartile = 1.160). Associations were stronger for individuals dying at older ages. Our findings are compatible with the view of mortality as a complex and highly polygenetic trait, not easily explainable by common genetic variants related to diseases and physiological traits. PMID- 23354975 TI - Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate. AB - We describe a female subject (DGAP100) with a 46,X,t(X;5)(p11.3;q35.3)inv(5)(q35.3q35.1)dn, severe psychomotor retardation with hypotonia, global postnatal growth restriction, microcephaly, globally reduced cerebral volume, seizures, facial dysmorphia and cleft palate. Fluorescence in situ hybridization and whole-genome sequencing demonstrated that the X chromosome breakpoint disrupts KDM6A in the second intron. No genes were directly disrupted on chromosome 5. KDM6A is a histone 3 lysine 27 demethylase and a histone 3 lysine 4 methyltransferase. Expression of KDM6A is significantly reduced in DGAP100 lymphoblastoid cells compared to control samples. We identified nine additional cases with neurodevelopmental delay and various other features consistent with the DGAP100 phenotype with copy number variation encompassing KDM6A from microarray databases. We evaluated haploinsufficiency of kdm6a in a zebrafish model. kdm6a is expressed in the pharyngeal arches and ethmoid plate of the developing zebrafish, while a kdm6a morpholino knockdown exhibited craniofacial defects. We conclude KDM6A dosage regulation is associated with severe and diverse structural defects and developmental abnormalities. PMID- 23354977 TI - Human loci involved in drug biotransformation: worldwide genetic variation, population structure, and pharmacogenetic implications. AB - Understanding the role of inheritance in individual variation in drug response is the focus of pharmacogenetics (PGx). A key part of this understanding is quantifying the role of genetic ancestry in this phenotypic outcome. To provide insight into the relationship between ethnicity and drug response, this study first infers the global distribution of PGx variation and defines its structure. Second, the study evaluates if geographic population structure stems from all PGx loci in general, or if structure is caused by specific genes. Lastly, we identify the genetic variants contributing the greatest proportion of such structure. Our study describes the global genetic structure of PGx loci across the 52 populations of the Human Genome Diversity Cell-Line Panel, the most inclusive set of human populations freely available for studies on human genetic variation. By analysing genetic variation at 1,001 single nucleotide polymorphisms (SNPs) involved in biotransformation of exogenous substances, we describe the between populations PGx variation, as well geographical groupings of diversity. In addition, with discriminant analysis of principal component (DAPC), we infer how many and which groups of populations are supported by PGx variation, and identify which SNPs actually contribute to the PGx structure between such groups. Our results show that intergenic, synonymous and non-synonymous SNPs show similar levels of genetic variation across the globe. Conversely, loci coding for Cytochrome P450s (mainly metabolizing exogenous substances) show significantly higher levels of genetic diversity between populations than the other gene categories. Overall, genetic variation at PGx loci correlates with geographic distances between populations, and the apportionment of genetic variation is similar to that observed for the rest of the genome. In other words, the pattern of PGx variation has been mainly shaped by the demographic history of our species, as in the case of most of our genes. The population structure defined by PGx loci supports the presence of six genetic clusters reflecting geographic location of samples. In particular, the results of the DAPC analyses show that 27 SNPs substantially contribute to the first three discriminant functions. Among these SNPs, some, such as the intronic rs1403527 of NR1I2 and the non-synonymous rs699 of AGT, are known to be associated with specific drug responses. Their substantial variation between different groups of populations may have important implications for PGx practical applications. PMID- 23354978 TI - Genetic variants associated with breast cancer risk for Ashkenazi Jewish women with strong family histories but no identifiable BRCA1/2 mutation. AB - The ability to establish genetic risk models is critical for early identification and optimal treatment of breast cancer. For such a model to gain clinical utility, more variants must be identified beyond those discovered in previous genome-wide association studies (GWAS). This is especially true for women at high risk because of family history, but without BRCA1/2 mutations. This study incorporates three datasets in a GWAS analysis of women with Ashkenazi Jewish (AJ) homogeneous ancestry. Two independent discovery cohorts comprised 239 and 238 AJ women with invasive breast cancer or preinvasive ductal carcinoma in situ and strong family histories of breast cancer, but lacking the three BRCA1/2 founder mutations, along with 294 and 230 AJ controls, respectively. An independent, third cohort of 203 AJ cases with familial breast cancer history and 263 healthy controls of AJ women was used for validation. A total of 19 SNPs were identified as associated with familial breast cancer risk in AJ women. Among these SNPs, 13 were identified from a panel of 109 discovery SNPs, including an FGFR2 haplotype. In addition, six previously identified breast cancer GWAS SNPs were confirmed in this population. Seven of the 19 markers were significant in a multivariate predictive model of familial breast cancer in AJ women, three novel SNPs [rs17663555(5q13.2), rs566164(6q21), and rs11075884(16q22.2)], the FGFR2 haplotype, and three previously published SNPs [rs13387042(2q35), rs2046210(ESR1), and rs3112612(TOX3)], yielding moderate predictive power with an area under the curve (AUC) of the ROC (receiver-operator characteristic curve) of 0.74. Population-specific genetic variants in addition to variants shared with populations of European ancestry may improve breast cancer risk prediction among AJ women from high-risk families without founder BRCA1/2 mutations. PMID- 23354980 TI - A new rapid methodological strategy to assess BRCA mutational status. AB - Hereditary cancers account for approximately 10 % of breast and ovarian cancers. Mutations of the BRCA1 and BRCA2 genes, encoding two proteins involved in DNA repair, underlie most cases of such hereditary cancers. Women with BRCA mutations develop breast cancer in 50-80 % of cases and ovarian cancer in 10-40 % of cases. Assessing BRCA mutational status is needed to direct the clinical management of women with predisposition to these hereditary cancers. However, BRCA screening constitutes a bottleneck in terms of costs and time to deliver results. We developed a PCR-based assay using 73 primer pairs covering the entire coding regions of BRCA1 and BRCA2. PCR primers, containing at the 5' end the universal M13 primer sequences, were pre-spotted in 96-well plates. Following PCR, direct sequencing was performed using M13 primers, allowing to standardize the conditions. PCR amplification and sequencing were successful for each amplicon. We tested and validated the assay on 10 known gDNAs from patients with Hereditary breast and ovarian cancer (HBOC). Our strategy is a promising time and cost effective method to detect BRCA mutations in the clinical setting, which is essential to formulate a personalized therapy for patients with HBOC. PMID- 23354982 TI - Time-dependent propensity score and collider-stratification bias: an example of beta2-agonist use and the risk of coronary heart disease. AB - Stratification and conditioning on time-varying cofounders which are also intermediates can induce collider-stratification bias and adjust-away the (indirect) effect of exposure. Similar bias could be expected when one conditions on time-dependent PS. We explored collider-stratification and confounding bias due to conditioning or stratifying on time-dependent PS using a clinical example on the effect of inhaled short- and long-acting beta2-agonist use (SABA and LABA, respectively) on coronary heart disease (CHD). In an electronic general practice database we selected a cohort of patients with an indication for SABA and/or LABA use and ascertained potential confounders and SABA/LABA use per three month intervals. Hazard ratios (HR) were estimated using PS stratification as well as covariate adjustment and compared with those of Marginal Structural Models (MSMs) in both SABA and LABA use separately. In MSMs, censoring was accounted for by including inverse probability of censoring weights.The crude HR of CHD was 0.90 [95 % CI: 0.63, 1.28] and 1.55 [95 % CI: 1.06, 2.62] in SABA and LABA users respectively. When PS stratification, covariate adjustment using PS, and MSMs were used, the HRs were 1.09 [95 % CI: 0.74, 1.61], 1.07 [95 % CI: 0.72, 1.60], and 0.86 [95 % CI: 0.55, 1.34] for SABA, and 1.09 [95 % CI: 0.74, 1.62], 1.13 [95 % CI: 0.76, 1.67], 0.77 [95 % CI: 0.45, 1.33] for LABA, respectively. Results were similar for different PS methods, but higher than those of MSMs. When treatment and confounders vary during follow-up, conditioning or stratification on time-dependent PS could induce substantial collider-stratification or confounding bias; hence, other methods such as MSMs are recommended. PMID- 23354981 TI - Offspring's blood pressure and metabolic phenotype after exposure to gestational hypertension in utero. AB - The aim of the study was to investigate the impact of de novo hypertension in pregnancy, i.e. gestational (non-proteinuric) hypertension (GH) and preeclampsia (PE), on the long-term metabolic outcome of the offspring. Data was obtained from the Northern Finland Birth Cohort 1986 (NFBC 1986), including 9,362 pregnancies and subsequent births between 1985 and 1986. Pregnancies were categorised into three groups: (1) GH with blood pressure (BP) >= 140/90 mmHg, (2) PE with BP >= 140/90 mmHg and proteinuria, and (3) reference group with normal BP. The final study population included 331 offspring of mothers with GH, 197 with PE and 5,045 offspring of normotensive mothers. The main outcome measures were systolic and diastolic blood pressure (SBP, DBP), mean arterial pressure (MAP), body mass index (BMI), and serum lipid, glucose and insulin levels of the 16 year-old offspring. The children of mothers with GH had higher BP compared to the reference group (SBP percentage difference 2.7 (95% CI 1.6, 3.8); DBP 3.4 (2.1, 4.6); MAP 3.1 (2.0, 4.1), P < 0.001 for all) and a tendency towards higher cholesterol and apolipoprotein B values. The offspring of mothers with PE had higher DBP and MAP, however after the adjustments this difference disappeared. Maternal de novo hypertension during pregnancy is associated with offspring's elevated blood pressure level already in adolescence. GH may also be associated with unfavourable lipid profile of the offspring. PMID- 23354983 TI - The association between frequency of vigorous physical activity and hepatobiliary cancers in the NIH-AARP Diet and Health Study. AB - Despite a potential preventive effect of physical activity on hepatobiliary cancer, little information is available on the relation between the two. We studied the association between frequency of vigorous physical activity and hepatobiliary cancer among 507,897 participants of the NIH-AARP Diet and Health Study, aged 50-71 years at baseline in 1995/1996. During 10 years of follow-up, 628 incident cases of liver cancer and 317 cases of extrahepatic biliary tract cancer were registered. Physical activity levels were assigned according to the frequency of engagement in 20 min or more of vigorous physical activity per week: never/rarely (lowest level), less than once per week, 1-2 times per week, 3-4 times per week, 5 or more times per week (highest level). Using Cox regression, multivariate-adjusted relative risks (RR) comparing the highest with the lowest level of physical activity revealed a statistically significant decreased risk for liver cancer (RR = 0.64, 95% confidence interval (CI) = 0.49-0.84, p-trend <0.001), particularly hepatocellular carcinoma (RR = 0.56, 95% CI = 0.41-0.78, p trend <0.001), independent of body mass index. By comparison, multivariate analyses indicated that physical activity was not statistically significantly associated with extrahepatic bile duct cancer (RR = 0.86, 95% CI = 0.45-1.65), ampulla of Vater cancer (RR = 0.66, 95% CI = 0.29-1.48), or gallbladder cancer (RR = 0.63, 95% CI = 0.33-1.21). These results suggest a potential preventive effect of physical activity on liver cancer but not extrahepatic biliary tract cancer, independent of body mass index. PMID- 23354984 TI - Pediatric population-based neuroimaging and the Generation R Study: the intersection of developmental neuroscience and epidemiology. AB - Neuroimaging studies of typically developing children and adolescents have provided valuable information on global and regional developmental trajectories of brain development. As these studies become larger and population-based, they are generating an intersection between the fields of developmental neuroscience and epidemiology. However, few of these studies have adequately probed the contribution of multiple environmental and genetic factors on brain development. Studies designed to optimally evaluate the role of multiple environmental and genetic factors on brain development require both large sample sizes and the prospective collection of multiple environmental factors. The Generation R Study is a large, prospective, prenatal-cohort study of nearly 10,000 children that began in 2002 in Rotterdam, the Netherlands. In September of 2009, 6-8 year old children from the Generation R Study were invited to participate in a magnetic resonance imaging component of the study. We provide an overview of the study design and experience for the first 801 children recruited for the neuroimaging component of the study. The protocol includes a 1-h neuropsychological assessment using the NEPSY-II, a mock scanning session, and a neuroimaging session that includes high-resolution structural, diffusion tensor, and resting-state functional MRI sequences. Image quality has been good to excellent in over 80% of the children to date. The infusion of imaging into the Generation R Study will set the stage for evaluating the role of multiple environmental and genetic factors in both typical and atypical neurodevelopment. PMID- 23354985 TI - Serum 25-hydroxyvitamin D levels and incident diabetes mellitus type 2: a competing risk analysis in a large population-based cohort of older adults. AB - Plausible mechanisms of how vitamin D deficiency may contribute to the development of diabetes mellitus have been proposed but longitudinal cohort studies have yielded heterogeneous results. In 7,791 initially diabetes-free participants of a German population-based cohort, aged 50-74 years, adjusted Cox regression models were employed to estimate hazard ratios (HR) with 95 % confidence intervals (CI) for the association of serum 25-hydroxyvitamin D (25(OH)D) quintiles and incident diabetes. Dose-response relationships were assessed with restricted cubic spline curves. Additionally, analyses accounting for the competing risks of diabetes and death were performed. During 8 years of follow-up, 829 study participants developed diabetes. In women, diabetes risk was significantly increased in the lowest 25(OH)D quintile (HR, 1.38; 1.09-1.75) and non-significantly increased in the 2nd quintile (HR, 1.24; 0.98-1.55) compared to women in 25(OH)D quintiles 3-5. The dose-response relationship showed a non linear inverse association with risk starting to increase at 25(OH)D levels below 70 nmol/L (statistically significant: below 40 nmol/L). In men, 25(OH)D levels were not associated with diabetes incidence. Renal dysfunction was an effect modifier with a more than doubled diabetes risk in 25(OH)D quintile 1 and an about 1.5-fold risk in quintile 2 compared to quintiles 3-5 if subjects had renal dysfunction. The observed associations were not influenced by the competing risk of death. In this large cohort study of older adults, serum 25(OH)D levels were inversely associated with incident diabetes in women but not in men. The association was particularly strong in subjects with renal dysfunction. PMID- 23354986 TI - The incidence of isolated single umbilical artery in twins and adverse pregnancy outcomes. AB - OBJECTIVES: The aim of this study was to estimate the incidence of single umbilical artery (SUA) in twin pregnancies and to investigate whether SUA in twin gestations is associated with adverse obstetric outcomes. METHODS: We performed a retrospective cohort study of consecutive twin pregnancies over 17 years at a tertiary care hospital. Primary exposure was SUA in one or both twins documented at routine second trimester anatomic survey. Adverse obstetric outcomes included small for gestational age (SGA), placental abruption, and preterm birth, evaluated in univariable and multivariable analyses. Analysis was performed both at the pregnancy level and at the fetal level using paired analyses to account for the non-independence of twin pairs. RESULTS: Of the 2378 twin pregnancies without major anatomic abnormalities, 1.7% (n = 40) had SUA. Only one pregnancy (one monochorionic twin pair) was complicated by both twins having SUA. Twin fetuses with SUA are at increased risk for SGA (aOR = 2.1 (1.2-4.1), p = 0.03) after adjusting for pertinent confounding factors, similar to the findings of previous studies in singleton pregnancies. In addition, twins with SUA may be at increased risk for preterm delivery before 28 weeks compared with twin pregnancies with normal three-vessel umbilical cords (adjusted odds ratio (aOR) 3.2 (1.3-7.89.4), p = 0.01). CONCLUSIONS: The incidence of SUA in twin gestations in this cohort is significantly less than the recently published data. Similar to reports in singleton gestations, SUA appears to be associated with an increased risk for SGA in twins. PMID- 23354987 TI - A rat in the labyrinth of anorexia nervosa: contributions of the activity-based anorexia rodent model to the understanding of anorexia nervosa. AB - Activity-based anorexia (ABA) is an analogous animal model of anorexia nervosa where food-restricted rats develop excessive running activity when given free access to a running wheel; their body weight sharply decreases, and finally self starvation and death ensue unless animals are removed from the experimental conditions. The parallel of this animal model with major signs in the human disorder has been the focus of much attention from researchers and clinicians as a platform for translational research. The paper reviews the historical antecedents of ABA, research characterizing its occurrence, and its main limitations and strengths as a model of AN. As a symptomatic model of AN, the ABA model can provide clinicians with innovative and alternative routes for improving the treatment of AN. PMID- 23354988 TI - Integrating Arden-Syntax-based clinical decision support with extended presentation formats into a commercial patient data management system. AB - The purpose of this study was to introduce clinical decision support (CDS) that exceeds conventional alerting at tertiary care intensive care units. We investigated physicians' functional CDS requirements in periodic interviews, and analyzed technical interfaces of the existing commercial patient data management system (PDMS). Building on these assessments, we adapted a platform that processes Arden Syntax medical logic modules (MLMs). Clinicians demanded data driven, user-driven and time-driven execution of MLMs, as well as multiple presentation formats such as tables and graphics. The used PDMS represented a black box insofar as it did not provide standardized interfaces for event notification and external access to patient data; enabling CDS thus required periodically exporting datasets for making them accessible to the invoked Arden engine. A client-server-architecture with a simple browser-based viewer allows users to activate MLM execution and to access CDS results, while an MLM library generates hypertext for diverse presentation targets. The workaround that involves a periodic data replication entails a trade-off between the necessary computational resources and a delay of generated alert messages. Web technologies proved serviceable for reconciling Arden-based CDS functions with alternative presentation formats, including tables, text formatting, graphical outputs, as well as list-based overviews of data from several patients that the native PDMS did not support. PMID- 23354990 TI - Brain perfusion asymmetry in patients with oral somatic delusions. AB - Oral cenesthopathy is a somatic delusion or hallucination involving the oral area and is categorized as a delusional disorder, somatic type. The pathophysiology of this intractable condition remains obscure. In this study, we clarified the pathophysiology of oral cenesthopathy by evaluating regional brain perfusion. We performed single photon emission computed tomography (SPECT) using (99m)Tc ethylcysteinate dimer in 16 subjects (cenesthopathy:control = 8:8). The SPECT images were visually assessed qualitatively, and quantitative analyses were also performed using a three-dimensional stereotactic region-of-interest template. The visual assessment revealed a right > left perfusion asymmetry in broad areas of the brain among the patients. The quantitative analysis confirmed that the regional cerebral blood flow values on the right side were significantly larger than those on the left side for most areas of the brain in the patients. A comparison of the R/(R + L) ratios in both groups confirmed the significant brain perfusion asymmetry between the two sides in the callosomarginal, precentral, and temporal regions in the patients. Qualitative evaluation of the SPECT images revealed right > left brain perfusion asymmetry in broad regions of the brain. Moreover, the quantitative analyses confirmed the perfusion asymmetry between the two sides in the frontal and temporal areas. Those may provide the key for elucidation of the pathophysiology of oral cenesthopathy. PMID- 23354991 TI - Meat quality characteristics of Turkish indigenous Hair goat kids reared under traditional extensive production system: effects of slaughter age and gender. AB - Meat quality characteristics of Turkish indigenous Hair goat kids reared under an extensive production system were investigated in this study. A total of 60 Hair goat kids (30 females and 30 males) were slaughtered at 3, 6, 9, and 12 months of ages. Slaughter age significantly affected meat quality characteristics. Cooking loss (P < 0.01) and shear force value (P < 0.001) increased with age. Meat color became darker red with increasing slaughter age (P < 0.001). The percentage of fat of musculus (M.) semimembranosus increased with age (P < 0.01). The percentage of saturated fatty acids was significantly higher (P < 0.01), whereas the percentage of unsaturated fatty acids was lower (P < 0.001) in the M. longissimus dorsi of the kids slaughtered at 3 months of age than those in the other age groups. The females had higher intramuscular fat than that in males (P < 0.001) and meat from male kids contained a higher percentage of polyunsaturated fatty acid than that from females (P < 0.01). In conclusion, meat from Hair kids slaughtered between 3 and 9 months of ages had better quality than those slaughtered at the other ages and also meat from male kids had better quality than those female kids slaughtered at the same age under extensive production system. PMID- 23354992 TI - Herd and individual animal prevalence of bovine brucellosis with associated risk factors on dairy farms in Haryana and Punjab in India. AB - Herd and individual animal prevalence along with associated risk factors of bovine brucellosis was assessed on dairy farms located in 22 districts in Haryana and Punjab of India. Examination of 4,580 female animals of 119 dairy farms by Rose Bengal test and enzyme-linked immunosorbent assay revealed that an overall herd prevalence was 65.54% (78/119) and individual animal prevalence was 26.50 % (1,214/4,580). Herd prevalence in Haryana was 62.79% which was not significantly different (P = 0.4208) from Punjab (72.72%). Individual animal prevalence was 34.15% in Punjab which was significantly higher (P < 0.0001) than Haryana (22.34%). Prevalence of brucellosis on dairy farms was detected in 20 of the 22 districts, of which 12 districts were in Haryana and 8 in Punjab. Risk factors such as species of animals, age of animals, herd size, awareness of dairymen for brucellosis, entry of a purchased animals on the farm, abortion on farm, use of calving pens, type of breeding, and type of farming were analyzed. The study indicated that the odds ratio (OR) was significant with risk factors of species (OR = 1.63; 95 %CI = 1.40-1.90; P < 0.0001), age (OR = 0.22; 95%CI = 0.17-0.29; P < 0.0001), awareness of brucellosis among dairymen (OR = 21.65; 95%CI = 2.63 178.04; P = 0.0042), entry of purchased animal on the farm (OR = 9.16; 95%CI = 2.38-35.18; P = 0.0012), abortion in animals (OR = 5.57; 95%CI = 1.92-16.10; P = 0.0015) and on cow farm (OR = 3.43; 95 %CI = 1.33-8.82; P = 0.0105). While the OR was insignificant (P > 0.05) with risk factors of herd size, use of calving pen on farms, type of breeding and on buffalo and mixed type of farms. PMID- 23354993 TI - Reproductive efficiency and herd demography of Nguni cattle in village-owned and group-owned enterprises under low-input communal production systems. AB - The objective of the study was to determine the herd demography and reproductive efficiency of the Nguni cattle in village-owned and group-owned enterprises under low-input communal production systems. Data on husbandry practices, reason of cattle entry/exist, herd structure, bulling rates, breeding females, age at first calving and calving interval were obtained from 22 village-owned and 19 group owned enterprises in a cross-sectional survey of an ecologically controlled low input cattle production system. Descriptive statistics and chi-square tests of association were computed on enterprise ownership patterns, husbandry practices and herd demography. An AN(C)OVA was used to determine significant factors affecting herd structure, mortality, age at first calving and calving interval in the enterprises. Village-owned enterprises had higher (p < 0.05) dipping frequency per season than group enterprises. The herd sizes were significantly higher (p < 0.05) in group-owned (29.9 +/- 3.23) than in village-owned (23.6 +/- 2.40) enterprises. Mortality rate was significantly lower (p < 0.05) in group owned (10.8%) than in village-owned enterprises (26.4 %). Group-owned enterprises had significantly more sales and programme retains than the village-owned enterprises (p < 0.05). There were no significant differences between enterprise ownership pattern on cattle production potential and age at first calving (p > 0.05). Significant differences were observed on the calving interval (p < 0.05) where the group-owned enterprises performed better (16.0 +/- 1.10 months) than village-owned enterprises (22.7 +/- 1.07 months). The bulling rate was higher in village-owned enterprises, while the proportion of breeding females was higher in group-owned enterprises. Farmers with a college education had Nguni animals with the shortest calving interval. It was concluded that group-owned enterprises had significantly better calving intervals, mortality rates and overall herd structure than village-owned enterprises. PMID- 23354994 TI - Fatty liver disease as a predictor of local recurrence following resection of colorectal liver metastases. AB - BACKGROUND: Obesity and tissue adiposity constitute a risk factor for several cancers. Whether tissue adiposity increases the risk of cancer recurrence after curative resection is not clear. The present study analysed the influence of hepatic steatosis on recurrence following resection of colorectal liver metastases. METHODS: A prospective cohort of patients who had primary resection of colorectal liver metastases in two major hepatobiliary units between 1987 and 2010 was studied. Hepatic steatosis was assessed in non-cancerous resected liver tissue. Patients were divided into two groups based on the presence of hepatic steatosis. The association between hepatic steatosis and local recurrence was analysed, adjusting for relevant patient, pathological and surgical factors using Cox regression and propensity score case-match analysis. RESULTS: A total of 2715 patients were included. The cumulative local (liver) disease-free survival rate was significantly better in the group without steatosis (hazard ratio (HR) 1.32, 95 per cent confidence interval 1.16 to 1.51; P < 0.001). On multivariable analysis, hepatic steatosis was an independent risk factor for local liver recurrence (HR 1.28, 1.11 to 1.47; P = 0.005). After one-to-one matching of cases (steatotic, 902) with controls (non-steatotic, 902), local (liver) disease-free survival remained significantly better in the group without steatosis (HR 1.27, 1.09 to 1.48; P = 0.002). Patients with steatosis had a greater risk of developing postoperative liver failure (P = 0.001). CONCLUSION: Hepatic steatosis was an independent predictor of local hepatic recurrence following resection with curative intent of colorectal liver metastases. PMID- 23354995 TI - Gene mutation profiles and prognostic implications in Korean patients with T lymphoblastic leukemia. AB - Genetic alterations implicated in the leukemogenesis of T cell acute lymphoblastic leukemia (T-ALL) have been identified in recent years. In this study, we investigated gene mutation profiles and prognostic implications in a series of Korean T-ALL patients. The study patients were 29 Korean patients with T-ALL; 13 adults (45 %) and 16 children (55 %; male-to-female ratio, 25:4). Clinical, hematologic, and cytogenetic findings were reviewed. We performed mutation analyses for NOTCH1, FBXW7, PHF6, and IL7R genes and survival analyses according to the mutational status. Gene mutations were identified in 66 % of the patients in our series (19/29). Eighteen patients (62 %) had NOTCH1/FBXW7 mutations. Sixteen patients (55 %) had NOTCH1 mutations including nine novel mutations, and eight patients (28 %) had known FBXW7 mutations. Eight patients (28 %; six males and two females) had PHF6 mutations including four novel mutations. Three patients (10 %) had IL7R mutations, which were all novel in frame insertion or deletion-insertions. The gene mutation profile combined with cytogenetics and FISH study for the p16 gene detected genetic aberrations in 90 % of patients (26/29). There was no significant difference in the frequency of gene mutations between the pediatric and adult patients with T-ALL. Survival analyses suggested a favorable prognostic implication of NOTCH1 mutations in adult T-ALL. Gene mutation studies for NOTCH1, FBXW7, PHF6, and IL7R could detect genetic alterations in a majority of Korean T-ALL patients with novel mutations. We observed similar mutation profiles between adult and pediatric T-ALL, and a favorable prognostic implication of NOTCH1 mutations in adult T-ALL. PMID- 23354996 TI - A common founder mutation p.P2063S in exon 36 of VWF in 11 unrelated Indian von Willebrand disease (VWD) families. PMID- 23354997 TI - Clinical evaluation of the European LeukemiaNet response criteria in patients with essential thrombocythemia treated with anagrelide. AB - This study investigates whether the response criteria proposed by the European LeukemiaNet (ELN) to evaluate cytoreductive therapies in essential thrombocythemia (ET) correlate with clinically relevant outcomes in patients receiving anagrelide. We evaluated 154 ET patients treated with anagrelide (upfront in 87) for a median of 2.9 years. Complete response (CR), partial response, and no response were observed in 56, 30.5, and 13.5 % patients, respectively. Only 38 patients (25 %) achieved a sustained CR. Overall, the aggregated time on CR and without CR was 200.1 and 333.6 person-years, respectively. The incidence rate of thrombosis and hemorrhage was independent of the CR status. The only factor associated with shorter survival after anagrelide start was the patient's age, whereas achieving a CR with anagrelide had no predictive value for subsequent survival. In conclusion, CR according to the ELN definition is not associated with any measurable clinical benefit in ET patients treated with anagrelide. PMID- 23354998 TI - Prior experience with negative spectral correlations promotes information integration during auditory category learning. AB - Complex sounds vary along a number of acoustic dimensions. These dimensions may exhibit correlations that are familiar to listeners due to their frequent occurrence in natural sounds-namely, speech. However, the precise mechanisms that enable the integration of these dimensions are not well understood. In this study, we examined the categorization of novel auditory stimuli that differed in the correlations of their acoustic dimensions, using decision bound theory. Decision bound theory assumes that stimuli are categorized on the basis of either a single dimension (rule based) or the combination of more than one dimension (information integration) and provides tools for assessing successful integration across multiple acoustic dimensions. In two experiments, we manipulated the stimulus distributions such that in Experiment 1, optimal categorization could be accomplished by either a rule-based or an information integration strategy, while in Experiment 2, optimal categorization was possible only by using an information integration strategy. In both experiments, the pattern of results demonstrated that unidimensional strategies were strongly preferred. Listeners focused on the acoustic dimension most closely related to pitch, suggesting that pitch-based categorization was given preference over timbre-based categorization. Importantly, in Experiment 2, listeners also relied on a two-dimensional information integration strategy, if there was immediate feedback. Furthermore, this strategy was used more often for distributions defined by a negative spectral correlation between stimulus dimensions, as compared with distributions with a positive correlation. These results suggest that prior experience with such correlations might shape short-term auditory category learning. PMID- 23354999 TI - Multicolour optical coding from a series of luminescent lanthanide complexes with a unique antenna. AB - The bis-tetrazolate-pyridine ligand H(2)pytz sensitises efficiently the visible and/or near-IR luminescence emission of ten lanthanide cations (Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, Yb). The Ln(III) complexes present sizeable quantum yields in both domains with a single excitation source. The wide range of possible colour combinations in water, organic solvents and the solid state makes the complexes very attractive for labelling and encoding. PMID- 23355000 TI - Biochemical evaluation of triploid progenies of diploid * tetraploid breeding populations of Camellia for genotypes rich in catechin and caffeine. AB - To verify the quality of triploid varieties of Camellia tea species at the secondary metabolite level, we tested caffeine and catechin profiles of 97 F(1) segregating progenies in two breeding populations with a common tetraploid parent and diploid parents of two geographic and varietal origins. Catechin and caffeine levels of the triploid progenies were quantified and compared against their diploid parent. Some of the progenies showed better performance than their diploid parent. Most of the progenies of the diploid C. sinensis * tetraploid cross showed heterosis for caffeine and EGCG. Progenies of the C. assamica subsp. lasiocalyx * tetraploid cross showed heterosis for +C, EC, EGC, and TC. The genomic contributions of the diploid parent seem to be the main factor in the variation between the two populations. Our studies showed quantitative enhancement of some of the quality-related parameters in tea, providing a platform to refocus on this classical breeding approach for developing quality cultivars in tea. PMID- 23355002 TI - Metastatic thyroid tumors: ultrasonographic features, prognostic factors and outcomes in 29 cases. AB - PURPOSE: Metastatic thyroid tumors (MTT) are rare and have a poor prognosis. The aim of this retrospective study was to determine the diagnostic features and clinical outcomes of MTT. METHODS: The study subjects comprised 29 patients (age range, 37-78 years) diagnosed with MTT and treated during a 22-year period between 1987 and 2008 at a single tertiary oncology referral center. RESULTS: The primary cancer was breast cancer in 10 patients, lung cancer in six, digestive tract in six, kidney in three, head and neck in three and sarcoma in one patient. In seven patients, the diagnoses of primary cancer and MTT were synchronous. In 22 patients, the mean latency between the diagnosis of the primary cancer and MTT was 66 months (range 7 months-16 years). Based on ultrasonography (US), MTTs were classified into two categories: diffuse type (DT) (n = 9) and nodular type (NT) (n = 18). Eight patients who underwent thyroid surgery showed no survival benefit, but none needed tracheostomy. CONCLUSIONS: MTT should be considered for patients with a history of malignant disease. The findings from US are useful to diagnose MTT. Careful preoperative evaluation can avoid unnecessary thyroidectomy. PMID- 23355001 TI - Multichannel vestibular prosthesis employing modulation of pulse rate and current with alignment precompensation elicits improved VOR performance in monkeys. AB - An implantable prosthesis that stimulates vestibular nerve branches to restore the sensation of head rotation and the three-dimensional (3D) vestibular ocular reflex (VOR) could benefit individuals disabled by bilateral loss of vestibular sensation. Our group has developed a vestibular prosthesis that partly restores normal function in animals by delivering biphasic current pulses via electrodes implanted in semicircular canals. Despite otherwise promising results, this approach has been limited by insufficient velocity of VOR response to head movements that should inhibit the implanted labyrinth and by misalignment between direction of head motion and prosthetically elicited VOR. We report that significantly larger VOR eye velocities in the inhibitory direction can be elicited by adapting a monkey to elevated baseline stimulation rate and current prior to stimulus modulation and then concurrently modulating ("co-modulating") both rate and current below baseline levels to encode inhibitory angular head velocity. Co-modulation of pulse rate and current amplitude above baseline can also elicit larger VOR eye responses in the excitatory direction than do either pulse rate modulation or current modulation alone. Combining these stimulation strategies with a precompensatory 3D coordinate transformation improves alignment and magnitude of evoked VOR eye responses. By demonstrating that a combination of co-modulation and precompensatory transformation strategies achieves a robust VOR response in all directions with significantly improved alignment in an animal model that closely resembles humans with vestibular loss, these findings provide a solid preclinical foundation for application of vestibular stimulation in humans. PMID- 23355003 TI - Increased generation of cyclopentenone prostaglandins after brain ischemia and their role in aggregation of ubiquitinated proteins in neurons. AB - The cyclopentenone prostaglandin (CyPG) J2 series, including prostaglandin J2 (PGJ2), Delta12-PGJ2, and 15-deoxy-?12,14-prostaglandin J2 (15d-PGJ2), are active metabolites of PGD2, exerting multiple effects on neuronal function. However, the physiologic relevance of these effects remains uncertain as brain concentrations of CyPGs have not been precisely determined. In this study, we found that free PGD2 and the J2 series CyPGs (PGJ2, Delta12-PGJ2, and 15d-PGJ2) were increased in post-ischemic rat brain as detected by UPLC-MS/MS with 15d-PGJ2 being the most abundant CyPG. These increases were attenuated by pre-treating with the cyclooxygenase (COX) inhibitor piroxicam. Next, effects of chronic exposure to 15d-PGJ2 were examined by treating primary neurons with 15d-PGJ2, CAY10410 (a 15d PGJ2 analog lacking the cyclopentenone ring structure), or vehicle for 24 to 96 h. Because we found that the concentration of free 15d-PGJ2 decreased rapidly in cell culture medium, freshly prepared medium containing 15d-PGJ2, CAY10410, or vehicle was changed twice daily to maintain steady extracellular concentrations. Incubation with 2.5 MUM 15d-PGJ2, but not CAY10410, increased the neuronal cell death without the induction of caspase-3 or PARP cleavage, consistent with a primarily necrotic mechanism for 15d-PGJ2-induced cell death which was further supported by TUNEL assay results. Ubiquitinated protein accumulation and aggregation was observed after 96 h 15d-PGJ2 incubation, accompanied by compromised 20S proteasome activity. Unlike another proteasome inhibitor, MG132, 15d-PGJ2 treatment did not activate autophagy or induce aggresome formation. Therefore, the cumulative cytotoxic effects of increased generation of CyPGs after stroke may contribute to delayed post-ischemic neuronal injury. PMID- 23355004 TI - The presence of Merkel cell polyomavirus is associated with deregulated expression of BRAF and Bcl-2 genes in non-small cell lung cancer. AB - Polyomaviruses such as BK virus (BKV), JC virus (JCV) and Merkel cell polyomavirus (MCPyV) are typically nononcogenic, although they have been detected in a variety of human neoplasms. The aim of our study was to determine the frequency of the most common polyomaviruses MCPyV, BKV and JCV as well as the gene expression profile of genes involved in oncogenesis including K-ras, BRAF, RKIP, Bax, Bcl-2, p53 and RB1 in a cohort of non-small cell lung cancer (NSCLC) patients. Real-time and nested polymerase chain reaction (PCR) were used to assess the presence of polyomaviruses DNA in tissue biopsies from 110 patients with primary NSCLC and 14 tissue specimens from macroscopically healthy sites of their lung. Real-time PCR was also used to determine the mRNA expression of K ras, BRAF, RKIP, Bax, Bcl-2, p53 and RB1 in selected samples. Results showed that ten NSCLC specimens were positive for the presence of MCPyV DNA (10/110, 9.1%), whereas no control sample was tested positive for the virus. The MCPyV-positive samples were predominantly obtained from male smokers (9/10). BKV and JCV DNA were not detected either in lung tissues biopsies or the control specimens. Interestingly, gene expression analysis revealed increased mRNA and protein expression of BRAF gene in association with BRAF phosphorylation in the MCPyV positive samples, whereas Bcl-2 gene expression was downregulated in the same type of samples. The detected MCPyV prevalence in NSCLC in combination with the deregulated expression of BRAF and Bcl-2 genes suggests that these events are likely to contribute to the pathogenesis of NSCLC. PMID- 23355005 TI - Reduction of ribosome level triggers flocculation of fission yeast cells. AB - Deletion of ribosomal protein L32 genes resulted in a nonsexual flocculation of fission yeast. Nonsexual flocculation also occurred when two other ribosomal protein genes, rpl21-2 and rpl9-2, were deleted. However, deletion of two nonribosomal protein genes, mpg and fbp, did not cause flocculation. Overall transcript levels of rpl32 in rpl32-1Delta and rpl32-2Delta cells were reduced by 35.9% and 46.9%, respectively, and overall ribosome levels in rpl32-1Delta and rpl32-2Delta cells dropped 31.1% and 27.8%, respectively, compared to wild-type cells. Interestingly, ribosome protein expression levels and ribosome levels were also reduced greatly in sexually flocculating diploid YHL6381/WT (h+/h-) cells compared to a mixture of YHL6381 (h+) and WT (h-) nonflocculating haploid cells. Transcriptome analysis indicated that the reduction of ribosomal levels in sexual flocculating cells was caused by more-extensive suppression of ribosomal biosynthesis gene expression, while the reduction of ribosomal levels caused by deleting ribosomal protein genes in nonsexual flocculating cells was due to an imbalance between ribosomal proteins. We propose that once the reduction of ribosomal levels is below a certain threshold value, flocculation is triggered. PMID- 23355006 TI - Conserved gene regulatory function of the carboxy-terminal domain of dictyostelid C-module-binding factor. AB - C-module-binding factor A (CbfA) is a jumonji-type transcription regulator that is important for maintaining the expression and mobility of the retrotransposable element TRE5-A in the social amoeba Dictyostelium discoideum. CbfA-deficient cells have lost TRE5-A retrotransposition, are impaired in the ability to feed on bacteria, and do not enter multicellular development because of a block in cell aggregation. In this study, we performed Illumina RNA-seq of growing CbfA mutant cells to obtain a list of CbfA-regulated genes. We demonstrate that the carboxy terminal domain of CbfA alone is sufficient to mediate most CbfA-dependent gene expression. The carboxy-terminal domain of CbfA from the distantly related social amoeba Polysphondylium pallidum restored the expression of CbfA-dependent genes in the D. discoideum CbfA mutant, indicating a deep conservation in the gene regulatory function of this domain in the dictyostelid clade. The CbfA-like protein CbfB displays ~25% sequence identity with CbfA in the amino-terminal region, which contains a JmjC domain and two zinc finger regions and is thought to mediate chromatin-remodeling activity. In contrast to CbfA proteins, where the carboxy-terminal domains are strictly conserved in all dictyostelids, CbfB proteins have completely unrelated carboxy-terminal domains. Outside the dictyostelid clade, CbfA-like proteins with the CbfA-archetypical JmjC/zinc finger arrangement and individual carboxy-terminal domains are prominent in filamentous fungi but are not found in yeasts, plants, and metazoans. Our data suggest that two functional regions of the CbfA-like proteins evolved at different rates to allow the occurrence of species-specific adaptation processes during genome evolution. PMID- 23355007 TI - Distinct and redundant roles of the two MYST histone acetyltransferases Esa1 and Sas2 in cell growth and morphogenesis of Candida albicans. AB - Candida albicans is associated with humans, as both a harmless commensal organism and a pathogen. Adaption to human body temperature is extremely important for its growth and morphogenesis. Saccharomyces cerevisiae Esa1, a member of the MYST family HATs (histone acetyltransferases) and the catalytic subunit of the NuA4 complex, and its homologues in other eukaryotes have been shown to be essential for cell growth. To investigate the functional roles of two MYST family HATs, Esa1 and Sas2 in C. albicans, we deleted ESA1 and SAS2 in the C. albicans genome and performed cell growth analyses. Our results demonstrated that C. albicans Esa1 is not essential for general growth but is essential for filamentous growth. The esa1/esa1 mutant cells exhibited sensitivity to thermal, genotoxic, and oxidative stresses but tolerance to cold, osmotic, and cell wall stresses. In contrast, the sas2/sas2 mutant adapted to growth at higher temperatures and promoted filament formation at lower temperatures, resembling the phenotype of a C. albicans strain overexpressing ESA1. Cells with deletions of both ESA1 and SAS2 were inviable, reflecting the functional redundancy in cell growth. C. albicans Esa1 and Sas2 have distinct and synergistic effects on histone acetylation at H4K5, H4K12, and H4K16. Esa1 contributes mainly to acetylation of H4K5 and H4K12, whereas Sas2 contributes to acetylation of H4K16. Our findings suggest that C. albicans Esa1 and Sas2 play opposite roles in cell growth and morphogenesis and contribute coordinately to histone acetylation and gene regulation. PMID- 23355008 TI - Effects of a defective endoplasmic reticulum-associated degradation pathway on the stress response, virulence, and antifungal drug susceptibility of the mold pathogen Aspergillus fumigatus. AB - Proteins that are destined for release outside the eukaryotic cell, insertion into the plasma membrane, or delivery to intracellular organelles are processed and folded in the endoplasmic reticulum (ER). An imbalance between the level of nascent proteins entering the ER and the organelle's ability to manage that load results in the accumulation of unfolded proteins. Terminally unfolded proteins are disposed of by ER-associated degradation (ERAD), a pathway that transports the aberrant proteins across the ER membrane into the cytosol for proteasomal degradation. The ERAD pathway was targeted in the mold pathogen Aspergillus fumigatus by deleting the hrdA gene, encoding the A. fumigatus ortholog of Hrd1, the E3 ubiquitin ligase previously shown to contribute to ERAD in other species. Loss of HrdA was associated with impaired degradation of a folding-defective ERAD substrate, CPY*, as well as activation of the unfolded-protein response (UPR). The DeltahrdA mutant showed resistance to voriconazole and reduced thermotolerance but was otherwise unaffected by a variety of environmental stressors. A double-deletion mutant deficient in both HrdA and another component of the same ERAD complex, DerA, was defective in secretion and showed hypersensitivity to ER, thermal, and cell wall stress. However, the DeltahrdA DeltaderA mutant remained virulent in mouse and insect infection models. These data demonstrate that HrdA and DerA support complementary ERAD functions that promote survival under conditions of ER stress but are dispensable for virulence in the host environment. PMID- 23355009 TI - Membrane environment imposes unique selection pressures on transmembrane domains of G protein-coupled receptors. AB - We have investigated the influence of the plasma membrane environment on the molecular evolution of G protein-coupled receptors (GPCRs), the largest receptor family in Metazoa. In particular, we have analyzed the site-specific rate variation across the two primary structural partitions, transmembrane (TM) and extramembrane (EM), of these membrane proteins. We find that TM domains evolve more slowly than do EM domains, though TM domains display increased rate heterogeneity relative to their EM counterparts. Although the majority of residues across GPCRs experience strong to weak purifying selection, many GPCRs experience positive selection at both TM and EM residues, albeit with a slight bias towards the EM. Further, a subset of GPCRs, chemosensory receptors (including olfactory and taste receptors), exhibit increased rates of evolution relative to other GPCRs, an effect which is more pronounced in their TM spans. Although it has been previously suggested that the TM's low evolutionary rate is caused by their high percentage of buried residues, we show that their attenuated rate seems to stem from the strong biophysical constraints of the membrane itself, or by functional requirements. In spite of the strong evolutionary constraints acting on the TM spans of GPCRs, positive selection and high levels of evolutionary rate variability are common. Thus, biophysical constraints should not be presumed to preclude a protein's ability to evolve. PMID- 23355010 TI - The 5S rDNA high dynamism in Diplodus sargus is a transposon-mediated mechanism. Comparison with other multigene families and Sparidae species. AB - There has been considerable discussion in recent years on the evolution of the tandemly repeated multigene families, since some organisms show a concerted model whereas others show a birth-and-death model. This controversial subject extends to several species of fish. In this study, three species of the Sparidae family (Pagrus pagrus, P. auriga and Diplodus sargus) and an interspecific hybrid (P. pagrus (?) * P. auriga (?)) have been studied at both molecular and cytogenetic level, taking three different multigene families (5S rDNA, 45S rDNA and U2 snDNA). Results obtained with the 5S rDNA in P. pagrus and P. auriga are characterized by a considerable degree of conservation at the two levels; however, an extraordinary variation was observed in D. sargus at the two levels, which has never been found in other fishes studied to date. As a consequence of this, the evolutionary model of the multigene families is discussed considering the results obtained and others from the bibliography. The result obtained in the hybrid allowed the recombination frequency in each multigene family to be estimated. PMID- 23355011 TI - Cyclic AMP-dependent regulation of tyrosine hydroxylase mRNA and immunofluorescence levels in rat retinal precursor cells. AB - Stimulation of tyrosine hydroxylase (TH) gene transcription by cyclic AMP (cAMP) has been clearly established in adrenal medula cells and neural-crest-derived cell lines but information on this mechanism is still lacking in dopaminergic neurons. Because they are easily amenable to in vitro experiments, dopaminergic amacrine cells of the retina might constitute a valuable model system to study this mechanism. We have used real-time reverse transcription with the polymerase chain reaction to quantify TH mRNA levels in the rat retina during post-natal development and in retinal precursor cells obtained from neonatal rats and cultured for 3 days in serum-free medium. Whereas the TH mRNA concentration remains consistantly low in control cultures, treatment with cAMP-increasing agents (forskolin, membrane depolarization, phosphodiesterase inhibitors) is sufficient to raise it to the level observed in adult retina (15-fold increase). Treatment of the cultured cells can be delayed by up to 2 days with identical results at the TH mRNA level, thus ruling out a survival-promoting effect of cAMP. TH immunofluorescence has confirmed cAMP-dependent regulation of TH expression at the protein level and indicates that the frequency of TH-positive cells in the cultures is similar to that observed in the adult retina. Selective phosphodiesterase inhibitors suggest that PDE4 is the major subtype involved in the dopaminergic amacrine cell response. Our data clearly establish the cAMP dependent regulation of TH mRNA and immunofluorescence levels in retinal precursor cells. The possible role of this regulation mechanism in the developmental activation of TH gene expression is discussed. PMID- 23355012 TI - Emergency management of lower gastrointestinal bleed in children. AB - Lower gastro intestinal bleed (LGIB) is defined as any bleeding that occurs distal to the ligament of Treitz (situated at the duodeno jejunal junction). It constitutes the chief complaint of about 0.3 % of children presenting to the pediatric emergency department(ED). Among Indian children the most common causes are colitis and polyps. In most of the cases of LGIB the bleeding is small and self limiting, but conditions like Meckel's diverticulum often presents with life threatening bleeds. The approach in ED should include in order of priority assessment and maintenance of hemodynamic stability, confirmation of LGIB and then to attempt for specific diagnoses and their management. This is achieved with help of rapid cardiopulmonary assessment, focused history and examination. The management of all serious hemodynamically significant bleeds includes, rapid IV access, volume replacement with normal saline 20 ml/kg, blood sampling (for cross matching, hematocrit, platelet, coagulogram and liver function tests), Inj. Vit K 5-10 mg IV, acid suppression with H2 antagonists/PPI and nasogastric lavage to rule out upper gastrointestinal bleed. Continuous ongoing monitoring of vital signs is important after stabilization. In ill looking infant, infectious colitis, Necrotizing enterocolitis (NEC), Hirschsprung enterocolitis and volvulus and in older infants and children, intussusceptions, typhoid fever, volvulus should be looked for. Proctosigmoidoscopy remains the first investigation to be done and reveals majority of etiology. Multidetector CT scan, Tc 99 m RBC scan, angiography and Push enteroscopy are the further investigation choices according to the clinical condition of the child. Intra operative enteroscopy is reserved for refractory cases with an obscure etiology. PMID- 23355013 TI - Soft plastic bag instead of hard plastic container for long-term storage of breast milk. AB - OBJECTIVE: To compare the fat content and contamination of expressed breast milk (EBM) before and after storage (30 d) in hard polypropylene containers (HC) and soft polyethylene bags (SB) containers. METHODS: Ninety specimens of EBM were collected into HC and separated into two HC and two SB. The fat content of each specimen of EBM in HC and SB was measured and cultures were performed. The specimens in the second HC and SB containers were kept frozen for 30 d before thawing and then measuring the fat content and performing cultures. RESULTS: The means +/- SD of the fat content of fresh and thawed EBM in HC were 2.98 +/- 0.97 and 2.66 +/- 0.88 g/100 ml, respectively, with a loss of 0.32 g/100 ml (p < 0.001). The means +/- SD of the fat content of fresh and thawed EBM in SB were 3.06 +/- 1.00 and 2.77 +/- 0.91 g/100 ml, respectively, with a mean loss of 0.29 g/100 ml during storage (p < 0.001). The loss of fat content during frozen storage did not differ significantly between the two types of containers (p = 0.53). All bacterial cultures of fresh and thawed EBM in HC and SB showed only nonpathogenic organisms. CONCLUSIONS: SB can replace HC for the long-term storage of frozen EBM of up to 30 d without deleterious effects on fat loss or contamination. PMID- 23355014 TI - Dexamethasone for management of neonatal meningitis. PMID- 23355015 TI - Omics methods for probing the mode of action of natural and synthetic phytotoxins. AB - For a little over a decade, omics methods (transcriptomics, proteomics, metabolomics, and physionomics) have been used to discover and probe the mode of action of both synthetic and natural phytotoxins. For mode of action discovery, the strategy for each of these approaches is to generate an omics profile for phytotoxins with known molecular targets and to compare this library of responses to the responses of compounds with unknown modes of action. Using more than one omics approach enhances the probability of success. Generally, compounds with the same mode of action generate similar responses with a particular omics method. Stress and detoxification responses to phytotoxins can be much clearer than effects directly related to the target site. Clues to new modes of action must be validated with in vitro enzyme effects or genetic approaches. Thus far, the only new phytotoxin target site discovered with omics approaches (metabolomics and physionomics) is that of cinmethylin and structurally related 5-benzyloxymethyl 1,2-isoxazolines. These omics approaches pointed to tyrosine amino-transferase as the target, which was verified by enzyme assays and genetic methods. In addition to being a useful tool of mode of action discovery, omics methods provide detailed information on genetic and biochemical impacts of phytotoxins. Such information can be useful in understanding the full impact of natural phytotoxins in both agricultural and natural ecosystems. PMID- 23355016 TI - Control of Panama disease of banana by rotating and intercropping with Chinese chive (Allium tuberosum Rottler): role of plant volatiles. AB - Intercropping and rotating banana (Musa spp.) with Chinese chive (Allium tuberosum Rottler) has been used as an effective method to control Panama disease (Fusarium wilt) of banana in South China. However, the underlying mechanism is unknown. In this study, we used aqueous leachates and volatiles from Chinese chive to evaluate their antimicrobial activity on Fusarium oxysporum f. sp. cubense race 4 (FOC), the causal agent of Panama disease in banana, and identified the antifungal compounds. Both leaf and root leachates of Chinese chive displayed strong inhibition against FOC, but the concentrated leachates showed lower inhibition than the original leachates. In a sealed system volatiles emitted from the leaves and roots of Chinese chive inhibited mycelial growth of FOC. Volatile compounds emitted from the intact growing roots mimicking natural environment inhibited spore germination of FOC. We identified five volatiles including 2-methyl-2-pentenal and four organosulfur compounds (dimethyl trisulfide, dimethyl disulfide, dipropyl disulfide, and dipropyl trisulfide) from the leaves and roots of Chinese chive. All these compounds exhibited inhibitory effects on FOC, but 2-methyl-2-pentenal and dimethyl trisulfide showed stronger inhibition than the other three compounds. 2-Methyl-2-pentenal at 50-100 MUl/l completely inhibited the mycelial growth of FOC. Our results demonstrate that antifungal volatiles released from Chinese chive help control Panama disease in banana. We conclude that intercropping and rotating banana with Chinese chive can control Panama disease and increase cropland biodiversity. PMID- 23355017 TI - Is fetal cerebral MRI worthwhile in antenatally diagnosed isolated cleft lip with or without palate? AB - OBJECTIVE: This study aims to evaluate the use of fetal brain magnetic resonance imaging (MRI) following an antenatal sonographic diagnosis of isolated cleft lip with or without cleft palate (CL/P). METHOD: This was a retrospective study of 92 fetuses antenatally diagnosed with isolated CL/P on screening ultrasound. All patients underwent expert diagnostic antenatal ultrasound, fetal brain MRI, and karyotype analysis. RESULTS: Five cases were excluded from the study as associated abnormalities were detected on expert ultrasound: corpus callosum agenesis (n = 1), retrognathism (n = 3), and ectrodactyly (n = 1). Fetal MRI diagnosed unsuspected midline cerebral abnormalities in four out of the 87 remaining cases (4.6%): vermis agenesis (n = 1), isolated arhinencephaly (n = 2), and suspicion of pituitary abnormality (n = 1). All karyotype analyses were normal. CONCLUSION: In CL/P, the incidence of associated cerebral abnormalities overlooked on ultrasound is 4.6%. Careful evaluation of midline structures by expert ultrasound in CL/P is necessary and may be sufficient. MRI can be useful if the US examination is limited or in case of family history. However, the choice to proceed to fetal MRI may vary from institution to institution. PMID- 23355018 TI - Sex differences in health-related quality of life impairment associated with eating disorder features: a general population study. AB - OBJECTIVE: To determine sex differences in the prevalence and impact of specific eating disorder features on health-related quality of life (HRQoL). METHOD: A general population sample of men (n = 1,479) and women (n = 1,555) completed interviews that assessed HRQoL (Medical Outcomes Study Short Form, SF-36), and current regular occurrence of binge eating, extreme dietary restriction, purging, and overevaluation of weight or shape. RESULTS: Men constituted a substantial minority (23-41%) of participants reporting eating disorder features. Objective binge eating had a greater impact on mental health impairment in men versus women, whereas the overevaluation of weight or shape had a greater impact on general and mental health impairment in women compared with men. DISCUSSION: Eating disorder features that impact on HRQoL are now common in men; however, the impact of specific features may differ between sexes. PMID- 23355019 TI - GIS-based pollution hazard mapping and assessment framework of shallow lakes: southeastern Pampean lakes (Argentina) as a case study. AB - The assessment of water vulnerability and pollution hazard traditionally places particular emphasis on the study on groundwaters more than on surface waters. Consequently, a GIS-based Lake Pollution Hazard Index (LPHI) was proposed for assessing and mapping the potential pollution hazard for shallow lakes due to the interaction between the Potential Pollutant Load and the Lake Vulnerability. It includes easily measurable and commonly used parameters: land cover, terrain slope and direction, and soil media. Three shallow lake ecosystems of the southeastern Pampa Plain (Argentina) were chosen to test the usefulness and applicability of this suggested index. Moreover, anthropogenic and natural medium influence on biophysical parameters in these three ecosystems was examined. The evaluation of the LPHI map shows for La Brava and Los Padres lakes the highest pollution hazard (~30 % with high to very high category) while Nahuel Ruca Lake seems to be the less hazardous water body (just 9.33 % with high LPHI). The increase in LPHI value is attributed to a different loading of pollutants governed by land cover category and/or the exposure to high slopes and influence of slope direction. Dissolved oxygen and biochemical oxygen demand values indicate a moderately polluted and eutrophized condition of shallow lake waters, mainly related to moderate agricultural activities and/or cattle production. Obtained information by means of LPHI calculation result useful to perform a local diagnosis of the potential pollution hazard to a freshwater ecosystem in order to implement basic guidelines to improve lake sustainability. PMID- 23355020 TI - Effect of power plant emission reductions on a nearby wilderness area: a case study in northwestern Colorado. AB - This study evaluates the effect of emission reductions at two coal-fired power plants in northwestern Colorado on a nearby wilderness area. Control equipment was installed at both plants during 1999-2004 to reduce SO2 and NOx emissions. One challenge was separating the effects of local from regional emissions, which also declined during the study period. The long-term datasets examined confirm that emission reductions had a beneficial effect on air and water quality in the wilderness. Despite a 75 % reduction in SO2 emissions, sulfate aerosols measured in the wilderness decreased by only 20 %. Because the site is relatively close to the power plants (<75 km), the slow rate of conversion of SO2 to sulfate, particularly under conditions of low relative humidity, might account for this less than one-to-one response. On the clearest days, emissions controls appeared to improve visibility by about 1 deciview, which is a small but perceptible improvement. On the haziest days, however, there was little improvement perhaps reflecting the dominance of regional haze and other components of visibility degradation particularly organic carbon and dust. Sulfate and acidity in atmospheric deposition decreased by 50 % near the southern end of the wilderness of which 60 % was attributed to power plant controls and the remainder to reductions in regional sources. Lake water sulfate responded rapidly to trends in deposition declining at 28 lakes monitored in and near the wilderness. Although no change in the acid-base status was observed, few of the lakes appear to be at risk from chronic or episodic acidification. PMID- 23355021 TI - Mobilization of aluminum by the acid percolates within unsaturated zone of sandstones. AB - The area of the Black Triangle has been exposed to extreme levels of acid deposition in the twentieth century. The chemical weathering of sandstones found within the Black Triangle became well-known phenomenon. Infiltration of acid rain solutions into the sandstone represents the main input of salt components into the sandstone. The infiltrated solutions--sandstone percolates--react with sandstone matrix and previously deposited materials such as salt efflorescence. Acidic sandstone percolates pH 3.2-4.8 found at ten sites within the National Park Bohemian Switzerland contained high Al-tot (0.8-10 mg L(-1)) concentrations and high concentrations of anions SO4 (5-66 mg L(-1)) and NO3 (2-42 mg L(-1)). A high proportion (50-98 %) of Al-tot concentration in acid percolates was represented by toxic reactive Al(n+). Chemical equilibrium modeling indicated as the most abundant Al species Al(3+), AlSO4 (+), and AlF(2+). The remaining 2-50 % of Al-tot concentration was present in the form of complexes with dissolved organic matter Al-org. Mobilization and transport of Al from the upper zones of sandstone causes chemical weathering and sandstone structure deterioration. The most acidic percolates contained the highest concentrations of dissolved organic material (estimated up to 42 mg L(-1)) suggesting the contribution of vegetation on sandstone weathering processes. Very low concentrations of Al-tot in springs at BSNP suggest that Al mobilized in unsaturated zone is transported deeper into the sandstone. This process of mobilization could represent a threat for the water quality small-perched aquifers. PMID- 23355022 TI - Depositional behaviour of C-org, N, P and K in the surface sediments of two shallow water bodies in a tropical coast, India. AB - The present paper deals with the distribution of sediment and sediment-bound nutrients in two important coastal lagoons of southern Kerala such as the Ashtamudi Estuarine Lagoon in the Kollam district and the Kadinamkulam Lagoon in the Thiruvananthapuram district. Among the two lagoons, the former is coast perpendicular, and the latter is coast parallel. An analysis of the textural characteristics reveals that, in both lagoons, the estuarine mouth and areas close to it are dominated by sand and sand-rich sediment species, indicating a high-energy depositional regime prevailing the region. On the other hand, the silt and clay dominant arms are almost sheltered and enjoy a low-energy depositional environment. The nutrient and organic carbon contents in the sheltered areas are significantly higher than the most dynamic high-energy estuarine mouth regions. This peculiar behaviour of these coastal water bodies has to be given adequate importance while laying down strategies for the conservation and management of these fragile aquatic systems in the south-western coast of India in particular and tropical coasts of the world in general. PMID- 23355023 TI - A method to assess soil erosion from smallholder farmers' fields: a case study from Malawi. AB - Soil erosion by water is a major threat to sustainable food production systems in Africa. This study presents a qualitative soil erosion assessment method that links the number of broken ridges (NBRS) observed on a smallholder farmer's field after a rain event to factors of soil erosion (e.g., rainfall intensity, slope steepness, crop canopy height, and conservation practice) and to soil loss data measured from a runoff plot and receiving small streams. The assessment method consists of a rapid survey of smallholder farmers combined with field monitoring. Results show an indirect relationship between NBRS and factors of soil erosion. Results also show a direct relationship between NBRS and suspended sediment concentrations measured from an experimental runoff plot and receiving streams that drain the sub-watersheds where farmers' fields are located. Given the limited human and financial resources available to soil erosion research in developing countries, monitoring NBRS is a simple, cost-effective, and reliable erosion assessment method for regions where smallholder farmers practice contour ridging. PMID- 23355024 TI - Residue levels of hexachlorocyclohexane and dichlorodiphenyltrichloroethane in human milk collected from Beijing. AB - Forty-eight human breast milk samples were collected from mothers in Beijing. The hexachlorocyclohexane (HCH) and dichlorodiphenyltrichloroethane (DDT) (including alpha-HCH, beta-HCH, gamma-HCH, delta-HCH, p,p'-DDE, p,p'-DDD, o,p'-DDT, and p,p' DDT) contents of the samples were determined by gas chromatography/electron capture detection and gas chromatography/mass spectrometry. alpha-HCH, beta-HCH, gamma-HCH, p,p'-DDE, p,p'-DDD, and p,p'-DDT were detected at rates of 20, 100, 10, 100, 10, and 22 %, respectively. The average residue levels in the samples were 174.6 ng/g fat for beta-HCH, 333.8 ng/g fat for p,p'-DDE, 6.57 ng/g fat for alpha-HCH, 7.67 ng/g fat for gamma-HCH, 4.18 ng/g fat for p,p'-DDD, and 11.4 ng/g fat for p,p'-DDT. The results showed that the infants' daily intake levels of HCH and DDT were 0.95 and 1.76 MUg/kg body weight/day, respectively. Our result suggested that the total residue level of these organochlorine pesticides in breast milk from Beijing decreased and was lower than that from other coastal and heavy industrial cities in China. On the other hand, the levels of HCH and DDT were higher than those from some developed countries, but lower than those from other developing countries such as India. PMID- 23355025 TI - Coral communities of the remote atoll reefs in the Nansha Islands, southern South China Sea. AB - During the months of May and June in the year 2007, a survey was conducted regarding coral reef communities in the remote atolls (Zhubi Reef and Meiji Reef) of Nansha Islands, southern South China Sea. The goals of the survey were to: (1) for the first time, compile a scleractinian coral check-list; (2) estimate the total richness, coral cover, and growth forms of the community; and (3) describe preliminary patterns of community structure according to geomorphological units. Findings of this survey revealed a total of 120 species of scleractinia belonging to 40 genera, while the average coral cover was 21 %, ranging from less than 10 % to higher than 50 %. Branching and massive corals were also found to be the most important growth forms of the whole coral community, while Acropora, Montipora, and Porites were the three dominant genera in the overall region, with their contributions to total coral cover measuring 21, 22, and 23 %, respectively. Overall, coral communities of the Nansha Islands were in a relative healthy condition with high species diversity and coral cover. Spatial pattern of coral communities existed among various geomorphological units. Mean coral cover was highest in the patch reef within the lagoon, followed by the fore reef slope, reef flat, and lagoon slope. The greatest contributors to total coral cover were branching Acropora (45 %) in the lagoon slope, branching Montipora (44 %) in the reef flat, and massive Porites (51 %) in the patch reef. Coral cover in the fore reef revealed a greater range of genera than in other habitats. The leeward fore reef slope had higher coral cover (> 50 %) when compared with the windward slope (< 10 %). The coral communities of the inner reef flat were characterized by higher coral cover (27 %) and dominant branching Montipora corals, while lower coral cover (4 %) was dominated by Psammocora with massive growth forms on the outer reef flat. Destructive fishing and coral bleaching were two major threats to coral communities in the study area. PMID- 23355026 TI - Iron and sulfur geochemistry in semi-arid mangrove soils (Ceara, Brazil) in relation to seasonal changes and shrimp farming effluents. AB - Iron and sulfur are key elements in the biogeochemistry of estuarine soils, in which Fe and sulfate reduction (SR) pathways are important for organic matter decomposition. In the semi-arid coast of NE Brazil, mangroves are characterized by large seasonal variations in weather and the presence of numerous shrimp farms. The objective was to determine the impacts of shrimp farm effluents on iron and sulfur geochemistry in mangrove soils under the semi-arid climate of NE Brazil. A seasonal study was made of two mangrove forest soils (SF, a mangrove forest that directly receives wastewater from shrimp ponds and CS, a control site). Pyrite Fe, oxyhydroxides Fe, acid volatile sulfide, degree of pyritization (DOP), pH, Eh, total organic carbon (TOC) and total S were determined. There was a clear decrease in pyritic Fe and DOP in the SF soils, which may be related to the anaerobic oxidation of pyrite coupled with nitrate reduction, or to the dominance of denitrification over SR. Lower TOC contents in the SF site suggest that below ground decomposition increased in response to eutrophication. The seasonal variations led to important changes in the semi-arid mangrove soils. During the dry period, both soils experienced oxidizing conditions with remarkable loss of reduced and oxidized forms of Fe, which may have important environmental implications as Fe is biolimiting for marine primary production. The data show that both factors (seasonal weather variations and shrimp effluents) play important roles in the geochemical processes that occur in these soils and, thus, may affect their functioning and maintenance. PMID- 23355027 TI - Factors related to nephrotic-range proteinuria in late-stage chronic kidney disease patients with diabetes mellitus. AB - PURPOSE: Diabetic nephropathy and proteinuria are important risk factors for both end-stage renal disease and cardiovascular events. The present study aimed to identify the factors associated with nephrotic-range proteinuria in patients with advanced diabetic nephropathy. METHODS: This cross-sectional study enrolled 386 diabetic patients with chronic kidney disease (CKD) stages 3-5, from our outpatient Department of Nephrology. Urinary protein-to-creatinine ratio was recorded. Additionally, other laboratory parameters, body mass index, blood pressure, comorbidities, and medications were also reviewed. RESULTS: The mean age of the patients was 65.1 +/- 11.6 years. Among patients with CKD stage 3 and 4, the odds ratio (OR) for nephrotic-range proteinuria in relation with systolic blood pressure significantly increased starting from 121 mmHg (OR 7.04 and 11.79 for systolic blood pressure of 121-140 and >=141 mmHg, respectively, in comparison with systolic blood pressure below 121 mmHg). In addition, serum phosphorus >=4.7 mg/dl was associated with significantly higher risk (OR 15.45) for severe proteinuria, compared with a phosphorus level <=2.6 mg/dl. Finally, hypertriglyceridemia >=241 mg/dl was also associated with higher OR for severe proteinuria, compared with a triglyceride level <=200 mg/dl. Similar associations were found in patients with CKD stage 5. CONCLUSIONS: Higher systolic blood pressure, serum phosphorus, and triglyceride levels are associated with nephrotic range proteinuria in patients with diabetic nephropathy and CKD stage 3-5. Further studies should clarify whether a reduction in serum phosphorus would lead to a decrease in proteinuria in these patients. PMID- 23355028 TI - Prevalence of abnormal urinary albumin excretion in elderly people: a Spanish survey. AB - OBJECTIVES: HERMEX is a population-based study, which tries to evaluate the prevalence of cardiovascular risk factors in the population of Extremadura, Spain. This report provides the data concerning albuminuria in the elderly people recruited in the survey. DESIGN AND METHODS: 3,402 subjects were randomly selected from the database of the Health Care System of Extremadura. The final sample included 2,813 subjects (mean age 51.2 years, 53.5 % female). Urinary albumin excretion rate (UAER) in the first morning urine sample was analyzed. Albuminuria was diagnosed when UAER (albumin-to-creatinine ratio) was >= 22 mg/g in men or >= 31 mg/g in women. RESULTS: The prevalence of abnormal UAER in the elderly population was 10.9 % (microalbuminuria: 8.9 %; overt proteinuria: 1.8 %). The younger subjects showed a lower prevalence of microalbuminuria (3.4 %, p < 0.001). Elderly patients showed a higher prevalence of cardiovascular risk factors than the younger ones. The elderly had higher systolic blood pressure and pulse pressure than the younger ones. Furthermore, the elderly subjects had lower plasma levels of HDL cholesterol, but higher triglycerides, glucose, creatinine, and glycosylated hemoglobin; no differences were found for total and LDL cholesterol. When the prevalence of causes of microalbuminuria was compared between age groups, we found a sharp increase in diabetic and, especially, hypertensive patients in the elderly group. The multivariate analysis showed an independent association of microalbuminuria with systolic blood pressure and plasma creatinine. CONCLUSIONS: A high prevalence of abnormal UAER in elderly people was detected in a randomly selected sample of Spanish general population. In most elderly patients, microalbuminuria was associated with high blood pressure and, less frequently, with diabetes mellitus. PMID- 23355029 TI - Relationship between serum fibroblast growth factor-23 level and mortality in chronic hemodialysis patients. AB - BACKGROUND: Fibroblast growth factor-23 (FGF23) is a phosphate-regulating hormone and is found to be markedly increased in patients with chronic kidney disease. The aim of the present study was to evaluate the relationship between serum FGF23 levels and mortality, including the impact of gender and cardiovascular disease (CVD), in a Japanese cohort of chronic hemodialysis (HD) patients. METHODS: Ninety-two maintenance dialysis patients (58 men; mean age 60.3 years) were included. Serum intact FGF23, calcium, phosphate, albumin, intact parathyroid hormone (PTH), and C-reactive protein were measured at baseline. CVD was defined as clinical symptoms and/or a history of CVD. RESULTS: During a median follow-up time of 53.2 months, 24 patients (26 %) died. Serum FGF23 levels were positively correlated with serum levels of calcium (r = 0.5433, P < 0.0001), phosphate (r = 0.5048, P < 0.0001), calcium * phosphate product (r = 0.6801, P < 0.0001), and intact PTH (r = 0.2710, P = 0.0090) (r = 0.27, P < 0.0001). In Cox proportional hazard models, serum FGF23 level was not associated with increased mortality risk, neither in crude nor in multivariate-adjusted models. However, in a subgroup analysis of women with previous CVD, serum FGF23 level above median was associated with higher cardiovascular event risk in crude models (hazard ratio 9.52, 95 % confidence interval 1.56-86.11, P = 0.0129). Kaplan-Meier analysis stratifying for the presence of CVD demonstrated a significant higher mortality risk in patients with history of CVD and higher serum FGF23 levels (P < 0.0001). CONCLUSION: Serum FGF23 level was not associated with increased mortality risk in this cohort of prevalent HD patients. These results suggest that the impact of FGF23 on mortality may be modified by gender and previous CVD and is blunted in the grade of hyperphosphatemia. PMID- 23355030 TI - Nano-electromanipulation of spin crossover nanorods: towards switchable nanoelectronic devices. AB - The nanoscale manipulation and charge transport properties of the [Fe(Htrz)2(trz)](BF4) spin-crossover compound is demonstrated. Such 1D spin crossover nanostructures are attractive building blocks for nanoelectronic switching and memory devices. PMID- 23355031 TI - Transcatheter aortic valve replacement requiring staged percutaneous coronary intervention in Japanese patients with severely calcified ascending aorta: a case report and institution series analysis. AB - Transcatheter aortic valve replacement (TAVR) has emerged as a less invasive therapeutic option for high-risk patients with aortic stenosis (AS) in Europe and US. Data on TAVR are relatively limited in Japan. We report a first TAVR case in Japan of successful TAVR following percutaneous coronary intervention (PCI). A 75 year-old man with stable angina pectoris and severe AS was considered to be at high risk for surgical AVR because of severely calcified ascending aorta. He underwent transfemoral TAVR after undergoing PCI of left circumflex artery. The procedure was successful and the patient was discharged on the 10th postoperative day. PMID- 23355032 TI - Novel and quick coronary image analysis by instant stent-accentuated three dimensional optical coherence tomography system in catheterization laboratory. AB - In order to confirm the relation between stent struts and the jailed side branch (SB), the actual wire re-crossing position and the optimal wire re-crossing position during a bifurcation stenting, we developed the instant stent accentuated three-dimensional optical coherence tomography (iSA 3D-OCT) system based on a novel algorithm. Stent struts in two-dimensional optical coherence tomography (2D-OCT) are represented as high-intensity line segments or spots in low-intensity background. Stent struts disappear and a vessel image is created by the mean filter followed by the minimum filter. A strut image is created by subtracting a vessel image from an original image, and accentuated. By adding a vessel image to a strut image, iSA 2D-OCT is created. It took only 3 s to accentuate stent struts of 100 frames by ImageJ with its macro program. By the iSA 3D-OCT system which consists of the console of OCT, the USB selector, USB cables, the USB flash drive, the computer, and three freeware programs, it took about 65 s from an export of the image data to an observation of iSA 3D-OCT semi automatically. During a bifurcation stenting procedure, we could confirm the relation between stent struts and the jailed SB, the actual wire re-crossing position and the optimal wire re-crossing position. Using the iSA 3D-OCT system, a detailed process during a bifurcation PCI can be observed in very short waiting time, about 65 s. It is expected to improve the outcome of a complicated bifurcation PCI by the iSA 3D-OCT system. PMID- 23355034 TI - Modification of histidine biosynthesis pathway genes and the impact on production of L-histidine in Corynebacterium glutamicum. AB - Histidine biosynthesis in Corynebacterium glutamicum is regulated not only by feedback inhibition by the first enzyme in the pathway, but also by repression control of the synthesis of the histidine enzymes. C. glutamicum histidine genes are located and transcribed in two unlinked loci, hisEG and hisDCB-orf1-orf2 hisHA-impA-hisFI. We constructed plasmid pK18hisDPtac to replace the native hisD promoter with the tac promoter, and overexpressed phosphoribosyl-ATP pyrophosphohydrolase, encoded by hisE, and ATP-phosphoribosyltransferase, encoded by hisG. The L-histidine titer at 0.85 g l(-1) was 80 % greater in the transformed bacterium and production of byproducts, L-alanine and L-tryptophan, was significantly decreased. However, accumulation of glutamic acid increased by 58 % (2.8 g l(-1)). This study represents the first attempt to substitute the histidine biosynthesis pathway promoter in the chromosome with a stronger promoter to increase histidine production. PMID- 23355033 TI - Prevalence of nonalcoholic steatohepatitis among patients with resectable intrahepatic cholangiocarcinoma. AB - BACKGROUND AND AIMS: The objective of this report was to determine the prevalence of underlying nonalcoholic steatohepatitis in resectable intrahepatic cholangiocarcinoma. METHODS: Demographics, comorbidities, clinicopathologic characteristics, surgical treatments, and outcomes from patients who underwent resection of intrahepatic cholangiocarcinoma at one of eight hepatobiliary centers between 1991 and 2011 were reviewed. RESULTS: Of 181 patients who underwent resection for intrahepatic cholangiocarcinoma, 31 (17.1 %) had underlying nonalcoholic steatohepatitis. Patients with nonalcoholic steatohepatitis were more likely obese (median body mass index, 30.0 vs. 26.0 kg/m(2), p < 0.001) and had higher rates of diabetes mellitus (38.7 vs. 22.0 %, p = 0.05) and the metabolic syndrome (22.6 vs. 10.0 %, p = 0.05) compared with those without nonalcoholic steatohepatitis. Presence and severity of hepatic steatosis, lobular inflammation, and hepatocyte ballooning were more common among nonalcoholic steatohepatitis patients (all p < 0.001). Macrovascular (35.5 vs. 11.3 %, p = 0.01) and any vascular (48.4 vs. 26.7 %, p = 0.02) tumor invasion were more common among patients with nonalcoholic steatohepatitis. There were no differences in recurrence-free (median, 17.0 versus 19.4 months, p = 0.42) or overall (median, 31.5 versus 36.3 months, p = 0.97) survival after surgical resection between patients with and without nonalcoholic steatohepatitis. CONCLUSIONS: Nonalcoholic steatohepatitis affects up to 20 % of patients with resectable intrahepatic cholangiocarcinoma. PMID- 23355035 TI - Improvement of expression level of keratinase Sfp2 from Streptomyces fradiae by site-directed mutagenesis of its N-terminal pro-sequence. AB - The keratinase Sfp2, produced by Streptomyces fradiae var. k11, is a serine alkaline protease first synthesized as pre-pro-mature precursor, of which the N terminal propeptide must be autocatalytically cleaved on the C-terminal of P1 amino acid to produce mature enzyme. Single amino acid substitutions were introduced at positions -1 and -2 to improve the expression level of mature Sfp2. The specific activity of L(-1)F mutant (48935 U/mg) was nine times that of wild type Sfp2, whereas the mutants L(-1)D, L(-1)G, L(-1)H, K(-2)E, and K(-2)L had 2 52 % of the specific activity of wild-type. The yield of mature Sfp2 of L(-1)F mutant was estimated to be 800 MUg/mg total protein and 112 mg/l culture supernatant, nine and twice that of wild-type, respectively. The L(-1)F mutant exhibited similar enzymatic properties to wild-type. PMID- 23355036 TI - Production of a chiral alcohol, 1-(3,4-dihydroxyphenyl) ethanol, by mushroom tyrosinase. AB - 1-(3,4-Dihydroxyphenyl) ethanol was produced biocatalytically for the first time using mushroom tyrosinase. 4-Ethylphenol at 1 mM was consumed over 12 min giving 0.23 mM 4-ethylcatechol and 0.36 mM (R/S)-1-(3,4-dihydroxyphenyl) ethanol (ee 0.5 %). Mushroom tyrosinase consumed 4-ethylphenol at 6.7 MUmol min(-1) mg protein( 1) while the rates of formation of 4-ethylcatechol and 1-(3,4-dihydroxyphenyl) ethanol were 1.1 and 1.9 MUmol min(-1) mg protein(-1). Addition of the ascorbic acid, as a reducing agent to biotransformation reactions, increased 4 ethylcatechol formation by 340 %. However, accumulation of 1-(3,4 dihydroxyphenyl) ethanol was not observed in the presence of ascorbic acid. While the 1-(3,4-dihydroxyphenyl) ethanol was racemic, it is the first chiral product produced by tyrosinase starting from a non-chiral substrate. PMID- 23355038 TI - Thrombocytosis and immunohistochemical expression of connexin 43 at diagnosis predict survival in advanced non-small-cell lung cancer treated with cisplatin based chemotherapy. AB - PURPOSE: Patients with advanced non-small-cell lung cancer (NSCLC) have poor survival, and platinum-based chemotherapy agents are the standard first-line chemotherapy agents for advanced NSCLC. This study aimed to identify predictive factors associated with the response to chemotherapy and survival in 258 patients with advanced NSCLC treated with platinum-based chemotherapy. METHODS: Stage IIIA IV NSCLC patients diagnosed in Kaifeng second people's hospital (Henan, China) between March 2002 and September 2011 were retrospectively reviewed. All of the patients had received platinum-based chemotherapy, and patients were followed up to date of death or last follow-up to obtain data of response to chemotherapy and survival. Potential prognostic factors such as gender, age, tumor size, tumor type, histologic stage, anemia, calcium levels, ECOG performance status (PS), thrombocytosis, TTF-1, p63, and connexin 43 were analyzed. Response to chemotherapy, overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan-Meier method and Cox regression model. RESULTS: A univariate analysis indicated that thrombocytosis and connexin 43 were found to be significant prognostic factors (p < 0.001) and ECOG PS, Hb levels, and p63 presented a tendency toward association with survival. Kaplan-Meier survival showed that the mean OS and PFS in chemotherapy responders with connexin 43 >= +2 were significantly longer than in chemotherapy responders with connexin 43 <= 1+. In contrast, thrombocytosis was associated with increased mortality and resistance to chemotherapy in chemotherapy responders. In addition, all 21 patients of the 5-year OS were from chemotherapy responders with connexin 43 >= +2 or non-thrombocytosis. CONCLUSIONS: Thrombocytosis and connexin 43 absence may be reliable surrogate markers for the prediction of chemotherapy response and prognosis for patients with advanced NSCLC, and assessment of these factors may identify a population of patients with advanced NSCLC that is likely to have a prolonged life expectancy. PMID- 23355037 TI - An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo. AB - PURPOSE: Multiple reports point to an important role for the phosphoinositide-3 kinase (PI3K) and AKT signaling pathways in tumor survival and chemoresistance in multiple myeloma (MM). The goals of our study were: (1) to generate the preclinical results necessary to justify a Phase I clinical trial of SF1126 in hematopoietic malignancies including MM and (2) to begin combining pan-PI3K inhibitors with other agents to augment antitumor activity of this class of agent in preparation for combination therapy in Phase I/II trials. METHODS: We determined the in vitro activity of SF1126 with 16 human MM cell lines. In vivo tumor growth suppression was determined with human myeloma (MM.1R) xenografts in athymic mice. In addition, we provide evidence that SF1126 has pharmacodynamic activity in the treatment of patients with MM. RESULTS: SF1126 was cytotoxic to all tested MM lines, and potency was augmented by the addition of bortezomib. SF1126 affected MM.1R cell line signaling in vitro, inhibiting phospho-AKT, phospho-ERK, and the hypoxic stabilization of HIF1alpha. Tumor growth was 94 % inhibited, with a marked decrease in both cellular proliferation (PCNA immunostaining) and angiogenesis (tumor microvessel density via CD31 immunostaining). Our clinical results demonstrate pharmacodynamic knockdown of p AKT in primary patient-derived MM tumor cells in vivo. CONCLUSIONS: Our results establish three important points: (1) SF1126, a pan-PI3K inhibitor has potent antitumor activity against MM in vitro and in vivo, (2) SF1126 displays augmented antimyeloma activity when combined with proteasome inhibitor, bortezomib/Velcade((r)), and (3) SF1126 blocks the IGF-1-induced activation of AKT in primary MM tumor cells isolated from SF1126-treated patients The results support the ongoing early Phase I clinical trial in MM and suggest a future Phase I trial in combination with bortezomib in hematopoietic malignancies. PMID- 23355039 TI - Correlation between expressions of ERCC1/TS mRNA and effects of gastric cancer to chemotherapy in the short term. AB - PURPOSE: To study the correlation between expression levels of ERCC1/TS mRNA and the susceptibility of preoperative chemotherapy for patients with gastric cancer. METHODS: A total of forty cases with advanced gastric cancer of T3-4N1-2M0 were treated with preoperative chemotherapy according to FLEEOX regimen based on endarterial-intravenous coadministration. Sufficient, fresh gastric tissue specimens were obtained with the help of gastroscope, and the expression levels of ERCC1/TS mRNA were detected by qRT-PCR before chemotherapy. The chemotherapeutic response was evaluated with Choi Criteria after chemotherapy, and pathologic remission extent was observed after surgery. The correlation between the expression levels of ERCC1/TS mRNA before chemotherapy and the chemotherapeutic effect based on imageology and pathology was analyzed. RESULTS: The response rate of Chemotherapy in this cohort was 80.0 % based on imageology and 51.43 % based on pathology. The expression levels of ERCC1/TS mRNA were significantly associated with imageology remission extent (P = 0.033, P = 0.025) and pathologic remission extent (P = 0.044, P = 0.016), respectively. The chemotherapeutic effect on patients with low-expression levels of ERCC1/TS mRNA was better. CONCLUSIONS: From the perspective of pathology and imageology evaluating the preoperative chemotherapeutic response for patients with gastric cancer, ERCC1 and TS were used as the molecular predictors and provided prognostic information in this study. PMID- 23355040 TI - Multicenter phase II study of S-1 and docetaxel combination chemotherapy for advanced or recurrent gastric cancer patients with peritoneal dissemination. AB - PURPOSE: Peritoneal dissemination is the most frequent and life-threatening mode of metastasis and recurrence in patients with gastric cancer. A multicenter phase II study was designed to evaluate the efficacy and tolerability of S-1 and docetaxel combination chemotherapy regimen for the treatment of advanced or recurrent gastric cancer patients with peritoneal dissemination. METHODS: Nineteen patients with histologically confirmed unresectable or recurrent gastric cancer with peritoneal dissemination were enrolled. Oral S-1 at 80 mg/m(2)/day was administered twice daily for 2 weeks, followed by 1 drug-free week. Docetaxel infusion at 40 mg/m(2) was performed on day 1, simultaneous with S-1 administration. The primary endpoints were overall survival (OS) and time to progression (TTP). The secondary endpoints were the response rates and safety status. RESULTS: Patients received a median of 4 cycles of the S-1 and docetaxel regimen (range 1-43). The disease control rate was 73.7 % (14/19). Median overall survival was 459 days (15.3 months), while median time to progression was 212 days (7.1 months). Neutropenia was the most common type of toxicity (n = 7, 36.8 %). CONCLUSIONS: Combination chemotherapy with S-1 and docetaxel is a tolerable and effective treatment for advanced or recurrent gastric cancer patients with peritoneal dissemination. PMID- 23355041 TI - A randomized phase II study of gemcitabine and S-1 combination therapy versus gemcitabine monotherapy for advanced biliary tract cancer. AB - PURPOSE: In order to confirm the impact of adding S-1 to gemcitabine, we conducted a randomized phase II study to compare the combination therapy of gemcitabine plus S-1 to gemcitabine monotherapy in patients with advanced biliary tract cancer. METHODS: Sixty-two patients with advanced cholangiocarcinoma or gallbladder cancer were randomized to either the combination therapy of gemcitabine and S-1 (gemcitabine 1,000 mg/m(2) on days 1 and 15 and S-1 40 mg/m(2) b.i.d. on days 1-14, repeated every 4 weeks) or gemcitabine monotherapy (gemcitabine 1,000 mg/m(2) on days 1, 8, and 15, repeated every 4 weeks). The primary endpoint of this study was response rate, and the regimen which showed the better response rate was selected as a candidate of phase III study. Tumor response was assessed every two cycles using Response Evaluation Criteria in Solid Tumors criteria version 1.0. RESULTS: The response rates of the combination therapy and the monotherapy were 20.0 and 9.4 %, respectively. The median time-to progressions and overall survivals of these two treatments were nearly the same (5.6 vs. 4.3 months; 8.9 vs. 9.2 months). Adverse events occurred more frequently in the combination arm. CONCLUSIONS: The combination therapy of gemcitabine and S 1 showed the better response rate, but the superiority of this combination therapy was not clear in total. Because the standard of care changed to the combination therapy with gemcitabine and cisplatin during this study, it is difficult to select this combination therapy with a 4-week regimen as a candidate of phase III study. PMID- 23355042 TI - Anti-tumour and anti-vascular effects of cediranib (AZD2171) alone and in combination with other anti-tumour therapies. AB - PURPOSE: Cediranib (AZD2171) is a highly potent inhibitor of all three vascular endothelial growth factor receptors. The aim of this preclinical study was to examine the effect of combining cediranib with mechanistically distinct anti tumour therapies. METHODS: Cediranib (1.5 or 3 mg/kg/day) was evaluated alone and in combination with either gefitinib, imatinib, ZD6126, saracatinib, selumetinib, bevacizumab, 5-fluorouracil (5-FU), docetaxel, oxaliplatin, gemcitabine, pemetrexed, irinotecan or cisplatin in human tumour xenograft models. Anti-tumour activity was measured by assessing the change in tumour volume following treatment compared with vehicle-treated time-matched controls. RESULTS: In all cases, the combination regimens, at tolerated doses and schedules, inhibited tumour growth to a greater extent than the corresponding monotherapy treatments. Compared with cediranib alone, statistically significant enhancements in anti tumour activity were observed with all combination regimens. Notably, after 14 days of treatment, the combination of cediranib with ZD6126 induced substantial tumour regression (60 % compared with pre-treatment volume), whilst treatment with each agent alone led only to partial growth inhibition. A combination of cediranib with gefitinib also induced tumour regressions, and cediranib combined with either gemcitabine or irinotecan was found to inhibit tumour growth profoundly (by 99 and 98 %, respectively). CONCLUSIONS: Combining cediranib with selected cytotoxic or targeted agents proved efficacious in a range of human tumour xenograft models. PMID- 23355043 TI - Systematic review and meta-analysis of laparoscopic versus open colectomy with end ileostomy for non-toxic colitis. AB - BACKGROUND: This review compared short-term outcomes after laparoscopic versus open subtotal colectomy for acute, colitis medically refractory. METHODS: A systematic review of the literature was carried out using MEDLINE, Embase and the Cochrane databases. Overall study quality was assessed by the modified Methodological Index for Non-Randomized Studies (MINORS). Meta-analysis was performed for conversion, reoperation, wound infection, ileus, gastrointestinal bleeding, intra-abdominal abscess, postoperative length of stay and mortality. RESULTS: The search identified nine non-randomized studies: six cohort studies and three case-matched series, comprising 966 patients in total. The pooled conversion rate was 5.5 (95 per cent confidence interval (c.i.) 3.6 to 8.4) per cent in the laparoscopic group. The pooled risk ratio of wound infection was 0.60 (95 per cent c.i. 0.38 to 0.95; P = 0.03) and that of intra-abdominal abscess was 0.27 (0.08 to 0.91; P = 0.04), both in favour of laparoscopic surgery. Pooled risk ratios for other complications showed no significant differences. Length of stay was significantly shorter after laparoscopic subtotal colectomy, with a pooled mean difference of 3.17 (95 per cent c.i. 2.37 to 3.98) days (P < 0.001). CONCLUSION: Where the procedure can be completed laparoscopically, there may be short-term benefits over open colectomy for colitis. These results cannot be generalized to critically ill patients in need of an emergency subtotal colectomy. PMID- 23355044 TI - Strengthening encoding via implementation intention formation increases prospective memory commission errors. AB - Prospective memory refers to the ability to remember to execute future intentions (e.g., taking medication with dinner). Although most prior research on prospective memory errors has focused on omission errors (i.e., failures to perform an intention in response to a target cue), there has been a recent surge in research on commission errors, the erroneous performance of a finished intention. Existing studies have examined factors at retrieval that lead to commission errors; the present study extends this research by investigating the impact of encoding strength. We found that relative to standard encoding, implementation intention encoding doubled the risk of commission errors in our laboratory paradigm for both young and older adults. This novel finding demonstrates the impact of encoding strength on commission errors and documents the potential challenges of deactivating the effects of implementation intentions upon completion of a prospective memory task. PMID- 23355045 TI - Greater visual averaging of face identity for own-gender faces. AB - Recent evidence suggests that observers can rapidly form an average representation based on a set of simultaneously presented faces. Here, we replicate this finding and show that the tendency to process sets of faces in terms of an average representation is greater for own-gender faces. Male and female participants viewed sets of four male or female faces before deciding whether or not a subsequently presented single test face had been present in the set. Incorrect endorsement that it was one of the set members was greater when the test face was a morphed average of the four faces than when it was an actual set member, and this effect was strongest when the gender of the faces was the same as the observer's. The finding that observers were more likely to incorrectly endorse own-gender (vs. other-gender) faces forms an exception to the often reported own-gender advantage in face recognition. PMID- 23355046 TI - Sources and temporal patterns of polychlorinated biphenyls around a large South American grain-shipping port (Paranagua Estuarine System, Brazil). AB - The Paranagua Estuarine System (PES) is an important estuarine environment on the Brazilian coast. The economic importance of the PES is mainly related to industries, fuel terminals, and the main South American grain-shipping port. The aim of this work was to determine the vertical distribution of polychlorinated biphenyls (PCBs) in three sediment cores from the PES. The methods included Soxhlet extraction, clean-up, and quantification by gas chromatography with electron capture detection. The concentrations of total PCBs ranged from lower than the detection limit to 6.65 ng g(-1). Low PCB concentrations were detected in P1 and P3, which were collected far away from direct human activities. In P2, the compositional pattern of PCB congeners showed greater concentrations of tetra and penta-chlorinated congeners associated with urban and port activities near Paranagua city. The differences in concentrations between the three sediment cores were attributed to the distance of the sampling points in relation to the possible sources of pollution, which are mostly related to Paranagua city. The vertical distribution of PCBs in the sediment core P2 was related to historical anthropogenic activities. The highest PCB input was from 1970 to the early 1990s, which coincides with a period of greater use of PCBs in Brazil as well as their greater worldwide production. PMID- 23355047 TI - A question about defining moral bioenhancement. PMID- 23355048 TI - Moral bioenhancement: a neuroscientific perspective. PMID- 23355049 TI - Moral enhancement, freedom, and what we (should) value in moral behaviour. AB - The enhancement of human traits has received academic attention for decades, but only recently has moral enhancement using biomedical means--moral bioenhancement (MB)--entered the discussion. After explaining why we ought to take the possibility of MB seriously, the paper considers the shape and content of moral improvement, addressing at some length a challenge presented by reasonable moral pluralism. The discussion then proceeds to this question: Assuming MB were safe, effective, and universally available, would it be morally desirable? In particular, would it pose an unacceptable threat to human freedom? After defending a negative answer to the latter question--which requires an investigation into the nature and value of human freedom--and arguing that there is nothing inherently wrong with MB, the paper closes with reflections on what we should value in moral behaviour. PMID- 23355050 TI - Preventive misconception and adolescents' knowledge about HIV vaccine trials. AB - OBJECTIVE: Adolescents have had very limited access to research on biomedical prevention interventions despite high rates of HIV acquisition. One concern is that adolescents are a vulnerable population, and trials carry a possibility of harm, requiring investigators to take additional precautions. Of particular concern is preventive misconception, or the overestimation of personal protection that is afforded by enrolment in a prevention intervention trial. METHODS: As part of a larger study of preventive misconception in adolescent HIV vaccine trials, we interviewed 33 male and female 16-19-year-olds who have sex with men. Participants underwent a simulated HIV vaccine trial consent process, and then completed a semistructured interview about their understanding and opinions related to enrolment in a HIV vaccine trial. A grounded theory analysis looked for shared concepts, and focused on the content and process of adolescent participants' understanding of HIV vaccination and the components of preventive misconception, including experiment, placebo and randomisation. RESULTS: Across interviews, adolescents demonstrated active processing of information, in which they questioned the interviewer, verbally worked out their answers based upon information provided, and corrected themselves. We observed a wide variety of understanding of research concepts. While most understood experiment and placebo, fewer understood randomisation. All understood the need for safer sex even if they did not understand the more basic concepts. CONCLUSIONS: Education about basic concepts related to clinical trials, time to absorb materials and assessment of understanding may be necessary in future biomedical prevention trials. PMID- 23355051 TI - Ni-catalyzed [4+3+2] cycloaddition of ethyl cyclopropylideneacetate and dienynes: scope and mechanistic insights. AB - A detailed study of the Ni-catalyzed [4+3+2] cycloaddition reaction between ethyl cyclopropylideneacetate and dienynes has been conducted, resulting in the development of a new method for the synthesis of compounds containing nine membered rings. We studied the reactivity of various dienynes, together with their substituent and conformational effects. The mechanism of the reaction was probed by examining the stoichiometric reactions of the Ni complexes and dienynes. PMID- 23355052 TI - The effect of parasocial interaction on intention to register as organ donors through entertainment-education programs in Korea. AB - This study is based on the theory of reasoned action and self-efficacy, and it examines the mediating role of attitude, subjective norm, and self-efficacy between parasocial interaction and the intention to donate organs. Judgment sampling was used and 329 respondents were participated in the survey. Participants consisted of 102 males (30.9%) and 227 females (69.1%), and their ages ranged from 13 to 77 years. The Cronbach's alpha for each scale was .81 for parasocial interaction scale (M = 3.01, SD = 0.55), .89 for attitude scale (M = 4.28, SD = 0.55), .89 for subjective norm (M = 4.28, SD = 0.55), and .76 for self efficacy (M = 3.31, SD = 0.89). The level of parasocial interaction was found to be significantly associated with attitude and subjective norms that predicted intention to register as organ donors. Although the mediating effect of self efficacy between parasocial interaction and intention has been proven, self efficacy showed a conflicting result in the process of model testing in that the level of parasocial interaction affected the degree of subjective norms, which in turn influenced intention by enhancing self-efficacy. The results indicate that parasocial interaction has an indirect effect on intention to register as organ donors through attitude and subjective norms. It is expected that this finding contributes to developing a number of strategies to encourage people's intention to register as organ donors. PMID- 23355053 TI - The quality of life and mortality risk of elderly people in rural China: the role of family support. AB - The number of elderly in China's population is projected to grow well beyond the capacity of the nation's social security system. Meanwhile, family care is being challenged by a decline in fertility and an increase in migration from rural to urban areas. This article examines the short-term, mid-term, and long-term effects of family support on elderly well-being in rural China, using 4-wave panel data on 1456 persons aged 60 and older in the Chaohu region of China. Findings showed that compared with living alone, being coresident with others lowered the mortality risk of several chronic diseases, but being coresident with adult children increased the mortality risk of cardiovascular diseases, though it was associated with a higher quality of life in the short and middle terms. Children's educational attainment and financial support increased the quality of life except for an increased risk of new incidence of cardiovascular disease in the middle term. PMID- 23355054 TI - The domestic environment and respiratory health of school children in Zongshan, China. AB - There have been many reports on the adverse impacts of exposures to particulate matter in the air but relatively few of these have been related to exposures to ultrafine particles (UFP) in the indoor environment. To investigate exposures to (UFP) in domestic environments, and the association with childhood respiratory symptoms in Zongshan, China a modified Thoracic Society questionnaire was completed by 359 households with children. Air quality monitoring took place in 37 households using a P-Trak instrument to determine concentration of UFPs in rooms. The mean number of UFP was 4.1 * 10(4) cm(-3). A range of factors was found to be associated with UFP concentration and self-reported childhood respiratory symptoms. In conclusion, the evidence suggests that behavioural and environmental factors contribute to increased UFP concentrations indoors although there was no statistically signification correlation between indoor ultrafine particle concentration and any reported repeated episodes of respiratory symptoms. PMID- 23355055 TI - Environmental secondhand smoke exposure and policy assessment at five venues in Zhejiang Province, China. AB - The objective of this study was to assess environmental secondhand smoke exposure and tobacco control policy at 5 venues. A cross-sectional study was conducted involving 134 settings and 2727 adults in Zhejiang, China. The results show that the proportions of venues that had complete smoking ban were as follows: health administrative organizations (71.9%), hospitals (70.0%), schools (66.7%), public transportation vehicles (24.0%), and government agencies (11.8%). The proportions of venues where smoking was noticed were as follows: public transportation vehicles (88.0%), government agencies (47.1%), hospitals (46.7%), health administrative organizations (40.6%), and schools (30.0%). Venues with completely indoor smoking ban were 5 times more likely to be smoke-free at the time of survey than other venues without smoking ban (odds ratio = 5.39, 95% confidence interval = 1.92-15.14). It indicated that implementation of indoor smoking ban can reduce indoor secondhand smoke exposure. PMID- 23355056 TI - Does absence matter?: a comparison of three types of father absence in rural Bangladesh. AB - This paper examines the effects of three different types of father absence on the timing of life history events among women in rural Bangladesh. Age at marriage and age at first birth are compared across women who experienced different father presence/absence conditions as children. Survival analyses show that daughters of fathers who divorced their mothers or deserted their families have consistently younger ages at marriage and first birth than other women. In contrast, daughters whose fathers were labor migrants have consistently older ages at marriage and first birth. Daughters whose fathers died when they were children show older ages at marriage and first birth than women with divorced/deserted fathers and women with fathers present. These effects may be mediated by high socioeconomic status and high levels of parental investment among the children of labor migrants, and a combination of low investment, high psychosocial stress, and low alloparental investment among women with divorced/deserted fathers. Our findings are most consistent with the Child Development Theory model of female life history strategies, though the Paternal Investment and Psychosocial Acceleration models also help explain differences between women in low paternal investment situations (e.g., father divorced/abandoned vs. father dead). Father absence in and of itself seems to have little effect on the life history strategies of Bangladeshi women once key reasons for or correlates of absence are controlled, and none of the models is a good predictor of why women with deceased fathers have delayed life histories compared with women whose fathers are present. PMID- 23355058 TI - Effects of exposure to a 50 Hz sinusoidal magnetic field during the early adolescent period on spatial memory in mice. AB - Adolescence is a critical developmental stage during which substantial remodeling occurs in brain areas involved in emotional and learning processes. Although a robust literature on the biological effects of extremely low frequency magnetic fields (ELF-MFs) has been documented, data on the effects of ELF-MF exposure during this period on cognitive functions remain scarce. In this study, early adolescent male mice were exposed from postnatal day (P) 23-35 to a 50 Hz MF at 2 mT for 60 min/day. On P36-45, the potential effects of the MF exposure on spatial memory performance were examined using the Y-maze and Morris water maze tasks. The results showed that the MF exposure did not affect Y-maze performance but improved spatial learning acquisition and memory retention in the water maze task under the present experimental conditions. PMID- 23355059 TI - The reversal of inhibitors in congenital hemophilia. AB - Hemophilias A and B are heritable bleeding disorders characterized by deficient baseline levels of factor VIII (fVIII) and factor IX (fIX), respectively. Standard treatment for acute bleeding events and for prophylaxis in patients with severe disease consists of recombinant fVIII and fIX infusions. The development of alloantibodies, or inhibitors, is a serious complication of congenital hemophilia that may impair the effectiveness of fVIII and fIX, leading to increased morbidity and cost of therapy. When inhibitors are present, bypassing agents such as recombinant activated factor VII and factor eight inhibitor bypass agent are available for treatment of bleeding events. Although usually effective, they are costly treatments. Immune-modulatory therapy may reverse inhibitors, allowing fVIII and fIX to be used again. Immune tolerance induction is the chief treatment option to decrease inhibitor levels, but about 20-30% of patients fail this treatment. Alternatively, multiple immune-modulating agents have been tried with limited success. Rituximab, an anti-CD20 monoclonal antibody, is one therapy that has been successful in reducing inhibitor titers in multiple case reports. Although current evidence is limited and questions regarding its use and place in therapy still exist, this agent shows promise for the future. PMID- 23355060 TI - Effect of oral digoxin in high-risk heart failure patients: a pre-specified subgroup analysis of the DIG trial. AB - AIMS: In the Digitalis Investigation Group (DIG) trial, digoxin reduced mortality or hospitalization due to heart failure (HF) in several pre-specified high-risk subgroups of HF patients, but data on protocol-specified 2-year outcomes were not presented. In the current study, we examined the effect of digoxin on HF death or HF hospitalization and all-cause death or all-cause hospitalization in high-risk subgroups during the protocol-specified 2 years of post-randomization follow-up. METHODS AND RESULTS: In the DIG trial, 6800 ambulatory patients with chronic HF, normal sinus rhythm, and LVEF <=45% (mean age 64 years, 26% women, 17% non whites) were randomized to receive digoxin or placebo. The three high-risk groups were defined as NYHA class III-IV symptoms (n = 2223), LVEF <25% (n = 2256), and cardiothoracic ratio (CTR) >55% (n = 2345). In all three high-risk subgroups, compared with patients in the placebo group, those in the digoxin group had a significant reduction in the risk of the 2-year composite endpoint of HF mortality or HF hospitalization: NYHA III-IV [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.57-0.75; P < 0.001], LVEF <25% (HR 0.61; 95% CI 0.53 0.71; P < 0.001), and CTR >55% (HR 0.65; 95% CI 0.57-0.75; P < 0.001). Digoxin associated HRs (95% CI) for 2-year all-cause mortality or all-cause hospitalization for subgroups with NYHA III-IV, LVEF <25%, and CTR >55% were 0.88 (0.80-0.97; P = 0.012), 0.84 (0.76-0.93; P = 0.001), and 0.85 (0.77-0.94; P = 0.002), respectively. CONCLUSIONS: Digoxin improves outcomes in chronic HF patients with NYHA class III-IV, LVEF <25%, or CTR >55%, and should be considered in these patients. PMID- 23355061 TI - Local effects of a global problem: modelling the risk of parasite-induced mortality in an intertidal trematode-amphipod system. AB - The interactive effects of climate change and parasitism are of concern because of potentially important consequences for host populations, communities and entire ecosystems. In marine environments, the absence of historic baseline data on parasitism and disease limits our ability to make realistic predictions about these consequences. Here, we adapt a simulation model developed for a Northern Hemisphere intertidal host-parasite system to a comparable system in the Southern Hemisphere. The entire life cycle of the intertidal trematode parasite Maritrema novaezealandensis was modelled in order to investigate the interactive effects of parasitic infections and increasing temperatures on the population dynamics of the amphipod host Paracalliope novizealandiae. Despite uncertainties associated with the model and its parameterisation, most temperature increases that were predicted to cause the collapse of the modelled amphipod population in the long term lay within the range of predicted warming for the study area. The high vulnerability of the amphipods in the modelled system illustrates a potentially important ecological mechanism by which consequences of a global problem might manifest on the local scale. PMID- 23355062 TI - L6 spinal nerve ligation produces prolonged development of mechanical allodynia and gradual increase of GFAP on ipsilateral dorsal horn. AB - BACKGROUND: L5/6 spinal nerve ligation (SNL), one of the most widely used approaches rat models for neuropathic pain, results in the rapid development of mechanical allodynia within 24-72 h. However, the result of a single L6 SNL remains unclear. METHODS: The first series of experiments were performed to examine the pain behavior of rats with different nerve ligations. Thirty-six rats were randomly assigned to four groups as follows: group I, controls (n = 6); group II, L5/6 nerve ligation (n = 6); group III, single L6 nerve ligation (n = 18); and group IV, the sham operation group (n = 6). The mechanical allodynia of rats was assessed using a 50 % paw withdrawal threshold (PWT), and tail antinociception was determined using the percentage of the maximal possible antinociceptive effect (% MPE). The second series of experiments were performed using Western blots to evaluate dorsal horn GFAP expression in different groups at different time points (D1, D7, D14, and D28). For this series of experiments, fifty-four rats were randomly divided into three groups: group I, controls (n = 6); group II, L5/6 nerve ligation (n = 24); and group III, L6 nerve ligation (n = 24). RESULTS: In this study, a single L6 SNL induced prolonged development (1-14 days) of mechanical allodynia and gradually increased expression of glial fibrillary acidic protein (GFAP) in the ipsilateral dorsal horn. Notably, once mechanical allodynia developed, both the severity of mechanical allodynia and the alteration of GFAP expression were similar regardless of the identity of the ligated nerve (L5/6 or L6 only). CONCLUSIONS: Single L6 SNL might be used as an effective model for researching the development period of neuropathic pain and is thus worth further investigation. PMID- 23355063 TI - Spontaneous resolution of Chiari I malformation and associated syringomyelia following parturition. PMID- 23355064 TI - Surgical treatment of hemifacial spasm with zone-4 offending vessel. AB - BACKGROUND: Increasing evidence shows that vascular compression on any of the four zones of facial nerve may cause hemifacial spasms. Vascular compression on zone 4 (the cisternal portion) of the nerve is quite common, but only a very small percentage of such compression will elicit hemifacial spasm, because zone 4 is less susceptible than zone 3 (the root exit zone). Therefore, it seems difficult for the neurosurgeons to distinguish the real culprit vessels in zone 4. Here, our experience in treating vascular compression located in zone 4 of the facial nerve is reported. METHODS: Twelve patients of HFS due to compression of zone 4 were treated with microvascular decompression (MVD) surgery with the aid of combined monitoring of abnormal muscle response (AMR) and Z-L response (ZLR). RESULTS: All of the 12 patients had a zone 4 compression. In addition, there were vascular compressions on zone 3 (the root exit zone) and/or zone 2 (the attached segment) in six cases. AMR was absent in two cases, unstable in one case, and persisted after vascular decompression in another one case. ZLR was stable before decompression of zone 4 and disappeared after decompression in all cases. After MVD surgery, 11 patients were cured and one patient achieved good resolution of spasm. One patient had postoperative transient tinnitus. CONCLUSIONS: The neurosurgeon should not ignore vascular compression at zone 4, especially when compressions at zones 2 and 3 co-exist. With the aid of AMR and ZLR, we are able to judge whether offending vessels exist at zone 4. PMID- 23355065 TI - Weight loss and regain in obese individuals: a link with adipose tissue metabolism indices? AB - This study was performed to examine whether changes in subcutaneous adipose tissue (SCAT) metabolism indices after weight loss were related to the magnitude of weight regain. Nine men and ten premenopausal women whose body mass index ranged from 30 to 42 kg/m(2), 35-48 years old, were studied before and after a 15 week weight loss program, as well as at a 17-22-month follow-up period. Although body composition was evaluated at all study periods, abdominal and femoral SCAT lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) activities, and alpha2- and beta-adrenoceptors (ARs) were measured before and after weight loss, exclusively. Although the SCAT-LPL activity did not change after weight loss in men, it tended to decrease in the femoral depot of women (p = 0.06). SCAT-HSL activity remained unchanged after weight reduction in men, while the post-weight loss lipase activity tended to be higher in both regions of women (p = 0.06). Although the post-weight loss number of beta-ARs was higher irrespective of the fat depot (0.001 < p < 0.05), the number of alpha2-ARs was increased in the femoral (p < 0.05), but not in the abdominal SCAT (p = 0.08) after weight reduction, in men. Neither the alpha2- nor the beta-AR density changed after weight reduction, in women. Abdominal SCAT-LPL activity after weight reduction was negatively related to weight regain indices, in women (-0.65 < Rho < -0.75; 0.01 < p < 0.05). Both the post-weight loss abdominal SCAT alpha2-AR density and the alpha2-/beta-AR balance were positively associated with weight regain indices, in men (0.69 < Rho < 0.88; 0.01 < p < 0.05). These results suggest that selected SCAT metabolism indices could predict failure to weight loss maintenance, in both genders. PMID- 23355066 TI - Influence of secreted factors from human adipose tissue on glucose utilization and proinflammatory reaction. AB - The objective of the present study was to characterize the nature of the autocrine/paracrine signal within human adipose tissue that may alter glucose metabolism and the inflammatory status in adipocytes. We prepared a conditioned medium from abdominal dermolipectomies in the absence (CM) or the presence (CMBSA) of bovine serum albumin (BSA), and we tested the influence of CM and CMBSA on glucose transport, maximal insulin response, and the expression of inflammation marker genes in differentiated human SGBS adipocytes. We found that CMBSA increased basal and reduced insulin-stimulated glucose incorporation along with a reduced mRNA level of the glucose transport GLUT4, and an increased expression of GLUT1. These effects were associated with a potent upregulation in the mRNA level of the proinflammatory cytokines IL-6 and MCP-1. These regulations were strongly attenuated in the absence of BSA during the preparation of CM, or after BSA depletion of CM, and were attributed to water-soluble molecules rather than lipids. Finally, fractionation of CMBSA by isoelectric focusing showed that part of its bioactivity could be reproduced with proteins with pHi ranging from 6.6 to 7.6. In conclusion, our results demonstrate that the production by human adipose tissue of autocrine/paracrine neutral proteins is able to increase the inflammatory status of the adipocytes and to deteriorate their glucose metabolism and maximal insulin response, and their release is greatly amplified by the presence of albumin. PMID- 23355067 TI - Blood plasma separation in elevated dimension T-shaped microchannel. AB - In recent years, microfluidic chips have proven ideal tools for biochemical analysis, which, however, demands a unique and compatible plasma separation scheme. Various research groups have established continuous flow separation methods in microfluidic devices; however, they have worked with relatively small dimension microchannels (similar to the blood cell diameter). The present work demonstrates separation of plasma by utilizing the hydrodynamic separation techniques in microchannels with size of the order of mm. The separation process exploits the phenomenon, which is very similar to that of plasma skimming explained under Zweifach-Fung bifurcation law. The present experiments demonstrates for, the first time, that applicability of the Zweifach-Fung bifurcation law can be extended to dimensions much higher than the suspended particle size. The T-microchannel device (comprising perpendicularly connected blood and plasma channels) were micro-fabricated using conventional PDMS micro molding techniques. Three variables (feed hematocrit, main channel width, and flow rate distributions) were identified as the important parameters which define the device's efficiency for the blood plasma separation. A plasma separation efficiency of 99.7 % was achieved at a high flow ratio. Novel concepts of 2-stage or multiple plasma channel designs are also proposed to yield high separation efficiency with undiluted blood. The possible underlying principle causing plasma separation (viz. aggregation and shear thinning) are investigated in detail as part of this work. The results are significant because they show nearly 100 % separations in microchannels which are much easier to fabricate than previously designed devices. PMID- 23355068 TI - Microfluidic fabrication of cell adhesive chitosan microtubes. AB - Chitosan has been used as a scaffolding material in tissue engineering due to its mechanical properties and biocompatibility. With increased appreciation of the effect of micro- and nanoscale environments on cellular behavior, there is increased emphasis on generating microfabricated chitosan structures. Here we employed a microfluidic coaxial flow-focusing system to generate cell adhesive chitosan microtubes of controlled sizes by modifying the flow rates of a chitosan pre-polymer solution and phosphate buffered saline (PBS). The microtubes were extruded from a glass capillary with a 300 MUm inner diameter. After ionic crosslinking with sodium tripolyphosphate (TPP), fabricated microtubes had inner and outer diameter ranges of 70-150 MUm and 120-185 MUm. Computational simulation validated the controlled size of microtubes and cell attachment. To enhance cell adhesiveness on the microtubes, we mixed gelatin with the chitosan pre-polymer solution. During the fabrication of microtubes, fibroblasts suspended in core PBS flow adhered to the inner surface of chitosan-gelatin microtubes. To achieve physiological pH values, we adjusted pH values of chiotsan pre-polymer solution and TPP. In particular, we were able to improve cell viability to 92 % with pH values of 5.8 and 7.4 for chitosan and TPP solution respectively. Cell culturing for three days showed that the addition of the gelatin enhanced cell spreading and proliferation inside the chitosan-gelatin microtubes. The microfluidic fabrication method for ionically crosslinked chitosan microtubes at physiological pH can be compatible with a variety of cells and used as a versatile platform for microengineered tissue engineering. PMID- 23355069 TI - Bio-inspired band-gap tunable elastic optical multilayer fibers. AB - The concentrically-layered photonic structure found in the tropical fruit Margaritaria nobilis serves as inspiration for photonic fibers with mechanically tunable band-gap. The fibers show the spectral filtering capabilities of a planar Bragg stack while the microscopic curvature decreases the strong directional chromaticity associated with flat multilayers. Elongation of the elastic fibers results in a shift of the reflection of over 200 nm. PMID- 23355070 TI - Short communication: isolation and phylogenetic analysis of an avian-origin H3N2 canine influenza virus in dog shelter, China. AB - A H3N2 canine influenza virus, A/canine/Guangdong/3/2011 (H3N2), was isolated from roaming dogs in rural China. Sequence and phylogenetic analysis of eight gene segments revealed that the A/canine/Guangdong/3/2011 (H3N2) was most similar to a recent H3N2 canine influenza virus isolated in cats from South Korea, which originated from an avian strain. To our knowledge, this is the first report of an avian-origin H3N2 CIV which was isolated from roaming dogs in China. The epidemiologic information provided herein suggests that continued study is required to determine if this virus could be established in the roaming dog population in rural China and pose potential threats to public health. PMID- 23355071 TI - Interfacial interactions involved in the biological assembly of Chandipura virus nucleocapsid protein. AB - The biological assembly of Chandipura virus nucleocapsid (N) protein has been modeled and the amino acid residues involved in specific intermolecular interactions among N monomers during oligomerisation have been predicted. PMID- 23355072 TI - Analysis of a QX-like avian infectious bronchitis virus genome identified recombination in the region containing the ORF 5a, ORF 5b, and nucleocapsid protein gene sequences. AB - The complete genome of a QX-like infectious bronchitis virus (IBV) strain Sczy3 isolated recently in Sichuan was sequenced. The genome contains 27,695 nucleotides (nt), and possesses a genomic structure similar to other IBV strains. Sequence comparisons demonstrated that the Sczy3 genome had the highest nt sequence identity with QX-like IBVs and was most dissimilar to the Massachusetts type IBV. Differences in the sequences of genes present in the Sczy3 genome and other IBVs gene sequences were also identified. Phylogenic analysis showed that the entire genome and most of the Sczy3 genes were located in the same cluster as LX4. Recombination analysis showed that Sczy3 is a chimeric strain derived from LX4 (major parental sequence) and H120 (minor parental sequence) suggesting that recombination occurred in a region containing the 3' terminal 5a sequence (83 nt), the 5' terminal 5b sequence (222 nt), and the 5' terminal nucleocapsid protein gene sequence (132 nt). Mutations and intergenic recombination may have played an important role in the evolution of IBVs. PMID- 23355073 TI - Metallothionein 1 h tumour suppressor activity in prostate cancer is mediated by euchromatin methyltransferase 1. AB - Metallothioneins (MTs) are a group of metal binding proteins thought to play a role in the detoxification of heavy metals. Here we showed by microarray and validation analyses that MT1h, a member of MT, is down-regulated in many human malignancies. Low expression of MT1h was associated with poor clinical outcomes in both prostate and liver cancer. We found that the promoter region of MT1h was hypermethylated in cancer and that demethylation of the MT1h promoter reversed the suppression of MT1h expression. Forced expression of MT1h induced cell growth arrest, suppressed colony formation, retarded migration, and reduced invasion. SCID mice with tumour xenografts with inducible MT1h expression had lower tumour volumes as well as fewer metastases and deaths than uninduced controls. MT1h was found to interact with euchromatin histone methyltransferase 1 (EHMT1) and enhanced its methyltransferase activity on histone 3. Knocking down of EHMT1 or a mutation in MT1h that abrogates its interaction with EHMT1 abrogated MT1h tumour suppressor activity. This demonstrates tumour suppressor activity in a heavy metal binding protein that is dependent on activation of histone methylation. PMID- 23355074 TI - Non-syndromic sensorineural prelingual deafness: the importance of genetic counseling in demystifying parents' beliefs about the cause of their children's deafness. AB - Recent advances in molecular genetics have allowed the determination of the genetic cause of some childhood non-syndromic deafness. In Portugal only a small proportion of families are referred to a clinical genetics service in order to clarify the etiology of the deafness and to provide genetic counseling. Consequently, there are no published studies of the prior beliefs of parents about the causes of hereditary deafness of their children and their genetic knowledge after receipt of genetic counseling. In order to evaluate the impact of genetic counseling, 44 parents of 24 children with the diagnosis of non-syndromic sensorineural prelingual deafness due to mutations in the GJB2 (connexin 26), completed surveys before and after genetic counseling. Before counseling 13.6 % of the parents knew the cause of deafness; at a post-counseling setting this percentage was significantly higher, with 84.1 % of the parents accurately identifying the etiology. No significant differences were found between the answers of mothers and fathers either before or after genetic counseling. Parents' level of education was a significant factor in pre-test knowledge. After genetic counseling 95.5 % of the parents stated that the consultation had met their expectations, 70.5 % remembered correctly the inheritance pattern, and 93.2 % correctly recalled the chance of risk of deafness. These results underline the importance of genetic counseling in demystifying parents' beliefs about the etiology of their children's deafness. PMID- 23355075 TI - Genetic counseling training and certification in Australasia. AB - The development of standards for training and certification is essential to the credibility and integrity of a developing profession. Training and certification of genetic counselors in Australasia has undergone a detailed review during the past few years, resulting in changes to the way certification is obtained. This paper presents an overview of the process of developing a robust training and certification program which reflects the social and cultural environment of genetic counselors working in Australasia. A brief history of the development of the profession in Australasia is provided, followed by a detailed discussion of the recent development of Masters programs and a portfolio of work required for certification. The importance of consultation within the profession and with our colleagues in the field of human genetics is considered, and we provide a discussion of defining moments that occurred during the review. This paper is intended to provide a detailed description of genetic counselor training and certification in Australasia. We anticipate that our insights into the process of redevelopment of training and certification guidelines may be helpful for genetic counselors working in countries where certification requirements are being developed. PMID- 23355076 TI - Adjuvant therapy in gastric cancer: what is the optimal approach? AB - Gastric cancer confers a poor prognosis even when diagnosed as localized disease. Multimodality therapy improves the cure rate of patients with localized cancer. However, adjunctive therapeutic approaches differ in different regions of the world. This review focuses on the current standards and unresolved issues based on updated literature on therapy for localized gastric cancer. In the USA, the Intergroup 0116 trial established the use of postoperative chemoradiotherapy as a standard for patients who have surgery first for treatment of gastric cancer. In Europe, the MAGIC trial investigating perioperative chemotherapy demonstrated a survival benefit for gastric cancer patients. Finally, in Asia, the ACTS-GC and CLASSIC trials investigating postoperative chemotherapy established this as the standard of care after primary surgery that included D2 dissection. It is clear, however, that surgery alone is insufficient to achieve the highest possible cure rates. PMID- 23355077 TI - The characterisation and determinants of quality of life in ANCA associated vasculitis. AB - OBJECTIVES: To contextualise and identify the determinants of poor health related quality of life (QOL) among patients with antineutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV). METHODS: A multicentre AAV case-control study was conducted using two matched groups of population and chronic disease controls. Measures of physical and mental QOL as well as putative bio psychosocial determinants of QOL impairment were collected. Concurrently, putative clinical QOL determinants were recorded. Conditional logistic regression analyses characterised group differences while multivariable logistic regression identified within-case QOL associations which were further quantified using population attributable risks (PAR). RESULTS: Cases (n=410) experienced similar QOL to chronic disease controls (n=318) (physical QOL: OR 0.7, 95% CI 0.4 to 1.1; mental QOL: OR 1.1, 95% CI 0.8 to 1.6). However, they were substantially more likely to report poor QOL compared to general population controls (n=470) (physical QOL: OR 7.0, 95% CI 4.4 to 11.1; mental QOL: OR 2.5, 95% CI 1.7 to 3.6). A few clinical, but many more bio-psychosocial factors were independently associated with poor QOL. In population terms, fatigue was found to be of principal importance (physical QOL: PAR 24.6%; mental QOL: PAR 47.4%). CONCLUSIONS: AAV patients experienced significant QOL impairment compared to the general population, but similar to those with other chronic diseases whose considerable needs are already recognised. Potentially modifiable clinical determinants have been identified; however bio-psychosocial interventions are likely to provide the greater QOL gains in this patient population. PMID- 23355078 TI - Early psoriatic arthritis: short symptom duration, male gender and preserved physical functioning at presentation predict favourable outcome at 5-year follow up. Results from the Swedish Early Psoriatic Arthritis Register (SwePsA). AB - OBJECTIVE: The Swedish Early Psoriatic Arthritis Register describes the course of early psoriatic arthritis (PsA) in a real life clinical setting in Sweden. The aim of this study was to obtain information on predictors of clinical outcomes over a 5-year period with special focus on effects of gender, joint patterns, diagnostic delay and initial disease activity. METHODS: In six centres, patients with signs suggestive of PsA were included in the Swedish Early Psoriatic Arthritis Register within 2 years of symptom onset. CASPAR (classification for psoriatic arthritis) criteria were fulfilled by 197 patients who had passed the 5 year follow-up. Disease activity was measured by the Disease Activity Score including 28 joints (DAS28) and the Disease Activity Index for Psoriatic Arthritis (DAPSA). Remission and minimal disease activity (MDA) were used as outcome measures. RESULTS: Mean age at inclusion was 46 years, younger in male than female patients (43 vs 48 years). Mean DAS28 was 3.7 and 3.0 at inclusion and 2.8 and 2.1 at follow-up for women and men, respectively-significantly higher in women at both visits. Likewise, DAPSA scores were significantly higher in women. The degree of improvement (change in DAS28 and DAPSA) was similar. Men achieved MDA or remission (50% vs 33%, 25% vs 13%, respectively) more often, and women had significantly more polyarthritis at inclusion (49% vs 27%) and after 5 years (25% vs 15%). Axial or mono/oligoarticular disease was predominant in men. Independent predictors of MDA at the 5-year follow-up were: shorter symptom duration; greater general well-being (global visual analogue scale); and low Health Assessment Questionnaire at inclusion. CONCLUSIONS: In early PsA, short delay between onset of symptoms and diagnosis, preserved function, and male gender are the most important predictors of favourable clinical outcome at the 5 year follow-up. Early recognition of PsA and active treatment may be important, particularly in women with polyarticular disease. PMID- 23355079 TI - Effect of tumour necrosis factor blockers on radiographic progression of psoriatic arthritis: a systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVES: We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) of psoriatic arthritis (PsA) to examine the effect of tumour necrosis factor (TNF) blockers on radiographic progression, and to determine whether treatment combining TNF blocker with methotrexate (MTX) was superior to TNF-blocker monotherapy. METHODS: We systematically reviewed articles published up to December 2012 in Embase and Medline, and from the two last EUropean League Against Rheumatism (EULAR) and American College or Rheumatology (ACR) meetings. The primary endpoint was the proportion of patients with no radiographic progression (non-progressors) at treatment week 24 (defined by change in modified total Sharp score (mTSS) <=0.5). The Mantel-Haenszel method was used to estimate ORs and 95% CIs of the effect of TNF blockers (with or without MTX) versus placebo (with or without MTX). Statistical heterogeneity was assessed by chi2 test. RESULTS: The search retrieved 207 articles; 5 (1110 patients) met the meta-analysis criteria. For patients receiving TNF blockers, 494/584 (84.5%) were considered non-progressors at treatment week 24 vs 362/526 (68.8%) receiving placebo (OR 2.68 (95% CI 1.99 to 3.60) p<0.001), without significant heterogeneity (I(2)=3%; p=0.39). Only three RCTs provided data on potential additional efficacy of MTX: two did not find significant difference, one suggested a benefit of combined therapy. CONCLUSIONS: For patients with PsA, control of structural damage is better at week 24 with TNF blockers than placebo. Due to the limited data, we were unable to conclude on the potential additional effect of MTX on structural damages. PMID- 23355080 TI - Characterisation of a novel Bacillus sp. SJ-10 beta-1,3-1,4-glucanase isolated from jeotgal, a traditional Korean fermented fish. AB - A novel beta-1,3-1,4-glucanase gene was identified in Bacillus sp. SJ-10 (KCCM 90078) isolated from jeotgal, a traditional Korean fermented fish. We analysed the beta-1,3-1,4-glucanase gene sequence and examined the recombinant enzyme. The open reading frame of the gene encoded 244 amino acids. The sequence was not identical to any beta-glucanases deposited in GenBank. The gene was cloned into pET22b(+) and expressed in Escherichia coli BL21. Purification of recombinant beta-1,3-1,4-glucanase was conducted by affinity chromatography using a Ni-NTA column. Enzyme specificity of beta-1,3-1,4-glucanase was confirmed based on substrate specificity. The optimal temperature and pH of the purified enzyme towards barley beta-glucan were 50 degrees C and pH 6, respectively. More than 80 % of activity was retained at temperatures of 30-70 degrees C and pH values of 4-9, which differed from all other bacterial beta-1,3-1,4-glucanases. The degradation products of barley beta-glucan by beta-1,3-1,4-glucanase were analysed using thin-layer chromatography, and ultimately glucose was produced by treatment with cellobiase. PMID- 23355081 TI - Comparative survival analysis of 12 histidine kinase mutants of Deinococcus radiodurans after exposure to DNA-damaging agents. AB - Bacteria are able to adapt to changes in the environment using two-component signal transduction systems (TCSs) composed of a histidine kinase (HK) and a response regulator (RR). Deinococcus radiodurans, one of the most resistant organisms to ionizing radiation, has 20 putative HKs and 25 putative RRs. In this study, we constructed 12 D. radiodurans mutant strains lacking a gene encoding a HK and surveyed their resistance to gamma-radiation, UV-B radiation (302 nm), mitomycin C (MMC), and H(2)O(2). Five (dr0860 (-), dr1174 (-), dr1556 (-), dr2244 (-), and dr2419 (-)) of the 12 mutant strains showed at least a one-log cycle reduction in gamma-radiation resistance. The mutations (1) dr1174, dr1227, and dr2244 and (2) dr0860, dr2416, and dr2419 caused decreases in resistance to UV radiation and MMC, respectively. Only the dr2416 and dr2419 mutant strains showed higher sensitivity to H(2)O(2) than the wild-type. Reductions in the resistance to gamma-radiation and H(2)O(2), but not to UV and MMC, were observed in the absence of DR2415, which seems to be a cognate RR of DR2416. This result suggests that DR2415/DR2416 (DrtR/S: DNA damage response TCS) may be another TCS responsible for the extreme resistance of D. radiodurans to DNA-damaging agents. PMID- 23355082 TI - Development of an albuminous reactive oxygen species assay for photosafety evaluation under experimental biomimetic conditions. AB - The generation of reactive oxygen species (ROS) from an ultraviolet (UV)-exposed chemical can be an experimental indicator of phototoxic potential. The aim of the present study was to develop a new ROS assay using serum albumin to provide photosafety assessment under experimental biomimetic conditions. To assess assay robustness, a validation study on an albuminous ROS (aROS) assay was conducted with a focus on intra- and inter-day precisions and Z'-factor reflecting both the assay signal-to-noise ratio and variation associated with signal measurements. In the aROS assay on quinine HCl (200 MUM), a typical phototoxic drug, both intra- and inter-day precisions (coefficient of variation; CV) were found to be below 4%, and the Z'-factors for singlet oxygen and superoxide suggested a large separation band between samples and blank signals. To evaluate the prediction capacity, the aROS and ROS assays were applied to 21 phototoxins and 10 non phototoxic chemicals. Upon aROS assay on these model chemicals, the individual specificity was 100%, and the positive and negative predictivities were found to be 100% and 81.8%, respectively. The aROS assay can be employed for poorly soluble chemicals for which the ROS assay is unavailable. Comparing the ROS assay data, there seemed to be a photochemical transition of some chemicals in albuminous solution. A molecular interaction between albumin and chemical was also assessed by UV and fluorescent spectroscopic analyses, and the results suggested the limited relationship between the albumin-chemical interaction and the photochemical change. The aROS assay may allow photosafety assessment of new drug entities with a wide range of applicability partly under experimental biomimetic conditions. PMID- 23355083 TI - Bronchial responsiveness to dry air hyperventilation in smokers may predict decline in airway status using indirect methods. AB - BACKGROUND: Disabling respiratory symptoms and rapid decline of lung function may occur in susceptible tobacco smokers. Bronchial hyperresponsiveness (BHR) elicited by direct challenge methods predicts worse lung function outcomes. The aim of this study was to evaluate whether BHR to isocapnic hyperventilation of dry air (IHDA) was associated with rapid deterioration in airway status and respiratory symptoms. METHODS: One hundred twenty-eight smokers and 26 age- and sex-matched healthy individuals with no history of smoking were investigated. All subjects completed a questionnaire. Spirometry and impulse oscillometry (IOS) measurements were recorded before and after 4 min of IHDA. The tests were repeated after 3 years in 102 smokers and 11 controls. RESULTS: Eighty-five smokers (66 %) responded to the challenge with a >=2.4-Hz increase in resonant frequency (F res), the cutoff limit defining BHR, as recorded by IOS. They had higher F res at baseline compared to nonresponding smokers [12.8 +/- 3.2 vs. 11.5 +/- 3.4 Hz (p < 0.05)] and lower FEV1 [83 +/- 13 vs. 89 +/- 13 % predicted (p < 0.05)]. Multivariable logistic regression analysis indicated that wheezing (odds ratio = 3.7, p < 0.01) and coughing (odds ratio = 8.1, p < 0.05) were significantly associated with hyperresponsiveness. An increase in F res was recorded after 3 years in responding smokers but not in nonresponders or controls. The difference remained when subjects with COPD were excluded. CONCLUSIONS: The proportion of hyperresponsive smokers was unexpectedly high and there was a close association between wheezing and coughing and BHR. Only BHR could discriminate smokers with rapid deterioration of airway status from others. PMID- 23355084 TI - Tumor necrosis factor-alpha plays an initiating role in extracorporeal circulation-induced acute lung injury. AB - BACKGROUND: Despite advances in critical care, the mortality rate for patients with acute lung injury (ALI) remains high. The aim of this study was to test the hypothesis that tumor necrosis factor-alpha (TNF-alpha) plays an initiating role in the onset of extracorporeal circulation (ECC)-induced ALI. METHODS: Eight New Zealand rabbits subjected to 1 h of ECC and 40 min of observation after termination of ECC were used for monitoring pulmonary nociceptor activity. Fifty Sprague-Dawley (SD) rats that received 2 h of ECC and 4 h of rest were used to measure the pulmonary function and inflammatory cytokines release, including total cells, neutrophils, and TNF-alpha in bronchoalveolar lavage (BAL) and white blood cell (WBC) and neutrophils in blood. An additional 40 SD rats were randomized to pretreatment with inhalation of phosphate buffer solution (control group), IgG (IgG inh group), or TNF-alpha antibody (anti-TNF-alpha inh group) and venous injection of TNF-alpha antibody (anti-TNF-alpha iv group). After 2 h of ECC and 4 h of rest, the arterial blood and BAL fluid were collected for measurement of arterial oxygen pressure (PaO2) and inflammatory cytokines release. The left-lower-lung tissues of animals were stained with hematoxylin & eosin (H&E). RESULTS: The results demonstrated that the activities of airway nociceptor and TNF-alpha release were similarly upregulated at the early stage and in a time-related manner in ECC-induced ALI. Pretreatment with TNF-alpha antibody inhalation, but not venous injection, improved pulmonary function, inhibited pulmonary inflammation, and attenuated pulmonary histopathological changes after ECC. CONCLUSION: We concluded that TNF-alpha played an important role in the pathogenesis of ALI and acted as an initiating cytokine at the early stage of ECC-induced ALI. PMID- 23355085 TI - Decoupling cell and matrix mechanics in engineered microtissues using magnetically actuated microcantilevers. AB - A novel bio-magnetomechanical microtissue system is described for magnetic actuation of arrays of 3D microtissues using microcantilevers. This system enables both in situ measurements of fundamental mechanical properties of engineered tissue, such as contractility and stiffness, as well as dynamic stimulation of the microtissues. Using this system, cell and extracellular matrix contributions to the tissue mechanical properties are decoupled for the first time under both static and dynamic loading conditions. PMID- 23355086 TI - Adverse postoperative outcomes in surgical patients with immune thrombocytopenia. AB - BACKGROUND: Patients with immune thrombocytopenia (ITP) are likely to have various medical co-morbidities, yet their global features regarding adverse postoperative outcomes and use of medical resources when undergoing major surgery are unknown. The objective of this study was to validate whether ITP is an independent risk factor for adverse postoperative outcomes, and to explore the potential clinical predictors of outcomes after major surgery among patients with ITP. METHODS: A retrospective population-based cohort study was conducted using Taiwan's National Health Insurance Research Database, controlling for preoperative co-morbidities by means of multiple logistic regression. Major postoperative complication and mortality rates, and in-hospital medical costs were analysed. RESULTS: The study included 11,085 surgical patients with ITP and 44,340 controls without ITP matched for sex, age, and type of surgery and anaesthesia. Surgical patients with ITP had a higher risk of postoperative death (odds ratio (OR) 1.89, 95 per cent confidence interval 1.57 to 2.27), and overall postoperative complications (OR 1.47, 1.39 to 1.56), and increased hospital stay (OR 1.90, 1.80 to 2.01), admission to the intensive care unit (OR 1.73, 1.63 to 1.83) and medical costs (OR 1.89, 1.79 to 1.99). Amount of preoperative platelet and/or red blood cell transfusion, emergency visits and admission to hospital for ITP care were identified as risk factors for adverse postoperative outcomes. CONCLUSION: Patients with ITP undergoing surgery are at increased risk of adverse perioperative events, particularly if blood or blood product transfusion are required preoperatively, or the procedure is done as an emergency. PMID- 23355087 TI - 3-Methylglutaconic aciduria--lessons from 50 genes and 977 patients. AB - Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3 methylglutaconic aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic aciduria (e.g. organic acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11% presented 3-methylglutaconic aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3 methylglutaconic aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature. PMID- 23355088 TI - Structural white matter changes in adolescents and young adults with maple syrup urine disease. AB - OBJECTIVE: To get insight into the nature of magnetic resonance (MR) white matter abnormalities of patients with classic maple syrup urine disease (MSUD) under diet control. METHODS: Ten patients with classic MSUD and one with a severe MSUD variant (mean age 21.5 +/- 5.1 years) on diet and 11 age and sex-matched healthy subjects were enrolled. Apart from standard MR sequences, diffusion weighted images (DWI), diffusion tensor images (DTI), and magnetization transfer images (MT) were obtained and comparatively analyzed for apparent diffusion coefficient (ADC), tensor fractional anisotropy (FA) and MT maps in 11 regions of interest (ROI) within the white matter. RESULTS: In MSUD patients DWI, DTI and FA showed distinct signal changes in the cerebral hemispheres, the dorsal limb of internal capsule, the brain stem and the central cerebellum. Signal intensity was increased in DWI with a reduced ADC and decreased values for FA. MT did not reveal differences between patients and control subjects. CONCLUSION: Signal abnormalities in the white matter of adolescents and young adults under diet control may be interpreted as consequence of structural alterations like dysmyelination. The reduced ADC and FA in the white matter with preserved MT indicate a reduction in fiber tracks. PMID- 23355090 TI - Fatigue assessment of Parkinson's disease patient in clinic: specific versus holistic. AB - Fatigue is a frequently encountered non-motor symptom in Parkinson's disease (PD). Being a subjective definition, with no biological markers, it is difficult to describe. Its definition is influenced by the background and culture of the patient. Subtypes of fatigue are peripheral fatigue and mental fatigue. The co existence of other non-motor symptoms in PD complicates its assessment. Fatigue could be present before, at the time of diagnosis of PD in untreated patients or during the course of the disease. Scales that can be used for evaluation include generic one for a holistic manner and those specifically designed for PD. A scale designed for fatigue should differentiate between PD patients with fatigue and those without fatigue. The next step is to choose between unidimensional which evaluate one dimension and multidimensional scales. We present the main scales which can be used for fatigue assessment and their properties. The scales are presented with some psychometric properties in non-PD population and those properties through validation in PD population. Scales have some properties which could be recommended for screening and/or rating of severity of fatigue in PD. PMID- 23355091 TI - Characterization of void space in polydisperse sphere packings: Applications to hard-sphere packings and to protein structure analysis. AB - The implementation of a method for the exact evaluation of the volume and surface area of cavities and free volumes in polydisperse sphere packings is described. The generalization of an algorithm for Voronoi tessellation by Tanemura et al. is presented, employing the radical plane construction, as a part of the method. We employ this method to calculate the equation of state for monodisperse and polydisperse hard-sphere fluids, crystals, and for the metastable amorphous branch up to random close packing or jamming densities. We compute the distribution of free volumes, and compare with previous results employing a heuristic definition of free volume. We show the efficacy of the method for analyzing protein structure, by computing various quantities such as the distribution of sizes of buried cavities and pockets, the scaling of solvent accessible area to the corresponding occupied volume, the composition of residues lining cavities, etc. PMID- 23355092 TI - Thermodynamic anomalies of a network former in a periodic field: Network former in a periodic field. AB - We study the effect of an external one-dimensional periodic field on thermodynamic anomalies associated with a two-dimensional model liquid with anisotropic interactions. The model system, a 50 : 50 binary mixture of two species of particles interacting with an angle-dependent Lennard-Jones potential, has a rich phase diagram and shows many features of network-forming liquids like water and silica such as a prominent minimum in the pressure-temperature isochore. Confining the system by a commensurate one-dimensional periodic field shifts the temperature of minimum pressure to higher temperatures. A mean-field theory of a lattice-gas in an external field which couples to internal orientational states reproduces these results. PMID- 23355093 TI - The origin of granular convection in vertically vibrated particle beds: The differential shear flow field. AB - This paper investigates the particle scale dynamics of granular convection in vertically vibrated granular beds. The onset of the convection is found to coincide with the noticeable particle transverse migrations from the side walls towards the centre of the bed, which only take place in the wake of the gravity wave front dividing the upward moving particles and the falling ones. The mechanism driving the particle inward flows and thus sustaining the complete convection rolls can be understood in light of a convection model based on void penetration. This stochastic convection model reveals that the underlying driving force is a distinctive differential shear flow field arising from the combined effect of frictional holdback by the walls and the downward pull of gravity. The changes of the convection pattern with inceasing acceleration amplitude, in terms of the convection strength and the thickness of the bottom of the convection rolls, can be accounted for by this model. PMID- 23355089 TI - Organic bases of late-life depression: a critical update. AB - Late-life depression (LLD) is frequently associated with cognitive impairment and increases the risk of subsequent dementia. Cerebrovascular disease, deep white matter lesions, Alzheimer disease (AD) and dementia with Lewy bodies (DLB) have all been hypothesized to contribute to this increased risk, and a host of studies have looked at the interplay between cerebrovascular disease and LLD. This has resulted in new concepts of LLD, such as "vascular depression", but despite multiple magnetic resonance imaging (MRI) studies in this field, the relationship between structural changes in human brain and LLD is still controversial. While pathological findings of suicide in some elderly persons revealed multiple lacunes, small vessel cerebrovascular disease, AD-related lesions or multiple neurodegenerative pathologies, recent autopsy data challenged the role of subcortical lacunes and white matter lesions as major morphological substrates of depressive symptoms as well as poorer executive function and memory. Several neuropathological studies, including a personal clinico-pathological study in a small cohort of elderly persons with LLD and age-matched controls confirmed that lacunes, periventricular and deep white matter demyelination as well as AD related lesions are usually unrelated to the occurrence of LLD. In the same line, neuropathological data show that early-onset depression is not associated with an acceleration of age-related neurodegenerative changes. Very recent data on the critical role of glia-modulating neuronal dysfunction and degeneration in depression are discussed. PMID- 23355094 TI - Relaxation of non-equilibrium entanglement networks in thin polymer films. AB - It is known that polymer films, prepared by spin coating, inherit non-equilibrium configurations which can affect macroscopic film properties. Here we present the results of crazing experiments that support this claim; our measurements indicate that the as-cast chain configurations are strongly stretched as compared to equilibrium Gaussian configurations. The results of our experiments also demonstrate that the entanglement network equilibrates on a time scale comparable to one reptation time. Having established that films can be prepared with an equilibrium entanglement network, we proceed by confining polymers to films in which the thickness is comparable to the molecular size. By stacking two such films, a bilayer is created with a buried entropic interface. Such an interface has no enthalpic cost, only an entropic penalty associated with the restricted configurations of molecules that cannot cross the mid-plane of the bilayer. In the melt, the entropic interface heals as chains from the two layers mix and entangle with one another; crazing measurements allow us to probe the dynamics of two films becoming one. Healing of the entropic interface is found to take less than one bulk reptation time. PMID- 23355095 TI - Assessment of exposure to organochlorine pesticides and levels of DNA damage in mother-infant pairs of an agrarian community. AB - Exposure to organochlorine pesticides was studied in a group of mother-infant pairs living in a rural area where agriculture is the main economic activity. Fumigation in this zone is performed with airplanes, thus affecting the inhabited areas around them, including schools. Heparinized venous blood of mothers and umbilical cords was used to evaluate the olive tail moment in the comet assay, and micronuclei, chromatin buds, and nucleoplasmic bridges in peripheral blood lymphocytes. Cord blood samples were taken at the moment of birth only from natural and normal parturitions. Determinations of hexachlorobenzene, aldrin, heptachlor epoxide, oxichlordane, t and c-chlordane, cis-nonachlor, mirex, alpha and beta-endosulfan, alpha, beta and gamma hexachlorocyclohexane, and p'p'-DDT, p'p'-DDE were conducted to establish the differential distribution of the toxicants between compartments, i.e., mother and umbilical cord. Significantly higher pesticide levels were found in umbilical cord plasma than in mothers' plasma for almost all compounds tested, except DDE and oxychlordane. Significantly higher olive tail moments were found in umbilical cords than in mothers, whereas micronuclei frequencies were higher in mothers than in umbilical cords. However, neither the levels of micronuclei nor the olive tail moment were correlated with pesticide levels. Given that no other exposure to toxic compounds has been identified in this region, the lack of correlation between genotoxicity biomarkers and pesticide levels may be due to the variability of the exposure and to endogenous processes related to lipid mobility during pregnancy, the metabolism of the compounds, and individual susceptibilities. PMID- 23355096 TI - Religion as dialogical resource: a socio-cultural approach. AB - William James proposed a psychological study of religion examining people's religious experiences, and to see in what sense these were good for them. The recent developments of psychology of religion moved far from that initial proposition. In this paper, we propose a sociocultural perspective to religion that renews with that initial stance. After recalling Vygtotsky's core ideas, we suggest that religion, as cultural and symbolic system, participates to the orchestration of human activities and sense-making. Such orchestration works both from within the person, through internalized values and ideas, and from without, through the person's interactions with others, discourses, cultural objects etc. This leads us to consider religions as supporting various forms of dialogical dynamics-intra-psychological dialogues, interpersonal with present, absent or imaginary others, as well as inter-group dialogues-which we illustrate with empirical vignettes. The example of religious tensions in the Balkans in the 90's highlights how much the historical-cultural embeddedness of these dynamics can also lead to the end of dialogicality, and therefore, sense-making. PMID- 23355097 TI - Prostate cancer and osteoporosis. AB - Adenocarcinoma of the prostate is one of the commonest cancers in the world. Due to a combination of earlier detection and better treatments, survival has increased dramatically. Prostate cancer itself is associated with lower bone density and increased fractures. This is compounded by the use of androgen deprivation therapy, which causes dramatic falls in circulating testosterone and estrogen, resulting in rapid falls in bone density, decreased muscle mass, and increased fracture rates. Bisphosphonates have been demonstrated to prevent and reverse this bone loss, but there are no anti-fracture data. Denosumab, a monoclonal antibody to RANKL, has recently been shown to increase bone density and reduce fracture rates. Prostate cancer also commonly metastasizes to bone where it can cause complications such as fracture and pain. Both zoledronic acid and denosumab have been demonstrated to reduce skeletal related events. Comparative studies would suggest that densosumab may have an advantage over zoledronic acid. PMID- 23355098 TI - Assays for prostate cancer : changing the screening paradigm? AB - Prostate cancer (PCa) screening and detection have changed dramatically since the introduction of serum prostate-specific antigen (PSA) testing. Despite the resulting improvement in early PCa detection and stage migration, in clinical practice the use of PSA testing may cause overdetection and ultimately overtreatment. As a consequence, novel biomarkers are needed to increase the specificity of PCa detection. The aim of this article is to present an overview of novel blood- and urine-based biomarkers that may optimize PCa detection, with improved identification of patients with significant PCa and avoidance of unnecessary prostate biopsies. A systematic and comprehensive PubMed search was performed using the MeSH search terms 'prostate cancer', 'biomarker', 'marker', and 'detection'. Results were restricted to the English language. Several blood- and urine-based biomarkers have the potential to improve prediction of the presence and/or significance of PCa. Ideally, biomarkers should be used in combination within multivariate models, leading to superior accuracy for prediction of any PCa or clinically significant PCa, compared with the use of a single marker. PMID- 23355099 TI - Extended adjuvant therapy with imatinib in patients with gastrointestinal stromal tumors : recommendations for patient selection, risk assessment, and molecular response monitoring. AB - On the basis of the recently published results of a clinical trial comparing 12 and 36 months of imatinib in adjuvant therapy for gastrointestinal stromal tumors (GISTs), which demonstrated clinical benefit of longer imatinib treatment in terms of delaying recurrences and improving overall survival, both the US Food and Drug Administration and the European Medicines Agency have updated their recommendations and approved 36 months of imatinib treatment in patients with v kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT)-positive GISTs (also known as CD117-positive GISTs) at high risk of recurrence after surgical resection of a primary tumor. This article discusses patient selection criteria for extended adjuvant therapy with imatinib, different classifications of risk of recurrence, and assessment of the response to therapy. PMID- 23355101 TI - Response acquisition with intermittent immediate and delayed conditioned reinforcement. AB - The acquisition of lever pressing by rats was studied under intermittent immediate and delayed conditioned reinforcement. Rats were exposed to two schedules operating concomitantly. One was a random-time schedule that delivered reinforcers on average of once per min. Each such reinforcer was paired with a 1 s illumination of a cue light located above the lever. The other was a tandem random-interval (RI) t1 - s fixed-time (FT) t2 - s schedule that controlled the rate and the delay of the illumination of the cue-light after a given lever press. For the RI, t1 was 7.5, 15 or 30 s. For the FT, t2 was 0, 1, 2, 4, 8, 16 or 32 s. Three rats each were exposed to each combination of RI and FT values for 40 sessions. Response rates decreased with longer response-conditioned reinforcer (S(r)) delays under the three different overall rates of S(r). At most response S(r) delays, absolute response rates were higher with RI 15 s than with RI 30 s but both were similar to those obtained with RI 7.5 s. The results were similar to those from previous research on response acquisition with delayed primary reinforcement. These findings suggest that a previously neutral stimulus that has been correlated with primary reinforcement can reinforce new responses even when the conditioned reinforcer is intermittent and delayed from the responses that produce it. PMID- 23355102 TI - Abnormal ductus venosus pulsatility index in the absence of concurrent umbilical vein pulsations does not indicate worsening fetal condition. AB - OBJECTIVE: Recordings of blood flow velocity waveforms in the ductus venosus (DV) and umbilical vein (UV) are routinely used in order to predict fetal condition in high-risk pregnancies. The aim of this study was to investigate the relationship between pathological blood flow in the two vessels and perinatal outcome. METHODS: High-risk pregnancies (n = 11 863) admitted from 1993 to 2011 for blood flow examination, including recordings of DV pulsatility index for veins (DV-PIV) and UV pulsations, were included. The results were related to perinatal outcome, using the last Doppler examination prior to delivery in the analysis. RESULTS: Abnormal DV-PIV was observed in 3.9% of cases, intra-abdominal UV pulsations in 1.3% and pulsations in the cord in 0.7%. As expected, the rate of UV pulsations increased with increasing DV-PIV Z-score. Fetuses with a pathological DV-PIV, but without UV pulsations, showed fewer signs of compromise. This was also true for cases with a DV-PIV >= 4 SDs above the mean (53.7% had steady flow in the UV). In contrast, the occurrence of UV pulsations seemed to be an indicator of fetal compromise, regardless of level of DV-PIV. CONCLUSIONS: Abnormal fetal venous blood velocity is related to adverse outcome in high-risk pregnancies. However, abnormal DV-PIV is not a reliable indicator of fetal compromise unless UV pulsations are concurrently present, and should not be regarded an indication for emergency delivery. PMID- 23355103 TI - Variability of state school-based hearing screening protocols in the United States. AB - The prevalence of hearing loss has increased among United States children. As schools commonly perform hearing screens, we sought to contrast current United States school-based hearing screening protocols. State department of health and education websites were reviewed to assess school hearing screening protocols for the fifty states and the District of Columbia. Individuals listed on these websites were contacted as necessary to confirm and/or acquire relevant data. School-based hearing screening is currently required in 34/51 (67 %) states. Of these 34 states, 28 (82 %) mandate grades for screening, but only 20 (59 %) require screening beyond 6th grade. Pure tone audiometry is the most common screening method (33/34 [97 %]). A majority of states screen at 1, 2 and 4 kHz usually at 20 or 25 dB hearing level. Six states recommend or require testing at 6 or 8 kHz, which is necessary to detect high-frequency hearing loss. The results indicate that United States school-based hearing screens vary significantly. They focus on low frequencies with few testing adolescents for whom high-frequency hearing loss has increased. Disparities in hearing loss detection are likely, particularly considering the evolution of hazardous noise exposures and rising prevalence of hearing loss. PMID- 23355100 TI - Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome : current status of clinical applications and future directions. AB - Prevalent as an acquired abnormality in cancer, the role of tumor protein p53 (TP53) as a germline mutation continues to evolve. The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood. In this article, we review the clinical relevance of germline mutations in the TP53 tumor suppressor gene to current healthcare practice, including the optimal ways to identify patients with Li Fraumeni syndrome (LFS), to recognize the core cancers associated with LFS, and to develop strategies for early detection of LFS-associated tumors. Several TP53 targeted approaches to improve outcomes in LFS patients are also reviewed. A case report is used to highlight special TP53 testing dilemmas and unique challenges associated with genetic testing decisions in the current age of rapidly advancing genomic technologies. PMID- 23355104 TI - The evaluation of a standardized call/recall system for childhood immunizations in Wandsworth, England. AB - To improve uptake of childhood immunizations in Wandsworth we developed a standardized call/recall system based on parents being sent three reminders and defaulters being referred to a Health Visitor. Thirty-two out of 44 primary care practices in the area implemented the intervention in September 2011. The aim of this study was to evaluate the implementation, delivery and impact on immunization uptake of the new call/recall system. To assess implementation and delivery, a mixed method approach was used including qualitative (structured interviews) and quantitative (data collected at three months post-implementation) assessment. To assess the impact, we used Student's t test to compare the difference in immunization uptake rates between intervention and non-intervention practices before and after implementation. The call/recall system was viewed positively by both parents and staff. Most children due or overdue immunizations were successfully captured by the 1st invitation reminder. After three invitations, between 87.3 % (MMR1) and 92.2 % (pre-school booster) of children identified as due or overdue immunizations successfully responded. Prior to implementation there was no difference in uptake rates between intervention and non-intervention practices. Post-implementation uptake rates for DTaP/IPV/Hib, MMR1, MMR2 and the pre-school booster were significantly greater in the intervention practices. Similar findings were seen for PCV and Hib/MenC boosters, although the differences were not statistically significant at the 5 % level. Following the successful implementation of a standardized call/recall system in Wandsworth, other regions or primary care practices may wish to consider introducing a similar system to help improve their immunization coverage levels. PMID- 23355106 TI - Risk model and nomogram for dysphagia and xerostomia prediction in head and neck cancer patients treated by radiotherapy and/or chemotherapy. AB - In our randomized trial on hyperbaric oxygen (HBO), it was shown that HBO could reduce dysphagia and xerostomia, which are frequently encountered after (chemo-) radiotherapy (RT) and/or surgery for head and neck cancer (HNC). A risk model and nomogram are developed to select those patients who most likely will respond to HBO treatment. A total of 434 HNC patients treated from 2000 to 2008 were analyzed and filled out the EORTC QLQC-30 and H&N35 questionnaires. Age, gender, chemotherapy, T and N stages, site, radiotherapy technique, RT boost, surgery of the primary tumor and neck, bilateral RT, and dose were analyzed in a statistical model. The discriminative value of the model was evaluated based on receiver operating characteristics (ROC), the area under the curve (AUC), sensitivity, specificity, and proportion of correctly classified measures. Significant factors in predicting swallowing problems are age, follow-up duration, tumor site, chemotherapy, surgery of the primary tumor and neck, and dose. For dry mouth, the significant factors are age, gender, tumor site, N stage, chemotherapy, and bilateral irradiation. For dysphagia and xerostomia, the area under the ROC curve is 0.7034 and 0.7224, respectively, with a specificity of 89/77%, sensitivity of 27/58%, and a positive predictive value of 83/67% for dysphagia and xerostomia, respectively. The developed predictive risk model could be used to select patients for costly hyperbaric oxygen treatment to prevent or reduce severe late side effects of HNC treatment. Our model serves as a guideline for the Department of Radiation Oncology to reduce costs by excluding patients not amenable to hyperbaric oxygen protocols. The nomogram presented is a useful tool for clinicians in assessing patient risks when deciding on follow-up strategies (e.g., hyperbaric oxygen treatment) after RT or surgery for HNC. PMID- 23355107 TI - The genetic contribution to severe post-traumatic osteoarthritis. AB - OBJECTIVE: to compare the combined role of genetic variants loci associated with risk of knee or hip osteoarthritis (OA) in post-traumatic (PT) and non-traumatic (NT) cases of clinically severe OA leading to total joint replacement. METHODS: A total of 1590 controls, 2168 total knee replacement (TKR) cases (33.2% PT) and 1567 total hip replacement (THR) cases (8.7% PT) from 2 UK cohorts were genotyped for 12 variants previously reported to be reproducibly associated with risk of knee or hip OA. A genetic risk score was generated and the association with PT and NT TKR and THR was assessed adjusting for covariates. RESULTS: For THR, each additional genetic risk variant conferred lower risk among PT cases (OR=1.07, 95% CI 0.96 to 1.19; p=0.24) than NT cases (OR 1.11, 95% CI 1.06 to 1.17; p=1.55*10 5). In contrast, for TKR, each risk variant conferred slightly higher risk among PT cases (OR 1.12, 95% CI 1.07 to 1.19; p=1.82*10-5) than among NT cases (OR 1.08, 95% CI 1.03 to 1.1; p=0.00063). CONCLUSIONS: Based on the variants reported to date PT TKR cases have at least as high a genetic contribution as NT cases. PMID- 23355108 TI - Simultaneous determination of 9-dehydro-17-hydro-andrographolide and sodium 9 dehydro-17-hydro-andrographolide-19-yl sulfate in rat plasma by UHPLC-ESI-MS/MS after administration of xiyanping injection: application to a pharmacokinetic study. AB - 9-Dehydro-17-hydro-andrographolide (DHA) and sodium 9-dehydro-17-hydro andrographolide-19-yl sulfate (DHAS) are active ingredients of xiyanping injection in clinical use. A simple, rapid and sensitive UHPLC-ESI-MS/MS method was developed for the determination of DHA and DHAS in rat plasma, and the pharmacokinetics of DHA and DHAS after intravenous administration of xiyanping injection was investigated. The plasma samples were treated with methanol to precipitate out protein, and the separation of DHA and DHAS was achieved on a Waters BEH C18 column with a mobile phase consisting of acetonitrile and 10 mmol/L ammonium acetate solution at a flow rate of 0.4 mL/min. DHA, DHAS and the internal standard (internal standard, IS) diethylstilbestrol were detected at negative ion mode. The precursor-product ion pairs used in multiple reaction monitoring mode were: m/z 349.1 -> 286.9 (DHA), m/z 428.9 -> 96.0 (DHAS) and m/z 267.1 -> 236.9 (IS). Calibration curves offered satisfactory linearity within the test range, and all correlation coefficients were >0.995. The lower limit of detection of DHA and DHAS in plasma samples were determined to be 0.1 ng/mL. The lower limit of quantitation was 0.5 ng/mL for DHA and DHAS. All the recoveries of the quality control samples were in the range of 86.0-102.4%. The ratios of matrix effect were between 89.2 and 105.1%. The method was fully validated and successfully applied to the pharmacokinetic study of DHA and DHAS in rats. The study showed that both DHA and DHAS were distributed and eliminated rapidly in rats. PMID- 23355110 TI - A low energy oxide-based electronic synaptic device for neuromorphic visual systems with tolerance to device variation. AB - Neuromorphic computing is an emerging computing paradigm beyond the conventional digital von Neumann computation. An oxide-based resistive switching memory is engineered to emulate synaptic devices. At the device level, the gradual resistance modulation is characterized by hundreds of identical pulses, achieving a low energy consumption of less than 1 pJ per spike. Furthermore, a stochastic compact model is developed to quantify the device switching dynamics and variation. At system level, the performance of an artificial visual system on the image orientation or edge detection with 16 348 oxide-based synaptic devices is simulated, successfully demonstrating a key feature of neuromorphic computing: tolerance to device variation. PMID- 23355111 TI - Post-mortem detection of gasoline residues in lung tissue and heart blood of fire victims. AB - The purpose of this study was to determine whether gasoline residues could be detected post-mortem in lung tissue and heart blood of fire victims. The lungs and heart blood were investigated to determine whether they were suitable samples for collection and could be collected without contamination during an autopsy. Three sets of test subjects (pig carcasses) were investigated under two different fire scenarios. Test subjects 1 were anaesthetized following animal ethics approval, inhaled gasoline vapours for a short period and then euthanized. The carcasses were clothed and placed in a house where additional gasoline was poured onto the carcass post-mortem in one fire, but not in the other. Test subjects 2 did not inhale gasoline, were clothed and placed in the house and had gasoline poured onto them in both fires. Test subjects 3 were clothed but had no exposure to gasoline either ante- or post-mortem. Following controlled burns and suppression with water, the carcasses were collected, and their lungs and heart blood were excised at a necropsy. The headspace from the samples was analysed using thermal desorption-gas chromatography-mass spectroscopy. Gasoline was identified in the lungs and heart blood from the subjects that were exposed to gasoline vapours prior to death (test subjects 1). All other samples were negative for gasoline residues. These results suggest that it is useful to analyse for volatile ignitable liquids in lung tissue and blood as it may help to determine whether a victim was alive and inhaling gases at the time of a fire. PMID- 23355112 TI - Effects of forward model errors on EEG source localization. AB - Subject-specific four-layer boundary element method (BEM) electrical forward head models for four participants, generated from magnetic resonance (MR) head images using NFT ( www.sccn.ucsd.edu/wiki/NFT ), were used to simulate electroencephalographic (EEG) scalp potentials at 256 recorded electrode positions produced by single current dipoles of a 3-D grid in brain space. Locations of these dipoles were then estimated using gradient descent within five template head models fit to the electrode positions. These were: a spherical model, three-layer and four-layer BEM head models based on the Montreal Neurological Institute (MNI) template head image, and these BEM models warped to the recorded electrode positions. Smallest localization errors (4.1-6.2 mm, medians) were obtained using the electrode-position warped four-layer BEM models, with largest localization errors (~20 mm) for most basal brain locations. When we increased the brain-to-skull conductivity ratio assumed in the template model scalp projections from the simulated value (25:1) to a higher value (80:1) used in earlier studies, the estimated dipole locations moved outwards (12.4 mm, median). We also investigated the effects of errors in co-registering the electrode positions, of reducing electrode counts, and of adding a fifth, isotropic white matter layer to one individual head model. Results show that when individual subject MR head images are not available to construct subject-specific head models, accurate EEG source localization should employ a four- or five-layer BEM template head model incorporating an accurate skull conductivity estimate and warped to 64 or more accurately 3-D measured and co-registered electrode positions. PMID- 23355114 TI - Stress in nurses: stress-related affect and its determinants examined over the nursing day. AB - BACKGROUND: Nurses are a stressed group and this may affect their health and work performance. The determinants of occupational stress in nurses and other occupational groups have almost invariably been examined in between subject studies. PURPOSE: This study aimed to determine if the main determinants of occupation stress, i.e. demand, control, effort and reward, operate within nurses. METHODS: A real time study using personal digital-assistant-based ecological momentary assessment to measure affect and its hypothesised determinants every 90 min in 254 nurses over three nursing shifts. The measures were negative affect, positive affect, demand/effort, control and reward. RESULTS: While the effects varied in magnitude between people, in general increased negative affect was predicted by high demand/effort, low control and low reward. Control and reward moderated the effects of demand/effort. High positive affect was predicted by high demand/effort, control and reward. CONCLUSIONS: The same factors are associated with variations in stress-related affect within nurses as between. PMID- 23355113 TI - Accuracy of weight perception among urban early adolescents with uncontrolled asthma and their caregivers. AB - BACKGROUND: Obesity is associated with poor asthma outcomes; weight loss improves such outcomes. Inaccurate recognition of obesity may impede weight control. PURPOSE: We examined perception of weight by early adolescents with uncontrolled asthma and their caregivers, and tested the relationship between medical visit frequency and accuracy of perceived weight status. METHODS: A total of 373 adolescents and their caregivers reported the adolescent's height/weight and weight perception; caregivers reported healthcare utilization. We measured height/weight. Logistic regression modeled accuracy of weight perception. RESULTS: A total of 43.7 % of the overweight/obese adolescents and caregivers accurately perceived weight status. BMI percentile [odds ratio (OR) = 1.19, confidence interval (CI) = 1.10-1.28] and total medical visits (OR = 1.18, CI = 1.05-1.33) were associated with higher accuracy in caregivers. Total medical visits (OR = 0.84, CI = 0.74-0.96) was associated with lower accuracy in adolescents. CONCLUSIONS: Accurate perception of weight status was poor for overweight adolescents with uncontrolled asthma and their caregivers. Frequent medical visits were associated with improved caregivers' but not adolescents' perceptions. PMID- 23355109 TI - Risk factors, pathophysiology, and treatment of hot flashes in cancer. AB - Hot flashes are prevalent and severe symptoms that can interfere with mood, sleep, and quality of life for women and men with cancer. The purpose of this article is to review existing literature on the risk factors, pathophysiology, and treatment of hot flashes in individuals with cancer. Electronic searches were conducted to identify relevant English-language literature published through June 15, 2012. Results indicated that risk factors for hot flashes in cancer include patient-related factors (eg, age, race/ethnicity, educational level, smoking history, cardiovascular risk including body mass index, and genetics) and disease related factors (eg, cancer diagnosis and dose/type of treatment). In addition, although the pathophysiology of hot flashes has remained elusive, these symptoms are likely attributable to disruptions in thermoregulation and neurochemicals. Therapies that have been offered or tested fall into 4 broad categories: pharmacological, nutraceutical, surgical, and complementary/behavioral strategies. The evidence base for this broad range of therapies varies, with some treatments not yet having been fully tested or showing equivocal results. The evidence base surrounding all therapies is evaluated to enhance hot flash treatment decision-making by clinicians and patients. PMID- 23355115 TI - Pushing the syndemic research agenda forward: a comment on Pitpitan et al. PMID- 23355116 TI - Getting closer--advancing the study of persons with chronic fatigue syndrome: a comment on Poeschla et al. PMID- 23355117 TI - Duel or diversion? Conscientiousness and executive function in the prediction of health and longevity. PMID- 23355118 TI - Dynamic spatial pattern formation in the sea urchin embryo. AB - The spatiotemporal evolution of various proteins during the endo-mesodermal specification of the sea urchin embryo in the form of an expanding torus has been known experimentally for some time, and the regulatory network that controls this dynamic evolution of gene expression has been recently partially clarified. In this paper we construct a relatively simple mathematical model of this process that retains the basic features of the gene network and is able to reproduce the spatiotemporal patterns observed experimentally. We show here that a mathematical model based only on the gene-protein interactions so far reported in the literature predicts the origin of the behaviour to lie on a delayed negative feed back loop due to the protein Blimp1 on the transcription of its corresponding mRNA. However though consistent with earlier results, this contradicts recent findings, where it has been established that the dynamical evolution of Wnt8 protein is independent of Blimp1. This leads us to offer a modified version of the original model based on observations in similar systems, and some more recent work in the sea urchin, assuming the existence of a mechanism involving inhibitory loop on wnt8 transcription. This hypothesis leads to a better match with the experimental results and suggests that the possibility of the existence of such an interaction in the sea urchin should be explored. PMID- 23355119 TI - The influence of genetic polymorphisms in XRCC3 and ADH5 genes on the frequency of genotoxicity biomarkers in workers exposed to formaldehyde. AB - The International Agency for Research on Cancer classified formaldehyde as carcinogenic to humans because there is "sufficient epidemiological evidence that it causes nasopharyngeal cancer in humans". Genes involved in DNA repair and maintenance of genome integrity are critically involved in protecting against mutations that lead to cancer and/or inherited genetic disease. Association studies have recently provided evidence for a link between DNA repair polymorphisms and micronucleus (MN) induction. We used the cytokinesis-block micronucleus (CBMN assay) in peripheral lymphocytes and MN test in buccal cells to investigate the effects of XRCC3 Thr241Met, ADH5 Val309Ile, and Asp353Glu polymorphisms on the frequency of genotoxicity biomarkers in individuals occupationally exposed to formaldehyde (n = 54) and unexposed workers (n = 82). XRCC3 participates in DNA double-strand break/recombination repair, while ADH5 is an important component of cellular metabolism for the elimination of formaldehyde. Exposed workers had significantly higher frequencies (P < 0.01) than controls for all genotoxicity biomarkers evaluated in this study. Moreover, there were significant associations between XRCC3 genotypes and nuclear buds, namely XRCC3 Met/Met (OR = 3.975, CI 1.053-14.998, P = 0.042) and XRCC3 Thr/Met (OR = 5.632, CI 1.673-18.961, P = 0.005) in comparison with XRCC3 Thr/Thr. ADH5 polymorphisms did not show significant effects. This study highlights the importance of integrating genotoxicity biomarkers and genetic polymorphisms in human biomonitoring studies. PMID- 23355120 TI - Predicting 30-day all-cause hospital readmissions. AB - Hospital readmission rate has been broadly accepted as a quality measure and cost driver. However, success in reducing readmissions has been elusive. In the US, almost 20 % of Medicare inpatients are rehospitalized within 30 days, which amounts to a cost of $17 billion. Given the skyrocketing healthcare cost, policymakers, researchers and payers are focusing more than ever on readmission reduction. Both hospital comparison of readmissions as a quality measure and identification of high-risk patients for post-discharge interventions require accurate predictive modeling. However, most predictive models for readmissions perform poorly. In this study, we endeavored to explore the full potentials of predictive models for readmissions and to assess the predictive power of different independent variables. Our model reached the highest predicting ability (c-statistic =0.80) among all published studies that used administrative data. Our analyses reveal that demographics, socioeconomic variables, prior utilization and Diagnosis-related Group (DRG) all have limited predictive power; more sophisticated patient stratification algorithm or risk adjuster is desired for more accurate readmission predictions. PMID- 23355121 TI - Health state utilities for skeletal-related events secondary to bone metastases. AB - INTRODUCTION: Patients with bone metastases often experience skeletal-related events (SREs). Although cost-utility models are used to examine treatments for metastatic cancer, limited information is available on utilities of SREs. The purpose of this study was to estimate the disutility of four SREs: spinal cord compression, pathological fracture, radiation to bone, and surgery performed to stabilize a bone. METHODS: General population participants from the UK and Canada completed time trade-off (TTO) interviews to assess the utility of health states drafted based on literature review, clinician interviews, and patient interviews. Respondents first rated a health state describing cancer with bone metastases. Then, the SREs were added to this health state. RESULTS: Interviews were completed with 187 participants (50.8 % male, 80.2 % white). Cancer with bone metastases without an SRE had a mean utility of 0.47 (SD = 0.43) on a standard utility scale (1 = full health, 0 = death). Of the SREs, spinal cord compression was associated with the greatest disutility (i.e., the utility decrease): -0.32 with paralysis and -0.22 without paralysis. Surgery had a disutility of -0.07. Leg, arm, and rib fractures had disutilities of -0.06, -0.04, and -0.03. Two weeks of daily radiation treatment had a disutility of -0.06, while two radiation appointments had the smallest impact on utility (-0.02). CONCLUSION: All SREs were associated with statistically significant utility decreases, suggesting a perceived impact on quality of life beyond the impact of cancer with bone metastases. The resulting disutilities may be used in cost-utility models examining treatments to prevent SREs secondary to bone metastases. PMID- 23355122 TI - Physical activity and cardiometabolic characteristics in overweight Latina women. AB - This community-based study examined physical activity (PA) in relation to cardiometabolic risk factors among 223 adult, immigrant Latina women who were overweight or obese. Participants were predominantly of Mexican descent, married and low-income. Data were obtained through accelerometer readings and clinical measures (e.g., BMI, waist circumference, blood pressure, lipid profile, fasting blood sugar). Findings showed that many women were active (mean step count = 8,575 +/- 3,191); 27.6 % achieved 10,000 steps per day, and only 11 % were sedentary. They engaged in short bouts of moderate PA rather than long-sustained moderate-to-vigorous activity. Three or more MetS traits were present in 45.3 % of the women, raising concerns about risk for diabetes and cardiovascular disease. More active women had lower BMI, weight, waist circumference, and triglycerides levels. Results point to the importance of targeting maintenance of PA in active women and intervening with culturally tailored programs to promote healthier behavior in those who are sedentary or somewhat active. PMID- 23355123 TI - Weight discordance and perinatal mortality in twins: analysis of the Southwest Thames Obstetric Research Collaborative (STORK) multiple pregnancy cohort. AB - OBJECTIVES: The degree of actual intertwin birth weight (BW) or ultrasound estimated fetal weight (EFW) discordance that justifies elective delivery is yet to be established. The main aim of this study was to ascertain the performance of BW and ultrasound EFW discordance in the prediction of perinatal loss in twin pregnancies. METHODS: This was a retrospective study of all twin pregnancy births from a large regional cohort of nine hospitals over a 10-year period. Intertwin BW and ultrasound EFW discordance were analyzed in relation to the occurrence of stillbirth or neonatal death of one or both twins from 26 weeks' gestation as obtained from a mandatory national register. Receiver-operating characteristics (ROC), survival and logistic regression analyses were performed to evaluate the contribution of weight discordance in determining perinatal loss. RESULTS: A total of 2161 twin pregnancies were included in the analysis. The area under the ROC curve for the prediction of perinatal loss was similar for BW and ultrasound EFW discordance (P = 0.62). Kaplan-Meier analysis showed that twins with BW or EFW of >= 25% discordance had a significantly lower survival trend than did those with lesser degrees of discordance (P < 0.001). The hazard ratios for the risk of total perinatal loss in twins with a BW or EFW discordance of >= 25% were 7.29 (95% CI, 4.37-12.00) and 7.28 (95% CI, 4.46-11.92), respectively. Logistic regression analysis demonstrated that BW discordance and gestational age, but not chorionicity or individual fetal size percentile, were independently associated with perinatal mortality. CONCLUSIONS: An EFW discordance of >= 25% represents the optimal cut-off for the prediction of stillbirth and neonatal mortality irrespective of chorionicity or individual fetal size. A policy of increased fetal surveillance commencing from 26 weeks' gestation might be reasonable for pregnancies beyond this cut-off, but this would require confirmation in large scale prospective trials. PMID- 23355124 TI - Overview of the i-SEARCH Global Study : Cardiovascular Risk Factors and Microalbuminuria in Hypertensive Individuals. AB - Microalbuminuria (MAU) is a highly predictive, sensitive, inexpensive and easily repeatable marker of cardiovascular risk and all-cause mortality in hypertensive patients. The international, observational, practice-based study i-SEARCH (Survey for Evaluating Microalbuminuria Routinely by Cardiologists in patients with Hypertension) was designed to assess the frequency with which MAU occurred in a large outpatient population who were currently treated or newly diagnosed with hypertension and were under professional care. The primary aim of the study was to define the prevalence of MAU in hypertensive outpatients attending a cardiologist or internist (i-SEARCH A) and to compare hypertensive outpatients with or without coronary artery disease (i-SEARCH B). A secondary objective was to establish a correlation between MAU and known cardiovascular risk factors. A total of 21 050 patients from 26 countries were included in the primary analysis. Overall, this study demonstrated a very high worldwide prevalence (58.4%) of MAU in high-risk cardiovascular patients, but with a considerable variation across countries. MAU was more prevalent in patients with coronary artery disease than in those without. It was also significantly related to the presence of specific predictors, including male gender, abnormally high waist circumference, increased blood pressure levels (systolic >=120 mmHg, diastolic >=100 mmHg), creatinine clearance >=50 mL/min, or clinical conditions such as diabetes mellitus, congestive heart failure, history of cerebral pathology, and peripheral arterial disease. Since the presence of MAU reflects long-term detrimental effects on the cardiovascular system, these results indicate the high, and in many cases hidden, burden of cardiovascular diseases among the hypertensive patients seen by cardiologists. This article discusses the main results of the study and the potential implications of ongoing analyses included in the core clinical study programme. PMID- 23355125 TI - Omega 3 : where do we stand? AB - Omega-3 fatty acids are essential polyunsaturated fatty acids that are crucial components of plasma membrane phospholipids. They influence cell structure and function and have anti-thrombotic and anti-arrhythmic properties, thus potentially exerting a favourable action on primary and secondary prevention of cardiovascular events. However, the supposed beneficial effect of omega-3 fatty acids in the management of cardiovascular risk has been evaluated only in a relatively small number of interventional studies, with results that are not consistent and are only suggestive of a putative beneficial effect of omega-3 supplementation on the prevention of cardiovascular mortality. Benefits have been reported mainly for the prevention of sudden death in patients with recent myocardial infarction and for primary and secondary prevention of nonfatal cardiac events in populations with high fish intake. Therefore, only ongoing trials will provide definitive data to elucidate whether omega-3 fatty acids could represent a new therapeutic approach for cardiovascular disease. PMID- 23355126 TI - Reduction of Cardiovascular Risk through Angiotensin II Type 1 Receptor Antagonism : Focus on Olmesartan Medoxomil. AB - It is well recognized that angiotensin II is involved in the pathogenesis of hypertension. Less well recognized - until recently, at least - is its involvement in the pathogenesis of atherosclerosis. However, it is now evident that angiotensin II promotes oxidative stress, vascular remodelling, inflammation, and the formation of atherosclerotic lesions. These actions, which are mediated almost exclusively by the angiotensin II type 1 (AT(1)) receptor, can be blocked by administration of angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]). Of the seven ARBs currently in clinical use, olmesartan is one of the most effective. The rapid and consistent antihypertensive efficacy of this drug, which allows a high proportion of patients to achieve their target blood pressure (BP), is associated with beneficial effects on oxidative stress, vascular remodelling, inflammation, and atherosclerotic lesion formation. These effects appear to be independent of the BP-lowering activity of olmesartan. In clinical trials, olmesartan has been shown to control microinflammation in hypertensive patients, to reduce oxidative stress in patients with type 2 diabetes mellitus, and to normalize the wall: lumen ratio of small resistance arteries (a measure of vascular remodelling) in patients with hypertension. Moreover, in a 2-year study involving hypertensive patients with carotid atherosclerosis (the MORE [Multicentre Olmesartan atherosclerosis Regression Evaluation] trial), olmesartan reduced the intima-media thickness of the carotid artery and significantly reduced the volume of large atherosclerotic plaques. These data suggest that olmesartan may reduce cardiovascular risk by simultaneously normalizing BP and reversing the proatherogenic effects of angiotensin II. PMID- 23355127 TI - Angiotensin II Blockade and Total Cardiovascular Risk : Beyond Blood Pressure Reduction. AB - Hypertension is one of the world's largest public health problems and it is both a disease and a risk factor for cardiovascular disease (CVD). The heart, the endothelium and the kidneys are the target organs of hypertension. Recently, several antihypertensive drugs have been introduced to the market; therefore, the choice is mainly determined by the patients' features. In particular, ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) demonstrate a larger reduction in cardiovascular risk than other antihypertensive treatments because of the existence of blood pressure independent effects. In fact, the angiotensin II pathway plays a major role in metabolic, haemodynamic and endothelial homeostasis. For these reasons, ACE inhibitors and ARBs have primary indications in patients with obesity, hypercholesterolaemia and diabetes mellitus because of their favourable metabolic properties. Furthermore, several large trials have demonstrated that they have favourable effects also in patients with left ventricular dysfunction or systolic heart failure, as well as other forms of heart disease. Drugs affecting the angiotensin II pathway may reduce endothelial dysfunction through several mechanisms including reduction of vascular permeability and oxidative stress. Another important effect of these drugs is neuroprotection. This is an important effect because in the near future, due to an aging population, an important goal for optimal antihypertensive treatment will be the prevention of cognitive decline. ACE inhibitors and ARBs are very important drugs in the modern management of the total cardiovascular risk in hypertensive patients. PMID- 23355128 TI - Cardiovascular risk in hypertension - can we ask for more? : focus on aliskiren. AB - The burden of cardiovascular (CV) disease remains high nowadays, despite the tremendous development in the therapeutic strategies that has occurred during the last 30 years. The growing focus on pharmacological strategies capable of interacting with key pathophysiological mechanisms has resulted in a better control of CV disease. The renin-angiotensin system (RAS) is involved in many pathophysiological processes underlying the development of major CV and renal diseases and, thus, it represents an 'ideal' target for the pharmacological treatment of these clinical conditions. Recently, in addition to the traditional therapeutic approaches, mostly based on the use of ACE inhibitors and/or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), the scientific and medical community have focused on a new therapeutic possibility to interfere with RAS activity. Indeed, the first compound of the new drug class of direct renin inhibitors, aliskiren, has been made available for clinical use. The therapeutic properties of aliskiren are of particular interest, since it interferes with the enzymatic activities of renin, the key rate-limiting step of the RAS cascade. This unique mechanism of action, e.g. occupation of the renin active site, provides an 'upstream' modulation in the RAS enzymatic-proteic cascade. This results in an inhibition of the biological properties of renin to promote the cleavage of the angiotensin I peptide from the angiotensinogen substrate.Clinical studies have demonstrated that the use of aliskiren provides antihypertensive efficacy comparable with, or even superior to, that observed with other classes of antihypertensive drugs. Also, the addition of aliskiren to different antihypertensive strategies results in a further significant increase in blood pressure (BP) reduction than those achieved with monotherapy based on diuretics, calcium-channel antagonists, ACE inhibitors and ARBs. The overall safety and tolerability of aliskiren are comparable with other classes of antihypertensive drugs and almost overlap with placebo. Recent evidence also demonstrates that aliskiren is effective in promoting the regression of organ damage (e.g. microalbuminuria and left ventricular hypertrophy), beyond its BP lowering properties and in addition to standard therapies, including ARBs. An ambitious programme of clinical development of this modern antihypertensive drug will investigate whether aliskiren may further limit the incidence of major CV and renal events in hypertensive patients with co-morbidities, treated with the available therapeutic strategies, including ACE inhibitors and ARBs. PMID- 23355129 TI - Smoking selectively accelerates carotid atherosclerosis in hypertensive patients. AB - BACKGROUND AND OBJECTIVES: Left ventricular hypertrophy, carotid atherosclerosis and renal dysfunction are indicators of target organ damage in hypertension, and independent risk factors for both fatal and non-fatal cardio- and cerebrovascular events. In the general population, smoking is associated with increases in left ventricular mass and carotid intima-media thickness (IMT), and impaired renal function. The aim of the present study was to evaluate whether smoking affects the development of target organ damage in patients with arterial hypertension. METHODS: 3192 hypertensive patients referred to the Hypertension Clinic of the "Federico II" University of Naples from January 2000 to July 2006 were retrospectively analysed. Subjects were aged from 18 to 75 years. Among these patients, 1391 were smokers and 1801 non-smokers. RESULTS: The duration and severity of hypertension was significantly shorter in smokers when compared with non-smokers. The maximum arterial IMT was significantly higher in smokers compared with non-smokers (1.7 +/- 0.1 mm vs 1.5 +/- 0.1, p < 0.0001), while left ventricular mass index was comparable between the two groups. In contrast, glomerular filtration rate was observed to be higher in smokers compared with non smokers. Logistic regression analysis showed that smoking, age, sex, duration of hypertension, systolic blood pressure and diastolic blood pressure were significantly correlated with IMT. Furthermore, a strong correlation was found between the number of cigarettes smoked per day and IMT. CONCLUSIONS: Together, these data indicate that in hypertensive patients who have a high risk of developing atherosclerosis, smoking could potentiate the development of atherosclerotic plaques. PMID- 23355130 TI - Efficacy and Acceptability of Indapamide Sustained Release in Elderly High-Risk Hypertensive Patients : the ARGUS Study. AB - OBJECTIVE: To assess the efficacy and acceptability of indapamide sustained release (SR) monotherapy in elderly high-risk patients with moderate to severe hypertension. METHODS: 1277 hypertensive patients older than 55 years with moderate to severe hypertension, including 91% with systolic blood pressure (SBP) >160 mmHg and at least one cardiovascular risk factor (age >65 years, male, diabetes mellitus, coronary heart disease [CHD], cerebrovascular disease, dyslipidaemia, obesity, smoking) were enrolled in this observational study. They received indapamide SR 1.5 mg, one tablet daily, for 3 months. Blood pressure (BP) was assessed monthly by sphygmomanometer. Statistical analyses were performed using the chi(2) test, analysis of variance, and the Newman-Keuls test. RESULTS: After 3 months of treatment with indapamide SR, SBP had decreased by 34 +/- 3 mmHg and diastolic BP (DBP) by 12 +/- 6 mmHg (both p < 0.001). Ninety-two percent of patients responded to therapy (SBP/DBP reduction >20/10 mmHg) and 52% were normalized (SBP <140 mmHg and DBP <90 mmHg). BP targets were reached in 48% of patients older than 65 years, 31% of diabetic patients, and 33% of patients with CHD. There were no changes in serum creatinine, glucose or lipid parameters, and 3% of patients had hypokalaemia (<3.5 mmol/L). The patients self-assessment scores regarding general state of health improved and 34% of patients reported 'excellent' health after treatment. CONCLUSIONS: In the high-risk patients of the ARGUS study, monotherapy with indapamide SR showed antihypertensive efficacy with good acceptability and no changes in metabolic parameters over a 3-month period. Indapamide SR monotherapy normalized BP in half of the patients treated and proved an appropriate first-line treatment in hypertensive patients older than 55 years with added cardiovascular risk factors. PMID- 23355132 TI - Magnetic navigation in adults with atrial isomerism (heterotaxy syndrome) and supraventricular arrhythmias. AB - AIMS: We analysed the type and mechanism of supraventricular arrhythmias encountered in a series of symptomatic adults with atrial isomerism undergoing catheter ablation procedures. METHODS AND RESULTS: The study population included consecutive adults with atrial isomerism who had previously undergone surgical repair or palliation of the associated anomalies. Patients underwent electrophysiological study for symptomatic arrhythmia in our institution between 2010 and 2012 using magnetic navigation in conjunction with CARTO RMT and three dimensional (3D) image integration. Eight patients (five females) with a median age of 33 years [interquartile range (IQR) 24-39] were studied. Access to the cardiac chambers of interest was obtained retrogradely via the aorta using remotely navigated magnetic catheters in six patients. Radiofrequency ablation successfully targeted twin atrioventricular (AV) nodal reentrant tachycardia in two patients, atrial fibrillation (AF) in three, focal atrial tachycardia (AT) mainly originating in the left-sided atrium in four patients, and macro-reentrant AT dependent on a right-sided inferior isthmus in three patients. The median fluoroscopy time was 3.0 min (IQR 2-11). After a median follow-up of 10 months (IQR 6-21), five of the ablated patients are free from arrhythmia; two patients experienced episodes of self-terminated AF and AT, respectively, within one month post-ablation; the remaining patient had only non-sustained AT during the electrophysiological study and was managed medically. CONCLUSION: Various supraventricular tachycardia mechanisms are possible in adults with heterotaxy syndrome, all potentially amenable to radiofrequency ablation. The use of remote magnetic navigation along with 3D mapping facilitated the procedures and resulted in a short radiation time. PMID- 23355133 TI - Acute and long-term outcome after catheter ablation of supraventricular tachycardia in patients after the Mustard or Senning operation for D transposition of the great arteries. AB - AIMS: Data about the acute and long-term outcome of catheter ablation in patients with D-transposition of the great arteries (d-TGA) post-Mustard/Senning operation are scarce. METHODS AND RESULTS: This single-centre retrospective analysis includes 26 patients (mean age 28.7 +/- 6.7 years, 8 females) after Mustard (n = 15) or Senning (n = 11) operation who underwent catheter ablation for intra atrial re-entrant tachycardia (IART) or atrioventricular nodal re-entrant tachycardia (AVNRT) from January 2004 to May 2011. The electrophysiological studies were performed using a three-dimensional mapping system (CARTO). Remote magnetic navigation (RMN) was available since 2008. Follow-up on an outpatient basis was conducted 3, 6, and 12 months after ablation and yearly thereafter. In the 26 patients, 34 procedures were performed (one procedure n = 19, two n = 6, and three n = 1). Overall, 34 tachycardia forms (IART n = 30; AVNRT n = 4) were ablated manually (n = 25) or by RMN (n = 9). Acute success reached in 29/34 forms (85.3%). Mean fluoroscopy time (FT) was 28.2 +/- 20.7 min and mean procedure duration (PD) was 290.9 +/- 107.6 min. After a mean follow-up of 34.1 +/- 24.5 months, 25/26 (96.2%) patients were free from IART or AVNRT. In the nine RMN ablations (mean follow-up 14.2 +/- 5.8 months) acute and long-term success was 100%. Fluoroscopy time and PD were significantly reduced using RMN compared with manual ablation (11.9 +/- 6.2 vs. 34.6 +/- 20.6 min, 225.7 +/- 24.1 vs. 312 +/- 118.2 min, P = 0.02). CONCLUSION: Catheter ablation of IART or AVNRT in patients post-Mustard/Senning operation for d-TGA has a high acute success rate. The recurrence rate for IART is about 30%; however, after a second ablation, long term results are excellent. Remote magnetic navigation seems to improve single procedure acute and long-term success and significantly reduces FT and PD. PMID- 23355134 TI - Wolff-Parkinson-White syndrome and antidromic atrioventricular reentrant tachycardia. PMID- 23355131 TI - Italian society of hypertension guidelines for conventional and automated blood pressure measurement in the office, at home and over 24 hours. AB - This article offers instructions and recommendations on how to perform blood pressure measurements in the doctor's office, in the patient's home and in ambulatory conditions over 24 hours. Great attention is paid to some of the general aspects of blood pressure measurement, including the accuracy of blood pressure measuring devices, the importance of a 'white-coat effect', and the need for patient education. This article also deals with a number of practical details, such as the importance of patient's relaxation and position, arm position and support, arm selection and cuff selection and application. Recommendations are provided on the observer's position and performance, and on the need to pay attention to specific factors affecting the blood pressure measurement in different patient populations, namely in children, elderly and obese people, pregnant women, patients with arrhythmias and patients on treatment. This article then separately focuses on the characteristics of auscultatory and automated measurements, the latter performed either in the office, at home or over 24 hours in ambulatory settings. Home blood pressure monitoring (HBPM) is becoming increasingly important in the diagnosis and management of arterial hypertension. The importance of HBPM in cardiovascular prevention, related to a deeper involvement of patients in their long-term management, and the wide diffusion of this approach in populations, is not always accompanied by adequate knowledge of how to make proper use of this technique, which emphasizes the need for more precise recommendations. This article summarizes the available evidence and provides recommendations on the use of home blood pressure monitoring in clinical practice and in research. It updates the previous recommendations on the same topic issued in 2000. The main topics addressed include the methodology of HBPM, focusing on measurement conditions and procedures, ranging from patient/subject position, to arm selection, arm position and support, cuff selection and application and data reporting, diagnostic and therapeutic thresholds, clinical applications in hypertension (with specific reference to special populations) and its applications in research. Special attention is given to device validation and selection as well as to patient education and to the need of HBPM to be guided by the physician in charge. The final section deals with the problems related to the implementation of these recommendations in clinical practice. Finally, the methodology and clinical impact of 24-hour ambulatory blood pressure monitoring are also addressed in detail, focusing on the parameters that can be derived from the analysis of 24 hour blood pressure recordings applied both to the diagnostic and prognostic evaluation of hypertensive patients and to the assessment of the effectiveness of antihypertensive treatment in controlling blood pressure through the day and night. Instructions to users on how to properly perform HBPM are provided as an appendix. PMID- 23355135 TI - The role of implantable cardiac defibrillators in cardiac sarcoidosis: saviour or sinner? PMID- 23355136 TI - Femtosecond laser-based mutagenesis strategy for micronomicin production enhancement of Micromonospora sagamiensis ATCC 21826. AB - In this work, a mutant MX3004 with improved micronomicin (MCR) production was derived from Micromonospora sagamiensis ATCC21826, which was treated with femtosecond laser under the optimized irradiation conditions of 75 mW and 180 s, with a maximum of positive mutation rate of 17.8 % and the mortality rate of 69.2 %. A novel high-throughput method was established using microplate reader by quantifying the concentration of MCR for efficient screening of positive mutant from large numbers of mutants. Consequently, MX3004 displayed the highest MCR production capacity of 126 U/ml and a stable heredity (ten generations). Moreover, under the optimal fermentation conditions in a 7.5 l fermenter, the MCR production of MX3004 reached the maximum of 263 U/ml, which was increased by 484 % compared with the parent strain. The results suggest that femtosecond laser is a suitable method for the MCR production improvement and the screening method has a great potential application for aminoglycoside antibiotic production. PMID- 23355137 TI - From crude glycerol to carotenoids by using a Rhodotorula glutinis mutant. AB - In this work eighteen red yeasts were screened for carotenoids production on glycerol containing medium. Strain C2.5t1 of Rhodotorula glutinis, that showed the highest productivity, was UV mutagenized. Mutant 400A15, that exhibited a 280 % increase in beta-carotene production in respect to the parental strain, was selected. A central composite design was applied to 400A15 to optimize carotenoids and biomass productions. Regression analyses of the quadratic polynomial equations obtained (R(2) = 0.87 and 0.94, for carotenoids and biomass, respectively) suggest that the models are reliable and significant (P < 0.0001) in the prediction of carotenoids and biomass productions on the basis of the concentrations of crude glycerol, yeast extract and peptone. Accordingly, total carotenoids production achieved (14.07 +/- 1.45 mg l(-1)) under optimized growth conditions was not statistically different from the maximal predicted (14.64 +/- 1.57 mg l(-1)) (P < 0.05), and it was about 100 % higher than that obtained under un-optimized conditions. Therefore mutant 400A15 may represent a biocatalyst of choice for the bioconversion of crude glycerol into value-added metabolites, and a tool for the valorization of this by-product of the biodiesel industry. PMID- 23355138 TI - Identification and characterization of non-saccharomyces spoilage yeasts isolated from Brazilian wines. AB - The industry of fine wines and also locally consumed table wines is emerging in Brazil with an increasing volume and economic impact. Enologists in this region currently lack information about the prevalence and characteristics of spoilage yeasts, which may contaminate and potentially undervalue Brazilian wines. Herein, we analyzed 50 local red wines including 27 fine wines (V. vinifera) and 23 table wines (V. labrusca). Presumptive spoilage yeasts were isolated on differential medium, and classified by RFLP-PCR and sequencing of the ITS1-5.8S-ITS2 and D1/D2 26S rDNA loci. The prevalence of spoilage yeasts in fine wines (11 %) was comparable to that reported in European and US wines, and significantly lower than that observed for local table wines (70 %). The majority of isolates belonged to Brettanomyces bruxelliensis, followed by Pichia guillermondii, and more rarely Candida wickerhamii and Trigonopsis cantarelli. The Brettanomyces isolates varied greatly in off-flavor production, displayed ethanol tolerance (>10 % by volume), tolerated sulfite (>=0.68 mg/l mSO2), and 39 % of them grew on ethanol as sole carbon source. We discuss the causes and consequences of spoilage yeasts in relation to the Brazilian wine industry. PMID- 23355139 TI - Improving yield performance of Pleurotus pulmonarius through hyphal anastomosis fusion of dikaryons. AB - High production and good quality are always the principal goals for agriculturally important crops, without the exception of mushrooms. P. pulmonarius is one of the commercially important edible mushrooms throughout the world. The yield performance improvement was carried out by cross bred P. pulmonarius with P. sapidus and P. ostreatus. The highest rate of 0.587 mm/days for spawn ramification and 53.33 % for percentage spawn productivity were obtained in hybrids LN LL910. The least day (11 and 12th) of the primodia mushroom sporophore were recorded in LL910 and LN 97 respectively, while longest day of 19th was recorded in wild type (NE 07). The highest biological efficiency (109.30 %) and production rate (3.77 %) obtained by LL910, while the least of 33.0 and 0.79 % were obtained by NE 07 for biological efficiency and production rate respectively. The morphological and molecular characterization of the hybrid strains established their true variation from their wild type. LL 910 (JF68088) is located at seventh subclusters from the root with boostrap value of 32 %, while only one parent (LAU 09: JF736658) out of the two has the close boostrap value of 43 % at the first subcluster to the root, with the other parent LAU 10 (JF736659) shows distance relationship after Blast. LN 97 (JF680992) is located at outgroup, while the parent strains NE 07 (boostrap value: 11 %) and LAU 09 (boostrap value: 44 %) located at tenth and second subclusters respectively. The results obtained from this study have shown the improved performance of the hybrids strain over wild type strains. PMID- 23355140 TI - Surveillance and analysis of enteroviruses in water environments in Shenzhen from 2010 to 2011. AB - To determine the prevalence of enteroviruses in aquatic environments in Shenzhen, water samples were collected monthly from April 2010 to December 2011. After concentration by the filter adsorption-beef extract elution method, the enteroviruses were propagated in RD cells. Thirty-five of 105 water samples (33.33 %) were positive for cytopathic effect. E11 and E12 were the most common serotypes and had high genetic diversity in part of the VP1 region. The high prevalence of enteroviruses in water suggests that surveillance of enteroviruses in aquatic environments and evaluation of the risk associated with enteroviruses in water to public health are needed. PMID- 23355141 TI - Evaporation-induced self-alignment and transfer of semiconductor nanowires by wrinkled elastomeric templates. AB - The evaporation-induced self-alignment of semiconductor nanowires is achieved using wrinkled elastomeric templates. The wrinkled templates, which have a surface topography that can be tuned via changes in the mechanical strain, are used as both a template to align the nanowires and as a stamp to transfer the aligned nanowires to target substrates. PMID- 23355142 TI - Evaluation of ultrasound for identification of abdominal wall myofascial components by novice learners. AB - BACKGROUND: Minimally invasive components separation (MICS) is believed to decrease wound complications by reducing local tissue damage and eliminating the interruption of blood supply to the overlying skin and soft tissue. One drawback to the MICS technique is the difficulty with identifying the correct location for entry into the anterior abdominal wall. We believe that ultrasound can be used to visually assist identification of the correct surgical entry site (the avascular space between the external and internal abdominal oblique muscles, lateral to the linea semilunaris). PURPOSE: The purpose of this study was to assess if novices can readily learn an ultrasound technique for identifying abdominal wall myofascial components via a video education tool. METHODS: This research was an institutional review board-approved, prospective, observational study. Ten surgical residents were asked to watch a 1-min training video containing basic instructions on ultrasound technique for identifying the myofascial anatomy of the anterior abdominal wall. After watching the educational video, the subjects were asked to identify the linea semilunaris first by external anatomy, then by ultrasound. A grader, blinded to the identification of the subject, recorded if the subject correctly identified the location of the linea semilunaris by each method (external anatomy only versus ultrasound guided). RESULTS: Ten subjects were evaluated. Nine of ten (90 %) subjects correctly identified the linea semilunaris with ultrasound. Only three of ten (30 %) subjects correctly identified the linea semilunaris by physical exam. CONCLUSIONS: Ultrasound technology can aid in identification of the abdominal wall musculofascial units in MICS and be easily taught via short video instruction to novices with excellent results. Further studies will be necessary to prove that ultrasound use can decrease complications associated with entry into the appropriate avascular space between the external and internal abdominal oblique muscles, lateral to the linea semilunaris. PMID- 23355143 TI - True benefit or selection bias: an analysis of laparoscopic versus open splenectomy from the ACS-NSQIP. AB - BACKGROUND: By virtue of the benefits associated with minimally invasive approaches, laparoscopic splenectomy (LS) is believed to have better patient related outcomes compared to open splenectomy (OS). However, there are limited data directly comparing the two techniques. METHODS: Patients who underwent elective LS and OS between 2005 and 2010 were identified from the public use file of the ACS-NSQIP database using the Current Procedural Terminology codes 38120 and 38100. Patients who had concomitant procedures were excluded. Because of the nonrandom assignment of surgical techniques, a selection bias could have been responsible for the differences in patient outcomes. Therefore, patient characteristics and comorbidities that were available and could have been potential confounders were compared and regression analysis was performed to determine independent risk factors associated with serious and overall morbidity as well as mortality. RESULTS: During the study period 1,644 and 851 patients underwent LS and OS, respectively. Compared to patients who underwent LS, patients who had OS had a longer median length of hospital stay (3 vs. 6 days, P < 0.0001) and higher incidences of serious (7 vs. 17 %, P < 0.0001) and overall morbidity (12 vs. 25 %, P < 0.0001) and mortality (1.4 vs. 3.3 %, P = 0.02). However, there were certain significant differences in the characteristics and comorbidities of the patients that could have confounded outcomes. On regression analysis, OS was not associated with higher mortality (OR = 1.43, 95 % CI 0.7 2.7, P = 0.28) but was associated with higher serious morbidity (OR = 1.8, 95 % CI 1.4-2.3, P = 0.001) and overall morbidity (OR = 2.0, 95 % CI 1.6-2.4, P = 0.0001). CONCLUSION: After adjusting for available confounders, patients who underwent LS had lower morbidity and similar mortality rates. Although certain confounders such as previous surgical history, underlying pathology, and spleen size could still have potentially influenced outcomes, the data suggest that patient outcomes after LS are excellent and when technically possible a minimally invasive technique should be the preferred approach for splenectomy. PMID- 23355144 TI - Laparoscopic pancreaticoduodenectomy: experience of 22 cases. AB - BACKGROUND: Laparoscopic pancreatic surgery has gradually expanded its applications to include pancreaticoduodenectomy. However, the benefits of the laparoscopic approach are still debated. This article aims to present data regarding the efficacy of laparoscopic pancreaticoduodenectomy in a single center. METHODS: From March 2003 to June 2010, a total of 22 patients underwent pancreaticoduodenectomy with a totally laparoscopic approach, using a five-trocar technique. Reconstruction of the digestive tract was adapted to the aspect of the pancreatic stump, with 6 patients having Wirsung duct occlusion and 16 patients pancreaticodigestive anastomosis. Patient selection, short-term outcomes, oncologic results, and technical issues were retrospectively reviewed. RESULTS: Mean operative time was 392 (range, 327-570) min. Conversion was required in 2 patients (9.1 %) as a result of bleeding and difficult dissection. Major intraoperative complications included an injury to the right hepatic artery (4.5 %). Postoperative mortality was 4.5 %. Surgery-related morbidity occurred in 14 patients (63.6 %) and included bleeding (n = 5), pancreatic fistula (n = 6), biliary fistula (n = 2), and dumping syndrome (n = 1). Pancreatic fistulas occurred in 4 patients with duct occlusion and in 2 patients with pancreaticojejunostomy, and they all healed with conservative treatment. Mean hospital stay was 23 (range, 12-35) days. Pathologic diagnoses were pancreatic ductal adenocarcinoma (n = 11), ampullary adenocarcinoma (n = 8), and duodenal adenocarcinoma (n = 3). The resection margins were all free from disease; the mean number of collected lymph nodes was 15 (range, 14-20). CONCLUSIONS: The complexity of pancreaticoduodenectomy entails some issues, including patient selection and management of the pancreatic stump, that are not related to the approach used. Laparoscopic pancreaticoduodenectomy is feasible, safe, and oncologically adequate, but only if performed in selected cases by highly skilled laparoscopic surgeons. Laparoscopy does not provide any significant advantage over traditional surgery, but it may improve postoperative outcomes in the so called excellence centers, once the learning curve has been overcome. Multicenter randomized trials are needed. PMID- 23355145 TI - How to successfully implement a robotic pediatric surgery program: lessons learned after 96 procedures. AB - BACKGROUND: Both our teams were the first to implement pediatric robotic surgery in France. The aim of this study was to define the key points we brought to light so other pediatric teams that want to set up a robotic surgery program will benefit. METHODS: We reviewed the medical records of all children who underwent robotic surgery between Nov 2007 and June 2011 in both departments, including patient data, installation and changes, operative time, hospital stay, intraoperative complications, and postoperative outcome. The department's internal organization, the organization within the hospital complex, and cost were evaluated. RESULTS: A total of 96 procedures were evaluated. There were 38 girls and 56 boys with average age at surgery of 7.6 years (range, 0.7-18 years) and average weight of 26 kg (range, 6-77 kg). Thirty-six patients had general surgery, 57 patients urologic surgery, and 1 thoracic surgery. Overall average operative time was 189 min (range, 70-550 min), and average hospital stay was 6.4 days (range, 2-24 days). The procedures of 3 patients were converted. Median follow-up was 18 months (range, 0.5-43 months). Robotic surgical procedure had an extra cost of 1934 compared to conventional open surgery. CONCLUSIONS: Our experience was similar to the findings described in the literature for feasibility, security, and patient outcomes; we had an overall operative success rate of 97 %. Three main actors are concerned in the implementation of a robotic pediatric surgery program: surgeons and anesthetists, nurses, and the administration. The surgeon is at the starting point with motivation for minimally invasive surgery without laparoscopic constraints. We found that it was possible to implement a long-lasting robotic surgery program with comparable quality of care. PMID- 23355146 TI - Laparoscopic adrenalectomy in patients with subclinical Cushing syndrome. AB - BACKGROUND: Subclinical Cushing syndrome in patients with adrenal incidentalomas has been associated with an increased prevalence of the metabolic syndrome and cardiovascular risk. The management of these patients, be it conservative or surgical, is still debated, but there is accumulating evidence that surgery is best and that laparoscopic adrenalectomy, when possible, is the most preferred procedure. Here we present the short- and long-term results of laparoscopic adrenalectomy for subclinical Cushing syndrome and determine the effect of this procedure on components of the metabolic syndrome. METHODS: Twenty-nine patients, 8 men and 21 women with adrenal incidentalomas and subclinical Cushing syndrome who underwent laparoscopic adrenalectomy, were studied retrospectively. They had undergone postoperative follow-up for improvement or worsening of their arterial blood pressure, body weight, and fasting glucose level for a mean period of 77 months. RESULTS: Preoperatively, 17 patients (58.6 %) had arterial hypertension, 14 (48.3 %) had a body mass index exceeding 27 kg/m(2), and 12 (41.4 %) had diabetes mellitus. Postoperatively, a decrease in mean arterial pressure was found in 12 patients (70.6 %), a decrease in body mass index in 6 patients (42.9 %), and an improvement in glycemic control in 5 patients (41.7 %). CONCLUSIONS: Laparoscopic adrenalectomy is beneficial in many patients with subclinical Cushing syndrome because it reduces arterial blood pressure, body weight, and fasting glucose levels. Prospective randomized studies are needed to compare laparoscopic adrenalectomy with a conservative approach and to confirm these results. PMID- 23355147 TI - Transumbilical thoracic sympathectomy with an ultrathin flexible endoscope in a series of 38 patients. AB - BACKGROUND: The newest trend in the field of thoracic surgery, thoracic natural orifice transluminal endoscopic surgery (NOTES), is still in the early stages of development and limited to animal experiments. Transumbilical endoscopic surgery could work as a viable intermediate step before pure NOTES. We describe our experiences performing transumbilical-diaphragmatic thoracic sympathectomy with an ultrathin flexible endoscope for palmar and axillary hyperhidrosis in human patients. METHODS: From April 2010 to January 2012, a total of 38 patients underwent transumbilical-diaphragmatic thoracic sympathectomy. Through the incision in the umbilicus, a newly developed long trocar was inserted into the abdominal cavity. An ultrathin endoscope was introduced through the long trocar and then passed through the rigid incision made in the left and right diaphragm and into the thoracic cavity. The ganglion was ablated at the desired thoracic level. RESULTS: Sympathectomy was performed successfully in all patients. Mean operation time was 68 +/- 16 (range, 48-107) minutes. There was no mortality and no conversion to open surgery during the operation of any patient. At a median follow-up of 11 (range, 4-12) months after surgery, no diaphragmatic hernia was observed. The rate of palmar hyperhidrosis and axillary hyperhidrosis resolution was 100 and 75 %, respectively. CONCLUSIONS: Transumbilical endoscopic thoracic sympathectomy is technically feasible and safe, which has the possible advantages of pure NOTES and can be performed in routine clinical practice. PMID- 23355148 TI - Dexmedetomidine impairs success of patient-controlled sedation in alcoholics during ERCP: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: There is a lack of studies about procedural sedation of alcoholics. Dexmedetomidine is recommended for procedural sedation and reported effective for alcohol withdrawal. We evaluated the suitability of dexmedetomidine for sedation of alcoholics during endoscopic retrograde cholangiopancreatography (ERCP). METHODS: Fifty patients with chronic alcoholism scheduled for elective ERCP were randomized 1:1 to receive dexmedetomidine (Dex group) (loading dose 1 MUg kg(-1) over 10 min, followed by constant intravenous infusion 0.7 MUg kg(-1) h(-1)) or saline placebo (P group). Patient-controlled sedation with propofol-alfentanil was used by patients as a rescue method. Sedation was considered as successful if no intervention of an anesthesiologist was needed. Consumption of sedatives was registered, and sedation levels and vital signs were monitored. RESULTS: Dexmedetomidine alone was insufficient in all patients. The mean +/- SD consumption of propofol was 159 +/- 72 mg in the P group, and 116 +/- 61 mg in the Dex group (p = 0.028). Sedation was successful in 19 of 25 (76 %) patients in the Dex group and in all patients in the P group (p = 0.022). The incidence of sedation adverse events did not differ between the groups. Dexmedetomidine was associated with delayed recovery. CONCLUSIONS: Patient-controlled sedation with propofol and alfentanil but not dexmedetomidine can be recommended for sedation of alcoholics during ERCP. PMID- 23355149 TI - Cold-start capability in virtual-reality laparoscopic camera navigation: a base for tailored training in undergraduates. AB - BACKGROUND: Frequently medical students have to fulfill the role as the camera operator in laparoscopic procedures. Published work concerning camera navigation skills, especially in medical students, is rare. Therefore, our purpose was to evaluate personal characteristics and abilities that may affect virtual-reality laparoscopic camera navigation (VR-LCN) performance in a large cohort of first time virtual-reality laparoscopy users. METHODS: First-time virtual-reality laparoscopy users (n = 488) were enrolled prospectively. The tasks included VR LCN using a 0 degrees and 30 degrees angled laparoscope separately. Scores were correlated with demographics and students' self-assessment in univariate and multivariate analyses. RESULTS: Six variables were associated with better VR-LCN results in the univariate analysis. On multivariate analysis, only male gender (odds ratio 2.3, 95 % confidence interval 1.4-3.9; p = 0.002) and higher self confidence to assist in a laparoscopic operation (odds ratio 1.7, 95 % confidence interval 1.1-2.6; p = 0.014) were identified as predictive factors for a better 30 degrees angled VR-LCN performance. CONCLUSIONS: Our study indicates that medical students' self-confidence regarding their ability to navigate a camera in a laparoscopic procedure and male gender predict a better first-time VR-LCN performance. These findings may provide a basis for a tailored educational approach. PMID- 23355150 TI - Image-guided laparoscopic surgery in an open MRI operating theater. AB - BACKGROUND: The recent development of open magnetic resonance imaging (MRI) has provided an opportunity for the next stage of image-guided surgical and interventional procedures. The purpose of this study was to evaluate the feasibility of laparoscopic surgery under the pneumoperitoneum with the system of an open MRI operating theater. METHODS: Five patients underwent laparoscopic surgery with a real-time augmented reality navigation system that we previously developed in a horizontal-type 0.4-T open MRI operating theater. RESULTS: All procedures were performed in an open MRI operating theater. During the operations, the laparoscopic monitor clearly showed the augmented reality models of the intraperitoneal structures, such as the common bile ducts and the urinary bladder, as well as the proper positions of the prosthesis. The navigation frame rate was 8 frames per min. The mean fiducial registration error was 6.88 +/- 6.18 mm in navigated cases. We were able to use magnetic resonance-incompatible surgical instruments out of the 5-Gs restriction area, as well as conventional laparoscopic surgery, and we developed a real-time augmented reality navigation system using open MRI. CONCLUSIONS: Laparoscopic surgery with our real-time augmented reality navigation system in the open MRI operating theater is a feasible option. PMID- 23355151 TI - Feasibility of NOTES omental plug repair of perforated peptic ulcers: results from a clinical pilot trial. AB - BACKGROUND: Ulcer perforation carries up to a 30 % 1-year mortality rate. Intervention-related adverse events are among statistically significant predictors of 1-year mortality. A natural orifice transluminal endoscopic surgical (NOTES) approach may be less invasive and may decrease procedure-related adverse events by diminishing the so-called second hit, thus leading to decreased morbidity and mortality. We sought to assess the feasibility of an endoscopic transluminal omental plug technique in patients with perforated gastroduodenal ulcers under laparoscopic guidance. METHODS: Patients with suspected acute gastroduodenal ulcer perforations were offered participation in this prospective pilot study. Closure of the perforation was attempted using the NOTES omental plug technique. Demographic, clinical, endoscopic, and radiographic data were abstracted, as were data for morbidity, mortality, and pilot data regarding quality of life (QOL). RESULTS: From February 2010 through February 2012, a total of 17 patients presented to a tertiary care center with clinically suspected perforated ulcer. Of seven patients (mean age 79 years, range 64-89 years) who consented to the study, three underwent the study procedure. All patients had multiple comorbidities. Two patients presented with 4-6 mm perforated peptic ulcers and underwent successful laparoscopic-assisted NOTES omental and falciform ligament patch closure, respectively. Postoperative radiographic contrast studies showed no leak, and patients were discharged home on postoperative days 3 and 4. The third patient had undergone enterocutaneous fistula repair with herniorrhaphy 6 weeks before. Although a transluminal endoscopic approach was feasible, the omentum was under too much tension to be secured. This procedure was converted to an open omental patch repair. For all but one patient who provided consent, obtaining QOL data was feasible. CONCLUSIONS: Initial results from a laparoscopic assisted NOTES approach for closure of perforated peptic ulcers appear promising and enable swift recovery in selected patients. This is especially important in elderly and/or immunocompromised patients. Technical details and patient selection criteria continue to evolve. PMID- 23355152 TI - Which should go first during same-day upper and lower gastrointestinal endoscopy? A randomized prospective study focusing on colonoscopy performance. AB - BACKGROUND: Same-day bidirectional endoscopy is commonly performed in clinical practice. However, the optimal sequence of procedures for same-day bidirectional endoscopy has not been established. The purpose of this study was to compare colonoscopy performance and quality between patients who underwent colonoscopy before or after esophagogastroduodenoscopy (EGD). METHODS: A total of 1,103 patients were prospectively randomized into either the EGD-colonoscopy or colonoscopy-EGD sequence groups. Three patients who had incomplete cecal intubation due to structural obstruction were excluded from the analysis. During colonoscopy, colonoscopic parameters including difficult cecal intubation (cecal intubation failure and prolonged insertion), insertion time, and adenoma detection rate were measured. Out of 1,100 patients, 524 patients without sedation completed a questionnaire designed to assess subjective discomfort experienced. RESULTS: The colonoscopy completion rate was 99.5 %, and the rate of difficult cecal intubation was 14.5 %. The time from insertion to reaching the cecum (minutes:seconds, 06:32 +/- 04:26 vs. 06:40 +/- 04:09, p = 0.649), difficult cecal intubation ratio (76 of 550 vs. 83 of 550, p = 0.593), and colonoscopic adenoma detection rate (29.8 vs. 25.5 %, p = 0.106) did not differ between the groups. On multivariate analysis, difficulty with cecal intubation increased specifically in women, in patients aged 55 years and over, in patients with poor bowel preparation, and in patients who had undergone previous abdominal surgery. Subjective discomfort after EGD was higher in the colonoscopy-EGD sequence group. CONCLUSIONS: The procedural sequence did not affect colonoscopy performance and quality in same-day bidirectional endoscopy, and factors such as old age, female gender, poor bowel preparation, and previous abdominal surgery were confirmed to adversely affect colonoscopy. In addition, the EGD-colonoscopy sequence induced less subjective discomfort during EGD. PMID- 23355153 TI - Esophageal foreign bodies and eosinophilic esophagitis--the need for esophageal mucosal biopsy: a 12-year survey across pediatric subspecialties. AB - BACKGROUND: Esophageal foreign body impaction (EFBI) is a common problem requiring urgent endoscopy. EFBI may be the first sign of underlying esophageal pathology, yet mucosal biopsies are rarely performed. METHODS: We report a retrospective analysis of 572 children requiring removal of an EFBI over a 12 year period by pediatric otolaryngologists (ENT), surgeons (PS), and gastroenterologists (PGI). The method of removal [direct laryngoscopy (DL), rigid endoscopy (RE), flexible endoscopy (FE)], type of foreign body (inanimate or food), whether mucosal biopsies were performed, and histologic findings of biopsy samples were recorded for each patient. RESULTS: Foreign body removal was most commonly performed by PGI (298 [52 %]); the remaining were equally distributed between ENT (136 [24 %]) and PS (138 [24 %]). The method of foreign body removal used by ENT was RE (89 %), DL (8 %), and FE (3 %). Pediatric surgery preferred FE (62 %), followed by RE (27 %) and DL (11 %). Pediatric gastroenterology used FE exclusively. Esophageal biopsies were never performed by ENT or PS; PGI performed esophageal biopsies more commonly in children with meat bolus impactions (50 %) than in children with inanimate foreign bodies (12 %). Mucosal pathology was more common in children with meat bolus impaction (100 %) than in children with inanimate foreign bodies (45 %). CONCLUSIONS: Esophageal mucosal biopsy should be considered for all children with EFBI not attributed to stricture, particularly those with meat bolus impaction. PMID- 23355154 TI - Perceiving haptic feedback in virtual reality simulators. AB - BACKGROUND: To improve patient safety, training of psychomotor laparoscopic skills is often done on virtual reality (VR) simulators outside the operating room. Haptic sensations have been found to influence psychomotor performance in laparoscopy. The emulation of haptic feedback is thus an important aspect of VR simulation. Some VR simulators try to simulate these sensations with handles equipped with haptic feedback. We conducted a survey on how laparoscopic surgeons perceive handles with and without haptic feedback. METHODS: Surgeons with different levels of experience in laparoscopy were asked to test two handles: Xitact IHP with haptic feedback and Xitact ITP without haptic feedback (Mentice AB, Gothenburg, Sweden), connected to the LapSim (Surgical Science AB, Sweden) VR simulator. They performed two tasks on the simulator before answering 12 questions regarding the two handles. The surgeons were not informed about the differences in the handles. RESULTS: A total of 85 % of the 20 surgeons who participated in the survey claimed that it is important that handles with haptic feedback feel realistic. Ninety percent of the surgeons preferred the handles without haptic feedback. The friction in the handles with haptic feedback was perceived to be as in reality (5 %) or too high (95 %). Regarding the handles without haptic feedback, the friction was perceived as in reality (45 %), too low (50 %), or too high (5 %). A total of 85 % of the surgeons thought that the handle with haptic feedback attempts to simulate the resistance offered by tissue to deformation. Ten percent thought that the handle succeeds in doing so. CONCLUSIONS: The surveyed surgeons believe that haptic feedback is an important feature on VR simulators; however, they preferred the handles without haptic feedback because they perceived the handles with haptic feedback to add additional friction, making them unrealistic and not mechanically transparent. PMID- 23355155 TI - Transoral endoscopic surgery versus conventional thoracoscopic surgery for thoracic intervention: safety and efficacy in a canine survival model. AB - PURPOSE: Transoral endoscopic surgery has been shown to be feasible and safe in both humans and animal models. The purpose of this study was to evaluate the safety and efficacy of transoral and conventional thoracoscopy for thoracic exploration, surgical lung biopsy, and pericardial window creation. METHODS: The animals (n = 20) were randomly assigned to the transoral endoscopic approach group (n = 10) or conventional thoracoscopic approach group (n = 10). Transoral thoracoscopy was performed with a flexible bronchoscope via an incision over the vestibulum oris. In conventional thoracoscopy, access to the thoracic cavity was obtained through a thoracic incision. Surgical outcomes (body weight, operating time, operative complications, and time to resumption of normal diet), physiologic parameters (respiratory rate, body temperature), inflammatory parameters [white blood cell (WBC) counts and C-reactive protein (CRP)], and pulmonary parameters (arterial blood gases) were compared for both procedures. RESULTS: The surgical lung biopsy and pericardial window creation were successfully performed in all animals except one animal in the transoral group. There was no significant difference in operating times between the groups. The increase in WBC in the transoral thoracoscopy group was significantly smaller on postoperative day 1 than in the conventional thoracoscopy group (p = 0.0029). The transoral group had an earlier return to preoperative body temperature (p = 0.041) and respiratory rate (p = 0.045) on day 7. With respect to pulmonary parameters, there was no significant difference in blood pH, pCO2, or PaCO2 between the transoral and transthoracic groups. All animals survived without complications 14 days after surgery. CONCLUSIONS: This study demonstrated that the transoral approach was comparable to conventional thoracoscopic surgery for lung biopsy and pericardial window creation in terms of safety and efficacy. PMID- 23355156 TI - Validation of the application of the Japanese curative criteria for superficial adenocarcinoma at the esophagogastric junction treated by endoscopic submucosal dissection: a long-term analysis. AB - BACKGROUND: A few studies have shown promising results with endoscopic submucosal dissection (ESD) for adenocarcinoma at the esophagogastric junction (EGJAC). However, curative criteria on the histology of EGJAC have not been developed, and long-term clinical results are lacking. The purpose of this study was to validate the application of the Japanese curative criteria to EGJAC after ESD. METHODS: Between September 2002 and March 2009, 1,350 superficial gastric neoplasms in 1,181 patients were treated by ESD at a single tertiary cancer center. For this retrospective cohort study, 49 patients with 50 superficial EGJACs were extracted from our database. Complications, en bloc resection rate, curative resection rate, overall survival, and cause-specific survival were evaluated in all patients. For assessment of curability, curative criteria proposed by the Japanese Gastric Cancer Association for early gastric carcinoma after endoscopic resection were used. RESULTS: Delayed bleeding and postoperative stenosis each occurred in three (6 %) patients but were managed endoscopically. No other major complications were observed related to ESD. The en bloc resection rate was 98 % (49/50), and the curative resection rate was 72 % (36/50). With a median follow up period of 47 (range 22-97) months, the overall survival rates and cause specific survival rates at 5 years were 86.2 % [95 % confidence interval (CI) 76 97] and 100 % (95 % CI 91-100), respectively. CONCLUSIONS: Endoscopic submucosal dissection with application of the Japanese curative criteria may be a feasible and effective treatment for curative intent in patients with superficial EGJAC. PMID- 23355157 TI - Responsiveness of quality of life instruments for the comparison of minimally invasive cholecystectomy procedures. AB - BACKGROUND: Traditional metrics of postoperative outcomes (morbidity and mortality) are not useful to compare minimally invasive procedures with each other. Patient reported outcomes, such as quality of life (QOL) scores, offer an alternative approach. Compared with a large body of data in cancer treatment, the responsiveness of these instruments for minimally invasive surgery is not well described. To better define expected differences, we analyzed the reported QOL outcomes in randomized, controlled trials (RCTs) comparing single and four-port laparoscopic cholecystectomy. METHODS: Searching Medline, Embase, Psychinfo, Scopus, and the Cochrane Library (1946 to Jan 2012), two independent reviewers identified RCTs comparing single with four-port cholecystectomy in adult patients using perioperative QOL assessments. The quality of the studies was assessed regarding trial design and QOL reporting. RevMan was used for mathematical analysis of the pooled outcome data using a random-effects model. Standardized mean difference estimation was utilized when pooling studies reporting different QOL tools. Statistical heterogeneity was assessed using chi(2) and I(2). RESULTS: Of 743 citations, 37 RCTs were identified. Five studies with a total of 502 patients compared single with four-port cholecystectomy on QOL and were included. Pooled analysis was performed using preoperative and 1-month postoperative outcomes. At 1 month postoperatively, the reported effect size of perioperative QOL changes was up to 5 points (~1/2 SD) on the global SF 12 score. The largest difference in change of perioperative physical functioning was 9.9 points (~1 SD). No difference between the treatments was demonstrated. CONCLUSIONS: Reporting of QOL may improve the comparison of minimally invasive surgical procedures. This systematic review reports clinically important changes and did not demonstrate a difference between treatments at 1 month postoperatively. The optimal timing and trial design for QOL tools in this setting needs to be defined further. PMID- 23355158 TI - Preoperative versus intraoperative endoscopic sphincterotomy in patients with gallbladder and suspected common bile duct stones: system review and meta analysis. AB - BACKGROUND: Conducting preoperative versus intraoperative endoscopic sphincterotomy in patients with gallbladder and suspected common bile duct stones remains controversial. We conducted a meta-analysis to evaluate the outcomes of preoperative endoscopic sphincterotomy (POES) versus intraoperative endoscopic sphincterotomy (IOES). METHODS: We searched multiple electronic databases for prospective, randomized, controlled trials related to safety and effectiveness of POES versus IOES. Relative risk ratios (RRs) were estimated with 95 % confidence intervals (CI) based on an intention-to-treat analysis. We considered the following outcomes: clearance rate, postprocedural complications, and hospital stay. RESULTS: Five trials with 631 patients (318 with POES, 313 with IOES) were analyzed. Although the overall rates of common bile duct stone clearance were similar between POES and IOES (RR 0.96, 95 % CI 0.91-1.01; p = 0.13), the failure rate of common bile duct cannulation during endoscopic retrograde cholangiopancreatography (ERCP) was significantly higher for IOES (RR 2.54, 95 % CI 1.23-5.26; p = 0.01). The pooled RR after POES for overall complication rates was similar to that for IOES (RR 1.56, 95 % CI 0.94-2.59; p = 0.09). However, compared with IOES, the RR risk of ERCP-related complications was significantly higher for POES (RR 2.27, 95 % CI 1.18-4.40, p = 0.01), especially in the patients at high risk of developing post-ERCP pancreatitis. There was no significant difference in morbidity after laparoscopic cholecystectomy or required subsequent open surgery between the two groups. In the subgroup analyses, the RR risks of post-ERCP pancreatitis were significantly higher for POES (RR 4.85, 95 % CI 1.41-16.66, p = 0.01), and mean hospital stay was longer in the POES group (RR 2.22, 95 % CI 1.98-246; p < 0.01). However, the rates of bleeding, perforation, cholangitis, cholecystitis, and gastric ulceration did not differ significantly between POES and IOES. CONCLUSIONS: With regard to the stone clearance and overall complication rates, POES is equal to IOES in patients with gallbladder and common bile duct stones. However, IOES is associated with a reduced incidence of ERCP-related pancreatitis and results in a shorter hospital stay. PMID- 23355159 TI - Intraperitoneal instillation of saline and local anesthesia for prevention of shoulder pain after laparoscopic cholecystectomy: a systematic review. AB - BACKGROUND: The laparoscopic technique has many advantages compared with open surgery for symptomatic cholecystolithiasis. Despite these advantages, many patients complain about shoulder pain (SP) after laparoscopic cholecystectomy. The purpose of this review was to evaluate intraperitoneal instillation (IPI) of saline and local anesthesia (LA) to minimize SP. METHODS: A search of the literature was conducted using PubMed and Excerpta Medica Database (EMBASE). Eligibility criteria were: randomized clinical trials (RCT) evaluating IPI of saline and/or LA to minimize incidence or severity of SP after laparoscopic cholecystectomy. Only papers published in English were included. Data extracted were year of publication, number of participants and allocation, timing of IPI, and nonsignificant or significant effect on incidence or severity of SP. RESULTS: A total of 24 RCTs were included in the review. Four RCTs reported results on IPI saline as intervention versus nothing as control. Seven RCTs reported results on IPI LA as intervention versus nothing as control. Sixteen RCTs reported results on IPI LA as intervention versus saline as control. IPI saline resulted in a significant reduction in SP severity compared with nothing. IPI LA was associated with an overall significant reduction of SP severity compared with nothing. Results regarding the effect IPI LA versus saline showed contradictory results in regards to both SP incidence and severity. CONCLUSIONS: Both IPI of saline and LA can be used to reduce SP severity after laparoscopic cholecystectomy. It is not possible to conclude whether the incidence of SP can be reduced with saline or LA, due to contradictive results. PMID- 23355160 TI - Transversus abdominis plane blocks and enhanced recovery pathways: making the 23 h hospital stay a realistic goal after laparoscopic colorectal surgery. AB - BACKGROUND: Although enhanced recovery pathways (ERPs) may permit early recovery and discharge after laparoscopic colorectal surgery (LC), most publications report that the mean hospital stay is 4 and 6 days. This study evaluates the addition of a transversus abdominis plane (TAP) block to the standard ERP. METHODS: In this study, 35 consecutive elective patients received a TAP block at the end of LC. The patients were matched by operation, diagnosis, age, gender, and body mass index (BMI) with 35 recent cases and followed in a prospective institutional review board (IRB)-approved database. All the patients were managed with a standardized ERP. The surgeon placed TAP blocks under laparoscopic guidance that infiltrated 15 ml of 0.5 % Marcaine on both sides of the abdomen. RESULTS: The cases included 8 low pelvic anastomoses, 4 proctectomies with or without an ileal pouch anal anastomosis, 5 sigmoid/left colectomies, 13 ileocolic/right colectomies, 1 total colectomy, and 5 others. The mean age was 59 years for the TAP group and 64.1 years for the control group (p = 0.21). The mean hospital stay was 2 days for the TAP patients and 3 days for the control patients (p = 0.000013). Of the 35 TAP patients, 13 went home on postoperative day (POD) 1 (37 %), 12 on POD 2 (34 %), 8 on POD 3 (23 %), and the remainder on POD 4. Of the 35 control patients, 1 went home on POD 1 (3 %), 10 on POD 2 (29 %), 10 on POD 3 (29 %), 11 on POD 4 (31 %), and the remainder on POD 5 to 8. The TAP patients required fewer narcotics postoperatively than the control patients (respective mean morphine equivalents, 31.08 vs. 85.41; p = 0.01). DISCUSSION: A bilateral TAP block significantly improved the results of an established ERP for patients undergoing LC. Surgeon-administered TAP blocks may be an economical and efficient method for improving the results of LC. PMID- 23355161 TI - Is single-incision laparoscopic cholecystectomy safe? Results of a systematic review and meta-analysis. AB - BACKGROUND: Single-incision laparoscopic cholecystectomy (SILC) is gaining popularity. It is not evident whether the benefits of this procedure overcome the potential increased risk. We performed a systematic review and meta-analysis to compare SILC with conventional multi-incision laparoscopic cholecystectomy (MILC). METHODS: Data from randomized, controlled trials published up to December 2011 and comparing SILC versus MILC were extracted. The primary end point was overall morbidity. A fixed-effect model was applied to summarize the study outcomes in the meta-analysis, and a random-effect model was used in the sensitivity analysis. The outcome measures were relative risk (RR) and mean difference (MD); a RR of <1.0 or a negative MD indicated a more favorable outcome after SILC. Publication bias was assessed by a funnel plot, and heterogeneity was tested by the I (2) measure and subgroup analyses. RESULTS: A total of 12 trials (996 patients) were included. Mortality was nil in both treatment groups; the overall RR for morbidity was 1.36 (p = 0.098). The mean operating time was 47.2 min for MILC and 58.1 min for SILC (MD 9.47 min; p < 0.001). The visual analog scale pain score at 24 h after surgery was 2.96 in MILC and 2.34 in SILC (MD 0.64; p = 0.058), but sensitivity analysis of the four studies deemed at low risk of bias for pain assessment, according to blinding and postoperative analgesic protocols, showed significance at -0.43 points (95 % confidence interval -0.87 to 0.00; p = 0.049). Cosmetic outcome scored better in the SILC group, with its standardized MD being equal to 1.16 (95 % confidence interval 0.57 to 1.75; p < 0.001). CONCLUSIONS: In selected patients, SILC has similar overall morbidity compared with MILC; further, it results in better cosmetic satisfaction and reduced postoperative pain despite longer operative time. PMID- 23355162 TI - Randomized clinical trial of fibrin glue versus tacked fixation in laparoscopic groin hernia repair. AB - BACKGROUND: Preliminary studies have indicated clinical advantages of mesh fixation using fibrin glue in transabdominal preperitoneal groin hernia repair (TAPP) compared with tack fixation. The aim of this randomized double-blinded, controlled, clinical trial is to compare fibrin glue with tacks fixation of mesh during TAPP. METHODS: One hundred and twelve men with unilateral inguinal hernia were enrolled. Primary outcome was pain during coughing on postoperative day 1. Secondary outcomes were postoperative scores of pain at rest, discomfort, and fatigue (day 1 and cumulated day 0-3), incidence of moderate/severe nausea and/or vomiting, foreign-body sensation, and recurrence after 6 months. Outcome measures were assessed by visual analogue scale (VAS, 0-100 mm), verbal rating scale (no, light, moderate or severe) and numerical rating scales (NRS, 1-10). RESULTS: One hundred patients were available for analysis. The fibrin group (n = 50) had significantly less pain during coughing on day 1 compared with the tacks group (n = 50) [median 23 (range 0-80) vs 35 (2-100) mm] (p = 0.020). Moreover, day 1 scores and all cumulated scores of pain during rest, discomfort, and fatigue were significantly lower in the fibrin group compared with the tacks group (all p values <= 0.02). There was no significant difference in the incidence of nausea and/or vomiting (p > 0.05) or recurrence (fibrin glue n = 2, tacks n = 0, p = 0.241). Incidence of foreign-body sensation was significantly lower in the fibrin group at 1 month (p = 0.006). CONCLUSIONS: Fibrin glue compared with tacks fixation improved the early postoperative outcome after TAPP. The trial was registered at clinicaltrials.gov NCT01000116. PMID- 23355163 TI - Laparoscopic cholecystectomy: first, do no harm; second, take care of bile duct stones. PMID- 23355164 TI - A 10-year study of rendezvous intraoperative endoscopic retrograde cholangiography during cholecystectomy and the risk of post-ERCP pancreatitis. AB - BACKGROUND: Rendezvous intraoperative endoscopic retrograde cholangiography (RV IOERC), also called guidewire-facilitated IOERC, is one of the single-stage options available for managing common bile duct stones (CBDS) during laparoscopic cholecystectomy. The objective of this study is to investigate procedure-related complications in IOERC patients and stone clearance. METHODS: All patients who underwent IOERC between January 2000 and December 2009 were identified from the local registry of Karolinska University Hospital in Huddinge. Medical charts and ERC reports were studied, and descriptive statistics were obtained. Outcomes were procedure-related complications, especially post-ERCP pancreatitis (PEP), stone clearance, and mortality. RESULTS: 307 patients were identified. In 264 of the patients, the rendezvous cannulation technique was successful (86 %); in the remaining 43 patients, conventional cannulation technique was necessary. In total, PEP occurred in seven patients (2.28 %). One of the PEP patients was in the rendezvous cannulated group (0.37 %), whereas six patients developed PEP in the nonrendezvous group (13.95 %, p < 0.001). The primary stone clearance rate was 88.27 % (271/307). There was no mortality within 90 days in the series. CONCLUSIONS: IOERC with RV cannulation technique for management of CBDS during laparoscopic cholecystectomy has a low PEP rate and a high stone clearance rate, making it a safe and feasible method for removing CBDS. However, the technique requires logistics to perform IOERC in the operating theater. The present data suggest that IOERC with RV cannulation is superior to conventional cannulation with respect to risk of PEP. PMID- 23355165 TI - A primer on standards setting as it applies to surgical education and credentialing. AB - BACKGROUND: Surgical technological advances in the past three decades have led to dramatic reductions in the morbidity associated with abdominal procedures and permanently altered the surgical practice landscape. Significant changes continue apace including surgical robotics, natural orifice-based surgery, and single incision approaches. These disruptive technologies have on occasion been injurious to patients, and high-stakes assessment before adoption of new technologies would be reasonable. METHODS: We reviewed the drivers for well established psychometric techniques available for the standards-setting process. RESULTS: We present a series of examples that are relevant in the surgical domain including standards setting for knowledge and skills assessments. CONCLUSIONS: Defensible standards for knowledge and procedural skills will likely become part of surgical clinical practice. Understanding the methodology for determining standards should position the surgical community to assist in the process and lead within their clinical settings as standards are considered that may affect patient safety and physician credentialing. PMID- 23355166 TI - Laparoscopic adrenalectomy for malignant lesions: surgical principles to improve oncologic outcomes. AB - BACKGROUND: Laparoscopic adrenalectomy (LA) is the treatment of choice for benign adrenal lesions. Size of the lesion and radiologic features define the risk for malignancy. In lesions at high risk of malignancy, the experience with the laparoscopic approach is limited and therefore controversial. The purpose of this study was to determine the feasibility and oncological safety of LA for malignant disease. METHODS: Retrospective analysis of prospectively collected database. All LA performed in our department from 2003 to 2011 were reviewed and demographic, perioperative, and follow-up data for those who had malignancy in the final histological report was analyzed. Data are presented as mean +/- standard deviation or median (range). RESULTS: Of 121 LA, we identified 20 patients with 21 malignant adrenal pathologies: 11 primary tumors, 5 adrenocortical carcinoma, 5 large B cell lymphoma, and 1 leiomyosarcoma. Ten metastatic lesions included 5 malignant melanoma (1 patient, both sides), 4 adenocarcinoma, and 1 renal cell carcinoma. There was no conversion to laparotomy. Tumor size was 4.5 (1-9.5) cm, operative duration was 79 (42-262) min, and estimated blood loss was 40 (0-250) ml. All patients resumed regular diet on postoperative day 1, and the median length of stay was 2 days after surgery. Two patients died at 6 and 24 months postoperatively. Three patients were lost to follow-up. All the rest of the patients were disease-free at a follow-up of 58 (7-96) months. CONCLUSIONS: LA for primary or metastatic malignant lesions is feasible and seems oncologically safe. Surgical principles should be the same for all LA: en bloc resection of all epinephric fat, minimal touch technique, and low threshold for conversion. Size of the lesion alone should not be an indication for open surgery. PMID- 23355168 TI - Transvaginal natural orifice transluminal endoscopic surgery in the morbidly obese. AB - BACKGROUND: The objective of this study is to assess the safety and efficacy of transvaginal (TV) natural orifice transluminal endoscopic surgery (NOTES) operations in morbidly obese patients. METHODS: One hundred seven NOTES operations have been performed at our institution to date, of which 17 were completed in patients with body mass index (BMI) between 35 and 45 kg/m(2). These included 14 cholecystectomies, one appendectomy, and two ventral hernia repairs. The patients had average age of 36.2 years (range 19-62 years) and average BMI of 38.9 kg/m(2) (range 35.2-44.9 kg/m(2)). The mean number of previous abdominal operations was 1. The TV cholecystectomies were hybrid NOTES procedures, while TV appendectomy and ventral hernia repair were pure NOTES. All operations were completed with standard straight laparoscopic instruments. RESULTS: The mean operative time was 60 min for cholecystectomy, 41 min for TV appendectomy, and 90 min for ventral hernia repair. No significant difference was encountered between the operative time for NOTES cholecystectomies in obese versus nonobese (60 vs. 61 min, p = 0.86). No conversions to traditional laparoscopy or open surgery were made, and no major complications were encountered. CONCLUSIONS: NOTES is an attractive alternative to laparoscopy in female patients with morbid obesity. The procedures are safe and have short operative times, good postoperative outcomes, and improved cosmesis compared with laparoscopy. PMID- 23355167 TI - Acute obstructive jaundice and chronic cirrhosis protect against the adverse renal effects of pneumoperitoneum: role of nitric oxide. AB - BACKGROUND: Obstructive jaundice and cirrhosis are associated with impaired renal function. Previously we demonstrated that increased intra-abdominal pressure (IAP, pneumoperitoneum) in normal rats induced renal dysfunction. This study investigated the renal effects of pneumoperitoneum in rats with acute jaundice and cirrhotic rats. METHODS: Following a baseline period, rats with obstructive jaundice or cirrhosis induced by acute or chronic bile duct ligation (BDL), respectively, and their sham-controls were subjected to consecutive IAPs of 10 and 14 mmHg for 45 min each. Urine flow (V), Na(+) excretion (UNaV), glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary NO metabolites ([Formula: see text]) and cGMP (UcGMP) were determined. RESULTS: Elevating IAP from 0 to 10 and 14 mmHg in normal rats caused IAP-dependent reductions in V, UNaV, GFR, RPF, [Formula: see text] and UcGMP. Basal renal function and hemodynamics were lower in rats with obstructive jaundice. In contrast to normal rats, application of elevated IAP of 10 and 14 mmHg significantly improved V, UNaV, GFR, RPF, and MAP along with increased [Formula: see text] and preserved UcGMP. Similarly, when identical IAP conditions were applied to cirrhotic rats, no deleterious changes in V, UNaV, GFR or RPF were observed. CONCLUSIONS: Application of pneumoperitoneum to rats with acute BDL improves kidney function and renal hemodynamics. Likewise, increased IAP does not exert adverse renal effects in cirrhotic rats. These effects are distinct from the deleterious renal consequences of increased IAP in normal rats. Perturbations in the generation of NO/cGMP during IAP in normal rats but not in rats with BDL or cirrhosis may contribute to these differences. PMID- 23355169 TI - Intra-abdominal collections following laparoscopic versus open appendicectomy: an experience of 516 consecutive cases at a district general hospital. AB - BACKGROUND: The objective of this study is to evaluate the incidence of intra abdominal collections (IACs) in all patients undergoing laparoscopic (LA) and open appendicectomy (OA) from April 2009 to October 2011 in a district general hospital with expertise in minimally invasive surgery (MIS). METHODS: A retrospective review of all patients undergoing appendicectomy in the specified time period was carried out. IACs were identified from various in-hospital data resources. Severity of appendicitis was assessed from histology reports. RESULTS: 516 patients were identified, of whom 242 (47 %) underwent OA and 274 (53 %) LA. Twenty-six (5 %) patients were found to have IACs postoperatively. Fifteen (5.5 %) IACs were identified in the laparoscopic group and 11 (4.5 %) in the open group. There was no statistically significant difference in the risk of developing IACs in open versus laparoscopic groups [odds ratio (OR) 1.22, confidence interval (CI) 0.55-2.70, P = 0.63]. Patients were twelve times more likely to develop IACs with an appendix identified as being necrotic or perforated on histology (OR 12.24, CI 5.29-28.32, P < 0.0001). There was a trend towards shorter total hospital stay in the LA (3.58 days, CI 3.0-4.1 days) compared with OA (4.31 days, CI 3.7-4.9 days, P = 0.082) group, although this was not statistically significant. CONCLUSIONS: Increased rates of IAC following LA have been identified in some studies. Our series shows that, in a centre with adequate MIS experience, the IAC rate following LA is comparable to that of the open approach and should not deter surgeons with adequate support and resources. PMID- 23355170 TI - Assessment of the financial implications for laparoscopic liver surgery: a single centre UK cost analysis for minor and major hepatectomy. AB - BACKGROUND: Laparoscopic hepatectomy is progressively gaining popularity. However, it is still unclear whether the laparoscopic approach offers cost advantages compared with the open approach, especially when major hepatectomies are required. Data providing useful insights into the costs of the laparoscopic approach for clinicians and hospitals are needed. The aim of this study is to assess the financial implications of the laparoscopic approach for two standardized minor and major hepatectomies: left lateral sectionectomy and right hepatectomy. METHODS: A cost comparison analysis of patients undergoing laparoscopic right hepatectomy (LRH) and laparoscopic left lateral sectionectomy (LLLS) versus the open counterparts was performed. Data considered for the comparison analysis were operative costs (theatre cost, consumables and surgeon/anaesthetic labour cost), postoperative costs (hospital stay, complication management and readmissions) and overall costs. RESULTS: A total of 149 patients were included: 38 patients underwent LRH and 46 open right hepatectomy (ORH); 46 patients underwent LLLS and 19 open left lateral sectionectomy (OLLS). For LRH the mean operative, postoperative and overall costs were L10,181, L4,037 and L14,218; for ORH the mean operative, postoperative and overall costs were L6,483 (p < 0.0001), L10,304 (p < 0.0001) and L16,787 (p = 0.886). Regarding LLLS, the mean operative, postoperative and overall costs were L5,460, L2,599 and L8,059; for OLLS the mean operative, postoperative and overall costs were L5,841 (p = 0.874), L5,796 (p < 0.0001) and L11,637 (p = 0.0001). CONCLUSION: Our data support the cost advantage of the laparoscopic approach for left lateral sectionectomy and the cost neutrality for right hepatectomy. PMID- 23355171 TI - Appraisal of the surgical management for pancreatic serous cystic neoplasms. PMID- 23355172 TI - Long-term comparison of laparoscopy-assisted distal gastrectomy and open distal gastrectomy in advanced gastric cancer. PMID- 23355173 TI - Evidence-based laparoscopic appendectomy practice requires national database studies. PMID- 23355175 TI - Mutations in PDYN are not responsible for multiple system atrophy. PMID- 23355176 TI - Risk factors and cerebrovascular disease. PMID- 23355178 TI - Vertebral body infarction revealed by diffusion-weighted magnetic resonance imaging. PMID- 23355179 TI - Antiretroviral treatment and malaria protection in HIV-infected Ugandan children. PMID- 23355177 TI - Widespread grey matter changes and hemodynamic correlates to interictal epileptiform discharges in pharmacoresistant mesial temporal epilepsy. AB - Focal onset epilepsies most often occur in the temporal lobes. To improve diagnosis and therapy of patients suffering from pharmacoresistant temporal lobe epilepsy it is highly important to better understand the underlying functional and structural networks. In mesial temporal lobe epilepsy (MTLE) widespread functional networks are involved in seizure generation and propagation. In this study we have analyzed the spatial distribution of hemodynamic correlates (HC) to interictal epileptiform discharges on simultaneous EEG/fMRI recordings and relative grey matter volume (rGMV) reductions in 10 patients with MTLE. HC occurred beyond the seizure onset zone in the hippocampus, in the ipsilateral insular/operculum, temporo-polar and lateral neocortex, cerebellum, along the central sulcus and bilaterally in the cingulate gyrus. rGMV reductions were detected in the middle temporal gyrus, inferior temporal gyrus and uncus to the hippocampus, the insula, the posterior cingulate and the anterior lobe of the cerebellum. Overlaps between HC and decreased rGMV were detected along the mesolimbic network ipsilateral to the seizure onset zone. We conclude that interictal epileptic activity in MTLE induces widespread metabolic changes in functional networks involved in MTLE seizure activity. These functional networks are spatially overlapping with areas that show a reduction in relative grey matter volumes. PMID- 23355180 TI - Probing the synthesis of two-dimensional boron by first-principles computations. PMID- 23355181 TI - Reversible cardiac dysfunction associated with hypocalcemia: a systematic review and meta-analysis of individual patient data. AB - Case reports have documented reversible cardiac dysfunction in the setting of severely depressed extracellular calcium concentrations. The present systematic review and meta-analyses of individual patient data were conducted to further characterize the cardiac dysfunction associated with low serum calcium levels in the clinical setting. We searched Ovid MEDLINE, Embase, PubMed databases and the Cochrane Library and the Registry of Clinical Trials from 1948 through August 2011. Studies that evaluated low serum calcium and cardiac dysfunction were identified and included for review. A total of 43 studies comprised of 47 individual cases met inclusion criteria. Univariate linear regression analysis showed a statistically significant correlation between corrected QT interval (QTc) length and corrected total serum calcium level (B = -23.19, SE = 8.04, P = 0.01), left ventricular ejection fraction and corrected total serum calcium (B = 5.16, SE = 1.29, P < 0.01) and ionized serum calcium (B = 5.48, SE = 2.04, P = 0.03). Hypocalcemia may be associated with reversible cardiac dysfunction including QTc interval prolongation and depressed left ventricular systolic function. The available evidence is very limited and does not provide a rationale for a certain threshold or a recommendation for calcium replacement. Future research is needed in this important and common metabolic disorder. PMID- 23355183 TI - Discovery of two transglutaminases derived from same zymogen for the Streptomyces hygroscopicus and analysis of their formation processes. AB - BACKGROUND: Transglutaminase (TGase) is secreted as a zymogen (Pro-TGase) and is then processed by removal of its N-terminal region through exogenous proteolytic activity. In this study it was discovered that the Pro-TGase from Streptomyces hygroscopicus was also activated by its TGase (processed through exogenous proteolytic activity), resulting in a different active form. RESULTS: The two TGases exhibited different ionic strengths, hydrophobicities, Km values and stabilities. Circular dichroism spectral analysis showed that the two enzymes had non-identical secondary structures, while liquid chromatography/mass spectrometry (LC-MS) analysis indicated that they differed in molecular mass by 111 Da. The formation of the TGase activated from Pro-TGase by TGase was delayed compared with that of TGase processed through exogenous proteolytic activity. Furthermore, it was found that the TGase activated from Pro-TGase by TGase did not activate Pro-TGase. CONCLUSION: Two TGases derived from the same zymogen from S. hygroscopicus were discovered. These two active forms of TGase may be due to different activation processes: one of them is catalysed by its own active TGase, while the other is activated by an exogenous protease. PMID- 23355184 TI - A robust and novel dynamic-ID-based authentication scheme for care team collaboration with smart cards. AB - Nowadays, users/patients may gain desired medical services on-line because of the rapid development of computer network technologies. Conventional healthcare services are provided by a single server. However, care team collaboration by integrating services is the key to improve financial and clinical performance. How a user/patient accesses desired medical services provided by multiple servers becomes a challenge to realize care team collaboration. User authentication plays an important role to protect resources or services from being accessed by unauthorized users. In this paper, we first discuss the perceived security drawbacks of pervasive smart-card-based remote user authentication schemes. Then, we propose a novel dynamic-ID-based user authentication scheme based on elliptic curve cryptosystem (ECC) for multi-server environment with smart cards. The proposed scheme ensures user anonymity and computational efficiency and complies with essential requirements of a secure smart-card-based authentication scheme for multi-server environment to enable care team collaboration. PMID- 23355182 TI - Qigong improves quality of life in women undergoing radiotherapy for breast cancer: results of a randomized controlled trial. AB - BACKGROUND: Radiotherapy may lead to side effects that undermine patients' quality of life (QOL). Although mind-body practices like qigong appear to improve QOL in cancer survivors, little is known about their benefits for patients who are receiving radiotherapy. Thus, in the current randomized controlled trial, the authors examined the efficacy of a qigong intervention on QOL in women with breast cancer during and after treatment. METHODS: Ninety-six women with breast cancer were recruited from a cancer center in Shanghai, China, and were randomized to a qigong group (N = 49) or a waitlist control group (N = 47). Women in the qigong group attended 5 weekly classes over 5 or 6 weeks of radiotherapy. QOL outcomes (ie, depressive symptoms, fatigue, sleep disturbance, and overall QOL) and cortisol slopes were assessed at baseline, during treatment, at the end of treatment, 1 month later, and 3 months later. RESULTS: The mean age of the women was 46 years (range, 25-64 years). Seven percent of women had stage 0 disease, 25% had stage I disease, 40% had stage II disease, and 28% had stage III disease. Fifty-four percent of women underwent mastectomy. Multilevel analyses revealed that women in the qigong group reported less depressive symptoms over time than women in the control group (P = .05). Women who had elevated depressive symptoms at the start of radiotherapy reported less fatigue (P < .01) and better overall QOL (P < .05) in the qigong group compared with the control group, and these findings were clinically significant. No significant differences were observed for sleep disturbance or cortisol slopes. CONCLUSIONS: The current results indicated that qigong may have therapeutic effects in the management of QOL among women who are receiving radiotherapy for breast cancer. Benefits were particularly evident for patients who had preintervention elevated levels of depressive symptoms. PMID- 23355185 TI - Designing an architectural style for Pervasive Healthcare systems. AB - Nowadays, the Pervasive Healthcare (PH) systems are considered as an important research area. These systems have a dynamic structure and configuration. Therefore, an appropriate method for designing such systems is necessary. The Publish/Subscribe Architecture (pub/sub) is one of the convenient architectures to support such systems. PH systems are safety critical; hence, errors can bring disastrous results. To prevent such problems, a powerful analytical tool is required. So using a proper formal language like graph transformation systems for developing of these systems seems necessary. But even if software engineers use such high level methodologies, errors may occur in the system under design. Hence, it should be investigated automatically and formally that whether this model of system satisfies all their requirements or not. In this paper, a dynamic architectural style for developing PH systems is presented. Then, the behavior of these systems is modeled and evaluated using GROOVE toolset. The results of the analysis show its high reliability. PMID- 23355186 TI - The development of adverse outcome pathways for mutagenic effects for the organization for economic co-operation and development. PMID- 23355187 TI - 'Flash study' on chorionicity determination from ultrasound images at 11-14 weeks' gestation in twin pregnancies. PMID- 23355188 TI - A simple method to estimate the exponential material parameters of heart valve tissue based on analogy between uniaxial tension and micropipette aspiration. AB - Micropipette aspiration (MA) has been widely used to measure the biomechanical properties of cells and biomaterials. To estimate material parameters from MA experimental data, analytical half-space models and inverse finite element (FE) analyses are typically used. The half-space model is easy to implement but cannot account for nonlinear material properties and complex geometrical boundary conditions that are inherent to MA. Inverse FE approaches can account for geometrical and material nonlinearities, but their implementation is resource intensive and not widely available. Here, by making analogy between an analytical uniaxial tension model and a FE model of MA, we proposed an easily implementable and accurate method to estimate the material parameters of tissues tested by MA. We first adopted a strain invariant-based isotropic exponential constitutive model and implemented it in both the analytical uniaxial tension model and the FE model. The two models were fit to experimental data generated by MA of porcine aortic valve tissue (45 spots on four leaflets) to estimate material parameters. We found no significant differences between the effective moduli estimated by the two models(p > 0.39),with the effective moduli estimated by the uniaxial tension model correlating significantly with those estimated by the FE model (p < 0.001; R2 = 0.96) with a linear regression slope that was not different than unity (p = 0.38).Thus, the analytical uniaxial tension model, which avoids solving resource intensive numerical problems, is as accurate as the FE model in estimating the effective modulus of valve tissue tested by MA. PMID- 23355190 TI - Unveiling the binding mode of adenosine deaminase inhibitors to the active site of the enzyme: implication for rational drug design : presented by Maria P. Abbracchio. PMID- 23355189 TI - Anti-inflammatory effects of inosine in allergic lung inflammation in mice: evidence for the participation of adenosine A2A and A 3 receptors. AB - Inosine, a naturally occurring purine formed from the breakdown of adenosine, is associated with immunoregulatory effects. Evidence shows that inosine modulates lung inflammation and regulates cytokine generation. However, its role in controlling allergen-induced lung inflammation has yet to be identified. In this study, we aimed to investigate the role of inosine and adenosine receptors in a murine model of lung allergy induced by ovalbumin (OVA). Intraperitoneal administration of inosine (0.001-10 mg/kg, 30 min before OVA challenge) significantly reduced the number of leukocytes, macrophages, lymphocytes and eosinophils recovered in the bronchoalveolar lavage fluid of sensitized mice compared with controls. Interestingly, our results showed that pre-treatment with the selective A2A receptor antagonist (ZM241385), but not with the selective A2B receptor antagonist (alloxazine), reduced the inhibitory effects of inosine against macrophage count, suggesting that A2A receptors mediate monocyte recruitment into the lungs. In addition, the pre-treatment of mice with selective A3 antagonist (MRS3777) also prevented inosine effects against macrophages, lymphocytes and eosinophils. Histological analysis confirmed the effects of inosine and A2A adenosine receptors on cell recruitment and demonstrated that the treatment with ZM241385 and alloxazine reverted inosine effects against mast cell migration into the lungs. Accordingly, the treatment with inosine reduced lung elastance, an effect related to A2 receptors. Moreover, inosine reduced the levels of Th2-cytokines, interleukin-4 and interleukin-5, an effect that was not reversed by A2A or A2B selective antagonists. Our data show that inosine acting on A2A or A3 adenosine receptors can regulate OVA-induced allergic lung inflammation and also implicate inosine as an endogenous modulator of inflammatory processes observed in the lungs of asthmatic patients. PMID- 23355191 TI - Catalytic asymmetric three-component synthesis of homoallylic amines. AB - It takes three to make things go right: The first direct asymmetric three component reaction of aldehydes, carbamates, and allyltrimethylsilane leading to enantioenriched homoallylic amines has been developed using a new chiral disulfonimide catalyst. The method employs readily available, inexpensive, and nontoxic starting materials and is applicable to both aromatic and aliphatic aldehydes. PMID- 23355192 TI - Self-healing polymer coatings based on crosslinked metallosupramolecular copolymers. AB - Self-healing coating based on metallopolymers are prepared and fully characterized. Iron bisterpyridine complexes are incorporated into a polymer network based on methacrylates, resulting in self-healing properties of these materials. Moreover, the influence of the comonomers on the thermal properties is studied in detail. PMID- 23355193 TI - Deep hypothermia protects against acute hypoxia in vivo in rats: a mechanism related to the attenuation of oxidative stress. AB - There is growing interest in using hypothermia to prevent hypoxic damage in clinical and experimental models, although the mechanisms regulated by hypothermia are still unclear. As reactive oxygen and nitrogen species are the main factors causing cellular damage, our objective was to study the scope of hypothermia in preventing hypoxia-induced oxidative damage. We analysed systemic and hepatic indicators of oxidative stress after an acute hypoxic insult (10% oxygen in breathing air) in normothermic (37 degrees C body temperature) and hypothermic conditions (22 degrees C) in rats. Exposure to hypoxia resulted in tissue damage (aspartate aminotransferase increased from 54.6 +/- 6.9 U l(-1) in control animals to 116 +/- 1.9 U l(-1) in hypoxia, and alanine aminotransferase increased from 19 +/- 0.8 to 34 +/- 2.9 U l(-1)), oxidative stress (nitric oxide metabolites increased from 10.8 +/- 0.4 MUM in control rats to 23 +/- 2.7 MUM in hypoxia, and thiobarbituric reactive substances increased from 3.3 +/- 0.2 to 5.9 +/- 0.4 nm) and antioxidant consumption (reduced/oxidized glutathione ratio changed from 9.8 +/- 0.3 to 6.8 +/- 0.3). In contrast, when hypothermia was applied prior to hypoxia, the situation was reversed, with a reduction in aspartate aminotransferase (from 116 +/- 1.9 in hypoxic animals to 63 +/- 7.8 U l(-1) in animals exposed to hypothermia followed by hypoxia), alanine aminotransferase (from 34 +/- 2.9 to 19 +/- 0.9 U l(-1)), oxidative stress (nitric oxide metabolites decreased from 23 +/- 2.7 to 17.8 +/- 1.9 MUM and thiobarbituric acid-reactive substances decreased from 5.9 +/- 0.4 to 4.3 +/- 0.2 nm) and antioxidant preservation (reduced/oxidized glutathione ratio changed from 6.8 +/- 0.3 to 11.1 +/- 0.1). Hypoxia induced a decrease in liver enzymatic antioxidant activities even during hypothermia. Both treatments, hypoxia and hypothermia, produced a similar increase in hepatic caspase-3 activity. In conclusion, hypothermia prevented the tissue damage and oxidative stress elicited by hypoxia. Our results provide new evidence concerning the protective mechanism of hypothermia in vivo. PMID- 23355195 TI - Ultrafast damage following radiation-induced oxidation of uracil in aqueous solution. PMID- 23355196 TI - Bright-field microscopy for HER2 gene assessment: not just DISH-ful thinking? PMID- 23355194 TI - Genome scan in familial late-onset Alzheimer's disease: a locus on chromosome 6 contributes to age-at-onset. AB - Alzheimer's disease (AD) is a common, genetically complex, fatal neurodegenerative disorder of late life. Although several genes are known to play a role in early-onset AD, identification of the genetic basis of late onset AD (LOAD) has been challenging, with only the APOE gene known to have a high contribution to both AD risk and age-at-onset. Here, we present the first genome scan analysis of the complete, well-characterized University of Washington LOAD sample of 119 pedigrees, using age-at-onset as the trait of interest. The analysis approach used allows for a multilocus trait model while at the same time accommodating age censoring, effects of APOE as a known genetic covariate, and full pedigree and marker information. The results provide strong evidence for linkage of loci contributing to age-at-onset to genomic regions on chromosome 6q16.3, and to 19q13.42 in the region of the APOE locus. There was evidence for interaction between APOE and the locus on chromosome 6q and suggestive evidence for linkage to chromosomes 11p13, 15q12-14, and 19p13.12. These results provide the first independent confirmation of an AD age-at-onset locus on chromosome 6 and suggest that further efforts towards identifying the underlying causal locus or loci are warranted. PMID- 23355197 TI - Thyrotropin receptor antibody assays: clinical utility. PMID- 23355198 TI - Comparison of fluorescence in situ hybridization (FISH) and dual-ISH (DISH) in the determination of HER2 status in breast cancer. AB - The determination of HER2 amplification is critical to selecting appropriate patients for HER2 targeted therapy in breast cancer. Dual in situ hybridization (DISH), an alternative to fluorescence in situ hybridization (FISH) and immunohistochemistry, is now available. To compare the FISH and DISH methods, we tested 251 samples enriched for common or difficult-to-assess HER2 anomalies. Seven samples failed DISH testing. There was a 64% (156/244) concordance between FISH and DISH by anomaly (kappa = 0.58, 95% confidence interval, 0.51-0.65; P < .0001) and an 83% (203/244) concordance by amplification status (kappa = 0.58; 95% confidence interval, 0.47-0.69; P < .0001). DISH resulted in lower estimates of HER2/ centromere 17 ratios than FISH, and many cases that were equivocal with FISH were normal with DISH. DISH did not detect any case with coamplification of HER2 and centromere 17. Using a cohort of difficult specimens, we observed less than 95% concordance between FISH and DISH. DISH may underestimate the HER2/chromosome 17 ratio, or FISH may overestimate this ratio. PMID- 23355200 TI - Napsin A expression in primary mucin-producing adenocarcinomas of the lung: an immunohistochemical study. AB - Immunohistochemical expression of napsin A in primary pulmonary mucinous tumors is not well established. Napsin A immunoreactivity was evaluated in 43 mucin producing adenocarcinomas of the lung consisting of 18 tumors formerly classified as mucinous bronchioloalveolar carcinoma, 15 colloid adenocarcinomas, 5 solid predominant adenocarcinomas with mucin production, and 5 adenocarcinomas with signet ring cell features, as well as in 25 extrapulmonary mucinous adenocarcinomas of different anatomic sites. Immunohistochemical expression of thyroid transcription factor 1 (TTF-1) was also compared. Thirty-three percent of mucinous lung tumors exhibited positive immunoreactivity for napsin A, whereas 42% expressed TTF-1. All 25 extrapulmonary mucinous adenocarcinomas lacked expression of napsin A and TTF-1. Mucin-producing neoplasms of the lung infrequently express napsin A, suggesting that immunohistochemical assessment of napsin A may have limited diagnostic usefulness for distinguishing primary and metastatic mucinous adenocarcinomas involving the lung. PMID- 23355199 TI - A broad survey of cathepsin K immunoreactivity in human neoplasms. AB - Cathepsin K is consistently and diffusely expressed in alveolar soft part sarcoma (ASPS) and a subset of translocation renal cell carcinomas (RCCs). However, cathepsin K expression in human neoplasms has not been systematically analyzed. We constructed tissue microarrays (TMA) from a wide variety of human neoplasms, and performed cathepsin K immunohistochemistry (IHC). Only 2.7% of 1,140 carcinomas from various sites exhibited cathepsin K labeling, thus suggesting that among carcinomas, cathepsin K labeling is highly specific for translocation RCC. In contrast to carcinomas, cathepsin K labeling was relatively common (54.6%) in the 414 mesenchymal lesions studied, including granular cell tumor, melanoma, and histiocytic lesions, but not paraganglioma, all of which are in the morphologic differential diagnosis of ASPS. Cathepsin K IHC can be helpful in distinguishing ASPS and translocation RCC from some but not all of the lesions in their differential diagnosis. PMID- 23355201 TI - Combined loss of E-cadherin and aberrant beta-catenin protein expression correlates with a poor prognosis for small intestinal adenocarcinomas. AB - Small intestinal adenocarcinomas (SIACs) are rare, and their molecular pathogenesis is largely unknown. To define the roles of E-cadherin and beta catenin, we performed immunohistochemistry for E-cadherin and beta-catenin in 194 surgically resected SIACs with tissue microarrays and compared the data with clinicopathologic factors, including survival rates of patients with SIAC. Loss of E-cadherin expression and aberrant beta-catenin expression were observed in 41.8% (81/194 cases) and 40.7% (79/194 cases) of SIACs, respectively. Combined loss of E-cadherin and aberrant beta-catenin expression was observed in 24.2% (47/194 cases) of SIACs, and this feature was most frequently observed in mucinous adenocarcinomas and signet ring cell carcinomas (P < .001), poorly differentiated and undifferentiated carcinomas (P < .001), and tumors with advanced pT classification (P = .03). Survival times for patients with SIAC with both loss of E-cadherin and aberrant beta-catenin expression (median, 13.9 months) were significantly shorter than those for patients without aberrant expression of both proteins (49.9 months), as determined by univariate (P < .001) and multivariate (P = .01) analyses. In conclusion, loss of E-cadherin and aberrant beta-catenin expression correlate with poorly differentiated tumors, advanced T classification, and decreased patient survival time; therefore, it could be a prognostic factor in patients with SIAC. PMID- 23355202 TI - Morphologic and immunocytochemical performances of effusion cell blocks prepared using 3 different methods. AB - With increased use of the ThinPrep method for nongynecologic specimens, cell blocks are more commonly prepared by harvesting cells that are fixed in CytoLyt solution. The current study compared morphologic and immunocytochemical performance of effusion cell blocks prepared using CytoLyt-prefixed thrombin clot (CTC) with plasma thrombin clot (PT) and HistoGel (HG) preparation. The study included a total of 25 malignant or benign serous fluids. Three individual cell block materials were simultaneously prepared from each of the 25 effusion specimens using the CTC, PT, or HG method. H&E staining and immunostaining for pancytokeratin (pan-CK), carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), B72.3, HBME-1, estrogen receptor (ER), progesterone receptor (PR), CD45, CD20, and CD3 were then performed. The CTC preparation revealed compatible cellularity and good cellular details. In addition, CTC cell blocks revealed a similar percentage of cells with positive immunostaining along with the strongest intensity and the least background staining. The CTC method can be used reliably as an adjunct to other preparation techniques. PMID- 23355203 TI - Facilitating the laboratory diagnosis of alpha1-antitrypsin deficiency. AB - alpha(1)-Antitrypsin (AAT) deficiency leads to deterioration of the lungs that can be prevented with diagnosis and treatment. Isoelectric focusing (IEF) electrophoresis is the current biochemical gold standard for detecting AAT deficiency variants but involves complex interpretation. Variant AAT samples were collected over a 2-year period. Stability of AAT for phenotype determination was assessed in whole blood, dried blood spots, and dried serum spots. A compendium displaying 13 common and 5 rare AAT phenotypes was created, and a detailed methodology describing how to recognize AAT banding patterns and interpret a rare phenotype accompanied these visual data. AAT was stable for IEF phenotype analysis for at least 1 week in whole blood and for 24 hours on dried serum spots. In conclusion, a reference compendium of known AAT phenotypes was established that can serve as a resource for interpreting AAT phenotypes. PMID- 23355204 TI - Analytical performance and clinical utility of a bioassay for thyroid-stimulating immunoglobulins. AB - The analytical performance and the clinical utility of a thyrotropin receptor (TSHR)-stimulating immunoglobulin (TSI) bioassay were compared with those of a TSHR-binding inhibitory immunoglobulin (TBII) assay. Limits of detection (LoD) and quantitation (LoQ), assay cutoff, and the half-maximal effective concentration (EC(50)) were measured. Dilution analysis was performed in sera of hyperthyroid patients with Graves disease (GD) during antithyroid treatment (ATD). Titer was defined as the first dilution step at which measurement of TSI or TBII fell below the assay cutoff. The LoD, LoQ, cutoff, and EC(50) of the bioassay were 251-, 298-, 814-, and 827-fold lower than for the TBII assay. There were 22%, 42%, 23%, and 14% more positive samples in the TSI bioassay at dilutions of 1:3, 1:9, 1:27, and 1:81 (P < .0001), respectively. Responders to ATD demonstrated marked differences in titers compared with nonresponders. The bioassay detected lower levels of TSHR autoantibodies, and the dilution analysis provided similar predictive values of both assays in GD. PMID- 23355205 TI - Establishment of a CYP2C19 genotyping assay for clinical use. AB - Conversion of clopidogrel (Plavix) to its active metabolite is catalyzed largely by the P450 enzyme 2C19 (CYP2C19). Numerous allelic variants of CYP2C19 exist. The *1 allele is considered wild type, whereas the *2 and *3 alleles have no in vivo enzymatic activity. Conversely, the *17 allele has increased expression, resulting in increased clopidogrel activation. Poor metabolizers (*2/*2 and *2/*3 genotypes) experience higher rates of therapeutic failure. For this reason, we have validated a CYP2C19 genotyping assay for the *1, *2, *3, and *17 alleles. Genomic DNA extracted from 30 deidentified EDTA whole-blood samples from patients was analyzed at 2 independent facilities using specific TaqMan realtime polymerase chain reaction primers and probes. Concordant genotypes were generated on all samples tested. Of the 30 samples, 15 were CYP2C19*1/*1, 8 were CYP2C19*1/*17, 5 were CYP2C19*1/*2, and 2 were CYP2C19*2/*17. There were no CYP2C19*3 alleles or *2/*2 homozygous genotypes detected. This CYP2C19 genotyping assay is appropriate for clinical testing, demonstrating excellent interlaboratory concordance, enabling the selection of the most effective clopidogrel treatment regimen for patients undergoing percutaneous coronary intervention. PMID- 23355206 TI - Nuclear protein dysregulation in lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia. AB - Waldenstrom macroglobulinemia (WM) is characterized by monoclonal gammopathy, usually IgM, in association with lymphoplasmacytic lymphoma (LPL). Little is known of the expression of nuclear proteins involved in B-cell development in LPL/WM. In this study, the expression patterns of PAX5/BSAP, MUM1/IRF4, and PRDM1/BLIMP1 were analyzed in plasma cells and lymphocytes in 29 cases of newly diagnosed LPL/WM by double immunohistochemical staining with CD138 and CD22. These patterns were compared with the expression profiles seen in normal bone marrow samples, reactive tonsils, and cases of plasma cell myeloma and marginal zone lymphoma. The median percentage of plasma cells coexpressing CD138 and PAX5 was significantly higher in LPL/WM compared with benign tissues (P = .001), marginal zone lymphoma (P = .002), and plasma cell myeloma (P < .0001), whereas the median percentage of plasma cells coexpressing CD138 and MUM1 was lower in LPL/WM than plasma cells in benign tissues (P = .02), marginal zone lymphoma (P = .001), and plasma cell myeloma (P = .0002). These findings show that a subset of plasma cells in LPL/WM demonstrates a nuclear protein expression pattern characteristic of the B-cell developmental program. Thus, the results better define the immunophenotypic profile of the neoplastic cells in LPL/WM. PMID- 23355207 TI - Immunohistochemical detection of hairy cell leukemia in paraffin sections using a highly effective CD103 rabbit monoclonal antibody. AB - Detection of the integrin subunit CD103 is a useful diagnostic tool in the diagnosis of hairy cell leukemia (HCL). Currently, flow cytometric analysis (FC) and frozen section immunohistochemistry (IHC) represent the only available methods of detection. This study is the first to describe the successful use of a CD103 antibody to identify HCL and HCL-variant in paraffin sections of formalin- or Bouin solution- fixed specimens (n = 68) using an immunoperoxidase technique. In other B-cell lymphoproliferative disorders that morphologically may resemble HCL, including chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 32), mantle cell lymphoma (n = 23), lymphoplasmacytic lymphoma (n = 27), follicular lymphoma (n = 7), and marginal zone lymphoma (n = 13), lymphoid cells are nonreactive for CD103. In HCL, the CD103 staining pattern is predominantly membranous with delineation of delicate cytoplasmic projections. This CD103 antibody is an extremely valuable addition to the IHC panel for the diagnosis of HCL, especially in cases lacking FC analysis. PMID- 23355208 TI - Expansion of a clonal CD8+CD57+ large granular lymphocyte population after autologous stem cell transplant in multiple myeloma. AB - Clonal expansions of large granular lymphocytes (LGLs) have been identified in patients following stem cell transplants and may represent posttransplant LGL leukemias or reactive immune responses. To differentiate between these 2 possibilities, we assessed peripheral blood and bone marrow of patients with myeloma after autologous stem cell transplant. All patients examined shortly after autologous stem cell transplant had significant increases in the LGLs in the peripheral blood and bone marrow (71% of lymphocytes) as compared with controls (39%). This increase was detectable years after transplant. The LGLs had a reproducible immunophenotype of CD8+CD57+ T cells without phenotypic abnormalities in 19 of 20 patients. Sixty-five percent of the post-autologous stem cell transplant patients had clonal T-cell receptor gene rearrangements in the bone marrow, yet no patients had neutropenia or splenomegaly. Although the LGL expansions were clonal and persistent, the lack of clinical sequelae suggests the clonal LGL expansion is a reactive, potentially beneficial, immune response to autologous stem cell transplant. PMID- 23355209 TI - Colorimetric in situ hybridization identifies MYC gene signal clusters correlating with increased copy number, mRNA, and protein in diffuse large B-cell lymphoma. AB - Abnormalities of the MYC oncogene on chromosome 8 are characteristic of Burkitt lymphoma and other aggressive B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). We recently described a colorimetric in situ hybridization (CISH) method for detecting extra copies of the MYC gene in DLBCL and the frequent occurrence of excess copies of discrete MYC signals in the context of diploidy or polyploidy of chromosome 8, which correlated with increased mRNA signals. We further observed enlarged MYC signals, which were counted as a single gene copy but, by their dimension and unusual shape, likely consisted of "clusters" of MYC genes. In this study, we sought to further characterize these clusters of MYC signals by determining whether the presence of these correlated with other genetic features, mRNA levels, protein, and overall survival. We found that MYC clusters correlated with an abnormal MYC locus and with increased mRNA. MYC mRNA correlated with protein levels, and both increased mRNA and protein correlated with poorer overall survival. MYC clusters were seen in both the germinal center and activated B-cell subtypes of DLBCL. Clusters of MYC signals may be an underappreciated, but clinically important, feature of aggressive B cell lymphomas with potential prognostic and therapeutic relevance. PMID- 23355212 TI - Confirming suboptimal adherence to HPV cotesting guidelines in an academic center in Vermont. PMID- 23355213 TI - Combined iron deficiency and thalassemia minor. PMID- 23355214 TI - The authors' reply. PMID- 23355215 TI - Can soluble Klotho protein be a potential tumor biomarker? PMID- 23355217 TI - Evaluation of the urinary threshold concentration of formoterol in sports drug testing. AB - The use of formoterol in sports is allowed by inhalation at the maximum recommended therapeutic dose. Recently, a threshold concentration of 30 ng.mL(-1) was defined by the World Anti-Doping Agency (WADA) to distinguish between therapeutic and forbidden use of formoterol. The objective of this work was to evaluate that threshold concentration. Concentrations of formoterol were measured in urine samples collected after administration of 18 ug of inhaled formoterol to five healthy volunteers, and in samples collected in routine doping tests belonging to athletes having declared inhaled formoterol use. Formoterol was detected up to 8 h after administration in all volunteers with concentrations up to 19.6 ng.mL(-1) . From 28 routine samples, 27 had less than 10 ng.mL(-1) of formoterol and only in one of the samples the concentration was 25 ng.mL(-1) . Therefore, administration of formoterol by inhalation at the maximum dose allowed by WADA will not produce false positive results using a threshold concentration of 30 ng.mL(-1) , and the experience up to now in routine doping tests indicates that the probability of obtaining urines with concentrations greater than 30 ng.mL(-1) is close to nil. For this reason, sports authorities should re-evaluate the need of a threshold concentration for formoterol and its practical usefulness. PMID- 23355216 TI - Mycophenolate mofetil has potent anti-inflammatory actions in a mouse model of acute lung injury. AB - Septic shock is a systemic inflammatory response syndrome, and it is the leading cause of death in intensive care units. Mycophenolate mofetil (MMF) is an immunosuppressant that has been shown to be effective in the treatment of various inflammatory diseases. In this study, the anti-inflammatory effect of MMF in a mouse model of acute lung injury (ALI) induced by lipopolysaccharide (LPS) was evaluated. ALI was induced by intrapleural injection of LPS (250 ng/cavity). The leukocyte migration, exudation, myeloperoxidase and adenosine deaminase activities, nitric oxide products, tumor necrosis factor alpha (TNF-alpha), and interleukin 1 beta (IL-1beta) levels, as well as mRNA expression of TNF-alpha and IL-1beta, were evaluated. This study showed that MMF significantly decreased all parameters studied in a manner comparable to treatment with dexamethasone. In conclusion, MMF has important anti-inflammatory effects that may be useful as an auxiliary treatment for septic shock. PMID- 23355218 TI - Hemiarthroplasty for proximal humerus fractures. AB - Proximal humerus fractures are common injuries that are increasing in incidence with the aging of the population. While nonoperative treatment of some fracture patterns results in clinical success, other, more displaced and comminuted fractures may require surgery to ensure a successful outcome. It is important to evaluate both patient and fracture characteristics in deciding upon the appropriate type of treatment. Every effort should be made to perform a humeral sparing procedure in younger patients. In the elderly, especially with more complex four-part fractures and fracture dislocations, hemiarthroplasty and reverse total shoulder arthroplasty are indicated to decrease complication rates and improve functional outcomes. In hemiarthroplasties, it is critical to achieve proper implant height and positioning of the tuberosities. For those patients or fractures in which the tuberosities are unlikely to heal or cannot be adequately reconstructed, reverse total shoulder arthroplasty should be considered. PMID- 23355219 TI - Pain-related work interference is a key factor in a worker/workplace model of work absence duration due to musculoskeletal conditions in Canadian nurses. AB - OBJECTIVE: To examine the role of pain experiences in relation to work absence, within the context of other worker health factors and workplace factors among Canadian nurses with work-related musculoskeletal (MSK) injury. METHODS: Structural equation modeling was used on a sample of 941 employed, female, direct care nurses with at least one day of work absence due to a work-related MSK injury, from the cross-sectional 2005 National Survey of the Work and Health of Nurses. RESULTS: The final model suggests that pain severity and pain-related work interference mediate the impact of the following worker health and workplace factors on work absence duration: depression, back problems, age, unionization, workplace physical demands and low job control. The model accounted for 14 % of the variance in work absence duration and 46.6 % of the variance in pain-related work interference. CONCLUSIONS: Our findings support a key role for pain severity and pain-related work interference in mediating the effects of workplace factors and worker health factors on work absence duration. Future interventions should explore reducing pain-related work interference through addressing workplace issues, such as providing modified work, reducing physical demands, and increasing job control. PMID- 23355220 TI - Further validation of a measure of injury-related injustice perceptions to identify risk for occupational disability: a prospective study of individuals with whiplash injury. AB - PURPOSE: Emerging evidence suggests that perceptions of injustice negatively impact return to work following whiplash injury. The Injustice Experiences Questionnaire (IEQ) is a recently developed measurement tool that may be used to assess injury-related perceptions of injustice following injury. To date, although research has supported the predictive validity of the IEQ, a clinical cut off for interpreting this measure has not been established. Increased support for the validity and clinical interpretation of the IEQ represents a first step towards identifying patients that might benefit from targeted intervention to mitigate the impact of perceived injustice. METHODS: The IEQ was completed by 103 whiplash-injured patients upon commencement and completion of a standardized multidisciplinary rehabilitation program. One year later, individuals reported on their employment activity, pain severity, and use of narcotics. A receiver operating characteristic (ROC) curve analysis was conducted to identify the post treatment IEQ score that was optimally associated with unemployment status at the follow-up. Secondary ROC curve analyses examined IEQ scores best associated with high pain severity and narcotic use 1 year following treatment. RESULTS: Results indicated that IEQ scores significantly discriminated individuals who returned and did not return to work at the follow-up. An IEQ score of 19 optimally identified participants in terms of follow-up employment status. IEQ scores at the end of treatment also discriminated individuals with high and low pain severity ratings and narcotic use status at the follow-up. Post-treatment IEQ scores of 18 and 20 optimally identified participants who had high pain severity ratings and who were using narcotics at the follow-up, respectively. CONCLUSIONS: These results further support the validity of the IEQ and provide a guideline for its clinical interpretation in patients with persistent pain and disability following musculoskeletal injury. IEQ scores above the identified cut off may represent a barrier to work return and may warrant targeted intervention. PMID- 23355221 TI - Relationship between polyphenol content and anti-influenza viral effects of berries. AB - BACKGROUND: Berries are known to have many kinds of biological activities. We focused on their antiviral effect, which has not yet been well evaluated. RESULTS: We compared the anti-influenza viral effects of berries belonging to the genus Vaccinium - 35 species of blueberry (Vaccinium cyanococcus), the Natsuhaze (Vaccinium oldhamii), bilberry (Vaccinium myrtillus) and cranberry (Vaccinium oxycoccos)- with those belonging to the genus Ribes, i.e. blackcurrant (Ribes nigrum). Only Elliott and Legacy among Northern Highbush varieties but many Rabbiteye varieties such as Austin, Baldwin, Brightblue, Festival, T-100 and Tifblue showed anti-influenza viral activity. Natsuhaze, bilberry, cranberry and blackcurrant had high antiviral effects. A relationship was observed between the antiviral effect and total polyphenol content. CONCLUSIONS: Antiviral effects were found to differ markedly between berry species. Rabbiteye varieties tended to have higher antiviral effects than Northern, Southern and Half Highbush blueberry varieties. We also found that Natsuhaze, which has recently been harvested in Japan as a potential functional food, had an antiviral effect comparable to that of bilberry, cranberry and blackcurrant. There was a positive relationship between antiviral activity and polyphenol content, indicating the possibility that polyphenol is one of the key factors in the antiviral effects of berries. PMID- 23355222 TI - Inflammasome activation restricts Legionella pneumophila replication in primary microglial cells through flagellin detection. AB - Microglial cells constitute the first line of defense of the central nervous system (CNS) against microbial invasion. Pathogens are detected thanks to an array of innate immune receptors termed pattern recognition receptors (PRRs). PRRs have been thoroughly characterized in bone marrow-derived macrophages, but the PRRs repertoire and functionality in microglial cells remain largely unknown. Microglial cells express various Toll-like Receptors and the Nod1/2 receptors. Recently, a novel innate immune signalling pathway, the inflammasome pathway has been uncovered. Inflammasome activation leads to caspase-1 activation, release of the proinflammatory cytokines, IL-1beta and IL-18 and cell death in a process termed pyroptosis. One inflammasome receptor, NLRP3, has been characterized in microglial cells and associated with response to infections and in the initiation of neuro-degeneration in an Alzheimer's disease model. Legionella pneumophila (L.pneumophila) is a flagellated bacterium replicating within macrophages. In bone marrow-derived macrophages, L. pneumophila is detected in a flagellin dependent manner by the Naip5-NLRC4 (Ipaf) inflammasome pathway. In this study, we decided to use L. pneumophila to investigate the presence and the functionality of this inflammasome in primary murine microglial cells. We show that microglial cells detect L. pneumophila infection in a flagellin-dependent manner leading to caspase-1-mediated bacterial growth restriction, infected cell death and secretion of the proinflammatory cytokines IL-1beta and IL18. Overall, our data demonstrate that microglial cells have a functional Naip5-NLRC4 inflammasome likely to be important to monitor and clear CNS infections by flagellated bacteria. PMID- 23355223 TI - Which newborns are too expensive to treat? A response to Dominic Wilkinson. PMID- 23355224 TI - Participant experience of invasive research in adults with intellectual disability. AB - Clinical research is a necessity if effective and safe treatments are to be developed. However, this may well include the need for research that is best described as 'invasive' in that it may be associated with some discomfort or inconvenience. Limitations in the undertaking of invasive research involving people with intellectual disabilities (ID) are perhaps related to anxieties within the academic community and among ethics committees; however, the consequence of this neglect is that innovative treatments specific to people with ID may not be developed. Such concerns are likely to continue while there is limited published knowledge regarding the actual experiences of people with ID who have participated in invasive clinical research. As part of a pilot study trialling the novel use of a surgically inserted device to curb overeating in people with Prader-Willi syndrome (PWS) we have investigated the experience of research through semistructured qualitative interviews involving three participants and their carers. Thematic analysis revealed that the adults with PWS and their family carers rated their participation positively, seeing it as a rewarding and enriching experience. This brief report discusses findings from our interview data in order to highlight strategies which may ensure that research is acceptable to participants, meets the necessary ethical standards and is able to achieve the aims set out by the researchers. To our knowledge, this is the first study to record experiences directly from people with PWS and their carers regarding their involvement in invasive clinical research. PMID- 23355225 TI - Elective non-therapeutic intensive care and the four principles of medical ethics. AB - The chronic worldwide lack of organs for transplantation and the continuing improvement of strategies for in situ organ preservation have led to renewed interest in elective non-therapeutic ventilation of potential organ donors. Two types of situation may be eligible for elective intensive care: patients definitely evolving towards brain death and patients suitable as controlled non heart beating organ donors after life-supporting therapies have been assessed as futile and withdrawn. Assessment of the ethical acceptability and the risks of these strategies is essential. We here offer such an ethical assessment using the four principles of medical ethics of Beauchamp and Childress applying them in their broadest sense so as to include patients and their families, their caregivers, other potential recipients of intensive care, and indeed society as a whole. The main ethical problems emerging are the definition of beneficence for the potential organ donor, the dilemma between the duty to respect a dying patient's autonomy and the duty not to harm him/her, and the possible psychological and social harm for families, caregivers other potential recipients of therapeutic intensive care, and society more generally. Caution is expressed about the ethical acceptability of elective non-therapeutic ventilation, along with some proposals for precautionary measures to be taken if it is to be implemented. PMID- 23355226 TI - Honouring the donor: in death and in life. AB - Elective ventilation (EV) is ventilation-not to save a patient's life, but with the expectation that s/he will die-in the hope that organs can be retrieved in the best possible state. The arguments for doing such a thing rest on the value of the lives being saved by the donated organs, maximally honouring the donor's wishes where the patient can be reasonably thought to wish to donate, and a general principle in favour of organ donation where possible as an expression of human solidarity. Arguments against include difficulties surrounding the patient's consent to donation (including the risk of them surviving in an unacceptably bad state), the possibility of changing our perception of organ donation and care in dying, and the moral distress potentially caused to intensive care unit (ICU) staff involved in EV. EV can occur before or after the patient is declared dead and it is EV before the declaration of death (EVb) that occasions the ethical worries. I argue that when we acknowledge the tragedy involved, attend sensitively to the grief proper to human death, and ensure that we are not working in an ethical and legal climate that increases the likelihood of inadvertent survival in an unacceptably bad state, EVb is ethically defensible. PMID- 23355227 TI - Authenticity or autonomy? When deep brain stimulation causes a dilemma. AB - While deep brain stimulation (DBS) for patients with Parkinson's disease has typically raised ethical questions about autonomy, accountability and personal identity, recent research indicates that we need to begin taking into account issues surrounding the patients' feelings of authenticity and alienation as well. In order to bring out the relevance of this dimension to ethical considerations of DBS, I analyse a recent case study of a Dutch patient who, as a result of DBS, faced a dilemma between autonomy and authenticity. This case study is meant to point out the normatively meaningful tension patients under DBS experience between authenticity and autonomy. PMID- 23355228 TI - Physician emigration, population health and public policies. PMID- 23355229 TI - Which newborn infants are too expensive to treat? Camosy and rationing in intensive care. AB - Are there some newborn infants whose short- and long-term care costs are so great that treatment should not be provided and they should be allowed to die? Public discourse and academic debate about the ethics of newborn intensive care has often shied away from this question. There has been enough ink spilt over whether or when for the infant's sake it might be better not to provide life-saving treatment. The further question of not saving infants because of inadequate resources has seemed too difficult, too controversial, or perhaps too outrageous to even consider. However, Roman Catholic ethicist Charles Camosy has recently challenged this, arguing that costs should be a primary consideration in decision making in neonatal intensive care. In the first part of this paper I will outline and critique Camosy's central argument, which he calls the 'social quality of life (sQOL)' model. Although there are some conceptual problems with the way the argument is presented, even those who do not share Camosy's Catholic background have good reason to accept his key point that resources should be considered in intensive care treatment decisions for all patients. In the second part of the paper, I explore the ways in which we might identify which infants are too expensive to treat. I argue that both traditional personal 'quality of life' and Camosy's 'sQOL' should factor into these decisions, and I outline two practical proposals. PMID- 23355231 TI - Effect of interfacial properties on polymer-nanocrystal thermoelectric transport. AB - The electrical behavior of a conducting-polymer/inorganic-nanowire composite is explained with a model in which carrier transport occurs predominantly through a highly conductive volume of polymer that exists at the polymer-nanowire interface. This result highlights the importance of controlling nanoscale interfaces for thermoelectric materials, and provides a general route for improving carrier transport in organic/inorganic composites. PMID- 23355230 TI - Use of biomarkers in the management of children with lupus. AB - Childhood systemic lupus erythematosus (SLE) is known to have a worse prognosis than adult-onset disease, and monitoring and treatment of the disease are still a challenge. Thus, there is an urgent need for highly reliable, non-invasive biomarkers for early detection of relapses, to avoid long-term complications and to optimize the management of children with LN. Recent studies of pediatric patients have yielded novel specific biomarkers for SLE diagnosis which can be used for monitoring disease activity and response to treatment. The most promising biomarkers in juvenile-onset SLE include cell-bound complement activation products, some genomic profiles, and urinary proteins such as neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, and alpha-1-acid glycoprotein. None of these might be suitable for use as a single SLE-biomarker. More likely a combination of novel biomarkers with traditionally used data, including autoantibodies and complement, might help to enhance sensitivity and specificity for early diagnosis, disease monitoring, and prediction of relapses.cp. PMID- 23355232 TI - Dynamic changes of 18F-FDG uptake in normal lung: probing a predictive model analysis. PMID- 23355233 TI - An electrophilic hypervalent iodine reagent for trifluoromethylthiolation. PMID- 23355234 TI - [Interpretation of D2 radical operation and en bloc mesogastric excision in gastric cancer]. AB - As a surgical oncology concept, complete mesenteric excision has been widely accepted. As to different organs, in addition to the rectum and the colon, the range or the criteria of the so-called complete mesenterium is not yet entirely clear. For the stomach, the mesogastric structure is so complicated, and the embryology and anatomy of the mesogastrium or the perigastric ligaments differed significantly. Even to perform a resection in accordance with the anatomy plane of mesogatrium, the mesogastric plane is still extended as compared to the current standard D2 radical resection. We therefore propose the concept of surgical mesogastrium, which means that the essence of en bloc mesogastric excision (EME) should be surgical mesogastric resection. In clinical practice, we found that a lot of symmetric similarity exists in stomach and colon, the morphological transformation from stomach to the colon can be accomplished to some extent by extension and folding of the stomach, and striking match exists in the morphology, distribution of the blood vessels, lymphatic drainage and mesenterium (mesogastrium or mesocolon). On this basis, we propose the plane of the surgical mesogastrium, which includes the gastrohepatic ligament, hepatoduodenal ligament, hepatopancreatic folds, splenicpancreatic folds, gastrophrenic ligament, gastrosplenic ligament, gastrocolic ligament (supracolic omentum) and omentum. This surgical mesogastric plane coincides with the current plane of D2 radical resection. This paper further discussed the N staging of gastric cancer. By comparative study of the stomach and the colon, we could re classify the stomach-associated lymph nodes into three groups, the perigastric, the middle and the roots, which may resolve the long-standing controversy between the Eastern and Western regarding this issue. In addition, we also agree with the presence of lymph node metastasis in the plane outside of the surgical mesogastrium, the so-called lateral lymph node metastasis. As for the N staging of gastrointestinal cancer, we must firstly define the lymph node metastasis as mesenteric (mesogastric or mesocolic lymph node) and extra-mesenteric (later lymph node). In case of lateral lymph node metastasis, which should be considered as M1 stage (distant metastasis) unless there is evidence to suggest lateral lymph node metastasis, otherwise extended lateral lymph node dissection should be avoided. In case of mesenteric (mesogastric or mesocolic) lymph node metastasis, classification should be in accordance with the current NCCN guideline, which was divided by the number of lymph node metastasis (N1-N3). PMID- 23355235 TI - [A pilot study of chemotherapy combined with intraperitoneal perfusion of cytokine-induced killer cells for advanced gastric cancer patients with ascites]. AB - OBJECTIVE: To investigate the efficacy and safety of chemotherapy combined with intraperitoneal perfusion of cytokine-induced killer (CIK) cells for advanced gastric cancer patients with ascites. METHODS: From January 2008 to December 2010, 42 advanced gastric cancer patients with ascites in Zhongshan Hospital of Fudan University were enrolled in the study. According to personal choice, patients were divided into 2 groups: XELOX chemotherapy alone (Capecitabine and Oxaliplatin) was applied in 22 patients (chemotherapy group) and XELOX combined with intraperitoneal perfusion of CIK cells in 20 patients (combination group). The efficacy, safety, and immunological function, including the time to progression (TTP), overall survival (OS), Karnofsky performance status (KPS) score, immunity index (CD4+/CD8+ ratio), volume of peritoneal fluid, were compared between two groups. RESULTS: Compared with the chemotherapy group after treatment, the combination group had a higher KPS score (78.0+/-9.8 vs. 70.0+/ 8.9, P=0.009), less volume of 2-cycle peritoneal fluid drainage [(4500+/-1218) ml vs. (5527+/-1460) ml, P=0.018 ], longer median TTP (4.0 vs. 2.5 months, P=0.001) and OS (11.0 vs. 6.0 months, P=0.006), higher ratio of CD4+/CD8+ (1.34+/-0.36 vs. 0.96+/-0.26, P=0.001). While no significant significances were found between the two groups in disease response rate (35.0% vs. 22.7%, P=0.499) and disease control rate (75.0% vs. 54.5%, P=0.209). There were no serious adverse reactions in the combination group. CONCLUSIONS: As compared with XELOX chemotherapy alone, the combination immunological treatment of XELOX chemotherapy and intraperitoneal perfusion of CIK cells possesses better efficacy for the advanced gastric cancer patients with ascites, which can prolong the survival and enhance the immunological function with favorable safety. PMID- 23355236 TI - [Clinical application of laparoscopy-assisted total proctocolectomy using medial to-lateral approach]. AB - OBJECTIVE: To investigate the safety and feasibility of laparoscopy-assisted total proctocolectomy using medial-to-lateral approach. METHODS: Between October 2005 and January 2012, 21 consecutive patients underwent laparoscopic-assisted total proctocolectomy by medial-to-lateral approach in Department of General Surgery in Nanfang Hospital. The clinical data and follow-up results were reviewed. RESULTS: Twenty cases underwent laparoscopic resection successfully, and 1 case (4.8%) was converted to open surgery because of serious peritoneal cavity adhesion. The mean operative time was (237.1+/-64.2) min and intraoperative blood loss was (90.0+/-77.7) ml. The mean time to first flatus was (2.7+/-0.8) days. The mean postoperative hospital stay was (11.8+/-5.7) days. Three patients (14.3%) experienced postoperative complications, including anastomotic leakage (n=1), lymphatic leakage (n=1), and anastomotic stricture (n=1). The median follow-up was 22 months (4-60 months). There were two deaths including one patient died of progressive disease 5 months after surgery and the other died of multiple organ failure. CONCLUSIONS: The advantages of laparoscopy assisted total proctocolectomy using medial-to-lateral approach include simplified surgical procedure, clearly revealed surgical plane, and shortened operative time. This procedure is safe and feasible in the experienced department of laparoscopic colorectal surgery. PMID- 23355237 TI - [Treatment and prognostic analysis of early stage of primary gastric diffuse large B-cell lymphoma]. AB - OBJECTIVE: To explore the prognostic factors and to compare chemotherapy alone versus surgical resection plus chemotherapy for early stage primary gastric diffuse large B-cell lymphomas (DLBCL). METHODS: Clinical data of 75 patients who were diagnosed as primary gastric DLBCL between January 1993 and August 2008 in Cancer Institute and Hospital of Tianjin Medical University were reviewed retrospectively. RESULTS: Among these 75 patients, 20 patients received chemotherapy alone and 55 underwent surgical resection plus chemotherapy. Complete remission rates were 65.0% (13/20) and 83.6% (46/55), effective rates were 75.0% (15/20) and 92.7% (51/55), and 5-year survival rates were 86.9% and 78.7% respectively in chemotherapy alone group and resection plus chemotherapy group, while the differences were not statistically significant (all P>0.05). Multivariate Cox regression model showed that international prognosis index (IPI) was the only independent prognostic factor (P<0.05, HR=11.350, 95%CI:1.011 127.371). CONCLUSIONS: In early stage of DLBCL, IPI is the only independent prognostic factor. The clinical outcomes are comparable between chemotherapy alone and surgical resection plus chemotherapy. PMID- 23355238 TI - [Clinicopathologic features and prognosis of gastric cancer in young patients]. AB - OBJECTIVE: To investigate the clinicopathologic features and prognosis of gastric cancer in young patients (YGC) in order to improve the treatment outcome of YGC. METHODS: Clinical data of 63 YGC patients (40 years of age and less) who underwent surgery from January 2004 to December 2006 were analyzed retrospectively. A total of 654 older gastric cancer patients (OGC, above 40 years) during the same period patients were selected and compared to the YGC patients. RESULTS: The proportions of female patients, patients with a family history or with undifferentiated tumor in YGC were significantly higher than OGC (all P<0.05). The curative resection rate of YGC patients was 61.9% (39/63), significantly lower than that of OGC (93.1%, 595/654, P<0.01). A total of 653 (91.1%) patients were followed up, with a period of time of 1 to 84 months. The 5 year survival rates for YGC and OGC patients were 40.5% and 55.6% respectively, and the difference was statistically significant (P<0.05). Cox proportional hazards model showed that the depth of invasion, lymph node metastasis, and radical surgery were the independent factors associated with the prognosis of YGC (all P<0.05). The stratified analysis showed that the 5-year survival rates for YGC and OGC patients undergoing radical surgery were 63.2% and 56.7% respectively and the difference was not statistically significant (P>0.05). The 5-year survival rates for YGC and OGC patients undergoing palliative surgery were 4.2% and 22.2% respectively and the difference was statistically significan t(P<0.05). CONCLUSION: Gastric cancer in young patients is highly malignant, with lower rate of curative resection and poorer prognosis. The long-term outcome of YGC is similar to that of OGC if radical resection is possible. PMID- 23355239 TI - [Transumbilical laparoendoscopic single-site surgery in the treatment of neonatal intestinal atresia and stenosis]. AB - OBJECTIVE: To summarize the experiences and advantages of laparoendoscopic single site (LESS) surgery for neonatal intestinal atresia and stenosis. METHODS: Twenty patients of neonatal intestinal atresia and stenosis were treated with LESS procedure in Huai'an Women and Children's Hospital of Jiangsu Province between October 2010 and April 2012. The clinical data were retrospectively analyzed. RESULTS: Among these patients, 13 were male, 7 were female. Age at admission ranged from 10 min to 1 d. Four cases were premature, and 3 were born with low birth weight (<2500 g). One was diagnosed with duodenal atresia, 1 with duodenal stenosis, 9 with jejunal atresia, 2 with jejunal stenosis, and 7 with ileal atresia. Laparoscopic exploration was performed in all the cases by transumbilical procedure, the proximal and distal ends were exteriorized from the umbilical port site for anastomosis. Twenty neonates with intestinal atresia and stenosis were performed using this new minimally invasive approach, with no cases converted to open operation or standard laparoscopy. The operative time was 35-60 (mean, 40) min. The intraoperative bleeding was 3-5 ml. Two cases were given up treatment by their parents on the second postoperative day. For the other 18 patients, oral intake started on postoperative day 5-10 (mean, 7), and discharged from hospital on the postoperative day 10-20 (mean, 13). The follow up ranged from 1 to 11 months, during which 1 case died, 3 cases were managed with conservative treatment for diarrhea or malnutrition. The other 14 cases grew up healthily. CONCLUSION: The technique of LESS in the treatment of neonatal atresia and stenosis is simple and the outcomes are satisfactory. PMID- 23355240 TI - [Value of multidetector CT on aiding intraoperative judgement of serosal invasion of gastric cancer]. AB - OBJECTIVE: To explore the value of multidetector CT on aiding intraoperative judgement of serosal invasion of gastric cancer. METHODS: Clinical data of 206 cases of gastric cancer undergoing radical surgery in the First Hosptial of China Medical University from August 2009 to June 2011 were analyzed retrospectively. Preoperative CT findings and intraoperative judgement of serosal invasion in gastric cancer were compared with pathological results in order to investigate their values. RESULTS: The sensitivity and specificity of preoperative CT findings and intraoperative judgement of serosal invasion were 88.5%, 81.5% and 98.9%, 61.3%, respectively. The accuracy of preoperative CT in diagnosing serosal invasion was higher than that of intraoperative judgement, while the difference was not statistically significant (84.5% vs. 77.2%, P=0.060). The rates of serosal invasion of normal type, reactive type, nodular type, tendonoid type and color-diffused type were 0 (0/29), 2.5% (1/40), 40.5% (15/37), 59.2% (29/49), and 82.4% (42/51) respectively. The accuracy of preoperative CT in diagnosing serosal invasion of gastric cancer with tendonoid type was higher than that of intraoperative judgement, and the difference was statistically significant (61.2% vs. 87.8%, P=0.002). CONCLUSIONS: Multidetector CT plays an important role in aiding intraoperation judgement of serosal invasion of gastric cancer. For gastric cancer with tendonoid and color-diffused macroscopic serosal appearance, surgeons should pay attention to the value of preoperative CT findings. PMID- 23355241 TI - [Prospective study of gracilis muscle repair of complex rectovaginal fistula and rectourethral fistula]. AB - OBJECTIVE: To assess the efficacy and experience of gracilis muscle transposition for complex rectovaginal fistula (RVF) and rectourethral fistula (RUF). METHODS: Nineteen patients underwent gracilis muscle transposition for complex RVF and RUF from May 2009 to November 2011 in the Beijing Shijitan Hospital and the clinical data were prospectively collected. The success rate and complications were recorded. SF-36 quality of life score, Wexner fecal incontinence score, and female sexual function score before surgery and 6 months after surgery were recorded. RESULTS: In 19 patients, there were 8 males (RUF) and 11 females (RUF). The times of failed attempt repair preoperatively ranged from 0-3 (mean, 1.0). The diameter of the fistula ranged from 0.5-3.0 cm (mean, 1.6), and all fistulas located above the sphincter. The operative time ranged from 145-400 minutes (median, 240). The postoperative hospital stay ranged from 10-39 days (median 21). Early postoperative complications included thigh pain and numbness in 2 cases, leg numbness in 2 cases. No long-term complications were noticed. The follow-up period ranged from 6-35 months (median, 18). The gracilis muscle transposition had a healing rate of 94.7% (18/19). As compared with the preoperative level, Wexner score decreased from 10.0+/-8.8 to 2.9+/-5.8, and the continence function improved significantly (P=0.002). Sexual function score of 11 female patients increased from 1.0+/-1.8 to 4.0+/-4.0, and the sexual function had a significant improvement after surgery (P=0.022). SF-36 quality of life scores improved significantly (P<0.001). CONCLUSIONS: Gracilis muscle transposition for complex rectovaginal fistula and rectourethral fistula has high success rate with mild and rare complications. PMID- 23355242 TI - [Prognostic value of metastatic lymph node ratio in gastric cancer patients undergoing radical gastrectomy]. AB - OBJECTIVE: To assess the prognostic value of metastatic lymph node ratio in gastric cancer patients undergoing radical gastrectomy (D2). METHODS: Prognostic analysis of 1042 gastric cancer patients undergoing radical gastrectomy (D2) was performed based on metastatic lymph node ratio (MLR), the N staging in the 6th and 7th edition of UICC staging system respectively. Homogeneity, discriminatory ability, and gradient monotonicity of these three staging methods were compared using linear trend chi(2), likelihood ratio chi(2) statistics and Akaike information criterion (AIC) calculations, respectively. The area under the ROC curve (AUC) was calculated to compare the prognostic value of these three staging methods. RESULTS: The 5-year survival rate of 1042 patients was 47.5%. The metastatic lymph node ratio (P<0.01) and N staging of the 7th edition UICC (P<0.05) were independent prognostic factors according to univariate and multivariate analyses. The AUC was 0.754 in MLR staging group, higher than that in N staging of the 6th (0.692) and 7th (0.705) edition of UICC group. Compared to the 6th and 7th edition of UICC N staging group, homogeneity and linear curve were better and AIC value was lower in MLR staging group (7240.017 vs. 7364.073 and 7325.731). CONCLUSION: Prognostic value of MLR staging is better than that of UICC N staging for patients undergoing radical gastric cancer resection. The MLR staging can be a new method of lymph node staging for gastric cancer patients. PMID- 23355243 TI - [Association between miR-34a expression and recurrence after radical resection of colorectal cancer]. AB - OBJECTIVE: To investigate the expression of miR-34a in stage II-III colorectal cancer and to elucidate its association with recurrence after radical resection. METHODS: miR-34a expression level was detected in colorectal cancer patients with recurrence (40 cases) and without recurrence (40 cases) within 3 years after radical operation by real-time RT-PCR. RESULTS: No association was observed between miR-34a and gender, age, location, local invasion, lymph node metastasis, cancer embolus, or tissue differentiation (all P>0.05). The expression level of miR-34a was lower in patients with recurrence compared to those without recurrence after radical surgery (P=0.039). Univariate analysis indicated that the median disease-free surviva l(DFS) of patients with low expression of miR-34a was worse as compared to those with high miR-34a expression (13.4 vs. 18.4 months, P=0.010), especially for stage III (P=0.003). In the recurrence group, the median DFS of patients with low miR-34a expression (n=14) was 13.4 months, which was shorter than that of patients with high miR-34a expression (n=26, 18.4 months, P=0.037). Multivariate analysis showed that miR-34a expression was an independent factor for colorectal cancer recurrence (RR=0.397, 95%CI:0.205-0.768, P=0.006). CONCLUSION: The down-regulated expression of miR-34a in colorectal cancer patients is associated with recurrence after radical operation. miR-34a may be a marker to predict tumor recurrence and metastasis of colorectal carcinoma. PMID- 23355244 TI - [Long-term outcomes and cause of high rate of loss to follow-up after laparoscopic adjustable gastric banding in obese patients]. AB - OBJECTIVE: To evaluate the long-term outcomes of weight loss and the cause of high rate of loss to follow-up after laparoscopic adjustable gastric banding (LAGB) in obese patients. METHODS: Clinical and follow-up data of 226 obese patients undergoing LAGB operation in the Changhai Hospital from June 2003 to June 2007 were analyzed retrospectively. RESULTS: A total of 125 patients were followed up for 3-7 years. Among these 125 cases, 115 (92.0%) presented weight loss after LAGB, 60 (48.0%) presented extra weight loss after LAGB. Another 105 cases (44.7%) were lost to follow-up. Most of patients who were loss to follow-up were younger (P<0.05). Gender, weight and BMI were not associated with the rate of loss to follow-up (all P>0.05). CONCLUSIONS: Laparoscopic adjustable gastric band surgery is a relatively simple and safe procedure among the bariatric surgery, but the follow-up protocol is complex and the rate of loss to follow-up is high. Postoperative follow-up should be emphasized. PMID- 23355245 TI - [Expression of PSF1 in colon cancer tissues and its effect on the proliferation of colon cancer cells]. AB - OBJECTIVE: To detect the expression of PSF1 (partner of Sld five 1) in colon cancer specimens, and to explore the effect of RNA interference targeting PSF1 on the proliferation of colon cancer cells and its mechanism. METHODS: Expression level of PSF1 protein in colon cancer specimens was detected by Western blot in 40 patients with colon cancer from May 2004 to December 2006. The short hairpin RNA (shRNA) plasmid targeting PSF1 was transfected into LOVO, HT-29 and HCT116 cells with liposome, then the expression level of PSF1 protein was measured by Western blot, the effect of PSF1 shRNA plasmid transfection on cell proliferation by MTT assay, anchorage-independent growth by soft agar colomy-formation assay, and PSF2, PSF3 and SLD5 mRNA expression by quantitative reverse transcription polymerase chain reaction. RESULTS: The relative expression level of PSF1 protein in colon cancer tissues was 0.485+/-0.113, which was significantly higher than that in adjacent normal mucosa tissues (0.056+/-0.014, P<0.01). Western blot showed that the expression level of PSF1 protein was significantly decreased in colon cancer cells transfected with PSF1 shRNA plasmid. After PSF1 shRNA plasmid transfection, cell proliferation was significantly suppressed, the soft agar colony-forming rates of LOVO, HT-29 and HCT116 cells were significantly lower than those in control groups (P<0.05), meanwhile the expression levels of PSF2, PSF3 and SLD5 mRNA were significantly decreased (P<0.05). CONCLUSIONS: PSF1 is significantly up-regulated in colon cancer tissues compared with adjacent normal mucosa tissues. ShRNA plasmid targeting PSF1 can inhibit the expression of PSF1 gene, suppress the proliferation of colon cancer cells, suggesting that it may be a new therapeutic target for colon cancer. PMID- 23355246 TI - [Preliminary study on glucose regulated protein 78 kD and heat shock protein 20 differential expression between left-sided colon carcinoma and right-sided colon carcinoma]. AB - OBJECTIVE: To analyze the differential protein expression of left-sided colon cancer and right-sided colon cancer. METHODS: Tissue samples of left-sided colon cancer (n=7) and right-sided colon cancer (n=7) were collected. Tissue protein was abstracted and two-dimensional gel electrophoresis (2-DE) was used to examine the gel images. Peptide mass fingerprintings (PMF) was acquired by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and the proteins were identified by data searching with bioinformatics. Immunohistochemical SP method was used for the detection of glucose regulated protein 78 kD (GRP78) and heat shock protein 20 (HSP20) in left-sided colon cancer (n=50) and right-sided colon cancer (n=50) tissues. RESULTS: Sixteen differentiating protein spots were identified. Compared with right-sided colon cancer, 10 proteins including GRP78 up-regulated and 6 proteins including HSP20 down-regulated in left-sided colon cancer. Immunohistochemical detection showed that in left and right sided colon cancer, the positive expression rate of GRP78 was 78% (39/50) and 56% (28/50) and the positive expression rate of HSP20 was 34% (17/50) and 72% (36/50), respectively, and the differences were statistically significant (both P<0.05). The positive rate of GRP78 was associated with tumor differentiation, infiltration layer, TNM staging, lymph node metastasis, and liver metastasis, while the positive rate of HSP20 was associated with tumor gross morphology, TNM staging, and lymph node metastasis (P<0.05). CONCLUSIONS: There are differentially expressed proteins between left-sided colon cancer and right-sided colon cancer, especially for GRP78 and HSP20, which may be the cause leading to the biological differences between left-sided and right-sided colon cancer. PMID- 23355247 TI - [Application of matrix assisted laser desorption ionization-time of flight-mass spectrometry in detecting K-ras gene mutation of colorectal cancer]. AB - OBJECTIVE: To investigate the clinical value of matrix assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS) in detecting K-ras gene mutation. METHODS: Sixty-one paraffin-embeded specimens of colorectal cancer were selected. MALDI-TOF-MS and regular sequencing were used to test the mutation of codon 12 and 13 in K-ras exon 2. RESULTS: Only 47 specimens could be detected successfully in regular sequencing, while all the specimens were tested successfully in MALDI-TOF-MS. Fourteen specimens had K-ras mutation in regular sequencing (30.0%), while 22 specimens had mutation in MALDI-TOF-MS (36.1%). Six specimens with mutation were found in MALDI-TOF-MS but were wild-type in regular sequencing. Same mutation types from 14 specimens were confirmed by both regular sequencing and MALDI-TOF-MS. MALDI-TOF-MS was able to detect the mutation in 2 specimens that was not identified in regular sequencing. CONCLUSIONS: MALDI-TOF MS is a feasible approach of K-ras gene mutation testing in colorectal cancer, which is less demanding in terms of specimen quality and is more sensitive as compared to regular sequencing. PMID- 23355248 TI - [Influence of oxaliplatin combined with LCP on proliferation and apoptosis of colon cancer cell line HT29]. AB - OBJECTIVE: To study the effects of oxaliplatin combined with low-molecular-weight citrus pectin (LCP) on cell proliferation and apoptosis in human colon carcinoma cell line HT29 in vitro. METHODS: Effects of oxaliplatin alone and oxaliplatin combined with LCP on HT29 cells proliferation were determined by MTT. Coefficient of drug interaction (CDI) was calculated. Influence of oxaliplatin alone and oxaliplatin combined with LCP on HT29 cell apoptosis was determined by fluorescence activated cell sorting (FACS). Protein expression change of procaspase-3, 8, 9, PARP was examined by Western blotting. RESULTS: Both oxaliplatin alone and oxaliplatin combined with LCP could suppress HT29 cell proliferation in both dose- and time-dependent manner. The inhibitory effect of oxaliplatin combined with LCP on HT29 cell proliferation was more significant (P<0.01) with a CDI less than 1. FACS analysis showed that oxaliplatin alone and combination therapy could increase the apoptosis proportion of HT29 cells. After the drug treatment for 6, 24, and 48 hours, the apoptosis rate of oxaliplatin alone group was (9.76+/-0.47)%, (20.45+/-0.74)%, (28.70+/-3.29)%, and apoptotic rate of the combination group was (20.63+/-0.69)%, (34.35+/-1.02)%, (49.47+/ 3.04)%, respectively, which was significantly higher as compared to oxaliplatin alone (P<0.01). Both oxaliplatin alone and combination therapy down-regulated expressions of procaspase-3, 9, and PARP protein. Procaspase-3, 9, PARP protein expression in combination group decreased more significantly, while procaspase-8 expression was not significantly different between the two groups. CONCLUSION: LCP can enhance the ability of oxaliplatin to inhibit cell proliferation and induce apoptosis, which may be associated with the activation of mitochondrial apoptosis pathway. PMID- 23355249 TI - [Effect of 5-fluorouracil on the expression of ATP-binding cassette superfamily G member 2 in human colon cancer cell SW480]. AB - OBJECTIVE: To investigate the effect of 5-fluorouracil (5-FU) on the expression of ATP-binding cassette superfamily G member 2 (ABCG2) in human colon cancer cell SW480. METHODS: SW480 cells were treated with various concentrations of 5-FU. CCK8 assay was utilized to detect the 5-FU IC50 to SW480 cells. Positive expression of ABCG2 was detected by flow cytometry, and mRNA expression of ABCG2 was detected by real time polymerase chain reaction (RT-PCR). RESULTS: The 5-FU IC50 to SW480 cells increased as the drug concentration increased (P<0.05). Flow cytometry revealed that positive expression rate of ABCG2 in normal SW480 cells (group A) was (6.26+/-0.86)%. Immediately after treatment with 5-FU for 48 hours, the positive expression rate of ABCG2 (group B) was (3.43+/-1.18)% (P<0.05). In the second passage of cells after treatment with 5-FU for 48 hours, the positive expression rate of ABCG2 (group C) was (12.91+/-3.42)% (P<0.05). The mRNA expression of ABCG2 detected by RT-PCR was in accordance with the results from flow cytometry. CONCLUSION: Expression of ABCG2 in SW480 cells can be affected by various concentrations of 5-FU. PMID- 23355250 TI - Supramolecular control of enzyme activity through cucurbit[8]uril-mediated dimerization. PMID- 23355251 TI - Workplace drug testing in Italy - critical considerations. AB - Workplace drug testing (WDT) was established in Italy on 30 October 2007. Two tiers of survey are required: the first tier concerns drug testing on urine samples, the second involves both urine and hair analysis. Between July 2008 and December 2011, 10 598 workers' urine samples and 72 hair samples for opiates, cocaine, cannabinoids, amphetamines, methylenedioxyamphetamines, methadone, and buprenorphine were tested in our laboratory. Urine analyses were performed by immunological screening (EMIT); hair analysis and confirmation tests in urine were performed by gas chromatography-mass spectrometry (GC-MS). Employees tested positive in urine for drugs of abuse numbered 2.8% in 2008, 2.03% in 2009, 1.62% in 2010, and 1.43% in 2011. As regards the second level of analysis, we observed that only one-third of the workers who had been tested positive for drugs of abuse were referred to an Addiction Treatment Unit in order to verify drug addiction. Our experience shows that, four years after approval of the law on WDT, the percentage of workers positive for drugs of abuse in urine has reduced in comparison to the first year. Moreover, our data show that most of the times employees who tested positive are tardily referred or not referred at all to a Public Addiction Treatment Unit to verify drug addiction. This makes us believe that the legal provisions are widely disregarded not paying the right tribute to the fact that Italy is one of few European countries with legislation on WDT. PMID- 23355252 TI - Involvement of nitric oxide through endocannabinoids release in microglia activation during the course of CNS regeneration in the medicinal leech. AB - The medicinal leech is notable for its capacity to regenerate its central nervous system (CNS) following mechanical trauma. Using an electrochemical nitric oxide (NO)-selective electrode to measure NO levels, we found that the time course of NO release in the injured leech CNS is partially under the control of endocannabinoids, namely, N-arachidonyl ethanolamide (AEA) and 2-arachidonyl glycerol (2-AG). Relative quantification of these endocannabinoids was performed by stable isotope dilution (2AGd8 and AAEd8) coupled to mass spectrometry in course of regeneration process or adenosine triphosphate (ATP) treatment. Data show that 2-AG levels rose to a maximum about 30 min after injury or ATP treatment, and returned to baseline levels 4 h after injury. In same conditions, AEA levels also rapidly (within 5 min) dropped after injury or ATP treatment to the nerve cord, but did not fully return to baseline levels within 4 h of injury. In correlation with these data, chemoattraction activities of endocannabinoids on isolated leech microglial cells have been shown in vitro and in vivo reflecting that control over NO production is accompanied by the controlled chemoattraction of microglia directed from the periphery to the lesion site for neuronal repair purposes. Taken together, our results show that in the leech, after injury concurrent with ATP production, purinergic receptor activation, NO production, microglia recruitment, and accumulation to lesion site, a fine imbalance occurs in the endocannabinoid system. These events can bring explanations about the ability of the leech CNS to regenerate after a trauma and the key role of endocannabinoids in this phenomenon. PMID- 23355253 TI - Hospital cost and quality performance in relation to market forces: an examination of U.S. community hospitals in the "post-managed care era". AB - Managed care substantially transformed the U.S. healthcare sector in the last two decades of the twentieth century, injecting price competition among hospitals for the first time in history. However, total HMO enrollment has declined since 2000. This study addresses whether managed care and hospital competition continued to show positive effects on hospital cost and quality performance in the "post managed care era." Using data for 1,521 urban hospitals drawn from the Healthcare Cost and Utilization Project, we examined hospital cost per stay and mortality rate in relation to HMO penetration and hospital competition between 2001 and 2005, controlling for patient, hospital, and other market characteristics. Regression analyses were employed to examine both cross-sectional and longitudinal variation in hospital performance. We found that in markets with high HMO penetration, increase in hospital competition over time was associated with decrease in mortality but no change in cost. In markets without high HMO penetration, increase in hospital competition was associated with increase in cost but no change in mortality. Overall, hospitals in high HMO penetration markets consistently showed lower average costs, and hospitals in markets with high hospital competition consistently showed lower mortality rates. Hospitals in markets with high HMO penetration also showed lower mortality rates in 2005 with no such difference found in 2001. Our findings suggest that while managed care may have lost its strength in slowing hospital cost growth, differences in average hospital cost associated with different levels of HMO penetration across markets still persist. Furthermore, these health plans appear to put quality of care on a higher priority than before. PMID- 23355254 TI - A partner-related risk behavior index to identify people at elevated risk for sexually transmitted infections. AB - The purpose of this study was to develop and test a sexual-partner-related risk behavior index to identify high-risk individuals most likely to have a sexually transmitted infection (STI). Patients from five STI and adolescent medical clinics in three US cities were recruited (N = 928; M age = 29.2 years). Data were collected using audio-computer-assisted self-interviewing. Of seven sexual partner-related variables, those that were significantly associated with the outcomes were combined into a partner-related risk behavior index. The dependent variables were laboratory-confirmed infection with Chlamydia trachomatis, Neisseria gonorrhoeae, and/or Trichomonas vaginalis. Nearly one-fifth of the sample (169/928; 18.4%) tested positive for an STI. Three of the seven items were significantly associated with having one or more STIs: sex with a newly released prisoner, sex with a person known or suspected of having an STI, and sexual concurrency. In combined form, this three-item index was significantly associated with STI prevalence (p < .001). In the presence of three covariates (gender, race, and age), those classified as being at-risk by the index were 1.8 times more likely than those not classified as such to test positive for an STI (p < .001). Among individuals at risk for STIs, a three-item index predicted testing positive for one or more of three STIs. This index could be used to prioritize and guide intensified clinic-based counseling for high-risk patients of STI and other clinics. PMID- 23355255 TI - Community health partnerships for chronic disease prevention among Latinos: the San Diego Prevention Research Center. AB - Over 20 years ago, university-community partnerships (i.e., Prevention Research Centers [PRCs]) across the United States were funded by the Centers for Disease Control and Prevention to conduct research and training in order to promote health and prevent disease in underserved populations. In 2004, the San Diego PRC (SDPRC) became the first PRC to focus on obesity prevention and control in a community of mostly Mexican Americans/Mexican immigrants. The SDPRC was also the first PRC to comprise a university-community partnership with a school of public health, a school of medicine, and a federally qualified health center. In conjunction with two additional funded community partners and involvement of a community advisory board, the SDPRC seeks to develop effective intervention strategies that ultimately lead to behavior change. Now in its second cycle of funding, the SDPRC has identified three primary principles that are important for these and similar efforts: (1) developing culturally appropriate interventions requires community engagement; (2) building the evidence in a systematic and rigorous way yields meaningful strategies for translation to practice; and (3) translating evidence-based interventions to practice involves capacity building for both researchers and community partners. This article describes these principles to help others involved in similar intervention efforts identify the best approach for promoting health in their own communities. PMID- 23355256 TI - Understanding problems with condom fit and feel: an important opportunity for improving clinic-based safer sex programs. AB - The purpose of this study was to investigate gender differences and other demographic correlates of condom fit and feel problems among a diverse sample of adult condom users and to examine men's and women's perceptions and experiences with condom fit and feel problems. Participants were recruited from an electronic mailing list. The analytic sample (N = 949) included self-identified heterosexual men (n = 771) and women (n = 178) who reported using condoms for penile-vaginal or penile-anal intercourse in the past 3 months. Both quantitative and qualitative methods were applied. Of the sample, 38.3% reported experiencing at least one condom fit or feel problem. Problems with condom fit during sex did not differ significantly by gender (p = .73). Perceptions of specific condom use problems were organized into five themes: (1) decreased sensation, (2) lack of naturalness, (3) condom size complaints, (4) decreased pleasure, and (5) pain and discomfort. In this diverse sample, there was a high prevalence of condom fit and feel issues among women as well as men. These issues, mostly focused on loss of pleasure, represent a substantial public health problem and thus warrant attention in safer sex programs. PMID- 23355257 TI - Mitochondrial DNA (mtDNA) in brain samples from patients with major psychiatric disorders: gene expression profiles, mtDNA content and presence of the mtDNA common deletion. AB - Several lines of evidence support a mitochondrial dysfunction in major psychiatric disorders. The objective of this study was to determine whether mitochondrial DNA (mtDNA) expression or content are implicated in the mitochondrial dysfunction observed in schizophrenia (SCH), bipolar disorder (BD), and major depressive disorder (MDD). MtDNA gene expression and mtDNA content (including the MT-ND4 deletion) were measured by RT-qPCR and qPCR, respectively. Post-mortem brain tissue from 60 subjects, divided evenly into four diagnostic groups (SCH, BD, MDD, and control (C)), was analyzed. MT-ND1 gene expression was significantly increased in the BD group compared with the C group. MDD and SCH patients showed a similar pattern of mtDNA expression, which was different from that in BD patients. Similarly, a larger number of MDD and SCH patients tended to have the MT-ND4 gene deleted compared with BD and C subjects. However, no other significant differences were observed in mtDNA gene expression and mtDNA content. Notably, high variability was observed in the mtDNA gene expression and content in each diagnostic group. Previous studies and the present work provide evidence for a role of mtDNA in SCH, BD and MDD. However, further studies with larger patient and control groups as well as by analyzing distinct brain regions are needed to elucidate the role of mtDNA in major psychiatric disorders. PMID- 23355258 TI - Effect of phytase from Aspergillus niger on plant growth and mineral assimilation in wheat (Triticum aestivum Linn.) and its potential for use as a soil amendment. AB - BACKGROUND: Extensive use of non-replenishable phosphate reserves as phosphate supplements in agriculture and animal feed poses a threat for environmental pollution and necessitated a search for alternative phosphate sources. Unlocking the phytate phosphorus using microbial phytase can provide an ecofriendly solution in agriculture. The aim of the present work was to evaluate the effect of phytase from Aspergillus niger NCIM 563 in degradation of phytate phosphorus to benefit plant nutrition and soil amendment in comparison with chemical fertilizers. RESULTS: An enzyme dose of 12 IU was sufficient to hydrolyze phytate and increase assimilation of phosphorus by about 74%. Phytase supplementation leads to increase in shoot:total length ratio by about 200%, indicating its growth-promoting effect. Consistency in phytase-induced growth was reflected at pot and tray levels, wherein shoot:total length ratio was observed to be 2.01 and 2.12 respectively. Mineral assimilation due to phytase was more efficient as compared to chemical fertilizers, thus overcoming the constraints of practicability and economics in the agriculture industry. Phytase was efficient in reducing the phytic acid content of soil by about 30% while simultaneously increasing the phytate phosphate availability by 1.18-fold. CONCLUSION: Phytase from A. niger showed improvement in phytate phosphorus and mineral availability. Besides a plant growth-promoting effect, reduction in use of chemical fertilizers and soil improvement could be achieved simultaneously for maintaining the sustainability of agriculture. PMID- 23355260 TI - Successful treatment of anti-erythropoietin antibody-mediated pure red cell aplasia with low-dose prednisolone. AB - The standard therapy for anti-erythropoietin (EPO) antibody-mediated pure red cell aplasia (PRCA) is cyclosporine (CyA) or prednisolone (PSL) 0.5-1.0 mg/kg. However, many patients with severe chronic kidney disease (CKD) and chronic heart failure cannot tolerate such an immunosuppressive regimen. An 86-year-old man with anemia related to CKD and chronic heart failure, who had received recombinant human erythropoietin subcutaneously, developed anti-EPO antibody mediated PRCA. The patient was treated with CyA followed by PSL (1.0 mg/kg); however, he was unable to tolerate this drug regimen. The PSL dose was reduced to 0.2 mg/kg. Surprisingly, his reticulocyte count increased 3 months later, and RBC transfusion was no longer required. Low-dose PSL is a treatment option for patients with anti-EPO antibody-mediated PRCA who cannot tolerate CyA and PSL (0.5-1.0 mg/kg). PMID- 23355259 TI - The glucocorticoid receptor gene polymorphism N363S predisposes to more severe toxic side effects during pediatric acute lymphoblastic leukemia (ALL) therapy. AB - The survival rates in childhood acute lymphoid leukemia (ALL) have improved dramatically; however, patients still suffer from a variety of drug-related toxicities. Individualized therapy regimens promise the least toxic therapy regimen with the best hematologic outcome. Our aim was to investigate whether increased individual glucocorticoid sensitivity due to the N363S polymorphism of the glucocorticoid receptor increased susceptibility to steroid-related toxicities during ALL therapy. A total of 346 pediatric ALL patients were involved in the present study. N363S carrier status was investigated by allele specific PCR. Clinical and laboratory signs of glucocorticoid-related toxicities, Day 8 prednisone response, and 5-year event-free survival were analyzed and compared retrospectively. Thirty-two of the 346 patients were heterozygous carriers (9.2 %). Hepatotoxicity (31.3 vs. 11.2 %, p = 0.004, carriers and non carriers, respectively) and glucose metabolism abnormalities (18.8 vs. 3.8 %, p = 0.001, carriers and non-carriers, respectively) were significantly more frequent among carriers. There was no difference in the incidence of hypertension and encephalopathy/psychosis among carriers and non-carriers. Carriers were also more prone to have a combination of toxicities. All 363S carriers were good prednisone responders (100 %) and had significantly better 5-year event-free survival rates (93.1 vs. 71.86 %, p = 0.012), whereas among non-carriers there were more poor prednisone responders (8.28 %) and worse 5-year event-free survival rates. Patients with the N363S polymorphism in the glucocorticoid receptor are more prone to steroid-related toxicity during ALL therapy and should be monitored more closely. Patients with N363S polymorphism of the glucocorticoid receptor may be appropriate candidates for inclusion in the design of individualized therapies. PMID- 23355261 TI - Global subendocardial late gadolinium enhancement on cardiac magnetic resonance imaging in severe cardiac AL amyloidosis. PMID- 23355262 TI - Primary testicular lymphoma: experience with 13 cases and literature review. AB - To summarize the clinicopathological features, therapeutic regimens, and outcomes for patients with primary testicular lymphoma (PTL), we retrospectively reviewed the medical records of 13 patients diagnosed with PTL between 2001 and 2012 at our hospital. Average age at diagnosis was 62.2 +/- 13.9 years, and all patients presented with painless testicular swelling. Diffuse large B-cell lymphoma was the dominant histotype (69.2 %). All 13 patients were treated with inguinal orchiectomy and received chemotherapy and/or radiotherapy. Complete follow-up data were available for 10 patients with an average follow-up duration of 28.4 +/ 30.9 months. Seven patients were evaluated as Ann Arbor stage I or II, and three as stage III or IV. Eight patients were found to have hypoechogenic and hypervascular signals in the testis on ultrasound examination. Complete remission was achieved in six patients, and four patients who were still undergoing chemotherapy during the last follow-up showed no signs of relapse. Of the 10 patients with complete follow-up records, three had relapses, which occurred in the CNS, epiglottis, and the nasal cavity. Time to relapse in these cases was 2, 7, and 11 months, respectively (3/10). The mean progression-free survival was 22.57 months (range 1.1-101.9 months). PMID- 23355263 TI - High-dose chemotherapy and autologous stem-cell transplantation in Korean patients with relapsed or refractory Hodgkin lymphoma. AB - High-dose chemotherapy and autologous stem-cell transplantation (HDCT-ASCT) is a standard therapy for patients with relapsed or refractory Hodgkin lymphoma (HL). However, its efficacy in Asian patients has not been well investigated. A retrospective analysis of outcomes in 10 consecutive patients who underwent ASCT for HL in a single Korean centre from August 2005 to September 2010 was conducted. The median age was 34.5 years (range 17-64 years) and seven patients were male. Six patients were of stage III-IV at presentation. B symptoms were present in six patients. International Prognostic Score (IPS) was as follows: IPS = 1 (n = 5), IPS = 2 (n = 1), IPS = 4 (n = 2), and IPS = 5 (n = 2). The analysis included nine patients with relapsed HL and one primary refractory case. Four patients were in second complete response and the others were in partial response after salvage chemotherapy. With a median follow-up duration of 58.0 months, 3 year progression-free survival rate and overall survival rate from ASCT were 40 and 76 %, respectively. The results suggest that the efficacy of high-dose chemotherapy followed by ASCT in Korean patients with refractory or relapsed HL is comparable to that in Western patients. PMID- 23355264 TI - Lymphocytopenia is associated with an increased risk of severe infections in patients with multiple myeloma treated with bortezomib-based regimens. AB - Bortezomib is a proteasome inhibitor with potent antimyeloma activity in relapsed/refractory multiple myeloma (MM) patients. We evaluated the types and factors affecting the onset of infectious complications and mortality owing to infection in MM patients treated with bortezomib-based regimens. We reviewed 139 patients with MM treated with regimens containing bortezomib in order to assess the types and factors affecting the development of severe infections. Infections occurred in 56 (40.3 %) of 139 patients and 83 (7.8 %) cases of the 1,069 evaluable cycles. Severe infections developed in 43 (30.9 %) patients and ten patients (7.1 %) died during bortezomib-based treatment. Multivariate analysis determined lymphocytopenia grade 3-4 (OR 3.17, 95 % CI 1.38-7.31, P = 0.007) and number of cycles <= 8 (OR 3.91, 95 % CI 1.39-11.02, P = 0.010) as risk factors associated with increased severe infection. This study showed that MM patients who received bortezomib-based regimens are at a higher risk of severe infections within eight cycles of treatment during especially severe lymphocytopenic periods. MM patients treated with bortezomib-based regimens should be closely monitored for the development of infectious complications during lymphocytopenia. PMID- 23355265 TI - Neural correlates of treatment response in depressed bipolar adolescents during emotion processing. AB - Depressive mood in adolescents with bipolar disorder (BDd) is associated with significant morbidity and mortality, but we have limited information about neural correlates of depression and treatment response in BDd. Ten adolescents with BDd (8 females, mean age = 15.6 +/- 0.9) completed two (fearful and happy) face gender labeling fMRI experiments at baseline and after 6-weeks of open treatment. Whole-brain analysis was used at baseline to compare their neural activity with those of 10 age and sex-matched healthy controls (HC). For comparisons of the neural activity at baseline and after treatment of youth with BDd, region of interest analysis for dorsal/ventral prefrontal, anterior cingulate, and amygdala activity, and significant regions identified by wholebrain analysis between BDd and HC were analyzed. There was significant improvement in depression scores (mean percentage change on the Child Depression Rating Scale-Revised 57 % +/- 28). Neural activity after treatment was decreased in left occipital cortex in the intense fearful experiment, but increased in left insula, left cerebellum, and right ventrolateral prefrontal cortex in the intense happy experiment. Greater improvement in depression was associated with baseline higher activity in ventral ACC to mild happy faces. Study sample size was relatively small for subgroup analysis and consisted of mainly female adolescents that were predominantly on psychotropic medications during scanning. Our results of reduced negative emotion processing versus increased positive emotion processing after treatment of depression (improvement of cognitive bias to negative and away from positive) are consistent with the improvement of depression according to Beck's cognitive theory. PMID- 23355266 TI - Molecular basis for sequence-dependent induced DNA bending. AB - With a growing understanding of the microstructural variations of DNA, it has become apparent that subtle conformational features are essential for specific DNA molecular recognition and function. DNA containing an A-tract has a narrow minor groove and a globally bent conformation but the structural features of alternating AT DNA are less well understood. Several studies indicate that alternating AT sequences are polymorphic with different global and local properties from A-tracts. The mobility of alternating AT DNA in gel electrophoresis is extensively reduced upon binding with minor-groove binding agents such as netropsin. Although this suggests that such complexes are bent, similarly to A-tract DNA, direct evidence and structural information on AT DNA and the induced conformational change is lacking. We have used NMR spectroscopy and residual dipolar coupling together with restrained molecular-dynamics simulations to determine the solution structures of an alternating AT DNA segment, with and without netropsin, in order to evaluate the molecular basis of the binding-induced effects. Complex formation causes a significant narrowing of the minor groove and a pronounced change in bending, from a slight bend towards the major groove for the free DNA to a pronounced bend towards the minor groove in the complex. This observation demonstrates that conformational features and the inherent malleability of AT sequences are essential for specific molecular recognition and function. These results take the field of DNA structures into new areas while opening up avenues to target novel DNA sequences. PMID- 23355267 TI - Advances in tubeless percutaneous nephrolithotomy and patient selection: an update. AB - Percutaneous nephrolithotomy (PCNL) is the gold standard for the treatment of large renal calculi. Recently, modifications to the standard PCNL with nephrostomy tube placement have evolved, most notably the introduction of tubeless PCNL. Tubeless PCNL appears to decrease postoperative discomfort and shorten hospital stays, without increasing complication rates in the appropriately selected patient population. Urologists have attempted to expand the role of tubeless PCNL in more complex clinical scenarios, including pediatric and geriatric patients, and in stones complicated by multiple access tracts, renal anomalies or previous renal surgery. In an attempt to further improve outcomes following tubeless PCNL, adjunct interventions such as the use of hemostatic agents along the percutaneous access tract and local tract anesthetic have also been evaluated. We report the most recent published data over the past year, reviewing the employment and efficacy of tubeless PCNL, and discuss the selection of appropriate patients for this modified procedure. PMID- 23355268 TI - mTOR and vascular remodeling in lung diseases: current challenges and therapeutic prospects. AB - Mammalian target of rapamycin (mTOR) is a major regulator of cellular metabolism, proliferation, and survival that is implicated in various proliferative and metabolic diseases, including obesity, type 2 diabetes, hamartoma syndromes, and cancer. Emerging evidence suggests a potential critical role of mTOR signaling in pulmonary vascular remodeling. Remodeling of small pulmonary arteries due to increased proliferation, resistance to apoptosis, and altered metabolism of cells forming the pulmonary vascular wall is a key currently irreversible pathological feature of pulmonary hypertension, a progressive pulmonary vascular disorder with high morbidity and mortality. In addition to rare familial and idiopathic forms, pulmonary hypertension is also a life-threatening complication of several lung diseases associated with hypoxia. This review aims to summarize our current knowledge and recent advances in understanding the role of the mTOR pathway in pulmonary vascular remodeling, with a specific focus on the hypoxia component, a confirmed shared trigger of pulmonary hypertension in lung diseases. We also discuss the emerging role of mTOR as a promising therapeutic target and mTOR inhibitors as potential pharmacological approaches to treat pulmonary vascular remodeling in pulmonary hypertension. PMID- 23355269 TI - The mechanical consequences of load bearing in the equine third metacarpal across speed and gait: the nonuniform distributions of normal strain, shear strain, and strain energy density. AB - Distributions of normal strain, shear strain, and strain energy density (SED) were determined across the midshaft of the third metacarpal (MCIII, or cannon bone) of 3 adult thoroughbred horses as a function of speed and gait. A complete characterization of the mechanical demands of the bone made through the stride and from mild through the extremes of locomotion was possible by using three 3 element rosette strain gauges bonded at the diaphyseal midshaft of the MCIII and evaluating the strain output with beam theory and finite element analysis. Mean +/- sd values of normal strain, shear strain, and SED increased with speed and peaked during a canter (-3560+/-380 microstrain, 1760+/-470 microstrain, and 119+/-23 kPa, respectively). While the location of these peaks was similar across animals and gaits, the resulting strain distributions across the cortex were consistently nonuniform, establishing between a 73-fold (slow trot) to a 330-fold (canter) disparity between the sites of maximum and minimum SED for each gait cycle. Using strain power density as an estimate of strain history across the bone revealed a 154-fold disparity between peak and minimum at the walk but fell to ~32-fold at the canter. The nonuniform, minimally varying, strain environment suggests either that bone homeostasis is mediated by magnitude-independent mechanical signals or that the duration of stimuli necessary to establish and maintain tissue integrity is relatively brief, and thus the vast majority of strain information is disregarded. PMID- 23355270 TI - BN/CC isosteric compounds as enzyme inhibitors: N- and B-ethyl-1,2-azaborine inhibit ethylbenzene hydroxylation as nonconvertible substrate analogues. AB - Good substrate gone bad! BN/CC isosterism of ethylbenzene leads to N-ethyl-1,2 azaborine and B-ethyl-1,2-azaborine. In contrast to ethylbenzene, which is the substrate for ethylbenzene dehydrogenase (EbDH), N-ethyl-1,2-azaborine (see scheme; Fc=Ferricenium tetrafluoroborate) and B-ethyl-1,2-azaborine are strong inhibitors of EbDH. Thus, the changes provided by BN/CC isosterism can lead to new biochemical reactivity. PMID- 23355271 TI - Retention of power conversion efficiency--from small area to large area polymer solar cells. AB - A light harvesting device geometry is implemented for polymer solar cells that retain efficiency when the device area is scaled up. Patterning devices and incorporating suitable fluorescent dye doped polymers in the spaces between the patterns leads to 12% efficiency enhancement. Vacuum free deposition of electrodes is carried out using meltable alloys giving rise to device efficiency of 6%. The fluorescent layer along with the electrode serves as an active encapsulant leading to improved device stability. PMID- 23355272 TI - DIP-STR: highly sensitive markers for the analysis of unbalanced genomic mixtures. AB - Samples containing highly unbalanced DNA mixtures from two individuals commonly occur both in forensic mixed stains and in peripheral blood DNA microchimerism induced by pregnancy or following organ transplant. Because of PCR amplification bias, the genetic identification of a DNA that contributes trace amounts to a mixed sample represents a tremendous challenge. This means that standard genetic markers, namely microsatellites, also referred as short tandem repeats (STR), and single-nucleotide polymorphism (SNP) have limited power in addressing common questions of forensic and medical genetics. To address this issue, we developed a molecular marker, named DIP-STR that relies on pairing deletion-insertion polymorphisms (DIP) with STR. This novel analytical approach allows for the unambiguous genotyping of a minor component in the presence of a major component, where DIP-STR genotypes of the minor were successfully procured at ratios up to 1:1,000. The compound nature of this marker generates a high level of polymorphism that is suitable for identity testing. Here, we demonstrate the power of the DIP-STR approach on an initial set of nine markers surveyed in a Swiss population. Finally, we discuss the limitations and potential applications of our new system including preliminary tests on clinical samples and estimates of their performance on simulated DNA mixtures. PMID- 23355273 TI - An eHealth system supporting palliative care for patients with non-small cell lung cancer: a randomized trial. AB - BACKGROUND: In this study, the authors examined the effectiveness of an online support system (Comprehensive Health Enhancement Support System [CHESS]) versus the Internet in relieving physical symptom distress in patients with non-small cell lung cancer (NSCLC). METHODS: In total, 285 informal caregiver-patient dyads were assigned randomly to receive, for up to 25 months, standard care plus training on and access to either use of the Internet and a list of Internet sites about lung cancer (the Internet arm) or CHESS (the CHESS arm). Caregivers agreed to use CHESS or the Internet and to complete bimonthly surveys; for patients, these tasks were optional. The primary endpoint-patient symptom distress-was measured by caregiver reports using a modified Edmonton Symptom Assessment Scale. RESULTS: Caregivers in the CHESS arm consistently reported lower patient physical symptom distress than caregivers in the Internet arm. Significant differences were observed at 4 months (P = .031; Cohen d = .42) and at 6 months (P = .004; d = .61). Similar but marginally significant effects were observed at 2 months (P = .051; d = .39) and at 8 months (P = .061; d = .43). Exploratory analyses indicated that survival curves did not differ significantly between the arms (log rank P = .172), although a survival difference in an exploratory subgroup analysis suggested an avenue for further study. CONCLUSIONS: The current results indicated that an online support system may reduce patient symptom distress. The effect on survival bears further investigation. PMID- 23355275 TI - Up-regulation of oxytocin receptor expression at term is related to maternal body mass index. AB - BACKGROUND: The likelihood of cesarean is in part related to maternal body mass index (BMI). Myometrial changes may be responsible. METHODS: Myometrial biopsies were collected from the upper edge of the hysterotomy from women undergoing scheduled cesarean with term, singleton gestations. Oxytocin receptor and connexin-43 mRNA protein expression was quantified with real-time polymerase chain reaction and Western blot. RESULTS: Twenty subjects were recruited: 13 repeat and 7 primary cesareans. Oxytocin receptor mRNA was associated with BMI among women undergoing primary (r = 0.75; p = 0.05) but not repeat cesarean (p > 0.05). Controlling for gestational age, this association strengthened (p = 0.004). Receptor protein expression showed a linear correlation with BMI in the primary cesarean group (p = 0.002). Connexin-43 mRNA expression was not related to BMI in women undergoing primary (r = -0.14, p = 0.76) or repeat (r = -0.01, p = 0.86) cesarean. CONCLUSIONS: Oxytocin receptor, but not connexin-43, expression is related to BMI, suggesting an alteration in oxytocin receptor expression or function related to obesity. PMID- 23355276 TI - Symptomatic internal carotid artery medialization: a rare anatomic variant resulting in cough, dysphonia, and dysphagia. PMID- 23355277 TI - Milestones in mission: the work of the American Cancer Society's mission delivery. AB - Since its founding in 1913, the American Cancer Society (the Society) has played a prominent role in the fight against cancer. Through its presence in over 5,000 communities around the nation, the Society has explored and pursued innovative ideas, searched for breakthroughs, and pushed to have the nation understand the complexities of the disease. Ongoing assessment of the cancer problem, thoughtful strategic planning, and promotion of evidence-based cancer control programs are integral to the Society's mission. This paper provides a summary of these efforts. PMID- 23355278 TI - Using expert panels to determine the level of cancer knowledge required of junior doctors in australia. Part 2: sources of variability. AB - This paper describes the sources of variability encountered in the use of an expert panel to review cancer-related knowledge items, necessary for medical students. Variability was observed in the interpretation of written material relating to the definition and rationale for the task to be completed by individual panel members, including the definition of a junior doctor, and levels of understanding and specificity. Panel sessions undertaken in phase II provided facilitated discussion and the ability to clearly define the aims and tasks required of participants, resulting in data of a higher quality. Consensus was achieved in a single session that would have likely taken several iterations of individual data collection to achieve. Eliminating phase I has the potential to remove the majority of variability encountered in this study. Subsequently, the resultant decrease in time demanded of participants would likely result in higher recruitment and participation rates. PMID- 23355279 TI - Perceptions of cancer controllability and cancer risk knowledge: the moderating role of race, ethnicity, and acculturation. AB - Literature suggests racial/ethnic minorities, particularly those who are less acculturated, have stronger fatalistic attitudes toward cancer than do non-Latino Whites. Knowledge of cancer prevention is also lower among racial/ethnic minorities. Moreover, low knowledge about cancer risk factors is often associated with fatalistic beliefs. Our study examined fatalism and cancer knowledge by race/ethnicity and explored whether race/ethnicity moderate the association of fatalism with knowledge of cancer prevention and risk factors. We analyzed data from the Health Information National Trends Survey (2008), a national probability survey, to calculate population estimates of the associations among race/ethnicity, fatalistic beliefs, and knowledge about cancer from multivariable logistic regression. Racial/ethnic minorities had higher odds of holding fatalistic beliefs and lower odds of having knowledge of cancer risk factors than non-Hispanic Whites, and important differences by acculturation among Latinos were observed. Limited evidence of the moderating effect of race/ethnicity on the relationship between fatalistic beliefs and cancer risk factor knowledge was observed. Knowledge of cancer risk factors is low among all race/ethnicities, while fatalistic beliefs about cancer are higher among racial/ethnic minorities compared with non-Hispanic Whites. Implications for cancer education efforts are discussed. PMID- 23355280 TI - Survivorship clinic group educational sessions: adoption, acceptance, and attendance. AB - The number of breast cancer survivors now exceeds 2.5 million in the USA. In the near future, it is likely that existing systems will not be sufficient to provide follow-up care and services for all these patients. Because survivors have many concerns in common and providers may not have enough time to address them individually, group educational sessions (GES) provide an opportunity to inform patients of current breast cancer-related health issues, treatment updates, and follow-up guidelines in an efficient and structured environment. At the University of California San Francisco Breast Care Center, we implemented a GES for patients referred into the Survivorship Clinic. To improve content and convenience, patients were asked at the end of each session to complete a survey measuring their satisfaction with the GES. Clinic staff tracked GES attendance, reasons for declining participation in the GES, and utilization of the Survivorship Clinic for follow-up care. Of the 381 patients referred to the Survivorship Clinic, 177 patients have attended the GES, and 204 ultimately have not attended the GES. Eighty four of the 177 patients who attended completed a survey at the end of the GES. Ninety-five percent of these patients agreed or somewhat agreed that the information presented was clear and understandable. Eighty-five percent of patients agreed or somewhat agreed that they learned about resources for recovery. Utilization of follow-up appointments within the Survivorship Clinic was significantly higher among those who attended the GES compared to those who did not attend. Overall, the GES allows for efficient patient education, and evaluation of the GES leads to new innovations to improve survivorship care. PMID- 23355281 TI - Evaluation of the impact of NCI's Summer Curriculum on Cancer Prevention on participants from low- and middle-income countries. AB - The National Cancer Institute (NCI) Summer Curriculum on Cancer Prevention provides scientists and health care professionals training in principles and practices of cancer prevention and control, and molecular biology and genetics of cancer. Originally intended for US scientists, the curriculum's enrollment of international scientists has increased steadily. The objective of the current study was to evaluate the curriculum's impact on knowledge, skills, and career accomplishments of the international participants from low- and middle-income countries. International participants from 1998 to 2009 completed questionnaires regarding knowledge, overall experience, and accomplishments directly associated with the curriculum. Almost all respondents agreed that the curriculum enhanced their knowledge and skills, prepared them to contribute to cancer control activities in their home countries, and addressed specific needs and achieve research goals. The NCI Summer Curriculum on Cancer Prevention gives international participants a unique opportunity to enhance their knowledge and effectively contribute to cancer control activities in their home country. PMID- 23355282 TI - Migration and father absence: shifting family structure in Mexico. AB - Despite many changing demographic processes in Mexico-declining adult mortality, rising divorce, and rising nonmarital fertility-Mexican children's family structure has been most affected by rising migration rates. Data from five national surveys spanning three decades demonstrate that since 1976, migration has shifted from the least common to the most common form of father household absence. Presently, more than 1 in 5 children experience a father's migration by age 15; 1 in 11 experiences his departure to the United States. The proportions are significantly higher among those children born in rural communities and those born to less-educated mothers. The findings emphasize the importance of framing migration as a family process with implications for children's living arrangements and attendant well-being, particularly in resource-constrained countries. The stability of children's family life in these regions constitutes a substantial but poorly measured cost of worldwide increases in migration. PMID- 23355283 TI - Impact of an antimicrobial stewardship program comprehensive care bundle on management of candidemia. AB - STUDY OBJECTIVE: To analyze the impact of a comprehensive care bundle directed by an antimicrobial stewardship team (AST) on the management of candidemia. DESIGN: Single-center, quasi-experimental study. SETTING: A 930-bed academic hospital. PATIENTS: Seventy-eight patients with candidemia were evaluated; 41 patients received the candidemia care bundle (AST group), and 37 did not (historical control group). MEASUREMENTS AND MAIN RESULTS: A candidemia care bundle was developed by an interdisciplinary AST, incorporating key elements from the Infectious Diseases Society of America's Clinical Practice Guidelines for the Management of Candidemia. The AST made prospective recommendations in accordance with the care bundle. Bundle elements were utilization of appropriate antifungal agents with appropriate duration of use, removal of intravenous catheters, repeat blood cultures, monitoring of time until clearance of candidemia, and performance of ophthalmologic examinations. Compliance with all candidemia care bundle elements was significantly higher in the AST group versus the control group (78.0% vs 40.5%, p=0.0016). Implementation of the care bundle significantly improved rates of ophthalmologic examination (97.6% vs 75.7%, p=0.0108), selection of appropriate antifungal therapy (100% vs 86.5%, p=0.0488), and compliance with an appropriate duration of therapy (97.6% vs 67.7%, p=0.0012). In addition, the AST group had fewer excess total days of therapy beyond the recommended duration than the control group (5 vs 83 total antifungal days). Length of hospitalization (20 vs 21 days, p=0.9184), time until clearance of candidemia (3 vs 3 days p=0.610), rate of persistent candidemia (22% vs 40.5%, p=0.126), and rate of recurrent candidemia (4.9% vs 5.4%, p=0.916) were similar in the AST group versus the control group. CONCLUSION: A comprehensive candidemia care bundle directed by our institution's AST improved the management of patients with candidemia. We encourage further exploration into the use of care bundles by ASTs as part of their multifaceted approach to promoting appropriate antimicrobial utilization and optimizing the management of patients with infectious diseases. PMID- 23355284 TI - A recyclable trinuclear bifunctional catalyst derived from a tetraoxo bis Zn(salphen) metalloligand. AB - A tetraoxo bis-Zn(salphen) supramolecular host can bind various divalent metal salts, thereby providing access to trinuclear bifunctional systems that incorporate both Lewis acid sites and dynamically bound nucleophilic anions. The formation of these trinuclear species was investigated and their stability features were also determined. The application of these trinuclear complexes as bifunctional catalysts was evaluated in the formation of cyclic organic carbonates from epoxides and CO(2). The catalytic data, in combination with control experiments, clearly demonstrate that these trinuclear compounds show much higher recycling potential compared to various control compounds and they can be used in up to five cycles without an observable loss in activity. Furthermore, this new recyclable catalytic system does not require any additives and can be applied under solvent-free conditions. PMID- 23355285 TI - The efficacy of passion fruit juice as an endodontic irrigant compared with sodium hypochlorite solution: an in vitro study. AB - AIM: To assess the effectiveness of several concentrations of two forms of passion fruit juice (PFJ) in the elimination of Enterococcus faecalis and to compare the antibacterial property of PFJ with sodium hypochlorite (NaOCl) as an intracanal irrigant. METHODS: Two types of PFJs, aqueous and alcohol extracts, were prepared and a minimum inhibitory concentration (MIC) test was performed with both the extracts against E. faecalis. Two concentrations of each extract were selected from the results given by the MIC test and subjected to a broth dilution test (BDT) for nine different time periods. After each time period, samples were inoculated in brain-heart infusion agar plates for 24 h at 37 degrees C and results were compared statistically. RESULTS: The MIC test showed that E. faecalis was sensitive to PFJ extracts at various concentrations. The results of the BDT showed a negative growth of E. faecalis by PFJ alcohol 20% at 30 min, PFJ aqueous 20% at 1 h, NaOCl 2.5% at 10 min and NaOCl 5.25% at 1 min. NaOCl showed a much better antibacterial efficacy than PFJ. CONCLUSIONS: The PFJ alcoholic and aqueous extracts had an antibacterial effect against E. faecalis. As PFJ shows promising results, further research in this field could lead to much better results as compared to NaOCl. PMID- 23355286 TI - Equisetum arvense hydro-alcoholic extract: phenolic composition and antifungal and antimycotoxigenic effect against Aspergillus flavus and Fusarium verticillioides in stored maize. AB - BACKGROUND: Maize is a very important cereal for human and animal diet, but it can be contaminated by moulds and their mycotoxins. On the other hand, natural plant products with antimicrobial properties could possibly used to control mycotoxigenic fungi in foods and feeds. In this study, Equisetum arvense extract was tested for the efficacy on Aspergillus section Flavi and Fusarium section Liseola growth. Natural contaminated maize was used in this study and extract was added under different water activities (a(w)) - 0.90 and 0.95 - for Aspergillus section Flavi and Fusarium section Liseola, respectively. Moulds were inoculated in maize and incubated during 30 days. RESULTS: We confirm that E. arvense extract may be effective for the inhibition of Aspergillus section Flavi in maize with high levels of this mould. Moreover, this extract showed a good inhibition of growth on Fusarium section Liseola levels. Aflatoxin and fumonisin production was not affected by the extract. CONCLUSIONS: E. arvense extract could be an alternative to synthetic fungicides to control maize mycobiota level in moist grain. PMID- 23355287 TI - Electrospun TiO2 nanorods with carbon nanotubes for efficient electron collection in dye-sensitized solar cells. AB - A high power conversion efficiency of 10.24% can be obtained in a dye-sensitized solar cell by incorporating multiwall carbon nanotubes inside a TiO2 nanorod photoanode. The multiwall carbon nanotubes in the nanorod can effectively collect and transport photogenerated electrons reducing the recombination as well as improving efficiency of the device. PMID- 23355290 TI - Bellman's GAP--a language and compiler for dynamic programming in sequence analysis. AB - MOTIVATION: Dynamic programming is ubiquitous in bioinformatics. Developing and implementing non-trivial dynamic programming algorithms is often error prone and tedious. Bellman's GAP is a new programming system, designed to ease the development of bioinformatics tools based on the dynamic programming technique. RESULTS: In Bellman's GAP, dynamic programming algorithms are described in a declarative style by tree grammars, evaluation algebras and products formed thereof. This bypasses the design of explicit dynamic programming recurrences and yields programs that are free of subscript errors, modular and easy to modify. The declarative modules are compiled into C++ code that is competitive to carefully hand-crafted implementations. This article introduces the Bellman's GAP system and its language, GAP-L. It then demonstrates the ease of development and the degree of re-use by creating variants of two common bioinformatics algorithms. Finally, it evaluates Bellman's GAP as an implementation platform of 'real-world' bioinformatics tools. AVAILABILITY: Bellman's GAP is available under GPL license from http://bibiserv.cebitec.uni-bielefeld.de/bellmansgap. This Web site includes a repository of re-usable modules for RNA folding based on thermodynamics. PMID- 23355291 TI - mRNAStab--a web application for mRNA stability analysis. AB - Eukaryotic gene expression is regulated both at the transcription and the mRNA degradation levels. The implementation of functional genomics methods that allow the simultaneous measurement of transcription (TR) and degradation (DR) rates for thousands of mRNAs is a huge improvement in this field. One of the best established methods for mRNA stability determination is genomic run-on (GRO). It allows the measurement of DR, TR and mRNA levels during cell dynamic responses. Here, we offer a software package that provides improved algorithms for determination of mRNA stability during dynamic GRO experiments. PMID- 23355292 TI - Obesity-related female infertility in medieval persian manuscripts. PMID- 23355293 TI - Predictive factors of type 2 diabetes remission 1 year after bariatric surgery: impact of surgical techniques. AB - Type 2 diabetes (T2D) remission after bariatric procedures has been highlighted in many retrospective and some recent prospective studies. However, in the most recent prospective study, more than 50 % of patients did not reach T2D remission at 1 year. Our aim was to identify baseline positive predictors for T2D remission at 1 year after bariatric surgery and to build a preoperative predictive score. We analysed the data concerning 161 obese operated on between June 2007 and December 2010. Among them, 46 were diabetic and were included in the study-11 laparoscopic adjustable gastric banding (LAGB), 26 Roux-en-Y gastric bypass (RYGB) and 9 sleeve gastrectomy (SG). We compared anthropometric and metabolic features during 1 year of follow-up. A receiver operating characteristic analysis was performed to predict T2D remission. RYGB and SG were similarly efficient for body weight loss and more efficient than LAGB; 62.8 % of patients presented with T2DM remission at 1 year, with no significant difference according to the surgical procedure. A 1-year body mass index (BMI) <35 kg m(-2) was predictive of T2DM remission whatever the procedure. The preoperative predictive factors of diabetes remission were baseline BMI <=50 kg m(-2), duration of type 2 diabetes <=4 years, glycated haemoglobin <=7.1 %, fasting glucose <1.14 g/l and absence of insulin therapy. A short duration of diabetes and good preoperative glycaemic control increase the rate of T2DM remission 1 year after surgery. Preoperative metabolic data could be of greater importance than the choice of bariatric procedure. PMID- 23355294 TI - Letter to the editor and comments on the article "gastric histopathologies in patients undergoing laparoscopic sleeve gastrectomies" by Salam Al Sabah et al. PMID- 23355295 TI - The distally based superficial sural flap for reconstruction of the foot and ankle in pediatric patients. AB - The distally based superficial sural flap has been used for coverage of defects in the foot and ankle for years. However, little attention has been received in the pediatric trauma population because of small sample volumes. The current study presents results using distally based superficial sural flaps for reconstruction of soft tissue defects of the foot and ankle in children. A retrospective study was performed to assess outcomes of 32 pediatric patients with defects of the foot and ankle requiring soft tissue coverage using distally based superficial sural flaps. The average patient age was 9 years. The etiology of the soft tissue defects included 31 traumatic events and 1 chronic ulcer with bone, tendon, or joint lesion exposure. Postoperative follow-up of the 32 patients ranged from 11 months to 7 years. All 32 flaps survived successfully. Complications included one wound dehiscence and three slight venous congestions. The distally based superficial sural flap is a good alternative for soft tissue defects of the foot and ankle in children. The surgical techniques in harvesting the flaps are easy to handle. PMID- 23355296 TI - Perioperative evaluation and outcomes of major limb replantations with ischemia periods of more than 6 hours. AB - Early revascularization is cardinal for successful replantation of proximal limb amputations. Prolonged ischemia time potentially leads to reperfusion syndrome and morbidity. The dilemma persists regarding safe duration of cold ischemia time for replantation. The study was conducted to evaluate retrospectively the outcomes of major replantation in terms of limb survival, reperfusion events, morbidity, and potential mortality with respect to the ischemia time and level of amputations. Fourteen patients with proximal amputations at the arm, elbow, and forearm with total ischemia time beyond 6 hours were replanted. All had warm ischemia time of less than 2 hours and were closely monitored to record and correct reperfusion events. Nine out of 14 limbs survived. Five patients had reperfusion events. Proximal limb amputations with larger muscle mass were at higher risk of developing reperfusion syndrome and such events had higher chances of limb loss. Major limb amputations within 2 hours of warm ischemia time even with prolonged cold ischemia can be successfully replanted with closed perioperative monitoring. PMID- 23355297 TI - The evolutionary paradox and the missing heritability of schizophrenia. AB - Schizophrenia is one of the most detrimental common psychiatric disorders, occurring at a prevalence of approximately 1%, and characterized by increased mortality and reduced reproduction, especially in men. The heritability has been estimated around 70% and the genome-wide association meta-analyses conducted by the Psychiatric Genomics Consortium have been successful at identifying an increasing number of risk loci. Various theories have been proposed to explain why genetic variants that predispose to schizophrenia persist in the population, despite the fitness reduction in affected individuals, a question known as the evolutionary paradox. In this review, we consider evolutionary perspectives of schizophrenia and of the empirical evidence that may support these perspectives. Proposed evolutionary explanations include balancing selection, fitness trade offs, fluctuating environments, sexual selection, mutation-selection balance and genomic conflicts. We address the expectations about the genetic architecture of schizophrenia that are predicted by different evolutionary scenarios and discuss the implications for genetic studies. Several potential sources of "missing" heritability, including gene-environment interactions, epigenetic variation, and rare genetic variation are examined from an evolutionary perspective. A better understanding of evolutionary history may provide valuable clues to the genetic architecture of schizophrenia and other psychiatric disorders, which is highly relevant to genetic studies that aim to detect genetic risk variants. PMID- 23355298 TI - Human variation 2.0: using GWAS to probe intermediate phenotypes. PMID- 23355299 TI - Stereoselective total synthesis of (+)-giganin and its C10 epimer by using late stage lithiation-borylation methodology. AB - The first total synthesis of (+)-giganin and its unnatural diastereoisomer (+) C10-epi-giganin has been completed in a total of 13 linear steps, and 7 % and 8 % overall yield, respectively (see scheme; (-)-sp= (-)-sparteine, (+)-sps=(+) sparteine surrogate). Lithiation-borylation methodology has been successfully applied in the key step, to couple together advanced intermediates with very high diastereoselectivity, thus demonstrating its power as a tool for total synthesis. PMID- 23355300 TI - Variants of the supplying vessels of the vascularized iliac bone graft and their relationship to important surgical landmarks. AB - The iliac bone crest is one of the most valuable regions for harvesting bone grafts, both vascularized and nonvascularized. Since the first commendable description of this region as a possible source for vascularized bone flaps by Taylor, little relevant information concerning the variations of the deep circumflex iliac vessels and their relationship to the neighboring structures has been published. The purpose of the current study was to examine this region clinically and anatomically, taking into consideration the former description by Taylor. We gathered all our findings on 216 iliac regions and proposed a new classification. In addition we measured the relationships between the deep circumflex iliac artery and important surgical landmarks. A comparison of our finding with other studies showed similarities and differences but was far more complete. Generally (92%) the deep circumflex iliac artery (DCIA) originated from external iliac artery (EIA) behind the inguinal ligament (IL) and passed cranio laterally toward the anterior superior iliac spine, where it divided into two important branches. Four variations were observed of the DCIA. The deep circumflex iliac vein (DCIV) ran over (82.5%) or under (17.5%) the EIA. The superficial circumflex iliac vein (SCIV) was observed draining into the DCIV in some dissections. Three different variations of the superficial circumflex iliac artery (SCIA) were observed. The anatomical knowledge of these variations and their correlation to important surgical landmarks can help in harvesting the DCIA flap more safely and thus increasing the success rate while reducing donor site morbidity. PMID- 23355301 TI - Simultaneous pharmacokinetic model for rolofylline and both M1-trans and M1-cis metabolites. AB - Rolofylline is a potent, selective adenosine A1 receptor antagonist that was under development for the treatment of patients with acute congestive heart failure and renal impairment. Rolofylline is metabolized primarily to the pharmacologically active M1-trans and M1-cis metabolites (metabolites) by cytochrome P450 (CYP) 3A4. The aim of this investigation was to provide a pharmacokinetic (PK) model for rolofylline and metabolites following intravenous administration to healthy volunteers. Data included for this investigation came from a randomized, double-blind, dose-escalation trial in four groups of healthy volunteers (N=36) where single doses of rolofylline, spanning 1 to 60 mg ,were infused over 1-2 h. The rolofylline and metabolite data were analyzed simultaneously using NONMEM. The simultaneous PK model comprised, in part, a two compartment linear PK model for rolofylline, with estimates of clearance and volume of distribution at steady-state of 24.4 L/h and 239 L, respectively. In addition, the final PK model contained provisions for both conversion of rolofylline to metabolites and stereochemical conversion of M1-trans to M1-cis. Accordingly, the final model captured known aspects of rolofylline metabolism and was capable of simultaneously describing the PK of rolofylline and metabolites in healthy volunteers. PMID- 23355302 TI - Angio CT assessment of anatomical variants in renal vasculature: its importance in the living donor. AB - BACKGROUND: Renal vasculature is known for having a broad spectrum of variants, which have been classically reported by anatomists. METHODS: The distribution and morphology of these variations can be explained by considering the embryology of the renal vessels. With the recent outburst of imaging techniques, it has been the radiologist's turn to take the baton, recognising and describing unconventional renal vascular patterns. RESULTS: Knowledge of these patterns has gained significance since the advent of the era of transplantation. For almost 60 years cadaveric donation has been the main source of kidneys suitable for transplantation. Living kidney donation demonstrates many advantages and stands out as the best alternative for organ procurement to meet the increasing demand. Since the dawn of laparoscopic nephrectomy as the technique of choice for organ procurement in living kidney donors, MDCT plays a key role as a noninvasive preoperative planning method for anatomic evaluation. As the field of view at laparoscopic surgery is limited, it is essential to meticulously assess the origin, number, division and course of arteries and veins. CONCLUSION: Awareness of the different anatomical variants allows the radiologist to enlighten the surgeon in order to avoid compromising the safety of the surgical procedure that could lead to significant complications. TEACHING POINTS: * Renal vasculature has many variants, which can be explained by considering the embryology of kidneys. * Living kidney donation demonstrates many advantages over cadaveric donation. * Angio CT evaluation of living kidney donors is a multiple phase study. * A detailed report describing the variants, their distribution and morphology will help surgeons. PMID- 23355303 TI - High-efficiency polymer solar cells enhanced by solvent treatment. AB - A significant enhancement of efficiency in thieno[3,4-b] thiophene/benzodithiophene:[6,6]-phenyl C71-butyric acid methyl ester (PTB7:PC70 BM) solar cells can be achieved by methanol treatment. The effects of methanol treatment are shown in an improvement of built-in voltage, a decrease in series resistance, an enhanced charge-transport property, an accelerated and enlarged charge extraction, and a reduced charge recombination, which induce a simultaneous enhancement in open-circuit voltage (Voc), short-circuit current (Jsc), and fill factor (FF) in the devices. PMID- 23355304 TI - Pancreatic lipase-colipase binds strongly to the thylakoid membrane surface. AB - BACKGROUND: Isolated thylakoid membranes, i.e. the photosynthetic membranes of green leaves, inhibit the activity of pancreatic lipase and colipase during hydrolysis of fat in vitro. This inhibition has been demonstrated to cause reduced food intake and improved hormonal and lipid profile in vivo. One of the reasons suggested for the inhibiting effect is binding of lipase-colipase to the thylakoid membrane surface. This prompted a study of the binding of lipase and colipase to thylakoids. RESULTS: The results showed that lipase and colipase strongly bind to the thylakoid membrane surface. The dissociation constant was determined at 1.2 * 10-8 mol L-1; binding decreased after treatment of thylakoids with pepsin/trypsin to 1.0 * 10-7 and to 0.6 * 10-7 mol L-1 after treatment with pancreatic juice. Similarly, delipidation of thylakoids caused a decrease in binding, the dissociation constant being 2.0 * 10-7 mol L-1. CONCLUSION: The binding of pancreatic lipase-colipase to the thylakoid membrane is strong and may explain the inhibition of lipase-colipase activity by thylakoids. After treatment with proteases to mimic intestinal digestion binding is decreased, but is still high enough to explain the observed metabolic effects of thylakoids in vivo. PMID- 23355305 TI - Comparative genomics of Blattabacterium cuenoti: the frozen legacy of an ancient endosymbiont genome. AB - Many insect species have established long-term symbiotic relationships with intracellular bacteria. Symbiosis with bacteria has provided insects with novel ecological capabilities, which have allowed them colonize previously unexplored niches. Despite its importance to the understanding of the emergence of biological complexity, the evolution of symbiotic relationships remains hitherto a mystery in evolutionary biology. In this study, we contribute to the investigation of the evolutionary leaps enabled by mutualistic symbioses by sequencing the genome of Blattabacterium cuenoti, primary endosymbiont of the omnivorous cockroach Blatta orientalis, and one of the most ancient symbiotic associations. We perform comparative analyses between the Blattabacterium cuenoti genome and that of previously sequenced endosymbionts, namely those from the omnivorous hosts the Blattella germanica (Blattelidae) and Periplaneta americana (Blattidae), and the endosymbionts harbored by two wood-feeding hosts, the subsocial cockroach Cryptocercus punctulatus (Cryptocercidae) and the termite Mastotermes darwiniensis (Termitidae). Our study shows a remarkable evolutionary stasis of this symbiotic system throughout the evolutionary history of cockroaches and the deepest branching termite M. darwiniensis, in terms of not only chromosome architecture but also gene content, as revealed by the striking conservation of the Blattabacterium core genome. Importantly, the architecture of central metabolic network inferred from the endosymbiont genomes was established very early in Blattabacterium evolutionary history and could be an outcome of the essential role played by this endosymbiont in the host's nitrogen economy. PMID- 23355306 TI - The spatiotemporal program of replication in the genome of Lachancea kluyveri. AB - We generated a genome-wide replication profile in the genome of Lachancea kluyveri and assessed the relationship between replication and base composition. This species diverged from Saccharomyces cerevisiae before the ancestral whole genome duplication. The genome comprises eight chromosomes among which a chromosomal arm of 1 Mb has a G + C-content much higher than the rest of the genome. We identified 252 active replication origins in L. kluyveri and found considerable divergence in origin location with S. cerevisiae and with Lachancea waltii. Although some global features of S. cerevisiae replication are conserved: Centromeres replicate early, whereas telomeres replicate late, we found that replication origins both in L. kluyveri and L. waltii do not behave as evolutionary fragile sites. In L. kluyveri, replication timing along chromosomes alternates between regions of early and late activating origins, except for the 1 Mb GC-rich chromosomal arm. This chromosomal arm contains an origin consensus motif different from other chromosomes and is replicated early during S-phase. We showed that precocious replication results from the specific absence of late firing origins in this chromosomal arm. In addition, we found a correlation between GC-content and distance from replication origins as well as a lack of replication-associated compositional skew between leading and lagging strands specifically in this GC-rich chromosomal arm. These findings suggest that the unusual base composition in the genome of L. kluyveri could be linked to replication. PMID- 23355307 TI - An integrated approach to endoscopic instrument tracking for augmented reality applications in surgical simulation training. AB - BACKGROUND: Despite the popular use of virtual and physical reality simulators in laparoscopic training, the educational potential of augmented reality (AR) has not received much attention. A major challenge is the robust tracking and three dimensional (3D) pose estimation of the endoscopic instrument, which are essential for achieving interaction with the virtual world and for realistic rendering when the virtual scene is occluded by the instrument. In this paper we propose a method that addresses these issues, based solely on visual information obtained from the endoscopic camera. METHODS: Two different tracking algorithms are combined for estimating the 3D pose of the surgical instrument with respect to the camera. The first tracker creates an adaptive model of a colour strip attached to the distal part of the tool (close to the tip). The second algorithm tracks the endoscopic shaft, using a combined Hough-Kalman approach. The 3D pose is estimated with perspective geometry, using appropriate measurements extracted by the two trackers. RESULTS: The method has been validated on several complex image sequences for its tracking efficiency, pose estimation accuracy and applicability in AR-based training. Using a standard endoscopic camera, the absolute average error of the tip position was 2.5 mm for working distances commonly found in laparoscopic training. The average error of the instrument's angle with respect to the camera plane was approximately 2 degrees . The results are also supplemented by video segments of laparoscopic training tasks performed in a physical and an AR environment. CONCLUSIONS: The experiments yielded promising results regarding the potential of applying AR technologies for laparoscopic skills training, based on a computer vision framework. The issue of occlusion handling was adequately addressed. The estimated trajectory of the instruments may also be used for surgical gesture interpretation and assessment. PMID- 23355308 TI - An improved high-throughput lipid extraction method for the analysis of human brain lipids. AB - We have developed a protocol suitable for high-throughput lipidomic analysis of human brain samples. The traditional Folch extraction (using chloroform and glass glass homogenization) was compared to a high-throughput method combining methyl tert-butyl ether (MTBE) extraction with mechanical homogenization utilizing ceramic beads. This high-throughput method significantly reduced sample handling time and increased efficiency compared to glass-glass homogenizing. Furthermore, replacing chloroform with MTBE is safer (less carcinogenic/toxic), with lipids dissolving in the upper phase, allowing for easier pipetting and the potential for automation (i.e., robotics). Both methods were applied to the analysis of human occipital cortex. Lipid species (including ceramides, sphingomyelins, choline glycerophospholipids, ethanolamine glycerophospholipids and phosphatidylserines) were analyzed via electrospray ionization mass spectrometry and sterol species were analyzed using gas chromatography mass spectrometry. No differences in lipid species composition were evident when the lipid extraction protocols were compared, indicating that MTBE extraction with mechanical bead homogenization provides an improved method for the lipidomic profiling of human brain tissue. PMID- 23355309 TI - IgE-mediated allergy to pholcodine and cross-reactivity to neuromuscular blocking agents: Lessons from flow cytometry. AB - BACKGROUND: Immunoglubulin E antibody-mediated allergic reactions to opioids are rare and difficult to document correctly. OBJECTIVE: Assessment of the basophil activation test in the diagnosis of IgE-mediated allergy to the antitussive pholcodine and associated sensitizations to neuromuscular blocking agents (NMBA). METHODS: Three patients with a suspected IgE-mediated allergy to pholcodine were investigated using skin tests, quantification of specific IgE, and flow cytometric activation of basophils. RESULTS AND CONCLUSION: Flow cytometric activation of basophils, with simultaneous analysis of CD63 appearance and median histamine content per cell, is the only technique capable to correctly document pholcodine allergy. The negative predictive value of basophil activation tests might help to elucidate on the controversial putative cross-reactivity between pholcodine and NMBA. PMID- 23355310 TI - Mycotic aneurysm of the abdominal aorta caused by Haemophilus influenzae type f. AB - Prior to the advent of the Haemophilus influenzae type b vaccine, invasive infections due to H. influenzae type f were rarely described. However, the epidemiology of H. influenzae is changing. While the incidence of invasive infections due to H. influenzae is declining in children, such infections are becoming more common in adults, particularly in the elderly. Here, we report an unusual case of infective aortic aneurysm caused by H. influenzae type f that underlines the emerging clinical relevance and pathogenic capability of this organism. PMID- 23355311 TI - Evaluation of Brilliance VRE agar for the detection of vancomycin-resistant enterococci in rectal swab specimens. PMID- 23355312 TI - Isolation and characterization of Pigmentiphaga-like isolates from human clinical material. AB - Species in the genus Pigmentiphaga are Gram-negative, catalase- and oxidase positive rods derived exclusively to date from environmental sources. Features of strains most like Pigmentiphaga daeguensis or Pigmentiphaga kullae from a case of suppurative otitis media in a 6-year-old female post-transplant recipient and in a human stool sample are described. PMID- 23355313 TI - Overdiagnosis among women attending a population-based mammography screening program. AB - Increased incidence of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC) after introduction of organized screening has prompted debate about overdiagnosis. The aim was to examine the excess in incidence of DCIS and IBC during the screening period and the deficit after women left the program, and thereby to estimate the proportion of overdiagnosis. Women invited to the Norwegian Breast Cancer Screening Program were analyzed for DCIS or IBC during the period 1995-2009. Incidence rate ratios (IRRs) were calculated for attended vs. never attended women. The IRRs were adjusted by Mantel-Haenszel (MH) method and applied to a set of reference rates and a reference population to estimate the proportion of overdiagnosis during the women's lifespan after the age of 50 years. A total of 702,131 women were invited to the program. An excess of DCIS and IBC was observed among women who attended screening during the screening period; prevalently invited women aged 50-51 years had a MH IRR of 1.86 (95% CI 1.65-2.09) and subsequently invited women aged 52-69 years had a MH IRR of 1.56 (95% CI 1.45-1.68). In women aged 70-79 years, a deficit of 30% (MH IRR 0.70, 95% CI 0.62-0.80) was observed 1-10 years after they left the screening program. The estimated proportion of overdiagnosis varied from 10 to 20% depending on outcome and whether the women were invited or actually screened. The results highlight the need for individual data with longitudinal screening history and long-term follow-up as a basis for estimating overdiagnosis. PMID- 23355314 TI - Enhancing electrocatalytic oxygen reduction on MnO(2) with vacancies. AB - Oxygen-vacant nanocrystalline MnO(2) has been prepared by the simple process of annealing pristine oxide in Ar or O(2) . Both experimental and computational studies indicate that the catalytic activity of MnO(2) towards oxygen reduction is enhanced by introducing a modest concentration of oxygen vacancies. PMID- 23355315 TI - An ex vivo study of selenium, genistein on the morphological and nuclear changes in anticancer drug-induced apoptosis in human peripheral blood lymphocytes. AB - Behavioral difference of cancer cells and normal cells to anticancer drugs is diverse. Debilitating side effects observed with certain chemotherapeutic and prophylactic anticancer drugs have lead to identification of natural agents that may offer protective role against the damage induced in normal cells. The present study aimed to determine the protective role of the micronutrient mineral selenium (Se) and plant product genistein (Gn) in synergy and single, against the apoptosis induced in human peripheral blood lymphocytes by the cytotoxic agents cisplatin and mitomycin C. We observed reduction in apoptotic potential of cisplatin and mitomycin C in lymphocytes by pre-treatment and post-treatment with selenium (30 MUM) and genistein (100 MUM). The intercellular interaction of Se + Gn in synergy is found to be more efficient in protecting lymphocytes than as individual. Moreover the beneficial results were well pronounced in pre-treatment than in post-treatment condition. The protective action of these natural compounds suggests that they might be useful immunomodulators during the course of chemotherapy and prophylaxis. PMID- 23355316 TI - Microsurgical anatomy of the infratemporal fossa. AB - The objective of this study is to clearly and precisely describe the topography and contents of the infratemporal fossa. Ten formalin-fixed, adult cadaveric specimens were studied. Twenty infratemporal fossa were dissected and examined using micro-operative techniques with magnifications of 3-40*. Information was obtained about the inter-relationships of the contents of the infratemporal fossa. The infratemporal fossa lies at the boundary of the head and neck, and the intracranial cavity. It is surrounded by the maxillary sinus anteriorly, the mandible laterally, the pterygoid process anteromedially, and the parapharyngeal space posteromedially. It contains the maxillary artery and its branches, the pterygoid muscles, the mandibular nerve, and the pterygoid venous plexus. The course and the anatomic variation of the maxillary artery and the branches of the mandibular nerve were demonstrated. The three-dimensional (3D) relationships between the important bony landmarks and the neurovascular bundles of the infratemporal fossa were also shown. The skull base anatomy of the infratemporal fossa is complex, requiring neurosurgeons and head and neck surgeons to have a precise knowledge of 3D details of the topography and contents of the region. A detailed 3D anatomic knowledge is mandatory to manage benign or malignant lesions involving the infratemporal fossa without significant postoperative complications. PMID- 23355317 TI - Organic vapor passivation of silicon at room temperature. AB - A simple, inexpensive, efficient, and scalable method to create air-stable organic surface passivation layers on silicon using a vapor-phase treatment is demonstrated. A variant of initiated chemical vapor deposition is used to synthesize a thin film that acts as both a passivation layer and an antireflective coating. The lowest surface recombination velocity reported to date is achieved and maintained during prolonged exposure to air. PMID- 23355318 TI - Dynamic change of TNIK in response to tumor necrosis factor alpha in a TRAF2 dependent manner. AB - TNIK (TRAF2- and NCK-interacting kinase) was named because of its association with TRAF2 (tumor necrosis factor receptor-associated factor 2). But the relationship between TNIK and TRAF2 is still elusive, in addition to which the involvement of TNIK in JNK activation by TNFalpha hints that there maybe a linkage between TNIK and TRAF2. In this work, we illustrated that TNIK protein levels were dynamic in response to TNFalpha stimulation in an ubiquitin-dependent manner. Further study showed that TRAF2 negatively modulated the levels of TNIK by regulating the ubiquitin conjugation. In conclusion, our data may give evidence that dynamic change of TNIK offers a way to protect cells from outside stimulus. PMID- 23355319 TI - Highly sensitive chemiluminescence immunoassay on chitosan membrane modified paper platform using TiO2 nanoparticles/multiwalled carbon nanotubes as label. AB - A highly sensitive chemiluminescence (CL) immunoassay was incorporated into a low cost microfluidic paper-based analytical device (MU-PAD) to fabricate a facile paper-based CL immunodevice (denoted as MU-PCLI). This MU-PCLI was constructed by covalently immobilizing capture antibody on a chitosan membrane modified MU-PADs, which was developed by simple wax printing methodology. TiO2 nanoparticles coated multiwalled carbon nanotubes (TiO2/MWCNTs) were synthesized as an amplification catalyst tag to label signal antibody (Ab2). After sandwich-type immunoreactions, the TiO2/MWCNTs were captured on the surface of MU-PADs to catalyze the luminol-p iodophenol-H2O2 CL system, which produced an enhanced CL emission. Using prostate specific antigen as a model analyte, the approach provided a good linear response range from 0.001 to 20 ng/mL with a low detection limit of 0.8 pg/mL under optimal conditions. This MU-PCLI showed good reproducibility, selectivity and stability. The assay results of prostate-specific antigen in clinical serum samples were in good agreement with that obtained by commercially used electrochemiluminescence methods at the Cancer Research Center of Shandong Tumor Hospital (Jinan, Shandong Province, China). This MU-PCLI could be very useful to realize highly sensitive, qualitative point-of-care testing in developing or developed countries. PMID- 23355320 TI - Sonographic confirmation of the correct placement of a nasoenteral tube in a woman with hyperemesis gravidarum: case report. AB - Hyperemesis gravidarum is a serious systemic disorder of pregnant women characterized by intractable vomiting resulting in metabolic, biochemical, and hematologic changes. Enteral nutrition has been used successfully and has a lower complication rate than parenteral nutrition. Tube feeding requires location of the feeding tube tip before the infusion of nutritional substance is started. We report a case of assisted feeding tube tip location using real time sonography in a pregnant women treated for hyperemesis gravidarum. Sonographic examination may be used as an alternative to x-ray for the confirmation of feeding tube location in pregnant women and thus eliminate exposure of the fetus to ionizing radiation. PMID- 23355321 TI - Photoisomerizable and thermoresponsive N-isopropylacrylamide-surfmer copolymer hydrogels prepared upon electrostatic self-assembly of an azobenzene bolaamphiphile. AB - Photoreactive and thermoresponsive N-isopropylacrylamide (NIPAM)-surfmer copolymer hydrogels containing 4,4'-di(6-sulfato-hexyloxy)azobenzene (DSHA) dianions are described. The functional hydrogels are obtained in a two steps. First a micellar aqueous solution of (11-(acryloyloxy)undecyl)trimethylammonium bromide (AUTMAB) and NIPAM is exposed to (60) Co-gamma irradiation, and a thermoresponsive copolymer gel is obtained. Second, DSHA is included by shrinking the gel at 50 degrees C and subsequent reswelling in an aqueous solution of DSHA disodium salt at 20 degrees C. Reswelling is accompanied by electrostatic adsorption of DSHA dianions at the positively charged AUTMAB headgroups replacing the bromide ions. Gels containing trans-DSHA are transparent yellow at room temperature (lambdamax = 370 nm), while gels containing cis-rich DSHA are orange (lambdamax = 460 and 330 nm). Energy dispersive X-ray measurements indicate that 41% of the bromide ions are exchanged if trans-DSHA is used for adsorption, and only 7.5% if cis-DSHA is used. The incorporation of DSHA lowers the lower critical solution temperature (LCST) from 34 to 32 degrees C. Below the LCST, DSHA can be switched from the trans- to the cis-rich state and vice versa upon irradiation with UV (lambda = 366 nm) or visible light (lambda >= 450 nm). Above the LCST no photoreaction takes place. PMID- 23355322 TI - Bladder cancer and seroreactivity to BK, JC and Merkel cell polyomaviruses: the Spanish bladder cancer study. AB - An infectious etiology for bladder cancer has long been suspected. Merkel cell virus (MCV), BKV and JCV polyomaviruses are possible causative agents but data remain scarce. Therefore, we evaluated the seroresponse to these three polyomaviruses in association with bladder cancer risk. 1,135 incident bladder cancer subjects from five Spanish regions and 982 hospital controls matched by sex, age and region were included. 99% of cases were urothelial-cell carcinomas. Antibody response against MCV, BKV and JCV was measured by enzyme immunoassay using Virus-Like-Particles. Our results show a similar seroprevalence in cases and controls: 64/60% for BKV, 83/82% for MCV and 87/83% for JCV. However, among seropositive subjects, higher median seroreactivities were observed in cases compared to controls for BKV (0.84 vs. 0.70, p-value = 0.009) and MCV (1.81 vs. 0.65, p-value < 0.001). Increased bladder cancer risk was observed for BKV (OR = 1.4, 95%CI 1.04-1.8) and for MCV (OR = 1.5, 95%CI 1.2-1.9), when comparing highest to lowest seroreactivity tertiles. The associations of BKV and MCV with bladder cancer were independent of each other and neither smoking status nor disease stage and grade modified them. Furthermore, no association was observed between seroresponse to JCV and bladder cancer. Therefore, we conclude that BKV and MCV polyomavirus infection could be related to an increased bladder cancer risk. PMID- 23355323 TI - Extraordinary branching pattern of the aortic arch. AB - A CT-scan of a 75-year-old patient showed an aneurysm of the descending aorta with a maximum diameter of 4.8 cm involving the left subclavian artery. Due to the fact that the patient had several comorbidities including a severe chronic obstructive pulmonary disease he was treated only conservatively. However, there were several interesting findings on the CT-scan: the branching pattern of the aortic arch revealed a left carotid artery arising as first side branch of the distal part of the ascending aorta. This vessel crosses the midline right in front of the trachea. Apart from that the patient did not have a brachiocephalic trunk: the right carotid artery arose as the first branch from the aortic arch and crossed the right subclavian artery anteriorly. Furthermore, the left subclavian seemed to arise from the descending aorta and not from the aortic arch. PMID- 23355324 TI - Straightened cervical lordosis causes stress concentration: a finite element model study. AB - In this study, we propose a finite element analysis of the complete cervical spine with straightened and normal physiological curvature by using a specially designed modelling system. An accurate finite element model is established to recommend plausible approaches to treatment of cervical spondylosis through the finite element analysis results. There are few reports of biomechanics influence of the straightened cervical curve. It is difficult to measure internal responses of cervical spine directly. However, the finite element method has been reported to have the capability to quantify both external and internal responses to mechanical loading, such as the strain and stress distribution of spinal components. We choose a subject with a straightened cervical spine from whom to collect the CT scan data, which formed the basis of the finite element analysis. By using a specially designed modelling system, a high quality finite element model of the complete cervical spine with straightened curvature was generated, which was then mapped to reconstruct a normal physiological curvature model by a volumetric mesh deformation method based on discrete differential properties. Then, the same boundary conditions were applied to do a comparison. The result demonstrated that the active movement range of straightened cervical spine decreased by 24-33 %, but the stress increased by 5-95 %. The stress was concentrated at the facet joint cartilage, uncovertebral joint and the disk. The results suggest that cervical lordosis may have a direct impact on cervical spondylosis treatment. These results may be useful for clinical treatment of cervical spondylosis with straightened curvature. PMID- 23355325 TI - Clinical psychologists' experiences of reflective staff groups in inpatient psychiatric settings: a mixed methods study. AB - Background Reflective practice groups have been recommended for improving staff wellbeing and team functioning in inpatient psychiatric services, and clinical psychologists have been identified as potential leaders in this type of work. Research is limited with little information about reflective practice group guidelines, prevalence and effectiveness. Aims The aims of this study were to describe clinical psychologists' practice in reflective groups for staff in inpatient psychiatric services and to explore how such groups are conceptualized and implemented. Methods Online questionnaires and follow-up interviews were used to gain broad descriptions of practice and in-depth information about participants' experiences. The sample consisted of 73 clinical psychologists working in the UK, six of whom were interviewed. Data were analysed using descriptive statistics, content analysis and thematic analysis. Results Clinical psychologists regularly facilitate reflective staff groups in inpatient psychiatric settings in the UK. Common outcomes related to staff wellbeing, service culture and teamwork. Engagement, group dynamics and lack of management support were common challenges. Group experiences were influenced by the organizational context. Conclusions Clinical psychologists' practices regarding reflective staff groups were in line with recent professional developments. Several difficulties were described, which may be indicative of both a difficulty inherent to the task and a training gap in reflective staff group process. The study had methodological limitations but offers a useful contribution to the literature, and enables practice and training implications to be drawn. The need for further research exploring facilitator characteristics, views of group participants and the impact of reflective staff groups on patients is indicated. KEY PRACTITIONER MESSAGE: The term 'reflective practice group' encompasses a range of practices, but a typical group structure was found with common aims, outcomes and challenges. Reflective staff groups are regularly facilitated by clinical psychologists in inpatient psychiatric settings in the UK and are influenced by practitioner experience as well as psychodynamic, systemic and group process theories. The safety required for reflective groups to function is influenced by the organizational context, and groups can contribute to shifts in culture toward including psychosocial perspectives. Reflective staff groups represent one type of contribution to an inpatient psychiatric service and team relationships; other processes to encourage alternative professional perspectives and values might also support change. More research is recommended to explore facilitator characteristics, the views of staff teams on reflective staff groups and the impact of these groups on patients. PMID- 23355327 TI - Chemistry in Sweden--a midsummer night's dream? PMID- 23355326 TI - alpha-Tocopherol binding to human serum albumin. AB - Given the ability of human serum albumin (HSA) to bind hydrophobic ligands, the binding mode of alpha-tocopherol, the most representative member of the vitamin E family, is reported. alpha-Tocopherol binds to HSA with Kd0 = (7.0 +/- 3.0) * 10( 6) M (pH 7.2, 25.0 degrees C). Competitive and allosteric modulation of alpha tocopherol binding to full-length and truncated (Asp1-Glu382) HSA by endogenous and exogenous ligands suggests that it accommodates preferentially in the FA3-FA4 site. As HSA is taken up into cells, colocalizes with the alpha-tocopherol transfer protein, and contributes to ligand secretion via ABCA1, it might participate in the distribution of alpha-tocopherol between plasma, cells, and tissues. PMID- 23355328 TI - New onset of atrial fibrillation in the hospitalized patient. AB - Atrial fibrillation (AF) is a common dysrhythmia that clinicians often encounter while caring for hospitalized patients. Although many patients will have carried a diagnosis of AF prior to hospital admission, this review will pertain to patients for whom a first documented episode of AF occurs during hospitalization. PMID- 23355329 TI - Triggering cell adhesion, migration or shape change with a dynamic surface coating. AB - There's an APP for that: cell-repellent APP (azido-[polylysine-g-PEG]) is used to create substrates for spatially controlled dynamic cell adhesion. The simple addition of a functional peptide to the culture medium rapidly triggers cell adhesion. This highly accessible yet powerful technique allows diverse applications, demonstrated through tissue motility assays, patterned coculturing and triggered cell shape change. PMID- 23355331 TI - Amine-functionalized polyglycidyl methacrylate microsphere as a unified template for the synthesis of gold nanoparticles and single-crystal gold plates. AB - Polyglycidyl methacrylate (PGMA) microspheres, crosslinked and surface functionalized by amine, can be used as a solid-state template for the synthesis of gold (Au) crystals in the forms of either nanoparticles (NPs) or plates. It is discovered that the polymer microsphere acts as an internal template to cultivate Au NPs inside the microsphere or an external template to generate the single crystal plates depending on the critical concentration (Ccr ) of gold ions. The ion-dipole interaction and the structure-dependent solubility of gold induce two distinct gold nanostructures in the presence of the functionalized polymer microspheres. The catalytic activity and long-term storage of the developed gold nanostructures that can be easily scaled-up for mass production through the developed novel methodology is demonstrated. PMID- 23355330 TI - Effectiveness of a multidimensional approach for prevention of ventilator associated pneumonia in 11 adult intensive care units from 10 cities of Turkey: findings of the International Nosocomial Infection Control Consortium (INICC). AB - PURPOSE: To evaluate the impact of the International Nosocomial Infection Control Consortium (INICC) multidimensional approach on the reduction of ventilator associated pneumonia (VAP) in adult patients hospitalized in 11 intensive care units (ICUs), from 10 hospitals, members of the INICC, in 10 cities of Turkey. METHODS: A prospective active before-after surveillance study was conducted to determine the effect of the INICC multidimensional approach in the VAP rate. The study was divided into two phases. In phase 1, active prospective surveillance of VAP was conducted using the definitions of the Centers for Disease Control and Prevention National Health Safety Network, and the INICC methods. In phase 2, we implemented the multidimensional approach for VAP. The INICC multidimensional approach included the following measures: (1) bundle of infection control interventions, (2) education, (3) outcome surveillance, (4) process surveillance, (5) feedback of VAP rates, and (6) performance feedback of infection control practices. We compared the rates of VAP obtained in each phase. A time series analysis was performed to assess the impact of our approach. RESULTS: In phase 1, we recorded 2,376 mechanical ventilator (MV)-days, and in phase 2, after implementing the multidimensional approach, we recorded 28,181 MV-days. The rate of VAP was 31.14 per 1,000 MV-days during phase 1, and 16.82 per 1,000 MV-days during phase 2, amounting to a 46 % VAP rate reduction (RR, 0.54; 95 % CI, 0.42 0.7; P value, 0.0001.) CONCLUSIONS: The INICC multidimensional approach was associated with a significant reduction in the VAP rate in these adult ICUs of Turkey. PMID- 23355332 TI - Role of 15-hydroxyeicosatetraenoic acid in hemozoin-induced lysozyme release from human adherent monocytes. AB - Natural hemozoin (nHZ), a lipid-bound ferriprotoporphyrin IX crystal produced by Plasmodium parasites after hemoglobin catabolism, seriously compromises the functions of human monocytes, and 15-hydroxyeicosatetraenoic acid (15-HETE) and 4 hydroxynonenal (4-HNE), two nHZ lipoperoxidation products, have been related to such a functional impairment. nHZ was recently shown to promote inflammation mediated lysozyme release from human monocytes through p38 mitogen-activated protein kinase- (MAPK)- and nuclear factor (NF)-kappaB-dependent mechanisms. This study aimed at identifying the molecule of nHZ lipid moiety that was responsible for these effects. Results showed that 15-HETE mimicked nHZ effects on lysozyme release, whereas 4-HNE did not. 15-HETE-enhanced lysozyme release was abrogated by anti-TNF-alpha and anti-IL-1beta-blocking antibodies and mimicked by recombinant cytokines; on the contrary, MIP-1alpha/CCL3 was not involved as a soluble mediator of 15-HETE effects. Moreover, 15-HETE early activated p38 MAPK and NF-kappaB pathways by inducing p38 MAPK phosphorylation; cytosolic I kappaBalpha phosphorylation and degradation; NF-kappaB nuclear translocation and DNA-binding. Inhibition of both routes through chemical inhibitors (SB203580, quercetin, artemisinin, and parthenolide) prevented 15-HETE-dependent lysozyme release. Collectively, these data suggest that 15-HETE plays a major role in nHZ enhanced monocyte degranulation. PMID- 23355333 TI - Molecular tools for sterile sperm detection to monitor Ceratitis capitata populations under SIT programmes. AB - BACKGROUND: The success of an area-wide sterile insect technique (SIT) programme against Ceratitis capitata (Wiedemann) (Diptera: Tephritidae) relies on the mating success of sterile males in the field. Limited information is available about the effectiveness of sterile males in achieving mates with wild females and how these matings contribute to reducing wild populations. To this end, firstly a mating competition test was performed in the laboratory with different release ratios (1:1:0, 1:1:1, 1:1:5, 1:1:10 and 1:1:20 for wild females:wild males:sterile VIENNA-8 males respectively) and different host fruit. Secondly, the same release ratios were evaluated under semi-natural conditions on caged trees and on sentinel host. RESULTS: By means of molecular markers, VIENNA-8 male sperm was positively detected in those females exposed to the male ratios 1:5, 1:10 and 1:20 in the laboratory. In the field test, sterile VIENNA-8 male matings and the C. capitata progeny on apples were positively correlated with the ratio of sterile males released and with the percentage of sterile matings respectively. CONCLUSIONS: These results confirm the validity of using the molecular detection of VIENNA-8 male sperm to predict the C. capitata population under semi-natural conditions. Implications of these results in measuring the efficacy of an SIT programme are discussed. PMID- 23355334 TI - Postmortem investigation of mylohyoid hiatus and hernia: aetiological factors of plunging ranula. AB - The mylohyoid hiatus and hernia were discovered in the nineteenth century and were considered to explain the origin of the plunging ranula from the sublingual gland. This formed the rationale for sublingual sialadenectomy for the treatment of plunging ranula. However, a more recent, extensive histological investigation reported that hernias contained submandibular gland, which supported an origin of the plunging ranula from the submandibular gland and submandibular sialadenectomy for the treatment of plunging ranula. We therefore decided to investigate the occurrence and location of the hiatus and the histological nature of the hernia. Twenty-three adult cadavers were dissected in the submandibular region. The locations and dimensions of mylohyoid hiatuses were measured before taking biopsies of hernias. Hiatuses with associated hernias were found in ten cadavers: unilateral in six; and bilateral in four, in one of which there were three hiatuses. Sublingual gland was identified in nine hernias and fat without gland in six. This investigation supports clinical and experimental evidence that the plunging ranula originates from the sublingual gland and may enter the neck through the mylohyoid muscle. It confirms the rationale of sublingual sialadenectomy for the treatment of plunging ranula. PMID- 23355335 TI - CYP2E1 polymorphisms and colorectal cancer risk: a HuGE systematic review and meta-analysis. AB - Studies investigating the associations between Cytochrome P4502E1 (CYP2E1) polymorphisms and colorectal cancer (CRC) risk report conflicting results. We conducted a meta-analysis to assess the association between CYP2E1 gene Rsa I/Pst I, Dral T/A and 96-bp insertion polymorphisms and CRC susceptibility. Two investigators independently searched the Medline, Embase, CNKI, Wanfang, and Chinese Biomedicine Databases. Summary odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for CYP2E1 polymorphisms and CRC were calculated in a fixed effect model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. Ultimately, 12, 5, and 4 studies were found to be eligible for meta-analyses of Rsa I/Pst I, Dral T/A, and 96-bp insertion polymorphisms, respectively. Our analysis suggested that the variant genotype of Rsa I/Pst I were associated with a significantly increased CRC risk (c2/c2 vs. c1/c1, OR = 1.36, 95 % CI = 1.04-1.77; recessive model, OR = 1.35, 95 % CI = 1.04-1.75). Moreover, similar results were observed between CYP2E1 96-bp insertion polymorphism and CRC risk (dominant model, OR = 1.25, 95 % CI = 1.07 1.45), while no association was observed between CYP2E1 Dral T/A polymorphism and CRC susceptibility in any genetic model. No publication bias was found in the present study. This meta-analysis shows that CYP2E1 Rsa I/Pst I and 96-bp insertion polymorphisms may be associated with CRC risk. The CYP2E1 Dral T/A polymorphism was not detected to be related to the risk for CRC. PMID- 23355336 TI - Molecular diagnosis and prognostic significance of lymph node micrometastasis in patients with histologically node-negative non-small cell lung cancer. AB - Lymph node metastasis is a major prognostic factor in resected non-small cell lung cancer (NSCLC). However, 30-40 % rate of recurrence after performing complete resection in node-negative patients suggests that their nodal staging is suboptimal. We aimed to evaluate the molecular diagnosis and prognostic significance of lymph node micrometastasis in patients with node-negative NSCLC. Primary tumor samples from 62 patients with resected stage I-IIB NSCLC were screened for fragile histidine triad (FHIT) and CDKN2A mRNA deletion using reverse transcriptase polymerase chain reaction (RT-PCR). The molecular alternations were found in tumors of 49 patients. A total of 269 lymph nodes from these 49 NSCLC patients with FHIT or/and CDKN2A deletion tumors were examined. Fifteen positive-control nodes and ten negative-control nodes were also analyzed for FHIT and CDKN2A mRNA deletion. Thirty-nine (22 %) and 22 (18 %) lymph nodes from the 49 patients with FHIT and CDKN2A mRNA deletion in primary tumor had FHIT and CDKN2A mRNA deletion, respectively. The types of FHIT and CDKN2A mRNA deletion in lymph nodes were identical with those in their primary tumors. By combination of two markers, 16 patients (32.7 %) were found to have nodal micrometastasis. Survival analysis showed that patients with nodal micrometastasis had reduced disease-free survival (P = 0.001) and overall survival (P = 0.002) rates. Multivariate analysis demonstrated that nodal micrometastasis was an independent predictor for worse prognosis. Thus, the detection of lymph node micrometastasis by FHIT and CDKN2A mRNA deletion RT-PCR will be helpful to predict the recurrence and prognosis of patients with completely resected stage I-IIB NSCLC. PMID- 23355337 TI - Expression of UbcH10 in pancreatic ductal adenocarcinoma and its correlation with prognosis. AB - The aim of this current study was to investigate the clinicopathologic features and prognostic significance of UbcH10 in pancreatic ductal adenocarcinoma (PDA). Real-time quantitative RT-PCR was employed to examine UbcH10 expression in 20 pairs of PDA and adjacent non-cancerous tissues. In addition, UbcH10 expression was analyzed by immunohistochemistry in 94 clinicopathologically characterized PDA cases. The correlation of UbcH10 expression with patients' survival rate was assessed by Kaplan-Meier and Cox regression. Our results showed that the expression levels of UbcH10 mRNA and protein in PDA tissues were both significantly higher than those in non-cancerous tissues. Simultaneously, high expression of UbcH10 was significantly correlated with the clinical stage (p<0.001), degree of histological differentiation (p<0.001), and lymph node metastasis (p=0.001). Moreover, high expression of UbcH10 was significantly associated with poor overall survival in PDA patients. In conclusion, UbcH10 might play a positive role in tumor development and could serve as an independent predictor of poor prognosis for PDA. PMID- 23355338 TI - Independent evaluation of low-level laser therapy at 635 nm for non-invasive body contouring of the waist, hips, and thighs. AB - INTRODUCTION: The non-invasive body-contouring segment continues to exhibit uninhibited growth, a trend that has provoked the emergence of numerous body contouring devices. One particular device, low-level laser therapy at 635 nm (LLLT-635), has exhibited promising clinical results. We performed an independent, physician-led trial to evaluate the utility of LLLT-635 nm for non invasive body contouring of the waist, hips, and thighs. METHODS: Eighty-six participants were retrospectively assessed at an individual clinic in the United States. A multi-head laser device was administered every-other-day for 2 weeks. Each treatment consisted of 20 minutes of anterior and posterior treatment. Patients received concurrent treatment of the waist, hips, and bilateral thighs. Circumferential measurements were evaluated at baseline and one week following the 2-week treatment administration phase. RESULTS: Compared with baseline, a statistically significant 2.99 in. (7.59 cm) mean loss was observed at the post procedure evaluation point (P < 0.0001). When analyzed individually, the waist, hips, and thighs each reported a statistically significant reduction of -1.12, 0.769, and -1.17, respectively. Furthermore, linear regression analysis revealed a weak linear dependence (r = 0.179) between the reported weight and circumference change. CONCLUSION: These data further validate the clinical efficacy and safety of LLLT at 635 nm. PMID- 23355340 TI - Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury. AB - Mitochondrial damage and dysfunction occur during ischemia and modulate cardiac function and cell survival significantly during reperfusion. We hypothesized that transplantation of autologously derived mitochondria immediately prior to reperfusion would ameliorate these effects. New Zealand White rabbits were used for regional ischemia (RI), which was achieved by temporarily snaring the left anterior descending artery for 30 min. Following 29 min of RI, autologously derived mitochondria (RI-mitochondria; 9.7 +/- 1.7 * 10(6)/ml) or vehicle alone (RI-vehicle) were injected directly into the RI zone, and the hearts were allowed to recover for 4 wk. Mitochondrial transplantation decreased (P < 0.05) creatine kinase MB, cardiac troponin-I, and apoptosis significantly in the RI zone. Infarct size following 4 wk of recovery was decreased significantly in RI mitochondria (7.9 +/- 2.9%) compared with RI-vehicle (34.2 +/- 3.3%, P < 0.05). Serial echocardiograms showed that RI-mitochondria hearts returned to normal contraction within 10 min after reperfusion was started; however, RI-vehicle hearts showed persistent hypokinesia in the RI zone at 4 wk of recovery. Electrocardiogram and optical mapping studies showed that no arrhythmia was associated with autologously derived mitochondrial transplantation. In vivo and in vitro studies show that the transplanted mitochondria are evident in the interstitial spaces and are internalized by cardiomyocytes 2-8 h after transplantation. The transplanted mitochondria enhanced oxygen consumption, high energy phosphate synthesis, and the induction of cytokine mediators and proteomic pathways that are important in preserving myocardial energetics, cell viability, and enhanced post-infarct cardiac function. Transplantation of autologously derived mitochondria provides a novel technique to protect the heart from ischemia-reperfusion injury. PMID- 23355342 TI - Impact of tachycardia and sympathetic stimulation by cold pressor test on cardiac diastology and arterial function in elderly females. AB - Abnormal vascular-ventricular coupling has been suggested to contribute to heart failure with preserved ejection fraction in elderly females. Failure to increase stroke volume (SV) during exercise occurs in parallel with dynamic changes in arterial physiology leading to increased afterload. Such adverse vascular reactivity during stress may reflect either sympathoexcitation or be due to tachycardia. We hypothesized that afterload elevation induces SV failure by transiently attenuating left ventricular relaxation, a phenomenon described in animal research. The respective roles of tachycardia and sympathoexcitation were investigated in n = 28 elderly females (70 +/- 4 yr) carrying permanent pacemakers. At rest, during atrial tachycardia pacing (ATP; 100 min(-1)) and during cold pressor test (hand immersed in ice water), we performed Doppler echocardiography (maximal untwist rate analyzed by speckle tracking imaging of rotational mechanics) and arterial tonometry (arterial stiffness estimated as augmentation index). Estimation of arterial compliance was based on an exponential relationship between arterial pressure and volume. We found that ATP produced central hypovolemia and a reduction in SV which was larger in patients with stiffer arteries (higher augmentation index). There was an associated adverse response of arterial compliance and vascular resistance during ATP and cold pressor test, causing an overall increase in afterload, but nonetheless enhanced maximal rate of untwist and no evidence of afterload-dependent failure of relaxation. In conclusion, tachycardia and cold provocation in elderly females produces greater vascular reactivity and SV failure in the presence of arterial stiffening, but SV failure does not arise secondary to afterload-dependent attenuation of relaxation. PMID- 23355341 TI - Intraventricular and interventricular cellular heterogeneity of inotropic responses to alpha(1)-adrenergic stimulation. AB - alpha1-Adrenergic receptors (alpha1-ARs) elicit a negative inotropic effect (NIE) in the mouse right ventricular (RV) myocardium but a positive inotropic effect (PIE) in the left ventricular (LV) myocardium. Effects on myofilament Ca(2+) sensitivity play a role, but effects on Ca(2+) handling could also contribute. We monitored the effects of alpha1-AR stimulation on contraction and Ca(2+) transients using single myocytes isolated from the RV or LV. Interestingly, for both the RV and LV, we found heterogeneous myocyte inotropic responses. alpha1 ARs mediated either a PIE or NIE, although RV myocytes had a greater proportion of cells manifesting a NIE (68%) compared with LV myocytes (36%). Stimulation of a single alpha1-AR subtype (alpha1A-ARs) with a subtype-selective agonist also elicited heterogeneous inotropic responses, suggesting that the heterogeneity arose from events downstream of the alpha1A-AR subtype. For RV and LV myocytes, an alpha1-AR-mediated PIE was associated with an increased Ca(2+) transient and a NIE was associated with a decreased Ca(2+) transient, suggesting a key role for Ca(2+) handling. For RV and LV myocytes, alpha1-AR-mediated decreases in the Ca(2+) transient were associated with increased Ca(2+) export from the cell and decreased Ca(2+) content of the sarcoplasmic reticulum. In contrast, for myocytes with alpha1-AR-induced increased Ca(2+) transients, sarcoplasmic reticulum Ca(2+) content was not increased, suggesting that other mechanisms contributed to the increased Ca(2+) transients. This study demonstrates the marked heterogeneity of LV and RV cellular inotropic responses to stimulation of alpha1-ARs and reveals a new aspect of biological heterogeneity among myocytes in the regulation of contraction. PMID- 23355343 TI - Time delay of baroreflex control and oscillatory pattern of sympathetic activity in patients with metabolic syndrome and obstructive sleep apnea. AB - The incidence and strength of muscle sympathetic nerve activity (MSNA) depend on the magnitude (gain) and latency (time delay) of the arterial baroreflex control (ABR). However, the impact of metabolic syndrome (MetS) and obstructive sleep apnea (OSA) on oscillatory pattern of MSNA and time delay of the ABR of sympathetic activity is unknown. We tested the hypothesis that MetS and OSA would impair the oscillatory pattern of MSNA and the time delay of the ABR of sympathetic activity. Forty-three patients with MetS were allocated into two groups according to the presence of OSA (MetS + OSA, n = 21; and MetS - OSA, n = 22). Twelve aged-paired healthy controls (C) were also studied. OSA (apnea hypopnea index > 15 events/h) was diagnosed by polysomnography. We recorded MSNA (microneurography), blood pressure (beat-to-beat basis), and heart rate (EKG). Oscillatory pattern of MSNA was evaluated by autoregressive spectral analysis and the ABR of MSNA (ABRMSNA, sensitivity and time delay) by bivariate autoregressive analysis. Patients with MetS + OSA had decreased oscillatory pattern of MSNA compared with MetS - OSA (P < 0.01) and C (P < 0.001). The sensitivity of the ABRMSNA was lower and the time delay was greater in MetS + OSA compared with MetS - OSA (P < 0.001 and P < 0.01, respectively) and C (P < 0.001 and P < 0.001, respectively). Patients with MetS - OSA showed decreased oscillatory pattern of MSNA compared with C (P < 0.01). The sensitivity of the ABRMSNA was lower in MetS - OSA than in C group (P < 0.001). In conclusion, MetS decreases the oscillatory pattern of MSNA and the magnitude of the ABRMSNA. OSA exacerbates these autonomic dysfunctions and further increases the time delay of the baroreflex response of MSNA. PMID- 23355345 TI - Assessing eradication strategies for rain-splashed and wind-dispersed crop diseases. AB - BACKGROUND: The eradicability of rain-splashed crop diseases was examined by modelling the spread of lupin anthracnose over a spatially heterogeneous landscape. Two hypotheses were investigated: (i) in most cases, rain-splashed diseases are unlikely to be eradicable because spread will be too extensive by the time the disease is detected; (ii) there are recognisable characteristics of an incursion that can be used to identify cases when the disease will be eradicable. RESULTS: Results indicate that the eradication of a rain-splashed crop disease is heavily dependent on the surveillance effort, on how detectable the disease is and on whether there are susceptible hosts outside the cropping area. These simple indicators can be used to estimate the potential for success of an eradication scheme. Eradication targeting only the crop area is destined to fail, unless it is certain that no susceptible host lies adjacent to the cropping area. CONCLUSION: A failed eradication attempt can be costly, and a simple set of indicators for the likelihood of success is extremely useful. These indicators can aid decision-makers when faced with a new incursion, identifying when there is little hope of success. (c) 2012 Society of Chemical Industry. PMID- 23355344 TI - Muscle metaboreflex-induced coronary vasoconstriction limits ventricular contractility during dynamic exercise in heart failure. AB - Muscle metaboreflex activation (MMA) during dynamic exercise increases cardiac work and myocardial O2 demand via increases in heart rate, ventricular contractility, and afterload. This increase in cardiac work should lead to metabolic coronary vasodilation; however, no change in coronary vascular conductance occurs. This indicates that the MMA-induced increase in sympathetic activity to the heart, which raises heart rate, ventricular contractility, and cardiac output, also elicits coronary vasoconstriction. In heart failure, cardiac output does not increase with MMA presumably due to impaired ability to improve left ventricular contractility. In this setting actual coronary vasoconstriction is observed. We tested whether this coronary vasoconstriction could explain, in part, the reduced ability to increase cardiac performance during MMA. In conscious, chronically instrumented dogs before and after pacing-induced heart failure, MMA responses during mild exercise were observed before and after alpha1 adrenergic blockade (prazosin 20-50 MUg/kg). During MMA, the increases in coronary vascular conductance, coronary blood flow, maximal rate of left ventricular pressure change, and cardiac output were significantly greater after alpha1-adrenergic blockade. We conclude that in subjects with heart failure, coronary vasoconstriction during MMA limits the ability to increase left ventricular contractility. PMID- 23355346 TI - Biodegradable microparticles with surface dimples as a bi-modal imaging contrast agent. AB - Fabrication of physically engineered colloids and their application to the biological fields is emerging importance because of their potential to provide an enhanced performance without altering the chemical properties of biomaterials used. A facile approach is reported to fabricate sub-10-MUm-sized PLGA microparticle with small dimples covering the surface by droplet imprinting. Optical and magnetic resonance bioimaging agents are easily co-encapsulated inside the microparticles to obtain a bi-modal imaging agent. Cell internalization efficacy of dimpled particles in DC 2.4 cell is enhanced compared with conventional smooth round-shaped colloids. Our result indicates that morphology-controlled microparticles show promise as a cell labeling with improved cell interaction. PMID- 23355347 TI - Gas dielectric transistor of CuPc single crystalline nanowire for SO2 detection down to sub-ppm levels at room temperature. PMID- 23355348 TI - Interactions of several single nucleotide polymorphisms and high body mass index on serum lipid traits. AB - The interactions between single nucleotide polymorphisms (SNPs) and high body mass index (BMI) on serum lipid profiles are limited. This study was undertaken to detect the interactions of 10 SNPs and high BMI on serum lipid traits in an isolated population. A total of 978 normal BMI (< 24 kg/m2) and 751 high BMI (>= 24 kg/m2) subjects of Bai Ku Yao were randomly selected from our previous stratified randomized cluster samples. Genotypes of rs2066715, rs1044925, low density lipoprotein receptor (LDL-R) Ava||, rs2070895, rs2000813, rs1801133, rs3757354, rs505151, rs2016520, and rs5888 SNPs were determined by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. The interactions were detected by factorial design covariance analysis. The genotypic and allelic frequencies of rs2070895 and rs505151 were different between normal and high BMI subjects, the genotypic frequency of rs2000813 and allelic frequency of rs3757354 were also different between normal and high BMI subjects (P < 0.01). The levels of total cholesterol (TC), apolipoprotein (Apo) A1 (rs2066715); TC, low-density lipoprotein cholesterol (LDL-C), ApoA1, ApoB, and ApoA1/ApoB (rs2070895); triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and ApoA1 (rs2000813); TC, HDL-C, LDL-C, ApoA1, and ApoB (rs1801133); HDL-C and ApoA1 (rs3757354) in normal BMI subjects were different among the genotypes (P < 0.01). The levels of LDL-C, ApoB, and ApoA1/ApoB (rs2066715); HDL-C, ApoA1, ApoB, and ApoA1/ApoB (rs2070895); TC, HDL-C, ApoA1, and ApoB (rs2000813); TC, TG, HDL-C, LDL-C, ApoA1, and ApoB (rs1801133); TC, TG, and ApoB (rs3757354); TG (rs505151); TG and ApoA1 and ApoB (rs2016520); and TC, HDL-C, LDL-C, ApoA1, and ApoB (rs5888) in high BMI subjects were also different among the genotypes (P < 0.01). The SNPs of rs2066715 (LDL-C and ApoA1/ApoB); rs2070895 (TC, LDL-C, ApoA1, and ApoB); rs2000813 (ApoB); rs1801133 (TC, TG, and LDL-C); rs3757354 (TC and TG); rs505151 (TG, HDL-C, ApoB, and ApoA1/ApoB); rs2016520 (TG and ApoA1/ApoB); and rs5888 (TG, ApoA1, and ApoB) interacted with high BMI to influence serum lipid levels (P < 0.01). The differences in serum lipid levels between normal and high BMI subjects might partly result from different interactions of several SNPs and high BMI. PMID- 23355349 TI - Laparoscopic splenectomy: a single center experience. Unusual cases and expanded inclusion criteria for laparoscopic approach. AB - Laparoscopic splenectomy (LS) is nowadays considered as the gold standard for most hematological diseases where splenectomy is necessary, but many questions still remain. The aim of this study was to analyze our 5-years experiences consisting of 48 consecutive LS cases in order to assess the optimal approach and the feasibility of the procedure also in malignant diseases and unusual cases such as a primary spleen lymphoma, a big splenic artery aneurism, or a spleen infarct due to a huge pancreatic pseudo-cyst. Forty-eight consecutive patients underwent LS from January 2006 to January 2011 with at least 1-year follow-up. Clinical data and immediate outcome were retrospectively recorded; age, diagnosis, operation time, perioperative transfusion requirement, conversion rate, accessory incision, hospital stay, and complications were analyzed. We had 14 cases of malignant splenic disease, the most frequent malignant diagnosis was non-Hodgkin's lymphoma (12/14, 85.7 %). Splenomegaly (interpole diameter (ID) >20 cm) was observed in 12 cases (25 %) and massive splenomegaly (ID >25 cm) in 3 cases (6.25 %). Conversion to laparotomy occurred in two patients (4.16 %), both associated to uncontrollable bleeding in patients with splenomegaly. Mean operative time was 138 +/- 22 min. Mean hospital stay was 4.5 days. Postoperative morbidity rate was 8.8 % for the benign group and 35.7 % in the malignant group. Mortality occurred in 1/48 patients (2.08 %), as a result of overwhelming post splenectomy infection (OPSI). LS can be performed safely for malignant splenic disease and splenomegaly without any statistically significant increase of morbidity and mortality rate. Conversion rate is increased for massive splenomegaly. LS should be considered as the preferential approach even in patients with malignant disease, splenomegaly, or unusual cases. Massive splenomegaly should be considered as relative contraindication to LS even at experienced centers. PMID- 23355350 TI - From new vistas to life lines: psychologists' satisfaction with supervision and confidence in supervising. AB - This study aimed to provide the first detailed survey of Irish psychologists' supervision practices as well as to identify what is related to satisfaction with supervisory support and to confidence in providing supervision. An online survey was distributed nationwide to Irish psychologists. Participants were mostly clinical and counselling psychologists. Three-quarters of the participants constituted 51% of the total population of Irish health service psychologists, the remainder working in various non-health service settings. The results showed that most Irish psychologists attend supervision but at a low frequency, typically once monthly. One-third were dissatisfied with their supervision, greater satisfaction being related to having more frequent clinical supervision and having external individual clinical supervision. Having a safe and trustworthy relationship with supervisors was a dominant issue, and two-thirds of psychologists wanted separation of their clinical and line management supervision. Although 70% were supervisors, only 40% were confident in their supervisory skills and just 16% had formal supervisor training. Independent predictors of supervisory confidence were experience as a psychologist, having formal supervisor training, experience as a supervisor and confidence as a therapist. A novel finding was that longer experience of personal therapy was related to greater confidence as a supervisor. This study indicates the need for access to more frequent clinical supervision to be facilitated for psychologists and for there to be clear separation of line management and clinical supervision. It is also essential that more resources are put into training supervisors. KEY PRACTITIONER MESSAGE: While most psychologists are engaged in supervision, frequency of attendance is low, with more satisfied psychologists having more frequent supervision. Most psychologists want separation of their clinical and line management supervision and have a preference for external supervision, safe and trustworthy relationships with supervisors being their primary concern. Only 16% of psychologists had formal training in supervision but having such training significantly contributed to greater confidence as a supervisor, indicating an urgent need to provide more supervisor training for psychologists. PMID- 23355352 TI - Chirality transfer in a methyl lactate-ammonia complex observed by matrix isolation vibrational circular dichroism spectroscopy. PMID- 23355351 TI - Simultaneous determination of seven lignans in Justicia procumbens by high performance liquid chromatography-photodiode array detection using relative response factors. AB - A simple and sensitive HPLC coupled with photodiode array (HPLC-PDA) method was developed for simultaneous determination of seven lignans in Justicia procumbens using relative response factors (RRFs). The chromatographic separation was performed on a Shiseido Capcell Pak C(18) column (250 * 4.6 mm id, 5 MUm), a gradient elution of acetonitrile/water, and a photodiode array detector. The column temperature was maintained at 35 degrees C and the detection wavelength was set at 256 nm. Chinensinaphthol methyl ether was selected as the reference compound for calculating the relative response factors of the lignans. It has shown that the RRFs for lignans are quite similar at 256 nm of detection under different analytical conditions (different columns and HPLC instruments). Using RRFs, not every lignan is needed as a reference standard, making the method ideal for rapid, routine analysis, especially for those laboratories where lignans standards are not readily available. An economic and practicable HPLC method using RRFs was established for the determination of seven lignans in J. procumbens. This method not only can determine multiple indexes in traditional Chinese medicines (TCMs) simultaneously, but also resolve the problem of lacking of chemical standards. It will be a good quality evaluation method and pattern for TCMs. PMID- 23355353 TI - Stimulus-sensitive myoclonus and cerebellar ataxia following chikungunya meningoencephalitis. AB - Chikungunya virus was initially thought to be a non-neurotropic virus, but recently neurological complications have been reported in patients with chikungunya virus infection. Here, we report a rare case of stimulus-sensitive myoclonus following chikungunya meningoencephalitis. The cranial MRI scan of the patient was normal, the cerebrospinal fluid contained 200 lymphocytes/mm(3), and the serum immunoglobulin M ELISA was positive for chikungunya. The patient improved completely after 1 month of treatment. This case study illustrates that chikungunya virus should also be considered in a febrile patient with myoclonus, especially in an endemic area. PMID- 23355354 TI - The pt-organometallic version of perigraniline: going blue. AB - Four conjugated push-pull organometallic polymers ([Pt]-AQ)n ([Pt] = trans bis(phenylacetylene)bis(tributylphosphine)platinum(II); AQ = 2-bromo-, 2,6 dibromo-, 2,6-diamino-, and unsubstituted anthraquinone diimine) were prepared and characterized by UV-vis spectroscopy and electrochemistry. A low-energy charge transfer, CT, band ([Pt]*->AQ; confirmed by density functional theory calculations), was found in the 445-500 nm window rather than the expected red shifted range above 630 nm. X-ray structures of four model compounds reveal that steric hindrance induces large dihedral angles between the C6 H4 and N?CC2 planes, rendering pi-orbital overlap difficult between the [Pt] and AQ units. The position of the CT band is mainly driven the reduction potential of the anthraquinone diimine unit. PMID- 23355355 TI - Progress in the understanding of the key pharmacophoric features of the antimalarial drug dihydroartemisinin: an experimental and theoretical charge density study. AB - The accurate, experimental charge density distribution, rho(r), of the potent antimalarial drug dihydroartemisinin (DHA) has been derived for the first time from single-crystal X-ray diffraction data at T=100(2) K. Gas-phase and solid state DFT simulations have also been performed to provide a firm basis of comparison with experimental results. The quantum theory of atoms in molecules (QTAIM) has been employed to analyse the rho(r) scalar field, with the aim of classifying and quantifying the key real-space elements responsible for the known pharmacophoric features of DHA. From the conformational perspective, the bicyclo[3.2.2]nonane system fixes the three-dimensional arrangement of the 1,2,4 trioxane bearing the active O-O redox centre. This is the most nucleophilic function in DHA and acts as an important CH???O acceptor. On the contrary, the rest of the molecular backbone is almost neutral, in accordance with the lipophilic character of the compound. Another remarkable feature is the C-O bond length alternation along the O-C-O-C polyether chain, due to correlations between pairs of adjacent C-O bonds. These bonding features have been related with possible reactivity routes of the alpha- and beta-DHA epimers, namely 1) the base catalysed hemiacetal breakdown and 2) the peroxide reduction. As a general conclusion, the base-driven proton transfer has significant non-local effects on the whole polyether chain, whereas DHA reduction is thermodynamically favourable and invariably leads to a significant weakening (or even breaking) of the O-O bond. The influence of the hemiacetal stereochemistry on the electronic properties of the system has also been considered. Such findings are discussed in the context of the known chemical reactivity of this class of important antimalarial drugs. PMID- 23355356 TI - Synthesis and antifeedant activity of novel alpha-asarone derivatives against stored-product pests. AB - BACKGROUND: Alpha-asarone (2,4,5-trimethoxypropenylbenzene) derivatives represent a new series of compounds that possess good antifeedant activity against different stored-product pests. RESULTS: A total of 23 novel alpha-asarone derivatives were synthesised and identified by (1) H NMR, (13) C NMR and IR, and their feeding deterrent activities were tested against Sitophilus granarius L., Trogoderma granarium Ev. and Tribolium confusum Duv. Ten compounds showed strong antifeedant activities. CONCLUSION: Some of the title compounds displayed very good and broad-spectrum activities against adult and larval Coleoptera. The results indicate that the presence of a double bond in the side chain and three methoxy groups is important for antifeedant activity. PMID- 23355359 TI - Highly selective detection of nitro explosives by a luminescent metal-organic framework. PMID- 23355360 TI - A vaccine against Streptococcus pyogenes: the potential to prevent rheumatic fever and rheumatic heart disease. AB - Streptococcus pyogenes causes severe, invasive infections such as the sequelae associated with acute rheumatic fever, rheumatic heart disease, acute glomerulonephritis, uncomplicated pharyngitis, and pyoderma. Efforts to produce a vaccine against S. pyogenes began several decades ago, and different models have been proposed. We have developed a vaccine candidate peptide, StreptInCor, comprising 55 amino acid residues of the C-terminal portion of the M protein and encompassing both the T- and B-cell protective epitopes. The present article summarizes data from the previous 5 years during which we tested the immunogenicity and safety of StreptInCor in different animal models. We showed that StreptInCor overlapping peptides induced cellular and humoral immune responses of individuals bearing different HLA class II molecules. These results are consistent with peptides that have a universal vaccine epitope. The tridimensional molecular structure of StreptInCor was elucidated by nuclear magnetic resonance spectroscopy, which showed that its structure is composed of two microdomains linked by an 18-residue alpha-helix. Additionally, we comprehensively evaluated the structural stability of the StreptInCor peptide in different physicochemical conditions using circular dichroism. Additional experiments were performed with inbred, outbred, and HLA class II transgenic mice. Analysis of several organs of these mice showed neither deleterious nor autoimmune reactions even after a long period of vaccination, indicating that the StreptInCor candidate peptide could be considered as an immunogenic and safe vaccine. PMID- 23355361 TI - Tolerability and pharmacokinetics of ranolazine following single and multiple sustained-release doses in Chinese healthy adult volunteers: a randomized, open label, Latin square design, phase I study. AB - BACKGROUND AND OBJECTIVES: Ranolazine was approved by the US Food and Drug Administration in January 2006 for the treatment of chronic angina pectoris, and is the first approved agent from a new class of anti-anginal drugs in almost 25 years. The primary objective of this study was to determine the concentration of ranolazine in human plasma using the liquid chromatography/tandem mass spectrometry (LC-MS/MS) method and to compare the pharmacokinetic properties of ranolazine after administration of single and multiple doses of ranolazine in healthy Chinese adult volunteers. METHODS: A randomized, open-label, single- and multiple-dose study design was used in the study. Subjects were randomized to receive a single dose of 500, 1,000, or 1,500 mg of ranolazine. Those who received the single dose continued on to the multiple-dose phase and received 500 mg twice daily for 7 days. In the single-dose phase, blood samples were collected from 0 to 48 h after drug administration. In the multiple-dose phase, samples were obtained before drug administration at 8:00 am and 8:00 pm on days 6 and 7 to determine the minimum steady-state plasma concentration (C(min,ss)) of ranolazine; on day 8, samples were collected from 0 to 48 h after drug administration. All values were expressed as means (standard deviations [SDs]). Adverse events (AEs) were monitored throughout the study via subject interview, vital signs, and blood sampling. RESULTS: The LC-MS/MS method was developed and validated. Twelve Chinese subjects (six men, six women) were enrolled in the single-dose phase of the pharmacokinetic study. The mean (SD) age of the subjects was 24.7 (1.6) years; their mean (SD) weight was 61.3 (6.4) kg, their mean (SD) height was 165.7 (4.5) cm, and their mean (SD) body mass index was 21.6 (6.6) kg/m(2). The main pharmacokinetic parameters [mean (SD)] for ranolazine after administration of a single oral dose of 500, 1,000, and 1,500 mg were as follows: maximum plasma concentration (C(max)) 741.5 (253.0), 1,355.0 (502.0), and 2,328.7 (890.5) ng/mL, respectively; area under the concentration-time curve from time zero to 48 h (AUC(48)) 9,071.9 (3,400.0), 16,573.5 (6,806.2), and 29,324.5 (10,857.2) ng.h/mL; AUC from time zero extrapolated to infinity (AUC(infinity)) 9,826.7 (3,152.0), 16,882.4 (6,790.8), and 29,923.5 (10,706.3) ng.h/mL; time to reach C(max) (t(max)) 5.3 (1.4), 4.2 (1.2), and 5.9 (2.8) h; elimination half life (t(1/2)) 6.4 (3.3), 6.4 (3.5), and 6.7 (4.3) h. Mean (SD) values for the main pharmacokinetic parameters for ranolazine after administration of multiple doses were as follows: steady-state C(max) (C(max,ss)) 1,732.9 (547.3) ng/mL; C(min,ss) 838.1 (429.8) ng/mL; steady-state AUC at time t (AUC(ss,(t))) 14,655.5 (5,624.2) ng.h/mL; average steady-state plasma drug concentration during multiple dose administration (C(av,ss)) 1,221.3 (468.7) ng/mL; t(max) 3.46 (1.48) h; t(1/2) 6.28 (2.48) h. CONCLUSION: In this group of healthy Chinese subjects, AUC and C(max) increased proportionally with the dose, whereas t(1/2) was independent of the dose. The pharmacokinetic properties of ranolazine were linear after administration of single oral doses of 500 to 1,500 mg. Compared with the pharmacokinetic parameters of the subjects who received a single dose, those who received multiple doses (twice daily) of ranolazine had a larger AUC from time zero to the time of the last measurable concentration (AUC(last)), AUC(infinity), C(max), and apparent total body clearance of drug from plasma after oral administration (CL/F), and shorter t(max) (all p < 0.05). Furthermore, some of the main pharmacokinetic parameters of ranolazine may reflect ethnic differences. This dosage was generally well tolerated by all the subjects. PMID- 23355358 TI - Whole grains, type 2 diabetes, coronary heart disease, and hypertension: links to the aleurone preferred over indigestible fiber. AB - Higher whole grain cereal intakes are associated with substantially lower risks of type 2 diabetes, coronary heart disease, and hypertension. These reduced risks have been established in large prospective studies that now include millions of person-years of follow-up. We analyze the results of 11 major prospective studies to provide recommendations about whole grain consumption. The following review establishes the amount of whole grains that should ideally be consumed based on prospective evidence; defines the nature of whole grains; identifies that the whole grain evidence is robust and not due to confounding; and provides a detailed assessment of several potential mechanisms for the effect of whole grains on health. We draw the following conclusions. Firstly, to maintain health, 40 grams or more of whole grains should be consumed daily. This is about a bowl of whole grain breakfast cereal daily, but 80% of the population does not achieve this. Secondly, aleurone in bran is a critical grain component generally overlooked in favor of indigestible fiber. Live aleurone cells constitute 50% of millers' bran. They store minerals, protein, and the antioxidant ferulic acid, and are clearly more than just indigestible fiber. Finally, we suggest potential roles for magnesium, zinc, and ferulic acid in the development of chronic disease. If the results of prospective studies were applied to the life-style practices of modern societies there exists the potential for enormous personal health and public financial benefits. PMID- 23355362 TI - A green and efficient protocol for large-scale production of glycyrrhizic acid from licorice roots by combination of polyamide and macroporous resin adsorbent chromatography. AB - A green and efficient method for large-scale preparation of glycyrrhizic acid from licorice roots was developed by combination of polyamide and macroporous resin. The entire preparation procedure consisted of two simple separation steps. The first step is to use polyamide resin to remove licorice flavoniods from the licorice crude extract. Subsequently, various macroporous resins were tried to purify glycyrrhizic acid, and HPD-400 showed the most suitable adsorption and desorption properties. Under the optimized conditions, a large-scale preparation of glycyrrhizic acid from licorice roots was carried out. A 20 kg raw material produced 0.43 kg of glycyrrhizic acid using green aqueous ethanol as the solvent. The purity of glycyrrhizic acid was increased from 11.40 to 88.95% with a recovery of 76.53%. The proposed method may be also extended to produce large scale other triterpenoid saponins from herbal materials. PMID- 23355364 TI - The elusive magic pill: finding effective therapies for mitochondrial disorders. AB - The incidence of mitochondrial diseases has been estimated at 11.5/100,000 (1:8500) worldwide. In the USA up to 4000 newborns annually are expected to develop a mitochondrial disease. More than 50 million adults in the USA also suffer from diseases in which primary or secondary mitochondrial dysfunction is involved. Mitochondrial dysfunction has been identified in cancer, infertility, diabetes, heart diseases, blindness, deafness, kidney disease, liver disease, stroke, migraine, dwarfism, and resulting from numerous medication toxicities. Mitochondrial dysfunction is also involved in normal aging and age-related neurodegenerative diseases, such as Parkinson and Alzheimer diseases. Yet most treatments available are based on empiric data and clinician experience because of the lack of randomized controlled clinical trials to provide evidence-based treatments for these disorders. Here we explore the current state of research for the treatment of mitochondrial disorders. PMID- 23355365 TI - Evaluation of shear bond strength of silorane resin to conventional, resin modified glass ionomers and nano-ionomer cements. AB - AIM: To evaluate the shear bond strength of silorane composite resin to conventional and resin-modified glass ionomer cements. MATERIALS AND METHODS: Shear bond strengths of Vitrebond (Group I), Ketac N100 (Group II) and Ketac Bond (Group III) glass ionomer cements to the composite Filtek P90 were evaluated. The bond strength was tested using a universal testing machine at a cross-head speed of 0.5 mm/min. Comparison between the groups was carried out using an analysis of variance test and pairwise comparison using Tukey's post-hoc test with a significance level of P <= 0.05. RESULTS: The measured bond strengths were 17.14 +/- 3.39 MPA for Group I (Vitrebond), 15.34 +/- 3.39 MPa for Group II (Ketac N100) and 14.12 +/- 2.79 MPa for Group III (Ketac Bond). Group I achieved higher bond strength than Groups II and III. CONCLUSIONS: Resin-modified glass ionomer cement (i.e. Vitrebond) appears to be preferable to nano-ionomer glass ionomer cement (i.e. Ketac N100) and conventional glass ionomer cement (i.e. Ketac Bond) as a base under low-shrink posterior composite (i.e. Filtek P90). PMID- 23355363 TI - Concise review: maturation phases of human pluripotent stem cell-derived cardiomyocytes. AB - Human pluripotent stem cell-derived cardiomyocytes (hPS-CM) may offer a number of advantages over previous cardiac models, however, questions of their immaturity complicate their adoption as a new in vitro model. hPS-CM differ from adult cardiomyocytes with respect to structure, proliferation, metabolism and electrophysiology, better approximating fetal cardiomyocytes. Time in culture appears to significantly impact phenotype, leading to what can be referred to as early and late hPS-CM. This work surveys the phenotype of hPS-CM, including structure, bioenergetics, sensitivity to damage, gene expression, and electrophysiology, including action potential, ion channels, and intracellular calcium stores, while contrasting fetal and adult CM with hPS-CM at early and late time points after onset of differentiation. PMID- 23355366 TI - Inhibitory potential of fatty acids on key enzymes related to type 2 diabetes. AB - This study aimed to examine the inhibitory mechanisms of fatty acids on key enzymes related to type 2 diabetes, and their effects on starch digestion rate. Among the 10 fatty acids analyzed, oleic acid showed the strongest anti-alpha glucosidase activity, followed by linoleic acid, and their activities were more potent than acarbose, but they possessed a weaker anti-alpha-amylase activity. Kinetic assays demonstrated that oleic acid and linoleic acid were competitive inhibitors, and their interactions with alpha-glucosidase exhibited a character of static quenching, which indicates that they would bind to alpha-glucosidase to form a complex. However, they had little effects on the secondary structures of alpha-glucosidase. In vitro study showed that oleic acid and linoleic acid were more potent than acarbose in inhibiting starch digestion. Taken together, these results conclude that oleic acid and linoleic acid possess potent inhibitory effects on alpha-glucosidase activity. PMID- 23355367 TI - Affinity, speciation, and molecular features of copper(II) complexes with a prion tetraoctarepeat domain in aqueous solution: insights into old and new results. AB - Characterization of the copper(II) complexes formed with the tetraoctarepeat peptide at low and high metal-to-ligand ratios and in a large pH range, would provide a breakthrough in the interpretation of biological relevance of the different metal complexes of copper(II)-tetraoctarepeat system. In the present work, the potentiometric, UV/Vis, circular dichroism (CD), and electron paramagnetic resonance (EPR) studies were carried out on copper(II) complexes with a PEG-ylated derivative of the tetraoctarepeats peptide sequence (Ac-PEG27 (PHGGGWGQ)4 -NH2 ) and the peptide Ac-(PHGGGWGQ)2 -NH2 . Conjugation of tetraoctarepeat peptide sequence with polyethyleneglycol improved the solubility of the copper(II) complexes. The results enable a straightforward explanation of the conflicting results originated from the underestimation of all metal-ligand equilibria and the ensuing speciation. A complete and reliable speciation is therefore obtained with the released affinity and binding details of the main complexes species formed in aqueous solution. The results contribute to clarify the discrepancies of several studies in which the authors ascribe the redox activity of copper(II)-tetraoctarepeat system considering only the average effects of several coexisting species with very different stoichiometries and binding modes. PMID- 23355368 TI - Determination of urinary 8-hydroxy-2'-deoxyguanosine by a combination of on-line molecularly imprinted monolithic solid phase microextraction with high performance liquid chromatography-ultraviolet detection. AB - 8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a sensitive biomarker for DNA oxidative damage. However, its determination in human urine is confounded by trace level and complex matrix. In this study, a new configuration of on-line solid phase microextraction coupled to high performance liquid chromatography-ultraviolet detection was established with molecularly imprinted monolithic column as extraction sorbent. The tailor made monolith exhibited high extraction efficiency with the enrichment factor 101.84 for 8-OHdG owing to its special porous structure and inherent selectivity. Under optimal condition, appreciable sensitivity had been achieved for this incorporation with limit of detection 2.04 nmol/L (S/N = 3) and limit of quantification 7.12 nmol/L (S/N = 10), respectively. Precise determination with wide range linearity (0.007-5.00 MUmol/L) afforded a practical alternative in urinary 8-OHdG analysis and 107 different subjects had been successfully analyzed. This newly developed method embodied useful prospect for the investigation of DNA oxidative damage with less expense, convenient maintenance and ease of operation. PMID- 23355369 TI - A repeated measures model for analysis of continuous outcomes in sequential parallel comparison design studies. AB - Previous authors have proposed the sequential parallel comparison design (SPCD) to address the issue of high placebo response rate in clinical trials. The original use of SPCD focused on binary outcomes, but recent use has since been extended to continuous outcomes that arise more naturally in many fields, including psychiatry. Analytic methods proposed to date for analysis of SPCD trial continuous data included methods based on seemingly unrelated regression and ordinary least squares. Here, we propose a repeated measures linear model that uses all outcome data collected in the trial and accounts for data that are missing at random. An appropriate contrast formulated after the model has been fit can be used to test the primary hypothesis of no difference in treatment effects between study arms. Our extensive simulations show that when compared with the other methods, our approach preserves the type I error even for small sample sizes and offers adequate power and the smallest mean squared error under a wide variety of assumptions. We recommend consideration of our approach for analysis of data coming from SPCD trials. PMID- 23355370 TI - The PI3K/AKT signaling pathway controls the quiescence of the low-Rhodamine123 retention cell compartment enriched for melanoma stem cell activity. AB - Melanoma is one of the most aggressive and extremely resistant to conventional therapies neoplasms. Recently, cellular resistance was linked to the cancer stem cell phenotype, still controversial and not well-defined. In this study, we used a Rhodamine 123 (Rh123) exclusion assay to functionally identify stem-like cells in metastatic human melanomas and melanoma cell lines. We demonstrate that a small subset of Rh123-low-retention (Rh123(low)) cells is enriched for stem cell like activities, including the ability to self-renew and produce nonstem Rh123(high) progeny and to form melanospheres, recapitulating the phenotypic profile of the parental tumor. Rh123(low) cells are relatively quiescent and chemoresistant. At the molecular level, we show that melanoma Rh123(low) cells overexpress HIF1alpha, pluripotency factor OCT4, and the ABCB5 marker of melanoma stem cells and downregulate the expression of Cyclin D1 and CDK4. Interestingly, a short treatment with LY294002, an inhibitor of the PI3K/AKT pathway, specifically reverts a subset of Rh123(high) cells to the Rh123(low) phenotype, whereas treatment with inhibitors of mammalian target of rapamycin, phosphatase and tensin homolog or mitogen-activated protein kinase signaling does not. This phenotypic switching was associated with reduced levels of the HIF1alpha transcript and an increase in the level of phosphorylated nuclear FOXO3a preferentially in Rh123(low) cells. Moreover, the Rh123(low) cells became less quiescent and displayed a significant increase in their melanosphere-forming ability. All the above indicates that the Rh123(low) melanoma stem cell pool is composed of cycling and quiescent cells and that the PI3K/AKT signaling while maintaining the quiescence of Rh123(low) G0 cells promotes the exit of cycling cells from the stem cell compartment. PMID- 23355371 TI - Solid lipid particles in lipid films to control the diffusive release of 2 heptanone. AB - BACKGROUND: Controlled-release formulations of bioactive agents are of increasing interest for effective pest control. Volatile 2-heptanone is a bioactive agent that has shown potential as a pesticide. The aim of this study was to investigate the kinetics of release of 2-heptanone incorporated into lipid films or composite solid lipid particle (SLP) films. RESULTS: Effective 2-heptanone diffusivity was estimated to be between 0.1 and 2.5 mm(2) day(-1) during the first week and between 0.05 and 0.1 mm(2) day(-1) during the next 5 weeks. The films that showed better retention of 2-heptanone were the paraffin lipid films. Inclusion of SLPs into paraffin films increased the release rate of 2-heptanone, mainly owing to a decrease in the film firmness as the composite SLP film became less crystalline and more brittle. In contrast, SLPs decreased the kinetics of 2 heptanone release in Acetem films owing to an increase in the film firmness. CONCLUSIONS: The results indicated that the use of SLPs as a method for controlled release can improve the delivery of the natural pesticide 2-heptanone if the SLPs have good compatibility with the matrix, leading to an increase in firmness of the films without increasing their porosity. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. PMID- 23355372 TI - The origin of isotope effects in sonoluminescence spectra of heavy and light water. AB - Bubble and peak: The isotope effects in the sonoluminescence spectra of light and heavy water under ultrasound indicate the formation of a non-equilibrium plasma inside the collapsing cavitation bubbles. The picture demonstrates the active cavitation zones in water at 204 kHz. PMID- 23355373 TI - Pharmacokinetics, tissue distribution and excretion of manganese (III) meso-tetra [3-(2-(2-methoxy)-ethoxy) ethoxy] phenyl porphyrin chloride, a novel superoxide dismutase mimic, in Wistar rats. AB - Manganese (III) 5, 10, 15, 20-tetrakis [3-(2-(2-methoxy)-ethoxy) ethoxy] phenyl porphyrin chloride, designated HSJ-0017, is a novel superoxide dismutase mimic. It exhibits strong free-radical scavenging activities in vitro and in vivo. The aim of the present study was to investigate the pharmacokinetics, tissue distribution and excretion of HSJ-0017 in Wistar rats following a single intravenous administration. Wistar rats were given different doses of HSJ-0017 by single intravenous injection. Biological samples of rats were collected and were assayed by the HPLC method. The pharmacokinetics, tissue distribution and excretion of HSJ-0017 were investigated. The pharmacokinetic data of HSJ-0017 in rats following intravenous injection was best-fit by a two-compartment model. T max of HSJ-0017 in plasma following intravenous injection was 0.083 h. AUC and plasma drug concentration were found to increase in a dose-related fashion. The highest concentrations of HSJ-0017 were detected in the liver (82.25 +/- 13.99 MUg/g) of rats, followed by the kidney, small intestine, lung, plasma, heart, spleen, and stomach within 2 h postdose. No HSJ-0017 was detected in the uterus, parorchis or brain of rats during the 24-h period of examination. The total cumulative excretion of HSJ-0017 in rat bile and urine were found to be 78.85 and 67.58 %, respectively. Our study has led to the view that the HSJ-0017 can be rapidly distributed to tissues after intravenous administration, but cannot diffuse through the blood-brain barrier. The faecal and biliary excretion of unchanged HSJ-0017 are the major routes of HSJ-0017 elimination. PMID- 23355375 TI - Despite warnings, some graduating otolaryngology residents planning to use codeine for posttonsillectomy pain control. PMID- 23355374 TI - Generation of ultra-high-molecular-weight polyethylene from metallocenes immobilized onto N-doped graphene nanoplatelets. AB - Catalytic natures of organometallic catalysts are modulated by coordinating organic ligands with proper steric and electronic properties to metal centers. Carbon-based nanomaterials such as graphene nanoplatelets are used with and without N-doping and multiwalled carbon nanotube as a ligand for ethylene polymerizations. Zirconocenes or titanocenes are immobilized on such nanomaterials. Polyethylenes (PEs) produced by such hybrids show a great increase in molecular weight relative to those produced by free catalysts. Specially, ultra-high-molecular-weight PEs are produced from the polymerizations at low temperature using the hybrid with N-doped graphene nanoplatelets. This result shows that such nanomaterials act a crucial role to tune the catalytic natures of metallocenes. PMID- 23355376 TI - Acute otitis media in infants: comment on treatment outcomes. PMID- 23355377 TI - Response to "Acute otitis media in infants: comment on treatment outcomes". PMID- 23355378 TI - Control of the helical chirality of enantiopure sulfinyl (Z)-azobenzene-based photoswitches. AB - A new class of enantiopure ortho,ortho-disubstituted azobenzene photoswitches has been synthesized from (S)-2-(p-tolylsulfinyl)benzoquinone and arylhydrazines. The sulfoxide acts as a unidirectional controller of the helical chirality that arises in the Z isomer after photoisomerization. Highly congested E-azobenzenes 5 c showed two atropisomeric diastereoconformers in the solid state that converged upon irradiation into a unique Z isomer with defined helicity (M), as evident in the X-ray structure. The chiroptical properties of this three-state enantiopure switch can be externally tuned both photochemically and/or thermally. Theoretical CD spectra calculated by using time-dependent DFT methods support the existence of two atropoisomeric E isomers and only one Z isomer with (M) helicity. Complementary to the classical azobenzene-based switches, the photoswiching event is promoted under green/blue light and do not occur under UV irradiation. PMID- 23355379 TI - Measurement of gingival thickness using digital vernier caliper and ultrasonographic method: a comparative study. AB - BACKGROUND: The measurement of the thickness of the gingival tissues has been done using different techniques. Trans-gingival probing with a graduated probe, use of vernier calipers, ultrasonography and cone-beam computed tomography (CBCT), have all been tried, but no one technique has been shown to be consistent and better than the others. The present study was done to evaluate and compare the gingival thickness as measured with a digital vernier caliper and ultrasonography. METHODS: A total of 30 systemically healthy, non-smokers were included in the study. The gingival measurements were made and recorded from the maxillary and mandibular lateral incisor areas at 2 locations: (a) at a point apical to the free gingival groove; and (b) at a point immediately coronal to the muco-gingival junction. RESULTS: The mean gingival thickness ranged from 0.56 to 1.02 mm. Males had a significantly thicker gingiva as compared to females (P < 0.10). Significant differences were not observed when the measurements made using the digital vernier caliper and those made with ultrasonography were compared. CONCLUSIONS: The thickness of the gingiva was in the range of 0.56-1.02 mm. A digital vernier caliper and ultrasonography both can be used to assess the gingival thickness with equal accuracy. PMID- 23355380 TI - Propolis extract promotes translocation of glucose transporter 4 and glucose uptake through both PI3K- and AMPK-dependent pathways in skeletal muscle. AB - It is well known that propolis has the ability to prevent hyperglycemia. However, the underlying mechanism is not yet fully understood. We therefore investigated whether a Brazilian propolis ethanol extract affects glucose uptake and translocation of insulin-sensitive glucose transporter (GLUT) 4 in skeletal muscle cells. In L6 myotubes, the extract at 1 MUg/mL significantly promoted GLUT4 translocation and glucose uptake activity. Regarding the mechanism of GLUT4 translocation, propolis extract induced both PI3K and AMPK phosphorylation in a dose-dependent manner in L6 myotubes. However, we could not define which pathway was preferentially associated with GLUT4 translocation, because both PI3K and AMPK inhibitors revealed off-target effects to each other. The main polyphenols found in the propolis extract, artepillin C, coumaric acid, and kaempferide, promoted GLUT4 translocation in L6 myotubes. Additionally, these compounds activated both PI3K- and AMPK-dependent dual-signaling pathways. However, only kaempferide increased glucose uptake activity under our experimental conditions. Single oral administrations of propolis extract, at 250 mg/kg body weight, lowered postprandial blood glucose levels in ICR mice. The extract promoted GLUT4 translocation in skeletal muscle of rats and mice, but did not inhibit alpha glucosidase activity in the small intestine under our experimental conditions. It was confirmed that propolis extract promoted phosphorylation of both PI3K and AMPK in rat skeletal muscle. In conclusion, we show that Brazilian propolis has the potential to prevent hyperglycemia through the promotion of GLUT4 translocation in skeletal muscle and that kaempferide is one of the candidates for active compound in propolis. PMID- 23355381 TI - Conservation of placentation during the tertiary radiation of mammals in South America. AB - The eutherian placenta is considered to possess great plasticity, but it is not clear how this variation reflects adaptation to different ecological niches. Because South America was isolated for most of the Tertiary, it represents a natural laboratory to examine this question. We here describe placentation in three South American groups: Xenarthra have been part of the fauna from at least the mid-Paleocene whereas caviomorph rodents and Neotropical primates are each derived from a single founder that reached South America in the Eocene and Oligocene, respectively. The common ancestor of Xenarthra had a villous, haemochorial placenta, from which the labyrinthine, endotheliochorial placenta of sloths later evolved. Placentation in Caviomorpha follows an extraordinary stable pattern, characterized by a haemomonochorial, labyrinthine and highly lobed structure with specialized growing areas. This pattern was present before arrival of these rodents in South America and enabled a successful radiation especially during the spread of grasslands. Neotropical primates have haemochorial, trabecular placentas with a specialized maternal blood supply; a pattern that contrasts with that of Old World monkeys and may have been present in the founder generation on arrival in South America. In conclusion, there is a dichotomy within Xenarthra but otherwise the ancient South American mammals do not show much variation in principal placental characters. Thus, the successful radiation of these three groups, and their adaptation to diverse ecological niches, did not require substantial alterations in placentation. PMID- 23355382 TI - Graphene/poly(ethylene-co-vinyl acetate) composite electrode fabricated by melt compounding for capillary electrophoretic determination of flavones in Cacumen platycladi. AB - In this report, a graphene/poly(ethylene-co-vinyl acetate) composite electrode was fabricated by melt compounding for the amperometric detection of capillary electrophoresis. The composite electrode was fabricated by packing a mixture of graphene and melted poly(ethylene-co-vinyl acetate) in a piece of fused silica capillary under heat. The structure of the composite was investigated by scanning electron microscopy and Fourier transform infrared spectroscopy. The results indicated that graphene sheets were well dispersed in the composite to form an interconnected conducting network. The performance of this unique graphene-based detector has been demonstrated by separating and detecting rutin, quercitrin, kaempferol, and quercetin in Cacumen platycladi in combination with capillary electrophoresis. The four flavones have been well separated within 9 min in a 50 cm-long capillary at a separation voltage of 12 kV using a 50 mM sodium borate buffer (pH 9.2). The graphene-based detector offered significantly lower operating potentials, substantially enhanced signal-to-noise characteristics, lower expense of operation, high resistance to surface fouling, and enhanced stability. It showed long-term stability and repeatability with relative standard deviations of <5% for the peak current (n = 15). PMID- 23355383 TI - Human bronchial epithelial cells exposed in vitro to cigarette smoke at the air liquid interface resemble bronchial epithelium from human smokers. AB - Organotypic culture of human primary bronchial epithelial cells is a useful in vitro system to study normal biological processes and lung disease mechanisms, to develop new therapies, and to assess the biological perturbations induced by environmental pollutants. Herein, we investigate whether the perturbations induced by cigarette smoke (CS) and observed in the epithelium of smokers' airways are reproducible in this in vitro system (AIR-100 tissue), which has been shown to recapitulate most of the characteristics of the human bronchial epithelium. Human AIR-100 tissues were exposed to mainstream CS for 7, 14, 21, or 28 min at the air-liquid interface, and we investigated various biological endpoints [e.g., gene expression and microRNA profiles, matrix metalloproteinase 1 (MMP-1) release] at multiple postexposure time points (0.5, 2, 4, 24, 48 h). By performing a Gene Set Enrichment Analysis, we observed a significant enrichment of human smokers' bronchial epithelium gene signatures derived from different public transcriptomics datasets in CS-exposed AIR-100 tissue. Comparison of in vitro microRNA profiles with microRNA data from healthy smokers highlighted various highly translatable microRNAs associated with inflammation or with cell cycle processes that are known to be perturbed by CS in lung tissue. We also found a dose-dependent increase of MMP-1 release by AIR-100 tissue 48 h after CS exposure in agreement with the known effect of CS on this collagenase expression in smokers' tissues. In conclusion, a similar biological perturbation than the one observed in vivo in smokers' airway epithelium could be induced after a single CS exposure of a human organotypic bronchial epithelium-like tissue culture. PMID- 23355384 TI - Compromised respiratory function in lethal influenza infection is characterized by the depletion of type I alveolar epithelial cells beyond threshold levels. AB - During influenza virus infection, it is unclear how much alveolar cell loss can be tolerated before the host succumbs to the disease. We sought to define relevant correlates of disease severity in the mouse influenza model, hypothesizing that a susceptibility threshold exists for alveolar epithelial cell loss. We compared lung pathology, virus spread, alveolar epithelial cell depletion, arterial blood oxygenation, physiological responses measured by unrestrained plethysmography, and oxygen consumption and carbon dioxide production by gas analysis in mice at intervals after infection with virus strains and doses that cause mild (x31) or severe (PR/8) influenza. Both mild and severe infections showed similar degrees of lung damage and virus dissemination until day 6 after inoculation but diverged in survival outcomes from day 9. Day 6 PR/8-infected mice had normal respiratory and gas exchange functions with 10% type I cell loss. However, day 10 PR/8-infected mice had 40% type I cell loss with a concomitant drastic decreases in tidal and minute volumes, Vo(2), Vco(2), and arterial blood oxygenation, compared with a maximum 3% type I cell loss for x31 on day 10 when they recovered body weight and respiratory functions. Alterations in breaths per minute, expiratory time, and metabolic rate were observed in both infections. A threshold for maintenance of proper respiratory function appears to be crossed once 10% of alveolar type I cells are lost. These data indicate that lethality in influenza virus infection is a matter of degree rather than quality. PMID- 23355386 TI - Catalytic asymmetric synthesis of mixed 3,3'-bisindoles and their evaluation as Wnt signaling inhibitors. AB - TOP class: The first efficient catalytic asymmetric coupling reaction of indoles with isatin-derived nitroalkenes was accomplished by using a complex consisting of a chiral imidazoline aminophenol ligand (1; see scheme) and Cu(OTf)(2). Biological activity of the newly formed chiral 3,3'-bisindoles was also confirmed in a Wnt signaling inhibitory assay. PMID- 23355385 TI - Exhaled breath condensate adenosine tracks lung function changes in cystic fibrosis. AB - Measurement of exhaled breath condensate (EBC) biomarkers offers a noninvasive means to assess airway disease, but the ability of EBC biomarkers to track longitudinal changes in disease severity remains unproven. EBC was collected from pediatric patients with cystic fibrosis (CF) during regular clinic visits over 1 yr. EBC biomarkers urea, adenosine (Ado), and phenylalanine (Phe) were measured by mass spectrometry, and biomarker ratios were used to control for variable dilution of airway secretions. EBC biomarker ratios were assessed relative to lung function in longitudinal, multivariate models and compared with sputum inflammatory markers and quality of life assessment (CFQ-R). EBC was successfully analyzed from 51 subjects during 184 visits (3.6 +/- 0.9 visits per subject). EBC Ado/urea ratio was reproducible in duplicate samples (r = 0.62, P < 0.01, n = 20) and correlated with sputum neutrophil elastase (beta = 2.5, P < 0.05). EBC Ado/urea correlated with the percentage predicted of forced expiratory volume in 1 s in longitudinal, multivariate models (beta = -2.9, P < 0.01); EBC Ado/Phe performed similarly (beta = -2.1, P < 0.05). In contrast, IL-8 and elastase measured in spontaneously expectorated sputum (n = 57 samples from 25 subjects) and the CFQ-R respiratory scale (n = 90 tests from 47 subjects) were not significantly correlated with lung function. EBC was readily collected in a clinic setting from a wide range of subjects. EBC Ado tracked longitudinal changes in lung function in CF, with results similar to or better than established measures. PMID- 23355387 TI - Regulation of L-threonine dehydrogenase in somatic cell reprogramming. AB - Increasing evidence suggests that metabolic remodeling plays an important role in the regulation of somatic cell reprogramming. Threonine catabolism mediated by L threonine dehydrogenase (TDH) has been recognized as a specific metabolic trait of mouse embryonic stem cells. However, it remains unknown whether TDH-mediated threonine catabolism could regulate reprogramming. Here, we report TDH as a novel regulator of somatic cell reprogramming. Knockdown of TDH inhibits, whereas induction of TDH enhances reprogramming efficiency. Moreover, microRNA-9 post transcriptionally regulates the expression of TDH and thereby inhibits reprogramming efficiency. Furthermore, protein arginine methyltransferase (PRMT5) interacts with TDH and mediates its post-translational arginine methylation. PRMT5 appears to regulate TDH enzyme activity through both methyltransferase dependent and -independent mechanisms. Functionally, TDH-facilitated reprogramming efficiency is further enhanced by PRMT5. These results suggest that TDH-mediated threonine catabolism controls somatic cell reprogramming and indicate the importance of post-transcriptional and post-translational regulation of TDH. PMID- 23355388 TI - Cost-effectiveness analysis of boceprevir for the treatment of chronic hepatitis C virus genotype 1 infection in Portugal. AB - BACKGROUND: The recent approval of two protease inhibitors, boceprevir and telaprevir, is likely to change the management of chronic hepatitis C virus (HCV) genotype 1 infection. OBJECTIVES: We evaluated the long-term clinical outcomes and the cost effectiveness of therapeutic strategies using boceprevir with peginterferon plus ribavirin (PR) in comparison with PR alone for treating HCV genotype 1 infection in Portugal. METHODS: A Markov model was developed to project the expected lifetime costs and quality-adjusted life-years (QALYs) associated with PR alone and the treatment strategies outlined by the European Medicines Agency in the boceprevir summary of product characteristics. The boceprevir-based therapeutic strategies differ according to whether or not the patient was previously treated and whether or not the patient had compensated cirrhosis. The model simulated the experience of a series of cohorts of chronically HCV-infected patients (each defined by age, sex, race and fibrosis score). All treatment-related inputs were obtained from boceprevir clinical trials - SPRINT-2, RESPOND-2 and PROVIDE. Estimates of the natural history parameters and health state utilities were based on published studies. Portugal specific annual direct costs of HCV health states were estimated by convening a panel of experts to derive health state resource use and multiplying the results by national unit costs. The model was developed from a healthcare system perspective with a timeframe corresponding to the remaining duration of the patients' lifetimes. Both future costs and QALYs were discounted at 5 %. To test the robustness of the conclusions, we conducted deterministic and probabilistic sensitivity analyses. RESULTS: In comparison with the treatment with PR alone, boceprevir-based regimens were projected to reduce the lifetime incidence of advanced liver disease, liver transplantation, and liver-related death by 45-51 % and increase life expectancy by 2.3-4.3 years. Although the addition of BOC increased treatment costs by ?13,300-?19,700, the reduction of disease burden resulted in a decrease of ?5,400-?9,000 in discounted health state costs and an increase of 0.68-1.23 in discounted QALYs per patient. The incremental cost effectiveness ratios of the boceprevir-based regimens compared with PR among previously untreated and previously treated patients were ?11,600/QALY and ?8,700/QALY, respectively. The results were most sensitive to variations in sustained virologic response rates, discount rates and age at treatment. CONCLUSIONS: Adding boceprevir to PR was projected to reduce the number of liver complications and liver-related deaths, and to be cost effective in treating both previously untreated and treated patients. PMID- 23355389 TI - Lifetime memories from persistently supple synapses. AB - It is here proposed that the evanescent network derived from malleable or supple synapses is the substrate for long-lasting memory. The subjective sense of memory permanence is not derived, as suggested by Bain and others, from the stabilization of synaptic structure which gives rise to consolidated distributed networks. This generally held wisdom that synapses are activated and ultimately stabilized to reflect the long-lasting substrate of memory is reinforced by increased interest in the importance of sparse coding in memory consolidation. One line of evidence for sparse coding derives from studies on the lateral nucleus neurons of the amygdala (for review, see Josselyn, 2010). These findings lead to the conclusion that a small number of neurons are both necessary and sufficient to retrieve the fear engram. Recently, it has been shown that sparse coding in the dentate gyrus of the hippocampus is sufficient for retrieving the fear conditioning engram (Liu et al., 2012). One implication of these findings is that memory is stored in selected cells and that this restricted storage is more or less permanent, as the authors note: "... Defined cell populations can form the cellular basis for fear memory engrams (Liu et al., 2012, p. 89)." But the problem with this model is that because new learning is incorporated into existing networks, stabilization would work against this integration. For this reason and because of obligatory processes of metabolic protein turnover and ongoing synaptic malleability, the "supple synapse" model is proposed (Routtenberg, A., Rekart, 2005; Routtenberg, 2008a,b). Specifically, long-lasting memory is derived from the instructive, use-dependent sampling of neural networks selected from a very large universe of networks that are evanescent because they are linked together by supple synapses. Importantly, if such suppleness did not exist, the stabilization of synapses would then prevent the physiological malleability of brain circuitry that is essential both for proper integrated information storage and for flexible information retrieval. A corollary of this proposal is that it suggests an alternative view of consolidation: the same agent which is disruptive immediately after learning is no longer effective later because the network, over time, becomes widely distributed and evanescent. Thus, time-dependence is replaced with space-dependence. PMID- 23355390 TI - Prevalence and characteristics of impacted maxillary canines in Southern Chinese children and adolescents. AB - AIM: The incidence of impacted maxillary canines in Caucasians reportedly ranges from 1% to 3%. The objectives of this study were to estimate the prevalence and determine the characteristics of impacted maxillary canines in southern Chinese children and adolescents. METHODS: This retrospective audit involved 533 subjects with impacted maxillary canines that had been treated between February 1982 and February 2009. A customized data entry form was prepared to record and evaluate the status of impacted canines. RESULTS: The 533 subjects (327 females and 206 males) with impacted maxillary canines, who were identified from the population of 26 039 subjects, represented a prevalence of 2.1%. Four hundred and forty-two (82.9%) of these subjects had unilaterally impacted canines, while 91 (17.1%) of them had bilateral impactions. In 442 subjects with unilateral canine impactions, 220 (49.8%) were buccally placed, 194 (43.9%) were palatally placed, and 28 (6.3%) of the canines were found to lie within the arch. CONCLUSIONS: The overall prevalence of impacted maxillary canines in this study of 2.1% was similar to the figures quoted for Caucasian populations. In subjects with unilateral impactions, buccally impacted canines demonstrated a slightly higher incidence (49.8%) compared to palatally impacted canines (43.9%). PMID- 23355391 TI - Nanoscale assembly of paramagnetic organic radicals on Au(111) single crystals. AB - The successful thin-film deposition of a pyrene-substituted nitronyl nitroxide radical under controlled conditions has been demonstrated. The electronic properties, chemical environment at the interface, and morphology of the thin films have been investigated by a multitechnique approach. Spectroscopic and morphological analyses indicate a Stranski-Krastanov growth mode and weak physisorption of molecules onto the metallic surface. Electron spin resonance (ESR) spectroscopy shows that evaporation processes and deposition do not affect the paramagnetic character of the molecules. Useful concepts for the engineering of new, purely organic-based magnets, which may open the way to fruitful exploitation of organic molecular-beam deposition for assembly on solid surfaces in view of future technological applications, are presented. PMID- 23355393 TI - One way and the other: the bidirectional relationship between ambivalence and body movement. AB - Prior research exploring the relationship between evaluations and body movements has focused on one-sided evaluations. However, people regularly encounter objects or situations about which they simultaneously hold both positive and negative views, which results in the experience of ambivalence. Such experiences are often described in physical terms: For example, people say they are "wavering" between two sides of an issue or are "torn." Building on this observation, we designed two studies to explore the relationship between the experience of ambivalence and side-to-side movement, or wavering. In Study 1, we used a Wii Balance Board to measure movement and found that people who are experiencing ambivalence move from side to side more than people who are not experiencing ambivalence. In Study 2, we induced body movement to explore the reverse relationship and found that when people are made to move from side to side, their experiences of ambivalence are enhanced. PMID- 23355392 TI - Noninvasive functional imaging of cerebral blood volume with vascular-space occupancy (VASO) MRI. AB - Functional MRI (fMRI) based on changes in cerebral blood volume (CBV) can probe directly vasodilatation and vasoconstriction during brain activation or physiologic challenges, and can provide important insights into the mechanism of blood oxygenation level-dependent (BOLD) signal changes. At present, the most widely used CBV fMRI technique in humans is called vascular-space-occupancy (VASO) MRI, and this article provides a technical review of this method. VASO MRI utilizes T1 differences between blood and tissue to distinguish between these two compartments within a voxel, and employs a blood-nulling inversion recovery sequence to yield an MR signal proportional to 1 - CBV. As such, vasodilatation will result in a VASO signal decrease and vasoconstriction will have the reverse effect. The VASO technique can be performed dynamically with a temporal resolution comparable with several other fMRI methods, such as BOLD or arterial spin labeling (ASL), and is particularly powerful when conducted in conjunction with these complementary techniques. The pulse sequence and imaging parameters of VASO can be optimized such that the signal change is predominantly of CBV origin, but careful considerations should be taken to minimize other contributions, such as those from the BOLD effect, cerebral blood flow (CBF) and cerebrospinal fluid (CSF). The sensitivity of the VASO technique is the primary disadvantage when compared with BOLD, but this technique is increasingly demonstrating its utility in neuroscientific and clinical applications. PMID- 23355394 TI - Lagging strand maturation factor Dna2 is a component of the replication checkpoint initiation machinery. AB - Initiation of the DNA replication checkpoint in yeast is mainly mediated by Mec1 protein kinase, the ortholog of human ATR, while its homolog Tel1, the ortholog of human ATM, has a minor replication checkpoint function. Checkpoint initiation requires stimulation of Mec1 kinase activity by specific activators. Saccharomyces cerevisiae Dna2, a nuclease-helicase that is essential for Okazaki fragment maturation, is employed specifically during S phase to stimulate Mec1 kinase and initiate the replication checkpoint. Mutations (W128A and Y130A) in the unstructured N terminus of Dna2 abrogate its checkpoint function in vitro and in vivo. Dna2 shows partial redundancy for the replication checkpoint with checkpoint initiators 9-1-1 (S. cerevisiae Ddc1-Mec3-Rad17 and human Rad9-Rad1 Hus1) and Dpb11, the ortholog of human TopBP1. A triple mutant that eliminates the checkpoint functions of all three initiators abrogates the Mec1-dependent checkpoint. PMID- 23355395 TI - The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis. AB - Pancreatic exocrine cell plasticity can be observed during development, pancreatitis with subsequent regeneration, and also transformation. For example, acinar-ductal metaplasia (ADM) occurs during acute pancreatitis and might be viewed as a prelude to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) development. To elucidate regulatory processes that overlap ductal development, ADM, and the progression of normal cells to PanIN lesions, we undertook a systematic approach to identify the Prrx1 paired homeodomain Prrx1 transcriptional factor as a highly regulated gene in these processes. Prrx1 annotates a subset of pancreatic ductal epithelial cells in Prrx1creER(T2)-IRES-GFP mice. Furthermore, sorted Prrx1(+) cells have the capacity to self-renew and expand during chronic pancreatitis. The two isoforms, Prrx1a and Prrx1b, regulate migration and invasion, respectively, in pancreatic cancer cells. In addition, Prrx1b is enriched in circulating pancreatic cells (Pdx1cre;LSL-Kras(G12D/+);p53(fl/+);R26YFP). Intriguingly, the Prrx1b isoform, which is also induced in ADM, binds the Sox9 promoter and positively regulates Sox9 expression. This suggests a new hierarchical scheme whereby a Prrx1-Sox9 axis may influence the emergence of acinar-ductal metaplasia and regeneration. Furthermore, our data provide a possible explanation of why pancreatic cancer is skewed toward a ductal fate. PMID- 23355396 TI - Bookmarking by specific and nonspecific binding of FoxA1 pioneer factor to mitotic chromosomes. AB - While most transcription factors exit the chromatin during mitosis and the genome becomes silent, a subset of factors remains and "bookmarks" genes for rapid reactivation as cells progress through the cell cycle. However, it is unknown whether such bookmarking factors bind to chromatin similarly in mitosis and how different binding capacities among them relate to function. We compared a diverse set of transcription factors involved in liver differentiation and found markedly different extents of mitotic chromosome binding. Among them, the pioneer factor FoxA1 exhibits the greatest extent of mitotic chromosome binding. Genomically, ~15% of the FoxA1 interphase target sites are bound in mitosis, including at genes that are important for liver differentiation. Biophysical, genome mapping, and mutagenesis studies of FoxA1 reveals two different modes of binding to mitotic chromatin. Specific binding in mitosis occurs at sites that continue to be bound from interphase. Nonspecific binding in mitosis occurs across the chromosome due to the intrinsic chromatin affinity of FoxA1. Both specific and nonspecific binding contribute to timely reactivation of target genes post mitosis. These studies reveal an unexpected diversity in the mechanisms by which transcription factors help retain cell identity during mitosis. PMID- 23355397 TI - Ability to determine the desferrioxamine-chelatable iron fractions of nontransferrin-bound iron using HPLC. AB - Iron is an essential element in human development. It is imperative for oxygen and electron transport and also for DNA and neurotransmitters synthesis. On the other hand, this metal is able to participate in Fenton's reaction that in turn leads to free radical damage. The most toxic fraction of iron - nontransferrin bound iron and its part desferrioxamine-chelatable iron - can serve as an exquisite biomarker in the identification of iron imbalance. The goal of the present study was to devise a simple, repeatable, and inexpensive method for the determination of desferrioxamine-chelatable iron in serum blood samples. The assay procedure is based on desferrioxamine complex formation with iron ions followed to ferrioxamine and its quantitative measurement using RP-HPLC method. The desferrioxamine-chelatable iron was extracted from blood by centrifugation and SPE method. Chromatographic separation was performed at 40 degrees C by step form gradient elution using Cadenza CD-C18 column (150 * 4.6 mm id, particle size of 3.0 MUm) connected with precolumn for contaminants removal. Gradient HPLC elution has been carried out with solvent A (10 mM Tris-HCl, pH 5.5) and solvent B (ACN). The flow rate was 1.2 mL/min, and the total separation time was 5 min. The linear quantitation range was 2.5-500 MUM (r = 0.9973), and the LOD and LOQ were 0.42 and 1.29 MUM, respectively. Proposed HPLC method allowed for the determination of desferrioxamine-chelatable iron fraction's of nontransferrin bound iron, both in the buffer and the serum supplemented with iron ions as well as in the patients' serum samples with good results of precision and recovery. The developed method found to be sufficiently precise and reproducible for established conditions and after validation and may be used for routine assay of desferrioxamine-chelatable iron in biological samples. PMID- 23355398 TI - Locomotor muscle profile of a deep (Kogia breviceps) versus shallow (Tursiops truncatus) diving cetacean. AB - When a marine mammal dives, breathing and locomotion are mechanically uncoupled, and its locomotor muscle must power swimming when oxygen is limited. The morphology of that muscle provides insight into both its oxygen storage capacity and its rate of oxygen consumption. This study investigated the m. longissimus dorsi, an epaxial swimming muscle, in the long duration, deep-diving pygmy sperm whale (Kogia breviceps) and the short duration, shallow-diving Atlantic bottlenose dolphin (Tursiops truncatus). Muscle myoglobin content, fiber type profile (based upon myosin ATPase and succinate dehydrogenase assays), and fiber size were measured for five adult specimens of each species. In addition, a photometric analysis of sections stained for succinate dehydrogenase was used to create an index of mitochondrial density. The m. longissimus dorsi of K. breviceps displayed significantly a) higher myoglobin content, b) larger proportion of Type I (slow oxidative) fibers by area, c) larger mean fiber diameters, and d) lower indices of mitochondrial density than that of T. truncatus. Thus, this primary swimming muscle of K. breviceps has greater oxygen storage capacity, reduced ATP demand, and likely a reduced rate of oxygen consumption relative to that of T. truncatus. The locomotor muscle of K. breviceps appears able to ration its high onboard oxygen stores, a feature that may allow this species to conduct relatively long duration, deep dives aerobically. PMID- 23355399 TI - Copper-catalyzed oxidative coupling of alkenes with aldehydes: direct access to alpha,beta-unsaturated ketones. PMID- 23355401 TI - Octreotide labeled aggregates containing platinum complexes as nanovectors for drug delivery. AB - The synthesis, formulation and a complete physico-chemical characterization, by dynamic light scattering and small angle neutron scattering techniques, of new liposomal aggregates obtained by co-assembling an amphiphilic molecule containing a platinum complex, Peg1500 -Lys(Pt-aminoEtGly)-Lys(C18)2, (abbreviated as (C18)2 PKAG-Pt), with a second amphiphilic monomer, (C18H37)2NCO(CH2)2CO(AdOO)5-Oct ((C18)2 L5-Oct), containing the octreotide bioactive peptide, is reported. Liposomes of (C18)2-PKAG-Pt present a radius of 48 nm, whereas the mixed aggregates (C18)2-PKAG-Pt/(C18)2L5-Oct at 90/10 M ratio give larger liposomes with a radius of 84 nm. In both cases, the bilayer thickness is ~5.3 nm. Encapsulation of doxorubicin in mixed liposomes is also obtained by using the pH gradient method. The obtained liposomes could represent a new target selective cargo system for delivery of cisplatin based drugs and/or doxorubicin on cells overexpressing the sstr2 and sstr5 somatostatin receptors. PMID- 23355402 TI - Pursed lips breathing: are we closer to understanding who might benefit? PMID- 23355403 TI - Obstructive sleep apnoea, motor vehicle accidents, and work performance. AB - The obstructive sleep apnoea (OSA) shows a very high prevalence in the middle-age work force population and, between all diseases and medical conditions, is the major risk factor for motor vehicle accidents (MVAs). OSA can be diagnosed and treated, with resultant reduction in MVAs to those seen in the healthy population. It is increasing evidence that it is a major risk factor for occupational accidents also in fields different from the professional transport and for work disability. It is likely that the treatment of OSA results in the reduction of occupational accidents and work performance improvement with expected benefits in work processes and business in general. It is therefore advisable to develop strategies for screening and treatment of OSA in workers. The risk assessment of OSA in workers may also help to reduce the burden on national health care systems. PMID- 23355404 TI - Early palliative care and metastatic non-small cell lung cancer: potential mechanisms of prolonged survival. AB - Patients with advanced cancer experience a significant burden of physical symptoms and psychological distress at the end of life, and many elect to receive aggressive cancer-directed therapy. The goal of palliative care is to relieve suffering and promote quality of life (QOL) for patients and families. Traditionally, both the public and medical community have conceptualized the need for patients to make a choice between pursuing curative therapy or receiving palliative care. However, practice guidelines from the World Health Organization and leadership from the oncology and palliative care communities advocate a different model of palliative care that is introduced from the point of diagnosis of life-threatening illness. Early palliative care has been shown to provide benefits in QOL, mood, and health care utilization. Additionally, preliminary research has suggested that in contrast to fears about palliative care hastening death, referral to palliative care earlier in the course of illness may have the potential to lengthen survival, particularly in patients with advanced nonsmall cell lung cancer. This review summarizes the literature on potential survival benefits of palliative care and presents a model of how early integrated palliative care could potentially influence survival in patients with advanced cancer. PMID- 23355405 TI - Reducing emergency room utilization in end-stage COPD - feasible or fantasy? AB - The emergency room (ER) is a common point of care transition for patients with end-stage chronic obstructive pulmonary disease. Many of these patients present to the ER because of dyspnea, anxiety and caregiver burden that is precipitated by fragmented and reactive systems of care that fail to meet their needs. This article uses an illustrative case report to outline the challenges patients and caregivers face and presents the core elements of care required to improve quality of care and decrease reliance on the ER. PMID- 23355406 TI - "Right Door," wrong floor: a canine deficiency in navigation. PMID- 23355407 TI - Haptoglobin gene polymorphisms in peri-implantitis and chronic periodontitis. AB - AIM: The haptoglobin-hemoglobin (Hp-Hb) complex plays a significant role in regulating immune responses and acts as a bacteriostatic agent. Haptoglobin polymorphisms result in different Hb binding affinities. This study sought to assess whether Hp 2-2 could be a genetic determinant for increasing the risk of peri-implantitis and chronic periodontitis. METHODS: Of the Iranian subjects referred to the Department of Periodontics, Shahid Beheshti University, Tehran, 203 were entered into the study, including 117 patients and 86 periodontally healthy individuals. Polymerase chain reaction (PCR) was performed for genotyping. Data were analyzed by Kruskal-Wallis test using the SPSS statistics software package. RESULTS: The prevalence of Hp 2-2, 2-1, and 1-1 did not differ significantly between patients and healthy subjects (P > 0.05). The highest frequencies of Hp 1-1, 2-1, and 2-2 genotypes were seen in the control (7%), peri implantitis (51%) and periodontitis (64%) groups, respectively. CONCLUSIONS: Haptoglobin polymorphisms may not play a role in development of peri-implantitis or chronic periodontitis among Iranians but we strongly suggest researchers to evaluate this polymorphism in further studies on larger sample sizes, different populations, and other types of periodontitis. PMID- 23355408 TI - Nickel-catalyzed coupling of thiomethyl-substituted 1,3-benzothiazoles with secondary alkyl Grignard reagents. PMID- 23355409 TI - Postnatal fate of the ultimobranchial remnants in the rat thyroid gland. AB - The ultimobranchial follicles (UBFs) are considered embryonic remnants from the ultimobranchial body (UBB). They are follicular structures that vary in size and appearance depending on the age of the rat. The main objective of this article was to study the progressive changes in shape, size, and frequency of the UBFs in the postnatal rat, from birth to old-age. To accomplish that objective, a systematic morphometric and incidental study of the UBF has been carried out in 110 Wistar rats of different ages and both sexes, divided into three groups: 1) young rats (5-90-day-old); 2) adult rats (6-15-month-old), and 3) old rats (18-24 month-old). The glands were serially sectioned and immunostained for calcitonin at five equidistant levels. According to our results, UBFs were observed in all thyroid glands but a more exhaustive sampling was occasionally necessary in male rats. In young rats, immature UBFs predominantly appeared whereas in adult rats, mature UBFs with cystic appearance and variable luminal content prevailed. We frequently found spontaneous anomalous UBFs in old rats, which we have termed as "ultimobranchial cystadenomata." Additionally, in young rats, UBF areas significantly increased with age and they were larger when compared to that of normal thyroid follicles. Likewise, in adult rats, UBFs were significantly larger than normal thyroid follicles but only in female rats. In general, UBFs in females were also significantly larger than those found in male rats. Finally, all these differences related to UBFs together with a higher incidence in females of UB cystadenomata suggest a sexual dimorphism in regard to the destiny of these embryonic remnants during postnatal thyroid development. PMID- 23355410 TI - Solid-phase microextraction based method for determination of essential oils components in herbal beverages. AB - A method employing the direct immersion solid-phase microextraction followed by GC-MS analysis is presented for the determination of essential oils components in herbal tea infusions, i.e. their direct content in the liquid phase. The extraction performances were compared using five different microextraction fibres. Significant parameters affecting sorption process such as sample amount, sorption and desorption time and temperature, stirring speed, pH adjustment and effect of ionic strength were optimised and discussed. By optimising the key parameters, a detection limits (LOD = S/N * 3) for ten target marker compounds were obtained in the range from 5.3 to 48.2 ng/mL with recoveries ranged between 93.03 and 100.50%. Intra-day and inter-day repeatability at three concentration levels were found to be 1.1-15.3 and 7.2-15.5% RSD, respectively. Finally, the optimised procedure enabling a rapid and simple analysis of essential oils was applied for the direct determination of these compounds in ten herbal tea infusions. PMID- 23355412 TI - Copper-catalyzed intermolecular aminocyanation and diamination of alkenes. AB - 'N' front and center: The facile construction of C-N bonds by the generation of nitrogen-centred radicals from N-fluorobenzenesulfonimide results in the aminative difuctionalization of alkenes. The first copper-catalyzed intermolecular aminocyanation of alkenes and diamination of styrenes were realized. Si-F and B-F interactions play a significant role in the reaction. PMID- 23355411 TI - Genetic tools to manipulate MRI contrast. AB - Advances in molecular biology in the early 1970s revolutionized research strategies for the study of complex biological processes, which, in turn, created a high demand for new means to visualize these dynamic biological changes noninvasively and in real time. In this respect, MRI was a perfect fit, because of the versatile possibility to alter the different contrast mechanisms. Genetic manipulations are now being translated to MRI through the development of reporters and sensors, as well as the imaging of transgenic and knockout mice. In the past few years, a new molecular biology toolset, namely optogenetics, has emerged, which allows for the manipulation of cellular behavior using light. This technology provides a few particularly attractive features for combination with newly developed MRI techniques for the probing of in vivo cellular and, in particular, neural processes, specifically the ability to control focal, genetically defined cellular populations with high temporal resolution using equipment that is magnetically inert and does not interact with radiofrequency pulses. Recent studies have demonstrated that the combination of optogenetics and functional MRI (fMRI) can provide an appropriate platform to investigate in vivo, at the cellular and molecular levels, the neuronal basis of fMRI signals. In addition, this novel combination of optogenetics with fMRI has the potential to resolve pre-synaptic versus post-synaptic changes in neuronal activity and changes in the activity of large neuronal networks in the context of plasticity associated with development, learning and pathophysiology. PMID- 23355413 TI - Pain-releasing action of platelet-activating factor (PAF) antagonists in neuropathic pain animal models and the mechanisms of action. AB - BACKGROUND: Platelet-activating factor (PAF) has been implicated in the pathology of neuropathic pain. Previous studies reported that PAF receptor (PAF-R) antagonists have varied anti-allodynia effects by route of administration and nerve injury models in rats. METHODS: The present study elucidated the effectiveness of PAF antagonists against neuropathic pain in four different models of peripheral nerve injury and provided insights into the mode of anti allodynia action. RESULTS: PAF antagonists, TCV-309, BN 50739 and WEB 2086 by intravenous (i.v.) and oral administration have potent and long-lasting anti allodynia action in mice neuropathic pain models. Treatment with PAF antagonists before surgery delayed the initiation of allodynia until the effects of these treatments were abolished. Intrathecal (i.t.) injection of the PAF antagonists and siRNA against PAF receptor ameliorated allodynia. I.t. injection of the glycine receptor (GlyR)alpha3 siRNA reduced the anti-allodynia effect of PAF antagonists. This evidence suggests that the anti-allodynia effect of PAF antagonists is at least in part mediated by spinal relief of PAF-induced dysfunction of GlyRalpha3. An analysis of the mode of anti-allodynia action of TCV-309 in vivo revealed a competitive action against PAF shortly after the injection of TCV-309, converting to a non-competitive action later. CONCLUSIONS: The present results revealed the effectiveness in anti-allodynia of PAF antagonists in different nerve injury models, and the unique mode of action; long lasting anti-allodynia effects mediated by spinal GlyRalpha3 with a competitive manner at the initial stage and the following non-competitive manner of inhibition. PMID- 23355414 TI - On the role of retrosplenial cortex in long-lasting memory storage. AB - The retrosplenial cortex (RSC) is involved in a range of cognitive functions. However, its precise involvement in memory processing is unknown. Pharmacological and behavioral experiments demonstrate that protein synthesis and c-Fos expression in the anterior part of RSC (aRSC) are necessary late after training to maintain for many days a fear-motivated memory. Long-lasting memory storage is regulated by D1/D5 dopamine receptors in aRSC and depends on the functional interplay between dorsal hippocampus and aRSC. These results suggest that the RSC recapitulates some of the molecular events that occur in the hippocampus to maintain memory trace over time. PMID- 23355415 TI - eChickAtlas: an introduction to the database. AB - The precise control of gene expression is critical in embryonic development. Quantitative assays, such as microarrays and RNA sequencing, provide gene expression levels for a large number of genes, but do not contain spatial information. In contrast, in situ methods, such as in situ hybridization and immunohistochemistry, provide spatial resolution, but poor quantification and can only reveal the expression of one, or very few genes at a time. Furthermore, the usual methods of documenting the results, by photographing whole mounts or sections, makes it very difficult to assess the three-dimensional (3D) relationships between expressing and nonexpressing cells. Optical projection tomography (OPT) can capture the full 3D expression pattern in a whole embryo at a reasonable level of resolution and at moderately high throughput. A large database containing spatio-temporal patterns of expression for the mouse (e-Mouse Atlas Project, EMAP, www.emouseatlas.org) has been created, incorporating 3D information. Like the mouse, the chick is an important model in developmental biology and translational studies. To facilitate comparisons between these important model organisms, we have created a 3D anatomical atlas, accompanied by an anatomical ontology of the chick embryo and a database of gene expression patterns during chick development. This database is publicly available (www.echickatlas.org). PMID- 23355416 TI - The resting electrophysiological profile in adults with ADHD and comorbid dysfunctional anger: a pilot study. AB - Although dysfunctional anger is not a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision [DSM-IV-TR]) diagnosis, it sometimes presents as a primary clinical complaint and as a comorbid feature in a subset of adults with attention-deficit/hyperactivity disorder (ADHD). No known studies have examined electroencephalographic (EEG) profiles in adults with comorbid dysfunctional anger and ADHD (ADHD + anger). Resting EEG was recorded in 14 ADHD + anger adults (11 males) and 14 controls. Relative power was assessed at standard frequencies, as was frontal absolute alpha power asymmetry. A modest increase was noted in beta1 power in the ADHD + anger group. Unexpectedly, relatively decreased left (or increased right) frontocortical activity (alpha assessed) was noted in the ADHD + anger group, which was also characterized by a more diffuse theta/beta ratio scalp distribution. Nonmedicated ADHD + anger adults exhibited modest resting cortical hyperarousal, consistent with the findings in a subset of children with ADHD characterized by anger-associated problems. The unexpected frontal alpha asymmetry may reflect enhanced activity of frontal inhibitory mechanisms. PMID- 23355418 TI - Reactions of hydrated singly charged first-row transition-metal ions M+(H2O)n (M=V, Cr, Mn, Fe, Co, Ni, Cu, and Zn) toward nitric oxide in the gas phase. AB - Reactions of M(+) (H2 O)n (M=V, Cr, Mn, Fe, Co, Ni, Cu, Zn; n<=40) with NO were studied by Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry. Uptake of NO was observed for M=Cr, Fe, Co, Ni, Zn. The number of NO molecules taken up depends on the metal ion. For iron and zinc, NO uptake is followed by elimination of HNO and formation of the hydrated metal hydroxide, with strong size dependence. For manganese, only small HMnOH(+) (H2 O)n-1 species, which are formed under the influence of room-temperature black-body radiation, react with NO. Here NO uptake competes with HNO formation, both being primary reactions. The results illustrate that, in the presence of water, transition-metal ions are able to undergo quite particular and diverse reactions with NO. HNO is presumably formed through recombination of a proton and (3) NO(-) for M=Fe, Zn, preferentially for n=15-20. For manganese, the hydride in HMnOH(+) (H2 O)n-1 is involved in HNO formation, preferentially for n<=4. The strong size dependence of the HNO formation efficiency illustrates that each molecule counts in the reactions of small ionic water clusters. PMID- 23355419 TI - Effects of casein phosphopeptide-amorphous calcium phosphate remineralizing paste and 8% arginine desensitizing paste on dentin permeability. AB - AIM: To compare the effects of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) paste and 8% arginine paste on dentin permeability. METHODS: Sixteen human third molars were sectioned to remove the roots and expose occlusal dentin surfaces. The pulpal side was flattened to obtain 1 mm remaining dentin thickness. Each specimen was attached on a Perspex plate and connected to a dentin-permeability measuring apparatus. The specimens were divided into two groups according to the tested products. Dentin permeability was measured under a simulated pulpal pressure after: (a) etching with 37% phosphoric acid; (b) application of CPP-ACP or 8% arginine paste; and (c) acid challenge with 2.6 mmol/L lactic acid. Twelve specimens were prepared so that the treated dentin surfaces could be examined using a scanning electron microscope. RESULTS: Dentin permeability after the application of 8% arginine paste was significantly reduced and lower than that of CPP-ACP paste (P < 0.01). Acid challenge with lactic acid significantly increased dentin permeability in both experimental groups (P < 0.01). The dentin surface treated with 8% arginine paste was covered with particles, but they were removed by acid challenge. Most dentinal tubules were patent when the CPP-ACP paste was applied. CONCLUSIONS: The application of 8% arginine paste decreased dentin permeability, but CPP-ACP paste did not. PMID- 23355420 TI - HEF1 promotes epithelial mesenchymal transition and bone invasion in prostate cancer under the regulation of microRNA-145. AB - The principal problem arising from prostate cancer (PCa) is its propensity to metastasize to bones, and it's crucial to understand the mechanism of tumor progression to metastasis in order to develop therapies that may reduce the morbidity and mortality of PCa patients. Although we had identified that microRNA(miR)-145 could repress bone metastasis of PCa via regulating epithelial mesenchymal transition (EMT) in previous study, it is still unknown how miR-145 regulated EMT. In the present study, we constructed a luciferase reporter system and identified HEF1 as a direct target of miR-145. More importantly, HEF1 was shown to promote migration, invasion and EMT of PC-3 cells, a human PCa cell line originated from a bone metastatic PCa specimen. And HEF1 was also shown to partially mediate miR-145 suppression of EMT and invasion. Furthermore, inhibition of HEF1 repressed bone invasion of PC-3 cells in vivo. Expression of HEF1 was negatively correlated with miR-145 in primary PCa and bone metastatic specimens, but HEF1 was higher in samples which were more likely to commit to bone metastasis or those with higher free prostate-specific antigen (fPSA) levels and Gleason scores. Taken together, these findings indicate that HEF1 promotes EMT and bone invasion in prostate cancer by directly targeted by miR-145, and miR 145 suppresses EMT and invasion, at least in part, through repressing HEF1. PMID- 23355421 TI - NiTi shape memory compression anastomosis clip in small- and large-bowel anastomoses: first experience. AB - The aim of the study was to present a clinical use of compression anastomosis clip (CAC) implants made of shape memory materials--nickel titanium alloys (NiTi). The concept involved in the use of CAC was to compress 2 bowel walls together, cause necrosis, and detach the CAC from the tissue to be expelled with the stool. The CAC is a double-ring elliptical device with a diameter of 30 mm. The device has the ability to recover its original closed shape when it senses a change in ambient temperature. In all, 20 anastomoses using CACs were performed: 6 of the small with the large bowel and 14 between the small bowel and small bowel. Two patients experienced complications. Although the anastomosis is not difficult to perform, the rules on how to apply the CAC must be well known. Because only a small number of anastomoses have been performed by us to date, this procedure requires further study. PMID- 23355422 TI - Education and training in NOTES: a systematic review. AB - INTRODUCTION: Since the first published work on natural orifice translumenal endoscopic surgery (NOTES) a decade ago, progress has been made in the domain of education and training, although questions posed by the original White Paper remain. This article aims to review the current status of education and training in NOTES. METHODS: A review of the literature was conducted to evaluate the following: (1) What are the current training methods/modalities used for NOTES; what is the level of evidence to support their use? (2) How has NOTES clinical training been quantified; what is the evidence relating to performance of different NOTES operators? (3) What clinical NOTES training programs have been established and what are the wider training needs? RESULTS: A total of 25 studies were included: 11 nonanimal studies, 8 animal studies, and 6 descriptions of education programs. Several animal and simulator models demonstrated construct validity, but no study showed human predictive validity. Logarithmic learning curves in animal models demonstrate 10 to 15 cases achieving a proficiency level. Current trends are that gastroenterologists prefer it for diagnostic and basic procedures, whereas surgeons prefer it for complex therapeutic cases. CONCLUSION: The development of a new specialty is intriguing but currently unviable. Training programs have been initiated, but information is limited; the common theme is surgeons receiving endoscopic training. Despite the research done, our knowledge of training and educating in NOTES procedures is limited, preventing a meta analysis or formal review from being performed. Further research is needed to integrate NOTES into routine clinical procedure. PMID- 23355423 TI - Forced degradation studies of clobetasol 17-propionate in methanol, propylene glycol, as bulk drug and cream formulations by RP-HPLC. AB - A rapid, simple, stability-indicating forced degradation study of clobetasol 17 propionate was conducted using RP-HPLC. The method was used to analyze clobetasol 17-propionate in methanol, propylene glycol, and a cream formulation. Isocratic elution of clobetasol and its degradation products was achieved using a Nova Pak(r) 4 MUm C18 150 mm * 3.9 mm id cartridge column and a mobile phase of methanol: water (68:32 v/v) at a flow rate of 0.9 mL min(-1). Quantitation was achieved with UV detection at 239 nm. Nondegraded clobetasol was eluted at a retention time of 6.0 min. Clobetasol 17-propionate was subjected to different stress conditions viz., acidic, basic, heat, oxidation, light, and neutral hydrolysis. The greatest degradation occurred under strong base and oxidative conditions. Strong base-degraded clobetasol produced additional peaks at retention times of 1.8, 4.0, 5.0, and 8.0 min and clobetasol oxidation degradation peaks eluted at 2.2 and 24 min. Complete validation was performed for linearity, accuracy, and precision over the concentration range 0.15-15 MUg mL( 1). All data were analyzed statistically and this RP-HPLC method proved to be accurate, precise, linear, and stability indicating for the quantitation of clobetasol 17-propionate in methanol, propylene glycol, and cream formulations. PMID- 23355424 TI - Replacing phosphorus with sulfur for the efficient hydrogenation of esters. AB - Catalyst tune-up: A readily available, air-stable amino-sulfide catalyst, [RuCl(2)(PPh(3)){HN(C(2)H(4)SEt)(2)}], has been developed. This complex displays outstanding efficiency for the hydrogenation of a broad range of substrates with C=X bonds (esters, ketones, imines), as well as for the acceptorless dehydrogenative coupling of ethanol to ethyl acetate. PMID- 23355425 TI - Water signal attenuation by D2O infusion as a novel contrast mechanism for 1H perfusion MRI. AB - Deuterium oxide (D2 O), which is commercially available and nonradioactive, was proposed as a perfusion tracer before the clinical usage of conventional gadolinium-based MRI contrast agents. However, the sensitivity of direct deuterium detection is the major challenge for its application. In this study, we propose a contrast-enhanced strategy to indirectly trace administered D2 O by monitoring the signal attenuation of (1) H MRI. Experiments on D2 O concentration phantoms and in vivo rat brains were conducted to prove the concept of the proposed contrast mechanism. An average maximum signal drop ratio of 5.25 +/- 0.91% was detected on (1) H MR images of rat brains with 2 mL of D2 O administered per 100 g of body weight. As a diffusible tracer for perfusion, D2 O infusion is a practicable method for the assessment of tissue perfusion and has the potential to provide different information from gadolinium-based contrast agents, which have limited permeability for blood vessels. Furthermore, the observed negative relaxivities of D2 O reveal the (1) H-D exchange effect. Therefore, applications of perfusion MRI with D2 O as a contrast agent are worthy of further investigation. PMID- 23355429 TI - Advanced MRI in malignant neoplasms of the uterus. AB - Conventional magnetic resonance imaging (MRI) such as T1-weighted and T2-weighted images of the female pelvis provide morphological information with excellent tissue contrast, which reflects the pathology of malignant diseases of the uterus. Owing to the recent improvement in hardware and software, in combination with extensive research in imaging techniques, not only MRI at higher magnetic field was facilitated, but also insight into tumor pathophysiology was provided. These methods include diffusion-weighted imaging (DWI), dynamic contrast-enhanced MRI (DCE-MRI) with pharmacokinetic analysis, and MR spectroscopy (MRS). The application of these techniques is expanding from the brain to the body because information on the tissue microenvironment and cytoarchitecture is helpful for lesion characterization, evaluation of treatment response after chemotherapy or radiation, differentiating posttherapeutic changes from residual active tumor, and for detecting recurrent cancer. These techniques may provide clues to optimize the treatment of patients with malignant diseases of the uterus. In the first half of this article we provide an overview of the technical aspects of MRI of the female pelvis, especially focusing on the state-of-the-art techniques such as 3 T MRI, DCE-MRI, DWI, etc. For the latter half we review the clinical aspects of these newly developed techniques, focusing on how these techniques are applicable, what has been revealed with respect to clinical impact, and the remaining problems. PMID- 23355428 TI - Computational tools and resources for prediction and analysis of gene regulatory regions in the chick genome. AB - The discovery of cis-regulatory elements is a challenging problem in bioinformatics, owing to distal locations and context-specific roles of these elements in controlling gene regulation. Here we review the current bioinformatics methodologies and resources available for systematic discovery of cis-acting regulatory elements and conserved transcription factor binding sites in the chick genome. In addition, we propose and make available, a novel workflow using computational tools that integrate CTCF analysis to predict putative insulator elements, enhancer prediction, and TFBS analysis. To demonstrate the usefulness of this computational workflow, we then use it to analyze the locus of the gene Sox2 whose developmental expression is known to be controlled by a complex array of cis-acting regulatory elements. The workflow accurately predicts most of the experimentally verified elements along with some that have not yet been discovered. A web version of the CTCF tool, together with instructions for using the workflow can be accessed from http://toolshed.g2.bx.psu.edu/view/mkhan1980/ctcf_analysis. For local installation of the tool, relevant Perl scripts and instructions are provided in the directory named "code" in the supplementary materials. PMID- 23355430 TI - MRI of ovarian masses. AB - MRI provides exquisite views of the pelvic anatomy through its high spatial resolution and tissue contrast, and as such plays a key role in the work up of ovarian lesions, identifying features that distinguish benign and malignant lesions. In the case of primary tumors it enables local staging and detection of metastatic disease to help guide management options such as complex surgery or the consideration of neoadjuvant chemotherapy. Functional MRI techniques such as diffusion-weighted MRI (DW-MRI), dynamic contrast-enhanced MRI (DCE-MRI) and tumor-selective molecular imaging are currently being evaluated as possible predictive and prognostic biomarkers in the context of ovarian malignancy, and may play a larger role in routine clinical practice in the future. Herein we provide an overview of the conventional and advanced MRI techniques used to characterize ovarian masses and of the role that MR plays in the staging, treatment selection and follow up of patients with ovarian cancer. PMID- 23355431 TI - Functional MRI of the kidneys. AB - Renal function is characterized by different physiologic aspects, including perfusion, glomerular filtration, interstitial diffusion, and tissue oxygenation. Magnetic resonance imaging (MRI) shows great promise in assessing these renal tissue characteristics noninvasively. The last decade has witnessed a dramatic progress in MRI techniques for renal function assessment. This article briefly describes relevant renal anatomy and physiology, reviews the applications of functional MRI techniques for the diagnosis of renal diseases, and lists unresolved issues that will require future work. PMID- 23355434 TI - Effects of solvent drying time and water storage on ultimate tensile strength of adhesives. AB - AIM: Simplified adhesives are a blend of monomers with solvents that are expected to evaporate before light curing. The aim of the present study was to evaluate the effects of drying time and water storage on the ultimate tensile strength (UTS) of three adhesives: Adper Single Bond 2 (ASB), One-Step Plus (OSP) and Clearfil S(3) Bond (CSB). METHODS: Dumbbell-shaped samples from each adhesive were prepared in three groups: (a) air drying prior to light curing; (b) no drying equal to active air drying; and (c) 3-h drying. Each group was further divided into two subgroups of no storage or 7 days' water storage, prior to the UTS measurement (n = 10). RESULTS: Material, drying-time, and storage had a significant effect on UTS, and the interactions of the factors were also significant (P < 0.05). OSP showed a higher evaporation rate under passive air drying, and OSP and CSB showed higher UTS values compared to ASB (P < 0.05). Air drying improved UTS in OSP and CSB, but not in ASB. Likewise, water storage only affected the UTS of OSP and CSB. CONCLUSIONS: The effects of air drying and water storage period on UTS are material dependent. Whenever solvent evaporation improved the UTS of adhesive, water storage decreased it. The all-in-one self etching adhesive can maximize its best properties when the solvent is dried for an extended period. PMID- 23355441 TI - Discovery of hepatitis C virus NS3 helicase inhibitors by a multiplexed, high throughput helicase activity assay based on graphene oxide. PMID- 23355432 TI - Hyperpolarized 129Xe MRI of the human lung. AB - By permitting direct visualization of the airspaces of the lung, magnetic resonance imaging (MRI) using hyperpolarized gases provides unique strategies for evaluating pulmonary structure and function. Although the vast majority of research in humans has been performed using hyperpolarized (3)He, recent contraction in the supply of (3)He and consequent increases in price have turned attention to the alternative agent, hyperpolarized (129) Xe. Compared to (3)He, (129)Xe yields reduced signal due to its smaller magnetic moment. Nonetheless, taking advantage of advances in gas-polarization technology, recent studies in humans using techniques for measuring ventilation, diffusion, and partial pressure of oxygen have demonstrated results for hyperpolarized (129)Xe comparable to those previously demonstrated using hyperpolarized (3)He. In addition, xenon has the advantage of readily dissolving in lung tissue and blood following inhalation, which makes hyperpolarized (129)Xe particularly attractive for exploring certain characteristics of lung function, such as gas exchange and uptake, which cannot be accessed using (3)He. Preliminary results from methods for imaging (129) Xe dissolved in the human lung suggest that these approaches will provide new opportunities for quantifying relationships among gas delivery, exchange, and transport, and thus show substantial potential to broaden our understanding of lung disease. Finally, recent changes in the commercial landscape of the hyperpolarized-gas field now make it possible for this innovative technology to move beyond the research laboratory. PMID- 23355442 TI - Ganglioside GM3 inhibits hepatoma cell motility via down-regulating activity of EGFR and PI3K/AKT signaling pathway. AB - Two related sublines derived from murine ascites hepatoma cell lines Hca-F25, which were selected for their markedly different metastatic potential to lymph nodes, were found to be distinct in their ganglioside patterns. The low metastatic cell line (HcaP) contained a major ganglioside GM3, whereas the high metastatic cell line (HcaF) contained a major ganglioside GM2. Suppression of GM3 by P4 enhanced the mobility and migration of the low metastatic HcaP cells in vitro. Increase in GM3 content in high metastatic HcaF cells by addition of exogenous GM3 inhibited the mobility and migration. These results suggested that the differences in lymphatic metastasis potential between these two cell lines could be attributed to the differences in their ganglioside compositions, and GM3 could suppress the motility and migration of these cells. Further, we investigated the mechanism by which GM3 suppressed the cell mobility and migration. The results showed that suppression of GM3 synthesis by P4 in low metastatic HcaP cells promoted PKB/Akt phosphorylation at Ser473 and Thr308, and phosphorylation of EGFR at the Tyr1173. In contrast, increase in GM3 content in high metastatic HcaF cells by addition of exogenous GM3 into the culture medium suppressed phosphorylation of PKB/Akt and EGFR at the same residues. Taken together, these results suggested that the mechanism of GM3-suppressed cell motility and migration may involve the inhibition of phosphorylation of EGFR and the activity of PI3K/AKT signaling pathway. PMID- 23355443 TI - Single-drop liquid phase microextraction accelerated by surface acoustic wave. AB - A single-drop liquid phase microextraction method is presented, in which surface acoustic wave (SAW) is used for accelerating extraction speed. A pair of interdigital transducers with 27.5 MHz center frequency is fabricated on a 128 degrees yx-LiNbO3 substrate. A radio frequency signal is applied to one of interdigital transducers to excite SAW. Plastic straw is filled with PDMS, leaving 1 mL for holding sample solution. Plastic straw with sample solution droplet is then dipping into extractant, into which SAW is radiated. Mass transportation from sample solution to extractant drop is accelerated due to acoustic streaming, and extraction time is decreased. An ionic liquid and an acid green-25 solution are used for extraction experiments. Results show that the extraction process is almost finished within 2 min, and extraction speed is increased with radio frequency signal power. PMID- 23355444 TI - Implementing global mental health. PMID- 23355445 TI - Using a health message with a testimonial to motivate colon cancer screening: associations with perceived identification and vividness. AB - Research suggests that testimonials, or first-person narratives, influence health behavior and health-related decision making, but few studies have examined conceptual factors that may be responsible for these effects. In the current study, older adults who were due for colorectal cancer screening read a message about screening that included a testimonial from a similar other who had previously made the screening decision. We assessed participants' identification with the testimonial character and the degree to which they found the message to be vivid. We explored associations between these factors and participants' knowledge following the message, mood, certainty about screening, and their behavioral intentions to look for more information about screening and to have a test in the next year. In bivariate analyses, identification and vividness were both significantly, positively associated with knowledge and behavioral intentions to have screening in the next year. However, multivariate analyses revealed that only vividness remained significantly associated with knowledge and intentions to be screened. PMID- 23355446 TI - Magnetic resonance imaging of time-varying magnetic fields from therapeutic devices. AB - While magnetic resonance imaging of static magnetic fields generated by external probes has been previously demonstrated, there is an unmet need to image time varying magnetic fields such as those generated by transcranial magnetic stimulators and radiofrequency hyperthermia probes. A method to image such time varying magnetic fields is introduced in this study. This article presents the theory behind the method and provides proof of concept by imaging time-varying magnetic fields generated by a figure-eight coil inside simple phantoms over a range of frequencies and intensities using a 7T small animal MRI scanner. The method was able to reconstruct the three-dimensional components of the oscillating magnetic field vector. PMID- 23355447 TI - The evaluation of a fall management program in a nursing home population. AB - PURPOSE OF THE STUDY: This study evaluates a nursing home Fall Management program to see if residents' mobility increased and injurious falls decreased. DESIGN AND METHODS: Administrative health care use and fall occurrence report data were analyzed from 2 rural health regions in Manitoba, Canada, from June 1, 2003 to March 31, 2008. A quasiexperimental, pre-post, comparison group design was used to compare rates of three outcomes, falls, injurious falls, and falls resulting in hospitalization, by RHA (program vs nonprogram nursing homes) and period (preprogram vs postprogram). Data collectors entered occurrence report information into spreadsheets. This was supplemented with administrative health care use data. RESULTS: The program appears to have benefitted residents-falls trended upward, injurious falls remained stable, and hospitalized falls decreased significantly (0.036-0.021 per person-year [ppy]; p = .043). Compared with nonprogram residents in the postperiod, both groups had the same fall rate, but program residents had significantly fewer injurious falls (0.596-0.746 ppy; p = .02) and hospitalized falls (0.02-0.041 ppy; p = .023). IMPLICATIONS: These results are among a small body of literature showing that Fall Management was associated with improved outcomes in program nursing homes from pre- to postperiod and compared with nonprogram nursing homes. This research provides some support for the benefits of being proactive and implementing injury prevention strategies universally and pre-emptively before a resident falls, helping to minimize injuries while keeping residents mobile and active. Larger scale research is needed to identify the true effectiveness of the Fall Management program and generalizability of results. PMID- 23355448 TI - Telecounseling for the linguistically isolated: a pilot study with older Korean immigrants. AB - PURPOSE: Responding to the critical needs of the linguistically isolated, this pilot study tested the use of telehealth technology in providing access to culturally and linguistically appropriate mental health services. The goal of the study was to explore the feasibility and preliminary efficacy of a telecounseling program in the client's native language. DESIGN AND METHODS: Using a small sample of older Korean immigrants living in a low-income housing facility in Orlando, Florida, who had concerns about depressive moods (n = 14), the pilot telecounseling program was implemented via videoconferencing. Four weekly sessions were conducted by 4 Korean mental health counselors based in New York. RESULTS: A high level of completion (86%) and overall satisfaction with the program were observed. Participants also exhibited a significant reduction in depressive symptom severity shortly after completion of the program. At the 3 month follow-up, the participants' depressive symptom scores remained significantly lower than those at the initial assessment. IMPLICATIONS: The findings support the value of telecounseling for linguistically isolated populations and suggest further efforts to extend such programs. PMID- 23355449 TI - Risk and protective factors associated with health-related quality of life among older gay and bisexual men living with HIV disease. AB - PURPOSE: To identify risk and protective factors associated with mental and physical health-related quality of life, after controlling for key background characteristics, in a population of older gay and bisexual men living with HIV disease. Previous research examining quality of life among persons living with HIV rarely includes older adults. DESIGN AND METHODS: Survey responses from 226 gay and bisexual men aged 50 and older, and living with HIV disease, which were part of the Caring and Aging with Pride study, were analyzed using multivariate linear regression models. RESULTS: Findings reveal that comorbidity, limitations in activities, and victimization are significant risk factors for decreased physical and mental health-related quality of life. Stigma and HIV progression did not contribute to the overall outcome variables in multivariate models. Social support and self-efficacy serve as protective factors although social support was only significant with mental health-related quality of life. IMPLICATIONS: Comorbidity, functional limitations, and lifetime victimization are risks to quality of life among older gay and bisexual men with HIV disease. Self efficacy and social support represent intrapersonal and interpersonal resources that can be enhanced through interventions to improve health-related quality of life. PMID- 23355450 TI - Body mass trajectories and mortality among older adults: a joint growth mixture discrete-time survival analysis. AB - PURPOSE OF THE STUDY: The aim of this study was to investigate heterogeneity in body weight trajectories among older adults and their association with mortality risks. DESIGN AND METHODS: Information on body mass index (BMI) and survival come from nine waves of the Health and Retirement Study, a 16-year survey of adults aged 51-61 at baseline (N = 9,703). We used a sex-stratified joint growth mixture discrete time survival model to characterize BMI trajectory groups and their associated mortality. RESULTS: Three distinct classes of BMI trajectories were identified: "stable overweight," "obese gaining," and "obese losing." Relative to the stable overweight class, which comprised about 90% of the sample, the obese gaining class had approximately 50% higher mortality risk; the highest mortality was found in the obese losing category (OR > 2.7, p < .001). The results were similar for men and women. IMPLICATIONS: The findings highlight substantial heterogeneity in weight trajectories of older Americans, as well as large survival differentials across the classes. The direction of weight changes appears inextricably linked to the overall BMI level in terms of predicting older adults' longevity. Weight loss is associated with particularly high mortality risk even when the typical BMI change is from obesity to overweight. PMID- 23355451 TI - Prevalence of cusp 7 in permanent mandibular first molars in an Indian population: a comparative study of variations in occlusal morphology. AB - AIM: The aims of the present study were to determine the prevalence of cusp 7 in permanent mandibular first molars in an Indian population, and to comparatively evaluate the variations in occlusal morphology of these teeth, including the difference in the number of cusps and fissure patterns. METHODS: A total of 1123 Indian participants from the Government College of Dentistry, Indore, Madhya Pradesh, India, were selected for the study. For the analyses of cusp 6 and cusp 7 in permanent mandibular first molars, the Arizona State University Dental Anthropology System was used. Groove patterns were analyzed and classified as Y, +, X, and ?. RESULTS: Of the 1123 individuals, 132 (11.75%) were found to have cusp 7, while 78 (6.95%) had cusp 6. Thus, a total of 210 participants had the six-cusped mandibular first molars, 98 (8.73%) had the four-cusped mandibular first molars, and two had the seven-cusped variant. Overall, the most common fissure pattern was the Y pattern (50.36%), while the least common was the X pattern (1.25%). Mandibular first molars with cusp 7 demonstrated a highly significant (P < 0.05) dominance of the ? pattern (36.80%) over the Y (30.74%), + (27.71%), and X (4.46%) fissure patterns. CONCLUSION: A significant prevalence of cusp 7 (11.25%) in permanent mandibular first molars was found in the present study in an Indian population. PMID- 23355452 TI - Safety information in drug labeling: a comparison of the USA, the UK, and Japan. AB - PURPOSE: Despite globalization of drug approvals, there is a disparity in drug safety regulations among the USA, Europe, and Japan. We sought to determine differences in safety information on drug labels among the three regions. METHODS: This was a cross-sectional study with quantitative survey of safety information on labels of 189 new molecular entities approved in the USA, the UK, and Japan. Outcome measures were the proportions of total safety information (PSI), of contraindications (PCI), and of boxed warnings (PBW) to all information on the label. We identified a boxed warning (BW) on US and Japanese labels through a manual search. These measures were analyzed according to therapeutic indications. RESULTS: On the Japanese labels, PSI was smaller than that on the US and UK labels for cardiovascular diseases. For neoplastic and immunologic diseases, PSI on the Japanese labels was larger than that on the UK labels. For nervous system diseases, PSI on the US labels was larger than that on the UK and the Japanese labels. PCI showed contrasting results with PSI except for neoplastic and immunologic diseases. BWs showed a poorer concordance between the USA and Japan in hematologic and genitourinary diseases than in other therapeutic areas. CONCLUSIONS: Substantial differences in safety information exist depending upon outcome measures and therapeutic areas among the US, the UK, and the Japanese labels. This underscores the need for further analyses to determine causes of these differences to optimize drug safety regulations. PMID- 23355453 TI - NHC-catalyzed hydroacylation of styrenes. AB - New hydroacylation catalysts: Highly electron-rich N-heterocyclic carbenes (NHCs) facilitate the intermolecular hydroacylation of unstrained olefins. This unprecedented organocatalytic coupling joins simple and abundant aldehydes and styrenes to yield valuable ketone products. EWG=electron-withdrawing group, EDG=electron-donating group. PMID- 23355454 TI - microRNA 21-mediated suppression of Sprouty1 by Pokemon affects liver cancer cell growth and proliferation. AB - Transcriptional repressor Pokemon is a critical factor in embryogenesis, development, cell proliferation, differentiation, and oncogenesis, thus behaving as an oncogene. Oncomine database suggests a potential correlation between the expressions of Pokemon and Sprouty1. This study investigated the regulatory role of Pokemon in Sprouty1 expression and the effect on liver cancer cell growth and proliferation, revealing a novel miR-21-mediated regulatory circuit. In normal (HL-7702) and cancer (QGY-7703) liver cell lines, Sprouty1 expression is inversely correlated with Pokemon levels. Targeted expression or siRNA-mediated silencing showed that Pokemon is a repressor of Sprouty1 expression at both mRNA and protein levels, but Pokemon cannot affect the promoter activity of Sprouty1. Sprouty1 is a target of miR-21 and interestingly, we found that miR-21 is up regulated by Pokemon in liver cancer cells. Luciferase reporter assays showed that Pokemon up-regulated miR-21 transcription in a dose-dependent manner, and ChIP assay exhibited a direct binding of Pokemon to the miR-21 promoter at -747 to -399 bp. Site-directed mutagenesis of the GC boxes at -684 to -679 bp and -652 to -647 bp of miR-21 promoter abolished the regulatory activity by Pokemon. Furthermore, we found that the modulation of Pokemon and miR-21 expression affected the growth and proliferation of liver cancer cells QGY-7703. In summary, our findings demonstrate that Pokemon suppresses Sprouty1 expression through a miR-21-mediated mechanism, affecting the growth and proliferation of liver cancer cells. This study recognized miR-21 and Sprouty1 as novel targets of the Pokemon regulatory network. PMID- 23355455 TI - Gene therapy clinical trials worldwide to 2012 - an update. AB - To date, over 1800 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical trials from official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our June 2012 update, we have entries on 1843 trials undertaken in 31 countries. We have analysed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our searchable database are available on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical. We also provide an overview of the progress being made in clinical trials of gene therapy approaches around the world and discuss the prospects for the future. PMID- 23355456 TI - The discovery of phenylbenzamide derivatives as Grb7-based antitumor agents. AB - Grb7 is a non-catalytic protein, the overexpression of which has been associated with the proliferative and migratory potentials of cancer cells. Virtual screening strategies involving a shape-based similarity search, molecular docking, and 2D-similarity searches complemented by experimental binding studies (Thermofluor and isothermal titration calorimetry) resulted in the identification of nine novel phenylbenzamide-based antagonists of the Grb7 SH2 domain. Moderate binding affinities were observed, ranging from K(d)=32.3 MUM for lead phenylbenzamide NSC 104999 (1) to K(d)=1.1 MUM for a structurally related compound, NSC 57148 (2). Deconvolution of the affinity data into its components revealed differences in lead binding, from being entropy based (lead 1) to enthalpically driven (NSC 100874 (3), NSC 55158 (4), and compound 2). Finally, the lead compound 1 was found to decrease the growth of MDA-MB-468 breast cancer cells, with an IC(50) value of 39.9 MUM. It is expected that these structures will serve as novel leads in the development of Grb7-based anticancer therapeutics. PMID- 23355458 TI - Towards comprehensive syntactic and semantic annotations of the clinical narrative. AB - OBJECTIVE: To create annotated clinical narratives with layers of syntactic and semantic labels to facilitate advances in clinical natural language processing (NLP). To develop NLP algorithms and open source components. METHODS: Manual annotation of a clinical narrative corpus of 127 606 tokens following the Treebank schema for syntactic information, PropBank schema for predicate-argument structures, and the Unified Medical Language System (UMLS) schema for semantic information. NLP components were developed. RESULTS: The final corpus consists of 13 091 sentences containing 1772 distinct predicate lemmas. Of the 766 newly created PropBank frames, 74 are verbs. There are 28 539 named entity (NE) annotations spread over 15 UMLS semantic groups, one UMLS semantic type, and the Person semantic category. The most frequent annotations belong to the UMLS semantic groups of Procedures (15.71%), Disorders (14.74%), Concepts and Ideas (15.10%), Anatomy (12.80%), Chemicals and Drugs (7.49%), and the UMLS semantic type of Sign or Symptom (12.46%). Inter-annotator agreement results: Treebank (0.926), PropBank (0.891-0.931), NE (0.697-0.750). The part-of-speech tagger, constituency parser, dependency parser, and semantic role labeler are built from the corpus and released open source. A significant limitation uncovered by this project is the need for the NLP community to develop a widely agreed-upon schema for the annotation of clinical concepts and their relations. CONCLUSIONS: This project takes a foundational step towards bringing the field of clinical NLP up to par with NLP in the general domain. The corpus creation and NLP components provide a resource for research and application development that would have been previously impossible. PMID- 23355459 TI - Network models of genome-wide association studies uncover the topological centrality of protein interactions in complex diseases. AB - BACKGROUND: While genome-wide association studies (GWAS) of complex traits have revealed thousands of reproducible genetic associations to date, these loci collectively confer very little of the heritability of their respective diseases and, in general, have contributed little to our understanding the underlying disease biology. Physical protein interactions have been utilized to increase our understanding of human Mendelian disease loci but have yet to be fully exploited for complex traits. METHODS: We hypothesized that protein interaction modeling of GWAS findings could highlight important disease-associated loci and unveil the role of their network topology in the genetic architecture of diseases with complex inheritance. RESULTS: Network modeling of proteins associated with the intragenic single nucleotide polymorphisms of the National Human Genome Research Institute catalog of complex trait GWAS revealed that complex trait associated loci are more likely to be hub and bottleneck genes in available, albeit incomplete, networks (OR=1.59, Fisher's exact test p < 2.24 * 10(-12)). Network modeling also prioritized novel type 2 diabetes (T2D) genetic variations from the Finland-USA Investigation of Non-Insulin-Dependent Diabetes Mellitus Genetics and the Wellcome Trust GWAS data, and demonstrated the enrichment of hubs and bottlenecks in prioritized T2D GWAS genes. The potential biological relevance of the T2D hub and bottleneck genes was revealed by their increased number of first degree protein interactions with known T2D genes according to several independent sources (p<0.01, probability of being first interactors of known T2D genes). CONCLUSION: Virtually all common diseases are complex human traits, and thus the topological centrality in protein networks of complex trait genes has implications in genetics, personal genomics, and therapy. PMID- 23355460 TI - Factors that physicians find encouraging and discouraging about electronic prescribing: a quantitative study. AB - To determine factors that physicians find encouraging and discouraging about e prescribing and to compare these factors based on physicians' adoption status, a cross-sectional study was conducted using an internet-based survey administered to a national convenience sample of primary care physicians. A scale was developed to measure factors related to the adoption of e-prescribing. Analysis procedures included exploratory factor analysis, multivariate analysis of variance, and Tukey's post-hoc tests. 443 surveys were received and seven e prescribing factors were identified. Pre-implementation and cost factors were found to be most discouraging, while software features were found to be most encouraging. The fact that current e-prescribers found e-prescribing factors to be more encouraging than future or non-e-prescribers suggests that 'fear of the unknown' may play a role in prescribers' perceptions of e-prescribing and associated software. These findings will enable consultants, vendors, and policymakers to facilitate the adoption of e-prescribing by directly targeting the factors that are most salient to physicians. PMID- 23355461 TI - The intended and unintended consequences of communication systems on general internal medicine inpatient care delivery: a prospective observational case study of five teaching hospitals. AB - BACKGROUND: Effective clinical communication is critical to providing high quality patient care. Hospitals have used different types of interventions to improve communication between care teams, but there have been few studies of their effectiveness. OBJECTIVES: To describe the effects of different communication interventions and their problems. DESIGN: Prospective observational case study using a mixed methods approach of quantitative and qualitative methods. SETTING: General internal medicine (GIM) inpatient wards at five tertiary care academic teaching hospitals. PARTICIPANTS: Clinicians consisting of residents, attending physicians, nurses, and allied health (AH) staff working on the GIM wards. METHODS: Ethnographic methods and interviews with clinical staff (doctors, nurses, medical students, and AH professionals) were conducted over a 16-month period from 2009 to 2010. RESULTS: We identified four categories that described the intended and unintended consequences of communication interventions: impacts on senders, receivers, interprofessional collaboration, and the use of informal communication processes. The use of alphanumeric pagers, smartphones, and web-based communication systems had positive effects for senders and receivers, but unintended consequences were seen with all interventions in all four categories. CONCLUSIONS: Interventions that aimed to improve clinical communications solved some but not all problems, and unintended effects were seen with all systems. PMID- 23355462 TI - Computerized provider documentation: findings and implications of a multisite study of clinicians and administrators. AB - OBJECTIVE: Clinical documentation is central to the medical record and so to a range of healthcare and business processes. As electronic health record adoption expands, computerized provider documentation (CPD) is increasingly the primary means of capturing clinical documentation. Previous CPD studies have focused on particular stakeholder groups and sites, often limiting their scope and conclusions. To address this, we studied multiple stakeholder groups from multiple sites across the USA. METHODS: We conducted 14 focus groups at five Department of Veterans Affairs facilities with 129 participants (54 physicians or practitioners, 34 nurses, and 37 administrators). Investigators qualitatively analyzed resultant transcripts, developed categories linked to the data, and identified emergent themes. RESULTS: Five major themes related to CPD emerged: communication and coordination; control and limitations in expressivity; information availability and reasoning support; workflow alteration and disruption; and trust and confidence concerns. The results highlight that documentation intertwines tightly with clinical and administrative workflow. Perceptions differed between the three stakeholder groups but remained consistent within groups across facilities. CONCLUSIONS: CPD has dramatically changed documentation processes, impacting clinical understanding, decision-making, and communication across multiple groups. The need for easy and rapid, yet structured and constrained, documentation often conflicts with the need for highly reliable and retrievable information to support clinical reasoning and workflows. Current CPD systems, while better than paper overall, often do not meet the needs of users, partly because they are based on an outdated 'paper-chart' paradigm. These findings should inform those implementing CPD systems now and future plans for more effective CPD systems. PMID- 23355463 TI - Enhancing patient safety and quality of care by improving the usability of electronic health record systems: recommendations from AMIA. AB - In response to mounting evidence that use of electronic medical record systems may cause unintended consequences, and even patient harm, the AMIA Board of Directors convened a Task Force on Usability to examine evidence from the literature and make recommendations. This task force was composed of representatives from both academic settings and vendors of electronic health record (EHR) systems. After a careful review of the literature and of vendor experiences with EHR design and implementation, the task force developed 10 recommendations in four areas: (1) human factors health information technology (IT) research, (2) health IT policy, (3) industry recommendations, and (4) recommendations for the clinician end-user of EHR software. These AMIA recommendations are intended to stimulate informed debate, provide a plan to increase understanding of the impact of usability on the effective use of health IT, and lead to safer and higher quality care with the adoption of useful and usable EHR systems. PMID- 23355464 TI - Humanization of antibodies using heavy chain complementarity-determining region 3 grafting coupled with in vitro somatic hypermutation. AB - A method for simultaneous humanization and affinity maturation of monoclonal antibodies has been developed using heavy chain complementarity-determining region (CDR) 3 grafting combined with somatic hypermutation in vitro. To minimize the amount of murine antibody-derived antibody sequence used during humanization, only the CDR3 region from a murine antibody that recognizes the cytokine hbetaNGF was grafted into a nonhomologous human germ line V region. The resulting CDR3 grafted HC was paired with a CDR-grafted light chain, displayed on the surface of HEK293 cells, and matured using in vitro somatic hypermutation. A high affinity humanized antibody was derived that was considerably more potent than the parental antibody, possessed a low pm dissociation constant, and demonstrated potent inhibition of hbetaNGF activity in vitro. The resulting antibody contained half the heavy chain murine donor sequence compared with the same antibody humanized using traditional methods. PMID- 23355465 TI - MicroRNA-92a negatively regulates Toll-like receptor (TLR)-triggered inflammatory response in macrophages by targeting MKK4 kinase. AB - Toll-like receptors (TLRs) play a critical role in the initiation of immune responses against invading pathogens. MicroRNAs have been shown to be important regulators of TLR signaling. In this study, we have found that the stimulation of multiple TLRs rapidly reduced the levels of microRNA-92a (miRNA-92a) and some other members of the miRNA-92a family in macrophages. miR-92a mimics significantly decreased, whereas miR-92a knockdown increased, the activation of the JNK/c-Jun pathway and the production of inflammatory cytokines in macrophages when stimulated with ligands for TLR4. Furthermore, mitogen-activated protein kinase kinase 4 (MKK4), a kinase that activates JNK/stress-activated protein kinase, was found to be directly targeted by miR-92a. Similar to the effects of the miR-92a mimics, knockdown of MKK4 inhibited the activation of JNK/c-Jun signaling and the production of TNF-alpha and IL-6. In conclusion, we have demonstrated that TLR-mediated miR-92a reduction feedback enhances TLR-triggered production of inflammatory cytokines in macrophages, thus outlining new mechanisms for fine-tuning the TLR-triggered inflammatory response. PMID- 23355466 TI - Gedunin inactivates the co-chaperone p23 protein causing cancer cell death by apoptosis. AB - Pharmacological inhibition of Hsp90 is an exciting option for cancer therapy. The clinical efficacy of Hsp90 inhibitors is, however, less than expected. Binding of the co-chaperone p23 to Hsp90 and induced overexpression of anti-apoptotic proteins Hsp70 and Hsp27 are thought to contribute to this outcome. Herein, we report that the natural product gedunin may provide a new alternative to inactivate the Hsp90 machine. We show that gedunin directly binds to p23 and inactivates it, without overexpression of Hsp27 and relatively modest induction of Hsp70. Using molecular docking and mutational analysis, we mapped the gedunin binding site on p23. Functional analysis shows that gedunin inhibits the p23 chaperoning activity, blocks its cellular interaction with Hsp90, and interferes with p23-mediated gene regulation. Cell treatment with gedunin leads to cancer cell death by apoptosis through inactivation of p23 and activation of caspase 7, which cleaves p23 at the C terminus. These results provide important insight into the molecular mechanism of action of this promising lead compound. PMID- 23355467 TI - Role of fat body lipogenesis in protection against the effects of caloric overload in Drosophila. AB - The Drosophila fat body is a liver- and adipose-like tissue that stores fat and serves as a detoxifying and immune responsive organ. We have previously shown that a high sugar diet leads to elevated hemolymph glucose and systemic insulin resistance in developing larvae and adults. Here, we used stable isotope tracer feeding to demonstrate that rearing larvae on high sugar diets impaired the synthesis of esterified fatty acids from dietary glucose. Fat body lipid profiling revealed changes in both carbon chain length and degree of unsaturation of fatty acid substituents, particularly in stored triglycerides. We tested the role of the fat body in larval tolerance of caloric excess. Our experiments demonstrated that lipogenesis was necessary for animals to tolerate high sugar feeding as tissue-specific loss of orthologs of carbohydrate response element binding protein or stearoyl-CoA desaturase 1 resulted in lethality on high sugar diets. By contrast, increasing the fat content of the fat body by knockdown of king-tubby was associated with reduced hyperglycemia and improved growth and tolerance of high sugar diets. Our work supports a critical role for the fat body and the Drosophila carbohydrate response element-binding protein ortholog in metabolic homeostasis in Drosophila. PMID- 23355468 TI - The effect of including the C2 insert of nonmuscle myosin II-C on neuritogenesis. AB - The functional role of the C2 insert of nonmuscle myosin II-C (NM II-C) is poorly understood. Here, we report for the first time that the expression of the C2 insert-containing isoform, NM II-C1C2, is inducible in Neuro-2a cells during differentiation both at mRNA and protein levels. Immunoblot and RT-PCR analysis reveal that expression of NM II-C1C2 peaks between days 3 and 6 of differentiation. Localization of NM II-C1C2 in Neuro-2a cells suggests that the C2 insert-containing isoform is localized in the cytosol and along the neurites, specifically at the adherence point to substratum. Inhibition of endogenous NM II C1C2 using siRNA decreases the neurite length by 43% compared with control cells treated with nonspecific siRNA. Time lapse image analysis reveals that neurites of C2-siRNA-treated cells have a net negative change in neurite length per minute, leading to a reduction of overall neurite length. During neuritogenesis, NM II-C1C2 can interact and colocalize with beta1-integrin in neurites. Altogether, these studies indicate that NM II-C1C2 may be involved in stabilizing neurites by maintaining their structure at adhesion sites. PMID- 23355469 TI - Nuclear envelope composition determines the ability of neutrophil-type cells to passage through micron-scale constrictions. AB - Neutrophils are characterized by their distinct nuclear shape, which is thought to facilitate the transit of these cells through pore spaces less than one-fifth of their diameter. We used human promyelocytic leukemia (HL-60) cells as a model system to investigate the effect of nuclear shape in whole cell deformability. We probed neutrophil-differentiated HL-60 cells lacking expression of lamin B receptor, which fail to develop lobulated nuclei during granulopoiesis and present an in vitro model for Pelger-Huet anomaly; despite the circular morphology of their nuclei, the cells passed through micron-scale constrictions on similar timescales as scrambled controls. We then investigated the unique nuclear envelope composition of neutrophil-differentiated HL-60 cells, which may also impact their deformability; although lamin A is typically down-regulated during granulopoiesis, we genetically modified HL-60 cells to generate a subpopulation of cells with well defined levels of ectopic lamin A. The lamin A overexpressing neutrophil-type cells showed similar functional characteristics as the mock controls, but they had an impaired ability to pass through micron-scale constrictions. Our results suggest that levels of lamin A have a marked effect on the ability of neutrophils to passage through micron-scale constrictions, whereas the unusual multilobed shape of the neutrophil nucleus is less essential. PMID- 23355470 TI - Tubulin polymerization promoting protein 1 (Tppp1) phosphorylation by Rho associated coiled-coil kinase (rock) and cyclin-dependent kinase 1 (Cdk1) inhibits microtubule dynamics to increase cell proliferation. AB - Tubulin polymerization promoting protein 1 (Tppp1) regulates microtubule (MT) dynamics via promoting MT polymerization and inhibiting histone deacetylase 6 (Hdac6) activity to increase MT acetylation. Our results reveal that as a consequence, Tppp1 inhibits cell proliferation by delaying the G1/S-phase and the mitosis to G1-phase transitions. We show that phosphorylation of Tppp1 by Rho associated coiled-coil kinase (Rock) prevents its Hdac6 inhibitory activity to enable cells to enter S-phase. Whereas, our analysis of the role of Tppp1 during mitosis revealed that inhibition of its MT polymerizing and Hdac6 regulatory activities were necessary for cells to re-enter the G1-phase. During this investigation, we also discovered that Tppp1 is a novel Cyclin B/Cdk1 (cyclin dependent kinase) substrate and that Cdk phosphorylation of Tppp1 inhibits its MT polymerizing activity. Overall, our results show that dual Rock and Cdk phosphorylation of Tppp1 inhibits its regulation of the cell cycle to increase cell proliferation. PMID- 23355471 TI - The allosteric mechanism induced by protein kinase A (PKA) phosphorylation of dematin (band 4.9). AB - Dematin (band 4.9) is an F-actin binding and bundling protein best known for its role within red blood cells, where it both stabilizes as well as attaches the spectrin/actin cytoskeleton to the erythrocytic membrane. Here, we investigate the structural consequences of phosphorylating serine 381, a covalent modification that turns off F-actin bundling activity. In contrast to the canonical doctrine, in which phosphorylation of an intrinsically disordered region/protein confers affinity for another domain/protein, we found the converse to be true of dematin: phosphorylation of the well folded C-terminal villin-type headpiece confers affinity for its intrinsically disordered N-terminal core domain. We employed analytical ultracentrifugation to demonstrate that dematin is monomeric, in contrast to the prevailing view that it is trimeric. Next, using a series of truncation mutants, we verified that dematin has two F-actin binding sites, one in the core domain and the other in the headpiece domain. Although the phosphorylation-mimicking mutant, S381E, was incapable of bundling microfilaments, it retains the ability to bind F-actin. We found that a phosphorylation-mimicking mutant, S381E, eliminated the ability to bundle, but not bind F-actin filaments. Lastly, we show that the S381E point mutant caused the headpiece domain to associate with the core domain, leading us to the mechanism for cAMP-dependent kinase control of dematin's F-actin bundling activity: when unphosphorylated, dematin's two F-actin binding domains move independent of one another permitting them to bind different F-actin filaments. Phosphorylation causes these two domains to associate, forming a compact structure, and sterically eliminating one of these F-actin binding sites. PMID- 23355473 TI - Charge composition features of model single-span membrane proteins that determine selection of YidC and SecYEG translocase pathways in Escherichia coli. AB - We have investigated the features of single-span model membrane proteins based upon leader peptidase that determines whether the proteins insert by a YidC/Sec independent, YidC-only, or YidC/Sec mechanism. We find that a protein with a highly hydrophobic transmembrane segment that inserts into the membrane by a YidC/Sec-independent mechanism becomes YidC-dependent if negatively charged residues are inserted into the translocated periplasmic domain or if the hydrophobicity of the transmembrane segment is reduced by substituting polar residues for nonpolar ones. This suggests that charged residues in the translocated domain and the hydrophobicity within the transmembrane segment are important determinants of the insertion pathway. Strikingly, the addition of a positively charged residue to either the translocated region or the transmembrane region can switch the insertion requirements such that insertion requires both YidC and SecYEG. To test conclusions from the model protein studies, we confirmed that a positively charged residue is a SecYEG determinant for the endogenous proteins ATP synthase subunits a and b and the TatC subunit of the Tat translocase. These findings provide deeper insights into how pathways are selected for the insertion of proteins into the Escherichia coli inner membrane. PMID- 23355472 TI - Conserved structural chemistry for incision activity in structurally non homologous apurinic/apyrimidinic endonuclease APE1 and endonuclease IV DNA repair enzymes. AB - Non-coding apurinic/apyrimidinic (AP) sites in DNA form spontaneously and as DNA base excision repair intermediates are the most common toxic and mutagenic in vivo DNA lesion. For repair, AP sites must be processed by 5' AP endonucleases in initial stages of base repair. Human APE1 and bacterial Nfo represent the two conserved 5' AP endonuclease families in the biosphere; they both recognize AP sites and incise the phosphodiester backbone 5' to the lesion, yet they lack similar structures and metal ion requirements. Here, we determined and analyzed crystal structures of a 2.4 A resolution APE1-DNA product complex with Mg(2+) and a 0.92 A Nfo with three metal ions. Structural and biochemical comparisons of these two evolutionarily distinct enzymes characterize key APE1 catalytic residues that are potentially functionally similar to Nfo active site components, as further tested and supported by computational analyses. We observe a magnesium water cluster in the APE1 active site, with only Glu-96 forming the direct protein coordination to the Mg(2+). Despite differences in structure and metal requirements of APE1 and Nfo, comparison of their active site structures surprisingly reveals strong geometric conservation of the catalytic reaction, with APE1 catalytic side chains positioned analogously to Nfo metal positions, suggesting surprising functional equivalence between Nfo metal ions and APE1 residues. The finding that APE1 residues are positioned to substitute for Nfo metal ions is supported by the impact of mutations on activity. Collectively, the results illuminate the activities of residues, metal ions, and active site features for abasic site endonucleases. PMID- 23355474 TI - Improved Bloch-Siegert based B1 mapping by reducing off-resonance shift. AB - An MRI method based on the Bloch-Siegert (BS) shift phenomenon was recently proposed as a fast and precise way to map a radio frequency (RF) transmit field (B1(+) field). For MRI at high field, the mapping sensitivity of this approach was limited by tissue heating associated with a BS irradiation pulse. To mitigate this, we investigated the possibility of lowering the off-resonance frequency of this pulse since theoretical analysis indicated that the sensitivity of Bloch Siegert based B1(+) mapping could be substantially improved when irradiating closer to resonance. Using optimized irradiation pulse shape and gradient crushers to minimize direct excitation effects, in vivo experiments on human brains at 7 T confirmed improved sensitivity with this approach. Improved sensitivity translated into an 80% reduction in B1(+) estimation errors without increasing tissue heating. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. PMID- 23355475 TI - The National Cancer Institute best case series program: a summary of cases of cancer patients treated with unconventional therapies in India. AB - OBJECTIVES: The National Cancer Institute (NCI) Best Case Series (BCS) Program provides an independent review of medical records, imaging, and pathology of cancer patients treated with unconventional therapies. The goal of the NCI BCS Program is to identify preliminary evidence of tumor regression and assess whether there is sufficient evidence to move forward with NCI-initiated research. The objective was to review case reports submitted by 4 practitioners from India who used ayurvedic and homeopathic therapies to treat cancer. DESIGN: Retrospective review of case reports of 4 practitioners from India who used ayurvedic and homeopathic therapies to treat cancer. RESULTS: A total of 68 cases were submitted to the NCI BCS Program. Fifty-one percent of the cases represented homeopathy and 49% ayurveda. Of the 68 cases, 32 (47%) of the cases were collectively designated as "persuasive" (P) or "supportive"(S), and 36 (53%) as "not evaluable." Forty-one (60%) patients did not have any prior conventional treatment. CONCLUSION: The challenge for submitters rests in their ability to supply sufficient documentation for the NCI BCS Program. The NCI BCS Program represents a unique avenue for the rigorous evaluation of "best cases" to identify complementary and alternative medicine modalities that are promising for prospective preclinical evaluation or prospective research. PMID- 23355476 TI - Exogenous high-mobility group box 1 protein prevents postinfarction adverse myocardial remodeling through TGF-beta/Smad signaling pathway. AB - High-mobility group box 1 (HMGB1) has been reported to attenuate ventricular remodeling, but its mechanism remains mostly unresolved. Transforming growth factor-beta (TGF-beta) is a crucial mediator in the pathogenesis of post infarction remodeling. Our study focused on the effects of HMGB1 on ventricular remodeling, and explored whether or not these effects were depended upon the TGF beta signaling pathway. Rats underwent coronary artery ligation. An intramyocardium injection of phosphate buffered saline (PBS) with or without HMGB1 was administered 3 weeks after myocardial infarction (MI). At 4 weeks after the treatment, HMGB1 significantly increased the left ventricular ejection fraction (LVEF) (P < 0.05), decreased the left ventricular end diastolic dimension (LVEDD; P < 0.05), left ventricular end systolic dimension (LVESD) (P < 0.05) and the infarct size (P < 0.05) compared with control group. The expressions of collagen I, collagen III, and tissue inhibitor of metalloproteinase 2 (TIMP2) were also decreased, while the matrix metalloproteinases 2 (MMP2) and MMP9 expressions were upregulated by HMGB1 injection (P < 0.05) compared with control group. No effect on TIMP3 was observed. Furthermore, TGF-beta1 and phosphor-Smad2 (p-Smad2) were significantly suppressed and Smad7 was increased in HMGB1-treated group (P < 0.05) compared with control group, no effects on p-Smad3 and p-p38 were observed. HMGB1 also upregulated Smad 7 expression and decreased the level of collagen I on cardiac fibroblasts (P < 0.05). Silencing of Smad7 gene by small interfering RNA abolished the fibrogenic effects of HMGB1 on cardiac fibroblasts (P < 0.05). These finding suggested that HMGB1 injection modulated ventricular remodeling may function through the possible inhibition of TGF-beta/Smad signaling pathway. PMID- 23355477 TI - Waiting times and socioeconomic status. Evidence from Norway. AB - We investigate whether socioeconomic status, measured by income and education, affects waiting time when controls for severity and hospital-specific conditions are included. We also examine which aspects of the hospital supply (attachment to local hospital, traveling time, or choice of hospital) matter most for unequal treatment of different socioeconomic groups. The study uses administrative data from all elective inpatient and outpatient stays in somatic hospitals in Norway. The main results are that we find very little indication of discrimination with regard to income and education when both severity and aspects of hospital supply are controlled for. This result holds for both men and women. PMID- 23355478 TI - Boron carbides as efficient, metal-free, visible-light-responsive photocatalysts. PMID- 23355479 TI - Alkyne metathesis on the rise. AB - The early years of alkyne metathesis were marked by a somewhat ironic state of affairs: the proposed mechanism was swiftly validated and more than one effective catalyst became available shortly after the discovery of this transformation; surprisingly, however, the impact on synthesis remained very limited for a long period of time. Recent advances, however, suggest that this situation is about to change: the remarkable activity, functional-group tolerance, and reliability of the latest generation of catalysts open the door for highly advanced applications. The resulting (cyclo)alkynes are amenable to numerous postmetathetic transformations, which diversify the product portfolio and bring many different structural motifs into reach. Since the catalysts have also evolved from the glovebox to the benchtop, there should be little barrier left for a wider use of this reaction in organic synthesis. PMID- 23355480 TI - Efficient stacking on protein amide fragments. AB - The less polar pi-surface of protein amide groups is exposed in many receptor binding sites, either as part of the backbone or in Gln/Asn side chains. Using quantum chemical calculations and Protein Data Bank (PDB) searches on model systems, we investigate the energetics and geometric preferences for the stacking on amide groups of a large number of heteroarenes that are relevant to medicinal chemistry. From this study, we discern that the stacking energy of an aromatic ligand substituent can be improved by: 1) orienting the fragment dipole vector such that it is aligned in an antiparallel fashion with the dipole of the interacting protein amide group, 2) increasing its dipole moment, and 3) decreasing its pi-electron density. These guidelines should be helpful to more rationally exploit this interaction type in future structure-based drug design. PMID- 23355481 TI - Longitudinal evaluation of hepatic lipid deposition and composition in ob/ob and ob/+ control mice. AB - Obesity is associated with insulin resistance (IR) and hepatosteatosis. Understanding the link between IR and hepatosteatosis could be relevant to chronic clinical outcomes. The objective of this study was to quantitatively assess lipid deposition (fractional lipid mass, fLM) and composition (fraction of polyunsaturated lipids, fPUL and mean chain length, MCL) in livers of ob/ob mice, a genetic model of obesity and mild diabetes, and ob/+ heterozygous control animals in a noninvasive manner using (1) H-MRS at 9.4T. For accurate quantification, intensity values were corrected for differences in T2 values while T1 effects were considered minimal due to the long TR values used. Values of fLM, fPUL and MCL were derived from T2 -corrected signal intensities of lipids and water resonance. Hepatic lipid signals were compared with fasted plasma insulin, glucose and lipid levels. Statistically significant correlations between fPUL and fasting plasma insulin/glucose levels were found in adolescent ob/ob mice. A similar correlation was found between fLM and fasting plasma insulin levels; however, the correlation between fLM and fasting plasma glucose levels was less obvious in adolescent ob/ob mice. These correlations were lost in adult ob/ob mice. The study showed that in adolescent ob/ob mice, there was an obvious link between lipid deposition/composition in the liver and plasma insulin/glucose levels. This correlation was lost in adult animals, probably due to the limited lipid storage capacity of the liver. PMID- 23355482 TI - Effect of sodium hypochlorite under several formulations on root canal dentin microhardness. AB - AIM: The aim of the present study was to evaluate the effect of three different formulations of sodium hypochlorite on the microhardness of root canal dentin in cervical and apical segments. METHODS: Twenty-four extracted human teeth had their roots sectioned along their long axes in a buccolingual direction. One half of each root was selected, and transversely sectioned resulting in two segments, cervical and apical, with similar lengths. The specimens were divided into three groups (n = 16), according to the sodium hypochlorite formulation used: (a) group 1, 2.5% sodium hypochlorite; (b) group 2, Chlor-XTRA; and (c) group 3, 5.5% sodium hypochlorite gel. These groups were subdivided in two subgroups (n = 8): cervical and apical root segments. Before testing the substances, dentin microhardness was measured on each section, 100 MUm from the root canal with a Knoop tester. After 15 min of application, a new measurement was performed on each segment. Data were collected and registered for statistical treatment. RESULTS: In both segments, the substances reduced dentin microhardness. No differences were observed between the groups, independent of the analyzed segment (P > 0.05). CONCLUSIONS: All substances reduced dentin microhardness. Chlor-XTRA and 5.5% sodium hypochlorite gel promoted a reduction similar to the 2.5% sodium hypochlorite solution. PMID- 23355483 TI - Pre-osteoblastic cell response on three-dimensional, organic-inorganic hybrid material scaffolds for bone tissue engineering. AB - Engineering artificial scaffolds that enhance cell adhesion and growth in three dimensions is essential to successful bone tissue engineering. However, the fabrication of three-dimensional (3D) tissue scaffolds exhibiting complex micro- and nano-features still remains a challenge. Few materials can be structured in three dimensions, and even those have not been characterized for their mechanical and biological properties. In this study, we investigate the suitability of three novel materials of different chemical compositions in bone tissue regeneration: a hybrid material consisting of methacryloxypropyl trimethoxysilane and zirconium propoxide, a hybrid organic-inorganic material of the above containing 50 mole% 2 (dimethylamino)ethyl methacrylate (DMAEMA) and a pure organic material based on polyDMAEMA. More specifically, we study the mechanical properties of the aforementioned materials and evaluate the biological response of pre-osteoblastic cells on them. We also highlight the use of a 3D scaffolding technology, Direct femtosecond Laser Writing (DLW), to fabricate complex structures. Our results show that, while all three investigated materials could potentially be used as biomaterials in tissue engineering, the 50% DMAEMA composite exhibits the best mechanical properties for structure fabrication with DLW and strong biological response. PMID- 23355484 TI - Comparison and validation of genomic predictors for anticancer drug sensitivity. AB - BACKGROUND: An enduring challenge in personalized medicine lies in selecting the right drug for each individual patient. While testing of drugs on patients in large trials is the only way to assess their clinical efficacy and toxicity, we dramatically lack resources to test the hundreds of drugs currently under development. Therefore the use of preclinical model systems has been intensively investigated as this approach enables response to hundreds of drugs to be tested in multiple cell lines in parallel. METHODS: Two large-scale pharmacogenomic studies recently screened multiple anticancer drugs on over 1000 cell lines. We propose to combine these datasets to build and robustly validate genomic predictors of drug response. We compared five different approaches for building predictors of increasing complexity. We assessed their performance in cross validation and in two large validation sets, one containing the same cell lines present in the training set and another dataset composed of cell lines that have never been used during the training phase. RESULTS: Sixteen drugs were found in common between the datasets. We were able to validate multivariate predictors for three out of the 16 tested drugs, namely irinotecan, PD-0325901, and PLX4720. Moreover, we observed that response to 17-AAG, an inhibitor of Hsp90, could be efficiently predicted by the expression level of a single gene, NQO1. CONCLUSION: These results suggest that genomic predictors could be robustly validated for specific drugs. If successfully validated in patients' tumor cells, and subsequently in clinical trials, they could act as companion tests for the corresponding drugs and play an important role in personalized medicine. PMID- 23355485 TI - Effects of sediment composition on cadmium bioaccumulation in the clam Meretrix meretrix Linnaeus. AB - Sediment particulates can be ingested by benthic animals, and the bioavailability of associated metals strongly depends on their speciation in the sediments. Different sedimentary components have distinct physiochemical characteristics and result in different biological responses from animals. Therefore, the bioaccumulation of particle-bound trace metals may be different. In the present study, bioaccumulation of cadmium adsorbed on various (hydr)oxide minerals, that is, ferric hydroxide, aluminum hydroxide, and manganese dioxide, in the clam Meretrix meretrix Linnaeus was studied. The results showed that the accumulation rate of cadmium varied for different mineral-adsorbed cadmium. The bioaccumulation of metal (hydr)oxide-adsorbed cadmium in M. meretrix followed the order Cd-MnO2 > Cd-Al(OH)3 > Cd-Fe(OH)3 . The type of mineral determines both the assimilation efficiency and ingestion rate, and consequently controls the bioaccumulation of adsorbed cadmium. PMID- 23355486 TI - A branched domino reaction: asymmetric organocatalytic two-component four-step synthesis of polyfunctionalized cyclohexene derivatives. PMID- 23355487 TI - A comparison of scoring models for computerised mental health screening for federal prison inmates. AB - BACKGROUND: There are high rates of mental disorder in correctional environments, so effective mental health screening is needed. Implementation of the computerised mental health screen of the Correctional Service of Canada has led to improved identification of offenders with mental health needs but with high rates of false positives. AIMS: The goal of this study is to evaluate the use of an iterative classification tree (ICT) approach to mental health screening compared with a simple binary approach using cut-off scores on screening tools. METHODS: A total of 504 consecutive admissions to federal prison completed the screen and were also interviewed by a mental health professional. Relationships between screening results and more extended assessment and clinical team discussion were tested. RESULTS: The ICT was more parsimonious in identifying probable 'cases' than standard binary screening. ICT was also highly accurate at detecting mental health needs (AUC=0.87, 95% CI 0.84-0.90). The model identified 118 (23.4%) offenders as likely to need further assessment or treatment, 87% of whom were confirmed cases at clinical interview. Of the 244 (48.4%) offenders who were screened out, only 9% were clinically assessed as requiring further assessment or treatment. Standard binary screening was characterised by more false positives and a comparable false negative rate. CONCLUSIONS: The use of ICTs to interpret screening data on the mental health of prisoners needs further evaluation in independent samples in Canada and elsewhere. This first evaluation of the application of such an approach offers the prospect of more effective and efficient use of the scarce resource of mental health services in prisons. Although not required, the use of computers can increase the ease of implementing an ICT model. PMID- 23355488 TI - Polycyclic peptide therapeutics. AB - Owing to their excellent binding properties, high stability, and low off-target toxicity, polycyclic peptides are an attractive molecule format for the development of therapeutics. Currently, only a handful of polycyclic peptides are used in the clinic; examples include the antibiotic vancomycin, the anticancer drugs actinomycin D and romidepsin, and the analgesic agent ziconotide. All clinically used polycyclic peptide drugs are derived from natural sources, such as soil bacteria in the case of vancomycin, actinomycin D and romidepsin, or the venom of a fish-hunting coil snail in the case of ziconotide. Unfortunately, nature provides peptide macrocyclic ligands for only a small fraction of therapeutic targets. For the generation of ligands of targets of choice, researchers have inserted artificial binding sites into natural polycyclic peptide scaffolds, such as cystine knot proteins, using rational design or directed evolution approaches. More recently, large combinatorial libraries of genetically encoded bicyclic peptides have been generated de novo and screened by phage display. In this Minireview, the properties of existing polycyclic peptide drugs are discussed and related to their interesting molecular architectures. Furthermore, technologies that allow the development of unnatural polycyclic peptide ligands are discussed. Recent application of these technologies has generated promising results, suggesting that polycyclic peptide therapeutics could potentially be developed for a broad range of diseases. PMID- 23355490 TI - Synthesis of fluorinated building blocks by transition-metal-mediated hydrodefluorination reactions. AB - The activation and functionalization of carbon-fluorine bonds can be considered as a major challenge in organometallic chemistry. The growing demand for means to introduce fluorine into new materials or into biologically active molecules has inspired the development of diverse synthetic strategies. Hydrodefluorination is regarded as a promising approach to access partially fluorinated building blocks from readily available perfluorinated bulk chemicals. We provide an overview of transition-metal-based complexes and catalysts that were developed to mediate hydrodefluorination reactions. Special emphasis will be placed on discussing the underlying mechanistic patterns and their impact on scope and selectivity. In addition, future requirements for further developing this field will be highlighted. PMID- 23355489 TI - Ataxia telangiectasia mutated (ATM) is dispensable for endonuclease I-SceI induced homologous recombination in mouse embryonic stem cells. AB - Ataxia telangiectasia mutated (ATM) is activated upon DNA double strand breaks (DSBs) and phosphorylates numerous DSB response proteins, including histone H2AX on serine 139 (Ser-139) to form gamma-H2AX. Through interaction with MDC1, gamma H2AX promotes DSB repair by homologous recombination (HR). H2AX Ser-139 can also be phosphorylated by DNA-dependent protein kinase catalytic subunit and ataxia telangiectasia- and Rad3-related kinase. Thus, we tested whether ATM functions in HR, particularly that controlled by gamma-H2AX, by comparing HR occurring at the euchromatic ROSA26 locus between mouse embryonic stem cells lacking either ATM, H2AX, or both. We show here that loss of ATM does not impair HR, including H2AX dependent HR, but confers sensitivity to inhibition of poly(ADP-ribose) polymerases. Loss of ATM or H2AX has independent contributions to cellular sensitivity to ionizing radiation. The ATM-independent HR function of H2AX requires both Ser-139 phosphorylation and gamma-H2AX/MDC1 interaction. Our data suggest that ATM is dispensable for HR, including that controlled by H2AX, in the context of euchromatin, excluding the implication of such an HR function in genomic instability, hypersensitivity to DNA damage, and poly(ADP-ribose) polymerase inhibition associated with ATM deficiency. PMID- 23355491 TI - Funding HIV-vaccine research in developing countries-what is wrong with IAVI's recommendation? AB - The International AIDS Vaccine Initiative recommends targeting resources to research institutions in developing countries in order to accelerate the development of an effective HIV vaccine. In contrast, this paper shows that neither lump-sum nor in-kind transfers are an effective policy. We analyze several financing mechanisms as a means to overcome the lack of depth in HIV vaccine research in a non-cooperative framework. At first, we point to cases in which financial support is actually counterproductive. Then we analyze whether in kind transfers are preferable to lump-sum transfers. Even if donors prefer aid in kind because the incentives for moral hazard of recipients can be reduced, we demonstrate that it is effective only if recipients have cost advantages. PMID- 23355492 TI - Two-year clinical study on postoperative pulpal complications arising from the absence of a glass-ionomer lining in deep occlusal resin-composite restorations. AB - AIM: To observe the effects of glass-ionomer cement (GIC) lining on the risk of pulpal complications in deep occlusal cavities with resin-based restorations. METHODS: Fifty-three patients, aged 18-30 years, who had one or two deep occlusal carious lesions (>=3 mm in depth) in molars, were recruited. Dental caries were removed, and the prepared cavity was restored with resin composite using one of two restorative procedures: (a) without GIC lining; and (b) with (resin-modified) GIC lining. Restored teeth were evaluated for any pulpal complications (subjective symptoms, objective signs or loss of tooth vitality) at 1 month (baseline), 1 year, and 2 years after restoration. RESULTS: After excluding shallow cavities, 31 restorations without GIC lining, and 31 restorations with GIC lining, were placed and recalled at baseline without any pulpal complications. At the 1- and 2-year recalls, six patients who had restorations in group 1, and 13 in group 2, had dropped out. None of the remaining teeth in the two groups exhibited pulpal complications at either recall period, regardless of GIC lining placement. CONCLUSIONS: The absence of GIC lining does not increase the risk of pulpal complications in deep occlusal cavities restored with resin based restorations in either the short or long term. PMID- 23355493 TI - Occupational exposure to anaesthetic gases and high-frequency audiometry. AB - OBJECTIVES: Occupational exposure to anaestethic gases has been suggested to induce auditory damages. The aim of this study is to investigate high-frequency audiometric responses in subjects exposed to anaesthetic gases, in order to highlight the possible effects on auditory system. METHODS: The study was performed on a sample of 30 medical specialists of Messina University Anaesthesia and Intensive care. We have used tonal audiometry as well as high-frequency one. We have compared the responses with those obtained in a similar control group not exposed to anaesthetic gases. Results were compared statistically. RESULTS: Results show a strong correlation (p = 0.000) between left and right ear responses to all the audiometric tests. The exposed and the control group run though the standard audiometry analysis plays different audiometric responses up only to higher frequencies (2000 HZ p = 0.009 and 4000 Hz p = 0.04); in high frequency audiometry, as all other frequencies, the attention is drew to the fact that the sample groups distinguish themselves in a significantly statistic way (10,000 Hz p = 0.025, 12,000 Hz p = 0.008, 14,000 Hz p = 0.026, 16,000 Hz p = 0.08). The highest values are the ones related to exposed subjects both in standard (2000 Hz p = 0.01, 4000 Hz p = 0.02) and in high-frequency audiometry (10,000 Hz p = 0.011, 12,000 Hz p = 0.004, 14,000 Hz p = 0.012, 16,000 Hz p = 0.004). CONCLUSION: Results, even if preliminary and referred to a low-range sample, show an involvement of the anatomic structure responsible for the perception of high-frequency audiometric responses in subjects exposed to anaesthetic gases. PMID- 23355494 TI - Relation between respiratory function tests and life habits of the university students. AB - Among the university students especially in adolescence period, smoking habits and unhealthy lifestyles are major problems in social life. In this study, it is intended to reveal smoking habits and lifestyles of the students from Suleyman Demirel University and to determine the effects of smoking and lifestyles on pulmonary functions. MATERIALS AND METHODS: Participants were 94 university students who were getting formal education in the Suleyman Demirel University central campus. Data were analysed by analysis of variance and chi-square tests. For all analysis, p value of <0.05 was considered significant. RESULTS: Students' mean age was 19.9 +/- 0.9 years, and of all the students 74 (78.7%) were undergraduate students; remaining 20 (21.3%) were graduate students. Of all the students, 27 (28.7%), which comprised the largest group of the students, were living in state dormitory. Body mass index (BMI) was examined for the study group; according to BMI, body weight was generally within normal limits but 17.39% of girls' were found to be underweight. CONCLUSIONS: Respiratory parameters can be affected by many factors. Smoking habit of university students can be prevented, and it is an important point that they have a healthy lifestyle both for their own health and for future generations. PMID- 23355495 TI - 3D interconnected porous HA scaffolds with SiO2 additions: effect of SiO2 content and macropore size on the viability of human osteoblast cells. AB - 3D interconnected porous scaffolds of HA and HA with various additions of SiO2 were fabricated using a polymeric template technique, to make bioceramic scaffolds consisting of macrostructures of the interconnected macropores. Three different sizes of the polyurethane template were used in the fabrication process to form different size interconnected macropores, to study the effect of pore size on human osteoblast cell viability. The template used allowed fabrication of scaffolds with pore sizes of 45, 60, and 75 ppi, respectively. Scanning microscopy was used extensively to observe the microstructure of the sintered samples and the characteristics of cells growing on the HA surfaces of the interconnected macropores. It has been clearly demonstrated that the SiO2 addition has influenced both the phase transformation of HA to TCP (beta-TCP and alpha-TCP) and also affected the human osteoblast cell viability grown on these scaffolds. PMID- 23355496 TI - The childhood executive function inventory: confirmatory factor analyses and cross-cultural clinical validity in a sample of 8- to 11-year-old children. AB - OBJECTIVE: The aim was to investigate the psychometric characteristics of the French adaptation of the Childhood Executive Functioning Inventory (CHEXI) in children and to explore the cross-cultural validity of the CHEXI in discriminating between children with ADHD and controls in two culturally different samples (Belgian and Swedish). METHOD: Study I included normally developing children (n = 242), whereas Study II included both children diagnosed with ADHD (n = 87) and controls (n = 87). CHEXI ratings were collected from parents. RESULTS: Confirmatory factor analyses replicated the two-factor solution, referred to as inhibition and working memory, which had been identified previously. Both subscales had good psychometric properties. Furthermore, the CHEXI was found to discriminate, with high sensitivity and specificity, between children with ADHD and controls in both cultural samples. CONCLUSION: The CHEXI can be considered as a valuable screening measure for ADHD in children, but the cross-cultural clinical implications of ratings have to be considered. PMID- 23355497 TI - Criminal thinking styles and emotional intelligence in Egyptian offenders. AB - BACKGROUND: The Psychological Inventory of Criminal Thinking Styles (PICTS) has been applied extensively to the study of criminal behaviour and cognition. Increasingly growing evidence indicates that criminal thinking styles vary considerably among individuals, and these individual variations appear to be crucial for a full understanding of criminal behaviour. AIMS: This study aimed to examine individual differences in criminal thinking as a function of emotional intelligence. METHODS: A group of 56 Egyptian male prisoners completed the PICTS and Bar-On Emotional Quotient Inventory (EQ-i). The correlations between these assessments were examined using a series of Pearson correlations coefficients, with Bonferroni correction. RESULTS: General criminal thinking, reactive criminal thinking and five criminal thinking styles (mollification, cutoff, power orientation, cognitive indolence and discontinuity) negatively correlated with emotional intelligence. On the other hand, proactive criminal thinking and three criminal thinking styles (entitlement, superoptimism and sentimentality) did not associate with emotional intelligence. CONCLUSIONS: Emotional intelligence is an important correlate of individual differences in criminal thinking, especially its reactive aspects. Practical implications of this suggestion were discussed. PMID- 23355499 TI - Stretchable conductors based on silver nanowires: improved performance through a binary network design. PMID- 23355498 TI - Synergism between obesity and alcohol in increasing the risk of hepatocellular carcinoma: a prospective cohort study. AB - Obesity and alcohol interact to increase the risk of death from liver failure in men. In the present study, we aimed to examine whether obesity and alcohol were multiplicative or additive in increasing the risk of hepatocellular carcinoma (HCC) in both men and women. We conducted a prospective, population-based study of 23,712 Taiwanese residents (50.3% men) from 7 townships who underwent an evaluation for liver disease and were followed for 11.6 years for incident HCC. The mean age was 47 (standard deviation, 10) years and the mean body mass index (weight (kg)/height (m)(2)) was 24 (standard deviation, 3). Overall, 305 cases of HCC were identified over 275,126 person-years of follow-up. Age, male sex, alcohol drinking, cigarette smoking, elevated alanine aminotransferase, serum hepatitis B surface antigen, anti-hepatitis C virus positivity, and diabetes mellitus were each statistically significant predictors of incident HCC in univariate analyses (P < 0.05). Alcohol use and obesity (body mass index >=30) showed a synergistic association with the risk of incident HCC in both unadjusted analyses (hazard ratio = 7.19, 95% confidence interval: 3.69, 14.00; P < 0.01) and multivariable-adjusted analyses (age, sex, smoking, serum alanine aminotransferase, serum hepatitis B surface antigen, anti-hepatitis C virus antibody, and diabetes mellitus) (hazard ratio = 3.82, 95% confidence interval: 1.94, 7.52; P < 0.01). Relative excess risks due to interaction, attributable proportion, and synergy index were 4.83, 0.67, and 4.53, respectively, suggesting a multiplicative interaction between alcohol use and obesity. Obesity and alcohol synergistically increase the risk of incident HCC. PMID- 23355500 TI - Antitumor and antiangiogenic active dendrimer/5-fluorouracil conjugates. AB - Antitumor and antiangiogenic active dendritic compounds conjugated with 5 fluorouracil (5-FU) were synthesized and characterized. First, the core structure based on ascorbic acid and dicarboxylic acid was synthesized, amidated with ethylenediamine. For the synthesis of higher generated dendrimer, it was reacted further with methyl acrylate to increase molecular weight through Michael addition reaction, followed by the continuous repeating amidation reaction, finally, used to synthesize covalently bound dendrimer/5-FU conjugates. The in vitro cytotoxicities of the conjugates was evaluated with mouse mammary carcinoma, mouse leukemia, and human histiocytic lymphoma as cancer cell lines and mouse liver cells as a normal cell line, and showed lower values than 5-FU. The in vivo antitumor activities of the conjugates against mice bearing sarcoma 180 tumor cell line were better than 5-FU. Especially, Second generated dendrimer (G-2)/5-FU conjugates showed excellent in vivo antitumor as well as antiangiogenic activities evaluated by the embryo chorioallantoic membrane assay due to slow hydrolysis rate and the amount of 5-FU released. PMID- 23355501 TI - Activation of multiple C-H bonds promoted by gold in AuNbO(3)(+) clusters. AB - Single, double, triple: Highly selective double H atom abstraction (HAA) from ethane and triple HAA from n-butane by AuNbO(3)(+) clusters have been characterized by mass spectrometry and DFT calculations. The multiple HAAs are initiated by oxygen-centered radicals and promoted by gold. The gold atoms act as electron acceptors during the triple HAAs and help to store a pair of valence electrons between Au and Nb atoms. PMID- 23355502 TI - Predicting outcomes of vocational rehabilitation in patients with brain tumours. AB - OBJECTIVE: The aim of this study was to examine the outcome of a vocational rehabilitation programme for patients with brain tumours and to determine whether the outcome could be predicted at point of referral to the service. METHODS: Data was collected for 34 patients with brain tumours referred to the Macmillan vocational rehabilitation service. Work status at baseline (time of referral) and at discharge was compared. Logistic regression analyses were computed to identify which variables (demographic, tumour and treatment, functional and vocational) predicted work status at discharge from the service. RESULTS: Significantly, more patients were working at discharge from the service than at baseline. Having at least some physical disability decreased the likelihood of being in work at discharge from the service. CONCLUSIONS: The vocational rehabilitation programme for brain tumour survivors showed significant improvement over time. Functional ability affected the likelihood of working to some extent. Vocational rehabilitation services should be available to patients with brain tumours and should focus on supporting patients wishing to return to or maintain their current work. However, more support for brain tumour patients with physical impairments is needed. PMID- 23355504 TI - Large-scale hierarchically structured conjugated polymer assemblies with enhanced electrical conductivity. AB - Stripes on a plane: A set of highly ordered microscopic stripes (purple; see scheme) were produced over a large area by using controlled evaporative self assembly in a cylinder-on-Si geometry of conjugated homopolymers or all conjugated diblock copolymer (P3BHT). The crystallinity of the as-prepared assemblies of P3BHT was greatly improved following chloroform vapor annealing, resulting in a fourfold increase in electrical conductivity. PMID- 23355505 TI - Separation of the role of treating clinician and expert. PMID- 23355506 TI - Isolation of Arthrobacter species from the phyllosphere and demonstration of their epiphytic fitness. AB - Bacteria of the genus Arthrobacter are common inhabitants of the soil environment, but can also be recovered from leaf surfaces (the phyllosphere). Using enrichment cultures on 4-chlorophenol, we succeeded in specifically isolating Arthrobacter bacteria from ground cover vegetation in an apple orchard. Based on 16S rRNA gene sequencing, the isolates were found to belong to at least three different species of Arthrobacter. Compared to the model bacterial epiphyte Pantoea agglomerans, the Arthrobacter isolates performed as well or even better in a standardized laboratory test of phyllosphere fitness. A similar performance was observed with the well-characterized soil isolate Arthrobacter chlorophenolicus A6. These findings suggest that the frequently reported presence of Arthrobacter strains on plant foliage can be explained by the capacity to multiply and persist in the phyllosphere environment. As bacteria from the genus Arthrobacter are known for their ability to degrade a wide variety of organic pollutants, their high phyllosphere competency marks them as a promising group for future studies on phyllosphere-based bioremediation, for example, as foliar bioaugmentation on ground cover or buffer-zone vegetation to prevent pesticides from reaching soil, surface-, or groundwater. PMID- 23355507 TI - The multiradical character of one- and two-dimensional graphene nanoribbons. AB - When is an acene stable? The pronounced multiradical character of graphene nanoribbons of different size and shape was investigated with high-level multireference methods. Quantitative information based on the number of effectively unpaired electrons leads to specific estimates of the chemical stability of graphene nanostructures. PMID- 23355508 TI - Chitosan electrodeposition for microrobotic drug delivery. AB - A method to functionalize steerable magnetic microdevices through the co electrodeposition of drug loaded chitosan hydrogels is presented. The characteristics of the polymer matrix have been investigated in terms of fabrication, morphology, drug release and response to different environmental conditions. Modifications of the matrix behavior could be achieved by simple chemical post processing. The system is able to load and deliver 40-80 MUg cm(-2) of a model drug (Brilliant Green) in a sustained manner with different profiles. Chitosan allows a pH responsive behavior with faster and more efficient release under slightly acidic conditions as can be present in tumor or inflamed tissue. A prototype of a microrobot functionalized with the hydrogel is presented and proposed for the treatment of posterior eye diseases. PMID- 23355510 TI - Head progression distance in prolonged second stage of labor: relationship with mode of delivery and fetal head station. AB - OBJECTIVE: To evaluate the clinical significance of fetal head progression distance (HPD), measured by transperineal ultrasound, during prolonged second stage of labor. METHODS: In this prospective study, a single operator, who was blinded to the results of the digital examination, assessed using transperineal ultrasound women at >= 37 weeks of gestation with failure to progress in the second stage of labor. Patients had an empty urinary bladder and the examination was performed during maternal pushing. HPD was defined as the length of the line perpendicular to the infrapubic line that would connect it to the lowest part of the fetal bony skull. We analyzed associations between HPD and digital examination of fetal head station, fetomaternal characteristics, mode of delivery and perinatal outcome. RESULTS: Sixty-five patients in prolonged second stage of labor participated in the study. The overall mean HPD was 6.50 (+/- 1.35; 95% CI, 6.16-6.83) cm. No correlation was found between HPD and head position or mode of delivery, but HPD was positively correlated with fetal head station and neonatal head circumference measured after delivery. Logistic regression and receiver operating characteristics curve analysis demonstrated no significant predictive value of HPD with respect to mode of delivery. CONCLUSION: Although HPD in prolonged second stage of labor could not predict mode of delivery, it may have a role as an ancillary tool for fetal head station assessment. PMID- 23355509 TI - Dynamic and reversible surface topography influences cell morphology. AB - Microscale and nanoscale surface topography changes can influence cell functions, including morphology. Although in vitro responses to static topography are novel, cells in vivo constantly remodel topography. To better understand how cells respond to changes in topography over time, we developed a soft polyacrylamide hydrogel with magnetic nickel microwires randomly oriented in the surface of the material. Varying the magnetic field around the microwires reversibly induced their alignment with the direction of the field, causing the smooth hydrogel surface to develop small wrinkles; changes in surface roughness, DeltaRRMS , ranged from 0.05 to 0.70 MUm and could be oscillated without hydrogel creep. Vascular smooth muscle cell morphology was assessed when exposed to acute and dynamic topography changes. Area and shape changes occurred when an acute topographical change was imposed for substrates exceeding roughness of 0.2 MUm, but longer-term oscillating topography did not produce significant changes in morphology irrespective of wire stiffness. These data imply that cells may be able to use topography changes to transmit signals as they respond immediately to changes in roughness. PMID- 23355511 TI - Synthetic octacalcium phosphate-enhanced reparative dentine formation via induction of odontoblast differentiation. AB - Synthetic octacalcium phosphate (OCP) has been suggested to be a useful biomaterial for the regeneration of hard tissues, including bone. However, it remains unknown whether OCP induces dentine formation by dental pulp. We investigated biomineralization of dental pulp exposed to synthetic OCP in vitro and in vivo. When dental pulp was exposed directly to OCP, rapid formation of reparative dentine (RD) was induced and expression of dentine sialoprotein synthesis was observed in dental pulp adjacent to newly synthesized RD. OCP inhibited the proliferation of rat pulp cells and also promoted their odontoblastic differentiation in vitro, as alkaline phosphatase activity, mineralization of pulp cells and the expression level of dentine sialophosphoprotein were enhanced. Direct contact between OCP and pulp cells is required for OCP to exhibit its effects in vitro. The expression level of Runx2, a transcription factor whose downregulation is closely related to odontoblast differentiation, was downregulated in pulp cells cultured with OCP. Structural changes of OCP during culture were determined by Fourier transform infrared spectroscopy. OCP tended to be converted to carbonate hydroxyapatite after incubation with or without pulp cells, which may be analogous to biological apatite crystals. Taken together, our data suggest that synthetic OCP supports RD formation by dental pulp and downregulation of Runx2 may be involved in that stimulatory activity. Furthermore, OCP-apatite conversion is involved in this stimulatory capacity of OCP. PMID- 23355513 TI - Tunable substrates unveil chemical complementation of a genetic cell migration defect. AB - Cell migration is dependent on a number of physical and chemical parameters of the substrate that influence cellular signaling events as cell surface receptors interact with the substrate. These events can strengthen or loosen the contact of the cell with its environment and need to be orchestrated for efficient motility. A set of tunable substrates was used in combination with quantitative imaging to probe for potentially subtle differences in genetically modified and chemically treated rapidly migrating cells. As model cell, Plasmodium sporozoites were used, the forms of malaria parasites transmitted by the mosquito to the host. Sporozoites lacking a substrate-binding surface protein moved on different surfaces with consistently lower efficiency and were more sensitive to adhesion ligand spacing than wild type sporozoites. Addition of an actin filament stabilizing chemical agent temporarily increased sporozoite motility on soft but not on hard substrates. Defined conditions were found where the chemical completely compensates the reduced migration capacity of the genetically modified parasites. As the onset of motility was delayed for sporozoites on unfavourable gels it is suggested that the parasite can slowly adjust to environmental elasticity, possibly by adapting the interplay between surface adhesins and actin filament dynamics. This demonstrates the utility of tunable substrates to dissect molecular function in cell adhesion and motility. PMID- 23355512 TI - Hydrogel-PLGA delivery system prolongs 2-methoxyestradiol-mediated anti-tumor effects in osteosarcoma cells. AB - Osteosarcoma is a bone tumor that affects children and young adults. 2 Methoxyestradiol (2-ME), a naturally occurring estrogen metabolite, kills osteosarcoma cells, but does not affect normal osteoblasts. In order to effectively target osteosarcoma and improve the therapeutic index of the drug 2 ME, we have encapsulated 2-ME in a composite of oligo-(polyethylene glycol) fumarate (OPF) hydrogel and poly (lactic-co-glycolic acid) (PLGA) microspheres and investigated the effect of polymer composition on 2-ME release kinetics and osteosarcoma cell survival. The in vitro study shows that 2-ME can be released in a controlled manner over 21-days. The initial burst releases observed on day 1 were 50% and 32% for OPF and OPF/PLGA composites, respectively. The extended release kinetics show that 100% of the encapsulated 2-ME is released by day 12 from OPF, whereas the OPF/PLGA composites showed a release of 85% on day 21. 2-ME released from the polymers was biologically active and blocked osteosarcoma cell proliferation in vitro. Also, comparison of 2-ME delivery in osteosarcoma cells in culture, shows that direct treatment has no effect after 3 days, whereas polymer-mediated delivery produces anti-tumor effects that could be sustained for 21 days. These findings show that the OPF and PLGA polymeric system may prove to be useful in controlled and sustained delivery of 2-ME and could be further explored in the treatment of osteosarcoma. PMID- 23355514 TI - Editorial: molecular endocrinology articles in the spotlight for February 2013. PMID- 23355516 TI - Fatal Wedelia glauca intoxication in calves following natural exposure. AB - A group of 342 beef calves, corralled in the Patagonia region of Argentina, were fed alfalfa hay that had been inadvertently contaminated with Wedelia glauca. A total of 147 (43%) calves died within 4 days. Pathologic findings in 2 calves were diffuse centrilobular hepatic necrosis and hemorrhage with edema in the gallbladder, common bile duct, and choledochoduodenal junction. Epidermal fragments of W. glauca were identified in rumen contents by microscopy. Intact W. glauca plants and leaf fragments were found in the hay. Patches of defoliated W. glauca were also identified in the alfalfa pasture from which the hay had been baled. PMID- 23355517 TI - Spontaneous histologic lesions of the adult naked mole rat (Heterocephalus glaber): a retrospective survey of lesions in a zoo population. AB - Naked mole rats (NMRs; Heterocephalus glaber) are highly adapted, subterranean, eusocial rodents from semiarid regions of the eastern horn of Africa and the longest-living rodent known with a maximum life span of up to 30 years. They are a unique model for aging research due to their physiology, extreme longevity, and, when compared to mice and rats, resistance to cancer. Published surveys of disease in NMRs are sparse. Captive colonies in zoological collections provide an opportunity to monitor spontaneous disease over time in a seminatural environment. This retrospective study describes common lesions of a zoo population over a 15-year period during which 138 adult NMRs were submitted for gross and histologic evaluation. Of these, 61 (44.2%) were male, 77 (55.8%) female, 45 (32.6%) died, and 93 (67.4%) were euthanized. The most frequent cause of death or reason for euthanasia was conspecific trauma (bite wounds) and secondary complications. Some common histologic lesions and their prevalence were renal tubular mineralization (82.6%), hepatic hemosiderosis (64.5%), bite wounds (63.8%), chronic progressive nephropathy (52.9%), and calcinosis cutis (10.1%). In sum, 104 (75.4%) NMRs had more than one of the most prevalent histologic lesions. No malignant neoplasms were noted; however, there was a case of renal tubular adenomatous hyperplasia with nuclear atypia and compression that in rats is considered a preneoplastic lesion. This retrospective study confirms the NMR's relative resistance to cancer in spite of development of other degenerative diseases and highlights the utility of zoological databases for baseline pathological data on nontraditional animal models. PMID- 23355518 TI - Lumbar vertebral body bone microstructural scaling in small to medium-sized strepsirhines. AB - Bone mass, architecture, and tissue mineral density contribute to bone strength. As body mass (BM) increases any one or combination of these properties could change to maintain structural integrity. To better understand the structural origins of vertebral fragility and gain insight into the mechanisms that govern bone adaptation, we conducted an integrative analysis of bone mass and microarchitecture in the last lumbar vertebral body from nine strepsirhine species, ranging in size from 42 g (Microcebus rufus) to 2,440 g (Eulemur macaco). Bone mass and architecture were assessed via uCT for the whole body and spherical volumes of interest (VOI). Allometric equations were estimated and compared with predictions for geometric scaling, assuming axial compression as the dominant loading regime. Bone mass, microarchitectural, and vertebral body geometric variables predominantly scaled isometrically. Among structural variables, the degree of anisotropy (Tb.DA) was the only parameter independent of BM and other trabecular architectural variables. Tb.DA was related to positional behavior. Orthograde primates had higher average Tb.DA (1.60) and more craniocaudally oriented trabeculae while lorisines had the lowest Tb.DA (1.25), as well as variably oriented trabeculae. Finally, lorisines had the highest ratio of trabecular bone volume to cortical shell volume (~3x) and while there appears to be flexibility in this ratio, the total bone volume (trabecular + cortical) scales isometrically (BM(1.23) , r(2) = 0.93) and appears tightly constrained. The common pattern of isometry in our measurements leaves open the question of how vertebral bodies in strepsirhine species compensate for increased BM. PMID- 23355519 TI - Diffusion tensor imaging of white matter tracts in the dog brain. AB - Diffusion weighted imaging sequences are now widely available on Magnetic Resonance Imaging (MRI) scanners. Diffusion Tensor Imaging (DTI) of the brain is able to show white matter tracts and is now commonly used in human medicine to study brain anatomy, tumors, structural pathways,... The purpose of this study was to show the interest of DTI to reveal the white matter fibers in the dogs' brain. DTI MR Images for this study were obtained with a 3 T system of 4 dogs euthanized for other reasons than neurological disorders. Combined fractional anisotropic (FA) and directional maps were obtained in the first 2 hours after death. The heads were amputated immediately after scanning and stored in 10% formalin until preparation for dissection. An experienced anatomist tracked white matter tracts with clinical relevance using the scanner software. The selected tracts were REFVIDume rendered and correlated with gross dissection. Using DTI we were able to track relevant neurological connections, such as the corticospinal tract, the optic and the cerebellar tract. The three dimensional anatomy is better presented using modern visualization techniques. DTI seems to be a valuable tool in order to present clinically relevant white matter tracts to neurological clinicians and researchers. PMID- 23355521 TI - Notch signaling: genetics and structure. AB - Receptors of the Notch family mediate cell-cell interactions during animal development, and aberrations in Notch signaling have been implicated in human disease. Studies in Caenorhabdits elegans have made essential contributions towards understanding the biological roles and molecular mechanism of this fundamental signaling system. A major development in the field since the original version of this chapter (LIN-12/Notch signaling in C. elegans) has been an explosion in information about the structural biology of Notch signaling; crystallographic determinations of structures, including structures of C. elegans components, have contributed much to the current understanding of molecular mechanism. Thus, here, we not only cover the genetics of Notch in C. elegans, focusing on conserved core components and modulators, we have also included structural information about these components, describing the key events occurring during ligand binding and transcriptional control of target genes. In addition to text, we include Tables listing core components and key modulators of the signaling pathway along with their orthologs in Drosophila and mammals, a Table listing validated target genes in various processes in C. elegans, and animated features to illustrate structural attributes. PMID- 23355522 TI - Ascaroside signaling in C. elegans. AB - Over the past 10 years, the relevance of small-molecule signaling for many aspects of C. elegans development and behavior has become apparent. One prominent group of small-molecule signals are the ascarosides, which control dauer entry and exit as well as a variety of sex-specific and social behaviors, including male attraction, hermaphrodite repulsion, olfactory plasticity, and aggregation. This wide range of biological functions is facilitated by a great diversity of ascaroside chemical structures. These are based on the sugar ascarylose, which is linked to fatty acid-like side chains of varying lengths and often decorated further with building blocks derived from amino acids, folate, and other primary metabolites. Different ascarosides or combinations of ascarosides mediate different phenotypes, and even small differences in chemical structures are often associated with strongly altered activity profiles. Additional complexity arises from concentration-dependent effects and synergism between different ascarosides. The ascarosides are sensed by several types of chemosensory head neurons, including the ASK, ASI, and ADL neurons as well as the male-specific CEM neurons. Ascaroside perception is mediated by diverse families of G-protein coupled membrane receptors that act upstream of conserved signal transduction pathways, including insulin/IGF-1 signaling and transforming growth factor beta (TGF-beta) signaling. Biosynthesis of the ascarosides appears to integrate input from several primary metabolic pathways, including peroxisomal beta-oxidation of long chain fatty acids and amino acid catabolism. Life stage, sex, as well as food availability and other environmental factors affect ascaroside biosynthesis, suggesting that ascaroside signaling communicates detailed information about life history and metabolic state. PMID- 23355523 TI - Novel KLK4 and MMP20 mutations discovered by whole-exome sequencing. AB - Non-syndromic amelogenesis imperfecta (AI) is a collection of isolated inherited enamel malformations that follow X-linked, autosomal-dominant, or autosomal recessive patterns of inheritance. The AI phenotype is also found in syndromes. We hypothesized that whole-exome sequencing of AI probands showing simplex or recessive patterns of inheritance would identify causative mutations among the known candidate genes for AI. DNA samples obtained from 12 unrelated probands with AI were analyzed. Disease-causing mutations were identified in three of the probands: a novel single-nucleotide deletion in both KLK4 alleles (g.6930delG; c.245delG; p.Gly82Alafs*87) that shifted the reading frame, a novel missense transition mutation in both MMP20 alleles (g.15390A>G; c.611A>G; p.His204Arg) that substituted arginine for an invariant histidine known to coordinate a structural zinc ion, and a previously described nonsense transition mutation in a single allele of FAM83H (c.1379G>A; g.5663G>A; p.W460*). Erupted molars and cross sections from unerupted parts of the mandibular incisors of Mmp20 null mice were characterized by scanning electron microscopy. Their enamel malformations closely correlated with the enamel defects displayed by the proband with the MMP20 mutation. We conclude that whole-exome sequencing is an effective means of identifying disease-causing mutations in kindreds with AI, and this technique should prove clinically useful for this purpose. PMID- 23355524 TI - Periodontal pathogen accelerates lipid peroxidation and atherosclerosis. AB - Recent studies have shown an association between periodontal disease and cardiovascular disease. We previously reported that intravenous challenge with Aggregatibacter actinomycetemcomitans (Aa) accelerated atherosclerosis in apolipoprotein E-deficient spontaneously hyperlipidemic (Apoe(shl)) mice. In this study, we investigated whether live cells were required for atherosclerosis induction or whether lipopolysaccharide (LPS) alone was sufficient to increase atherosclerotic damage. Mice were injected intravenously with live Aa HK1651, heat-killed (H.K.) Aa, or Aa LPS 3 times a week for 3 weeks and were sacrificed at 15 weeks of age. The areas of the aortic sinus that were covered with atherosclerotic plaques were significantly larger in mice treated with live Aa, H.K. Aa, or Aa LPS compared with vehicle-challenged mice. The order of the extent of atherosclerosis was live Aa > H.K. Aa > Aa LPS > sham. Toll and nucleotide oligomerization domain (NOD)-like receptor mRNA expression significantly increased in the live Aa, H.K. Aa, and Aa LPS treatment groups. Aa challenge markedly promoted the oxidation of LDL through oxidative stress involving NADPH oxidase- and myeloperoxidase-derived reactive oxygen species. These results suggested that Aa promoted innate immune signaling and low-density lipoprotein (LDL) oxidation and may facilitate atheroma development. PMID- 23355525 TI - Functional connectivity of human chewing: an fcMRI study. AB - Mastication is one of the most important orofacial functions. The neurobiological mechanisms of masticatory control have been investigated in animal models, but less so in humans. This project used functional connectivity magnetic resonance imaging (fcMRI) to assess the positive temporal correlations among activated brain areas during a gum-chewing task. Twenty-nine healthy young-adults underwent an fcMRI scanning protocol while they chewed gum. Seed-based fcMRI analyses were performed with the motor cortex and cerebellum as regions of interest. Both left and right motor cortices were reciprocally functionally connected and functionally connected with the post-central gyrus, cerebellum, cingulate cortex, and precuneus. The cerebellar seeds showed functional connections with the contralateral cerebellar hemispheres, bilateral sensorimotor cortices, left superior temporal gyrus, and left cingulate cortex. These results are the first to identify functional central networks engaged during mastication. PMID- 23355526 TI - Sporadic unilateral retinoblastoma or first sign of bilateral disease? AB - BACKGROUND: A small number of children with unilateral retinoblastoma later develop retinoblastoma in the contralateral eye (metachronous bilateral retinoblastoma). METHODS: We analysed the clinical and genetic characteristics of children with sporadic unilateral retinoblastoma to identify risk factors for the development of metachronous bilateral disease. RESULTS: Fifteen (3.1%) of 480 children with unilateral retinoblastoma later developed metachronous bilateral retinoblastoma (latency period >30 days). The maximum latency period was 2.3 years after initial diagnosis. Nine (22.5%) of 40 children with a RB1 mutation detectable in blood developed metachronous bilateral disease while all 155 children proved to be without a germline RB1 mutation remained unilaterally affected. Clinically, the risk of developing metachronous bilateral retinoblastoma was higher for age at diagnosis <=0.5 years compared with >0.5 years (19.6% vs 1.2%), and for multifocal compared with unifocal unilateral retinoblastoma (17.1% vs 2.2%). CONCLUSIONS: This study shows that an oncogenic RB1 mutation in the blood is a risk factor for metachronous bilateral retinoblastoma. Additional clinical risk factors for metachronous bilateral disease are diagnosis at young age (<=0.5 years) and multifocal unilateral retinoblastoma. Early genetic analysis may identify children at high risk of developing metachronous bilateral disease and may help to preserve vision using risk-adapted follow-up and early treatment. PMID- 23355527 TI - Long-term outcomes of primary trabeculectomy in diabetic patients with primary open angle glaucoma. AB - AIMS: To evaluate primary trabeculectomy with adjunctive mitomycin-C (MMC) in diabetic patients with primary open angle glaucoma (POAG). METHODS: Patients with diabetes mellitus (DM) without retinopathy who had >=6 months of postoperative follow-up were retrospectively compared with a control group selected from the pool of patients without DM matched case-by-case to the diabetic group by age, gender, race, preoperative intraocular pressure (IOP) and lens status. Surgical success was defined as IOP <=15 and >5 mm Hg (+/- glaucoma medications) without complications or additional glaucoma surgery. RESULTS: 41 eyes (29 patients) with DM and 81 eyes (64 patients) without DM were compared. Kaplan-Meier cumulative survival rates at 60 months were 57.8+/-9.3% (DM group) and 68.6+/-5.3% (control group), and the mean trabeculectomy survival times were 63 months (DM group, 95% CI 50.3 to 75.7) and 74.6 months (control group, 95% CI 67.1 to 82.1; p=0.095). Mean postoperative IOP of control group was statistically significant lower at 2 , 3-, 6- and 7-year follow-up visits (p<0.05). Rates of postoperative complications and additional glaucoma surgeries required were not different between the two groups. CONCLUSIONS: POAG patients with DM without retinopathy undergoing primary trabeculectomy with MMC do not achieve the same long-term IOP control and may have a lower long-term surgical survival rate compared with patients without DM. PMID- 23355528 TI - Profibrotic cytokines in aqueous humour correlate with aqueous flare in patients with rhegmatogenous retinal detachment. AB - BACKGROUND: Aqueous flare as determined by laser flare photometry in the anterior chamber is a strong preoperative predictor for proliferative vitreoretinopathy (PVR) in patients with primary retinal detachment (RD). We analysed various cytokines in aqueous humour samples in relation to aqueous flare and postoperative PVR incidence in patients with RD. METHODS: Preoperatively, the aqueous flare of patients with RD was measured quantitatively with a laser flare metre and aqueous humour samples were collected and analysed for interferon gamma, tumour necrosis factor alpha, monocyte chemoattractant protein (MCP)-1, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, vascular endothelial growth factor (VEGF)-A, platelet derived growth factor (PDGF)-aa, transforming growth factor (TGF)-beta1, TGF-beta2, TGF-beta3, fibroblast growth factor (FGF)-aa and FGF-bb by multiplex fluorescent bead-based immunoassays. Three months after RD surgery patients were examined for PVR development. RESULTS: Of 67 consecutive patients, 10 developed at least PVR grade C. Patients with flare values >15 pc/ms (n=20) and the 10 patients with postoperative PVR all had significantly elevated levels of IL-6, IL-8, MCP-1 and TGF-beta1 in aqueous humour (p<=0.05). Levels of VEGF-A, PDGF-aa and TGF-beta2 were not significantly changed. Other cytokines were below the detection threshold. Eight of the 10 patients (80%) with PVR had elevated flare values of >15 pc/ms and 8 of the 20 patients (40%) with flare >15 pc/ms developed PVR. The OR for PVR with flare values >15 pc/ms was 30.7 (p=0.0001). CONCLUSIONS: Laser flare photometry allows simple risk estimation for later PVR development. Elevated laser flare values correspond to an altered profibrotic intraocular cytokine milieu. These factors therefore constitute promising targets for a prophylactic intervention. PMID- 23355529 TI - Riboflavin/ultravoilet light-mediated crosslinking for fungal keratitis. PMID- 23355530 TI - In vitro induction of protein complexes between bevacizumab, VEGF-A165 and heparin: explanation for deposits observed on endothelial veins in monkey eyes. AB - PURPOSE: By investigating the effects of intravitreal bevacizumab on retinal vessels of monkeys, we found that bevacizumab accumulated locally at high concentration within individual blood vessels. It formed electron-dense fibrous deposits between endothelial cells and erythrocytes or granulocytes inducing retinal vein thrombosis. To better characterise the observed deposits, we investigated in vitro whether these deposits result from a complex between bevacizumab, vascular endothelial growth factor (VEGF)-A(165) and heparin. METHODS: Cynomolgus monkeys were intravitreally injected with 1.25 mg bevacizumab. The eyes were enucleated between 1 and 14 days after injection and investigated by electron microscopy and immunohistochemistry. Human umbilical vein endothelial cells (HUVEC) were incubated with bevacizumab, VEGF-A(165) and heparin at different concentrations. Treatments with ranibizumab served as control. Bevacizumab and ranibizumab were detected immunohistochemically using Cy 3 or immunogold labelled antibodies. RESULTS: Treated animals showed bevacizumab locally at high concentration within retinal blood vessels. Electron-dense deposits inside retinal vessels and between erythrocytes were detected in three out of four treated monkeys. In vitro, many globular aggregates heavily stained with anti-human IgG were only observed with equimolar amounts (240 nM) of bevacizumab and VEGF-A(165) and 0.2 U/ml heparin and not after ranibizumab treatment. The immunogold labelling specifically localised ultrastructurally the complexes formed between bevacizumab, VEGF-A(165) and heparin at the surfaces of HUVEC cells. CONCLUSIONS: Heparin promotes bevacizumab immune complex deposition on to endothelial cells. Our in vitro results could explain the presence of deposits observed on endothelial veins in monkey eyes intravitreally injected with bevacizumab. PMID- 23355531 TI - Lateral gene transfer from the dead. AB - In phylogenetic studies, the evolution of molecular sequences is assumed to have taken place along the phylogeny traced by the ancestors of extant species. In the presence of lateral gene transfer, however, this may not be the case, because the species lineage from which a gene was transferred may have gone extinct or not have been sampled. Because it is not feasible to specify or reconstruct the complete phylogeny of all species, we must describe the evolution of genes outside the represented phylogeny by modeling the speciation dynamics that gave rise to the complete phylogeny. We demonstrate that if the number of sampled species is small compared with the total number of existing species, the overwhelming majority of gene transfers involve speciation to and evolution along extinct or unsampled lineages. We show that the evolution of genes along extinct or unsampled lineages can to good approximation be treated as those of independently evolving lineages described by a few global parameters. Using this result, we derive an algorithm to calculate the probability of a gene tree and recover the maximum-likelihood reconciliation given the phylogeny of the sampled species. Examining 473 near-universal gene families from 36 cyanobacteria, we find that nearly a third of transfer events (28%) appear to have topological signatures of evolution along extinct species, but only approximately 6% of transfers trace their ancestry to before the common ancestor of the sampled cyanobacteria. PMID- 23355533 TI - Gene expression analysis reveals an angiogenic profile in uterine leiomyoma pseudocapsule. AB - The pseudocapsule (PC) of the uterine leiomyoma (UL) is an anatomic entity that surrounds the myoma separating it from the myometrium (UM). Although a number of microarray experiments have identified differences in gene expression profile in the UL when compared with the UM, there is a lack of systematic studies on the PC. In this study, quantitative RT-PCR analysis was performed on 18 matched PC, UL and UM specimens and results showed that the PC displays a specific gene expression profile. The low expression level of insulin-like growth factor (IGF 2), a fibroid specific marker, that we found in the PC and the UM when compared with the UL, clearly indicates that the PC is in structural continuity with the UM. However, the significant increase in endoglin expression level in PC with respect to the UL and UM indicates that an active neoangiogenesis is present in PC. Conversely, other angiogenic factors such as von Willebrand factor (vWF) and vascular endothelial growth factor A (VEGF-A) seem to have little influence on the PC angiogenesis. Because the endoglin is preferentially expressed in proliferating endothelial cells, whereas the vWF and VEGF-A are preferentially expressed in preexisting endothelial cells, our idea is that the angiogenic activity in the PC is linked to wound healing. The angiogenic activity is also sustained by intermediate expression level of cystein-rich angiogenesis inducer 61, connective tissue growth factor and collagen 4alpha2 genes all involved in the neoangiogenesis, that we detected in the PC. Taken together our data demonstrate that the specific expression pattern observed in the PC could be the response of the uterine wall's smooth cells to the tension imposed by the tumor. As a consequence, a neovascular structure is generated involving regenerative processes. For these reasons, we suggest that the laparoscopic intracapsular myomectomy (LIM), a new surgical technique that preserves the PC during the UL removal, should always be preferred, to favor a faster and proper uterine healing. PMID- 23355534 TI - Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells. AB - Von Willebrand disease (VWD) is a heterogeneous bleeding disorder caused by decrease or dysfunction of von Willebrand factor (VWF). A wide range of mutations in the VWF gene have been characterized; however, their cellular consequences are still poorly understood. Here we have used a recently developed approach to study the molecular and cellular basis of VWD. We isolated blood outgrowth endothelial cells (BOECs) from peripheral blood of 4 type 1 VWD and 4 type 2 VWD patients and 9 healthy controls. We confirmed the endothelial lineage of BOECs, then measured VWF messenger RNA (mRNA) and protein levels (before and after stimulation) and VWF multimers. Decreased mRNA levels were predictive of plasma VWF levels in type 1 VWD, confirming a defect in VWF synthesis. However, BOECs from this group of patients also showed defects in processing, storage, and/or secretion of VWF. Levels of VWF mRNA and protein were normal in BOECs from 3 type 2 VWD patients, supporting the dysfunctional VWF model. However, 1 type 2M patient showed decreased VWF synthesis and storage, indicating a complex cellular defect. These results demonstrate for the first time that isolation of endothelial cells from VWD patients provides novel insight into cellular mechanisms of the disease. PMID- 23355535 TI - Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms. AB - A study has shown that MYD88 (L265P) is a recurring somatic mutation in Waldenstrom's macroglobulinemia (WM). We developed an allele-specific polymerase chain reaction (PCR) for this mutation, and analyzed bone marrow or peripheral blood samples from 58 patients with WM, 77 with IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), 84 with splenic marginal zone lymphoma (SMZL), and 52 with B-cell chronic lymphoproliferative disorders (B-CLPD). MYD88 (L265P) was detected in 58/58 (100%) patients with WM, 36/77 (47%) with IgM-MGUS, 5/84 (6%) with SMZL, and 3/52 (4%) with B-CLPD. Compared to IgM-MGUS patients with wild-type MYD88, those carrying MYD88 (L265P) showed significantly higher levels of IgM (P < .0001) and presented Bence-Jones proteinuria more frequently at diagnosis (P = .002). During follow-up, 9 patients with IgM-MGUS progressed to WM or to marginal zone lymphoma. Using a case-control approach, the risk of evolution of patients carrying MYD88 (L265P) was significantly higher than that of patients with wild-type MYD88 (odds ratio 4.7, 95% confidence interval 0.8 to 48.7, P = .047). These findings indicate that the allele-specific PCR we developed is a useful diagnostic tool for patients with WM or IgM-MGUS. In this latter condition, MYD88 (L265P) is associated with greater disease burden and higher risk of disease progression, and the mutation may therefore also represent a useful prognostic marker. PMID- 23355536 TI - Control of iron deficiency anemia in low- and middle-income countries. AB - Despite worldwide economic and scientific development, more than a quarter of the world's population remains anemic, and about half of this burden is a result of iron deficiency anemia (IDA). IDA is most prevalent among preschool children and women. Among women, iron supplementation improves physical and cognitive performance, work productivity, and well-being, and iron during pregnancy improves maternal, neonatal, infant, and even long-term child outcomes. Among children, iron may improve cognitive, psychomotor, and physical development, but the evidence for this is more limited. Strategies to control IDA include daily and intermittent iron supplementation, home fortification with micronutrient powders, fortification of staple foods and condiments, and activities to improve food security and dietary diversity. The safety of routine iron supplementation in settings where infectious diseases, particularly malaria, are endemic remains uncertain. The World Health Organization is revising global guidelines for controlling IDA. Implementation of anemia control programs in developing countries requires careful baseline epidemiologic evaluation, selection of appropriate interventions that suit the population, and ongoing monitoring to ensure safety and effectiveness. This review provides an overview and an approach for the implementation of public health interventions for controlling IDA in low- and middle-income countries, with an emphasis on current evidence-based recommendations. PMID- 23355532 TI - Molecular adaptation during a rapid adaptive radiation. AB - "Explosive" adaptive radiations on islands remain one of the most puzzling evolutionary phenomena and the evolutionary genetic processes behind such radiations remain unclear. Rapid morphological and ecological evolution during island radiations suggests that many genes may be under fairly strong selection, although this remains untested. Here, we report that during a rapid recent diversification in the Hawaiian endemic plant genus Schiedea (Caryophyllaceae), 5 in 36 studied genes evolved under positive selection. Positively selected genes are involved in defence mechanisms, photosynthesis, and reproduction. Comparison with eight mainland plant groups demonstrates both the relaxation of purifying selection and more widespread positive selection in Hawaiian Schiedea. This provides compelling evidence that adaptive evolution of protein-coding genes may play a significant role during island adaptive radiations. PMID- 23355537 TI - How I assess comorbidities before hematopoietic cell transplantation. AB - The hematopoietic cell transplantation-comorbidity index (HCT-CI) is a comorbidity tool suited for recipients of HCT. The index has been shown to sensitively capture the prevalence and magnitude of severity of various organ impairments before HCT and to provide valuable prognostic information after HCT. Many investigators have validated the discriminative power of the HCT-CI, but others have not. One concern is the consistency in comorbidity coding across different evaluators, particularly in view of the relatively recent addition of the HCT-CI to the transplant evaluation process. In this article, comorbidity scoring was tested across different evaluators, and only a fair interobserver agreement rate could be detected. To address these issues, a brief training program is proposed here, consisting of systematic methodology for data acquisition and consistent guidelines for comorbidity coding that were summarized in a Web-based calculator. In a validation patient cohort, this training program was shown to improve the interevaluator agreement on HCT-CI scores to an excellent rate with weighted kappa values in the range of 0.89 to 0.97. This proposed training program will facilitate reliable assessment of comorbidities in the clinic and for research studies leading to standardization of the use of comorbidities in prediction of HCT outcomes. PMID- 23355538 TI - CD161 defines the subset of FoxP3+ T cells capable of producing proinflammatory cytokines. AB - Regulatory FoxP3+CD4+ T cells (Treg) are vital for maintaining the balance between tolerance, adequate immune response, and autoimmunity. Despite this immunoregulatory role, it has been shown that Treg may also produce proinflammatory cytokines. Here we present a distinct population of Treg, defined by CD161 expression, as the major source of FoxP3+ Treg-derived proinflammatory cytokines. CD161+ Treg can be followed throughout development, from thymus and cord blood to healthy child and adult samples. CD161+ Treg display anergy, are suppressive in cocultures with conventional T cells (Tconv), and possess a predominantly demethylated Treg-specific demethylated region of the FOXP3 locus. In addition to the production of interleukin (IL) 17A, interferon gamma, and IL 2, CD161+FoxP3+ cells share markers with Tconv, including expression of the transcription factors retinoic acid-related orphan receptor Cv2 (RORCv2) and T cell-specific T-box transcription factor (Tbet). Expression of CD161 and enrichment for cytokine production are stable characteristics of CD161+ Treg upon both short- and longer-term culture in vitro. Additionally, CD161+ Treg are highly enriched within the inflammatory environment of childhood arthritis, suggesting a role in disease. Our data therefore demonstrate that CD161+FoxP3+ T cells are a novel Treg subset, found in health and disease, which display high proinflammatory potential but also exhibit hallmark Treg characteristics. PMID- 23355541 TI - Five English hospital trusts have higher than expected deaths, finds new mortality measure. PMID- 23355539 TI - Lapatinib-mediated cyclooxygenase-2 expression via epidermal growth factor receptor/HuR interaction enhances the aggressiveness of triple-negative breast cancer cells. AB - Lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) kinase inhibitor, showed clinical benefits in advanced HER2-positive breast cancer patients. Because some triple-negative breast cancers (TNBCs) frequently overexpress EGFR, the antitumor activity of lapatinib in such diseases was also tested. However, the results showed a worse event-free survival rate. It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells. In this study, our results demonstrated that lapatinib facilitated axillary and lung metastases of triple-negative MDA-MB-231 breast cancer cells without affecting their viability, leading to worse survival in orthotopic xenograft mice. The lapatinib-increased motility was attributed by the elevation of EGFR through the downregulation of microRNA-7 and by the subsequent overexpression of cyclooxygenase-2 (COX-2). Strikingly, independent of its kinase activity, the elevated EGFR at least partly stabilized COX-2 expression by enhancing the binding of HuR to COX-2 mRNA. Our results suggest that lapatinib may increase the migration and invasion of MDA-MB-231 cells by upregulating EGFR and COX-2 through the downregulation of microRNA-7, providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib based treatment. These findings also shed new light on the molecular mechanism of COX-2 mRNA stabilization by EGFR in a kinase-independent manner. PMID- 23355542 TI - Evaluation of a liquid dispenser for assay development and enzymology in 1536 well format. AB - Although developments in liquid dispensers have made the use of 1536-well plates for high-throughput screening (HTS) standard, there is still a gap in dispenser technology for performing matrix experiments with several components. Experiments such as those performed during assay development and enzymological studies are therefore still performed by manual pipetting in lower-density plates. We have evaluated a new dispenser, the Certus liquid dispenser (Gyger Fluidics GmbH, Switzerland), that is capable of flexible dispensing in 1536-well format, with a dead volume of less than 200 uL. Taking advantage of the precision of the dispenser for volumes down to 50 nL, we have created concentration gradients on plates by dispensing different volumes of reagent and then backfilling with buffer. Using this method and the flexibility of the dispenser software, we have performed several multidimensional experiments varying two to three components, including an assay development for an HTS, a mode of inhibition study, and a cofactor optimization, in which we determined 32 KM values. Overall, the flexibility of the plate layout for multiple components, the accuracy to dispense volumes ranging 2 log orders, and minimal reagent usage enable this dispenser for complex biochemical experiments. PMID- 23355543 TI - The Salt Overly Sensitive (SOS) pathway: established and emerging roles. AB - Soil salinity is a growing problem around the world with special relevance in farmlands. The ability to sense and respond to environmental stimuli is among the most fundamental processes that enable plants to survive. At the cellular level, the Salt Overly Sensitive (SOS) signaling pathway that comprises SOS3, SOS2, and SOS1 has been proposed to mediate cellular signaling under salt stress, to maintain ion homeostasis. Less well known is how cellularly heterogenous organs couple the salt signals to homeostasis maintenance of different types of cells and to appropriate growth of the entire organ and plant. Recent evidence strongly indicates that different regulatory mechanisms are adopted by roots and shoots in response to salt stress. Several reports have stated that, in roots, the SOS proteins may have novel roles in addition to their functions in sodium homeostasis. SOS3 plays a critical role in plastic development of lateral roots through modulation of auxin gradients and maxima in roots under mild salt conditions. The SOS proteins also play a role in the dynamics of cytoskeleton under stress. These results imply a high complexity of the regulatory networks involved in plant response to salinity. This review focuses on the emerging complexity of the SOS signaling and SOS protein functions, and highlights recent understanding on how the SOS proteins contribute to different responses to salt stress besides ion homeostasis. PMID- 23355544 TI - Genome-wide analysis of histone modifications: H3K4me2, H3K4me3, H3K9ac, and H3K27ac in Oryza sativa L. Japonica. AB - While previous studies have shown that histone modifications could influence plant growth and development by regulating gene transcription, knowledge about the relationships between these modifications and gene expression is still limited. This study used chromatin immunoprecipitation followed by high throughput sequencing (ChIP-Seq), to investigate the genome-wide distribution of four histone modifications: di and trimethylation of H3K4 (H3K4me2 and H3K4me3) and acylation of H3K9 and H3K27 (H3K9ac and H3K27ac) in Oryza sativa L. japonica. By analyzing published DNase-Seq data, this study explored DNase-Hypersensitive (DH) sites along the rice genome. The histone marks appeared mainly in generic regions and were enriched around the transcription start sites (TSSs) of genes. This analysis demonstrated that the four histone modifications and the DH sites were all associated with active transcription. Furthermore, the four histone modifications were highly concurrent with transcript regions-a promising feature that was used to predict missing genes in the rice gene annotation. The predictions were further validated by experimentally confirming the transcription of two predicted missing genes. Moreover, a sequence motif analysis was constructed in order to identify the DH sites and many putative transcription factor binding sites. PMID- 23355545 TI - Tamiflu: 14 flu seasons and still questions. PMID- 23355546 TI - Attachment and health care utilization among middle-aged and older African descent men: dismissiveness predicts less frequent digital rectal examination and prostate-specific antigen screening. AB - Although health care utilization occurs in interpersonal contexts, little is known regarding how interpersonal preferences or styles among patients may be relevant. A small body of work has identified links between attachment-a dispositional style of relating to others-and patterns of health care use. The current report examined how attachment characteristics predicted the frequency of digital rectal exam and prostate-specific antigen testing in a sample of African descent men. Four hundred and fourteen African-descent men aged 45 to 70 years completed measures of prostate screening and attachment, together with measures of traditional predictors of screening (demographics, insurance, family history, physician variables, knowledge, perceived risk, and accessibility). Consistent with predictions, dismissiveness-the most common relational style among older men predicted less frequent prostate-specific antigen testing and digital rectal examination. However, attachment security-a comfort with intimate relationships also predicted lower screening frequency. Identifying the interpersonal characteristics predicting screening may help identify men at risk of suboptimal health care use and guide the development of interventions suited to the normative relational preferences of current cohorts of older, African-descent men. PMID- 23355548 TI - Carvedilol: the beta-blocker of choice for portal hypertension? PMID- 23355550 TI - Authors' response: Metformin and risk of hepatocellular carcinoma--a study focused on anti-diabetic agents. PMID- 23355549 TI - Sex-specific associations between body mass index, waist circumference and the risk of Barrett's oesophagus: a pooled analysis from the international BEACON consortium. AB - OBJECTIVE: Barrett's oesophagus is a precursor lesion of oesophageal adenocarcinoma, a cancer that, in the USA, has increased in incidence over 600% during the past 40 years. Barrett's oesophagus and oesophageal adenocarcinoma are much more common among men than among women; this finding is unexplained and most earlier studies lacked sufficient numbers of women to evaluate sex-specific risk factors. We leveraged the power of an international consortium to assess sex specific relationships between body mass index (BMI), abdominal circumference and Barrett's oesophagus. DESIGN: Four case-control studies provided a total of 1102 cases (316 women, 786 men) and 1400 population controls (436 women, 964 men) for analysis. Study-specific estimates, generated using individual participant data, were combined using random effects meta-analysis. RESULTS: Waist circumference was significantly associated with Barrett's oesophagus, even after adjustment for BMI; persons in the highest versus the lowest quartiles of waist circumference had approximately 125% and 275% increases in the odds of Barrett's oesophagus among men and women, respectively (OR 2.24, 95% CI 1.08 to 4.65, I(2)=57; OR 3.75, 95% CI 1.47 to 9.56, I(2)=0). In contrast, there was no evidence of a significant association between BMI and the risk of Barrett's oesophagus, with or without adjustment for waist circumference. CONCLUSIONS: Waist circumference, independent of BMI, was found to be a risk factor for Barrett's oesophagus among both men and women. Future studies examining the biological mechanisms of this association will extend our knowledge regarding the pathogenesis of Barrett's oesophagus. PMID- 23355551 TI - Anteromedial subtalar dislocation. AB - Subtalar dislocation is the simultaneous dislocation of the talocalcaneal and talonavicular joints of the foot, typically caused by falls from heights, twisting leg injuries and motor vehicle accidents. The dislocation can occur medially, lateral, anterior or posterior, but most commonly occurs from inversion injury producing a medial dislocation. These dislocations may be accompanied by fractures. Careful physical examination must be performed to assess for neurovascular compromise. Most subtalar dislocations can be treated with closed reduction under sedation. However, if the dislocation is associated with an open fracture it may require reduction in the operating room. Treatment should include postreduction plain x-ray and CT scan to evaluate for proper alignment and for fractures. This article presents a case of medial subtalar dislocation in a 23 year-old football player. PMID- 23355552 TI - Aborted sudden cardiac death (SCD) in a patient with hypertrophic cardiomyopathy (HCM) with low-risk factors for SCD. AB - Remarkable advancements have been made in understanding the pathophysiology of hypertrophic cardiomyopathy (HCM), since the first implantable cardioverter defibrillator (ICD) was placed in a human, more than 25 years ago to prevent sudden cardiac death (SCD). ICD has become the cornerstone in the management of HCM, with an ability to change the natural course of this complex disease. American College of Cardiology/American Heart Association guidelines have been charted out to help risk stratify asymptomatic or minimally symptomatic adults with HCM, in order to prevent SCD in such individuals. Our patient with left ventricular outflow tract gradient <30 mm Hg, left ventricular wall thickness < 30 mm, negative medical history of syncope and no family history of SCD, would have been at low risk for SCD. PMID- 23355553 TI - A crossed brain stem syndrome without crossed sensory symptomatology. AB - Lateral medullary infarction (LMI) or Wallenberg syndrome is a type of brain stem stroke, more specifically, a type of crossed brain stem syndrome. LMI is a well described entity with several documented typical characteristics including pain and temperature impairment in the ipsilateral to the lesion side of the face and the contralateral side of the trunk and limbs. We present a case of LMI which describes a patient who presented with atypical features of analgesia and thermanaesthesia on the contralateral side of the face and absence of sensory deficit on the ipsilateral side. We attributed this pattern of involvement to a lesion that affects the ventral trigeminothalamic tract and spares the dorsolateral part of the medulla where the spinal trigeminal tract and its nucleus lie. This case report highlights the presence of atypical presentations of LMI that may initially challenge the physician's diagnostic reasoning. PMID- 23355554 TI - Congenital circumflex coronary artery fistulae; presentation and diagnosis. AB - Small fistulae between coronary arteries and the pulmonary artery are common, but abnormal vascular communications between the coronary arteries and other cardiac structures are rare. They were first described by Krause in 1865. We report two cases of fistulous connexions between the circumflex coronary artery and the coronary sinus. PMID- 23355555 TI - A case of symptomatic Rathke's cyst. AB - Rathke's cleft cyst is a benign growth found on the pituitary gland in the brain, specifically a fluid-filled cyst in the posterior portion of the anterior pituitary gland. It occurs when the Rathke's pouch does not develop properly, and ranges in size from 2 to 40 mm in diameter. Asymptomatic cysts are common, detected during autopsies of 2-26% of individuals who have died of unrelated causes. Symptomatic cysts are rare and only approximately 150 cases have been reported. Females are twice as likely as males to have a cyst. Symptomatic cysts can trigger visual disturbances, pituitary dysfunction and headaches. Here we present a case of a 40-year-old female patient who presented with complains of visual disturbances, headache and amenorrhoea. On investigations, MRI of brain revealed findings suggestive of Rathke's cleft cyst. PMID- 23355556 TI - The value of history and goals of care with code status; even in an emergency setting. AB - This is a case report involving an elderly Jehovah's Witness woman with a history of chronic anaemia who suffers cardiac arrest and is resuscitated. This case illustrates, even in an emergency setting, (1) the value of obtaining relevant history, (2) addressing code status within the framework of achievable goals of care and (3) the need to revise both history and goals of care, as more information becomes available. We also propose aspects of this discussion that would benefit from future research. PMID- 23355557 TI - Huge gallstone complicating laparoscopic cholecystectomy. AB - Gallstone disease is common in the western world and is most often diagnosed on ultrasound scanning. This case is of a 57-year-old woman with a history of biliary colic who was admitted as a day case for a laparoscopic cholecystectomy. This was converted to open because of the technical difficulty related to a huge gallstone in the gallbladder measuring 60 mm*30 mm*35 mm, the largest we have seen. Review of her ultrasound scan showed this large stone present at the time. Several factors are known to increase the risk of conversion to open, and these patients require a longer in-hospital stay postoperatively. Prior knowledge of these factors may advocate preoperative admission to a unit with inpatient beds available, not a day case unit. This will help save costs involved in ambulance transfers of day case patients to inpatient units and support the efficient use of our elective and emergency services. PMID- 23355558 TI - Atypical giant haemangioma of liver with systemic inflammatory manifestations. AB - Haemangioma is the most common benign tumour of the liver. Most of them are small in size (less than 4 cm) and are often asymptomatic and discovered incidentally on modern diagnostic imaging. Lesions with a diameter larger than 4 cm are called giant haemangiomas, and these are usually located in the right hepatic lobe. Although haemangioma is the most frequent benign tumour of the liver, 'giant' haemangiomas are rare. Such lesions may give rise to symptoms requiring treatment. In this case report, we describe the case of a 50-year-old Indian man who presented with giant liver haemangioma and systemic inflammatory manifestations. PMID- 23355559 TI - Successful treatment of resistant SAPHO syndrome with anti-TNF therapy. AB - A 42-year-old Caucasian woman with SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis and osteitis) refractory to non-steroidal anti-inflammatory drugs, sulfasalzine, methotrexate, bisphosphonates and steroids was successfully treated with antitumour necrosis factor therapy (infliximab). This case was a diagnostic challenge leading to extensive investigations for infection and malignancy and delayed diagnosis for several years. We report the significant improvement in clinical, radiological and laboratory markers of disease activity on infliximab and the steroid sparing effect of such therapy. PMID- 23355560 TI - A diagnostic dilemma of central skull base osteomyelitis mimicking neoplasia in a diabetic patient. AB - We present a case which illustrates the diagnostic difficulty in distinguishing between osteomyelitis of the central skull base and base of skull tumours. A woman in her early forties presented with seizures and multiple cranial nerve palsies. She also had a background of chronic otalgia and poorly controlled diabetes mellitus. The clinical diagnosis of skull base osteomyelitis (SBO) was made, but both MRI and bone scans were unable to distinguish this from a skull base malignancy on imaging criteria. Eventually biopsies were required to exclude the diagnosis of malignancy and the patient was treated for central SBO. PMID- 23355561 TI - Prosthetic valve endocarditis caused by Propionibacterium species successfully treated with coadministered rifampin: report of two cases. AB - We describe two cases of prosthetic valve endocarditis caused by Propionibacterium spp. successfully treated with a combination of rifampin and intravenous penicillin. Rifampin was chosen due to its promising activity against planktonic and biofilm Propionibacterium, its favourable minimal inhibitory concentrations, its excellent oral bioavailability and tissue penetration. PMID- 23355562 TI - Immunocompetent young man with cerebral abscess and cortical venous infarction mimicking cerebritis caused by Gemella morbillorum. AB - Gemella morbillorum is an anaerobic gram-positive diplococcus and in most cases a harmless commensal, which occasionally causes infections in the central nervous system. We report on an immunocompetent young man with focal neurological symptoms and cephalgia caused by a cerebral abscess. Although successful treatment was done with neurosurgical intervention and antibiotic therapy, he suffered from a venous infarction 5 weeks after first diagnosis, which mimicked cerebritis as an early stage of relapsing abscess. Imaging and investigation of cerebrospinal fluid was necessary for sufficient differential diagnosis and antibiotic therapy could be stopped after altogether 8 weeks of treatment. In summary, G morbillorum causes not only biphasic infections, but also can be accompanied by infarction in the central nervous system despite sufficient antibiotic therapy. PMID- 23355563 TI - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL): a rare cause of dementia. AB - The clinical course of a 60-year-old gentleman with a history of atypical migraine, recurrent encephalopathic episodes and progressive cognitive impairment is presented. He was diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, a rare genetic disorder of the cerebral blood vessels caused by mutations in the Notch 3 gene on chromosome 19. The diagnosis was confirmed by MRI, skin biopsy and genetic testing. His cognitive function has progressively deteriorated and he continues to receive supportive care provision. The course and review of the condition are highlighted. PMID- 23355564 TI - Acute stroke in a patient with advanced uraemia: should thrombolysis be given? AB - A 65-year-old gentleman with stage 5 chronic kidney disease developed an acute posterior circulation stroke, which was treated with intravenous thrombolytic therapy. This was complicated by a retroperitoneal haemorrhage. The patient made an excellent neurological recovery and was discharged to home, independently mobile, having been established on haemodialysis. This case highlights the challenges of managing acute ischaemic stroke in patients with advanced uraemia. PMID- 23355565 TI - Extensive dural sinus thrombosis and bilateral lateral rectus palsy as an uncommon complication of chronic suppurative otitis media. AB - Dural venous sinus thrombosis, especially of the sigmoid sinus, is a known but uncommon intracranial extradural complication of chronic suppurative otitis media. Even rarer is the simultaneous occurrence of bilateral abducens palsy in the same patient. We report the case of an adolescent male who presented with signs of raised intracranial pressure, diplopia and bilateral lateral rectus palsy associated with a history of left ear discharge and neck swelling. Extensive dural sinus thrombosis extending right up to the left internal jugular vein was confirmed on CT imaging. The patient was successfully treated with thrombolytic agents and antibiotic therapy. The pathophysiology of the concurrent complications is discussed. PMID- 23355566 TI - Huge bilateral renal angiomyolipoma. PMID- 23355567 TI - Multiple brain parenchymal neurocysticercosis with extraocular muscle cysticercosis affecting levator palpebral superioris and superior rectus complex: an unusual association. AB - An 8-year-old girl presented to the neurology department with a complaint of insidious onset of left-sided ptosis and restricted elevation of the left eye. A CT scan orbit and brain revealed a ring-enhancing lesion in the levator palpebral superioris (LPS) and superior rectus (SR) muscle complex of the left eye and left parietal and right temporal region. She was started on steroid, followed by albendazole with improvement. The LPS/SR complex is the least common site of involvement among extraocular muscles in ocular cysticercosis. Specially, with brain neurocysticercosis (NCC), it is extremely rare. We report an unusual association of multiple brain NCC with ocular cysticercosis involving LPS and SR muscle. PMID- 23355568 TI - Abdominal aortic pseudocoarctation associated with renal artery occlusion. PMID- 23355569 TI - Platypnea-Orthodeoxia syndrome after repair of a paraesophageal hernia. AB - The Platypnea-Orthodeoxia syndrome is characterised by dyspnoea and deoxygenation accompanying a change from the recumbent to the upright position. An 81-year-old woman had an elective paraesophageal hernia repair. She developed dyspnoea and hypoxemia post-operatively that was worse when upright. An agitated saline echocardiogram revealed a right-to-left shunt through a patent foramen ovale that increased when the patient was upright. Over 3 weeks the patients' shunt, dyspnoea and hypoxemia improved and she was discharged home. PMID- 23355570 TI - Metastatic renal cell carcinoma to the thyroid gland 24 years after the primary tumour. AB - Among the metastases to thyroid gland, metastases from renal cell carcinoma (RCC) are not rare and their frequent macroscopic looks are similar to primary thyroid tumours. We report an unusual case of thyroid metastases from renal carcinoma in a 72 -year-old man presented with a 1-year history of choking spells, stridor and dyspnoea. Patient underwent right nephrectomy for RCC, 24 years ago. In the present case, a right hemithyroidectomy was performed for a suspected anaplastic thyroid carcinoma. Histological examination showed a metastases of a clear cell renal carcinoma. Although the RCC showed an indolent biological behaviour, the late thyroid metastases have concurred with a poor prognosis and the patient died 5 months after surgery. The interest of this case lies in the long progression free survival of the RCC preceded by the diagnosis of the thyroid nodule and the discrepancy between the clinical-radiological and the histological assessment. PMID- 23355571 TI - Idiopathic granulomatous mastitis, erythema nodosum and bilateral ankle arthritis in an Iranian woman. AB - Here we report a case of idiopathic granulomatous mastitis (IGM) associated with erythema nodosum (EN) and ankle arthritis. The skin, joint and mammary symptoms improved with corticosteroid. Coincidence of granulomatous mastitis, EN and arthritis is a rare feature. PMID- 23355572 TI - Cerebral multicystic lesions in a child with neurofibromatosis. AB - Neurofibromatosis type 1 (NF-1) is an autosomal dominant neurocutaneous syndrome, with frequent involvement of the central nervous system (CNS). As well as abnormal cellular differentiation, disordered cell migration during development is the most common cause of the various brain lesions. Cystic lesions are rarely observed in neurocutaneous diseases, and the origin of the cysts is not known. This paper presents a rare case, a child at the age of 3, who was diagnosed as NF 1 and was observed to have asymptomatic cystic lesions in right temporal lobe in radiological examination of CNS. This study draws attention to the relationship between these rare cystic lesions of unknown origin and neurocutaneous diseases. PMID- 23355573 TI - Enteric adenocarcinoma lung: a rare presentation in an Omani woman. AB - Pulmonary adenocarcinoma is a common neoplasm, yet the one with enteric or intestinal differentiation poses a diagnostic challenge to pathologists as it shares a common immunohistochemical profile with metastatic colorectal carcinoma. We report a case of a 61-year-old woman. She was on surveillance when incidentally she was discovered to have multiple bilateral lung nodules on imaging; the largest was surgically removed for histological examination. Morphology was consistent with a moderately differentiated adenocarcinoma .The tumour cells were positive for cytokeratin (CK) 7, CDX2, CK20 and were negative for thyroid transcription factor 1. The morphology and immune histochemical profile raised the differential diagnosis of a metastatic colorectal carcinoma and a primary lung adenocarcinoma with enteric differentiation. On the basis of morphology and CK7 positivity we established the diagnosis of enteric-type adenocarcinoma of primary lung origin. She has completed planned courses of palliative chemotherapy and remains on surveillance. PMID- 23355574 TI - All tied up in knots. PMID- 23355575 TI - Right-sided infective endocarditis presenting with purpuric skin rash and cardiac failure in a patient without fever. AB - We describe the case of a 70-year-old woman who presented with symptoms of cardiac failure, and was found on clinical examination to have a purpuric rash over her lower extremities. Further evaluation of cardiac failure revealed tricuspid regurgitation with two large tricuspid valve vegetations. Blood cultures yielded a growth of Streptococcus viridans. She was treated with an intravenous ceftriaxone and gentamicin and made a complete recovery with resolution of the rash. PMID- 23355576 TI - Acute Legionella pneumophila infection masquerading as acute alcoholic hepatitis. AB - A middle-aged man had deteriorated rapidly in hospital after being misdiagnosed with acute alcoholic hepatitis. Acute Legionnaires disease (Legionellosis) was subsequently diagnosed on rapid antigen urinary testing and further confirmed serologically. This led to appropriate antibiotic treatment and complete clinical resolution. Physicians caring for patients with alcohol-related liver disease should consider Legionella pneumophila in their differential diagnosis even with a paucity of respiratory symptoms. PMID- 23355577 TI - Outpatient management of Gitelman's syndrome in pregnancy. AB - Gitelman's syndrome is a congenital renal tubular defect which affects the apical membrane of the distal convoluted tubule of the renal system. The syndrome is characterised by hypokalaemia, hypomagnesaemia, metabolic alkalosis and hypocalcuria. There are only a few cases describing the impact of Gitelman's syndrome on pregnancy and the foetus. Although most pregnancies have favourable outcomes, fetal demise has been reported in the third trimester. We report the successful outcome of pregnancy in a patient with Gitelman's syndrome who continued on amiloride in pregnancy to optimise potassium and magnesium levels and review the literature for pregnancy outcomes of this condition. PMID- 23355578 TI - Orbital varix thrombosis: a rare cause of unilateral proptosis. AB - Orbital varices are thin walled, low flow, distensible veins which may rarely present with periorbital pain, proptosis or visual loss. Most orbital varices may be managed conservatively and only warrant surgery in the presence of recurrent thrombosis, disfiguring proptosis or acute visual loss. This report concerns an 84-year-old Caucasian woman who was admitted following a fall and noted to have isolated proptosis of the right eye, with vertical diplopia. All biochemical and haematological investigations were normal. A CT scan of the orbits demonstrated a serpiginous soft tissue mass within the superior portion of the right orbit, consistent with a thrombosed orbital varix. Conservative management was agreed with prism glasses and ophthalmological follow-up. PMID- 23355579 TI - Dietary small bowel obstruction. PMID- 23355580 TI - Alveolar bone exostoses subsequent to orthodontic implant placement. AB - Alveolar bone exostoses (ABE), also known as a buttress bone formation, are not uncommon to the literature. Although, exostoses in response to the trauma from occlusion are a popular concept proposed more than 45 years ago, still the aetiological factors behind this development are unclear. Various risks and complications associated with orthodontic implants have been published, but buttress bone formation subsequent to this procedure has not been reported till date. This article describes a case of ABE, subsequent to the placement of orthodontic mini implants, where after careful evaluation, resective osseous surgery was performed. PMID- 23355582 TI - Isolated B-cell non-Hodgkin's lymphoma of the parotid gland presenting as an ulcerating facial mass and sepsis during an acute medical take. AB - Lymphoma presenting as a parotid gland tumour without systemic involvement is rare, especially with respect to a non-Hodgkin's lymphoma. Furthermore, when such cases present there is often a low degree of clinical suspicion as there may be few clinical features to suggest the diagnosis. We describe an unexpected case that presented during an acute medical intake. The case was an 84-year-old man presenting acutely unwell with an ulcerating mass over the right side of the face, septicaemia and acute kidney injury. Following aggressive initial management the patient improved. Later cytological examination of a fine needle aspiration from the mass confirmed a B-cell non-Hodgkin's lymphoma. He had no evidence of other systemic involvement or of B-symptoms. We report on the case and briefly review the available literature relating to the prevalence of non Hodgkin's lymphoma of the parotid gland. PMID- 23355581 TI - Primary abdominal nocardiosis masquerading as tubercular pelvic inflammatory disease in an immunocompetent individual. AB - We report the case of a 30-year-old housewife who presented with fever and lower abdominal pain, and was diagnosed with an adnexal collection. Initial evaluation was suggestive of tubercular pelvic inflammatory disease (PID). Subsequently, from a culture of pus aspirated from the collection grew out Nocardia species. She was treated with amikacin and cotrimoxazole and made a complete recovery. Clinical and laboratory evaluation for immunosuppression was negative. Primary abdominal nocardiosis is an unusual cause for PID and an important differential diagnosis for tuberculosis. PMID- 23355583 TI - Progressive multifocal leukoencephalopathy during treatment with rituximab and CHOP chemotherapy in a patient with a diffuse large B-cell lymphoma. AB - A 74-year-old woman with a diffuse large B-cell lymphoma was treated with rituximab and CHOP chemotherapy. After three cycles of chemotherapy she developed progressive symptoms of motor imbalance, fatigue, weight loss and impaired cognitive function, which was interpreted as toxicity of the CHOP chemotherapy. The sixth cycle CHOP chemotherapy was withheld and three additional cycles of rituximab were given. Two weeks later, neurological symptoms appeared, including abducens nerve palsy of her left eye, ataxia and hemiparesis of her right body. MRI of the brain revealed two hyperintense lesions on T2-weighted and fluid attenuated inversion recovery images without oedema or gadolinium enhancement. A PCR on John Cunningham (JC) virus DNA in cerebrospinal fluid was negative, but subsequent brain biopsy diagnosed progressive multifocal leukoencephalopathy (PML). She rapidly deteriorated and died. Awareness of PML during immunosuppressive therapy can be lifesaving, since only immune reconstitution can prevent mortality in these patients. PMID- 23355584 TI - Combined infection of vertebroplasty and aortic graft after intravesical BCG treatment. AB - We report a 58-year-old man with spondylodiscitis by Mycobacterium bovis-BCG 3 years after intravesical BCG treatment, and shortly after a vertebroplasty. Further examination showed a psoas abscess and oedema around an endovascular aortic graft, which had been placed 1 year earlier. Puncture of the psoas abscess also grew M bovis-BCG. The patient recovered with a combination of antituberculous treatment and surgery. With hindsight a mycotic aneurysm had been present at the time of aortic graft placement and spondylodiscitis at the time of vertebroplasty. This case shows that low grade and longstanding infections may occur following intravesical BCG installation. PMID- 23355585 TI - Acute myocardial infarction and heart block: a challenge to emergency physicians. AB - We present the case of a patient who underwent an acute ST-elevation myocardial infarction of the inferior wall and transitory total heart block in the first hours of his clinical presentation. There was no haemodynamic instability before the thrombolytic therapy was performed 8 h after the onset of pain. There was no block recurrence. The current case shows a possible complication during the thrombolytic therapy and the urge for a quick decision by the emergency physician. Pacemaker implantation should be considered in the event of the patient's haemodynamic worsening once the success of the therapy is a reflex of the arrhythmia reversion most of the times. PMID- 23355586 TI - Near-fatal small bowel ischaemia secondary to sacrocolpopexy mesh. AB - A 74-year-old woman presenting with acute abdominal pain underwent surgery for suspected small bowel ischaemia. At laparotomy, a sacrocolpopexy mesh in the pelvis, which had been inserted 8 years previously, was found to be causing strangulation of a 2-m length of the small bowel. Following resection and primary anastomosis, the patient spent several days in intensive care before her eventual discharge. This unusual life-threatening complication should be considered in patients presenting with abdominal pain even many years following abdominal sacrocolpopexy. PMID- 23355587 TI - Punctate keratopathy of West Indians in patients undergoing photorefractive surgery. AB - We present two cases of patients with corneal lesions compatible with punctate keratopathy of West Indians who underwent photorefractive keratectomy and laser assisted in situ keratomileusis. Both had good postoperative results. The corneal lesions did not interfere with the refractive surgery. PMID- 23355588 TI - Innovative endovascular technique for treatment of rare cause of haemoptysis in young. AB - A 17-year-old boy reported for evaluation of two episodes of massive haemoptysis. His clinical examination was unremarkable and investigations (haemogram, coagulogram, serological tests for connective tissue disorders) were normal. A 64 slice CT angiography revealed a saccular aneurysm of 3.8*3.7*3.3 cm arising from the right lower lobe pulmonary artery which was confirmed by cardiac catheterisation. The aneurysm was successfully blocked with a 16-14 Amplatzer duct occluder. A repeat CT angiogram performed after 15 days revealed the device in situ obliterating the aneurysm. Pulmonary artery aneurysm is an extremely rare cause of massive haemoptysis and indicates imminent rupture of the aneurysm which can be rapidly fatal. This case highlights the importance of using an innovative endovascular technique for treatment of a rare cause of haemoptysis. PMID- 23355589 TI - Rifampicin pharmacokinetics in extreme prematurity to treat congenital tuberculosis. AB - Little evidence is available on the pharmacokinetics of antituberculous medication in premature infants. We report rifampicin (RMP) pharmacokinetics in an extremely premature, low-birthweight female infant born to a mother with known miliary tuberculosis. Intravenous RMP, isoniazid (INH), ciprofloxacin and amikacin were used, as the enteral route was not possible. Area under the curve calculations revealed low average RMP concentrations at doses of 5-10 mg/kg. We review the literature with regard to the dosing regimen and therapeutic drug levels of RMP and INH in premature infants and discuss issues of management. Evidence from this case suggests 10 mg/kg/day is the minimum dose required. PMID- 23355590 TI - Bronchial arterial embolisation for massive haemoptysis in cavitary sarcoidosis. AB - A 48-year-old non-smoking man with a 6-year history of pulmonary cavitary sarcoidosis presented with acute onset of haemoptysis of approximately 600 ml. Prior episodes of haemoptysis had resolved only after serial upper lobe wedge resections bilaterally and steroids. A chest CT identified bilateral upper lobe cavitary lesions with extravasation of contrast from a large right upper lobe cavity. The patient underwent urgent bronchial angiography and subsequent bronchial artery embolisation of a left bronchial artery and three right bronchial arteries. He was started on methotrexate and steroids for refractory sarcoidosis. Two years after embolisation, the patient remained haemoptysis-free with his sarcoid well controlled on methotrexate monotherapy. PMID- 23355591 TI - Iatrogenic paraformaldehyde orofacial chemical burn. PMID- 23355592 TI - Juvenile systemic lupus erythematosus with primary neuropsychiatric presentation. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple manifestations in several organs and systems. Neuropsychiatric manifestations can occur in 22-95% of paediatric cases, being much less frequent as an initial clinical event. We report a case of SLE, presenting primarily with neuropsychiatric symptoms. An African-descendant 7-year-old girl was admitted with a 4-day history of ataxia, diplopia and morning vomiting, as well as severe headache, psychiatric symptoms and cognitive dysfunction beginning 1 year prior to admission. Brain MRI was suggestive of encephalitis. Investigation excluded infectious aetiology. Immunological markers revealed high titre of antinuclear and anti-double-stranded DNA antibodies. Neuropsychiatric lupus (NPL) was considered, and cyclophosphamide and methylprednisolone pulses were started, with good initial response. Clinical deterioration motivated therapy with azathioprine with subsequent clinical stabilisation and a latent cognitive dysfunction. In unusual encephalitis presentation, a wide range of differential diagnosis has to be considered. Primary NPL presents difficult diagnostic and therapeutic challenges. PMID- 23355593 TI - Giant gastric folds in a patient with hypoalbuminaemia. PMID- 23355594 TI - Cardiopulmonary arrest owing to oesophageal achalasia recovered completely with cardiopulmonary resuscitation followed by therapeutic hypothermia. AB - We report the first case of cardiopulmonary arrest (CPA), caused by oesophageal achalasia, which recovered completely with cardiopulmonary resuscitation (CPR) followed by therapeutic hypothermia. A 53-year-old woman arrived at our hospital with recovery of spontaneous circulation (ROSC) after cardiac arrest. Dysphagia, vomiting and general fatigue had progressed for a week before. After an ambulance was called for severe dyspnoea, she collapsed in CPA. Emergency medical technicians arrived and CPR was started immediately. She experienced CPA and ROSC twice during transport to the hospital. On arrival, the patient was in respiratory distress prompting immediate intubation to eliminate airway obstruction. A CT scan revealed a transformed, occluded trachea owing to a dilated oesophagus. A large amount of food, air and saliva was suctioned with a nasogastric tube, and the patient was admitted to the intensive care unit for therapeutic hypothermia. Neurological recovery was evident. On the 11th day, pneumatic dilatation was performed and she was discharged on the 33rd day. PMID- 23355595 TI - Solar retinopathy secondary to sungazing. AB - A young woman presented with a 2-day history of bilateral central scotoma and metamorphopsia following an episode of direct sun-gazing lasting 1-2 min. On examination, visual acuity was reduced to 6/9 bilaterally. Fundal examination revealed discrete yellow lesions at both maculae consistent with solar burns. Optical coherence tomography revealed retinal pigment epithelial defects at both fovea, which improved over time. The patient was managed conservatively. There was full resolution of symptoms in the left eye; however, a central scotoma persisted in the right eye at follow-up 1 year later. PMID- 23355596 TI - Basic and advanced imaging of a case of Balo's concentric sclerosis. PMID- 23355597 TI - Catastrophic osteomyelitis following percutaneous wire fixation of a distal radial fracture: a cautionary tale of poor patient selection followed by surgical mishap. AB - We present a case of distal radius fracture. Several sequential unfortunate events resulted in a poor outcome. The patient was poorly selected because the degree of early dementia was not fully appreciated, due to intermittent periods of lucidity. Having elected to treat this distal radius fracture with Kirschner wires, a wire snapped during the procedure and was deemed safe to leave within the medullary cavity. Subsequently, the patient was left in a cast for 4 weeks without regular pin site inspection. When the cast was removed a gross osteomyelitis had developed. This series of events, led to unnecessary morbidity and extended the immobilisation time with reduced wrist function. This case highlights the importance of careful patient selection, surgical tactics and continuity of care. PMID- 23355598 TI - Penile elephantiasis: a rare consequence of inappropriate use of condom as external urinary collection receptacle. PMID- 23355600 TI - Cardiac anatomy: what the electrophysiologist needs to know. PMID- 23355601 TI - Cervical cancer screening among young adult women in the United States. AB - BACKGROUND: Cervical cancer screening guidelines have evolved significantly in the last decade for young adult women, with current recommendations promoting later initiation and longer intervals. METHODS: Using self-reported cross sectional National Health Interview Survey (NHIS) 2000-2010 data, trends in Papanicolaou (Pap) testing among women ages 18-29 years were examined. NHIS 2010 data were used to investigate age at first Pap test (N = 2,198), time since most recent Pap test (n = 1,622), and predictors of Pap testing within the last 12 months (n = 1,622). RESULTS: The percentage of 18-year-olds who reported ever having a Pap test significantly decreased from 49.9% in 2000 to 37.9% in 2010. Mean age at first Pap test in 2010 was significantly younger for non-Hispanic black women (16.9 years), women < high school education (16.9 years), women who received the HPV vaccine (17.1 years), and women who have ever given birth (17.3 years). The majority reported their last Pap test within the previous 12 months (73.1%). Usual source of healthcare (OR, 2.31) and current birth control use (OR, 1.64) significantly increased chances of having a Pap test within the previous 12 months. CONCLUSIONS: From 2000 to 2010, there was a gradual decline in Pap test initiation among 18-year-olds; however, in 2010, many women reported <=12 months since last screening. Evidence-based guidelines should be promoted, as screening young adult women for cervical cancer more frequently than recommended can cause considerable harms. IMPACT: A baseline of cervical cancer screening among young adult women in the United States to assess adherence to evidence-based screening guidelines. PMID- 23355603 TI - Only one in four people with uncontrolled epilepsy sees a specialist. PMID- 23355602 TI - Drinking water arsenic in northern chile: high cancer risks 40 years after exposure cessation. AB - BACKGROUND: Millions of people worldwide are exposed to arsenic-contaminated water. In the largest city in northern Chile (Antofagasta), more than 250,000 people were exposed to high arsenic drinking water concentrations from 1958 until 1970 when a water treatment plant was installed. Because of its unique geology, limited water sources, and good historical records, lifetime exposure and long term latency patterns can be assessed in this area with better accuracy than in other arsenic-exposed areas worldwide. METHODS: We conducted a population-based case-control study in northern Chile from October 2007 to December 2010 involving 232 bladder and 306 lung cancer cases and 640 age- and gender-matched controls, with detailed information on past exposure and potential confounders, including smoking and occupation. RESULTS: Bladder cancer ORs for quartiles of average arsenic concentrations in water before 1971 (<11, 11-90, 91-335, and >335 MUg/L) were 1.00, 1.36 [95% confidence interval (CI), 0.78-2.37], 3.87 (2.25-6.64), and 6.50 (3.69-11.43), respectively. Corresponding lung cancer ORs were 1.00, 1.27 (0.81-1.98), 2.00 (1.24-3.24), and 4.32 (2.60-7.17). Bladder and lung cancer ORs in those highly exposed in Antofagasta during 1958 to 1970 but not thereafter were 6.88 (3.84-12.32) and 4.35 (2.57-7.36), respectively. CONCLUSIONS: The lung and bladder cancer risks that we found up to 40 years after high exposures have ended are very high. IMPACT: Our findings suggest that prevention, treatment, and other mortality reduction efforts in arsenic-exposed countries will be needed for decades after exposure cessation. PMID- 23355604 TI - Germany donates ?1bn to Global Fund to Fight Aids, Tuberculosis and Malaria. PMID- 23355605 TI - Labour's plans for health and social care would not require more "top-down" NHS changes, says Burnham. PMID- 23355607 TI - Bio-sample preparation and gas chromatographic determination of benzodiazepines- a review. AB - Benzodiazepines have become commonly prescribed medicines worldwide in the therapy of anxiety, sleep disorders and convulsive attacks because they are relatively safe, with mild side effects. The availability of rapid, sensitive and selective analytical methods is essential for the determination of these drugs in clinical and forensic cases. Benzodiazepines are usually present at trace levels (MUg/mL or ng/mL) in a complex biological matrix, and the potentially interfering compounds need to be removed before analysis. Therefore, a sample preparation technique is often mandatory, both to extract the drugs of interest from the matrices and to increase their concentration. An extended and comprehensive review is presented herein, focusing on bio-sample preparation (pretreatment, extraction and derivatization) and gas chromatographic methods applied for the quantification of 1,4-benzodiazepines. PMID- 23355606 TI - Synchrony of anterior cingulate cortex and insular-striatal activation predicts ambiguity aversion in individuals with low impulsivity. AB - Personal attitude toward ambiguity contributes to individual differences in decision making in uncertain situations. Operationally, these attitudes reflect the various coping strategies elected to overcome the limited information. A key brain region involved in cognitive control for performance adjustments is the dorsal anterior cingulate cortex (dACC). To test how dACC functional network connectivity would be modulated by uncertainty and differ between individuals, 24 healthy participants underwent functional MRI in 3 sequential runs: 1 resting state and 2 decision-making task runs. Individuals with lower nonplanning impulsiveness made greater use of a Pass option and avoided uncertain ambiguous situations. Seed-based functional connectivity analysis during the task runs revealed that stronger activation synchrony between the left dACC and the right anterior insula correlated with greater use of a Pass response option. During the resting-state, stronger resting-state functional connectivity between the left dACC and the ventral striatum predicted the adoption of Pass as a behavioral strategy and correlated with stronger task-activated synchrony between the dACC and the right anterior insula. Our findings indicate that that the synchrony between the dACC and insula-striatal circuitry was greater in individuals with low compared with high nonplanning impulsiveness and contributed to adopting Pass as a useful behavioral strategy. PMID- 23355608 TI - Distinct spatiotemporal patterns and PARP dependence of XRCC1 recruitment to single-strand break and base excision repair. AB - Single-strand break repair (SSBR) and base excision repair (BER) of modified bases and abasic sites share several players. Among them is XRCC1, an essential scaffold protein with no enzymatic activity, required for the coordination of both pathways. XRCC1 is recruited to SSBR by PARP-1, responsible for the initial recognition of the break. The recruitment of XRCC1 to BER is still poorly understood. Here we show by using both local and global induction of oxidative DNA base damage that XRCC1 participation in BER complexes can be distinguished from that in SSBR by several criteria. We show first that XRCC1 recruitment to BER is independent of PARP. Second, unlike SSBR complexes that are assembled within minutes after global damage induction, XRCC1 is detected later in BER patches, with kinetics consistent with the repair of oxidized bases. Third, while XRCC1-containing foci associated with SSBR are formed both in eu- and heterochromatin domains, BER complexes are assembled in patches that are essentially excluded from heterochromatin and where the oxidized bases are detected. PMID- 23355609 TI - Importance of adenosine-to-inosine editing adjacent to the anticodon in an Arabidopsis alanine tRNA under environmental stress. AB - In all organisms, transfer RNAs (tRNAs) undergo extensive post-transcriptional modifications. Although base modifications in the anticodon are known to alter decoding specificity or improve decoding accuracy, much less is known about the functional relevance of modifications in other positions of tRNAs. Here, we report the identification of an A-to-I tRNA editing enzyme that modifies the tRNA Ala(AGC) in the model plant Arabidopsis thaliana. The enzyme is homologous to Tad1p, a yeast tRNA-specific adenosine deaminase, and it selectively deaminates the adenosine in the position 3'-adjacent to the anticodon (A37) to inosine. We show that the AtTAD1 protein is exclusively localized in the nucleus. The tad1 loss-of-function mutants isolated in Arabidopsis show normal accumulation of the tRNA-Ala(AGC), suggesting that the loss of the I37 modification does not affect tRNA stability. The tad1 knockout mutants display no discernible phenotype under standard growth conditions, but produce less biomass under environmental stress conditions. Our results provide the first evidence in support of a physiological relevance of the A37-to-I modification in eukaryotes. PMID- 23355610 TI - Helicobacter pylori DprA alleviates restriction barrier for incoming DNA. AB - Helicobacter pylori is a Gram-negative bacterium that colonizes human stomach and causes gastric inflammation. The species is naturally competent and displays remarkable diversity. The presence of a large number of restriction-modification (R-M) systems in this bacterium creates a barrier against natural transformation by foreign DNA. Yet, mechanisms that protect incoming double-stranded DNA (dsDNA) from restriction enzymes are not well understood. A DNA-binding protein, DNA Processing Protein A (DprA) has been shown to facilitate natural transformation of several Gram-positive and Gram-negative bacteria by protecting incoming single stranded DNA (ssDNA) and promoting RecA loading on it. However, in this study, we report that H. pylori DprA (HpDprA) binds not only ssDNA but also dsDNA thereby conferring protection to both from various exonucleases and Type II restriction enzymes. Here, we observed a stimulatory role of HpDprA in DNA methylation through physical interaction with methyltransferases. Thus, HpDprA displayed dual functional interaction with H. pylori R-M systems by not only inhibiting the restriction enzymes but also stimulating methyltransferases. These results indicate that HpDprA could be one of the factors that modulate the R-M barrier during inter-strain natural transformation in H. pylori. PMID- 23355611 TI - A red/far-red light-responsive bi-stable toggle switch to control gene expression in mammalian cells. AB - Growth and differentiation of multicellular systems is orchestrated by spatially restricted gene expression programs in specialized subpopulations. The targeted manipulation of such processes by synthetic tools with high-spatiotemporal resolution could, therefore, enable a deepened understanding of developmental processes and open new opportunities in tissue engineering. Here, we describe the first red/far-red light-triggered gene switch for mammalian cells for achieving gene expression control in time and space. We show that the system can reversibly be toggled between stable on- and off-states using short light pulses at 660 or 740 nm. Red light-induced gene expression was shown to correlate with the applied photon number and was compatible with different mammalian cell lines, including human primary cells. The light-induced expression kinetics were quantitatively analyzed by a mathematical model. We apply the system for the spatially controlled engineering of angiogenesis in chicken embryos. The system's performance combined with cell- and tissue-compatible regulating red light will enable unprecedented spatiotemporally controlled molecular interventions in mammalian cells, tissues and organisms. PMID- 23355612 TI - RNase H2 roles in genome integrity revealed by unlinking its activities. AB - Ribonuclease H2 (RNase H2) protects genome integrity by its dual roles of resolving transcription-related R-loops and ribonucleotides incorporated in DNA during replication. To unlink these two functions, we generated a Saccharomyces cerevisiae RNase H2 mutant that can resolve R-loops but cannot cleave single ribonucleotides in DNA. This mutant definitively correlates the 2-5 bp deletions observed in rnh201Delta strains with single rNMPs in DNA. It also establishes a connection between R-loops and Sgs1-mediated replication reinitiation at stalled forks and identifies R-loops uniquely processed by RNase H2. In mouse, deletion of any of the genes coding for RNase H2 results in embryonic lethality, and in humans, RNase H2 hypomorphic mutations cause Aicardi-Goutieres syndrome (AGS), a neuroinflammatory disorder. To determine the contribution of R-loops and rNMP in DNA to the defects observed in AGS, we characterized in yeast an AGS-related mutation, which is impaired in processing both substrates, but has sufficient R loop degradation activity to complement the defects of rnh201Delta sgs1Delta strains. However, this AGS-related mutation accumulates 2-5 bp deletions at a very similar rate as the deletion strain. PMID- 23355613 TI - Molecular paleontology: a biochemical model of the ancestral ribosome. AB - Ancient components of the ribosome, inferred from a consensus of previous work, were constructed in silico, in vitro and in vivo. The resulting model of the ancestral ribosome presented here incorporates ~20% of the extant 23S rRNA and fragments of five ribosomal proteins. We test hypotheses that ancestral rRNA can: (i) assume canonical 23S rRNA-like secondary structure, (ii) assume canonical tertiary structure and (iii) form native complexes with ribosomal protein fragments. Footprinting experiments support formation of predicted secondary and tertiary structure. Gel shift, spectroscopic and yeast three-hybrid assays show specific interactions between ancestral rRNA and ribosomal protein fragments, independent of other, more recent, components of the ribosome. This robustness suggests that the catalytic core of the ribosome is an ancient construct that has survived billions of years of evolution without major changes in structure. Collectively, the data here support a model in which ancestors of the large and small subunits originated and evolved independently of each other, with autonomous functionalities. PMID- 23355614 TI - UV damage regulates alternative polyadenylation of the RPB2 gene in yeast. AB - Alternative polyadenylation (APA) is conserved in all eukaryotic cells. Selective use of polyadenylation sites appears to be a highly regulated process and contributes to human pathogenesis. In this article we report that the yeast RPB2 gene is alternatively polyadenylated, producing two mRNAs with different lengths of 3'UTR. In normally growing wild-type cells, polyadenylation preferentially uses the promoter-proximal poly(A) site. After UV damage transcription of RPB2 is initially inhibited. As transcription recovers, the promoter-distal poly(A) site is preferentially used instead, producing more of a longer form of RPB2 mRNA. We show that the relative increase in the long RPB2 mRNA is not caused by increased mRNA stability, supporting the preferential usage of the distal poly(A) site during transcription recovery. We demonstrate that the 3'UTR of RPB2 is sufficient for this UV-induced regulation of APA. We present evidence that while transcription initiation rates do not seem to influence selection of the poly(A) sites of RPB2, the rate of transcription elongation is an important determinant. PMID- 23355615 TI - MCPIP1 ribonuclease exhibits broad-spectrum antiviral effects through viral RNA binding and degradation. AB - Monocyte chemoattractant protein 1-induced protein 1 (MCPIP1), belonging to the MCPIP family with highly conserved CCCH-type zinc finger and Nedd4-BP1, YacP Nuclease domains, has been implicated in negative regulation of the cellular inflammatory responses. In this report, we demonstrate for the first time that this RNA-binding nuclease also targets viral RNA and possesses potent antiviral activities. Overexpression of the human MCPIP1, but not MCPIP2, MCPIP3 or MCPIP4, inhibited Japanese encephalitis virus (JEV) and dengue virus (DEN) replication. The functional analysis of MCPIP1 revealed that the activities of RNase, RNA binding and oligomerization, but not deubiqutinase, are required for its antiviral potential. Furthermore, infection of other positive-sense RNA viruses, such as sindbis virus and encephalomyocarditis virus, and negative-sense RNA virus, such as influenza virus, as well as DNA virus, such as adenovirus, can also be blocked by MCPIP1. Moreover, the endogenous MCPIP1 gene expression was induced by JEV and DEN infection, and knockdown of MCPIP1 expression enhanced the replication of JEV and DEN in human cells. Thus, MCPIP1 can act as a host innate defense via RNase activity for targeting and degrading viral RNA. PMID- 23355616 TI - Effects of DNA methylation on nucleosome stability. AB - Methylation of DNA at CpG dinucleotides represents one of the most important epigenetic mechanisms involved in the control of gene expression in vertebrate cells. In this report, we conducted nucleosome reconstitution experiments in conjunction with high-throughput sequencing on 572 KB of human DNA and 668 KB of mouse DNA that was unmethylated or methylated in order to investigate the effects of this epigenetic modification on the positioning and stability of nucleosomes. The results demonstrated that a subset of nucleosomes positioned by nucleotide sequence was sensitive to methylation where the modification increased the affinity of these sequences for the histone octamer. The features that distinguished these nucleosomes from the bulk of the methylation-insensitive nucleosomes were an increase in the frequency of CpG dinucleotides and a unique rotational orientation of CpGs such that their minor grooves tended to face toward the histones in the nucleosome rather than away. These methylation sensitive nucleosomes were preferentially associated with exons as compared to introns while unmethylated CpG islands near transcription start sites became enriched in nucleosomes upon methylation. The results of this study suggest that the effects of DNA methylation on nucleosome stability in vitro can recapitulate what has been observed in the cell and provide a direct link between DNA methylation and the structure and function of chromatin. PMID- 23355620 TI - Reply to: Gilligan T. Is there such a thing as cancer treatment that isn't worth its cost? The oncologist 2012;17:3-4. PMID- 23355617 TI - Expanded target and cofactor repertoire for the transcriptional activator LysM from Sulfolobus. AB - Previously, Lrp-like transcriptional regulator LysM from the hyperthermoacidophilic crenarchaeon Sulfolobus solfataricus was proposed to have a single target, the lysWXJK operon of lysine biosynthesis, and a single effector molecule, l-lysine. Here we identify ~70 novel binding sites for LysM in the S. solfataricus genome with a LysM-specific nanobody-based chromatin immunoprecipitation assay coupled to microarray hybridization (ChIP-chip) and in silico target site prediction using an energy-based position weight matrix, and validate these findings with in vitro binding. LysM binds to intergenic and coding regions, including promoters of various amino acid biosynthesis and transport genes. We confirm that l-lysine is the most potent effector molecule that reduces, but does not completely abolish, LysM binding, and show that several other amino acids and derivatives, including d-lysine, l-arginine, l homoarginine, l-glutamine and l-methionine and branched-chain amino acids l leucine, l-isoleucine and l-valine, significantly affect DNA-binding properties of LysM. Therefore, it appears from this study that LysM is a much more versatile regulator than previously thought, and that it uses a variety of amino acids to sense nutritional quality of the environment and to modulate expression of the metabolic machinery of Sulfolobus accordingly. PMID- 23355621 TI - In reply. PMID- 23355622 TI - Erlotinib and gefitinib, epidermal growth factor receptor kinase inhibitors, may treat non-cancer-related tumor necrosis factor-alpha mediated inflammatory diseases. PMID- 23355623 TI - Vascular endothelial adrenomedullin-RAMP2 system is essential for vascular integrity and organ homeostasis. AB - BACKGROUND: Revealing the mechanisms underlying the functional integrity of the vascular system could make available novel therapeutic approaches. We previously showed that knocking out the widely expressed peptide adrenomedullin (AM) or receptor activity-modifying protein 2 (RAMP2), an AM-receptor accessory protein, causes vascular abnormalities and is embryonically lethal. Our aim was to investigate the function of the vascular AM-RAMP2 system directly. METHODS AND RESULTS: We generated endothelial cell-specific RAMP2 and AM knockout mice (E RAMP2(-/-) and E-AM(-/-)). Most E-RAMP2(-/-) mice died perinatally. In surviving adults, vasculitis occurred spontaneously. With aging, E-RAMP2(-/-) mice showed severe organ fibrosis with marked oxidative stress and accelerated vascular senescence. Later, liver cirrhosis, cardiac fibrosis, and hydronephrosis developed. We next used a line of drug-inducible E-RAMP2(-/-) mice (DI-E-RAMP2(-/ )) to induce RAMP2 deletion in adults, which enabled us to analyze the initial causes of the aforementioned vascular and organ damage. Early after the induction, pronounced edema with enhanced vascular leakage occurred. In vitro analysis revealed the vascular leakage to be caused by actin disarrangement and detachment of endothelial cells. We found that the AM-RAMP2 system regulates the Rac1-GTP/RhoA-GTP ratio and cortical actin formation and that a defect in this system causes the disruption of actin formation, leading to vascular and organ damage at the chronic stage after the gene deletion. CONCLUSIONS: Our findings show that the AM-RAMP2 system is a key determinant of vascular integrity and homeostasis from prenatal stages through adulthood. Furthermore, our models demonstrate how endothelial cells regulate vascular integrity and how their dysregulation leads to organ damage. PMID- 23355624 TI - Variation exists in rates of admission to intensive care units for heart failure patients across hospitals in the United States. AB - BACKGROUND: Despite increasing attention on reducing relatively costly hospital practices while maintaining the quality of care, few studies have examined how hospitals use the intensive care unit (ICU), a high-cost setting, for patients admitted with heart failure (HF). We characterized hospital patterns of ICU admission for patients with HF and determined their association with the use of ICU-level therapies and patient outcomes. METHODS AND RESULTS: We identified 166 224 HF discharges from 341 hospitals in the 2009-2010 Premier Perspective database. We excluded hospitals with <25 HF admissions, patients <18 years old, and transfers. We defined ICU as including medical ICU, coronary ICU, and surgical ICU. We calculated the percent of patients admitted directly to an ICU. We compared hospitals in the top quartile (high ICU admission) with the remaining quartiles. The median percentage of ICU admission was 10% (interquartile range, 6%-16%; range, 0%-88%). In top-quartile hospitals, treatments requiring an ICU were used less often; the percentage of ICU days receiving mechanical ventilation was 6% for the top quartile versus 15% for the others; noninvasive positive pressure ventilation, 8% versus 19%; vasopressors and/or inotropes, 9% versus 16%; vasodilators, 6% versus 12%; and any of these interventions, 26% versus 51%. Overall HF in-hospital risk-standardized mortality was similar (3.4% versus 3.5%; P=0.2). CONCLUSIONS: ICU admission rates for HF varied markedly across hospitals and lacked association with in-hospital risk-standardized mortality. Greater ICU use correlated with fewer patients receiving ICU interventions. Judicious ICU use could reduce resource consumption without diminishing patient outcomes. PMID- 23355625 TI - Association of cigarette smoking with skin colour in Japanese women. AB - OBJECTIVES: Having a lighter skin tone is highly valued among many Asian women. If skin colour is affected by smoking, women may be motivated to avoid tobacco or quit smoking. The present study examined the association of tobacco smoking with skin colour in Japanese women. METHOD: Information on smoking habits was obtained through a self-administered questionnaire completed by 939 Japanese women aged 20 74 in Gifu, Japan, during 2003-2006. Skin colour was examined on the inner side of the upper and lower arm and on the forehead using a Mexameter device (a narrow band reflective spectrophotometer), which expressed results as a melanin index and erythema index. RESULTS: Current smokers had higher melanin indices than never-smokers and former smokers for all measured sites. The number of cigarettes smoked per day, the years of smoking and pack-years were significantly positively associated with melanin indices for all measured sites after adjustments for age, body mass index, lifetime sun exposure, and room temperature and humidity. Smoking was also significantly associated with erythema indices on the inner upper and lower arms. CONCLUSIONS: These data suggest that smoking is associated with a darker skin colour. If our findings are confirmed by further studies, they could be used in antismoking campaigns or by smoking cessation services. PMID- 23355626 TI - Suppression of pro-inflammatory T-cell responses by human mesothelial cells. AB - BACKGROUND: Human gammadelta T cells reactive to the microbial metabolite (E)-4 hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) contribute to acute inflammatory responses. We have previously shown that peritoneal dialysis (PD) associated infections with HMB-PP producing bacteria are characterized by locally elevated gammadelta T-cell frequencies and poorer clinical outcome compared with HMB-PP negative infections, implying that gammadelta T cells may be of diagnostic, prognostic and therapeutic value in acute disease. The regulation by local tissue cells of these potentially detrimental gammadelta T-cell responses remains to be investigated. METHODS: Freshly isolated gammadelta or alphabeta T cells were cultured with primary mesothelial cells derived from omental tissue, or with mesothelial cell-conditioned medium. Stimulation of cytokine production and proliferation by peripheral T cells in response to HMB-PP or CD3/CD28 beads was assessed by flow cytometry. RESULTS: Resting mesothelial cells were potent suppressors of pro-inflammatory gammadelta T cells as well as CD4+ and CD8+ alphabeta T cells. The suppression of gammadelta T-cell responses was mediated through soluble factors released by primary mesothelial cells and could be counteracted by SB-431542, a selective inhibitor of TGF-beta and activin signalling. Recombinant TGF-beta1 but not activin-A mimicked the mesothelial cell mediated suppression of gammadelta T-cell responses to HMB-PP. CONCLUSIONS: The present findings indicate an important regulatory function of mesothelial cells in the peritoneal cavity by dampening pro-inflammatory T-cell responses, which may help preserve the tissue integrity of the peritoneal membrane in the steady state and possibly during the resolution of acute inflammation. PMID- 23355627 TI - The impact of pre-transplant dialysis on simultaneous pancreas-kidney versus living donor kidney transplant outcomes. AB - BACKGROUND: Pre-transplant dialysis is known to affect kidney graft survival. Here, we report the impact of pre-transplant dialysis on patient and graft survival of type 1 diabetic recipients of either a simultaneous pancreas-kidney (SPK) or living donor kidney (LDK) transplant. METHODS: Using the Organ Procurement Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database, 6822 adult type 1 diabetic recipients transplanted through 2000-2011 were identified. Patients were categorized based on pre-transplant dialysis time (DT): preemptive recipients (P-LDK, n = 498; P-SPK, n = 1529), recipients with <1 year of DT (0-1 year DT; LDK n = 582, SPK n = 1700), and those with 1-2 years DT (1-2 year DT; LDK n = 301, SPK n = 2212). Seven-year patient and kidney survival were examined. RESULTS: Compared with the P-SPK group, both 0-1 year DT and 1-2 year DT SPK recipients had lower 7-year patient survival (89, 84 & 84% respectively; log-rank P-value versus P-SPK = 0.01 & <0.001). For LDK groups, DT > 1 year was associated with inferior patient survival (7-year survival 76% versus 87% for P-LDK, P-value versus P-LDK = 0.009). Comparing P-LDK to all other SPK groups, there was no significant difference in 7-year patient or kidney survival. CONCLUSIONS: Preemptive transplantation is associated with the highest patient survival in both LDK and SPK. Compared with the P-LDK group, DT > 1 year is associated with lower patient survival among LDK recipients, but there is no difference in survival with dialysis up to 2 years with SPK. These results highlight the differential impact of DT on LDK and SPK transplantation. PMID- 23355628 TI - Comparison of absolute serum creatinine changes versus Kidney Disease: Improving Global Outcomes consensus definitions for characterizing stages of acute kidney injury. AB - BACKGROUND: The Kidney Disease: Improving Global Outcomes (KDIGO) system for classification of acute kidney injury (AKI) severity utilizes a staging schema based on relative changes in serum creatinine (sCr) concentration and urine output. This study compares the in-hospital mortality associated with KDIGO defined AKI stages and AKI stages defined by absolute sCr increases ('Delta Creatinine'). METHODS: The study included an analysis of hospital discharge and laboratory data from an urban academic medical center over a 1-year period. Including adult in-patients undergoing two or more sCr measurements, the study classified AKI stages using the KDIGO consensus standards as well as absolute increases in sCr ('Delta-Creatinine'); Stage 0, sCr increase <0.3 mg/dL, Stage 1, sCr increase 0.3-0.69 mg/dL, Stage 2, sCr increase 0.7-1.19 mg/dL and Stage 3, sCr increase >=1.2 mg/dL or initiation of renal replacement therapy. The Delta Creatinine cut-points were defined to optimize discrimination of in-patient mortality between AKI stages. The associations between KDIGO and Delta-Creatinine AKI stages and in-hospital mortality were compared using the time-dependent hazard ratios (HRs) and the net reclassification improvement (NRI). RESULTS: Of the 19 878 hospitalizations included in the analysis, the prevalence of AKI was 23.4% as defined by the KDIGO criteria. The Delta-Creatinine system discriminated the differences between adjacent AKI stages (i.e. 1 versus 0, 2 versus 1, 3 versus 3) earlier than the KDIGO system. The NRI between Delta-Creatinine and KDIGO for the prediction of mortality was 9.7% [95% confidence interval (CI) 6.2 13.2%]. Stratification by age, sex, race and history of chronic kidney disease (CKD) resulted in similar NRI values. CONCLUSION: The Delta-Creatinine system, based on the absolute increases in sCr, provides a promising alternative to the KDIGO system for characterizing the severity of AKI and its associations with in patient mortality. PMID- 23355631 TI - Alzheimer disease biomarker testing in cerebrospinal fluid: a method to harmonize assay platforms in the absence of an absolute reference standard. PMID- 23355629 TI - Effects of angiotensin receptor blockade (ARB) on mortality and cardiovascular outcomes in patients with long-term haemodialysis: a randomized controlled trial. AB - BACKGROUND: Hypertension is a major risk factor for death and cardiovascular disease (CVD) in patients undergoing chronic haemodialysis (HD), but there is uncertainty surrounding the effects of blood pressure (BP) lowering on this high risk patient group. METHODS: In a multicenter, prospective, randomized, open label, blinded-endpoint trial, 469 patients with chronic HD and elevated BP (140 199/90-99 mmHg) were assigned to receive the angiotensin receptor blockade (ARB) olmesartan (at a dose of 10-40 mg daily; n = 235) or another treatment that does not include angiotensin receptor blockers and angiotensin-converting enzyme (ACE) inhibitors (n = 234). The primary outcomes were the following: (i) composite of death, nonfatal stroke, nonfatal myocardial infarction and coronary revascularization and (ii) all-cause death. RESULTS: During a mean follow-up of 3.5 years, the mean BP was 0.9/0.0 mmHg lower in the olmesartan group than in the control group (not significant). A total of 68 patients (28.9%) in the olmesartan group and 67 patients (28.6%) in the control group had subsequent primary composite endpoints [hazard ratio (HR) in the olmesartan group 1.00, 95% confidence interval (CI) 0.71-1.40, P = 0.99]. All-cause deaths occurred in 38 patients (16.2%) in the olmesartan group and 39 (16.7%) in the control group (HR, 0.97; 95% CI, 0.62-1.52, P = 0.91). Olmesartan did not alter the risks of serious adverse events. CONCLUSIONS: BP-lowering treatment with an ARB did not significantly lower the risks of major cardiovascular events or death among patients with hypertension on chronic HD. (Cochrane Renal Group Prospective Trial Register number CRG010600030). PMID- 23355630 TI - Molecular pathways: adiponectin and leptin signaling in cancer. AB - The increasing percentage of obese individuals in the population and its independent association of increased risk for the development of cancer have heightened the necessity to understand the molecular mechanisms that underlie this connection. The deregulation of adipokines in the setting of obesity and their impact on cancer progression and metastasis is one such area of research. Adipokines are bioactive proteins that mediate metabolism, inflammation, angiogenesis, and proliferation. Altered levels of adipokines or their cognate receptors in cancers can ultimately lead to an imbalance in downstream molecular pathways. Discovery of adipokine receptors in various cancers has highlighted the potential for novel therapeutic targets. Leptin and adiponectin represent two adipokines that elicit generally opposing molecular effects. Epidemiologic studies have highlighted associations between increased serum leptin levels and increased tumor growth, whereas adiponectin exhibits an inverse correlation with cancer development. This review addresses the current level of understanding of molecular pathways activated by adiponectin and leptin to identify the areas of intervention and facilitate advancement in the field. PMID- 23355632 TI - MORE SPIKELETS1 is required for spikelet fate in the inflorescence of Brachypodium. AB - Grasses produce florets on a structure called a spikelet, and variation in the number and arrangement of both branches and spikelets contributes to the great diversity of grass inflorescence architecture. In Brachypodium (Brachypodium distachyon), the inflorescence is an unbranched spike with a terminal spikelet and a limited number of lateral spikelets. Spikelets are indeterminate and give rise to a variable number of florets. Here, we provide a detailed description of the stages of inflorescence development in Brachypodium. To gain insight into the genetic regulation of Brachypodium inflorescence development, we generated fast neutron mutant populations and screened for phenotypic mutants. Among the mutants identified, the more spikelets1 (mos1) mutant had an increased number of axillary meristems produced from inflorescence meristem compared with the wild type. These axillary meristems developed as branches with production of higher order spikelets. Using a candidate gene approach, mos1 was found to have a genomic rearrangement disrupting the expression of an ethylene response factor class of APETALA2 transcription factor related to the spikelet meristem identity genes branched silkless1 (bd1) in maize (Zea mays) and FRIZZY PANICLE (FZP) in rice (Oryza sativa). We propose MOS1 likely corresponds to the Brachypodium bd1 and FZP ortholog and that the function of this gene in determining spikelet meristem fate is conserved with distantly related grass species. However, MOS1 also appears to be involved in the timing of initiation of the terminal spikelet. As such, MOS1 may regulate the transition to terminal spikelet development in other closely related and agriculturally important species, particularly wheat (Triticum aestivum). PMID- 23355634 TI - Dry weight partitioning and hydraulic traits in young Pinus taeda trees fertilized with nitrogen and phosphorus in a subtropical area. AB - Plants of Pinus taeda L. from each of four families were fertilized with nitrogen (N), phosphorus (P) or N + P at planting. The H family had the highest growth in dry mass while the L family had the lowest growth. Measurements of plant hydraulic architecture traits were performed during the first year after planting. Stomatal conductance (gs), water potential at predawn (Psipredawn) and at midday (Psimidday), branch hydraulic conductivity (ks and kl) and shoot hydraulic conductance (K) were measured. One year after planting, dry weight partitioning of all aboveground organs was performed. Phosphorus fertilization increased growth in all four families, while N fertilization had a negative effect on growth. L family plants were more negatively affected than H family plants. This negative effect was not due to limitations in N or P uptake because plants from all the families and treatments had the same N and P concentration in the needles. Phosphorus fertilization changed some hydraulic parameters, but those changes did not affect growth. However, the negative effect of N can be explained by changes in hydraulic traits. L family plants had a high leaf dry weight per branch, which was increased by N fertilization. This change occurred together with a decrease in shoot conductance. Therefore, the reduction in gs was not enough to avoid the drop in Psimidday. Consequently, stomatal closure and the deficient water status of the needles resulted in a reduction in growth. In H family plants, the increase in the number of needles per branch due to N fertilization was counteracted by a reduction in gs and also by a reduction in tracheid lumen size and length. Because of these two changes, Psimidday did not drop and water availability in the needles was adequate for sustained growth. In conclusion, fertilization affects the hydraulic architecture of plants, and different families develop different strategies. Some of the hydraulic changes can explain the negative effect of N fertilization on growth. PMID- 23355633 TI - A robust and sensitive synthetic sensor to monitor the transcriptional output of the cytokinin signaling network in planta. AB - Cytokinins are classic plant hormones that orchestrate plant growth, development, and physiology. They affect gene expression in target cells by activating a multistep phosphorelay network. Type-B response regulators, acting as transcriptional activators, mediate the final step in the signaling cascade. Previously, we have introduced a synthetic reporter, Two Component signaling Sensor (TCS)::green fluorescent protein (GFP), which reflects the transcriptional activity of type-B response regulators. TCS::GFP was instrumental in uncovering roles of cytokinin and deepening our understanding of existing functions. However, TCS-mediated expression of reporters is weak in some developmental contexts where cytokinin signaling has a documented role, such as in the shoot apical meristem or in the vasculature of Arabidopsis (Arabidopsis thaliana). We also observed that GFP expression becomes rapidly silenced in TCS::GFP transgenic plants. Here, we present an improved version of the reporter, TCS new (TCSn), which, compared with TCS, is more sensitive to phosphorelay signaling in Arabidopsis and maize (Zea mays) cellular assays while retaining its specificity. Transgenic Arabidopsis TCSn::GFP plants exhibit strong and dynamic GFP expression patterns consistent with known cytokinin functions. In addition, GFP expression has been stable over generations, allowing for crosses with different genetic backgrounds. Thus, TCSn represents a significant improvement to report the transcriptional output profile of phosphorelay signaling networks in Arabidopsis, maize, and likely other plants that display common response regulator DNA-binding specificities. PMID- 23355635 TI - Climatic control of tracheid production of black spruce in dense mesic stands of eastern Canada. AB - Inferences on climate change effects are reliable only if they are based on a causal relationship rather than simple statistical predictive capacity. To assess for causal links between climate and mature black spruce (Picea mariana (Mills.) BSP) radial growth, we combined the use of wood anatomy, cambium phenology, climate and soil measurements (air temperature and humidity, precipitations, soil temperature and water content, photosynthetically active radiation), and a model selection approach proceeding backwards from a full model. Results show that the number of tracheids is responsible for 88% of the variation in ring width whereas mean tracheid diameter accounts for the remaining 12%. The number of tracheids produced depends on factors related to photosynthesis during tracheid production, i.e., daily light intensity and maximum temperature between the day of initiation and the day of cessation of tracheid production, plus soil temperature during August of the previous year which is an important period for determining the number of new needles produced. It is also important to consider duration of the period for tracheid production. These results imply that short-term climate change should increase black spruce radial growth. They also suggest that the typical use of post-growth ring width sampling individually linked to air temperature and precipitations is not sufficient to infer climate change effects accurately on radial growth where there is no strong single climatic limitation but multiple limitations instead. PMID- 23355636 TI - Characterisation of predominant molecular patterns of Burkholderia pseudomallei in Taiwan. AB - BACKGROUND: The soil-dwelling pathogen Burkholderia pseudomallei is the cause of melioidosis. In this study, the geographical and temporal distributions of predominant molecular patterns occurring in clinical and environmental isolates of B. pseudomallei were characterised. METHODS: A collection of 194 human and 59 soil B. pseudomallei isolates obtained in Taiwan were analysed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). RESULTS: Five predominant PFGE types (VI, X, XI, XV and XVI) among human isolates were identified between 2004 and 2010. Among them, types VI, X and XI correspond to ST58, and types XV and XVI correspond to ST99. The distribution of B. pseudomallei with distinct PFGE or MLST types was clustered in different towns in southern Taiwan. Clusters of B. pseudomallei have successively appeared in the town of Jiading, which is located in the Er-Ren River Basin of southern Taiwan. CONCLUSIONS: Burkholderia pseudomallei isolates were geographically and temporally clustered in Taiwan. This finding supports the contention that the Er Ren River Basin now constitutes the highest risk area for melioidosis in Taiwan. PMID- 23355637 TI - Metabolites of PPI-2458, a selective, irreversible inhibitor of methionine aminopeptidase-2: structure determination and in vivo activity. AB - The natural product fumagillin exhibits potent antiproliferative and antiangiogenic properties. The semisynthetic analog PPI-2458, [(3R,4S,5S,6R)-5 methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1 oxaspiro[2.5]octan-6-yl] N-[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate, demonstrates rapid inactivation of its molecular target, methionine aminopeptidase-2 (MetAP2), and good efficacy in several rodent models of cancer and inflammation with oral dosing despite low apparent oral bioavailability. To probe the basis of its in vivo efficacy, the metabolism of PPI-2458 was studied in detail. Reaction phenotyping identified CYP3A4/5 as the major source of metabolism in humans. Six metabolites were isolated from liver microsomes and characterized by mass spectrometry and nuclear resonance spectroscopy, and their structures were confirmed by chemical synthesis. The synthetic metabolites showed correlated inhibition of MetAP2 enzymatic activity and vascular endothelial cell growth. In an ex vivo experiment, MetAP2 inhibition in white blood cells, thymus, and lymph nodes in rats after single dosing with PPI-2458 and the isolated metabolites was found to correlate with the in vitro activity of the individual species. In a phase 1 clinical study, PPI-2458 was administered to patients with non-Hodgkin lymphoma. At 15 mg administered orally every other day, MetAP2 in whole blood was 80% inactivated for up to 48 hours, although the exposure of the parent compound was only ~10% that of the summed cytochrome P450 metabolites. Taken together, the data confirm the participation of active metabolites in the in vivo efficacy of PPI-2458. The structures define a metabolic pathway for PPI 2458 that is distinct from that of TNP-470 ([(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2 methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] N-(2 chloroacetyl)carbamate). The high level of MetAP2 inhibition achieved in vivo supports the value of fumagillin-derived therapeutics for angiogenic diseases. PMID- 23355638 TI - A physiologically based pharmacokinetic model to predict disposition of CYP2D6 and CYP1A2 metabolized drugs in pregnant women. AB - Conducting pharmacokinetic (PK) studies in pregnant women is challenging. Therefore, we asked if a physiologically based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women. We refined and verified our previously published pregnancy PBPK model by incorporating cytochrome P450 CYP1A2 suppression (based on caffeine PK) and CYP2D6 induction (based on metoprolol PK) into the model. This model accounts for gestational age dependent changes in maternal physiology and hepatic CYP3A activity. For verification, the disposition of CYP1A2-metabolized drug theophylline (THEO) and CYP2D6-metabolized drugs paroxetine (PAR), dextromethorphan (DEX), and clonidine (CLO) during pregnancy was predicted. Our PBPK model successfully predicted THEO disposition during the third trimester (T3). Predicted mean postpartum to third trimester (PP:T3) ratios of THEO area under the curve (AUC), maximum plasma concentration, and minimum plasma concentration were 0.76, 0.95, and 0.66 versus observed values 0.75, 0.89, and 0.72, respectively. The predicted mean PAR steady state plasma concentration (Css) ratio (PP:T3) was 7.1 versus the observed value 3.7. Predicted mean DEX urinary ratio (UR) (PP:T3) was 2.9 versus the observed value 1.9. Predicted mean CLO AUC ratio (PP:T3) was 2.2 versus the observed value 1.7. Sensitivity analysis suggested that a 100% induction of CYP2D6 during T3 was required to recover the observed PP:T3 ratios of PAR Css, DEX UR, and CLO AUC. Based on these data, it is prudent to conclude that the magnitude of hepatic CYP2D6 induction during T3 ranges from 100 to 200%. Our PBPK model can predict the disposition of CYP1A2, 2D6, and 3A drugs during pregnancy. PMID- 23355639 TI - Specialist clinics for reducing emergency admissions in patients with heart failure: a systematic review and meta-analysis of randomised controlled trials. AB - Unplanned admissions for heart failure are common and some are considered preventable. OBJECTIVE: Undertake a systematic literature review and meta analysis to evaluate the effectiveness of specialist clinics in reducing unplanned hospital admissions in people with heart failure. DATA SOURCES: 18 databases were searched from inception to June 2010. Relevant websites and reference lists of included studies were checked for additional publications. STUDY SELECTION: Randomised controlled trials in Organisation for Economic Co operation and Development countries that evaluated the effectiveness of specialist clinic interventions for heart failure compared with usual care, where unplanned heart failure admissions or readmissions were an outcome. DATA EXTRACTION: Data were extracted by one reviewer and checked by a second reviewer. RESULTS: 10 of 17 randomised controlled trials met the inclusion criteria. Specialist clinics showed a reduction in unplanned admissions at 12 months (pooled risk ratio (RR) for five studies 0.51 (95% CI 0.33 to 0.76); absolute risk reduction 16 per 100 (95% CI 12 to 20)). Studies with initial frequent (weekly/fortnightly) appointments reducing in frequency over the study duration demonstrated a 58% RR reduction in unplanned admissions (pooled RR for three studies 0.42 (95% CI 0.27 to 0.65); absolute risk reduction 14 per 100 (95% CI 7 to 20)). Clinics conducted on a monthly or 3 monthly basis throughout or tailored to the individual patients did not show an effect. CONCLUSIONS: Specialist clinics for patients with heart failure can reduce the risk of unplanned admissions; these were most effective when there was a high intensity of clinic appointments close to the time of discharge which then reduced over the follow-up period. PMID- 23355640 TI - Thrombus management in the catheterisation laboratory in the setting of primary percutaneous coronary intervention: what is the current evidence? PMID- 23355641 TI - Correspondence:. PMID- 23355643 TI - Acute myocardial infarction and electrically induced left bundle branch block: is a diagnosis possible? PMID- 23355645 TI - Ambulatory test result follow-up represents a serious problem and solutions are needed. PMID- 23355646 TI - Identification of sperm head proteins involved in zona pellucida binding. AB - STUDY QUESTION: Which human sperm proteins interact with zona pellucida (ZP) glycoproteins, ZPA/2, ZPB/4 and ZPC/3? SUMMARY ANSWER: Co-precipitation experiments with recombinant human ZP (rhZP) coated beads demonstrated interactions with various proteins, including glutathione S-transferase M3 (GSTM) with ZPB/4 and voltage-dependent anion channel 2 (VDAC2) with ZPA/2 and ZPC/3. WHAT IS KNOWN ALREADY: Regarding sperm-ZP binding, several target spot/proteins have been detected in several species, but not all have been characterized. The limit of these studies was that a mixture of the different ZP glycoproteins was used and did not allow the identification of the specific ZP glycoprotein (ZPA/2, ZPC/3 or ZPB/4) involved in the interaction with the sperm proteins. STUDY DESIGN, SIZE, DURATION: To identify the human sperm proteins interacting with the oocyte ZP, we combined two approaches: immunoblot of human spermatozoa targeted by antisperm antibodies (ASAs) from infertile men and far western blot of human sperm proteins overlayd by each of the rhZP proteins. MATERIALS, SETTING, METHODS: We used rhZP expressed in Chinese hamster ovary (CHO) cells and ASA eluted from infertile patients undergoing IVF failure. Sperm proteins separated by two-dimensional (2D) electrophoresis recognized by both sperm-eluted ASAs from infertile patients and rhZP were identified by mass spectrometry (MALDI-MS/MS). Some of these proteins were further validated by co-precipitation experiments with rhZP and functional zona binding tests. MAIN RESULTS AND THE ROLE OF CHANCE: We identified proteins that are glycolytic enzymes such as pyruvate kinase 3, enolase 1, glyceraldehyde-3-phosphate dehydrogenase, aldolase A, triosephosphate isomerase, detoxification enzymes such as GSTM or phospholipid hydroperoxide glutathione peroxidase, ion channels such as VDAC2 and structural proteins such as outer dense fibre 2. Several of the proteins were localized on the sperm head. However, these proteins have also been described to exert other functions in the flagellum. Co-precipitation experiments with rhZP-coated beads confirmed the direct interaction of GSTM with ZP4 and of VDAC2 with ZP2 and ZP3. LIMITATIONS, REASONS FOR CAUTION: We used recombinant ZP in place of native ZP. Thus, the post translational modifications of the proteins, such as glycosylations, can be different and can influence their function. However, CHO cell-expressed rhZP are functional, e.g. can bind human spermatozoa and induce the acrosome reaction. Moreover, the identification of relevant proteins was limited by the need for sufficient amounts of proteins on the preparative 2D-gel to be subsequently analysed in MALDI-TOF MS/MS. WIDER IMPLICATIONS OF THE FINDINGS: Our results bring new insights on the ability of sperm proteins to exert several functions depending on their sub-cellular localization, either the head or flagellum. Their multiple roles suggest that these sperm proteins are multifaceted or moonlighting proteins. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the grant ReproRio (CNRS, INRA, INSERM and CEA) and the Societe d'Andrologie de Langue Francaise. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 23355644 TI - Highly impulsive rats: modelling an endophenotype to determine the neurobiological, genetic and environmental mechanisms of addiction. AB - Impulsivity describes the tendency of an individual to act prematurely without foresight and is associated with a number of neuropsychiatric co-morbidities, including drug addiction. As such, there is increasing interest in the neurobiological mechanisms of impulsivity, as well as the genetic and environmental influences that govern the expression of this behaviour. Tests used on rodent models of impulsivity share strong parallels with tasks used to assess this trait in humans, and studies in both suggest a crucial role of monoaminergic corticostriatal systems in the expression of this behavioural trait. Furthermore, rodent models have enabled investigation of the causal relationship between drug abuse and impulsivity. Here, we review the use of rodent models of impulsivity for investigating the mechanisms involved in this trait, and how these mechanisms could contribute to the pathogenesis of addiction. PMID- 23355647 TI - Left main coronary artery compression by a left sinus of Valsalva aneurysm. AB - Myocardial ischaemia due to extrinsic left main coronary artery compression is unusual. Most cases are related to pulmonary hypertension with severe main pulmonary artery dilatation. An extremely rare cause is a left sinus of Valsalva aneurysm (SVA). We describe the case of a patient diagnosed of left SVA after a coronary angiography and aortography, whose initial clinical manifestation was an acute coronary syndrome complicated with an out-hospital resuscitated sudden cardiac death. PMID- 23355649 TI - Bullet embolization from an aorto-caval fistula to the heart. AB - Bullet emboli to the heart as a result of penetrating trauma are rare. We report a case of a 19-year old male who suffered a gunshot wound to the abdomen, resulting in an aorto-caval fistula and subsequent venous embolization of the bullet to the right ventricle. Successful surgical removal of the foreign body under cardiopulmonary bypass was performed. PMID- 23355648 TI - Wound complications after median sternotomy: a single-centre study. AB - OBJECTIVES: Sternal wound complications following median sternotomy remain a challenge in cardiac surgery. Changes in both patient profile and type of operations have been observed in recent years. Therefore, we analysed current wound healing complications after median sternotomy at our centre. METHODS: All adult patients undergoing a median sternotomy between January 2009 and April 2011 were included in this retrospective analysis. Transplants and assist devices implantations were omitted. We assessed outcome, prognostic factors and microbiological results of standardized wound swabs. RESULTS: In total, 1297 patients with an average age of 67.0 +/- 12.7 years were analysed. Operation types included 598 solitary coronary artery bypass grafts (CABGs), 213 solitary valve procedures, 105 CABGs with aortic valve replacement and 116 solitary aortic operations or conduit implantations. Furthermore, 255 of the remaining 265 were combined or otherwise complex procedures. Superficial healing disorders occurred in 43 patients (3.3%), while 33 (2.5%) developed deep wound complications. Six patients with sternal wound complications (7.9%) died in-hospital. In 7 patients, no pathogen was identified and the wound appeared uninfected (21% of all deep complications or 0.05% of all patients). These healing disorders were considered deep dehiscences. Patients with insulin-dependent diabetes mellitus, BMI of >40 kg/m(2) and who underwent reoperation were prone to superficial infections. Risk factors for all deep sternal wound complications were insulin-dependent diabetes mellitus, COPD and reoperation. Moreover, multivariate analysis revealed 'emergency' as an independent prognostic factor for all sternal wound complications. Microbial swabs of the sternal wound were taken in 82 of the 1297 patients (6.6%). Pathogens of the normal skin flora represented the majority of pathogens in both superficial and deep wound complications. Eight patients with deep, but only 2 patients with superficial complications suffered from polymicrobial infections. All deep polymicrobial infections involved coagulase negative Staphylococci. CONCLUSIONS: Wound complications following median sternotomy remain a challenge to cardiac surgery. Redo and emergency operations are the most important risk factors in this contemporary series. More efforts seem mandatory to decrease this arduous morbidity and the costs of prolonged treatment. PMID- 23355650 TI - Haemodynamically irrelevant pericardial effusion is associated with increased mortality in patients with chronic heart failure. AB - AIMS: Pericardial effusion (PE) is a common finding in cardiac patients with chronic heart failure. The prognostic relevance of a small, haemodynamically non compromising PE in such patients, however, remains to be determined. METHODS AND RESULTS: All patients referred to our heart failure clinic and having a baseline echocardiography and follow-up clinical visits were included. Patients with a haemodynamically relevant PE, acute myo-/pericarditis, systemic sclerosis, rheumatoid arthritis, heart transplantation, heart surgery within the last 6 months or malignancies within the last 3 years were excluded. Patients with or without a haemodynamically irrelevant PE were compared regarding all-cause mortality as the primary and cardiovascular death or need for heart transplantation as secondary outcomes. A total of 897 patients (824 patients in the control vs. 73 patients in the PE group) were included. In the PE group, left ventricular ejection fraction (LVEF) was lower [31%, interquartile range (IQR): 18.0-45.0] than in controls (34%, IQR: 25.0-47.0; P = 0.04), while the end systolic diameters of the left ventricle and the left atrium were larger (P = 0.01 and P = 0.001, respectively). Similarly, in patients with PE, the right ventricle (RV) systolic function was lower (P < 0.005 for both the fractional area change and the tricuspid annulus movement), the dimensions of RV and right atrium (RA) were larger (P < 0.05 for RV and P < 0.01 for RA), and the degree of tricuspid regurgitation was higher (P < 0.0001). Furthermore, in the PE group, the heart rate was higher (P < 0.001) and the leukocyte count as well as CRP values were increased (P = 0.004 and P < 0.0001, respectively); beta-blocker use was less frequent (P = 0.04), while spironolactone use was more frequent (P = 0.03). The overall survival was reduced in the PE group compared with controls (P = 0.02). Patients with PE were more likely to suffer cardiovascular death (1-year estimated event-free survival: 86 +/- 5 vs. 95 +/- 1%; P = 0.01) and to require heart transplantation (1-year estimated event-free survival: 88 +/- 4 vs. 95 +/- 1%; P = 0.009). A multivariate Cox proportional hazard model revealed the following independent predictors of mortality: (a) PE (P = 0.04, hazard ratio (HR): 1.95, 95% confidence interval (CI): 1.0-3.7), (b) age (P = 0.04, HR: 1.02, 95% CI: 1.0-1.04) and (c) LVEF <35% (P = 0.03, HR: 1.7, 95% CI: 1.1-2.8). CONCLUSION: In chronic heart failure, even minor PEs are associated with an increased risk of all-cause mortality, cardiac death, and need for transplantation. PMID- 23355651 TI - Tricuspid valve regurgitation in patients with heart failure: does it matter? PMID- 23355652 TI - Cardiac resynchronization therapy: state of the art 2013. AB - Cardiac resynchronization therapy (CRT) is currently an established device therapy for heart failure (HF) patients. Cumulated knowledge on the pathophysiological mechanisms, implantation techniques, advancement of device based technologies, and clinical trial experience has impacted on this evolving therapy significantly in the last few years. This article will address the updated CRT guideline and potentially new indications of CRT such as patients with New York Heart Association Class I, normal QRS duration, and non-HF patients with pacing indications. Furthermore, important but unresolved issues will also be discussed which include the impact of QRS morphology and QRS duration on CRT response, new approaches for placement of left ventricular (LV) lead, multisite LV pacing, and the role of HF disease monitoring program. PMID- 23355653 TI - Atrial fibrillation guidelines across the Atlantic: a comparison of the current recommendations of the European Society of Cardiology/European Heart Rhythm Association/European Association of Cardiothoracic Surgeons, the American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society, and the Canadian Cardiovascular Society. PMID- 23355655 TI - Spatial analysis of health effects of large industrial incinerators in England, 1998-2008: a study using matched case-control areas. AB - OBJECTIVES: To assess whether residential proximity to industrial incinerators in England is associated with increased risk of cancer incidence and mortality. DESIGN: Retrospective study using matched case-control areas. SETTING: Five circular regions of radius 10 km near industrial incinerators in England (case regions) and five matched control regions, 1998-2008. PARTICIPANTS: All cases of diseases of interest within the circular areas. PRIMARY AND SECONDARY OUTCOME MEASURES: Counts of childhood cancer incidence (<15 years); childhood leukaemia incidence (<15 years); leukaemia incidence; liver cancer incidence; lung cancer incidence; non-Hodgkin's lymphoma incidence; all-cause mortality; infant mortality (<1 year) and liver cancer mortality. RESULTS: The estimated relative risks for case circles versus control circles for the nine outcomes considered range from 0.94 to 1.14, and show neither elevated risk in case circles compared to control areas nor elevated risk with proximity to incinerators within case circles. CONCLUSIONS: This study applies statistical methods for analysing spatially referenced health outcome data in regions with a hypothesised exposure relative to matched regions with no such exposure. There is no evidence of elevated risk of cancer incidence or mortality in the vicinity of large industrial incinerators in England. PMID- 23355657 TI - Correction. PMID- 23355656 TI - Semen quality of fertile Japanese men: a cross-sectional population-based study of 792 men. AB - OBJECTIVES: To establish a base line for future studies on temporal trends, to describe potential geographical differences in semen quality and reference values for studies of men from the general population. DESIGN: Cross-sectional study of fertile men from four areas in Japan. Inclusion criteria were: age 20-45 years at the time of invitation, and both the man and his mother had to be born in Japan. Additionally, the current pregnancy of the female partner had to be achieved by normal sexual relations without any fertility treatment. SETTING: Four Japanese study centres at urban areas located in Sapporo, Osaka, Kanazawa and Fukuoka. PARTICIPANTS: 792 men, median age 31.4 years, included from 1999 to 2002. OUTCOME MEASURES: Semen volume, sperm concentration, total sperm count, sperm motility and sperm morphology. RESULTS: Semen volumes, percentages of motile spermatozoa and morphologically normal spermatozoa differed slightly between the four groups, whereas no differences in sperm concentrations or total sperm counts were found. In total, 1.2% of men had a sperm concentration below 5 million/ml, 2.1% below 10 million/ml, 3.5% below 15 million/ml and 16.3% below 40 million/ml. For morphology, 14.7% had less than 5% normal spermatozoa. Reproductive hormone levels varied significantly, however, only little from a biological point of view. CONCLUSIONS: This is the first cross-sectional study on semen quality covering fertile men from the major regions of Japan. It showed that semen quality of fertile Japanese men is comparable to that of the best in European regions. The results may serve as reference values for studies of men from the general population. PMID- 23355658 TI - The use of individual patient-level data (IPD) to quantify the impact of pretreatment predictors of response to treatment in chronic hepatitis B patients. AB - OBJECTIVES: Evidence synthesis is an integral part decision-making by reimbursement agencies. When direct evidence is not available, network-meta analysis (NMA) techniques are commonly used. This approach assumes that the trials are sufficiently similar in terms of treatment-effect modifiers. When imbalances in potential treatment-effect modifiers exist, the NMA approach may not produce fair comparisons. The objective of this study was to identify and quantify the interaction between treatment-effect and potential treatment-effect modifiers, including time-of-response measurement and baseline viral load in chronic hepatitis B (CHB) patients. DESIGN: Retrospective patient-level data econometric analysis. PARTICIPANTS: 1353 individuals from two randomised controlled trials of nucleoside-naive CHB taking 0.5 mg entecavir (n=679) or 100 mg lamivudine (n=668) daily for 48 weeks. INTERVENTIONS: Hepatitis B virus (HBV) DNA levels for both drugs were measured at baseline and weeks 24, 36 and 48. Generalised estimating equation for repeated binary responses was used to identify treatment-effect modifiers for response defined at <=400 or <=300 copies/ml. PRIMARY OUTCOME MEASURES: OR at 48 weeks. RESULTS: The OR for the time of-response measurement and treatment-effect interaction term was 1.039 (p=0.00) and 1.035 (p=0.00) when response was defined at <=400 or <=300 copies/ml, respectively. The baseline HBV DNA and treatment-effect interaction OR was 0.94 (p=0.047) and 0.95 (p=0.096), respectively, for the two response definitions suggesting evidence of interaction between baseline disease activity and treatment effect. The interaction between HBeAg status and treatment effect was not statistically significant. CONCLUSIONS: The measurement time point seems to modify the relative treatment effect of entacavir compared to lamivudine, measured on the OR scale. Evidence also suggested that differences in baseline viral load may also alter relative treatment effect. Meta-analyses should account for such modifiers when generating relative efficacy estimates. PMID- 23355654 TI - Implementation of standardized assessment and reporting of myocardial infarction in contemporary randomized controlled trials: a systematic review. AB - Myocardial infarction (MI) is a key endpoint in randomized controlled trials (RCTs), but heterogeneous definitions limit comparisons across RCTs or meta analyses. The 2000 European Society of Cardiology/American College of Cardiology MI redefinition and the 2007 universal MI definition consensus documents made recommendations to address this issue. In cardiovascular randomized trials, we evaluated the impact of implementation of three key recommendations from these reports-troponin use to define MI; separate reporting of spontaneous and procedure-related MI; and infarct size reporting. We searched ClinicalTrials.gov and MEDLINE databases for cardiovascular RCTs with more than 500 patients in which enrolment began between September 2000 and July 2012 and that listed MI in the primary endpoint. We searched English-language publications with primary results or design papers. Of 3222 studies screened, 96 (3.0%) met our criteria. We extracted enrolment start date, number of patients and MI events, follow-up duration, and coronary revascularization rate. Data extraction quality was assessed by duplicated extractions. Of 96 RCTs, 80 had a primary results publication, comprising 608 091 patients and 43 621 endpoint MIs. Myocardial infarction represented 45.3% (95% confidence interval, 40.2-50.4) of events in the primary composite endpoint. Troponin defined MI in 57% (53/93) of trials with an MI definition available. Of these RCTs, three used troponin only if creatine kinase-MB was unavailable, six used troponin to define peri-procedural MI, seven specified the 99th percentile as the MI decision limit, and three reported spontaneous and procedure-related MI separately. None reported biomarker-based infarct size, but five reported MI as multiples of the assay upper limit of normal. Although MI is a major component of cardiovascular RCT primary endpoints, standardized MI reporting and implementation of consensus document recommendations for MI definition are limited. Developing appropriate strategies for uniform implementation is required. PMID- 23355659 TI - Police officers: a high-risk group for the development of mental health disturbances? A cohort study. AB - OBJECTIVES: Policing is generally considered a high-risk profession for the development of mental health problems, but this assumption lacks empirical evidence. Research question of the present study is to what extent mental health disturbances, such as (very) severe symptoms of anxiety, depression and hostility are more prevalent among police officers than among other occupational groups. DESIGN: Multicomparative cross-sectional study using the data of several cross sectional and longitudinal studies in the Netherlands. PARTICIPANTS: Two samples of police officers (N=144 and 503), employees of banks (N=1113) and employees of banks who were robbed (N=144); employees of supermarkets (N=335), and a psychiatric hospital (N=219), employees of a governmental social welfare organisation (N=76), employees who followed a training based on rational-motive therapy to strengthen their assertiveness (N=710), soldiers before deployment (N=278) and before redeployment (N=236) and firefighters (N=123). The numbers refer to respondents with complete data. PRIMARY OUTCOMES: Prevalence of severe (subclinical level) and very severe symptoms (clinical level) were computed using the Dutch norm tables (80th percentile and 95th percentile, respectively) of the Symptom Check List Revised (SCL-90-R). All comparisons were controlled for age, gender and education. RESULTS: Multivariate logistic regression and analyses showed that the prevalence of clinical and subclinical levels of symptoms of anxiety, depression and hostility among police officers were not significantly higher than among comparison groups. The same pattern was found for the other SCL 90-R subscales. CONCLUSIONS: We found no indications that self-reported mental health disturbances were more prevalent among police officers than among groups of employees that are not considered high-risk groups, such as employees of banks, supermarkets, psychiatric hospital and soldiers before deployment. PMID- 23355660 TI - Emergency department visits for fall-related fractures among older adults in the USA: a retrospective cross-sectional analysis of the National Electronic Injury Surveillance System All Injury Program, 2001-2008. AB - OBJECTIVES: To describe the demographic characteristics and incidence of unintentional fall-related fractures among older adults treated in the US hospital emergency departments (EDs). DESIGN: Retrospective observational study. SETTINGS: Hospitals' ED participants in the National Electronic Injury Surveillance System All Injury Program (NEISS-AIP). PARTICIPANTS: The NEISS-AIP was used to generate national estimates of hospital ED visits for unintentional fall-related fracture among adults aged 65 years or older between 2001 and 2008. Census population estimates were used as the denominator to calculate age specific and age-adjusted fracture rates per 100 000 persons. MAIN OUTCOME MEASURES: Fall-related fracture rates and ED disposition. RESULTS: On the basis of 70 199 cases, an estimated 4.05 million older adults were treated in US hospital EDs for fall-related fracture during the 8-year period. Two-thirds of the injuries occurred at home and 69.5% (95% CI 59.7% to 77.8%) of the affected individuals were white. Fall-related fracture rates increased gradually with age and were on average twofold higher among women. Of those hospitalised, women and fractures of the lower trunk represented 75.2% and 65.1% of the admissions, respectively. The estimated number of fall-related fractures treated in EDs increased from 574 500 in 2001 to 714 800 in 2008, a 24.4% increase. By gender, a non-significant upward trend in age-adjusted fall-related fracture rates was predominantly seen among men at an annual rate of 1.9% (95% CI -0.1% to 4.0%), whereas fracture rates among women remained stable at 0.9% (95% CI -0.7% to 2.5%) per year. CONCLUSIONS: The oldest old, women and lower trunk fractures account for the majority of fall-related fractures among persons aged 65 years or older treated in US hospital EDs. Increasing ED visits and hospitalisations for fall related fracture among older adults deserve further research. PMID- 23355661 TI - Cardiovascular and non-cardiovascular hospital admissions associated with atrial fibrillation: a Danish nationwide, retrospective cohort study. AB - OBJECTIVE: To examine the excess risk of hospitalisation in patients with incident atrial fibrillation (AF). DESIGN: A nationwide, retrospective cohort study. SETTING: Denmark. PARTICIPANTS: Data on all admissions in Denmark from 1997 to 2009 were collected from nationwide registries. After exclusion of subjects previously admitted for AF, data on 4 602 264 subjects and 10 779 945 hospital admissions contributed to the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Age-stratified and sex-stratified admission rates were calculated for cardiovascular and non-cardiovascular admissions. Temporal patterns of readmission, relative risk and duration of frequent types of admission were calculated. RESULTS: Of 10 779 945 hospital admissions, 729 088(6.8%) were associated with AF. Admissions for cardiovascular reasons after 1, 3 and 6 months occurred for 6.0, 14.3 and 28.4% of AF patients versus 0.2, 0.6 and 1.8 of non-AF patients. Admissions for non-cardiovascular reasons after 1, 3 and 6 months comprised 6.8, 16.1 and 33.3% of AF patients and 1.2, 3.2 and 9.7% of non-AF patients. When stratified for age, AF was associated with similar cardiovascular admission rates across all age groups, while non-cardiovascular admission rates were higher in older patients. Within each age group and for both cardiovascular and non-cardiovascular admissions, AF was associated with higher rates of admission. When adjusted for age, sex and time period, patients with AF had a relative risk of 8.6 (95% CI 8.5 to 8.6) for admissions for cardiovascular reasons and 4.0 (95% CI 4.0 to 4.0) for admission for non-cardiovascular reasons. CONCLUSIONS: This study confirms that the burden of AF is considerable and driven by both cardiovascular and non-cardiovascular admissions. These findings underscore the importance of using clinical and pharmacological means to reduce the hospital burden of AF in Western healthcare systems. PMID- 23355662 TI - Heat-related respiratory hospital admissions in Europe in a changing climate: a health impact assessment. AB - OBJECTIVES: Respiratory diseases are ranked second in Europe in terms of mortality, prevalence and costs. Studies have shown that extreme heat has a large impact on mortality and morbidity, with a large relative increase for respiratory diseases. Expected increases in mean temperature and the number of extreme heat events over the coming decades due to climate change raise questions about the possible health impacts. We assess the number of heat-related respiratory hospital admissions in a future with a different climate. DESIGN: A Europe-wide health impact assessment. SETTING: An assessment for each of the EU27 countries. METHODS: Heat-related hospital admissions under a changing climate are projected using multicity epidemiological exposure-response relationships applied to gridded population data and country-specific baseline respiratory hospital admission rates. Times-series of temperatures are simulated with a regional climate model based on four global climate models, under two greenhouse gas emission scenarios. RESULTS: Between a reference period (1981-2010) and a future period (2021-2050), the total number of respiratory hospital admissions attributed to heat is projected to be larger in southern Europe, with three times more heat attributed respiratory hospital admissions in the future period. The smallest change was estimated in Eastern Europe with about a twofold increase. For all of Europe, the number of heat-related respiratory hospital admissions is projected to be 26 000 annually in the future period compared with 11 000 in the reference period. CONCLUSIONS: The results suggest that the projected effects of climate change on temperature and the number of extreme heat events could substantially influence respiratory morbidity across Europe. PMID- 23355663 TI - Does implementation of the IMCI strategy have an impact on child mortality? A retrospective analysis of routine data from Egypt. AB - BACKGROUND: Between 1999 and 2007, the Ministry of Health and Population in Egypt scaled up the Integrated Management of Childhood Illness (IMCI) strategy in 84% of public health facilities. OBJECTIVES: This retrospective analysis, using routinely available data from vital registration, aimed to assess the impact of IMCI implementation between 2000 and 2006 on child mortality. It also presents a systematic and comprehensive approach to scaling-up IMCI interventions and information on quality of child health services, using programme data from supervision and surveys. METHODS: We compared annual levels of under-five mortality in districts before and after they had started implementing IMCI. Mortality data were obtained from the National Bureau for Statistics for 254 districts for the years 2000-2006, 41 districts of which were excluded. For assessment of programme activities, we used information from the central IMCI data base, annual progress reports, follow-up after training visits and four studies on quality of child care in public health facilities. RESULTS: Across 213 districts retained in the analysis, the estimated average annual rate of decline in under-five mortality was 3.3% before compared with 6.3% after IMCI implementation (p=0.0001). In 127 districts which started implementing IMCI between 2002 and 2005, the average annual rate of decline of under-five mortality was 2.6% (95% CI 1.1% to 4.1%) before compared with 7.3% (95% CI 5.8% to 8.7%) after IMCI implementation (p<0.0001). IMCI implementation also led to marked improvements in the quality of child health services. INTERPRETATION: IMCI implementation was associated with a doubling in the annual rate of under-five mortality reduction (3.3% vs 6.3%). This mortality impact is plausible, since substantial improvements occurred in quality of care provided to sick children in health facilities implementing IMCI. PMID- 23355664 TI - Framework of policy recommendations for implementation of evidence-based practice: a systematic scoping review. AB - OBJECTIVES: Evidence-based practice (EBP) may help improve healthcare quality. However, not all healthcare professionals and managers use EBP in their daily practice. We systematically reviewed the literature to summarise self-reported appreciation of EBP and organisational infrastructure solutions proposed to promote EBP. DESIGN: Systematic review. Two investigators independently performed the systematic reviewing process. INFORMATION SOURCES: MEDLINE, EMBASE and Cochrane Library were searched for publications between 2000 and 2011. ELIGIBILITY CRITERIA FOR INCLUDED STUDIES: Reviews and surveys of EBP attitude, knowledge, awareness, skills, barriers and facilitators among managers, doctors and nurses in clinical settings. RESULTS: We found 31 surveys of fairly good quality. General attitude towards EBP was welcoming. Respondents perceived several barriers, but also many facilitators for EBP implementation. Solutions were proposed at various organisational levels, including (inter)national associations and hospital management promoting EBP, pregraduate and postgraduate education, as well as individual support by EBP mentors on the wards to move EBP from the classroom to the bedside. CONCLUSIONS: More than 20 years after its introduction, the EBP paradigm has been embraced by healthcare professionals as an important means to improve quality of patient care, but its implementation is still deficient. Policy exerted at microlevel , middlelevel and macrolevel, and supported by professional, educational and managerial role models, may further facilitate EBP. PMID- 23355665 TI - Abdominal fat distribution and its relationship to brain changes: the differential effects of age on cerebellar structure and function: a cross sectional, exploratory study. AB - OBJECTIVES: To investigate whether the metabolically important visceral adipose tissue (VAT) relates differently to structural and functional brain changes in comparison with body weight measured as body mass index (BMI). Moreover, we aimed to investigate whether these effects change with age. DESIGN: Cross-sectional, exploratory. SETTING: University Clinic, Integrative Research and Treatment Centre. PARTICIPANTS: We included 100 (mean BMI=26.0 kg/m², 42 women) out of 202 volunteers randomly invited by the city's registration office, subdivided into two age groups: young-to-mid-age (n=51, 20-45 years of age, mean BMI=24.9, 24 women) versus old (n=49, 65-70 years of age, mean BMI=27.0, 18 women). MAIN OUTCOME MEASURES: VAT, BMI, subcutaneous abdominal adipose tissue, brain structure (grey matter density), functional brain architecture (eigenvector centrality, EC). RESULTS: We discovered a loss of cerebellar structure with increasing VAT in the younger participants, most significantly in regions involved in motor processing. This negative correlation disappeared in the elderly. Investigating functional brain architecture showed again inverse VAT cerebellum correlations, whereas now regions involved in cognitive and emotional processing were significant. Although we detected similar results for EC using BMI, significant age interaction for both brain structure and functional architecture was only found using VAT. CONCLUSIONS: Visceral adiposity is associated with cerebellar changes of both structure and function, whereas the regions involved contribute to motor, cognitive and emotional processes. Furthermore, these associations seem to be age dependent, with younger adults' brains being adversely affected. PMID- 23355666 TI - Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. AB - OBJECTIVES: To synthesise current evidence for the effects of exenatide and liraglutide on heart rate, blood pressure and body weight. DESIGN: Meta-analysis of available data from randomised controlled trials comparing Glucagon-like peptide-1 (GLP-1) analogues with placebo, active antidiabetic drug therapy or lifestyle intervention. PARTICIPANTS: Patients with type 2 diabetes. OUTCOME MEASURES: Weighted mean differences between trial arms for changes in heart rate, blood pressure and body weight, after a minimum of 12-week follow-up. RESULTS: 32 trials were included. Overall, GLP-1 agonists increased the heart rate by 1.86 beats/min (bpm) (95% CI 0.85 to 2.87) versus placebo and 1.90 bpm (1.30 to 2.50) versus active control. This effect was more evident for liraglutide and exenatide long-acting release than for exenatide twice daily. GLP-1 agonists decreased systolic blood pressure by -1.79 mm Hg (-2.94 to -0.64) and -2.39 mm Hg (-3.35 to -1.42) compared to placebo and active control, respectively. Reduction in diastolic blood pressure failed to reach statistical significance (-0.54 mm Hg ( 1.15 to 0.07) vs placebo and -0.50 mm Hg (-1.24 to 0.24) vs active control). Body weight decreased by -3.31 kg (-4.05 to -2.57) compared to active control, but by only -1.22 kg (-1.51 to -0.93) compared to placebo. CONCLUSIONS: GLP-1 analogues are associated with a small increase in heart rate and modest reductions in body weight and blood pressure. Mechanisms underlying the rise in heart rate require further investigation. PMID- 23355667 TI - Determinants of self-reported smoking and misclassification during pregnancy, and analysis of optimal cut-off points for urinary cotinine: a cross-sectional study. AB - OBJECTIVES: To estimate the prevalence and factors associated with smoking and misclassification in pregnant women from INMA (INfancia y Medio Ambiente, Environment and Childhood) project, Spain, and to assess the optimal cut-offs for urinary cotinine (UC) that best distinguish daily and occasional smokers with varying levels of second-hand smoke (SHS) exposure. DESIGN: We used logistic regression models to study the relationship between sociodemographic variables and self-reported smoking and misclassification (self-reported non-smokers with UC >50 ng/ml). Receiver operating characteristic (ROC) curves were used to calculate the optimal cut-off point for discriminating smokers. The cut-offs were also calculated after stratification among non-smokers by the number of sources of SHS exposure. The cut-off points used to discriminate smoking status were the level of UC given by Youden's index and for 50 and 100 ng/ml for daily smokers, or 25 and 50 ng/ml for occasional smokers. PARTICIPANTS: At the third trimester of pregnancy, 2263 pregnant women of the INMA Project were interviewed between 2004 and 2008 and a urine sample was collected. RESULTS: Prevalence of self reported smokers at the third trimester of pregnancy was 18.5%, and another 3.9% misreported their smoking status. Variables associated with self-reported smoking and misreporting were similar, including born in Europe, educational level and exposure to SHS. The optimal cut-off was 82 ng/ml (95% CI 42 to 133), sensitivity 95.2% and specificity 96.6%. The area under the ROC curve was 0.986 (95% CI 0.982 to 0.990). The cut-offs varied according to the SHS exposure level being 42 (95% CI 27 to 57), 82 (95% CI 46 to 136) and 106 ng/ml (95% CI 58 to 227) for not being SHS exposed, exposed to one, and to two or more sources of SHS, respectively. The optimal cut-off for discriminating occasional smokers from non smokers was 27 ng/ml (95% CI 11 to 43). CONCLUSIONS: Prevalence of smoking during pregnancy in Spain remains high. UC is a reliable biomarker for classifying pregnant women according to their smoking status. However, cut-offs would differ based on baseline exposure to SHS. PMID- 23355668 TI - Optimising drug prescribing and dispensing in subjects at risk for drug errors due to renal impairment: improving drug safety in primary healthcare by low eGFR alerts. AB - OBJECTIVES: To assess the risk of medication errors in subjects with renal impairment (defined as an estimated glomerular filtration rate (eGFR) <=40 ml/min/1.73 m(2)) and the effectiveness of automatic eGFR <=40-alerts relayed to community pharmacists. DESIGN: Clinical survey. SETTING: The city of Zwolle, The Netherlands, in a primary care setting including 22 community pharmacists and 65 general practitioners. PARTICIPANTS: All adults who underwent ambulatory creatine measurements which triggered an eGFR <=40-alert. PRIMARY AND SECONDARY OUTCOME MEASURES: The total number of ambulatory subjects with an eGFR <=40-alert during the study period of 1 year and the number of medication errors related to renal impairment. The type and number of proposed drug adjustments recommended by the community pharmacist and acceptance rate by the prescribing physicians. Classification of all medication errors on their potential to cause an adverse drug event (ADE) and the actual occurrence of ADEs (limited to those identified through hospital record reviews) 1 year after the introduction of the alerts. RESULTS: Creatine measurements were performed in 25 929 adults. An eGFR <=40 alert was indicated for 5.3% (n=1369). This group had a median (IQR) age of 78 (69, 84) years, and in 73% polypharmacy (>=5 drugs) was present. In 15% (n=211) of these subjects, a medication error was detected. The proportion of errors increased with age. Pharmacists recommended 342 medication adjustments, mainly concerning diuretics (22%) and antibiotics (21%). The physicians' acceptance rate was 66%. Of all the medication errors, 88% were regarded as potential ADEs, with most classified as significant or serious. At follow-up, the ADE risk (n=40) appeared highest when the proposed medication adjustments were not implemented (38% vs 6%). CONCLUSIONS: The introduction of automatic eGFR-alerts identified a considerable number of subjects who are at risk for ADEs due to renal impairment in an ambulatory setting. The nationwide implementation of this simple protocol could identify many potential ADEs, thereby substantially reducing iatrogenic complications in subjects with impaired renal function. PMID- 23355669 TI - The daily 10 kcal expenditure deficit: a before-and-after study on low-cost interventions in the work environment. AB - OBJECTIVES: To evaluate whether four types of low-cost interventions in the working environment can promote the small everyday lifestyle adaptations that can halt the epidemics of obesity and hypertension when maintained long term. DESIGN: A single-blind uninterrupted time-series intervention study consisting of four study periods: run-in (2 weeks), baseline (2 weeks), intervention (2 weeks), and after intervention 2 weeks). SETTING: University Medical Centre with over 11 000 employees, over 1000 hospital beds and over 2000 customers visiting the hospital restaurant each day. PARTICIPANTS: Hospital staff and visitors. INTERVENTIONS: (1) Point-of-decision prompts on hospital elevator doors promoting stair use. (2) Point-of-purchase prompts in the hospital restaurant promoting reduced-salt soup. (3) Point-of-purchase prompts in the hospital restaurant promoting lean croissants. (4) Reversal of the accessibility and availability of diet margarine and butter in the hospital restaurant. MAIN OUTCOME MEASURES: (1) Number of passages through 15 different parts of the hospital staircases. (2) Number and ratio of normal-salt and reduced-salt soup purchased. (3) Number and ratio of butter croissants and lean croissants purchased. (4) Number and ratio of diet margarine and butter purchased. RESULTS: Elevator signs increased the mean 24-h number of stair passages per measurement site (baseline: 992 +/- 479 on week days and 208 +/- 116 on weekend days) by 11.2% (95% CI 8.7% to 13.7%). This effect was maintained at least 2 weeks after the point-of-decision prompts were removed. Point-of-purchase prompts promoting low-salt soup and lean croissants did not result in altered purchase behaviour. The ratio between the purchase of margarine and butter was changed sevenfold (p<0.01) by reversing the positions of these products in the hospital restaurant. CONCLUSIONS: Healthy lifestyle adaptations in the working environment can be effectively promoted by making healthy choices easier than unhealthy ones. Educational prompts at points-of-decision moderately increase stair climbing, but do not affect healthy food choices. PROTOCOL REGISTRATION: Clinicaltrials.gov identifier number: NCT01574040. PMID- 23355670 TI - The beliefs and expectations of patients and caregivers about home haemodialysis: an interview study. AB - OBJECTIVES: To explore the beliefs and expectations of patients and their caregivers about home haemodialysis in Italy where the prevalence of home haemodialysis is low. DESIGN: Semistructured, qualitative interview study with purposive sampling and thematic analysis. SETTING: Four dialysis centres in Italy without home haemodialysis services (Bari, Marsala, Nissoria and Taranto). PARTICIPANTS: 22 patients receiving in-centre haemodialysis and 20 of their identified caregivers. RESULTS: We identified seven major themes that were central to patient and caregiver perceptions of home haemodialysis in regions without established services. Three positive themes were: flexibility and freedom (increased autonomy, minimised wasted time, liberation from strict dialysis schedules and gaining self-worth); comfort in familiar surroundings (family presence and support, avoiding the need for dialysis in hospital) and altruistic motivation to do home haemodialysis as an exemplar for other patients and families. Four negative themes were: disrupting sense of normality; family burden (an onerous responsibility, caregiver uncertainty and panic and visually confronting); housing constraints; healthcare by 'professionals' not 'amateurs' (relinquishing security and satisfaction with in-centre services) and isolation from peer support. CONCLUSIONS: Patients without direct experience or previous education about home haemodialysis and their caregivers recognise the autonomy of home haemodialysis but are very concerned about the potential burden and personal sacrifice home haemodialysis will impose on caregivers and feel apprehensive about accepting the medical responsibilities of dialysis. To promote acceptance and uptake of home haemodialysis among patients and caregivers who have no experience of home dialysis, effective strategies are needed that provide information about home haemodialysis to patients and their caregivers, assure access to caregiver respite, provide continuous availability of medical and technical advice and facilitate peer patient support. PMID- 23355671 TI - The TrueBlue model of collaborative care using practice nurses as case managers for depression alongside diabetes or heart disease: a randomised trial. AB - OBJECTIVES: To determine the effectiveness of collaborative care in reducing depression in primary care patients with diabetes or heart disease using practice nurses as case managers. DESIGN: A two-arm open randomised cluster trial with wait-list control for 6 months. The intervention was followed over 12 months. SETTING: Eleven Australian general practices, five randomly allocated to the intervention and six to the control. PARTICIPANTS: 400 primary care patients (206 intervention, 194 control) with depression and type 2 diabetes, coronary heart disease or both. INTERVENTION: The practice nurse acted as a case manager identifying depression, reviewing pathology results, lifestyle risk factors and patient goals and priorities. Usual care continued in the controls. MAIN OUTCOME MEASURE: A five-point reduction in depression scores for patients with moderate to-severe depression. Secondary outcome was improvements in physiological measures. RESULTS: Mean depression scores after 6 months of intervention for patients with moderate-to-severe depression decreased by 5.7+/-1.3 compared with 4.3+/-1.2 in control, a significant (p=0.012) difference. (The plus-minus is the 95% confidence range.) Intervention practices demonstrated adherence to treatment guidelines and intensification of treatment for depression, where exercise increased by 19%, referrals to exercise programmes by 16%, referrals to mental health workers (MHWs) by 7% and visits to MHWs by 17%. Control-practice exercise did not change, whereas referrals to exercise programmes dropped by 5% and visits to MHWs by 3%. Only referrals to MHW increased by 12%. Intervention improvements were sustained over 12 months, with a significant (p=0.015) decrease in 10-year cardiovascular disease risk from 27.4+/-3.4% to 24.8+/-3.8%. A review of patients indicated that the study's safety protocols were followed. CONCLUSIONS: TrueBlue participants showed significantly improved depression and treatment intensification, sustained over 12 months of intervention and reduced 10-year cardiovascular disease risk. Collaborative care using practice nurses appears to be an effective primary care intervention. TRIAL REGISTRATION: ACTRN12609000333213 (Australia and New Zealand Clinical Trials Registry). PMID- 23355672 TI - Is it intelligent to intercalate? A two centre cross-sectional study exploring the value of intercalated degrees, and the possible effects of the recent tuition fee rise in England. AB - AIMS AND OBJECTIVES: To explore the value of intercalated degrees, including student perceptions and academic sequelae. To gauge the likely effect of the recent tuition fee rise and to identify any differences in intercalated degrees between Bristol and Sheffield universities. DESIGN: Cross-sectional study using questionnaires. SETTING: Bristol and Sheffield Medical Schools, UK. PARTICIPANTS: 1484 medical students in their clinical years were e-mailed the questionnaire. 578 students responded: 291 from Bristol and 287 from Sheffield (n=578; mean age=22.41; SD 1.944; 38.9% male; 61.1% female). The response rate from previous intercalators was 52.5% from Bristol and 58.7% from Sheffield, while for non intercalators it was 27.7% and 34.6%, respectively. MAIN OUTCOME MEASURES: (1) Student preconceptions, opinions, results and academic sequelae from intercalated degrees at both centres. (2) Students' attitudes concerning the effect of the increase in tuition fees. RESULTS: Those with clinical academic supervisors gained significantly more posters (p=0.0002) and publications (p<0.0001), and also showed a trend to gain more first class honours (p=0.055). Students at Sheffield had a significantly greater proportion of clinical academic supervisors than students at Bristol (p<0.0001). 89.2% said that an intercalated degree was the right decision for them; however, only 27.4% stated they would have intercalated if fees had been L9000 per annum. CONCLUSIONS: Students clearly value intercalated degrees, feel they gained a substantial advantage over their peers as well as skills helpful for their future careers. The rise in tuition fees is likely to reduce the number of medical students opting to undertake an intercalated degree, and could result in a further reduction in numbers following an academic path. Sheffield University have more intercalating students supervised by clinical academics. Clinical academics appear more effective as supervisors for medical students undertaking an intercalated degree in terms of results and additional academic sequelae. PMID- 23355673 TI - Direct treatment comparison of DAbigatran and RIvaroxaban versus NAdroparin in the prevention of venous thromboembolism after total knee arthroplasty surgery: design of a randomised pilot study (DARINA). AB - INTRODUCTION: Two novel agents, dabigatran and rivaroxaban, recently gained market authorisation for prevention of venous thromboembolism (VTE) after hip and knee arthroplasty. However, safety data of the new oral anticoagulants with a long-term use of 42 days are not available for total knee arthroplasty (TKA). Furthermore, there are no clinical trials comparing dabigatran and/or rivaroxaban with nadroparin, which is used in most Dutch departments of orthopaedic surgery. Our aim is to compare the 42-day use of dabigatran and rivaroxaban versus nadroparin after TKA in a clinical explorative pilot study by assessing the incidence of major bleeding and clinically relevant non-major bleeding using a standardised model of bleeding definitions. METHODS AND ANALYSIS: A randomised open-label pilot study was conducted. Patients >=18 years and weighing more than 40 kg who were scheduled for a primary elective TKA were included. Patients were randomly assigned to three groups. Patients took either a daily oral dose of dabigatran etexilate 220 mg (n=50), 10 mg of oral rivaroxaban (n=50) or subcutaneous nadroparin 0.3 ml (n=50) for 42 days. The primary safety outcome measure was the incidence of bleeding events. Major bleeding events and clinically relevant non-major bleeding events were defined according to accepted guidelines. The secondary measures of this study were the occurrence of VTE, time until the bleeding event, compliance, duration of hospital stay, rehospitalisation, outpatient clinic visits and interventions following complications. Additionally, coagulation monitoring, knee flexion range of motion and Knee injury and Osteoarthritis Outcome Score were evaluated. DISSEMINATION: The results of this trial provided insight into the validity of design for an adequately powered multicentre study investigating the safety of the new oral anticoagulants compared with nadroparin, an anticoagulant applied for prevention of VTE after knee arthroplasty in the Dutch situation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT01431456. PMID- 23355674 TI - A clustered randomised trial examining the effect of social marketing and community mobilisation on the age of uptake and levels of alcohol consumption by Australian adolescents. AB - INTRODUCTION: Throughout the world, alcohol consumption is common among adolescents. Adolescent alcohol use and misuse have prognostic significance for several adverse long-term outcomes, including alcohol problems, alcohol dependence, school disengagement and illicit drug use. The aim of this study was to evaluate whether randomisation to a community mobilisation and social marketing intervention reduces the proportion of adolescents who initiate alcohol use before the Australian legal age of 18, and the frequency and amount of underage adolescent alcohol consumption. METHOD AND ANALYSIS: The study comprises 14 communities matched with 14 non-contiguous communities on socioeconomic status (SES), location and size. One of each pair was randomly allocated to the intervention. Baseline levels of adolescent alcohol use were estimated through school surveys initiated in 2006 (N=8500). Community mobilisation and social marketing interventions were initiated in 2011 to reduce underage alcohol supply and demand. The setting is communities in three Australian states (Victoria, Queensland and Western Australia). Students (N=2576) will complete school surveys in year 8 in 2013 (average age 12). PRIMARY OUTCOMES: (1) lifetime initiation and (2) monthly frequency of alcohol use. Reports of social marketing and family and community alcohol supply sources will also be assessed. Point estimates with 95% CIs will be compared for student alcohol use in intervention and control communities. Changes from 2006 to 2013 will be examined; multilevel modelling will assess whether random assignment of communities to the intervention reduced 2013 alcohol use, after accounting for community level differences. Analyses will also assess whether exposure to social marketing activities increased the intervention target of reducing alcohol supply by parents and community members. TRIAL REGISTRATION: ACTRN12612000384853. PMID- 23355675 TI - Does an intensive self-management structured education course improve outcomes for children and young people with type 1 diabetes? The Kids In Control OF Food (KICk-OFF) cluster-randomised controlled trial protocol. AB - INTRODUCTION: The Kids In Control OF Food (KICk-OFF) is a cluster-randomised controlled trial, which aims to determine the efficacy of a 5 day structured education course for 11-year-olds to 16-year-olds with type 1 diabetes (T1DM) when compared with standard care, and its cost effectiveness. Less than 15% of children and young people with T1DM in the UK meet the recommended glycaemic target. Self-management education programmes for adults with T1DM improve clinical and psychological outcomes, but none have been evaluated in the paediatric population. KICk-OFF is a 5-day structured education course for 11 year-olds to 16- year-olds with T1DM. It was developed with input from young people, parents, teachers and educationalists. METHODS AND ANALYSIS: 36 paediatric diabetes centres across the UK randomised into intervention and control arms. Up to 560 participants were recruited prior to centre randomisation. KICk-OFF courses are delivered in the intervention centres, with standard care continued in the control arm. Primary outcomes are change in glycaemic control (HbA1c) and quality of life between baseline and 6 months postintervention, and the incidence of severe hypoglycaemia. Sustained change in self-management behaviour is assessed by follow-up at 12 and 24 months. Health economic analysis will be undertaken. Data will be reported according to the CONSORT statement for cluster-randomised clinical trials. All analyses will be by intention-to-treat with a two-sided p value of <0.05 being regarded as statistically significant. The study commenced in 2008. Data collection from participants is ongoing and the study will be completed in 2013. ETHICS: The study has been approved by the Sheffield Research Ethics Committee. DISSEMINATION: Results will be reported in peer reviewed journals and conferences. TRIAL REGISTRATION: Current Controlled Trials ISRCTN37042683. PMID- 23355676 TI - APR-246/PRIMA-1(MET) rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations. AB - p53 and p63 share extensive sequence and structure homology. p53 is frequently mutated in cancer, whereas mutations in p63 cause developmental disorders manifested in ectodermal dysplasia, limb defects, and orofacial clefting. We have established primary adult skin keratinocytes from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients with p63 mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients. We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification. Treatment of these patient keratinocytes with the mutant p53 targeting compound APR-246/PRIMA-1(MET) (p53 reactivation and induction of massive apoptosis) that has been successfully tested in a phase I/II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models. This rescue coincides with restoration of p63 target-gene expression. Our data show that EEC patient keratinocytes with p63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant p63-associated developmental abnormalities. PMID- 23355677 TI - Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR 246/PRIMA-1MET. AB - Ectodermal dysplasia is a group of congenital syndromes affecting a variety of ectodermal derivatives. Among them, ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome is caused by single point mutations in the p63 gene, which controls epidermal development and homeostasis. Phenotypic defects of the EEC syndrome include skin defects and limbal stem-cell deficiency. In this study, we designed a unique cellular model that recapitulated major embryonic defects related to EEC. Fibroblasts from healthy donors and EEC patients carrying two different point mutations in the DNA binding domain of p63 were reprogrammed into induced pluripotent stem cell (iPSC) lines. EEC-iPSC from both patients showed early ectodermal commitment into K18(+) cells but failed to further differentiate into K14(+) cells (epidermis/limbus) or K3/K12(+) cells (corneal epithelium). APR 246 (PRIMA-1(MET)), a small compound that restores functionality of mutant p53 in human tumor cells, could revert corneal epithelial lineage commitment and reinstate a normal p63-related signaling pathway. This study illustrates the relevance of iPSC for p63 related disorders and paves the way for future therapy of EEC. PMID- 23355678 TI - Ancient and historic dispersals of sweet potato in Oceania. PMID- 23355680 TI - Entropic force between membranes reexamined. PMID- 23355681 TI - Chimps play fair in the ultimatum game. PMID- 23355683 TI - Policies to enhance economic feasibility of a sustainable energy transition. PMID- 23355686 TI - No REST for fibroids. PMID- 23355685 TI - Carbohydrate-based vaccines with a glycolipid adjuvant for breast cancer. AB - Globo H (GH) is a hexasaccharide specifically overexpressed on a variety of cancer cells and therefore, a good candidate for cancer vaccine development. To identify the optimal carrier and adjuvant combination, we chemically synthesized and linked GH to a carrier protein, including keyhole limpet hemocyanion, diphtheria toxoid cross-reactive material (CRM) 197 (DT), tetanus toxoid, and BSA, and combined with an adjuvant, and it was administered to mice for the study of immune response. Glycan microarray analysis of the antiserum obtained indicated that the combination of GH-DT adjuvanted with the alpha galactosylceramide C34 has the highest enhancement of anti-GH IgG. Compared with the phase III clinical trial vaccine, GH-keyhole limpet hemocyanion/QS21, the GH DT/C34 vaccine elicited more IgG antibodies, which are more selective for GH and the GH-related epitopes, stage-specific embryonic antigen 3 (SSEA3) and SSEA4, all of which were specifically overexpressed on breast cancer cells and breast cancer stem cells with SSEA4 at the highest level (>90%). We, therefore, further developed SSEA4-DT/C34 as a vaccine candidate, and after immunization, it was found that the elicited antibodies are also IgG-dominant and very specific for SSEA4. PMID- 23355687 TI - Diagnosis and management of giant cell arteritis and polymyalgia rheumatica: challenges, controversies and practical tips. AB - Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory rheumatic diseases that may present to a variety of disciplines and specialities. The mainstay of treatment is glucocorticoids (steroids); together PMR and GCA now represent one of the most common reasons for medium-to-high dose, long-term glucocorticoid treatment in primary care. However, adverse effects of glucocorticoids are common in these patients. Management of both diseases involves balancing the symptoms and risks of the disease against the adverse effects and risks of glucocorticoids. The crucial first step in management is to make a firm, well-documented diagnosis, since once glucocorticoids are started they can mask the symptoms of a number of other diseases. Diagnosis however can be challenging and there are still substantial gaps in the evidence for treatment. PMID- 23355688 TI - Radioactive in situ hybridization for Epstein-Barr virus-encoded small RNA supports presence of Epstein-Barr virus in the multiple sclerosis brain. PMID- 23355689 TI - Antireflux surgery after congenital diaphragmatic hernia repair: a plea for a tailored approach. AB - OBJECTIVES: Preventive antireflux surgery (ARS) at the moment of congenital diaphragmatic hernia (CDH) repair has been suggested by some authors, particularly in subgroups with a liver herniated in the chest or patch requirement. We evaluated the incidence and associated factors of gastro oesophageal reflux disease (GERD) and the need for subsequent ARS in our CDH patients. METHODS: We retrospectively reviewed our CDH database. Demographics, prenatal assessment of severity, prenatal treatment, type of repair, intraoperative findings and incidences of gastro-oesophageal reflux and ARS were recorded. RESULTS: CDH repair was performed in 77 infants between July 1993 and November 2009. Eight died after repair. Seven were lost to follow-up. The median follow-up was 4.0 (0.16-14.88) years. Fourteen of these 62 patients were prenatally treated with fetoscopic endoluminal tracheal occlusion (FETO) because of severe pulmonary hypoplasia. After CDH repair, GERD was diagnosed in 31 patients. In all of them, medical antireflux treatment was started. Thirteen (42%) patients needed ARS at a median age of 64 (37-264) days. One year after starting medical treatment, 14 (45%) patients were completely off antireflux medication. In CDH subgroups with patch repair, liver herniated in the chest or previous FETO, the incidences of gastro-oesophageal reflux and ARS were 61 and 32%, 73 and 38% and 71 and 43%, respectively. Univariable analysis of associated potentially predisposing factors shows that patch repair, liver herniated in the chest, pulmonary hypertension, high-frequency oscillatory ventilation and FETO are associated with subsequent ARS. On multivariable analysis, liver herniated in the chest was the only independent predictor for both gastro-oesophageal reflux and ARS. CONCLUSIONS: Of all CDH patients, 50% developed gastro-oesophageal reflux and 21% required ARS. For both, liver in the chest was the only independent predictor. Routine ARS in certain subgroups at the time of CDH repair seems not to be justified. Foetal endoluminal tracheal occlusion creates a new cohort of survivors with an increased risk for undergoing ARS. The surgical group, in particular, reflects a more complex gastro-oesophageal reflux physiopathology. PMID- 23355690 TI - The effects of lung resection on physiological motor activity of the oesophagus. AB - OBJECTIVES: To assess the modifications of oesophageal function after major lung resection and whether these modifications are correlated with the extent of resection (pneumonectomy vs others). METHODS: In the last 5 years, 40 consecutive surgical patients with lung cancer were prospectively enrolled and divided in two groups: Group A (n = 20) patients scheduled for elective pneumonectomy and Group B (n = 20) for more limited resections (lobectomy or bilobectomy). In addition to routine evaluations, all patients underwent preoperative (within 5 days) and postoperative (6 months) oesophageal manometry to assess the lower oesophageal sphincter (LES), the oesophageal body and the upper oesophageal sphincter functions. Symptoms scoring questionnaires were recorded for each patient and the oesophageal dislocation assessed by radiological examinations. RESULTS: Thirty three (15 of Group A and 18 of Group B) patients completed the study. After operation, we found that LES resting pressure was significantly lower in Group A compared with Group B (P = 0.01); conversely, the relaxing pressure resulted as being higher in Group A than in Group B (P = 0.01). In Group A compared with Group B, a significant reduction of amplitude and that of wave duration of oesophageal contractions were seen at the upper (0.0001 and 0.02, respectively), middle (0.0003 and 0.002, respectively) and lower (0.0001 and 0.0004, respectively) oesophageal body. In addition, 12 of 15 (80%) patients of Group A and 3 of 18 (17%) of Group B presented a lack of regular peristaltic movement (P = 0.001). Despite chest CT scan showing a shift of the oesophagus in 11 of 15 (73%) and 2 of 18 (11.1%) patients of Groups A and B (P = 0.001), the oesophagus dislocation resulted 'severe' on barium swallow study in only two patients of Group A. The manometric alterations were subclinical; heartburn was recorded in three patients (two of Group A and one of Group B) and epigastric pain in four (two for each group). No other symptoms were observed. CONCLUSIONS: Pneumonectomy may cause significant oesophageal motility disorders that are mostly subclinical. Thus, this type of surgery should not be denied to patients if required to treat their cancer. PMID- 23355691 TI - Towards an integrated approach to mitral valve disease: implementation of an interventional mitral valve programme and its impact on surgical activity. AB - OBJECTIVES: Transcatheter-based treatment of valvular heart disease has increasingly been implemented for the treatment of high-risk patients. The impact of these new treatment modalities on surgical valve programmes is unclear at present. We sought to evaluate the impact of an interventional mitral valve programme on surgical mitral valve activity and to assess the risk profiles of the respective patient populations. METHODS: Between 2007 and 2011, 1112 patients underwent mitral valve surgery for isolated or combined procedures. An interventional mitral valve programme was initiated in 2008, with 270 patients treated from 2008 to 2011. Data were prospectively entered into a database and retrospectively analysed. RESULTS: From 2007 to 2011, surgical mitral valve activity increased by 29.9% compared with a 9.8% increase nationwide (P = 0.09). Compared with the year before the introduction of a MitraClip programme, mean logistic EuroSCORE I of surgical patients was similar in 2011 (2007: 9.4 +/- 10.4 vs 2011: 9.5 +/- 10.5; P = 0.92), while overall 30-day mortality decreased from 7.2 to 4.4% (P = 0.22). The risk profile of surgical patients decreased significantly regarding several parameters. For isolated mitral valve repair, 30 day mortality was 1.5% (6 of 406) in all patients during the study period. Mean logistic EuroSCORE I of transcatheter patients was significantly higher when compared with that of surgical patients (28.8 +/- 18.8 vs 9.5 +/- 10.5%; P < 0.01). CONCLUSIONS: Since the implementation of an interventional mitral valve programme, surgical mitral valve activity has increased over the following years. The risk profile of surgical patients decreased regarding several important parameters, although the overall logistic EuroSCORE I remained unchanged. An integrated approach to mitral valve disease with complementary surgical and non surgical treatment options may possibly help in relieving the undertreatment of patients with severe mitral regurgitation. PMID- 23355692 TI - Reengineered carbonyl reductase for reducing methyl-substituted cyclohexanones. AB - The carbonyl reductase from Candida parapsilosis (CPCR2) is a versatile biocatalyst for the production of optically pure alcohols from ketones. Prochiral ketones like 2-methyl cyclohexanone are, however, only poorly accepted, despite CPCR2's large substrate spectrum. The substrate spectrum of CPCR2 was investigated by selecting five amino positions (55, 92, 118, 119 and 262) and exploring them by single site-saturation mutagenesis. Screening of CPCR2 libraries with poor (14 compounds) and well-accepted (2 compounds) substrates showed that only position 55 and position 119 showed an influence on activity. Saturation of positions 92, 118 and 262 yielded only wild-type sequences for the two well-accepted substrates and no variant converted one of the 14 other compounds. Only the variant (L119M) showed a significantly improved activity (7 fold on 2-methyl cyclohexanone; vmax = 33.6 U/mg, Km = 9.7 mmol/l). The L119M substitution exhibited also significantly increased activity toward reduction of 3-methyl (>2-fold), 4-methyl (>5-fold) and non-substituted cyclohexanone (>4 fold). After docking 2-methyl cyclohexanone into the substrate-binding pocket of a CPCR2 homology model, we hypothesized that the flexible side chain of M119 provides more space for 2-methyl cyclohexanone than branched L119. This report represents the first study on CPCR2 engineering and provides first insights how to redesign CPCR2 toward a broadened substrate spectrum. PMID- 23355693 TI - Going DEEP: guidelines for building simulation-based team assessments. AB - BACKGROUND: Whether for team training, research or evaluation, making effective use of simulation-based technologies requires robust, reliable and accurate assessment tools. Extant literature on simulation-based assessment practices has primarily focused on scenario and instructional design; however, relatively little direct guidance has been provided regarding the challenging decisions and fundamental principles related to assessment development and implementation. OBJECTIVE: The objective of this manuscript is to introduce a generalisable assessment framework supplemented by specific guidance on how to construct and ensure valid and reliable simulation-based team assessment tools. The recommendations reflect best practices in assessment and are designed to empower healthcare educators, professionals and researchers with the knowledge to design and employ valid and reliable simulation-based team assessments. OVERVIEW: Information and actionable recommendations associated with creating assessments of team processes (non-technical 'teamwork' activities) and performance (demonstration of technical proficiency) are presented which provide direct guidance on how to Distinguish the underlying competencies one aims to assess, Elaborate the measures used to capture team member behaviours during simulation activities, Establish the content validity of these measures and Proceduralise the measurement tools in a way that is systematically aligned with the goals of the simulation activity while maintaining methodological rigour (DEEP). SUMMARY: The DEEP framework targets fundamental principles and critical activities that are important for effective assessment, and should benefit healthcare educators, professionals and researchers seeking to design or enhance any simulation-based assessment effort. PMID- 23355694 TI - Martelella endophytica sp. nov., an antifungal bacterium associated with a halophyte. AB - A Gram-staining-negative, non-spore-forming endophytic bacterium, designated strain YC6887(T), was isolated from a root sample of a halophyte, Rosa rugosa, collected from a tidal flat area of Namhae Island, located at the southern end of Korea. Strain YC6887(T) was found to exhibit inhibitory activity against oomycete plant pathogens. The cells were non-motile and aerobic rods. The strain was able to grow at 4-40 degrees C (optimum 28-30 degrees C) and at pH 5.0-9.0 (optimum pH 7.0-8.5). Strain YC6887(T) was able to grow at NaCl concentrations of 0-9 % (w/v) with optimum growth at 4-5 % (w/v) NaCl, but NaCl is not essential for growth. Comparison of 16S rRNA gene sequences showed that the strain was a member of the genus Martelella, a member of order Rhizobiales, exhibiting highest similarity with Martelella mediterranea (98.6 %). The DNA-DNA relatedness between strain YC6887(T) and M. mediterranea MACL11(T) was 19.8 +/- 6.8. Chemotaxonomically, strain YC6887(T) contained C19 : 0 cyclo omega8c (28.0 %) and C18 : 1omega7c (17.9 %) as predominant fatty acids, confirming the affiliation of strain YC6887(T) with the genus Martelella. The major respiratory quinone was Q 10 and the DNA G+C content was 62.1 mol%. On the basis of phylogenetic analysis, physiological and biochemical characterization and DNA-DNA hybridization data, strain YC6887(T) should be classified as representing a novel species of the genus Martelella, for which the name Martelella endophytica sp. nov. is proposed. The type strain is YC6887(T) ( = KCCM 43011(T) = NBRC 109149(T)). PMID- 23355695 TI - Thermococcus prieurii sp. nov., a hyperthermophilic archaeon isolated from a deep sea hydrothermal vent. AB - A novel hyperthermophilic, anaerobic archaeon, strain Bio-pl-0405IT2(T), was isolated from a hydrothermal chimney sample collected from the East Pacific Rise at 2700 m depth in the 'Sarah Spring' area (7 degrees 25' 24" S 107 degrees 47' 66" W). Cells were irregular, motile cocci (0.8-1.5 um in diameter) and divided by constriction. Growth was observed at temperatures between 60 degrees C and 95 degrees C with an optimum at 80 degrees C. The pH range for growth was between pH 4.0 and pH 8.0 with an optimum around pH 7.0. Strain Bio-pl-0405IT2(T) grew at salt concentrations of 1-5 % (w/v) NaCl with an optimum at 2 %. The novel isolate grew by fermentation or sulphur respiration on a variety of organic compounds. It was a chemoorganoheterotrophic archaeon growing preferentially with yeast extract, peptone and tryptone as carbon and energy sources and sulphur and organic compounds as electron acceptors; it also grew on maltose and starch. Sulphur or l-cystine were required for growth and were reduced to hydrogen sulfide. The strain was resistant to rifampicin, chloramphenicol, vancomycin and kanamycin (all at 100 ug ml(-1)) but was sensitive to tetracycline. The G+C content of its genomic DNA was 53.6 mol%. Phylogenetic analysis of the almost complete 16S rRNA gene sequence (1450 bp) of strain Bio-pl-0405IT2(T) showed that the novel isolate belonged to the genus Thermococcus. DNA-DNA hybridization values with the two closest relatives Thermococcus hydrothermalis AL662(T) and Thermococcus celer JCM 8558(T) were below the threshold value of 70 %. On the basis of the physiological and genotypic distinctness, we propose a novel species, Thermococcus prieurii sp. nov. The type strain is Bio-pl-0405IT2(T) ( = CSUR P577(T)= JCM 16307(T)). PMID- 23355696 TI - Paenisporosarcina indica sp. nov., a psychrophilic bacterium from a glacier, and reclassification of Sporosarcina antarctica Yu et al., 2008 as Paenisporosarcina antarctica comb. nov. and emended description of the genus Paenisporosarcina. AB - A Gram-stain-positive, aerobic, spore-forming, rod-shaped bacterium, PN2(T), was isolated from a soil sample collected near the Pindari glacier. It contained anteiso-C15 : 0, iso-C15 : 0 and C16 : 1omega7c alcohol as the predominant fatty acids, MK-7 as the major menaquinone and A4alpha type (l-Lys-d-Glu) peptidoglycan. Based on these characteristics, strain PN2(T) was assigned to the genus Paenisporosarcina. Phylogenetic analysis based on 16S rRNA gene sequence placed strain PN2(T) within the genus Paenisporosarcina and showed a sequence similarity of 98.5-99.0 % with members of this genus. Paenisporosarcina macmurdoensis CMS 21w(T), Paenisporosarcina quisquiliarum SK 55(T) and Sporosarcina antarctica N-05(T) were identified as the most closely related species with 16S rRNA gene sequence similarities of 98.6 %, 99.0 % and 98.4 %, respectively. The values for DNA-DNA relatedness between strain PN2(T) and P. macmurdoensis, P. quisquiliarum and S. antarctica were below the 70 % threshold value (32.0 %, 42.0 % and 38.0 % respectively). In addition, strain PN2(T) exhibited a number of phenotypic differences from P. macmurdoensis, P. quisquiliarum and S. antarctica. Based on the cumulative differences, strain PN2(T) was identified as representing a novel species and the name Paenisporosarcina indica sp. nov. was proposed. The type strain of Paenisporosarcina indica sp. nov. is PN2(T) (LMG 23933(T) = JCM 15114(T)). Furthermore, based on the morphological and chemotaxonomic characteristics, the species Sporosarcina antarctica was reclassified as a species of the genus Paenisporosarcina and renamed Paenisporosarcina antarctica comb. nov. In addition, an emended description of the genus Paenisporosarcina is presented. PMID- 23355697 TI - Streptomyces wuyuanensis sp. nov., an actinomycete from soil. AB - A novel actinomycete, strain FX61(T), was isolated from a saline sample collected from the Inner Mongolian Autonomous Region in China and subjected to a taxonomic study using a polyphasic approach. The predominant menaquinones were MK-9(H6), MK 9(H8) and MK-9(H4). The major fatty acids were iso-C16 : 0, anteiso-C15 : 0, iso C15 : 0, iso-C16 : 1 H, C16 : 0, iso-C14 : 0 and anteiso-C17 : 0. The phospholipid profile contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, two phosphatidylinositol mannosides and an unidentified phospholipid. The G+C content of the genomic DNA was 72 mol%. The 16S rRNA gene sequence of the isolate had greater than 98 % similarity with those of Streptomyces griseoincarnatus ATCC 23623(T) (98.2 %), Streptomyces labedae DSM 41446(T) (98.2 %), Streptomyces variabilis ATCC 19815(T) (98.2 %), Streptomyces erythrogriseus ATCC 27427(T) (98.2 %), Streptomyces matensis ATCC 23935(T) (98.2 %), Streptomyces althioticus ATCC 19724(T) (98.2 %) and Streptomyces luteosporeus ATCC 33049(T) (98.0 %), showing that the novel strain should be assigned to the genus Streptomyces. DNA-DNA hybridizations with the seven above-mentioned members of the genus Streptomyces showed 29.8, 28.5, 27.0, 25.5, 25.0, 23.5 and 22.0 % relatedness, respectively. On the basis of the phenotypic characteristics and genotypic distinctiveness, strain FX61(T) should be classified as a novel species of the genus Streptomyces, for which the name Streptomyces wuyuanensis sp. nov. is proposed. The type strain is FX61(T) (= CGMCC 4.7042(T) = KCTC 29112(T)). PMID- 23355698 TI - Fictibacillus phosphorivorans gen. nov., sp. nov. and proposal to reclassify Bacillus arsenicus, Bacillus barbaricus, Bacillus macauensis, Bacillus nanhaiensis, Bacillus rigui, Bacillus solisalsi and Bacillus gelatini in the genus Fictibacillus. AB - A Gram-positive-staining, aerobic, endospore-forming bacterium (Ca7(T)) was isolated from a bioreactor showing extensive phosphorus removal. Based on 16S rRNA gene sequence similarity comparisons, strain Ca7(T) was grouped in the genus Bacillus, most closely related to Bacillus nanhaiensis JSM 082006(T) (100 %), Bacillus barbaricus V2-BIII-A2(T) (99.2 %) and Bacillus arsenicus Con a/3(T) (97.7 %). Moderate 16S rRNA gene sequence similarities were found to the type strains of the species Bacillus gelatini and Bacillus rigui (96.4 %), Bacillus macauensis (95.1 %) and Bacillus solisalsi (96.1 %). All these species were grouped into a monophyletic cluster and showed very low sequence similarities (<94 %) to the type species of the genus Bacillus, Bacillus subtilis. The quinone system of strain Ca7(T) consists predominantly of menaquinone MK-7. The polar lipid profile exhibited the major compounds diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. In addition, minor compounds of an unidentified phospholipid and an aminophospholipid were detected. No glycolipids were found in strain Ca7(T), which was consistent with the lipid profiles of B. nanhaiensis, B. barbaricus, B. arsenicus, B. rigui, B. solisalsi, B. macauensis and B. gelatini, but in contrast to B. subtilis. The diagnostic diamino acid of the peptidoglycan was meso-diaminopimelic acid and the polyamine pattern contained predominantly spermidine and spermine. The major fatty acids, which were iso-C15 : 0, anteiso-C15 : 0 and C16 : 0, supported the grouping of strain Ca7(T) in the family Bacillaceae. The strain showed DNA-DNA similarities of 48 % (reciprocal 47 %) to B. nanhaiensis DSM 23009(T), 31 % (reciprocal 36 %) to B. barbaricus V2-BIII-A2(T) and 29 % (reciprocal 39 %) to B. arsenicus DSM 15822(T), respectively. These results clearly demonstrate that strain Ca7(T) is a representative of a novel species, which can be differentiated from its closest relatives by physiological and biochemical tests. Because of the low sequence similarity of strain Ca7(T) to B. subtilis, which was shared by B. nanhaiensis, B. barbaricus, B. arsenicus, B. gelatini, B. rigui, B. solisalsi and B. macauensis, and their unique lipid patterns, we propose that strain Ca7(T) represents a novel species in a novel genus for which the name Fictibacillus phosphorivorans gen. nov., sp. nov. is proposed. The type strain is Ca7(T) (= CCM 8426(T) = LMG 27063(T)). In addition we propose the reclassification of B. nanhaiensis, B. barbaricus, B. arsenicus, B. rigui, B. macauensis, B. solisalsi and B. gelatini as Fictibacillus nanhaiensis comb. nov., Fictibacillus barbaricus comb. nov., Fictibacillus arsenicus comb. nov., Fictibacillus rigui comb. nov., Fictibacillus macauensis comb. nov., Fictibacillus solisalsi comb. nov. and Fictibacillus gelatini comb. nov., respectively [type strains JSM 082006(T) (= DSM 23009(T) = KCTC 13712(T)), V2-BIII-A2(T) ( = CCM 4982(T) = DSM 14730(T)), Con a/3(T) ( = MTCC 4380(T) = DSM 15822(T) = JCM 12167(T)), WPCB074(T) ( = KCTC 13278(T) = JCM 16348(T)), ZFHKF-1(T) ( = JCM 13285(T) = DSM 17262(T)), YC1(T) ( = KCTC 13181(T) = CGMCC 1.6854(T)) and LMG 21881(T) ( = DSM 15866(T)), respectively]. PMID- 23355699 TI - Morphology and phylogenies of two hypotrichous brackish-water ciliates from China, Neourostylopsis orientalis n. sp. and Protogastrostyla sterkii (Wallengren, 1900) n. comb., with establishment of a new genus Neourostylopsis n. gen. (Protista, Ciliophora, Hypotrichia). AB - This paper investigates the morphology, infraciliature and small-subunit (SSU) rRNA gene sequences of two hypotrichous ciliates, Neourostylopsis orientalis n. sp., and Protogastrostyla sterkii (Wallengren, 1900) n. comb. (basionym Gastrostyla sterkii), collected from coastal waters in southern China. Neourostylopsis orientalis n. sp. is diagnosed mainly by the arrangement of brownish cortical granules, the numbers of adoral membranelles and frontal and transverse cirri and the characteristics of its midventral cirral pairs. The SSU rRNA gene phylogeny strongly supports the establishment of the new genus Neourostylopsis n. gen., which is characterized mainly by the following features: frontal and transverse cirri clearly differentiated, buccal cirri present, two frontoterminal cirri, midventral complex composed of midventral pairs only and not exceeding the halfway point of the cell, more than one row of marginal cirri on each side which derive from individual anlagen within each parental row, caudal cirri lacking. Thus, two new combinations are required: Neourostylopsis songi (Lei et al., 2005) n. comb., and Neourostylopsis flavicana (Wang et al., 2011) n. comb. Additionally, improved diagnoses for both Metaurostylopsis and Apourostylopsis are supplied in this study. Protogastrostyla sterkii (Wallengren, 1900) n. comb. differs from the similar congener Protogastrostyla pulchra mainly in body shape, ratio of buccal field to body length in vivo and molecular data. Based on the present studies, we conclude that the estuarine population of P. pulchra collected by J. Gong and others [Gong et al., J Eukaryot Microbiol (2007) 54, 468-478] is a population of P. sterkii. PMID- 23355700 TI - Moniliella byzovii sp. nov., a chlamydospore-forming black yeast isolated from flowers. AB - Yeasts of the genus Moniliella were isolated from 651 flower samples collected in Vietnam, using an enrichment medium containing 50 % glucose. Species of the genus Moniliella were found in 5 % of the samples and 54 strains were isolated. The strains were identified based on D1/D2 LSU rRNA gene sequences as M. megachiliensis (15 strains), M. dehoogii (14 strains), and M. mellis (2 strains). The remaining 23 strains could not be reliably placed under any known species. Among them, 12 strains isolated from flowers of Ipomoea pes-caprae and Calotropis gigantea were peculiar for the intensive formation of chlamydospores. These strains could be subdivided into pigmented and non-pigmented groups. Both groups were identical in PCR fingerprints generated with primer (GAC)5 and in D1/D2 and ITS sequences. The yeast was closely related to M. fonsecae but differed from the latter by 52 nt (or 10.3 % of divergence) in the D1/D2 sequence and 71 nt (or 16.9 % of divergence) in the ITS sequence. The name Moniliella byzovii sp. nov. is proposed for this novel species. The type strain is TBY 2041.7(T) = CBS 12757(T) = NRRL Y-63661(T). The MycoBank number is MB 803186. PMID- 23355701 TI - Consultation generates range of ideas for tackling bovine TB. PMID- 23355702 TI - FSA investigates authenticity of meat products. PMID- 23355703 TI - Principal role for Glasgow academic. PMID- 23355704 TI - Royal opening for Edinburgh university's farm animal practice. PMID- 23355707 TI - RVN to be removed from the nurses' register. PMID- 23355708 TI - Divorce the most common reason for surrendering dogs to breed rescues. PMID- 23355709 TI - New look for Animal Welfare Foundation. PMID- 23355710 TI - Lameness in dairy cows: the developing story. PMID- 23355711 TI - Enhancing the sensitivity of tests for bovine TB. PMID- 23355712 TI - Tuberculin manufacturing source and breakdown incidence rate of bovine tuberculosis in British cattle, 2005-2009. AB - The single intradermal comparative cervical tuberculin (SICCT) test is the primary test used for surveillance for bovine tuberculosis (bTB) in cattle in Great Britain (GB). The tuberculin used can, with other factors, influence test accuracy. In this analysis, the detection of infected cattle in GB 2005-2009 was compared between SICCT tests using tuberculins manufacturered by different manufacturers. Higher rates of reactors (adjusted rate 209 vs 186 per 100,000 tests, P = 0.003) and herd bTB incidents (adjusted total breakdown rate 5.1 vs 4.5 per 100 herd-years at risk, P < 0.001) were detected using tuberculin manufactured at Weybridge compared with Lelystad. However, confirmation of infection in reactors by postmortem evidence was higher with Lelystad tuberculin (adjusted percent 44.1 vs 47.1, P = 0.018). The findings, overall, suggest slightly higher test sensitivity and lower test specificity associated with Weybridge tuberculin compared with Lelystad. Assuming effective adjustment for confounding, the overall impact of tuberculin manufacturing source (2007-2009), was calculated to range somewhere between 315 false positive breakdowns, and 1086 bTB breakdowns missed (624 confirmed) as a result of using Weybridge and Lelystad tuberculin, respectively. However, animals that tested negative to the SICCT were not slaughtered at the time of the tests, so definitive conclusions are not possible. PMID- 23355713 TI - Should Burns have been a vet?: judging from his writings, he would have been very good at it, says Craig Sharp. PMID- 23355714 TI - New UK veterinary school. PMID- 23355715 TI - Approaches to surveillance. PMID- 23355716 TI - Investigation of respiratory disease in IBR vaccinated dairy herds. PMID- 23355717 TI - Chlamydia in cases of cattle pneumonia in Scotland. PMID- 23355718 TI - Scaffold technologies for controlling cell behavior in tissue engineering. PMID- 23355721 TI - RYK is not mutated in autosomal dominant Robinow syndrome. PMID- 23355722 TI - The role of NADRIN, a Rho GTPase-activating protein, in the morphological differentiation of astrocytes. AB - Reorganization of the actin cytoskeleton caused by inactivation of the Rho GTPase RhoA is critical for the morphological differentiation of astrocytes into process bearing stellate cells. The molecular mechanisms underlying the RhoA inactivation and, in particular, the factors that inactivate RhoA, remain to be elucidated. We show here that the expression of a GTPase-activating protein (GAP) for Rho GTPases, neuron-associated developmentally regulated protein (NADRIN) also known as RICH and ARHGAP17, was significantly increased in stellate astrocytes and induced expression of NADRIN accelerated the morphological differentiation of cultured astrocytes into stellate cells. A GAP activity-negative mutant or truncated forms of NADRIN failed to induce the stellation. Immunoprecipitation analyses revealed that, in response to inductive signals such as dibutyryl cyclic AMP and epidermal growth factor, NADRIN formed a complex with ezrin-radixin moesin (ERM) protein by interacting with ERM-binding phosphoprotein 50 via its carboxy-terminal PSD95/DlgA/ZO-1-binding motif. We also showed that NADRIN formed a dimer via the interaction between the amino- and carboxy-terminal domains, which was disrupted in response to the inductive signals. These results suggest that the inductive signals cause the structural change of NADRIN, which allows NADRIN to associate with the ERM protein complex, where it inactivates RhoA and leads to the morphological differentiation of astrocytes. PMID- 23355723 TI - Photo quiz: an 80-year-old female with acute myeloid leukemia and induction associated neutropenic fever. PMID- 23355724 TI - Anaerobic thioglycolate broth culture for recovery of Propionibacterium acnes from shoulder tissue and fluid specimens. PMID- 23355725 TI - Reply to "Anaerobic thioglycolate broth culture for recovery of propionibacterium acnes from shoulder tissue and fluid specimens". PMID- 23355726 TI - Phenotypic identification of Staphylococcus intermedius may be inaccurate. PMID- 23355727 TI - Reply to "Phenotypic identification of Staphylococcus intermedius may be inaccurate". PMID- 23355730 TI - Fer kinase limits neutrophil chemotaxis toward end target chemoattractants. AB - Neutrophil recruitment and directional movement toward chemotactic stimuli are important processes in innate immune responses. This study examines the role of Fer kinase in neutrophil recruitment and chemotaxis to various chemoattractants in vitro and in vivo. Mice targeted with a kinase-inactivating mutation (Fer(DR/DR)) or wild type (WT) were studied using time-lapse intravital microscopy to examine leukocyte recruitment and chemotaxis in vivo. In response to keratinocyte-derived cytokine, no difference in leukocyte chemotaxis was observed between WT and Fer(DR/DR) mice. However, in response to the chemotactic peptide WKYMVm, a selective agonist of the formyl peptide receptor, a 2-fold increase in leukocyte emigration was noted in Fer(DR/DR) mice (p < 0.05). To determine whether these defects were due to Fer signaling in the endothelium or other nonhematopoietic cells, bone marrow chimeras were generated. WKYMVm-induced leukocyte recruitment in chimeric mice (WT bone marrow to Fer(DR/DR) recipients or vice versa) was similar to WT mice, suggesting that Fer kinase signaling in both leukocytes and endothelial cells serves to limit chemotaxis. Purified Fer(DR/DR) neutrophils demonstrated enhanced chemotaxis toward end target chemoattractants (WKYMVm and C5a) compared with WT using an under-agarose gel chemotaxis assay. These defects were not observed in response to intermediate chemoattractants (keratinocyte-derived cytokine, MIP-2, or LTB(4)). Increased WKYMVm-induced chemotaxis of Fer(DR/DR) neutrophils correlated with sustained PI3K activity and reduced reliance on the p38 MAPK pathway compared with WT neutrophils. Together, these data identify Fer as a novel inhibitory kinase for neutrophil chemotaxis toward end target chemoattractants through modulation of PI3K activity. PMID- 23355731 TI - Serotonin skews human macrophage polarization through HTR2B and HTR7. AB - Besides its role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5HT) regulates inflammation and tissue repair via a set of receptors (5HT(1-7)) whose pattern of expression varies among cell lineages. Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair, we evaluated whether 5HT modulates human macrophage polarization. 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting IL-10 production, upregulated the expression of M2 polarization-associated genes (SERPINB2, THBS1, STAB1, COL23A1), and reduced the expression of M1-associated genes (INHBA, CCR2, MMP12, SERPINE1, CD1B, ALDH1A2). Whereas only 5HT(7) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines, both 5HT(2B) and 5HT(7) receptors mediated the pro-M2 skewing effect of 5HT. In fact, blockade of both receptors during in vitro monocyte-to-macrophage differentiation preferentially modulated the acquisition of M2 polarization markers. 5HT(2B) was found to be preferentially expressed by anti-inflammatory M2(M-CSF) macrophages and was detected in vivo in liver Kupffer cells and in tumor-associated macrophages. Therefore, 5HT modulates macrophage polarization and contributes to the maintenance of an anti-inflammatory state via 5HT(2B) and 5HT(7), whose identification as functionally relevant markers for anti-inflammatory/homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies. PMID- 23355732 TI - Tumor-derived gammadelta regulatory T cells suppress innate and adaptive immunity through the induction of immunosenescence. AB - Fundamentally understanding the suppressive mechanisms used by different subsets of tumor-infiltrating regulatory T (Treg) cells is critical for the development of effective strategies for antitumor immunotherapy. gammadelta Treg cells have recently been identified in human diseases including cancer. However, the suppressive mechanisms and functional regulations of this new subset of unconventional Treg cells are largely unknown. In the current studies, we explored the suppressive mechanism(s) used by breast tumor-derived gammadelta Treg cells on innate and adaptive immunity. We found that gammadelta Treg cells induced immunosenescence in the targeted naive and effector T cells, as well as dendritic cells (DCs). Furthermore, senescent T cells and DCs induced by gammadelta Treg cells had altered phenotypes and impaired functions and developed potent suppressive activities, further amplifying the immunosuppression mediated by gammadelta Treg cells. In addition, we demonstrated that manipulation of TLR8 signaling in gammadelta Treg cells can block gammadelta Treg-induced conversion of T cells and DCs into senescent cells in vitro and in vivo. Our studies identify the novel suppressive mechanism mediated by tumor-derived gammadelta Treg cells on innate and adaptive immunity, which should be critical for the development of strong and innovative approaches to reverse the tumor-suppressive microenvironment and improve effects of immunotherapy. PMID- 23355733 TI - Cigarette smoke exposure inhibits contact hypersensitivity via the generation of platelet-activating factor agonists. AB - Previous studies have established that pro-oxidative stressors suppress host immunity because of their ability to generate oxidized lipids with platelet activating factor receptor (PAF-R) agonist activity. Although exposure to the pro oxidative stressor cigarette smoke (CS) is known to exert immunomodulatory effects, little is known regarding the role of PAF in these events. The current studies sought to determine the role of PAF-R signaling in CS-mediated immunomodulatory effects. We demonstrate that CS exposure induces the generation of a transient PAF-R agonistic activity in the blood of mice. CS exposure inhibits contact hypersensitivity in a PAF-R-dependent manner as PAF-R-deficient mice were resistant to these effects. Blocking PAF-R agonist production either by systemic antioxidants or treatment with serum PAF-acetyl hydrolase enzyme blocked both the CS-mediated generation of PAF-R agonists and PAF-R-dependent inhibition of contact hypersensitivity (CHS) reactions, indicating a role for oxidized glycerophosphocholines with PAF-R agonistic activity in this process. In addition, cyclooxygenase-2 inhibition did not block PAF-R agonist production but prevented CS-induced inhibition of CHS. This suggests that cyclooxygenase-2 acts downstream of the PAF-R in mediating CS-induced systemic immunosuppression. Moreover, CS exposure induced a significant increase in the expression of the regulatory T cell reporter gene in Foxp3(EGFP) mice but not in Foxp3(EGFP) mice on a PAF-R-deficient background. Finally, regulatory T cell depletion via anti CD25 Abs blocked CS-mediated inhibition of CHS, indicating the potential involvement of regulatory T cells in CS-mediated systemic immunosuppression. These studies provide the first evidence, to our knowledge, that the pro oxidative stressor CS can modulate cutaneous immunity via the generation of PAF-R agonists produced through lipid oxidation. PMID- 23355734 TI - Plasmacytoid dendritic cells play a key role in tumor progression in lipopolysaccharide-stimulated lung tumor-bearing mice. AB - The antitumor activity of LPS was first described by Dr. William Coley. However, its role in lung cancer remains unclear. The aim of our study was to elucidate the dose-dependent effects of LPS (0.1-10 MUg/mouse) in a mouse model of B16-F10 induced metastatic lung cancer. Lung tumor growth increased at 3 and 7 d after the administration of low-dose LPS (0.1 MUg/mouse) compared with control mice. This was associated with an influx of plasmacytoid dendritic cells (pDCs), regulatory T cells, myeloid-derived suppressor cells, and CD8(+) regulatory T cells. In contrast, high-dose LPS (10 MUg/mouse) reduced lung tumor burden and was associated with a greater influx of pDCs, as well as a stronger Th1 and Th17 polarization. Depletion of pDCs during low-dose LPS administration resulted in a decreased lung tumor burden. Depletion of pDCs during high-dose LPS treatment resulted in an increased tumor burden. The dichotomy in LPS effects was due to the phenotype of pDCs, which were immunosuppressive after the low-dose LPS, and Th1- and T cytotoxic-polarizing cells after the high-dose LPS. Adoptive transfer of T cells into nude mice demonstrated that CD8(+) T cells were responsible for pDC recruitment following low-dose LPS administration, whereas CD4(+) T cells were required for pDC influx after the high-dose LPS. In conclusion, our data suggest differential effects of low-dose versus high-dose LPS on pDC phenotype and tumor progression or regression in the lungs of mice. PMID- 23355735 TI - Resistin-like molecule alpha promotes pathogenic Th17 cell responses and bacterial-induced intestinal inflammation. AB - Resistin-like molecule (RELM)alpha belongs to a family of secreted mammalian proteins that have putative immunomodulatory functions. Recent studies have identified a pathogenic role for RELMalpha in chemically induced colitis through effects on innate cell populations. However, whether RELMalpha regulates intestinal adaptive immunity to enteric pathogens is unknown. In this study, we employed Citrobacter rodentium as a physiologic model of pathogenic Escherichia coli-induced diarrheal disease, colitis, and Th17 cell responses. In response to Citrobacter, RELMalpha expression was induced in intestinal epithelial cells, infiltrating macrophages, and eosinophils of the infected colons. Citrobacter infected RELMalpha(-/-) mice exhibited reduced infection-induced intestinal inflammation, characterized by decreased leukocyte recruitment to the colons and reduced immune cell activation compared with wild-type (WT) mice. Interestingly, Citrobacter colonization and clearance were unaffected in RELMalpha(-/-) mice, suggesting that the immune stimulatory effects of RELMalpha following Citrobacter infection were pathologic rather than host-protective. Furthermore, infected RELMalpha(-/-) mice exhibited decreased CD4(+) T cell expression of the proinflammatory cytokine IL-17A. To directly test whether RELMalpha promoted Citrobacter-induced intestinal inflammation via IL-17A, infected WT and IL-17A(-/ ) mice were treated with rRELMalpha. RELMalpha treatment of Citrobacter-infected WT mice exacerbated intestinal inflammation and IL-17A expression whereas IL-17A( /-) mice were protected from RELMalpha-induced intestinal inflammation. Finally, infected RELMalpha(-/-) mice exhibited reduced levels of serum IL-23p19 compared with WT mice, and RELMalpha(-/-) peritoneal macrophages showed deficient IL-23p19 induction. Taken together, these data identify a proinflammatory role for RELMalpha in bacterial-induced colitis and suggest that the IL-23/Th17 axis is a critical mediator of RELMalpha-induced inflammation. PMID- 23355736 TI - Sustained and incomplete recovery of naive CD8+ T cell precursors after sepsis contributes to impaired CD8+ T cell responses to infection. AB - Patients who survive severe sepsis often display compromised immune function with impairment in innate and adaptive immune responses. These septic patients are highly susceptible to "secondary" infections with intracellular pathogens that are usually controlled by CD8(+) T cells. It is not known when and if this observed immunoparalysis of CD8(+) T cell immunity recovers, and the long-term consequences of sepsis on the ability of naive CD8(+) T cells to respond to subsequent infections are poorly understood. In this study, using the cecal ligation and puncture mouse model of sepsis, we show that sepsis induces a rapid loss of naive CD8(+) T cells. However, IL-15-dependent numerical recovery is observed a month after initial septic insult. Numerical recovery is accompanied by IL-15-dependent phenotypic changes where a substantial proportion of naive (Ag inexperienced) CD8(+) T cells display a "memory-like" phenotype (CD44(hi)/CD11a(hi)). Importantly, the impairment of naive CD8(+) T cells to respond to viral and bacterial infection was sustained for month(s) after sepsis induction. Incomplete recovery of naive CD8(+) T cell precursors was observed in septic mice, suggesting that the availability of naive precursors contributes to the sustained impairment in primary CD8(+) T cell responses. Thus, sepsis can result in substantial and long-lasting changes in the available CD8(+) T cell repertoire affecting the capacity of the host to respond to new infections. PMID- 23355738 TI - Crystal structure of IL-17 receptor B SEFIR domain. AB - IL-17 cytokines play a crucial role in a variety of inflammatory and autoimmune diseases. They signal through heterodimeric receptor complexes consisting of members of IL-17R family. A unique intracellular signaling domain was identified within all IL-17Rs, termed similar expression to fibroblast growth factor genes and IL-17R (SEFIR). SEFIR is also found in NF-kappaB activator 1 (Act1), an E3 ubiquitin ligase, and mediates its recruitment to IL-17Rs. In this study, to our knowledge, we report the structure of the first SEFIR domain from IL-17RB at 1.8A resolution. SEFIR displays a five-stranded parallel beta-sheet that is wrapped by six helices. Site-directed mutagenesis on IL-17RB identified helix alphaC as being critical for its interaction with Act1 and IL-25 (IL-17E) signaling. Using the current SEFIR structure as a template, the key functional residues in Act1 are also mapped as part of helix alphaC, which is conserved in IL-17RA and RC, suggesting this helix as a common structural signature for heterotypic SEFIR SEFIR association. In contrast, helix alphaB' is important for homodimerization of Act1, implicating a dual ligand-binding model for SEFIR domain, with distinct structural motifs participating in either homotypic or heterotypic interactions. Furthermore, although the IL-17RB-SEFIR structure resembles closest to the Toll/IL-1R domain of TLR10 with low sequence homology, substantial differences were observed at helices alphaC, alphaD, and DD' loop. To our knowledge, this study provides the first structural view of the IL-17R intracellular signaling, unraveling the mechanism for the specificity of SEFIR versus Toll/IL-1R domain in their respective signaling pathways. PMID- 23355737 TI - CD8alpha+ dendritic cell trans presentation of IL-15 to naive CD8+ T cells produces antigen-inexperienced T cells in the periphery with memory phenotype and function. AB - Various populations of memory phenotype CD8(+) T cells have been described over the last 15-20 y, all of which possess elevated effector functions relative to naive phenotype cells. Using a technique for isolating Ag-specific cells from unprimed hosts, we recently identified a new subset of cells, specific for nominal Ag, but phenotypically and functionally similar to memory cells arising as a result of homeostatic proliferation. We show in this study that these virtual memory (VM) cells are independent of previously identified innate memory cells, arising as a result of their response to IL-15 trans presentation by lymphoid tissue-resident CD8alpha(+) dendritic cells in the periphery. The absence of IL-15, CD8(+) T cell expression of either CD122 or eomesodermin or of CD8a(+) dendritic cells all lead to the loss of VM cells in the host. Our results show that CD8(+) T cell homeostatic expansion is an active process within the nonlymphopenic environment, is mediated by IL-15, and produces Ag-inexperienced memory cells that retain the capacity to respond to nominal Ag with memory-like function. Preferential engagement of these VM T cells into a vaccine response could dramatically enhance the rate by which immune protection develops. PMID- 23355741 TI - Cutting edge: An inactive chromatin configuration at the IL-10 locus in human neutrophils. AB - To identify the molecular basis of IL-10 expression in human phagocytes, we evaluated the chromatin modification status at their IL-10 genomic locus. We analyzed posttranslational modifications of histones associated with genes that are active, repressed, or poised for transcriptional activation, including H3K4me3, H4Ac, H3K27Ac, and H3K4me1 marks. Differently from autologous IL-10 producing monocytes, none of the marks under evaluation was detected at the IL-10 locus of resting or activated neutrophils from healthy subjects or melanoma patients. By contrast, increased H3K4me3, H4Ac, H3K4me1, and H3K27Ac levels were detected at syntenic regions of the IL-10 locus in mouse neutrophils. Altogether, data demonstrate that human neutrophils, differently from either monocytes or mouse neutrophils, cannot switch on the IL-10 gene because its locus is in an inactive state, likely reflecting a neutrophil-specific developmental outcome. Implicitly, data also definitively settle a currently unsolved issue on the capacity of human neutrophils to produce IL-10. PMID- 23355739 TI - A role for Ly108 in the induction of promyelocytic zinc finger transcription factor in developing thymocytes. AB - The promyelocytic zinc finger transcription factor (PLZF) is required for the development of activated phenotypes in NKT and other innate T lymphocytes. Although strong TCR stimulation has been implicated in the induction of PLZF, the factors regulating PLZF expression are incompletely understood. We show in this study that costimulation of preselection double-positive thymocytes through the signaling lymphocyte activation molecule family receptor Ly108 markedly enhanced PLZF expression compared with that induced by TCR stimulation alone. Costimulation with Ly108 increased expression of early growth response protein (Egr)-2 and binding of Egr-2 to the promoter of Zbtb16, which encodes PLZF, and resulted in PLZF levels similar to those seen in NKT cells. In contrast, costimulation with anti-CD28 failed to enhance Egr-2 binding and Zbtb16 expression. Moreover, mice lacking Ly108 showed decreased numbers of PLZF expressing CD4(+) T cells. Together, these results support a potential role for Ly108 in the induction of PLZF. PMID- 23355740 TI - Mouse tumor vasculature expresses NKG2D ligands and can be targeted by chimeric NKG2D-modified T cells. AB - Tumor angiogenesis plays an important role in the development of solid tumors, and targeting the tumor vasculature has emerged as a strategy to prevent growth and progression of solid tumors. In this study, we show that murine tumor vasculature expresses Rae1, a ligand for a stimulatory NK receptor NKG2D. By genetic modification of T cells with an NKG2D-based chimeric Ag receptor, referred to as chNKG2D in which the NKG2D receptor is fused to the signaling domain of CD3zeta-chain, T cells were capable of targeting tumor vasculature leading to reduced tumor angiogenesis and tumor growth. This occurred even in tumors where the tumor cells themselves did not express NKG2D ligands. H5V, an endothelial cell line, expresses Rae1 and was lysed by chNKG2D-bearing T cells in a perforin-dependent manner. In vitro capillary tube formation was inhibited by chNKG2D T cells through IFN-gamma and cell-cell contact mechanisms. The in vivo antiangiogenesis effects mediated by chNKG2D-bearing T cells at the tumor site were dependent on IFN-gamma and perforin. These results provide a novel mechanism for NKG2D-based targeting of solid tumors. PMID- 23355742 TI - Multiple tumor-associated microRNAs modulate the survival and longevity of dendritic cells by targeting YWHAZ and Bcl2 signaling pathways. AB - Tumors use a wide array of immunosuppressive strategies, such as reducing the longevity and survival of dendritic cells (DCs), to diminish immune responses and limit the effect of immunotherapy. In this study, we found that tumors upregulate the expression of multiple microRNAs (miRNAs), such as miR-16-1, miR-22, miR-155, and miR-503. These tumor-associated miRNAs influenced the survival and longevity of DCs by affecting the expression of multiple molecules that are associated with apoptotic signaling pathways. Specifically, miR-22 targeted YWHAZ to interrupt the PI3K/Akt and MAPK signaling pathways, and miR-503 downregulated Bcl2 expression. The result of the increased expression of miR-22 and miR-503 in the tumor-associated DCs was their reduced survival and longevity. Thus, tumor associated miRNAs can target multiple intracellular signaling molecules to cause the apoptosis of DCs in the tumor environment. Use of miR-22 and miR-503 as inhibitors may therefore represent a new strategy to improve DC-based immunotherapies against tumors. PMID- 23355743 TI - Clinical evidence for the role of Trichomonas vaginalis in regulation of secretory leukocyte protease inhibitor in the female genital tract. AB - BACKGROUND: Secretory leukocyte protease inhibitor (SLPI) is responsible for regulating inflammatory damage to and innate and adaptive immune responses in the vaginal mucosa. Depressed cervicovaginal SLPI levels have been correlated with both Trichomonas vaginalis infection and poor reproductive health outcomes. METHODS: We measured levels of SLPI in 215 vaginal specimens collected from adolescent and young adult females aged 14-22 years. Log-transformed SLPI values were compared by analysis of variance or by an unpaired t test before and after adjustment for confounding effects through the propensity score method. RESULTS: Females receiving hormonal contraceptives and those with an abnormal vaginal pH had lower SLPI levels as compared to their peers. After propensity score adjustment for race, behavioral factors, hormonal use, and other sexually transmitted infections (STIs), SLPI levels were lower in females with a positive T. vaginalis antigen test result, a vaginal pH >4.5, vaginal leukocytosis, and recurrent (vs initial) T. vaginalis infection, with the lowest levels observed in those with the highest T. vaginalis loads. CONCLUSIONS: The SLPI level was reduced by >50% in a T. vaginalis load-dependent manner. Future research should consider whether identifying and treating females with low levels of T. vaginalis infection (before they become wet mount positive) would prevent the loss of SLPI and impaired vaginal immunity. The SLPI level could be used as a vaginal-health marker to evaluate interventions and vaginal products. PMID- 23355745 TI - Classification of follicular cell-derived thyroid cancer by global RNA profiling. AB - The incidence of thyroid cancer is increasing worldwide and thyroid nodules are a frequent clinical finding. Diagnosing follicular cell-derived cancers is, however, challenging both histopathologically and especially cytopathologically. The advent of high-throughput molecular technologies has prompted many researchers to explore the transcriptome and, in recent years, also the miRNome in order to generate new molecular classifiers capable of classifying thyroid tumours more accurately than by conventional cytopathological and histopathological methods. This has led to a number of molecular classifiers that may differentiate malignant from benign thyroid nodules. Molecular classification models based on global RNA profiles from fine-needle aspirations are currently being evaluated; results are preliminary and lack validation in prospective clinical trials. There is no doubt that molecular classification will not only contribute to our biological insight but also improve clinical and pathological examinations, thus advancing thyroid tumour diagnosis and ultimately preventing superfluous surgery. This review evaluates the status of classification and biological insights gained from molecular profiling of follicular cell-derived thyroid cancers. PMID- 23355744 TI - Disruption of uridine homeostasis links liver pyrimidine metabolism to lipid accumulation. AB - We report in this study an intrinsic link between pyrimidine metabolism and liver lipid accumulation utilizing a uridine phosphorylase 1 transgenic mouse model UPase1-TG. Hepatic microvesicular steatosis is induced by disruption of uridine homeostasis through transgenic overexpression of UPase1, an enzyme of the pyrimidine catabolism and salvage pathway. Microvesicular steatosis is also induced by the inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme of the de novo pyrimidine biosynthesis pathway. Interestingly, uridine supplementation completely suppresses microvesicular steatosis in both scenarios. The effective concentration (EC(50)) for uridine to suppress microvesicular steatosis is approximately 20 uM in primary hepatocytes of UPase1-TG mice. We find that uridine does not have any effect on in vitro DHODH enzymatic activity. On the other hand, uridine supplementation alters the liver NAD(+)/NADH and NADP(+)/NADPH ratios and the acetylation profile of metabolic, oxidation reduction, and antioxidation enzymes. Protein acetylation is emerging as a key regulatory mechanism for cellular metabolism. Therefore, we propose that uridine suppresses fatty liver by modulating the liver protein acetylation profile. Our findings reveal a novel link between uridine homeostasis, pyrimidine metabolism, and liver lipid metabolism. PMID- 23355746 TI - Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism. AB - BACKGROUND: Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterised by abnormal central nervous system white matter. Mutations in POLR3A and POLR3B genes were recently reported to cause four clinically overlapping hypomyelinating leukodystrophy phenotypes. Our aim was to investigate the presence and frequency of POLR3A and POLR3B mutations in patients with genetically unexplained hypomyelinating leukodystrophies with typical clinical and/or radiologic features of Pol III-related leukodystrophies. METHODS: The entire coding region and the flanking exon/intron boundaries of POLR3A and/or POLR3B genes were amplified and sequenced in 14 patients. RESULTS: Recessive mutations in POLR3A or POLR3B were uncovered in all 14 patients. Eight novel mutations were identified in POLR3A: six missenses, one nonsense, and one frameshift mutation. Seven patients carried compound heterozygous mutations in POLR3B, of whom six shared the common mutation in exon 15 (p.V523E). Seven novel mutations were identified in POLR3B: four missenses, two splice sites, and one intronic mutation. CONCLUSIONS: To date, our group has described 37 patients, of whom 27 have mutations in POLR3A and 10 in POLR3B, respectively. Altogether, our results further support the proposal that POLR3A and POLR3B mutations are a major cause of hypomyelinating leukodystrophies and suggest that POLR3A mutations are more frequent. PMID- 23355747 TI - How Financial Literacy Affects Household Wealth Accumulation. AB - This study isolates the causal effects of financial literacy and schooling on wealth accumulation using a new household dataset and an instrumental variables (IV) approach. Financial literacy and schooling attainment are both strongly positively associated with wealth outcomes in linear regression models, whereas the IV estimates reveal even more potent effects of financial literacy. They also indicate that the schooling effect only becomes positive when interacted with financial literacy. Estimated impacts are substantial enough to imply that investments in financial literacy could have large wealth payoffs. PMID- 23355748 TI - Spatial Navigation Strategies in Peromyscus: a Comparative Study. AB - A male advantage in spatial abilities is predicted to evolve in species where males rely on expansion of home territory to locate dispersed mates during the breeding season. We sought to examine mechanistic underpinnings of this evolved trait by comparing spatial navigational abilities in two species of Peromyscus that employ widely different reproductive strategies. Males and females from outbred stocks of deer mice (P. maniculatus bairdii) in which males engage in territorial expansion and mate search and California mice (P. californicus insignis), in which males do not, were administered tasks that assessed spatial learning and memory, and activity and exploratory behaviours. The maze employed for these studies included four spatial cues that could be used to aid in locating 1 of 12 potential escape holes. As predicted, male deer mice outperformed conspecific females and California mice males in maze performance and memory, and this difference appeared to be due to extent to which animals used spatial cues to guide maze navigation. Consistent with territorial expansion as a component of competition for mates, male deer mice were more active and engaged in more exploratory and less anxiety-related behaviours than conspecific females and California mice males. The results have implications for understanding and studying the cognitive and behavioural mechanisms that have evolved through male-male competition that involves territorial expansion and mate search. PMID- 23355749 TI - Dispersion and Filtration of Carbon Nanotubes (CNTs) and Measurement of Nanoparticle Agglomerates in Diesel Exhaust. AB - Carbon nanotubes (CNTs) tend to form bundles due to their geometry and van der Walls forces, which usually complicates studies of the CNT properties. Dispersion plays a significant role in CNT studies and we summarize dispersion techniques to generate airborne CNTs from suspensions or powders. We describe in detail our technique of CNT aerosolization with controlled degree of agglomeration using an electrospray system. The results of animal inhalation studies using the electrosprayed CNTs are presented. We have performed filtration experiments for CNTs through a screen filter. A numerical model has been established to simulate the CNT filtration experiments. Both the modeling and experimental results show that the CNT penetration is less than the penetration for a sphere with the same mobility diameter, which is mainly due to the larger interception length of the CNTs. There is a need for instruments capable of fast and online measurement of gas-borne nanoparticle agglomerates. We developed an instrument Universal NanoParticle Analyzer (UNPA) and the measurement results for diesel exhaust particulates are presented. The results presented here are pertinent to non spherical aerosol particles, and illustrate the effects of particle morphology on aerosol behaviors. PMID- 23355750 TI - Influences of Culture and Visual Context on Real-Time Social Categorization. AB - Social categorization is often thought to be based on facial features and immune to visual context. Moreover, East Asians have been argued to attend to context more than Westerners. American and Chinese participants were presented with faces varying along a White-Asian morph continuum either in American, neutral, or Chinese contexts. American contexts made White categorizations more likely, and Chinese contexts made Asian categorizations more likely. Further, the compatibility between facial and contextual cues influenced the directness of participants' hand trajectories en route to selecting a category response. Even when an ultimate response was not biased by context, the trajectory was nevertheless partially attracted to the category response associated with the context. Importantly, such partial attraction effects in hand trajectories revealed that the influence of context began earlier in time for Chinese relative to American participants. Together, the results show that context systematically influences social categorization, sometimes altering categorization responses and other times only temporarily altering the process. Further, the timing of contextual influences differs by culture. The findings highlight the role of contextual and cultural factors in social categorization. PMID- 23355751 TI - 3,2-Hydroxypyridinone (3,2-HOPO) vinyl sulfonamide and acrylamide linkers: Aza Michael addition reactions and the preparation of poly-HOPO chelators. AB - The HOPO vinyl sulfonamide 3 and the corresponding HOPO acrylamide 10, were easily prepared by short synthetic sequences. Investigation of the aza-Michael reactions of these linkers showed that they proceed at a higher rate in solvent systems containing water. The scope and limits of the aza-Michael reactions of 3 and 10 were examined. Reagents 3 and 10 reacted cleanly with piperazine to give the corresponding adducts which were deprotected to give the di-HOPO ligands 7 and 16. Reaction of HOPO acrylamide 10 with 1,4,7-triazacyclononane gave the tris adduct 17 which was deprotected to give the desired tris-HOPO ligand 18. Overall, the aza-Michael reactions of 3 and 10 appear to be governed not only by the solvent but also by the nature of the amine and the solubility of the reaction intermediates. PMID- 23355752 TI - Autocovariance Structures for Radial Averages in Small Angle X-Ray Scattering Experiments. AB - Small-angle X-ray scattering (SAXS) is a technique for obtaining low-resolution structural information about biological macromolecules, by exposing a dilute solution to a high-intensity X-ray beam and capturing the resulting scattering pattern on a two-dimensional detector. The two-dimensional pattern is reduced to a one-dimensional curve through radial averaging; that is, by averaging across annuli on the detector plane. Subsequent analysis of structure relies on these one-dimensional data. This paper reviews the technique of SAXS and investigates autocorrelation structure in the detector plane and in the radial averages. Across a range of experimental conditions and molecular types, spatial autocorrelation in the detector plane is present and is well-described by a stationary kernel convolution model. The corresponding autocorrelation structure for the radial averages is non-stationary. Implications of the autocorrelation structure for inference about macromolecular structure are discussed. PMID- 23355753 TI - Approach and Avoidance of Emotional Faces in Happy and Sad Mood. AB - Since the introduction of the associative network theory, mood-congruent biases in emotional information processing have been established in individuals in a sad and happy mood. Research has concentrated on memory and attentional biases. According to the network theory, mood-congruent behavioral tendencies would also be predicted. Alternatively, a general avoidance pattern would also be in line with the theory. Since cognitive biases have been assumed to operate strongly in case of social stimuli, mood-induced biases in approach and avoidance behavior towards emotional facial expressions were studied. 306 females were subjected to a highly emotional fragment of a sad or a happy movie, to induce either a sad mood or a happy mood. An Approach-Avoidance Task was implemented, in which single pictures of faces (with angry, sad, happy, or neutral expression) and non-social control pictures were presented. In contrast to our expectations, mood states did not produce differential behavioral biases. Mood-congruent and mood-incongruent behavioral tendencies were, however, present in a subgroup of participants with highest depressive symptomatology scores. This suggests that behavioral approach avoidance biases are not sensitive to mood state, but more related to depressive characteristics. PMID- 23355754 TI - Socially Anxious Individuals Get a Second Chance After Being Disliked at First Sight: The Role of Self-Disclosure in the Development of Likeability in Sequential Social Contact. AB - Socially anxious individuals (SAs) not only fear social rejection, accumulating studies show that SAs are indeed judged as less likeable after social interaction with others. This study investigates if SAs already make a more negative impression on others in the very first seconds of contact. The study further investigates the development of likeability and the role of self-disclosure herein in two sequential social interactions: first after an unstructured waiting room situation and next after a 'getting acquainted' conversation. Results showed that high SAs (n = 24) elicited a more negative first impression than low SAs (n = 22). Also, although high SAs improved from the first to the second task, they were rated as less likeable after both interactions. The level of self-disclosure behaviour was the strongest predictor for the development of likeability during the sequential social tasks. The absence of an interaction between group and self disclosure in predicting the development of likeability suggests that this is true for both groups. Thus, high SAs can improve their negative first impression if they are able to increase their self-disclosure behaviour. However, SAs showed a decreased level of self-disclosure behaviour during both social interactions. Targeting self-disclosure behaviour may improve the negative impression SAs elicit in others. PMID- 23355755 TI - Who Deserves Help? Evolutionary Psychology, Social Emotions, and Public Opinion about Welfare. AB - Evidence suggests that our foraging ancestors engaged in the small-scale equivalent of social insurance as an essential tool of survival and evolved a sophisticated psychology of social exchange (involving the social emotions of compassion and anger) to regulate mutual assistance. Here, we hypothesize that political support for modern welfare policies are shaped by these evolved mental programs. In particular, the compassionate motivation to share with needy nonfamily could not have evolved without defenses against opportunists inclined to take without contributing. Cognitively, such parasitic strategies can be identified by the intentional avoidance of productive effort. When detected, this pattern should trigger anger and down-regulate support for assistance. We tested predictions derived from these hypotheses in four studies in two cultures, showing that subjects' perceptions of recipients' effort to find work drive welfare opinions; that such perceptions (and not related perceptions) regulate compassion and anger (and not related emotions); that the effects of perceptions of recipients' effort on opinions about welfare are mediated by anger and compassion, independently of political ideology; and that these emotions not only influence the content of welfare opinions but also how easily they are formed. PMID- 23355756 TI - Reactivation of a Ruthenium-Based Olefin Metathesis Catalyst. AB - 1(st) Generation Hoveyda-Grubbs olefin metathesis catalyst was purposely decomposed in the presence of ethylene yielding inorganic species that are inactive in the ring-closing metathesis (RCM) of benchmark substrate diethyldiallyl malonate (DEDAM). The decomposed catalyst was treated with 1-(3,5 diisopropoxyphenyl)-1-phenylprop-2-yn-1-ol (3) to generate an olefin metathesis active ruthenium indenylidene-ether complex in 43 % yield. This complex was also prepared independently by reacting RuCl(2)(p-cymene)(PCy(3)) with organic precursor 3. The activity of the isolated reactivated catalyst in the RCM of DEDAM is similar to that of the independently prepared complex. PMID- 23355757 TI - Q-learning for estimating optimal dynamic treatment rules from observational data. AB - The area of dynamic treatment regimes (DTR) aims to make inference about adaptive, multistage decision-making in clinical practice. A DTR is a set of decision rules, one per interval of treatment, where each decision is a function of treatment and covariate history that returns a recommended treatment. Q learning is a popular method from the reinforcement learning literature that has recently been applied to estimate DTRs. While, in principle, Q-learning can be used for both randomized and observational data, the focus in the literature thus far has been exclusively on the randomized treatment setting. We extend the method to incorporate measured confounding covariates, using direct adjustment and a variety of propensity score approaches. The methods are examined under various settings including non-regular scenarios. We illustrate the methods in examining the effect of breastfeeding on vocabulary testing, based on data from the Promotion of Breastfeeding Intervention Trial. PMID- 23355758 TI - Re: Age-specific incidence of breast cancer subtypes: understanding the Black White crossover. PMID- 23355759 TI - Detection of mesothioloma remains a conundrum. PMID- 23355760 TI - Pleural plaques and the risk of pleural mesothelioma. AB - BACKGROUND: The association between pleural plaques and pleural mesothelioma remains controversial. The present study was designed to examine the association between pleural plaques on computed tomography (CT) scan and the risk of pleural mesothelioma in a follow-up study of asbestos-exposed workers. METHODS: Retired or unemployed workers previously occupationally exposed to asbestos were invited to participate in a screening program for asbestos-related diseases, including CT scan, organized between October 2003 and December 2005 in four regions in France. Randomized, independent, double reading of CT scans by a panel of seven chest radiologists focused on benign asbestos-related abnormalities. A 7-year follow-up study was conducted in the 5287 male subjects for whom chest CT scan was available. Annual determination of the number of subjects eligible for free medical care because of pleural mesothelioma was carried out. Diagnosis certification was obtained from the French mesothelioma panel of pathologists. Survival regression based on the Cox model was used to estimate the risk of pleural mesothelioma associated with pleural plaques, with age as the main time variable and time-varying exposure variables, namely duration of exposure, time since first exposure, and cumulative exposure index to asbestos. All statistical tests were two-sided. RESULTS: A total of 17 incident cases of pleural mesothelioma were diagnosed. A statistically significant association was observed between mesothelioma and pleural plaques (unadjusted hazard ratio (HR) = 8.9, 95% confidence interval [CI] = 3.0 to 26.5; adjusted HR = 6.8, 95% CI = 2.2 to 21.4 after adjustment for time since first exposure and cumulative exposure index to asbestos). CONCLUSION: The presence of pleural plaques may be an independent risk factor for pleural mesothelioma. PMID- 23355761 TI - PKB/Akt-dependent regulation of cell motility. AB - The prosurvival activity of phosphoinositide 3 kinase (PI3K)/Akt (also known as protein kinase B, PKB) pathway has been investigated in great detail in human physiology and disease. Accumulating evidence is emerging that this signaling axis also actively engages with the migratory process in motile cells, including metastatic cancer cells. Interference with the role of PI3K/Akt-mediated cell motility impairs cellular development and attenuates malignant progression of cancer metastasis. Because metastasis is responsible for 90% of mortality in cancer patients, the acceleration of cancer cell spreading observed in association with hyperactivation of the PI3K pathway, triggered for example by chemotherapy/radiotherapy in the clinic, has heightened awareness of the conflict between "good drugs" and unfavorable effects. Here, we discuss recent studies on PI3K/Akt-regulated cell motility in both physiological and pathological settings, with the aim of a better understanding of how activities of the PI3K/Akt axis initiate and transmit "migratory signals" that stimulate cell movement. We focus in particular on its direct influence on cell migration and invasion, epithelial mesenchymal transition, and cancer metastasis. PMID- 23355762 TI - Microneedle Biosensor: A Method for Direct Label-free Real Time Protein Detection. AB - Here we present the development of an array of electrical micro-biosensors in a microfluidic channel, called microneedle biosensors. A microneedle biosensor is a real-time, label-free, direct electrical detection platform, which is capable of high sensitivity detection, measuring the change in ionic current and impedance modulation, due to the presence or reaction of biomolecules such as proteins and nucleic acids. In this study, we successfully fabricated and electrically characterized the sensors and demonstrated successful detection of target protein. In this study, we used biotinylated bovine serum albumin as the receptor and streptavidin as the target analyte. PMID- 23355763 TI - Psychical research and the origins of American psychology: Hugo Munsterberg, William James and Eusapia Palladino. AB - Largely unacknowledged by historians of the human sciences, late-19th-century psychical researchers were actively involved in the making of fledgling academic psychology. Moreover, with few exceptions historians have failed to discuss the wider implications of the fact that the founder of academic psychology in America, William James, considered himself a psychical researcher and sought to integrate the scientific study of mediumship, telepathy and other controversial topics into the nascent discipline. Analysing the celebrated exposure of the medium Eusapia Palladino by German-born Harvard psychologist Hugo Munsterberg as a representative example, this article discusses strategies employed by psychologists in the United States to expel psychical research from the agenda of scientific psychology. It is argued that the traditional historiography of psychical research, dominated by accounts deeply averse to its very subject matter, has been part of an ongoing form of 'boundary-work' to bolster the scientific status of psychology. PMID- 23355764 TI - Contested psychiatric ontology and feminist critique: 'Female Sexual Dysfunction' and the Diagnostic and Statistical Manual. AB - In this article I discuss the emergence of Female Sexual Dysfunction (FSD) within American psychiatry and beyond in the postwar period, setting out what I believe to be important and suggestive questions neglected in existing scholarship. Tracing the nomenclature within successive editions of the American Psychiatric Association's Diagnostic and Statistical Manual (DSM), I consider the reification of the term 'FSD', and the activism and scholarship that the rise of the category has occasioned. I suggest that analysis of FSD benefits from scrutiny of a wider range of sources (especially since the popular and scientific cross-pollinate). I explore the multiplicity of FSD that emerges when one examines this wider range, but I also underscore a reinscribing of anxieties about psychogenic aetiologies. I then argue that what makes the FSD case additionally interesting, over and above other conditions with a contested status, is the historically complex relationship between psychiatry and feminism that is at work in contemporary debates. I suggest that existing literature on FSD has not yet posed some of the most important and salient questions at stake in writing about women's sexual problems in this period, and can only do this when the relationship between 'second-wave' feminism, 'post-feminism', psychiatry and psychoanalysis becomes part of the terrain to be analysed, rather than the medium through which analysis is conducted. PMID- 23355765 TI - Temperament and Social Problem Solving Competence in Preschool: Influences on Academic Skills in Early Elementary School. AB - The goals of the current study were to examine whether children's social problem solving (SPS) skills are a mechanism through which temperament influences later academic achievement and whether sex moderates these associations. Participants included 1,117 children enrolled in the NICHD Early Child Care Study. During preschool, mothers and childcare providers rated children's temperamental shyness and inhibitory control, and SPS was assessed using a hypothetical-reflective measure during a laboratory visit. During kindergarten and first grade, teacher report of math and language skills was collected. Results indicated that high ratings of inhibitory control in preschool, but not shyness, predicted better kindergarten and first grade academic skills. Furthermore, children's SPS competence mediated the relations between both shyness and inhibitory control on later academic skills. The child's sex did not moderate these associations. Results suggest that preventative efforts targeting early SPS skills may buffer against later academic adjustment problems among temperamentally extreme children. PMID- 23355767 TI - Selectivity Enhancement for Chloride Ion by In(III)-Porphyrin-Based Polymeric Membrane Electrode Operated in Pulsed Chronopotentiometric Mode. AB - A robust selectivity enhancement of an In(III)-porphyrin ionophore-based chloride selective electrode under pulsed chronopotentiometric measurement mode that enables the detection of chloride ions in the presence of a normally interfering concentration of salicylate ions is described. This enhancement is achieved by the rapid depletion of the surface concentration of the more dilute lipophilic anion during an initial anodic current pulse period due to extraction of this preferred anion into the membrane phase. Measurement of chloride with a detection limit of 8 mM and near Nernstian response slope in the presence of 1 mM salicylate is possible using the pulstrode method. PMID- 23355766 TI - Current trends in negative immuno-synergy between two sexually transmitted infectious viruses: HIV-1 and HSV-1/2. AB - In the current era of effective anti-retroviral therapy, immuno-compromised patients with HIV-1 infection do live long enough to suffer diseases caused by many opportunistic infections, such as herpes simplex virus type 1 and/or type 2 (HSV-1/2). An estimated two-third of the 40 million individuals that have contracted HIV-1 worldwide are co-infected with HSV-1/2 viruses, the causative agents of ocular oro-facial and genital herpes. The highest prevalence of HIV and HSV-1/2 infections are confined to the same regions of Sub-Saharan Africa. HSV 1/2 infections affect HIV-1 immunity, and vice versa. While important research gains have been made in understanding herpes and HIV immunity, the cellular and molecular mechanisms underlying the crosstalk between HSV-1/2 and HIV co infection remain to be fully elucidated. Understanding the mechanisms behind the apparent HSV/HIV negative immuno-synergy maybe the key to successful HSV and HIV vaccines; both are currently unavailable. An effective herpes immunotherapeutic vaccine would in turn - indirectly - contribute in reducing HIV epidemic. The purpose of this review is: (i) to summarize the current trends in understanding the negative immuno-crosstalk between HIV and HSV-1/2 infections; and (ii) to discuss the possibility of developing a novel mucosal herpes immunotherapeutic strategy or even a combined or chimeric immunotherapeutic vaccine that simultaneously targets HIV and HSV-1/2 infections. These new trends in immunology of HSV-1/2 and HIV co-infections should become part of current efforts in preventing sexually transmitted infections. The alternative is needed to balance the ethical and financial concerns associated with the rising number of unsuccessful mono-valent clinical vaccine trials. PMID- 23355768 TI - Understanding the Behavioral Determinants of Mental Health Service Use by Urban, Under-Resourced Black Youth: Adolescent and Caregiver Perspectives. AB - Black adolescents with mental health problems are less likely than non-Black adolescents with mental health problems to receive treatment, primarily for non financial reasons including negative perceptions of services and providers, and self-stigma associated with experiencing mental health problems. To better understand these obstacles, 16 adolescents and 11 caregivers, recruited from two K-8th grade elementary-middle schools, participated in four focus groups guided by the unified theory of behavior to explore mental health help-seeking behaviors and perceptions of mental health services. In the focus groups, caregivers acknowledged more positive attitudes about seeking mental health services than adolescents, but both expected the experience of actually doing so to be negative. Adolescents and caregivers also acknowledged social norms that inhibit their mental health help-seeking. Therefore, we conclude that interventions targeting expectancies and social norms might increase the connection of urban, under-resourced Black adolescents and their families to mental health services, and be particularly important given the long-term consequences of untreated mental health problems for this group. PMID- 23355770 TI - Peripheral capillary nonperfusion and full-field electroretinographic changes in eyes with frosted branch-like appearance retinal vasculitis. AB - We report a patient with frosted branch-like appearance retinal vasculitis associated with peripheral capillary nonperfusion and full-field electroretinographic changes. A 62-year-old man presented with sudden bilateral decreased vision accompanied by headaches. His best-corrected visual acuity was 0.01 in both eyes. Fundus examination and fluorescein angiography showed bilateral frosted branch-like appearance retinal vasculitis, and spectral-domain optical coherence tomography showed severe macular edema in both eyes. The cerebrospinal fluid analyses showed an increased lymphocyte count and protein levels. He was treated with systemic corticosteroid therapy, and his best corrected visual acuity improved to 0.8 OD and 1.0 OS at 6 months after onset. However, fluorescein angiography showed a lack of capillary perfusion in the periphery, and the oscillatory potentials on full-field electroretinography were severely reduced in both eyes. These findings indicated extensive retinal ischemia and inner retinal dysfunction, and that fluorescein angiography and full field electroretinograms can be useful during follow-up of eyes with frosted branch-like appearance retinal vasculitis. PMID- 23355771 TI - Safety of besifloxacin ophthalmic suspension 0.6% in refractive surgery: a retrospective chart review of post-LASIK patients. AB - BACKGROUND: To evaluate the safety of besifloxacin ophthalmic suspension 0.6% when used in laser-assisted in situ keratomileusis (LASIK) prophylactic antibiotic regimens. METHODS: Retrospective surveillance of LASIK surgery cases where besifloxacin ophthalmic suspension 0.6% or moxifloxacin ophthalmic solution 0.5% were prescribed as prophylactic medications. Surgeons from nine US surgical centers provided retrospective case information on surgical outcomes from consecutive cases and reported any adverse events related to the antibacterial used. The primary endpoint was the incidence of adverse drug reactions. RESULTS: A total of 801 case reports (801 eyes; 534 besifloxacin, 267 moxifloxacin) were obtained. The mean (standard deviation [SD]) age at time of surgery was 36.1 (10.6) years. The mean (SD) duration of antibiotic treatment was 8.6 (2.2) days in the besifloxacin group and 8.0 (2.3) in the moxifloxacin group; daily dosing frequency was higher in the moxifloxacin group preoperatively, on the day of surgery, and postoperatively. There were no reports of adverse drug reactions for the 801 eyes in this surveillance. There were no differences between the besifloxacin and moxifloxacin treatment groups in rates of unexpected corneal findings (2.1% vs 1.5%, P = 0.949). The distribution of final visual acuity for the besifloxacin and moxifloxacin groups were similar (P = 0.793). Most cases had a final visual acuity of 20/20 or better. CONCLUSION: In this retrospective surveillance study, the prophylactic use of besifloxacin ophthalmic suspension 0.6% and moxifloxacin ophthalmic solution 0.5% in patients undergoing LASIK surgery was not associated with any adverse drug reactions. PMID- 23355772 TI - Clinical manifestations of optic pit maculopathy as demonstrated by spectral domain optical coherence tomography. AB - PURPOSE: The purpose of this retrospective study was to evaluate the characteristic features, including spectral-domain optical coherence tomography (SD-OCT), clinical course, and outcome of treatment if given for patients with optic disc pit maculopathy. METHODS: We investigated a consecutive series of patients with a diagnosis of optic pit maculopathy treated between 2001 and 2012 at the Bascom Palmer Eye Institute. Patients were divided into two main groups, ie, patients who were observed without surgery and patients who received surgical intervention. The main outcome measures were presenting and final visual acuity, and changes in SD-OCT imaging were recorded. Other data including age, gender, eye, age of onset, length of follow-up, location of optic pit, and location of fluid by OCT were also recorded. RESULTS: On OCT, 67% (12/18) of the eyes showed schisis-like cavities, 22% (4/18) had only subretinal fluid, and 17% (3/18) had only a schisis-like cavity without subretinal fluid. In the patients managed by observation, visual acuity was >=20/200 in 6/8 eyes initially and 6/8 eyes at last follow-up. Ten of 18 patients received either focal laser, surgery or both. Six of 10 eyes undergoing surgery had initial visual acuity >= 20/200, and 8 of 10 eyes undergoing surgery had a visual acuity of >=20/200 at last follow-up. CONCLUSION: In this study, many eyes were observed and remained stable during follow-up. In eyes with reduced vision, surgical intervention produced variable outcomes, and persistent intraretinal/subretinal fluid was a common occurrence. PMID- 23355773 TI - Changes in the foveal microstructure after intravitreal bevacizumab application in patients with retinal vascular disease. AB - PURPOSE: To investigate changes in the area of the foveal avascular zone (FAZ) in patients with retinal vascular disease. PATIENTS AND METHODS: This retrospective, consecutive study examined 53 eyes of 53 patients with macular edema due to branch retinal vein occlusion in 25 patients (47.2%) and nonproliferative diabetic retinopathy in 28 patients (52.8%). The macular edema was treated with an intravitreal injection of 0.05 mL equal to 1.25 mg bevacizumab. Before and 6-8 weeks after the injection, best corrected visual acuity, slit lamp biomicroscopy of the anterior segment and fundus, optical coherence tomography, and fluorescein angiography were conducted. The FAZ was manually circumscribed on early-phase angiography images and the area of the FAZ was measured. RESULTS: The preoperative overall mean FAZ area was 0.327 +/- 0.126 mm(2) (median 0.310 mm(2)). At the control consultation, the overall mean area was significantly larger (0.422 +/- 0.259 mm(2); median 0.380 mm(2); P < 0.001). In the nonproliferative diabetic retinopathy subpopulation, the mean area was 0.361 +/- 0.129 mm(2) (median 0.330 mm(2)) before bevacizumab application and 0.434 mm(2) at the follow-up visit (mean increase 0.071 mm(2)/19.7%). In the branch retinal vein occlusion group, the baseline FAZ area was 0.290 +/- 0.115 mm(2) and 0.407 +/- 0.350 mm(2) at follow-up (median 0.330 mm(2); mean increase 0.117 mm(2)/40.3%). No cases of severe operation-associated complications were observed. CONCLUSION: The results confirm the safety of intravitreal bevacizumab injection in patients with macular edema due to nonproliferative diabetic retinopathy and branch retinal vein occlusion. The enlargement of the FAZ could be equivalent to an increase in retinal ischemia. These results may be transient; a potential vascular risk, however, when applying antivascular endothelial growth factor therapy in eyes with preexistent vascular disease must be considered. PMID- 23355774 TI - Management of chronic pain in elderly, frail patients: finding a suitable, personalized method of control. AB - The elderly population is projected to make up 20% of the total United States population by the year 2030. In addition, epidemiological data suggests increasing prevalence of chronic pain and frailty with advancing age. Pain, being a subjective symptom, is challenging to manage effectively. This is more so in elderly populations with age-specific physiological changes that affect drug action and metabolism. Elderly patients are also more likely to have multiple chronic health pathologies, declining function, and frailty. The barriers present for patients, providers, and health systems also negatively impact efficient and effective pain control. These factors result in disproportionate utilization of health resources by the older population group. The scientific literature is lagging behind in age-specific studies for the elderly population. As a result, there is a lack of age-specific standardized management guidelines for various health problems, including chronic pain. Increasing efforts are now being directed to studies on pain control in the elderly. However, pain management remains inconsistent and suboptimal. This article is an attempt to suggest an informed, comprehensive guide to achieve effective pain control in the presence of these limitations. PMID- 23355776 TI - Design, physicochemical characterization, and optimization of organic solution advanced spray-dried inhalable dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) microparticles and nanoparticles for targeted respiratory nanomedicine delivery as dry powder inhalation aerosols. AB - Novel advanced spray-dried and co-spray-dried inhalable lung surfactant-mimic phospholipid and poly(ethylene glycol) (PEG)ylated lipopolymers as microparticulate/nanoparticulate dry powders of biodegradable biocompatible lipopolymers were rationally formulated via an organic solution advanced spray drying process in closed mode using various phospholipid formulations and rationally chosen spray-drying pump rates. Ratios of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine PEG (DPPE-PEG) with varying PEG lengths were mixed in a dilute methanol solution. Scanning electron microscopy images showed the smooth, spherical particle morphology of the inhalable particles. The size of the particles was statistically analyzed using the scanning electron micrographs and SigmaScan(r) software and were determined to be 600 nm to 1.2 MUm in diameter, which is optimal for deep-lung alveolar penetration. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were performed to analyze solid-state transitions and long-range molecular order, respectively, and allowed for the confirmation of the presence of phospholipid bilayers in the solid state of the particles. The residual water content of the particles was very low, as quantified analytically via Karl Fischer titration. The composition of the particles was confirmed using attenuated total-reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy and confocal Raman microscopy (CRM), and chemical imaging confirmed the chemical homogeneity of the particles. The dry powder aerosol dispersion properties were evaluated using the Next Generation ImpactorTM (NGITM) coupled with the HandiHaler(r) dry powder inhaler device, where the mass median aerodynamic diameter from 2.6 to 4.3 MUm with excellent aerosol dispersion performance, as exemplified by high values of emitted dose, fine particle fraction, and respirable fraction. Overall, it was determined that the pump rates defined in the spray-drying process had a significant effect on the solid-state particle properties and that a higher pump rate produced the most optimal system. Advanced dry powder inhalers of inhalable lipopolymers for targeted dry powder inhalation delivery were successfully achieved. PMID- 23355775 TI - Muscular effects of statins in the elderly female: a review. AB - Statins have demonstrated substantial benefits in supporting cardiovascular health. Older individuals are more likely to experience the well-known muscle related side effects of statins compared with younger individuals. Elderly females may be especially vulnerable to statin-related muscle disorder. This review will collate and discuss statin-related muscular effects, examine their molecular and genetic basis, and how these apply specifically to elderly women. Developing strategies to reduce the incidence of statin-induced myopathy in older adult women could contribute to a significant reduction in the overall incidence of statin-induced muscle disorder in this vulnerable group of patients. Reducing statin-related muscle disorder would likely improve overall patient compliance, thereby leading to an increase in improved short- and long-term outcomes associated with appropriate use of statins. PMID- 23355777 TI - Different corrosive effects on hydroxyapatite nanocrystals and amine fluoride based mouthwashes on dental titanium brackets: a comparative in vitro study. AB - Titanium plates treated in vitro with a mouthwash containing amine fluoride (100 ppm F-) and another containing zinc-substituted carbonate-hydroxyapatite have been analyzed by scanning electron microscopy and atomic force microscopy to evaluate the modification of the surface roughness induced by treatment with these two different mouthwashes. The treatment with F--based mouthwash produces a roughness characterized by higher peaks and deeper valleys in the streaks on the titanium bracket surface compared with those observed in the reference polished titanium plates. This effect causes a mechanical weakness in the metallic dental implant causing bacterial growth and therefore promotes infection and prosthesis contamination. However, the in vitro treatment with a mouthwash containing zinc substituted carbonate-hydroxyapatite reduced the surface roughness by filling the streaks with an apatitic phase. This treatment counteracts the surface oxidative process that can affect the mechanical behavior of the titanium dental implant, which inhibits the bacterial growth contaminating prostheses. PMID- 23355778 TI - Effects, experiences, and impact of stigma on patients with bipolar disorder. AB - BACKGROUND: Many people with mental illness experience stigma that has impacted their lives. In this study, we validated the Inventory of Stigmatizing Experiences (ISE) as a tool to help quantify the stigma experienced by patients with bipolar disorder and its impact on their lives. The ISE has two components, ie, the Stigma Experiences Scale (SES) and the Stigma Impact Scale (SIS), which were administered to a population of Argentinean patients with bipolar disorder. We characterized the differences between these two populations using the SES and SIS. Finally, we compared SES and SIS scores with those in a population of Canadian patients with bipolar disorder. METHODS: The SES and SIS scales were administered to tertiary care patients with bipolar I and II disorder in Argentina (n = 178) and Canada (n = 214). RESULTS: In this study, we validated both SES (Kuder-Richardson coefficient of reliability, 0.78) and SIS (Cronbach's alpha, 0.91) scales in a population of Argentinean patients with bipolar disorder. There were no significant differences in stigma between patients with bipolar I or II disorder on SES or SIS. However, over 50% of all respondents believed that the average person is afraid of those with mental illnesses, that stigma associated with mental illness has affected their quality of life, and that their self-esteem has suffered due to stigma. In comparison with the Canadian population, Argentinean participants scored lower on both the SES and SIS, which may be due to cultural differences or to differences in population characteristics. CONCLUSION: Stigma associated with mental illness is serious and pervasive. If we are to find successful strategies to mitigate stigma, it is first important to understand how patients perceive such stigma. The ISE is a valuable tool which allows us to do this with high reliability among cultures. PMID- 23355779 TI - Symptomatic or prophylactic treatment of weekend migraine: an open-label, nonrandomized, comparison study of frovatriptan versus naproxen sodium versus no therapy. AB - BACKGROUND: Migraine often occurs during weekends. The efficacy of frovatriptan, naproxen sodium, or no therapy for the acute or prophylactic treatment of weekend migraineurs was tested in an open-label, nonrandomized pilot study. METHODS: Twenty-eight subjects (mean age 36 +/- 12 years, including 18 females) suffering from migraine without aura were followed up for six consecutive weekends. No treatment was administered during the first two weekends. On the third and fourth weekends, patients were given frovatriptan 2.5 mg and on the fifth and sixth weekends naproxen sodium 500 mg. Treatment was taken on Saturday and Sunday morning, regardless of the occurrence of migraine. Efficacy was evaluated through a diary, where patients reported the severity of migraine on a scale from 0 (no migraine) to 10 (severe migraine) and use of rescue medication. RESULTS: The migraine severity score was significantly lower with frovatriptan (4.8 [95% confidence interval (CI) 3.8-5.9]) than with naproxen sodium (5.7 [CI 5.1-6.4], P< 0.05 versus frovatriptan) or no therapy (6.6 [6.2-7.0], P< 0.01 versus frovatriptan). The difference in favor of frovatriptan was more striking in patients not taking rescue medication (frovatriptan, 1.9 [1.5-2.3]) versus naproxen sodium 3.6 [3.0-4.2], P< 0.001) and versus no therapy (5.1 [4.4-5.8], P< 0.001) and on the second day of treatment. The rate of use of rescue medication was significantly (P< 0.05) lower on frovatriptan (12.5%) than on naproxen sodium (31.3%) or no therapy (56.3%). CONCLUSION: This pilot study provides the first evidence of the efficacy of a second-generation triptan as symptomatic or prophylactic treatment for weekend migraine. PMID- 23355780 TI - Sensory integration dysfunction affects efficacy of speech therapy on children with functional articulation disorders. AB - BACKGROUND: Articulation disorders in young children are due to defects occurring at a certain stage in sensory and motor development. Some children with functional articulation disorders may also have sensory integration dysfunction (SID). We hypothesized that speech therapy would be less efficacious in children with SID than in those without SID. Hence, the purpose of this study was to compare the efficacy of speech therapy in two groups of children with functional articulation disorders: those without and those with SID. METHOD: A total of 30 young children with functional articulation disorders were divided into two groups, the no-SID group (15 children) and the SID group (15 children). The number of pronunciation mistakes was evaluated before and after speech therapy. RESULTS: There were no statistically significant differences in age, sex, sibling order, education of parents, and pretest number of mistakes in pronunciation between the two groups (P > 0.05). The mean and standard deviation in the pre- and post-test number of mistakes in pronunciation were 10.5 +/- 3.2 and 3.3 +/- 3.3 in the no-SID group, and 10.1 +/- 2.9 and 6.9 +/- 3.5 in the SID group, respectively. Results showed great changes after speech therapy treatment (F = 70.393; P < 0.001) and interaction between the pre/post speech therapy treatment and groups (F = 11.119; P = 0.002). CONCLUSIONS: Speech therapy can improve the articulation performance of children who have functional articulation disorders whether or not they have SID, but it results in significantly greater improvement in children without SID. SID may affect the treatment efficiency of speech therapy in young children with articulation disorders. PMID- 23355781 TI - Reliability and validity of the Thai version of the Calgary Depression Scale for Schizophrenia. AB - AIM: The purpose of this study was to assess the reliability and validity of the Thai version of the Calgary Depression Scale for Schizophrenia (CDSS) for the evaluation of depression in patients with schizophrenia. METHODS: Sixty patients with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders: Fourth Edition; Text Revision (DSM-IV-TR) criteria were recruited to the study The Thai version of the CDSS, the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale, 17-item version (HDRS-17), and the Positive and Negative Syndrome Scale (PANSS) were administered. A major depressive episode diagnosed by a psychiatrist according to the DSM-IV-TR was used as a gold standard. RESULTS: The internal consistency of the Thai version of the CDSS was very good (Cronbach's alpha = 0.869). The inter-rater reliability was found to be in substantial agreement with the intra-class correlation coefficient of 0.979. The test-retest reliability over a period of 3 days was high, with an intra-class correlation coefficient of 0.861. The Thai version of the CDSS showed significant correlations with the MADRS (r = 0.887), the HDRS-17 (r = 0.865), and the depression item of the Positive and Negative Syndrome Scale (PANSS-G6) (r = 0.833). The areas under the receiver operating characteristic curve of the CDSS, MADRS, HDRS-17, and PANSS-G6 against the DSM-IV-TR criteria for major depressive episode were 0.993, 0.954, 0.966, and 0.933, respectively. The optimal cut-off score to discriminate between depressed and non-depressed patients was 6/7, with a sensitivity of 92.31% and specificity of 97.87%. CONCLUSION: The Thai version of the CDSS is a reliable and valid measure for the evaluation of depression in Thai patients with schizophrenia. PMID- 23355782 TI - Dosing frequency and adherence in chronic psychiatric disease: systematic review and meta-analysis. AB - BACKGROUND: The purpose of this study was to investigate the impact of dosing frequency on adherence in severe chronic psychiatric and neurological diseases. METHODS: A systematic literature review was conducted for articles in English from medical databases. Diseases were schizophrenia, psychosis, epilepsy, bipolar disorder, and major depressive disorder. RESULTS: Of 1420 abstracts screened, 12 studies were included. Adherence measures included Medication Event Monitoring System (MEMS((r))), medication possession ratio, medication persistence, and refill adherence. Three schizophrenia and one epilepsy study used MEMS, and all showed a trend towards higher adherence rates with less frequent dosing regimens. Three depression and one schizophrenia study used the medication possession ratio; the pooled odds ratio of being adherent was 89% higher (ie, 1.89, 95% credibility limits 1.71-2.09) on once-daily versus twice-daily dosing. Two studies in depression and one in all bupropion patients assessed medication persistence and refill adherence. The pooled odds ratio for the two depression studies using medication persistence was 2.10 (95% credibility limits 1.86-2.37) for once-daily versus twice-daily dosing. For refill adherence after 9 months, 65%-75% of patients on once-daily versus 56% on twice-daily dosing had at least one refill. In all but one of the studies using other measures of adherence, adherence rates were higher with once-daily dosing compared with more frequent dosing regimens. No relevant studies were identified for bipolar disorder or psychosis. CONCLUSION: Differences in study design and adherence measures used across the studies were too large to allow pooling of all results. Despite these differences, there was a consistent trend of better adherence with less frequent dosing. PMID- 23355783 TI - Weight gain, metabolic disturbances, and physical health care in a Brazilian sample of outpatients with schizophrenia. AB - BACKGROUND: In the last few decades, a large number of studies have produced compelling evidence that patients with schizophrenia are at increased risk for developing several medical conditions and diseases, including obesity, metabolic disturbances, and cardiovascular diseases. Several protocols have been designed with the aim of reducing such risk. OBJECTIVE: To investigate current physical health status in a population of outpatients with schizophrenia. METHODS: A cross sectional study was conducted in our outpatient clinic, selecting subjects who met DSM-IV diagnosis criteria for schizophrenia. Data were collected regarding clinical characteristics, lifestyle, medication in use, and biometric and laboratory parameters. RESULTS: A total of 261 patients were included. We found a high prevalence of elevated body mass index (BMI . 25) (70%), dyslipidemia (73.2%), and metabolic syndrome (28.7%). Patients' ages were associated with worsened lipid profiles, but other variables, such as disorder duration or type of antipsychotic in use, were not associated with any metabolic disturbance. Despite the increased prevalence of these conditions, only a small portion of the sample was under regular medical treatment. CONCLUSION: Outpatients with schizophrenia show signs of poor physical health conditions. These findings reinforce the need for an intensive and appropriate approach to assure that these patients receive adequate clinical referral and treatment. PMID- 23355784 TI - Capgras-like syndrome in a patient with an acute urinary tract infection. AB - Delusional misidentification syndromes are a group of delusional phenomena in which patients misidentify familiar persons, objects, or themselves, believing that they have been replaced or transformed. In 25%-40% of cases, misidentification syndromes have been reported in association with organic illness. We report an acute episode of Capgras-like delusion lasting 8 days, focused on the idea that people were robots with human bodies, in association with an acute urinary infection. To our knowledge, this is the first case report associating urinary tract infection with Capgras-like syndrome. Awareness of the prevalence of delusional misidentification syndromes associated with acute medical illness should promote diligence on the part of clinicians in recognizing this disorder. PMID- 23355785 TI - A review of electroencephalographic changes in diabetes mellitus in relation to major depressive disorder. AB - A bidirectional relationship exists between diabetes mellitus (DM) and major depressive disorder (MDD), with depression commonly reported in both type 1 DM (T1DM) and type 2 DM (T2DM), and depressive symptoms associated with a higher incidence of diabetes. However, how the two conditions are pathologically connected is not completely understood. Similar neurophysiological abnormalities have been reported in both DM and MDD, including elevated electroencephalographic (EEG) activity in low-frequency slow waves and increased latency and/or reduced amplitude of event-related potentials. It is possible that this association reflects some common underlying pathology, and it has been proposed that diabetes may place patients at risk for depression through a biological mechanism linking the metabolic changes of DM to changes in the central nervous system. In this review we will discuss EEG abnormalities in DM, as well as the biological mechanisms underlying various EEG parameters, in order to evaluate whether or not a common EEG biosignature exists between DM and MDD. Identifying such commonalities could significantly inform the current understanding of the mechanisms that subserve the development of the two conditions. Moreover, this new insight may provide the basis for informing new drug discovery capable of mitigating and possibly even preventing both conditions. PMID- 23355786 TI - Effect of TNF antagonists on the productivity of daily work of patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a significant cause of work disability and job loss. The resulting economic burden experienced by patients has received considerable research attention. This research assesses the effect of tumor necrosis factor (TNF) antagonists (infliximab, etanercept) on the ability of RA patients living in Japan to work and participate in society. A total of 42 patients with active RA were enrolled and given biological therapy for 12 months (mo). Of these patients, 14 were employed full-time, 6 were employed part-time, and 22 were not employed. Twenty-six patients were given infliximab, and sixteen were given etanercept. The amount of domestic labor performed before the biologics served as a baseline and was assigned a value of 0%. After treatment with biologics, the productivity was evaluated using the visual analog scale (VAS; -100 to +100 mm). The administration of TNF antagonists to RA patients who exhibited an insufficient response to medical treatment significantly improved the Disease Activity Score 28 (DAS 28) after both 6 mo and 12 mo (P < 0.0001). A significant correlation was found between the improvement in their DAS 28 and improvements in their work situation (Productivity VAS) (P < 0.05). Of particular interest is the significant correlation between the values of baseline mHAQ and the percent changes of Productivity VAS that was observed after 6 mo and 12 mo (P < 0.05). Our findings indicate that medical treatment of RA with TNF antagonists improves the patients' ability to perform their jobs and housekeeping. Because loss of productivity is an important contributor to the indirect costs of RA, our findings are relevant for the pharmacoeconomic assessment of treatments. PMID- 23355787 TI - Health care costs before and after diagnosis of depression in patients with unexplained pain: a retrospective cohort study using the United Kingdom General Practice Research Database. AB - PURPOSE: To assess the impact of pain severity and time to diagnosis of depression on health care costs for primary care patients with pre-existing unexplained pain symptoms who subsequently received a diagnosis of depression. PATIENTS AND METHODS: This retrospective cohort study analyzed 4000 adults with unexplained pain (defined as painful physical symptoms [PPS] without any probable organic cause) and a subsequent diagnosis of depression, identified from the UK General Practice Research Database using diagnostic codes. Patients were categorized into four groups based on pain severity (milder or more severe; based on number of pain-relief medications and use of opioids) and time to diagnosis of depression (<=1 year or>1 year from PPS index date). Annual health care costs were calculated (2009 values) and included general practitioner (GP) consultations, secondary care referrals, and prescriptions for pain-relief medications for the 12 months before depression diagnosis and in the subsequent 2 years. Multivariate models of cost included time period as a main independent variable, and adjusted for age, gender, and comorbidities. RESULTS: Total annual health care costs before and after depression diagnosis for the four patient groups were higher for the groups with more severe pain (L819-L988 versus L565 L628; P < 0.001 for all pairwise comparisons) and highest for the group with more severe pain and longer time to depression diagnosis in the subsequent 2 years (P < 0.05). Total GP costs were highest in the group with more severe pain and longer time to depression diagnosis both before and after depression diagnosis (P < 0.05). In the second year following depression diagnosis, this group also had the highest secondary care referral costs (P < 0.01). The highest drug costs were in the groups with more severe pain (P < 0.001), although costs within each group were similar before and after depression diagnosis. CONCLUSION: Among patients with unexplained pain symptoms, significant pain in combination with longer time from pain symptoms to depression diagnosis contribute to higher costs for the UK health care system. PMID- 23355788 TI - Topical niacinamide 4% and desonide 0.05% for treatment of axillary hyperpigmentation: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Axillary hyperpigmentation is a frequent cause of cosmetic consultations in dark-skinned women from tropical areas, including Latin America. Currently, there is no widely accepted treatment for the disorder, but it is usually treated with bleaching agents because it is considered a variant of inflammatory hyperpigmentation. The purpose of this study was to assess the efficacy of niacinamide 4% and desonide 0.05% emulsions compared with placebo in the treatment of axillary hyperpigmentation. METHODS: Twenty-four women aged 19 27 years with hyperpigmented axillae (phototype III-V) were randomly assigned to receive the study treatments in the axillary region. Improvement was assessed at baseline, then clinically and by colorimetry 9 weeks later. Quantitative evaluation including melanin, inflammatory infiltrates, NKI/Beteb, CD1a, CD68, and collagen type IV content was performed by histochemistry and immunohistochemistry, assisted by computerized morphometric analysis. RESULTS: Both niacinamide and desonide induced significant colorimetric improvement compared with placebo; however, desonide showed a better depigmenting effect than niacinamide. A good to excellent response was achieved in 24% of cases for niacinamide, 30% for desonide, and 6% for placebo. We observed a marked disruption of the basal membrane in axillary hyperpigmentation and an inflammatory infiltrate that improved after treatment. Decreased pigmentation in the desonide-treated axillae was associated with recovery of disruption at the basal membrane. CONCLUSION: Niacinamide and desonide showed depigmenting properties in women with axillary hyperpigmentation. These findings may be explained by their antimelanogenic and anti-inflammatory properties, respectively. PMID- 23355789 TI - Androgen deprivation therapy in advanced prostate cancer: is intermittent therapy the new standard of care? AB - PURPOSE: Intermittent androgen deprivation is increasingly used as an alternative to continuous life-long androgen deprivation therapy for men with advanced or recurrent prostate cancer. RECENT FINDINGS: Two recent phase iii trials have clarified the benefits of intermittent therapy. The Canadian-led pr.7 trial in men with nonmetastatic disease and prostate-specific antigen recurrence after definitive local therapy showed that intermittent therapy resulted in survival equivalent to that with continuous therapy, with significant improvements in quality of life. Patients on intermittent therapy experienced improved bone health, fewer metabolic and hematologic disturbances, fewer hot flashes, and improved sexual function. In men with metastatic disease, the data are less clear. The long-awaited results of the Southwest Oncology Group 9346 trial, comparing intermittent with continuous therapy in metastatic disease, showed no difference in overall survival. Post hoc stratification analysis showed a worse outcome in patients with "minimal" metastatic disease, and no difference in those with widespread bone metastases. The significance of that observation is in dispute. The present review also addresses practical issues in the use of intermittent therapy, including patient selection, follow-up, and therapy cycling. SUMMARY: The recent results of randomized clinical trials now establish that intermittent androgen deprivation therapy is an approach that should be considered the standard of care in most patients with nonmetastatic prostate cancer requiring hormonal therapy and in selected patients with metastatic disease. KEY POINTS: Level i evidence supports the oncologic equivalence of intermittent compared with continuous androgen blockade in men with biochemical failure.Compared with continuous androgen deprivation, intermittent therapy demonstrates improved quality of life and fewer side effects.Patient selection for intermittent therapy is important to maintain good oncologic results.Monitoring of prostate-specific androgen response and duration of off treatment intervals allow for stratification of patients by risk of progression. PMID- 23355790 TI - Targeting the androgen receptor in the management of castration-resistant prostate cancer: rationale, progress, and future directions. AB - Since the year 2000, tremendous progress has been made in the understanding of castration-resistant prostate cancer (crpc), a disease state now recognized to retain androgen receptor (ar)-dependency in most cases. That understanding led to the rational design of novel therapeutic agents targeting hormonal pathways in metastatic crpc. Two new drugs-the CYP17 inhibitor abiraterone acetate and the potent ar antagonist enzalutamide-were recently shown to prolong overall survival after chemotherapy treatment in patients with metastatic disease, with the former agent also demonstrating impressive activity in the pre-chemotherapy setting. Other new drugs targeting the ar-as well as drugs targeting heat shock proteins that protect cytoplasmic ar from degradation-are currently undergoing clinical development.This review briefly describes the molecular mechanisms underlying castration resistance and hormonal dependence in prostate tumours and summarizes the current ongoing and completed clinical trials that are targeting hormonal pathways in metastatic crpc. Potential mechanisms of resistance to these novel hormonal agents are reviewed. Finally, future research directions, including questions about drug sequencing and combination, are discussed. PMID- 23355791 TI - Management of castration-resistant prostate cancer: a global approach. AB - Treatment options for castration-resistant prostate cancer (crpc) have evolved since the start of the 2000s, with most of the new effective therapies appearing since 2010. In 2004, docetaxel was the first chemotherapeutic agent to improve survival in crpc, but little else was available once patients recurred. Since 2010, four new options have been shown to improve survival in patients with refractory or recurring disease after docetaxel. In the management of bone metastases, two bone-targeted therapies have been shown to reduce the risk of bone complications, and they are part of the overall management strategy in crpc patients. Therapeutic options before chemotherapy have shown promising results and may soon become available in Canada. The present article reviews the treatment options that have shown to be effective in crpc and also some of the ongoing work in the field. PMID- 23355793 TI - The changing landscape in prostate cancer. PMID- 23355792 TI - Patient preference and the impact of decision-making aids on prostate cancer treatment choices and post-intervention regret. AB - The number of prostate cancer survivors is rapidly growing in the Western world. As a result of better oncologic outcomes, more patients are living longer with the adverse effects of treatment, which can be both functional and psychological. Clinicians, in an era of shared decision-making, must not only cure the cancer, but also ensure that, after treatment, their patients experience the best quality of life and minimal post-treatment decisional regret. To participate in the decision-making process, men and their involved partners and family need to fully understand the relative benefits and harms of prostate cancer treatments.Patient preference studies indicate that men with prostate cancer are not well informed. Decision-making aids are a positive treatment adjunct both to convey information and to allow patients to explore their own beliefs and values during the decision making process. The evidence suggests that decision-making aids better prepare patients for involvement in treatment decisions, but further studies are required to investigate the relationship between the use of decision-making aids and post treatment decisional regret in prostate cancer. PMID- 23355794 TI - The importance of local control in high-risk locally advanced prostate cancer. AB - Prostate cancer is a common malignancy worldwide, and in Canada, it is the most frequently diagnosed cancer in men. The stratification of prostate cancer into risk categories has allowed for improved counselling of patients and provides guidance for treatment selection. However, the exact definition of high-risk prostate cancer remains controversial, and that lack of consensus remains a barrier to assessing available data from various institutions and from clinical trials. The proportion of patients with locally advanced high-risk disease has fallen in the last 20 years largely because of screening for prostate-specific antigen, but management in this population continues to be an important clinical problem. A factor that has emerged in recent years is the importance of local disease control, with data from multiple randomized trials suggesting that local therapy improves progression-free survival, disease-free survival, and overall survival. Further research in this population is necessary to improve outcomes. PMID- 23355795 TI - AGE-LDL activates Toll like receptor 4 pathway and promotes inflammatory cytokines production in renal tubular epithelial cells. AB - BACKGROUND/AIMS: Accumulation of advanced glycation end-products, the well recognized pro-inflammatory molecules, has been detected in renal tissues including tubules. The aim of the present study was to investigate the role of advanced glycation end-products modified low density lipoprotein (AGE-LDL) in inflammatory cytokines production in human proximal tubular epithelial cells and the underlying mechanism. METHODS: The Interleukin-6 (IL-6) and Interleukin-8 (IL 8) production was examined by real-time PCR and ELISA. The expression of Toll like receptor 2 and 4 (TLR2/4) was detected by flow cytometry and western blot. The interaction of TLR2/4 with AGE-LDL was examined by co-immunoprecipitation assay. The involvement of MyD88 and the downstream molecules in inflammatory cytokines production was examined by siRNA and pharmacologic inhibitors, respectively. RESULTS: AGE-LDL interacted with TLR2 and TLR4. TLR4 siRNA showed stronger inhibition on AGE-LDL-induced IL-6 and IL-8 production than that of TLR2 siRNA. Silencing MyD88, but not TRIF, inhibited AGE-LDL-induced IL-6 and IL-8 production. AGE-LDL stimulation led to phosphorylation of JNK, p38, Akt and the p65 subunit of nuclear factor-kappaB (NF-kappaB). Pharmacologic inhibitor of Akt suppressed AGE-LDL-induced activation of NF-kappaB, but the inhibitor of JNK, p38 or ERK1/2 had no effect. Blocking MyD88, p38, JNK, Akt or NF-kappaB attenuated AGE-LDL-triggered IL-6 production. CONCLUSION: AGE-LDL induced IL-6 and IL-8 production via TLR2/4-MyD88-dependent pathway in tubular epithelial cells. These data suggest that activation of TLRs signaling in tubular epithelial cells by AGE LDL might be a novel mechanism for the tubulointerstitial inflammation. PMID- 23355796 TI - Fatty acid and transcriptome profiling of longissimus dorsi muscles between pig breeds differing in meat quality. AB - Fat and lean pig breeds show obvious differences in meat quality characteristics including the fatty acid composition of muscle. However, the molecular mechanism underlying these phenotypes differences remains unknown. This study compared meat quality traits between Lantang (a Chinese indigenous breed) and Landrace (a typical lean breed). The Lantang pigs showed higher L* values and intramuscular fat content, lower pH(45min), pH(24h) and shear force in longissimus dorsi (LD) muscle than Landrace (P < 0.05). Fatty acid analysis demonstrated the lower monounsaturated fatty acids (MUFA) and higher polyunsaturated fatty acids (PUFA) percentage in Lantang LD than that in Landrace LD (P < 0.05). To further identify candidate genes for fatty acid composition, the transcriptome of LD muscle from the two breeds were measured by microarrays. There were 586 transcripts differentially expressed, of which 267 transcripts were highly expressed in Lantang pigs. After the validation by real-time quantitative PCR, 13 genes were determined as candidate genes for fatty acid composition of muscle, including Stearoyl-CoA desaturase (SCD). Then, a SCD over-expression plasmid was transfected into C2C12 cells to reveal the effect of SCD on the fatty acid composition in vitro. The results showed that SCD over-expression significantly increased PUFA proportion, while reduced that of saturated fatty acids (SFA) in C2C12 cells (P < 0.05). In summary, this study compared the differences of fatty acid composition and transcriptome in two breeds differing in meat quality, and further identified the novel role of SCD in the regulation of PUFA deposition. PMID- 23355798 TI - Maternal Caregiving Moderates the Relation Between Temperamental Fear and Social Behavior with Peers. AB - Temperament works in combination with a child's environment to influence early socioemotional development. We examined whether maternal caregiving behavior at infant age 9 months moderated the relation between infant temperamental fear (9 months) and observations of children's social behavior with an unfamiliar peer at age 2 in a typically-developing sample of 155 children. When infants received lower quality maternal caregiving, temperamental fear was inversely related to observed social engagement and aggression. These relations were nonsignificant when infants received higher quality maternal caregiving. Findings indicate that variations in temperamental fear may predict individual differences in future peer interactions, but sensitive, nonintrusive caregiving behaviors can attenuate these associations. PMID- 23355800 TI - Medulloblastoma or not? Crucial role in tumorigenesis of the timing of migration of cerebellar granule precursor cells, regulated by Nos2 and Tis21. PMID- 23355797 TI - Cell budding from normal appearing epithelia: a predictor of colorectal cancer metastasis? AB - BACKGROUND: Colorectal carcinogenesis is believed to be a multi-stage process that originates with a localized adenoma, which linearly progresses to an intra mucosal carcinoma, to an invasive lesion, and finally to metastatic cancer. This progression model is supported by tissue culture and animal model studies, but it is difficult to reconcile with several well-established observations, principally among these are that up to 25% of early stage (Stage I/II), node-negative colorectal cancer (CRC) develop distant metastasis, and that circulating CRC cells are undetectable in peripheral blood samples of up to 50% of patients with confirmed metastasis, but more than 30% of patients with no detectable metastasis exhibit such cells. The mechanism responsible for this diverse behavior is unknown, and there are no effective means to identify patients with pending, or who are at high risk for, developing metastatic CRC. NOVEL FINDINGS: Our previous studies of human breast and prostate cancer have shown that cancer invasion arises from the convergence of a tissue injury, the innate immune response to that injury, and the presence of tumor stem cells within tumor capsules at the site of the injury. Focal degeneration of a capsule due to age or disease attracts lymphocyte infiltration that degrades the degenerating capsules resulting in the formation of a focal disruption in the capsule, which selectively favors proliferating or "budding" of the underlying tumor stem cells. Our recent studies suggest that lymphocyte infiltration also triggers metastasis by disrupting the intercellular junctions and surface adhesion molecules within the proliferating cell buds causing their dissociation. Then, lymphocytes and tumor cells are conjoined through membrane fusion to form tumor-lymphocyte chimeras (TLCs) that allows the tumor stem cell to avail itself of the lymphocyte's natural ability to migrate and breach cell barriers in order to intravasate and to travel to distant organs. Our most recent studies of human CRC have detected nearly identical focal capsule disruptions, lymphocyte infiltration, budding cells, and the formation of TLCs. Our studies have further shown that age- and type-matched node-positive and -negative CRC have a significantly different morphological and immunohistochemical profile and that the majority of lymphatic ducts with disseminated cells are located within the mucosa adjacent to morphologically normal appearing epithelial structures that express a stem cell-related marker. NEW HYPOTHESIS: Based on these findings and the growth patterns of budding cells revealed by double immunohistochemistry, we further hypothesize that metastatic spread is an early event of carcinogenesis and that budding cells overlying focal capsule disruptions represent invasion- and metastasis-initiating cells that follow one of four pathways to progress: (1) to undergo extensive in situ proliferation leading to the formation of tumor nests that subsequently invade the submucosa, (2) to migrate with associated lymphocytes functioning as "seeds" to grow in new sites, (3) to migrate and intravasate into pre-existing vascular structures by forming TLCs, or (4) to intravasate into vascular structures that are generated by the budding cells themselves. We also propose that only node-positive cases harbor stem cells with the potential for multi-lineage differentiation and unique surface markers that permit intravasation. PMID- 23355801 TI - Incorrect ICBM-DTI-81 atlas orientation and white matter labels. PMID- 23355802 TI - Sensory receptors-design principles revisited. PMID- 23355803 TI - Sodium channel beta2 subunit promotes filopodia-like processes and expansion of the dendritic tree in developing rat hippocampal neurons. AB - The beta2 auxiliary subunit of voltage-gated sodium channels (VGSCs) appears at early stages of brain development. It is abundantly expressed in the mammalian central nervous system where it forms complexes with different channel isoforms, including Na(v)1.2. From the structural point of view, beta2 is a transmembrane protein: at its extracellular N-terminus an Ig-like type C2 domain mediates the binding to the pore-forming alpha subunit with disulfide bonds and the interactions with the extracellular matrix. Given this structural versatility, beta2 has been suggested to play multiple functions ranging from channel targeting to the plasma membrane and gating modulation to control of cell adhesion. We report that, when expressed in Chinese Hamster Ovary cells CHO-K1, the subunit accumulates at the perimetral region of adhesion and particularly in large lamellipodia-like membrane processes where it induces formation of filopodia-like structures. When overexpressed in developing embryonic rat hippocampal neurons in vitro, beta2 specifically promotes formation of filopodia like processes in dendrites leading to expansion of the arborization tree, while axonal branching remains unaltered. In contrast to this striking and highly specific effect on dendritic morphology, the targeting of functional sodium channels to the plasma membrane, including the preferential localization of Na(v)1.2 at the axon, and their gating properties are only minimally affected. From these and previously reported observations it is suggested that beta2, among its multiple functions, may contribute to promote dendritic outgrowth and to regulate neuronal wiring at specific stages of neuronal development. PMID- 23355804 TI - CT perfusion improves diagnostic accuracy and confidence in acute ischaemic stroke. AB - BACKGROUND AND OBJECTIVE: CT perfusion (CTP) is rapid and accessible for emergency ischaemic stroke diagnosis. The feasibility of introducing CTP and diagnostic accuracy versus non-contrast CT (NCCT) in a tertiary hospital were assessed. METHODS: All patients presenting <9 h from stroke onset or with wake-up stroke were eligible for CTP (Siemens 16-slice scanner, 2*24 mm slabs) unless they had estimated glomerular filtration rate (eGFR)<50 ml/min or diabetes with unknown eGFR. NCCT was assessed by a radiologist and stroke neurologist for early ischaemic change and hyperdense arteries. CTP was assessed for prolonged time to peak and reduced cerebral blood flow. Technical adequacy was defined as 2 CTP slabs of sufficient quality to diagnose stroke. RESULTS: Between January 2009 and September 2011, 1152 ischaemic stroke patients were admitted, 475 (41%) were <9 h/wake-up onset. Of these, 276 (58%) had CTP. Reasons for not performing CTP were diabetes with unknown eGFR (48 (10%)), known kidney disease (36 (8%)), established infarct on NCCT (27 (6%)), posterior circulation syndrome (25 (5%)) and patient motion/instability (16 (3%)). Clinician discretion excluded a further 47 (10%). CTP was more frequently diagnostic than NCCT (80% vs 50%, p<0.001). Non diagnostic CTP was due to lacunar infarction (28 (10%)), infarct outside slab coverage (21 (8%)), technical failure (4 (1%)) and reperfusion (2 (0.7%)). Normal CTP in 86/87 patients with stroke mimics supported withholding tissue plasminogen activator. CTP technical adequacy improved from 56% to 86% (p<0.001) after the first 6 months. Median time for NCCT/CTP/arch-vertex CT angiogram (including processing and interpretation) was 12 min. No clinically significant contrast nephropathy occurred. CONCLUSIONS: CTP in suspected stroke is widely applicable, rapid and increases diagnostic confidence. PMID- 23355805 TI - Daily or alternative, that is the question: steroid therapy for Duchenne muscular dystrophy patients. PMID- 23355806 TI - Lifetime risks for aneurysmal subarachnoid haemorrhage: multivariable risk stratification. AB - OBJECTIVE: The overall incidence of aneurysmal subarachnoid haemorrhage (aSAH) in western populations is around 9 per 100 000 person-years, which confers to a lifetime risk of around half per cent. Risk factors for aSAH are usually expressed as relative risks and suggest that absolute risks vary considerably according to risk factor profiles, but such estimates are lacking. We aimed to estimate incidence and lifetime risks of aSAH according to risk factor profiles. METHODS: We used data from 250 patients admitted with aSAH and 574 sex-matched and age-matched controls, who were randomly retrieved from general practitioners files. We determined independent prognostic factors with multivariable logistic regression analyses and assessed discriminatory performance using the area under the receiver operating characteristic curve. Based on the prognostic model we predicted incidences and lifetime risks of aSAH for different risk factor profiles. RESULTS: The four strongest independent predictors for aSAH, namely current smoking (OR 6.0; 95% CI 4.1 to 8.6), a positive family history for aSAH (4.0; 95% CI 2.3 to 7.0), hypertension (2.4; 95% CI 1.5 to 3.8) and hypercholesterolaemia (0.2; 95% CI 0.1 to 0.4), were used in the final prediction model. This model had an area under the receiver operating characteristic curve of 0.73 (95% CI 0.69 to 0.76). Depending on sex, age and the four predictors, the incidence of aSAH ranged from 0.4/100 000 to 298/100 000 person-years and lifetime risk between 0.02% and 7.2%. CONCLUSIONS: The incidence and lifetime risk of aSAH in the general population varies widely according to risk factor profiles. Whether persons with high risks benefit from screening should be assessed in cost-effectiveness studies. PMID- 23355807 TI - Improving delirium care through early intervention: from bench to bedside to boardroom. AB - Delirium is a complex neuropsychiatric syndrome that impacts adversely upon patient outcomes and healthcare outcomes. Delirium occurs in approximately one in five hospitalised patients and is especially common in the elderly and patients who are highly morbid and/or have pre-existing cognitive impairment. However, efforts to improve management of delirium are hindered by gaps in our knowledge and issues that reflect a disparity between existing knowledge and real-world practice. This review focuses on evidence that can assist in prevention, earlier detection and more timely and effective pharmacological and non-pharmacological management of emergent cases and their aftermath. It points towards a new approach to delirium care, encompassing laboratory and clinical aspects and health services realignment supported by health managers prioritising delirium on the healthcare change agenda. Key areas for future research and service organisation are outlined in a plan for improved delirium care across the range of healthcare settings and patient populations in which it occurs. PMID- 23355808 TI - High-sensitivity troponin assay improves prediction of cardiovascular risk in patients with cerebral ischaemia. AB - BACKGROUND AND PURPOSE: Clinical scores are recommended for predicting cardiovascular risk in patients with cerebral ischaemia to inform secondary prevention. Blood biomarkers may improve prediction beyond clinical scores. METHODS: Within the observational Find-AF trial (ISRCTN46104198), 197 patients >18 years of age with cerebral ischaemia and without atrial fibrillation had blood sampled at baseline. The predictive value of five biomarkers for a combined vascular endpoint (acute coronary syndrome, stroke, cardiovascular death) and all cause mortality was determined, alone and in addition to the Essen Stroke Risk Score (ESRS), Stroke Prognostic Instrument 2 (SPI-2) and National Institutes of Health Stroke Scale (NIH-SS). RESULTS: There were 23 vascular events (11.7%) and 13 deaths (6.6%) to 1 year follow-up. In multivariate analyses of all markers, only high-sensitivity troponin T (hsTropT) remained independently predictive for vascular events (p=0.045) and all-cause mortality (p=0.004). hsTropT was higher in patients with a vascular event (median 12.7 ng/ml vs 5.1 ng/ml), and patients with hsTropT above the median of 6.15 ng/ml had vascular events more frequently (HR 3.86, p=0.008). For prediction of vascular events as well as all-cause mortality, hsTropT significantly improved multivariate Cox regression models with ESRS, SPI-2 or NIH-SS. The c-statistic increased non-significantly from 0.695 (ESRS) or 0.710 (hsTropT) to 0.747 (ESRS+hsTropT) and from 0.699 (SPI-2) to 0.763 (SPI-2+hsTropT). No patient with a low-risk ESRS and an hsTropT below the median had a vascular event or died. CONCLUSIONS: hsTropT predicts vascular events and all-cause mortality in patients with acute cerebral ischaemia and improves prediction beyond established clinical scores. PMID- 23355809 TI - The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation--implications for diagnosis and management. AB - BACKGROUND: Population-based studies suggest the m.3243A>G mutation in MTTL1 is the most common disease-causing mtDNA mutation, with a carrier rate of 1 in 400 people. The m.3243A>G mutation is associated with several clinical syndromes including mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), maternally inherited deafness and diabetes (MIDD) and progressive external ophthalmoplegia (PEO). Many patients affected by this mutation exhibit a clinical phenotype that does not fall within accepted criteria for the currently recognised classical mitochondrial syndromes. METHODS: We have defined the phenotypic spectrum associated with the m.3243A>G mtDNA mutation in 129 patients, from 83 unrelated families, recruited to the Mitochondrial Disease Patient Cohort Study UK. RESULTS: 10% of patients exhibited a classical MELAS phenotype, 30% had MIDD, 6% MELAS/MIDD, 2% MELAS/chronic PEO (CPEO) and 5% MIDD/CPEO overlap syndromes. 6% had PEO and other features of mitochondrial disease not consistent with another recognised syndrome. Isolated sensorineural hearing loss occurred in 3%. 28% of patients demonstrated a panoply of clinical features, which were not consistent with any of the classical syndromes associated with the m.3243A>G mutation. 9% of individuals harbouring the mutation were clinically asymptomatic. CONCLUSION: Following this study we propose guidelines for screening and for the management of confirmed cases. PMID- 23355810 TI - Fish in the matrix: motor learning in a virtual world. AB - One of the large remaining challenges in the field of zebrafish neuroscience is the establishment of techniques and preparations that permit the recording and perturbation of neural activity in animals that can interact meaningfully with the environment. Since it is very difficult to do this in freely behaving zebrafish, I describe here two alternative approaches that meet this goal via tethered preparations. The first uses head-fixation in agarose in combination with online imaging and analysis of tail motion. In the second method, paralyzed fish are suspended with suction pipettes in mid-water and nerve root recordings serve as indicators for intended locomotion. In both cases, fish can be immersed into a virtual environment and allowed to interact with this virtual world via real or fictive tail motions. The specific examples given in this review focus primarily on the role of visual feedback~- but the general principles certainly extend to other modalities, including proprioception, hearing, balance, and somatosensation. PMID- 23355812 TI - The mouse olfactory peduncle. 2.The anterior limb of the anterior commissure. AB - The central core of the olfactory peduncle [the tissue connecting the olfactory bulb (OB) to the forebrain] includes a white matter tract that extends caudally to the anterior commissure (AC). The purpose of the present study was to examine this "anterior limb of the anterior commissure" (ALAC) to determine if the axons that progress through it segregate on the basis of their point of origin, neurotransmitter type, size, or shape. While local differences in axon density were observed in the ALAC, they were not consistent between samples of the anterior and posterior peduncle, and no other compartmentalization within the tract was observed. The innervation of the caudal olfactory peduncle by neuromodulatory fibers was examined to determine if they enter the region via the ALAC. Cholinergic fibers (CHAT) densely filled the peduncle, followed in order by serotonergic, noradrenergic, histaminergic, and orexinergic processes. Differences in the distribution of the fibers were noted for each system. While each axon type could be observed in the ALAC, it is probable that they enter the peduncle though several routes. Data for axon caliber in the ALAC was compared to information previously collected on the peduncle's other white matter region, the lateral olfactory tract (LOT). Axons in the ALAC were smaller, suggesting that the olfactory system is organized with a fast system for distributing incoming sensory information and a more economical, distributed system for subsequent processing. PMID- 23355811 TI - Revealing the secrets of neuronal circuits with recombinant rabies virus technology. AB - An understanding of how the brain processes information requires knowledge of the architecture of its underlying neuronal circuits, as well as insights into the relationship between architecture and physiological function. A range of sophisticated tools is needed to acquire this knowledge, and recombinant rabies virus (RABV) is becoming an increasingly important part of this essential toolbox. RABV has been recognized for years for its properties as a synapse specific trans-neuronal tracer. A novel genetically modified variant now enables the investigation of specific monosynaptic connections. This technology, in combination with other genetic, physiological, optical, and computational tools, has enormous potential for the visualization of neuronal circuits, and for monitoring and manipulating their activity. Here we will summarize the latest developments in this fast moving field and provide a perspective for the use of this technology for the dissection of neuronal circuit structure and function in the normal and diseased brain. PMID- 23355814 TI - What is social about social perception research? AB - A growing consensus in social cognitive neuroscience holds that large portions of the primate visual brain are dedicated to the processing of social information, i.e., to those aspects of stimuli that are usually encountered in social interactions such as others' facial expressions, actions, and symbols. Yet, studies of social perception have mostly employed simple pictorial representations of conspecifics. These stimuli are social only in the restricted sense that they physically resemble objects with which the observer would typically interact. In an equally important sense, however, these stimuli might be regarded as "non-social": the observer knows that they are viewing pictures and might therefore not attribute current mental states to the stimuli or might do so in a qualitatively different way than in a real social interaction. Recent studies have demonstrated the importance of such higher-order conceptualization of the stimulus for social perceptual processing. Here, we assess the similarity between the various types of stimuli used in the laboratory and object classes encountered in real social interactions. We distinguish two different levels at which experimental stimuli can match social stimuli as encountered in everyday social settings: (1) the extent to which a stimulus' physical properties resemble those typically encountered in social interactions and (2) the higher-level conceptualization of the stimulus as indicating another person's mental states. We illustrate the significance of this distinction for social perception research and report new empirical evidence further highlighting the importance of mental state attribution for perceptual processing. Finally, we discuss the potential of this approach to inform studies of clinical conditions such as autism. PMID- 23355813 TI - Thinking in spatial terms: decoupling spatial representation from sensorimotor control in monkey posterior parietal areas 7a and LIP. AB - Perhaps the simplest and most complete description of the cerebral cortex is that it is a sensorimotor controller whose primary purpose is to represent stimuli and movements, and adaptively control the mapping between them. However, in order to think, the cerebral cortex has to generate patterns of neuronal activity that encode abstract, generalized information independently of ongoing sensorimotor events. A critical question confronting cognitive systems neuroscience at present therefore is how neural signals encoding abstract information emerge within the sensorimotor control networks of the brain. In this review, we approach that question in the context of the neural representation of space in posterior parietal cortex of non-human primates. We describe evidence indicating that parietal cortex generates a hierarchy of spatial representations with three basic levels: including (1) sensorimotor signals that are tightly coupled to stimuli or movements, (2) sensorimotor signals modified in strength or timing to mediate cognition (examples include attention, working memory, and decision-processing), as well as (3) signals that encode frankly abstract spatial information (such as spatial relationships or categories) generalizing across a wide diversity of specific stimulus conditions. Here we summarize the evidence for this hierarchy, and consider data showing that signals at higher levels derive from signals at lower levels. That in turn could help characterize neural mechanisms that derive a capacity for abstraction from sensorimotor experience. PMID- 23355816 TI - Concealed semantic and episodic autobiographical memory electrified. AB - Electrophysiology-based concealed information tests (CIT) try to determine whether somebody possesses concealed information about a crime-related item (probe) by comparing event-related potentials (ERPs) between this item and comparison items (irrelevants). Although the broader field is sometimes referred to as "memory detection," little attention has been paid to the precise type of underlying memory involved. This study begins addressing this issue by examining the key distinction between semantic and episodic memory in the autobiographical domain within a CIT paradigm. This study also addresses the issue of whether multiple repetitions of the items over the course of the session habituate the brain responses. Participants were tested in a 3-stimulus CIT with semantic autobiographical probes (their own date of birth) and episodic autobiographical probes (a secret date learned just before the study). Results dissociated these two memory conditions on several ERP components. Semantic probes elicited a smaller frontal N2 than episodic probes, consistent with the idea that the frontal N2 decreases with greater pre-existing knowledge about the item. Likewise, semantic probes elicited a smaller central N400 than episodic probes. Semantic probes also elicited a larger P3b than episodic probes because of their richer meaning. In contrast, episodic probes elicited a larger late positive complex (LPC) than semantic probes, because of the recent episodic memory associated with them. All these ERPs showed a difference between probes and irrelevants in both memory conditions, except for the N400, which showed a difference only in the semantic condition. Finally, although repetition affected the ERPs, it did not reduce the difference between probes and irrelevants. These findings show that the type of memory associated with a probe has both theoretical and practical importance for CIT research. PMID- 23355815 TI - Synaptic depression in the CA1 region of freely behaving mice is highly dependent on afferent stimulation parameters. AB - Persistent synaptic plasticity has been subjected to intense study in the decades since it was first described. Occurring in the form of long-term potentiation (LTP) and long-term depression (LTD), it shares many cellular and molecular properties with hippocampus-dependent forms of persistent memory. Recent reports of both LTP and LTD occurring endogenously under specific learning conditions provide further support that these forms of synaptic plasticity may comprise the cellular correlates of memory. Most studies of synaptic plasticity are performed using in vitro or in vivo preparations where patterned electrical stimulation of afferent fibers is implemented to induce changes in synaptic strength. This strategy has proven very effective in inducing LTP, even under in vivo conditions. LTD in vivo has proven more elusive: although LTD occurs endogenously under specific learning conditions in both rats and mice, its induction has not been successfully demonstrated with afferent electrical stimulation alone. In this study we screened a large spectrum of protocols that are known to induce LTD either in hippocampal slices or in the intact rat hippocampus, to clarify if LTD can be induced by sole afferent stimulation in the mouse CA1 region in vivo. Low frequency stimulation at 1, 2, 3, 5, 7, or 10 Hz given in the range of 100 through 1800 pulses produced, at best, short-term depression (STD) that lasted for up to 60 min. Varying the administration pattern of the stimuli (e.g., 900 pulses given twice at 5 min intervals), or changing the stimulation intensity did not improve the persistency of synaptic depression. LTD that lasts for at least 24 h occurs under learning conditions in mice. We conclude that a coincidence of factors, such as afferent activity together with neuromodulatory inputs, play a decisive role in the enablement of LTD under more naturalistic (e.g., learning) conditions. PMID- 23355817 TI - Dopaminergic foundations of schizotypy as measured by the German version of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE)-a suitable endophenotype of schizophrenia. AB - The concept of schizotypy or "psychosis proneness" captures individual differences in perceptual, cognitive, and affective experiences that may relate to a range of psychotic disorders. The concept is an important way to assess the contribution of pre-existing psychological and genetically based biological features to the development of illnesses such as schizophrenia (so called endophenotypes). The Oxford-Liverpool Inventory of Feelings and Experiences (O LIFE) is a widely used multi-dimensional measure of the construct and consists of four scales which mirror several groups of psychotic symptoms: Unusual Experiences (UnEx; positive symptoms), Cognitive Disorganization (CogDis; cognitive symptoms), Introvertive Anhedonia (IntAn; negative symptoms), and Impulsive Nonconformity (ImpNon; impulsive and antisocial symptoms). For the purpose of evaluating the suitability of schizotypy as an endophenotype of schizophrenia the current version of the O-LIFE was translated into German: its psychometric properties (including re-test reliability and construct validity) were examined in a large sample (n > 1200) and compared to those of the English original. The German version was both highly reliable and consistent with the original. The study aimed to show that schizotypy as measured by the O-LIFE can indeed be regarded as an endophenotype of schizophrenia in terms of genetic associations regarding relevant dopamine-related candidate polymorphisms of schizotypy [i.e., Val(158)Met-polymorphism of the COMT gene, uVNTR of the MAOA gene, Taq1A-polymorphism of the DRD2 gene, VNTR of the SLC6A3 (DAT) gene]. We also wanted to compare the genetic associations of the O-LIFE to those published using other operationalizations of schizotypy. Our results show a large number of significant associations and borderline-significant trends between the O-LIFE sub scales and a range of genes, thereby supporting using the O-LIFE in the search for endophenotypic markers. PMID- 23355818 TI - Erratum: search-related suppression of hippocampus and default network activity during associative memory retrieval. PMID- 23355819 TI - The effect of alcohol and placebo on post-error adjustments. AB - Several studies have shown detrimental effects of alcohol on post-error adjustments. In contrast to previous studies, which focused on only one aspect of post-error adaptive behavior, we compared the effect of alcohol and placebo on post-error slowing (PES), post-error reduction of interference (PERI) and post error improvement of accuracy (PIA). Moreover, we used a between-subjects design (N = 45) comparing a control condition to both an alcohol and an alcohol-placebo condition as to disentangle physiological and expectancy effects of alcohol. In a standard Stroop congruency task, we found that intoxicated participants as well as participants with the incorrect belief of being intoxicated showed significant decreased PES compared to a control group. Furthermore, we found evidence for a condition-independent post-error increase of interference and post-error decrease of accuracy. The underlying mechanisms of the post-error adaptation effects are discussed in terms of the orienting account (Notebaert et al., 2009). PMID- 23355820 TI - Spatiotemporal imaging of complexity. AB - What are the functional neuroimaging measurements required for more fully characterizing the events and locations of neocortical activity? A prime assumption has been that modulation of cortical activity will inevitably be reflected in changes in energy utilization (for the most part) changes of glucose and oxygen consumption. Are such a measures complete and sufficient? More direct measures of cortical electrophysiological activity show event or task-related modulation of amplitude or band-limited oscillatory power. Using magnetoencephalography (MEG), these measures have been shown to correlate well with energy utilization sensitive BOLD fMRI. In this paper, we explore the existence of state changes in electrophysiological cortical activity that can occur independently of changes in averaged amplitude, source power or indices of metabolic rates. In addition, we demonstrate that such state changes can be described by applying a new measure of complexity, rank vector entropy (RVE), to source waveform estimates from beamformer-processed MEG. RVE is a non-parametric symbolic dynamic informational entropy measure that accommodates the wide dynamic range of measured brain signals while resolving its temporal variations. By representing the measurements by their rank values, RVE overcomes the problem of defining embedding space partitions without resorting to signal compression. This renders RVE-independent of absolute signal amplitude. In addition, this approach is robust, being relatively free of tunable parameters. We present examples of task-free and task-dependent MEG demonstrating that RVE provides new information by uncovering hidden dynamical structure in the apparent turbulent (or chaotic) dynamics of spontaneous cortical activity. PMID- 23355821 TI - Computational modeling of the effects of amyloid-beta on release probability at hippocampal synapses. AB - The role of amyloid beta (Abeta) in brain function and in the pathogenesis of Alzheimer's disease (AD) remains elusive. Recent publications reported that an increase in Abeta concentration perturbs pre-synaptic release in hippocampal neurons. In particular, it was shown in vitro that Abeta is an endogenous regulator of synaptic transmission at the CA3-CA1 synapse, enhancing its release probability. How this synaptic modulator influences neuronal output during physiological stimulation patterns, such as those elicited in vivo, is still unknown. Using a realistic model of hippocampal CA1 pyramidal neurons, we first implemented this Abeta-induced enhancement of release probability and validated the model by reproducing the experimental findings. We then demonstrated that this synaptic modification can significantly alter synaptic integration properties in a wide range of physiologically relevant input frequencies (from 5 to 200 Hz). Finally, we used natural input patterns, obtained from CA3 pyramidal neurons in vivo during free exploration of rats in an open field, to investigate the effects of enhanced Abeta on synaptic release under physiological conditions. The model shows that the CA1 neuronal response to these natural patterns is altered in the increased-Abeta condition, especially for frequencies in the theta and gamma ranges. These results suggest that the perturbation of release probability induced by increased Abeta can significantly alter the spike probability of CA1 pyramidal neurons and thus contribute to abnormal hippocampal function during AD. PMID- 23355822 TI - Development of a physiologically based computational kidney model to describe the renal excretion of hydrophilic agents in rats. AB - A physiologically based kidney model was developed to analyze the renal excretion and kidney exposure of hydrophilic agents, in particular contrast media, in rats. In order to study the influence of osmolality and viscosity changes, the model mechanistically represents urine concentration by water reabsorption in different segments of kidney tubules and viscosity dependent tubular fluid flow. The model was established using experimental data on the physiological steady state without administration of any contrast media or drugs. These data included the sodium and urea concentration gradient along the cortico-medullary axis, water reabsorption, urine flow, and sodium as well as urea urine concentrations for a normal hydration state. The model was evaluated by predicting the effects of mannitol and contrast media administration and comparing to experimental data on cortico medullary concentration gradients, urine flow, urine viscosity, hydrostatic tubular pressures and single nephron glomerular filtration rate. Finally the model was used to analyze and compare typical examples of ionic and non-ionic monomeric as well as non-ionic dimeric contrast media with respect to their osmolality and viscosity. With the computational kidney model, urine flow depended mainly on osmolality, while osmolality and viscosity were important determinants for tubular hydrostatic pressure and kidney exposure. The low diuretic effect of dimeric contrast media in combination with their high intrinsic viscosity resulted in a high viscosity within the tubular fluid. In comparison to monomeric contrast media, this led to a higher increase in tubular pressure, to a reduction in glomerular filtration rate and tubular flow and to an increase in kidney exposure. The presented kidney model can be implemented into whole body physiologically based pharmacokinetic models and extended in order to simulate the renal excretion of lipophilic drugs which may also undergo active secretion and reabsorption. PMID- 23355823 TI - Hydrogen sulfide: both feet on the gas and none on the brake? PMID- 23355824 TI - Alexander Leaf, MD (1920-2012)-A tribute to a life in physiology and medicine. PMID- 23355825 TI - Yoga on our minds: a systematic review of yoga for neuropsychiatric disorders. AB - BACKGROUND: The demand for clinically efficacious, safe, patient acceptable, and cost-effective forms of treatment for mental illness is growing. Several studies have demonstrated benefit from yoga in specific psychiatric symptoms and a general sense of well-being. OBJECTIVE: To systematically examine the evidence for efficacy of yoga in the treatment of selected major psychiatric disorders. METHODS: Electronic searches of The Cochrane Central Register of Controlled Trials and the standard bibliographic databases, MEDLINE, EMBASE, and PsycINFO, were performed through April 2011 and an updated in June 2011 using the keywords yoga AND psychiatry OR depression OR anxiety OR schizophrenia OR cognition OR memory OR attention AND randomized controlled trial (RCT). Studies with yoga as the independent variable and one of the above mentioned terms as the dependent variable were included and exclusion criteria were applied. RESULTS: The search yielded a total of 124 trials, of which 16 met rigorous criteria for the final review. Grade B evidence supporting a potential acute benefit for yoga exists in depression (four RCTs), as an adjunct to pharmacotherapy in schizophrenia (three RCTs), in children with ADHD (two RCTs), and Grade C evidence in sleep complaints (three RCTs). RCTs in cognitive disorders and eating disorders yielded conflicting results. No studies looked at primary prevention, relapse prevention, or comparative effectiveness versus pharmacotherapy. CONCLUSION: There is emerging evidence from randomized trials to support popular beliefs about yoga for depression, sleep disorders, and as an augmentation therapy. Limitations of literature include inability to do double-blind studies, multiplicity of comparisons within small studies, and lack of replication. Biomarker and neuroimaging studies, those comparing yoga with standard pharmaco- and psychotherapies, and studies of long-term efficacy are needed to fully translate the promise of yoga for enhancing mental health. PMID- 23355826 TI - Learner-Controlled Self-Observation is Advantageous for Motor Skill Acquisition. AB - There were two main objectives of this research. First, we wanted to examine whether video feedback of the self (self-observation) was more effective for motor skill learning when the choice to view the video was provided to the learner (learner-controlled, LC) as opposed to an experimenter-controlled (EC) delivery. Secondly, we explored whether there were differences in the self regulatory processes of self-efficacy and intrinsic motivation, as well as perceived choice between the LC and EC conditions. Two groups (LC and EC) of children (M age of 11.2 years; SD = 1.89) attempted to learn a progression of trampoline skills during a 2-day acquisition phase in which video self observation was available. The second acquisition day was followed by a no self observation retention test 1 day later. It was hypothesized that, during retention, the LC group would be more self-efficacious about their ability to progress through the trampoline skills, show greater intrinsic motivation and perceived choice, and go further in skill progression than the EC group. Analysis of the acquisition data showed the LC group had greater increases in self efficacy as compared to the EC group. Results of the retention test showed that the participants in the LC group obtained higher scores on the intrinsic motivation and perceived choice measures and had higher skill progression scores as compared to the EC group. Regression analysis showed that group assignment and self-efficacy were significant predictors of the physical performance benefits noted in retention. These findings are discussed within Zimmerman's (2004) self regulation of learning model. PMID- 23355827 TI - Imagining Other People's Experiences in a Person with Impaired Episodic Memory: The Role of Personal Familiarity. AB - Difficulties remembering one's own experiences via episodic memory may affect the ability to imagine other people's experiences during theory of mind (ToM). Previous work shows that the same set of brain regions recruited during tests of episodic memory and future imagining are also engaged during standard laboratory tests of ToM. However, hippocampal amnesic patients who show deficits in past and future thinking, show intact performance on ToM tests, which involve unknown people or fictional characters. Here we present data from a developmental amnesic person (H.C.) and a group of demographically matched controls, who were tested on a naturalistic test of ToM that involved describing other people's experiences in response to photos of personally familiar others ("pToM" condition) and unfamiliar others ("ToM" condition). We also included a condition that involved recollecting past experiences in response to personal photos ("EM" condition). Narratives were scored using an adapted Autobiographical Interview scoring procedure. Due to the visually rich stimuli, internal details were further classified as either descriptive (i.e., details that describe the visual content of the photo) or elaborative (i.e., details that go beyond what is visually depicted in the photo). Relative to controls, H.C. generated significantly fewer elaborative details in response to the pToM and EM photos and an equivalent number of elaborative details in response to the ToM photos. These data converge with previous neuroimaging results showing that the brain regions underlying pToM and episodic memory overlap to a greater extent than those supporting ToM. Taken together, these results suggest that detailed episodic representations supported by the hippocampus may be pivotal for imagining the experiences of personally familiar, but not unfamiliar, others. PMID- 23355828 TI - Interactive Multimodal Ambulatory Monitoring to Investigate the Association between Physical Activity and Affect. AB - Although there is a wealth of evidence that physical activity has positive effects on psychological health, a large proportion of people are inactive. Data regarding counts, steps, and movement patterns are limited in their ability to explain why people remain inactive. We propose that multimodal ambulatory monitoring, which combines the assessment of physical activity with the assessment of psychological variables, helps to elucidate real world physical activity. Whereas physical activity can be monitored continuously, psychological variables can only be assessed at discrete intervals, such as every hour. Moreover, the assessment of psychological variables must be linked to the activity of interest. For example, if an inactive and overweight person is physically active once a week, psychological variables should be assessed during this episode. Linking the assessment of psychological variables to episodes of an activity of interest can be achieved with interactive monitoring. The primary aim of our interactive multimodal ambulatory monitoring approach was to intentionally increase the number of e-diary assessments during "active" episodes. We developed and tested an interactive monitoring algorithm that continuously monitors physical activity in everyday life. When predefined thresholds are surpassed, the algorithm triggers a signal for participants to answer questions in their electronic diary. Using data from 70 participants wearing an accelerative device for 24 h each, we found that our algorithm quadrupled the frequency of e-diary assessments during the activity episodes of interest compared to random sampling. Multimodal interactive ambulatory monitoring appears to be a promising approach to enhancing our understanding of real world physical activity and movement. PMID- 23355829 TI - The role of the environment in eliciting phantom-like sensations in non-amputees. AB - Following the amputation of a limb, many amputees report that they can still vividly perceive its presence despite conscious knowledge that it is not physically there. However, our ability to probe the mental representation of this experience is limited by the intractable and often distressing pain associated with amputation. Here, we present a method for eliciting phantom-like experiences in non-amputees using a variation of the rubber hand illusion in which a finger has been removed from the rubber hand. An interpretative phenomenological analysis revealed that the structure of this experience shares a wide range of sensory attributes with subjective reports of phantom limb experience. For example, when the space where the ring finger should have been on the rubber hand was stroked, 93% of participants (i.e., 28/30) reported the vivid presence of a finger that they could not see and a total of 57% (16/28) of participants who felt that the finger was present reported one or more additional sensory qualities such as tingling or numbness (25%; 7/28) and alteration in the perceived size of the finger (50%; 14/28). These experiences indicate the adaptability of body experience and share some characteristics of the way that phantom limbs are described. Participants attributed changes to the shape and size of their "missing" finger to the way in which the experimenter mimed stroking in the area occupied by the missing finger. This alteration of body perception is similar to the phenomenon of telescoping experienced by people with phantom limbs and suggests that our sense of embodiment not only depends on internal body representations but on perceptual information coming from peripersonal space. PMID- 23355831 TI - A feeling for numbers: shared metric for symbolic and tactile numerosities. AB - Evidence for an approximate analog system of numbers has been provided by the finding that the comparison of two numerals takes longer and is more error-prone if the semantic distance between the numbers becomes smaller (so-called numerical distance effect). Recent embodied theories suggest that analog number representations are based on previous sensory experiences and constitute therefore a common magnitude metric shared by multiple domains. Here we demonstrate the existence of a cross-modal semantic distance effect between symbolic and tactile numerosities. Participants received tactile stimulations of different amounts of fingers while reading Arabic digits and indicated verbally whether the amount of stimulated fingers was different from the simultaneously presented digit or not. The larger the semantic distance was between the two numerosities, the faster and more accurate participants made their judgments. This cross-modal numerosity distance effect suggests a direct connection between tactile sensations and the concept of numerical magnitude. A second experiment replicated the interaction between symbolic and tactile numerosities and showed that this effect is not modulated by the participants' finger counting habits. Taken together, our data provide novel evidence for a shared metric for symbolic and tactile numerosities as an instance of an embodied representation of numbers. PMID- 23355830 TI - 1 < 2 and 2 < 3: non-linguistic appreciations of numerical order. AB - Ordinal understanding is involved in understanding social hierarchies, series of actions, and everyday events. Moreover, an appreciation of numerical order is critical to understanding number at a highly abstract, conceptual level. In this paper, we review findings concerning the development and expression of ordinal numerical knowledge in preverbal human infants in light of literature about the same cognitive abilities in non-human animals. We attempt to reconcile seemingly contradictory evidence, provide new directions for prospective research, and evaluate the shared basis of ordinal knowledge among non-verbal organisms. Our review of the research leads us to conclude that both infants and non-human animals are adapted to respond to monotonic progressions in numerical order, consonant with mathematical definitions of numerical order. Further, we suggest that patterns in the way that infants and non-human animals process numerical order can be accounted for by changes across development, the conditions under which representations are generated, or both. PMID- 23355832 TI - Transfer Function between EEG and BOLD Signals of Epileptic Activity. AB - Simultaneous electroencephalogram (EEG)-functional Magnetic Resonance Imaging (fMRI) recordings have seen growing application in the evaluation of epilepsy, namely in the characterization of brain networks related to epileptic activity. In EEG-correlated fMRI studies, epileptic events are usually described as boxcar signals based on the timing information retrieved from the EEG, and subsequently convolved with a hemodynamic response function to model the associated Blood Oxygen Level Dependent (BOLD) changes. Although more flexible approaches may allow a higher degree of complexity for the hemodynamics, the issue of how to model these dynamics based on the EEG remains an open question. In this work, a new methodology for the integration of simultaneous EEG-fMRI data in epilepsy is proposed, which incorporates a transfer function from the EEG to the BOLD signal. Independent component analysis of the EEG is performed, and a number of metrics expressing different models of the EEG-BOLD transfer function are extracted from the resulting time courses. These metrics are then used to predict the fMRI data and to identify brain areas associated with the EEG epileptic activity. The methodology was tested on both ictal and interictal EEG-fMRI recordings from one patient with a hypothalamic hamartoma. When compared to the conventional analysis approach, plausible, consistent, and more significant activations were obtained. Importantly, frequency-weighted EEG metrics yielded superior results than those weighted solely on the EEG power, which comes in agreement with previous literature. Reproducibility, specificity, and sensitivity should be addressed in an extended group of patients in order to further validate the proposed methodology and generalize the presented proof of concept. PMID- 23355833 TI - Retinoic acid-related orphan receptors alpha and gamma: key regulators of lipid/glucose metabolism, inflammation, and insulin sensitivity. AB - Retinoic acid-related orphan receptors RORalpha and RORgamma play a regulatory role in lipid/glucose homeostasis and various immune functions, and have been implicated in metabolic syndrome and several inflammatory diseases. RORalpha deficient mice are protected against age- and diet-induced obesity, hepatosteatosis, and insulin resistance. The resistance to hepatosteatosis in RORalpha-deficient mice is related to the reduced expression of several genes regulating lipid synthesis, transport, and storage. Adipose tissue-associated inflammation, which plays a critical role in the development of insulin resistance, is considerably diminished in RORalpha-deficient mice as indicated by the reduced infiltration of M1 macrophages and decreased expression of many proinflammatory genes. Deficiency in RORgamma also protects against diet-induced insulin resistance by a mechanism that appears different from that in RORalpha deficiency. Recent studies indicated that RORs provide an important link between the circadian clock machinery and its regulation of metabolic genes and metabolic syndrome. As ligand-dependent transcription factors, RORs may provide novel therapeutic targets in the management of obesity and associated metabolic diseases, including hepatosteatosis, adipose tissue-associated inflammation, and insulin resistance. PMID- 23355834 TI - Preparing synthetic biology for the world. AB - Synthetic Biology promises low-cost, exponentially scalable products and global health solutions in the form of self-replicating organisms, or "living devices." As these promises are realized, proof-of-concept systems will gradually migrate from tightly regulated laboratory or industrial environments into private spaces as, for instance, probiotic health products, food, and even do-it-yourself bioengineered systems. What additional steps, if any, should be taken before releasing engineered self-replicating organisms into a broader user space? In this review, we explain how studies of genetically modified organisms lay groundwork for the future landscape of biosafety. Early in the design process, biological engineers are anticipating potential hazards and developing innovative tools to mitigate risk. Here, we survey lessons learned, ongoing efforts to engineer intrinsic biocontainment, and how different stakeholders in synthetic biology can act to accomplish best practices for biosafety. PMID- 23355835 TI - Vaccines and immunotherapy against fungi: the new frontier. PMID- 23355836 TI - The kallikrein-kinin system in experimental Chagas disease: a paradigm to investigate the impact of inflammatory edema on GPCR-mediated pathways of host cell invasion by Trypanosoma cruzi. AB - Chronic chagasic myocarditis (CCM) depends on Trypanosoma cruzi persistence in the myocardium. Studies of the proteolytic mechanisms governing host/parasite balance in peripheral sites of T. cruzi infection revealed that tissue culture trypomastigotes (TCTs) elicit inflammatory edema and stimulate protective type-1 effector T cells through the activation of the kallikrein-kinin system. Molecular studies linked the proinflammatory phenotype of Dm28c TCTs to the synergistic activities of tGPI, a lipid anchor that functions as a Toll-like receptor 2 (TLR2) ligand, and cruzipain, a kinin-releasing cysteine protease. Analysis of the dynamics of inflammation revealed that TCTs activate innate sentinel cells via TLR2, releasing CXC chemokines, which in turn evoke neutrophil/CXCR2 dependent extravasation of plasma proteins, including high molecular weight kininogen (HK), in parasite-laden tissues. Further downstream, TCTs process surface bound HK, liberating lysyl-BK (LBK), which then propagates inflammatory edema via signaling of endothelial G-protein-coupled bradykinin B(2) receptors (BK(2)R). Dm28 TCTs take advantage of the transient availability of infection promoting peptides (e.g., bradykinin and endothelins) in inflamed tissues to invade cardiovascular cells via interdependent signaling of BKRs and endothelin receptors (ETRs). Herein we present a space-filling model whereby ceramide enriched endocytic vesicles generated by the sphingomyelinase pathway might incorporate BK(2)R and ETRs, which then trigger Ca(2+)-driven responses that optimize the housekeeping mechanism of plasma membrane repair from cell wounding. The hypothesis predicts that the NF-kappaB-inducible BKR (BK(1)R) may integrate the multimolecular signaling platforms forged by ceramide rafts, as the chronic myocarditis progresses. Exploited as gateways for parasite invasion, BK(2)R, BK(1)R, ET(A)R, ET(B)R, and other G protein-coupled receptor partners may enable persistent myocardial parasitism in the edematous tissues at expense of adverse cardiac remodeling. PMID- 23355838 TI - Active penetration of Trypanosoma cruzi into host cells: historical considerations and current concepts. AB - In the present short review, we analyze past experiments that addressed the interactions of intracellular pathogenic protozoa (Trypanosoma cruzi, Toxoplasma gondii, and Plasmodium) with host cells and the initial use of the term active penetration to indicate that a protozoan "crossed the host cell membrane, penetrating into the cytoplasm." However, the subsequent use of transmission electron microscopy showed that, for all of the protozoans and cell types examined, endocytosis, classically defined as involving the formation of a membrane-bound vacuole, took place during the interaction process. As a consequence, the recently penetrated parasites are always within a vacuole, designated the parasitophorous vacuole (PV). PMID- 23355839 TI - Recognition of the mycobacterial cord factor by Mincle: relevance for granuloma formation and resistance to tuberculosis. AB - The world's most successful intracellular bacterial pathogen, Mycobacterium tuberculosis (MTB), survives inside macrophages by blocking phagosome maturation and establishes chronic infection characterized by the formation of granulomas. Trehalose-6,6-dimycolate (TDM), the mycobacterial cord factor, is the most abundant cell wall lipid of virulent mycobacteria, is sufficient to cause granuloma formation, and has long been known to be a major virulence factor of MTB. Recently, TDM has been shown to activate the Syk-Card9 signaling pathway in macrophages through binding to the C-type lectin receptor Mincle. The Mincle Card9 pathway is required for activation of macrophages by TDM in vitro and for granuloma formation in vivo following injection of TDM. Whether this pathway is also exploited by MTB to reprogram the macrophage into a comfortable niche has not been explored yet. Several recent studies have investigated the phenotype of Mincle-deficient mice in mycobacterial infection, yielding divergent results in terms of a role for Mincle in host resistance. Here, we review these studies, discuss possible reasons for discrepant results and highlight open questions in the role of Mincle and other C-type lectin receptors in the infection biology of MTB. PMID- 23355837 TI - NET balancing: a problem in inflammatory lung diseases. AB - Neutrophil extracellular traps (NETs) are beneficial antimicrobial defense structures that can help fight against invading pathogens in the host. However, recent studies reveal that NETs exert adverse effects in a number of diseases including those of the lung. Many inflammatory lung diseases are characterized with a massive influx of neutrophils into the airways. Neutrophils contribute to the pathology of these diseases. To date, NETs have been identified in the lungs of cystic fibrosis (CF), acute lung injury (ALI), allergic asthma, and lungs infected with bacteria, virus, or fungi. These microbes and several host factors can stimulate NET formation, or NETosis. Different forms of NETosis have been identified and are dependent on varying types of stimuli. All of these pathways however appear to result in the formation of NETs that contain DNA, modified extracellular histones, proteases, and cytotoxic enzymes. Some of the NET components are immunogenic and damaging to host tissue. Innate immune collectins, such as pulmonary surfactant protein D (SP-D), bind NETs, and enhance the clearance of dying cells and DNA by alveolar macrophages. In many inflammatory lung diseases, bronchoalveolar SP-D levels are altered and its deficiency results in the accumulation of DNA in the lungs. Some of the other therapeutic molecules under consideration for treating NET-related diseases include DNases, antiproteases, myeloperoxidase (MPO) inhibitors, peptidylarginine deiminase-4 inhibitors, and anti-histone antibodies. NETs could provide important biological advantage for the host to fight against certain microbial infections. However, too much of a good thing can be a bad thing. Maintaining the right balance of NET formation and reducing the amount of NETs that accumulate in tissues are essential for harnessing the power of NETs with minimal damage to the hosts. PMID- 23355840 TI - Immunoregulatory CD4(-)CD8(-) T cells as a potential therapeutic tool for transplantation, autoimmunity, and cancer. AB - A central objective in organ transplantation and the treatment or prevention of autoimmune disease is the achievement of antigen-specific immune tolerance. An additional challenge in bone marrow transplantation for the treatment of hematological malignancies is the prevention of graft-vs-host disease (GVHD) while maintaining graft-vs-tumor activity. Interestingly, CD4(-)CD8(-) (double negative, DN) T cells, which exhibit a unique antigen-specific immunoregulatory potential, appear to exhibit all of the properties to respond to these challenges. Herein, we review the therapeutic potential of immunoregulatory DN T cells in various immunopathological settings, including graft tolerance, GVHD, cancer, and autoimmunity. PMID- 23355841 TI - Contribution of proteomic studies towards understanding plant heavy metal stress response. AB - Modulation of plant proteome composition is an inevitable process to cope with the environmental challenges including heavy metal (HM) stress. Soil and water contaminated with hazardous metals not only cause permanent and irreversible health problems, but also result substantial reduction in crop yields. In course of time, plants have evolved complex mechanisms to regulate the uptake, mobilization, and intracellular concentration of metal ions to alleviate the stress damages. Since, the functional translated portion of the genome plays an essential role in plant stress response, proteomic studies provide us a finer picture of protein networks and metabolic pathways primarily involved in cellular detoxification and tolerance mechanism. In the present review, an attempt is made to present the state of the art of recent development in proteomic techniques and significant contributions made so far for better understanding the complex mechanism of plant metal stress acclimation. Role of metal stress-related proteins involved in antioxidant defense system and primary metabolism is critically reviewed to get a bird's-eye view on the different strategies of plants to detoxify HMs. In addition to the advantages and disadvantages of different proteomic methodologies, future applications of proteome study of subcellular organelles are also discussed to get the new insights into the plant cell response to HMs. PMID- 23355842 TI - Mathematical modeling of an oscillating gene circuit to unravel the circadian clock network of Arabidopsis thaliana. AB - The Arabidopsis thaliana circadian clock is an interconnected network highly tractable to systems approaches. Most elements in the transcriptional translational oscillator were identified by genetic means and the expression of clock genes in various mutants led to the founding hypothesis of a positive negative feedback loop being the core clock. The identification of additional clock genes beyond those defined in the core led to the use of systems approaches to decipher this angiosperm oscillator circuit. Kinetic modeling was first used to explain periodicity effects of various circadian mutants. This conformed in a flexible way to experimental details. Such observations allowed a recursive use of hypothesis generating from modeling, followed by experimental corroboration. More recently, the biochemical finding of new description of a DNA-binding activity for one class of clock components directed improvements in feature generation, one of which revealed that the core of the oscillator is a negative negative feedback loop. The recursive use of modeling and experimental validation has thus revealed many essential transcriptional components that drive negative arms in the circadian oscillator. What awaits is to more fully describe the positive arms and an understanding of how additional pathways converge on the clock. PMID- 23355843 TI - Recent advances in the composition and heterogeneity of the Arabidopsis mitochondrial proteome. AB - Mitochondria are important organelles for providing the ATP and carbon skeletons required to sustain cell growth. While these organelles also participate in other key metabolic functions across species, they have a specialized role in plants of optimizing photosynthesis through participating in photorespiration. It is therefore critical to map the protein composition of mitochondria in plants to gain a better understanding of their regulation and define the uniqueness of their metabolic networks. To date, <30% of the predicted number of mitochondrial proteins has been verified experimentally by proteomics and/or GFP localization studies. In this mini-review, we will provide an overview of the advances in mitochondrial proteomics in the model plant Arabidopsis thaliana over the past 5 years. The ultimate goal of mapping the mitochondrial proteome in Arabidopsis is to discover novel mitochondrial components that are critical during development in plants as well as genes involved in developmental abnormalities, such as those implicated in mitochondrial-linked cytoplasmic male sterility. PMID- 23355844 TI - The genetic mechanisms of the influence of the light regime on the lifespan of Drosophila melanogaster. PMID- 23355845 TI - Advances in non-coding RNA profiling for neurological diseases. PMID- 23355846 TI - Melanocortin receptor 1 and black pigmentation in the Japanese ornamental carp (Cyprinus carpio var. Koi). AB - Colors and their patterns are fascinating phenotypes with great importance for fitness under natural conditions. For this reason and because pigmentation is associated with diseases, much research was devoted to study the genetics of pigmentation in animals. Considerable contribution to our understanding of color phenotypes was made by studies in domesticated animals that exhibit dazzling variation in color traits. Koi strains, the ornamental variants of the common carp, are a striking example for color variability that was selected by man during a very short period on an evolutionary timescale. Among several pigmentation genes, genetic variation in Melanocrtin receptor 1 was repeatedly associated with dark pigmentation phenotypes in numerous animals. In this study, we cloned Melanocrtin receptor 1 from the common carp. We found that alleles of the gene were not associated with the development of black color in Koi. However, the mRNA expression levels of the gene were higher during dark pigmentation development in larvae and in dark pigmented tissues of adult fish, suggesting that variation in the regulation of the gene is associated with black color in Koi. These regulatory differences are reflected in both the timing of the dark pigmentation development and the different mode of inheritance of the two black patterns associated with them. Identifying the genetic basis of color and color patterns in Koi will promote the production of this valuable ornamental fish. Furthermore, given the rich variety of colors and patterns, Koi serves as a good model to unravel pigmentation genes and their phenotypic effects and by that to improve our understanding of the genetic basis of colors also in natural populations. PMID- 23355874 TI - TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity. AB - The tumor-suppressor genes TSC1 and TSC2 are mutated in tuberous sclerosis, an autosomal dominant multisystem disorder. The gene products of TSC1 and TSC2 form a protein complex that inhibits the signaling of the mammalian target of rapamycin complex1 (mTORC1) pathway. mTORC1 is a crucial molecule in the regulation of cell growth, proliferation and survival. When the TSC1/TSC2 complex is not functional, uncontrolled mTORC1 activity accelerates the cell cycle and triggers tumorigenesis. Recent studies have suggested that TSC1 and TSC2 also regulate the activities of Rac1 and Rho, members of the Rho family of small GTPases, and thereby influence the ensuing actin cytoskeletal organization at focal adhesions. However, how TSC1 contributes to the establishment of cell polarity is not well understood. Here, the relationship between TSC1 and the formation of the actin cytoskeleton was analyzed in stable TSC1-expressing cell lines originally established from a Tsc1-deficient mouse renal tumor cell line. Our analyses showed that cell proliferation and migration were suppressed when TSC1 was expressed. Rac1 activity in these cells was also decreased as was formation of lamellipodia and filopodia. Furthermore, the number of basal actin stress fibers was reduced; by contrast, apical actin fibers, originating at the level of the tight junction formed a network in TSC1-expressing cells. Treatment with Rho-kinase (ROCK) inhibitor diminished the number of apical actin fibers, but rapamycin had no effect. Thus, the actin fibers were regulated by the Rho ROCK pathway independently of mTOR. In addition, apical actin fibers appeared in TSC1-deficient cells after inhibition of Rac1 activity. These results suggest that TSC1 regulates cell polarity-associated formation of actin fibers through the spatial regulation of Rho family of small GTPases. PMID- 23355875 TI - Detection of low-abundance KRAS mutations in colorectal cancer using microfluidic capillary electrophoresis-based restriction fragment length polymorphism method with optimized assay conditions. AB - Constitutively active KRAS mutations have been found to be involved in various processes of cancer development, and render tumor cells resistant to EGFR targeted therapies. Mutation detection methods with higher sensitivity will increase the possibility of choosing the correct individual therapy. Here, we established a highly sensitive and efficient microfluidic capillary electrophoresis-based restriction fragment length polymorphism (uCE-based RFLP) platform for low-abundance KRAS genotyping with the combination of uCE and RFLP techniques. By using our self-built sensitive laser induced fluorescence (LIF) detector and a new DNA intercalating dye YOYO-1, the separation conditions of uCE for PhiX174 HaeIII DNA marker were first optimized. Then, a Mav I digested 107-bp KRAS gene fragment was directly introduced into the microfluidic device and analyzed by uCE, in which field amplified sample stacking (FASS) technique was employed to obtain the enrichment of the RFLP digestion products and extremely improved the sensitivity. The accurate analysis of KRAS statuses in HT29, LS174T, CCL187, SW480, Clone A, and CX-1 colorectal cancer (CRC) cell lines by uCE-based RFLP were achieved in 5 min with picoliter-scale sample consumption, and as low as 0.01% of mutant KRAS could be identified from a large excess of wild-type genomic DNA (gDNA). In 98 paraffin-embedded CRC tissues, KRAS codon 12 mutations were discovered in 28 (28.6%), significantly higher than that obtained by direct sequencing (13, 13.3%). Clone sequencing confirmed these results and showed this system could detect at least 0.4% of the mutant KRAS in CRC tissue slides. Compared with direct sequencing, the new finding of the uCE-based RFLP platform was that KRAS mutations in codon 12 were correlated with the patient's age. In conclusion, we established a sensitive, fast, and cost-effective screening method for KRAS mutations, and successfully detected low-abundance KRAS mutations in clinical samples, which will allow provision of more precise individualized cancer therapy. PMID- 23355877 TI - Psychophysiological correlates of the disposition effect. AB - We assess the psychophysiological characteristics underlying the disposition effect and find that subjects showing greater disposition effect are those who sweat more and present lower body temperature and heart rate. PMID- 23355876 TI - Constitutively active CCR5 chemokine receptors differ in mediating HIV envelope dependent fusion. AB - The CCR5 chemokine receptor is a rhodopsin-like G protein-coupled receptor that mediates the effects of pro-inflammatory beta-chemokines. CCR5 is also the major co-receptor for entry of human immunodeficiency virus (HIV) into human cells. G protein-coupled receptors exist in ensembles of active and inactive conformations. Active receptor conformations can be stabilized by mutations. Although binding of the HIV envelope protein to CCR5 stimulates cellular signaling, the CCR5 conformation that induces fusion of the viral membrane with cellular membranes is not known. We mutated conserved amino acids to generate constitutively active CCR5 receptors, which are stabilized in active conformations, and tested the ability of constitutively active CCR5 receptors to mediate HIV envelope-directed membrane fusion. Mutation of the Asp3.49(125) and Arg6.32(225) residues of CCR5 did not cause constitutive activity, but Lys or Pro substitutions for Thr2.56(82), in the TxP motif, caused high basal inositol phosphate signaling. Signaling did not increase in response to MIP-1beta, suggesting that the Thr2.56(82) mutants were fully stabilized in active conformations. The Thr2.56(82)Lys mutation severely decreased cell surface CCR5 expression. Combining the Thr2.56(82)Lys mutation with an Arg6.32(225)Gln mutation partially reversed the decrease in expression. Mutants with Thr2.56(82)Lys substitutions were poor mediators of HIV envelope-directed membrane fusion, but mutants with the Thr2.65(82)Pro substitution exhibited full co-receptor function. Our results suggest that the Thr2.65(82)Lys and Thr2.65(82)Pro mutations stabilize distinct constitutively active CCR5 conformations. Lys in position 2.65(82) stabilizes activated receptor conformations that appear to be constitutively internalized and do not induce envelope-dependent membrane fusion, whereas Pro stabilizes activated conformations that are not constitutively internalized and fully mediate envelope directed membrane fusion. PMID- 23355878 TI - The association of 25(OH)D with blood pressure, pulse pressure and carotid-radial pulse wave velocity in African women. AB - High susceptibility of the African population to develop cardiovascular disease obliges us to investigate possible contributing risk factors. Our aim was to determine whether low 25(OH)D status is associated with increased blood pressure and carotid-radial pulse wave velocity in black South African women. We studied 291 urban women (mean age: 57.56+/-9.00 yrs.). 25(OH)D status was determined by serum 25(OH)D levels. Women were stratified into sufficient (>30 ng/ml), and insufficient/deficient (<30 ng/ml) groups. Cardiovascular variables were compared between groups. Women with low 25(OH)D levels had significantly higher SBP (150.8+/-27.1 vs. 137.6+/-21.0), DBP (94.7+/-14.5 vs. 89.3+/-12.3) and PP (53.15(50.7;55.7) vs. 46.3(29.4;84.6)) compared to women with sufficient levels. No significant difference was observed with regards to c-rPWV. ANCOVA analyses still revealed significant differences between the two groups with regards to SBP, DBP as well as PP. Partial correlations revealed significant inverse association between SBP and 25(OH)D (p = .04;r = -.12). Women with low 25(OH)D levels were ~2 times more likely to have high SBP (95% CI: 3.23;1.05). To conclude, women with deficient/insufficient 25(OH)D had significantly higher SBP compared to women with a sufficient 25(OH) status. PMID- 23355879 TI - Local and regional processes in community assembly. AB - Controversy on whether local (deterministic) or regional (stochastic) factors control the structure of communities persists after decades of research. The main reason for why it has not been resolved may lie in the nature of evidence which largely comes from realized natural communities. In such communities assembly history leaves a mark that may support either set of factors. To avoid the confounding effects of assembly history we controlled for these effects experimentally. We created a null community by mixing 17 rock pool communities. We then divided the null community into replicates and distributed among treatments representing a gradient of factors from local to regional. We hypothesized that if deterministic factors dominate the assembly of communities, community structures should show a corresponding gradient from being very similar and convergent to dissimilar and divergent. In contrast, if local processes are predominantly stochastic in nature, such a gradient of community configurations should emerge even in the homogeneous setting. Our results appear to partially support both hypotheses and thus suggest that both deterministic and stochastic processes contribute to the assembly of communities. Furthermore, we found that to satisfactorily explain patterns observed in natural communities environmental heterogeneity and regional processes must also be considered. In conclusion, although deterministic mechanisms seem to be important in the assembly of communities, in natural systems their signal may be diluted and masked whenever other factors exert meaningful influence. Such factors increase the number of possible paths to the point that the number of paths equals the number of communities in a metacommunity. PMID- 23355880 TI - Assessing species habitat using Google Street View: a case study of cliff-nesting vultures. AB - The assessment of a species' habitat is a crucial issue in ecology and conservation. While the collection of habitat data has been boosted by the availability of remote sensing technologies, certain habitat types have yet to be collected through costly, on-ground surveys, limiting study over large areas. Cliffs are ecosystems that provide habitat for a rich biodiversity, especially raptors. Because of their principally vertical structure, however, cliffs are not easy to study by remote sensing technologies, posing a challenge for many researches and managers working with cliff-related biodiversity. We explore the feasibility of Google Street View, a freely available on-line tool, to remotely identify and assess the nesting habitat of two cliff-nesting vultures (the griffon vulture and the globally endangered Egyptian vulture) in northwestern Spain. Two main usefulness of Google Street View to ecologists and conservation biologists were evaluated: i) remotely identifying a species' potential habitat and ii) extracting fine-scale habitat information. Google Street View imagery covered 49% (1,907 km) of the roads of our study area (7,000 km2). The potential visibility covered by on-ground surveys was significantly greater (mean: 97.4%) than that of Google Street View (48.1%). However, incorporating Google Street View to the vulture's habitat survey would save, on average, 36% in time and 49.5% in funds with respect to the on-ground survey only. The ability of Google Street View to identify cliffs (overall accuracy = 100%) outperformed the classification maps derived from digital elevation models (DEMs) (62-95%). Nonetheless, high-performance DEM maps may be useful to compensate Google Street View coverage limitations. Through Google Street View we could examine 66% of the vultures' nesting-cliffs existing in the study area (n = 148): 64% from griffon vultures and 65% from Egyptian vultures. It also allowed us the extraction of fine-scale features of cliffs. This World Wide Web-based methodology may be a useful, complementary tool to remotely map and assess the potential habitat of cliff-dependent biodiversity over large geographic areas, saving survey-related costs. PMID- 23355881 TI - Antibacterial properties of the mammalian L-amino acid oxidase IL4I1. AB - L-amino acid oxidases (LAAO) are flavoproteins that catalyze the oxidative deamination of L-amino acids to a keto-acid along with the production of H2O2 and ammonia. Interleukin 4 induced gene 1 (IL4I1) is a secreted LAAO expressed by macrophages and dendritic cells stimulated by microbial derived products or interferons, which is endowed with immunoregulatory properties. It is the first LAAO described in mammalian innate immune cells. In this work, we show that this enzyme blocks the in vitro and in vivo growth of Gram negative and Gram positive bacteria. This antibiotic effect is primarily mediated by H2O2 production but is amplified by basification of the medium due to the accumulation of ammonia. The depletion of phenylalanine (the primary amino acid catabolized by IL4I1) may also participate in the in vivo inhibition of staphylococci growth. Thus, IL4I1 plays a distinct role compared to other antibacterial enzymes produced by mononuclear phagocytes. PMID- 23355882 TI - Suppression of AKT anti-apoptotic signaling by a novel drug candidate results in growth arrest and apoptosis of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is the third most common cause of cancer fatalities worldwide, with limited treatment options and five year survival rates of between <5 and 15%. To address this medical need, we conducted a screen of a drug-like small molecule library for HCC-selective cytotoxins. We report here the identification of a disubstituted aminothiazole termed HBF-0079, with remarkable selective toxicity for HCC-derived cell lines versus non-HCC liver lines and most other cancer lines. HBF-0079 caused irreversible growth arrest and apoptosis of the HCC lines Huh7, Hep3B, HepaRG as well as the hepatoblastoma line HepG2, with CC50 values from ~0.7-7.7 uM, while more than 45 uM was needed to achieve CC50 values for the immortalized normal hepatocyte lines THLE-2 and PH5CH. Of the sixty cancer lines from the National Cancer Institute panel, only five exhibited >50% growth inhibition by HBF-0079. In Huh7 cells, HBF-0079 induced cell cycle arrest in G1 and concomitant apoptosis, and its effects were irreversible after removal of the compound. These observations corroborate a loss of AKT phosphorylation at the mTORC2-targeted residue S473, with concurrent loss of phosphorylation of the mTORC1 targets SK6 and 4EBP1 in Huh7 but not PH5CH cells. Finally, growth of Hep3B-derived tumors in a murine xenograft model was significantly repressed by the compound through either systemic or intratumoral administration of formulated HBF-0079. The potential for development of this drug candidate is discussed. PMID- 23355883 TI - DNA damage and transcriptional changes in the gills of mytilus galloprovincialis exposed to nanomolar doses of combined metal salts (Cd, Cu, Hg). AB - Aiming at an integrated and mechanistic view of the early biological effects of selected metals in the marine sentinel organism Mytilus galloprovincialis, we exposed mussels for 48 hours to 50, 100 and 200 nM solutions of equimolar Cd, Cu and Hg salts and measured cytological and molecular biomarkers in parallel. Focusing on the mussel gills, first target of toxic water contaminants and actively proliferating tissue, we detected significant dose-related increases of cells with micronuclei and other nuclear abnormalities in the treated mussels, with differences in the bioconcentration of the three metals determined in the mussel flesh by atomic absorption spectrometry. Gene expression profiles, determined in the same individual gills in parallel, revealed some transcriptional changes at the 50 nM dose, and substantial increases of differentially expressed genes at the 100 and 200 nM doses, with roughly similar amounts of up- and down-regulated genes. The functional annotation of gill transcripts with consistent expression trends and significantly altered at least in one dose point disclosed the complexity of the induced cell response. The most evident transcriptional changes concerned protein synthesis and turnover, ion homeostasis, cell cycle regulation and apoptosis, and intracellular trafficking (transcript sequences denoting heat shock proteins, metal binding thioneins, sequestosome 1 and proteasome subunits, and GADD45 exemplify up-regulated genes while transcript sequences denoting actin, tubulins and the apoptosis inhibitor 1 exemplify down-regulated genes). Overall, nanomolar doses of co-occurring free metal ions have induced significant structural and functional changes in the mussel gills: the intensity of response to the stimulus measured in laboratory supports the additional validation of molecular markers of metal exposure to be used in Mussel Watch programs. PMID- 23355884 TI - Auditory cortical and hippocampal-system mismatch responses to duration deviants in urethane-anesthetized rats. AB - Any change in the invariant aspects of the auditory environment is of potential importance. The human brain preattentively or automatically detects such changes. The mismatch negativity (MMN) of event-related potentials (ERPs) reflects this initial stage of auditory change detection. The origin of MMN is held to be cortical. The hippocampus is associated with a later generated P3a of ERPs reflecting involuntarily attention switches towards auditory changes that are high in magnitude. The evidence for this cortico-hippocampal dichotomy is scarce, however. To shed further light on this issue, auditory cortical and hippocampal system (CA1, dentate gyrus, subiculum) local-field potentials were recorded in urethane-anesthetized rats. A rare tone in duration (deviant) was interspersed with a repeated tone (standard). Two standard-to-standard (SSI) and standard-to deviant (SDI) intervals (200 ms vs. 500 ms) were applied in different combinations to vary the observability of responses resembling MMN (mismatch responses). Mismatch responses were observed at 51.5-89 ms with the 500-ms SSI coupled with the 200-ms SDI but not with the three remaining combinations. Most importantly, the responses appeared in both the auditory-cortical and hippocampal locations. The findings suggest that the hippocampus may play a role in (cortical) manifestation of MMN. PMID- 23355885 TI - Gender differences in electrophysiological gene expression in failing and non failing human hearts. AB - The increasing availability of human cardiac tissues for study are critically important in increasing our understanding of the impact of gender, age, and other parameters, such as medications and cardiac disease, on arrhythmia susceptibility. In this study, we aimed to compare the mRNA expression of 89 ion channel subunits, calcium handling proteins, and transcription factors important in cardiac conduction and arrhythmogenesis in the left atria (LA) and ventricles (LV) of failing and nonfailing human hearts of both genders. Total RNA samples, prepared from failing male (n = 9) and female (n = 7), and from nonfailing male (n = 9) and female (n = 9) hearts, were probed using custom-designed Taqman gene arrays. Analyses were performed to explore the relationships between gender, failure state, and chamber expression. Hierarchical cluster analysis revealed chamber specific expression patterns, but failed to identify disease- or gender dependent clustering. Gender-specific analysis showed lower expression levels in transcripts encoding for K(v)4.3, KChIP2, K(v)1.5, and K(ir)3.1 in the failing female as compared with the male LA. Analysis of LV transcripts, however, did not reveal significant differences based on gender. Overall, our data highlight the differential expression and transcriptional remodeling of ion channel subunits in the human heart as a function of gender and cardiac disease. Furthermore, the availability of such data sets will allow for the development of disease-, gender , and, most importantly, patient-specific cardiac models, with the ability to utilize such information as mRNA expression to predict cardiac phenotype. PMID- 23355886 TI - No evidence for cardiac dysfunction in Kif6 mutant mice. AB - A KIF6 variant in man has been reported to be associated with adverse cardiovascular outcomes after myocardial infarction. No clear biological or physiological data exist for Kif6. We sought to investigate the impact of a deleterious KIF6 mutation on cardiac function in mice. Kif6 mutant mice were generated and verified. Cardiac function was assessed by serial echocardiography at baseline, after ageing and after exercise. Lipid levels were also measured. No discernable adverse lipid or cardiac phenotype was detected in Kif6 mutant mice. These data suggest that dysfunction of Kif6 is linked to other more complex biological/biochemical parameters or is unlikely to be of material consequence in cardiac function. PMID- 23355887 TI - Inflammation subverts hippocampal synaptic plasticity in experimental multiple sclerosis. AB - Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP) induction was favored over long term depression (LTD) in EAE, as shown by a significant rightward shift in the frequency-synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1beta (IL-1beta) perfusion, and both EAE and IL-1beta inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1beta expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1beta signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS. PMID- 23355888 TI - Brain microbial populations in HIV/AIDS: alpha-proteobacteria predominate independent of host immune status. AB - The brain is assumed to be a sterile organ in the absence of disease although the impact of immune disruption is uncertain in terms of brain microbial diversity or quantity. To investigate microbial diversity and quantity in the brain, the profile of infectious agents was examined in pathologically normal and abnormal brains from persons with HIV/AIDS [HIV] (n = 12), other disease controls [ODC] (n = 14) and in cerebral surgical resections for epilepsy [SURG] (n = 6). Deep sequencing of cerebral white matter-derived RNA from the HIV (n = 4) and ODC (n = 4) patients and SURG (n = 2) groups revealed bacterially-encoded 16 s RNA sequences in all brain specimens with alpha-proteobacteria representing over 70% of bacterial sequences while the other 30% of bacterial classes varied widely. Bacterial rRNA was detected in white matter glial cells by in situ hybridization and peptidoglycan immunoreactivity was also localized principally in glia in human brains. Analyses of amplified bacterial 16 s rRNA sequences disclosed that Proteobacteria was the principal bacterial phylum in all human brain samples with similar bacterial rRNA quantities in HIV and ODC groups despite increased host neuroimmune responses in the HIV group. Exogenous viruses including bacteriophage and human herpes viruses-4, -5 and -6 were detected variably in autopsied brains from both clinical groups. Brains from SIV- and SHIV-infected macaques displayed a profile of bacterial phyla also dominated by Proteobacteria but bacterial sequences were not detected in experimentally FIV-infected cat or RAG1-/- mouse brains. Intracerebral implantation of human brain homogenates into RAG1-/- mice revealed a preponderance of alpha-proteobacteria 16 s RNA sequences in the brains of recipient mice at 7 weeks post-implantation, which was abrogated by prior heat treatment of the brain homogenate. Thus, alpha-proteobacteria represented the major bacterial component of the primate brain's microbiome regardless of underlying immune status, which could be transferred into naive hosts leading to microbial persistence in the brain. PMID- 23355889 TI - Sources of variability in platelet accumulation on type 1 fibrillar collagen in microfluidic flow assays. AB - Microfluidic flow assays (MFA) that measure shear dependent platelet function have potential clinical applications in the diagnosis and treatment of bleeding and thrombotic disorders. As a step towards clinical application, the objective of this study was to measure how phenotypic and genetic factors, as well as experimental conditions, affect the variability of platelet accumulation on type 1 collagen within a MFA. Whole blood was perfused over type 1 fibrillar collagen at wall shear rates of 150, 300, 750 and 1500 s-1 through four independent channels with a height of 50 um and a width of 500 um. The accumulation of platelets was characterized by the lag time to 1% platelet surface coverage (Lag(T)), the rate of platelet accumulation (V(PLT)), and platelet surface coverage (SC). A cohort of normal donors was tested and the results were correlated to plasma von Willebrand factor (VWF) levels, platelet count, hematocrit, sex, and collagen receptors genotypes. VWF levels were the strongest determinant of platelet accumulation. VWF levels were positively correlated to V(PLT) and SC at all wall shear rates. A longer Lag(T) for platelet accumulation at arterial shear rates compared to venous shear rates was attributed to the time required for plasma proteins to adsorb to collagen. There was no association between platelet accumulation and hematocrit or platelet count. Individuals with the AG genotype of the GP6 gene had lower platelet accumulation than individuals with the AA genotype at 150 s-1 and 300 s-1. Recalcified blood collected into sodium citrate and corn trypsin inhibitor (CTI) resulted in diminished platelet accumulation compared to CTI alone, suggesting that citrate irreversibly diminishes platelet function. This study the largest association study of MFA in healthy donors (n = 104) and will likely set up the basis for the determination of the normal range of platelet responses in this type of assay. PMID- 23355890 TI - Sexual orientation and functional pain in U.S. young adults: the mediating role of childhood abuse. AB - OBJECTIVE: Pain without known pathology, termed "functional pain," causes much school absenteeism, medication usage, and medical visits. Yet which adolescents are at risk is not well understood. Functional pain has been linked to childhood abuse, and sexual orientation minority youth (gay, lesbian, bisexual, "mostly heterosexual," and heterosexual with same-sex sexual contact) are more likely to be victims of childhood abuse than heterosexuals, thus may be at greater risk of functional pain. METHODS: We examined sexual orientation differences in past-year prevalence of functional headache, pelvic, and abdominal pain and multiple sites of pain in 9,864 young adults (mean age = 23 years) from a large U.S. cohort. We examined whether childhood abuse accounted for possible increased risk of functional pain in sexual minority youth. RESULTS: Sexual minority youth, except for gays and lesbians, were at higher risk of functional pelvic and abdominal pain and multiple sites of pain than heterosexuals. Gay and lesbian youth had elevated prevalence only of abdominal pain. Childhood abuse accounted for 14% to 33% of increased experience of multiple sites of pain in minority youth. CONCLUSIONS: Youth who identify as "mostly heterosexual" or bisexual or who identify as heterosexual and have had same-sex partners comprised 18% of our sample. Clinicians should be aware that patients with these orientations are at elevated risk of functional pain and may be in need of treatment for sequelae of childhood abuse. Conventional categorization of sexual orientation as heterosexual or homosexual may fail to distinguish a large number of youth who do not wholly identify with either group and may be at elevated risk of health problems. PMID- 23355891 TI - Low cost tuberculosis vaccine antigens in capsules: expression in chloroplasts, bio-encapsulation, stability and functional evaluation in vitro. AB - Tuberculosis (TB) caused by Mycobacterium tuberculosis is one of the leading fatal infectious diseases. The development of TB vaccines has been recognized as a major public health priority by the World Health Organization. In this study, three candidate antigens, ESAT-6 (6 kDa early secretory antigenic target) and Mtb72F (a fusion polyprotein from two TB antigens, Mtb32 and Mtb39) fused with cholera toxin B-subunit (CTB) and LipY (a cell wall protein) were expressed in tobacco and/or lettuce chloroplasts to facilitate bioencapsulation/oral delivery. Site-specific transgene integration into the chloroplast genome was confirmed by Southern blot analysis. In transplastomic leaves, CTB fusion proteins existed in soluble monomeric or multimeric forms of expected sizes and their expression levels varied depending upon the developmental stage and time of leaf harvest, with the highest-level of accumulation in mature leaves harvested at 6PM. The CTB ESAT6 and CTB-Mtb72F expression levels reached up to 7.5% and 1.2% of total soluble protein respectively in mature tobacco leaves. Transplastomic CTB-ESAT6 lettuce plants accumulated up to 0.75% of total leaf protein. Western blot analysis of lyophilized lettuce leaves stored at room temperature for up to six months showed that the CTB-ESAT6 fusion protein was stable and preserved proper folding, disulfide bonds and assembly into pentamers for prolonged periods. Also, antigen concentration per gram of leaf tissue was increased 22 fold after lyophilization. Hemolysis assay with purified CTB-ESAT6 protein showed partial hemolysis of red blood cells and confirmed functionality of the ESAT-6 antigen. GM1-binding assay demonstrated that the CTB-ESAT6 fusion protein formed pentamers to bind with the GM1-ganglioside receptor. The expression of functional Mycobacterium tuberculosis antigens in transplastomic plants should facilitate development of a cost-effective and orally deliverable TB booster vaccine with potential for long-term storage at room temperature. To our knowledge, this is the first report of expression of TB vaccine antigens in chloroplasts. PMID- 23355892 TI - Global transcriptional profiling of longitudinal clinical isolates of Mycobacterium tuberculosis exhibiting rapid accumulation of drug resistance. AB - The identification of multidrug resistant (MDR), extensively and totally drug resistant Mycobacterium tuberculosis (Mtb), in vulnerable sites such as Mumbai, is a grave threat to the control of tuberculosis. The current study aimed at explaining the rapid expression of MDR in Directly Observed Treatment Short Course (DOTS) compliant patients, represents the first study comparing global transcriptional profiles of 3 pairs of clinical Mtb isolates, collected longitudinally at initiation and completion of DOTS. While the isolates were drug susceptible (DS) at onset and MDR at completion of DOTS, they exhibited identical DNA fingerprints at both points of collection. The whole genome transcriptional analysis was performed using total RNA from H37Rv and 3 locally predominant spoligotypes viz. MANU1, CAS and Beijing, hybridized on MTBv3 (BuG@S) microarray, and yielded 36, 98 and 45 differentially expressed genes respectively. Genes encoding transcription factors (sig, rpoB), cell wall biosynthesis (emb genes), protein synthesis (rpl) and additional central metabolic pathways (ppdK, pknH, pfkB) were found to be down regulated in the MDR isolates as compared to the DS isolate of the same genotype. Up regulation of drug efflux pumps, ABC transporters, trans-membrane proteins and stress response transcriptional factors (whiB) in the MDR isolates was observed. The data indicated that Mtb, without specific mutations in drug target genes may persist in the host due to additional mechanisms like drug efflux pumps and lowered rate of metabolism. Furthermore this population of Mtb, which also showed reduced DNA repair activity, would result in selection and stabilization of spontaneous mutations in drug target genes, causing selection of a MDR strain in the presence of drug pressures. Efflux pump such as drrA may play a significant role in increasing fitness of low level drug resistant cells and assist in survival of Mtb till acquisition of drug resistant mutations with least fitness cost. PMID- 23355894 TI - Preference for the nearer of otherwise equivalent navigational goals quantifies behavioral motivation and natural selection. AB - Navigation and environmental perception precede most actions in mobile organisms. Navigation is based upon the fundamental assumption of a ubiquitous Preference for the Nearest of otherwise equivalent navigational goals (PfN). However, the magnitude and triggers for PfN are unknown and there is no clear evidence that PfN exists. I tested for PfN in human participants on a retrieval task. Results of these experiments provide the first evidence for PfN. Further, these data quantify the three primary PfN triggers and provide an experimental structure for using PfN as a behavioral metric across domains. Surprisingly, PfN exists at a high, but not universal, magnitude. Further, PfN derives most from the absolute distance to the farthest of multiple goals (d(f)), with little influence of the distance to the nearest goal (d(n)). These data provide previously unavailable quantification of behavioral motivation across species and may provide a measurable index of selection. These methods hold particular import for behavioral modification because proximity is a powerful determinant of decision outcomes across most behaviors. PMID- 23355893 TI - LIGHT/TNFSR14 can regulate hepatic lipase expression by hepatocytes independent of T cells and Kupffer cells. AB - LIGHT/TNFSF14 is a costimulatory molecule expressed on activated T cells for activation and maintenance of T cell homeostasis. LIGHT over expressed in T cells also down regulates hepatic lipase levels in mice through lymphotoxin beta receptor (LTbetaR) signaling. It is unclear whether LIGHT regulates hepatic lipase directly by interacting with LTbetaR expressing cells in the liver or indirectly by activation of T cells, and whether Kupffer cells, a major cell populations in the liver that expresses the LTbetaR, are required. Here we report that LIGHT expression via an adenoviral vector (Ad-LIGHT) is sufficient to down regulate hepatic lipase expression in mice. Depletion of Kupffer cells using clodronate liposomes had no effect on LIGHT-mediated down regulation of hepatic lipase. LIGHT-mediated regulation of hepatic lipase is also independent of LIGHT expression by T cells or activation of T cells. This is demonstrated by the decreased hepatic lipase expression in the liver of Ad-LIGHT infected recombination activating gene deficient mice that lack mature T cells and by the Ad-LIGHT infection of primary hepatocytes. Hepatic lipase expression was not responsive to LIGHT when mice lacking LTbetaR globally or only on hepatocytes were infected with Ad-LIGHT. Therefore, our data argues that interaction of LIGHT with LTbetaR on hepatocytes, but not Kupffer cells, is sufficient to down regulate hepatic lipase expression and that this effect can be independent of LIGHT's costimulatory function. PMID- 23355895 TI - In vivo cell reprogramming towards pluripotency by virus-free overexpression of defined factors. AB - The ability to induce the reprogramming of somatic mammalian cells to a pluripotent state by the forced expression of specific transcription factors has helped redefine the rules of cell fate and plasticity, as well as open possibilities for disease modeling, drug screening and regenerative medicine. Here, we hypothesized that the non-viral forced expression of the four originally discovered defined factors (OKSM) in adult mice could result in in vivo reprogramming of cells in the transfected tissue in situ. We show that a single hydrodynamic tail-vein (HTV) injection of two plasmids encoding for Oct3/4, Sox2, Klf4 and c-Myc respectively, are highly expressed in the liver tissue of Balb/C adult mice. Hallmark pluripotency markers were upregulated within 24-48 h after injection, followed by down-regulation of all major hepatocellular markers. Generation of transcriptionally reprogrammed cells in vivo was further confirmed by positive staining of liver tissue sections for all major pluripotency markers in Balb/C mice and the Nanog-GFP reporter transgenic strain (TNG-A) with concomitant upregulation of GFP expression in situ. No signs of physiological or anatomical abnormalities or teratoma formation were observed in the liver examined up to 120 days. These findings indicate that virus-free expression of OKSM factors in vivo can transcriptionally reprogram cells in situ rapidly, efficiently and transiently, absent of host tissue damage or teratoma formation. PMID- 23355896 TI - Impact of mobility impairment on indirect costs and health-related quality of life in multiple sclerosis. AB - This study was conducted to estimate the indirect costs and health-related quality of life (HRQoL) (utilities) of multiple sclerosis (MS) patients in the United States (US), and to determine the impact of worsening mobility on these parameters. In collaboration with the North American Research Committee on Multiple Sclerosis (NARCOMS) registry we conducted a cross-sectional study of participants who completed the biannual update and supplemental spring 2010 survey. Demographic, employment status, income, mobility impairment, and health utility data were collected from a sample of registry participants who met the study criteria and agreed to participate in the supplemental Mobility Study. Mean annual indirect costs per participant in 2011US$ and mean utilities for the population and for cohorts reporting different levels of mobility impairment were estimated. Analyses included 3,484 to 3,611 participants, based on survey completeness. Thirty-seven percent of registrants were not working or attending school and 46.7% of these reported retiring early. Indirect costs per participant per year, not including informal caregiver cost, were estimated at $30,601+/ 31,184. The largest relative increase in indirect costs occurred at earlier mobility impairment stages, regardless of the measure used. Participants' mean utility score (0.73+/-0.18) was lower than that of a similarly aged sample from the general US population (0.87). As with indirect costs, larger decrements in utility were seen at earlier mobility impairment stages. These results suggest that mobility impairment may contribute to increases in indirect costs and declines in HRQoL in MS patients. PMID- 23355897 TI - Magnetic shielding accelerates the proliferation of human neuroblastoma cell by promoting G1-phase progression. AB - Organisms have been exposed to the geomagnetic field (GMF) throughout evolutionary history. Exposure to the hypomagnetic field (HMF) by deep magnetic shielding has recently been suggested to have a negative effect on the structure and function of the central nervous system, particularly during early development. Although changes in cell growth and differentiation have been observed in the HMF, the effects of the HMF on cell cycle progression still remain unclear. Here we show that continuous HMF exposure significantly increases the proliferation of human neuroblastoma (SH-SY5Y) cells. The acceleration of proliferation results from a forward shift of the cell cycle in G1-phase. The G2/M-phase progression is not affected in the HMF. Our data is the first to demonstrate that the HMF can stimulate the proliferation of SH-SY5Y cells by promoting cell cycle progression in the G1-phase. This provides a novel way to study the mechanism of cells in response to changes of environmental magnetic field including the GMF. PMID- 23355898 TI - Comparison of the distal gut microbiota from people and animals in Africa. AB - The gut microbiota plays a key role in the maintenance of healthy gut function as well as many other aspects of health. High-throughput sequence analyses have revealed the composition of the gut microbiota, showing that there is a core signature to the human gut microbiota, as well as variation in its composition between people. The gut microbiota of animals is also being investigated. We are interested in the relationship between bacterial taxa of the human gut microbiota and those in the gut microbiota of domestic and semi-wild animals. While it is clear that some human gut bacterial pathogens come from animals (showing that human--animal transmission occurs), the extent to which the usually non pathogenic commensal taxa are shared between humans and animals has not been explored. To investigate this we compared the distal gut microbiota of humans, cattle and semi-captive chimpanzees in communities that are geographically sympatric in Uganda. The gut microbiotas of these three host species could be distinguished by the different proportions of bacterial taxa present. We defined multiple operational taxonomic units (OTUs) by sequence similarity and found evidence that some OTUs were common between human, cattle and chimpanzees, with the largest number of shared OTUs occurring between chimpanzees and humans, as might be expected with their close physiological similarity. These results show the potential for the sharing of usually commensal bacterial taxa between humans and other animals. This suggests that further investigation of this phenomenon is needed to fully understand how it drives the composition of human and animal gut microbiotas. PMID- 23355899 TI - National surveillance of influenza-associated encephalopathy in Japan over six years, before and during the 2009-2010 influenza pandemic. AB - Influenza-associated encephalopathy (IAE) is a serious complication of influenza and is reported most frequently in Japan. This paper presents an assessment of the epidemiological characteristics of influenza A (H1N1) 2009-associated encephalopathy in comparison to seasonal IAE, based on Japanese national surveillance data of influenza-like illness (ILI) and IAE during flu seasons from 2004-2005 through 2009-2010. In each season before the pandemic, 34-55 IAE cases (mean 47.8; 95% confidence interval: 36.1-59.4) were reported, and these cases increased drastically to 331 during the 2009 pandemic (6.9-fold the previous seasons). Of the 331 IAE cases, 322 cases were reported as influenza A (H1N1) 2009-associated encephalopathy. The peaks of IAE were consistent with the peaks of the influenza epidemics and pandemics. A total of 570 cases of IAE (seasonal A, 170; seasonal B, 50; influenza A (H1N1) 2009, 322; unknown, 28) were reported over six seasons. The case fatality rate (CFR) ranged from 4.8 to 18.2% before the pandemic seasons and 3.6% in the 2009 pandemic season. The CFR of pandemic IAE was 3.7%, which is lower than that of influenza A-/B-associated encephalopathy (12.9%, p<0.001; 14.0%, p = 0.002; respectively). The median age of IAE was 7 years during the pandemic, which is higher than that of influenza A /B-associated encephalopathy (4, p<0.001; 4.5, p = 0.006; respectively). However, the number of pandemic-IAE cases per estimated ILI outpatients peaked in the 0-4 year age group and data both before and during the pandemic season showed a U shape pattern. This suggests that the high incidence of influenza infection in the 0-4 year age group may lead to a high incidence of IAE in the same age group in a future influenza season. Further studies should include epidemiologic case definitions and clinical details of IAE to gain a more accurate understanding of the epidemiologic status of IAE. PMID- 23355900 TI - The duration of a co-occurring sound modulates visual detection performance in humans. AB - BACKGROUND: The duration of sounds can affect the perceived duration of co occurring visual stimuli. However, it is unclear whether this is limited to amodal processes of duration perception or affects other non-temporal qualities of visual perception. METHODOLOGY/PRINCIPAL FINDINGS: Here, we tested the hypothesis that visual sensitivity--rather than only the perceived duration of visual stimuli--can be affected by the duration of co-occurring sounds. We found that visual detection sensitivity (d') for unimodal stimuli was higher for stimuli of longer duration. Crucially, in a cross-modal condition, we replicated previous unimodal findings, observing that visual sensitivity was shaped by the duration of co-occurring sounds. When short visual stimuli (~24 ms) were accompanied by sounds of matching duration, visual sensitivity was decreased relative to the unimodal visual condition. However, when the same visual stimuli were accompanied by longer auditory stimuli (~60-96 ms), visual sensitivity was increased relative to the performance for ~24 ms auditory stimuli. Across participants, this sensitivity enhancement was observed within a critical time window of ~60-96 ms. Moreover, the amplitude of this effect correlated with visual sensitivity enhancement found for longer lasting visual stimuli across participants. CONCLUSIONS/SIGNIFICANCE: Our findings show that the duration of co occurring sounds affects visual perception; it changes visual sensitivity in a similar way as altering the (actual) duration of the visual stimuli does. PMID- 23355901 TI - Mobilization of endothelial progenitors by recurrent bacteremias with a periodontal pathogen. AB - BACKGROUND: Periodontal infections are independent risk factors for atherosclerosis. However, the exact mechanisms underlying this link are yet unclear. Here, we evaluate the in vivo effects of bacteremia with a periodontal pathogen on endothelial progenitors, bone marrow-derived cells capable of endothelial regeneration, and delineate the critical pathways for these effects. METHODS: 12-week old C57bl6 wildtype or toll-like receptor (TLR)-2 deficient mice were repeatedly intravenously challenged with 109 live P. gingivalis 381 or vehicle. Numbers of Sca1+/flk1+ progenitors, circulating angiogenic cells, CFU Hill, and late-outgrowth EPC were measured by FACS/culture. Endothelial function was assessed using isolated organ baths, reendothelization was measured in a carotid injury model. RANKL/osteoprotegerin levels were assessed by ELISA/qPCR. RESULTS: In wildtype mice challenged with intravenous P.gingivalis, numbers of Sca1+/flk1+ progenitors, CAC, CFU-Hill, and late-outgrowth EPC were strongly increased in peripheral circulation and spleen, whereas Sca1+/flk1+ progenitor numbers in bone marrow decreased. Circulating EPCs were functional, as indicated by improved endothelial function and improved reendothelization in infected mice. The osteoprotegerin/RANKL ratio was increased after P. gingivalis challenge in the bone marrow niche of wildtype mice and late-outgrowth EPC in vitro. Conversely, in mice deficient in TLR2, no increase in progenitor mobilization or osteoprotegerin/RANKL ratio was detected. CONCLUSION: Recurrent transient bacteremias, a feature of periodontitis, increase peripheral EPC counts and decrease EPC pools in the bone marrow, thereby possibly reducing overall endothelial regeneration capacity, conceivably explaining pro-atherogenic properties of periodontal infections. These effects are seemingly mediated by toll-like receptor (TLR)-2. PMID- 23355902 TI - Cell type-dependent induction of DNA damage by 1800 MHz radiofrequency electromagnetic fields does not result in significant cellular dysfunctions. AB - BACKGROUND: Although IARC clarifies radiofrequency electromagnetic fields (RF EMF) as possible human carcinogen, the debate on its health impact continues due to the inconsistent results. Genotoxic effect has been considered as a golden standard to determine if an environmental factor is a carcinogen, but the currently available data for RF-EMF remain controversial. As an environmental stimulus, the effect of RF-EMF on cellular DNA may be subtle. Therefore, more sensitive method and systematic research strategy are warranted to evaluate its genotoxicity. OBJECTIVES: To determine whether RF-EMF does induce DNA damage and if the effect is cell-type dependent by adopting a more sensitive method gammaH2AX foci formation; and to investigate the biological consequences if RF EMF does increase gammaH2AX foci formation. METHODS: Six different types of cells were intermittently exposed to GSM 1800 MHz RF-EMF at a specific absorption rate of 3.0 W/kg for 1 h or 24 h, then subjected to immunostaining with anti-gammaH2AX antibody. The biological consequences in gammaH2AX-elevated cell type were further explored with comet and TUNEL assays, flow cytometry, and cell growth assay. RESULTS: Exposure to RF-EMF for 24 h significantly induced gammaH2AX foci formation in Chinese hamster lung cells and Human skin fibroblasts (HSFs), but not the other cells. However, RF-EMF-elevated gammaH2AX foci formation in HSF cells did not result in detectable DNA fragmentation, sustainable cell cycle arrest, cell proliferation or viability change. RF-EMF exposure slightly but not significantly increased the cellular ROS level. CONCLUSIONS: RF-EMF induces DNA damage in a cell type-dependent manner, but the elevated gammaH2AX foci formation in HSF cells does not result in significant cellular dysfunctions. PMID- 23355903 TI - Oxygen tension modulates differentiation and primary macrophage functions in the human monocytic THP-1 cell line. AB - The human THP-1 cell line is widely used as an in vitro model system for studying macrophage differentiation and function. Conventional culture conditions for these cells consist of ambient oxygen pressure (~20% v/v) and medium supplemented with the thiol 2-mercaptoethanol (2-ME) and serum. In consideration of the redox activities of O2 and 2-ME, and the extensive experimental evidence supporting a role for reactive oxygen species (ROS) in the differentiation and function of macrophages, we addressed the question of whether culturing THP-1 cells under a more physiologically relevant oxygen tension (5% O2) in the absence of 2-ME and serum would alter THP-1 cell physiology. Comparisons of cultures maintained in 18% O2versus 5% O2 indicated that reducing oxygen tension had no effect on the proliferation of undifferentiated THP-1 cells. However, decreasing the oxygen tension to 5% O2 significantly increased the rate of phorbol ester-induced differentiation of THP-1 cells into macrophage-like cells as well as the metabolic activity of both undifferentiated and PMA-differentiated THP-1 cells. Removal of both 2-ME and serum from the medium decreased the proliferation of undifferentiated THP-1 cells but increased metabolic activity and the rate of differentiation under either oxygen tension. In differentiated THP-1 cells, lowering the oxygen tension to 5% O2 decreased phagocytic activity, the constitutive release of beta-hexosaminidase and LPS-induced NF-kappaB activation but enhanced LPS-stimulated release of cytokines. Collectively, these data demonstrate that oxygen tension influences THP-1 cell differentiation and primary macrophage functions, and suggest that culturing these cells under tightly regulated oxygen tension in the absence of exogenous reducing agent and serum is likely to provide a physiologically relevant baseline from which to study the role of the local redox environment in regulating THP-1 cell physiology. PMID- 23355904 TI - Multiple infections with Cardinium and two strains of Wolbachia in the spider mite Tetranychus phaselus Ehara: revealing new forces driving the spread of Wolbachia. AB - Cytoplasmic incompatibility (CI) has been proposed as a major mechanism by which certain strains of Wolbachia to invade and persist in host populations. However, mechanisms that underlie the invasion and persistence of non-CI strains are less well understood. Here, we established a spider mite Tetranychus phaselus population multiply infected by Cardinium as well as two distinct lineages of Wolbachia, designated wCon and wOri, to study the forces driving the spread of the non-CI strain of Wolbachia wOri. Interestingly, we found that wOri provided a longevity advantage to its female hosts under ideal conditions, making wOri stay longer in this population, and then being transmitted to more offspring. Furthermore, the lifespan of uninfected females was reduced when mated with multiple-infected males. As a result, the uninfected population is attenuated by the multiple-infected males. Thus, we infer that the host age effects of multiple infection may represent sufficient forces driving the spread of wOri through the host population. PMID- 23355905 TI - Neurocranial osteology and neuroanatomy of a late Cretaceous titanosaurian sauropod from Spain (Ampelosaurus sp.). AB - Titanosaurians were a flourishing group of sauropod dinosaurs during Cretaceous times. Fossils of titanosaurians have been found on all continents and their remains are abundant in a number of Late Cretaceous sites. Nonetheless, the cranial anatomy of titanosaurians is still very poorly known. The Spanish latest Cretaceous locality of "Lo Hueco" yielded a relatively well preserved, titanosaurian braincase, which shares a number of phylogenetically restricted characters with Ampelosaurus atacis from France such as a flat occipital region. However, it appears to differ from A. atacis in some traits such as the greater degree of dorsoventral compression and the presence of proatlas facets. The specimen is, therefore, provisionally identified as Ampelosaurus sp. It was CT scanned, and 3D renderings of the cranial endocast and inner-ear system were generated. Our investigation highlights that, although titanosaurs were derived sauropods with a successful evolutionary history, they present a remarkably modest level of paleoneurological organization. Compared with the condition in the basal titanosauriform Giraffatitan brancai, the labyrinth of Ampelosaurus sp. shows a reduced morphology. The latter feature is possibly related to a restricted range of head-turning movements. PMID- 23355906 TI - Analysis of FGF-dependent and FGF-independent pathways in otic placode induction. AB - The inner ear develops from a patch of thickened cranial ectoderm adjacent to the hindbrain called the otic placode. Studies in a number of vertebrate species suggest that the initial steps in induction of the otic placode are regulated by members of the Fibroblast Growth Factor (FGF) family, and that inhibition of FGF signaling can prevent otic placode formation. To better understand the genetic pathways activated by FGF signaling during otic placode induction, we performed microarray experiments to estimate the proportion of chicken otic placode genes that can be up-regulated by the FGF pathway in a simple culture model of otic placode induction. Surprisingly, we find that FGF is only sufficient to induce about 15% of chick otic placode-specific genes in our experimental system. However, pharmacological blockade of the FGF pathway in cultured chick embryos showed that although FGF signaling was not sufficient to induce the majority of otic placode-specific genes, it was still necessary for their expression in vivo. These inhibitor experiments further suggest that the early steps in otic placode induction regulated by FGF signaling occur through the MAP kinase pathway. Although our work suggests that FGF signaling is necessary for otic placode induction, it demonstrates that other unidentified signaling pathways are required to co-operate with FGF signaling to induce the full otic placode program. PMID- 23355907 TI - Comprehensive phylogenetic analysis of bacterial group II intron-encoded ORFs lacking the DNA endonuclease domain reveals new varieties. AB - Group II introns are self-splicing RNAs that act as mobile retroelements in the organelles of plants, fungi and protists. They are also widely distributed in bacteria, and are generally assumed to be the ancestors of nuclear spliceosomal introns. Most bacterial group II introns have a multifunctional intron-encoded protein (IEP) ORF within the ribozyme domain IV (DIV). This ORF encodes an N terminal reverse transcriptase (RT) domain, followed by a putative RNA-binding domain with RNA splicing or maturase activity and, in some cases, a C-terminal DNA-binding (D) region followed by a DNA endonuclease (En) domain. In this study, we focused on bacterial group II intron ORF phylogenetic classes containing only reverse transcriptase/maturase open reading frames, with no recognizable D/En region (classes A, C, D, E, F and unclassified introns). On the basis of phylogenetic analyses of the maturase domain and its C-terminal extension, which appears to be a signature characteristic of ORF phylogenetic class, with support from the phylogeny inferred from the RT domain, we have revised the proposed new class F, defining new intron ORF varieties. Our results increase knowledge of the lineage of group II introns encoding proteins lacking the En-domain. PMID- 23355908 TI - The spectrum of SWI/SNF mutations, ubiquitous in human cancers. AB - SWI/SNF is a multi-subunit chromatin remodeling complex that uses the energy of ATP hydrolysis to reposition nucleosomes, thereby modulating gene expression. Accumulating evidence suggests that SWI/SNF functions as a tumor suppressor in some cancers. However, the spectrum of SWI/SNF mutations across human cancers has not been systematically investigated. Here, we mined whole-exome sequencing data from 24 published studies representing 669 cases from 18 neoplastic diagnoses. SWI/SNF mutations were widespread across diverse human cancers, with an excess of deleterious mutations, and an overall frequency approaching TP53 mutation. Mutations occurred most commonly in the SMARCA4 enzymatic subunit, and in subunits thought to confer functional specificity (ARID1A, ARID1B, PBRM1, and ARID2). SWI/SNF mutations were not mutually-exclusive of other mutated cancer genes, including TP53 and EZH2 (both previously linked to SWI/SNF). Our findings implicate SWI/SNF as an important but under-recognized tumor suppressor in diverse human cancers, and provide a key resource to guide future investigations. PMID- 23355909 TI - Nonalcoholic fatty liver disease and the renin-angiotensin system: Implications for treatment. AB - Nonalcoholic fatty liver disease (NAFLD) is the commonest liver disease in Western countries. Treatment of NAFLD is currently based on lifestyle measures and no effective pharmacologic treatment is available so far. Emerging evidence, mainly from animal studies, suggests that the renin-angiotensin-aldosterone system may be of major importance in the pathogenesis of NAFLD and indicates that angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) as a potentially useful therapeutic approach. However, data from human studies are limited and contradictory. In addition, there are few randomized controlled trials (RCTs) on the effects of ACE-I or ARB in patients with NAFLD and most data are from retrospective studies, pilot prospective studies and post hoc analyses of clinical trials. Accordingly, more and larger RCTs are needed to directly assess the effectiveness of ACE-I and ARBs in NAFLD. PMID- 23355910 TI - Is nonalcoholic fatty liver disease the hepatic expression of the metabolic syndrome? AB - Nonalcoholic fatty liver disease (NAFLD) is generally considered as the hepatic manifestation of the metabolic syndrome (MS). Although there is no doubt that NAFLD is tightly linked to the MS, the diagnosis of NAFLD encompasses a broad range of histological entities and as a composite phenotype may be hindering attempts to understand the mechanistic basis of these variants. The awareness that NAFLD is not solely and invariably associated with the MS is a useful means to help direct future studies. We should be aware that mechanisms other than insulin resistance may contribute to the chronic inflammatory processes that underpin the development of liver fat accumulation and the subsequent architectural distortion of the liver. Further studies with special focus on hemoglobin as a risk factor for the development of NAFLD in the absence of MS should be performed. PMID- 23355911 TI - Management of alcoholic hepatitis: Current concepts. AB - Alcoholic hepatitis is a devastating form of acute liver injury seen in chronic alcohol abusers with significant morbidity and mortality. It is a multisystem disease that is precipitated by ingesting large quantities of alcohol with genetic and environmental factors playing a role. Prognostic criteria have been developed to predict disease severity and these criteria can serve as indicators to initiate medical therapy. Primary therapy remains abstinence and supportive care, as continued alcohol abuse is the most important risk factor for disease progression. The cornerstone of supportive care remains aggressive nutritional support, and although acute alcoholic hepatitis has been extensively studied, few specific medical therapies have been successful. Corticosteroids remain the most effective medical therapy available in improving short term survival in a select group of patients with alcoholic hepatitis; however, the long-term outcome of drug therapies is still not entirely clear and further clinical investigation is necessary. While liver transplantation for acute alcoholic hepatitis have demonstrated promising results, this practice remains controversial and has not been advocated universally, with most transplant centers requiring a prolonged period of abstinence before considering transplantation. Extracorporeal liver support devices, although still experimental, have been developed as a form of liver support to give additional time for liver regeneration. These have the potential for a significant therapeutic option in the future for this unfortunately dreadful disease. PMID- 23355913 TI - Role of cytokine receptor-like factor 1 in hepatic stellate cells and fibrosis. AB - AIM: To elucidate the role of cytokine receptor-like factor 1 (CRLF1) in hepatic stellate cells and liver fibrosis. METHODS: Rat hepatic stellate cells (HSCs) were isolated by Nykodenz gradient centrifugation and activated by culturing in vitro. Differentially expressed genes in quiescent and culture activated HSCs were identified using microarrays. Injections of carbon tetrachloride (CCl(4)) for 4 wk were employed to induce liver fibrosis. The degree of fibrosis was assessed by Sirius red staining. Adenovirus expressing CRLF1 was injected through tail vein into mice to achieve overexpression of CRLF1 in the liver. The same adenovirus was used to overexpress CRLF1 in quiescent HSCs cultured in vitro. Expression of CRLF1, CLCF1 and ciliary neurotrophic factor receptor (CNTFR) in hepatic stellate cells and fibrotic livers was analyzed by semi-quantitative reverse transcription-polymerase chain reaction and Western blotting. Expression of profibrotic cytokines and collagens was analyzed by the same method. RESULTS: CRLF1 is a secreted cytokine with unknown function. Human mutations suggested a role in development of autonomous nervous system and a role of CRLF1 in immune response was implied by its similarity to interleukin (IL)-6. Here we show that expression of CRLF1 was undetectable in quiescent HSCs and was highly upregulated in activated HSCs. Likewise, expression of CRLF1 was very low in normal livers, but was highly upregulated in fibrotic livers, where its expression correlated with the degree of fibrosis. A cofactor of CLRF1, cardiotrophin-like cytokine factor 1 (CLCF1), and the receptor which binds CRLF1/CLCF1 dimer, the CNTFR, were expressed to similar levels in quiescent and activated HSCs and in normal and fibrotic livers, indicating a constitutive expression. Overexpression of CLRF1 alone in the normal liver did not stimulate expression of profibrotic cytokines, suggesting that the factor itself is not pro-inflammatory. Ectopic expression in quiescent HSCs, however, retarded their activation into myofibroblasts and specifically decreased expression of type III collagen. Inhibition of type III collagen expression by CRLF1 was also seen in the whole liver. Our results suggest that CLRF1 is the only component of the CRLF1/CLCF1/CNTFR signaling system that is inducible by a profibrotic stimulus and that activation of this system by CLRF1 may regulate expression of type III collagen in fibrosis. CONCLUSION: By regulating activation of HSCs and expression of type III collagen, CRLF1 may have an ability to change the composition of extracellular matrix in fibrosis. PMID- 23355914 TI - Prevalence of HIV and HCV infections in two populations of Malian women and serological assays performances. AB - AIM: To estimate the prevalence of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections in women in Mali and to evaluate the performance of serological assays. METHODS: Two prospective studies were conducted in 2009 and 2010 in Mali. They concerned first, 1000 pregnant women attending six reference health centers in Bamako (Malian capital) between May 26 and June 16, 2009; and secondly, 231 women over 50 years who consulted general practitioners of two hospitals in Bamako between October 25 and December 24, 2010. Blood samples were collected and kept frozen in good condition before analysis. All samples depicted as positive using HIV/HCV enzyme immuno-assay screening assays were submitted to confirmation analysis. Molecular markers of HCV were characterized. RESULTS: The seroprevalence of HIV and HCV in the population of pregnant women was 4.1% and 0.2% respectively. Among older women the seroprevalence was higher and similar for HIV and HCV (6.1% vs 6.5%). The anti-HIV prevalence was not different in young and older women (4.1% vs 6.1%). In contrast, the anti-HCV prevalence was higher in older compared to younger women (6.5% vs 0.2%, P < 0.01). Of 2 pregnant women who were HCV seropositive, only one was polymerase chain reaction (PCR) reactive and infected by genotype 2, with a viral load of 1600 IU/mL. Regarding older women who were HCV seropositive, 13 out of 15 were PCR reactive, infected by genotype 1 or 2. Globally HCV genotype 2 was predominant. The positive predictive value (PPV) measured with VIKIA HIV test in young women was 100% therefore significantly higher than the 87.5% measured in older women (P < 0.05). Conversely, the PPV measured with Monolisa HCV assay in older women was 88.2% and higher than the 14.3% measured in younger women (P < 0.01). CONCLUSION: Whereas HIV prevalence was similar in both subpopulations HCV was more frequent among older women (P < 0.01). The PPV of screening assays varied with the age of the subjects. PMID- 23355915 TI - Ultrasonogram of hepatocellular carcinoma is associated with outcome after radiofrequency ablation. AB - AIM: To investigate the association between B-mode ultrasound classification of small hepatocellular carcinoma (HCC) and outcome after radiofrequency ablation (RFA). METHODS: Ninety-seven cases of HCC treated using RFA between April 2001 and March 2006 were reviewed. Ultrasound images were classified as follows: type 1, with halo (n = 29); and type 2, without halo (n = 68). Type 2 was further categorized into three subgroups: type 2a, homogenous hyperechoic (n = 9); type 2b, hypoechoic with smooth margins (n = 43); and type 2c (n = 16), hypoechoic with irregular or unclear margins. Patients with type 2a HCC were excluded from analysis due to the small number of cases. RESULTS: Two year recurrence rates for type 2b, type 1 and type 2c were 26%, 42% and 69%, respectively, with significant differences between type 2b and type 2c (P < 0.01), and between type 1 and type 2c (P < 0.05). Five year survival rates were 89%, 43% and 65%, respectively. Survival was significantly longer for type 2b than for other types (type 1 vs type 2b, P < 0.01; type 2b vs type 2c, P < 0.05). On univariate analysis, factors contributing to recurrence were number of tumors, tumor stage, serum level of lens culinaris agglutinin-reactive alpha-fetoprotein and ultrasound classification (P < 0.05). Factors contributing to survival were tumor stage and ultrasound classification (P < 0.05). Multivariate analysis identified ultrasound classification as the only factor independently associated with both recurrence and survival (P < 0.05). CONCLUSION: B-mode ultrasound classification of small HCC is a predictive factor for outcome after RFA. PMID- 23355912 TI - Hepatitis C virus-related hepatocellular carcinoma: An insight into molecular mechanisms and therapeutic strategies. AB - Hepatitis C virus (HCV) infects more than 170 million people worldwide, and thereby becomes a series global health challenge. Chronic infection with HCV is considered one of the major causes of end-stage liver disease including cirrhosis and hepatocellular carcinoma. Although the multiple functions of the HCV proteins and their impacts on the modulation of the intracellular signaling transduction processes, the drive of carcinogenesis during the infection with HCV, is thought to result from the interactions of viral proteins with host cell proteins. Thus, the induction of mutator phenotype, in liver, by the expression of HCV proteins provides a key mechanism for the development of HCV-associated hepatocellular carcinoma (HCC). HCC is considered one of the most common malignancies worldwide with increasing incidence during the past decades. In many countries, the trend of HCC is attributed to several liver diseases including HCV infection. However, the development of HCC is very complicated and results mainly from the imbalance between tumor suppressor genes and oncogenes, as well as from the alteration of cellular factors leading to a genomic instability. Besides the poor prognosis of HCC patients, this type of tumor is quite resistance to the available therapies. Thus, understanding the molecular mechanisms, which are implicated in the development of HCC during the course of HCV infection, may help to design a general therapeutic protocol for the treatment and/or the prevention of this malignancy. This review summarizes the current knowledge of the molecular mechanisms, which are involved in the development of HCV-associated HCC and the possible therapeutic strategies. PMID- 23355916 TI - Surgically induced weight loss by gastric bypass improves non alcoholic fatty liver disease in morbid obese patients. AB - AIM: To evaluate the effects of surgical weight loss (Roux-en-Y gastric bypass with a modified Fobi-Capella technique) on non alcoholic fatty liver disease in obese patients. METHODS: A group of 26 morbidly obese patients aged 45 +/- 2 years and with a body mass index > 40 kg/m(2) who underwent open surgical weight loss operations had paired liver biopsies, the first at surgery and the second after 16 +/- 3 mo of weight loss. Biopsies were evaluated and compared in a blinded fashion. The presence of metabolic syndrome, anthropometric and biochemical variables were also assessed at baseline and at the time of the second biopsy. RESULTS: Percentage of excess weight loss was 72.1% +/- 6.6%. There was a reduction in prevalence of metabolic syndrome from 57.7% (15 patients) to 7.7% (2 patients) (P < 0.001). Any significance difference was observed in aspartate aminotransferase or alanine aminotransferase between pre and postsurgery. There were improvements in steatosis (P < 0.001), lobular (P < 0.001) and portal (P < 0.05) inflammation and fibrosis (P < 0.001) at the second biopsy. There were 25 (96.1%) patients with non alcoholic steatohepatitis (NASH) in their index biopsy and only four (15.3%) of the repeat biopsies fulfilled the criteria for NASH. The persistence of fibrosis (F > 1) was present in five patients at second biopsy. Steatosis and fibrosis at surgery were predictors of significant fibrosis postsurgery. CONCLUSION: Restrictive mildly malabsorptive surgery provides significant weight loss, resolution of metabolic syndrome and associated abnormal liver histological features in most obese patients. PMID- 23355917 TI - Efficacy of 3 years of adefovir monotherapy in chronic hepatitis B patients with lamivudine resistance. AB - AIM: To study the effect of rescue monotherapy with adefovir (ADV) in patients with chronic hepatitis B (CHB) who developed drug resistance to lamivudine (LAM). METHODS: A total of 76 treated CHB patients with resistance to LAM were enrolled in the present study. The patients' baseline characteristics, such as age, gender, blood tests and hepatitis B virus (HBV) DNA were collected; therapy duration and the response of each patient were also recorded. ADV monotherapy was set as the observation group A. Twenty-four patients with LAM resistance, who were set as group B, accepted combined therapy with LAM + ADV. Patients were followed up at 0, 12, 24, 52, 104 and 156 wk. Hepatitis B surface antigen status, hepatitis B e antigen (HBeAg)/anti-HBe status, HBV DNA level and biochemical indexes were monitored. Sequencer of HBV polymerase gene was performed on the ABI 3730 automated sequencer. If no desired effects had been achieved during the course of treatment, patients' choices were also taken into account. The control group was tested at the same time. RESULTS: In the two groups, 27 cases developed viral breakthrough after LAM treatment response. The remaining 49 cases underwent biochemical rebound accompanied by rtM204I/V or rtL180M mutation. In group A, 52 cases finished 156 wk of ADV monotherapy; of whom, 36 cases were HBeAg positive and 16 HBeAg negative. In patients whose baseline HBV DNAs were 10(3)-10(5) copies/mL, 88.8% of patients' HBV DNAs were lower than the lower test limit (10(3) copies/mL) after 12 to 156 wk of ADV treatment. In patients whose baseline HBV DNAs were >= 10(6) copies/mL, 41.1%-47.0% of patients' HBV DNAs were lower than the lower test limit after the same course of ADV therapy (chi(2) were 4.35 5.4, 41.1%-47.0% vs 88.8% group 10(3)-10(5) copies/mL, P < 0.01). In group A, seroconversion of HBeAg developed in 8 of 36 cases (22.2%). In group B, 24 cases finished 156 wk of LAM + ADV; of whom, 17 cases were HBeAg positive and 7 HBeAg negative. In patients whose baseline HBV DNAs were 10(3)-10(5) copies /mL, 81.8% of patients' HBV DNAs were lower than the lower test limit (10(3) copies/mL) after 12 to 156 wk of treatment. In the patients whose baseline HBV DNAs were >= 10(6) copies/mL, 46.1%-53.8% of patients' HBV DNAs were lower than the lower test limit after the same course of LAM + ADV therapy (chi(2) were 4.1-5.0, 46.1% 53.8% vs 81.8% group 10(3)-10(5) copies/mL, P < 0.05-0.01). In group B, 4 of 17 cases (23.5%) developed seroconversion of HBeAg. Treatment outcomes in groups A and B were comparable. CONCLUSION: In both group A and B, the ratios of virological response have similar efficacy in patients with lower baseline HBV DNAs. PMID- 23355919 TI - Estrium Whey induced hepatitis in a patient with metastatic breast cancer: Case report. AB - Estrium Whey is an alternative nutritional support therapy for women. It's enhanced with specific nutrients including phytoestrogens, folate, antioxidants and fiber to support healthy estrogen detoxification and hormone balance. We describe the first case of hepatotoxicity due to Estrium Whey in a 51-year old female with metastatic breast cancer with clinical, laboratory and histopathological changes. PMID- 23355918 TI - Acute abdomen and ascites as presenting features of autosomal dominant polycystic kidney disease. AB - We describe a patient with sudden onset of abdominal pain and ascites, leading to the diagnosis of autosomal dominant polycystic kidney disease (ADPKD). Her presentation was consistent with acute liver cyst rupture as the cause of her acute illness. A review of literature on polycystic liver disease in patients with ADPKD and current management strategies are presented. This case alerts physicians that ADPKD could occasionally present as an acute abdomen; cyst rupture related to ADPKD may be considered in the differential diagnoses of acute abdomen. PMID- 23355920 TI - Hepatic sarcoidosis complicating treatment-naive viral hepatitis. AB - Hepatic sarcoidosis is usually asymptomatic but rarely leads to adverse liver related outcome. Co-existence of viral hepatitis and hepatic sarcoidosis is a rare, but recognised phenomenon. Obtaining a balance between immune suppression and anti-viral therapy may be problematic. Immunosuppression in the presence of viral hepatitis can lead to rapid deterioration of liver disease. Similarly, anti viral therapy may exacerbate granulomatous hepatitis. Here we present two cases of viral hepatitis co-existing with sarcoidosis that illustrate successful management strategies. In one, hepatitis B replication was suppressed with oral anti-viral therapy before commencing prednisolone. In the second, remission of hepatic sarcoidosis was achieved with prednisolone, before treating hepatitis C and obtaining a sustained virological response with pegylated interferon and ribavirin therapy. PMID- 23355921 TI - Complications arising in simple and polycystic liver cysts. AB - Liver cysts are common, affecting 5%-10% of the population. Most are asymptomatic, however 5% of patients develop symptoms, sometimes due to complications and will require intervention. There is no consensus on their management because complications are so uncommon. The aim of this study was to perform a collected review of how a series of complications were managed at our institutions. Six different patients presenting with rare complications of liver cysts were obtained from Hepatobiliary Units in the United Kingdom and The Netherlands. History and radiological imaging were obtained from case notes and computerised radiology. As a result, 1 patient admitted with inferior vena cava obstruction was managed by cyst aspiration and lanreotide; 1 patient with common bile duct obstruction was first managed by endoscopic retrograde cholangiopancreatography and stenting, followed by open fenestration; 1 patient with ruptured cysts and significant medical co-morbidities was managed by percutaneous drainage; 1 patient with portal vein occlusion and varices was managed by open liver resection; 1 patient with infected cysts was treated with intravenous antibiotics and is awaiting liver transplantation. The final patient with a simple liver cyst mimicking a hydatid was managed by open liver resection. In conclusion, complications of cystic liver disease are rare, and we have demonstrated in this series that both operative and non-operative strategies have defined roles in management. The mainstays of treatment are either aspiration/sclerotherapy or, alternatively laparoscopic fenestration. Medical management with somatostatin analogues is a potentially new and exciting treatment option but requires further study. PMID- 23355922 TI - Atrial embolism caused by portal vein embolization: Treatment by percutaneous withdrawal and stenting. AB - Hepatectomy remains the only curative treatment for many primary and secondary liver cancers. Portal vein embolization (PVE) has been used to increase the volume of the future liver remnant and thus lower the risk of small-for-size syndrome and postoperative liver failure. This technique has proven its safety, with a low post-procedure morbidity rate. Here, we describe a very rare case in which a young patient suffered a glue embolism to the right atrial cavity following PVE in preparation for a major hepatectomy for colorectal metastasis. The foreign body was withdrawn from the heart with a femoral, percutaneous device and trapped against the wall of the femoral vein with a self-expanding metal stent. Our report shows that this previously unknown complication of PVE can be resolved without recourse to sternotomy and open heart surgery. PMID- 23355923 TI - Liver metastasis of endometrial stromal sarcoma. AB - Resection of liver metastases from gynaecological tumours is uncommon. Endometrial stromal sarcomas (ESS) are low incidence gynecological tumours which can originate in previous sites of endometriosis or following metaplasia of the pelvic peritoneal wall, and which are exceptionally associated with liver metastasis. We present a 68-year-old woman with a ESS and metachronic liver metastasis treated by liver resection. There is very little literature on clinical management about liver metastasis from ESS, but extrapolating the data obtained with liver metastasis from sarcomas and uterine tumours, we should recommend resection as this is considered a resectable extrauterine metastasis. In cases with more sites of extrauterine disease, liver resection should also be performed if the other sites are resectable. PMID- 23355924 TI - Life-threatening hemorrhage after liver radiofrequency ablation successfully controlled by transarterial embolization. AB - A 59-year-old man underwent liver radiofrequency ablation under laparotomy for recurrent hepatic carcinoma located in the caudate lobe, however, near-fatal bleeding occurred 1 wk after the operation. The intra-operative ultrasound study during laparotomy revealed left hepatic artery pseudoaneurysm. Suture and packing with ribbon gauze was used to obtain hemostasis. A secondary hemorrhage followed 11 h later and hepatic angiography was performed immediately. Bleeding from the pseudoaneurysm in a branch of the left hepatic artery was found and the artery branch was embolized with coils. Other than slight bile leakage, post embolization continued satisfactorily. Bleeding did not reoccur. The follow up visit 1 mo later found the pseudoaneurysm disappearing and no tumor recurrence. PMID- 23355925 TI - Complexity of molecular alterations impacts pancreatic cancer prognosis. AB - Individualized cancer treatment (e.g. targeted therapy) based on molecular alterations has emerged as an important strategy to improve the current standard of-care chemotherapy. A large number of studies have demonstrated the importance of biomarkers not only in predicting prognosis but more importantly in predicting the response towards therapies. For example, amplification or mutation status of the two biomarkers HER2 (human epidermal growth factor 2) and BRCA (breast cancer) can be used to decide on a specific targeted therapy in breast cancer. However, no biomarkers with a similar clinical impact have been identified in pancreatic ductal adenocarcinoma. Although many genome-wide and proteome-based high-throughput studies have identified candidate genes or proteins as promising biomarkers, none of them were eventually transferred into the clinical setting. Notably, the most reliable markers for predicting prognosis are still the tumor stage and grade and biomarkers for therapy response remain undefined. One reason lies in the lack of systemic approaches to analyze the complexity of dominating cancer pathways and the impact of such signal complexity on prognosis and therapy response. PMID- 23355926 TI - Successive Standardization of Rectangular Arrays. AB - In this note we illustrate and develop further with mathematics and examples, the work on successive standardization (or normalization) that is studied earlier by the same authors in [1] and [2]. Thus, we deal with successive iterations applied to rectangular arrays of numbers, where to avoid technical difficulties an array has at least three rows and at least three columns. Without loss, an iteration begins with operations on columns: first subtract the mean of each column; then divide by its standard deviation. The iteration continues with the same two operations done successively for rows. These four operations applied in sequence completes one iteration. One then iterates again, and again, and again, ... In [1] it was argued that if arrays are made up of real numbers, then the set for which convergence of these successive iterations fails has Lebesgue measure 0. The limiting array has row and column means 0, row and column standard deviations 1. A basic result on convergence given in [1] is true, though the argument in [1] is faulty. The result is stated in the form of a theorem here, and the argument for the theorem is correct. Moreover, many graphics given in [1] suggest that except for a set of entries of any array with Lebesgue measure 0, convergence is very rapid, eventually exponentially fast in the number of iterations. Because we learned this set of rules from Bradley Efron, we call it "Efron's algorithm". More importantly, the rapidity of convergence is illustrated by numerical examples. PMID- 23355927 TI - The cost of implementing a nationwide program to decrease the epilepsy treatment gap in a high gap country. AB - Healthcare systems in many low income countries have evolved to provide services for acute, infections and are poorly structured for the provision of chronic, non communicable diseases which are increasingly common. Epilepsy is a common chronic neurologic condition and antiepileptic drugs are affordable, but the epilepsy treatment gap remains >90% in most African countries. The World Health Organization has recently released evidence-based guidelines for epilepsy care provision at the primary care level. Based upon these guidelines, we estimated all direct costs associated with epilepsy care provision as well as the cost of healthcare worker training and social marketing. We developed a model for epilepsy care delivery primarily by primary healthcare workers. We then used a variety of sources to develop cost estimates for the actual implementation and maintenance of this program being as comprehensive as possible to include all costs incurred within the health sector. Key sensitivity analyses were completed to better understand how changes in costs for individual aspects of care impact the overall cost of care delivery. Even after including the costs of healthcare worker retraining, social marketing and capital expenditures, epilepsy care can be provided at less than $25.00 per person with epilepsy per year. This is substantially less than for drugs alone for other common chronic conditions. Implementation of epilepsy care guidelines for patients receiving care at the primary care level is a cost effective approach to decreasing the epilepsy treatment gap in high gap, low income countries. PMID- 23355928 TI - Dengue: a new challenge for neurology. AB - Dengue infection is a leading cause of illness and death in tropical and subtropical regions of the world. Forty percent of the world's population currently lives in these areas. The clinical picture resulting from dengue infection can range from relatively minor to catastrophic hemorrhagic fever. Recently, reports have increased of neurological manifestations. Neuropathogenesis seems to be related to direct nervous system viral invasion, autoimmune reaction, metabolic and hemorrhagic disturbance. Neurological manifestations include encephalitis, encephalopathy, meningitis, Guillain-Barre syndrome, myelitis, acute disseminated encephalomyelitis, polyneuropathy, mononeuropathy, and cerebromeningeal hemorrhage. The development of neurological symptoms in patients with positive Immunoglobulin M (IgM) dengue serology suggests a means of diagnosing the neurological complications associated with dengue. Viral antigens, specific IgM antibodies, and the intrathecal synthesis of dengue antibodies have been successfully detected in cerebrospinal fluid. However, despite diagnostic advancements, the treatment of neurological dengue is problematic. The launch of a dengue vaccine is expected to be beneficial. PMID- 23355929 TI - Relationship between early and late stages of information processing: an event related potential study. AB - The brain is capable of elaborating and executing different stages of information processing. However, exactly how these stages are processed in the brain remains largely unknown. This study aimed to analyze the possible correlation between early and late stages of information processing by assessing the latency to, and amplitude of, early and late event-related potential (ERP) components, including P200, N200, premotor potential (PMP) and P300, in healthy participants in the context of a visual oddball paradigm. We found a moderate positive correlation among the latency of P200 (electrode O2), N200 (electrode O2), PMP (electrode C3), P300 (electrode PZ) and the reaction time (RT). In addition, moderate negative correlation between the amplitude of P200 and the latencies of N200 (electrode O2), PMP (electrode C3), P300 (electrode PZ) was found. Therefore, we propose that if the secondary processing of visual input (P200 latency) occurs faster, the following will also happen sooner: discrimination and classification process of this input (N200 latency), motor response processing (PMP latency), reorganization of attention and working memory update (P300 latency), and RT. N200, PMP, and P300 latencies are also anticipated when higher activation level of occipital areas involved in the secondary processing of visual input rise (P200 amplitude). PMID- 23355930 TI - Status epilepticus in the elderly: epidemiology, clinical aspects and treatment. AB - The aim of the study was to review the epidemiology, clinical profile and discuss the etiology, prognosis and treatment options in patients aged 60 years or older presenting with status epilepticus. We performed a systematic review involving studies published from 1996 to 2010, in Medline/PubMed, Scientific Electronic Library on line (Scielo), Latin-American and Caribbean Center of Health Sciences Information (Lilacs) databases and textbooks. Related articles published before 1996, when relevant for discussing epilepsy in older people, were also included. Several population studies had shown an increased incidence of status epilepticus after the age of 60 years. Status epilepticus is a medical and neurological emergency that is associated with high morbidity and mortality, and is a major concern in the elderly compared to the general population. Prompt diagnosis and effective treatment of convulsive status epilepticus are crucial to avoid brain injury and reduce the fatality rate in this age group. PMID- 23355931 TI - Intracranial metallic foreign bodies in a man with a headache. AB - We report the case of a 22-year old man with intracranial metallic foreign bodies who presented complaining of a headache. His history of headaches had begun when he was five years old and continued with increasing severity. Six months before hospital admission, nausea and vomiting began to accompany his headache. Computed tomography scan revealed that 2 metallic foreign bodies were located adjacent to the vertex and another was next to the ambient cistern. The location and position of foreign bodies suggested that they were introduced in infancy through the anterior fontanelle before its closure in an unsuccessful homicide attempt. This case is one of the few reported cases combining headache and intracranial foreign bodies and we discuss the relationship between headache and these metallic materials. PMID- 23355932 TI - A rare case of spinal dural arteriovenous fistula. AB - Spinal dural arteriovenous fistula (SDAVF) is a rare vascular malformation of the spine. Only a limited number of cases of SDAVF have been reported in the current literature. We describe the case of a 74 year old male who presented with gradually progressive bilateral lower extremity weakness and bladder dysfunction and was subsequently diagnosed with SDAVF affecting both the thoracic and lumbar spine. The patient later underwent embolization with some improvement in his neurologic symptoms. PMID- 23355933 TI - Successful colonoscopic approach in a child with intussusception associated with enterohemorrhagic Escherichia coli O157 infection. AB - The pathogenesis of intussusception caused by enterohemorrhagic Escherichia coli (E. coli) O157 infection is unknown. In our case, colonoscopy was useful for confirming O157 infection. The intussusception was caused by focally damaged edematous mucosa in the cecum. This case helped in elucidating the pathogenesis of the disease. PMID- 23355934 TI - Myasis occuring in a neonate. AB - Myasis is the infestation of skin by larvae or maggots of a variety of flies. It is a condition that occurs more commonly in adults who are living and/or have visited tropical countries. It rarely occurs in neonates, and even when seen, only few larvae are extracted. This case report describes myasis occurring in an 11-day-old female who had 47 larvae in her skin. PMID- 23355935 TI - Update on statural growth and pubertal development in obese children. AB - Childhood obesity is a growing and alarming problem, associated with several short-term and long-term metabolic and cardiovascular complications. In addition, it has also been suggested that excess adiposity during childhood influences growth and pubertal development. Several studies have shown that during pre pubertal years, obese patients present higher growth velocity and that this pre pubertal advantage tends to gradually decrease during puberty, leading to similar final heights between obese and non-obese children. Excess body weight might also influence pubertal onset, leading to earlier timing of puberty in girls. In addition, obese girls are at increased risk of hyperandrogenism and polycystic ovary syndrome. In boys, a clear evidence does not exist: some studies suggesting an earlier puberty associated with the obesity status, whereas other have found a delayed pubertal onset. Overall, the existing evidence of an association between obesity and modification of growth and pubertal patterns underlines a further reason for fighting the epidemics of childhood obesity. PMID- 23355936 TI - Robotic-assisted gastroplication in a morbidly obese adolescent: early improvement in metabolic and neurohormonal parameters. AB - Bariatric surgery has to be considered in the management of severely obese adolescents when all conservative measures have been proven to be unresponsive. Short term metabolic and neurohormonal profile changes after robotic-assisted gastroplication are evaluated. The benefits and the usefulness of this surgical - reversal procedure in adolescent need to be defined. Fiveteen years old girl with body mass index 42.2 kg/m(2), hyperinsulinism, hyperandrogenism, amenorrhea, polycystic ovarian syndrome, hypertension with left ventricular hypertrophy. Gastric volume after surgical procedure reduction was 80-100 mL. One month postoperatively significant weigh loss was obtained. Insulin levels, insulin resistance, leptin and ghrelin concentration were substantially ameliorated. We can conclude that bariatric surgery should be considered for a minority of severely obese adolescents under the supervision of a multidisciplinary pediatric team. Our experience confirmed that the gastroplication is safe, feasible and effective and furthermore is a reversible technique. The early improvement of the obesity co-morbities is allowed. The increased surgical accuracy in robotic assistance could limit postoperative complications rate in obese adolescents. PMID- 23355937 TI - Feasibility of a novel web-based physical activity questionnaire for young children. AB - Accurate assessment of children's physical activity is critical in determining associations between childhood physical activity and health later in life. We have developed a web-based questionnaire, KidActive-Q, to assess physical activity in early childhood. The feasibility and reproducibility of KidActive-Q were assessed in a sample of 20 children aged 2 to 6 years. The questionnaire was distributed to parents via e-mail on two occasions. The median time required to complete KidActive-Q was 2.5 minutes. All the parents reported that the questionnaire was easy or very easy to fill. The intraclass correlations for test retest reliability were 0.60 (95% confidence interval: 0.31-0.88) for daily time spent outdoors, and 0.85 (95% confidence interval: 0.72-0.97) for daily time watching television. Our results suggest that KidActive-Q is a user-friendly tool for assessing physical activity in early childhood. To our knowledge, this is the first web-based questionnaire specifically developed for young children. PMID- 23355938 TI - Deep vein thrombosis, ecythyma gangrenosum and heparin-induced thrombocytopenia occurring in a man with a heterozygous Factor V Leiden mutation. AB - Skin necrosis and limb gangrene are occasional thrombotic manifestations of anticoagulation therapy. We report a man heterozygous for the Factor V Leiden (FVL) mutation, and with a history of recurrent deep venous thrombosis, who initially presented with a necrotic skin lesion of the right flank while on warfarin therapy with a therapeutic international normalized ratio. Warfarin was discontinued and he received intravenous heparin. Thereafter he developed thrombocytopenia and pedal erythema and was diagnosed with heparin-induced thrombocytopenia (HIT). Heparin was replaced with argatroban. He ultimately underwent bilateral below-knee amputations for the thrombotic complications of the HIT. The initial necrotic lesion healed with antibiotics and wound care. Pathologic examination of multiple biopsy specimens revealed two separate lesions. One was necrotic tissue infiltrated with methicillin resistant Staphylococcus aureus having features of ecthyma gangrenosum. The second showed thrombotic changes consistent with HIT. The case illustrates the differential diagnosis of skin necrosis and limb gangrene in patients on warfarin and heparin, and also the clinical complexities that can occur in a FVL heterozygote. PMID- 23355939 TI - Bone turnover markers in patients with type 1 Gaucher disease. AB - Bone complications occur frequently in Gaucher disease (GD) and reduce the quality of life of these patients. Skeletal involvement is an important indication for treatment to ameliorate symptoms and reduce the risk of irreversible and debilitating disease. Bone biomarkers have been used to assess disease status and the response to therapy in a number of bone disorders. Here, we examine the literature for evidence of abnormalities in bone turnover markers in patients with type 1 GD to assess whether they might be useful for the assessment of bone involvement in GD. We have found that bone biomarkers in GD show highly variable results which do not currently support their routine use for clinical assessment of bone status, as an indication for therapy initiation, or for monitoring the response to therapy. A greater understanding of bone markers and their relation to the bone manifestations of GD is required. PMID- 23355940 TI - FLT3/ITD associated with an immature immunophenotype in PML-RARalpha leukemia. AB - Acute promyelocytic leukemia (APL) is characterized by the specific PML-RARalpha fusion gene resulting from translocation t(15;17) (q22;q12). Internal tandem duplication (ITD) of the FLT3 gene has been observed in approximately 35% of APLs, and large-scale studies have identified the presence of ITD as an adverse prognostic factor for acute myeloblastic leukemia (AML) patients. Aberrant expressions of surface antigens, such as CD2, CD34, and CD56, have been found in APL, but the implications of this are not well understood. We investigated the incidence of the FLT3/ITD mutation and FLT3/D835 (I836) point mutation in 25 APL patients. Incidence ratios of FLT3/ITD, D835 (I836), and both FLT3/ITD and D835 (I836) were 36%, 36% and 8%, respectively. FLT3/ITD(+) cases showed a predominance of the bcr3 isoform (P=0.008) and M3v morphology (P<0.001). We found that all FLT3/ITD(+) cases expressed CD2 (9 of 9) more frequently than that of FLT3/ITD(-) (1 of 16) (P<0.001), while only one of the CD2(+) cases (1 of 10, 10%) did not harbor FLT3/ITD, and all CD2(+)CD34(+) cases (5 of 5, 100%) harbored FLT3/ITD. In addition, quantitative polymerase chain reaction analysis showed that FLT3 mRNA was more abundantly expressed in FLT3/ITD(+) than that in FLT3/ITD(-) (P=0.025), while there was no difference between D835(I836) (+) and D835(I836)(-) with regards to aberrant surface-antigen expression, expression levels of FLT3 mRNA, M3v morphology, and the bcr3 isoform of PML-RARalpha mRNA. This study demonstrates that the presence of FLT3/ITD, but not D835 (I836), is closely related to aberrant CD2 expression and high expression levels of FLT3 mRNA. Our findings also suggest that FLT3/ITD as a secondary genetic event may block differentiation at the immature stage of APL. PMID- 23355941 TI - Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patients. AB - Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is mediated by different mechanisms that can be classified as BCR ABL dependent or BCR-ABL independent pathways. BCR-ABL dependent mechanisms are most frequently associated with point mutations in tyrosine kinase domain (TKD) of BCR-ABL1 and also with BCR-ABL gene amplification. Many different types and frequencies of mutations have been reported in different studies, probably due to the different composition of study cohorts. Since no reports are available from Malaysia, this study was undertaken to investigate the frequency and pattern of BCR-ABL kinase domain mutations using dHPLC followed by sequencing, and also status of BCR-ABL gene amplification using fluorescence in situ hybridization (FISH) on 40 IM resistant Malaysian CML patients. Mutations were detected in 13 patients (32.5%). Five different types of mutations (T315I, E255K, Y253H, M351T, V289F) were identified in these patients. In the remaining 27 IM resistant CML patients, we investigated the contribution made by BCR-ABL gene amplification, but none of these patients showed amplification. It is presumed that the mechanisms of resistance in these 27 patients might be due to BCR-ABL independent pathways. Different mutations confer different levels of resistance and, therefore, detection and characterization of TKD mutations is highly important in order to guide therapy in CML patients. PMID- 23355942 TI - Effects of iron supplementation on red blood cell hemoglobin content in pregnancy. AB - Although a mild degree of anemia is common in the third trimester of pregnancy, it remains a challenge to establish whether a decrease in hemoglobin (Hb) concentration is physiological or pathological. The World Health Organization suggested a Hb concentration of 110 g/L to discriminate anemia. Several European investigators recommended Hb cut-off values of between 101-110 g/L. The aim of this study was to establish short-term effects of iron supplementation on the hemoglobin content of reticulocytes (Ret-He) and red blood cells (RBC-He) in case of suspected iron deficient erythropoiesis (IDE) in the third trimester of pregnancy. Twenty-five subjects with suspected IDE during pregnancy (Hb <=110g/L, Ret-He <29.6 pg, zinc protoporphyrin >75 mol/mol hem) participated in the study. After iron supplementation, reticulocyte counts increased from 0.061+/ 0.015*10(12)/L to 0.079+/-0.026*10(12)/L and Ret-He increased from 23.6+/-2.8 pg to 28.3+/-2.6 pg (P=<0.001). RBC-He increased from 26.9+/-1.9 pg to 27.4+/-1.8 pg (not significant, NS) and Ret-He/RBC-He ratio increased from 0.97+/-0.06 towards 1.07+/-0.05 (P=<0.001). Hb concentrations demonstrated an obvious increase from 105+/-6 g/L towards 115+/-5 g/L (P<=0.001) after supplementation. An obvious increase in RBC distribution width was observed from 45.0+/-3.6 fL towards 52.3+/ 7.0 fL (P<=0.001). We recommend that Ret-He and Ret-He/RBC-He ratio be integrated into the protocols for anemia screening and for monitoring effects of iron supplementation during pregnancy. In particular, the parameters should be considered in subjects with Hb results in the controversial range of 101-108 g/L. PMID- 23355943 TI - Allogeneic stem cell transplantation in acute myeloid leukemia. AB - We report a case series of 12 patients with acute myeloid leukemia who underwent allogeneic stem cell transplant with a matched related donor. Male to female ratio was 1:1. The main complication post-transplant was graft-versus-host disease (n=7 patients). Transplant-related mortality involved one patient; cause of death was multi-organ failure. After a median follow up of 36.0+/-11.3 months, overall survival was 16%. PMID- 23355944 TI - Successful autologous stem cell collection with filgrastim and plerixafor after long-term lenalidomide therapy for multiple myeloma. AB - Novel agents such as lenalidomide have demonstrated responses similar to high dose melphalan and autologous stem cell transplant in multiple myeloma. For patients who are started on lenalidomide, it is advisable to collect stem cells early if future transplant is contemplated. We are reporting a patient who underwent successful stem cell mobilization after 68 cycles of lenalidomide. A 60 year old male presented with back pain. He was diagnosed with stage IIA, IgA multiple myeloma. He was enrolled in a clinical trial and was randomized to receive lenalidomide plus dexamethasone. He received a total of 68 cycles of lenalidomide before progressing. He underwent mobilization of stem cells using filgrastim and plerixafor. He underwent successful stem cell transplant. Longer duration of lenalidomide adversely effects stem cell mobilization. To the best of our knowledge, there has been no other case reported in which stem cell mobilization was feasible after such a long (68 months) duration of uninterrupted lenalidomide therapy. PMID- 23355945 TI - A novel t(2;10)(q31;p12) balanced translocation in acute myeloid leukemia. AB - We describe a case of acute myeloid leukemia M5 showing a balanced t(2;10) (q31;p12) translocation. This has never been described before as the sole cytogenetic abnormality in a bone marrow cell clone at onset. Using fluorescence in situ hybridization with properly designed bacterial artificial chromosome probes, we mapped the breakpoint regions on both derivative chromosomes 2 and 10: der(2) and der(10), respectively. The MPP7 gene, disrupted by the breakpoint on chromosome 10, was juxtaposed upstream of both HNRNA3 and NFE2L2 genes on chromosome 2, without the formation of any fusion gene. Using real-time quantitative polymerase chain reaction, we tested the possible disregulation of any of the breakpoint-associated genes as a consequence of the translocation, but we found no statistically significant alteration. Considering the potential role of this clonal cytogenetic abnormality in leukemogenesis, we speculate that this translocation could have an impact on additional genes mapping outside the breakpoint regions. However, the limited amount of RNA material available prevented us from testing this hypothesis in this present case. PMID- 23355947 TI - Valley polarized quantum Hall effect and topological insulator phase transitions in silicene. AB - The electronic properties of silicene are distinct from both the conventional two dimensional electron gas and the famous graphene due to strong spin orbit interaction and the buckled structure. Silicene has the potential to overcome limitations encountered for graphene, in particular the zero band gap and weak spin orbit interaction. We demonstrate a valley polarized quantum Hall effect and topological insulator phase transitions. We use the Kubo formalism to discuss the Hall conductivity and address the longitudinal conductivity for elastic impurity scattering in the first Born approximation. We show that the combination of an electric field with intrinsic spin orbit interaction leads to quantum phase transitions at the charge neutrality point, providing a tool to experimentally tune the topological state. Silicene constitutes a model system for exploring the spin and valley physics not accessible in graphene due to the small spin orbit interaction. PMID- 23355946 TI - Form Follows Function: Advances in Trilayered Structure Replication for Aortic Heart Valve Tissue Engineering. AB - Tissue engineering the aortic heart valve is a challenging endeavor because of the particular hemodynamic and biologic conditions present in the native aortic heart valve. The backbone of an ideal valve substitute should be a scaffold that is strong enough to withstand billions of repetitive bending, flexing and stretching cycles, while also being slowly degradable to allow for remodeling. In this review we highlight three overlooked aspects that might influence the long term durability of tissue engineered valves: replication of the native valve trilayered histoarchitecture, duplication of the three-dimensional shape of the valve and cell integration efforts focused on getting the right number and type of cells to the right place within the valve structure and driving them towards homeostatic maintenance of the valve matrix. We propose that the trilayered structure in the native aortic valve that includes a middle spongiosa layer cushioning the motions of the two external fibrous layers should be our template for creation of novel scaffolds with improved mechanical durability. Furthermore, since cells adapt to micro-loads within the valve structure, we believe that interstitial cell remodeling of the valvular matrix will depend on the accurate replication of the structures and loads, resulting in successful regeneration of the valve tissue and extended durability. PMID- 23355948 TI - Circumnutation on the water surface: female flowers of Vallisneria. AB - Circumnutation, the helical movement of growing organ tips, is ubiquitous in land plants. The mechanisms underlying circumnutation have been debated since Darwin's time. Experiments in space and mutant analyses have revealed that internal oscillatory (tropism-independent) movement and gravitropic response are involved in circumnutation. Female flower buds of tape grass (Vallisneria asiatica var. biwaensis) circumnutate on the water surface. Our observations and experiments with an artificial model indicated that gravitropism is barely involved in circumnutation. Instead, we show that helical intercalary growth at the base of peduncle plays the primary role in all movements in Vallisneria. This growth pattern produces torsional bud rotation, and gravity and buoyancy forces have a physical effect on the direction of peduncle elongation, resulting in bud circumnutation on the water surface. In contrast to other water-pollinated hydrophilous plants, circumnutation in Vallisneria enables female flowers to actively collect male flowers from a larger surface area of water. PMID- 23355949 TI - Interlayer catalytic exfoliation realizing scalable production of large-size pristine few-layer graphene. AB - Mass production of reduced graphene oxide and graphene nanoplatelets has recently been achieved. However, a great challenge still remains in realizing large quantity and high-quality production of large-size thin few-layer graphene (FLG). Here, we create a novel route to solve the issue by employing one-time-only interlayer catalytic exfoliation (ICE) of salt-intercalated graphite. The typical FLG with a large lateral size of tens of microns and a thickness less than 2 nm have been obtained by a mild and durative ICE. The high-quality graphene layers preserve intact basal crystal planes owing to avoidance of the degradation reaction during both intercalation and ICE. Furthermore, we reveal that the high quality FLG ensures a remarkable lithium-storage stability (>1,000 cycles) and a large reversible specific capacity (>600 mAh g(-1)). This simple and scalable technique acquiring high-quality FLG offers considerable potential for future realistic applications. PMID- 23355950 TI - Efficient production of adenovirus vector lacking genes of virus-associated RNAs that disturb cellular RNAi machinery. AB - First-generation adenovirus vectors (FG AdVs) are widely used in basic studies and gene therapy. However, virus-associated (VA) RNAs that act as small interference RNAs are indeed transcribed from the vector genome. These VA RNAs can trigger the innate immune response. Moreover, VA RNAs are processed to functional viral miRNAs and disturb the expressions of numerous cellular genes. Therefore, VA-deleted AdVs lacking VA RNA genes would be advantageous for basic studies, both in vitro and in vivo. Here, we describe an efficient method of producing VA-deleted AdVs. First, a VA RNA-substituted "pre-vector" lacking the original VA RNA genes but alternatively possessing an intact VA RNA region flanked by a pair of FRTs was constructed. VA-deleted AdVs were efficiently obtained by infecting 293hde12 cells, which highly express FLP, with the pre vector. The resulting transduction titers of VA-deleted AdVs were sufficient for practical use. Therefore, VA-deleted AdVs may be substitute for current FG AdV. PMID- 23355951 TI - Linking mantle upwelling with the lithosphere descent [corrected] and the Japan Sea evolution: a hypothesis. AB - Recent seismic tomography studies image a low velocity zone (interpreted as a high temperature anomaly) in the mantle beneath the subducting Pacific plate near the Japanese islands at the depth of about 400 km. This thermal feature is rather peculiar in terms of the conventional view of mantle convection and subduction zones. Here we present a dynamic restoration of the thermal state of the mantle beneath this region assimilating geophysical, geodetic, and geological data up to 40 million years. We hypothesise that the hot mantle upwelling beneath the Pacific plate partly penetrated through the subducting plate into the mantle wedge and generated two smaller hot upwellings, which contributed to the rapid subsidence in the basins of the Japan Sea and to back-arc spreading. Another part of the hot mantle migrated upward beneath the Pacific lithosphere, and the presently observed hot anomaly is a remnant part of this mantle upwelling. PMID- 23355953 TI - The natural ocean acidification and fertilization event caused by the submarine eruption of El Hierro. AB - The shallow submarine eruption which took place in October 10(th) 2011, 1.8 km south of the island of El Hierro (Canary Islands) allowed the study of the abrupt changes in the physical-chemical properties of seawater caused by volcanic discharges. In order to monitor the evolution of these changes, seven oceanographic surveys were carried out over six months (November 2011-April 2012) from the beginning of the eruptive stage to the post-eruptive phase. Here, we present dramatic changes in the water column chemistry including large decreases in pH, striking effects on the carbonate system, decreases in the oxygen concentrations and enrichment of Fe(II) and nutrients. Our findings highlight that the same volcano which was responsible for the creation of a highly corrosive environment, affecting marine biota, has also provided the nutrients required for the rapid recuperation of the marine ecosystem. PMID- 23355952 TI - A custom magnetoencephalography device reveals brain connectivity and high reading/decoding ability in children with autism. AB - A subset of individuals with autism spectrum disorder (ASD) performs more proficiently on certain visual tasks than may be predicted by their general cognitive performances. However, in younger children with ASD (aged 5 to 7), preserved ability in these tasks and the neurophysiological correlates of their ability are not well documented. In the present study, we used a custom child sized magnetoencephalography system and demonstrated that preserved ability in the visual reasoning task was associated with rightward lateralisation of the neurophysiological connectivity between the parietal and temporal regions in children with ASD. In addition, we demonstrated that higher reading/decoding ability was also associated with the same lateralisation in children with ASD. These neurophysiological correlates of visual tasks are considerably different from those that are observed in typically developing children. These findings indicate that children with ASD have inherently different neural pathways that contribute to their relatively preserved ability in visual tasks. PMID- 23355955 TI - Accelerating Pathology Image Data Cross-Comparison on CPU-GPU Hybrid Systems. AB - As an important application of spatial databases in pathology imaging analysis, cross-comparing the spatial boundaries of a huge amount of segmented micro anatomic objects demands extremely data- and compute-intensive operations, requiring high throughput at an affordable cost. However, the performance of spatial database systems has not been satisfactory since their implementations of spatial operations cannot fully utilize the power of modern parallel hardware. In this paper, we provide a customized software solution that exploits GPUs and multi-core CPUs to accelerate spatial cross-comparison in a cost-effective way. Our solution consists of an efficient GPU algorithm and a pipelined system framework with task migration support. Extensive experiments with real-world data sets demonstrate the effectiveness of our solution, which improves the performance of spatial cross-comparison by over 18 times compared with a parallelized spatial database approach. PMID- 23355954 TI - Unveiling LOX-1 receptor interplay with nanotopography: mechanotransduction and atherosclerosis onset. AB - Lectin-like ox-LDL receptors (LOX-1) play a crucial role in the ox-LDL-induced pathological transformation of vessel-wall components, a crucial early step in atherogenesis. LOX-1 dynamics is quantitatively investigated in human endothelial cells (HUVECs) exposed to environmental nanotopographies. We demonstrate distinct nanotopography-induced cell phenotypes, characterized by different morphology, LOX-1 diffusivity and oligomerization state: HUVECs on flat surfaces exhibit the behavior found in pro-atherogenic conditions, while growth on nanogratings can interfere with LOX-1 dynamics and lead to a behavior characteristic of normal, non-pathological conditions. PMID- 23355956 TI - Increased survivin expression contributes to apoptosis-resistance in IPF fibroblasts. AB - Fibroblasts perform critical functions during the normal host response to tissue injury, but the inappropriate accumulation and persistent activation of these cells results in the development of tissue fibrosis. The mechanisms accounting for the aberrant accumulation of fibroblasts during fibrotic repair are poorly understood, although evidence supports a role for fibroblast resistance to apoptosis as a contributing factor. We have shown that TGF-beta1 and endothelin-1 (ET-1), soluble mediators implicated in fibrogenesis, promote fibroblast resistance to apoptosis. Moreover, we recently found that ET-1 induced apoptosis resistance in normal lung fibroblasts through the upregulation of survivin, a member of the Inhibitor of Apoptosis (IAP) protein family. In the current study, we sought to determine the role of survivin in the apoptosis resistance of primary fibroblasts isolated from the lungs of patients with Idiopathic Pulmonary Fibrosis (IPF), a fibrotic lung disease of unclear etiology for which there is no definitive therapy. First, we examined survivin expression in lung tissue from patients with IPF and found that there is robust expression in the fibroblasts residing within fibroblastic foci (the "active" lesions in IPF which correlate with mortality). Next, we show that survivin expression is increased in fibroblasts isolated from IPF lung tissue compared to cells from normal lung tissue. Consistent with a role in fibrogenesis, we demonstrate that TGF-beta1 increases survivin expression in normal lung fibroblasts. Finally, we show that inhibition of survivin enhances susceptibility of a subset of IPF fibroblasts to apoptosis. Collectively, these findings suggest that increased survivin expression represents one mechanism contributing an apoptosis-resistant phenotype in IPF fibroblasts. PMID- 23355957 TI - MicroRNA Profiling Reveals Distinct Mechanisms Governing Cardiac and Neural Lineage-Specification of Pluripotent Human Embryonic Stem Cells. AB - Realizing the potential of human embryonic stem cells (hESCs) has been hindered by the inefficiency and instability of generating desired cell types from pluripotent cells through multi-lineage differentiation. We recently reported that pluripotent hESCs maintained under a defined platform can be uniformly converted into a cardiac or neural lineage by small molecule induction, which enables lineage-specific differentiation direct from the pluripotent state of hESCs and opens the door to investigate human embryonic development using in vitro cellular model systems. To identify mechanisms of small molecule induced lineage-specification of pluripotent hESCs, in this study, we compared the expression and intracellular distribution patterns of a set of cardinal chromatin modifiers in pluripotent hESCs, nicotinamide (NAM)-induced cardiomesodermal cells, and retinoic acid (RA)-induced neuroectodermal cells. Further, genome scale profiling of microRNA (miRNA) differential expression patterns was used to monitor the regulatory networks of the entire genome and identify the development initiating miRNAs in hESC cardiac and neural lineage-specification. We found that NAM induced nuclear translocation of NAD-dependent histone deacetylase SIRT1 and global chromatin silencing, while RA induced silencing of pluripotence-associated hsa-miR-302 family and drastic up-regulation of neuroectodermal Hox miRNA hsa-miR 10 family to high levels. Genome-scale miRNA profiling indentified that a unique set of pluripotence-associated miRNAs was down-regulated, while novel sets of distinct cardiac- and neural-driving miRNAs were up-regulated upon the induction of lineage-specification direct from the pluripotent state of hESCs. These findings suggest that a predominant epigenetic mechanism via SIRT1-mediated global chromatin silencing governs NAM-induced hESC cardiac fate determination, while a predominant genetic mechanism via silencing of pluripotence-associated hsa-miR-302 family and drastic up-regulation of neuroectodermal Hox miRNA hsa-miR 10 family governs RA-induced hESC neural fate determination. This study provides critical insight into the earliest events in human embryogenesis as well as offers means for small molecule-mediated direct control and modulation of hESC pluripotent fate when deriving clinically-relevant lineages for regenerative therapies. PMID- 23355958 TI - Functionally Diverse Nylon-3 Copolymers from Readily Accessible beta-Lactams. AB - A new family of beta-lactams is described that enables anionic ring-opening polymerization (AROP) to prepare nylon-3 materials bearing diverse appended functionality, including carboxylic acid, thiol, hydroxyl and secondary amine groups. Nylon-3 copolymers generated with the new beta-lactams are shown to display distinctive self-assembly behavior and biological properties. PMID- 23355959 TI - Positively Charged Dendron Micelles Display Negligible Cellular Interactions. AB - PEGylated dendron-based copolymers (PDC) with different end-group functionalities (-NH(2), -COOH, and -Ac) were synthesized and self-assembled into dendron micelles to investigate the effect of terminal surface charges on size, morphology, and cellular interactions of the micelles. All of the dendron micelles exhibited similar sizes (20-60 nm) and spherical morphologies, as measured using dynamic light scattering and transmission electron microscopy, respectively. The cellular interactions of dendron micelles were evaluated using confocal microscopy and flow cytometry. Surprisingly, although amine-terminated dendrimers are known to strongly interact with cells non-specifically, all of the surface-modified dendron micelles exhibited charge-independent low-levels of cellular interaction. The unexpected results, particularly from the amine terminated dendron micelles, could be attributed to: i) minimal end-group effects, as each PDC has an approximately 10-fold lower charge-number-to molecular-weight ratio compared to the dendrimer; and ii) intra- and intermolecular hydrogen bonding between positively charged terminal groups with poly(ethylene glycol) (PEG) backbones, which leads to the sequestration of the charges, as demonstrated by atomistic molecular dynamics simulations. With the narrow size distribution, uniform morphologies, and low levels of non-specific cellular interactions, the dendron micelles offer a promising drug delivery platform. PMID- 23355961 TI - Patents on Technologies of Human Tissue and Organ Regeneration from Pluripotent Human Embryonic Stem Cells. AB - Human embryonic stem cells (hESCs) are genetically stable with unlimited expansion ability and unrestricted plasticity, proffering a pluripotent reservoir for in vitro derivation of a large supply of disease-targeted human somatic cells that are restricted to the lineage in need of repair. There is a large healthcare need to develop hESC-based therapeutic solutions to provide optimal regeneration and reconstruction treatment options for the damaged or lost tissue or organ that have been lacking. In spite of controversy surrounding the ownership of hESCs, the number of patent applications related to hESCs is growing rapidly. This review gives an overview of different patent applications on technologies of derivation, maintenance, differentiation, and manipulation of hESCs for therapies. Many of the published patent applications have been based on previously established methods in the animal systems and multi-lineage inclination of pluripotent cells through spontaneous germ-layer differentiation. Innovative human stem cell technologies that are safe and effective for human tissue and organ regeneration in the clinical setting remain to be developed. Our overall view on the current patent situation of hESC technologies suggests a trend towards hESC patent filings on novel therapeutic strategies of direct control and modulation of hESC pluripotent fate, particularly in a 3-dimensional context, when deriving clinically-relevant lineages for regenerative therapies. PMID- 23355962 TI - Development of merosporangia in Linderina pennispora (Kickxellales, Kickxellaceae). AB - The vegetative and sporulating structures of Linderina pennispora are described using scanning and transmission electron microscopy. The vegetative hyphae and sporangiophores were regularly septate, possessed a two-layered wall, and coated with rod-shaped, 0.2-0.7 MUm long, 0.15-0.25 MUm wide ornamentations. The sporangiophore was erect, cylindrical, and narrower (4-8 MUm) than the vegetative mycelium (8-12 MUm). The mature sporocladium was ovoid to dome-shaped, sessile, non-septate, 18-24 MUm diam, possessed a two-layered wall, and coated with rod shaped ornamentations. Mature pseudophialides were ellipsoid, 2.0-2.5 MUm wide, 4 7 MUm long, possessed a two-layered wall, and formed in a series of concentric groups radiating from the "apex" of the sporocladium. The pseudophialides had a round, ca. 1.5 MUm diam, base with a narrower, 0.7-0.8 MUm diam lobed, cylindrical neck structure in the distal region which extended to the pseudophialide neck. The merosporangia were obovate, 3-4 MUm wide near the base, and narrowed distally to 2.0-2.5 MUm wide, 18-23 MUm long, possessed a three layered wall, with regular surface annulation with interconnecting ridges, but lacked rod-shaped ornamentations. The merosporangia contained a single, obovate, 2.3-2.5 MUm diam merosporangiospore, with a ca. 1 MUm diam papilla-like base, that possessed a four-layered wall. Detached merosporangia had a single, acicular, unbranched, 3-5 MUm long, ca. 0.1 MUm diam "appendage" that was attached to the merosporangiospore inner cell wall layer and passed through the septum plug to the pseudophialide. PMID- 23355963 TI - Homortomyces gen. nov., a new dothidealean pycnidial fungus from the Cradle of Humankind. AB - Homortomyces is introduced as a new coelomycetous genus associated with leaf spots onCombretum erythrophyllum trees growing near and around the Sterkfontein caves, Maropeng, South Africa. Based on its transversely septate, brown conidia, the presence of paraphyses, and percurrent proliferation of the conidiogenous cells, the genus resembles Stilbospora (Melanoconidaceae, Diaporthales). It is distinct in having pycnidial condiomata, conidia lacking mucoid sheaths, and becoming muriform when mature. Its morphology and phylogenetic placement based on analyses of sequence data for the large subunit nuclear ribosomal RNA gene (LSU, 28S) as well as the ITS and 5.8S rRNA gene of the nrDNA operon, show that Homortomyces represents a novel genus in Dothideomycetes, although its familial relationships remain unresolved. PMID- 23355964 TI - A new Leucoagaricus species of section Piloselli (Agaricales, Agaricaceae) from Spain. AB - The new species Leucoagaricus variicolor is described from a public park in Zaragoza, Spain, based on both morphological and molecular characters. Illustrations of fresh basidiomata in situ and of the main macro- and micromorphological features are added. Leucoagaricusvariicolor belongs to section Piloselli and is compared with similar taxa. PMID- 23355965 TI - Ascus apical apparatus and ascospore characters in Xylariaceae. AB - Members of Xylariaceae (Ascomycota) are recognized and classified mainly on the morphological features of their sexual state. In a number of genera high morphological variation of stromatal characters has made confident recognition of generic and specific boundaries difficult. There are, however, a range of microscopical characteristics which can in most cases make distinctions, especially at generic level, even in the absence of molecular data. These include details of the apical apparatus in the ascus (e.g. disc-shaped, inverted hat shaped, rhomboid, composed of rings, amyloid, non-amyloid); position and length of the germ slit; and presence and type of ascospore wall ornamentation as seen by scanning electron microscopy (SEM). Unfortunately many of the classical studies on xylariaceous genera omitted these features and were undertaken long before the development of scanning electron microscopy. More recent studies have, however, demonstrated their value as diagnostic characters in the family. Camillea is for example, instantly recognizable by its rhomboid or diamond shaped apical apparatus, and the distinctive inverted hat or urniform type is usually prominent in Xylaria, Rosellinia, Kretzschmaria, and Nemania. At least six categories of apical apparatus based on shape and size can be recognized. Ascospore ornamentation as seen by SEM has been exceptionally useful and provided the basis for separating Camillea from Biscogniauxia and other xylariaceous genera. PMID- 23355966 TI - A new species of the lenticel fungal genus Claviradulomyces (Ostropales) from the Brazilian Atlantic forest tree Xylopia sericea (Annonaceae). AB - Claviradulomyces xylopiae sp. nov. is introduced for a fungus occurring in association with abnormal (enlarged, spongy) lenticels of Xylopia sericea (Annonaceae), a common tree of the Atlantic forest and Cerrado ecosystems in Brazil. This is the second species described in the genus and, although it is morphologically distinct from the type species, C. dabeicola from West Africa, it possesses the same characteristics. Apothecial ascomata have periphysoids and paraphyses that are inflated apically (clavate), and ornamented with denticles (raduliform). Furthermore, similar to the type species, it also has long cylindric or acerose, aseptate ascospores and conidia. An additional asexual morph was produced in culture and is described. Molecular studies of C. dabeicola and the new species confirmed a placement in Ostropales, although a relationship to Odontotremataceae was not supported. Both species were consistently in association with abnormal lenticular development on their woody hosts. It remains to be ascertained, however, if these are the causal agents of the bark disorders, or, simply, opportunistic colonisers. The finding of the second species in the genus Claviradulomyces on a plant from a distantly related family to that of the host of C. dabeicola (Erythroxylaceae) for the genus on a different continent suggests that fungi in this genus may be common on lenticels of other woody plants, and could even have a pantropical distribution. It is possible that fungi in the genus have remained unreported until now because lenticels have remained neglected as a habitat surveyed by mycologists. PMID- 23355967 TI - Shivasia gen. nov. for the Australasian smut Ustilago solida that historically shifted through five different genera. AB - The generic position of the enigmatic smut fungus Ustilago solida is evaluated applying molecular phylogenetic analyses using ITS and LSU rDNA sequences as well as light and scanning electron microscopical investigations of several collections of this species. Ustilago solida has previously been included in five different genera (Ustilago, Urocystis, Sorosporium, Cintractia, and Tolyposporium), however, molecular analyses revealed that this smut does not belong to any of these genera and represents a distinct ustilaginalean lineage. The closest known phylogenetic relative of Ustilago solida is Heterotolyposporium lepidospermatis, the type species of the monotypic genus Heterotolyposporium. Both smuts differ considerably in both LSU sequences and in several morphological traits, such as the structure of sori and the characteristics of spore balls. Accordingly, the new genus Shivasia is described to accommodate Ustilago solida. This smut infects different Schoenus species (Cyperaceae) in Australia and New Zealand. The description of Shivasia increases the number of endemic smut genera in Australasia to ten. Compared to all other continents the number of endemic smut genera is exceptionally high, which may point at fast evolving characters and/or may be caused by the regional history, including the long-term geographic isolation of Australasia. PMID- 23355968 TI - Addressing the conundrum of unavailable name-bearing types. AB - Access to name-bearing type material can be a particular frustration for those mycologists in the tropics, or working outside established institutions, where the specimens are known to exist but cannot be examined. They can be inaccessible because of loans policies and the inability of mycologists to make personal visits. Each case has to be considered separately, but a pragmatic nine-point approach is presented which may provide some guidance as to what can be done in such instances. A postscript draws attention to 12 points to consider when designated or handling name-bearing types. PMID- 23355970 TI - Clarifications needed concerning the new Article 59 dealing with pleomorphic fungi. AB - The new rules formulated in Article 59 of the International Code of Nomenclature for algae, fungi, and plants (ICN) will cause numerous, often undesirable, name changes, when only phylogenetically defined clades are named. Our task is to name fungal taxa and not just clades. Two suggestions are made here that may help to alleviate some disadvantages of the new system. (1) Officially an epithet coined in a list-demoted genus that is older than the oldest one available in the list accepted genus would have to be recombined in the accepted genus. We recommend that individual authors and committees establishing lists of protected names should generally not recombine older epithets from a demoted genus into the accepted genus, when another one from pre-2013 is available in that genus. (2) Because the concepts of correlated teleomorph and anamorph genera are often incongruent, enforced congruence leads to a loss of information. Retaining the most suitable generic name is imperative, even when this is subordinated to another, list-accepted, generic name. Some kind of cryptic dual generic nomenclature is bound to persist. We therefore strongly recommend the retention of binomials in genera where they are most informative. With these recommendations, the upheaval of fungal nomenclature ensuing from the loss of the former Art. 59 can be reduced to an unavoidable minimum. PMID- 23355969 TI - Two novel species of Aspergillus section Nigri from indoor air. AB - Aspergillus floridensis and A. trinidadensis spp. nov. are described as novel uniseriate species of Aspergillus section Nigri isolated from air samples. To describe the species we used phenotypes from 7-d Czapek yeast extract agar culture (CYA), creatine agar culture (CREA) and malt extract agar culture (MEA), with support by molecular analysis of the beta-tubulin, calmodulin, RNA polymerase II (RPB2), and translation elongation factor-alpha (TEF) gene amplified and sequenced from 56 air isolates and one isolate from almonds belonging to Aspergillus sectionNigri.Aspergillus floridensis is closely related to A. aculeatus, and A. trinidadensis is closely related to A. aculeatinus. Aspergillus brunneoviolaceus (syn. A. fijiensis) and A. uvarum are reported for the first time from the USA and from the indoor air environment. The newly described species do not produce ochratoxin A. PMID- 23355960 TI - Advances in biomimetic regeneration of elastic matrix structures. AB - Elastin is a vital component of the extracellular matrix, providing soft connective tissues with the property of elastic recoil following deformation and regulating the cellular response via biomechanical transduction to maintain tissue homeostasis. The limited ability of most adult cells to synthesize elastin precursors and assemble them into mature crosslinked structures has hindered the development of functional tissue-engineered constructs that exhibit the structure and biomechanics of normal native elastic tissues in the body. In diseased tissues, the chronic overexpression of proteolytic enzymes can cause significant matrix degradation, to further limit the accumulation and quality (e.g., fiber formation) of newly deposited elastic matrix. This review provides an overview of the role and importance of elastin and elastic matrix in soft tissues, the challenges to elastic matrix generation in vitro and to regenerative elastic matrix repair in vivo, current biomolecular strategies to enhance elastin deposition and matrix assembly, and the need to concurrently inhibit proteolytic matrix disruption for improving the quantity and quality of elastogenesis. The review further presents biomaterial-based options using scaffolds and nanocarriers for spatio-temporal control over the presentation and release of these biomolecules, to enable biomimetic assembly of clinically relevant native elastic matrix-like superstructures. Finally, this review provides an overview of recent advances and prospects for the application of these strategies to regenerating tissue-type specific elastic matrix structures and superstructures. PMID- 23355971 TI - The treasure trove of yeast genera and species described by Johannes van der Walt (1925-2011). AB - Yeast taxonomy and systematics have in recent years been dealt with intensively primarily by a small group of individual researchers with particular expertise. Amongst these was Johannes P. van der Walt, who had a major role in shaping our current understanding of yeast biodiversity and taxonomy. Van der Walt based his taxonomic studies not only on available cultures, but also by going into the field to isolate yeasts from various substrates. This pioneering work led to the discovery of many new genera and species, which were deposited in the Centraalbureau voor Schimmelcultures (CBS) collections for future studies in taxonomy, genomics, and industrial uses. These treasures collected during more than 60 years provide an outstanding legacy to the yeast community and will continue to exist in his absence. This contribution provides a comprehensive overview of the current nomenclatural and taxonomic status of the yeast genera and species introduced by van der Walt during his career. PMID- 23355972 TI - Westerdykella reniformis sp. nov., producing the antibiotic metabolites melinacidin IV and chetracin B. AB - Westerdykella reniformis Ebead & Overy sp. nov. is described based on morphology and phylogenetic analyses using ITS, nLSU rDNA, and beta-tubulin gene sequences. Westerdykella reniformis is characterized by the production of cleistothecioid ascomata, containing small globose to subglobose asci with 32, aseptate, dark colored, pronouncedly reniform ascospores having a concave central groove. The isolate was obtained from a red alga (Polysiphonia sp.) collected from the tidal zone in Canada at low tide. Organic extracts enriched in extrolites, obtained from fermentation on a rice-based media, inhibited the growth of methicillin resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), S. warneri, and Proteus vulgaris. Presented here is the identification of the compounds responsible for the observed antimicrobial activity, the taxonomic description of W. reniformis, and a dichotomous key to the known species of Westerdykella based on macro- and micromorphological characters. PMID- 23355973 TI - Re-thinking cell cycle regulators: the cross-talk with metabolism. AB - Analysis of genetically engineered mice deficient in cell cycle regulators, including E2F1, cdk4, and pRB, showed that the major phenotypes are metabolic perturbations. These key cell cycle regulators contribute to lipid synthesis, glucose production, insulin secretion, and glycolytic metabolism. It has been shown that deregulation of these pathways can lead to metabolic perturbations and related metabolic diseases, such as obesity and type II diabetes. The cyclin-cdk Rb-E2F1 pathway regulates adipogenesis in addition to its well-described roles in cell cycle regulation and cancer. It was also shown that E2F1 directly participates in the regulation of pancreatic growth and function. Similarly, cyclin D3, cdk4, and cdk9 are also adipogenic factors with strong effects on whole organism metabolism. These examples support the emerging notion that cell cycle regulatory proteins also modulate metabolic processes. These cell cycle regulators are activated by insulin and glucose, even in non-proliferating cells. Most importantly, these cell cycle regulators trigger the adaptive metabolic switch that normal and cancer cells require in order to proliferate. These changes include increased lipid synthesis, decreased oxidative metabolism, and increased glycolytic metabolism. In summary, these factors are essential regulators of anabolic biosynthetic processes, blocking at the same time oxidative and catabolic pathways, which is reminiscent of cancer cell metabolism. PMID- 23355976 TI - Caryospora duszynskii (Apicomplexa: Eimeriidae) From the Speckled Kingsnake, Lampropeltis holbrooki (Reptilia: Ophidia), in Arkansas, With a Summary of Previous Reports. PMID- 23355977 TI - Mathematical modeling of intercalation batteries at the cell level and beyond. AB - Mathematical modeling of lithium ion batteries is a key feature for a profound understanding of the whole spectrum of phenomena occurring in such electrochemical systems. Due to their inherent multi-scale nature, batteries cannot be described with a single equation. It is necessary to couple the physical chemistry, reaction kinetics, ion flow, heat generation, et cetera, appropriately to obtain a coupled set of equations (a model) which has predictive efficiency. To adapt ideas and expertise obtained in the field of modeling to future type of batteries, new electrode or electrolyte materials or to improve the model reliability, a universal basis is desirable. In this sense, we carefully derive the commonly used set of equations based on the most general form of linear non-equilibrium thermodynamics. Due to chemical and physical assumptions the set of equations is reduced to facilitate numerical computations. Transport equations for a general electrolyte are derived and different electroneutrality assumptions are applied to obtain Poisson-Nernst-Planck-type equations or a generalized Ohmic law. Electrodes are described with single and many particle models, e.g. for phase separating materials, and the transition to porous electrode theory is given. A mathematical treatment of the intercalation reaction is finally presented, based on surface charge densities and electrode potentials. PMID- 23355975 TI - The SycN/YscB chaperone-binding domain of YopN is required for the calcium dependent regulation of Yop secretion by Yersinia pestis. AB - Numerous Gram-negative bacterial pathogens employ type III secretion systems (T3SSs) to inject effector proteins into eukaryotic cells. The activation of the type III secretion (T3S) process is tightly controlled in all T3SSs. In Yersinia pestis, the secretion of effector proteins, termed Yersinia outer proteins (Yops), is regulated by the activity of the YopN/SycN/YscB/TyeA complex. YopN is a secreted protein that interacts with the SycN/YscB chaperone via an N-terminal chaperone-binding domain (CBD) and with TyeA via a C-terminal TyeA-binding domain (TBD). Efficient YopN secretion is dependent upon its N-terminal secretion signal (SS), CBD, and the SycN/YscB chaperone. In this study, we investigate the role of the YopN CBD in the regulation of Yop secretion. Analysis of YopE/YopN hybrid proteins in which the YopN SS or SS and CBD were replaced with the analogous regions of YopE indicated that the YopN CBD or SycN/YscB chaperone play a role in the regulation of Yop secretion that is independent of their established roles in YopN secretion. To further analyze the role of the YopN CBD in the regulation of Yop secretion a series of tetra-alanine substitution mutants were generated throughout the YopN CBD. A number of these mutants exhibited a defect in the regulation of Yop secretion but showed no defect in YopN secretion or in the interaction of YopN with the SycN/YscB chaperone. Finally, conditions were established that enabled YopN and TyeA to regulate Yop secretion in the absence of the SycN/YscB chaperone. Importantly, a number of the YopN CBD mutants maintained their defect in the regulation of Yop secretion even under the established SycN/YscB chaperone-independent conditions. These studies establish a role for the CBD region of YopN in the regulation of Yop secretion that is independent from its role in YopN secretion or in the binding of the SycN/YscB chaperone. PMID- 23355978 TI - A robust tool highlights the influence of bird migration on influenza A virus evolution. AB - One of the fundamental unknowns in the field of influenza biology is a panoramic understanding of the role wild birds play in the global maintenance and spread of influenza A viruses. Wild aquatic birds are considered a reservoir host for all lowly pathogenic avian influenza A viruses (AIV) and thus serve as a potential source of zoonotic AIV, such as Australasian-origin H5N1 responsible for morbidity and mortality in both poultry and humans, as well as genes that may contribute to the emergence of pandemic viruses. Years of broad, in-depth wild bird AIV surveillance have helped to decipher key observations and ideas regarding AIV evolution and viral ecology including the trending of viral lineages, patterns of gene flow within and between migratory flyways and the role of geographic boundaries in shaping viral evolution (Bahl et al. 2009; Lam et al. 2012). While these generally 'virus-centric' studies have ultimately advanced our broader understanding of AIV dynamics, recent studies have been more host focused, directed at determining the potential impact of host behaviour on AIV, specifically, the influence of bird migration upon AIV maintenance and transmission. A large number of surveillance studies have taken place in Alaska, United States-a region where several global flyways overlap-with the aim of detecting the introduction of novel, Australasian-origin highly pathogenic H5N1 AIV into North America. By targeting bird species with known migration habits, long-distance migrators were determined to be involved in the intercontinental movement of individual AIV gene segments, but not entire viruses, between the Australasian and North American flyways (Koehler et al. 2008; Pearce et al. 2010). Yet, bird movement is not solely limited to long-distance migration, and the relationship of resident or nonmigratory and intermediate-distance migrant populations with AIV ecology has only recently been explored by Hill et al. (2012) in this issue of Molecular Ecology. Applying a uniquely refined, multidimensional approach, Hill et al. validate the innovative use of stable isotope assays for qualifying migration status of wild mallards within the Pacific flyway. The authors reveal that AIV prevalence and diversity did not differ in wintering mallard ducks with different migration strategies, and while migrant mallards do indeed introduce AIV, these viruses do not circulate as the predominant viruses in resident birds. On the other hand, resident mallards from more temperate regions act as reservoirs, possibly contributing to the unseasonal circulation and extended transmission period of AIV. This study highlights the impact of animal behaviour on shaping viral evolution, and the unique observations made will help inform prospective AIV surveillance efforts in wild birds. PMID- 23355974 TI - Biological and clinical implications of cancer stem cells in primary brain tumors. AB - Despite therapeutic advances, glioblastoma multiforme (GBM) remains a lethal disease. The infiltrative nature of this disease and the presence of a cellular population resistant to current medical treatments account for the poor prognosis of these patients. Growing evidence indicates the existence of a fraction of cancer cells sharing the functional properties of adult stem cells, including self-renewal and a greater ability to escape chemo-radiotherapy-induced death stimuli. Therefore, these cells are commonly defined as cancer stem cells (GBM SCs). The initial GBM-SC concept has been challenged, and refined according to the emerging molecular taxonomy of GBM. This allowed to postulate the existence of multiple CSC types, each one driving a given molecular entity. Furthermore, it is becoming increasingly clear that GBM-SCs thrive through a dynamic and bidirectional interaction with the surrounding microenvironment. In this article, we discuss recent advances in GBM-SC biology, mechanisms through which these cells adapt to hostile conditions, pharmacological strategies for selectively killing GBM-SCs, and how novel CSC-associated endpoints have been investigated in the clinical setting. PMID- 23355979 TI - Next-generation sequencing sheds light on intricate regulation of insect gut microbiota. AB - Next-generation sequencing (NGS) technologies are getting cheaper and easier and hence becoming readily accessible for many researchers in biological disciplines including ecology. In this issue of Molecular Ecology, Sudakaran et al. (2012) show how the NGS revolution contributes to our better and more comprehensive understanding of ecological interactions between gut symbiotic microbiota and the host organism. Using the European red firebug Pyrrhocoris apterus as a model system, they demonstrated that the gut microbiota consists of a small number of major bacterial phylotypes plus other minor bacterial associates. The major bacteria are localized in a specific anoxic section of the midgut and quantitatively account for most of the gut microbiota irrespective of host's geographic populations. The specific gut microbiota is established through early nymphal development of the host insect. Interestingly, the host feeding on different food, namely linden seeds, sunflower seeds or wasp larvae, scarcely affected the symbiont composition, suggesting homoeostatic control over the major symbiotic microbiota in the anoxic section of the midgut. Some of the minor components of the gut microbiota, which conventional PCR/cloning/sequencing approaches would have failed to detect, were convincingly shown to be food derived. These findings rest on the robust basis of high-throughput sequencing data, and some of them could not be practically obtained by conventional molecular techniques, highlighting the significant impact of NGS approaches on ecological aspects of host-symbiont interactions in a nonmodel organism. PMID- 23355980 TI - [Refrigerant silk]. PMID- 23355981 TI - How pernicious parasites turn victims into zombies. PMID- 23355982 TI - The two-factor model of psychopathic personality: evidence from the psychopathic personality inventory. AB - Psychopathy or psychopathic personality disorder represents a constellation of traits characterized by superficial charm, egocentricity, irresponsibility, fearlessness, persistent violation of social norms, and a lack of empathy, guilt, and remorse. Factor analyses of the Psychopathic Personality Inventory (PPI)typically yield two factors: Fearless Dominance (FD) and Self-Centered Impulsivity (SCI). Additionally, the Coldheartedness (CH) subscale typically does not load on either factor. The current paper includes a meta-analysis of studies that have examined theoretically important correlates of the two PPI factors and CH. Results suggest that (a) FD and SCI are orthogonal or weakly correlated, (b) each factor predicts distinct (and sometimes opposite) correlates, and (c) the FD factor is not highly correlated with most other measures of psychopathy. This pattern of results raises important questions about the relation between FD and SCI and the role of FD in conceptualizations of psychopathy. Our findings also indicate the need for future studies using the two-factor model of the PPI to conduct moderational analyses to examine potential interactions between FD and SCI in the prediction of important criterion measures. PMID- 23355983 TI - Predicting PPIs. PMID- 23355984 TI - A genetically encoded probe for EM. PMID- 23355986 TI - Mapping microbes on the move. PMID- 23355985 TI - Tagging newborn proteins: version 2.0. PMID- 23355987 TI - Synthetic polarization. PMID- 23355988 TI - Dye shines bright. PMID- 23355989 TI - Crystal clear. PMID- 23355990 TI - Physics in one dimension. PMID- 23355991 TI - [Tuberculosis Annual Report 2010--(7) Tuberculosis characteristics upon diagnosis 2]. AB - From 2007 to 2010, 229 newly notified tuberculosis (TB) cases with HIV infection were reported. These cases were detected in 204 (89.1%) male and 25 (10.9%) female patients; 50 (21.8%) of these patients were foreigners. The present TB surveillance system does not provide reliable data on whether HIV tests were performed for TB cases; therefore, we report only those TB patients with HIV infection. In 2010, the proportion of newly notified TB cases with diabetes mellitus was 13.3% (3,085/23,261); diabetes was observed in 15.4% of male patients and 9.7% of female patients. In 2010, drug susceptibility test (DST) results were obtained for 8,380 (72.9%) of 11,495 culture-positive pulmonary TB cases through the TB surveillance system. The proportion of multi-drug resistant TB (MDR-TB), isoniazid resistance, and rifampicin resistance among the newly identified cases was 0.5%, 4.1%, and 0.7%, respectively. Among previously tested cases, the proportion was 3.9%, 11.4%, and 5.2%, respectively. Resistance thus appears to have remained stable over the past 4 years (2007-2010). From 2007 to 2010, among the new pulmonary TB cases in foreign nationals, MDR-TB was observed in 2.9% of male patients and 4.2% of female patients. PMID- 23355992 TI - Binary ultrasonography for the internist: yes or no, that's the question! AB - The authors discuss the pros and cons with regard to ultrasound for the internist. They state that ultrasonography is seldom used by internists and they suggest several reasons for this. After a brief review of the literature they conclude that using ultrasound would probably benefit patients and would lead to a more rapid diagnosis and an increase in safety while performing invasive diagnostic and therapeutic interventions. The authors suggest that internists use ultrasound in a different way compared with radiologists, cardiologists, etc. They introduce the term binary ultrasound: ultrasound should be used to answer clinical questions with a yes or a no. PMID- 23355993 TI - Childhood obesity: a call for help in the battle of the bulge. PMID- 23355994 TI - Antibiotics and OC effectiveness. PMID- 23355995 TI - Discoloration of both lower extremities. PMID- 23355996 TI - Infectious diseases: West Nile virus on the rise. PMID- 23355997 TI - Bacterial meningitis: tailoring management to patient characteristics. PMID- 23355998 TI - Understanding electrolytes: important diagnostic clues to patient status. PMID- 23355999 TI - A patient with unilateral idiopathic sudden sensorineural hearing loss. PMID- 23356000 TI - Children and radiation risk in the age of increased utilization of CT. PMID- 23356001 TI - Use of percutaneous drainage for treatment of pyogenic liver abscess. PMID- 23356002 TI - Saving a free flap with close clinical postoperative monitoring. PMID- 23356003 TI - Perimenopausal sleep disturbance: beyond estrogen replacement. PMID- 23356004 TI - Leadership case study: Ian W Jones, MPAS, CCPA, PA-C. PMID- 23356006 TI - A baby died. PMID- 23356005 TI - Strategies to manage the patient with health anxiety. PMID- 23356007 TI - Case of the month. Penile cancer. PMID- 23356008 TI - Predicting the secondary structure of proteins using machine learning algorithms. AB - The functions of proteins in living organisms are related to their 3-D structure, which is known to be ultimately determined by their linear sequence of amino acids that together form these macromolecules. It is, therefore, of great importance to be able to understand and predict how the protein 3D-structure arises from a particular linear sequence of amino acids. In this paper we report the application of Machine Learning methods to predict, with high values of accuracy, the secondary structure of proteins, namely alpha-helices and beta sheets, which are intermediate levels of the local structure. PMID- 23356009 TI - Bloat free genetic programming: application to human oral bioavailability prediction. AB - Being able to predict the human oral bioavailability for a potential new drug is extremely important for the drug discovery process. This problem has been addressed by several prediction tools, with Genetic Programming providing some of the best results ever achieved. In this paper we use the newest developments of Genetic Programming, in particular the latest bloat control method, Operator Equalisation, to find out how much improvement we can achieve on this problem. We show examples of some actual solutions and discuss their quality, comparing them with previously published results. We identify some unexpected behaviours related to overfitting, and discuss the way for further improving the practical usage of the Genetic Programming approach. PMID- 23356010 TI - A novel ensemble approach for multicategory classification of DNA microarray data using biological relevant gene sets. AB - An important emerging medical application domain for microarray technology is clinical decision support in the form of diagnosis of diseases. For this task, several computational methods ranging from statistical alternatives to more complex hybrid systems have been previously proposed in the literature. In this work we study the utilisation of several ensemble alternatives for the task of classifying microarray data by using prior knowledge known to be biologically relevant to the target disease. The experimental results using different datasets and several gene sets show that the proposal is able to outperform previous approaches by introducing diversity as different gene sets. PMID- 23356011 TI - Gene order computation using Alzheimer's DNA microarray gene expression data and the Ant Colony Optimisation algorithm. AB - As Alzheimer's Disease (AD) is the most common form of dementia, the study of AD related genes via biocomputation is an important research topic. One method of studying AD-related gene is to cluster similar genes together into a gene order. Gene order is a good clustering method as the results can be optimal globally while other clustering methods are only optimal locally. Herein we use the Ant Colony Optimisation (ACO)-based algorithm to calculate the gene order from an Alzheimer's DNA microarray dataset. We test it with four distance measurements: Pearson distance, Spearmen distance, Euclidean distance, and squared Euclidean distance. Our computing results indicate: a different distance formula generated a different quality of gene order, the squared Euclidean distance approach produced the optimal AD-related gene order. PMID- 23356012 TI - Extracting templates from radiology reports using sequence alignment. AB - Health care providers often dictate their reports by filling in slots in templates. These slots can be filled with a variety of different procedures, measurements, or findings. Many radiologists currently create their own personalised templates, costing time and leading to inconsistencies across physicians. We present a sequence alignment method Radiology Content Alignment (RADICAL) that uses dynamic programming to efficiently extract templates that are common across sets of reports, and give examples of the extracted templates and the contents of their slots. PMID- 23356013 TI - Small Ancestry Informative Marker panels for complete classification between the original four HapMap populations. AB - A protocol for the identification of Ancestry Informative Markers (AIMs) from genome-wide Single Nucleotide Polymorphism (SNP) data is proposed. The protocol consists of three main steps: identification of potential positive selection regions via F(ST) extremity measurement, SNP screening via two-stage attribute selection and classification model construction using a Naive Bayes classifier. The two-stage attribute selection is composed of a newly developed round robin Symmetrical Uncertainty (SU) ranking technique and a wrapper embedded with a Naive Bayes classifier. The protocol has been applied to the HapMap Phase II data. Two AIM panels, which consist of 10 and 16 SNPs that lead to complete classification between CEU, CHB, JPT and YRI populations, are identified. Moreover, the panels are at least four times smaller than those reported in previous studies. The results suggest that the protocol could be useful in a scenario involving a larger number of populations. PMID- 23356014 TI - Selection and mapping of DNA structural features for short gene recognition. AB - This paper presents two new approaches for short gene recognition in DNA sequences. Three of fourteen DNA structural features are selected based on their classification power by a modified auto-regressive model method. Experiments on human genome show that the method is superior to existing exon detection algorithms. However, this method requires computing time. To overcome this problem, the DNA structural features are mapped to a set of new values. The three signals generated by the mapped feature values are normalised and averaged before their power spectral density is estimated. The computational complexity is reduced substantially using the feature mapping method. PMID- 23356015 TI - Formation and speciation characteristics of brominated trihalomethanes in seawater chlorination. AB - Formation character of brominated-trihalomethanes (Br-THMs) in chlorinated seawater and its dependence on applied chlorine dose, reaction time, and temperature were investigated in the laboratory. Seawater was collected from the east coast of India and a chlorine dose of 1, 3, 5, and 10 ppm was each applied at a temperature of 20, 30, and 40 degrees C to investigate the yield and kinetics of Br-THMs formation. Qualitative and quantitative estimation of THM formation at various intervals of time ranging from 5 min to 168 h was determined by a gas chromatograph equipped with an electron capture detector (GC-ECD). Chlorine dose, chlorine contact time, and reaction temperature positively affected the load of THMs. The ratio of chlorine dose to halogen incorporation decreased from 12% to 5% with increasing applied chlorine dose from 1 to 10 ppm. Significant levels of THMs were found to be formed within 0.5 h of reaction, followed by a very slow rate of formation. Elevated temperature favored both increased rate of formation and overall THM yield. The formation order of different trihalomethane species at all studied temperatures was observed to be bromodichloromethane (CHCl2Br) < dibromochloromethane (CHClBr2) < bromoform (CHBr3). Formation of chloroform was not observed, and bromoform was the dominant (96% to 98%) among the three THM species formed. PMID- 23356016 TI - Interlaboratory study of free cyanide methods compared to total cyanide measurements and the effect of preservation with sodium hydroxide for secondary- and tertiary-treated waste water samples. AB - Several methods exist for the measurement of cyanide levels in treated wastewater,typically requiring preservation of the sample with sodium hydroxide to minimize loss of hydrogen cyanide gas (HCN). Recent reports have shown that cyanide levels may increase with chlorination or preservation. In this study, three flow injection analysis methods involving colorimetric and amperometric detection were compared within one laboratory, as well as across separate laboratories and equipment. Split wastewater samples from eight facilities and three different sampling periods were tested. An interlaboratory confidence interval of 3.5 ppb was calculated compared with the intralaboratory reporting limit of 2 ppb. The results show that free cyanide measurements are not statistically different than total cyanide levels. An artificial increase in cyanide level is observed with all methods for preserved samples relative to nonpreserved samples, with an average increase of 2.3 ppb. The possible loss of cyanide without preservation is shown to be statistically insignificant if properly stored up to 48 hours. The cyanide increase with preservation is further substantiated with the method of standard additions and is not a matrix interference. The increase appears to be correlated with the amount of cyanide observed without preservation, which appears to be greater in those facilities that disinfect their wastewater with chlorine, followed by dechlorination with sodium bisulfite. PMID- 23356017 TI - Ozone and UV254 radiation for municipal wastewater disinfection. AB - Bench-scale experiments were conducted with municipal wastewater effluent samples to examine the feasibility of combined application of ozone and ultraviolet (UV) radiation for disinfection. Effluent samples displayed rapid initial ozone demand, which promotes ozone transfer but diminishes disinfection efficacy. Ozone doses up to 10 mg/L yielded only trace quantities of residual ozone; despite the fact that initial ozone demand was never exceeded, quantifiable (though variable) inactivation of E. coli was observed, along with modest improvements of UV transmittance. Results from collimated beam experiments demonstrated that compliance with effluent discharge permit limitations could be achieved consistently with a UV254 dose of 12.4 mJ/cm2 at a pre-ozonation dose of 2 to 3 mg/L. In the absence of pre-ozonation, consistent compliance was observed at a UV dose of 16.5 mJ/cm2. No evidence of synergism between ozone and UV254 radiation was found in the measured inactivation responses of E. coli. PMID- 23356018 TI - Electropolymerization treatment of phenol wastewater and the reclamation of phenol. AB - Electrochemical treatment of phenol wastewater was carried out with stainless steel anodes, and phenol removal was achieved through the electropolymerization process. The effects of phenol concentration and bath voltage were discussed. The original chemical oxygen demand (COD) value was approximately 500 mg/L. After electropolymerization treatment, phenol concentration was 0.087 mmol/ L with a removal efficiency of 95.6%, and COD was 68 mg/L with a removal efficiency of 86.5%. During treatment, the average current efficiency was 60.36% and power consumption was 27.62 kJ/kg (6.96 kWh/ton). The electropolymerization reaction was analyzed by cyclic voltammetry, and the polyphenol product was analyzed by scanning electron microscopy and infrared spectroscopy. PMID- 23356019 TI - Ferrous iron phosphorus in sediments: development of a quantification method through 2,2'-bipyridine extraction. AB - The role of ferrous iron in the phosphorus cycle of an aquatic ecosystem is poorly understood because of a lack of suitable methods to quantitatively evaluate ferrous iron phosphorus (FIP) phases. Using sediments sampled from Fubao Bay of Dianchi Lake in China, a novel extraction method for FIP using 2,2' bipyridine was explored. Total phosphorus and iron in the sediments ranged from 1.0 to 5.0 mg/g (dry weight) and 28.5 to 90.6 mg/g, respectively. Organic content (as indicated by loss on ignition or LOI) and iron(II) ranged from 3.1 to 27.0% and 26.5 to 64.9 mg/g, respectively. The dissolution dynamics of FIP extraction with a low solid/liquid ratio (1:25) indicated that a single application of 0.2% 2,2'-bipyridine extracted both iron(II) (Fe(II)) and phosphorus (as PO4(3-)) in sediments with different organic contents with low efficiency. The extraction efficiency of Fe(II) was improved by alteration of the solid/liquid ratio, but the effect was limited. However, addition of a 1:1000 solid/liquid ratio of 0.5 M potassium chloride to a 0.2% 2,2'-bipyridine solution significantly accelerated extraction of FIP with the release of Fe(II) and phosphorus toward equilibrium at approximately 150 hours. Further investigation demonstrated that 2,2'-bipyridine exhibited a higher selectivity in distinguishing FIP from phosphorus bound to ferric (Fe(III)) oxides or precipitated by calcium (Ca2+). Air-drying sediments significantly decreased the amount of extracted FIP, which indicates that fresh, wet sediment should be used in this type of FIP extraction. Based on experimental results using the proposed extraction protocol, (1) FIP in sediments of Fubao Bay had a predominant status in the lake sediment and accounted for 23.4 to 39.8% of total phosphorus, and (2) Fe(II)(FIP) released in the extraction is directly proportional to phosphorus(FIP) (Fe(II)(FIP) = 2.84 x P(FIP) + 0.0007; R2 = 0.97) with an average molar ratio of Fe(II)(FIP)/P(FIP) of 2.7. This study shows that FIP extraction with 2,2'-bipyridine is a robust method for releasing ferrous iron associated with phosphorus. Further, the high percentage of FIP in total phosphorus (40%) measured in the study site using this extraction method suggests that FIP might have been often underestimated in previous studies. PMID- 23356020 TI - Can nonloricate ciliate assemblages be a surrogate to analyze taxonomic relatedness pattern of ciliated protozoan communities for marine bioassessment? A case study in Jiaozhou Bay, Northern China. AB - Congruency using nonloricate ciliates as a surrogate to analyze taxonomic distinctness pattern of ciliated protozoan communities for assessing water quality was studied. The results showed that (1) with significant consistency with the total ciliate communities, the spatial pattern of nonloricate ciliates was significantly correlated with the changes of environmental status; (2) four taxonomic relatedness measures were significantly correlated with those of the total ciliate communities; (3) spatial variations in four taxonomic diversity indices of nonloricate ciliates were significantly related with the changes of environmental variables, especially nutrients; and (4) the paired taxonomic biodiversity indices of nonloricate ciliates showed a clear decreasing trend of departure from the expected taxonomic breadth in response to water quality. These results suggest that nonloricate ciliate assemblages can be used as a potential surrogate of ciliate communities to assess marine water quality using taxonomic distinctness measures, especially the paired indices based on presence or absence data. PMID- 23356021 TI - Fate of florfenicol in a simulated aquatic ecosystem and effects on sediment microflora. AB - Four controlled microcosms were prepared, one of which served as control, whereas the other three received treatments of 10, 50, and 150 mg/L of florfenicol, an antibacterial drug developed initially for aquaculture applications. Water and sediment samples were collected according to a pre-set time schedule to determine its fate in the aquatic environment. The results demonstrated that florfenicol amine was not detectable in any treatment groups. The half-life of florfenicol in pond water was 30.76, 52.92, and 51.48 hours for the 10, 50, and 150 mg/L treatment groups, respectively; the corresponding half-lives in sediment were 25.42, 38.40, and 53.59 days. Further, the 50 and 150 mg/L florfenicol treatment groups inhibited alkaline protease activity; however, all treatment groups inhibited sediment microflora structural diversity. PMID- 23356022 TI - Preparation of mulberry branch biomass char and its usage in wastewater treatment. AB - Biomass char was prepared from mulberry branches by physical activation. An examination by Fourier transform infrared spectroscopy (FTIR) indicated that the functional groups of Si-O were mostly burnt out, significantly decreasing the ash content Analysis of data from a scanning electron microscope (SEM) and a Brunauer Emmett-Teller (BET) test also revealed increased surface roughness and pore structure, which improved the adsorption capacity of biomass char after preparation. The optimum conditions for preparation were found to be pyrolysis at 700 degrees C for 30 minutes, and then activation at 750 degrees C for one hour, with 3.4% steam content for the activating agent. The prepared biomass char was then employed to adsorb ammonium, copper(II) actetate [Cu(II)] and hexavalent chromium [Cr(VI)] in a solution. The results indicated that the prepared biomass char had a better adsorptive performance than the raw material. Moreover, the removal of determinands increased along with the dosage, and the highest adsorption efficiency of ammonium, copper(II) acetate [Cu(II)] and hexavalent chromium [Cr(VI)] were found to be 20%, 100% and 50%, respectively. The adsorptions of ammonium and hexavalent chromium [Cr(VI)] can be simulated by a pseudo-second order model, while the adsorption of copper(II) acetate [Cu(II)] is better simulated by a pseudo-first order model. The adsorption isotherms of copper(II) acetate [Cu(II)] by biomass char were also investigated, and the Langmuir isotherm was found to best describe the adsorption process. PMID- 23356023 TI - The chemotherapy of leprosy: an interpretive history. PMID- 23356024 TI - Developing new MDT regimens for MB patients; time to test ROM 12 month regimens globally. PMID- 23356025 TI - Chemotherapy of leprosy has changed (almost) everything. PMID- 23356026 TI - Relapses in multibacillary leprosy patients: a retrospective cohort of 11 years in Colombia. AB - OBJECTIVES: To determine the frequency and factors associated with relapse in multibacillary leprosy. DESIGN: We performed a retrospective cohort study on multibacillary leprosy patients treated at Centro Dermatologico Federico Lleras Acosta between January 1994 and December 2004. By survival analysis we studied the incidence density for recurrence and bacillary index conversion. The assessment of risk factors associated with the occurrence of relapse was constructed using a Cox regression model. RESULTS: We included 299 cases of which 243 received WHO-MB MDT on a regular basis, and followed them up to assess the frequency of relapses. We obtained 490 person-years of follow-up and an incidence density of 6.70 relapses/100 patient-years that was higher than most of the data reported in the literature. The relapse rate was 9.80 per 100 person-years when the initial bacillary index was > or = 2.0 and 5.60 relapses/100 patient-years when it was < 2 (P = 0.03). The relapse rate increased to 7.70/100 patient-years among those treated with WHO-MB 24 month fixed-dose, and it reduced to 5.70/100 patient-years when treated until smear negative. The variables that showed association with relapse were: initial bacillary index > or = 2.0, antireactional treatment and clinical classification of lepromatous leprosy. For each variable, the risk was four to five times more likely to present relapse. We also found that 21 patients' BI became negative per 100 treated for 1 year with WHO-MB MDT. CONCLUSIONS: We found a high relapse rate associated with initial high bacillary index in the Colombian population. Among the patients who received MDT on a regular basis 33 out of 165 (20%) relapsed. PMID- 23356027 TI - OFLOXACIN multicentre trial in MB leprosy FUAM-Manaus and ILSL-Bauru, Brazil. AB - Recently antimicrobials of the fluoroquinolone class (pefloxacin and ofloxacin) were found far more effective against Mycobacterium leprae in studies with both mice and patients than dapsone and clofazimine. As multicentre trial participants, we evaluated the therapeutic efficacy, in terms of rate of relapse, of two new multidrug regimens containing ofloxacin, comparing them to 1 year and 2 years of standard WHO-MDT regimen in multibacillary (MB) leprosy patients. A total of 198MB patients were recruited to participate in a randomized, double blind trial. Among those, 53 patients were treated with 1 year of WHO-MDT (a regimen including dapsone, clofazimine, and rifampin), 55 patients received 1 year of WHO-MDT plus an initial 1 month of daily ofloxacin, 63 patients were treated with 1 month of daily rifampin and daily ofloxacin, whereas 27 were treated with 2 years of WHO-MDT. Patients were regularly monitored for signs of relapse, in at least 7 years follow-up after being released from treatment. RESULTS: Relapse occurred in those treated with 1-month regimen alone at a significant higher rate (P < 0.001): 388%, whereas in the other three regimens that included WHO-MDT it ranged from 0 to 5%. This study found that a short course treatment for MB patients with rifampicin-ofloxacin combination had a higher failure rate. The addition of one month of daily ofloxacin to 12 months MB WHO-MDT did not increase its efficacy. PMID- 23356028 TI - Drug-resistant leprosy: monitoring and current status. PMID- 23356029 TI - Assessing and improving adherence with multidrug therapy. AB - INTRODUCTION: Adherence with multidrug therapy (MDT) in the treatment of leprosy is important to minimise the risk of relapse and avoid the emergence of drug resistance. Adherence is defined as the extent to which the patient's behaviour matches recommendations from the prescriber. This paper reviews the methods for assessing adherence with MDT in leprosy, and community approaches to improving adherence based on evidence from the treatment of tuberculosis (TB) and HIV, as well as leprosy. METHODS: To identify and summarise the available literature regarding the assessment of treatment regularity in leprosy, a literature search of MEDLINE was conducted using the following search terms: 'leprosy' AND ('adherence' OR 'compliance' OR 'concordance'). To identify evidence for interventions that have involved community members in HIV, TB or leprosy adherence support, a literature search was conducted using the key terms and medical subject headings 'treatment or adherence' 'community,' 'HIV, TB or Leprosy' and 'low and middle income countries' combined using Boolean operators. RESULTS: Leprosy programmes routinely use defaulting and treatment completion as proxy measures of adherence as recommended by the WHO global strategy. However, a number of other methods have been used to assess adherence including questionnaires, pill counts, as well as direct measures based on testing urine for the presence of dapsone. Direct methods were extensively used during the dapsone mono-therapy era but there is little evidence of their use in MDT. Use of multiple methods of assessing adherence improves the accuracy and reliability of the results. Community activities in TB and HIV such as variants of treatment observation, and/or wider programmes of counselling or direct support to the patient or their family or to increase community or social support were shown to improve treatment outcomes. Outcomes evaluated included treatment default and completion, clinical indicators, and adherence (pill-count, self report). CONCLUSIONS: Adherence is very important in leprosy and regular assessment of medication adherence together with constructive feedback and counselling of patients is likely to be beneficial. Leprosy programme can learn from adherence support interventions developed by both TB and HIV programmes. PMID- 23356030 TI - Patient-related factors predicting the effectiveness of rifampicin chemoprophylaxis in contacts: 6 year follow up of the COLEP cohort in Bangladesh. AB - OBJECTIVES: The COLEP trial in Bangladesh showed a 57% reduction in leprosy incidence among contacts of newly diagnosed patients in the first 2 years after chemoprophylaxis with single dose rifampicin (SDR). We assessed the impact of this intervention after 6 years and identified characteristics of the leprosy index patients predicting the effectiveness of this intervention. DESIGN: The cohort of 1037 patients and their 28 092 contacts that participated in the randomised placebo controlled field trial with single dose rifampicin was followed for 6 years. The leprosy status of contacts was established at 2, 4 and 6 years after the intervention. We assessed the association between characteristics of the index leprosy patients and the development of clinical leprosy among their contacts using logistic regression. RESULTS: The protective effect of SDR was seen only in the first 2 years, with no additional effect after 4 and 6 years. However, the total impact of the intervention was still statistically significant (P = 0.025) after 6 years and no excess cases were observed in the SDR arm at a later stage. The intervention prevented leprosy in contacts that actually received SDR, but did not offer protection to members of the same contact group who did not take chemoprophylaxis. The intervention was most effective in contact groups of female index patients, an enhanced effect was also observed in contact groups of patients belonging to a cluster of two or more leprosy patients at intake as well. CONCLUSION: These easy to recognise patient characteristics indicate a possible enhanced risk of transmission of Mycobacterium leprae to contacts in the vicinity of patients and are useful for deciding about preventive measures, such as early detection or chemoprophylaxis. PMID- 23356031 TI - Hemolytic anemia in patients receiving daily dapsone for the treatment of leprosy. AB - INTRODUCTION: Multidrug therapy for leprosy is currently done with dapsone, clofazimine and rifampicin. Dapsone is known to cause hemolytic anemia (HA) and this adverse event during MDT seems to be more frequent than reported. The aim of this report is to discuss and grade HA due to dapsone during MDT treatment for leprosy. METHODS: This is a retrospective study of 194 leprosy patients from a Leprosy Control Programme Unit in Vit6ria-ES, Brazil. RESULTS: HA was observed in 48 (24.7%) patients and occurred within the first 3 months in 51% of these. Mean hematocrit levels fell from 38.5 to 31.5 and hemoglobin from 12.8 to 10.3. CONCLUSION: Dapsone used in the MDT regime for leprosy decreases the hematocrit and hemoglobin levels due to a low grade hemolysis, which can result in significant anemia. PMID- 23356032 TI - Primary results of clinical trial for uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): reactions frequency in multibacillary patients. AB - SETTINGS: Many believe that the regular treatment for multibacillary (MB) leprosy cases could be shortened. A shorter treatment, allowing for uniform treatment for all cases, makes case classification superfluous and therefore simplifies leprosy control. OBJECTIVE: To evaluate the association of the treatment duration with the frequency of reactions among MB patients. METHODS: An open-label randomised clinical trial to compare the present routine treatment with one lasting six months. Patients were recruited between March 2007 and February 2012. We analysed the frequency of first reaction with the Kaplan-Meier method and of recurrent reaction with a Poisson regression, using the treatment group and baciloscopic index level (BI) as independent variables. Logistic regression was used to evaluate the statistical association of different reaction types and the treatment group. RESULTS: Among those with BI < 3, we found a statistical significant difference of reaction frequencies between the treatment groups from 6 to 18 months since the beginning of treatment. This difference disappears at 2 years after the start of treatment. Multiple reactions were associated with the treatment group and with BI > or = 3. No specific types of reactions were associated with treatment duration. CONCLUSION: Although this is the first report of U-MDT/CT-BR, the results presented here support the possibility of use of UMDT in the field. PMID- 23356033 TI - One in a million: A common goal for an uncommon cause connects patients who share a rare disease. PMID- 23356034 TI - Raising the bar for HIV awareness: where can you find your target audience? PMID- 23356035 TI - Running rogue. PMID- 23356036 TI - Rebrand Rx: a name change provides the remedy for marketplace confusion. PMID- 23356038 TI - The inside track: brand enthusiasm starts within your organization. PMID- 23356037 TI - An ounce of prevention: a multiyear campaign elevates the issue of teen medicine abuse. PMID- 23356039 TI - Doing more with less: in an era of reform, organizations are cutting costs and focusing on quality. PMID- 23356040 TI - Seeking medical help to conceive. AB - BACKGROUND: The demand for therapies to assist conception is growing in a number of countries including Canada. This study provides estimates of the number and characteristics of couples who sought medical help for conception and identifies the interventions and/or techniques they used. DATA AND METHODS: The data are from the Infertility Component of the 2009/2010 Canadian Community Health Survey. The analysis examines couples in which the woman was aged 18 to 44, resulting in 3,656 respondents. Percentages, means and confidence intervals were calculated. Two logistic regression models were run to estimate associations between socio demographic characteristics and seeking medical help to conceive. RESULTS: About three in four couples reported having tried to become pregnant. Of these, 15% had sought medical help for conception. Among those who had sought help for conception, 68% reported tracking the menstrual cycle and ovulation; 42% reported using fertility-enhancing drugs; 19% reported using assisted reproductive techniques; and 29% reported "other" medical treatment. INTERPRETATION: Given the trend toward delayed childbearing, the demand for medical help to conceive may be greater in the future. PMID- 23356041 TI - The physical and mental health of Inuit children of teenage mothers. AB - BACKGROUND: The physical and mental health of children of teenage mothers differs from that of children of older mothers. Compared with the overall population of Canada, Inuit experience first-time pregnancy earlier. However, little population based research has examined health outcomes for Inuit children of women who began childbearing in their teens. DATA AND METHODS: This study uses data from the 2006 Aboriginal Children's Survey to compare physical and mental health outcomes of 2- to 5-year-old Inuit children of teenage and older mothers. RESULTS: The physical and mental health outcomes of Inuit children differed depending on whether their mother had been a teenager or aged 25 or older when she began childbearing. Although some differences were explained by socio-economic factors, others, namely, ear infections, dental problems and hyperactivity/inattention, were not. INTERPRETATION: Further research is needed to determine what underlies differences in the mental and physical health of Inuit children of teenage and older mothers. PMID- 23356042 TI - Social participation and the health and well-being of Canadian seniors. AB - BACKGROUND: Social participation has been associated with health and well-being in older adults. DATA AND METHODS: Data from the 2008/2009 Canadian Community Health Survey (CCHS)-Healthy Aging were used to examine the relationship between frequent social participation and self-perceived health, loneliness and life dissatisfaction in a sample of 16,369 people aged 65 or older. Multivariate logistic regression was used to identify significant relationships, while adjusting for potential confounders. The mediating role of social support and the prevalence of reported barriers to greater social participation were also examined. RESULTS: An estimated 80% of seniors were frequent participants in at least one social activity. As the number of different types of frequent social activities increased, so did the strength of associations between social participation and positive self-perceived health, loneliness, and life dissatisfaction. The associations generally remained significant, but were attenuated by individual social support dimensions. The desire to be more involved in social activities was reported by 21% of senior men and 27% of senior women. INTERPRETATION: Social participation is an important correlate of health and well-being in older adults. It may be that social support gained through social contacts is as important in these associations as the number of activities in which one participates frequently. PMID- 23356043 TI - The difference in hypertension control between older men and women. AB - BACKGROUND: In Canada, as elsewhere, control of hypertension in older persons who are using antihypertensive medication is more likely in men than in women. The reasons for the observed difference are not known. DATA AND METHODS: Data are from cycle 1 of the 2007 to 2009 Canadian Health Measures Survey (CHMS). The CHMS includes a comprehensive questionnaire, automated blood pressure (BP) measures, and a variety of biological and anthropometric assessments. Frequencies, means, cross-tabulations and multivariate models were produced to study differences between the sexes in hypertension control in a weighted sample representative of the household population aged 60 to 79. RESULTS: The prevalence of hypertension was nearly equal among older men (60%) and women (59%), and the percentage of those with hypertension who were receiving pharmaceutical treatment was not statistically different (84% and 89%, respectively). However, despite current treatment, hypertension was uncontrolled in a substantially higher percentage of women (30%) than men (17%). The difference persisted when age, socio-economic status, co-morbidity, category of medication, anthropometry, and other correlates of hypertension were taken into account. INTERPRETATION: The factors considered in the analysis do not account for the advantage to older men in hypertension control. The findings underscore the importance of efforts to control blood pressure in older women. PMID- 23356044 TI - Iron sufficiency of Canadians. AB - BACKGROUND: Iron deficiency is the most common nutritional deficiency in the world, but little is known about the iron status of people in Canada, where the last estimates are from 1970-1972. DATA AND METHODS: The data are from cycle 2 (2009 to 2011) of the Canadian Health Measures Survey, which collected blood samples from a nationally representative sample of Canadians aged 3 to 79. Descriptive statistics (percentages, arithmetic means, geometric means) were used to estimate hemoglobin and serum ferritin concentrations, and other markers of iron status. Analyses were performed by age/sex group, household income, self perceived health, diet, and use of iron supplements. World Health Organization reference values (2001) were used to estimate the prevalence of iron sufficiency and anemia. RESULTS: The overall prevalence of anemia was low in the 2009-to-2011 period--97% of Canadians had sufficient hemoglobin levels. Generally, hemoglobin concentration increased compared with 1970-1972; however, at ages 65 to 79, rates of anemia were higher than in 1970-1972. Depleted iron stores were found in 13% of females aged 12 to 19 and 9% of females aged 20 to 49. Lower household income was associated with a lower prevalence of hemoglobin sufficiency, but was not related to lower serum ferritin sufficiency. Self-perceived health and diet were not significantly associated with hemoglobin and serum ferritin levels. INTERPRETATION: The lack of a relationship between iron status and diet may be attributable to the use of questions about food consumption frequency that were not specifically designed to estimate dietary iron intake. Factors other than iron intake might have contributed to the increase in the prevalence of anemia among seniors. PMID- 23356045 TI - Health behaviour changes after diagnosis of chronic illness among Canadians aged 50 or older. AB - Changes in health behaviours (smoking, physical activity, alcohol consumption, and fruit and vegetable consumption) after diagnosis of chronic health conditions (heart disease, cancer, stroke, respiratory disease, and diabetes) were examined among Canadians aged 50 or older. Results from 12 years of longitudinal data from the Canadian National Population Health Survey indicated relatively modest changes in behaviour. Although significant decreases in smoking were observed among all groups except those with respiratory disease, at least 75% of smokers did not quit. No significant changes emerged in the percentage meeting physical activity recommendations, except those with diabetes, or in excessive alcohol consumption, except those with diabetes and respiratory disease. The percentage reporting the recommended minimum fruit and vegetable intake did not increase significantly among any group. PMID- 23356046 TI - Seniors' use of and unmet needs for home care, 2009. AB - Based on data from the 2009 Canadian Community Health Survey-Healthy Aging, this article provides current information about home care use and unmet home care needs of community-dwelling seniors aged 65 or older. Home care is assistance received at home for a health-related reason in the 12 months before the interview. It includes formal care provided by paid workers or volunteer organizations and informal care provided by family, friends and/or neighbours. In 2009, 25% of seniors received home care services. The percentage receiving home care increased with age and ill health. As well, seniors who lived alone were more likely to have received home care than were those who lived with others. Housework and transportation were the most common types of care reported. Family, friends and neighbours provided the majority of care across all care types. Nearly 180,000 seniors (4%) reported having unmet needs for professional home care. PMID- 23356047 TI - Acute care hospital days and mental diagnoses. AB - BACKGROUND: Data from the Discharge Abstract Database of the Canadian Institute for Health Information were used to examine acute care hospital days for patients with a mental condition coded as the most responsible diagnosis or a comorbid diagnosis. In 2009/2010, patients with a mental diagnosis represented 11.8% of people who had been hospitalized and 25.5% of acute care hospital days. Those for whom the mental condition was the most responsible diagnosis accounted for 9.0% of hospital days (1.2 million), and those with a comorbid mental diagnosis accounted for 16.5% of hospital days (2.3 million). Mental diagnoses were often associated with physical conditions. The average hospitalization with a mental diagnosis was two and a half times as long as the average for hospitalizations without a mental diagnosis. About one-quarter of hospital days with a mental diagnosis were designated as alternate level of care days. PMID- 23356048 TI - Comparison of the efficiency of the bumble bees Bombus impatiens and Bombus ephippiatus (Hymenoptera: Apidae) as pollinators of tomato in greenhouses. AB - Experiments were conducted in a commercial tomato, Solanum lycopersicum L. (Solanaceae) greenhouse to compare the relative foraging effort and efficiency of two bumble bee species: Bombus impatiens Cresson, a species from northeastern North America, commercially reared and used for pollination in Mexico; and B. ephippiatus Say, a native species of Mexico and central America. B. ephippiatus was as efficient in pollination of tomatoes as B. impatiens, as indicated by all variables of fruit quality: fruit weight, number of seed per fruit, and maximum fruit diameter. The two species had similar levels of hourly and daily foraging activity. They had the same response to temperature fluctuation. Pollination rates by both species were similar and close to 100% throughout the sample period. However, B. impatiens showed greater foraging activity during the first half of the 27-d sample period, whereas B. ephipiatus had greater relative activity during the last half. This study establish that B. ephippiatus is as efficient as B. impatiens as a pollinator of tomatoes in greenhouses and thus a candidate as a managed pollinator. However, standard reliable methods for mass rearing of B. ephippiatus are not yet available. Such methods are necessary to ensure healthy colonies and optimum pollination for producers and will reduce the pressure for the unregulated collection of queens in the field and the subsequent reduction of populations of this species. PMID- 23356049 TI - Evaluation of lysozyme-HCl for the treatment of chalkbrood disease in honey bee colonies. AB - Chalkbrood, caused by Ascosphaera apis (Maassen and Claussen) Olive and Spiltor, is a cosmopolitan fungal disease of honey bee larvae (Apis mellifera L.) for which there is no chemotherapeutic control. We evaluated the efficacy of lysozyme HCl, an inexpensive food-grade antimicrobial extracted from hen egg white, for the treatment of chalkbrood disease in honey bee colonies. Our study compared three doses of lysozyme-HCl in sugar syrup (600, 3,000, and 6,000 mg) administered weekly for 3 wk among chalkbrood-inoculated colonies, colonies that were inoculated but remained untreated, and colonies neither inoculated or treated. Lysozyme-HCl at the highest dose evaluated was found to suppress development of chalkbrood disease in inoculated colonies to levels observed in uninoculated, untreated colonies, and did not adversely affect adult bee survival or brood production. Honey production was significantly negatively correlated with increased disease severity but there were no significant differences in winter survival among treatment groups. Based on our results, lysozyme-HCl appears to be a promising, safe therapeutic agent for the control of chalkbrood in honey bee colonies. PMID- 23356050 TI - Determination of acute oral toxicity of flumethrin in honey bees. AB - Flumethrin is one of many pesticides used for the control and treatment of varroatosis in honey bees and for the control of mosquitoes and ticks in the environment. For the control of varroatosis, flumethrin is applied to hives formulated as a plastic strip for several weeks. During this time, honey bees are treated topically with flumethrin, and hive products may accumulate the pesticide. Honey bees may indirectly ingest flumethrin through hygienic behaviors during the application period and receive low doses of flumethrin through comb wax remodeling after the application period. The goal of our study was to determine the acute oral toxicity of flumethrin and observe the acute effects on motor coordination in honey bees (Apis mellifera anatoliaca). Six doses (between 0.125 and 4.000 microg per bee) in a geometric series were studied. The acute oral LD50 of flumethrin was determined to be 0.527 and 0.178 microg per bee (n = 210, 95% CI) for 24 and 48 h, respectively. Orally administered flumethrin is highly toxic to honey bees. Oral flumethrin disrupted the motor coordination of honey bees. Honey bees that ingested flumethrin exhibited convulsions in the antennae, legs, and wings at low doses. At higher doses, partial and total paralysis in the antennae, legs, wings, proboscises, bodies, and twitches in the antennae and legs were observed. PMID- 23356051 TI - Comparative toxicity of acaricides to honey bee (Hymenoptera: Apidae) workers and queens. AB - Acaricides are used to treat honey bee (Apis mellifera L.) colonies to control the varroa mite (Varroa destructor Anderson & Trueman), a worldwide threat to honey bee health. Although acaricides control a serious honey bee parasite and mitigate bee loss, they may cause harm to bees as well. We topically applied five acaricides, each with a different mode of action, to young adult queen and worker bees to generate dose-response curves and LD50. Twenty-four hours after treatment, queens were found to be three-times more tolerant of tau-fluvalinate and six-times more tolerant of thymol than workers when adjusted for body weight differences between workers (108 mg) and queens (180 mg). Queens survived the highest administered doses of fenpyroximate (1620 microg/g) and coumaphos (2700 microg/g) indicating that queens are at least 11-fold more tolerant of coumaphos and at least 54-fold more tolerant of fenpyroximate than workers. However, queens treated with as little as 54 microg/g of fenpyroximate exhibited reduced survival over 6 wk after treatment. Amitraz was the only acaricide tested for which queens were not more tolerant than workers. The striking difference in acaricide tolerance of queen and worker honey bees suggests physiological differences in how the two castes are affected by xenobiotics. PMID- 23356052 TI - Aphid feeding behavior in relation to potato virus Y (PVY) acquisition. AB - Potato virus Y (PVY) is transmitted by aphids in a nonpersistent manner and aphid species differ in their ability to transmit PVY. During host selection, aphids will land and probe on nonhost plant species and this behavior is an important component of the epidemiology of many aphid-transmitted viruses. In this study, we hypothesized that host selection behavior varies between aphid species and the host or nonhost status of the plant and this behavior will modulate their ability to acquire PVY. Three potato colonizers, Myzus persicae (Sulzer), Macrosiphum euphorbiae (Thomas), and Aphis nasturtii (Kaltenbach) and three casual visitors to potato fields, Myzus cerasi (F.), Rhopalosiphum padi (L.), and Sitobion avenae (F.) were evaluated using two acquisition assays. In one assay, the normal host selection and feeding behavior of aphid species were eliminated using an artificial diet while the other considered the normal host selection and feeding behavior of aphid species on potato plants. PVY acquisition rates of aphid species widely differed between the two assays indicating the impact of host selection and feeding behavior on PVY acquisition. This behavior varied greatly between potato colonizers and noncolonizers. We recommend that laboratory evaluations of PVY vector efficiency consider the normal host selection and feeding behavior of aphid species on potatoes. PMID- 23356053 TI - A new approach for the identification of aphid vectors (Hemiptera: Aphididae) of potato virus Y. AB - Potato virus Y (PVY) is one of the most economically important viruses affecting potato crops worldwide. PVY can be transmitted from potato to potato by several aphid species, most of which do not colonize the potato crop. New methods including preservation of viral RNA on stylets of aphids collected from yellow pan trap samples, polymerase chain reaction detection of PVY from the stylets of one aphid, and aphid identification using DNA barcoding were used to identify possible PVY vectors from field samples. In total, 65 aphid taxa were identified from the samples that tested positive for PVY. Among those, 45 taxa had never been evaluated for their ability to transmit PVY, and 7 were previously labeled as nonvectors. These results demonstrated that the list of PVY vectors is likely longer than previously reported and that most (if not all) species of aphids could be considered as potential vectors. This premise has important implications in the management of PVY in seed potato production. PMID- 23356054 TI - Control of grasshoppers by combined application of Paranosema locustae and an insect growth regulator (IGR) (cascade) in rangelands in China. AB - The relatively low direct mortality caused by Paranosema locustae (Canning) has limited its application for controlling grasshopper when densities are high, and this study sought to determine if the simultaneous use of this pathogen and the IGR, Flufenoxuron (Cascade) could provide effective control. Nine treatments were tested: 45% Malathion EC at 1500 ml/ha, 5% Cascade at 150 ml/ha, 5% Cascade at 75 ml/ha, 5% Cascade at 37.5 ml/ha, P. locustae at 7.5 x 10(9) spores/ha, combinations of 5% Cascade at 75 ml/ha and P. locustae at 7.5 x 10(9) spores/ha, applied in different rations (1:1, 1:2, 1:3) in the same plot, the untreated control. P. locustae was applied on nonoverlapping plots with the IGR. The different in-plot combinations of P. locustae and Cascade in different ratios provided significantly better overall control of grasshoppers (all species) than the treatment of 5% Cascade of 150 ml/ha after 5d, but combinations were not significantly different from the other concentrations of Cascade after 12 and 31 d. When results were examined separately for specific species of grasshoppers, reduction of Dasyhippus harbipes (Fischer-Waldheim), was higher than that of Myrmeleotettix palpalis (Zubovsky). While combinations showed significant differences in the infection of different grasshopper species at 5 and 12 d posttreatment, no significant differences in rate of infection among the primary species (M. palpalis, D. harbipes, and Oedaleus asiaticus Bei-Bienko) were detected 31 d posttreatment. Our study found that P. locustae by itself could control grasshopper populations at medium densities but the combined application of P. locustae and Cascade at a ratio of 1:2 was more effective against high density grasshopper populations. PMID- 23356055 TI - Establishment of an artificial diet for successive rearing of Apolygus lucorum (Hemiptera: Miridae). AB - The plant bug Apolygus lucorum (Meyer-Dur) is a major pest on Bt cotton and multiple crops in northern China. A modified NI artificial diet called T7 was developed to rear this pest for 10 successive generations both individually and in groups. This T7 diet was similar in components and preparation process to the NI diet used for Lygus hesperus in North America, but was comprised of more whole chicken eggs, soybean lecithin, and Vanderzant vitamin mixture, and less brewer's yeast, wheat germ, lima bean meal, soy flour, and sugars than NI diet. While being reared individually on T7 diet, A. lucorum nymphs had a developmental duration of approximately 12 d and survival rate of approximately 80%, which was not significantly different from that on green beans. While being reared in groups, nymphal survival rate was above 81% (indeed above 90% for the first four generations), the weight of adults was heavier than on green beans and the average fecundity had a logistic increase through generations. The replacement rate of A. lucorum populations was expected to be approximately 29 times per generation while being reared at a density of 100 nymphs per box (20 x 12 x 7 cm). This is the first successful artificial diet reported for rearing A. lucorum and is superior to green beans. The diet offers an economic means for producing natural enemies for biological control of this pest on Bt cotton. The possibility of further improvement of the present artificial diet is also discussed. PMID- 23356056 TI - Towards the development of an autocontamination trap system to manage populations of emerald ash borer (Coleoptera: Buprestidae) with the native entomopathogenic fungus, Beauveria bassiana. AB - Emerald ash borer, Agrilus planipennis Fairmaire (Coleoptera: Buprestidae) is an invasive species from Asia that was discovered in North America Canada, in 2002. Herein, we describe studies to develop an autocontamination trapping system to disseminate Beauveria bassiana to control beetle populations. The standard trap for emerald ash borer in Canada is a light green prism trap covered in an insect adhesive and baited with (Z)-3-hexenol. We compared of green multifunnel traps, green intercept panel traps (both with and without fluon coating) and green prism traps for capturing emerald ash borer in a green ash plantation. The coated green multifunnel traps captured significantly more males and more females than any other trap design. We examined the efficacy of two native B. bassiana isolates, INRS-CFL and L49-1AA. In a field experiment the INRS-CFL isolate attached to multifunnel traps in autocontamination chambers retained its pathogenicity to emerald ash borer adults for up to 43 d of outdoor exposure. Conidia germination of the INRS-CFL isolate was >69% after outdoor exposure in the traps for up to 57 d. The L49-1AA isolate was not pathogenic in simulated trap exposures and the germination rate was extremely low (<5.3%). Mean (+/- SEM) conidia loads on ash borer adults after being autocontaminated in the laboratory using pouches that had been exposed in traps out of doors for 29 d were 579,200 (+/- 86,181) and 2,400 (+/- 681) for the INRS-CFL and the LA9-1AA isolates, respectively. We also examined the fungal dissemination process under field conditions using the L49 1AA isolate in a green ash plantation. Beetles were lured to baited green multifunnel traps with attached autocontamination chambers. Beetles acquired fungal conidia from cultures growing on pouches in the chambers and were recaptured on Pestick-coated traps. In total, 2,532 beetles were captured of which 165 (6.5%) had fungal growth that resembled B. bassiana. Of these 25 beetles were positive for the L49-1AA isolate. PMID- 23356057 TI - Hot-water phytosanitary treatment against Ceratitis capitata (Diptera: Tephritidae) in 'Ataulfo' mangoes. AB - We determined the thermal death rate constants and mortality curves for the eggs and different instars of Ceratitis capitata (Mediterranean fruit fly) (Wiedemann) submerged in isolation in water at 44, 46, and 48 degrees C and submerged within fruits of Mangifera indica (mango) (L.) in water at 43.1, 44.1, 45.1, and 46.1 degrees C. The first instar was the most tolerant to this treatment, with estimated times for achieving 99.9968% mortality of 103.28, 92.73, and 92.49 min at temperatures of 43.1, 44.1, and 45.1 degrees C, respectively. The results of the study indicate that 'Ataulfo' mangoes weighing < 329 +/- 2.11 g and at risk immature Mediterranean fruit fly infestation should be immersed for 95 min at 46.1-47 degrees C to ensure that the fruit pulp remains at this temperature for 10 min. An efficacy test was conducted that involved treating 730 mangoes, with an average weight of 326 +/- 2.11 g (mean +/- SE) and infested with 84 +/- 1.15 first instars. In this test, none of the 61,720 larvae treated survived. The confirmatory test was performed using commercial equipment in which 1,112 infested mango fruit weighing an average of 329 +/- 2.11 g were treated. Each fruit was previously infested with an average of 59 +/- 0.61 first instars (= 65,825 total larvae) of which none survived. The data collected on mango quality indicate that hot water immersion for 95 min at 46.1-47 degrees C can produce a more uniform fruit-color and positively modify the pH (producing more palatable fruits), but can also produce a loss of firmness and weight (5%). Taking all factors into consideration, we conclude that this treatment is sufficient to meet quarantine restrictions against C. capitata while maintaining market quality at least for 15 d. PMID- 23356058 TI - Host status of commercial mango cultivars to Thaumatotibia leucotreta (Lepidoptera: Tortricidae) in South Africa. AB - The objective of this study was to determine the host status of commercially cultivated mango fruit, Mangifera indica L. (Anacardiaceae) to Thaumatotibia leucotreta (Meyrick) (Lepidoptera: Tortricidae) in South Africa. T. leucotreta was monitored with parapheromone traps in mango orchards in Limpopo and Mpumalanga from 2007 to 2010. Fruit were inspected for the presence of T leucotreta eggs in mango orchards. Mango fruit of the cultivars 'Tommy Atkins', 'Kent', 'Keitt', and 'Sensation' were artificially infested with T. leucotreta eggs on the tree to determine if the larvae were able to develop in fruit. Mature fruit of these cultivars were harvested and were then exposed to T leucotreta eggs and the larval development monitored. Before harvest, fruit were inspected for natural infestations and a packhouse survey was conducted during the 2009 2010 season to determine if any infested fruit were present. T. leucotreta was present in all mango orchards where monitoring was done with traps but no eggs were found on the fruit, which suggests the presence of antixenosis. Development occurred in mature harvested fruit of all cultivars that had been exposed to T. leucotreta eggs. Depending on the cultivar, between 0 and 5.05% of immature fruit on the tree supported development and demonstrate antibiosis. No naturally infested fruit were found in the orchards or during the packhouse survey. Mango in South Africa is not a natural host for T. leucotreta. Mature mango fruit is an acceptable host for T. leucotreta larval development under artificial conditions. The latex plays an important role in the resistance mechanism of mango fruit to T. leucotreta. PMID- 23356059 TI - Cold tolerance and disinfestation of Bactrocera invadens (Diptera: Tephritidae) in 'Hass' avocado. AB - Bactrocera invadens (Diptera: Tephritidae) has spread rapidly across Africa and currently poses a phytosanitary threat to the fruit industry of South Africa. In reaction a cold mitigating treatment to provide phytosanitary security to importing countries was developed in Nairobi, Kenya. Using laboratory reared fruit flies, the rate of development in 'Hass' avocado (Persea americana Miller) was determined at 28 degrees C. Fruit ripeness or softness was found to be a factor improving larval fruit fly survival. Using this information the egg and larval developmental stages were subjected to 2 degrees C cold treatment and it was found that the third instars were the most cold tolerant life stage and that it was expected that between 16 and 17 d treatment would provide phytosanitary security. There were no survivors in the treatment of an estimated 153,001 individuals in four replicates at an average fruit pulp temperature of 2 degrees C satisfying the Probit 9 level of efficiency at a confidence of >95%. These data provide evidence that a continuous cold treatment of 1.5 degrees C or lower for 18 d would provide phytosanitary security in that any consignment entering an importing country poses no risk of accidental importation of B. invadens. PMID- 23356060 TI - Irradiation for quarantine control of the invasive light brown apple moth (Lepidoptera: Tortricidae) and a generic dose for tortricid eggs and larvae. AB - The effects of irradiation on egg, larval, and pupal development, and adult reproduction in light brown apple moth, Epiphyas postvittana (Walker) (Lepidoptera: Tortricidae),were examined. Eggs, neonates, third instars, fifth instars, and early stage pupae were irradiated at target doses of 60, 90, 120, or 150 Gy or left untreated as controls in replicated factorial experiments and survival to the adult stage was recorded. Tolerance to radiation generally increased with increasing age and developmental stage. A radiation dose of 120 Gy applied to eggs and neonates prevented adult emergence. A dose of 150 Gy prevented adult emergence in larvae at all stages. In large-scale validation tests, a radiation dose of 150 Gy applied to fifth instars in diet, apples or peppers resulted in no survival to the adult stage in 37,947 treated individuals. Pupae were more radio tolerant than larvae, and late stage pupae were more tolerant than early stage pupae. Radiation treatment of late pupae at 350 and 400 Gy resulted in three and one fertile eggs in 4,962 and 4,205 total eggs laid by 148 and 289 mating pairs, respectively. For most commodities, the fifth instar is the most radio tolerant life stage likely to occur with the commodity; a minimum radiation dose of 150 Gy will prevent adult emergence from this stage and meets the zero tolerance requirement for market access. For traded commodities such as table grapes that may contain E. postvittana pupae, a radiation dose > 400 Gy may be necessary to completely sterilize emerging adults. After review of the literature, a generic radiation treatment of 250 Gy is proposed for tortricid eggs and larvae in regulated commodities. PMID- 23356061 TI - Parasitism by Ixodiphagus wasps (Hymenoptera: Encyrtidae) in Rhipicephalus sanguineus and Amblyomma ticks (Acari: Ixodidae) in three regions of Brazil. AB - Hymenopteran parasitoids have been shown to be of potential value in tick biocontrol. Tick parasitoids has been reported only once in Brazil, over 95 yr ago when Ixodiphagus hookeri (Howard) was reported parasitizing Rhipicephalus sanguineus (Latreille) nymphs in Rio de Janeiro. Herein, we report the occurrence of Ixodiphagus spp. in ticks from three different regions of Brazil. In the state of Maranhao, in northeastern Brazil, parasitoids were detected in R. sanguineus nymphs on three occasions, during August 2009 and September 2010 (dry season), and January 2011 (rainy season). All parasitoids found in northeastern Brazil were identified as I. hookeri. In the state of Mato Grosso do Sul (west-central Brazil), one Amblyomma sp. engorged nymph was shown to be parasitized by I. hookeri. In the state of Rondonia (northern Brazil), one Amblyomma sp. engorged nymph was parasitized by Ixodiphagus texanus (Howard). Because Ixodiphagus spp. are present in ecologically distinct and geographically distant areas of Brazil, they are of potential use for biocontrol in the country. PMID- 23356062 TI - Short and long-term effects of endosulfan, cypermethrin, spinosad, and methoxyfenozide on adults of Chrysoperla externa (Neuroptera: Chrysopidae). AB - The susceptibility assessment of natural enemies to pesticides is relevant before the use of selective pesticides and biological control agents within the framework of integrated pest management programs. Chrysoperla externa (Hagen) (Neuroptera: Chrysopidae) is a predator considered a potential biocontrol agent of agricultural pests in the Neothropical Region. The aim of this study was to evaluate the short and long-term effects of two broad spectrum insecticides (cypermethrin and endosulfan) and two biorational (spinosad and methoxyfenozide) registered in Argentina on young C. externa adults under laboratory conditions by ingestion through drinking water. The assessed end-points were: survivorship during preoviposition period, preoviposition time, fecundity and fertility of females, and survivorship of the progeny. Total survivorship of adults was adversely affected only by cypermethrin that reduced the survivorship of adults irrespective of sex. Although endosulfan did not induce significant total mortality, it reduced the survivorship of females. All tested insecticides delayed the reproductive maturity of adults. Cypermethrin, endosulfan, and spinosad reduced the fecundity of females. Fertility was affected only by spinosad. Methoxyfenozide was the insecticide inducing the lowest effects on reproductive parameters. No effects were observed on the survival of progeny with any of the tested compounds. In accordance with the International Organization for Biological Control and Noxious Animals and Plants guidelines the insecticides were classified according to its lethal effects in the following toxicity classes: methoxyfenozide, spinosad, and endosulfan class 1 (innocuous): cypermethrin class 2 (moderately toxic). However if sublethal effects are taken into account, spinosad and endosulfan should not be considered innocuous. PMID- 23356063 TI - Using sex pheromone trapping to explore threats to wheat from Hessian fly (Diptera: Cecidomyiidae) in the Upper Great Plains. AB - Before embarking on the 5-10 yr effort it can take to transfer plant resistance (R) genes to adapted crop cultivars, a question must be asked: is the pest a sufficient threat to warrant this effort? We used the recently discovered female produced sex pheromone of the Hessian fly, Mayetiola destructor (Say) (Diptera: Cecidomyiidae),to explore this question for populations in the Upper Great Plains. Methods for pheromone trapping were established and trapping data were used to explore geographic distribution, phenology, and density. The pheromone lure remained attractive for up to 10 d and only attracted male Hessian flies. Traps placed within the crop canopy caught flies but traps placed above the crop canopy did not. Hessian flies were trapped throughout North Dakota starting in the spring and continuing through the summer and autumn. Densities were low in the spring but increased greatly during the early part of the summer, with peak adult emergence taking place at a time (July/August) when spring wheat was being harvested and winter wheat had not yet been planted. In the autumn, adults were found at a time when winter wheat seedlings are growing. The discovery of flies on Conservation Reserve Program land supports the idea that pasture grasses serve as alternate hosts. We conclude that the Hessian fly is a risk to wheat in the Upper Great Plains and predict that global warming and the increasing cultivation of winter wheat will add to this risk. PMID- 23356064 TI - Improved chemical control for the Mexican rice borer (Lepidoptera Crambidae) in sugarcane: larval exposure, a novel scouting method, and efficacy of a single aerial insecticide application. AB - A three-treatment aerial application insecticide experiment was conducted in five commercial sugarcane, Saccharum spp., fields in south Texas to evaluate the use of pheromone traps for improving chemical control of the Mexican rice borer, Eoreuma loftini (Dyar), in 2009 and 2010. A threshold of 20 moths/trap/wk was used to initiate monitoring for larval infestations. The percentage of stalks with larvae on plant surfaces was directly related to the number of moths trapped. Reductions in borer injury and adult emergence were detected when a threshold of >5% of stalks with larvae present on plant surfaces was used to trigger insecticide applications. Novaluron provided superior control compared with beta-cyfluthrin; novaluron treated plots were associated with a 14% increase in sugar production. A greenhouse experiment investigating establishment and behavior of E. loftini larvae on two phenological stages of stalkborer resistant, HoCP 85-845, and susceptible, HoCP 00-950, sugarcane cultivars determined that more than half of larvae on HoCP 00-950 and > 25% on HoCP 85-845 tunneled inside leaf mid-ribs within 1 d of eclosion, protected therein from biological and chemical control tactics. Exposure time of larvae averaged < 1 wk for all treatments and was shortest on immature HoCP 00-950 and longest on mature HoCP 85 845. This study shows a short window of vulnerability of E. loftini larvae to insecticide applications, and demonstrates the potential utility of pheromone traps for improving insecticide intervention timing such that a single properly timed application may be all that is required. PMID- 23356065 TI - Development of a plant-based threshold for tarnished plant bug (Hemiptera: Miridae) in cotton. AB - The tarnished plant bug, Lygus lineolaris (Palisot de Beauvois), is an important pest of cotton, Gossypium hirsutum L., in the mid-southern United States. It is exclusively controlled with foliar insecticide applications, and sampling methods and thresholds need to be revisited. The current experiment was designed to establish a plant-based threshold during the flowering period of cotton development. Experiments were conducted in MisSissippi in 2005 and 2006, Arkansas in 2005, and Louisiana in 2005 through 2008. Treatments consisted of various combinations of thresholds based on the percentage of dirty squares that were compared with the current threshold with a drop cloth or automatic weekly applications. Dirty squares were characterized as those with yellow staining on the developing bud resulting from tarnished plant bug excrement. Treatments consisted of 5, 10, 20, and 30% dirty squares. Each plot was sampled weekly, and insecticides were applied when the mean of all replications of a particular treatment reached the designated threshold. At the end of the season, plots were harvested and lint yields were recorded. Differences were observed in the number of applications and yields among the different treatments. The 10% dirty squares threshold resulted in a similar economic return compared with the drop cloth. A threshold of 10% dirty squares resulted in a similar number of insecticide applications, yields, and economic returns compared with that observed with the drop cloth. These results suggest that a threshold of 10% dirty squares could be used to trigger insecticide applications targeting tarnished plant bugs in flowering cotton. PMID- 23356066 TI - Efficacy of imidacloprid, trunk-injected into Acer platanoides, for control of adult Asian longhorned beetles (Coleoptera: Cerambycidae). AB - Feeding experiments with Asian longhorned beetles (Anoplophora glabripennis (Motschulsky)) in a quarantine laboratory were used to assess the effectiveness of imidacloprid in reducing adult fecundity and survival. The beetles were fed twigs and leaves cut between June-September 2010 from Norway maples (Acer platanoides L.) in the beetle-infested area of Worcester, MA. Treated trees had been trunk-injected once with imidacloprid in spring 2010 under the U.S. Department of Agriculture-Animal and Plant Health Inspection Service operational eradication program. The 21 d LC50 value for adult beetles feeding on twig bark from imidacloprid-injected trees was 1.3 ppm. Adult reproductive output and survival were significantly reduced when beetles fed on twig bark or leaves from treated trees. However, results varied widely, with many twig samples having no detectable imidacloprid and little effect on the beetles. When twigs with > 1 ppm imidacloprid in the bark were fed to mated beetles, the number of larvae produced was reduced by 94% and median adult survival was reduced to 14 d. For twigs with < 1 ppm imidacloprid, 68% of reproductively mature mated beetles survived 21 d and 56% of unmated recently eclosed beetles survived 42 d. For twigs with < 1 ppm, beetles ingested an average of 30 nanograms of imidacloprid per day. Bark consumption was reduced at higher imidacloprid levels (> 1 ppm). When given a choice of control twigs and twigs from injected trees, beetles did not show a strong preference. PMID- 23356068 TI - Developmental biology of an exotic scale, Acutaspis albopicta (Hemiptera: Diaspididae). AB - Acutaspis albopicta (Cockerell) is one of seven exotic scale species detected on shipments of'Hass' avocados entering California from Mexico. Here, we present the results of experiments to elucidate basic life history parameters of this species. The scale only reproduces sexually with unmated females producing no offspring. Unmated females survived up to 14 wk after settling on host fruits, whereas males survived for up to 62 h, with the majority dying within 46 h after emergence. Females laid a mean of 52.0 +/- 2.8 eggs (range, 5-171 eggs). Lower humidity (50%) was detrimental to the survival of male scales compared with high humidity (75%), especially during the pupal stage. The optimal temperature for development of both sexes was 25 degrees C. At this temperature, females developed from first instars to adults in approximately 28 d, whereas males emerged from their pupal cases after approximately 37 d. The adjusted lower developmental thresholds for females and males were 13.2 and 13.4 degrees C, respectively. The upper developmental threshold for both females and males was approximately 32 degrees C. Total development from first instar to adult female was 329 degree days and to emerged male, 433 degree days. PMID- 23356067 TI - Identification of a male-produced aggregation pheromone for Monochamus scutellatus scutellatus and an attractant for the congener Monochamus notatus (Coleoptera: Cerambycidae). AB - We report identification and field testing of 2-(undecyloxy)-ethanol (monochamol) as a sex-specific, aggregation pheromone component produced by males of Monochamus scutellatus scutellatus (Say) (Coleoptera: Cerambycidae), a longhorned beetle native to North America. A congener, Monochamus notatus (Drury), which uses the same hosts as M. s. scutellatus, also was attracted to this compound in field trials, suggesting it may be a pheromone component for this species as well. Panel traps were deployed along transects at each of five field sites in May 2010 to test attraction of native beetle species to a suite of cerambycid pheromone components, including monochamol, 3-hydroxyhexan-2-one, (2R*,3R*)- and (2R*, 3S*)-2,3-hexanediol, racemic (E/Z)-fuscumol, and (E/Z)-fuscumol acetate. In total, 209 adult M. s. scutellatus (136 females, 73 males) and 20 M. notatus (16 females, four males) were captured, of which 86 and 70%, respectively, were captured in traps baited with monochamol (means significantly different). Analysis of headspace volatiles from adult M. s. scutellatus by coupled gas chromatography-mass spectrometry and gas chromatography-electroantennogram detection confirmed that monochamol was produced only by males. Monochamol was not found in headspace extracts from adult M. notatus. This study provides further evidence that monochamol is a pheromone component common to several species in the genus Monochamus. The pheromone component should prove useful for monitoring native species for management purposes or conservation efforts, and for quarantine monitoring for exotic species. PMID- 23356069 TI - Hunting billbug (Coleoptera: Curculionidae) life cycle and damaging life stage in North Carolina, with notes on other billbug species abundance. AB - In the southeastern United States, hunting billbug, Sphenophorus venatus vestitus Chittenden, adults are often observed in turfgrass, but our knowledge of their biology and ecology is limited. Field surveys and experiments were conducted to determine the species composition, life cycle, damaging life stage, and distribution of billbugs within the soil profile in turfgrass in North Carolina. Linear pitfall trapping revealed six species of billbug, with the hunting billbug making up 99.7% of all beetles collected. Data collected from turf plus soil sampling suggest that hunting billbugs have two overlapping generations per year in North Carolina and that they overwinter as both adults and larvae. Field experiments provided evidence that adult hunting billbugs are capable of damaging warm season turfgrasses. PMID- 23356070 TI - Developing detection and monitoring strategies for Planococcus minor (Hemiptera: Pseudococcidae). AB - A pheromone-based system to locate and monitor Planococcus minor (Maskell), a pest of over 250 plants including citrus, grape, and cacao, was tested. The difficulty in distinguishing P. minor from the citrus mealybug, P. citri, makes finding and evaluating the impact of the pest challenging. Studies conducted in Puerto Rico determined that synthetic P. minor pheromone lures preaged 120 d in the field caught similar number of males as lures not aged (fresh). Molecular analysis of trapped mealybug males using mitochondrial cytochrome oxidase-1, the internal transcriber space two locus, and 28S-D2 gene showed the pheromone traps to be species specific. Traps baited with P. minor pheromone were used to monitor the pest in south Florida and to locate potential infestations. P. minor males were found at all locations studied in South Florida and were present in low numbers (1.03 +/- 0.69 mean +/- SE/trap/14 d). Over 14,000 terminals, fruit, and flowers were visually inspected over a 6 mo period of peak trap catches before the first adult P. minor female was found. The synthetic pheromone lures proved to be an effective tool to locate and monitor this pest new to the continental United States. PMID- 23356071 TI - Use of light traps and differing light color to investigate seasonal abundance of the date palm pest, Oryctes agamemnon arabicus (Coleoptera: Scarabaeidae). AB - Oryctes agamemnon arabicus (Fairmaire) (Coleoptera: Scarabaeidae) is a date palm insect pest that causes damage to trunk and roots and can damage grass lawns in the United Arab Emirates (UAE) and other countries such as Oman, Saudi Arabia, and Tunisia. The goal of this study was to monitor population dynamics and to evaluate six light colors (white, green, red, yellow, blue, and infrared) and two lamp types (mercury and energy-saving) in light traps. Experiments were performed on a date palm farm during a 2 yr period (2010 and 2011). It was found that this insect is a univoltine pest with a single population peak. Adults appeared in the field around middle of April and early May and the population continued to build until maximum numbers were reached in mid June. No adults were found after the end of September. Photoperiod showed a significant correlation with the changes in adult population size. White light emitted from mercury lamps attracted significantly more O. agamemnon arabicus adults compared with the other tested light colors. Increasing the wattage of mercury lamps from 160 to 250 watt did not significantly increase the number of collected insects. The results demonstrated that light traps equipped with 160-watt mercury lamps emitting white light collected significantly the highest number of this insect among the other tested lamps. PMID- 23356072 TI - Evidence for potential of managing some African fruit fly species (Diptera: Tephritidae) using the mango fruit fly host-marking pheromone. AB - We investigated conspecific and heterospecific oviposition host discrimination among four economically important fruit fly pests of mango in Africa (Ceratitis capitata, Wiedemann; C. fasciventris, Bezzi; C. rosa, Karsch, and C. cosyra, Walker) with regard to host-marking behavior and fecal matter aqueous solutions. The objective of the study was to get insight into the potential of managing these pests using the host-marking technique. Observations were done on mango slices marked by the flies and treated with aqueous solutions of fecal matter of the flies, respectively. In both host-marking and fecal matter experiments, C. cosyra, which is the most destructive species of the four on mango, was exceptional. It only discriminated against hosts treated with its fecal matter but with lower sensitivity while C. capitata and C.fasciventris discriminated against hosts marked by it or treated with its fecal matter and with higher sensitivity. Our results provide evidence for potential of managing some of the major fruit fly species infesting mango in Africa using the host-marking pheromone of the mango fruit fly, C. cosyra. PMID- 23356073 TI - Inexpensive trap for monitoring the green June beetle. AB - Green June beetle, Cotinis nitida (L.), is an important pest of grapes, peaches, blackberries, blueberries, apples, and pears. Currently, there is no inexpensive, commercially available lure or trap that could serve monitoring green June beetle adults. The objective of this study was to develop and optimize an inexpensive bottle trap baited with isopropanol to attract and capture green June beetle adults. Bottle traps baited with 8 mm diameter cotton wicked dispensers emitted from 9 to 43 ml isopropanol in 48 h and maintained that alcohol at a fairly constant concentration compared with the prototypical bottle trap with large surface evaporation of isopropanol poured into the bottom of the trap. Over 5 d, the isopropanol in the wicked dispensers remained at the same stable concentration of 45-44.5%, whereas isopropanol concentration in the bottom of prototypical traps dropped from 45% to approximately 11% after 24 h and to 0.2% by 48 h. Bottle traps with isopropanol dispensers and cotton wicks of 4, 6, or 8 mm in diameter caught significantly more green June beetles than did prototypical bottle traps with no dispensers. Isopropanol concentrations of 45.5, 66, and 91% attracted more green June beetle adults than the lower concentrations. Significantly more green June beetle adults were attracted to traps with dispensers set at 1.3 m height than those at lower heights, and traps topped with a blue, orange, or white band captured more green June beetle adults than those with bands of other colors. The optimized bottle trap is made from recycled transparent polyethylene terephthalate beverage bottle (710-ml; 24 oz.) with a blue, orange, or white band, baited with an 8 mm cotton wick dispenser of 45.5% isopropanol and hung at a height of 1.3 m. Cost and uses for this trap are discussed. PMID- 23356074 TI - Biological control strategies for the South American tomato moth (Lepidoptera: Gelechiidae) in greenhouse tomatoes. AB - The South American tomato pinworm, Tuta absoluta (Meyrick) has been introduced into new geographic areas, including the Mediterranean region, where it has become a serious threat to tomato production. Three greenhouse trials conducted in tomato crops during 2009 and 2010 explored control strategies using the egg parasitoid Trichogramma achaeae Nagaraja and Nagarkatti compared with chemical control. The effectiveness of the predator Nesidiocoris tenuis (Reuter) was also tested. In greenhouses with early pest infestations (discrete generations), periodic inundative releases (eight releases at a rate of 50 adults/m2, twice a week) were necessary to achieve an adequate parasitism level (85.63 +/- 5.70%) early in the growing season. However, only one inoculative release (100 adults/m2) was sufficient to achieve a comparatively high parasitism level (91.03 +/- 12.58%) under conditions of high pest incidence and overlapping generations. Some intraguild competition was observed between T. achaeae and the predator, N. tenuis. This mirid species is commonly used in Mediterranean greenhouse tomato crops for the control of the sweetpotato whitefly, Bemisia tabaci (Gennadius). Tomato cultivars were also observed to influence the activity of natural enemies, mainly N. tenuis (whose average numbers ranged between 0.17 +/- 0.03 and 0.41 +/- 0.05 nymphs per leaf depending on the cultivar). This may be because of differences in plant nutrients in different cultivars, which may affect the feeding of omnivorous insects. In contrast, cultivar effects on T. achaeae were less apparent or possibly nonexistent. Nevertheless, there was an indirect effect in as much as T. achaeae was favored in cultivars not liked by N. tenuis. PMID- 23356075 TI - Effects of reduced-risk pesticides and plant growth regulators on rove beetle (Coleoptera: Staphylinidae) adults. AB - In many regions, pest management of greenhouse crops relies on the use of biological control agents; however, pesticides are also widely used, especially when dealing with multiple arthropod pests and attempting to maintain high esthetic standards. As such, there is interest in using biological control agents in conjunction with chemical control. However, the prospects of combining natural enemies and pesticides are not well known in many systems. The rove beetle, Atheta coriaria (Kraatz), is a biological control agent mainly used against fungus gnats (Bradysia spp.). This study evaluated the effects of reduced-risk pesticides and plant growth regulators on A. coriaria adult survival, development, and prey consumption under laboratory conditions. Rove beetle survival was consistently higher when adults were released 24 h after rather than before applying pesticides. The pesticides acetamiprid, lambda-cyhalothrin, and cyfluthrin were harmful to rove beetle adults, whereas Beauveria bassiana (Balsamo) Vuillemin, azadirachtin, and organic oils (cinnamon oils, rosemary oil, thyme oil, and clove oil) were nontoxic to A. coriaria adults. Similarly, the plant growth regulators acymidol, paclobutrazol, and uniconazole were not harmful to rove beetle adults. In addition, B. bassiana, azadirachtin, kinoprene, organic oils, and the plant growth regulators did not negatively affect A. coriaria development. However, B. bassiana did negatively affect adult prey consumption. This study demonstrated that A. coriaria may not be used when applying the pesticides, acetamiprid, lambda-cyhalothrin, and cyfluthrin, whereas organic oils, B. bassiana, azadirachtin, and the plant growth regulators evaluated may be used in conjunction with A. coriaria adults. As such, these compounds may be used in combination with A. coriaria in greenhouse production systems. PMID- 23356076 TI - Efficacy of commercially available ultrasonic pest repellent devices to affect behavior of bed bugs (Hemiptera: Cimicidae). AB - Little is known about the potential for acoustic communication in bed bugs, Cimex lectularius L. (Hemiptera: Cimicidae), or the use of sound as cues in host location, although many hemipterans are known to communicate with sound. Most behavioral research has focused on bed bug pheromones that are used in aggregation and as alarm signals. We investigated the influence of sound as a deterrent and as an attractant, either of which could ultimately be used to monitor and control bed bugs. Female bed bugs were tested in two-choice tests with four different commercially available ultrasonic repellent devices. We found that female bed bugs were equally likely to occur in arenas with or without sound produced by ultrasonic devices. These devices did not repel or attract bed bugs during choice trials. However, more bed bugs preferred the middle corridor between the test (sound) and control (no sound) arenas when the sound devices were played. Bed bugs were also more likely to exit the middle corridor during control trials compared with treatment trials with ultrasonic devices. Our results confirm that commercial devices producing ultrasound are not a promising tool for repelling bed bugs. PMID- 23356077 TI - Repellent, antifeedant, and toxic activities of Lantana camara leaf extract against Reticulitermes flavipes (Isoptera: Rhinotermitidae). AB - This study investigated biological activity of chloroform extract of dry Lantana camara 'Mozelle' leaves against the eastern subterranean termite, Reticulitermes flavipes (Kollar), an important structural pest. Repellent activity was assessed using a paper-disc choice test and a sand arena choice test. Antifeedant and toxic properties were assessed using a no-choice paper test and a topical application method. In the choice tests, significantly fewer termites made contact with treated paper-discs at test concentrations > or = 0.016 mg/cm2 (equivalent to 0.0023 wt:wt) or tunneled into treated sand at test concentrations > or = 0.125 mg/g, compared with control. In the no-choice tests, termite feeding activity was significantly reduced and termite mortality was greatly increased in treatments than control. Exposure to filter paper treated at 0.212 and 0.106 mg/cm2 (equivalent to 0.03 and 0.015 wt:wt) resulted in > 90% mortality and 78% reduction in feeding, and approximately 52% mortality and 40% reduction in feeding, respectively. Top-dorsal application led to > 60% mortality at 4 microg/termite. This study showed that the chloroform leaf extract of L. camara had excellent repellent and moderate toxic and antifeedant activities. PMID- 23356078 TI - Susceptibility and selectivity of Cnaphalocrocis medinalis (Lepidoptera: Pyralidae) to different cry toxins. AB - Effectiveness of four Cry toxins (Cry1Ac, Cry1Aa, Cry1Ab, and Cry1C) on Cnaphalocrocis medinalis (Guenee) (Lepidoptera: Pyralidae), collected from paddy fields in Jiaxing, Zhejiang Province, China, was evaluated in the laboratory. Bioassays showed that C. medinalis had different susceptibilities against four Cry toxins. The LC50 values of Cry1Ac, Cry1Ab, Cry1Aa, and Cry1C against C. medinalis were 0.405, 1.111, 1.939, and 1.246 microg/ml, respectively. Furthermore, the mortality of C. medinalis against different Cry toxins showed different results over time and LT50 values of Cry1Ac, Cry1Ab, Cry1Aa, and Cry1C against C. medinalis were 1.5, 2.3, 1.6, and 2.2 d, respectively. Preference of the larvae to Cry toxins revealed that C. medinalis larvae had no significant feeding preference on leaves without Bacillus thuringiensis (Bacillales: Bacillaceae; [Bt]) toxin compared with those containing Bt toxin. However, different Cry toxins had different attractive abilities to C. medinalis larvae. During 8 h after infestation, C. medinalis larvae preferred the leaves with Cry1Ab (22.4-27.6%) over those with Cry1Ac or Cry1C. PMID- 23356079 TI - Resistance monitoring and assessment of resistance risk to pymetrozine in Laodelphax striatellus (Hemiptera: Delphacidae). AB - Laodelphax striatellus (Fallen) is a major pest of cultivated rice. Pymetrozine, a pyridine azomethine compound, represents a novel insecticide with a selective activity against sucking pests. The resistance of L. striatellus to thiamethoxam, nitenpyram, chlorpyrifos, and pymetrozine in five field populations, collected from Jiangsu, Anhui, and Zhejiang in China, was monitored from 2009 to 2011 in laboratory. All the populations kept susceptible to minor resistance to thiamethoxam and nitenpyram in the 3 yr (0.6- to 2.2-fold and 0.8- to 3.8-fold, respectively), while the insects developed low to high level resistance to chlorpyrifos (9.7- to 76.1-fold). Three populations were all susceptible to pymetrozine (1.1- to 2.1-fold) in 2009, but the Wuxi and Yancheng populations developed low level resistance to pymetrozine (5.5-fold and 5.3-fold, respectively) in 2011. Meanwhile, the resistance level of the selected strain reared in laboratory increased by 1.0-fold after 12-generation selection with pymetrozine. The realized heritability (h2) of resistance at different selection stages was estimated as 0.0470 (F1 to F13) and 0.2070 (F5 to F13) by using threshold trait analysis. It suggested that L. striatellus had the definite risk of resistance to pymetrozine. PMID- 23356080 TI - Genetic structure and gene flow among Brazilian populations of Heliothis virescens (Lepidoptera: Noctuidae). AB - Population genetic studies are essential to the better application of pest management strategies, including the monitoring of the evolution of resistance to insecticides and genetically modified plants. Bacillus thuringiensis Berliner (Bt) crops have been instrumental in controlling tobacco budworm, Heliothis virescens (F.) (Lepidoptera: Noctuidae), a pest that has developed resistance to many common insecticides once used for its management. In our study, microsatellite markers were applied to investigate the genetic structure and patterns of gene flow among Brazilian populations of H. virescens from cotton, Gossypium hirsutum L., and soybean, Glycine max (L.) Merr., fields, aiming to propose means to improve its management in the field. In total, 127 alleles were found across nine microsatellites loci for 205 individuals from 12 localities. Low levels of gene flow and moderate to great genetic structure were found for these populations. Host plant association, crop growing season, and geographic origin were not responsible for the genetic structuring among Brazilian populations of H. virescens. Other factors, such as demographic history and seasonal variability of intrapopulation genetic variation, were suggested to be molding the current pattern of genetic variability distribution. PMID- 23356081 TI - Phylogeography of Anastrepha obliqua inferred with mtDNA sequencing. AB - Anastrepha obliqua (Macquart) (Diptera: Tephritidae), the West Indian fruit fly, is a frugivorous pest that occasionally finds its way to commercial growing areas outside its native distribution. It inhabits areas in Mexico, Central and South America, and the Caribbean with occasional infestations having occurred in the southern tier states (California, Florida, and Texas) of the United States. This fly is associated with many plant species and is a major pest of mango and plum. We examine the genetic diversity of the West Indian fruit fly based on mitochondrial COI and ND6 DNA sequences. Our analysis of 349 individuals from 54 geographic collections from Mexico, Central America, the Caribbean, and South America detected 61 haplotypes that are structured into three phylogenetic clades. The distribution of these clades among populations is associated with geography. Six populations are identified in this analysis: Mesoamerica, Central America, Caribbean, western Mexico, Andean South America, and eastern Brazil. In addition, substantial differences exist among these genetic types that warrants further taxonomic review. PMID- 23356082 TI - Expression of cytoplasmic incompatibility and host fitness effects in field populations of Sogatella furcifera infected with Cardinium. AB - 'Candidatus Cardinium' is a maternally inherited intracellular bacterium that infects a wide range of arthropods and causes diverse reproductive alterations of its arthropod hosts, including cytoplasmic incompatibility (CI), parthenogenesis and feminization. CI is the most common effect and is expressed as a reduction in the number of offspring in crosses between infected males and uninfected females (or females infected with a different bacterial strain). The white-backed planthopper Sogatella furcifera (Horvath) is a major rice pest in Asia and is a vector of the Southern rice black-streaked dwarf virus (SRBSDV). In this study, we found severe CI expression induced by Cardinium in Yunnan and Guangxi populations of S. furcifera by performing four crosses of Cardinium-infected (C) and uninfected (U) planthoppers: female U x male U, female U x male C, Female C x Male U, Female C x Male C. Investigations of the fitness costs and benefits of Cardinium infection in these populations showed that it had no effect on the fecundity of females, but could shorten the developmental time of nymphs. PMID- 23356083 TI - Inheritance of resistance to Aphis glycines in soybean P746 from China. AB - The soybean aphid (Aphis glycines Matsumura) is one of the most serious pests of soybean (Glycine max [L.] Merrill) worldwide. Aphid resistance genes have been identified. However, little is known about genes for resistance to Chinese soybean aphid strains. The objective of this study was to identify the type of aphid resistance in the soybean cultivar P746 and to determine the inheritance of the resistance. In choice and no-choice tests, significant differences in the average number of aphids and the damage index were observed between P746 and the susceptible cultivar Dongnong 47 11 d and 21 d after aphid infestation. F2 plants and their F2:3 families were tested to identify the mode of inheritance of resistance. The 240 F2 plants segregated into 178 resistant and 62 susceptible plants, which matched an expected 3:1 ratio for inheritance of a single dominant trait. Segregation among F2:3 families also matched a 1:2:1 ratio. These results indicated that a single, dominant gene mediated aphid resistance in P746. This information will be useful to soybean breeders developing antibiosis-resistant soybean cultivars. PMID- 23356084 TI - Evaluation of canola cultivars for resistance to Helicoverpa armigera (Lepidoptera: Noctuidae) using demographic parameters. AB - The cotton bollworm, Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae) is one of the most important pests on a wide range of crops worldwide. The antibiotic resistance of 10 canola cultivars ('Sarigol', 'Hayula420', 'Opera', 'Okapi', 'Modena', 'RGS003', 'Zarfam', 'Licord', 'Talaye', and 'SLM046') to H. arimgera was evaluated using demographic parameters including life table, reproduction, development, and adult longevity. Larval period ranged from 18.8 to 16.1 d on Hayula420 and RGS003, respectively. The longest development time of immature stages was on Sarigol and Hayula420 (36.8 d) and the shortest one was on Zarfam (34.8 d). The highest daily and total fecundity (1,082.4 and 254.8 eggs, respectively) was on RGS003 and the lowest was on Talaye (517.0 and 41.4 eggs, respectively). The r(m) values varied from 0.153 on Sarigol to 0.179 on Opera. The net reproductive rate (R0) was calculated to be lowest on Talaye (157.4) and highest on RGS003 (331.5). The comparison of demographic parameters of H. armigera on different cultivars of canola and the cluster analysis revealed that Hayula420, Talaye, Sarigol, and SLM046 were the most resistant cultivars to this insect. Such results could be useful to develop an integrated pest management strategy of H. armigera on canola cultivars. PMID- 23356085 TI - Multiple categories of resistance to wheat curl mite (Acari: Eriophyidae) expressed in accessions of Aegilops tauschii. AB - The wheat curl mite, Aceria tosichella Keifer, is an important pest in the western plains of the United States as well as in most major wheat-growing regions of the world. This mite is a vector of the economically important diseases wheat streak mosaic virus (WSMV), Triticum mosaic virus (TriMV), and High Plains virus (HPV). This study looked at seven accessions of Aegilops tauschii (Coss) Schmal to determine if they exhibit antibiosis, tolerance, and/or antixenosis to the wheat curl mite using 'Jagger', a known wheat curl mite susceptible variety, and OK05312, a known wheat curl mite-resistant variety, as controls. Four of the seven tested accessions showed antibiotic effects on the population growth of wheat curl mite, as demonstrated by low number of wheat curl mite adults and nymphs at the end of the experiment. Three accessions and the commercial wheat variety Jagger showed some level of tolerance to wheat curl mite infestations, as demonstrated by a significantly reduced percentage proportional tissue dry weight and by tolerance index values. Four accessions demonstrated a strong antixenotic effect on the wheat curl mite, as demonstrated by significantly reduced numbers of mite adults at the end of the experiment. This study also established an effective method for determining antixenosis to the wheat curl mite in wheat that can be used for future experiments. All accessions demonstrated at least one type of plant resistance that could provide a genetic source for control of the wheat curl mite that may have the potential to be transferred into commercial wheat varieties. PMID- 23356087 TI - Attractiveness of an aggregation pheromone lure and chicken droppings to adults and larvae of Alphitobius diaperinus (Coleoptera: Tenebrionidae). AB - The chemical cues by which lesser mealworm, Alphitobius diaperinus (Panzer) (Coleoptera: Tenebrionidae) beetles find each other are still unknown. Laboratory two-choice pitfall bioassays were conducted to evaluate the attractiveness of synthetic aggregation pheromone lure to lesser mealworm adults and larvae. All components of this synthetic aggregation pheromone lure, including: (R)-(+) limonene, (E)-beta-ocimene, (S)-(+)-linalool, (R)-(+)-daucene, and 2-nonanone were also tested singly. Chicken dropping volatile compounds and fresh chicken droppings (CD) were evaluated singly or in combination with the pheromone lure. In Arkansas, trapping experiments were conducted in different poultry houses with low, moderate, and high lesser mealworm populations to evaluate the attraction of pheromone lure. Laboratory two-choice pitfall bioassay was found to be a useful and convenient tool for evaluating the attractants before testing them in the poultry house. Greater attraction of adults and larvae to a dose of 20-30 microg pheromone lure was identified in laboratory two-choice pitfall bioassays. Adults and larvae were highly attractive to a combination of fresh CD and pheromone lure, whereas, a combination of chicken dropping volatile and pheromone lure was not significantly attractive. The low attraction of limonene and linalool in the laboratory two-choice pitfall bioassays suggest that either they are nonattractive or attractive only at a narrow range of concentrations. Higher numbers of lesser mealworm adults and larvae were found in traps treated with pheromone lure as compared with untreated controls in field experiments. Results indicate a potential for combining the pheromone lure with the attractive CD compounds to enhance trap efficacy. PMID- 23356086 TI - Ozone toxicity and walking response of populations of Sitophilus zeamais (Coleoptera: Curculionidae). AB - Ozone is a recognized alternative to the fumigants methyl bromide and phosphine for the control of stored product insects. However, as with fumigants in general, the potential sublethal effects of ozone on targeted insect species may compromise its efficacy and has yet to be investigated. Here, we determined ozone toxicity of 30 field-collected populations of the maize weevil, Sitophilus zeamais (Coleoptera: Curculionidae), and assessed the walking response of adult insects from these populations to sublethal ozone exposure. Time-mortality toxicity to ozone at 50 ppm concentration in a continuous 2 liter/min flow indicated uniform susceptibility among the populations studied without any indication of ozone resistance (toxicity ratios [at LT50] > two-fold). In contrast, there was significant variation in walking activity among the maize weevil populations, which was not correlated with ozone susceptibility. This was not surprising because of the relatively uniform susceptibility to ozone among the maize weevil populations. Respiration rate affected ozone toxicity but not walking activity, whereas body mass was negatively correlated with walking activity but was not correlated with ozone toxicity. Based on our data, lower respiration rates may potentially lead to reduced ozone uptake whereas larger body mass limits walking activity. Ozone seems a promising alternative fumigant with low short-term risk of resistance development because of the high susceptibility and low variability of response to this compound. Furthermore, ozone reduces walking activity of S. zeamais that implies it likely reduces the chances of insects escaping exposure at the early stages of fumigation. PMID- 23356088 TI - Efficacy of amitraz-impregnated collars on white-tailed deer (Artiodactyla: Cervidae) in reducing free-living populations of lone star ticks (Acari: Ixodidae). AB - Over a 7 yr period, we monitored the effect of a commercially available, amitraz impregnated anti-tick collar in controlling free-living populations of lone star ticks, Amblyomma americanum (L.) when manually fitted around necks of white tailed deer, Odocoileus virginianus (Zimmermann). Study animals in treatment and control groups were confined in 38.8 ha game-fenced and densely vegetated treatment plots in South Texas. Tick densities during years 1 and 7 served as untreated pre- and posttreatment comparisons and treatments occurred during years 2 through 5. Reductions in tick densities in the treatment plot were compared against tick densities in a control plot having similar vegetation and numbers of untreated deer. During years of treatment, indices of control pressure ranged from 18.2 to 82.6 for nymphs and 16.9-78.7 for adults, and efficacy, expressed as percentage control during the final year of treatment, was 77.2 and 85.0%, respectively, for nymphal and adult ticks. These data show that acaricidal collar treatments provide efficacies very similar to those achieved with the existing ivermectin-medicated bait and '4-Poster' topical treatment technologies to control ticks feeding on wild white-tailed deer. PMID- 23356089 TI - Attraction of alates of Cryptotermes brevis (Isoptera: Kalotermitidae) to different light wavelengths in South Florida and the Azores. AB - The termite Cryptotermes brevis (Walker) (Isoptera: Kalotermitidae) is an urban pest that causes much damage to wood structures. Little has been done concerning the use of control methods for alates. C. brevis is known to have phototropic behavior during the dispersal flights, and this knowledge has been applied for preventative control in the Azores where this species is a serious urban pest. We were interested in determining whether there was a light wavelength preference by the alates of C. brevis to optimize light traps against this species. Six light wavelengths were tested: 395 nm (UV), 460-555 nm (white), 470 nm (blue), 525 nm (green), 590 nm (yellow), and 625 nm (red) in choice chambers, with dark chambers as controls. Two populations were tested, one population in Florida and one population in the Azores (Terceira Island). We found consistent results for both populations, with a preference for the light wavelengths in the white, blue, and green spectrum (460-550 nm). This information can be used to build more effective light traps that can be used by home owners in the Azores to help control this pest. PMID- 23356090 TI - Medical inpatients' adherence to outpatient psychiatric aftercare: a prospective study of patients evaluated by an inpatient consultation liaison psychiatry service. AB - OBJECTIVE: This study sought to determine whether patients on psychiatric medication evaluated by inpatient consultation psychiatrists followed up with psychiatric aftercare and continued psychiatric medication 8 weeks post discharge. Barriers to care and their effect on aftercare follow-up were assessed. METHOD: This was a prospective study of a consecutive sample of adults who received a psychiatric consultation and were prescribed psychotropic medication during hospitalization on the general medical or surgical inpatient units at the University of Maryland Medical Center. Baseline information was collected from 36 patients who received an inpatient psychiatric consultation and were: (1) prescribed psychiatric medications; and (2) discharged to home. Follow up data was collected from 21 (58.3%) of these patients 8 weeks post-discharge. RESULTS: Of 36 patients who provided baseline data, 93% recognized they had a psychiatric disorder, 90% recognized the importance of taking psychiatric medication, and 80% recognized the importance of psychiatric aftercare. Aftercare recommendations were included in only 33% of patient discharge instructions. Of 21 patients providing follow-up data, 57% reported receiving psychiatric aftercare. Patients who did not receive psychiatric aftercare were significantly more likely to be at risk for poor literacy (88.9% vs. 33.3% Fisher's exact test = 0.024) and were less often given psychiatric aftercare instructions at discharge (22% vs. 42%). CONCLUSIONS: Poor communication of aftercare instructions as well as poor literacy may be associated with lack of psychiatric aftercare. Consultation psychiatrists should assess literacy and insure aftercare information is provided to patients. PMID- 23356091 TI - No correlation between plasma NMDA-related glutamatergic amino acid levels and cognitive function in medicated patients with schizophrenia. AB - OBJECTIVE: Disrupted glutamatergic neurotransmission and cognitive functions are key components in the pathophysiology of schizophrenia. Changes in levels of serum/plasma glutamatergic amino acids, such as glutamate, glycine, and L- and D serine may be possible clinical markers. Following our recent findings that peripheral blood levels of endogenous glycine, alanine, and especially D-serine may reflect the degree/change in symptoms in schizophrenia, here we investigated whether these plasma amino acid levels may also reflect the status of cognitive functions in schizophrenia. METHODS: One hundred eight Japanese patients with schizophrenia were evaluated with cognitive assessment batteries at the time that plasma glutamatergic amino acid levels were measured using high-performance liquid chromatography. For analyzing cognitive functions, batteries for reflection prefrontal cortex cognitive functions, verbal fluency tests, the Stroop test, and the digit span forward and backward tests were administered. RESULTS: Results failed to show a relationship between any plasma glutamatergic amino acid level and cognitive batteries. CONCLUSIONS: Our results suggest that plasma glutamatergic amino acid levels may be significant biological markers that reflect the condition or a dramatic change at the time of testing, especially in severely affected patients, but they do not reflect cognitive function. PMID- 23356092 TI - Spirituality and religion in outpatients with schizophrenia: a multi-site comparative study of Switzerland, Canada, and the United States. AB - OBJECTIVE: To assess the importance of spirituality and religious coping among outpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder living in three countries. METHOD: A total of 276 outpatients (92 from Geneva, Switzerland, 121 from Trois-Rivieres, Canada, and 63 from Durham, North Carolina), aged 18-65, were administered a semi-structured interview on the role of spirituality and religiousness in their lives and to cope with their illness. RESULTS: Religion is important for outpatients in each of the three country sites, and religious involvement is higher than in the general population. Religion was helpful (i.e., provided a positive sense of self and positive coping with the illness) among 87% of the participants and harmful (a source of despair and suffering) among 13%. Helpful religion was associated with better social, clinical and psychological status. The opposite was observed for the harmful aspects of religion. In addition, religion sometimes conflicted with psychiatric treatment. CONCLUSIONS: These results indicate that outpatients with schizophrenia or schizoaffective disorder often use spirituality and religion to cope with their illness, basically positively, yet sometimes negatively. These results underscore the importance of clinicians taking into account the spiritual and religious lives of patients with schizophrenia. PMID- 23356093 TI - Temporal relationships of emotional avoidance in a patient with anorexia nervosa- a time series analysis. AB - OBJECTIVE: Anorexia nervosa (AN) is a serious eating disorder marked by self induced underweight. In patients with AN, the avoidance of emotions appears to be a central feature that is reinforced during the acute state of the disorder. This single case study investigated the role of emotional avoidance of a 25-year-old patient with AN during her inpatient treatment. METHOD: Throughout the course of 96 days, the patient answered questions daily about her emotional avoidance, pro anorectic beliefs, perfectionism, and further variables on an electronic diary. The patient's daily self-assessment of emotional avoidance was described in terms of mean value, range, and variability for the various treatment phases. Temporal relationships between emotional avoidance and further variables were determined using a time series approach (vector autoregressive (VAR) modelling). RESULTS: Diary data reflect that the patient's ability to tolerate unpleasant emotions appeared to undergo a process of change during inpatient treatment. Results of the time series analysis indicate that the more the patient was able to deal with negative emotions on any one day (t-1), the less she would be socially avoidant, cognitively confined to food and eating, as well as feeling less secure with her AN, and less depressive on the following day (t). CONCLUSIONS: The findings show that for this patient emotional avoidance plays a central role in the interacting system of various psychosocial variables. Replication of these results in other patients with AN would support the recommendation to focus more on emotional regulation in the treatment of AN. PMID- 23356094 TI - Psychiatric morbidity as a risk factor for hospital readmission for acute myocardial infarction: an 8-year follow-up study in Spain. AB - BACKGROUND AND OBJECTIVE: Most previous studies assess the effect of depression and other psychiatric variables as risk factors for acute myocardial infarction; however, studies that assess the effect of psychiatric disorders as a whole are scarce, compared with other non-psychiatric factors. The aim of this study is to assess the importance of psychiatric morbidity, compared with other risk factors, in hospital readmission for acute myocardial infarction. METHODS: This is a 8 year follow-up study in which the Hospital Discharge Administrative Database was used. RESULTS: From the total sample (11,062 patients), 590 patients (4.88%) were diagnosed with some mental disorder. Psychiatric disorders were more common in women than in men with myocardial infarction (4.76 % and 6.20%, respectively, p value = 0.002). For those who have had recurrence of stroke, mental disease influences in the consecutive readmission for AMI with the same severity as did tobacco, diabetes, or obesity. CONCLUSIONS: The main finding of this study is the enormous impact of psychiatric disorders on readmissions for AMI, comparable to diabetes, obesity, cerebral vascular disease, and hypertension. Interestingly, the efforts made to treat and prevent psychiatric disorders in AMI patients are clearly lower than those health authorities make with respect to classic risk factors. PMID- 23356095 TI - Factors associated with low bone density among women with major depressive disorder. AB - OBJECTIVE: Previous studies have suggested that depression might be associated with low bone mineral density (BMD) in women with depression. The aim of this study was to investigate the association between the BMD of women with major depressive disorder and correlated factors. METHOD: This prospective cross sectional study explored the association between bone density and major depressive disorder in women. One hundred women diagnosed with major depressive disorder were enrolled. The diagnoses were made by board-certificated psychiatrists using the Mini International Neuropsychiatric Interview (MINI). The Beck Depression Inventory (BDI) was administered. The bone density of the hip was measured with dual X-ray densitometry (DEXA) using a Hologic Delphi QDR-2000 densitometer. RESULTS: We found age, family history of osteoporosis, consumption of coffee, and consumption of tea to be associated with low BMD in single-variate analysis. Depression was also related to BMD, in that the worse the depression, the lower the BMD. Multi-variate analysis by linear regression revealed an equation of BMD = 0.91 - 0.004 x (severity of depression) + 0.07 x (tea consumption)--0.06 x (family history of osteoporosis)--0.04 x age. CONCLUSION: These results suggest that depression is associated with lower BMD, and the associated factors should be considered in depressive women. The findings of this research may be useful for improving the care of women with major depressive disorder in terms of developing appropriate and effective care plans. PMID- 23356096 TI - Factors associated with the type of psychotropic medications purchased for common mental disorders in the largest managed care organization in Israel. AB - OBJECTIVE: To evaluate patient and physician characteristics associated with the type of psychotropic medications (anti-anxiety, antidepressant, or both) purchased. METHODS: The Clalit Health Care Services is the largest managed care health fund in Israel, a country that employs a universal healthcare system. We randomly sampled 30,000 primary care patients over the age of 22 as of January, 2006. RESULTS: Overall, 2,217 purchased either antidepressant or antianxiety medications at least once during the year 2006 and had no prior purchases during the last quarter of 2005. The majority (1,518; 68.4%) purchased only anti-anxiety medications and as many as 264 (12%) purchased both anti-anxiety and antidepressant medications. The remaining 435 (19.6%) patients purchased only antidepressant medications. Physician level characteristics explained only a small portion of the variance and, thus, were not included in further analysis. Several patient level characteristics, including age, somatic, and psychiatric diagnosis were associated with the purchase of different types of medications. CONCLUSIONS: Contrary to clinical guidelines, the purchase of anti-anxiety medications is more prevalent than the purchase of antidepressant medications. In a managed care setting, patient characteristics have a greater role in determining purchasing patterns than provider characteristics; potentially, because of the managed care characteristics that actively guide the care provided to patients. PMID- 23356097 TI - The ethics of postmarketing observational studies of drug safety under section 505(o)(3) of the Food, Drug, and Cosmetic Act. AB - In 2007, Congress granted the Food and Drug Administration (FDA) new powers to order pharmaceutical companies to conduct drug safety studies and clinical trials in the postmarketing period after drugs are approved The methodologies include observational studies that examine patients' insurance claims data and clinical records to infer whether drugs are safe in actual clinical practice. Such studies offer a valuable tool for improving drug safety, but they raise ethical and privacy concerns because they would entail widespread use of patients' health information in commercial research by drug manufacturers. This is the first article to explore the ethics of these section 505(0)(3) observational studies, so named after the section of the Food, Drug, and Cosmetic Act that authorizes them. Data access problems threaten to make the FDA's section 505(0)(3) study requirements unenforceable. Under existing federal privacy regulations, it appears highly unlikely that pharmaceutical companies will have reliable access to crucial data resources, such as insurance claims data and healthcare records, to use in these studies. State privacy laws present another potential barrier to data access. If pharmaceutical companies do manage to gain access to the needed data, this will raise serious privacy concerns because section 505(0)(3) observational studies do not appear to be covered by any of the major federal regulations that afford ethical and privacy protections to persons whose data are used in research. If the FDA's program of section 505(o)(3) observational studies fails because of the above problems, this failure will have a number of bad consequences: the public will be exposed to avoidable drug safety risks; taxpayers may be forced to bear the costs of having the FDA conduct drug safety investigations that would have been funded by drug manufacturers if data had been available; and, perhaps most troubling, the FDA may be forced to order postmarketing clinical trials to answer questions that could have been answered using observational studies. Problems with access to data for section 505(0)(3) studies thus could directly imperil human research subjects by forcing a needless over-reliance on risky postmarketing drug safety trials. This Article concludes by describing a promising new legal pathway for resolving these problems. Congress has provided the FDA a new set of powers that if skillfully exercised will allow the agency: (1) to facilitate pharmaceutical companies' appropriate access to data for use in section 505(0)(3) observational studies, (2) to impose strict ethical and privacy protections for persons whose data are used in these studies, and (3) to mobilize private-sector funding to generate much-needed evidence of the safety of FDA-approved drugs. PMID- 23356099 TI - Deficiencies of the FDA in evaluating generic formulations: addressing narrow therapeutic index drugs. AB - Generic drugs represent a significant portion of the medical arsenal in treating disease. As copies of originator drugs, these drugs have been permitted abbreviated approval under the Hatch-Waxman Act. Yet with the current cost focus upon generic formulations, potential safety issues with generics have arisen. Although there is an established criterion of "bioequivalence" that generic formulations must demonstrate, narrow-therapeutic index drugs for sensitive clinical circumstances such as epilepsy, antiplatelet therapies, and mental health treatments may require different regulatory treatment than other generic drugs. Further, in these circumstances, differences in generic formulations may lead to adverse clinical outcomes due to less stringent bioequivalence tolerances. Yet there is no mandate for comparison between different generic formulations. Countries outside the United States advocate for narrowing tolerance ranges for these high risk health situations and the drugs for their treatment. We argue in this paper that additional patient safety matters must be taken into account for narrow therapeutic disease drugs, and regulatory bodies should emphasize greater tightness in bioequivalence before these narrow therapeutic drug generic formulations are approved. PMID- 23356100 TI - When the First Amendment and public health collide: the Court's increasingly strict constitutional scrutiny of health regulations that restrict commercial speech. PMID- 23356101 TI - "Well beyond" permissible: how severing the Leadership Act's policy requirement affirms our commitment to First Amendment values. PMID- 23356098 TI - Paying for prevention: challenges to health insurance coverage for biomedical HIV prevention in the United States. AB - Reducing the incidence of HIV infection continues to be a crucial public health priority in the United States, especially among populations at elevated risk such as men who have sex with men, transgender women, people who inject drugs, and racial and ethnic minority communities. Although most HIV prevention efforts to date have focused on changing risky behaviors, the past decade yielded efficacious new biomedical technologies designed to prevent infection, such as the prophylactic use of antiretroviral drugs and the first indications of an efficacious vaccine. Access to prevention technologies will be a significant part of the next decade's response to HIV and advocates are mobilizing to achieve more widespread use of these interventions. These breakthroughs, however, arrive at a time of escalating healthcare costs; health insurance coverage therefore raises pressing new questions about priority-setting and the allocation of responsibility for public health. The goals of this Article are to identify legal challenges and potential solutions for expanding access to biomedical HIV prevention through health insurance coverage. This Article discusses the public policy implications of HIVprevention coverage decisions, assesses possible legal grounds on which insurers may initially deny coverage for these technologies, and evaluates the extent to which these denials may survive external and judicial review. Because several of these legal grounds may be persuasive, particularly denials on the basis of medical necessity, this Article also explores alternative strategies for financing biomedical HIV prevention efforts. PMID- 23356102 TI - Cure unwanted? Exploring the chronic Lyme disease controversy and why conflicts of interest in practice guidelines may be guiding us down the wrong path. PMID- 23356103 TI - State acquisition of hospitals: Federal court finds hospital authorities have state-action immunity to engage in anticompetitive activity--Federal Trade Commission v. Phoebe Putney Health System, Inc. PMID- 23356104 TI - California Medicaid amendments: Supreme Court vacates and remands supremacy clause private right of action issue based on changed conditions--Douglas v. Independent Living Center of Southern California. PMID- 23356105 TI - Federal Circuit holds isolated DNA is patent-eligible--Association for Molecular Pathology v. United States Patent and Trademark Office (Myriad III). PMID- 23356106 TI - RE: body mass indices in deployed military personnel and tobacco product usage. PMID- 23356107 TI - "A paradox: military graduate medical education, an open letter to GME". PMID- 23356108 TI - Re: "Spice, bath salts, and the U.S. Military: the emergence of synthetic cannabinoid receptor agonists and cathinones in the U.S. Armed Forces". PMID- 23356109 TI - The U.S. Air Force Diabetes and Obesity Research Working Group: a model for building military-specific clinical research infrastructure. PMID- 23356110 TI - Tobacco product usage among deployed male and female military personnel in Kuwait. PMID- 23356111 TI - Traumatic event management in Afghanistan: a field report on combat applications in regional command-south. AB - This article provides information on the use of Traumatic Event Management (TEM) strategies to debrief combat arms personnel whose units sustained traumatic losses in Afghanistan. The specific focus is on the application of Event-Driven Battlemind Psychological Debriefings to combat units. This article offers the first published account of TEM services employed in southern Afghanistan during intensive surge operations in 2009-2010. This article unfolds in three parts: (1) background to the region in which the debriefings occurred; (2) three case examples with a data summary of types of incidents observed; and (3) discussion of observations, lessons learned, and recommendations for training future clinicians to provide effective debriefings to combat arms personnel. PMID- 23356112 TI - Occurrence of secondary insults of traumatic brain injury in patients transported by critical care air transport teams from Iraq/Afghanistan: 2003-2006. AB - Traumatic brain injury patients are susceptible to secondary insults to the injured brain. A retrospective cohort study was conducted to describe the occurrence of secondary insults in 63 combat casualties with severe isolated traumatic brain injury who were transported by the U.S. Air Force Critical Care Air Transport Teams (CCATT) from 2003 through 2006. Data were obtained from the Wartime Critical Care Air Transport Database, which describes the patient's physiological state and care as they are transported across the continuum of care from the area of responsibility (Iraq/Afghanistan) to Germany and the United States. Fifty-three percent of the patients had at least one documented episode of a secondary insult. Hyperthermia was the most common secondary insult and was associated with severity of injury. The hyperthermia rate increased across the continuum, which has implications for en route targeted temperature management. Hypoxia occurred most frequently within the area of responsibility, but was rare during CCATT flights, suggesting that concerns for altitude-induced hypoxia may not be a major factor in the decision when to move a patient. Similar research is needed for polytrauma casualties and analysis of the association between physiological status and care across the continuum and long-term outcomes. PMID- 23356113 TI - Myopericarditis and pericarditis in the deployed military member: a retrospective series. AB - In this study, we investigated the incidence and etiology of pericarditis and myopericarditis of military members deployed to Iraq and Kuwait from 2004 through 2008. The importance of acute pericarditis and myopericarditis in the deployed military service member has resurfaced with the reintroduction of the smallpox vaccination by the U.S. Department of Defense in 2002. There are limited epidemiologic data on acute pericarditis and myopericarditis in the general population. As a primary evacuation node for cardiology patients between 2004 and 2008, the United States Military Hospital Kuwait cardiology clinic was uniquely situated to reliably extrapolate epidemiologic data for U.S. Armed Service Members serving in the Middle East. Between these years, approximately 721,600 service members served in Kuwait and Iraq. A total of 70 cases of pericarditis and 9 cases of myopericarditis were diagnosed. This yields an estimated incidence of 7.4 and 0.95 cases per 100,000 per year for pericarditis and myopericarditis, respectively. A total of eleven patients had received the smallpox vaccine 4 to 30 days before being diagnosed with pericarditis or myopericarditis. Four of the eleven patients (36.3%) had pericarditis, with a mean duration of 28.3 days since vaccination. Seven of these eleven (63.6%) patients had myopericarditis, with a mean duration of 13.7 days since smallpox vaccination. The incidence of pericarditis and myopericarditis was lower than previously reported incidence rates in the population. In all cases of myopericarditis and pericarditis, smallpox vaccination was preferentially related to myopericarditis versus pericarditis. PMID- 23356114 TI - Ultrasound in the austere environment: a review of the history, indications, and specifications. AB - In the last 10 years, the use of ultrasound has expanded because of its portability, safety, real-time image display, and rapid data collection. Simultaneously, more people are going into the backcountry for enjoyment and employment. Increased deployment for the military and demand for remote medicine services have led to innovative use and study of ultrasound in extreme and austere environments. Ultrasound is effective to rapidly assess patients during triage and evacuation decision making. It is clinically useful for assessment of pneumothorax, pericardial effusion, blunt abdominal trauma, musculoskeletal trauma, high-altitude pulmonary edema, ocular injury, and obstetrics, whereas acute mountain sickness and stroke are perhaps still best evaluated on clinical grounds. Ultrasound performs well in the diverse environments of space, swamp, jungle, mountain, and desert. Although some training is necessary to capture and interpret images, real-time evaluation with video streaming is expected to get easier and cheaper as global communications improve. Although ultrasound is not useful in every situation, it can be a worthwhile tool in the austere or deployed environment. PMID- 23356115 TI - Emergency physician evaluation of a novel surgical cricothyroidotomy tool in simulated combat and clinical environments. AB - We sought to investigate the performance of a novel cricothyroidotomy CRIC device compared to the traditional surgical in both simulated combat environments and the emergency department (ED) setting. Twenty U.S. Army staff and resident emergency medicine physicians were randomized to device and simulated setting order and performed cricothyroidotomies in the standard manner and with the CRIC device via the TraumaMan surgical simulator in three simulated settings: the ED, a day combat environment, and a night combat environment. Differences in procedural completion for the two methods in different settings were compared by two-tailed paired t-tests. The occurrence of major and minor procedural complications and questions presented as 5-point Likert scales to describe participants' preferences of cricothyroidotomy methods were compared by chi2 analysis. Time to incision, time to procedural completion, and rate of major and minor complications were not significantly different between the standard surgical method and the CRIC device (p > 0.05). In the simulated ED setting, 60% of participants preferred the standard surgical method (95% confidence interval: 38.5-81.5), whereas in the simulated combat settings, 50% of participants preferred each device (95% confidence interval: 28.1-71.9). In our population, we observed similar operator performance characteristics and physician preferences between the 2 methods in all simulated cricothyroidotomy settings. PMID- 23356116 TI - Vehicle-mounted high-power microwave systems and health risk communication in a deployed environment. AB - Vehicle-mounted high-power microwave systems have been developed to counter the improvised explosive device threat in southwest Asia. Many service members only vaguely comprehend the nature of these devices and the nonionizing radio frequency (RF) radiation they emit. Misconceptions about the health effects of RF radiation have the potential to produce unnecessary anxiety. We report an incident in which concern for exposure to radiation from a high-power microwave device thought to be malfunctioning led to an extensive field investigation, multiple evaluations by clinicians in theater, and subsequent referrals to an Occupational Health clinic upon return from deployment. When acute exposure to RF does occur, the effects are thermally mediated and immediately perceptible- limiting the possibility of injury. Unlike ionizing radiation, RF radiation is not known to cause cancer and the adverse health effects are not cumulative. Medical officers counseling service members concerned about potential RF radiation exposure should apply established principles of risk communication, attend to real and perceived risks, and enlist the assistance of technical experts to properly characterize an exposure when appropriate. PMID- 23356117 TI - Examining the association between binge drinking and propensity to join the military. AB - It is unclear to what degree previous and/or current alcohol consumption predicts enlistment into the military. The current investigation explored the extent to which binge drinking was related to propensity to join the military among a national sample of high school seniors (n = 14,577) responding to the 2008 Monitoring the Future survey. Independent sample t-tests and logistic regression analyses were employed to explore the research question. Results indicated that twelfth grade students who intended to join the military after graduating from high school binge drank a significantly greater number of days (p < 0.001, Cohen's d = -0.22) than those not intending to enlist. Even after controlling for various sociodemographic and lifetime drinking characteristics, binge drinkers had a higher propensity to join the military (odds ratio = 1.079, Wald = 5.53, df = 1, p < 0.05) than those who did not binge. Moreover, as binge drinking increased, so did one's propensity to join the military. Our findings lend credence to the notion that high school binge drinkers may be self-selecting into military service. These findings underscore the importance of adequately assessing the frequency of high-risk alcohol consumption and their associated correlates among potential military recruits before accession. PMID- 23356118 TI - The association of self-reported measures with poor training outcomes among male and female U.S. Navy recruits. AB - This prospective study evaluated the association of self-reported health habits and behaviors in 2,930 Navy recruits with poor training outcomes, defined as graduating late or separating from training. Although 17% of the men and 21% of the women had a poor training outcome, results suggest that some self-reported measures were associated with poor training outcomes. Men who did not run or jog at least 1 month before basic training or had a previous lower limb injury without complete recovery and women reporting the same or less physical activity compared with their same-age counterparts were more likely to have a poor training outcome. An important first step in decreasing poor training outcomes is encouraging incoming recruits to participate in physical activity and taking steps to identify and rehabilitate recruits who are not completely healed from a lower limb musculoskeletal injury before reporting to basic training. PMID- 23356119 TI - Prevalence and characteristics of military malingering. AB - The authors' principle objective was determining the prevalence and characteristics of medical malingering in the military. The authors accessed an electronic database used by the Department of Defense to monitor and manage military health care activities worldwide. The authors searched the database from 2006 to 2011 in the Northern Regional Medical Command for all instances where a health care provider, consequent to an outpatient medical visit, diagnosed malingering, factitious disorder with psychological symptoms, or factitious disorder with physical symptoms. During the time period studied, the Northern Regional Medical Command reported 28,065,568 health care visits. During the same time period, clinicians diagnosed 1,074 individuals with malingering, factitious disorder with predominantly psychological signs and symptoms, or factitious disorder with predominantly physical signs and symptoms. The typical subject diagnosed with one of these disorders was young, male, nonmarried, and enlisted. Although most diagnoses came from a mental health clinic, other medical specialties also contributed to the total tally. These diagnoses are extremely rare based on the findings from this study of outpatient medical care visits. PMID- 23356120 TI - Analysis of injuries from the Army Ten Miler: A 6-year retrospective review. AB - A number of long-distance running events are held each year in the United States; the Army Ten Miler (ATM) is one such race held annually in Washington, DC. The purpose of the present study was to retrospectively analyze medical encounters for runners participating in the ATM from 1998 to 2004. Of the estimated 91,750 runners over the 6-year period, 73,100 participants finished the race and were included in the data analysis. Demographic and injury data were collected from medical records of participants who received medical care while participating in the ATM, and injury-related factors were assessed. The most common category of injury was musculoskeletal (44%), followed by medical-related problems (27%) and dermatological injuries (27%). Similar to marathon and ironman races, ATM injury rates correlate with race-day temperature and dew point. Overall, however, the injury rates observed at the ATM were relatively low compared to those reported for longer distance events. Finally, we detail the medical coverage provided at the ATM, as this coverage could be used as a guide for similarly distanced races. PMID- 23356121 TI - The association between occupation and the incidence of knee disorders in young military recruits. AB - OBJECTIVE: To investigate the association between occupational risk factors and the incidence of knee disorders in a young adult population. METHODS: Israeli recruits to the Israel Defense Forces go through a rigorous medical investigation. Study participants were classified by prior knee condition status and divided into 5 categories of prospective occupational exposure to physical activity according to their assigned military duties, and were then followed for 30 months for the development of severe knee disorders (SKD). Logistic regression analysis was used to estimate the occupational risks for incident SKD, adjusted for any previous mild or moderate disorder, body mass index, and body height at induction. RESULTS: The study population consisted of 76,491 males. SKD developed in 615 (0.8%). Compared to administrative workers as referents, a higher risk of developing SKD was manifest among high intensity combat occupations, (odds ratios [OR] 2.15), those in moderate intensity combat occupations (OR 2.57) and maintenance (OR 1.59). Drivers did not demonstrate increased risk of knee disorders compared to referents. CONCLUSIONS: Occupational factors during military service are associated with incident SKD, even when taking into account previous knee disorders, body mass index, and height, which also had independent effects in our study population. PMID- 23356122 TI - Recommendations for biomonitoring of emergency responders: focus on occupational health investigations and occupational health research. AB - The disaster environment frequently presents rapidly evolving and unpredictable hazardous exposures to emergency responders. Improved estimates of exposure and effect from biomonitoring can be used to assess exposure-response relationships, potential health consequences, and effectiveness of control measures. Disaster settings, however, pose significant challenges for biomonitoring. A decision process for determining when to conduct biomonitoring during and following disasters was developed. Separate but overlapping decision processes were developed for biomonitoring performed as part of occupational health investigations that directly benefit emergency responders in the short term and for biomonitoring intended to support research studies. Two categories of factors critical to the decision process for biomonitoring were identified: Is biomonitoring appropriate for the intended purpose and is biomonitoring feasible under the circumstances of the emergency response? Factors within these categories include information needs, relevance, interpretability, ethics, methodology, and logistics. Biomonitoring of emergency responders can be a valuable tool for exposure and risk assessment. Information needs, relevance, and interpretability will largely determine if biomonitoring is appropriate; logistical factors will largely determine if biomonitoring is feasible. The decision process should be formalized and may benefit from advance planning. PMID- 23356123 TI - The addition of body armor diminishes dynamic postural stability in military soldiers. AB - Poor postural stability has been identified as a risk factor for lower extremity musculoskeletal injury. The additional weight of body armor carried by Soldiers alters static postural stability and may predispose Soldiers to lower extremity musculoskeletal injuries. However, static postural stability tasks poorly replicate the dynamic military environment, which places considerable stress on the postural control system during tactical training and combat. Therefore, the purpose of this study was to examine the effects of body armor on dynamic postural stability during single-leg jump landings. Thirty-six 101st Airborne Division (Air Assault) Soldiers performed single-leg jump landings in the anterior direction with and without wearing body armor. The dynamic postural stability index and the individual stability indices (medial-lateral stability index, anterior-posterior stability index, and vertical stability index) were calculated for each condition. Paired sample t-tests were performed to determine differences between conditions. Significant differences existed for the medial lateral stability index, anterior-posterior stability index, vertical stability index, and dynamic postural stability index (p < 0.05). The addition of body armor resulted in diminished dynamic postural stability, which may result in increased lower extremity injuries. Training programs should address the altered dynamic postural stability while wearing body armor in attempts to promote adaptations that will result in safer performance during dynamic tasks. PMID- 23356124 TI - Effect of an accelerometer on body weight and fitness in overweight and obese active duty soldiers. AB - This study evaluated whether using a web-linked accelerometer, plus mandatory physical training, is associated with various weight- and fitness-related outcomes in overweight/obese active duty soldiers. Soldiers who failed the height/weight standards of the Army Physical Fitness Test (APFT) were randomized to use a Polar FA20 accelerometer device (polar accelerometer group [PA], n = 15) or usual care (UC, n = 13) for 6 months. Both groups received 1.5 hours of lifestyle instruction. We collected data at baseline, 2, 4, and 6 months, and evaluated group differences in temporal changes in study outcomes. At 6 months, 1/28 subjects (UC) passed the APFT height/weight standards. There were no group differences in changes in weight (PA: -0.1 kg vs. UC: +0.3 kg; p = 0.9), body fat (PA: -0.9% vs. UC: -1.1%; p = 0.9), systolic blood pressure (PA: +1.3 mm Hg vs. UC: -2.1 mm Hg; p = 0.2), diastolic blood pressure (PA: +3.8 mm Hg vs. UC: -2.4 mm Hg; p = 0.3), or resting heart rate in beats per minute (bpm) (PA: +7.8 bpm vs. UC: +0.1 bpm; p = 0.2). These results suggest that using an accelerometer with web-based feedback capabilities plus mandatory physical training does not assist in significant weight loss or ability to pass the APFT height/weight standards among overweight/obese soldiers. PMID- 23356125 TI - Sequential real-time PCR assays applied to identification of genomic signatures in formalin-fixed paraffin-embedded tissues: a case report about brucella-induced osteomyelitis. AB - Brucellosis is a zoonotic infection transmitted from animals to human by ingestion of infected food products, direct contact with an infected animal, or inhalation of aerosols. Brucella infection-induced osteomyelitis may present only with nonspecific clinical and radiographic findings, mild elevations in serum inflammatory markers, as well as nonspecific histological changes. We studied a case of an Iraqi war veteran with multifocal vertebral body and left iliac bone lesions on radio nucleotide scans and magnetic resonance imaging, clinically suspected osteomyelitis possibly because of Brucella. Although histomorphological findings were nonspecific, consisting of chronic inflammatory cell infiltrate and reactive fibrosis, tissue gram and silver impregnation stains of bone biopsies were informative, revealing gram-negative coccobacilli consistent in size with Brucella species. Total nucleic acids were extracted from formalin-fixed paraffin embedded tissues and amplified by sequential real-time polymerase chain reaction, targeting genes coding (1) outer membrane protein (omp-31) of Brucella species and (2) insertion sequence (IS711) of Brucella abortus (b-abt). Polymerase chain reaction results confirmed B. abortus as the causative pathogens for presumed diagnosis of Brucella osteomyelitis. PMID- 23356126 TI - Service utilization following participation in cognitive processing therapy or prolonged exposure therapy for post-traumatic stress disorder. AB - This study evaluated the impact of a course of prolonged exposure or cognitive processing therapy on mental health and medical service utilization and health care service costs provided by the Department of Veterans Affairs (VA). Data on VA health service utilization and health care costs were obtained from national VA databases for 70 veterans who completed prolonged exposure or cognitive processing therapy at a Midwestern VA medical center. Utilization of services and cost data were examined for the year before and after treatment. Results demonstrated a significant decrease in the use of individual and group psychotherapy. Direct costs associated with mental health care decreased by 39.4%. Primary care and emergency department services remained unchanged. PMID- 23356127 TI - Dehydroepiandrosterone and dehydroepiandrosterone sulfate: anabolic, neuroprotective, and neuroexcitatory properties in military men. AB - Evidence links dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) to crucial military health issues, including operational stress, resilience, and traumatic brain injury. This study evaluated the anabolic, neuroprotective, and neuroexcitatory properties of DHEA(S) in healthy military men. A salivary sample was obtained from 42 men and assayed for DHEA(S), testosterone, nerve growth factor (NGF; which supports nerve cell proliferation), and salivary alpha amylase (sAA; a proxy of sympathetic nervous system function). Separate regression analyses were conducted with DHEA and DHEAS as independent variables, and testosterone, NGF, and sAA as dependent variables, respectively. The models explained 23.4% of variance in testosterone (p < 0.01), 17.2% of variance in NGF (p < 0.01), and 7.4% of variance in sAA (p = 0.09). Standardized beta coefficients revealed that DHEA independently influenced testosterone (beta = 0.40, p < 0.01), whereas DHEAS independently influenced NGF (beta = 0.48, p < 0.01) and sAA (beta = 0.36, p < 0.05). DHEA demonstrated anabolic properties, whereas DHEAS demonstrated neuroprotective and neuroexcitatory properties in military men. This area of study has broad implications for stress inoculation, traumatic brain injury rehabilitation, and regenerative medicine in military personnel. PMID- 23356128 TI - Unmet need for treatment of substance use disorders and serious psychological distress among veterans: a nationwide analysis using the NSDUH. AB - Many veterans returning from Afghanistan and Iraq experience serious mental health (MH) concerns including substance use disorders (SUD), post-traumatic stress disorder, traumatic brain injury, depression, or serious psychological distress (SPD). This article uses data from the 2004 to 2010 National Survey on Drug Use and Health to examine the prevalence of unmet MH needs among veterans aged 21 to 34 in the general population. The prevalence of untreated SUD among veterans (16%) was twice as high as untreated SPD (8%), a nonspecific diagnosis of serious MH concerns. Surprisingly, similar rates of untreated SUD and SPD were found among a nonveteran comparison sample matched on gender and age. These findings suggest that reducing unmet need for MH treatment for veterans in the general population may require improving outreach to all Americans and creating greater acceptance for MH treatment. The need for further analyses of reasons for not obtaining treatment is discussed. PMID- 23356129 TI - Increased adolescent overweight and obesity documentation through a simple electronic medical record intervention. AB - OBJECTIVE: The purpose of this project was to improve provider documentation of adolescent overweight and obesity through body mass index percentile (BMI%) documentation in the military's electronic medical record (EMR). METHODS: Using the FOCUS-PDCA (Find-Organize-Clarify-Understand-Select-Plan-Do-Check-Act) model, we developed an intervention to improve rates of diagnosis of overweight/obesity in our adolescent medicine clinic. Medical technicians documented the patient's BMI% and growth chart in the EMR. Pre- and postintervention chart reviews of approximately 300 consecutive patient encounters compared the rates of overweight/obesity with provider-documented diagnosis. RESULTS: A total of 333 pre- and 328 postintervention clinic encounters were reviewed. The rate of overweight and obesity calculated was similar between pre- and postintervention groups (30% vs. 31%). Correct diagnosis increased from 40% to 64% after the intervention. Females and patients seen by resident physicians were less likely to receive a correct diagnosis at baseline, but these differences were mitigated in the postintervention group. In multivariate analyses, only the intervention and provider type were predictive of an improvement in correct diagnosis. CONCLUSION: BMI% documentation in our EMR was an effective way to improve documentation of overweight/obese adolescent patients and may be particularly helpful for resident physicians. PMID- 23356130 TI - [Quantum-chemical basics of pharmacokinetics (literary review and own investigations)]. AB - The work is devoted to the use of quantum-pharmacological approaches in pharmacokinetic investigations. The main objective of the pharmacological researches is to find new, more active and less toxic drugs. To date, such a search is carried out empirically. The current approach can not fully meet the needs of medicine in the new drugs, requires considerable time and financial costs and does not meet modern standards of bioethics. Quantum pharmacology leads to the synthesis of drugs with desired properties is much faster and more efficient. Computer prediction of pharmacokinetic and biopharmaceutical properties of biologically active substances can make 50-70% more effective development of original drugs. PMID- 23356131 TI - [Assessment of an association between fatty acid structure of lipids in pulmonary surfactant and 137Cs content in the body of children, residents of radiation contaminated areas]. AB - An evaluation of correlation between fatty acid composition in pulmonary surfactant lipids and 137Cs content in the body of children, residents of radiation-contaminated areas revealed that a increased incorporation of 137Cs promotes a disruption of fatty acid balance towards an increase in the saturation of the surfactant lipid complex, a destruction of lecithin fraction of surfactant, a decrease in antioxidant properties of surfactant system, an activation of lipid peroxidation processes in the respiratory area of lung by lipoxygenase type, a disturbance of polyunsaturated fatty acid metabolism on the stage of bioregulators-eicosanoid formation. PMID- 23356132 TI - [Galectines as prognostic factors for the malignant lymphoproliferative diseases]. AB - Galectines are a family of carbohydrate-binding proteins with an affinity for beta-galactosides. Galectines is differentially expressed by various normal and pathological tissues and appears to be functionally polyvalent, with a wide range of biological activity. The intracellular and extracellular activity of galectines has been described. Evidence points to galectin and its ligands as one of the master regulators of such immune responses as T-cell homeostasis and survival, T-cell immune disorders, inflammation and allergies as well as host pathogen interactions. Galectines expression or overexpression in tumors and/or the tissue surrounding them must be considered as a sign of the malignant tumor progression that is often related to the long-range dissemination of tumoral cells (metastasis), to their dissemination into the surrounding normal tissue, and to tumor immune-escape. Elevated levels of galectines have been found to be significantly associated with higher risk progressing of the lymphoproliferative disease. The targeted inhibition of Galectines expression is what should be developed for therapeutic applications against cancer progression. Galectines are the promising molecular target for the development of new and original diagnostic and therapeutic tools. PMID- 23356133 TI - [The toxic effects of chemotherapy on the gastrointestinal tract]. AB - In modern oncology chemotherapy (CT), along with the surgical technique and radiotherapy is a leader in the treatment of cancer patients. More than 60% of patients receiving chemotherapy at different stages of treatment. Recently, modern chemotherapy has become more urgent personal approach to the choice of drugs and their doses, aimed at reducing the toxicity of chemotherapy. Complications of chemotherapy significantly degrade the effectiveness of the treatment of patients with malignant tumors, because they require lower doses of anticancer drug, or lengthening the intervals between cycles of chemotherapy, which affects treatment outcomes and quality of life. This paper presents a literature review of toxic effects of cytostatic drugs on the gastrointestinal tract. PMID- 23356134 TI - [Peculiarities of formation, clinical presentations and therapy of diffuse nontoxic goiter of children]. AB - The paper deals with the peculiarities of formation, clinical presentations and therapy of diffuse nontoxic goiter of children. The paper highlights the connection of the disease with the genetic predisposition, the impact of natural and anthropogenic strumagenes, immune processes. The clinical presentations of the diffuse nontoxic goiter are diffuse enlargement of thyroid gland, normal or high level of thyrotropichypophysis hormone when the content of thyroxin and triiodothyronine is normal, which is treated as the subclinic hypothyroidism syndrome. The variety of the disease pathogenesis theories leads to testing of different therapeutic methods, the principal ones among them are the use of iodine preparation and replacement therapy. PMID- 23356135 TI - [To the problem of parapsoriasis: classification problems (literature review and personal observations)]. AB - In the presented article we discuss the problems of lichenoid and plaque parapsoriasis. The difference in Russian and English classifications are discussed in the historical aspect, as well as review of the literature, and personal authors' observations of nine patients with "small plaque parapsoriasis". PMID- 23356136 TI - [State of the dopamine system activity, as one of factors for the development of arterial hypertension and obesity]. AB - The discovery of 5 subtypes of dopamine receptors revealed their important role in development of arterial hypertension and obesity. Reduce of their functional activity or number with age conduces to the increase of tone of the sympathetic nervous system, dyspoiesis of leptin, hyperphagia, development of obesity and arterial hypertension. Prescription of dopamine agonists conduces to reduction of in, normalization of leptin, diminishing of appetite and body mass, decrease of blood pressure. Combination of arterial hypertension and obesity is recommended to determine dopamine excretion and to appoint dopamine agonists at level of < 600 nmol/24 hours. PMID- 23356137 TI - [Comparative data charasteristic of laboratory examination of patients with chronic heart failure of ishemic origin with systolic left ventricular dysfunction and preserved left ventricular ejection fraction]. AB - 581 patients with chronic heart failure (CHF) of ischemic origin with systolic left ventricular dysfunction (SLVD) and preserved left ventricular ejection fraction (PLVEF) were examined. The aim of the study was to investigate the comparative aspect of laboratory examination of patients with chronic heart failure of ischemic origin with left ventricular systolic dysfunction and patients with heart failure and preserved left ventricular ejection fraction. The study found no differences in the groups on the basic parameters: the number of white blood cells, hemoglobin concentration, red blood cell count, platelet count, the number of potassium and sodium ions. At the same time, patients with CHF and left ventricular systolic dysfunction characterized by the presence of a moderate decline in glomerular filtration rate, including more frequent patients with lymphocytopenia, hypoholesteremia, hyperuricemia. For patients with chronic heart failure and preserved left ventricular ejection fraction the following characteristics have been characterized: normal or increased glomerular filtration rate, hypercholesterolemia. PMID- 23356138 TI - [Serum level of S100B as a marker of progression of vascular mild cognitive impairment into subcortical vascular dementia and therapy effectiveness]. AB - We evaluated serum level of S100B in 11 patients with subcortical vascular dementia (SVD) and 19 patients with subcortical vascular mild cognitive impairment (SVMCI). Comparable groups were age-matched (79.18 +/- 7.76 in SVD group, 77.84 +/- 3.83 in SVMCI; P = 0.53). 22 patients were assessed after 1 month therapy. It was shown that the serum S100B level significantly increased- (0.065 +/- 0.020) micro/l (P = 0.0005) in SVD patients comparing to SVMCI ones - (0.043 +/- 0.010) microg/l. S100B level was significantly correlated with the clinical parameters: MMSE performance (r(s) = -0.61), CDR (r(s) = 0.58), attention task (r(s) = -0.46), pseudobulbar syndrome severity (r(s) = 0.37) and walking alteration (r(s)= 0.37). In patients with reduction of S100B level due to therapy (positive dynamics, n = 12) we registered significant improvement of some clinical parameters: MMSE, attention level, walking. In patients with increasing of S100B level (negative dynamics, n = 10) we didn't registered improvement of any clinical parameters. We made the conclusion that the serum level of S100B could be used as marker of progression SVMCI into SVD and therapy effectiveness. PMID- 23356139 TI - [The efficiency of complex recovery treatment of chronic obstructive pulmonary disease patients using subalin]. AB - The expediency of complex recovery treatment of chronic obstructive pulmonary disease (COPD) patients on the base of artificial rock salt aerosol medium (haloaerosoltherapy) and probiotic drug subalin intake was grounded. It was revealed that additional prescription of subalin results in the more expressed lipoperoxidation's inhibition, especially in patients with COPD II st. and more considerable decrease of endogenic intoxication at COPD III st. It was shown that complex treatment with subalin usage promoted the relief of desease's clinical duration in remoted period. PMID- 23356140 TI - [The role of disbalance of zinc and copper in school age children with community aquired pheumonia]. AB - The article analyzed 60 patients with community-aquired pneumonia from ages 6 to 18 years. The dependences of trace levels of zinc and copper in the serum of these children on the activity of the inflammatory process. Analysis of survey results showed that in children with community-aquired pneumonia was observed imbalance of trace elements Zn, Cu. Severity of such violations depended mainly on severity disease and to a lesser extent on age. Normalization of detected metabolic microelement content in a period of convalescence practically advancing. In children at acute stage of community-aquired pneumonia inflammation was observed with pronounced zinc deficiency (P < 0,001), and its content in blood serum is directly dependent on the acuity and severity of inflammation. Use of the drug, which contains zinc as part of adjuvant therapy in community-aquired pneumonia in children led to more rapid normalization of serum microelement parameters, apparently due to modulating effects on microelement status and immune status. To increase the effectiveness of treatment of community-aquired pneumonia in school-age children, its recommended to use zinc containing drug. PMID- 23356141 TI - [Bronchial hyperresponsiveness and factors of bronchial inflammation under the exercise-induced asthma in schoolchildren]. AB - 88 schoolchildren with bronchial asthma were observed at the department of pulmonary disease and allergology of the Chernivtsi regional children clinical hospital. The study showed that the content of aldehyde- and ketoderivatives of 2,4-dinitrophenylhydrazones of neutral character in the expired air condensate (AKDNPH) was presumably higher in patients with the exercise-induced bronchial asthma thus indicating the more significant activity of the inflammatory process in bronchi under the studied phenotype of the disease. Non-specific bronchial hyperresponsiveness was presumably higher in children suffering exercise-induced bronchial asthma due to bronchial hyperresponsiveness as well as hyperreactivity when compared with the patients having activity independent asthma attacks. The factor of bronchial spasm was significantly associated with the content of AKDNPH of the basic character and nitric oxide metabolites in the expired air condensate in the patients with the exercise-induced bronchial asthma. PMID- 23356142 TI - [Drug with a high metabolic activity, cocarnit, in the treatment of diabetic cardiac autonomic neuropathy]. AB - Left ventricular diastolic dysfunction in patients with diabetes is formed in the absence of atherosclerotic changes as a consequence of diabetic cardiac autonomic neuropathy in the early stages of diabetes. Progression of autonomic cardiac neuropathy in cardio-vascular type is associated with the violation of energy supply of cells, protein synthesis, electrolyte exchange, the exchange of trace elements, oxidation reduction processes, oxygen-transport function of blood, so that metabolic therapy is carried out to optimize the processes of formation and energy costs. The drug cocarnit activates processes of aerobic oxidation of glucose, as well as providing regulatory influence on the oxidation of fatty acids. Applying of cocarnit in complex therapy in patients with diabetic cardiac autonomic neuropathy found improvement of left ventricular diastolic function, and positive dynamics in the efferent activity balance of the sympathetic and parasympathetic control of heart rate variability, which provides the regression of clinical symptoms. PMID- 23356143 TI - [Quantitative analysis of individual groups of microorganisms, extracted from atherosclerotic lesions in the coronary arteries in patients depending upon ASP299GLY polymorphism of TLR4 gene]. AB - The estimation data of contamination by separate groups of microorganisms and dependence of the microbial content level upon TLR4 gene 896A/G polymorphism in 20 samples of atherosclerotic lesions in coronary arteries has been presented. The presence of TLR4 gene polymorphic allele G in the individual genotype determines the increased contamination of atherosclerotic plaque tissues by the representatives of the following genera: Lactobacillus sp., Enterobacterium sp., Sneathia sp./Leptotrihia sp./Fusobacterium sp., Mobiluncus sp./Corynebacterium sp., Peptostreptococcus sp. The emergence of new correlation pairs with participation of Lachnobacterium sp./Corynebacterium sp. among the carriers of G allele has been revealed via the intragroup correlation analysis. The obtained results confirm the possible involvement of the represented groups of microorganisms in the pathogenesis of atherosclerosis and the role of the TLR4 gene polymorphic variant G in the increased microbial contamination of the coronary arteries tissues. PMID- 23356144 TI - [Role of hypophyseal-gonadal system in the genesis of functional pathologies of the digestive system in adolescents]. AB - In different types of functional disorders of the digestive system in adolescents were revealed the same changes of the hormonal state of hypophisial-gonad system. It indicates on dominative role of neuroendocrinal mechanisms in pathogenesis of these diseases. PMID- 23356146 TI - [Trocar hernia: causes, treatment, methods of prevention]. AB - The paper presents the results of the study 41 patients with trocar hernias after various laparoscopic operations. It is established that the main reason is the expansion of trocar hernia injury when removing the drug without further suturing of the aponeurosis. Proposed closure of the aponeurosis, while the length of the wound more than 2 cm - alloplastica. PMID- 23356145 TI - [Antibacterial therapy in surgery of patients with acute destructive appendicitis]. AB - Character of microflora of exsudate of abdominals and mucosis microflora of vermicular appendix is studied for patients with the destructive forms of appendicitis with the purpose of development of variants of antibacterial therapy at surgical treatment of patients with acute appendicitis. The patients with the destructive forms of appendicitis, which were on treatment in a municipal clinical hospital N 4 Kyiv for period 2004-2010. An Inflammatory-destructive process in an appendix is conditioned by both aerobic (Escherichia coli - 46,6 %, Enterobacter - 4,2 %, Citrobacter - 4,2 %, Klebsiella - 3,3 %, Pseudomonas aeruginosa - 5,8 %, Staphylococcus - 4,2 %) and anaerobic microorganisms (Bacteroides - 100 %) and increase Candida - 17,5 %. Antibacterial therapy is effective at 46,7 % patients with acute appendicitis. At 49,6 % patients acute appendicitis develops on a background dysbiotic intestinal disturbances. Clinically the effective charts of empiric antibacterial monotherapy 6 days it is been: Moxifloxacini intravenously 400 mgs one time in twenty-four hours during, Ertapenemi for a 1 g one time in twenty-four hours intravenously and combined - Aztreonami for a 1 g twice in twenty-four hours and of Clindamycini for 600 mgs twice in twenty-four hours, intramuscular during; Cefepimumi for a 1 g twice in twenty-four hours and of Clindamycini for 600 mgs twice in twenty-four hours, intramuscular. PMID- 23356147 TI - [The use of phytotherapy for treatment of thyroid diseases]. AB - The main tasks during treatment of hyperplastic thyroid diseases--to stop the growth of thyroid nodules; compensation of hypothyrosis; normalization of thyroid size. One of the perspective methods in combine therapy of diffuse and mix goiter is a phytotherapy. The most often for thyroid diseases we have used the plant drug Polentilla alba, which on Ukrainian market was registered as "Alba". Investigation has shown, that phytodrug of Polentilla alba could be recommended for monotherapy and for combine conservative therapy of diffuse and mix benign euthyroid goiter, and also for complex treatment of toxic and hypothyroid goiters. PMID- 23356148 TI - [Role of hormonal disturbances in sterility development for patients with benign formations of ovaries]. AB - The article presents hormonal analysis of hypothalamus-hypophysis-ovaries system of 14 patients with sterility as well as of other 15 patients without sterility suffering from benign tumors or tumorous formations. The control group included 6 healthy women. The concentration of hormones in blood serum (FSH-follicle stimulating hormone, LH-lutein hormone, Prolactinum, Testosteronum, Oestradiolum, Progesterone) has been tested in dynamics of a menstrual cycle. Correlation of results of hormonal and histological analysis of a capsule of formation and a biopsy of a tissue of an ovary of these patients has revealed that formation occurrence irrespective of its histological type leads to suppression of the follicular apparatus. These disturbances are more symptomatic for patients with both epithelial cystomas and sterility. It gives evidence that these disturbances can cause sterility. Hormonal disturbances of patients with benign tumors or tumorous formations depend on formation presence, rather than of its histological type. Spontaneous recovery of reproductive function is marked at 35 % of patients. Efficiency of surgery treatment and rehabilitation therapy within the first year after surgery made up 60 %. PMID- 23356149 TI - [The introduction of the achievements of medical science in public health practice with using modern information technologies]. AB - The article analyzes some factors that complicate the availability of scholarly communication professionals of health of Ukraine to introduce the achievements of medical science into practice. Improved access will help the implementation created by the Ministry of Health of Ukraine United e-data-processing system. PMID- 23356150 TI - [Government control of medical and pharmaceutical activity is in single medical space of Ukraine (theoretical and methodological foundations)]. AB - In the article the issue of the day of selection in Ukraine of right of health protection is considered in the separate field of law, as it is done in the USA, countries of European Union and Russia. At the same time author not supporter of selection of pharmaceutical right in separate industry, and suggests to examine a medical and pharmaceutical right as subindustries of the system of right for a health protection are in Ukraine. PMID- 23356151 TI - [Incidence and severity of the digestive system diseases in the armed forces of Ukraine]. AB - The paper presents an analysis of the level and structure of morbidity Armed Forces of Ukraine diseases of the digestive system. The highest rates of total incidence of disease in the class XI 2008-2011, recorded among conscripts, the lowest--in the military under the contract. PMID- 23356152 TI - [Investigation indicators of physical activity in different categories of students]. AB - The article presents the results of the study of dynamics of changes in the basic indicators of physical activity in different age groups of students studying in secondary schools, colleges and universities of the country. The studies revealed that there were three periods when naturally there is a temporary decrease in physical activity of students and changes in its structure. The reasons for this are the child's adaptation to the conditions of education in elementary school, intensive preparation of the alder pupils for entry to higher education and the lack of an effective system of independent physical training graduate students in most universities. Due to fact that there are objective reasons for these periods is explained by the need to develop special training programs for the respective categories of students. PMID- 23356153 TI - [Patient safety and quality of medical care. Editorial: From evidence-based medicine to PDCA cycle]. PMID- 23356154 TI - [Patient safety and quality of medical care. Topics: I. Incident and accident in hospital: current situation; 1. Importance of an incident & occurrence-reporting system in patient safety management]. PMID- 23356155 TI - [Patient safety and quality of medical care. Topics: I. Incident and accident in hospital: Current situation: 2. Severity of medication error and its preventive measures]. PMID- 23356156 TI - [Patient safety and quality of medical care. Topics: I. Incident and accident in hospital: Current situation; 3. Updated evidence-based preventive strategies for healthcare-associated infections]. PMID- 23356157 TI - [Patient safety and quality of medical care. Topics: I. Incident and accident in hospital: Current situation; 4. Accidental falls and prevention program among inpatients]. PMID- 23356158 TI - [Patient safety and quality of medical care. Topics: I. Incident and accident in hospital: Current situation; 5. Frequency and prevention of medical near miss/adverse event related to use/management of drainage tube or other tubes]. PMID- 23356159 TI - [Patient safety and quality of medical care. Topics: II. Measurement and improvement of quality of medical care; 1. Measurement of quality of healthcare: Promotion project by Ministry of Health, Labour and Welfare]. PMID- 23356160 TI - [Patient safety and quality of medical care. Topics: II. Measurement and improvement of quality of medical care; 2. Indicators and improvement of quality of medical care based on DPC data]. PMID- 23356161 TI - [Patient safety and quality of medical care. Topics: II. Measurement and improvement of quality of medical care; 3. Improvement of medical care: experiences of a teaching hospital in Tokyo]. PMID- 23356162 TI - [Patient safety and quality of medical care. Topics: II. Measurement and improvement of quality of medical care; 4. Quality assurance and improvement in healthcare]. PMID- 23356163 TI - [Patient safety and quality of medical care. Topics: II. Measurement and improvement of quality of medical care; 5. Measurement and improvement of quality of healthcare: lessons from other countries]. PMID- 23356164 TI - [Patient safety and quality of medical care. Topics: III. Management of patient safety and quality of medical care: theory and practice; 1. Theories and practices of patient safety and quality management]. PMID- 23356165 TI - [Patient safety and quality of medical care. Topics: III. Management of patient safety and quality of medical care: theory and practice; 2. Human factors in medical care]. PMID- 23356166 TI - [Patient safety and quality of medical care. Topics: III. Management of patient safety and quality of medical care: theory and practice; 3. Developing organizational culture for patient safety and quality of medical care]. PMID- 23356167 TI - [Patient safety and quality of medical care. Topics: III. Management of patient safety and quality of medical care: theory and practice; 4. Patient safety and quality improvement education for undergraduate medical students]. PMID- 23356168 TI - [Patient safety and quality of medical care. Topics: III. Management of patient safety and quality of medical care: theory and practice; 5. Patient safety education at the healthcare setting]. PMID- 23356169 TI - [Discussion meeting on patient safety and quality of medical care]. PMID- 23356170 TI - [Case report; Multiple gastrointestinal stromal tumors associated with neurofibromatosis type I preoperatively diagnosed by endoscopic ultrasound-guided fine-needle aspiration: report of a case and review of literature]. PMID- 23356171 TI - [Case report; A case of hypermagnesemia accompanied with disturbance of consciousness induced by acute kidney injury]. PMID- 23356172 TI - [Case report; A case of IgG4-related tubulointerstitial nephritis diagnosed after the beginning of hemodialysis treatment]. PMID- 23356173 TI - [Case report; A case of Morvan syndrome: a paraneoplastic manifestation of angioimmunoblastic T-cell lymphoma]. PMID- 23356174 TI - [Case report: A case of drug-induced interstitial pneumonitis by everolimus eluting coronary stent]. PMID- 23356175 TI - [The cutting-edge of medicine; Management and therapy for airway mucus hypersecretion]. PMID- 23356176 TI - [The cutting-edge of medicine; Towards adult stem cell-based therapy for intestinal diseases]. PMID- 23356177 TI - [General physician and internist: preface]. PMID- 23356178 TI - [General physician and internist: 1. From the standpoint of Japanese Board of Medical Specialties]. PMID- 23356179 TI - [General physician and internist: 2. Necessity and perspective of generalist physician specialization]. PMID- 23356180 TI - [General physician and internist: 3. Certification of physician qualification in Japan--from the stand point of the Japan Medical Association]. PMID- 23356181 TI - [General physician and internist: 4. From the standpoint of Japan Primary Care Association]. PMID- 23356182 TI - [General physician and internist: 5. Reconstruction of the department of internal medicine by generalists--their roles, characteristics and education system]. PMID- 23356183 TI - [General physician and internist: 6. What is the fellow of Japanese Society of Internal Medicine?]. PMID- 23356184 TI - [Series: Knowledge of emergency required for internist; management of anaphylaxis]. PMID- 23356185 TI - [Report from the 15th Tokai Chapter Educational Seminar: clinical case seminar: an elderly man with massive ascites]. PMID- 23356186 TI - [Guidance for vaccination in adult]. PMID- 23356187 TI - [Series: Let's think-clinical quiz (question); A case of 79 year-old male with recurrent congestive heart failure caused by chronic hemolytic anemia]. PMID- 23356188 TI - [Series: For attending physicians; professionalism; next step of evidence-based medicine: health literacy and communication]. PMID- 23356189 TI - [Series: Diagnosis at a glance]. PMID- 23356191 TI - Hyponatremia now--a goldmine or a dead end? AB - Hyponatremia is a clinically relevant disorder. Ten to twenty per cent of patients in hospitals are affected by it. Hyponatremia is found to occur in almost every clinical department. Recently, vasopressin antagonists have been licensed to treat hyponatremia of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). They provide physicians with the first specific and effective therapy of this hyponatremia. This opens up new avenues for clinical research into the symptoms, findings and consequences of hyponatremia. PMID- 23356192 TI - The synthesis of 3,5,6,7-tetrasubstituted isoxazolo[4,5-b]pyridines and an evaluation of their in vitro antiproliferative activity. AB - BACKGROUND: Derivatives of isoxazolopyridines exhibit diverse biological activity. One method of synthesizing isoxazolo[4,5-b]pyridines is Friedlander condensation. OBJECTIVES: To establish the conditions necessary for conventional and microwave synthesis of new 3,5,6,7-tetrasubstituted isoxazolo[4,5-b]pyridines and their antiproliferative activity. MATERIAL AND METHODS: The substrates in the synthesis of new isoxazolo[4,5-b]pyridines were 4-amino-5-benzoylisoxazole-3 carboxamide and selected carbonyl compounds containing a reactive a-methylene group. Reactions were carried out using classical methods in the presence of catalysts ZnCl2 or In (OTf)3, and in a microwave reactor in the presence of ZnCl2 under solvent-free conditions. Selected compounds were tested in vitro on eight tumor cell lines to assess their antiproliferative activity. RESULTS AND DISCUSSION: A series of new derivatives of 3,5,6,7-tetrasubstituted isoxazolo [4,5-b]pyridines was obtained from Friedlander condensation of 4-amino-5 benzoyloisoxazolo-3-carboxamide with selected carbonyl compounds with an active methylene group. The compounds were obtained by conventional and microwave methods, in the presence of catalysts ZnCl2 or In (OTf)3. The structures of the products were determined on the basis of elemental analysis and infrared (IR), Nuclear Magnetic Resonance (1H NMR) and Mass Spectrometry (MS) data. Selected compounds were tested in vitro on eight tumor cell lines in the direction of antiproliferative activity. CONCLUSIONS: Only the use of conventional heating in a thermostated oil bath in the presence of catalysts ZnCl2, or In (OTF)3 or microwave irradiation in the presence ZnCl2 in the solvent-free conditions allowed good yields of the new derivatives of poly-substituted isoxazolo[4,5 b]pyridines to be obtained. Among the compounds tested in vitro only 6-benzoyl-5, 7-difenyloisoxazolo[4,5-b]pyridine showed antyproliferative activity at a concentration of 3.9 microg/ml. PMID- 23356193 TI - Maternal plasma levels of endothelial dysfunction mediators including AM, CGRP, sICAM-1 and tHcy in pre-eclampsia. AB - BACKGROUND: Pre-eclampsia is a pregnancy-specific disorder of widespread vascular endothelial dysfunction that occurs after twenty weeks of gestation. OBJECTIVES: The aim of the present study was to compare maternal circulating levels of endothelial dysfunction mediators, including the vascular actions of adrenomedullin (AM) and calcitonin gene-related peptide (CGRP), the angiogenic factor of soluble intracellular adhesion molecule-1 (sICAM-1) and the pro-oxidant activity factor of total homocysteine (tHcy), in the plasma of normal and pre eclampsia pregnancies. Furthermore, the authors investigated whether magnesium sulfate therapy is involved in modulating the circulating levels of these four molecules, thus helping to prevent pre-eclampsia. MATERIAL AND METHODS: A total of 85 pregnant women were involved in this study, including 30 healthy pregnant women, 15 with pregnancy-induced hypertension (PIH) and 40 with pre-eclampsia (PE). The maternal levels of AM, CGRP, sICAM-1 and tHcy in plasma were determined by enzyme-linked immunoassay (ELISA). Furthermore, the effects of magnesium sulfate therapy on the plasma levels of these four molecules were compared. Results. Compared to healthy pregnancies, maternal circulating concentration of AM, sICAM-1 and tHcy were significantly higher, while the plasma level of CGRP is significantly lower in pregnant women with hypertension or pre-eclampsia (P < 0.05). Magnesium sulfate therapy can effectively suppress the level of AM, sICAM 1 and tHcy, while increasing the level of CGRP in maternal circulation (P < 0.05). CONCLUSIONS: Present results indicated that AM, CGRP, sICAM-1 and tHcy may be involved in the development and maintenance of hypertension during pregnancy. By modulating these four mediators, magnesium sulfate may inhibit the progress of pre-eclampsia. PMID- 23356194 TI - Cross-protection among unrelated leptospira pathogens serovars: an unfinished story. AB - BACKGROUND: The World Health Organization considers leptospirosis the most neglected zoonotic disease in the last decades. One of the major obstacles in the developing of vaccines for the prevention of leptospirosis is the absence of cross-protection among unrelated serovars. It is accepted that cross-protection among related serovars is due to antibodies generated against lipopolysaccharides (LPs), whereas a cross-protection among unrelated serovars is rarely observed. OBJECTIVES: The objective of the study was to ascertain the existence of cross protection among vaccine strains of different serovars. RESULTS: The results of this research demonstrated that a cross-protection among unrelated Leptospira serovars strain is possible. The Canicola strain is able to induce protection against homologous, Ballum and Copenhageni strains. The Mozdok strain induced protection only against a homologous challenge. Other strains showed a moderate cross-protection against a heterologous challenge. CONCLUSIONS: These findings suggest that the Canicola and Mozdok strains are ideal candidates for developing a new vaccine formulation for use in Cuba. PMID- 23356195 TI - Invasive properties, adhesion patterns and phylogroup profiles among Escherichia coli strains isolated from children with inflammatory bowel disease. AB - BACKGROUND: A great deal of evidence indicates a link between Escherichia coli (E. coli) and Crohn's disease in adult patients, but there is lack of information on the association of these bacilli with inflammatory bowel disease (IBD) among children. OBJECTIVES: The study was carried out to determine the distribution of phylogenetic group, the adherence patterns and invasive properties of E. coli isolated from children with IBD and non-IBD chronic bowel diseases. MATERIAL AND METHODS: A total of 22 E. coli isolated from biopsy specimens from children with IBD and 21 E. coli strains obtained from children with indeterminate colitis and intestinal polyps were examined for adherence and internalization to the Int407 cell line. Genes involved in epithelial cell invasion and genes specific to E. coli phylogroups were determined by polymerase chain reaction (PCR). RESULTS: The undefined adherence pattern predominated among the isolated E. coli, although most of them demonstrated the afaD and aggB genes encoding invasions of diffusely adhering and enteroaggregative E. coli. Regardless of the clinical entity, most E. coli were internalized by Int407 epithelial cells and belonged to the B2 and D phylogroups. CONCLUSIONS: The wide distribution of adhesive E. coli capable of entering Int407 cells but also having genes encoding adhesins and invasins characteristic to pathogenic E. coli strains seems to indicate that these E. coli may represent a large group of pathogenic E. coli strains contributing to chronic intestinal disorders. PMID- 23356196 TI - Data dimensionality reduction in anthropometrical investigations. AB - BACKGROUND: Very often it is necessary to make a decision or to establish a diagnosis on the basis of great amounts of different kinds of data. In this paper the principal component analysis procedure was applied to anthropometrical data analysis. OBJECTIVES: The aim was to simplify the process of decision making by data dimensionality reduction. A second aim was to check how the reduction affected an analysis of the pubertal growth process. MATERIAL AND METHODS: A group of 400 boys was investigated. Three main components were calculated and interpreted. In order to investigate growth changes, the variability of each component was approximated by fourth order polynomials. RESULTS: It was shown that the loss of information resulting from data dimensionality reduction is about 25%, so the three calculated principal components contained 75% of the entire information. It seems possible to make an appropriate decision on the basis of that amount of information. CONCLUSIONS: The results obtained fully supported using the approach presented for data analysis in the case under consideration. PMID- 23356197 TI - Comparison of apoptotic gene expression profiles between Peyronie's disease plaque and tunica albuginea. AB - BACKGROUND: The fibrotic plaques of Peyronie/s disease and other localized fibrotic conditions have been considered to be the result of an abnormal wound healing process. The potential role of regulatory disorders of apoptosis in abnormal wound healing may also play a role in the development of Peyronie's disease. OBJECTIVES: To examine the phenomenon of apoptosis in Peyronie's disease, authors quantified differential levels of gene expression of apoptotic proteins, Fas, Fas Ligand, Bcl-2, p53, Caspase 3 and 8 in Peyronie's plaque and tunica albuginea. MATERIAL AND METHODS: Eight patients with Peyronie's disease undergoing surgical correction of the curvature had biopsy specimens taken from both the Peyronie's plaque and normal tunica albuginea. Messenger RNA expression of the apoptotic proteins in the plaque and normal tunica was measured by reverse transcriptase PCR. RESULTS: Apoptotic gene expression was lower than the housekeeping gene's in half of the tunica albuginea samples and two thirds of the plaque samples. Overall mRNA expressions in the plaque were not significantly different from the normal tunica albuginea. CONCLUSIONS: The fibrotic plaques of Peyronie's disease and other localized fibrotic conditions have been considered to be the result of an abnormal wound healing process. The potential role of regulatory disorders of apoptosis in abnormal wound healing may also play a role in the development of Peyronie's disease. In this study, the lower expression of apoptotic genes may cause the persistence of collagen producing cells which were up-regulated for unknown reasons and consequently result in plaque formation. Similar expression levels of apoptotic genes in both tunica albuginea and Peyronie's plaques may be due to the generalized physiopathologic alterations in tunica albuginea that lead to plaque formation at a vulnerable region subjected to recurrent traumas. PMID- 23356198 TI - Long term efficacy of laparoscopic adjustable gastric banding--retrospective analysis. AB - BACKGROUND: Laparoscopic procedures have emerged over the past decade for treatment of obesity. Laparoscopic adjustable gastric banding is the easiest surgical technique for morbid obesity. OBJECTIVES: The authors analyzed the long term results of laparoscopic adjustable gastric banding in their center. MATERIAL AND METHODS: A total of 172 consecutive patients who had undergone laparoscopic adjustable gastric banding between May 2005 and February 2011 in authors clinic were contacted for evaluation. The main outcome measures were complications, secondary operations, percent excess weight loss, mortality, patient satisfaction and band removal rate. RESULTS: The follow-up rate was 62.2%. Mean age of patients was 30.6 years. Mean body mass index of patients was 48.47 +/- 7.8 kg/m2. Median follow-up interval was 36 months (min 8, max 81) and band removal rate was 19.1%. There was one mortality. Of all patients, 33 had band removal. The band was removed laparoscopically in 21 patients. The main reason for band removal was slippage followed by band erosion. After band removal, 4 patients had re-banding, 5 had Roux-en-Y gastric bypass. Overall, the mean percent excess weight loss was 50.6 +/- 7.8% (range, 5-100%). Mean percent excess weight loss for those who had band removal was 27.8 +/- 5.78% (range 12.5-34.1%). Overall satisfaction index was rated as "good" for 42% of patients. CONCLUSIONS: Despite a low satisfaction index, considerable mean percent excess weight loss and vast improvement in co-morbidities is achieved after laparoscopic adjustable gastric banding. The authors conclude that laparoscopic adjustable gastric banding can be utilized as the initial surgical procedure in morbid obesity. PMID- 23356199 TI - Ten years single center experience in percutaneous transhepatic decompression of biliary tree in patients with malignant obstructive jaundice. AB - BACKGROUND: Percutaneous transhepatic biliary drainage (PTBD) is a method of biliary tree decompression, applied as palliative treatment in patients with malignant biliary tree critical stenosis/obstruction, but also as a potentially curative treatment in patients with non-malignant biliary tree stenosis. Novel instrumentation dedicated to PTBD has been designed in recent years, which makes it possible to perform more advanced procedures in patients with severe extensive malignant biliary tree stenosis/obstruction. OBJECTIVES: The first primary goal of the study was to compare both the rate and types of short- and long-term complications in patients who had undergone PTBD between 2000 and 2006 with patients treated between 2007 and 2011. The second primary goal of the study was to work out an original algorithm of efficient management in patients undergoing PTBD. An additional goal was to assess the efficacy of PTBD and the overall survival of the patients. MATERIAL AND METHODS: One-hundred twenty-eight consecutive PTBD procedures performed between 2000 and 2006 in patients with malignant biliary jaundice were analyzed retrospectively. Similarly, retrospective analysis of 73 consecutive procedures in patients with malignant biliary jaundice performed between 2007 and 2011 was carried out. Subsequently, the results of both subsets were compared to each other. The PTBD procedure was guided fluoroscopy each time. PTBD involved external biliary drainage and/or stenting of the strictured/occluded segments of extra- and intrahepatic biliary ducts. RESULTS: The analysis demonstrated a statistically significant decrease in the overall incidence of short- and long-term complications in patients undergoing PTBD in 2007-2011 in comparison to the subset treated in 2000-2006. Among the early complications, a significant decrease in sub- and pericapsular contrasted bile leaks was shown. The evaluation of long-term complications demonstrated lower incidence of the falling out of the draining catheter. The implementation of novel instrumentation made it possible to perform biliary stenting in 63.7% cases of common bile duct (CBD) obstruction (vs. 37.5% in procedures carried out in 2000-2006). However, no statistically significant difference in survival between the two analyzed subsets was demonstrated. CONCLUSIONS: The analysis of rate and types of complications made it possible to establish authors own algorithm of management in different types of biliary obstructions and strictures. The modification of procedure technique, pos tinterventional management and usage of the new generation of low-profile instrumentation for percutaneous access dedicated to PTBD has resulted in a significant reduction of the complication rate in the last 5 years. Higher frequency of CBD stenting improves the quality of life in this subset of patients. PMID- 23356200 TI - Diagnostic value of ultrasonography in appendicitis. AB - BACKGROUND: Clinical diagnosis of appendicitis is often difficult in atypical patients. OBJECTIVES: The authors aim to determine the diagnostic accuracy of ultrasonography (US) for acute appendicitis. MATERIAL AND METHODS: 121 consecutive patients with right lower abdomen pain were evaluated. Of them, 25 were excluded due to not having performed a preoperative US and 5 were obese (Body Mass Index > 30). A total of 91 patients were evaluated. The patients were assessed clinically and radiologically. Blood and urine analysis was carried out in all patients. US was performed with a Toshiba Fomio 8 brand machine with 3.75 and 8 MHz linear probes. Patients underwent an operation and an appendicectomy was done. Specimens were sent for histopathology to confirm appendicitis. RESULTS: Ultrasound supported the diagnosis of acute appendicitis in 58 (63.7%) patients. In the US with positive findings, 55 patients (94.8%) had inflamed appendices on histopathology and 5 (8.6%) had normal appendices. The overall sensitivity of ultrasonography was 71.4% and specificity was 78.5%. Positive predictive value (PPV), negative predictive value (NPV) and the diagnostic accuracy of ultrasonography are 94.8%, 33.3%, and 72.5% respectively. CONCLUSIONS: All diagnostic tests are adjunctive to the clinician. US should be the first step in the care of patients with right lower abdominal pain after the physical examination. PMID- 23356201 TI - An assessment of relationships between the five-factor personality model and the morphology and function of the stomathognatic system. AB - BACKGROUND: The personality as a system of genetically predetermined features is responsible for modifying relations between an individual's genotype and phenotype. The key element linking personality with facial morphology is the muscular system. OBJECTIVES: The aim of this study was to investigate the association between facets of the five-factor personality model (FFM) domains and both the morphology and function of the stomathognatic system. MATERIAL AND METHODS: Two hundred volunteers (100 female and 100 male) aged 20 to 25 (mean age: 23.4) underwent anthropometric measurements to calculate the anterior face height ratio N-Sn/Sn-Gn. For cephalometric analysis, standard right-profile images of the face were used. Calibration was performed with a 100-mm metal ruler placed next to each photographed individual. The Revised NEO Personality Inventory (NEO-PI-R), which includes 240 statements, was used for personality assessment in order to investigate the five main personality domains: neuroticism, extraversion, openness to experience, agreeableness, conscientiousness and six facets within each domain. RESULTS: The results show significant correlations between factors of the personality such as neuroticism (r = 0.3488; p = 0.0000) and extraversion (r = -0.3405; p = 0.0000) and the inclination angle (FH/HOR) as the predictor of the function of the stomathognatic system. Additionally, the correlation analysis revealed a significant positive association between the anterior face height ratio and anxiety (r = 0.3952; p = 0.0000). CONCLUSIONS: The results of this study indicate a selective association between personality and both the morphology and function of the stomathognatic system PMID- 23356202 TI - The effect of menopause on bone tissue in former swimmers and in non-athletes. AB - BACKGROUND: An increased loss of bone density during the first years after menopause induces osteoporosis. OBJECTIVES: The aim of the research presented in this paper was to ascertain the difference in the rate of involutional changes in bone tissue in former athletes and in non-athletes of the same age. MATERIAL AND METHODS: The research involved 18 former swimmers and 18 females of similar age who had never practiced sports. The subjects were subdivided into two subgroups: Subgroup I had been post-menopausal for < or = 5 years, and Subgroup II for > 5 years; this was done to assess bone mineral content relative to the length of the postmenopausal time period. Bone mineral content (BMC) and bone mineral density (BMD) were measured in lumbar vertebrae by dual-emission X-ray absorptiometry (DXA). Bone strength was measured in the heel using the bone stiffness index. Each subject was examined twice, with a one-year period in between. A diagnostic questionnaire was used to compile date on the subjects' physical activity and their gonad functioning. Dietary habits (calcium intake) were established by three interviews and the Dieta 4.0 computer program. Results. Anthropometric features did not differentiate the subjects in the subgroups. Former athletes in both subgroups spent off-work time on physical activities significantly more frequently. In both groups, calcium intake was sufficient and did not exceed 3/4 of the daily norm. A higher calcium intake was found in former athletes compared to non-athletes. The subjects in Subgroup I had significantly greater BMC and BMD than those in Subgroup II. In Subgroup I, the second examination showed somewhat lower reductions in BMC and BMD among the former athletes than among the non athletes. In Subgroup II, BMC and BMD increased somewhat among the former athletes, while non-significant reductions were observed in the BMC and BMD of the non-athletes. All the subjects undertook pharmacologic treatment after the first examination, which caused improvement of bone parameters in the second examination. CONCLUSIONS: The rate of bone mass loss in former athletes proved to be consistent with the involutional process and similar to that of non-athletes. The reduced BMD in the lumbar vertebrae of 22% of the women in the study demonstrates the need for regular densitometric examinations in postmenopausal females. PMID- 23356203 TI - Assessment of economic effectiveness in treatment of neuropathic pain and refractory angina pectoris using spinal cord stimulation. AB - BACKGROUND: The implementation of new diagnostic and therapeutic technologies is related to expanding financial needs. The escalation of expenses for health protection and simultaneous economic problems has resulted in an interest in the subject of economic assessment. Decision makers in the health sector should have reasonable tools that will allow them to make complex evaluations of the economic suitability of health technologies. Economic analysis should also prove that launching new procedures can save money. Numerous studies indicate that chronic pain and psycho-sociological variables lead to a worse quality of life. Chronic pain issues are a major public health problem, by virtue of the difficulties in efficient therapy and the social costs reflected in incapability of work and disability. Spinal cord stimulation is the most efficacious procedure in the treatment of chronic pain. OBJECTIVES: The aim of the study was to estimate the costs of treatment of 37 patients suffering from refractory angina pectoris and neuropathic pain who underwent SCS surgery between 2002 and 2008 in the Neurosurgery Clinic of the 10th Military Hospital in Bydgoszcz in the period of two years before and two years after spinal cord stimulation. The authors also assessed quality of life, using the SF 36 questionnaire, and degree of pain using VAS. MATERIAL AND METHODS: The issue was examined with a cost-benefit analysis. Cost was understood as the expenses made two years before and two years after the SCS procedure. The benefits were health care expenses saved by implementation of the SCS procedure. All the costs included in both alternative treatment techniques in a period of 5 years underwent a discounting procedure. The authors also included the price of the neurostimulator under a sensitivity analysis. To assess the quality of life before and after the SCS procedure, a SF 36 questionnaire was used, and to assess the level of pain before and after the SCS procedure, the VAS scale. RESULTS: The costs of treatment of refractory angina pectoris and neuropathic pain are lower when using spinal cord stimulation. In the case of refractory angina pectoris, savings reached 46% whereas in the case of neuropathic pain, 13.2%. The costs of the purchase of the device returned in three years for angina pectoris and seven years for neuropathic pain. SCS in both cases brought a reduction of the level of pain and an improvement to quality of life. CONCLUSIONS: SCS in both neuropathic pain and refractory angina pectoris is a procedure that brings benefits in the form of savings. After using SCS in both cases, the quality of life improved and the level of pain was reduced. PMID- 23356204 TI - Heidelberg edge perimeter employment in glaucoma diagnosis--preliminary report. AB - In recent years, the authors have seen huge progress in the diagnosis of eye diseases. One of the new diagnostic devices is HEP (Heidelberg Edge Perimeter) - for early diagnosis of glaucoma and its progression. It combines visual field test and HRT (Heidelberg Retina Tomograph), which allows authors to obtain the image of the mutual relation between the structure and the function of the sight organ. It could be also used to assess patients with impaired retina, optic nerve and neurological deficits. The SAP function is more suitable for the detection and monitoring of neurological deficits, moderately advanced and advanced glaucoma as well as other diseases associated with extensive or deep visual field deficits, such as ischemic optic neuropathy. FDF stimulus was designed specifically to detect early glaucoma-related changes in the visual field. For about a year, the Ophthalmology Clinic in Wroclaw has owned a new, unique HEP perimeter. The authors present examples of patients diagnosed and treated at the Clinic, with respect to whom the perimeter results obtained using Octopus type perimeter and HEP contour perimeter have been compared. This method has its advantages: it is non-invasive, objective, provides the opportunity to repeat and compare results obtained from subsequent tests. The disadvantages are the difficulty in adapting to a new stimulus, which is not a circular light stimulus, but an outline that is hard to notice for some patients. Although according to the manufacturer the testing time should not exceed 4-5 minutes, it takes 14-15 minutes in many patients. The test is not suitable for patients showing lower manual skills and less attention and those who tire out easily. The HEP perimeter is an innovative method for diagnosing the earliest changes in ganglion cells, that is pre-perimetric glaucoma, or when changes in the visual field are undetectable in a standard test. PMID- 23356205 TI - Treatment of Helicobacter pylori infection in the aspect of increasing antibiotic resistance. AB - In the present work, the problem of Helicobacter pylori infection in the world and its increasing antibiotic resistance are analyzed. The authors discuss the efficacy of treatment, noting that the clarithromycin--and metronidazole resistance of H. pylori is the main cause of this treatment failure. Because of this phenomenon, a quadruple therapy is being introduced and clarithromycin is being replaced by new antibiotics. The authors also present various schemes of triple and quadruple therapy as well as sequential therapy. Attention is directed to the fact that, in order to obtain better results of the eradication, the treatment should be prolonged from 7 to 10 or even 14 days, and that the doses of the drugs should be increased. PMID- 23356206 TI - Massage therapy in myofascial TMD pain management. AB - Myofascial pain located in the area of the head is a very common disease of the stomatognathic system. The fact that the mechanism of its development is very complex may cause a variety of problems in diagnosis and therapy. Patients diagnosed with this type of affliction usually need a variety of different therapies. Massage therapy can be a significant method of treatment of myofascial pain. That kind of therapy is clinically useful as it improves the subjective and objective health status of the patient and is easy to follow. The aim of this paper is to show the physiological effect and different massage techniques applied in myofascial pain treatment. The authors would also like to present the protocol for dealing with patients who demand that kind of therapy for masseter and temporal muscles. PMID- 23356207 TI - Quantitative purity-activity relationships of natural products: the case of anti tuberculosis active triterpenes from Oplopanax horridus. AB - The present study provides an extension of the previously developed concept of purity-activity relationships (PARs) and enables the quantitative evaluation of the effects of multiple minor components on the bioactivity of residually complex natural products. The anti-tuberculosis active triterpenes from the Alaskan ethnobotanical Oplopanax horridus were selected as a case for the development of the quantitative PAR (QPAR) concept. The residual complexity of the purified triterpenes was initially evaluated by 1D- and 2D-NMR and identified as a combination of structurally related and unrelated impurities. Using a biochemometric approach, the qHNMR purity and anti-TB activity of successive chromatographic fractions of O. horridus triterpenes were correlated by linear regression analysis to generate a mathematical QPAR model. The results demonstrate that impurities, such as widely occurring monoglycerides, can have a profound impact on the observed antimycobacterial activity of triterpene-enriched fractions. The QPAR concept is shown to be capable of providing a quantitative assessment in situations where residually complex constitution contributes toward the biological activity of natural products. PMID- 23356208 TI - Synthesis and reactivity of the unsaturated trinuclear phosphanido complex [(C6F5)2Pt(MU-PPh2)2Pt(MU-PPh2)2Pt(PPh3)]. AB - The reaction of [NBu(4)][(C(6)F(5))(2)Pt(MU-PPh(2))(2)Pt(MU-PPh(2))(2)Pt(O,O acac)] (48 VEC) with [HPPh(3)][ClO(4)] gives the 46 VEC unsaturated [(C(6)F(5))(2)Pt(1)(MU-PPh(2))(2)Pt(2)(MU-PPh(2))(2)Pt(3)(PPh(3))](Pt(2)-Pt(3)) (1), a trinuclear compound endowed with a Pt-Pt bond. This compound displays amphiphilic behavior and reacts easily with nucleophiles L, yielding the saturated complexes [(C(6)F(5))(2)Pt(II)(MU-PPh(2))(2)Pt(II)(MU PPh(2))(2)Pt(II)(PPh(3))L] [L = PPh(3) (2), py (3)]. The reaction with the electrophile [Ag(OClO(3))PPh(3)] affords the adduct 1.AgPPh(3), which evolves, even at low temperature, to a mixture in which [(C(6)F(5))(2)Pt(III)(MU PPh(2))(2)Pt(III)(MU-PPh(2))(2)Pt(II)(PPh(3))(2)](2+)(Pt(III)-Pt(III)) and 2 (plus silver metal) are present. The nucleophilic nature of 1 is also demonstrated through its reaction with cis-[Pt(C(6)F(5))(2)(THF)(2)], which results in the formation of [Pt(4)(MU-PPh(2))(4)(C(6)F(5))(4)(PPh(3))] (4). The structure and NMR features indicate that 1 can be better considered as a Pt(II) Pt(III)-Pt(I) complex instead of a Pt(II)-Pt(II)-Pt(II) derivative. Theoretical calculations (density functional theory) on similar model compounds are in agreement with the assigned oxidation states of the metal centers. The strong intermetallic interactions resulting in a Pt(2)-Pt(3) metal-metal bond and the respective bonding mechanism were verified by employing a multitude of computational techniques (natural bond order analysis, the Laplacian of the electron density, and localized orbital locator profiles). PMID- 23356209 TI - Transumbilical single-incision laparoscopic fundoplication: a new technique for liver retraction using cyanoacrylate. AB - BACKGROUND/AIM: Single-incision laparoscopic fundoplication is not widespread because of its technical difficulty. An additional stay suture or retractor is often needed for liver retraction during the procedure. Here, we share our 7 cases to demonstrate the feasibility of transumbilical single-incision laparoscopic fundoplication with a new technique for liver retraction without any stay suture or retractor. PATIENTS AND METHODS: From March 2010 to October 2011, 3 patients with achalasia underwent a transumbilical single-incision laparoscopic Heller-Dor operation, and 4 patients with hiatus hernia underwent transumbilical single-incision laparoscopic hernioplasty and Nissen fundoplication. The procedures were attempted transumbilically by using three rigid trocars (one was 10 mm, and two were 5 mm) inserted through the 2-cm umbilicus incision. Conventional laparoscopic instruments were used. Adequate retraction of the liver was achieved by binding the lateral left lobe of the liver to the diaphragm with cyanoacrylate. RESULTS: The pneumoperitoneal time was 115-170 minutes, and blood loss was 15-50 mL. There were no intra- or postoperative complications. The hospital stay was under 6 days for all patients. The umbilical incision healed well with satisfactory cosmetic effect. CONCLUSIONS: The transumbilical single incision laparoscopic technique in the treatment of achalaisa and hiatus hernia is feasible for an experienced laparoscope surgeon with excellent cosmetic effect. Cyanoacrylate, when used as described, offers a safe and simple solution to the problem of liver retraction, thus obviating the need for a stay suture or liver retractor. PMID- 23356210 TI - A phase 1, randomized ascending single-dose study of antagonist anti-human CD40 ASKP1240 in healthy subjects. AB - This first-in-human, phase I study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ASKP1240 in healthy subjects. Twelve sequential groups (each 6 active and 3 placebo) were randomly assigned to placebo or single ascending doses of intravenous ASKP1240 (0.00003-10 mg/kg). ASKP1240 exhibited nonlinear pharmacokinetics, with mean maximal serum concentrations and area under the serum concentration-time curves ranging from 0.7 to 251.6 MUg/mL and 6.5 to 55409.6 h.MUg/mL following doses 0.1 mg/kg-10 mg/kg, respectively. CD40 receptor occupancy by ASKP1240, which was dose dependent, reached a maximum at doses above 0.01 mg/kg. ASKP1240 was well tolerated, with no evidence of cytokine release syndrome or thromboembolic events. Treatment emergent antibodies to ASKP1240 were detected in 5/70 (7.1%) ASKP1240 recipients. In conclusion, antagonism of the CD40/CD154 interaction with ASKP1240 was safe and well tolerated at the doses tested. PMID- 23356211 TI - Half antibody fragments improve biosensor sensitivity without loss of selectivity. AB - We show for the first time that half antibody fragments obtained by reduction via tris(2-carboxyethyl)phosphine (TCEP) gave a larger response with shear-mode resonating mass sensors than physisorbed whole antibody or antibody immobilized via Protein G. The reduced antibody is shown to preserve the antigen-binding region and was determined via the antigen binding response. Reduction exposed the native thiol group in the antibody that readily chemisorbed onto the gold-coated sensor surfaces with the right orientation for antigen binding. Comparing responses obtained on a quartz crystal microbalance for the detection of pathogenic Escherichia coli O157:H7 using TCEP-reduced antibody with native antibody showed that the proposed method enhances device sensitivity. Examining the half antibody fragments for detection of the pathogen in the presence of the nonpathogenic wild strain showed that the antibody fragments retained their specific antigen binding capability without loss of selectivity. PMID- 23356212 TI - Safety and efficacy of open irrigated-tip catheter ablation of Wolff-Parkinson White syndrome in children and adolescents. AB - BACKGROUND: Irrigated-tip catheter technology has been used for the elimination of resistant accessory pathways (AP) in adults with Wolff-Parkinson-White (WPW) syndrome. However, there are persistent concerns regarding the safety of irrigated catheters in the pediatric population. In this report we present our experience, in terms of effectiveness and safety, of irrigated catheter technology in children and adolescents who underwent ablation of WPW. METHODS: We prospectively followed up all patients less than 18 years old (n = 41, mean age of 12.8 years old) who were referred to our center for radiofrequency (RF) catheter ablation of WPW between January 2010 and July 2011. Catheter ablation was performed in all patients using an open irrigated-tip catheter (Celsius Thermocool 3.5 mm, 7F, B-type, Biosense Webster, Diamond Bar, CA, USA). Power was started from 15 W up to 30 W in right-sided AP; RF pulses in left-sided APs were delivered at 40 W while 20 W was delivered inside the coronary sinus. RESULTS: Mean procedure time was 26.4 minutes and mean fluoroscopy time was 12.2 minutes. Overall procedural success was obtained in 39/41 (95.1%) patients after the first procedure. No complications were observed after the procedure. All patients attended their scheduled follow-up visit at 3, 6, and 12 months and no recurrences were observed based on 12-lead electrocardiogram and 24-hour Holter monitoring. CONCLUSIONS: RF ablation of APs using open irrigated-tip catheters can be performed in children and adolescents with a high acute and long-term success rate, very short procedure times, and acceptable fluoroscopy times. PMID- 23356213 TI - The impact of including children with intellectual disability in general education classrooms on the academic achievement of their low-, average-, and high-achieving peers. AB - BACKGROUND: This study aimed at assessing the impact of including children with intellectual disability (ID) in general education classrooms with support on the academic achievement of their low-, average-, and high-achieving peers without disability. METHOD: A quasi-experimental study was conducted with an experimental group of 202 pupils from classrooms with an included child with mild or moderate ID, and a control group of 202 pupils from classrooms with no included children with special educational needs (matched pairs sample). The progress of these 2 groups in their academic achievement was compared over a period of 1 school year. RESULTS: No significant difference was found in the progress of the low-, average , or high-achieving pupils from classrooms with or without inclusion. CONCLUSIONS: The results suggest that including children with ID in primary general education classrooms with support does not have a negative impact on the progress of pupils without disability. PMID- 23356215 TI - Common mycorrhizal networks amplify size inequality in Andropogon gerardii monocultures. AB - Arbuscular mycorrhizal fungi can interconnect plant root systems through hyphal common mycorrhizal networks, which may influence the distribution of limiting mineral nutrients among interconnected individuals, potentially affecting competition and consequent size inequality. Using a microcosm model system, we investigated whether the members of Andropogon gerardii monocultures compete via common mycorrhizal networks. We grew A. gerardii seedlings with isolated root systems in individual, adjacent containers while preventing, disrupting or allowing common mycorrhizal networks among them. Fertile soil was placed within the containers, which were embedded within infertile sand. We assessed mycorrhizas, leaf tissue mineral nutrient concentrations, size hierarchies and the growth of nearest neighbors. Plants interconnected by common mycorrhizal networks had 8% greater colonized root length, 12% higher phosphorus and 35% higher manganese concentrations than plants severed from common mycorrhizal networks. Interconnected plants were, on average, 15% larger and had 32% greater size inequality, as reflected by Gini coefficients, than those with severed connections. Only with intact common mycorrhizal networks were whole-plant dry weights negatively associated with those of their neighbors. In the absence of root system overlap, common mycorrhizal networks likely promote asymmetric competition below ground, thereby exaggerating size inequality within A. gerardii populations. PMID- 23356214 TI - Targeted therapies in colorectal cancer-an integrative view by PPPM. AB - In developed countries, colorectal cancer (CRC) is the third most common malignancy, but it is the second most frequent cause of cancer-related death. Clinicians are still faced with numerous challenges in the treatment of this disease, and future approaches which target the molecular features of the disorder will be critical for success in this disease setting. Genetic analyses of many solid tumours have shown that up to 100 protein-encoding genes are mutated. Within CRC, numerous genetic alterations have been identified in a number of pathways. Therefore, understanding the molecular pathology of CRC may present information on potential routes for treatment and may also provide valuable prognostic information. This will be particularly pertinent for molecularly targeted treatments, such as anti-vascular endothelial growth factor therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. KRAS and BRAF mutations have been shown to predict response to anti-EGFR therapy. As EGFR can also signal via the phosphatidylinositol 3-kinase (PI3K) kinase pathway, there is considerable interest in the potential roles of members of this pathway (such as PI3K and PTEN) in predicting treatment response. Therefore, a combined approach of new techniques that allow identification of these biomarkers alongside interdisciplinary approaches to the treatment of advanced CRC will aid in the treatment decision-making process and may also serve to guide future therapeutic approaches. PMID- 23356216 TI - Identification of a distinct mutation spectrum in the SMPD1 gene of Chinese patients with acid sphingomyelinase-deficient Niemann-Pick disease. AB - BACKGROUND: Clinical observations and molecular analysis of the SMPD1 gene in Chinese patients with acid sphingomyelinase deficiency Niemann-Pick disease (NPD) are scarce. METHODS: A cohort of 27 Chinese patients diagnosed with acid sphingomyelinase deficiency, within the past five years, were collected and investigated for genotype, phenotype, and their correlations. RESULTS: The majority of our patients (25/27) were under 18 years of age. From the cohort group, eight (30%) fulfilled characters of type A. Four other patients experienced neurologic involvement after two years of age, these were classified as intermediate type. The remaining fifteen presented without clear neurologic involvement and were regarded as type B. One patient, from the type B group, presented with the unusual symptom of a secondary amenorrhea. Three patients, one from the type B group and two from the intermediate group, presented with pronounced proteinuria, in the late stages of the disease, indicating possible kidney involvement in NPD. Twenty-four SMPD1 gene mutations had been identified; eighteen of these are novel ones. These included four exonic small deletions/duplications (c.4delC, c.147_150del4, c.842-849dup8, c.1307-1312dup6), one termination mutation (p.Glu248X), and thirteen exonic point mutations (p.Gly336Ser, p.Trp342Cys, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser, p.Trp437Arg, p.Thr451Pro, p.His461Pro, p.Ala484Val, p.Ser486Arg, p.Tyr500His, p.Pro533Leu, p.Val559Leu). Notably, eight mutations had more than one occurrence with c.4delC and p.Glu248X accounting for ~30% of all alleles. Correlation analysis of genotype and phenotype indicated eight mutations, c.842-849dup8, p.Glu248X, p.Arg230Cys, p.Trp437Arg, p.His461Pro, p.Ala484Val p.Ser486Arg, and p.Pro533Leu,to be severe mutations. Five mutations, c.4delC, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser and p.Val559Leu were projected to be mild mutations. Interestingly, three intermediate individuals carried combinations of a mild mutation, c.4delC, on one allele and a severe mutation on the other allele. CONCLUSIONS: The Chinese population may have a comparably high incidence of sphingomyelinase-deficient Niemann-Pick disease type A. This study has identified some novel genotype and phenotype correlations in this rare and devastating disorder. PMID- 23356217 TI - Exploring the relationship between negative urgency and dysregulated eating: etiologic associations and the role of negative affect. AB - Negative urgency (i.e., the tendency to engage in rash action in response to negative affect) has emerged as a critical personality trait contributing to individual differences in binge eating. However, studies investigating the extent to which genetic and/or environmental influences underlie the effects of negative urgency on binge eating are lacking. Moreover, it remains unclear whether negative urgency-binge eating associations are simply a result of the well established role of negative affect in the development/maintenance of binge eating. The current study addresses these gaps by examining phenotypic and etiologic associations between negative urgency, negative affect, and dysregulated eating (i.e., binge eating, emotional eating) in a sample of 222 same-sex female twin pairs from the Michigan State University Twin Registry. Negative urgency was significantly associated with both dysregulated eating symptoms, even after controlling for the effects of negative affect. Genetic factors accounted for the majority (62-77%) of this phenotypic association, although a significant proportion of this genetic covariation was due to genetic influences in common with negative affect. Nonshared environmental factors accounted for a relatively smaller (23-38%) proportion of the association, but these nonshared environmental effects were independent of negative affect. Findings suggest that the presence of emotion-based rash action, combined with high levels of negative affect, may significantly increase genetic risk for dysregulated eating. PMID- 23356218 TI - Emotion-modulated startle in psychopathy: clarifying familiar effects. AB - The behavior of psychopathic individuals is thought to reflect a core fear deficit that prevents these individuals from appreciating the consequences of their choices and actions. However, growing evidence suggests that psychopathy related emotion deficits are moderated by attention and, thus, may not reflect a reduced capacity for emotion responding. The present study attempts to reconcile this attention perspective with one of the most cited findings in psychopathy, which reports emotion-modulated startle deficits among psychopathic individuals during picture viewing. In this study, we evaluate the potential effects of a putative attention bottleneck on the emotion processing of psychopathic offenders during picture viewing by manipulating picture familiarity and examining emotion modulated startle and late positive potential (LPP). As predicted, psychopathic individuals displayed the classic deficit in emotion-modulated startle during novel pictures, but they showed no deficit in emotion-modulated startle during familiar pictures. Conversely, results for LPP responses revealed psychopathy related differences during familiar pictures and no psychopathy-related differences during novel pictures. Important differences related to the two factors of psychopathy are also discussed. Overall, the results of this study not only highlight the differential importance of perceptual load on emotion processing in psychopathy, but also raise interesting questions about the varied effects of attention on psychopathy-related emotion deficits. PMID- 23356219 TI - Regulation of Bacillus subtilis DesK thermosensor by lipids. AB - Temperature sensing is essential for the survival of living cells. The membrane bound thermosensor DesK from Bacillus subtilis is a key representative of histidine kinases receptors able to remodel membrane lipid composition when the temperature drops below ~30 degrees C. Although the receptor is well studied, a central issue remains: how does the compositional and functional diversity of the surrounding membrane modulate receptor function? Reconstituting full-length DesK into proteoliposomes of well-defined and controlled lipid composition represents a minimal synthetic approach to systematically address this question. Thus DesK has been reconstituted in a variety of phospholipid bilayers and its temperature regulated autokinase activity determined as function of fatty acyl chain length, lipid head-group structure and phase preference. We show that the head group structure of lipids (both in vitro and in vivo) has little effect on DesK thermosensing, whereas properties determined by the acyl chain of lipids, such as membrane thickness and phase separation into coexisting lipid domains, exert a profound regulatory effect on kinase domain activation at low temperatures. These experiments suggest that the non-polar domain of glycerolipids is essential to regulate the allosteric structural transitions of DesK, by activating the autophosphorylation of the intracellular kinase domain in response to a decrease in temperature. PMID- 23356220 TI - Tight junction-related human diseases. AB - Tight junctions are intercellular junctions adjacent to the apical ends of paracellular spaces. They have two classical functions, the barrier function and the fence function. The former regulates the passage of ions, water and various molecules through paracellular spaces, and is thus related to edema, jaundice, diarrhea and blood-borne metastasis. The latter function maintains cell polarity by forming a fence to prevent intermixing of molecules in the apical membrane with those in the lateral membrane. This function is deeply involved in cancer cell properties in terms of loss of cell polarity. Recently, two novel aspects of tight junctions have been reported. One is their involvement in signal transduction. The other is that fact that tight junctions are considered to be a crucial component of innate immunity. In addition, since some proteins comprising tight junctions work as receptors for viruses and extracellular stimuli, pathogenic bacteria and viruses target and affect the tight junction functions, leading to diseases. In this review, the relationship between tight junctions and human diseases will be described. PMID- 23356221 TI - Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 in gastric cancer. AB - Gastric cancer is one of the most common malignancies worldwide and patients with advanced gastric cancer still have poor clinical outcomes. The overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) mRNA in colorectal cancer and its correlation with clinicopathological factors were recently reported by us. In this study, we show LGR5 mRNA overexpression in human gastric cancer specimens by quantitative RT-PCR and in situ hybridization and assess a correlation with clinicopathological factors. The mean expression of LGR5 mRNA in cancerous tissues was five times higher than that in normal tissue (P = 0.0002). Furthermore, LGR5 mRNA expression show marked variation among cases and significantly increased in cases where lymphatic invasion was present compared with those where it was absent (P = 0.0056). Although the mean expression level of LGR5 was observed to be higher in nodal metastasis and venous invasion positive cases compared to negative cases, a significant difference was not observed. These results suggest that LGR5 can be a biomarker for malignancy in gastric cancer. PMID- 23356222 TI - Immunohistochemical analysis of aromatase in metastatic lymph nodes of breast cancer. AB - Aromatase is the key enzyme in intratumoral estrogen production in postmenopausal breast cancer and third generation aromatase inhibitors suppress this enzymatic reaction effectively. Aromatase inhibitor is administered to metastatic breast cancer patients customarily in which estrogen receptor had been demonstrated only in the primary tumor, not the metastatic sites. The status of aromatase in metastatic sites has not been well-characterized to date. We immunolocalized aromatase in 46 estrogen receptor positive primary breast cancers and paired metastatic lymph nodes, using immunohistochemistry. Immunoreactivity was detected in 44/46 primary tumors and 40/46 metastatic lymph nodes. A significant correlation was detected between the status of aromatase in primary and metastatic sites. Aromatase immunoreactivity was correlated with age, size of primary tumor and Ki-67 index. Aromatase immunoreactivity was also detected in adipose tissue surrounding the lymph nodes. In conclusion, aromatase status in primary tumors generally represents its status in metastatic lymph nodes. This indicates that the endocrine environment of estrogen receptor positive tumors remain stable during the metastatic process. PMID- 23356223 TI - Morphophenotype of floating colonies derived from a single cancer cell has a critical impact on tumor-forming activity. AB - The anchorage-independent colony growth of cancer cells is reportedly correlated with the tumor-forming activity; however, the correlation between the morphophenotype of each colony and the tumor-forming activity has not been clarified. To assess this problem, we cultured single A549 cells (human lung adenocarcinoma cell line) in growth medium in individual wells (n = 426) for 14 days under anchorage-independent conditions and analyzed the resulting growth characteristics. The single A549 cells formed various sizes of floating colonies. The proportion of large colonies (>400 MUm) was 3.8% and this proportion increased dramatically with the exogenous addition of EGF (21.6%) or HGF (27.6%). Morphologically, the floating colonies could be divided into: (ii) Type A, spheroid colony; and (ii) Type B, dispersed villous colony. The Type B colonies expressed significantly higher levels of epithelial-mesenchymal transition (EMT) related mRNAs (Snail 1, ZEB 1, and ZEB2) than the Type A colonies. Furthermore, the subcutaneous injection of a single cell-derived colony with a large size and a Type B morphology resulted in more efficient tumor formation. The present results indicated that the morphophenotypes of floating colonies derived from single cancer cells have a critical impact on tumor-forming activity. PMID- 23356224 TI - The F-prostaglandin receptor is a novel marker for tumor endothelial cells in renal cell carcinoma. AB - Tumor angiogenesis is necessary for tumor progression and metastasis; therefore, tumor blood vessels are potential therapeutic targets in anticancer therapy. We previously reported that tumor endothelial cells (TECs) exhibit different phenotypes compared with normal endothelial cells (NECs), and microarray analyses of mouse TECs and NECs have shown that several genes are upregulated in TECs compared with NECs. Among these genes, the expression levels of prostaglandin F receptor (PTGFR) mRNA, which encodes the prostaglandin F receptor (FP), were higher in TECs than in NECs. It has been reported that FP and its ligand, prostaglandin F(2alpha) , are involved in tumor angiogenesis. However, there have been no reports of the expression of PTGFR in the tumor vessels of renal cell carcinoma (RCC). Thus, we isolated human TECs (hTECs) from RCCs. The expression levels of PTGFR mRNA were also upregulated in hTECs. In addition, immunostaining showed that the PTGFR was expressed in human tumor blood vessels in vivo. These findings suggested that PTGFR is a novel TEC marker and that it may be a novel target for antiangiogenic therapy for RCC. PMID- 23356225 TI - Unique mutation, accelerated mTOR signaling and angiogenesis in the pulmonary cysts of Birt-Hogg-Dube syndrome. AB - Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors and pulmonary cysts with repeated pneumothorax. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is known to be involved in the signaling of mammalian target of rapamycin (mTOR). We investigated the lung of a BHD patient who presented with a unique mutation. A 33-year-old woman visited our hospital due to repeated pneumothorax. Histopathologic study of the resected lung demonstrated multiple epithelial cysts. An increase of blood vessels was observed in the vicinity of subpleural cysts. Genomic DNA analysis revealed heterozygous mutation at the 3' end of intron 5 of the FLCN gene. Total mRNA and protein were extracted from the resected lung tissue. RT-PCR and sequence analysis demonstrated the production of exon 6-skipped FLCN mRNA. In Western blotting, the band intensities of phospho mTOR, phospho-S6, phospho-Akt, hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF) were increased in the BHD lung compared with normal lungs. Histopathologic analysis demonstrated strong immunostainings of mTOR signaling molecules in cyst-lining cells. Collective data indicates that dysregulation of mTOR signaling facilitates S6-mediated protein synthesis and HIF 1alpha-mediated angiogenesis, which may contribute to the development of pulmonary cysts in this disorder. PMID- 23356226 TI - Intracaval and intracardiac extension of invasive thymoma complicated by superior and inferior vena cava syndrome. AB - We present a case of an aged male with invasive thymoma that extended into the right atrium and led to superior and inferior vena cava syndrome. The patient initially presented with edema of the face and bilateral lower extremities. Echocardiography revealed a mass within the right atrium. Imaging studies demonstrated an anterior mediastinal tumor that continuously occupied the bilateral brachiocephalic veins, superior vena cava, and right atrium. Pathological diagnosis of the tumor biopsy was highly suspicious of thymoma. Due to the high risk of wide spread of the tumor, treatments including resection of the tumor were impossible. Several days later he died, and an autopsy was performed. The tumor was type B2 thymoma invading bilateral brachiocephalic veins, superior vena cava and right atrium. Multiple tumor emboli within the pulmonary arteries were identified. Direct cause of death was deemed to be tumor strangulation at the tricuspid orifice. In addition to the superior vena cava syndrome, inferior vena cava syndrome including ectasia of the intrahepatic vessels was confirmed along with pericarditis. To our knowledge, this is the first English report of an autopsy case of intracardiac thymoma extension, and a detailed literature review of similar cases is also presented. PMID- 23356227 TI - Proliferative glomerulonephritis with discrete deposition of monoclonal immunoglobulin gamma1 CH 2 heavy chain and kappa light chain: a new variant of monoclonal immunoglobulin deposition disease. AB - A 45-year-old man presented with moderate proteinuria and hematuria. A renal biopsy showed mesangial/endocapillary proliferative glomerulonephritis, linear deposition of monoclonal immunoglobulin gamma1 C(H) 2 heavy chain along glomerular and tubular basement membranes (GBMs and TBMs), granular deposition of kappa light chain within the mesangial area, and continuous linear deposits of finely granular electron-dense materials along GBMs and TBMs. Dual immunostaining showed essentially discrete glomerular localization of gamma1 C(H) 2 heavy chain and kappa light chain. Monoclonal protein was not detected in urine and serum. A bone marrow aspiration showed no abnormalities. Steroid therapy led to the improvement of proteinuria and hematuria. We would classify this case as a new variant of monoclonal immunoglobulin deposition disease, light chain/heavy chain deposition disease. In contrast with light and heavy chain deposition disease, the remarkable characteristics of this variant are separate deposition of monoclonal heavy chain and light chain, deposition of largely deleted gamma heavy chain lacking the C(H) 1 domain, and good response to steroid therapy. PMID- 23356228 TI - Primary dural lymphoma: a novel concept of heterogeneous disease. AB - Spinal primary dural lymphoma (PDL) is uncommon with a total of 37 previous well documented cases reported, including one diagnosed in the authors' institution. More recently we encountered an additional case of spinal PDL that, similarly to our previous case, was grade 1-2 follicular B-cell PDL. Our two cases were diagnosed over a 3-year interval in a 72-year-old female and a 74-year-old male, respectively. An exhaustive literature review on PDL was performed consequently to reveal that: (i) spinal and cerebral sites of involvement by PDL are constantly mutually exclusive; and (ii) unlike cerebral PDL, which is usually of marginal zone B-cell type, only two of the 38 cases of spinal PDL were diagnosed as such, diffuse large B-cell lymphoma being the most commonly encountered type in the spine. This divergence infers that, in contrast to the prevailing concept that PDL is a unique disease group, PDL appears to be rather heterogeneous with a difference in predilection of lymphoma type for the anatomical site of dural involvement. Such a site-specific lymphoma-type predilection phenomenon, well recognized in other organ systems, has not been acknowledged in PDL. This report brings new insights into PDL, and may contribute to a better understanding of nervous system pathophysiology and lymphoma classification. PMID- 23356229 TI - Plasmacytoid urothelial carcinoma: first case reported in the ureter. PMID- 23356230 TI - CROES survey-based studies: the role of expert opinion in endourologic research. PMID- 23356231 TI - Assessment of the use of the speculum for intravitreal injections of anti-VEGF. PMID- 23356232 TI - Cell line identity finding by fingerprinting, an optimized resource for short tandem repeat profile authentication. AB - The generation of biological data on wide panels of tumor cell lines is recognized as a valid contribution to the cancer research community. However, research laboratories can benefit from this knowledge only after the identity of each individual cell line used in the experiments is verified and matched to external sources. Among the methods employed to assess cell line identity, DNA fingerprinting by profiling Short Tandem Repeat (STR) at variable loci has become the method of choice. However, the analysis of cancer cell lines is sometimes complicated by their intrinsic genetic instability, resulting in multiple allele calls per locus. In addition, comparison of data across different sources must deal with the heterogeneity of published profiles both in terms of number and type of loci used. The aim of this work is to provide the scientific community a homogeneous reference dataset for 300 widely used tumor cell lines, profiled in parallel on 16 loci. This large dataset is interfaced with an in-house developed software tool for Cell Line Identity Finding by Fingerprinting (CLIFF), featuring an original identity score calculation, which facilitates the comparison of STR profiles from different sources and enables accurate calls when multiple loci are present. CLIFF additionally allows import and query of proprietary STR profile datasets. PMID- 23356233 TI - Longer pre-hospital delay in first myocardial infarction among patients with diabetes: an analysis of 4266 patients in the northern Sweden MONICA Study. AB - BACKGROUND: Reperfusion therapy reduces both morbidity and mortality in myocardial infarction, but the effectiveness depends on how fast the patient receives treatment. Despite the time-dependent effectiveness of reperfusion therapy, many patients with myocardial infarction have delays in seeking medical care. The aim of this study was to describe pre-hospital delay in a first myocardial infarction among men and women with and without diabetes and to describe the association between pre-hospital delay time and diabetes, sex, age, symptoms and size of residential area as a proxy for distance to hospital. METHODS: This population based study was based on data from 4266 people aged 25 74 years, with a first myocardial infarction registered in the Northern Sweden MONICA myocardial infarction registry between 2000 and 2008. RESULTS: The proportion of patients with delay times >= 2 h was 64% for patients with diabetes and 58% for patients without diabetes. There was no difference in delay time >= 2 h between men and women with diabetes. Diabetes, older age and living in a town or rural areas were factors associated with pre-hospital delay times >= 2 h. Atypical symptoms were not a predictor for pre-hospital delay times >= 2 h, OR 0.59 (0.47; 0.75). CONCLUSIONS: A higher proportion of patients with diabetes have longer pre-hospital delay in myocardial infarction than patients without diabetes. There are no differences in pre-hospital delay between men and women with diabetes. The largest risk difference for pre-hospital delay >= 2 h is between women with and without diabetes. Diabetes, older age and living in a town or rural area are predictors for pre-hospital delay >= 2 h. PMID- 23356235 TI - A molecular complex of bovine milk protein and oleic acid selectively kills cancer cells in vitro and inhibits tumour growth in an orthotopic rat bladder tumour model. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Novel intravesical therapies are needed for superficial bladder cancer that reduce the risk of infection associated with Bacillus Calmette-Guerin (BCG) and further destabilization of the urothelium associated with cytotoxic chemotherapy. Experimental therapies to date have included photodynamic therapy, oncolytic viruses, gene therapy (antisense oligonucleotides and silencing RNA), cytokine therapy, death receptor agonists (tumour-necrosis-factor-related apoptosis inducing ligand and anti-DR5 monoclonal antibody), naturally occurring substances (curcumin and deguelin) and human alpha-lactalbumin made lethal to tumour cells (HAMLET). HAMLET, a natural occurring product in milk, induces apoptosis in urothelial cancer cells but has limitations in clinical application because of its human source. A previous study in patients with bladder cancer has demonstrated that intravesical HAMLET (daily for 5 days before tumour resection) caused selective apoptotic tumour cell death. BAMLET, the bovine equivalent of HAMLET, is a complex of bovine alpha-lactalbumin and oleic acid (bLAC) that has been shown in vitro to accumulate in the endolysosomal compartment of tumour cells and induce leakage of lysosomal cathepsins into the cytosol followed by activation of the pro-apoptotic protein Bax. This is the first in vivo study to show that BAMLET (bLAC) induces apoptosis in urothelial cancer cells and controls the growth of high risk urothelial cancer in a syngeneic rat orthotopic model. This same bladder cancer model system has been used to test other novel therapies, including BCG, and therefore provides a relative comparison of its effectiveness with other intravesical therapies. OBJECTIVE: To investigate the efficacy of a complex of bovine alpha-lactalbumin and oleic acid (bLAC) to kill urothelial cancer cells in vitro and inhibit tumour growth and progression in a high risk bladder tumour model. MATERIALS AND METHODS: The cytotoxicity of bLAC to a large panel of urothelial cell cancer (UCC) cells was tested by the MTT (3 (4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay, using bLA, the folded alpha-lactalbumin without oleic acid, as a control. The mechanism of bLAC-inducing cell death was evaluated by annexin V staining, TUNEL (terminal deoxynucleotidyl transferase mediated nick end labelling) assay and sub-G1 DNA analysis. The selective bLAC cytotoxicity was examined using multicellular spheroids consisting of UCC and non-transformed fibroblasts. Rats bearing orthotopic tumour received intravesical instillations (twice weekly, for 3 weeks) of bLAC, bLA, BCG or saline, starting 6 days after UCC (AY-27) cell inoculation. Animals were monitored for survival, toxicity and tumour growth control. RESULTS: A dose-dependent bLAC-inducing apoptotic-like cell death was shown in UCC cells tested, including cells refractory to classic apoptosis-inducing agents, whereas bLA showed little cytotoxicity. bLAC selectively destroyed cancer cells in spheroids. Intravesical bLAC therapy demonstrated marked reduction in tumour growth/progression and significantly prolonged animal survival vs saline instillations (P = 0.004, log-rank test) and showed comparable efficacy with BCG (standard) therapy. CONCLUSION: The findings identify bLAC as a new candidate for UCC therapy and suggests that topical administration of bLAC alone or with BCG to prevent progression of bladder cancer warrants further exploration. PMID- 23356234 TI - Silencing of mutant p53 by siRNA induces cell cycle arrest and apoptosis in human bladder cancer cells. AB - BACKGROUND: p53 is the most frequently mutated tumor-suppressor gene in human cancers. It has been reported that mutations in p53 result not only in the loss of its ability as a tumor suppressor, but also in the gain of novel cancer related functions that contribute to oncogenesis. The present study evaluated the potential of silencing of mutant p53 by small interfering RNA in the treatment of bladder cancer cells in vitro. METHODS: We used the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay to assess cell viability and flow cytometry to detect cell cycle alterations and apoptosis. The related molecular mechanisms were assessed by western blotting. We also used the MTT assay and flow cytometry to investigate if silencing of mutant p53 by knockdown with small interfering (si)RNA would change the sensitivity to cisplatin treatment. RESULTS: Using 5637 and T24 human bladder cancer cell lines characterized by mutations in p53, we found that silencing of the mutant p53 by RNA interference induced evident inhibition of cell proliferation and viability, which was related to the induction of G2 phase cell cycle arrest and apoptosis. Moreover, our study also showed that the p53-targeting siRNA cooperated with cisplatin in the inhibition of bladder cancer cells. CONCLUSIONS: These findings suggest that RNA interference targeting mutant p53 may be a promising therapeutic strategy for the treatment of bladder cancer. PMID- 23356237 TI - Sensitivity to speaker control in the online comprehension of conditional tips and promises: an eye-tracking study. AB - Statements of the form if... then... can be used to communicate conditional speech acts such as tips and promises. Conditional promises require the speaker to have perceived control over the outcome event, whereas conditional tips do not. In an eye-tracking study, we examined whether readers are sensitive to information about perceived speaker control during processing of conditionals embedded in context. On a number of eye-tracking measures, we found that readers are sensitive to whether or not the speaker of a conditional has perceived control over the consequent event; conditional promises (which require the speaker to have perceived control over the consequent) result in processing disruption for contexts where this control is absent. Conditional tips (which do not require perceived control) are processed equivalently easily regardless of context. These results suggest that readers rapidly utilize pragmatic information related to perceived control in order to represent conditional speech acts as they are read. PMID- 23356236 TI - A HT/PEXEL motif in Toxoplasma dense granule proteins is a signal for protein cleavage but not export into the host cell. AB - Apicomplexan parasites, such as Toxoplasma gondii and Plasmodium, secrete proteins for attachment, invasion and modulation of their host cells. The host targeting (HT), also known as the Plasmodium export element (PEXEL), directs Plasmodium proteins into erythrocytes to remodel the host cell and establish infection. Bioinformatic analysis of Toxoplasma revealed a HT/PEXEL-like motif at the N-terminus of several hypothetical unknown and dense granule proteins. Hemagglutinin-tagged versions of these uncharacterized proteins show co localization with dense granule proteins found on the parasitophorous vacuole membrane (PVM). In contrast to Plasmodium, these Toxoplasma HT/PEXEL containing proteins are not exported into the host cell. Site directed mutagenesis of the Toxoplasma HT/PEXEL motif, RxLxD/E, shows that the arginine and leucine residues are permissible for protein cleavage. Mutations within the HT/PEXEL motif that prevent protein cleavage still allow for targeting to the PV but the proteins have a reduced association with the PVM. Addition of a Myc tag before and after the cleavage site shows that processed HT/PEXEL protein has increased PVM association. These findings suggest that while Toxoplasma and Plasmodium share similar HT/PEXEL motifs, Toxoplasma HT/PEXEL containing proteins interact with but do not cross the PVM. PMID- 23356238 TI - Divided attention can enhance memory encoding: the attentional boost effect in implicit memory. AB - Distraction during encoding has long been known to disrupt later memory performance. Contrary to this long-standing result, we show that detecting an infrequent target in a dual-task paradigm actually improves memory encoding for a concurrently presented word, above and beyond the performance reached in the full attention condition. This absolute facilitation was obtained in 2 perceptual implicit tasks (lexical decision and word fragment completion) but not in a conceptual implicit task (semantic classification). In the case of recognition memory, the facilitation was relative, bringing accuracy in the divided attention condition up to the level of accuracy in the full attention condition. The findings follow from the hypothesis that the attentional boost effect reflects enhanced visual encoding of the study stimulus consequent to the transient orienting response to the dual-task target. PMID- 23356239 TI - Reducing the familiarity of conjunction lures with pictures. AB - Four experiments were conducted to test whether conjunction errors were reduced after pictorial encoding and whether the semantic overlap between study and conjunction items would impact error rates. Across 4 experiments, compound words studied with a single-picture had lower conjunction error rates during a recognition test than those words studied with 2 pictures. This effect occurred even when participants were asked to respond quickly (Experiment 3) or to respond positively to any word that overlapped with the study phase (Experiment 2), as well as when the number of pictures shown at study was manipulated within participants (Experiment 4). The effect of semantic overlap was ambiguous, with only Experiment 2 showing a difference between high and low overlap items. Overall, these results are inconsistent with a metacognitive interpretation of the role of pictures in reducing memory errors and are more consistent with impoverished familiarity after single-picture encoding. PMID- 23356240 TI - Time and outcome framing in intertemporal tradeoffs. AB - A robust anomaly in intertemporal choice is the delay-speedup asymmetry: Receipts are discounted more, and payments are discounted less, when delayed than when expedited over the same interval. We developed 2 versions of the tradeoff model (Scholten & Read, 2010) to address such situations, in which an outcome is expected at a given time but then its timing is changed. The outcome framing model generalizes the approach taken by the hyperbolic discounting model (Loewenstein & Prelec, 1992): Not obtaining a positive outcome when expected is a worse than expected state, to which people are over-responsive, or hypersensitive, and not incurring a negative outcome when expected is a better than expected state, to which people are under-responsive, or hyposensitive. The time framing model takes a new approach: Delaying a positive outcome or speeding up a negative one involves a loss of time to which people are hypersensitive, and speeding up a positive outcome or delaying a negative one involves a gain of time to which people are hyposensitive. We compare the models on their quantitative predictions of indifference data from matching and preference data from choice. The time framing model systematically outperforms the outcome framing model. PMID- 23356241 TI - When does memory monitoring succeed versus fail? Comparing item-specific and relational encoding in the DRM paradigm. AB - We compared the effects of item-specific versus relational encoding on recognition memory in the Deese-Roediger-McDermott paradigm. In Experiment 1, we directly compared item-specific and relational encoding instructions, whereas in Experiments 2 and 3 we biased pleasantness and generation tasks, respectively, toward one or the other type of processing. A read condition was tested in each experiment for comparison purposes. Across experiments, item-specific and relational encoding both boosted correct recognition relative to reading, but only item-specific encoding typically reduced false recognition. Signal-detection measures revealed that less information was encoded about critical items after item-specific than after relational encoding. In contrast, item-specific and relational encoding led to equivalent increases in strategic monitoring at test (e.g., use of a distinctiveness heuristic). Thus, monitoring at test was less successful after relational than item-specific encoding because more information had been encoded about critical lures. PMID- 23356242 TI - Relatively random: context effects on perceived randomness and predicted outcomes. AB - This article concerns the effect of context on people's judgments about sequences of chance outcomes. In Experiment 1, participants judged whether sequences were produced by random, mechanical processes (such as a roulette wheel) or skilled human action (such as basketball shots). Sequences with lower alternation rates were judged more likely to result from human action. However, this effect was highly context-dependent: A moderate alternation rate was judged more likely to indicate a random physical process when encountered among sequences with lower alternation rates than when embedded among sequences with higher alternation rates. Experiment 2 found the same effect for predictions of the next outcome following a streak: A streak of 3 at the end of the sequence was judged less likely to continue by participants who had encountered shorter terminal streaks in previous trials than by those who had encountered longer ones. These contrast effects (a) help to explain variability in the types of sequences that are judged to be random and that elicit the gambler's fallacy, and urge caution about attempts to establish universal parameterizations of these effects; (b) are congruent with theories of sequence judgment that emphasize the importance of people's actual experiences with sequences of different kinds; (c) provide a link between models of sequence judgment and broader accounts of psychophysical/economic judgment; and (d) may offer new insight into individual differences in randomness judgments and sequence predictions. PMID- 23356243 TI - Discounting of delayed rewards is not hyperbolic. AB - Delay discounting refers to decision-makers' tendency to value immediately available goods more than identical goods available only after some delay. In violation of standard economic theory, decision-makers frequently exhibit dynamic inconsistency; their preferences change simply due to the passage of time. The standard explanation for this behavior has appealed to the nature of decision makers' discount functions, specifically positing a hyperbolic discount function. Though this explanation has been largely accepted, there has been surprisingly little work examining whether preference reversals are actually consistent with hyperbolic discounting. The current study holds hyperbolic discounting to the same empirical standard that exponential discounting has been held to and finds that choice behavior is not consistent with hyperbolic discounting. Despite the overwhelming focus placed on hyperbolic discounting, the current findings cast doubt on hyperbolic discounting as an explanation of decision-makers' undesirable preference reversals and as an explanation of delay discounting behavior in general. PMID- 23356245 TI - The validity and reliability of developmental test of visual perception-2nd edition (DTVP-2). AB - The Developmental Test of Visual Perception-2nd edition (DTVP-2) is frequently used by occupational therapists to evaluate school-age children. It is important that therapists use assessments with established validity and reliability. This study investigated the convergent validity and internal consistency of the DTVP 2. Forty-five healthy participants from Australia, aged 6-12 years, completed the DTVP-2, the Beery-Buktenica Developmental Test of Visual-Motor Integration-6th edition (VMI), and the Test of Visual Perceptual Skills-3rd edition (TVPS-3). A Spearman rho correlation coefficient was used to investigate the DTVP-2's convergent validity and Cronbach alpha coefficients were used to determine the DTVP-2's internal consistency. Statistically significant correlations between the DTVP-2, VMI, and TVPS-3 total scale scores and subscale scores were found. Internal consistency of items for the DTVP-2, VMI, and TVPS-3 total scores was >0.80 and internal consistency of items for subscale scores was >0.70. The DTVP-2 exhibited evidence of convergent validity with the VMI and TVPS-3, and moderate to high levels of internal consistency. PMID- 23356244 TI - Gender affects semantic competition: the effect of gender in a non-gender-marking language. AB - English speakers tend to produce fewer pronouns when a referential competitor has the same gender as the referent than otherwise. Traditionally, this gender congruence effect has been explained in terms of ambiguity avoidance (e.g., Arnold, Eisenband, Brown-Schmidt, & Trueswell, 2000; Fukumura, Van Gompel, & Pickering, 2010). However, an alternative hypothesis is that the competitor's gender congruence affects semantic competition, making the referent less accessible relative to when the competitor has a different gender (Arnold & Griffin, 2007). Experiment 1 found that even in Finnish, which is a nongendered language, the competitor's gender congruence results in fewer pronouns, supporting the semantic competition account. In Experiment 2, Finnish native speakers took part in an English version of the same experiment. The effect of gender congruence was larger in Experiment 2 than in Experiment 1, suggesting that the presence of a same-gender competitor resulted in a larger reduction in pronoun use in English than in Finnish. In contrast, other nonlinguistic similarity had similar effects in both experiments. This indicates that the effect of gender congruence in English is not entirely driven by semantic competition: Speakers also avoid gender-ambiguous pronouns. PMID- 23356247 TI - Omega-3 fatty acid ethyl ester supplementation decreases very-low-density lipoprotein triacylglycerol secretion in obese men. AB - Dysregulated VLDL-TAG (very-low-density lipoprotein triacylglycerol) metabolism in obesity may account for hypertriacylglycerolaemia and increased cardiovascular disease. omega-3 FAEEs (omega-3 fatty acid ethyl esters) decrease plasma TAG and VLDL concentrations, but the mechanisms are not fully understood. In the present study, we carried out a 6-week randomized, placebo-controlled study to examine the effect of high-dose omega-3 FAEE supplementation (3.2 g/day) on the metabolism of VLDL-TAG in obese men using intravenous administration of d5 glycerol. We also explored the relationship of VLDL-TAG kinetics with the metabolism of VLDL-apo (apolipoprotein) B-100 and HDL (high-density lipoprotein) apoA-I. VLDL-TAG isotopic enrichment was measured using gas chromatography-mass spectrometry. Kinetic parameters were derived using a multicompartmental model. Compared with placebo, omega-3 FAEE supplementation significantly lowered plasma concentrations of total (-14%, P<0.05) and VLDL-TAG (-32%, P<0.05), as well as hepatic secretion of VLDL-TAG (-32%, P<0.03). The FCR (fractional catabolic rate) of VLDL-TAG was not altered by omega-3 FAEEs. There was a significant association between the change in secretion rates of VLDL-TAG and VLDL-apoB-100 (r=0.706, P<0.05). However, the change in VLDL-TAG secretion rate was not associated with change in HDL-apoA-I FCR (r=0.139, P>0.05). Our results suggest that the TAG lowering effect of omega-3 FAEEs is associated with the decreased VLDL-TAG secretion rate and hence lower plasma VLDL-TAG concentration in obesity. The changes in VLDL-TAG and apoB-100 kinetics are closely coupled. PMID- 23356248 TI - The comparative effect of subjective and objective after-action reviews on team performance on a complex task. AB - The after-action review (AAR; also known as the after-event review or debriefing) is an approach to training based on a review of trainees' performance on recently completed tasks or performance events. Used by the military for decades, nonmilitary organizations' use of AARs has increased dramatically in recent years. Despite the prevalence of AARs, empirical research investigating their effectiveness has been limited. This study sought to investigate the comparative effectiveness of objective AARs (reviews based on an objective recording and playback of trainees' recent performance) and subjective AARs (reviews based on a subjective, memory-based recall of trainees' recent performance). One hundred eighty-eight individuals, participating in 47 4-person teams, were assigned to 1 of 3 AAR conditions and practiced and tested on a cognitively complex performance task. Although there were no significant differences between objective and subjective AAR teams across the 5 training outcomes, AAR teams had higher levels of team performance, team efficacy, openness of communication, and cohesion than did non-AAR teams but no differences in their levels of team declarative knowledge. Our results suggest that AARs are effective at enhancing training outcomes. Furthermore, AARs may not be dependent on objective reviews and therefore may be a viable training intervention when objective reviews are not feasible or possible. PMID- 23356246 TI - Japan Diabetes Outcome Intervention Trial-1 (J-DOIT1), a nationwide cluster randomized trial of type 2 diabetes prevention by telephone-delivered lifestyle support for high-risk subjects detected at health checkups: rationale, design, and recruitment. AB - BACKGROUND: Lifestyle modifications are considered the most effective means of delaying or preventing the development of type 2 diabetes (T2DM). To contain the growing population of T2DM, it is critical to clarify effective and efficient settings for intervention and modalities for intervention delivery with a wide population reach.The Japan Diabetes Outcome Intervention Trial-1 (J-DOIT1) is a cluster randomized controlled trial to test whether goal-focused lifestyle coaching delivered by telephone can prevent the development of T2DM in high-risk individuals in a real-world setting. This paper describes the study design and recruitment of the study subjects. METHODS: For the recruitment of study subjects and their follow-up annually over 3 years, we employed health checkups conducted annually at communities and worksites. Health care divisions recruited from communities and companies across Japan formed groups as a cluster randomization unit. Candidates for the study, aged 20-65 years with fasting plasma glucose (FPG) of 5.6-6.9 mmol/l, were recruited from each group using health checkups results in 2006. Goal-focused lifestyle support is delivered by healthcare providers via telephone over a one-year period. Study subjects will be followed up for three years by annual health checkups. Primary outcome is the development of diabetes defined as FPG>=7.0 mmol/l on annual health checkup or based on self report, which is confirmed by referring to medical cards. RESULTS: Forty-three groups (clusters), formed from 17 health care divisions, were randomly assigned to an intervention arm (22 groups) or control arm (21 clusters) between March 2007 and February 2008. A total of 2840 participants, 1336 from the intervention and 1504 from the control arm, were recruited. Consent rate was about 20%, with no difference between the intervention and control arms. There were no differences in cluster size and characteristics of cluster between the groups. There were no differences in individual characteristics between the study arms. CONCLUSION: We have launched J-DOIT1, a nation-wide trial to prevent the development of T2DM in high-risk individuals using telephone-delivered intervention. This trial is expected to contribute to evidence-based real-world preventive practices. TRIAL REGISTRATION: UMIN000000662. PMID- 23356250 TI - Influence of lime juice on the severity of sickle cell anemia. AB - BACKGROUND AND OBJECTIVES: The pain in sickle cell anemia (SCA) is often triggered by dehydration, acidosis, and fever that are usually due to malaria. Intake of lime juice was recently demonstrated to facilitate clearance of the malaria parasite. It was therefore sought to determine whether regular intake of lime juice will ameliorate crisis, especially recurrent bone pain. DESIGN: In this preliminary, open-labeled, randomized study, the effects of lime juice on the clinical and some laboratory characteristics of children with SCA were tested. RESULTS: Among the 113 children with SCA studied in two hospitals, the 58 receiving lime treatment had lower rates of significant painful episodes than the 55 without lime (37 versus 83 crises in 6 months, and 0.64+/-0.11 versus 1.51+/ 0.34 average rates per child, p<0.001). Also, fewer subjects than the controls had significant painful episodes (50.0% versus 92.7%); febrile illness (46.6% versus 87.3%) and admission rate (3.4% versus 34.5%) (p<0.001). The mean hematocrit of the subjects (26.23+/-2.03%) at the end of the study was also higher, p<0.001. However, transfusion rate, presence of hepatomegaly, splenomegaly, and jaundice was similar. Treatment with lime did not cause any significant side-effect. CONCLUSIONS: Regular intake of lime juice may be of great therapeutic and nutritional relevance in children with SCA. PMID- 23356251 TI - The dependence of FMD% on baseline diameter: a problem solved by allometric scaling. PMID- 23356252 TI - The ATP synthase: the understood, the uncertain and the unknown. AB - The ATP synthases are multiprotein complexes found in the energy-transducing membranes of bacteria, chloroplasts and mitochondria. They employ a transmembrane protonmotive force, Deltap, as a source of energy to drive a mechanical rotary mechanism that leads to the chemical synthesis of ATP from ADP and Pi. Their overall architecture, organization and mechanistic principles are mostly well established, but other features are less well understood. For example, ATP synthases from bacteria, mitochondria and chloroplasts differ in the mechanisms of regulation of their activity, and the molecular bases of these different mechanisms and their physiological roles are only just beginning to emerge. Another crucial feature lacking a molecular description is how rotation driven by Deltap is generated, and how rotation transmits energy into the catalytic sites of the enzyme to produce the stepping action during rotation. One surprising and incompletely explained deduction based on the symmetries of c-rings in the rotor of the enzyme is that the amount of energy required by the ATP synthase to make an ATP molecule does not have a universal value. ATP synthases from multicellular organisms require the least energy, whereas the energy required to make an ATP molecule in unicellular organisms and chloroplasts is higher, and a range of values has been calculated. Finally, evidence is growing for other roles of ATP synthases in the inner membranes of mitochondria. Here the enzymes form supermolecular complexes, possibly with specific lipids, and these complexes probably contribute to, or even determine, the formation of the cristae. PMID- 23356253 TI - Type IV secretion machinery: molecular architecture and function. AB - Bacteria have evolved several secretion machineries to bring about transport of various virulence factors, nutrients, nucleic acids and cell-surface appendages that are essential for their pathogenesis. T4S (Type IV secretion) systems are versatile secretion systems found in various Gram-negative and Gram-positive bacteria and in few archaea. They are large multisubunit translocons secreting a diverse array of substrates varying in size and nature from monomeric proteins to nucleoprotein complexes. T4S systems have evolved from conjugation machineries and are implicated in antibiotic resistance gene transfer and transport of virulence factors in Legionella pneumophila causing Legionnaires' disease, Brucella suis causing brucellosis and Helicobacter pylori causing gastroduodenal diseases. The best-studied are the Agrobacterium tumefaciens VirB/D4 and the Escherichia coli plasmid pKM101 T4S systems. Recent structural advances revealing the cryo-EM (electron microscopy) structure of the core translocation assembly and high-resolution structure of the outer-membrane pore of T4S systems have made paradigm shifts in the understanding of T4S systems. The present paper reviews the advances made in biochemical and structural studies and summarizes our current understanding of the molecular architecture of this mega-assembly. PMID- 23356254 TI - Mechanism and function of DHHC S-acyltransferases. AB - Protein S-palmitoylation is a reversible post-translational modification of proteins with fatty acids. In the last 5 years, improved proteomic methods have increased the number of proteins identified as substrates for palmitoylation from tens to hundreds. Palmitoylation regulates protein membrane interactions, activity, trafficking and stability and can be constitutive or regulated by signalling inputs. A family of PATs (protein acyltransferases) is responsible for modifying proteins with palmitate or other long-chain fatty acids on the cytoplasmic face of cellular membranes. PATs share a signature DHHC (Asp-His-His Cys) cysteine-rich domain that is the catalytic centre of the enzyme. The biomedical importance of members of this family is underscored by their association with intellectual disability, Huntington's disease and cancer in humans, and raises the possibility of DHHC PATs as targets for therapeutic intervention. In the present paper, we discuss recent progress in understanding enzyme mechanism, regulation and substrate specificity. PMID- 23356255 TI - Adaptation of low-resolution methods for the study of yeast microsomal polytopic membrane proteins: a methodological review. AB - Most integral membrane proteins of yeast with two or more membrane-spanning sequences have not yet been crystallized and for many of them the side on which the active sites or ligand-binding domains reside is unknown. Also, bioinformatic topology predictions are not yet fully reliable. However, so-called low resolution biochemical methods can be used to locate hydrophilic loops or individual residues of polytopic membrane proteins at one or the other side of the membrane. The advantages and limitations of several such methods for topological studies with yeast ER integral membrane proteins are discussed. We also describe new tools that allow us to better control and validate results obtained with SCAM (substituted cysteine accessibility method), an approach that determines the position of individual residues with respect to the membrane plane, whereby only minimal changes in the primary sequence have to be introduced into the protein of interest. PMID- 23356256 TI - Chemical approaches for profiling dynamic palmitoylation. AB - Protein palmitoylation is a critical post-translational modification important for membrane compartmentalization, trafficking and regulation of many key signalling proteins. Recent non-radioactive chemo-proteomic labelling methods have enabled a new focus on this emerging regulatory modification. Palmitoylated proteins can now be profiled in complex biological systems by MS for direct annotation and quantification. Based on these analyses, palmitoylation is clearly widespread and broadly influences the function of many cellular pathways. The recent introduction of selective chemical labelling approaches has opened new opportunities to revisit long-held questions about the enzymatic regulation of this widespread post-translational modification. In the present review, we discuss the impact of new chemical labelling approaches and future challenges for the dynamic global analysis of protein palmitoylation. PMID- 23356257 TI - Palmitoylation of influenza virus proteins. AB - Influenza viruses contain two palmitoylated (S-acylated) proteins: the major spike protein HA (haemagglutinin) and the proton-channel M2. The present review describes the fundamental biochemistry of palmitoylation of HA: the location of palmitoylation sites and the fatty acid species bound to HA. Finally, the functional consequences of palmitoylation of HA and M2 are discussed regarding association with membrane rafts, entry of viruses into target cells by HA mediated membrane fusion as well as the release of newly assembled virus particles from infected cells. PMID- 23356258 TI - Chemical proteomics: a powerful tool for exploring protein lipidation. AB - The study of post-translational modifications such as protein lipidation is a non trivial challenge of the post-genomic era. In recent years the field of chemical proteomics has greatly advanced our ability to identify and quantify protein lipidation. In the present review, we give a brief overview of the tools available to study protein acylation, prenylation and cholesterylation, and their application in the identification and quantification of protein lipidation in health and disease. PMID- 23356259 TI - Palmitoylation and the trafficking of peripheral membrane proteins. AB - Palmitoylation, the attachment of palmitate and other fatty acids on to cysteine residues, is a common post-translational modification of both integral and peripheral membrane proteins. Dynamic palmitoylation controls the intracellular distribution of peripheral membrane proteins by regulating membrane-cytosol exchange and/or by modifying the flux of the proteins through vesicular transport systems. PMID- 23356260 TI - Regulation of large conductance calcium- and voltage-activated potassium (BK) channels by S-palmitoylation. AB - BK (large conductance calcium- and voltage-activated potassium) channels are important determinants of physiological control in the nervous, endocrine and vascular systems with channel dysfunction associated with major disorders ranging from epilepsy to hypertension and obesity. Thus the mechanisms that control channel surface expression and/or activity are important determinants of their (patho)physiological function. BK channels are S-acylated (palmitoylated) at two distinct sites within the N- and C-terminus of the pore-forming alpha-subunit. Palmitoylation of the N-terminus controls channel trafficking and surface expression whereas palmitoylation of the C-terminal domain determines regulation of channel activity by AGC-family protein kinases. Recent studies are beginning to reveal mechanistic insights into how palmitoylation controls channel trafficking and cross-talk with phosphorylation-dependent signalling pathways. Intriguingly, each site of palmitoylation is regulated by distinct zDHHCs (palmitoyl acyltransferases) and APTs (acyl thioesterases). This supports that different mechanisms may control substrate specificity by zDHHCs and APTs even within the same target protein. As palmitoylation is dynamically regulated, this fundamental post-translational modification represents an important determinant of BK channel physiology in health and disease. PMID- 23356261 TI - Palmitoylation-dependent regulation of glutamate receptors and their PDZ domain containing partners. AB - In recent years, it has become clear that both AMPA (alpha-amino-3-hydroxy-5 methylisoxazole-4-propionic acid)- and NMDA (N-methyl-D-aspartate)-type glutamate receptors, and many of their interacting partners, are palmitoylated proteins. Interfering with palmitoylation dramatically affects receptor trafficking and distribution and, in turn, can profoundly alter synaptic transmission. Increased knowledge of synaptic palmitoylation not only will aid our understanding of physiological neuronal regulation, but also may provide insights into, and even novel treatments for, neuropathological conditions. In the present paper, we review recent advances regarding the regulation of ionotropic glutamate receptor trafficking and function by palmitoylation. PMID- 23356262 TI - The role of palmitoylation in regulating Ras localization and function. AB - Ras GTPases are important regulators of pathways controlling proliferation, differentiation and transformation. Three ubiquitously expressed almost identical Ras genes are not functionally redundant; this has been attributed to their distinctive trafficking and localization profiles. A palmitoylation cycle controls the correct compartmentalization of H-Ras and N-Ras. We review recent data that reveal how this cycle can be regulated by membrane organization to influence the spatiotemporal signalling of Ras. PMID- 23356263 TI - Palmitoylation, pathogens and their host. AB - S-Palmitoylation, the only reversible post-translational lipid modification, confers unique biochemical and functional properties to proteins. Although it has long been known that viral proteins are palmitoylated, recent studies reveal that this modification plays a critical role for pathogens of all kinds and at multiple steps of their life cycle. The present review examines the involvement of S-palmitoylation in infection by viruses, bacteria and parasites and illustrates how pathogens have evolved to manipulate the host palmitoylation machinery. PMID- 23356264 TI - Palmitoylation of serotonin receptors. AB - The covalent attachment of palmitic acid to one or more cysteine residues (S palmitoylation) is a widespread modification of signalling proteins. With the finding that palmitoylation is a dynamic process, it is now widely accepted that repeated cycles of palmitoylation/depalmitoylation could be involved in the regulation of multiple signalling processes. Palmitoylation also represents a common post-translational modification of the GPCRs (G-protein-coupled receptors). Functionally, palmitoylation of GPCRs has been shown to play a central role in the regulation of multiple receptor functions, including determining the efficiency and selectivity of G-protein coupling, receptor phosphorylation and desensitization, endocytosis and transport to the plasma membrane. The present review summarizes our current knowledge of the palmitoylation of serotonin (5-hydroxytryptamine) receptors and its role in the regulation of receptor functions. PMID- 23356265 TI - Regulation of the cardiac Na(+) pump by palmitoylation of its catalytic and regulatory subunits. AB - The Na+/K+-ATPase (Na+ pump) is the principal consumer of ATP in multicellular organisms. In the heart, the Na+ gradient established by the pump is essential for all aspects of cardiac function, and appropriate regulation of the cardiac Na+ pump is therefore crucial to match cardiac output to the physiological requirements of an organism. The cardiac pump is a multi-subunit enzyme, consisting of a catalytic alpha-subunit and regulatory beta- and FXYD subunits. All three subunits may become palmitoylated, although the functional outcome of these palmitoylation events is incompletely characterized to date. Interestingly, both beta- and FXYD subunits may be palmitoylated or glutathionylated at the same cysteine residues. These competing chemically distinct post-translational modifications may mediate functionally different effects on the cardiac pump. In the present article, we review the cellular events that control the balance between these modifications, and discuss the likely functional effects of pump subunit palmitoylation. PMID- 23356266 TI - Metabolic triad in brain aging: mitochondria, insulin/IGF-1 signalling and JNK signalling. AB - Mitochondria generate second messengers, such as H2O2, that are involved in the redox regulation of cell signalling and their function is regulated by several cytosolic signalling pathways. IIS [insulin/IGF1 (insulin-like growth factor 1) signalling] in the brain proceeds mainly through the PI3K (phosphatidylinositol 3 kinase)-Akt (protein kinase B) pathway, which is involved in the regulation of synaptic plasticity and neuronal survival via the maintenance of the bioenergetic and metabolic capacities of mitochondria. Conversely, the JNK (c-Jun N-terminal kinase) pathway is induced by increased oxidative stress and JNK translocation to the mitochondrion results in impairment of energy metabolism. Moreover, IIS and JNK signalling interact with and antagonize each other. This review focuses on functional outcomes of a metabolic triad that entails the co-ordination of mitochondrial function (energy transducing and redox regulation), IIS and JNK signalling, in the aging brain and in neurodegenerative disorders, such as Alzheimer's disease. PMID- 23356267 TI - Glutathione and gamma-glutamylcysteine in the antioxidant and survival functions of mitochondria. AB - Mitochondria are both the main producers and targets of ROS (reactive oxygen species). Among the battery of antioxidants that protect mitochondria from ROS, GSH is thought to be essential for the organelle antioxidant function. However, mitochondria cannot synthesize GSH de novo, thus depending on an efficient transport from the cytosol to maintain their redox status. In the present article, we review recent data suggesting that the cellular redox control might not be the main function of GSH, and that its immediate precursor, gammaGC (gamma glutamylcysteine), can take over the antioxidant role of GSH and protect the mitochondria from excess ROS. Together, GSH and gammaGC may thus represent an as yet unrecognized defence system relevant for degenerative processes associated with the imbalance in the cellular redox control. PMID- 23356269 TI - Platelet mitochondrial function: from regulation of thrombosis to biomarker of disease. AB - Circulating blood platelets contain small numbers of fully functional mitochondria. Accumulating evidence demonstrates that these mitochondria regulate the pro-thrombotic function of platelets through not only energy generation, but also redox signalling and the initiation of apoptosis. Beyond its regulation of haemostasis, platelet mitochondrial function has also traditionally been used to identify and study mitochondrial dysfunction in human disease, owing to the easy accessibility of platelets compared with other metabolically active tissues. In the present article, we provide a brief overview of what is currently known about the function of mitochondria in platelets and review how platelet mitochondria have been used to study mitochondrial function in human disease. PMID- 23356268 TI - Beyond retrograde and anterograde signalling: mitochondrial-nuclear interactions as a means for evolutionary adaptation and contemporary disease susceptibility. AB - Although there is general agreement that most forms of common disease develop as a consequence of a combination of factors, including genetic, environmental and behavioural contributors, the actual mechanistic basis of how these factors initiate or promote diabetes, cancer, neurodegenerative and cardiovascular diseases in some individuals but not in others with seemingly identical risk factor profiles, is not clearly understood. In this respect, consideration of the potential role for mitochondrial genetics, damage and function in influencing common disease susceptibility seems merited, given that the prehistoric challenges were the original factors that moulded cellular function, and these were based upon the mitochondrial-nuclear relationships that were established during evolutionary history. These interactions were probably refined during prehistoric environmental selection events that, at present, are largely absent. Contemporary risk factors such as diet, sedentary lifestyle and increased longevity, which influence our susceptibility to a variety of chronic diseases were not part of the dynamics that defined the processes of mitochondrial-nuclear interaction, and thus cell function. Consequently, the prehistoric challenges that contributed to cell functionality and evolution should be considered when interpreting and designing experimental data and strategies. Although several molecular epidemiological studies have generally supported this notion, studies that probe beyond these associations are required. Such investigation will mark the initial steps for mechanistically addressing the provocative concept that contemporary human disease susceptibility is the result of prehistoric selection events for mitochondrial-nuclear function, which increased the probability for survival and reproductive success during evolution. PMID- 23356270 TI - Role of p90(RSK) in regulating the Crabtree effect: implications for cancer. AB - High glucose inhibits mitochondrial respiration, known as the 'Crabtree effect', in cancer cells and possibly other cell types. The upstream pathways regulating this phenomenon are poorly understood. In diabetes, where glucose levels are elevated, the p90(RSK) (p90 ribosomal S6 kinase) has received much attention as a potential upstream mediator of the effects of high glucose. Evidence is also emerging that p90(RSK) may play a role in cancer cell signalling, although the role of p90(RSK) in regulating cancer cell metabolism is unclear. In the present paper, we provide an overview of the Crabtree effect and its relationship to mitochondrial metabolism. Furthermore, preliminary data are presented suggesting a role for p90(RSK) and its upstream components, the ERK (extracellular-signal regulated kinase) family of MAPKs (mitogen-activated protein kinases), in the Crabtree effect. PMID- 23356272 TI - G-protein-coupled receptors: from structural insights to functional mechanisms. AB - The papers resulting from the recent Biochemical Society Focused Meeting 'G Protein-Coupled Receptors: from Structural Insights to Functional Mechanisms' held in Prato in September 2012 are introduced in the present overview. A number of future goals for GPCR (G-protein-coupled receptor) research are considered, including the need to develop biophysical and computational methods to explore the full range of GPCR conformations and their dynamics, the need to develop methods to take this into account for drug discovery and the importance of relating observations on isolated receptors or receptors expressed in model systems to receptor function in vivo. PMID- 23356271 TI - Convergent mechanisms for dysregulation of mitochondrial quality control in metabolic disease: implications for mitochondrial therapeutics. AB - Mitochondrial dysfunction is associated with a broad range of pathologies including diabetes, ethanol toxicity, metabolic syndrome and cardiac failure. It is now becoming clear that maintaining mitochondrial quality through a balance between biogenesis, reserve capacity and mitophagy is critical in determining the response to metabolic or xenobiotic stress. In diseases associated with metabolic stress, such as Type II diabetes and non-alcoholic and alcoholic steatosis, the mitochondria are subjected to multiple 'hits' such as hypoxia and oxidative and nitrative stress, which can overwhelm the mitochondrial quality control pathways. In addition, the underlying mitochondrial genetics that evolved to accommodate high-energy demand, low-calorie supply environments may now be maladapted to modern lifestyles (low-energy demand, high-calorie environments). The pro-oxidant and pro-inflammatory environment of a sedentary western lifestyle has been associated with modified redox cell signalling pathways such as steatosis, hypoxic signalling, inflammation and fibrosis. These data suggest that loss of mitochondrial quality control is intimately associated with the aberrant activation of redox cell signalling pathways under pathological conditions. In the present short review, we discuss evidence from alcoholic liver disease supporting this concept, the insights obtained from experimental models and the application of bioenergetic-based therapeutics in the context of maintaining mitochondrial quality. PMID- 23356273 TI - Arresting inflammation: contributions of plasma membrane and endosomal signalling to neuropeptide-driven inflammatory disease. AB - GPCR (G-protein-coupled receptor) signalling at the plasma membrane is under tight control. In the case of neuropeptides such as SP (substance P), plasma membrane signalling is regulated by cell-surface endopeptidases (e.g. neprilysin) that degrade extracellular neuropeptides, and receptor interaction with beta arrestins, which uncouple receptors from heterotrimeric G-proteins and mediate receptor endocytosis. By recruiting GPCRs, kinases and phosphatases to endocytosed GPCRs, beta-arrestins assemble signalosomes that can mediate a second wave of signalling by internalized receptors. Endosomal peptidases, such as ECE-1 (endothelin-converting enzyme-1), can degrade SP in acidified endosomes, which destabilizes signalosomes and allows receptors, freed from beta-arrestins, to recycle and resensitize. By disassembling signalosomes, ECE-1 terminates beta arrestin-mediated endosomal signalling. These mechanisms have been studied in model cell systems, and the relative importance of plasma membrane and endosomal signalling to complex pathophysiological processes, such as inflammation, pain and proliferation, is unclear. However, deletion or inhibition of metalloendopeptidases that control neuropeptide signalling at the plasma membrane and in endosomes has marked effects on inflammation. Neprilysin deletion exacerbates inflammation because of diminished degradation of pro-inflammatory SP. Conversely, inhibition of ECE-1 attenuates inflammation by preventing receptor recycling/resensitization, which is required for sustained pro inflammatory signals from the plasma membrane. beta-Arrestin deletion also affects inflammation because of the involvement of beta-arrestins in pro inflammatory signalling and migration of inflammatory cells. Knowledge of GPCR signalling in specific subcellular locations provides insights into pathophysiological processes, and can provide new opportunities for therapy. Selective targeting of beta-arrestin-mediated endosomal signalling or of mechanisms of receptor recycling/resensitization may offer more effective and selective treatments than global targeting of cell-surface signalling. PMID- 23356274 TI - How ligands and signalling proteins affect G-protein-coupled receptors' conformational landscape. AB - The dynamic character of GPCRs (G-protein-coupled receptors) is essential to their function. However, the details of how ligands and signalling proteins stabilize a receptor conformation to trigger the activation of a given signalling pathway remain largely unexplored. Multiple data, including recent results obtained with the purified ghrelin receptor, suggest a model where ligand efficacy and functional selectivity are directly related to different receptor conformations. Importantly, distinct effector proteins (G-proteins and arrestins) as well as ligands are likely to affect the conformational landscape of GPCRs in different manners, as we show with the isolated ghrelin receptor. Such modulation of the GPCR conformational landscape by pharmacologically distinct ligands and effector proteins has major implications for the design of new drugs that activate specific signalling pathways. PMID- 23356275 TI - Fluorescent ligands to investigate GPCR binding properties and oligomerization. AB - Fluorescent ligands for GPCRs (G-protein-coupled receptors) have been synthesized for a long time but their use was usually restricted to receptor localization in the cell by fluorescent imaging microscopy. During the last two decades, the emergence of new fluorescence-based strategies and the concomitant development of fluorescent measurement apparatus have dramatically widened the use of fluorescent ligands. Among the various strategies, TR (time-resolved)-FRET (fluorescence resonance energy transfer) approaches exhibit an interesting potential to study GPCR interactions with various partners. We have derived various sets of ligands that target different GPCRs with fluorophores, which are compatible with TR-FRET strategies. Fluorescent ligands labelled either with a fluorescent donor (such as europium or terbium cryptate) or with a fluorescent acceptor (such as fluorescein, dy647 or Alexa Fluor(r) 647), for example, kept high affinities for their cognate receptors. These ligands turn out to be interesting tools to develop FRET-based binding assays. We also used these fluorescent ligands to analyse GPCR oligomerization by measuring FRET between ligands bound to receptor dimers. In contrast with FRET strategies, on the basis of receptor labelling, the ligand-based approach we developed is fully compatible with the study of wild-type receptors and therefore with receptors expressed in native tissues. Therefore, by using fluorescent analogues of oxytocin, we demonstrated the existence of oxytocin receptor dimers in the mammary gland of lactating rats. PMID- 23356276 TI - The orthosteric agonist-binding pocket in the prototypic class B G-protein coupled secretin receptor. AB - Class B GPCRs (G-protein-coupled receptors) share heptahelical topology and G protein binding with other superfamily members, yet have unique structures and modes of activation. Natural ligands for these receptors are moderate-length peptides with C-terminal alpha-helices. NMR and crystal structures of the peptide bound disulfide-bonded receptor N-terminal domains demonstrate that these helices occupy a conserved groove; however, the details of this interaction vary from one receptor to another. In this review, we focus on the prototypic secretin receptor and use extensive intrinsic photoaffinity labelling, structure-activity series, alanine-replacement mutagenesis and fluorescence analysis to define the molecular basis for this interaction. Additionally, experimental validation of predictions coming from in silico molecular modelling has provided a basis for enhancement of binding affinity. Such insights will be useful in the rational development of drugs acting at this important group of targets. PMID- 23356277 TI - The importance of interactions with helix 5 in determining the efficacy of beta adrenoceptor ligands. AB - Structures of the inactive state of the thermostabilized beta1-adrenoceptor have been determined bound to eight different ligands, including full agonists, partial agonists, inverse agonists and biased agonists. Comparison of the structures shows distinct differences within the binding pocket that correlate with the pharmacological properties of the ligands. These data suggest that full agonists stabilize a structure with a contracted binding pocket and a rotamer change of serine (5.46) compared with when antagonists are bound. Inverse agonists may prevent both of these occurrences, whereas partial agonists stabilize a contraction of the binding pocket but not the rotamer change of serine (5.46). It is likely that subtle changes in the interactions between transmembrane helix 5 (H5) and H3/H4 on agonist binding promote the formation of the activated state. PMID- 23356278 TI - Deciphering the specific role of G(alphai/o) isoforms: functional selective oxytocin ligands and somatostatin SST5 receptor mutants. AB - Receptor coupling to different G-proteins and beta-arrestins has been described for a number of GPCRs (G-protein-coupled receptors), suggesting a multi-state model of receptor activation in which each receptor can assume a number of different active conformations, each capable of promoting the coupling to a specific effector. Consistently, functional-selective ligands and biased agonists have been described to be able to induce and/or stabilize only a subset of specific active conformations. Furthermore, GPCR mutants deficient in selective coupling have been reported. Functional selective ligands and receptor mutants thus constitute unique tools to dissect the specific roles of different effectors, in particular among the Gi/o family. In the present mini-review, we focus on (i) the identification of functional selective OXT (oxytocin)-derived peptides capable of activating single Gi/o isoforms, namely Gi1 or Gi3; and (ii) the characterization of an SS (somatostatin) receptor SST5 mutant selectively impaired in its GoA coupling. These analogues and receptor mutants represent unique tools for examining the contribution of Gi/o isoforms in complex biological responses and open the way for the development of drugs with peculiar selectivity profiles. PMID- 23356279 TI - Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function. AB - Type 2 diabetes is a major global health problem and there is ongoing research for new treatments to manage the disease. The GLP-1R (glucagon-like peptide-1 receptor) controls the physiological response to the incretin peptide, GLP-1, and is currently a major target for the development of therapeutics owing to the broad range of potential beneficial effects in Type 2 diabetes. These include promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of beta-cell mass, improved peripheral insulin sensitivity and promotion of weight loss. Despite this, our understanding of GLP-1R function is still limited, with the desired spectrum of GLP-1R-mediated signalling yet to be determined. We review the current understanding of GLP-1R function, in particular, highlighting recent contributions in the field on allosteric modulation, probe-dependence and ligand-directed signal bias and how these behaviours may influence future drug development. PMID- 23356280 TI - The activation of the CGRP receptor. AB - The CGRP (calcitonin gene-related peptide) receptor is a family B GPCR (G-protein coupled receptor). It consists of a GPCR, CLR (calcitonin receptor-like receptor) and an accessory protein, RAMP1 (receptor activity modifying protein 1). RAMP1 is needed for CGRP binding and also cell-surface expression of CLR. CLR is an example of a family B GPCR. Unlike family A GPCRs, little is known about how these receptors are activated by their endogenous ligands. This review considers what is known about the activation of family B GPCRs and then considers how this might be applied to CLR, particularly in light of new knowledge of the crystal structures of family A GPCRs. PMID- 23356281 TI - Preparation of purified GPCRs for structural studies. AB - Since the publication of the first X-ray structure of a GPCR (G-protein couple receptor) in 2000, the rate at which subsequent ones have appeared has steadily increased. This has required the development of new methodology to overcome the challenges presented by instability of isolated GPCRs, combined with a systematic optimization of existing approaches for protein expression, purification and crystallization. In addition, quality control measures that are predictive of successful outcomes have been identified. Repeated attempts at solving the structures of GPCRs have highlighted experimental approaches that are most likely to lead to success, and have allowed definition of a first-pass protocol for new receptors. PMID- 23356282 TI - Enlightening G-protein-coupled receptors on the plasma membrane using super resolution photoactivated localization microscopy. AB - The possibility to visualize and image the arrangement of proteins within the cell at the molecular level has always been an attraction for scientists in biological research. In particular, for signalling molecules such as GPCRs (G protein-coupled receptors), the existence of protein aggregates such as oligomers or clusters has been the topic of extensive debate. One of the reasons for this lively argument is that the molecular size is below the diffraction-limited resolution of the conventional microscopy, precluding the direct visualization of protein super-structures. On the other hand, new super-resolution microscopy techniques, such as the PALM (photoactivated localization microscopy), allow the limit of the resolution power of conventional optics to be broken and the localization of single molecules to be determined with a precision of 10-20 nm, close to their molecular size. The application of super-resolution microscopy to study the spatial and temporal organization of GPCRs has brought new insights into receptor arrangement on the plasma membrane. Furthermore, the use of this powerful microscopy technique as a quantitative tool opens up the possibility for investigating and quantifying the number of molecules in biological assemblies and determining the protein stoichiometry in signalling complexes. PMID- 23356284 TI - Characterization of the dynamic events of GPCRs by automated computational simulations. AB - The recent advances in membrane protein crystallography have provided extremely valuable structural information of the superfamily of GPCRs (G-protein-coupled receptors). This has been particularly true for a few receptors whose structure was solved several times under different biochemical conditions. It follows that the mechanisms of receptor conformational equilibrium and related dynamic events can be explored by computational simulations. In the present article, we summarize our recent understanding of several dynamic features of GPCRs, accomplished through the use of MD (molecular dynamics) simulations. Our pipeline for the MD simulations of GPCRs, implemented in the web service http://gpcr.usc.es, is updated in the present paper and illustrated by recent applications. Special emphasis is put on the A2A adenosine receptor, one of the selected cases where crystal structures in several conformations and conditions exist, and on the dimerization process of the CXCR4 (CXC chemokine receptor 4). PMID- 23356283 TI - Insights into the molecular evolution of oxytocin receptor ligand binding. AB - The design and development of selective ligands for the human OT (oxytocin) and AVP (arginine vasopressin) receptors is a big challenge since the different receptor subtypes and their native peptide ligands display great similarity. Detailed understanding of the mechanism of OT's interaction with its receptor is important and may assist in the ligand- or structure-based design of selective and potent ligands. In the present article, we compared 69 OT- and OT-like receptor sequences with regards to their molecular evolution and diversity, utilized an in silico approach to map the common ligand interaction sites of recently published G-protein-coupled receptor structures to a model of the human OTR (OT receptor) and compared these interacting residues within a selection of different OTR sequences. Our analysis suggests the existence of a binding site for OT peptides within the common transmembrane core region of the receptor, but it appears extremely difficult to identify receptor or ligand residues that could explain the selectivity of OT to its receptors. We remain confident that the presented evolutionary overview and modelling approach will aid interpretation of forthcoming OTR crystal structures. PMID- 23356285 TI - Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists. AB - The TSHR (thyrotropin receptor) is activated endogenously by the large hormone thyrotropin and activated pathologically by auto-antibodies. Both activate and bind at the extracellular domain. Recently, SMLs (small-molecule ligands) have been identified, which bind in an allosteric binding pocket within the transmembrane domain. Modelling driven site-directed mutagenesis of amino acids lining this pocket led to the delineation of activation and inactivation sensitive residues. Modified residues showing CAMs (constitutively activating mutations) indicate signalling-sensitive positions and mark potential trigger points for agonists. Silencing mutations lead to an impairment of basal activity and mark contact points for antagonists. Mapping these residues on to a structural model of TSHR indicates locations where an SML may switch the receptor to an inactive or active conformation. In the present article, we report the effects of SMLs on these signalling-sensitive amino acids at the TSHR. Surprisingly, the antagonistic effect of SML compound 52 was reversed to an agonistic effect, when tested at the CAM Y667A. Switching agonism to antagonism and the reverse by changing either SMLs or residues covering the binding pocket provides detailed knowledge about discriminative pharmacophores. It prepares the basis for rational optimization of new high-affinity antagonists to interfere with the pathogenic activation of the TSHR. PMID- 23356286 TI - Ligand bias at the MU-opioid receptor. AB - Ligand bias refers to the ability of a drug at a receptor to activate selectively particular cell signalling pathways over others, in a way that cannot be explained by traditional models of receptor theory. For a physiologically and therapeutically important GPCR (G-protein-coupled receptor) such as the MOPr (MU opioid receptor), the role of ligand bias is currently being explored, not only in order to understand the molecular function of this receptor, but also with a view to developing better analgesic drugs with fewer adverse effects. In this short review, the ways to detect and quantify agonist bias at MOPr are discussed, along with the possible significance of MOPr ligand bias in the therapeutic use of opioid drugs. An important conclusion of this work is that attempts to define ligand bias at any GPCR on the basis of the visual inspection of concentration response curves or comparison of maximum response (Emax) values can be misleading. Instead, reliable estimations of relative agonist efficacy are needed to calculate bias effectively. PMID- 23356287 TI - Molecular mechanisms of platelet P2Y(12) receptor regulation. AB - Platelets are critical for haemostasis, however inappropriate activation can lead to the development of arterial thrombosis, which can result in heart attack and stroke. ADP is a key platelet agonist that exerts its actions via stimulation of two surface GPCRs (G-protein-coupled receptors), P2Y(1) and P2Y(12). Similar to most GPCRs, P2Y receptor activity is tightly regulated by a number of complex mechanisms including receptor desensitization, internalization and recycling. In the present article, we review the molecular mechanisms that underlie P2Y(1) and P2Y(12) receptor regulation, with particular emphasis on the structural motifs within the P2Y(12) receptor, which are required to maintain regulatory protein interaction. The implications of these findings for platelet responsiveness are also discussed. PMID- 23356288 TI - Atypical chemokine receptors: from silence to sound. AB - ACRs (atypical chemokine receptors) were initially referred to as 'silent' receptors on the basis of a lack of signalling and functional activities that are typically observed with conventional chemokine receptors. Although ACRs do not directly induce cell migration, they indirectly control leucocyte recruitment by shaping chemokine gradients in tissues through degradation, transcytosis or local concentration of their cognate ligands. Recent evidence also suggests that these biological activities are supported by G-protein-independent, beta-arrestin dependent signalling events. In the present article, we review current knowledge on structural and signalling properties of ACRs that are changing our view on this entire class of receptors from silent to endogenous beta-arrestin-biased signalling receptors. PMID- 23356289 TI - Microvesiculation and disease. AB - The important roles of extracellular vesicles in the pathogenesis of various diseases are rapidly being elucidated. As important vehicles of intercellular communication, extracellular vesicles, which comprise microvesicles and exosomes, are revealing important roles in cancer tumorigenesis and metastases and in the spread of infectious disease. The September 2012 Focused Meeting 'Microvesiculation and Disease' brought together researchers working on extracellular vesicles. The papers in this issue of Biochemical Society Transactions review work in areas including HIV infection, kidney disease, hypoxia-mediated tumorigenesis and down-regulation of immune cell functions in acute myeloid leukaemia by tumour-derived exosomes. In all cases, microvesicles and exosomes have been demonstrated to be important factors leading to the pathophysiology of disease or indeed as therapeutic vehicles in possible new treatments. The aim was, having enhanced our molecular understanding of the contribution of microvesicles and exosomes to disease in vitro, to begin to apply this knowledge to in vivo models of disease. PMID- 23356290 TI - Exosomes as a novel way of interneuronal communication. AB - Exosomes are small extracellular vesicles which stem from endosomes fusing with the plasma membrane; they contain lipids, proteins and RNAs that are able to modify receiving cells. Functioning of the brain relies on synapses, and certain patterns of synaptic activity can change the strength of responses at sparse groups of synapses, to modulate circuits underlying associations and memory. These local changes of the synaptic physiology in one neuron driven by another have, so far, been explained by classical signal transduction modulating transcription, translation and post-translational modifications. We have accumulated in vitro evidence that exosomes released by neurons in a way depending on synaptic activity can be recaptured by other neurons. Some lipids, proteins and RNAs contained in exosomes secreted by emitting neurons could directly modify signal transduction and protein expression in receiving cells. Exosomes may be an ideal mechanism for anterograde and retrograde information transfer across synapses underlying local changes in synaptic plasticity. Exosomes might also participate in the spreading across the nervous system of pathological proteins such as PrPSc (abnormal disease-specific conformation of prion protein), APP (amyloid precursor protein) fragments, phosphorylated tau or alpha-synuclein. PMID- 23356292 TI - Microvesicles and exosomes as vehicles between protozoan and host cell communication. AB - Cells release extracellular vesicles in response to external factors or in a physiological way. Microvesicles and exosomes originate in cells in different ways and, depending on their contents, may have multiple biological effects on other cells and the environment. The host cell-parasite relationship could be changed dramatically by the plasticity of a new type of communication through extracellular vesicles. In the present paper, we discuss how protozoans use this new resource to evade the immune system and establish infection. PMID- 23356291 TI - Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes). AB - Body fluids of cancer patients contain TEXs (tumour-derived exosomes). Tumours release large quantities of TEXs, and the protein content of exosome or MV (microvesicle) fractions isolated from patients' sera is high. TEXs down-regulate functions of immune cells, thus promoting tumour progression. We isolated TEXs from tumour cell supernatants and sera of patients with solid tumours or AML (acute myelogenous leukaemia). The molecular profile of TEXs was distinct from that of circulating exosomes derived from normal cells. TEXs were co-incubated with activated T-cells, conventional CD4(+) CD25(neg) T-cells or CD56(+) CD16(+) NK (natural killer) cells respectively. TEXs down-regulated CD3zeta and JAK3 (Janus kinase 3) expression in primary activated T-cells and mediated Fas/FasL (Fas ligand)-driven apoptosis of CD8(+) T-cells. TEXs promoted CD4(+) CD25(neg) T cell proliferation and their conversion into CD4(+) CD25(hi)FOXP3+ (FOXP3 is forkhead box P3) Treg cells (regulatory T-cells), which also expressed IL-10 (interleukin 10), TGFbeta1 (transforming growth factor beta1), CTLA-4 (cytotoxic T-lymphocyte antigen 4), GrB (granzyme B)/perforin and effectively mediated suppression. Neutralizing antibodies specific for TGFbeta1 and/or IL-10 inhibited the ability of TEXs to expand Treg cells. TEXs obtained at diagnosis from AML patients' sera were positive for blast-associated markers CD33, CD34, CD117 and TGFbeta1, and they decreased cytotoxic activity of NK cells isolated from NC (normal control) donors, induced Smad phosphorylation and down-regulated NKG2D receptor expression. Correlations between the TEX molecular profile or TEX protein levels and clinical data in cancer patients suggest that TEX-mediated effects on immune cells are prognostically important. In contrast with exosomes released by normal cells, TEXs have immunosuppressive properties and are involved in regulating peripheral tolerance in patients with cancer. PMID- 23356293 TI - Interplay of host-pathogen microvesicles and their role in infectious disease. AB - The release of extracellular vesicles, whether MVs (microvesicles) or exosomes, from host cells or intracellular pathogens is likely to play a significant role in the infection process. Host MVs may fuse with pathogen surfaces to deliver host complement regulatory proteins. They may also deliver cytokines that enhance invasion. Decoy functions are also possible. Whereas host MVs may direct pathogens away from their target cells, pathogen MVs may in turn redirect complement membrane-attack complexes away from their target pathogen. An understanding of the mechanisms of this interplay, bringing about both immune evasion and enhanced invasion, will help to direct future research with a view to rendering pathogens more susceptible to immune attack or in improving drug efficacy. It should also be possible to use MVs or exosomes isolated directly from the pathogens, or from the cells infected with pathogens, to provide alternative vaccination strategies. PMID- 23356294 TI - Exosomes and communication between tumours and the immune system: are all exosomes equal? AB - Communication between cells is particularly important during tumour progression. Communication can take place through direct cell-cell interactions, but also through extracellular secretion of mediators acting at a distance. These mediators can be either soluble molecules or more complex structures called membrane vesicles, enclosing soluble factors within a lipid bilayer. A variety of extracellular membrane vesicles have been described, for instance microvesicles, ectosomes and a subtype called exosomes. The role of exosomes in tumour progression has been studied extensively in the last 10 years. In the present mini-review, we discuss our recent results, first showing the heterogeneity of the vesicles called exosomes and the probable existence of subpopulations of these exosomes, and secondly demonstrating that in vivo secretion of exosomes by some tumours can promote tumour progression, but that such a function cannot be generalized to all tumours and all exosomes. PMID- 23356295 TI - Interactions of human monocytes with TMVs (tumour-derived microvesicles). AB - The tumour microenvironment represents a dynamic complex milieu, which includes tumour cells, cells of the immune system and other (cellular and non-cellular) components. The role of these particular 'puzzle pieces' may change substantially due to their mutual interactions. The present review concerns different opinions on interactions that occur between monocytes, tumour cells and TMVs (tumour derived microvesicles). PMID- 23356296 TI - Role of extracellular membrane vesicles in intercellular communication of the tumour microenvironment. AB - Over the last few decades, extensive studies by several groups have introduced the concept of cell-derived secreted extracellular membrane vesicles as carriers of complex molecular information. Owing to their pleiotropic biological effects and involvement in a wide variety of biological processes, extracellular membrane vesicles have been implicated in physiological as well as pathological events, including tumour development and metastasis. In the present review, we discuss the role of secreted membrane vesicles in intercellular communication with a focus on tumour biology. Of particular interest is the potential role of extracellular vesicles as orchestrators of common features of the malignant tumour microenvironment, e.g. coagulation activation and angiogenesis. PMID- 23356297 TI - The cis-acting signals that target proteins to exosomes and microvesicles. AB - Proteins bud from cells in small single-membraned vesicles (~50-250 nm) that have the same topology as the cell. Known variously as exosomes and microvesicles (EMVs), these extracellular organelles are enriched for specific proteins, lipids, carbohydrates and nucleic acids. EMV biogenesis plays critical roles in protein quality control and cell polarity, and, once released, EMVs can transmit signals and molecules to neighbouring cells via a non-viral pathway of intercellular vesicle traffic. In the present paper, we discuss the cis-acting targeting signals that target proteins to EMVs and mediate protein budding from the cell. PMID- 23356298 TI - Role of stem-cell-derived microvesicles in the paracrine action of stem cells. AB - The paracrine theory has recently changed the view of the biological action of stem cells and of the subsequent potential application of stem cells in regenerative medicine. Indeed, most of the beneficial effects of stem-cell-based therapy have been attributed to soluble factors released from stem cells. In this context, MVs (microvesicles) released as exosomes from the endosomal compartment, or as shedding vesicles from the cell surface, may play a relevant role in the intercellular communication between stem and injured cells. By transferring proteins, bioactive lipids, mRNA and microRNA, MVs act as vehicles of information that may lead to alteration of the phenotype of recipient cells. The exchange of information between stem cells and tissue-injured cells is reciprocal. The MV mediated transfer of tissue-specific information from the injured cells to stem cells may reprogramme the latter to gain phenotypic and functional characteristics of the cell of origin. On the other hand, MVs released from stem cells may confer a stem-cell-like phenotype to injured cells, with the consequent activation of self-regenerative programmes. In fact, MVs released from stem cells retain several biological activities that are able to reproduce the beneficial effects of stem cells in a variety of experimental models. PMID- 23356299 TI - Extracellular vesicles in the circulation: are erythrocyte microvesicles a confounder in the plasma haemoglobin assay? AB - Blood contains a mixture of extracellular vesicles from different cell types, primarily platelets, endothelial cells, leucocytes and erythrocytes. Erythrocytes are the most abundant cell type in blood and could, especially in certain pathologies, represent an important source of vesicles. Since erythrocytes contain the haemoglobin components iron and haem, which are potentially toxic, it is important to investigate the contribution of vesicle-associated haemoglobin to total cell-free haemoglobin levels. To our knowledge, this is the first time that cell-free plasma haemoglobin has been differentiated into vesicle-associated and molecular species. We investigated the contribution of vesicle-associated haemoglobin in residual patient material that was routinely analysed for total cell-free plasma haemoglobin. All patient samples included in the study were haemolytic with total cell-free haemoglobin concentration ranging from 80 to 2500 mg/l. In the majority of the samples, total cell-free haemoglobin concentration was between 100 and 200 mg/l. No haemoglobin could be detected in the vesicle fraction, indicating that the contribution of vesicle-associated haemoglobin to total cell free-haemoglobin levels in plasma is negligible. It is important to investigate whether erythrocyte vesicles are not formed in blood or that their production is not increased during pathologies associated with haemolysis or that the clearance rate of the vesicles surpasses the formation rate. PMID- 23356300 TI - The role of microvesicles in cancer progression and drug resistance. AB - Microvesicles are shed constitutively, or upon activation, from both normal and malignant cells. The process is dependent on an increase in cytosolic Ca2+, which activates different enzymes, resulting in depolymerization of the actin cytoskeleton and release of the vesicles. Drug resistance can be defined as the ability of cancer cells to survive exposure to a wide range of anti-cancer drugs, and anti-tumour chemotherapeutic treatments are often impaired by innate or acquired MDR (multidrug resistance). Microvesicles released upon chemotherapeutic agents prevent the drugs from reaching their targets and also mediate intercellular transport of MDR proteins. PMID- 23356301 TI - Coxsackievirus B transmission and possible new roles for extracellular vesicles. AB - Coxsackievirus B1, a member of the Picornaviridae family is a non-enveloped single-stranded RNA virus associated with human diseases including myocarditis and pancreatitis. Infection of the intestinal mucosa, lined by polarized epithelial cells, requires interaction of coxsackievirus with apically located DAF (decay-accelerating factor) before transport to the basolaterally located CAR (coxsackie and adenovirus receptor), where entry is mediated by endocytosis. As with many other non-enveloped viruses, coxsackievirus has to induce lysis of host cells in order to perpetuate infection. However, recent evidence indicates that virus spread to secondary sites is not only achieved by a lytic mechanism and a non-lytic cell-cell strategy has been suggested for coxsackievirus B3. A physical interaction between infected and non-infected cells has been shown to be an efficient mechanism for retroviral transmission and one type of extracellular vesicle, the exosome, has been implicated in HIV-1 transmission. HIV-1 also takes advantage of depolymerization of actin for spread between T-cells. Calpain mediated depolymerization of the actin cytoskeleton, as a result of increases in intracellular calcium concentration during coxsackievirus infection, would result in a release of host cell-derived microvesicles. If so, we speculate that maybe such microvesicles, increasingly recognized as major vehicles mediating intercellular communication, could play a role in the intercellular transmission of non-enveloped viruses. PMID- 23356302 TI - A 32-month follow-up study of nanovesicle concentrations in blood from 12 patients with gastrointestinal stromal tumour treated with imatinib. AB - Clinical studies have indicated that the NV (nanovesicle) concentration in blood samples is a potential indicator of clinical status and can be used to follow the development of the disease. For 32 months, we monitored the effect of imatinib treatment on NV concentrations in blood samples from 12 patients with GIST (gastrointestinal stromal tumour). The NV concentration before the treatment increased with respect to control by a factor of 3.5 on average (range 2.6-9.2). The first week after initiation of the treatment, the NV concentration increased considerably, by a factor of 13 on average (range 5.9-21.2), whereas on average, after 1 month, it decreased to the level of the control and remained at that level for at least 1.5 years. Recent assessment (after 2.5 years) showed a somewhat increased NV concentration, by a factor of 2 on average (range 0.7-3.9). Low NV concentrations in blood samples during the treatment reflect a favourable effect of imatinib in these patients and no remission of the disease was hitherto observed. PMID- 23356303 TI - Lytic viruses infecting organisms from the three domains of life. AB - It is probably a biological constant that viruses are found associated with all known life and that they play an essential role in the ecology and evolution of all lifeforms. Lytic viruses have now been discovered that infect organisms from each of the three domains of life. Recently, a new lysis system has been described for two archaeal viruses. This lysis system appears to be novel and distinct from previously described virus-encoded lysis systems. A comparison of lytic viruses from each of the three domains may provide insights concerning the evolution of viruses. PMID- 23356305 TI - Structure and dynamics of the crenarchaeal nucleoid. AB - Crenarchaeal genomes are organized into a compact nucleoid by a set of small chromatin proteins. Although there is little knowledge of chromatin structure in Archaea, similarities between crenarchaeal and bacterial chromatin proteins suggest that organization and regulation could be achieved by similar mechanisms. In the present review, we describe the molecular properties of crenarchaeal chromatin proteins and discuss the possible role of these architectural proteins in organizing the crenarchaeal chromatin and in gene regulation. PMID- 23356306 TI - Cis-regulatory logic in archaeal transcription. AB - For cellular fitness and survival, gene expression levels need to be regulated in response to a wealth of cellular and environmental signals. TFs (transcription factors) execute a large part of this regulation by interacting with the basal transcription machinery at promoter regions. Archaea are characterized by a simplified eukaryote-like basal transcription machinery and bacteria-type TFs, which convert sequence information into a gene expression output according to cis regulatory rules. In the present review, we discuss the current state of knowledge about these rules in archaeal systems, ranging from DNA-binding specificities and operator architecture to regulatory mechanisms. PMID- 23356307 TI - Thermococcus kodakarensis DNA replication. AB - DNA replication plays an essential role in all life forms. Research on archaeal DNA replication began approximately 20 years ago. Progress was hindered, however, by the lack of genetic tools to supplement the biochemical and structural studies. This has changed, however, and genetic approaches are now available for several archaeal species. One of these organisms is the thermophilic euryarchaeon Thermococcus kodakarensis. In the present paper, the recent developments in the biochemical, structural and genetic studies on the replication machinery of T. kodakarensis are summarized. PMID- 23356304 TI - End-resection at DNA double-strand breaks in the three domains of life. AB - During DNA repair by HR (homologous recombination), the ends of a DNA DSB (double strand break) must be resected to generate single-stranded tails, which are required for strand invasion and exchange with homologous chromosomes. This 5'-3' end-resection of the DNA duplex is an essential process, conserved across all three domains of life: the bacteria, eukaryota and archaea. In the present review, we examine the numerous and redundant helicase and nuclease systems that function as the enzymatic analogues for this crucial process in the three major phylogenetic divisions. PMID- 23356308 TI - Evolutionary advantages of polyploidy in halophilic archaea. AB - Several species of haloarchaea have been shown to be polyploid and thus this trait might be typical for and widespread in haloarchaea. In the present paper, nine different possible evolutionary advantages of polyploidy for haloarchaea are discussed, including low mutation rate, radiation/desiccation resistance, gene redundancy and survival over geological times and at extraterrestrial sites. Experimental indications exist for all but one of these evolutionary advantages. Several of the advantages require gene conversion, which has been shown to be present and active in haloarchaea. PMID- 23356309 TI - Regulatory RNAs in archaea: first target identification in Methanoarchaea. AB - sRNAs (small non-coding RNAs) representing important players in many cellular and regulatory processes have been identified in all three domains of life. In Eukarya and Bacteria, functions have been assigned for many sRNAs, whereas the sRNA populations in Archaea are considerably less well characterized. Recent analyses on a genome-wide scale particularly using high-throughput sequencing techniques demonstrated the presence of high numbers of sRNA candidates in several archaea. However, elucidation of the molecular mechanism of sRNA action, as well as understanding their physiological roles, is in general still challenging, particularly in Archaea, since efficient genetic tools are missing. The identification of cellular targets of identified archaeal sRNAs by experimental approaches or computational prediction programs has begun only recently. At present, targets have been identified for one archaeal sRNA, sRNA162 in Methanosarcina mazei, which interacts with the 5' region of its targets, a cis encoded and a trans-encoded target, blurring the paradigm of a border between cis and trans-encoded sRNAs. Besides, the first experimental implications have been obtained in Haloarchaea and Pyrobaculum that archaeal sRNAs also target 3' regions of mRNAs. The present review summarizes our current knowledge on archaeal sRNAs and their biological functions and targets. PMID- 23356310 TI - Translation initiation in the crenarchaeon Sulfolobus solfataricus: eukaryotic features but bacterial route. AB - The formation of the translation initiation complex represents the rate-limiting step in protein synthesis. Translation initiation in the crenarchaeon Sulfolobus solfataricus depends on several translation IFs (initiation factors), some of which have eukaryal but no bacterial counterparts. In the present paper, we review the current knowledge of the structure, function and evolution of the IFs in S. solfataricus in the context of eukaryotic and bacterial orthologues. Despite similarities between eukaryotic and S. solfataricus IFs, the sequence of events in translation initiation in S. solfataricus follows the bacterial mode. PMID- 23356311 TI - Archaeal transcription: making up for lost time. AB - In recent years, emerging structural information on the aRNAP (archaeal RNA polymerase) apparatus has shown its strong evolutionary relationship with the eukaryotic counterpart, RNA Pol (polymerase) II. A novel atomic model of SshRNAP (Sulfolobus shibatae RNAP) in complex with dsDNA (double-stranded DNA) constitutes a new piece of information helping the understanding of the mechanisms for DNA stabilization at the position downstream of the catalytic site during transcription. In Archaea, in contrast with Eukarya, downstream DNA stabilization is universally mediated by the jaw domain and, in some species, by the additional presence of the Rpo13 subunit. Biochemical and biophysical data, combined with X-ray structures of apo- and DNA-bound aRNAP, have demonstrated the capability of the Rpo13 C-terminus to bind in a sequence-independent manner to downstream DNA. In the present review, we discuss the recent findings on the aRNAP and focus on the mechanisms by which the RNAP stabilizes the bound DNA during transcription. PMID- 23356312 TI - Archaeology of RNA polymerase: factor swapping during the transcription cycle. AB - All RNAPs (RNA polymerases) repeatedly make use of their DNA template by progressing through the transcription cycle multiple times. During transcription initiation and elongation, distinct sets of transcription factors associate with multisubunit RNAPs and modulate their nucleic-acid-binding and catalytic properties. Between the initiation and elongation phases of the cycle, the factors have to be exchanged by a largely unknown mechanism. We have shown that the binding sites for initiation and elongation factors are overlapping and that the binding of the factors to RNAP is mutually exclusive. This ensures an efficient exchange or 'swapping' of factors and could furthermore assist RNAP during promoter escape, enabling robust transcription. A similar mechanism applies to the bacterial RNAP system. The elongation factors are evolutionarily conserved between the bacterial (NusG) and archaeo-eukaryotic (Spt5) systems; however, the initiation factors [sigma and TBP (TATA-box-binding protein)/TF (transcription factor) B respectively] are not. Therefore we propose that this factor-swapping mechanism, operating in all three domains of life, is the outcome of convergent evolution. PMID- 23356313 TI - Modern biophysical approaches probe transcription-factor-induced DNA bending and looping. AB - The genetic information of every living organism is stored in its genomic DNA that is perceived as a chemically stable and robust macromolecule. But at the same time, to fulfil its functions properly, it also needs to be highly dynamic and flexible. This includes partial melting of the double helix or compaction and bending of the DNA often brought about by protein factors that are able to interact with DNA stretches in a specific and non-specific manner. The conformational changes in the DNA need to be understood in order to describe biological systems in detail. As these events play out on the nanometre scale, new biophysical approaches have been employed to monitor conformational changes in this regime at the single-molecule level. Focusing on transcription factor action on promoter DNA, we discuss how current biophysical techniques are able to quantitatively describe this molecular process. PMID- 23356314 TI - The ring of confidence: a haloarchaeal CRISPR/Cas system. AB - To survive the constant invasions by foreign genetic elements, prokaryotes have evolved various defensive systems. Almost all sequenced archaea, and half of the analysed bacteria use the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (CRISPR-associated) system, a recently identified prokaryotic immune system that can fend off invading elements in a sequence specific manner. Few archaeal CRISPR/Cas systems have been analysed so far, and the molecular details of many of the steps involved in adaptation and defence are yet to be understood. In the present paper, we summarize our current knowledge about the CRISPR/Cas system in Haloferax volcanii, an extremely halophilic archaeon that was isolated from the Dead Sea. H. volcanii encodes a type I-B CRISPR/Cas system, and carries three CRISPR loci and eight Cas proteins. Although in laboratory culture for more than three decades, this defence system was shown to be still active. All three CRISPR loci are transcribed and processed into mature crRNAs (CRISPR RNAs). Cells challenged with engineered plasmids can recognize and eliminate these invading elements if they contain the correct PAM (protospacer adjacent motif) and a sequence that can be recognized by one of the CRISPR spacers. PMID- 23356315 TI - Attack from both ends: mRNA degradation in the crenarchaeon Sulfolobus solfataricus. AB - RNA stability control and degradation are employed by cells to control gene expression and to adjust the level of protein synthesis in response to physiological needs. In all domains of life, mRNA decay can commence in the 5'-3' as well as in the 3'-5'-direction. Consequently, mechanisms are in place conferring protection on mRNAs at both ends. Upon deprotection, dedicated enzymes/enzyme complexes access either end and trigger 5'-3' or 3'-5'-directional decay. In the present paper, we first briefly review the general mRNA decay pathways in Bacteria and Eukarya, and then focus on 5'-3' and 3'-5'-directional decay in the crenarchaeon Sulfolobus solfataricus, which is executed by a RNase J like ribonuclease and the exosome complex respectively. In addition, we describe mechanisms that stabilize mRNAs at the 5'- as well as at the 3'-end. PMID- 23356316 TI - Hot and sweet: protein glycosylation in Crenarchaeota. AB - Every living cell is covered with a dense and complex array of covalently attached sugars or sugar chains. The majority of these glycans are linked to proteins via the so-called glycosylation process. Protein glycosylation is found in all three domains of life: Eukarya, Bacteria and Archaea. However, on the basis of the limit in analytic tools for glycobiology and genetics in Archaea, only in the last few years has research on archaeal glycosylation pathways started mainly in the Euryarchaeota Haloferax volcanii, Methanocaldococcus maripaludis and Methanococcus voltae. Recently, major steps of the crenarchaeal glycosylation process of the thermoacidophilic archaeon Sulfolobus acidocaldarius have been described. The present review summarizes the proposed N-glycosylation pathway of S. acidocaldarius, describing the phenotypes of the mutants disrupted in N-glycan biosynthesis as well as giving insights into the archaeal O-linked and glycosylphosphatidylinositol anchor glycosylation process. PMID- 23356317 TI - Archaeal biofilms: widespread and complex. AB - Biofilms or multicellular structures become accepted as the dominant microbial lifestyle in Nature, but in the past they were only studied extensively in bacteria. Investigations on archaeal monospecies cultures have shown that many archaeal species are able to adhere on biotic and abiotic surfaces and form complex biofilm structures. Biofilm-forming archaea were identified in a broad range of extreme and moderate environments. Natural biofilms observed are mostly mixed communities composed of archaeal and bacterial species of various abundances. The physiological functions of the archaea identified in such mixed communities suggest a significant impact on the biochemical cycles maintaining the flow and recycling of the nutrients on earth. Therefore it is of high interest to investigate the characteristics and mechanisms underlying the archaeal biofilm formation. In the present review, I summarize and discuss the present investigations of biofilm-forming archaeal species, i.e. their diverse biofilm architectures in monospecies or mixed communities, the identified EPSs (extracellular polymeric substances), archaeal structures mediating surface adhesion or cell-cell connections, and the response to physical and chemical stressors implying that archaeal biofilm formation is an adaptive reaction to changing environmental conditions. A first insight into the molecular differentiation of cells within archaeal biofilms is given. PMID- 23356318 TI - Atypical protein kinases of the RIO family in archaea. AB - Atypical protein kinases of the RIO (right open reading frame) kinase family are found in all three domains of life, emphasizing their essential function. In all archaeal genomes sequenced to date, typically two, but at least one, members of the RIO kinase family have been identified. Although the function of RIO kinases in Archaea remains to be resolved, bioinformatics analysis (e.g. comparison of the phylogenetic distribution and gene neighbourhood analysis, as well as interaction analysis) in combination with the available phosphoproteome study of Sulfolobus solfataricus provided some first hints to the possible function as well as revealed some putative target proteins for RIO kinases in Archaea. This study suggests a possible function of archaeal RIO kinases in RNA and/or DNA binding/processing translation initiation or ribosomal biogenesis resembling the assumed physiological role in yeast. PMID- 23356319 TI - Genetic manipulation in Sulfolobus islandicus and functional analysis of DNA repair genes. AB - Recently, a novel gene-deletion method was developed for the crenarchaeal model Sulfolobus islandicus, which is a suitable tool for addressing gene essentiality in depth. Using this technique, we have investigated functions of putative DNA repair genes by constructing deletion mutants and studying their phenotype. We found that this archaeon may not encode a eukarya-type of NER (nucleotide excision repair) pathway because depleting each of the eukaryal NER homologues XPD, XPB and XPF did not impair the DNA repair capacity in their mutants. However, among seven homologous recombination proteins, including RadA, Hel308/Hjm, Rad50, Mre11, HerA, NurA and Hjc, only the Hjc nuclease is dispensable for cell viability. Sulfolobus encodes redundant BER (base excision repair) enzymes such as two uracil DNA glycosylases and two putative apurinic/apyrimidinic lyases, but inactivation of one of the redundant enzymes already impaired cell growth, highlighting their important roles in archaeal DNA repair. Systematically characterizing these mutants and generating mutants lacking two or more DNA repair genes will yield further insights into the genetic mechanisms of DNA repair in this model organism. PMID- 23356320 TI - C/D box sRNA, CRISPR RNA and tRNA processing in an archaeon with a minimal fragmented genome. AB - The analysis of deep sequencing data allows for a genome-wide overview of all the small RNA molecules (the 'sRNome') that are present in a single organism. In the present paper, we review the processing of CRISPR (clustered regularly interspaced short palindromic repeats) RNA, C/D box sRNA (small non-coding RNA) and tRNA in Nanoarchaeum equitans. The minimal and fragmented genome of this tiny archaeon permits a sequencing depth that enables the identification of processing intermediates in the study of RNA processing pathways. These intermediates include circular C/D box sRNA molecules and tRNA half precursors. PMID- 23356321 TI - A brief history of the discovery of hyperthermophilic life. AB - Hyperthermophiles, growing optimally at 80 degrees C and above were first discovered in 1981. They represent the upper temperature border of life and are found within water-containing terrestrial and submarine environments of active volcanism and geothermally heated subterranean rocks. The energy-yielding reactions represent mainly anaerobic and aerobic types of respiration rather than fermentation. Within the ss (single-stranded) rRNA phylogenetic tree, hyperthermophiles occupy all of the short deep branches closest to the root. Members of the deepest branch-offs are represented by the newly found Nanoarchaeota and Korarchaeota. PMID- 23356322 TI - Evolution of Na(+) and H(+) bioenergetics in methanogenic archaea. AB - Methanogenic archaea live at the thermodynamic limit of life and use sophisticated mechanisms for ATP synthesis and energy coupling. The group of methanogens without cytochromes use an Na(+) current across the membrane for ATP synthesis, whereas the cytochrome-containing methanogens have additional coupling sites that also translocate protons. The ATP synthase in this group is promiscuous and uses Na(+) and H(+) simultaneously. PMID- 23356323 TI - CoA biosynthesis in archaea. AB - CoA is a ubiquitous molecule in all three domains of life and is involved in various metabolic pathways. The enzymes and reactions involved in CoA biosynthesis in eukaryotes and bacteria have been identified. By contrast, the proteins/genes involved in CoA biosynthesis in archaea have not been fully clarified, and much has to be learned before we obtain a general understanding of how this molecule is synthesized. In the present paper, we review the current status of the research on CoA biosynthesis in the archaea, and discuss important questions that should be addressed in the near future. PMID- 23356324 TI - Add salt, add sugar: N-glycosylation in Haloferax volcanii. AB - Although performed by members of all three domains of life, the archaeal version of N-glycosylation remains the least understood. Studies on Haloferax volcanii have, however, begun to correct this situation. A combination of bioinformatics, molecular biology, biochemical and mass spectrometry approaches have served to delineate the Agl pathway responsible for N-glycosylation of the S-layer glycoprotein, a reporter of this post-translational modification in Hfx. volcanii. More recently, differential N-glycosylation of the S-layer glycoprotein as a function of environmental salinity was demonstrated, showing that this post translational modification serves an adaptive role in Hfx. volcanii. Furthermore, manipulation of the Agl pathway, together with the capability of Hfx. volcanii to N-glycosylate non-native proteins, forms the basis for establishing this species as a glyco-engineering platform. In the present review, these and other recent findings are addressed. PMID- 23356325 TI - Membrane vesicles, nanopods and/or nanotubes produced by hyperthermophilic archaea of the genus Thermococcus. AB - Thermococcus species produce MVs (membrane vesicles) into their culture medium. These MVs are formed by a budding process from the cell envelope, similar to ectosome formation in eukaryotic cells. The major protein present in MVs of Thermococci is a peptide-binding receptor of the OppA (oligopeptide-binding protein A) family. In addition, some of them contain a homologue of stomatin, a universal membrane protein involved in vesiculation. MVs produced by Thermococcus species can recruit endogenous or exogenous plasmids and plasmid transfer through MVs has been demonstrated in Thermococcus kodakaraensis. MVs are frequently secreted in clusters surrounded by S-layer, producing either big protuberances (nanosphere) or tubular structures (nanotubes). Thermococcus gammatolerans and T. kodakaraensis produce nanotubes containing strings of MVs, resembling the recently described nanopods in bacteria, whereas Thermococcus sp. 5-4 produces filaments whose internal membrane is continuous. These nanotubes can bridge neighbouring cells, forming cellular networks somehow resembling nanotubes recently observed in Firmicutes. As suggested for bacteria, archaeal nanopods and/or nanotubes could be used to expand the metabolic sphere around cells and/or to promote intercellular communication. PMID- 23356327 TI - From archaeon to eukaryote: the evolutionary dark ages of the eukaryotic cell. AB - The evolutionary origin of the eukaryotic cell represents an enigmatic, yet largely incomplete, puzzle. Several mutually incompatible scenarios have been proposed to explain how the eukaryotic domain of life could have emerged. To date, convincing evidence for these scenarios in the form of intermediate stages of the proposed eukaryogenesis trajectories is lacking, presenting the emergence of the complex features of the eukaryotic cell as an evolutionary deus ex machina. However, recent advances in the field of phylogenomics have started to lend support for a model that places a cellular fusion event at the basis of the origin of eukaryotes (symbiogenesis), involving the merger of an as yet unknown archaeal lineage that most probably belongs to the recently proposed 'TACK superphylum' (comprising Thaumarchaeota, Aigarchaeota, Crenarchaeota and Korarchaeota) with an alphaproteobacterium (the protomitochondrion). Interestingly, an increasing number of so-called ESPs (eukaryotic signature proteins) is being discovered in recently sequenced archaeal genomes, indicating that the archaeal ancestor of the eukaryotic cell might have been more eukaryotic in nature than presumed previously, and might, for example, have comprised primitive phagocytotic capabilities. In the present paper, we review the evolutionary transition from archaeon to eukaryote, and propose a new model for the emergence of the eukaryotic cell, the 'PhAT (phagocytosing archaeon theory)', which explains the emergence of the cellular and genomic features of eukaryotes in the light of a transiently complex phagocytosing archaeon. PMID- 23356326 TI - Genomics and biology of Rudiviruses, a model for the study of virus-host interactions in Archaea. AB - Archaeal viruses, especially viruses that infect hyperthermophilic archaea of the phylum Crenarchaeota, constitute one of the least understood parts of the virosphere. However, owing to recent substantial research efforts by several groups, archaeal viruses are starting to gradually reveal their secrets. In the present review, we summarize the current knowledge on one of the emerging model systems for studies on crenarchaeal viruses, the Rudiviridae. We discuss the recent advances towards understanding the function and structure of the proteins encoded by the rudivirus genomes, their role in the virus life cycle, and outline the directions for further research on this model system. In addition, a revised genome annotation of SIRV2 (Sulfolobus islandicus rod-shaped virus 2) is presented. Future studies on archaeal viruses, combined with the knowledge on viruses of bacteria and eukaryotes, should lead to a better global understanding of the diversity and evolution of virus-host interactions in the viral world. PMID- 23356328 TI - Sulfolobus islandicus: a model system for evolutionary genomics. AB - Sulfolobus islandicus has been developed as a model system for combining approaches of evolutionary and molecular biology in Archaea. We describe how the application of this interdisciplinary approach can lead to novel hypotheses derived from patterns of natural variation that can be tested in the laboratory when combined with a diversity of natural variants and versatile genetic markers. We review how this approach has highlighted the importance of recombination as an evolutionary parameter and provided insight into a molecular mechanism of recombination that may be unique in the archaeal domain. We review the development and improvement of the model system S. islandicus that will enable us to study the mechanism and genomic architecture of recombination guided by evolutionary genomic analysis of Nature's ongoing experiments in wild populations. PMID- 23356330 TI - Fovea and foveation in Parkinson's disease. AB - Nondemented Parkinson's disease (PD) patients report problems on nonmotor tasks that depend on visual or visuospatial abilities. In PD, foveal vision is impaired. Experimental studies in humans and monkeys established that foveal processing and visuospatial attention may be linked through saccadic eye movements. Saccadic eye movements "bring" eccentric targets to the direct sight line for closer scrutiny by foveal processing. This is called foveation. This review musters the arguments for impaired foveal vision and impaired cortical control of voluntary saccades in PD. Retinal impairment of spatial contrast vision is selective in PD. Thus, the reviewed literature includes a brief survey of the physiology of foveal pathways. This is necessary to understand the specificity of the retinopathy of PD, documented by clinical evidence, relying on psychophysical, electrophysiological, and imaging techniques. These have recently been supplanted by the results of retinal imaging using Optical Coherence Tomography (OCT). Studies of cortical mechanisms in PD reviewed here relied on neuropsychological, electrophysiological (EEG), and imaging techniques. Impaired functional anatomy and electrophysiology in PD are reviewed. The exact relationship of retinal foveal deficits and visuospatial attention and postural control impairment in PD remain challenging research questions. This review will hopefully will provide useful material for future studies. PMID- 23356329 TI - Line bisection in Parkinson's disease: investigation of contributions of visual field, retinal vision, and scanning patterns to visuospatial function. AB - Parkinson's disease (PD) is characterized by disorders of visuospatial function that can impact everyday functioning. Visuospatial difficulties are more prominent in those whose motor symptoms begin on the left body side (LPD) than the right body side (RPD) and have mainly been attributed to parietal dysfunction. The source of visuospatial dysfunction is unclear, as in addition to subcortical-cortical changes, there are irregularities of visual scanning and potentially of retinal-level vision in PD. To assess these potential contributors, performance on a visuospatial task--line bisection--was examined together with retinal structure (nerve fiber layer thickness, measured by optical coherence tomography [OCT]), retinal function (contrast sensitivity, measured by frequency-doubling technology [FDT]), and visual scanning patterns. Participants included 20 nondemented patients (10 LPD, 10 RPD) and 11 normal control (NC) adults. Relative to the other groups, LPD were expected to show rightward bias on horizontal line bisection, especially within the left visual hemispace, and downward bias on vertical bisection. LPD relative rightward bias was confirmed, though not mainly within the left hemispace and not correlated with retinal structure or function. Retinal thinning was seen in LPD relative to RPD. Qualitative visualization of eye movements suggested greater LPD exploration of the right than left side of the line during horizontal bisection, and some overall compression of scanning range in RPD (both orientations) and LPD (primarily vertical). Results indicated that rightward visuospatial bias in our LPD sample arose not from abnormalities at the retinal level but potentially from attentional biases, reflected in eye movement patterns. PMID- 23356331 TI - Identification of a novel HLA-A allele, A*02:357, in a Chinese individual. AB - Human leukocyte antigen (HLA)-A*02:357 differs from A*02:01:01:01 by a single nucleotide at position 840 from A to T exon 4, leading to amino acid substitution from Arg to Ser. PMID- 23356332 TI - Measuring exertion during caregiving of children and young adults with cerebral palsy who require assistance for mobility and self-care. AB - Our purpose was to compare objective and subjective measures of energy exertion during caregiving tasks. Participants were primary caregivers (N = 19) of children and young adults (aged 3 -22 years) with cerebral palsy (CP) who require assistance for mobility and self-care (67% classified in level V on the Gross Motor Function Classification System). Measures of exertion were collected during two caregiving tasks: (1) transfers and (2) dressing. Objective measures included volume of oxygen (V02), heart rate (HR), and the subjective measure was a rating of perceived exertion (Borg RPE). Controlling for baseline status, perceived exertion correlated with VO2 (0.43, p < .01) and HR (0.29, p < .01) during the tasks. Caregivers with high baseline HR and VO2, had high Borg RPE scores following a task. Correlations were found between HR and VO2 during caregiving tasks (0.63, p < .01). Patterns of association with caregiver and child characteristics were similar for VO2 and Borg RPE. Subjective measures of exertion appear to capture the strain of caregiving. Understanding a caregiver's perception of exertion can guide therapists in assessing the need for equipment, pharmacological, or respite interventions. PMID- 23356333 TI - Evaluation of the antioxidant activity of several naturally occurring coumarins and their synthesized analogues by "ferric reducing antioxidant power" assay. AB - Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. According to our continuing investigations of biological effects of several coumarins, the structure-antioxidant activity relationships (SARs) of six naturally occurring coumarins and their 16 synthesized analogues were established. For this purpose, the very reliable colorimetric assay (ferric reducing antioxidant power) modified to be used in 96 well microplates was used. This approach, which determines the reducing capacity of tested compounds directly, has previously been used for the determination of SARs of flavonoids, but has not been used for SAR determination of coumarins. It is known that the biological properties and consequently, therapeutic application of simple coumarins depends upon the pattern of substitution. It was established that 7,8-dihydroxy- and 6,7-dihydroxy-4-methylcoumarins have shown excellent ferric-reducing properties. PMID- 23356334 TI - Implementation of active support in Victoria, Australia: an exploratory study. AB - BACKGROUND: Active support is an effective intervention to support engagement of residents with intellectual disability in group homes. This survey explored resident characteristics of the people supported by organisations implementing active support, the provision of active support, its procedures and systems, and resident engagement in meaningful activity and relationships. METHOD: Information was collected through questionnaires and direct observation of 33 group homes from 6 organisations in Victoria, Australia, with a 5-10-year history of implementing active support. RESULTS: Residents with lower support needs were engaged with little staff contact or assistance. Use of active support systems and structures was mixed. Only one organisation consistently provided good active support. CONCLUSIONS: Administrative systems and structures are not sufficient to change staff interaction and thus resident experience. Shared supported accommodation services may represent an inefficient use of resources for more able residents, as staff resources are not maximised to support for resident engagement. PMID- 23356335 TI - Clinical efficacy and cost-effectiveness of HP-human FSH (Fostimon(r)) versus rFSH (Gonal-F(r)) in IVF-ICSI cycles: a meta-analysis. AB - Clinical efficacy of human-derived follicle-stimulating hormone (FSH) versus recombinant FSH (rFSH) in IVF-ICSI cycles has long been compared, but no clear evidence of the superiority of a preparation over the other has been found. Human gonadotropins have been often grouped together, but a different glycosylation may be present in each preparation, therefore influencing the specific bioactivity. To exclude confounding factors, a meta-analysis and a cost-effectiveness analysis were designed to compare effectiveness and cost-effectiveness of a specific highly purified human FSH (HP-hFSH) (Fostimon(r)) versus rFSH (Gonal-F(r)) in IVF/ICSI cycles. Research methodology filters were applied in MEDLINE, Current Contents and Web of Science from 1980 to February 2012. Eight randomized trials met selection criteria. The meta-analysis showed no significant differences between rFSH and HP-hFSH treatment in live-birth rate (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.63-1.11), clinical pregnancy rate (OR 0.85, 95% CI 0.68-1.07), number of oocytes retrieved, number of mature oocytes and days of stimulation. The cost-effectiveness ratio was ? 7174 in the rFSH group and ? 2056 in the HP-hFSH group. HP-hFSH is as effective as rFSH in ovarian stimulation for IVF-ICSI cycles, but the human preparation is more cost-effective. PMID- 23356336 TI - Effectiveness evaluation of glyphosate oxidation employing the H(2)O(2)/UVC process: toxicity assays with Vibrio fischeri and Rhinella arenarum tadpoles. AB - The H(2)O(2)/UVC process was applied to the photodegradation of a commercial formulation of glyphosate in water. Two organisms (Vibrio fischeri bacteria and Rhinella arenarum tadpoles) were used to investigate the toxicity of glyphosate in samples M(1,) M(2), and M(3) following different photodegradation reaction times (120, 240 and 360 min, respectively) that had differing amounts of residual H(2)O(2). Subsamples of M(1), M(2), and M(3) were then used to create samples M(1,E), M(2,E) and M(3,E) in which the H(2)O(2) had been removed. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in tadpoles to determine possible sub-lethal effects. In V. fischeri, M(1,E), which was collected early in the photodegradation process, caused 52% inhibition, while M(3,E), which was collected at the end of the photodegradation process, caused only 17% inhibition. Survival of tadpoles was 100% in samples M(2), M(3), and in M(1,E), M(2,E) and M(3,E). The lowest percentages of enzymatic inhibition were observed in samples without removal of H(2)O(2): 13.96% (AChE) and 16% (BChE) for M(2), and 24.12% (AChE) and 13.83% (BChE) for M(3). These results show the efficiency of the H(2)O(2)/UVC process in reducing the toxicity of water or wastewater polluted by commercial formulations of glyphosate. According to the ecotoxicity assays, the conditions corresponding to M(2) (11 +/- 1 mg a.e. L(-1) glyphosate and 11 +/- 1 mg L(-1) H(2)O(2)) could be used as a final point for glyphosate treatment with the H(2)O(2)/UV process. PMID- 23356337 TI - Electrospray ionization mass spectrometry (ESI-MS) monitoring of the photolysis of diazinon in aqueous solution: degradation route and toxicity of by-products against Artemia salina. AB - The photolytic degradation of diazinon, an organophosphorus pesticide, in aqueous medium under assorted pH values was continuously monitored by direct infusion electrospray ionization mass spectrometry (ESI-MS). The results indicated that the UV radiation was quite efficient in promoting the pesticide degradation at the three pH levels evaluated (5, 7 and 8). The m/z of the most abundant ions observed in the mass spectra (MS), in conjunction with the fragmentation patterns of such ionic species (MS/MS data), made possible the proposition of chemical structures for the main by-products formed. As a result, routes for the photodegradation of diazinon in aqueous solution could thus be suggested. In the assays using Artemia salina (brine shrimp) it was verified that the photodegradation products exhibited much lower toxicity than the primary substrate. Aiming at mimicking the conditions ordinarily found in water treatment plants, an additional series of tests was conducted with a solution containing sodium hypochlorite and diazinon. This solution, when not exposed to UV radiation, exhibited high toxicity against the microorganisms. Under the influence of UV radiation, however, the toxicity rates decreased dramatically. This result is relevant because it points toward the confident application of UV radiation to neutralize the deleterious effects caused by diazinon (and perhaps other organophosphorus pesticides) as well as sodium hypochlorite to the environment. PMID- 23356339 TI - Removal of ethylenthiourea and 1,2,4-triazole pesticide metabolites from water by adsorption in commercial activated carbons. AB - This study evaluated the adsorption capacity of ethylenthiourea (ETU) and 1H 1,2,4-triazole (1,2,4-T) for two commercial activated carbons: charcoal-powdered activated carbon (CPAC) and bovine bone-powdered activated carbon (BPAC). The tests were conducted at a bench scale, with ETU and 1,2,4-T diluted in water, for isotherm and adsorption kinetic studies. The removal of the compounds was accompanied by a total organic carbon (TOC) analysis and ultraviolet (UV) reduction analysis. The coals were characterized by their surface area using nitrogen adsorption/desorption, by a scanning electron microscopy and energy dispersive X-ray spectroscopy (SEM/EDS) and by a zero charge point analysis (pHpcz). The results showed that adsorption kinetics followed a pseudo-second order model for both coals, and the adsorption isotherms for CPAC and BPAC were adjusted to the Langmuir and Freundlich isotherms, respectively. The CPAC removed approximately 77% of the ETU and 76% of the 1,2,4-T. The BPAC was ineffective at removing the contaminants. PMID- 23356338 TI - Matrix effects in analysis of dialkyl phosphate metabolites of organophosphate pesticides in urine by gas chromatography/tandem mass spectrometer. AB - Urinary dialkyl phosphate metabolites (DAPs) are used as biomarkers to evaluate human exposure to organophosphate pesticides. The objective was to evaluate potential artifacts in urinary DAPs analysis during sample preparation and method calibration. Diluted urine pools were commonly used to prepare calibration standards to minimize the effects due to the complexity of urine matrix. Matrix effects on measurements of DAPs were evaluated by spiking known amount of standards into distilled water, synthetic urine and diluted urine pool. Different matrices resulted in similar concentrations detected for all target compounds, except dimethylphosphate (DMP) with the deviation of measurement as large as eight times the spiked amount. In this study, we also found that urinary particles, which usually appeared after thawing frozen human urine samples, could affect the measurements of DAPs, especially DMP and diethylthiophosphate (DETP). Results of DAPs measurements in three types of sample matrices, i.e. urine without particles, urine with particles and particles only were compared. DETP could be subject to large error during this preparation step. The use of deuterated and (13)C(12)-labeled DAPs as internal standards is also evaluated. Overall, these issues can cause misidentification and inaccuracies, which may significantly affect the data quality. PMID- 23356340 TI - Solid phase extraction with silicon dioxide microsphere adsorbents in combination with gas chromatography-electron capture detection for the determination of DDT and its metabolites in water samples. AB - The goal of the present study was to investigate the feasibility of silicon dioxide (SiO(2)) microspheres without special modification to enrich dichlorodiphenyltrichloroethane (DDT) and its main metabolites, p,p' dichlorodiphenyl-2,2-dichloroethylene (p,p'-DDD) and p,p' dichlorodiphenyldichloroethylene (DDE) in combination with gas chromatography electron-capture detection. The experimental results indicated that an excellent linear relationship between the recoveries and the concentrations of DDT and its main metabolites was obtained in the range of 0.2-30 ng mL(-1) and the correlation coefficients were in the range of 99.96-99.99%. The detection limits based on the ratio of signal to the baseline noise (S/N = 3) were 2.2, 2.9, 3.8 and 4.1 ng L(-1) for p,p'-DDD, p,p'-DDT, o,p'-DDT, and p,p'-DDE, respectively. The precisions of the proposed method were all below 10% (n = 6). Four real water samples were utilized for validation of the proposed method, and satisfactory spiked recoveries in the range of 72.4-112.9% were achieved. These results demonstrated that the developed method was a simple, sensitive, and robust analytical method for the monitoring of pollutants in the environment. PMID- 23356341 TI - Isolation and characterization of a Sphingomonas sp. strain F-7 degrading fenvalerate and its use in bioremediation of contaminated soil. AB - A fenvalerate-degrading bacterial strain F-7 was isolated from long-term contaminated sludge. Based on morphological, physiological and biochemical characterization, and phylogenetic analysis of 16S rRNA gene sequence, strain F-7 was identified as Sphingomonas sp. The bacterium could utilize fenvalerate as the sole source of carbon. An amount measuring 100 mg L(-1) fenvalerate was completely degraded within 72 h and 3-phenoxybenzoic acid (3-PBA) was detected as a major metabolite. The result indicates that S. sp. F-7 might metabolize fenvalerate by hydrolysis of carboxylester linkage. It was capable of degrading permethrin, fenpropathrin, beta-cypermethrin, cyhalothrin, deltamethrin, bifenthrin and 3-PBA. Further studies demonstrated that the strain was multi resistant to heavy metals and antibiotics. In addition, degradative enzymes involved were confirmed as intracellular distributed and constitutively expressed. Furthermore, application of the strain was found to accelerate the removal of fenvalerate in soil. This is the first report of fenvalerate degrading strain isolated from S. sp. These results might help with future research in better understanding of pyrethroid biodegradation and highlight S. sp. F-7 might have potential for practical application in bioremediation of fenvalerate contaminated sites. PMID- 23356342 TI - New bacterial strain of the genus Ochrobactrum with glyphosate-degrading activity. AB - Thirty bacterial strains with various abilities to utilize glyphosate as the sole phosphorus source were isolated from farm soils using the glyphosate enrichment cultivation technique. Among them, a strain showing a remarkable glyphosate degrading activity was identified by biochemical features and 16S rRNA sequence analysis as Ochrobactrum sp. (GDOS). Herbicide (3 mM) degradation was induced by phosphate starvation, and was completed within 60 h. Aminomethylphosphonic acid was detected in the exhausted medium, suggesting glyphosate oxidoreductase as the enzyme responsible for herbicide breakdown. As it grew even in the presence of glyphosate concentrations as high as 200 mM, Ochrobactrum sp. could be used for bioremediation purposes and treatment of heavily contaminated soils. PMID- 23356343 TI - Glucose, stem dry weight variation, principal component and cluster analysis for some agronomic traits among 16 regenerated Crotalaria juncea accessions for potential cellulosic ethanol. AB - The objectives of this research were to identify candidate sunn hemp accessions having high concentrations of cellulose for use as parents in breeding for cellulose and to determine variability for glucose content and some important agronomic traits among sunn hemp accessions. Since sunn hemp is an under-utilized species, glucose content and agronomic trait variation is essential for the identification of superior sunn hemp accessions for use as potential ethanol for biofuel. Sixteen sunn hemp accessions including the following plant introductions (expressed as glucose concentration) and stem dry weights were studied. "Sixteen sunn hemp accessions including the following plant introductions (expressed as glucose concentration) and stem dry weights were studied." In addition, to verify variability, these traits plus morphological, phenological, and seed reproductive traits were analyzed using multivariate and cluster analysis. The accessions, PI 250487, PI 337080, and PI 219717 produced the highest glucose concentrations (859, 809, and 770 mg g(-1) stem dry weight, respectively), however PI 468956 produced the highest stem dry weight (258 g). Branching significantly correlated with foliage (r(2) = 0.67**) and relative maturity (r(2) = 0.60*), while maturity had a significantly negative correlation with seed number (r(2) = -0.67**) and plant width (r(2) = -0.53*) as well. Seed number significantly correlated with plant width (r(2) = 0.57*). Average linkage cluster analysis grouped the 16 sunn hemp accessions into well-defined phenotypes with four distinct seed-producing groups and one outlier. Based on multivariate and cluster analysis, sufficient variation among these16 sunn hemp accessions exists to support the development of cellulosic ethanol producing cultivars with improved architecture, early maturity, seed yield, glucose concentrations, and stem dry weights. PMID- 23356344 TI - Elevated concentrations of trace elements in soil do not necessarily reflect metals available to plants. AB - Bioaccumulation and entry of trace elements from soil into the food chain have made trace-elements major environmental pollutants. The main objective of this investigation was to study the impact of mixing native agricultural soil with municipal sewage sludge (SS) or SS mixed with yard waste (SS+YW) compost on total concentration of trace elements in soil, metals available to plants, and mobility of metals from soil into peppers and melon fruits. Regardless of soil treatment, the average concentrations of Ni, Cd, Pb, Cr, Cu, Zn, and Mo in melon fruits were 5.2, 0.7, 3.9, 0.9, 34.3, 96.1, and 3.5MUg g(-1), respectively. Overall concentrations of Ni, Cd, Pb, and Zn in melon fruits were significantly greater (P < 0.05) than pepper fruits. No significant differences were found in Cr, Cu, and Mo concentrations between pepper and melon fruits at harvest time. Total metal concentrations and metal ions in soil available to melon and pepper plants were also determined. Total concentration of each metal in the soil was significantly greater than concentration of metal ions available to plants. Elevated Ni and Mo bioaccumulation factor (BAF > 1) of melon fruits of plants grown in SS+YW mixed soil is a characteristic that would be less favorable when plants grown on sites having high concentrations of these metals. PMID- 23356345 TI - Effects of organic amendments on the mobility of Pb and Zn from mine tailings added to semi-arid soils. AB - The effects of mine tailings and three organic amendments (compost, bokashi and vermicompost) on the mobility factor for Pb and Zn and on the potential C and N mineralization in semi-arid agricultural and rangeland soils were examined. During the experiment, soil samples were analyzed periodically for CO(2)-C evolution, inorganic N, dehydrogenase activity and percent Pb and Zn mobility during 169 d of incubation. The dehydrogenase activity and CO(2)-C evolved were strongly inhibited by mine tailings mixed with organic compost in both agricultural and rangeland soils (37 to 43 %), followed by N mineralization in treatments with mine tailings plus bokashi or compost (13 to 26.5 %) at 169 d incubation. The highest % mobility of Pb and Zn were observed in soils amended with mine tailings alone, while the lowest was observed in agricultural soils treated with vermicompost plus mine tailings. The CO(2)-C evolved was fitted to first order E, while the cumulative N mineralization was fitted to the linearized power function. Mine tailings were found to influence the potential C and N mineralization rate constants in both soils. The models for C and N mineralization could be used to evaluate the effects of mine tailings, which include intrinsic parameters in the soil. PMID- 23356346 TI - Benign lower limb amyotrophy due to TARDBP mutation or post-polio syndrome? PMID- 23356347 TI - Disclosure, sex and moral agency: a response to Groves, Maman and Moodley. PMID- 23356348 TI - Effect of cryopreserved amniotic membrane on the development of adhesions and fibrosis after extraocular muscle surgery in rabbits. AB - PURPOSE: To histopathologically evaluate the effect of cryopreserved human amniotic membrane (AM) transplant on preventing the development of postoperative adhesions after extraocular muscle surgery. METHODS: Ten albino rabbits were used. The superior rectus muscles were bilaterally resected. In right eyes, the muscle was wrapped with cryopreserved human AM (group AM). In left eyes, the muscle was not wrapped with AM and served as a control group (group C). The rabbits were killed, and the eyes were enucleated 6 weeks after surgery to perform histopathological examination. RESULTS: On histopathological examination, the AM was present in eight eyes, surrounded by periamniotic inflammation, with no adhesions detected between rectus muscle and sclera, conjunctiva and Tenon's capsule in the segment where the AM was present, but detected elsewhere. Adhesions were detected in the other two eyes of group AM, in which the AM was absent, and in all group C eyes. When comparing eye pairs of each rabbit, AM eyes showed significantly less adhesions between the muscle and sclera (p = 0.009) and between the muscle and Tenon's capsule and conjunctiva (p = 0.008), in the region of AM application, and significantly more foreign body inflammation (p = 0.031), than C eyes. The differences between AM and C eye pairs, in terms of conjunctival inflammation and vascularity and muscle fibrosis, were insignificant (p > 0.05). CONCLUSIONS: Cryopreserved AM is effective in reducing postoperative extraocular muscle adhesions. Its application is, therefore, recommended during strabismus reoperations. PMID- 23356349 TI - Dynamic regulation of autophagy and endocytosis for cell remodeling during early development. AB - Fertilization triggers cell remodeling from each gamete to a totipotent zygote. Using Caenorhabditis elegans as a model system, it has been revealed that lysosomal degradation pathways play important roles in cellular remodeling during this developmental transition. Endocytosis and autophagy, two pathways leading to the lysosomes, are highly upregulated during this period. A subset of maternal membrane proteins is selectively endocytosed and degraded in the lysosomes before the first mitotic cell division. Autophagy is also induced shortly after fertilization and executes the degradation of paternally inherited embryonic organelles, e.g. mitochondria and membranous organelles. This mechanism underlies the maternal inheritance of the mitochondrial genome. Autophagy is also required for the removal of extra P-granule (germ granules in C. elegans) components in somatic cells of early embryos and thereby for the specific distribution of P granules to germ cells. This review focuses on recent advances in the study of the physiological roles and mechanisms of lysosomal pathways during early development in C. elegans. PMID- 23356350 TI - First keto-functionalized microporous Al-based metal-organic framework: [Al(OH)(O2C-C6H4-CO-C6H4-CO2)]. AB - Based on the V-shaped linker molecule 4,4'-benzophenonedicarboxylic acid, the new carbonyl-functionalized metal-organic framework (MOF) [Al(OH)(O(2)C-C(6)H(4)-CO C(6)H(4)-CO(2))], denoted as CAU-8, was discovered employing high-throughput methods. The compound is obtained from 4,4'-benzophenonedicarboxylic acid, Al(2)(SO(4))(3).18H(2)O in a mixture of N,N-dimethylformamide (DMF) and water under solvothermal conditions. The structure was determined from single-crystal X ray diffraction data (I4(1)/a, a = b = 13.0625(5), c = 52.565(2) A). The framework is based on infinite inorganic building units of trans-connected, corner-sharing AlO(6)-polyhedra. Parallel Al-O-chains are arranged in layers perpendicular to [001]. Within a layer an interchain distance of ~1.1 nm is observed. The orientation of the Al-O-chains within neighboring layers is perpendicular to each other, along [100] and [010], respectively, and an ABCDA stacking of these layers is observed. The interconnection of these orthogonally oriented chains by the V-shaped dicarboxylate ions results in the formation a three-dimensional framework structure containing one-dimensional channels with a diameter of about 8 A. The pore walls are lined by the keto-groups. CAU-8 was thoroughly characterized by X-ray powder diffraction (XRPD), thermogravimetric measurements, IR- and Raman-spectroscopy, elemental analysis, and gas sorption experiments using N(2) and H(2) as adsorptives. CAU-8 is stable up to 350 degrees C in air and exhibits a moderate porosity with a specific surface area of S(BET) = 600 m(2)/g and a micropore volume of 0.23 cm(3)/g. Moreover, a detailed topological analysis of the framework was carried out, and an approach for the topological analysis of MOFs based on infinite 1-periodic building units is proposed. PMID- 23356352 TI - Abnormal heart rate recovery in stable heart failure patients. AB - BACKGROUND: Heart rate decrease after exercise, that is associated with reactivation of parasympathetic system, is important, as it is also associated with mortality. Previous studies have shown that this is an independent mortality predictor in patients having no coronary artery disease and having normal left ventricular function. In our study, we aimed to study heart rate recovery (HRR) after exercise in patients having impaired left ventricular function. METHODS: One hundred and two consecutive patients (68 males, 34 females) requested to perform an exercise stress test were included in our study. Patients were divided into two groups as those having a normal heart rate reserve (Group1, n = 72) and those having an abnormal heart rate reserve (Group2, n = 30). RESULTS: In Group1 and Group2, resting heart rate averages were found to be 83.61 +/- 18.01/min and 85.10 +/- 13.40/min, respectively (P > 0.05), and maximum heart rates during exercise were 141.42 +/- 19.70/min and 121.17 +/- 19.01/min while those in Group1 had statistically significantly higher heart rates (P < 0.001). A statistically significant positive association was found in the correlation test carried out between the maximum heart rate during the treadmill exercise test and ejection fraction (EF) value (r = 0.201; P < 0.05). Metabolic equivalents of task values obtained during the treadmill exercise test in Group1 and Group2 were 9.48 +/- 2.28 and 8.36 +/- 2.50, respectively, and the difference between the said values was statistically significant (P < 0.05). CONCLUSIONS: We believe that the association between low EF and abnormal HRR is worth studying and randomized large-scale studies are needed to determine mortality risk. PMID- 23356351 TI - Can we prevent or treat multiple sclerosis by individualised vitamin D supply? AB - Apart from its principal role in bone metabolism and calcium homeostasis, vitamin D has been attributed additional effects including an immunomodulatory, anti-inflammatory, and possibly even neuroprotective capacity which implicates a possible role of vitamin D in autoimmune diseases like multiple sclerosis (MS). Indeed, several lines of evidence including epidemiologic, preclinical, and clinical data suggest that reduced vitamin D levels and/or dysregulation of vitamin D homeostasis is a risk factor for the development of multiple sclerosis on the one hand, and that vitamin D serum levels are inversely associated with disease activity and progression on the other hand. However, these data are not undisputable, and many questions regarding the preventive and therapeutic capacity of vitamin D in multiple sclerosis remain to be answered. In particular, available clinical data derived from interventional trials using vitamin D supplementation as a therapeutic approach in MS are inconclusive and partly contradictory. In this review, we summarise and critically evaluate the existing data on the possible link between vitamin D and multiple sclerosis in light of the crucial question whether optimization of vitamin D status may impact the risk and/or the course of multiple sclerosis. PMID- 23356353 TI - Qualitative systematic reviews of treatment burden in stroke, heart failure and diabetes - methodological challenges and solutions. AB - BACKGROUND: Treatment burden can be defined as the self-care practices that patients with chronic illness must perform to respond to the requirements of their healthcare providers, as well as the impact that these practices have on patient functioning and well being. Increasing levels of treatment burden may lead to suboptimal adherence and negative outcomes. Systematic review of the qualitative literature is a useful method for exploring the patient experience of care, in this case the experience of treatment burden. There is no consensus on methods for qualitative systematic review. This paper describes the methodology used for qualitative systematic reviews of the treatment burdens identified in three different common chronic conditions, using stroke as our exemplar. METHODS: Qualitative studies in peer reviewed journals seeking to understand the patient experience of stroke management were sought. Limitations of English language and year of publication 2000 onwards were set. An exhaustive search strategy was employed, consisting of a scoping search, database searches (Scopus, CINAHL, Embase, Medline & PsycINFO) and reference, footnote and citation searching. Papers were screened, data extracted, quality appraised and analysed by two individuals, with a third party for disagreements. Data analysis was carried out using a coding framework underpinned by Normalization Process Theory (NPT). RESULTS: A total of 4364 papers were identified, 54 were included in the review. Of these, 51 (94%) were retrieved from our database search. Methodological issues included: creating an appropriate search strategy; investigating a topic not previously conceptualised; sorting through irrelevant data within papers; the quality appraisal of qualitative research; and the use of NPT as a novel method of data analysis, shown to be a useful method for the purposes of this review. CONCLUSION: The creation of our search strategy may be of particular interest to other researchers carrying out synthesis of qualitative studies. Importantly, the successful use of NPT to inform a coding frame for data analysis involving qualitative data that describes processes relating to self management highlights the potential of a new method for analyses of qualitative data within systematic reviews. PMID- 23356355 TI - In response to community violence: coping strategies and involuntary stress responses among Latino adolescents. AB - Among poor, urban adolescents, high rates of community violence are a pressing public health concern. This study relies on a contextual framework of stress and coping to investigate how coping strategies and involuntary stress responses may both mediate and moderate the relation between exposure to community violence and psychological well-being. Our sample consists of 223 ninth grade Latino adolescents from poor, urban families. In response to community violence, these adolescents reported using an array of coping strategies as well as experiencing a number of involuntary stress responses; the most frequent coping responses were turning to religion and seeking social support. Hierarchical regression analyses demonstrated that involuntary stress responses mediated the relations between both witnessing or being victimized by violence and poorer psychological functioning, while coping strategies moderated these relations. These findings suggest that the negative psychological effects of exposure to community violence may, in part, be explained by involuntary stress responses, while religious-based coping may serve as a protective factor. PMID- 23356354 TI - Mediators of the relationship between acculturative stress and internalization symptoms for immigrant origin youth. AB - The present study examines the generational differences in the relation between acculturative stress and internalizing symptoms (i.e., anxiety and depression) with a sample of 304 urban residing first- and second-generation immigrant adolescents. In addition, the role of perceptions of social support-a critical element to healthy immigrant adolescent adaptation-is explored as a mediator of this relation. Results indicate that first-generation adolescents report more acculturative stress and internalizing symptoms than do second generation. Employing a moderated mediation framework (Preacher, Rucker, & Hayes, 2007), we find that perceptions of both emotional and academic social support mediate the relation between acculturative stress and internalizing symptoms for the first generation but not for the second. Our findings serve to expand the discourse of the "immigrant paradox" (Garcia Coll & Marks, 2011). PMID- 23356356 TI - Pregnant African American women's attitudes toward perinatal depression prevention. AB - Depression during the perinatal period is common, debilitating, and consequential for women and their children, particularly among low income African American women. Viable approaches to prevention of depression have emerged. Yet little is known about women's preferences for approaches to preventing depression. A sample of 60 pregnant, low-income African American women seeking routine prenatal care was presented with standardized descriptions of three approaches to depression prevention (pharmacotherapy and two psychosocial approaches) and measures of preferences, perceived credibility, and personal reactions to each approach. Women also completed measures of perceived barriers and facilitators and current depression. Consistent with expectations, both of the psychosocial approaches were rated as more strongly preferred, more credible, and associated with more positive personal reactions relative to the pharmacotherapy approach. Depression did not alter women's preferences among the approaches. Contrary to prediction, women with clinically significant levels of depression did not find the pharmacotherapy approach to be more credible or to have more favorable personal reactions to it than women with low depression symptom levels. Exploration of women's perceptions of barriers revealed the importance of logistics, beliefs, and stigma barriers whereas women reported that concern about depression being impairing and ease of pragmatics would both facilitate engagement with preventive interventions. The findings suggest the need to examine the role of preferences in tests of the effectiveness of approaches to the prevention of perinatal depression in order to enhance service delivery among low income African American women. PMID- 23356357 TI - Emotional adjustment and distressed interpersonal relations among low-income African American mothers: moderating effects of demanding kin relations. AB - Association of mothers' emotional adjustment and negative kin relations with distressed interpersonal relations was examined. Among 115 low-income African American mothers, relationship of depressive symptoms, self-esteem, and demanding kin relations with psychological control and stressful interpersonal relations was assessed. Depressive symptoms and demanding kin relations were positively associated with mothers' use of psychological control in parenting. Interaction of self-esteem with demanding kin relations revealed that self-esteem was negatively associated with psychological control for mothers with high-demanding kin relations but not for mothers with low-demanding kin relations. Mothers' depressive symptoms and demanding kin relations were positively associated with their stressful interpersonal relations. Findings were discussed in terms of the need for research on the beneficial and detrimental aspects of families' social network. PMID- 23356358 TI - Black adolescents' relationships with natural mentors: associations with academic engagement via social and emotional development. AB - This study aimed to identify types of natural mentoring relationships that Black adolescents may experience and to connect these relationship types to academic outcomes via social and emotional development. Data were collected from 259 adolescents attending 3 middle schools in a Midwestern metropolitan area. Adolescents reported on whether or not they had a relationship with a natural mentor and answered several questions about characteristics of the relationship, as well as reporting on a number of indicators of positive development. Cluster analyses suggested two different types of natural mentoring relationships among study youth: less connected and more connected. We found that in comparison with youth without a natural mentor, youth who had a more connected natural mentoring relationship had greater student-reported academic engagement via higher social skills and psychological well-being and greater teacher-reported academic engagement via elevated social skills. We found that youth with less connected natural mentoring relationships did not differ from their counterparts without natural mentors on social skills, psychological well-being, or student- or teacher-reported academic engagement. Findings from the current study suggest that characteristics of the mentoring relationship may determine whether these relationships contribute to more positive outcomes among Black youth. Further, findings suggest that social and emotional development may transmit the positive effects of more connected natural mentoring relationships on Black youths' academic engagement. PMID- 23356359 TI - Clusters of CRIS scores and psychological adjustment. AB - Cluster analyses on racial identity attitudes as assessed with the Cross Racial Identity Scale (Vandiver et al., 2000) provided strong support for six theoretically meaningful clusters. We labeled these Afrocentric, Assimilated, Conflicted, Low Race Salience, Negative Race Salience, and Multiculturalist. We also examined whether individuals in different clusters varied on symptoms of psychological distress, as well as personal and status-based rejection sensitivity. Participants in the Conflicted cluster reported greater psychological distress and personal rejection sensitivity than those in the Multiculturalist and Low Race Salience clusters. Our findings suggest that bivariate relationships between nigrescence attitudes and psychological functioning may mask nuances that are evident with person-centered analyses. We discuss the implications of these findings for racial identity research. PMID- 23356360 TI - Perceptions of racial confrontation: the role of color blindness and comment ambiguity. AB - Because of its emphasis on diminishing race and avoiding racial discourse, color blind racial ideology has been suggested to have negative consequences for modern day race relations. The current research examined the influence of color blindness and the ambiguity of a prejudiced remark on perceptions of a racial minority group member who confronts the remark. One hundred thirteen White participants responded to a vignette depicting a White character making a prejudiced comment of variable ambiguity, after which a Black target character confronted the comment. Results demonstrated that the target confronter was perceived more negatively and as responding less appropriately by participants high in color blindness, and that this effect was particularly pronounced when participants responded to the ambiguous comment. Implications for the ways in which color blindness, as an accepted norm that is endorsed across legal and educational settings, can facilitate Whites' complicity in racial inequality are discussed. PMID- 23356361 TI - The multi-dimensional model of Maori identity and cultural engagement: item response theory analysis of scale properties. AB - We argue that there is a need for culture-specific measures of identity that delineate the factors that most make sense for specific cultural groups. One such measure, recently developed specifically for Maori peoples, is the Multi Dimensional Model of Maori Identity and Cultural Engagement (MMM-ICE). Maori are the indigenous peoples of New Zealand. The MMM-ICE is a 6-factor measure that assesses the following aspects of identity and cultural engagement as Maori: (a) group membership evaluation, (b) socio-political consciousness, (c) cultural efficacy and active identity engagement, (d) spirituality, (e) interdependent self-concept, and (f) authenticity beliefs. This article examines the scale properties of the MMM-ICE using item response theory (IRT) analysis in a sample of 492 Maori. The MMM-ICE subscales showed reasonably even levels of measurement precision across the latent trait range. Analysis of age (cohort) effects further indicated that most aspects of Maori identification tended to be higher among older Maori, and these cohort effects were similar for both men and women. This study provides novel support for the reliability and measurement precision of the MMM-ICE. The study also provides a first step in exploring change and stability in Maori identity across the life span. A copy of the scale, along with recommendations for scale scoring, is included. PMID- 23356363 TI - Benzenesulfonamides with benzimidazole moieties as inhibitors of carbonic anhydrases I, II, VII, XII and XIII. AB - A series of benzenesulfonamide derivatives, bearing benzimidazole moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CAs). Their binding affinities to recombinant human CA isozymes I, II, VII, XII and XIII were determined by the thermal shift assay. A group of compounds containing a benzimidazole substituent in the para position of the benzenesulfonamide ring was found to exhibit higher binding potency toward tested CAs than meta-substituted benzenesulfonamides. Some of these compounds exhibited nanomolar affinities and selectivity toward the CA isozymes tested. PMID- 23356365 TI - The history of arboviral infections of horses in Australia is being rewritten. PMID- 23356366 TI - Descriptive overview of the 2011 epidemic of arboviral disease in horses in Australia. AB - OBJECTIVE: To provide an overview and descriptive analysis of the 2011 arboviral disease epidemic in horses that involved three important Australian mosquito borne viruses: Murray Valley encephalitis virus, West Nile virus (Kunjin strain) and Ross River virus. METHODS: Data from states affected between January and June 2011 were collated and comprised reports of horses showing signs of neuromuscular disease and the associated laboratory findings. A summary of the data is presented, together with a spatiotemporal analysis of cases and preliminary assessment of rainfall patterns and case distribution. RESULTS: A total of 982 cases of equine arboviral disease were reported across Australia between January and June 2011. The majority of cases were reported from south-east Australia and included horses that developed neurological signs consistent with encephalitis. It was the largest epidemic of equine arboviral disease in Australia's history. Two likely causes for this unprecedented epidemic were the unusual weather events that preceded the epidemic and the emergence of a new strain of Kunjin virus. CONCLUSIONS: The epidemic highlights to horse owners and policy makers the potential for future outbreaks of arboviral diseases and the need for vigilance. It also highlights the complex interactions among hosts, vectors and climatic conditions that are required for such an outbreak to occur. PMID- 23356367 TI - The feral horse foot. Part A: observational study of the effect of environment on the morphometrics of the feet of 100 Australian feral horses. AB - AIM: To better understand the morphology of, and the effect of different travel patterns and varying substrate environments on, the feral horse foot to better manage the feet of domestic horses. METHODS: The left forefeet of 20 adult feral horses from each of five geographically separated populations in Australia (n = 100) were investigated. Populations were selected on the basis of substrate hardness under foot and the amount of travel typical for the population. Feet were radiographed and photographed and 40 morphometric measurements of each foot were obtained. RESULTS: Of the 40 parameters, 37 differed significantly (P < 0.05) among the populations, which suggested that substrate hardness and travel distance have an effect on foot morphology. Harder substrates and longer travel distances were associated with short hoof walls and minimal hoof wall flaring. Softer substrates and moderate travel distances were associated with long flared walls, similar to that of typical untrimmed feet of domestic horses. CONCLUSIONS: The morphology of the feral horse foot appeared to be affected by the distance travelled and by the abrasive qualities and mechanical properties of the substrate under foot. There were marked differences in some conformation parameters between the feral horses in the current study and domestic horses in previous studies. Although the conformation of the feral horse foot may have some prescriptive value, concerns regarding abnormal foot anatomy warrant further investigation. PMID- 23356368 TI - The feral horse foot. Part B: radiographic, gross visual and histopathological parameters of foot health in 100 Australian feral horses. AB - BACKGROUND: It has been proposed that the feral horse foot is a benchmark model for foot health in horses. However, the foot health of feral horses has not been formally investigated. OBJECTIVES: To investigate the foot health of Australian feral horses and determine if foot health is affected by environmental factors, such as substrate properties and distance travelled. METHODS: Twenty adult feral horses from five populations (n = 100) were investigated. Populations were selected on the basis of substrate hardness and the amount of travel typical for the population. Feet were radiographed and photographed, and digital images were surveyed by two experienced assessors blinded to each other's assessment and to the population origin. Lamellar samples from 15 feet from three populations were investigated histologically for evidence of laminitis. RESULTS: There was a total of 377 gross foot abnormalities identified in 100 left forefeet. There were no abnormalities detected in three of the feet surveyed. Each population had a comparable prevalence of foot abnormalities, although the type and severity of abnormality varied among populations. Of the three populations surveyed by histopathology, the prevalence of chronic laminitis ranged between 40% and 93%. CONCLUSIONS: Foot health appeared to be affected by the environment inhabited by the horses. The observed chronic laminitis may be attributable to either nutritional or traumatic causes. Given the overwhelming evidence of suboptimal foot health, it may not be appropriate for the feral horse foot to be the benchmark model for equine foot health. PMID- 23356369 TI - Resolution of hyphaema following intracameral injection of tenecteplase in a Stock Horse. AB - Intracameral injection of tissue plasminogen activator has been suggested as a means of hastening the clearance of blood from the anterior chamber and reducing the risk of synechia and fibrotic membrane formation in horses with hyphaema. The following report describes a case of ocular trauma in which intracameral injection of tenecteplase (TNK), a new-generation plasminogen activator, resulted in rapid resolution of hyphaema and successful outcome. However, a large dose (1 mg) was administered and may have been associated with retinopathy and keratopathy. TNK may be an effective treatment for equine hyphaema and further controlled clinical or experimental studies are required to determine its efficacy and safety profiles. PMID- 23356370 TI - Cat admissions to RSPCA shelters in Queensland, Australia: description of cats and risk factors for euthanasia after entry. AB - OBJECTIVE: A lack of information limits understanding of the excess cat problem and development of effective management strategies. This study describes cats entering Royal Society for the Prevention of Cruelty to Animals (RSPCA) Queensland shelters and identifies risk factors for euthanasia. METHODS: Data for cats entering relevant shelters (July 2006-June 2008) were obtained from the RSPCA's electronic database. Univariable and multivariable logistic regression analyses were conducted to identify risk factors for euthanasia. RESULTS: Of 33,736 cats admitted, 46% were adult cats (>=3 months) and 54% were kittens (<3 months). The most common reason for admission was stray (54%), followed by owner surrender (44%). Euthanasia was the most common outcome (65%), followed by adoption (30%). The odds of euthanasia were lower for kittens and for cats that were desexed prior to admission. Of the strays, 8% had been desexed. For cats of similar age, sex, desexed and feral status, stray cats were more likely to be adopted than owner-surrenders. CONCLUSIONS: Strategies are needed to reduce numbers of cats admitted and euthanased. Given the high proportion of admissions that were kittens, reducing the incidence of delayed sterilisation of owned cats may be an important strategy for reducing the number of unwanted kittens. Many cats admitted as strays were rehomable, but given the high proportion of admissions that are strays, further research on stray populations is needed. Future studies of cats entering shelters would be enhanced if data collection definitions, categories and methods were standardised. PMID- 23356371 TI - Identification and antibiotic susceptibility of bacterial isolates from dogs with otitis externa in Australia. AB - OBJECTIVE: To identify and quantify the five most frequently isolated significant bacterial microorganisms, and their antibiotic susceptibility, from bacterial cultures of samples taken from the ears of dogs with otitis externa. METHODS: Bacterial culture and susceptibility testing data for ear swabs from dogs with presumed otitis externa were collated and evaluated. RESULTS: The five most frequently isolated microorganisms were: Pseudomonas aeruginosa, Staphylococcus pseudintermedius, Proteus sp., beta-haemolytic streptococci and Escherichia coli. Susceptibility to gentamicin was very high for most isolates, whereas for polymyxin B, high levels of resistance were seen. Beta-haemolytic streptococci had high levels of resistance to all of the antibiotics tested. CONCLUSIONS: This study provides veterinarians with Australian data to assist in cytological interpretation and initial empirical therapy of canine otitis externa. PMID- 23356372 TI - Syncope associated with swallowing in two British Bulldogs with unilateral carotid body tumours. AB - Carotid body tumours were diagnosed in two British Bulldogs that each had a history of syncopal episodes induced by eating, drinking or pulling on the leash. In both dogs, a cervical mass was identified using computed tomography (CT) or magnetic resonance imaging, with carotid body tumour (CBT) being the histopathological diagnosis. A heart base mass was also identified in one dog by both CT and echocardiography. Swallowing syncope has been reported in the human literature in association with cervical mass lesions, but this is the first report in dogs. The present cases emphasise the value of advanced imaging of the head and neck in dogs presenting with clinical signs of syncope associated with swallowing and the importance of careful manipulation of the neck in patients with CBTs. PMID- 23356373 TI - Validation and evaluation of a commercially available ELISA for the detection of antibodies specific to bovine viral diarrhoea virus (bovine pestivirus). AB - OBJECTIVE: To compare the performance of an enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies specific to bovine viral diarrhoea virus (BVDV) with a virus neutralisation test (VNT) and agarose gel immunodiffusion (AGID) test. DESIGN: A total of 125 cattle serum samples were tested by a commercially available ELISA for antibodies specific to BVDV and by a VNT as the reference standard. A comparison between AGID and ELISA for detection of BVDV antibodies was also carried out, using 1182 serum samples from unvaccinated South Australian cattle. METHODS: Two-graph receiver operating characteristics (TG-ROC) analysis was used to confirm that the manufacturer's recommended cut-off value for the ELISA was appropriate. Two-by-two tables were constructed to analyse the concordance of serological results among the three assays. McNemar tests were used to assess the agreement among serological tests. RESULTS AND CONCLUSIONS: Using the manufacturer's cut-off threshold, supported by TG-ROC analysis, the ELISA's sensitivity and specificity were calculated to be 96.7% and 97.1%, respectively, compared with the VNT. Compared with AGID, ELISA with specific BVDV antibodies may be more sensitive and detect 5.8% more samples than AGID. McNemar test also showed a significant difference (P < 0.001) between AGID and ELISA. PMID- 23356374 TI - Serious injuries to Australian veterinarians working with cattle. AB - OBJECTIVE: To describe the factors associated with serious injuries sustained during cattle-associated activities by veterinarians responding to the Health Risks of Australian Veterinarians (HRAV) survey. METHODS: Responses from the HRAV survey were reviewed and the factors associated with serious injuries reported by veterinarians while working with cattle were analysed. All veterinarians who had graduated from Australian veterinary schools between 1960 and 2000 were eligible for inclusion in the survey. RESULTS: The survey identified 474 serious injuries sustained while undertaking cattle-associated activities. Most cattle-associated injuries (82%) were sustained in stock or handling yards and 57% of reported injuries were sustained while undertaking pregnancy testing or undertaking examinations. Nearly 80% of all cattle-associated injuries were sustained as a result of the veterinarian being kicked or struck (49%) or pushed against or stepped on (30%). The part of the body most commonly injured was the upper limbs. Fractures were the most common type of serious injury sustained. The use of safety precautions at the time of the injury was reported by 62% of those veterinarians reporting injury. CONCLUSIONS: This study describes factors associated with serious injuries while working with cattle, as reported by veterinarians responding to the HRAV survey. Findings from this study will facilitate discussions aimed at addressing injury prevention for cattle veterinarians, including improving the awareness of safe handling practices and safety precautions. PMID- 23356375 TI - Response to laboratory selection with cyromazine and susceptibility to alternative insecticides in sheep blowfly larvae from the New South Wales Monaro. AB - OBJECTIVE: To determine the significance of cyromazine resistance in blowfly larvae from a region where resistance has been previously confirmed and to measure susceptibility of the cyromazine-resistant blowflies to ivermectin and spinosad. METHODS: Blowfly larvae from five properties located within 5 km of where cyromazine-resistant Lucilia cuprina were detected in 2011 were tested for resistance to cyromazine. The original cyromazine-resistant 'Nimmitabel' strain was reared for 13 generations on homogenised liver containing cyromazine at a concentration lethal to susceptible larvae. Larval development bioassays in which batches of neonate larvae were transferred onto homogenised bovine liver containing cyromazine or dicyclanil were used to determine whether the level of resistance had increased. The sensitivities of the 'Nimmitabel' strain to ivermectin and spinosad were also measured. RESULTS: Cyromazine-resistant larvae were identified in samples from four of the five properties near to the site of the original resistance detection. The 'Nimmitabel' strain responded to laboratory selection by becoming more resistant to cyromazine (8*) and to dicyclanil (3*). No larvae died after feeding on homogenate containing cyromazine at a concentration lethal to susceptible larvae. There was no cross-resistance to ivermectin or spinosad in the 'Nimmitabel' strain. CONCLUSION: The modest increases in resistance to cyromazine and dicyclanil following laboratory selection suggest that unless the situation worsens considerably, it is unlikely that this resistance will have a significant effect on flystrike protection provided by these insecticides if applied as directed on product labels. Moreover, cyromazine-resistant larvae remained susceptible to ivermectin and spinosad. PMID- 23356376 TI - Development of a chick bioassay for determination of infectivity of viral pathogens in poultry litter. AB - OBJECTIVE: To develop a chicken bioassay to detect infective viral pathogens in poultry litter and to determine the effects of type of chicken and age of exposure, as well as the effect of simulated litter transportation, on the level of viral infectivity detected. DESIGN: A 5 * 2 * 2 factorial design, plus negative controls. Five chicken litters, including two with deliberate contamination (one transported and one not), two chicken types (specific-pathogen free (SPF) Leghorns and Cobb broilers) and two ages at initial exposure (days 1 and 8). Two replicates of each treatment combination. METHODS: The 10 chickens in each of 22 isolators were either exposed (20 isolators) or not (2 isolators) to 8 L of previously used or deliberately contaminated poultry litter in two deep scratch trays. At day 35 post-exposure, sera were assayed for antibodies against chicken anaemia virus (CAV), infectious bronchitis virus (IBV), infectious bursal disease virus (IBDV), Newcastle disease virus (NDV) and fowl adenovirus (FAV). Spleen samples were tested for Marek's disease virus (MDV) using real-time polymerase chain reaction. RESULTS: The bioassay detected CAV, IBDV and FAV, but not NDV, IBV or MDV, in chickens exposed to infected litters. Infection in SPF chickens was detected with greater sensitivity than in the broiler chickens. Sensitivity increased with age at exposure in broiler but not SPF chickens. Simulated transportation for 24 h had little effect on pathogen detection. CONCLUSION: A bioassay based on the exposure of day-old SPF chickens to poultry litter and measurement of seroconversion at day 35 post-exposure is a useful semi quantitative assay for viral infectivity in poultry litter, with overnight transportation of litter having little effect on the level of viral infectivity detected. This bioassay has applications in research on litter treatment protocols. PMID- 23356378 TI - Hydraulic limits on maximum plant transpiration and the emergence of the safety efficiency trade-off. AB - Soil and plant hydraulics constrain ecosystem productivity by setting physical limits to water transport and hence carbon uptake by leaves. While more negative xylem water potentials provide a larger driving force for water transport, they also cause cavitation that limits hydraulic conductivity. An optimum balance between driving force and cavitation occurs at intermediate water potentials, thus defining the maximum transpiration rate the xylem can sustain (denoted as E(max)). The presence of this maximum raises the question as to whether plants regulate transpiration through stomata to function near E(max). To address this question, we calculated E(max) across plant functional types and climates using a hydraulic model and a global database of plant hydraulic traits. The predicted E(max) compared well with measured peak transpiration across plant sizes and growth conditions (R = 0.86, P < 0.001) and was relatively conserved among plant types (for a given plant size), while increasing across climates following the atmospheric evaporative demand. The fact that E(max) was roughly conserved across plant types and scales with the product of xylem saturated conductivity and water potential at 50% cavitation was used here to explain the safety-efficiency trade off in plant xylem. Stomatal conductance allows maximum transpiration rates despite partial cavitation in the xylem thereby suggesting coordination between stomatal regulation and xylem hydraulic characteristics. PMID- 23356379 TI - Organizational stressors associated with job stress and burnout in correctional officers: a systematic review. AB - BACKGROUND: In adult correctional facilities, correctional officers (COs) are responsible for the safety and security of the facility in addition to aiding in offender rehabilitation and preventing recidivism. COs experience higher rates of job stress and burnout that stem from organizational stressors, leading to negative outcomes for not only the CO but the organization as well. Effective interventions could aim at targeting organizational stressors in order to reduce these negative outcomes as well as COs' job stress and burnout. This paper fills a gap in the organizational stress literature among COs by systematically reviewing the relationship between organizational stressors and CO stress and burnout in adult correctional facilities. In doing so, the present review identifies areas that organizational interventions can target in order to reduce CO job stress and burnout. METHODS: A systematic search of the literature was conducted using Medline, PsycINFO, Criminal Justice Abstracts, and Sociological Abstracts. All retrieved articles were independently screened based on criteria developed a priori. All included articles underwent quality assessment. Organizational stressors were categorized according to Cooper and Marshall's (1976) model of job stress. RESULTS: The systematic review yielded 8 studies that met all inclusion and quality assessment criteria. The five categories of organizational stressors among correctional officers are: stressors intrinsic to the job, role in the organization, rewards at work, supervisory relationships at work and the organizational structure and climate. The organizational structure and climate was demonstrated to have the most consistent relationship with CO job stress and burnout. CONCLUSIONS: The results of this review indicate that the organizational structure and climate of correctional institutions has the most consistent relationship with COs' job stress and burnout. Limitations of the studies reviewed include the cross-sectional design and the use of varying measures for organizational stressors. The results of this review indicate that interventions should aim to improve the organizational structure and climate of the correctional facility by improving communication between management and COs. PMID- 23356380 TI - Asynchronous web-based learning, a practical method to enhance teaching in emergency medicine. AB - Abstract Objective: To compare medical knowledge acquisition among emergency medicine (EM) residents who attend weekly core content lectures with those absent but asynchronously viewing the same lectures in a Web-based electronic platform. SUBJECTS AND METHODS: During the study period all EM residents attending or absent from weekly educational conferences were given a quiz on the covered material. During Phase 1, absentees were not given supplemental educational content for missed lectures. During Phase 2, absentees were sent a link to an online multimedia module containing an audiovisual recording of the actual missed lecture with presentation slides. Scores between attendees and absentees during both phases were compared using a repeated-measures analysis to evaluate the effect of the supplemental online module on knowledge acquisition. RESULTS: Thirty-nine EM residents (equally distributed in postgraduate years 1-4) were studied during a 15-week period. Overall and after adjusting for sex and postgraduate year level, both lecture attendance (b=27; 95% confidence interval, 22-32; p<0.0001) and Web-based learning (b=32; 95% confidence interval, 26-37; p<0.0001) were associated with significant increases in test scores compared with residents who were absent and not receiving supplemental Web-based learning. Neither the self-perceived level of mastery with the lecture topic nor the amount of reported reading was found to be a predictor of test scores. CONCLUSIONS: In an EM residency program, asynchronous Web-based learning may result in medical knowledge acquisition similar to or better than attending traditional core content lectures. The percentage of curriculum delivery by asynchronous learning that may be used to achieve overall terminal learning objectives in medical knowledge acquisition requires further study. PMID- 23356381 TI - Teledentistry: distant diagnosis of oral disease using e-mails. AB - OBJECTIVE: The purpose of this study was to evaluate the applicability of telediagnosis in oral medicine, through the transmission of clinical digital images by e-mail. SUBJECTS AND METHODS: The sample included 60 consecutive patients who sought oral medicine services at the Federal University of Parana, in the state of Parana, located in southern Brazil. The clinical history and oral lesion images were recorded using clinical electronic charts and a digital camera, respectively, and sent by e-mail to two oral medicine consultants. The consultants provided a maximum of two clinical hypotheses for each case, which were compared with biopsy results that served as the gold standard. RESULTS: In 31 of the 60 cases (51.7%), both consultants made the correct diagnosis; in 17 cases (28.3%), only one consultant made the correct diagnosis; and in 12 cases (20%), neither consultant made the correct diagnosis. Therefore, in 80% of cases, at least one consultant provided the correct diagnosis. The agreement between the first consultant and the gold standard was substantial (kappa=0.669), and the agreement between the second consultant and the gold standard was fair (kappa=0.574). CONCLUSIONS: The use of information technology can increase the accuracy of consultations in oral medicine. As expected, the participation of two remote experts increased the possibility of correct diagnosis. PMID- 23356382 TI - Nursing interventions in a telemonitoring program. AB - BACKGROUND: The use of telemonitoring of patients with chronic illness in their homes is growing. Current literature does not describe what types of patient problems are addressed by nurses in these programs and what actions are taken in response to identified problems. This study defined and analyzed patient problems and nursing actions delivered in a telemonitoring program focused on chronic disease management. SUBJECTS AND METHODS: Data were drawn from a clinical trial that evaluated telemonitoring in patients with comorbid diabetes and hypertension. Using study patient records, patient problems and nursing actions were coded using an inductive approach. RESULTS: In total, 2,336 actions were coded for 68 and 65 participants in two intervention groups. The most frequent reasons for contact were reporting information to the primary care provider and lifestyle information related to diabetes and hypertension (e.g., diet, smoking cessation, foot care, and social contacts). The most frequent mode of contact was the study sending a letter to a participant. CONCLUSIONS: Detailed descriptions of interventions delivered facilitate analysis of the unique contributions of nurses in the expanding market of telemonitoring, enable identification of the appropriate number and combination of interventions needed to improve outcomes, and make possible more systematic translation of findings to practice. Furthermore, this information can inform calculation of appropriate panel sizes for care managers and the competencies needed to provide this care. PMID- 23356383 TI - Use of telemedicine to diagnose tinea in Kenyan schoolchildren. AB - OBJECTIVE: Internet-based telemedicine has the potential to alleviate the problem of limited access to healthcare in developing countries. The Mashavu project aims to deploy kiosks that transmit health data and pictures from patients in underdeveloped countries who have no immediate access to healthcare to clinics for analysis by trained personnel. To test this principle, we investigated whether dermatophytic fungal infections (tinea) could be diagnosed by Kenyan clinicians solely from pictures of the lesions. SUBJECTS AND METHODS: Six physicians, five physician assistants, and five nurses from Nyeri Provincial Hospital took a test consisting of 15 pictures of potassium hydroxide (KOH) prep confirmed tinea lesions and 15 pictures of KOH prep-negative lesions obtained from local children. RESULTS: The mean (standard deviation) sensitivity and specificity for the whole group were 73% (19%) and 83% (11%), respectively. The physicians had the highest sensitivity and specificity, although only sensitivity reached statistical significance when compared with physician assistants. CONCLUSIONS: These results suggest that telemedicine can be used to diagnose simple skin conditions in a low resource setting with reasonable sensitivity and specificity. PMID- 23356384 TI - Metacognitive beliefs and processes in clinical anxiety in children. AB - Recent research has explored the role of metacognitive beliefs and processes in clinical anxiety in youth. The aim of this study was to examine the relationship between metacognitions and anxiety in 7- to 12-year-old children with and without clinical anxiety disorders. A secondary aim of the study was to investigate the psychometric properties of the recently developed Metacognitions Questionnaire for Children (MCQ-C). The sample consisted of 83 children (60.2% female; Oceanian 71.1%), comprising 49 children with anxiety disorders and 34 nonclinical children. All children completed self-report measures of anxiety, emotional difficulties, and metacognitions. A subsample of 7- to 8-year-old participants was used to explore whether young children could wholly comprehend all items on the MCQ-C. Positive and negative metacognitive beliefs and cognitive monitoring were significantly correlated with anxiety and emotional difficulties. Clinical children endorsed significantly more negative and more positive metacognitive beliefs than nonclinical children. Each subscale of the MCQ-C had poor internal consistency. Support for the criterion and convergent validity of the MCQ-C was found. The results suggest that certain metacognitions play a role in clinical anxiety in children but that psychometrically and developmentally validated measures of these concepts in younger individuals are needed. PMID- 23356385 TI - Synthesis, spectroscopic, and analyte-responsive behavior of a polymerizable naphthalimide-based carboxylate probe and molecularly imprinted polymers prepared thereof. AB - A naphthalimide-based fluorescent indicator monomer 1 for the integration into chromo- and fluorogenic molecularly imprinted polymers (MIPs) was synthesized and characterized. The monomer was equipped with a urea binding site to respond to carboxylate-containing guests with absorption and fluorescence changes, namely a bathochromic shift in absorption and fluorescence quenching. Detailed spectroscopic analyses of the title compound and various models revealed the signaling mechanism. Titration studies employing benzoate and Z-L-phenylalanine (Z-L-Phe) suggest that indicator monomers such as the title compound undergo a mixture of deprotonation and complex formation in the presence of benzoate but yield hydrogen-bonded complexes, which are desirable for the molecular imprinting process, with weakly basic guests like Z-l-Phe. Compound 1 could be successfully employed in the synthesis of monolithic and thin-film MIPs against Z-L-Phe, Z-L glutamic acid, and penicillin G. Chromatographic assessment of the selectivity features of the monoliths revealed enantioselective discrimination and clear imprinting effects. Immobilized on glass coverslips, the thin-film MIPs of 1 displayed a clear signaling behavior with a pronounced enantioselective fluorescence quenching dependence and a promising discrimination against cross analytes. PMID- 23356387 TI - In situ strain-level detection and identification of Vibrio parahaemolyticus using surface-enhanced Raman spectroscopy. AB - The outer membrane of a bacterium is composed of chemical and biological components that carry specific molecular information related to strains, growth stages, expressions to stimulation, and maybe even geographic differences. In this work, we demonstrate that the biochemical information embedded in the outer membrane can be used for rapid detection and identification of pathogenic bacteria using surface-enhanced Raman spectroscopy (SERS). We used seven different strains of the marine pathogen Vibrio parahaemolyticus as a model system. The strains represent four genetically distinct clades isolated from clinical and environmental sources in Washington, U.S.A. The unique quasi-3D (Q3D) plasmonic nanostructure arrays, optimized using finite-difference time domain (FDTD) calculations, were used as SERS-active substrates for sensitive and reproducible detection of these bacteria. SERS barcodes were generated on the basis of SERS spectra and were used to successfully detect individual strains in both blind samples and mixtures. The sensing and detection methods developed in this work could have broad applications in the areas of environmental monitoring, biomedical diagnostics, and homeland security. PMID- 23356386 TI - Human monoclonal antibody MBL-HCV1 delays HCV viral rebound following liver transplantation: a randomized controlled study. AB - Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-alpha and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n=6) or placebo (n=5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log10 IU/mL) from baseline was significantly greater (p=0.02) for the antibody-treated group (range -3.07 to -3.34) compared to placebo group (range -0.331 to -1.01) on days 3 through 6 posttransplant. MBL-HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, p<0.001). As with other HCV monotherapies, antibody-treated subjects had resistance associated variants at the time of viral rebound. A combination study of MBL-HCV1 with a direct-acting antiviral is underway. PMID- 23356388 TI - Infrequent attention to dietary and physical activity behaviours in conversations in Swedish child health services. AB - AIM: To investigate conversations between nurses and parents in Swedish child health services and to assess to what extent attention is directed towards dietary and physical activity behaviours in children. METHODS: Twenty-three nurses audio-recorded one session each. Recordings were assessed and topics were classified according to predetermined categories. RESULTS: The three most frequent topics of conversation concerned physical examinations of the child (30% of session time), talking to the child to establish or maintain contact and interest (15%), and development of language skills (12%). Dietary habits came on fourth place (10%), and physical activity ranked 14 (4%). CONCLUSION: Attention to dietary and physical activity behaviours in children is infrequent in Swedish child health services. Concern is raised about the efficacy of prevention efforts against childhood obesity. PMID- 23356389 TI - Analysis of the inhibition potential of zosuquidar derivatives on selected bacterial and fungal ABC transporters. AB - The increasing number of multidrug-resistant pathogenic microorganisms is a serious public health issue. Among the multitude of mechanisms that lead to multidrug resistance, the active extrusion of toxic compounds, mediated by MDR efflux pumps, plays an important role. In our study we analyzed the inhibitory capability of 26 synthesized zosuquidar derivatives on three ABC-type MDR efflux pumps, namely Saccharomyces cerevisiae Pdr5 as well as Lactococcus lactis LmrA and LmrCD. For Pdr5, five compounds could be identified that inhibited rhodamine 6G transport more efficiently than zosuquidar. One of these is a compound with a new catechol acetal structure that might represent a new lead compound. Furthermore, the determination of IC(50) values for rhodamine 6G transport of Pdr5 with representative compounds reveals values between 0.3 and 0.9 MUM. Thus the identified compounds are among the most potent inhibitors known for Pdr5. For the ABC-type efflux pumps LmrA and LmrCD from L. lactis, seven and three compounds, which inhibit the transport activity more than the lead compound zosuquidar, were found. Interestingly, transport inhibition for LmrCD was very specific, with a drastic reduction by one compound while its diastereomers showed hardly an effect. Thus, the present study reveals new potent inhibitors for the ABC-type MDR efflux pumps studied with the inhibitors of Pdr5 and LmrCD being of particular interest as these proteins are well known model systems for their homologs in pathogenic fungi and Gram-positive bacteria. PMID- 23356390 TI - Contemporaneous comparison of open vs minimally-invasive radical prostatectomy for high-risk prostate cancer. AB - OBJECTIVES: To analyze pathological and short-term oncological outcomes in men undergoing open and minimally-invasive radical prostatectomy (MIRP) for high-risk prostate cancer (HRPC; prostate-specific antigen level [PSA] >20 ng/mL, >= cT2c, Gleason score 8-10) in a contemporaneous series. PATIENTS AND METHODS: In total, 913 patients with HRPC were identified in the Johns Hopkins Radical Prostatectomy Database subsequent to the inception of MIRP at this institution (2002-2011) Of these, 743 (81.4%) underwent open radical retropubic prostatectomy (ORRP), 105 (11.5%) underwent robot-assisted laparoscopic radical prostatectomy (RALRP) and 65 (7.1%) underwent laparoscopic radical prostatectomy (LRP) for HRPC. Appropriate comparative tests were used to evaluate patient and prostate cancer characteristics. Proportional hazards regression models were used to predict biochemical recurrence. RESULTS: Age, race, body mass index, preoperative PSA level, clinical stage, number of positive cores and Gleason score at final pathology were similar between ORRP and MIRP. On average, men undergoing MIRP had smaller prostates and more organ-confined (pT2) disease (P = 0.02). The number of surgeons and surgeon experience were greatest for the ORRP cohort. Overall surgical margin rate was 29.4%, 34.3% and 27.7% (P = 0.52) and 1.9%, 2.9% and 6.2% (P = 0.39) for pT2 disease in men undergoing ORRP, RALRP and LRP, respectively. Biochemical recurrence-free survival among ORRP, RALRP and LRP was 56.3%, 67.8% and 41.1%, respectively, at 3 years (P = 0.6) and the approach employed did not predict biochemical recurrence in regression models. CONCLUSIONS: At an experienced centre, MIRP is comparable to open radical prostatectomy for HRPC with respect to surgical margin status and biochemical recurrence. PMID- 23356392 TI - Accuracy of patient self-report as a measure of inhaled asthma medication use. AB - BACKGROUND AND OBJECTIVE: Measuring adherence to inhaled asthma treatment is a key priority for asthma care. The aim of this study was to determine the relationship between self-report and actual medication use as measured by electronic monitoring for single and combination inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA) metered-dose inhaler therapy. METHODS: In this retrospective analysis from a previously completed prospective 24-week randomized, controlled trial of single or combination ICS/LABA therapy, medication use in the week prior to study visits determined by self-report questionnaire and electronic monitoring was compared. One hundred eleven participants received 125 ug fluticasone dipropionate and 25 ug salmeterol, two actuations twice daily, by either separate or combination ICS/LABA inhalers. Paired data for self-report and electronic monitoring were analysed. Measurement of agreement was by Bland-Altman-like plots by visit with calculation of limits of agreement. RESULTS: For single and combination ICS/LABA therapy, self-report consistently overestimated actual inhaler use assessed by electronic monitoring by a mean of 2.2-8.4 inhalations over a 1-week period, with limits of agreement ranging from +/-15.8 to 25.6 inhalations. Participants who underused their inhalers tended to overreport their use, while those who overused tended to underreport their medication use. The greater the degree of underuse, the greater the magnitude of overreport, and likewise, the greater the degree of overuse, the greater the magnitude of underreport. CONCLUSIONS: Self-report is inaccurate in measuring actual use of inhaled asthma treatment with patients who underuse their maintenance therapy overreporting their use and those who overuse their therapy underreporting their use. PMID- 23356391 TI - The ADAMTS18 gene is responsible for autosomal recessive early onset severe retinal dystrophy. AB - BACKGROUND: Inherited retinal dystrophies, including Retinitis Pigmentosa and Leber Congenital Amaurosis among others, are a group of genetically heterogeneous disorders that lead to variable degrees of visual deficits. They can be caused by mutations in over 100 genes and there is evidence for the presence of as yet unidentified genes in a significant proportion of patients. We aimed at identifying a novel gene for an autosomal recessive form of early onset severe retinal dystrophy in a patient carrying no previously described mutations in known genes. METHODS: An integrated strategy including homozygosity mapping and whole exome sequencing was used to identify the responsible mutation. Functional tests were performed in the medaka fish (Oryzias latipes) model organism to gain further insight into the pathogenic role of the ADAMTS18 gene in eye and central nervous system (CNS) dysfunction. RESULTS: This study identified, in the analyzed patient, a homozygous missense mutation in the ADAMTS18 gene, which was recently linked to Knobloch syndrome, a rare developmental disorder that affects the eye and the occipital skull. In vivo gene knockdown performed in medaka fish confirmed both that the mutation has a pathogenic role and that the inactivation of this gene has a deleterious effect on photoreceptor cell function. CONCLUSION: This study reveals that mutations in the ADAMTS18 gene can cause a broad phenotypic spectrum of eye disorders and contribute to shed further light on the complexity of retinal diseases. PMID- 23356395 TI - Primary choriocarcinoma of the colon: a case report and review of the literature. AB - Choriocarcinoma usually arises in the uterus and gonads. Primary choriocarcinoma (PCC) in an extragenital organ is rare. When it occurs in the gastrointestinal tract, the stomach is the most common site. Only 12 cases of PCC of the colon have been reported in the world literature. Most cases were associated with adenocarcinoma. We report the case of a 36-year-old man with PCC of the colon and review the clinical characteristics of previously documented cases. PMID- 23356396 TI - Traffic routes and signals for the tonoplast. AB - Tonoplast, the membrane delimiting plant vacuoles, regulates ion, water and nutrient movement between the cytosol and the vacuolar lumen through the activity of its membrane proteins. Correct traffic of proteins from the endoplasmic reticulum (ER) to the tonoplast requires (i) approval by the ER quality control, (ii) motifs for exit from the ER and (iii) motifs that promote sorting to the tonoplast. Recent evidence suggests that this traffic follows different pathways that are protein-specific and could also reflect vacuole specialization for lytic or storage function. The routes can be distinguished based on their sensitivity to drugs such as brefeldin A and C834 as well as using mutant plants that are defective in adaptor proteins of vesicle coats, or dominant-negative mutants of Rab GTPases. PMID- 23356394 TI - An exceptionally simple strategy for DNA-functionalized up-conversion nanoparticles as biocompatible agents for nanoassembly, DNA delivery, and imaging. AB - Lanthanide-doped up-conversion nanoparticles (UCNPs) have shown promise in biomedical applications. However, as the UCNPs are normally capped with hydrophobic ligands, it remains challenging to prepare biocompatible UCNPs with specific molecular recognition capabilities. We herein report an exceptionally simple strategy to prepare uniform DNA-modified UCNPs as versatile bioprobes. The approach can directly convert as-prepared hydrophobic UCNPs into water-soluble DNA-UCNPs without any chemical modification of UCNPs or oligonucleotides. Furthermore, DNA molecules on the DNA-UCNPs retain their biorecognition ability, allowing programmable assembly of hybrid nanostructures. More importantly, we show that these DNA-UCNPs are capable of crossing cell membranes without the need of transfection agents, and their use as agents for bioimaging and DNA delivery are also demonstrated. Finally, DNA aptamer-conjugated UCNPs can be readily used for targeted imaging of cancer cells. PMID- 23356397 TI - Optic nerve head morphology in young patients after antiglaucomatous filtering surgery. AB - PURPOSE: To compare the optic nerve head appearance in glaucomatous eyes before and after marked reduction of intraocular pressure (IOP). METHODS: The hospital based observational case-series study included selected glaucoma patients for whom optic disc photographs taken before and 1 week to 5 months after surgical reduction of IOP were morphometrically examined. RESULTS: The study included 23 eyes of 16 patients (mean age: 28.7 +/- 6.0 years). Mean preoperative IOP was 31.6 +/- 7.7 mmHg (22-52 mmHg), and mean IOP drop was 21.5 +/- 8.4 mmHg (11-45 mmHg). The horizontal disc diameter decreased significantly (p < 0.001) after surgery, while the vertical disc diameter did not change markedly (p = 0.54). The width of the neuroretinal rim increased significantly in all disc quadrants (all p-values <= 0.01), optic cup depth decreased (p < 0.001), and reflectivity of the inner retinal surface increased significantly (p < 0.001). Some eyes showed a pronounced reduction in beta zone of parapapillary atrophy parallel to an increase in horizontal disc diameter, and some eyes showed an enlargement of beta zone parallel to a reduction in horizontal disc diameter. CONCLUSIONS: After marked reduction of high IOP, some eyes of young adult patients with glaucoma can show a horizontal shrinkage of the optic nerve head, in addition to a partial restoration of the neuroretinal rim and a flattening of the optic cup. In addition, beta zone of parapapillary atrophy can decrease or increase, complementarily to changes in the horizontal disc diameter. These findings may be of interest for the biomechanics of the optic nerve head and the precision of imaging techniques. PMID- 23356398 TI - Sequential photooxidation of a Pt(II) (diimine)cysteamine complex: intermolecular oxygen atom transfer versus sulfinate formation. AB - The thiolato complex [platinum(II) (bipyridine)(N,S-aminoethanethiolate)](+)Ch(-) (1) undergoes sequential reactions with singlet oxygen to initially form the corresponding sulfenato complex [platinum(II) (bipyridine)(N,S(?O) aminoethansulfenate)](+) (2) followed by a much slower reaction to the corresponding sulfinato complex. In contrast with many platinum dithiolato complexes, 1 does not produce any singlet oxygen, but its rate constant for singlet oxygen removal (k(T)) is quite large (3.2 * 10(7) M(-1) s(-1)) and chemical reaction accounts for ca. 25% of the value of k(T). The behavior of 1 is strikingly different from that of the complex platinum(II) (bipyridine)(1,2 benzenditholate) (4). The latter complex reacts with (1)O(2) (either from an external sensitizer or via a self-sensitized pathway) to form a sulfinato complex. These two very different reactivity pathways imply different mechanistic pathways: The reaction of 1 with (1)O(2) must involve O-O bond cleavage and intermolecular oxygen atom transfer, while the reactive intermediate in complex 4 collapses intramolecularly to the sulfinato moiety. PMID- 23356399 TI - Development of a validated UPLC-qTOF-MS Method for the determination of curcuminoids and their pharmacokinetic study in mice. AB - BACKGROUND: A specific and sensitive UPLC-qTOF-MS/MS method has been developed for the simultaneous determination of curcuminoids. These Curcuminoids comprises of curcumin, a principal curcuminoid and other two namely, demethoxycurcumin, and bisdemethoxycurcumin obtained from rhizomes of Curcuma longa an ancient Indian curry spice turmeric, family (Zingiberaceae). METHODS: These analytes were separated on a reverse phase C18 column by using a mobile phase of acetonitrile: 5% acetonitrile in water with 0.07% acetic acid (75:25 v/v), flow rate of 100 MUL/min was maintained. The qTOF-MS was operated under multiple reaction monitoring (MRM) mode using electro-spray ionization (ESI) technique with positive ion polarity. The major product ions in the positive mode for curcuminoids were at m/z 369.1066, 339.1023 and 309.0214 respectively. The recovery of the analytes from mouse plasma was optimized using solid phase extraction technique. RESULTS: The total run time was 5 min and the peaks of the compounds, bisdemethoxycurcumin, demethoxycurcumin and curcumin occurred at 2.06, 2.23 and 2.40 min respectively. The calibration curves of bisdemethoxycurcumin, demethoxycurcumin and curcumin were linear over the concentration range of 2-1000 ng/mL (r2, 0.9951), 2-1000 ng/mL (r2, 0.9970) and 2-1000 ng/mL (r2, 0.9906) respectively.Intra-assay and inter-assay accuracy in terms of % bias for curcumin was in between -7.95to +6.21, and -7.03 to + 6.34; for demethoxycurcumin was 6.72 to +6.34, and -7.86 to +6.74 and for bisdesmetoxycurcumin was -8.23 to +6.37 and -8.47 to +7.81. The lower limit of quantitation for curcumin, demethoxycurcumin and bisdemethoxycurcumin was 2.0 ng/mL. Analytes were stable under various conditions (in autosampler, during freeze-thaw, at room temperature, and under deep-freeze conditions). This validated method was used during pharmacokinetic studies of curcumin in the mouse plasma. CONCLUSIONS: A specific, accurate and precise UPLC-qTOF-MS/MS method for the determination of curcumin, demethoxycurcumin and bisdemethoxycurcumin both individually and simultaneously was optimized. PMID- 23356400 TI - Cell exclusion in couette flow: evaluation through flow visualization and mechanical forces. AB - Cell exclusion is the phenomenon whereby the hematocrit and viscosity of blood decrease in areas of high stress. While this is well known in naturally occurring Poiseuille flow in the human body, it has never previously been shown in Couette flow, which occurs in implantable devices including blood pumps. The high-shear stresses that occur in the gap between the boundaries in Couette flow are known to cause hemolysis in erythrocytes. We propose to mitigate this damage by initiating cell exclusion through the use of a spiral-groove bearing (SGB) that will provide escape routes by which the cells may separate themselves from the plasma and the high stresses in the gap. The force between two bearings (one being the SGB) in Couette flow was measured. Stained erythrocytes, along with silver spheres of similar diameter to erythrocytes, were visualized across a transparent SGB at various gap heights. A reduction in the force across the bearing for human blood, compared with fluids of comparable viscosity, was found. This indicates a reduction in the viscosity of the fluid across the bearing due to a lowered hematocrit because of cell exclusion. The corresponding images clearly show both cells and spheres being excluded from the gap by entering the grooves. This is the first time the phenomenon of cell exclusion has been shown in Couette flow. It not only furthers our understanding of how blood responds to different flows but could also lead to improvements in the future design of medical devices. PMID- 23356401 TI - How do general practitioners experience providing care to refugees with mental health problems? A qualitative study from Denmark. AB - BACKGROUND: Refugees are a particularly vulnerable group in relation to the development of mental illness and many may have been subjected to torture or other traumatic experiences. General practitioners are gatekeepers for access to several parts of the psychiatric system and knowledge of their patients' refugee background is crucial to secure adequate care. The aim of this study is to investigate how general practitioners experience providing care to refugees with mental health problems. METHODS: The study was conducted as part of an EU project on European Best Practices in Access, Quality and Appropriateness of Health Services for Immigrants in Europe (EUGATE). Semi-structured interviews were carried out with nine general practitioners in the vicinity of Copenhagen purposively selected from areas with a high proportion of immigrants. The analysis of the interviews is inspired by qualitative content analysis. RESULTS: One of the main themes identified in the analysis is communication. This includes the use of professional interpreters and that communication entails more than sharing a common language. Quality of care is another theme that emerges and includes awareness of possible trauma history, limited possibilities for refugees to participate in certain treatments due to language barriers and feelings of hopelessness in the general practitioners. The general practitioners may also choose different referral pathways for refugees and they report that their patients lack understanding regarding the differences between psychological problems and physical symptoms. CONCLUSION: General practitioners experience that providing care to refugees differs from providing care for patients from the majority population. The different strategies employed by the general practitioners in the health care treatment of refugees may be the result of the great diversity in the organisation of general practice in Denmark and the lack of a national strategy in the health care management of refugees. The findings from this study suggest that the development of conversational models for general practitioners including points to be aware of in the treatment of refugee patients may serve as a support in the management of refugee patients in primary care. PMID- 23356402 TI - Langmuir monolayers of monocationic lipid mixed with cholesterol or fluorocholesterol: DNA adsorption studies. AB - Monolayers of the cationic lipid DOTAP (1,2-dioleoyl-3-trimethylammonium-propane) and cholesterol or heptafluorocholesterol were prepared, and their interaction with DNA was characterized. The mixture of DOTAP with each of the sterols at 1:1 molar ratios leads to monolayers in a liquid expanded state, similarly to that of DOTAP alone. The area per molecule of the mixtures was smaller than that expected according to the additivity rule applicable if the two components are either completely miscible or immiscible within the monolayer. The observed negative deviation from the additivity indicates the existence of additional attractive interactions between the components. The surface potential of DOTAP monolayer is positive (+560 mV). It decreases only slightly after the addition of cholesterol (+540 mV) but drastically after the addition of heptafluorocholesterol (+20 mV) in the 1:1 mixtures at a surface pressure of 35 mN/m. This difference is attributed to the negative dipole moment of the fluorinated component. The adsorption of DNA is similar for both systems, which supports the possibility of using fluorinated cholesterol as helper lipid in DNA transfection vectors. PMID- 23356403 TI - Extracorporeal shockwave therapy shows a number of treatment related chondroprotective effect in osteoarthritis of the knee in rats. AB - BACKGROUND: Extracorporeal shockwave therapy (ESWT) shows chondroprotective effect in osteoarthritis of the rat knees. However, the ideal number of ESWT is unknown. This study investigated the effects of different numbers of ESWT in osteoarthritis of the knee in rats. METHODS: Forty-five male Sprague-Dawley rats were divided into five groups. Group I underwent sham arthrotomy without anterior cruciate ligament transection (ACLT) or medial meniscectomy (MM) and received no ESWT. Group II underwent ACLT + MM and received no ESWT. Group III underwent ACLT + MM, and received ESWT once a week for one treatment. Group IV underwent ACLT + MM and received ESWT twice a week for 2 treatments. Group V underwent ACLT + MM and received ESWT three times a week for 3 treatments. Each treatment consisted of 800 impulses of shockwave at 14 Kv to the medial tibia condyle. The evaluations included radiographs of the knee, histomorphological examination and immunohistochemical analysis at 12 weeks. RESULTS: At 12 weeks, group II and V showed more radiographic arthritis than groups I, III and IV. On histomorphological examination, the Safranin O matrix staining in groups III and IV are significantly better than in groups II and V, and the Mankin scores in groups III and IV are less than groups II and V. Groups III and IV showed significant decreases of Mankin score and increase of Safranin O stain as compared to group I. Group V showed significant increases of Mankin score and a decrease of Safranin O stain as compared to group II. In articular cartilage, group II showed significant increase of MMP13 and decrease of collagen II as compared to group I. Groups III and IV showed significant decrease of MMP13 and increase of collagen II as compared to group I. Group V showed significant increase of MMP13 and decrease of collagen II as compared to group II. In subchondral bone, vWF, VEGF, BMP-2 and osteocalcin significantly decreased in groups II and V, but increased in groups III and IV relative to group I. CONCLUSIONS: ESWT shows a number of treatment related chondroproctective effect in osteoarthritis of the knee in rats. PMID- 23356404 TI - Xerostomia in hereditary gelsolin amyloidosis. AB - Hereditary gelsolin amyloidosis (AGel amyloidosis) is a rare, dominantly inherited systemic disease with worldwide distribution, caused by c.654G > A or c.654G > T gelsolin gene mutation. The disease mainly manifests with late-onset dystrophy of the cornea, laxity of the skin and dysfunction of the cranial nerves whereas the oral manifestations have remained less-studied. To examine if AGel amyloidosis also affects salivary gland function, we studied 27 patients. In a questionnaire, 89% of them reported oral dryness, and 74% oral and ocular dryness. Unstimulated (UWS) and stimulated whole salivary flow (SWS) rates were measured, and salivary proteins were analyzed in the patients and controls. Hyposalivation according to UWS was detected in 67% of the patients, while decreased SWS occurred in 63% of the patients and 19% of the controls (p = 0.001). The secretion rates of salivary total protein and IgA were significantly lower in patients than controls. Histopathological analyses of labial salivary gland biopsies showed deposition of gelsolin amyloid, atrophy and inflammation. This study showed that AGel amyloidosis belongs to the differential diagnostic choices to be kept in mind in the patients presenting with xerostomia, low secretion rates of salivary total protein and IgA and/or deposition of amyloid in the minor salivary glands. AGel amyloidosis patients should be advised for efficient dental care. PMID- 23356405 TI - The HSP90 inhibitor NVP-AUY922-AG inhibits the PI3K and IKK signalling pathways and synergizes with cytarabine in acute myeloid leukaemia cells. AB - Heat shock protein 90 (HSP90; HSP90AA1) is a molecular chaperone involved in signalling pathways for cell proliferation, survival, and cellular adaptation. Inhibitors of HSP90 are being examined as anti-cancer agents, but the critical molecular mechanism(s) of their activity remains unresolved. HSP90 inhibition potentially facilitates the simultaneous targeting of multiple molecules within tumour cells and represents an attractive therapeutic proposition. Here, we investigated HSP90 as a molecular target for acute myeloid leukaemia (AML) using the novel HSP90 inhibitor NVP-AUY922-AG. NVP-AUY922-AG induced dose-dependent killing in myeloid cell lines and primary AML blasts. In primary blasts, cell death in response to NVP-AUY922-AG was seen at concentrations almost 2 logs lower than cytarabine (Ara-C) (50% lethal dose = 0.12 MU mol/l +/- 0.28). NVP-AUY922-AG was significantly less toxic to normal bone marrow (P = 0.02). In vitro response to NVP-AUY922-AG did not correlate with response to Ara-C (r(2) = 0.0006). NVP AUY922-AG was highly synergistic with Ara-C in cell lines and in 20/25 of the primary samples tested. NVP-AUY922-AG induced increases in HSP70 expression and depletion of total AKT, IKKalpha and IKKbeta in cell lines and primary blasts. This study shows that the novel HSP90 inhibitor NVP-AUY922-AG has significant single agent activity in AML cells and is synergistic with Ara-C. PMID- 23356406 TI - Synthesis and biological evaluation of asymmetric indole curcumin analogs as potential anti-inflammatory and antioxidant agents. AB - Abstract A series of asymmetric indole curcumin analogs were synthesized and evaluated as possible inhibiters of pro-inflammatory enzymes such as COX-2, pro inflammatory cytokines as TNF-alpha and IL-6, trypsin and beta-glucuronidase. They were also tested for antioxidant activities. The results showed that compounds 5e and 5h were found to be the most potent inhibitors of COX-2 (83.33%, 82.50%) and beta-glucuronidase (67.80%, 64.12%). All the synthesized compounds exhibited promising activity against IL-6 in a range of 71-100% at 10 uM concentration. Compounds 5f, 5h, 5e, 5c and 5d showed significant inhibition against TNF-alpha (28-51%) and IL-6 (87-98%) with low toxicity (45-51%) against CCK-8 cells. With few exceptions, all other compounds were found to be good to excellent inhibitors of IL-6 and moderate inhibitors of TNF-alpha; however, the toxicity profiles of these compounds need to be ameliorated in further optimization studies. Amongst the tested compounds, 5c, 5b, 5j and 5g were found to possess excellent reducing activity and 5b, 5c and 5h were moderate DPPH (1,1 diphenyl-2-picryl hydrazine) radical scavengers. PMID- 23356407 TI - Galectin-1 prolongs survival of mouse liver allografts from Flt3L-pretreated donors. AB - Liver allografts are spontaneously accepted across MHC barriers in mice. The mechanisms underlying this phenomenon remain poorly understood. Galectin-1, an endogenous lectin expressed in lymphoid organs, plays a vital role in maintaining central and peripheral tolerance. This study was to investigate the role of galectin-1 in spontaneous tolerance of liver allografts in mice, and to evaluate the therapeutic effects of galectin-1 on liver allograft rejection induced by donor Flt3L pretreatment. Blockade of the galectin-1 pathway via neutralizing antigalectin-1 mAb did not affect survival of the liver allografts from B6 donors into C3H recipients. Administration of rGal-1 significantly prolonged survival of liver allografts from Flt3L-pretreated donors and ameliorated Flt3L-triggered liver allograft rejection. This effect was associated with increased apoptosis of T cells in both allografts and spleens, decreased frequencies of Th1 and Th17 cells, decreased expression of Th1-associated cytokines (IL-12, IL-2 and IFN gamma), Th17-associated cytokines (IL-23 and IL-17) and granzyme B, in parallel with selectively increased IL-10 expression in liver allografts. In vitro, galectin-1 inhibited Flt3L-differentiated DC-mediated proliferation of allo CD4(+) T cells and production of IFN-gamma and IL-17. These data provide new evidence of the potential regulatory effects of galectin-1 in alloimmune responses in a murine model of liver transplantation. PMID- 23356408 TI - A new approach for diffusive sampling based on SPME for occupational exposure assessment. AB - Passive sampling is a well-established methodology for the evaluation of exposures to environmental volatile organic compounds (VOCs). The solid-phase microextraction (SPME) technique is a reliable means of sampling VOCs in air. SPME is also being applied as a passive sampler to determine time-weighted average exposure. The use of SPME as a diffusive sampler was evaluated. The passive sampler is based on the use of a cylindrical diffusion cell (porous hydrophobic polyethylene) with an 80 MUm carboxen/polydimethylsiloxane fiber to obtain radial diffusion of the analytes to the sorbent. Standard atmospheres of organic vapors in air were used to determine the experimental uptake rates for toluene and chlorobenzene. Toluene concentrations between 2 and 38 mg/m(3) with sampling times between 15 and 60 min were evaluated, as well as chlorobenzene concentrations between 2 and 47 mg/m(3) with sampling times between 30 and 60 min. The mean diffusive uptake rate was 2.14 mL/min for toluene and 2.57 mL/min for chlorobenzene, and no statistical significant effects of concentration and sampling time were observed under the studied conditions for the two compounds. Relative standard deviation ranged from 2.6 to 6.5%. The performance of the sampler under varying concentrations of toluene was also tested, showing that the sampler reflects the average exposure concentration. Effects of temperature, relative humidity, velocity of the air, back diffusion, competitive adsorption, and the stability of chlorobenzene in the sampler were also studied. Sampler behavior was tested in gas stations, and the results were successfully compared with a 3M-3500 diffusive sampler. The results are promising for using this new SPME device for diffusive monitoring for occupational exposure assessment. PMID- 23356409 TI - Classification of broncholiths and clinical outcomes. AB - BACKGROUND AND OBJECTIVE: We evaluated effective treatments of broncholithiasis based on its radiographical and bronchoscopic features. METHODS: This retrospective study conducted at Samsung Medical Center, Korea enrolled patients who were suspected of having broncholithiasis based on chest computed tomography (CT). The broncholiths were classified as intraluminal, mixed (both intraluminal and extraluminal) and extraluminal based on chest CT and bronchoscopic findings. RESULTS: The study enrolled 46 patients between 1995 and 2009. Symptoms included cough (n = 21, 45.7%), hemoptysis (n = 19, 41.3%) and purulent sputum (n = 11, 23.9%). Cough was more common in intraluminal boncholiths than in other type of broncholiths (P = 0.03). Based on chest CT, there were 15 (32.6%) intraluminal, 15 (32.6%) mixed and 16 (34.8%) extraluminal broncholiths. All 15 intraluminal broncholiths were removed completely via flexible (n = 2) or rigid (n = 13) bronchoscopy. For the 15 mixed broncholiths, seven (46.7%) bronchoscopic interventions were performed, but complete removal of the broncholiths was not accomplished. Six (40%) mixed and four (25%) extraluminal broncholiths were treated by surgical resection for symptom control. None of the patients who underwent surgical resection suffered morbidity or postoperative mortality. CONCLUSIONS: The treatment of broncholithiasis should be based on chest CT and bronchoscopic findings. Intraluminal broncholiths can be removed via bronchoscopy, while surgery should be considered for symptomatic mixed or extraluminal broncholiths. PMID- 23356411 TI - Bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC): a review of the literature and a practical approach to therapy. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Bladder preservation therapies for muscle-invasive bladder cancer (MIBC) have been developed to address the needs of two cohorts: patients with severe medical co-morbidities for whom radical cystectomy is too high risk and patients with limited disease who wish to avoid aggressive surgery. There are multiple bladder preservation options, although the trimodal approach of maximal transurethral resection with chemoradiotherapy is the most strongly supported. While outcomes are worse for patients unfit for surgery than those otherwise fit for surgery, bladder preservation approaches still offer curative potential. We present a comprehensive review of the literature and outline a practical approach to bladder preservation therapy for MIBC. This review aims to help urologists easily navigate through the decision tree of therapeutic options. Radical cystectomy (RC) is associated with considerable morbidity. Aside from the perioperative period, RC with urinary diversion poses great potential for long-term complications and morbidity. Bladder preservation therapies for muscle-invasive bladder cancer (MIBC) have been developed to address the needs of two cohorts: patients with severe medical co-morbidities for whom a radical surgery is too high risk and patients with limited disease who wish to avoid radical surgery. The goal of achieving complete response to treatment while maintaining bladder form and function has led to the development of multimodal approaches to this disease. There are multiple bladder preservation options, although the trimodal approach of maximal transurethral resection with chemoradiotherapy is the most strongly supported. In medically operable patients ('fit' for surgery), there is abundant evidence to support trimodal therapy as an acceptable treatment option for highly selected patients with MIBC with favourable pathological parameters. While outcomes are worse for medically inoperable patients ('unfit' for surgery), bladder preservation approaches still offer curative potential. However, prospective trials comparing the above regimens to RC are still needed to better define their role in the treatment of MIBC. We present a comprehensive review of the literature and outline a practical approach to bladder preservation therapy for MIBC. PMID- 23356412 TI - Age and gender interactions in short distance triathlon performance. AB - This study investigated the participation and performance trends as well as the age and gender interaction at the Olympic distance 'Zurich Triathlon' (1.5 km swim, 40 km cycle and 10 km run) from 2000 to 2010 in 7,939 total finishers (1,666 females and 6,273 males). Female triathletes aged from 40 to 54 years significantly (P < 0.05) increased their participation while the participation of younger females and males remained stable. Males of 50-54 years of age and females of 45-49 years of age improved their total race time. For elite top five overall triathletes, mean gender differences in swimming, cycling, running and overall race time were 15.2 +/- 4.6%, 13.4 +/- 2.3%, 17.1 +/- 2.5%, and 14.8 +/- 1.8%, respectively. For both elite and age group athletes, the gender difference in cycling time was significantly (P <0.001) lower than for swimming and running. The gender difference in overall Olympic distance triathlon performance increased after the age of 35 years, which appeared earlier compared to long distance triathlon as suggested by previous studies. Future investigations should compare gender difference in performance for different endurance events across age to confirm a possible effect of exercise duration on gender difference with advancing age. PMID- 23356413 TI - An overview of the domestication and impact of the Salmonella mobilome. AB - Salmonella spp. are accountable for a large fraction of the global infectious disease burden, with most of their infections being food- or water-borne. The phenotypic features and adaptive potential of Salmonella spp. appear to be driven to a large extent by mobile or laterally acquired genetic elements. A better understanding of the conduct and diversification of these important pathogens consequently requires a more profound insight into the different mechanisms by which these pivotal elements establish themselves in the cell and affect its behavior. This review, therefore, provides an overview of the physiological impact and domestication of the Salmonella mobilome. PMID- 23356410 TI - HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs? AB - Histone deacetylase (HDAC) inhibitors have been demonstrated to be beneficial in animal models of neurodegenerative diseases. Such results were mainly associated with the epigenetic modulation caused by HDACs, especially those from class I, via chromatin deacetylation. However, other mechanisms may contribute to the neuroprotective effect of HDAC inhibitors, since each HDAC may present distinct specific functions within the neurodegenerative cascades. Such an example is HDAC6 for which the role in neurodegeneration has been partially elucidated so far. The strategy to be adopted in promising therapeutics targeting HDAC6 is still controversial. Specific inhibitors exert neuroprotection by increasing the acetylation levels of alpha-tubulin with subsequent improvement of the axonal transport, which is usually impaired in neurodegenerative disorders. On the other hand, an induction of HDAC6 would theoretically contribute to the degradation of protein aggregates which characterize various neurodegenerative disorders, including Alzheimer's, Parkinson's and Hutington's diseases. This review describes the specific role of HDAC6 compared to the other HDACs in the context of neurodegeneration, by collecting in silico, in vitro and in vivo results regarding the inhibition and/or knockdown of HDAC6 and other HDACs. Moreover, structure, function, subcellular localization, as well as the level of HDAC6 expression within brain regions are reviewed and compared to the other HDAC isoforms. In various neurodegenerative diseases, the mechanisms underlying HDAC6 interaction with other proteins seem to be a promising approach in understanding the modulation of HDAC6 activity. PMID- 23356414 TI - Microdeletion of exon 3 in the HBA2 gene associated with mild alpha-thalassemia trait. AB - A mother and son presented with mild symptoms of thalassemia trait. Polymerase chain reaction (PCR) amplification of their globin genes revealed a previously unreported 203 bp microdeletion in the HBA2 gene (NG_000006.1:g.34305_34507del; HBA2:c301-30_*44del). Both mother and son were heterozygous for the deletion which included DNA coding for all of exon 3. DNA sequence analysis revealed a six nucleotide repeat (5'-CGGGCC-3') flanking the breakpoint, suggesting that the microdeletion may have arisen as a result of reciprocal recombination within the HBA2 alleles. PMID- 23356415 TI - Direct peel monitoring of xenobiotics in fruit by direct analysis in real time coupled to a linear quadrupole ion trap-orbitrap mass spectrometer. AB - Study of xenobiotics present in fruit peel by exposing it (without any pretreatment) to direct analysis in real time coupled to a high-resolution orbitrap mass spectrometer (DART-HRMS) is reported for the first time. Variables such as DART gas heater temperature and pressure, source-to-MS distance, and sample velocity are investigated. The analysis of one sample by DART-MS lasts ca. 1 min, and the benefits of both high-resolution and tandem mass spectrometry to elucidate nontarget or unknown compounds are combined. Identification of postharvest fungicides, antioxidants, and sugars in fruit peel is performed in the positive ion mode. A possible elemental formula is suggested for marker components. The lowest imazalil concentration that could be detected by this system is 1 ng (equivalent to a concentration of ca. 300 MUg kg(-1)), which is well below the maximum residue limit. For oranges and apples, direct peel exposition demonstrated good interday precision (within 20% for any concentration) and proper linearity (R(2) >= 0.99), with a dynamic range from 1 to 2500 ng for apple. A comparison of the results obtained using the direct peel screening DART-based method is made with those obtained by DART analysis of solvent extracts, as well as those obtained analyzing these extracts by ultrahigh performance liquid chromatography orbitrap mass spectrometry (UHPLC-Orbitrap). The results are in good agreement. Thus, the proposed method proves to be quantitatively accurate with indisputable identification specificity. As an independent method, the approach of direct scanning of peel is of high interest and of potential future within food analysis to guarantee safety, quality, and authenticity. PMID- 23356416 TI - Side-effects of plant domestication: ecosystem impacts of changes in litter quality. AB - Domestication took plants from natural environments to agro-ecosystems, where resources are generally plentiful and plant life is better buffered against environmental risks such as drought or pathogens. We hypothesized that predictions derived from the comparison of low vs high resource ecosystems (faster-growing plants promoting faster nutrient cycling in the latter) extrapolate to the process of domestication. We conducted the first comprehensive assessment of the consequences of domestication on litter quality and key biogeochemical processes by comparing 24 domesticated crops against their closest wild ancestors. Twelve litter chemistry traits, litter decomposability and indicators of soil carbon (C) and nitrogen (N) cycling were assessed in each domesticated vs wild ancestor pair. These assessments were done in microbial-poor and microbial-rich soils to exemplify intensively and extensively managed agricultural soils, respectively. Plant domestication has increased litter quality, encouraging litter decomposability (36% and 44% increase in the microbial-rich and microbial-poor soils, respectively), higher soil NO3 - availability and lower soil C : N ratios. These effects held true for the majority of the crops surveyed and for soils with different microbial communities. Our results support ecological theory predictions derived from the comparison of low- and high-resource ecosystems, suggesting a parallelism between ecosystem-level impacts of natural and artificial selection. PMID- 23356417 TI - Sizing by weighing: characterizing sizes of ultrasmall-sized iron oxide nanocrystals using MALDI-TOF mass spectrometry. AB - We present a rapid and reliable method for determining the sizes and size distributions of <5 nm-sized iron oxide nanocrystals (NCs) using matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry (MS). MS data were readily converted to size information using a simple equation. The size distribution obtained from the mass spectrum is well-matched with the data from transmission electron microscopy, which requires long and tedious analysis work. The size distribution obtained from the mass spectrum is highly resolved and can detect size differences of only a few angstroms. We used this MS-based technique to investigate the formation of iron oxide NCs, which is not easy to monitor with other methods. From ex situ measurements, we observed the transition from molecular precursors to clusters and then finally to NCs. PMID- 23356418 TI - Circumferential left atrium resection for treating a giant left atrium. AB - BACKGROUND: An enlarged left atrium (LA) is a major risk factor for atrial fibrillation (AF) recurrence after a maze operation. METHODS: Between 2000 and 2009, 35 patients underwent circumferential left atrium resection (CLAR), during mitral valve surgery. All patients had continuous AF. RESULTS: Hospital mortalities occurred in two patients (5.7%). Postoperative bleeding occurred in two patients (5.7%). The average follow-up was 64 months. The mean New York Heart Association (NYHA) functional class had significantly decreased to 1.16 +/- 0.37 from 2.77 +/- 0.65 (p < 0.01). The mean LA dimension and the cardiothoracic ratio had significantly decreased to 52.8 +/- 7.9 mm, and 0.55 +/- 0.06 from 72.6 +/- 11.0 mm, and 0.66 +/- 0.11, respectively (p < 0.01). The mean early postoperative LA volume had decreased to 178 +/- 68 mL (102-343 mL) from 332 +/- 133 mL (124 655 mL) (p < 0.001). These LA volume reductions had been maintained until the last echocardiogram, which was done at an average of 29 months. In patients who underwent the maze procedure, the rate of sinus rhythm restoration was 82.1%, 81.5%, and 74% at three to six months, one year, and the last visit, respectively. CONCLUSION: CLAR significantly reduced the LA volume. CLAR had an additional beneficial effect with the maze procedure of a relative rate of sinus rhythm restoration. To clarify the role of CLAR in marked symptom improvements after mitral valve surgery in patients with a giant LA, well-designed comparative studies are required. PMID- 23356419 TI - Evaluation of the food grade expression systems NICE and pSIP for the production of 2,5-diketo-D-gluconic acid reductase from Corynebacterium glutamicum. AB - 2,5-diketo-D-gluconic acid reductase (2,5-DKG reductase) catalyses the reduction of 2,5-diketo-D-gluconic acid (2,5-DKG) to 2-keto-L-gulonic acid (2-KLG), a direct precursor (lactone) of L-ascorbic acid (vitamin C). This reaction is an essential step in the biocatalytic production of the food supplement vitamin C from D-glucose or D-gluconic acid. As 2,5-DKG reductase is usually produced recombinantly, it is of interest to establish an efficient process for 2,5-DKG reductase production that also satisfies food safety requirements. In the present study, three recently described food grade variants of the Lactobacillales based expression systems pSIP (Lactobacillus plantarum) and NICE (Lactococcus lactis) were evaluated with regard to their effictiveness to produce 2,5-DKG reductase from Corynebacterium glutamicum. Our results indicate that both systems are suitable for 2,5-DKG reductase expression. Maximum production yields were obtained with Lb. plantarum/pSIP609 by pH control at 6.5. With 262 U per litre of broth, this represents the highest heterologous expression level so far reported for 2,5-DKG reductase from C. glutamicum. Accordingly, Lb. plantarum/pSIP609 might be an interesting alternative to Escherichia coli expression systems for industrial 2,5-DKG reductase production. PMID- 23356420 TI - Cost effectiveness of transcatheter aortic valve replacement compared to medical management in inoperable patients with severe aortic stenosis: Canadian analysis based on the PARTNER Trial Cohort B findings. AB - OBJECTIVE: The only effective treatment for severe aortic stenosis (AS) is valve replacement. However, many patients with co-existing conditions are ineligible for surgical valve replacement, historically leaving medical management (MM) as the only option which has a poor prognosis. Transcatheter Aortic Valve Replacement (TAVR) is a less invasive replacement method. The objective was to estimate cost-effectiveness of TAVR via transfemoral access vs MM in surgically inoperable patients with severe AS from the Canadian public healthcare system perspective. METHODS: A cost-effectiveness analysis of TAVR vs MM was conducted using a deterministic decision analytic model over a 3-year time horizon. The PARTNER randomized controlled trial results were used to estimate survival, utilities, and some resource utilization. Costs included the valve replacement procedure, complications, hospitalization, outpatient visits/tests, and home/nursing care. Resources were valued (2009 Canadian dollars) using costs from the Ontario Case Costing Initiative (OCCI), Ontario Ministry of Health and Long Term Care and Ontario Drug Benefits Formulary, or were estimated using relative costs from a French economic evaluation or clinical experts. Costs and outcomes were discounted 5% annually. The effect of uncertainty in model parameters was explored in deterministic and probabilistic sensitivity analysis. RESULTS: The incremental cost-effectiveness ratio (ICER) was $32,170 per quality-adjusted life year (QALY) gained for TAVR vs MM. When the time horizon was shortened to 24 and 12 months, the ICER increased to $52,848 and $157,429, respectively. All other sensitivity analysis returned an ICER of less than $50,000/QALY gained. LIMITATIONS: A limitation was lack of availability of Canadian-specific resource and cost data for all resources, leaving one to rely on clinical experts and data from France to inform certain parameters. CONCLUSIONS: Based on the results of this analysis, it can be concluded that TAVR is cost-effective compared to MM for the treatment of severe AS in surgically inoperable patients. PMID- 23356421 TI - Length of stay and hospital costs among high-risk patients with hospital-origin Clostridium difficile-associated diarrhea. AB - OBJECTIVE: Hospital-onset Clostridium difficile-associated diarrhea (HO-CDAD) has been associated with longer length of stay (LOS) and higher hospital costs among patients in general. The burden of HO-CDAD is unknown among patients who may be at particular risk of poor outcomes: older patients, those with complex or chronic conditions (renal disease, cancer, inflammatory bowel disease [IBD]), and those with concomitant antibiotic (CAbx) use during treatment for CDAD. RESEARCH DESIGN AND METHODS: A retrospective analysis (2005-2011) of the Health Facts(r) database (Cerner Corp., Kansas City, MO) containing comprehensive clinical records from 186 US hospitals identified hospitalized adult patients with HO-CDAD based on a positive C. difficile toxin collected >48 h after admission. Control patients were required to have total hospital LOS >=2 days. Separate logistic regression models to estimate propensities were developed for each study group, with HO-CDAD vs controls as the outcome. Differences in LOS and costs were calculated between cases and controls for each group. RESULTS: A total of 4521 patients with HO-CDAD were identified. Mean age was 70 years, 54% were female, and 13% died. After matching, LOS was significantly greater among HO-CDAD patients (vs controls) in each group except IBD. The significant difference in LOS ranged from 3.0 (95% CI = 1.4-4.6) additional days in older patients to 7.8 (95% CI = 5.7-9.9) days in patients with CAbx exposure. HO-CDAD was associated with significantly higher costs among older patients (p < 0.001) and among those with renal impairment (p = 0.012) or CAbx use (p < 0.001). LIMITATIONS: Missing cost data and potential misclassification of colonized patients as infected. CONCLUSIONS: Renal impairment, advanced age, cancer, and CAbx use are associated with significantly longer LOS among HO-CDAD patients, with CAbx users being the most resource intensive. Early identification and aggressive treatment of HO-CDAD in these groups may be warranted. PMID- 23356423 TI - Optic disc progression and rates of visual field change in treated glaucoma. AB - PURPOSE: To investigate the relationship between optic disc progression and rates of visual field (VF) change in patients with treated glaucoma. METHODS: Glaucoma patients with repeatable VF loss, >=8 SITA-Standard 24-2 VF tests and good quality optic disc stereophotographs evaluated over a 10-year period were included. Optic disc photographs were reviewed for signs of glaucoma progression (neuroretinal rim change, widening of retinal nerve fibre layer defect, disc haemorrhage and enlargement of beta-zone parapapillary atrophy) by two glaucoma specialists masked to their temporal sequence. Disagreements were adjudicated by a third grader. VF progression was evaluated using automated pointwise linear regression (PLR) and defined as at least two adjacent test points progressing >1.0 dB/year at p < 0.01. VF progression outcomes were compared with photograph review results. RESULTS: Three-hundred and eighty nine eyes (389 patients; mean age 64.9 +/- 13.0 years; mean baseline MD, -7.1 +/- 5.1 dB) were included. Most patients had primary open angle glaucoma (54%). Eighty-two eyes (21%) had confirmed optic disc progression and 115 eyes (29%) met the VF PLR criteria. Eyes with documented optic disc progression had more rapid rates of VF change (-0.66 +/- 0.7 versus -0.36 +/- 0.7 dB/year, p < 0.01) and met the VF PLR endpoint more often (univariate OR = 1.85, p = 0.02; multivariate OR = 1.78, p = 0.03) than eyes without optic disc progression. There was moderate spatial consistency between the location of the optic disc progression and the hemifield with more rapid progression (81%, kappa = 0.40). CONCLUSIONS: Treated glaucomatous eyes with documented optic disc progression are at increased risk of diminished visual function over time and may require more aggressive therapy to prevent future vision loss. Among the indicators of structural progression, disc haemorrhage was the single most significant predictor for VF deterioration. PMID- 23356422 TI - Healthcare resource utilization and direct costs associated with frequent nausea in episodic migraine: results from the American Migraine Prevalence and Prevention (AMPP) Study. AB - BACKGROUND: Nausea is a common migraine symptom that is associated with impaired quality-of-life and functional disability. In this study, population-based data were used to elucidate the relationship between nausea frequency and headache related healthcare utilization and costs in persons with migraine. RESEARCH DESIGN AND METHODS: Participants with episodic migraine who completed the 2009 American Migraine Prevalence and Prevention (AMPP) Study survey rated their headache-related nausea as occurring never, rarely, =half the time with their headaches, and completed questions on symptom frequency and healthcare resource utilization. MAIN OUTCOME MEASURES: Ordinal logistic regression models were used to assess the association between nausea frequency and headache-related healthcare utilization. Healthcare cost equivalents were calculated. RESULTS: Among the 6488 respondents with episodic migraine, the number of respondents observed across headache-related nausea frequency strata were 6.9% for never, 14.5% for rarely, 29.1% for =half the time. In unadjusted models, the odds of having >=1 healthcare encounter for headache in the preceding year increased with frequency of nausea for primary care/obstetrics-gynecology visits (OR = 1.41; 95% CI = 1.30-1.52, p < 0.001), nurse practitioner/physician assistant visits (OR = 1.52; 95% CI = 1.25 1.85, p < 0.001), neurology/headache clinic visits (OR = 1.33, 95% CI = 1.18 1.51, p < 0.001), pain clinic visits (OR = 1.31, 95% CI = 1.01-1.71, p < 0.05), emergency department visits (OR = 1.85; 95% CI = 1.56-2.19, p < 0.01), and overnight hospital stays (OR = 1.50, 92% CI = 1.12-2.00, p < 0.01). The odds of having >=1 lifetime CT scan or MRI also increased with the frequency of nausea (p < 0.001 for both). Results remained significant in these analyses when controlling for sociodemographics and overall symptom severity except in the case of pain clinic visits (p < 0.107). Visits for Mental Health and visits for Chiropractic/Alternative care did not differ significantly by nausea group in unadjusted or adjusted models. Mean estimated direct headache-related healthcare cost equivalents per person per year generally increased with increasing headache related nausea frequency across categories of healthcare utilization. Average per person healthcare cost for nausea >=half the time vs nausea never was $179 and $49 yearly for outpatient services, $183 vs $20 yearly for overnight hospital stays, and $314 vs $257 for lifetime diagnostic services/imaging. CONCLUSIONS: Direct costs of migraine increase with increasing frequency of migraine associated nausea. Both frequency and severity of headache-related nausea should be monitored as part of ongoing care of persons with migraine. Headache-related nausea, like headache pain, should be considered an area of central concern during clinical, diagnostic, and treatment optimization assessments. STUDY LIMITATIONS: This study relied on self-reported headache frequency and healthcare costs which are subject to recall bias and under-reporting; however, reporting bias is unlikely to be different as a function of nausea frequency. In addition, medication use costs and indirect costs (which may be higher than direct costs for migraine) were not assessed. PMID- 23356425 TI - In situ synthesis and ferroelectric, SHG response, and luminescent properties of a novel 3D acentric zinc coordination polymer. AB - The 3D acentric metal-organic framework (MOF) of [Zn(Mitz)Cl](n) [1; Mitz = 3 tetrazolyl-6-methyl-5-(4-pyridyl)-2-pyridone] was obtained from in situ [2 + 3] cycloaddition reactions of milrinone [=3-cyano-6-methyl-5-(4-pyridyl)-2-pyridone] with sodium azide in the presence of ZnCl(2) as the Lewis acid. The compound is a typical ferroelectric material with an electric hysteresis loop showing a remnant polarization (P(r)) of ca. 0.21 MUC/cm(2) and a coercive field (E(c)) of 2600 V/cm. Powdered samples of 1 display strong second-harmonic-generation responses of ~2 times larger than that of KH(2)PO(4). Photoluminescent study show that complex 1 and the milrinone ligand exhibit maximal emission peaks at around 409 and 401 nm, respectively, in the solid state at room temperature. PMID- 23356424 TI - Analysis of the clinical factors associated with anal function after intersphincteric resection for very low rectal cancer. AB - BACKGROUND: Intersphincteric resection (ISR) has been used to avoid permanent colostomy in very low rectal cancer patients. This study aimed to assess the surgical safety and oncologic and functional outcomes of ISR. METHODS: The records of 30 consecutive very low rectal cancer patients who underwent ISR without neoadjuvant therapy were retrospectively analyzed; survival and locoregional recurrence rates were calculated by the Kaplan-Meier method. Incontinence was assessed by a functionality questionnaire and the Wexner score. RESULTS: The median distance between the distal margin of the dentate line was 10 mm. A total of 12, 4, and 14 patients underwent partial ISR, subtotal ISR, and total ISR, respectively. The mean distal resection margin was negative in all cases, and circumferential resection margin was positive in two cases. Morbidity was 33.3%: anastomotic stricture in seven patients, colonic J-pouch prolapse in two patients, and an anovaginal fistula in one patient. During the median, 56.2 month follow-up period, local, distant, and combined recurrences occurred in four, three, and two patients, respectively. The 5-year overall and disease-free survival rates were 76.5% and 68.4%, respectively. Local recurrence rates were 5.2% for the patients with Tis-T2 tumors as compared with 45.5% for those with T3 tumors (P = 0.008). The mean Wexner scores and stool frequencies, 12 months after stoma closure in 19 patients, were 11.5 and 6.6 per 24 h, respectively. Significant differences were not seen in the Wexner scores between partial ISR and subtotal/total ISR (11.8 +/- 2.6 and 9.1 +/- 5.6). Stool frequency (P = 0.02), urgency (P = 0.04), and fragmentation (P = 0.015) were worse in patients with anastomotic stricture than in those without; there was no symptom improvement in patients with anastomotic stricture. CONCLUSIONS: The anastomotic strictures in patients undergoing ISR may have negatively affected anal function. For total ISR patients, at least, informed consent stating the possibility of a permanent colostomy is necessary. PMID- 23356426 TI - Ultrasonic evaluation of the abductor hallucis muscle in hallux valgus: a cross sectional observational study. AB - BACKGROUND: The aim of the study was to investigate the abductor hallucis muscle characteristics, defined as dorso-plantar (DP) thickness, medio-lateral (ML) width, and cross-sectional area (CSA) in relation to the severity of hallux valgus using musculoskeletal ultrasound. One hundred and two feet, mean (SD) age of 60.3 (20.54) years old, displaying varying severities of hallux valgus were stratified into four groups representing the four grades of the Manchester Scale (grade 0: no deformity, grade 1: mild deformity, grade 2: moderate deformity and grade 3: severe deformity). METHODS: The abductor hallucis muscle was imaged in each foot using a portable ultrasound system. The mean (SD) DP thickness, ML width, and CSA measurements were compared across the four Manchester Scale grades using a one-way ANOVA. RESULTS: Significant differences in DP thickness were found between feet with no hallux valgus (grade 0) and feet with hallux valgus grade 2 (p=0.001) and 3 (p<0.001). Significant differences were also found in ML width between feet with no hallux valgus (grade 0) and feet with grade 2 hallux valgus (p=0.010). Significant differences in CSA were found between feet with no hallux valgus (grade 0) and feet with grade 2 (p<0.001) and grade 3 (p<0.001) hallux valgus. No significant differences in these three muscle characteristics were found between grades 1, 2 and 3 (p>0.0125). CONCLUSIONS: We speculate that morphological changes to the abductor hallucis muscle occur early in the development of the deformity. PMID- 23356427 TI - Synthesis and carbonic anhydrase inhibitory properties of 1,3-dicarbonyl derivatives of methylaminobenzene-sulfonamide. AB - Abstract 1,3-Dicarbonyl derivatives of methylaminobenzene-sulfonamide were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase (hCA) I and hCA II were evaluated. hCA I and hCA II from human erythrocytes were purified by a simple one-step procedure by using Sepharose 4B-L tyrosine-sulfanilamide affinity column. Our results show that the synthesized compounds inhibited the activity of carbonic anhydrase (CA) I and CA II. Among them, 2b and 2e were found to be the most active (IC50=2.12 and 2.52 uM) for hCA I and hCA II, respectively. PMID- 23356428 TI - Phage lysin to control the overgrowth of normal flora in processed sputum samples for the rapid and sensitive detection of Mycobacterium tuberculosis by luciferase reporter phage assay. AB - BACKGROUND: Phage lysin, extracted from three bacteriophages was used in place of antibiotics to control the overgrowth of normal flora in processed sputum samples leading to the sensitive detection of Mycobacterium tuberculosis using diagnostic luciferase reporter phage assay (DLRPA). METHODS: A total of 129 sputum samples were processed by modified Petroff's method. Two Lowenstein Jensen slopes were inoculated from the processed sputum deposit thus obtained. The remaining deposits were transferred to 7 ml of Middlebrook 7H9 complete medium supplemented with phage lysin and incubated at 37 degrees C. DLRPA was done using phAE129 at days 7, 9, 14 and 21. At the end of day 21, the samples were centrifuged and the pellets were inoculated on to 2 more LJ slopes to validate DLRPA results. RESULTS: The sensitivity and specificity of DLRPA in detecting M. tuberculosis from sputum specimens was 90% and 81% respectively compared to conventional LJ culture. The agreement between the methods was 87%. The rate of contamination for DLRPA using phage lysin was 9.3%. CONCLUSION: Phage lysin can be used to decontaminate sputum samples for the detection of M. tuberculosis by DLRPA directly from processed sputum specimens. PMID- 23356429 TI - Kinetics and thermodynamics of DNA, RNA, and hybrid duplex formation. AB - The rates of duplex formation for two octamers of DNA (5' d-CACGGCTC/5' d GAGCCGTG and 5' d-CACAGCAC/5' d-GTGCTGTG), the homologous RNA, and both sets of hybrids in 1 M NaCl buffer have been measured using stopped-flow spectroscopy. In addition, the thermodynamic parameters, DeltaH degrees and DeltaS degrees , have been determined for the same sequences under the same buffer conditions using optical melting techniques. These data reveal a linear free energy relationship between the free energy of activation for denaturation and the change in free energy for formation of the duplexes. This relationship indicates that these duplex formation reactions occur through a common unstructured transition state that is more similar to the single strands in solution than to the ensuing duplex. In addition, these data confirm that the greater stability of RNA duplexes relative to that of homologous DNA and hybrid duplexes is controlled by the denaturation rate and not the duplex formation rate. PMID- 23356430 TI - Volumetric and functional assessment using cardiac magnetic resonance imaging in young children exposed to acute pulmonary regurgitation: is pulmonary regurgitation just a long-term matter? AB - BACKGROUND: The early effect of pulmonary regurgitation (PR) on both ventricular volume and function has not been well established in children. We evaluated the early effect of PR on both ventricular volume and function in young children. METHODS: Among patients who underwent total repair of pulmonary atresia with ventricular septal defect between January 2007 and December 2008, cardiac magnetic resonance imaging (CMRI) was performed in 12 patients at a median interval of 15.6 months (6-22 months). Valveless right ventricular outflow tract (RVOT) reconstruction was performed in five patients (valveless group) and RVOT reconstruction using valved conduit in seven patients (valve group). Age and weight at operation, and the interval between the operation and CMRI were not different between the groups. RESULTS: We observed a higher pulmonary regurgitant fraction (p = 0.003), a higher right ventricular end-diastolic volume index (RVEDVI) (p = 0.003), a higher right ventricular end-systolic volume index (p = 0.003), a higher left ventricular end-diastolic volume index (p = 0.010), a higher left ventricular end-systolic volume index (p = 0.018), and a lower left ventricular ejection fraction (LVEF; p = 0.048) in the valveless group. Right ventricular ejection fraction (RVEF) was not different between two groups. The RVEDVI was negatively correlated with RVEF (rho = -0.601, p = 0.039) and LVEF (rho = -0.580, p = 0.048). CONCLUSIONS: Both ventricular volumes increased and left ventricular function was compromised, but right ventricular function was preserved early after the exposure to PR in children. Right ventricular volume was associated with both ventricular functions. PMID- 23356431 TI - Welcome to a decade of action that can make a change! AB - The Journal of Trauma Management and Outcomes welcomes the launch of the UN Decade of Action for Road Safety 2011-2020. More than 100 countries around the world will kick off the first global Decade of Action for Road Safety 2011-2020, a decade that we believe can make a change! PMID- 23356432 TI - The implications of stigma and anonymity for self-disclosure in health blogs. AB - The reported study examines the implications of anonymity and stigma in the form of illness-related embarrassment for self-disclosure in the context of health blogging. Drawing from theorizing about anonymous communication and stigma, anonymity is argued to be strategically used by individuals who are embarrassed by their illness and to moderate the relationship between embarrassment and self disclosure. Data from 114 individuals who blog about their experiences coping with a health condition were examined to test study hypotheses. Illness-related embarrassment was positively associated with anonymity. Additionally, anonymity moderated the relationship between embarrassment and self-disclosure. Among bloggers with relatively higher levels of anonymity, illness-related embarrassment was positively associated with self-disclosure. The results suggest that anonymity is strategically used and fosters self-disclosure among individuals who are embarrassed by their illness. PMID- 23356433 TI - Somatotyping using 3D anthropometry: a cluster analysis. AB - Somatotyping is the quantification of human body shape, independent of body size. Hitherto, somatotyping (including the most popular method, the Heath-Carter system) has been based on subjective visual ratings, sometimes supported by surface anthropometry. This study used data derived from three-dimensional (3D) whole-body scans as inputs for cluster analysis to objectively derive clusters of similar body shapes. Twenty-nine dimensions normalised for body size were measured on a purposive sample of 301 adults aged 17-56 years who had been scanned using a Vitus Smart laser scanner. K-means Cluster Analysis with v-fold cross-validation was used to determine shape clusters. Three male and three female clusters emerged, and were visualised using those scans closest to the cluster centroid and a caricature defined by doubling the difference between the average scan and the cluster centroid. The male clusters were decidedly endomorphic (high fatness), ectomorphic (high linearity), and endo-mesomorphic (a mixture of fatness and muscularity). The female clusters were clearly endomorphic, ectomorphic, and the ecto-mesomorphic (a mixture of linearity and muscularity). An objective shape quantification procedure combining 3D scanning and cluster analysis yielded shape clusters strikingly similar to traditional somatotyping. PMID- 23356434 TI - Pseudoaneurysm of the superior gluteal artery following bone marrow biopsy. PMID- 23356435 TI - Assessment of the contribution of electron microscopy to nanoparticle characterization sampled with two cascade impactors. AB - This study assessed the contribution of electron microscopy to the characterization of nanoparticles and compared the degree of variability in sizes observed within each stage when sampled by two cascade impactors: an Electrical Low Pressure Impactor (ELPI) and a Micro-Orifice Uniform Deposit Impactor (MOUDI). A TiO(2) nanoparticle (5 nm) suspension was aerosolized in an inhalation chamber. Nanoparticles sampled by the impactors were collected on aluminum substrates or TEM carbon-coated copper grids using templates, specifically designed in our laboratories, for scanning and transmission electron microscopy (SEM, TEM) analysis, respectively. Nanoparticles were characterized using both SEM and TEM. Three different types of diameters (inner, outer, and circular) were measured by image analysis based on count and volume, for each impactor stage. Electron microscopy, especially TEM, is well suited for the characterization of nanoparticles. The MOUDI, probably because of the rotation of its collection stages, which can minimize the resuspension of particles, gave more stable results and smaller geometric standard deviations per stage. Our data suggest that the best approach to estimate particle size by electron microscopy would rely on geometric means of measured circular diameters. Overall, the most reliable data were provided by the MOUDI and the TEM sampling technique on carbon coated copper grids for this specific experiment. This study indicates interesting findings related to the assessment of impactors combined with electron microscopy for nanoparticle characterization. For future research, since cascade impactors are extensively used to characterize nano-aerosol exposure scenarios, high-performance field emission scanning electron microscopy (FESEM) should also be considered. PMID- 23356436 TI - Extended vs standard lymph node dissection in robot-assisted radical prostatectomy for intermediate- or high-risk prostate cancer: a propensity-score matching analysis. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Although lymph node dissection (LND) is known as the most accurate method of nodal staging, the therapeutic role of LND remains undetermined. This is mainly because of the lack of randomized prospective studies and the fact that retrospective analyses often result in bias and misinterpretation. To overcome the limitation of retrospective analysis, we matched preoperative variables using propensity scores and compared the outcomes between patients treated with robot-assisted eLND and sLND. In the matched cohort, robot-asssited eLND achieved an increased detection rate of lymph node metastases; however, the therapeutic benefit was not statistically significant between the two groups on short-term follow-up. OBJECTIVE: To compare the pathological and biochemical outcomes between extended lymph node dissection (eLND) and standard lymph node dissection (sLND) in patients undergoing robot assisted radical prostatectomy for intermediate- or high-risk prostate cancer. PATIENTS AND METHODS: A total of 905 patients underwent robot-assisted radical prostatectomy and lymph node dissection (LND) by a single surgeon between June 2006 and January 2011. Of these, 170 patients who underwent robot-assisted eLND and 294 patients who underwent robot-assisted sLND for intermediate- or high-risk prostate cancer were included in the study. Propensity-score matching was performed using the preoperative variables which included age, body mass index, prostate-specific antigen, clinical stage, biopsy Gleason score 1 and 2, total number of biopsied cores, number of positive cores and prostate volumes. Pathological and biochemical outcomes were assessed according to the extent of LND. RESULTS: The median (range) follow-up period was 36 (12-77) months and the median number of lymph nodes removed was 21 and 12 in the eLND and sLND groups, respectively. Propensity-score matching resulted in 141 patients in each group. Although patients who underwent eLND had a higher clinical stage, biopsy Gleason score and number of positive cores than those treated with sLND in the entire cohort, there were no preoperative between-group differences in the matched cohort. In the matched cohort, lymph node metastases were detected at a significantly higher rate in the eLND than in the sLND group (12.1 vs. 5.0%, P = 0.033). In the matched cohort, the 3-year biochemical recurrence-free survival rates were 77.8 and 73.5% in the eLND and sLND groups, respectively, which was not significant (hazard ratio 0.85, P = 0.497). CONCLUSION: Robot-assisted eLND achieved an increased lymph node yield and higher detection rate of lymph node metastases; however, robotic eLND did not alter biochemical outcomes in a short term follow-up. PMID- 23356437 TI - Temporal dynamics of fine roots under long-term exposure to elevated CO2 in the Mojave Desert. AB - Deserts are considered 'below-ground dominated', yet little is known about the impact of rising CO(2) in combination with natural weather cycles on long-term dynamics of root biomass. This study quantifies the temporal dynamics of fine root production, loss and standing crop in an intact desert ecosystem exposed to 10 yr of elevated CO(2). We used monthly minirhizotron observations from 4 yr (2003-2007) for two dominant shrub species and along community transects at the Nevada Desert free-air CO(2) enrichment Facility. Data were synthesized within a Bayesian framework that included effects of CO(2) concentration, cover type, phenological period, antecedent soil water and biological inertia (i.e. the influence of prior root production and loss). Elevated CO(2) treatment interacted with antecedent soil moisture and had significantly greater effects on fine-root dynamics during certain phenological periods. With respect to biological inertia, plants under elevated CO(2) tended to initiate fine-root growth sooner and sustain growth longer, with the net effect of increasing the magnitude of production and mortality cycles. Elevated CO(2) interacts with past environmental (e.g. antecedent soil water) and biological (e.g. biological inertia) factors to affect fine-root dynamics, and such interactions are expected to be important for predicting future soil carbon pools. PMID- 23356438 TI - LIGHT/HVEM/LTbetaR interaction as a target for the modulation of the allogeneic immune response in transplantation. AB - The exchange of information during interactions of T cells with dendritic cells, B cells or other T cells regulates the course of T, B and DC-cell activation and their differentiation into effector cells. The tumor necrosis factor superfamily member LIGHT (homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes) is transiently expressed upon T cell activation and modulates CD8 T cell-mediated alloreactive responses upon herpes virus entry mediator (HVEM) and lymphotoxin beta receptor (LTbetaR) engagement. LIGHT-deficient mice, or WT mice treated with LIGHT-targeting decoy receptors HVEM-Ig, LTbetaR-Ig or sDcR3-Ig, exhibit prolonged graft survival compared to untreated controls, suggesting that LIGHT modulates the course and severity of graft rejection. Therefore, targeting the interaction of LIGHT with HVEM and/or LTbetaR using recombinant soluble decoy receptors or monoclonal antibodies represent an innovative therapeutic strategy for the prevention and treatment of allograft rejection and for the promotion of donor-specific tolerance. PMID- 23356439 TI - Perturbations of Plasmodium Puf2 expression and RNA-seq of Puf2-deficient sporozoites reveal a critical role in maintaining RNA homeostasis and parasite transmissibility. AB - Malaria's cycle of infection requires parasite transmission between a mosquito vector and a mammalian host. We here demonstrate that the Plasmodium yoelii Pumilio-FBF family member Puf2 allows the sporozoite to remain infectious in the mosquito salivary glands while awaiting transmission. Puf2 mediates this solely through its RNA-binding domain (RBD) likely by stabilizing or hastening the degradation of specific mRNAs. Puf2 traffics to sporozoite cytosolic granules, which are negative for several markers of stress granules and P-bodies, and disappear rapidly after infection of hepatocytes. In contrast to previously described Plasmodium berghei pbpuf2(-) parasites, pypuf2(-) sporozoites have no apparent defect in host infection when tested early in salivary gland residence, but become progressively non-infectious and prematurely transform into EEFs during prolonged salivary gland residence. The premature overexpression of Puf2 in oocysts causes striking deregulation of sporozoite maturation and infectivity while extension of Puf2 expression in liverstages causes no defect, suggesting that the presence of Puf2 alone is not sufficient for its functions. Finally, by conducting the first comparative RNA-seq analysis of Plasmodium sporozoites, we find that Puf2 may play a role in directly or indirectly maintaining the homeostasis of specific transcripts. These findings uncover requirements for maintaining a window of opportunity for the malaria parasite to accommodate the unpredictable moment of transmission from mosquito to mammalian host. PMID- 23356440 TI - Within- and between-task consistency in hand use as a means of characterizing hand preferences in captive chimpanzees (Pan troglodytes). AB - There remain considerable questions regarding the evidence for population-level handedness in nonhuman primates when compared with humans. One challenge in comparing human and nonhuman primate handedness involves the procedures used to characterize individual handedness. Studies of human handedness use consistency in hand use within and between tasks as a basis for hand preference classification. In contrast, studies of handedness in nonhuman primates use statistical criteria for classifying handedness. In this study, we examined within- and between-task consistency in hand use as a means of characterizing individual handedness in a sample of 300 captive chimpanzees (Pan troglodytes). Chimpanzees showed population-level right-handedness for both within- and between tasks consistency, though the proportion of right-handed chimpanzees was lower than what has typically been reported for humans. We further found that there were small, but significant, associations in hand use between measures. There were no significant sex or colony effects on the distribution of handedness. The results are discussed in the context of theories on the evolution of handedness in nonhuman primates. PMID- 23356441 TI - A fermented soy permeate improves the skeletal muscle glucose level without restoring the glycogen content in streptozotocin-induced diabetic rats. AB - Exercise is essential into the therapeutic management of diabetic patients, but their level of exercise tolerance is lowered due to alterations of glucose metabolism. As soy isoflavones have been shown to improve glucose metabolism, this study aimed to assess the effects of a dietary supplement containing soy isoflavones and alpha-galactooligosaccharides on muscular glucose, glycogen synthase (GSase), and glycogen content in a type 1 diabetic animal model. The dietary supplement tested was a patented compound, Fermented Soy Permeate (FSP), developed by the French Company Sojasun Technologies. Forty male Wistar rats were randomly assigned to control or diabetic groups (streptozotocin, 45 mg/kg). Each group was then divided into placebo or FSP-supplemented groups. Both groups received by oral gavage, respectively, water or diluted FSP (0.1 g/day), daily for a period of 3 weeks. At the end of the protocol, glycemia was noticed after a 24-h fasting period. Glucose, total GSase, and the glycogen content were determined in the skeletal muscle (gastrocnemius). Diabetic animals showed a higher blood glucose concentration, but a lower glucose and glycogen muscle content than controls. Three weeks of FSP consumption allowed to restore the muscle glucose concentration, but failed to reduce glycemia and to normalize the glycogen content in diabetic rats. Furthermore, the glycogen content was increased in FSP-supplemented controls compared to placebo controls. Our results demonstrated that diabetic rats exhibited a depleted muscle glycogen content ( 25%). FSP-supplementation normalized the muscle glucose level without restoring the glycogen content in diabetic rats. However, it succeeded to increase it in the control group (+20%). PMID- 23356442 TI - Induction of apoptosis in HeLa cells via caspase activation by resveratrol and genistein. AB - Selectively inducing apoptosis in cancer cells is a much desired strategy when tolerance toward side effects is minimal during chemotherapy. In our search for natural products that can induce apoptosis in human cervical cancer cells (HeLa), we selected resveratrol and genistein for our study. We conducted several experiments to test whether genistein can synergistically enhance the apoptotic potential of resveratrol at doses lower than the usual cytotoxic dose. Both resveratrol and genistein were able to induce apoptosis by enhancing the activities of caspase-9 and caspase-3 by themselves and also in combination. After 24 h of exposure to resveratrol and genistein, individually or in combination, lowered mitochondrial membrane potential was observed in HeLa cells. In addition, the mitochondrial membrane potential in HeLa cells was decreased, forcing JC-1 to stay in the monomeric form. The monomeric JC-1(5,5',6,6' tetrachloro-1,1',3,3'-tetraethyl benzimedazolyl carbocyanine iodide) emitted green fluorescence. In the control group, the color of the fluorescence was red due to aggregation of JC-1 in the physiological pH. The treatment groups exhibited DNA fragmentation as the hallmark of apoptotic nuclear features. We also detected an obvious decrease in the level of HDM2 gene expression after both individual and combination treatments with resveratrol and genistein. Our findings suggest that resveratrol and genistein when combined can induce apoptosis at doses lower than usual doses, through the activation of caspases cascade, and by decreasing the expression of HDM2. PMID- 23356444 TI - Deficiency of a new protein associated with cardiac syndrome X; called adropin. AB - The pathophysiology of cardiac syndrome X (CSX) is still unclear, but most patients with CSX have endothelial dysfunction. It has been shown that adropin uniquely effects the regulation of endothelial function. The purpose of the study was to evaluate the role of adropin in CSX. Eighty-six consecutive cardiac syndrome X-diagnosed patients and 86 age-sex matched healthy subjects were enrolled into the study. Serum adropin levels, nitrite/nitrate levels were measured in each subject. The adropin levels were significantly lower in patients with CSX than healthy subjects (1.7 +/- 0.8 ng/mL and 3.4 +/- 1.8 ng/mL, respectively; P < 0.001). The BMI values of patients with CSX were significantly higher than control subjects (28.1 +/- 2.4 kg/m(2) and 26.0 +/- 3.7 kg/m(2) , respectively; P < 0.001). Plasma nitrite/nitrate levels were lower in patients with CSX than control subjects (15.9 +/- 1.6 MUmol/L vs. 25.4 +/- 2.8 MUmol/L, respectively; P < 0.001), and they have a significantly positive correlation with plasma adropin levels (r = 0.463, P < 0.001). In the multiple linear regression analysis, nitrite/nitrate levels, BMI, and adropin were found to be independent risk factors for CSX. A ROC curve is used to identify the ability of adropin levels to predict the cardiac syndrome X. The area under the ROC curve was 0.854 for adropin levels (P = 0.0001). The sensitivity and specificity values of adropin levels were 90.7 and 70.9%, respectively (cut-off value 2.73). In conclusion, lower serum adropin levels were associated with CSX. Adropin is an independent risk factor for CSX. PMID- 23356443 TI - Expression of glioma-associated oncogene 2 (Gli 2) is correlated with poor prognosis in patients with hepatocellular carcinoma undergoing hepatectomy. AB - BACKGROUND: Our previous studies showed that glioma-associated oncogene (Gli)2 plays an important role in the proliferation and apoptosis resistance of hepatocellular carcinoma (HCC) cells. The aim of this study was to explore the clinical significance of Gli2 expression in HCC. METHODS: Expression of Gli2 protein was detected in samples from 68 paired HCC samples, the corresponding paraneoplastic liver tissues, and 20 normal liver tissues using immunohistochemistry. Correlation of the immunohistochemistry results with clinicopathologic parameters, prognosis, and the expression of E-cadherin, N cadherin, and vimentin were analyzed. RESULTS: Immunohistochemical staining showed high levels of Gli2 protein expression in HCC, compared with paraneoplastic and normal liver tissues (P < 0.05). This high expression level of Gli2 was significantly associated with tumor differentiation, encapsulation, vascular invasion, early recurrence, and intra-hepatic metastasis (P < 0.05). There was a significantly negative correlation between Gli2 and E-cadherin expression (r = -0.302, P < 0.05) and a significantly positive correlation between expression of Gli2 and expression of vimentin (r = -0.468, P < 0.05) and N-cadherin (r = -0.505, P < 0.05). Kaplan-Meier analysis showed that patients with overexpressed Gli2 had significantly shorter overall survival and disease free survival times (P < 0.05). Multivariate analysis suggested that the level of Gli2 expression was an independent prognostic factor for HCC. CONCLUSIONS: Expression of Gli2 is high in HCC tissue, and is associated with poor prognosis in patients with HCC after hepatectomy. PMID- 23356445 TI - Relationship between bronchial hyperresponsiveness and lung function in children age 5 and 6 with and without asthma. AB - BACKGROUND AND OBJECTIVE: It is unknown whether wheezy children have bronchial hyperresponsiveness (BHR) or which lung function parameters are correlated with BHR in children. We evaluated the relationship between BHR parameters and the lung functions by minimizing the effects of age and height in asthmatic, non asthmatic wheezers and healthy children. METHODS: The subjects comprised of 154 children aged 5 and 6 years (78 males, 76 females), who were divided into three groups: asthmatics, non-asthmatic wheezers and healthy controls. Spirometry and a methacholine inhalation challenge by the oscillation method were performed. RESULTS: The age of the study cohort was 5.9 +/- 0.2 years (mean +/- standard deviation), and the height was 114.4 +/- 5.3 cm. No significant differences in height, weight, body mass index or lung function were observed in the three groups. The minimal dose of methacholine to start bronchoconstriction, a parameter of bronchial sensitivity, was lower in asthmatics and non-asthmatic wheezers than that in controls. The speed of bronchoconstriction in response to methacholine, a parameter of bronchial reactivity, was strongly correlated with baseline respiratory resistance (Rrs cont) in all three groups. CONCLUSIONS: Our data suggest that it not possible to distinguish preschool children with asthma from non-asthmatic wheezers based on their bronchial sensitivity and that the baseline Rrs has a strong effect on the bronchial reactivity in children. PMID- 23356446 TI - Prolyl endopeptidase activity in bronchoalveolar lavage fluid: a novel diagnostic biomarker in a guinea pig model of invasive pulmonary aspergillosis. AB - Improved diagnostics are needed to detect invasive pulmonary aspergillosis, a life-threatening infection caused by the pathogenic fungus Aspergillus fumigatus. We are investigating secreted fungal proteases as novel biomarkers for the diagnosis of this disease. Although the A. fumigatus genome encodes a multitude of secreted proteases, few have been experimentally characterized. Here, we employed an unbiased combinatorial library of internally quenched fluorogenic probes to detect infection-associated proteolysis in the lungs of guinea pigs experimentally infected with A. fumigatus. Comparative protease activity profiling revealed a prolyl endopeptidase activity that is reproducibly induced during infection but is not observed in healthy animals. This proteolytic activity was found in four independent animal experiments involving two A. fumigatus isolates. We synthesized a small, focused fluorogenic probe library to define the substrate specificity of the prolyl endopeptidase substrate motif and to identify optimal Probe sequences. These efforts resulted in the identification of a panel of six individual substrate-based fluorescent probes capable of detecting infection in guinea pigs with high statistical significance (P<0.005 in most cases). Receiver operating characteristic analyses demonstrated that this fluorogenic assay could detect A. fumigatus infection-associated proteolysis with comparable sensitivity and specificity as existing diagnostic procedures, suggesting that further optimization of the methodology may lead to improved diagnostics options for invasive pulmonary aspergillosis. PMID- 23356447 TI - High prevalence of spondyloarthritis and ankylosing spondylitis among familial Mediterranean fever patients and their first-degree relatives: further evidence for the connection. AB - INTRODUCTION: Familial Mediterranean fever (FMF) is an auto-inflammatory disease characterized by recurrent attacks of fever and serositis. Limited data suggest that the prevalence of sacroiliitis is increased in patients with FMF. In our present study, we assessed the prevalence of spondyloarthritis (SpA), including ankylosing spondylitis (AS), among a cohort of FMF patients and their unaffected first-degree relatives (FDRs). METHODS: The current study cohort comprised a consecutive group of 201 unrelated patients with FMF and 319 FDRs (>=16 years old). These subjects were examined according to a standard protocol. RESULTS: A total of 157 FMF patients (78.1%) and 233 (73%) unaffected FDRs reported back pain. Fifteen FMF patients (7.5%) and nine unaffected FDRs fulfilled the modified New York (mNY) criteria for AS. One additional FDR with AS was identified after review of the medical records. None of the FMF patients with AS was HLA-B27 positive. The allele frequency of M694V among the FMF patients with radiographic sacroiliitis was significantly higher in comparison with those without sacroiliitis (OR 4.3). When compared with the general population, the risk ratios for SpA and AS among the FDRs of our FMF patients were 3.3 (95% CI; 2.0 to 5.5) and for AS 2.9 (95% CI; 1.3 to 6.4), respectively. CONCLUSIONS: Our study suggests that a) factors other than HLA-B27 play a role in the association of FMF and SpA/AS; b) MEFV gene variations may be one of the geographic/region-specific potential pathogenetic links between these two disorders in the Turkish population. PMID- 23356449 TI - Saccharification of recalcitrant biomass and integration options for lignocellulosic sugars from Catchlight Energy's sugar process (CLE Sugar). AB - BACKGROUND: Woody biomass is one of the most abundant biomass feedstocks, besides agriculture residuals in the United States. The sustainable harvest residuals and thinnings alone are estimated at about 75 million tons/year. These forest residuals and thinnings could produce the equivalent of 5 billion gallons of lignocellulosic ethanol annually. Softwood biomass is the most recalcitrant biomass in pretreatment before an enzymatic hydrolysis. To utilize the most recalcitrant lignocellulosic materials, an efficient, industrially scalable and cost effective pretreatment method is needed. RESULTS: Obtaining a high yield of sugar from recalcitrant biomass generally requires a high severity of pretreatment with aggressive chemistry, followed by extensive conditioning, and large doses of enzymes. Catchlight Energy's Sugar process, CLE Sugar, uses a low intensity, high throughput variation of bisulfite pulping to pretreat recalcitrant biomass, such as softwood forest residuals. By leveraging well proven bisulfite technology and the rapid progress of enzyme suppliers, CLE Sugar can achieve a high yield of total biomass carbohydrate conversion to monomeric lignocellulosic sugars. For example, 85.8% of biomass carbohydrates are saccharified for un-debarked Loblolly pine chips (softwood), and 94.0% for debarked maple chips (hardwood). Furan compound formation was 1.29% of biomass feedstock for Loblolly pine and 1.10% for maple. At 17% solids hydrolysis of pretreated softwood, an enzyme dose of 0.075 g Sigma enzyme mixture/g dry pretreated (unwashed) biomass was needed to achieve 8.1% total sugar titer in the hydrolysate and an overall prehydrolysate liquor plus enzymatic hydrolysis conversion yield of 76.6%. At a much lower enzyme dosage of 0.044 g CTec2 enzyme product/g dry (unwashed) pretreated softwood, hydrolysis at 17% solids achieved 9.2% total sugar titer in the hydrolysate with an overall sugar yield of 85.0% in the combined prehydrolysate liquor and enzymatic hydrolysate. CLE Sugar has been demonstrated to be effective on hardwood and herbaceous biomass, making it truly feedstock flexible. CONCLUSIONS: Different options exist for integrating lignocellulosic sugar into sugar-using operations. A sugar conversion plant may be adjacent to a CLE Sugar plant, and the CLE Sugar can be concentrated from the initial 10% sugar as needed. Concentrated sugars, however, can be shipped to remote sites such as ethanol plants or other sugar users. In such cases, options for shipping a dense form of sugars include (1) pretreated biomass with enzyme addition, (2) lignocellulosic sugar syrup, and (3) lignocellulosic sugar solid. These could provide the advantage of maximizing the use of existing assets. PMID- 23356448 TI - Apoptosis-associated biomarkers in tuberculosis: promising for diagnosis and prognosis prediction. AB - BACKGROUND: Apoptosis-associated biomarkers are rarely studied, especially their role in predicting the development of tuberculosis (TB) from latent TB infection and in prognostication. METHODS: Patients with TB and interferon-gamma release assay (IGRA)-positive and IGRA-negative family contacts were evaluated to analyze changes in apoptosis-associated serum biomarkers, which included decoy receptor 3 (DcR3), prostaglandin 2 (PGE2), and lipoxin. The prognostic implications of these serum biomarkers were also analyzed. RESULTS: One hundred TB patients and 92 IGRA negative and 91 IGRA-positive family contacts were recruited. The DcR3 and PGE2 levels decreased from the IGRA-negative group to the IGRA-positive group, and peaked in the TB group. Lipoxin decreased to trough in the TB group. The three apoptosis serum markers and age were independent factors discriminating active TB from latent TB infection. In active TB, older age, co-morbidity, and higher serum DcR3 and monocyte chemotactic protein (MCP)-1 were independently associated with poorer six-month survival. CONCLUSION: Apoptosis-associated serum biomarkers change along with the status of Mycobacterium tuberculosis infection. In close contacts with positive IGRA, high DcR3 and PGE2 and low lipoxin may increase the probability of active TB. Older age, co-morbidity, and high DcR3 and MCP-1 levels might be important prognostic factors that warrant further investigation. PMID- 23356450 TI - Simulating the pyrolysis of polyazides: a mechanistic case study of the [[P(N3)6] anion. AB - Pyrolysis of the homoleptic azido complex [P(N(3))(6)](-) was simulated using density functional theory based molecular dynamics and analyzed further using electronic-structure calculations in atom-centered basis sets to calculate the geometries and electronic structures. Simulations at 600 and 1200 K predict a thermally induced and, on the simulation time scale, irreversible dissociation of an azido anion. The ligand loss is accompanied by a barrierless (free-energy) transition of the geometry of the complex coordination sphere from octahedral to trigonal bipyramidal. [P(N(3))(5)] is fluxional and engages in pseudorotation via a Berry mechanism. PMID- 23356451 TI - Pain assessment: the roles of physician certainty and curiosity. AB - Undertreatment of pain is common even when caused by serious illness. We examined whether physician-patient communication (particularly language indicating physician certainty) was associated with incomplete (i.e., premature closure) of pain assessment among patients with serious illness. Standardized patients (SPs) trained to portray patients with serious illness conducted unannounced, covertly audio-recorded visits to 20 consenting family physicians and 20 medical specialists. We coded extent of pain assessment, physician voice tone, and a measure of the degree to which physicians explored and validated patient concerns. To assess physician certainty, we searched transcripts for use of words that conveyed certainty using the Linguistic Inquiry and Word Count program. SP role fidelity was 94%, and few physicians were suspicious that they had seen an SP (14% of visits). Regression analyses showed that physicians who used more certainty language engaged in less thorough assessment of pain (beta = -0.48, p < .05). Conversely, physicians who engaged in more exploring and validating of patient concerns (beta = 0.27, p < .05) had higher ratings on anxiety/concerned voice tone (beta = 0.25, p <.01) and engaged in more thorough assessment of pain. Together, these three factors accounted for 38% of the variance in pain assessment. Physicians who convey certainty in discussions with patients suffering from pain may be more likely to close prematurely their assessment of pain. We found that expressions of physician concern and responsiveness (curiosity) were associated with superior pain assessment. Further study is needed to determine whether these associations are causal and mutable. PMID- 23356452 TI - Persistent ovarian masses and pregnancy outcomes. AB - OBJECTIVE: To determine if persistent ovarian masses in pregnancy are associated with increased adverse outcomes. METHODS: This is a retrospective cohort of 126 pregnant women with a persistent ovarian mass measuring 5 cm or greater who delivered at two university hospitals between 2001 and 2009. Maternal outcomes included gestational age (GA) at diagnosis, delivery and surgery as well as miscarriage, preterm birth (PTB), ovarian torsion and hospital admission for pain. Neonatal outcomes included birth weight, respiratory distress syndrome (RDS), intra-ventricular hemorrhage (IVH), death and sepsis. RESULTS: A total of 1225 ovarian masses were identified (4.9%) in 24,868 patients. A persistent ovarian mass was found in 0.7%. Average GA at diagnosis was 17.8 weeks. Miscarriage rate was 3.3%. Average GA at delivery was 37.9 weeks. Of the patients, 8.5% had ovarian torsion, 10.3% had admission for pain and 9.3% had PTBs. The mean cesarean delivery rate was 46.3%. The average neonatal weight was 3273 g. There was one neonatal death in this cohort. The rate of RDS was 2.8%, IVH 0.9% and neonatal sepsis 1.9%. The most common surgical pathologic diagnosis was dermoids (37.6%). No overt malignancies were seen. CONCLUSION: A persistent ovarian mass in pregnancy does not confer an increased risk of adverse pregnancy outcomes. PMID- 23356453 TI - Giant right coronary artery draining into the coronary sinus. PMID- 23356454 TI - Sanguinarine and its potent antineoplastic effects in systemic malignancies. PMID- 23356455 TI - Effectiveness of a cognitive-behavioral group intervention for knee osteoarthritis pain: protocol of a randomized controlled trial. AB - BACKGROUND: Knee osteoarthritis is the most common type of arthritis, with pain being its most common symptom. Little is known about the psychological aspects of knee osteoarthritis pain. There is an emerging consensus among osteoarthritis specialists about the importance of addressing not only biological but also psychosocial factors in the assessment and treatment of osteoarthritis. As few studies have evaluated the effect of psychological interventions on knee osteoarthritis pain, good quality randomized controlled trials are needed to determine their effectiveness. METHODS/DESIGN: We intend to conduct a 6-week single-blinded randomized controlled trial with a 12-month follow-up. Altogether, 108 patients aged from 35 to 75 years with clinical symptoms and radiographic grading (KL 2-4) of knee osteoarthritis will be included. The clinical inclusion criteria are pain within the last year in or around the knee occurring on most days for at least one month, and knee pain of >= 40 mm on a 100-mm visual analogue scale in the WOMAC pain subscale for one week prior to study entry. Patients with any severe psychiatric disorder, other back or lower limb pain symptoms more aggravating than knee pain, or previous or planned lower extremity joint surgery will be excluded. The patients will be randomly assigned to a combined GP care and cognitive-behavioral intervention group (n = 54) or to a GP care control group (n = 54). The cognitive-behavioral intervention will consist of 6 weekly group sessions supervised by a psychologist and a physiotherapist experienced in the treatment of pain. The main goals of the intervention are to reduce maladaptive pain coping and to increase the self-management of pain and disability. The follow-up-points will be arranged at 3 and 12 months. The primary outcome measure will be the WOMAC pain subscale. Secondary outcome measures will include self-reports of pain and physical function, a health related quality of life questionnaire, and various psychological questionnaires. Personnel responsible of the data analysis will be blinded. DISCUSSION: This study addresses the current topic of non-pharmacological conservative treatment of knee OA-related pain. We anticipate that these results will provide important new insights to the current care recommendations. TRIAL REGISTRATION: Current Controlled Trials ISRCTN64794760. PMID- 23356457 TI - How do dentists and their teams incorporate evidence about preventive care? An empirical study. AB - OBJECTIVES: To identify how dentists and their teams adopt evidence-based preventive care. METHODS: A qualitative study using grounded theory methodology was conducted. We interviewed 23 participants working in eight dental practices about their experience and work processes, while adopting evidence-based preventive care. During the study, Charmaz's grounded theory methodology was employed to examine the social process of adopting preventive dental care in dental practices. Charmaz's iteration of the constant comparative method was used during the data analysis. This involved coding of interview transcripts, detailed memo-writing and drawing diagrams. The transcripts were analyzed as soon as possible after each round of interviews in each dental practice. Coding was conducted primarily by AS, supported by team meetings and discussions when researchers compared their interpretations. RESULTS: Participants engaged in a slow process of adapting evidence-based protocols and guidelines to the existing logistics of the practices. This process was influenced by practical, philosophical, and historical aspects of dental care, and a range of barriers and facilitators. In particular, dentists spoke spontaneously about two deeply held 'rules' underpinning continued restorative treatment, which acted as barriers to provide preventive care: (i) dentists believed that some patients were too 'unreliable' to benefit from prevention; and (ii) dentists believed that patients thought that only tangible restorative treatment offered 'value for money'. During the adaptation process, some dentists and teams transitioned from their initial state - selling restorative care - through an intermediary stage - learning by doing and educating patients about the importance of preventive care and finally to a stage where they were offering patients more than just restorative care. Resources were needed for the adaptation process to occur, including: the ability to maintain the financial viability of the practice, appropriate technology, time, and supportive dental team relationships. CONCLUSIONS: The findings from this study show that with considerable effort, motivation and coordination, it is possible for dental practices to work against the dental 'mainstream' and implement prevention as their clinical norm. This study has shown that dental practice is not purely scientific, but it includes cultural, social, and economic resources that interfere with the provision of preventive care. PMID- 23356458 TI - Supramolecular switching between flat sheets and helical tubules triggered by coordination interaction. AB - Here we report the spontaneous formation of switchable sheets in aqueous solution, which is based on bent-shaped aromatic amphiphiles containing m pyridine units at the terminals and a hydrophilic dendron at the apex. The aromatic segments self-assemble into flat sheets consisting of a zigzag conformation through pi-pi stacking interactions. Notably, the sheets reversibly transform into helical tubules at higher concentration and into discrete dimeric macrocycles at a lower concentration in response to Ag(I) ions through reversible coordination interactions between the pyridine units of the aromatic segments and the Ag(I) ions. While maintaining the coordination bonding interactions, the helical tubules reversibly transform into the dimeric macrocycles in response to the variation in concentration. PMID- 23356459 TI - Tick-borne diseases in the South-East need human studies: Lyme disease, STARI and beyond. PMID- 23356456 TI - Bronchoalveolar lavage as a tool to predict, diagnose and understand bronchiolitis obliterans syndrome. AB - Bronchiolitis obliterans syndrome (BOS), a condition of irreversible small airway fibrosis, is the principal factor limiting long-term survival after lung transplantation. Bronchoscopy and bronchoalveolar lavage (BAL), techniques central to lung transplant clinical practice, provide a unique opportunity to interrogate the lung allograft during BOS development and identify potential disease mechanisms or biomarkers. Over the past 20 years, numerous studies have evaluated the BAL cellular composition, cytokine profiles and protein constituents in lung transplant recipients with BOS. To date, however, no summative evaluation of this literature has been reported. We developed and applied objective criteria to qualitatively rank the strength of associations between BAL parameters and BOS in order to provide a comprehensive and systematic assessment of the literature. Our analysis indicates that several BAL parameters, including neutrophil count, interleukin-8, alpha defensins and MMP-9, demonstrate highly replicable associations with BOS. Additionally, we suggest that considerable opportunity exists to increase the knowledge gained from BAL analyses in BOS through increased sample sizes, covariant adjustment and standardization of the BAL technique. Further efforts to leverage analysis of BAL constituents in BOS may offer great potential to provide additional in-depth and mechanistic insights into the pathogenesis of this complex disease. PMID- 23356460 TI - Response and biological subtype of myeloma are independent prognostic factors and combine to define outcome after high-dose therapy. PMID- 23356461 TI - Protective effect of melatonin and 1,25-dihydroxyvitamin D3 on renal ischemia reperfusion injury in rats. AB - Ischemia-reperfusion (I/R) injury induces the generation of reactive oxygen species (ROS) which affect many organs. This study was designed to investigate the roles of melatonin and 1,25-dihydroxyvitamin D3 (VD3) on renal I/R injury. Thirty male Wistar albino rats were divided into five groups: group 1, control; group 2, right nephrectomy (RN) + I/R in the contralateral kidney; group 3, melatonin + RN + I/R; group 4, VD3 + RN + I/R; and group 5, melatonin + VD3 + RN + I/R. Melatonin (10 mg/kg), VD3 (0.5 MUg/kg), and melatonin plus VD3 were injected intraperitoneally for 7 days before renal I/R. After 7 days, right nephrectomy was initially performed and left renal artery was clamped for 45 min. After 45-min reperfusion, the serum and kidney tissue samples were obtained for assays. Melatonin and VD3 had an ameliorative effect on biochemical parameters such as serum creatinine (SCr) and blood urea nitrogen (BUN). Renal tissue malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO) levels, and superoxide dismutase (SOD) activity were determined. Renal I/R decreased the kidney tissue GSH levels and SOD activity and increased the NO levels as compared with control group. However, melatonin and VD3 and melatonin plus VD3 treatment significantly increased the tissue GSH levels and SOD activity and decreased the NO levels compared with those of I/R group. Meanwhile, MDA levels were not different between the control and I/R groups. But, MDA levels decreased in all treated groups compared to I/R and control groups. These data support that melatonin and VD3 have beneficial effects on renal injury. PMID- 23356463 TI - Genital lichen sclerosus/balanitis xerotica obliterans in men with penile carcinoma: a critical analysis. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The European Association of Urology guidelines identify lichen sclerosus (LS) as a strong risk factor for penile squamous cell carcinoma (pSCC). However, this statement is based on the findings of case-control studies (Level of Evidence 2a) and a direct causal relationship between LS/balanitis xerotica obliterans (BXO) and pSCC remains to be established. Firm guidelines with respect to the appropriate follow up policy for LS/BXO are lacking, whereas the impact of synchronous LS/BXO on the prognosis of pSCC remains to be determined. The presence of histologically confirmed synchronous LS/BXO in patients diagnosed with pSCC is relatively high, although it is not associated with an increased risk of adverse histopathological features. LS/BXO can develop in extragenital skin grafts used for reconstruction after organ-sparing surgery for pSCC. OBJECTIVES: To determine the rate of lichen sclerosus/balanitis xerotica obliterans (LS/BXO) in patients with penile squamous cell carcinoma (pSCC) and establish whether the presence of LS/BXO is associated with adverse histopathological features of pSCC. To report the phenomenon of LS involving non-genital skin grafts in patients who underwent organ-sparing surgery and split-skin graft (SSG) reconstruction PATIENTS AND METHODS: Between January 2002 and January 2010, 223 men underwent surgical treatment for pSCC. A group of 52 patients with histologically-confirmed synchronous LS was identified (group A; overall rate of LS/BXO = 23.3%) and compared with a group of patients without synchronous LS (group B; n = 171; 76.7%). A subgroup of patients who underwent surgical excision and SSG reconstruction was also identified The histology reports of graft biopsies obtained during follow-up were reviewed and the rate of LS involving the graft was also recorded. RESULTS: Mean (range) age at diagnosis was 60.9 (34-81) years and 60.7 (28-89) years for groups A and B, respectively (P = 0.958). The mean (range) duration of follow-up was 38.3 (4-92) months for group A and 45.5 (4-107) months for group B (P = 0.162) No statistically significant differences were noted between groups A and B in terms of tumour grade (P = 0.091), stage (P = 0.697), presence of lymphovascular invasion (P = 0.333), histological subtype (P = 0.107), associated carcinoma in situ (P = 0.246) or nodal status at initial diagnosis (P = 0.555). In the subgroup of 188 patients who underwent SSG reconstruction, 41 (21.8%) patients had histologically confirmed synchronous LS; in this subgroup, 26 (13.8%) patients underwent graft biopsy during follow-up. Genital LS involving the graft was identified in seven specimens, although none of these seven cases had associated recurrent pSCC. CONCLUSIONS: The presence of histologically-confirmed synchronous LS in patients with pSCC is relatively high but is not associated with increased rates of adverse histopathological features, including carcinoma in situ. LS can develop in extragenital skin grafts, although its association with the long-term risk for recurrent pSCC is not apparent in the present study. PMID- 23356464 TI - The relation of racial identity, ethnic identity, and racial socialization to discrimination-distress: a meta-analysis of Black Americans. AB - This meta-analysis synthesized the results of 27 studies examining the relations of racial identity, ethnic identity, and racial socialization to discrimination distress for Black Americans. The purpose was to uncover which constructs connected to racial identity, ethnic identity, and racial socialization most strongly correlate with racial discrimination and psychological distress. Discrimination significantly related to aspects of racial identity, including immersion-emersion, public regard, encounter, Afrocentricity/racial centrality/private regard, and internalization. Distress significantly correlated with preencounter/assimilation, encounter, public regard, immersion-emersion, and Afrocentricity/racial centrality/private regard. Several of these relationships were significantly moderated by the measure of racial identity or demographic variables (gender or age). Implications of these findings are discussed. PMID- 23356465 TI - Uniformity of evidence-based treatments in practice? Therapist effects in the delivery of cognitive processing therapy for PTSD. AB - OBJECTIVE: Various factors contribute to the effective implementation of evidence based treatments (EBTs). In this study, cognitive processing therapy (CPT) was administered in a Veterans Affairs (VA) posttraumatic stress disorder (PTSD) specialty clinic in which training and supervision were provided following VA implementation guidelines. The aim was to (a) estimate the proportion of variability in outcome attributable to therapists and (b) identify characteristics of those therapists who produced better outcomes. METHOD: We used an archival database of veterans (n = 192) who completed 12 sessions of CPT by therapists (n = 25) who were trained by 2 nationally recognized trainers, 1 of whom also provided weekly group supervision. Multilevel modeling was used to estimate therapist effects, with therapists treated as a random factor. The supervisor was asked to retrospectively rate each therapist in terms of perceived effectiveness based on supervision interactions. Using single case study design, the supervisor was interviewed to determine what criteria she used to rate the therapists and emerging themes were coded. RESULTS: When initial level of severity on the PTSD Checklist (PCL; McDonald & Calhoun, 2010; Weathers, Litz, Herman, Huska, & Keane, 1993) was taken into account, approximately 12% of the variability in the PCL at the end of treatment was due to therapists. The trainer, blind to the results, identified the following characteristics and actions of effective therapists: effectively addressing patient avoidance, language used in supervision, flexible interpersonal style, and ability to develop a strong therapeutic alliance. CONCLUSIONS: This study adds to the growing body of literature documenting the importance of the individual therapist as an important factor in the change process. PMID- 23356466 TI - Openness, right-wing authoritarianism, and antigay prejudice in college students: a mediational model. AB - Research has indicated that people who are more open to novel and diverse experiences express less prejudicial views concerning minority group members. The openness-prejudice relationship, however, may be mediated by the degree to which individuals adhere to traditional social convention and absolutist thinking patterns. Thus, informed by the Dual-Process Cognitive-Motivational Model of ideology and prejudice (Duckitt, 2001; Duckitt & Sibley, 2009) and the Five Factor Model of personality (Costa & McCrae, 1992; McCrae & Costa, 2003), we investigated right-wing authoritarianism (RWA) as a mediator of the relationship between openness and antigay prejudice. Participants were college students from universities in the mid-Atlantic (Sample 1, n = 199) and southeastern (Sample 2, n = 244) United States. Hypotheses were tested in both samples. First, bivariate relations among openness, RWA, and antigay prejudice were assessed. Second, RWA was tested was a mediator of the relationship between openness and antigay prejudice. Results supported expected bivariate associations in that openness negatively, and RWA positively, associated with antigay prejudice. Moreover, results showed that RWA mediates the negative relationship between openness and antigay prejudice. Implications of the supported model are discussed with respect to antigay prejudice theory as well as prejudice-reduction interventions for use on college campuses. PMID- 23356467 TI - Romantic attachment and relationship functioning in same-sex couples. AB - The present study was designed to investigate links between dimensions of romantic attachment and relationship functioning in a cross-sectional sample of people in same-sex relationships, with the goals of replicating basic findings from research on heterosexual couples and advancing understanding of unique issues faced by same-sex couples. The sample included 274 female couples, 188 male couples, 34 women whose female partners did not participate, and 39 men whose male partners did not participate. Participants were recruited from geographically diverse regions of the United States and Canada and provided data by responding to pencil-and-paper surveys. Attachment insecurity in both self and partner were linked with poor relationship functioning across a range of variables (satisfaction, commitment, trust, communication, problem intensity). The pattern of results was identical for women and men, but the effects were stronger in male couples for some associations between attachment variables and indices of positive relationship functioning. Monogamy was positively associated with relationship quality only when participants or their partners reported moderate or high levels of attachment anxiety. Contrary to hypothesis, attachment did not moderate links between minority stressors and relationship functioning. PMID- 23356468 TI - Racial and ethnic minority college students' stigma associated with seeking psychological help: Examining psychocultural correlates. AB - Many college students underuse professional psychological help for mental health difficulties. The stigma associated with seeking such help appears to be one of the reasons for this underuse. Levels of psychological distress and past use of counseling/psychotherapy have been found to be important correlates of stigma associated with seeking psychological help (Obasi & Leong, 2009; Vogel, Wade, & Haake, 2006). For racial and ethnic minorities, the hindering effects of self stigma and perceived stigmatization by others on treatment seeking may further be compounded by their relationships with their own ethnic groups, with other ethnic groups, and with the dominant society. This study used structural equation modeling (SEM) to test a model that explored the effects of psychological distress and psychocultural variables (i.e., ethnic identity, other-group orientation, perceived discrimination) on perceived stigmatization by others and self-stigma for seeking psychological help, controlling for past use of counseling/psychotherapy. The sample consisted of 260 African American, 166 Asian American, and 183 Latino American students. SEM multigroup analyses indicated measurement invariance, but partial structural invariance, across racial/ethnic groups. Across all 3 groups, higher levels of psychological distress and perceived racial/ethnic discrimination, respectively, predicted higher levels of perceived stigmatization by others for seeking psychological help, which, in turn, predicted greater self-stigma for seeking psychological help. Higher levels of other-group orientation predicted lower levels of self-stigma of seeking psychological help across groups. Higher levels of ethnic identity predicted lower levels of self-stigma of seeking psychological help only for African Americans. Implications for research and practice are discussed. PMID- 23356469 TI - The Intuitive Eating Scale-2: item refinement and psychometric evaluation with college women and men. AB - The 21-item Intuitive Eating Scale (IES; Tylka, 2006) measures individuals' tendency to follow their physical hunger and satiety cues when determining when, what, and how much to eat. While its scores have demonstrated reliability and validity with college women, the IES-2 was developed to improve upon the original version. Specifically, we added 17 positively scored items to the original IES items (which were predominantly negatively scored), integrated an additional component of intuitive eating (Body-Food Choice Congruence), and evaluated its psychometric properties with 1,405 women and 1,195 men across three studies. After we deleted 15 items (due to low item-factor loadings, high cross-loadings, and redundant content), the results supported the psychometric properties of the IES-2 with women and men. The final 23-item IES-2 contained 11 original items and 12 added items. Exploratory and second-order confirmatory factor analyses upheld its hypothesized 4-factor structure (its original 3 factors, plus Body-Food Choice Congruence) and a higher order factor. The IES-2 was largely invariant across sex, although negligible differences on 1 factor loading and 2 item intercepts were detected. Demonstrating validity, the IES-2 total scores and most IES-2 subscale scores were (a) positively related to body appreciation, self esteem, and satisfaction with life; (b) inversely related to eating disorder symptomatology, poor interoceptive awareness, body surveillance, body shame, body mass index, and internalization of media appearance ideals; and (c) negligibly related to social desirability. IES-2 scores also garnered incremental validity by predicting psychological well-being above and beyond eating disorder symptomatology. The IES-2's applications for empirical research and clinical work are discussed. PMID- 23356470 TI - Over a half-century encapsulated: a multicultural content analysis of the Journal of Counseling Psychology, 1954-2009. AB - Articles including multicultural content published in the Journal of Counseling Psychology (JCP), from 1954 to 2009, were examined for themes. Multicultural content in this study was broadly defined to include the following identities: race/ethnicity, gender/sex, religion/spirituality, sexual orientation, social status, disability, age, and intersections. Inclusion of articles focused on each of these identity domains was reported by decade. Gender/sex was the most prevalent multicultural identity found in the JCP, followed by race/ethnicity. The most common themes for multicultural articles, in order, were counseling process, vocation/career, and psychological processes/interventions. Academic achievement, discrimination/minority stress, and research methodology were the other common themes that were found across multicultural research. Implications of these findings are discussed. PMID- 23356471 TI - Asymptomatic oral yeast carriage and antifungal susceptibility profile of HIV infected patients in Kunming, Yunnan Province of China. AB - BACKGROUND: Oral Candida colonization and its relation with predisposing factors in HIV-infected patients have received wide concerns during recent decades. In this study, we investigated asymptomatic oral Candida carriage rate, species distribution and antifungal susceptibility of 604 HIV-infected patients and 851 healthy individuals in Kunming, Yunnan Province of China. METHODS: Mucosal swab sampling was taken from each subject and CHROMagar Candida agar medium and API 20C AUX system were used to identify yeast isolates. In vitro antifungal susceptibility was tested by the broth microdilution method according to the M27 A2 document of the Clinical and Laboratory Standard Institute (CLSI). RESULTS: The oral yeast colonization rate in HIV-infected patients (49.5%) was higher than that of healthy subjects (20.7%). Candida albicans constituted the most frequent species, accounting for 82.2% of yeast isolates. The remaining species were composed of C. glabrata, C. parapsilosis, C. krusei, C. tropicalis, C. rugosa, C. norvegensis, Pichia ohmeri and Saccharomyces cerevisiae. In HIV-infected patients, asymptomatic oral yeast colonization was associated with low CD4 cell count (<200 cells/mm3) and lack of highly active antiretroviral therapy (HAART). Different Candida species isolated from our samples presented different susceptibility to voriconazole, fluconazole and itraconazole. Amphotericin B had the best inhibiting effect for all isolates. CONCLUSION: Oral yeast colonization in Han Chinese patients with HIV from Kunming had common and unique features and was associated with CD4 cell number and HARRT. Amphotericin B should be used with first priority in controlling Candida infection in Han Chinese patients from Kunming. Our results provide first hand information on monitoring oral yeasts colonization in HIV-infected patients from Kunming, China. PMID- 23356473 TI - C-alkylation of chiral tropane- and homotropane-derived enamines. AB - The synthesis and alkylation of chiral, nonracemic tropane- and homotropane derived enamines is examined as an approach to enantioenriched alpha-alkylated aldehydes. The two bicyclic N auxiliaries, which differ by a single methylene group, give opposite senses of asymmetric induction on alkylation with EtI and provide modestly enantioenriched 2-ethylhexanal (following hydrolysis of the alkylated iminium). The observed stereoselectivity is supported by density functional studies of ethylation for both enamines. PMID- 23356474 TI - Elevated CO2 enrichment induces a differential biomass response in a mixed species temperate forest plantation. AB - In a free-air carbon dioxide (CO(2)) enrichment study (BangorFACE), Alnus glutinosa, Betula pendula and Fagus sylvatica were planted in areas of one-, two- and three-species mixtures (n = 4). The trees were exposed to ambient or elevated CO(2) (580 MUmol mol(-1)) for 4 yr, and aboveground growth characteristics were measured. In monoculture, the mean effect of CO(2) enrichment on aboveground woody biomass was + 29, + 22 and + 16% for A. glutinosa, F. sylvatica and B. pendula, respectively. When the same species were grown in polyculture, the response to CO(2) switched to + 10, + 7 and 0% for A. glutinosa, B. pendula and F. sylvatica, respectively. In ambient atmosphere, our species grown in polyculture increased aboveground woody biomass from 12.9 +/- 1.4 to 18.9 +/- 1.0 kg m(-2), whereas, in an elevated CO(2) atmosphere, aboveground woody biomass increased from 15.2 +/- 0.6 to 20.2 +/- 0.6 kg m(-2). The overyielding effect of polyculture was smaller (+ 7%) in elevated CO(2) than in an ambient atmosphere (+ 18%). Our results show that the aboveground response to elevated CO(2) is affected significantly by intra- and interspecific competition, and that the elevated CO(2) response may be reduced in forest communities comprising tree species with contrasting functional traits. PMID- 23356475 TI - Pharmacokinetics and elimination efficiency of linezolid during dialysis. AB - Linezolid (LZD) is an option for treating infections caused by multi-resistant Gram-positive bacteria. The protein-binding rate of LZD markedly influences its elimination by dialysis, with limited data suggesting that LZD is cleared by intermittent hemodialysis. Here, we investigated the protein-binding rate and elimination efficiency of LZD in a sepsis patient receiving dialysis. The oral administration of LZD at 600 mg/day resulted in protein-binding and free rates of the drug of 20.4% and 79.6%, respectively, 24 h after administration. By comparing the LZD concentration before and after dialysis, the elimination efficiency of free LZD as a result of dialysis was found to be 40.6%. Our sepsis patient showed higher plasma concentrations of LZD at trough after hemodialysis than the reported concentrations in normal renal function patients. However, it is not clear from our present findings if a relationship exists between myelosuppression and plasma LZD concentration. PMID- 23356476 TI - Neighbourhood safety and leisure-time physical activity among Dutch adults: a multilevel perspective. AB - BACKGROUND: Several neighbourhood elements have been found to be related to leisure-time walking and cycling. However, the association with neighbourhood safety remains unclear. This study aimed to assess the association of neighbourhood-level safety with leisure-time walking and cycling among Dutch adults. METHODS: Data were derived from the national health survey (POLS) 2006 2009, with valid data on 20046 respondents residing in 2127 neighbourhoods. Multilevel logistic regression models were used to examine the association between neighbourhood-level safety (general safety and specific safety components: physical disorder, social disorder, crime-related fear, traffic safety) and residents' engagement in outdoor leisure-time walking and cycling for at least 30 minutes per week. RESULTS: An increase in neighbourhood safety (both general safety and each of the safety components) was significantly associated with an increase in leisure-time cycling participation. Associations were strongest for general safety and among older women. In the general population, neighbourhood safety was not significantly associated with leisure-time walking. However, among younger and older adult men and lower educated individuals, an increase in general safety was associated with a decrease in leisure-time walking participation. CONCLUSIONS: In the Netherlands, neighbourhood safety appears to be related to leisure-time cycling but not to walking. Leisure-time cycling may best be encouraged by improving different safety components at once, rather than focusing on one safety aspect such as traffic safety. Special attention is needed for older women. PMID- 23356478 TI - Periconceptional factors affect the risk of neural tube defects in offspring: a hospital-based case-control study in China. AB - OBJECTIVE: To explore the periconceptional factors affecting the risk of neural tube defects (NTDs), we carried out a hospital-based case-control study in China. METHODS: A 1:1 matched case-control study was conducted. With self-designed questionnaires, we solicited relevant information from 459 case mothers and 459 control mothers selected in two provinces of China through face-to-face interviews. Univariate and multivariate conditional logistic regression analyses were conducted to evaluate the effect values by odds ratios (ORs) and 95% confidence intervals (95%CIs) with SAS9.1.3.software. RESULTS: Daily passive tobacco smoke exposure was a risk factor for total NTDs (OR = 8.688, 95%CI = 2.329-32.404). Diet adjustment in the first trimester (OR = 0.061, 95%CI = 0.014 0.274), periconceptional folic acid intake (OR = 0.059, 95%CI = 0.011-0.321) and health education (OR = 0.251, 95%CI = 0.081-0.781) were protective factors for total NTDs. Differences in factors and their effects on NTDs were found for the three subtypes of NTDs: anencephaly, spina bifida and encephalocele. CONCLUSIONS: Daily passive tobacco smoke exposure, diet adjustment in the first trimester, periconceptional folic acid intake and health education were associated with NTDs. PMID- 23356479 TI - Synthesis of Cu2SnSe3 nanocrystals for solution processable photovoltaic cells. AB - This paper describes the synthesis of ternary chalcogenide Cu(2)SnSe(3) nanocrystals as an alternative solar absorber material to conventional quaternary CuIn(x)Ga(1-x)Se(2). We used the hot coordination solvent method with hexadecylamine as the capping ligand for the first time for this material system. Using a variety of characterization techniques, such as X-ray diffraction, selected area electron diffraction, convergent beam electron diffraction, and Raman spectroscopy, the nanocrystals were found to be monoclinic Cu(2)SnSe(3) with an optical energy band gap of 1.3 eV and have a narrow size distribution. These nanocrystals are shown to be photosensitive in the range of wavelengths corresponding to the solar spectrum, which makes them highly promising as alternative photon absorber materials for photovoltaic applications. PMID- 23356477 TI - Bench-to-bedside review: functional hemodynamics during surgery - should it be used for all high-risk cases? AB - The administration of a fluid bolus is done frequently in the perioperative period to increase the cardiac output. Yet fluid loading fails to increase the cardiac output in more than 50% of critically ill and surgical patients. The assessment of fluid responsiveness (the slope of the left ventricular function curve) prior to fluid administration may thus not only help in detecting patients in need of fluids but may also prevent unnecessary and harmful fluid overload. Unfortunately, commonly used hemodynamic parameters, including the cardiac output itself, are poor predictors of fluid responsiveness, which is best assessed by functional hemodynamic parameters. These dynamic parameters reflect the response of cardiac output to a preload-modifying maneuver (for example, a mechanical breath or passive leg-raising), thus providing information about fluid responsiveness without the actual administration of fluids. All dynamic parameters, which include the respiratory variations in systolic blood pressure, pulse pressure, stroke volume and plethysmographic waveform, have been repeatedly shown to be superior to commonly used static preload parameters in predicting the response to fluid loading. Within their respective limitations, functional hemodynamic parameters should be used to guide fluid therapy as part of or independently of goal-directed therapy strategies in the perioperative period. PMID- 23356481 TI - Ethanol and biogas production after steam pretreatment of corn stover with or without the addition of sulphuric acid. AB - BACKGROUND: Lignocellulosic biomass, such as corn stover, is a potential raw material for ethanol production. One step in the process of producing ethanol from lignocellulose is enzymatic hydrolysis, which produces fermentable sugars from carbohydrates present in the corn stover in the form of cellulose and hemicellulose. A pretreatment step is crucial to achieve efficient conversion of lignocellulosic biomass to soluble sugars, and later ethanol. This study has investigated steam pretreatment of corn stover, with and without sulphuric acid as catalyst, and examined the effect of residence time (5-10 min) and temperature (190-210 degrees C) on glucose and xylose recovery. The pretreatment conditions with and without dilute acid that gave the highest glucose yield were then used in subsequent experiments. Materials pretreated at the optimal conditions were subjected to simultaneous saccharification and fermentation (SSF) to produce ethanol, and remaining organic compounds were used to produce biogas by anaerobic digestion (AD). RESULTS: The highest glucose yield achieved was 86%, obtained after pretreatment at 210 degrees C for 10 minutes in the absence of catalyst, followed by enzymatic hydrolysis. The highest yield using sulphuric acid, 78%, was achieved using pretreatment at 200 degrees C for 10 minutes. These two pretreatment conditions were investigated using two different process configurations. The highest ethanol and methane yields were obtained from the material pretreated in the presence of sulphuric acid. The slurry in this case was split into a solid fraction and a liquid fraction, where the solid fraction was used to produce ethanol and the liquid fraction to produce biogas. The total energy recovery in this case was 86% of the enthalpy of combustion energy in corn stover. CONCLUSIONS: The highest yield, comprising ethanol, methane and solids, was achieved using pretreatment in the presence of sulphuric acid followed by a process configuration in which the slurry from the pretreatment was divided into a solid fraction and a liquid fraction. The solid fraction was subjected to SSF, while the liquid fraction, together with the filtered residual from SSF, was used in AD. Using sulphuric acid in AD did not inhibit the reaction, which may be due to the low concentration of sulphuric acid used. In contrast, a pretreatment step without sulphuric acid resulted not only in higher concentrations of inhibitors, which affected the ethanol yield, but also in lower methane production. PMID- 23356482 TI - Gene body methylation shows distinct patterns associated with different gene origins and duplication modes and has a heterogeneous relationship with gene expression in Oryza sativa (rice). AB - Whole-genome duplication (WGD) has been recurring and single-gene duplication is also widespread in angiosperms. Recent whole-genome DNA methylation maps indicate that gene body methylation (i.e. of coding regions) has a functional role. However, whether gene body methylation is related to gene origins and duplication modes has yet to be reported. In rice (Oryza sativa), we computed a body methylation level (proportion of methylated CpG within coding regions) for each gene in five tissues. Body methylation levels follow a bimodal distribution, but show distinct patterns associated with transposable element-related genes; WGD, tandem, proximal and transposed duplicates; and singleton genes. For pairs of duplicated genes, divergence in body methylation levels increases with physical distance and synonymous (Ks) substitution rates, and WGDs show lower divergence than single-gene duplications of similar Ks levels. Intermediate body methylation tends to be associated with high levels of gene expression, whereas heavy body methylation is associated with lower levels of gene expression. The biological trends revealed here are consistent across five rice tissues, indicating that genes of different origins and duplication modes have distinct body methylation patterns, and body methylation has a heterogeneous relationship with gene expression and may be related to survivorship of duplicated genes. PMID- 23356483 TI - Lonely no more: remembering text messaging in mHealth conversations. PMID- 23356484 TI - Infertility in rats subjected to genitofemoral nerve section is not associated with testicular damage. AB - This work was aimed at assessing the relationship between testicular ascent and infertility induced by genitofemoral nerve (GFN) section in rats. Eighteen male rats were assigned to three experimental groups as follows: (i) Group SGFN was subjected to surgical section of genitofemoral nerve; (ii) Group Sham; (iii) Control group. The GFN was cut at puberty (28D), and the contralateral testis removed at 90D, with fertility tests at 120D. At 150D, maturity index, epithelial area and histopathological index of seminiferous tubules of all rats were determined and statistically compared between superior and inferior testicle poles, and between groups. There were no differences in testicular parameters, sperm morphology or sperm concentrations (P > 0.05). Section of NGF interfered with fertility (58.3 +/- 15.4 in SGFN versus 83.3 +/- 10.5 in Sham) and litter size (6.2 +/- 1.1 in SGFN versus 10.7 +/- 1.4 in Sham). Cremaster of SGFN group showed early neuropathy. The GFN section induced partial testicular ascent and diminished fertility without damage on testicular morphology or spermatic parameters, because, cremaster could affect the contractibility and ejaculation mechanisms in which it participates. The study of the damage on cremaster induced by an injury on GFN could have an overview of the mechanisms inherent in the testicular ascent induced by this iatrogenic alteration and their potential risks on fertility. PMID- 23356485 TI - Risk assessment of the introduction of porcine reproductive and respiratory syndrome virus via boar semen into Switzerland as an example of a PRRSV-free country. AB - Switzerland is currently porcine reproductive and respiratory syndrome virus (PRRSV) free, but semen imports from PRRSV-infected European countries are increasing. As the virus can be transmitted via semen, for example, when a free boar stud becomes infected, and the risk of its import in terms of PRRSV introduction is unknown, the annual probability to accidentally import the virus into Switzerland was estimated in a risk assessment. A quantitative stochastic model was set up with data comprised by import figures of 2010, interviews with boar stud owners and expert opinion. It resulted in an annual median number of 0.18 imported ejaculates (= imported semen doses from one collection from one donor) from PRRSV-infected boars. Hence, one infected ejaculate would be imported every 6 years and infect a mean of 10 sows. These results suggest that under current circumstances, there is a substantial risk of PRRSV introduction into Switzerland via imported boar semen and that measures to enhance safety of imports should be taken. The time from infection of a previously negative boar stud to its detection had the highest impact on the number of imported 'positive' ejaculates. Therefore, emphasis should be placed on PRRSV monitoring protocols in boar studs. Results indicated that a substantial increase in safety could only be achieved with much tighter sampling protocols than currently performed. Generally, the model could easily be customized for other applications like other countries or regions or even sow farms that want to estimate their risk when purchasing semen from a particular boar stud. PMID- 23356486 TI - Lenalidomide in lymphomas and chronic lymphocytic leukemia. AB - INTRODUCTION: Lenalidomide , a thalidomide analog, is representative of a new class of antineoplastic drugs which has been especially effective in certain hematologic malignancies such as myeloma and myelodysplasia. Lenalidomide has anti-inflammatory, anti-angiogenic and immunomodulatory properties, and targets tumor cells by direct cytotoxicity and, indirectly by interfering with several components of the tumor microenvironment [1]. Lenalidomide retains antitumor activity equal to or greater than the parent compound, thalidomide, but with less toxicity [2]. AREAS COVERED: This paper summarizes what is known about the mechanisms of action of lenalidomide, and recent clinical results in lymphoma and chronic lymphocytic leukemia. A literature review was accomplished by searching the PubMed database for papers in English. Publications from 2000 through November 2012 were analyzed. Search terms used were lenalidomide, lymphoma, chronic lymphocytic leukemia, and Hodgkin's lymphoma. A manual search of conference proceedings from the previous 5 years of the American Society of Clinical Oncology, American Society of Hematology, America Association of Cancer Research, and the European Hematology Association was also conducted. Relevant references in chosen papers were also considered. EXPERT OPINION: The data suggest that lenalidomide will play a major role in the management of certain lymphoid neoplasms such as B-cell lymphoma, chronic lymphocytic leukemia and, perhaps, T-cell lymphoma. PMID- 23356487 TI - Marked host specificity and lack of phylogeographic population structure of Campylobacter jejuni in wild birds. AB - Zoonotic pathogens often infect several animal species, and gene flow among populations infecting different host species may affect the biological traits of the pathogen including host specificity, transmissibility and virulence. The bacterium Campylobacter jejuni is a widespread zoonotic multihost pathogen, which frequently causes gastroenteritis in humans. Poultry products are important transmission vehicles to humans, but the bacterium is common in other domestic and wild animals, particularly birds, which are a potential infection source. Population genetic studies of C. jejuni have mainly investigated isolates from humans and domestic animals, so to assess C. jejuni population structure more broadly and investigate host adaptation, 928 wild bird isolates from Europe and Australia were genotyped by multilocus sequencing and compared to the genotypes recovered from 1366 domestic animal and human isolates. Campylobacter jejuni populations from different wild bird species were distinct from each other and from those from domestic animals and humans, and the host species of wild bird was the major determinant of C. jejuni genotype, while geographic origin was of little importance. By comparison, C. jejuni differentiation was restricted between more phylogenetically diverse farm animals, indicating that domesticated animals may represent a novel niche for C. jejuni and thereby driving the evolution of those bacteria as they exploit this niche. Human disease is dominated by isolates from this novel domesticated animal niche. PMID- 23356488 TI - Biofilm formation by clinical isolates and the implications in chronic infections. AB - BACKGROUND: Biofilm formation is a major virulence factor contributing to the chronicity of infections. To date few studies have evaluated biofilm formation in infecting isolates of patients including both Gram-positive and Gram-negative multidrug-resistant (MDR) species in the context of numerous types of infectious syndromes. Herein, we investigated the biofilm forming capacity in a large collection of single patient infecting isolates and compared the relationship between biofilm formation to various strain characteristics. METHODS: The biofilm forming capacity of 205 randomly sampled clinical isolates from patients, collected from various anatomical sites, admitted for treatment at Brooke Army Medical Center (BAMC) from 2004-2011, including methicillin-resistant/methicillin susceptible Staphylococcus aureus (MRSA/MSSA) (n=23), Acinetobacter baumannii (n=53), Pseudomonas aeruginosa (n=36), Klebsiella pneumoniae (n=54), and Escherichia coli (n=39), were evaluated for biofilm formation using the high throughput microtiter plate assay and scanning electron microscopy (SEM). Relationships between biofilm formation to clonal type, site of isolate collection, and MDR phenotype were evaluated. Furthermore, in patients with relapsing infections, serial strains were assessed for their ability to form biofilms in vitro. RESULTS: Of the 205 clinical isolates tested, 126 strains (61.4%) were observed to form biofilms in vitro at levels greater than or equal to the Staphylococcus epidermidis, positive biofilm producing strain, with P. aeruginosa and S. aureus having the greatest number of biofilm producing strains. Biofilm formation was significantly associated with specific clonal types, the site of isolate collection, and strains positive for biofilm formation were more frequently observed to be MDR. In patients with relapsing infections, the majority of serial isolates recovered from these individuals were observed to be strong biofilm producers in vitro. CONCLUSIONS: This study is the first to evaluate biofilm formation in a large collection of infecting clinical isolates representing diverse types of infections. Our results demonstrate: (1) biofilm formation is a heterogeneous property amongst clinical strains which is associated with certain clonal types, (2) biofilm forming strains are more frequently isolated from non-fluid tissues, in particular bone and soft tissues, (3) MDR pathogens are more often biofilm formers, and (4) strains from patients with persistent infections are positive for biofilm formation. PMID- 23356489 TI - Incidence and persistence/recurrence of men's sexual difficulties: findings from the Australian Longitudinal Study of Health and Relationships. AB - This study presents data on the prevalence, incidence, and persistence/recurrence of 8 sexual difficulties among men. Participants were 3,157 Australian men who were administered 2 computer-assisted interviews approximately 12 months apart. Analyses were based on a weighted sample of 2,158 men who were 20-64 years of age, sexually active in the past 12 months, and in the same heterosexual relationship at both interviews. Upon recruitment, a third of men (34%) reported having 1 or more sexual difficulties. At follow-up, 21% reported a new sexual difficulty. The 2 highest incident difficulties were "lacking interest in having sex" (11%) and "reaching orgasm too quickly" (7%). In addition, 51% of men with 1 or more sexual difficulties at recruitment reported having at least 1 of these difficulties again at follow-up. While "trouble keeping an erection" had the highest persistence/recurrence (48%), "taking too long to orgasm" had the lowest (24%). Logistic regression modeling revealed a greater incidence of orgasmic difficulties among older and less educated men. There were few sociodemographic predictors of persistence/recurrence. These data should assist clinicians and other health service providers in identifying the potential challenges faced by men who experience sexual difficulties. PMID- 23356490 TI - After Newtown--public opinion on gun policy and mental illness. PMID- 23356492 TI - Biological roles of cAMP: variations on a theme in the different kingdoms of life. AB - Cyclic AMP (cAMP) plays a key regulatory role in most types of cells; however, the pathways controlled by cAMP may present important differences between organisms and between tissues within a specific organism. Changes in cAMP levels are caused by multiple triggers, most affecting adenylyl cyclases, the enzymes that synthesize cAMP. Adenylyl cyclases form a large and diverse family including soluble forms and others with one or more transmembrane domains. Regulatory mechanisms for the soluble adenylyl cyclases involve either interaction with diverse proteins, as happens in Escherichia coli or yeasts, or with calcium or bicarbonate ions, as occurs in mammalian cells. The transmembrane cyclases can be regulated by a variety of proteins, among which the alpha subunit and the betagamma complex from G proteins coupled to membrane receptors are prominent. cAMP levels also are controlled by the activity of phosphodiesterases, enzymes that hydrolyze cAMP. Phosphodiesterases can be regulated by cAMP, cGMP or calcium calmodulin or by phosphorylation by different protein kinases. Regulation through cAMP depends on its binding to diverse proteins, its proximal targets, this in turn causing changes in a variety of distal targets. Specifically, binding of cAMP to regulatory subunits of cAMP-dependent protein kinases (PKAs) affects the activity of substrates of PKA, binding to exchange proteins directly activated by cAMP (Epac) regulates small GTPases, binding to transcription factors such as the cAMP receptor protein (CRP) or the virulence factor regulator (Vfr) modifies the rate of transcription of certain genes, while cAMP binding to ion channels modulates their activity directly. Further studies on cAMP signalling will have important implications, not only for advancing fundamental knowledge but also for identifying targets for the development of new therapeutic agents. PMID- 23356491 TI - The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. AB - There is a lack of contemporary prospective data examining the adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) and Stanford V (SV; doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisone) regimens in older Hodgkin lymphoma (HL) patients. Forty-four advanced-stage, older HL patients (aged >=60 years) were treated on the randomized study, E2496. Toxicities were mostly similar between chemotherapy regimens, although 24% of older patients developed bleomycin lung toxicity (BLT), which occurred mainly with ABVD (91%). Further, the BLT-related mortality rate was 18%. The overall treatment-related mortality for older HL patients was 9% vs. 0.3% for patients aged <60 years (P < 0.001). Among older patients, there were no survival differences between ABVD and SV. According to age, outcomes were significantly inferior for older versus younger patients (5-year failure-free survival: 48% vs. 74%, respectively, P = 0.002; 5-year overall survival: 58% and 90%, respectively, P < 0.0001), although time-to-progression (TTP) was not significantly different (5-year TTP: 68% vs. 78%, respectively, P = 0.37). Furthermore, considering progression and death without progression as competing risks, the risk of progression was not different between older and younger HL patients (5 years: 30% and 23%, respectively, P = 0.30); however, the incidence of death without progression was significantly increased for older HL patients (22% vs. 9%, respectively, P < 0.0001). Altogether, the marked HL age-dependent survival differences appeared attributable primarily to non-HL events. PMID- 23356493 TI - High-normal blood pressure is associated with increased resting sympathetic activity but normal responses to stress tests. AB - OBJECTIVE: High-normal blood pressure (BP) increases the risk of cardiovascular (CV) disease. The mechanisms underlying this increased risk are not clear. Sympathetic activation appears to be a potential mechanism linking high-normal BP to CV disease. This study examined whether high-normal BP compared with optimal BP is linked to sympathoexcitation at rest and/or during laboratory stressors. METHODS: Heart rate (HR), BP and muscle sympathetic nerve activity (MSNA) were obtained at rest and during stress tests (sustained handgrip and mental stress) in 18 subjects (15 males and three females) with high-normal BP (systolic BP of 130-139 mmHg, diastolic BP of 85-89 mmHg, or both) and in 12 subjects (10 males and two females) with optimal BP (< 120/80 mmHg) matched for age (34 +/- 3 years in both groups) and body mass index (25 +/- 2 kg/m(2) in both groups). RESULTS: Despite the higher resting BP levels, MSNA was higher in subjects with high normal BP than in the optimal BP group (26 +/- 3 vs 18 +/- 2 bursts/min, p< 0.05). During sustained handgrip, MSNA increased by 37 +/- 14% in high-normal BP group compared with an increase of 49 +/- 15% in optimal BP group (p = 0.55). Changes during mental stress were 50 +/- 28% and 37 +/- 12%, respectively (p = 0.73). There were no significant differences in SBP responses to handgrip and mental stress between the high-normal and optimal BP groups. Baseline HR and chronotropic responses to stress tests were comparable between the two groups. CONCLUSION: In comparison with optimal BP, high-normal BP is associated with increased resting MSNA, but normal neural and circulatory responses to stress tests. These findings suggest that tonic activation of the sympathetic nervous system may precede overt arterial hypertension and contribute to an excess risk of CV disease in subjects with high-normal BP. PMID- 23356494 TI - The PRAISE study: a prospective, multi-center, randomized, double blinded, placebo-controlled study for the evaluation of iloprost in the early postoperative period after liver transplantation (ISRCTN12622749). AB - BACKGROUND: Liver graft dysfunction can deteriorate to complete organ failure and increases perioperative morbidity and mortality after liver transplantation. Therapeutic strategies reducing the rate of graft dysfunction are of current clinical relevance. One approach is the systemic application of prostaglandins, which were demonstrated to be beneficial in reducing ischemia-reperfusion injury. Preliminary data indicate a positive effect of prostacyclin analogue iloprost on allograft viability after liver transplantation. The objective of the study is to evaluate the impact of iloprost in a multi-center trial. METHODS/DESIGN: A prospective, double-blinded, randomized, placebo-controlled multicenter study in a total of 365 liver transplant recipients was designed to assess the effect of intravenous iloprost after liver transplantation. Primary endpoint will be the primary graft dysfunction characterized as presentation of one or more of the following criteria: ALAT or ASAT level>2000 IU/ml within the first 7 postoperative days, bilirubine >= 10 mg/dl on postoperative day 7; INR >= 1.6 on postoperative day 7 or initial non-function. Secondary endpoints are parameters of post-transplant morbidity, like rates of infections, biliary complications, need of clotting factors or renal replacement therapy and the graft and patient survival. DISCUSSION: A well-established treatment concept to avoid graft dysfunction after liver transplantation does not exist at the moment. If the data of this research project confirm prior findings, iloprost would improve the general outcome after liver transplantation. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00003514. Current Controlled Trials Register: ISRCTN12622749. PMID- 23356495 TI - Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke. AB - INTRODUCTION: Stem cell therapy can promote good recovery from stroke. Several studies have demonstrated that mesenchymal stem cells (MSC) are safe and effective. However, more information regarding appropriate cell type is needed from animal model. This study was targeted at analyzing the effects in ischemic stroke of acute intravenous (i.v.) administration of allogenic bone marrow- (BM MSC) and adipose-derived-stem cells (AD-MSC) on functional evaluation results and brain repair markers. METHODS: Allogenic MSC (2 * 106 cells) were administered intravenously 30 minutes after permanent middle cerebral artery occlusion (pMCAO) to rats. Infarct volume and cell migration and implantation were analyzed by magnetic resonance imaging (MRI) and immunohistochemistry. Function was evaluated by the Rogers and rotarod tests, and cell proliferation and cell-death were also determined. Brain repair markers were analyzed by confocal microscopy and confirmed by western blot. RESULTS: Compared to infarct group, function had significantly improved at 24 h and continued at 14 d after i.v. administration of either BM-MSC or AD-MSC. No reduction in infarct volume or any migration/implantation of cells into the damaged brain were observed. Nevertheless, cell death was reduced and cellular proliferation significantly increased in both treatment groups with respect to the infarct group. At 14 d after MSC administration vascular endothelial growth factor (VEGF), synaptophysin (SYP), oligodendrocyte (Olig-2) and neurofilament (NF) levels were significantly increased while those of glial fiibrillary acid protein (GFAP) were decreased. CONCLUSIONS: i.v. administration of allogenic MSC - whether BM-MSC or AD-MSC, in pMCAO infarct was associated with good functional recovery, and reductions in cell death as well as increases in cellular proliferation, neurogenesis, oligodendrogenesis, synaptogenesis and angiogenesis markers at 14 days post infarct. PMID- 23356496 TI - Morphological evidences of Bio-Oss(r) colonization by CD44-positive cells. AB - OBJECTIVES: Our objectives were to examine vascular and cellular colonization in anorganic bovine bone (ABB) after 6 months of healing in human maxillary sinus augmentation grafts. MATERIAL AND METHODS: Fifty unilateral maxillary sinus augmentation procedures were performed on 50 consecutive patients. Bone cores were obtained through the implant receptor sites 6 months later and evaluated with morphological image analysis and immunohistochemical techniques. RESULTS: Image analysis revealed a mean of 35.44 +/- 16% vital bone, 31.66 +/- 15% non mineralized tissue, and 32.72 +/- 25% remnant ABB particles. In our patients, neovascularization in 46.3% of cases was demonstrated within ABB particles 6 months after sinus floor augmentation surgery. Neovascularization of ABB particles was inversely related to age, directly to osteoclast number per mm2, and not influenced by habits or disease. CD44-positive cells colonization was found in 74% of cases. An important correlation was found regarding CD44 expression and number of vessel in ABB particles (r = 0.624 P < 0.001, Pearson). Osteopontin expression was detected on the interstitial boundary of bone with ABB particles and within the osteocyte lacunae and bone canaliculi and was relationship with presence of CD44-positive cells inside ABB particles (r = 0.388, P = 0.046, Pearson). CONCLUSION: In conclusion, images compatible with osteone colonized by osteocytes CD44 positive and neovascularization in ABB particles were observed after 6 months of graft maturation. These biologic events have not previously been morphologically and immunohistochemically documented. PMID- 23356497 TI - K2FeGe3Se8: a new antiferromagnetic iron selenide. AB - A new iron selenide, K2FeGe3Se8, has been obtained by spontaneous crystallization. It adopts a new structure type in the noncentrosymmetric monoclinic space group P2(1). In the structure, FeSe4 and GeSe4 tetrahedra are connected alternately via corner-sharing to form one-dimensional (1D) (infinity)(1)[FeGeSe6]6- chains along the a-direction. These chains are further linked by sharing Ge2Se6 units to generate two-dimensional (2D) (infinity)(2)[FeGe3Se8]2- layers stacked parallel to the ac-plane and separated by K+ cations. Deduced from temperature-dependent susceptibility measurement and specific heat measurement under different magnetic fields, K2FeGe3Se8 exhibits an antiferromagnetic transition at 10 K. Furthermore, the magnetic property shows anisotropy between directions parallel and perpendicular to the plane of (infinity)(2)[FeGe3Se8]2- layer. The diffuse reflectance spectra measurement indicates that the band gap of K2FeGe3Se8 is 1.95(2) eV, consistent with the calculated values of 1.80 and 1.53 eV in the spin-up and spin-down directions, respectively. Based on electronic structure calculation, the spin of the Fe2+ cation is 1.85, which is comparable to the experimental value. PMID- 23356499 TI - Can surgical outcomes be prevented by postoperative admission to critical care? PMID- 23356498 TI - Brain death induces renal expression of heme oxygenase-1 and heat shock protein 70. AB - BACKGROUND: Kidneys derived from brain dead donors have lower graft survival and higher graft-function loss compared to their living donor counterpart. Heat Shock Proteins (HSP) are a large family of stress proteins involved in maintaining cell homeostasis. We studied the role of stress-inducible genes Heme Oxygenase-1 (HO 1), HSP27, HSP40, and HSP70 in the kidney following a 4 hour period of brain death. METHODS: Brain death was induced in rats (n=6) by inflating a balloon catheter in the epidural space. Kidneys were analysed for HSPs using RT-PCR, Western blotting, and immunohistochemistry. RESULTS: RT-PCR data showed a significant increase in gene expression for HO-1 and HSP70 in kidneys of brain dead rats. Western blotting revealed a massive increase in HO-1 protein in brain dead rat kidneys. Immunohistochemistry confirmed these findings, showing extensive HO-1 protein expression in the renal cortical tubules of brain dead rats. HSP70 protein was predominantly increased in renal distal tubules of brain dead rats treated for hypotension. CONCLUSION: Renal stress caused by brain death induces expression of the cytoprotective genes HO-1 and HSP70, but not of HSP27 and HSP40. The upregulation of these cytoprotective genes indicate that renal damage occurs during brain death, and could be part of a protective or recuperative mechanism induced by brain death-associated stress. PMID- 23356500 TI - Serum hepcidin is associated with parameters of glucose metabolism in women with gestational diabetes mellitus. AB - OBJECTIVES: Hepcidin is considered a major regulator of iron metabolism. Despite previous studies showing elevated ferritin and hepcidin levels in type 2 diabetes mellitus (DM), no study has investigated hepcidin levels in pregnant women with gestational DM (GDM). METHODS: A case-control study was conducted in 30 cases of GDM, 47 pregnant women with impaired glucose tolerance (IGT) and 72 pregnant women with normal glucose tolerance (control) between April 2009 and July 2011. Serum hepcidin and other iron metabolism parameters were analyzed in all groups. RESULTS: Serum ferritin and serum iron were significantly elevated in the GDM group compared to controls (p = 0.014, p = 0.018, respectively) and to the IGT group (p = 0.021, p = 0.008, respectively). Hepcidin levels were elevated significantly in the diabetic patients compared to the IGT group (p = 0.011) and controls (p = 0.002). We found no correlation between hepcidin and other iron metabolism parameters (Hb, serum iron and ferritin), whereas positive correlations were found between hepcidin and parameters of glucose metabolism (fasting blood glucose, fasting insulin level and glucose value response to glucose challenge test). CONCLUSIONS: Serum hepcidin concentrations were increased in pregnant women with IGT and GDM and this was not related to inflammation parameters. PMID- 23356501 TI - Monthly CERA treatment maintains stable hemoglobin levels in routine clinical practice of peritoneal dialysis patients. AB - Data on routine use of continuous erythropoietin receptor activator (CERA) in peritoneal dialysis patients are scarce. This study aimed to assess the efficacy of CERA administered once monthly in maintaining stable Hb levels in patients on peritoneal dialysis under routine medical practice. This was a 12-month, observational, prospective and multicenter study. A total of 83 patients with anemia secondary to chronic kidney disease (CKD) on peritoneal dialysis for more than 3 months, on once-monthly subcutaneous CERA treatment, were followed up over a period of 1 year. Efficacy evaluation included Hb levels, mean time in which the Hb level was maintained within target range, CERA doses and number of dose changes. Median Hb level (interquartile range [IQR]) remained stable during the evaluation period [11.8 +/- 1.4 g/dL at baseline, 11.8 +/- 1.4 g/dL at month 6 and 11.8 +/- 1.5 g/dL at month 12 (p > 0.05)]. The median (IQR) time of Hb level maintained within target range (11-13 mg/dL) was 6 (4-10) months. Ferritin, transferrin saturation index, and Fe were also stable and well maintained during the 12 months (p > 0.05). CERA mean dose (SD) was [115.4 (56.2) MUg baseline; 117.2 (58.5) MUg 6 months; 126.0 (65.9) MUg 12 months (p = 0.127)]. The mean number of CERA dose changes per patient during the study was 1.6 (SD 1.3). Serious adverse events were not related to CERA treatment. The results suggest that once-monthly CERA successfully corrects anemia and maintains stable Hb levels within the recommended target range on peritoneal dialysis under routine medical practice. PMID- 23356502 TI - Effect of replacing polyol by organosolv and kraft lignin on the property and structure of rigid polyurethane foam. AB - BACKGROUND: Lignin is one of the three major components in plant cell walls, and it can be isolated (dissolved) from the cell wall in pretreatment or chemical pulping. However, there is a lack of high-value applications for lignin, and the commonest proposal for lignin is power and steam generation through combustion. Organosolv ethanol process is one of the effective pretreatment methods for woody biomass for cellulosic ethanol production, and kraft process is a dominant chemical pulping method in paper industry. In the present research, the lignins from organosolv pretreatment and kraft pulping were evaluated to replace polyol for producing rigid polyurethane foams (RPFs). RESULTS: Petroleum-based polyol was replaced with hardwood ethanol organosolv lignin (HEL) or hardwood kraft lignin (HKL) from 25% to 70% (molar percentage) in preparing rigid polyurethane foam. The prepared foams contained 12-36% (w/w) HEL or 9-28% (w/w) HKL. The density, compressive strength, and cellular structure of the prepared foams were investigated and compared. Chain extenders were used to improve the properties of the RPFs. CONCLUSIONS: It was found that lignin was chemically crosslinked not just physically trapped in the rigid polyurethane foams. The lignin-containing foams had comparable structure and strength up to 25-30% (w/w) HEL or 19-23% (w/w) HKL addition. The results indicated that HEL performed much better in RPFs and could replace more polyol at the same strength than HKL because the former had a better miscibility with the polyol than the latter. Chain extender such as butanediol could improve the strength of lignin-containing RPFs. PMID- 23356503 TI - Are ectomycorrhizal fungi alleviating or aggravating nitrogen limitation of tree growth in boreal forests? AB - Symbioses between plant roots and mycorrhizal fungi are thought to enhance plant uptake of nutrients through a favourable exchange for photosynthates. Ectomycorrhizal fungi are considered to play this vital role for trees in nitrogen (N)-limited boreal forests. We followed symbiotic carbon (C)-N exchange in a large-scale boreal pine forest experiment by tracing (13) CO(2) absorbed through tree photosynthesis and (15) N injected into a soil layer in which ectomycorrhizal fungi dominate the microbial community. We detected little (15) N in tree canopies, but high levels in soil microbes and in mycorrhizal root tips, illustrating effective soil N immobilization, especially in late summer, when tree belowground C allocation was high. Additions of N fertilizer to the soil before labelling shifted the incorporation of (15) N from soil microbes and root tips to tree foliage. These results were tested in a model for C-N exchange between trees and mycorrhizal fungi, suggesting that ectomycorrhizal fungi transfer small fractions of absorbed N to trees under N-limited conditions, but larger fractions if more N is available. We suggest that greater allocation of C from trees to ectomycorrhizal fungi increases N retention in soil mycelium, driving boreal forests towards more severe N limitation at low N supply. PMID- 23356504 TI - Worry and intention among Japanese women: implications for an audience segmentation strategy to promote mammography adoption. AB - We examined the predictive validity of a segmentation strategy based on intention and cancer worry for mammography adoption and explored key factors for promoting mammography adoption in each segment. A questionnaire survey was completed by 641 women aged 40-59 years. Among them, 559 answered a follow-up survey after 15 months. They were categorized into five segments: maintenance group (S5), higher implementation intention group (S4), higher goal intention group (S3), higher worry group (S2), or lower worry group (S1). The odds of participants in each segment adopting mammography during the follow-up period were calculated. Logistic regression analysis was conducted to identify psychological predictors (five attitudes to mammography and perceived health competence) of transition to upper segments (S1 vs. S2, S2 vs. S3, S3 vs. S4, S4 vs. S5). Compared to S5, other segments did not undertake mammography at significant rates during the follow-up. The following were significant predictors for inclusion in upper segments: Lack of importance and perceived health competence were associated with inclusion in S2; lack of importance and barriers to screening were associated with inclusion in S3; perceived health competence was associated with inclusion in S4; and lack of importance was associated with inclusion in S5. These results confirm the predictive validity of a segmentation strategy, and indicate that there might be specific key factors for each segment in promoting mammography adoption. PMID- 23356505 TI - Effect of folic acid and zinc sulphate on endocrine parameters and seminal antioxidant level after varicocelectomy. AB - Varicocele is among the most common problems which may lead to male infertility. Spermatogenesis is impaired as a consequence of this vascular defect, through mechanisms that are not well described. This study aimed to evaluate serum hormonal level (inhibin B, FSH and testosterone) and seminal plasma antioxidant defence levels after folic acid and zinc sulphate administration in varicocelectomised patients. Participants were randomly allocated to four experimental groups. Our randomisation schedule was as follows: zinc sulphate/folic acid, folic acid, zinc sulphate and placebo. The patients underwent varicocelectomy, before which a blood and semen sample were obtained and also three and six months after varicocelectomy for evaluation of blood hormonal level (FSH, testosterone, inhibin B) and seminal oxidative stress status (nitric oxide, superoxide dismutase, total antioxidant capacity). Patients in different groups took orally one capsule per day after dinner following varicocelectomy for 6 months. A significant rise in peripheral blood inhibin B and seminal plasma activity was detected in the zinc sulphate/folic acid group after 6 months. The present clinical trial indicates a change in the hormonal status of varicocelectomised patients following long-term administration of zinc sulphate and folic acid. PMID- 23356506 TI - Detection and quantification of natural contaminants of wine by gas chromatography-differential ion mobility spectrometry (GC-DMS). AB - Rapid and direct, in situ headspace screening for odoriferous volatile organic compounds (VOCs) present in fresh grapes and in wines is a very promising method for quality control because the economic value of a wine is closely related to its aroma. Long used for the detection of VOCs in complex mixtures, miniature differential ion mobility spectrometry (DMS) seems therefore adequate for in situ trace detection of many kinds of VOCs of concern appearing in the headspace of selected foodstuffs. This work aims at a rapid detection, identification, and quantification of some natural and volatile contaminants of wine such as geosmin, 2-methylisoborneol (2-MIB), 1-octen-3-ol, 1-octen-3-one, and pyrazines (2 isopropyl-3-methoxypyrazine, IPMP, and 3-isobutyl-2-methoxypyrazine, IBMP). In the present study, these compounds were spiked at a known concentration in wine and analyzed with a hyphenated trap-GC-DMS device. The detection of all target compounds at concentrations below the human olfactory threshold was demonstrated. PMID- 23356507 TI - Association between paraoxonase gene and stroke in the Han Chinese population. AB - BACKGROUND: The human paraoxonase (PON) gene family has three isoforms: PON1, PON2 and PON3. These genes are implicated as potential risk factors of cerebrovascular disease and can prevent oxidative modification of low-density lipoproteins and atherosclerosis. This study evaluated the association between the genetic variants of all three PON genes and the risks of total stroke, ischemic stroke and hemorrhagic stroke in the Han Chinese population. METHODS: A total of 1016 subjects were recruited, including 508 healthy controls and 498 patients (328 with ischemic stroke and 170 with hemorrhagic stroke). A total of 11 single nucleotide polymorphisms (SNPs) covering the PON genes were genotyped for statistical analysis. Two of the 11 SNPs (rs662 and rs854560) were contextualized in a meta-analysis of ischemic stroke. RESULTS: The presence of rs705381 (-162) in the promoter region of PON1 was significantly associated with total stroke (P(adjusted) = 0.0007, OR = 0.57 [95% CI = 0.41-0.79]) and ischemic stroke (P(adjusted) = 0.0017, OR = 0.54 [95% CI = 0.37-0.79]) when analyzed using a dominant model, but was not associated with hemorrhagic stroke. There was also a nominal association between rs854571 (-824) and total stroke. Meta-analysis demonstrated a significant nominal association between rs662 and ischemic stroke, but there was no evidence of an association between rs662 and ischemic stroke risk in a single site association study. CONCLUSIONS: These findings indicate that polymorphisms of PON1 gene may be a risk factor of stroke. PMID- 23356508 TI - Atopy is a risk factor for respiratory symptoms in COPD patients: results from the EUROSCOP study. AB - BACKGROUND: The pathogenesis of COPD is complex and remains poorly understood. The European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP) investigated long-term effects of budesonide; 18% of the COPD participants were atopic. So far effects of atopy on the long-term course of COPD have not been elucidated. METHODS: Factors related to the presence of atopy (positive phadiatop) in 1277 mild-to-moderate COPD patients participating in EUROSCOP were analysed using regression analysis. Incidence and remission of respiratory symptoms during 3-year follow-up were analysed using generalised estimating equations models, and association of atopy with lung function decline using linear mixed effects models. RESULTS: Independent predisposing factors associated with the presence of atopy were: male gender (OR: 2.21; 95% CI: 1.47 3.34), overweight/obese (OR: 1.41; 95% CI: 1.04-1.92) and lower age (OR: 0.98; 95% CI: 0.96-0.99). Atopy was associated with a higher prevalence of cough (OR: 1.71; 95% CI: 1.26-2.34) and phlegm (OR: 1.50; 95% CI: 1.10-2.03), but not with lung function levels or FEV1 decline. Atopic COPD patients not treated with budesonide had an increased incidence of cough over time (OR: 1.79, 95% CI: 1.03 3.08, p = 0.038), while those treated with budesonide had increased remission of cough (OR: 1.93, 95% CI: 1.11-3.37, p = 0.02) compared to non-atopic COPD patients. CONCLUSIONS: Atopic COPD patients are more likely male, have overweight/obesity and are younger as compared with non-atopic COPD patients. Atopy in COPD is associated with an increased incidence and prevalence of respiratory symptoms. If atopic COPD patients are treated with budesonide, they more often show remission of symptoms compared to non-atopic COPD patients who are treated with budesonide. We recommend including atopy in the diagnostic work up and management of COPD. PMID- 23356509 TI - Asenapine for the treatment of manic and mixed episodes associated with bipolar I disorder: from clinical research to clinical practice. AB - INTRODUCTION: Asenapine is a sublingually administered second-generation antipsychotic with proven efficacy for the treatment of moderate to severe manic episodes associated with bipolar I disorder in adults. Its relatively favorable weight and metabolic profile, as well as the lack of appreciable activity at muscarinic cholinergic receptors and the sublingual administration are of clinical interest. AREAS COVERED: This paper comprises a review and commentary regarding the use of sublingual asenapine in the treatment of acute manic and mixed episodes of bipolar disorder. Basic principles in dosing, switching, management of side effects and co-administration with other medications are provided. EXPERT OPINION: Asenapine displays quick and reliable effects on manic symptoms, very low risk of depressive switches, efficacy on depressive symptoms during manic and mixed episodes, usually good tolerability and continued longer term efficacy on residual and subthreshold symptoms. The fast-dissolving sublingual route of administration may favor those who have difficulties in swallowing medications. Also, the sublingual administration reduces the risk of overdose when more than the prescribed tablets are swallowed. The relatively low metabolic risk and the lack of anticholinergic side effects contribute to making this medication a useful tool for the treatment of patients with bipolar disorder. PMID- 23356511 TI - Anxiety and female sexual functioning: an empirical study. AB - Previous research regarding anxiety and female sexual functioning has yielded conflicting conclusions. This study examined the effect of state/trait anxiety and anxiety sensitivity on sexual responding and the propensity toward sexual inhibition/excitation in women without an anxiety disorder (n = 100, M age = 28.8 years) compared with women with an anxiety disorder (panic disorder or generalized anxiety disorder, n = 30, M age = 30.2 years). Participants completed self-report measures of state and trait anxiety, anxiety sensitivity, sexual functioning, and sexual inhibition/excitation. Women with an anxiety disorder reported worse sexual functioning compared with those without an anxiety disorder (except for desire, lubrication, and pain) and a greater propensity toward sexual inhibition, because of the threat of performance failure and its consequences. Dispositional anxiety and related worries significantly predicted various types of sexual dysfunctions. Findings suggested the importance of considering the relation between anxiety and sexual functioning to design optimal prevention and therapeutic interventions for women with anxiety disorders. PMID- 23356512 TI - Synthesis of 3,5-disubstituted pyrazoles via Cope-type hydroamination of 1,3 dialkynes. AB - An efficient method for the synthesis of 3,5-disubstituted pyrazoles is described. The reactions of 1,3-dialkynes with hydrazine proceeded smoothly in dimethyl sulfoxide under mild reaction conditions to produce 3,5-disubstituted pyrazoles in satisfactory to excellent yields. A one-pot procedure of the transformation has been developed. PMID- 23356510 TI - Thiol/disulfide redox states in signaling and sensing. AB - Rapid advances in redox systems biology are creating new opportunities to understand complexities of human disease and contributions of environmental exposures. New understanding of thiol-disulfide systems have occurred during the past decade as a consequence of the discoveries that thiol and disulfide systems are maintained in kinetically controlled steady states displaced from thermodynamic equilibrium, that a widely distributed family of NADPH oxidases produces oxidants that function in cell signaling and that a family of peroxiredoxins utilize thioredoxin as a reductant to complement the well-studied glutathione antioxidant system for peroxide elimination and redox regulation. This review focuses on thiol/disulfide redox state in biologic systems and the knowledge base available to support development of integrated redox systems biology models to better understand the function and dysfunction of thiol disulfide redox systems. In particular, central principles have emerged concerning redox compartmentalization and utility of thiol/disulfide redox measures as indicators of physiologic function. Advances in redox proteomics show that, in addition to functioning in protein active sites and cell signaling, cysteine residues also serve as redox sensors to integrate biologic functions. These advances provide a framework for translation of redox systems biology concepts to practical use in understanding and treating human disease. Biological responses to cadmium, a widespread environmental agent, are used to illustrate the utility of these advances to the understanding of complex pleiotropic toxicities. PMID- 23356513 TI - Impact of climate changes from Middle Miocene onwards on evolutionary diversification in Eurasia: insights from the mesobuthid scorpions. AB - The aridification from Middle Miocene onwards has transformed the Asian interior into an arid environment, and the Pleistocene glacial-interglacial oscillations exerted further ecological impact. Therefore, both aridification and glaciation would have considerably influenced the evolution of many mid-latitude species in temperate Asia. Here, we tested this perspective by a phylogeographic study of the mesobuthid scorpions across temperate Asia using one mitochondrial and three nuclear genes. Concordant mitochondrial and nuclear gene trees were obtained, which are consistent with species tree inferred using a Bayesian approach. The age of the most recent common ancestor (MRCA) of all the studied scorpions was estimated to be 12.49 Ma (late Middle Miocene); Mesobuthus eupeus diverged from the clade composing Mesobuthus caucasicus and Mesobuthus martensii in early Late Miocene (10.21 Ma); M. martensii diverged from M. caucasicus at 5.53 Ma in Late Miocene. The estimated MRCA ages of M. martensii and the Chinese lineage of M. eupeus were 2.37 and 0.68 Ma, respectively. Central Asia was identified as the ancestral area for the lineage leading to M. martensii and M. caucasicus and the Chinese lineage of M. eupeus. The ancestral habitat of the genus Mesobuthus is likely to have been characterized by an arid environment; a shift towards more humid habitat occurred in the MRCA of M. martensii and a lineage of M. caucasicus, finally leading to the adaptation of M. martensii to humid environment. Our data strongly support the idea that the stepwise intensified aridifications from Mid-Miocene onwards drove the diversification of mesobuthid scorpions, and suggest that M. martensii and M. eupeus observed today in China originated from an ancestral lineage distributed in Central Asia. Both the colonization and the ensuing evolution of these species in East Asia appear to have been further moulded by Quaternary glaciations. PMID- 23356515 TI - Cerebral oximetry during extracorporeal cardiopulmonary resuscitation. PMID- 23356514 TI - A phase I study of pulse high-dose vorinostat (V) plus rituximab (R), ifosphamide, carboplatin, and etoposide (ICE) in patients with relapsed lymphoma. AB - Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that >=2.5 MUmol/l concentrations of vorinostat synergize with both etoposide and platinums, we hypothesized that pulse high-dose vorinostat could safely augment the anti-tumour activity of (R)ICE [(rituximab), ifosphamide, carboplatin, etoposide] chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 d in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty nine patients [median age 56 years, median 2 prior therapies, 14 chemoresistant (of 27 evaluable), 2 prior transplants] were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily * 5 d. Common dose limiting toxicities included infection (n = 2), hypokalaemia (n = 2), and transaminitis (n = 2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4.5 MUmol/l (range 4.2 6.0 MUmol/l) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High-dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted. PMID- 23356516 TI - Hydrogen bonding and proton transfer to ruthenium hydride complex CpRuH(dppe): metal and hydride dichotomy. AB - The combination of variable temperature (190-297 K) IR and NMR spectroscopy studies with quantum-chemical calculations at the DFT/B3PW91 and AIM level had the aim to determine the mechanism of proton transfer to CpRuH(dppe) (1, dppe = Ph(2)P(CH(2))(2)PPh(2)) and the structures of intermediates. Dihydrogen bond (DHB) formation was established in the case of interaction with weak proton donors like CF(3)CH(2)OH. Low-temperature protonation (at about 200 K) by stronger proton donors leads via DHB complex to the cationic nonclassical complex [CpRu(eta(2)-H(2))(dppe)](+) (2). Thermodynamic parameters of DHB formation (for CF(3)CH(2)OH: DeltaH degrees (HB) = -4.9 +/- 0.2 kcal.mol(-1), DeltaS degrees (HB) = -17.8 +/- 0.7 cal.mol(-1).K(-1)) and proton transfer (for (CF(3))(2)CHOH: DeltaH degrees (PT) = -5.2 +/- 0.3 kcal.mol(-1), DeltaS degrees (PT) = -23 +/- 1 cal.mol(-1).K(-1)) were determined. Above 240 K 2 transforms into trans [CpRu(H)(2)(dppe)](+) (3) yielding a mixture of 2 and 3 in 1:2 ratio. Kinetic analysis and activation parameters for the "[Ru(eta(2)-H(2))](+) -> trans [Ru(H)(2)](+)" transformation indicate reversibility of this process in contrast to irreversible intramolecular isomerization of the Cp* analogue. Calculations show that the driving force of this process is greater stability (by 1.5 kcal.mol(-1) in DeltaE scale) of the dihydride cation in comparison with the dihydrogen complex. The calculations of the potential energy profile indicate the low barrier for deprotonation of 2 suggesting that the formation of trans [CpRu(H)(2)(dppe)](+) proceeds via deprotonation of [Ru(eta(2)-H(2))](+) to DHB complex, formation of hydrogen bond with Ru atom and subsequent proton transfer to the metal site. PMID- 23356517 TI - MDM2 SNP309 promoter polymorphism and p53 mutations in urinary bladder carcinoma stage T1. AB - BACKGROUND: Urinary bladder carcinoma stage T1 is an unpredictable disease that in some cases has a good prognosis with only local or no recurrence, but in others can appear as a more aggressive tumor with progression to more advanced stages. The aim here was to investigate stage T1 tumors regarding MDM2 promoter SNP309 polymorphism, mutations in the p53 gene, and expression of p53 and p16 measured by immunohistochemistry, and subsequently relate these changes to tumor recurrence and progression. We examined a cohort of patients with primary stage T1 urothelial carcinoma of the bladder and their tumors. METHODS: After re evaluation of the original slides and exclusions, the study population comprised 141 patients, all with primary stage T1 urothelial carcinoma of the bladder. The hospital records were screened for clinical parameters and information concerning presence of histologically proven recurrence and progression. The paraffin embedded tumor material was evaluated by immunohistochemistry. Any mutations found in the p53 gene were studied by single-strand conformation analysis and Sanger sequencing. The MDM2 SNP309 polymorphism was investigated by pyrosequencing. Multivariate analyses concerning association with prognosis were performed, and Kaplan-Meier analysis was conducted for a combination of changes and time to progression. RESULTS: Of the 141 patients, 82 had at least one MDM2 SNP309 G allele, and 53 had a mutation in the p53 gene, but neither of those anomalies was associated with a worse prognosis. A mutation in the p53 gene was associated with immunohistochemically visualized p53 protein expression at a cut off value of 50%. In the group with p53 mutation Kaplan-Meier analysis showed higher rate of progression and shorter time to progression in patients with immunohistochemically abnormal p16 expression compared to them with normal p16 expression (p = 0.038). CONCLUSIONS: MDM2 SNP309 promoter polymorphism and mutations in p53 were not associated with worse prognosis in this cohort of patients with primary stage T1 urinary bladder carcinoma. However, patients with abnormal p16 expression and a mutated p53 gene had a higher rate of and a shorter time to progression, and p53 gene mutation was associated with an abnormal immunohistochemistry for p53 at a cut-off of 50%. PMID- 23356519 TI - Triggers of migraine and tension-type headache in China: a clinic-based survey. AB - BACKGROUND AND PURPOSE: Identification of the trigger factors of headache could be an important aspect of preventive management, but the characteristics of primary headache triggers in China are unknown. This study was performed to estimate the frequencies of the putative headache triggers, which are endorsed by patients with migraine and tension-type headache (TTH). METHODS: From July 2011 to December 2011, a cross-sectional survey was conducted in the neurological clinic of a tertiary care hospital in Chongqing. All consecutive patients with the chief complaint of headache were interviewed by a board-certified headache specialist. The diagnoses were made according to International Classification of Headache Disorders - 2nd edition. Patients with migraine and TTH were recruited. RESULTS: The number of investigated patients was 1219, of whom 394 were migraine and 344 were TTH; and 80.2% migraineurs and 67.4% TTH patients reported trigger factors. The most common triggers for both migraine and TTH were sleep disturbance, negative affect and sunlight. Menstrual cycle (OR 3.6, 95%CI 1.2, 11.2), change of the weather (OR 3.1, 95%CI 1.9, 4.8), noise (OR 2.2, 95%CI 1.1, 4.4) and alcohol (OR 1.8, 95%CI 0.7, 1.8) were more associated with migraineurs. Negative affect was more associated with TTH (OR 2.0, 95%CI 1.3, 2.9). CONCLUSIONS: Trigger factors were frequent among both migraine and TTH patients. Avoidance of all headache triggers is impractical. Learning to cope with triggers is important to headache prevention. PMID- 23356520 TI - Arthrogryposis multiplex congenita-like syndrome associated with median cleft lip and palates: first prenatally detected case. AB - An early second-trimester prenatal ultrasound diagnosis of an arthrogryposis multiplex congenita-like syndrome associated with median clefts is reported. A molecular biological work-up was performed to search for a potentially overlapping syndrome and dysostosis. Autopsy and postmortem radiogram were performed to confirm the ultrasound diagnosis. Prenatal diagnosis enabled early detection of multiple fetal malformations, thus allowing early termination of pregnancy. Moreover, three-dimensional ultrasound with volume rendering in the maximum surface mode demonstrated its value in diagnosing oro-facial clefts, even at an early stage of fetal development. PMID- 23356518 TI - Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells. AB - BACKGROUND: The bark of magnolia has been used in Oriental medicine to treat a variety of remedies, including some neurological disorders. Magnolol (Mag) and honokiol (Hon) are isomers of polyphenolic compounds from the bark of Magnolia officinalis, and have been identified as major active components exhibiting anti oxidative, anti-inflammatory, and neuroprotective effects. In this study, we investigate the ability of these isomers to suppress oxidative stress in neurons stimulated by the ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) and oxidative and inflammatory responses in microglial cells activated by interferon-gamma (IFNgamma) and lipopolysaccharide (LPS). We also attempt to elucidate the mechanism and signaling pathways involved in cytokine-induced production of reactive oxygen species (ROS) in microglial cells. METHODS: Dihydroethidium (DHE) was used to assay superoxide production in neurons, while CM-H2DCF-DA was used to test for ROS production in murine (BV-2) and rat (HAPI) immortalized microglial cells. NADPH oxidase inhibitors (for example, diphenyleneiodonium (DPI), AEBSF, and apocynin) and immunocytochemistry targeting p47phox and gp91phox were used to assess the involvement of NADPH oxidase. Western blotting was used to assess iNOS and ERK1/2 expression, and the Griess reaction protocol was employed to determine nitric oxide (NO) concentration. RESULTS: Exposure of Hon and Mag (1-10 MUM) to neurons for 24 h did not alter neuronal viability, but both compounds (10 MUM) inhibited NMDA-stimulated superoxide production, a pathway known to involve NADPH oxidase. In microglial cells, Hon and Mag inhibited IFNgamma+/-LPS-induced iNOS expression, NO, and ROS production. Studies with inhibitors and immunocytochemical assay further demonstrated the important role of IFNgamma activating the NADPH oxidase through the p-ERK-dependent pathway. Hon and, to a lesser extent, Mag inhibited IFNgamma induced p-ERK1/2 and its downstream pathway for ROS and NO production. CONCLUSION: This study highlights the important role of NADPH oxidase in mediating oxidative stress in neurons and microglial cells and has unveiled the role of IFNgamma in stimulating the MAPK/ERK1/2 signaling pathway for activation of NADPH oxidase in microglial cells. Hon and Mag offer anti-oxidative or anti inflammatory effects, at least in part, through suppressing IFNgamma-induced p ERK1/2 and its downstream pathway. PMID- 23356522 TI - The development of pointing perception in infancy: effects of communicative signals on covert shifts of attention. AB - The present study aims to investigate the interplay of verbal and nonverbal communication with respect to infants' perception of pointing gestures. Infants were presented with still images of pointing hands (cue) in combination with an acoustic stimulus. The communicative content of this acoustic stimulus was varied from being human and communicative to artificial. Saccadic reaction times (SRTs) from the cue to a peripheral target were measured as an indicator of the modulation of covert attention. A significant cueing effect (facilitated SRTs for congruent compared with incongruent trials) was only present in a condition with additional communicative and referential speech. In addition, the size of the cueing effect increased the more human and communicative the acoustic stimulus was. This indicates a beneficial effect of verbal communication on the perception of nonverbal communicative pointing gestures, emphasizing the important role of verbal communication in facilitating social understanding across domains. These findings additionally suggest that human and communicative (ostensive) signals are not qualitatively different from other less social signals but just quantitatively the most attention grabbing among a number of other signals. PMID- 23356523 TI - An examination of stereotype threat effects on girls' mathematics performance. AB - Stereotype threat has been proposed as 1 potential explanation for the gender difference in standardized mathematics test performance among high-performing students. At present, it is not entirely clear how susceptibility to stereotype threat develops, as empirical evidence for stereotype threat effects across the school years is inconsistent. In a series of 3 studies, with a total sample of 931 students, we investigated stereotype threat effects during childhood and adolescence. Three activation methods were used, ranging from implicit to explicit. Across studies, we found no evidence that the mathematics performance of school-age girls was impacted by stereotype threat. In 2 of the studies, there were gender differences on the mathematics assessment regardless of whether stereotype threat was activated. Potential reasons for these findings are discussed, including the possibility that stereotype threat effects only occur in very specific circumstances or that they are in fact occurring all the time. We also address the possibility that the literature regarding stereotype threat in children is subject to publication bias. PMID- 23356521 TI - Reciprocal interactions of mouse bone marrow-derived mesenchymal stem cells and BV2 microglia after lipopolysaccharide stimulation. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) are immunosuppressive, but we lack an understanding of how these adult stem cells are in turn affected by immune cells and the surrounding tissue environment. As MSCs have stromal functions and exhibit great plasticity, the influence of an inflamed microenvironment on their responses is important to determine. MSCs downregulate microglial inflammatory responses, and here we describe the mutual effects of coculturing mouse bone marrow MSCs with BV2 microglia in a lipopolysaccharide (LPS) inflammatory paradigm. METHODS: Mouse MSCs were cultured from femoral and tibial bone marrow aspirates and characterized. MSCs were cocultured with BV2 microglia at four seeding-density ratios (1:0.2, 1:0.1, 1:0.02, and 1:0.01 (BV2/MSC)), and stimulated with 1 MUg/ml LPS. In certain assays, MSCs were separated from BV2 cells with a cell-culture insert to determine the influence of soluble factors on downstream responses. Inflammatory mediators including nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and chemokine (C-C motif) ligand 2 (CCL2) were measured in cocultures, and MSC and BV2 chemotactic ability determined by migration assays. RESULTS: We demonstrated MSCs to increase expression of NO and IL-6 and decrease TNF-alpha in LPS-treated cocultures. These effects are differentially mediated by soluble factors and cell-to-cell contact. In response to an LPS stimulus, MSCs display distinct behaviors, including expressing IL-6 and very high levels of the chemokine CCL2. Microglia increase their migration almost fourfold in the presence of LPS, and interestingly, MSCs provide an equal impetus for microglia locomotion. MSCs do not migrate toward LPS but migrate toward microglia, with their chemotaxis increasing when microglia are activated. Similarly, MSCs do not produce NO when exposed to LPS, but secrete large amounts when exposed to soluble factors from activated microglia. This demonstrates that certain phenotypic changes of MSCs are governed by inflammatory microglia, and not by the inflammatory stimulus. Nonetheless, LPS appears to "prime" the NO-secretory effects of MSCs, as prior treatment with LPS triggers a bigger NO response from MSCs after exposure to microglial soluble factors. CONCLUSIONS: These effects demonstrate the multifaceted and reciprocal interactions of MSCs and microglia within an inflammatory milieu. PMID- 23356524 TI - Sensitive perception of a person's direction of walking by 4-year-old children. AB - Watch any crowded intersection, and you will see how adept people are at reading the subtle movements of one another. While adults can readily discriminate small differences in the direction of a moving person, it is unclear if this sensitivity is in place early in development. Here, we present evidence that 4 year-old children are sensitive to small differences in a person's direction of walking (~7 degrees ) far beyond what has been previously shown. This sensitivity only occurred for perception of an upright walker, consistent with the recruitment of high-level visual areas. Even at 4 years of age, children's sensitivity approached that of adults'. This suggests that the sophisticated mechanisms adults use to perceive a person's direction of movement are in place and developing early in childhood. Although the neural mechanisms for perceiving biological motion develop slowly, they are refined enough by age 4 to support subtle perceptual judgments of heading. These judgments may be useful for predicting a person's future location or even their intentions and goals. PMID- 23356525 TI - Children's use of moral behavior in selective trust: discrimination versus learning. AB - Does valence play a role in children's sensitivity to and use of moral information in the service of selective learning? In the present experiment, we explored this question by presenting 3- to 5-year-old children with informants who behaved in ways consistent or inconsistent with sociomoral norms, such as helping a peer retrieve a toy or deliberately tearing a peer's artwork. "Good" versus "bad" informants were contrasted with putatively neutral-behaving informants. In an effort to specify the role that moral information plays in guiding children's selective trust, we measured children's ability to discriminate the informants as well as their willingness to learn from them. We found that children were significantly more likely to discriminate negatively behaving agents from neutral ones than they were to discriminate positively behaving agents from neutral ones. In contrast, children did not differ in the degree to which they used negative versus positive moral information in their selective learning; both types of information were used to guide trust across domains of knowledge. Results are discussed in terms of the positive-negative asymmetry observed and the different forms that a negativity bias might take. PMID- 23356526 TI - Age and time-to-death trajectories of change in indicators of cognitive, sensory, physical, health, social, and self-related functions. AB - Mortality-related processes are known to modulate late-life change in cognitive abilities, but it is an open question whether and how precipitous declines with impending death generalize to other domains of functioning. We investigated this notion by using 13-year longitudinal data from now-deceased participants in the Berlin Aging Study (N = 439; 70-103 years at first occasion; M = 87 years). Using time metrics of chronological age and time-to-death, we compared changes in key indicators of cognitive, sensory, physical, health, social, and self-related domains. Across variables and domains, mortality models revealed steeper average rates of change than age models. However, some domain indicators were more prone to mortality-related change than others. Examining between-person differences, we found that sociodemographic characteristics (surviving to an older age at death, being a woman, lower socioeconomic status) and proxies of pathologies (comorbidities, disability, and suspected dementia) related to lower levels of late-life functioning. In contrast, little evidence was found for correlates of differential change. Our results illustrate both the pervasive nature of progressive processes leading toward death and their domain specificity. Inquiries with more closely spaced multidomain measurements are needed to identify invariant and variable aspects of the end-of-life "cascade." PMID- 23356527 TI - Developmental differences in the relative weighing of informants' social attributes. AB - We examined whether similarity, familiarity, and reliability cues guide children's learning and whether these cues are weighed differently with age. Three- to 5-year-olds (n = 184) met 2 informant puppets, 1 of which was similar (Experiment 1) or familiar (Experiment 2) to the participants. Initially, children's preference for either informant was measured. Children selected similar and familiar informants--over dissimilar and unfamiliar ones--as information sources at above-chance levels. In Experiment 1 the similar informant later provided accurate or inaccurate information (counterbalanced). Children's initial preference for similar sources was modified by reliability cues. However, 5-year-olds continued to be influenced by similarity, being less likely to avoid inaccurate sources if similar than dissimilar. In Experiment 2 the familiar informant was later portrayed as interpersonally similar or dissimilar (counterbalanced). Only 5-year-olds were influenced by similarity, preferentially interacting with similar informants regardless of familiarity. These results suggest that similarity influences children's learning and that children's relative weighing of social cues varies with age--with younger children being especially focused on familiarity and older children being particularly attentive to similarity. PMID- 23356528 TI - Revisiting the effect of reminders on infants' media memories: does the encoding format matter? AB - With the present research, the authors examined whether reminders could maintain 18-month-olds' memories generated from picture books and videos. Infants (N = 98) were shown a series of target actions in a picture book or on video. Either 24 hr or 2 weeks prior to a 4-week deferred imitation test, they were exposed to a reminder, a partial presentation of the original media demonstration. After both reminder delays, groups that received a video demonstration and a video reminder (video/video) performed significantly better than did the video-reminder-only control group (x/video), but groups that received a picture-book demonstration and a picture-book reminder (book/book) did not perform better than did the picture-book-reminder-only control (x/book). Additionally, if reminders did not veridically match the conditions of encoding (e.g., video demonstration and a book reminder, video/book or vice versa), infants also failed to perform better than controls. Theoretical implications for the understanding of long-term memory processing during early childhood and practical implications for early multimedia usage are discussed. PMID- 23356529 TI - A comparison of the Niagara and Medcomp catheters for continuous renal replacement therapy. AB - PURPOSE: The choice of vascular access catheter may affect filter life during continuous renal replacement therapy (CRRT). In particular, differences in catheter design might affect the incidence of circuit clotting related to catheter malfunction. DESIGN AND SETTING: Sequential controlled study in a tertiary, adult intensive care unit (ICU). AIM: To compare circuit life when CRRT was performed with a Niagara catheter or a Medcomp catheter. PATIENTS AND MEASUREMENTS: We studied 46 patients with acute kidney injury requiring CRRT, all delivered with catheters in the femoral position. We obtained information on age, gender, disease severity score [acute physiology and chronic health evaluation (APACHE II) and APACHE III], filter life, heparin dose per hour, daily systemic hemoglobin concentration, platelet count, international normalized ratio (INR), and activated partial thromboplastin time (APTT) during CRRT. RESULTS: We studied 254 circuits in 46 patients. Of these, 26 patients (140 circuits) used the Niagara catheter and 20 patients (114 circuits) used the Medcomp catheter. Median circuit life in the two groups were 11 h and 7.3 h, respectively (p < 0.01). Patients using Medcomp catheters had a lower platelet count (p = 0.04) and a lower hemoglobin concentration (p = 0.01), but INR (p = 0.16), APTT (p = 0.46), anticoagulant treatment (p = 0.89), and heparin dose per hour (p = 0.24) were similar. After correcting for confounding variables by multivariable linear regression analysis, it was found that the choice of catheter is not an independent predictor of circuit life. On Kaplan-Meier survival analysis, circuit life was not significantly different between the two catheters (p = 0.87). CONCLUSION: The choice of either the Niagara or Medcomp catheter does not appear to be a significant independent determinant of circuit life during CRRT. PMID- 23356530 TI - Neuronal apoptosis in the neonates born to preeclamptic mothers. AB - OBJECTIVE: Preeclampsia may result in uteroplacental insufficiency and chronic intrauterine fetal distress. The aim of this study is to address this issue investigating neuronal apoptosis in an experimental model of preeclampsia and to evaluate the neurological outcome of the perinatal asphyxia in the neonates born to preeclamptic mother. MATERIALS AND METHODS: Two out of four pregnant Sprague Dawley rats (preeclamptic group) were given water containing 1.8% NaCl on gestation day 15 and 22 in order to establish the model of preeclampsia whereas other two (non-preeclamptic group) received normal diet. A model of perinatal asphyxia was established on the postnatal 7th day to one preeclamptic and one non preeclamptic dam. Overall 23 pups born to overall four dams were decapitated to assess neuronal apoptosis by the TUNEL assay. RESULTS: The number of apoptotic neuronal cells was significantly higher in the preeclampsia groups in comparison with the control group (p = 0.006 and p = 0.006, respectively). It was also significantly higher in the asphyctic/non-preeclamptic group than the count in the control group (p = 0.01). There was also significant difference between both asphyctic groups (p = 0.003). CONCLUSION: We conclude that preeclampsia causes small babies for the gestational age and cerebral hypoplasia. Both preeclampsia and perinatal asphyxia can cause increased neuronal apoptosis in the neonatal brains. However, the prognosis for neurological outcome is much worse when the perinatal asphyxia occurs in newborns born to preeclamptic mothers. PMID- 23356532 TI - The motives for and consequences of viewing television medical dramas. AB - Although television medical dramas have been popular for a long time and have delivered health- and medical-related information to audiences, few studies have focused on audience's view. This study explores motives for and consequences of viewing medical dramas from the uses and gratifications (U&G) perspective. A survey identified college students' motives toward medical drama viewing and the relationship of the motives with individuals' health information orientation, audience activity (selectivity, attention, involvement), and their use of health information learned from the dramas. Although viewers' primary motive for viewing medical drama was not to gather health information, only health information motive, among all motives, directly predicted use of health information from medical dramas. Viewers' entertainment-related motives toward medical drama viewing indirectly and positively predicted use of information in the dramas via involvement with those dramas, and indirectly and negatively via attention to the story in those dramas. Theoretical and practical implications of these findings are discussed. PMID- 23356533 TI - Low-dose CT measurements of airway dimensions and emphysema associated with airflow limitation in heavy smokers: a cross sectional study. AB - BACKGROUND: Increased airway wall thickness (AWT) and parenchymal lung destruction both contribute to airflow limitation. Advances in computed tomography (CT) post-processing imaging allow to quantify these features. The aim of this Dutch population study is to assess the relationships between AWT, lung function, emphysema and respiratory symptoms. METHODS: AWT and emphysema were assessed by low-dose CT in 500 male heavy smokers, randomly selected from a lung cancer screening population. AWT was measured in each lung lobe in cross sectionally reformatted images with an automated imaging program at locations with an internal diameter of 3.5 mm, and validated in smaller cohorts of patients. The 15th percentile method (Perc15) was used to assess the severity of emphysema. Information about respiratory symptoms and smoking behavior was collected by questionnaires and lung function by spirometry. RESULTS: Median AWT in airways with an internal diameter of 3.5 mm (AWT3.5) was 0.57 (0.44 - 0.74) mm. Median AWT in subjects without symptoms was 0.52 (0.41-0.66) and in those with dyspnea and/or wheezing 0.65 (0.52-0.81) mm (p<0.001). In the multivariate analysis only AWT3.5 and emphysema independently explained 31.1%and 9.5%of the variance in FEV1%predicted, respectively, after adjustment for smoking behavior. CONCLUSIONS: Post processing standardization of airway wall measurements provides a reliable and useful method to assess airway wall thickness. Increased airway wall thickness contributes more to airflow limitation than emphysema in a smoking male population even after adjustment for smoking behavior. PMID- 23356534 TI - Parasitic plant litter input: a novel indirect mechanism influencing plant community structure. AB - Parasitic plants have major impacts on plant community structure through their direct negative influence on host productivity and competitive ability. However, the possibility that these parasites may also have indirect impacts on community structure (via the mechanism of nutrient-rich litter input) while long hypothesized, has remained unsupported until now. Using the hemiparasite Rhinanthus minor, we established experimental grassland mesocosms to quantify the impacts of Rhinanthus litter and parasitism across two soil fertility levels. We measured the biomass and tissue nutrient concentration of three functional groups within these communities to determine their physiological response to resource abstraction and litter input by the parasite. We show that Rhinanthus alters the biomass and nutrient status of co-occurring plants with contrasting effects on different functional groups via the mechanism of nutrient-rich litter input. Critically, in the case of grass and total community biomass, this partially negates biomass reductions caused directly by parasitism. This demonstrates that the influence of parasitic plant litter on plant community structure can be of equal importance to the much-reported direct impacts of parasitism. We must consider both positive indirect (litter) and negative direct (parasitism) impacts of parasitic plants to understand their role in structuring plant communities. PMID- 23356535 TI - Lack of association between a functional variant of the BRCA-1 related associated protein (BRAP) gene and ischemic stroke. AB - BACKGROUND: Atherosclerosis shares common pathogenic features with myocardial infarction (MI) and ischemic stroke. BRCA-1 associated protein (BRAP), a newly identified risk gene for MI, aggravates the inflammatory response in atherosclerosis. The aim of this study was to test the association between the BRAP gene and stroke in a Taiwanese population. METHODS: A total of 1,074 stroke patients and 1,936 controls were genotyped for the functional SNP rs11066001. In our previous studies, the rare allele of this SNP has been repeatedly shown to exert a recessive effect. Therefore, in the current study, we tested for the same recessive model. First, the genotype distributions between all the controls and all the stroke cases were compared. Then to reduce heterogeneity, we explored several population subsets by selecting young stroke subjects (using 45 years of age as the cutoff point), age- and sex-comparable controls, plaque-free controls, and stroke subtypes. RESULTS: We did not find any significant association for the entire data set (OR = 0.94, p = 0.74) or for the subset analyses using age- and sex-comparable controls (p = 0.70) and plaque-free controls (p = 0.91). Analyses of the four stroke subtypes also failed to show any significant associations (p = 0.42 - 0.98). For both young and old subjects, the GG genotype of rs11066001 was similar in the stroke cases and unmatched controls (8.1% vs. 9.4% in young subjects and 8.0% vs. 7.8% in old subjects). Comparing stroke cases with plaque free controls also failed to find any significant association. CONCLUSIONS: The BRAP polymorphism may not play an important role in ischemic stroke in the studied population. PMID- 23356536 TI - An update on the pharmacological management of endometriosis. AB - INTRODUCTION: Endometriosis is a common disease that causes pain symptoms and/or infertility in women in their reproductive years. The disease is characterised by the presence of endometrium-like tissue - glands and stroma - outside the uterine cavity. Different treatment options exist for endometriosis including medical and surgical treatments or a combination of the two approaches. The most commonly used medications are non-steroidal anti-inflammatory drugs, GnRH agonists, androgen derivatives such as danazol, combined oral contraceptive pills, progestogens and more recently the levonorgestrel intrauterine system. AREAS COVERED: The authors review current medical treatments used for symptomatic endometriosis and also discuss new treatment approaches. The authors conducted a literature search for randomised controlled trials related to medical treatments of endometriosis in humans, searched the Cochrane library for reviews and also searched for registered trials that have not yet been published on ClinicalTrials.gov. EXPERT OPINION: The medical treatment of endometriosis is effective at treating pain and preventing recurrence of disease after surgery. Remarkably, the oral contraceptive pill taken continuously is as effective as GnRH-a, while causing far less side-effects. Conversely, no treatment currently exists for enhancing fecundity in women whose infertility is associated with endometriosis. As all existing therapies of endometriosis are contraceptive, great efforts should be targeted at researching novel products that reduce the disease expression without shuttering ovulation. PMID- 23356537 TI - Surviving a gender-variant childhood: the views of transgender adults on the needs of gender-variant children and their parents. AB - Adults with gender-variant childhoods have often lived traumatic lives because of the attitudes and limited understanding that people in their environment had of the concept of gender variance. This study explores the childhoods of transgender adults with the aim to understand their gender-related difficulties as children, in order to identify their needs and the needs of their parents at that time. The authors conducted a semi-structured survey with 110 transgender adults in order to explore their retrospective childhood experiences. Responses were analyzed through content and thematic coding. Their needs most commonly identified as children were for educated authority figures; acceptance and support to discuss their gender variance; freedom of identity expression; validation; and recognition. The needs most commonly allocated to their parents were access to information, education to increase other's awareness, peer support, and access to educated professionals. PMID- 23356538 TI - Most methylation-susceptible DNA sequences in human embryonic stem cells undergo a change in conformation or flexibility upon methylation. AB - DNA methylation in eukaryotes occurs on the cytosine bases in CG, CHG, and CHH (where H indicates non-G nucleotides) contexts and provides an important epigenetic mark in various biological processes. However, the structural and physical properties of methylated DNA are poorly understood. Using nondenaturing polyacrylamide gel electrophoresis, we performed a systematic study of the influence of DNA methylation on the conformation and physical properties of DNA for all CG, CHG, and CHH contexts. In the CG context, methylated multimers of the CG/CG-containing unit fragment migrated in gels slightly faster than their unmethylated counterparts. In the CHG context, both homo- and hemimethylation caused retarded migration of multimers of the CAG/CTG-containing fragment. In the CHH context, methylation caused or enhanced retarded migration of the multimers of CAA/TTG-, CAT/ATG-, CAC/GTG-, CTA/TAG-, or CTT/AAG-containing fragments. These results suggest that methylation increases DNA rigidity in the CG context and introduces distortions into several CHG and CHH sequences. More interestingly, we found that nearly all of the methylation repertoires in the CHG context and 98% of those in the CHH context in human embryonic stem cells were species that undergo conformational changes upon methylation. Similarly, most of the methylation repertoires in the Arabidopsis CHG and CHH contexts were sequences with methylation-induced distortion. We hypothesize that the methylation-induced properties or conformational changes in DNA may facilitate nucleosome formation, which provides the essential mechanism for alterations of chromatin density. PMID- 23356539 TI - Longitudinal development of gross motor function among Dutch children and young adults with cerebral palsy: an investigation of motor growth curves. AB - AIM: The aim of this study was to describe patterns for gross motor development by level of severity in a Dutch population of individuals with cerebral palsy (CP). METHOD: This longitudinal study included 423 individuals (260 males, 163 females) with CP. The mean age at baseline was 9 years 6 months (SD 6y 2mo, range 1-22y). The level of severity of CP among participants, according to the Gross Motor Function Classification System (GMFCS), was 50% level I, 13% level II, 14% level III, 13% level IV, and 10% level V. Participants had been assessed up to four times with the Gross Motor Function Measure (GMFM-66) at 1- or 2-year intervals between 2002 and 2009. Data were analysed using non-linear mixed effects modelling. For each GMFCS level, patterns were created by contrasting a stable limit model (SLM) with a peak and decline model (PDM), followed by estimating limits and rates of gross motor development. RESULTS: The SLM showed a better fit for all GMFCS levels than the PDM. Within the SLM, significant differences between GMFCS levels were found for both the limits (higher values for lower GMFCS levels) and the rates (higher values for GMFCS levels I-II vs level IV and for GMFCS levels I-IV vs level V) of gross motor development. INTERPRETATION: The results validate the existence of five distinct patterns for gross motor development by level of severity of CP. PMID- 23356540 TI - Integration of pulp and paper technology with bioethanol production. AB - BACKGROUND: Despite decades of work and billions of dollars of investments in laboratory and pilot plant projects, commercial production of cellulosic ethanol is only now beginning to emerge. Because of: (1)high technical risk coupled with; (2) high capital investment cost relative to ethanol product value, investors have not been able to justify moving forward with large scale projects on woody biomass. RESULTS: Both issues have been addressed by targeting pulp and paper industry processes for application in bioethanol production, in Greenfield, Repurpose and Co-Location scenarios. Processes commercially proven in hundreds of mills for many decades have been tailored to the recalcitrance of the biomass available. Economically feasible cellulosic bioethanol can be produced in Greenfield application with hardwoods, but not softwoods, using kraft mill equipment. Both types of wood species can profitably produce ethanol when kraft mill or newsprint assets are Repurposed to a biorefinery. A third situation which can generate high financial returns is where excess kraft pulp is available at a mill which has no excess drying capacity. Each scenario is supported by laboratory simulation, engineering and financial analysis. While pretreatment is critical to providing access of the biomass to enzymes, capital investment per unit of ethanol produced can be attractive, even if ethanol yield is modest. CONCLUSIONS: Three guiding principles result in attractive economics: (1) re-use existing assets to the maximum extent; (2) keep the process as simple as possible; (3) match the recalcitrance of the biomass with the severity of the pretreatment. PMID- 23356541 TI - Acceptance of repeat worksite HIV voluntary counselling and testing in a rural South African factory. AB - In response to the human immunodeficiency virus (HIV) pandemic, many employers in sub-Saharan Africa have introduced voluntary counselling and testing (VCT) for HIV. To assess the factors that predict repeat VCT attendance at 12-month follow up we analysed data from a nurse-administered questionnaire that was distributed to factory workers in a rural South African factory. Employees were offered VCT for HIV in 2009 and again 12 months later. Odds ratios examined factors associated with attendance at follow-up. Totally, 2138 employees accepted VCT at initial assessment and 406 attended at follow-up. After controlling for socio demographic factors (age, gender, marital status and education), elevated blood glucose was associated with increased likelihood of attendance at follow-up; positive HIV status was a key risk factor for non-attendance at follow-up. This study underscores the importance of determining those groups at risk of non attendance at employer-provided repeat VCT clinics; differences between employee groups might usefully inform targeted promotional activities to encourage attendance. PMID- 23356542 TI - Clinical experiences of different dosing schedules of rituximab in pemphigus with various disease severities. AB - BACKGROUND: Rituximab, a monoclonal antibody directed against B lymphocytes, has been found to be a therapeutic agent for severe, refractory autoimmune bullous diseases. However, a dosing schedule or treatment indication of rituximab has not yet been established. OBJECTIVES: We investigated the efficacy of rituximab and different dosing schedules for different disease severities, retrospectively. METHODS: A total of 23 patients with pemphigus who received rituximab were evaluated by a review of medical records. Group 1 patients (n = 10) with severe pemphigus were treated with three or four infusions of rituximab at a dose of 375 mg/m(2) at 1-week intervals. Group 2 (n = 13) patients with mild to moderate pemphigus were treated with two infusions of rituximab at the same dose. Late end points, occurrence of relapse and adverse events and numbers of B cells were evaluated. RESULTS: The mean follow-up period was 25.6 months in group 1 and 17.8 months in group 2. In group 1, six patients (60.0%) achieved complete remission (CR), including two patients off therapy (CR OFF) and four patients on therapy (CR ON). The other four patients (40.0%) achieved partial remission on therapy (PR ON). In group 2, nine patients (69.2%) achieved CR (4 CR OFF, 5 CR ON) and four patients (30.8%) achieved PR ON. During the follow-up period, relapse occurred in five patients of group 1 and three patients of group 2. No serious adverse events were observed in any patients. CONCLUSIONS: We concluded that rituximab is an effective and safe treatment method not only in severe, recalcitrant pemphigus but also in mild to moderate pemphigus. Low dose of rituximab seemed to be sufficient to treat mild to moderate pemphigus. PMID- 23356543 TI - Hemilabile beta-aminophosphine ligands derived from 1,3,5-triaza-7 phosphaadamantane: application in aqueous ruthenium catalyzed nitrile hydration. AB - A series of beta-aminophosphines derived from 1,3,5-triaza-7-phosphaadamantane (PTA) are described. PTA-CHPhNHPh (1), PTA-CH(p-C(6)H(4)OCH(3))NHPh (2), and PTA CPh(2)NHPh (3) were prepared in good yield (62-77%) by reaction of lithiated PTA with the corresponding imine followed by hydrolysis. Compounds 1 and 2 were synthesized as pairs of diastereomers which were separated by successive recrystallization from THF/hexane. Compounds 1-3 are somewhat soluble in water (S(25)(o) = 4.8 (1), 4.9 (2), 2.7 (3) g/L). Upon coordination to Ru(II) arene centers both monodentate (kappa(1)-P) [RuCl(2)(eta(6)-toluene)(1-3)] and bidentate (kappa(2)-P,N) [RuCl(eta(6)-toluene)(1-3)]Cl coordination modes were observed. Ru(II) arene complexes 4-6 exhibited hemilabile behavior transitioning between kappa(1)-P and kappa(2)-P,N coordination upon change in solvent or addition of a coordinating ligand such as Cl(-) or CH(3)CN. Complexes (4-6) were found to be active air stable catalysts for the aqueous phase hydration of various nitriles with TOF up to 285 h(-1) and TON of up to 97,000 observed. PMID- 23356545 TI - Comparison of 12-hour creatinine clearance and estimated glomerular filtration rate in renal transplant recipients. AB - Glomerular filtration rate (GFR) is an essential clinical assessment of renal function post-renal transplantation. Creatinine clearance (CrCl) measured over 12 h and estimated GFR (e-GFR) (calculated by the Modification of diet in renal disease equation) were compared in 28 stable renal transplant recipients (RTRs). This single center study included 14 African American (AA) and 14 Caucasian (CC) recipients. The 12-h creatinine clearance (CrCl-12 h) was determined by monitored urine collection and by e-GFR on two occasions (two phases) separated by at least 2 weeks. Statistics included mixed model analysis of CrCl-12 h and e-GFR relative to race, phase, and difference between parameters. In the first phase, the e-GFR was higher in AA males (58.4 +/- 14.8 mL/min) than the CC males (46.2 +/- 10.2 mL/min) (p = 0.032), whereas the CrCl-12 h of AA males (70.8 +/- 8.7 mL/min) and CC males (63.3 +/- 21.7 mL/min) was not different (p = 0.740). During the second phase, the e-GFR in AA and CC RTRs was 55.4 +/- 10.1 mL/min and 47.6 +/- 10.7 mL/min (p = 0.117), respectively, whereas CrCl-12 h in AAs was 64.71 +/- 17.9 mL/min and in CCs was 62.0 +/- 14.9 mL/min (p = 1.000). The CrCl-12 h was higher than the e-GFR (p < 0.001) irrespective of race or phase. CrCl-12 h was not different on both occasions (p = 0.289) in all the patients. CrCl-12 h was consistently greater than e-GFR. The difference between these e-GFR estimates may have an importance in the care of RTRs. PMID- 23356544 TI - The effect of acute kidney injury on long-term health-related quality of life: a prospective follow-up study. AB - INTRODUCTION: Acute kidney injury (AKI) is a serious complication in critically ill patients admitted to the Intensive Care Unit (ICU). We hypothesized that ICU survivors with AKI would have a worse health-related quality of life (HRQOL) outcome than ICU survivors without AKI. METHODS: We performed a long-term prospective observational study. Patients admitted for > 48 hours in a medical surgical ICU were included and divided in two groups: patients who fulfilled RIFLE criteria for AKI and patients without AKI. We used the Short-Form 36 to evaluate HRQOL before admission (by proxy within 48 hours after admission of the patient), at ICU discharge, hospital discharge, 3 and 6 months following ICU discharge (all by patients). Recovery in HRQOL from ICU-admission onwards was assessed using linear mixed modelling. RESULTS: Between September 2000 and January 2007 all admissions were screened for study participation. We included a total of 749 patients. At six months after ICU discharge 73 patients with AKI and 325 patients without AKI could be evaluated. In survivors with and without AKI, the pre-admission HRQOL (by proxy) and at six months after ICU discharge was significantly lower compared with an age matched general population. Most SF-36 dimensions changed significantly over time from ICU discharge. Change over time of HRQOL between the different AKI Rifle classes (Risk, Injury, Failure) showed no significant differences. At ICU discharge, scores were lowest in the group with AKI compared with the group without AKI for the physical functioning, role physical and general health dimensions. However, there were almost no differences in HRQOL between both groups at six months. CONCLUSIONS: The pre-admission HRQOL (by proxy) of AKI survivors was significantly lower in two dimensions compared with the age matched general population. Six months after ICU discharge survivors with and without AKI showed an almost similar HRQOL. However, compared with the general population with a similar age, HRQOL was poorer in both groups. PMID- 23356546 TI - Assessment of sperm hyperactivated motility and acrosome reaction can discriminate the use of spermatozoa for conventional in vitro fertilisation or intracytoplasmic sperm injection: preliminary results. AB - Basic semen analysis is insufficient for determining the fertility potential. The aim of this study was to determine if hyperactivated motility (HAM) and acrosome reaction (AR) can be useful tests for evaluating semen quality during male infertility evaluations and to help the clinician decide whether regular insemination or intracytoplasmic sperm injection (ICSI) is preferable during in vitro fertilisation. A prospective study was conducted. Patients with normal sperm according to World Health Organization guidelines who underwent IVF treatment and planned regular insemination were asked to participate. A portion of sperm sample was evaluated for HAM and AR on day of ovum pick up. In HAM assessment, 93.3% of patients with increased HAM had a high fertilisation rate compared with 64% in the group without increased HAM (P = 0.059). For the AR evaluation, 91.7% of samples with a low rate of spontaneous AR had a high fertilisation rate compared with 39.3% in the group with a high rate of spontaneous AR (P = 0.004). PMID- 23356548 TI - Molecularly designed layer-by-layer (LbL) films to detect catechol using information visualization methods. AB - The control of molecular architectures has been exploited in layer-by-layer (LbL) films deposited on Au interdigitated electrodes, thus forming an electronic tongue (e-tongue) system that reached an unprecedented high sensitivity (down to 10(-12) M) in detecting catechol. Such high sensitivity was made possible upon using units containing the enzyme tyrosinase, which interacted specifically with catechol, and by processing impedance spectroscopy data with information visualization methods. These latter methods, including the parallel coordinates technique, were also useful for identifying the major contributors to the high distinguishing ability toward catechol. Among several film architectures tested, the most efficient had a tyrosinase layer deposited atop LbL films of alternating layers of dioctadecyldimethylammonium bromide (DODAB) and 1,2-dipalmitoyl-sn-3 glycero-fosfo-rac-(1-glycerol) (DPPG), viz., (DODAB/DPPG)5/DODAB/Tyr. The latter represents a more suitable medium for immobilizing tyrosinase when compared to conventional polyelectrolytes. Furthermore, the distinction was more effective at low frequencies where double-layer effects on the film/liquid sample dominate the electrical response. Because the optimization of film architectures based on information visualization is completely generic, the approach presented here may be extended to designing architectures for other types of applications in addition to sensing and biosensing. PMID- 23356547 TI - Dispersal and gene flow in free-living marine nematodes. AB - Dispersal and gene flow determine connectivity among populations, and can be studied through population genetics and phylogeography. We here review the results of such a framework for free-living marine nematodes. Although field experiments have illustrated substantial dispersal in nematodes at ecological time scales, analysis of the genetic diversity illustrated the importance of priority effects, founder effects and genetic bottlenecks for population structuring between patches <1 km apart. In contrast, only little genetic structuring was observed within an estuary (<50 km), indicating that these small scale fluctuations in genetic differentiation are stabilized over deeper time scales through extensive gene flow. Interestingly, nematode species with contrasting life histories (extreme colonizers vs persisters) or with different habitat preferences (algae vs sediment) show similar, low genetic structuring. Finally, historical events have shaped the genetic pattern of marine nematodes and show that gene flow is restricted at large geographical scales. We also discuss the presence of substantial cryptic diversity in marine nematodes, and end with highlighting future important steps to further unravel nematode evolution and diversity. PMID- 23356549 TI - Demographic and population-genetic tests provide mixed support for the abundant centre hypothesis in the endemic plant Leavenworthia stylosa. AB - The abundant centre hypothesis (ACH) assumes that population abundance, population size, density and per-capita reproductive output should peak at the centre of a species' geographic range and decline towards the periphery. Increased isolation among and decreased reproductive output within edge populations should reduce within-population genetic diversity and increase genetic differentiation among edge relative to central populations. The ACH also predicts asymmetrical gene flow, with net movement of migrants from the centre to edges. We evaluated these ecological assumptions and population-genetic predictions in the endemic flowering plant Leavenworthia stylosa. Although populations were more spatially isolated near range edges, the geographic centre was surrounded by and not coincident with areas of peak population abundance, and plant density increased towards range edges. Per-capita seed number was not associated with distance to the range centre, but seed number/m(2) increased near range edges. In support of ACH predictions, allelic diversity at 12 microsatellite loci declined with distance from the range centre, and pairwise FST values were higher between edge populations than between central populations. Coalescent analyses confirmed that gene flow was most infrequent between edge populations, but there was not an asymmetric pattern of gene flow predicted by the ACH. This study shows that among-population demographic variability largely did not support the ACH, while patterns of genetic diversity, differentiation and gene flow were generally consistent with its predictions. Such mixed support has frequently been observed in tests of the ACH and raises concerns regarding the generality of this hypothesis for species range limits. PMID- 23356550 TI - Liver manipulation during liver surgery in humans is associated with hepatocellular damage and hepatic inflammation. AB - BACKGROUND: Manipulation of the liver during liver surgery results in profound hepatocellular damage. Experimental data show that mobilization-induced hepatocellular damage is related to hepatic inflammation. To date, information on this link in humans is lacking. As it is possible to modulate inflammation, it is clinically relevant to unravel this relationship. AIM: This observational study aimed to establish the association between liver mobilization and hepatic inflammation in humans. METHODS: Consecutive patients requiring mobilization of the right hemi-liver during liver surgery were studied. Plasma samples and liver biopsies were collected prior to and directly after mobilization and after transection of the liver. Hepatocellular damage was assayed by liver fatty acid binding protein (L-FABP) and aminotransferase levels. Hepatic inflammation was determined by (a) immunohistochemical identification of myeloperoxidase (MPO) and CD68- positive cells and (b) hepatic gene expression of inflammatory and cell adhesion molecules (IL-1beta, IL-6, IL-8, VCAM-1 and ICAM-1). RESULTS: A total of 25 patients were included. L-FABP levels increased significantly during mobilization (301 +/- 94 ng/ml to 1599 +/- 362 ng/ml, P = 0.008), as did ALAT levels (36 +/- 5 IU/L to 167 +/- 21 IU/L, P < 0.001). A significant increase in MPO (P = 0.001) and CD68 (P = 0.002) positive cells was noticed in the liver after mobilization. The number of MPO-positive cells correlated with the duration of mobilization (Pearson correlation=0.505, P = 0.033). Hepatic gene expression of pro-inflammatory cytokines IL-1beta and IL-6, chemo-attractant IL-8 and adhesion molecule ICAM-1 increased significantly during liver manipulation. CONCLUSIONS: Liver mobilization is associated with hepatocellular damage and liver inflammation, as shown by infiltration of inflammatory cells and upregulation of genes involved in acute inflammation. PMID- 23356551 TI - Improving prostate cancer detection in veterans through the development of a clinical decision rule for prostate biopsy. AB - BACKGROUND: We sought to improve prostate cancer (PC) detection through developing a prostate biopsy clinical decision rule (PBCDR), based on an elevated PSA and laboratory biomarkers. This decision rule could be used after initial PC screening, providing the patient and clinician information to consider prior to biopsy. METHODS: This case-control study evaluated men from the Tampa, Florida, James A. Haley (JH) Veteran's Administration (VA) (N = 1,378), from January 1, 1998, through April 15, 2005. To assess the PBCDR we did all of the following: 1) Identified biomarkers that are related to PC and have the capability of improving the efficiency of PC screening; 2) Developed statistical models to determine which can best predict the probability of PC; 3) Compared each potential model to PSA alone using Receiver Operator Characteristic (ROC) curves, to evaluate for improved overall effectiveness in PC detection and reduction in (negative) biopsies; and 4) Evaluated dose-response relationships between specified lab biomarkers (surrogates for extra-prostatic disease development) and PC progression. RESULTS: The following biomarkers were related to PC: hemoglobin (HGB) (OR = 1.42 95% CI 1.27, 1.59); red blood cell (RBC) count (OR = 2.52 95% CI 1.67, 3.78); PSA (OR = 1.04 95% CI 1.03, 1.05); and, creatinine (OR = 1.55 95% CI 1.12, 2.15). Comparing all PC stages versus non-cancerous conditions, the ROC curve area under the curve (AUC) enlarged (increasing the probability of correctly classifying PC): PSA (alone) 0.59 (95% CI 0.55, 0.61); PBCDR model 0.68 (95% CI 0.65, 0.71), and the positive predictive value (PPV) increased: PSA 44.7%; PBCDR model 61.8%. Comparing PC (stages II, III, IV) vs. other, the ROC AUC increased: PSA (alone) 0.63 (95% CI 0.58, 0.66); PBCDR model 0.72 (95% CI 0.68, 0.75), and the PPV increased: 20.6% (PSA); PBCDR model 55.3%. CONCLUSIONS: These results suggest evaluating certain common biomarkers in conjunction with PSA may improve PC prediction prior to biopsy. Moreover, these biomarkers may be more helpful in detecting clinically relevant PC. Follow-up studies should begin with replicating the study on different U.S. VA patients involving multiple practices. PMID- 23356552 TI - Sexual arousal decreases the functional synchronization between cortical areas in young men. AB - The prefrontal cortex and its connections with other cortical areas participate in processing erotic stimuli and hence sexual arousal. Visual erotic stimuli elicit sexual arousal that is associated with changes in electroencephalographic activity. The electroencephalographic correlation analysis provides information on the functional synchronization among areas. This study analyzed the functional interaction among the prefrontal, parietal, and temporal cortices during sexual arousal in young men induced by observing erotic photographs. In 2 groups of heterosexual men-an erotic stimulation group and a neutral stimulation group-the authors recorded electroencephalograms at the F3, F4, T3, T4, P3, and P4 derivations under 2 conditions: baseline and visual stimulation. Heart rate was monitored as a measure of peripheral activation. Participants in the erotic stimulation group reported a moderate degree of sexual arousal and a decrease in heart rate. Decreased inter- and intrahemispheric correlations of the fast frequencies were obtained only in erotic stimulation. These data support differential hemisphere participation in modulating sexual arousal and show that decreased synchronization patterns between prefrontal and posterior cortices (parietal and temporal) favor sexual arousal in young men. The results of this study may contribute to a better understanding of the central nervous system's mechanisms that underlie sexual arousal. PMID- 23356554 TI - Addressing the gaps in preparation for quarantine. AB - INTRODUCTION: In the event of an outbreak of a communicable respiratory illness, quarantine may become necessary. The New York Institute for All Hazard Preparedness (NYIAHP) of the State University of New York (SUNY) Downstate Medical Center, in cooperation with the New York City Department of Health and Mental Hygiene's Healthcare Emergency Preparedness Program, (NYC DOHMH-HEPP) quarantine working group, has developed a series of clinical protocols to help health care facilities respond to such an event. PROBLEM: Two full-scale exercises (FSEs) were designed and conducted a year apart in the quarantine unit at Kings County Hospital Center (KCHC) to test the efficacy and feasibility of these quarantine protocols. The goal of these exercises was to identify the gaps in preparedness for quarantine and increase hospital readiness for such an event. METHODS: Evaluators monitored for efficient management of critical physical plants, personnel and material resources. Players were expected to integrate and practice emergency response plans and protocols specific to quarantine. In developing the exercise objectives, five activities were selected for evaluation: Activation of the Unit, Staffing, Charting/Admission, Symptom Monitoring and Infection Control, and Client Management. RESULTS: The results of the initial FSE found that there were incomplete critical tasks within all five protocols: These deficiencies were detailed in an After Action Report and an Improvement Plan was presented to the KCHC Disaster Preparedness Committee a month after the initial FSE. In the second FSE a year later, all critical tasks for Activation of the unit, Staffing and Charting/Admission were achieved. Completion of critical tasks related to Symptom Monitoring and Infection Control and Client Management was improved in the second FSE, but some tasks were still not performed appropriately. CONCLUSION: In short, these exercises identified critical needs in disaster preparedness of the KCHC Quarantine Unit. The lessons learned from this logistical exercise enabled the planning group to have a better understanding of leadership needs, communication capabilities, and infection control procedures. Kings County Hospital Center performed well during these exercises. It was clear that performance in the second exercise was improved, and many problems noted in the first exercise were corrected. Staff also felt better prepared the second time. This supports the idea that frequent exercises are vital to maintain disaster readiness. PMID- 23356555 TI - Can elevated CO2 and ozone shift the genetic composition of aspen (Populus tremuloides) stands? AB - The world's forests are currently exposed to increasing concentrations of carbon dioxide (CO2) and ozone (O3). Both pollutants can potentially exert a selective effect on plant populations. This, in turn, may lead to changes in ecosystem properties, such as carbon sequestration. Here, we report how elevated CO2 and O3 affect the genetic composition of a woody plant population via altered survival. Using data from the Aspen free-air CO2 enrichment (FACE) experiment (in which aspen clones were grown in factorial combinations of CO2 and O3), we develop a hierarchical Bayesian model of survival. We also examine how survival differences between clones could affect pollutant responses in the next generation. Our model predicts that the relative abundance of the tested clones, given equal initial abundance, would shift under either elevated CO2 or O3 as a result of changing survival rates. Survival was strongly affected by between-clone differences in growth responses. Selection could noticeably decrease O3 sensitivity in the next generation, depending on the heritability of growth responses and the distribution of seed production. The response to selection by CO2, however, is likely to be small. Our results suggest that the changing atmospheric composition could shift the genotypic composition and average pollutant responses of tree populations over moderate timescales. PMID- 23356556 TI - Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes. AB - AIM: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of empagliflozin in patients with type 2 diabetes following oral administration of 10, 25 or 100 mg doses once daily over 28 days. METHODS: A total of 78 patients were assigned to empagliflozin 10 mg (n = 16), 25 mg (n = 16) or 100 mg (n = 30) or placebo (n = 16) for 28 days. Assessments included adverse events (AEs) and pharmacokinetic and pharmacodynamic endpoints. RESULTS: Empagliflozin exposure increased dose-proportionally over the dose range 10-100 mg and showed linear pharmacokinetics with respect to time. Urinary glucose excretion (UGE) increased from baseline to day 1 by 74, 90 and 81 g with empagliflozin 10, 25 and 100 mg, respectively. The increases in UGE were maintained over 28 days with multiple dosing. Virtually no change in UGE was observed in the placebo group. Significant reductions from baseline in mean daily plasma glucose and fasting plasma glucose were observed with empagliflozin compared with placebo. The incidence of AEs was similar in the empagliflozin and placebo groups (50.0, 56.3 and 66.7% with empagliflozin rising doses and 62.5% with placebo). The most frequently reported AEs were pollakiuria (10.3%), nasopharyngitis (9.0%), constipation (9.0%) and headache (7.7%). CONCLUSIONS: Oral administration of empagliflozin at doses of 10, 25 or 100 mg once daily over 28 days resulted in significant increases in UGE and reductions in blood glucose compared with placebo, and were well tolerated in patients with type 2 diabetes. PMID- 23356557 TI - Clinical utility and cost of non-invasive prenatal testing with cfDNA analysis in high-risk women based on a US population. AB - OBJECTIVE: Evaluate the clinical and economic consequences of fetal trisomy 21 (T21) screening with non-invasive prenatal testing (NIPT) in high-risk pregnant women. METHODS: Using a decision-analytic model, we estimated the number of T21 cases detected, the number of invasive procedures performed, corresponding euploid fetal losses and total costs for three screening strategies: first trimester combined screening (FTS), integrated screening (INT) or NIPT, whereby NIPT was performed in high-risk patients (women 35 years or older or women with a positive conventional screening test). Modeling was based on a 4 million pregnant women cohort in the US. RESULTS: NIPT, at a base case price of $795, was more clinically effective and less costly (dominant) over both FTS and INT. NIPT detected 4823 T21 cases based on 5330 invasive procedures. FTS detected 3364 T21 cases based on 108 364 procedures and INT detected 3760 cases based on 108 760 procedures. NIPT detected 28% and 43% more T21 cases compared to INT and FTS, respectively, while reducing invasive procedures by >95% and reducing euploid fetal losses by >99%. Total costs were $3786M with FTS, $3919M with INT and $3403M with NIPT. CONCLUSIONS: NIPT leads to improved T21 detection and reduction in euploid fetal loss at lower total healthcare expenditures. PMID- 23356558 TI - Genome-wide analysis validates aberrant methylation in fragile X syndrome is specific to the FMR1 locus. AB - BACKGROUND: Fragile X syndrome (FXS) is a common form of inherited intellectual disability caused by an expansion of CGG repeats located in the 5' untranslated region (UTR) of the FMR1 gene, which leads to hypermethylation and silencing of this locus. Although a dramatic increase in DNA methylation of the FMR1 full mutation allele is well documented, the extent to which these changes affect DNA methylation throughout the rest of the genome has gone unexplored. METHODS: Here we examined genome-wide methylation in both peripheral blood (N = 62) and induced pluripotent stem cells (iPSCs; N = 10) from FXS individuals and controls. RESULTS: We not only found the expected significant DNA methylation differences in the FMR1 promoter and 5' UTR, we also saw that these changes inverse in the FMR1 gene body. Importantly, we found no other differentially methylated loci throughout the remainder of the genome, indicating the aberrant methylation of FMR1 in FXS is locus-specific. CONCLUSIONS: This study provides a comprehensive methylation profile of FXS and helps refine our understanding of the mechanisms behind FMR1 silencing. PMID- 23356560 TI - Happy faces are preferred regardless of familiarity--sad faces are preferred only when familiar. AB - Familiarity leads to preference (e.g., the mere exposure effect), yet it remains unknown whether it is objective familiarity, that is, repetitive exposure, or subjective familiarity that contributes to preference. In addition, it is unexplored whether and how different emotions influence familiarity-related preference. The authors investigated whether happy or sad faces are preferred or perceived as more familiar and whether this subjective familiarity judgment correlates with preference for different emotional faces. An emotional face- happy or sad--was paired with a neutral face, and participants rated the relative preference and familiarity of each of the paired faces. For preference judgment, happy faces were preferred and sad faces were less preferred, compared with neutral faces. For familiarity judgment, happy faces did not show any bias, but sad faces were perceived as less familiar than neutral faces. Item-by-item correlational analyses show preference for sad faces--but not happy faces- positively correlate with familiarity. These results suggest a direct link between positive emotion and preference, and argue at least partly against a common cause for familiarity and preference. Instead, facial expression of different emotional valence modulates the link between familiarity and preference. PMID- 23356559 TI - Attention orienting by gaze and facial expressions across development. AB - Processing of facial expressions has been shown to potentiate orienting of attention toward the direction signaled by gaze in adults, an important social cognitive function. However, little is known about how this social attention skill develops. This study is the first to examine the developmental trajectory of the gaze orienting effect (GOE), its modulations by facial expressions, and its links with theory of mind (ToM) abilities. Dynamic emotional stimuli were presented to 222 participants (7-25 years old) with normal trait anxiety using a gaze-cuing paradigm. The GOE was found as early as 7 years of age and decreased linearly until 12-13 years, at which point adult levels were reached. Both fearful and surprised expressions enhanced the GOE compared with neutral expressions. The GOE for fearful faces was also larger than for joyful and angry expressions. These effects did not interact with age and were not driven by intertrial variance. Importantly, the GOE did not correlate with ToM abilities as assessed by the "Reading the Mind in the Eyes" test. The implication of these findings for clinical and typically developing populations is discussed. PMID- 23356561 TI - Conditioned fear modulates visual selection. AB - Eye movements reflect the dynamic interplay between top-down- and bottom-up driven processes. For example, when we voluntarily move our eyes across the visual field, salient visual stimuli in the environment may capture our attention, our eyes, or modulate the trajectory of an eye movement. Previous research has shown that the behavioral relevance of a salient stimulus modulates these processes. This study investigated whether a stimulus signaling an aversive event modulates saccadic behavior. Using a differential fear-conditioning procedure, we presented a threatening (conditional stimulus: CS+) and a nonthreatening stimulus distractor (CS-) during an oculomotor selection task. The results show that short-latency saccades deviated more strongly toward the CS+ than toward the CS- distractor, whereas long-latency saccades deviated more strongly away from the CS+ than from the CS- distractor. Moreover, the CS+ distractor captured the eyes more often than the CS- distractor. Together, these results demonstrate that conditioned fear has a direct and immediate influence on visual selection. The findings are interpreted in terms of a neurobiological model of emotional visual processing. PMID- 23356562 TI - The effects of alcohol on the emotional displays of Whites in interracial groups. AB - Discomfort during interracial interactions is common among Whites in the U.S. and is linked to avoidance of interracial encounters. While the negative consequences of interracial discomfort are well-documented, understanding of its causes is still incomplete. Alcohol consumption has been shown to decrease negative emotions caused by self-presentational concern but increase negative emotions associated with racial prejudice. Using novel behavioral-expressive measures of emotion, we examined the impact of alcohol on displays of discomfort among 92 White individuals interacting in all-White or interracial groups. We used the Facial Action Coding System and comprehensive content-free speech analyses to examine affective and behavioral dynamics during these 36-min exchanges (7.9 million frames of video data). Among Whites consuming nonalcoholic beverages, those assigned to interracial groups evidenced more facial and speech displays of discomfort than those in all-White groups. In contrast, among intoxicated Whites there were no differences in displays of discomfort between interracial and all White groups. Results highlight the central role of self-presentational concerns in interracial discomfort and offer new directions for applying theory and methods from emotion science to the examination of intergroup relations. PMID- 23356563 TI - There's more to anxiety than meets the eye: isolating threat-related attentional engagement and disengagement biases. AB - Threat-related attentional biases represent a basic survival mechanism. These biases include an engagement bias involving rapid direction of attention toward threat and a disengagement bias involving slow direction of attention away from threat. The exact nature of these biases in healthy and anxious individuals remains controversial because of the challenges associated with accurately isolating each of these attentional biases. Combining a cognitive attentional task with classical conditioning using electric stimulation, we created a new paradigm that makes it possible to more clearly isolate these attentional biases. Utilizing this novel paradigm, we detected both types of attentional bias and differentiated between levels of trait anxiety, in which low- and high-trait anxiety individuals showed equal levels of engagement bias, but only high-trait anxiety individuals showed impaired disengagement from threat. PMID- 23356564 TI - A winning smile? Smile intensity, physical dominance, and fighter performance. AB - The smile is perhaps the most widely studied facial expression of emotion, and in this article we examine its status as a sign of physical dominance. We reason, on the basis of prior research, that prior to a physical confrontation, smiles are a nonverbal sign of reduced hostility and aggression, and thereby unintentionally communicate reduced physical dominance. Two studies provide evidence in support of this prediction: Study 1 found that professional fighters who smiled more in a prefight photograph taken facing their opponent performed more poorly during the fight in relation to their less intensely smiling counterparts. In Study 2, untrained observers judged a fighter as less hostile and aggressive, and thereby less physically dominant when the fighters' facial expression was manipulated to show a smiling expression in relation to the same fighter displaying a neutral expression. Discussion focused on the reasons why smiles are associated with decreased physical dominance. PMID- 23356565 TI - I feel your fear: shared touch between faces facilitates recognition of fearful facial expressions. AB - Embodied simulation accounts of emotion recognition claim that we vicariously activate somatosensory representations to simulate, and eventually understand, how others feel. Interestingly, mirror-touch synesthetes, who experience touch when observing others being touched, show both enhanced somatosensory simulation and superior recognition of emotional facial expressions. We employed synchronous visuotactile stimulation to experimentally induce a similar experience of "mirror touch" in nonsynesthetic participants. Seeing someone else's face being touched at the same time as one's own face results in the "enfacement illusion," which has been previously shown to blur self-other boundaries. We demonstrate that the enfacement illusion also facilitates emotion recognition, and, importantly, this facilitatory effect is specific to fearful facial expressions. Shared synchronous multisensory experiences may experimentally facilitate somatosensory simulation mechanisms involved in the recognition of fearful emotional expressions. PMID- 23356566 TI - How trait anxiety, interpretation bias and memory affect acquired fear in children learning about new animals. AB - Cognitive models of vulnerability to anxiety propose that information processing biases such as interpretation bias play a part in the etiology and maintenance of anxiety disorders. However, at present little is known about the role of memory in information processing accounts of child anxiety. The current study investigates the relationships between interpretation biases, memory and fear responses when learning about new stimuli. Children (aged 8-11 years) were presented with ambiguous information regarding a novel animal, and their fear, interpretation bias, and memory for the information was measured. The main findings were: (1) trait anxiety and interpretation bias significantly predicted acquired fear; (2) interpretation bias did not significantly mediate the relationship between trait anxiety and acquired fear; (3) interpretation bias appeared to be a more important predictor of acquired fear than trait anxiety per se; and (4) the relationship between interpretation bias and acquired fear was not mediated by the number of negative memories but was mediated by the number of positive and false-positive memories. The findings suggest that information processing models of child anxiety need to explain the role of positive memory in the formation of fear responses. PMID- 23356567 TI - Buddhist-inspired meditation increases the value of calm. AB - Most studies of meditation have focused on "actual affect" (how people actually feel). We predict that meditation may even more significantly alter "ideal affect" (how people ideally want to feel). As predicted, meditators ideally wanted to feel calm more and excited less than nonmeditators, but the groups did not differ in their actual experience of calm or excited states (Study 1). We ruled out self-selection and nonspecific effects by randomly assigning participants to meditation classes, an improvisational theater class, or a no class control (Study 2). After eight weeks, meditators valued calm more but did not differ in their actual experience of calm compared with the other groups. There were no differences in ideal or actual excitement, suggesting that meditation selectively increases the value placed on calm. These findings were not due to expectancy effects (Study 3). We discuss the implications of these findings for understanding how meditation alters affective life. PMID- 23356568 TI - Effects of pioglitazone and vildagliptin on coagulation cascade in diabetes mellitus--targeting thrombogenesis. AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) is intricately allied with an increased risk of atherothrombotic disease. Thrombosis is the cause of mortality in 80% of patients with diabetes mellitus. Endothelial abnormalities lead to elevated inflammatory and coagulation biomarkers as seen in diabetes. Progression of atherothrombotic disease in diabetes has been linked with elevated levels of various coagulation factors including fibrinogen, plasminogen activator inhibitor 1, and von Willebrand factor. AREAS COVERED: We review the existing evidence and most recent data elucidating the various inflammatory and coagulation biomarkers that are elevated in T2DM leading to thrombosis as well as the anti-inflammatory, anticoagulant and antithrombotic mechanisms of pioglitazone and vildagliptin in addition to their effect on glucose metabolism that may halt the progression of atherothrombotic disease. EXPERT OPINION: The review highlights the pleiotropic effects of pioglitazone and vildagliptin on metabolic, inflammatory and coagulation processes that have the potential to influence cardiovascular disease progression at various points in the disease process, including hemostatic disturbances, inflammation, plaque rupture and atherogenesis in T2DM. Finally, the paper suggests a possible decline in T2DM-associated cardiovascular comorbidities once the antithrombotic potential of pioglitazone and vildagliptin is established through clinical investigation. PMID- 23356569 TI - African-Americans' perceptions of health care provider cultural competence that promote HIV medical self-care and antiretroviral medication adherence. AB - Most studies of cultural competence in healthcare examine healthcare providers' definitions of cultural competence practices. This study is unique in that it examines the relationship between African-American patients' perceptions of the cultural competence of their HIV healthcare providers and the adherence of these patients to medical self-care and antiretroviral therapy (ART). This cross sectional, exploratory, descriptive study was conducted at the Ruth Rothstein CORE Center in Chicago, Illinois. The sample consisted of 202 HIV-positive African-Americans who completed surveys during clinic visits. Multiple measures were used, including the Patient Assessments of Cultural Competency survey instrument developed by the Department of Health and Human Services Agency for Healthcare Research and Quality. Medical self-care was measured using the advice and instructions scale and the self-care symptom management for people living with HIV/AIDS categorical scale. ART adherence was measured using the Adherence Behaviors Self-Report and Adherence Self-Report scales. The data revealed many significant correlations between variables. The more patients believed that providers should integrate culture in HIV treatment; the better their reported health (F1,138=0.151, P=0.05) and the more they followed their provider's advice and instructions (medical self-care; F1,138=0.029, P=0.05). Participants who trusted their providers engaged in more medical self-care (F1,138=0.280, P=0.01). More shared treatment decisions were reported among participants who had higher levels of education (F1,127=0.337, P=0.05). Findings of this study indicate the need for increased attention to the role of cultural competence in HIV/AIDS care. Understanding patient perceptions of provider cultural competence has the potential to improve HIV treatment adherence and health outcomes. PMID- 23356571 TI - Online cancer news: trends regarding article types, specific cancers, and the cancer continuum. AB - The Internet is one of the fastest growing news sources for many worldwide (Pew Research Center's Project for Excellence in Journalism, 2011), and cancer news is one frequently consumed form of online health information (Google, Inc., 2007). This content analysis of online cancer news (n = 862) retrieved from the four most frequented news websites describes trends regarding specific cancers, stages in the cancer continuum, and types of news articles. In general, treatment information received the most attention in online cancer news. Breast cancer received the most attention of each specific cancer, followed by digestive and genitourinary cancers. Research reports and profiles of people (more than 60% of which were about celebrities) were the most common article types. Risk, uncertainty, and clinical trials were also present across several types of cancer news articles. Implications of content trends are discussed as relevant to consumers, producers, health campaign designers, and researchers alike. PMID- 23356570 TI - Plasma thioredoxin levels during post-cardiac arrest syndrome: relationship with severity and outcome. AB - INTRODUCTION: Despite experimental evidence, clinical demonstration of acute state of oxidative stress and inflammation during post-cardiac arrest syndrome is lacking. Plasma level of thioredoxin (TRX), a redox-active protein induced under conditions of oxidative stress and inflammation, is increased in various critical care conditions. We determined plasma TRX concentrations after cardiac arrest and assessed relationships with severity and outcome. METHODS: Retrospective study of consecutive patients admitted to a single academic intensive care unit (ICU) for out-of-hospital cardiac arrest (between July 2006 and March 2008). Plasma levels of TRX were measured at admission, day (D) 1, 2 and 3. RESULTS: Of 176 patients included, median TRX values measured in ICU survivors and non-survivors were, respectively: 22 ng/mL (7.8 to 77) vs. 72.4 (21.9 to 117.9) at admission (P < 0.001); 5.9 (3.5 to 25.5) vs. 23.2 (5.8 to 81.4) at D1 (P = 0.003); 10.8 (3.6 to 50.8) vs. 11.7 (4.5 to 66.4) at D2 (P = 0.22); and 16.7 (5.3 to 68.3) vs. 17 (4.3 to 62.9) at D3 (P = 0.96). Patients dying within 24 hours had significantly (P < 0.001) higher TRX levels (118.6 ng/mL (94.8 to 280)) than those who died after 24 hours or survived (50.8 (13.9 to 95.7) and 22 (7.8 to 77)). The area under the ROC curve to predict early death was 0.84 (0.76 to 0.91). CONCLUSIONS: Our data show for the first time that TRX levels were elevated early following cardiac arrest, suggestive of oxidative stress and inflammation occurring with this condition. Highest values were found in the most severe patients. TRX could be a useful tool for further exploration and comprehension of post-cardiac arrest syndrome. PMID- 23356572 TI - Invasive mould disease involving the gastrointestinal tract caused by Neosartorya pseudofischeri in a haematological patient. PMID- 23356573 TI - Seq2Ref: a web server to facilitate functional interpretation. AB - BACKGROUND: The size of the protein sequence database has been exponentially increasing due to advances in genome sequencing. However, experimentally characterized proteins only constitute a small portion of the database, such that the majority of sequences have been annotated by computational approaches. Current automatic annotation pipelines inevitably introduce errors, making the annotations unreliable. Instead of such error-prone automatic annotations, functional interpretation should rely on annotations of 'reference proteins' that have been experimentally characterized or manually curated. RESULTS: The Seq2Ref server uses BLAST to detect proteins homologous to a query sequence and identifies the reference proteins among them. Seq2Ref then reports publications with experimental characterizations of the identified reference proteins that might be relevant to the query. Furthermore, a plurality-based rating system is developed to evaluate the homologous relationships and rank the reference proteins by their relevance to the query. CONCLUSIONS: The reference proteins detected by our server will lend insight into proteins of unknown function and provide extensive information to develop in-depth understanding of uncharacterized proteins. Seq2Ref is available at: http://prodata.swmed.edu/seq2ref. PMID- 23356574 TI - Determinants of change in oral health-related quality of life over 7 years among older Japanese. AB - Because there are more elderly people than ever before and because they are living for longer periods of time, it is essential to understand the determinants of healthy ageing. This study examined changes in oral health-related quality of life (OHRQoL) among Japanese elderly over a 7-year period. A sample of independently living individuals (aged 60+ years) underwent a questionnaire and dental examination at baseline and 7 years afterwards. The Geriatric Oral Health Assessment Index (GOHAI) was used to assess the impact of oral conditions. Occlusal force and salivary flow were also assessed. Of the 411 participants assessed at baseline, 130 (31.6%) accepted to participate after 7 years. There were no significant differences between those lost to follow-up and those assessed at 7 years, except that a higher proportion of the latter rated their baseline general health as good. Among the latter, the overall mean GOHAI score did not change significantly (11.8 at baseline and 11.1 at follow-up; P = 0.16). However, after controlling for age, gender and baseline GOHAI score, participants who had lost teeth or experienced a decline in occlusal force after 7 years had higher follow-up GOHAI scores (indicating poorer OHRQoL). Unfavourable changes in clinical oral status over time are reflected in poorer self-rated oral health. PMID- 23356575 TI - An unusual cause of perirenal hemorrhage. PMID- 23356576 TI - The harmonic ratio of trunk acceleration predicts falling among older people: results of a 1-year prospective study. AB - BACKGROUND: Gait variables derived from trunk accelerometry may predict the risk of falls; however, their associations with falls are not fully understood. The purpose of the study was to determine which gait variables derived from upper and lower trunk accelerometry are associated with the incidence of falls, and to compare the discriminative ability of gait variables and physical performance. METHODS: This study was a 1-year prospective study. Older people (n = 73) walked normally while wearing accelerometers attached to the upper and lower trunk. Participants were classified as fallers (n = 16) or non-fallers (n = 57) based on the incidence of falls over 1 year. The harmonic ratio (HR) of the upper and lower trunk was measured. Physical performance was measured in five chair stands and in the timed up and go test. RESULTS: The HR of the upper and lower trunk were consistently lower in fallers than non-fallers (P < 0.05). Upper trunk HR, was independently associated with the incidence of falls (P < 0.05) after adjusting for confounding factors including physical performances. Consequently, upper trunk HR showed high discrimination for the risk of falls (AUC = 0.81). CONCLUSIONS: HR derived from upper trunk accelerometry may predict the risk of falls, independently of physical performance. The discriminative ability of HR for the risk of falls may have some validity, and further studies are needed to confirm the clinical relevance of trunk HR. PMID- 23356577 TI - Oxidation mode of pyranose 2-oxidase is controlled by pH. AB - Pyranose 2-oxidase (P2O) from Trametes multicolor is a flavoenzyme that catalyzes the oxidation of d-glucose and other aldopyranose sugars at the C2 position by using O2 as an electron acceptor to form the corresponding 2-keto-sugars and H2O2. In this study, the effects of pH on the oxidative half-reaction of P2O were investigated using stopped-flow spectrophotometry. The results showed that flavin oxidation occurred via different pathways depending on the pH of the environment. At pH values lower than 8.0, reduced P2O reacts with O2 to form a C4a hydroperoxyflavin intermediate, leading to elimination of H2O2. At pH 8.0 and higher, the majority of the reduced P2O reacts with O2 via a pathway that does not allow detection of the C4a-hydroperoxyflavin, and flavin oxidation occurs with decreased rate constants upon the rise in pH. The switching between the two modes of P2O oxidation is controlled by protonation of a group which has a pK(a) of 7.6 +/- 0.1. Oxidation reactions of reduced P2O under rapid pH change as performed by stopped-flow mixing were different from the same reactions performed with enzyme pre-equilibrated at the same specified pH values, implying that the protonation of the group which controls the mode of flavin oxidation cannot be rapidly equilibrated with outside solvent. Using a double-mixing stopped-flow experiment, a rate constant for proton dissociation from the reaction site was determined to be 21.0 +/- 0.4 s-1. PMID- 23356578 TI - Role of SMG-1-mediated Upf1 phosphorylation in mammalian nonsense-mediated mRNA decay. AB - SMG-1, a member of the PIKK (phosphoinositide 3-kinase-related kinase) family, plays a critical role in the mRNA quality control system known as nonsense mediated mRNA decay (NMD). NMD protects cells from the accumulation of aberrant mRNAs with premature termination codons (PTCs) which encode nonfunctional or potentially harmful truncated proteins. SMG-1 directly phosphorylates Upf1 helicase, another key component of NMD, upon recognition of PTC on postspliced mRNA during the initial round of translation. Phosphorylated-Upf1 recruits the SMG-5/SMG-7 complex to induce ribosome dissociation and decapping-mediated decay. Phospho-Upf1 also recruits the SMG-6 endonuclease which might be involved in endo cleavage. Upf1 ATPase/helicase activities are likely required for the activation of other mRNA decay enzymes and the mRNA-protein complex dissociation to complete NMD. At present, a variety of tools are available that can specifically suppress NMD, and it has become possible to examine the contribution of NMD in a variety of physiological and pathological conditions. PMID- 23356579 TI - Children's thoughts on the social exclusion of peers with intellectual or learning disabilities. AB - BACKGROUND: Previous research has shown that children with intellectual or learning disabilities are at risk for social exclusion by their peers but little is known of children's views on this topic. In this study, we used concept mapping to investigate elementary school children's thoughts on why they believe their peers with intellectual or learning disabilities are sometimes socially excluded at school. METHOD: Participants were 49 grade five and six children who attended inclusive classrooms. Interviews were digitally recorded and transcribed. We extracted 49 unique statements from the transcribed data, and then invited participants to sort the statements into meaningful categories. RESULTS: Sorted data were entered into matrices, which were summed and analysed with multi-dimensional scaling and cluster analysis. A four-cluster solution provided the best conceptual fit for the data. Clusters reflected themes on (1) the thoughts and actions of other children; (2) differences in learning ability and resource allocation; (3) affect, physical characteristics and schooling; and (4) negative thoughts and behaviours. CONCLUSIONS: The overarching reason for social exclusion focused on differences between children with and without disabilities. This study also provided evidence that children are effective, reliable and competent participants in concept mapping. Educational and research implications are discussed. PMID- 23356580 TI - The effect of atorvastatin and simvastatin on vitamin D, oxidative stress and inflammatory marker concentrations in patients with type 2 diabetes: a crossover study. AB - The pleiotropic effect of statins may be mediated in part through raising 25 hydroxy vitamin D (25OHD) concentrations. It has also been shown that an increase in oxidative stress and inflammatory markers are a feature of the patients with type 2 diabetes (T2DM). A cross-over study of 26 patients with T2DM taking either simvastatin 40 mg or atorvastatin 10 mg was undertaken. After 3 months on one statin, lipids, C-reactive protein (hsCRP), 25OHD and malondialdehyde (MDA) were measured repeatedly. The same procedure was then followed taking the other statin. Despite similar lipid-lowering, the mean 25OHD was higher on atorvastatin compared with simvastatin and the mean MDA and hsCRP levels lower, irrespective of which statin the patients were taking before crossover. The changes in 25OHD predicted changes in CRP and MDA levels. Thus, compared with simvastatin, atorvastatin shows apparently beneficial pleiotropic effects with respect to 25OHD concentrations as well as markers of oxidative stress and inflammation in patients with T2DM. PMID- 23356581 TI - P-glycoprotein (PGP) polymorphisms and sexual dysfunction in female patients with depression and SSRI-associated sexual side effects. AB - Sexual dysfunction is common with selective serotonin reuptake inhibitor use for major depressive disorder. Studies have shown associations between genetic variation in the adenosine triphosphate (ATP)-binding cassette, subfamily B, member 1 gene (ABCB1), which encodes the drug efflux transporter P-glycoprotein (PGP), and selective serotonin reuptake inhibitor response. This study measured functionally implicated ABCB1 variants (rs2235015, rs1128503, rs2032582, and rs1045642) and sexual dysfunction using the Changes in Sexual Functioning Questionnaire. This study included outpatients (18-40 years of age) treated for major depressive disorder with a selective serotonin reuptake inhibitor for 6 weeks. Changes in Sexual Functioning Questionnaire outcomes were stratified by ABCB1 genotype and PGP substrate status. The authors recruited 82 individuals (22 men and 57 women). Women receiving a PGP substrate with a rs1128503 TT genotype had a significantly lower Changes in Sexual Functioning Questionnaire total score (37.2 +/- 5.4), indicating greater sexual dysfunction, than did those with the CT (42.9 +/- 6.3) or CC genotypes (46.6 +/- 5.6), F(2) = 6.00, p = .005, p = .02, with multiple testing correction. The results indicate a relationship between genotypes at rs1128503, total sexual dysfunction, and PGP substrates use for women and may explain some of the sexual dysfunction variability seen with selective serotonin reuptake inhibitor treatment. Results need to be confirmed with a larger sample size that includes men. PMID- 23356582 TI - Structural consequences of the N7 and C8 translocation on the metal binding behavior of adenine. AB - 7-Deaza-8-aza-adenine, namely 4-aminopyrazolo[3,4-d]pyrimidine (H4app), is a bioisoster of adenine (Hade) resulting from the translocation of N7 and C8 atoms on the purine moiety. With the aim of studying the influence of this translocation on the metal binding abilities of H4app, we have prepared and structurally characterized two ternary copper(II) complexes having H4app and one N-benzyl-iminodiacetate chelator (MEBIDA or FBIDA, with a methyl or fluoro group in para- of the benzyl aromatic ring): [Cu(2)(MEBIDA)(2)(MU(2)-N1,N8 H4app)(H(2)O)(2)].4H(2)O (1) and [Cu(4)(FBIDA)(4)(MU(2)-N8,N9 H4app)(2)(H(2)O)].3.5H(2)O (2). Furthermore, thermal, spectral, and magnetic properties have been also investigated. In 1, H(N9)4app is disordered over two equally pondered positions and the MU(2)-N1,N8 coordination mode is assisted by N6-H...O and N9-H...O intramolecular interactions, respectively. The acyclic nonlinear molecular topology of 2 is strongly influenced by two intramolecular H bonding interactions (O-H...O-carboxylate) involving the apical aqua ligand of a terminal Cu(II) atom. Thus, both compounds have in common the Cu-N8 bond. In order to better understand our limited structural information, DFT calculations for the individual tautomers of H4app as well as mononuclear Cu(II) model systems have been carried out. According to previous results, we conclude that H(N9)4app is the most stable tautomer followed by H(N8)4app. When N9 and N8 are metalated, then the tautomer H(N1)4app can come into play as observed in compound 2. Likewise, the findings concerning compound 1 suggest that the formation of a Cu N1 bond in H4app results was favored compared to neutral adenine, for which only one case has been reported with such coordination despite the large variety of related Cu(II)-Hade described in the literature. PMID- 23356583 TI - UDP-glucosyltransferase UGT84A2/BRT1 is required for Arabidopsis nonhost resistance to the Asian soybean rust pathogen Phakopsora pachyrhizi. AB - Nonhost resistance (NHR) of plants to fungal pathogens comprises different defense layers. Epidermal penetration resistance of Arabidopsis to Phakopsora pachyrhizi requires functional PEN1, PEN2 and PEN3 genes, whereas post-invasion resistance in the mesophyll depends on the combined functionality of PEN2, PAD4 and SAG101. Other genetic components of Arabidopsis post-invasion mesophyll resistance remain elusive. We performed comparative transcriptional profiling of wild-type, pen2 and pen2 pad4 sag101 mutants after inoculation with P. pachyrhizi to identify a novel trait for mesophyll NHR. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis and microscopic analysis confirmed the essential role of the candidate gene in mesophyll NHR. UDP glucosyltransferase UGT84A2/bright trichomes 1 (BRT1) is a novel component of Arabidopsis mesophyll NHR to P. pachyrhizi. BRT1 is a putative cytoplasmic enzyme in phenylpropanoid metabolism. BRT1 is specifically induced in pen2 with post invasion resistance to P. pachyrhizi. Silencing or mutation of BRT1 increased haustoria formation in pen2 mesophyll. Yet, the brt1 mutation did not affect NHR to P. pachyrhizi in wild-type plants. We assign a novel function to BRT1, which is important for post-invasion NHR of Arabidopsis to P. pachyrhizi. BRT1 might serve to confer durable resistance against P. pachyrhizi to soybean. PMID- 23356584 TI - Heterogeneity of fibrosis patterns in non-alcoholic fatty liver disease supports the presence of multiple fibrogenic pathways. AB - BACKGROUND: Adult non-alcoholic fatty liver disease (NAFLD) involves lobular necroinflammatory activity and fibrosis is typically centrilobular, whereas paediatric NAFLD has predominantly portal fibrosis. The reasons for these differences are unclear. We aimed to determine (a) how centrilobular and portal fibrosis in children relate to histological parameters; and (b) whether atypical fibrosis patterns exist in adults that are unexplained by current fibrogenesis models. METHODS: Histological features of paediatric (n = 38) and adult (n = 56) NAFLD were assessed using conventional scoring systems. Keratin-7 immunostaining was used to assess hepatic progenitor cell numbers and the ductular reaction. Centrilobular and portal components of fibrosis were independently scored and fibrosis patterns were classified according to accepted types. Post-treatment (rosiglitazone/gastric banding) biopsies were also examined in adults. RESULTS: Twenty-six children (68.4%) had portal-predominant fibrosis, although the typical "adult" pattern was seen in 11 (28.9%). Portal fibrosis was associated with a ductular reaction (P = 0.021) and hepatic progenitor cell expansion (P < 0.001), whereas centrilobular fibrosis was associated with lobular inflammation (P = 0.026) and ballooning (P = 0.001). Before intervention, six adults (10.7%) had atypical fibrosis including 3 (5.4%) with a previously unrecognized pattern of very fine, non-zonal sinusoidal fibrosis. Despite improvements in steatosis and inflammation, more patients developed this unusual pattern after intervention with most having had surgery (9 of 10 adults; P < 0.001). CONCLUSION: Differing associations with portal and centrilobular fibrosis in children and atypical fibrosis patterns in adults suggest that multiple fibrogenic pathways exist in NAFLD. This has implications for therapy and understanding pathogenesis. PMID- 23356587 TI - Peripheral platelet count correlates with liver atrophy and predicts long-term mortality on the liver transplant waiting list. AB - Several studies have shown a direct role of liver atrophy in the pathogenesis of thrombocytopenia of cirrhosis via reduced production of thrombopoeitin. About 181 patients listed for liver transplantation at a single transplant center were evaluated at the time of listing with laboratory tests and volumetric liver measurements using computed tomography. Expected normal liver volume was calculated using the Heinemann formula. Liver volume ratio (LVR) was calculated as actual liver volume over expected liver volume. Patients were predominantly male (70.7%), with viral hepatitis (60.2%), had a mean age of 51.8 years (SD 8.7), model for end stage liver disease (MELD) of 14 (SD 6.4), LVR of 0.95 (SD 0.3), and platelet count of 105,000/mcL (SD 66,000). Platelet count (P < 0.0001) correlated more strongly with LVR than MELD, MELD components (P = 0.27) or serum albumin (P = 0.003). Platelet count (HR 0.987, 95% CI 0.979-0.994, P = 0.001) was a strong independent predictor of mortality. Patients with platelet count < 100,000/mcL had a shorter survival (935 vs. 1396 days, P = 0.002) and higher death rate (42.2% vs. 23.6%, P = 0.01), but no different transplantation rate (36.7% vs. 33.3%, P = 0.64) compared to those with platelet count >= 100,000/mcL. Low platelet count corresponds to higher waiting list mortality and is a sign of advanced liver atrophy. PMID- 23356585 TI - Hsp90, an unlikely ally in the war on cancer. AB - On the surface heat shock protein 90 (Hsp90) is an unlikely drug target for the treatment of any disease, let alone cancer. Hsp90 is highly conserved and ubiquitously expressed in all cells. There are two major isoforms alpha and beta encoded by distinct genes and together they may constitute 1%-3% of the cellular protein. Deletion of the protein is embryonic lethal and there are no recognized polymorphisms suggesting an association or causal relationship with any human disease. With respect to cancer, the proteins absence from two recent high profile articles, 'Hallmarks of cancer: the next generation' [Hanahan & Weinberg (2011) Cell 144, 646-674] and 'Comprehensive molecular portraits of human breast tumours' [Koboldt et al. (2012) Nature] underlines the perception that it is an unlikely bona fide target to treat this disease. Yet, to date, there are 17 distinct Hsp90 inhibitors in clinical trials for multiple indications in cancer. The protein has been championed for over 20 years by the National Cancer Institute (Bethesda, MD, USA) as a cancer target since the discovery of the antitumor activity of the natural product geldanamycin. This review aims to look at the conundrum of why Hsp90 can even be considered a druggable target for the treatment of cancer. We propose that in contrast to the majority of chemotherapeutics our growing armamentarium of investigational Hsp90 drugs represents an elegant choice that offers real hope in the long-term treatment of certain cancers. PMID- 23356588 TI - A comparative study of neonatal outcomes in placenta previa versus cesarean for other indication at term. AB - OBJECTIVE: Currently, no ACOG guidelines address the issue of the optimal timing of delivery in placenta previa. Though there is an increased risk of neonatal morbidity and mortality when electively delivered preterm, it is unclear whether adverse neonatal outcomes exist when these pregnancies make it beyond term. By comparing neonatal outcomes amongst pregnancies with placenta previa versus those from cesarean for another indication at term, the objective of this study was to determine whether placenta previa is an independent risk factor for adverse neonatal outcomes at term. METHODS: We conducted a population-based cohort-study using the CDC's Linked Birth-Infant Death data from the United States. The effect of placenta previa on the risk of adverse neonatal outcomes was estimated using unconditional logistic regression analysis, adjusting for relevant confounders. RESULTS: Our cohort consisted of 3,550,842 deliveries meeting inclusion criteria. The incidence of placenta previa at term was 1.3/1000 (n = 4,492), accounting for 40.6% of all previa cases. Relative to cesareans for other indications, pregnancies with placenta previa had an increased risk of IUGR 3.20 [2.50-4.10], SGA 2.70 [2.45-2.97], respiratory distress 3.82 [2.91-5.00], prolonged ventilation 3.41 [2.70-4.32] and neonatal anemia 6.87 [4.43-10.65]. Rates of meconium aspiration syndrome, seizures, birth injury and overall infant mortality do not appear to be affected by this condition. CONCLUSION: Relative to cesareans for other indications, placenta previa is associated with increased morbidity, but not mortality, at term. This information might be helpful in the development of future guidelines, which are currently needed to guide and standardize clinical practice regarding the optimal timing of delivery in placenta previa. PMID- 23356586 TI - Microsomal triglyceride transfer protein -164 T > C gene polymorphism and risk of cardiovascular disease: results from the EPIC-Potsdam case-cohort study. AB - BACKGROUND: The microsomal triglyceride transfer protein (MTTP) is encoded by the MTTP gene that is regulated by cholesterol in humans. Previous studies investigating the effect of MTTP on ischemic heart disease have produced inconsistent results. Therefore, we have tested the hypothesis that the rare allele of the -164T > C polymorphism in MTTP alters the risk of cardiovascular disease (CVD), depending on the cholesterol levels. METHODS: The -164T > C polymorphism was genotyped in a case-cohort study (193 incident myocardial infarction (MI) and 131 incident ischemic stroke (IS) cases and 1 978 non-cases) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, comprising 27 548 middle-aged subjects. The Heinz Nixdorf Recall study (30 CVD cases and 1 188 controls) was used to replicate our findings. RESULTS: Genotype frequencies were not different between CVD and CVD free subjects (P = 0.79). We observed an interaction between the -164T > C polymorphism and total cholesterol levels in relation to future CVD. Corresponding stratified analyses showed a significant increased risk of CVD (HR(additve) = 1.38, 95% CI: 1.07 to 1.78) for individuals with cholesterol levels <200 mg/dL in the EPIC-Potsdam study. HR(additive) was 1.06, 95% CI: 0.33 to 3.40 for individuals in the Heinz Nixdorf Recall study. A borderline significant decrease in CVD risk was observed in subjects with cholesterol levels >= 200 mg/dL (HR(additve) = 0.77, 95% CI: 0.58 to 1.03) in the EPIC-Potsdam study. A similar trend was observed in the independent cohort (HR(additve) = 0.60, 95% CI: 0.29 to 1.25). CONCLUSIONS: Our study suggests an interaction between MTTP -164T > C functional polymorphism with total cholesterol levels. Thereby risk allele carriers with low cholesterol levels may be predisposed to an increased risk of developing CVD, which seems to be abolished among risk allele carriers with high cholesterol levels. PMID- 23356589 TI - Survey of renewable chemicals produced from lignocellulosic biomass during ionic liquid pretreatment. AB - BACKGROUND: Lignin is often overlooked in the valorization of lignocellulosic biomass, but lignin-based materials and chemicals represent potential value-added products for biorefineries that could significantly improve the economics of a biorefinery. Fluctuating crude oil prices and changing fuel specifications are some of the driving factors to develop new technologies that could be used to convert polymeric lignin into low molecular weight lignin and or monomeric aromatic feedstocks to assist in the displacement of the current products associated with the conversion of a whole barrel of oil. We present an approach to produce these chemicals based on the selective breakdown of lignin during ionic liquid pretreatment. RESULTS: The lignin breakdown products generated are found to be dependent on the starting biomass, and significant levels were generated on dissolution at 160 degrees C for 6 hrs. Guaiacol was produced on dissolution of biomass and technical lignins. Vanillin was produced on dissolution of kraft lignin and eucalytpus. Syringol and allyl guaiacol were the major products observed on dissolution of switchgrass and pine, respectively, whereas syringol and allyl syringol were obtained by dissolution of eucalyptus. Furthermore, it was observed that different lignin-derived products could be generated by tuning the process conditions. CONCLUSIONS: We have developed an ionic liquid based process that depolymerizes lignin and converts the low molecular weight lignin fractions into a variety of renewable chemicals from biomass. The generated chemicals (phenols, guaiacols, syringols, eugenol, catechols), their oxidized products (vanillin, vanillic acid, syringaldehyde) and their easily derivatized hydrocarbons (benzene, toluene, xylene, styrene, biphenyls and cyclohexane) already have relatively high market value as commodity and specialty chemicals, green building materials, nylons, and resins. PMID- 23356590 TI - Posttraumatic stress disorder symptom severity and HIV-risk behaviors among substance-dependent inpatients. AB - Despite findings that the co-occurrence of posttraumatic stress disorder (PTSD) and substance use disorders (SUD) is associated with heightened risk for a variety of risky behaviors, few studies have examined behaviors linked to heightened risk for HIV infection and transmission in particular, or explored the unique associations between specific PTSD symptom clusters and these HIV-risk behaviors. Therefore, the goal of this study was to examine the associations between PTSD symptom severity and HIV-risk behaviors (i.e., risky sexual behavior [RSB] and injection drug use [INJ]) within an ethnically diverse sample of 85 SUD patients in residential SUD treatment. Participants completed a battery of questionnaires assessing PTSD symptom severity and HIV-risk behaviors, including RSB and INJ. Results demonstrated significant positive associations between PTSD symptom severity and RSB; however, no significant relationship between PTSD symptom severity and INJ was found. Furthermore, the severity of hyperarousal symptoms in particular was found to significantly predict RSB above and beyond age and all other PTSD symptom clusters. Results of this study suggest that PTSD symptoms (and, more specifically, the hyperarousal symptoms of PTSD) may heighten the risk for some forms of HIV-risk behaviors (RSB) but not others (INJ). Results highlight the importance of identifying and targeting hyperarousal symptoms in the treatment of SUD patients experiencing symptoms of PTSD in order to reduce HIV infection or transmission risk. PMID- 23356591 TI - A point-of-sale communications campaign to provide consumers safety information on drug-dietary supplement interactions: a pilot study. AB - Concurrent use of dietary supplements with over-the-counter and prescription pharmaceuticals has become increasingly common, and with this trend, so has the incidence of adverse drug-supplement interactions. In the current market, consumers have no way to distinguish between safe and potentially harmful supplements. Thus, the primary objective of this study was to test the hypothesis that messages designed to increase consumers' awareness of potential health risks of concurrent use of dietary supplements with over-the-counter and prescription pharmaceuticals would promote further consideration and action, as evidenced by (a) seeking additional information from an authoritative source or qualified health care professional and (b) changing dietary supplement usage patterns. To test this hypothesis, an innovative consumer information delivery system, referred to as the Buyer Information Network (BuyIN), was utilized. BuyIN uses currently available, Web-enabled point-of-sale (POS) technology to provide up-to date, evidence-based, health- and safety-related messages to consumers at the retail checkout counter. Results showed that more than one-fourth (27.1%) of consumers (n = 199) who purchased targeted items reported they were aware of the messages. Of this subgroup of aware consumers, 11.2% reported that they sought additional information from a physician or pharmacist, 11.5% reported that they visited the website listed on the coupon, and 10.5% indicated that they changed their dietary supplement usage patterns as a result of the messages. Future research should include a large-scale study of a fully implemented and capable system at multiple test sites around the country, including investigating the utility of BuyIN in different retail settings. PMID- 23356592 TI - Injury versus noninjury factors as predictors of postconcussive symptoms following mild traumatic brain injury in children. AB - OBJECTIVE: To examine the relative contributions of injury characteristics and noninjury child and family factors as predictors of postconcussive symptoms (PCS) following mild traumatic brain injury (TBI) in children. METHOD: Participants were 8- to 15-year-old children, 186 with mild TBI and 99 with mild orthopedic injuries (OI). Parents and children rated PCS shortly after injury and at 1, 3, and 12 months postinjury. Hierarchical regression analyses were conducted to predict PCS from (1) demographic variables; (2) premorbid child factors (WASI IQ; WRAT-3 Reading; Child Behavior Checklist; ratings of preinjury PCS); (3) family factors (Family Assessment Device General Functioning Scale; Brief Symptom Inventory; and Life Stressors and Social Resources Inventory); and (4) injury group (OI, mild TBI with loss of consciousness [LOC] and associated injuries [AI], mild TBI with LOC but without AI, mild TBI without LOC but with AI, and mild TBI without LOC or AI). RESULTS: Injury group predicted parent and child ratings of PCS but showed a decreasing contribution over time. Demographic variables consistently predicted symptom ratings across time. Premorbid child factors, especially retrospective ratings of premorbid symptoms, accounted for the most variance in symptom ratings. Family factors, particularly parent adjustment, consistently predicted parent, but not child, ratings of PCS. CONCLUSIONS: Injury characteristics predict PCS in the first months following mild TBI but show a decreasing contribution over time. In contrast, noninjury factors are more consistently related to persistent PCS. PMID- 23356593 TI - Impairments in real-world executive function increase from childhood to adolescence in autism spectrum disorders. AB - OBJECTIVE: Although several studies have investigated developmental trajectories of executive functioning (EF) in individuals with autism spectrum disorders (ASD) using lab-based tasks, no study to date has directly measured how EF skills in everyday settings vary at different ages. The current study seeks to extend prior work by evaluating age-related differences in parent-reported EF problems during childhood and adolescence in a large cross-sectional cohort of children with ASD. METHOD: Children (N = 185) with an ASD without intellectual disability participated in the study. Participants were divided into four groups based on age (5-7, 8-10, 11-13, and 14-18-year-olds). The four age groups did not differ in IQ, sex ratio, or autism symptoms. RESULTS: There were significant age effects (i.e., worsening scores with increasing age) in three of G. A. Gioia, P. K. Isquith, S. Guy, and L. Kenworthy's (2000) BRIEF: Behavior Rating Inventory of Executive Function, Odessa, FL, Psychological Assessment Resources scale scores: Initiate (p = .007), working memory (p = .003), and organization of materials (p = .023). In addition, analysis of the BRIEF scale profile revealed that, although multiple scales were elevated, the shift scale showed the greatest problems in both the youngest and oldest age cohorts. CONCLUSIONS: Older children with ASD show greater EF problems compared with the normative sample than younger children with ASD. Specifically, there is a widening divergence from the normative sample in metacognitive executive abilities in children with ASD as they age. This, in combination with significant, albeit more stable, impairments in flexibility, has implications for the challenges faced by high-functioning individuals with ASD as they attempt to enter mainstream work and social environments. PMID- 23356595 TI - Theory of mind deficits in Parkinson's disease: a product of executive dysfunction? AB - OBJECTIVE: Patients with Parkinson's disease (PD) can perform poorly on tasks involving theory of mind (ToM): the ability to reason about mental states. We investigated whether patients' ToM deficits were independent of executive dysfunction. METHOD: Experiment 1 aimed to establish that ToM deficits were present, and 2 following experiments manipulated the working memory (WM) demands of the ToM task. RESULTS: In Experiment 1, 15 patients with PD performed significantly more poorly than controls on a false belief vignette task but not on a faux pas task. Errors were related to poor verbal fluency. In Experiment 2, 24 patients with PD made fewer errors on shorter false belief vignettes than the original FBT, and errors on the latter were related to WM impairment. In Experiment 3, the FBT was presented as a comic strip visible throughout questioning, reducing WM demands. Patients (n = 24) made memory errors but no false belief errors on the comic strip. They exhibited no verbal fluency or WM impairments, but did exhibit deficits on a black-and-white Stroop task. False belief errors were not correlated with executive performance. CONCLUSIONS: PD patients made very few ToM errors that were independent of errors on memory questions, so in this sample, ToM deficits per se appear unlikely. However, patients still made errors on ToM tasks when associated incidental WM demands were considerably reduced, highlighting the need for future investigations of ToM in PD to account for the role of more general cognitive restrictions exhibited by even some medicated, early stage patients. PMID- 23356594 TI - Impaired implicit sequence learning in Parkinson's disease patients with freezing of gait. AB - OBJECTIVE: Freezing of gait (FOG) in Parkinson's disease (PD) may involve specific impairments in acquiring automaticity under working memory load. This study examined whether implicit sequence learning, with or without a secondary task, is impaired in patients with FOG. METHOD: Fourteen freezers (FRs), 14 nonfreezers (nFRs), and 14 matched healthy controls (HCs) performed a serial reaction time (SRT) task with a deterministic stimulus sequence under single-task (ST) and dual-task (DT) conditions. The increase in reaction times (RTs) for random compared with sequenced blocks was used as a measure of implicit sequence learning. Neuropsychological tests assessing global cognitive functioning and executive dysfunction were administered in order to investigate their relation to sequence learning. RESULTS: nFRs and HCs showed significant implicit sequence learning effects (p < 0.001). FRs demonstrated a tendency to learn sequence specific information in the SRT-ST task (p = 0.07) but not in the SRT-DT task (p = 0.69). Severity of FOG, however, correlated positively with SRT-DT task performance (r = -0.56; p < 0.05). CONCLUSIONS: The present results suggest that PD patients suffering from FOG pathology exhibit a specific impairment in the acquisition of automaticity. When working memory capacity is supplementarily loaded by adding a DT, sequence learning in FRs becomes increasingly impaired. These findings indicate that therapies should focus on extensive training in acquiring novel motor activities and reducing working memory load to improve learning in FOG. PMID- 23356597 TI - High-level, but not low-level, motion perception is impaired in patients with schizophrenia. AB - OBJECTIVE: Smooth pursuit eye movements are compromised in patients with schizophrenia and their first-degree relatives. Although research has demonstrated that the motor components of smooth pursuit eye movements are intact, motion perception has been shown to be impaired. In particular, studies have consistently revealed deficits in performance on tasks specific to the high order motion area V5 (middle temporal area, MT) in patients with schizophrenia. In contrast, data from low-level motion detectors in the primary visual cortex (V1) have been inconsistent. METHOD: To differentiate between low-level and high level visual motion processing, we applied a temporal-order judgment task for motion events and a motion-defined figure-ground segregation task using patients with schizophrenia and healthy controls. Successful judgments in both tasks rely on the same low-level motion detectors in the V1; however, the first task is further processed in the higher-order motion area MT in the magnocellular (dorsal) pathway, whereas the second task requires subsequent computations in the parvocellular (ventral) pathway in visual area V4 and the inferotemporal cortex (IT). These latter structures are supposed to be intact in schizophrenia. RESULTS: Patients with schizophrenia revealed a significantly impaired temporal resolution on the motion-based temporal-order judgment task but only mild impairment in the motion-based segregation task. CONCLUSIONS: These results imply that low-level motion detection in V1 is not, or is only slightly, compromised; furthermore, our data restrain the locus of the well-known deficit in motion detection to areas beyond the primary visual cortex. PMID- 23356598 TI - Semantic processing in connected speech at a uniformly early stage of autopsy confirmed Alzheimer's disease. AB - OBJECTIVE: The aim of the present study was to quantify the semantic content of connected speech produced by patients at a uniformly early stage of pathologically proven Alzheimer's disease (AD). A secondary aim was to establish whether semantic units were reduced globally, or whether there was a disproportionate reduction of specific classes of information. METHOD: Discourse samples were obtained from 18 AD patients and 18 matched controls, all pathologically confirmed. Semantic unit identification was scored overall and for four subclasses: subjects, locations, objects, and actions. Idea density and efficiency were calculated. RESULTS: AD transcripts showed significantly reduced units overall, particularly actions and subjects, as well as reduced efficiency. Total semantic units and a combination of subject-, location-, and object-related units ("noun" units) correlated with the Expression subscore on the Cambridge Cognitive Examination (CAMCOG). Subject related units correlated with the CAMCOG Abstract Thinking scale. Logistic regression analyses confirmed that all measures that were lower in AD than controls were predictive of group membership. An exploratory comparison between units expressed mainly using nouns and those mainly using verbs showed that the latter was the stronger of these two predictors. CONCLUSIONS: The present study adds a lexico-semantic dimension to the linguistic profile based on discourse analysis in typical AD, recently described by the same authors. 2012, 83(11): 1056-1062). The suggestion of differential importance of verb and noun use in the present study may be related to the reduction in syntactic complexity that was reported, using the same set of discourse samples, in the earlier study. PMID- 23356596 TI - Visual search and the aging brain: discerning the effects of age-related brain volume shrinkage on alertness, feature binding, and attentional control. AB - OBJECTIVE: Decline in visuospatial abilities with advancing age has been attributed to a demise of bottom-up and top-down functions involving sensory processing, selective attention, and executive control. These functions may be differentially affected by age-related volume shrinkage of subcortical and cortical nodes subserving the dorsal and ventral processing streams and the corpus callosum mediating interhemispheric information exchange. METHOD: Fifty five healthy adults (25-84 years) underwent structural MRI and performed a visual search task to test perceptual and attentional demands by combining feature conjunction searches with "gestalt" grouping and attentional cueing paradigms. RESULTS: Poorer conjunction, but not feature, search performance was related to older age and volume shrinkage of nodes in the dorsolateral processing stream. When displays allowed perceptual grouping through distractor homogeneity, poorer conjunction-search performance correlated with smaller ventrolateral prefrontal cortical and callosal volumes. An alerting cue attenuated age effects on conjunction search, and the alertness benefit was associated with thalamic, callosal, and temporal cortex volumes. CONCLUSION: Our results indicate that older adults can capitalize on early parallel stages of visual information processing, whereas age-related limitations arise at later serial processing stages requiring self-guided selective attention and executive control. These limitations are explained in part by age-related brain volume shrinkage and can be mitigated by external cues. PMID- 23356600 TI - Rhythmic auditory stimulation influences syntactic processing in children with developmental language disorders. AB - OBJECTIVE: Children with developmental language disorders have been shown to be impaired not only in language processing (including syntax), but also in rhythm and meter perception. Our study tested the influence of external rhythmic auditory stimulation (i.e., musical rhythm) on syntax processing in children with specific language impairment (SLI; Experiment 1A) and dyslexia (Experiment 1B). METHOD: Children listened to either regular or irregular musical prime sequences followed by blocks of grammatically correct and incorrect sentences. They were required to perform grammaticality judgments for each auditorily presented sentence. RESULTS: Performance of all children (SLI, dyslexia, and controls) in the grammaticality judgments was better after regular prime sequences than after irregular prime sequences, as shown by d' data. The benefit of the regular prime was stronger for SLI children (partial eta2 = .34) than for dyslexic children (partial eta2 = .14), who reached higher performance levels. CONCLUSION: Together with previous findings on deficits in temporal processing and sequencing, as well as with the recent proposition of a temporal sampling (oscillatory) framework for developmental language disorders (U. A. Goswami, 2011, Temporal sampling framework for developmental dyslexia, Trends in Cognitive Sciences, Vol. 15, pp. 3-10), our results point to potential avenues in using rhythmic structures (even in nonverbal materials) to boost linguistic structure processing. PMID- 23356601 TI - Effortful and automatic cognitive inhibition in adults with Tourette's syndrome. AB - OBJECTIVE: Inhibition has been widely investigated in Tourette's syndrome (TS), but some inhibitory processes have received more attention than others. This study examined the relatively underresearched construct of cognitive inhibition in adults with TS and no comorbidities (TS-alone), using tasks thought to tap automatic (without conscious intent) and effortful (with deliberate intent) inhibitory processes. METHOD: Adult participants with TS-alone (n = 20) and healthy controls (n = 21) were compared on a retrieval-induced forgetting task thought to tap automatic cognitive inhibition and a directed forgetting task thought to tap effortful cognitive inhibition. Both tasks involved effortful memory as well as the key inhibitory effects. RESULTS: Both the TS-alone and control groups showed typical inhibitory effects on both tasks, but the TS-alone group showed generally poorer effortful memory on both tasks. CONCLUSIONS: The findings appear to indicate intact cognitive inhibition in adults with TS-alone, with some evidence of impairment in effortful processing. This highlights the importance of using tasks related to different inhibitory processes to explore cognitive performance in TS-alone, and suggests that any inhibitory impairment associated with TS-alone is mild and relatively circumscribed. PMID- 23356599 TI - The apolipoprotein E genotype predicts longitudinal transitions to mild cognitive impairment but not to Alzheimer's dementia: findings from a nationally representative study. AB - OBJECTIVE: The epsilon4 allele of the apolipoprotein E (APOE) genotype is the most widely accepted genetic risk factor for Alzheimer's dementia (AD), but findings on whether it is a risk factor for the AD prodrome, mild cognitive impairment (MCI), have been inconsistent. In a prospective longitudinal design, we investigated (a) whether transitions to MCI and other forms of neurocognitive impairment without dementia (CIND) are more frequent among normal epsilon4 carriers than among noncarriers and (b) whether subsequent transitions to AD from MCI and from other forms of CIND are more frequent among epsilon4 carriers than among noncarriers. METHOD: The frequency of the epsilon4 allele was studied in older adults (mean age > 70), who had participated in two or more waves of neuropsychological testing and diagnosis in the Aging, Demographics, and Memory Study (ADAMS) of the United States Department of Health and Human Services, National Institutes of Health, National Institute on Aging's Health and Retirement Study, conducted by the University of Michigan. The association between epsilon4 and longitudinal transitions to specific types of CIND and dementia can be determined with this data set. RESULTS: Epsilon 4 increased the rate of progression from normal functioning to MCI (58% of new diagnoses were carriers) but not to other forms of CIND. The rate of progression to AD from MCI or from other forms of CIND was not increased by epsilon4. CONCLUSIONS: The results support the hypothesis that epsilon4 is a risk factor for transitions from normal functioning to MCI but not for subsequent transitions to AD. In the ADAMS sample, the reason epsilon4 is elevated in AD individuals is because it is already elevated in MCI individuals, who are the primary source of new AD diagnoses. PMID- 23356602 TI - Endoscopic ultrasound-guided choledochoduodenostomy and duodenal stenting in patients with unresectable periampullary cancer: one-step procedure by using linear echoendoscope. AB - OBJECTIVE: Describe a case series of endoscopic ultrasound (EUS)-guided choledochoduodenostomy (EUS-CD) associated with duodenal self-expandable metal stents (SEMS) placement using solely the linear echoendoscope in seven patients with obstructive jaundice and duodenal obstruction due to unresectable periampullary cancer. MATERIAL AND METHODS: EUS-CD in the first portion of the duodenum, associated with duodenal SEMS placement was performed in seven patients with unresectable periampullary cancer with obstructive jaundice and invasive duodenal obstruction. Laboratory tests and clinical follow-up were performed until patient's death. The procedure was performed by an experienced endoscopist under conscious sedation. The puncture position was chosen based on EUS evaluation, at the common bile duct (CBD) above the tumor, through the distal part of the duodenal bulb. After that, the needle was withdrawn and a wire-guided needle knife was used to enlarge the site puncture in the duodenal wall. Then, a partially covered SEMS was passed over the guide, through the choledochoduodenal fistula. Duodenal SEMS placement was performed during the same endoscopic procedure. RESULTS: The procedure was performed in seven patients, ranging between 34 and 86 years. Technical success of EUS-CD, by the stent placement, occurred in 100% of the cases. There were no early complications. Duodenal SEMS placement was effective in 100% of the cases that remained alive after a follow up of 7 and 30 days. CONCLUSION: The results suggest therapeutic EUS one-step procedure drainage as an alternative for these patients, with good clinical success, feasible technique and safety. PMID- 23356603 TI - From hybrids to hermaphrodites in population genetics. AB - A report on the 46th annual PopGroup conference, Glasgow, UK, December 18-21, 2012. PMID- 23356605 TI - Lost in the map. AB - Organismal development and evolution are complex, multifaceted processes that depend intimately on context. They are subject to environmental influences, chance appearance and fixation of mutations, and numerous other idiosyncrasies. Genomics is detailing the molecular signature of effects of these mechanisms on phenotypes, but because numerous distinct evolutionary explanations can produce a given genomic pattern, the molecular details, rather than elucidating process, typically distract from explanatory insight and contribute little to predictive capability. While genomic research has burgeoned, direct study of evolutionary and developmental processes has lagged. We advocate for reinvigoration of direct study of process, along with refocusing of attention on questions of broad biological import, as more productive of urgently needed insights, which genomic approaches are not providing. PMID- 23356604 TI - Chromosomal evolution of Escherichia coli for the efficient production of lycopene. AB - BACKGROUND: Plasmid-based overexpression of genes has been the principal strategy for metabolic engineering. However, for biotechnological applications, plasmid based expression systems are not suitable because of genetic instability, and the requirement for constant selective pressure to ensure plasmid maintenance. RESULTS: To overcome these drawbacks, we constructed an Escherichia coli lycopene production strain that does not carry a plasmid or an antibiotic marker. This was achieved using triclosan-induced chromosomal evolution, a high gene copy expression system. The engineered strain demonstrated high genetic stability in the absence of the selective agent during fermentation. The replacement of native appY promoter with a T5 promoter, and the deletion of the iclR gene in E. coli CBW 12241 further improved lycopene production. The resulting strain, E. coli CBW 12241(DeltaiclR, PT5-appY), produced lycopene at 33.43 mg per gram of dry cell weight. CONCLUSIONS: A lycopene hyper-producer E. coli strain that does not carry a plasmid or antibiotic marker was constructed using triclosan-induced chromosomal evolution. The methods detailed in this study can be used to engineer E. coli to produce other metabolites. PMID- 23356606 TI - Evolution of the storage effect. AB - The storage effect, a mechanism that promotes species coexistence in temporally variable environments, poses a dilemma to evolutionary ecologists. Ecological studies have demonstrated its importance in natural communities, but evolutionary models have predicted that selection either impedes coexistence or diminishes the storage effect if there is coexistence. Here, we develop a lottery model of competition in which two species experience a trade-off in competitive ability between two types of years. We use an adaptive evolution framework to determine conditions favoring the evolution of the storage effect. Storage evolves via divergence of relative performance in the two environments under a wide range of biologically realistic conditions. It evolves between two initially identical species (or lineages) when the trade-off in performance is strong enough. It evolves for species having different initial trade-offs for both weak and strong trade-offs. Our simple 2-species-2-environment scenario can be extended to multiple species and environmental conditions. Results indicate that the storage effect should evolve in a broad range of situations that involve a trade-off in competitive ability among years, and are consistent with empirical observations. The findings show that storage can evolve in a manner and under conditions similar to other types of resource partitioning. PMID- 23356607 TI - Interspecific competition alters nonlinear selection on offspring size in the field. AB - Offspring size is one of the most important life-history traits with consequences for both the ecology and evolution of most organisms. Surprisingly, formal estimates of selection on offspring size are rare, and the degree to which selection (particularly nonlinear selection) varies among environments remains poorly explored. We estimate linear and nonlinear selection on offspring size, module size, and senescence rate for a sessile marine invertebrate in the field under three different intensities of interspecific competition. The intensity of competition strongly modified the strength and form of selection acting on offspring size. We found evidence for differences in nonlinear selection across the three environments. Our results suggest that the fitness returns of a given offspring size depend simultaneously on their environmental context, and on the context of other offspring traits. Offspring size effects can be more pervasive with regards to their influence on the fitness returns of other traits than previously recognized, and we suggest that the evolution of offspring size cannot be understood in isolation from other traits. Overall, variability in the form and strength of selection on offspring size in nature may reduce the efficacy of selection on offspring size and maintain variation in this trait. PMID- 23356608 TI - Coevolution and the architecture of mutualistic networks. AB - Although coevolution is widely recognized as an important evolutionary process for pairs of reciprocally specialized species, its importance within species-rich communities of generalized species has been questioned. Here we develop and analyze mathematical models of mutualistic communities, such as those between plants and pollinators or plants and seed-dispersers to evaluate the importance of coevolutionary selection within complex communities. Our analyses reveal that coevolutionary selection can drive significant changes in trait distributions with important consequences for the network structure of mutualistic communities. One such consequence is greater connectance caused by an almost invariable increase in the rate of mutualistic interaction within the community. Another important consequence is altered patterns of nestedness. Specifically, interactions mediated by a mechanism of phenotype matching tend to be antinested when coevolutionary selection is weak and even more strongly antinested as increasing coevolutionary selection favors the emergence of reciprocal specialization. In contrast, interactions mediated by a mechanism of phenotype differences tend to be nested when coevolutionary selection is weak, but less nested as increasing coevolutionary selection favors greater levels of generalization in both plants and animals. Taken together, our results show that coevolutionary selection can be an important force within mutualistic communities, driving changes in trait distributions, interaction rates, and even network structure. PMID- 23356609 TI - Simulation-based likelihood approach for evolutionary models of phenotypic traits on phylogeny. AB - Phylogenetic comparative methods (PCMs) have been used to test evolutionary hypotheses at phenotypic levels. The evolutionary modes commonly included in PCMs are Brownian motion (genetic drift) and the Ornstein-Uhlenbeck process (stabilizing selection), whose likelihood functions are mathematically tractable. More complicated models of evolutionary modes, such as branch-specific directional selection, have not been used because calculations of likelihood and parameter estimates in the maximum-likelihood framework are not straightforward. To solve this problem, we introduced a population genetics framework into a PCM, and here, we present a flexible and comprehensive framework for estimating evolutionary parameters through simulation-based likelihood computations. The method does not require analytic likelihood computations, and evolutionary models can be used as long as simulation is possible. Our approach has many advantages: it incorporates different evolutionary modes for phenotypes into phylogeny, it takes intraspecific variation into account, it evaluates full likelihood instead of using summary statistics, and it can be used to estimate ancestral traits. We present a successful application of the method to the evolution of brain size in primates. Our method can be easily implemented in more computationally effective frameworks such as approximate Bayesian computation (ABC), which will enhance the use of computationally intensive methods in the study of phenotypic evolution. PMID- 23356610 TI - A parametric method for assessing diversification-rate variation in phylogenetic trees. AB - Phylogenetic hypotheses are frequently used to examine variation in rates of diversification across the history of a group. Patterns of diversification-rate variation can be used to infer underlying ecological and evolutionary processes responsible for patterns of cladogenesis. Most existing methods examine rate variation through time. Methods for examining differences in diversification among groups are more limited. Here, we present a new method, parametric rate comparison (PRC), that explicitly compares diversification rates among lineages in a tree using a variety of standard statistical distributions. PRC can identify subclades of the tree where diversification rates are at variance with the remainder of the tree. A randomization test can be used to evaluate how often such variance would appear by chance alone. The method also allows for comparison of diversification rate among a priori defined groups. Further, the application of the PRC method is not restricted to monophyletic groups. We examined the performance of PRC using simulated data, which showed that PRC has acceptable false-positive rates and statistical power to detect rate variation. We apply the PRC method to the well-studied radiation of North American Plethodon salamanders, and support the inference that the large-bodied Plethodon glutinosus clade has a higher historical rate of diversification compared to other Plethodon salamanders. PMID- 23356611 TI - Disentangling evolutionary cause-effect relationships with phylogenetic confirmatory path analysis. AB - Confirmatory path analysis is a statistical technique to build models of causal hypotheses among variables and test if the data conform with the causal model. However, classical path analysis techniques ignore the nonindependence of observations due to phylogenetic relatedness among species, possibly leading to spurious results. Here, we present a simple method to perform phylogenetic confirmatory path analysis (PPA). We analyzed simulated datasets with varying amounts of phylogenetic signal in the data and a known underlying causal structure linking the traits to estimate Type I error and power. Results show that Type I error for PPA appeared to be slightly anticonservative (range: 0.047 0.072) but path analysis models ignoring phylogenetic signal resulted in much higher Type I error rates, which were positively related to the amount of phylogenetic signal (range: 0.051 for lambda= 0 to 0.916 for lambda= 1). Further, the power of the test was not compromised when accounting for phylogeny. As an example of the application of PPA, we revisit a study on the correlates of aggressive broodmate competition across seven avian families. The use of PPA allowed us to gain greater insight into the plausible causal paths linking species traits to aggressive broodmate competition. PMID- 23356612 TI - Phylogenetic inference of nuptial trait evolution in the context of asymmetrical introgression in North American darters (teleostei). AB - Introgressive hybridization and incomplete lineage sorting complicate the inference of phylogeny, and available species-tree methods do not simultaneously account for these processes. Both hybridization and ancestral polymorphism have been invoked to explain divergent phylogenies inferred from different datasets for Stigmacerca, a clade of 11 North American darter species. Species of Stigmacerca are characterized by a mating system involving parental care with males guarding nesting territories and fertilized eggs. Males of four species of Stigmacerca develop egg-mimic nuptial structures on their second dorsal fins during the breeding season. Previous phylogenies suggest contrasting scenarios for the evolution of this nuptial trait. Using a combination of coalescent-based methods, we analyzed a dataset comprising a mitochondrial gene and 15 nuclear loci to estimate relationships and simultaneously test for introgressive hybridization. Our analyses identified several instances of interspecific gene flow involving both cytoplamsmic haplotypes and nuclear alleles. The new phylogeny was used to infer a single origin and recent loss of egg-mimic structures in Stigmacerca and led to the discovery of a phylogenetically distinct species. Our results highlight the limited strategies available to account for introgressive hybridization in the inference of species relationships and the likely effects of this process on reconstructing trait evolution. PMID- 23356613 TI - Diversity-dependent cladogenesis and trait evolution in the adaptive radiation of the auks (aves: alcidae). AB - Through the course of an adaptive radiation, the evolutionary speed of cladogenesis and ecologically relevant trait evolution are expected to slow as species diversity increases, niches become occupied, and ecological opportunity declines. We develop new likelihood-based models to test diversity-dependent evolution in the auks, one of only a few families of seabirds adapted to underwater "flight," and which exhibit a large variety of bill sizes and shapes. Consistent with the expectations of adaptive radiation, we find both a decline in rates of cladogenesis (a sixfold decline) and bill shape (a 64-fold decline) evolution as diversity increased. Bill shape diverged into two clades at the basal cladogenesis event with one clade possessing mostly long, narrow bills used to forage primarily on fish, and the other with short thick bills used to forage primarily on plankton. Following this initial divergence in bill shape, size, a known correlate of both prey size and maximum diving depth, diverged rapidly within each of these clades. These results suggest that adaptive radiation in foraging traits underwent initial divergence in bill shape to occupy different food resources, followed by size differentiation to subdivide each niche along the depth axis of the water column. PMID- 23356614 TI - Elevated rates of morphological and functional diversification in reef-dwelling haemulid fishes. AB - The relationship between habitat complexity and species richness is well established but comparatively little is known about the evolution of morphological diversity in complex habitats. Reefs are structurally complex, highly productive shallow-water marine ecosystems found in tropical (coral reefs) and temperate zones (rocky reefs) that harbor exceptional levels of biodiversity. We investigated whether reef habitats promote the evolution of morphological diversity in the feeding and locomotion systems of grunts (Haemulidae), a group of predominantly nocturnal fishes that live on both temperate and tropical reefs. Using phylogenetic comparative methods and statistical analyses that take into account uncertainty in phylogeny and the evolutionary history of reef living, we demonstrate that rates of morphological evolution are faster in reef-dwelling haemulids. The magnitude of this effect depends on the type of trait; on average, traits involved in the functional systems for prey capture and processing evolve twice as fast on reefs as locomotor traits. This result, along with the observation that haemulids do not exploit unique feeding niches on reefs, suggests that fine-scale trophic niche partitioning and character displacement may be driving higher rates of morphological evolution. Whatever the cause, there is growing evidence that reef habitats stimulate morphological and functional diversification in teleost fishes. PMID- 23356615 TI - Adaptation from restricted geometries: the shell inclination of terrestrial gastropods. AB - The adaptations that occur for support and protection can be studied with regard to the optimal structure that balances these objectives with any imposed constraints. The shell inclination of terrestrial gastropods is an appropriate model to address this problem. In this study, we examined how gastropods improve shell angles to well-balanced ones from geometrically constrained shapes. Our geometric analysis and physical analysis showed that constantly coiled shells are constrained from adopting a well-balanced angle; the shell angle of such basic shells tends to increase as the spire index (shell height/width) increases, although the optimum angle for stability is 90 degrees for flat shells and 0 degrees for tall shells. Furthermore, we estimated the influences of the geometric rule and the functional demands on actual shells by measuring the shell angles of both resting and active snails. We found that terrestrial gastropods have shell angles that are suited for balance. The growth lines of the shells indicated that this adaptation depends on the deflection of the last whorl: the apertures of flat shells are deflected downward, whereas those of tall shells are deflected upward. Our observations of active snails demonstrated that the animals hold their shells at better balanced angles than inactive snails. PMID- 23356617 TI - Evolution of static allometries: adaptive change in allometric slopes of eye span in stalk-eyed flies. AB - Julian Huxley showed that within-species (static) allometric (power-law) relations can arise from proportional growth regulation with the exponent in the power law equaling the factor of proportionality. Allometric exponents may therefore be hard to change and act as constraints on the independent evolution of traits. In apparent contradiction to this, many empirical studies have concluded that static allometries are evolvable. Many of these studies have been based, however, on a broad definition of allometry that includes any monotonic shape change with size, and do not falsify the hypothesis of constrained narrow sense allometry. Here, we present the first phylogenetic comparative study of narrow-sense allometric exponents based on a reanalysis of data on eye span and body size in stalk-eyed flies (Diopsidae). Consistent with a role in sexual selection, we found strong evidence that male slopes were tracking "optima" based on sexual dimorphism and relative male trait size. This tracking was slow, however, with estimated times of 2-3 million years for adaptation to exceed ancestral influence on the trait. Our results are therefore consistent with adaptive evolution on million-year time scales, but cannot rule out that static allometry may act as a constraint on eye-span adaptation at shorter time scales. PMID- 23356616 TI - Altitudinal clinal variation in wing size and shape in African Drosophila melanogaster: one cline or many? AB - Geographical patterns of morphological variation have been useful in addressing hypotheses about environmental adaptation. In particular, latitudinal clines in phenotypes have been studied in a number of Drosophila species. Some environmental conditions along latitudinal clines-for example, temperature-also vary along altitudinal clines, but these have been studied infrequently and it remains unclear whether these environmental factors are similar enough for convergence or parallel evolution. Most clinal studies in Drosophila have dealt exclusively with univariate phenotypes, allowing for the detection of clinal relationships, but not for estimating the directions of covariation between them. We measured variation in wing shape and size in D. melanogaster derived from populations at varying altitudes and latitudes across sub-Saharan Africa. Geometric morphometrics allows us to compare shape changes associated with latitude and altitude, and manipulating rearing temperature allows us to quantify the extent to which thermal plasticity recapitulates clinal effects. Comparing effect vectors demonstrates that altitude, latitude, and temperature are only partly associated, and that the altitudinal shape effect may differ between Eastern and Western Africa. Our results suggest that selection responsible for these phenotypic clines may be more complex than just thermal adaptation. PMID- 23356618 TI - Experimental evolution of heterotrophy in a green alga. AB - Laboratory populations of a green alga cultured in the dark with an organic substrate evolved into efficient heterotrophs with faster growth, higher fitness, and increased responsiveness to substrate concentration. Their phenotypes were almost entirely attributable to selection, rather than to history or ancestry. The fitness of evolved lines in the light was uniformly depressed, presumably through the accumulation of conditionally deleterious genes governing photosynthesis. Some evolved lines were no longer able to grow in the light and are thereby permanently isolated from their ancestors. Specialized autotrophs and heterotrophs may often evolve in algae through long-term shifts in the conditions of growth. PMID- 23356619 TI - An experimental test of the transmission-virulence trade-off hypothesis in a plant virus. AB - The transmission-virulence trade-off hypothesis is one of the few adaptive explanations of virulence evolution, and assumes that there is an overall positive correlation between parasite transmission and virulence. The shape of the transmission-virulence relationship predicts whether virulence should evolve toward either a maximum or to an intermediate optimum. A positive correlation between each of these traits and within-host growth is often suggested to underlie the relationship between virulence and transmission. There are few experimental tests of this hypothesis; this study reports on the first empirical test on a plant pathogen. We infected Brassica rapa plants with nine natural isolates of Cauliflower mosaic virus and then estimated three traits: transmission, virulence, and within-host viral accumulation. As predicted by the trade-off hypothesis, we observed a positive correlation between transmission and virulence, suggestive of the existence of an intermediate optimum. We discovered the unexpected existence of two groups of within-host accumulation, differing by at least an order of magnitude. When accumulation groups were not accounted for, within-host accumulation was correlated neither to virulence nor transmission, although our results suggest that within each group these correlations exist. PMID- 23356620 TI - Evidence for selection on a chordate histocompatibility locus. AB - Allorecognition is the ability of an organism to differentiate self or close relatives from unrelated individuals. The best known applications of allorecognition are the prevention of inbreeding in hermaphroditic species (e.g., the self-incompatibility [SI] systems in plants), the vertebrate immune response to foreign antigens mediated by MHC loci, and somatic fusion, where two genetically independent individuals physically join to become a chimera. In the few model systems where the loci governing allorecognition outcomes have been identified, the corresponding proteins have exhibited exceptional polymorphism. But information about the evolution of this polymorphism outside MHC is limited. We address this subject in the ascidian Botryllus schlosseri, where allorecognition outcomes are determined by a single locus, called FuHC (Fusion/HistoCompatibility). Molecular variation in FuHC is distributed almost entirely within populations, with very little evidence for differentiation among different populations. Mutation plays a larger role than recombination in the creation of FuHC polymorphism. A selection statistic, neutrality tests, and distribution of variation within and among different populations all provide evidence for selection acting on FuHC, but are not in agreement as to whether the selection is balancing or directional. PMID- 23356621 TI - Transitions from reproductive systems governed by two self-incompatible loci to one in fungi. AB - Self-incompatibility (SI), a reproductive system broadly present in plants, chordates, fungi, and protists, might be controlled by one or several multiallelic loci. How a transition in the number of SI loci can occur and the consequences of such events for the population's genetics and dynamics have not been studied theoretically. Here, we provide analytical descriptions of two transition mechanisms: linkage of the two SI loci (scenario 1) and the loss of function of one incompatibility gene within a mating type of a population with two SI loci (scenario 2). We show that invasion of populations by the new mating type form depends on whether the fitness of the new type is lowered, and on the allelic diversity of the SI loci and the recombination between the two SI loci in the starting population. Moreover, under scenario 1, it also depends on the frequency of the SI alleles that became linked. We demonstrate that, following invasion, complete transitions in the reproductive system occurs under scenario 2 and is predicted only for small populations under scenario 1. Interestingly, such events are associated with a drastic reduction in mating type number. PMID- 23356622 TI - Genetic compatibility affects division of labor in the Argentine ant Linepithema humile. AB - Division of labor is central to the organization of insect societies. Within colony comparisons between subfamilies of workers (patrilines or matrilines) revealed genetic effects on division of labor in many social insect species. Although this has been taken as evidence for additive genetic effects on division of labor, it has never been experimentally tested. To determine the relative roles of additive and nonadditive genetic effects (e.g., genetic compatibility, epistasis, and parent-of-origin imprinting effects) on worker behavior, we performed controlled crosses using the Argentine ant Linepithema humile. Three of the measured behaviors (the efficiency to collect pupae, the foraging propensity, and the distance between non-brood-tenders and brood) were affected by the maternal genetic background and the two others (the efficiency to feed larvae and the distance between brood-tenders and brood) by the paternal genetic background. Moreover, there were significant interactions between the maternal and paternal genetic backgrounds for three of the five behaviors. These results are most consistent with parent-of-origin and genetic compatibility effects on division of labor. The finding of nonadditive genetic effects is in strong contrast with the current view and has important consequences for our understanding of division of labor in insect societies. PMID- 23356623 TI - How to measure maturation: a comparison of probabilistic methods used to test for genotypic variation and plasticity in the decision to mature. AB - Maturation is a developmental trait that plays a key role in shaping organisms' life-history. However, progress in understanding how maturation phenotypes evolve has been held back by confusion over how best to model maturation decisions and a lack of studies comparing genotypic variation in maturation. Here, we fitted probabilistic maturation reaction norms (PMRNs) to data collected from five clones of Daphnia magna and five of Daphnia pulex collected from within and between different populations. We directly compared the utility of modeling approaches that assume maturation to be a process with an instantaneous rate with those that do not by fitting maturation rate and logistic regression models, and emphasize similarities and differences between them. Our results demonstrate that in Daphnia, PMRNs using a logistic regression approach were simpler to use and provided a better fit to the data. The decision to mature was plastic across a range of growth trajectories and dependent upon both body size and age. However, the age effect was stronger in D. magna than D. pulex and varied considerably between clones. Our results support the idea that maturation thresholds can evolve but also suggest that the notion of a threshold based on a single fixed state is an oversimplification that underestimates the adaptability of these important traits. PMID- 23356624 TI - Evolutionarily stable size of a megagametophyte: evolution of tiny megagametophytes of angiosperms from large ones of gymnosperms. AB - To examine the factors favoring large megagametophytes of gymnosperms and tiny ones of angiosperms, a game model for seed production was developed in which megagametophytes growing in the same female parent compete for resources provided by the parent. In the model, megagametophytes may continue to grow until seed completion or may cease to grow at a certain time and regrow at pollination or fertilization. Autonomous abortion of unpollinated or unfertilized megagametophytes may occur either at pollination or fertilization. Those megagametophytes absorb a certain amount of resources before abortion, due to constraints in the signal process, in addition to the resources absorbed before pollination or fertilization. It was found that both growth habits can be the ESS: megagametophytes continue to grow without cessation and monopolize resources, such as gymnosperms, or cease to grow until fertilization to reduce the loss of resources due to autonomous abortion, such as angiosperms. The former and the latter are the ESS if the time interval between pollination and fertilization is long and short, respectively. Thus, the fertilization interval may be a critical factor selecting for large megagametophytes of gymnosperms or tiny ones of angiosperms. PMID- 23356625 TI - Adaptive divergence in Darwin's race: how coevolution can generate trait diversity in a pollination system. AB - Understanding how reciprocal selection shapes interacting species in Darwin's coevolutionary race is a captivating pursuit in evolutionary ecology. Coevolving traits can potentially display following three patterns: (1) geographical variation in matched traits, (2) bias in trait matching, and (3) bimodal distribution of a trait in certain populations. Based on the framework of adaptive dynamics, we present an evolutionary model for a coevolving pollination system involving the long-proboscid fly (Moegistorhynchus longirostris) and the long-tubed iris (Lapeirousia anceps). The model successfully demonstrates that Darwin's hypothesis can lead to all three patterns if costs are involved. Geographical variation in matched traits could be driven by geographical variation in environmental factors that affect the cost rate of trait escalation. Unequal benefits derived from the interaction by the fly and the flower could potentially cause the bias in trait matching of the system. Different cost rates to trait elongation incurred by the two species and weak assortative interactions in the coevolutionary race can drive divergent selection (i.e., an evolutionary branching) that leads to the bimodal distribution of traits. Overall, the model highlights the importance of assortative interactions and the balance of costs incurred by coevolving species as factors determining the eventual phenotypic outcome of coevolutionary interactions. PMID- 23356627 TI - Recurrent evolution of dioecy in bryophytes. AB - The origin and maintenance of separate sexes (dioecy) is an enduring evolutionary puzzle. Although both hermaphroditism and dioecy occur in many diverse clades, we know little about the long-term evolutionary consequences of changing sexual system. Here we find evidence for at least 133 transitions between sexual systems in mosses, representing an almost unparalleled lability in the evolution of their sexual systems. Furthermore, in contrast to predictions, the transition rate from hermaphroditism to dioecy was approximately twice as high as the reverse transition. Our results also suggest that hermaphrodites may have higher rates of diversification than dioecious mosses. These results illustrate the utility of mosses for understanding the genomic and macroevolutionary consequences of hermaphroditism and dioecy. PMID- 23356626 TI - Testing models of sex ratio evolution in a gynodioecious plant: female frequency covaries with the cost of male fertility restoration. AB - In many gynodioecious species, cytoplasmic male sterility genes (CMS) and nuclear male fertility restorers (Rf) jointly determine whether a plant is female or hermaphrodite. Equilibrium models of cytonuclear gynodioecy, which describe the effect of natural selection within populations on the sex ratio, predict that the frequency of females in a population will primarily depend on the cost of male fertility restoration, a negative pleiotropic effect of Rf alleles on hermaphrodite fitness. Specifically, when the cost of restoration is higher, the frequency of females at equilibrium is predicted to be higher. To test this prediction, we estimated variation in the cost of restoration across 26 populations of Lobelia siphilitica, a species in which Rf alleles can have negative pleiotropic effects on pollen viability. We found that L. siphilitica populations with many females were more likely to contain hermaphrodites with low pollen viability. This is consistent with the prediction that the cost of restoration is a key determinant of variation in female frequency. Our results suggest that equilibrium models can explain variation in sex ratio among natural populations of gynodioecious species. PMID- 23356628 TI - Correlation between Anolis lizard dewlap phenotype and environmental variation indicates adaptive divergence of a signal important to sexual selection and species recognition. AB - Although the importance of signals involved in species recognition and sexual selection to speciation is widely recognized, the processes that underlie signal divergence are still a matter of debate. Several possible processes have been hypothesized, including genetic drift, arbitrary sexual selection, and adaptation to local signaling environments. We use comparative analyses to investigate whether the remarkable geographic variation of dewlap phenotype in a Hispaniolan trunk Anolis lizard (A. distichus) is a result of adaptive signal divergence to heterogeneous environments. We recover a repeated pattern of divergence in A. distichus dewlap color, pattern, and size with environmental variation across Hispaniola. These results are aligned with ecological models of signal divergence and provide strong evidence for dewlap adaptation to local signaling environments. We also find that A. distichus dewlaps vary with the environment in a different manner to other previously studied anoles, thus expanding upon previous predictions on the direction dewlaps will diverge in perceptual color space in response to the environment. PMID- 23356629 TI - Degree of specialization is related to body size in herbivorous insects: a phylogenetic confirmation. AB - Numerous studies have suggested a general relationship between the degree of host specialization and body size in herbivorous animals. In insects, smaller species are usually shown to be more specialized than larger-bodied ones. Various hypotheses have attempted to explain this pattern but rigorous proof of the body size-diet breadth relationship has been lacking, primarily because the scarceness of reliable phylogenetic information has precluded formal comparative analyses. Explicitly using phylogenetic information for a group of herbivores (geometrid moths) and their host plant range, we perform a comparative analysis to study the body size-diet breadth relationship. Considering several alternative measures of body size and diet breadth, our results convincingly demonstrate without previous methodological issues-a first for any taxon-a positive association between these traits, which has implications for evaluating various central aspects of the evolutionary ecology of herbivorous insects. We additionally demonstrate how the methods used in this study can be applied in assessing hypotheses to explain the body size-diet breadth relationship. By analyzing the relationship in tree feeders alone and finding that the positive relationship remains, the result suggests that the body size-diet breadth relationship is not solely driven by the type of host plant that species feed on. PMID- 23356630 TI - The genetic architecture of growth rate in juvenile Takifugu species. AB - Closely related species have often evolved dramatic differences in body size. Takifugu rubripes (fugu) is a large marine pufferfish whose genome has been sequenced, whereas T. niphobles is the smallest species among Takifugu. We show that, unsurprisingly, the juvenile growth rate of T. rubripes is higher than that of T. niphobles in a laboratory setting. We produced F(2) progenies of their F(1) hybrids and found one quantitative trait locus (QTL) significantly associated with variation in juvenile body size. This QTL region (3.5 Mb) contains no known genes directly related to growth phenotype (such as IGFs) except Fgf21, which inhibits growth hormone signaling in mouse. The QTL in Takifugu spp. is distinct from the region previously known to control body size variations in stickleback or tilapia. Our results suggest that in the fish tested herein, genomic regions underlying body size evolution might have different genetic origins. They also suggest that many diverse traits in Takifugu spp. are amenable to genetic mapping. PMID- 23356631 TI - Trade-offs, spatial heterogeneity, and the maintenance of microbial diversity. AB - Specialization and concomitant trade-offs are assumed to underlie the non-neutral coexistence of lineages. Trade-offs across heterogeneous environments can promote diversity by preventing competitive exclusion. However, the importance of trade offs in maintaining diversity in natural microbial assemblages is unclear, as trade-offs are frequently not detected in artificial evolution experiments. Stressful conditions associated with patches of heavy-metal enriched serpentine soils provide excellent opportunities for examining how heterogeneity may foster genetic diversity. Using a spatially replicated design, we demonstrate that rhizobium bacteria symbiotic with legumes inhabiting contrasting serpentine and nonserpentine soils exhibit a trade-off between a genotype's nickel tolerance and its ability to replicate rapidly. Furthermore, we detected adaptive divergence in rhizobial assemblages across soil type heterogeneity at multiple sites, suggesting that this trade-off may promote the coexistence of phenotypically distinct bacterial lineages. Trade-offs and adaptive divergence may be important factors maintaining the tremendous diversity within natural assemblages of bacteria. PMID- 23356632 TI - Five-year multicenter study of magnetic attachments used for natural overdenture abutments. AB - The purpose of this study was to examine a longitudinal clinical performance of magnetic attachments used for natural overdenture abutments. The study included 131 patients who had used removable prostheses (complete overdentures 31%, partial dentures 69%) more than 5 years (40-90 years old) with 211 magnetic attachments on natural abutments (Magfit 400 or 600; Aichi Steel co., Aichi, Japan) treated in 15 clinics using a standardized protocol. Analyses were performed on the degree of patient satisfaction regarding retention, complications of magnets (corrosion, detachment from denture base), abutments (pain during mastication, periodontal pocket formation, inflammation, mobility), and dentures (fracture etc.). Ninety-seven percent of patients were satisfied with the retention and stability of their dentures. No corrosion of magnet was observed, and 19 magnets were detached. Most frequent complication of abutments was periodontal pocket formation (52%), followed by the inflammation (29%), increase in mobility (27%) and pain (4%). Magnetic attachment on natural tooth abutments provided a viable and long-term treatment option. PMID- 23356634 TI - Cytomegalovirus infection in infants admitted to a neonatal intensive care unit. AB - OBJECTIVES: To determine the incidence of congenital cytomegalovirus (CMV) infection and the frequency of postnatal infection in a neonatal intensive care unit (NICU). METHODS: Urine samples of 135 infants who were admitted to the NICU during a 6 month period were evaluated to detect CMV using a nested PCR assay. A breast milk sample was obtained to determine viral excretion. Clinical characteristics of infected and non-infected infants were compared. RESULTS: Congenital CMV infection was confirmed in two (1.48%) infants. Post-natal infection was documented in four of 36 (11.1%) infants that were evaluated. CMV excretion was detected in 43 of 116 mothers. Gestational age of infants born to mothers who excreted CMV was shorter than that of infants of mothers with negative results (33.1 versus 34.2 weeks; p = 0.07). CONCLUSIONS: CMV excretion in breast milk is frequent and is associated to congenital and postnatal infection. Further studies are necessary to assess the impact of CMV infection during pregnancy and neonatal outcomes. PMID- 23356633 TI - Assessment of cardiometabolic risk and prevalence of meeting treatment guidelines among patients with type 2 diabetes stratified according to their use of insulin and/or other diabetic medications: results from INSPIRE ME IAA. AB - AIM: Visceral adipose tissue (VAT) and liver fat (LF) are strongly associated with type 2 diabetes. It is not known, however, how diabetes treatment and/or risk factor management modulates the association between VAT, LF and diabetes. The aim was to determine the level of VAT and LF in patients with type 2 diabetes according to their treatment status and achievement of the American Diabetes Association's (ADA) diabetes management goals. METHODS: We performed a cross sectional analysis of the baseline data of the International Study of the Prediction of Intra-Abdominal Adiposity and its Relationship with Cardiometabolic risk/Intra-Abdominal Adiposity (INSPIRE ME IAA), a 3-year prospective cardiometabolic imaging study conducted in 29 countries. Patients (n = 3991) were divided into four groups: (i) those without type 2 diabetes (noT2D n = 1003 men, n = 1027 women); (ii) those with type 2 diabetes but not treated with diabetes medications (T2Dnomeds n = 248 men, n = 198 women); (iii) those with type 2 diabetes and treated with diabetes medications but not yet using insulin (T2Dmeds ins n = 591 men, n = 484 women) and (iv) those with type 2 diabetes and treated with insulin (T2Dmeds+ins n = 233 men, n = 207 women). Abdominal and liver adiposity were measured by computed tomography. RESULTS: Fewer patients with high VAT or LF achieved the ADA's goals for high-density lipoprotein cholesterol (HDL C) or triglycerides compared to patients with low VAT or LF. Visceral adiposity (p = 0.02 men, p = 0.003 women) and LF (p = 0.0002 men, p = 0.0004 women) increased among patients who met fewer of the ADA treatment criteria, regardless of type 2 diabetes treatment. CONCLUSION: Residual cardiometabolic risk exists among patients with type 2 diabetes characterized by elevated VAT and LF. PMID- 23356635 TI - Is beer consumption related to measures of abdominal and general obesity? A systematic review and meta-analysis. AB - A systematic review was conducted to assess the evidence linking beer consumption to abdominal and general obesity. Following a systematic search strategy, 35 eligible observational studies and 12 experimental studies were identified. Regarding abdominal obesity, most observational data pointed towards a positive association or no association between beer intake and waist circumference or waist-to-hip ratio in men, whereas results for women were inconsistent. Data from a subset of studies indicated that beer intake > 500 mL/day may be positively associated with abdominal obesity. Regarding general obesity, most observational studies pointed towards an inverse association or no association between beer intake and body weight in women and a positive association or no association in men. Data from six experimental studies in men, in which alcoholic beer was compared with low-alcoholic beer, suggested that consumption of alcoholic beer (for 21-126 days) results in weight gain (0.73 kg; P < 0.0001), but data from four studies comparing intake of alcoholic beer with intake of no alcohol did not support this finding. Generally, experimental studies had low-quality data. In conclusion, the available data provide inadequate scientific evidence to assess whether beer intake at moderate levels (<500 mL/day) is associated with general or abdominal obesity. Higher intake, however, may be positively associated with abdominal obesity. PMID- 23356636 TI - Vitamin D and dental caries in controlled clinical trials: systematic review and meta-analysis. AB - Vitamin D has been used to prevent and treat dental caries. The objective of this study was to conduct a systematic review of controlled clinical trials (CCTs) assessing the impact of vitamin D on dental caries prevention. Random-effects and meta-regression models were used to evaluate overall and subgroup-specific relative-rate estimates. Twenty-four CCTs encompassing 2,827 children met the inclusion criteria. Twenty-two of the 24 CCTs predated modern clinical trial design, some of which nonetheless reported characteristics such as pseudo randomization (n = 2), blinding (n = 4), or use of placebos (n = 8). The relative rate estimates of the 24 CCTs exhibited significant heterogeneity (P < 0.0001), and there was evidence of significant publication bias (P < 0.001). The pooled relative-rate estimate of supplemental vitamin D was 0.53 (95% CI, 0.43-0.65). No robust differences were identified between the caries-preventive effects of vitamin D(2) , vitamin D(3) , and ultraviolet radiation (Prob > F = 0.22). The analysis of CCT data identified vitamin D as a promising caries-preventive agent, leading to a low-certainty conclusion that vitamin D may reduce the incidence of caries. PMID- 23356637 TI - Dietary treatments for childhood constipation: efficacy of dietary fiber and whole grains. AB - Constipation in children is defined on the basis of several clusters of symptoms, and these symptoms are likely to persist into adulthood. The aim of this review article is to summarize the current literature on the use of dietary fiber and whole grains as treatments for childhood constipation. Current recommendations for fiber intake in children vary substantially among organizations, suggesting that the function of fiber in children is not fully understood. Additionally, no formal definition of "whole grain" exists, which further complicates the interpretation of the literature. Few randomized controlled trials have examined the effect of dietary fiber supplementation in children with constipation. Currently, no randomized controlled trials have investigated the efficacy of whole grains in treating childhood constipation. This is an area that warrants further attention. Increasing the intake of dietary fiber and/or whole grain has the potential to relieve childhood constipation; however, additional randomized controlled trials are necessary to make a formal recommendation. PMID- 23356638 TI - How prevalent is vitamin B(12) deficiency among vegetarians? AB - Vegetarians are at risk for vitamin B(12) (B12) deficiency due to suboptimal intake. The goal of the present literature review was to assess the rate of B12 depletion and deficiency among vegetarians and vegans. Using a PubMed search to identify relevant publications, 18 articles were found that reported B12 deficiency rates from studies that identified deficiency by measuring methylmalonic acid, holo-transcobalamin II, or both. The deficiency rates reported for specific populations were as follows: 62% among pregnant women, between 25% and almost 86% among children, 21-41% among adolescents, and 11-90% among the elderly. Higher rates of deficiency were reported among vegans compared with vegetarians and among individuals who had adhered to a vegetarian diet since birth compared with those who had adopted such a diet later in life. The main finding of this review is that vegetarians develop B12 depletion or deficiency regardless of demographic characteristics, place of residency, age, or type of vegetarian diet. Vegetarians should thus take preventive measures to ensure adequate intake of this vitamin, including regular consumption of supplements containing B12. PMID- 23356639 TI - A systematic review and meta-analysis of micronutrient intakes during pregnancy in developed countries. AB - Micronutrient status during pregnancy influences maternal and fetal health, birth outcomes, and the risk of chronic disease in offspring. Research reporting dietary intake during pregnancy in nationally representative population samples, however, is limited. This review summarizes the micronutrient intakes of pregnant women from developed countries and compares them with relevant national recommendations. A systematic search without date limits was conducted. All studies reporting the micronutrient intakes of pregnant women were considered, irrespective of design. Two authors independently identified studies for inclusion and assessed methodological quality. Nutritional adequacy was summarized, with confounding factors considered. Meta-analysis data are reported for developed countries collectively, by geographical region, and by dietary methodology. Pregnant women in developed countries are at risk of suboptimal micronutrient intakes. Folate, iron, and vitamin D intakes were consistently below nutrient recommendations in each geographical region, and calcium intakes in Japan were below the Japanese recommendations and the average intake levels in other developed countries. Research examining the implications of potential nutrient insufficiency on maternal and offspring health outcomes is needed along with improvements in the quality of dietary intake reporting. PMID- 23356640 TI - Assessing the molecular structure basis for biomass recalcitrance during dilute acid and hydrothermal pretreatments. AB - The production of cellulosic ethanol from biomass is considered a promising alternative to reliance on diminishing supplies of fossil fuels, providing a sustainable option for fuels production in an environmentally compatible manner. The conversion of lignocellulosic biomass to biofuels through a biological route usually suffers from the intrinsic recalcitrance of biomass owing to the complicated structure of plant cell walls. Currently, a pretreatment step that can effectively reduce biomass recalcitrance is generally required to make the polysaccharide fractions locked in the intricacy of plant cell walls to become more accessible and amenable to enzymatic hydrolysis. Dilute acid and hydrothermal pretreatments are attractive and among the most promising pretreatment technologies that enhance sugar release performance. This review highlights our recent understanding on molecular structure basis for recalcitrance, with emphasis on structural transformation of major biomass biopolymers (i.e., cellulose, hemicellulose, and lignin) related to the reduction of recalcitrance during dilute acid and hydrothermal pretreatments. The effects of these two pretreatments on biomass porosity as well as its contribution on reduced recalcitrance are also discussed. PMID- 23356641 TI - Endoplasmic reticulum lectin XTP3-B inhibits endoplasmic reticulum-associated degradation of a misfolded alpha1-antitrypsin variant. AB - The endoplasmic reticulum (ER) is an organelle that synthesizes many secretory and membrane proteins. However, proteins often fold incorrectly. Terminally misfolded polypeptides in the ER are retro-translocated to the cytosol, where they are ultimately degraded by the ubiquitin-proteasome system, a process termed ER-associated degradation (ERAD). By recognizing the specific structures of N linked oligosaccharides attached to polypeptides, lectins play an important role in the quality control of glycoproteins in the ER. Mammalian OS-9 and XTP3-B are ER-resident lectins that contain mannose 6-phosphate receptor homology (MRH) domains, which recognize sugar moieties; OS-9 has one MRH domain and XTP3-B has two. Both are involved in ERAD, but the functional differences between the two are poorly understood. The present study analyzed the function of human XTP3-B, and found, by frontal affinity chromatography analysis, that its C-terminal MRH domain specifically recognized the Man9 GlcNAc2 (M9) glycan in vitro and M9 glycans on an ERAD substrate NHK, a terminally misfolded alpha1-antitrypsin variant, in vivo. Furthermore, endogenous XTP3-B was a component of the HRD1 SEL1L membrane-embedded ubiquitin ligase complex, an association that was stabilized by a direct interaction with SEL1L. The lectin activity of XTP3-B was required for its binding to NHK, but not for its association with SEL1L. Unlike OS-9, XTP3-B did not enhance the degradation of misfolded glycoproteins, but instead inhibited the degradation of NHK bearing M9 oligosaccharides. Therefore, we propose that XTP3-B recognizes M9 glycans on unfolded polypeptides, thereby acting as a negative regulator of ERAD, and also protects newly synthesized immature polypeptides from premature degradation. PMID- 23356642 TI - Association of matrix metalloproteinase-9 level with the risk of renal involvement for Henoch-Schonlein purpura in children. AB - Matrix metalloproteinase-9 (MMP-9) is an enzyme that implicates in the pathogenesis of renal diseases. Henoch-Schonlein purpura nephritis (HSPN) is the most serious long-term complication of Henoch-Schonlein purpura, and it is one of the most common renal diseases in children. There was no any meta-analysis to explore the association of MMP-9 level with the risk of HSPN, and this meta analysis was performed to evaluate the association between MMP-9 level and HSPN risk in children. A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases. Eight articles were identified for the analysis of association between MMP-9 level and HSPN risk in children. In this meta-analysis, urinary MMP-9 level was associated with the risk of HSPN [odds ratio (OR) = 77.21, 95% confidence interval (CI): 54.56-99.86, p < 0.00001]. Furthermore, there was a notably difference for the association of the serum MMP-9 level with HSPN risk (OR = 135.91, 95% CI: 82.54 189.27, p < 0.00001). In conclusion, urinary/serum MMP-9 level is associated with the risk of HSPN. However, the data used for the meta-analysis in this article were from some low-level studies with small samples, and more studies should be performed in the future. PMID- 23356644 TI - Resonance Raman and electrocatalytic behavior of thiolate and imidazole bound iron porphyrin complexes on self assembled monolayers: functional modeling of cytochrome P450. AB - Electrodes bearing thiolate and imidazole coordinated iron porphyrin catalysts are constructed and characterized using resonance Raman spectroscopy, absorption spectroscopy, and electrochemistry. The cyclic voltammetry data and their pH dependences are used to establish the nature of the exchangeable trans ligands in both of these cases. In situ monitoring of partially reduced oxygen species (PROS) produced during O(2) reduction using rotating ring disc electrochemistry (RRDE) experiments provide direct insight into the "push-effect" of the thiolate ligand. The thiolate bound iron porphyrin electrode generates highly oxidizing species on the electrode during electrocatalytic O(2) reductions which are very reactive. These surfaces can utilize these oxidants to catalytically hydroxylate strong C-H bonds using molecular O(2) with turnover numbers as high as 200. PMID- 23356643 TI - SOX11 contributes to the regulation of GDF5 in joint maintenance. AB - BACKGROUND: Individual skeletal elements of the vertebrate limbs arise through a segmentation process introducing joints in specific locations. However, the molecular pathways controlling joint formation and subsequent joint maintenance are largely unknown. In this study, we focused on SOX11, and its contribution to the regulation of GDF5, a secreted signal necessary for proper joint formation and postnatal joint homeostasis. RESULTS: Sox11 is initially expressed broadly in the murine cartilage condensations at early stages of skeletal development, but its expression is specifically increased in the forming joint interzone as is forms. SOX11 overexpression can directly activate GDF5 expression both in vitro and in micromass cell cultures prepared from chick limb buds. Conserved SOX family binding sites are present in the 5' UTR region of the GDF5 gene and we show SOX11 can specifically bind to one of them. While misexpression of Sox11 in developing chick limbs through RCAS virus infection does not induce Gdf5 expression in ectopic locations, it does enhance its expression. To explore the roles of Sox11 in joint homeostasis, we analyzed adult knee joints in an osteoarthritis mouse model where the medial meniscus and the medial collateral ligament were removed. We also analyzed knee joints from human subjects who underwent total knee replacement surgery. We find that SOX11 is mainly expressed in the weight-bearing areas of knee joints, and its expression is decreased in degraded cartilage during progression of knee osteoarthritis in both mice and humans. CONCLUSIONS: This work implicates SOX11 as a potential regulator of GDF5 expression in joint maintenance and suggests a possible role in the pathogenesis of osteoarthritis. PMID- 23356645 TI - In vitro dermal absorption of di(2-ethylhexyl) adipate (DEHA) in a roll-on deodorant using human skin. AB - In vitro dermal absorption experiments were conducted using a roll-on deodorant that contains 1.56% di(2-ethylhexyl) adipate (DEHA), a plasticizer widely used in consumer products. Human skin specimens were fitted in Bronaugh flow-through Teflon diffusion cells. The diffusion cells were maintained at 32 degrees C to reflect the skin temperature. Two amounts (low dose: 5 mg of the product; high dose: 100 mg) were applied, in triplicate, each on four different human skins. DEHA was determined in the receiver solution at 6-h intervals, using headspace solid-phase microextraction gas chromatography-mass spectrometry (GC-MS). After 24 h, the experiment was terminated and masses of DEHA in the skin depot, skin wash, and upper and lower chambers of the diffusion cell were determined. A significant portion of applied DEHA, 28% in the low amount application and 34% in the high one, was found in the skin depot. In comparison, only 0.04% and 0.002% of applied DEHA were found in the receiver solutions for the low and high doses, respectively. Under our experimental conditions, an apparent steady-state flux of low DEHA mass penetrating from skin into the receiver solution was observed with a penetration rate of 2.2 ng/cm(2)/h for both the low and high doses. The average mass recovery was 81% for the low dose application and 56% for the high dose. PMID- 23356646 TI - In vivo efficacy of ferrihydrite as an enterosorbent for arsenic: short-term evaluation in rodents. AB - The use of dietary adsorbents to reduce arsenic (As) exposure is innovative. Ferrihydrite successfully sorbs arsenite and asenate over a wide range of pH conditions and the As-ferrihydrite complexes are stable in gastrointestinal (GIT) models. Our objectives were to (1) compare structural characteristics (using x ray diffraction and Fourier-transform infrared [FTIR] spectroscopy) and As binding affinities of industrially produced ferrihydrite (IDF) and lab synthesized ferrihydrite and (2) evaluate the efficacy of the material displaying the best sorption capability as an As enterosorbent in a short-term mammalian model. Lab-synthesized ferrihydrite displayed superior binding affinity for both arsenate and arsenite in vitro, which led to its use in the in vivo portion of the study. Young Sprague-Dawley male rats were fed either a control diet or a 0.5% w/w ferrihydrite feed. After 1 wk of acclimation, rats were given 0.5 ml of 500 mg/L arsenate or arsenite via gavage with or without ferrihydrite. Rats were then transferred to metabolism cages, and urine collected after 24 and 48 h was analyzed for total As. Rats were evaluated daily for signs of morbidity and mortality for up to 1 wk. Ferrihydrite reduced mean urinary As levels by 74.9% and 43.6% after 24 h and 49.1% and 39.5% after 48 h for arsenite- and arsenate treated groups, respectively. Importantly, treatment groups receiving ferrihydrite displayed no signs of As-related toxicity. All As reductions were statistically significant except for arsenate treatments at 24 h. Data suggest that, as an enterosorbent, ferrihydrite reduces bioavailability after As exposures. PMID- 23356648 TI - Magnesium in drinking water modifies the association between nitrate ingestion and risk of death from esophageal cancer. AB - The objective of this study was to explore whether magnesium (Mg) levels in drinking water modified the effects of nitrate on esophageal cancer risk occurrence. A matched cancer case-control study was used to investigate the relationship between the risk of death from esophageal cancer and exposure to nitrate in drinking water in Taiwan. All esophageal cancer deaths of Taiwan residents from 2006 through 2010 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Controls were deaths from other causes and were pair-matched to cancer cases by gender, year of birth, and year of death. Information on the levels of nitrate-nitrogen (NO(3)-N) and Mg in drinking water were collected from Taiwan Water Supply Corporation (TWSC). The municipality of residence for cancer cases and controls was presumed to be the source of the subject's NO(3)-N and Mg exposure via drinking water. Evidence of an interaction was noted between drinking water NO(3)-N and Mg intake. This is the first study to report effect modification by Mg intake originating from drinking water on an association between NO(3)-N exposure and increased risk mortality attributed to esophageal cancer. PMID- 23356647 TI - Recurring BALB/c mouse lung inflammatory responses to episodic allergen exposure. AB - This study detailed the sequence of recurring inflammatory events associated with episodic allergen exposures of mice resulting in airway hyperreactivity, sustained inflammation, goblet-cell hyperplasia, and fibrogenesis that characterize a lung with chronic asthma. Ovalbumin (OVA)-sensitized female BALB/c mice were exposed to saline-control or OVA aerosols for 1 h per day for episodes of 3 d/wk for up to 8 wk. Lung inflammation was assessed by inflammatory cell recoveries using bronchoalveolar lavages (BAL) and tissue collagenase dispersions. Cell accumulations were observed within airway submucosal and associated perivascular spaces using immunohistochemical and tinctorial staining methods. Airway responsiveness to methacholine aerosols were elevated after 2 wk and further enhanced to a sustained level after wk 4 and 8. Although by wk 8 diminished OVA-induced accumulations of eosinophils, neutrophils, and monocyte macrophages were observed, suggesting diminished responsiveness, the BAL recovery of lymphocytes remained elevated. Airway but not perivascular lesions persisted with a proliferating cell population, epithelial goblet-cell hyperplasia, and evidence of enhanced collagen deposition. Examination of lung inflammatory cell content before the onset of the first, second, and fourth OVA exposure episodes demonstrated enhancements in residual BAL lymphocyte and BAL and tissue eosinophil recoveries with each exposure episode. Although tissue monocyte macrophage numbers returned to baseline prior to each exposure episode, the greatest level of accumulation was observed after wk 4. These results provide the basis for establishing the inflammatory and exposure criteria by which episodic environmental exposures to allergen might result in the development of a remodeled lung in asthma. PMID- 23356649 TI - Highway proximity associations with blood markers of inflammation: evidence for a role for IL-1beta. AB - Cardiovascular disease is known to be associated with proximity to major roadways and highways. Thus, blood samples from 20 near highway and 20 urban background residents were analyzed for presence of cytokines and other biomarkers. Near highway participants displayed significantly lower socioeconomic status (SES) and significantly higher occupational vehicle exhaust exposure and higher low-density lipoprotein (LDL) levels. Controlling for exposure to vehicle exhaust on the job, interleukin-6 (IL-6) was numerically higher in near highway participants. Using logistic regression analyses, IL-1beta was significantly elevated near highway. It is interesting that elevations were found in IL-1beta, a key cytokine linked to inflammation from particulate matter (PM). More studies are needed with larger sample sizes to assess the possible role of IL-1beta. PMID- 23356650 TI - Manioc flour consumption as a risk factor for lead poisoning in the Brazilian Amazon. AB - Recent studies reported elevated blood lead (Pb) levels in riparian populations of the Amazon. For this reason, the aim of the present study was to assess the risk to riparians in the Brazilian Amazon to Pb exposure due to the intake of contaminated manioc flour. Lead levels were determined in whole blood (n = 74) and in manioc flour samples (n = 30) in three different communities. Mean blood Pb levels were 16.8 MUg/dl, with individuals living in Acaituba presenting the highest mean blood Pb level (22.4 MUg/dl), followed by Nova Canaa (17.3 MUg/dl) and Santa Cruz (9.8 MUg/dl). The minimum blood Pb level found was 0.83 MUg/dl and the maximum was 44.3 MUg/dl. The estimated daily intake (EDI) was calculated and compared to the benchmark dose lower confidence limit (BMDL) for neurotoxicity. Mean Pb in manioc flour was 0.34 MUg/g while EDI was 79 MUg/d, corresponding to 260% of the BMDL (varying from 168 to 308%). This finding is of great importance since this high EDI may exert adverse effects on the nervous system of this population. Manioc flour intake may thus present considerable risk of Pb exposure in this region. Risk management strategies and further studies on adverse effects in this population are needed. PMID- 23356651 TI - Breaking the cycle: extending the persistent pain cycle diagram using an affective pictorial metaphor. AB - The persistent pain cycle diagram is a common feature of pain management literature. but how is it designed and is it fulfilling its potential in terms of providing information to motivate behavioral change? This article examines on line persistent pain diagrams and critically discusses their purpose and design approach. By using broad information design theories by Karabeg and particular approaches to dialogic visual communications in business, this article argues the need for motivational as well as cognitive diagrams. It also outlines the design of a new persistent pain cycle that is currently being used with chronic pain patients in NHS Bradford, UK. This new cycle adopts and then visually extends an established verbal metaphor within acceptance and commitment therapy (ACT) in an attempt to increase the motivational aspects of the vicious circle diagram format. PMID- 23356652 TI - Responsiveness of a modified version of the postural assessment scale for stroke patients and longitudinal change in postural control after stroke- Postural Stroke Study in Gothenburg (POSTGOT) . AB - BACKGROUND: Responsiveness data certify that a change in a measurement output represents a real change, not a measurement error or biological variability. The objective was to evaluate the responsiveness of the modified version of the Postural Assessment Scale for Stroke Patients (SwePASS) in patients with a first event of stroke. An additional aim was to estimate the change in postural control during the first 12 months after stroke onset. METHODS: The SwePASS assessments were conducted during the first week and 3, 6 and 12 months after stroke in 90 patients. Svensson's method, Relative Position (RP), Relative Concentration (RC) and Relative Rank Variance (RV), were used to estimate the scale's responsiveness and the patients' change in postural control over time. RESULTS: From the first week to 3 months after stroke, the patients improved in terms of postural control with 2 to 12 times larger systematic changes in Relative Position (RP), for which 9 items and the total score showed a significant responsiveness to change when compared to the intrarater reliability measurement error of the SwePASS reported in a previous study. When SwePASS was used to assess change in postural control between the first week and 3 months, 74% of the patients received higher scores while 10% received lower scores, RP 0.31 (95% CI 0.219-0.402). The corresponding figures between 3 and 6 and between 6 and 12 months were 37% and 16%, RP 0.09 (95% CI 0.030-0.152), and 18% and 26%, RP -0.07 (95% CI -0.134- (-0.010)), respectively. CONCLUSIONS: The SwePASS is responsive to change. Postural control evaluated using the SwePASS showed an improvement during the first 6 months after stroke. The measurement property, in the form of responsiveness, shows that the SwePASS scoring method can be considered for use in rehabilitation when assessing postural control in patients after stroke, especially during the first 3 months. PMID- 23356653 TI - Effect of the cp4-epsps gene on metal bioavailability in maize and soybean using bionic gastrointestinal tracts and ICP-MS determination. AB - The transformation and metabolism of dietary compounds are affected significantly by gut microbiota. Hence, gut microbiota are used to improve bionic gastrointestinal tracts. The effect of the cp4-epsps gene on metal bioavailability was proved by the comparison of the affinity-liposome metal content ratio (AMCR) in transgenic and conventional crops. The bioavailability of V, Mn, Co, Ga, Ag, Ba, and Pb in roundup ready soybean decreased significantly because the ratio of AMCR (R(AMCR)) in the transgenic crop and its corresponding conventional type ranged from 0.36 to 0.69. In roundup ready maize, metal bioavailability decreased for Li and Cr (i.e., R(AMCR) was 0.26 and 0.39, respectively) but increased for V, Co, and Pb (i.e., R(AMCR) was 1.48, 2.07, and 2.12, respectively). Compared with conventional crops, safe dosage and maximum consumption of roundup ready crops were 1.59 times for soybean and 0.78 times for maize. PMID- 23356654 TI - Early HIV disclosure and nondisclosure among men and women on antiretroviral treatment in Uganda. AB - Efforts to expand access to HIV care and treatment often stress the importance of disclosure of HIV status to aid adherence, social support, and continued resource mobilization. We argue that an examination of disclosure processes early in the process of seeking testing and treatment can illuminate individual decisions and motivations, offering insight into potentially improving engagement in care and adherence. We report on baseline data of early HIV disclosure and nondisclosure, including reasons for and responses to disclosure from a cohort of men and women (n=949) currently accessing antiretroviral treatment in two regions of Uganda. We found early disclosures at the time of suspicion or testing positive for HIV by men and women to be largely for the purposes of emotional support and friendship. Responses to these selected disclosures were overwhelmingly positive and supportive, including assistance in accessing treatment. Nonetheless, some negative responses of worry, fear, or social ostracism did occur. Individuals deliberately chose to not disclose their status to partners, relatives, and others in their network, for reasons of privacy or not wanting to cause worry from the other person. These data demonstrate the strategic choices that individuals make early in the course of suspicion, testing, and treatment for HIV to mobilize resources and gain emotional or material support, and similarly their decisions and ability to maintain privacy regarding their status. PMID- 23356655 TI - The impact of socioenvironmental characteristics on domains of oral health related quality of life in Brazilian schoolchildren. AB - BACKGROUND: Recent researches have pointed out the need to consider the functional and psychosocial dimensions of oral health, such as Oral Health related Quality of Life (OHRQoL). The aim of this study was to investigate the influence of oral health status, socioeconomic factors and home environment of children on the four health domains of Child Perceptions Questionnaire (CPQ11 14). METHODS: A cross-sectional study was conducted in Brazil with a sample of 286 schoolchildren aged 12 years and their parents. The schoolchildren were clinically examined, and participants were asked to complete the CPQ11-14, as well as a questionnaire about home environment. In addition, a questionnaire was sent to each child's parents asking them about family socioeconomic status. The chi-square test and Poisson's regression analysis were performed. RESULTS: After adjusting for potential confounders, variables sex, monthly family income, mothers' education showed a statistically significant association with all health domains of the CPQ11-14. The family structure and presence of bleeding impacted on emotional (p = 0.0135), and social (p = 0.0010) well-being health domain scores. Orthodontic treatment need showed a strong negative effect on functional limitations domain score (p = 0.0021). CONCLUSIONS: Clinical and socio environmental factors had different impacts on domains of oral health-related quality of life, demonstrating the need to consider these conditions in planning strategies for the oral health of schoolchildren. PMID- 23356656 TI - Normative and counter-normative stress messages and symptom reporting: implications for health promotion and a methodological artefact for stress research. AB - OBJECTIVES: There is increasing use of counter-normative health messages (i.e., evidence-based health information about cause-effect relationships that run counter to shared normative beliefs, e.g., stress can lead to personal growth). The current studies examine the effect of normative and counter-normative messages about stress on levels of symptom reporting. Predictions are derived from reactance, social comparison, and self-enhancement theories. METHOD AND DESIGN: Two studies focus on the development of the messages, and two experimental studies examine the effect of manipulating normative and counter normative messages on symptom reports. The final study controls for mere measurement effects and explores the role of stress process variables (appraisals and coping). RESULTS: Exposure to a normative message (stress causes ill health) results in reduced symptom reporting compared to a counter-normative message (stress provides challenge, growth, and development) and control groups. The results suggest that people may use symptom reporting strategically to indicate coping. Based on the argument that beliefs about stress and health are stored as mental models, the theoretical associations derived from stress theory are only observed when a normative message is presented. CONCLUSIONS: Counter-normative stress messages may carry no tangible benefits compared to normative messages. Some stress research may suffer from inherent methodological bias when normative information is provided in information and consent sheets. Statement of contribution What is already known on this subject? At present, nothing is known about counter-normative health messages, despite the fact that they are becoming widely used as a public intervention. What does this study add? A clear operational definition of counter-normative messages. A test of three competing theories for counter-normative messages that focus of the stress-symptom link. Demonstrating for the first time, that in the domain of stress and health, counter-normative messages are at best ineffective. Demonstrating for the first time that only when the stress-coping-symptom links are made explicit do the theoretical associations observed in the literature emerge. This may be a potential methodological artefact in stress research that needs to be controlled. PMID- 23356657 TI - Attitudes & effectiveness of professional programs for primary prevention of violence: exploratory validation of the PREVENT primary prevention of violence self-assessment. AB - The PREVENT (Preventing Violence through Education, Networking, and Technical Assistance) project trained violence practitioners across the USA in Primary Prevention of Violence techniques (PPV). The purpose of this study is to describe the development and psychometric properties of the subscales of the PREVENT PPV Self Assessment. Of 800 participants, 585 responded (73.1%). We analyzed the data using factor analyses, reliabilities and LISREL structural equation measurement models. The Perceived PPV Project Success subscale exhibited a one-factor structure (R2 = .534, X2/df = 1.28, p = .277, GFI = .99, NNFI = .99); PPV Self Efficacy and Support showed a four-factor structure (R2 = .583, X2/df = 3.7, p = .00, GFI = .94, NNFI = .93); Perceived PPV Collaboration showed a three factor structure (R2 = .544, X2/df = 4.20, p = .00, GFI = .92, NNFI = .93); Anticipated Future PPV Work yielded a three-factor structure (R(2) = .656, X(2)/df = 4.76, p = .00, GFI = .94, NNFI = .91); and PPV Confidence a marginally acceptable two factor structure (R2 = .759, X2/df = 11.1, p = .00, GFI = .95, NNFI = .99). Perceived PPV Project Success demonstrated very strong predictive validity (chi2/df = 2.33, p = .0167, GFI = .984, RMSEA = .0585) of increased time devoted to PPV. These construct validated subscales represent a rich source of material for assessing professionals' attitudes and perseverance towards personal implementation of PPV. From these results, we recommend specific items from each subscale for further use by PPV trainers. PMID- 23356658 TI - Introduction of the AmpliChip CYP450 Test to a South African cohort: a platform comparative prospective cohort study. AB - BACKGROUND: Adverse drug reactions and lack of therapeutic efficacy associated with currently prescribed pharmacotherapeutics may be attributed, in part, to inter-individual variability in drug metabolism. Studies on the pharmacogenetics of Cytochrome P450 (CYP) enzymes offer insight into this variability. The objective of this study was to compare the AmpliChip CYP450 Test(r) (AmpliChip) to alternative genotyping platforms for phenotype prediction of CYP2C19 and CYP2D6 in a representative cohort of the South African population. METHODS: AmpliChip was used to screen for thirty-three CYP2D6 and three CYP2C19 alleles in two different cohorts. As a comparison cohort 2 was then genotyped using a CYP2D6 specific long range PCR with sequencing (CYP2D6 XL-PCR + Sequencing) platform and a PCR-RFLP platform for seven CYP2C19 alleles. RESULTS: Even though there was a low success rate for the AmpliChip, allele frequencies for both CYP2D6 and CYP2C19 were very similar between the two different cohorts. The CYP2D6 XL-PCR + Sequencing platform detected CYP2D6*5 more reliably and could correctly distinguish between CYP2D6*2 and *41 in the Black African individuals. Alleles not covered by the AmpliChip were identified and four novel CYP2D6 alleles were also detected. CYP2C19 PCR-RFLP identified CYP2C19*9,*15, *17 and *27 in the Black African individuals, with *2, *17 and *27 being relatively frequent in the cohort. Eliminating mismatches and identifying additional alleles will contribute to improving phenotype prediction for both enzymes. Phenotype prediction differed between platforms for both genes. CONCLUSION: Comprehensive genotyping of CYP2D6 and CYP2C19 with the platforms used in this study, would be more appropriate than AmpliChip for phenotypic prediction in the South African population. Pharmacogenetically important novel alleles may remain undiscovered when using assays that are designed according to Caucasian specific variation, unless alternate strategies are utilised. PMID- 23356659 TI - Exploring experiences and understandings of pain in adults with intellectual disabilities. AB - BACKGROUND: People with intellectual disabilities (ID) are at risk that their health problems, many of which cause pain, go unrecognised and untreated. Their understanding and personal experiences of pain have received little research attention. METHOD: Information was collected from 15 adults with ID using semi structured interviews about their experiences and understanding of pain. Transcripts were analysed using content analysis. RESULTS: Participants described pain using negative meanings and strong imagery, with various causes of pain suggested, but said little about how they coped with pain. Participants varied in whether they reported pains to carers, some choosing to hide the experience. There seemed a general belief that others can tell when someone is in pain. CONCLUSIONS: Conversations regarding pain with adults with ID are a real challenge; health-care staff need to think carefully about the questions they ask. Possessing verbal skills cannot be taken as an indication that pain will be communicated. PMID- 23356660 TI - Multicenter prospective study for clinical and endoscopic efficacies of leukocytapheresis therapy in patients with ulcerative colitis. AB - OBJECTIVE: This study aimed to assess the efficacy and tolerability of leukocytapheresis (LCAP) and to investigate predictive factors for mucosal healing and a sustained clinical response in steroid-free and steroid-refractory patients with ulcerative colitis (UC). MATERIAL AND METHODS: Thirty-one steroid free or steroid-refractory patients with active UC were enrolled. Five or ten consecutive sessions of LCAP were performed in each patient. The efficacy and tolerability was then evaluated at weeks 3 and 6. Endoscopic examination was performed at week 6 to evaluate the mucosal healing, and the sustained cumulative response rate was evaluated at 12 months. RESULTS: At week 6, the mean Mayo clinical activity score had decreased significantly from 8.0 to 4.6 in the steroid-free patients and from 8.3 to 3.9 in the steroid-refractory patients. Rachmilewitz's endoscopic index had also decreased significantly from 9.1 to 6.1 in the steroid-free patients and from 10.0 to 5.7 in the steroid-refractory patients. Forty-seven percent of the steroid-free patients and 33% of the steroid refractory patients achieved mucosal healing. The peripheral platelet counts had decreased significantly at weeks 3 and 6 in the mucosal healing group, compared with the non-mucosal healing group. The patients with a more than 15% platelet reduction had a significantly higher cumulative response rate, compared with the patients without a platelet reduction (p = 0.015). CONCLUSIONS: LCAP is beneficial for the induction of mucosal healing in steroid-free and steroid refractory patients with UC. The degree of platelet reduction during LCAP might be a predictive marker for mucosal healing and a sustained clinical response. PMID- 23356661 TI - QM/MM modelling of ketosteroid isomerase reactivity indicates that active site closure is integral to catalysis. AB - Ketosteroid isomerase (Delta5-3-keto steroid isomerase or steroid Delta isomerase) is a highly efficient enzyme at the centre of current debates on enzyme catalysis. We have modelled the reaction mechanism of the isomerization of 3-oxo-Delta5-steroids into their Delta4-conjugated isomers using high-level combined quantum mechanics/molecular mechanics (QM/MM) methods, and semi empirical QM/MM molecular dynamics simulations. Energy profiles were obtained at various levels of QM theory (AM1, B3LYP and SCS-MP2). The high-level QM/MM profile is consistent with experimental data. QM/MM dynamics simulations indicate that active site closure and desolvation of the catalytic Asp38 occur before or during formation of dienolate intermediates. These changes have a significant effect on the reaction barrier. A low barrier to reaction is found only when the active site is closed, poising it for catalysis. This conformational change is thus integral to the whole process. The effects on the barrier are apparently largely due to changes in solvation. The combination of high-level QM/MM energy profiles and QM/MM dynamics simulation shows that the reaction involves active site closure, desolvation of the catalytic base, efficient isomerization and re opening of the active site. These changes highlight the transition between the ligand binding/releasing form and the catalytic form of the enzyme. The results demonstrate that electrostatic interactions (as a consequence of pre-organization of the active site) are crucial for stabilization during the chemical reaction step, but closure of the active site is essential for efficient catalysis to occur. PMID- 23356662 TI - Cerebro vascular reactivity (CVR) of middle cerebral artery in response to CO2 5% inhalation in preeclamptic women. AB - OBJECTIVE: To compare the cerebro vascular reactivity (CVR) of middle cerebral artery (MCA) in response to CO2 5% inhalation between preeclamptic and normotensive pregnant women, also, between mild and severe preeclampsia. STUDY DESIGN: A comparative study was performed on 61 women with preeclampsia and 65 normotensive pregnant women who were in the third trimester of gestation. MCA transcranial Doppler ultrasound was used to measure CVR in response to CO2 5% inhalation. Pulsatility index (PI), resistance index (RI), blood pressure, maternal age, gestational age and gravidity were also recorded. RESULTS: Baseline PI and RI were lower in the preeclamptic group (p < 0.05). Inhalation of CO2 5% caused significant increase in CVR among normotensive pregnant women in comparison with preeclamptic group (1.006 +/- 0.229 versus 0.503 +/- 0.209, p = 0.0001). Significantly, more cerebral vasodilatation was found among mild preeclamptic women in comparison with severe preeclamptic women (0.583 +/- 0.193 versus 0.383 +/- 0.173, p = 0.0001). The receiver operating characteristics curve analysis revealed acceptable difference between CO2 stimulation test of preeclamptic and normotensive women (Area under curve = 0.973, p = 0.0001). CONCLUSION: CVR in response to CO2 5% is less in preeclamptic pregnant women than normotensives, also, in severe preeclampsia, it is less than mild preeclampsia. PMID- 23356663 TI - Corneal collagen cross-linking (CXL) for the treatment of melting keratitis in cats and dogs: a pilot study. AB - OBJECTIVE: UV-A/riboflavin cross-linking (CXL) of corneal collagen fibers is an established, highly promising therapy for corneal melting in physician-based ophthalmology. A prospective pilot study was conducted to demonstrate proof of principle of this novel method for the treatment of melting corneal ulcers in dogs and cats. PROCEDURES: After obtaining owner consent, CXL was performed in three cats and three dogs with corneal melting, which either affected the entire corneal surface or was resistant to conventional antibiotic and anticollagenolytic therapy, and affected parts or all of the corneal surface. Medical therapy was continued in all patients. The available follow-up ranged from 2 to 22.5 months and involved slit-lamp examination, fluorescein staining, and photographic documentation during all rechecks. RESULTS: Surgical stabilization of the cornea was not necessary in any case, because progression of corneal melting was arrested in all cases within 1-20 days of CXL treatment. Corneal re-epithelization occurred within 7-40 days in all eyes. At 40 days after CXL, all eyes presented a quiescent corneal state without signs of active inflammation and with beginning scar formation. The complications observed in three of the six animals included a corneal sequestrum, superficial corneal stromal pigmentation, and bullous keratopathy. CONCLUSIONS: This study shows the feasibility of CXL to treat progressive corneal melting in veterinary patients. CXL may represent a cost-efficient and safe alternative therapy in the treatment for corneal melting in veterinary ophthalmology. More investigations comparing the effectivity and complication rate of CXL to those of standard medical treatment are necessary. PMID- 23356664 TI - The difficult relationship between occlusal interferences and temporomandibular disorder - insights from animal and human experimental studies. AB - The aetiology of temporomandibular disorder (TMD) is multifactorial, and numerous studies have addressed that occlusion may be of great importance. However, whether occlusion plays a crucial role in the pathogenesis of TMD remains controversial. Study designs utilising animal models have been used to study the effects of artificial occlusal alterations. Experimental traumatic occlusion affects blood flow in the temporomandibular joint and results in changes in the condylar cartilage, and artificial occlusal interference induces masticatory muscle nociceptive responses that are associated with peripheral sensitisation and lead to central sensitisation, which maintains masticatory muscle hyperalgesia. The possibility that occlusal interference results in TMD has been investigated in humans using a double-blind randomised design. Subjects without a history of TMD show fairly good adaptation to interferences. In contrast, subjects with a history of TMD develop a significant increase in clinical signs and self-report stronger symptoms (occlusal discomfort and chewing difficulties) in response to interferences. Meanwhile, psychological factors appear meaningful for symptomatic responses to artificial interferences in subjects with a history of TMD. Thus, individual differences in vulnerability to occlusal interferences do exist. Although there are advantages and disadvantages to using human and animal occlusal interference models, these approaches are indispensable for discovering the role of occlusion in TMD pathogenesis. PMID- 23356666 TI - Aliphatic alcohol contaminants of illegally produced spirits inhibit phagocytosis by human granulocytes. AB - CONTEXT: Unregulated production of spirits in many countries leads to products containing appreciable levels of aliphatic alcohols (AAs) and is the main source of human exposure to these substances worldwide. Previous studies have confirmed that alcohol abuse can lead to ethanol-induced immunosuppression and thereby increased susceptibility to infectious diseases. Granulocytes, as professional phagocytic cells, play a crucial role in engulfment and killing of pathogenic microorganisms. Thus, a decrease in their phagocytic activity has been invoked as a factor in the impaired antimicrobial defense observed in alcoholics. However, AAs consumed as contaminants of illicit spirits may also influence phagocytosis, thereby contributing to a further decrease in microbicidal activity but, so far, this has not been studied. OBJECTIVE: Therefore, the aim of this study was to measure granulocyte phagocytosis following treatment of granulocytes with those higher alcohols found in illegal spirits. MATERIALS AND METHODS: Granulocytes were isolated from human peripheral blood. Then phagocytosis of opsonized zymosan particles by granulocytes treated with AAs individually and in combination was determined. RESULTS: These alcohols inhibited phagocytosis in a concentration dependent manner and at lower concentrations when combined than when tested individually. DISCUSSION AND CONCLUSION: Due to their synergistic effects, it is possible that, in combination with ethanol, they may inhibit phagocytosis in a clinically meaningful way in episodic heavy drinkers. PMID- 23356665 TI - The evolution of antibiotic susceptibility and resistance during the formation of Escherichia coli biofilms in the absence of antibiotics. AB - BACKGROUND: Explanations for bacterial biofilm persistence during antibiotic treatment typically depend on non-genetic mechanisms, and rarely consider the contribution of evolutionary processes. RESULTS: Using Escherichia coli biofilms, we demonstrate that heritable variation for broad-spectrum antibiotic resistance can arise and accumulate rapidly during biofilm development, even in the absence of antibiotic selection. CONCLUSIONS: Our results demonstrate the rapid de novo evolution of heritable variation in antibiotic sensitivity and resistance during E. coli biofilm development. We suggest that evolutionary processes, whether genetic drift or natural selection, should be considered as a factor to explain the elevated tolerance to antibiotics typically observed in bacterial biofilms. This could be an under-appreciated mechanism that accounts why biofilm populations are, in general, highly resistant to antibiotic treatment. PMID- 23356667 TI - Environment-mediated morph-linked immune and life-history responses in the aposematic wood tiger moth. AB - 1. Warning signals are expected to evolve towards conspicuousness and monomorphism, and thereby hamper the evolution of multiple colour morphs. Here, we test fitness responses to different rearing densities to explain colour polymorphism in aposematic wood tiger moth (Parasemia plantaginis) males. 2. We used larval lines sired by white or yellow adult males selected for small or large melanization patterns of coloration. We reared these selected lines either solitarily (favourable conditions) or in aggregations (challenged conditions), and followed their performance to adult stage. We tested whether differences in larval density affected life-history traits, adult melanin expression, adult morph (white or yellow) survival and immunological responses. 3. We found that the aggregated environment increased mortality of larvae, but decreased larval developmental time and pupa weight. Adult wing melanin pigmentation was dependent on larval melanin expression but not rearing density. We also confirmed that adult wing coloration had a genetic basis (h(2) = 0.42) and was not influenced by larval growth density. Adult yellow males survived better from aggregations in comparison with white males, which may be related to differences in immune defence. White males had better encapsulation ability, whereas yellow males had increased lytic activity of haemolymph in the aggregations. 4. Our main results highlight, that morph-linked immune responses mediated by differential growth density may facilitate the maintenance of colour polymorphism in aposematic species. In nature, risk of diseases and parasites vary spatially and temporally. Therefore, both yellow and white adult morphs can be maintained due to their differential investment in immune defence in heterogeneous environments. PMID- 23356668 TI - Stem cell transplantation in amyotrophic lateral sclerosis patients: methodological approach, safety, and feasibility. AB - Amyotrophic lateral sclerosis is characterized by the selective death of motor neurons. Stem cells have been proposed as a potential therapeutic strategy. The safety of stem cell transplantation into the frontal motor cortex to improve upper motor neuron function is described. Sixty-seven patients with definite amyotrophic lateral sclerosis were included. After giving their informed consent, the patients underwent magnetic resonance imaging, functional rating, pulmonary function test, and laboratory tests. Their bone marrow was stimulated with daily filgrastim (300 ug) given subcutaneously for 3 days. Peripheral blood mononuclear cells were obtained by leukapheresis. Isolated CD133(+) stem cells were suspended in 300 ul of the patient's cerebrospinal fluid and implanted into the motor cortex. Adverse events were recorded at each step of the procedure and were classified according to the Common Terminology Criteria for Adverse Events v3.0. The survival at 1 year was 90% after transplantation. with a mean long-term survival rate of 40.17 months from diagnosis. The most common adverse events were in grades I-II and involved transient skin pain (19.5% of patients) attributed to the insertion of the Mahurkar catheter into the subclavian vein, minor scalp pain (15.9%), and headache (12.2%) from the surgical procedure. Several patients (1.5 - 4.5%) reported diverse grade I adverse events. There were two deaths, one considered to be associated with the procedure (1.5%) and the other associated with the disease. Autologous stem cell transplantation into the frontal motor cortex is safe and tolerated well by patients. Further controlled studies are required to define the efficacy of this procedure. PMID- 23356669 TI - thin films of poly(isoprene-b-ethylene oxide) diblock copolymers on mica: an atomic force microscopy study. AB - The structural behavior of three amphiphilic semicrystalline poly(isoprene-b ethylene oxide) block copolymers (PI-b-PEO) with different PEO volume fraction (f(PEO) = 0.32, 0.49, and 0.66), spin-coated on freshly cleaved mica surfaces from aqueous solutions, was investigated by atomic force microscopy. We focus on the dependence of the resulting thin film nanostructures on the molecular characteristics (f(PEO) and molecular weight) and the adsorbed amount. The nanostructures obtained immediately after spin-coating were robust and remained unchanged after annealing and/or aging. The PEO affinity for the highly hydrophilic mica and the tendency of the hydrophobic and low surface energy PI to dewet and be at the free interface caused the soft PI-b-PEO micelles to collapse leading to the formation of 2D dendritic networks over mica. We show that, for all three polymers, the dendritic monolayer thickness can be predicted by a model consisting of a PEO crystallized layer (directly on top of mica) of the same thickness in all cases and a PI brush layer on top. In thicker areas, polymer material self-assembled into conelike multilamellar bilayers on top of the monolayer and oriented parallel to the substrate for both symmetric and asymmetric diblock copolymers with the lowest f(PEO). We compare the lateral morphology of the films and discuss the thickness heterogeneity, which results from the coupling and competition of crystallization kinetics, phase separation, and wetting/dewetting phenomena highlighting the role of the two blocks to inhibit or enhance certain morphologies. We show that the deviation of the f(PEO) = 0.32 thin film from its bulk phase structure (cylinders in hexagonal lattice) continues for several lamellar bilayers away from the substrate. For the asymmetric PI-b-PEO polymer with the higher PEO volume fraction (f(PEO) = 0.66) and higher APT, laterally extensive stacks of flat-on lamellar crystallites formed on the surface demonstrating the crucial role of the PEO crystallization. PMID- 23356670 TI - Role of NO in ischemia/reperfusion injury. PMID- 23356671 TI - Electroacupuncture preconditioning reduces cerebral ischemic injury via BDNF and SDF-1alpha in mice. AB - BACKGROUND: This study was designed to determine if electroacupuncture (EA) preconditioning improves tissue outcome and functional outcome following experimentally induced cerebral ischemia in mice. In addition, we investigated whether the expression of brain-derived neurotrophic factor (BDNF) and stromal cell derived factor-1alpha (SDF-1alpha) and infarct volume were related with improvement in neurological and motor function by interventions in this study. METHODS: After treatment with EA at the acupoints 'Baihui (GV20)' and 'Dazhui (GV14)' for 20 min, BDNF was assessed in the cortical tissues based on Western blot and the SDF-1alpha and vascular endothelial growth factor (VEGF) levels in the plasma determined by ELISA. To assess the protective effects of EA against ischemic injury, the mice received once a day 20 min EA preconditioning for three days prior to the ischemic event. Focal cerebral ischemia was then induced by photothrombotic cortical ischemia. Infarct volumes, neurobehavioral deficit and motor deficit were evaluated 24 h after focal cerebral ischemia. RESULTS: The expression of BDNF protein increased significantly from 6 h, reaching a plateau at 12 h after the end of EA treatment in the cerebral cortex. Furthermore, SDF 1alpha, not VEGF, increased singnificantly from 12 h to 48 h after EA stimulation in the plasma. Moreover, EA preconditioning reduced the infarct volume by 43.5% when compared to control mice at 24 h after photothrombotic cortical ischemia. Consistent with a smaller infarct size, EA preconditioning showed prominent improvement of neurological function and motor function such as vestibule-motor function, sensori-motor function and asymmetric forelimb use. The expression of BDNF colocalized within neurons and SDF-1alpha colocalized within the cerebral vascular endothelium was observed throughout the ischemic cortex by EA. CONCLUSIONS: Pretreatment with EA increased the production of BDNF and SDF 1alpha, which elicited protective effects against focal cerebral ischemia. These results suggest a novel mechanism of EA pretreatment-induced tolerance against cerebral ischemic injury. PMID- 23356672 TI - "They give us hope": HIV-positive caregivers' perspectives on the role of social support for health. AB - A number of studies indicate that social support is associated with better health outcomes among HIV-positive caregivers of children, suggesting its potential importance for interventions aimed at safeguarding the well-being of this population. However, there is very little published literature assessing the support-health relationship or evaluating applied social support interventions with HIV-positive populations in HIV-endemic contexts of the developing world. The global literature on social support and health suggests that, in order to refine theory and improve interventions, greater attention should be paid to specific dimensions of support, such as types and sources, as well as the processes through which support may be affecting health outcomes. This article presents and discusses data from in-depth interviews with 12 HIV-positive primary caregivers of children living in an HIV-endemic, low-resourced, urban South African community. The primary aim of this qualitative work was to provide further insight into survey findings of a positive relationship between social support and self-reported general health and functioning, by exploring caregivers' personal experiences of being supported within their community, and their perceptions on how this "informal" support may be influencing their health. Our qualitative data highlight the importance of instrumental and emotional support for this population, the relevance of support provider characteristics and some of the processes or pathways that are likely explaining the support health link. These processes include psychological factors such as mastery and hope, coping strategies and positive health behaviours. We provide recommendations for future research to further this work, and discuss implications for health interventions. PMID- 23356673 TI - Outpatient Foley catheter versus inpatient prostaglandin E2 gel for induction of labour: a randomised trial. AB - BACKGROUND: Induction of labour (IOL) is one of the commonest obstetric interventions, with significant impact on both the individual woman and health service delivery. Outpatient IOL is an attractive option to reduce these impacts. To date there is little data comparing outpatient and inpatient IOL methods, and potential safety concerns (hyperstimulation) if prostaglandins, the standard inpatient IOL medications, are used in the outpatient setting. The purpose of this study was to assess feasibility, clinical effectiveness and patient acceptability of outpatient Foley catheter (OPC) vs. inpatient vaginal PGE2 (IP) for induction of labour (IOL) at term. METHODS: Women with an unfavourable cervix requiring IOL at term (N=101) were randomised to outpatient care using Foley catheter (OPC, n=50) or inpatient care using vaginal PGE2 (IP, n=51). OPC group had Foley catheter inserted and were discharged overnight following a reassuring cardiotocograph. IP group received 2 mg/1 mg vaginal PGE2 if nulliparous or 1 mg/1 mg if multiparous. Main outcome measures were inpatient stay (prior to birth, in Birthing Unit, total), mode of birth, induction to delivery interval, adverse reactions and patient satisfaction. RESULTS: OPC group had shorter hospital stay prior to birth (21.3 vs. 32.4 hrs, p< .001), IP were more likely to achieve vaginal birth within 12 hours of presenting to Birthing Unit (53% vs. 28%, p= .01). Vaginal birth rates (66% OPC Vs. 71% IP), total induction to delivery time (33.5 hrs vs. 31.3 hrs) and total inpatient times (96 hrs OPC Vs. 105 hrs IP) were similar. OPC group felt less pain (significant discomfort 26% Vs 58%, p=.003), and had more sleep (5.8 Vs 3.4 hours, p< .001), during cervical preparation, but were more likely to require oxytocin IOL (88 Vs 59%, p=.001). CONCLUSIONS: OPC was feasible and acceptable for IOL of women with an unfavourable cervix at term compared to IP, however did not show a statistically significant reduction in total inpatient stay and was associated with increased oxytocin IOL. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN:12609000420246. PMID- 23356674 TI - A nationwide seroepidemiology of hepatitis C virus infection in South Korea. AB - BACKGROUND & AIMS: The aim of this study was to reveal nationwide seroprevalence of HCV infection in South Korea by a large-scale survey. METHODS: From January to December 2009, a total of 291 314 adults underwent health check-up in 29 centres nationwide. The data concerning anti-HCV antibody and biochemical tests were obtained from all participants. Among subjects with positive anti-HCV, such data as HCV RNA, genotypes and treatment detail were additionally analysed. RESULTS: Using an estimated 2009 population of Korea, the age, sex and area-adjusted anti HCV positive rate was 0.78%. Anti-HCV prevalence in female patients (0.83%) was higher than that in male patients (0.75%). Gradual increase in anti-HCV positivity was observed, from 0.34% in those aged 20-29 years to 2.31% in those >70 years. The age- and sex-adjusted anti-HCV prevalence varied in different areas, being higher in Busan and Jeonnam (1.53-2.07%), mid-level in Seoul and surrounding districts (0.50-0.61%) and lower in Jeju (0.23%). The comparative analysis of laboratory variables between anti-HCV (+) and anti-HCV (-) group revealed significantly higher levels of alanine aminotransferase and lower levels of serum lipids in anti-HCV (+) group. Among 1 718 anti-HCV positive subjects, serum HCV RNA was measured only in 478 people, of whom 268 (56.1%) patients had detectable HCV RNA in serum. Among 50 patients for whom assessment of response to antiviral therapy was feasible, overall sustained virological response was achieved in 84% of patients. CONCLUSION: The prevalence of HCV infection is low in South Korea. Studies to analyse risk factors are warranted to reduce HCV infection. PMID- 23356675 TI - Interleukin-1beta receptor expressed by modified vaccinia virus Ankara interferes with interleukin-1beta activity produced in various virus-infected antigen presenting cells. AB - BACKGROUND: Modified vaccinia virus Ankara (MVA) is a highly attenuated virus and a promising vaccine vector with potent immune stimulating properties. Deletion of the gene encoding the viral interleukin-1beta receptor (vIL-1betaR) in MVA (MVADeltaIL-1betaR) was previously shown to enhance memory T cell function. Here, we investigated the influence of vIL-1betaR on blocking interleukin-1beta (IL 1beta) upon MVA infection in various antigen presenting cells of murine and human origin, and analyzed whether inflammasome function contributes to IL-1beta production in different cell types. FINDINGS: Extending previous studies, immunizing mice with low doses of MVADeltaIL-1betaR still showed enhanced memory CD8(+) T cell activation compared to MVA wild-type (MVAwt) immunization. In vitro, murine myeloid dendritic cells, and activated, but not naive primary macrophages were identified as potent producers of IL-1beta upon infection with MVA. Importantly, free IL-1beta was only detected in the absence of vIL-1betaR. Moreover, MVADeltaIL-1betaR increased amounts of bioactive IL-1beta compared to MVAwt after infection of human THP-1 cells, as detected using a reporter system that only responds to active and free IL-1beta. The MVA-mediated induction of IL 1beta was confirmed to depend on inflammasome function in human and murine cells, however in murine cells this apparently involves caspase-1-independent pathways. CONCLUSIONS: MVA lacking IL-1beta blocking activity leads to increased concentrations of free IL-1beta upon infection of murine and human antigen presenting cells; this is likely responsible for enhanced memory T cell activation upon MVADeltaIL-1betaR immunization of mice. Moreover, our results suggest that MVA-mediated IL-1beta induction is a multifactorial process. PMID- 23356676 TI - Bioconversion of lignocellulose: inhibitors and detoxification. AB - Bioconversion of lignocellulose by microbial fermentation is typically preceded by an acidic thermochemical pretreatment step designed to facilitate enzymatic hydrolysis of cellulose. Substances formed during the pretreatment of the lignocellulosic feedstock inhibit enzymatic hydrolysis as well as microbial fermentation steps. This review focuses on inhibitors from lignocellulosic feedstocks and how conditioning of slurries and hydrolysates can be used to alleviate inhibition problems. Novel developments in the area include chemical in situ detoxification by using reducing agents, and methods that improve the performance of both enzymatic and microbial biocatalysts. PMID- 23356677 TI - An epidemiological survey on road traffic crashes in Iran: application of the two logistic regression models. AB - Risk factors of human-related traffic crashes are the most important and preventable challenges for community health due to their noteworthy burden in developing countries in particular. The present study aims to investigate the role of human risk factors of road traffic crashes in Iran. Through a cross sectional study using the COM 114 data collection forms, the police records of almost 600,000 crashes occurred in 2010 are investigated. The binary logistic regression and proportional odds regression models are used. The odds ratio for each risk factor is calculated. These models are adjusted for known confounding factors including age, sex and driving time. The traffic crash reports of 537,688 men (90.8%) and 54,480 women (9.2%) are analysed. The mean age is 34.1 +/- 14 years. Not maintaining eyes on the road (53.7%) and losing control of the vehicle (21.4%) are the main causes of drivers' deaths in traffic crashes within cities. Not maintaining eyes on the road is also the most frequent human risk factor for road traffic crashes out of cities. Sudden lane excursion (OR = 9.9, 95% CI: 8.2 11.9) and seat belt non-compliance (OR = 8.7, CI: 6.7-10.1), exceeding authorised speed (OR = 17.9, CI: 12.7-25.1) and exceeding safe speed (OR = 9.7, CI: 7.2 13.2) are the most significant human risk factors for traffic crashes in Iran. The high mortality rate of 39 people for every 100,000 population emphasises on the importance of traffic crashes in Iran. Considering the important role of human risk factors in traffic crashes, struggling efforts are required to control dangerous driving behaviours such as exceeding speed, illegal overtaking and not maintaining eyes on the road. PMID- 23356678 TI - A Rasch analysis of the Hospital Anxiety and Depression Scale (HADS) among cancer survivors. AB - OBJECTIVE: The Hospital Anxiety and Depression Scale (HADS) is commonly used to assess distress among individuals with cancer. However, previous studies cast doubt on the most appropriate dimensional structure for the HADS, suggesting that 1- or 3-dimensional structures might offer superior fit to the original 2 dimensional one. This article is the first to use Rasch analysis to examine the psychometric properties of the subscales corresponding to each of these alternative structures. METHOD: The HADS was completed by 1,360 cancer survivors. Rasch analyses were conducted to examine summary and individual model fit statistics, person separation index, response format, item bias, redundancy, and dimensionality. RESULTS: The HADS-Total scale was found to be multidimensional, and it was necessary to remove almost half of the items to achieve fit. Analyses only partially supported the original structure, as both HADS-Anxiety and HADS Depression showed initial model misfit and item deletion was necessary to achieve fit. Within the 3-dimensional structures, the Rasch statistics for the anxiety subscales were within acceptable range and no adjustment was needed. Analyses did not support adding Item 7 to HADS-Depression. CONCLUSIONS: Results supported modified versions of the HADS-Anxiety and HADS-Depression; however, combining all items to form HADS-Total is not recommended. Numerous studies using classical test theory and Rasch analyses have corroborated the exclusion of some items (e.g., Item 7) and appropriateness of the subscales defined by a 3-dimensional structure. Further research is required to identify the incremental validity of potential revised subscales. PMID- 23356679 TI - The clinical utility of the Maslach Burnout Inventory in a clinical population. AB - This replication study examines the use of the Maslach Burnout Inventory (MBI GS), a self-report questionnaire on burnout, as a clinical diagnostic instrument for measuring clinical burnout. The MBI and Mini International Neuropsychiatric Interview (MINI), a semistructured interview based on classifications in the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994), were administered to 419 outpatients at a Dutch multicenter institution specializing in the treatment of work-related psychological problems. MBI scores indicative of the presence of burnout were compared to the primary DSM-IV diagnosis as established by the MINI. The DSM-IV diagnosis "undifferentiated somatoform disorder" was used as a proxy measure for clinical burnout. The results showed that the psychometric properties of the MBI were good. The factorial validity of the MBI could be confirmed. Several decision rules or cutoff points were assessed to determine the discriminant validity of the MBI. None of these cutoff points proved to be sufficiently discriminable, however. Receiver operating characteristic analyses revealed that the MBI showed the highest sum of sensitivity (78%) and specificity (48%) with a cutoff point of 3.50 on the Exhaustion subscale, with a kappa agreement of .25 with the structured diagnostic interview. The practical implication is that the MBI should not be used by itself as a diagnostic tool in a patient population, because of a resultant high probability of overdiagnosing burnout. PMID- 23356680 TI - Multifactor modeling of emotional and behavioral risk of preschool-age children. AB - Screening for emotional and behavioral risk has become more prevalent with young children; however, not much is known about the latent structure for many of the brief instruments currently being used to assess children. Information concerning the latent structure of an instrument is necessary to support use of the scoring information. The underlying structure of the Behavioral and Emotional Screening System, Teacher Rating Form-Preschool (Kamphaus & Reynolds, 2007) was investigated. A sample of ratings of more than 1,400 preschoolers was used to test 4 different confirmatory factor analysis models: (a) unidimensional model, (b) correlated factor model, (c) higher order factor model, and (d) bifactor model. Results showed support for the bifactor model, suggesting that an overall score is useful for interpreting preschoolers' level of emotional and behavioral risk. Relationships between items and the maladaptive risk general factor varied according to content area. PMID- 23356681 TI - A tool for the culturally competent assessment of suicide: the Cultural Assessment of Risk for Suicide (CARS) measure. AB - Despite important differences in suicide presentation and risk among ethnic and sexual minority groups, cultural variations have typically been left out of systematic risk assessment paradigms. A new self-report instrument for the culturally competent assessment of suicide, the Cultural Assessment of Risk for Suicide (CARS) measure, was administered to a diverse sample of 950 adults from the general population. Exploratory factor analysis yielded a 39-item, 8-factor structure subsumed under and consistent with the Cultural Theory and Model of Suicide (Chu, Goldblum, Floyd, & Bongar, 2010), which characterizes the vast majority of cultural variation in suicide risk among ethnic and sexual minority groups. Psychometric properties showed that the CARS total and subscale scores demonstrated good internal consistency, convergent validity with scores on other suicide-related measures (the Suicide Ideation Scale, the Beck Depression Inventory suicide item, and the Beck Hopelessness Scale), and an ability to discriminate between participants with versus without history of suicide attempts. Regression analyses indicated that the CARS measure can be used with a general population, providing information predictive of suicidal behavior beyond that of minority status alone. Minorities, however, reported experiencing the CARS cultural risk factors to a greater extent than nonminorities, though effect sizes were small. Overall, results show that the CARS items are reliable, and the instrument identifies cultural suicide risk factors not previously attended to in suicide assessment. The CARS is the first to operationalize a systematic model that accounts for cultural competency across multiple cultural identities in suicide risk assessment efforts. PMID- 23356682 TI - Quantifying diagnostic uncertainty using item response theory: the Posterior Probability of Diagnosis Index. AB - Using traditional Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (American Psychiatric Association, 2000) diagnostic criteria, clinicians are forced to make categorical decisions (diagnosis vs. no diagnosis). This forced choice implies that mental and behavioral health disorders are categorical and does not fully characterize varying degrees of uncertainty associated with a particular diagnosis. Using an item response theory (latent trait model) framework, we describe the development of the Posterior Probability of Diagnosis (PPOD) Index, which answers the question: What is the likelihood that a patient meets or exceeds the latent trait threshold for a diagnosis? The PPOD Index is based on the posterior distribution of theta (latent trait score) for each patient's profile of symptoms. The PPOD Index allows clinicians to quantify and communicate the degree of uncertainty associated with each diagnosis in probabilistic terms. We illustrate the advantages of the PPOD Index in a clinical sample (N = 321) of children and adolescents with oppositional defiant disorder. PMID- 23356683 TI - Exploratory and higher order factor analysis of the WJ-III full test battery: a school-aged analysis. AB - Development of the Woodcock-Johnson (3rd ed.; WJ-III; Woodcock, McGrew & Mather, 2001a) was guided in part by Carroll's (1993) 3-stratum theory of cognitive abilities and based on confirmatory factor analysis (CFA), even though Carroll used exploratory factor analysis (EFA) to derive his theory. Using CFA, McGrew and Woodcock (2001) found a 9-factor model across all age ranges. To determine if the 9-factor structure holds for the full WJ-III battery, we applied currently recognized best practices in EFA to 2 school-aged 42-subtest correlation matrices (ages 9-13 and 14-19 years). Six factors emerged at the 9-13 age range, while 5 factors were indicated at the 14-19 age range. The resulting 1st-order factors displayed patterns of both convergence with and divergence from the WJ-III results presented in the Technical Manual. These results also revealed a robust manifestation of general intelligence (g) that dwarfed the variance attributed to the lower order factors. It is surprising that this study represents the first time the WJ-III full battery was subjected to EFA analyses given the instrument's significant use by practitioners and that it served as the initial evidentiary basis for Cattell-Horn-Carroll (CHC) theory. The lack of confirmation of CFA results with EFA methods in the current study permits questioning of the structure of the WJ-III and its relationship with CHC theory. Additional independent, structural analyses are clearly indicated for the WJ-III full test battery before we can be confident in its structure. PMID- 23356684 TI - Effect of thermal behavior of beta-lactoglobulin on the oxidative stability of menhaden oil-in-water emulsions. AB - This study reports how emulsion oxidative stability was affected by the interfacial structure of beta-lactoglobulin due to different heat treatments. Four percent (v/v) menhaden oil-in-water emulsions, stabilized by 1% (w/v) beta lactoglobulin at pH 7, were prepared by homogenization under different thermal conditions. Oxidative stability was monitored by the ferric thiocyanate peroxide value assay. Higher oxidative stability was attained by beta-lactoglobulin in the molten globule state than in the native or denatured state. From atomic force microscopy of beta-lactoglobulin adsorbed onto highly ordered pyrolytic graphite in buffer, native beta-lactoglobulin formed a relatively smooth interfacial layer of 1.2 GPa in Young's modulus, whereas additional aggregates of similar stiffness were found when beta-lactoglobulin was preheated to the molten globule state. For denatured beta-lactoglobulin, although aggregates were also observed, they were larger and softer (Young's modulus = 0.45 GPa), suggesting increased porosity and thus an offset in the advantage of increased layer coverage on oxidative stability. PMID- 23356685 TI - When is a carer's employment at risk? Longitudinal analysis of unpaid care and employment in midlife in England. AB - This article examines the thresholds at which provision of unpaid care affects employment in England. Previous research has shown that providing care for 20 or more hours a week has a negative effect on employment. The present article explores the impact of a lower threshold and asks whether provision of care for 10 or more hours a week has a negative effect on employment. The article focuses on women and men aged between 50 and State Pension Age (60 for women, 65 for men). The study uses data from the first four waves of the English Longitudinal Study of Ageing (ELSA), collected in 2002/2003, 2004/2005, 2006/2007 and 2008/2009. Across these waves, there are 17,123 people aged 50-59/64 years, of whom 9% provide unpaid care to an adult. Using logistic regression analysis of the longitudinal data, the study finds that employed women in their fifties who start providing care for <10 hours a week are significantly more likely to remain in employment one wave later than similar women who have not started to provide care. In contrast, employed women in their fifties who start providing care for 10 or more hours a week are significantly less likely to remain in employment one wave later than similar women who have not started to provide care. Employed men aged between 50 and State Pension Age, who provide care for 10 or more hours a week at the beginning of the period have a significantly reduced employment rate one wave later than those who do not provide care. The study therefore suggests that carers' employment may be negatively affected when care is provided at a lower intensity than is generally estimated in England. This has important implications for local authorities, who have a duty to provide services to carers whose employment is at risk. PMID- 23356686 TI - Echogenicity changes in the fetal brain, a 6-year follow-up study. AB - OBJECTIVE: To asses the relation between echogenicity changes in the fetal brain and neurodevelopmental outcome until 6 years of age. METHODS: Fetuses (n = 124) from pregnancies affected by hypertensive disorders (n = 64) or preterm labor (n = 60) at risk for preterm birth (26-34 weeks gestation) were studied. Moderate echogenicity changes (periventricular grade IB, II; intraventricular grade II III; local basal ganglia/thalami) in the fetal and neonatal brain were related to neurological outcome and Griffiths mental developmental scales quotients at 1, 2 and 6 years. Multiple regression analysis tested the influence of moderate echogenicity changes and perinatal clinical characteristics on composite outcome (death or abnormal neurodevelopment). RESULTS: Moderate echogenicity changes were present in 37/124 (30%) fetuses. Median gestational age and weight at birth were respectively 31 weeks (range 26-43), 1314 g (range 550-4330), mortality was 19%, follow-up loss 10%. Composite outcome was abnormal in 47/124 (38%). Fetal and neonatal moderate intraventricular echodensities were related to cerebral palsy at 6 years (p < 0.04). In the multiple regression analysis only gestational age was related to composite outcome (p = 0.005). CONCLUSIONS: Moderate intraventricular echodensities in the fetal brain related to cerebral palsy at 6 years of age. Gestational age at birth was the main predictor of abnormal composite outcome. PMID- 23356687 TI - Echocardiographic diagnosis and transcatheter occlusion of pulmonary arteriovenous fistula in cyanotic newborn. AB - Pulmonary arteriovenous malformation (PAVM) is a rare cause of cyanosis in newborn. A 12-day-old male newborn (2.8 kg) was referred to our hospital with the complaints of cyanosis and respiratory distress. On two-dimensional echocardiography, the right pulmonary artery (PA) appeared larger than left PA and the left atrium, left ventricle were dilated. The right heart chambers were in normal limits. A color flow Doppler echocardiogram revealed a turbulent flow due to a PAVM originating from medium branch of right PA, and continuous wave Doppler showed continuous flow pattern. Agitated saline injection resulted in the delayed appearance of the contrast in the left-side chambers three to four heart cycles after appearance in the right-side chambers; the study was considered positive and indicative of an intrapulmonary shunt. Selective angiography of the right PA confirmed the diagnosis of a large solitary PAVM in the right middle lobe with a feeding artery. Amplatzer vascular plug I, which is designed to close abnormal vascular structures, was chosen to close the PAVM. The deployment of device performed safely and the oxygen saturation of baby increased to 95% immediately after deployment. Heart failure and respiratory distress also resolved after the procedure. PMID- 23356688 TI - Assessment of the use of spectral domain optical coherence tomography (SD-OCT) for evaluation of the healthy and pathological cornea in dogs and cats. AB - PURPOSE: Morphologic evaluation of the cornea is based on the slit-lamp examination. In human ophthalmology, optical coherence tomography (OCT) has opened a new field in the clinical approach to anterior segment disorders and more specifically the cornea. The aim of our study is to describe spectral domain OCT examination of the cornea in dogs and cats in clinical practice conditions. MATERIAL AND METHODS: One hundred eyes were examined from 52 dogs and 41 cats presented to a private practice referral center with an Optovue iVue SD-OCT device. Sixteen healthy animals were used as control group, and the others were examined for various corneal conditions. All animals were examined after sedation or anesthesia. RESULTS: Normal and pathological aspects of canine and feline cornea were described for various conditions such as corneal ulcers, microbial keratitis, corneal sequestrum, infiltrations, foreign bodies, corneal dystrophies, and surgical conditions. CONCLUSION: SD-OCT examination of normal and pathological corneal conditions in dogs and cats gave an accurate evaluation of each component of the cornea. The advantage of the technique is the in vivo, real-time evaluation of all corneal layers with the absence of corneal contact. Constraints included the necessity of sedation for precise focus and the low quality of images obtained with too pigmented or thickened corneas. PMID- 23356690 TI - Special issue preface: complex systems in neurobiology. PMID- 23356689 TI - Surgery for acute gallbladder disease in Sweden 1989-2006--a register study. AB - OBJECTIVE: Since early 1970s, prospective randomized controlled trials have emphasized the advantages of early cholecystectomy in patients with acute cholecystitis, compared to elective delayed cholecystectomy. The aim of this investigation was to study surgery for acute gallbladder disease in Sweden during a 15-year period when open cholecystectomy was replaced by a laparoscopic procedure. MATERIAL AND METHODS: Data from the Swedish National Patient Register and the Cause of Death Register 1988-2006 comprising hospital stays with a primary diagnosis of gallbladder/gallstone disease in Sweden were retrieved. Patients were analyzed with reference to timing of cholecystectomy, length of hospital stay, and mortality. RESULTS: Emergency cholecystectomy at index (first) admission or at readmission within 2 years of index admission was performed in 32.2% and 6.1% of patients, respectively. Elective cholecystectomy within 2 years of index admission was performed in 20.3% patients, whereas 41.3% of all patients did not undergo cholecystectomy within 2 years. Standardized mortality ratio did not significantly change during the audit period. Total hospital stay (days at index stay and subsequent stay(s) for biliary diagnoses within 2 years) was shorter for patients who had emergency cholecystectomy at first admission compared to patients with later or no cholecystectomy within 2 years. CONCLUSIONS: Around 30% of patients with acute gallbladder disease were operated with cholecystectomy during the first admission with no time trend from 1990 through 2004. A total of 40% of patients with acute gallbladder disease were not cholecystectomized within 2 years. Analysis of outcome of long-term conservative treatment is warranted. PMID- 23356691 TI - Complexity in neurobiology: perspectives from the study of noise in human motor systems. AB - This article serves as an introduction to the themed special issue on "Complex Systems in Neurobiology." The study of complexity in neurobiology has been sensitive to the stochastic processes that dominate the micro-level architecture of neurobiological systems and the deterministic processes that govern the macroscopic behavior of these systems. A large body of research has traversed these scales of interest, seeking to determine how noise at one spatial or temporal scale influences the activity of the system at another scale. In introducing this special issue, we pay special attention to the history of inquiry in complex systems and why scientists have tended to favor linear, causally driven, reductionist approaches in Neurobiology. We follow this with an elaboration of how an alternative approach might be formulated. To illustrate our position on how the sciences of complexity and the study of noise can inform neurobiology, we use three systematic examples from the study of human motor control and learning: 1) phase transitions in bimanual coordination; 2) balance, intermittency, and discontinuous control; and 3) sensorimotor synchronization and timing. Using these examples and showing that noise is adaptively utilized by the nervous system, we make the case for the studying complexity with a perspective of understanding the macroscopic stability in biological systems by focusing on component processes at extended spatial and temporal scales. This special issue continues this theme with contributions in topics as diverse as neural network models, physical biology, motor learning, and statistical physics. PMID- 23356692 TI - When physics is not "just physics": complexity science invites new measurement frames for exploring the physics of cognitive and biological development. AB - The neurobiological sciences have struggled to resolve the physical foundations for biological and cognitive phenomena with a suspicion that biological and cognitive systems, capable of exhibiting and contributing to structure within themselves and through their contexts, are fundamentally distinct or autonomous from purely physical systems. Complexity science offers new physics-based approaches to explaining biological and cognitive phenomena. In response to controversy over whether complexity science might seek to "explain away" biology and cognition as "just physics," we propose that complexity science serves as an application of recent advances in physics to phenomena in biology and cognition without reducing or undermining the integrity of the phenomena to be explained. We highlight that physics is, like the neurobiological sciences, an evolving field and that the threat of reduction is overstated. We propose that distinctions between biological and cognitive systems from physical systems are pretheoretical and thus optional. We review our own work applying insights from post-classical physics regarding turbulence and fractal fluctuations to the problems of developing cognitive structure. Far from hoping to reduce biology and cognition to "nothing but" physics, we present our view that complexity science offers new explanatory frameworks for considering physical foundations of biological and cognitive phenomena. PMID- 23356693 TI - Fractal fluctuations and complexity: current debates and future challenges. AB - Complexity is perhaps one of the less properly understood concepts, even within the scientific community. Recent theoretical and experimental advances, however, based on the close relationship between the complexity of the system and the presence of 1/f fluctuations in its macroscopic behavior, have opened new domains of investigation, which consider fundamental questions as well as more applied perspectives. These approaches allow a better understanding of how essential macroscopic functions could emerge from complex interactive networks. In this review we present the current state of the theoretical debate about the origins of 1/f fluctuations, with special focus on recent hypotheses that establish a direct link between complexity and fractal fluctuations. Further, we clarify some lines of opposition, especially between idiosyncratic versus nomothetic conceptions, and global versus componential approaches. Finally, we discuss the deep questioning that this approach can generate with regard to current theories of motor control and psychological processes, as well as some future developments which may be evoked, especially in the domain of physical medicine and rehabilitation. PMID- 23356694 TI - Plasticity, learning, and complexity in spiking networks. AB - Complexity is widespread in neuronal spike trains and propagation of spike activity, in that variations in measurements of neural activity are irregular, heterogeneous, non-stationary, transient, and scale-free. There are numerous possible reasons for this complexity, and numerous possible consequences for neural and behavioral function. The present review is focused on relationships among neural plasticity, learning, and complex spike dynamics in animal nervous systems, including those of humans. The literature on complex spike dynamics and mechanisms of synaptic plasticity are reviewed for the purpose of considering the roles that each might play for the other. That is, the roles of complex spike dynamics in learning and regulatory functions are considered, as well as the roles of learning and regulatory functions in generating complex spike dynamics. Experimental and computational studies from a range of disciplines and perspectives are discussed, and it is concluded that cognitive science and neuroscience have much to gain from investigating the adaptive aspects of complex spike dynamics for neural and cognitive function. PMID- 23356695 TI - Landscape dynamics of motor learning and development. AB - Learning and development over the lifespan influence the dynamics of the human motor system. Our ideas about the dynamics of motor learning and development are grounded in the phenomena of the continuous evolution of movement patterns and outcomes over multiple time scales. In this review, we present examples of time scales distinguishing properties of motor learning and development, including the direction of change in the complexity of motor behavior, the transient and persistent processes of learning, scaling and transition properties of change, and consolidation effects of motor learning. The pathways of changes in movement dynamics over the lifespan are channelled by the confluence of constraints to action embedded in the interaction of the individual with the environment and with tasks at hand. PMID- 23356696 TI - Antimicrobial and antiproliferative activities of stingless bee Melipona scutellaris geopropolis. AB - BACKGROUND: Geopropolis is a type of propolis containing resin, wax, and soil, collected by threatened stingless bee species native to tropical countries and used in folk medicine. However, studies concerning the biological activity and chemical composition of geopropolis are scarce. In this study, we evaluated the antimicrobial and antiproliferative activity of the ethanolic extract of geopropolis (EEGP) collected by Melipona scutellaris and its bioactive fraction against important clinical microorganisms as well as their in vitro cytotoxicity and chemical profile. METHODS: The antimicrobial activity of EEGP and fractions was examined by determining their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against six bacteria strains as well as their ability to inhibit Streptococcus mutans biofilm adherence. Total growth inhibition (TGI) was chosen to assay the antiproliferative activity of EEGP and its bioactive fraction against normal and cancer cell lines. The chemical composition of M. scutellaris geopropolis was identified by reversed-phase high performance liquid chromatography and gas chromatography-mass spectrometry. RESULTS: EEGP significantly inhibited the growth of Staphylococcus aureus strains and S. mutans at low concentrations, and its hexane fraction (HF) presented the highest antibacterial activity. Also, both EEGP and HF inhibited S. mutans biofilm adherence (p < 0.05) and showed selectivity against human cancer cell lines, although only HF demonstrated selectivity at low concentrations. The chemical analyses performed suggest the absence of flavonoids and the presence of benzophenones as geopropolis major compounds. CONCLUSIONS: The empirical use of this unique type of geopropolis by folk medicine practitioners was confirmed in the present study, since it showed antimicrobial and antiproliferative potential against the cancer cell lines studied. It is possible that the major compounds found in this type of geopropolis are responsible for its properties. PMID- 23356697 TI - Who wears the pants in a mute swan pair? Deciphering the effects of male and female age and identity on breeding success. AB - Traditionally, many breeding traits (e.g. the timing and size of clutches) were considered to be female-only traits in that males played little-to-no role in their expression. Although the contribution of males to such breeding traits, as well as other aspects of reproduction, is increasingly recognized, few studies have demonstrated the effects of male age and life history on breeding traits and, importantly, whether these effects are underlined by additive-genetic variation. Here, we take advantage of a long-term data set on mute swans (Cygnus olor) to demonstrate that the ages of both the male and female parents play significant roles in the timing and size of clutches, although recruitment success did not show similar effects. Individual males varied significantly in their influence on the timing of egg laying. We decomposed this variation using an 'animal model'; competing models that were the source of this variation as additive-genetic or permanent-environmental variation was not statistically distinguishable. Our results add to the growing evidence that reproductive performance should be considered as a product of the identity and condition of both parents. PMID- 23356698 TI - Saengmaeksan inhibits inflammatory mediators by suppressing RIP-2/caspase-1 activation. AB - BACKGROUND AND OBJECTIVES: Saengmaeksan (SMS) is a Korean herbal prescription consisting of three different herbal drugs: Liriopis Tuber (tuber of Liriope platyphylla, Liliaceae), Ginseng Radix (root of Panax ginseng) and Schisandrae Fructus (fruit of Schisandra chinensis). SMS is commonly used in Korea to treat various diseases that involve the respiratory and cardiovascular systems. However, to date, the mechanism underlying the anti-inflammatory effects of SMS is not clearly understood. In this study, we attempt to determine the effects of SMS on lipopolysaccharide (LPS)-induced inflammatory responses in mouse peritoneal macrophages. METHODS: Cell viability was measured by using a 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and nitric oxide (NO) levels were measured by using Griess reagent. The tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 levels secreted by the cells were measured using a modified enzyme-linked immunosorbent assay. Expression of cyclooxygenase (COX)-2 and nuclear factor-kappa B (NF-kappaB), respectively was investigated using a western blot analysis. A caspase colorimetric assay kit was used to assay enzymatic caspase-1 activity. RESULTS: The findings of this study showed that SMS reduced TNF-alpha and IL-6 production induced by LPS. During the inflammatory process, COX-2 and NO levels were increased in mouse peritoneal macrophages, but SMS decreased the enhanced levels of COX-2 and the production of NO. In addition, SMS suppressed the activation of NF-kappaB and receptor interacting protein 2/caspase-1. DISCUSSION AND CONCLUSION: Our results provide novel insights into the pharmacological actions of SMS, a molecule that can potentially be exploited in the treatment of inflammatory diseases. PMID- 23356699 TI - RAMESES publication standards: meta-narrative reviews. AB - BACKGROUND: Meta-narrative review is one of an emerging menu of new approaches to qualitative and mixed-method systematic review. A meta-narrative review seeks to illuminate a heterogeneous topic area by highlighting the contrasting and complementary ways researchers have studied the same or a similar topic. No previous publication standards exist for the reporting of meta-narrative reviews. This publication standard was developed as part of the RAMESES (Realist And MEta narrative Evidence Syntheses: Evolving Standards) project. The project's aim is to produce preliminary publication standards for meta-narrative reviews. DESIGN: A mixed method study synthesising data between 2011 to 2012 from a literature review, online Delphi panel and feedback from training, workshops and email list. METHODS: We: (a) collated and summarized existing literature on the principles of good practice in meta-narrative reviews; (b) considered the extent to which these principles had been followed by published reviews, thereby identifying how rigor may be lost and how existing methods could be improved; (c) used a three-round online Delphi method with an interdisciplinary panel of national and international experts in evidence synthesis, meta-narrative reviews, policy, and/or publishing to produce and iteratively refine a draft set of methodological steps, and publication standards; (d) provided real-time support to ongoing meta narrative reviews and the open-access RAMESES online discussion list so as to capture problems and questions as they arose; and (e) synthesized expert input, evidence review, and real-time problem analysis into a definitive set of standards. RESULTS: We identified nine published meta-narrative reviews, provided real-time support to four ongoing reviews, and captured questions raised in the RAMESES discussion list. Through analysis and discussion within the project team, we summarized the published literature, and common questions and challenges into briefing materials for the Delphi panel, comprising 33 members. Within three rounds this panel had reached consensus on 20 key publication standards, with an overall response rate of 90%. CONCLUSIONS: This project used multiple sources to draw together evidence and expertise in meta-narrative reviews. For each item we have included an explanation for why it is important and guidance on how it might be reported. Meta-narrative review is a relatively new method for evidence synthesis and as experience and methodological developments occur, we anticipate that these standards will evolve to reflect further theoretical and methodological developments. We hope that these standards will act as a resource that will contribute to improving the reporting of meta-narrative reviews. PMID- 23356700 TI - Geographic parthenogenesis and plant-enemy interactions in the common dandelion. AB - BACKGROUND: Many species with sexual and asexual variants show a pattern of geographic parthenogenesis where asexuals have broader and higher-latitude distribution than sexuals. Because sexual reproduction is often considered a costly evolutionary strategy that is advantageous in the face of selection by coevolving pests and pathogens, one possible explanation for geographic parthenogenesis is that populations at higher latitudes are exposed to fewer pests and pathogens. We tested this hypothesis in the common dandelion (Taraxacum officinale), a species with well-established geographic parthenogenesis, by screening prevalence and effects of several specialized pests and pathogens in natural dandelion populations. RESULTS: We did a population survey of 18 dandelion populations along a geographic transect that ranged from the area where sexual and asexual dandelions co-occur northward into the area where only asexuals occur. In addition we used four southern and four northern populations in a 8x8 cross-inoculation greenhouse experiment in which plants were exposed experimentally to each other's natural field soil microbial communities. The cross-inoculation experiment indicated a higher pathogenicity of soil microbial communities from the southern, mostly sexual, populations compared to soil microbial communities from the northern asexual populations. Northern dandelion populations also showed reduced infestation by a specialized seed-eating weevil. A similar trend of reduced rust fungus infection in northern populations was observed but this trend was not statistically significant. CONCLUSIONS: The prevalence of pests and pathogens decreased along the south-to-north axis of geographic parthenogenesis. This highlights the potential of biotic interactions in shaping patterns of geographic parthenogenesis. PMID- 23356703 TI - Prothrombotic mechanisms and anticoagulant therapy in dogs with immune-mediated hemolytic anemia. AB - OBJECTIVE: To review the pathophysiology of thrombosis in hemolytic disease, and the efficacy of thromboprophylaxis in dogs with immune-mediated hemolytic anemia (IMHA). DATA SOURCES: Computerized searches of Pubmed, INDEX VETERINARIUS, and the journal database of the Veterinary Information Network, and a manual search of bibliographies of published manuscripts. HUMAN DATA SYNTHESIS: Experimental data suggest that hemolysis leads to the induction of the potent procoagulant tissue factor on monocytes and endothelial cells and subsequent activation of coagulation. In addition, damaged red cells, activated platelets, and small cell derived membrane vesicles called microparticles may contribute to coagulation by providing membrane surfaces containing exposed anionic phospholipids that serve as docking sites for prothrombinase (factor Va-factor Xa) and tenase (factor VIIIa-factor IXa) complexes of the coagulation cascade. Some microparticles also contain tissue factor, further fueling coagulation. Thromboprophylaxis for hemolytic disease in people primarily targets the coagulation cascade rather than platelets, as most thromboemboli are of venous rather than arterial origin. The use of unfractionated heparin is closely monitored to ensure therapeutic levels are reached. VETERINARY DATA SYNTHESIS: Thromboembolic disease is a major factor affecting survival in dogs with IMHA. It is likely that hemolysis contributes to the prothrombotic state. Thrombosis occurs in both veins and arteries, with pulmonary thromboembolism (a venous thrombus) occurring very commonly. Evidence suggests that tissue factor mediates the development of the prothrombotic state. Heparin, and the anti-platelet agents aspirin, and clopidogrel have been used for thromboprophylaxis in dogs with IMHA. However, a lack of validated therapeutic endpoints and controlled studies make it difficult to determine if survival is affected or if 1 drug is more effective than another. CONCLUSIONS: Prospective clinical trials comparing individually adjusted heparin or other anti-coagulant drugs to anti-platelet drugs are needed to make evidence-based recommendations for thromboprophylaxis in dogs with IMHA. PMID- 23356704 TI - Effects of compressive abdominal bandaging and transrectal palpation on intra abdominal pressures in horses. AB - OBJECTIVE: To determine the effect of an abdominal support wrap and transrectal abdominal palpation on intra-abdominal pressures (IAPs) measured directly from the peritoneal space. DESIGN: Prospective, experimental study. SETTING: A university-based equine research facility. ANIMALS: Ten healthy adult horses, 5 males and 5 females. INTERVENTIONS: IAPs were measured through an intraperitoneal cannula zeroed at a height midway between the height of the tuber ishii and point of the shoulder. Triplicate measurements were obtained at rest, during transrectal palpation, after placement of an abdominal support wrap, and during transrectal palpation with the support wrap still in place. Simultaneous mean arterial pressures were obtained using a tail cuff and abdominal perfusion pressures were calculated using the measured IAP minus the measured mean arterial pressures. MEASUREMENTS AND MAIN RESULTS: Baseline direct pressure measurements were subatmospheric (-4.5 +/- 3.0 cm H(2) O). IAPs were not significantly affected by transrectal palpation, but were significantly increased after placement of an abdominal support wrap (-1.19 +/- 3.01 cm H(2) O; P = 0.01). Abdominal perfusion pressures were not significantly affected by either transrectal palpation or application of the support wrap. CONCLUSION: IAPs were significantly increased after application of an abdominal support wrap commonly used after exploratory laparotomy. Further investigations are warranted to determine the clinical implications of abdominal bandaging on IAP and its implications on postoperative complications including intra-abdominal hypertension. However, transrectal abdominal palpation likely does not contribute to abdominal hypertension in normal horses. PMID- 23356705 TI - Gunshot wounds in military working dogs in Operation Enduring Freedom and Operation Iraqi Freedom: 29 cases (2003-2009). AB - OBJECTIVE: To describe the patient population, injuries, and treatment received on the battlefield, and ultimate outcome of U.S. military working dogs that incurred gunshot wound (GSW) injury in Operation Enduring Freedom (Afghanistan) or Operation Iraqi Freedom (Iraq). DESIGN: Retrospective study between January 2003 and December 2009. ANIMALS: Twenty-nine military working dogs from the U.S. military with confirmed GSW injuries incurred in combat in Operation Enduring Freedom or Operation Iraqi Freedom. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical data from battlefield treatment, which includes care from the point of injury through arrival to, but not including, a designated veterinary treatment facility. Twenty-nine dogs were injured between 2003 and 2009. All but one of the injuries were from high caliber, high velocity weapons. Of the 29 injured dogs, 11 survived the injuries and 18 died (38% survival rate). Of the dogs that died, all but 1 died from catastrophic nonsurvivable injuries before treatment or evacuation could be instituted. The thorax was the most common site of injury (50%) followed by extremity wounds (46%). The leading cause of death from GSWs was from thoracic wounds, followed by head wounds. Dogs with extremity wounds as their only injury were most likely to survive, and dogs with multiple injuries were least likely to survive. All surviving dogs received treatment at the point of injury by military medics and dog handlers consistent with Tactical Combat Casualty Care guidelines for combat injuries in human service members. Of the 11 that survived, all dogs returned to full duty with subsequent deployment to combat zones. Location of wounds and injury severity at the time of presentation to veterinary care was not correlated with length of time until return to duty. PMID- 23356701 TI - What is metabolic syndrome, and why are children getting it? AB - Metabolic syndrome comprises a cluster of cardiovascular risk factors (hypertension, altered glucose metabolism, dyslipidemia, and abdominal obesity) that occur in obese children. However, metabolic syndrome can also occur in lean individuals, suggesting that obesity is a marker for the syndrome, not a cause. Metabolic syndrome is difficult to define, due to its nonuniform classification and reliance on hard cutoffs in the evaluation of disorders with non-Gaussian distributions. Defining the syndrome is even more difficult in children, owing to racial and pubertal differences and lack of cardiovascular events. Lipid partitioning among specific fat depots is associated with insulin resistance, which can lead to mitochondrial overload and dysfunctional subcellular energy use and drive the various elements of metabolic syndrome. Multiple environmental factors, in particular a typical Western diet, drive mitochondrial overload, while other changes in Western society, such as stress and sleep deprivation, increase insulin resistance and the propensity for food intake. These culminate in an adverse biochemical phenotype, including development of altered glucose metabolism and early atherogenesis during childhood and early adulthood. PMID- 23356706 TI - Falsely increased plasma lactate concentration due to ethylene glycol poisoning in 2 dogs. AB - OBJECTIVE: To describe false increases in plasma lactate concentration measured on point-of-care analyzers in 2 dogs with ethylene glycol (EG) intoxication. CASE SUMMARY: Two dogs presenting with EG intoxication had extreme increases of plasma lactate concentrations recorded on a point-of-care machine. Laboratory analysis by spectrophotometry of lactate concentration determined these lactate measurements to be erroneous. False increases in plasma lactate concentration were demonstrated in 2 out of 3 point-of-care machines tested. NEW OR UNIQUE INFORMATION PROVIDED: Glycolate, a toxic metabolite of EG, can interfere with the measurement of plasma lactate by some analyzers and this may delay the correct diagnosis of EG toxicity if not recognized. PMID- 23356710 TI - Lactation reduces glial activation induced by excitotoxicity in the rat hippocampus. AB - Motherhood induces a series of adaptations in the physiology of the female, including an increase of maternal brain plasticity and a reduction of cell damage in the hippocampus caused by kainic acid (KA) excitotoxicity. We analysed the role of lactation in glial activation in the hippocampal fields of virgin and lactating rats after i.c.v. application of 100 ng of KA. Immunohistochemical analysis for glial fibrillary acidic protein (GFAP) and ionised calcium binding adaptor molecule 1 (Iba-1), which are markers for astrocytes and microglial cell surface proteins, respectively, revealed differential cellular responses to KA in lactating and virgin rats. A significant astrocyte and microglial response in hippocampal areas of virgin rats was observed 24 h and 72 h after KA. By contrast, no increase in either GFAP- or Iba-1-positive cells was observed in response to KA in the hippocampus of lactating rats. Western blot analysis of GFAP showed an initial decrease at 24 h after KA treatment, with an increase at 72 h in the whole hippocampus of virgin but not of lactating rats. The number of GFAP-positive cells was increased by lactation in the dentate gyrus of the hippocampus but not in CA1 and CA3 areas. The present results indicate that lactating rats exhibit diminished responses of astrocyte and microglial cells in the hippocampus to damage induced by KA, supporting the notion that the maternal hippocampus is resistant to excitotoxic insults. PMID- 23356711 TI - Does arterio-venous fistula creation affects development of pulmonary hypertension in hemodialysis patients? AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a common complication in hemodialysis (HD) patients and its pathogenesis is not explained clearly. Arterio venous fistulas (AVFs) creation may contribute to the development of PAH because of increased pulmonary artery blood flow. However, it was not prospectively evaluated that effect of AVF on the development of PAH. AIM: We aimed to evaluate the effects of AVF on PAH and the relationship between blood flow rate of AVF and pulmonary artery pressure (PAP) in HD patients. PATIENTS AND METHOD: The prospective study included 50 patients with end-stage renal disease. Before an AVF was surgically created for hemodialysis, the patients were evaluated by echocardiography. Then, an AVF was surgically created in the patients. After mean 76.14 +/- 11.37 days, the second evaluation was performed by echocardiography. RESULTS: Before AVF creation, 17 (34%) out of 50 patients had PAH. The systolic PAP was significantly higher in the patients with PAH compared with patients without PAH (47.82 +/- 9.82 mmHg vs. 30.15 +/- 5.70 mmHg, respectively, p = 0.001). In the second evaluation, 19 (38%) out of 50 patients had PAH. The systolic PAP values were significantly higher in the patients with PAH compared with patients without PAH (47.63 +/- 8.92 mmHg vs. 25.03 +/- 7.69 mmHg, P = 0.001, respectively). There was no relationship between the blood flow rate of AVF and PAP. CONCLUSION: PAH is a common problem in HD patients. AVF has no significant effect on the development of PAH within a short period. Similarly, blood flow rate of AVF also did not affect remarkably the systolic PAP. PMID- 23356712 TI - Special Issue from the NSERC Bioconversion network workshop: pretreatment and fractionation of biomass for biorefinery/biofuels. PMID- 23356713 TI - Comparison of survival of patients with metastases from known versus unknown primaries: survival in metastatic cancer. AB - BACKGROUND: Cancer of unknown primary site (CUP) is considered an aggressive metastatic disease but whether the prognosis differs from metastatic cancers of known primary site is not known. Such data may give insight into the biology of CUP and the metastatic process in general. METHODS: 6,745 cancer patients, with primary metastatic cancer at diagnosis, were identified from the Swedish Cancer Registry, and were compared with 2,881 patients with CUP. Patients were diagnosed and died between 2002 and 2008. The influence of the primary site, known or unknown, on survival in patients with metastases at specific locations was investigated. Hazard ratios (HRs) of death were estimated for several sites of metastasis, where patients with known primary sites were compared with CUP patients. RESULTS: Overall, patients with metastatic cancers with known primary sites had decreased hazards of death compared to CUP patients (HR = 0.69 [95% CI = 0.66-0.72]). The exceptions were cancer of the pancreas (1.71 [1.54-1.90]), liver (1.58 [1.36-1.85]), and stomach (1.16 [1.02-1.31]). For individual metastatic sites, patients with liver or bone metastases of known origin had better survival than those with CUP of the liver and bone. Patients with liver metastases of pancreatic origin had an increased risk of death compared with patients with CUP of the liver (1.25 [1.06-1.46]). The median survival time of CUP patients was three months. CONCLUSIONS: Patients with CUP have poorer survival than patients with known primaries, except those with brain and respiratory system metastases. Of CUP sites, liver metastases had the worst prognosis. Survival in CUP was comparable to that in metastatic lung cancer. The aggressive behavior of CUP may be due to initial immunosuppression and immunoediting which may allow accumulation of mutations. Upon escape from the suppressed state an unstoppable tumor spread ensues. These novel data on the epidemiology of the metastatic process at the population level demonstrated large survival differences in organ defined metastases depending on the original cancer. PMID- 23356714 TI - Development and evaluation of a replicon particle vaccine expressing the E2 glycoprotein of bovine viral diarrhea virus (BVDV) in cattle. AB - BACKGROUND: Bovine viral diarrhea virus is one of the most significant and costly viral pathogens of cattle worldwide. Alphavirus-derived replicon particles have been shown to be safe and highly effective vaccine vectors against a variety of human and veterinary pathogens. Replicon particles are non-propagating, DIVA compatible, and can induce both humoral and cell mediated immune responses. This is the first experiment to demonstrate that Alphavirus-based replicon particles can be utilized in a standard prime/boost vaccination strategy in calves against a commercially significant bovine pathogen. FINDINGS: Replicon particles that express bovine viral diarrhea virus sub-genotype 1b E2 glycoprotein were generated and expression was confirmed in vitro using polyclonal and monoclonal antibodies specific to E2. Vaccine made from particles was generated in Vero cells and administered to BVDV free calves in a prime/boost regimen at two dosage levels. Vaccination resulted in neutralizing antibody titers that cross neutralized both type 1 and type 2 BVD genotypes following booster vaccination. Additionally, high dose vaccine administration demonstrated some protection from clinical disease and significantly reduced the degree of leukopenia caused by viral infection. CONCLUSIONS: Replicon particle vaccines administered in a prime/boost regimen expressing BVDV E2 glycoprotein can induce cross-neutralizing titers, reduce leukopenia post challenge, and mitigate clinical disease in calves. This strategy holds promise for a safe and effective vaccine to BVDV. PMID- 23356715 TI - Fetal frontomaxillary facial angle between 11 and 13 + 6 weeks of gestation in a Brazilian population: influence of different races. AB - OBJECTIVE: To evaluate the influence of different races over the measurement of the frontomaxillary facial angle between 11 and 13 + 6 weeks of pregnancy in a Brazilian population. METHODS: A cross-sectional study was conducted with 332 healthy pregnant women, with a crown-rump length (CRL) between 47 and 84 mm. Such measurements were taken abdominally, using the mid-sagittal plane, and the angle was measured by tracing a line over the palate and a line from the anterosuperior maxillary angle all the way to the external part of the forehead. As for the reference intervals, a simple linear regression between the frontomaxillary facial angle and the CRL was used, as well as Pearson's correlation coefficient (r). To evaluate the difference between races, a variance analysis was used (ANOVA). To calculate reproducibility, the intraclass correlation coefficient (ICC) was used. RESULTS: The means for the fetal frontomaxillary facial angle in white, black and mixed races were 81.8 +/- 6.6; 82.2 +/- 6.1 and 81.4 +/- 6.2 mm, respectively. There was no statistical difference between races (p = 0.713). A decreasing correlation between the frontomaxillary facial angle and the CRL was observed for the black (r = -0.450) and mixed (r = -0.212) races. Excellent intraobserver reproducibility was observed, as well as a satisfactory interobserver reproducibility, with ICC of 0.858 and 0.605, respectively. CONCLUSION: There were no significative statistical differences in the measurement of the fetal frontomaxillary facial angle between 11 and 13 + 6 weeks of pregnancy in the different races in a Brazilian population. PMID- 23356716 TI - Miniaturized handheld confocal microscopy identifies focal brain invasion in a mouse model of aggressive meningioma. AB - Invasion of the brain parenchyma by a meningioma classified by histological criteria as World Health Organization (WHO) grade I meningioma, implies that the tumor has greater likelihood of recurrence and a biological behavior similar to the more aggressive WHO grade II meningiomas. It is therefore important to detect microscopic foci of brain invasion during surgery in order to maximize the resection and/or adapt imaging follow-up. In this study, we tested the sensitivity of two handheld confocal imaging devices to detect foci of brain invasion in two types of meningioma mouse models: in a genetically engineered mouse model and in a syngeneic xenograft model. Confocal imaging offered precise images of meningothelial and fibroblastic mouse meningiomas as well as malignant meningiomas, which corresponded exactly to the pathological findings. Imaging showed a sharp definition of the brain-tumor interface and enabled identification of embedded nerves and vessels. Importantly, in both mouse models used in this study, extension of tumor along Virchow-Robin spaces into adjacent brain was detected by imaging. In conclusion, this novel technique, following validation in clinical trials, may open new possibilities for use in operating rooms to influence both decision making during the surgery and planning for additional treatments. PMID- 23356717 TI - A trial of patient-oriented problem-solving system for immunology teaching in China: a comparison with dialectic lectures. AB - BACKGROUND: The most common teaching method used in China is lecturing, but recently, efforts have been widely undertaken to promote the transition from teacher-centered to student-centered education. The patient-oriented problem solving (POPS) system is an innovative teaching-learning method that permits students to work in small groups to solve clinical problems, promotes self learning, encourages clinical reasoning and develops long-lasting memory. To our best knowledge, however, POPS has never been applied in teaching immunology in China. The aim of this study was to develop POPS in teaching immunology and assess students' and teachers' perception to POPS. METHODS: 321 second-year medical students were divided into two groups: I and II. Group I, comprising 110 students, was taught by POPS, and 16 immunology teachers witnessed the whole teaching process. Group II including the remaining 211 students was taught through traditional lectures. The results of the pre- and post-test of both groups were compared. Group I students and teachers then completed a self structured feedback questionnaire for analysis before a discussion meeting attended only by the teachers was held. RESULTS: Significant improvement in the mean difference between the pre- and post-test scores of those in Groups I and II was seen, demonstrating the effectiveness of POPS teaching. Most students responded that POPS facilitates self-learning, helps them to understand topics and creates interest, and 88.12% of students favored POPS over simple lectures. Moreover, while they responded that POPS facilitated student learning better than lectures, teachers pointed out that limited teaching resources would make it difficult for wide POPS application in China. CONCLUSIONS: While POPS can break up the monotony of dialectic lectures and serve as a better teaching method, it may not be feasible for the current educational environment in China. The main reason for this is the relative shortage of teaching resources such as space, library facilities and well-trained teachers. PMID- 23356718 TI - Parent- and self-reported dimensions of oppositionality in youth: construct validity, concurrent validity, and the prediction of criminal outcomes in adulthood. AB - BACKGROUND: Different dimensions of oppositional defiant disorder (ODD) have been found as valid predictors of further mental health problems and antisocial behaviors in youth. The present study aimed at testing the construct, concurrent, and predictive validity of ODD dimensions derived from parent- and self-report measures. METHOD: Confirmatory factor analyses were performed to test a three dimensional model (ODD-irritability, ODD-headstrong, and ODD-hurtful) and a two dimensional model (ODD-irritability, ODD-headstrong/hurtful) based on items of the Child Behavior Checklist (CBCL) and the Youth Self Report (YSR) collected in a Swiss community study of 1,031 adolescents (519 boys, 512 girls) aged between 10.7 and 17.9 (M = 13.85, SD = 1.63) years. Logistic regression analyses were applied to predict scores in the clinical range of concurrent CBCL/YSR anxiety/depression, CBCL/YSR-attention problems, and CBCL/YSR-delinquent behavior and depression as measured by the Center for Epidemiological Studies Depression Scale (CES-D) as well as to predict the presence of adult criminal convictions. RESULTS: CFA findings were in favor of a three-dimensional model rather than a two-dimensional model of ODD. The CBCL/YSR-ODD-irritability scale was related to concurrent self-reported depression, but also to attention problems and delinquent behavior. CBCL/YSR-ODD-hurtful and less strongly also the combined YSR headstrong/hurtful scale predicted adult criminal outcomes. CONCLUSIONS: As proposed by the DSM-5 workgroup, different ODD-dimensions were confirmed by the present study. ODD-irritability predicts psychiatric comorbidity and ODD-hurtful symptoms should be specifically considered in youth at risk for criminal outcomes. PMID- 23356719 TI - Kinetic and equilibrium aspects of adsorption and desorption of class II hydrophobins HFBI and HFBII at silicon oxynitride/water and air/water interfaces. AB - Hydrophobins are relatively small globular proteins produced by filamentous fungi. They display unusual high surface activity and are implied as mediators of attachment to surfaces, which has resulted in high scientific and technological interest. In this work we focus on kinetic and equilibrium aspects of adsorption and desorption properties of two representatives of class II hydrophobins, namely HFBI and HFBII, at a negatively charged hydrophilic solid/water interface and at the air/water interface. The layers formed at the air/liquid interface were examined in a Langmuir trough, whereas layers formed at the solid/liquid interface were studied using dual polarization interferometry (DPI) under different flow conditions. For comparison, another globular protein, lysozyme, was also investigated. It was found that both the adsorbed amount and the adsorption kinetics were different for HFBI and HFBII, and the adsorption behavior of both hydrophobins on the negatively charged surface displayed some unusual features. For instance, even though the adsorption rate for HFBI was slowed down with increasing adsorbed amount as expected from packing constraints at the interface, the adsorption kinetics curves for HFBII displayed a region indicating adsorption cooperativity. Further, it was found that hydrophobin layers formed under flow partly desorbed when the flow was stopped, and the desorption rate for HFBII was enhanced in the presence of hydrophobins in solution. PMID- 23356720 TI - Cost-utility analysis of the inhaled steroids available in a developing country for the management of pediatric patients with persistent asthma. AB - INTRODUCTION: The choice among the different treatments available can have a great impact on the costs of asthma, OBJECTIVES: The objective of this study was to estimate the incremental cost-utility ratio of three inhaled corticosteroids (ICs): budesonide (BUD), fluticasone propionate (FP), and ciclesonide, compared to beclomethasone dipropionate (BDP) (the only IC included in the Compulsory Health Insurance Plan of Colombia), METHODS: A Markov-type model was developed to estimate costs and health outcomes of a simulated cohort of patients less than 18 years of age with persistent asthma treated over a 12-month period. Effectiveness parameters were obtained from a systematic review of the literature. Cost data were obtained from a hospital's bills and from the national manual of drug prices. The study assumed the perspective of the national healthcare in Colombia. The main outcome was the variable "quality-adjusted life years" (QALY), RESULTS: While treatment with BDP was associated with the lowest cost (L106.16 average cost per patient during 12 months), treatment with FP resulted in the greatest gain in QUALYs (0.9325 QALYs). FP was associated with a greater gain in QALYs compared to BUD and ciclesonide (0.9325 vs. 0.8999 and 0.9051 QALYs, respectively) at lower costs (L231.19 vs. L309.27 and L270.15, respectively), thus leading to dominance. The incremental cost-utility ratio of FP compared to BDP was L19,835.28 per QALY, CONCLUSIONS: BDP is the most cost-effective therapy for treating pediatric patients with persistent asthma when willingness to pay (WTP) is less than L21,129.22/QALY, otherwise, FP is the most cost-effective therapy. PMID- 23356721 TI - Small bowel angiodysplasia and novel disease associations: a cohort study. AB - OBJECTIVE: Gastrointestinal angiodysplasias recurrently bleed, accounting for 3 5% of obscure gastrointestinal bleeding. The advent of small bowel capsule endoscopy (SBCE) has led to an increased recognition of small bowel angiodysplasias (SBAs) but little is known about their etiology. Previous small cohorts and case reports suggest an equal gender incidence and associations with cardiovascular disease, renal impairment, and coagulopathies. METHODS: Patients with SBA were identified from our SBCE database. A control group, in whom gastrointestinal bleeding had been excluded, was also identified. Information on patient demographics, past medical/surgical/social history and medications was prospectively obtained. RESULTS: A total of 82 patients and 95 controls were identified. Data was available from 81% (n = 66) of SBA patients. The mean age of patients and controls was 66.9 years (35-90) and 69.2 years (54-77), and 60% (n = 40) and 58% (n = 55) were females, respectively. There was a higher rate of all comorbidities in the SBA group 92% (61/66) versus controls 76% (72/95) p < 0.002. Significant associations were found with: hypertension (odds ratio [OR] 2.8), ischemic heart disease (OR 4.25), arrhythmias (OR 4.36), valvular heart disease (OR 18), congestive heart failure (OR 4.22), chronic kidney disease (CKD) (OR 8.4), chronic respiratory conditions (OR 2.0), and previous venous thromboembolism (VTE) (OR 6.4). Anticoagulant use was higher in patients with SBA, 50% (n = 33) versus 27% (n = 26) of controls, p < 0.002, specifically warfarin and asasantin retard. CONCLUSIONS: SBA occurs in elderly patients with cardiovascular disease and CKD, as previously suggested. This study identifies a previously unrecognised risk in females, patients with chronic respiratory conditions and VTE, and the use of warfarin and asasantin retard. These associations should raise awareness of possible underlying SBA in risk patients with anemia. PMID- 23356722 TI - Intra and inter-user reliability of central corneal thickness measurements obtained in healthy feline eyes using a portable spectral-domain optical coherence tomography device. AB - OBJECTIVE: To determine the intra and inter-user reliability of central corneal thickness (CCT) measurements obtained using a portable spectral-domain optical coherence tomography (SD-OCT) device in healthy feline eyes. ANIMALS: Twenty clinically normal cats. PROCEDURES: Gentle manual restraint was utilized for proper animal positioning. Central corneal thickness measurements were obtained from both eyes of each animal three times by two operators in succession. A 6 mm, corneal pachymetry protocol was performed using the Optovue(r) iVue SD-OCT system. The CCT was automatically calculated using the pachymetry software generated from eight radial scans, 6 mm in length. The CCT was recorded for each operator and compared statistically for both intra and inter-user reliability. RESULTS: Twenty cats (11 CM, 9 SF) with a mean age of 4.7 years were examined. The mean CCT for all eyes examined was 629.08 +/- 47.05 MUm. No significant difference in CCT was found based on the eye examined (OD vs. OS) or age of the animal. However, the CCT of spayed females was significantly higher (42.64 +/- 18.0 MUm) as compared to castrated males (P = 0.03). There was no significant difference in CCT measurements between replicates performed by the same operator or between operators. The mean difference in CCT between operators was 0.38 MUm. The coefficient of variation for each user and between users was very low (range 0.68-1.5%). The intra-class correlation coefficient comparing operators was 0.975. CONCLUSIONS: The Optovue(r) iVue SD-OCT device is capable of obtaining CCT measurements with excellent intra and interoperator reliability in healthy feline eyes. PMID- 23356723 TI - Association between CD8+ T-cell subsets and cardiovascular disease. AB - BACKGROUND: The findings of experimental studies suggest that the immune system plays a key role in atherosclerosis, but the clinical importance of different immune cells in cardiovascular disease remains poorly characterized. In this study we investigated the association between CD8(+) T cells and carotid disease as well as development of cardiovascular disease events. METHODS: The study cohort comprised 700 subjects from the cardiovascular arm of the Malmo Diet and Cancer Study. Peripheral blood mononuclear cells, obtained at the 1991-1994 baseline investigation and stored at -140 degrees C, were thawed and the different CD8(+) T-cell populations analysed by flow cytometry. Baseline carotid intima-media thickness and stenosis were assessed by ultrasonography and clinical events were monitored through validated national registers. RESULTS: Subjects with a high fraction of CD8(+) T cells were characterized by decreased cytokine release from activated leucocytes, metabolic signs of insulin resistance and increased incidence of coronary events; hazard ratios (95% confidence intervals) for the second and third tertiles of CD8(+) T cells were 2.57 (1.16, 5.67) and 2.61 (1.19, 5,71), respectively, in a Cox proportional hazards regression model. Correlations were found between the fraction of CD8(+) CD25(+) T cells and the degree of carotid stenosis (r = 0.11, P < 0.01), and between the CD8(+) CD56(-) IFN-gamma(+) T-cell fraction and the degree of stenosis (r = -0.18, P < 0.005). The association between CD8(+) CD56(-) IFN-gamma(+) T cells and carotid stenosis remained significant after controlling for major cardiovascular disease risk factors. CONCLUSION: This study provides prospective clinical evidence for a role of CD8(+) T cells in cardiovascular disease and suggests the existence of CD8(+) T-cell subsets with different pathological functions. PMID- 23356724 TI - Myogenic tone is impaired at low arterial pressure in mice deficient in the low voltage-activated CaV 3.1 T-type Ca(2+) channel. AB - AIM: Using mice deficient in the CaV 3.1 T-type Ca(2+) channel, the aim of the present study was to elucidate the molecular identity of non-L-type channels involved in vascular tone regulation in mesenteric arteries and arterioles. METHODS: We used immunofluorescence microscopy to localize CaV 3.1 channels, patch clamp electrophysiology to test the effects of a putative T-type channel blocker NNC 55-0396 on whole-cell Ca(2+) currents, pressure myography and Ca(2+) imaging to test diameter and Ca(2+) responses of the applied vasoconstrictors, and Q-PCR to check mRNA expression levels of several Ca(2+) handling proteins in wild-type and CaV 3.1(-/-) mice. RESULTS: Our data indicated that CaV 3.1 channels are important for the maintenance of myogenic tone at low pressures (40 80 mm Hg), whereas they are not involved in high-voltage-activated Ca(2+) currents, Ca(2+) entry or vasoconstriction to high KCl in mesenteric arteries and arterioles. Furthermore, we show that NNC 55-0396 is not a specific T-type channel inhibitor, as it potently blocks L-type and non-L-type high-voltage activated Ca(2+) currents in mouse mesenteric vascular smooth muscle cell. CONCLUSION: Our data using mice deficient in the CaV 3.1 T-type channel represent new evidence for the involvement of non-L-type channels in arteriolar tone regulation. We showed that CaV 3.1 channels are important for the myogenic tone at low arterial pressure, which is potentially relevant under resting conditions in vivo. Moreover, CaV 3.1 channels are not involved in Ca(2+) entry and vasoconstriction to large depolarization with, for example, high KCl. Finally, we caution against using NNC 55-0396 as a specific T-type channel blocker in native cells expressing high-voltage-activated Ca(2+) channels. PMID- 23356726 TI - RAMESES publication standards: realist syntheses. AB - BACKGROUND: There is growing interest in realist synthesis as an alternative systematic review method. This approach offers the potential to expand the knowledge base in policy-relevant areas - for example, by explaining the success, failure or mixed fortunes of complex interventions. No previous publication standards exist for reporting realist syntheses. This standard was developed as part of the RAMESES (Realist And MEta-narrative Evidence Syntheses: Evolving Standards) project. The project's aim is to produce preliminary publication standards for realist systematic reviews. DESIGN: A mixed method study synthesising data between 2011-2012 from a literature review, online Delphi panel and feedback from training, workshops and email list. METHODS: We: (a) collated and summarized existing literature on the principles of good practice in realist syntheses; (b) considered the extent to which these principles had been followed by published syntheses, thereby identifying how rigour may be lost and how existing methods could be improved; (c) used a three-round online Delphi method with an interdisciplinary panel of national and international experts in evidence synthesis, realist research, policy and/or publishing to produce and iteratively refine a draft set of methodological steps and publication standards; (d) provided real-time support to ongoing realist syntheses and the open-access RAMESES online discussion list to capture problems and questions as they arose; and (e) synthesized expert input, evidence syntheses and real-time problem analysis into a definitive set of standards. RESULTS: We identified 35 published realist syntheses, provided real-time support to 9 ongoing syntheses and captured questions raised in the RAMESES discussion list. Through analysis and discussion within the project team, we summarized the published literature and common questions and challenges into briefing materials for the Delphi panel, comprising 37 members. Within 3 rounds this panel had reached consensus on 19 key publication standards, with an overall response rate of 91%. CONCLUSIONS: This project used multiple sources to develop and draw together evidence and expertise in realist synthesis. For each item we have included an explanation for why it is important and guidance on how it might be reported. Realist synthesis is a relatively new method for evidence synthesis and as experience and methodological developments occur, we anticipate that these standards will evolve to reflect further methodological developments. We hope that these standards will act as a resource that will contribute to improving the reporting of realist syntheses. PMID- 23356725 TI - Genome-wide analysis of histone modifiers in tomato: gaining an insight into their developmental roles. AB - BACKGROUND: Histone post-translational modifications (HPTMs) including acetylation and methylation have been recognized as playing a crucial role in epigenetic regulation of plant growth and development. Although Solanum lycopersicum is a dicot model plant as well as an important crop, systematic analysis and expression profiling of histone modifier genes (HMs) in tomato are sketchy. RESULTS: Based on recently released tomato whole-genome sequences, we identified in silico 32 histone acetyltransferases (HATs), 15 histone deacetylases (HDACs), 52 histone methytransferases (HMTs) and 26 histone demethylases (HDMs), and compared them with those detected in Arabidopsis (Arabidopsis thaliana), maize (Zea mays) and rice (Oryza sativa) orthologs. Comprehensive analysis of the protein domain architecture and phylogeny revealed the presence of non-canonical motifs and new domain combinations, thereby suggesting for HATs the existence of a new family in plants. Due to species specific diversification during evolutionary history tomato has fewer HMs than Arabidopsis. The transcription profiles of HMs within tomato organs revealed a broad functional role for some HMs and a more specific activity for others, suggesting key HM regulators in tomato development. Finally, we explored S. pennellii introgression lines (ILs) and integrated the map position of HMs, their expression profiles and the phenotype of ILs. We thereby proved that the strategy was useful to identify HM candidates involved in carotenoid biosynthesis in tomato fruits. CONCLUSIONS: In this study, we reveal the structure, phylogeny and spatial expression of members belonging to the classical families of HMs in tomato. We provide a framework for gene discovery and functional investigation of HMs in other Solanaceae species. PMID- 23356727 TI - The STROBE statement and neuropsychology: lighting the way toward evidence-based practice. AB - Reporting appropriate research detail across clinical disciplines is often inconsistent or incomplete. Insufficient report detail reduces confidence in findings, makes study replication more difficult, and decreases the precision of data available for critical review including meta-analysis. In response to these concerns, cooperative attempts across multiple specialties have developed explicit research reporting standards to guide publication detail. These recommendations have been widely adopted by high impact medical journals, but have not yet been widely embraced by neuropsychology. The STROBE Statement (STrengthening the Reporting of Observational studies in Epidemiology) is particularly relevant to neuropsychology since clinical research is often based on non-funded studies of patient samples. In this paper we describe the STROBE Statement and demonstrate how STROBE criteria, applied to reporting of neuropsychological findings, will maintain neuropsychology's position as a leader in quantifying brain-behavior relationships. We also provide specific recommendations for data reporting and disclosure of perceived conflicts of interest that will further enhance reporting transparency for possible perceived sources of bias. In an era in which evidence-based practice assumes an increasingly prominent role, improved reporting standards will promote better patient care, assist in developing quality practice guidelines, and ensure that neuropsychology remains a vigorous discipline in the clinical neurosciences that consciously aspires to high methodological rigor. PMID- 23356728 TI - Comprehensive review of generalized anxiety disorder in primary care in Europe. AB - OBJECTIVE: This review aims to summarize meta-analyses and other relevant data relating to the efficacy and safety of the various treatment options for generalized anxiety disorder (GAD) in Europe. In addition, it will provide an overview of the prevalence, burden, and recognition of the disorder, with a view to raise awareness of GAD and inform primary care practitioners. RESEARCH DESIGN AND METHODS: Relevant research or review articles on psychological or pharmacological treatments for GAD published in the English language between March 2006 and March 2012 were identified via a literature search in PubMed and ISI Web of Knowledge and from the Cochrane Library. Other relevant references/clinical guidelines were individually selected by the authors. RESULTS: Prevalence rates of GAD vary across Europe but its economic and social burden is increasing. A large proportion of patients with GAD present with symptoms in primary care. However, due to the disorder's complexity and the incidence of comorbid diseases, some primary care physicians may lack the knowledge or confidence to effectively recognize, manage, and/or treat the disorder. This is despite psychological and pharmacological treatments being available for the effective management of GAD. CONCLUSIONS: GAD remains a difficult disorder to detect and comorbid complications add to its economic and social burden. Early detection and intervention reduces the societal burden and improves GAD patients' quality of life and functional ability. Primary care practitioners play a key role in identifying and treating patients with GAD. PMID- 23356730 TI - Antipsychotic polypharmacy increases metabolic dysregulation in female rats. AB - Antipsychotic polypharmacy refers to the clinical practice of treating a patient with two or more antipsychotic drugs concurrently. There is abundant evidence in the clinical literature that treatment with antipsychotic polypharmacy is associated with an increased prevalence of drug side effects compared with monotherapy. This includes drug-induced metabolic side effects, such as glucose intolerance and insulin resistance. As these metabolic side effects have been accurately modeled in preclinical rodent paradigms using drug monotherapy, the goal of the present study was to determine the metabolic effects of antipsychotic polypharmacy using an established rodent model. In the first experiment, adult female rats were treated with clozapine (5 mg/kg), risperidone (1 mg/kg), vehicle, or clozapine + risperidone. In the second experiment, rats were treated with clozapine (5 mg/kg), haloperidol (0.1 mg/kg), vehicle, or clozapine + haloperidol. Animals were then subjected to a glucose tolerance test. Compared with vehicle-treated control animals, risperidone and haloperidol had no effect on any of the metabolic indices when administered on their own. Addition of risperidone to clozapine significantly increased fasting glucose, fasting insulin, and insulin resistance compared with the clozapine-only group. The addition of haloperidol to clozapine significantly increased fasting insulin levels, insulin resistance, and glucose intolerance compared with clozapine-only rats. These results are consistent with clinical studies and therefore indicate that animal models can successfully be used to study the metabolic side effects of antipsychotic drugs. Future studies related to understanding the physiological mechanisms involved remain a priority. PMID- 23356729 TI - Early and prolonged exposure to reward delay: effects on impulsive choice and alcohol self-administration in male rats. AB - Naturally occurring impulsive choice has been found to positively predict alcohol consumption in rats. However, the extent to which experimental manipulation of impulsive choice may modify alcohol consumption remains unclear. In the present study, we sought to: (a) train low levels of impulsive choice in rats using early, prolonged exposure to reward delay, and (b) determine the effects of this manipulation on subsequent alcohol consumption. During a prolonged training regimen, three groups of male, adolescent Long-Evans rats (21-22 days old at intake) responded on a single lever for food rewards delivered after either a progressively increasing delay, a fixed delay, or no delay. Posttests of impulsive choice were conducted, as was an evaluation of alcohol consumption using a limited-access, two-bottle test. Following delay-exposure training, both groups of delay-exposed rats made significantly fewer impulsive choices than did rats in the no-delay group. In addition, fixed-delay rats consumed significantly more alcohol during daily, 30-min sessions than no-delay rats. Possible mechanisms of these effects are discussed, as is the significance of these findings to nonhuman models of addiction. PMID- 23356731 TI - Analysis of cigarette purchase task instrument data with a left-censored mixed effects model. AB - The drug purchase task is a frequently used instrument for measuring the relative reinforcing efficacy (RRE) of a substance, a central concept in psychopharmacological research. Although a purchase task instrument, such as the cigarette purchase task (CPT), provides a comprehensive and inexpensive way to assess various aspects of a drug's RRE, the application of conventional statistical methods to data generated from such an instrument may not be adequate by simply ignoring or replacing the extra zeros or missing values in the data with arbitrary small consumption values, for example, 0.001. We applied the left censored mixed effects model to CPT data from a smoking cessation study of college students and demonstrated its superiority over the existing methods with simulation studies. Theoretical implications of the findings, limitations of the proposed method, and future directions of research are also discussed. PMID- 23356732 TI - Minimally invasive transcrestal guided sinus lift (TGSL): a clinical prospective proof-of-concept cohort study up to 52 months. AB - PURPOSE: This study describes a new procedure for sinus elevation using computer guided planning and guided surgical approach through the use of computer-aided design (CAD)/computer-aided manufacturing (CAM)-generated surgical template in combination with expander-condensing osteotomes thus providing a minimally invasive surgical technique. MATERIALS AND METHODS: Sixty-six consecutive patients were treated with 136 implants placed by transcrestal-guided sinus floor elevation technique and the patients were followed for at least 3 years in function. The drilling protocol is customized based on the bone density of each implant site to achieve an insertion torque ranging between 45 and 55 Ncm. Titanium temporary abutments were connected to the implants with prosthetic screws tightened to 35 Ncm and an acrylic resin provisional restoration was adapted and delivered immediately. Six months after initial loading, a definitive CAD/CAM-generated restoration was delivered. Outcome measurements assessed were implant and prosthesis survival rate, biological or biomechanical complications, marginal bone level changes, total alveolar ridge bone height before and after procedure, periodontal parameters measured as well as patient's perception of pain levels during recovery period. RESULTS: Mean follow-up was 43.96 (range from 36 to 52) months. Cumulative implant survival rate was 98.53% at 3 years. No biological or mechanical complications were encountered and no prosthetic failures occurred during the entire follow-up period. Mean marginal bone loss (MBL) during the first year of function was 0.33 +/- 0.36 mm, while at the 3-year follow-up, the mean MBL was 0.51 +/- 0.29 mm. The mean residual bone height of the alveolar crest prior to grafting was of 6.7 +/- 1.6 mm (range 5.1-9.2 mm), while, the mean bone height gained was 6.4 +/- 1.6 mm (range 3.2-8.1 mm). All patients reported low levels of pain and found to have normal periodontal parameters. CONCLUSION: This proof-of-concept study suggests that the use of guided surgery to perform transcrestal maxillary sinus floor elevation for alveolar ridge height augmentation is a successful minimally invasive technique for the short- to medium-term follow-up, thus avoiding the extended treatment time and morbidities associated with maxillary sinus floor augmentation. PMID- 23356733 TI - Understanding of alkaline pretreatment parameters for corn stover enzymatic saccharification. AB - BACKGROUND: Previous research on alkaline pretreatment has mainly focused on optimization of the process parameters to improve substrate digestibility. To achieve satisfactory sugar yield, extremely high chemical loading and enzyme dosages were typically used. Relatively little attention has been paid to reduction of chemical consumption and process waste management, which has proven to be an indispensable component of the bio-refineries. To indicate alkali strength, both alkali concentration in pretreatment solution (g alkali/g pretreatment liquor or g alkali/L pretreatment liquor) and alkali loading based on biomass solids (g alkali/g dry biomass) have been widely used. The dual approaches make it difficult to compare the chemical consumption in different process scenarios while evaluating the cost effectiveness of this pretreatment technology. The current work addresses these issues through pretreatment of corn stover at various combinations of pretreatment conditions. Enzymatic hydrolysis with different enzyme blends was subsequently performed to identify the effects of pretreatment parameters on substrate digestibility as well as process operational and capital costs. RESULTS: The results showed that sodium hydroxide loading is the most dominant variable for enzymatic digestibility. To reach 70% glucan conversion while avoiding extensive degradation of hemicellulose, approximately 0.08 g NaOH/g corn stover was required. It was also concluded that alkali loading based on total solids (g NaOH/g dry biomass) governs the pretreatment efficiency. Supplementing cellulase with accessory enzymes such as alpha-arabinofuranosidase and beta-xylosidase significantly improved the conversion of the hemicellulose by 6-17%. CONCLUSIONS: The current work presents the impact of alkaline pretreatment parameters on the enzymatic hydrolysis of corn stover as well as the process operational and capital investment costs. The high chemical consumption for alkaline pretreatment technology indicates that the main challenge for commercialization is chemical recovery. However, repurposing or co-locating a biorefinery with a paper mill would be advantageous from an economic point of view. PMID- 23356734 TI - TaASR1, a transcription factor gene in wheat, confers drought stress tolerance in transgenic tobacco. AB - Abscisic acid (ABA)-, stress-, and ripening-induced (ASR) proteins are reported to be involved in abiotic stresses. However, it is not known whether ASR genes confer drought stress tolerance by utilizing the antioxidant system. In this study, a wheat ASR gene, TaASR1, was cloned and characterized. TaASR1 transcripts increased after treatments with PEG6000, ABA and H(2)O(2). Overexpression of TaASR1 in tobacco resulted in increased drought/osmotic tolerance, which was demonstrated that transgenic lines had lesser malondialdehyde (MDA), ion leakage (IL) and reactive oxygen species (ROS), but higher relative water content (RWC) and superoxide dismutase (SOD) and catalase (CAT) activities than wild type (WT) under drought stress. Overexpression of TaASR1 in tobacco also enhanced the expression of ROS-related and stress-responsive genes under osmotic stress. In addition, transgenic lines exhibited improved tolerance to oxidative stress by retaining more effective antioxidant system. Finally, TaASR1 was localized in the cell nucleus and functioned as a transcriptional activator. Taken together, our results showed that TaASR1 functions as a positive factor under drought/osmotic stress, involved in the regulation of ROS homeostasis by activating antioxidant system and transcription of stress-associated genes. PMID- 23356735 TI - How community organizations moderate the effect of armed conflict on migration in Nepal. AB - This study analyses micro-level variability in migration during armed conflict in Nepal. The analysis is based on a multi-dimensional model of individual out migration that examines the economic, social, and political consequences of conflict and how community organizations condition the experience of these consequences and systematically alter migration patterns. Detailed data on violent events and individual behaviour during the Maoist insurrection in Nepal and multi-level event-history analysis were used to test the model. The results indicate that community organizations reduced the effect of conflict on out migration by providing resources that helped people cope with danger, as well as with the economic, social, and political consequences of the conflict. The evidence suggests that the conflict caused the population to be systematically redistributed in a way that will probably affect its future socio-demographic composition--the extent of the redistribution depending on the resources available in each community. PMID- 23356736 TI - Major cluster of chilblain cases in a cold dry Western Australian winter. AB - AIM: Primary chilblains are an idiopathic cold-induced vasculopathy affecting the soft tissues of the hands and feet. Secondary chilblains occur in different forms of vasculitis and chronic autoimmune connective tissue disorders. Idiopathic chilblains are rarely reported in children and may generate significant anxiety to doctors and patients. We describe a cluster of idiopathic chilblains encountered over the winter of 2010 in Perth, Western Australia. METHODS: This is a retrospective review of patients identified from a prospectively compiled database of all new cases seen in our department. Data on history, examination, investigations, prescribed treatments and outcomes were collected. RESULTS: Thirty-two patients with isolated idiopathic chilblains were included, including 20 females and 12 males with a median age at onset of 13.5 years. Lesions were papular with signs of peripheral vasoconstriction causing acrocyanosis, and uncomfortable due to pain and/or pruritis in most. Thickening of the small joints was common where lesions involved these areas. Ulceration of lesions also occurred in some. One patient required hospitalisation for secondary bacterial infection. Most received some form of treatment including non-steroidal anti inflammatory drugs, prednisolone or nifedipine. Most patients improved spontaneously with warmer weather or responded to cold protection advice. All had resolved completely by late spring (November). CONCLUSION: Our cluster of chilblains was associated with an unusually cold winter in Perth 2010. It is the largest series reported in the literature, suggesting that chilblains may be more common than previously thought. Chilblains are almost always benign in nature and patients are systemically well and usually need no further investigation and only symptomatic treatment. Prompt recognition can avoid excessive investigation and anxiety, allowing appropriate simple advice and treatment. PMID- 23356737 TI - Risk factors for peripartum hysterectomy following uterine rupture. AB - OBJECTIVE: To investigate risk factors for hysterectomy following uterine rupture. METHODS: A population-based study comparing all uterine ruptures with and without hysterectomy between 1988 and 2011 was conducted. Stratified analysis was performed using a multiple logistic regression analysis. RESULTS: Peripartum hysterectomy complicated 20.7% (n = 34) of uterine ruptures during the study period (n = 164). Independent risk factors for hysterectomy following uterine rupture, from a multivariable logistic regression model, were relaparotomy (OR = 32.2, 95% CI = 2.5-421.9), extended tears involving the uterine cervix (OR = 6.1, 95% CI = 1.5-24.7), severe bleeding requiring packed cells transfusions (OR = 13.7, 95% CI = 3.2-58.5) and grand multiparity (>=5 deliveries, OR = 11.4 95% CI = 2.7-47.1). CONCLUSION: Hysterectomy is not common following uterine rupture. Independent risk factors for hysterectomy include relaparotomy, extended tears involving the uterine cervix, severe bleeding requiring packed cells transfusions and grand multiparity. Trained obstetricians should be involved in cases of uterine rupture and the possibility for conducting hysterectomy should be emphasized. PMID- 23356738 TI - Changes in red blood cell membrane structure in type 2 diabetes: a scanning electron and atomic force microscopy study. AB - Red blood cells (RBCs) are highly deformable and possess a robust membrane that can withstand shear force. Previous research showed that in diabetic patients, there is a changed RBC ultrastructure, where these cells are elongated and twist around spontaneously formed fibrin fibers. These changes may impact erythrocyte function. Ultrastructural analysis of RBCs in inflammatory and degenerative diseases can no longer be ignored and should form a fundamental research tool in clinical studies. Consequently, we investigated the membrane roughness and ultrastructural changes in type 2 diabetes. Atomic force microscopy (AFM) was used to study membrane roughness and we correlate this with scanning electron microscopy (SEM) to compare results of both the techniques with the RBCs of healthy individuals. We show that the combined AFM and SEM analyses of RBCs give valuable information about the disease status of patients with diabetes. Effectiveness of treatment regimes on the integrity, cell shape and roughness of RBCs may be tracked, as this cell's health status is crucial to the overall wellness of the diabetic patient. PMID- 23356740 TI - A comparison of the signalling properties of two tyramine receptors from Drosophila. AB - In invertebrates, the phenolamines, tyramine and octopamine, mediate many functional roles usually associated with the catecholamines, noradrenaline and adrenaline, in vertebrates. The alpha- and beta-adrenergic classes of insect octopamine receptor are better activated by octopamine than tyramine. Similarly, the Tyramine 1 subgroup of receptors (or Octopamine/Tyramine receptors) are better activated by tyramine than octopamine. However, recently, a new Tyramine 2 subgroup of receptors was identified, which appears to be activated highly preferentially by tyramine. We examined immunocytochemically the ability of CG7431, the founding member of this subgroup from Drosophila melanogaster, to be internalized in transfected Chinese hamster ovary (CHO) cells by different agonists. It was only internalized after activation by tyramine. Conversely, the structurally related receptor, CG16766, was internalized by a number of biogenic amines, including octopamine, dopamine, noradrenaline, adrenaline, which also were able to elevate cyclic AMP levels. Studies with synthetic agonists and antagonists confirm that CG16766 has a different pharmacological profile to that of CG7431. Species orthologues of CG16766 were only found in Drosophila species, whereas orthologues of CG7431 could be identified in the genomes of a number of insect species. We propose that CG16766 represents a new group of tyramine receptors, which we have designated the Tyramine 3 receptors. PMID- 23356741 TI - Cholesteryl phosphocholine--a study on its interactions with ceramides and other membrane lipids. AB - We prepared cholesteryl phosphocholine (CholPC) by chemical synthesis and studied its interactions with small (ceramide and cholesterol) and large headgroup (sphingomyelin (SM) and phosphatidylcholine) colipids in bilayer membranes. We established that CholPC could form bilayers (giant uni- and multilamellar vesicles, as well as extruded large unilamellar vesicles) with both ceramides and cholesterol (initial molar ratio 1:1). The extruded bilayers appeared to be fluid, although highly ordered, even when the ceramide had an N-linked palmitoyl acyl chain. In binary systems containing CholPC and either palmitoyl SM or 1,2 dipalmitoyl-sn-glycero-3-phospholine, CholPC markedly destabilized the gel phase of the respective large headgroup lipid. In 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC) bilayers, CholPC was much less efficient than cholesterol in ordering the acyl chains. In complex bilayers containing POPC and cholesterol or palmitoyl ceramide, CholPC appeared to prefer interacting with the small headgroup lipids over POPC. When the degree of order in CholPC/PCer bilayers was compared to Chol/PSM bilayers, CholPC/PCer bilayers were more disordered (based on DPH anisotropy). This finding may result from different headgroup orientation and dynamics in CholPC and PSM. Our results overall can be understood if one takes into account the molecular shape of CholPC (large polar headgroup and modest size hydrophobic part) when interpreting molecular interactions between small and large headgroup colipids. The results are also consistent with the proposed umbrella model" for explaining cholesterol/colipid interactions. PMID- 23356739 TI - Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells. AB - BACKGROUND: Post-translational modifications (PTMs) of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of interest as potential cancer chemopreventive agents. In this study we assessed the effects of the phytocompounds garcinol and curcumin on histone and p53 modification in cancer cells, focussing on the breast tumour cell line MCF7. METHODS: Cell viability/proliferation assays, cell cycle analysis by flow cytometry, immunodetection of specific histone and p53 acetylation marks, western blotting, siRNA and RT-qPCR. RESULTS: Although treatment with curcumin, garcinol or the garcinol derivative LTK-14 hampered MCF7 cell proliferation, differential effects of these compounds on histone modifications were observed. Garcinol treatment resulted in a strong reduction in H3K18 acetylation, which is required for S phase progression. Similar effects of garcinol on H3K18 acetylation were observed in the osteosarcoma cells lines U2OS and SaOS2. In contrast, global levels of acetylated H4K16 and trimethylated H4K20 in MCF7 cells were elevated after garcinol treatment. This was accompanied by upregulation of DNA damage signalling markers such as gammaH2A.X, H3K56Ac, p53 and TIP60. In contrast, exposure of MCF7 cells to curcumin resulted in increased global levels of acetylated H3K18 and H4K16, and was less effective in inducing DNA damage markers. In addition to its effects on histone modifications, garcinol was found to block CBP/p300-mediated acetylation of the C-terminal activation domain of p53, but resulted in enhanced acetylation of p53K120, and accumulation of p53 in the cytoplasmic compartment. Finally, we show that the elevation of H4K20Me3 levels by garcinol correlated with increased expression of SUV420H2, and was prevented by siRNA targeting of SUV420H2. CONCLUSION: In summary, although garcinol and curcumin can both inhibit histone acetyltransferase activities, our results show that these compounds have differential effects on cancer cells in culture. Garcinol treatment alters expression of chromatin modifying enzymes in MCF7 cells, resulting in reprogramming of key histone and p53 PTMs and growth arrest, underscoring its potential as a cancer chemopreventive agent. PMID- 23356744 TI - A case-mix-adjusted comparison of early oncological outcomes of open and robotic prostatectomy performed by experienced high volume surgeons. PMID- 23356742 TI - Differential unfolded protein response during Chikungunya and Sindbis virus infection: CHIKV nsP4 suppresses eIF2alpha phosphorylation. AB - Chikungunya (CHIKV) and Sindbis (SINV) are arboviruses belonging to the alphavirus genus within the Togaviridae family. They cause frequent epidemics of febrile illness and long-term arthralgic sequelae that affect millions of people each year. Both viruses replicate prodigiously in infected patients and in vitro in mammalian cells, suggesting some level of control over the host cellular translational machinery that senses and appropriately directs the cell's fate through the unfolded protein response (UPR). The mammalian UPR involves BIP (or GRP78), the master sensor in the endoplasmic reticulum (ER) together with the three downstream effector branches: inositol-requiring ser/thr protein kinase/endonuclease (IRE-1), PKR-like ER resident kinase (PERK) and activating transcription factor 6 (ATF-6). Through careful analysis of CHIKV and SINV infections in cell culture we found that the former selectively activates ATF-6 and IRE-1 branches of UPR and suppresses the PERK pathway. By separately expressing each of the CHIKV proteins as GFP-fusion proteins, we found that non structural protein 4 (nsP4), which is a RNA-dependent-RNA polymerase, suppresses the serine-51 phosphorylation of eukaryotic translation initiation factor, alpha subunit (eIF2alpha), which in turn regulates the PERK pathway. This study provides insight into a mechanism by which CHIKV replication responds to overcome the host UPR machinery. PMID- 23356745 TI - Comprehensive analysis of clinical trials data shows unequivocally that Phosphodiesterase Inhibitors (PDEi) improve orgasm. The power of meta-analysis? PMID- 23356746 TI - Is there enough evidence for the use of intravesical instillations of glycosaminoglycan analogues in interstitial cystitis? PMID- 23356747 TI - A case-mix-adjusted comparison of early oncological outcomes of open and robotic prostatectomy performed by experienced high volume surgeons. AB - OBJECTIVE: To compare early oncological outcomes of robot assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) performed by high volume surgeons in a contemporary cohort. METHODS: We reviewed patients who underwent radical prostatectomy for prostate cancer by high volume surgeons performing RALP or ORP. Biochemical recurrence (BCR) was defined as PSA >= 0.1 ng/mL or PSA >= 0.05 ng/mL with receipt of additional therapy. A Cox regression model was used to evaluate the association between surgical approach and BCR using a predictive model (nomogram) based on preoperative stage, grade, volume of disease and PSA. To explore the impact of differences between surgeons, multivariable analyses were repeated using surgeon in place of approach. RESULTS: Of 1454 patients included, 961 (66%) underwent ORP and 493 (34%) RALP and there were no important differences in cancer characteristics by group. Overall, 68% of patients met National Comprehensive Cancer Network (NCCN) criteria for intermediate or high risk disease and 9% had lymph node involvement. Positive margin rates were 15% for both open and robotic groups. In a multivariate model adjusting for preoperative risk there was no significant difference in BCR rates for RALP compared with ORP (hazard ratio 0.88; 95% CI 0.56-1.39; P = 0.6). The interaction term between nomogram risk and procedure type was not statistically significant. Using NCCN risk group as the covariate in a Cox model gave similar results (hazard ratio 0.74; 95% CI 0.47-1.17; P = 0.2). The interaction term between NCCN risk and procedure type was also non-significant. Differences in BCR rates between techniques (4.1% vs 3.3% adjusted risk at 2 years) were smaller than those between surgeons (2.5% to 4.8% adjusted risk at 2 years). CONCLUSIONS: In this relatively high risk cohort of patients undergoing radical prostatectomy we found no evidence to suggest that ORP resulted in better early oncological outcomes then RALP. Oncological outcome after radical prostatectomy may be driven more by surgeon factors than surgical approach. PMID- 23356748 TI - Non-steroidal anti-inflammatory drugs for lower urinary tract symptoms in benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: To assess the effects of non-steroidal anti-inflammatory drugs (NSAIDs) in men with benign prostatic hyperplasia (BPH) using systematic review and meta-analysis of clinical trials. SUBJECTS: Men treated with NSAIDs in comparison with placebo or other BPH medications. METHODS: All aspects of the Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) statement were followed. Trials were eligible for inclusion provided they (i) randomized men with BPH to receive NSAIDs in comparison with placebo or other BPH medications, and (ii) included clinical outcomes such as urological symptom scales, symptoms or urodynamic measurements. Data analysis was performed using REVIEW MANAGER Version 5.0 software. Study weight was calculated by the inverse variances of the study effect estimates. RESULTS: In all, 183 men from three randomized, placebo-controlled trials (lasting 4-24 weeks) were assessed. NSAIDs improved urinary symptom scores and flow measures. The weighted mean difference for the International Prostate Symptom Score (IPSS) was -2.89 IPSS points (95% CI -3.84 to -1.95, P < 0.001, n = 3 studies). The weighted mean difference for peak urine flow was 0.89 mL/s (95% CI 0.21-1.58, P = 0.01, n = 3 studies) and for reported adverse effects was 1.51 (95% CI 0.66-3.43, P = 0.32, n = 3 studies,). All patients assigned to NSAIDs continued the treatment. There were no serious adverse effects and there were no withdrawals or losses to follow-up. CONCLUSION: The evidence suggests that NSAIDs improve urinary symptoms and flow measures. Their long-term effectiveness, safety and ability to prevent BPH complications are not known. PMID- 23356749 TI - Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo-controlled studies. AB - OBJECTIVES: To compare effects of tadalafil on ejaculatory and orgasmic function in patients presenting with erectile dysfunction (ED). To determine the effects of post-treatment ejaculatory dysfunction (EjD) and orgasmic dysfunction (OD) on measures of sexual satisfaction. PATIENTS AND METHODS: Data from 17 placebo controlled 12-week trials of tadalafil (5, 10, 20 mg) as needed in patients with ED were integrated. EjD and OD severities were defined by patient responses to the International Index of Erectile Function, question 9 (IIEF-Q9; ejaculation) and IIEF-Q10 (orgasm), respectively. Satisfaction was evaluated using the intercourse and overall satisfaction domains of the IIEF and Sexual Encounter Profile question 5. Analyses of covariance were performed to compare mean ejaculatory function and orgasmic function, and chi-squared tests evaluated differences in endpoint responses to IIEF-Q9 and IIEF-Q10. RESULTS: A total of 3581 randomized subjects were studied. Treatment with tadalafil 10 or 20 mg was associated with significant increases in ejaculatory and orgasmic function (vs placebo) across all baseline ED, EjD, and OD severity strata. In the tadalafil group, 66% of subjects with severe EjD reported improved ejaculatory function compared with 36% in the placebo group (P < 0.001). Similarly, 66% of the tadalafil-treated subjects (vs 35% for placebo; P < 0.001) with severe OD reported improvement. Residual severe EjD and OD after treatment had negative impacts on sexual satisfaction. Limitations of the analysis include its retrospective nature and the use of an instrument (IIEF) with as yet unknown performance in measuring treatment responses for EjD and OD. CONCLUSIONS: Tadalafil treatment was associated with significant improvements in ejaculatory function, orgasmic function and sexual satisfaction. Proportions of subjects reporting improved ejaculatory or orgasmic function were ~ twofold higher with tadalafil than with placebo. These findings warrant corroboration in prospective trials of patients with EjD or OD (without ED). PMID- 23356750 TI - Diagnostic tests in urology: percutaneous biopsy of renal masses. PMID- 23356753 TI - Leading and educating leaders. PMID- 23356751 TI - Upper gastrointestinal bleeding: incidence, etiology and outcomes in a population based setting. AB - OBJECTIVE: The authors aimed to investigate the incidence and outcomes of acute upper gastrointestinal bleeding (AUGIB) and to examine the role of drugs potentially associated with AUGIB. METHODS: The study was prospective, population based and consisted of all patients who underwent upper gastrointestinal endoscopy (UGE), during the year of 2010 at the National University Hospital of Iceland. Drug intake of NSAIDs, low-dose aspirin (LDA), warfarin, SSRIs and bisphosphonates prior to GIB was prospectively registered and also checked in a Pharmaceutical Database covering all prescriptions in Iceland. An age- and gender matched control group consisted of patients who underwent UGE during the study period and were without GIB. RESULTS: A total of 1731 patients underwent 2058 UGEs. Overall, 156 patients had AUGIB. The crude incidence for AUGIB was 87/100,000 inhabitants per year. The most common etiologies were duodenal (21%) and gastric ulcers (15%). Use of LDA (40% vs. 30%), NSAIDs (20% vs. 8%), warfarin (15% vs. 7%), combination of NSAIDs + LDA (8% vs. 1%) and SSRIs + LDA (8% vs. 3%) were significantly more common among bleeders than non-bleeders. Three patients (1.9%) had emergency surgery and two patients died of AUGIB. Independent predictors of clinically significant bleeding were gastric ulcer (OR 6.6, p = 0.012) and NSAIDs (OR 6.6, p = 0.004). CONCLUSIONS: LDA, NSAIDs and warfarin play an important role in AUGIB etiology and particularly combinations of drugs. Gastric ulcer and NSAIDs were independent predictors of severe bleeding. Mortality and the need for surgery during hospitalization was low in this population-based setting. PMID- 23356754 TI - On teaching leadership and management. PMID- 23356752 TI - Pegylated interferon monotherapy in patients with chronic hepatitis C with low viremia and its relationship to mutations in the NS5A region and the single nucleotide polymorphism of interleukin-28B. AB - AIM: Previous studies have suggested that patients with chronic hepatitis C with a low pretreatment hepatitis C virus (HCV) level have a high sustained virological response (SVR) rate, and that there would be a subpopulation of patients in which HCV can be eradicated with pegylated interferon (PEG IFN) alone without a decrease in SVR. However, the efficacy of PEG IFN monotherapy in patients with low HCV RNA levels is unclear. Several studies have reported that interferon sensitivity-determining region (ISDR) and the single-nucleotide polymorphism (SNP) of interleukin-28B (IL-28B) contribute to IFN response, but these relationships are controversial. The aim of this study was to determine whether the SNP of IL-28B (rs8099917) and amino acid substitutions in the ISDR among patients with low HCV levels affect the response to PEG IFN monotherapy. METHODS: One hundred and four patients with low-level HCV infection were studied. Low HCV level was defined as 100 KIU/mL or less. RESULTS: SVR was achieved in 94 patients (92.2%). HCV levels (<=50 KIU/mL) and ISDR (>=2 mutations) were associated with SVR on univariate analysis. The rates of SVR in the patients with IL-28B genotypes TT, TG and GG were 94.5%, 77.8% and 100%, respectively. The G allele tended to be associated with poor response to IFN therapy (P = 0.0623). On multivariate analysis, the ISDR was the factor predictive of SVR (P = 0.004). CONCLUSION: The ISDR is significantly associated with a good response to PEG IFN monotherapy in patients with low HCV levels. PMID- 23356755 TI - 'Empowering employment' for practice nurses. PMID- 23356756 TI - The challenge of leadership education in primary care in the UK. PMID- 23356757 TI - Leadership training: fitness for purpose or fitness for the future? PMID- 23356758 TI - Revalidation: helping leaders to promote insight and avoid isolation. PMID- 23356759 TI - Building a clinical leadership community to drive improvement: a multi-case educational study to inform 21st century clinical commissioning, professional capability and patient care. AB - The new NHS requires transformational leadership; people with the knowledge and motivation to make effective change combined with an understanding of the system they work in. The aim of the Practice Leaders' Programme (PLP) is to generate the conditions needed to focus the energy and collaborative creativity required for innovation to enhance leadership skills across the health economy improving patient care. The PLP engaged 60 local leaders from central England in a new approach enabling them to influence others. It has informed educational policy and practice and helped change professional behaviours. Each participant implemented improvements in care and participated in six action learning sets (ALS) and up to six coaching sessions. Evidence of progress, learning and impact was identified in project reports, reflective diaries and evaluations. The ALS brought together key individuals from clinical and management disciplines across a diverse organisation to redesign a system by developing a shared vision for improving the quality of patient care. The links forged, the projects initiated, and the skills cultivated through the PLP produced ongoing benefits and outcomes beyond the course itself. Coaching sessions helped participants focus their efforts to achieve maximum impact and to become resilient in managing service change effectively. The programme has evolved over four years, building on recommendations from external evaluation which identified statistically significant increases in leadership competences. Further enhancement of this programme secured an International Health Improvement Award. Three key findings of positive impact have emerged; personal growth, service improvement, and legacy and sustainability. PMID- 23356760 TI - The Medical Leadership Competency Framework: challenges raised for GP educators by a pilot study of culture in general practice. PMID- 23356761 TI - The Medical Leadership Competency Framework: response to challenges raised for GP educators. PMID- 23356762 TI - Translation of the Medical Leadership Competency Framework into a multisource feedback form for doctors in training using a verbal protocol technique. AB - This study describes the use of think-aloud techniques to capture the reactions of doctors in training, educational supervisors and clinical directors to a draft multisource feedback (MSF) tool. The tool is based on the competencies described in the Medical Leadership Competency Framework (MLCF), which is now a part of most postgraduate medical curricula. In order to reflect properly the extent to which doctors in training have developed the appropriate competencies, the MSF needs to modify the terminology used in the MLCF. This study of 24 doctors, of whom nine were doctors in training, showed that the draft MSF tested needed to be modified in order to differentiate clearly between situations where the assessed doctor had not had adequate opportunity to demonstrate competence, and those where competence was deemed inadequate. More senior doctors tended to favour longer, more detailed MSF questionnaires, possibly reflecting their experience of how MSF can prove valuable in personal development. However, some educational supervisors found an estimated completion time of 25 minutes to be a deterrent. Five doctors from general practice, two of whom were trainees, were included in this small qualitative study, which identified a greater facility for observing and assessing leadership competency development in primary care than in hospital specialities. This finding needs to be tested in a large-scale study of a modified MSF tool. PMID- 23356763 TI - An educational leadership responsibility in primary care: ensuring the physical space for learning aligns with the educational mission. PMID- 23356764 TI - Developing the high-flying registrar: a qualitative evaluation of the Severn Deanery education scholar programme. AB - The introduction of the Education Scholarship and Education Fellowship programmes in the Severn Deanery in 2008 was in response to an emergent need for a more formalised career structure for the most able GPSTs and specifically for identified education scholars to progress over time from a scholar to temporary and substantive training programme director (TPD) posts. As a result, two scholars have progressed to being appointed as fellows (one-year fixed-term TPDs) over the last three years and one of these is now a TPD. This qualitative research study sought to identify the value and acceptance of the scholar scheme within the Severn Deanery and in particular assess the impact of the scholar scheme in terms of educational benefits, impact on professional practice and future career opportunities. It also undertook to examine the key factors affecting the quality of experience of the scholar scheme (e.g.induction, mentorship, autonomous vs. prescribed education opportunities etc.). Findings showed unequivocal and universal support for the scheme. PMID- 23356765 TI - Extending GP training and the development of leadership skills: the experience of the North Western Deanery pilot. PMID- 23356766 TI - Developing innovative leaders through undergraduate medical education. PMID- 23356767 TI - A leadership programme in GP training: an action learning approach. PMID- 23356768 TI - Leadership and management: a teaching framework. PMID- 23356769 TI - Development of a leadership strategy for the Royal College of General Practitioners. PMID- 23356770 TI - Education and training for healthcare leadership. PMID- 23356771 TI - Letter to the editor--reply to Hopayian. PMID- 23356772 TI - Effects of glycine-arginine-alpha-ketoisocaproic acid supplementation in college age trained females during multi-bouts of resistance exercise. AB - Glycine-arginine-alpha-ketoisocaproic acid (GAKIC) has been proposed to increase anaerobic high-intensity exercise performance in male subjects. However, the effects of GAKIC ingestion in female subjects have not been studied. Therefore, the purpose of this study was to investigate the effects of GAKIC supplementation on total load volume (i.e., mass lifted) and metabolic parameters during repeated bouts of submaximal leg extensions in college-age females. Nine resistance trained females participated in a randomized, counterbalanced, double blind study. Subjects were randomly assigned to placebo or GAKIC (10.2 g) and performed six sets of 50% of one repetition maximum leg extensions (two legs simultaneously) to failure. One week later, subjects ingested the other supplement and performed the same exercise protocol. Furthermore, blood lactic acid, blood glucose, and heart rate were also measured preexercise and 5 s after the completion of the exercise protocol (postexercise). GAKIC supplementation significantly increased leg extension total load volume (GAKIC = 1721.7 +/- 479.9 kg; placebo = 1479.1 +/- 396.8 kg, p < .01). Heart rate and blood lactic acid were significantly increased (p < .01 for both measures) postexercise compared to preexercise, but were not significantly different between GAKIC and placebo (p = .40 for heart rate; p = .88 for lactic acid). Blood glucose was significantly decreased (p = .03) postexercise compared to preexercise, but was not significantly different (p = .78) between GAKIC and placebo. Collectively, these findings suggest that GAKIC increased lower body resistance performance in trained college-age females; however, these findings are not necessarily generalizable. PMID- 23356773 TI - A microsatellite-based linkage map of salt tolerant tilapia (Oreochromis mossambicus x Oreochromis spp.) and mapping of sex-determining loci. AB - BACKGROUND: Tilapia is the common name for a group of cichlid fishes and is one of the most important aquacultured freshwater food fish. Mozambique tilapia and its hybrids, including red tilapia are main representatives of salt tolerant tilapias. A linkage map is an essential framework for mapping QTL for important traits, positional cloning of genes and understanding of genome evolution. RESULTS: We constructed a consensus linkage map of Mozambique tilapia and red tilapia using 95 individuals from two F1 families and 401 microsatellites including 282 EST-derived markers. In addition, we conducted comparative mapping and searched for sex-determining loci on the whole genome. These 401 microsatellites were assigned to 22 linkage groups. The map spanned 1067.6 cM with an average inter-marker distance of 3.3 cM. Comparative mapping between tilapia and stickleback, medaka, pufferfish and zebrafish revealed clear homologous relationships between chromosomes from different species. We found evidence for the fusion of two sets of two independent chromosomes forming two new chromosome pairs, leading to a reduction of 24 chromosome pairs in their ancestor to 22 pairs in tilapias. The XY sex determination locus in Mozambique tilapia was mapped on LG1, and verified in five families containing 549 individuals. The major XY sex determination locus in red tilapia was located on LG22, and verified in two families containing 275 individuals. CONCLUSIONS: A first-generation linkage map of salt tolerant tilapia was constructed using 401 microsatellites. Two separate fusions of two sets of two independent chromosomes may lead to a reduction of 24 chromosome pairs in their ancestor to 22 pairs in tilapias. The XY sex-determining loci from Mozambique tilapia and red tilapia were mapped on LG1 and LG22, respectively. This map provides a useful resource for QTL mapping for important traits and comparative genome studies. The DNA markers linked to the sex-determining loci could be used in the selection of YY males for breeding all-male populations of salt tolerant tilapia, as well as in studies on mechanisms of sex determination in fish. PMID- 23356774 TI - Temporal alterations and cellular mechanisms of transmural repolarization during progression of mouse cardiac hypertrophy and failure. AB - AIM: The remodelling of transmural dispersion of repolarization (TDR) in human heart failure (HF) and in different animal models of cardiac hypertrophy or HF remains a controversial topic. We hypothesize that TDR may exhibit temporal alterations, depending on the stage of the disease. METHODS: We systematically investigated the temporal alterations of TDR during the development of cardiac hypertrophy and HF in the mouse pressure-overload model using electrophysiological and molecular biology techniques. RESULTS: A progressive prolongation of QT interval and changes in the amplitude of the J wave at 2, 5, 9 and 13 weeks were found in anesthetized aorta-banded mice. Action potential duration (APD) at 90% repolarization (APD90) in subendocardial myocytes of the left ventricular free wall remained unchanged at the hypertrophic stage (2 and 5 weeks), but was significantly prolonged in HF mice at 9 and 13 weeks. However, APD90 in subepicardial myocytes exhibited a significant prolongation at 2 weeks and did not progressively extend from 2 weeks to 13 weeks in banded mice. Thus, non-parallel prolongation of APD in subendocardial and subepicardial myocytes led to a reduction in TDR at hypertrophic stage and an amplification of TDR at HF stage. Further experiments revealed that asynchronous down-regulation of voltage dependent potassium currents (I(to,f), I(K,slow) and I(ss)) and L-type calcium currents (I(Ca-L)) in subendocardial and subepicardial myocytes may contribute to the dynamic remodelling of transmural APD. CONCLUSION: The two distinct TDR modes were revealed during the progression of mouse cardiac hypertrophy and failure, indicating that the remodelling of TDR depends on the stage of the disease. PMID- 23356775 TI - Reaffirmed limitations of meta-analytic methods in the study of mild traumatic brain injury: a response to Rohling et al. AB - In 2009 Pertab, James, and Bigler published a critique of two prior meta-analyses by Binder, Rohling, and Larrabee (1997) and Frencham, Fox, and Maybery (2005) that showed small effect size difference at least 3 months post-injury in individuals who had sustained a mild traumatic brain injury (mTBI). The Binder et al. and Frencham et al. meta-analyses have been widely cited as showing no lasting effect of mTBI. In their critique Pertab et al. (2009) point out many limitations of these two prior meta-analyses, demonstrating that depending on how inclusion/exclusion criteria were defined different meta-analytic findings occur, some supporting the persistence of neuropsychological impairments beyond 3 months. Rohling et al. (2011) have now critiqued Pertab et al. (2009). Herein we respond to the Rolling et al. (2011) critique reaffirming the original findings of Pertab et al. (2009), providing additional details concerning the flaws in prior meta-analytic mTBI studies and the effects on neuropsychological performance. PMID- 23356776 TI - Immediate hypersensitivity to platelet concentrate: allergic or not? PMID- 23356777 TI - Gentamicin-induced macular toxicity in 25-gauge sutureless vitrectomy. AB - We report a case of a 52-year-old man who developed superficial and intraretinal hemorrhages, retinal edema and extensive cotton-wool patches, 2 weeks after the subconjuctival injection of gentamicin at the end of a 25 gauge sutureless vitrectomy (pars plana vitrectomy) for the repair of a, macula on, retinal detachment in his left eye. Fluorescein angiography revealed sharply defined zones of retinal vascular non-perfusion, mostly confined to the posterior pole and visual acuity deteriorated to 1/20 and remained unchanged during the follow up time. Our case illustrates the possibility of aminoglycoside toxicity after 25 gauge transconjunctaval sutureless PPV when the latter is administered subconjuctivally. It emphasizes that less toxic subconjuctival antibiotics may be considered for sutureless surgery, since if aminoglycoside toxicity occurs, the patient's vision may be permanently affected. PMID- 23356778 TI - A probabilistic clustering theory of the organization of visual short-term memory. AB - Experimental evidence suggests that the content of a memory for even a simple display encoded in visual short-term memory (VSTM) can be very complex. VSTM uses organizational processes that make the representation of an item dependent on the feature values of all displayed items as well as on these items' representations. Here, we develop a probabilistic clustering theory (PCT) for modeling the organization of VSTM for simple displays. PCT states that VSTM represents a set of items in terms of a probability distribution over all possible clusterings or partitions of those items. Because PCT considers multiple possible partitions, it can represent an item at multiple granularities or scales simultaneously. Moreover, using standard probabilistic inference, it automatically determines the appropriate partitions for the particular set of items at hand and the probabilities or weights that should be allocated to each partition. A consequence of these properties is that PCT accounts for experimental data that have previously motivated hierarchical models of VSTM, thereby providing an appealing alternative to hierarchical models with prespecified, fixed structures. We explore both an exact implementation of PCT based on Dirichlet process mixture models and approximate implementations based on Bayesian finite mixture models. We show that a previously proposed 2-level hierarchical model can be seen as a special case of PCT with a single cluster. We show how a wide range of previously reported results on the organization of VSTM can be understood in terms of PCT. In particular, we find that, consistent with empirical evidence, PCT predicts biases in estimates of the feature values of individual items and also predicts a novel form of dependence between estimates of the feature values of different items. We qualitatively confirm this last prediction in 3 novel experiments designed to directly measure biases and dependencies in subjects' estimates. PMID- 23356779 TI - Disentangling decision models: from independence to competition. AB - A multitude of models have been proposed to account for the neural mechanism of value integration and decision making in speeded decision tasks. While most of these models account for existing data, they largely disagree on a fundamental characteristic of the choice mechanism: independent versus different types of competitive processing. Five models, an independent race model, 2 types of input competition models (normalized race and feed-forward inhibition [FFI]) and 2 types of response competition models (max-minus-next [MMN] diffusion and leaky competing accumulators [LCA]) were compared in 3 combined computational and experimental studies. In each study, difficulty was manipulated in a way that produced qualitatively distinct predictions from the different classes of models. When parameters were constrained by the experimental conditions to avoid mimicking, simulations demonstrated that independent models predict speedups in response time with increased difficulty, while response competition models predict the opposite. Predictions of input-competition models vary between specific models and experimental conditions. Taken together, the combined computational and empirical findings provide support for the notion that decisional processes are intrinsically competitive and that this competition is likely to kick in at a late (response), rather than early (input), processing stage. PMID- 23356781 TI - Critical branching neural networks. AB - It is now well-established that intrinsic variations in human neural and behavioral activity tend to exhibit scaling laws in their fluctuations and distributions. The meaning of these scaling laws is an ongoing matter of debate between isolable causes versus pervasive causes. A spiking neural network model is presented that self-tunes to critical branching and, in doing so, simulates observed scaling laws as pervasive to neural and behavioral activity. These scaling laws are related to neural and cognitive functions, in that critical branching is shown to yield spiking activity with maximal memory and encoding capacities when analyzed using reservoir computing techniques. The model is also shown to account for findings of pervasive 1/f scaling in speech and cued response behaviors that are difficult to explain by isolable causes. Issues and questions raised by the model and its results are discussed from the perspectives of physics, neuroscience, computer and information sciences, and psychological and cognitive sciences. PMID- 23356782 TI - Correcting the SIMPLE model of free recall. AB - The scale-invariant memory, perception, and learning (SIMPLE) model developed by Brown, Neath, and Chater (2007) formalizes the theoretical idea that scale invariance is an important organizing principle across numerous cognitive domains and has made an influential contribution to the literature dealing with modeling human memory. In the context of free recall data, however, there is a previously unreported conceptual error in the specification of the SIMPLE model. We show that the error matters not only in theory but also in practice by reapplying the corrected SIMPLE model to the benchmark data reported by Murdock (1962). The corrected model makes different predictions about serial position curves, shows better fit to the Murdock (1962) data, and infers different parameters that require substantively different psychological interpretation. PMID- 23356783 TI - A study of the use and interpretation of standardized suicide risk assessment: measures within a psychiatrically hospitalized correctional population. AB - The reliability, validity, and utility of the Adult Suicidal Ideation Questionnaire (ASIQ), Beck Hopelessness Scale (BHS), Beck Scale for Suicide Ideation (BSS), and Reasons for Attempting Suicide Questionnaire (RASQ) with correctional mental health populations was evaluated. Evidence was found indicating good to excellent reliability for all measures. Each of the measures significantly differentiated multiple attempters from single attempters and nonattempters, providing evidence of convergent and divergent validity. Logistic regression and receiver operating characteristic analyses revealed strong associations between multiple attempts and the ASIQ, BSS, and RASQ, but not the BHS. Implications for suicide risk assessment processes in correctional settings are discussed. PMID- 23356780 TI - Cognitive control over learning: creating, clustering, and generalizing task-set structure. AB - Learning and executive functions such as task-switching share common neural substrates, notably prefrontal cortex and basal ganglia. Understanding how they interact requires studying how cognitive control facilitates learning but also how learning provides the (potentially hidden) structure, such as abstract rules or task-sets, needed for cognitive control. We investigate this question from 3 complementary angles. First, we develop a new context-task-set (C-TS) model, inspired by nonparametric Bayesian methods, specifying how the learner might infer hidden structure (hierarchical rules) and decide to reuse or create new structure in novel situations. Second, we develop a neurobiologically explicit network model to assess mechanisms of such structured learning in hierarchical frontal cortex and basal ganglia circuits. We systematically explore the link between these modeling levels across task demands. We find that the network provides an approximate implementation of high-level C-TS computations, with specific neural mechanisms modulating distinct C-TS parameters. Third, this synergism yields predictions about the nature of human optimal and suboptimal choices and response times during learning and task-switching. In particular, the models suggest that participants spontaneously build task-set structure into a learning problem when not cued to do so, which predicts positive and negative transfer in subsequent generalization tests. We provide experimental evidence for these predictions and show that C-TS provides a good quantitative fit to human sequences of choices. These findings implicate a strong tendency to interactively engage cognitive control and learning, resulting in structured abstract representations that afford generalization opportunities and, thus, potentially long-term rather than short-term optimality. PMID- 23356784 TI - Predictors of suicidal ideation in late childhood and adolescence: a 5-year follow-up of two nationally representative cohorts in the Republic of Korea. AB - This study explores the trajectory of suicidal ideation in childhood and adolescence and identifies its strong predictors. Secondary data obtained from two nationally representative cohorts of South Korean youth were longitudinally analyzed using frequencies, percentages, and discrete time survival analysis. This study revealed an increase in the occurrence of suicidal ideation in adolescence, a higher prevalence of suicidal ideation among females than among males, and differences in predictors of suicide ideation by developmental stages and gender. The results suggest that multifaceted factors specific to developmental stages and gender should be simultaneously considered to diminish the occurrences of suicidal ideation. PMID- 23356785 TI - Suicide clusters: a review of risk factors and mechanisms. AB - Suicide clusters, although uncommon, cause great concern in the communities in which they occur. We searched the world literature on suicide clusters and describe the risk factors and proposed psychological mechanisms underlying the spatio-temporal clustering of suicides (point clusters). Potential risk factors include male gender, being an adolescent or young adult, drug or alcohol abuse, and past history of self-harm. However, the majority of studies lack methodological rigor. Many different psychological mechanisms are described, including contagion, imitation, suggestion, learning, and assortative relating, but supporting empirical evidence is generally lacking. More scientifically rigorous studies are needed to improve understanding of suicide clusters. PMID- 23356786 TI - Design and synthesis of cyclopropylamide analogues of combretastatin-A4 as novel microtubule-stabilizing agents. AB - A series of novel cyclopropylamide analogues of combretastatin-A4 (CA-4) were designed and synthesized. Most of them had significant in vitro antiproliferative activities, particularly for compounds 7i4, 7c4, 8a4, and 8c4. Moreover, compound 8c4 was also equally potent against paclitaxel resistant cancer cells. Interestingly, the novel cyclopropylamide analogues had different binding mechanisms from CA-4. Instead of inhibiting tubulin polymerization, these CA-4 derivatives were able to stimulate tubulin polymerization. Flow cytometry revealed that compound 8c4 arrested A549 cancer cells in the G2/M phase and resulted in cellular apoptosis. Further immunofluorescence assays revealed that compound 8c4 induced mitotic arrest in A549 cells through disrupting microtubule dynamics. In addition, compound 8c4 also effectively inhibited the tumor growth in the A549 xenograft model without causing significant loss of body weight. Compound 8c4 represents a novel class of microtubule-stabilizing agent and can be used as a promising lead for the development of new antitumor agents. PMID- 23356787 TI - Risk, governance and the experience of care. AB - Drawing on perspectives from the governmentality literature and the sociology of risk, this article explores the strategies, tools and mechanisms for managing risk in acute hospital trusts in the United Kingdom. The article uses qualitative material from an ethnographic study of four acute hospital trusts undertaken between 2008 and 2010 focusing on the provision of dignified care for older people. Extracts from ethnographic material show how the organisational mechanisms that seek to manage risk shape the ways in which staff interact with and care for patients. The article bridges the gap between the sociological analysis of policy priorities, management strategy and the organisational cultures of the NHS, and the everyday interactions of care provision. In bringing together this ethnographic material with sociological debates on the regulation of healthcare, the article highlights the specific ways in which forms of governance shape how staff care for their patients challenging the possibility of providing dignified care for older people. PMID- 23356788 TI - Mucoadhesive chitosan-dextran sulfate nanoparticles for sustained drug delivery to the ocular surface. AB - PURPOSE: To characterize nanoparticles produced by self-assembly of oppositely charged polymers, cationic chitosan (CS), and anionic dextran sulfate (DS), for drug delivery to the ocular surface. The goal is to overcome the short residence time of topical drugs through their sustained release from mucoadhesive nanoparticles. METHODS: Chitosan-dextran sulfate nanoparticles (CDNs) were produced by mixing CS and DS; polyethylene glycol-400 was used as a surface stabilizing agent. Fourier transform infrared spectroscopy (FTIR) spectra of CS, DS, and CDNs were determined in the wavenumber range of 4,000-700 cm(-1) to assess the ionic interactions in the formation of CDNs. The physicochemical properties, entrapment efficacy, and dissolution profile of CDNs were investigated using Rhodamine B (RhB) and Nile Red (NR) as drug analogs. The mucoadhesiveness of the CDNs was assessed by imaging the retention of the fluorescein isothiocyanate-labeled CDNs on the cornea ex vivo, which was subjected to shear stress by a steady stream of saline solution. RESULTS: CDNs were obtained by the polyelectrolyte complexation technique. The FTIR spectra of CDNs showed spectral shifts in the amine and sulfate regions, confirming an involvement of electrostatic interactions between cationic CS and anionic DS. The CDNs were spherical in shape and segregated. They possessed a particle size of ~400 nm with a polydispersity index of 0.3 and exhibited a zeta potential of ~40 mV. A high entrapment efficacy of up to 80% was observed with both RhB and NR. In the dissolution experiments, NR was released from CDNs within 60 min, but RhB was not released. This indicates that the release of drugs could depend on their molecular interactions with the particle. Exposure of CDNs to lysozyme, which is found in tears, had no effect on the mean particle size or the surface charge. Instillation of NR, RhB, and FITC in the presence of saline irrigation resulted in their rapid disappearance (<5 min) from the corneal surface. In contrast, fluorescent CDNs showed retention on the cornea even after 60 min. CONCLUSIONS: Cationic and biocompatible mucoadhesive CDNs have been developed for sustained drug delivery to the ocular surface. The CDNs were stable to lysozyme and showed prolonged adherence to the corneal surface. PMID- 23356789 TI - A new iridoid glycoside and potential MRB inhibitory activity of isolated compounds from the rhizomes of Cyperus rotundus L. AB - A new iridoid glycoside, rotunduside (1), along with four known iridoid glycosides, 10-O-p-hydroxybenzoyltheviridoside (2), 10-O-vanilloyltheviridoside (3), 6"-O-(trans-p-coumaroyl)-procumbide (4) and loganic acid (5), was isolated from the rhizomes of Cyperus rotundus L. Their chemical structures were elucidated on the basis of UV, IR, MS and NMR spectroscopic analyses. In addition, the macrophages respiratory burst (MRB) inhibitory activity of the isolated compounds was reported. Compound 2 exhibited considerable MRB inhibitory activity in the test with IC50 value of ~37 MUM. PMID- 23356790 TI - Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. AB - BACKGROUND: Despite the overall high degree of response to pharmacotherapy, consensus is lacking on how to judge clinical response or define optimal treatment/remission when treating adults with attention-deficit/hyperactivity disorder (ADHD). This study examined clinical response and symptomatic remission in analyses of 2 studies of lisdexamfetamine dimesylate (LDX) in adults with ADHD. METHODS: In a 4-week, double-blind, forced-dose trial, adults with ADHD were randomized to LDX 30, 50, and 70 mg/day (mg/d) or placebo. In a second, open label, follow-up trial, adults entering from the 4-week study were titrated to an "optimal" LDX dose (30 mg/d [n=44], 50 mg/d [n=112], and 70 mg/d [n=171]) over 4 weeks, and maintained for 11 additional months. The ADHD Rating Scale IV (ADHD-RS IV) with adult prompts and the Clinical Global Impressions-Improvement (CGI-I) scale assessed efficacy. Clinical response was defined, post hoc, as >=30% reduction from baseline in ADHD-RS-IV and CGI-I rating of 1 or 2; symptomatic remission was defined as ADHD-RS-IV total score <=18. Log rank analysis examined overall significance among the treatment groups in time to response or remission. RESULTS: Four hundred and fourteen participants in the 4-week study and 345 in the open-label, extension study were included in the efficacy populations. All LDX groups improved by ADHD-RS-IV and CGI-I scores in both studies. In the 4-week study (n=414), 69.3% responded and 45.5% achieved remission with LDX (all doses); 37.1% responded and 16.1% achieved remission with placebo; time (95% CI) to median clinical response (all LDX doses) was 15.0 (15.0, 17.0) days and to remission was 31.0 (28.0, 37.0) days (P<.0001 overall). In the open-label study, with LDX (all doses), 313 (95.7%) and 278 (85.0%) of 327 participants with evaluable maintenance-phase data met criteria for response and remission, respectively. Of participants who completed dose optimization, 75.2% remained responders and 65.7% remained in remission in the 12-month study. Overall, 285 (82.6%) and 227 (65.8%) of 345 participants were responders and remitters, respectively, at their final visits. CONCLUSION: In the long-term study, with open-label, dose-optimized LDX treatment, most adults with ADHD achieved clinical response and/or symptomatic remission; almost two-thirds maintained symptomatic remission over the remaining 11 months. TRIAL REGISTRATION: Clinical Trial Numbers: NCT00334880 and NCT01070394CLINICAL TRIAL REGISTRY: clinicaltrials.gov. PMID- 23356791 TI - Formaldehyde metabolism and formaldehyde-induced stimulation of lactate production and glutathione export in cultured neurons. AB - Formaldehyde is endogenously produced in the human body and brain levels of this compound are elevated in neurodegenerative conditions. Although the toxic potential of an excess of formaldehyde has been studied, little is known on the molecular mechanisms underlying its neurotoxicity as well as on the ability of neurons to metabolize formaldehyde. To address these topics, we have used cerebellar granule neuron cultures as model system. These cultures express mRNAs of various enzymes that are involved in formaldehyde metabolism and were remarkably resistant toward acute formaldehyde toxicity. Cerebellar granule neurons metabolized formaldehyde with a rate of around 200 nmol/(h * mg) which was accompanied by significant increases in the cellular and extracellular concentrations of formate. In addition, formaldehyde application significantly increased glucose consumption, almost doubled the rate of lactate release from viable neurons and strongly accelerated the export of the antioxidant glutathione. The latter process was completely prevented by inhibition of the known glutathione exporter multidrug resistance protein 1. These data indicate that cerebellar granule neurons are capable of metabolizing formaldehyde and that the neuronal glycolysis and glutathione export are severely affected by the presence of formaldehyde. PMID- 23356792 TI - Cost-effectiveness of single-dose tamsulosin and dutasteride combination therapy compared with tamsulosin monotherapy in patients with benign prostatic hyperplasia in the UK. AB - OBJECTIVE: To estimate the long-term cost-effectiveness of single-dose dutasteride/tamsulosin combination therapy as a first-line treatment for benign prostatic hyperplasia (BPH) from the perspective of the UK National Health Service (NHS). METHODS: A Markov state transition model was developed to estimate healthcare costs and patient outcomes, measured by quality-adjusted life years (QALYs), for patients aged >=50 years with diagnosed BPH and moderate to severe symptoms. Costs and outcomes were estimated for two treatment comparators: oral, daily, single-dose combination therapy (dutasteride 0.5 mg + tamsulosin 0.4 mg), and oral daily tamsulosin (0.4 mg) over a period up to 25 years. The efficacy of comparators was taken from results of the Combination of Avodart and Tamsulosin (CombAT) trial. RESULTS: Cumulative discounted costs per patient were higher with combination therapy than with tamsulosin, but QALYs were also higher. After 25 years, the incremental cost-effectiveness ratio for combination therapy was L12,219, well within the threshold range (L20,000-L30,000 per QALY) typically applied in the NHS. Probabilistic sensitivity analysis showed that the probability of combination therapy being cost-effective given the threshold range is between 78% and 88%. CONCLUSION: Single-dose combination dutasteride/tamsulosin therapy has a high probability of being cost-effective in comparison to tamsulosin monotherapy in the UK's NHS. PMID- 23356793 TI - Surprisingly high number of Twintrons in vertebrates. AB - Twintrons represent a special intronic arrangement in which introns of two different types occupy the same gene position. Consequently, alternative splicing of these introns requires two different spliceosomes competing for the same RNA molecule. So far, only two twintrons have been described in insects. Surprisingly, we discovered several such arrangements in vertebrate genomes, which are quite conserved throughout the lineages. PMID- 23356795 TI - Refugee children: rights and wrongs. PMID- 23356794 TI - Identification and physiological characterization of phosphatidic acid phosphatase enzymes involved in triacylglycerol biosynthesis in Streptomyces coelicolor. AB - BACKGROUND: Phosphatidic acid phosphatase (PAP, EC 3.1.3.4) catalyzes the dephosphorylation of phosphatidate yielding diacylglycerol (DAG), the lipid precursor for triacylglycerol (TAG) biosynthesis. Despite the importance of PAP activity in TAG producing bacteria, studies to establish its role in lipid metabolism have been so far restricted only to eukaryotes. Considering the increasing interest of bacterial TAG as a potential source of raw material for biofuel production, we have focused our studies on the identification and physiological characterization of the putative PAP present in the TAG producing bacterium Streptomyces coelicolor. RESULTS: We have identified two S. coelicolor genes, named lppalpha (SCO1102) and lppbeta (SCO1753), encoding for functional PAP proteins. Both enzymes mediate, at least in part, the formation of DAG for neutral lipid biosynthesis. Heterologous expression of lppalpha and lppbeta genes in E. coli resulted in enhanced PAP activity in the membrane fractions of the recombinant strains and concomitantly in higher levels of DAG. In addition, the expression of these genes in yeast complemented the temperature-sensitive growth phenotype of the PAP deficient strain GHY58 (dpp1lpp1pah1). In S. coelicolor, disruption of either lppalpha or lppbeta had no effect on TAG accumulation; however, the simultaneous mutation of both genes provoked a drastic reduction in de novo TAG biosynthesis as well as in total TAG content. Consistently, overexpression of Lppalpha and Lppbeta in the wild type strain of S. coelicolor led to a significant increase in TAG production. CONCLUSIONS: The present study describes the identification of PAP enzymes in bacteria and provides further insights on the genetic basis for prokaryotic oiliness. Furthermore, this finding completes the whole set of enzymes required for de novo TAG biosynthesis pathway in S. coelicolor. Remarkably, the overexpression of these PAPs in Streptomyces bacteria contributes to a higher productivity of this single cell oil. Altogether, these results provide new elements and tools for future cell engineering for next-generation biofuels production. PMID- 23356796 TI - Lignosulfonate and elevated pH can enhance enzymatic saccharification of lignocelluloses. AB - BACKGROUND: Nonspecific (nonproductive) binding (adsorption) of cellulase by lignin has been identified as a key barrier to reduce cellulase loading for economical sugar and biofuel production from lignocellulosic biomass. Sulfite Pretreatment to Overcome Recalcitrance of Lignocelluloses (SPORL) is a relatively new process, but demonstrated robust performance for sugar and biofuel production from woody biomass especially softwoods in terms of yields and energy efficiencies. This study demonstrated the role of lignin sulfonation in enhancing enzymatic saccharification of lignocelluloses - lignosulfonate from SPORL can improve enzymatic hydrolysis of lignocelluloses, contrary to the conventional belief that lignin inhibits enzymatic hydrolysis due to nonspecific binding of cellulase. RESULTS: The study found that lignosulfonate from SPORL pretreatment and from a commercial source inhibits enzymatic hydrolysis of pure cellulosic substrates at low concentrations due to nonspecific binding of cellulase. Surprisingly, the reduction in enzymatic saccharification efficiency of a lignocellulosic substrate was fully recovered as the concentrations of these two lignosulfonates increased. We hypothesize that lignosulfonate serves as a surfactant to enhance enzymatic hydrolysis at higher concentrations and that this enhancement offsets its inhibitive effect from nonspecific binding of cellulase, when lignosulfonate is applied to lignocellulosic solid substrates. Lignosulfonate can block nonspecific binding of cellulase by bound lignin on the solid substrates, in the same manner as a nonionic surfactant, to significantly enhance enzymatic saccharification. This enhancement is linearly proportional to the amount of lignosulfonate applied which is very important to practical applications. For a SPORL-pretreated lodgepole pine solid, 90% cellulose saccharification was achieved at cellulase loading of 13 FPU/g glucan with the application of its corresponding pretreatment hydrolysate coupled with increasing hydrolysis pH to above 5.5 compared with only 51% for the control run without lignosulfonate at pH 5.0. The pH-induced lignin surface modification at pH 5.5 further reduced nonspecific binding of cellulase by lignosulfonate. CONCLUSIONS: The results reported in this study suggest significant advantages for SPORL pretreatment in terms of reducing water usage and enzyme dosage, and simplifying process integration, i.e., it should eliminate washing of SPORL solid fraction for direct simultaneous enzymatic saccharification and combined fermentation of enzymatic and pretreatment hydrolysates (SSCombF). Elevated pH 5.5 or higher, rather than the commonly believed optimal and widely practiced pH 4.8-5.0, should be used in conducting enzymatic saccharification of lignocelluloses. PMID- 23356799 TI - Evidence-based medicine: a science of uncertainty and an art of probability. PMID- 23356798 TI - A study investigating patients' experience of hospital and home iontophoresis for hyperhidrosis. AB - Iontophoresis is an effective and safe treatment for hyperhidrosis. We investigated patients' experiences with the Idrostar(r) home iontophoresis unit (STD Pharmaceuticals, Hereford, UK) considering compliance and efficacy. PMID- 23356800 TI - Communicating evidence in shared decision making. PMID- 23356797 TI - Development of a high density 600K SNP genotyping array for chicken. AB - BACKGROUND: High density (HD) SNP genotyping arrays are an important tool for genetic analyses of animals and plants. Although the chicken is one of the most important farm animals, no HD array is yet available for high resolution genetic analysis of this species. RESULTS: We report here the development of a 600 K Affymetrix(r) Axiom(r) HD genotyping array designed using SNPs segregating in a wide variety of chicken populations. In order to generate a large catalogue of segregating SNPs, we re-sequenced 243 chickens from 24 chicken lines derived from diverse sources (experimental, commercial broiler and layer lines) by pooling 10 15 samples within each line. About 139 million (M) putative SNPs were detected by mapping sequence reads to the new reference genome (Gallus_gallus_4.0) of which ~78 M appeared to be segregating in different lines. Using criteria such as high SNP-quality score, acceptable design scores predicting high conversion performance in the final array and uniformity of distribution across the genome, we selected ~1.8 M SNPs for validation through genotyping on an independent set of samples (n = 282). About 64% of the SNPs were polymorphic with high call rates (>98%), good cluster separation and stable Mendelian inheritance. Polymorphic SNPs were further analysed for their population characteristics and genomic effects. SNPs with extreme breach of Hardy-Weinberg equilibrium (P < 0.00001) were excluded from the panel. The final array, designed on the basis of these analyses, consists of 580,954 SNPs and includes 21,534 coding variants. SNPs were selected to achieve an essentially uniform distribution based on genetic map distance for both broiler and layer lines. Due to a lower extent of LD in broilers compared to layers, as reported in previous studies, the ratio of broiler and layer SNPs in the array was kept as 3:2. The final panel was shown to genotype a wide range of samples including broilers and layers with over 100 K to 450 K informative SNPs per line. A principal component analysis was used to demonstrate the ability of the array to detect the expected population structure which is an important pre-investigation step for many genome-wide analyses. CONCLUSIONS: This Affymetrix(r) Axiom(r) array is the first SNP genotyping array for chicken that has been made commercially available to the public as a product. This array is expected to find widespread usage both in research and commercial application such as in genomic selection, genome-wide association studies, selection signature analyses, fine mapping of QTLs and detection of copy number variants. PMID- 23356801 TI - Authority, health advocacy organizations, and scientific evidence. PMID- 23356802 TI - Teaching critical appraisal of medical evidence. PMID- 23356804 TI - When research evidence is misleading. PMID- 23356806 TI - N-of-1 trials: individualized medication effectiveness tests. PMID- 23356805 TI - Effective ways to communicate risk and benefit. PMID- 23356807 TI - Medicine, the law, and conceptions of evidence. PMID- 23356808 TI - Evidence-based guidelines and quality measures in the care of older adults. PMID- 23356809 TI - Public deliberation in decisions about health research. PMID- 23356810 TI - Paradigms, coherence, and the fog of evidence. PMID- 23356811 TI - Evidence-based medicine: a short history of a modern medical movement. PMID- 23356812 TI - The median isn't the message. PMID- 23356813 TI - The message isn't as mean as we may think. PMID- 23356814 TI - A call to integrate ethics and evidence-based medicine. PMID- 23356815 TI - Cost of hemodialysis versus fomepizole-only for treatment of ethylene glycol intoxication. PMID- 23356816 TI - A retrospective review of isolated duloxetine-exposure cases. AB - BACKGROUND: Duloxetine is a serotonin norepinephrine reuptake inhibitor (SNRI) approved in the US for the treatment of major depression, generalized anxiety, fibromyalgia, diabetic peripheral neuropathy, and chronic musculoskeletal pain. Given the limited published information regarding human overdoses to this medication, our goal was to characterize such exposures. METHODS: We retrospectively reviewed a state poison system's database for all single agent exposures to duloxetine from 2004-2011. Data collected included age, gender, circumstances surrounding exposure, symptoms, and outcome. Patients with co ingestants, confirmed non-exposure, unknown outcomes, or other coding errors were excluded. RESULTS: 159 cases were identified. 106 were included for review. Of 61 pediatric and adolescent cases (0-19 years old) identified, 53 involved unintentional overdose. Three patients experienced symptoms and none were admitted. All intentional ingestions(8) were seen in the emergency department, two patients experienced symptoms. No intentional ingestion was admitted for medical care. Fifty-one adult cases were included for review. Four adult patients were admitted following intentional duloxetine overdose with resolution of symptoms within 24 hours. Three adults were evaluated in a HCF following non-self harm exposures to duloxetine. None of these patients were admitted. The remaining 15 adult patients with non-self-harm exposures were safely managed at home. CONCLUSION: The majority of non-self-harm duloxetine-exposed adult and pediatric/adolescent patients were safely managed at home and when evaluated in a healthcare facility, did not require further hospitalization. Intentional pediatric/adolescent and adult duloxetine exposures were managed in a healthcare facility but rarely resulted in further hospitalization, serious morbidity, or mortality. PMID- 23356817 TI - C-reactive protein value in organophosphate-poisoned patients - Promises and pitfalls. PMID- 23356819 TI - Contributions of molecular properties to drug promiscuity. AB - In contrast to designed polypharmacology that can result in efficient drugs for complex disorders, unintended drug promiscuity has detrimental contribution to side effects and toxicology. Characterization of promiscuous compounds enhances the understanding of complex interaction patterns and aids the design of compounds with broader selectivity against off-targets that has a major impact on medicinal chemistry outcome. In this Miniperspective we provide insights to the effect of physicochemical parameters on promiscuity. Information collected from recent, large-scale in vitro studies enabled us to discuss the relationships between physicochemical properties and promiscuity in detail. In light of these data, lipophilicity and basic character have the highest influence. On the basis of the accumulated knowledge, we propose the extensive use of pre- and postsynthesis metrics, as well as strict control of physicochemical properties during medicinal chemistry optimizations. PMID- 23356818 TI - Ethnic differences in atrial fibrillation identified using implanted cardiac devices. AB - INTRODUCTION: Atrial fibrillation (AF) is suggested to be less common among black and Asian individuals, which could reflect bias in symptom reporting and access to care. In the Asymptomatic AF and Stroke Evaluation in Pacemaker Patients and the AF Reduction Atrial Pacing Trial (ASSERT), patients with hypertension but no history of AF had AF recorded via an implanted pacemaker or defibrillator, thus allowing both symptomatic and asymptomatic AF incidence to be determined without ascertainment bias. METHODS AND RESULTS: The ASSERT enrolled 2,580 patients in 23 countries in North America, Europe, and Asia. AF was defined as device-recorded AF episodes >190/min, lasting either for >6 minutes or >6 hours in duration. All ethnic groups with >50 patients were enrolled. Ethnic groups studied include Europeans (n = 1900), black Africans (n = 73), Chinese (n = 89), and Japanese (n = 105) patients. Compared to Europeans, black Africans had more risk factors for AF such as heart failure (27.8 vs 14.6%) and diabetes (41.7 vs 26.3%). At 2.5 years follow-up, all 3 non-European races had a lower incidence of AF (8.3%, 10.1%, and 9.5% vs 18.0%, respectively, for AF>6 minutes, P < 0.006). When adjusted for baseline difference, Chinese had a lower incidence of AF > 6 minutes (P < 0.007), and Japanese and black Africans had a lower incidence of AF > 6 hours (P < 0.04 and P = 0.057, respectively). CONCLUSIONS: Black Africans, Chinese, and Japanese had lower incidence of AF compared to Europeans. In the case of black Africans, this is despite an increased prevalence of AF risk factors. PMID- 23356820 TI - Elevated intraocular pressure in the early postoperative period following excimer laser penetrating keratoplasty for keratoconus. AB - BACKGROUND AND OBJECTIVE: To assess the incidence of elevated intraocular pressure (IOP) in the early postoperative period after excimer laser penetrating keratoplasty for keratoconus and reveal potential associations with anterior segment parameters. PATIENTS AND METHODS: This prospective, interventional study consisted of 40 patients with keratoconus who were treated with excimer laser penetrating keratoplasty. Corneal pachymetry, anterior chamber depth, anterior chamber volume, and anterior segment angle were measured by Scheimpflug camera preoperatively and 2 months postoperatively. IOP was obtained using Goldmann applanation tonometry. Student's t tests and Pearson correlation were applied. A P value of .05 or less was considered significant. RESULTS: IOP increased from 16.3 +/- 3.5 preoperatively to 19.3 +/- 5.2 mm Hg postoperatively (P = .007). Significant differences were detected in corneal pachymetry (P < .008), anterior chamber depth (P < .001), and anterior chamber volume (P = .03). Postoperative IOP was significantly correlated with anterior segment angle, anterior chamber depth, and corneal pachymetry. CONCLUSION: Elevated IOP in the early postoperative period after excimer laser penetrating keratoplasty is significantly correlated with changes in the anterior chamber architecture. PMID- 23356821 TI - "Iris-assisted," open-sky, continuous curvilinear capsulorhexis technique for combined cataract extraction and corneal transplantation. AB - The authors describe "iris-assisted," open-sky, continuous curvilinear capsulorhexis (CCC) in a triple procedure combining corneal transplantation, cataract extraction, and intraocular lens implantation. They do not use miotics or mydriatics. Patients receive oral acetazolamide (250 mg), intravenous mannitol (5 mL/kg), and Honan balloon at 30 mm Hg for 20 to 30 minutes before surgery. After trephination and excision of recipient cornea, the pupil assumes a mid dilated position. After injection of 2.3% hyaluronic acid into the anterior chamber, a central linear incision is made in the anterior capsule using a cystotome needle and a CCC is made (approximately 5.5 mm) along the pupillary margin with CCC forceps. The mid-dilated iris can "assist" by resisting posterior pressure to reduce the risk of capsular extension. The nucleus passes through the capsulorhexis following hydrodissection. The keratoplasty is completed followed by cortex removal and in-the-bag intraocular lens implantation, which are facilitated by the CCC in a closed system. PMID- 23356822 TI - Sustainable development and public health: rating European countries. AB - BACKGROUND: Sustainable development and public health quite strongly correlate, being connected and conditioned by one another. This paper therein attempts to offer a representation of Europe's current situation of sustainable development in the area of public health. METHODS: A dataset on sustainable development in the area of public health consisting of 31 European countries (formally proposed by the European Union Commission and EUROSTAT) has been used in this paper in order to evaluate said issue for the countries listed thereof. A statistical method which synthesizes several indicators into one quantitative indicator has also been utilized. Furthermore, the applied method offers the possibility to obtain an optimal set of variables for future studies of the problem, as well as for the possible development of indicators. RESULTS: According to the results obtained, Norway and Iceland are the two foremost European countries regarding sustainable development in the area of public health, whereas Romania, Lithuania, and Latvia, some of the European Union's newest Member States, rank lowest. The results also demonstrate that the most significant variables (more than 80%) in rating countries are found to be "healthy life years at birth, females" (r2 = 0.880), "healthy life years at birth, males" (r2 = 0.864), "death rate due to chronic diseases, males" (r2 = 0.850), and "healthy life years, 65, females" (r2 = 0.844). CONCLUSIONS: Based on the results of this paper, public health represents a precondition for sustainable development, which should be continuously invested in and improved.After the assessment of the dataset, proposed by EUROSTAT in order to evaluate progress towards the agreed goals of the EU Sustainable Development Strategy (SDS), this paper offers an improved set of variables, which it is hoped, may initiate further studies concerning this problem. PMID- 23356824 TI - Molecular basis for the p and P(k) phenotypes in three Chinese individuals. PMID- 23356823 TI - An oral preparation of Lactobacillus acidophilus for the treatment of uncomplicated acute watery diarrhoea in Vietnamese children: study protocol for a multicentre, randomised, placebo-controlled trial. AB - BACKGROUND: Diarrhoeal disease is a major global health problem, particularly affecting children under the age of 5 years. Besides oral rehydration solution, probiotics are also commonly prescribed to children with acute watery diarrhoea in some settings. Results from randomised clinical trials (RCTs) in which investigators studied the effect of probiotics on diarrhoeal symptoms have largely shown a positive effect; yet, the overall quality of the data is limited. In Vietnam, probiotics are the most frequently prescribed treatment for children hospitalised with acute watery diarrhoea, but there is little justification for this treatment in this location. We have designed a RCT to test the hypothesis that an oral preparation of Lactobacillus acidophilus is superior to placebo in the treatment of acute watery diarrhoea in Vietnamese children. METHODS: This RCT was designed to study the effect of treatment with L. acidophilus (4 * 109 colony forming units/day) for 5 days for acute watery diarrhoea against a placebo in 300 children ages 9 to 60 months admitted to hospitals in Vietnam. Clinical and laboratory data plus samples will be collected on admission, daily during hospitalisation, at discharge, and at follow-up visits for a subset of participants. The primary end point will be defined as the time from the first dose of study medication to the start of the first 24-hour period without diarrhoea as assessed by the on-duty nurse. Secondary endpoints include the time to cessation of diarrhoea as recorded by parents or guardians in an hourly checklist, stool frequency over the first 3 days, treatment failure, rotavirus and norovirus viral loads, and adverse events. DISCUSSION: The existing evidence for the use of probiotics in treating acute watery diarrhoea seems to favour their use. However, the size of the effect varies across publications. An array of different probiotic organisms, doses, treatment durations, study populations, designs, settings, and aetiologies have been described. In this trial, we will investigate whether probiotics are beneficial as an adjuvant treatment for children with acute watery diarrhoea in Vietnam, with the aim of guiding clinical practice through improved regional evidence. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88101063. PMID- 23356825 TI - Thiophene-fused bisdehydro[12]annulene that undergoes transannular alkyne cycloaddition by either light or heat. AB - A new bisdehydro[12]annulene derivative having a thiophene-fused structure has been synthesized. This highly twisted pi-conjugated macrocycle with two acetylene moieties in close proximity produces a [2+2]-type alkyne cycloadduct by either photoirradiation or mild heating without any transition metals. Theoretical calculations reveal that the thermal reaction proceeds through successive 8pi and 4pi electrocyclic reactions, while the photochemical reaction is an asynchronous concerted [2+2] cycloaddition. The fused structure with the less-aromatic thiophene ring is crucial for achieving this reaction. The cycloadduct, thiophene fused biphenylene, has significant potential as a new polycyclic pi-scaffold for electronic applications. PMID- 23356826 TI - Two new glycosides from Vitex negundo. AB - Two new glycosides, 2-methyl pyromeconic acid 3-O-beta-D-glucopyranoside-6'-(O-4" hydroxybenzoate) (1), 6'-O-p-hydroxybenzoyl-gardoside (2) and four known iridoid glycosides (3-6) were isolated from the whole plant of Vitex negundo. Their structures were elucidated on the basis of spectroscopic methods including HR-ESI MS, 1D and 2D NMR. PMID- 23356827 TI - Life in and after the Armed Forces: social networks and mental health in the UK military. AB - This study focuses on the influence of structural aspects of social integration (social networks and social participation outside work) on mental health (common mental disorders (CMD), that is, depression and anxiety symptoms, post-traumatic stress disorder (PTSD) symptoms and alcohol misuse). This study examines differences in levels of social integration and associations between social integration and mental health among service leavers and personnel still in service. Data were collected from regular serving personnel (n=6,511) and regular service leavers (n=1,753), from a representative cohort study of the Armed Forces in the UK. We found that service leavers reported less social participation outside work and a general disengagement with military social contacts in comparison to serving personnel. Service leavers were more likely to report CMD and PTSD symptoms. The increased risk of CMD but not PTSD symptoms, was partially accounted for by the reduced levels of social integration among the service leavers. Maintaining social networks in which most members are still in the military is associated with alcohol misuse for both groups, but it is related to CMD and PTSD symptoms for service leavers only. PMID- 23356828 TI - Relationship between premature ejaculation and postcircumcisional mucosal cuff length. AB - OBJECTIVE: The aims of this study were to investigate the effect of circumcision conditions on postcircumcisional mucosal cuff length (MCL), and to determine the relationship between premature ejaculation (PE) and MCL. MATERIAL AND METHODS: Circumcision histories and penile measurements were taken for 200 circumcised men. They were asked to complete the Premature Ejaculation Diagnostic Tool (PEDT) questionnaire, and to measure and report intravaginal ejaculation latency time (IELT). RESULTS: The mean age of all participants was 35.1 +/- 8.5 (19-46) years. The mean MCL, penile skin length and total penile length of all participants were 14.6 +/- 3.4 mm, 122 +/- 11.8 mm and 136.6 +/- 13.9 mm, respectively. Mean age at circumcision was 6.5 +/- 5.8 years. Only 26 (13%) of the participants had been circumcised by a surgeon, and they had significantly shorter MCL than those who had been circumcised by others (p = 0.041). All 200 men enrolled in the study completed a PEDT, but only 141 of them measured correctly and reported their IELT. The mean PEDT score was 5.6 +/- 5.9 and IELT was 3.8 +/- 1.9 min. There was a strong and a negative correlation between PEDT scores and IELT (p = 0.000, and r = -0.785), but no correlation was shown between the mean penile measurements and PEDT and IELT scores of volunteers (p > 0.05). CONCLUSIONS: Although the MCL did not change according to the place where it was performed, it was shorter in patients who had been circumcised by surgeons. The study results also demonstrated that there was no relationship between MCL or penile length and PE in terms of PEDT score and IELT in circumcised men. PMID- 23356829 TI - Extended pelvic lymphadenectomy and various radical prostatectomy techniques: is pelvic drainage necessary? AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The occurence of lymphoceles in patients after radical prostatectomy is well known (2-10%). It appears that patients undergoing open extraperitoneal radical prostatectomy develop more lymphoceles than patients undergoing robot-assisted radical prostatectomy with transperitoneal access. The present study investigates in a prospective randomized manner whether the time of drainage (1 vs 7 days) makes a difference or whether drainage is even necessary. The study data, collected in the same institution, are compared with the incidence of lymphocele in patients treated by robot-assisted radical prostatectomy. OBJECTIVE: To investigate whether routine drainage is advisable after open extended pelvic lymph node dissection (ePLND) and retropubic radical prostatectomy (RRP) by measuring the incidence of lymphoceles and comparing these results with those of a series of robot-assisted radical prostatectomy (RARP) and ePLND. PATIENTS AND METHODS: A total of 331 consecutive patients underwent ePLND and RRP or RARP. The first 132 patients underwent open ePLND and RRP and received two pelvic drains; these patients were prospectively randomized into two groups: group 1 (n = 66), in which the drains were shortened on postoperative (PO) days 3 and 5 and removed on PO day 7, and group 2 (n = 66), in which the drains were removed on PO day 1. The next 199 patients were assigned to two consecutive groups not receiving drainage: group 3 (n = 73) undergoing open ePLND and RRP, followed by group 4 (n = 126) treated by transperitoneal robot-assisted ePLND and RARP. All patients had ultrasonographic controls 5 and 10 days and 3 and 12 months after surgery. RESULTS: Lymphoceles were detected in 6.6% of all patients, 3.3% of whom were asymptomatic and 3.3% of whom were symptomatic. Symptomatic lymphoceles were detected in 0% of group 1, 8% of group 2, 7% of group 3 and 1% of group 4, with groups 2 and 3 differing significantly from group 4 (P < 0.05). In total, 5% of all patients undergoing open RRP (groups 1-3) had symptomatic lymphoceles vs 1% of patients undergoing RARP (group 4) (P = 0.06). Nodal-positive patients had significantly more symptomatic lymphoceles than nodal-negative patients (10% vs 2%) (P < 0.02). CONCLUSIONS: Symptomatic lymphoceles occur less frequently after open RRP and pelvic drainage over 7 days than after open RRP and pelvic drainage over 1 day or without drainage. Patients undergoing RARP without drainage had significantly fewer lymphoceles than patients receiving open RRP without drainage. PMID- 23356830 TI - A novel approach for the detection of early gastric cancer: fluorescence spectroscopy of gastric juice. AB - OBJECTIVE: This study aimed to investigate the efficacy of fluorescence spectroscopy of gastric juice for early gastric cancer (EGC) screening. METHODS: Gastric juice was collected from 101 participants who underwent endoscopy in the Outpatient Endoscopy Center of Peking University Third Hospital. The participants were divided into three groups: the normal mucosa or chronic non-atrophic gastritis (NM-CNAG) group (n = 35), advanced gastric cancer (AGC) group (n = 33) and EGC group (n = 33). Fluorescence spectroscopic analysis was performed in all the gastric juice samples and the maximum fluorescence intensity of the first peak (P1 FI) was measured. RESULTS: The mean fluorescence intensity of P1 FI of gastric juice in AGC (92.1 +/- 10.7) and EGC (90.8 +/- 12.0) groups was significantly higher than that in the NM-CNAG group (55.7 +/- 7.5) (AGC vs NM CNAG, P = 0.006 and EGC vs NM-CNAG, P = 0.015, respectively). The areas under the receiver operating characteristic curves for the detection of AGC and EGC were 0.681 (95% confidence interval [CI] 0.553-0.810, P = 0.010) and 0.655 (95% CI 0.522-0.787, P = 0.028). With the P1 FI of >=47.7, the sensitivity, specificity and accuracy for detecting EGC were 69.7%, 57.1% and 63.2%, respectively. CONCLUSIONS: The enhancement of P1 FI of gastric juice occurs at the early stage of gastric cancer. Fluorescence spectroscopy of gastric juice may be used as a novel screening tool for the early detection of gastric cancer. PMID- 23356831 TI - Conserved loci of leaf and stem rust fungi of wheat share synteny interrupted by lineage-specific influx of repeat elements. AB - BACKGROUND: Wheat leaf rust (Puccinia triticina Eriks; Pt) and stem rust fungi (P. graminis f.sp. tritici; Pgt) are significant economic pathogens having similar host ranges and life cycles, but different alternate hosts. The Pt genome, currently estimated at 135 Mb, is significantly larger than Pgt, at 88 Mb, but the reason for the expansion is unknown. Three genomic loci of Pt conserved proteins were characterized to gain insight into gene content, genome complexity and expansion. RESULTS: A bacterial artificial chromosome (BAC) library was made from P. triticina race 1, BBBD and probed with Pt homologs of genes encoding two predicted Pgt secreted effectors and a DNA marker mapping to a region of avirulence. Three BACs, 103 Kb, 112 Kb, and 166 Kb, were sequenced, assembled, and open reading frames were identified. Orthologous genes were identified in Pgt and local conservation of gene order (microsynteny) was observed. Pairwise protein identities ranged from 26 to 99%. One Pt BAC, containing a RAD18 ortholog, shares syntenic regions with two Pgt scaffolds, which could represent both haplotypes of Pgt. Gene sequence is diverged between the species as well as within the two haplotypes. In all three BAC clones, gene order is locally conserved, however, gene shuffling has occurred relative to Pgt. These regions are further diverged by differing insertion loci of LTR retrotransposon, Gypsy, Copia, Mutator, and Harbinger mobile elements. Uncharacterized Pt open reading frames were also found; these proteins are high in lysine and similar to multiple proteins in Pgt. CONCLUSIONS: The three Pt loci are conserved in gene order, with a range of gene sequence divergence. Conservation of predicted haustoria expressed secreted protein genes between Pt and Pgt is extended to the more distant poplar rust, Melampsora larici-populina. The loci also reveal that genome expansion in Pt is in part due to higher occurrence of repeat-elements in this species. PMID- 23356833 TI - Efficacy and safety of incobotulinum toxin A in periocular rhytides and masseteric hypertrophy: side-by-side comparison with onabotulinum toxin A. AB - BACKGROUND: Incobotulinum is a newly developed botulinum toxin A in which the complexing proteins had been removed. OBJECTIVE: The aim was to compare the efficacy and safety of incobotulinum with onabotulinum in treating periocular rhytides and masseteric hypertrophy. METHODS: A randomized, double-blind, split face study was planned. Fifty-six patients were treated for periocular rhytides and the other 56 patients were treated for masseteric hypertrophy. Onabotulinum was injected on one side of the face and incobotulinum was injected on the other side of the face. The degree of periocular rhytides and masseteric hypertrophy was rated using Fitzpatrick Wrinkle Classification System (FWCS) and 10-point visual analogue scale (VAS) (0: the minimum to 10: the maximum). Objective and subjective rating was performed at pretreatment and every posttreatment follow-up visit by investigators and subjects. RESULT: The efficacy and safety of incobotulinum were not inferior to those of onabotulinum in treating periocular rhytides and masseteric hypertrophy up to 16 weeks after injection. There were no noteworthy differences in the onset time of effect between two botulinum toxins for periocular wrinkles and masseteric hypertrophy. No adverse event was reported. CONCLUSION: Incobotulinum provided non-inferior efficacy and safety for the treatment of periocular rhytides and masseteric hypertrophy compared with classic onabotulinum. PMID- 23356834 TI - Hospitalizations for suicide-related drug poisonings and co-occurring alcohol overdoses in adolescents (ages 12-17) and young adults (ages 18-24) in the United States, 1999-2008: results from the Nationwide Inpatient Sample. AB - Drug poisoning is the leading method of suicide-related deaths among females and third among males in the United States. Alcohol can increase the severity of drug poisonings, yet the prevalence of alcohol overdoses in suicide-related drug poisonings (SRDP) remains unclear. Data from the Nationwide Inpatient Sample was examined to determine rates of inpatient hospital stays for SRDP and co-occurring alcohol overdoses in adolescents (ages 12-17) and young adults (ages 18-24) between 1999 and 2008. Among adolescents, there were 14,615 hospitalizations for drug poisonings in 2008, of which 72% (10,462) were suicide-related at a cost of $43 million. Rates of SRDP in this age group decreased between 1999 and 2008. The prevalence of co-occurring alcohol overdoses increased from 5% in 1999 to 7% in 2008. Among young adults, there were 32,471 hospitalizations for drug poisonings in 2008, of which 64% (20,746) were suicide-related at a cost of $110 million. Rates of SRDP did not change significantly between 1999 and 2008. The prevalence of co-occurring alcohol overdoses increased from 14% in 1999 to 20% in 2008. Thus, while rates of SRDP decreased for adolescents and remained unchanged for young adults, the prevalence of co-occurring alcohol overdoses increased for both age groups. Such hospitalizations provide important opportunities to employ intervention techniques to prevent further suicide attempts. PMID- 23356835 TI - Dynamic computed tomography appearance of tumor response after stereotactic body radiation therapy for hepatocellular carcinoma: How should we evaluate treatment effects? AB - AIM: To evaluate the dynamic computed tomography (CT) appearance of tumor response after stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) and reconsider response evaluation criteria for SBRT that determine treatment outcomes. METHODS: Fifty-nine patients with 67 tumors were included in the study. Of these, 56 patients with 63 tumors underwent transarterial chemoembolization using lipiodol prior to SBRT that was performed using a 3-D conformal method (median, 48 Gy/four fractions). Dynamic CT scans were performed in four phases, and tumor response was evaluated by comparing tumor appearance on CT prior SBRT and at least 6 months after SBRT. The median follow-up time was 12 months. RESULTS: The dynamic CT appearance of tumor response was classified into the following: type 1, continuous lipiodol accumulation without early arterial enhancement (26 lesions, 38.8%); type 2, residual early arterial enhancement within 3 months after SBRT (17 lesions, 25.3%); type 3, residual early arterial enhancement more than 3 months after SBRT (19 lesions, 28.4%); and type 4, shrinking low-density area without early arterial enhancement (five lesions, 7.5%). Only two tumors with residual early arterial enhancement did not demonstrate remission more than 6 months after SBRT. CONCLUSION: The dynamic CT appearance after SBRT for HCC was classified into four types. Residual early arterial enhancement disappeared within 6 months in most type 3 cases; therefore, early assessment within 3 months may result in a misleading response evaluation. PMID- 23356836 TI - pH-Dependent photoreaction pathway of the all-trans form of Anabaena sensory rhodopsin. AB - Anabaena sensory rhodopsin (ASR) is well-known as the only retinal protein that achieves the photochromic reaction between the all-trans form (AT-ASR) and the 13 cis form (C-ASR). Although it is known that the structure of the hydrogen-bonding network of ASR is pH-dependent, it is so far unclear how pH affects the photoreaction of ASR. We investigated the pH dependence of the photoreaction of AT-ASR by means of time-resolved absorption spectroscopy and found it to be extremely dependent on pH. At pH 7 and 9, not only the L intermediate but also the K intermediate consisted of two decay components. The formation ratios of the two distinct L intermediates L(fast):L(slow) at pH 7 and 9 were different from each other, although the K(fast):K(slow) ratio was pH-independent. The photoreaction at pH 5 was entirely different from that at pH 7 and 9. Two K intermediates existed, but their formation ratio and lifetimes were different at pH 7 and 9. Moreover, only one L intermediate exists, with a longer lifetime relative to pH 7 and 9. The final product of the photoreaction of AT-ASR was C ASR at all pH values. Finally, we successfully determined the pH-related photoreaction pathway of AT-ASR. PMID- 23356837 TI - Febrile illness management in children under five years of age: a qualitative pilot study on primary health care workers' practices in Zanzibar. AB - BACKGROUND: In Zanzibar, malaria prevalence dropped substantially in the last decade and presently most febrile patients seen in primary health care facilities (PHCF) test negative for malaria. The availability of rapid diagnostic tests (RDTs) allows rural health workers to reliably rule out malaria in fever patients. However, additional diagnostic tools to identify alternative fever causes are scarce, often leaving RDT-negative patients without a clear diagnosis and management plan. This pilot study aimed to explore health workers' practices with febrile children and identify factors influencing their diagnostic and management decisions in non-malarial fever patients. METHODS: Semi-structured key informant interviews were conducted with 12 health workers in six PHCFs in North A district, Zanzibar, April to June 2011. Interviews were coded using Atlas.ti to identify emerging themes that play a role in the diagnosis and management of febrile children. RESULTS: The following themes were identified: 1) health workers use caregivers' history of illness and RDT results for initial diagnostic and management decisions, but suggest caregivers need more education to prevent late presentation and poor health outcomes; 2) there is uncertainty regarding viral versus bacterial illness and health workers feel additional point-of-care diagnostic tests would help with differential diagnoses; 3) stock-outs of medications and limited caregivers' resources are barriers to delivering good care; 4) training, short courses and participation in research as well as; 5) weather also influences diagnostic decision-making. CONCLUSIONS: This pilot study found that health workers in Zanzibar use caregiver history of fever and results of malaria RDTs to guide management of febrile children. However, since most febrile children test negative for malaria, health workers believe additional training and point-of-care tests would improve their ability to diagnose and manage non-malarial fevers. Educating caregivers on signs and symptoms of febrile illness, as well as the introduction of additional tests to differentiate between viral and bacterial illness, would be important steps to get children to PHCFs earlier and decrease unnecessary antibiotic prescribing without compromising patient safety. More research is needed to expand an understanding of what would improve fever management in other resource-limited settings with decreasing malaria. PMID- 23356838 TI - Diagnostic accuracy of panoramic radiography, stereo-scanography and cone beam CT for assessment of mandibular third molars before surgery. AB - OBJECTIVE: To compare the diagnostic accuracy of panoramic imaging, stereo scanography and cone beam computed tomography (CBCT) for assessment of mandibular third molars. MATERIAL AND METHODS: One hundred and twelve patients (147 third molars) underwent radiographic examination by panoramic imaging, stereo scanography and CBCT. Tooth angulation, root morphology, number of roots and relation to the mandibular canal were assessed. The same variables were assessed intra- and post-operatively and served as reference for the radiographic assessments. The diagnostic accuracy for each variable was compared between the three modalities and accuracy was further expressed as sensitivity and specificity and tested between the modalities for identifying the relation to the mandibular canal. RESULTS: There were no significant differences between the modalities regarding tooth angulation, root morphology and number of roots. However, CBCT was more accurate than stereo-scanography for determining root bending in the bucco-lingual plane (p = 0.02). Moreover, sensitivity for direct contact to the mandibular canal (panoramic imaging: 0.29, stereo-scanography: 0.57, CBCT: 0.67) was higher for CBCT than for panoramic images (p = 0.05) and specificity for no direct contact to the mandibular canal (panoramic imaging: 0.78, stereo-scanography: 0.53, CBCT: 0.68) was higher for panoramic images and CBCT than for scanograms (p < 0.001). CONCLUSION: Panoramic imaging, stereo scanography and CBCT seem equally valuable for examination of tooth angulation, number and morphology of roots of mandibular third molars. However, CBCT was more accurate for assessment of root bending in the bucco-lingual plane and more accurate than panoramic images to identify direct contact to the mandibular canal. PMID- 23356839 TI - A pragmatic randomised controlled trial of the effectiveness and cost effectiveness of 'PhysioDirect' telephone assessment and advice services for physiotherapy. AB - BACKGROUND: As a result of long delays for physiotherapy for musculoskeletal problems, several areas in the UK have introduced PhysioDirect services in which patients telephone a physiotherapist for initial assessment and treatment advice. However, there is no robust evidence about the effectiveness, cost-effectiveness or acceptability to patients of PhysioDirect. OBJECTIVE: To investigate whether or not PhysioDirect is equally as clinically effective as and more cost-effective than usual care for patients with musculoskeletal (MSK) problems in primary care. DESIGN: Pragmatic randomised controlled trial to assess equivalence, incorporating economic evaluation and nested qualitative research. Patients were randomised in 2 : 1 ratio to PhysioDirect or usual care using a remote automated allocation system at the level of the individual, stratifying by physiotherapy site and minimising by sex, age group and site of MSK problem. For the economic analysis, cost consequences included NHS and patient costs, and the cost of lost production. Cost-effectiveness analysis was carried out from the perspective of the NHS. Interviews were conducted with patients, physiotherapists and their managers. SETTING: Four community physiotherapy services in England. PARTICIPANTS: Adults referred by general practitioners or self-referred for physiotherapy for a MSK problem. INTERVENTIONS: Patients allocated to PhysioDirect were invited to telephone a senior physiotherapist for initial assessment and advice using a computerised template, followed by face-to-face care when necessary. Patients allocated to usual care were put on to a waiting list for face-to-face care. MAIN OUTCOME MEASURES: Primary outcome was the Short Form questionnaire-36 items, version 2 (SF-36v2) Physical Component Score (PCS) at 6 months after randomisation. Secondary outcomes included other measures of health outcome [Measure Yourself Medical Outcomes Profile, European Quality of Life-5 Dimensions (EuroQol health utility measure, EQ-5D), global improvement, response to treatment], wait for treatment, time lost from work and usual activities, patient satisfaction. Data were collected by postal questionnaires at baseline, 6 weeks and 6 months, and from routine records by researchers blind to allocation. RESULTS: A total of 1506 patients were allocated to PhysioDirect and 743 to usual care. Patients allocated to PhysioDirect had a shorter wait for treatment than those allocated to usual care [median 7 days vs 34 days; arm-time ratio 0.32, 95% confidence interval (CI) 0.29 to 0.35] and had fewer non-attended face-to-face appointments [incidence rate ratio 0.55 (95% CI 0.41 to 0.73)]. The primary outcome at 6 months' follow-up was equivalent between PhysioDirect and usual care [mean PCS 43.50 vs 44.18, adjusted difference in means -0.01 (95% CI 0.80 to 0.79)]. The secondary measures of health outcome all demonstrated equivalence at 6 months, with slightly greater improvement in the PhysioDirect arm at 6 weeks' follow-up. Patients were equally satisfied with access to care but slightly less satisfied overall with PhysioDirect compared with usual care. NHS costs (physiotherapy plus other relevant NHS costs) per patient were similar in the two arms [PhysioDirect L 198.98 vs usual care L 179.68, difference in means L 19.30 (95% CI -L 37.60 to L 76.19)], while QALYs gained were also similar [difference in means 0.007 (95% CI -0.003 to 0.016)]. Incremental cost per QALY gained was L 2889. The probability that PhysioDirect was cost-effective at a L 20,000 willingness-to-pay threshold was 88%. These conclusions about cost effectiveness were robust to sensitivity analyses. There was no evidence of difference between trial arms in cost to patients or value of lost production. No adverse events were detected. CONCLUSIONS: Providing physiotherapy via PhysioDirect is equally clinically effective compared with usual waiting list based care, provides faster access to treatment, appears to be safe, and is broadly acceptable to patients. PhysioDirect is probably cost-effective compared with usual care. PMID- 23356840 TI - SGLT2 inhibitors: a promising new therapeutic option for treatment of type 2 diabetes mellitus. AB - BACKGROUND: Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose reabsorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications. Sodium glucose cotransporter 2 (SGLT2) has a key role in reabsorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes. OBJECTIVE: To discuss the therapeutic potential of SGLT2 inhibitors currently in clinical development. KEY FINDINGS: A number of preclinical and clinical studies of SGLT2 inhibitors have demonstrated a good safety profile and beneficial effects in lowering plasma glucose levels, diminishing glucotoxicity, improving glycemic control and reducing weight in diabetes. Of all the SGLT2 inhibitors, dapagliflozin is a relatively advanced compound with regards to clinical development. SUMMARY: SGLT2 inhibitors are emerging as a promising therapeutic option for the treatment of diabetes. Their unique mechanism of action offers them the potential to be used in combination with other oral anti-diabetic drugs as well as with insulin. PMID- 23356841 TI - Characterization of monocarboxylate uptake and immunohistochemical demonstration of monocarboxylate transporters in cultured rabbit corneal epithelial cells. AB - OBJECTIVES: This study aimed to characterize the mechanisms of monocarboxylate uptake by cultured rabbit corneal epithelial cells (RCECs) using l- and d-lactic acids as model substrates. METHODS: l-/d-Lactic acid uptake was evaluated by measuring the accumulation in confluent RCECs. Also, we demonstrated the distribution of monocarboxylate transporters (MCTs) in RCECs by immunohistochemistry. KEY FINDINGS: The accumulation of (14) C-labelled l- and d lactic acids was dependent on time, pH and temperature. The Arrhenius plots of the uptake were biphasic. The initial uptake of (14) C-labelled l-lactic acid exhibited concentration dependence and was greater than that of the d-isomer. The initial uptake of (14) C-labelled l- and d-lactic acids involved saturable and nonsaturable processes; the saturable process exhibited higher affinity for l lactic acid than for the d-isomer. l-/d-lactic acid uptake was inhibited by chiral monocarboxylate in a stereoselective manner. The uptake of (14) C-labelled l- and d-lactic acids was sensitive to metabolic inhibitors and other monocarboxylates. MCT expression in RCECs was confirmed immunohistochemically. In particular, MCT2 expression was detected in RCECs, whereas MCT1, MCT4 and MCT5 expression was detected in the surface layer. CONCLUSION: These results indicate that the carrier-mediated transport system specific for monocarboxylates elicits lactic acid uptake in RCECs. Therefore, the transcorneal permeation of drugs with a monocarboxylic moiety may be dependent on the activity of a specific pH dependent transporter as well as passive diffusion according to the pH-partition theory. PMID- 23356842 TI - Effect of ciprofloxacin and grapefruit juice on oral pharmacokinetics of riluzole in Wistar rats. AB - OBJECTIVES: The objective of this study was to explore potential drug-drug/food interactions of ciprofloxacin and grapefruit juice, known hepatic cytochrome P450 (CYP) 1A2 inhibitors, on single-dose oral pharmacokinetics of riluzole, a substrate of CYP 1A2 enzymes. METHODS: Pharmacokinetic parameters of riluzole were determined in Wistar rats after single-dose co-administration with ciprofloxacin and grapefruit juice. In-vitro metabolic inhibition studies using rat and human liver microsomes and intestinal absorption studies of riluzole in a rat everted gut-sac model were conducted to elucidate the mechanism of interaction. A validated HPLC method was employed to quantify riluzole in the samples obtained in various studies. KEY FINDINGS: Co-administration of ciprofloxacin with riluzole caused significant increase in systemic exposure of riluzole (area under the curve, maximum plasma concentration and mean residence time were found to increase). Co-administration of grapefruit juice with riluzole did not cause any significant difference in the pharmacokinetic parameters of riluzole. In-vitro metabolism studies demonstrated significant inhibition of riluzole metabolism when it was co-incubated with ciprofloxacin or grapefruit juice. No significant change was observed in apparent permeability of riluzole. CONCLUSIONS: Co-administration of ciprofloxacin with riluzole increases the systemic levels of riluzole and thereby the oral pharmacokinetic properties of riluzole while co-administration of grapefruit juice with riluzole has no significant effect. PMID- 23356843 TI - Pharmacokinetics, biodistribution and toxicology following intravenous and oral administration of DSM-RX78 and EFB-1, two new 2-(2-fluorobenzamido)benzoate-based PDE4 inhibitors, to rats. AB - OBJECTIVES: The aim of this study was to determine the pharmacokinetic profile, biodistribution and toxicity of ethyl 2-(2-fluorobenzamido)benzoate (EFB-1) and methyl 2-(2-fluorobenzamido)benzoate (DSM-RX 78), two phosphodiesterase IV inhibitors, which potently attenuate haemorrhagic shock-induced lung injury in rat. METHODS: Quantification of DSM-RX78, EFB-1 and 2-(2-fluorobenzamido)benzoate (SMP-3) in plasma was carried out by HPLC. Furthermore, the pharmacokinetics and biodistribution of intravenously (1.0 and 3.0 mg/kg) and orally (40.0 mg/kg) administered DSM-RX78, EFB-1, and SMP-3 were determined in Sprague-Dawley rats. Toxicity and histological analyses were also evaluated herein. KEY FINDINGS: A liquid chromatography method has been developed for the quanification of EFB-1, DSM-RX78 and SMP-3 in rat plasma. The method was sensitive with good linearity (r(2) = 0.9990) over a range of 1.56-0.0975 MUg/ml. The mean kinetic parameters of DSM-RX 78 and EFB-1 following intravenous administration were as follows: elimination half-life (t1/2) 8.98 and 8.77 min; clearance (Cl) 24.57 and 22.31 ml/min/kg; AUC(0-) (infinity) 41.76 and 48.03 min mg/l. CONCLUSIONS: The pharmacokinetics, toxicity and biodistribution of DSM-RX78 and EFB-1 were determined for the first time. The results showed that the pharmacokinetic profiles of DSM-RX78 and EFB-1 were similar, and that EFB-1 had a better safety profile than DSM-RX78. Therefore, EFB-1 was suitable as a lead compound for the development of new agents in the treatment of neutrophilic inflammatory diseases. PMID- 23356844 TI - In-vitro and in-vivo evaluation of austocystin D liposomes. AB - OBJECTIVES: The purpose this study is to enhance the anti-tumour activity of austocystin D (AD) by AD-loaded liposomes (AD-Ls). METHODS: AD-Ls were prepared by the film dispersion-ultrasonication method and characterized in terms of particle size and zeta potential, encapsulation efficiency and in-vitro drug release. In vivo, the pharmacokinetics, biodistribution and anti-tumour effect were also compared with those of the solution. KEY FINDINGS: The obtained liposomes were a mildly translucent suspension, with a particle size of 71.26 +/- 6.43 nm, a polydispersity index of 0.259 +/- 0.017 and a zeta potential of -9.9 +/- 1.8 mV. Transmission electron microscope examination showed that the liposomes had a spherical shape and a multilayer structure. The encapsulation efficiency ofAD-Ls was 83.74 +/- 1.26%. AD was continuously released from liposomes up to 72 h in in-vitro experiments. The growth of HT-29 tumours in animal models was controlled more effectively by AD-LS than by AD solution. Pharmacokinetic study showed that AD-Ls had higher t1/2beta and mean retention time. Biodistribution results in tumour-bearing mice showed that the AD-LS could target to liver and tumour. CONCLUSIONS: This study indicates that AD-Ls are a potential carrier of AD for the treatment of tumours in the liver, increasing the cure efficiency and decreasing the side effects on other tissues. PMID- 23356845 TI - Synthesis and characterisation of novel Co(II) complexes of pyrazole carboxylate derivated of sulfonamide as carbonic anhydrase inhibitors. AB - OBJECTIVES: Two new metal complexes, diaquabis(4-benzoyl-1,5-diphenyl-N-(5 sulfamoyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-3-carboxamide)cobalt(II) dihydrate (2) and diaquabis(ethyl-1-(3-nitrophenyl)-5-phenyl-3-(5-sulfamoyl-1,3,4 thiadiazol-2-ylcarbamoyl)-1H-pyrazole-4-carboxylate)cobalt(II) monohydrate (4), containing sulfonamide have been synthesized by the reaction of Co(II) with 4 benzoyl-1,5-diphenyl-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)-1H-pyrazole-3 carboxamide (1) and ethyl-1-(3-nitrophenyl)-5-phenyl-3-(5-sulfamoyl-1,3,4 thiadiazol-2-ylcarbamoyl)-1H-pyrazole-4-carboxylate (3), respectively. METHODS: The structures of Co(II) complexes 2 and 4 have been characterised by spectroscopic methods and elemental analyses. Human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from erythrocyte cells by affinity chromatography. The inhibitory effects of ligands 3 and 4, acetazolamide as a control compound and the newly synthesized complexes on the activity of hydratase and esterase of these isoenzymes have been studied in vitro. KEY FINDINGS: The concentration of compounds 2 and 4 producing a 50% inhibition of hydratase activity (IC(50) values) were 0.473 +/- 0.025 and 0.065 +/- 0.002 MUm for hCA-I and 0.213 +/- 0.015 and 0.833 +/- 0.021 MUm for hCA-II, respectively. The IC(50) values of synthesized compounds 2 and 4 for esterase activity were, 0.058 +/- 0.006 and 0.297 +/- 0.015 MUm for hCA-I and 0.110 +/- 0.010 and 0.052 +/- 0.002 MUm for hCA-II, respectively. In relation to esterase activity, the inhibition equilibrium constants (K(i) ) were determined as 0.039 +/- 0.004 and 0.247 +/- 0.035 MUm on hCA-I and 0.078 +/- 0.002 and 0.363 +/- 0.015 MUm on hCA-II for 2 and 4, respectively. CONCLUSIONS: The synthesized compounds 2 and 4 had effective inhibitory activity (P < 0.0001) on hCA-I and hCA-II than the corresponding free ligands, 1 and 3, and acetazolamide. Compounds 2 and 4 might be considered as potential inhibitors. PMID- 23356846 TI - Delayed delivery of intravenous gentamicin in neonates: impact of infusion variables. AB - OBJECTIVE: To investigate infusion variables that delay delivery of gentamicin through neonatal infusion lines. METHODS: Infusions were set up to simulate administration of gentamicin to neonates. The primary infusion was 10% dextrose (Baxter Colleague pump). A syringe driver was used to deliver a coloured marker via the T-connection over 35 min followed by a 1 ml normal saline flush over 35 min. Effects of dextrose concentration, primary infusion rate, dose volume and angle of the primary line were investigated. Gentamicin adsorption to in-line filters (Poisdyne Neo) and administration protocols from different neonatal intensive care units were also investigated. KEY FINDINGS: Low dose volumes (<0.4 ml) infused into slow-flowing glucose (dextrose) lines (3.8-4 ml/h) did not mix well at the T-connection. Coloured solutions formed an upper layer that moved in a retrograde direction towards the primary infusion bag. Gentamicin did not adsorb onto Posidyne Neo filters. Comparison of infusion protocols for gentamicin administration showed that slow infusion (30 min) into slow-flowing lines (4 ml/h) containing 10% glucose gave low recovery of drug during the infusion (<30% of intended dose). CONCLUSIONS: Poor mixing at the T-connection appears to be the cause of delayed and/or incomplete gentamicin delivery for low dose volumes and slow infusion rates. PMID- 23356847 TI - Stability studies of binary and ternary mixtures containing morphine, midazolam, levomepromazine and hyoscine butylbromide for parenteral administration. AB - OBJECTIVES: [corrected] Parenteral (intravenous or subcutaneous) administration is routinely used in palliative medicine because patients are not able to take drugs orally. To avoid excessive injections, several drugs are usually given in the same dose, but the stability of these drugs when mixed is not always known. The aim of this study was to evaluate the stability of several mixtures of drugs (morphine, midazolam, levomepromazine and hyoscine butylbromide) kept under different storage conditions. METHODS: Stability was evaluated on the basis of percentage of drug remaining, pH, change of colour and gas or precipitate formation. KEY FINDINGS: The most notable results of the study showed that levomepromazine is rapidly degraded in 0.9% NaCl in all cases, and at high concentrations, morphine can precipitate when stored at 4 degrees C. CONCLUSIONS: Mixtures containing levomepromazine are rapidly degraded under experimental conditions. PMID- 23356848 TI - Phosphoenolpyruvate, a glycolytic intermediate, as a cytoprotectant and antioxidant in ex-vivo cold-preserved mouse liver: a potential application for organ preservation. AB - OBJECTIVES: The aim of this study was to examine the effect of phosphoenolpyruvate (PEP), a glycolytic intermediate, on organ damage during cold preservation of liver. METHODS: An ex-vivo mouse liver cold-preservation model and an in-vitro liver injury model induced by hydrogen peroxide in HepG2 cells were leveraged. KEY FINDINGS: PEP attenuated the elevation of aminotransferases and lactate dehydrogenase leakage during organ preservation, histological changes and changes in oxidative stress parameters (measured as thiobarbituric acid reactive substance and glutathione content) induced by 72 h of cold preservation of the liver. The effects were comparable with the University of Wisconsin solution, a gold standard organ preservation agent. The decrease in ATP content in liver during the cold preservation was attenuated by PEP treatment. PEP prevented the cellular injury and increases in intracellular reactive oxygen species in HepG2 cells. In addition, PEP scavenged hydroxyl radicals, but had no effect on superoxide anion as evaluated by an electron paramagnetic resonance spin-trapping technique. CONCLUSIONS: PEP significantly attenuated the injury, oxidative stress and ATP depletion in liver during cold preservation. The antioxidative potential of PEP was confirmed by in-vitro examination. We suggest that PEP acts as a glycolytic intermediate and antioxidant, and is particularly useful as an organ preservation agent in clinical transplantation. PMID- 23356849 TI - Synthesis and plasma pharmacokinetics in CD-1 mice of a 18beta-glycyrrhetinic acid derivative displaying anti-cancer activity. AB - OBJECTIVES: The plasma pharmacokinetic profile in CD-1 mice of a novel 18beta glycyrrhetinic acid (GA) derivative, which displays in vitro anti-cancer activity, was assessed. METHODS: This study involved an original one-step synthesis of N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl) glycyrrhetinamide, (2) a compound that displays marked anti-proteasome and anti kinase activity. The bioselectivity profile of 2 on human normal NHDF fibroblasts vs human U373 glioblastoma cells was assessed. Maximal tolerated dose (MTD) profiling of 2 was carried out in CD1 mice, and its serum pharmacokinetics were profiled using an acute intravenous administration of 40 mg/kg body weight. KEY FINDINGS: Compound 2 displayed IC(50) in vitro growth inhibitory concentrations of 29 and 8 MUm on NHDF fibroblasts and U373 glioblastoma cells, respectively, thus a bioselectivity index of ~4. The intravenous pharmacokinetic parameters revealed that 2 was rapidly distributed (t(1/2dist) of ~3 min) but slowly eliminated (t(1/2elim) = ~77 min). CONCLUSIONS: This study describes an original and reliable nanoemulsion of a GA derivative with both anti-proteasome and anti kinase properties and that should be further tested in vivo using various human xenograft or murine syngeneic tumour models with both single and chronic intravenous administration. PMID- 23356850 TI - N'-Formyl-2-(5-nitrothiophen-2-yl)benzothiazole-6-carbohydrazide as a potential anti-tumour agent for prostate cancer in experimental studies. AB - OBJECTIVES: Benzothiazoles (BZTs) represent organic compounds with different biological actions. In this study we aimed to investigate ten newly synthesized BZT derivatives as potential anti-tumour agents against prostate cancer in vitro and in vivo. METHODS: The cytotoxic effect of these compounds was screened on the human prostate cancer cell lines PC-3 and LNCaP. The most effective compound, N' formyl-2-(5-nitrothiophen-2-yl)benzothiazole-6-carbohydrazide, was further characterized regarding its dose- and time-dependent effects on cell viability and proliferation (XTT test) as well as on adhesion and spreading (real-time cell analyzer xCelligence), migration (scratch-wound repair assay) and invasion (Boyden chamber) of the cells. This BZT derivative was also tested as an inhibitor of angiogenesis (chicken chorioallantoic membrane assay), clonogenic activity (soft agar) and matrix metalloproteinase 9 (gelatin zymography). KEY FINDINGS: N'-Formyl-2-(5-nitrothiophen-2-yl)benzothiazole-6-carbohydrazide significantly inhibited all tested properties of the prostate cancer cell lines and showed low toxic in vitro and in vivo effects. The in vitro anti-tumour activity of this compound was confirmed by the in vivo effects on PC-3 xenografts in nude mice. Tumour growth was decreased in treated compared with untreated mice. CONCLUSIONS: These results suggest the potential capacity of BZTs and in particular N'-formyl-2-(5-nitrothiophen-2-yl)benzothiazole-6-carbohydrazide as anti-tumour agents for the treatment of prostate cancer. PMID- 23356851 TI - Dramatic increase in hepatic and biliary curcumin exposure by modulation of its elimination pathway in rats. AB - OBJECTIVES: Curcumin, a major component of the food spice turmeric (Curcuma longa), has multiple beneficial effects on diseases of the liver and bile duct. We have investigated whether modulation of the curcumin elimination pathway could increase its hepatic and biliary exposure in rats. METHODS: Probenecid, an inhibitor of the metabolism and biliary excretion of curcumin, was used as a modulator. After intravenous administration of curcumin at a dose of 18 mg/kg/h without (control) or with co-infusion of probenecid (230 mg/kg/h) in rats, the pharmacokinetic parameters of curcumin were estimated. KEY FINDINGS: Coadministration of probenecid significantly increased the total area under the plasma (1.88-fold) and bile (6.73-fold) concentration-time curves from 0 to 80 min of curcumin relative to those in the controls. The tissue-to-plasma concentration ratio in the liver was also dramatically increased (69.3-fold) by probenecid. These results may be attributed to the dual inhibitory effects of probenecid, to a greater extent, on metabolism via glucuronidation, and to a lesser extent, on the biliary excretion of curcumin via the multidrug resistance associated protein 2. CONCLUSIONS: The probenecid-mediated increase in hepatic and biliary exposure of curcumin suggested that the use of combination drug regimens involving curcumin and modulators of elimination may be an innovative approach for the therapeutic use of curcumin. PMID- 23356853 TI - Effect of protamine on the accumulation of gentamicin in opossum kidney epithelial cells. AB - OBJECTIVES: The purpose of this study was to examine whether or not protamine, an arginine-rich basic protein mixture, inhibits the accumulation of gentamicin, a nephrotoxic drug, in cultured opossum kidney (OK) epithelial cells. METHODS: The effect of protamine from salmon on accumulation and binding of [(3) H]gentamicin was investigated in OK cells. KEY FINDINGS: Protamine inhibited the binding and accumulation of [(3) H]gentamicin in a concentration-dependent manner. The accumulation of [(14) C]inulin, a marker of fluid-phase endocytosis, was not affected by protamine at concentrations up to 1 mm. l-Arginine at concentrations up to 10 mm had no significant effect on the accumulation of [(3) H]gentamicin. On the other hand, preincubation with 100 MUm protamine for 5 min decreased the accumulation of [(3) H]gentamicin to almost the same extent as coincubation with 100 MUm protamine for 60 min. CONCLUSIONS: Our results indicate that protamine decreases the accumulation of gentamicin in OK cells. These findings suggest that protamine or its derivatives might be useful in preventing the nephrotoxicity of aminoglycoside antibiotics including gentamicin. PMID- 23356852 TI - Implication of eIF2alpha kinase GCN2 in induction of apoptosis and endoplasmic reticulum stress-responsive genes by sodium salicylate. AB - OBJECTIVES: Sodium salicylate (NaSal) can disturb cell viability by affecting the activity of multiple cellular molecules. In this work, we investigated the involvement of stress-responsive kinase GCN2 in regulating cell death and expression of stress genes in mouse embryonic fibroblasts (MEFs) upon exposure to NaSal. METHODS: Cell viability was assayed using the 3-(4,5-dimethylthiazol-2yl) 2,5-diphenyltetrazolium bromide (MTT) method, and apoptosis was evaluated by annexin V and propidium iodide staining. A polymerase chain reaction (PCR) array approach was used to analyse differential expression of a panel of 84 endoplasmic reticulum (ER) stress-associated genes. Gene reporter assays were carried out to determine activity of ER stress element (ERSE), and the protein levels of activating transcription factor 6 (ATF6) and C/EBP homologous protein (CHOP) were determined by western blot. KEY FINDINGS: NaSal treatment resulted in reduction of cellular viability and induction of apoptosis in wild-type but not Gcn2(-/-) cells. Many genes with important functions in protein synthesis/degradation, transcriptional regulation and apoptosis were induced by NaSal and most of these were dependent on GCN2. The activation of ERSE within Ddit3 and the production of CHOP and ATF6 induced by NaSal required GCN2. CONCLUSIONS: Our data provide evidence for the involvement of GCN2 in apoptosis and gene expression triggered by NaSal, and contributes to the understanding of molecular events occurring in NaSal-treated cells. PMID- 23356854 TI - Effects of Pueraria mirifica and miroestrol on the antioxidation-related enzymes in ovariectomized mice. AB - OBJECTIVES: The influences of Pueraria candollei var. mirifica (PM), a Thai medicinal plant with long tradition of medicinal consumption among menopausal women for rejuvenation and estrogen hormone replacement, on oxidative status in ovariectomized (OVX) mice were determined. METHODS: The crude extract of PM and its active phytoestrogen, miroestrol (MR), were given to OVX mice. The effect of them on antioxidation enzymes and glutathione (GSH) levels in livers and uteri were examined in OVX mice and compared with the synthetic estradiol hormone. KEY FINDINGS: Ovariectomy significantly decreased total GSH content, reduced GSH content, and the ratio of GSH to oxidized glutathione (GSSG) in both the livers and the uteri of mice. Moreover, an ovariectomy reduced the activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT). The crude extract of PM as well as MR significantly increased levels of GSH, levels of reduced GSH, and the ratio of GSH/GSSG in both the livers and the uteri, while estradiol did not. In addition, the potential of PM and MR to return the activities of GPx, SOD, and CAT to normal levels was noted. CONCLUSIONS: These observations support using PM and MR as promising alternative medicine candidates for hormone replacement therapy of estradiol because of their ability to improve GSH levels and the activities of antioxidative enzymes, especially in OVX mice. PMID- 23356855 TI - Potentiation of antioxidative and anti-inflammatory properties of cultured wild ginseng root extract through probiotic fermentation. AB - OBJECTIVES: This work aimed to determine some pharmacological properties of non fermented (WG) and fermented (FWG) extracts of cultured wild ginseng root. METHODS: WG was treated with Bifidobacterium longum to generate FWG. Ginsenoside patterns were analysed using thin-layer chromatography and high-performance liquid chromatography. The effect of WG and FWG on reactive oxygen species (ROS) was examined in lipopolysaccharide-stimulated RAW264.7 macrophage cells. Intracellular ROS were detected by flow cytometry. Nitrite in culture supernatant fractions was determined using the Griess reaction. 1,1-Diphenyl-2-picrylhydrazyl was used to determine anti-radical activity. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. KEY FINDINGS: FWG was rich in ginsenosides Rg3 and Rh2, compared with WG. FWG diminished the enhanced ROS level more strongly than WG in lipopolysaccharide-stimulated RAW264.7 macrophage cells. Both WG and FWG decreased the nitrite levels in stimulated macrophage cells with half-maximal inhibitory concentration (IC50) values of 2.7 and 1.5 mg/ml, respectively, implying that FWG had an enhanced anti inflammatory activity. Neither WG nor FWG exhibited cytotoxicity on the macrophage cells. In the radical scavenging assay, the IC50 values of WG and FWG were 32.6 and 0.78 mg/ml, respectively, suggesting that FWG had an increased scavenging activity. CONCLUSIONS: FWG possesses enhanced antioxidative and anti inflammatory activity, indicating that fermentation of cultured wild ginseng root extract with a probiotic bacterium can strengthen some of its desirable effects. PMID- 23356857 TI - Housing assistance and case management: improving access to substance use disorder treatment for homeless veterans. AB - The problem of waiting list attrition in addiction treatment programs is widespread, and homeless and marginally housed individuals are particularly susceptible. This naturalistic, retrospective study describes an intervention (Transitional Supportive Housing and Case Management) that effectively promoted treatment admission for this high-risk group above and beyond that which could be explained by certain pretreatment factors. The clinical records of 211 military veterans referred to intensive outpatient addiction treatment were reviewed for factors related to treatment program admission, including 3 interventions designed to prevent waiting list attrition. Chi-square tests evaluated univariate predictors of treatment entry, and a hierarchical binary logistic regression evaluated several variables simultaneously. Results showed that fewer than 50% of wait-listed patients achieved treatment admission. Univariate predictors of treatment entry were not having a current partner, having a legal problem, and having had past substance use disorder treatment. The logistic regression showed that patients who received the intervention were 4.5 times more likely to enter the treatment program, and individuals with a current legal problem were 2.5 times more likely to enter treatment. Participation in a weekly support group and/or contact with a psychiatric nurse practitioner did not increase the likelihood of program admission. It may be possible to enhance treatment entry for the homeless and marginally housed by providing case management and housing services. Future research is needed to determine how the individual-level factors predicting treatment entry in this study can be used to tailor other interventions to further address the problem of waiting list attrition. PMID- 23356856 TI - Multilocus loss of DNA methylation in individuals with mutations in the histone H3 lysine 4 demethylase KDM5C. AB - BACKGROUND: A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment. RESULTS: Using a genome wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5, SCMH1, CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D. In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP. CONCLUSIONS: We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain. PMID- 23356858 TI - Pharmacotherapy for alcohol dependence: perceived treatment barriers and action strategies among Veterans Health Administration service providers. AB - Although access to and consideration of pharmacological treatments for alcohol dependence are consensus standards of care, receipt of these medications by patients is generally rare and highly variable across treatment settings. The goal of the present project was to survey and interview the clinicians, managers, and pharmacists affiliated with addiction treatment programs within Veterans Health Administration (VHA) facilities to learn about their perceptions of barriers and facilitators regarding greater and more reliable consideration of pharmacological treatments for alcohol dependence. Fifty-nine participants from 19 high-adopting and 11 low-adopting facilities completed the survey (facility level response rate = 50%) and 23 participated in a structured interview. The top 4 barriers to increased consideration and use of pharmacotherapy for alcohol dependence were consistent across high- and low-adopting facilities and included perceived low patient demand, pharmacy procedures or formulary restrictions, lack of provider skills or knowledge regarding pharmacotherapy for alcohol dependence, and lack of confidence in treatment effectiveness. Low patient demand was rated as the most important barrier for oral naltrexone and disulfiram, whereas pharmacy or formulary restrictions were rated as the most important barrier for acamprosate and extended-release naltrexone. The 4 strategies rated across low- and high-adopting facilities as most likely to facilitate consideration and use of pharmacotherapy for alcohol dependence were more education to patients about existing medications, more education to health care providers about medications, increased involvement of physicians in treatment for alcohol dependence, and more compelling research on existing medications. This knowledge provides a foundation for designing, deploying, and evaluating targeted implementation efforts. PMID- 23356859 TI - Formulation and characterization of Brucea javanica oil microemulsion for improving safety. AB - OBJECTIVE: This study engaged in investigation of optimal formulation, characteristics analysis of Brucea javanica oil microemulsion (BJOM) in order to address safety concerns and make recommendations for improvements in BJOM safety during clinical use in vivo. METHODS: Pseudo-ternary phase diagram techniques were used to determine the appropriate ratio of surfactant, cosurfactant and oil phases. Subsequent stability testing of BJOM was performed by dilution, centrifugation and accelerated stability testing. The results were expounded through additional assessment utilizing the classical thermostat method to establish the shelf life of the material. These results were utilized to evaluate the safety of BJOM by haemolytic, irritative and allergic testing in vitro. In addition, the cytotoxicity of BJOM was examined using the tetrazolium salt 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), with particular emphasis given to potential uses in cancer treatment. RESULTS: The most suitable method of preparation for BJOM was found to be a one to one ratio (Km 1:1) of Solutol HS15 surfactant matched with sorbitol cosurfactant in the ratio. The microemulsion droplets of BJOM possessed a spherical shape, uniform size and average diameter of 23.8 nm. The expiration date of BJOM was found to be 568 d. The safety study demonstrated no hemolysis activity at the experimental BJOM concentrations; however, mild hemolysis was observed at higher concentrations of Brucea javanica oil emulsion (BJOE), a common commercially available product. Irritation observed upon BJOM treatment can be primarily attributed to Brucea javanica oil (BJO) with little influence of BJOM excipients. In addition, BJOM caused no observed hypersensitivity or other visible allergic reactions in guinea pigs. The anticancer activity curves of BJOM and BJOE demonstrate that both BJOM and BJOE inhibit Hela cells, with BJOM demonstrating significantly more dramatic anticancer activity. CONCLUSION: An optimal formulation of BJOM superior to commercially available products and safe for medical application such as intravenous injection has been outlined along with its anticancer activity rating. PMID- 23356860 TI - Deformable liposomes by reverse-phase evaporation method for an enhanced skin delivery of (+)-catechin. AB - BACKGROUND: (+)-catechin, as the most common catechin isomer, is recognized to be an antioxidant which benefits the skin in many ways. The purpose of the present study was to prepare and evaluate a suitable liposomal delivery systems for (+) catechin topical application. METHODS: In this study, catechin-loaded conventional liposomal delivery system, deformable conventional liposomal delivery system and deformable liposomes prepared by reverse-phase evaporation (REV) method were compared. The three systems were characterized for liposome particle size, zeta-potential, entrapment efficiency, drug release, permeability across porcine skin and catechin deposition in the skin. RESULTS: It was revealed that the size of deformable conventional liposomes before freeze-drying and deformable REV liposomes after freeze-drying range from 335.6 +/- 71.7 nm to 551.1 +/- 53.4 nm, respectively, which were considered to be suitable for skin delivery. The deformable REV liposomes had a higher aqueous volume and thus were able to entrap greater amounts of hydrophilic (+)-catechin (50.0 +/- 5.9%) compared to conventional (30.0 +/- 3.8%) and deformable conventional liposomes (36.1 +/- 4.6%). All liposomal formulations exhibited a prolonged catechin release. Compared to deformable liposomes, the REV deformable liposomes showed a significantly better deposition of (+)-catechin while catechin solution did not permeate into the porcine ear skin. CONCLUSION: Among all formulations studied, deformable REV liposomes were considered to be favorable for catechin topical delivery. PMID- 23356862 TI - Design and methods for evaluating an early childhood obesity prevention program in the childcare center setting. AB - BACKGROUND: Many unhealthy dietary and physical activity habits that foster the development of obesity are established by the age of five. Presently, approximately 70 percent of children in the United States are currently enrolled in early childcare facilities, making this an ideal setting to implement and evaluate childhood obesity prevention efforts. We describe here the methods for conducting an obesity prevention randomized trial in the child care setting. METHODS/DESIGN: A randomized, controlled obesity prevention trial is currently being conducted over a three year period (2010-present). The sample consists of 28 low-income, ethnically diverse child care centers with 1105 children (sample is 60% Hispanic, 15% Haitian, 12% Black, 2% non-Hispanic White and 71% of caregivers were born outside of the US). The purpose is to test the efficacy of a parent and teacher role-modeling intervention on children's nutrition and physical activity behaviors. . The Healthy Caregivers-Healthy Children (HC2) intervention arm schools received a combination of (1) implementing a daily curricula for teachers/parents (the nutritional gatekeepers); (2) implementing a daily curricula for children; (3) technical assistance with meal and snack menu modifications such as including more fresh and less canned produce; and (4) creation of a center policy for dietary requirements for meals and snacks, physical activity and screen time. Control arm schools received an attention control safety curriculum. Major outcome measures include pre-post changes in child body mass index percentile and z score, fruit and vegetable and other nutritious food intake, amount of physical activity, and parental nutrition and physical activity knowledge, attitudes, and beliefs, defined by intentions and behaviors. All measures were administered at the beginning and end of the school year for year one and year two of the study for a total of 4 longitudinal time points for assessment. DISCUSSION: Although few attempts have been made to prevent obesity during the first years of life, this period may represent the best opportunity for obesity prevention. Findings from this investigation will inform both the fields of childhood obesity prevention and early childhood research about the effects of an obesity prevention program housed in the childcare setting. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: NCT01722032. PMID- 23356861 TI - The clinical and cost-effectiveness of the BRinging Information and Guided Help Together (BRIGHT) intervention for the self-management support of people with stage 3 chronic kidney disease in primary care: study protocol for a randomized controlled trial. AB - BACKGROUND: Improving the quality of care for people with vascular disease is a key priority. Chronic kidney disease (CKD) has recently been included as a target condition for general practices to add to registers of chronic conditions as part of the Quality and Outcome Framework. This paper outlines the implementation and evaluation of a self-management intervention involving an information guidebook, tailored access to local resources and telephone support for people with stage 3 chronic kidney disease. METHODS/DESIGN: The study involves a multi-site, longitudinal patient-level randomized controlled trial. The study will evaluate the clinical use and cost-effectiveness of a complex self-management intervention for people with stage 3 chronic kidney disease in terms of self-management capacity, health-related quality of life and blood pressure control compared to care as usual. We describe the methods of the patient-level randomized controlled trial. DISCUSSION: The management of chronic kidney disease is a developing area of research. The BRinging Information and Guided Help Together (BRIGHT) trial aims to provide evidence that a complementary package of support for people with vascular disease that targets both clinical and social need broadens the opportunities of self-management support by addressing problems related to social disadvantage. TRIAL REGISTRATION: Trial registration reference: ISRCTN45433299. PMID- 23356863 TI - Photoabsorption of acridine yellow and proflavin bound to human serum albumin studied by means of quantum mechanics/molecular dynamics. AB - Attempting to unravel mechanisms in optical probing of proteins, we have performed pilot calculations of two cationic chromophores-acridine yellow and proflavin-located at different binding sites within human serum albumin, including the two primary drug binding sites as well as a heme binding site. The computational scheme adopted involves classical molecular dynamics simulations of the ligands bound to the protein and subsequent linear response polarizable embedding density functional theory calculations of the excitation energies. A polarizable embedding potential consisting of point charges fitted to reproduce the electrostatic potential and isotropic atomic polarizabilities computed individually for every residue of the protein was used in the linear response calculations. Comparing the calculated aqueous solution-to-protein shifts of maximum absorption energies to available experimental data, we concluded that the cationic proflavin chromophore is likely not to bind albumin at its drug binding site 1 nor at its heme binding site. Although agreement with experimental data could only be obtained in qualitative terms, our results clearly indicate that the difference in optical response of the two probes is due to deprotonation, and not, as earlier suggested, to different binding sites. The ramifications of this finding for design of molecular probes targeting albumin or other proteins is briefly discussed. PMID- 23356864 TI - Contraction of the anterior prostate is required for the initiation of micturition. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: In a recent rtMRI study, we were able to show that, during initiation of voiding, there was both funnelling of the bladder neck and simultaneous contraction of the ventral prostate. We presumed that the vertical contraction of the ventral prostate contributes to the initiation of successful micturition. The question remained as to whether this shortening of the ventral prostate is predominantly caused by contractile elements in the organ itself, or by surrounding contractile elements of the pelvic floor. In our study we provide insight in to anatomical changes, and biometric and functional analysis of the prostate during micturition. A sagittal contraction of the ventral prostate and the longitudinal smooth muscle elements at the onset of voiding, which can be observed on MRI, is likely to shorten and open up the prostatic urethra. OBJECTIVE: To investigate if in vitro contractile strength of the prostate and the prostatic urethra might correlate with the shortening of the ventral prostate seen on real-time magnetic resonance imaging (rtMRI). Micturition is a complex process that includes anatomical and neurological interactions for successful voiding. Recently we described on rtMRI that vertical contraction of the ventral prostate precedes initiation of male micturition and may contribute to the funnelling of the bladder neck. PATIENTS AND METHODS: In all, 10 patients undergoing radical prostatectomy (RP) were enrolled. Approval was obtained from all patients and by the local Ethics Committee. Preoperative rtMRI during voiding was performed as described before in eight patients undergoing RP, measuring the difference of the cranio-caudal distance of the ventral prostate (VP). To roughly estimate the amount of force required to deform the prostate in a vertical direction as seen on rtMRI, we uniaxially compressed the organ immediately after surgery by the same distance, assuming incompressibility and isotropy of prostatic tissue. A muscle strip (3 * 3 mm) from the ventral prostate, dorsal prostate and prostatic urethra was obtained after pathological evaluation. Contraction was elicited by electrical field stimulation (EFS: 0.1 ms pulses at 2, 4, 8, 16, 32 and 64 Hz for 4 s). RESULTS: There was a mean cranio-caudal contraction of the ventral prostate by 7.6 mm at the onset of micturition on rtMRI (P = 0.002). The mean (sd) contractile force of strips elicited by EFS at 32 Hz was 1472.44 (706.88) mN for the ventral prostate, 1044.24 (894.66) mN for the dorsal prostate, and 639.10 (785.06) mN for the prostatic urethra (P = 0.02). Extrapolating these values to the whole organ diameter, we calculated comparable force as observed in compression experiments. CONCLUSIONS: Our functional and biometric in vitro analyses of prostate tissue showed sufficient contractile strength of the ventral prostate to induce a shortening of the organ as seen on rtMRI. There was significant higher contractile strength in the ventral prostate than in the dorsal prostate or the proximal urethra. The consistency of in vivo and in vitro results underlines the significance of the ventral prostate for the initiation of normal micturition. PMID- 23356865 TI - Identification of alpha-tocopherol and alpha-tocopheryl acetate from the cuticle of soybean pods armyworm (Spodoptera cosmioides). AB - The chemical composition of the soybean pods armyworm Spodoptera cosmioides (Walker, 1858) (Lepidoptera: Noctuidae) and Anticarsia gemmatalis Hubner, 1818 (Lepidoptera: Erebidae) larval cuticles was evaluated using gas chromatography coupled to a mass detector (GC-MS). Among the usual lipids found in the insect cuticle, alpha-tocopherol and alpha-tocopheryl acetate were also isolated from S. cosmioides. On the other hand, no vitamin E derivative was found in A. gemmatalis exuvia. This is the first report of vitamin E occurrence in the insect's cuticle. PMID- 23356866 TI - The basis examination of leukocyte-platelet aggregates with CD45 gating as a novel platelet activation marker. AB - INTRODUCTION: Platelet activation in circulation is considered to be associated with thrombosis and inflammation; thus, sensitive and easy-to-use markers are necessary. In this study, we established a simple and rapid protocol to clinically examine leukocyte-platelet aggregate formation associated with activated platelets in circulation. METHODS: Whole blood was stained with PC5 conjugated anti-CD45 monoclonal antibody and fluorescent isothiocyanate conjugated anti-CD41 monoclonal antibody for leukocyte-platelet aggregate analysis. For platelet activation, 5 MUm thrombin receptor-activated peptide (TRAP) or 2 MUg/mL collagen was added. Samples were analyzed by EPICS XL (Beckman Coulter, Miami, FL, USA). Monocytes, neutrophils, and lymphocytes were gated based on differences in CD45 fluorescence intensity and side scatter. For each gate, the percentage (%) of platelets expressing CD41 was analyzed. Same drawing sample was stained with anti-CD62P monoclonal antibody. Platelet CD62P expression was then analyzed with gating for platelet cell population. RESULTS: We analyzed leukocyte-platelet aggregates and platelet CD62P expression in 18 healthy individuals. Leukocyte-platelet aggregates, mainly monocyte-platelet aggregates, increased when platelets were activated by platelet agonists. Monocyte-platelet aggregates and neutrophil-platelet aggregates also increased over time with mild platelet activation. CONCLUSION: Leukocyte-platelet aggregates, mainly monocyte platelet aggregates, appear to be a sensitive marker of platelet activation in circulation. PMID- 23356867 TI - Solution structure, dynamics and binding studies of a family 11 carbohydrate binding module from Clostridium thermocellum (CtCBM11). AB - Non-catalytic cellulosomal CBMs (carbohydrate-binding modules) are responsible for increasing the catalytic efficiency of cellulosic enzymes by selectively putting the substrate (a wide range of poly- and oligo-saccharides) and enzyme into close contact. In the present study we carried out an atomistic rationalization of the molecular determinants of ligand specificity for a family 11 CBM from thermophilic Clostridium thermocellum [CtCBM11 (C. thermocellum CBM11)], based on a NMR and molecular modelling approach. We have determined the NMR solution structure of CtCBM11 at 25 degrees C and 50 degrees C and derived information on the residues of the protein that are involved in ligand recognition and on the influence of the length of the saccharide chain on binding. We obtained models of the CtCBM11-cellohexaose and CtCBM11-cellotetraose complexes by docking in accordance with the NMR experimental data. Specific ligand-protein CH-pi and Van der Waals interactions were found to be determinant for the stability of the complexes and for defining specificity. Using the order parameters derived from backbone dynamics analysis in the presence and absence of ligand and at 25 degrees C and 50 degrees C, we determined that the protein's backbone conformational entropy is slightly positive. This data in combination with the negative binding entropy calculated from ITC (isothermal titration calorimetry) studies supports a selection mechanism where a rigid protein selects a defined oligosaccharide conformation. PMID- 23356868 TI - The Holliday junction resolvase RecU is required for chromosome segregation and DNA damage repair in Staphylococcus aureus. AB - BACKGROUND: The Staphylococcus aureus RecU protein is homologous to a Bacillus subtilis Holliday junction resolvase. Interestingly, RecU is encoded in the same operon as PBP2, a penicillin-binding protein required for cell wall synthesis and essential for the full expression of resistance in Methicillin Resistant S. aureus strains. In this work we have studied the role of RecU in the clinical pathogen S. aureus. RESULTS: Depletion of RecU in S. aureus results in the appearance of cells with compact nucleoids, septa formed over the DNA and anucleate cells. RecU-depleted cells also show increased septal recruitment of the DNA translocase SpoIIIE, presumably to resolve chromosome segregation defects. Additionally cells are more sensitive to DNA damaging agents such as mitomycin C or UV radiation. Expression of RecU from the ectopic chromosomal spa locus showed that co-expression of RecU and PBP2 was not necessary to ensure correct cell division, a process that requires tight coordination between chromosome segregation and septal cell wall synthesis. CONCLUSIONS: RecU is required for correct chromosome segregation and DNA damage repair in S. aureus. Co-expression of recU and pbp2 from the same operon is not required for normal cell division. PMID- 23356869 TI - Politics of love: narrative structures, intertextuality and social agency in the narratives of parents with disabled children. AB - Recent research has highlighted how parental narratives can be important in the resistance against disabling processes. This article contains analyses of enabling language in narratives published by Scandinavian disability rights organizations. First, drawing on the work of Fisher and Goodley, I point out that the material constitute a threefold: normality narratives, resistance narratives, and narratives that demonstrate an appreciation of the present and the child's individual alterity. Second, I demonstrate that the last narrative draws on Romanticism rather than linguistic resources from disability culture. Third, I show that these narratives are hyperboles - texts that strengthen and emphasise the valuation to the point where the narrative structure transcends narrative consistency. Fourth, drawing on the work of Kristeva, I argue that this form of narration constitutes an intimate politics of love. PMID- 23356870 TI - The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells. AB - The role of hydrogen sulfide (H2 S) in inflammation remains unclear with both pro and anti-inflammatory actions of this gas described. We have now assessed the effect of GYY4137 (a slow-releasing H2 S donor) on lipopolysaccharide (LPS) evoked release of inflammatory mediators from human synoviocytes (HFLS) and articular chondrocytes (HAC) in vitro. We have also examined the effect of GYY4137 in a complete Freund's adjuvant (CFA) model of acute joint inflammation in the mouse. GYY4137 (0.1-0.5 mM) decreased LPS-induced production of nitrite (NO2 (-) ), PGE2 , TNF-alpha and IL-6 from HFLS and HAC, reduced the levels and catalytic activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced LPS-induced NF-kappaB activation in vitro. Using recombinant human enzymes, GYY4137 inhibited the activity of COX-2, iNOS and TNF-alpha converting enzyme (TACE). In the CFA-treated mouse, GYY4137 (50 mg/kg, i.p.) injected 1 hr prior to CFA increased knee joint swelling while an anti inflammatory effect, as demonstrated by reduced synovial fluid myeloperoxidase (MPO) and N-acetyl-beta-D-glucosaminidase (NAG) activity and decreased TNF-alpha, IL-1beta, IL-6 and IL-8 concentration, was apparent when GYY4137 was injected 6 hrs after CFA. GYY4137 was also anti-inflammatory when given 18 hrs after CFA. Thus, although GYY4137 consistently reduced the generation of pro-inflammatory mediators from human joint cells in vitro, its effect on acute joint inflammation in vivo depended on the timing of administration. PMID- 23356871 TI - Efficacy of intratympanic steroid therapy for idiopathic sudden sensorineural hearing loss: comparison with systemic steroid therapy and combined therapy. AB - CONCLUSION: Intratympanic steroid therapy (IT-S) was as effective as systemic steroid therapy (SST) or combined therapy (CT) and could be considered a first line therapeutic modality for idiopathic sudden sensorineural hearing loss (SSNHL). Due to its known safety and efficacy, IT-S will be particularly suitable for patients with SSNHL who have chronic diseases such as diabetes mellitus, hypertension, or chronic renal failure. OBJECTIVES: Systemic high dose steroid therapy is the main therapeutic modality for SSNHL. Comparable therapeutic efficacies for IT-S and CT with SST and IT-S for SSNHL have been reported recently. We compared the efficacy of IT-S, SST, and CT for treating SSNHL. METHODS: A retrospective, multicenter study investigating the therapeutic efficacy of SST, IT-S, and CT for SSNHL was designed and involved 735 patients with idiopathic SSNHL who were diagnosed and treated at seven tertiary referral medical centers of the Catholic University of Korea between 2007 and 2011. Patients were divided into three groups according to the treatment methods they received: IT-S group, SST group, and CT group (SS plus IT-S). Hearing was evaluated by pure tone audiogram performed before initial treatment and at 4 weeks following the final treatment. More than a 10 dB HL decrease in average air conduction threshold of hearing at 500, 1000, 2000, and 3000 Hz was defined as improved hearing. RESULTS: Among 735 patients with SSNHL, 94 were included in the IT-S group, 444 in the SST, and 197 in the CT group. Age, gender, interval from disease onset to start of treatment, and initial hearing level were not different among the three groups. Patients who had concomitant medical disorders such as diabetes mellitus, hypertension, or chronic renal failure were more frequently treated with IT-S. No difference in the level of hearing gain or ratio of hearing improvement was observed among the three groups (p = 0.147 and p = 0.067, respectively). PMID- 23356872 TI - Importance of vertical pathology of debulking specimens during Mohs micrographic surgery for lentigo maligna and melanoma in situ. AB - BACKGROUND: Recent Recovery Audit Contractor audits have targeted Mohs micrographic surgery (MMS) if permanent-section pathology codes have been used on the same day. In lentigo maligna (LM) or melanoma in situ (MIS) cases, this is done to further evaluate the tumor for staging. OBJECTIVE: To determine the percentage of LM, MIS, and thin invasive melanomas upstaged when a central debulking specimen from MMS is sent for permanent vertical sections. METHODS: A single-center retrospective study examining LM, MIS, and thin melanomas treated with MMS between January 1, 2004, and September 30, 2011, at Vanderbilt University was performed. The elements needed for staging, sex, age, tumor location, size, and previous skin cancer history were obtained. RESULTS: Fourteen of 173 cases (8.1%; 95% confidence interval = 4.9-13.1%) were identified in which the tumor was upstaged; 13 of the cases initially diagnosed as LM or MIS were invasive (average Breslow depth 0.69 mm). One melanoma at 0.6 mm depth on initial biopsy increased to 1.2 mm after the debulking specimen from Mohs surgery was examined histologically. Debulking in four cases revealed a depth of 1 mm or greater. No differences existed in characteristics between upstaged and nonupstaged cases. CONCLUSION: When performing MMS for LM or MIS, it is appropriate and necessary to send the central debulking specimen for permanent histology for accurate tumor staging. PMID- 23356873 TI - Differential induction of mitochondrial machinery by light intensity correlates with changes in respiratory metabolism and photorespiration in rice leaves. AB - The light responsiveness of mitochondrial function was investigated through changes in mitochondrial composition and metabolism in rice (Oryza sativa) shoots. The mitochondrial proteome and metabolite abundances under low light, (LL, 100 MUmol m(-2) s(-1) ), and high light (HL, 700 MUmol m(-2) s(-1) ) were measured along with information on shoot photosynthetic, respiratory and photorespiratory activity. Specific steps in mitochondrial tricarboxylic acid (TCA) cycle metabolism were decreased under HL, correlating with lower respiration rate under HL. The abundance of mitochondrial enzymes in branch chain metabolism was reduced under HL/LL, and correlated with a decrease in the abundance of a range of amino acids in the HL/LL. Mitochondrial nucleoside diphosphate kinase was increased under LL/HL treatments. Significant accumulation of glycine decarboxylase P, T subunits and serine hydroxymethyltransferase occurred in response to light. The abundance of the glycine decarboxylase (GDC) H subunit proteins was not changed by HL/LL treatments, and the abundance of GDC L subunit protein was halved under HL, indicating a change in the stoichiometry of GDC subunits, while photorespiration was fourfold higher in LL- than in HL treated plants. Insights into these light-dependent phenomena and their importance for understanding the initiation of photorespiration in rice and adaptation of mitochondria to function in photosynthetic cells are discussed. PMID- 23356874 TI - When the job has lost its appeal: Intentions to quit among direct care workers. AB - BACKGROUND: Previous research indicates that work stress contributes to intentions to quit among direct care workers (DCWs) who provide services to people with intellectual and developmental disability (IDD). Though resources can help DCWs cope and remain in a job, little is known about how various dimensions of work stress and resources (social and personal resources) are associated with intentions to quit. METHODS: A total of 323 DCWs from 5 community-based IDD organisations completed a self-administered survey. We conducted multiple regression analyses to examine main and interaction effects of work stress and resources (work social support and internal locus of control) on intentions to quit. RESULTS: Work overload was a significant stressor, and work social support (i.e., supervisory support) was associated with low intentions to quit. The association between locus of control and intention to quit depended on the levels of a stressor: DCWs' lack of participation in decision-making. CONCLUSIONS: Supervisory support and an internal locus of control may assist DCWs in managing their stress. PMID- 23356876 TI - Meloxicam as an adjuvant to peginterferon-alpha-2a and ribavirin treatment for genotype 1 chronic hepatitis C: A randomized trial. AB - AIM: In this multicenter, randomized trial, we evaluated the effectiveness of meloxicam - a non-steroidal anti-inflammatory drug - as an adjuvant for enhancing antiviral efficacy and preventing neutropenia during the treatment of patients with genotype 1 chronic hepatitis C using peginterferon and ribavirin. METHODS: A total of 60 patients were randomly assigned, in a 1:1 ratio, to either the meloxicam or the control group after stratification by neutrophil count. Both groups received weekly peginterferon-alpha-2a (180 MUg) and a weight-based dose of ribavirin for 48 weeks. The meloxicam group received meloxicam (10 mg/day) for the first 8 weeks after initiation of treatment. RESULTS: Through intent-to-treat analysis, we found that the sustained virological response rate in the meloxicam group (19/30, 63.3%) was significantly higher than in the control group (11/30, 36.7%, P < 0.05). The relapse rate was more than twice as high (45%) in the control group than in the meloxicam group (19.0%); however, this difference was not statistically significant. The rate of neutrophil decrease, calculated by dividing the lowest value observed during the first 8 weeks by pretreatment count, was significantly smaller in the meloxicam group (55.1 +/- 14.3%) than in the control group (62.3 +/- 9.6%, P < 0.05). CONCLUSION: Meloxicam enhanced antiviral efficacy and reduced the decline in neutrophil counts for the peginterferon and ribavirin treatment of genotype 1 chronic hepatitis C. This drug could be a reasonable adjuvant for the treatment of patients with chronic hepatitis C. The present study including a small number of patients warrants larger clinical trials. PMID- 23356875 TI - Screening for tuberculosis and the use of a borderline zone for the interpretation of the interferon-gamma release assay (IGRA) in Portuguese healthcare workers. AB - INTRODUCTION: The effect of using a borderline zone for the interpretation of the interferon-gamma release assay (IGRA) on the prediction of progression to active tuberculosis (TB) in healthcare workers (HCW) is analysed. METHODS: Data from a published study on TB screening in Portuguese HCW is reanalysed using a borderline zone for the interpretation of the IGRA. Testing was performed with the QuantiFERON-TB Gold In-Tube (QFT). The borderline zone for the QFT was defined as interferon (INF) in QFT >=0.2 to <0.7 IU/mL. An X-ray was performed when the IGRA was positive (>=0.35 IU/mL) or typical symptoms were present. Sputum analysis was performed according to the X-ray or the presence of typical symptoms. RESULTS: The cohort comprised 2,884 HCW with a QFT that could be interpreted. In 1,780 (61.7%) HCW, the QFT was <0.2 IU/mL. A borderline result was found in 341 (11.8%) and a QFT >0.7 IU/mL in 763 (26.3%) HCW. Fifty-seven HCW had a TB in their medical history, eight had a TB at the time of screening and progression to active TB was observed in four HCW. Two out of eight HCW (25%) with active TB at the time of screening had a QFT result falling into the borderline zone. One out of four HCW (25%) who progressed towards active TB after being tested with QFT had QFT results falling into the borderline zone. A second IGRA was performed in 1,199 HCW. In total, 292 (24.4%) HCW had at least one of the two IGRA results pertaining to the borderline zone. CONCLUSION: Using a borderline zone for the QFT from 0.2 to 0.7 IU/mL should be administered with care, as active TB as well as progression to active TB might be overlooked. Therefore, the borderline zone should be restricted to populations with a low TB risk only. PMID- 23356877 TI - Children's reporting of food insecurity in predominately food insecure households in Texas border colonias. AB - BACKGROUND: Food insecurity is associated with detrimental physical, psychological, behavioral, social, and educational functioning in children and adults. Greater than one-quarter of all Hispanic households in the U.S. are food insecure. Hispanic families in the U.S. comprise 30% of households with food insecurity at the child level, the most severe form of the condition. METHODS: Food security discordance was evaluated among 50 Mexican-origin children ages 6 11 and their mothers living in Texas border colonias from March to June 2010. Mothers and children were interviewed separately using promotora-researcher administered Spanish versions of the Household Food Security Survey Module and the Food Security Survey Module for Youth. Cohen's kappa statistic (kappa) was used to analyze dyadic agreement of food security constructs and level of food security. RESULTS: Eighty percent of mothers reported household food insecurity while 64% of children identified food insecurity at the child level. There was slight inter-rater agreement in food security status (kappa = 0.13, p = 0.15). Poor agreement was observed on the child hunger construct (kappa = -0.06, p = 0.66) with fair agreement in children not eating for a full day (kappa = 0.26, p < 0.01) and relying on low-cost foods (kappa = 0.23, p = 0.05). CONCLUSIONS: Mother and child-reported household and child-level food insecurity among this sample of limited-resource Mexican-origin colonias residents far surpass national estimates. While the level of dyadic agreement was poor, discordance may be attributable to parental buffering, social desirability in responses, and/or the age of children included in the present analysis. Future research should continue to explore how food security is understood from the perspectives and experiences of children and adolescents. PMID- 23356879 TI - Synthesis and structure-activity relationship studies of novel dual inhibitors of soluble epoxide hydrolase and 5-lipoxygenase. AB - Current research leads to the assumption that drugs affecting more than one target could result in a more efficient treatment of diseases and fewer safety concerns. Administration of drugs inhibiting only one branch of the arachidonic acid cascade is usually accompanied by side effects. We therefore designed and synthesized a library of hybrid molecules incorporating an imidazo[1,2-a]pyridine and an urea moiety as novel soluble epoxide hydrolase (sEH)/5-lipoxygenase (5-LO) dual inhibitors. Evaluation of the compounds was accomplished by in vitro testing using recombinant enzyme assays. PMID- 23356878 TI - Next-generation text-mining mediated generation of chemical response-specific gene sets for interpretation of gene expression data. AB - BACKGROUND: Availability of chemical response-specific lists of genes (gene sets) for pharmacological and/or toxic effect prediction for compounds is limited. We hypothesize that more gene sets can be created by next-generation text mining (next-gen TM), and that these can be used with gene set analysis (GSA) methods for chemical treatment identification, for pharmacological mechanism elucidation, and for comparing compound toxicity profiles. METHODS: We created 30,211 chemical response-specific gene sets for human and mouse by next-gen TM, and derived 1,189 (human) and 588 (mouse) gene sets from the Comparative Toxicogenomics Database (CTD). We tested for significant differential expression (SDE) (false discovery rate -corrected p-values < 0.05) of the next-gen TM-derived gene sets and the CTD derived gene sets in gene expression (GE) data sets of five chemicals (from experimental models). We tested for SDE of gene sets for six fibrates in a peroxisome proliferator-activated receptor alpha (PPARA) knock-out GE dataset and compared to results from the Connectivity Map. We tested for SDE of 319 next-gen TM-derived gene sets for environmental toxicants in three GE data sets of triazoles, and tested for SDE of 442 gene sets associated with embryonic structures. We compared the gene sets to triazole effects seen in the Whole Embryo Culture (WEC), and used principal component analysis (PCA) to discriminate triazoles from other chemicals. RESULTS: Next-gen TM-derived gene sets matching the chemical treatment were significantly altered in three GE data sets, and the corresponding CTD-derived gene sets were significantly altered in five GE data sets. Six next-gen TM-derived and four CTD-derived fibrate gene sets were significantly altered in the PPARA knock-out GE dataset. None of the fibrate signatures in cMap scored significant against the PPARA GE signature. 33 environmental toxicant gene sets were significantly altered in the triazole GE data sets. 21 of these toxicants had a similar toxicity pattern as the triazoles. We confirmed embryotoxic effects, and discriminated triazoles from other chemicals. CONCLUSIONS: Gene set analysis with next-gen TM-derived chemical response-specific gene sets is a scalable method for identifying similarities in gene responses to other chemicals, from which one may infer potential mode of action and/or toxic effect. PMID- 23356880 TI - Bioactives and nutraceutical phytochemicals naturally occurring in virgin olive oil. The case study of the Nocellara del Belice Italian olive cultivar. AB - This work reports on the composition and bionutritional value of organic virgin olive oil from the Nocellara del Belice variety, one cultivated in the olive areas of the Sicily region, Italy. Destoned oils obtained by processing olives with a destoning-based procedure were compared with conventional oils. This innovative technique, consisting in removing the stone from fruits prior to processing, strongly enhanced the already high-quality level of the conventional product. An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols). It had higher levels of oleocanthal (p-HPEA-EDA), a nutraceutical compound exerting actions against COX1 and COX2 (cycloxygenases). Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the lipoxygenase (LOX)-pathway (one having as precursors the polyunsaturated fatty acids containing a cis-cis-1,4-pentadiene system). Among the other bioactives, we highlight its significant levels of trans beta-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids). Its enhanced nutritional value was also attributable to the increased intensity of valuable tasting notes. PMID- 23356881 TI - Teachers' implicit personality theories about the gifted: an experimental approach. AB - The implicit theories teachers hold about the gifted influence their perception of and behavior toward highly able students, thus impacting the latter's educational opportunities. Two persistent stereotypes about the gifted can be distinguished: the harmony hypothesis (gifted students are superior in almost all domains) and the disharmony hypothesis (giftedness implies maladaptive social behavior and emotional problems). The present study investigated whether teachers' implicit personality theories about the gifted are in line with the harmony or the disharmony hypothesis. Using an experimental vignette approach, we examined 321 prospective and practicing teachers' implicit personality theories (based on the big five personality framework) about students described along three dimensions (ability level, gender, and age, resulting in 8 different vignettes), controlling for teachers' age, gender, experience with gifted students, and knowledge about giftedness. Ability level had the strongest effect on teachers' ratings (partial eta2 = .60). Students described as gifted were perceived as more open to new experiences, more introverted, less emotionally stable, and less agreeable (all ps < .001). No differences were found for conscientiousness. Gender and its interaction with ability level had a small effect (partial eta2s = .04 and .03). Thus, teachers' implicit personality theories about the gifted were in line with the disharmony hypothesis. Possible consequences for gifted identification and education are discussed. PMID- 23356882 TI - Androgen modulates cardiac fibrosis contributing to gender differences on heart failure. AB - Chronic heart failure (HF) is a major health problem throughout the world. Gender has significant effects on the pathophysiology of HF. Low levels of free testosterone are independently associated with increased chronic HF symptoms and mortality. Cardiac fibrosis plays a pivotal role in structural remodeling in HF. Transforming growth factor (TGF)-beta, angiotensin II and oxidative stress contribute to the activity/extent of cardiac fibrosis. Androgen deficiency can up regulate TGF-beta expression under angiotensin II stimulation in vivo. In this review, we summarized the potential mechanisms accounting for the effects of androgen on cardiac fibrosis through regulating fibrocytes activity under TGF, which can explain wound healing and cardiac fibrosis in male with acute myocardial injury and chronic HF. PMID- 23356883 TI - Revealing the excited-state dynamics of the fluorescent protein Dendra2. AB - Green-to-red photoconversion is a reaction that occurs in a limited number of fluorescent proteins and that is currently mechanistically debated. In this contribution, we report on our investigation of the photoconvertible fluorescent protein Dendra2 by employing a combination of pump-probe, up-conversion and single photon timing spectroscopic techniques. Our findings indicate that upon excitation of the neutral green state an excited state proton transfer proceeds with a time constant of 3.4 ps between the neutral green and the anionic green states. In concentrated solution we detected resonance energy transfer (25 ps time constant) between green and red monomers. The time-resolved emission spectra suggest also the formation of a super-red species, first observed for DsRed (a red fluorescent protein from the corallimorph species Discosoma) and consistent with peculiar structural details present in both proteins. PMID- 23356884 TI - Rationale and design of South Asian Birth Cohort (START): a Canada-India collaborative study. AB - BACKGROUND: People who originate from the Indian subcontinent (South Asians) suffer among the highest rates of type 2 diabetes in the world. Prior evidence suggests that metabolic risk factors develop early in life and are influenced by maternal and paternal behaviors, the intrauterine environment, and genetic factors. The South Asian Birth Cohort Study (START) will investigate the environmental and genetic basis of adiposity among 750 South Asian offspring recruited from highly divergent environments, namely, rural and urban India and urban Canada. METHODS: Detailed information on health behaviors including diet and physical activity, and blood samples for metabolic parameters and DNA are collected from pregnant women of South Asian ancestry who are free of significant chronic disease. They also undergo a provocative test to diagnose impaired glucose tolerance and gestational diabetes. At delivery, cord blood and newborn anthropometric indices (i.e. birth weight, length, head circumference and skin fold thickness) are collected. The mother and growing offspring are followed prospectively and information on the growth trajectory, adiposity and health behaviors will be collected annually up to age 3 years. Our aim is to recruit a minimum of 750 mother-infant pairs equally divided between three divergent environments: rural India, urban India, and Canada. SUMMARY: The START cohort will increase our understanding of the environmental and genetic determinants of adiposity and related metabolic abnormalities among South Asians living in India and Canada. PMID- 23356885 TI - Factors influencing intracytoplasmic sperm injection (ICSI) outcome in men with azoospermia. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The management of patients with non-obstructive azoospermia (NOA) and some cases of obstructive azoospermia involves testicular sperm extraction (TESE or micro-dissection TESE) combined with intracytoplasmic sperm injection (ICSI). Several studies have investigated the effect of the male age, the cause of azoospermia, testicular histopathology, the type of sperm used, and the use of pentoxyphilline, on the ICSI cycle outcome in men with azoospermia. The present study showed that none of these factors influenced the ICSI outcome in men with azoospermia, thus once sperm is found in an azoospermic male, no other male factor seems to influence the ICSI outcome. To our knowledge this is the first study to comment on the outcome of ICSI in men with NOA based on testicular histopathology. OBJECTIVES: To access the effect of: male age, the cause of azoospermia (obstructive azoospermia vs non-obstructive azoospermia [NOA]), testicular histopathology, the type of sperm used (fresh vs frozen-thawed), and the use of pentoxyphilline on the intracytoplasmic sperm injection (ICSI) cycle outcome in men with azoospermia. To our knowledge this is the first study to comment on the outcome of ICSI in men with NOA based on testicular histopathology. PATIENTS AND METHODS: A retrospective analysis of 137 testicular sperm extraction-ICSI cycles performed between 2001-2010, involving 103 men with azoospermia, with 26 couples having repeat cycles. RESULTS: Analysis of the results did not show any statistically significant differences in the fertilization, embryo cleavage, clinical pregnancy, live birth and miscarriage rates in relation to the male age, cuase of azoospermia, testicular histopathology, type of sperm used and the use of pentoxyphilline. CONCLUSION: Once sperm is found in a man with azoospermia, no other male factor seems to influence the ICSI outcome. PMID- 23356886 TI - Improved efficacy of proton pump inhibitor - amoxicillin - clarithromycin triple therapy for Helicobacter pylori eradication in low clarithromycin resistance areas or for tailored therapy. AB - OBJECTIVE: Standard triple therapy for Helicobacter pylori eradication is no longer effective as an empiric choice in most areas. Even in low clarithromycin resistance areas, results >=95% are infrequently achieved. This study was designed to search for a version of standard triple therapy for use low prevalence areas or as tailored therapy that is highly effective irrespective of CYP2C19 genotype. DESIGN: Two prospective pilot single center studies were performed in Thailand. H. pylori-infected subjects were randomized to 7- or 14 day regimens using a high-dose proton pump inhibitor (PPI) triple therapy consisting of lansoprazole (60 mg) twice daily, amoxicillin 1 g twice daily, and long-acting clarithromycin MR 1 g once daily. H. pylori was defined as positive H. pylori culture; or two positive tests (rapid urease test and histology); CYP2C19 genotyping was performed. H. pylori eradication was evaluated by (13) C UBT 4 or more weeks after treatment. RESULTS: Hundred and ten subjects were enrolled (55 each to the 7- and 14-day regimens). Antibiotic susceptibility testing (25 strains) showed 40% metronidazole resistance but no clarithromycin resistance. CYP2C19 genotyping (64 subjects) revealed 56.3% rapid metabolizer, 29.7% intermediate metabolizer, and 14% poor metabolizer. The eradication rate with the 14-day regimen was 100% (95% CI = 93.5-100%) and 92.7% (95% CI = 82-97%) with the 7-day regimen. The difference was related to improved eradication at 14 days in rapid metabolizers (i.e. 100 vs 88.2%). CONCLUSION: Triple therapy using a 14-day high-dose PPI and long-acting clarithromycin provided an excellent cure rate (100%) regardless of the CYP2C19 genotype. PMID- 23356887 TI - All-trans retinoic acid-loaded lipid nanoparticles as a transdermal drug delivery carrier. AB - The objective of this study was to investigate the effects of drug amounts (0.1%, 0.2% and 0.3% w/w), amounts of the oil (10%, 15% and 20% w/w of lipid matrix) and types of the oil (soybean oil (S), medium chain triglycerides (M), oleic acids (O) and linoleic acids (L)) in lipid matrix of all-trans retinoic acid (ATRA) loaded nanostructured lipid carriers (NLCs) for transdermal drug delivery. The ATRA-loaded solid lipid nanoparticles (SLNs) were formulated with 30% w/w cetyl palmitate. All lipid nanoparticles had average sizes between 130 and 241 nm and had negative zeta potentials. The drug loading of all formulations was higher than 95%. The release of drug from all lipid nanoparticles followed zero-order kinetics. The amount of drug released from all the NLCs and SLNs was significantly greater than the drug released from the ATRA suspension. The ATRA flux of the SLNs was higher than the NLCs. The flux of the NLCs containing oleic acid was significantly higher than the other types of oils. The chemical stability at 4 degrees C, the percentage of ATRA remaining in all the lipid nanoparticles tested was higher than 80%. It can be concluded that both the SLNs and NLCs are promising dermal drug delivery systems for ATRA. PMID- 23356889 TI - Childhood trauma and psychosis: new perspectives on aetiology and treatment. PMID- 23356888 TI - AdE-1, a new inotropic Na(+) channel toxin from Aiptasia diaphana, is similar to, yet distinct from, known anemone Na(+) channel toxins. AB - Heart failure is one of the most prevalent causes of death in the western world. Sea anemone contains a myriad of short peptide neurotoxins affecting many pharmacological targets, several of which possess cardiotonic activity. In the present study we describe the isolation and characterization of AdE-1 (ion channel modifier), a novel cardiotonic peptide from the sea anemone Aiptasia diaphana, which differs from other cnidarian toxins. Although AdE-1 has the same cysteine residue arrangement as sea anemone type 1 and 2 Na(+) channel toxins, its sequence contains many substitutions in conserved and essential sites and its overall homology to other toxins identified to date is low (<36%). Physiologically, AdE-1 increases the amplitude of cardiomyocyte contraction and slows the late phase of the twitch relaxation velocity with no induction of spontaneous twitching. It increases action potential duration of cardiomyocytes with no effect on its threshold and on the cell's resting potential. Similar to other sea anemone Na(+) channel toxins such as Av2 (Anemonia viridis toxin II), AdE-1 markedly inhibits Na(+) current inactivation with no significant effect on current activation, suggesting a similar mechanism of action. However, its effects on twitch relaxation velocity, action potential amplitude and on the time to peak suggest that this novel toxin affects cardiomyocyte function via a more complex mechanism. Additionally, Av2's characteristic delayed and early after depolarizations were not observed. Despite its structural differences, AdE-1 physiologic effectiveness is comparable with Av2 with a similar ED(50) value to blowfly larvae. This finding raises questions regarding the extent of the universality of structure-function in sea anemone Na(+) channel toxins. PMID- 23356890 TI - Anxiety symptoms severity and short-term clinical outcome in first-episode psychosis. AB - AIM: In psychotic disorders, a limited number of studies have documented the presence of symptoms of anxiety, especially in first-episode psychosis (FEP). There is a growing interest in better understanding how these symptoms may affect the severity of psychotic symptoms and clinical outcome. This study examined the association between symptoms of anxiety, as measured by the Hamilton Anxiety Rating Scale (HARS) and the Positive and Negative Syndrome Scale (PANSS), and short-term clinical outcome. We first examined the potential association between anxiety symptom severity among FEP patients and remission. A secondary objective explored the relation between the PANSS single item subscale 'anxiety' item and the total score value of the HARS. METHOD: Data were collected on 201 FEP patients divided into remitted and unremitted groups based on clinical data at 6 months. Anxiety ratings were compared between 67 remitted and 99 unremitted patients with the HARS, and for 72 remitted and 103 unremitted patients with the (G2) PANSS. RESULTS: A significant interaction Time * Group was observed on the HARS and on the PANSS G2 item. Looking at the two time points specifically, groups did not significantly differ at baseline on either the HARS or the PANSS. At 6 months, these two groups were significantly different on both anxiety rating scores - HARS [t(170) = 3.48, P = 0.001)] and PANSS G2 [t(173) = 2.51, P = 0.013)]. CONCLUSION: Anxiety severity is marked in FEP, and appears to be linked to poor short-term clinical outcome. The PANSS single item (G2) seems to represent a good indicator of anxiety as it significantly correlates with a more systematic measure of anxiety, namely the HARS score. Anxiety severity appears to vary across diagnosis type. PMID- 23356891 TI - Positive symptoms in at-risk mental state: the importance of differentiating within the scope. PMID- 23356892 TI - Novel ATP2A2 mutations in a large sample of individuals with Darier disease. AB - Darier disease (DD) is a rare autosomal dominantly inherited skin disorder caused by mutations in ATP2A2, which is expressed in both the skin and the brain and encodes for SERCA2. We have screened the coding regions of ATP2A2 in a total of 95 unrelated individuals with DD to identify the pathogenic mutations. We identified 66 potentially pathogenic mutations in ATP2A2 for 74 of the 95 individuals with DD of which 45 (68%) are thought to be novel. Forty-nine (74%) are unique to an individual and 17 (26%) were found in more than one individual or overlap with previously identified variants. The results suggest that mutations in ATP2A2 may not be as family-specific as first thought. The spectrum of mutations identified will inform understanding of the pathogenesis of DD. PMID- 23356893 TI - The AJT report: news and issues that affect organ and tissue transplantation. PMID- 23356894 TI - Literature watch: implications for transplantation. PMID- 23356895 TI - DCD ECD kidneys-can you make a silk purse from a sow's ear? PMID- 23356896 TI - Program-specific reports for pancreas transplantation: comparing apples and oranges, apples after oranges and apples alone. PMID- 23356897 TI - Vital signs: HIV infection, testing, and risk behaviors among youths--United States. AB - BACKGROUND: In 2009, 6.7% of the estimated 1.1 million persons living with human immunodeficiency virus (HIV) infection in the United States were youths (defined in this report as persons aged 13-24 years); more than half of youths with HIV (59.5%) were unaware of their infection. METHODS: CDC used National HIV Surveillance System data to estimate, among youths, prevalence rates of diagnosed HIV infection in 2009 and the number of new infections (incidence) in 2010. To assess the -prevalence of risk factors and HIV testing among youths, CDC used the 2009 and 2011 Youth Risk -Behavior Surveillance -System for 9th-12th grade students and the 2010 National Health Interview Survey (NHIS) for persons 18-24 years. RESULTS: Prevalence of diagnosed HIV was 69.5 per 100,000 youths at the end of 2009. Youths accounted for 12,200 (25.7%) new HIV infections in 2010. Of these, 7,000 (57.4%) were among blacks/African Americans, 2,390 (19.6%) among Hispanics/Latinos, and 2,380 (19.5%) among whites; 8,800 (72.1%) were attributed to male-to-male sexual contact. The percentage of youths tested for HIV overall was 12.9% among high school students and 34.5% among those aged 18-24 years; it was lower among males than females, and lower among whites and Hispanics/Latinos than blacks/African Americans. CONCLUSIONS: A disproportionate number of new HIV infections occurs among youths, especially blacks/African Americans, Hispanics/Latinos, and men who have sex with men (MSM). The percentage of youths tested for HIV, however, was low, particularly among males. Implications for Public Health: More effort is needed to provide effective school- and community based interventions to ensure all youths, particularly MSM, have the knowledge, skills, resources, and support necessary to avoid HIV infection. Health-care providers and public health agencies should ensure that youths are tested for HIV and have -access to sexual health services, and that HIV-positive youths receive ongoing health-care and prevention services. PMID- 23356898 TI - Fever, abdominal pain and renal failure in a kidney transplant recipient. PMID- 23356899 TI - Incorporation of donor risk into liver allocation algorithms. PMID- 23356900 TI - Effect of exercise in heart transplant recipients. PMID- 23356902 TI - PACE evolves. PMID- 23356903 TI - Is mammary not otherwise specified-type sarcoma with CD10 expression a distinct entity? A rare case report with immunohistochemical and ultrastructural study. AB - Mammary sarcoma is extremely rare and the diagnosis is established only after metaplastic carcinomas and malignant phyllodes tumours are excluded. A rare case of not otherwise specified-type sarcoma with CD10 expression in the left breast in a 45-year-old female was presented. It was a high-grade tumour composed of spindle cells histologically. The immunohistochemical results showed that CD10, vimentin and EGFR were positive diffusely and SMA presented focally, whereas epithelial markers and other myoepithelial or myogenic markers were all negative. The electron microscope investigation demonstrated fibroblast-like features. The exact entity of the tumour remains to be studied because it resembles undifferentiated sarcoma or sarcomatoid metaplastic carcinoma to some degree, as well as high-grade malignant phyllodes tumour in particular. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9019879588725702. PMID- 23356905 TI - Carbohydrates and exercise performance in non-fasted athletes: a systematic review of studies mimicking real-life. AB - There is a consensus claiming an ergogenic effect of carbohydrates ingested in the proximity of or during a performance bout. However, in performance studies, the protocols that are used are often highly standardized (e.g. fasted subjects, constant exercise intensity with time-to-exhaustion tests), and do not necessarily reflect competitive real-life situations. Therefore, we aimed at systematically summarizing all studies with a setting mimicking the situation of a real-life competition (e.g., subjects exercising in the postprandial state and with time-trial-like performance tests such as fixed distance or fixed time tests). We performed a PubMed search by using a selection of search terms covering inclusion criteria for sport, athletes, carbohydrates, and fluids, and exclusion criteria for diseases and animals. This search yielded 16,658 articles and the abstract of 16,508 articles contained sufficient information to identify the study as non-eligible for this review. The screening of the full text of the remaining 150 articles yielded 17 articles that were included in this review. These articles described 22 carbohydrate interventions covering test durations from 26 to 241 min (mostly cycling). We observed no performance improvement with half of the carbohydrate interventions, while the other half of the interventions had significant improvement between 1% and 13% (improvement with one of five interventions lasting up to 68 min and with 10 of 17 interventions lasting between 70 and 241 min). Thus, when considering only studies with a setting mimicking real-life competition, there is a mixed general picture about the ergogenic effect of carbohydrates ingested in the proximity of or during a performance bout with an unlikely effect with bouts up to perhaps 70 min and a possible but not compelling ergogenic effect with performance durations longer than about 70 min. PMID- 23356904 TI - Characterisation of the bacterial microbiota of the vagina of dairy cows and isolation of pediocin-producing Pediococcus acidilactici. AB - BACKGROUND: Uterine infections in dairy cows lower profitability of dairy operations. Infections of the reproductive tract are related to the overgrowth of pathogenic bacteria during the first three weeks after parturition. However, alterations in the vaginal microbiota composition in the first weeks after parturition remain poorly documented. RESULTS: In this study, bacteria isolated from the vagina of healthy pregnant, and infected postpartum cows were characterised by random amplification of polymorphic DNA (RAPD) analysis and partial 16S ribosomal RNA (rDNA) gene sequencing. Populations of bacilli and lactic acid bacteria of the genera Enterococcus, Lactobacillus, and Pediococcus were present in both healthy and infected cows. Infected cows had a significant increase in the vaginal enteric bacteria population which consisted mainly of Escherichia coli. Three E. coli isolates harboured the gene coding for Shiga-like toxin (SLT) I or II. Several isolates of the Pediococcus acidilactici were found to produce the bacteriocin pediocin AcH/PA-1. Quantitative PCR analyses of vaginal mucus samples collected from ten metritic cows before and after parturition confirmed the presence of the Lactobacillus group (Lactobacillus spp., Pediococcus spp., Leuconostoc spp., and Weissella spp.); Enterobacteriaceae, E. coli, and bacilli. The presence of the pediocin AcH/PA-1 structural gene and SLT genes were also confirmed with qPCR. CONCLUSIONS: In conclusion, overgrowth of pathogenic bacteria, particularly E. coli, after parturition likely contributes to the development of metritis. Our microbiota analysis extends the information related to the composition of commensal bacteria in the bovine female reproductive tract and may facilitate the development of novel intervention strategies for prevention of uterine infections in dairy cows. PMID- 23356907 TI - Phthalocyanine-peptide conjugates: receptor-targeting bifunctional agents for imaging and photodynamic therapy. AB - The synthesis of a series of new zinc phthalocyanine-peptide conjugates targeting the gastrin-releasing peptide (GRP) and integrin receptors is reported. Two alternative synthetic methods based on Sonogashira cross-coupling of an iodinated zinc phthalocyanine with acetylenic bombesin or arginine-glycine-aspartic acid (RGD) derivatives, either in solution or on solid phase, are presented. The water soluble conjugates were screened for their photodynamic efficacy against several cancer cell lines expressing different levels of GRP and integrin receptors, and their intracellular localization was evaluated via confocal fluorescence microscopy. Variations in photocytotoxicity between the conjugates correlate to differences in hydrophobicity as well as receptor-mediated cell uptake. In the case of the phthalocyanine-bombesin conjugate, competition experiments confirm the involvement of the GRP receptor in both the phototherapeutic activity as well as intracellular localization. These findings warrant further in vivo studies to evaluate the potential of this conjugate as photosensitizer for photodynamic therapy (PDT) of cancers overexpressing the GRP receptor. PMID- 23356906 TI - Sorting short fragments of single-stranded DNA with an evolving electric double layer. AB - We demonstrate a new procedure for separation of single-stranded DNA (ssDNA) fragments that are anchored to the surface of a gold electrode by end hybridization. The new separation procedure takes advantage of the strong yet evolving nonuniform electric field near the gold surface in contact with a buffer solution gradually being diluted with deionized water. Separation of short ssDNA fragments is demonstrated by monitoring the DNA at the gold surface with in situ fluorescence measurement. The experimental results can be rationalized with a simple theoretical model of electric double layer that relates the strength of the surface pulling force to the ionic concentration of the changing buffer solution. PMID- 23356908 TI - Microparticles containing propolis and metronidazole: in vitro characterization, release study and antimicrobial activity against periodontal pathogens. AB - Ethylcellulose microparticles containing metronidazole and propolis extractive solution were prepared and evaluated in vitro against periodontal pathogens. Scanning electron microscopy, particle size analysis, drug entrapment efficiency and drug release of microparticles were determined. The antimicrobial activity of microparticles was evaluated against microorganisms of periodontal importance (Enterococcus faecalis, Streptococcus pyogenes, Streptococcus mutans, Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli). It was obtained particles with regular morphology, mean diameter of 1.23 um, and entrapment efficiency for propolis and metronidazole were 91.41% and 22.23%, respectively. In vitro release studies of propolis and metronidazole from microparticles showed prolonged drug release and controlled by Fickian diffusion. Both propolis and metronidazole displayed activity against the tested strains. Moreover, the results showed that the strains of E. faecalis, S. pyogenes and S. mutans were more susceptible to the propolis and E. faecalis to the metronidazole. It was also observed that the amount of metronidazole to inhibit the microorganism strains in the physical mixture with propolis was smaller than in the metronidazole alone, suggesting potentiation effect between propolis and metronidazole. These microparticles would be useful for developing intermediary or eventual dosage form to be administered into the periodontal pocket more easily and safely. PMID- 23356910 TI - Fourteen-year oncological and functional outcomes of high-intensity focused ultrasound in localized prostate cancer. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: High-intensity focused ultrasound (HIFU) is an alternative treatment option for localized prostate cancer (PCa), which is applied for over 15 years. There are conflicting recommendations for HIFU among urological societies, which can be explained by the lack of prospective controlled studies, reports on preselected patient populations and limited follow-up providing little information on overall and cancer-specific survival. We report on a large, unselected consecutive patient series of patients who have undergone primary HIFU for clinically localized PCa with the longest follow-up in current literature. Our results improve the understanding of the oncological efficacy, morbidity and side effects of primary HIFU. OBJECTIVE: To assess the safety, functional and oncological long-term outcomes of high-intensity focused ultrasound (HIFU) as a primary treatment option for localized prostate cancer (PCa). PATIENTS AND METHODS: We conducted a retrospective single-centre study on 538 consecutive patients who underwent primary HIFU for clinically localized PCa between November 1997 and September 2009. Factors assessed were: biochemical disease-free survival (BDFS) according to Phoenix criteria (prostate-specific antigen nadir + 2 ng/mL); metastatic-free, overall and PCa-specific survival; salvage treatment; side effects; potency; and continence status. RESULTS: The mean (sd; range) follow-up was 8.1 (2.9; 2.1 14.0) years. The actuarial BDFS rates at 5 and 10 years were 81 and 61%, respectively. The 5-year BDFS rates for low-, intermediate- and high-risk patients were 88, 83 and 48%, while the 10-year BDFS rates were 71, 63 and 32%, respectively. Metastatic disease was reported in 0.4, 5.7 and 15.4% of low-, intermediate- and high-risk patients, respectively. The salvage treatment rate was 18%. Seventy-five (13.9%) patients died. PCa-specific death was registered in 18 (3.3%) patients (0, 3.8 and 11% in the low-, intermediate- and high-risk groups, respectively). Side effects included bladder outlet obstruction (28.3%), Grade I, II and III stress urinary incontinence (13.8, 2.4 and 0.7%, respectively) and recto-urethral fistula (0.7%). Preserved potency was 25.4% (in previously potent patients). CONCLUSIONS: The study demonstrates the efficacy and safety of HIFU for localized PCa. HIFU is a therapeutic option for patients of advanced age, in the low- or intermediate-risk groups, and with a life expectancy of ~10 years. PMID- 23356909 TI - High proportion of granzyme B+ intraepithelial lymphocytes contributes to epithelial apoptosis in Helicobacter pylori-associated lymphocytic gastritis. AB - BACKGROUND: Helicobacter pylori infection has been linked to the development of lymphocytic gastritis (LG) characterized by >=25 intraepithelial lymphocytes (IELs) per 100 epithelial cells. We hypothesize that the changes in the subpopulation and/or cytotoxicity of IELs leading to epithelial cell apoptosis may be involved in the pathogenesis of H. pylori-associated LG. MATERIALS AND METHODS: We examined IEL subpopulations and the expression of cytotoxic molecules by IELs in biopsy specimens from 36 patients with H. pylori-associated LG by immunostainings for CD3, CD4, CD8, T-cell-restricted intracellular antigen-1 (TIA 1), and granzyme B (GrB) and compared the results with those obtained from 49 patients with H. pylori-associated gastritis (HPG). To investigate whether the IEL-mediated cytotoxicity is related to the increase of epithelial apoptosis, we performed a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay using ApopTag detection kit. RESULTS: Between LG and HPG groups, significant differences in the number of CD3+, CD4+, CD8+, TIA-1+ or GrB+ IELs, and ApopTag indices were found. Among the CD3+ IELs, the proportion of CD8+ IELs or TIA-1+ IELs did not differ between two groups. The LG group showed a selective increase in GrB-positive, phenotypically activated IELs, which was paralleled by an increase in ApopTag indices. In contrast, the HPG group showed more heterogeneous IEL subpopulations with more CD4+ IELs and less GrB+ IELs compared with the LG group, and we did not find any significant variable contributing to the epithelial apoptosis in the HPG group. CONCLUSIONS: This study shows that in addition to the numerical increase in the IELs, there are significant changes in the subpopulations and cytotoxicity of IELs between HPG and H. pylori-associated LG. In particular, enhanced GrB-associated cytotoxicity of the IELs in H. pylori associated LG contributes to an increase in epithelial apoptosis. PMID- 23356911 TI - Paraneoplastic pemphigus mimicking toxic epidermal necrolysis associated with B cell lymphoma. PMID- 23356912 TI - Utility of computed tomography fusion imaging for the evaluation of the ablative margin of radiofrequency ablation for hepatocellular carcinoma and the correlation to local tumor progression. AB - AIM: To demonstrate the usefulness of the computed tomography (CT) fusion imaging for the evaluation of treatment effect of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODS: Eighty-five patients with 94 HCC with complete ablation judged on conventional side-by-side interpretation of pre-RFA and post-RFA CT at the time of RFA were included in this retrospective study. CT data was retrospectively used to create fusion images of pre-RFA and post-RFA CT using automatic rigid registration and manual correction referring to intrahepatic structures and hepatic contours around a tumor. Clinical factors including a minimal ablative margin (MAM) measured on fusion images were examined to prove risk factors for local tumor progression (LTP). RESULTS: LTP was observed in 13 (13.8%) tumors with a median follow up of 21.0 months (range, 2 75). The mean MAM on the fusion image was 1.4 +/- 3.1 mm and 23 tumors (24.5%) were judged to be protruding from the ablation zone. Multivariate analysis revealed that protruding from the ablation zone was the only significant factor for LTP (hazard ratio, 7.09; 95% confidential interval, 2.26-22.3; P < 0.001). CONCLUSION: Some HCC were assessed as incomplete ablation on the CT fusion images, although considered completely ablated on side-by-side images at the time of treatment, and incomplete ablation was revealed to be the only independent risk factor for LTP. The CT fusion imaging enables quantitative and accurate evaluation of treatment effect of RFA. PMID- 23356913 TI - Immunohistochemical features of multifocal melanoacanthoma in the hard palate: a case report. AB - BACKGROUND: Melanoacanthoma (MA) has been described in the oral mucosa as a solitary lesion or, occasionally, as multiple lesions. MA mainly affects dark skinned patients and grows rapidly, showing a plane or slightly raised appearance and a brown to black color. The differential diagnosis includes oral nevi, amalgam tattoos, and melanomas. We report here the case of a 58-year-old black woman who presented multiple pigmented lesions on the hard palate. CASE PRESENTATION: Based on the differential diagnosis of melanoma, a punch biopsy (4 mm in diameter) was performed. The material was fixed in 10% formalin, embedded in paraffin, and stained with hematoxylin-eosin or submitted to immunohistochemical analysis. Immunohistochemistry using antibodies against protein S-100, melan-A, HMB-45, MCM-2, MCM-5, Ki-67 and geminin was performed. Immunohistochemical analysis revealed strong cytoplasmic immunoreactivity of dendritic melanocytes for proteinS-100, HMB-45 and melan-A.Positive staining for proliferative markers (MCM-2, MCM-5, Ki-67) was only observed in basal and suprabasal epithelial cells, confirming the reactive etiology of the lesion. The diagnosis was oral Melanoacanthoma (MA). CONCLUSION: The patient has been followed up for 30 months and shows no clinical alterations. MA should be included in the differential diagnosis of pigmented lesions of the oral cavity. PMID- 23356915 TI - Disability and family in the People's Republic of China: implementation, benefits, and comparison of two mutual support groups. AB - BACKGROUND: The authors and 2 Chinese parents established 2 support groups in China. One group was for parents of children with autism, and the other was for young adults with either mental health issues or intellectual disability, and their parents. The purpose of this study was to examine the meaning and effectiveness of these groups from the parents' perspectives. METHOD: Qualitative interviews and questionnaires were completed by members of the groups, across the first 16 months. Facilitator monthly reports were also analysed. RESULTS: Members of both groups found the groups provided a feeling of belonging and a place to interact with similar people. Differences existed relating to perspectives on the purpose of the groups and how families benefited, as well as in participation rates. Suggestions were provided by members. CONCLUSIONS: Implications of the differences in participation and desires of the parents are considered, including the understanding and perceptions of various disabilities in China. PMID- 23356914 TI - Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. AB - Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor-protein (MCP), C3 and factor B (CFB). At 5 years, death-censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M-TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence-related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies. PMID- 23356916 TI - Collaborating to nurse the heart and spirit. PMID- 23356917 TI - Walking the copyright tightrope. PMID- 23356918 TI - A few minutes with Michelle R. Tinkham. PMID- 23356922 TI - Implementing a bariatric surgery program. AB - The number of people who are obese or morbidly obese is increasing in the United States. Currently, the most effective means of losing a substantial amount of weight and maintaining the weight loss is bariatric surgery, and health care providers, especially those in surgical services, must be able to safely care for patients undergoing these surgeries. Financial implications of starting a bariatric surgery program and the ongoing costs must be fully understood and supported by both administrators and employees. Special equipment and supplies are needed to handle the higher weight of bariatric patients, and careful planning is required for adequate medical and nursing expertise, staffing, equipment, supplies, facility resources, and patient support services. PMID- 23356923 TI - Perioperative nursing care of the patient undergoing bariatric revision surgery. AB - Obesity has become a major health concern in the United States. The number of patients seeking bariatric surgery has grown exponentially in recent years because of the proven success of weight-loss surgery, greater public acceptance, and the increasing number of insurers who will pay for these surgeries. Patients may seek bariatric revision procedures if the primary procedure does not achieve the desired results, if he or she gains back the weight lost after the primary procedure, if the comorbid conditions associated with obesity were not resolved, or if severe adverse effects and complications have occurred as a result of the primary bariatric procedure. Perioperative nurses must be knowledgeable about how to care for bariatric surgery patients with skill and compassion. PMID- 23356924 TI - Evaluation of or staffing and postoperative patient outcomes. AB - The purpose of this cross-sectional cohort study was to evaluate the relationship between the number of OR personnel involved in a surgery and subsequent postoperative outcomes. We collected data from a sample of general surgery patients (N = 911) by using the American College of Surgeons National Surgical Quality Improvement Project processes. Data obtained from electronic medical records about the number of different personnel involved in the surgeries were used to create total OR staffing and nurse staffing variables for each surgery. Two associations approached statistical significance after we controlled for significant risk factors, including OR duration. A higher number of total nursing personnel involved in a surgical procedure was associated with any postoperative complication at the P = .095 level. A higher number of total OR personnel was associated with surgical site infections at the P = .057 level. We recommend further evaluation of these measures in multiple hospital settings. PMID- 23356925 TI - The lived spiritual experiences of patients transitioning through major outpatient surgery. AB - Dramatic changes in outpatient surgery have occurred in recent years, but the basic care needs of surgical patients remain constant. Most outpatients face the same spiritual and coping issues that inpatients do, but outpatient surgery requires that patients cope with the surgery at an accelerated pace. This phenomenological study describes the meanings of the lived spiritual experiences of patients transitioning through major outpatient surgery. Analysis of interviews with participants resulted in four distinct themes: a point in time, holy other, vulnerability in the OR, and appraisals of uncertainty. Ways that health care providers can provide holistic case include developing an understanding of the patient's overall experience, understanding the patient's goals, and supporting the patient's own coping mechanisms and resources. Additional research should be conducted to explore interventions related to patients' spiritual well-being in outpatient settings. PMID- 23356926 TI - Pursuing Magnet designation: the role of structural empowerment. PMID- 23356927 TI - Standardizing the management of reusable medical equipment. PMID- 23356929 TI - Turn the other cheek. PMID- 23356930 TI - Changes in screen time activity in Norwegian children from 2001 to 2008: two cross sectional studies. AB - BACKGROUND: There has been an increase in screen-based communication, leading to concerns about the negative health effects of screen-based activities in children and adolescents. The present study aimed to (1) analyze changes in screen time activity in Norwegian children from 2001 to 2008, and (2) to analyze associations between the changes in screen time activity over time and sex, grade level and parental educational level. METHODS: Within the project Fruits and Vegetables Make the Marks (FVMM), 1488 6th and 7th grade pupils from 27 Norwegian elementary schools completed a questionnaire including a question about time spent on television viewing and personal computer use in 2001 and 1339 pupils from the same schools completed the same questionnaire in 2008. Data were analyzed by multilevel linear mixed models. RESULTS: The proportions of 6th and 7th grade pupils at the 27 schools that reported screen time activity outside school of 2 hours/day or more decreased from 55% to 45% (p<0.001) from 2001 to 2008 when adjusting for sex, grade level and parental education. The decrease was most evident in 6th graders (51% to 37%) and in children with highly educated parents (54% to 39%). CONCLUSION: The present study shows that there has been a marked reduction in screen time activity outside school in this group of Norwegian 10-12 year olds from 2001 to 2008. PMID- 23356931 TI - Lectin binding pattern in the uterus of pregnant mice infected with Tritrichomonas foetus. AB - Bovine genital tritrichomonosis is caused by the protozoon Tritrichomonas foetus and leads to embryonic death and abortion. The complexity of handling bovine experimental systems has led to the development of alternative models. The infection has been reproduced in pregnant BALB/c mice. In the pathogenesis of the disease, adhesion of the protozoon to host cell surface glycoproteins is important. Labelling with soya bean agglutinin (SBA) and peanut agglutinin (PNA) lectins increases in the luminal and glandular uterine epithelium of non-pregnant infected mice. The aim of the present study was to determine whether these changes also occur in pregnant infected BALB/c mice. Female BALB/c mice were inoculated intravaginally with T. foetus and, 15 +/- 3 days post infection, were paired with males overnight. Infected and control mice were sacrificed 6, 8 and 10 days later. Samples of uterus were labelled with a panel of biotinylated lectins. Infected mice showed increased binding of PNA and SBA. There was also increased binding of concanavalin (Con-A) by luminal epithelium and Ricinus communis agglutinin (RCA-1) by glandular epithelium at day 6 post coitum. These changes may be due to the production of enzymes by T. foetus, which could act to enhance adhesion and colonization and thus favour infection. PMID- 23356932 TI - Cellular differentiation and proliferation in the ovine lung during gestation and early postnatal development. AB - This study investigates epithelial cell differentiation and proliferation in specific anatomical regions of the ovine lung during prenatal and postnatal development. Immunohistochemistry was used to identify ciliated epithelial cells, Clara cells, neuroepithelial bodies and type II pneumocytes in the lungs of preterm (67, 127 and 140 days of gestation), full-term (147 days) and postnatal (9, 16 and 91 days old) lambs. Differentiation of ciliated epithelial cells was seen at 67 days of gestation and at term for Clara cells. Neuroepithelial bodies were first detected at 127 days of gestation. From 16 to 91 days of age there was a significant (P <0.05) increase in beta-tubulin (present in ciliated epithelial cells) and Clara cell protein (present in Clara cells) in multiple regions of the lung. Detection of Ki67, a marker of proliferation, in preterm lambs showed a reduction in proliferation index in multiple anatomical regions of the lung between 70 days of gestation and term. Cell proliferation increased following parturition, and then decreased between 16 and 91 days of age, with the largest reduction occurring in the alveolar compartment. Knowledge of which cells are present at specific times of lung development provides valuable information on the anatomy of the ovine lung, improving its use as a model for ovine and human neonatal disease. In addition, the antibodies used here will be valuable for future studies requiring the identification and quantification of respiratory epithelial cell phenotypes in the sheep lung. PMID- 23356933 TI - Mucinous cystadenoma in the lung of a captive-born moustached tamarin (Saguinus mystax). AB - A 2-year-old, captive-born, male moustached tamarin was subjected to necropsy examination after a fatal head trauma. A solitary, circumscribed, subpleural mass (0.6 cm diameter) was found in the right caudal lung lobe. The mass was diagnosed as a mucinous cystadenoma. Histochemical and immunohistochemical tests were performed to further characterize the tumour. Surfactant proteins A, B, C and D were not found in the neoplastic cells, suggesting that the tumour arose from a non-surfactant-producing alveolar lining cell. Pulmonary mucinous cystadenomas are uncommon benign tumours in man and have not been reported previously in animals. PMID- 23356934 TI - Investigation of fungal iterative polyketide synthase functions using partially assembled intermediates. AB - Iterative polyketide synthases (PKSs) are large, multifunctional enzymes that resemble eukaryotic fatty acid synthases but can make highly functionalized secondary metabolites using complex and unresolved programming rules. During biosynthesis of the kinase inhibitor hypothemycin by Hypomyces subiculosus , a highly reducing iterative PKS, Hpm8, cooperates with a nonreducing iterative PKS, Hpm3, to construct the advanced intermediate dehydrozearalenol (DHZ). The identity of putative intermediates in the formation of the highly reduced hexaketide portion of DHZ were confirmed by incorporation of (13)C-labeled N acetylcysteamine (SNAC) thioesters using the purified enzymes. The results show that Hpm8 can accept SNAC thioesters of intermediates that are ready for transfer from its acyl carrier protein domain to its ketosynthase domain and assemble them into DHZ in cooperation with Hpm3. Addition of certain structurally modified analogues of intermediates to Hpm8 and Hpm3 can produce DHZ derivatives. PMID- 23356935 TI - Super-resolution fingerprinting detects chemical reactions and idiosyncrasies of single DNA pegboards. AB - We employ the single-particle fluorescence nanoscopy technique points accumulation for imaging in nanoscale topography (PAINT) using site-specific DNA probes to acquire two-dimensional density maps of specific features patterned on nanoscale DNA origami pegboards. We show that PAINT has a localization accuracy of ~10 nm that is sufficient to reliably distinguish dense (>10(4) features MUm( 2)) sub-100 nm patterns of oligonucleotide features. We employ two-color PAINT to follow enzyme-catalyzed modification of features on individual origami and to show that single nanopegboards exhibit stable, spatially heterogeneous probe binding patterns, or "fingerprints." Finally, we present experimental and modeling evidence suggesting that these fingerprints may arise from feature spacing variations that locally modulate the probe binding kinetics. Our study highlights the power of fluorescence nanoscopy to perform quality control on individual soft nanodevices that interact with and position reagents in solution. PMID- 23356936 TI - Negotiating safer sex: a detailed analysis of attitude functions, anticipated emotions, relationship status and gender. AB - OBJECTIVE: Because interpersonal discussion about condom use can encourage subsequent condom use, this project aims to examine the psychological antecedents of intentions to discuss or request the use of condoms with a sexual partner. METHOD: The data were collected from 849 heterosexual college students in the U.S.A. through an online survey. The survey contained several measures related to attitude functions (i.e., motivations), efficacy, norms and intentions to discuss condom use with a sexual partner. RESULTS: Participants' attitude functions weakly predicted intentions to discuss condom use. Communication efficacy was a more important predictor of intentions for females (vs. males) and for those in other relationships or not in a relationship (vs. long-term monogamous relationships). Anticipated negative emotions were a stronger predictor of intentions for those in long-term monogamous relationships (vs. other relationships or not in a relationship). IMPLICATIONS: Future research needs to consider more detailed attitude functions and anticipated emotions. Furthermore, background variables (e.g., gender and relationship status) can be moderators in addition to being distal predictors. PMID- 23356937 TI - Plants used in artisanal fisheries on the Western Mediterranean coasts of Italy. AB - BACKGROUND: Artisanal fisheries in the Mediterranean, especially in Italy, have been poorly investigated. There is a long history of fishing in this region, and it remains an important economic activity in many localities. Our research entails both a comprehensive review of the relevant literature and 58 field interviews with practitioners on plants used in fishing activities along the Western Mediterranean Italian coastal regions. The aims were to record traditional knowledge on plants used in fishery in these regions and to define selection criteria for plant species used in artisanal fisheries, considering ecology and intrinsic properties of plants, and to discuss the pattern of diffusion of shared uses in these areas. METHODS: Information was gathered both from a general review of ethnobotanical literature and from original data. A total of 58 semi-structured interviews were carried out in Liguria, Latium, Campania and Sicily (Italy). Information on plant uses related to fisheries were collected and analyzed through a chi-square residual analysis and the correspondence analysis in relation to habitat, life form and chorology. RESULTS: A total of 60 plants were discussed as being utilized in the fisheries of the Western Italian Mediterranean coastal regions, with 141 different uses mentioned. Of these 141 different uses, 32 are shared among different localities. A multivariate statistical analysis was performed on the entire dataset, resulting in details about specific selection criteria for the different usage categories (plants have different uses that can be classified into 11 main categories). In some uses, species are selected for their features (e.g., woody), or habitat (e.g., riverine), etc. The majority of uses were found to be obsolete (42%) and interviews show that traditional fishery knowledge is in decline. There are several reasons for this, such as climatic change, costs, reduction of fish stocks, etc. CONCLUSIONS: Our research correlates functional characteristics of the plants used in artisanal fishery and habitats, and discusses the distribution of these uses. This research is the first comprehensive outline of plant role in artisanal fisheries and traditional fishery knowledge in the Mediterranean, specifically in Italy. PMID- 23356938 TI - Overdrive pacing using an ICD with an unexpected AV response: what is the cause? PMID- 23356939 TI - Fibronectin coating of oxygenator membranes enhances endothelial cell attachment. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) can replace the lungs' gas exchange capacity in refractory lung failure. However, its limited hemocompatibility, the activation of the coagulation and complement system as well as plasma leakage and protein deposition hamper mid- to long-term use and have constrained the development of an implantable lung assist device. In a tissue engineering approach, lining the blood contact surfaces of the ECMO device with endothelial cells might overcome these limitations. As a first step towards this aim, we hypothesized that coating the oxygenator's gas exchange membrane with proteins might positively influence the attachment and proliferation of arterial endothelial cells. METHODS: Sheets of polypropylene (PP), polyoxymethylpentene (TPX) and polydimethylsiloxane (PDMS), typical material used for oxygenator gas exchange membranes, were coated with collagen, fibrinogen, gelatin or fibronectin. Tissue culture treated well plates served as controls. Endothelial cell attachment and proliferation were analyzed for a period of 4 days by microscopic examination and computer assisted cell counting. RESULTS: Endothelial cell seeding efficiency is within range of tissue culture treated controls for fibronectin treated surfaces only. Uncoated membranes as well as all other coatings lead to lower cell attachment. A confluent endothelial cell layer develops on fibronectin coated PDMS and the control surface only. CONCLUSIONS: Fibronectin increases endothelial cells' seeding efficiency on different oxygenator membrane material. PDMS coated with fibronectin shows sustained cell attachment for a period of four days in static culture conditions. PMID- 23356942 TI - Effect of high exogenous electric pulses on protein conformation: myoglobin as a case study. AB - Protein folding and unfolding under the effect of exogenous perturbations remains a topic of great interest, further enhanced by recent technological developments in the field of signal generation that allow the use of intense ultrashort electric pulses to directly interact at microscopic level with biological matter. In this paper, we show results from molecular dynamics (MD) simulations of a single myoglobin molecule in water exposed to pulsed and static electric fields, ranging from 10(8) to 10(9) V/m, compared to data with unexposed conditions. We have found that the highest intensity (10(9) V/m) produced a fast transition (occurring within a few hundreds of picoseconds) between folded and unfolded states, as inferred by secondary structures and geometrical analysis. Fields of 10(8) V/m, on the contrary, produced no significant denaturation, although a relevant effect on the protein dipolar behavior was detected. PMID- 23356940 TI - Permanent genetic resources added to molecular ecology resources database 1 October 2012-30 November 2012. AB - This article documents the addition of 153 microsatellite marker loci to the Molecular Ecology Resources Database. Loci were developed for the following species: Brassica oleracea, Brycon amazonicus, Dimorphandra wilsonii, Eupallasella percnurus, Helleborus foetidus, Ipomoea purpurea, Phrynops geoffroanus, Prochilodus argenteus, Pyura sp., Sylvia atricapilla, Teratosphaeria suttonii, Trialeurodes vaporariorum and Trypanosoma brucei. These loci were cross tested on the following species: Dimorphandra coccicinea, Dimorphandra cuprea, Dimorphandra gardneriana, Dimorphandra jorgei, Dimorphandra macrostachya, Dimorphandra mollis, Dimorphandra parviflora and Dimorphandra pennigera. PMID- 23356941 TI - The Francisella tularensis LVS DeltapdpC mutant exhibits a unique phenotype during intracellular infection. AB - BACKGROUND: A prerequisite for the virulence of the facultative intracellular bacterium Francisella tularensis is effective intramacrophage proliferation, which is preceded by phagosomal escape into the cytosol, and ultimately leads to host cell death. Many components essential for the intracellular life cycle are encoded by a gene cluster, the Francisella pathogenicity island (FPI), constituting a type VI secretion system. RESULTS: We characterized the FPI mutant DeltapdpC of the live vaccine strain (LVS) of F. tularensis and found that it exhibited lack of intracellular replication, incomplete phagosomal escape, and marked attenuation in the mouse model, however, unlike a phagosomally contained FPI mutant, it triggered secretion of IL-1beta, albeit lower than LVS, and markedly induced LDH release. CONCLUSIONS: The phenotype of the DeltapdpC mutant appears to be unique compared to previously described F. tularensis FPI mutants. PMID- 23356943 TI - Rhabdomyosarcoma in an adult hand. AB - Rhabdomyosarcoma (RMS) is a malign tumour which arises from cells committed to a skeletal muscle lineage. It constitutes 4%-8% of all childhood malignancies but is rare in adults. The rare pleomorphic subtype occurs almost exclusively in adults and most often involves the extremities. RMS of the hand or foot comprise a minority of extremity cases. An adult patient with rhabdomyosarcoma in the hand, which is very rare, is presented in this article. General characteristics of the tumour and the treatment strategies are discussed. PMID- 23356944 TI - Hyaluronic acid, an important factor in the wound healing properties of amniotic fluid: in vitro studies of re-epithelialisation in human skin wounds. AB - Foetal wounds are unique in their ability to heal rapidly without forming scars. The amniotic fluid, rich in nutrients, growth factors, and hyaluronic acid, surrounds the foetus and is essential to foetal wound healing. The wound healing properties of foetal wounds may be the result of high concentrations of hyaluronic acid. This study aimed to verify that amniotic fluid induces re epithelialisation in human skin wounds in vitro and to study whether this ability is dependent on hyaluronic acid. Standard deep dermal wounds were produced in vitro in human skin. The skin samples, with a central wound, were incubated in different culture media. Varying concentrations of amniotic fluid and amniotic fluid with added hyaluronidase were tested, and re-epithelialisation was assessed at 3, 7, and 12 days using light microscopy, after staining with haematoxylin and eosin. Amniotic fluid 50% resulted in a significantly higher (p < 0.05) grade of re-epithelialisation than Dulbecco's modified Eagle's medium and 10% amniotic fluid at all time points. When 50% amniotic fluid was compared with 10% foetal calf serum, no significant difference was found in grades of re-epithelialisation on days 3 and 12 and significantly higher grades of re-epithelialisation on day 7 (p < 0.05). Degradation of hyaluronic acid in the medium that contained 50% amniotic fluid gave significantly impaired re-epithelialisation (p < 0.05) on culture days 3 and 7. In conclusion, amniotic fluid promotes accelerated re epithelialisation and hyaluronic acid is an important ingredient. PMID- 23356945 TI - Assessment of the usefulness of three-dimensional scanner in aesthetic evaluation of post-traumatic rhinoplasty. AB - Preoperative, accurate measurement of spatial parameters of the external nose could be essential in the postoperative assessment of rhinoplasty. The aim of the study was to analyse the relevance of three-dimensional (3D) imaging in aesthetic evaluation after operation, to provide a standardised algorithm of nasal shape measurements, which will enable the development of software for assessing the nose before and after rhinoplasty, to perform analysis of spatial changes of both its shape and asymmetry by the new protocol of measurements. Fifty-four patients were examined preoperatively and 6 months postoperatively. The following nasal parameters were determined: rates of proportion, angles, and spatial parameters. After the operation, statistically significant differences were observed in all parameters. In conclusion, a 3D scanner can be used as a tool to assess the results of rhinoplasty. This protocol of measurements describes spatial changes of the nose shape resulting from the operation. PMID- 23356946 TI - Chemical synthesis and characterization of epicatechin glucuronides and sulfates: bioanalytical standards for epicatechin metabolite identification. AB - The monoglucuronides and sulfates of epicatechin, 3'-O-methylepicatechin, and 4' O-methylepicatechin, respectively, were synthesized as authentic bioanalytical standards. Reversed-phase HPLC methods capable of baseline separation of the glucuronides and sulfates have been developed. Both the epicatechin glucuronides and sulfates were stable in the solid state when stored under ambient conditions and in aqueous solution when stored refrigerated. These results should prove invaluable to the research community as analytical standards as well as in future studies of the biological and pharmacological effects of epicatechin in humans. PMID- 23356947 TI - Exogenous melatonin improves Malus resistance to Marssonina apple blotch. AB - We examined whether exogenously applied melatonin could improve resistance to Marssonina apple blotch (Diplocarpon mali) by apple [Malus prunifolia (Willd.) Borkh. cv. Donghongguo]. This serious disease leads to premature defoliation in the main regions of apple production. When plants were pretreated with melatonin, resistance was increased in the leaves. We investigated the potential roles for melatonin in modulating levels of hydrogen peroxide (H2O2), as well the activities of antioxidant enzymes and pathogenesis-related proteins during these plant-pathogen interactions. Pretreatment enabled plants to maintain intracellular H2O2 concentrations at steady-state levels and enhance the activities of plant defence-related enzymes, possibly improving disease resistance. Because melatonin is safe and beneficial to animals and humans, exogenous pretreatment might represent a promising cultivation strategy to protect plants against this pathogen infection. PMID- 23356949 TI - Molecular diagnosis of T cell-mediated rejection in human kidney transplant biopsies. AB - Histologic diagnosis of T cell-mediated rejection is flawed by subjective assessments, nonspecific lesions and arbitrary rules. This study developed a molecular test for T cell-mediated rejection. We used microarray results from 403 kidney transplant biopsies to derive a classifier assigning T cell-mediated rejection scores to all biopsies, and compared these with histologic assessments. The score correlated with histologic lesions of T cell-mediated rejection (infiltrate, tubulitis). The accuracy of the classifier for the histology diagnoses was 89%. Very high and low molecular scores corresponded with unanimity among three pathologists on the presence or absence of T cell-mediated rejection, respectively. The molecular score had low sensitivity (50%) and positive predictive value (62%) for the histology diagnoses. However, histology showed similar disagreement between pathologists--only 45-56% sensitivity of one pathologist with diagnoses of T cell-mediated rejection by another. Discrepancies between molecular scores and histology were mostly when histology was ambiguous ("borderline") or unreliable, e.g. in cases with scarring or inflammation induced by tissue injury. Vasculitis (isolated v-lesion TCMR) was particularly discrepant, with most cases exhibiting low TCMR scores. We propose new rules to integrate molecular tests and histology into a precision diagnostic system that can reduce errors, ambiguity and interpathologist disagreement. PMID- 23356951 TI - A virtual reality-based vocational training system (VRVTS) for people with schizophrenia in vocational rehabilitation. AB - Employment provides schizophrenic patients with a positive identity and hope. Cognitive impairments have been suggested to slow down the progress in work rehabilitation. The purpose of this study was to investigate the efficacy and effectiveness of VR as a cognitive intervention for enhancing vocational outcomes. 95 inpatients with schizophrenia were randomly assigned to a virtual reality-based vocational training group (VRG), a therapist-administered group (TAG) and a conventional group (CG). Twenty-five of them in each group had completed the study. Their performances were evaluated, before and after interventions, by Brief Neuropsychological Cognitive Examination, Digit Vigilance Test, Rivermead Behavioural Memory Test, Wisconsin Card Sorting Test (WCST) and Vocational Cognitive Rating Scale. Patients in the VRG were found to perform better than patients in the TAG and CG in cognitive functioning, as shown by the WCST-percentage of error (F (2, 72)=7.146, p<0.001) and the WCST-percentage of conceptual level response (F (2, 72)=8.722, p<0.001). The post-hoc test revealed that the VRG showed a better performance than both the TAG (p=0.03) and the CG (p<0.001) in the WCST-percentage of error. The VRG also showed a better performance than patients in both the TAG (p=0.01) and the CG (p<0.001) in the WCST-percentage of conceptual level response. The VRG also showed a better self efficacy score than CG. Both VRG and TAG showed a better work performance as reflected by the on-site tests. Further studies on the use of VR in schizophrenia rehabilitation and for vocational success are discussed. PMID- 23356950 TI - Abnormal expression of glutamate transporters in temporal lobe areas in elderly patients with schizophrenia. AB - Glutamate transporters facilitate the buffering, clearance and cycling of glutamate and play an important role in maintaining synaptic and extrasynaptic glutamate levels. Alterations in glutamate transporter expression may lead to abnormal glutamate neurotransmission contributing to the pathophysiology of schizophrenia. In addition, alterations in the architecture of the superior temporal gyrus and hippocampus have been implicated in this illness, suggesting that synapses in these regions may be remodeled from a lifetime of severe mental illness and antipsychotic treatment. Thus, we hypothesize that glutamate neurotransmission may be abnormal in the superior temporal gyrus and hippocampus in schizophrenia. To test this hypothesis, we examined protein expression of excitatory amino acid transporter 1-3 and vesicular glutamate transporter 1 and 2 in subjects with schizophrenia (n=23) and a comparison group (n=27). We found decreased expression of EAAT1 and EAAT2 protein in the superior temporal gyrus, and decreased EAAT2 protein in the hippocampus in schizophrenia. We didn't find any changes in expression of the neuronal transporter EAAT3 or the presynaptic vesicular glutamate transporters VGLUT1-2. In addition, we did not detect an effect of antipsychotic medication on expression of EAAT1 and EAAT2 proteins in the temporal association cortex or hippocampus in rats treated with haloperidol for 9 months. Our findings suggest that buffering and reuptake, but not presynaptic release, of glutamate is altered in glutamate synapses in the temporal lobe in schizophrenia. PMID- 23356953 TI - Primary central nervous system histiocytic sarcoma presenting as a postradiation sarcoma: case report and literature review. AB - Histiocytic sarcoma (HS) is a rare neoplasm that occurs most commonly in the intestinal tract, skin, soft tissue, and lymph node. The incidence of primary central nervous system (CNS) HS is even rarer, with a total of 6 cases reported in the literature. An etiologic link has not been identified for CNS HS, and the current case of primary CNS HS is unique in that an etiologic link to prior radiation therapy is identified, associated with complex cytogenetic abnormalities in the tumor. Although radiation-associated sarcomas can present as any number of different pathologic entities, this is the first reported case of a radiation-associated CNS HS. The pathologic and immunophenotypic characteristics of this case, with a nearly obscuring heavy inflammatory infiltrate and expression of monocytic/histiocytic markers (CD163, CD68, CD4, fascin), are characteristic of CNS HS. A discussion of the differential diagnosis and review of relevant literature are presented. PMID- 23356952 TI - Towards an effective control programme of soil-transmitted helminth infections among Orang Asli in rural Malaysia. Part 1: prevalence and associated key factors. AB - BACKGROUND: Despite the continuous efforts to improve the quality of life of Orang Asli (Aborigines) communities, these communities are still plagued with a wide range of health problems including parasitic infections. The first part of this study aimed at determining the prevalence of soil-transmitted helminth (STH) infections and identifying their associated factors among rural Orang Asli children. METHODS: A cross-sectional study was carried out among 484 Orang Asli children aged <= 15 years (235 females and 249 males) belonging to 215 households from 13 villages in Lipis district, Pahang, Malaysia. Faecal samples were collected and examined by using formalin-ether sedimentation, Kato Katz and Harada Mori techniques. Demographic, socioeconomic, environmental and behavioural information were collected by using a pre-tested questionnaire. RESULTS: Overall, 78.1% of the children were found to be infected with one or more STH species. The prevalence of trichuriasis, ascariasis and hookworm infections were 71.7%, 37.4% and 17.6%, respectively. Almost all, three quarters and one fifth of trichuriasis, ascariasis and hookworm infections, respectively, were of moderate to-heavy intensities. Multiple logistic regression analysis showed that age of >= 6 years (school-age), using unsafe water supply as a source for drinking water, absence of a toilet in the house, large family size (>= 7 members), not washing hands before eating, and not washing hands after defecation were the key factors significantly associated with STH among these children. CONCLUSION: This study reveals an alarmingly high prevalence of STH among Orang Asli children and clearly brings out an urgent need to implement school-based de-worming programmes and other control measures like providing a proper sanitation, as well as a treated drinking water supply and proper health education regarding good personal hygiene practices. Such an integrated control program will help significantly in reducing the prevalence and intensity of STH in Orang Asli communities. PMID- 23356954 TI - Doing a protist book. PMID- 23356956 TI - What makes a P450 tick? AB - The cytochromes P450 (P450s) are probably nature's most versatile enzymes in terms of both their vast substrate range and the diverse types of molecular transformations performed across the P450 enzyme superfamily. The P450s exquisitely perform highly specific oxidative chemistry, utilizing a sophisticated catalytic reaction mechanism. Recent studies have provided the first definitive characterization of the transient reaction cycle intermediate (compound I) responsible for the majority of P450 oxidative reactions. This major advance comes at a time when P450 engineering has facilitated the elucidation of several mammalian P450 structures and generated P450 variants with novel substrate specificity and reactivity. This review describes recent advances in P450 research and the ramifications for biotechnological and biomedical exploitation of these enzymes. PMID- 23356955 TI - Whole body methionine kinetics, transmethylation, transulfuration and remethylation during pregnancy. AB - BACKGROUND & AIMS: There is evidence from a study of pregnant American women that methionine transmethylation (TM) and remethylation (RM) rates increases and transulfuration (TS) decreases as pregnancy progresses from trimester 1 to 3. To determine whether pregnant Indian women can make this adaptation successfully, methionine kinetics, TS, TM, and RM were measured in Indian women in early and late pregnancy. METHODS: Measurements were made in the postabsorptive and fed states in the 1st and 3rd trimesters of pregnancy by infusing 1-(13)C,(2)H3 methionine in 24 women, 12 with low (<=150 pmol L(-1)) and 12 with normal (>=200 pmol L(-1)) vitamin B12 status at recruitment. RESULTS: From trimester 1 to 3, except RM which decreased significantly, there was no change in any weight specific methionine kinetic parameter. When expressed per whole body, methionine flux from protein breakdown increased significantly from trimester 1 to 3 in the fed and postabsorptive states. Flux to protein synthesis also increased significantly in the fed state. Rates of TM, TS and RM did not change, regardless of vitamin B12 status at recruitment. Protein and methionine intakes correlated with TM and RM rates and the change in RM from trimester 1 to 3 correlated with the change in dietary protein intake. CONCLUSION: These results suggest that methionine flux and its utilization for protein synthesis increases in Indian women as pregnancy progresses from trimester 1 to 3. TM and RM rates do not increase however, possibly because of inadequate protein intake and not because of vitamin B12 deficiency at trimester 1. PMID- 23356959 TI - Controlling the orbital sequence in individual Cu-phthalocyanine molecules. AB - We report on the controlled change of the energetic ordering of molecular orbitals. Negatively charged copper(II)phthalocyanine on NaCl/Cu(100) undergoes a Jahn-Teller distortion that lifts the degeneracy of two frontier orbitals. The energetic order of the levels can be controlled by Au and Ag atoms in the vicinity of the molecule. As only one of the states is occupied, the control of the energetic order is accompanied by bistable changes of the charge distribution inside the molecule, rendering it a bistable switch. PMID- 23356958 TI - Changes in alcohol use and relationship satisfaction in Norwegian couples during pregnancy. AB - BACKGROUND: Numerous studies have documented a profound reduction in alcohol use among pregnant women, whereas research on expectant fathers has been scarce. The aim of this study was to measure changes in alcohol consumption from before pregnancy to 17 weeks in gestation for mothers and fathers, differentiating between parents with and without any previous children, and to measure how level and change in alcohol consumption into early pregnancy was associated with relationship satisfaction. METHODS: The data collection was conducted as part of the Norwegian Mother and Child Cohort Study (MoBa) at the Norwegian Institute of Public Health. This cohort now includes 108,000 children, 90,700 mothers and 71,500 fathers recruited from 1999 to 2008. The present study comprises 82 362 couples. Alcohol consumption was assessed using a questionnaire including items about usual drinking frequency, quantities, and number of occasions with heavy episodic drinking (HED). Relationship satisfaction was measured by five items scored on a Likert agreement scale. RESULTS: The findings indicate that both mothers and fathers reduce their drinking significantly during pregnancy. Reduction was apparent for all three measures of alcohol consumption. First-time fathers reduced their alcohol consumption more than experienced fathers, from initially higher levels. The gap between the fathers and their pregnant partner was greater for first-time parents compared to parents with previous children. Drinking pre-pregnancy and relationship satisfaction during pregnancy were weakly related within each partner, whereas no association across partners was observed. CONCLUSIONS: Both expectant mothers and fathers changed their alcohol consumption patterns when expecting a child. Almost all mothers stopped drinking, whereas fathers reduced their drinking to a considerable degree. Relationship satisfaction was only slightly related to their drinking patterns. The findings may have important policy implications, mainly with regard to developing alcohol preventive strategies. PMID- 23356957 TI - Characterizing genic and nongenic molecular markers: comparison of microsatellites and SNPs. AB - The implications of transitioning to single nucleotide polymorphism (SNPs) from microsatellite markers (MSs) have been investigated in a number of population genetics studies, but the effect of genomic location on the amount of information each type of marker reveals has not been explored in detail. We developed novel SNP markers flanking 1 kb regions of 13 genic (within gene or <1 kb away from gene) and 13 nongenic (>10 kb from annotated gene) MSs in the threespine stickleback genome to obtain comparable data for both types of markers. We analysed patterns of genetic diversity and divergence on various geographic scales after converting the SNP loci within each genomic region into haplotypes. Marker type (SNP haplotype or MS) and location (genic or nongenic) significantly affected most estimates of population diversity and divergence. Between-lineage divergence was significantly higher in SNP haplotypes (genic and nongenic), however, within-lineage divergence was similar between marker types. Most divergence and diversity measures were uncorrelated between markers, except for population differentiation which was correlated between MSs and SNP haplotypes (both genic and nongenic). Broad-scale population structure and assignment were similarly resolved by both marker types, however, only the MSs were able to delimit fine-scale population structuring, particularly when genic and nongenic markers were combined. These results demonstrate that estimates of genetic variability and differentiation among populations can be strongly influenced by marker type, their genomic location in relation to genes and by the interaction of these two factors. This highlights the importance of having an awareness of the inherent strengths and limitations associated with different molecular tools to select the most appropriate methods for accurately addressing various ecological and evolutionary questions. PMID- 23356960 TI - Development of mental health problems and overweight between ages 4 and 11 years: a population-based longitudinal study of Australian children. AB - OBJECTIVE: To investigate timing and strength of associations between mental health and overweight in childhood; to investigate how the cumulative burden of each of these problems affects the other. METHODS: Participants were 3197 children in the population-based Longitudinal Study of Australian Children. At 4 biennial waves spanning ages 4-5 to 10-11 years, parents and teachers reported child mental health on the Strengths and Difficulties Questionnaire, and researchers measured body mass index (BMI). Outcomes were analyzed both continuously and dichotomized (clinical vs no mental health problems; overweight vs not overweight). RESULTS: Approximately 30% of participants had overweight and/or mental health problems at some point between ages 4-5 and 10-11 years. Small positive cross-sectional mental health-BMI associations emerged at 8-9 years and strengthened by 10-11 years. In longitudinal analyses, more episodes of overweight predicted higher Total Difficulties scores by 10-11 years, mainly reflecting greater Peer Problems and, to a lesser degree, Emotional Symptoms than never-overweight children; though modest, these associations were robust to a range of sensitivity analyses. In post hoc analyses, overweight in late childhood was more strongly associated with poorer mental health at 10-11 years than early and fluctuating childhood overweight. Associations were smaller and less robust for mental health problems prospectively predicting higher BMI. CONCLUSIONS: Relationships between poorer mental health and higher BMI emerged then strengthened in middle to late childhood. In childhood, it appears that overweight precedes mental health problems, particularly peer problems and-on a lower level-emotional problems, rather than the reverse. PMID- 23356961 TI - Parent partnerships in communication and decision making about subspecialty referrals for children with special needs. AB - OBJECTIVE: To describe factors that influence parent-clinician partnerships in information exchange and shared decision making (SDM) when children with special health care needs are referred to subspecialists. METHODS: We conducted focus groups with parents of children with special health care needs and pediatric primary care and subspecialty clinicians about how to include parents as partners in information exchange and SDM. Five parent and 5 clinician groups were held to identify themes to inform the development of interventions to promote parent partnerships; evaluate a prototype referral care plan and related parent supports as one example of a partnership tool; and compare the views of parents and clinicians. We used investigator triangulation and member checking to improve validity. RESULTS: Nineteen parents and 23 clinicians participated. Parents discussed partnerships more easily than clinicians did, though clinicians offered more ideas as sessions progressed. Parents and clinicians agreed on the importance of 3-way communication and valued primary care involvement in all stages of referral and consultation. SDM was seen by all as important; clinicians cited difficulties inherent in discussing unclear options, while parents cited insufficient information as a barrier to understanding. Use of a brief referral care plan, with parent coaching, was embraced by all parents and most clinicians. Clinicians cited time pressures and interference with work flow as potential barriers to its use. CONCLUSIONS: Parents and clinicians endorse partnership in referrals, though relatively greater enthusiasm from parents may signal the need for work in implementing this partnership. Use of a care plan to support parent engagement appears promising as a partnership tool. PMID- 23356962 TI - Interferon-alpha plus adefovir combination therapy versus interferon-alpha monotherapy for chronic hepatitis B treatment: A meta-analysis. AB - AIM: The therapeutic effect of interferon (IFN)-alpha plus adefovir (ADV) combination therapy versus IFN-alpha monotherapy in chronic hepatitis B (CHB) treatment remains under debate. The objective of the present study was to compare the efficacy between these two regimens in CHB treatment. METHODS: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, National Knowledge Infrastructure, WANFANG and VIP databases were searched until 15 April 2012. All randomized controlled trials (RCT) comparing IFN-alpha plus ADV combination therapy versus IFN-alpha monotherapy for treating CHB patients were included. Review Manager ver. 5.1.0 was used for meta analysis. RESULTS: Our results showed that the rate of undetectable serum hepatitis B virus (HBV) DNA was significantly higher in the IFN-alpha plus ADV combination group than in the IFN-alpha monotherapy group, both at 24 weeks (relative risk [RR] = 1.74, 95% confidence interval [CI] = 1.47-2.05, P < 0.00001) and 48 weeks (RR = 1.56, 95% CI = 1.35-1.80, P < 0.00001) of treatment and after treatment (RR = 1.35, 95% CI = 1.10-1.66, P = 0.004). The serum hepatitis B e-antigen (HBeAg) negativation and HBeAg seroconversion rates were also higher in the combination group. However, a greater hepatitis B surface antigen loss rate was not found in the combination group. Forty-eight weeks of combination therapy improved the alanine aminotransferase normalization rate, but did not improve the rate of undetectable HBV DNA or that of HBeAg seroconversion as compared with 24 weeks of combination therapy. CONCLUSION: Based on the current studies, the efficacy of IFN-alpha plus ADV combination therapy is superior to IFN-alpha monotherapy. PMID- 23356963 TI - The effect of fat pad modification during ablation of atrial fibrillation: late gadolinium enhancement MRI analysis. AB - BACKGROUND: Magnetic resonance imaging (MRI) can visualize locations of both the ablation scar on the left atrium (LA) after atrial fibrillation (AF) ablation and epicardial fat pads (FPs) containing ganglionated plexi (GP). METHODS: We investigated 60 patients who underwent pulmonary vein antrum (PVA) isolation along with LA posterior wall and septal debulking for AF. FPs around the LA surface in well-known GP areas (which were considered as the substitution of GP areas around the LA) were segmented from the dark-blood MRI. Then the FP and the ablation scar image visualized by late gadolinium enhancement (LGE)-MRI on the LA were merged together. Overlapping areas of FP and the ablation scar image were considered as the ablated FP areas containing GP. Patients underwent 24-hour Holter monitoring after ablation for the analysis of heart rate variability. RESULTS: Ablated FP area was significantly wider in patients without AF recurrence than those in patients with recurrence (5.6 +/- 3.1 cm(2) vs 4.2 +/- 2.7 cm(2) , P = 0.03). The mean values of both percentage of differences greater than 50 ms in the RR intervals (pRR > 50) and standard deviation of RR intervals over the entire analyzed period (SDNN), which were obtained from 24-hour Holter monitoring 1-day post-AF ablation, were significantly lower in patients without recurrence than those in patients with recurrence (5.8 +/- 6.0% vs 14.0 +/- 10.1%; P = 0.0005, 78.7 +/- 32.4 ms vs 109.2 +/- 43.5 ms; P = 0.005). There was a significant negative correlation between SDNN and the percentage of ablated FP area (Y = -1.3168X + 118.96, R(2) = 0.1576, P = 0.003). CONCLUSION: Extensively ablating LA covering GP areas along with PVA isolation enhanced the denervation of autonomic nerve system and seemed to improve procedural outcome in patients with AF. PMID- 23356964 TI - Flavone tetraglycosides and benzyl alcohol glycosides from the Mongolian medicinal plant Dracocephalum ruyschiana. AB - From an extract of the aerial parts of Dracocephalum ruyschiana, five new flavone tetraglycosides, five new benzyl alcohol glycosides, and 19 known compounds were isolated. The tetraglycosides contain a 7-O-beta-d-glucopyranosyl-(1->2)-beta-d glucopyranosyl-(1->2)-[alpha-l-rhamnopyranosyl-(1->6)]-beta-d-glucopyranosyl moiety. The benzyl alcohol glycosides had acyl groups on their glycosyl or aglycone moieties. The compounds were tested for antioxidant activity using DPPH. Although the new compounds were not active, phenylpropanoylquinic acid derivatives were revealed as radical scavengers in D. ruyschiana. PMID- 23356965 TI - Atmospheric measurements of the physical evolution of aircraft exhaust plumes. AB - Drawing from a series of field measurement activities including the Alternative Aviation Fuels Experiments (AAFEX1 and AAFEX2), we present experimental measurements of particle number, size, and composition-resolved mass that describe the physical and chemical evolution of aircraft exhaust plumes on the time scale of 5 s to 2-3 min. As the plume ages, the particle number emission index initially increases by a factor of 10-50, due to gas-to-particle formation of a nucleation/growth mode, and then begins to fall with increased aging. Increasing the fuel sulfur content causes the initial increase to occur more rapidly. The contribution of the nucleation/growth mode to the overall particle number density is most pronounced at idle power and decreases with increasing engine power. Increasing fuel sulfur content, but not fuel aromatic content causes the nucleation/growth mode to dominate the particle number emissions at higher powers than for a fuel with "normal" sulfur and aromatic content. Particle size measurements indicate that the observed particle number emissions trends are due to continuing gas-to-particle conversion and coagulation growth of the nucleation/growth mode particles, processes which simultaneously increase particle mass and reduce particle number density. Measurements of nucleation/growth mode mass are consistent with the interpretation of particle number and size data and suggest that engine exit plane measurements may underestimate the total particle mass by as much as a factor of between 5 and 10. PMID- 23356966 TI - Time series analysis of fine particulate matter and asthma reliever dispensations in populations affected by forest fires. AB - BACKGROUND: Several studies have evaluated the association between forest fire smoke and acute exacerbations of respiratory diseases, but few have examined effects on pharmaceutical dispensations. We examine the associations between daily fine particulate matter (PM2.5) and pharmaceutical dispensations for salbutamol in forest fire-affected and non-fire-affected populations in British Columbia (BC), Canada. METHODS: We estimated PM2.5 exposure for populations in administrative health areas using measurements from central monitors. Remote sensing data on fires were used to classify the populations as fire-affected or non-fire-affected, and to identify extreme fire days. Daily counts of salbutamol dispensations between 2003 and 2010 were extracted from the BC PharmaNet database. We estimated rate ratios (RR) and 95% confidence intervals (CIs) for each population during all fire seasons and on extreme fire days, adjusted for temperature, humidity, and temporal trends. Overall effects for fire-affected and non-fire-affected populations were estimated via meta-regression. RESULTS: Fire season PM2.5 was positively associated with salbutamol dispensations in all fire affected populations, with a meta-regression RR (95% CI) of 1.06 (1.04-1.07) for a 10 ug/m3 increase. Fire season PM2.5 was not significantly associated with salbutamol dispensations in non-fire-affected populations, with a meta-regression RR of 1.00 (0.98-1.01). On extreme fire days PM2.5 was positively associated with salbutamol dispensations in both population types, with a global meta-regression RR of 1.07 (1.04 - 1.09). CONCLUSIONS: Salbutamol dispensations were clearly associated with fire-related PM2.5. Significant associations were observed in smaller populations (range: 8,000 to 170,000 persons, median: 26,000) than those reported previously, suggesting that salbutamol dispensations may be a valuable outcome for public health surveillance during fire events. PMID- 23356967 TI - Kidney transplants with progressing chronic diseases express high levels of acute kidney injury transcripts. AB - We previously reported that kidney transplants with early acute injury express transcripts indicating injury repair--the acute kidney injury signal. This study investigated the significance of this signal in transplants with other conditions, including rejection and recurrent disease. The injury signal was elevated in biopsies in many different conditions, including T cell-mediated rejection and potentially progressive diseases such as antibody-mediated rejection and glomerulonephritis. A high injury signal correlated with poor function and with inflammation in areas of fibrosis, but not with fibrosis without inflammation. In multivariate survival analysis, the injury signal in late kidney transplant biopsies strongly predicted future graft loss, similar to a published molecular risk score derived in late kidneys. Indeed, the injury signal shared many individual transcripts with the risk score, e.g. ITGB6, VCAN, NNMT. The injury signal was a better predictor of future graft loss than fibrosis, inflammation or expression of collagen genes. Thus the acute injury signal, first defined in early reversible injury, is present in many diseases as a reflection of parenchymal distress, where its significance is dictated by the inducing insult, i.e. treatable/self-limited versus untreatable and sustained. Progression in troubled transplants is primarily a function of ongoing parenchymal injury by disease, not fibrogenesis. PMID- 23356968 TI - Towards an effective control programme of soil-transmitted helminth infections among Orang Asli in rural Malaysia. Part 2: Knowledge, attitude, and practices. AB - BACKGROUND: In the first part of this study, we investigated the prevalence and associated key factors of soil-transmitted helminth (STH) infections among Orang Asli children in rural Malaysia; an alarming high prevalence and five key factors significantly associated with infections were reported. Part 2 of this study aims to evaluate the knowledge, attitude and practices (KAP) on STH infections among Orang Asli in Peninsular Malaysia. METHODS: A cross-sectional study was carried out among 215 households from 13 villages in Lipis district, Pahang, Malaysia. Demographic and socioeconomic information of the participants and their KAP on STH were collected by using a pre-tested questionnaire. RESULTS: Overall, 61.4% of the participants had prior knowledge about intestinal helminths with a lack of knowledge on the transmission (28.8%), signs and symptoms (29.3%) as well as the prevention (16.3%). Half of the respondents considered STH as harmful, while their practices to prevent infections were still inadequate. Significant associations between the KAP and age, gender, educational and employment status, family size, and household monthly income were reported. Moreover, significantly lower prevalence of STH infections was reported among children of respondents who wear shoes/slippers when outside the house (72.8%; 95% CI= 62.6, 80.5 vs 87.0%; 95% CI= 81.4, 91.1), wash their hands before eating (32.4%; 95% CI= 24.3, 42.2 vs 51.4%; 95% CI= 44.7, 60.1), and wash their hands after defecation (47.8%; 95% CI= 35.7, 57.1 vs 69.2%; 95% CI= 63.7, 78.7) as compared to their counterparts. Multiple logistic regression analysis indicated that the educational level of the respondents was the most important factor significantly associated with the KAP on STH among this population. CONCLUSION: This study reveals inadequate knowledge, attitude and practices on STH infections among Orang Asli in rural Malaysia. Hence, there is a great need for a proper health education programme and community mobilisation to enhance prevention and instil better knowledge on STH transmission and prevention. This is crucial for an effective and sustainable STH control programme to save the lives and future of the most vulnerable children in rural Malaysia. PMID- 23356969 TI - A severe haemolytic transfusion reaction caused by anti-Le(a) active at 37 degrees C. PMID- 23356970 TI - Undetected vitamin B12 deficiency due to false normal assay results. PMID- 23356972 TI - Genotyping patients' and donors' blood groups for efficient blood therapy. PMID- 23356971 TI - Blood transfusions with high levels of contaminating soluble HLA-I correlate with levels of soluble CD8 in recipients' plasma; a new control factor in soluble HLA I-mediated transfusion-modulated immunomodulation? AB - BACKGROUND: The cause of transfusion-related immunomodulation (TRIM) has proved tantalisingly elusive. An ever-growing body of evidence indicates that the infusion of large amounts of soluble and cell-associated antigens into a recipient can somehow induce TRIM. One soluble molecule that has been implicated in TRIM is soluble human leucocyte antigen I (sHLA-I). However, patients infused with large amounts of sHLA-I do not always and unambiguously experience TRIM. As soluble CD8 (sCD8) molecules have been shown to capable of binding membrane and soluble HLA-I molecules, we focused on sCD8 as a possible modulator of sHLA-I mediated TRIM. MATERIAL AND METHODS: To this aim we compared the up-regulation of circulating sCD8 in plasma from patients suffering from the same pathology, but chronically transfused with two different blood derivatives: pre- and post storage leucodepleted red blood cells which contain low and high levels of contaminating sHLA-I, respectively. RESULTS: Significantly larger amounts of sCD8 circulating molecules were detectable in the plasma of patients transfused with post-storage leucodepleted red blood cells whose supernatants contained significantly larger amounts of sHLA-I contaminating molecules. CONCLUSION: With the limitation of indirect evidence, this report introduces a new facet of the bioactivity of sCD8 as a possible modulator of sHLA-I-mediated TRIM. PMID- 23356973 TI - Molecular virology in transfusion medicine laboratory. PMID- 23356974 TI - Target of prophylaxis in severe haemophilia: more than factor levels. PMID- 23356976 TI - Enantioselective iodolactonization of disubstituted olefinic acids using a bifunctional catalyst. PMID- 23356975 TI - How to write a scientific manuscript for publication. PMID- 23356977 TI - Perihepatic lymph node enlargement is a negative predictor for sustained responses to pegylated interferon-alpha and ribavirin therapy for Japanese patients infected with hepatitis C virus genotype 1. AB - AIM: Although perihepatic lymph node enlargement (PLNE) is reportedly associated with the negative outcome of interferon therapy for chronic hepatitis C, there were limitations in that the results were obtained in patients with various genotypes, viral loads and treatment regimens. We aimed to precisely clarify the significance of PLNE in interferon therapy for chronic hepatitis C. METHODS: Between December 2004 and June 2005, 112 patients with hepatitis C virus (HCV) genotype 1 and HCV RNA of more than 100 KIU/mL were enrolled, who underwent pegylated interferon-alpha plus ribavirin therapy thereafter. PLNE was defined as a perihepatic lymph node of more than 1 cm in the longest axis by ultrasonography. RESULTS: The sustained virological response (SVR) rate was lower in patients with PLNE (4/22, 18.2%) than in those without (37/90, 41.1%; P = 0.045) and viral load decline was smaller in patients with PLNE than in those without (P = 0.028). The proportion of PLNE positive patients was the smallest in the SVR group (P = 0.033) among the patient groups divided by the treatment outcome. PLNE was retained as a negative predictor for SVR by multivariate logistic regression analysis (P = 0.012). Furthermore, PLNE was not significantly associated with the mutations at HCV core protein and at interferon sensitivity determining region, or interleukin-28B polymorphism in 45 patients with HCV genotype 1, enrolled between December 2011 and March 2012. CONCLUSION: PLNE is a negative predictor for SVR in patients with HCV genotype 1 and HCV RNA of more than 100 KIU/mL treated with pegylated interferon-alpha plus ribavirin, independent of other known predictors for SVR. PMID- 23356978 TI - Annual reproductive cycle of males of the flat-faced fruit-eating bat, Artibeus planirostris (Chiroptera: Phyllostomidae). AB - Artibeus planirostris is an endemic species of Phyllostomid bat from the Neotropical region. Some studies have indicated that it exhibits seasonal bimodal polyestry; however, others postulate that it may be able to produce young at any time during the year. Thus, the aim of this study was to evaluate the annual variations in testicular and epididymal parameters of this species in southeast Brazil and try to understand how the reproduction of this species is regulated in this environment. Sixty mature male specimens, collected between June 2009 and May 2010, were submitted to morphometric and immunohistochemical analysis. Our study showed that A. planirostris presented a continuously active pattern of spermatogenesis throughout the year, presenting spermatozoa inside its cauda epididymis in all months, but with two pronounced peaks of spermatogenic production, one in September and other in February. We propose that the males developed these two peaks in order to produce sufficient sperm for the reproduction in a harem system and to synchronize with the female reproductive cycle, which had a bimodal polyestric pattern. Control of this variation is directly linked to the expression of the androgen receptor (AR) in Sertoli cells and to serum testosterone levels, which appear to synchronize to establish these two peaks. In the months preceding the two peaks, the testis have a higher expression of the AR, which possibly stimulates the increase in PCNA, and drives a gradual increase in the testicular parameters. Taken together the results suggest that if sperm storage happens in this species, it is of short duration. PMID- 23356980 TI - Targeting cell cycle regulation in cancer therapy. AB - Cell proliferation is an essential mechanism for growth, development and regeneration of eukaryotic organisms; however, it is also the cause of one of the most devastating diseases of our era: cancer. Given the relevance of the processes in which cell proliferation is involved, its regulation is of paramount importance for multicellular organisms. Cell division is orchestrated by a complex network of interactions between proteins, metabolism and microenvironment including several signaling pathways and mechanisms of control aiming to enable cell proliferation only in response to specific stimuli and under adequate conditions. Three main players have been identified in the coordinated variation of the many molecules that play a role in cell cycle: i) The cell cycle protein machinery including cyclin-dependent kinases (CDK)-cyclin complexes and related kinases, ii) The metabolic enzymes and related metabolites and iii) The reactive oxygen species (ROS) and cellular redox status. The role of these key players and the interaction between oscillatory and non-oscillatory species have proved essential for driving the cell cycle. Moreover, cancer development has been associated to defects in all of them. Here, we provide an overview on the role of CDK-cyclin complexes, metabolic adaptations and oxidative stress in regulating progression through each cell cycle phase and transitions between them. Thus, new approaches for the design of innovative cancer therapies targeting crosstalk between cell cycle simultaneous events are proposed. PMID- 23356981 TI - Programming of human endometrial-derived stromal cells (EnSCs) into pre oligodendrocyte cells by overexpression of miR-219. AB - Oligodendrocytes are myelinating cells in the central nervous system that form the myelin sheath of axons to support rapid nerve conduction. MicroRNAs have critical roles in oligodendrocyte development. Several studies have shown that miR-219 is necessary to promote oligodendrocyte differentiation through repressing negative regulators of oligodendrocyte development. Human endometrial derived stromal cells (EnSCs) are abundant and available adult stem cells with low immunological incompatibility, which could be considered for cell replacement therapy in future. After induction of EnSCs by FGF2, EGF and PDGF-AA, they were infected by miR-219-GFP-expressing lentiviruses. The cells were analyzed for expression of stage-specific oligodendrocyte cells markers. Quantitative RT-PCR and immunocytochemistry analyses showed that stage-specific markers Nestin, Olig2, Sox10, PDGFRa, CNP, A2B5, O4, and MBP are expressed in their specific stages through differentiation protocol. Results showed that expression of pre oligodendrocyte markers in miR-219-GFP-expressing cells were higher than triiodothyronine (T3) treated cells. In conclusion, the EnSCs could be programmed into pre-oligodendrocyte cells by overexpression of miR-219, and may convince to consider these cells as safe source for cell replacement therapy of neurodegenerative diseases. PMID- 23356982 TI - ADAM17 regulates self-renewal and differentiation of U87 glioblastoma stem cells. AB - Glioblastoma stem cells (GSCs) play an important role in the progression and recurrence of malignant glioblastoma because of their potential for self-renewal, multilineage differentiation and tumor initiation. A disintegrin and metalloproteinase 17 (ADAM17) is responsible for the proteolytic cleavage of Notch within its extracellular domain leading to the activation of Notch signaling, which is involved in the formation and maintenance of GSCs. Here, we show that glioma cells expressing the stem cell marker CD133 coexpress higher levels of ADAM17 than matched CD133-glioma cells. Knockdown of the ADAM17 gene in U87 GSCs down-regulated the expression of CD133, inhibited secondary neurosphere formation and induced multi-lineage differentiation. Furthermore, knockdown of ADAM17 inhibited Hes1 and Hes5 and activated Notch1 expression, which may explain the ADAM17 shRNA-induced suppression of self-renewal and differentiation of U87 GSCs. Our results suggest that ADAM17 may maintain the stemness of GSCs by promoting their self-renewal and inhibiting their differentiation via Notch signaling. PMID- 23356979 TI - Flufenamic acid as an ion channel modulator. AB - Flufenamic acid has been known since the 1960s to have anti-inflammatory properties attributable to the reduction of prostaglandin synthesis. Thirty years later, flufenamic acid appeared to be an ion channel modulator. Thus, while its use in medicine diminished, its use in ionic channel research expanded. Flufenamic acid commonly not only affects non-selective cation channels and chloride channels, but also modulates potassium, calcium and sodium channels with effective concentrations ranging from 10(-6)M in TRPM4 channel inhibition to 10( 3)M in two-pore outwardly rectifying potassium channel activation. Because flufenamic acid effects develop and reverse rapidly, it is a convenient and widely used tool. However, given the broad spectrum of its targets, experimental results have to be interpreted cautiously. Here we provide an overview of ion channels targeted by flufenamic acid to aid in interpreting its effects at the molecular, cellular, and system levels. If it is used with good practices, flufenamic acid remains a useful tool for ion channel research. Understanding the targets of FFA may help reevaluate its physiological impacts and revive interest in its therapeutic potential. PMID- 23356983 TI - A method to achieve homogeneous dispersion of large transmembrane complexes within the holes of carbon films for electron cryomicroscopy. AB - Difficulties associated with using X-ray crystallography for structural studies of large macromolecular complexes have made single particle cryo-electron microscopy (cryoEM) a key technique in structural biology. The efficient application of the single particle cryoEM approach requires the sample to be vitrified within the holes of carbon films, with particles well dispersed throughout the ice and adopting multiple orientations. To achieve this, the carbon support film is first hydrophilised by glow discharge, which allows the sample to spread over the film. Unfortunately, for transmembrane complexes especially, this procedure can result in severe sample adsorption to the carbon support film, reducing the number of particles dispersed in the ice. This problem is rate-limiting in the single particle cryoEM approach and has hindered its widespread application to hydrophobic complexes. We describe a novel grid preparation technique that allows for good particle dispersion in the ice and minimal hydrophobic particle adhesion to the support film. This is achieved by hydrophilisation of the carbon support film by the use of selected detergents that interact with the support so as to achieve a hydrophilic and neutral or selectively charged surface. PMID- 23356984 TI - Glucocorticoids and osteocyte autophagy. AB - Glucocorticoids are used for the treatment of inflammatory and autoimmune diseases. While they are effective therapy, bone loss and incident fracture risk are high. While previous studies have found GC effects on both osteoclasts and osteoblasts, our work has focused on the effects of GCs on osteocytes. Osteocytes exposed to low dose GCs undergo autophagy while osteocytes exposed to high doses of GCs or for a prolonged period of time undergo apoptosis. PMID- 23356986 TI - Direct depiction of bone microstructure using MRI with zero echo time. AB - This paper reports a proof of principle of direct depiction of trabecular bone microstructure in vitro by means of magnetic resonance imaging (MRI). Such depiction is achieved by (1)H imaging of water embedded in the bone matrix. The fast transverse relaxation of this compartment with T2(*) on the order of a few hundreds of microseconds is addressed by a three-dimensional MRI technique with zero echo time (ZTE). ZTE imaging at an isotropic spatial resolution of 56 MUm is demonstrated in a trabecular bone specimen extracted from a bovine bone. In the MR images, the trabecular bone structure is clearly depicted and a high level of robustness against off-resonance artefacts is observed. The structural accuracy of the MR data is investigated by comparison with x-ray micro-computed tomography. PMID- 23356985 TI - Inactivation of Lrp5 in osteocytes reduces young's modulus and responsiveness to the mechanical loading. AB - Low-density-lipoprotein receptor-related protein 5 (Lrp5) is a co-receptor in Wnt signaling, which plays a critical role in development and maintenance of bone. Osteoporosis-pseudoglioma syndrome, for instance, arises from loss-of-function mutations in Lrp5, and global deletion of Lrp5 in mice results in significantly lower bone mineral density. Since osteocytes are proposed to act as a mechanosensor in the bone, we addressed a question whether a conditional loss-of function mutation of Lrp5 selective to osteocytes (Dmp1-Cre;Lrp5(f/f)) would alter responses to ulna loading. Loading was applied to the right ulna for 3 min (360 cycles at 2Hz) at a peak force of 2.65 N for 3 consecutive days, and the contralateral ulna was used as a non-loaded control. Young's modulus was determined using a midshaft section of the femur. The results showed that compared to age-matched littermate controls, mice lacking Lrp5 in osteocytes exhibited smaller skeletal size with reduced bone mineral density and content. Compared to controls, Lrp5 deletion in osteocytes also led to a 4.6-fold reduction in Young's modulus. In response to ulna loading, mineralizing surface, mineral apposition rate, and bone formation rate were diminished in mice lacking Lrp5 in osteocytes by 52%, 85%, and 69%, respectively. Collectively, the results support the notion that the loss-of-function mutation of Lrp5 in osteocytes causes suppression of mechanoresponsiveness and reduces bone mass and Young's modulus. In summary, Lrp5-mediated Wnt signaling significantly contributes to maintenance of mechanical properties and bone mass. PMID- 23356987 TI - Male mice housed in groups engage in frequent fighting and show a lower response to additional bone loading than females or individually housed males that do not fight. AB - Experiments to investigate bone's physiological adaptation to mechanical loading frequently employ models that apply dynamic loads to bones in vivo and assess the changes in mass and architecture that result. It is axiomatic that bones will only show an adaptive response if the applied artificial loading environment differs in a significant way from that to which the bones have been habituated by normal functional loading. It is generally assumed that this normal loading is similar between experimental groups. In the study reported here we found that this was not always the case. Male and female 17-week-old C57BL/6 mice were housed in groups of six, and a single episode (40 cycles) of non-invasive axial loading, engendering 2,200 MUepsilon on the medial surface of the proximal tibiae in sample mice, was applied to right tibiae on alternate days for two weeks. This engendered an adaptive increase in bone mass in females, but not males. Observation revealed the main difference in behaviour between males and females was that males were involved in fights 1.3 times per hour, whereas the females never fought. We therefore housed all mice individually. In females, there was a similar significant osteogenic response to loading in cortical and trabecular bone of both grouped and individual mice. In contrast, in males, adaptive increases in the loaded compared with non-loaded control bones was only apparent in animals housed individually. Our interpretation of these findings is that the frequent vigorous fighting that occurs between young adult males housed in groups could be sufficient to engender peak strains and strain rates that equal or exceed the stimulus derived from artificial loading. This indicates the importance of ensuring that physical activity is consistent between groups. Reducing the background level of the naturally engendered strain environment allows adaptive responses to artificial loading to be demonstrated at lower loads. PMID- 23356989 TI - Vasodilation to PTH (1-84) in bone arteries is dependent upon the vascular endothelium and is mediated partially via VEGF signaling. AB - BACKGROUND: Intermittent PTH administration directly stimulates osteoblasts; however, mechanisms of bone accrual that are independent of the direct actions on osteoblasts may be under-appreciated. Our aims were to decipher (1) whether PTH 1 84 augments vasodilation of the femoral principal nutrient artery (PNA), (2) whether 15 days of intermittent PTH 1-84 augments endothelium-dependent and/or independent vasodilation of the femoral PNA, and (3) the signaling mechanisms involved. METHODS: Experiment 1: Femoral PNAs from male Wistar rats were exposed to cumulative doses of PTH 1-84 with and without an anti-vascular endothelial growth factor antibody and/or the endothelial NO synthase inhibitor l-NAME. Experiment 2: Male Wistar rats were administered PTH and/or the anti-VEGF antibody for 2 weeks. Subsequently, endothelium-dependent vasodilation to acetylcholine and endothelium-independent vasodilation to sodium nitroprusside were assessed. In addition, endothelium-dependent signaling pathways were analyzed by use of l-NAME and/or and the cyclooxygenase inhibitor indomethacin. RESULTS: Cumulative doses of PTH 1-84 induced vasodilation of the femoral PNA, which was reduced by 38% and 87% with the anti-VEGF antibody and l-NAME, respectively. Secondly, 2 weeks of intermittent PTH 1-84 administration doubled trabecular bone volume, augmented bone formation parameters and reduced osteoclast activity. In addition, PTH enhanced endothelium-dependent vasodilation via up-regulation of NO. Co-administration of the anti-VEGF antibody (1) inhibited the PTH-induced increase in bone volume and remodeling parameters and (2) blunted the augmented vasodilator responsiveness of the PNA. Finally, endothelium-dependent vasodilation in PTH-treated rats was highly correlated with trabecular bone volume. CONCLUSION: As hypothesized, PTH enhanced endothelium dependent vasodilation of the femoral PNA via augmented NO production and was mediated partially through VEGF signaling. Further, vasodilation to PTH appears independent of vascular smooth muscle cell participation. More importantly, the strong association between vasodilation and bone volume suggests that bone arteriolar function is critical for PTH-induced bone anabolism. PMID- 23356990 TI - Effects of minodronic acid and alendronate on bone remodeling, microdamage accumulation, degree of mineralization and bone mechanical properties in ovariectomized cynomolgus monkeys. AB - Suppression of bone remodeling by bisphosphonates leads to accumulation of microdamage in bone. If this microdamage develops due to suppressed repair of remodeling only, more potent bisphosphonates should cause more damage. In this study, we evaluated the effects of reduced bone turnover produced by a potent bisphosphonate, minodronic acid, on microdamage accumulation, the degree of mineralization and mechanical properties of bone in ovariectomized cynomolgus monkeys, and compared these effects with those of alendronate. Sixty female monkeys aged 9-17 years old were divided into five groups. The sham group and the ovariectomized group were treated daily for 17 months with lactose vehicle. The other three groups were treated daily with minodronic acid at a dose of 0.015 mg/kg or 0.15 mg/kg, or alendronate at 0.5mg/kg orally. After sacrifice, lumbar vertebrae and left femurs were subjected to histomorphometry, microdamage, mineralization analyses, and mechanical testing. Minodronic acid suppressed bone remodeling of cancellous and cortical bone in a dose-dependent manner and the higher dose of minodronic acid suppressed bone remodeling more strongly than alendronate. The lower dose of minodronic acid did not increase microdamage accumulation and compressive strength, but the higher dose of minodronic acid and alendronate resulted in similar increases in cancellous microdamage accumulation and ultimate load in lumbar vertebra. There were no significant differences among the groups in microdamage, degree of mineralization and mechanical properties in cortical bone of the femoral shaft; however, only alendronate showed a tendency to increase highly mineralized osteons and microdamage. These findings suggest that microdamage caused by minodronic acid is less than that expected based on the extent of remodeling suppression, in comparison with alendronate although this was not reflected in any significant change of mechanical properties. PMID- 23356991 TI - Risk assessment for incident fracture: fall history and bone mineral density in combination with clinical risk factors. PMID- 23356988 TI - Bone mineralization is elevated and less heterogeneous in adults with type 2 diabetes and osteoarthritis compared to controls with osteoarthritis alone. AB - PURPOSE: The purpose of this study was to determine whether trabecular bone mineralization differed in adults with type 2 diabetes compared to adults without type 2 diabetes. METHODS: Proximal femur specimens were obtained following a total hip replacement procedure from men and women >=65 years of age with and without type 2 diabetes. A scanning electron microscope was used for quantitative backscattered electron imaging (qBEI) analysis of trabecular bone samples from the femoral neck. Gray scale images (pixel size=5.6 MUm(2)) were uploaded to ImageJ software and gray level (GL) values were converted to calcium concentrations (weight [wt] % calcium [Ca]) using data obtained with energy dispersive X-ray spectrometry. The following bone mineralization density distribution (BMDD) outcomes were collected: the weighted mean bone calcium concentration (CaMEAN), the most frequently occurring bone calcium concentration (CaPEAK) and mineralization heterogeneity (CaWIDTH). Differences between groups were assessed using the Student's t-test for normally distributed data and Mann Whitney U-test for non-normally distributed data. An alpha value of <0.05 was considered significant. RESULTS: Thirty-five Caucasian participants were recruited (mean [standard deviation, SD] age, 75.5 [6.5]years): 14 adults with type 2 diabetes (years since type 2 diabetes diagnosis, 13.5 [7.4]years) and 21 adults without type 2 diabetes. In the adults with type 2 diabetes, bone CaMEAN was 4.9% greater (20.36 [0.98]wt.% Ca versus 19.40 [1.07]wt.% Ca, p=0.015) and CaWIDTH was 9.4% lower (median [interquartile range] 3.55 [2.99-4.12]wt.% Ca versus 3.95 [0.71]wt.% Ca, p<0.001) compared to controls. There was no between group difference in CaPEAK (21.12 [0.97]wt.% Ca for type 2 diabetes versus 20.44 [1.30]wt.% Ca for controls, p=0.121). CONCLUSION: The combination of elevated mean calcium concentration in bone and lower mineralization heterogeneity in adults with type 2 diabetes may have deleterious effects on the biomechanical properties of bone. These microscopic alterations in bone mineralization, which may be mediated by suppressed bone remodeling, further elucidate higher fracture risk in adults with type 2 diabetes. PMID- 23356994 TI - A gold nanoparticles-based colorimetric assay for alkaline phosphatase detection with tunable dynamic range. AB - In this report, a simple and label-free colorimetric assay was developed for detecting alkaline phosphatase (ALP). Based on the conjugated gold nanoparticle/adenosine triphosphate (AuNP/ATP) sensing system, this assay is highly sensitive and selective. In this system, ATP induces the aggregation of cetyltrimethylammonium bromide (CTAB)-capped AuNPs and ALP stimulates the disaggregation of AuNPs by converting ATP into adenosine through an enzymatic dephosphorylation reaction. Hence, the presence of ALP can be visually observed (gray-to-red color change) and monitored by the shift of the surface plasmon resonance (SPR) absorption band of AuNPs. Furthermore, the dynamic range of the method can be varied by addition of different metal ions (e.g. 100-600unit/L to 5.0-100unit/L and 0.2-20unit/L in the presence of Ca(2+) and Pb(2+), respectively). The feasibility of this sensitive and specific assay with a tunable dynamic range was demonstrated to be consistent even in human serum samples. PMID- 23356995 TI - Multilayer hemin/G-quadruplex wrapped gold nanoparticles as tag for ultrasensitive multiplex immunoassay by chemiluminescence imaging. AB - A multilayer hemin/G-quadruplex DNAzyme wrapped gold nanoparticle (M DNAzyme/AuNP) tag was designed for ultrasensitive chemiluminescence (CL) imaging. By combining with a disposable protein array, an ultrasensitive and high throughput multiplex CL immunoassay method was proposed for simultaneous detection of four cancer biomarkers. The M-DNAzyme/AuNP tag was prepared by assembling high ratio of alkylthiol-capped signal DNA containing multiple G quadruplex sequences to biotinylated DNA on AuNPs and then reacting with hemin to form multilayer hemin/G-quadruplex DNAzyme units. It could be bound to the biotinylated secondary antibody of sandwich immunocomplex by biotin-streptavidin conjugation to catalyze a CL reaction on a protein array, which produced strong CL emission. Under optimal conditions, the CL signals could be simultaneously collected by a charge-coupled device for ultrasensitive multiplex CL imaging of cancer biomarkers. Using alpha-fetoprotein, human chorionic gonadotrophin-beta, carcinoma antigen 125, and carcinoembryonic antigen as model analytes, the proposed immunoassay method showed high sensitivities and wide linear ranges in a simple, cheap and high throughput way. The M-DNAzyme/AuNP as a universal signal tag as well as the protein chip could be suitable for mass production for economical, portable and multianalyte assay, showing a promising potential in application to clinic and other relative fields. PMID- 23356992 TI - Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses. AB - BACKGROUND: Neuronal activity alters calcium ion (Ca2+) dynamics in astrocytes, but the physiologic relevance of these changes is controversial. To examine this issue further, we generated an inducible transgenic mouse model in which the expression of an inositol 1,4,5-trisphosphate absorbent, "IP3 sponge", attenuates astrocytic Ca2+ signaling. RESULTS: Attenuated Ca2+ activity correlated with reduced astrocytic coverage of asymmetric synapses in the hippocampal CA1 region in these animals. The decreased astrocytic 'protection' of the synapses facilitated glutamate 'spillover', which was reflected by prolonged glutamate transporter currents in stratum radiatum astrocytes and enhanced N-methyl-D aspartate receptor currents in CA1 pyramidal neurons in response to burst stimulation. These mice also exhibited behavioral impairments in spatial reference memory and remote contextual fear memory, in which hippocampal circuits are involved. CONCLUSIONS: Our findings suggest that IP3-mediated astrocytic Ca2+ signaling correlates with the formation of functional tripartite synapses in the hippocampus. PMID- 23356993 TI - Rhodium-catalyzed chemo- and regioselective cross-dimerization of two terminal alkynes. AB - Cross-dimerization of terminal arylacetylenes and terminal propargylic alcohols/amides has been achieved in the presence of a rhodium catalyst. This method features high chemo- and regioselectivities rendering convenient and atom economical access to functionalized enynes. PMID- 23356996 TI - Real-time, in situ DNA hybridization detection with attomolar sensitivity without amplification using (pb(Mg1/3Nb2/3)O3)0.65-(PbTiO3)0.35 piezoelectric plate sensors. AB - In this paper we have investigated real-time, in situ DNA hybridization detection using piezoelectric plate sensors (PEPSs) consisting of a highly piezoelectric lead magnesium niobate-lead titanate (PMN-PT) layer 8MUm in thickness thinly coated with Cr/Au electrodes and electrically insulated with 3 mercaptopropyltrimethoxysilane (MPS) encapsulation. With probe complementary DNA (cDNA) immobilized on the PEPS surface and by monitoring the first longitudinal extension mode (LEM) resonance frequency shift of the PEPS we detected hybridization of the target DNA (tDNA) to the probe cDNA on the PEPS surface in real time at concentration 1.6*10(-18)M with a signal to noise ratio of 8 without isolation and amplification at room temperature in 30min in phosphate buffered saline (PBS) solution. The detection was validated in situ by two different methods: (1) the detection of fluorescently labeled microspheres coated with reporter cDNA complementary to the tDNA but different from the probe cDNA; (2) fluorescent visualization. PMID- 23356997 TI - A Rat Basophilic Leukaemia cell sensor for the detection of pathogenic viruses. AB - A Rat Basophilic Leukemia (RBL) cell sensor is developed for the detection and identification of pathogenic viruses. Recombinant sdAb-Fc antibodies were constructed by linking virus-specific single domain antibody to mouse IgE-Fc fragment. The sdAb-Fc can bind to FcepsilonRI receptors on RBL cells and can be cross-linked by target viruses leading to cell activation and Ca(2+) influx reflected by the increase of intracellular fluorescence. The responses of RBL cells to viruses in real time could be observed using fluorescence microscopy. 10(3) TCID50 of H5N1 viruses and 10 LD50 of rabies viruses could be detected in less than three minutes. An excess quantity of non-relevant viruses did not interfere with the recognition of target viruses. PMID- 23356998 TI - Integrating solid-state sensor and microfluidic devices for glucose, urea and creatinine detection based on enzyme-carrying alginate microbeads. AB - A solid-state sensor embedded microfluidic chip is demonstrated for the detection of glucose, urea and creatinine in human serum. In the presented device, magnetic powder-containing enzyme-carrying alginate microbeads are immobilized on the surface of an electrolyte-insulator-semiconductor (EIS) sensor by means of a step like obstacle in the microchannel and an external magnetic force. The sample is injected into the microchannel and reacts with the enzyme contained within the alginate beads; prompting the release of hydrogen ions. The sample concentration is then evaluated by measuring the resulting change in the voltage signal of the EIS sensor. The reaction time and alginate bead size are optimized experimentally using a standard glucose solution. The experimental results show that the device has a detection range of 2-8mM, 1-16mM and 10(-2)-10mM for glucose, urea and creatinine, respectively. Furthermore, it is shown that the device is capable of sequentially measuring all three indicators in a human serum sample. Finally, it is shown that the measured values of the glucose, urea and creatinine concentrations obtained using the device deviate from those obtained using a commercial kit by just 5.17%, 6.22% and 13.53%, respectively. This method can be extended to sequentially measure multiple blood indicators in the sample chip by replacing different types of enzyme in alginate bead and can address the enzyme preservation issue in the microfluidic device. Overall, the results presented in this study indicate that the microfluidic chip has significant potential for blood monitoring in point-of-care applications. PMID- 23356999 TI - New analytical applications of gold nanoparticles as label in antibody based sensors. AB - Gold nanoparticles (AuNPs) with optical and electrochemical distinctiveness as well as biocompatibility characteristics have proven to be powerful tools in nanomedicinal application. This review article discusses recent advances in the application of AuNPs as label in bioanalytical devices, especially electrochemical immunosensors, rapid and point-of-care (PoC) tests. A crucial assessment regarding implementation of different formats of antibodies allowing rapid and sensitive analysis of a range of analytes is also provided in this study. In addition to this, different approaches to minimize antibodies into Fab, scFv or even single-domain antibody fragments like VHHs will be reviewed. Given the high level of target specificity and affinity, such biomolecules are considered to be excellent elements for on-site or PoC analysis. PMID- 23357000 TI - A label-free impedimetric DNA sensing chip integrated with AC electroosmotic stirring. AB - AC electroosmosis (ACEO) flow and label-free electrochemical impedance spectroscopy are employed to increase the hybridization rate and specifically detect target DNA (tDNA) concentrations. A low-ionic-strength solution, 6.1MUS/cm 1mM Tris (pH 9.3), was used to produce ACEO and proved the feasibility of hybridization. Adequate voltage parameters for the simultaneous ACEO driving and DNA hybridization in the 1mM Tris solution were 1.5 Vpp and 200Hz. Moreover, an electrode set with a 1:4 ring width-to-disk diameter ratio exhibited a larger ACEO velocity above the disk electrode surface to improve collecting efficiency. The ACEO-integrated DNA sensing chips could reach 90% saturation hybridization within 117s. The linear range and detection limit of the sensors was 10aM-10pM and 10aM, respectively. The label-free impedimetric DNA sensing chips with integrated ACEO stirring can perform rapid hybridization and highly-sensitive detections to specifically measure tDNA concentrations. PMID- 23357001 TI - Optical ATP biosensor for extracellular ATP measurement. AB - Extracellular Adenosine-5'-triphosphate (ATP) is an important multi-functional molecule which can mediate numerous physiological activities by activating purinergic P2 receptors. The objective of this study was to develop a novel optical ATP sensor for in-situ extracellular ATP measurement in biological tissues. The optical ATP sensor was made by applying two layers of sol-gel coating to the end of an optical fiber probe end. The first layer contained ruthenium complex for sensing changes in oxygen concentration which resulted from oxidation of ATP by glycerol kinase and glycerol 3-phosphate oxidase entrapped in the second layer. It was demonstrated that the optical ATP sensor was capable of detecting ATP concentration at a broad range of 10(-3)mM to 1.5mM.A compensation method was established to enable the optical sensor to determine ATP concentration at different oxygen levels. This study also demonstrated the capability of ATP sensor to measure extracellular ATP content in biological tissues (i.e., porcine intervertebral disc). In addition, it was shown that the optical ATP sensor was not affected by pH and derivatives of extracellular ATP. Therefore, the newly developed optical ATP sensor is a good option for in-situ extracellular ATP measurement. PMID- 23357002 TI - Selective and quantitative cell detection based both on aptamers and the conventional cell-staining methods. AB - Aptamer-based biochips for selective cell detection and quantitation in combination of the recent biochip technology and the conventional cell staining methods are described. Using a model system comprising HER2- or PSMA-positive cells as the analytes and single-stranded RNA aptamers specific for HER2 or PSMA as immobilized ligands on chips, we could demonstrate that aptamers were equivalent or superior to antibodies in terms of specificity and sensitivity, respectively. In particular, our PSMA-specific sensor was found to have the characteristics of good stability, reproducibility and reusability, with detection limit as low as 10(3) LNCaP cells. In conclusion, we could show the suitability of nucleic acid aptamers as low molecular weight receptors on biochips for sensitive and specific cell detection and quantitation for future diagnostics development. PMID- 23357003 TI - A molecular beacon and graphene oxide-based fluorescent biosensor for Cu(2+) detection. AB - In this work, we report a "turn-on" fluorescent strategy for the direct detection of Cu(2+) in solutions using molecular beacons (MBs) and graphene oxide (GO). MBs are special single-stranded DNA and carry fluorescence sources. GO is a new nanomaterial having remarkable physical properties. In the sensing system, GO was used as an efficient fluorescence quencher upon the adsorption of MBs, which reduced the background signal and made the detection method highly sensitive. In the presence of Cu(2+), the MBs were cut into short pieces and released by the GO, leading to fluorescence restoration. The detection limit of the sensing strategy was ~50nM, which is sufficiently sensitive for practical applications. The sensing method also exhibited high selectivity in testing samples containing other metal ions. The application of the method for drinking water is demonstrated. PMID- 23357004 TI - Registration of the protein with compact disk. AB - CD-based optico-acoustical biosensor (OAB) was used for detection of various types of proteins represented by bovine serum albumin (BSA), heme-containing myoglobin (Mb), monoclonal antibody against viral protein marker of hepatitis B (anti-HBsAg) and membrane-bound cytochrome P450scc (P450scc). We applied standard compact disc reader (CD-ROM) as an optical analyzer and a standard compact disc (CD) as a biochip containing immobilized protein molecules. This biosensor can translate into a digital code the changes of optical signal from the proteins and their complexes immobilized on the CD surface. Then, the digital code is translated into an acoustic series or, in other words, into a "music of proteins". We demonstrate the use of the OAB for direct detection of proteins with different molecular weights, such as BSA, Mb, P450scc, anti-HBsAg with the concentration detection limit (DL) about 10(-7)M. By signal amplification achieved with autometallography, a higher sensitivity level (DL~10(-9)M) for the detection of myoglobin was obtained. The method of OAB-detection of proteins is cheap: it requires no special equipment like spectrometers, refractometers and other devices. Due to the fact that acoustic series of the protein complexes antigen/antibody differs from that of single proteins, the OAB-detection is of particular interest for rapid assay in yes/no data type and for home diagnostics. Combination of the OAB with a mass spectrometer allowed the detection and identification of the target proteins fished out directly onto a standard CD surface. PMID- 23357005 TI - Heart type fatty acid binding protein: structure, function and biosensing applications for early detection of myocardial infarction. AB - Heart type fatty acid binding protein (HFABP) as an early marker of cardiac injury holds a promising future with studies indicating surpassing performance as compared to myoglobin. As a plasma marker, this cytoplasmic protein owing to its small size (~15kDa) and water solubility, appears readily in the blood-stream following cardiomyocyte damage, reaching peak levels within 6h of symptom onset. Low plasma levels of HFABP as compared to tissue levels indicate that minute amounts of the protein when released during myocardial infarction leads to a greater proportional rise. These parameters of kinetic release make it an ideal candidate for rapid assessment of acute myocardial infarction (AMI). The need for development of rapid immunoassays and immunotests so as to use HFABP as an early marker for AMI exclusion is tremendous. In the present review, we outline the various immunoassays and immunosensors developed so far for the detection of HFABP in buffer, plasma or whole blood. The principles behind the detection techniques along with their performance parameters compared to standard ELISA techniques are elucidated. PMID- 23357007 TI - Quantitative analysis of membrane protein transport across the nuclear pore complex. AB - Nuclear transport of the Saccharomyces cerevisiae membrane proteins Src1/Heh1 and Heh2 across the NPC is facilitated by a long intrinsically disordered linker between the nuclear localization signal (NLS) and the transmembrane domain. The import of reporter proteins derived from Heh2 is dependent on the FG-Nups in the central channel, and the linker can position the transport factor-bound NLS in the vicinity of the FG-Nups in the central channel, while the transmembrane segment resides in the pore membrane. Here, we present a quantitative analysis of karyopherin-mediated import and passive efflux of reporter proteins derived from Heh2, including data on the mobility of the reporter proteins in different membrane compartments. We show that membrane proteins with extralumenal domains up to 174 kDa, terminal to the linker and NLS, passively leak out of the nucleus via the NPC, albeit at a slow rate. We propose that also during passive efflux, the unfolded linker facilitates the passage of extralumenal domains through the central channel of the NPC. PMID- 23357006 TI - An approach toward SNP detection by modulating the fluorescence of DNA-templated silver nanoclusters. AB - A rapid, homogeneous, and in-situ labelable format designed to detect single nucleotide polymorphism (SNP) is presented. Fluorescent silver nanoclusters produced following hydride-mediated reduction of Ag(+) bound to a partial double stranded oligodeoxynucleotide were employed as probes for SNPs. The sensing mechanism is based on the fluorescence enhancement of silver nanoclusters through an irreversible cluster transfer upon hybridization. The key element of our design is modulating the "turn on" mechanism by introducing a competitor that can be displaced in response to a target DNA. In a controlled model system, the fluorescence intensity of silver nanoclusters is approximately 3-fold enhanced upon hybridization with a perfectly matched target DNA, and single-base mismatch detection is achieved within 5min, regardless of the position of mismatches. Human aldehyde dehydrogenase 2 (ALDH2), which is responsible for the oxidation of aldehydes to carboxylic acids, is then utilized as a target for SNP. Upon addition of a perfectly matched sequence, dramatically enhanced fluorescence intensity is observed (ca. 48-fold), and prompt SNP genotyping is accomplished. PMID- 23357008 TI - The successful use of simple tube duodenostomy in large duodenal perforations from varied etiologies. AB - INTRODUCTION: Tube decompression of the duodenum is an old but underutilized technique known to decrease morbidity and mortality in patients with difficult to manage duodenal injuries. Broad arrays of techniques have been described in the literature and are reviewed, but most are complex procedures not appropriate for the management of an unstable patient. PRESENTATION OF CASE: In this paper we describe the technique of tube duodenostomy and the successful application in three cases of large defects (>3cm) which two of these cases had failed previous repair attempts. The defects were caused by very different etiologies, including blunt trauma, peptic ulcer disease and erosion from cancer. All were finally managed by application of tube duodenostomy with success. DISCUSSION: Patients with "difficult to manage duodenum" usually present with hemodynamic instability with hostile abdomen. Complex procedures in an unstable patient are associated with adverse outcomes. In patients with significant comorbidities and instability the damage control principle of trauma surgery is gaining popularity. Tube duodenostomy technique described in this paper fits in well with that principle. CONCLUSION: Application of tube duodenostomy instead of a complex procedure in an unstable patient provides an opportunity to stabilize the patient, converting an impending catastrophe to a future scheduled surgery. PMID- 23357009 TI - Small bowel lesion due to spiral tacks after laparoscopic intraperitoneal onlay mesh repair for incisional hernia. AB - INTRODUCTION: Laparoscopic intraperitoneal onlay mesh (IPOM) repair has become a widely accepted operative technique for incisional hernias. However, tack fixation poses the risk of adhesions and injury to the intestine. We report the case of spiral tacks adherent to the small bowel after IPOM repair for incisional hernia. PRESENTATION OF CASE: 64 years old male patient who underwent laparoscopic IPOM repair for incisional hernia 1 year after open sigmoid resection. A laminated polypropylene mesh was fixed with titanium spiral tacks. 4 years later, elective open cholecystectomy was performed. Two spiral tacks integrated in the seromusular layer of the small bowel were encountered. Tacks were removed and bowel lesions oversewn with interrupted seromuscular stitches. DISCUSSION: According to the current literature, complications related to metal spiral tacks in IPOM mesh repair such as intestinal perforation or strangulation ileus seem to be rare. To our knowledge, spiral tacks adherent to the intestine have not yet been published to date. Alternative techniques for mesh fixation are transfascial sutures with single stitches, continuous sutures or fibrin glue, as already used in TAPP and TEP procedures for inguinal hernia repair. The ideal and safest technique for mesh fixation in IPOM repair for incisional hernias remains controversial. CONCLUSION: Spiral tacks used for intraperitoneal mesh fixation can lead to adhesions and bowel lesions. Sutures, absorbable tacks or fibrin glue are alternatives for mesh fixation. Further clinical trials are needed to evaluate the safest technique of laparoscopic IPOM incisional hernia repair. PMID- 23357010 TI - Necrotizing cellulitis of the abdominal wall, caused by Pediococcus sp., due to rupture of a retroperitoneal stromal cell tumor. AB - INTRODUCTION: Soft tissue necrotizing infections are a significant cause of morbidity and mortality. The aim of this study is to present a patient with necrotizing infection of abdominal wall resulting from the rupture of a retroperitoneal stromal tumor. PRESENTATION OF CASE: We present a 60-year-old Caucasian male patient with necrotizing infection of abdominal wall secondary to the rupture of a retroperitoneal stromal tumor. The patient was initially treated with debridement and fasciotomy of the anterior abdominal wall. Laparotomy revealed purulent peritonitis caused by infiltration and rupture of the splenic flexure by the tumor. Despite prompt intervention the patient died 19 days later. The isolated microorganism causing the infection was the rarely identified as cause of infections in humans Pediococcus sp., a gram-positive, catalase-negative coccus. DISCUSSION: Necrotizing infections of abdominal wall are usually secondary either to perineal or to intra-abdominal infections. Gastrointestinal stromal cell tumors could be rarely complicated with perforation and abscess formation. In our case, the infiltrated by the extra-gastrointestinal stromal cell tumor ruptured colon was the source of the infection. The pediococci are rarely isolated as the cause of severe septicemia. CONCLUSION: Ruptured retroperitoneal stromal cell tumors are extremely rare cause of necrotizing fasciitis, and before this case, Pediococcus sp. has never been isolated as the responsible agent. PMID- 23357011 TI - Short communication: the effect of temperature on performance of milk ketone test strips. AB - Ketosis is estimated to affect 15% of early lactation dairy cows. A ketone test strip (Keto-Test; Elanco Animal Health, Greenfield, IN) allows producers a method to determine the concentration of beta-hydroxybutyrate (BHBA) in milk to track individual animal and herd incidence of ketosis. The objective of this study was to determine the effect of altering the temperature of milk and the test strips at the time of the test on the reliability of the Keto-Test. A total of 118 Holstein cows, ranging from 5 to 17 DIM, were selected from a commercial Holstein dairy herd in Michigan. A milk sample was collected from the right rear quarter of each cow during the a.m. milking. Each sample was tested under 4 temperature conditions: (1) Keto-Test strips and milk at room temperature (RT; 24.0 +/- 0.1 degrees C; control; manufacturer's instructions), (2) cold strips (10.8 +/- 0.9 degrees C) and milk at RT, (3) cold strips and fresh milk, and (4) strips at RT and fresh milk. Milk was recorded as negative (0-99 MUmol/L), weak positive (100 199 MUmol/L), positive (200-499 MUmol/L), or highly positive (>= 500 MUmol/L). Blood samples were collected immediately following milk collection and analyzed for BHBA concentration using a ketone test meter. Cows with blood BHBA concentration of >= 1,400 MUmol/L were considered positive for subclinical ketosis. Accuracy of the Keto-Test strips under the 4 conditions was determined by the kappa coefficient of agreement, using the result of condition 1 as the accepted true value. Additionally, sensitivity and specificity were calculated using the blood BHBA concentrations and results of each of the 4 conditions. Using the Keto-Test 60.2% of cows tested negative for milk BHBA, 24.6% tested weak positive, 14.4% tested positive, and 0.8% tested highly positive. The weighted kappa coefficient of agreement between the control condition (1) and condition 2, 3, and 4 and 95% lower and upper confidence intervals were as follows: condition 2=0.71 (0.62, 0.80), condition 3=0.69 (0.60, 0.78), and condition 4=0.63 (0.54, 0.73). These results indicate good agreement between the outcome of condition 1 and conditions 2, 3, and 4. The sensitivities/specificities for 1, 2, 3, and 4 were as follows: 0.77/0.79, 0.74/0.75, 0.69/0.88, and 0.69/0.84, indicating that the test in all temperature conditions had a strong ability to detect the presence of BHBA in milk. In conclusion, the reliability of the Keto-Test strips was not dependent on the temperature of the milk or the test strips. PMID- 23357012 TI - Comparison of random regression and repeatability models to predict breeding values from test-day records of Norwegian goats. AB - One aim of the research was to challenge a previously selected repeatability model with 2 other repeatability models. The main aim, however, was to evaluate random regression models based on the repeatability model with lowest mean squared error of prediction, using Legendre polynomials up to third order for both animal additive genetic and permanent environmental effects. The random regression and repeatability models were compared for model fit (using likelihood ratio testing, Akaike information criterion, and the Bayesian information criterion) and the models' mean-squared errors of prediction, and by cross validation. Cross-validation was carried out by correlating excluded observations in one data set with the animals' breeding values as predicted from the pedigree only in the remaining data, and vice versa (splitting proportion: 0.492). The data was from primiparous goats in 2 closely tied buck circles (17 flocks) in Norway, with 11,438 records for daily milk yield and 5,686 to 5,896 records for content traits (fat, protein, and lactose percentages). A simple pattern was revealed; for daily milk yield with about 5 records per animal in first lactation, a second-order random regression model should be chosen, whereas for content traits that had only about 3 observations per goat, a first-order polynomial was preferred. The likelihood-ratio test, Akaike information criterion, and mean-squared error of prediction favored more complex models, although the results from the latter and the Bayesian information criterion were in the direction of those obtained with cross-validation. As the correlation from cross-validation was largest with random regression, genetic merit was predicted more accurate with random regression models than with the repeatability model. PMID- 23357013 TI - Artificial insemination field data on the use of sexed and conventional semen in nulliparous Holstein heifers. AB - This study investigated conception rates and other reproductive outcomes achieved with artificial insemination (AI) of nulliparous Holstein heifers using sexed and conventional semen in a commercial Australian dairy herd in central western New South Wales from January 2004 to April 2009. Retrospective data from on-farm records of 9,870 inseminations of 4,456 heifers were analyzed using several mixed models to assess the effect of temperature and humidity surrounding breeding, insemination sire, artificial insemination technician, service number, and heifer weight and age at breeding on reproductive traits (conception rates, sex ratios, gestation length, and abortion and stillbirth rates). Semen was used from 15 sexed sires and 41 unsexed sires. Sexed semen was primarily used at first and second service. Empirical conception rates of 31.6 and 39.6% were achieved for sexed and unsexed semen respectively, whereas model-based predictions were lower, at 21.3 and 32.1%. Conception rates were significantly affected by insemination sire, sex-sorting, heifer age at breeding, temperature and humidity surrounding breeding, service number, and AI technician. Sexed semen yielded 86% heifers, compared with 48% for conventional semen. Significant predictors of calf sex included semen sexing, gestation length, and insemination sire. Twinning rate was high, at 3.6% for both semen types, and gestation length and heifer weight at breeding were significant predictors of twinning. Abortion rates for sexed and unsexed conceptions were similar at 6.1 and 6.5%, respectively, and were affected by heifer age at breeding. Stillbirth rate was affected by calf sex, twinning, gestation length, and AI technician; semen sorting, age at breeding, and temperature and humidity were marginally significant predictors. No abnormalities were observed in the development of offspring, except for a marginally higher stillbirth rate for sexed calves, a finding that needs further investigation. Many variables influence the breeding outcomes associated with the application of sex-sorted sperm on commercial dairy farms. Recognition and management of these variables will increase the economic return from the investment in sex-sorted sperm. PMID- 23357014 TI - Optical backscatter method for determining thermal denaturation of beta lactoglobulin and other whey proteins in milk. AB - The heat denaturation of whey proteins affects the functional properties of milk. Correlations of beta-lactoglobulin (beta-LG) denaturation to gelation time, gel firmness, and gel moisture content have been widely documented. Currently, no technique is available for quantifying beta-LG denaturation in milk without altering its native composition or requiring a laborious procedure. The goal of this study was to establish if an optical backscatter response of whey protein denaturation during milk heat treatment could be determined that would be the basis for an inline optical measurement technology. The experimental design consisted of 1 factor (time at 80 degrees C) and 6 levels (0, 3, 5, 7, 12, and 25 min). Physicochemical analysis performed indicated that beta-LG denaturation followed a first-order response during thermal treatment. The light backscatter response, measured as a ratio of two 25-nm wave bands (832.5 nm/382.5 nm), significantly correlated to beta-LG denaturation and had a 14% increase for milk with 75% beta-LG denaturation. The strength of the optical response at the proposed wave bands and their correlation to denaturation suggests that light backscatter could potentially be used to measure beta-LG and other whey protein denaturation inline. PMID- 23357015 TI - Veterinary herd health management programs on dairy farms in the Netherlands: use, execution, and relations to farmer characteristics. AB - Veterinary herd health management (VHHM) programs are of growing importance to the dairy industry; they support farmers in the shift from curative to preventive health management, caused by increased herd sizes and quality standards in dairy farming. Farmers participating in VHHM are visited every 4 to 6 wk by their veterinarian, who checks the animals and herd management to intervene in a proactive way with problems regarding animal health and animal welfare. At present, no good overview exists of how VHHM is executed on Dutch dairy farms, and whether different farmers require different types of VHHM. Aims of this study were to (1) map out how many farmers participate in VHHM, (2) describe how VHHM is executed on the farms, and (3) see whether certain farmer characteristics are related to farmers' participation in VHHM. In 2011, a questionnaire was sent to 5,000 Dutch dairy farmers per e-mail. Part 1 of the questionnaire focused on participation in and execution of VHHM and part 2 focused on farmer characteristics regarding external information. Returned questionnaires (n=1,013) were summarized and statistically analyzed. In this study 68.6% of the responding farmers participated in any form of VHHM. The most important activities were fertility checks and advice about fertility; the least important were housing and claw health. Relationships between farmer characteristics (use of and trust in information) and participation in VHHM were found. PMID- 23357016 TI - Short communication: effects of frequency of feed delivery and bunk space on the feeding behavior of limit-fed dairy heifers. AB - The objective of this experiment was to determine the interaction between feed bunk space and frequency of feed provision on the feeding behavior patterns and growth of growing dairy heifers fed a limited amount. Sixteen Holstein dairy heifers (183.4 +/- 9.1 d of age, mean +/- standard deviation) were divided into 4 groups of 4. The groups were exposed to each of 4 treatments, using a 4 * 4 Latin square design with a 2 * 2 factorial arrangement of treatments, over 21-d periods (14-d adaptation period, 7-d data collection periods). The treatments were arranged in 2 feed delivery frequencies (once per day at 1200 h: 1 */d, and twice per day at 1200 and 1400 h: 2 */d) and 2 levels of feed bunk space (adequate feed bunk space: 0.40 m/heifer, and reduced feed bunk space: 0.29 m/heifer). Pen dry matter intake (DMI) was recorded daily, average daily gain (ADG) was recorded weekly, and variability in ADG was calculated from the standard deviation of ADG. Feeding, unrewarded behavior (time at feed bunk without feed present), and competitive behavior were recorded using time-lapse video. Feeding and unrewarded behavior were measured for the last 7 d of each period, whereas competitive behavior was recorded on d 16, 18, and 20 of each period. Lying time was recorded for the last 7 d of each period. A tendency for interaction between feed bunk space and frequency of feed delivery on the feed efficiency of limit-fed dairy heifers was noted. Heifers provided restricted bunk space were reported as being less efficient when fed 2 */d; however, no other interactions were found. Although DMI and variability in ADG were similar between treatments, ADG was higher (1.0 vs. 0.9 kg/d) when heifers were provided with 0.40 m of feed bunk space and tended to be higher when fed 1 */d compared with that of heifers given restricted bunk space or fed 2 */d. Heifers fed 1 */d spent more time feeding throughout the day (70.5 vs. 58.9 min/d) than heifers fed 2 */d. Heifers fed at a restricted bunk space or fed 1 */d were approximately 25% more variable in feeding time than heifers fed 2 */d or with adequate bunk space. Heifers spent a similar amount of time in unrewarded visits to the feed bunk (28.9 min/d). Although feed bunk space did not affect competition (3.6 displacements/d), heifers fed 1 */d were displaced twice as frequently than heifers fed 2 */d. Regardless of treatment, heifers spent a similar amount of time lying down and standing without eating. Overall, providing sufficient feed bunk space to allow all limit-fed heifers to feed simultaneously improves feed efficiency and ADG and reduces variability in feeding time. Additionally, although delivering feed 1 */d resulted in increased competition, it also enabled heifers to gain adequate weight and spend more time feeding each day. PMID- 23357017 TI - Effects of Bos taurus autosome 9-located quantitative trait loci haplotypes on the disease phenotypes of dairy cows with experimentally induced Escherichia coli mastitis. AB - Several quantitative trait loci (QTL) affecting mastitis incidence and mastitis related traits such as somatic cell score exist in dairy cows. Previously, QTL haplotypes associated with susceptibility to Escherichia coli mastitis in Nordic Holstein-Friesian (HF) cows were identified on Bos taurus autosome 9. In the present study, we induced experimental E. coli mastitis in Danish HF cows to investigate the effect of 2 E. coli mastitis-associated QTL haplotypes on the cows' disease phenotypes and recovery in early lactation. Thirty-two cows were divided in 2 groups bearing haplotypes with either low (HL) or high (HH) susceptibility to E. coli. In addition, biopsies (liver and udder) were collected from half of the cows (n=16), resulting in a 2 * 2 factorial design, with haplotype being one factor (HL vs. HH) and biopsy being the other factor (biopsies vs. no biopsies). Each cow was inoculated with a low E. coli dose (20 to 40 cfu) in one front quarter at time 0 h. Liver biopsies were collected at 144, 12, 24, and 192 h; udder biopsies were collected at 24h and 192 h post-E. coli inoculation. The clinical parameters: feed intake, milk yield, body temperature, heart rate, respiration rate, rumen motility; and the paraclinical parameters: bacterial counts, somatic cell count (SCC), and milk amyloid A levels in milk; and white blood cell count, polymorphonuclear neutrophilic leukocyte (PMNL) count, and serum amyloid A levels in blood were recorded at different time points post-E. coli inoculation. Escherichia coli inoculation changed the clinical and paraclinical parameters in all cows except one that was not infected. Clinically, the HH group tended to have higher body temperature and heart rate than the HL group did. Paraclinically, the HL group had faster PMNL recruitment and SCC recovery than the HH group did. However, we also found interactions between the effects of haplotype and biopsy for body temperature, heart rate, and PMNL. In conclusion, when challenged with E. coli mastitis, HF cows with the specific Bos taurus autosome 9-located QTL haplotypes were associated with differences in leukocyte kinetics, with low-susceptibility cows having faster blood PMNL recruitment and SCC recovery and a tendency for a milder clinical response than the high-susceptibility cows did. PMID- 23357018 TI - Short communication: urea transporter protein UT-B in the bovine parotid gland. AB - Ruminant nutrition relies upon the symbiotic relationship that exists with microbial populations in the rumen. Urea transported across the ruminal epithelia and secreted by the salivary glands is a key source of nitrogen for microbial growth in the rumen. As ruminal urea transport can be mediated by specific UT-B urea transporters, this study investigated whether UT-B urea transporters were also present in the bovine salivary gland. Western blotting experiments detected only small amounts of UT-B protein in whole-cell lysate from the bovine parotid gland. In contrast, strong 32 to 34 and 40 kDa UT-B proteins were detected in parotid plasma membrane-enriched protein, showing the importance of using enriched samples. These signals were also detected in rumen and correspond to bovine UT-B1 and UT-B2 urea transporters, respectively. Further immunolocalization studies identified that these proteins were located in the ductal system of the parotid gland. This study, therefore, confirmed the presence of UT-B urea transporter protein in the bovine parotid salivary gland. PMID- 23357019 TI - Lactobacillus helveticus as a tool to change proteolysis and functionality in Swiss-type cheeses. AB - Lactobacillus helveticus exhibits a great biodiversity in terms of protease gene content, with 1 to 4 cell envelope proteinases. Among them, proteinases PrtH and PrtH2 were shown to have different cleavage specificity on pure alpha(s1)-casein. The aim of this work was to investigate the proteolytic activity of 2L. helveticus strains in cheese matrix: ITGLH77 (PrtH2 only) and ITGLH1 (at least 2 proteinases, PrtH and PrtH2). Cell viability, proteolysis, autolysis, and stretchability of experimental Emmental cheeses were measured during ripening. The peptides identified by mass spectrometry showed very different profiles in the 2 cheeses. Regardless of the casein origin, the number of different peptides containing more than 20 amino acids was greater in cheeses manufactured with strain ITGLH77. This accumulation of large peptides, including those from alpha(s1)- and alpha(s2)-caseins, was in agreement with the lower overall extent of proteolysis obtained in ITGLH77 cheeses, which can be attributed to the presence of one cell envelope proteinase of the lactobacilli strains or lesser release of intracellular peptidases into the cheese aqueous phase. In parallel, stretchability was measured throughout ripening time. Emmental strands observed by confocal laser scanning microscopy showed microstructure similar to that of mozzarella strands. Stretchability was correlated with a specific type of peptide (hydrophobic), as shown by principal component analysis, and with a lower degree of proteolysis. PMID- 23357020 TI - Short communication: role of Mycoplasma arginini in mastitis caused by Streptococcus dysgalactiae. AB - We performed a comparative study on the development of mastitis induced by Mycoplasma arginini or Streptococcus dysgalactiae after challenging the cows. Mycoplasma arginini did not cause any clinical symptoms on its own, resulting in only a transient increase of somatic cell count (SCC; increase ranging from 0.5 * 10(6) to 0.8 * 10(6) cells/mL) and a slight decrease of milk production (10%) for 5 d. In contrast, Strep. dysgalactiae induced more severe clinical signs in animals and SCC increased to 1.60 * 10(6) to 2.11 * 10(6) cells/mL for 10 d. In addition, milk production decreased (22.9 to 27.0%) for 10 d. After 3 mo (2 mo after the first challenge), animals that were challenged previously with M. arginini were rechallenged with Strep. dysgalactiae. Severe clinical mastitis developed, with very high SCC (5.00 * 10(6) to 21.5 * 10(6) cells/mL), and a very significant reduction of milk production (28.6 to 68.7%), which lasted more than 4 wk, was observed. The severe clinical mastitis developed not only in cows inoculated with Strep. dysgalactiae andM. arginini in the same udder quarter but also in cows infected in the quarter previously not challenged with mycoplasma. Cows challenged first with Strep. dysgalactiae and rechallenged with M. arginini 2 mo later developed only slight changes in both SCC and milk production, similar to those when the cows were challenged with M. arginini alone. We conclude that M. arginini infection does not cause remarkable mastitis (characterized by decrease in milk production and increase of SCC) but it significantly predisposes animals to infection with Strep. dysgalactiae, leading to severe clinical mastitis. PMID- 23357021 TI - Effect of drying methods of microencapsulated Lactobacillus acidophilus and Lactococcus lactis ssp. cremoris on secondary protein structure and glass transition temperature as studied by Fourier transform infrared and differential scanning calorimetry. AB - Protective mechanisms of casein-based microcapsules containing mannitol on Lactobacillus acidophilus and Lactococcus lactis ssp. cremoris, changes in their secondary protein structures, and glass transition of the microcapsules were studied after spray- or freeze-drying and after 10 wk of storage in aluminum foil pouches containing different desiccants (NaOH, LiCl, or silica gel) at 25 degrees C. An in situ Fourier transform infrared analysis was carried out to recognize any changes in fatty acids (FA) of bacterial cell envelopes, interaction between polar site of cell envelopes and microcapsules, and alteration of their secondary protein structures. Differential scanning calorimetry was used to determine glass transition of microcapsules based on glass transition temperature (T(g)) values. Hierarchical cluster analysis based on functional groups of cell envelopes and secondary protein structures was also carried out to classify the microencapsulated bacteria due to the effects of spray- or freeze-drying and storage for 10 wk. The results showed that drying process did not affect FA and secondary protein structures of bacteria; however, those structures were affected during storage depending upon the type of desiccant used. Interaction between exterior of bacterial cell envelopes and microencapsulant occurred after spray- or freeze-drying; however, these structures were maintained after storage in foil pouch containing sodium hydroxide. Method of drying and type of desiccants influenced the level of similarities of microencapsulated bacteria. Desiccants and method of drying affected glass transition, yet no T(g) <=25 degrees C was detected. This study demonstrated that the changes in FA and secondary structures of the microencapsulated bacteria still occurred during storage at T(g) above room temperature, indicating that the glassy state did not completely prevent chemical activities. PMID- 23357022 TI - Evaluation of reproductive and economic outcomes of dairy heifers inseminated at induced estrus or at fixed time after a 5-day or 7-day progesterone insert-based ovulation synchronization protocol. AB - The objectives of the current experiment were to evaluate the reproductive performance and economic outcome of 3 synchronization strategies for first artificial insemination (AI) of dairy heifers. Holstein heifers from 2 herds (site A, California, n=415; site B, Idaho, n=425) were assigned to 1 of 3 treatments. Heifers assigned to the AI on estrus (AIE) treatment received an injection of 25mg of PGF(2alpha) at enrollment (d 0) and every 11 d thereafter until AI occurred. Heifers assigned to the CIDR5 treatment received a controlled internal drug release insert (CIDR) containing 1.38 g of progesterone, which was removed 5 d later concomitantly with an injection of 25mg of PGF(2alpha), and received fixed-time AI (TAI) concomitantly with an injection of 100 MUg of GnRH 53 to 60 h later. Heifers assigned to the CIDR7 treatment received a CIDR insert, which was removed 7 d later concomitantly with an injection of 25mg of PGF(2alpha), and received TAI concomitantly with an injection of 100 MUg of GnRH 53 to 60 h later. Heifers were observed for estrus and inseminated up to 98 and 73 d after enrollment in sites A and B, respectively. Thereafter, heifers were moved to pens with bulls and considered failure to conceive to AI if still not pregnant at the end of the observation period. Economic outcomes were based on cost of synchronization protocol (CIDR treatment=$11, PGF(2alpha) or GnRH treatments=$2.5/treatment, estrous detection=$0.80/heifer per day), rearing cost ($2.75/heifer per day), and economic loss if a heifer did not conceive to first AI ($150). Input cost of the reproductive programs=synchronization protocol cost + semen cost + rearing cost + replacement cost. Pregnancy per AI (P/AI) 38 +/- 3 d after first AI was greatest for AIE heifers (61.1%) followed by CIDR5 (44.8%) and CIDR7 (35.7%) heifers. Furthermore, P/AI 73 +/- 7 d after first AI was greatest for AIE (58.8%) and tended to be greater for CIDR5 (42%) than for CIDR7 (34.1%) heifers. The percentage of heifers that had spontaneous luteolysis from CIDR insertion to CIDR removal was reduced for CIDR5 compared with CIDR7 (13.8 vs 31.8%). Pregnancy rate was greatest for AIE heifers but did not differ between CIDR5 [adjusted hazard ratio (95% confidence interval)=0.75 (0.63, 0.90)] and CIDR7 [adjusted hazard ratio (95% confidence interval)=0.65 (0.54, 0.77)] heifers. Consequently, rearing cost and input cost of AIE heifers ($67.1 +/- 4.4 and -$107.1 +/- 7.0, respectively) were reduced compared with CIDR5 ($86.9 +/- 5.1 and -$143.4 +/- 8.1, respectively) and CIDR7 ($98.3 +/- 5.1 and -$156.5 +/- 8.2, respectively) heifers, but no differences were observed between CIDR5 and CIDR7 heifers. PMID- 23357023 TI - Validation of housekeeping genes as internal controls for studying gene expression during Pacific oyster (Crassostrea gigas) development by quantitative real-time PCR. AB - Hatchery-reared larvae of the Pacific oyster (Crassostrea gigas) often suffer from massive mortality induced by Ostreid herpesvirus 1 (OsHV-1) infection, indicating the importance of better understanding of oyster immune defense systems. The accuracy of measurements of gene expression levels based on quantitative real-time PCR assays relies on the use of housekeeping genes as internal controls; however, few studies have focused on the selection of such internal controls. In this study, we conducted a comprehensive investigation of internal control genes during oyster development in virus-infected and uninfected samples. Transcriptome data for 38 developmental stages were downloaded and the gene expression patterns were classified into 30 clusters. A total of 317 orthologs of classical housekeeping genes in the oyster genome were annotated. After combining the expression profiles and oyster housekeeping gene dataset, 14 candidate internal controls were selected for further investigation: Elongation factor-1alpha (EF-1alpha), 18S rRNA (18S), 28S rRNA (28S), Glyceraldehyde 3 phosphate dehydrogenase (GAPDH), beta-actin (ACT), Ribosomal protein L7 (RL7), Ribosomal protein L27 (RL27), Ribosomal protein L36 (RL36), Ribosomal protein S18 (RS18), Heterogeneous nuclear ribonucleoprotein A2/B1 (RO21), Eukaryotic translation elongation factor 2 (EF2), Ubiquitin-conjugating enzyme E2D2 (UBCD1), S-phase kinase-associated protein 1 (SKP1) and Heterogeneous nuclear ribonucleoprotein Q (HNRPQ). RNA was extracted from oyster larvae infected with OsHV-1 (group A; GA), and OsHV-1 free larvae (group B; GB). The expression levels of the 14 candidate internal controls were studied in GA and GB larvae by real time PCR. Their expression stabilities were further analyzed using the GeNorm program. RL7 and RS18 were the most stable genes in both OsHV-1 infected (GA) and uninfected (GB) larvae. These results suggest that RL7 and RS18 could be used as internal controls for studying gene expression in normal growing oyster larvae and in OsHV-1 infected larvae. These high quality internal controls will be a valuable resource in future studies of oyster larval mortality. PMID- 23357024 TI - Molecular identification and expression analysis of the CC chemokine gene in rock bream (Oplegnathus fasciatus) and the biological activity of the recombinant protein. AB - We identified the CC chemokine cDNA designated as RbCC1 (CC chemokine 1 in rock bream, Oplegnathus fasciatus), which was isolated using expressed sequence tag (EST) analysis of a lipopolysaccharide (LPS)-stimulated rock bream liver cDNA library. The full-length RbCC1 cDNA (850 bp) contained an open reading frame (ORF) of 366 bp encoding 122 amino acids. Results from our phylogenetic analysis demonstrated that the RbCC1 was closest relationship to the orange-spotted grouper and Mi-iyu croaker CC chemokines located within the fish CC chemokine group. RbCC1 was significantly expressed in the intestine, spleen, liver, and PBLs (peripheral blood leukocytes). Rock bream PBLs were stimulated with several mitogens, LPS and Con A/PMA which significantly induced the expression of RbCC1 mRNA in the PBLs. The RbCC1 mRNA expression in several tissues under conditions of bacterial and viral challenge was examined. The experimental challenge revealed that the kidney and spleen of fish infected with Streptococcus iniae showed the most significant increases in RbCC1 expression compared to the control. In the case of RSIV infection, the RbCC1 mRNA expression was markedly up regulated in the liver. In this study, recombinant RbCC1 (approximately 53 kDa) was produced using an Escherichia coli expression system followed by purification. Subsequently, the addition of purified rRbCC1 was examined to investigate the impact on the proliferative and chemotactic activity on kidney leukocytes from rock bream. The results demonstrated that the rRbCC1 induces significant biological activity on kidney leukocyte proliferation and attraction at concentrations in the range of 10-300 MUg/mL and suggests that rRbCC1 could be utilized as an immune-stimulant and/or molecular adjuvant to enhance the immune effects of vaccines. PMID- 23357025 TI - Interleukin-17 in pearl oyster (Pinctada fucata): molecular cloning and functional characterization. AB - IL-17 from pearl oyster Pinctada fucata, one of mollusk, was identified and characterized, and its genomic structure and promoter were analyzed. The full length cDNA of P. fucata IL-17 (PfIL-17) is 907 bp with an open reading frame of 585 bp encoding a putative protein of 194 amino acids. The deduced PfIL-17 contains a 19 amino acid signal peptide and a conserved IL-17 domain. Multiple sequence alignments and phylogenetic analysis revealed that PfIL-17 has lower similarity with other invertebrate IL-17 and was clustered with CgIL-17, but not clustered with other invertebrate IL-17. Gene expression analysis indicated that PfIL-17 took part in the immune response to LPS and poly(I:C) stimulation, and dual-luciferase reporter assays showed that PfIL-17 could active vertebrate target genes containing the NF-kappaB binding site and involve NF-kappaB signal pathway in HEK293 cells. Combined with the results mentioned above, it is suggested that PfIL-17 might involve and activate NF-kappaB signal pathway against extracellular pathogens. PMID- 23357026 TI - Variability of motor cortical excitability using a novel mapping procedure. AB - The purpose of this study was to assess the reliability of a novel TMS motor cortex mapping procedure. The procedure was designed to take less time and be more clinically useful by delivering fewer MEPS over fewer skull locations. Resting motor evoked potentials (MEPs) were recorded from the first dorsal interosseus muscle of 6 individuals over a fixed 15-point grid. Mean MEP amplitudes, map center of gravity (CoG), and stimulus-response characteristics were assessed before and after a 30-min rest session. As a novel feature, subregions of the map were analyzed for regions of highest test-retest reliability for use as a global measure of cortical excitability. Mean MEP amplitudes between sessions were highly reliable (ICC=0.90-0.92). Reproducibility of MEPs was highest along an axis approximately 45 degrees to the nasion-inion. Stimulus-response MEP amplitudes showed moderate to high reliability (ICC 0.54 0.95). Mean CoG shift between sessions was 2.79+/-1.2mm. This mapping procedure is reliable and allows efficient assessment of motor cortex excitability. PMID- 23357027 TI - Inducible gene expression in postmitotic neurons by an in vivo electroporation based tetracycline system. AB - In vivo electroporation has been widely used to transfect foreign genes into neural progenitors and analyze the function of genes of interest in the developing nervous system. However, it has not been thoroughly examined in the conditional regulation of exogenous genes in postmitotic neurons. Here we show that the combination of in vivo electroporation and the newest version of the tetracycline (Tet)-controlled gene regulatory (Tet-On) system efficiently induced gene expression in various types of neurons in mouse embryonic and postnatal tissues. In pyramidal neurons of the cerebral cortex, tetracycline-responsive element (TRE)-driven gene expression was induced in the presence of doxycycline (Dox). The induction occurred in a dose-dependent manner. The Dox-dependent induction was also observed in cerebellar Purkinje cells and spinal cord neurons. Moreover, the TRE-driven inducible expression of mammalian Barh1 (Mbh1) mimicked the phenotype of the ubiquitous expression of Mbh1 in the spinal cord. These results indicate that the combination of the Tet-On system and in vivo electroporation is useful for analyzing gene function specifically in postmitotic neurons. PMID- 23357028 TI - Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications. AB - The pharmacologic management of insomnia has long been dominated by agents that facilitate gamma amino butyric acid inhibition. These agents have served as the clinical model for understanding the pharmacodynamic effects of insomnia agents according to which sleep effects parallel plasma drug levels (pharmacokinetic effects). Agents with other mechanisms also exist for treating insomnia; however, their effects are less well understood. Many of these diminish the activity in one or more of the key wake-promoting systems. This review focuses on one such mechanism, blockade of the wake promoting effects of histamine via H1 receptor antagonism. Although drugs with H1 antagonist effects have long been available, this review was prompted by new studies of a selective H1 antagonist, which provide the first indication of the effects that are specifically associated with H1 antagonism. The findings do not conform to our long-standing model of insomnia agents in that factors other than drug blood level are needed to explain the clinical effects. We suggest a model for understanding these unique effects based on a review of the basic neurobiology of the histamine system. In addition to drug blood level, clinical effects reflect circadian variation in activity in the histamine system and other parallel wake promoting systems as well as factors such as pain and stress. We hypothesize that significant sleep enhancing effects are likely when the histamine system is relatively active and the activity in other parallel wake promoting systems is relatively minimal. Although the focus of this review is on the novel properties of H1 antagonism, the principles that emerge from this analysis are most likely relevant to all agents that selectively block wake promoting systems, and as such, this review provides a new paradigm for understanding the effects of insomnia medications. PMID- 23357029 TI - Synthesis of novel inhibitors blocking Wnt signaling downstream of beta-catenin. AB - Large scale screening of libraries consisting of natural and small molecules led to the identification of many small molecule inhibitors repressing Wnt/beta Catenin signaling. However, targeted synthesis of novel Wnt pathway inhibitors has been rarely described. We developed a modular and expedient way to create the aromatic ring system with an aliphatic ring in between. Our synthesis opens up the possibility, in principle, to substitute all positions at the ring system with any desired substituent. Here, we tested five different haloquinone analogs carrying methoxy- and hydroxy-groups at different positions. Bona fide Wnt activity assays in cell culture and in Xenopus embryos revealed that two of these compounds act as potent inhibitors of aberrant activated Wnt/beta-Catenin signaling. PMID- 23357030 TI - Developmental differences in auditory detection and localization of approaching vehicles. AB - Pedestrian safety is a significant problem in the United States, with thousands being injured each year. Multiple risk factors exist, but one poorly understood factor is pedestrians' ability to attend to vehicles using auditory cues. Auditory information in the pedestrian setting is increasing in importance with the growing number of quieter hybrid and all-electric vehicles on America's roadways that do not emit sound cues pedestrians expect from an approaching vehicle. Our study explored developmental differences in pedestrians' detection and localization of approaching vehicles. Fifty children ages 6-9 years, and 35 adults participated. Participants' performance varied significantly by age, and with increasing speed and direction of the vehicle's approach. Results underscore the importance of understanding children's and adults' use of auditory cues for pedestrian safety and highlight the need for further research. PMID- 23357031 TI - Comparison of driving simulator performance with real driving after alcohol intake: a randomised, single blind, placebo-controlled, cross-over trial. AB - The purpose of this study was to establish and validate a driving simulator method for assessing drug effects on driving. To achieve this, we used ethanol as a positive control, and examined whether ethanol affects driving performance in the simulator, and whether these effects are consistent with performance during real driving on a test track, also under the influence of ethanol. Twenty healthy male volunteers underwent a total of six driving trials of 1h duration; three in an instrumented vehicle on a closed-circuit test track that closely resembled rural Norwegian road conditions, and three in the simulator with a driving scenario modelled after the test track. Test subjects were either sober or titrated to blood alcohol concentration (BAC) levels of 0.5g/L and 0.9g/L. The study was conducted in a randomised, cross-over, single-blind fashion, using placebo drinks and placebo pills as confounders. The primary outcome measure was standard deviation of lateral position (SDLP; "weaving"). Eighteen test subjects completed all six driving trials, and complete data were acquired from 18 subjects in the simulator and 10 subjects on the test track, respectively. There was a positive dose-response relationship between higher ethanol concentrations and increases in SDLP in both the simulator and on the test track (p<0.001 for both). In the simulator, this dose-response was evident already after 15min of driving. SDLP values were higher and showed a larger inter-individual variability in the simulator than on the test track. Most subjects displayed a similar relationship between BAC and SDLP in the simulator and on the test track; however, a few subjects showed striking dissimilarities, with very high SDLP values in the simulator. This may reflect the lack of perceived danger in the simulator, causing reckless driving in a few test subjects. Overall, the results suggest that SDLP in the driving simulator is a sensitive measure of ethanol impaired driving. The comparison with real driving implies relative external validity of the simulator. PMID- 23357032 TI - The distribution of sleepiness, sleep and work hours during a long distance morning trip: a comparison between night- and non-night workers. AB - Few studies have examined the extent of driver sleepiness during a long distance morning trip. Sleepiness at this time may be high because of night work, waking early to commence work or travel, sleep disorders and the monotony of driving long distances. The objective of this study was to estimate the prevalence of chronic sleepiness (Epworth sleepiness score >=10) and sleep restriction (<=5h) in a sample of 649 drivers. Participants driving between 08:00 and 10:00 on three highways in regional Australia participated in a telephone interview. Approximately 18% of drivers reported chronic sleepiness. The proportions of night workers (NW) and non-night workers (NNW) with chronic sleepiness were not significantly different but males reported a significantly greater proportion of chronic sleepiness than females. The NW group had a significantly greater proportion of drivers with <=5h of sleep in the previous 24 and 48h, fewer nights of full sleep (<=4), acute sleepiness and longer weekly work hours. The NW group reported driving a significantly longer distance at Time 1 (Mean=140.29+/ 72.17km, versus 117.55+/-89.74km) and an additional longer distance to complete the journey (Mean=89.33+/-95.23km, versus 64.77+/-94.07km). The high proportions of sleep restriction and acute sleepiness among the NW group, and the amount of chronic sleepiness in the NW and NNW groups reported during a long distance morning trip may be of concern for driver safety. PMID- 23357033 TI - The effect of road and environmental characteristics on pedestrian hit-and-run accidents in Ghana. AB - The number of pedestrians who have died as a result of being hit by vehicles has increased in recent years, in addition to vehicle passenger deaths. Many pedestrians who were involved in road traffic accident died as a result of the driver leaving the pedestrian who was struck unattended at the scene of the accident. This paper seeks to determine the effect of road and environmental characteristics on pedestrian hit-and-run accidents in Ghana. Using pedestrian accident data extracted from the National Road Traffic Accident Database at the Building and Road Research Institute (BRRI) of the Council for Scientific and Industrial Research (CSIR), Ghana, a binary logit model was employed in the analysis. The results from the estimated model indicate that fatal accidents, unclear weather, nighttime conditions, and straight and flat road sections without medians and junctions significantly increase the likelihood that the vehicle driver will leave the scene after hitting a pedestrian. Thus, integrating median separation and speed humps into road design and construction and installing street lights will help to curb the problem of pedestrian hit-and-run accidents in Ghana. PMID- 23357034 TI - Elevated occupational transportation fatalities among older workers in Oregon: an empirical investigation. AB - Older workers have an elevated risk of being killed on the job, and transportation incidents involving vehicles or mobile machinery are especially deadly for this group. The present study was designed to address the research gap in understanding contributing factors to these incidents and recommend evidence based guidelines for interventions. We gathered and analyzed data from several sources, including the Oregon Fatality Assessment and Control Evaluation program, the Oregon Workers' Compensation system, the Census of Fatal Occupational Injuries, the Bureau of Labor Statistics, and peer reviewed research literatures. Rates and rate ratios (RR) were used to evaluate excess risk among groups. The results of this study show that older workers in Oregon have an elevated risk of fatality both in all events (RR=3.0, 95% CI 2.2-4.0) and transportation events (RR=3.6, 95% CI 2.4-5.4). Additional analyses and extant literature supports our hypotheses that multiple risk factors contribute to the phenomenon, including (a) hazard exposure, (b) organization of work, (c) physical fragility, and (d) normative cognitive, sensory, and psychomotor changes that occur with age. The evidence-based framework proposed may provide valuable guidance for developing safety interventions that protect older workers. PMID- 23357035 TI - Synthesis and biological evaluation of novel 2,4-disubstituted quinazoline analogues as GPR119 agonists. AB - GPR119 agonist has emerged as a promising target for the treatment of type 2 diabetes. A series of novel 2,4-disubstituted quinazoline analogues was prepared and evaluated their agonistic activity against human GPR119. The analogues bearing azabicyclic amine substituents (12a, 12c and 12g) exhibited better EC(50) values than that of OEA though they appeared to be partial agonists. PMID- 23357036 TI - Evolvosides C-E, flavonol-4'-O-triglycosides from evolvulus alsinoides and their anti-stress activity [corrected]. AB - Phytochemical investigation of the n-butanol fraction of Evolvulus alsinoides (Linn.) led to the isolation of three new phenolic glycosides, evolvosides C, D and E (1-3) along with six known compounds (4-9). The structures of the compounds were elucidated on the basis of spectroscopic analysis, viz. 1D and 2D NMR experiments, chemical study, and comparison with literature data. Evolvoside C (1) was characterized as kaempferol 4'-O-beta-D-glucopyranosyl-(1->2)-alpha-L rhamnopyranosyl-(1->6)-beta-D-glucopyranoside, whereas evolvosides D and E (2-3) were found to be mono and di-O-methyl derivatives of 1. The new compounds (1-3) represent rare triglycoside derivatives of flavonol at C-4'. The isolated compounds (1-6) were screened for acute stress-induced biochemical changes in male Sprague-Dawley rats at a dose of 40 mg/kg body weight. Compounds 1 and 2 displayed anti-stress effects by normalizing hyperglycemia, plasma corticosterone, plasma creatine kinase, and adrenal hypertrophy. Compounds 3 and 6 were also found to be effective in normalizing most of these stress parameters, whereas compounds 4 and 5 were ineffective in normalizing most of these effects. PMID- 23357037 TI - Synthesis and evaluation as potential anticancer agents of novel tetracyclic indenoquinoline derivatives. AB - We report the synthesis and evaluation as potential anticancer agents of a series of tetracyclic indenoquinolines. The compounds, which are obtained through the photoisomerization of Diels-Alder adducts formed between purpurogallin derivatives and nitrosobenzene, have in vitro antiproliferative activities in the MUM to nM range against breast (MCF-7), lung epithelial (A-549), and cervical (HeLa) adenocarcinoma cells. The cytotoxicities of several of the novel tetracycles are comparable to or better than that of camptothecin. A strong correlation between the activity of the compounds and their aromaticity and planarity was observed, suggesting a mode of action similar to that of topoisomerase poisons. PMID- 23357038 TI - N1,N3-disubstituted uracils as nonnucleoside inhibitors of HIV-1 reverse transcriptase. AB - A series of phenyloxyethyl and cinnamyl derivatives of substituted uracils were synthesized and found to exhibit potent activity against HIV-RT and HIV replication in cell culture. In general, the cinnamyl derivatives proved superior to the phenyloxyethyl derivatives, however 1-[2-(4-methylphenoxy)ethyl]-3-(3,5 dimethylbenzyl)uracil (19) exhibited the highest activity (EC(50)=0.27 MUM) thus confirming that the 3-benzyluracil fragment in the NNRTI structure can be regarded as a functional analogue of the benzophenone pharmacophore typically found in NNRTIs. PMID- 23357039 TI - Towards new boron carriers for boron neutron capture therapy: metallacarboranes bearing cobalt, iron and chromium and their cholesterol conjugates. AB - A method for the synthesis of cholesterol-metallacarborane conjugates bearing cobalt, iron and chromium was developed. Effective incorporation of the cholesterol conjugate bearing cobalt into liposome membrane was revealed. Using the metallacarborane-encrusted liposomes as boron delivery system in vivo biodistribution experiments in tumor-bearing mice, high accumulation and selective delivery of boron into tumor tissues was observed. The results demonstrate that the cholesterol-metallacarborane conjugates can be considered as a potential candidate for boron delivery vehicle in BNCT. PMID- 23357041 TI - DNA-maleimide: an improved maleimide compound for electrophoresis-based titration of reactive thiols in a specific protein. AB - BACKGROUND: Thiol-mediated redox regulation of proteins plays a key role in many cellular processes. METHODS: To understand the redox status of cysteinyl thiol groups of the desired proteins, we developed a new maleimide reagent: a maleimide conjugated single strand DNA, DNA-maleimide (DNA-Mal). RESULTS: DNA-Mal labelled proteins run as a distinct band on SDS-PAGE, with a discrete 9.32 kDa mobility shift per label regardless of the protein species or electrophoretic conditions. CONCLUSIONS: DNA-Mal labels free thiols like standard maleimide reagents, but possesses practical advantages in titration of the number and relative content of free thiols in a protein. GENERAL SIGNIFICANCE: The versatility of DNA molecule enhances the application of DNA-Mal in a broader range of cysteine containing proteins. PMID- 23357042 TI - Fracture-dislocations of the femoral head. AB - This review describes bone and nerve injury mechanisms during a femoral head fracture-dislocation and outlines a novel classification system that uses computed tomography scanning (CT scan) to help determine how to best treat these fractures in an emergency setting or in chronic cases. A series of 55 cases with CT scan performed in the emergency department (ED) and an average follow-up of 9 years (range 3-13) was used as a basis to develop the classification system; this system takes into account the size of the fragments and any associated acetabular wall or femoral neck fractures. The suggested course of action is based on the CT scan results after the hip joint is reduced. Conservative treatment is indicated every time the head fragments and any potential acetabular wall fragments are properly reduced and there are no foreign bodies (37.7%). Osteochondral head fragments below the fovea must be removed (36.3%). Fragments that are one-third or one-quarter of the head size can either be removed (7.2%) or reduced and fixed (5.4%). A novel medial approach is described that provides minimally invasive access to the anterior-inferior part of the femoral head, which should extend the indications for preservation of one-third head fragments. If the femoral neck is also fractured or a one-half head fragment exists in elderly patients, a total hip replacement should be considered right way (9%). At the latest follow-up, osteoarthritis was present in 43.7% of cases, but was mostly well tolerated - 94% of patients had a WOMAC score between 80 and 100 with signs of osteoarthritis visible on radiographs. Paradoxically, avascular necrosis (9%) is due to small head fractures. The results of our series are compared with the few series that have been published since CT scanning has been systematically used in the ED. PMID- 23357040 TI - Edible blue-green algae reduce the production of pro-inflammatory cytokines by inhibiting NF-kappaB pathway in macrophages and splenocytes. AB - BACKGROUND: Chronic inflammation contributes to the development of pathological disorders including insulin resistance and atherosclerosis. Identification of anti-inflammatory natural products can prevent the inflammatory diseases. METHODS: Anti-inflammatory effects of blue-green algae (BGA), i.e., Nostoc commune var. sphaeroides Kutzing (NO) and Spirulina platensis (SP), were compared in RAW 264.7 and mouse bone marrow-derived macrophages (BMM) as well as splenocytes from apolipoprotein E knockout (apoE(-/-)) mice fed BGA. RESULTS: When macrophages pretreated with 100MUg/ml NO lipid extract (NOE) or SP lipid extract (SPE) were activated by lipopolysaccharide (LPS), expression and secretion of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNFalpha), interleukin 1beta (IL-1beta), and IL-6, were significantly repressed. NOE and SPE also significantly repressed the expression of TNFalpha and IL-1beta in BMM. LPS-induced secretion of IL-6 was lower in splenocytes from apoE(-/-) fed an atherogenic diet containing 5% NO or SP for 12weeks. In RAW 264.7 macrophages, NOE and SPE markedly decreased nuclear translocation of NF-kappaB. The degree of repression of pro-inflammatory gene expression by algal extracts was much stronger than that of SN50, an inhibitor of NF-kappaB nuclear translocation. Trichostatin A, a pan histone deacetylase inhibitor, increased basal expression of IL-1beta and attenuated the repression of the gene expression by SPE. SPE significantly down-regulated mRNA abundance of 11 HDAC isoforms, consequently increasing acetylated histone 3 levels. CONCLUSION: NOE and SPE repress pro inflammatory cytokine expression and secretion in macrophages and splenocytes via inhibition of NF-kappaB pathway. Histone acetylation state is likely involved in the inhibition. GENERAL SIGNIFICANCE: This study underscores natural products can exert anti-inflammatory effects by epigenetic modifications such as histone acetylation. PMID- 23357044 TI - Determination of hemocoagulase agkistrodon in a pharmaceutical preparation by high-performance liquid chromatography with pre-column derivatization and fluorescence detection. AB - Currently, there is no analytical method for the quantification of hemocoagulase agkistrodon (HCA) in pharmaceutical preparations. This study presents a pre column derivatization method for the quantification of HCA, a compound extracted from the venom of Agkistrodon acutus, in a pharmaceutical preparation (trade name Suling). In the proposed method, 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate was used to tag the HCA substrate, and the derivatives were analyzed by high performance liquid chromatography with fluorescence detection. Complete and homogeneous derivatization of HCA was confirmed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry analysis. The specificity of the method was validated by forced degradation, and interference was assessed using a placebo. Under the optimum chromatographic conditions, the calibration curve was linear over a range of 10 to 500 ng/mL, featuring a correlation coefficient of 0.9999. The limits of detection and quantification of the method were 0.57 and 1.6 ng/mL, respectively. The percentage recovery of HCA in quality control samples ranged from 97.49 to 99.15%. Overall, this novel method can be applied to the quantitative determination of HCA in pharmaceutical preparations. PMID- 23357043 TI - Gas chromatographic method for the determination of residual monomers, 2 (acryloyloxy)ethyl isocyanate and 2-(methacryloyloxy)ethyl isocyanate, as curing agents in an ultraviolet curable adhesive. AB - A gas chromatographic method is described for the determination of residual 2 (acryloyloxy)ethyl isocyanate (AOI) and 2-(methacryloyloxy)ethyl isocyanate (MOI) as curing agents in an ultraviolet curable adhesive. Pre-column derivatization was employed in the determination of AOI and MOI as a means of enhancing the response of the flame ionization detector. Urethane derivatives of AOI and MOI were derived using methanol for 30 min at room temperature. The accuracies (n = 5, three concentration levels) were in the range of 113.4 to 126.7%, and precisions (n = 5, three concentration levels) were in the range of 0.8 to 4.3% for AOI-OMe. Furthermore, the accuracies were in the range of 79.5 to 108.6% and the precisions were in the range of 1.0 to 2.4% for MOI-OMe. The correlation coefficients of six calibration standards were all greater than 0.9999 for AOI OMe and greater than 0.9998 for MOI-OMe over the range from 10 to 100 ug/mL. PMID- 23357045 TI - New approaches to the kinetic study of alcoholic fermentation by chromatographic techniques. AB - The kinetics of the fermentation process has gained increasing interest, not only in the scientific community, but in the industrial world as well. Information concerning the improvement of batch fermentation performance may potentially be valuable for the designing of scale-up processes. Intensive studies have been conducted with the use of various chromatographic techniques, such as conventional gas chromatography, reversed-flow gas chromatography (RFGC), high performance liquid chromatography, field-flow fractionation and others. In the present study, specific focus is placed on the employment of RFGC, a method that can successfully be applied for the determination of physicochemical quantities, such as reaction rate constants and activation energies, at each phase of the alcoholic fermentation. In contrast to conventional chromatographic techniques, RFGC can lead to substantial information referring to the evaluation of fermentation kinetics at any time of the process. Moreover, gravitational field flow fractionation, a sub-technique of field-flow fractionation, presents the ability to monitor the proliferation of Saccharomyces cerevisiae cells through their elution profiles that can be related to the different cell growth stages. The combination of the two techniques can provide important information for kinetic study and the distinction of the growth phases of yeast cell proliferation during alcoholic fermentations conducted under different environmental conditions. PMID- 23357046 TI - Simultaneous determination of oridonin, ponicidin and rosmarinic acid from Herba Isodi Rubescentis extract by LC-MS-MS in rat plasma. AB - An analytical method was developed for the simultaneous quantification of oridonin, ponicidin and rosmarinic acid in rat plasma using liquid chromatography tandem mass spectrometry with electrospray ionization in positive and negative ion modes of operation. Multiple reaction monitoring was used for quantification using the precursor to product ion pairs of m/z 359.100 -> 160.9 (rosmarinic acid), m/z 150.1 -> 106.9 (acetaminophen as internal standard 1), m/z 365.1 -> 347.3 (oridonin), m/z 363.3 -> 345.2 (ponicidin) and m/z 258.3 -> 201.0 (dextrorphan as internal standard 2). Optimum chromatographic separation was achieved with a BDS Hypersil C18 column (100 * 2.1 mm, 2.4 um) and a mobile phase consisting of acetonitrile-5mM ammonium acetate containing 0.1% acetic acid (25:75, v/v). The analytes were extracted from rat plasma using a single liquid liquid extraction technique and the calibration curve was linear within the concentration range of 2-1,000.0 ng/mL for three analytes. The extraction recovery was above 70%, the intra-day and inter-day precision of the quality control (QC) samples was less than 12.45% and the accuracy of the QC samples was 96.99-105.79% of the nominal values. The method was sensitive and reliable and was successfully applied to a pharmacokinetic and bioavailability study of Herba Isodi Rubescentis extract in rats. PMID- 23357047 TI - Myocardial 'no-reflow'--diagnosis, pathophysiology and treatment. AB - In acute ST-segment elevation myocardial infarction (STEMI), improvement in reperfusion strategies has contributed to improvement in mortality. Nonetheless up to 40-50% of patients who achieve satisfactory epicardial patency do not necessarily achieve patency at the coronary microvascular level, a condition referred to as the 'no-reflow' phenomenon. The 'no-reflow' phenomenon is associated with a worse prognosis at follow up. The pathogenic mechanisms underlying the 'no-reflow' phenomenon is complex and dynamic. This includes a variable combination of mechanisms including distal atherothrombotic embolisation, ischaemic injury, reperfusion injury and heightened susceptibility of coronary microcirculation to injury. Accurate detection of 'no-reflow' is crucial because it is independently associated with adverse ventricular remodelling and patient prognosis. The diagnosis of 'no-reflow' can be made using angiography, electrocardiography, nuclear scintigraphy, myocardial contrast echocardiography or cardiovascular magnetic resonance (CMR). Despite our improved understanding on the pathogenesis and diagnosis of 'no-reflow', the treatment of 'no-reflow' remains the 'Achilles heel' in the treatment of patients with acute myocardial infarction. Several therapeutic strategies have been tested for the prevention and treatment of 'no-reflow', however none have been associated with improvement in clinical outcomes. Therefore there exists a need for 'in-lab' tools that will be able to aid early identification of patients at increased risk of 'no-reflow'. This may enable patients at heightened risk of 'no-reflow' to be treated with the most appropriate individualised treatment early. We review the pathogenic mechanisms and diagnostic techniques of the 'no-reflow' phenomenon as well as the prevention and treatment strategies of the candidate mechanisms. PMID- 23357048 TI - Novel rat model reveals important roles of beta-adrenoreceptors in stress-induced cardiomyopathy. AB - BACKGROUND: Stress-induced cardiomyopathy (SIC), also known as Takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular akinesia involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC but the pathophysiological pathways and receptors involved are unknown. METHODS: Sprague Dawley rats (~300 g) were injected with a single dose of the beta-adrenergic agonist isoprenaline (ISO, i.p.) and echocardiography was used to study cardiac function. The akinetic part of the left ventricle was biopsied in six SIC patients. Amount of intracellular lipid and glycogen as well as degree of permanent cardiac damage were assessed by histology. RESULTS: In rats, ISO at doses >= 50 mg/kg induced severe SIC-like regional akinesia that completely resolved within seven days. Intracellular lipid content was higher in akinetic, but not in normokinetic myocardium in both SIC patients and rats. beta2-receptor blockade or Gi-pathway inhibition was associated with less widespread akinesia and low lipid accumulation but significantly increased acute mortality. CONCLUSIONS: We provide a novel rat model of SIC that supports the hypothesis of circulating catecholamines as initiators of SIC. We propose that the beta adrenoreceptor pathway is important in the setting of severe catecholamine overstimulation and that perturbations of cardiac metabolism occur in SIC. PMID- 23357049 TI - Bacterial pathogens and flora isolated from farm-cultured eels (Anguilla japonica) and their environmental waters in Korean eel farms. AB - The purpose of this study was to investigate bacterial pathogens and flora in both sick and clinically healthy eels, Anguilla japonica, and the environmental rearing waters of Korean eel farms. Between 2003 and 2010, a total of 621 sick eels were submitted for diagnosis, while 216 healthy eels and 87 environmental water samples were collected during a survey of 26 eel farms in Korea. Seven different bacterial species were obtained from 183 isolates, which were recovered from the internal organs of the 621 sick eels. The most frequently isolated bacterium was Edwardsiella tarda (71.0%), followed by Aeromonas hydrophila (9.3%), Citrobacter freundii (7.7%), Aeromonas veronii (6.0%), Listonella anguillarum (2.7%), Plesiomonas shigelloides (2.2%), and Pseudomonas anguilliseptica (1.1%). From the eel and water samples of the survey, a total of 472 isolates from 34 different species belonging to 15 genera of bacteria were isolated. The most prevalent genus of bacteria was Aeromonas spp. (141/472, 29.8%). Among the 34 types of bacterial species, C. freundii (20.1%) and A. hydrophila (19.9%) were the most frequently isolated. The results of this study indicate that a wide range of bacterial species, which can act as primary or opportunistic pathogens, may be recovered from clinically healthy eels and rearing waters. This study provides baseline information about bacterial pathogens and floral contamination for the control and treatment of bacteria in Korean eel farms. PMID- 23357050 TI - Autoantibodies to 60kDa SS-A/Ro yield a specific nuclear myriad discrete fine speckled immunofluorescence pattern. AB - OBJECTIVES: To report on a novel immunofluorescence pattern specifically associated with antibodies to SS-A/Ro. METHODS: A novel immunofluorescence pattern, herein designated SS-A/Ro pattern, was characterized as myriad discrete fine speckles throughout the nucleus. Eighty-six sequential samples presenting the SS-A/Ro pattern and 64 samples presenting non-SS-A/Ro nuclear fine speckled pattern at the ANA-HEp-2 routine were screened for SS-A/Ro reactivity. Conversely, 48 samples with known reactivity to 60kDa SS-A/Ro, 13 samples with exclusive reactivity to 52kDa SS-A/Ro, and 48 SS-A/Ro-negative samples were analyzed for the ANA-HEp-2 pattern. RESULTS: Eighty-five of the 86 samples (98.8%) presenting the SS-A/Ro pattern and 15 of the 64 (23.4%) samples with non SS-A/Ro fine speckled pattern reacted with 60kDa SS-A/Ro. Conversely, 44 (91.6%) of 48 samples with known reactivity to 60kDa SS-A/Ro presented the SS-A/Ro pattern and four (8.4%) presented non-SS-A/Ro fine speckled pattern. None of the 48 anti-SS-A/Ro-negative samples and none of anti-52kDa SS-A/Ro-positive samples yielded the SS-A/Ro pattern. This immunofluorescence pattern was observed in different commercial HEp-2 cell slides and in homemade HEp-2 cell slides. CONCLUSIONS: The SS-A/Ro pattern belongs to the group of immunofluorescence patterns that hold strong association with the respective autoantibody specificities, such as those associated with CENP-F and NuMA-1. The identification of the SS-A/Ro pattern at the ANA-HEp-2 screening routine shall lead to specific tests for the identification of anti-SS-A/Ro antibodies. PMID- 23357052 TI - Early life exposures to home dampness, pet ownership and farm animal contact and neuropsychological development in 4 year old children: a prospective birth cohort study. AB - Exposure to biocontaminants is associated with behavioural problems and poorer cognitive function. Our study assesses the associations between early life exposure to home dampness, pets and farm animal contact and cognitive function and social competences in 4-year old children, and the associations between these indoor factors and microbial compounds (bacterial endotoxin and fungal extracellular polysaccharides). A Spanish population-based birth-cohort enrolled 482 children, and 424 of them underwent psychometric testing at 4 years of age, including the McCarthy Scales of Child Abilities (MSCA) and the California Preschool Social Competence Scale (CPSCS). Information on pet ownership, farm animal contact and home dampness was periodically reported by the parents through questionnaires. Microbial compounds were measured in living room sofa dust collected at the age of 3 months. Persistent home dampness during early life significantly decreased the general score of MSCA by 4.9 points (95% CI: -8.9; 0.8), and it decreased the CPSCS by 6.5 points (95% CI: -12.2; -0.9) in the child's bedroom. Cat or dog ownership were not associated with the outcomes, but occasional farm animal contact increased the general cognitive score of MSCA by 5.6 points (95% CI: 1.8; 9.3). Cat and dog ownership were associated with higher levels of endotoxins in home dust. None of the measured microbial compounds were related with the psychometric tests scores. In conclusion, damp housing in early life may have adverse effects on neuropsychological development at 4 years old. More research is needed to explore the possible involvement of mycotoxins in the observed results. PMID- 23357051 TI - A novel KIT-deficient mouse mast cell model for the examination of human KIT mediated activation responses. AB - Activation of KIT, by its ligand, stem cell factor (SCF), results in the initiation of signal transduction pathways that influence mast cell survival and proliferation. Activating mutations in KIT have thus been linked to clonal MC proliferation associated with systemic mastocytosis. SCF also modulates MC function by inducing MC chemotaxis and by potentiating antigen (Ag)/IgE-mediated MC degranulation. Thus, mutations in KIT also have the potential to affect these processes in allergic and other mast cell-related diseases. Studies to determine how native and mutated KIT may modulate MC chemotaxis and activation have, however, been limited due to the lack of availability of a suitable functional MC line lacking native KIT which would allow transduction of KIT constructs. Here we describe a novel mouse MC line which allows the study of normal and mutated KIT constructs. These cells originated from a bone marrow-derived mouse MC culture out of which a rapidly dividing mast cell sub-population spontaneously arose. Over time, these cells lost KIT expression while continuing to express functional high affinity receptors for IgE (FcepsilonRI). As a consequence, these cells degranulated in response to Ag/IgE but did not migrate nor show any evidence of potentiation of Ag/IgE degranulation in response to SCF. Retroviral transduction of the cells with a human (hu)KIT construct resulted in surface expression of huKIT which responded to huSCF by potentiation of Ag/IgE-induced degranulation and chemotaxis. This cell line thus presents a novel system to delineate how MC function is modulated by native and mutated KIT and for the identification of novel inhibitors of these processes. PMID- 23357053 TI - Assessment of general pre and postoperative anxiety in patients undergoing tooth extraction: a prospective study. AB - Our aim was to analyse the amount of anxiety and fear felt before, immediately after, and one week after, dental extraction. We studied 70 patients (35 men and 35 women (mean (SD) age 43 (+/-10) years), who were listed for dental extraction under local anaesthesia in a private clinic that specialised in oral surgery. Patients were evaluated on 3 consecutive occasions: immediately preoperatively, immediately postoperatively, and 7 days later. Each patient's anxiety was measured using Spielberger's State-Trait Anxiety Inventory (Spanish version), the Modified Corah Dental Anxiety Scale (MDAS) and the Dental Fear Survey. There were significant differences in the STAI-Trait scale between before and 7 days after extraction (p=0.04), and in the MDAS between before and immediately after extraction (p=0.02), and between immediately after and 7 days after extraction (p=<0.001). The DFS also differed between before and immediately after extraction (p=0.002), and between immediately and 7 days after extraction (p<0.001). Dental anxiety immediately after tooth extraction may be influenced by operative techniques (type of anaesthesia, duration of operation, or position of tooth extracted), but anxiety at 7 days after extraction is not. PMID- 23357054 TI - Two initiation sites of early detection of colon cancer revealed by localization of pERK1/2 in the nuclei or in aggregates at the perinuclear region of the tumor cells. AB - We have used human specimens and antibodies to pERK1/2 to detect early development of colon cancer using indirect immunocytochemistry. Two distinct sites were stained; one at the tip of the colon crypts and the other in the stromal tissue associated with the colonic tissue. These foci represent early stages of colon cancer initiation sites as established by enhanced Kirsten Rat Sarcoma Virus (KRAS) and the lack of p53 staining. The enhanced KRAS coincides with the initiation of tumor growth revealed by pERK1/2, both in the tip of the colon crypts, as well as in the stromal initiation site of the colon tumors. Foci of pERK1/2 staining were also detected in 50% of stromal tissue and tips of colon crypts, which were classified as normal tissues, adjacent to the malignant tissue according to general morphology. However, in colon specimens, where no malignancy was observed, no accumulation of pERK1/2 was observed. The staining of pERK1/2 at the stromal foci of the apparently non-malignant tissue appeared as aggregates in the perinuclear region, while in the colon epithelium it appeared in the cell nuclei. In low-grade colon cancer that was still free of induced mutated p53, staining of pERK1/2 was prominent in the cell nuclei, both in the stroma tissue and the tip of the colon crypts. In the intermediate stage, that exhibited significant p53 staining, only a fraction of p53-free tumor cells was labeled with pERK1/2 antibody, while in high-grade tumors, all cells of tumors were labeled with antibodies to p53, but not with antibodies to pERK1/2. We suggest that the down regulation in pERK1/2 labeling is due to the mitogenic capacity of the tumor cells, which are shifted from being driven by nuclear pERK1/2 to mutated p53 expression. We also found that the cytoplasm of low grade tumors was positive for epiregulin, while this labeling decreased in high-grade tumors. We found that the tumors arising from the stroma demonstrated poor structural differentiation, while the tumors initiating from the epithelial cells of the colon demonstrated high structural differentiation. We conclude that pERK1/2 is a sensitive marker of early colon cancer, which disappears at later stages of cancer development. Moreover, pERK1/2 staining can distinguish between tumor cells originating from the tip of the colon crypts and those developing in the stroma, which is present in the close vicinity to colon epithelial tissue, and thus can assist in selecting the appropriate therapy. PMID- 23357055 TI - First-line eradication therapy for Helicobacter pylori: time for a change? PMID- 23357056 TI - Is there a single therapeutic target for chronic pancreatitis pain? PMID- 23357057 TI - Pseudomelanic polyposis of the colon. PMID- 23357058 TI - Changes in antioxidant levels. PMID- 23357059 TI - Recent-onset dysphagia in a young man. PMID- 23357060 TI - Limitations of patient selection and other issues in chronic pancreatitis antioxidant trial. PMID- 23357061 TI - Reply: budesonide. PMID- 23357062 TI - An unusual cause of recurrent intestinal obstruction. PMID- 23357063 TI - Reply: ANTICIPATE study. PMID- 23357064 TI - Reply: risk of colorectal cancer. PMID- 23357065 TI - Regarding: a tale of two cohorts. PMID- 23357066 TI - Subtypes of genotype 3 hepatitis E virus in pigs. AB - The prevalence of hepatitis E virus (HEV) RNA in faecal and bile samples from pigs in abattoirs in Eastern and South Western China from 2006 to 2011 was determined by reverse transcriptase PCR. HEV-3 was detected in 4/5952 (0.07%) pigs and HEV-4 was detected in 287/5952 (4.8%) pigs. Two HEV-3 subtype 3a strains from South Western China had 87.1-89.7% sequence identity. Two HEV-3 subtype 3b strains from Eastern China had 91.8-93.8% sequence identity and were similar to strains reported previously in Eastern and Central China. The distinct subtypes of HEV-3 in different regions of China suggested multiple origins of HEV infection. PMID- 23357067 TI - Cholesterol accumulation in prostate cancer: a classic observation from a modern perspective. AB - Prostate cancer (PCa) is the most common cancer in men in developed countries. Epidemiological studies have associated high blood-cholesterol levels with an increased risk of PCa, whilst cholesterol-lowering drugs (statins) reduce the risk of advanced PCa. Furthermore, normal prostate epithelial cells have an abnormally high cholesterol content, with cholesterol levels increasing further during progression to PCa. In this review, we explore why and how this occurs. Concurrent to this observation, intense efforts have been expended in cardiovascular research to better understand the regulators of cholesterol homeostasis. Here, we apply this knowledge to elucidate the molecular mechanisms driving the accumulation of cholesterol in PCa. For instance, recent evidence from our group and others shows that major signalling players in prostate growth and differentiation, such as androgens and Akt, modulate the key transcriptional regulators of cholesterol homeostasis to enhance cholesterol levels. This includes adjusting central carbon metabolism to sustain greater lipid synthesis. Perturbations in cholesterol homeostasis appear to be maintained even when PCa approaches the advanced, 'castration-resistant' state. Overall, this provides a link between cholesterol accumulation and PCa cell growth. Given there is currently no cure for castration-resistant PCa, could cholesterol metabolism be a novel target for PCa therapy? Overall, this review presents a picture that cholesterol metabolism is important for PCa development: growth-promoting factors stimulate cholesterol accumulation, which in turn presents a possible target for chemotherapy. Consequently, we recommend future investigations, both to better elucidate the mechanisms driving this accumulation and applying it in novel chemotherapeutic strategies. PMID- 23357068 TI - Prevalence of and examination of exposure factors for Salmonella on commercial egg-laying farms in Barbados. AB - During January-March 2009, an outbreak of Salmonella was diagnosed in four commercial egg-laying farms in Barbados. During the outbreak, 511 layers died while 3257 layers were voluntarily culled from one affected farm. Salmonella ser Enteritidis was identified in avian tissues (ovaries, liver, and uterus), and egg samples submitted to the Ministry of Agriculture, Food, Fisheries, and Water Resource Management (MAFFW) Veterinary Services (VS) Laboratory by managers of the affected farms. As a result of this outbreak, MAFFW VS conducted a survey to investigate the prevalence of Salmonella on commercial egg-laying farms in Barbados. In addition, the relationships between farm-level exposure factors and diagnosis of Salmonella were examined. This paper describes the results of this survey. Nineteen of 26 farms (73%; 95% CI=56-90%) were classified as positive for Salmonella. The odds of testing positive for Salmonella were 10 times higher in large farms, compared to small farms (OR=10.80; 95% CI=1.01, 115.10; p=0.04). More small farms (8/11) cleaned and disinfected poultry facilities quarterly or more often than large farms did (1/10) (p<0.01). Prevalence of Salmonella in commercial egg-laying farms in Barbados is high. Salmonella ser Enteritidis was the most common serotype identified in study farms, and this is a public health issue of concern. This is the first prevalence survey of Salmonella in egg-laying farms in Barbados. Study results can be used as a baseline for future control programmes aimed at reducing the prevalence of Salmonella in egg-laying farms in the country. PMID- 23357069 TI - Location-independent and location-linked representations of sound objects. AB - For the recognition of sounds to benefit perception and action, their neural representations should also encode their current spatial position and their changes in position over time. The dual-stream model of auditory processing postulates separate (albeit interacting) processing streams for sound meaning and for sound location. Using a repetition priming paradigm in conjunction with distributed source modeling of auditory evoked potentials, we determined how individual sound objects are represented within these streams. Changes in perceived location were induced by interaural intensity differences, and sound location was either held constant or shifted across initial and repeated presentations (from one hemispace to the other in the main experiment or between locations within the right hemispace in a follow-up experiment). Location-linked representations were characterized by differences in priming effects between pairs presented to the same vs. different simulated lateralizations. These effects were significant at 20-39 ms post-stimulus onset within a cluster on the posterior part of the left superior and middle temporal gyri; and at 143-162 ms within a cluster on the left inferior and middle frontal gyri. Location independent representations were characterized by a difference between initial and repeated presentations, independently of whether or not their simulated lateralization was held constant across repetitions. This effect was significant at 42-63 ms within three clusters on the right temporo-frontal region; and at 165 215 ms in a large cluster on the left temporo-parietal convexity. Our results reveal two varieties of representations of sound objects within the ventral/What stream: one location-independent, as initially postulated in the dual-stream model, and the other location-linked. PMID- 23357070 TI - What can we learn from T2* maps of the cortex? AB - Studies have shown that T2* contrast can reveal features of cortical anatomy. However, understanding the relationship between T2* contrast and the underlying cyto- and myelo-architecture is not an easy task, given the number of confounds, such as myelin, iron, blood vessels and structure orientation. Moreover, it is difficult to obtain reliable T2* measurements in the cortex due to its thin and folded geometry and the presence of artifacts. This review addresses issues associated with T2* mapping in the human cortex. After describing the theory behind T2* relaxation, a list of practical steps is proposed to reliably acquire and process T2* data and then map these values within the cortex using surface based analysis. The last section addresses the question: "What can we gain from T2* cortical mapping?", with particular emphasis on Brodmann mapping. PMID- 23357071 TI - The human brain pacemaker: Synchronized infra-slow neurovascular coupling in patients undergoing non-pulsatile cardiopulmonary bypass. AB - In non-pulsatile cardiopulmonary bypass surgery, middle cerebral artery blood flow velocity (BFV) is characterized by infra-slow oscillations of approximately 0.06Hz, which are paralleled by changes in total EEG power variability (EEG-PV), measured in 2s intervals. Since the origin of these BFV oscillations is not known, we explored their possible causative relationships with oscillations in EEG-PV at around 0.06Hz. We monitored 28 patients undergoing non-pulsatile cardiopulmonary bypass using transcranial Doppler sonography and scalp electroencephalography at two levels of anesthesia, deep (prevalence of burst suppression rhythm) and moderate (prevalence of theta rhythm). Under deep anesthesia, the EEG bursts suppression pattern was highly correlative with BFV oscillations. Hence, a detailed quantitative picture of the coupling between electrical brain activity and BFV was derived, both in deep and moderate anesthesia, via linear and non linear processing of EEG-PV and BFV signals, resorting to widely used measures of signal coupling such as frequency of oscillations, coherence, Granger causality and cross-approximate entropy. Results strongly suggest the existence of coupling between EEG-PV and BFV. In moderate anesthesia EEG-PV mean dominant frequency is similar to frequency of BFV oscillations (0.065+/-0.010Hz vs 0.045+/-0.019Hz); coherence between the two signals was significant in about 55% of subjects, and the Granger causality suggested an EEG-PV->BFV causal effect direction. The strength of the coupling increased with deepening anesthesia, as EEG-PV oscillations mean dominant frequency virtually coincided with the BFV peak frequency (0.062+/-0.017Hz vs 0.060+/-0.024Hz), and coherence became significant in a larger number (65%) of subjects. Cross-approximate entropy decreased significantly from moderate to deep anesthesia, indicating a higher level of synchrony between the two signals. Presence of a subcortical brain pacemaker that drives vascular infra-slow oscillations in the brain is proposed. These findings allow to suggest an original hypothesis explaining the mechanism underlying infra-slow neurovascular coupling. PMID- 23357072 TI - Long-range neural synchronization supports fast and efficient reading: EEG correlates of processing expected words in sentences. AB - Word reading is heavily influenced by the information provided by previous context. In this study, we analyzed the neurophysiological bases of sentence reading through the EEG activity elicited during reading the same word embedded in differently constraining contexts: a) a low-constraining context; b) a high constraining semantic compositional context; c) a high-constraining collocational context in which the item was in final position of a multi-word fixed-order expression. Cloze-probability of the two high-constraining contexts was equated. Before reading the target word we observed increased EEG gamma phase synchronization for the high-constraining compositional context and increased EEG theta synchronization for the collocational context (both compared to the low constraining condition). After reading the target word we observed increased frontal positive EEG evoked activity (~220ms) for the high-constraining compositional context but an even earlier (~120ms) effect for the high constraining collocational condition that was distributed over the scalp. A positive correlation was found only between the increased theta synchronization and the early EEG effect for the high-constraining collocational condition. Results indicate that long-range frontal-occipital interactions in the theta band - indexing working memory operations - support early visual-orthographic analysis of an incoming stimulus (such as the expected word); gamma-phase synchronization better represents binding operations between feed-forward activation and matching feedback. These data suggest that internal linguistic knowledge stored in long term memory - if unambiguously pre-activated - supports the low-level perceptual processes involved in reading. PMID- 23357073 TI - Coherence between magnetoencephalography and hand-action-related acceleration, force, pressure, and electromyogram. AB - Hand velocity and acceleration are coherent with magnetoencephalographic (MEG) signals recorded from the contralateral primary sensorimotor (SM1) cortex. To learn more of this interaction, we compared the coupling of MEG signals with four hand-action-related peripheral signals: acceleration, pressure, force, and electromyogram (EMG). Fifteen subjects performed self-paced repetitive hand action tasks for 3.5min at a rate of about 3Hz. Either acceleration, pressure or force signal was acquired with MEG and EMG signals during (1) flexions-extensions of right-hand fingers, with thumb touching the other fingers (acceleration; free), (2) dynamic index-thumb pinches against an elastic rubber ball attached to a pressure sensor (pressure and acceleration; squeeze), and (3) brief fixed finger-position index-thumb pinches against a rigid load cell (force; fixed pinch). Significant coherence occurred between MEG and all the four peripheral measures at the fundamental frequency of the hand action (F0) and its first harmonic (F1). In all tasks, the cortical sources contributing to the cross correlograms were located at the contralateral hand SM1 cortex, with average inter-source distance (mean+/-SEM) of 9.5+/-0.3mm. The coherence was stronger with respect to pressure (0.40+/-0.03 in squeeze) and force (0.38+/-0.04 in fixed pinch) than acceleration (0.24+/-0.03 in free) and EMG (0.25+/-0.02 in free, and 0.29+/-0.04 in fixed-pinch). The results imply that the SM1 cortex is strongly coherent at F0 and F1 with hand-action-related pressure and force, in addition to the previously demonstrated EMG, velocity, and acceleration. All these measures, especially force and pressure, are potential tools for functional mapping of the SM1 cortex. PMID- 23357074 TI - A reference-channel based methodology to improve estimation of event-related hemodynamic response from fNIRS measurements. AB - Functional near-infrared spectroscopy (fNIRS) uses near-infrared light to measure cortical concentration changes in oxygenated (HbO) and deoxygenated hemoglobin (HbR) held to be correlated with cognitive activity. Providing a parametric depiction of such changes in the classic form of stimulus-evoked hemodynamic responses (HRs) can be attained with this technique only by solving two problems. One problem concerns the separation of informative optical signal from structurally analogous noise generated by a variety of spurious sources, such as heart beat, respiration, and vasomotor waves. Another problem pertains to the inherent variability of HRs, which is notoriously contingent on the type of experiment, brain region monitored, and human phenotype. A novel method was devised in the present context to solve both problems based on a two-step algorithm combining the treatment of noise-only data extrapolated from a reference-channel and a Bayesian filter applied on a per-trial basis. The present method was compared to two current methods based on conventional averaging, namely, a typical averaging method and an averaging method implementing the use of a reference-channel. The result of the comparison, carried out both on artificial and real data, revealed a sensitive accuracy improvement in HR estimation using the present method relative to each of the other methods. PMID- 23357075 TI - Multiscale adaptive generalized estimating equations for longitudinal neuroimaging data. AB - Many large-scale longitudinal imaging studies have been or are being widely conducted to better understand the progress of neuropsychiatric and neurodegenerative disorders and normal brain development. The goal of this article is to develop a multiscale adaptive generalized estimation equation (MAGEE) method for spatial and adaptive analysis of neuroimaging data from longitudinal studies. MAGEE is applicable to making statistical inference on regression coefficients in both balanced and unbalanced longitudinal designs and even in twin and familial studies, whereas standard software platforms have several major limitations in handling these complex studies. Specifically, conventional voxel-based analyses in these software platforms involve Gaussian smoothing imaging data and then independently fitting a statistical model at each voxel. However, the conventional smoothing methods suffer from the lack of spatial adaptivity to the shape and spatial extent of region of interest and the arbitrary choice of smoothing extent, while independently fitting statistical models across voxels does not account for the spatial properties of imaging observations and noise distribution. To address such drawbacks, we adapt a powerful propagation-separation (PS) procedure to sequentially incorporate the neighboring information of each voxel and develop a new novel strategy to solely update a set of parameters of interest, while fixing other nuisance parameters at their initial estimators. Simulation studies and real data analysis show that MAGEE significantly outperforms voxel-based analysis. PMID- 23357076 TI - Isolating age-group differences in working memory load-related neural activity: assessing the contribution of working memory capacity using a partial-trial fMRI method. AB - Previous studies examining age-group differences in working memory load-related neural activity have yielded mixed results. When present, age-group differences in working memory capacity are frequently proposed to underlie these neural effects. However, direct relationships between working memory capacity and working memory load-related activity have only been observed in younger adults. These relationships remain untested in healthy aging. Therefore, the present study examined patterns of working memory load-related activity in 22 younger and 20 older adults and assessed the contribution of working memory capacity to these load-related effects. Participants performed a partial-trial delayed response item recognition task during functional magnetic resonance imaging. In this task, participants encoded either 2 or 6 letters, maintained them during a delay, and then indicated whether a probe was present in the memory set. Behavioral results revealed faster and more accurate responses to load 2 versus 6, with age-group differences in this load condition effect for the accuracy measure. Neuroimaging results revealed one region (medial superior frontal gyrus) that showed age-group differences in load-related activity during the retrieval period, with less (greater) neural activity for the low versus high load condition in younger (older) adults. Furthermore, for older adults, load-related activity did not vary as a function of working memory capacity. Thus, working memory-related activity varies with healthy aging, but these patterns are not due solely to working memory capacity. Neurocognitive aging theories that feature capacity will need to account for these results. PMID- 23357078 TI - Neuroanatomic overlap between intelligence and cognitive factors: morphometry methods provide support for the key role of the frontal lobes. AB - Evidence from neuroimaging studies suggests that intelligence differences may be supported by a parieto-frontal network. Research shows that this network is also relevant for cognitive functions such as working memory and attention. However, previous studies have not explicitly analyzed the commonality of brain areas between a broad array of intelligence factors and cognitive functions tested in the same sample. Here fluid, crystallized, and spatial intelligence, along with working memory, executive updating, attention, and processing speed were each measured by three diverse tests or tasks. These twenty-one measures were completed by a group of one hundred and four healthy young adults. Three cortical measures (cortical gray matter volume, cortical surface area, and cortical thickness) were regressed against psychological latent scores obtained from a confirmatory factor analysis for removing test and task specific variance. For cortical gray matter volume and cortical surface area, the main overlapping clusters were observed in the middle frontal gyrus and involved fluid intelligence and working memory. Crystallized intelligence showed an overlapping cluster with fluid intelligence and working memory in the middle frontal gyrus. The inferior frontal gyrus showed overlap for crystallized intelligence, spatial intelligence, attention, and processing speed. The fusiform gyrus in temporal cortex showed overlap for spatial intelligence and attention. Parietal and occipital areas did not show any overlap across intelligence and cognitive factors. Taken together, these findings underscore that structural features of gray matter in the frontal lobes support those aspects of intelligence related to basic cognitive processes. PMID- 23357077 TI - Methylene blue potentiates stimulus-evoked fMRI responses and cerebral oxygen consumption during normoxia and hypoxia. AB - Methylene blue USP (MB) at low doses has metabolic-enhancing and antioxidant properties and exhibits experimental neurotherapeutic benefits, but little is known about its in vivo effects on cerebral blood flow (CBF), functional evoked responses, and the associated changes in cerebral metabolic rate of oxygen (CMRO2). This study used magnetic resonance imaging (MRI) to evaluate the in vivo effects of a single intravenous MB therapeutic dose (0.5mg/kg) on basal CBF, blood oxygenation level-dependent (BOLD) and CBF responses to hypercapnic (5% CO2 in air) inhalation, as well as changes in BOLD, CBF, and CMRO2 during forepaw stimulation in the rat brain. MB did not have significant effects on arterial oxygen saturation, heart rate and fMRI responses to hypercapnia. However, MB significantly potentiated forepaw-evoked BOLD and CBF changes under normoxia. To further evaluate in vivo effects of MB under metabolic stress conditions, MRI measurements were also made under mild hypoxia (15% O2). Hypoxia per se increased evoked functional MRI responses. MB under hypoxia further potentiated forepaw evoked BOLD, CBF and oxygen consumption responses relative to normoxia. These findings provide insights into MB's effects on cerebral hemodynamics in vivo and could help to optimize treatments in neurological diseases with mitochondrial dysfunction and oxidative stress. PMID- 23357079 TI - Differential activation of brain regions involved with error-feedback and imitation based motor simulation when observing self and an expert's actions in pilots and non-pilots on a complex glider landing task. AB - In this fMRI study we investigate neural processes related to the action observation network using a complex perceptual-motor task in pilots and non pilots. The task involved landing a glider (using aileron, elevator, rudder, and dive brake) as close to a target as possible, passively observing a replay of one's own previous trial, passively observing a replay of an expert's trial, and a baseline do nothing condition. The objective of this study is to investigate two types of motor simulation processes used during observation of action: imitation based motor simulation and error-feedback based motor simulation. It has been proposed that the computational neurocircuitry of the cortex is well suited for unsupervised imitation based learning, whereas, the cerebellum is well suited for error-feedback based learning. Consistent with predictions, pilots (to a greater extent than non-pilots) showed significant differential activity when observing an expert landing the glider in brain regions involved with imitation based motor simulation (including premotor cortex PMC, inferior frontal gyrus IFG, anterior insula, parietal cortex, superior temporal gyrus, and middle temporal MT area) than when observing one's own previous trial which showed significant differential activity in the cerebellum (only for pilots) thought to be concerned with error-feedback based motor simulation. While there was some differential brain activity for pilots in regions involved with both Execution and Observation of the flying task (potential Mirror System sites including IFG, PMC, superior parietal lobule) the majority was adjacent to these areas (Observation Only Sites) (predominantly in PMC, IFG, and inferior parietal loblule). These regions showing greater activity for observation than for action may be involved with processes related to motor-based representational transforms that are not necessary when actually carrying out the task. PMID- 23357080 TI - Haplotype analysis of eight genes of the monoubiquitinated FANCD2-DNA damage repair pathway in breast cancer patients. AB - BACKGROUND: Ten genes are associated with increased susceptibility to inherited breast cancer have also been associated with population breast cancer risk, and all are involved directly or indirectly in the monoubiquitinated FANCD2-DNA damage repair pathway. We analyzed 13 haplotype blocks in eight of these genes to estimate the breast cancer risk conferred by individual haplotypes. METHODS: Haplotype blocks were constructed with 48 tag single-nucleotide polymorphisms (tSNPs) identified in eight breast cancer susceptibility genes, TP53, PTEN, CHEK2, ATM, NBS1, RAD50, BRIP1, and PALB2. Genotyping was performed by SNPscan on 734 female patients and 672 female age-matched controls. RESULTS: Forty-five tSNPs were successfully genotyped by SNPscan, and call rates for each tSNP were above 98.9%. Thirteen haplotype blocks of eight genes were constructed with 41 successfully genotyped tSNPs. We found that seven haplotypes from four haplotype blocks located within three genes (NBS1, PTEN, and BRIP1) were significantly associated with breast cancer risk. Among these, four haplotypes (ATC in block 1 of NBS1, GCCCC and GCCCT in block 2 of NBS1, and GCT in block 2 of BRIP1) were correlated with breast cancer risk in sporadic cases (OR (95% CI) 1.350(1.124 1.623), 0.752(0.584-0.969), 0.803(0.649-0.993), and 0.776(0.604-0.997), respectively), and only one haplotype (GGCCT in block 2 of NBS1) was significantly associated with breast cancer risk in familial and early-onset cases (OR(95% CI) 1.902(1.134-3.191)). CONCLUSIONS: Four haplotypes within two genes (NBS1 and BRIP1) involved in the monoubiquitinated FANCD2-DNA damage-repair pathway are significantly associated with increased sporadic breast cancer risk, while one haplotype within NBS1 is correlated with an increased risk of familial or early-onset breast cancer, indicating that specific haplotypes may be distinct predictors of breast cancer. PMID- 23357081 TI - A historical perspective on the specific activity of radiopharmaceuticals: what have we learned in the 35years of the ISRC? AB - Specific Activity (SA), defined as the amount of radioactivity per unit mass of a compound is arguably one of the most important parameters in radiopharmaceutical development, particularly in quality control of carbon-11 and fluorine-18 labeled compounds. This review article will outline the progression of improvements in SA over the last few decades. The International Symposium of Radiopharmaceutical Chemistry (ISRC/ISRS) abstracts were an excellent source of materials for this review and will be referenced throughout. PMID- 23357082 TI - Synthesis and application of a novel cysteine-based DTPA-NCS for targeted radioimmunotherapy. AB - INTRODUCTION: For the development of safe and effective protein-based radiolabeled complexes such as radioimmunotherapy (RIT), the selection of the radionuclides and the chelating agents used for the radiolabeling of tumor targeting molecules is a critical factor. We aim to synthesize a novel bifunctional chelating agent containing the isothiocyanate group for easy conjugation with antibodies having the characteristics of high stable chelation with therapeutic radionuclides. METHODS: We have synthesized the DTPA analogue retaining L-cysteine as a core ligand of the thiol group. The chelating power of cysteine-based DTPA-NCS (cys-DTPA-NCS) was compared with that of commercial rho SCN-Bn-DTPA. In an application, the cetuximab was radioimmunoconjugated with (177)Lu using cys-DTPA-NCS. The affinity was tested in a cell line overexpressing EGFR. A therapy study was conducted in nude mice with subcutaneous HT-29 xenografts. RESULTS: The cys-DTPA-NCS presents an excellent ability to chelate as compared to the rho-SCN-Bn-DTPA. For mean ratio chemical labeling yields of 95%, the result was 0.97. (177)Lu-cys-DTPA-NCS-cetuximab was prepared under ambient condition with a high radiolabeling yield and the radiochemical purity was sustained for at least 6days. The IC50 value of the (177)Lu-labeled cetuximab was 10nM (95% confidence). The stability and therapeutic efficacy of the candidate radiopharmaceutical were verified. CONCLUSION: The new DTPA derivative, cys-DTPA NCS, is a good bifunctional chelating agent that can be used for protein-based radiopharmaceutical using lanthanides such as (177)Lu and (90)Y. The prepared (177)Lu-cys-DTPA-NCS-cetuximab can be used for the diagnosis and treatment of human colorectal tumor. PMID- 23357083 TI - Evaluation of backbone-cyclized HER2-binding 2-helix affibody molecule for in vivo molecular imaging. AB - INTRODUCTION: Affibody molecules, small scaffold proteins, have demonstrated an appreciable potential as imaging probes. Affibody molecules are composed of three alpha-helices. Helices 1 and 2 are involved in molecular recognition, while helix 3 provides stability. The size of Affibody molecules can be reduced by omitting the third alpha-helix and cross-linking the two remaining, providing a smaller molecule with better extravasation and quicker clearance of unbound tracer. The goal of this study was to develop a novel 2-helix Affibody molecule based on backbone cyclization by native chemical ligation (NCL). METHODS: The HER2 targeting NCL-cyclized Affibody molecule ZHER2:342min has been designed, synthesized and site-specifically conjugated with a DOTA chelator. DOTA ZHER2:342min was labeled with (111)In and (68)Ga. The binding affinity of DOTA ZHER2:342min was evaluated in vitro. The targeting properties of (111)In- and (68)Ga-DOTA-ZHER2:342min were evaluated in mice bearing SKOV-3 xenografts and compared with the properties of (111)In- and (68)Ga-labeled PEP09239, a DOTA conjugated 2-helix Affibody analogue cyclized by a homocysteine disulfide bridge. RESULTS: The dissociation constant (KD) for DOTA-ZHER2:342min binding to HER2 was 18nM according to SPR measurements. DOTA-ZHER2:342min was labeled with (111)In and (68)Ga. Both conjugates demonstrated bi-phasic binding kinetics to HER2 expressing cells, with KD1 in low nanomolar range. Both variants demonstrated specific uptake in HER2-expressing xenografts. Tumor-to-blood ratios at 2h p.i. were 6.1+/-1.3 for (111)In- DOTA-ZHER2:342min and 4.6+/-0.7 for (68)Ga-DOTA ZHER2:342min. However, the uptake of DOTA-ZHER2:342min in lung, liver and spleen was appreciably higher than the uptake of PEP09239-based counterparts. CONCLUSIONS: Native chemical ligation enables production of a backbone-cyclized HER2-binding 2-helix Affibody molecule (ZHER2:342min) with low nanomolar target affinity and specific tumor uptake. PMID- 23357084 TI - Imaging brain gene expression profiles by antipsychotics: region-specific action of amisulpride on postsynaptic density transcripts compared to haloperidol. AB - Induction of motor disorders is considered the clinical landmark differentiating typical from atypical antipsychotics, and has been mainly correlated to dopamine D2 receptors blockade in striatum. This view is challenged by benzamides, such as amisulpride, which display low liability for motor side effects despite being D2/D3 receptors high-affinity blocking agents. These effects have been explained with the prominent presynaptic action of amisulpride or with the fast dissociation at D2 receptors, but there is scarce information on the effects of amisulpride on postsynaptic signaling. We carried out a molecular imaging study of gene expression after acute administration of haloperidol (0.8 mg/kg), amisulpride (10 or 35 mg/kg), or vehicle, focusing on postsynaptic genes that are key regulators of synaptic plasticity, such as Arc, c-fos, Zif-268, Norbin, Homer. The last one has been associated to schizophrenia both in clinical and preclinical studies, and is differentially induced by antipsychotics with different D2 receptors affinity. Topography of gene expression revealed that amisulpride, unlike haloperidol, triggers transcripts expression peak in medial striatal regions. Correlation analysis of gene expression revealed a prevalent correlated gene induction within motor corticostriatal regions by haloperidol and a more balanced gene induction within limbic and motor corticostriatal regions by amisulpride. Despite the selective dopaminergic profile of both compounds, our results demonstrated a differential modulation of postsynaptic molecules by amisulpride and haloperidol, the former impacting preferentially medial regions of striatum whereas the latter inducing strong gene expression in lateral regions. Thus, we provided a possible molecular profile of amisulpride, putatively explaining its "atypical atypicality". PMID- 23357085 TI - Sight of conspecific images induces changes in neurochemistry in zebrafish. AB - Zebrafish are gaining popularity in behavioural brain research as this species combines practical simplicity with system complexity. The dopaminergic system has been thoroughly investigated using mammals. Dopamine plays important roles in motor function and reward. Zebrafish have dopamine receptors homologous to mammalian counterparts, and dopamine receptor antagonists as well as alcohol have been shown to exert significant effects on this species as measured using HPLC or behavioural methods. The sight of conspecifics was previously shown to be rewarding in zebrafish but whether this stimulus affects the dopaminergic system has not been studied. Here, we present animated images of zebrafish to the experimental zebrafish subject for varying lengths of time and quantify the amount of dopamine, DOPAC, serotonin and 5HIAA extracted from the subject's brain immediately after the stimulus presentation using HPLC with electrochemical detection. We find conspecific images to induce a robust behavioural response (attraction) in experimental zebrafish. Importantly, dopamine and DOPAC levels significantly increased in response to the presentation of conspecific images but not to scrambled images. Last, serotonin and 5HIAA levels did not significantly change in response to the conspecific images. We conclude that our findings, together with pervious studies, now conclusively demonstrate that the behavioural response induced by the appearance of conspecifics is mediated, at least partly, by the dopaminergic system in zebrafish. PMID- 23357086 TI - Effects of immobilization stress on emotional behaviors in dopamine D3 receptor knockout mice. AB - A central problem in understanding the dopamine system in anxiety and depression is to specify functions of different members of the dopamine receptor family. Recent studies have reported that the dopamine D2/D3 receptor agonist pramipexole exerts an antidepressant-like effect in the chronic mild stress model and in the behavioral despair model, suggesting dopamine D3 receptor may be an important target for antidepressant actions. The aim of the present study was to examine the role of dopamine D3 receptor on the anxiety-like and depression-like behaviors induced by immobilization stress. We subjected D3 receptor knockout (D3KO) mice to a series of behavioral paradigms after acute (1 h) or chronic (1 h a day for 14 days) immobilization stress. The results showed that immobilization stress significantly altered the anxiety-like behaviors (open field test and elevated plus maze) and depression-like behaviors (tail suspension test) in both D3KO mice and their wild-type littermates. Moreover, further analysis of the data indicated that the D3KO mice, but not their littermates, failed to show a change in immobility time in the tail suspension test after the acute and chronic stress as compared to intact controls, suggesting an increased resistance to the immobilization stress given before behavioral tests. Although our study did not suggest a significant role of D3 receptor in regulating basal anxiety-like and depression-like behaviors, it demonstrated the mice lacking D3 receptor might be more resistant to stressful procedure than their WT littermates. PMID- 23357087 TI - Capacity for colonization and degradation of horse manure and wheat-straw-based compost by different strains of Agaricus subrufescens during the first two weeks of cultivation. AB - The potential of Agaricus subrufescens strains to colonize and transform horse manure and wheat-straw-based mushroom compost under the physico-chemical conditions typically used for Agaricus bisporus was assessed. Lignocellulolytic activities, H2O2 production and substrate transformation (assessed via CP/MAS NMR of (13)C) for certain A. subrufescens strains were similar or even greater than those obtained for an A. bisporus strain used as control. Moreover, the functional diversity of the microbial communities of the substrate was not altered by the growth of A. subrufescens after 2weeks. These findings obtained with mesocosms simulating the incubation phase of the mushroom production process hold promise for the improvement of cultivation of this tropical Agaricus species on European standard mushroom compost. PMID- 23357088 TI - Cellulose degradation by one mesophilic strain Caulobacter sp. FMC1 under both aerobic and anaerobic conditions. AB - Caulobacteria are presumed to be responsible for considerable mineralization of organic material in aquatic environments. In this study, a facultative, mesophilic and cellulolytic bacterium Caulobacter sp. FMC1 was isolated from sediments which were taken from a shallow freshwater lake and then enriched with amendment of submerged macrophyte for three months. This strain seemed to evolve a capacity to adapt redox-fluctuating environments, and could degrade cellulose both aerobically and anaerobically. Cellulose degradation percentages under aerobic and anaerobic conditions were approximately 27% and 10% after a 240-h incubation in liquid mediums containing 0.5% cellulose, respectively. Either cellulose or cellobiose alone was able to induce activities of endoglucanase, exoglucanase, and beta-1,4-glucosidase. Interestingly, ethanol was produced as the main fermentative product under anaerobic incubation on cellulose. These results could improve our understanding about cellulose-degrading process in aquatic environments, and were also useful in optimizing cellulose bioconversion process for bioethanol production. PMID- 23357089 TI - Effects of vaccination against reproductive diseases on reproductive performance of lactating dairy cows submitted to AI. AB - Four experiments evaluated the effects of vaccination against bovine herpesvirus 1 (BoHV-1), bovine viral diarrhea virus (BVDV), and Leptospira spp. on reproductive performance of lactating dairy cows without (experiments 1, 2, and 3) or with previous vaccination against these diseases (experiment 4). Cows were assigned to a fixed-time AI protocol (FTAI; d -11 to 0) in all experiments, as well as AI 12 h upon estrus detection in experiment 3. Pregnancy status was determined with transrectal ultrasonography on d 30 and 71 (d 60 for experiment 3) after AI. Pregnancy loss was considered in cows pregnant on d 30 but non pregnant on the subsequent evaluation. In experiment 1, 853 cows received (VAC) or not (CON) vaccination against BoHV-1, BVDV, and Leptospira spp. at the beginning of the FTAI (d -11) and 30 d after AI. Pregnancy loss was reduced (P = 0.03) in VAC cows compared with CON. In experiment 2, 287 cows received VAC or CON 30 d prior to (d -41) and at the beginning (d -11) of the FTAI. Pregnancy rates on d 30 and 71 were greater (P <= 0.03) in VAC cows compared with CON. In experiment 3, 1680 cows with more than 28 d in milk were randomly assigned to receive VAC or CON with doses administered 14 d apart, and inseminated within 15 135 d after the second dose. Pregnancy rates on d 30 and 60 were greater (P <= 0.02) in VAC cows compared with CON. In experiment 4, 820 cows received (REVAC) or not (CON) revaccination against BoHV-1, BVDV, and Leptospira spp. at the beginning of the FTAI protocol (d -11). Pregnancy rates and loss were similar (P >= 0.54) between treatments. Hence, vaccinating naive cows against BoHV-1, BVDV, and Leptospira spp. improved reproductive efficiency in dairy production systems, particularly when both doses were administered prior to AI. PMID- 23357090 TI - Confirming candidate genes for longevity by RT-qPCR using two different genetic backgrounds and selection methods. AB - Elucidating genes that affect life span or that can be used as biomarkers for ageing has received attention in diverse studies in recent years. Using model organisms and various approaches several genes have been linked to the longevity phenotype. For Drosophila melanogaster those studies have usually focussed on one sex and on flies originating from one genetic background, and results from different studies often do not overlap. Using D. melanogaster selected for increased longevity we aimed to find robust longevity related genes by examining gene expression in both sexes of flies originating from different genetic backgrounds. Further, we compared expression changes across three ages, when flies were young, middle aged or old, to examine how candidate gene expression changes with the onset of ageing. We selected 10 genes based on their expression differences in prior microarray studies. For about 50% of these we confirmed their potential as a candidate longevity gene. We found one robust candidate gene for longevity, CG32638. Three other genes, CG8934, mRpS10 and Spn43Ad, showed a tendency to be involved in life span determination in both backgrounds tested. PMID- 23357091 TI - Infants' use of contextual cues in the generalization of effective actions from imitation. AB - We examined infants' ability to generalize effective actions in an imitation task. In Experiment 1, 15-month-olds imitated effective and ineffective actions on two similarly designed toys. They were then shown a third toy of the same design with both actions available. Children reliably touched and manipulated the effective action handle first and more persistently. In Experiment 2, however, 15 month-olds did not generalize the efficacy of the action when the test toy was different from the two demonstration toys. Experiment 3 replicated the findings of Experiment 2 but also showed that infants generalized efficacy when the demonstration toys differed from one another as well as from the test toy. Our findings are consistent with a computational model that uses certain rational pedagogical assumptions. Overall, the results suggest that 15-month-olds are sensitive to the sampling information they observe and use this information to guide whether to generalize efficacy information they learn from imitation. PMID- 23357092 TI - Rhythm implicitly affects temporal orienting of attention across modalities. AB - Here we present two experiments investigating the implicit orienting of attention over time by entrainment to an auditory rhythmic stimulus. In the first experiment, participants carried out a detection and discrimination tasks with auditory and visual targets while listening to an isochronous, auditory sequence, which acted as the entraining stimulus. For the second experiment, we used musical extracts as entraining stimulus, and tested the resulting strength of entrainment with a visual discrimination task. Both experiments used reaction times as a dependent variable. By manipulating the appearance of targets across four selected metrical positions of the auditory entraining stimulus we were able to observe how entraining to a rhythm modulates behavioural responses. That our results were independent of modality gives a new insight into cross-modal interactions between auditory and visual modalities in the context of dynamic attending to auditory temporal structure. PMID- 23357093 TI - Fluorescence in situ hybridization method using a peptide nucleic acid probe for identification of Lactobacillus spp. in milk samples. AB - Lactobacillus species constitute one of the dominant and beneficial bacteria in our body and are used in developed countries as a microbial adjuvant. Identification of these probiotic bacteria is traditionally performed by culture based techniques. However, such methods are very time-consuming and can give inaccurate results, especially when Lactobacillus is present in mixed bacterial complex communities. Our study aimed to accurately identify Lactobacillus spp. using a novel Peptide Nucleic Acid (PNA) Fluorescence In Situ Hybridization (FISH) probe. The probe (Lac663) was tested on 36 strains belonging to different Lactobacillus species and on 20 strains of other bacterial species. The sensitivity and specificity of the method were 100% (95% confidence interval (CI), 88.0 to 100.0%) and 95.0% (95% CI, 73.1 to 99.7%), respectively. Additionally, we tested the applicability of the method on milk samples added with Lactobacillus strains at probiotic range concentrations and other taxonomically related bacteria, as well as pathogenic bacteria. The Lac663 probe bound exclusively to Lactobacillus strains and the described PNA-FISH method was capable of directly quantifying Lactobacillus spp. in concentrations at which these potential probiotic bacteria are considered to have an effective benefit on human health. PMID- 23357094 TI - Choice of valve prosthesis in a rare clinical condition: aortic stenosis due to alkaptonuria. AB - Alkaptonuria is a rare inherited disorder of tyrosine metabolism, which results in deposition of homogentisic acid in the connective tissues. The accumulation of homogentisic acid in connective tissue causes the syndrome known as ochronosis, which is typically manifested by skin pigmentation, degenerative arthropathy and discolouration of urine. Cardiovascular involvement is a much less common complication of alkaptonuria but poses a greater risk to the patient's health. We present the case of a 65 year-old man with aortic stenosis and a previous diagnosis of alkaptonuria who underwent successful aortic valve replacement with a mechanical prosthesis. PMID- 23357095 TI - Totally endoscopic atrial septal repair with or without robotic assistance: a systematic review and meta-analysis of case series. AB - OBJECTIVE: To evaluate the safety and efficacy of totally endoscopic repair of atrial septal defect (ASD). METHODS: A review of the literature was conducted. Studies were obtained from the following sources: MEDLINE, EMBASE, Web of Science and CENTRAL Library. Inclusion criteria were: (1) randomised controlled trials, non-randomised trials, observational studies, case series, and full text conference proceedings; (2) use of totally endoscopy closure of ASD; and (3) outcomes reported as clinical efficacy. When available, we also quantified the complication rates from each included study. Meta-analysis was performed on outcomes with a random-effects model. RESULTS: Six studies met all inclusion criteria. The pooled average success rate of totally endoscopic ASD repair was 94.8% from a total of 114 cases (95% CI, 88.0% to 97.8%), with a minimal heterogeneity in the group of studies (Q value x(2)=1.807, I(2)=0.000). In the studies with no robotic assistance, an average success rate of totally endoscopic ASD repair was 96.9% (95% CI, 85.9-99.4%), with a minimal heterogeneity in the two studies (Q value x(2)=0.683, I(2)=0.000). There were few complications for totally endoscopic ASD repair in the studies with and without robotic assistance. There were no statistically significant differences in success rates between robotically and non-robotically assisted totally endoscopic repairs (p>0.05). CONCLUSIONS: Totally endoscopic ASD repair was associated with a high success rate and a low complication rate. There is a need for prospective controlled clinical trials comparing totally endoscopic and conventional surgical repair of ASD. PMID- 23357096 TI - A systematic approach towards the development of a set of quality indicators for public reporting in community-based maternity care. AB - OBJECTIVE: to demonstrate the process and outcome of a systematic approach towards the development of a set of quality indicators for public reporting on quality of community-based maternity care. DESIGN AND SETTING: a four-stepped approach was adopted. Firstly, we defined key elements of community-based maternity care, by performing a systematic search on care guidelines/ standards. Secondly, the literature was searched for existing indicators for maternity care, which were subsequently categorised according to the key elements and systematically selected on suitability of public presentation. The emerging set of indicators suitable for public reporting was presented to five health-care professionals using a Delphi technique (step 3). Based on the comments of the professionals, the set was adjusted and subsequently presented to the health-care consumers (a sample of pregnant women) in step four to test its validity, after which the final set was composed. PARTICIPANTS: health-care professionals in the field of maternity care and pregnant women. FINDINGS: key elements of community based maternity care were extracted from eight guidelines and care standards. We then extracted 10 documents with 223 indicators in total, from which 19 indicators covering the key elements were included in the first set and presented to experts. Based on their comments three indicators were deleted and four indicators were added to the set or slightly rephrased. These were subsequently judged by 13 pregnant women. Seventy-five per cent of the indicators were judged positively by them; no indicator was judged negatively. The set of indicators was thus left unchanged after this final step. KEY CONCLUSIONS AND IMPLICATIONS FOR CLINICAL PRACTICE: the systematic approach adopted in this study resulted in an indicator set that was considered valid by both maternity care professionals and pregnant women, and is likely to satisfy the essential requirements on clinimetric properties. The next step will be to pilot test the indicator set on feasibility in daily clinical practice and to refine the set when necessary. In the future, maternity care professionals may use the set to present the quality of care they provide and to define issues of improvement. Pregnant women may use the information to make a founded choice between maternity care professionals, which ultimately should result in improved safety and quality of maternity care as well as patient satisfaction. Although we focused on the Dutch, community based maternity care system, the approach used may be extrapolated to other care processes and health-care systems. Extrapolation of the results itself (i.e. the indicator set) may need to be limited to systems with an emphasis on community based maternity care. PMID- 23357097 TI - Polymorphism of CLOCK gene rs 4580704 C > G is associated with susceptibility of Alzheimer's disease in a Chinese population. AB - BACKGROUND AND AIMS: The association of polymorphism of circadian locomotor output cycle kaput (CLOCK) gene rs 4580704 C/G with susceptibility of Alzheimer's disease (AD) was examined in the present study. METHODS: This was a case/control study and investigated the association of polymorphism of CLOCK gene rs 4580704 C/G with susceptibility of AD. Genotypes of apolipoprotein E (APOE) and CLOCK gene rs 4580704 C/G were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) detection method. RESULTS: This study was comprised of 296 unrelated AD patients and 423 controls. We performed an analysis the association of polymorphism of CLOCK gene rs 4580704 C/G with susceptibility of AD. In the whole sample or APOEepsilon4 noncarriers, prevalence of C carriers in CLOCK gene rs 4580704 in AD patients was significantly higher than in controls (in the whole sample: chi(2) = 13.773, p <0.0001; in APOEepsilon4 noncarriers: chi(2) = 51.588, p <0.0001). However, among APOEepsilon4 carriers, prevalence of C carriers in CLOCK gene rs 4580704 between patients and controls was not statistically significant (chi(2) = 0.753, p = 0.386). CONCLUSIONS: Among APOEepsilon4 noncarriers, C carriers in CLOCK gene rs 4580704 were associated with a high susceptibility of AD; however, among APOEepsilon4 carriers the functional polymorphism of clock gene rs 4580704 C/G was not associated with AD susceptibility. PMID- 23357098 TI - Repeatability of static posturography on the follow-up of vestibular rehabilitation. AB - BACKGROUND AND AIMS: We undertook this study to estimate the limits of agreement of repeated measures of static posturography on healthy adults and to assess the use of those limits on the interpretation of variations observed during vestibular rehabilitation of patients with chronic, peripheral vestibular disease. METHODS: Twenty healthy adults and 30 vestibular patients accepted to participate. At baseline and at weeks 4, 6 and 8 of follow-up, posturography was performed with the eyes open or closed, while adding or not a layer of foam rubber to the base of support. The Dizziness Handicap Inventory was administered to patients prior to rehabilitation and at week 8. RESULTS: At baseline, a difference between groups was observed on the sway area (p < 0.05). Healthy subjects showed no statistical difference among the four recordings (repeatability of measurements from 85-100%). Vestibular patients showed differences among the four recordings on the area and the length/average speed of sway (p <0.05); individual differences from baseline exceeding the limits of agreement were observed on the sway area. A decrease on the Dizziness Handicap Inventory (>=18 points) was observed on 19 patients, from whom 12 (63, 95% CI 53 73%) showed a change on the sway area (eyes closed) that was larger than the limits of agreement. CONCLUSIONS: In healthy subjects, intra-subject repeated recordings of the area and the length/average speed of sway may be reliable at intervals of 4, 6 and 8 weeks. The sway area (without vision) may be a useful sway component, among others, to follow-up vestibular patients with chronic, peripheral disease during rehabilitation. PMID- 23357099 TI - Protective effect of galantamine against oxidative damage using human lymphocytes: a novel in vitro model. AB - BACKGROUND AND AIMS: Neurodegenerative disorders such as Alzheimer's disease are characterized in the initial stages by an increase in reactive oxygen species that trigger apoptosis or programmed cell death. It has been suggested that the synthetic alkaloid galantamine may offer protection against this cell loss. This investigation sought to assess the protective effect of galantamine against oxidative damage induced by hydrogen peroxide (H2O2) using human lymphocytes cultured in vitro as a model. METHODS: Cell death can be measured indirectly using cell viability testing with trypan blue. Determination of the galantamine concentrations used was made possible by the negative correlation found between galantamine concentration and average mitotic index (MI). RESULTS: Average viability of lymphocytes treated with low and medium concentrations of galantamine was significantly higher than the control. CONCLUSION: Galantamine does indeed demonstrate a protective capacity against cell damage induced by hydrogen peroxide. This finding supports the possible use of the drug in treatment of neurodegenerative diseases related to oxidative stress. PMID- 23357100 TI - Myospherulosis. AB - Myospherulosis is a rare tumor caused by interaction of extravasated erythrocytes and exogenous or endogenous lipids. Fifty-nine articles presented 181 patients with myospherulosis since first description in 1969. Myospherulosis seems to occur in any age and in any part of the body; however, most frequent sites are paranasal sinus and subcutaneous tissue. In most cases, exogenous lipids from postoperative packing are damaging the erythrocytes, but also spontaneous cases are described. Diagnosis is made by histology but can be already suggested by radiographic imaging. Differential diagnoses include infections by fungi or algae due to histopathologic similarity. Besides that, radiographic imaging and morphology can wrongly be interpreted as carcinomas, metastases, osteofibrosis, or echinococcosis. Myospherulosis is a benign process, with symptoms deriving from the space occupying character and surgical excision can bring cure. We discuss the clinical presentation, diagnosis, and treatment and provide a systematic review of the literature on myospherulosis. PMID- 23357101 TI - Acute hepatic arterial dissection during transarterial embolotherapy: retrograde infusion in the acute setting is a feasible option. PMID- 23357102 TI - A new technique for intracorporeal liver retraction in laparoscopic surgery. PMID- 23357103 TI - Stapler's malfunction during laparoscopic sleeve gastrectomy: an unusual but correctable complication. PMID- 23357104 TI - Reply: Gastric bypass--a combined restrictive and malabsorbtive procedure or a malabsorbtive procedure alone? PMID- 23357107 TI - Variability of new bone mineral metabolism markers in patients treated with maintenance hemodialysis: implications for clinical decision making. PMID- 23357106 TI - Abundance, distribution, mobility and oligomeric state of M2 muscarinic acetylcholine receptors in live cardiac muscle. AB - M2 muscarinic acetylcholine receptors modulate cardiac rhythm via regulation of the inward potassium current. To increase our understanding of M2 receptor physiology we used Total Internal Reflection Fluorescence Microscopy to visualize individual receptors at the plasma membrane of transformed CHO(M2) cells, a cardiac cell line (HL-1), primary cardiomyocytes and tissue slices from pre- and post-natal mice. Receptor expression levels between individual cells in dissociated cardiomyocytes and heart slices were highly variable and only 10% of murine cardiomyocytes expressed muscarinic receptors. M2 receptors were evenly distributed across individual cells and their density in freshly isolated embryonic cardiomyocytes was ~1MUm(-2), increasing at birth (to ~3MUm(-2)) and decreasing back to ~1MUm(-2) after birth. M2 receptors were primarily monomeric but formed reversible dimers. They diffused freely at the plasma membrane, moving approximately 4-times faster in heart slices than in cultured cardiomyocytes. Knowledge of receptor density and mobility has allowed receptor collision rate to be modeled by Monte Carlo simulations. Our estimated encounter rate of 5-10 collisions per second, may explain the latency between acetylcholine application and GIRK channel opening. PMID- 23357108 TI - Chronic kidney disease: a clinical model of premature aging. AB - Premature aging is a process associated with a progressive accumulation of deleterious changes over time, an impairment of physiologic functions, and an increase in the risk of disease and death. Regardless of genetic background, aging can be accelerated by the lifestyle choices and environmental conditions to which our genes are exposed. Chronic kidney disease is a common condition that promotes cellular senescence and premature aging through toxic alterations in the internal milieu. This occurs through several mechanisms, including DNA and mitochondria damage, increased reactive oxygen species generation, persistent inflammation, stem cell exhaustion, phosphate toxicity, decreased klotho expression, and telomere attrition. Because recent evidence suggests that both increased local signaling of growth factors (through the nutrient-sensing mammalian target of rapamycin) and decreased klotho expression are important modulators of aging, interventions that target these should be tested in this prematurely aged population. PMID- 23357109 TI - Correlation dimension estimates of human postural sway. AB - Human postural sway during quiet standing demonstrates a complex structured dynamics, which has been studied by applying numerous methods, such as linear system identification methods, stochastic analysis, and nonlinear system dynamics tools. Although each of the methods applied revealed some particular features of the sway data none of them have succeeded to present a global picture of the quiet stance dynamics, which probably has both stochastic and deterministic properties. In this study we have started applying ergodic theory of dynamical systems to explore statistical characteristic of the sway dynamics observed in successive trials of a subject, different subjects in an age group, and finally different age groups constituted by children, adults, and elderly subjects. Five successive 180-s long trials were performed by each of 28 subjects in four age groups at quiet stance with eyes open. Stationary and ergodic signal characteristics of five successive center of pressure time series collected from a subject in antero-posterior direction (CoPx) were examined. 97% of the trials were found to be stationary by applying Run Test while children and elderly groups demonstrated significant nonstationary behavior. On the other hand 13 out of 24 subjects were found to be nonergodic. We expected to observe differences in complexity of CoPx dynamics due to aging (Farmer, Ott, & Yorke, 1983). However linear metrics such as standard deviation and Fourier spectra of CoPx signals did not show differences due to the age groups. Correlation dimension (Dk) estimates of stationary CoPx signals being an invariant measure of nonlinear system dynamics were computed by using the average displacement method (Eckmann & Ruelle, 1985). Postural dynamics was expanded in m-dimensional space through CoPx signal by introducing optimum time delays, taucritical. 112 out of 136 stationary CoPx signals for 24 stationary subjects converged to Dk estimates. Average of Dk estimates for children and adult groups was 3.67+/-0.28, whereas mean of Dk estimates for elderly subjects was 4.12+/-0.59. Nonlinear metrics of postural sway (taucritical, msaturated, and Dk estimates) showed significant differences with respect to the age groups. Dk estimates computed from ergodic subjects' CoPx sway trajectories revealed that human quiet standing demonstrates multiple degree of freedom dynamics having a fractal structure with a considerable level of noise embedded in the signal whose characteristics is determined individually for each subject. Furthermore by using ergodic theory of complex systems, we have been able to show that the ability to independently control multiple degrees of freedom has been affected by aging. PMID- 23357110 TI - Insulin induces neurite outgrowth via SIRT1 in SH-SY5Y cells. AB - Insulin plays diverse roles, including learning and memory, in the central nervous system. SIRT1 has been reported to be involved in the processes of normal learning, memory, and synaptic plasticity. However, whether insulin is directly involved in regulating SIRT1 expression in neurons or whether it affects synapses remains largely unknown. Here, we show that insulin promotes neurite outgrowth and increases SIRT1 expression in SH-SY5Y cells. LY294002, a phosphatidylinositol 3-kinase inhibitor, inhibited the expression of insulin-induced increases in SIRT1. Conversely, the downregulation of SIRT1 using a SIRT1 inhibitor and SIRT1 siRNA resulted in a significant reduction in the length of neurite outgrowth. Taken together, these results suggest that the regulation of SIRT1 by insulin is important for the neurite outgrowth of neuroblastoma cells. PMID- 23357111 TI - Task-modulated activation and functional connectivity of the temporal and frontal areas during speech comprehension. AB - There is general consensus in the literature that a distributed network of temporal and frontal brain areas is involved in speech comprehension. However, how active versus passive tasks modulate the activation and the functional connectivity of the critical brain areas is not clearly understood. In this study, we used functional magnetic resonance imaging (fMRI) to identify intelligibility and task-related effects in speech comprehension. Participants performed a semantic judgment task on normal and time-reversed sentences, or passively listened to the sentences without making an overt response. The subtraction analysis demonstrated that passive sentence comprehension mainly engaged brain areas in the left anterior and posterior superior temporal sulcus and middle temporal gyrus (aSTS/MTG and pSTS/MTG), whereas active sentence comprehension recruited bilateral frontal regions in addition to the aSTS/MTG and pSTS/MTG regions. Functional connectivity analysis revealed that during passive sentence comprehension, the left aSTS/MTG was functionally connected with the left Heschl's gyrus (HG) and bilateral superior temporal gyrus (STG) but no area was functionally connected with the left pSTS/MTG; during active sentence comprehension, however, both the left aSTS/MTG and pSTS/MTG were functionally connected with bilateral superior temporal and inferior frontal areas. While these results are consistent with the view that the ventral stream of the temporo frontal network subserves semantic processing, our findings further indicate that both the activation and the functional connectivity of the temporal and frontal areas are modulated by task demands. PMID- 23357112 TI - High-frequency rTMS improves facial mimicry and detection responses in an empathic emotional task. AB - In this study, we analysed facial expression detection and facial mimicry behaviour in response to an emotional empathic task. We posited that a "simulation mechanism" may be related to emotional face detection and that this mechanism could be supported by prefrontal cortical structures. To evaluate our hypothesis, we requested 16 subjects to emotionally empathise with facial stimuli and applied high frequency repeated transcranial magnetic stimulation (rTMS) to the medial prefrontal cortex (MPFC) in order to induce an increased response to the facial expressions of emotion. To determine whether emotional content affects empathic behaviour, we also varied the stimulus valence (negative vs. positive vs. neutral faces). We found that autonomic (facial zygomatic and corrugator electromyography (EMG) subjective response) and detection (correct responses (CRs); response times (RTs)) measures were modulated by the MPFC activity. Specifically, when prefrontal structures were activated, subjects displayed an increased performance in CRs and reduced RTs for face recognition, as well as increased emotion-specific EMG responses in comparison to sham effects and control site stimulation. In fact, the zygomatic muscle was more responsive in cases of positive emotion (happiness), whereas corrugator activity was more robust during periods of negative emotion (fear, anger, disgust). However, an overall stronger effect was observed in response to negative, and potentially aversive, faces when compared with responses to positive and neutral faces. Finally, a direct correlation was found between the psychophysiological responses and detection measures. In summary, these results suggest that a "simulation mechanism" underlies emotion detection in an empathic situation that includes both EMG and behavioural responses. This mechanism appears to be supported and regulated by the MPFC area. PMID- 23357113 TI - Estrogen receptors and lesion-induced response of striatal dopamine receptors. AB - Neuroprotection by 17beta-estradiol and an estrogen receptor (ER) agonist against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion were shown to implicate protein kinase B (Akt) signaling in mice. In order to evaluate the associated mechanisms, this study compared estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) intact or knockout (KO) and wild-type (WT) C57Bl/6 male mice following MPTP treatment of 7, 9, 11mg/kg and/or 17beta estradiol. Striatal D1 and D2 dopamine (DA) receptors were measured by autoradiography with the specific ligands [(3)H]-SCH 23390 and [(3)H]-raclopride, respectively and signaling by Western blot for Akt, glycogen synthase kinase 3beta (GSK3beta) and extracellular-regulated signal kinases (ERK1 and ERK2). Control ERKObeta mice had lower striatal [(3)H]-SCH 23390 specific binding than WT and ERKOalpha mice; both KO mice had lower [(3)H]-raclopride specific binding. Striatal D1 receptors decreased with increasing doses of MPTP in correlation with striatal DA concentrations in ERKOalpha mice and remained unchanged in WT and ERKObeta mice. Striatal D2 receptors decreased with increasing doses of MPTP in correlation with striatal DA concentrations in WT and ERKOalpha mice and increased in ERKObeta mice. In MPTP-lesioned mice, 17beta-estradiol treatment increased D1 receptors in ERKOalpha and ERKObeta mice and D2 receptors in WT and ERKObeta mice. MPTP did not affect striatal pAkt/Akt and pGSK3beta/GSK3beta levels in WT and ERKOalpha mice, while in vehicle-treated ERKObeta mice these levels were higher and increased with MPTP lesioning. Striatal pERK1/ERK1 and pERK2/ERK2 levels showed to a lesser extent a similar pattern. In conclusion, ERs affected the response of striatal DA receptors to a MPTP lesion and post receptor signaling. PMID- 23357114 TI - Parallel dopamine D1 receptor activity dependence of l-Dopa-induced normal movement and dyskinesia in mice. AB - l-3,4-Dihydroxyphenylalanine (l-Dopa)-induced dyskinesia (LID) in Parkinson's disease (PD) is a major clinical problem. The prevailing view is that in PD patients and animal PD models dyskinesia develops after repeated l-dopa use or priming, independent of l-dopa's anti-PD therapeutic effect that occurs immediately. Here we show that in mice with severe and consistent dopamine (DA) loss in the dorsal striatum, rendered by transcription factor Pitx3 null mutation, the very first injection of l-dopa or D1-like agonist SKF81297 induced both normal ambulatory and dyskinetic movements. Furthermore, the robust stimulating effects on normal and dyskinetic movements had an identical time course and parallel dose-response curves. In contrast, D2-like agonist ropinirole stimulated normal and dyskinetic movements relatively modestly. These results demonstrate that severe DA loss in the dorsal striatum sets the stage for dyskinesia to occur on the first exposure to l-dopa or a D1 agonist without any priming. These results also indicate that l-dopa stimulated both normal and dyskinetic movements primarily via D1 receptor activation and that proper D1 agonism is potentially an efficacious therapy for PD motor deficits. PMID- 23357116 TI - Working memory training is associated with lower prefrontal cortex activation in a divergent thinking task. AB - Working memory (WM) training has been shown to lead to improvements in WM capacity and fluid intelligence. Given that divergent thinking loads on WM and fluid intelligence, we tested the hypothesis that WM training would improve performance and moderate neural function in the Alternate Uses Task (AUT)-a classic test of divergent thinking. We tested this hypothesis by administering the AUT in the functional magnetic resonance imaging scanner following a short regimen of WM training (experimental condition), or engagement in a choice reaction time task not expected to engage WM (active control condition). Participants in the experimental group exhibited significant improvement in performance in the WM task as a function of training, as well as a significant gain in fluid intelligence. Although the two groups did not differ in their performance on the AUT, activation was significantly lower in the experimental group in ventrolateral prefrontal and dorsolateral prefrontal cortices-two brain regions known to play dissociable and critical roles in divergent thinking. Furthermore, gain in fluid intelligence mediated the effect of training on brain activation in ventrolateral prefrontal cortex. These results indicate that a short regimen of WM training is associated with lower prefrontal activation-a marker of neural efficiency-in divergent thinking. PMID- 23357115 TI - The GluK4 kainate receptor subunit regulates memory, mood, and excitotoxic neurodegeneration. AB - Though the GluK4 kainate receptor subunit shows limited homology and a restricted expression pattern relative to other kainate receptor subunits, its ablation results in distinct behavioral and molecular phenotypes. GluK4 knockout mice demonstrated impairments in memory acquisition and recall in a Morris water maze test, suggesting a previously unreported role for kainate receptors in spatial memory. GluK4 knockout mice also showed marked hyperactivity and impaired pre pulse inhibition, thereby mirroring two of the hallmark endophenotypes of patients with schizophrenia and bipolar disorder. Furthermore, we found that GluK4 is a key mediator of excitotoxic neurodegeneration: GluK4 knockout mice showed robust neuroprotection in the CA3 region of the hippocampus following intrahippocampal injection of kainate and widespread neuroprotection throughout the hippocampus following hypoxia-ischemia. Biochemical analysis of kainate- or sham-treated wild-type and GluK4 knockout hippocampal tissue suggests that GluK4 may act through the JNK pathway to regulate the molecular cascades that lead to excitotoxicity. Together, our findings suggest that GluK4 may be relevant to the understanding and treatment of human neuropsychiatric and neurodegenerative disorders. PMID- 23357117 TI - Temporal association between changes in primary sensory cortex and corticomotor output during muscle pain. AB - BACKGROUND: Integration of information between multiple cortical regions is thought to underpin the experience of pain. Yet studies tend to focus on pain related changes in discrete cortical regions. Although altered processing in the primary motor (M1) and sensory cortex (S1) is implicated in pain, the temporal relationship between these regions is unknown and may provide insight into the interaction between them. METHODS: We used recordings of somatosensory-evoked potentials (SEPs) and transcranial magnetic stimulation to investigate the temporal relationship between altered excitability of the primary sensory cortex and corticomotor output during and after muscle pain induced by hypertonic saline infusion into the right first dorsal interosseous. SEPs and motor-evoked potentials (MEPs) were recorded in 12 healthy individuals. RESULTS: Participants reported an average pain intensity of 5.4 (0.5) on a 10-cm visual analogue scale. The area of the N20-P25-N33 complex of the SEP was reduced during and after pain, but MEP amplitudes were suppressed only after pain had resolved. CONCLUSIONS: Our data show that pain reduces sensory processing before motor output is altered. This temporal dispersion, coupled with the lack of correlation between pain induced changes in S1 and M1 excitability, imply either that independent processes are involved, or that reduced excitability of S1 during acute experimental muscle pain mediates latent reductions in motor output via processes that are non-linear and potentially involve activation of a wider brain network. PMID- 23357118 TI - Impaired structural hippocampal plasticity is associated with emotional and memory deficits in the olfactory bulbectomized rat. AB - Disturbances in olfactory circuitry have been associated with depression in humans. The olfactory bulbectomized (OBX lesion) has been largely used as a model of depression-like behavior in the rat. However, quantitative neuronal rearrangements in key brain regions in this animal model have not been evaluated yet. Accordingly, we investigated changes in hippocampal plasticity as well as behavioral deficits in this animal model. OBX-induced behavioral deficits were studied in a battery of tests, namely the open field test (OFT), forced swim test (FST), and spatial memory disturbances in the Morris water maze (MWM). To characterize the neuronal remodeling, neuroanatomical rearrangements were investigated in the CA1 hippocampus and piriform cortex (PirC), brain regions receiving inputs from the olfactory bulbs and associated with emotional or olfactory processes. Additionally, cell proliferation and survival of newborn cells in the adult dentate gyrus (DG) of the hippocampus were also determined. OBX induced hyperlocomotion and enhanced rearing and grooming in the OFT, increased immobility in the FST as well as required a longer time to find the hidden platform in the MWM. OBX also induced dendritic atrophy in the hippocampus and PirC. In addition, cell proliferation was decreased while the survival remained unchanged in the DG of these animals. These various features are also observed in depressed subjects, adding further support to the validity and usefulness of this model to evaluate potential novel antidepressants. PMID- 23357119 TI - Quercetin up-regulates mitochondrial complex-I activity to protect against programmed cell death in rotenone model of Parkinson's disease in rats. AB - We tested quercetin, a dietary bioflavonoid with potent free radical scavenging action and antioxidant activity, for its neuroprotective effects in rotenone induced hemi-parkinsonian rats. Rats were infused unilaterally with rotenone into the substantia nigra, and quercetin (25-75mg/kg, i.p.) was administered at 12-h intervals for 4days, and analyzed on the 5th day. Amphetamine- or apomorphine induced unilateral rotations were significantly reduced in quercetin-treated rats, when analyzed on 14th or 16th day post-surgery, respectively. Quercetin possessed potent hydroxyl radical scavenging action in a cells-free, Fenton-like reaction in test tubes, and in isolated mitochondria when measured by salicylate hydroxylation method. We observed dose-dependent attenuation of the rotenone induced loss in striatal dopamine, and nigral oxidized and reduced glutathione, as well as the increases in endogenous antioxidant enzymes (catalase and superoxide dismutase) activities supporting the notion that quercetin-effect is mediated via its powerful hydroxyl radicals-scavenging and antioxidant actions. Quercetin's dose-dependent ability to up-regulate mitochondrial complex-I activity, as evidenced by NADH-oxidation, and as seen in blue native polyacrylamide gel electrophoresis (PAGE) staining in both the contra- and ipsi lateral nigra suggests the containment of reactive oxygen production at the mitochondrial level. Rotenone-induced induction of NADH-diaphorase activity in the nigral neurons, and its attenuation by quercetin pointed to the possible involvement of nitric oxide too. Reversal of neuronal death induced by rotenone as observed by increased tyrosine hydroxylase-positive cells and decreased TdT mediated dUTP nick end-labeling (TUNEL) staining in the substantia nigra confirmed the potential of quercetin to revamp dopaminergic cells following oxidative stress mediated programmed cell death and neuronal demise. The present study strongly implicates quercetin's potential ability to repair mitochondrial electron transport defects and to up-regulate its function as the basis of neuroprotection observed in a mitochondrial neurotoxin-induced Parkinsonism. PMID- 23357120 TI - Phase sensitivity of complex cells in primary visual cortex. AB - Neurons in the primary visual cortex are often classified as either simple or complex based on the linearity (or otherwise) of their response to spatial luminance contrast. In practice, classification is typically based on Fourier analysis of a cell's response to an optimal drifting sine-wave grating. Simple cells are generally considered to be linear and produce responses modulated at the fundamental frequency of the stimulus grating. In contrast, complex cells exhibit significant nonlinearities that reduce the response at the fundamental frequency. Cells can therefore be easily and objectively classified based on the relative modulation of their responses - the ratio of the phase-sensitive response at the fundamental frequency of the stimulus (F1) to the phase-invariant sustained response (F0). Cells are classified as simple if F1/F0>1 and complex if F1/F0<1. This classification is broadly consistent with criteria based on the spatial organisation of cells' receptive fields and is accordingly presumed to reflect disparate functional roles of simple and complex cells in coding visual information. However, Fourier analysis of spiking responses is sensitive to the number of spikes available - F1/F0 increases as the number of spikes is reduced, even for phase-invariant complex cells. Moreover, many complex cells encountered in the laboratory exhibit some phase sensitivity, evident as modulation of their responses at the fundamental frequency. There currently exists no objective quantitative means of assessing the significance or otherwise of these modulations. Here we derive a statistical basis for objectively assessing whether the modulation of neuronal responses is reliable, thereby adding a level of statistical certainty to measures of phase sensitivity. We apply our statistical analysis to neuronal responses to moving sine-wave gratings recorded from 367 cells in cat primary visual cortex. We find that approximately 60% of complex cells exhibit statistically significant (alpha<0.01) modulation of their responses to optimal moving gratings. These complex cells are phase sensitive and reliably encode spatial phase. PMID- 23357122 TI - Visual depth perception in normal and deprived rats: effects of environmental enrichment. AB - A proper maturation of stereoscopic functions requires binocular visual experience and early disruption of sensory-driven activity can result in long term or even permanent visual function impairment. Amblyopia is one paradigmatic case of visual system disorder, with early conditions of functional imbalance between the two eyes leading to severe deficits of visual acuity and depth perception abilities. In parallel to the reduction of neural plasticity levels, the brain potential for functional recovery declines with age. Recent evidence has challenged this traditional view and experimental paradigms enhancing experience-dependent plasticity in the adult brain have been described. Here, we show that environmental enrichment (EE), a condition of increased cognitive and sensory-motor stimulation, restores experience-dependent plasticity of stereoscopic perception in response to sensory deprivation well after the end of the critical period and reinstates depth-perception abilities of adult amblyopic animals in the range of normal values. Our results encourage efforts in the clinical application of paradigms based on EE as an intervention strategy for treating amblyopia in adulthood. PMID- 23357121 TI - HCN4 subunit expression in fast-spiking interneurons of the rat spinal cord and hippocampus. AB - Hyperpolarisation-activated (Ih) currents are considered important for dendritic integration, synaptic transmission, setting membrane potential and rhythmic action potential (AP) discharge in neurons of the central nervous system. Hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels underlie these currents and are composed of homo- and hetero-tetramers of HCN channel subunits (HCN1-4), which confer distinct biophysical properties on the channel. Despite understanding the structure-function relationships of HCN channels with different subunit stoichiometry, our knowledge of their expression in defined neuronal populations remains limited. Recently, we have shown that HCN subunit expression is a feature of a specific population of dorsal horn interneurons that exhibit high-frequency AP discharge. Here we expand on this observation and use neuroanatomical markers to first identify well-characterised neuronal populations in the lumbar spinal cord and hippocampus and subsequently determine whether HCN4 expression correlates with high-frequency AP discharge in these populations. In the spinal cord, HCN4 is expressed in several putative inhibitory interneuron populations including parvalbumin (PV)-expressing islet cells (84.1%; SD: +/ 2.87), in addition to all putative Renshaw cells and Ia inhibitory interneurons. Similarly, virtually all PV-expressing cells in the hippocampal CA1 subfield (93.5%; +/-3.40) and the dentate gyrus (90.9%; +/-6.38) also express HCN4. This HCN4 expression profile in inhibitory interneurons mirrors both the prevalence of Ih sub-threshold currents and high-frequency AP discharge. Our findings indicate that HCN4 subunits are expressed in several populations of spinal and hippocampal interneurons, which are known to express both Ih sub-threshold currents and exhibit high-frequency AP discharge. As HCN channel function plays a critical role in pain perception, learning and memory, and sleep as well as the pathogenesis of several neurological diseases, these findings provide important insights into the identity and neurochemical status of cells that could underlie such conditions. PMID- 23357123 TI - Phylogeny of the land snail family Clausiliidae (Gastropoda: Pulmonata). AB - Clausiliidae is one of the most speciose and best-studied families of land snails. The family contributes to land snail diversity on a global scale, with three main centres of diversity: (1) western Eurasia (six subfamilies recognized), (2) East Asia (two subfamilies recognized) and (3) the neotropics (one subfamily recognized i.e. Neniinae). Despite a wealth of shell-morphological and anatomical studies, a well-supported phylogeny is lacking for the family. To provide a phylogenetic framework and reevaluate morphological and biogeographic observations on the family, we compiled a dataset consisting of partial 28S rRNA, histone H3 and histone H4 nucleotide sequences covering all clausiliid subfamilies, and 23 out of 25 tribes. Our analyses (MrBayes, BEAST, PhyML) divide the family into seven highly supported clades, which were retrieved by at least two of the three markers used, and which are more or less geographically confined. Three of these clades coincide with subfamilies recognized in the current classification (Alopiinae, Garnieriinae, Laminiferinae). The monophyly of four of the remaining six hitherto accepted subfamilies is not supported, with the New World subfamily Neniinae divided across two clades. All shell morphological characters used in classical clausiliid classification were homoplasious at the subfamily level, with the exception of the type of shell aperture formation. In contrast to previous interpretations, our results suggest that the so-called 'apostrophic' aperture found in the neotropical clausiliids, and in a European (Laminiferinae) and a SE Asian (Garnieriinae) subfamily, is in fact the plesiomorphic condition among extant Clausiliidae. The widespread and fragmented geographic distribution of this type of aperture may therefore be considered relictual. Based on an inferred Late Cretaceous or Early Cenozoic European origin of the clade of extant Clausiliidae, the ancestor(s) of the neotropical Clausiliidae must have colonized the New World after the Atlantic Ocean had opened. A taxonomic revision is proposed. PMID- 23357124 TI - A simple, reliable M'Fadyean stain for visualizing the Bacillus anthracis capsule. AB - The simple polychrome methylene blue (PMB) staining procedure for blood or tissue smears from dead animals (M'Fadyean reaction) established in 1903 remained accepted as a highly reliable, rapid diagnostic test for anthrax for six decades while that disease was still common in livestock throughout the world. Improvements in disease control led to anthrax becoming rare in industrialized countries and less frequent in developing countries with the result that quality controlled, commercially produced PMB became hard to obtain by the 1980s. Mixed results with alternative methylene blue-based stains then led to diagnosis failures, confusion among practitioners and mistrust of this procedure as a reliable test for anthrax. We now report that, for laboratories needing a reliable M'Fadyean stain at short notice, the best approach is to have available commercially pure azure B ready to constitute into a solution of 0.03 g azure B in 3 ml of 95% ethanol or methanol to which is then added 10 ml of 0.01% KOH (0.23% final azure B concentration) and which can then be used immediately and through to the end of the tests. Stored in the dark at room temperature, the shelf life is at least 12 months. Smears should be fixed with ethanol or methanol (95-100%), not by heat, and the stain left for 5 min before washing off for optimum effect. PMID- 23357125 TI - Factor mixture analysis of DSM-IV symptoms of major depression in a treatment seeking clinical population. AB - BACKGROUND: There is a paucity of empirical studies examining the latent structure of depression symptoms within clinical populations. OBJECTIVE: The current study aimed to evaluate the latent structure of DSM-IV major depression utilising dimensional, categorical, and hybrid models of dimensional and categorical latent variables in a large treatment-seeking population. METHODS: Latent class models, latent factor models, and factor mixture models were fit to data from 1165 patients currently undergoing online treatment for depression. RESULTS: Model fit statistics indicated that a two-factor model fit the data the best when compared to a one-factor model, latent class models, and factor mixture models. CONCLUSIONS: The current study suggests that the structure of depression consists of two underlying dimensions of depression severity when compared to categorical or a mixture of both categorical and dimensional structures. For clinical samples, the two latent factors represent psychological and somatic symptoms. PMID- 23357126 TI - Cognitive and psychosocial functioning in bipolar disorder with and without psychosis during early remission from an acute mood episode: a comparative longitudinal study. AB - BACKGROUND: The current investigation aimed to extend previous findings, which linked psychosis in bipolar disorder (BD) to cognitive impairment during hospital discharge and readmission, by examining the recovery of patients with psychosis who were not re-hospitalized. The study compared mood, cognitive and functional outcomes in patients who had, versus had not, experienced psychosis during a recent psychiatric hospitalization. The hypothesis was that patients admitted to the hospital with psychosis would exhibit more residual symptoms, greater cognitive deficits, and lower psychosocial functioning than patients who presented to care without psychosis. Group differences were expected to emerge both at the time of hospital discharge and at a 3-month follow up. METHOD: Fifty five participants (ages 18-59, 25 women, 20 with psychosis) with BD I disorder completed both assessments, which included a clinical and diagnostic interview, functional evaluation, and the administration of mood measures and a neuropsychological battery. RESULTS: The groups were comparable with respect to illness history (e.g., number of previous hospitalizations, age of onset, employment). At discharge and follow-up, the group with psychosis exhibited more mood symptoms, obtained lower GAF scores, and performed more poorly on measures of memory and executive functioning. At follow-up, participants with psychosis exhibited poorer psychosocial adaptation. LIMITATIONS: It is possible that some of the observed group differences in cognitive functioning emerged due to differences in medication efficacy or side effects. CONCLUSION: The results of this study support the hypothesis that psychosis in BD predicts limited recovery during early remission from mood disturbance, regardless of illness history. PMID- 23357127 TI - [Humanity and human DNA]. PMID- 23357129 TI - Coronary artery disease and ventricular tachyarrhythmia: pathophysiology and treatment. AB - Ventricular tachyarrhythmias are common consequences of coronary artery disease. During the prehospital phase of acute myocardial infarction (MI), ischemia induced electrophysiological changes and genetic factors are responsible for their occurrence, but the precise pathophysiologic mechanisms are ill-understood. Primary percutaneous coronary interventions (PCIs) have decreased the incidence of ventricular tachyarrhythmias during subsequent stages, and future treatments ameliorating reperfusion injury may provide further progress. In the chronic phase, antiarrhythmic drug therapy targeted toward arrhythmogenic substrate has relatively limited value, but alternative approaches are still uncertain. By contrast, prompt arrhythmia termination by implantable cardioverter defibrillators (ICDs) is highly effective, although risk-stratification algorithms in candidate patients are inadequate. This review explores current views in the pathophysiology and treatment of ventricular tachyarrhythmias at different clinical stages. PMID- 23357128 TI - Inflammation and atherosclerosis: direct versus indirect mechanisms. AB - It is now widely accepted that the development of atherosclerotic lesions involves a chronic inflammatory response that includes both innate and adaptive immune mechanisms. However, it is still unclear precisely what induces the inflammatory response. Furthermore, inflammation within the blood vessel can be divided into direct mechanisms where the primary inflammatory events occur within the intima of the blood vessel and contribute to both the initiation and progression of the plaques and indirect mechanisms where inflammation at nonvascular sites can contribute to the progression of the lesions. The direct mechanisms include lipid deposition and modification, influx of lipoprotein associated factors and microparticles derived from many different cell types, and possibly bacterial and viral infection of vascular cells. Indirect mechanisms derive from inflammation related to autoimmune diseases, smoking, respiratory infection, and pollution exposure, and possibly periodontal disease and gastric infection. The mechanisms include secretion of cytokines and other inflammatory factors into the circulation with subsequent uptake into the plaques, egress and recruitment of activated inflammatory cells, formation of dysfunctional HDL and crossreactive autoantibodies. PMID- 23357130 TI - Mandibular cortical shape index in non-standardised panoramic radiographs for identifying patients with osteoporosis as defined by the German Osteology Organization. AB - The aim of this prospective controlled study was to determine the validity of the mandibular cortical shape index (CI) on panoramic radiographs in distinguishing patients with osteoporosis as defined by the German Osteology Organization (Dachverbands der Deutschsprachigen Osteologischen Fachgesellschaften, DVO). The study group contained 50 patients (33 female, 17 male, mean age: 74.9 years), who had a high risk of osteoporosis. 50 young patients (33 female, 17 male, mean age: 37.9 years) with no anamnestic evidence of osteoporosis served as control. Three blinded observers evaluated panoramic views of the study and the control group in a mixed manner regarding the mandibular cortical shape index. The study group underwent bone mineral density measurement using dual energy X-ray absorptiometry and received a diagnosis according to the Organization's guidelines (normal, osteopenia, osteoporosis). The CI showed a high sensitivity of 72.2% and a high specificity of 93.9% with a highly significant predictive value (Chi-square = 22.96, p < 0.001), while the observer's agreement was moderate (kappa = 0.47). We concluded that patients with a cortical shape index of the category assessed as "severe" on non-standardised panoramic radiographs have a higher risk of suffering systemic osteoporosis. The CI in panoramic radiographs is a good screening tool, which could be implemented in the routine assessment of panoramic radiographs in elder patients. PMID- 23357131 TI - Lower eyelid suspension using polypropylene suture for the correction of punctal ectropion. AB - OBJECTIVE: To evaluate the efficacy and complications of lower eyelid suspension with the modified Safdarjung hospital technique using 5:0 polypropylene suture for punctal ectropion. STUDY DESIGN: Prospective case series. METHOD: Thirty one eyelids in 19 patients with mild and moderate ectropion and all types of laxity including involutional and paralytic were included. All patients underwent lower eyelid suspension with the modified Safdarjung hospital technique. A 5:0 polypropylene suture was passed in the pre-tarsal plane between the attachments of the lateral and medial canthal tendons near their insertion at the orbital rim. Successful outcome was judged by the anatomical restoration of the apposition of the punctum to the globe in the upward gaze and the physiological relief of epiphora. The recurrence of lid laxity, overall lid/globe apposition and complications were also noted. RESULTS: At 1 year follow up anatomical success was achieved in 28 (90%) patients and functional success noted in 27 (87%) patients. Recurrence of lid laxity was noted in 2 patients. There was a suture exposure in one case and a suture granuloma in another case. The results did not correlate to the degree of ectropion and type of laxity. CONCLUSION: Lower eyelid suspension using 5:0 polypropylene suture is a useful procedure for the treatment of involutional and paralytic punctal ectropion. It is simple and effective with minimal complications. However, the effect on scleral show and the concern related to suture material biodegradation over years needs to be further evaluated. PMID- 23357132 TI - Chondrosarcoma of the mandibular condyle in a patient with Werner syndrome: a case report. AB - Werner syndrome, also called progeria of the adult and pangeria is a rare autosomal recessive disorder that affects connective tissue throughout the body. It is associated with premature ageing and an increased risk of cancer and other diseases. The mean survival for patients with Werner syndrome is 47 years. Death usually occurs when patients are aged 30-65 years because of atherosclerosis or malignant tumours. The purpose of this paper is to present a patient with Werner syndrome exhibiting a chondrosarcoma of the left temporomandibular joint and ramus. To the best of our knowledge this is the first case, of a Werner syndrome patient with an associated head and neck chondrosarcoma being reported. The diagnostic procedure followed and management of the patient are outlined in the paper as well. PMID- 23357133 TI - Hyperlipoproteinemia(a): clinical significance and treatment options. AB - Recent epidemiologic and Mendelian randomization studies together have provided evidence that lipoprotein(a) (Lp(a)) plays a causal role in the pathogenesis of atherosclerosis and cardiovascular disease (CVD). The risk association with CVD is weak but seems continuous in shape and without an obvious threshold for Lp(a) levels. A plasma concentration of 60 mg/dl compared to usual levels is associated with an odds ratio for coronary heart disease of about 1.5 after adjustment for other cardiovascular risk factors. Niacin (nicotinic acid) is the pharmacologic means of choice for decreasing elevated Lp(a) levels but the drug is often poorly tolerated due to adverse reactions. Dietary measures, exercise and other lipid lowering drugs, especially statins, fibrates and ezetimibe, are without effect. In patients with severe progressive cardiovascular disease and very high Lp(a) levels, lipoprotein apheresis may be used to effectively decrease Lp(a) concentrations. The method is expensive and impractical for most patients and its feasibility depends by and large on the healthcare reimbursement system of the respective country. No established treatment, however, selectively reduces Lp(a) without influencing other lipoproteins. Moreover, despite the clear association of hyperlipoproteinemia(a) with cardiovascular risk, no rigorously designed study to date has demonstrated that lowering Lp(a) concentrations has beneficial effects on cardiovascular endpoints. Randomized trials to this effect are urgently needed. PMID- 23357134 TI - Nicotinic acid as a lipid-modifying drug--a review. AB - Nicotinic acid has complex effects on lipoprotein metabolism; it increases HDL cholesterol, decreases triglycerides and LDL cholesterol. It also reduces lipoprotein(a) levels by about 25% and exerts certain effects that may be antiatherogenic. Studies performed in the pre-statin era demonstrated a good effectiveness of nicotinic acid on the development of atherosclerotic lesions and on the morbidity and mortality due to cardiovascular diseases. Because of its HDL cholesterol raising properties, nicotinic acid appears to be an ideal companion to statins since low HDL cholesterol concentration has been shown to negatively influence statin-treated patients even when ideal LDL cholesterol concentrations have been reached. In the AIM-HIGH study nicotinic acid did not lead to an improvement in the cardiovascular event rate compared to placebo; however this study has been criticized because of several drawbacks. The results of a large study testing the effect of nicotinic acid in high-risk statin-treated patients are expected to be published in 2013. At present, nicotinic acid can be administered in addition to a statin to patients with a combined hyperlipidemia when the target value of LDL cholesterol has not been reached, and alone to patients suffering from a statin intolerance. An elevation of lipoprotein(a) is not officially recognized as an indication to start a therapy with nicotinic acid. The combination of modified-release nicotinic acid with laropiprant is much better tolerated than previous formulations. New drugs which act on the receptor involved in the action of nicotinic acid are in development. PMID- 23357135 TI - Current standards in diagnosis and therapy of hyperlipoproteinemia. AB - Raised lipid parameters, especially increased LDL-cholesterol and lipoprotein(a) (Lp(a)) levels, are severe risk factors for atherosclerosis. Targets in the therapy of hyperlipoproteinemia are dependent on other risk factors including diabetes mellitus and manifest cardiovascular disease. Fasting levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides are measured for diagnosis of this disease. Lp(a) should be evaluated in instances of positive family history for cardiovascular disease and/or severe progress of cardiovascular disease or premature cardiovascular events. The basis of therapy includes diet measures as well as weight reduction and lifestyle modifications (raised physical activity after excluding contraindications). Numerous patients require lipid-lowering drug therapy, including most importantly statins but also bile acid sequestrants, ezetimibe, fibrates, nicotinic acid or omega-3-fatty acids. Special forms of hyperlipoproteinemia such as chylomicronemia syndrome and raised Lp(a) are described herein. PMID- 23357136 TI - Lipoprotein apheresis: state of the art and novelties. AB - Lipoprotein apheresis (LA) is an extracorporeal technique which permits the unselective or specific removal of lipoproteins, namely Low Density Lipoproteins (LDL), as well as other apolipoprotein B100-containing lipoproteins from plasma. LA represents a selective upgrade (with both clinical and metabolic advantages) from conventional forms of extracorporeal therapy such as plasma-exchange (PEX) which was used in the seventies to treat severe hypercholesterolemia. The primary reason for using is the treatment of homo-, double- (or compound) and heterozygous familial hypercholesterolemia (Hoz-, DHtz,- Htz,-FH). This technique has also been shown to be efficacious in the treatment of other severe forms of hyperlipoproteinemia such as: hyperLp(a)lipoproteinemia, the familial combined hyperlipoproteinemia and other varieties associated with an elevated cardiovascular risk (CVR) when used in patients who are poor- or non-responders to pharmacological treatment following specific guidelines for the reduction of cholesterol in plasma. Patients with these severe forms of dyslipidemia and, particularly, those affected by FH are subject to coronary ischemic events and thus require an intensive, efficacious, continuous, and personalized form of therapy. A therapy based solely on current available drugs does not achieve the desired results in the Hoz- and DHtz forms of FH or in approximately 10-20% of the Htz form. For the aforementioned clinical conditions, LA treatment offers a necessary therapeutic approach. LA can also be applied in the prevention of secondary recurrence of coronary ischemic events and of arterial stenosis which appears, rather frequently after vascular surgery (coronary by-pass, percutaneous transluminal angioplasty). Clinical trials have shown that statins provide a major reduction in cardiovascular morbidity and mortality, but often fail to attain desirable LDL-cholesterol target level in Hoz- and DHtz- (Compound) FH high cardiovascular risk patients. Intolerance to statins is also relatively frequent in Htz-FH and non-FH patients. LA has effectively replaced pharmacological cholesterol-lowering therapy for decades. Young high CVR risk patients survived to adulthood thanks only to LA. More recently, promising novel compounds aimed at other molecular targets are being studied for the treatment of severe dyslipidemia: Lomitapide, Mipomersen, PCSK9 inhibitors and HDL-enhancers. It is expected that these potent new agents will be combined with LA in the treatment of the most severe forms of hyperlipidemia. PMID- 23357137 TI - Lipoprotein apheresis--more than just cholesterol reduction? AB - Lipoprotein apheresis is a well-established extracorporeal treatment in modality of severe hyperlipoproteinemia. Besides the reduction of LDL cholesterol and modifications to physiology of lipoprotein and lipid metabolism, Lipoprotein apheresis may have crucial effects on many other atherogenic factors as vascular inflammation, rheology and gene expressions in blood cells. These different effects of lipoprotein apheresis treatments are reviewed with respect to oxidative stress in plasma, red and white blood cells and in consequence to progression of atherosclerosis. However, in consideration of these reviewed aspects as a factor of biocompatibility lipoprotein apheresis remains safe. PMID- 23357138 TI - Therapeutic apheresis in transplantation medicine, experience with cardiac and lung transplantation in Jena. AB - Immunological problems like preformed donor specific antibodies (DSA) or high degree of immunization complicate the transplantation (TX) and can limit the therapeutic success. Essential pillars of antihumoral therapy are the extracorporeal procedures like therapeutic plasma exchange (TPE) and high plasma volume immunoadsorption (IA). Both extracorporeal treatments have the ability to remove pre-existing or newly formed antibodies quickly and effectively. In the last 5 years a total of 27 patients, 12 heart transplant (HTX) patients, 3 patients after combined lung and heart transplantation (Lu/HTX) and 12 lung transplant (LuTX) patients were treated for prevention (6 patients) or in case of rejection (20 patients) with TPE, cascade filtration (CF) or IA. 6 HTX recipients and 5 LuTX recipients were tested positive for HLA-ab either donor specific or de novo HLA-ab. Altogether 7 patients were tested positive for non-HLA-ab. 6 patients were treated prior to TX with 1-3 TPEs. After TX we treated 24 patients initially with TPE and performed on average 4 TPEs (1-11) for antibody elimination. 22 of 27 treated patients survived with stable graft function. The extracorporeal procedures we performed are qualified for rescue therapy of antibody mediated rejection (AMR). PMID- 23357139 TI - Differences in the atherogenic risk of patients treated by lipoprotein apheresis according to their lipid pattern. AB - In high-risk patients who are already on a maximal lipid-lowering therapy, a lipoprotein apheresis is an important therapeutic option in preventing further progress of vascular complications as it may decrease both LDL-cholesterol (LDL C) and lipoprotein(a) (Lp(a)) levels. We looked at the occurrence of cardiovascular events before apheresis and during apheresis in three groups defined by their lipid patterns at the start of an apheresis treatment: Group 1 (LDL-C >= 3.4 mmol/l and Lp(a) <= 600 mg/l; n = 35), Group 2 (LDL-C <= 3.4 mmol/l and Lp(a) >= 600 mg/l n = 37) and Group 3 (LDL-C >= 3.4 mmol/l and Lp(a) >= 600 mg/l; n = 15). Group 2 shows a time period of about 10 years from the first event until the start of apheresis treatment (compared to 2-6 years in the other two groups). Before the start of apheresis treatment 2.1 events per patient had occurred in Group 1, 3.4 events per patient in Group 2 and 1.8 events per patient in Group 3. Under apheresis therapy just 0.9 events per patient occurred in Group 1, 0.5 in Group 2 and 0.5 in Group 3. When comparing the two years before the start of apheresis treatment with the first two years under apheresis we saw the following reduction rates of cardiovascular events: Group 1-54%; Group 2-83%; Group 3-83.5%. Our results show that the reduction of cardiovascular events due to lipoprotein apheresis is especially high in patients with elevated levels of Lp(a) compared to patients with elevated LDL-C only indicating that physicians should be more focused on the risk factor elevated Lp(a). PMID- 23357140 TI - Factors inducing cardiovascular events in patients treated by lipoprotein apheresis. AB - Lipoprotein apheresis is indicated in patients at high risk for cardiovascular disease due to severe hyperlipoproteinemia, which is not adequately controlled by diet and medication. This extracorporeal therapy reduces the event rate, although it does not completely abolish new events. We compared atherogenic risk factors in patients who were treated in 2009 and 2010 with lipoprotein apheresis and who suffered events (n 20) with patients who did not (n 44). Among the 45 cardiovascular events that occurred four were strokes, one was myocardial infarction, and two were bypass operations (one coronary and one peripheral). The following risk factors were found to be associated with events: male gender, coexisting diabetes/glucose intolerance and elevation of Lp(a) concentrations. In addition, the history of previous cardiovascular events, the efficiency of the lipoprotein apheresis therapy as judged by the reduction rates of LDL-C and of Lp(a), and the duration of the extracorporeal treatment (patients with events had started treatment with lipoprotein apheresis more recently) may play a role. We did not observe any influence of family history, of the underlying lipid disorder or lipid levels, of arterial hypertension or of smoking habits. Evidently, apheresis therapy of longer duration (more than two years) stabilizes the cardiovascular situation of the patients. Patients on apheresis therapy should be regularly assessed with respect to their risk factor and vascular situation. Lipoprotein apheresis therapy is important for the reduction of cardiovascular events, but optimization of additional modifiable risk factors should also be undertaken. PMID- 23357141 TI - Current situation of lipoprotein apheresis in Saxony. AB - This paper summarizes the situation pertinent to treatment via lipoprotein apheresis in the federal state of Saxony, Germany in 2010. In total, 119 predominately male patients were treated in 10 centers; the majority of the patients was older than the mean age of the general population. Several risk factors were present, particularly a familial predisposition and hypertension. All patients had experienced cardiovascular events and the majority was taking statins. Patient data from the University Hospital Carl Gustav Carus in Dresden concurred with data derived from patients treated at nephrological practices. In the mean, patients attended the centers for about 6 years, the majority weekly. LDL cholesterol concentrations prior to apheresis were clearly higher than target levels; apheresis sessions decreased LDL cholesterol by 69%. Lipoprotein(a) levels could be measured in 75 patients and were effectively reduced by lipoprotein apheresis. In Saxony, 29 patients per 1 million inhabitants received lipoprotein apheresis, which is higher than the proportion of patients treated in Germany as a whole. The need for this extracorporeal treatment seems to be much greater than its current utilization. Among the patients only one homozygous patient with familial hypercholesterolemia was observed. Physicians should be actively informed about this therapeutic possibility to reduce the cardiovascular risk efficiently. The introduction of new drugs may alter the position of lipoprotein apheresis within the therapeutic spectrum. PMID- 23357142 TI - Lipoprotein apheresis standard for apheresis competence centers--an updated synthesis and amendment to pre-existing standards. AB - With several techniques of selective apheresis treatment, some of which have been established for over 30 years, severe and pharmacologically unmanageable dyslipidemia can be treated successfully. The long-term lowering of LDL cholesterol and lipoprotein(a) by 60-80 percent, together with pleiotropic effects, allow for significant risk reduction in otherwise progressive chronic atherosclerotic disease, i.e. chronic coronary artery disease in most apheresis patients, and improvement of quality of life. For various reasons, worldwide only an estimated 2500 patients, among them 1400 to 1500 in Germany, are regularly treated by apheresis. This relatively small number of apheresis patients in Germany is being cared for in more than 200 centers, by more than 750 physicians approved for extracorporeal treatment, resulting in unraveling of expertise and diversity of treatment strategies instead of the needed concentration. Here we present a comprehensive standard for competence centers in apheresis treatment, which is an updated synthesis and amendment to previously published standards, based on the experience from more than 30,000 apheresis treatments in our own center. The presented standard provides a guideline for apheresis treatments, comprising all procedures, indications, detailing the application procedure, as well as suggestions for supportive care in extracorporeal therapy. In the absence of large studies of sufficient quality, this standard represents our "good clinical practice" and refers the "best available evidence", providing the indispensable basis for working in an apheresis center. The apheresis standard also aims to contribute to quality assurance, another intention is to increase the acceptance of this valuable treatment, with a view to admitting more patients in need to apheresis programs, on the basis of reliable cost reimbursement. PMID- 23357143 TI - The evidence-base for the efficacy of lipoprotein apheresis in combating cardiovascular disease. AB - OBJECTIVE: To review the evidence supporting the use of lipoprotein apheresis to treat severe forms of dyslipidaemia that predispose to cardiovascular disease and are refractory to conventional therapy. METHODS: Review of relevant publications based on personal knowledge and a search of the literature from the past 10 years using PubMed. RESULTS: There is good evidence that drastic lowering of LDL by lipoprotein apheresis increases longevity in homozygous familial hypercholesterolaemia (FH) and decreases cardiovascular morbidity in FH heterozygotes refractory to or intolerant of statins. Lipoprotein apheresis may also decrease cardiovascular events in patients with raised levels of Lp(a) but further data are needed. CONCLUSIONS: Lipoprotein apheresis currently provides a therapeutic life-line for a small number of very high risk patients. It remains to be seen what effect the recent emergence of several novel and powerful lipid lowering drugs will have on its future role in that respect. PMID- 23357144 TI - How will new medications affect the lipoprotein apheresis situation in Germany? AB - Regular lipid apheresis is a treatment modality for patients with severe drug resistant LDL-hypercholesterolemia or lipoprotein(a) elevation and premature atherosclerosis. A number of new approaches is currently being developed which can significantly decrease LDL-cholesterol levels alone or in combination with statins. If proven to be safe, these drugs may significantly reduce the necessity for regular lipid apheresis since more patients will achieve LDL-cholesterol treatment targets by drug therapy alone. PMID- 23357145 TI - A three month-old infant with severe hyperchylomicronemia: molecular diagnosis and extracorporeal treatment. AB - OBJECTIVE: Chylomicronemia syndrome presenting in childhood is a rare recessive disorder due to mutations of lipoprotein lipase (LPL) and more rarely of APOC2, APOA5, GPIHBP1 or LMF1 genes. It often requires urgent and suitable treatment to avoid acute pancreatitis. The aim of this study was the molecular characterization and treatment of a 3 month-old infant with plasma triglycerides (TG) > 300 mmol/L. METHODS: All candidate genes were sequenced. The patient was submitted to one plasma-exchange (PEX) procedure and subsequently to a rigid lipid-lowering diet (milk: Monogen((r))). RESULTS: The proband was homozygous for a novel LPL mutation (c.242G > A, p.G81D) which in silico results pathogenic. After PEX, which was well tolerated, TG dropped to 64 mmol/L. During 5-month follow-up there was a clear trend towards lower and stable TG values. CONCLUSION: PEX is applicable in subjects with very low body weight when the extreme severity of the clinical picture has no therapeutic alternatives. PMID- 23357146 TI - The decrease of mean platelet volume after extracorporeal LDL-cholesterol elimination. AB - OBJECTIVE: Mean platelet volume is arousing increasing interest as a new independent cardiovascular risk factor. Large platelets are likely to be more reactive. If mean platelet volume would drop after LDL-lowering therapy, decreased MPV could be one of the markers of successful therapy. Therefore, we investigated mean platelet volume after extracorporeal LDL-cholesterol elimination. METHODS: Mean platelet volume was investigated in patients with severe familial hypercholesterolemia long-term treated (3-12 years) by LDL apheresis (immunoapheresis) or cascade filtration. Plasma was obtained by centrifugation. Adsorbers Lipopak 400 were used for immunoapheresis and filters Evaflux 4A were used for cascade filtration. 95 pair samples were measured (before and after the procedures) in a group of 12 patients--each patient 8 times in 4 years. RESULTS: Mean platelet volume before the procedures was 10.891 fl, CI 10.25-11.53. Mean platelet volume after the procedures decreased--10.478 fl, CI 09.84-11.11. The difference is statistically significant (p = 0.036). Mean platelet volume did not correlate with age, sex, platelet count, duration of therapy. At the same time, we used rheohemapheresis in the therapy of 40 patients with age-related macular degeneration. But mean platelet volume was not changed. CONCLUSION: Mean platelet volume is easily available and is often disregarded, and sometimes may suggest the need for a careful assessment in patients with familial hypercholesterolemia. Mean platelet volume could be one of the markers of therapeutic efficacy in patients with familial hypercholesterolemia treated by extracorporeal LDL-cholesterol elimination that is simple and inexpensive. PMID- 23357147 TI - Acute and chronic effects of therapeutic apheresis. AB - In most patients only a few sessions of apheresis treatment are necessary to see the benefit. This is the case of immunological diseases when the production of a pathologic component is limited in time or in microcirculation disturbances when changes of vascular function may occur. In the first instance the acute effect is likely due to the removal of the corresponding antibody, while in the second case the improvement of the endothelium-dependent vasodilation and the reduction of blood viscosity play a major role. In long-term treatment, as in the case of patients affected by familial hypercholesterolemia, the chronic effects of apheresis may lead to the repair of morphological alterations in the vascular wall. We report the recovery from ulcers in two hemodialysis patients suffering from peripheral arterial disease as the result of twenty-two sessions of rheopheresis. The reasons that justify these chronic actions may involve pleiotropic effects that are different according to the apheresis technique used. PMID- 23357148 TI - How to optimize lipoprotein apheresis treatment--a second look. AB - BACKGROUND: Lipoprotein apheresis (LA) is used in hypercholesterolemic patients suffering from cardiovascular disease (CHD) if a modified diet and lipid-lowering drug regimens had failed. During the first LA treatments LDL-cholesterol (LDL-C) and lipoprotein (a) (Lp(a)) can be decreased very effectively when using generally accepted formulas for calculating plasma (PV) (e.g. Pearson) or blood volumes (BV) as a basis for calculating treatment volume (e.g. Nadler). With respect to LDL-C and Lp(a) levels after LA treatment not all treated patients on steady state with apheresis treatment procedures may achieve the desired target concentrations for LDL-C (<70 mg/dl) and Lp(a) (<30 mg/dl). Are there further ways to increase the effectiveness of LA? METHODS: Over months or years of LA the treated volumes were stepwise increased in patients to achieve target cholesterol concentrations but not sufficiently in all cases. Therefore the patients' actual LA treatment volumes were compared to the calculated PV or BV. To possibly optimize the treatment capacity of LA procedures independent of calculated PV or BV the capacity threshold was determined in addition. During LA procedures every 20 min cholesterol, triglycerides, LDL-C, HDL-C and Lp(a) concentrations were determined and related to the hematocrit to exclude dilution effects. RESULTS: In patients undergoing regular LA treated volumes vs. calculated volumes were different: for PV 28 +/- 18% (n = 7); for BV 28 +/- 20% (n = 6). The mean treated volumes were 1.3 fold larger than the calculated volumes to achieve cholesterol target levels in most LA treatments. With respect to the capacity threshold we observed in only 1 of 13 patients an ineffective long treatment time. No LA procedure failed due to exhausted capacity. CONCLUSIONS: Lipoprotein apheresis treatment is a very effective treatment procedure in lowering LDL-C and Lp(a). However, not in all procedures the optimal treatment volume for LA patients may be calculated. However calculations of PV and BV are more or less error-prone. An increase of 1.3 fold in the calculated volumes may be the first step in optimizing individual LA treatment options. In addition, to exclude an exhaustion of LA procedures the determination of the individual capacity threshold in every LA patient may be further helpful to adjust treatment volumes. To substantiate our demand on changed treatment volumes further data are necessary. PMID- 23357149 TI - Effect of specific lipoprotein(a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography. AB - AIM: To evaluate the effect of specific lipoprotein(a) [Lp(a)] apheresis on coronary atherosclerosis progression in coronary heart disease (CHD) patients with elevated Lp(a) levels. METHODS: A total of 30 subjects (mean age 53.5 +/- 8.3 years, 70% male) with CHD verified by angiography, Lp(a) > 50 mg/dL, and low density lipoprotein cholesterol (LDL-C) <= 2.5 mmol/L on chronic statin treatment were prospectively evaluated for 18 months. Patients were allocated to receive specific Lp(a) apheresis, which was carried out weekly with Lp(a) Lipopak((r)) columns (POCARD Ltd., Russia) (n = 15), or atorvastatin only (n = 15). Blinded quantitative coronary angiography analyses of percent diameter stenosis and minimal lumen diameter (MLD) were performed at baseline and after the 18-month treatment period. RESULTS: By the single specific Lp(a) apheresis procedure, Lp(a) level decreased by an average of 73 +/- 12% to a mean of 29 +/- 16 mg/dL, and mean Lp(a)-corrected LDL-C decreased by 7% to a mean of 1.4 mmol/L. Median percent diameter stenosis was reduced by -2.0 (95% confidence interval [CI], -5.0 0.0) with apheresis (p < 0.01 in comparison with baseline), and increased by 3.5 (0.0-6.9) with atorvastatin (p < 0.001 between the groups). The effect on MLD was more favorable with apheresis than with atorvastatin: 0.20 +/- 0.39 mm, as compared with 0.01 +/- 0.34 mm, p = 0.04. Lp(a) apheresis had greater efficacy regarding the amount of regressed/stabilized coronary segments than atorvastatin alone in the majority of patients (chi-square test 13.61, p < 0.005). CONCLUSION: Specific Lp(a) apheresis for 18 months produced coronary atherosclerosis regression in stable CHD patients with high Lp(a) levels and reached LDL-C goals. PMID- 23357150 TI - Cascade plasma filtration during the first year after CABG in patients with hyperlipidemia refractory to statins. AB - OBJECTIVE: To evaluate the effect of a 12-month course of weekly lipid apheresis on vein graft patency after coronary artery bypass grafting (CABG) in patients with hyperlipidemia refractory to statins. METHODS: In a 12-month prospective controlled clinical trial we enrolled 34 male patients (mean age 57 +/- 8 years) who passed through successful CABG and low-density lipoprotein cholesterol (LDL C) level >2.6 mmol/L prior to the operation despite statin treatment. Patients were allocated into 2 groups: active (n = 17, weekly apheresis by cascade plasma filtration (CPF) plus atorvastatin), and control (n = 17, atorvastatin alone). Graft patency was evaluated by multislice computed tomography at 3 months and by angiography at 12 months after an operation. RESULTS: Both groups were comparable in clinical and biochemical characteristics. During each CPF procedure, LDL-C level decreased by 64 +/- 9%, apoB - by 65 +/- 8%, Lp(a) - by 52 +/- 15%,; these changes were significant compared to baseline and the control group. Mean net difference in LDL-C level between apheresis and control groups was 1.1 +/- 0.3 mmol/L. Vein graft patency at study end was 88.2% (45 of 51) in the apheresis group versus 72.7% (40 of 55) in the control group (p = 0.05). Use of apheresis was associated with decreased vein graft occlusions by 46%: relative risk 0.54; 95% confidence interval 0.27 to 1.02; p = 0.05. CONCLUSION: Our data suggest that the use of lipoprotein apheresis with CPF results in a better vein graft patency during the first year after CABG in patients with hyperlipidemia refractory to statins. PMID- 23357151 TI - Lipoprotein apheresis of hypercholesterolemic patients mediates vasoprotective gene expression in human endothelial cells. AB - OBJECTIVE: Hypercholesterolemia is an important risk factor of cardiovascular diseases. Lipoprotein apheresis is an efficient strategy to reduce the serum low density lipoprotein (LDL)-cholesterol and lipoprotein(a) levels and cardiovascular complications in patients with severe hypercholesterolemia. The underlying molecular mechanisms are not well-understood. In this study, we analyzed the impact of lipoprotein apheresis on gene expression in human endothelial cells. METHODS: Human endothelial cells were stimulated with serum of hypercholesterolemic patients before and after lipoprotein apheresis. The expression of endothelial lipoprotein receptors, nitric oxide (NO) synthase and adhesion molecules was quantified by real-time PCR and Western blot. RESULTS: Lipoprotein apheresis reduced the expression of the lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) in endothelial cells. Low-density lipoprotein (LDL) receptor expression remained unchanged. The mRNA expression of the endothelial nitric oxide synthase (eNOS) was increased with serum of hypercholesterolemic patients after lipoprotein apheresis. In contrast, endothelial expression of vascular cell adhesion molecule 1 (VCAM-1) was reduced in response to serum after lipoprotein apheresis. CONCLUSION: Lipoprotein apheresis reduced the expression of the proatherosclerotic oxLDL receptor LOX-1 and adhesion molecule VCAM-1 and increased the expression of vasoprotective and NO generating eNOS in human endothelial cells in response to serum of hypercholesterolemic patients. These novel molecular mechanisms may account for the antiatherosclerotic and vasoprotective potential of lipoprotein apheresis in patients with hypercholesterolemia. PMID- 23357153 TI - Homocysteine in lipoprotein apheresis patients--retrospective data analysis in apheresis center of a university hospital. AB - INTRODUCTION: There is an obvious contrast between the data from the epidemiological studies on hyperhomocysteinemia and the negative results of the homocysteine-lowering clinical trials. Moderate hyperhomocysteinemia might only be relevant in certain subgroups of subjects. The current study was focused on lipoprotein apheresis patients; the study goals were to determine the prevalence of hyperhomocysteinemia, to identify the association between homocysteine levels and cardiovascular events and to test the effects of lipoprotein apheresis and of the conventional homocysteine-lowering therapy. MATERIALS AND METHODS: Sixty patients from our Lipoprotein Apheresis Center (37 males, 23 females, age 63.1 +/ 10.8 years) were included in the study. All patients' records were reviewed with respect to age, sex, BMI, dyslipidemias, arterial hypertension, diabetes mellitus and incidence of vascular events in coronaries, carotids and lower extremities. Homocysteine was measured before and immediately after the apheresis procedure. We also observed the effects of conventional homocysteine-lowering therapy. RESULTS: The prevalence of hyperhomocysteinemia was 50%. Homocysteine levels correlated positively with number of cardiovascular events (p < 0.03) and serum creatinine (p < 0.0001) and negatively with serum HDL-cholesterol (p < 0.03). Neither oral nor intravenous medication with vitamin B and folic acid showed a significant homocysteine lowering effect. The median relative change value of homocysteine after apheresis session was -12% but was not statistically significant. CONCLUSIONS: The prevalence of hyperhomocysteinemia in lipoprotein apheresis patients is high. Neither apheresis nor more conventional methods appear to markedly influence homocysteine serum levels. PMID- 23357152 TI - Iron deficiency and its management in patients undergoing lipoprotein apheresis. Comparison of two parenteral iron formulations. AB - OBJECTIVES: There is evidence of iron deficiency (ID) in patients treated with lipoprotein apheresis. Aim of this study was to assess ID in apheresis patients and to study its management comparing safety and efficacy of two approved intravenous (i.v.) iron formulations. METHODS: Inclusion criteria were defined as a) serum ferritin < 300 MUg/l and transferrin saturation < 20%, b) ferritin < 100 MUg/l. Both iron deficient alone and ID anemic (IDA) patients were included. Other causes for anemia were ruled out by thorough history-taking and examination/blood tests. Patients were treated with six different lipoprotein apheresis methods: DALI, Liposorber D, TheraSorb LDL, HELP, MONET and Lipidfiltration. 50 patients were randomized to either ferric carboxymaltose (FCM, 500-1000 mg as single shot infusion over 20 min) or ferric gluconate (FG, 62.5 mg once weekly). RESULTS: 50 of 67 patients of our Lipoprotein Apheresis Center showed iron deficiency. Both i.v. iron formulations studied were equally safe (no serious adverse events (SAEs), 6 patients/group showed adverse events (AEs)) and both effective (clinically and with respect to laboratory data) in lipoprotein apheresis patients, however FCM led to a more rapid and steeper rise of iron parameters. CONCLUSIONS: ID and IDA are common findings in lipoprotein apheresis patients. The pathogenesis remains yet poorly understood and is probably multifactorial. Differential diagnosis of ID/IDA is as essential as differential therapy. Handled with care, older i.v. iron preparations like FG appear to be safe and effective in lipoprotein apheresis patients. However, novel formulations like FCM can be administered rapidly at higher doses due to high complex stability, allowing faster filling of iron stores. Newer laboratory parameters (Reticulocyte-He, low/medium/high fluorescence reticulocytes (LFR/MFR/HFR)) assessing iron status may be helpful in early detection of ID and in monitoring iron replacement therapy. PMID- 23357154 TI - Lipoprotein apheresis reduces adipocyte fatty acid-binding protein serum levels. AB - BACKGROUND AND METHODS: Adipocyte fatty acid-binding protein (FABP4) is a member of the intracellular lipid-binding protein family highly expressed in adipocytes and macrophages. Recent studies indicate a key role for circulating FABP4 in the pathogenesis of atherosclerosis and type 2 diabetes. We described an additional role for FABP4 in the development of cardiac dysfunction in obesity. Therefore, FABP4 seems to be a target in the prevention and treatment of metabolic and cardiovascular disorders in obesity with high potential for future therapeutic applications. However, a safe pharmacological therapy is not yet available. Lipoprotein apheresis is an established therapy for severe and otherwise untreatable hypercholesterolemia which increases life expectancy in patients at high-risk for cardiovascular events. We therefore investigated the acute effect of lipoprotein apheresis on FABP4 serum levels in 64 high-risk patients (25 women, 39 men) under regular apheresis treatment. RESULTS: FABP4 levels were significantly reduced by 23.2 +/- 1.8% by apheresis treatment. Although women had higher FABP4 levels than men (53.5 +/- 8.3 ng/ml vs. 30.7 +/- 4.3 ng/ml), reduction rate after lipoprotein apheresis was similar in both genders. Among the apheresis methods investigated, immunoadsorption of lipoproteins was most effective in lowering circulating FABP4. CONCLUSION: These data suggest that the reduction of FABP4 serum levels may contribute to the preventive effect of lipoprotein apheresis on cardiovascular events. PMID- 23357155 TI - Regular lipoprotein apheresis maintains residual cardiovascular and microvascular function in patients with advanced atherosclerotic disease. AB - OBJECTIVE: To determine whether previously demonstrated beneficial short-term effects on cardiovascular function in regular users of lipoprotein apheresis would be sustainable over time. METHODS: Regular users of lipoprotein apheresis (n = 17) were studied between February 2009 and July 2010. All patients were examined for endothelial and autonomic function at baseline and at one year of regular treatment. Microvascular function was determined by flicker-induced vasodilation of retinal vessels using the Dynamic Vessel Analyzer. Autonomic regulation of blood pressure and heart rate upon cardiovascular perturbation by deep breathing at 0.1 Hz and orthostatic challenge was evaluated by trigonometric regressive spectral analysis. RESULTS: The acute improvement of cardiovagal function and venular endothelial function seen after a single lipoprotein apheresis was not evident at one year of regular treatment. However, baroreflex sensitivity showed an improved recovery after orthostatic challenge as compared to baseline measurements. Initially compromised autonomic and microvascular function had not further deteriorated at one year of regular lipoprotein apheresis treatment. CONCLUSION: In patients with advanced atherosclerotic disease regular lipoprotein apheresis treatment maintains residual cardiovascular functioning over time. PMID- 23357156 TI - Metabolomic distinction of microvascular effects of lipoprotein apheresis--a pilot study. AB - OBJECTIVE: The study of small-molecule metabolites may assist in cardiovascular risk monitoring during therapy. We assessed whether acute changes in the metabolome by lipoprotein apheresis are able to predict changes in microvascular function. METHODS: We performed mass-spectrometry-based profiling of 186 metabolites in peripheral plasma of 21 hyperlipidemic patients before and after a single session of lipoprotein apheresis. To evaluate the capability of metabolites to predict microvascular outcome after apheresis, patients were stratified according to improvement and deterioration of retinal endothelial function. Endothelial function was assessed as the relative change in retinal vessel diameter in response to flicker light stimulation. RESULTS: We observed pronounced but not uniform changes in the metabolome after a single session of lipoprotein apheresis. Improvements in microvascular function were associated with a decline in lysophosphatidylcholines C14:0, C16:0, C16:1, C18:0, C18:1, C18:2, C20:4, C28:0, C28:1; in the amino acid serine and the dicarboxyacylcarnitine C12-DC. A positive relationship was found for methionine and ornithine. Applying decision tree and receiver-operator characteristic curve analysis, a change in serine of smaller than 11% by lipoprotein apheresis predicted an improvement of microvascular function with high sensitivity. CONCLUSION: Lipoprotein apheresis elicits changes in the metabolome favoring an anti-atherosclerotic environment. Monitoring the serine profile may assist in risk management of patients undergoing regular lipoprotein apheresis. PMID- 23357157 TI - Differential effects of lipoprotein apheresis by lipidfiltration or dextran sulfate adsorption on lipidomic profile. AB - OBJECTIVE AND METHODS: Acute modification of plasma lipidomic profile was assessed by top-down shotgun profiling on a LTQ Orbitrap hybrid mass spectrometer in 14 patients treated with two different apheresis techniques: plasma lipidfiltration (LF) and whole blood dextran sulfate adsorption (DSA). RESULTS: Patients treated with DSA revealed a significantly more pronounced reduction of LDL-cholesterol (LDL-C), a diminished decrease of HDL-cholesterol (HDL-C) and triglycerides (TG), and a similar reduction in lipoprotein (a) (Lp(a)) level. Against the overall tendency of reduction of lipid metabolites of all lipid classes in post-apheresis plasma, independent of apheresis technology applied, a highly significant increase of phosphatidylethanolamines (PE) in response to DSA was observed. CONCLUSION: These data indicate that DSA technology may be associated with an activation or damage of blood cells at contact surface which subsequently leads to a massive liberation of cellular and membrane PE's. Pathophysiological consequences, especially with respect to coagulation system and oxidative stress, have to be further elucidated. PMID- 23357158 TI - Single whole blood dextran sulfate adsorption favorably affects systemic oxidative balance in lipoprotein apheresis patients. AB - OBJECTIVE AND METHODS: The acute changes of circulating oxidative stress parameters were compared in 16 patients undergoing two different apheresis techniques: plasma lipidfiltration (LF) or whole blood dextran sulfate adsorption (DSA). RESULTS: Immediately after apheresis LF was associated with an increase in systemic phagocyte count, enhanced formation of reactive oxygen species and decreased activity of the antioxidant enzyme paraoxonase. After DSA, circulating phagocyte oxidant generating activity was significantly lower. Compared to LF, the systemic level of oxidized LDL and antioxLDL antibodies showed a larger decrease in DSA. All measured oxidative stress parameters returned to nearly pre apheresis level at day three after apheresis, CONCLUSION: The data show a more pronounced leukocyte activation immediately after LF in contrast to DSA, possibly as a consequence of necessity of prior separation of blood plasma. The pathophysiological importance of the short-term oxidative burden after a single apheresis session remains to be determined. PMID- 23357159 TI - Neurologic diseases of the central nervous system with pathophysiologically relevant autoantibodies--perspectives for immunoadsorption. AB - Immediate antibody elimination, pulsed induction of antibody redistribution, and immunomodulation are major forces of efficacy of therapeutic apheresis (i.e. plasma exchange [PE] or immunoadsorption [IA]) for autoimmune neurologic disorders. Therapeutic apheresis can offer rapid response for severe acute neurologic symptoms, and stable rehabilitation in long-term clinical courses being refractory to drug based strategies or complicated by drug side effects. PE or IA in these situations must be considered as part of multimodal or escalating immune treatment strategies in combination or in competition with intravenously administered immunoglobulins (ivIg), corticosteroids, the full spectrum of immunosuppressive drugs, and bioengineered antibodies. Selective IA is increasingly replacing PE due to its superior safety profile and increasing knowledge on pathogenic relevance of autoantibodies. Recent experiences in autoimmune diseases of the central nervous system, e.g. multiple sclerosis, neuromyelitis optica, and autoimmune encephalitis confirmed this concept. PMID- 23357160 TI - Immunoadsorption in steroid-refractory multiple sclerosis: clinical experience in 60 patients. AB - BACKGROUND: Multiple sclerosis (MS) is the most common autoimmune inflammatory demyelinating disease of the central nervous system with a frequently relapsing or progressive course. For steroid-resistant relapse, plasma exchange (PE) has been established as guidelines-recommended treatment option. While PE is a non selective extracorporeal blood purification process with elimination of plasma and subsequent substitution, immunoadsorption (IA) is a selective technique for the removal of autoantibodies and immune complexes with less adverse effects. So far there are only few reports on the treatment of MS by IA. The aim of this retrospective study was to assess the efficacy and safety of IA as an escalation therapy in MS patients. PATIENTS AND METHODS: A total of 60 patients with steroid refractory MS relapse were treated by IA and analyzed retrospectively. Patients received six standardized IA sessions using a non-regenerable tryptophan immunoadsorber, at average 58 days after first indications of relapse. The treated plasma volume was two liters per IA session. Outcome was measured as improvement in relapse symptoms. From the pilot phase of the study comprising the first fourteen patients, detailed neurological examinations before and after IA such as Expanded Disability Status Scale (EDSS), Functional System Score (FS) and visual acuity are reported. Of the following 46 patients, only qualitative data regarding the therapeutic success, and in addition clinical data on tolerability, are presently available. RESULTS: In 53 of 60 patients clinically relevant improvement of the main symptom of MS relapse was noted after IA, there was no change in six patients, deterioration in one. This corresponds to a response rate of 88%. Symptomatic improvement was first registered on average after the third IA. 87.5% of patients could be treated through a peripheral venous access. Only 12.5% needed a central venous catheter. In four of 396 single treatments (1%) significant complications occurred, mild side effects or discomfort were registered 16 times (4%). If peripheral venous access was chosen, missed puncture or puncture hematoma occurred in 22 cases (5.5%). CONCLUSION: Immunoadsorption for the treatment of steroid-refractory MS relapse is safe and effective. The response rate was 88% and non-inferior to previous results with plasma exchange. Due to good tolerability, the treatment with immunoadsorption, which is usually possible through a peripheral venous access, can be performed on an outpatient basis. PMID- 23357161 TI - Immunoadsorption in steroid-refractory multiple sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disorder, with involvement of both the humoral and cellular components of the immune system. The use of plasma exchange (PE) in steroid-refractory relapses has become an integral part of national and international guidelines for the treatment of steroid-resistant relapses of MS with an efficacy of 40-70%. So far, 6 studies of immunoadsorption (IA) treatment in different forms of MS have been published, 4 of them in steroid-refractory MS relapses. These 4 studies revealed a significant clinical improvement in 73-85% of patients with steroid-refractory MS relapses. However in MS patients with non active relapsing-remitting or secondary progressive course, there was no clinical improvement. Despite the limited number of patients and studies, these data suggest a reasonably similar efficacy of IA in the treatment of steroid refractory MS relapses compared to PE. More prospective trials are needed to confirm and extend these results. PMID- 23357162 TI - Rheohaemapheresis in the treatment of nonvascular age-related macular degeneration. AB - PURPOSE: To evaluate the experience with rheohaemapheresis (RH) in the treatment of age-related macular degeneration (AMD). METHODS: Thirty-eight patients were each treated with 8 procedures of RH (14 males, 24 females). The control group consisted of 34 random patients (30 females, 4 males) with the dry form of AMD but not treated by RH. Our modification of the cascade method (named rheohaemapheresis) was used for plasma separation. After plasma separation (blood cell separator, Cobe Spectra, Denver, CO, USA), the separated plasma was pumped through a rheofilter (Evaflux 4A, Kuraray, Osaka, Japan) to remove lipoproteins and other high-molecular-weight rheologic factors. RESULTS: In treated patients, best-corrected visual acuity (BCVA) increased significantly from 0.61 (0.06-1.00) to 0.68 (0.35-1.00) after 2.5 years (p = 0.035). We found no significant changes or differences in scotopic activity, whereas cone response and paramacular activity in the more peripheral region between 14 degrees and 22 degrees of eccentricity were significantly higher in treated patients after 2.5 years. CONCLUSION: RH therapy favourably influenced BCVA. During 2.5 years after the therapy, no progression of dry to wet AMD was observed in our patients. RH reduced the area of drusenoid retinal pigment epithelium detachment (which increased during the natural course of dry form AMD). RH influenced rheological markers and probably improved metabolism in the affected retinal areas which lead to the aforementioned positive results. PMID- 23357163 TI - Immunoadsorption for connective tissue disease. AB - Distinct connective tissue diseases (CTD's) such as systemic lupus erythematosus (SLE), systemic sclerosis, mixed connective tissue disease as well as dermato- and polymyositis comprise a group of diseases, where autoantibodies are not merely indicators of autoimmune disease, but also play an relevant role in the underlying pathogenicity. This knowledge led to the development of antibody targeting therapies using rituximab or belimumab. Upon this, therapeutic plasma exchange, and more recently immunoadsorption (IAS) have been successfully applied to remove pathogenic autoantibodies under various conditions in some of these CTD's. While the technique of IAS is superior to plasma exchange in regard to specificity and efficacy, the clinical use of IAS in CTD's is currently restricted to a small proportion of clinical situations with either refractory disease or the necessity to avoid aggressive immunosuppressive regimens. Despite the presence of a large number of case series and few controlled trials using IAS, there is a need for further prospective randomized trials to clearly define the role of IAS in these CTD's. PMID- 23357164 TI - Detection of antibodies in eluates of immunoadsorption causing humoural rejection in patients after solid organ transplantation. AB - The influence of antibodies (AB) against human leukocyte antigen (HLA) on antibody mediated rejection (AMR) is still discussed controversially. Here we demonstrate to what extent post transplant detected HLA-AB and non-HLA-AB against Angiotensin II type 1 receptor (AT1 R-AB), endothelin-1 type A receptor (ETA R AB) and glycoprotein (GP) IIb/IIIa, Ia/IIa, Ib/IX affect the graft outcome. A total of 13 transplant recipients (9 kidneys and 4 hearts) suffering from AMR were analysed. Before immunoadsorption (IA) treatment HLA-AB (CDC) in sera were detected in 27% versus 39% in eluates and 46% versus 87% by using ELISA. We could not find any AB against GP in sera. In eluates, however, we could detect AB against GP: GP IIb/IIIa in 86% of all samples with titres from 1:1 to 1:32, GP Ib/IX (up to 1:32) in 76% and GP Ia/IIa with titres from 1:1 to 1:16 in 82%. Further we detected anti-endothelial cell antibodies (AECA) against receptors AT1 and ETA in sera before IA in 22%, after IA in 10% and in eluates in 42% of all samples. The antibody titres vary from 1:1 to 1:256. Our investigation pointed out, that AMR is still possible without detectable AB in serum and consolidates the hypothesis that clinical relevant non-HLA-AB and HLA-AB are partly fixed on the graft. IA is qualified to detach these fixed AB. PMID- 23357165 TI - Living donor kidney transplantation in patients with donor-specific HLA antibodies enabled by anti-CD20 therapy and peritransplant apheresis. AB - OBJECTIVE: Due to increasing waiting times for deceased donor kidneys, living donor kidney transplantation is increasingly performed in the presence of donor specific antibodies (DSA). METHODS: Twenty-three patients with Luminex-detected DSA were successfully desensitized by anti-CD20 therapy and immunoadsorption (N = 19) or plasmapheresis (N = 4) and received a kidney transplant from a living donor. Twelve of the 23 patients (52%) had a positive CDC and/or ELISA crossmatch result before desensitization. Six patients were negative in CDC as well as ELISA screening but positive in Luminex for DSA. RESULTS: The 23 patients received a median of 8 apheresis treatments before and 5 treatments after transplantation. Induction therapy was performed with either thymoglobulin (N = 11) or basiliximab (N = 12). The 2-year graft survival rate was 100%. At last follow up, a median of 12 months after transplantation, median serum creatinine was 1.42 mg/dL, median MDRD-GFR 59.5 mL/min/1.73 m(2), and median urinary protein-to-creatinine ratio 0.12. Ten out of fourteen patients (71%) who had completed the first year after transplantation by the time of analysis had no DSA by day 360. Acute T-cell mediated rejection was diagnosed in one patient (4%), and antibody-mediated changes were found in 5 patients (22%). Four out of these 5 patients showed evidence of persistent (N = 2) or reemerging plus/minus de novo DSA (N = 2) on day 360, and the 2 patients with persistent DSA lost their allograft subsequently on days 750 and 810, respectively. Infectious complications were infrequent. CONCLUSIONS: Our previously described treatment algorithm for desensitization of living donor kidney transplant recipients with DSA results in good graft outcomes with a low rate of side effects. PMID- 23357166 TI - Immunoadsorption therapy for dilated cardiomyopathy and pulmonary arterial hypertension. AB - Dilated cardiomyopathy (DCM) which is a common cause of heart failure is often related to elevated levels of autoantibodies (AABs) against cardiac structural or functional proteins. Among several AABs which react against cardiac cellular proteins that have been detected in sera from DCM patients, those against beta(1) adreno-receptors (beta(1)-ARs) appeared particularly relevant from a pathophysiological point of view. During the last 15 years several studies evaluating the short-term efficacy of immunoadsorption (IA) in idiopathic DCM have shown improvement in cardiac function and patient outcome. However, the invasive and complicated aspects of the IA, which is also costly, have limited its broad clinical application as long as only its short-term efficacy has been definitely proved. Autoimmunity is also suspected to play a key role in the pathogenesis of pulmonary arterial hypertension (PAH). Recently we identified functional AABs against the alpha(1)-AR and/or the endothelin-A-receptor (ETA) in sera of patients with PAH. These AABs activate the receptors like corresponding agonists but, unlike the agonists, the AABs induce long-lasting stimulatory effects and do not desensitize the receptors. The AABs against the alpha(1)-AR and the ETA-receptor belong to IgG3 and IGg2 subclass, respectively, and can be removed by IA. The first 5 potential transplant candidates with idiopathic PAH who underwent IA showed good results after this therapy. This update aims to summarize the present knowledge about the role of AABs in the etiopathogenesis of DCM and PAH and the potential therapeutic benefits of AAB removal by IA. Special attention is focused on the therapeutic benefits of IA for patients with life threatening end-stage disease where all pharmacological therapeutic options are exhausted. PMID- 23357167 TI - Ig apheresis for the treatment of severe DCM patients. AB - BACKGROUND: Autoantibodies against beta1-adrenoreceptor (AR) are considered by many authors to be the most significant in autoimmune process during DCM. Immunoadsorption (IA) of immunoglobulins (Ig apheresis) is a logic approach to remove autoantibodies against beta1-AR and other antibodies. The effect of Ig apheresis and the role of anti-beta1-AR in DCM are still an issue for discussion. METHODS: We have performed a prospective case-control study in 16 patients with DCM, NYHA Class II-IV congestive heart failure, positive and negative for anti beta1-AR. RESULTS: We observed a clinically significant mean change of exercise tolerance compared with controls (6 MWT distance increased from 420 +/- 130 m to 550 +/- 150 m, p < 0.05). Systolic function improved rapidly by increase in LVEF from 28.6 +/- 5.2% to 33.0 +/- 10.3%, LV end-systolic and end-diastolic volumes decreased from 166 +/- 58 mL to 148 +/- 50 mL and from 235 +/- 73 mL to 220 +/- 73 mL, respectively, whereas in the control group there was no significant change in clinical variables. The improved quality of life and cardiac function in apheresis group as well as negative changes in control group didn't correlate with the presence of anti-beta1-AR. CONCLUSIONS: Ig apheresis for the treatment of DCM patients is associated with the improvement of quality of life and cardiac function regardless of the presence of anti-beta1-AR. We suggest that IgG apheresis is a safe and effective method for DCM patients. PMID- 23357168 TI - Immunoadsorption in patients with autoimmune ion channel disorders of the peripheral nervous system. AB - Autoimmune ion channel disorders of the peripheral nervous system include myasthenia gravis, the Lambert-Eaton myasthenic syndrome, acquired neuromyotonia and autoimmune autonomic ganglionopathies. These disorders are characterized by the common feature of being mediated by IgG autoantibodies against identified target antigens, i.e. the acetylcholine receptor, the voltage-gated calcium and potassium channels, and the neuronal acetylcholine receptor. Moreover, experimental animal models have been identified for these diseases that respond to immunotherapy and are improved by plasmapheresis. On this basis, autoimmune ion channel disorders represent the ideal candidate for therapeutic apheresis. Immunoadsorption can be the treatment of choice when intensive apheretic protocols or long-term treatments must be performed, in patients needing frequent apheresis to keep a stable clinical condition, in case of unresponsiveness to corticosteroids and immunosuppressive treatments, or failure with TPE or intravenous immunoglobulins, and in patients with severe contraindications to long-term corticosteroids. PMID- 23357169 TI - Long term outcome of patients with acquired haemophilia--a monocentre interim analysis of 82 patients. AB - BACKGROUND: Acquired haemophilia (AH) is a rare condition leading to life threatening bleedings with a mortality ranging between 7.9 and 22%. Due to the low incidence of AH, randomized studies are not available, but observational studies with a long term follow up are of high interest. METHODS: Our haemophilia centre has documented since 1994 the treatment of 82 patients with AH, suffering from severe and moderate AH. Patient's clinical data, treatment schedules and long term outcomes were analyzed. RESULTS: In 73% of patients the first manifestation of AH was a severe life threatening bleeding. These patients were successfully treated via a multimodal immunomodulating regime (Bonn Protocol) with an overall response rate of 93% after a median treatment time of 16 d (95% CI: 13-18.9 d). Solid cancer, lymphoma, surgery and an adjacent autoimmune disease were the main "associated conditions" of AH (AHSAC). In patients with less severe AH, conventional immunosuppressive treatment was successful in 11 patients after a median of 3.9 months (range 1-12), 5 patients failed and were treated successfully second line via the Bonn protocol. In both treatment groups no bleeding associated fatalities occurred. Four patients required an additional treatment of acute bleedings with bypassing agents leading to fatal thrombotic events. CONCLUSION: Our data show that an optimal treatment schedule in AH should be adapted to the patient's individual risk profile considering the severity of bleeding and comorbidities. Idiopathic AH predisposes to severe AH requiring a more intensive treatment compared to AHSAC. In the latter, the so called "bystander immunological phenomena" induced by the primary disorder might have an important impact on the inhibitor development. Therefore the differentiation between idiopathic AH and AHSAC should be considered for a treatment decision. PMID- 23357170 TI - Structural basis of signaling blockade by anti-IL-13 antibody Lebrikizumab. AB - The cytokine interleukin 13 (IL-13) is a major effector molecule for T-helper type 2 inflammation and is pathogenic in allergic diseases such as asthma. The effects of IL-13 are mediated via a pathway that is initiated by binding to a heterodimeric receptor consisting of IL-13Ralpha1 and IL-4Ralpha. Antibodies raised against IL-13 can block its inflammatory effects by interfering with binding to either of the two receptor polypeptides. Lebrikizumab is a monoclonal anti-IL-13 antibody that has shown clinical benefit in a phase II study for the treatment of moderate-to-severe uncontrolled asthma. Here we report the molecular structure of IL-13 in complex with the Fab from lebrikizumab by X-ray crystallography at 1.9A resolution. We show that lebrikizumab inhibits IL-13 signaling by binding to IL-13 with very high affinity and blocking IL-13 binding to IL-4Ralpha. In addition, we use site-directed mutations to identify the most important antibody contributors to binding. Our studies define key features of lebrikizumab binding and its mechanism of action that may contribute to its clinical effects. PMID- 23357171 TI - Novel interaction of the bacterial-Like DnaG primase with the MCM helicase in archaea. AB - DNA priming and unwinding activities are coupled within bacterial primosome complexes to initiate synthesis on the lagging strand during DNA replication. Archaeal organisms contain conserved primase genes homologous to both the bacterial DnaG and archaeo-eukaryotic primase families. The inclusion of multiple DNA primases within a whole domain of organisms complicates the assignment of the metabolic roles of each. In support of a functional bacterial-like DnaG primase participating in archaeal DNA replication, we have detected an interaction of Sulfolobus solfataricus DnaG (SsoDnaG) with the replicative S. solfataricus minichromosome maintenance (SsoMCM) helicase on DNA. The interaction site has been mapped to the N-terminal tier of SsoMCM analogous to bacterial primosome complexes. Mutagenesis within the metal binding site of SsoDnaG verifies a functional homology with bacterial DnaG that perturbs priming activity and DNA binding. The complex of SsoDnaG with SsoMCM stimulates the ATPase activity of SsoMCM but leaves the priming activity of SsoDnaG unchanged. Competition for binding DNA between SsoDnaG and SsoMCM can reduce the unwinding ability. Fluorescent gel shift experiments were used to quantify the binding of the ternary SsoMCM-DNA-SsoDnaG complex. This direct interaction of a bacterial-like primase with a eukaryotic-like helicase suggests that formation of a unique but homologous archaeal primosome complex is possible but may require other components to stimulate activities. Identification of this archaeal primosome complex broadly impacts evolutionary relationships of DNA replication. PMID- 23357172 TI - The energy and work of a ligand-gated ion channel. AB - Ligand-gated ion channels are allosteric membrane proteins that isomerize between C(losed) and O(pen) conformations. A difference in affinity for ligands in the two states influences the C<->O "gating" equilibrium constant. The energies associated with adult-type mouse neuromuscular nicotinic acetylcholine receptor (AChR) channel gating have been measured by using single-channel electrophysiology. Without ligands, the free energy, enthalpy and entropy of gating are DeltaG0=+8.4, DeltaH0=+10.9 and TDeltaS0=+2.5kcal/mol (-100mV, 23 degrees C). Many mutations throughout the protein change DeltaG0, including natural ones that cause disease. Agonists and most mutations change approximately independently the ground-state energy difference; thus, it is possible to forecast and engineer AChR responses simply by combining perturbations. The free energy of the low<->high affinity change for the neurotransmitter at each of two functionally equivalent binding sites is DeltaGB(ACh)=-5.1kcal/mol. DeltaGB(ACh) is set mainly by interactions of ACh with just three binding site aromatic groups. For a series of structurally related agonists, there is a correlation between the energies of low- and high-affinity binding, which implies that gating commences with the formation of the low-affinity complex. Brief, intermediate states in binding and gating have been detected. Several proposals for the nature of the gating transition-state energy landscape and the isomerization mechanism are discussed. PMID- 23357174 TI - Proteins and domains vary in their tolerance of non-synonymous single nucleotide polymorphisms (nsSNPs). AB - The widespread application of whole-genome sequencing is identifying numerous non synonymous single nucleotide polymorphisms (nsSNPs), many of which are associated with disease. We analyzed nsSNPs from Humsavar and the 1000 Genomes Project to investigate why some proteins and domains are more tolerant of mutations than others. We identified 311 proteins and 112 Pfam families, corresponding to 2910 domains, as diseasesusceptible and 32 proteins and 67 Pfam families (10,783 domains) as diseaseresistant based on the relative numbers of disease-associated and neutral polymorphisms. Proteins with no significant difference from expected numbers of disease and polymorphism nsSNPs are classified as other. This classification takes into account the phenotypes of all known mutations in the protein or domain rather than simply classifying based on the presence or absence of disease nsSNPs. Of the two hypotheses suggested, our results support the model that disease-resistant domains and proteins are more able to tolerate mutations rather than having more lethal mutations that are not observed. Disease-resistant proteins and domains show significantly higher mutation rates and lower sequence conservation than disease-susceptible proteins and domains. Disease-susceptible proteins are more likely to be encoded by essential genes, are more central in protein-protein interaction networks and are less likely to contain loss-of function mutations in healthy individuals. We use this classification for nsSNP phenotype prediction, predicting nsSNPs in disease-susceptible domains to be disease and those in disease-resistant domains to be polymorphism. In this way, we achieve higher accuracy than SIFT, a state-of-the-art algorithm. PMID- 23357175 TI - Molecular monitoring of antimalarial drug resistance among Plasmodium falciparum field isolates from Odisha, India. AB - In the absence of definite marker for artemisinin (ART) resistance, molecular monitoring of its partner drug sulfadoxine pyrimethamine (SP) in artemisinin based combination therapy (ACTs) together with chloroquine (CQ) for which ART is negatively correlated, may predict the effectiveness of ACT. We analyzed 201 Plasmodium falciparum field isolates for drug resistance markers for CQ (pfcrt and pfmdr1), pyrimethamine (pfdhfr) and sulfadoxine (pfdhps). Our study reveals high prevalence and non-random association of resistant mutants (K76T and N86Y) of CQ markers (pfcrt and pfmdr1). The predominance of highly resistant pfdhfr genotypes for SP with intragenic and intergenic pair-wise linkage disequilibrium between single nucleotide polymorphisms of resistant mutants of pfdhfr (C59R and S108N) and pfdhps (S436A, A437G, K540E) warn on further inclusion of SP in ACT. These findings suggest the replacement of SP in ACT with alternative partner drug for better efficacy. PMID- 23357173 TI - The tropomyosin binding region of cardiac troponin T modulates crossbridge recruitment dynamics in rat cardiac muscle fibers. AB - The cardiac muscle comprises dynamically interacting components that use allosteric/cooperative mechanisms to yield unique heart-specific properties. An essential protein in this allosteric/cooperative mechanism is cardiac muscle troponin T (cTnT), the central region (CR) and the T2 region of which differ significantly from those of fast skeletal muscle troponin T (fsTnT). To understand the biological significance of such sequence heterogeneity, we replaced the T1 or T2 domain of rat cTnT (RcT1 or RcT2) with its counterpart from rat fsTnT (RfsT1or RfsT2) to generate RfsT1-RcT2 and RcT1-RfsT2 recombinant proteins. In addition to contractile function measurements, dynamic features of RfsT1-RcT2- and RcT1-RfsT2-reconstituted rat cardiac muscle fibers were captured by fitting the recruitment-distortion model to the force response of small amplitude (0.5%) muscle length changes. RfsT1-RcT2 fibers showed a 40% decrease in tension and a 44% decrease in ATPase activity, but RcT1-RfsT2 fibers were unaffected. The magnitude of length-mediated increase in crossbridge (XB) recruitment (E0) decreased by ~33% and the speed of XB recruitment (b) increased by ~100% in RfsT1-RcT2 fibers. Our data suggest the following: (1) the CR of cTnT modulates XB recruitment dynamics; (2) the N-terminal end region of cTnT has a synergistic effect on the ability of the CR to modulate XB recruitment dynamics; (3) the T2 region is important for tuning the Ca(2+) regulation of cardiac thin filaments. The combined effects of CR-tropomyosin interactions and the modulating effect of the N-terminal end of cTnT on CR-tropomyosin interactions may lead to the emergence of a unique property that tunes contractile dynamics to heart rates. PMID- 23357176 TI - Behavioural alterations relevant to developmental brain disorders in mice with neonatally induced ventral hippocampal lesions. AB - Neonatal lesioning of the ventral hippocampus (vHc) in rats has served as a useful heuristic animal model to elucidate neurodevelopmental mechanisms of schizophrenia (SCZ). In the current study we have established that this procedure can be applied to model SCZ symptomatology in mice. Neonatal mice (postnatal day 6) were anaesthetised by hypothermia and electrolytic lesions of the vHc were induced. We observed locomotor hyperactivity at prepubertal and adult age and hypersensitivity to amphetamine. Furthermore, working memory deficits were observed in Y-maze (spontaneous alternation) and T-maze (exploration of a novel arm) test protocols. Decreased anxious behaviour in the elevated plus maze and increased sociability were also observed. These changes were dependent on lesion size. No differences were observed in prepulse inhibition of the startle reflex, latent inhibition, spatial memory (Morris water maze), problem solving capacities (syringe puzzle) and ability to discriminate between different unfamiliar mice. The presented findings might further help to identify neurobiological mechanisms of neurodevelopmental disorders. PMID- 23357177 TI - Long-term effects of selective immunolesions of cholinergic neurons of the nucleus basalis magnocellularis on the ascending cholinergic pathways in the rat: a model for Alzheimer's disease. AB - Alzheimer's disease is associated with a significant decrease in the cholinergic input to the neocortex. In a rat model of this depletion, we analyzed the subsequent long-term changes in cholinergic fiber density in two well-defined areas of the frontal and parietal cortices: Fr1, the primary motor cortex, and HL, the hindlimb area of the somatosensory (parietal) cortex, two cortical cholinergic fields that receive inputs from the nucleus basalis magnocellularis (nBM). A specific cholinergic lesion was induced by the intraparenchymal injection of 192 IgG-saporin into the nBM. Choline acetyltransferase (ChAT) immunohistochemistry was applied to identify the loss of cholinergic neurons in the nBM, while acetylcholinesterase (AChE) enzyme histochemistry was used to analyze the decreases in the number of cholinoceptive neurons in the nBM and the cholinergic fiber density in the Fr1 and HL cortical areas in response to the nBM lesion. The immunotoxin differentially affected the number of ChAT- and AChE positive neurons in the nBM. 192 IgG-saporin induced a massive, irreversible depletion of the ChAT-positive (cholinergic) neurons (to 11.7% of the control level), accompanied by a less dramatic, but similarly persistent loss of the AChE positive (cholinoceptive) neurons (to 59.2% of the control value) in the nBM within 2 weeks after the lesion. The difference seen in the depletion of ChAT- and AChE-positive neurons is due to the specificity of the immunotoxin to cholinergic neurons. The cholinergic fiber densities in cortical areas Fr1 and HL remained similarly decreased (to 62% and 68% of the control values, respectively) up to 20 weeks. No significant rebound in AChE activity occurred either in the nBM or in the cortices during the period investigated. This study therefore demonstrated that, similarly to the very extensive reduction in the number of ChAT-positive neurons in the nBM, cortical areas Fr1 and HL underwent long lasting reductions in the number of AChE-positive fibers in response to specific cholinergic lesioning of the nBM. PMID- 23357178 TI - Differential effects on mood of 12-15 (SMR) and 15-18 (beta1) Hz neurofeedback. AB - The common assumption in EEG-neurofeedback is one of functional specificity of the trained spectral bands, though it has been posited that only a nonspecific generalised learning process may be engaged. Earlier we reported differential effects on attention in healthy participants measured with continuous performance tests and the P300, following training of the sensory-motor rhythm band (SMR, 12 15 Hz) compared with the adjacent beta1 (15-18 hz) band. Here previously unreported results are presented with phenomenological data from an activation checklist in support of the putative calming effect of SMR neurofeedback. While within sessions both protocols induced tiredness, this was paralleled by an increase in calmness only following SMR training. The differential effect on mood was theoretically consistent and extends evidence of cognitive functional specificity with neurofeedback to affective processes. PMID- 23357179 TI - Preeclampsia-like symptoms induced in mice by fetoplacental expression of STOX1 are reversed by aspirin treatment. AB - Preeclampsia (PE) is a common human-specific pregnancy disorder defined by hypertension and proteinuria during gestation and responsible for maternal and fetal morbimortality. STOX1, encoding a transcription factor, was the first gene associated with PE as identified by positional cloning approaches. Its overexpression in choriocarcinoma cells mimics the transcriptional consequences of PE in the human placenta. Here, we created transgenic mouse strains overexpressing human STOX1. Wild-type female mice crossed with transgenic male mice reproduce accurately the symptoms of severe PE: gestational hypertension, proteinuria, and elevated plasma levels of soluble fms-like tyrosine kinase 1 and soluble endoglin. Placental and kidney histology were altered. Symptoms were prevented or alleviated by aspirin treatment. STOX1-overexpressing mice constitute a unique model for studying PE, allow testing therapeutic approaches, and assessing the long-term effects of the preeclamptic syndrome. PMID- 23357180 TI - STOX1: a new player in preeclampsia? PMID- 23357181 TI - Sympathetic nervous system and hypertension. PMID- 23357183 TI - Does fenofibrate lower blood pressure? PMID- 23357182 TI - The brain subfornical organ mediates leptin-induced increases in renal sympathetic activity but not its metabolic effects. AB - The adipocyte-derived hormone leptin acts within the central nervous system to decrease food intake and body weight and to increase renal and thermogenic brown adipose tissue sympathetic nerve activity (SNA). Previous studies have focused on hypothalamic brain regions, although recent findings have identified leptin receptors (ObR) in a distributed brain network, including the circumventricular subfornical organ (SFO), a forebrain region devoid of a blood-brain barrier. We tested the hypothesis that ObR in the SFO are functionally linked to leptin induced decreases in food intake and body weight and increases in SNA. SFO targeted microinjections of an adenovirus encoding Cre-recombinase in ObR(flox/flox) mice resulted in selective ablation of ObR in the SFO. Interestingly, deletion of ObR in the SFO did not influence the decreases in either food intake or body weight in response to daily systemic or cerebroventricular administration of leptin. In line with these findings, reduction in SFO ObR did not attenuate leptin-mediated increases in thermogenic brown adipose tissue SNA. In contrast, increases in renal SNA induced by systemic or cerebroventricular administration of leptin were abolished in mice with SFO targeted deletion of ObR. These results demonstrate that ObR in the SFO play an important role in leptin-induced renal sympathoexcitation, but not in the body weight, food intake, or brown adipose tissue SNA thermogenic effects of leptin. These findings highlight the concept of a distributed brain network of leptin action and illustrate that brain regions, including the SFO, can mediate distinct cardiovascular and metabolic responses to leptin. PMID- 23357184 TI - Association between long-term air pollution and increased blood pressure and hypertension in China. AB - Several studies have investigated the short-term effects of ambient air pollutants in the development of high blood pressure and hypertension. However, little information exists regarding the health effects of long-term exposure. To investigate the association between residential long-term exposure to air pollution and blood pressure and hypertension, we studied 24 845 Chinese adults in 11 districts of 3 northeastern cities from 2009 to 2010. Three-year average concentration of particles with an aerodynamic diameter <=10 um (PM(10)), sulfur dioxide (SO(2)), nitrogen dioxides (NO(2)), and ozone (O(3)) were calculated from monitoring stations in the 11 districts. We used generalized additive models and 2-level logistic regressions models to examine the health effects. The results showed that the odds ratio for hypertension increased by 1.12 (95% confidence interval [CI], 1.08-1.16) per 19 MUg/m(3) increase in PM(10), 1.11 (95% CI, 1.04 1.18) per 20 MUg/m(3) increase in SO(2), and 1.13 (95% CI, 1.06-1.20) per 22 MUg/m(3) increase in O(3). The estimated increases in mean systolic and diastolic blood pressure were 0.87 mm Hg (95% CI, 0.48-1.27) and 0.32 mm Hg (95% CI, 0.08 0.56) per 19 MUg/m(3) interquartile increase in PM(10), 0.80 mm Hg (95% CI, 0.46 1.14) and 0.31 mm Hg (95% CI, 0.10-0.51) per 20 MUg/m(3) interquartile increase in SO(2), and 0.73 mm Hg (95% CI, 0.35-1.11) and 0.37 mm Hg (95% CI, 0.14-0.61) per 22 MUg/m(3) interquartile increase in O(3). These associations were only statistically significant in men. In conclusion, long-term exposure to PM(10), SO(2), and O(3) was associated with increased arterial blood pressure and hypertension in the study population. PMID- 23357186 TI - A scalp disorder: dermatoscopy as a useful diagnostic tool. PMID- 23357185 TI - Distribution of early structural lung changes due to cystic fibrosis detected with chest computed tomography. AB - OBJECTIVE: To examine the distribution of early structural lung changes in clinically stable infants and young children with cystic fibrosis using chest computed tomography (CT). STUDY DESIGN: This cross-sectional study included 62 children aged 1-6 years with volume-controlled volumetric chest CT scans performed under general anesthesia as part of an early surveillance program. Each lobe was scored for presence and extent of bronchiectasis, mucus plugging, and air trapping using a semiquantitative score. The topographic distribution of structural abnormalities was evaluated by comparing the presence and extent of abnormalities in different lung regions and examining relationships between components. RESULTS: Although bronchiectasis was most common in the right upper lobe, overall changes in lung structure were not more common or more extensive in the upper lobes. Rather, bronchiectasis was more common in the right lung (right lung 0.95, left lung 0.68, P = .003), and mucus plugging (upper 0.41, middle 0.41, lower 0.72, P = .028) and air trapping (upper 0.79, middle 0.48, lower 0.96, P < .001) were more common in the lower lobes. The extents of bronchiectasis (P < .001) and air trapping (P = .011) were greater in the right lung. Scans with bronchiectasis were also more likely to have coexisting mucus plugging (P = .008) and air trapping (P < .001). CONCLUSION: Early structural lung disease is heterogeneously distributed in the lung. Quantitative scoring tools for studies using chest CT as an end point, and mechanistic studies that seek to better understand the pathogenesis of early cystic fibrosis lung disease, should take account of this differential topographic expression of disease early in life. PMID- 23357187 TI - Prevalence of severe obesity among New Zealand adolescents and associations with health risk behaviors and emotional well-being. AB - OBJECTIVE: To describe the prevalence of severe obesity among New Zealand young people attending secondary school and the associations of severe obesity with health risk behaviors and emotional well-being. STUDY DESIGN: A random sample of 9107 secondary school students in New Zealand participated in a 2007 health survey. Participants had their height and weight measured and answered an anonymous survey on multiple aspects of their health and well-being. RESULTS: Overall, 2.5% of students met the International Obesity Task Force definition of severe obesity. Students with severe obesity had more weight-related concerns, were more likely to have used unhealthy weight control strategies, and were more likely to experience bullying compared with healthy weight students. For example, students with severe obesity were 1.7 times more likely to have been bullied at school (95% CI 1.2-2.7) and 1.9 times more likely to vomit for weight loss (95% CI 1.1-3.3) than were healthy weight students. Indicators of emotional well-being and most health risk behaviors were similar among young people with severe obesity and a healthy weight. CONCLUSIONS: Clinicians who work with young people with severe obesity should prioritize discussing issues of bullying and healthy weight control strategies with families and their children. PMID- 23357188 TI - Reducing suffering in experimental autoimmune encephalomyelitis (EAE). AB - This report is based on discussions and submissions from an expert working group consisting of veterinarians, animal care staff and scientists with expert knowledge relevant to the field. It aims to facilitate the implementation of the Three Rs (replacement, reduction and refinement) in the use of animal models or procedures involving experimental autoimmune encephalomyelitis (EAE), an experimental model used in multiple sclerosis research. The emphasis is on refinement since this has the greatest potential for immediate implementation. Specific welfare issues are identified and discussed, and practical measures are proposed to reduce animal use and suffering. Some general issues for refinement are summarised to help achieve this, with more detail provided on a range of specific measures to reduce suffering. PMID- 23357189 TI - Susceptibility to ischemia-induced ventricular fibrillation in isolated female rat hearts varies moderately with estrous cycle stage. AB - INTRODUCTION: The vast majority of studies employing the isolated perfused rat heart model to study ischemic arrhythmias have used male rats only. The objective of this study was to determine the susceptibility to ischemia-induced ventricular fibrillation (VF) in isolated female rat hearts in each stage of the estrous cycle that corresponds with a different endogenous reproductive hormonal environment. METHODS: Hearts were isolated from female rats under pentobarbital anesthesia and perfused with modified Krebs solution containing 3mM K(+). Experiments were grouped according to estrous cycle stage that was determined by prior vaginal lavage (n=10-13 per group). A group of male rat hearts was used as the control. Regional ischemia was induced by coronary ligation and maintained for 30min. The incidence of VF was determined from the ECG. RESULTS: The incidence of VF in male hearts was 100%, while the incidence of VF in female hearts was also high but varied moderately with stage of the estrous cycle (diestrus 70%, metestrus 100%, proestrus 90%, estrus 69%; P>0.05). Compared to male hearts, the onset of VF was similar in all groups except for hearts excised from rats in proestrus, in which it was delayed. There was no difference between groups in an arrhythmia score, ischemic zone size, or baseline electrocardiographic or hemodynamic variables. DISCUSSION: In conclusion, the susceptibility of isolated female rat hearts to ischemic VF is comparable to that of male rat hearts, meaning that isolated female rat hearts can be used as controls in studies to assess antiarrhythmic drug efficacy. Since female rats can be used for isolated heart studies of ischemic VF, the need to cull female rats is reduced. However, the variation in VF susceptibility in female rat hearts that is associated with the different stages of the estrous cycle may affect statistical power that could potentially lead to Type II statistical errors. This problem can be prevented with careful randomization. PMID- 23357190 TI - Polyphasic chlorophyll a fluorescence kinetics and leaf protein analyses to track dynamics of photosynthetic performance in mulberry during progressive drought. AB - Modulation of photosynthesis and the underlying mechanisms were studied in mulberry (Morus indica L. genotype V1) under progressive drought stress conditions. Five months old potted mulberry plants were arranged in a semi controlled glasshouse chamber in completely randomized block design with four replications. On day 1 (D1), the plants were subjected to two watering treatments: well-watered (WW) and water-stressed (WS). In WS plants, watering was completely withheld for next 10days (D1-D10), whereas the WW plants were maintained at 100% pot water holding capacity. Photosynthetic performance was tracked periodically (from D0 to D10) through measurements of leaf gas exchange and chlorophyll a fluorescence (OJIP) transients and additionally leaf protein analyses were performed on D10. Down-regulation in net CO(2) fixation (P(n)) was primarily mediated through stomatal limitation which concurrently reduced transpiration rate (E), stomatal conductance (g(s)) and intercellular CO(2) concentration (C(i)). The OJIP transients and other associated biophysical parameters elucidated the events of photoacclimatory changes in photosystem II (PSII) with progressive increase in drought stress. Down-regulation of PSII activity occurred predominantly due to increase in inactive reaction centers (RCs), decrease in electron transport per RC (ET(O)/RC) as well as per leaf cross section (ET(O)/CS(m)) and enhanced energy dissipation. The L and K-bands appeared only in the stage of extreme drought severity indicating the ability of genotype V1 to resist drought-induced damage on structural stability of PSII and imbalance between the electrons at the acceptor and donor sides of PSII, respectively. Drought-induced changes in leaf protein analyses revealed significant up regulation of important proteins associated to photostability of thylakoid membrane including oxygen evolving enhancer, chlorophyll a/b binding proteins, rubisco and rubisco activase. Further, the antioxidative defense proteins including peroxiredoxin and NADH ubiquinone oxidoreductase were also enhanced. In conclusion, our data demonstrate an integrated down-regulation of the photosynthetic process to maintain intrinsic balance between electron transfer reactions and reductive carbon metabolism without severe damage to PSII structural and functional integrity. PMID- 23357192 TI - Empirical modeling of renal motion for improved targeting during focused ultrasound surgery. AB - Non-invasive surgery looks at ways of eliminating physical contact with the target tissues while maintaining necessary levels of accuracy. Focused Ultrasound Surgery (FUS) is one such treatment modality, which uses a tightly focused beam of high intensity ultrasound to ablate tumors in various parts of the body. For trans-abdominal access, respiration induced movement of the tissue targets remains a major issue during FUS. Respiration induced movements are known to be significant in liver and kidney. In this paper, we attempt to address this problem using non-linear prediction and modeling techniques as applicable to kidney movement patterns. Kidney movement patterns are known to be three dimensional and vastly complicated compared to movement patterns of the liver. Monitoring and quantification of the nature and extent of kidney movement is yet to be explored in depth for effective compensation and accurate targeting. Apart from the respiratory cycle, the movement of the kidney is also affected by several factors, such as the movement of the ribs, spleen and liver. Modeling of these movements is imperative for motion adaptive FUS. Since kidney movements are highly subject specific, generic statistical models cannot be used for compensation. The system latency and real-time performance of the imaging modality also induce additional parametric dependence in target tracking. In this work, we focus on empirical modeling and prediction of the kidney movement to for error analysis and computing system latency. The accuracy of existing modeling techniques is compared with a newly developed empirical model. From the study conducted in healthy volunteers, it was found that the kidney movement was complex and subject specific and could be effectively modeled using the new shape function based model. The model was further fine-tuned using Kalman filter based predictors and Adaptive Neuro-Fuzzy Inference System (ANFIS) which gave more than 85% accuracy in prediction. PMID- 23357193 TI - Radical radiotherapy for radiation-induced malignancy in the context of Hereditary retinoblastoma. PMID- 23357194 TI - Zolendronic acid-induced retrobulbar optic neuritis: a case report. PMID- 23357195 TI - Association of infant pneumococcal vaccination with pneumococcal pneumonia among mothers: a nested case-control study using the GPRD. AB - Since implementation of infant immunization with 7-valent pneumococcal conjugate vaccine (PCV7), increased rates of pneumococcal pneumonia have been reported among adults. Using a cohort of mother-infant pairs identified from the General Practice Research Database in the UK we found that from 2006 to 2010 the annual incidence rate of pneumococcal pneumonia among mothers increased from 61/100,000 to 81/100,000. We identified 43 cases of pneumococcal pneumonia in mothers and 430 control mother-infant pairs. The conditional odds ratio of pneumococcal pneumonia in mothers whose infants received a three-dose series of PCV7 compared to mothers whose infants received zero, one, or two doses was 4.0 (95% confidence interval [95%CI]: 1.0-15.8), and 11.0 (95%CI: 1.2-98.6) when compared with mothers whose infants received no vaccinations. The incidence of pneumococcal pneumonia may have increased in mothers following the introduction of PCV7, possibly because mothers whose infants received PCV7 are at increased risk for pneumococcal pneumonia. Though there is a chance of bias inherent to observational studies, the study findings support close monitoring of adult pneumococcal disease and potential role of adult vaccination needs to be explored. PMID- 23357196 TI - Strengthening vaccination policies in Latin America: an evidence-based approach. AB - Despite many successes in the region, Latin American vaccination policies have significant shortcomings, and further work is needed to maintain progress and prepare for the introduction of newly available vaccines. In order to address the challenges facing Latin America, the Commission for the Future of Vaccines in Latin America (COFVAL) has made recommendations for strengthening evidence-based policy-making and reducing regional inequalities in immunisation. We have conducted a comprehensive literature review to assess the feasibility of these recommendations. Standardisation of performance indicators for disease burden, vaccine coverage, epidemiological surveillance and national health resourcing can ensure comparability of the data used to assess vaccination programmes, allowing deeper analysis of how best to provide services. Regional vaccination reference schemes, as used in Europe, can be used to develop best practice models for vaccine introduction and scheduling. Successful models exist for the continuous training of vaccination providers and decision-makers, with a new Latin American diploma aiming to contribute to the successful implementation of vaccination programmes. Permanent, independent vaccine advisory committees, based on the US Advisory Committee on Immunization Practices (ACIP), could facilitate the uptake of new vaccines and support evidence-based decision-making in the administration of national immunisation programmes. Innovative financing mechanisms for the purchase of new vaccines, such as advance market commitments and cost front loading, have shown potential for improving vaccine coverage. A common regulatory framework for vaccine approval is needed to accelerate delivery and pool human, technological and scientific resources in the region. Finally, public-private partnerships between industry, government, academia and non-profit sectors could provide new investment to stimulate vaccine development in the region, reducing prices in the long term. These reforms are now crucial, particularly as vaccines for previously neglected, developing-world diseases become available. In summary, a regionally-coordinated health policy will reduce vaccination inequality in Latin America. PMID- 23357197 TI - Immunization with recombinant subolesin does not reduce tick infection with tick borne encephalitis virus nor protect mice against disease. AB - Tick-borne encephalitis (TBE) is a growing zoonotic disease caused by tick-borne encephalitis virus (TBEV) infection. Although effective vaccines for TBEV are available, on-going vaccination efforts are insufficient to prevent increase in TBE cases annually. Vaccination with arthropod vector antigens to reduce vector infestations and vector capacity allows control of several vector-borne diseases by targeting their common vector. Subolesin (SUB) is a tick protective antigen that has a role in tick innate immunity and other molecular pathways and has been shown to protect against tick infestations and infection by vector-borne pathogens. However, SUB expression and the effect of SUB immunization have not been evaluated for tick-borne viruses. Herein, we showed that SUB expression is downregulated during Ixodes ricinus tick feeding but induced in ticks infected with TBEV, thus supporting a role for this molecule in tick innate immune response to virus infection. Immunization with recombinant SUB reduced SUB mRNA levels in nymphs co-feeding with infected females and suggested and effect on tick infestations in mice. However, SUB immunization did not reduce tick infection with TBEV nor protect mice against TBE. These results suggested that SUB is not a good candidate antigen for vaccination against TBEV and support the characterization of tick-pathogen interactions to identify mechanisms that could be targeted to reduce TBEV infection and transmission by ticks. PMID- 23357198 TI - Oral administration of an adenovirus vector encoding both an avian influenza A hemagglutinin and a TLR3 ligand induces antigen specific granzyme B and IFN-gamma T cell responses in humans. AB - PURPOSE: To test the safety and immunogenicity of an orally delivered avian influenza vaccine. The vaccine has a non-replicating adenovirus type 5 vector backbone which expresses hemagglutinin from avian influenza and a TLR3 ligand as an adjuvant. METHODS: Forty-two subjects were randomized into 3 groups dosed with either 1*10(10), 1*10(9), or 1*10(8) IU of the vaccine administered in capsules. Twelve subjects were vaccinated with identical capsules containing placebo. A portion of the 1*10(9) dose group were immunized a second time 4 weeks after the first immunization. The safety of the vaccine was assessed by measuring the frequency and severity of adverse events in placebo versus vaccine treated subjects. IFN-gamma and granzyme B ELISpot assays were used to assess immunogenicity. RESULTS: The vaccine had a positive safety profile with no treatment emergent adverse events reported above grade 1, and with an adverse event frequency in the treated groups no greater than placebo. Antigen specific cytotoxic and IFN-gamma responses were induced in a dose dependent manner and cytotoxic responses were boosted after a second vaccination. CONCLUSION: This first in man clinical trial demonstrates that an orally delivered adenovirus vectored vaccine can induce immune responses to antigen with a favorable safety profile. CLINICAL TRIAL REGISTRATION NUMBER: NCT01335347. PMID- 23357199 TI - Caesarean section rates are increasing worldwide. Preface. PMID- 23357200 TI - Robotic surgery - advance or gimmick? AB - Robotic surgery is increasingly implemented as a minimally invasive approach to a variety of gynaecological procedures. The use of conventional laparoscopy by a broad range of surgeons, especially in complex procedures, is hampered by several drawbacks. Robotic surgery was created with the aim of overcoming some of the limitations. Although robotic surgery has many advantages, it is also associated with clear disadvantages. At present, the proof of superiority over access by laparotomy or laparoscopy through large randomised- controlled trials is still lacking. Until results of such trials are present, a firm conclusion about the usefulness of robotic surgery cannot be drawn. Robotic surgery is promising, making the advantages of minimally invasive surgery potentially available to a large number of surgeons and patients in the future. PMID- 23357201 TI - Liver cirrhosis in glycogen storage disease Ib. AB - Glycogen storage disease Ib is an inborn error of carbohydrate metabolism leading to impaired glycogenolysis and gluconeogenesis. Cardinal symptoms include fasting hypoglycemia, lactic acidosis and hepatomegaly as well as neutropenia. We report for the first time on the development of liver cirrhosis in a nine-year-old boy in the course of glycogen storage disease Ib and discuss possible underlying pathomechanisms. PMID- 23357202 TI - Looking at eye dominance from a different angle: is sighting strength related to hand preference? AB - Sighting dominance (the behavioural preference for one eye over the other under monocular viewing conditions) has traditionally been thought of as a robust individual trait. However, Khan and Crawford (2001) have shown that, under certain viewing conditions, eye preference reverses as a function of horizontal gaze angle. Remarkably, the reversal of sighting from one eye to the other depends on which hand is used to reach out and grasp the target. Their procedure provides an ideal way to measure the strength of monocular preference for sighting, which may be related to other indicators of hemispheric specialisation for speech, language and motor function. Therefore, we hypothesised that individuals with consistent side preferences (e.g., right hand, right eye) should have more robust sighting dominance than those with crossed lateral preferences. To test this idea, we compared strength of eye dominance in individuals who are consistently right or left sided for hand and foot preference with those who are not. We also modified their procedure in order to minimise a potential image size confound, suggested by Banks et al. (2004) as an explanation of Khan and Crawford's results. We found that the sighting dominance switch occurred at similar eccentricities when we controlled for effects of hand occlusion and target size differences. We also found that sighting dominance thresholds change predictably with the hand used. However, we found no evidence for relationships between strength of hand preference as assessed by questionnaire or by pegboard performance and strength of sighting dominance. Similarly, participants with consistent hand and foot preferences did not show stronger eye preference as assessed using the Khan and Crawford procedure. These data are discussed in terms of indirect relationships between sighting dominance, hand preference and cerebral specialisation for language and motor control. PMID- 23357203 TI - Learning by doing? The effect of gestures on implicit retrieval of newly acquired words. AB - Meaningful gestures enhance speech comprehensibility. However, their role during novel-word acquisition remains elusive. Here we investigate how meaningful versus meaningless gestures impact on novel-word learning and contrast these conditions to a purely verbal training. After training, neuronal processing of the novel words was assessed by blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI), disclosing that networks affording retrieval differ depending on the training condition. Over 3 days participants learned pseudowords for common objects (e.g., /klira/ -cap). For training they repeated the novel word while performing (i) an iconic, (ii) a grooming or (iii) no gesture. For the two conditions involving gestures, these were either actively repeated or passively observed during training. Behaviorally no substantial differences between the five different training conditions were found while fMRI disclosed differential networks affording implicit retrieval of the learned pseudowords depending on the training procedure. Most notably training with actively performed iconic gestures yielded larger activation in a semantic network comprising left inferior frontal (BA47) and inferior temporal gyri. Additionally hippocampal activation was stronger for all trained compared to unknown pseudowords of identical structure. The behavioral results challenge the generality of an 'enactment-effect' for single word learning. Imaging results, however, suggest that actively performed meaningful gestures lead to a deeper semantic encoding of novel words. The findings are discussed regarding their implications for theoretical accounts and for empirical approaches of gesture based strategies in language (re)learning. PMID- 23357205 TI - Folic acid-conjugated graphene oxide for cancer targeted chemo-photothermal therapy. AB - Nanographene oxide (NGO), a new type of nanomaterial for anticancer drugs delivery and near-infrared (NIR)-mediated photothermal ablation of tumors, has been used in the combination of photothermal therapy and chemotherapy. Herein, targeted chemo-photothermal therapy based on polyvinylpyrrolidone (PVP) functionalized NGO was achieved. Folic acid (FA), a common target molecule to cancer cells, was conjugated to NGO via covalent amide bond. The obtained FA-NGO PVP was proved to be an ideal pH-responsive nanocarrier for delivery of an anticancer drug doxorubicin (DOX) with the loading ratio more than 100%. In vitro experiments were then performed with the combination of chemotherapy and NIR photothermal therapy. The results demonstrated that the targeted chemo photothermal therapy could specifically deliver drug and heat to tumor sites and showed excellent efficacy of anticancer therapy. Thus, FA-NGO-PVP could be used as a novel nanomaterial for selective chemo-photothermal therapy. PMID- 23357204 TI - Neural correlates of executive functions in healthy G2019S LRRK2 mutation carriers. AB - INTRODUCTION: The G2019S mutation in the leucine rich repeat kinase 2 (LRRK2) gene is prevalent among Ashkenazi Jewish patients with Parkinson's disease (PD). Cognitive deficits are common in early stage PD. We aimed to characterize the effect of the G2019S mutation on neural mechanisms of executive function processing by testing whether healthy mutation carriers who are an "at risk" population for the future development of PD differed from non-carriers on an functional magnetic resonance imaging (fMRI) Stroop interference task. METHODS: Cognitive performance and task related cerebral activity were measured in 40 healthy first-degree relatives of Ashkenazi PD patients (19 carriers and 21 non carriers of the G2019S mutation). Both regional differences in neural activity and seed region driven functional connectivity methods were performed using fMRI. RESULTS: Compared to non-carriers, mutation carriers had greater baseline deactivation and increased task related activity in the right inferior parietal lobe, right precuneus and right fusiform gyrus. Whole brain functional connectivity analysis revealed stronger coupling between these regions and both basal ganglia structures as well as cortical regions in the carrier group. Non manifesting G2019S mutation carriers and non-carriers performed similarly on the task and on all other assessed measures, so behavioral differences in task performance and baseline cognitive functions cannot explain the observed imaging differences. CONCLUSIONS: G2019S carriers, at risk for developing PD, had similar behavioral performance as non-carriers during the Stroop task, but increased activity in brain regions that have previously been found to be part of the ventral attention system together with stronger coupling between task related areas and structures that make up the ventral and dorsal attention system as well as the basal ganglia-thalamocortical network. This suggests a neural compensatory mechanism that enables intact cognitive performance in asymptomatic mutation carriers. PMID- 23357206 TI - Does photodissociation of molecular oxygen from myoglobin and hemoglobin yield singlet oxygen? AB - Time-resolved luminescence measurements in the near-infrared region indicate that photodissociation of molecular oxygen from myoglobin and hemoglobin does not produce detectable quantities of singlet oxygen. A simple and highly sensitive method of luminescence quantification is developed and used to determine the upper limit for the quantum yield of singlet oxygen production. The proposed method was preliminarily evaluated using model data sets and confirmed with experimental data for aqueous solutions of 5,10,15,20-tetrakis(4-N-methylpyridyl) porphyrin. A general procedure for error estimation is suggested. The method is shown to provide a determination of the integral luminescence intensity in a wide range of values even for kinetics with extremely low signal-to-noise ratio. The present experimental data do not deny the possibility of singlet oxygen generation during the photodissociation of molecular oxygen from myoglobin and hemoglobin. However, the photodissociation is not efficient to yield singlet oxygen escaped from the proteins into the surrounding medium. The upper limits for the quantum yields of singlet oxygen production in the surrounding medium after the photodissociation for oxyhemoglobin and oxymyoglobin do not exceed 3.4*10(-3) and 2.3*10(-3), respectively. On the average, no more than one molecule of singlet oxygen from every hundred photodissociated oxygen molecules can succeed in escaping from the protein matrix. PMID- 23357207 TI - Peroxynitrite alters GABAergic synaptic transmission in immature rat hippocampal slices. AB - Increasing of peroxynitrite (ONOO(-)) production during ischemia in the immature brain was considered to be associated with impaired cognitive function. GABAergic synapses played an important role in memory formation including the induction of long-term potentiation (LTP) and long-term depression (LTD) in hippocampus. In the present study, we examined the effects of acute exposure of the ONOO(-) donor, SIN-1 on GABAergic synaptic transmission in immature rat hippocampal slices with whole-cell patch-clamp recordings. The results showed that SIN-1 increased the peak amplitude of evoked inhibitory postsynaptic currents (eIPSCs) and decreased paired pulse ratio via the formation of ONOO(-). In addition, it also increased the frequency of spontaneous (but not miniature) IPSCs in a dose dependent manner without altering amplitudes or rise and decay times of both (sIPSCs and mIPSCs). It further demonstrated that the presynaptic action of SIN-1 was external calcium dependent and was not related to the changes of interneuron excitability. This study provides electrophysiological evidences from developing hippocampal slices to support that SIN-1 enhances action potential-dependent GABA release. It suggests that the potentiation effect of ONOO(-) may contribute to hyperexcitability and seizures and may underlie one of the mechanisms by which ischemia increases seizure susceptibility in the immature brain. PMID- 23357208 TI - Clinical and neurocognitive markers of suicidality in young adults. AB - BACKGROUND: Suicide represents a leading cause of death in young people, yet relatively little is known regarding the neurobiological sequelae of preceding suicidal thoughts and behaviours. Although some studies have reported cognitive deficits associated with suicidality, very few studies have been undertaken in young people, especially from non-clinical contexts. AIMS: To quantify cognitive deficits associated with suicidality using a representative sample of young people, recruited from the general community using media advertisements. METHOD: 304 adults (18-29 years) undertook the Mini-International Neuropsychiatric Inventory (MINI) suicidality module, along with Cambridge Gamble and Stop-Signal tasks. Suicidality was defined as non-zero MINI scores (broad definition) and a past history of suicide attempt(s) (narrow definition). Clinical features and cognitive performance were compared between those with and those without suicidality, using analysis of variance/chi-square; findings were further explored using linear regression. RESULTS: Suicidality was relatively common (broad definition: 14.8%; narrow definition: 5.3%) in young people and was associated with impaired decision-making on the Cambridge Gamble task (p < 0.05, Bonferroni corrected at the analysis level of each suicidality definition). Linear regression demonstrated that decision-making performance was associated with a significant incremental benefit with respect to predicting suicidality, over and above the utility of demographic and clinical variables considered (p < 0.05 uncorrected). CONCLUSIONS: Impaired decision-making exists in young people with suicidality, and may thereby predispose towards a range of suicidal thoughts and behaviours. Further work is needed to clarify the chain of progression from such thoughts/behaviours, which are relatively common, through to actual suicide, which is not. PMID- 23357209 TI - The involvement of 5-lipoxygenase activating protein in anxiety-like behavior. AB - The 5-lipoxygenase is an enzyme widely expressed in the central nervous system, where its activity is dependent on the presence the 5-lipoxygenase activating protein (FLAP) for the formation of leukotrienes, potent bioactive lipid mediators. Emerging evidence has shown that the FLAP/leukotriene pathway may play a role in neuropsychiatric disease contexts. In this study we investigated whether genetic deficiency of FLAP (FLAPKO) modulated some behavioral aspects in mice, and if this effect was age-dependent. While we observed that FLAPKO mice at 3 and 6 months of age did not different from wild type animals in the elevated plus maze, at 12 months of age they manifested a significant increase in anxiety like behavior. By contrast, we observed no differences between FLAPKO mice and their controls at any of the three ages considered when they were tested for working memory in the Y maze paradigm. Additionally, while we found that cFOS protein and message levels were reduced in the brains of animals lacking FLAP, no changes for other transcription factors were detected. Taken together our findings suggest a novel role for FLAP in the pathogenesis of anxiety-like behavior. Future studies of FLAP neurobiology may be attractive for development of anxiolytic therapeutics. PMID- 23357210 TI - Long-term effects of doxazosin, finasteride and combination therapy on quality of life in men with benign prostatic hyperplasia. AB - PURPOSE: We examined the effects of doxazosin, finasteride and combination therapy among men with benign prostatic hyperplasia on quality of life assessed with MOS-SF-36 (Medical Outcomes Study Short-Form 36) and 2 disease specific instruments (BII, benign prostatic hyperplasia Impact Index and I-PSS-QoL, International Prostate Symptom Score-QoL) during 4 years. MATERIALS AND METHODS: The MTOPS (Medical Therapy of Prostatic Symptoms) study was a multicenter, randomized, double-blind, placebo controlled clinical trial with a primary outcome of time to benign prostatic hyperplasia progression. Change in quality of life was a secondary outcome. A total of 2,872 men enrolled in the MTOPS study who had 3 baseline quality of life measures and at least 1 followup measure by any of the quality of life instruments were analyzed. RESULTS: Compared with men assigned to placebo, men assigned to doxazosin and combination experienced a statistically significant improvement in the BII at year 4. Men assigned to each of the drug groups also experienced a significant improvement in the I-PSS-QoL compared with those assigned to placebo. Considering longitudinal changes during 4 years, a significant improvement in BII and I-PSS-QoL scores was observed in men assigned to the drug groups compared with those assigned to placebo. However, there were no significant differences for the MOS-SF-36 subscales and summary scores when drug groups were compared with the placebo group. CONCLUSIONS: The quality of life of men treated with doxazosin, finasteride, and the drugs combined generally improved when assessed with the BII and the I-PSS-QoL compared with those treated with placebo. Quality of life did not show improvement when measured by the MOS-SF-36. PMID- 23357211 TI - The relation between adult dark spermatogonia and other parameters of fertility potential in cryptorchid testes. AB - PURPOSE: The fertility potential of boys with cryptorchidism may be related to the number of adult dark spermatogonia per tubular transverse section in testicular biopsies taken at orchiopexy. Placental-like alkaline phosphatase positive gonocytes in testes within year 1 of life indicate preserved ability for germ cell transformation. We related these parameters to the total number of tubular germ cells and other factors associated with fertility potential. MATERIALS AND METHODS: The study comprised 89 boys 0.7 to 3 years old (median age 1.8) who underwent bilateral testicular biopsy at bilateral orchiopexy and provided blood samples for gonadotropins and inhibin B. RESULTS: Of 76 boys with adult dark spermatogonia 44 (58%) had a normal mean number of spermatogonia per tubular transverse section compared to 2 of 13 (15%) without adult dark spermatogonia (p <0.05). In the 30 boys with good fertility potential, including a normal mean number of tubular germ cells, and normal gonadotropins and inhibin B, the mean number of adult dark tubular germ cells was 0.081 vs 0.031 in the 38 with low fertility potential, including impaired tubular germ cells and/or low inhibin B but no reactive increase in gonadotropins (p <0.05). In the 21 patients with increased gonadotropins the mean number of adult dark spermatogonia per tubular transverse section was 0.063. Of the 20 boys with normal mean adult dark spermatogonia per tubular transverse section 12 (60%) had good fertility potential, including a normal mean number of tubular germ cells, normal gonadotropins and normal inhibin B, compared to only 18 of 69 (26%) with an impaired mean number of adult dark spermatogonia per tubular transverse section (p <0.05). Of 46 boys with a normal mean number of tubular germ cells 26 (57%) had placental-like alkaline phosphatase positive cells compared to 14 of 43 (33%) with a decreased mean number of tubular germ cells (p <0.05). CONCLUSIONS: The number of placental-like alkaline phosphatase positive gonocytes and adult dark spermatogonia per tubular transverse section are important parameters related to the fertility potential of boys with cryptorchid testes. PMID- 23357212 TI - Compliance with semen analysis. AB - PURPOSE: We calculated the compliance rate and determined which population of men would be more or less likely to be compliant with semen analysis followup based on demographic information and complication rates. MATERIALS AND METHODS: We retrospectively reviewed the records of 946 consecutive patients who underwent vasectomy at an ambulatory clinic, as performed by 1 urologist. Standard followup consisted of a telephone call or prebooked appointment 2 months after vasectomy and 2 semen analyses 4 months after vasectomy. RESULTS: Average +/- SD patient age was 33.6 +/- 5.4 years. Of the 946 study patients 47.9% did not submit a negative semen sample, 15.7% submitted 1 and 36.4% submitted the required 2 negative samples to confirm successful vasectomy according to the sampling protocol. Mean time to semen analysis was 4.53 +/- 2.14 months. Complications included infection in 1.9% of cases, hematoma in 1% and sperm granuloma in 0.5%. Men 34 years or younger, men with 3 or more children and men without complications were more likely to be noncompliant with semen analysis. CONCLUSIONS: The number of men who provided samples for semen analysis in this study was low, although they were given written and verbal reminders. This poor patient compliance is similar to that in previous studies. We identified a subset of patients with poor compliance, which may allow urologists to target preprocedure counseling more appropriately. PMID- 23357213 TI - Desmopressin add-on therapy for refractory nocturia in men receiving alpha blockers for lower urinary tract symptoms. AB - PURPOSE: Alpha-blockers improve lower urinary tract symptoms associated with benign prostatic obstruction. Nocturia, a storage symptom, is a common complaint in men. However, it does not fully respond to alpha-blocker therapy, likely due to its multifactorial pathophysiology. We evaluated the efficacy and safety of desmopressin as add-on therapy for refractory nocturia in men previously treated with an alpha-blocker for lower urinary tract symptoms. MATERIALS AND METHODS: Eligible patients were men 50 years old or older with lower urinary tract symptoms and persistent nocturia despite alpha-blocker treatment for a minimum of 4 weeks. The optimum dose of oral desmopressin was determined during a 4-week dose titration period and this dose was maintained for 24 weeks. Flow volume charts, International Prostate Symptom Score total and subscores, uroflowmetry and post-void residual urine volume were assessed. RESULTS: A total of 216 patients were enrolled in the study. Of these patients there were 158 (76%) with nocturnal polyuria, 15 (7.2%) with decreased nocturnal bladder capacity and 35 (16.8%) with nocturia due to both causes. The number of nocturnal voids significantly decreased from a baseline mean of 7.0 to 5.7 episodes for 3 days at the 24-week visit. The average International Prostate Symptom Score total and subscore significantly decreased by 4 weeks and were maintained at 24 weeks. In patients younger than 65 years, International Prostate Symptom Score voiding subscores were significantly improved at 24 weeks compared to those age 65 years or older. CONCLUSIONS: Desmopressin add-on therapy for refractory nocturia in men previously treated with an alpha-blocker for lower urinary tract symptoms improved voiding symptoms as well as nocturia, storage symptoms. PMID- 23357214 TI - Urological manifestations of Duchenne muscular dystrophy. AB - PURPOSE: Duchenne muscular dystrophy is a dystrophinopathy affecting males that is associated with multiple organ system complications. To our knowledge urological complications of Duchenne muscular dystrophy have been described only anecdotally to date. MATERIALS AND METHODS: We reviewed the medical charts of 135 patients with Duchenne or Duchenne-Becker muscular dystrophy for demographics and disease progression, urological diagnoses, intervention and followup. RESULTS: Of 135 patients 67 (50%) had at least 1 documented urological diagnosis and 38 (28%) had multiple manifestations. Lower urinary tract symptoms were the most common urological diagnosis (32% of patients). Survival analysis revealed a median age at onset of lower urinary tract symptoms of 23 years (95% CI 17.7-23.9). Intervention was required in 12 patients (9%), most commonly due to nephrolithiasis. Urological morbidity increased with Duchenne muscular dystrophy progression when stratified by clinical progression. Lower urinary tract symptoms were more common in nonambulatory patients (40.7% vs 19%, p = 0.007), those with a diagnosis of scoliosis (44% vs 19.7%, p = 0.003) and/or scoliosis spine surgery (60% vs 22%, p <0.001), and those on invasive respiratory support (53% vs 29%, p = 0.046). Likewise, nephrolithiasis was more common in nonambulatory patients (10% vs 0%, p = 0.017), those with scoliosis (12% vs 0%, p = 0.004) and/or scoliosis spine surgery (20% vs 1%, p <0.001), and those on invasive respiratory support (29% vs 3%, p <0.001). Only 28% of patients with a urological manifestation were referred to urology. CONCLUSIONS: As these patients transition into adolescence and adulthood, the increased prevalence of urological manifestations warrants increased awareness and referral to urologists. PMID- 23357215 TI - Lower health related quality of life and psychosocial difficulties in children with monosymptomatic nocturnal enuresis--is snoring a marker of severity? AB - PURPOSE: Sleep disordered breathing in children is linked to numerous negative psychosocial consequences, including lower health related quality of life, increased behavioral problems and impaired neuropsychological functioning. We examined whether snoring, which is the least severe form of sleep disordered breathing, or health related quality of life could account for the increased rate of psychosocial difficulty in children with monosymptomatic nocturnal enuresis. MATERIALS AND METHODS: Patients diagnosed with monosymptomatic nocturnal enuresis seen at an outpatient pediatric urology clinic completed measures of health related quality of life (Obstructive Sleep Apnea Syndrome-18-Item Questionnaire), sleep disordered breathing (Pediatric Sleep Questionnaire) and psychosocial difficulty (Pediatric Symptom Checklist). Patients were categorized into 2 groups (snoring vs no snoring) based on the Pediatric Symptom Checklist snoring subscale score. RESULTS: Included in the study were 62 males and 45 females with a mean +/ SD age of 9.09 +/- 2.58 years and a mean body mass index of 21.00 +/- 6.93 kg/m(2) (range 13 to 49). The sample was evenly split between 56 snorers (52.3%) and 51 nonsnorers (47.7%). Compared to children with monosymptomatic nocturnal enuresis who did not snore, MANCOVA results revealed that patients with monosymptomatic nocturnal enuresis who snored had significantly more externalizing problems and total psychosocial problems, in addition to significantly more impairment in all areas of health related quality of life. CONCLUSIONS: Snoring in children with monosymptomatic nocturnal enuresis puts them at increased risk for behavioral and psychosocial problems, in addition to impaired health related quality of life. These findings support the need for future studies of the neurological links between sleep disordered breathing and monosymptomatic nocturnal enuresis. PMID- 23357216 TI - Suicide ideation and attempt in a community cohort of urban Aboriginal youth: a cross-sectional study. AB - BACKGROUND: There has been increasing attention over the last decade on the issue of indigenous youth suicide. A number of studies have documented the high prevalence of suicide behavior and mortality in Australia and internationally. However, no studies have focused on documenting the correlates of suicide behavior for indigenous youth in Australia. AIMS: To examine the prevalence of suicide ideation and attempt and the associated factors for a community1 cohort of Koori2 (Aboriginal) youth. METHOD: Data were obtained from the Victorian Aboriginal Health Service (VAHS) Young People's Project (YPP), a community initiated cross-sectional data set. In 1997/1998, self-reported data were collected for 172 Koori youth aged 12-26 years living in Melbourne, Australia. The data were analyzed to assess the prevalence of current suicide ideation and lifetime suicide attempt. Principal components analysis (PCA) was used to identify closely associated social, emotional, behavioral, and cultural variables at baseline and Cox regression modeling was then used to identify associations between PCA components and suicide ideation and attempt. RESULTS: Ideation and attempt were reported at 23.3% and 24.4%, respectively. PCA yielded five components: (1) emotional distress, (2) social distress A, (3) social distress B, (4) cultural connection, (5) behavioral. All were positively and independently associated with suicide ideation and attempt, while cultural connection showed a negative association. CONCLUSIONS: Suicide ideation and attempt were common in this cross-section of indigenous youth with an unfavorable profile for the emotional, social, cultural, and behavioral factors. PMID- 23357217 TI - The emergency telephone conversation in the context of the older person in suicidal crisis: a qualitative study. AB - BACKGROUND: Suicide in older people is a significant public health issue with a predicted future increase. Contemporary research directs considerable attention toward physical, mental, and social risk factors that contribute to suicidality in older people; still, little is understood about the fundamental meanings that older people in suicidal crisis attribute to these factors. AIMS: The aim of this qualitative study was to describe, analyze, and compare counselors' and older peoples' perceptions of the suicidal crisis during an emergency telephone conversation. METHODS: Data collection consisted of individual interviews with telephone counselors (N = 7) working within an emergency mental health triage service, and listening to telephone calls (N = 14) received by the service responding to people aged 65 years and over in suicidal crisis. Triangulation of the two data sets resulted in the emergence of three key themes. RESULTS: We found (1) congruence in the way risk factors were perceived by counselors and communicated during telephone conversations, (2) dissension between counselors' perceptions of end-of-life issues and older people's feelings of ambivalence about wanting to die and not knowing what to do and (3) the need for working side by-side with the older person, exploring acute changes and immediate capacity for change. CONCLUSIONS: An explicit focus on risk factors alone may preclude counselors from gaining a deeper understanding of suicidal crisis in an older person's life. This research has begun to capture and illuminate how telephone counselors can deliver effective crisis intervention as older people struggle and make meaning through their suffering. PMID- 23357218 TI - Adolescent survivors after suicide: Australian young people's bereavement narratives. AB - BACKGROUND: While the research literature exploring suicide bereavement has expanded in recent years, this has been primarily quantitative and has focused more on the bereavement experience of parents and siblings. The bereavement experience of young people affected through the suicide death of a friend remains under-conceptualized and not well understood. AIMS: To develop an understanding of the experiences of young people bereaved by the suicide of a friend. METHOD: Ten young people participated in a pilot study with in-depth interviews to explore their suicide bereavement experiences. Narrative inquiry methodology was utilized to analyze the qualitative data. RESULTS: The findings indicated multiple grief experiences caused by suicide. Four themes reported are meaning making, feeling guilt, risky coping behavior, and relating to friends following suicide loss. CONCLUSIONS: Implications include the need for increased awareness that friends of young people who die by suicide may have significant health and well-being challenges associated with bereavement, and that friends in these circumstances may not readily present at services for assistance. PMID- 23357219 TI - Mediating effects of coping style on associations between mental health factors and self-harm among adolescents. AB - BACKGROUND: There is evidence for an association between suicidal behavior and coping style among adolescents. AIMS: The aims of this study were to examine associations between coping style, mental health factors, and self-harm thoughts and acts among Irish adolescents, and to investigate whether coping style mediates associations between mental health factors (depression, anxiety, and self-esteem) and self-harm. METHOD: A cross-sectional school-based survey was carried out. Information was obtained on history of self-harm, life events, and demographic, psychological, and lifestyle factors. RESULTS: Emotion-oriented coping was strongly associated with poorer mental health and self-harm thoughts and acts. Problem-Oriented Coping was associated with better mental health. Mediating effects of Emotion-Oriented Coping on associations between mental health factors and deliberate self-harm (DSH) was found for both genders and between Problem-Oriented Coping and mental health factors for girls. Similar mediating effects of coping style were found when risk of self-harm thoughts was examined. LIMITATIONS: Since the methodology used was cross-sectional, it is impossible to draw conclusions regarding causal relationships between coping style and associated factors. The coping measure used was brief. CONCLUSIONS: Promotion of positive coping skills and reduction of emotion-focused approaches may build resilience to self-harm thoughts and acts among adolescents experiencing mental health problems. PMID- 23357220 TI - Cox-2 gene variants in migraine. AB - PURPOSE: Migraine is a multifactorial and complex disorder, and any clear diagnostic marker to assess the status of the migraineurs has not been established, yet. Nonsteroidal anti-inflammatory drugs reduce production of prostanoids including PGE2 by inhibiting COX-1 and/or COX-2, and thereby suppress inflammatory pain in patients suffering from rheumatoid arthritis, osteoarthritis, and migraine. Thus, COX-2 regulation is important in the pathogenesis and treatment of migraine. We prospectively investigated COX-2-765G >C and COX-2-1195A->G gene polymorphisms which may account for an increased risk of migraine. METHODS: The present analyses are based on 144 case subjects with migraine disease and 123 non-case subjects. Genotyping of COX-2 gene polymorphisms (COX-2-765G->C, COX-2-1195A->G) was detected by PCR-RFLP. RESULTS: We, for the first time, demonstrated positive association of COX-2 gene variants with an increased risk for development of migraine. Carriers of COX-2-765 C+ genotype in controls were higher than in the patients (57.7% and 36.1% respectively; P<0.0001) and the frequencies of G+ genotype in patients were higher than in the controls (97.9% and 88.6% respectively; P: 0.002). In addition, frequencies of COX-2-765 GG and GC genotypes in patients were higher than in the controls (P<0.0001, P<0.0001 respectively). It seems that COX-2-765 G+ genotype had increased and COX-2-765 C+ genotype had decreased risk for migraine. In COX-2-1195 polymorphism only AG genotype was statistically significantly different in patients than in the controls (P<0.05). CONCLUSIONS: Our findings have suggested that COX-2-765 G+ genotype could facilitate the development of migraine disease. PMID- 23357221 TI - Identification of a novel missense mutation of PEX7 gene in an Iranian patient with rhizomelic chondrodysplasia punctata type 1. AB - Deficiency in the PTS2 protein import pathway due to mutations in PEX7 gene results in the rhizomelic chondrodysplasia punctata (RCDP) type 1. In the present study, we have reported a novel missense mutation, W75R, in the PEX7 gene in an Iranian patient with the RCDP type 1. The inability of PEX7 protein to transport PTS2 containing proteins including peroxisomal 3-ketoacyl-CoA thiolase and PTS2 EGFP protein to the surface of the peroxisomes showed that the W75R mutation in PEX7 gene severely impaired the function of PEX7 protein and was responsible for RCDP type 1 in this patient. PMID- 23357222 TI - Transcriptional regulation of the purine de novo synthesis gene Prat in Drosophila melanogaster. AB - The first step of the purine de novo synthesis pathway is catalyzed by amidophosphoribosyltransferase (E.C.2.4.2.14) which is encoded by two Prat genes in D. melanogaster, Prat and Prat2. Prat is a retrogene duplication of Prat2, where each gene has a distinct expression pattern. Prat transcription is restricted to proliferating tissues such as imaginal discs and the female germ line. Three conserved putative DNA replication-related element binding factor (DREF) sites lie upstream of the Prat coding region. These elements are upstream of many genes important in cell proliferation. We have found that DREF binds directly upstream of Prat and that the DRE sites associated with its activity are necessary for Prat expression; furthermore, we have determined that a second cis acting element is present upstream of the Prat gene. Finally, the genes Distal less, Mi-2 and dMyc, which influence Dref activity, do not appear to affect Prat transcription. PMID- 23357223 TI - Gene expression signature of human HepG2 cell line. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is associated with various clinico-pathological characteristics such as genetic mutations and viral infections. Therefore, numerous laboratories look out for identifying always new putative markers for the improvement of HCC diagnosis/prognosis. Many molecular profiling studies investigated gene expression changes related to HCC. HepG2 represents a pure cell line of human liver carcinoma, often used as HCC model due to the absence of viral infection. In this study we compare gene expression profiles associated with HepG2 (as HCC model) and normal hepatocyte cells by microarray technology. Hierarchical cluster analysis of genes evidenced that 2646 genes significantly down-regulated in HepG2 cells compared to hepatocytes whereas a further 3586 genes significantly up regulated. By using the Ingenuity Pathway Analysis (IPA) program, we have classified the genes that were differently expressed and studied the functional networks correlating these genes in the complete human interactome. Moreover, to confirm the differentially expressed genes as well as the reliability of our microarray data, we performed a quantitative Real time RT-PCR analysis on 9 up regulated and 11 down-regulated genes, respectively. In conclusion this work i) provides a gene signature of human hepatoma cells showing genes that change their expression as a consequence of liver cancer in the absence of any genetic mutations or viral infection, ii) evidences new differently expressed genes found in our signature compared to previous published studies and iii) suggests some genes on which to focus future studies to understand if they can be used to improve the HCC prognosis/diagnosis. PMID- 23357224 TI - Increased acetabular subchondral bone density is associated with cam-type femoroacetabular impingement. AB - OBJECTIVE: Femoroacetabular impingement (FAI) has been associated with significant acetabular cartilage damage and subsequent degenerative arthritis. Subchondral bone, often neglected in osteoarthritis studies, may play an important role in the degenerative cascade. Hence the goal of this study was to assess acetabular subchondral bone mineral density (BMD) in subjects with asymptomatic or symptomatic cam deformities compared to normal control subjects. The relationship between BMD and the alpha angle, a quantitative measure of the deformity, was also analyzed. METHODS: Patients diagnosed with symptomatic cam FAI were recruited ('Surgical') as well as subjects from the general asymptomatic population, classified from CT imaging as normal ('Control') or having a cam deformity ('Bump') based on their alpha angle measurement. There were 12 subjects in each group. All subjects underwent a CT scan with a calibration phantom. BMD was calculated in regions of interest around the acetabulum from CT image intensity and the phantom calibration. BMD was compared between groups using spine BMD as a covariate. The relationship between BMD and alpha angle was assessed by linear regression. RESULTS: In the antero-superior regions bone density was 15-34% higher in the Bump group (P < 0.05) and 14-38% higher in the Surgical group (P < 0.05) compared to Controls. BMD correlated positively with the alpha angle measurements (R(2) = 0.44, P < 0.001). CONCLUSION: BMD was elevated in subjects with cam-type deformities, with the severity of the deformity more correlative than symptom status. Similarities to the symptomatic group suggest that hips with an asymptomatic deformity may already be in early stages of joint degeneration. PMID- 23357225 TI - Association study of candidate genes for the progression of hand osteoarthritis. AB - OBJECTIVE: Although a few consistent osteoarthritis (OA) susceptibility genes have been identified, little is known on OA progression. Since OA progression is clinically the most relevant phenotype, we investigate the association between asporin (ASPN), bone morphogenetic protein 5 (BMP5) and growth differentiation factor 5 (GDF5) polymorphisms and progression of hand OA. METHODS: Single nucleotide polymorphisms (SNPs) ASPN rs13301537, BMP5 rs373444 and GDF5 rs143383 were genotyped in 251 hand OA patients from the Genetics osteoARthritis and Progression (GARP) study and 725 controls. In a case-control comparison we assessed the association between these SNPs and radiographic progression of hand OA over 6 years, which was based on change in osteophytes or joint space narrowing (JSN), above the smallest detectable change. SNPs with suggestive evidence for association were further analysed for their effect on progression over 2 years, and for the mean change in osteophytes and JSN. RESULTS: The minor allele of ASPN SNP rs13301537 was associated with hand OA progression over 6 years (odds ratio (OR) (95% CI) 1.49 (1.06-2.07); P = 0.020). The mean change in osteophytes and JSN was higher in carriers of the minor allele compared to homozygous carriers of the common allele with mean difference of 0.73 (95% CI - 0.07-1.56; P = 0.073) and 0.82 (95% CI 0.12-1.52; P = 0.022), respectively. An association with similar effect size was found between ASPN SNP rs13301537 and 2 year progression, and the mean change in osteophytes and JSN was significantly higher in homozygotes. CONCLUSION: ASPN is associated with hand OA progression. This gives insight in the pathogenesis of hand OA progression and identified a potential target for therapeutic approaches. PMID- 23357226 TI - Identification of chlorinated solvents degradation zones in clay till by high resolution chemical, microbial and compound specific isotope analysis. AB - The degradation of chlorinated ethenes and ethanes in clay till was investigated at a contaminated site (Vadsby, Denmark) by high resolution sampling of intact cores combined with groundwater sampling. Over decades of contamination, bioactive zones with degradation of trichloroethene (TCE) and 1,1,1 trichloroethane (1,1,1-TCA) to 1,2-cis-dichloroethene (cis-DCE) and 1,1 dichloroethane, respectively, had developed in most of the clay till matrix. Dehalobacter dominated over Dehalococcoides (Dhc) in the clay till matrix corresponding with stagnation of sequential dechlorination at cis-DCE. Sporadically distributed bioactive zones with partial degradation to ethene were identified in the clay till matrix (thickness from 0.10 to 0.22 m). In one sub section profile the presence of Dhc with the vcrA gene supported the occurrence of degradation of cis-DCE and VC, and in another enriched delta(13)C for TCE, cis DCE and VC documented degradation. Highly enriched delta(13)C for 1,1,1-TCA (250/00) and cis-DCE (-40/00) suggested the occurrence of abiotic degradation in a third sub-section profile. Due to fine scale heterogeneity the identification of active degradation zones in the clay till matrix depended on high resolution subsampling of the clay till cores. The study demonstrates that an integrated approach combining chemical analysis, molecular microbial tools and compound specific isotope analysis (CSIA) was required in order to document biotic and abiotic degradations in the clay till system. PMID- 23357227 TI - Postmortem diagnosis of unsuspected diabetes mellitus. AB - Vitreous glucose, blood beta-hydroxybutyrate and glycated hemoglobin were systematically measured in a series of 500 medico-legal autopsies in order to characterize the glycemic control during the weeks preceding death and identify ketoacidosis as the cause of death in diagnosed and unsuspected diabetics. Unenhanced CT-scans, histology and toxicology were performed in all cases. 16 cases of diabetic ketoacidosis were identified based on the results of all investigations. Among those, 13 cases concerned individuals with pre-existing diagnoses of diabetes mellitus whereas 3 cases concerned individuals with undiagnosed diabetes. A recent cocaine use was observed in 2 cases. C-reactive protein, interleukin-6 and interleukin-10 were measured and proved to be increased in all cases of diabetic ketoacidosis, whereas markers of generalized, bacterial infection and sepsis were normal in most of these cases. The results of this study highlight the usefulness of systematically performing biochemistry to identify ketoacidosis in unsuspected diabetics. It also emphasizes the role of toxicology and biochemistry to support the diagnosis of diabetic ketoacidosis and delineate the pathophysiological mechanisms that may disrupt the metabolic balance and finally lead to death in diabetic individuals. PMID- 23357228 TI - Distribution of opiates in femoral blood and vitreous humour in heroin/morphine related deaths. AB - The distribution of free morphine (FM), codeine and 6-acetylmorphine (6AM) in vitreous humour (VH) and femoral blood (FB) was measured in 70 cases involving heroin/morphine. The relationship between tissue drug concentrations was assessed with respect to case circumstances. Total morphine (TM) concentrations in FB are also reported. The relative concentrations of FM in VH and FB were influenced by survival time. In rapid deaths (<3h after drug intake; n=34) the median FM concentration in VH (0.13 mg/L) was significantly lower than the corresponding result for FB (0.25mg/L; p<.01). In delayed deaths (>3h; n=12) the VH concentration (median 0.15 mg/L) was higher than in FB (0.092 mg/L; p>.05). Free morphine VH/FB ratios were significantly higher in delayed (median 1.3) compared to rapid deaths (0.64). Although these findings indicate a lag in the distribution of morphine into the VH, overlaps were observed in the VH/FB ratio in rapid and delayed death groups which limits the interpretive use of VH/FB ratios. Codeine and 6AM appeared to distribute more rapidly into the VH. Despite the observation that all opiate analytes were correlated between FB and VH (r >= 61; p<.01), our results indicate that in the absence of a blood sample, blood concentrations cannot be reliably inferred from that measured in the VH. In the absence of additional toxicological evidence, the use of FM to TM ratios in blood as an indicator of survival time is not advised. PMID- 23357229 TI - Can we infer post mortem interval on the basis of decomposition rate? A case from a Portuguese cemetery. AB - Post mortem interval estimation is crucial in forensic sciences for both positive identification and reconstruction of perimortem events. However, reliable dating of skeletonized remains poses a scientific challenge since human remains decomposition involves a set of complex and highly variable processes. Many of the difficulties in determining post mortem interval and/or the permanence of a body in a specific environment relates with the lack of systematic observations and research in human body decomposition modalities in different environments. In March 2006, in order to solve a problem of misidentification, a team of the South Branch of Portuguese National Institute of Legal Medicine carried out the exhumation of 25 identified individuals buried for almost five years in the same cemetery plot. Even though all individuals shared similar post mortem intervals, they presented different stages of decomposition. In order to analyze the post mortem factors associated with the different stages of decomposition displayed by the 25 exhumed individuals, the stages of decomposition were scored. Information regarding age at death and sex of the individuals were gathered and recorded as well as data in the cause of death and grave and coffin characteristics. Although the observed distinct decay stages may be explained by the burial conditions, namely by the micro taphonomic environments, individual endogenous factors also play an important role on differential decomposition as witnessed by the present case. PMID- 23357230 TI - The dose response functions of ionization chambers in photon dosimetry - Gaussian or non-Gaussian? AB - This study is concerned with the spatial resolution of air-filled ionization chambers in photon-beam dosimetry, i.e. with their dose response functions. These act as convolution kernels K(x,y), transforming true dose profiles D(x,y) into the measured signal profiles M(x,y). One-dimensional dose response functions have been experimentally determined for nine types of cylindrical ionization chambers both in their lateral and longitudinal directions, as well as across two plane parallel chambers and for the single chambers of two 2D arrays. All these 1D dose response functions are closely described by Gaussian functions. The associated energy-dependent values of the standard deviations sigma have been measured for 6 and 15 MV photons with an uncertainty of 0.02mm. At depths beyond secondary electron fluence build-up, there was no detectable depth dependence of the sigma values. The general occurrence of Gaussian dose response functions, their extension beyond the geometrical boundaries of the chambers, and the energy dependence of their standard deviations can be understood by considering the underlying system of convolutions, which is the origin of the influences of secondary electron transport. Monte-Carlo simulations of the convolution kernels for a cylindrical, a square, and a flat ionization chamber and their Fourier analysis have been employed to show that the Gaussian convolution kernels are approximations to the true dose response functions, valid in the clinically relevant domain of the spatial frequency. This paper is conceived as the starting point for the deconvolution methods to be described in a further publication. PMID- 23357231 TI - Therapy-related myeloid neoplasms with isolated del(20q): comparison with cases of de novo myelodysplastic syndrome with del(20q). AB - The isolated deletion of chromosome 20q [del(20q)] has been observed in both de novo and therapy-related cases of myelodysplastic syndrome (MDS). The clinicopathologic features of de novo MDS with isolated del(20q) are well characterized. However, relatively little is known about therapy-related myeloid neoplasms (t-MNs) with isolated del(20q). In this study, we identified five cases of t-MN and 26 cases of de novo MDS with isolated del(20q) over a 10-year period. All cases had a long latency interval from the treatment of the primary malignancy to the onset of t-MN, and all were associated with frequent bone marrow dysplasia. The del(20q) was the sole abnormality detected at the time of diagnosis of t-MN in three cases, six years prior to diagnosis in one case, and at the time of relapse of acute myeloid leukemia (AML) in one case. Three patients with therapy-related MDS (t-MDS) had a relatively indolent clinical course, whereas two patients presented with AML or developed AML shortly after t MDS. The patients with de novo MDS with isolated del(20q) presented frequently with anemia and thrombocytopenia which were associated with bone marrow dysplasia. The median overall survival was 64 months. In all cases, del(20q) was present at the time of diagnosis. PMID- 23357232 TI - A quantitative affinity-based technique for the identification of potential lead compounds. AB - Here, we describe the development and validation of a quantitative analytical method for rapid evaluation of protein-compound interactions. The method uses size-exclusion chromatography in a 96-well format with liquid chromatography/mass spectrometry (qSEC-LC/MS) by which the amount of a compound that was originally in complex with a target protein is determined as an indicator of the binding affinity. Proof of concept of this new analytical approach was performed using a thrombin-inhibitor model. The results showed that the qSEC-LC/MS could be developed into an effective affinity-based analytical technique, despite a few limitations such as difficulty in determining the K(d) value accurately. PMID- 23357233 TI - Method to convert N-terminal glutamine to pyroglutamate for characterization of recombinant monoclonal antibodies. AB - Cyclization of N-terminal glutamine to pyroglutamate is a common modification of recombinant monoclonal antibodies that has often been identified by liquid chromatography mass spectrometry (LC-MS) analysis using separated fractions. An alternative approach of using glutaminyl-peptide cyclotransferase to convert the N-terminal glutamine to pyroglutamate was developed in the current study. Enzymatic conversion of the N-terminal glutamine to pyroglutamate not only provides an identification of the N-terminal amino acids without fraction collection but also can significantly simplify the chromatograms to assist fraction collections for the characterization of other antibody variants. PMID- 23357234 TI - Colorimetric detection of metallothioneins using a thymine-rich oligonucleotide Hg complex and gold nanoparticles. AB - A simple and sensitive method for label-free, colorimetric detection of metallothioneins (MTs) has been developed by using a thymine (T)-rich oligonucleotide (TRO)-Hg-AuNP system. In this colorimetric strategy, the thiol groups of MTs could interact with mercury from the T-Hg(2+)-T complex to release TRO, resulting in a color change of the system. The response signals linearly correlated with the concentration of MTs over the range of 2.56 * 10(-8) to 3.08 * 10(-7) mol L(-1), and the limit of detection was 7.67 * 10(-9) mol L(-1). The relative standard deviation and the recovery were 2.3-4.8% (n = 11) and 94.2 103.9%, respectively. The proposed method avoids the label and derivatization steps in common methods, allows direct analysis of the samples by the naked eye without costly instruments, and is reliable, inexpensive, and sensitive. PMID- 23357235 TI - Isolation and characterization of DNA aptamers against Escherichia coli using a bacterial cell-systematic evolution of ligands by exponential enrichment approach. AB - Aptamers are powerful capturing probes against various targets such as proteins, small organic compounds, metal ions, and even cells. In this study, we isolated and characterized single-stranded DNA (ssDNA) aptamers against Escherichia coli. A total of 28 ssDNAs were isolated after 10 rounds of selection using a bacterial cell-SELEX (systematic evolution of ligands by exponential enrichment) process. Other bacterial species (Klebsiella pneumoniae, Citrobacter freundii, Enterobacter aerogenes, and Staphylococcus epidermidis) were used for counter selection to enhance the selectivity of ssDNA aptamers against E. coli. Finally, four ssDNA aptamers showed high affinity and selectivity to E. coli, The dissociation constants (K(d)) of these four ssDNA aptamers to E. coli were estimated to range from 12.4 to 25.2 nM. These aptamers did not bind to other bacterial species, including four counter cells, but they showed affinity to different E. coli strains. The binding of these four aptamers to E. coli was observed directly by fluorescence microscopy. PMID- 23357236 TI - Quantitative profiling of PrP(Sc) peptides by high-performance liquid chromatography mass spectrometry to investigate the diversity of prions. AB - Prions are proteins that can exist in two (or more) folding states, a normal or cellular form and a series of infectious or prion forms, which are prone to aggregate. The prion form can induce conversion of the cellular form and so transmit phenotypic effects of this structural rearrangement within and between cells and organisms. The conversion of PrP(C), the mammalian prion glycoprotein, to its prion form, PrP(Sc), in the brain is a precursor to progressive neurological degeneration, and the various folded forms of PrP(Sc) (defined by the size and glycosylation of protease-resistant core peptides of the PrP aggregates, PrP(res)) are characteristic of a particular neurodegenerative phenotype or prion disease. Here, quantitative multiplex mass spectrometry was used for N-terminal amino acid profiling (N-TAAP) of PrP(res) from sheep affected by scrapie, the prion disease of small ruminants, to rapidly assess the diversity of prions within particular flocks. In 29 cases, PrP(res) concentrations varied from below the limit of detection (350 fmol/g) to 15 pmol/g wet brain. Although most had a single N-TAAP profile, two novel variants were identified: one common to the ARH/ARQ animals in this study and one in an animal of the wild-type sheep PrP genotype (ARQ/ARQ). PMID- 23357237 TI - Multicolor fluorescence imaging of whole-mount Drosophila testes for studying spermatogenesis. AB - Drosophila testes are generally considered a useful model for studying the fundamental developmental processes of heterogametic organisms. However, immunostaining of the whole Drosophila testis is often associated with insufficient resolution at the subcellular level, poor reproducibility, and incomplete staining of fixed preparations. The main problem for adequate staining is poor permeability of the organs for antibodies and antibody-coupled fluorophores. To overcome this problem we developed a protocol for whole-mount testis immunostaining yielding high-quality preparations for confocal microscopy. Many subcellular structures can be successfully resolved, such as the spectrosome, fusome, nuage granules, apoptotic bodies, and protein crystals. This method preserves the inner architecture of the testes, enabling 3D image reconstruction from a set of confocal sections. It allows one to combine the simultaneous detection of fluorescently tagged and immunostained proteins as well as TUNEL analysis for apoptosis detection. PMID- 23357238 TI - A homogeneous fluorescence anisotropy assay for measuring transglutaminase 2 activity. AB - Transglutaminases catalyze the covalent linkage of protein polypeptides through their glutamine and lysine side chains. Tissue transglutaminase 2 (TG2) has been of particular interest given its potential role in several disorders, including a variety of cancers and neurodegenerative diseases. Here we report a biochemical assay that monitors TG2 activity by following an increase in the fluorescence anisotropy of a fluorescein-labeled substrate peptide as it conjugates to a bovine serum albumin (BSA) cosubstrate of larger hydrodynamic mass. The resulting homogeneous assay is sensitive to low TG2 concentrations (pM range) and is readily adapted to higher throughput formats. PMID- 23357239 TI - Construction of yeast strains useful for screening drugs that inhibit glucose uptake and glycolysis. AB - The budding yeast Saccharomyces cerevisiae expresses different isoforms of glucose transporters (HXTs) in response to different levels of glucose. Here, we constructed reporter strains in which the nourseothricin (NAT) resistance gene is expressed under the control of the HXT1, 2, or 3 promoter. The resulting HXT-NAT reporter strains exhibited a strict growth dependence on glucose, and their growth could be easily controlled and optimized by adjusting glucose concentration, demonstrating the value of the reporter strains for studying the molecular basis of differential expression of HXT genes, as well as for screening drugs that inhibit glucose uptake and glycolysis. PMID- 23357240 TI - Drunk, but not blind: the effects of alcohol intoxication on change blindness. AB - Alcohol use has long been assumed to alter cognition via attentional processes. To better understand the cognitive consequences of intoxication, the present study tested the effects of moderate intoxication (average BAC between .071 and .082) on attentional processing using complex working memory capacity (WMC) span tasks and a change blindness task. Intoxicated and sober participants were matched on baseline WMC performance, and intoxication significantly decreased performance on the complex span tasks. Surprisingly, intoxication improved performance on the change blindness task. The results are interpreted as evidence that intoxication decreases attentional control, causing either a shift towards more passive processing and/or a more diffuse attentional state. This may result in decreased performance on tasks where attentional control or focus are required, but may actually facilitate performance in some contexts. PMID- 23357241 TI - Survival of the selfish: contrasting self-referential and survival-based encoding. AB - Processing information in the context of personal survival scenarios elicits a memory advantage, relative to other rich encoding conditions such as self referencing. However, previous research is unable to distinguish between the influence of survival and self-reference because personal survival is a self referent encoding context. To resolve this issue, participants in the current study processed items in the context of their own survival and a familiar other person's survival, as well as in a semantic context. Recognition memory for the items revealed that personal survival elicited a memory advantage relative to semantic encoding, whereas other-survival did not. These findings reinforce suggestions that the survival effect is closely tied with self-referential encoding, ensuring that fitness information of potential importance to self is successfully retained in memory. PMID- 23357242 TI - Prognostic significance of exercise-induced right ventricular dysfunction in asymptomatic degenerative mitral regurgitation. AB - BACKGROUND: The role of exercise-induced pulmonary hypertension in decision making regarding surgical timing for asymptomatic chronic mitral regurgitation is controversial. We reasoned that the exercise-induced pulmonary hypertension response could not be interpreted without knowledge of right ventricular (RV) function. The aim of this study was to assess the role of RV measures at rest and during exercise as predictors of prognosis in asymptomatic mitral regurgitation. METHODS AND RESULTS: Comprehensive resting and exercise echocardiography was performed in 196 consecutive patients (56+/-13 years; 64% male) with isolated moderate to severe mitral regurgitation (effective regurgitant orifice area, 38+/ 18 mm(2)) and preserved left ventricular function in whom initial management was expectant. Left ventricular and RV longitudinal strain were analyzed at rest using velocity vector imaging. Tricuspid annular plane systolic excursion and systolic pulmonary arterial pressure were measured at rest and during exercise. Valve surgery was performed in 88 patients (45%) over 27+/-15 months. After adjustment for age and sex in a Cox proportional-hazards model, exercise tricuspid annular plane systolic excursion (hazard ratio, 0.26; P<0.001), was associated with valve surgery-free survival, independent of resting left ventricular strain (hazard ratio, 1.09; P=0.027), exercise systolic pulmonary arterial pressure (hazard ratio, 1.03; P<0.001), and resting RV strain (hazard ratio, 1.10; P=0.004). In sequential Cox models, a model based on clinical data and left ventricular strain (chi(2), 15.9) was improved by RV strain and RV chamber size (chi(2), 28.8; P=0.003) and exercise systolic pulmonary arterial pressure (chi(2), 40.1; P=0.002) and further increased by exercise tricuspid annular plane systolic excursion (chi(2), 52.2; P=0.002). CONCLUSIONS: Exercise induced RV dysfunction provides important incremental prognostic value in the management of asymptomatic mitral regurgitation. PMID- 23357243 TI - Coronary artery dimensions in febrile children without Kawasaki disease. AB - BACKGROUND: Coronary artery (CA) dilatation on echocardiography is a criterion for treatment with intravenous immunoglobulin for incomplete Kawasaki disease (KD). However, CA dimensions for febrile children are unknown. We compared CA dimensions in children with febrile illnesses other than KD to those of normal afebrile children and to KD patients. METHODS AND RESULTS: We performed echocardiograms in 43 patients who met the following inclusion criteria: (1) age 3 months to 18 years, (2) daily fever >38 degrees C for >=96 hours, and (3) a diagnosis other than KD. These subjects had mean CA z scores greater than normative values (left main CA=0.66+/-0.75, P<0.001; right CA=0.28+/-0.81, P=0.03; left anterior descending CA=0.35+/-1.0, P=0.03). Maximum CA z score >2 was found in 2 subjects (osteomyelitis, Mycoplasma pneumonia). Among demographic and laboratory measures, only higher platelet count was associated with greater left anterior descending CA z scores (P=0.004) and maximum CA z score (P=0.03). Non-KD febrile subjects, compared with 144 KD patients, had smaller CA z scores (P=0.04, P<0.001, and P<0.001 for left main CA, right CA, and left anterior descending CA, respectively), and lower white blood cell count, erythrocyte sedimentation rate, and platelet count (all P<0.001). A maximum CA z score cutoff of 2.0 had specificity of 95% (95% confidence interval, 84%-99%) and sensitivity of 32% (95% confidence interval, 25%-41%) in distinguishing non-KD febrile from KD patients; for maximum CA z score of 2.5, specificity was 98% and sensitivity was 20%. CONCLUSIONS: This pilot study found that mean CA dimensions in children with non-KD febrile illnesses are larger than those in normative afebrile subjects but smaller than dimensions in patients with KD. Future studies should augment the available data on CA dimensions in children with more severe febrile illnesses. PMID- 23357244 TI - Regions of low endothelial shear stress colocalize with positive vascular remodeling and atherosclerotic plaque disruption: an in vivo magnetic resonance imaging study. AB - BACKGROUND: Local hemodynamic factors, particularly low endothelial shear stress (ESS), play a role in the focal formation of atherosclerosis. We used in vivo MRI to investigate the role of the magnitude of ESS on vascular remodeling, plaque burden, and disruption using a rabbit model of controlled atherothrombosis. METHODS AND RESULTS: Atherosclerosis was induced in New Zealand white rabbits by cholesterol diet and endothelial denudation. MRI was performed before (pretrigger) and after (posttrigger) inducing plaque disruption with Russell viper venom and histamine. Of the 134 vascular segments studied, 28 contained thrombus (disrupted) and 106 did not (nondisrupted). Disrupted plaques were histologically characterized by a thin, inflamed fibrous cap, a dense lipid core, and mural thrombus. Pretriggered MRI revealed that disrupted plaques clustered at regions with low mean ESS (11.55+/-5.3 versus 20.9+/-9.74 dynes/cm(2); P<0.001) and low peak ESS (21.5+/-11.2 versus 49.2+/-21.5 dynes/cm(2); P<0.001) compared with nondisrupted plaques. The peak ESS negatively correlated with the plaque area (r=-0.56, P<0.001) and remodeling ratio (r=-0.4, P=0.008). There was also a negative correlation between the mean ESS and the remodeling ratio (r=-0.55, P<0.001). Both the peak ESS and the mean ESS did not correlate with the % stenosis; there was a weak but statistically significant correlation with the % cross-sectional narrowing (r=0.3, P=0.002 and r=0.2, P=0.04, respectively). Receiver operating characteristic analysis showed that both mean (AUC=0.78; 95% CI, 0.69-0.87) and peak ESS (AUC=0.85; 95% CI, 0.78-0.93) identified disrupted plaques. CONCLUSIONS: We demonstrated that low ESS is associated with plaque burden, positive vascular remodeling, and plaque disruption in a rabbit model. Assessment of ESS by noninvasive MRI might be useful for assessing atherosclerotic risk. PMID- 23357245 TI - Genome sequence of the plant growth promoting strain Bacillus amyloliquefaciens subsp. plantarum B9601-Y2 and expression of mersacidin and other secondary metabolites. AB - The plant-associated Bacillus amyloliquefaciens subsp. plantarum strain B9601-Y2, isolated from wheat rhizosphere, is a powerful plant growth-promoting rhizobacterium. Its relative large genome size of 4.24Mbp, exceeding that of other representatives of the B. amyloliquefaciens subsp. plantarum taxon, is mainly due to the presence of 18 DNA-islands containing remnants of phages, a unique restriction modification system, a gene cluster for mersacidin synthesis, and an orphan gene cluster devoted to non-ribosomal synthesis of an unidentified peptide. Like other members of the taxon, the Y2 genome contains giant gene clusters for non-ribosomal synthesis of the polyketides macrolactin, difficidin, and bacillaene, the antifungal lipopeptides bacillomycin D, and fengycin, the siderophore bacillibactin, and the dipeptide bacilysin. A gene cluster encoding enzymes for a degradative pathway with 2-keto-3-deoxygluconate and 2-keto-3-deoxy phosphogluconate as intermediates was explored by genome mining and found as being a unique feature for representatives of the plantarum subspecies. A survey of the Y2 genome against other B. amyloliquefaciens genomes revealed 130 genes only occurring in subsp. plantarum but not in subsp. amyloliquefaciens. Notably, the surfactin gene cluster is not functional due to a large deletion removing parts of the Srf synthetases B and C. Expression of polyketides, lipopeptides, mersacidin, and of the growth hormone indole-3-acetic acid in Y2 was demonstrated by matrix-assisted laser desorption ionization-time of flight mass spectroscopy and high-performance liquid chromatography, respectively. PMID- 23357246 TI - A hospital-based study on seroprevalence of leptospirosis among febrile cases in northeastern Malaysia. AB - OBJECTIVE: To determine the seroprevalence of leptospirosis among febrile inpatient cases in northeastern Malaysia. METHODS: A hospital-based cross sectional study was conducted among 999 febrile cases admitted to 10 hospitals in northeastern Malaysia. A survey using a proforma sheet was used to obtain sociodemographic and occupational information. Serum samples were screened for leptospirosis by IgM enzyme-linked immunosorbent assay test (IgM ELISA) and confirmed by microscopic agglutination test (MAT). RESULTS: There was an equivalent distribution of males and females in the 999 respondents enrolled in the study. The majority were Malay (94.7%) and their mean age was 39.4 (standard deviation 17.6) years. The overall seroprevalence of leptospirosis was 8.4% (95% confidence interval (CI) 6.8-10.3) (n=84). The high-risk occupational group was found to have a higher seroprevalence, which was 56% (95% CI 45.3-66.1) (n=47). The predominant serogroup was Sejroe (82.1%, 95% CI 72.6-88.8) (n=69). CONCLUSIONS: This study revealed a possible high seroprevalence of leptospirosis among febrile cases, indicating the need to review the importance of adding leptospirosis to the case investigation of febrile illness, especially among high risk occupational groups in Malaysia, as well as in other endemic countries. PMID- 23357247 TI - Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement in congenital pulmonary airway malformation. PMID- 23357248 TI - Exendin-4 increases bone mineral density in type 2 diabetic OLETF rats potentially through the down-regulation of SOST/sclerostin in osteocytes. AB - AIM: Glucagon-like peptide-1 (GLP-1) receptor participates in the control of bone resorption in GLP-1 knockout mice. Also, GLP-1 induces an insulin- and parathyroid hormone-independent osteogenic action through osteoclasts and osteoblasts in insulin-resistant and type 2 diabetic rats. Osteocytes are now considered central to bone homeostasis. A secreted product of osteocytes, sclerostin, inhibits bone formation. However, the effect of GLP-1 on osteocytes remains unclear. Therefore, we investigated the effect of GLP-1 on bone mineral density (BMD), and the cellular and molecular mechanisms associated with osteocytes. MAIN METHODS: We investigated the presence of GLP-1 receptors in osteocyte-like MLO-Y4 cells and osteocytes of rat femurs through RT-PCR, Western blot and confocal microscopy, and investigated the effect of exendin-4 on the expression of mRNA (by quantitative real-time RT-PCR) and protein (by Western blot) of SOST/sclerostin in osteocyte-like MLO-Y4 cells during culture under normal or high-glucose (30 mM) conditions, and measured circulating levels of sclerostin, osteocalcin, and tartrate-resistant alkaline phosphatase (TRAP) 5b and femoral BMD in type 2 diabetic OLETF rats treated with exendin-4. KEY FINDINGS: GLP-1 receptor was present on MLO-Y4 cells and osteocytes of rat femurs. Exendin-4 reduced the mRNA expression and protein production of SOST/sclerostin under normal or high-glucose conditions in MLO-Y4 cells. Exendin 4 reduced serum levels of sclerostin, increased serum levels of osteocalcin, and increased femoral BMD in type 2 diabetic OLETF rats. SIGNIFICANCE: These findings suggest that exendin-4 might increase BMD by decreasing the expression of SOST/sclerostin in osteocytes in type 2 diabetes. PMID- 23357249 TI - Erythropoiesis-stimulating agents (ESAs): do they still have a role in chemotherapy-induced anemia (CIA)? AB - PURPOSE: Anemia in cancer patients can be a result of the underlying cancer or related to treatment. Erythropoiesis-stimulating agents (ESAs) are an important option for many patients with chemotherapy-induced anemia, but are immersed in controversy. This article aims to reconcile conflicting opinions and provide expert guidance for appropriate ESA use. METHODS: Teleconference, email, and a face-to-face meeting were used to assess ESA therapy "interpretive" data, which included two current meta-analyses, expert guidelines, and regulatory approved indications from Canada, Europe, and the USA. RESULTS: Risks and benefits are associated with both red blood cell transfusions and ESA therapy, including improvements in hemoglobin levels and quality of life. ESAs have been associated with concerns regarding survival and progression of cancer, particularly when used in patients with cancer-related anemia. CONCLUSION: Although safety concerns do exist, ESA therapy can be considered for use in patients with chemotherapy induced anemia in accordance with Health Canada labeling. PMID- 23357250 TI - Comparison of diagnostic value of multidetector computed tomography and X-ray in the detection of body packing. AB - OBJECTIVE: Radiologists and other clinicians are facing an increasing number of illegal drug-related medical conditions. We aimed to draw attention to this growing global problem and to highlight some of the important points related to diagnosis and follow-up of body packing. We compare the diagnostic performance of unenhanced multidetector CT (MDCT) and abdomen X-ray for the detection of drug filled packets. MATERIALS AND METHODS: Sixty-seven suspects, who underwent both CT and X-ray examinations, have been included in the study. All MDCT and X-ray images were independently and retrospectively reviewed by two observers with different degrees of experience in abdomen imaging. Fifty-two of them were identified as body packers finally. Interobserver agreement, sensitivity, specificity, positive and negative predictive value were calculated. RESULTS: Two types of packets with different characteristics were identified in all body packers. Type 1 packets (solid-state drug) were found in 41 patients and type 2 packets (liquid cocaine) in 11 patients. All statistical analyses concern the detection of any packets. That is, the whole evaluation has been performed per patient. Sensitivity/specificity values of type 1 and type 2 packets for MDCT were 100-98%/100-100% and 100-100%/100-100%, respectively. Besides, sensitivity/specificity values of type 1 and type 2 packets for X-ray were 93 90%/100-91% and 64-45%/73-71%, respectively. In addition, interobserver agreements for detection of any packets were excellent (kappa=0.96) and good (kappa=0.75) for interpretation of MDCT and X-ray, respectively. CONCLUSION: Unenhanced MDCT is a fast, accurate and easily used diagnostic tool with high sensitivity and specificity for the exact diagnosis of body packing. PMID- 23357252 TI - Bicellar systems as new delivery strategy for topical application of flufenamic acid. AB - In this work, bicellar systems, bilayered disc-shaped nanoaggregates formed in water by phospholipids, are proposed as a novel strategy for delivery of the anti inflammatory flufenamic acid (FFA) to the skin. A comparative percutaneous penetration study of this drug in bicellar systems and other vehicles was conducted. The effects induced on the skin by the application of FFA in the different vehicles were analyzed by attenuated total reflectance-fourier transform infrared (ATR-FTIR). Additionally, using the microscopic technique freeze-substitution transmission electron microscopy (FSTEM) and X-ray scattering technique using synchrotron radiation (SAXS-SR), we studied the possible microstructural and organizational changes that were induced in the stratum corneum (SC) lipids and the collagen of the skin by the application of FFA bicellar systems. Bicellar systems exhibited a retarder effect on the percutaneous absorption of FFA with respect to the other vehicles without promoting disruption in the SC barrier function of the skin. Given that skin disruption is one of the main effects caused by inflammation, prevention of disruption and repair of the skin microstructure should be prioritized in anti inflammatory formulations. PMID- 23357251 TI - The influence of upper limb position on the effect of a contrast agent in chest CT enhancement. AB - PURPOSE: To compare the influence of two different upper limb positions on contrast agent effects in chest CT enhancement. MATERIALS AND METHODS: In 142 patients undergoing contrast-enhanced CT chest scanning, an indwelling venous catheter was placed in the right hand and iodinated contrast agent was injected through a high-pressure single syringe pump. The patients were divided into three age groups (<40 years; 40-60 years; and >60 years) and randomly assigned to one of two upper limb position groups: (1) supine position, both upper limbs extended and raised above head in the same horizontal plane as the body; and (2) supine position, both upper limbs raised and crossed on the forehead, with the right arm on top. Differences in mean CT values on the two sides of the thoracic inlet along the right subclavian vein were used to evaluate the effects of the contrast agent. RESULTS: Although contrast agent effects were not significantly different among the three age groups with either limb position, there was a significant difference between patients adopting the second limb positions (Chi-square value was 5.936, P<0.05). An excellent or good contrast agent effect was observed in 63.08% of patients assuming the first limb position, as compared with 81.69% assuming the second position. CONCLUSION: For contrast-enhanced CT chest scans, use of the second limb position can reduce retention of the contrast agent in the right axillary vein and the right subclavian vein outside the thorax, increase contrast agent utilization, and decrease artifacts caused by high-density, local retention of the contrast agent. PMID- 23357253 TI - Drug-inorganic-polymer nanohybrid for transdermal delivery. AB - For transdermal drug delivery, we prepared a drug-inorganic nanohybrid (FB-LDH) by intercalating a transdermal model drug, flurbiprofen (FB), into the layered double hydroxides (LDHs) via coprecipitation reaction. The X-ray diffraction patterns and FT-IR spectra of the FB-LDH indicated that the FB molecules were successfully intercalated via electrostatic interaction within the LDH lattices. The in vitro drug release revealed that the Eudragit((r)) S-100 in release media could facilitate the drug out-diffusion by effectively replacing the intercalated drug and also enlarging the lattice spacing of the FB-LDH. In this work, a hydrophobic gel suspension of the FB-LDH was suggested as a transdermal controlled delivery formulation, where the suspensions were mixed with varying amounts of Eudragit((r)) S-100 aqueous solution. The Frantz diffusion cell experiments using mouse full-skins showed that a lag time and steady-state flux of the drug could be controlled from 12.8h and 3.28MUgcm(-2)h(-1) to less than 1h and 14.57MUgcm(-2)h(-1), respectively, by increasing the mass fraction of Eudragit((r)) S-100 solution in gel suspensions from 0% to 20% (w/w), respectively. Therefore, we conclude gel formulation of the FB-LDH have a potential for transdermal controlled drug delivery. PMID- 23357254 TI - A new paradigm in dermatopharmacokinetics - Confocal Raman spectroscopy. AB - Confocal Raman spectroscopy (CRS) is a novel approach which has been used to determine stratum corneum thickness and to profile endogenous skin components. However, the utility of this technique for probing drug disposition in vivo has not been explored to date. In this paper we report the use of CRS to investigate the fate of ibuprofen after application from simple formulations which were previously investigated using the tape-stripping approach. Ibuprofen was prepared in propylene glycol (PG) and propylene glycol/water (PG/H2O) solutions. The formulations were then applied to the volar aspect of the forearm of human volunteers. The results confirmed that ibuprofen distribution profiles in the stratum corneum were comparable to previously published data from tape stripping experiments. We propose CRS as a non-invasive method for dermatopharmacokinetic evaluation of topical pharmaceutical formulations. PMID- 23357255 TI - In vivo/in vitro pharmacokinetic and pharmacodynamic study of spray-dried poly (dl-lactic-co-glycolic) acid nanoparticles encapsulating rifampicin and isoniazid. AB - Poly-(dl-lactic-co-glycolic) acid (PLGA) nanoparticles were prepared by a double emulsion solvent evaporation spray-drying technique and coated with polyethylene glycol (PEG 1% v/v). The PLGA nanoparticles had a small size (229+/-7.6 to 382+/ 23.9nm), uniform size distribution and positive zeta potential (+12.45+/-4.53mV). In vitro/in vivo assays were performed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) performance of these nanoparticles following nanoencapsulation of the anti-tuberculosis drugs rifampicin (RIF) and isoniazid (INH). The results demonstrated the potential for the reduction in protein binding of these drugs by protection in the polymer core. Furthermore, in vitro efficacy was demonstrated using Mycobacterium tuberculosis (M. tb.) (strain H37Rv). Sustained drug release over seven days were observed for these drugs following once-off oral administration in mice with subsequent drug distribution of up to 10 days in the liver and lungs for RIF and INH, respectively. It was concluded by these studies combined with our previous reports that spray-dried PLGA nanoparticles demonstrate potential for the improvement of tuberculosis chemotherapy by nanoencapsulation of anti-tuberculosis drugs. PMID- 23357256 TI - Modelling of the break force of tablets under diametrical compression. AB - A numerical method to predict the break force of curved faced tablets is proposed. The constitutive model and the failure criteria necessary to obtain predictions consistent with experimental data are identified. A modified Drucker Prager cap model together with a maximum principal stress based failure criteria was found sufficient to predict the break force of tablets under diametrical compression loading. The conditions for the validity of the method were identified with reference to practical tablet shapes and failure patterns. Under these conditions the numerical procedures can be used as a practical tool to predict tablet breakage as an alternative to the empirical methods currently used in pharmaceutical product design and process development. PMID- 23357257 TI - Biocompatibility of boron nitride nanotubes: an up-date of in vivo toxicological investigation. AB - Boron nitride nanotubes (BNNTs) represent an innovative and extremely intriguing class of nanomaterials, and preliminar but encouraging studies about their applications in biomedicine have emerged in the latest years. As a consequence, a systematic investigation of their biosafety has become of fundamental importance in the biomedical research. Extending our previous pilot in vivo study, here we present biocompatibility data of BNNTs injected in rabbits at a dose up to 10mg/kg. No significant adverse effects were found up to 7 days since their administration, and no impairments in blood, liver and kidney functionality were highlighted. Moreover, a terminal half-life circulation of about 90min was found. All the collected data are very promising, suggesting the optimal biocompatibility of BNNTs, and thus enabling their exploitation in nanomedicine as nanotransducers and nanocarriers. PMID- 23357258 TI - Modified TEWL in vitro measurements on transdermal patches with different additives with regard to water vapour permeability kinetics. AB - Water vapour permeability (WVP) and water absorption capacity (WAC) influence physicochemical properties and wearability of transdermal patches considerably. For determination of WVP, a modified transepidermal water loss (TEWL) measurement was developed. These measurements continuously measure WVP of transdermal patches in vitro along with time required to reach steady state, and its magnitude according to the type of polymer used. Additionally, WAC of the patches was examined and related to WVP. According to literature in the field of WVP determination, usually selected points are taken from the evaporation time curve and averaged over a given time span without knowing whether steady state has already been reached or not. The latter causes errors upon averaging. The advantage of the in vitro TEWL measurement presented includes reproducibly adjustable conditions for every time span desired, thus providing information on the kinetics of the experiment and avoiding biased results from averaging. Knowing the shape of the evaporation time curve and thus the kinetics of the experiment allows for focusing on the relevant part of the measurement, i.e. the determination of the steady state level and the time to reach it. Four different polymers (P1-P4) based on sugar-modified polyacrylates were investigated with regard to WVP and WAC of the matrices prepared thereof along with the influence of drug loading and the incorporation of a variety of additives commonly used for transdermal patches. A clear correlation between WVP and the hydrophilicity in terms of the number of free hydroxyl groups of the polymer was elaborated. Additives of higher hydrophilicity compared to that of the polymer itself led to higher WVPs and vice versa. The combination of the model drug lidocaine in its free base form together with the additive succinic acid (Suc) resulted in ionization of the drug and thus in substantially increased WVPs. Addition of alpha-tocopherol acetate (Toc) into P3 and P4 and Suc into the drug-free matrix of P3 decreased WVP probably by affecting the structure of the polymer network. The same effects were found for WAC upon incorporation of succinic acid into drug loaded matrices of P3 and P4 (drug-loaded patches of P1 and P2 were not tested) but not for additives which were likely to modify the polymer network structure. PMID- 23357259 TI - [Tumor genetic heterogeneity]. AB - Although the majority of spontaneous tumors derive from a single cell, people have come to realize intra-tumor heterogeneity of individual tumors. Human cancers frequently display substantial difference in phenotypic features, such as the degree of differentiation, cell proliferation rate, invasion and metastatic potential, response to therapy and many other aspects. Molecular biology studies have confirmed the occurrence of new mutations during the process of tumor progression, which provide more powerful evidences to show the existence of intra tumor genetic heterogeneity. This re-view will focus on recent major advances in the study of tumor genetic heterogeneity. Considering that genetic heterogene-ity analysis can provide important information to indicate how long normal cells transform into tumor cells and how to spread and migrate, we firstly describe experimental evidences of intra-tumor genetic heterogeneity. Then we discuss the research value of genetic diversity in the evolutionary history of human individual tumor, introduce the two modes of the genetic heterogeneity - cancer stem cell model and the clonal evolution model, and summarize the implications of in-tra-tumor heterogeneity studies in metastasis and therapy. In addition, the article presents the research methods of genetic heterogeneity, including specific gene and genome-wide level, pointing out their strengths and limitations. PMID- 23357260 TI - [The regulation of anoikis in tumor invasion and metastasis]. AB - As a barrier to metastasis of cancer, cells that lost contact with the neighbouring cells or extracellular matrix(Extracellular matrix, ECM) will be subjected to apoptosis. This cell death process has been termed "anoikis". When normal epithelial cells or solid tumor cells without metastatic potential detach from the primary site, and then enter into the circulatory system, the anoikis mechanism will be activated. The significance of anoikis is to prevent the shedding cells from growing and implanting into other inappropriate sites. Tumor cells, especially several malignant cells that is prone to transfer to distant sites, have properties of anti-anoikis, which facilitates metastasis as well as invasion of tumor cells. The studies found that tumor cells can resist anoikis through multiple mechanisms: the pro-survival pathways are activated by cells autocrine growth factors and paracrine factors derived from neighboring cells; cells change the pattern of integrin expression so that they can receive survival signals from new environment; reactive oxygen species (ROS) activates growth factor receptors in a ligand-independent way to avoid apoptosis; and epithelial mesenchymal transformation(EMT) is activated etc.. All of these mechanisms lead to activation of survival signals and inhibition of apoptotic pathways, and ultimately cause resistance to anoikis as well as metastasis. This paper summarizes the key mechanisms of the current studies on metastasis, which also suggest important targets for cancer therapy. PMID- 23357261 TI - [Bioinformatics advances in protein ubiquitination]. AB - Ubiquitin-proteasome system (UPS) mediates 80% to 85% of the protein degradation in eukaryotic cells. The characteristics of UPS pathway are dependent on ATP, efficient and highly selective. Ubiquitination not only participates in protein degradation, but also directly affects protein activity and localization. Ubiquitination can regulate multiple cellular processes including cell cycle progression, apoptosis, transcriptional regulation, DNA damage repair and immune response. More and more datasets about UPS are published, and it is necessary to organize and analyze these data efficiently. We re-view the related bioinformatics studies in UPS datasets, such as collection of UPS related proteins, construction and analysis of ubiquitination networks, prediction of ubiquitination sites and motifs. Some potential perspectives are also discussed. PMID- 23357262 TI - [Research progress in G protein-coupled receptor 40]. AB - GPR40 is one of the G protein-coupled receptors, which has 7 transmembrance spanning helical bundles. GPR40 distributes in pancreas and central nervous system. It can be bound by medium and long chain fatty acid and activate the intracellular signal pathways, which in turn regulates the function of cells. In b-cell, intracellular calcium concentration elevates when GPR40 is binding to fatty acid, thereby promoting the release of insulin. According to the theory, new drugs, the agonist of GPR40, have been used for prepreventing and treating the diabete as. In the nervous system, GPR40 is involved in neurogenesis, but the mechanism how GPR40 works is unclear until now. In this review, the research progress of GPR40 was reviewed, especially about the structure and characteristics of GPR40 gene, ligands and function. We focused on the problems encountered in the current research and the hot points in the future. PMID- 23357263 TI - [Research progress of conserved non-coding elements in metazoan]. AB - In addition to protein coding sequence, the organism genome contains a significant amount of regulatory DNA. Comparative genomics reveals that the organism genomes of vertebrates, tunicate, cephalochordate, flies, and nematodes contain cis-regulatory elements with highly conserved non-coding elements (CNEs). CNEs that cluster around trans-dev genes are part of core gene regulatory networks (GRNs), and usually, they can act as transcriptional enhancers. In this review, we described the identification of CNEs and summarized their key properties across the metazoans, and then discussed the evolution of CNEs after large-scale genome duplication events and the role of CNEs in the evolution of ani-mal body plan. PMID- 23357264 TI - [Expression regulation of plant ascorbate peroxidase and its tolerance to abiotic stresses]. AB - Ascorbate peroxidase (APX), a type I heme peroxidase, catalyzes oxidation of ascorbic acid. It possesses a high degree of specificity to ascorbic acid. APX gene cluster consists of four sub-clusters: the gene clusters of cytosol, chloroplast, mitochondria, and peroxidase. As a key component of hydrogen peroxide detoxification system, the ascorbate-glutathione cycle, APX plays a vital role in the metabolism of H2O2 of plant cells. Studies showed that APX is one of the most important enzymes, which modulate the cellular H2O2 level in redox signaling system. The expression mechanisms of APX isoenzymes are quite complex. Briefly, cytosolic APX is regulated by a variety of signals; two chloroplastic APX isoenzymes are tissue-dependently regulated by alternative splicing. Generated APXs could regulate redox signaling in cells, which further boosts plants tolerance to abiotic stresses. This review focuses on recent advances concerning catalytic prop-erties, physiological function, and gene expressing regulation and abio-stress responding mechanism of APX. PMID- 23357265 TI - [Variable lymphocyte receptors: the novel tool for clinical diagnosis and therapy]. AB - Monoclonal antibodies, which are widely applied to the diagnosis and therapy of cancers as well as autoimmune diseases, have been made significant progresses. Currently, the monoclonal antibodies for clinical applications are mostly based on the modified immunoglobulins. However, the variable lymphocyte receptors (VLRs), which are recently discovered as specific antigen receptors of jawless vertebrates, provide a new perspective for the development of antibody reagents and drugs. Compared with immunoglobulins, the antigen-binding specificity, affinity and stability of VLRs-based antibodies are better. In addition, the production technology of antigen-specific monoclonal VLRs has become more and more mature. Therefore, the VLRs have a higher clinical value and may become the next-generation antibody drug. This review focuses on the basic feature, production method and application prospect of VLRs, which provides valuable clues for the applications of VLRs in the field of clinical diagnosis and therapy. PMID- 23357266 TI - [Mitochondrial 12S rRNA A1555G mutation associated with nonsyndromic hearing loss in twenty-five Han Chinese pedigrees]. AB - Mitochondrial 12S rRNA A1555AG mutation is one of the important causes of aminoglycoside-induced and nonsyndromic deafness. We report here the clinical, genetic and molecular characterization of 25 Chinese families carrying the A1555G mutation.Clinical and genetic characterizations of these Chinese families exhibited a wide range of penetrance, severity and age-at-onset of hearing impairment. The average penetrances of deafness were 28.1% and 21.5%, respectively, when aminoglycoside-induced hearing loss was included or excluded. Furthermore, the average age-of-onset for deafness without aminoglycoside exposure ranged from 1 and 15 years old. Their mitochondrial genomes exhibited distinct sets of polymorphisms including 16 novel variants, belonging to ten Eastern Asian haplogroups A, B, D, F, G, M, N and R, respectively. Strikingly, these Chinese families carrying mitochondrial haplogroup B exhibited higher penetrance and expressivity of hearing loss. In addition, 7 known secondary mutations and 21 variants resided at the highly conservative residues may enhance the penetrace of hearing loss in these Chinese families. Moreover, the absence of mutation in GJB2 gene suggested that GJB2 may not be a modifier for the phenotypic expression of the A1555G mutation in these Chinese families. These observations suggested that mitochondrial haplotypes and other modifiers may modulate the variable penetrance and expressivity of deafness among these Chinese families. PMID- 23357267 TI - [Association study between Y-chromosome haplo group and susceptibility to spermatogenisis impairment in Han People from Southwest China]. AB - Idiopathic azoospermia and oligospermia are one of the most important reasons for male infertility. Abnormal karyotype and azoospermia factor (AZF) microdeletion are two widely acknowledged reasons, but the most causes remain unclear. Y chromosome, as the male-specific chromosome, is closely related to the development of male reproductive system. To understand better the etiology of idiopathic azoospermia and oligospermia, we investigated the possible association between Y-haplogroup distributions and susceptibility to idiopathic azoospermia and severe oligospermia. Peripheral blood was collected from 193 men with normal reproductive history, 193 men with idiopathic azoospermia, and 72 men with idiopathic severe oligospermia. All the subjects underwent karyotyping and AZF deletion analysis to screen out those with AZF deletion and abnormal karyotype. The comparison of Y-haplogroup distribution between experimental group and control group was performed with SPSS V.18.0 software. Significant difference of Y-haplogroup distribution was observed in D1*, F*, K*, N1* and O3*(P=0.032, 0.022, 0.009, 0.009, 0.017, <0.05). The results suggest that Y chromosome haplogroup plays a important role in spermatogenic impairment. PMID- 23357268 TI - [BRPF2, a novel transcript of BRPF1 and their expression in mice tissues]. AB - In order to identify a novel transcript of BRPF1 (BRPF2), a clone separated from mouse cDNA library was sequenced and submitted to GenBank. The expressions of BRPF1 and BRPF2 in different mice tissues were detected using RT-PCR and Northern blotting assays. The preliminary protein functions and conservative domains were analyzed by bioinformatic methods. The results indicated that BRPF2 was a novel transcript of BRPF1. Both BRPF1 and BRPF2 transcripts could be detected in most mice tissues, including liver, embryo, epididymis, testis, ovary and muscle. However, only BRPF2 transcript could be detected in the spleen. BRPF1 mRNA encoded 1 246 aa and the predicted molecular mass was 140 kDa, while BRPF2 encoded 442 aa, partly owing to the absence of a new stop codon. The results of CDD analysis suggested that BRPF2 lost the bromodomain and the PWWP domain compared to BRPF1. Because the bromodomain and the PWWP domain are the critical structures of BRPF1 to interact with histones and recruit the other transcriptional factors, BRPF2 (without these two critical domains) may serve as a negative regulatory factor of BRPF1 and be involved in the chromosome remodeling and transcriptional regulating. PMID- 23357269 TI - [Relative quantification of mRNA transcription of Cry1 in different tissues of sheep in oestrous cycle by real-time quantitative PCR]. AB - Studies have shown that clock gene Cry1 may have important roles in the endocrine process of seasonal reproduction in mammals. In this study, Duolang sheep (non seasonal reproduction sheep breed) and Chinese Merino (seasonal reproduction sheep breed) were used to determine the expression change of Cry1 in hypothalamus pituitary-ovary axis in different stage of estrous cycle by quantitative real time PCR. The results showed that the Cry1 mRNA was expressed in all tested tissues, in which the expression levels in pineal gland and thyroid gland were higher than in other tissues. As far as different sheep breeds were concerned, the tissue expression profiles of Cry1 at different stage of estrous cycle were broadly similar. Besides hypothalamus, the expression levels of Cry1 in ovary, uterus, pineal gland, pituitary gland, and thyroid gland were all reached to peak in proestrus. The differences of expression change extent for Cry1 in vary, uterus, pineal gland, and pituitary gland in proestrus and oestrus were significant between different sheep breeds. The results suggested that Cry1 may play roles in switching on the estrus and seasonal reproduction. PMID- 23357270 TI - [Expression and functional analysis of SUA41gene in Arabidopsis thaliana]. AB - In plants, multiple floral induced-pathways including photoperiod signaling, vernalization signaling, autonomous pathway, gibberellin signaling, and thermosensory signaling are well known to mediate signaling from different cues to confer flowering regulation. SUA41 (SUMO substrate 41) is a SUMO (Small ubiquitin modifier) substrate screened out in our laboratory. Previous reports indicate that the SUA41 gene is involved in autonomous pathway to regulate flowering time of Arabidopsis, but its mechanism remains to be elucidated. In this study, the spatiotemporal expression pattern for SUA41, responses of its mutant to environmental factors, and its regulation of mechanism of flowering time were investigated. The sua41 mutant flowered earlier than Col-0 at both normal temperature (22C) and low temperature (16C) under long day (LD) or short day (SD) conditions. In addition, the flowering times of sua41 had no significant difference between 22C and 16C conditions. Over-expression of SUA41 rescued the early flowering phenotype of the sua41 mutant. Expression of SUA41 was at similar levels in seedlings, roots, stems, leaves, flowers, or the samples at all developmental stages examined, suggesting that SUA41 is a constitutive expression gene. Expression of SUA41 mRNA was not responsive to GA treatment, but highly induced by low temperature and inhibited in fve and fca mutants defective in the thermosensory pathway. Compared with Col-0, the expression levels of FT and SOC1 increased, whereas the expression level of FLC mRNA decreased and CO expression was not significantly altered in the sua41 mutant. The results showed that the SUA41 gene plays a role in not only the autonomous pathway but also the thermosensory pathway to regulate flowering time of Arabidopsis. PMID- 23357271 TI - [Promotion of tuition quality in Genetics by developing an excellent instructional system]. AB - This article, which is based on the requirements for developing the course of Genetics as an outstanding course, summarizes the experience of engendering an excellent instructional system, expatiates on the effects of its application to the teaching process of "Genetics" and next step work for continuing this instructional system. The course quality of "Genetics" has been improved under the excellent instructional system by including different teaching methods, renovating the teaching contents, innovating the teaching means, developing a practical courseware, writing extractive textbooks, reforming experimental teaching, and constructing an instructional network, together with teaching methods related to scientific research. PMID- 23357272 TI - [A new method to determine the proportion of characters F2 in the Mendelian inheritance-the observation method of dominant traits]. AB - A new method, the observation method of dominant traits, which can be used for determining the proportion of characters from F2 under the Mendelian Inheritance, was discovered. The principle of this method is that people can conclude a general formula:3n1 (n1: the number of dominant characters types in F2) based on the proportion of characters from F2 under the Mendelian Inheritance. This method is more convenient and time-saving than common tests in teaching and practice of classic genetics. PMID- 23357273 TI - [A new agroinoculation technology for foreign gene expression in plants by means of transient expression]. AB - Due to the laborious and scale-up limitation we have developed a simple method named "seed absorption" to express foreign proteins in plants by means of transient expression. It has been shown that the reporter gene GFP was expressed successfully in tomato (Solanum lycopersicum L.) plants by seed absorbing Agrobacterium suspension containing TMV-based p35S-30B-GFP vector. Various factors influencing the gene expression were optimized including Agrobacterium cell density and other inoculation conditions. This method has the special advantages as simple work process, ease to scale-up, and further expanding the host range of plant bioreactor than previous methods. We assume that the seed absorption method will facilitate the industrial scale production of the recombinant pharmaceutical proteins in plants. PMID- 23357274 TI - A pediatric cervical spine clearance protocol to reduce radiation exposure in children. AB - BACKGROUND: To minimize radiation exposure in children and reduce resource use, we implemented an age-specific algorithm to evaluate cervical spine injuries at a Level 1 trauma center. The effects of protocol implementation on computed tomography (CT) use in children (<= 10 y) were determined. METHODS: With institutional review board approval, we conducted a retrospective review using the institutional trauma registry. All pediatric patients (<= 10 y) (n = 324) between January 2007 and present were reviewed. We excluded cases in which no imaging or outside imaging was performed. Patients were evaluated by physical exam alone, with the aid of plain radiograms or with cervical spine CT. All patients who required head CT also had CT of cervical spine to C3. We analyzed demographic, injury, and outcome data using STATA to perform chi-square and t test, and to determine P value. P < 0.05 was defined as significant. We used the WinDose program to calculate the radiation-effective dose used in cervical spine CT. RESULTS: There were 123 and 124 patients in the pre-protocol and post protocol groups, respectively. Demographics, GCS, and injury analysis, specifically head-neck and face Injury Severity Scores showed no significant difference between groups. There was a 60% (P < 0.001) decrease in the use of full CTs after protocol implementation. We estimated that the protocol reduced the exposed area by 50% and decreased the radiation dose to the thyroid by > 80%. We extrapolated the combined effect results in a threefold reduction in radiation exposure. CONCLUSIONS: Implementation of a cervical spine protocol led to a significant reduction in radiation exposure among children. PMID- 23357275 TI - Twenty years of pediatric gunshot wounds: an urban trauma center's experience. AB - BACKGROUND: Pediatric gunshot wounds remain an important cause of morbidity and mortality in the United States. Recent experience in the urban pediatric population has not been extensively documented. METHODS: A retrospective review of the trauma registry identified all pediatric (age 0-16 y) gunshot wound injuries between October 1991 and August 2011. We evaluated demographic, injury location, disposition, and outcome data. We applied descriptive statistics and chi(2) with significance level set to P <= 0.05. RESULTS: We treated 740 patients at our trauma center. Patients tended to be male (82%) and African American (72%), and most frequently were shot in the abdomen, back, or pelvic regions (26%). Patients with head or neck injuries experienced the highest mortality rate (35%), whereas the mortality rate overall was 12.7%. A total of 23% of patients were discharged directly, but 32% required an operation. We grouped data into five equal time periods, demonstrating that after decreasing through the 1990s, pediatric gunshot wounds presenting to our hospital are steadily increasing. CONCLUSIONS: We identified certain demographic and temporal trends regarding pediatric gunshot wounds, and the overall number of injuries appears to be increasing. PMID- 23357277 TI - Calcific retropharyngeal tendinitis of the longus colli muscle. Answer to the e quid "Acute cervical pain and dysphagia in a 43 year-old man". PMID- 23357278 TI - Tryptophan-47 in the active site of Methylophaga sp. strain SK1 flavin monooxygenase is important for hydride transfer. AB - Flavin-dependent monooxygenase (FMO) from Methylophaga sp. strain SK1 catalyzes the NADPH- and oxygen-dependent hydroxylation of a number of xenobiotics. Reduction of the flavin cofactor by NADPH is required for activation of molecular oxygen. The role of a conserved tryptophan at position 47 was probed by site directed mutagenesis. FMOW47A resulted in an insoluble inactive protein; in contrast, FMOW47F was soluble and active. The spectrum of the flavin in the mutant enzyme was redshifted, indicating a change in the flavin environment. The kcat values for NADPH, trimethylamine, and methimazole, decreased 5-8-fold. Primary kinetic isotope effect values were higher, indicating that hydride transfer is more rate-limiting in the mutant enzyme. This is supported by a decrease in the rate constant for flavin reduction and in the solvent kinetic isotope effect values. Results from molecular dynamics simulations show reduced flexibility in active site residues and, in particular, the nicotinamide moiety of NADP+ in FMOW47F. This was supported by thermal denaturation experiments. Together, the data suggests that W47 plays a role in maintaining the overall protein flexibility that is required for conformational changes important in hydride transfer. PMID- 23357279 TI - Cytochrome P450 107U1 is required for sporulation and antibiotic production in Streptomyces coelicolor. AB - The filamentous bacterium Streptomyces coelicolor has a complex life cycle involving the formation of hair-like aerial mycelia on the colony surface, which differentiate into chains of spores. Genes required for the initiation of aerial mycelium formation have been termed 'bld' (bald), describing the smooth, undifferentiated colonies of mutant strains. We report the identification of a new bld gene designated as sco3099 and biochemical analysis of its encoded enzyme, cytochrome P450 (P450, or CYP) 107U1. Deletion of sco3099 resulted in a mutant defective in aerial hyphae sporulation and sensitive to heat shock, indicating that P450 107U1 plays a key role in growth and development of S. coelicolor. This is the first P450 reported to participate in a sporulation process in Streptomycetes. The substrate and catalytic properties of P450 107U1 were further investigated in mass spectrometry-based metabolomic studies. Glycocholic acid (from the medium) was identified as a substrate of P450 107U1 and was oxidized to glyco-7-oxo-deoxycholic acid. Although this reaction is apparently not relevant to the observed sporulation deficiency, it suggests that P450 107U1 might exert its physiological function by oxidizing other steroid-like molecules. PMID- 23357281 TI - Variation in orthostatic vital sign testing in an urban academic emergency department. PMID- 23357280 TI - Knockdown of pyruvate carboxylase or fatty acid synthase lowers numerous lipids and glucose-stimulated insulin release in insulinoma cells. AB - We previously showed that knockdown of the anaplerotic enzyme pyruvate carboxylase in the INS-1 832/13 insulinoma cell line inhibited glucose-stimulated insulin release and glucose carbon incorporation into lipids. We now show that knockdown of fatty acid synthase (FAS) mRNA and protein also inhibits glucose stimulated insulin release in this cell line. Levels of numerous phospholipids, cholesterol esters, diacylglycerol, triglycerides and individual fatty acids with C14-C24 side chains were acutely lowered about 20% in glucose-stimulated pyruvate carboxylase knockdown cells over a time course that coincides with insulin secretion. In FAS knockdown cells glucose carbon incorporation into lipids and the levels of the subclasses of phospholipids and cholesterol ester species were lower by 20-30% without inhibition of glucose oxidation. These studies suggest that rapid lipid modification is essential for normal glucose-stimulated insulin secretion. PMID- 23357282 TI - Treadmill exercise induces age-related changes in aversive memory, neuroinflammatory and epigenetic processes in the rat hippocampus. AB - It has been described that exercise can modulate both inflammatory response and epigenetic modifications, although the effect of exercise on these parameters during the normal brain aging process yet remains poorly understood. Here, we investigated the effect of aging and treadmill exercise on inflammatory and epigenetic parameters specifically pro and anti-inflammatory cytokines levels, activation of NF-kB and histone H4 acetylation levels in hippocampus from Wistar rats. Additionally, we evaluated aversive memory through inhibitory avoidance task. Rats of 3 and 20 months of age were assigned to non-exercised (sedentary) and exercised (running daily for 20 min for 2 weeks) groups. The effect of daily forced exercise in the treadmill was assessed. The levels of inflammatory and epigenetic parameters were determined 1h, 18 h, 3 days or 7 days after the last training session of exercise. It was observed an age-related decline on aversive memory, as well as aged rats showed increased hippocampal levels of inflammatory markers, such as TNFalpha, IL1-beta and NF-kB and decreased IL-4 levels, an anti inflammatory cytokine. Moreover, lower levels of global histone H4 acetylation were also observed in hippocampi from aged rats. Interestingly, there was a significant correlation between the biochemical markers and the inhibitory avoidance test performance. The forced exercise protocol ameliorated aging related memory decline, decreased pro-inflammatory markers and increased histone H4 acetylation levels in hippocampi 20-months-old rats, while increased acutely IL-4 levels in hippocampi from young adult rats. Together, these results suggest that an imbalance of inflammatory markers might be involved to the aging-related aversive memory impairment. Additionally, our exercise protocol may reverse aging related memory decline through improving cytokine profile. PMID- 23357283 TI - A quantitative analysis of the effects of qualitatively different reinforcers on fixed ratio responding in inbred strains of mice. AB - Previous studies of inbred mouse strains have shown reinforcer-strain interactions that may potentially mask differences among strains in memory performance. The present research examined the effects of two qualitatively different reinforcers (heterogeneous mix of flavored pellets and sweetened condensed milk) on responding maintained by fixed-ratio schedules of reinforcement in three inbred strains of mice (BALB/c, C57BL/6, and DBA/2). Responses rates for all strains were a bitonic (inverted U) function of the size of the fixed-ratio schedule and were generally higher when responding was maintained by milk. For the DBA/2 and C57BL/6 and to a lesser extent the BALB/c, milk primarily increased response rates at moderate fixed ratios, but not at the largest fixed ratios tested. A formal model of ratio-schedule performance, Mathematical Principles of Reinforcement (MPR), was applied to the response rate functions of individual mice. According to MPR, the differences in response rates maintained by pellets and milk were mostly due to changes in motoric processes as indicated by changes in the minimum response time (delta) produced by each reinforcer type and not specific activation (a), a model term that represents value and is correlated with reinforcer magnitude and the break point obtained under progressive ratio schedules. MPR also revealed that, although affected by reinforcer type, a parameter interpreted as the rate of saturation of working memory (lambda), differed among the strains. PMID- 23357284 TI - Tone-detection training enhances spectral integration mediated by intracortical pathways in primary auditory cortex. AB - Auditory-cued behavioral training can alter neural circuits in primary auditory cortex (A1), but the mechanisms and consequences of experience-dependent cortical plasticity are not fully understood. To address this issue, we trained adult rats to detect a 5 kHz target in order to receive a food reward. After 14 days training we identified three locations within A1: (i) the region representing the characteristic frequency (CF) 5 kHz, (ii) a nearby region with CF ~10 kHz, and (iii) a more distant region with CF ~20 kHz. In order to compare functional connectivity in A1 near to, vs. far from, the representation of the target frequency, we placed a 16-channel multiprobe in middle- (~10 kHz) and high- (~20 kHz) CF regions and obtained current-source density (CSD) profiles evoked by a range of tone stimuli (CF+/-1-3 octaves in quarter-octave steps). Our aim was to construct "CSD receptive fields" (CSD RFs) in order to determine the laminar and spectral profile of tone-evoked current sinks, and infer changes to thalamocortical and intracortical inputs. Behavioral training altered CSD RFs at the 10 kHz, but not 20 kHz, site relative to CSD RFs in untrained control animals. At the 10 kHz site, current sinks evoked by the target frequency were enhanced in layer 2/3, but the initial current sink in layer 4 was not altered. The results imply training-induced plasticity along intracortical pathways connecting the target representation with nearby cortical regions. Finally, we related behavioral performance (sensitivity index, d') to CSD responses in individual animals, and found a significant correlation between the development of d' over training and the amplitude of the target-evoked current sink in layer 2/3. The results suggest that plasticity along intracortical pathways is important for auditory learning. PMID- 23357285 TI - Enzymatic synthesis of 2-aminoethyl beta-D-galactopyranoside catalyzed by Aspergillus oryzae beta-galactosidase. AB - Glycosidases provide a powerful resource for in vitro synthesis of novel anomerically pure glycosides. Generation of new low molecular weight galactosides is of interest since they are potential galectin inhibitors. Galectins are molecular targets for cancer therapy and thus their inhibitors are potential antitumor agents. Here we report the enzymatic synthesis and structural characterization of 2-aminoethyl beta-D-galactopyranoside. Critical parameters for transgalactosylation using either soluble or immobilized enzyme were investigated and optimized for the galactoside synthesis. We found that 0.2 M lactose, and 0.5 M 2-aminoethanol at 50 degrees C for 30 min were the optimal conditions for synthesis. 2-Aminoethanol proved to be an enzyme inhibitor, fitting a mixed inhibition model with inhibition constants, K(ic)=0.31+/-0.04 M and K(iu)=0.604+/-0.035 M. PMID- 23357286 TI - Stochastic comparisons of mixtures of parametric families in stochastic epidemics. AB - The paper is first concerned with the stochastic comparisons for mixed Erlang random variables when the arbitrary mixing distributions are ordered by increasing directionally convex order or an univariate ordering. Similar results for mixtures of gamma, lognormal, geometric and Poisson families are given. The main results are applied for the analysis of the effect of the positive correlation and the variation of the parameters of some measures in stochastic epidemics, that are mixtures of parametric families as earlier with environmental parameters, arising from extensions that we provide of the SEIR model with vaccination and isolation for structured populations by [2] and the SIR model with term-time forcing, by [11]. Unlike the previous stochastic epidemic models, we consider parameter uncertainty with arbitrary mixing distributions, and stochastic dependencies among them. We rank the probabilities that the severity (active severity) of the epidemic in the household after the first removal exceeds a fixed level conditioning on a threshold parameter, we bound the expected value of increasing convex functions of the severity (active severity), we calculate and compare the basic reproduction numbers, for the SEIR model with vaccination and isolation; and in addition, we bound the number of type-i individuals infected from type-i infectives and the times until either a recovery or a state change happens, for the SIR model with term-time forcing. Using the positive quadrant dependence of the parameter vector, the mixture models are compared with models having the same marginal distributions for the mixing variables but independent components. They assess on the development of some public health policies (vaccination, household isolation, other structuring patterns). PMID- 23357287 TI - Virus dynamics in the presence of synaptic transmission. AB - Traditionally, virus dynamics models consider populations of infected and target cells, and a population of free virus that can infect susceptible cells. In recent years, however, it has become. clear that direct cell-to-cell transmission can also play an important role for the in vivo spread of viruses, especially retroviruses such as human T lymphotropic virus-1 (HTLV-1) and Human immunodeficiency virus (HIV). Such cell-to-cell transmission is thought to occur through the formation of virological synapses that are formed between an infected source cell and a susceptible target cell. Here we formulate and analyze a class of virus dynamics models that include such cell-cell synaptic transmission. We explore different "strategies" of the virus defined by the number of viruses passed per synapse, and determine how the choice of strategy influences the basic reproductive ratio, R0, of the virus and thus its ability to establish a persistent infection. We show that depending on specific assumptions about the viral kinetics, strategies with low or intermediate numbers of viruses transferred may correspond to the highest values of R0. We also explore the evolutionary competition of viruses of different strains, which differ by their synaptic strategy, and show that viruses characterized by synaptic strategies with the highest R0 win the evolutionary competition and exclude other, inferior, strains. PMID- 23357289 TI - Alterations in T-lymphocyte subpopulations in patients with complicated liver cirrhosis. AB - AIM: To investigate possible alterations of T-lymphocyte subpopulations in patients with cirrhosis complicated with infection and variceal bleeding, and to evaluate the relationship between T-lymphocyte subpopulations and outcome. PATIENTS AND METHODS: This was a prospective study on 99 patients with liver cirrhosis, who were admitted to a university hospital over a period of 18 months. Twenty-six patients (37.6%, group A) were admitted for reasons other than infection or bleeding, 24 (34.7%, group B) presented with sepsis, and 19 (27.5%, group C) were admitted with variceal bleeding. A group of 30 healthy individuals admitted to the hospital without cirrhosis and served as the control group. We evaluated T-cell subsets CD3, CD4, CD5, CD8, CD56, and CD20 as well as CD14 and CD64 subsets of monocytes and neutrophils by using flow cytometry. Measurements for group A were taken only on admission, while for patients of group B and C measurements were repeated on the third and the last hospital day. RESULTS: T cell subsets (CD3, CD4, CD5, CD8, CD56, and CD20 as well as CD14 and CD64 subsets of monocytes and neutrophils) were reduced in septic cirrhotics, but this reduction was not statistically significant compared to the other groups. A significant decrease was observed in T helper cells between cirrhotic patients with and without variceal bleeding (day 3: CD4: 293 +/- 214 versus 442 +/- 277 [P < 0.049]; discharge day: CD4:178 +/- 113 versus 442 +/- 277 [P < 0.003]). Concerning phagocytic potential as detected by CD14 and/or CD64 expression on monocytes and neutrophils, a significant decrease was noted in septic versus nonseptic cirrhotics (day 1: 61.66 +/- 40.16 versus 252 +/- 73 [P < 0.039]; day 3: 66.99 +/- 34.64 versus 252 +/- 73 [P < 0.042]). CONCLUSIONS: Our study showed that the T helper cells and phagocytic potential of monocytes and neutrophils are decreased in patients with liver cirrhosis complicated by sepsis and variceal bleeding. Particularly, these abnormalities seem to be more pronounced in cirrhosis with variceal bleeding. To our knowledge, this is the first study to show these T-cell abnormalities in patients with cirrhosis. Further studies are needed to confirm these findings. PMID- 23357288 TI - The impact of bubbles on measurement of drug release from echogenic liposomes. AB - Echogenic liposomes (ELIP) encapsulate gas bubbles and drugs within lipid vesicles, but the mechanisms of ultrasound-mediated drug release from ELIP are not well understood. The effect of cavitation activity on drug release from ELIP was investigated in flowing solutions using two fluorescent molecules: a lipophilic drug (rosiglitazone) and a hydrophilic drug substitute (calcein). ELIP samples were exposed to pulsed Doppler ultrasound from a clinical diagnostic ultrasound scanner at pressures above and below the inertial and stable cavitation thresholds. Control samples were exposed to a surfactant, Triton X-100 (positive control), or to flow alone (negative control). Fluorescence techniques were used to detect release. Encapsulated microbubbles reduced the measured fluorescence intensity and this effect should be considered when assessing drug release from ELIP. The origin of this effect is not specific to ELIP. Release of rosiglitazone or calcein compared to the negative control was only observed with detergent treatment, but not with ultrasound exposure, despite the presence of stable and inertial cavitation activity. Release of rosiglitazone or calcein from ELIP exposed to diagnostic ultrasound was not observed, even in the presence of cavitation activity. Ultrasound-mediated drug delivery strategies with ELIP will thus rely on passage of the drug-loaded liposomes to target tissues. PMID- 23357290 TI - Assessment of ceftaroline fosamil in the treatment of community-acquired bacterial pneumonia due to Streptococcus pneumoniae: insights from two randomized trials. AB - Ceftaroline fosamil resulted in higher cure rates than ceftriaxone in patients with community-acquired bacterial pneumonia in 2 randomized trials (FOCUS 1 and FOCUS 2). The present analysis examines the subgroup of patients with Streptococcus pneumoniae infection to determine whether the apparent difference in cure rates persists after adjusting for potential covariates. We retrospectively pooled subjects with S. pneumoniae isolated at baseline in the original studies and employed logistic regression to evaluate the independent relationship between clinical cure and treatment with ceftaroline. Covariates evaluated included demographics, severity of illness, bacteremia, and pathogen characteristics. The final cohort included 139 subjects (69 ceftaroline, 70 ceftriaxone). Unadjusted cure rates were 85.5% and 68.6% (P = 0.009) in the ceftaroline and ceftriaxone groups, respectively. After logistic regression, ceftaroline remained associated with higher cure rates. Our findings indicate that ceftaroline may result in improved outcomes of S. pneumoniae pneumonia. Formal clinical trials are warranted to confirm this hypothesis. PMID- 23357291 TI - Tigecycline: an update. AB - Tigecycline is a broad-spectrum antibiotic with activity against difficult-to treat pathogens such as methicillin-resistant Staphylococcus aureus, vancomycin resistant Enterococcus spp., Acinetobacter baumannii, and Gram-negative bacterial strains that produce extended-spectrum beta-lactamases. Minimal organ toxicity and lack of dosage adjustment in most patients are important considerations for tigecycline use. Tigecycline has been shown to be as effective and safe as standard antimicrobial therapy for treatment of adults with complicated intra abdominal infections, complicated skin and skin structure infections, and community-acquired bacterial pneumonia. The clearest applications of tigecycline are for on-label indications. Whether tigecycline should be utilized as therapy for other infections including hospital-acquired infections with a high likelihood of multidrug-resistant pathogens is a complex issue that requires ongoing assessment. This article offers an updated overview of tigecycline clinical studies, current microbial resistance patterns, pharmacokinetic/pharmacodynamic investigations, and safety analyses. PMID- 23357292 TI - Cloning and expression of an envelope gene of West Nile virus and evaluation of the protein for use in an IgM ELISA. AB - West Nile virus (WNV) is a neurotropic flavivirus that has emerged globally as a significant cause of viral encephalitis. The early confirmatory diagnosis of WNV infections is important for timely clinical management and epidemiologic control in areas where multiple flaviviruses are endemic. The coexistence of WNV along with other members of flaviviruses like dengue and Japanese encephalitis in India has complicated the serodiagnosis due to cross-reactive antigens. In the present study, the development and evaluation of a highly sensitive and specific IgM enzyme-linked immunosorbent assay (ELISA) using the recombinant envelope protein (rWNV-Env) for rapid, early, and accurate diagnosis of WNV are reported. The gene coding for the envelope protein of WNV was cloned and expressed in pET 28a vector followed by purification of recombinant protein by affinity chromatography. An indirect IgM microplate ELISA using purified rWNV-Env protein was optimized having no cross reactivity with healthy human serum. Furthermore, the specificity of this assay was confirmed by cross checking with serum samples obtained from patients with dengue and Japanese encephalitis viruses. The comparative evaluation of this rWNV-Env protein-specific IgM ELISA with plaque reduction neutralization test assay using 105 acute phase of clinical samples revealed 95% concordance with sensitivity and specificity of 92% and 97%, respectively. The positive and negative predictive values of recombinant-based Env ELISA were 94% and 96%, respectively. The recombinant envelope protein-based WNV-specific ELISA reported in this study will be useful for rapid screening of large numbers of clinical samples in endemic areas during outbreaks. PMID- 23357293 TI - Update of dalbavancin spectrum and potency in the USA: report from the SENTRY Antimicrobial Surveillance Program (2011). AB - Dalbavancin (DAL) is an investigational lipoglycopeptide with a prolonged serum half-life allowing once weekly dosing. DAL potency was assessed in the 2011 SENTRY Antimicrobial Surveillance Program among 1555 isolates sampled from all 9 US Census regions. Monitored Gram-positive cocci included Staphylococcus aureus (SA; 1,036/50.4% MRSA), coagulase-negative staphylococci (CoNS; 115), Enterococcus faecalis (25), E. faecium (31), Streptococcus pyogenes (155), Streptococcus agalactiae (153), and viridans group streptococci (VGS; 40). All susceptibility (S) testing used Clinical and Laboratory Standards Institute reference broth microdilution methods and interpretations. DAL (MIC(50/90), 0.06/0.06 MUg/mL) was 8- and 16-fold more active than daptomycin (DAP) and vancomycin (VAN), respectively against SA, with MSSA and MRSA having the same MIC(90) results. CoNS was slightly more DAL-S (MIC(50), <=0.03MUg/mL). The highest staphylococcal DAL MIC was only 0.25 MUg/mL. beta-Haemolytic streptococci (betaHS) and VGS had DAL MIC results ranging from <=0.03 to 0.25 MUg/mL (MIC(90), 0.06-0.12 MUg/mL), and only enterococci showed elevated DAL MIC results. VanA phenotype-resistant E. faecalis or E. faecium had DAL MIC values at >=1 MUg/mL; VanB strains were DAL-S (MIC, <=0.25 MUg/mL). All cited DAL quantitative values were consistent with earlier surveillance data (2006-2009), without evidence of MIC creep. In conclusion, year 2011 SENTRY Program data for DAL documents sustained potent activity against SA, CoNS, betaHS, VGS, and VAN-S enterococci, which averaged 4- to 32-fold greater than VAN, DAP, or linezolid. PMID- 23357294 TI - Molecular epidemiological typing of enteropathogenic Escherichia coli strains from Australian patients. AB - Enteropathogenic Escherichia coli (EPEC) are an important cause of diarrhoea worldwide, particularly in children. Sixty-one EPEC strains isolated from stool specimens of symptomatic persons from 2008 to 2011 were characterised for the prevalence of diarrhoea-associated putative virulence genes. Phylogenetic typing, serotyping, multilocus variable-number repeat analysis (MLVA), and multilocus sequence typing (MLST) were also performed. The EPEC isolates were highly heterogeneous, representing all 4 phylogenetic groups and comprising 59 MLVA types, 49 MLST types, and 43 serotypes. This diversity is indicative of the complexity of the human enteric EPEC population, which may be either commensal or pathogenic. PMID- 23357296 TI - Down-regulation of cellular protein heme oxygenase 1 inhibits proliferation of classical swine fever virus in PK-15 cells. AB - Heme oxygenase 1 (HO-1) is an inducible enzyme that exerts potent antioxidant and anti-inflammatory effects, which also plays a critical role in host defenses against microbial, and particularly viral, infections. In our previous study, up regulation of HO-1 was observed in peripheral blood leukocytes (PBLs) by genomic expression profiling, following infection of pigs with virulent classical swine fever virus (CSFV), the causative agent of a highly contagious disease threatening global pig industry (Shi et al., 2009). To study the potential involvement of HO-1 in CSFV proliferation, the role of its down-regulation in CSFV-infected PK-15 cells was further investigated. Results showed that infection with virulent CSFV strain Shimen significantly up-regulated the expression of HO 1 and that its down-regulation by small interfering RNA (siRNA) could inhibit CSFV proliferation as measured by genomic replication and production of infectious virus. The study revealed the involvement of HO-1 in CSFV proliferation, indicating that HO-1 is a potential target for inhibition of CSFV replication. PMID- 23357295 TI - A novel aminoacid determinant of HIV-1 restriction in the TRIM5alpha variable 1 region isolated in a random mutagenic screen. AB - Human-derived antiretroviral transgenes are of great biomedical interest and are actively pursued. HIV-1 is efficiently inhibited at post-entry, pre-integration replication stages by point mutations in the variable region 1 (v1) of the human restriction factor TRIM5alpha. Here we use a mutated megaprimer approach to create a mutant library of TRIM5alphaHu v1 and to isolate a mutation at Gly330 (G330E) that inhibits transduction of an HIV-1 vector as efficiently as the previously described mutants at positions Arg332 and Arg335. As was the case for these other mutations, modification of the local v1 charge toward increased acidity was key to inhibiting HIV-1. G330E TRIM5alphaHu also disrupted replication-competent HIV-1 propagation in a human T cell line. Interestingly, G330E did not enhance restriction of HIV-1 when combined with mutations at Arg332 or Arg335. Accordingly, the triple mutant G330E-R332G-R335G bound purified recombinant HIV-1 capsid tubes less efficiently than the double mutant R332G R335G did. In a structural model of the TRIM5alphaHu PRYSPRY domain, the addition of G330E to the double mutant R332G-R335G caused extensive changes to the capsid binding surface, which may explain why the triple mutant was no more restrictive than the double mutant. The HIV-1 inhibitory potential of Gly330 mutants was not predicted by examination of natural TRIM5alpha orthologs that are known to strongly inhibit HIV-1. This work underlines the potential of random mutagenesis to isolate novel variants of human proteins with antiviral properties. PMID- 23357297 TI - The complete genome sequences of a Peruvian and a Colombian isolate of Andean potato latent virus and partial sequences of further isolates suggest the existence of two distinct potato-infecting tymovirus species. AB - The complete genomic RNA sequences of the tymovirus isolates Hu and Col from potato which originally had been considered to be strains of the same virus species, i.e. Andean potato latent virus (APLV), were determined by siRNA sequencing and assembly, and found to share only c. 65% nt sequence identity. This result together with those of serological tests and comparisons of the coat protein gene sequences of additional tymovirus isolates from potato suggest that the species Andean potato latent virus should be subdivided into two species, i.e. APLV and Andean potato mild mosaic virus (APMMV). Primers were designed for the broad specificity detection of both viruses. PMID- 23357298 TI - Transforming growth factor-beta regulates the expression of anosmin (KAL-1) in human retinal pigment epithelial cells. AB - In a microarray analysis of human retinal pigment epithelial cells (HRPE) treated with TGF-beta, in addition to the alteration of a number of known Extracellular matrix (ECM)-related genes regulated by TGF-beta, we found a significant increase in the expression of Kallmann Syndrome (KAL)-1 gene, that codes for the protein anosmin-1. Enhanced expression of KAL-1 by TGF-beta was validated by real-time PCR analysis. In in vitro experiments, TGF-beta receptor inhibitor abolished TGF beta-induced expression of KAL-1. Immunofluorescence staining showed increased presence of anosmin-1 in TGF-beta treated HRPE cells, with distinct localization at the intercellular junctions. Treatment of HRPE cells with TGF-beta enhanced secretion of anosmin-1 and the release of anosmin-1 was further augmented by heparin sulfate. Enhanced secretion of anosmin-1 in the presence of TGF-beta and heparin was also observed in other ocular cells such as corneal epithelial and corneal fibroblast cultures. The role of anosmin-1, a protein with adhesion functions, in retinal structure, function and pathology has not been known and remains to be investigated. PMID- 23357299 TI - Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels. AB - BACKGROUND: Several evidences support the existence of cytokine deregulation in acute myeloid leukemia (AML) patients that may be associated with pathogenesis, disease progression and patient survival. METHODS: In the present study, we analyzed plasma levels of pro- and anti-inflammatory cytokines in AML patients and age-matched healthy donors. TNF-alpha, IL-6, IL-1beta, IL-2, IFN-gamma, IL 17A, IL-12p70, IL-8, IL-10, IL-4 and IL-5 were analyzed using fluorescent bead based technology and TGF-beta by ELISA technique. Because age-associated differences in cytokine profiles have been described, patients and healthy individuals were divided into two age groups: up to 65 years and over 65 years. RESULTS: Our results showed that plasma TNF-alpha, IL-6 and IL-10 levels were higher in AML patients from both groups of age. IL-8 was increased in AML patients less than 65 years while the plasma concentrations of IL-4, IL-5 and IL 12p70 were significantly higher only in elderly AML patients compared with aged matched healthy controls. Moreover, plasma levels of IL-6 and IL-10 were associated with patient survival and event-free survival. CONCLUSIONS: An aberrant production of the pro-inflammatory cytokines IL-6 and TNF-alpha and the anti-inflammatory cytokine IL-10 is observed in AML patients. Low levels of IL-6 and high levels of IL-10 represent favorable prognostic factors for survival in AML patients. These results support the idea that cytokine deregulation may be useful as a marker for predicting clinical evolution in AML patients. PMID- 23357300 TI - Role of inflammatory gene polymorphisms in left ventricular dysfunction (LVD) susceptibility in coronary artery disease (CAD) patients. AB - RATIONALE: Inflammation exacerbates a number of deleterious effects on the heart, most notable being left ventricular dysfunction (LVD). A promoter polymorphism of the NFKB1 gene (encodes p50 subunit) results in lower protein levels of NFkB p50 subunits, which in its dimmer (p50) form has anti-inflammatory effects. The active NFkB transcription factor promotes the expression of over 150 target genes including IL6 and TNF-alpha. Therefore, the aim of the present study was to assess the association of NFKB1, IL6 and TNF-alpha gene polymorphisms with LVD in coronary artery disease (CAD) patients. METHODS AND RESULTS: The present study included a total of 830 subjects (600 CAD patients and 230 controls) and was carried out in two (primary and replication) cohorts. CAD patients with reduced left ventricle ejection fraction (LVEF <=45%) were categorized having LVD. The NFKB1 -94 ATTG ins/del (rs28362491), IL6 -174 G/C (rs1800795) and TNF-alpha -308 G/A (rs1800629) polymorphisms were genotyped by PCR/ARMS-PCR methods. The results of the primary cohort were validated in a replicative cohort and pooled by meta analysis using Fisher's and Mantel-Haenszel test. The analysis showed that NFKB1 ATTG/ATTG genotype was significantly associated with LVD (Fisher's method p value=0.007, Mantel-Haenszel OR=2.34), LV end diastole (p-value=0.013), end systole (p-value=0.011) dimensions, LV mass (p-value=0.024), mean LVEF (p value=0.001) and myocardial infarction (p-value=0.043). CONCLUSION: Our data suggests that NFKB1 -94 ATTG ins/del polymorphism plays significant role in conferring susceptibility of LVD and ATTG/ATTG genotype may modulate risk of heart failure by increasing ventricular remodeling and worsening LV function. PMID- 23357301 TI - High plasma levels of soluble ST2 but not its ligand IL-33 is associated with severe forms of pediatric dengue. AB - Identification of early determinants of dengue disease progression, which could potentially enable individualized patient care are needed at present times. Soluble ST2 (sST2) has been recently reported to be elevated in the serum of children older than 2 years old and adults with dengue infection and it was correlated with secondary infections as well as with severe presentations of the disease. The mechanism by which secreted ST2 is linked to severe dengue and plasma leakage remains unclear. One possibility is that IL-33 ligand may be elevated, contributing to membrane bound ST2 as part of the immune activation in dengue infection. We determined plasma levels of sST2 and the ligand IL-33 in 66 children with acute secondary dengue infections clinically classified using the guidelines of the World Health Organization, 2009. Dengue infection showed significant increases in cytokines IL-12p70, IL-10, IL-8, IL-6, IL-1beta and TNFalpha measured by flow cytometry based assay compared to uninfected individuals. In contrast, IL-33 levels remained unchanged between infected and uninfected individuals. The levels of sST2 positively correlated with values of IL-6 and IL-8 and inversely correlated with number of median value of platelet levels. In addition to circulating cytokine positive correlations we found that sST2 and isoenzyme creatine kinase-MB (CK-MB), a marker of myocardial muscle damage present in severe dengue cases were associated. Our pediatric study concluded that in dengue infections sST2 elevation does not involve concomitant changes of IL-33 ligand. We propose a study to assess its value as a predictor factor of disease severity. PMID- 23357302 TI - Prognostic value of circulating levels of stem cell growth factor beta (SCGF beta) in patients with Chagas' disease and idiopathic dilated cardiomyopathy. AB - Chagas' disease (CD) often leads to dilated cardiomyopathy (DCM), and during its chronic stage hematopoietic stem or progenitor cells are involved in its pathological process. However, it is not clear whether stem cell growth factor (SCGF) beta can be regulated in patients with CD and idiopathic DCM. In present study, we aim to investigate the plasma SCGF beta concentration and its correlation with echocardiographic parameters and clinical outcome. In this prospective cohort study, SCGF beta levels were quantified in patients with CD (n=94), DCM (n=48), and control healthy subjects (n=25). In comparison with healthy subjects, no statistical difference can be detected in NYHA classes I-II patients. However, SCGF beta was significantly increased in advanced heart failure patients (NYHA III-IV), compared to CD patients without heart failure. There was no group difference between CD and DCM. However, despite this significant increase in advanced heart failure patients, SCGF beta had no significant correlation with echocardiographic parameters, and it cannot be used as a prognostic marker for mortality and heart transplantation. To our best knowledge, this is the first report of SCGF beta in heart failure patients. Although it is significantly increased in advanced heart failure patients caused by CD or DCM, its prognostic value for end points is minor. PMID- 23357303 TI - Stage specific effect of leptin on the expressions of estrogen receptor and extracellular matrix in a model of chondrocyte differentiation. AB - Endochondral ossification is a dynamic process. The interaction between leptin and estrogen in this process is complicated. Whether there is a stage specific crosstalk between leptin and estrogen in the differentiation process of the chondrocytes in the growth plate remains unknown. The aim of our study was to investigate the effect of leptin on the expression of estrogen receptors and extracellular matrix in ATDC5 cells, an in vitro model of endochondral ossification. First, we quantified the physiological expressions of estrogen receptors alpha, beta (ERalpha, ERbeta), leptin receptor (Ob-Rb), type II and type X collagens in definite stages of endochondral ossification in ATDC5 cells using real-time PCR. Dynamic and stage specific expression characteristics of these target genes were observed. Simultaneous expressions of Ob-Rb with ERalpha or ERbeta in ATDC5 cells were also found with dual-label confocal immunofluorescency. Then using Western blotting analysis and/or real-time PCR, we detected that, leptin treatment up-regulated the expressions of ERalpha, ERbeta and type II collagen, but down-regulated type X collagen expression and the ERalpha/ERbeta ratio in the chondrogenic differentiation stage. Meanwhile, leptin down-regulated the expressions of ERalpha, type II and type X collagens, and the ERalpha/ERbeta ratio, but up-regulated the expression of ERbeta in the hypertrophic differentiation stage. Significant positive correlation existed between ERalpha and type II collagen expression, and between the ratio of ERalpha/ERbeta and type X collagen production. In summary, the crosstalk between leptin and estrogen receptor might be differentiation stage specific in ATDC5 cells. PMID- 23357304 TI - Maraviroc reduces cytokine expression and secretion in human adipose cells without altering adipogenic differentiation. AB - Maraviroc (MVC) is a drug approved for use as part of HAART in treatment experienced HIV-1 patients with CCR5-tropic virus. Despite the current concerns on the alterations in adipose tissue that frequently appear in HIV-infected patients under HAART, there is no information available on the effects of MVC on adipose tissue. Here we studied the effects of MVC during and after the differentiation of human adipocytes in culture, and compared the results with the effects of efavirenz (EFV). We measured the acquisition of adipocyte morphology; the gene expression levels of markers for mitochondrial toxicity, adipogenesis and inflammation; and the release of adipokines and cytokines to the medium. Additionally, we determined the effects of MVC on lipopolysaccharide (LPS) induced pro-inflammatory cytokine expression in adipocytes. Unlike EFV-treated pre-adipocytes, MVC-treated pre-adipocytes showed no alterations in the capacity to differentiate into adipocytes and accumulated lipids normally. Consistent with this, there were no changes in the mRNA levels of PPARgamma or SREBP-1c, two master regulators of adipogenesis. In addition, MVC caused a significant decrease in the gene expression and release of pro-inflammatory cytokines, whereas EFV had the opposite effect. Moreover, MVC lowered inflammation-related gene expression and inhibited the LPS-induced expression of pro-inflammatory genes in differentiated adipocytes. We conclude that MVC does not alter adipocyte differentiation but rather shows anti-inflammatory properties by inhibiting the expression and secretion of pro-inflammatory cytokines. Collectively, our results suggest that MVC may minimize adverse effects on adipose tissue development, metabolism, and inflammation, and thus could be a potentially beneficial component of antiretroviral therapy. PMID- 23357305 TI - Prophylactic mastectomy in patients at high risk: is there a role for sentinel lymph node biopsy? AB - INTRODUCTION: Prophylactic mastectomy (PM) rates in the United States are rising due to determination of increased Gail risk, moderate-high risk lesions, a strong family history, and gene mutation carriers. The role of sentinel lymph node biopsy (SLNB) in PM remains controversial. This report sought to examine clinical utility of SLNB in PM. METHODS: A total of 292 patients underwent bilateral or contralateral PM (1999-2011). SLNB was performed on the PM side in 195 (66.7%) patients with standard techniques. Clinicopathologic data were analyzed for the incidence of occult cancer in prophylactic breast and/or axilla. Univariate analysis was used to determine factors that predict SLN positivity. RESULTS: The median patient age was 49 years (range, 19-79 years). Contralateral invasive breast cancer (64.7%) was the most common indication for PM. A total of 209 (71.5%) invasive breast cancer and 49 (16.7%) in situ cancers (n = 38 ductal carcinoma in situ, n = 10 lobular carcinoma in situ) were identified on the therapeutic mastectomy side, with a median tumor size of 1.5 cm. 58.6% were estrogen receptor positive and 4.7% were multicentric. Three (1%) ductal carcinoma in situ, 4 (1.3%) lobular carcinoma in situ, and 5 (1.7%) atypical ductal, and 1 (0.3%) lobular hyperplasia were identified in PM breast. No invasive breast cancer or positive SLN was identified in PM breast and/or axilla. CONCLUSION: Although a minimally invasive procedure, the utility of SLNB in patients with absent or contralateral early disease is limited. Advanced T stage, multicentricity, or receptor status on the therapeutic side or a finding of in situ or atypical hyperplasia in prophylactic breast specimen yielded no positive SLN. Routine SLNB in pure bilateral PM can safely be omitted, which reduces axillary morbidity and operative time and/or cost. Selective use of SLNB for contralateral recurrent and/or locally advanced cancers warrants further investigation. PMID- 23357306 TI - Effect of adopting host-country nationality on perinatal mortality rates and causes among immigrants in Brussels. AB - OBJECTIVES: Perinatal mortality rates vary between ethnic groups but the relation with immigrant status is unclear. Previous research suggested that birth outcomes may either improve or deteriorate with duration of residence, depending on the migrant group. The objectives of this study are to describe and measure inequalities in pregnancy outcomes, perinatal mortality and causes of perinatal deaths according to current citizenship versus national origin of the mother, in Brussels. STUDY DESIGN: This is a population-based cohort study using data from linked birth and death certificates from the Belgian civil registration system. The data relate to all babies born between 1998 and 2008, whose mothers were living in Brussels, irrespective of the place of delivery. We used a logistic regression to estimate the odds ratios (ORs) for the association between mortality, causes of deaths and nationality. RESULTS: Women from Morocco, sub Saharan Africa and Turkey experience an 80% excess in perinatal mortality (p<0.0001) compared to Belgians, but this excess of perinatal mortality is not observed for mothers with Belgian citizenship at delivery. For sub-Saharan African women, this excess is caused mainly by immaturity-related conditions and reflects a high rate of preterm deliveries, low birth weight and a low socio economic level. Moroccan and Turkish mothers have favourable pregnancy outcomes that persist after adopting Belgian nationality, but they experience a strong excess of perinatal mortality, mainly due to congenital anomalies and asphyxia or unexplained deaths prior to the onset of labour. CONCLUSION: In Brussels, perinatal mortality varies according to nationality but those differences do not persist after adopting Belgian nationality. The explanation of this positive effect is probably due to a mix of determinants such as acculturation, use of health services or cultural contexts. Further analysis should help to better understand the results observed. PMID- 23357307 TI - Novel pyrazole derivatives as neutral CB1 antagonists with significant activity towards food intake. AB - In spite of rimonabant's withdrawal from the European market due to its adverse effects, interest in the development of drugs based on CB1 antagonists is revamping on the basis of the peculiar properties of this class of compounds. In particular, new strategies have been proposed for the treatment of obesity and/or related risk factors through CB1 antagonists, i.e. by the development of selectively peripherally acting agents or by the identification of neutral CB1 antagonists. New compounds based on the lead CB1 antagonist/inverse agonist rimonabant have been synthesized with focus on obtaining neutral CB1 antagonists. Amongst the new derivatives described in this paper, the mixture of the two enantiomers (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(2-cyclohexyl-1 hydroxyethyl)-4-methyl-1H-pyrazole ((+/-)-5), and compound 5-(4-chlorophenyl)-1 (2,4-dichlorophenyl)-3-[(Z)-2-cyclohexyl-1-fluorovinyl]-4-methyl-1H-pyrazole ((Z) 6), showed interesting pharmacological profiles. According to the preliminary pharmacological evaluation, these novel pyrazole derivatives showed in fact both neutral CB1 antagonism behaviour and significant in vivo activity towards food intake. PMID- 23357308 TI - Synthesis of some new 2-(3-pyridyl)-4,5-disubstituted thiazoles as potent antimicrobial agents. AB - As a part of ongoing studies in developing new potent antimicrobial agents, a series of novel 2-(3-pyridyl)-4,5-disubstituted thiazoles was efficiently synthesized and characterized by spectral and elemental analyses. The newly synthesized compounds were evaluated for their in vitro antimicrobial activity against ten bacterial and five fungal human pathogenic strains using the disc diffusion assay. Among the synthesized compounds, 5-acetyl-4-methyl-2-(3 pyridyl)thiazole (5) exhibited twofold antibacterial activity of ampicillin in inhibiting the growth of Staphylococcus epidermidis (MIC 0.24 MUg/mL) and also showed equipotent antifungal activity with amphotricin B against Geotricum candidum (MIC 0.48 MUg/mL). From structure-activity relationship (SAR) point of view, increasing the size of the substitutions either at position 4 or 5 on the thiazole nucleus decreased the antimicrobial activity. PMID- 23357309 TI - Microfluidics assisted synthesis and bioevaluation of sinomenine derivatives as antiinflammatory agents. AB - Sinomenine (1) is currently used for the treatment of rheumatoid arthritis (RA) in China and there is still room for the improvement of its efficacy. In present study, capillary based microfluidic system was effectively applied for the syntheses of two novel series of sinomenine derivatives. The Heck reactions in microreactor gave much higher conversions compared to the batch ones. The two step synthesis of the isoxazoline in microreactor greatly shortened the reaction time without any isolation of intermediates. The inhibitory activity of synthesized compounds on the TNF-alpha-induced nuclear factor kappa B (NF-kappaB) activation was evaluated in vitro. Among the compounds, 3c and 3g showed the potent inhibitory activity. Furthermore, 3g exhibited the antiinflammatory effect in vivo. PMID- 23357310 TI - Exploring nature profits: development of novel and potent lipophilic antioxidants based on galloyl-cinnamic hybrids. AB - Phenolic acids are ubiquitous antioxidants accounting for approximately one third of the phenolic compounds in our diet. Their importance was supported by epidemiological studies that suggest an inverse relationship between dietary intake of phenolic antioxidants and the occurrence of diseases, such as cancer and neurodegenerative disorders. However, until now, most of natural antioxidants have limited therapeutic success a fact that could be related with their limited distribution throughout the body and with the inherent difficulties to attain the target sites. The development of phenolic antioxidants based on a hybrid concept and structurally based on natural hydroxybenzoic (gallic acid) and hydroxycinnamic (caffeic acid) scaffolds seems to be a suitable solution to surpass the mentioned drawbacks. Galloyl-cinnamic hybrids were synthesized and their antioxidant activity as well as partition coefficients and redox potentials evaluated. The structure-property-activity relationship (SPAR) study revealed the existence of a correlation between the redox potentials and antioxidant activity. The galloyl-cinnamic acid hybrid stands out as the best antioxidant supplementing the effect of a blend of gallic acid plus caffeic acid endorsing the hypothesis that the whole is greater than the sum of the parts. In addition, some hybrid compounds possess an appropriate lipophilicity allowing their application as chain-breaking antioxidant in biomembranes or other type of lipidic systems. Their predicted ADME properties are also in accordance with the general requirements for drug-like compounds. Accordingly, these phenolic hybrids can be seen as potential antioxidants for tackling the oxidative status linked to the neurodegenerative, inflammatory or cancer processes. PMID- 23357311 TI - Introducing new dimensions in MIA-QSAR: a case for chemokine receptor inhibitors. AB - Multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR) is a very simple correlative method that uses pixels (binaries) of chemical structures built from 2D viewer programs as descriptors; structural changes correspond to different pixel coordinates, which explain the variance in the bioactivities block. The MIA-QSAR method has shown to be predictive and capable of encoding some chemical information, but introduction of more descriptive information, such as atom size and colors to differentiate atom types, would improve predictability and interpretability. The bioactivities of a series of chemokine receptor (CCR2) inhibitors have been modeled using both conventional and atom color/size-dependent MIA-QSAR (namely aug-MIA-QSAR); the latter showed to be better. Moreover, the results were comparable to those obtained by 3D methodologies, indicating that 2D shape and substituent size are more significant descriptors than the conformational profiles required by field fit techniques. PMID- 23357312 TI - Paeonol suppresses oxidized low-density lipoprotein induced endothelial cell apoptosis via activation of LOX-1/p38MAPK/NF-kappaB pathway. AB - Paeonol is an active compound isolated from traditional Chinese medicine, and has been shown to have anti-atherosclerosis, anti-inflammatory, antioxidant effects. The present investigation was undertaken to determine the suppression effects of paeonol on oxidized low-density lipoprotein (ox-LDL) induced endothelial cell line HUVEC apoptosis and to uncover some of the underlying mechanisms of these effects. Cell viability and lactate dehydrogenase (LDH) were measured to evaluate the cell injuries. Apoptosis was evaluated by Hoechst 33342 staining and flow cytometry. Intracellular reactive oxygen species (ROS) generation was detected by 2',7'-dichlorofluorescein diacetate (DCFH-DA). Real-time PCR was used to confirm the expression of LOX-1 mRNA. Western blotting was used to evaluate the protein expression of LOX-1 and Bcl-2, as well as caspase-3 cleavage, p38-mitogen activated protein kinase (p38MAPK) phosphorylation. NF-kappaB nuclear translocation was detected by Western blotting and immunofluorescence. Caspase-3 activity was measured using a colorimetric protease assay kit. The results showed that ox-LDL significantly decreased cell viability and increased the LDH release, as well as the apoptotic rate (P<0.01). Pre-treatment of paeonol resulted in remarkable increase of cell viability, decrease of LDH release and cell apoptosis in a concentration-dependent manner. Besides, ox-LDL caused the up-regulation of LOX-1, the down-regulation of Bcl-2, the phosphorylation of p38MAPK, the translocation of NF-kappaB and the activation of caspase-3. Paeonol pre-treatment reversed these effects introduced by ox-LDL. Moreover, paeonol also showed its inhibition effects on ox-LDL induced ROS overproduction. These results indicate the preventive effects of paeonol on ox-LDL induced endothelial cell apoptosis. The effects might, at least partly, be obtained via inhibition of LOX-1-ROS- p38MAPK-NF-kappaB signaling pathway. PMID- 23357314 TI - Differences of calcium binding proteins immunoreactivities in the young hippocampal CA1 region from the adult following transient ischemic damage. AB - It has been reported that the young were much more resistant to transient cerebral ischemia than in the adult. In the present study, we examined that about 90% of CA1 pyramidal cells in the adult gerbil hippocampus died at 4days after ischemia-reperfusion; however, in the young hippocampus, about 56% of them died at 7days after ischemia-reperfusion. We compared immunoreactivities and levels of calcium binding proteins (CBPs), such as calbindin 28k (CB-D28k), calretinin (CR) and parvalbumin (PV). The immunoreactivities and protein levels of all the CBPs in the young sham were higher than those in the adult sham. In the adult, the immunoreactivities and protein levels of all the CBPs were markedly decreased at 4days after ischemia-reperfusion, however, in the young, they were apparently maintained. At 7days after ischemia-reperfusion, they were decreased in the young, however, they were much higher than those in the adult. In brief, the immunoreactivities and levels of CBPs were not decreased in the ischemic CA1 region of the young 4days after transient cerebral ischemia. This finding indicates that the longer maintenance of CBPs may contribute to a less and more delayed neuronal death/damage in the young. PMID- 23357313 TI - Comparative analysis of interactions of RASSF1-10. AB - Members of the RASSF family (RASSF1-10) have been identified as candidate tumour suppressors that are frequently downregulated by promoter hypermethylation in cancers. These proteins carry a common Ras-association (RA) and SARAH domain (RASSF1-6) that can potentially bind Ras oncoproteins and mediate protein-protein interactions with other SARAH domain proteins. However, there is a notable lack of comparative characterisation of the RASSF family, as well as molecular and structural information that facilitate their tumour suppressive functions. As part of our comparative analysis, we modelled the RA and SARAH domains of the RASSF members based on existing structures and predicted their potential interactions. These in silico predictions were compared to in vitro interaction studies with Ras and MST kinase (a SARAH domain-containing protein). Our data shows a diversity of interaction within the RASSF family RA domain, whereas the SARAH domain-mediated interactions for RASSF1-6 are consistent with the predictions. This suggests that different members, despite shared general architecture, could have distinct functional properties. Additionally, we identify a new interacting partner for MST kinase in the form of RASSF7. Current data supports an interaction model where RASSF serves as an adaptor for the assembly of multiple protein complexes and further functional interactions, involving MST kinases and other SARAH domain proteins, which could be regulated by Ras. PMID- 23357315 TI - Effects of blockade of NMDA receptors on cerebral oxygen consumption during hyperosmolar BBB disruption in rats. AB - Hyperosmolar blood-brain barrier (BBB) disruption has been reported to increase cerebral O2 consumption. This study was performed to test whether blockade of N methyl-d-aspartate (NMDA) receptor would affect cerebral O2 consumption during hyperosmolar BBB disruption. A competitive NMDA receptor antagonist CGS-19755 10mg/kg was injected iv 15min before intracarotid infusion of 25% mannitol. Twelve min after BBB disruption, the BBB transfer coefficient (Ki) of (14)C-alpha aminoisobutyric acid ((14)C-AIB) was measured. Regional cerebral blood flow (rCBF), regional arteriolar and venular O2 saturation (SaO2 and SvO2 respectively), and O2 consumption were determined using (14)C-iodoantipyrine autoradiography and cryomicrospectrophotometry in alternate slices of the brain tissue. The Ki of (14)C-AIB was markedly increased with hyperosmolar mannitol in both the control (5.8*) and the CGS treated rats (5.2*). With BBB disruption, the O2 consumption was significantly increased (+39%) only in the control but not in the CGS treated rats and was significantly lower (-29%) in the CGS treated than the control rats. The distribution of SvO2 was significantly shifted to the higher concentrations with CGS treatment. Our data demonstrated an increase of O2 consumption by hyperosmolar BBB disruption and attenuation of the increase with NMDA blockade without affecting the degree of BBB disruption. PMID- 23357316 TI - Antimicrobial and antifungal activities of Lactobacillus curvatus strain isolated from homemade Azerbaijani cheese. AB - The aims of this study were to characterize inhibitory activity spectra, some probiotic properties and safety of Lactobacillus curvatus A61 for its future application in production of fermented foods. The studied strain was isolated from traditional homemade cheese manufactured in Azerbaijan. The cell-free supernatant of culture of Lb. curvatus A61 inhibited the growth of tested LAB, as well as of Listeria monocytogenes and Bacillus cereus strains. The strain presented antifungal activity and inhibited the growth of Cladosporium and Fusarium ssp. during co-cultivation on agar media. PCR amplification with specific primers revealed the presence of curvacin A encoding gene in Lb. curvatus A61. Bacteriocin produced by the studied strain was heat stable and active in a broad pH range, and in the presence of Triton X-20, Triton X-80, Triton X-100, beta-mercaptoethanol, Na-EDTA, SDS and NaCl. The mode of action of bacteriocin against selected indicator strains was found to be bacteriostatic. Lb. curvatus A61 was resistant to physiological concentrations of bile salts and showed high auto-aggregation ability, as well as co-aggregation ability with pathogenic L. monocytogenes strains. It was sensitive to chloramphenicol, penicillin, tetracycline, ciprofloxacin and vancomycin, but resistant to ampicillin and gentamicin. PMID- 23357317 TI - Architectural analysis of clear corneal incision techniques in cataract surgery using Fourier-domain OCT. AB - BACKGROUND AND OBJECTIVE: To compare the architecture of single plane self sealing clear corneal incision (SP-CCI) and shallow grooved self-sealing clear corneal incision (SG-CCI) after cataract surgery using Fourier-domain optical coherence tomography (FD-OCT). PATIENTS AND METHODS: An FD-OCT system with a corneal adaptor module was used to image the corneal incisions in radial sections in 44 eyes. A line scan pattern was used to measure the corneal incision, positioning the caliper mark perpendicular to the limbus. Measurements were performed immediately after cataract surgery and at postoperative days 1, 7, and 30. Incisions were analyzed regarding length, location, angle, architecture, and anatomic imperfections. RESULTS: All incisions were located superiorly (temporal, 24 eyes; nasal, 20 eyes). The mean SG-CCI length (20 eyes) was 1.79 +/- 0.31 mm (range: 0.93-2.64 mm) and the mean incision angle was 37 +/- 7 degrees (range: 24 34 degrees). The mean SP-CCI length (22 eyes) was 1.64 +/- 0.22 mm (range: 1.25 2.36 mm) and the mean incision angle was 38.5 +/- 5 degrees (range: 27-52 degrees) (P < .05). Anatomic imperfections were observed at postoperative day 1 in 19 eyes for SP-CCI and 14 eyes for SG-CCI. No patient presented endophthalmitis during 30 days of follow-up. CONCLUSION: Epithelial imperfection at the corneal incision site was observed in more than 36% of the wounds (36% in SP-CCI and 45% in SG-CCI) at postoperative day 1 with spontaneous resolution. SG CCI had the greatest length and lowest angle of corneal incision. Reduced incision length and inappropriate construction may determine risk factors for wound architectural imperfections. Further studies including more patients with an architectural analysis of clear corneal incisions are needed to confirm these preliminary results. PMID- 23357318 TI - Intraoperative use of AS-OCT during intrastromal corneal ring segment implantation. AB - BACKGROUND AND OBJECTIVE: To evaluate femtosecond laser-created tunnels intraoperatively by anterior segment optical coherence tomography (AS-OCT) during intrastromal corneal ring segment implantation. PATIENTS AND METHODS: The study prospectively examined 13 eyes of 11 patients who underwent intrastromal corneal ring segment surgery with the aid of femtosecond laser. All eyes had keratoconus as the primary diagnosis. Eyes were examined by AS-OCT to image the tunnel immediately after femtosecond laser and before ring segment implantation. Tunnel depth was calculated automatically using the software's flap tool and calipers. RESULTS: The presence of air bubbles demonstrated the tunnel successfully by AS OCT. Tunnel depth was measured at eight locations in four cross-sections of high resolution cornea images. An overall evaluation was also made by changing the scan direction 360 degrees . After confirmation that a uniform tunnel was satisfactorily created at the aimed depth, surgery proceeded with segment implantation. CONCLUSION: AS-OCT can be used intraoperatively to assess femtosecond laser-created tunnel in intrastromal corneal ring segment implantation. The qualitative and quantitative evaluation of the intrastromal tunnel by AS-OCT before implantation of the ring segments is a practical intraoperative approach that may offer a safer surgery. PMID- 23357319 TI - High-resolution OCT: an innovative tool for posterior segment imaging. AB - Optimal management of posterior segment disorders requires a high-resolution and preferably noninvasive imaging tool for better definition of diseases. High resolution optical coherence tomography can provide noninvasive, high-definition imaging of the posterior segment, allowing earlier diagnosis, better follow-up of chronic cases, and more accurate and timely monitoring of the effect of therapeutic agents. Recent findings suggest an individualized approach to vitreoretinal and choroidal diseases is possible based not only on traditional ophthalmic investigations, but also on high-resolution optical coherence tomography. This innovative tool has the combined advantages of high speed, high resolution, and safe use. PMID- 23357320 TI - Characteristic SD-OCT findings in preeclampsia. AB - High-resolution spectral-domain optical coherence tomography of a patient affected by acute macular edema secondary to preeclampsia is described. The particular optical coherence tomography pattern was characterized by bilateral macular edema with a tent-shaped organization, associated with massive neurosensorial retinal detachment. Many hyperreflective irregular dots were evident in the context of a subfoveal clear cystic lesion. A different hyperreflective irregularity was detected in the retinal pigment epithelium. The central role of spectral-domain optical coherence tomography among instrumental imaging procedures and for final successful diagnosis in this particular macular edema is emphasized. PMID- 23357321 TI - Retinal and choroidal findings in oxalate retinopathy using EDI-OCT. AB - A 55-year-old woman with extensive retinal crystalline deposition secondary to primary hyperoxaluria presented with bilateral loss of vision secondary to oxalate retinopathy. Enhanced depth imaging optical coherence tomography revealed intraretinal, subretinal, and intraretinal and subretinal pigment epithelium, and choroidal focal hyperreflective structures consistent with both neurosensory and uveal deposition of oxalate crystals. Serial optical coherence tomography revealed continued crystalline deposition with progressive retinal atrophy. PMID- 23357322 TI - Automated detection of the foveal center improves SD-OCT measurements of central retinal thickness. AB - BACKGROUND AND OBJECTIVE: To investigate the performance of an automated foveal center detection algorithm on spectral-domain optical coherence tomography (SD OCT). PATIENTS AND METHODS: Fifty normal eyes and 50 eyes with early stage dry age-related macular degeneration (AMD) were analyzed. The actual scan center (SC), automatically detected foveal center (AF), and manually identified foveal center (MF) were compared. RESULTS: The mean of the radial distances was 89 +/- 120 MUm from MF to SC and 54 +/- 41 MUm from MF to AF for normal eyes and 179 +/- 125 MUm from SC to MF and 104 +/- 62 MUm from AF to MF for eyes with AMD. The differences were statistically significant (P < .001). CONCLUSION: The automated algorithm designed to detect the foveal center was more accurate in detecting the foveal center than relying on the fixation target of the SD-OCT instrument. PMID- 23357323 TI - Choroidal thickness measurement in highly myopic eyes using SD-OCT. AB - BACKGROUND AND OBJECTIVE: To measure macular choroidal thickness (CT) using spectral-domain optical coherence tomography (OCT) and to investigate the correlation between CT and age, degree of myopia, and history of macular choroidal neovascularization (CNV). PATIENTS AND METHODS: A cross-sectional study included 187 highly myopic eyes of 187 patients examined between January and December 2010. The choroid was imaged with spectral-domain OCT by changing the reference position from the vitreous to the choroid. CT was measured from the outer border of the hyperreflective line corresponding to the retinal pigment epithelium to the inner scleral border. RESULTS: The mean age was 47.21 +/- 14.24 years, the mean spherical equivalent refractive error was -13.66 +/- 5.77, and the mean subfoveal CT was 100.71 +/- 59.98 MUm. CT was correlated negatively with age (P < 10(-3)) and refractive error (P < 10(-3)). Forty-two eyes had a history of CNV, the mean CT was 55.45 +/- 24.46 MUm, and this was significantly thinner than in eyes without CNV (P < 10(-3)). CONCLUSION: In highly myopic eyes, the choroid is thin and undergoes further attenuation with age and increasing myopia. In addition, these findings suggest that the choroid may play a role in the pathogenesis of CNV. PMID- 23357324 TI - Contrast sensitivity and color vision in eyes with retinitis pigmentosa and good visual acuity: correlations with SD-OCT findings. AB - BACKGROUND AND OBJECTIVE: To investigate the morphological substrate of the changes in visual function in eyes with retinitis pigmentosa and good visual acuity using spectral-domain optical coherence tomography (SD-OCT). PATIENTS AND METHODS: A total of 30 eyes of 17 patients with retinitis pigmentosa and visual acuity of 20/40 or better underwent contrast sensitivity and color vision testing. The retinal thickness at the fovea and macula and the length of the photoreceptor inner/outer segment (IS/OS) junction were assessed by SD-OCT. Structural-functional correlations were investigated. RESULTS: Contrast sensitivity correlated well with IS/OS length (Spearman r = 0.719, P < .001) and foveal thickness (r = 0.672, P < .001) and moderately with macular thickness (r = 0.422, P = .025). Moreover, color vision correlated significantly with IS/OS length (r = -0.725, P < .001) and foveal thickness (r = -0.661, P < .001). CONCLUSION: In eyes with retinitis pigmentosa and good visual acuity, the structural changes observed on OCT scans correspond well to subtle measures of central visual function, complementary to visual acuity testing. PMID- 23357325 TI - Intraoperative SD-OCT in macular surgery. AB - BACKGROUND AND OBJECTIVE: Intraoperative use of spectral-domain optical coherence tomography (SD-OCT) using an OCT-mounted surgical microscope could provide additional information to predict visual outcomes of macular surgery and identify intraoperative changes in the macular anatomy that affect visual recovery. PATIENTS AND METHODS: This interventional retrospective case study included 5 eyes of 5 consecutive patients with various macular pathologies. All patients underwent the standard surgery for idiopathic macular holes and epiretinal membranes (ERMs) using the same 25-gauge three-port pars plana technique. If present, the ERM was removed. The dye procedure was then repeated to stain and remove the internal limiting membrane (ILM). OCT images were obtained with the retinal map or cross-section program preincision, post-hyaloid elevation (if applicable), post-residual ERM peel (if applicable), and post-ILM peel. RESULTS: In 3 of 5 patients, the intraoperative scan revealed an increased area of subretinal hyporeflectivity corresponding with a clinically visible "cuff" of retinal detachment. In 2 patients, the SD-OCT scan taken immediately after ERM removal helped find a cleavage plane for the subsequent ILM peeling, which could be further confirmed by a scan taken immediately after it. In 2 cases, the scans identified intraoperative complications that otherwise would not have been noted and allowed the surgeon to modify the next procedures during surgery. CONCLUSION: Use of this technology in an operative setting can provide greater insight into the changes in retinal anatomy created during macular surgery. PMID- 23357326 TI - Further advances in optical coherence tomography 2012. PMID- 23357327 TI - Rates of abnormal retinal nerve fiber layer and ganglion cell layer OCT scans in healthy myopic eyes: Cirrus versus RTVue. AB - BACKGROUND AND OBJECTIVE: To compare rates of abnormal peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell layer scans acquired with Cirrus HD-OCT (Carl Zeiss Meditec, Inc., Dublin, CA) and RTVue-100 (Optovue Inc., Fremont, CA) in healthy myopic eyes. PATIENTS AND METHODS: Forty-one non glaucomatous myopic eyes (41 individuals) were scanned with Cirrus to measure RNFL and ganglion cell-inner plexiform layer (GCIPL) and with RTVue to measure peripapillary RNFL and ganglion cell complex (GCC) thicknesses. Rates of abnormal scans were calculated and compared between devices. Inter-device agreement in falsely classifying scans as abnormal was also assessed. RESULTS: The rate of abnormal average and four-quadrant RNFL was 4.8% to 7.3% on Cirrus and 2.4% to 9.7% on RTVue (P > .05). The overall rate of abnormal scans was 19.2% on Cirrus and 29.3% on RTVue (P = .3). Rates of abnormal Cirrus average and segmental GCIPL (12.2% to 17%) were similar to those of RTVue average and segmental GCC (9.7% to 14.6%) (P > .05). The overall rate of abnormal GCIPL (36.6%) was higher than that of GCC (14.6%) (P = .023). The inter-device agreement was poor for average RNFL (kappa = -0.09), very good for average ganglion cell (kappa = 0.81), and fair for overall RNFL (kappa = 0.35) and overall ganglion cell (kappa = 0.34). CONCLUSION: The high rates of abnormal RNFL and ganglion cell layer scans on both devices call for caution, particularly when attempting to diagnose glaucoma in myopic eyes using these devices. The RNFL and ganglion cell layer analyses may not be interchangeable on either of these devices. These two devices are not interchangeable for classifying healthy myopic eyes based on RNFL or ganglion cell layer analysis. PMID- 23357328 TI - Correlation between retinal nerve fiber layer thickness and visual field sensitivity: diffuse atrophy imaging study. AB - BACKGROUND AND OBJECTIVE: To identify the correlation between retinal nerve fiber layer (RNFL) thickness and visual field sensitivity in healthy eyes with preperimetric and perimetric glaucoma and to estimate the functional RNFL loss in eyes with pre-perimetric glaucoma. PATIENTS AND METHODS: One hundred and two eyes with glaucoma and diffuse RNFL atrophy and 102 healthy eyes were enrolled. The correlation between optical coherence tomography (OCT)-measured RNFL thickness of the superior (clock-hour segments 10, 11, 12, 1, 2, and 3) and inferior (clock hour segments 5, 6, 7, and 8) area and the average total deviations of the inferior and superior hemifields in standard automated perimetry (SAP) were evaluated using the simple linear model, respectively. The OCT-measured RNFL thickness was assumed to comprise functional and residual thicknesses; the residual thickness was calculated from the simple linear model and the eyes with severe diffuse RNFL atrophy. Functional RNFL thickness was compared between groups. RESULTS: Twenty-seven eyes had preperimetric and 75 eyes had perimetric glaucoma. The coefficient of determination (R(2)) of the simple linear model was 0.71 to 0.77 for the correlation between RNFL thickness and total deviation of SAP. The estimated residual thickness was 50.4 to 56.5 MUm. On comparison with normal eyes, eyes with preperimetric glaucoma were estimated to have 37% to 41% functional RNFL loss. CONCLUSION: The correlation between RNFL thickness and SAP sensitivity was well explained by the simple linear model. Approximately 40% loss of the functional RNFL was found in preperimetric glaucoma. PMID- 23357329 TI - Intrasession reproducibility of RNFL thickness measurements using SD-OCT in eyes with keratoconus. AB - BACKGROUND AND OBJECTIVE: To evaluate the intrasession reproducibility of the peripapillary retinal nerve fiber layer (RNFL) thickness measurements obtained by spectral-domain optical coherence tomography (SD-OCT) in eyes with keratoconus and normal eyes. PATIENTS AND METHODS: Peripapillary RNFL thickness measurements with SD-OCT were repeated three times during the same visit using the eye tracker and retest function in one eye of each participant. Reproducibility was evaluated using within-subject standard deviation (Sw), coefficient of variation (CV), and intraclass correlation coefficient (ICC). RESULTS: For the overall global RNFL thickness, the values of the three parameters were Sw (+/- 1.96 standard error) 1.43 +/- 0.24, CV 1.28%, ICC (95% confidence interval) 0.969 (range: 0.947-0.983) in control eyes and Sw (+/- 1.96 standard error) from 1.41 +/- 0.26 to 1.57 +/- 0.34, CV from 1.18% to 1.37%, and ICC (95% confidence interval) from 0.951 (range: 0.909-0.976) to 0.977 (range: 0.938-0.993) in eyes with keratoconus. CONCLUSION: Measurement of peripapillary RNFL thickness by SD-OCT shows a good intrasession reproducibility in eyes with keratoconus. PMID- 23357330 TI - Dynamic gonioscopy using optical coherence tomography. AB - BACKGROUND AND OBJECTIVE: To describe the use of anterior segment optical coherence tomography (AS-OCT) in studying the dynamic changes of the anterior chamber angle by corneal indentation. PATIENTS AND METHODS: In a prospective observational study, the anterior segments of 21 eyes were imaged using AS-OCT. After the initial scan, a second scan was executed on the same areas with a central corneal indentation. An evaluation of the reopening of the angle and its measurement were performed. RESULTS: With AS-OCT, the indirect signs were accurate enough to guide the diagnosis in all plateau iris confirmed by ultrabiomicroscopy. The angle widths were significantly increased after indentation. CONCLUSION: This method would appear to offer a convenient and rapid method of assessing the configuration of the anterior chamber; it may help during the routine clinical assessment and treatment of patients with narrow or closed angles, particularly when gonioscopy is difficult to interpret. PMID- 23357331 TI - Alternative Complex III from phototrophic bacteria and its electron acceptor auracyanin. AB - Alternative Complex III (ACIII) is a multisubunit integral membrane protein electron transfer complex that is proposed to be an energy-conserving functional replacement for the bacterial cytochrome bc1 or b6f complexes. Clues to the structure and function of this novel complex come from its relation to other bacterial enzyme families. The ACIII complex has menaquinone: electron acceptor oxidoreductase activity and contains protein subunits with multiple Fe-S centers and c-type hemes. ACIII is found in a diverse group of bacteria, including both phototrophic and nonphototrophic taxa. In the phototrophic filamentous anoxygenic phototrophs, the electron acceptor is the small blue copper protein auracyanin instead of a soluble cytochrome. Recent work on ACIII and the copper protein auracyanin is reviewed with focus on the photosynthetic systems and potential electron transfer pathways and mechanisms. Taken together, the ACIII complexes constitute a unique system for photosynthetic electron transfer and energy conservation. This article is part of a Special Issue entitled: Respiratory Complex III and related bc complexes. PMID- 23357332 TI - Biphasic reduction of cytochrome b559 by plastoquinol in photosystem II membrane fragments: evidence for two types of cytochrome b559/plastoquinone redox equilibria. AB - In photosystem II membrane fragments with oxidized cytochrome (Cyt) b559 reduction of Cyt b559 by plastoquinol formed in the membrane pool under illumination and by exogenous decylplastoquinol added in the dark was studied. Reduction of oxidized Cyt b559 by plastoquinols proceeds biphasically comprising a fast component with a rate constant higher than (10s)(-1), named phase I, followed by a slower dark reaction with a rate constant of (2.7min)(-1) at pH6.5, termed phase II. The extents of both components of Cyt b559 reduction increased with increasing concentrations of the quinols, with that, maximally a half of oxidized Cyt b559 can be photoreduced or chemically reduced in phase I at pH6.5. The photosystem II herbicide dinoseb but not 3-(3,4-dichlorophenyl)-1,1 dimethylurea (DCMU) competed with the quinol reductant in phase I. The results reveal that the two components of the Cyt b559 redox reaction reflect two redox equilibria attaining in different time domains. One-electron redox equilibrium between oxidized Cyt b559 and the photosystem II-bound plastoquinol is established in phase I of Cyt b559 reduction. Phase II is attributed to equilibration of Cyt b559 redox forms with the quinone pool. The quinone site involved in phase I of Cyt b559 reduction is considered to be the site regulating the redox potential of Cyt b559 which can accommodate quinone, semiquinone and quinol forms. The properties of this site designated here as QD clearly suggest that it is distinct from the site QC found in the photosystem II crystal structure. PMID- 23357333 TI - Schirmer strip vs. capillary tube method: non-invasive methods of obtaining proteins from tear fluid. AB - Human tear fluid is a complex mixture containing over 500 solute proteins, lipids, electrolytes, mucins, metabolites, hormones and desquamated epithelial cells as well as foreign substances from the ambient air. Little is known to date about the function of most tear components. The efficient and gentle collection of tear fluid facilitates closer investigation of these matters. The objective of the present paper was to compare two commonly used methods of obtaining tear fluid, the capillary tube and Schirmer strip methods, in terms of usefulness in molecular biological investigation of tear film. The comparative protein identification methods Bradford and Western Blot were used in the analyses to this end. The surfactant proteins (SP) A-D recently described as present on the eye surface were selected as the model proteins. Both methods feature sufficient uptake efficiency for proteins in or extraction from the sampling means used (capillary tube/Schirmer strip). The total protein concentration can be determined and the proteins in the tears can be detected - besides the hydrophilic SP-A and D also the non-water-soluble proteins of smaller size such as SP-B and C. Thus both methods afford a suitable basis for comparative analysis of the physiological processes in the tear fluid of healthy and diseased subjects. On the whole, the Schirmer strip has several advantages over the capillary tube. PMID- 23357335 TI - The role of phosphodiesterases in hippocampal synaptic plasticity. AB - Phosphodiesterases (PDEs) degrade cyclic nucleotides, signalling molecules that play important roles in synaptic plasticity and memory. Inhibition of PDEs may therefore enhance synaptic plasticity and memory as a result of elevated levels of these signalling molecules, and this has led to interest in PDE inhibitors as cognitive enhancers. The development of new mouse models in which PDE subtypes have been selectively knocked out and increasing selectivity of PDE antagonists means that this field is currently expanding. Roles for PDE2, 4, 5 and 9 in synaptic plasticity have so far been demonstrated and we review these studies here in the context of cyclic nucleotide signalling more generally. The role of other PDE families in synaptic plasticity has not yet been investigated, and this area promises to advance our understanding of cyclic nucleotide signalling in synaptic plasticity in the future. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. PMID- 23357334 TI - Separation of emetic and anorexic responses of exendin-4, a GLP-1 receptor agonist in Suncus murinus (house musk shrew). AB - The use of glucagon-like peptide-1 (7-36) amide (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus is commonly associated with nausea and vomiting. Therefore, the present studies investigated the potential of GLP-1 receptor ligands to modulate emesis and feeding in Suncus murinus. Exendin-4, a selective GLP-1 receptor agonist, was administered subcutaneously (1-30 nmol/kg) or intracerebroventricularly (0.03-3 nmol) after 12-h of fasting. In other studies, animals were pretreated with the GLP-1 receptor antagonist, exendin (9 39), or saline (5 MUl) 15 min prior to exendin-4 (3 nmol, i.c.v.). Behaviour of animals and food and water intake were then recorded for 1-2 h; c-Fos expression was also assessed in the brains of animals in the i.c.v. studies. The subcutaneous administration of exendin-4 reduced food and water intake (p < 0.001) and induced emesis in 40% of animals (p > 0.05). The intracerebroventricular administration of exendin-4 also prevented feeding, and induced emesis (p < 0.01). In these studies, exendin (9-39) (30 nmol, i.c.v.) antagonised emesis induced by exendin-4 and the increased c-Fos expressions in the brainstem and hypothalamus (p < 0.05), but it was ineffective in reversing the exendin-4-induced inhibition of food and water intake (p > 0.05). These data suggest that exendin-4 exerts its emetic effects in the brainstem and/or hypothalamus via GLP-1 receptors. The action of exendin-4 to suppress feeding may involve non-classical GLP-1 receptors or other mechanisms. PMID- 23357336 TI - The intersections of NMDAR-dependent synaptic plasticity and cell survival. AB - The discovery of a requirement for N-methyl d-aspartate receptor (NMDAR) activation in long-term potentiation (LTP) set off an explosion of interest in the mechanisms of NMDAR-dependent synaptic plasticity. Meanwhile other research has advanced our understanding of how NMDAR activation regulates neuronal death and survival. Surprisingly, there have been few attempts to correlate these important areas of research. Here we review current knowledge of the various mechanisms of NMDAR-dependent synaptic plasticity that are shared with neuronal survival and death, while drawing comparisons with the proneurotrophin/neurotrophin receptor and intracellular signaling systems. Our conclusion is that NMDAR-dependent LTP and long-term depression (LTD) share many common mechanisms with cell survival and cell death, respectively. The intersections of plasticity and cell survival may represent novel avenues for neuroprotection. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. PMID- 23357337 TI - Determination of peak deflections from human surrogates using chestbands in side impact tests. AB - To understand the biomechanics of the human body in motor vehicle environments, physical models including anthropomorphic test devices (ATD) and biological models (postmortem human surrogates) are used, and sled tests are conducted. Deflection is often used as a biomechanical variable to characterize the effects of impact loading and derive injury criteria. The objective of the present study was to evaluate different techniques and recommend a methodology to determine the peak thorax and abdominal deflections from temporal contours using chestbands in oblique lateral impacts. The side impact ATD WorldSID representing human surrogates was positioned on a seat. The seat was rigidly fixed to the platform of an acceleration sled. The oblique load-wall fixed to the sled consisted of separate and adjustable plates to contact the shoulder, thorax, abdomen, and pelvis. Two 59-gage chestbands were wrapped on the thorax and abdomen. Tests were conducted at low, medium, and high velocities (3.4, 6.7, and 7.5m/s) and three methods, termed the spine-sternum, bilateral, and spine-box, were used to determine the global peak deflection and its angulation. Results indicated that all three methods produced very similar angulations, for all velocity tests, and at both thorax and abdominal regions. However, maximum deflections were the lowest in the spine-sternum, followed by bilateral and spine-box methods, with one exception. Based on the development of deflection contours, locations used in the definitions of the origin, and accuracy in identifying critical locations/points in time-varying contours, results of the present study indicate that the bilateral method is the optimum procedure to determine the oblique peak deflection vector in biomechanical tests. PMID- 23357338 TI - Bivariate piecewise stationary segmentation; improved pre-treatment for synchronization measures used on non-stationary biological signals. AB - Analysis of synchronization between biological signals can be helpful in characterization of biological functions. Many commonly used measures of synchronicity assume that the signal is stationary. Biomedical signals are however often strongly non stationary. We propose to use a bivariate piecewise stationary pre-segmentation (bPSP) of the signals of interest, before the computation of synchronization measures on biomedical signals to improve the performance of standard synchronization measures. In prior work we have shown how this can be achieved by using the auto-spectrum of either one of the signals under investigation. In this work we show how major improvements of the performance of synchronization measures can be achieved using the cross-spectrum of the signals to detect stationary changes which occur independently in either signal. We show on synthetic as well as on real biological signals (epileptic EEG and uterine EMG) that the proposed bPSP approach increases the accuracy of the measures by making a good tradeoff between the stationarity assumption and the length of the analyzed segments, when compared to the classical windowing method. PMID- 23357339 TI - Spatial summation of vibrotactile sensations at the foot. AB - Thresholds for the perception of vibration on the hand reduce with increasing area of excitation when the thresholds are mediated by the Pacinian channel (a phenomenon known as spatial summation) but thresholds are generally independent of the area of excitation when they are mediated by non-Pacinian channels. The effect of the area of excitation on vibrotactile thresholds at the sole of the foot has not been thoroughly investigated. In the study reported in this paper, thresholds for the perception of 20 Hz vibration and 160 Hz vibration were determined on the foot (at the big toe (hallux), the medial (inside) ball, the lateral (outside) ball, and the heel) and on the hand (at the thenar eminence and at the fingertip) in 12 male subjects using four probe diameters: 1mm (0.19 cm(2) excitation area), 3mm (0.38 cm(2)), 6 mm (0.78 mm(2)) and 10 mm (1.53 cm(2)) with a 2mm gap between the vibrating probe and a fixed surround. On both the hand and the foot, thresholds for the perception of 160 Hz vibration decreased as the probe diameter increased. There was no overall consistent change in thresholds for the perception of 20 Hz vibration. Thresholds for the perception of 160 Hz vibration were lowest at the fingertip and highest at the big toe. Thresholds for 20 Hz vibration were also lowest at the fingertip. It is concluded that on the sole of the foot there is evidence of spatial summation in the perception of 160 Hz vibration, mediated by the Pacinian channel, but not in the perception of 20 Hz vibration, mediated by a non-Pacinian channel. The findings show that vibrotactile thresholds at the foot obtained with different areas of excitation, or an unknown area of excitation, should not be compared. It is concluded that there is a need to standardise methods of measuring the vibrotactile thresholds at the foot that are obtained for clinical applications. PMID- 23357340 TI - Technology-driven and evidence-based genomic analysis for integrated pediatric and prenatal genetics evaluation. AB - The first decade since the completion of the Human Genome Project has been marked with rapid development of genomic technologies and their immediate clinical applications. Genomic analysis using oligonucleotide array comparative genomic hybridization (aCGH) or single nucleotide polymorphism (SNP) chips has been applied to pediatric patients with developmental and intellectual disabilities (DD/ID), multiple congenital anomalies (MCA) and autistic spectrum disorders (ASD). Evaluation of analytical and clinical validities of aCGH showed > 99% sensitivity and specificity and increased analytical resolution by higher density probe coverage. Reviews of case series, multi-center comparison and large patient control studies demonstrated a diagnostic yield of 12%-20%; approximately 60% of these abnormalities were recurrent genomic disorders. This pediatric experience has been extended toward prenatal diagnosis. A series of reports indicated approximately 10% of pregnancies with ultrasound-detected structural anomalies and normal cytogenetic findings had genomic abnormalities, and 30% of these abnormalities were syndromic genomic disorders. Evidence-based practice guidelines and standards for implementing genomic analysis and web-delivered knowledge resources for interpreting genomic findings have been established. The progress from this technology-driven and evidence-based genomic analysis provides not only opportunities to dissect disease-causing mechanisms and develop rational therapeutic interventions but also important lessons for integrating genomic sequencing into pediatric and prenatal genetic evaluation. PMID- 23357341 TI - Genetics of nonalcoholic Fatty liver disease: an overview. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world today. Its incidence in adults and children is rising rapidly due to the ongoing epidemics of obesity and type 2 diabetes. Hence, it has become a global public health issue. Environmental factors have been found to play a major role in the etiology of NAFLD, especially for genetically susceptible populations. Among these, one of the most important factors is junk food, especially the typical "Western-style" diet rich in simple carbohydrates, saturated fat, and highly processed food materials. Genetic predisposition to NAFLD does occur; however, a precise definition of genetic factors responsible for NAFLD is still lacking. Specific variants of different genes have been shown to present a risk for NAFLD. Genetic studies might be helpful in the management of the disease by developing novel treatment strategies based on individual's genotype. PMID- 23357342 TI - The genetic and molecular basis of plant resistance to pathogens. AB - Plant pathogens have evolved numerous strategies to obtain nutritive materials from their host, and plants in turn have evolved the preformed physical and chemical barriers as well as sophisticated two-tiered immune system to combat pathogen attacks. Genetically, plant resistance to pathogens can be divided into qualitative and quantitative disease resistance, conditioned by major gene(s) and multiple genes with minor effects, respectively. Qualitative disease resistance has been mostly detected in plant defense against biotrophic pathogens, whereas quantitative disease resistance is involved in defense response to all plant pathogens, from biotrophs, hemibiotrophs to necrotrophs. Plant resistance is achieved through interception of pathogen-derived effectors and elicitation of defense response. In recent years, great progress has been made related to the molecular basis underlying host-pathogen interactions. In this review, we would like to provide an update on genetic and molecular aspects of plant resistance to pathogens. PMID- 23357343 TI - Production of transgenic Korean native cattle expressing enhanced green fluorescent protein using a FIV-based lentiviral vector injected into MII oocytes. AB - The potential benefits of generating and using transgenic cattle range from improvements in agriculture to the production of large quantities of pharmaceutically relevant proteins. Previous studies have attempted to produce transgenic cattle and other livestock by pronuclear injection and somatic cell nuclear transfer, but these approaches have been largely ineffective; however, a third approach, lentivirus-mediated transgenesis, has successfully produced transgenic livestock. In this study, we generated transgenic (TG) Korean native cattle using perivitelline space injection of viral vectors, which expressed enhanced green fluorescent protein (EGFP) systemically. Two different types of lentiviral vectors derived from feline immunodeficiency virus (FIV) and human immunodeficiency virus (HIV) carrying EGFP were injected into the perivitelline space of MII oocytes. EGFP expression at 8-cell stage was significantly higher in the FIV group compared to the HIV group (47.5%+/-2.2% v.s. 22.9%+/-2.9%). Eight cell embryos that expressed EGFP were cultured into blastocysts and then transferred into 40 heifers. Ten heifers were successfully impregnated and delivered 10 healthy calves. All of these calves expressed EGFP as detected by in vivo imaging, PCR and Southern blotting. In addition, we established an EGFP expressing cell line from TG calves, which was followed by nuclear transfer (NT). Recloned 8-cell embryos also expressed EGFP, and there were no differences in the rates of fusion, cleavage and development between cells derived from TG and non TG calves, which were subsequently used for NT. These results illustrate that FIV based lentiviruses are useful for the production of TG cattle. Moreover, our established EGFP cell line can be used for additional studies that involve induced pluripotent stem cells. PMID- 23357344 TI - Recycling isolation of plant DNA, a novel method. AB - DNA is one of the most basic and essential genetic materials in the field of molecular biology. To date, isolation of sufficient and good-quality DNA is still a challenge for many plant species, though various DNA extraction methods have been published. In the present paper, a recycling DNA extraction method was proposed. The key step of this method was that a single plant tissue sample was recycled for DNA extraction for up to four times, and correspondingly four DNA precipitations (termed as the 1st, 2nd, 3rd and 4th DNA sample, respectively) were conducted. This recycling step was integrated into the conventional CTAB DNA extraction method to establish a recycling CTAB method. This modified CTAB method was tested in eight plant species, wheat, sorghum, barley, corn, rice, Brachypodium distachyon, Miscanthus sinensis and tung tree. The results showed that high-yield and good-quality DNA samples could be obtained by using this new method in all the eight plant species. The DNA samples were good templates for PCR amplification of both ISSR and SSR markers. The recycling method can be used in multiple plant species and can be integrated with multiple conventional DNA isolation methods, and thus is an effective and universal DNA isolation method. PMID- 23357345 TI - Rapid evolution of the mammalian HILS1 gene and the nuclear condensation process during mammalian spermiogenesis. PMID- 23357346 TI - Do we need to wait longer for cardiac arrest survivor to wake up in hypothermia era? AB - Before the era of therapeutic hypothermia, a practice parameter including absent or extensor motor response at day 3 and the presence of myoclonus status epilepticus within 24 hours was used to assist prognostication of poor neurologic outcomes. There are conflicting results concerning whether hypothermia influences the reliability of the predictors and the accurate predictors and optimal timing for assessing neurologic recovery are largely unknown. Several prognostic indicators other than guidelines are also applied to help determining prognosis, including electroencephalogram, cerebral computed tomographic scan, and cerebral perfusion scintigraphy single-photon emission computed tomographic scan. Here, we present a cardiac arrest survivor treated with therapeutic hypothermia waked up finally on the 13th day, although clinical and laboratory examinations after return of spontaneous circulation all indicated poor neurologic prognosis. However, life support was reported to be withdrawn within 3 to 5 days in 25% to 50% cardiac arrest survivors treated with hypothermia when grave prognosis was predicted. The clinical course of the patient raises some important questions concerning the accuracy of current predictors, the optimal observation period for neurologic recovery, and the appropriate timing to determine withdrawal of life support in cardiac arrest victims receiving therapeutic hypothermia. PMID- 23357348 TI - Minimally invasive prostatic urethral lift: surgical technique and multinational experience. AB - BACKGROUND: Many men with benign prostatic hyperplasia (BPH) are dissatisfied with current treatment options. Although transurethral resection of the prostate (TURP) remains the gold standard, many patients seek a less invasive alternative. OBJECTIVE: We describe the surgical technique and results of a novel minimally invasive implant procedure that offers symptom relief and improved voiding flow in an international series of patients. DESIGN, SETTING, AND PARTICIPANTS: A total of 102 men with symptomatic BPH were consecutively treated at seven centers across five countries. Patients were evaluated up to a median follow-up of 1 yr postprocedure. Average age, prostate size, and International Prostate Symptom Score (IPSS) were 68 yr, 48 cm(3), and 23, respectively. SURGICAL PROCEDURE: The prostatic urethral lift mechanically opens the prostatic urethra with UroLift implants that are placed transurethrally under cystoscopic visualization, thereby separating the encroaching prostatic lobes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were evaluated pre- and postoperatively by the IPSS, Quality of-Life (QOL) scale, Benign Prostatic Hyperplasia Impact Index, maximum flow rate (Qmax), and adverse event reports including sexual function. RESULTS AND LIMITATIONS: All procedures were completed successfully with a mean of 4.5 implants without serious adverse effects. Patients experienced symptom relief by 2 wk that was sustained to 12 mo. Mean IPSS, QOL, and Qmax improved 36%, 39%, and 38% by 2 wk, and 52%, 53%, and 51% at 12 mo (p<0.001), respectively. Adverse events were mild and transient. There were no reports of loss of antegrade ejaculation. A total of 6.5% of patients progressed to TURP without complication. Study limitations include the retrospective single-arm nature and the modest patient number. CONCLUSIONS: Prostatic urethral lift has promise for BPH. It is minimally invasive, can be done under local anesthesia, does not appear to cause retrograde ejaculation, and improves symptoms and voiding flow. This study corroborates prior published results. Larger series with randomisation, comparator treatments, and longer follow-up are underway. PMID- 23357349 TI - Influence of preoperative and postoperative pelvic floor muscle training (PFMT) compared with postoperative PFMT on urinary incontinence after radical prostatectomy: a randomized controlled trial. AB - BACKGROUND: The efficacy of preoperative pelvic floor muscle training (PFMT) for urinary incontinence (UI) after open radical prostatectomy (ORP) and robot assisted laparoscopic radical prostatectomy (RARP) is still unclear. OBJECTIVE: To determine whether patients with additional preoperative PFMT regain urinary continence earlier than patients with only postoperative PFMT after ORP and RARP. DESIGN, SETTING, AND PARTICIPANTS: A randomized controlled trial enrolled 180 men who planned to undergo ORP/RARP. INTERVENTION: The experimental group (E, n=91) started PFMT 3 wk before surgery and continued after surgery. The control group (C, n=89) started PFMT after catheter removal. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was time to continence. Patients measured urine loss daily (24-h pad test) until total continence (three consecutive days of 0 g of urine loss) was achieved. Secondary end points were 1 h pad test, visual analog scale (VAS), International Prostate Symptom Score (IPSS), and quality of life (King's Health Questionnaire [KHQ]). Kaplan-Meier analysis and Cox regression with correction for two strata (age and type of surgery) compared time and continence. The Fisher exact test was applied for the 1-h pad test and VAS; the Mann-Whitney U test was applied for IPSS and KHQ. RESULTS AND LIMITATIONS: Patients with additional preoperative PFMT had no shorter duration of postoperative UI compared with patients with only postoperative PFMT (p=0.878). Median time to continence was 30 and 31 d, and median amount of first-day incontinence was 108 g and 124 g for groups E and C, respectively. Cox regression did not indicate a significant difference between groups E and C (p=0.773; hazard ratio: 1.047 [0.768-1.425]). The 1-h pad test, VAS, and IPSS were comparable between both groups. However, "incontinence impact" (KHQ) was in favor of group E at 3 mo and 6 mo after surgery. CONCLUSIONS: Three preoperative sessions of PFMT did not improve postoperative duration of incontinence. TRIAL REGISTRATION: Netherlands Trial Register No. NTR 1953. PMID- 23357350 TI - ESUT expert group on laparoscopy proposes uniform terminology during radical prostatectomy: we need to speak the same language. PMID- 23357351 TI - Predictors of health-related quality of life and adjustment to prostate cancer during active surveillance. AB - BACKGROUND: Active surveillance (AS) is emerging as an alternative approach to limit the risk of overtreatment and impairment of quality of life (QoL) in patients with low-risk localised prostate cancer. Although most patients report high levels of QoL, some men may be distressed by the idea of living with untreated cancer. OBJECTIVE: To identify factors associated with poor QoL during AS. DESIGN, SETTING, AND PARTICIPANTS: Between September 2007 and March 2012, 103 patients participated in the Prostate Cancer Research International Active Surveillance (PRIAS) QoL study. Mental health (Symptom Checklist-90), demographic, clinical, and decisional data were assessed at entrance in AS. Health-related QoL (HRQoL) Functional Assessment of Cancer Therapy-Prostate version and Mini-Mental Adjustment to Cancer outcomes were assessed after 10 mo of AS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariate logistic regression models were used to identify predictors of low (<25th percentile) HRQoL, adjustment to cancer, and a global QoL index at 10 mo after enrollment. RESULTS AND LIMITATIONS: The mean age of the study patients was 67 yr (standard deviation: +/-7 yr). Lack of partner (odds ratio [OR]: 0.08; p=0.009) and impaired mental health (OR: 1.2, p=0.1) were associated with low HRQoL (p=0.006; area under the curve [AUC]: 0.72). The maladaptive adjustment to cancer (p=0.047; AUC: 0.60) could be predicted by recent diagnosis (OR: 3.3; p=0.072). Poor global QoL (overall p=0.02; AUC: 0.85) was predicted by impaired mental health (OR: 1.16; p=0.070) and time from diagnosis to enrollment in AS <5 mo (OR: 5.52; p=0.009). Influence of different physicians on the choice of AS (OR: 0.17; p=0.044), presence of a partner (OR: 0.22; p=0.065), and diagnostic biopsy with >18 core specimens (OR: 0.89; p=0.029) were predictors of better QoL. Limitations of this study were the small sample size and the lack of a control group. CONCLUSIONS: Factors predicting poor QoL were lack of a partner, impaired mental health, recent diagnosis, influence of clinicians and lower number of core samples taken at diagnostic biopsy. Educational support from physicians and emotional/social support should be promoted in some cases to prevent poor QoL. PMID- 23357352 TI - Phylogenetic analyses of RPB1 and RPB2 support a middle Cretaceous origin for a clade comprising all agriculturally and medically important fusaria. AB - Fusarium (Hypocreales, Nectriaceae) is one of the most economically important and systematically challenging groups of mycotoxigenic phytopathogens and emergent human pathogens. We conducted maximum likelihood (ML), maximum parsimony (MP) and Bayesian (B) analyses on partial DNA-directed RNA polymerase II largest (RPB1) and second largest subunit (RPB2) nucleotide sequences of 93 fusaria to infer the first comprehensive and well-supported phylogenetic hypothesis of evolutionary relationships within the genus and 20 of its near relatives. Our analyses revealed that Cylindrocarpon formed a basal monophyletic sister to a 'terminal Fusarium clade' (TFC) comprising 20 strongly supported species complexes and nine monotypic lineages, which we provisionally recognize as Fusarium (hypothesis F1). The basal-most divergences within the TFC were only significantly supported by Bayesian posterior probabilities (B-PP 0.99-1). An internode of the remaining TFC, however, was strongly supported by MP and ML bootstrapping and B-PP (hypothesis F2). Analysis of seven Fusarium genome sequences and Southern analysis of fusaria elucidated the distribution of genes required for synthesis of 26 families of secondary metabolites within the phylogenetic framework. Diversification time estimates date the origin of the TFC to the middle Cretaceous 91.3 million years ago. We also dated the origin of several agriculturally important secondary metabolites as well as the lineage responsible for Fusarium head blight of cereals. Dating of several plant-associated species complexes suggests their evolution may have been driven by angiosperm diversification during the Miocene. Our results support two competing hypotheses for the circumscription of Fusarium and provide a framework for future comparative phylogenetic and genomic analyses of this agronomically and medically important genus. PMID- 23357353 TI - A white collar 1-like protein mediates opposite regulatory functions in Mucor circinelloides. AB - Protein ubiquitylation plays a major role in the regulation of many cellular processes by altering the stability, localization or function of target proteins. CrgA is a protein of Mucor circinelloides that shows the characteristics of ubiquitin ligases and is involved in the regulation of carotenogenesis and asexual sporulation in this fungus. CrgA, which belongs to a poorly characterized group of proteins present in almost all eukaryotes, represses carotenogenesis through the proteolysis-independent mono- and di-ubiquitylation of Mcwc-1b, a White Collar-1-like protein which, when it is non-ubiquitylated, activates carotenogenesis. Using a proteomic approach, this work shows that the regulation of M. circinelloides vegetative development by CrgA is also mediated by Mcwc-1b, although, in this case, the non-ubiquitylated Mcwc-1b form acts as a repressor. High levels of a protein that contains a classical Rossmann-fold NAD(P)H/NAD(P)(+) binding domain for NAD(P)H binding and is similar to NmrA NADP(H) sensor-like proteins occur when Mcwc-1b is inactivated by ubiquitylation. A role for this protein in the regulation of sporulation is suggested because its over-expression suppresses the sporulation defect in a crgADelta mutant. NmrA like proteins are repressors that interact with GATA transcription factors and have been shown to be related to cell differentiation in Magnaporthe oryzae and Dictyostelium discoideum. This proteomic approach also revealed that CrgA regulates the carbon and energy metabolism and that Mcwc-1b is the main, but not the only, target of CrgA. PMID- 23357354 TI - Disruption of heat shock factor 1 reduces the formation of conidia and thermotolerance in the mycoparasitic fungus Coniothyrium minitans. AB - Coniothyrium minitans is a bio-control agent of Sclerotinia spp., and has the ability to produce abundant conidia to infect the host fungi. Mediation of heat shock factors (HSFs) is required to adapt to the acute temperatures, and to regulate the expression of heat shock proteins (HSPs) to function as molecular chaperones to assist in development, protein folding and stability. A heat shock factor 1 (HSF1) gene was identified from a T-DNA insertion mutant that lost the ability to form conidia in liquid culture as well as on solid media. Null mutants lacking CmHSF1 were constructed by gene disruption strategy. Mutants lacking CmHSF1 had reduced in conidial production and displayed decreased tolerance to heat and other abiotic stresses as compared to the wild type parent. Over expression strains could recover faster from heat and abiotic stresses such as, ethanol, oxidative or osmotic stresses with or without heat shock. In over expression strains, conidial germination was increased, and parasitic ability on sclerotia of Sclerotinia sclerotiorum was enhanced by 0.42-5.92% compared to the wild type strain. Increased expression levels in wild strain ZS-1 were observed when the fungus was grown at 37 degrees C or 45 degrees C with other abiotic stresses. CmHSF1 plays an important role in conidial production, conidial germination, and tolerance against heat and other abiotic stresses. PMID- 23357355 TI - Alternative cycling modes of the Na(+)/K(+)-ATPase in the presence of either Na(+) or Rb(+). AB - A comprehensive study of the interaction between Na(+) and K(+) with the Na(+)/K(+)-ATPase requires dissecting the incidence of alternative cycling modes on activity measurements in which one or both of these cations are absent. With this aim, we used membrane fragments containing pig-kidney Na(+)/K(+)-ATPase to perform measurements, at 25 degrees C and pH=7.4, of ATPase activity and steady state levels of (i) intermediates containing occluded Rb(+) at different [Rb(+)] in media lacking Na(+), and (ii) phosphorylated intermediates at different [Na(+)] in media lacking Rb(+). Most relevant results are: (1) Rb(+) can be occluded through an ATPasic cycling mode that takes place in the absence of Na(+) ions, (2) the kinetic behavior of the phosphoenzyme formed by ATP in the absence of Na(+) is different from the one that is formed with Na(+), and (3) binding of Na(+) to transport sites during catalysis is not at random unless rapid equilibrium holds. PMID- 23357356 TI - New generation of efficient peptide-based vectors, NickFects, for the delivery of nucleic acids. AB - Harnessing of a branched structure is a novel approach in the design of cell penetrating peptides and it has provided highly efficient transfection reagents for intracellular delivery of nucleic acids. The new stearylated TP10 analogs, NickFects, condense plasmid DNA, splice correcting oligonucleotides and short interfering RNAs into stable nanoparticles with a size of 62-160nm. Such nanoparticles have a negative surface charge (-11 to -18mV) in serum containing medium and enable highly efficient gene expression, splice correction and gene silencing. One of the novel peptides, NickFect51 is capable of transfecting plasmid DNA into a large variety of cell lines, including refractory suspension and primary cells and in several cases exceeds the transfection level of commercially available reagent LipofectamineTM 2000 without any cytotoxic side effects. Additionally we demonstrate the advantages of NickFect51 in a protein production system, QMCF technology, for expression and production of recombinant proteins in hardly transfectable suspension cells. PMID- 23357357 TI - Effect of phospholipid composition on discoidal HDL formation. AB - Discoidal high-density lipoprotein (HDL) particles are known to fractionalize into several discrete populations. Factors regulating their size are, however, less understood. To reveal the effect of lipid composition on their formation and characteristics, we prepared several reconstituted HDLs (rHDLs) with 1-palmitoyl 2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphoserine (POPS), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), and sphingomyelin at phospholipid to apolipoprotein A-I ratios of 100 and 25. When reconstitution was conducted at 37 degrees C, the efficiency of rHDL formation from POPC was decreased as compared with that conducted at 4 degrees C. Moreover, large rHDLs with a Stokes diameter of 9.6nm became dominant over small rHDL with a diameter of 7.9nm, which was distinctly observed at 4 degrees C. The aminophospholipids POPS and POPE promoted the formation of small rHDLs at 37 degrees C, but fluorescence experiments revealed that they did so in a different fashion: Fluorescence lifetime data suggested that the head group of POPS reduces hydrophobic hydration, especially in small rHDLs, suggesting that this lipid stabilizes the saddle-shaped bilayer structure in small rHDLs. Fluorescence lifetime and anisotropy data showed that incorporation of POPE increases acyl chain order and water penetration into the head group region in large rHDLs, suggesting that POPE destabilizes the planar bilayer structure. These results imply that these aminophospholipids contribute to the formation of small rHDLs under biological conditions. PMID- 23357358 TI - Membrane fusion and vesicular transformation induced by Alzheimer's amyloid beta. AB - Amyloid beta (Abeta) peptides, produced through endo-proteolytic cleavage of amyloid precursor protein, are thought to be involved in the death of neural cells in Alzheimer's disease (AD). Although the mechanisms are not fully known, it has been suggested that disruption of cellular activity due to Abeta interactions with the cell membrane may be one of the underlying causes. Here in, we have investigated the interaction between Abeta-42 and biomimetic lipid membranes and the resulting perturbations in the lipid vesicles. We have shown that Abeta oligomeric species localized closer to the membrane surface. Localization of the fibrillar species of Abeta-42, although varied, was not as closely associated with the membrane surface. We have demonstrated that the presence of Abeta-42 leads to an increase in membrane surface area, inducing lipid temporal vesicular transformation. Furthermore, we have unequivocally shown that Abeta-peptides mediate membrane fusion. Although membrane fusion induced by Abeta has been hypothesized/proposed, this is the first time it has been visually captured. This fusion may be one of the mechanisms behind the membrane increase in surface area and the resulting vesicular transformation. We have shown that the longer 'amyloidogenic' isoform causes vesicular transformation more readily, and has a higher membrane fusogenic potential than Abeta-40. Although not core to this study, it is hugely interesting to observe the high agreement between membrane dynamics and the reported amyloidogenicity of the peptides and aggregation species opening up the potential role of vesicular dynamics for profiling and biosensing of Abeta-induced neuro-toxicity. PMID- 23357360 TI - Improvement of p-cymene antinociceptive and anti-inflammatory effects by inclusion in beta-cyclodextrin. AB - Previously, we have demonstrated the analgesic-like property of p-cymene in rodents. Short half-life is a limitation for p-cymene application and several approaches have been used to improve pharmaceutical properties of monoterpenes, including the employment of drug-delivery systems. Here, we used p-cymene/beta cyclodextrin (beta-CD) complex and p-cymene (PC) isolated to evaluated whether the complex formulation is able to improve the antinociceptive activity of this monoterpene. Male mice (26-30g) were pretreated with PC/beta-CD (20 or 40mg/kg, p.o.), PC (20 or 40mg/kg, p.o.) or vehicle (distilled water), 0.5h before painful tests and antinociceptive effect was evaluated at times: 0.5, 1, 2, 4, 8, and 16h after treatment. We evaluated the analgesic-like effect of PC/beta-CD and PC in acetic acid-induced abdominal writhes, hot-plate, carrageenan-induced paw edema and in rota-rod apparatus. Our results demonstrated that acute treatment with complex PC/beta-CD produced an antinocicepitve effect (p<0.01 or p<0.001) for 8h followed whereas isolated PC produced the same effect for 2h. Similar results were obtained in hot-plate test, PC/beta-CD, in all doses, significantly reduces (p<0.01 or p<0.001) nociceptive behavior for 8h while isolated PC for 1h, did so only in higher dose. Such results were unlikely to be caused by motor abnormality. Systemic pretreatment with PC/beta-CD and PC inhibited the development paw edema by carrageenan 1%, but PC/beta-CD did so during a longer period when compared with isolated monoterpene alone. Our results provide evidence to propose that the complex with beta-CD improved analgesic and anti inflammatory effects of p-cymene. PMID- 23357359 TI - FTIR spectroscopic imaging of protein aggregation in living cells. AB - Protein misfolding and aggregation are the hallmark of a number of diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and the prion diseases. In all cases, a naturally occurring protein misfolds and forms aggregates that are thought to disrupt cell function through a wide range of mechanisms that are yet to be fully unraveled. Fourier transform infrared (FTIR) spectroscopy is a technique that is sensitive to the secondary structure of proteins and has been widely used to investigate the process of misfolding and aggregate formation. This review focuses on how FTIR spectroscopy and spectroscopic microscopy are being used to evaluate the structural changes in disease-related proteins both in vitro and directly within cells and tissues. Finally, ongoing technological advances will be presented that are enabling time-resolved FTIR imaging of protein aggregation directly within living cells, which can provide insight into the structural intermediates, time scale, and mechanisms of cell toxicity associated with aggregate formation. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies. PMID- 23357361 TI - beta-Asarone induces senescence in colorectal cancer cells by inducing lamin B1 expression. AB - Colorectal cancer is a leading cause of cancer mortality with a complex carcinogenesis that includes reduced cellular senescence. Lamin proteins are decreased in senescing cells, and frequently decreased in malignancies. This study identified a new drug candidate for colorectal cancer that appears to target cell senescence via a lamin protein. beta-Asarone (1-propenyl-2,4,5 methoxybenzol) is a compound from the traditional medical herb Acorus calamus Linn. This study tested the in vitro and in vivo effects of beta-asarone on colorectal cancer cells by testing cell viability using human colorectal cell lines HT29 and SW480 in MTT assays; tumorigenesis using xenografts in nude mice and a mouse model of colorectal cancer; cell senescence using senescence associated beta-galactosidase activity; and expression of cancer and senescence related proteins, specifically lamins, Oct-1, p53, p21, and p15, by Western blot. beta-Asarone appeared to increase expression of lamin B1, p53, p21, but not lamin A/C. beta-Asarone regulates p15 expression by regulation of Oct-1 binding. Collectively, the results suggested that beta-asarone inhibits colon cancer formation in vivo and in vitro by inducing senescence. Since beta-asarone induced lamin B1 expression, a model is proposed in which beta-asarone inhibits colorectal cancer by inducing senescence through lamin B1. PMID- 23357362 TI - Testing of Perilla frutescens extract and Vicenin 2 for their antispasmodic effect. AB - Gastrointestinal discomfort is frequently observed. The effects of Perilla frutescens extract and Vicenin 2 (a compound in this extract) were assayed in rat ileum with or without stimulation with acetylcholine or Ba(2+). Both had no direct spasmolytic effect, but both decreased acetylcholine- or Ba(2+)-induced contraction of rat ileum indicating an antispasmodic effect. This is valuable because effects were only observed when spasms were induced and may disturb the patient. The extract and the compound may be used to maintain and improve gut health. PMID- 23357363 TI - Anti-inflammatory and antimicrobial properties of pyrroloquinazoline alkaloids from Adhatoda vasica Nees. AB - Adhatoda vasica Nees, Acanthaceae, is well known plant in Ayurveda and Unani medicine. The purpose of this study was to characterize the most bioactive phytochemicals viz., vasicine, vasicinone, vasicine acetate, 2-acetyl benzyl amine, vasicinolone present in the chloroform fraction having anti-inflammatory and antimicrobial activities. The anti-inflammatory activity was tested by using carrageenan and CFA-model induced paw oedema. The antimicrobial activity of isolated compounds was assessed by using the microdilution method. The observed results revealed that vasicine showed most potent anti-inflammatory effects (59.51%) at the dose of 20.0mg/kg at 6h after carrageenan injection and maximum inhibition rate was observed of vasicinone (63.94%) at the dose of 10.0mg/kg at 4 days after CFA injection. The strong antibacterial activity was exhibited by vasicine at 20MUg/ml dose against E. coli and also demonstrated maximum antifungal activity against C. albicans at the dose of >55MUg/ml. All the five alkaloids demonstrated significant anti-inflammatory and antimicrobial activities. PMID- 23357364 TI - Recent advances in bioprocessing application of membrane chromatography. AB - Compared to traditional chromatography using resins in packed-bed columns, membrane chromatography is a relatively new and immature bioseparation technology based on the integration of membrane filtration and liquid chromatography into a single-stage operation. Over the past decades, advances in membrane chemistry have yielded novel membrane devices with high binding capacities and improved mass transfer properties, significantly increasing the bioprocessing efficiency for purification of biomolecules. Due to the disposable nature, low buffer consumption, and reduced equipment costs, membrane chromatography can significantly reduce downstream bioprocessing costs. In this review, we discuss technological merits and disadvantages associated with membrane chromatography as well as recent bioseparation applications with a particular attention on purification of large biomolecules. PMID- 23357366 TI - RANKL-associated suppression of particle-induced osteolysis in an aged model of Calcitonin and alpha-CGRP deficiency. AB - An aging population with higher bone turnover intensifies the need for joint replacement surgery. However, particle-induced osteolysis (PIO) remains a major cause of early implant loosening. Differences in bone remodeling between young and aged Calcitonin (CT)- and alpha-CGRP (Calcitonin gene-related peptide) deficient mice (Calca(-/-)) might modify our previous findings regarding CT/alpha CGRP in PIO. This may have important implications for PIO in an aging population. Four groups of twelve-month-old wild-type and Calca(-/-) mice underwent either SHAM surgery with and without CT, or polyethylene-particle implantation with related treatment. Morphometric changes were detected using MU-CT, histomorphometric analysis and by counting TRAP(+) cells (osteoclast-staining). Bone remodeling was assessed using serum and urinary markers. There was no osteolysis in aged particle-treated Calca(-/-) animals and the effect of CT on PIO was reduced compared to wild-type mice. However, there were significantly higher numbers of TRAP(+) cells in Calca(-/-) animals, and bone remodeling markers revealed a significant increase in OPG/OCN and a significant reduction in RANKL compared to aged wild-type mice. CT/alpha-CGRP modulates bone cell activity in PIO in aged mice in a way that is distinct from young animals. This may have implications for the treatment of PIO in the periprosthetic surface of joint replacements in an aging population. PMID- 23357365 TI - Point-of-care assays for tuberculosis: role of nanotechnology/microfluidics. AB - Tuberculosis (TB) remains one of the most devastating infectious diseases and its eradication is still unattainable given the limitations of current technologies for diagnosis, treatment and prevention. The World Health Organization's goal to eliminate TB globally by 2050 remains an ongoing challenge as delayed diagnosis and misdiagnosis of TB continue to fuel the worldwide epidemic. Despite considerable improvements in diagnostics for the last few decades, a simple and effective point-of-care TB diagnostic test is yet not available. Here, we review the current assays used for TB diagnosis, and highlight the recent advances in nanotechnology and microfluidics that potentially enable new approaches for TB diagnosis in resource-constrained settings. PMID- 23357367 TI - Magnetic resonance imaging of Fe3O4@SiO2-labeled human mesenchymal stem cells in mice at 11.7 T. AB - Fe(3)O(4)@SiO(2) core-shell nanoparticles were synthesized and used to label human mesenchymal stem cells (hMSCs) for in vitro and in vivo magnetic resonance imaging study. The diameter of the nanoparticles is 24-30 nm with a Fe(3)O(4) core of ~8 nm and a SiO(2) shell of ~8 nm. Transverse relaxivity of the nanoparticles dispersed in water is measured to be ~106 mM(-1) s(-1). After incubation with hMSCs for 12 h at a concentration of 100 MUg Fe/mL, cellular uptake of Fe(3)O(4)@SiO(2) is 20-100 pg Fe/cell, which are located predominantly in the cytoplasm of cells. This level of uptake exhibits no significant influence on hMSCs' viability and differentiation. In vitro imaging of Fe(3)O(4)@SiO(2) labeled hMSCs evenly distributed in agarose gel yields single cell sensitivity at 11.7 T. In vivo imaging of Fe(3)O(4)@SiO(2)-labeled hMSCs injected into the left brain hemisphere of nude mice yields imaging sensitivity of ~130 hMSCs. PMID- 23357368 TI - Three-dimensional modeling of angiogenesis in porous biomaterial scaffolds. AB - Vascularization of biomaterial scaffolds is essential for the successful clinical application of engineered tissues. Experimental studies are often performed to investigate the role of scaffold architecture on vascularized tissue formation. However, experiments are expensive and time-consuming and synthesis protocols often do not allow for independent investigation of specific scaffold properties. Computational models allow for rapid screening of potential material designs with control over scaffold properties that is difficult in laboratory settings. We have developed and tested a three-dimensional agent-based framework for investigating the effect of scaffold pore architecture on angiogenesis. Software agents represent endothelial cells, interacting together and with their micro environment, leading to the invasion of blood vessels into the scaffold. A rule base, driven by experimental findings, governs the behavior of individual agents. 3D scaffold models with well-defined homogeneous and heterogeneous pore architectures were simulated to investigate the impact of various design parameters. Simulation results indicate that pores of larger size with higher interconnectivity and porosity support rapid and extensive angiogenesis. The developed framework can be used to screen biomaterial scaffold designs for optimal vascularization and investigate complex interactions among invading blood vessels and their micro-environment. PMID- 23357370 TI - The activity against Ehrlich's ascites tumors of doxorubicin contained in self assembled, cell receptor targeted nanoparticle with simultaneous oral delivery of the green tea polyphenol epigallocatechin-3-gallate. AB - Doxorubicin (DOX) is a well-known anticancer drug used for the treatment of a wide variety of cancers. However, undesired toxicity of DOX limits its uses. To address the issue of minimizing toxicity of DOX by making it targeted towards cancer cells, DOX was entrapped in self-assembled 6-O-(3-hexadecyloxy-2 hydroxypropyl)-hyaluronic acid (HDHA) nanoparticles. We hypothesized that by encapsulating the drug in biodegradable nanoparticles, its therapeutic efficacy would improve, if targeted against cancer cells. We synthesized cell receptor targeted, DOX loaded HDHA nanoparticles (NPs) and non-targeted DOX loaded O hexadecylated dextran (HDD) nanoparticles (NPs) and characterized them for their entrapment efficiency, percent yield, drug load, surface morphology, particle size and in vitro drug release. The anticancer efficacy of DOX loaded HDHA-NPs was evaluated by measuring the changes in tumor volumes, tumor weights, and mean survival rate of Swiss albino mice grafted with Ehrlich's ascites carcinoma (EAC) cells. For this, the animals were given HDHA-DOX-NPs (1.5 mg/kg b.wt.) intravenously and a green tea polyphenol, Epigallocatechin-3-gallate (EGCG) (20 mg/kg b.wt.), orally through gavage. The targeted NP dose with EGCG significantly increased mean survival time of the animals and enhanced the therapeutic efficacy of the drug compared to the non-targeted NPs and free DOX. Further, we showed that these NPs (HDD and HDHA) were more active in the presence of EGCG than DOX alone in inducing apoptosis in EAC cells as evident by an increase in sub-G1 cells (percent), Annexin V positive cells and chromatin condensation along with the reduction in mitochondrial membrane potential (MMP). The study demonstrates that DOX loaded HDHA-NPs along with EGCG significantly inhibit the growth of EAC cells with ~38-fold dose advantage compared to DOX alone and thus opens a new dimension in cancer chemotherapy. PMID- 23357369 TI - Spatial patterning of endothelium modulates cell morphology, adhesiveness and transcriptional signature. AB - Microscale and nanoscale structures can spatially pattern endothelial cells (ECs) into parallel-aligned organization, mimicking their cellular alignment in blood vessels exposed to laminar shear stress. However, the effects of spatial patterning on the function and global transcriptome of ECs are incompletely characterized. We used both parallel-aligned micropatterned and nanopatterned biomaterials to evaluate the effects of spatial patterning on the phenotype of ECs, based on gene expression profiling, functional characterization of monocyte adhesion, and quantification of cellular morphology. We demonstrate that both micropatterned and aligned nanofibrillar biomaterials could effectively guide EC organization along the direction of the micropatterned channels or nanofibrils, respectively. The ability of ECs to sense spatial patterning cues were abrogated in the presence of cytoskeletal disruption agents. Moreover, both micropatterned and aligned nanofibrillar substrates promoted an athero-resistant EC phenotype by reducing endothelial adhesiveness for monocytes and platelets, as well as by downregulating the expression of adhesion proteins and chemokines. We further found that micropatterned ECs have a transcriptional signature that is unique from non-patterned ECs, as well as from ECs aligned by shear stress. These findings highlight the importance of spatial patterning cues in guiding EC organization and function, which may have clinical relevance in the development of vascular grafts that promote patency. PMID- 23357371 TI - In vitro and in vivo hemostatic capabilities of a functionally integrated platelet-mimetic liposomal nanoconstruct. AB - There is significant clinical interest in synthetic platelet substitutes that can mimic platelet's hemostastic functionalities while allowing scale-up, minimal biological contamination, and long shelf-life. To this end, mimicking active platelet's hemostatically relevant matrix-adhesion properties and aggregation properties independently and then integrating them via heteromultivalent ligand decoration on a single synthetic particle can lead to an efficient platelet substitute design. We have recently reported on the feasibility of this approach in vitro, using liposomes as model particles. Building on these studies, here we demonstrate the capability of optimizing the platelet-mimetic properties of our liposomal constructs in vitro via modulating the ligand-decoration densities and ligand ratios. In addition, we demonstrate the enhanced hemostatic efficacy of the functionally-integrated platelet-mimetic constructs in vivo. Liposomes were surface-decorated with collagen- and VWF-binding peptides (CBP and VBP) to mimic platelet adhesion and a fibrinogen-mimetic peptide (FMP) to promote platelet aggregation. Modulation of VBP- and CBP-densities and relative ratios enabled optimizing construct adhesion under varying shear-flow conditions. Modulation of FMP-density enabled enhancement of construct-promoted platelet aggregation. The VBP-, CBP- and FMP-decorations were integrated on a single liposome, and these functionally-integrated constructs showed significantly higher hemostatic efficacy in vivo in a mouse tail-transection model compared to 'adhesion-only' or 'aggregation-only' constructs. PMID- 23357372 TI - Effect of RGD nanospacing on differentiation of stem cells. AB - Nanopatterns of a cell-adhesive peptide arginine-glycine-aspartate (RGD) on a persistently non-fouling poly(ethylene glycol) hydrogel were prepared, and behaviours of mesenchymal stem cells (MSCs) on patterns of five RGD nanospacings from 37 to 124 nm were examined under a full level of serum for eight days. Besides cell adhesion, osteogenic and adipogenic inductions of MSCs from rat bone marrow were observed in corresponding media. We not only confirmed the nanospacing dependence of cell spreading previously reported in other cell types (non-stem cells) such as less spreading in the case of nanospacings larger than the critical 70 nm, but also found the effect of RGD nanospacing on lineage commitments of stem cells. Both osteogenic and adipogenic inductions resulted in higher differentiation extents on patterns of large nanospacings than of small nanospacings. Under co-induction in the mixed osteogenic/adipogenic media, osteogenesis was predominant over adipogenesis on patterns of large RGD nanospacings, although a less cell spreading itself was beneficial not for osteogenesis but for adipogenesis according to previous studies without nanopatterns. The effect of RGD nanospacing on lineage commitments of stem cells is unexpected and cannot be interpreted via the cell spreading effect. Thus, the differentiation of stem cells might be regulated inherently by nanospacing of bioactive ligands on the material surfaces. PMID- 23357373 TI - Directing nuclear deformation on micropillared surfaces by substrate geometry and cytoskeleton organization. AB - We have recently demonstrated strong nuclear deformation of SaOs-2 osteosarcoma cells on poly-L-lactic acid (PLLA) micropillar substrates. In the present study, we first demonstrated that chemical and mechanical properties of the micropillar substrates have no dominant effect on deformation. However, SaOs-2 nucleus deformation could be strongly modulated by varying the pillar size and spacing, highlighting the importance of geometric constraints for shaping the nucleus. Furthermore, comparing the capacity for nuclear deformation in three different osteosarcoma cell lines (SaOs-2, MG-63 and OHS-4) revealed strong cell-type specific differences. Surprisingly, the highly-deformable SaOs-2 cell line displayed the highest cell stiffness as assessed by AFM-based colloidal force spectroscopy and featured a more prominent array of actin fibres above the nucleus, suggesting a link between actin-mediated cell stiffness and cell nucleus deformation. In contrast, in MG-63 and OHS-4 cells dense microtubule and vimentin networks seem to facilitate some nuclear deformation even in the absence of a prominent actin cytoskeleton. Together these results suggest that an interaction of all three cytoskeletal elements is needed for efficient nuclear deformation. In conclusion, the dominant parameters influencing nuclear deformation on micropillar substrates are not their material properties but the substrate geometry together with cell phenotype and cytoskeleton organization. PMID- 23357374 TI - The promotion of osseointegration of titanium surfaces by coating with silk protein sericin. AB - A promising strategy to influence the osseointegration process around orthopaedic titanium implants is the immobilization of bioactive molecules. This recruits appropriate interaction between the surface and the tissue by directing cells adhesion, proliferation, differentiation and active matrix remodelling. In this study, we aimed to investigate the functionalization of metallic implant titanium with silk protein sericin. Titanium surface was immobilized with non-mulberry Antheraea mylitta sericin using glutaraldehyde as crosslinker. To analyse combinatorial effects the sericin immobilized titanium was further conjugated with integrin binding peptide sequence Arg-Gly-Asp (RGD) using ethyl (dimethylaminopropyl) carbodiimide and N-hydroxysulfosuccinimide as coupling agents. The surface of sericin immobilized titanium was characterized biophysically. Osteoblast-like cells were cultured on sericin and sericin/RGD functionalized titanium and found to be more viable than those on pristine titanium. The enhanced adhesion, proliferation, and differentiation of osteoblast cells were observed. RT-PCR analysis showed that mRNA expressions of bone sialoprotein, osteocalcin and alkaline phosphatase were upregulated in osteoblast cells cultured on sericin and sericin/RGD immobilized titanium substrates. Additionally, no significant amount of pro-inflammatory cytokines TNF-alpha, IL 1beta and nitric oxide production were recorded when macrophages cells and osteoblast-macrophages co culture cells were grown on sericin immobilized titanium. The findings demonstrate that the sericin immobilized titanium surfaces are potentially useful bioactive coated materials for titanium-based medical implants. PMID- 23357376 TI - Health system goals: a discrete choice experiment to obtain societal valuations. AB - OBJECTIVE: To improve previous approaches to health system goals valuation. METHODS: We reviewed literature on health system performance and previous comparative performance assessments, and combined this with literature on process utility to create a theoretical foundation for health system goals. We used a discrete choice experiment to elicit goal weights. To obtain social justice weights respondents were placed behind a 'veil of ignorance'. To ensure that respondents understood their task, we instructed them in a classroom setting. RESULTS: We identified five health system goals. All five goals significantly affected choice behavior. An equitable distribution of health obtained the highest weight (0.34), followed by average level of health (0.29) and financial fairness (0.24). Both process outcomes (utility derived from the process and its distribution) received much lower weights (0.07 and 0.06, respectively). CONCLUSIONS: Our framework adds to that of the World Health Organization. We demonstrated the feasibility of measuring societal valuation of health system goals with a multi-attribute technique based on trade-offs. Our weights placed much greater emphasis on health and health inequality than on process outcomes. Our study improves the methodology of international health system performance comparison and thereby enhances global evidence-based health policy information. PMID- 23357377 TI - Acute painless vision loss in a young person. PMID- 23357375 TI - Age-related differences in agenda-driven monitoring of format and task information. AB - Age-related source memory deficits may arise, in part, from changes in the agenda driven processes that control what features of events are relevant during remembering. Using fMRI, we compared young and older adults on tests assessing source memory for format (picture, word) or encoding task (self-, other referential), as well as on old-new recognition. Behaviorally, relative to old new recognition, older adults showed disproportionate and equivalent deficits on both source tests compared to young adults. At encoding, both age groups showed expected activation associated with format in posterior visual processing areas, and with task in medial prefrontal cortex. At test, the groups showed similar selective, agenda-related activity in these representational areas. There were, however, marked age differences in the activity of control regions in lateral and medial prefrontal cortex and lateral parietal cortex. Results of correlation analyses were consistent with the idea that young adults had greater trial-by trial agenda-driven modulation of activity (i.e., greater selectivity) than did older adults in representational regions. Thus, under selective remembering conditions where older adults showed clear differential regional activity in representational areas depending on type of test, they also showed evidence of disrupted frontal and parietal function and reduced item-by-item modulation of test-appropriate features. This pattern of results is consistent with an age related deficit in the engagement of selective reflective attention. PMID- 23357379 TI - Acutely irreducible ankle fracture dislocation: a report of a Bosworth fracture and its management. AB - BACKGROUND: Acutely irreducible ankle fractures are uncommon. Irreducibility caused by interposition of soft tissue and entrapment of fracture fragments has been well described. An irreducible ankle fracture due to a locked fibular shaft fragment behind the tibia, a Bosworth fracture, is a rare injury. CASE REPORT: We describe a Bosworth fracture in a 19-year-old man subsequent to a fall. CONCLUSION: The Bosworth fracture dislocation is a rare injury to the ankle, the correct diagnosis of which depends on awareness of the variant and careful evaluation of the initial clinical and radiographic features. As with our patient, a good outcome is achievable despite the severe nature of these injuries. PMID- 23357378 TI - Prehospital electrocardiographic manifestations of acute myocardial ischemia independently predict adverse hospital outcomes. AB - BACKGROUND: Prehospital electrocardiography (PH ECG) is becoming the standard of care for patients activating Emergency Medical Services for symptoms of acute coronary syndrome (ACS). Little is known about the prognostic value of ischemia found on PH ECG. OBJECTIVE: The purpose of this study was to determine whether manifestations of acute myocardial ischemia on PH ECG are predictive of adverse hospital outcomes. METHODS: This study was a retrospective analysis of all PH ECGs recorded in 630 patients who called 911 for symptoms of ACS and were enrolled in a prospective clinical trial. ST-segment monitoring software was added to the PH ECG device with automatic storage and transmission of ECGs to the destination Emergency Department. Patient medical records were reviewed for adverse hospital outcomes. RESULTS: In 630 patients who called 911 for ACS symptoms, 270 (42.9%) had PH ECG evidence of ischemia. Overall, 37% of patients with PH ECG ischemia had adverse hospital outcomes compared with 27% of patients without PH ECG ischemia (p < 0.05). Those with PH ECG ischemia were 1.55 times more likely to have adverse hospital outcomes than those without PH ECG ischemia (95% CI 1.09-2.21; p < 0.05), after controlling for other predictors of adverse hospital outcomes (i.e., age, sex, and medical history). CONCLUSIONS: Evidence of ischemia on PH ECG is an independent predictor of adverse hospital outcomes. ST segment monitoring in the prehospital setting can identify high-risk patients with symptoms of ACS and provide important prognostic information at presentation to the Emergency Department. PMID- 23357380 TI - Food poisoning associated with Kudoa septempunctata. AB - BACKGROUND: Kudoa septempunctata is a recently identified cause of food poisoning. We report three cases of food poisoning due to ingestion of this parasite. CASE REPORTS: Among the 358 people exposed during the same catered meal, 94 (including our 3 patients) developed vomiting and diarrhea within 1-9 h after ingestion of raw muscle from contaminated aquacultured olive flounders (Paralichthys olivaceus). These symptoms occurred frequently but were temporary; only 1 patient was hospitalized for dehydration and was discharged 2 days later. CONCLUSION: In Japan, cases of food poisoning due to eating olive flounder have increased during recent years. This increase should prompt heightened awareness among clinicians diagnosing food poisoning. PMID- 23357381 TI - Pediatric lateral patellar dislocation: is there a role for plain radiography in the emergency department? AB - BACKGROUND: Osteochondral fractures are reported to complicate patellar dislocations in 5-95% of patients. For this reason, post-reduction radiographs are recommended for the routine evaluation of patellar dislocations in all patients. To date, no data have been reported regarding the impact plain radiography has on the Emergency Department (ED) management of pediatric patients with lateral patellar dislocations. STUDY OBJECTIVES: To estimate the incidence of fractures detected by post-reduction plain radiographs in pediatric patients presenting with unreduced lateral patellar dislocations and to examine differences in ED management between patients with and without radiographically apparent fractures. METHODS: Retrospective review of records for pediatric patients who presented to an ED, received a diagnosis of lateral patellar dislocation, and underwent a reduction procedure. RESULTS: Of 80 patients who met criteria for inclusion in the study, 8 patients (10%; 95% CI 3-17) had a fracture identified. All patients, regardless of their radiographic findings, had their dislocation reduced uneventfully and were discharged with knee immobilization and a plan for outpatient follow-up. There were no statistically significant differences between those patients who had a detected fracture as compared to those without in terms of intravenous line placement (p = 1.000), parenteral analgesic administration (p = 0.965), procedural sedation administration (p = 0.922), ED length of stay (p = 0.706), or provision of a prescription for an oral analgesic upon discharge (p = 0.103). CONCLUSION: Osteochondral fractures were detected by plain radiography in 10% of patients presenting with lateral patellar dislocation and did not alter ED management. Pediatric patients with lateral patellar dislocations may be candidates for discharge from the ED after reduction without plain radiography. The modality by which to best determine the presence of a complicating osteochondral fracture (i.e., plain radiography, computed tomography, magnetic resonance imaging, or arthroscopy) may be left to the discretion of the orthopedic surgeon accepting the child in follow-up. Further study is needed to determine if forgoing plain radiographs in the ED decreases length of stay and reduces patient costs. PMID- 23357382 TI - CD11a regulates effector CD8 T cell differentiation and central memory development in response to infection with Listeria monocytogenes. AB - beta2 (CD18) integrins with alpha-chains CD11a, -b, -c, and -d are important adhesion molecules necessary for leukocyte migration and cellular interactions. CD18 deficiency leads to recurrent bacterial infections and poor wound healing due to reduced migration of leukocytes to inflammatory sites. CD8 T cells also upregulate CD11a, CD11b, and CD11c upon activation. However, the role these molecules play for CD8 T cells in vivo is not known. To determine the function of individual beta2 integrins, we examined CD8 T cell responses to Listeria monocytogenes infection in CD11a-, CD11b-, and CD11c-deficient mice. The absence of CD11b or CD11c had no effect on the generation of antigen-specific CD8 T cells. In contrast, the magnitude of the primary CD8 T cell response in CD11a deficient mice was significantly reduced. Moreover, the response in CD11a(-/-) mice exhibited reduced differentiation of short-lived effector cells (KLRG1(hi) CD127(lo)), although cytokine and granzyme B production levels were unaffected. Notably, CD11a deficiency resulted in greatly enhanced generation of CD62L(+) central memory cells. Surprisingly, CD8 T cells lacking CD11a mounted a robust secondary response to infection. Taken together, these findings demonstrated that CD11a expression contributes to expansion and differentiation of primary CD8 T cells but may be dispensable for secondary responses to infection. PMID- 23357383 TI - Role of enteroaggregative Escherichia coli virulence factors in uropathogenesis. AB - A multiresistant clonal Escherichia coli O78:H10 strain qualifying molecularly as enteroaggregative Escherichia coli (EAEC) was recently shown to be the cause of a community-acquired outbreak of urinary tract infection (UTI) in greater Copenhagen, Denmark, in 1991. This marks the first time EAEC has been associated with an extraintestinal disease outbreak. Importantly, the outbreak isolates were recovered from the urine of patients with symptomatic UTI, strongly implying urovirulence. Here, we sought to determine the uropathogenic properties of the Copenhagen outbreak strain and whether these properties are conferred by the EAEC specific virulence factors. We demonstrated that through expression of aggregative adherence fimbriae, the principal adhesins of EAEC, the outbreak strain exhibited pronouncedly increased adherence to human bladder epithelial cells compared to prototype uropathogenic strains. Moreover, the strain was able to produce distinct biofilms on abiotic surfaces, including urethral catheters. These findings suggest that EAEC-specific virulence factors increase uropathogenicity and may have played a significant role in the ability of the strain to cause a community-acquired outbreak of UTI. Thus, inclusion of EAEC specific virulence factors is warranted in future detection and characterization of uropathogenic E. coli. PMID- 23357384 TI - Pathology and pathophysiology of inhalational anthrax in a guinea pig model. AB - Nonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's "Animal Rule." However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of the Bacillus anthracis Ames strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50 of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 * 10(4) spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans. PMID- 23357386 TI - The surface layer of Tannerella forsythia contributes to serum resistance and oral bacterial coaggregation. AB - Tannerella forsythia is an anaerobic, Gram-negative bacterium involved in the so called "red complex," which is associated with severe and chronic periodontitis. The surface layer (S-layer) of T. forsythia is composed of cell surface glycoproteins, such as TfsA and TfsB, and is known to play a role in adhesion/invasion and suppression of proinflammatory cytokine expression. Here we investigated the association of this S-layer with serum resistance and coaggregation with other oral bacteria. The growth of the S-layer-deficient mutant in a bacterial medium containing more than 20% non-heat-inactivated calf serum (CS) or more than 40% non-heat-inactivated human serum was significantly suppressed relative to that of the wild type (WT). Next, we used confocal microscopy to perform quantitative analysis on the effect of serum. The survival ratio of the mutant exposed to 100% non-heat-inactivated CS (76% survival) was significantly lower than that of the WT (97% survival). Furthermore, significant C3b deposition was observed in the mutant but not in the WT. In a coaggregation assay, the mutant showed reduced coaggregation with Streptococcus sanguinis, Streptococcus salivarius, and Porphyromonas gingivalis but strong coaggregation with Fusobacterium nucleatum. These results indicated that the S-layer of T. forsythia plays multiple roles in virulence and may be associated with periodontitis. PMID- 23357385 TI - The type VI secretion system encoded in Salmonella pathogenicity island 19 is required for Salmonella enterica serotype Gallinarum survival within infected macrophages. AB - Salmonella enterica serotype Gallinarum is the causative agent of fowl typhoid, a disease characterized by high morbidity and mortality that causes major economic losses in poultry production. We have reported that S. Gallinarum harbors a type VI secretion system (T6SS) encoded in Salmonella pathogenicity island 19 (SPI-19) that is required for efficient colonization of chicks. In the present study, we aimed to characterize the SPI-19 T6SS functionality and to investigate the mechanisms behind the phenotypes previously observed in vivo. Expression analyses revealed that SPI-19 T6SS core components are expressed and produced under in vitro bacterial growth conditions. However, secretion of the structural/secreted components Hcp1, Hcp2, and VgrG to the culture medium could not be determined, suggesting that additional signals are required for T6SS-dependent secretion of these proteins. In vitro bacterial competition assays failed to demonstrate a role for SPI-19 T6SS in interbacterial killing. In contrast, cell culture experiments with murine and avian macrophages (RAW264.7 and HD11, respectively) revealed production of a green fluorescent protein-tagged version of VgrG soon after Salmonella uptake. Furthermore, infection of RAW264.7 and HD11 macrophages with deletion mutants of SPI-19 or strains with genes encoding specific T6SS core components (clpV and vgrG) revealed that SPI-19 T6SS contributes to S. Gallinarum survival within macrophages at 20 h postuptake. SPI-19 T6SS function was not linked to Salmonella-induced cytotoxicity or cell death of infected macrophages, as has been described for other T6SS. Our data indicate that SPI-19 T6SS corresponds to a novel tool used by Salmonella to survive within host cells. PMID- 23357389 TI - Diphtheria - 'The strangling angel' of children. AB - Diphtheria, an acute infectious condition caused by Corynebacterium diphtheriae, was once a major killer of children. Although the mortality rates dropped dramatically in the mid-twentieth century, due to a combination of improved standards of living and immunization programs, outbreaks are still occurring. Two children, aged four and five years respectively, are reported to demonstrate characteristic features of lethal cases. Death in case 1 was due to an extensive upper airway pseudomembrane causing acute respiratory failure. The diagnosis of diphtheria was only made at postmortem. Death in case 2 was due to acute cardiac failure with heart block complicating diphtheria. Other mechanisms in fatal cases involve disseminated intravascular coagulation, renal and endocrine failure. Declining levels of immunity among adults has resulted in a change in the epidemiological pattern of the disease with an older age of victims in recent outbreaks. As a result of population shifts and failure to immunize children it is likely that forensic pathologists may see more cases of diphtheria in the future. Due to the rarity of cases in Western communities and atypical presentations, the diagnosis may only be established at autopsy. PMID- 23357388 TI - RfaL is required for Yersinia pestis type III secretion and virulence. AB - Yersinia pestis, the causative agent of plague, uses a type III secretion system (T3SS) to inject cytotoxic Yop proteins directly into the cytosol of mammalian host cells. The T3SS can also be activated in vitro at 37 degrees C in the absence of calcium. The chromosomal gene rfaL (waaL) was recently identified as a virulence factor required for proper function of the T3SS. RfaL functions as a ligase that adds the terminal N-acetylglucosamine to the lipooligosaccharide core of Y. pestis. We previously showed that deletion of rfaL prevents secretion of Yops in vitro. Here we show that the divalent cations calcium, strontium, and magnesium can partially or fully rescue Yop secretion in vitro, indicating that the secretion phenotype of the rfaL mutant may be due to structural changes in the outer membrane and the corresponding feedback inhibition on the T3SS. In support of this, we found that the defect can be overcome by deleting the regulatory gene lcrQ. Consistent with a defective T3SS, the rfaL mutant is less virulent than the wild type. We show here that the virulence defect of the mutant correlates with a decrease in both T3SS gene expression and ability to inject innate immune cells, combined with an increased sensitivity to cationic antimicrobial peptides. PMID- 23357390 TI - Medico-legal implications of traumatic cataract. AB - Traumatic cataract is due to lens damage when mechanical, irradiative, electrical or chemical agents injury the globe. The appearance of a traumatic cataract is typically short and unilateral with rare spontaneous resolution and often involves other ocular anatomical areas. Medico-legal evaluation of the appearance and the consequences of a traumatic cataract requires a correct methodological approach with the support of qualified ophthalmological competences. PMID- 23357387 TI - Pathogenicity of Yersinia pestis synthesis of 1-dephosphorylated lipid A. AB - Synthesis of Escherichia coli LpxL, which transfers a secondary laurate chain to the 2' position of lipid A, in Yersinia pestis produced bisphosphoryl hexa acylated lipid A at 37 degrees C, leading to significant attenuation of virulence. Our previous observations also indicated that strain chi10015(pCD1Ap) (DeltalpxP32::P(lpxL) lpxL) stimulated a strong inflammatory reaction but sickened mice before recovery and retained virulence via intranasal (i.n.) infection. The development of live, attenuated Y. pestis vaccines may be facilitated by detoxification of its lipopolysaccharide (LPS). Heterologous expression of the lipid A 1-phosphatase, LpxE, from Francisella tularensis in Y. pestis yields predominantly 1-dephosphorylated lipid A, as confirmed by mass spectrometry. Results indicated that expression of LpxE on top of LpxL provided no significant reduction in virulence of Y. pestis in mice when it was administered i.n. but actually reduced the 50% lethal dose (LD(50)) by 3 orders of magnitude when the strain was administered subcutaneously (s.c.). Additionally, LpxE synthesis in wild-type Y. pestis KIM6+(pCD1Ap) led to slight attenuation by s.c. inoculation but no virulence change by i.n. inoculation in mice. In contrast to Salmonella enterica, expression of LpxE does not attenuate the virulence of Y. pestis. PMID- 23357391 TI - Mechanisms of chronic pain from whiplash injury. AB - This article is to provide insights into the mechanisms underlying chronic pain from whiplash injury. Studies show that injury produces plasticity changes of different neuronal structures that are responsible for amplification of nociception and exaggerated pain responses. There is consistent evidence for hypersensitivity of the central nervous system to sensory stimulation in chronic pain after whiplash injury. Tissue damage, detected or not by the available diagnostic methods, is probably the main determinant of central hypersensitivity. Different mechanisms underlie and co-exist in the chronic whiplash condition. Spinal cord hyperexcitability in patients with chronic pain after whiplash injury can cause exaggerated pain following low intensity nociceptive or innocuous peripheral stimulation. Spinal hypersensitivity may explain pain in the absence of detectable tissue damage. Whiplash is a heterogeneous condition with some individuals showing features suggestive of neuropathic pain. A predominantly neuropathic pain component is related to a higher pain/disability level. PMID- 23357392 TI - Prevalence and medical risks of body packing in the Amsterdam area. AB - AIM: Body packing is a way to deliver packets of drugs across international borders by ingestion. The aim of the study was to provide an estimate of the medical risks of body packing, describe predictors for hospital referral in detained body packers and provide an estimate for the prevalence of body packing in the Amsterdam area. METHODS: From May 2007 to December 2008, we studied medical records of body packers immediately detained after arrival at Amsterdam Schiphol airport, hospital records of both detained body packers and self referrers at two emergency departments of hospitals in Amsterdam and records kept by forensic physicians in charge of post-mortem examinations of all unnatural deaths in the area (years 2005-2009). RESULTS: In airport detainees, the hospital referral rate was 4.2% (30 out of 707 detained body packers), the surgery rate was 1.3%. Significant predictors of hospital referral were delayed production of drug packets after arrest, cigarette smoking and country of departure. The surgery rate in self-referrers was comparable to the rate observed in those referred from the detention centre to hospital (30% vs. 31%). In addition, from 2005 to 2009, 20 proven cases of lethal body packing were identified. Based on our data, it is estimated that minimally 38% of all incoming body packers were missed by airport controls. CONCLUSION: The risk for lethal complications due to body packing is low on a population basis and comparable to other studies. This also applies for the hospital referral and surgery rates found in this study. Cigarette smoking has not yet been described in the literature as a potential predictor for hospital referral in detained body packers and therefore deserves attention in future research. A substantial fraction of body packers manages to remain undiscovered. PMID- 23357393 TI - Are frontal sinuses useful indicators of sex? AB - Accurate sex prediction of skeletonised human remains excludes one-half of the population, enabling a more focussed search of missing persons' files. The skull is useful in sex assessment of skeletonised remains; however, its fragmentation precludes the use of all conventional craniofacial markers. The frontal bone may be recovered intact in fragmented remains and the sinuses therein may be useful in sex differentiation. A total of 100 paranasal sinus view radiographs of 50 males and females each were evaluated for potential differences in frontal sinus configuration following the methods of Yoshino et al. (Forensic Sci Int 1987; 34:289-99.) and Tang et al. (Forensic Sci Int 2009; 183:104.e1-3.). Data were assessed through univariate and multivariate statistics. The univariate Mann Whitney U-test revealed statistically insignificant sexual dimorphism (p > 0.05) for the frontal sinuses. Moreover, multivariate logistic regression equations allowed correct sex identification in 60% of cases only. Possible reasons for the low sexual dimorphism may be frontal sinus' high inter-individual variability; also, existing techniques that employ frontal sinus classification systems may lead to a loss of information when features that require visual observation are grouped and assigned class numbers. The results herein suggest that frontal sinuses may have limited application as the sole predictor of sex. PMID- 23357394 TI - Forensic and clinical carbon monoxide (CO) poisonings in Turkey: A detailed analysis. AB - Carbon monoxide (CO) is produced by incomplete combustion of organic compounds. Its intoxication usually results from inhalation of fumes from improper heating stoves, motor vehicles, or smoke from fires. It can reversibly bind various heme containing proteins such as hemoglobin, myoglobin, cytochrome p450 and cytochrome oxidases. Among them, it has a high affinity for hemoglobin (230-270 times more avidly than oxygen) with which it forms carboxy-hemoglobin (HbCO) leading to decrease in oxygen-carrying capacity followed by end-organ hypoxia. A tissue hypoxia may then result in transient or permanent damage of important organs like central nervous system and even death. CO poisonings from different reasons are an important cause of morbidity and mortality in Turkey. The purpose of this study on CO poisonings in Turkey is to sum up and analyze the best available researches in both forensic and clinical toxicology fields. This was achieved by synthesizing the results of Turkish and English papers on forensic and clinical CO poisoning cases conducted in universities, institutes, hospitals and other official or private organizations in Turkey. Total of 47,523 medico-legal autopsy data collected from 9 different forensic medicine branches and emergency rooms in different year intervals were reviewed and 980 CO poisoning cases were determined. To calculate the frequency of CO poisoning within all the autopsies carried out and fatal poisoning cases, the number of cases was divided by the total number of medico-legal autopsies and total fatal poisoning cases. The mean age of cases, the source of CO gas, the most common seasons and months, gender, and blood HbCO levels were also taken into consideration if the data is available. Under the light of the findings, we may suggest that determination of affecting factors in CO poisoning is going to be one of the key subjects for planning preventive interventions. PMID- 23357395 TI - Frequency of signs of excited delirium syndrome in subjects undergoing police use of force: Descriptive evaluation of a prospective, consecutive cohort. AB - There has, to date, been no prospective description of the frequency with which police officers encounter individuals who display signs of excited delirium syndrome (ExDS). The ability to document the relationship between signs of excited delirium and subject outcomes and then determine the underlying pathophysiology that results in morbidity and mortality is necessary in order to determine the case definition for ExDS in live individuals. We prospectively evaluated the frequency of signs of ExDS in a cohort of consecutive subjects undergoing use of force by law enforcement officers (LEOs) and determined the frequency with which those features were encountered alone and in combination. Data were collected prospectively for all subjects undergoing use of force (UOF) by LEOs in a single police agency from August 2006 until August 2009. Ten previously published signs of ExDS were prospectively recorded by officers: pain tolerance, constant/near constant physical activity, not responding to police presence, superhuman strength, rapid breathing, not tiring despite heavy physical exertion, naked/inappropriately clothed, sweating profusely, hot to the touch, and attraction to/destruction of glass/reflective surfaces. UOF occurred in 1269 of 1.56 million police-public interactions (0.08%, 95% CI 0.08, 0.086). Of subjects undergoing police use of force, 1101/1269 or 86.8% (95% CI 84.8%, 88.6%) were assessed as having effects of emotional disturbance, drugs, alcohol or a combination of these comorbidities at the scene at the time of the UOF and 837/1269 or 66% (95% CI 63.3, 68.6) were violent at the time of the UOF. Excluding violence, 655/1269 (51.6% 95% CI 48.8, 54.4) had no signs of ExDS at the time of UOF and another 405/1269 (31.9% 95% CI 29.4, 34.6%)) had only one or two signs of ExDS at the time of UOF. The remaining 209/1269 (16.5%, 95% CI 14.5, 18.6) had 3 or more concomitant signs of ExDS at the time of UOF. One person died in our cohort who was experiencing 10 concomitant features of ExDS at the time of the UOF event. With only one death in our 3 year prospective cohort, we cannot comment on causality or correlation between number of Excited Delirium signs and mortality. Further study must be undertaken to determine whether correlation exists between higher numbers of ExDS signs and physiologic measures of acute underlying pathology in live subjects. CONCLUSIONS: Law enforcement officers and other prehospital care providers can recognize and describe symptoms of ExDS in the field at the time of interaction. Even though police use of force is rare over 15%, or approximately 1 in 6, of individuals undergoing police UoF have 3 or more concomitant signs of Excited Delirium at the time of the UoF event. The single death in our cohort occurred in an individual with 10 concomitant signs of ExDS. Future work including further clinical outcome data will determine whether higher numbers of concomitant signs of ExDS predicts subject morbidity or mortality and whether any specific symptoms or symptom cluster is associated with death. If so, a case definition will be able to be fully described. PMID- 23357397 TI - Evaluation of the allele-sharing approach, known as the IBS method, in kinship analysis. AB - To infer relatedness from genetic data based on short tandem repeats, the exact method, in which shared allele frequencies are applied to relevant equations, has been conventionally used. An alternative approach is the IBS method that is based on the number of shared alleles between individuals. In the present study, the performance of the IBS method in pairwise kinship analysis was compared with the exact method using simulated data of 10,000 genotype pairs for 15 loci in the ABI Identifiler system. The likelihood ratio in allele-sharing of zero, one and two was calculated from joint probabilities based on allele frequencies of the Japanese population. Whereas the IBS method generally produced lower values of combined indices, smaller deviations of the distributions were evident. The threshold for identification of full siblings relative to non-relatives was comparable with that of the exact method, indicating that both inference powers were almost identical. The likelihood ratio in the IBS method depends on the heterozygosity at a locus, and heterozygosities of the 15 loci were consistent across various population groups, particularly in East Asians. The convenience of fixed LR values in the IBS method is beneficial for cases with uncertain allele frequencies and rare alleles. PMID- 23357396 TI - The role of the Armanni-Ebstein lesion, hepatic steatosis, biochemical analysis and second generation anti-psychotic drugs in fatal diabetic ketoacidosis. AB - Diabetic ketoacidosis (DKA) is an acute severe complication of diabetes and characterized by a complex disordered metabolic state due to an absolute or relative insulin deficiency, leads to hyperglycaemia, ketoacidosis and ketonuria. DKA can cause sudden unexpected death and often yields minimal and/or subtle autopsy findings or a negative autopsy and the diagnosis mainly depends upon biochemical analysis of body fluids. This communication highlights the role of Armanni-Ebstein lesion, hepatic steatosis, biochemical analysis and second generation anti-psychotic drugs in 25 adult cases of fatal diabetic ketoacidosis. The study recognises and reconfirms that fatal DKA occurs in both type I and II diabetes. The macroscopic autopsy features observed in this study are non specific and do not guide the pathologist towards the diagnosis of fatal DKA. Once other possibilities have been excluded, the Armanni-Ebstein lesion alone or the combination of hepatic steatosis and Armanni-Ebstein lesion in an otherwise negative autopsy of a sudden unexpected death should raise the suspicion of DKA as the cause of death and indicate biochemical analysis of body fluids. Our findings also remind forensic pathologists to search for fatal DKA in sudden unexpected death with a negative autopsy, where there is a history of second generation anti-psychotic treatment. PMID- 23357398 TI - Lethal fish hook attachment - An unusual occurrence. AB - A 39-year-old fisherman is reported who was dragged into the water from a boat after he became entangled in fishing line. His death was attributed to salt water drowning. At autopsy the cause of death was confirmed and the mechanism of the lethal event elucidated. Specifically, a large fish hook attached to line was embedded in his right wrist. The hook had passed beneath flexor tendons and had firmly attached him to fishing line that was being dropped from the vessel. There were no other significant injuries or underlying diseases present. This case demonstrates another rare situation in the commercial fishing industry that may result in a victim being dragged from a boat and drowned. PMID- 23357399 TI - Petechial hemorrhages of the tympanic membrane in attempted suicide by hanging: A case report. AB - It is important to determine whether a person has been strangulated and the diagnosis is not always straightforward since ligature marks are not always present. In forensic medicine the physical examination recommended is careful inspection of the head and neck region, oral cavity, examination of the eyes including the conjunctiva on both the upper and lower eyelids and photo documentation. Petechial hemorrhages of the conjunctiva are considered marker of life threatening hanging or strangulation. Hemorrhage from ears, perforated tympanic membrane and haematotympanum are scarcely described in case reports of strangulated patients. To our knowledge we are the first to report petechial hemorrhages of the tympanic membrane in a patient following attempted suicide by hanging. We believe that the petechial hemorrhages develop from the capillaries located in lamina propria of the epidermal layer above the fibrous layer. This assumption is made on the basis of our assessment of a normal tympanic membrane with light microscopy. Petechial hemorrhages of the tympanic membrane might in fact be the only sign of life threatening pressure applied to the neck. This is a very important finding and prospective studies should be conducted for further clarification on the matter. PMID- 23357400 TI - A case of "precocious" mummification. AB - Mummification is a peculiar transformative process consisting of the total drying of the body soft tissues. It is produced, in particular conditions, between 6 and 12 months after death. "Precocious" mummification has been reported in countries where recorded weather conditions are more extreme than in Italy, in a confined environment, or with particular micro-climate conditions. Here we present a case of mummification produced in a central region of Italy in four weeks. We also analyze conditions allowing for the rapidity of this phenomenon. PMID- 23357401 TI - Nitric oxide-mediated activity in anti-cancer photodynamic therapy. AB - Cell recurrence in cancer photodynamic therapy (PDT) is an important issue that is poorly understood. It is becoming clear that nitric oxide (NO) is a modulator of PDT. By acting on the NF-kappaB/Snail/RKIP survival/anti-apoptotic loop, NO can either stimulate or inhibit apoptosis. We found that pheophorbide a/PDT (Pba/PDT) induces the release of NO in B78-H1 murine amelanotic melanoma cells in a concentration-dependent manner. Low-dose PDT induces low NO levels by stimulating the anti-apoptotic nature of the above loop, whereas high-dose PDT stimulates high NO levels inhibiting the loop and activating apoptosis. When B78 H1 cells are treated with low-dose Pba/PDT and DETA/NO, an NO-donor, intracellular NO increases and cell growth is inhibited according to scratch wound and clonogenic assays. Western blot analyses showed that the combined treatment reduces the expression of the anti-apoptotic NF-kappaB and Snail gene products and increases the expression of the pro-apoptotic RKIP gene product. The combined effect of Pba and DETA/NO was also tested in C57BL/6 mice bearing a syngeneic B78-H1 melanoma. We used pegylated Pba (mPEG-Pba) due to its better pharmacokinetics compared to free Pba. mPEG-Pba (30 mg/Kg) and DETA/NO (0.4 mg/Kg) were i.p. injected either as a single molecule or in combination. After photoactivation at 660 nM (fluence of 193 J/cm(2)), the combined treatment delays tumor growth more efficiently than each individual treatment (p<0.05). Taken together, our results showed that the efficacy of PDT is strengthened when the photosensitizer is used in combination with an NO donor. PMID- 23357402 TI - Towards the validation of a lung tumorigenesis model with mainstream cigarette smoke inhalation using the A/J mouse. AB - A generally accepted and validated laboratory model for smoking-associated pulmonary tumorigenesis would be useful for both basic and applied research applications, such as the development of early diagnostic endpoints or the evaluation of modified risk tobacco products, respectively. The A/J mouse is susceptible for developing both spontaneous and induced lung adenomas and adenocarcinomas, and increased lung tumor multiplicities were also observed in previous cigarette smoke inhalation studies. The present study was designed to collect data useful towards the validation of an 18-month mainstream smoke (MS) inhalation model. Male and female A/J mice were exposed whole-body at three MS concentration levels for 6h/day, and the results were compared to a previous study in the same laboratory and with a similar design. A linear MS concentration dependent increase in lung tumorigenesis was observed with similar slopes for both sexes and both studies and a maximal 5-fold increase in multiplicity beyond sham control. The minimal detectable difference in lung tumor multiplicity for the current study was 37%. In the larynx, papillomas were detectable in all MS exposed groups in a non-concentration dependent manner. No other extra-pulmonary MS-dependent neoplastic lesions were found. Gene expression signatures of lung tumor tissues allowed a clear differentiation of sham- and high dose MS-exposed mice. In combination with data from previous smoke inhalation studies with A/J mice, the current data suggest that this model for MS inhalation-induced pulmonary tumorigenesis is reliable and relevant, two crucial requirements towards validation of such a model. PMID- 23357404 TI - Fuzzy and hard clustering analysis for thyroid disease. AB - Thyroid hormones produced by the thyroid gland help regulation of the body's metabolism. A variety of methods have been proposed in the literature for thyroid disease classification. As far as we know, clustering techniques have not been used in thyroid diseases data set so far. This paper proposes a comparison between hard and fuzzy clustering algorithms for thyroid diseases data set in order to find the optimal number of clusters. Different scalar validity measures are used in comparing the performances of the proposed clustering systems. To demonstrate the performance of each algorithm, the feature values that represent thyroid disease are used as input for the system. Several runs are carried out and recorded with a different number of clusters being specified for each run (between 2 and 11), so as to establish the optimum number of clusters. To find the optimal number of clusters, the so-called elbow criterion is applied. The experimental results revealed that for all algorithms, the elbow was located at c=3. The clustering results for all algorithms are then visualized by the Sammon mapping method to find a low-dimensional (normally 2D or 3D) representation of a set of points distributed in a high dimensional pattern space. At the end of this study, some recommendations are formulated to improve determining the actual number of clusters present in the data set. PMID- 23357405 TI - RADStation3G: a platform for cardiovascular image analysis integrating PACS, 3D+t visualization and grid computing. AB - RADStation3G is a software platform for cardiovascular image analysis and surgery planning. It provides image visualization and management in 2D, 3D and 3D+t; data storage (images or operational results) in a PACS (using DICOM); and exploitation of patients' data such as images and pathologies. Further, it provides support for computationally expensive processes with grid technology. In this article we first introduce the platform and present a comparison with existing systems, according to the platform's modules (for cardiology, angiology, PACS archived enriched searching and grid computing), and then RADStation3G is described in detail. PMID- 23357407 TI - Oncochannels. AB - A hallmark of tumour cells is an aberrant expression of ion channels. Research of the recent years clearly indicates that the change in the "channelome" that accompanies tumourigenesis is not just an epiphenomenon of neoplastic transformation. This is deduced from the fact that experimental interference with the channelome often impairs survival, proliferation, malignant progression, invasive behaviour, or therapy resistance of the tumour cells. Rather, the channelome of the tumour cell does induce onogenic processes and keeps them running. The involved ion channels are often overexpressed in several tumour entities suggesting their high oncogenic potency. The present review article aims to summarize our current knowledge on these "oncochannels", how they crosstalk within the signalling of a tumour cell and how they exert their oncogenic function. PMID- 23357406 TI - Mechanical regulation of native and the recombinant calcium channel. AB - L-type calcium channels are modulated by a host of mechanisms that include voltage, calcium ions (Ca(2+) dependent inactivation and facilitation), cytosolic proteins (CAM, CAMKII, PKA, PKC, etc.), and oxygen radicals. Here we describe yet another Ca(2+) channel regulatory mechanism that is induced by pressure-flow (PF) forces of ~25dyn/cm(2) producing 35-60% inhibition of channel current. Only brief periods (300ms) of such PF pulses were required to suppress reversibly the current. Recombinant Ca(2+) channels (alpha1c77/beta2a/alpha2delta and alpha1c77/beta1/alpha2delta), expressed in HEK293 cells, were similarly suppressed by PF pulses. To examine whether Ca(2+) released by PF pulses triggered from different sub-cellular compartments (SR, ER, mitochondria) underlies the inhibitory effect of PF on the channel current, pharmacological agents and ionic substitutions were employed to probe this possibility. No significant difference in effectiveness of PF pulses to suppress ICa or IBa (used to inhibit CICR) was found between control cells and those exposed to U73122 and 2-APB (PLC and IP3R pathway modulators), thapsigargin and BAPTA (SERCA2a modulator), dinitrophenol, FCCP and Ru360 (mitochondrial inhibitors), l-NAME (NOS inhibitor signaling), cAMP and Pertussis toxin (Gi protein modulator). We concluded that the rapid and reversible modulation of the Ca(2+) channel by PF pulses is independent of intracellular release of Ca(2+) and Ca(2+) dependent inactivation of the channel and may represent direct mechanical regulatory effect on the channel protein in addition to previously reported Ca(2+)-release or entry dependent mechanism. PMID- 23357408 TI - The endothelial glycocalyx as a potential modifier of the hemolytic uremic syndrome. AB - Atypical hemolytic uremic syndrome (HUS) is a renal disease due to complement dysregulation. Many of the known causes of atypical HUS originate from genetic mutations of complement regulatory proteins, such as complement factor H (CFH) and thrombomodulin. However, atypical HUS has only a genetic penetrance of 40-50% of the cases and usually appears in adulthood. We introduce a novel factor that may be involved in the onset and development of atypical HUS, i.e. the endothelial surface glycocalyx. The glycocalyx is a highly interactive matrix covering the luminal side of vascular endothelial cells and consists of glycosaminoglycans, proteoglycans and glycoproteins, which has an important role in maintaining homeostasis of the vasculature. The surface-bound glycocalyx glycosaminoglycan constituent heparan sulfate is crucial for CFH binding and function, both in recognition of host tissue and prevention of spontaneous complement activation via the alternative pathway. Most of the clinically relevant genetic mutations in CFH result in incorrect binding to heparan sulfate. In addition, a role between proper function of thrombomodulin and the endothelial glycocalyx has also been observed. We suggest that not only changes in binding properties of the complement regulatory proteins play a role but also changes in the endothelial glycocalyx are involved in increased risk of clinical manifestation of atypical HUS. Finally, vascular glycocalyx heterogeneity in turn could dictate the specific vulnerability of the glomerular vascular bed in atypical HUS and may provide new therapeutic targets to intervene with endothelial cell activation and local complement pathway regulation. PMID- 23357409 TI - Understanding hyponatremia in the emergency department. PMID- 23357410 TI - Arterial erectile dysfunction: different severities of endothelial apoptosis between diabetic patients "responders" and "non responders" to sildenafil. AB - BACKGROUND: The low pharmacological response to phosphodiesterase type 5 inhibitors represents an expression of higher endothelial damage in certain categories of patients with erectile dysfunction and high cardiovascular risk. The present study evaluated this objective in type 2 diabetic patients with erectile dysfunction, classified as "non responders" to Sildenafil. METHODS: Eighteen "responder" and twelve "non responder" type 2 diabetic patients were evaluated, relatively to different levels of endothelial damage, through the diagnostic use of a new immunophenotype of circulating endothelial progenitor cells (CD45neg/CD34pos/CD144pos) and endothelial microparticles (CD45neg/CD144pos/Annexin Vpos), recently developed and published by our group. RESULTS: "Non responder" patients showed a significant higher severity [8.0+/-3.0 (International Index of Erectile Function-abbreviated version with 5 questions) vs 14.0+/-3.0] and duration (10.0+/-2.0 vs 7.0+/-2.0 years) of erectile dysfunction, higher level of penile arterial insufficiency (peak systolic velocity=13.0+/-16.0 vs 28.0+/-26.0cm/s; acceleration time=153+/-148 vs 125+/-128 mm/s) and finally a significant higher level of endothelial apoptosis [0.15+/ 0.13 vs 0.05+/-.0.03% (serum concentrations of endothelial microparticles)] associated with higher serum concentrations of circulating late immunophenotype of endothelial progenitor cells (0.40+/-0.35 vs 0.12+/-.0.10%). CONCLUSIONS: The results of this study corroborate the clinical value of the low clinical response to phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction in the patients with high cardiovascular risk profile, such as diabetics. In addition, the markers used in this study confirm their potential application in clinical practice as useful indicators of endothelial alteration. However, in the future we will have to assess a larger number of patients and for a longer period of observation in order to better understand the causal and temporal relations. PMID- 23357411 TI - Left/right neck rotation judgments are affected by age, gender, handedness and image rotation. AB - Understanding motor imagery of the hands and feet has led to promising new treatments for neurological and chronic pain disorders. We aimed to extend this line of research to the neck with a view to developing the definitive platform study upon which clinical and experimental studies can be based. In a cross sectional experiment with a convenience sample, volunteers were shown 40 photographs of a model with their head turned to the left or right. Images were presented in random order and orientation. Participants judged the direction of neck rotation. They also completed a left/right hand judgment task. 1361 pain free participants volunteered. Mean +/- standard deviation response time (RT) for making left/right judgments of neck rotation was 1.621 +/- 0.501 s. Median accuracy was 92.5%. RT was related to age, gender, and handedness (p < 0.001). That is, RT increased with age, was greater in females than in males and was greater in left-handers than in right-handers. Accuracy reduced with age (p < 0.001), but was unaffected by gender or handedness. Judgments were more accurate when images showed a neck rotated to the right than when they showed a neck rotated to the left (p < 0.001). The magnitude of image rotation affected both response time and accuracy (p < 0.001). In general, the performance parameters established for left/right limb judgments also apply for left/right neck rotation judgments. The current work establishes the definitive normative values against which clinical and experimental groups can be compared and reveals unpredicted effects of the direction neck rotation and the orientation of the image. PMID- 23357412 TI - Glycolytic oscillations in a model of a lactic acid bacterium metabolism. AB - Glycolytic oscillations in yeast have been extensively studied. It is still unclear, if these oscillations are caused by the allosteric enzyme phosphofructokinase or the stoichiometry of glycolysis which contains an autocatalysis with respect to ATP. Bacterial glycolysis shows a different stoichiometry, however, also containing a stoichiometric autocatalysis. For Escherichia coli, the regulation of the enzyme phosphofructokinase is also assumed to be a major reason for oscillations to occur. We investigated glycolytic oscillations in a quantitative kinetic model for Streptococcus pyogenes set-up on the basis of experimental data. We found oscillations within physiologically feasible parameter ranges. We investigated the origin of these oscillations and conclude that, again, both the stoichiometry of the system, as well as its allosterically regulated enzymes can give rise to these oscillations. For the analysis we employed established and new optimization methods for finding oscillatory regimes and present these in the context of this study. PMID- 23357413 TI - Variant of the Thermomyces lanuginosus lipase with improved kinetic stability: a candidate for enzyme replacement therapy. AB - Lipases with high kinetic stability and enzymatic efficiency in the human gastro intestinal tract may help against exocrine pancreatic insufficiency. Here we mimic gastric conditions to study how bile salts and pH affect the stability and activity of Thermomyces lanuginosus lipase (TlL) and its stabler variant StL using spectroscopy, calorimetry and gel electrophoresis. Both enzymes resist trypsin digestion with and without bile salts. Bile salts activate native TlL and StL equally well, bind weakly to denatured TlL and StL at lower pH and precipitate native TlL and StL at pH 4. StL refolds more efficiently than TlL from gastric pH in bile salts, regaining activity when refolding from pH as low as 1.8 and above while TlL cannot go below pH 2.6. StL also unfolds 10-40 fold more slowly in the denaturant guanidinium chloride and the anionic surfactant SDS. We ascribe StL's superior performance to general alterations in its electrostatic potential which makes it more acid-resistant. These superior properties make StL a good candidate for pancreatic enzyme replacement therapy. PMID- 23357414 TI - Fostering informed decisions: a randomized controlled trial assessing the impact of a decision aid among men registered to undergo mass screening for prostate cancer. AB - OBJECTIVE: Screening asymptomatic men for prostate cancer is controversial and informed decision making is recommended. Within two prostate cancer screening programs, we evaluated the impact of a print-based decision aid (DA) on decision making outcomes. METHODS: Men (N=543) were 54.9 (SD=8.1) years old and 61% were African-American. The 2(booklet type: DA vs. usual care (UC))* 2(delivery mode: Home vs. Clinic) randomized controlled trial assessed decisional and screening outcomes at baseline, 2-months, and 13-months. RESULTS: Intention-to-treat linear regression analyses using generalized estimating equations revealed that DA participants reported improved knowledge relative to UC (B=.41, p<.05). For decisional conflict, per-protocol analyses revealed a group by time interaction (B=-.69, p<.05), indicating that DA participants were less likely to report decisional conflict at 2-months compared to UC participants (OR=.49, 95% CI: .26 .91, p<.05). CONCLUSION: This is the first randomized trial to evaluate a DA in the context of free mass screening, a challenging setting in which to make an informed decision. The DA was highly utilized by participants, improved knowledge and reduced decisional conflict. PRACTICE IMPLICATIONS: These results are valuable in understanding ways to improve the decisions of men who seek screening and can be easily implemented within many settings. PMID- 23357415 TI - Communicative and critical health literacy, and self-management behaviors in end stage renal disease patients with diabetes on hemodialysis. AB - OBJECTIVE: Health literacy (HL) has been linked to disease self-management and various health outcomes, and can be separated into components of functional, communicative and critical skills. The high comorbidity between diabetes and end stage renal disease (ESRD) poses concerns for compromised disease self management. This study aimed to identify the relationships between HL and self management behaviors in end-stage renal disease patients with diabetes. METHODS: Self-report questionnaires measuring HL and self-management with the functional, communicative and critical HL scale and Summary of Diabetes Self-Care Activities, respectively, were implemented with a sample of 63 patients. Socio-demographic and clinical characteristics were obtained from medical records. RESULTS: Self management in diabetes was associated with communicative and critical HL, but not functional HL. Educational attainment was associated only with functional HL. No relationship between HL and glycated hemoglobin (HbA1c) was identified. CONCLUSION: Communicative and critical HL skills are associated with self management in ESRD patients with diabetes. Education levels are not related to self-management. PRACTICE IMPLICATIONS: Healthcare professionals and health information aiming to improve self-management in ESRD patients with diabetes should consider their capacities of communicative and critical HL instead of solely assessing functional HL. PMID- 23357416 TI - Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay: a quantitative method for oxidative stress assessment of nanoparticle-treated cells. AB - No consensus exists on how to address possible toxicity of nanomaterials as they interfere with most in vitro screening tests based on colorimetric and fluorimetric probes such as the dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay for detection of oxidative species. In the present research, nanomaterial interaction with DCFH-DA was studied in relation to its nature and/or assay conditions (cell-based and time exposure) by incubating Rhodamine (Rhd)-labeled 25nm and 50nm silica (SiO2), naked and oleic acid coated magnetite, (Fe3O4) and maghemite (Fe2O3) iron oxide, titanium dioxide (TiO2) and poly(ethylene oxide) poly(lactide/glycolide) acid (PLGA-PEO) nanoparticles (NPs) with metabolically active rat hepatocytes for 4 and 24-h periods. Data indicated that nanoparticle uptake correlated with quenching of dye fluorescence emission. In spite of their masking effect, the oxidative potential of NPs could be detected at a limited threshold concentration when exposed for periods of time longer than those frequently used for this test. However, changes in the experimental conditions did not systematically result in free radical formation for all nanomaterials tested. Overall data indicate that despite the quenching effect of nanoparticles on DCFH-DA assay, it can be considered as a useful tool for quantitative measurement of NPs-induced oxidative stress by minor modifications of standardized protocols. PMID- 23357417 TI - alpha-Lipoic acid attenuates coxsackievirus B3-induced ectopic calcification in heart, pancreas, and lung. AB - Ectopic mineralization of soft tissues is known to be a typical response to systemic imbalance of various metabolic factors as well as tissue injury, leading to severe clinical consequences. In this study, coxsackievirus B3 (CVB3) infection in mice resulted in significant tissue injury, especially in the heart and pancreas. Inflammatory damage and apoptotic cell death were observed in CVB3 infected heart and pancreas tissues. Along with tissue damage, substantial ectopic calcification was detected in CVB3-infected heart, pancreas, and lung tissues, as determined by von Kossa staining and calcium content quantification. In addition, CVB3 infection induced upregulation of osteogenic signals, including six genes (BMP2, SPARC, Runx2, osteopontin, collagen type I, and osterix) in the heart, three genes (SPARC, osteopontin, and collagen type I) in the pancreas, and two genes (BMP2 and alkaline phosphatase) in the lung, as determined by quantitative real-time PCR analysis. Intriguingly, we showed that alpha-lipoic acid diminished CVB3-mediated inflammatory and apoptotic tissue damage, subsequently ameliorating ectopic calcification via the suppression of osteogenic signals. Collectively, our data provide evidence that ectopic calcification induced by CVB3 infection is implicated in the induction of osteogenic propensity, and alpha-lipoic acid may be a potential therapeutic agent to ameliorate pathologic calcification. PMID- 23357418 TI - RAD23A negatively regulates RIG-I/MDA5 signaling through promoting TRAF2 polyubiquitination and degradation. AB - RIG-I/MDA5 plays a pivotal role in innate immunity by detecting intracellular double-stranded RNA (dsRNA) and activating the transcription of type I interferons and proinflammatory factors, but the exactly regulating mechanism of RIG-I/MDA5 signaling remains elusive. In this study, UbL-UBA domain containing protein RAD23A was identified as a negative regulator of RIG-I/MDA5-mediated signaling activation through a small interfering RNA (siRNA)-based screening. Knockdown of RAD23A augmented the expression of RIG-I/MDA5-mediated expression of proinflammatory cytokines and IFN-beta whereas ectopic expression of RAD23A showed the converse effect. Moreover, we confirmed the interaction between RAD23A and tumor necrosis factor receptor-associated factor 2 (TRAF2), an essential mediator of RIG-I/MDA5 signaling, and found that RAD23A down-regulated TRAF2 protein level through ubiquitin-proteasome system. Therefore, this study identified RAD23A as a novel negative regulator of RIG-I/MDA5 mediated anti-virus response. PMID- 23357419 TI - Cell-cell communication induces random spikes of spontaneous calcium oscillations in multi-BV-2 microglial cells. AB - As the first and main form of active immune defense in the central nervous system, microglial cells usually exhibit complicated intracellular calcium (Ca2+) activity that can regulate the downstream components of signaling cascades. In the present work, spontaneous oscillations of the cytosolic calcium concentration ([Ca2+]c) in multi-BV-2 microglial cells were observed by video microscopy. These cells exhibited random spikes of Ca2+ oscillations. Cross-correlation analysis of the temporal dependence of the oscillations indicated the existence of cell-cell communication mediated by extracellular messengers. Numerical simulations based on a simple mathematical model suggested that these communications could induce random spikes of spontaneous Ca oscillations in the multi-cell system. Short-time imaging analysis of random spikes in different regions of a single cell showed that spontaneous Ca2+ oscillations resulted from Ca2+ wave generated by other cells as well as from calcium elevation inside the cell. Taken together, our data demonstrate that cell-cell communication existed between the BV-2 microglial cells in vitro and further resulted in the random spikes of spontaneous Ca2+ oscillations. PMID- 23357420 TI - A maternally inherited diabetes and deafness patient with the 12S rRNA m.1555A>G and the ND1 m.3308T>C mutations associated with multiple mitochondrial deletions. AB - Maternally inherited diabetes and deafness (MIDD) is a mitochondrial syndrome characterized by the onset of sensorineural hearing loss and diabetes in adults. Some patients may have other additional clinical features common in mitochondrial disorders such as pigmentary retinopathy, ptosis, cardiomyopathy, myopathy and renal affections. We report a 40-year-old Tunisian patient presenting maternally inherited type 2 diabetes and deafness (MIDD). A molecular genetic analysis was conducted in the patient and his twin sister, but no reported mutations in the tRNA(Leu(UUR)) and tRNA(Glu) genes were found, especially the two mitochondrial m.3243A>G and the m.14709T>C mutations in muscle and blood leukocytes. The results showed the presence of the mitochondrial NADH deshydrogenase 1 (ND1) homoplasmic m.3308T>C mutation the 2 tested tissues (blood leukocytes and skeletal muscle) of the proband and in the patient's sister blood leukocytes. In addition, we identified the mitochondrial 12S rRNA m.1555A>G mutation in muscle and blood leukocytes. The Long-range PCR amplification revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient's skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of MIDD in whom we detected the 12S rRNA m.1555A>G and the ND1 m.3308T>C mutations with mitochondrial multiple deletions. PMID- 23357422 TI - N-Acetylglucosaminyltransferase V triggers overexpression of MT1-MMP and reinforces the invasive/metastatic potential of cancer cells. AB - N-Acetylglucosaminyltransferase V (GnT-V) is an enzyme that catalyzes the formation of a beta1,6-N-acetylglucosamine (GlcNAc) side chain to a core mannosyl residue in N-linked glycoproteins. Besides its direct function of producing aberrant glycoproteins, it promotes cancer progression by its involvement in the stimulation of oncoproteins. Herein, we report that GnT-V guided the transcriptional activation of membrane-type matrix metalloproteinase-1 (MT1-MMP) in cancer cells. The activated MT1-MMP expression had dual effects on cancer progression. It not only promoted proteolytic activity for cancer cells per se, but also led to the activation of MMP-2. Consequently, the activation of the two MMPs triggered by GnT-V intensified the invasive potential. A quantitative analysis using clinical tissues revealed a relatively strong correlation between GnT-V overexpression and MT1-MMP upregulation. In this study, we report for the first time that GnT-V directs cancer progression by modulating MMPs in cancer. PMID- 23357421 TI - Manganese efflux in Parkinsonism: insights from newly characterized SLC30A10 mutations. AB - Although manganese (Mn) is required for normal cellular function, overexposure to this metal may cause an extrapyramidal syndrome resembling Parkinson's disease (PD). Notably, high whole-blood Mn levels have been reported in patients with idiopathic PD. Because Mn is both essential at low dose and toxic at higher dose; its transport and homeostasis are tightly regulated. Previously, the only protein known to be operant in cellular Mn export was the iron-regulating transporter, ferroportin (Fpn). The causal role for Mn in PD has yet to be fully understood, but evidence of a familial predisposition to PD associated with Mn toxicity is mounting. A recently discovered mutation in SLC30A10 identified its gene product as putatively involved in Mn efflux. Patients with the SLC30A10 mutation display Parkinsonian-like gate disturbances and hypermanganesemia. This review will address Mn transport proteins, the newly discovered SLC30A10 mutations and their implications to Parkinsonism and Mn regulation. PMID- 23357423 TI - The role of C-terminal amino acid residues of a Delta6-fatty acid desaturase from blackcurrant. AB - Delta6-fatty acid desaturase is an important enzyme in the catalytic synthesis of polyunsaturated fatty acids. Using domain swapping and a site-directed mutagenesis strategy, we found that the region of the C-terminal 67 amino acid residues of Delta6-fatty acid desaturase RnD6C from blackcurrant was essential for its catalytic activity and that seven different residues between RnD6C and RnD8A in that region were involved in the desaturase activity. Compared with RnD6C, the activity of the following mutations, V394A, K395I, F411L, S436P, VK3945AI and IS4356VP, was significantly decreased, whereas the activity of I417T was significantly increased. The amino acids N, T and Y in the last four residues also play a certain role in the desaturase activity. PMID- 23357424 TI - Lipophilicity of flavonoid complexes with iron(II) and their interaction with liposomes. AB - We studied complex formation of flavonoids quercetin and taxifolin with iron(II) and the complex influence on phase transitions of phospholipid bilayer. UV-Vis spectroscopy revealed that the stoichiometry of flavonoid/iron complexes was equal to 3:2 and 2:1. Molecular modeling and experimental measurements demonstrated the increase of flavonoids lipophilicity after the complex formation. A considerable influence of quercetin-iron complex on Palmitoyl-Oleoyl Phosphatidylethanolamine transitions from bilayer to hexagonal HII phase was detected by differential scanning calorimetry. The obtained data are related to flavonoid/iron complexes bioavailability, their influence on cell membrane functioning, and should be considered in designing liposomal vehicles for drug and gene delivery. PMID- 23357425 TI - Functional characterization of a rice de novo DNA methyltransferase, OsDRM2, expressed in Escherichia coli and yeast. AB - DNA methylation of cytosine nucleotides is an important epigenetic modification that occurs in most eukaryotic organisms and is established and maintained by various DNA methyltransferases together with their co-factors. There are two major categories of DNA methyltransferases: de novo and maintenance. Here, we report the isolation and functional characterization of a de novo methyltransferase, named OsDRM2, from rice (Oryza sativa L.). The full-length coding region of OsDRM2 was cloned and transformed into Escherichia coli and Saccharomyces cerevisiae. Both of these organisms expressed the OsDRM2 protein, which exhibited stochastic de novo methylation activity in vitro at CG, CHG, and CHH di- and tri-nucleotide patterns. Two lines of evidence demonstrated the de novo activity of OsDRM2: (1) a 5'-CCGG-3' containing DNA fragment that had been pre-treated with OsDRM2 protein expressed in E. coli was protected from digestion by the CG-methylation-sensitive isoschizomer HpaII; (2) methylation-sensitive amplified polymorphism (MSAP) analysis of S. cerevisiae genomic DNA from transformants that had been introduced with OsDRM2 revealed CG and CHG methylation levels of 3.92-9.12%, and 2.88-6.93%, respectively, whereas the mock control S. cerevisiae DNA did not exhibit cytosine methylation. These results were further supported by bisulfite sequencing of the 18S rRNA and EAF5 genes of the transformed S. cerevisiae, which exhibited different DNA methylation patterns, which were observed in the genomic DNA. Our findings establish that OsDRM2 is an active de novo DNA methyltransferase gene with conserved activity in both prokaryotic and eukaryotic non-host species. PMID- 23357426 TI - Effect of glassy modes on electron spin-lattice relaxation in solid ethanol. AB - Electron spin-lattice relaxation (SLR) of TEMPO radical was measured in the crystalline and glassy states of deuterated ethanol in the temperature range 5 80K using X-band electron paramagnetic resonance (EPR). The measured SLR rates are higher in the glassy than in crystalline state and the excess SLR rate in glassy state is much lower than in ethanol. This result suggests that extra modes in glassy state, i.e. glassy modes, produce the excess SLR rate via the electron nuclear dipolar (END) interaction between the electron spin of radical and the matrix protons or deuterons. Using the soft-potential model and assuming the END interaction between the electron spin and the matrix protons, the contributions to SLR rate of various mechanisms of glassy modes were theoretically analyzed. The evaluations of SLR rates in glassy ethanol indicate two main mechanisms of glassy modes: thermally activated relaxation of double-well systems and phonon induced relaxation of quasi-harmonic local modes. The SLR rates induced by these mechanisms correlate well with the experimental data. PMID- 23357427 TI - Probing alanine transaminase catalysis with hyperpolarized 13CD3-pyruvate. AB - Hyperpolarized metabolites offer a tremendous sensitivity advantage (>10(4) fold) when measuring flux and enzyme activity in living tissues by magnetic resonance methods. These sensitivity gains can also be applied to mechanistic studies that impose time and metabolite concentration limitations. Here we explore the use of hyperpolarization by dissolution dynamic nuclear polarization (DNP) in mechanistic studies of alanine transaminase (ALT), a well-established biomarker of liver disease and cancer that converts pyruvate to alanine using glutamate as a nitrogen donor. A specific deuterated, (13)C-enriched analog of pyruvic acid, (13)C3D(3)-pyruvic acid, is demonstrated to have advantages in terms of detection by both direct (13)C observation and indirect observation through methyl protons introduced by ALT-catalyzed H-D exchange. Exchange on injecting hyperpolarized (13)C3D(3)-pyruvate into ALT dissolved in buffered (1)H(2)O, combined with an experimental approach to measure proton incorporation, provided information on mechanistic details of transaminase action on a 1.5s timescale. ALT introduced, on average, 0.8 new protons into the methyl group of the alanine produced, indicating the presence of an off-pathway enamine intermediate. The opportunities for exploiting mechanism-dependent molecular signatures as well as indirect detection of hyperpolarized (13)C3-pyruvate and products in imaging applications are discussed. PMID- 23357428 TI - Genetic algorithms and solid state NMR pulse sequences. AB - The use of genetic algorithms for the optimisation of magic angle spinning NMR pulse sequences is discussed. The discussion uses as an example the optimisation of the C7(2)(1) dipolar recoupling pulse sequence, aiming to achieve improved efficiency for spin systems characterised by large chemical shielding anisotropies and/or small dipolar coupling interactions. The optimised pulse sequence is found to be robust over a wide range of parameters, requires only minimal a priori knowledge of the spin system for experimental implementations with buildup rates being solely determined by the magnitude of the dipolar coupling interaction, but is found to be less broadbanded than the original C7(2)(1) pulse sequence. The optimised pulse sequence breaks the synchronicity between r.f. pulses and sample spinning. PMID- 23357429 TI - Selective spectral modulation of strongly coupled spins with an echo top refocusing pulse in PRESS sequences. AB - The double spin echo is the basis of the point resolved spectroscopy (PRESS) sequence. In this study we sought to investigate the effects of a broadband 180 degrees pulse - incorporated in the PRESS sequence at the location of the first echo (gPRESS) - on the citrate resonances, chosen as a model of strongly coupled spin system. A significant signal modulation generated by the additional 180 degrees pulse was predicted with simulations and observed experimentally in the citrate resonances. No effects were observed on the singlet resonance of glycine and the weakly coupled resonances of lactate. The phenomenon observed in gPRESS was attributed to the off-diagonal Hamiltonian elements responsible for a coherence transfer occurring throughout the evolution periods. The results of this study show that it is necessary to assess the effects of broadband 180 degrees pulses on strongly coupled spin systems, since these pulses can selectively modify the spectral shape of strongly coupled resonances. PMID- 23357430 TI - NMR identification of endogenous metabolites interacting with fatted and non fatted human serum albumin in blood plasma: Fatty acids influence the HSA metabolite interaction. AB - Metabolites and their concentrations are direct reporters on body biochemistry. Thanks to technical developments metabolic profiling of body fluids, such as blood plasma, by for instance NMR has in the past decade become increasingly accurate enabling successful clinical diagnostics. Human Serum Albumin (HSA) is the main plasma protein (~60% of all plasma protein) and responsible for the transport of endogenous (e.g. fatty acids) and exogenous metabolites, which it achieves thanks to its multiple binding sites and its flexibility. HSA has been extensively studied with regard to its binding of drugs (exogenous metabolites), but only to a lesser extent with regard to its binding of endogenous (non-fatty acid) metabolites. To obtain correct NMR measured metabolic profiles of blood plasma and/or potentially extract information on HSA and fatty acids content, it is necessary to characterize these endogenous metabolite/plasma protein interactions. Here, we investigate these metabolite-HSA interactions in blood plasma and blood plasma mimics. The latter contain the roughly twenty metabolites routinely detected by NMR (also most abundant) in normal relative concentrations with fatted or non-fatted HSA added or not. First, we find that chemical shift changes are small and seen only for a few of the metabolites. In contrast, a significant number of the metabolites display reduced resonance integrals and reduced free concentrations in the presence of HSA or fatted HSA. For slow exchange (or strong) interactions, NMR resonance integrals report the free metabolite concentration, while for fast exchange (weak binding) the chemical shift reports on the binding. Hence, these metabolites bind strongly to HSA and/or fatted HSA, but to a limited degree because for most metabolites their concentration is smaller than the HSA concentration. Most interestingly, fatty acids decrease the metabolite-HSA binding quite significantly for most of the interacting metabolites. We further find that competition between the metabolites for binding is absent for most of these metabolites. These mappings in plasma mimics may thus open new opportunities for improved metabolic profiling of blood plasma. For instance, correct metabolite concentrations can be determined for the non-interacting metabolites and/or concentration corrections made for interacting metabolites. Secondly, the interacting metabolites could be used to act as reporters on HSA and fatty acid concentration in plasma, and thus potentially act as biomarker in diagnostic studies of trauma or cardiovascular diseases. Finally, we find in the blood plasma mimics that after ultrafiltration, commonly used to remove the protein from plasma, the measured concentration equals the total metabolite concentration, except for the strongest binding metabolite citrate. PMID- 23357431 TI - Effectiveness of flavour nutrient learning and mere exposure as mechanisms to increase toddler's intake and preference for green vegetables. AB - Children's consumption of vegetables is still below recommendations. Since preference is the most important predictor of children's intake and most children dislike vegetables, new strategies are needed to increase their preferences for vegetables. Flavour nutrient learning (FNL) could be an effective mechanism to change preferences. Forty healthy toddlers were included in a randomized intervention study. During an intervention period of 7weeks, they consumed vegetable soups (endive and spinach) twice per week. Half of the group received a high-energy variant of one soup (e.g. HE spinach) and a low energy variant of the other (LE endive), whereas for the other half the order was reversed (HE endive, LE spinach). Primary outcome measures were preference and ad libitum consumption (with a maximum of 200g) of both vegetable products (LE), measured before, shortly after the intervention period, and 2 and 6months following conditioning to assess longer-term effects. After completion of the intervention period, 28 children (14 girls and 14 boys, age 35months; SD+/-8.3) met criteria for FNL to occur, and were included in further data analysis. Results showed a significant increase (~58g) in ad libitum intake for both vegetable soups (stable over time), but irrespective of the energy content. This indicates a robust effect of mere exposure on intake, but no FNL. For preference, however, results showed a significant shift in liking for the vegetable soup consistently paired with high energy, supporting FNL. PMID- 23357432 TI - Protective actions of progesterone in the cardiovascular system: potential role of membrane progesterone receptors (mPRs) in mediating rapid effects. AB - The protective functions of progesterone in the cardiovascular system have received little attention even though evidence has accumulated that progesterone lowers blood pressure, inhibits coronary hyperactivity and has powerful vasodilatory and natriuretic effects. One possible reason why potential beneficial actions of progesterone on cardiovascular functions have not been extensively studied is that divergent effects to those of progesterone have been observed in many clinical trials with synthetic progestins such as medroxyprogesterone acetate which are associated with increased risk of coronary disease. Evidence that progesterone exerts protective effects on cardiovascular functions is briefly reviewed. The finding that progesterone administration decreases blood vessel vasoconstriction in several animal models within a few minutes suggests that rapid, nongenomic progesterone mechanisms are of physiological importance in regulating vascular tone. Rapid activation of second messenger pathways by progesterone has been observed in vascular endothelial and smooth muscle cells, resulting in alterations in endothelial nitric oxide synthase (eNOS) activity and calcium influx, respectively. Both nuclear progesterone receptors (PRs) and novel membrane progesterone receptors (mPRs) are candidates for the intermediaries in these rapid, cell-surface initiated progesterone actions in endothelial and smooth muscle vascular cells. PRs have been detected in both cell types. New data are presented showing mPRalpha, mPRbeta and mPRgamma are also present in human endothelial and smooth muscle vascular cells. Preliminary evidence suggests mPRs mediate rapid progestin signaling in these endothelial cells, resulting in down-regulation of cAMP production and increased nitric oxide synthesis. The role of mPRs in progesterone regulation of cardiovascular functions warrants further investigation. PMID- 23357433 TI - New metabolites from fungal biotransformation of an oral contraceptive agent: methyloestrenolone. AB - Fungal cell cultures were used for the first time for the biotransformation of methyloestrenolone (1), an oral contraceptive. Fermentation of 1 with Macrophomina phaseolina, Aspergillus niger, Gibberella fujikuroi, and Cunninghamella echinulata produced eleven metabolites 2-12, six of which 2-5, 11 and 12 were found to be new. These metabolites were resulted from the hydroxylation at C-1, C-2, C-6, C-10, C-11, and C-17alpha-CH3, as well as aromatization of ring A of the steroidal skeleton of substrate 1. The transformed products were identified as 17alpha-methyl-6beta,17beta-dihydroxyestr-4-en-3-one (2), 17alpha-(hydroxymethyl)-11beta,17beta-dihydroxyestr-4-en-3-one (3), 17alpha methyl-2alpha,11beta,17beta-trihydroxyestr-4-en-3-one (4), 17alpha-methyl 1beta,17beta-dihydroxyestr-4-en-3-one (5), 17alpha-methyl-11alpha,17beta dihydroxyestr-4-en-3-one (6), 17alpha-methyl-11beta,17beta-dihydroxyestr-4-en-3 one (7), 17alpha-methyl-10beta,17beta-dihydroxyestr-4-en-3-one (8), 17alpha (hydroxymethyl)-17beta-hydroxyestr-4-en-3-one (9), 17alpha-methylestr-1,3,5(10) trien-3,17beta-diol (10), 17alpha-methyl-3,17beta-dihydroxyestr-1,3,5(10)-trien-6 one (11), and 17alpha-methyl-6beta,10beta,17beta-trihydroxyestr-4-en-3-one (12). PMID- 23357434 TI - Genetic risk factors for glucocorticoid-induced osteonecrosis: a meta-analysis. AB - Glucocorticoid-induced osteonecrosis is a common and severe adverse event. We conducted a meta-analysis to investigate whether polymorphisms in target genes were associated with the risk of corticosteroid-induced osteonecrosis. Published literature from PubMed and EMBASE were searched for eligible publications. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a fixed- or random-effects model. There were 23 articles with 35 genes described the relationship between polymorphisms and glucocorticoid-induced osteonecrosis. Meta analyses were carried out for those SNPs with three or more eligible studies, which included four SNPs located in three genes (PAI-1, MTHFR, ABCB1). The meta analysis revealed that the PAI-1 4G allele was associated with an increased risk of osteonecrosis compared with the 5G allele (combined studies: OR=1.932, 95% CI=1.145-3.261). The OR for the 4G/4G vs. 5G/5G genotype of PAI-1 was 3.217 (95% CI 1.667-6.209 with combined studies), The relative risk of osteonecrosis was increased in the 4G allele vs. 5G/5G and 4G/4G genotype vs. 5G allele, with odds ratios of 2.304 (95% CI=1.235-4.299) and 2.307 (95% CI=1.527-3.485) in combined studies, respectively. The ABCB1 C3435T genotype distributions available confirmed that the C allele increased osteonecrosis risk compared with the T allele (OR 1.668, 95% CI=1.214-2.293) and TT genotype (OR 2.946, 95% CI=1.422 6.101). There was no evidence for significant association between MTHFR C677T and ABCB1 G2677T/A polymorphisms and risk of osteonecrosis. Results of this meta analysis indicate that the PAI-1 4G/5G and ABCB1 C3435T polymorphisms may be risk factors for osteonecrosis. PMID- 23357435 TI - In this issue/abstract thinking: NAC attack: is N-acetylcysteine ready for prime time in child and adolescent psychiatry? PMID- 23357436 TI - Cyberbullying and the digital self. PMID- 23357437 TI - Psychotherapy for youth at risk for bipolar disorder. PMID- 23357438 TI - Toward a better understanding of attention-deficit/hyperactivity disorder across the lifespan. PMID- 23357439 TI - Early intervention for symptomatic youth at risk for bipolar disorder: a randomized trial of family-focused therapy. AB - OBJECTIVE: Depression and brief periods of (hypo)mania are linked to an increased risk of progression to bipolar I or II disorder (BD) in children of bipolar parents. This randomized trial examined the effects of a 4-month family-focused therapy (FFT) program on the 1-year course of mood symptoms in youth at high familial risk for BD, and explored its comparative benefits among youth in families with high versus low expressed emotion (EE). METHOD: Participants were 40 youth (mean 12.3+/-2.8 years, range 9-17) with BD not otherwise specified, major depressive disorder, or cyclothymic disorder who had a first-degree relative with BD I or II and active mood symptoms (Young Mania Rating Scale [YMRS]>11 or Child Depression Rating Scale>29). Participants were randomly allocated to FFT-High Risk version (FFT-HR; 12 sessions of psychoeducation and training in communication and problem-solving skills) or an education control (EC; 1-2 family sessions). RESULTS: Youth in FFT-HR had more rapid recovery from their initial mood symptoms (hazard ratio = 2.69, p = .047), more weeks in remission, and a more favorable trajectory of YMRS scores over 1 year than youth in EC. The magnitude of treatment effect was greater among youth in high-EE (versus low-EE) families. CONCLUSIONS: FFT-HR may hasten and help sustain recovery from mood symptoms among youth at high risk for BD. Longer follow-up will be necessary to determine whether early family intervention has downstream effects that contribute to the delay or prevention of full manic episodes in vulnerable youth. PMID- 23357440 TI - The effect of cognitive-behavioral therapy versus treatment as usual for anxiety in children with autism spectrum disorders: a randomized, controlled trial. AB - OBJECTIVE: To examine the efficacy of a modular cognitive-behavioral therapy (CBT) protocol relative to treatment as usual (TAU) among children with high functioning autism spectrum disorders (ASD) and clinically significant anxiety. METHOD: A total of 45 children (7-11 years of age) with high-functioning ASD and clinically significant anxiety were randomized to receive 16 sessions of weekly CBT or TAU for an equivalent duration. After screening, assessments were conducted at baseline, post-treatment, and 3-month follow-up. Raters were blind to treatment condition. RESULTS: Youth receiving CBT showed substantial improvement relative to TAU on primary anxiety outcomes. Of 24 children randomized to the CBT arm, 18 (75%) were treatment responders, versus only 3 of 21 children (14%) in the TAU arm. Gains were generally maintained at 3-month follow-up for CBT responders. CONCLUSIONS: Relative to usual care, CBT adapted for anxious youth with high-functioning ASD demonstrates large effects in reducing anxiety symptoms. This study contributes to the growing literature supporting adapted CBT approaches for treating anxiety in youth with ASD. PMID- 23357441 TI - Childhood gender nonconformity, bullying victimization, and depressive symptoms across adolescence and early adulthood: an 11-year longitudinal study. AB - OBJECTIVE: Childhood gender nonconformity has been associated with increased risk of caregiver abuse and bullying victimization outside the home, but it is unknown whether as a consequence children who are nonconforming are at higher risk of depressive symptoms. METHOD: Using data from a large national cohort (N = 10,655), we examined differences in depressive symptoms from ages 12 through 30 years by gender nonconformity before age 11 years. We examined the prevalence of bullying victimization by gender nonconformity, then ascertained whether increased exposure to abuse and bullying accounted for possible increased risk of depressive symptoms. We further compared results stratified by sexual orientation. RESULTS: Participants in the top decile of childhood gender nonconformity were at elevated risk of depressive symptoms at ages 12 through 30 years (for females, 0.19 standard deviations more depressive symptoms than conforming females; for males, 0.34 standard deviations more symptoms than conforming males). By ages 23 to 30 years, 26% of participants in the top decile of childhood nonconformity had probable mild or moderate depression versus 18% of participants who were conforming (p<.001). Abuse and bullying victimization accounted for approximately half the increased prevalence of depressive symptoms in youth who were nonconforming versus conforming. Gender-nonconforming heterosexuals and males were at particularly elevated risk for depressive symptoms. CONCLUSION: Gender nonconformity was a strong predictor of depressive symptoms beginning in adolescence, particularly among males and heterosexuals. Physical and emotional bullying and abuse, both inside and outside the home, accounted for much of this increased risk. PMID- 23357442 TI - Does childhood attention-deficit/hyperactivity disorder predict risk-taking and medical illnesses in adulthood? AB - OBJECTIVE: To test whether children with attention-deficit/hyperactivity disorder (ADHD), free of conduct disorder (CD) in childhood (mean = 8 years), have elevated risk-taking, accidents, and medical illnesses in adulthood (mean = 41 years); whether development of CD influences risk-taking during adulthood; and whether exposure to psychostimulants in childhood predicts cardiovascular disease. We hypothesized positive relationships between childhood ADHD and risky driving (in the past 5 years), risky sex (in the past year), and between risk taking and medical conditions in adulthood; and that development of CD/antisocial personality (APD) would account for the link between ADHD and risk-taking. We report causes of death. METHOD: Prospective 33-year follow-up of 135 boys of white ethnicity with ADHD in childhood and without CD (probands), and 136 matched male comparison subjects without ADHD (comparison subjects; mean = 41 years), blindly interviewed by clinicians. RESULTS: In adulthood, probands had relatively more risky driving, sexually transmitted disease, head injury, and emergency department admissions (p< .05-.01). Groups did not differ on other medical outcomes. Lifetime risk-taking was associated with negative health outcomes (p = .01-.001). Development of CD/APD accounted for the relationship between ADHD and risk-taking. Probands without CD/APD did not differ from comparison subjects in lifetime risky behaviors. Psychostimulant treatment did not predict cardiac illness (p = .55). Probands had more deaths not related to specific medical conditions (p = .01). CONCLUSIONS: Overall, among children with ADHD, it is those who develop CD/APD who have elevated risky behaviors as adults. Over their lifetime, those who did not develop CD/APD did not differ from comparison subjects in risk-taking behaviors. Findings also provide support for long-term safety of early psychostimulant treatment. PMID- 23357443 TI - Emotion regulation and heterogeneity in attention-deficit/hyperactivity disorder. AB - OBJECTIVE: How best to capture heterogeneity in attention-deficit/hyperactivity disorder (ADHD) using biomarkers has been elusive. This study evaluated whether emotion reactivity and regulation provide a means to achieve this. METHOD: Participants were classified into three groups: children with ADHD plus low prosocial behavior (hypothesized to be high in callous/unemotional traits; n = 21); children with ADHD with age-appropriate prosocial behavior (n = 54); and typically developing children (n = 75). Children completed a task with four conditions: negative induction, negative suppression, positive induction, and positive suppression of affect. The task required children to view an emotion laden film clip, while either facially mimicking (induction) or masking (suppression) the emotion of the main character. Parasympathetic and sympathetic nervous system activity were assessed via respiratory sinus arrhythmia (RSA) and cardiac pre-ejection period (PEP), respectively. Symptoms of anxiety, conduct, and oppositional defiant disorders were treated as covariates. RESULTS: The ADHD typical-prosocial group displayed atypically elevated parasympathetic reactivity (emotion dysregulation) during positive induction, along with increased sympathetic activity (elevated arousal) across conditions. In contrast, the ADHD low-prosocial group displayed reduced parasympathetic reactivity and reduced sympathetic activity (low emotional arousal) across baseline and task conditions. Thus, both ADHD groups had altered patterns of autonomic functioning, but in two distinct forms. CONCLUSION: Although ADHD is heterogeneous clinically, results suggest that ADHD is also heterogeneous with regard to physiological indices of emotion and regulation. Future studies of emotion, regulation, and ADHD should take this into account. Further study of physiological responding in ADHD may yield clinically and etiologically distinct domains or groups. PMID- 23357444 TI - Separating the domains of oppositional behavior: comparing latent models of the conners' oppositional subscale. AB - OBJECTIVE: Although oppositional defiant disorder (ODD) is usually considered the mildest of the disruptive behavior disorders, it is a key factor in predicting young adult anxiety and depression and is distinguishable from normal childhood behavior. In an effort to understand possible subsets of oppositional defiant behavior (ODB) that may differentially predict outcome, we used latent class analysis of mother report on the Conners' Parent Rating Scales Revised Short Forms (CPRS-R:S). METHOD: Data were obtained from mother report for Dutch twins (7 years old, n = 7,597; 10 years old, n = 6,548; and 12 years old, n = 5,717) from the Netherlands Twin Registry. Samples partially overlapped at ages 7 and 10 years (19% overlapping) and at ages 10 and 12 years (30% overlapping), but not at ages 7 and 12 years. Oppositional defiant behavior was measured using the six item Oppositional subscale of the CPRS-R:S. Multilevel LCA with robust standard error estimates was performed using the Latent Gold program to control for twin twin dependence in the data. Class assignment across ages was determined and an estimate of heritability for each class was calculated. Comparisons with maternal report Child Behavior Checklist (CBCL) scores were examined using linear mixed models at each age, corrected for multiple comparisons. RESULTS: The LCA identified an optimal solution of four classes across age groups. Class 1 was associated with no or low symptom endorsement (69-75% of the children); class 2 was characterized by defiance (11-12%); class 3 was characterized by irritability (9-11%); and class 4 was associated with elevated scores on all symptoms (5-8%). Odds ratios for twins being in the same class at each successive age point were higher within classes across ages than between classes. Heritability within the two "intermediate" classes was nearly as high as for the class with all symptoms, except for boys at age 12. Children in the Irritable class were more likely to have mood symptoms on the CBCL scales than children in the Defiant class but demonstrated similar scores on aggression and externalizing scales. Children in the All Symptoms class were higher in both internalizing and externalizing scales and subscales. CONCLUSIONS: The LCA indicates four distinct latent classes of oppositional defiant behavior, in which the distinguishing feature between the two intermediate classes (classes 2 and 3) is the level of irritability and defiance. Implications for the longitudinal course of these symptoms, association with other disorders, and genetics are discussed. PMID- 23357445 TI - Gray matter volume in adolescent anxiety: an impact of the brain-derived neurotrophic factor Val(66)Met polymorphism? AB - OBJECTIVE: Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val(66)Met polymorphism may modulate such brain morphometry profiles. METHOD: Using voxel-based morphometry and magnetic resonance imaging, associations of BDNF and clinical anxiety with regional GMVs of anterior cingulate cortex, insula, amygdala, and hippocampus were examined in 39 affected (17 Met allele carriers, 22 Val/Val homozygotes) and 63 nonaffected adolescents (27 [corrected] Met allele carriers, 36 [corrected] Val/Val homozygotes). RESULTS: Amygdala and anterior hippocampal GMVs were significantly smaller in patients than in healthy comparison adolescents, with a reverse pattern for the insula. Post-hoc regression analyses indicated a specific contribution of social phobia to the GMV reductions in the amygdala and hippocampus. In addition, insula and dorsal anterior cingulate cortex (ACC) GMVs were modulated by BDNF genotype. In both regions, and GMVs were larger in the Val/Val homozygote patients than in individuals carrying the Met allele. CONCLUSIONS: These results implicate reduced GMV in the amygdala and hippocampus in pediatric anxiety, particularly social phobia. In addition, the data suggest that genetic factors may modulate differences in the insula and dorsal ACC. PMID- 23357446 TI - Characterization of adolescent prescription drug abuse and misuse using the Researched Abuse Diversion and Addiction-related Surveillance (RADARS((r))) System. AB - OBJECTIVE: To describe the characteristics and health effects of adolescent (age 13-19 years) prescription drug abuse and misuse using the Researched Abuse Diversion and Addiction-Related Surveillance (RADARS((r))) System. METHOD: Secondary analysis of data collected from RADARS System participating poison centers was performed. Data for all intentional exposures from 2007 through 2009 were used to describe adolescent prescription opioid (oxycodone, fentanyl, hydrocodone, hydromorphone, morphine, methadone, buprenorphine, and tramadol) and stimulant (methylphenidate and amphetamines) exposures. RESULTS: A total of 16,209 intentional adolescent exposures to prescription drugs were identified, 68% to opioids and 32% to stimulants. The mean age was 16.6 years (SD +/- 1.7 years). Slightly more than half (52.4%) of drug mentions involved females. The five most frequently misused or abused drugs were hydrocodone (32%), amphetamines (18%), oxycodone (15%), methylphenidate (14%), and tramadol (11%). Of all exposures, 38% were classified as suspected suicidal. Of adolescents who intentionally exposed themselves to prescription drugs, 30% were treated in a health care facility, 2,792 of whom were admitted to the hospital, including 1,293 to the intensive care unit. A total of 17.2% of intentional exposures were associated with no effect, 38.9% minor effects, 23.3% moderate effects, 3.6% major effects, and 0.1% were associated with death. Oxycodone and methadone were associated with the most deaths. No deaths were associated with exposures to stimulants. CONCLUSIONS: Prescription drug misuse and abuse poses an important health problem and results in thousands of hospitalizations of adolescents per year. Further work is needed to develop focused interventions and educational programs to prevent prescription drug abuse and misuse by adolescents. PMID- 23357447 TI - Another look at the Treatment of Early-Age Mania (TEAM) trial. PMID- 23357448 TI - Dr. Vitiello et al. reply. PMID- 23357450 TI - Risk factors and outcomes in transfusion-associated circulatory overload. AB - BACKGROUND: Transfusion-associated circulatory overload is characterized by new respiratory distress and hydrostatic pulmonary edema within 6 hours after blood transfusion, but its risk factors and outcomes are poorly characterized. METHODS: Using a case control design, we enrolled 83 patients with severe transfusion associated circulatory overload identified by active surveillance for hypoxemia and 163 transfused controls at the University of California, San Francisco (UCSF) and Mayo Clinic (Rochester, Minn) hospitals. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression, and survival and length of stay were analyzed using proportional hazard models. RESULTS: Transfusion-associated circulatory overload was associated with chronic renal failure (OR 27.0; 95% CI, 5.2-143), a past history of heart failure (OR 6.6; 95% CI, 2.1-21), hemorrhagic shock (OR 113; 95% CI, 14.1-903), number of blood products transfused (OR 1.11 per unit; 95% CI, 1.01-1.22), and fluid balance per hour (OR 9.4 per liter; 95% CI, 3.1-28). Patients with transfusion associated circulatory overload had significantly increased in-hospital mortality (hazard ratio 3.20; 95% CI, 1.23-8.10) after controlling for Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score, and longer hospital and intensive care unit lengths of stay. CONCLUSIONS: The risk of transfusion-associated circulatory overload increases with the number of blood products administered and a positive fluid balance, and in patients with pre-existing heart failure and chronic renal failure. These data, if replicated, could be used to construct predictive algorithms for transfusion-associated circulatory overload, and subsequent modifications of transfusion practice might prevent morbidity and mortality associated with this complication. PMID- 23357452 TI - Acupuncture--help, harm, or placebo? AB - The most recent meta-analysis appearing in Fertility and Sterility on acupuncture was reevaluated in view of the marked heterogeneity of interventions, controls, data analysis, and timing of interventions in the trials that were included. After removing some of the trials and data based on more rigorous standards for a high quality meta-analysis, a significant benefit of the intervention could no longer be shown. When studies with and without placebo controls were analyzed separately, a placebo effect was suggested. Individual trials with a confidence limit below unity emphasized the potential for a detrimental impact on outcomes, which should be considered both in using acupuncture clinically as an adjunct for IVF and in design of future trials. Much more data that includes a placebo control will be required before a conclusion can be made that acupuncture has a true treatment effect on IVF outcomes. However, unless the timing and method of the acupuncture are standardized, practitioners will still have difficulty being sure that their particular method will help beyond the apparent benefit provided by a placebo. PMID- 23357453 TI - Epigenetic disturbances in in vitro cultured gametes and embryos: implications for human assisted reproduction. AB - Although assisted reproductive technology (ART) has become a routine practice for human infertility treatment, the etiology of the increased risks for perinatal problems in ART-conceived children is still poorly understood. Data from mouse experiments and the in vitro production of livestock provide strong evidence that imprint establishment in late oocyte stages and reprogramming of the two germline genomes for somatic development after fertilization are vulnerable to environmental cues. In vitro culture and maturation of oocytes, superovulation, and embryo culture all represent artificial intrusions upon the natural development, which can be expected to influence the epigenome of the resultant offspring. However, in this context it is difficult to define the normal range of epigenetic variation in humans from conception throughout life. With the notable exception of a few highly penetrant imprinting mutations, the phenotypic consequences of any observed epigenetic differences between ART and non-ART groups remain largely unclear. The periconceptional period is not only critical for embryonal, placental, and fetal development, as well as the outcome at birth, but suboptimal in vitro culture conditions may also lead to persistent changes in the epigenome influencing disease susceptibilities later in life. The epigenome appears to be most plastic in the late stages of oocyte and the early stages of embryo development; this plasticity steadily decreases during prenatal and postnatal life. Therefore, when considering the safety of human ART from an epigenetic point of view, our main concern should not be whether or not a few rare imprinting disorders are increased, but rather we must be aware of a functional link between interference with epigenetic reprogramming in very early development and adult disease. PMID- 23357451 TI - Mechanism of resistance to S138A substituted enfuvirtide and its application to peptide design. AB - T-20 (enfuvirtide) resistance is caused by the N43D primary resistance mutation at its presumed binding site at the N-terminal heptad repeat (N-HR) of gp41, accompanied by the S138A secondary mutation at the C-terminal HR of gp41 (C-HR). We have discovered that modifying T-20 to include S138A (T-20S138A) allows it to efficiently block wild-type and T20-resistant viruses, by a mechanism that involves improved binding of T-20S138A to the N-HR that contains the N43D primary mutation. To determine how HIV-1 in turn escapes T-20S138A we used a dose escalation method to select T-20S138A-resistant HIV-1 starting with either wild type (HIV-1WT) or T-20-resistant (HIV-1N43D/S138A) virus. We found that when starting with WT background, I37N and L44M emerged in the N-HR of gp41, and N126K in the C-HR. However, when starting with HIV-1N43D/S138A, L33S and I69L emerged in N-HR, and E137K in C-HR. T-20S138A-resistant recombinant HIV-1 showed cross resistance to other T-20 derivatives, but not to C34 derivatives, suggesting that T-20S138A suppressed HIV-1 replication by a similar mechanism to T-20. Furthermore, E137K enhanced viral replication kinetics and restored binding affinity with N-HR containing N43D, indicating that it acts as a secondary, compensatory mutation. We therefore introduced E137K into T-20S138A (T 20E137K/S138A) and revealed that T-20E137K/S138A moderately suppressed replication of T-20S138A-resistant HIV-1. T-20E137K/S138A retained activity to HIV-1 without L33S, which seems to be a key mutation for T-20 derivatives. Our data demonstrate that secondary mutations can be consistently used for the design of peptide inhibitors that block replication of HIV resistant to fusion inhibitors. PMID- 23357454 TI - Feedback to professionals on patient-centered fertility care is insufficient for improvement: a mixed-method study. AB - OBJECTIVE: To determine the effect of audits and feedback on the level of patient centeredness in fertility care, and to obtain a more in-depth understanding of professionals' views on patient-centered care and achieving improvements. DESIGN: Mixed-method design, using semistructured in-depth interviews and patient questionnaires. SETTING: Fifteen Dutch fertility clinics. PATIENT(S): Women in infertility treatment (quantitative section) and fertility care professionals (qualitative section). INTERVENTION(S): Audit of the level of patient centeredness of care, and feedback provided to clinics by a personalized paper based feedback report. MAIN OUTCOME MEASURE(S): Quantitative section: the patient reported differences in the level of patient-centered fertility care between 2009 and 2011 measured by the Patient-Centeredness Questionnaire-Infertility. Qualitative section: professionals views on improving patient-centered fertility care arranged into a Hibbard framework for behavioral change. RESULT(S): Multilevel regression analysis showed no statistically significant differences between the overall levels of patient-centeredness in 2009 and 2011. Qualitative research showed that professionals' urge to change and their ability to translate feedback were suboptimal to achieve behavioral change. CONCLUSION(S): Audits and feedback alone are not enough to improve the level of patient-centeredness in fertility care. Increasing professionals' desire to change and their ability to translate feedback about their performance into an optimal quality improvement strategy appear to be the key issues. PMID- 23357455 TI - Intracytoplasmic morphologically selected sperm injection versus intracytoplasmic sperm injection: a step toward a clinical algorithm. AB - OBJECTIVE: To study the advantage of intracytoplasmic morphologically selected sperm injection (IMSI) versus intracytoplasmic sperm injection (ICSI) in the first artificial reproductive technology (ART) cycle and in consecutive cycles. DESIGN: A cohort study. SETTING: Single outpatient fertility center. PATIENT(S): Couples presenting with male factor infertility, requiring ovum micromanipulation. INTERVENTION(S): The ICSI or IMSI was performed according to the couple's choice. MAIN OUTCOME MEASURE(S): Clinical intrauterine pregnancies and deliveries. RESULT(S): A total of 1,891 IVF-ICSI cycles and 577 IVF-IMSI cycles were included. In the first IVF treatment, pregnancy rates (PRs) were 46% and 47%, respectively, and delivery rates were 23% versus 30%, respectively. In the second cycle to follow a failed ICSI, PRs and delivery rates were significantly higher for patients who chose to shift to the IMSI technique compared with patients who chose to go through a second IVF-ICSI cycle (56% vs. 38% PRs and 28% vs. 18% delivery rates, respectively). In the following cycles a significant difference was demonstrated in both PR and delivery rates in favor of patients shifting between treatments. In a multivariate analysis an approximate threefold increased chance existed for both pregnancy and delivery only in the case of couples failing an ICSI attempt who shifted to IMSI. CONCLUSION(S): Our present experience supports refraining from repeated IMSI cycles. In light of improved PRs and delivery rates, we recommend promoting the IMSI method for couples who failed ICSI cycle, once or more. PMID- 23357456 TI - Novel technologies for selecting the best sperm for in vitro fertilization and intracytoplasmic sperm injection. AB - The increasing focus on developing new tools to more accurately diagnose and select individual sperm before intracytoplasmic sperm injection will allow us to counsel and treat couples with greater confidence and efficiency. Current sperm selection techniques are based on the premise that if an ejaculated spermatozoon has cleared spermatogenesis with the correct morphology and/or membrane properties then it is most likely normal. Techniques that are designed to prepare a clean "normal" sperm population or that assist in selecting an individual "normal" spermatozoon are currently being investigated. The use of techniques, including density-gradient preparation, electrophoretic separation, microfluidics, high-magnification sperm morphology selection, and hyaluronic acid binding, is discussed. The research evidence that supports the interrelated developmental and genetic integrity of the selected sperm, particularly sperm DNA damage and clinical outcome evidence are presented. PMID- 23357457 TI - Seasonal effects on vitamin D status influence outcomes of lifestyle intervention in overweight and obese women with polycystic ovary syndrome. AB - OBJECTIVE: To investigate the effect of undertaking lifestyle interventions during periods of seasonal change on vitamin D status and health outcomes in overweight/obese women with polycystic ovary syndrome (PCOS). DESIGN: Retrospective, unplanned secondary analysis of two cohorts during different seasons. SETTING: Outpatient clinical research unit. PATIENT(S): Fifty overweight/obese women with PCOS. INTERVENTION(S): Twenty-week lifestyle modification program (Clinical Trials registration no.: ACTRN12606000198527); one cohort started in winter and finished in summer, and one started in summer and finished in winter. MAIN OUTCOME MEASURE(S): 25-Hydroxyvitamin D (25OH-D), weight, waist circumference (WC), body composition, cardiovascular disease (CVD) risk factors, and menstrual cycle length. RESULT(S): Baseline 25OH-D levels were 27.6 +/- 9.0 nmol/L. The winter cohort had lower 25OH-D levels at baseline, which increased over 20 weeks, whereas the summer cohort started with higher levels which decreased. Changes in 25OH-D were inversely correlated with changes in WC and cholesterol when controlling for baseline values, such that increases in 25OH D were associated with greater reductions in WC and cholesterol. CONCLUSION(S): Obesity and CVD risk profiles improved in vitamin D-deficient women with PCOS after a 20-week lifestyle intervention during which vitamin D status improved with seasonal change. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12606000198527. PMID- 23357458 TI - Association of maternal and fetal MTHFR A1298C polymorphism with the risk of pregnancy loss: a study of an Indian population and a meta-analysis. AB - OBJECTIVE: To study the genetic association between methylenetetrahydrofolate reductase (MTHFR) A1298 polymorphism and recurrent pregnancy loss (RPL). DESIGN: Prospective case-control study, systematic review, and meta-analysis using an electronic database up to July 27, 2012. SETTING: Meta-analysis of four studies on RPL and three studies on spontaneously aborted embryos, including the present study. PATIENT(S): A total of 129 RPL patients and 202 healthy control women with successful pregnancy were analyzed including 40 spontaneously aborted embryos and 40 aborted embryos as control samples. For meta-analysis, 1,080 case and 709 control subjects were included of RPL and 375 case and 384 control samples of spontaneously aborted embryos. INTERVENTION(S): Blood was collected by peripheral venous punctures, and spontaneously aborted embryos were collected by curettage or manual vacuum aspiration. Meta-analysis was done on the basis of heterogeneity of the studies. MAIN OUTCOME MEASURE(S): Genotyping was done by polymerase chain reaction (PCR)-restriction-fragment-length polymorphism (RFLP). DNA sequencing was used to ascertain PCR-RFLP results. Age-adjusted odds ratios were calculated by logistic regression analysis. Meta-analysis on this polymorphism was conducted to support our findings. RESULT(S): We found that presence of rare allele "C" and heterozygous and rare homozygous genotypes significantly increased the risk of RPL. No significant change in the fetal MTHFR A1298C genotype frequency was observed, regardless of chromosomal integrity. Meta-analysis of A1298C polymorphism on both RPL and in spontaneously aborted embryos showed significantly increased risk in the carriers of AC and CC genotypes. CONCLUSION(S): The data of the present study clearly suggests that MTHFR A1298C polymorphism is a genetic risk factor for pregnancy loss. PMID- 23357459 TI - Basic concepts of epigenetics. AB - Several types of epigenetic marks facilitate the complex patterning required for normal human development. These epigenetic marks include DNA methylation at CpG dinucleotides, covalent modifications of histone proteins, and noncoding RNAs (ncRNAs). They function in a highly orchestrated manner, regulating mitotically heritable differences in gene expression potential without altering the primary DNA sequence. In germ cells and the developing embryo, genome-wide epigenetic reprogramming drives the erasure and reestablishment of correct epigenetic patterns at critical developmental time periods and in specific cell types. Two specific types of epigenetic regulation established in early development include X-chromosome inactivation and genomic imprinting; they regulate gene expression in a dosage-dependent and parent-of-origin-specific manner, respectively. Both genetic and environmental factors impact epigenetic marks, generating phenotypic variation that ranges from normal variation to human disease. Aberrant epigenetic patterning can lead to a variety of human disorders, including subfertility and imprinting disorders. PMID- 23357460 TI - High-dose cytarabine-based consolidation shows superior results for older AML patients with intermediate risk cytogenetics in first complete remission. AB - We evaluated outcomes in two consecutive groups of AML patients age>60 years in CR after 7+3 induction therapy. Group 1 received consolidation with cytarabine 1.5g/m(2) q12h*6+daunorubicin for two cycles, while group 2 received consolidation with 7+3 followed by mitoxantrone+etoposide. For patients with intermediate-risk cytogenetics, group 1 had a significantly superior DFS (p=0.046), and a trend toward better OS (p=0.087). The treatment group remained a significant predictor of DFS on multivariate analysis. The results indicate that a high-dose cytarabine-containing consolidation regimen produces superior outcomes in AML patients age>60 years with intermediate-risk cytogenetics. PMID- 23357461 TI - Does CA125 binding to mesothelin impact the detection of malignant mesothelioma? AB - The biomarker mesothelin is a useful diagnostic tool in malignant mesothelioma (MM) patients. It has high specificity but a sensitivity of only 50%. As mesothelin binds CA125, and as CA125 is often elevated in MM, we asked whether this binding affected measurable mesothelin levels in a relevant clinical setting. Mesothelin and CA125 concentrations were measured in the serum of 41 patients with MM. An assay was developed to detect mesothelin bound to CA125. Mesothelin was demonstrated to be bound by CA125 in 9 of 41 MM patients. This binding could be broken by the addition of sodium dodecyl sulphate and diethylenetriaminepenta acetic acid (DTPA) to the samples, however this did not lead to any change in the mesothelin level measured. We therefore conclude that binding of mesothelin to CA125 does not alter the measurement of mesothelin for the detection of MM. PMID- 23357462 TI - Network-based approach identified cell cycle genes as predictor of overall survival in lung adenocarcinoma patients. AB - Lung adenocarcinoma is the most common type of primary lung cancer. The purpose of this study was to delineate gene expression patterns for survival prediction in lung adenocarcinoma. Gene expression profiles of 82 (discovery set) and 442 (validation set 1) lung adenocarcinoma tumor tissues were analyzed using a systems biology-based network approach. We also examined the expression profiles of 78 adjacent normal lung tissues from 82 patients. We found a significant correlation of an expression module with overall survival (adjusted hazard ratio or HR=1.71; 95% CI=1.06-2.74 in discovery set; adjusted HR=1.26; 95% CI=1.08-1.49 in validation set 1). This expression module contained genes enriched in the biological process of the cell cycle. Interestingly, the cell cycle gene module and overall survival association were also significant in normal lung tissues (adjusted HR=1.91; 95% CI, 1.32-2.75). From these survival-related modules, we further defined three hub genes (UBE2C, TPX2, and MELK) whose expression-based risk indices were more strongly associated with poor 5-year survival (HR=3.85, 95% CI=1.34-11.05 in discovery set; HR=1.72, 95% CI=1.21-2.46 in validation set 1; and HR=3.35, 95% CI=1.08-10.04 in normal lung set). The 3-gene prognostic result was further validated using 92 adenocarcinoma tumor samples (validation set 2); patients with a high-risk gene signature have a 1.52-fold increased risk (95% CI, 1.02-2.24) of death than patients with a low-risk gene signature. These results suggest that a network-based approach may facilitate discovery of key genes that are closely linked to survival in patients with lung adenocarcinoma. PMID- 23357464 TI - Concurrent chemoradiotherapy for large-volume locally-advanced non-small cell lung cancer. AB - PURPOSE: Patients with large volume stage III non-small cell lung cancer (NSCLC) are often excluded from concurrent chemoradiotherapy (CRT) protocols due to fears about excessive toxicity and poor survival. Patients with N3 nodal disease may be excluded for the same reason. We have routinely accepted fit patients in both the above groups for CRT if they met our planning parameters. We analyzed toxicity and survival outcomes for patients undergoing CRT with a planning target volume (PTV) exceeding 700 cc, either with or without N3 nodal disease, or a PTV less then 700 cc with N3 disease. MATERIALS AND METHODS: Single center, retrospective study of patients with stage III NSCLC treated with CRT between 2004 and 2011. RESULTS: 121 patients were eligible, with 81% (98/121) having a PTV>700 cc (of whom 33% (32/98) had N3 nodal disease) and 19% (23/121) having N3 disease and a PTV<=700 cc. Grade >=3 esophagitis and pneumonitis were recorded in respectively 34% and 4% of all patients. Median follow-up for all patients was 37.6 months (mo). Median overall (OS) and progression-free (PFS) survivals were 15.7 mo and 11.6 mo, respectively, OS for all patients with PTV>700 cc was 14.5 mo (19.5 mo with N3 and 13.2 mo without N3), compared to 26.5 mo for PTV<=700 cc with N3 (p=0.009). About 1 in 4 patients with PTV>700 cc died within 6 mo of starting radiotherapy (this was associated with Charlson comorbidity index [CCI]>=1), while about 18% were alive at 3 years. CONCLUSION: Patients undergoing CRT for stage III NSCLC with a PTV>700 cc, with or without N3 nodal disease, had a significantly shorter OS than patients with PTV<=700 cc with N3. Patients with PTV>700 cc and with CCI>=1, had a significantly higher risk of early death but longer-term survivors with PTV>700 cc are observed. The PTV and CCI should be considered in clinical decision making and used as stratification factors in future trials. PMID- 23357465 TI - Colorimetric and ratiometric near-infrared fluorescent cyanide chemodosimeter based on phenazine derivatives. AB - Two new near-infrared chemodosimeters for cyanide anion based on 5,10-dihexyl 5,10-dihydrophenazine were designed and synthesized. With dicyano-vinyl groups as the recognition site and electron-withdrawing groups on both sides, probe 1 exhibited an intramolecular charge transfer (ICT) absorption band at 545 nm and emission band at 730 nm, respectively, and thus showed an ICT block process and realized an "on-off" response after bilateral reaction with cyanide anions in CH3CN. Probe 2 utilized an unreactive formyl group instead of one of the two reactive dicyano-vinyl groups as the electron-withdrawing component. Due to the unilateral recognition process the ICT of probe 2 was redirected and lead to a remarkably colorimetric and ratiometric near-infrared (NIR) fluorescent response for cyanine. Both probes provided high sensitivity and selectivity with apparent response signals which can be observed by naked eyes, even in the copresence of various other interference anions. Optical spectroscopic techniques, NMR titration measurements, and density functional theory calculations were conducted to rationalize the sensing mechanisms of these two probes. PMID- 23357463 TI - Farletuzumab in lung cancer. AB - Folate is essential for proliferating cells and folate transport pathways and folate-dependent metabolic processes show promise as targets for anti-neoplastic therapy. Folate receptor alpha (FOLR1), a folate transporter, is an attractive target for anti-neoplastic therapy due to its high affinity for folate, restricted range of expression in normal tissue and differential over-expression in malignant tissue. FOLR1 is expressed in non-small cell lung cancer, with a higher expression in adenocarcinoma compared with squamous cell carcinoma. Farletuzumab is a monoclonal antibody targeting FOLR1 which in pre-clinical studies led to cytotoxicity of FOLR1-expressing cells, inhibited tumor growth in animal models and showed limited reactivity with normal tissue. In phase I/II trials, farletuzumab was well tolerated as a single-agent and in combination, without additive toxicity with chemotherapy. An ongoing phase II, double blind, placebo-controlled study is evaluating farletuzumab in patients with FOLR1 expressing metastatic adenocarcinoma of lung. PMID- 23357466 TI - Laparoscopic repair of post-cesarean section uterine scar defects diagnosed in nonpregnant women. AB - Herein we describe laparoscopic repair of uterine scar defects after cesarean section and pregnancy outcomes in a series of 13 patients. Defects and the residual anterior uterine wall were evaluated using ultrasound and magnetic resonance imaging (MRI). Patients' clinical symptoms were recorded. Pregnancy outcomes were investigated after laparoscopic surgical repair. Intervention included laparoscopic repair of the defect, including excision of fibrotic tissue and laparoscopic closure of the anterior uterine wall. The defect was completely corrected using this technique in all 13 patients. Four patients became pregnant spontaneously, 3 delivered via cesarean section between 38 and 39 weeks, and 1 is currently pregnant. Evaluation of uterine scar defects after cesarean section can be performed using ultrasound and MRI, and the defect can be repaired via laparoscopy, with reproducible postoperative anatomic and functional outcomes. PMID- 23357467 TI - Antipsychotic drugs in cocaine dependence: a systematic review and meta-analysis. AB - A systematic review and meta-analysis to evaluate the efficacy of antipsychotic drugs in subjects with cocaine dependence is presented. Twelve randomized, double blind, placebo-controlled clinical trials involving 681 patients were included. Five outcome measures were evaluated: number of dropouts, cocaine use assessed by means of urine benzoylecgonine tests, self-reported cocaine use, craving and Addiction Severity Index. On average, 48% of the enrolled participants were lost to follow-up. In comparison to placebo, antipsychotics did not significantly reduce cocaine use (WMD=0.01, 95%CI=-0.12 to 0.13) or improve retention in treatment (RR 0.91, 95%CI=0.82-1.02). Risperidone reduced slightly dropouts in comparison to placebo (RR=0.87; 95%CI=0.79-0.97). To date there is insufficient evidence to justify the use of antipsychotic drugs for cocaine dependence. PMID- 23357468 TI - Abstinence self-efficacy in people with severe mental illness. AB - To validate the Brief Situational Confidence Questionniare (BSCQ) with people diagnosed with severe mental illness (N=129), we examined the associations between abstinence self-efficacy (BSCQ) and alcohol consumption level (within the previous 6months), drug use, and problems related to substance use while controlling for key symptoms of major mental illness and motives for alcohol use (Drinking Motives Questionnaire). Regression models revealed that abstinence self efficacy was a significant predictor of all three substance use measures suggesting that, even when controlling for psychiatric symptoms and substance use motives, abstinence self-efficacy accounts for unique variance in alcohol use, drug use, and related problems. This study is limited by the cross sectional design and lack of structured diagnostic interviewing. PMID- 23357469 TI - All's well that ends well: alternative polyadenylation and its implications for stem cell biology. AB - Stem cell quiescence, activation, and differentiation are governed by a complex network of molecular pathways. There has been a growing recognition that posttranscriptional modifications, such as alternative polyadenylation (APA) of transcripts, play an important role in regulating gene expression and function. Recent analyses of stem cell populations have suggested that APA controls stem cell fate and behavior. Here, we review recent developments that have shaped our understanding of the control of stem cell behavior by APA and we highlight promising areas for future investigation. PMID- 23357471 TI - Social competition factor influences the neural response to rewards: an ERP study. AB - To study if the neural system responds the same or differently to the same rewards in different social competition conditions, event-related brain potentials (ERPs) were recorded as 18 participants engaged in two kinds of decision tasks. In the auction condition (the competition condition), participants were instructed to bid against their competitors and then informed the outcome (failing and gaining no money, or winning and gaining a certain amount of money); in the lottery condition (the neutral condition), subjects were asked to play a lottery against the computer and then informed the outcome (the same as in auction). Scalp ERPs revealed that, in the outcome phase, failing (rewards=0) in auction induced a larger late positive complex response (in the time window of 700-1200ms) than that in lottery; while winning (rewards>0) in lottery induced a larger late positive complex response (in the time window of 500-800ms) than that in auction. The present data suggest, when evaluating rewards, our neural systems care about not only rewards themselves, but also how the rewards have been obtained. PMID- 23357470 TI - Heroin-induced conditioned immunomodulation requires expression of IL-1beta in the dorsal hippocampus. AB - Opioid-associated environmental stimuli elicit robust immune-altering effects via stimulation of a neural circuitry that includes the basolateral amygdala and nucleus accumbens. These brain regions are known to have both direct and indirect connections with the hippocampus. Thus, the present study evaluated whether the dorsal hippocampus (DH), and more specifically interleukin-1 beta (IL-1beta) within the DH, is necessary for the expression of heroin-induced conditioned immunomodulation. Rats received five Pavlovian pairings of systemic heroin administration (1.0mg/kg, SC) with placement into a distinct environment (conditioned stimulus, CS). Six days after conditioning, a GABAA/B agonist cocktail or IL-1beta small interfering RNA (siRNA) was microinfused into the DH to inhibit neuronal activity or IL-1beta gene expression prior to CS or home cage exposure. Control animals received saline or negative control siRNA microinfusions. Furthermore, all rats received systemic administration of lipopolysaccharide (LPS) to stimulate proinflammatory nitric oxide production. CS exposure suppressed LPS-induced nitric oxide production relative to home cage exposure. Inactivation of, or IL-1beta silencing in, the DH disrupted the CS induced suppression of nitric oxide production relative to vehicle or negative control siRNA treatment. These results are the first to show a role for DH IL 1beta expression in heroin-conditioned suppression of a proinflammatory immune response. PMID- 23357472 TI - Mild hypothermia reduces activated caspase-3 up to 1 week after a focal cerebral ischemia induced by endothelin-1 in rats. AB - Hypothermia is a promising neuroprotective therapy that has been shown to reduce apoptosis after an ischemic insult. This study evaluated the effect of mild hypothermia on activated caspase-3 up to 1 week after the induction of a stroke. Endothelin-1 (Et-1) was used to elicit transient focal cerebral ischemia in rats. Twenty minutes after the ischemic insult, a state of mild hypothermia (33 degrees C) was imposed for a duration of 2h. The functional outcome, infarct volume and activated caspase-3 immunoreactivity (IR) were assessed at 8, 24 and 72h, and one week after the insult. During the experiment the cerebral blood flow (CBF) was measured via Laser Doppler Flowmetry. Hypothermia improved the neurological outcome at all of the time points studied compared to the normothermic group, and was associated with a reduction in infarct volume. In both groups, activated caspase-3 IR peaked 24h after the Et-1 induced insult and hypothermia significantly reduced the number of apoptotic cells at 8h, 24h and 1 week after ischemia. Furthermore, the hypothermic treatment did not affect the CBF in the Et 1 model. These findings indicate that in the Et-1 model, hypothermia exerts a long lasting effect on stroke-induced apoptosis. PMID- 23357473 TI - Contact lens prescribing pattern in India--2011. AB - PURPOSE: To understand the pattern of prescribing contact lenses (CL) among Indian practitioners. METHODS: Survey forms were sent to 257 practitioners across the country to collect information about their last 10 CL fits, location and type of practice, years of experience and educational qualification. A logistic regression analysis was performed to determine any association of various factors to the lens fitting pattern and chi-square test was used to compare proportions. The data were analyzed using SPSS v.16. RESULTS: CL fitting details from 227 practitioners were acquired representing a total of 2270 fits. The mean age of patients was 26.8+/-7.4 years and 67% of them were females. Ninety-eight percent of patients wore soft CL comprising 24% toric lenses. Ninety percent patients preferred disposable modality with 65% of these opting for monthly disposable lenses. Twenty-eight percent of the lenses dispensed were silicone hydrogel (SiH) lenses. Optometry practices located in metropolitan cities dispensed significantly higher numbers of disposable (p<0.001) and SiH lenses (p<0.001). Logistic regression analysis showed Fellowship of International Association of Contact Lens Educators (FIACLE) (OR: 13.79, 95% CI: 2.61-72.70), post graduate degree (OR: 3.87, 95% CI: 0.87-17.12) and years of experience were directly associated with fitting of advanced CL. CONCLUSION: The CL prescribing patterns in India elicited from this survey suggest the dominance (90%) of prescribing of disposable soft CL. Higher level of education, greater experience and a FIACLE status were significantly associated with advanced fitting. PMID- 23357474 TI - Response to "Kerasoft IC compared to Rose-K in the management of corneal ectasias". PMID- 23357475 TI - Calcium-dependent mechanisms involved in the modulation of tyrosine hydroxylase by endothelins in the olfactory bulb of normotensive rats. AB - Endothelins (ETs) are widely expressed in the olfactory bulb (OB) and other brain areas where they function as neuropeptides. In a previous study we reported that in the OB ET-1 and ET-3 participate in the long-term regulation of tyrosine hydroxylase (TH), the key enzyme in catecholamine biosynthesis. ETs stimulate TH activity by increasing total and phosphorylated enzyme levels as well as its mRNA. ET-1 response is mediated by a super high affinity ETA receptor coupled to adenylyl cyclase/protein kinase A and Ca(2+)/calmodulin-dependent protein kinase II (CaMK-II) activation whereas that of ET-3 through an atypical receptor coupled not only to these signaling pathways but also to phospholipase C (PLC)/protein kinase C pathway. Given the participation of PLC and CaMKII in the regulation of TH by ETs in the OB we sought to establish the contribution of calcium to ETs response. Present findings show that calcium released from ryanodine-sensitive channels and extracellular calcium were necessary to stimulate TH by ETs through CaMK-II. On the other hand, intracellular calcium released by the endoplasmic reticulum partially mediated ETs-evoked increase in TH mRNA but calcium influx and CaMK-II inhibition abolished the response. However calcium mechanisms were not involved in ETs-evoked increase in TH protein content. Present findings support that different sources of calcium contribute to the long-term modulation of TH activity and expression mediated by ETs in the rat OB. PMID- 23357476 TI - Motor behavior correlates with striatal [18F]-DOPA uptake in MPTP-lesioned primates. AB - The MPTP-lesioned monkey is considered as the best animal model for Parkinson's disease (PD). It has damage to dopaminergic cell groups and motor dysfunction similar to that seen in PD. Correlations between these two parameters have been described but there is a lack of formal statistical analyses on dopaminergic function as assessed by [(18)F]-F-DOPA PET and objectively rated motor behavior in longitudinal experiments. Eight rhesus monkeys received two MPTP infusions: first in one carotid artery, and after eight weeks in the other. Motor behavior and [(18)F]-F-DOPA uptake were measured at three stages: baseline, unilateral and bilateral. We correlated movement with radiotracer uptake across these three stages. MPTP caused the expected parkinsonian motor signs which were accompanied by lower radioactivity concentrations in the striatum. There were significant correlations between dopaminergic function and behavior. In conclusion, striatal [(18)F]-F-DOPA uptake correlates inversely with the severity of motor impairment in MPTP-lesioned non-human primates. Both behavioral scoring and [(18)F]-F-DOPA PET scans are useful and sensitive methods to monitor dopaminergic degeneration within subjects. PMID- 23357477 TI - Expression and activity of PARP family members in the hippocampus during systemic inflammation: their role in the regulation of prooxidative genes. AB - Poly(ADP-ribose)polymerase-1 (PARP-1) plays an important role in DNA repair processes during oxidative/genotoxic stress, in regulation of transcription factors and in cell death mechanisms. However, little is known about the physiopathological role of other PARP family members. In this study we analyzed, for the first time, expression of PARP family genes in the hippocampus of mice subjected to lipopolysaccharide (LPS)-evoked systemic inflammatory response (SIR). Moreover, the effect of SIR on PARP activity and on its role in gene expression was evaluated. Our data indicated that SIR enhances PARP-1, -3, -9, 12 and -14 gene expressions in mouse hippocampus. PARP activity in the hippocampus was also considerably elevated during SIR with a maximum value at 12h after LPS administration, indicating significant formation and accumulation of poly(ADP-ribose) (PAR) - this reaction's product. Concomitantly, higher expression of genes for inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-alpha and NADPH oxidase subunits occurred in the hippocampus during the first hours of SIR. The inhibitor of PARP, i.e. 3-aminobenzamide (3-AB; 30mg/kg b.w.), protected the hippocampal cells against PAR formation and expression of the gene for iNOS. However, PARP activity had no effect on the mRNA level of COX-2, TNF-alpha and NADPH oxidase in the hippocampus. Bioinformatic analysis predicted that interaction between PARP/PAR and 41 transcription factors may be important for regulation of expression of 139 genes from the group of 262 that changed expression in the hippocampus during SIR. Summarizing, enhancement of gene expression and activity of PARP family members by SIR could lead, through modification of the protein poly(ADP-ribosylation) process, to changes in the proteins' activity. A higher level of PAR and PARP/PAR protein interaction may affect the functioning of several transcription factors. PARP activity plays a role in regulation of expression of iNOS, the main enzyme responsible for oxidative/nitrosative stress in SIR. PMID- 23357478 TI - Extracellular cyclic GMP and its derivatives GMP and guanosine protect from oxidative glutamate toxicity. AB - Cell death in response to oxidative stress plays a role in a variety of neurodegenerative diseases and can be studied in detail in the neuronal cell line HT22, where extracellular glutamate causes glutathione depletion by inhibition of the glutamate/cystine antiporter system xc(-), elevation of reactive oxygen species and eventually programmed cell death caused by cytotoxic calcium influx. Using this paradigm, we screened 54 putative extracellular peptide or small molecule ligands for effects on cell death and identified extracellular cyclic guanosine monophosphate (cGMP) as a protective substance. Extracellular cGMP was protective, whereas the cell-permeable cGMP analog 8-pCPT-cGMP or the inhibition of cGMP degradation by phosphodiesterases was toxic. Interestingly, metabolites GMP and guanosine were even more protective than cGMP and the inhibition of the conversion of GMP to guanosine attenuated its effect, suggesting that GMP offers protection through its conversion to guanosine. Guanosine increased system xc(-) activity and cellular glutathione levels in the presence of glutamate, which can be explained by transcriptional upregulation of xCT, the functional subunit of system xc(-). However, guanosine also provided protection when added late in the cell death cascade and significantly reduced the number of calcium peaking cells, which was most likely not mediated by transcriptional mechanisms. We observed no changes in the classical protective pathways such as phosphorylation of Akt, ERK1/2 or induction of Nrf2 or ATF4. We conclude that extracellular guanosine protects against endogenous oxidative stress by two probably independent mechanisms involving system xc(-) induction and inhibition of cytotoxic calcium influx. PMID- 23357479 TI - Bis(propyl)-cognitin protects against glutamate-induced neuro-excitotoxicity via concurrent regulation of NO, MAPK/ERK and PI3-K/Akt/GSK3beta pathways. AB - We have previously reported that bis(propyl)-cognitin (B3C), similar to memantine (MEM), is an uncompetitive N-methyl-d-aspartate receptor antagonist with fast off rate property. In the current study, we further demonstrated that in primary cultures of rat cerebellar granule neurons (CGNs), 2h pretreatment of B3C (IC50, 0.45MUM) prevented glutamate-induced excitotoxicity 10 times more potently than memantine (IC50, 4.58 MUM), as evidenced by cell viability and lactate dehydrogenase release assays. Additionally, B3C pretreatment could inhibit the increase of intracellular nitric oxide (NO) and the activation of phosphorylated ERK, and reverse the suppression of phosphorylated Akt and GSK3beta caused by glutamate. Furthermore, the neuroprotection of B3C was abolished by phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002. Meanwhile, pharmacological inhibition showed that neither the single specific inhibitors of nitric oxide synthase (L-NMMA), MEK1/2 (U0126) and GSK3beta (SB415286 and LiCl) nor the combinations of any two of them could fully protect against glutamate induced apoptosis. However, the co-application of these three inhibitors produced nearly 100% inhibition of glutamate-induced apoptosis. These results taken together suggest that B3C elicits neuroprotection against glutamate-induced neurotoxicity in CGNs via concurrent inhibition of NO, MAPK/ERK pathways and activation of PI3-K/Akt/GSK3beta pathway. Combining these and our previous publications, it is conjectured that the dimer might be an ideal candidate drug in delaying the course of neurodegeneration related with Alzheimer's disease. PMID- 23357480 TI - Rapamycin decreases tau phosphorylation at Ser214 through regulation of cAMP dependent kinase. AB - Preventing or reducing tau hyperphosphorylation is considered to be a therapeutic strategy in the treatment of Alzheimer's disease (AD). Rapamycin may be a potential therapeutic agent for AD, because the rapamycin-induced autophagy may enhance the clearance of the hyperphosphorylated tau. However, recent rodent studies show that the protective effect of rapamycin may not be limited in the autophagic clearance of the hyperphosphorylated tau. Because some tau-related kinases are targets of the mammalian target of rapamycin (mTOR), we assume that rapamycin may regulate tau phosphorylation by regulating these kinases. Our results showed that in human neuroblastoma SH-SY5Y cells, treatment with rapamycin induced phosphorylation of the type IIalpha regulatory (RIIalpha) subunit of cAMP-dependent kinase (PKA). Rapamycin also induced nuclear translocation of the catalytic subunits (Cat) of PKA and decreases in tau phosphorylation at Ser214 (pS214). The above effects of rapamycin were prevented by pretreatment with the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor U0126. In addition, these effects of rapamycin might not depend on the level of tau expression, because similar results were obtained in both the non-tau-expressing wild type human embryonic kidney 293 (HEK293) cells and HEK293 cells stably transfected with the longest isoform of recombinant human tau (tau441; HEK293/tau441). These findings suggest that rapamycin decreases pS214 via regulation of PKA. Because tau phosphorylation at Ser214 may prime tau for further phosphorylation by other kinases, our findings provide a novel possible mechanism by which rapamycin reduces or prevents tau hyperphosphorylation. PMID- 23357481 TI - Effects of the neoclerodane Hardwickiic acid on the presynaptic opioid receptors which modulate noradrenaline and dopamine release in mouse central nervous system. AB - We have comparatively investigated the effects of Hardwickiic acid and Salvinorin A on the K(+)-evoked overflow of [(3)H]noradrenaline ([(3)H]NA) and [(3)H]dopamine ([(3)H]DA) from mouse hippocampal and striatal nerve terminals, respectively. The K(+)-evoked overflow of [(3)H]DA was inhibited in presence of Salvinorin A (100 nM) but not in presence of Hardwickiic acid (100 nM). Hardwickiic acid (100 nM) mimicked Salvinorin A (100 nM) in facilitating K(+) evoked hippocampal [(3)H]NA overflow and the two compounds were almost equipotent. Facilitation of [(3)H]NA overflow caused by 100 nM Hardwickiic acid was prevented by the kappa-opioid receptor (KOR) antagonist norbinaltorphimine (norBNI, 100 nM) and by the selective delta-opioid receptor (DOR) antagonist naltrindole (100 nM), but was not altered by 100 nM D-Phe-Cys-Tyr-D-Trp-Arg-Thr Pen-Thr-NH2 (CTAP), a selective MU-opioid receptor (MOR) antagonist. We conclude that Hardwickiic acid modulates hippocampal [(3)H]NA overflow evoked by a mild depolarizing stimulus by acting at presynaptic opioid receptor subtypes. PMID- 23357482 TI - The role of mitochondrial dehydrogenases in the generation of oxidative stress. AB - In addition to complexes in the respiratory chain, few dehydrogenases playing key roles in the physiological metabolism in neurons, are able to generate reactive oxygen species (ROS) in mitochondria. One of them is the Krebs cycle enzyme, alpha-ketoglutarate dehydrogenase (alpha-KGDH), which is capable of producing superoxide and hydrogen peroxide by the E3 subunit of the enzyme regulated by changes in the NADH/NAD(+) ratio. Mutations in the E3 subunit known to be related to diseases in humans were shown to have increased ROS-forming ability. alpha Glycerophosphate dehydrogenase (alpha-GPDH) located on the outer surface of the inner membrane can also generate ROS, which is stimulated by Ca(2+). ROS production by alpha-GPDH is unique as it does not require Ca(2+) uptake and it is observed in respiring as well as damaged, bioenergetically incompetent mitochondria. The possible role of ROS generation by these dehydrogenases in brain pathology is discussed in this review. PMID- 23357483 TI - Altered Kir and gap junction channels in temporal lobe epilepsy. AB - Since astrocytes may sense and respond to neuronal activity these cells are now considered important players in brain signaling. Astrocytes form large gap junction coupled syncytia allowing them to clear the extracellular space from K+ and neurotransmitters accumulating during neuronal activity, and redistribute it to sites of lower extracellular concentrations. Increasing evidence suggests a crucial role for dysfunctional astrocytes in the etiology of epilepsy. Notably, alterations in expression, localization and function of astroglial K+ channels as well as impaired K+ buffering was observed in specimens from patients with pharmacoresistant temporal lobe epilepsy and in chronic epilepsy models. Altered astroglial gap junction coupling has also been reported in epileptic tissue which, however, seems to play a dual role: (i) junctional coupling counteracts hyperactivity by facilitating clearance of elevated extracellular K+ and glutamate while (ii) it also provides a pathway for energetic substrates and fuels neuronal activity. Dysfunctional astrocytes should be considered promising targets for new therapeutic strategies. PMID- 23357484 TI - Vascular peroxidase 1: a novel enzyme in promoting oxidative stress in cardiovascular system. AB - Vascular peroxidase 1 (VPO1) is a recently identified novel family member of peroxidases in cardiovascular system. As an enzyme that is downstream of NADPH oxidases (NOX), VPO1 functions to utilize NOX - derived hydrogen peroxide (H2O2) to produce hypochlorous acid (HOCl), a strong oxidant which is believed to greatly promote oxidative stress. Under multiple conditions, NOX is activated concomitantly with an increase in superoxide anion (O2(.-)) and H2O2 production. The latter is converted to HOCl by VPO1. In this process (O2(.-) -> H2O2 -> HOCl), the oxidant reactivities of reactive oxygen species (ROS) are significantly increased and therefore the oxidative stress is dramatically amplified. Several lines of evidence suggest that the NOX/VPO1 pathway - mediated oxidative stress plays an important role in myocardial ischemia-reperfusion injury, endothelial cell apoptosis and/or smooth muscle cell proliferation. In addition, VPO1 can be secreted into the extracellular space to participate in extracellular matrix formation, suggesting that VPO1 may also play a role in cardiovascular remodeling (such as fibrosis). This function is independent of the peroxidase activity of VPO1. PMID- 23357485 TI - Cauda equina syndrome caused by lumbosacral epidural lipomatosis. A case report. PMID- 23357486 TI - Simplified behaviors from increased heterogeneity: I. 2-D uranium transport experiments at the decimeter scale. AB - Intermediate scale tank studies were conducted to examine the effects of physical heterogeneity of aquifer material on uranium desorption and subsequent transport in order to bridge the scaling gap between bench and field scale systems. Uranium contaminated sediment from a former uranium mill field site was packed into two 2 D tanks with internal dimensions of 2.44*1.22*0.076 m (tank 1) and 2.44*0.61*0.076 m (tank 2). Tank 1 was packed in a physically homogenous manner, and tank 2 was packed with long lenses of high and low conductivities resulting in different flow fields within the tanks. Chemical gradients within the flow domain were altered by temporal changes in influent water chemistry. The uranium source was desorption from the sediment. Despite the physical differences in the flow fields, there were minimal differences in global uranium leaching behavior between the two tanks. The dominant uranium species in both tanks over time and space was Ca2UO2(CO3)3(0). However, the uranium/alkalinity relationships varied as a function of time in tank 1 and were independent of time in tank 2. After planned stop-flow events, small, short-lived rebounds were observed in tank 1 while no rebound of uranium concentrations was observed in tank 2. Despite appearing to be in local equilibrium with respect to uranium desorption, a previously derived surface complexation model was insufficient to describe uranium partitioning within the flow domain. This is the first in a pair of papers; the companion paper presents an intermediate scale 3-D tank experiment and inter-tank comparisons. For these systems, physical heterogeneity at or above the decimeter scale does not affect global scale uranium desorption and transport. Instead, uranium fluxes are controlled by chemistry dependent desorption patterns induced by changing the influent ionic composition. PMID- 23357487 TI - Statins are associated with reduced risk of esophageal cancer, particularly in patients with Barrett's esophagus: a systematic review and meta-analysis. AB - BACKGROUND & AIMS: The incidence of esophageal cancer is increasing in the United States, especially among patients with Barrett's esophagus (BE). Statins might prevent this cancer. We performed a systematic review with a meta-analysis of studies that evaluated the effect of statins on the risk of esophageal cancer. METHODS: We conducted a systematic search of Medline, Embase, and Web of Science through August 2012. Studies were included if they evaluated exposure to statins, reported the development of esophageal cancer, and reported relative risks or odds ratios (OR), or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CI) were calculated using the random-effects model. The analysis included 13 studies (including a post hoc analysis of 22 randomized controlled trials) reporting 9285 cases of esophageal cancer among 1,132,969 patients. RESULTS: A meta-analysis of the studies showed a significant (28%) reduction in the risk of esophageal cancer among patients who took statins (adjusted OR, 0.72; 95% CI, 0.60-0.86), although there was considerable heterogeneity among studies. In analyzing a subset of patients known to have BE (5 studies, 312 esophageal adenocarcinomas [EAC] developed in 2125 patients), statins were associated with a significant (41%) decrease in the risk of EAC, after adjusting for potential confounders (adjusted OR, 0.59; 95% CI, 0.45-0.78) with consistent results among all studies. The number needed to treat with statins to prevent 1 case of EAC in patients with BE was 389. CONCLUSIONS: Based on meta-analysis of observational studies, statin use may be associated with lower risk of esophageal cancer, particularly risk of EAC in patients with BE. PMID- 23357488 TI - A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn's disease who lose responsiveness to infliximab. AB - BACKGROUND & AIMS: Patients with Crohn's disease who become unresponsive to therapy with tumor necrosis factor antagonists are managed initially with either empiric dose escalation or testing-based strategies. The comparative cost effectiveness of these 2 strategies is unknown. We investigated whether a testing based strategy is more cost effective than an empiric dose-escalation strategy. METHODS: A decision analytic model that simulated 2 cohorts of patients with Crohn's disease compared outcomes for the 2 strategies over a 1-year time period. The incremental cost-effectiveness ratio of the empiric strategy was expressed as cost per quality-adjusted life-year (QALY) gained, compared with the testing based strategy. We performed 1-way, probabilistic, and prespecified secondary analyses. RESULTS: The testing strategy yielded similar QALYs compared with the empiric strategy (0.801 vs 0.800, respectively) but was less expensive ($31,870 vs $37,266, respectively). In sensitivity analyses, the incremental cost effectiveness ratio of the empiric strategy ranged from $500,000 to more than $5 million per QALY gained. Similar rates of remission (63% vs 66%) and response (28% vs 26%) were achieved through differential use of available interventions. The testing-based strategy resulted in a higher percentage of surgeries (48% vs 34%) and lower percentage use of high-dose biological therapy (41% vs 54%). CONCLUSIONS: A testing-based strategy is a cost-effective alternative to the current strategy of empiric dose escalation for managing patients with Crohn's disease who have lost responsiveness to infliximab. The basis for this difference is lower cost at similar outcomes. PMID- 23357489 TI - Combined endoscopy, aspiration, and biopsy analysis for identifying infectious colitis in patients with ileocecal ulcers. AB - BACKGROUND & AIMS: The ileocecal area is commonly involved in infection and inflammatory colonic diseases, but differential diagnosis can be difficult. We identified definitive endoscopic findings and a sample collection method for diagnosing infectious colitis. METHODS: In a retrospective study, we analyzed data on 128 patients with ileocecal ulcer who underwent colonoscopy from 2007 2011 at the National Center for Global Health and Medicine in Tokyo, Japan. We collected information on location, size, number, and distinctive endoscopic findings and estimated diagnostic odds ratios (ORs). The sensitivities of microscopy, culture, polymerase chain reaction, and histologic methods in identifying patients with infection were compared with those of standard stool, endoscopic aspirated intestinal fluid, or biopsy analyses. RESULTS: Of the 128 patients, 100 had infections, and 28 had Crohn's disease, Behcet's disease, or other inflammatory diseases. Predictive endoscopic findings were as follows: for amebiasis of the cecum (OR, 17.8), with exudates (OR, 13.9) and round-shaped ulcer (OR, 5.77); for tuberculosis (TB) with transverse-shaped ulcer (OR, 175), scar (OR, 34.6), linear-shaped ulcer (OR, 23.9), or >=10 mm (OR, 14.0); for cytomegalovirus with round-shaped ulcer (OR, 4.09); and for Campylobacter with cecal valve lesion (OR, 58.3) or >=10 mm (OR, 10.4). The sensitivity of endoscopic sample collection was significantly higher than that of standard stool sample collection for the diagnosis of amebiasis, TB, non-TB mycobacteria, and other bacteria (P < .05). The methods that detected infection with the highest levels of sensitivity were biopsy with histology for amebiasis, biopsy with culture for TB, biopsy with polymerase chain reaction for cytomegalovirus, and aspiration of intestinal fluid with culture for Campylobacter. CONCLUSIONS: Combining results from endoscopic analysis with appropriate sample collection and pathogen detection methods enables infectious colitis to be differentiated from other noninfectious colonic diseases. PMID- 23357491 TI - A positive diagnostic strategy is noninferior to a strategy of exclusion for patients with irritable bowel syndrome. AB - BACKGROUND & AIMS: Guidelines recommend a positive strategy based on symptom criteria to diagnose patients with irritable bowel syndrome (IBS). We conducted a randomized noninferiority trial to determine whether a positive diagnostic strategy is noninferior to a strategy of exclusion, with regard to patients' health-related quality of life (HRQOL). METHODS: We studied 302 patients (18-50 years old) from primary care who were suspected of having IBS and referred by general practitioners. Patients who fulfilled the Rome III criteria for IBS with no alarm signals were randomly assigned to groups assessed by a strategy of exclusion (analyses of blood, stool samples for intestinal parasites, and sigmoidoscopies with biopsies) or a positive strategy (analyses of blood cell count and C-reactive protein). Patients were followed for 1 year. The primary end point was difference in change of HRQOL from baseline to 1 year between groups (on the basis of the Short Form 36 health survey, physical component summary, and noninferiority margin of 3 points). Secondary outcomes were change in gastrointestinal symptoms, satisfaction with management, and use of resources. Findings of diagnostic misclassification were registered. RESULTS: A positive strategy was noninferior to a strategy of exclusion (difference, 0.64; 95% confidence interval, -2.74 to 1.45). The positive diagnostic strategy had lower direct costs. Each approach had similar effects on symptoms, satisfaction, and subsequent use of health resources. No cases of inflammatory bowel disease, colorectal cancer, or celiac disease were found. CONCLUSIONS: In diagnosing IBS in primary care, use of a positive diagnostic strategy is noninferior to using a strategy of exclusion with regard to the patients' HRQOL. Our findings support the current guideline recommendations. PMID- 23357490 TI - Cost-effectiveness of universal serologic screening to prevent nontraumatic hip and vertebral fractures in patients with celiac disease. AB - BACKGROUND & AIMS: Patients with asymptomatic or poorly managed celiac disease can experience bone loss, placing them at risk for hip and vertebral fractures. We analyzed the cost-effectiveness of universal serologic screening (USS) vs symptomatic at-risk screening (SAS) strategies for celiac disease because of the risk of nontraumatic hip and vertebral fractures if untreated or undiagnosed. METHODS: We developed a lifetime Markov model of the screening strategies, each with male or female cohorts of 1000 patients who were 12 years old when screening began. We screened serum samples for levels of immunoglobulin A, compared with tissue transglutaminase and total immunoglobulin A, and findings were confirmed by mucosal biopsy. Transition probabilities and quality of life estimates were obtained from the literature. We used generalizable cost estimates and Medicare reimbursement rates and ran deterministic and probabilistic sensitivity analyses. RESULTS: For men, the average lifetime costs were $8532 and $8472 for USS and SAS strategies, respectively, corresponding to average quality-adjusted life year gains of 25.511 and 25.515. Similarly for women, costs were $11,383 and $11,328 for USS and SAS strategies, respectively, corresponding to quality-adjusted life year gains of 25.74 and 25.75. Compared with the current standard of care (SAS), USS produced higher average lifetime costs and lower quality of life for each sex. Deterministic and probabilistic sensitivity analyses showed that the model was robust to realistic changes in all the variables, making USS cost-ineffective on the basis of these outcomes. CONCLUSIONS: USS and SAS are similar in lifetime costs and quality of life, although the current SAS strategy was overall more cost-effective in preventing bone loss and fractures among patients with undiagnosed or subclinical disease. On the basis of best available supportive evidence, it is more cost-effective to maintain the standard celiac screening practices, although future robust population-based evidence in other health outcomes could be leveraged to reevaluate current screening guidelines. PMID- 23357492 TI - Efficacy, safety, and long-term results of endoscopic treatment for early stage adenocarcinoma of the esophagus with low-risk sm1 invasion. AB - BACKGROUND & AIMS: Patients with early-stage mucosal (T1a) esophageal adenocarcinoma (EAC) are increasingly treated by endoscopic resection. EACs limited to the upper third of the submucosa (pT1b sm1) could also be treated by endoscopy. We assessed the efficacy, safety, and long-term effects of endoscopic therapy for these patients. METHODS: We analyzed data from 66 patients with sm1 low-risk lesions (macroscopically polypoid or flat, with a histologic pattern of sm1 invasion, good-to-moderate differentiation [G1/2], and no invasion into lymph vessels or veins) treated by endoscopic therapy at the HSK Hospital Wiesbaden from 1996 through 2010. The efficacy of endoscopic therapy was assessed on the basis of rates of complete endoluminal remission (CER), metachronous neoplasia, lymph node events, and long-term remission (LTR). Safety was assessed on the basis of rate of complications. RESULTS: Remissions were assessed in 61 of the 66 patients; 53 of the 61 achieved CER (87%). Of patients with small focal neoplasias <=2 cm, 97% achieved CER (for those with tumors >=2 cm, 77%; P = .026). Metachronous neoplasias were observed in 10 of 53 patients (19%; 9 of the 10 underwent repeat endoscopic resection). One patient developed a lymph node metastasis (1.9%). Fifty-one patients achieved LTR (84%); 90% of those with focal lesions <=2 cm achieved LTR after a mean follow-up period of 47 +/- 29.1 months (range, 8-120 months). No tumor-associated deaths were observed, and the estimated 5-year survival rate was 84%. The rate of major complications from endoscopic resection was 1.5%, and no patients died. CONCLUSIONS: Endoscopic therapy appears to be a good alternative to esophagectomy for patients with pT1b sm1 EAC, on the basis of macroscopic and histologic analyses. The risk of developing lymph node metastases after endoscopic resection for sm1 EAC is lower than the risk of surgery. PMID- 23357494 TI - Feasibility of using wire-guided needle-knife electrocautery for refractory biliary and pancreatic strictures. AB - BACKGROUND: Endoscopic management of biliary or pancreatic strictures by stent insertion is well established. However, some high-grade strictures are refractory to dilation and stent placement with conventional methods. OBJECTIVE: To evaluate the safety and efficacy of the wire-guided electrotomy technique in dilating stiff biliary and/or pancreatic stenoses when ordinary methods failed. DESIGN: Retrospective analysis of a prospective database. SETTING: Tertiary referral university hospital. PATIENTS: This study involved 279 patients with biliary or pancreatic strictures who underwent ERCP for stenting. INTERVENTION: After conventional dilation failed, wire-guided needle-knife electrocautery was attempted to facilitate insertion of the dilating devices and eventually endoprosthesis. MAIN OUTCOME MEASUREMENTS: The successful treatment and drainage of biliary or pancreatic strictures. RESULTS: With wire-guided needle-knife cauterization, the success rate of stricture dilatation increased from 95.7% (267 of 279 patients) to 98.9% (276 of 279 patients). Dilation of stenoses was successful in 9 of 10 patients (90%) by using electrocautery with the wire-guided needle-knife technique. Postprocedure adverse events included self-limited bleeding, mild acute pancreatitis, hyperamylasemia, cholangitis, and biliary perforation. No procedure-related death occurred. LIMITATIONS: Retrospective, single-center study and small sample size. CONCLUSIONS: Wire-guided needle-knife electroincision appears to be effective for traversing refractory biliary or pancreatic strictures and can be considered as an alternative approach to conventional methods. However, the safety of such a technique needs to be further evaluated. PMID- 23357493 TI - Chemoembolization and radioembolization for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) continues to represent a major worldwide problem. Although treatments such as resection, transplantation, and ablation may provide a chance for a cure, these options are often precluded because of advanced disease presentation. Palliative treatments include transarterial embolization and systemic therapies. This review will summarize the state of the science for embolic therapies in HCC (conventional and drug-eluting chemoembolization, radioembolization) as well as discuss related topics including HCC staging, assessment of response, and ongoing clinical trials. PMID- 23357495 TI - End-stage renal disease is associated with worse outcomes in hospitalized patients with peptic ulcer bleeding. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) are at increased risk of peptic ulcer bleeding (PUB). To our knowledge, there are no population-based studies of the impact of ESRD on PUB. OBJECTIVE: To determine nationwide impact of ESRD on outcomes of hospitalized patients with PUB. DESIGN: Cross-sectional study. SETTING: Hospitals from a 2008 Nationwide Inpatient Sample. PATIENTS: We used the International Classification of Diseases, the 9th Revision, Clinical Modification codes to identify patients who had a primary discharge diagnosis of PUB. MAIN OUTCOME MEASUREMENT: In-hospital mortality, length of stay, and hospitalization charges. INTERVENTIONS: Comparison of PUB outcomes in patients with and without ESRD. RESULTS: Of a total of 102,525 discharged patients with PUB, 3272 had a diagnosis of both PUB and ESRD, whereas 99,253 had a diagnosis of PUB alone without ESRD. The mortality of ESRD patients with PUB was significantly higher than that of the control group without ESRD (4.8% vs 1.9%, P < .0001). On multivariate analysis, patients with PUB and ESRD had greater mortality than patients admitted to the hospital with PUB alone (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI], 1.3-3.4), were more likely to undergo surgery (aOR 1.4; 95% CI, 1.2-1.7), and had a longer hospital stay (aOR 2.1; 95% CI, 1.2-2.9). These patients also incurred higher hospitalization charges ($54,668 vs $32,869, P < .01) compared with patients with PUB alone. LIMITATIONS: Administrative data set. CONCLUSIONS: ESRD is associated with a significant health care burden in hospitalized patients with PUB. The presence of ESRD contributes to a higher mortality rate, longer hospital stay, and increased need for surgery. PMID- 23357496 TI - The AIMS65 score compared with the Glasgow-Blatchford score in predicting outcomes in upper GI bleeding. AB - INTRODUCTION: We previously derived and validated the AIMS65 score, a mortality prognostic scale for upper GI bleeding (UGIB). OBJECTIVE: To validate the AIMS65 score in a different patient population and compare it with the Glasgow Blatchford risk score (GBRS). DESIGN: Retrospective cohort study. PATIENTS: Adults with a primary diagnosis of UGIB. MAIN OUTCOME MEASUREMENTS: PRIMARY OUTCOME: inpatient mortality. SECONDARY OUTCOMES: composite clinical endpoint of inpatient mortality, rebleeding, and endoscopic, radiologic or surgical intervention; blood transfusion; intensive care unit admission; rebleeding; length of stay; timing of endoscopy. The area under the receiver-operating characteristic curve (AUROC) was calculated for each score. RESULTS: Of the 278 study patients, 6.5% died and 35% experienced the composite clinical endpoint. The AIMS65 score was superior in predicting inpatient mortality (AUROC, 0.93 vs 0.68; P < .001), whereas the GBRS was superior in predicting blood transfusions (AUROC, 0.85 vs 0.65; P < .01) The 2 scores were similar in predicting the composite clinical endpoint (AUROC, 0.62 vs 0.68; P = .13) as well as the secondary outcomes. A GBRS of 10 and 12 or more maximized the sum of the sensitivity and specificity for inpatient mortality and rebleeding, respectively. The cutoff was 2 or more for the AIMS65 score for both outcomes. LIMITATIONS: Retrospective, single-center study. CONCLUSION: The AIMS65 score is superior to the GBRS in predicting inpatient mortality from UGIB, whereas the GBRS is superior for predicting blood transfusion. Both scores are similar in predicting the composite clinical endpoint and other outcomes in clinical care and resource use. PMID- 23357497 TI - Breaks in the wall: increased gaps in the intestinal epithelium of irritable bowel syndrome patients identified by confocal laser endomicroscopy (with videos). AB - BACKGROUND: Altered intestinal permeability and mucosal inflammation have been reported in irritable bowel syndrome (IBS) patients. Increased cell extrusion in the epithelium as measured by epithelial gaps may be associated with barrier dysfunction and may lead to mucosal inflammation. Confocal laser endomicroscopy can be used to identify and quantitate epithelial gaps in the small intestine. OBJECTIVE: To determine the epithelial gap density in IBS and healthy control patients. DESIGN: Prospective, controlled cohort study. SETTING: A tertiary referral center. PATIENTS: In IBS and control patients undergoing routine colonoscopy, probe-based confocal laser endomicroscopy was used to image the terminal ileum. MAIN OUTCOME MEASUREMENTS: The primary outcome was the density of epithelial gaps (gaps/cells counted) in adequately imaged villi using pCLE. Images were reviewed by 2 blinded reviewers. RESULTS: We recruited 18 healthy controls and 16 IBS patients. The median epithelial gap densities for control and IBS patients were 6 and 32 gaps per 1000 cells, respectively (P < .001). There was a trend toward higher gap density in female (P = .07) and younger (rho = 0.43, P = .07) patients. Using 3% (90% of the control population) as the cutoff for abnormal gap density, we found the diagnostic accuracy for IBS to be as follows: 62% sensitivity, 89% specificity, 83% positive predictive value, and 73% negative predictive value. LIMITATIONS: A single-center study, small number of patients. CONCLUSIONS: IBS patients have significantly more epithelial gaps in their small intestine compared with healthy controls, which suggests that increased epithelial cell extrusion may be a cause of altered intestinal permeability observed in IBS. PMID- 23357498 TI - A case of Zollinger-Ellison syndrome diagnosed by duodenal ulcer perforation into the gallbladder. PMID- 23357499 TI - Location of bile leak predicts the success of ERCP performed for postoperative bile leaks. AB - BACKGROUND: ERCP is effective for treating a bile leak (BL) after cholecystectomy (CCY), but few data exist on its effectiveness after hepatobiliary surgery (HBS). OBJECTIVE: To determine the effectiveness of ERCP for treating BLs after HBS compared with BLs after cholecystectomy and to identify factors associated with treatment success. DESIGN: Retrospective cohort. SETTING: Academic tertiary-care referral center. PATIENTS: Patients referred from 2001 to 2009 for ERCP treatment of BL after cholecystectomy or HBS. INTERVENTIONS: ERCP. MAIN OUTCOME MEASUREMENTS: Resolution of BL after a single ERCP. RESULTS: A total of 223 patients were identified and 46 were excluded. Fifty underwent ERCP for treatment of BL after HBS and 127 after CCY. A single ERCP was successful at resolving BL in 89% of patients. Failure occurred in 7 HBS patients (14%) and 12 CCY patients (9%) (P = .379). After multiple ERCPs, success improved to 95% of the CCY group and 86% of the HBS group (P = .033). HBS patients underwent 30% more ERCPs (P = .049). ERCP was 3.3 times more likely to be successful in patients with cystic duct or duct of Luschka BLs (P = .028). Patients undergoing biliary stent placement were significantly more likely to have successful outcomes (odds ratio 71.0, P < .001). Surgical history or biliary sphincterotomy did not affect outcome. Odds of treatment failure were 3.5 times higher for each additional ERCP performed (P < .001). LIMITATIONS: Single-center, retrospective study. CONCLUSIONS: ERCP is effective for treating postoperative BLs. Location of a BL and placement of a biliary stent are the best predictors of endoscopic treatment success. PMID- 23357500 TI - The DNA methylomes of serous borderline tumors reveal subgroups with malignant- or benign-like profiles. AB - Serous borderline tumors (SBOTs) are a challenging group of ovarian tumors positioned between benign and malignant disease. We have profiled the DNA methylomes of 12 low-grade serous carcinomas (LGSCs), 19 SBOTs, and 16 benign serous tumors (BSTs) across 27,578 CpG sites to further characterize the epigenomic relationship between these subtypes of ovarian tumors. Unsupervised hierarchical clustering of DNA methylation levels showed that LGSCs differ distinctly from BSTs, but not from SBOTs. Gene ontology analysis of genes showing differential methylation at linked CpG sites between LGSCs and BSTs revealed significant enrichment of gene groups associated with cell adhesion, cell-cell signaling, and the extracellular region, consistent with a more invasive phenotype of LGSCs compared with BSTs. Consensus clustering highlighted differences between SBOT methylomes and returned subgroups with malignant- or benign-like methylation profiles. Furthermore, a two-loci DNA methylation signature can distinguish between these SBOT subgroups with benign- and malignant like methylation characteristics. Our findings indicate striking similarities between SBOT and LGSC methylomes, supporting a common origin and the view that LGSC may arise from SBOT. A subgroup of SBOTs can be classified into tumors with a benign- or a malignant-like methylation profile that may help in identifying tumors more likely to progress into LGSCs. PMID- 23357502 TI - Entamoeba histolytica exacerbates epithelial tight junction permeability and proinflammatory responses in Muc2(-/-) mice. AB - Human mucin-2 (MUC-2) is the first line of innate host defense in preventing pathogen-induced epithelial injury. Entamoeba histolytica (Eh) colonizes the mucus layer by binding of the parasite's surface galactose lectin to galactose and N-acetyl-d-galactosamine residues on colonic MUC-2, preventing parasite contact-dependent cytolysis of epithelial cells. We quantified early innate responses to Eh in wild-type and MUC-2-deficient mice (Muc2(-/-)) using closed colonic loops. Eh infection in wild-type but not Muc2(-/-) mice induced a time dependent increase in (3)H-labeled mucin and nonmucin glycoprotein secretions. Immunohistochemical staining revealed intense MUC-2 secretion, which formed a thick, protective mucus plug overlying the surface epithelium, entrapping Eh. In Muc2(-/-) mice, Eh induced a pronounced time-dependent secretory exudate with increased gross pathology scores and serum albumin leakage. Colonic pathology, secretory responses, and increased proinflammatory cytokine secretions of TNF alpha, IFN-gamma, and IL-13 correlated with altered expression of the tight junction proteins claudin-2, occludin, and ZO-1. We identified the putative Eh virulence factor that elicits the proinflammatory responses and alters tight junction permeability as Eh cysteine protease A5 (EhCP-A5). The present findings demonstrate that colonic mucins confer both luminal and epithelial barrier functions and that, in the absence of MUC-2, mice are more susceptible to Eh induced secretory and proinflammatory responses mediated by EhCP-A5. PMID- 23357503 TI - Single nucleotide polymorphism array analysis of uveal melanomas reveals that amplification of CNKSR3 is correlated with improved patient survival. AB - Metastatic death from uveal melanoma occurs almost exclusively with tumors showing monosomy of chromosome 3. However, approximately 5% of patients with a disomy 3 uveal melanoma develop metastases, and a further 5% of monosomy 3 uveal melanoma patients exhibit disease-free survival for >5 years. In the present study, whole-genome microarrays were used to interrogate four clinically well defined subgroups of uveal melanoma: i) disomy 3 uveal melanoma with long-term survival; ii) metastasizing monosomy 3 uveal melanoma; iii) metastasizing disomy 3 uveal melanoma; and iv) monosomy 3 uveal melanoma with long-term survival. Cox regression and Kaplan-Meier survival analysis identified that amplification of the CNKSR3 gene (log-rank, P = 0.022) with an associated increase in its protein expression (log-rank, P = 0.011) correlated with longer patient survival. Although little is known about CNKSR3, the correlation of protein expression with increased survival suggests a biological function in uveal melanoma, possibly working to limit metastatic progression of monosomy 3 uveal melanoma cells. PMID- 23357504 TI - [Cholecalciferol or calcidiol?]. PMID- 23357505 TI - Organic functionalization of 3C-SiC surfaces. AB - We demonstrate the functionalization of n-type (100) and (111) 3C-SiC surfaces with organosilanes. Self-assembled monolayers (SAMs) of amino propyldiethoxymethylsilane (APDEMS) and octadecyltrimethoxysilane (ODTMS) are formed via wet chemical processing techniques. Their structural, chemical, and electrical properties are investigated using static water contact angle measurements, atomic force microscopy, and X-ray photoelectron spectroscopy, revealing that the organic layers are smooth and densely packed. Furthermore, combined contact potential difference and surface photovoltage measurements demonstrate that the heterostructure functionality and surface potential can be tuned by utilizing different organosilane precursor molecules. Molecular dipoles are observed to significantly affect the work functions of the modified surfaces. Furthermore, the magnitude of the surface band bending is reduced following reaction of the hydroxylated surfaces with organosilanes, indicating that partial passivation of electrically active surface states is achieved. Micropatterning of organic layers is demonstrated by lithographically defined oxidation of organosilane-derived monolayers in an oxygen plasma, followed by visualization of resulting changes of the local wettability, as well as fluorescence microscopy following immobilization of fluorescently labeled BSA protein. PMID- 23357506 TI - Physiological and biochemical responses of Microcystis aeruginosa to glyphosate and its Roundup(r) formulation. AB - Glyphosate may have dual effect on bloom algae as a phosphorus source or pesticide. The physiological and biochemical responses of Microcystis aeruginosa (M. aeruginosa) to glyphosate and its formulation in the common herbicide, Roundup((r)), were compared. The result suggested that both the cell numbers and Chl-a content of M. aeruginosa increased when the glyphosate concentration increased from 0.01 to 5mg P L(-1). However, Roundup((r)) showed low-dose (below 1mg P L(-1)) stimulation and high-dose (above 1mg P L(-1)) inhibition on M. aeruginosa cell density and Chl-a content (hormesis effect). Phosphate was more available than glyphosate or Roundup((r)), and Roundup((r)) was more toxic than glyphosate itself at 3mg P L(-1). Analysis of the maximum yield of PSII indicated that glyphosate stimulated the photosynthesis process while Roundup((r)) inhibited the photosynthesis of M. aeruginosa. The photosynthesis process was enhanced on the 21st day compared with that on the 14th day in all P mediums. The extracellular alkaline phosphatase activity (APA) decreased with the increasing glyphosate or Roundup((r)) concentration. The change pattern of APA was similar in both the glyphosate and Roundup((r)) mediums. PMID- 23357507 TI - Co-destruction of organic pollutants in municipal solid waste leachate and dioxins in fly ash under supercritical water using H2O2 as oxidant. AB - Supercritical water oxidation (SCWO), with hydrogen peroxide as oxidant, is applied to the co-disposal of two distinct waste streams: municipal solid waste leachate and incineration fly ash. The chemical oxygen demand (COD) removal efficiency increases rapidly with rising temperature and excess oxygen. Rising residence time from 1 to 2 min has surprisingly little effect. The addition of fly ash accelerates COD conversion markedly and also polychlorinated dibenzo-p dioxins and dibenzofurans (PCDD/Fs, dioxins) in the original fly ash are efficiently destroyed. High-chlorinated PCDD/Fs are more likely to be destroyed than low-chlorinated PCDD/Fs, at all experimental conditions. In addition, PCDDs are much more reactive than PCDFs, since the PCDDs/PCDFs ratio declines from 0.17 to 0.12 as excess oxygen rises from 0% to 300%. PMID- 23357508 TI - High intensity magnetic separation for the clean-up of a site polluted by lead metallurgy. AB - The industrial history in the district of Linares (Spain) has had a severe impact on soil quality. Here we examined soil contaminated by lead and other heavy metals in "La Cruz" site, a brownfield affected by metallurgical residues. Initially, the presence of contaminants mainly associated with the presence of lead slag fragments mixed with the soil was evaluated. The subsequent analysis showed a quasi-uniform distribution of the pollution irrespective of the grain size fractions. This study was accompanied by a characterization of the lead slag behavior under the presence of a magnetic field. Two main magnetic components were detected: first a ferromagnetic and/or ferrimagnetic contribution, second a paramagnetic and/or antiferromagnetic one. It was also established that the slag was composed mainly of lead spherules and iron oxides embedded in a silicate matrix. Under these conditions, the capacity of magnetic separation to remove pollutants was examined. Therefore, two high intensity magnetic separators (dry and wet devices, respectively) were used. Dry separation proved to be successful at decontaminating soil in the first stages of a soil washing plant. In contrast, wet separation was found effective as a post-process for the finer fractions. PMID- 23357509 TI - Synthesis of hierarchically structured ZnO spheres by facile methods and their photocatalytic deNOx properties. AB - This paper presents novel and facile methods for the fabrication of a series ZnO spheres by template-free, carbon template and hydrated-salt assisted solvothermal process, respectively. Phase purity and crystalline structure of the products were studied by X-ray diffraction analysis. SEM was employed to investigate the morphology and the fabrication of the monodisperse. BET analysis revealed that the as-prepared samples possessed huge specific surface area. UV-vis diffuse reflectance spectroscopy showed that these ZnO hollow spheres have a higher absorption. The as-prepared samples showed excellent photocatalytic activity for the decomposition of NOx gas under both visible-light and UV light irradiation (lambda>510, 400, 290nm), being superior to that of commercial TiO2 powders. PMID- 23357510 TI - Evaluation of pharmaceuticals and personal care products with emphasis on anthelmintics in human sanitary waste, sewage, hospital wastewater, livestock wastewater and receiving water. AB - We investigated 33 pharmaceuticals and personal care products (PPCPs) with emphasis on anthelmintics and their metabolites in human sanitary waste treatment plants (HTPs), sewage treatment plants (STPs), hospital wastewater treatment plants (HWTPs), livestock wastewater treatment plants (LWTPs), river water and seawater. PPCPs showed the characteristic specific occurrence patterns according to wastewater sources. The LWTPs and HTPs showed higher levels (maximum 3000 times in influents) of anthelmintics than other wastewater treatment plants, indicating that livestock wastewater and human sanitary waste are one of principal sources of anthelmintics. Among anthelmintics, fenbendazole and its metabolites are relatively high in the LWTPs, while human anthelmintics such as albendazole and flubendazole are most dominant in the HTPs, STPs and HWTPs. The occurrence pattern of fenbendazole's metabolites in water was different from pharmacokinetics studies, showing the possibility of transformation mechanism other than the metabolism in animal bodies by some processes unknown to us. The river water and seawater are generally affected by the point sources, but the distribution patterns in some receiving water are slightly different from the effluent, indicating the influence of non-point sources. PMID- 23357511 TI - Assessment of the developmental neurotoxicity of compounds by measuring locomotor activity in zebrafish embryos and larvae. AB - The developmental neurotoxic potential of the majority of environmental chemicals and drugs is currently undetermined. Specific in vivo studies provide useful data for hazard assessment but are not amenable to screen thousands of untested compounds. In this study, methods which use zebrafish embryos, eleutheroembryos and larvae as model organisms, were proposed as alternatives for developmental neurotoxicity (DNT) testing. The evaluation of spontaneous tail coilings in zebrafish embryos aged 24-26 hours post fertilization (hpf) and the swimming activity of eleutheroembryos at 120 and larvae at 144 hpf, i.e. parameters for locomotor activity, were investigated as potential endpoints for DNT testing, according to available standard protocols. The overall performance and predictive value of these methods was then examined by testing a training set of 10 compounds, including known developmental neurotoxicants and compounds not considered to be neurotoxic. The classification of the selected compounds as either neurotoxic or non-neurotoxic, based on the effects observed in zebrafish embryos and larvae, was compared to available mammalian data and an overall concordance of 90% was achieved. Furthermore, the specificity of the selected endpoints for DNT was evaluated as well as the potential similarities between zebrafish and mammals with regard to mechanisms of action for the selected compounds. Although further studies, including the screening of a large testing set of compounds are required, we suggest that the proposed methods with zebrafish embryos and larvae might be valuable alternatives for animal testing for the screening and prioritization of compounds for DNT. PMID- 23357512 TI - A dynamic model of the marriage market-part 1: matching algorithm based on age preference and availability. AB - The matching algorithm in a dynamic marriage market model is described in this first of two companion papers. Iterative Proportional Fitting is used to find a marriage function (an age distribution of new marriages for both sexes), in a stable reference population, that is consistent with the one-sex age distributions of new marriages, and includes age preference. The one-sex age distributions (which are the marginals of the two-sex distribution) are based on the Picrate model, and age preference on a normal distribution, both of which may be adjusted by choice of parameter values. For a population that is perturbed from the reference state, the total number of new marriages is found as the harmonic mean of target totals for men and women obtained by applying reference population marriage rates to the perturbed population. The marriage function uses the age preference function, assumed to be the same for the reference and the perturbed populations, to distribute the total number of new marriages. The marriage function also has an availability factor that varies as the population changes with time, where availability depends on the supply of unmarried men and women. To simplify exposition, only first marriage is treated, and the algorithm is illustrated by application to Zambia. In the second paper, remarriage and dissolution are included. PMID- 23357513 TI - The role of p53 on survival of upper urinary tract urothelial carcinoma: a systematic review and meta-analysis. AB - A systematic review and meta-analysis of the published literature that investigated the p53 expression and its effects on upper urinary tract urothelial carcinoma (UUTUC) prognosis was conducted. PubMed, Cochrane Library, OVID, and Scopus databases were searched for bibliographic information of articles about p53 expression evaluated by immunohistochemistry and survival in UUTUC from inception until June 2012. Seven articles met the eligibility criteria for this systematic review. The eligible studies included a total of 514 patients with a mean number of 73.4 patients per study (range, 42-154). None of the 7 included studies were based on the data of prospective analysis of survival. The threshold for dichotomizing the level of p53 also varied widely among studies, from 10% to 50%. When only unadjusted survival data were included, the pooled hazard ratio (HR) was statistically significant for disease-free (pooled HR, 1.70 [95% CI, 1.22-2.38), cancer-specific (pooled HR, 2.11 [95% CI, 1.13-3.93]), and overall survival (pooled HR, 1.55 [95% CI, 1.03-2.35]). There was no between-study heterogeneity in the effect of p53 status on all of the meta-analyses, with a P value >.05 and I(2) generally toward <50%. There was no clear evidence of funnel plot asymmetry, and no evidence of publication bias was found. Results of the meta-analysis suggest that p53 overexpression might be a prognostic factor for patients with UUTUC. These results need to be further confirmed by an adequately designed prospective study with larger populations. PMID- 23357514 TI - The OSIRIS Weight of Evidence approach: ITS mutagenicity and ITS carcinogenicity. AB - Risk assessment of chemicals usually implies data evaluation of in vivo tests in rodents to conclude on their hazards. The FP7 European project OSIRIS has developed integrated testing strategies (ITS) for relevant toxicological endpoints to avoid unnecessary animal testing and thus to reduce time and costs. This paper describes the implementation of ITS mutagenicity and carcinogenicity in the public OSIRIS webtool. The data requirements of REACH formed the basis for these ITS. The main goal was to implement procedures to reach a conclusion on the adequacy and validity of available data. For the mutagenicity ITS a quantitative Weight of Evidence approach based on Bayesian statistics was developed and implemented. The approach allows an overall quality assessment of all available data for the five types of mutagenicity data requirements: in vitro bacterial mutagenicity, in vitro and in vivo chromosome aberration, in vitro and in vivo mammalian mutagenicity. For the carcinogenicity ITS a tool was developed to evaluate the quality of studies not conforming (entirely) to guidelines. In a tiered approach three quality aspects are assessed: documentation (reliability), study design (adequacy) and scope of examination (validity). The quality assessment is based on expert and data driven quantitative Weight of Evidence. PMID- 23357515 TI - Hyperphenylalaninemia in the Czech Republic: genotype-phenotype correlations and in silico analysis of novel missense mutations. AB - BACKGROUND: Hyperphenylalaninemia (HPA) is one of the most common inherited metabolic disorders caused by deficiency of the enzyme phenylalanine hydroxylase (PAH). HPA is associated with mutations in the PAH gene, which leads to reduced protein stability and/or impaired catalytic function. Currently, almost 700 different disease-causing mutations have been described. The impact of mutations on enzyme activity varies ranging from classical PKU, mild PKU, to non-PKU HPA phenotype. METHODS: We provide results of molecular genetic diagnostics of 665 Czech unrelated HPA patients, structural analysis of missense mutations associated with classical PKU and non-PKU HPA phenotype, and prediction of effects of 6 newly discovered HPA missense mutations using bioinformatic approaches and Molecular Dynamics simulations. RESULTS: Ninety-eight different types of mutations were indentified. Thirteen of these were novel (6 missense, 2 nonsense, 1 splicing, and 4 small gene rearrangements). Structural analysis revealed that classical PKU mutations are more non-conservative compared to non PKU HPA mutations and that specific sequence and structural characteristics of a mutation might be critical when distinguishing between non-PKU HPA and classical PKU mutations. The greatest impact was predicted for the p.(Phe263Ser) mutation while other novel mutations p.(Asn167Tyr), p.(Thr200Asn), p.(Asp229Gly), p.(Leu358Phe), and p.(Ile406Met) were found to be less deleterious. PMID- 23357516 TI - Gender patterns in the contribution of different types of violence to posttraumatic stress symptoms among South African urban youth. AB - OBJECTIVE: Identifying the comparative contributions of different forms of violence exposure to trauma sequelae can help to prioritize interventions for polyvictimized youth living in contexts of limited mental health resources. This study aimed to establish gender patterns in the independent and comparative contributions of five types of violence exposure to the severity of posttraumatic stress symptoms among Xhosa-speaking South African adolescents. METHOD: Xhosa speaking adolescents (n=230) attending a high school in a low-income urban community in South Africa completed measures of violence exposure and posttraumatic stress symptoms. RESULTS: While witnessing of community violence was by far the most common form of violence exposure, for the sample as a whole only sexual victimization and being a direct victim of community violence, together with gender, contributed independently to the severity of posttraumatic stress symptoms. When the contribution of different forms of violence was examined separately for each gender, only increased exposure to community and sexual victimization were associated with symptom severity among girls, while increased exposure to direct victimization in both the community and domestic settings were associated with greater symptom severity in boys. CONCLUSIONS: The findings provide some preliminary motivation for focusing trauma intervention initiatives in this community on girls who have experienced sexual abuse compounded by victimization in the community, and boys who have been direct victims of either domestic or community violence. Further research is required to establish whether the risk factors for posttraumatic stress symptoms identified among adolescents in this study are consistent across different communities in South Africa, as well as across other resource-constrained contexts. PMID- 23357517 TI - Current state of experimental imaging modalities for risk assessment of abdominal aortic aneurysm. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a major cause of death in developed countries. Patients often lack clinical symptoms, most acute AAA patients do not survive rupture, and subsequent surgical repair has a significant postoperative mortality. Diagnostics for AAAs are currently centered on aneurysm diameter, but recent studies claim this method to be insufficiently accurate. More accurate diagnostic criteria need to be indentified to minimize the amount of unnecessary interventions and to provide earlier diagnosis of rupture-prone AAAs. METHODS: A literature study using the MEDLINE database followed by manual cross-referencing provided original studies concerning AAA diagnostics. RESULTS: The currently validated imaging modalities such as ultrasound, computed tomography, and magnetic resonance imaging allow AAA research to develop in several directions. Some studies investigate whether clinically visible entities like thrombus, calcification, and vascular anatomy could be implemented directly into clinical practice through use of ultrasound or computed tomography. Experimental studies on intravascular ultrasound, positron emission tomography computed tomography, ultrasound particle image velocimetry and superparamagnetic particles in magnetic resonance imaging propose new methodologies to benefit AAA research. Other studies focus on available technology toward inflammation, metabolism, and the effects of hemodynamics on vascular integrity. CONCLUSIONS: Contradictory outcomes, low availability of experimental imaging modalities, and an often small population size hamper research in this field. Introducing new techniques and biomarkers in current or experimental modalities may prove to be the next step in the development of new diagnostic criteria for the risk assessment of AAA rupture. Until then, the AAA diameter remains the gold standard as a clinical risk factor. PMID- 23357518 TI - Frequency-domain optical coherence tomography assessment of very late vascular response after carotid stent implantation. AB - Intravascular optical coherence tomography is a high-resolution invasive imaging modality that allows the evaluation of vascular responses after stent implantation in a micron-scale level. We describe for the first time two patients with very late vascular response after carotid artery stenting that exhibit two different patterns of low-signal intensity (LSI), "ill-appearing" neointima: the first patient shows layered LSI neointima leading to stent restenosis, coupled with the presence of intraluminal thrombus, whereas the second patient demonstrates another pattern of non-restenotic LSI stent strut coverage, suggestive of lipid laden neointima (ie, "neoatherosclerosis"), recently associated with stent failure in coronary arteries. PMID- 23357519 TI - High-definition video-assisted transaxillary first rib resection for thoracic outlet syndrome. AB - Transaxillary first rib resection is a well-established effective surgical treatment for patients with symptomatic thoracic outlet syndrome, but surgical access may be limited and visualization is constrained. The use of high definition video-assisted imaging overcomes these limitations. The use of high definition video-assisted visualization of the anatomy enhances the surgeon's tactile feedback of the rib from the small open wound and is effective in providing better surgical access and allows clear identification of vital structures for the operating surgical team. This technique enhances the appreciation of anatomic detail, situational awareness of the team, and allows for more efficient assistance to the surgeon. Improved visualization also facilitates effective education of nurses, residents, and students. PMID- 23357520 TI - Selective coverage of the left subclavian artery without revascularization in patients with bilateral patent vertebrobasilar junctions during thoracic endovascular aortic repair. AB - OBJECTIVE: The primary purpose of the current study was to evaluate the safety and effectiveness of selective coverage of the left subclavian artery (LSCA) without revascularization during thoracic endovascular aortic repair (TEVAR) in patients with bilateral patent vertebrobasilar junctions. The secondary purpose was to assess morphologic change of the vertebral artery (VA) after the procedure. METHODS: Among 126 patients who underwent TEVAR between 2006 and 2011, 29 patients requiring LSCA coverage without preemptive revascularization were retrospectively analyzed in this study. The patients were a mean age of 63.1 years (range, 45-84 years). The mean follow-up period was 19.9 months (range, 1 63 months). Bilateral patent vertebrobasilar junctions were evaluated by contrast enhanced computed tomography (CT), time-of flight magnetic resonance angiography, or conventional angiography. Neurologic complications, such as spinal cord ischemia (SCI) or cerebrovascular accidents, were analyzed. Preprocedural and postprocedural changes in VAs were evaluated on follow-up contrast-enhanced CT. RESULTS: The overall 30-day mortality was 6.9% (2 of 29). None of the patients had SCI or a stroke of posterior circulation alone. Cerebrovascular accidents from embolic infarctions occurred in two patients (7.4%). Transient left arm ischemic symptoms were present in five patients (18.5%), but none required secondary interventions. Delayed development of type I endoleak occurred due to stent deformity in one patient, who underwent surgery. One patient required reintervention after the 10-month follow-up contrast-enhanced CT showed a pseudoaneurysm had developed at the distal margin of the previously placed stent graft. Hypertrophy of the right VA after TEVAR was seen in seven of 27 patients (25.9%); two patients showed bilateral hypertrophy of VAs. CONCLUSIONS: LSCA coverage without revascularization can be safely performed during TEVAR in patients with bilateral patent vertebrobasilar junctions. Hypertrophy of the right VA was noted in 25.9% of patients after LSCA coverage. PMID- 23357521 TI - Directed neurectomy for treatment of chronic postsurgical neuropathic pain. AB - BACKGROUND: Chronic neurogenic pain after surgery, especially inguinal herniorrhaphy, remains a major cause of morbidity. The traditional treatment of postinguinal herniorrhaphy neurogenic pain has included triple neurectomy with the removal of any mesh. This report describes a directed, minimally invasive surgical neurectomy that provided pain relief in 28 patients with minimal morbidity. METHODS: After temporary but successful proximal peripheral nerve blockade, the nerve was blocked in the operating room using a small amount of blue dye mixed with the local anesthetic. After confirming pain relief with the dye-anesthetic mixture, the patient was then sedated, and all blue-stained tissue was excised through a small incision, avoiding both the previous surgical scar and mesh. RESULTS: All but 1 of the 28 patients had complete relief for a minimum of 12 months when discharged from follow-up. CONCLUSIONS: This simple directed neurectomy method typically provides long-term relief for patients suffering from chronic postsurgical neurogenic pain. PMID- 23357522 TI - The role of miRNA-29 family in cancer. AB - The miRNA-29 family of microRNAs (miRNAs), including miR-29a, miR-29b and miR 29c, was recently reported to be aberrantly expressed in multiple cancers. Increasing evidence shows that the abnormal expression of miR-29 family is associated with tumorigenesis and cancer progression, making miR-29s a well analyzed group of miRNAs in cancer research. Here, in this review we aim to provide an overview of the role of miR-29 family in the pathophysiologic changes of cancer cells and the epigenetic and immune regulation through the biological function of miR-29s. PMID- 23357523 TI - Superior haemodynamic stability during off-pump coronary surgery with thoracic epidural anaesthesia: results from a prospective randomized controlled trial. AB - OBJECTIVES: Off-pump coronary artery bypass (OPCAB) surgery is a technically more demanding strategy of myocardial revascularization compared with the standard on pump technique. Thoracic epidural anaesthesia, by reducing sympathetic stress, may ameliorate the haemodynamic changes occurring during OPCAB surgery. The aim of this randomized controlled trial was to evaluate the impact of thoracic epidural anaesthesia on intraoperative haemodynamics in patients undergoing OPCAB surgery. METHODS: Two hundred and twenty-six patients were randomized to either general anaesthesia plus epidural (GAE) (n = 109) or general anaesthesia (GA) only (n = 117). Mean arterial blood pressure (MAP), heart rate (HR) and central venous pressure (CVP) were measured before sternotomy and subsequently after positioning the heart for each distal anastomosis. RESULTS: Both groups were well balanced with respect to baseline characteristics and received a standardized anaesthesia. The MAP decreased in both groups with no significant difference (mean difference (GAE minus GA) -1.11, 95% CI -3.06 to 0.84, P = 0.26). The HR increased in both groups after sternotomy but was significantly less in the GAE group (mean difference (GAE minus GA) -4.29, 95% CI -7.10 to -1.48, P = 0.003). The CVP also increased in both groups after sternotomy, but the difference between the groups varied over time (P = 0.05). A difference was observed at the third anastomosis when the heart was in position for the revascularization of the circumflex artery (mean difference (GAE minus GA) +2.09, 95% CI 0.21-3.96, P = 0.03), but not at other time points. The incidence of new arrhythmias was also significantly lower in the GAE compared with the GA group (OR = 0.41, 95% CI 0.22 0.78, P = 0.01). CONCLUSION: Thoracic epidural with general anaesthesia minimizes the intraoperative haemodynamic changes that occur during heart positioning and stabilization for distal coronary anastomosis in OPCAB surgery. PMID- 23357524 TI - Major cardiac rupture following surgical treatment for deep sternal wound infection. AB - We report a case of an 80-year old male patient who sustained a major rupture of the right ventricle after surgical revision of an infected sternotomy wound following coronary artery bypass surgery. The rupture of the right ventricle occurred despite an early wound debridement and the use of negative pressure wound therapy on the sternum that did not provide sufficient stability to the sternum after the sternal wires were removed. The rupture resulted in a major bleeding but by establishing emergent cardiopulmonary bypass, the patient was saved. PMID- 23357525 TI - Prophylactic flap coverage and the incidence of bronchopleural fistulae after pneumonectomy. AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'In pneumonectomy patients, is buttressing the bronchial stump associated with a reduced incidence of bronchopleural fistula?'. Fifty-seven papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. One prospective randomized controlled trial was identified, which found significantly lower rates of bronchopleural fistula and empyema after pneumonectomy with the use of pedicled intercostal flap buttressing. Intercostal muscle flaps and pericardial flaps have been used in case series of high-risk patients, e.g. those with neoadjuvant therapy or extended resections, with low rates of subsequent bronchopleural fistulae. There is the least-reported evidence for thoracodorsal artery perforator and omental flaps. There is relatively little published evidence beyond the single randomized trial identified, with only a few comparison studies to guide clinicians. We conclude that there is evidence for flap buttressing in reducing the risk of bronchopleural fistulae after pneumonectomy in diabetic patients. Flap coverage in other high-risk situations, such as extrapleural or completion pneumonectomy, has been reported in case series with good results. Of the reported techniques, the evidence is strongest for the pedicled inter-costal flap. PMID- 23357526 TI - Molecular communication between tumor-associated fibroblasts and head and neck squamous cell carcinoma. AB - Over the past few decades, it has become increasingly clear that the lethality of cancers depends on more than the malignant cells themselves. The environment those malignant cells are exposed to is just as important a determinant of their behavior. Head and neck squamous cell carcinoma (HNSCC) is both common and deadly. It is the 6th most frequently occurring cancers, and prognosis is still generally poor. Recent evidence indicates that activated fibroblasts residing within the tumor stroma play a significant role in promoting the aggressive spread often seen in head and neck cancer. Tumor associated fibroblasts (TAFs) have also been implicated in facilitating angiogenesis and suppressing the normal anti-tumor function of immune cells. Studying the signaling molecules involved in these processes will facilitate the development of promising targets and inhibitors to prevent tumor-associated fibroblasts from exerting their reinforcing effects on the tumor. In this article, we review the recent literature on the signals used in tumor associated fibroblast communication, with a focus on potential therapeutic targets. Further, we highlight the lead candidates for TAF-targeted therapeutic interventions. Future anti-cancer strategies may achieve better results than current approaches by targeting the support cells in tumor stroma in addition to the cancerous cells. PMID- 23357527 TI - Clinical factors predicting for prolonged enteral supplementation in patients with oropharyngeal cancer treated with chemoradiation. AB - OBJECTIVES: The purpose of this study is to determine the pre-treatment clinical factors associated with prolonged enteral feeding in patients with oropharyngeal cancer treated with chemoradiation. MATERIALS AND METHODS: One hundred and nine patients with stage III-IVB oropharyngeal carcinoma treated with definitive chemoradiation were analyzed. Feeding tube usage was defined as the duration of active usage for nutritional purposes. RESULTS: Median follow-up was 4.4 years and median feeding tube usage was 2.5 months. On multivariate analysis, increasing duration of feeding tube usage was associated with narcotic use before treatment (p = 0.04), living alone at the time of treatment (p = 0.04), and larger pre-treatment decrease in body-mass index (p = 0.01). Prolonged feeding tube usage was associated with decreased overall survival (p = 0.06) and disease free survival (p = 0.02) in univariate analysis. CONCLUSIONS: By identifying patients at risk for prolonged feeding tube usage, aggressive measures can be attempted to prevent feeding tube dependence. PMID- 23357528 TI - Dietary sodium intake and prevalence of overweight in adults. AB - OBJECTIVE: There has been no convincing evidence for a direct relation between sodium intake and being overweight. Therefore, we investigated the independent relationship between overweight and sodium intake in human subjects. METHODS: Of those aged 19 to 64 years who participated in the 4th Korea National Health and Nutrition Examination Survey, a total of 5955 participants (54% female) were included. Subjects were excluded if they reported unrealistic daily total energy intakes or intentional dietary changes, were pregnant, or were diagnosed with hypertension, diabetes, renal failure, liver cirrhosis, or thyroid disease. Overweight was defined as having a body mass index of 25 kg/m(2) or higher. Sodium intake was calculated from 24-h recall and categorized into quintiles. Multivariate logistic regression was used to test the relationship between sodium intake and being overweight. RESULTS: Compared to men in the lowest quintile, men in the 4th and 5th quintiles had an increased risk of being overweight with odds ratios (ORs) of 1.37 (95% confidence interval [CI], 1.02-1.82) and 1.67 (95% CI, 1.23-2.27) respectively, after adjusting for confounding factors including soft drink and energy intake. The P value for trend of ORs in each quintile for men was 0.0033. In women, compared to the lowest quintile, the highest quintile had an OR of 1.31(95% CI, 0.96-1.79) and showed a marginally significant trend towards increasing risk of being overweight (P value=.058). CONCLUSIONS: Our findings suggest an independent relationship between high sodium intake and an increased risk of being overweight in adults. PMID- 23357529 TI - Expression of p27Kip1, a cell cycle repressor protein, is inversely associated with potential carcinogenic risk in the genetic rodent models of obesity and long lived Ames dwarf mice. AB - INTRODUCTION: The association of genetic rodent models of obesity and cancer still remains a controversial issue. Although this controversy has largely been resolved in recent years for homozygous leptin receptor-deficient obese Zucker rats and homozygous long-lived Ames dwarf mice, it is still unresolved for homozygous leptin-deficient obese ob/ob mice. OBJECTIVE: The objective of the present study described below was to investigate whether the expression of the cell cycle repressor protein p27(Kip1) is (a) down-regulated in the tumor-free homozygous leptin receptor-deficient obese Zucker rats as well as tumor-free homozygous leptin-deficient obese ob/ob mice and (b) up-regulated in the tumor free homozygous long-lived Ames dwarf mice. METHODS: To achieve this objective, we first performed western immunoblot analysis of the hepatic expression of p27. We then performed western immunoblot analysis and proteomic analysis of the hepatic expression of the proteins involved in the upstream molecular signaling pathways for the expression of p27. Lastly, we analyzed the serum levels of glucose, insulin, and branched-chain amino acids, all of which have been shown to regulate, causally and inversely, the expression of p27. RESULTS/CONCLUSIONS: The results indicated that the hepatic expression of p27 was down-regulated in the homozygous leptin receptor-deficient obese Zucker rats and up-regulated in the homozygous long-lived Ames dwarf mice as expected. We also found that the hepatic expression of p27 was down-regulated in the homozygous leptin-deficient obese ob/ob mice. This last observation was not completely consistent with all of the results of the published studies where homozygous leptin-deficient obese ob/ob mice were used. PMID- 23357531 TI - Familial hypercholesterolemia affects microvascular autoregulation in children. AB - OBJECTIVE: Familial hypercholesterolemia (FH) impairs macrovascular endothelial function in childhood and causes an increase of cardiovascular risk in later life. Whether microvascular function is affected in children with FH is unknown. The aim of this study was to investigate the impact of FH on microvascular autoregulation in children by post occlusive reactive hyperemia (PORH). METHODS: PORH of the skin was assessed using laser Doppler fluxmetry. Baseline perfusion, biological zero, defined as no-flow laser Doppler signal during suprasystolic occlusion, peak perfusion after release of suprasystolic occlusion, as well as time to peak perfusion and recovery time, defined as time until baseline perfusion is resumed, were measured in 16 children, who were diagnosed with FH according to current guidelines, and in 91 healthy controls. RESULTS: In children with FH, peak perfusion was higher (FH: 1.60+/-0.68 vs. controls: 1.26+/-0.50 AU [arbitrary units], p=0.02), recovery time was longer (110+/-42.61 vs. 83.18+/ 35.08 s, p=0.01) and biological zero was lower than in controls (0.12+/-0.04 vs. 0.18+/-0.05 AU, p<0.001). Baseline perfusion and time to peak were not different between children with FH and controls (baseline perfusion: 0.43+/-0.21 vs. 0.38+/ 0.15 AU, p=0.18; time to peak: 15.44+/-12.25 vs. 18.18+/-17.79 s, p=0.56). CONCLUSION: For the first time the present study reveals an impact of FH on microvascular autoregulation in children: the differences of PORH between children with FH and controls indicate an affected autoregulation of microvascular blood flow in FH, which has its onset in childhood. PMID- 23357530 TI - Cellular mechanisms regulating fuel metabolism in mammals: role of adipose tissue and lipids during prolonged food deprivation. AB - Food deprivation in mammals results in profound changes in fuel metabolism and substrate regulation. Among these changes are decreased reliance on the counter regulatory dynamics by insulin-glucagon due to reduced glucose utilization, and increased concentrations of lipid substrates in plasma to meet the energetic demands of peripheral tissues. As the primary storage site of lipid substrates, adipose tissue must then be a primary contributor to the regulation of metabolism in food deprived states. Through its regulation of lipolysis, adipose tissue influences the availability of carbohydrate, lipid, and protein substrates. Additionally, lipid substrates can act as ligands to various nuclear receptors (retinoid x receptor (RXR), liver x receptor (LXR), and peroxisome proliferator activated receptor (PPAR)) and exhibit prominent regulatory capabilities over the expression of genes involved in substrate metabolism within various tissues. Therefore, through its control of lipolysis, adipose tissue also indirectly regulates the utilization of metabolic substrates within peripheral tissues. In this review, these processes are described in greater detail and the extent to which adipose tissue and lipid substrates regulate metabolism in food deprived mammals is explored with comments on future directions to better assess the contribution of adipose tissue to metabolism. PMID- 23357532 TI - Engineering enzymatic cascades on nanoscale scaffolds. AB - Scaffold proteins are involved in many enzyme cascades in signaling pathways and metabolic processes. The study of scaffolds occurring in biological systems advances at a rapid pace and recently developed engineered synthetic scaffolds enable the precise placement of components of an enzymatic cascade within nanometer distances. Recent experimental results demonstrate significantly increased throughput of enzymatic cascades as a result of the utilization of a scaffold, but our understanding of the mechanisms responsible for this increase is not complete. We discuss the physics of diffusive transport processes relevant for these unique reaction-diffusion systems. PMID- 23357533 TI - TCEA3 binds to TGF-beta receptor I and induces Smad-independent, JNK-dependent apoptosis in ovarian cancer cells. AB - TFIIS is a transcription elongation factor conserved in frog, mouse and human. Recently, knockdown of TCEA1, the most well-characterized isoform of TFIIS, by RNA silencing was reported to inhibit cancer cell proliferation and induce apoptosis in breast, lung and pancreatic cancer cell lines through activation of p53 (Hubbard et al., 2008 [1]). However, the functions of other TFIIS isoforms are poorly defined. The present study shows that TCEA3, an isoform of TFIIS, can trigger ovarian cancer-specific cell death by activating the JNK signaling pathway. TCEA3 expression is low in ovarian cancer cell lines compared to noncancerous ovarian epithelial cells. Suppression of TCEA3 in noncancerous ovarian epithelial cells promotes cell growth whereas ectopic expression of TCEA3 in ovarian cancer cell lines induces the caspase-dependent mitochondrial cell death pathway. Molecular and chemical inhibition assays show that the interaction of TCEA3 with TGFbeta receptor I induces cell death in ovarian cancer cell through Smad-independent activation of the JNK pathway. These results reveal that TCEA3 induces a novel apoptotic mechanism in OEC, which provides TCEA3 as a novel target to develop therapeutics of ovarian cancer. PMID- 23357534 TI - Phosphorylated Hsp27 activates ATM-dependent p53 signaling and mediates the resistance of MCF-7 cells to doxorubicin-induced apoptosis. AB - DNA damage activates p53 and its downstream target genes, which further leads to apoptosis or survival either by the cell cycle arrest or by DNA repair. In many tumors, the heat shock protein 27 (Hsp27) is expressed at high levels to provide protection against anticancer drugs. However, the roles of Hsp27 in p53-mediated cellular responses to DNA damage are controversial. Here, we investigated the interplay between the phosphorylation status of Hsp27 and p53 in kidney 293A (HEK293A) cells and found that over-expressing phosphorylated Hsp27 mimics (Hsp27 3D) activated p53/p21 in an ATM-dependent manner. In addition, incubation with doxorubicin (Dox), an anticancer drug, induced Hsp27 phosphorylation in human adenocarcinoma cells (MCF-7). In contrast, inhibition of Hsp27 phosphorylation retarded both p53 induction and p21 accumulation, and led to cell apoptosis. Furthermore, phosphorylated Hsp27 increased p53 nuclear importing and its downstream target gene expression such as p21 and MDM2, while de-phosphorylated Hsp27 impeded this procession. Taken together, our data suggest that Hsp27, in its phosphorylated or de-phosphorylated status, plays different roles in regulating p53 pathway and cell survival. PMID- 23357535 TI - Thrombin-induced NF-kappaB activation and IL-8/CXCL8 release is mediated by c-Src dependent Shc, Raf-1, and ERK pathways in lung epithelial cells. AB - In addition to its functions in thrombosis and hemostasis, thrombin also plays an important role in lung inflammation. Our previous report showed that thrombin activates the protein kinase C (PKC)alpha/c-Src and Gbetagamma/Rac1/PI3K/Akt signaling pathways to induce IkappaB kinase alpha/beta (IKKalpha/beta) activation, NF-kappaB transactivation, and IL-8/CXCL8 expressions in human lung epithelial cells (ECs). In this study, we further investigated the mechanism of c Src-dependent Shc, Raf-1, and extracellular signal-regulated kinase (ERK) signaling pathways involved in thrombin-induced NF-kappaB activation and IL 8/CXCL8 release. Thrombin-induced increases in IL-8/CXCL8 release and kappaB luciferase activity were inhibited by the Shc small interfering RNA (siRNA), p66Shc siRNA, GW 5074 (a Raf-1 inhibitor), and PD98059 (a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor). Treatment of A549 cells with thrombin increased p66Shc and p46/p52Shc phosphorylation at Tyr239/240 and Tyr317, which was inhibited by cell transfection with the dominant negative mutant of c-Src (c-Src DN). Thrombin caused time-dependent phosphorylation of Raf 1 and ERK, which was attenuated by the c-Src DN. Thrombin-induced IKKalpha/beta phosphorylation was inhibited by GW 5074 and PD98059. Treatment of cells with thrombin induced Gbetagamma, c-Src, and p66Shc complex formation in a time dependent manner. Taken together, these results show for the first time that thrombin activates Shc, Raf-1, and ERK through Gbetagamma, c-Src, and Shc complex formation to induce IKKalpha/beta phosphorylation, NF-kappaB activation, and IL 8/CXCL8 release in human lung ECs. PMID- 23357536 TI - The activation of alpha1-adrenoceptors is implicated in the antidepressant-like effect of creatine in the tail suspension test. AB - The antidepressant-like activity of creatine in the tail suspension test (TST) was demonstrated previously by our group. In this study we investigated the involvement of the noradrenergic system in the antidepressant-like effect of creatine in the mouse TST. In the first set of experiments, creatine administered by i.c.v. route (1 MUg/site) decreased the immobility time in the TST, suggesting the central effect of this compound. The anti-immobility effect of peripheral administration of creatine (1 mg/kg, p.o.) was prevented by the pretreatment of mice with alpha-methyl-p-tyrosine (100 mg/kg, i.p., inhibitor of tyrosine hydroxylase), prazosin (1 mg/kg, i.p., alpha1-adrenoceptor antagonist), but not by yohimbine (1 mg/kg, i.p., alpha2-adrenoceptor antagonist). Creatine (0.01 mg/kg, subeffective dose) in combination with subeffective doses of amitriptyline (1 mg/kg, p.o., tricyclic antidepressant), imipramine (0.1 mg/kg, p.o., tricyclic antidepressant), reboxetine (2 mg/kg, p.o., selective noradrenaline reuptake inhibitor) or phenylephrine (0.4 MUg/site, i.c.v., alpha1-adrenoceptor agonist) reduced the immobility time in the TST as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an activation of alpha1-adrenoceptor and that creatine produces synergistic effects in the TST with antidepressants that modulate noradrenaline transporter, suggesting that an improvement in the response to the antidepressant therapy may occur when creatine is combined with these antidepressants. Furthermore, the synergistic effect of creatine (0.01 mg/kg, p.o.) and reboxetine (2 mg/kg, p.o.) combination was abolished by the alpha1-adrenoceptor antagonist prazosin, indicating that the antidepressant-like effect of combined therapy is likely mediated by an activation of alpha1-adrenoceptor. PMID- 23357537 TI - The effect of short-term stress on serotonin gene expression in high and low resilient macaques. AB - Female cynomolgus monkeys exhibit different degrees of reproductive dysfunction with moderate metabolic and psychosocial stress. When stressed with a paradigm of relocation and diet for 60 days, or 2 menstrual cycles, highly stress resilient monkeys continue to ovulate during both stress cycles (HSR); medium stress resilient monkeys ovulate once (MSR) and stress sensitive monkeys do not ovulate for the entire 60 days (SS). This study examines serotonin-related gene expression in monkeys with different sensitivity to stress and exposed to 5 days of moderate stress. Monkeys were first characterized as HSR, MSR or SS. After resumption of menstrual cycles, each monkey was re-stressed for 5 days in the early follicular phase. The expression of 3 genes pivotal to serotonin neural function was assessed in the 3 groups of monkeys (n=4-5/group). Tryptophan hydroxylase 2 (TPH2), the serotonin reuptake transporter (SERT), and the 5HT1A autoreceptor mRNAs expression were determined at 4 morphological levels of the dorsal raphe nucleus with in situ hybridization (ISH) using digoxigenin incorporated riboprobes. In addition, cFos was examined with immunohistochemistry. Positive pixel area and/or cell number were measured. All data were analyzed with ANOVA (3 groups) and with a t-test (2 groups). After 5 days of stress, TPH2, SERT, 5HT1A and cFos were significantly lower in the SS group than the HSR group (p<0.05, all). This pattern of expression was the same as the pattern observed in the absence of stress in previous studies. Therefore, the ratio of the HSR/SS expression of each serotonergic gene was calculated in the presence and absence of stress. There was little or no difference in the ratio of HSR/SS gene expression in the presence or absence of stress. Moreover, cFos expression indicates that overall, cell activation in the dorsal raphe nucleus and periaquaductal gray is lower in SS than HSR animals. These data suggest that the serotonin system may set the sensitivity or resilience of the individual, but serotonin-related gene expression may not rapidly respond to moderate stress in nonhuman primates. PMID- 23357538 TI - Anxiogenic effects of brief swim stress are sensitive to stress history. AB - Stressors that are controllable not only protect an individual from the acute consequences of the stressor, but also the consequences of stressors that occur later. This phenomenon, termed "behavioral immunization", is studied in the rat by first administering tailshocks each of which can be terminated (escapable tailshock) by an instrumental wheel-turn response prior to exposure to a second stressor. Previous research has shown that exposure to escapable tailshock blocks the neurochemical and behavioral consequences of later inescapable tailshock or social defeat stress. Here we explored the generality of behavioral immunization by examining the impact of prior escapable tailshock on the behavioral consequences of cold swim stress. Exposure to a 5min cold-water (19 degrees C) swim caused an anxiety-like reduction in social interaction that was dependent upon 5-HT2C receptor activation. Rats with prior exposure to escapable tailshock did not develop the swim-induced anxiety. Plasticity in the medial prefrontal cortex, a hypothetical neural mechanism underlying behavioral immunization, is discussed. PMID- 23357539 TI - Asymmetric distribution of dynamic calcium signals in the node of mouse embryo during left-right axis formation. AB - In the node of mouse embryo, rotational movements of cilia generate an external liquid flow known as nodal flow, which determines left-right asymmetric gene expression. How nodal flow is converted into asymmetric gene expression is still controversial, but the increase of Ca(2+) levels in endodermal cells to the left of the node has been proposed to play a role. However, Ca(2+) signals inside the node itself have not yet been described. By our optimized Ca(2+) imaging method, we were able to observe dynamic Ca(2+) signals in the node in live mouse embryos. Pharmacological disruption of Ca(2+) signals did not affect ciliary movements or nodal flow, but did alter the expression patterns of the Nodal and Cerl-2 genes. Quantitative analyses of Ca(2+) signal frequencies and distributions showed that during left-right axis establishment, formerly symmetric Ca(2+) signals became biased to the left side. In iv/iv mutant embryos that showed randomized laterality due to ciliary immotility, Ca(2+) signals were found to be variously left-sided, right-sided, or bilateral, and thus symmetric on average. In Pkd2 mutant embryos, which lacked polycystin-2, a Ca(2+)-permeable cation channel necessary for left-right axis formation, the Ca(2+) signal frequency was lower than in wild-type embryos. Our data support a model in which dynamic Ca(2+) signals in the node are involved in left-right patterning. PMID- 23357540 TI - The 3'UTR of nanos2 directs enrichment in the germ cell lineage of the sea urchin. AB - Nanos is a translational regulator required for the survival and maintenance of primordial germ cells during embryogenesis. Three nanos homologs are present in the genome of the sea urchin Strongylocentrotus purpuratus (Sp), and each nanos mRNA accumulates specifically in the small micromere (sMic) lineage. We found that a highly conserved element in the 3' UTR of nanos2 is sufficient for reporter expression selectively in the sMic lineage: microinjection into a Sp fertilized egg of an RNA that contains the GFP open reading frame followed by Sp nanos2 3'UTR leads to selective reporter enrichment in the small micromeres in blastulae. The same result was seen with nanos2 from the sea urchin Hemicentrotus pulcherrimus (Hp). In both species, the 5'UTR alone is not sufficient for the sMic localization but it always increased the sMic reporter enrichment when present with the 3'UTR. We defined an element conserved between Hp and Sp in the nanos2 3'UTR which is necessary and sufficient for protein enrichment in the sMic, and refer to it as GNARLE (Global Nanos Associated RNA Lability Element). We also found that the nanos2 3'UTR is essential for the selective RNA retention in the small micromeres; GNARLE is required but not sufficient for this process. These results show that a combination of selective RNA retention and translational control mechanisms instills nanos accumulation uniquely in the sMic lineage. PMID- 23357542 TI - Paradoxical long-term proarrhythmic effects after ablating the "head station" ganglionated plexi of the vagal innervation to the heart. AB - BACKGROUND: The ganglionated plexi (GP) located at the junction of the superior vena cava, aorta, and right pulmonary artery (SVC-Ao GP) was proposed to be the "head station" between the extrinsic and the intrinsic cardiac autonomic nervous system (ECANS and ICANS, respectively). OBJECTIVE: To investigate the chronic effects after interrupting the ECANS-ICANS connections by ablating the SVC-Ao GP. METHODS: A right thoracotomy in 10 dogs allowed stimulation at the right superior and inferior pulmonary veins (RSPV and RIPV, respectively), right atrial appendage (RAA), and SVC to determine effective refractory period (ERP) and atrial fibrillation (AF) inducibility in the first operation. Group 1 (n = 5) received SVC-Ao GP ablation; group 2 (n = 5) received no ablation. A second operation and the same measurements were made 10 weeks later. A pacemaker with lead implanted at the RSPV recorded atrial fibrillation or tachycardia (AF/AT). RESULTS: During the first operation in group 1, ERPs increased significantly in the SVC but not at the RSPV, RIPV, or RAA site immediately after ablation, whereas ERPs decreased significantly in the RSPV, RIPV, and RAA but not the SVC in the second operation performed 10 weeks later (compared to the ERP in the first operation). ERPs decreased and AF/AT burden increased significantly from weeks 4 and 5, respectively, after the first operation in group 1 dogs. The ERP and AF/AT burden in group 2 remained unchanged between operations. CONCLUSIONS: Ablation of the head station GP between the ECANS and the ICANS prolonged the ERP acutely, but shortened regional ERPs and increased AF/AT burden chronically, suggesting that the ECANS may tonically inhibit the ICANS activity. PMID- 23357541 TI - Low-level vagus nerve stimulation upregulates small conductance calcium-activated potassium channels in the stellate ganglion. AB - BACKGROUND: Small conductance calcium-activated potassium (SK) channels are responsible for afterhyperpolarization that suppresses nerve discharges. OBJECTIVES: To test the hypothesis that low-level vagus nerve stimulation (LL VNS) leads to the upregulation of SK2 proteins in the left stellate ganglion. METHODS: Six dogs (group 1) underwent 1-week LL-VNS of the left cervical vagus nerve. Five normal dogs (group 2) were used as controls. SK2 protein levels were examined by using Western blotting. The ratio between SK2 and glyceraldehydes-3 phosphate-dehydrogenase levels was used as an arbitrary unit (AU). RESULTS: We found higher SK2 expression in group 1 (0.124 +/- 0.049 AU) than in group 2 (0.085 +/- 0.031 AU; P<.05). Immunostaining showed that the density of nerve structures stained with SK2 antibody was also higher in group 1 (11,546 +/- 7,271 MUm(2)/mm(2)) than in group 2 (5321 +/- 3164 MUm(2)/mm(2); P<.05). There were significantly more ganglion cells without immunoreactivity to tyrosine hydroxylase (TH) in group 1 (11.4%+/-2.3%) than in group 2 (4.9% +/- 0.7%; P<.05). The TH-negative ganglion cells mostly stained positive for choline acetyltransferase (95.9% +/- 2.8% in group 1 and 86.1% +/- 4.4% in group 2; P = .10). Immunofluorescence confocal microscopy revealed a significant decrease in the SK2 staining in the cytosol but an increase in the SK2 staining on the membrane of the ganglion cells in group 1 compared to group 2. CONCLUSIONS: Left LL-VNS results in the upregulation of SK2 proteins, increased SK2 protein expression in the cell membrane, and increased TH-negative (mostly choline acetyltransferase-positive) ganglion cells in the left stellate ganglion. These changes may underlie the antiarrhythmic efficacy of LL-VNS in ambulatory dogs. PMID- 23357543 TI - Residential mobility, neighbourhood deprivation and children's behaviour in the UK. AB - Using data from the first two waves (in 2001/02 and 2004) of the UK's Millennium Cohort Study (MCS), we attempted to separate the effect of residential mobility from the effect of neighbourhood deprivation on children's emotional and behavioural problems. Our sample was 23,162 children (aged 3-16 years) clustered in 12,692 families. We measured neighbourhood deprivation with the Index of Multiple Deprivation, a measure of neighbourhood-level socio-economic disadvantage, and residential mobility as household move between waves. Being in a lower deprivation neighbourhood at Wave 1 was related to lower scores of both emotional and behavioural problems 2 years later, even after adjustment for child's age and sex, family adversity, family structure and maternal psychological distress. However, children whose families subsequently moved-even within or between lower deprivation neighbourhoods-were at higher risk of emotional and behavioural problems. Adjusting for family socio-economic disadvantage at Wave 1 explained the association of residential mobility with emotional but not with behavioural problems, which remained significant even after accounting for change in family's socio-economic disadvantage between waves. PMID- 23357544 TI - The geography of antidepressant, antipsychotic, and stimulant utilization in the United States. AB - This paper analyzes local and regional geographic variability in the use of antidepressant, antipsychotic and stimulant medications in the United States. Using a data set that covers 60% of prescriptions written in the United States, we find that use of antidepressants in three digit postal codes ranged from less than 1% of residents to more than 40% residents. Stimulant and antipsychotic use exhibited similar levels of local geographic variability. A Kulldorf Spatial Scan identified clusters of elevated use of antidepressants (RR 1.46; p<0.001), antipsychotics (RR 1.42; p<0.001), and stimulants (RR 1.77; p<0.001). Using a multilevel model, we find that access to health care, insurance coverage and pharmaceutical marketing efforts explain much of the geographic variation in use. PMID- 23357546 TI - Importance of bacteriology in upper airways of patients with Cystic Fibrosis. AB - BACKGROUND: Recently the influence of the upper airways (UAW) on the general health of a patient with Cystic Fibrosis (CF) has been acknowledged. Surprisingly the microbiology of the upper compartment of the airways receives barely any attention in the treatment of CF. The aim of the present study was to investigate the microbiology of the upper airways in adult patients with CF, to correlate these findings with cultures from the lower airways (LAW) and with clinical characteristics. METHODS: In this cross-sectional study bacteriological and clinical data were gathered from 104 adult patients with CF. UAW samples for culture were collected by nasal lavage and middle meatal swabs; LAW cultures were performed on expectorated sputum or cough swabs. Each patient performed the Rhinosinusitis Outcome Measure (RSOM-31). RESULTS: In 72 patients (69.2%) UAW cultures yielded microorganisms other than normal nasal flora and in 50 patients (48.1%) Pseudomonas aeruginosa grew from the UAW cultures. Similarity between UAW and LAW cultures was determined in 50.0% of these 72 patients. In 3 patients P. aeruginosa was cultured from the UAW after successful eradication of P. aeruginosa from the LAW. P. aeruginosa in the UAW did not influence symptoms of sinonasal disease compared to other microorganisms. CONCLUSIONS: Comparison of UAW and LAW cultures in adult patients with CF showed one or more concordant microorganism in 50.0% of the patients. P. aeruginosa was most frequently cultured from the UAW. P. aeruginosa can be cultured from the UAW after eradication therapy which may suggest persistence of P. aeruginosa in the UAW. We feel this is may be a motive to include the UAW in eradication therapy in Cystic Fibrosis. PMID- 23357545 TI - Dietary essential amino acids are highly anabolic in pediatric patients with cystic fibrosis. AB - BACKGROUND: Current nutritional approaches have been partially successful in Cystic Fibrosis (CF). Essential amino acids mixtures with high Leucine levels (EAA) have anabolic properties in catabolic conditions, however data in CF are lacking. METHODS: On two days according a randomized crossover design, 15 pediatric CF patients ingested 6.7 g EAA versus mixture of total amino acids as present in whey. Whole body protein and Arginine metabolism (as EAA lack Arginine) were assessed by stable isotope methodology. RESULTS: Protein synthesis (P<0.05) but not protein breakdown was higher after EAA and 70% higher values for net anabolism (P<0.001)were found both in patients with and without nutritional failure. Arginine turnover was lower (P<0.001) and de novo Arginine synthesis tended lower (P=0.09) after EAA. Nitric oxide synthesis was not different. CONCLUSIONS: CF patients are highly responsive to EAA intake independent of their nutritional status. Addition of Arginine to the EAA mixture may be warranted in CF. PMID- 23357547 TI - Changes in knee joint muscle activation patterns during walking associated with increased structural severity in knee osteoarthritis. AB - PURPOSE: To determine whether alterations in knee joint muscle activation patterns during gait were related to structural severity determined by Kellgren Lawrence (KL) radiographic grades, for those with a moderate knee OA classification. SCOPE: Eighty-two individuals with knee OA, classified as moderate using a functional and clinical criterion were stratified on KL-grade (KL II, KL III and KL IV). Thirty-five asymptomatic individuals were matched for age and walking velocity. Lower limb motion and surface electromyograms from rectus femoris plus lateral and medial sites for the gastrocnemii, vastii and hamstring muscles were recorded during self-selected walking. Gait velocity and characteristics from sagittal plane knee angular displacement waveforms were calculated. Principal component analysis extracted amplitude and temporal features from electromyographic waveform. Analysis of variance models tested for main effects (group, muscle) and interactions (alpha=0.05) for these features. No differences in anthropometrics, velocity, knee muscle strength and symptoms were found among the three OA groups (p>0.05). Specific features from medial gastrocnemius, lateral hamstring and quadriceps amplitude and temporal patterns were significantly different among OA groups (p<0.05). CONCLUSIONS: Systematic alterations in specific knee joint muscle activation patterns were associated with increasing structural severity based on KL-grades whereas other alterations were associated with the presence of OA. PMID- 23357548 TI - Sulfur mustard induces an endoplasmic reticulum stress response in the mouse ear vesicant model. AB - The endoplasmic reticulum (ER) stress response is a cell survival pathway upregulated when cells are under severe stress. Severely damaged mouse ear skin exposed to the vesicant, sulfur mustard (bis-2-chloroethyl sulfide, SM), resulted in increased expression of ER chaperone proteins that accompany misfolded and incorrectly made proteins targeted for degradation. Time course studies with SM using the mouse ear vesicant model (MEVM) showed progressive histopathologic changes including edema, separation of the epidermis from the dermis, persistent inflammation, upregulation of laminin gamma2 (one of the chains of laminin-332, a heterotrimeric skin glycoprotein required for wound repair), and delayed wound healing from 24h to 168h post exposure. This was associated with time related increased expression of the cell survival ER stress marker, GRP78/BiP, and the ER stress apoptosis marker, GADD153/CHOP, suggesting simultaneous activation of both cell survival and non-mitochondrial apoptosis pathways. Dual immunofluorescence labeling of a keratinocyte migration promoting protein, laminin gamma2 and GRP78/BIP, showed colocalization of the two molecules 72h post exposure indicating that the laminin gamma2 was misfolded after SM exposure and trapped within the ER. Taken together, these data show that ER stress is induced in mouse skin within 24h of vesicant exposure in a defensive response to promote cell survival; however, it appears that this response is rapidly overwhelmed by the apoptotic pathway as a consequence of severe SM-induced injury. PMID- 23357549 TI - Hexavalent chromium at low concentration alters Sertoli cell barrier and connexin 43 gap junction but not claudin-11 and N-cadherin in the rat seminiferous tubule culture model. AB - Exposure to toxic metals, specifically those belonging to the nonessential group leads to human health defects and among them reprotoxic effects. The mechanisms by which these metals produce their negative effects on spermatogenesis have not been fully elucidated. By using the Durand's validated seminiferous tubule culture model, which mimics the in vivo situation, we recently reported that concentrations of hexavalent chromium, reported in the literature to be closed to that found in the blood circulation of men, increase the number of germ cell cytogenetic abnormalities. Since this metal is also known to affect cellular junctions, we investigated, in the present study, its potential influence on the Sertoli cell barrier and on junctional proteins present at this level such as connexin 43, claudin-11 and N-cadherin. Cultured seminiferous tubules in bicameral chambers expressed the three junctional proteins and ZO-1 for at least 12days. Exposure to low concentrations of chromium (10MUg/l) increased the trans epithelial resistance without major changes of claudin-11 and N-cadherin expressions but strongly delocalized the gap junction protein connexin 43 from the membrane to the cytoplasm of Sertoli cells. The possibility that the hexavalent chromium-induced alteration of connexin 43 indirectly mediates the effect of the toxic metal on the blood-testis barrier dynamic is postulated. PMID- 23357550 TI - All-or-none suppression of B cell terminal differentiation by environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. AB - Many environmental contaminants can disrupt the adaptive immune response. Exposure to the ubiquitous aryl hydrocarbon receptor (AhR) ligand 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and other agonists suppresses the antibody response. The underlying pathway mechanism by which TCDD alters B cell function is not well understood. The present study investigated the mechanism of AhR mediated pathways and mode of suppression by which TCDD perturbs terminal differentiation of B cells to plasma cells and thereby impairs antibody production. An integrated approach combining computational pathway modeling and in vitro assays with primary mouse B cells activated by lipopolysaccharide was employed. We demonstrated that suppression of the IgM response by TCDD occurs in an all-or-none (binary) rather than graded mode: i.e., it reduces the number of IgM-secreting cells in a concentration-dependent manner without affecting the IgM content in individual plasma cells. The mathematical model of the gene regulatory circuit underpinning B cell differentiation revealed that two previously identified AhR-regulated pathways, inhibition of signaling protein AP-1 and activation of transcription factor Bach2, could account for the all-or-none mode of suppression. Both pathways disrupt the operation of a bistable-switch circuit that contains transcription factors Bcl6, Prdm1, Pax5, and Bach2 and regulates B cell fate. The model further predicted that by transcriptionally activating Bach2, TCDD might delay B cell differentiation and increase the likelihood of isotype switching, thereby altering the antibody repertoire. In conclusion, the present study revealed the mode and specific pathway mechanisms by which the environmental immunosuppressant TCDD suppresses B cell differentiation. PMID- 23357551 TI - [Orbital mycetoma: a case report]. AB - INTRODUCTION: Mycetomas are pathological processes through which exogenous fungal or actinomycotic etiological agents produce grains. These etiological agents live in the soil and plants of endemic areas. They are introduced traumatically, primarily into the foot. The orbital location is rare. OBSERVATION: We report the case of a 17-year-old student admitted for progressive left proptosis over 2 years, following penetrating trauma by a fork in a rural setting. Examination revealed a heterogenous orbital mass with multiple fistulae, producing pus and black grains, and suggested, due to the color of the grains, a diagnosis of fungal mycetoma. MRI revealed a destructive process at the level of the lamina papracea of the ethmoid and the orbital floor. Anatomopathological examination confirmed the fungal nature of the infection, while culture in Sabouraud's medium was inconclusive. The outcome was favorable after exenteration and debridementof the ipsilateral maxillary sinus and nasal cavities, along with 4 months of ketoconazole. No recurrence has been observed for 14 months after surgery. DISCUSSION: Mycetomas are endemic to northwest Africa. Most frequently located in the foot, they are seldom seen in the orbit. The color of the grains provides a clue as to the etiology. Black-grain mycetomas are always fungal and are treated surgically--essentially like cancer--as the persistence of a single grain will cause a recurrence. CONCLUSION: The orbital location of a mycetoma is rare. In the present case report, the concept of port of entry, the clinical appearance, and the color of the grains guided the diagnosis. The histological examination of the surgical specimen confirmed the diagnosis. PMID- 23357552 TI - Alcohol consumption by parents of Pacific families residing in New Zealand: findings from the Pacific Islands Families Study. AB - Harmful alcohol consumption amongst Pacific people (those of Polynesian descent) is recognized as a public health priority in New Zealand, yet little epidemiological information exists on this pattern of drinking. Using a large birth cohort study, which includes the mother, father and child triad, this study aims to determine the prevalence and change in any harmful drinking levels prenatally, antenatally and in the postpartum period for mothers and fathers, and to measure the concordance of both partners' reports of that drinking in an ethnically representative sample of Pacific families within New Zealand. Participants were selected from births where at least one parent was identified as being of Pacific ethnicity and a New Zealand permanent resident (1376 mothers and 825 fathers at baseline); many of whom are young to middle aged adults. These participants have been prospectively followed-up multiple times since. The Alcohol Use Disorders Identification Test consumption questions (AUDIT-C) were used over successive measurement waves to define any and harmful drinking levels. Recommended screening thresholds were employed. Longitudinal analyses on complete cases and imputed data, accounting for differential attrition, were undertaken and reported. Clear temporal patterns of alcohol consumption emerged for both mothers and fathers, together with significant and important ethnic differences. Moreover, there was considerable movement in alcohol consumption categories between consecutive measurement waves for both mothers and fathers. Among couples, there was significant asymmetry in drinking patterns and poor statistical agreement. However, 9.1% (14.1% in imputed analyses) of Pacific children aged 2 years had both parents indicated for harmful drinking. The significant important heterogeneity and ethnic differences suggest that both ethnic-specific and pan-Pacific interventions and prevention strategies are likely needed for successful interventions. More emphasis should be placed on targeting and addressing parents' alcohol misuse, particularly in the antenatal or postnatal period. PMID- 23357553 TI - Dephosphorylation of GluN2B C-terminal tyrosine residues does not contribute to acute ethanol inhibition of recombinant NMDA receptors. AB - N-methyl-d-aspartate (NMDA) receptors are ion channels activated by the neurotransmitter glutamate and are highly expressed by neurons. These receptors are critical for excitatory synaptic signaling and inhibition of NMDA receptors leads to impaired cognition and learning. Ethanol inhibits NMDA currents at concentrations associated with intoxication and this action may underlie some of the behavioral effects of ethanol. Although numerous sites and mechanisms of action have been tested, the manner in which ethanol inhibits NMDA receptors remains unclear. Recent findings in the literature suggest that ethanol, via facilitation of tyrosine phosphatase activity, may dephosphorylate key tyrosine residues in the C-terminus of GluN2B subunits resulting in diminished channel function. To directly test this hypothesis, we engineered GluN2B mutants that contained phenylalanine in place of tyrosine at three different sites and transiently expressed them with the GluN1 subunit in human embryonic kidney (HEK) cells. Whole-cell patch clamp electrophysiology was used to record glutamate activated currents in the absence and presence of ethanol (10-600 mM). All mutants were functional and did not differ from one another with respect to current amplitude, steady-state to peak ratio, or magnesium block. Analysis of ethanol dose-response curves showed no significant difference in IC50 values between wild-type receptors and Y1252F, Y1336F, Y1472F or triple Y-F mutants. These findings suggest that dephosphorylation of C-terminal tyrosine residues does not account for ethanol inhibition of GluN2B receptors. PMID- 23357554 TI - Are brain and heart tissue prone to the development of thiamine deficiency? AB - Thiamine deficiency is a continuing problem leading to beriberi and Wernicke's encephalopathy. The symptoms of thiamine deficiency develop in the heart, brain and neuronal tissue. Yet, it is unclear how rapid thiamine deficiency develops and which organs are prone to development of thiamine deficiency. We investigated these issues in a thiamine deficient animal model. Twenty-four male Lewis rats were fed a thiamine deficient diet, which contained 0.04% of normal thiamine intake. Six control rats were fed 200 MUg of thiamine per day. Every week a group of six rats on the thiamine-deficient diet was sacrificed and blood, urine and tissue were stored. Blood and tissue transketolase activity, thiamine and thiamine metabolites were measured and PCR of thiamine transporter-1 (ThTr-1) was performed. Transketolase activity was significantly reduced in red blood cells, liver, lung, kidney and spleen tissue after two weeks of thiamine deficient diet. In brain tissue, transketolase activity was not reduced after up to four weeks of thiamine deficient diet. The amount of thiamine pyrophosphate was also significantly conserved in brain and heart tissue (decrease of 31% and 28% respectively), compared to other tissues (decrease of ~70%) after four weeks of thiamine deficient diet. There was no difference between tissues in ThTr-1 expression after four weeks of thiamine deficient diet. Despite the fact that the heart and the brain are predilection sites for complications from thiamine deficiency, these tissues are protected against thiamine deficiency. Other organs could be suffering from thiamine deficiency without resulting in clinical signs of classic thiamine deficiency in beriberi and Wernicke's encephalopathy. PMID- 23357555 TI - Chattering free adaptive multivariable sliding mode controller for systems with matched and mismatched uncertainty. AB - In this paper, a chattering free adaptive sliding mode controller (SMC) is proposed for stabilizing a class of multi-input multi-output (MIMO) systems affected by both matched and mismatched types of uncertainties. The proposed controller uses a proportional plus integral sliding surface whose gain is adaptively tuned to prevent overestimation. A vertical take-off and landing (VTOL) aircraft system is simulated to demonstrate the effectiveness of the proposed control scheme. PMID- 23357556 TI - Inhibition of formyl peptide-stimulated superoxide anion generation by Fal-002-2 occurs mainly through the blockade of the p21-activated kinase and protein kinase C signaling pathways in ratneutrophils. AB - In formyl-Met-Leu-Phe (fMLP)-stimulated rat neutrophils, a synthetic compound, 6 chloro-2-(2-chlorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Fal-002-2), inhibited superoxide anion (O2(*-)) generation with an IC50 value of about 11MUM, which was not mediated by scavenging the generated O2(*-) or by a cytotoxic effect on neutrophils. Fal-002-2 effectively attenuated the phosphorylation of Ser residues in p47(phox) and the association between p47(phox) and p22(phox) in fMLP-stimulated neutrophils. The interaction of p47(phox) with protein kinase C (PKC) isoforms (alpha, betaI, betaII, delta and zeta) was attenuated by Fal-002-2 with a similar IC50 value to that required for inhibition of O2(*-) generation, whereas Fal-002-2 had no prominent effect on PKC isoform membrane translocation and did not affect the kinase activity. Moreover, Fal-002-2 had no effect on the phosphorylation of Akt and downstream glycogen synthase kinase-3beta, only slightly affected the intracellular free Ca(2+) concentration, phosphorylation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase (MAPK), but effectively attenuated the downstream MAPK-activated protein kinase-2 phosphorylation. The interaction of p21-activated kinase (PAK) 1with p47(phox), phosphorylation of PAK1 (Thr423/Ser144) and the membrane recruitment of PAK1 were effectively inhibited by Fal-002-2. Fal-002-2 also blocked the activation of Rac1 and Cdc42 in a concentration range that effectively inhibited PAK activation. Taken together, these results suggest that Fal-002-2 inhibits fMLP-stimulated O2(*-) generation in neutrophils mainly through the blockade of PKC and PAK signaling pathways and partly through p38 MAPK signaling. PMID- 23357557 TI - Deoxynivalenol induces ectodomain shedding of TNF receptor 1 and thereby inhibits the TNF-alpha-induced NF-kappaB signaling pathway. AB - Trichothecene mycotoxins are known to inhibit eukaryotic translation and to trigger the ribotoxic stress response, which regulates gene expression via the activation of the mitogen-activated protein (MAP) kinase superfamily. In this study, we found that deoxynivalenol induced the ectodomain shedding of tumor necrosis factor (TNF) receptor 1 (TNFRSF1A) and thereby inhibited the TNF-alpha induced signaling pathway. In human lung carcinoma A549 cells, deoxynivalenol and 3-acetyldeoxynivalenol inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) induced by TNF-alpha more strongly than that induced by interleukin 1alpha (IL-1alpha), whereas T-2 toxin and verrucarin A exerted nonselective inhibitory effects. Deoxynivalenol and 3-acetyldeoxynivalenol also inhibited the nuclear factor kappaB (NF-kappaB) signaling pathway induced by TNF alpha, but not that induced by IL-1alpha. Consistent with these findings, deoxynivalenol and 3-acetyldeoxynivalenol induced the ectodomain shedding of TNF receptor 1 by TNF-alpha-converting enzyme (TACE), also known as a disintegrin and metalloproteinase 17 (ADAM17). In addition to the TACE inhibitor TAPI-2, the MAP kinase or extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126 and the p38 MAP kinase inhibitor SB203580, but not the c-Jun N-terminal kinase (JNK) inhibitor SP600125, suppressed the ectodomain shedding of TNF receptor 1 induced by deoxynivalenol and reversed its selective inhibition of TNF alpha-induced ICAM-1 expression. Our results demonstrate that deoxynivalenol induces the TACE-dependent ectodomain shedding of TNF receptor 1 via the activation of ERK and p38 MAP kinase, and thereby inhibits the TNF-alpha-induced NF-kappaB signaling pathway. PMID- 23357558 TI - Exploiting social evolution in biofilms. AB - Bacteria are highly social organisms that communicate via signaling molecules, move collectively over surfaces and make biofilm communities. Nonetheless, our main line of defense against pathogenic bacteria consists of antibiotics-drugs that target individual-level traits of bacterial cells and thus, regrettably, select for resistance against their own action. A possible solution lies in targeting the mechanisms by which bacteria interact with each other within biofilms. The emerging field of microbial social evolution combines molecular microbiology with evolutionary theory to dissect the molecular mechanisms and the evolutionary pressures underpinning bacterial sociality. This exciting new research can ultimately lead to new therapies against biofilm infections that exploit evolutionary cheating or the trade-off between biofilm formation and dispersal. PMID- 23357559 TI - Algorithm for NIV in chronic obstructive pulmonary disease: could this be applicable for every scenario? PMID- 23357560 TI - Response to letter to the editor. PMID- 23357562 TI - Environmental assessment of mercury pollution in urban tailings from gold mining. AB - It is well-known that small-scale artisanal mining is a source of mercury emissions into the environment, mainly from the use of rudimentary technologies that use mercury amalgamation in the extraction process. Mines near Andacollo, which is located in the Coquimbo region of Chile, use primitive methods to mine gold and copper. In this study, we determined the mercury content of gold mining wastes from Andacollo. At each site, we randomly sampled the soil at the surface and at a depth of 2 m following the ISO 10381 guidelines. Mercury analysis was performed with a direct mercury analyzer. At least one site was contaminated at a mercury concentration of 13.6+/-1.4 mg kg(-1), which was above the international recommendations that were set by the Canadian Council of Ministers of the Environment's soil quality guidelines (CA-SQG) and the Dutch guidelines (NL RIVM). At least four of the fourteen sites in this study were within the control and tolerance levels of these recommendations. Better characterization of these sites is required to establish whether they represent a risk to the local community. Based on the US-EPA recommendations, which have a higher tolerance limit, none of the fourteen sites should pose a risk to humans. PMID- 23357561 TI - Enhancing cancer screening in primary care: rationale, design, analysis plan, and recruitment results. AB - Colorectal cancer (CRC) is the third leading type of cancer and the third leading cause of cancer death in the United States. National policy-making organizations recognize and support a variety of CRC screening strategies among average-risk adults aged 50 and older based on strong evidence showing that screening decreases mortality from CRC and can also reduce the incidence of the disease. The goal of this study was to test a multi-level stepped intervention to increase CRC screening rates. We used a group-randomized trial design where the units of assignment were clinics and the units of observation were eligible patients receiving care at those clinics, with stratified random assignment of clinics to study conditions. The primary analysis was planned as a mixed-model logistic regression to account for the expected positive intraclass correlation associated with clinics. Our recruitment experience reflected the difficulties of conducting research in the real world where changes in economic conditions, staff turnover/layoff, inadequate medical records, and poor acceptance of research can significantly impact study plans. It demonstrated the problems that can emerge when procedures used in the study depart from those used in the pilot work to generate parameter estimates for power analysis. It also demonstrated the importance of allowing for attrition at the group and patient levels so that if recruitment falls short, it is possible to maintain adequate power with only a slight increase in the detectable difference. This experience should assist others planning group-randomized trials, whether in cancer screening or in other areas. PMID- 23357563 TI - Growth-disrupting, larvicidal and neurobehavioral toxicity effects of seed extract of Seseli diffusum against Aedes aegypti (L.) (Diptera: Culicidae). AB - Plant extracts that kill, deform the post-embryonic molting stages of mosquitoes could be a valuable approach in integrated vector management programmes to replace synthetic chemical pesticides, containing persistent toxic substances. Crude ethanolic seed extract was obtained by maceration of seeds of Indian celery, Seseli diffusum (Apiaceae). The ethanolic seed extract induced strong neurobehavioral toxicity against the 4th instar larvae of Aedes aegypti which resulted in a high level of larval knock-down with EC(50) of 238.15 ppm, after 4h of treatment. The extract at concentration of 200 ppm exhibited a potent larvicidal effect against 4th instar A. aegypti, produced 88% and 96% mortality, after 24 and 48 h of treatment with LC(50) of 126.13 ppm and LC(50) of 112.53 ppm, respectively. The ethanolic seed extract at higher concentration (>400 ppm) produced 100% mortality, after 24 h and 48 h of treatment. At lower concentration of 100 ppm, extract induced a high level of morphological deformities in larvae, after 48 h of treatment. A high level of growth and/or molting disrupting effect of extract against larvae was also observed which resulting in the formation of larval-pupal intermediates, after 48 h of treatment. At concentrations of 200-300 ppm, ethanolic seed extract induced morphological deformities in dead pupae, after 72 h of treatment. The results showed that S. diffusum is a promising candidate for the development of new botanical biopesticide having multiple potentials for controlling insect pest of medical and agricultural importance. PMID- 23357564 TI - An evaluation of 2,4-dichlorophenoxyacetic acid in the Amphibian Metamorphosis Assay and the Fish Short-Term Reproduction Assay. AB - 2,4-Dichlorophenoxyacetic acid (2,4-D) was evaluated in both the Amphibian Metamorphosis Assay (AMA) and the Fish Short Term Reproduction Assay (FSTRA). In the AMA, tadpoles were exposed to mean measured 2,4-D concentrations of 0 (water control), 0.273, 3.24, 38.0 and 113 mg acid equivalents (ae)/L for either seven or 21 days. In the FSTRA, fathead minnows were exposed to mean measured 2,4-D concentrations of 0 (water control), 0.245, 3.14, 34.0, and 96.5 mg ae/L for 21 days. The respective concentrations of 2,4-D were not overtly toxic to either Xenopus laevis tadpoles or fathead minnows (Pimephales promelas). In the AMA, there were no signs of either advanced or delayed development, asynchronous development, or significant histopathological effects of the thyroid gland among 2,4-D exposed tadpoles evaluated on either day seven or day 21 of the exposure. Therefore, following the AMA decision logic, 2,4-D is considered "likely thyroid inactive" in the AMA with a No Observable Effect Concentration (NOEC) of 113 mg ae 2,4-D/L. In the FSTRA, there were no significant differences between control and 2,4-D exposed fish in regard to fertility, wet weight, length, gonado-somatic indices, tubercle scores, or blood plasma concentrations of vitellogenin. Furthermore, there were no treatment-related histopathologic changes in the testes or ovaries in any 2,4-D exposed group. The only significant effect was a decrease in fecundity among fish exposed to 96.5 mg ae 2,4-D/L. The cause of the reduced fecundity at the highest concentration of 2,4-D tested in the assay was most likely due to a generalized stress response in the fish, and not due to a specific endocrine mode of action of 2,4-D. Based on fish reproduction, the NOEC in the FSTRA was 34.0 mg ae 2,4-D/L. PMID- 23357565 TI - Protective effect of silymarin against ethanol-induced gastritis in rats: role of sulfhydryls, nitric oxide and gastric sensory afferents. AB - Silymarin has been known to exert antioxidant, anti-carcinogenic and anti inflammatory effects. In this study, we examined the effect of silymarin on gastritis in rats. Oral administration of silymarin dose-dependently decreased gastric lesions in ethanol-induced gastritis model. Silymarin also significantly suppressed the development of gastric lesions in aspirin- or water immersion restraint stress-induced gastritis models. Further study demonstrated that the gastroprotective effect of silymarin was blocked by nitric oxide (NO) synthase inhibitor l-NAME, SH blocker N-ethylmaleimide or TRPV1 antagonist capsazepine in ethanol-induced gastritis model. In addition, ex vivo analysis revealed that ethanol-induced decrease in gastric mucus and non-protein sulfhydryl (NPSH) groups was significantly reversed by silymarin treatment and lipid peroxidation was also suppressed by silymarin in ethanol-induced gastritis model. Taken together, these results suggest that silymarin exerts gastroprotective effects and the gastroprotective effects of silymarin might be related to the protection of gastric mucosal NO and NP-SH and the modulation of capsaicin-sensitive gastric sensory afferents. PMID- 23357566 TI - Antioxidant potentials and anticholinesterase activities of methanolic and aqueous extracts of three endemic Centaurea L. species. AB - The methanol and aqueous extracts of three endemic Centaurea species (C. polypodiifolia var. pseudobehen, C. pyrrhoblephara and C. antalyense) were investigated for their antioxidant and cholinesterase inhibitory activities. The antioxidant activities of these extracts were evaluated by in vitro models including, phosphomolybdenum assay, free radical scavenging assays (DPPH and ABTS), beta-carotene/linoleic acid test system, metal chelating assay, FRAP assay, ferric and cupric reducing power. Cholinesterase inhibitory activities were examined using Ellman's colorimetric method. Total phenol, flavonoid, and saponin contents were also measured. Among the six Centaurea extracts evaluated, the highest antioxidant abilities were obtained from C. polypodiifolia var. pseudobehen. Methanolic extracts from C. polypodiifolia var. pseudobehen and C. antalyense had a noticeable inhibition towards AChE and BChE. These findings suggest that Centaurea species could be an anticholinesterase agent and antioxidant resource in some industries, such as food, pharmacology, and cosmetics. PMID- 23357567 TI - Formation of mainstream cigarette smoke constituents prioritized by the World Health Organization--yield patterns observed in market surveys, clustering and inverse correlations. AB - The WHO TobReg proposed mandating ceilings on selected smoke constituents determined from the market-specific median of nicotine-normalized yield distributions. Data validating this regulatory concept were obtained from essentially single-blend surveys. This process is strongly impacted by inverse correlations among yields. In the present study, 18 priority WHO smoke constituent yields (nicotine-normalized) were determined (using two smoking regimens) from 262 commercial brands including American, Virginia and local blends from 13 countries. Principal Component Analysis was used to identify yields patterns, clustering of blend types and the inverse correlations causing these clusters. Three principal components explain about 75% of total data variability. PC1 was sensitive to the relative levels of gas- and particle-phase compounds. PC2 and PC3 cluster American- and Virginia-blends, revealing inverse correlations: Nitrogen oxides and amino- or nitroso-aromatic compounds inversely correlate to either formaldehyde and acrolein, or benzo(a)pyrene and di hydroxybenzenes. These results can be explained by reviewing the processes determining each components smoke delivery. Regulatory initiatives simultaneously targeting selected smoke constituents in markets with mixed blend styles will be strongly impacted by the inverse correlations described. It is difficult to predict the ultimate impact of such regulations on public health, considering the complex chemistry of cigarette smoke formation. PMID- 23357568 TI - Failure of surgical and endovascular infrainguinal and iliac procedures in the management of peripheral arterial disease using data from electronic medical records. AB - PURPOSE: To understand rates of procedure failure among patients undergoing revascularization for peripheral arterial disease (PAD) in clinical practice. MATERIALS AND METHODS: This retrospective analysis of patients with PAD who underwent a PAD-related procedure used claims and electronic medical record data from 2005 to 2009. Procedures were grouped by type (endovascular [ie, angioplasty with/without stent, atherectomy] or surgical [ie, bypass surgery, endarterectomy, thrombectomy]) and site (ie, iliac, infrainguinal). The study assessed antiplatelet and anticoagulant agent use; procedure failure, defined as a subsequent procedure or amputation; and predictors of time to procedure failure. RESULTS: A sample of 248 patients with PAD who underwent a PAD-related procedure was identified. The population was 59% male, had a mean age of 73 years, and had a mean follow-up of 23 months. Endovascular procedures alone were performed in 37% of patients, with the remainder receiving surgery only or surgery with an endovascular procedure, and 79% of patients had an infrainguinal intervention. Antiplatelet and anticoagulant use rates after the procedure were 90% and 25%, respectively. After their initial procedure, 20% of patients required a second procedure or amputation, with an average failure time of 228 days. Patients treated with infrainguinal procedures had a significantly higher failure rate versus those treated with iliac procedures (23% vs 8%; P = .011). In multivariate analysis, patients without anticoagulant use before the procedure were at significantly lower failure risk (P = .022). CONCLUSIONS: Repeated intervention and/or major amputation after revascularization of PAD was common. Further investigation of the factors associated with procedure failure is warranted. PMID- 23357569 TI - OBSERVE-5 interim analysis: an observational postmarketing safety registry of etanercept for the treatment of psoriasis. AB - BACKGROUND: Etanercept is approved for the treatment of chronic moderate to severe plaque psoriasis in adults. OBJECTIVE: We sought to evaluate the long-term safety of etanercept in a real-world clinical setting. Assessment of etanercept efficacy was a secondary objective. METHODS: OBSERVE-5 is a 5-year observational safety registry initiated in May 2006 at multiple sites in the United States and Canada. Data collection includes the number of serious adverse events, serious infectious events, and prespecified events of medical interest. Efficacy data include body surface area assessments, physician and patient global assessments of psoriasis, and the Dermatology Life Quality Index. This interim analysis presents data from the first 3 years of the follow-up period. RESULTS: A total of 2511 patients were enrolled. Of 1890 patients continuing in the registry after 3 years, 113 were inactive for 1 to 2 years, and 115 were inactive for longer than 2 years. The 3-year incidence proportions of serious adverse events and serious infectious events based on Kaplan-Meier methodology were 0.14 and 0.04, respectively. The observed numbers of patients experiencing lymphoma, serious infectious events requiring hospitalization, nonmelanoma skin cancer, and malignancies excluding nonmelanoma skin cancer were not higher than the expected number of cases estimated from a large US administrative health claims database. LIMITATIONS: The registry lacks a control group, and the study is too small to measure the frequency of rare events. CONCLUSION: Etanercept demonstrated good tolerability in patients with plaque psoriasis in the clinical setting in this interim analysis. No new or unexpected safety concerns were observed. PMID- 23357570 TI - The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis. AB - BACKGROUND: Ipilimumab is a human antibody that inhibits cytotoxic T-lymphocyte associated antigen 4, leading to increases in T-cell activation and interleukin 2 secretion and has been approved for the treatment of advanced melanoma. Dermatologic adverse events such as rash, pruritus, and vitiligo have been reported in trials, with varying incidences. The overall incidence and risk of rash to ipilimumab is unknown. OBJECTIVE: We conducted a systematic review of the literature and performed a meta-analysis to ascertain the incidence and risk of developing rash among patients receiving ipilimumab. METHODS: Databases from PubMed and Web of Science from January 1998 until July 2011 and abstracts presented at the American Society of Clinical Oncology meetings from 2004 through 2011 were searched to identify relevant studies. The incidence and relative risk of rash were calculated using random effects or fixed effects model depending on the heterogeneity of included studies. RESULTS: A total of 1208 patients from clinical trials were included in this analysis. The overall incidence of all grade rash was 24.3% (95% confidence interval [CI] 21.4%-27.6%), with a relative risk of 4.00 (95% CI 2.63-6.08, P < .001). The overall incidence of high-grade rash was 2.4% (95% CI 1.1%-5.1%), with a relative risk of 3.31 (95% CI 0.70 15.76, P = .13). LIMITATIONS: The ability to detect rash may vary among institutions. CONCLUSION: There is a significant risk of developing rash in patients with cancer receiving ipilimumab. There was no statistically significant difference in the risk of rash based on dose or underlying tumor. Adequate monitoring and early intervention are recommended to prevent decreased quality of life and inconsistent dosing. PMID- 23357571 TI - Clinical analysis of fulminant type 1 diabetes in China and comparison with a nationwide survey in Japan. AB - OBJECTIVES: To report 26 cases of fulminant type 1 diabetes found in Guangdong Medical College Futian Hospital and Central South University Second Xiangya Hospital in China and to study the difference between Chinese and Japanese patients. METHODS: The clinical and biochemical characteristics of 26 patients who had been diagnosed with fulminant type 1 diabetes mellitus in China were analyzed retrospectively and then compared with those characteristics of 161 patients from a nationwide survey in Japan at the time of diagnosis and follow-up 6 months. RESULTS: The mean values of the characteristics from these two data sets, including fasting and postprandial serum C-peptide concentration, serum sodium and potassium level, positive for GADAb were significantly different (P=0.003, P=0.005, P=0.035, P=0.030, P<0.001, respectively). CONCLUSIONS: The clinical and biochemical characteristics of Chinese patients did not largely differ from those of Japanese patients. Further studies are needed for some unique characteristics found in our group. PMID- 23357572 TI - Clinical audit concerning the quality of management in patients with classic form of congenital adrenal hyperplasia. AB - OBJECTIVE: High Authority for Health (HAS) edited in April 2011 a national program of care and diagnostic (PNDS) concerning congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency in agreement with the international recommendation 2002 and 2010. To reduce long-term complications and improve the quality of life to our patients, we had tested our professional practices. PATIENTS: All patients aged more than 18 years with classic CAH of the adult endocrine units in the Nancy's University Hospital Center. METHODS: We have made a clinical audit. We checked all medical records to see whether the recommendation were applied or not between the last consultation before (Tour 1; T1) and after (Tour 2; T2) the introduction of the national guidelines. RESULTS: Twenty-seven medicals records with classic CAH were analyzed. The collection of clinical data must be more systematic because if the weight appeared in 89% of cases, body mass index missed (26% only in T1), the measure of the blood pressure remained insufficient (74% in T2). Concerning the therapeutic balance, 17 hydroxyprogesterone, testosterone, renin were correctly prescribed (>80%), Delta4 androstenedione in improvement (from 67% to 100%) some in defect (stable with 68% sodium and potassium). The evaluation of the fertility considerably progressed on the other hand the markers of bone metabolism were still often too much lacking. CONCLUSIONS: Change in compliance since national guidelines is a slow process. PMID- 23357573 TI - Increasing alpha angle is predictive of athletic-related "hip" and "groin" pain in collegiate National Football League prospects. AB - PURPOSE: The first purpose was to evaluate radiographic pathomorphology/abnormalities in a cohort of high-level collegiate football players screened with hip radiographs. The second purpose was to define the radiographic predictors of athletic-related "hip" and "groin" symptoms in this cohort of high-level athletes. METHODS: The study population included all male collegiate football players undergoing evaluation and hip radiography at the National Football League (NFL) Scouting Combine in 2009 and 2010. All radiographs were evaluated with a detailed evaluation for hip pathomorphology. Symptoms were recorded as symptomatic or asymptomatic with respect to athletic-related groin/hip pain for comparative purposes. RESULTS: There were 125 players (239 hips) who had hip radiographs and were included in the final cohort. Ninety percent of players (87% of hips) in this cohort had at least 1 finding consistent with cam-type and/or pincer-type femoroacetabular impingement (FAI). There were 75 hips in the symptomatic group and 164 hips in the asymptomatic group. Although the symptomatic group had a greater prevalence of cam-type FAI (P = .009), combined-type FAI (P < .001), and osteitis pubis (P = .014), increasing alpha angle (larger cam deformities) was the only independent predictor of athletic related groin pain (P = .01). There was no correlation, however, between FAI and body mass index (P = .659), player position (P = .166), or whether a player was drafted by an NFL team (P = .430). CONCLUSIONS: Radiographic signs of FAI were frequently seen in collegiate NFL prospects who were screened with hip radiographs. Although patients with radiographic evidence of osteitis pubis, cam- and combined-type FAI, and larger cam deformities showed a statistically higher prevalence of symptoms, increasing alpha angle (larger cam deformity) was the only independent predictor of athletic-related hip/groin pain. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23357574 TI - Effect of high carbon dioxide atmosphere packaging and soluble gas stabilization pre-treatment on the shelf-life and quality of chicken drumsticks. AB - The effects of an aerobic modified atmosphere packaging (MAP) (70% CO2, 15% O2 and 15% N2) with and without a CO2 3-h soluble gas stabilization (SGS) pre treatment of chicken drumsticks were determined for various package and product quality characteristics. The CO2 dissolved into drumsticks was determined. The equilibrium between CO2 dissolved in drumsticks and CO2 in head space was reached within 48h after packaging, showing highest values of CO2 in SGS pre-treated samples. This greater availability of CO2 resulted in lower counts of TAB and Pseudomonas in SGS than in MAP drumsticks. Package collapse was significantly reduced in SGS samples. The average of CO2 dissolved in the MAP treatment was 567mg CO2kg(-1) of chicken and, 361mg CO2kg(-1) of chicken during the MAP treatment, in SGS pre-treated samples. This difference could be the quantity of CO2 dissolved during SGS pre-treatment. These results highlight the advantages of using SGS versus traditional MAP for chicken products preservation. PMID- 23357575 TI - Sensory evaluation of boar loins: trained assessors' olfactory acuity affects the perception of boar taint compounds. AB - This study investigated the impact of assessors' varying olfactory acuity on the perceived intensity of androstenone and skatole odour and flavour in boar loins. To discriminate sensitive (SENS) and highly sensitive (SENSHIGH) panellists, two levels of androstenone were used on smell strips. Sensitivity was defined as the correct identification of the androstenone strip in three replicate triangle tests. Judges then assessed loins from boars, castrated pigs and gilts. SENSHIGH assessors scored low-fat boar loins with 1.5 to 2.0MUg of androstenone per gram of melted back fat which is significantly different from castrate and gilt loins for androstenone odour and flavour whereas SENS assessors were less discriminating. Panellists' olfactory acuity should thus be considered for selection and training. The presented paper strip system is suggested for objective screening and training purposes and to be used as quantitative references in descriptive analysis. PMID- 23357576 TI - X-linked intellectual disability gene CUL4B targets Jab1/CSN5 for degradation and regulates bone morphogenetic protein signaling. AB - Cullin 4B (CUL4B) is a scaffold protein involved in the assembly of cullin-RING ubiquitin ligase (E3) complexes. Contemporary reports have identified multiple mutations of CUL4B gene as being causally associated with X-linked intellectual disability (XLID). Identifying the specific protein substrates will help to better understand the physiological functions of CUL4B. The current study identified Jun activation domain-binding protein (Jab1/CSN5) in the COP9 signalosome (CSN) complex as a novel proteolytic target for the CUL4B ubiquitin ligase complex. The impaired degradation of Jab1 was observed in cells after RNAi mediated CUL4B depletion. Integrity of DDB1-CUL4B-ROC1 was further demonstrated to be indispensable for the degradation of Jab1. In addition, the degradation of Jab1 is independent of CUL4A, a cullin family member closely related to CUL4B. In vitro and in vivo ubiquitination assays revealed that CUL4B promoted the polyubiquitination of Jab1. Interestingly, CUL4B-silenced cells were shown to exhibit abnormal upregulation of bone morphogenetic protein (BMP) signaling. Furthermore, in vivo studies of embryonic fibroblasts in Cul4b-deficient mice demonstrated Jab1 accumulation and increased activation of the BMP signaling pathway. Together, the current findings demonstrate the CUL4B E3 ubiquitin ligase plays a key role in targeting Jab1 for degradation, potentially revealing a previously undocumented mechanism for regulation of the BMP signaling pathway involved with the CUL4B-based E3 complex. This observation may provide novel insights into the molecular mechanisms underlying CUL4B-associated XLID pathogenesis. PMID- 23357577 TI - Zebrafish embryo as a tool to study tumor/endothelial cell cross-talk. AB - Tumor/endothelial cell cross-talk plays a pivotal role in the growth, neovascularization and metastatic dissemination of human cancer. Recent observations have shown that the teleost zebrafish (Danio rerio) may represent a powerful experimental platform in cancer research. Various tumor models have been established in zebrafish adults, juveniles, and embryos and novel genetic tools and high resolution in vivo imaging techniques have been exploited. In particular, grafting of mammalian tumor cells in zebrafish embryo body may simulate early stages of tumor development, neovascularization, and local invasion whereas the injection of cancer cells in the bloodstream of zebrafish embryo may allow the study of metastatic homing and colonization. This review focuses on the recent advances in tumor xenotransplantation in zebrafish embryo for the in vivo study of the cancer neovascularization, invasion and metastatic processes. This article is part of a Special Issue entitled: Animal Models of Disease. PMID- 23357578 TI - Reconstruction of blast injuries of the hand and upper limb. AB - Over recent years, hand surgeons in the Middle East and Arabic region have particularly had to deal with an increasing number of war blast injuries to the upper extremity, in the acute, subacute and chronic phases. Many have been referred from War Zone countries such as Iraq and, more recently, Syria, where the resources to treat such complex injuries are scarce. The present article is a comprehensive review of the basic principles of management of blast injuries based on the available literature merged with the authors' personal experience of these injuries. The state of the art in treatment of blast injuries to the hand, from ammunition physics and wound ballistics to radiological investigation and, ultimately, the principles of surgical management are discussed. PMID- 23357580 TI - Electronic structure and optical properties of resin. AB - We used the density of functional theory (DFT) to study the electronic structure and density of states of resin by ab initio calculation. The results show the band gap of resin is 1.7 eV. The covalent bond is combined C/O atoms with H atoms. The O 2p orbital is the biggest effect near the Fermi level. The results of optical properties show the reflectivity is low, and the refractive index is 1.7 in visible light range. The highest absorption coefficient peak is in 490 nm and the value is 75,000. PMID- 23357579 TI - Viewing the dynamics and control of visual attention through the lens of electrophysiology. AB - How we find what we are looking for in complex visual scenes is a seemingly simple ability that has taken half a century to unravel. The first study to use the term visual search showed that as the number of objects in a complex scene increases, observers' reaction times increase proportionally (Green & Anderson, 1956). This observation suggests that our ability to process the objects in the scenes is limited in capacity. However, if it is known that the target will have a certain feature attribute, for example, that it will be red, then only an increase in the number of red items increases reaction time. This observation suggests that we can control which visual inputs receive the benefit of our limited capacity to recognize the objects, such as those defined by the color red, as the items we seek. The nature of the mechanisms that underlie these basic phenomena in the literature on visual search have been more difficult to definitively determine. In this paper, I discuss how electrophysiological methods have provided us with the necessary tools to understand the nature of the mechanisms that give rise to the effects observed in the first visual search paper. I begin by describing how recordings of event-related potentials from humans and nonhuman primates have shown us how attention is deployed to possible target items in complex visual scenes. Then, I will discuss how event-related potential experiments have allowed us to directly measure the memory representations that are used to guide these deployments of attention to items with target-defining features. PMID- 23357582 TI - Laoxyuris laonasti n. gen., n. sp. (Nematoda: Syphaciinae) parasite of Laonastes aenigmamus (Rodentia: Diatomyidae): morphology, biology, taxonomy, phylogeny. AB - A new Oxyurid genus and species are described in a rodent recently discovered in Lao PDR: Laonastes aenigmamus which happens to be the single survivor of the Diatomyidae, a family considered to be extinct since the Miocene. The morphological characters of the new parasite species allow classifying it within the Syphaciinae Railliet, 1916, a subfamily whose members are exclusively parasites of Lagomorpha and Rodents. Male Syphaciinae have developed several types of ventral cuticular ornamentation used to firmly grip the female during mating. The ornamental characters observed in the new species include a finger like appendix, which, until now, has not been described in the subfamily. The originality of this apparatus justifies the creation of a new genus and a new species for the pinworm parasite of Laonastes. Using morphological characters, the new species is analyzed phylogenetically to describe its affinities with representatives of the main groups distinguished within the Syphaciinae. The phylogenetic study produces a cladogram similar to the phylogeny recently proposed for the hosts of the subfamily and in agreement with a close association of the Diatomyidae with the Ctenodactylidae. Such a phenomenon of cophylogeny is interpreted as the result of the existence of a strict specificity between the Syphaciinae and their respective hosts, due to the very close adaptation of their life cycle with the behaviors of their hosts. In Lagomorpha and Rodents, caecotrophy and grooming activities allow a direct transmission of the parasite eggs and favor successive self-infestations, increasing the chances for the parasite to maintain itself in the same host species but decreasing the probability of host switching. The resulting high host specificity allowed the Syphaciinae to out-compete other pinworms and maintain themselves in their specific host over millions of years. PMID- 23357583 TI - Pathogen typing in the genomics era: MLST and the future of molecular epidemiology. AB - Multi-locus sequence typing (MLST) is a high-resolution genetic typing approach to identify species and strains of pathogens impacting human health, agriculture (animals and plants), and biosafety. In this review, we outline the general concepts behind MLST, molecular approaches for obtaining MLST data, analytical approaches for MLST data, and the contributions MLST studies have made in a wide variety of areas. We then look at the future of MLST and their relative strengths and weaknesses with respect to whole genome sequence typing approaches that are moving into the research arena at an ever-increasing pace. Throughout the paper, we provide exemplar references of these various aspects of MLST. The literature is simply too vast to make this review comprehensive, nevertheless, we have attempted to include enough references in a variety of key areas to introduce the reader to the broad applications and complications of MLST data. PMID- 23357581 TI - No evidence for positive selection at two potential targets for malaria transmission-blocking vaccines in Anopheles gambiae s.s. AB - Human malaria causes nearly a million deaths in sub-Saharan Africa each year. The evolution of drug-resistance in the parasite and insecticide resistance in the mosquito vector has complicated control measures and made the need for new control strategies more urgent. Anopheles gambiae s.s. is one of the primary vectors of human malaria in Africa, and parasite-transmission-blocking vaccines targeting Anopheles proteins have been proposed as a possible strategy to control the spread of the disease. However, the success of these hypothetical technologies would depend on the successful ability to broadly target mosquito populations that may be genetically heterogeneous. Understanding the evolutionary pressures shaping genetic variation among candidate target molecules offers a first step towards evaluating the prospects of successfully deploying such technologies. We studied the population genetics of genes encoding two candidate target proteins, the salivary gland protein saglin and the basal lamina structural protein laminin, in wild populations of the M and S molecular forms of A. gambiae in Mali. Through analysis of intraspecific genetic variation and interspecific comparisons, we found no evidence of positive natural selection at the genes encoding these proteins. On the contrary, we found evidence for particularly strong purifying selection at the laminin gene. These results provide insight into the patterns of genetic diversity of saglin and laminin, and we discuss these findings in relation to the potential development of these molecules as vaccine targets. PMID- 23357584 TI - Cyclopamine and jervine induce COX-2 overexpression in human erythroleukemia cells but only cyclopamine has a pro-apoptotic effect. AB - Erythroleukemia is generally associated with a very poor response and survival to current available therapeutic agents. Cyclooxygenase-2 (COX-2) has been described to play a crucial role in the proliferation and differentiation of leukemia cells, this enzyme seems to play an important role in chemoresistance in different cancer types. Previously, we demonstrated that diosgenin, a plant steroid, induced apoptosis in HEL cells with concomitant COX-2 overexpression. In this study, we investigated the antiproliferative and apoptotic effects of cyclopamine and jervine, two steroidal alkaloids with similar structures, on HEL and TF1a human erythroleukemia cell lines and, for the first time, their effect on COX-2 expression. Cyclopamine, but not jervine, inhibited cell proliferation and induced apoptosis in these cells. Both compounds induced COX-2 overexpression which was responsible for apoptosis resistance. In jervine-treated cells, COX-2 overexpression was NF-kappaB dependent. Inhibition of NF-kappaB reduced COX-2 overexpression and induced apoptosis. In addition, cyclopamine induced apoptosis and COX-2 overexpression via PKC activation. Inhibition of the PKC pathway reduced both apoptosis and COX-2 overexpression in both cell lines. Furthermore, we demonstrated that the p38/COX-2 pathway was involved in resistance to cyclopamine-induced apoptosis since p38 inhibition reduced COX-2 overexpression and increased apoptosis in both cell lines. PMID- 23357586 TI - Lipase-immobilized biocatalytic membranes for biodiesel production. AB - Microbial lipase from Candida rugosa (Amano AY-30) has good transesterification activity and can be used for biodiesel production. In this study, polyvinylidene fluoride (PVDF) membrane was grafted with 1,4-diaminobutane and activated by glutaraldehyde for C. rugosa lipase immobilization. After immobilization, the biocatalytic membrane was used for producing biodiesel from soybean oil and methanol via transesterification. Response Surface Methodology (RSM) in combination with a 5-level-5-factor central composite rotatable design (CCRD) was employed to evaluate the effects of reaction time, reaction temperature, enzyme amount, substrate molar ratio and water content on the yield of soybean oil methyl ester. By ridge max analysis, the predicted and experimental yields under the optimum synthesis conditions were 97% and 95%, respectively. The lipase immobilized PVDF membrane showed good reuse ability for biodiesel production, enabling operation for at least 165 h during five reuses of the batch, without significant loss of activity. PMID- 23357585 TI - Medication beliefs and self-reported adherence among community-dwelling older adults. AB - BACKGROUND: Nonadherence to medications among older adults can compromise quality care. Among older adults with chronic diseases, nonadherence rates can reach 50%. Individual-level obstacles to full adherence may come from psychological, illness (and disability due to aging or other impairments), and tangible barriers. In this study, we examine the barriers associated with nonadherence among community dwelling older persons participating in Aging Service Network nutrition programs. OBJECTIVE: The goal of this study was to examine the relation of psychological, illness, and tangible barriers to reported medication adherence among older adults in a community, nonmedical setting. METHODS: Older adults (N = 299) receiving congregate meals participated in a study of factors associated with medication-taking behaviors and adherence. Self-reported medication nonadherence was measured by using the Morisky Medication Adherence Scale. Psychological barriers were assessed by using a risk/benefit score (perceived concerns vs necessity of medications). Illness barriers reviewed included overall cognitive functioning, disability, medical burden, and depression. Tangible barriers included number of medications, difficulty handling medication, and perceived cost. RESULTS: Most participants took multiple medications (mean, 4.8) each day, and 4 of 10 older adults (41% [122 of 299]) reported at least 1 nonadherent behavior. The psychological barrier of a low risk/benefit score (odds ratio = 0.73 [95% CI, 0.6-0.94]) and the tangible barrier of difficulty opening the medication bottle (odds ratio = 2.16 [95% CI, 1.3-3.6]) were independently associated with nonadherence. CONCLUSIONS: In a community-dwelling sample of older adults, nonadherence to medication was associated with both tangible and psychological barriers. Beliefs about medication can be powerful barriers to a successful adherence strategy. Adherence interventions should address the multilevel barriers (psychological, illness, and tangible) to adherence among older adults. PMID- 23357587 TI - Catalytic conversion of bio-oil to oxygen-containing fuels by simultaneous reactions with 1-butanol and 1-octene over solid acids: Model compound studies and reaction pathways. AB - Upgrading bio-oil by addition reactions across olefins represents a route to refine bio-oil to combustible and stable oxygen-containing fuels. Development and application of highly active strong solid acid catalysts with good hydrothermal stability has become a key determinant for success, because bio-oil's complexity includes large amounts of water. Temperatures of 120 degrees C or more are needed for satisfactory kinetics. Batch upgrading of a model bio-oil (phenol/water/acetic acid/acetaldehyde/hydroxyacetone/d-glucose/2 hydroxymethylfuran) over five water-tolerant solid acid catalysts (Dowex50WX2, Amberlyst15, Amberlyst36, silica sulfuric acid (SSA) and Cs(2.5)H(0.5)PW(12)O(40) supported on K-10 clay (Cs(2.5)/K-10, 30wt.%)) with 1-octene/1-butanol were studied at 120 degrees C/3h. SSA, , exhibited the highest water tolerance and activity. Upgrading using olefin/1-butanol is complex, involving many simultaneous competing esterification, etherification, olefin hydration, phenol alkylation, aldol condensation, sugar dehydration etc. reactions. PMID- 23357588 TI - One-pot bioconversion of sucrose to trehalose using enzymatic sequential reactions in combined cross-linked enzyme aggregates. AB - Amylosucrase (AS), maltooligosyltrehalose synthase (MTS), and maltooligosyltrehalose trehalohydrolase (MTH) were used in combined cross-linked enzyme aggregates (combi-CLEAs) to achieve one-step bioconversion of sucrose to trehalose. Combi-CLEAs of three enzymes were successfully established with acetone and glutaraldehyde (GA) as a precipitant and a cross-linker, respectively. The optimum enzyme ratio was 8:0.5:0.5 (AS, 4mg:MTS, 0.25mg:MTH, 0.25mg). To improve trehalose production, bovine serum albumin was co-aggregated with enzymes as a proteic feeder. The trehalose production yield of combi-CLEAs was about 8% in each cycle on the basis of substrate added up to 400mM. Finally, the combi-CLEAs used in this experiment showed reusability of about five cycles without any activity loss. PMID- 23357589 TI - Drying and re-cultivation of aerobic granules. AB - Aerobic granules stored in liquid medium can lose structural integrity during storage. This study demonstrated that the aerobic granules cultivated by seeding activated sludge into column-type sequential batch reactors and fed with synthetic wastewater at organic loading rate of 1.5 kg/m3-d can be dried by acetone gradient method to moisture content less than 1%. Then, the dried granules can be reactivated through a re-cultivation process to recover their organic degradation capacity in 12 h, or their appearance in 5 d. During the drying and recovery, the granules experienced volume and weight losses by >80% and >85%, respectively, with minimal loss in structural integrity. The microbial communities of the dried and re-cultivated granules were probed using polymerase chain reaction-denaturing gradient gel electrophoresis technique. The family Xanthomonadaceae and the family Comamonas can survive in dried granules and could contribute to maintain structural integrity in re-cultivation stage. PMID- 23357590 TI - Wheat flour based propionic acid fermentation: an economic approach. AB - A process for the fermentative production of propionic acid from whole wheat flour using starch and gluten as nutrients is presented. Hydrolysis of wheat flour starch using amylases was optimized. A batch fermentation of hydrolysate supplemented with various nitrogen sources using Propionibacterium acidipropionici NRRL B 3569 was performed. The maximum production of 48.61, 9.40, and 11.06 g of propionic acid, acetic acid and succinic acid, respectively, was found with wheat flour hydrolysate equivalent to 90 g/l glucose and supplemented with 15 g/l yeast extract. Further, replacement of yeast extract with wheat gluten hydrolysate showed utilization of gluten hydrolysate without compromising the yields and also improving the economics of the process. The process so developed could be useful for production of animal feed from whole wheat with in situ production of preservatives, and also suggest utilization of sprouted or germinated wheat for the production of organic acids. PMID- 23357591 TI - Insular thyroid carcinoma: a retrospective clinicopathologic study. AB - BACKGROUND: Poorly differentiated carcinoma is a rare epithelial tumor that falls between well-differentiated thyroid carcinoma and anaplastic thyroid carcinoma in terms of morphologic appearance and biologic behavior. An insular variant was characterized in 1983. Further study of this neoplasm is warranted owing to its high aggressiveness, propensity to local recurrence and distant metastases, and high associated mortality. Since insular thyroid carcinoma may have varied presentations, treatment should be individualized. PURPOSE: To describe the experience of a major tertiary medical center with insular thyroid carcinoma over a 7-year period. MATERIAL AND METHODS: The study sample consisted of 17 patients with poorly differentiated thyroid cancer, insular variant, who were treated and followed at the Department of Otolaryngology, Head and Neck Surgery of Rabin Medical Center, Israel, in 1992-2009. The medical files were reviewed for background data, clinicopathologic features, treatment, and outcome. RESULTS: The study group included 10 men and 7 women with a mean age of 63 years (range 16 78). Initial treatment was total thyroidectomy, in a single session (n=9) or two sessions (n=8), followed by radioiodine ablation. In addition, five patients received postoperative external beam radiation and one patient received chemotherapy. Nine patients had extrathyroidal extension, seven had vascular invasion, and four had multifocal disease. Distant metastases were present in four patients. Follow-up ranged from 6 months to 12 years. At present, 11 patients are alive and well. Five died of disease, and one died of another cause. CONCLUSION: Insular thyroid carcinoma is aggressive and difficult to treat. Surgery remains the mainstay of treatment, though multimodality therapy is usually required. PMID- 23357592 TI - Sudden sensorineural hearing loss: results of intratympanic steroids as salvage treatment. AB - OBJECTIVE: The aim of the present study was to verify the efficacy and the safety of intratympanic dexamethasone to treat sudden sensorineural hearing loss as salvage therapy. MATERIALS AND METHODS: A prospective study was conducted on patients affected by idiopathic sudden hearing loss who were treated before with some systemic therapy, but without recovery of the hearing The patients able to undergo the study, but who refused salvage treatment were considered as control group. A solution of Dexamethasone 4 mg/ml was then injected through the posterior-inferior quadrant filling completely the middle ear. The follow-up in the following 6 months included an audiogram every month. RESULTS: The number of patients treated with salvage therapy was 36. The patients who refused treatment were further 10. The salvage treatment was done with a mean delay of 24.3 days from the onset of symptoms. Mean hearing threshold after the onset of sudden hearing loss at PTA was 66.5 dB. After the failed treatment the mean PTA was 59.6 dB. The mean PTA after the intratympanic steroid administration was 46.8 dB, with a mean improvement of 12.8 dB. No hearing change was noted in the 10 patients who refused salvage therapy. The patients that assumed systemic steroid as first therapy showed a better PTA threshold after the salvage intratympanic treatment (p<0.01). A significant difference (p<0.05) of hearing recovery was evidenced between non-smoker patients and those with smoking habit. CONCLUSIONS: Our data showed that a salvage treatment with intratympanic dexamethasone should be suggested to all patients who failed the first systemic treatment. The systemic steroid therapy done before the salvage treatment seems to exert a protective role for the inner ear, as shown by our series. On the contrary the smoke habit is a negative prognostic factor in the hearing recovery. PMID- 23357593 TI - Sarcoidosis-like granulomatosis of the hypopharynx as a complication of anti-TNF therapy. AB - INTRODUCTION: Sarcoidosis is a multisystem granulomatous disease of unknown etiology, occasionally presenting with signs and symptoms that occur within the head and neck. Recently, granulomatous reactions and cases of sarcoidosis have been reported in patients treated with anti-TNF agents. METHODS: This report describes a 56-year-old man who developed sarcoidosis in the hypopharynx during adalimumab therapy for psoriatic arthritis. A retrospective review of the literature was performed using the PubMed database. RESULTS: In our patient, a chronic granulomatous reaction consistent with sarcoidosis developed after 2 years of continuous treatment with adalimumab. The diagnosis of sarcoidosis was established by the typical well-formed non caseating granulomas on biopsy, after excluding all other granulomatous conditions. Following withdrawal of anti-TNF agents and a course of steroids, the clinical picture resolved. CONCLUSIONS: The development of sarcoidosis during treatment with TNF-a antagonists represents a rare and paradoxical adverse event. To our knowledge this is the first case of sarcoidosis of the hypopharynx reported in the literature. PMID- 23357594 TI - Chronic oroantral fistula: combined endoscopic and intraoral approach under local anesthesia. AB - OBJECTIVE: To evaluate the outcome of combined surgical treatment of oroantral communications associated with chronic maxillary sinusitis. PATIENTS AND METHODS: 8 consecutive patients affected by complicated oroantral fistula were included in the study. The protocol consisted of: clinical, endoscopic and radiological preoperative evaluation (panoramic tomogram and computed tomography); systemic antibiotic and steroid therapy 2 weeks before surgery; one-stage surgical procedure under local anaesthesia consisting in uncinectomy with enlargement of the osteomeatal complex through endoscopic nasal approach associated with the closure of the oroantral communication by means of a mucoperiosteal flap; postoperative antibiotic and cortisone-based therapy. Follow-up consisted of weekly clinical evaluation during the first month, and nasal endoscopy at 3, 8 and 24 weeks after surgery. RESULTS: After surgical treatment, all patients were symptom-free and had no endoscopic and radiological evidences of maxillary sinusitis at the 6-month follow-up. No recurrent oroantral fistulas were found. CONCLUSIONS: The current prospective study showed that a one-stage, combined endoscopic and intraoral approach under local anaesthesia represents a feasible and minimally invasive procedure for the long-term effective treatment of chronic complicated oroantral communications. Moreover, it represents an easily applicable approach also in outpatient clinics with minor patient discomfort. PMID- 23357595 TI - Preoperative subclinical hypothyroidism in patients with papillary thyroid carcinoma. AB - OBJECTIVE: To assess the effect of preoperative subclinical hypothyroidism on prognosis and on the tumour's clinicopathological features at initial diagnosis of papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: 328 patients who underwent surgery for PTC between January 2001 and December 2006 were enrolled in this study. Of these, we compared 35 patients with preoperative subclinical hypothyroidism with 257 patients who were euthyroid before the operation, with respect to clinicopathological characteristics and prognosis. RESULTS: No significant differences were observed in tumour size, extrathyroidal extension, and multifocality between subclinical hypothyroidism and euthyroid patients. Patients with subclinical hypothyroidism had a considerably lower percentage of lymph node metastasis than did euthyroid patients (8.6% vs. 21.8%, p=0.068). Although preoperative subclinical hypothyroidism decreased the risk of lymph node metastasis at 0.313 of odds ratio in the multivariate analysis, its significance was not verified (95% confidence internal, 0.089-1.092; p=0.068). Patients with preoperative subclinical hypothyroidism tended to have a better prognosis than did preoperative euthyroid patients, for both recurrence (2.9% vs. 14.0%, p=0.099) and 7-year disease-free survival (97.1% vs. 87.8%, p=0.079), during the 82-month mean follow-up period. However, even as thyroid-stimulating hormone (TSH) concentration increased, there were no consistent relationships observed between the TSH levels and the prognostic parameters. CONCLUSION: We could find neither a consistent positive nor a negative linear relationship between TSH levels and several prognostic parameters, indicating that subclinical hypothyroidism with elevated TSH is not an independent predictor of tumour aggressiveness and poor prognosis in PTC. PMID- 23357596 TI - Microbial transformation of cycloastragenol. AB - The microbial transformation of cycloastragenol by the fungi Cunninghamella blakesleeana NRRL 1369 and Glomerella fusarioides ATCC 9552, and the bacterium Mycobacterium sp. NRRL 3805 were investigated. Both fungi mainly provided hydroxylated metabolites together with products formed by cyclization, dehydrogenation and Baeyer-Villiger oxidation resulting in a ring cleavage. The bacteria yielded only a single oxidation product, namely, 3-oxo-cycloastragenol. Structures of the metabolites were elucidated by 1-D ((1)H,(13)C), 2-D NMR (COSY, HMBC, HMQC) and HRMS analyses. PMID- 23357597 TI - Structure and cytotoxicity of steroidal glycosides from Allium schoenoprasum. AB - A phytochemical analysis of the whole plant of Allium schoenoprasum, has led to the isolation of four spirostane-type glycosides (1-4), and four known steroidal saponins. Their structures were elucidated mainly by 2D NMR spectroscopic analysis and mass spectrometry as (20S,25S)-spirost-5-en-3beta,12beta,21-triol 3 O-alpha-L-rhamnopyranosyl-(1->2)-beta-D-glucopyranoside (1), (20S,25S)-spirost-5 en-3beta,11alpha,21-triol 3-O-alpha-L-rhamnopyranosyl-(1->2)-beta-D glucopyranoside (2), laxogenin 3-O-alpha-L-rhamnopyranosyl-(1->2)-[beta-D glucopyranosyl-(1->4)]-beta-D-glucopyranoside (3), and (25R)-5alpha-spirostan 3beta,11alpha-diol 3-O-beta-D-glucopyranosyl-(1->3)-[beta-D-glucopyranosyl-(1 >4)]-beta-D-galactopyranoside (4). Four of the isolated compounds were tested for cytotoxic activity against the HCT 116 and HT-29 human colon cancer cell lines. PMID- 23357598 TI - Efficacy of a single high oxfendazole dose against gastrointestinal nematodes in naturally infected pigs. AB - The goal of the current experiment was to assess the clinical efficacy of oxfendazole (OFZ) administered as a single oral dose (30 mg/kg) to pigs naturally parasitized with Ascaris suum, Oesophagostomum spp., Metastrongylus spp. and Trichuris suis. Thirty-six local ecotype piglets were divided into three independent experiments, named I, II and III (n=12 each), respectively. Each experiment involved two different groups (n=6): Untreated Control and OFZ treated. Animals were naturally parasitized with A. suum (Experiments I, II and III), Oesophagostomum spp. (Experiments I and II), T. suis (Experiments II and III) and Metastrongylus spp. (Experiment I). Pigs in the treated group received OFZ (Synanthic((r)), Merial Ltd., 9.06% suspension) orally at 30 mg/kg dose. At five (5) days post-treatment, animals were sacrificed and the clinical efficacy of the OFZ treatment was established following the currently available WAAVP guidelines for a controlled efficacy test. None of the animals involved in this experiment showed any adverse events during the study. OFZ treatment given as a single 30 mg/kg oral dose showed a 100% efficacy against all the nematode parasites present in the three experiments. In conclusion, under the current experimental conditions, OFZ orally administered to naturally parasitized piglets at a single dose of 30 mg/kg was safe and highly efficacious (100%) against adult stages of A. suum, Oesophagostomum spp., T. suis and Metastrongylus spp. PMID- 23357599 TI - Smallholder pig production: prevalence and risk factors of ectoparasites. AB - A cross-sectional study was carried out in the Mbeya Region, Tanzania, with the aim of describing the distribution and diversity of ectoparasites on pigs, within confinement and free-range production systems of smallholder farms. A total of 128 farms were surveyed, with 96 practising confinement and 32 practising free range production systems. The prevalence of ectoparasites on pigs within confinement and free-range production systems was 24% and 84%, respectively. Logistic regression analyses revealed that keeping pigs in a free-range system and the presence of neighbouring pigs were risk factors for ectoparasites. Within the confinement system, contact with neighbouring pigs and the time interval (in months) since last ectoparasitic treatment were additionally identified as risk factors. The prevalence of Haematopinus suis was 20% in confined pigs and 63% among free-range pigs. Free-ranging of pigs and presence of neighbouring pigs were also identified as risk factors for the presence of lice. Three species of fleas were identified; Tunga penetrans, Echidnophaga gallinacea and Ctenocephalides canis. The prevalence of fleas was 5% and 13% within confined and free-range, respectively. Two pigs (2%) were found infested with Sarcoptes scabiei var. suis. Ticks found belonged to four genera; Amblyomma spp., Rhipicephalus spp., Haemaphysalis spp., and Boophilus spp. The prevalence of hard ticks among the free-range pigs was 50%. Ectoparasites were more prevalent in the free-range system although highly prevalent within both production systems. Keeping pigs in a free-range system and contact with neighbouring pigs were main risk factors for the presence of ectoparasites. Confinement was highly effective as a preventive tool against hard ticks. PMID- 23357600 TI - Imaging of valvular heart disease. AB - Imaging plays a fundamental role in the current diagnosis and treatment of valvular heart disease (VHD) and in the preclinical and clinical research aiming at the development of novel pharmacologic or interventional therapies. Doppler echocardiography remains the primary imaging technique for the clinical management of VHD. However, the multifaceted and complex nature of VHD and the rapid development of transcatheter valve therapies has led to a spectacular increase in the use of multimodality imaging in the past decade. The purpose of this article is to review the current and emerging roles of the different imaging modalities in the diagnosis and treatment of VHD and to present the new directions for future research and clinical applications. PMID- 23357601 TI - The role of noninvasive imaging in coronary artery disease detection, prognosis, and clinical decision making. AB - A vast array of noninvasive imaging modalities is available for the evaluation of the presence and severity of coronary artery disease (CAD). Choosing the right test can be challenging but is critical for proper patient diagnosis and management. Presently available imaging tests for CAD include: (1) nuclear myocardial perfusion imaging procedures (single-photon emission tomography) and positron emission tomography, (2) stress echocardiography, (3) computed tomography coronary angiography, and (4) cardiac magnetic resonance imaging. Exercise treadmill testing electrocardiography is another alternative that we will discuss briefly. Selection of the most appropriate imaging modality requires knowledge of the clinical question being addressed, patient characteristics (pretest probability and prevalence of disease), the strengths, limitations, risks, costs, and availability of each procedure. To assist with test selection, we review the relevant literature in detail to consider the relative merits of cardiac imaging modalities for: (1) detection of CAD, (2) risk stratification and prognostication, and (3) guiding clinical decision making. PMID- 23357602 TI - Alteration of serum sex hormonal profile in male gasoline filling station workers in respect to their polymorphism of glutathione S-transferase M1. AB - Alterations in offspring sex ratio at birth and level of serum testosterone in filling-station workers have been reported. To determine the association of glutathione S-transferase M1 (GSTM1) polymorphism with serum levels of total testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) of male filling-station workers, the present study was carried out on 114 gasoline workers and 100 age- and sex-matched controls with no occupational exposure to gasoline. We have found no significant difference between the workers and controls for levels of sex hormones in the presence of active GSTM1 genotype. Among subjects with the GSTM1 null genotype, there was significant difference between exposed and unexposed subjects for the concentration of testosterone (t=4.37, df=97, P<0.001). To investigate whether one null genotype could be compensated by an active genotype for the other isoenzyme, the mean concentrations of sex hormones was compared between the exposed and control groups with respect to their combinations of the GSTM1 and GSTT1 genotypes. The exposed group having either "null GSTM1/positive GSTT1" (t=2.76, df=72, P=0.007) or "null GSTM1/null GSTT1" (t=4.91, df=23, P<0.001) combinations had a lower testosterone compared with the controls. It seems that GSTM1 polymorphism has more effect on serum testosterone compared to the GSTT1 polymorphism, in exposed workers. PMID- 23357603 TI - Role of L-thyroxin in counteracting rotenone induced neurotoxicity in rats. AB - A key feature of Parkinson's disease is the dopaminergic neuronal cell loss in the substantia nigra pars compacta. Many triggering pathways have been incriminated in the pathogenesis of this disease including inflammation, oxidative stress, excitotoxicity and apoptosis. Thyroid hormone is an essential agent for the growth and maturation of neurons; moreover, it has variable mechanisms for neuroprotection. So, we tested the efficacy of (L)-thyroxin as a neuroprotectant in rotenone model of Parkinson's disease in rats. Thirty Sprague Dawley rats aged 3 months were divided into 3 equal groups. The first received daily intraperitoneal injections of 0.5% carboxymethyl cellulose (CMC) 3 mL/Kg. The second group received rotenone suspended in 0.5% CMC intraperitoneally at a dose of 3 mg/kg, daily. The third group received the same rotenone regimen subcutaneous l-thyroxine at a dose of 7.5 MUg daily. All animals were evaluated regarding locomotor disturbance through blinded investigator who monitored akinesia, catalepsy, tremors and performance in open field test. After 35 days the animals were sacrificed and their brains were immunostained against anti tyrosine hydroxylase and iba-1. Photomicrographs for coronal sections of the substantia nigra and striatum were taken and analyzed using image J software to evaluate cell count in SNpc and striatal fibers density and number of microglia in the nigrostriatal system. The results were then analyzed statistically. Results showed selective protective effects of thyroxin against rotenone induced neurotoxicity in striatum, however, failed to exert similar protection on SN. Moreover, microglial elevated number in nigrostriatal system that was induced by rotenone injections was diminished selectively in striatum only in the l-thyroxin treated group. One of the possible mechanisms deduced from this work was the selective regulation of microglia in striatal tissues. Thus, this study provides an insight into thyroxin neuroprotection warranting further investigation as therapeutic option for Parkinson's disease patients. PMID- 23357604 TI - Ginkgo biloba extract reduces high-glucose-induced endothelial reactive oxygen species generation and cell adhesion molecule expression by enhancing HO-1 expression via Akt/eNOS and p38 MAP kinase pathways. AB - AIM: Hyperglycemia is one of the major risk factors leading to vascular complications in clinical diabetes mellitus. Ginkgo biloba extract (GBE), an antioxidant herbal medicine, possesses anti-inflammatory effects. We examined whether GBE can reduce high glucose-induced endothelial adhesiveness to monocytes, an in vitro sign mimicking in vivo early atherogenesis, through selective regulation of heme oxygenase (HO)-1 expression. METHODS: Human aortic endothelial cells (HAECs) were cultured with normal glucose or high glucose (25 mM) for 4 days and subsequently combined with GBE (EGb761, Dr. Willmar Schwabe, Karlsruhe, Germany) treatment in the last 18 h of the 4-day period. The endothelial reactive oxygen species (ROS) generation, adhesion molecule expression and the adhesiveness to monocytes were examined. The specific signal pathways such as HO-1 were also examined. RESULTS: High glucose increased ROS generation, adhesion molecule expression and the adhesiveness to monocytes in HAECs. These high glucose-induced phenomena could be suppressed by GBE (100 MUg/ml)-induced HO-1 expression in a dose-dependent and time-dependent manner. In addition, jun N-terminal kinases inhibitor or phosphoinositide 3 kinase inhibitor could reduce GBE-induced HO-1 expression. Furthermore, HO-1 inhibitor, HO-1 siRNA, endothelial nitric oxide synthase (eNOS) siRNA, or nuclear factor erythroid 2-related factor (Nrf) 2 siRNA blocked the cytoprotective effects of GBE. Meanwhile, p38/mitogen-activated protein kinase (MAPK) inhibitor could also reduce the effects of GBE on HO-1 induction. CONCLUSION: GBE could reduce high glucose-induced endothelial adhesion via enhancing HO-1 expression through the Akt/eNOS and p38/MAPK pathways. Our findings suggest a potential strategy targeting on HO-1 induction by GBE for endothelial protection in the presence of high glucose such as that in diabetes mellitus. PMID- 23357605 TI - Evaluation of protective efficacy conferred by a recombinant Mycobacterium bovis BCG expressing a fusion protein of Ag85A-ESAT-6. AB - BACKGROUND: We previously constructed a recombinant bacille Calmette-Guerin (rBCG AE) strain that could express a fused Ag85A-ESAT-6 protein. That study suggested that the rBCG-AE strain was able to induce a higher titer of antibody and elicit a more long-lived and stronger Th1-type cellular immune responses than the parental BCG strain, the rBCG-A strain (i.e., expressing Ag85A), or the rBCG-E strain (i.e., expressing ESAT-6). METHODS: In the current study, we further investigated the strain's protective efficacy against Mycobacterium tuberculosis H37Rv infection in BALB/c mice through evaluating organ bacterial loads, lung histopathology, lung immunohistochemistry, and net weight gain or loss by using conventional BCG, rBCG-A, and rBCG-E as the controls. RESULTS: From the 3rd to 9th weeks after the challenge infection, the bacterial counts were significantly lower in tissues (e.g., spleen and lung tissues) in the mice immunized with rBCG AE than in the control group, but were higher than the counts in the BCG group. The pathological damage in the lung tissues of the rBCG-AE group gradually improved from the 6th to 9th weeks after being infected with M. tuberculosis H37Rv, but the score of pathological changes in the rBCG-AE group was obviously higher than the score in the BCG group. There was no difference in the percentage of IFN-gamma and iNOS positive cells in the lung tissues of the rBCG-AE and BCG groups. CONCLUSION: The results suggest that rBCG-AE can not promote protective efficacy against M. tuberculosis H37Rv infection, compared to the BCG vaccine. PMID- 23357606 TI - Epidemiology and antimicrobial resistance among commonly encountered bacteria associated with infections and colonization in intensive care units in a university-affiliated hospital in Shanghai. AB - BACKGROUND/PURPOSE: The aim of this study was to classify intensive care unit (ICU) bacterial strains as either ICU-acquired or ICU-on-admission and to compare their epidemiological and antibiogram characteristics. METHODS: The study was performed in a 1300-bed university-affiliated hospital from January 1, 2006 to December 31, 2010. Based on the time of ICU admission, ICU isolates were classified as ICU-acquired strains (appearing more than 48 hours after admission) or ICU-on-admission strains (appearing 48 hours or less from admission). The microbiological data before ICU admission, the microbiological data, and susceptibility testing were compared between the ICU-acquired and ICU-on admission bacterial isolates. RESULTS: The most common ICU-acquired strains were Acinetobacter baumannii (19.5%), Pseudomonas aeruginosa (15.6%), Stenotrophomonas maltophilia (11.5%), Staphylococcus aureus (10.7%), Enterococcus spp. (10.6%), and Klebsiella pneumoniae (9.7%). There were significant differences between ICU acquired and ICU-on-admission isolates in the susceptibility rates of Gram negative bacteria to antibiotics, especially the susceptibility of A. baumannii to imipenem [23.8% (ICU-acquired) vs. 44.4% (ICU-on-admission), p < 0.001] and meropenem (24.1% vs. 37.8%, p < 0.001), and the susceptibility of P. aeruginosa to imipenem (39.3% vs. 76.1%, p < 0.001) and meropenem (58.5% vs. 76.1%, p < 0.05). Furthermore, decreased susceptibility rates of A. baumannii and P. aeruginosa to carbapenems were correlated with an extended ICU stay (p < 0.05). CONCLUSION: Because of decreasing susceptibility rates of pathogens (especially ICU-acquired strains) and a significant correlation with the length of ICU stay, intensivists should consider a patient's time of ICU admission and previous microbiological data and should distinguish ICU-acquired strains from non-ICU acquired strains so as to initiate optimized empirical antibiotic therapy against ICU-acquired infections. PMID- 23357607 TI - Haemophilus parainfluenzae urethritis among homosexual men. AB - Haemophilus parainfluenzae is a common inhabitant of the human upper respiratory tract of the normal oral microflora. We report three men who had been having unprotected sex with men (MSM) and subsequently acquired H. parainfluenzae urethritis, which was confirmed by 16S rRNA gene sequencing analysis. Two men were treated with ceftriaxone and doxycycline, and the third man was treated with clarithromycin. All three patients responded to treatment. This case series highlights the potential role of H. parainfluenzae as a sexually transmitted genitourinary pathogen. PMID- 23357608 TI - Rothia prosthetic knee joint infection. AB - Rothia species - Gram-positive pleomorphic bacteria that are part of the normal oral and respiratory flora - are commonly associated with dental cavities and periodontal disease although systemic infections have been described. We describe a 53-year-old female with rheumatoid arthritis complicated by prosthetic knee joint infection due to Rothia species, which was successfully treated by surgical removal of prosthesis and prolonged antimicrobial therapy. The issue of antibiotic prophylaxis before dental procedures among patients with prosthetic joint replacements is discussed. PMID- 23357609 TI - Risk score for predicting in-hospital/30-day mortality for patients undergoing valve and valve/coronary artery bypass graft surgery. AB - BACKGROUND: Risk scores are simplified linear formulas for predicting mortality or other adverse outcomes at the bedside without personal digital assistants or calculators. Although risk scores are available for valve surgery, they do not predict short-term mortality (within 30 days of surgery) after hospital discharge. METHODS: New York's Cardiac Surgery Reporting System 2007 to 2009 data were matched to vital statistics data to identify valve surgery with and without concomitant coronary artery bypass graft (CABG) surgery deaths occurring in the index admission or within 30 days after the procedure in any location. Risk scores were created to easily predict these outcomes by modifying more complicated logistic regression models. RESULTS: There were 13,455 isolated valve surgery patients and 8,373 valve/CABG surgery patients in the study. The respective in-hospital/30-day mortality rates were 4.03% and 6.60%. There are 11 risk factors comprising the isolated valve surgery score, with risk factor scores ranging from 1 to 8, and the highest observed total score is 28. There are 14 risk factors comprising the valve/CABG surgery score, with risk factor scores ranging from 1 to 6, and the highest observed total score is 19. The scores accurately predicted mortality in 2007 to 2009 as well as in 2004 to 2006, and were strongly correlated with complications and length of stay. CONCLUSIONS: The risk scores that were developed provide quick and accurate estimates of patients' chances of short-term mortality after cardiac valve surgery. PMID- 23357610 TI - Neuroendocrine carcinoma of the uterine cervix: the role of multimodality therapy in early-stage disease. AB - BACKGROUND: Neuroendocrine carcinomas (NECs) of the cervix comprise only 2% of all cervical cancers. Prospective data is limited and treatment guidelines rely on retrospective reviews and literature from lung NEC. The objective of this study was to report our experience in the management of this rare disease. METHODS: This was an IRB-approved retrospective review. Study criteria included patients with cervical NEC diagnosed between 1990 and 2012. Demographic, treatment and survival data was collected. Progression free survival (PFS) and overall survival (OS) were assessed. RESULTS: Twenty-six patients met inclusion criteria. Advanced-stage disease (II-IV) was diagnosed in 58% (n=15) of patients. Of the eleven patients with stage I disease, five were treated with platinum based neoadjuvant chemotherapy (NACT), six with initial radical surgery, and seven received adjuvant therapy including chemotherapy and/or radiation. Nine patients (82%) are currently without evidence of disease (NED). Patients with stage I disease had significantly improved PFS and OS compared to stages II-IV with a median OS that was not reached and 12.1 months, respectively (p=0.0013). The majority of stage I patients with lymph node metastasis and large tumors achieved durable remission with triple-modality therapy including NACT and surgery followed by adjuvant therapy. CONCLUSIONS: Cervical NEC is an aggressive disease associated with a high mortality rate. Patients with advanced-stage disease have a poor prognosis regardless of therapy. However, multimodality with consideration of triple-modality therapy in early-stage disease has the potential for complete response and long-term survival, supporting the goal of curative intent in these patients. PMID- 23357611 TI - Analysis of secondary cytoreduction for recurrent ovarian cancer by robotics, laparoscopy and laparotomy. AB - OBJECTIVE: Analysis of perioperative outcomes and survival of patients with recurrent ovarian cancer undergoing secondary cytoreduction by robotics, laparoscopy, or laparotomy. METHODS: Retrospective analysis of 52 selected patients with recurrent ovarian cancer undergoing secondary cytoreduction by laparoscopy (9), laparotomy (33) or robotics (10) between January 2006 and December 2010. Comparison was made by a total of 21 factors including age, BMI, number of previous surgeries, tumor type and grade, number of procedures, and 15 types of procedures performed at secondary cytoreduction. RESULTS: For all patients, the mean operating time was 213.8 min, mean blood loss 657.4 ml; and mean hospital stay 7.5 days. Complete debulking was achieved in 75% of patients. Postoperative complications were noted in 36.5% of patients. Overall and progression-free survival at 3-years were 58.8% and 34.1%, respectively. Laparoscopy and robotics had reduced blood loss and hospital stay, while no differences were observed among the three groups for operating time, complications, complete debulking, and survival. CONCLUSION: Selected patients with recurrent ovarian cancer benefit from a laparoscopic or robotic secondary cytoreduction without compromising survival. Robotics and laparoscopy provide similar perioperative outcomes, and reduced blood loss and shorter hospital stay as compared to laparotomy. Laparotomy seems preferable for patients with widespread peritoneal implants, multiple sites of recurrence, and/or extensive adhesions. PMID- 23357612 TI - Mixtures of endocrine disruptors: how similar must mechanisms be for concentration addition to apply? AB - Must molecular mechanisms be the same for concentration addition to predict the effect of a mixture or is it sufficient for compounds to affect similar pathways or common outcomes? Does concentration addition provide a closer approximation to observations than alternative models such as independent action? Suppose effects are mediated by hormone A through receptor R, synthesis of A is reduced by compound B, and that C is a competitive antagonist to A. Both B and C reduce levels of the receptor-ligand complex AR but via different specific mechanisms. Are combinations of B and C concentration additive? We used simple pharmacodynamic models, deriving mathematical models using equilibrium binding and mass balance. Assume A binds the receptor at one site of R with effects proportional to the concentration of AR. Let C act as a competitive antagonist via the Gaddum equation. Let B affect synthesis of A via a function g(B). We derive a model describing the joint response surface of B and C, and a function describing its isoboles. Under concentration addition, the isoboles must be negatively sloped straight lines. We show that linearity of the isoboles depends crucially on g(B). The mixture is concentration additive if g"(B), the second derivative of g(B) with respect to B, is always zero. Responses are greater than concentration additive if g"(B) is always positive and less than concentration additive if g"(B) is always negative. We describe functions g(B) that lead to all three cases as well as one that is greater than concentration additive in some regions and less than concentration additive in others. At least in this simple model, concentration addition cannot be assumed: mixtures of competitive antagonists and compounds that alter hormone synthesis can lead to results that are concentration additive, greater than concentration additive or less than concentration additive. Nevertheless, concentration addition appears to provide a closer approximation to the pharmacodynamic model examined here than independent action. Care needs to be taken in extrapolating to other situations, but analysis of simple pharmacodynamic models appears to be a useful strategy. PMID- 23357614 TI - Evaluation of the effect of information integration in displays for ICU nurses on situation awareness and task completion time: A prospective randomized controlled study. AB - OBJECTIVE: The study measured whether nurses' situation awareness would increase and task completion time decrease when they used an integrated information display compared to traditional displays for medication management, patient awareness and team communication. SETTING: The Burn Trauma Intensive Care Unit (BTICU) at the University Hospital, University of Utah Health Science Center, Salt Lake City, Utah, USA. PARTICIPANTS: 12 experienced BTICU nurses. MEASURES: Situation awareness (accuracy of the participants' answer) and task completion time (response time from seeing the question to submitting the answer) were measured using paper prototypes of both displays. STUDY DESIGN: Counter-balanced (on display order), repeated-measures design. MAIN RESULTS: Nurses had a higher situation awareness when using the integrated display, with an overall accuracy of 85.3% compared to 61.8% with the traditional displays (odds ratio 3.61, P<.001, 95% CI=2.34...5.57). Task completion times were nearly half with integrated displays compared to traditional displays (median 26.0 and 42.1s, hazard ratio 2.31, P<.001, CI=1.83...2.93). CONCLUSIONS: An integrated ICU information display increased nurses' situation awareness and decreased task completion time. Information integration has the potential to decrease errors, increase nurses' productivity and may allow nurses to react faster to a patient's clinical needs. Bidirectional device communication is needed for these displays to achieve full potential in improving patient safety. PMID- 23357615 TI - Estimated contribution of hemoglobin and myoglobin to near infrared spectroscopy. AB - We calculated the light absorbing potential (LAP) of hemoglobin (Hb) and myoglobin (Mb) in mammalian skeletal muscle at rest based on analysis of published chemical and morphometric data (Part 1), interpreted changes in total[Hb+Mb] from NIRS during exercise (Part 2), and estimated the potential contribution of Hb and Mb to changes in NIRS from rest to exercise (Part 3). Part 1: [Hb] in skeletal muscle was estimated from microvascular volume, systemic blood [Hb], and microvascular hematocrit and saturation at rest and during exercise. Part 2: Changes in total[Hb+Mb] (as t[Hb+Mb]) during cycling or knee extension exercise were interpreted using the results of Part 1. Part 3: Using estimates of mean microvascular PO2, Hb and Mb contribution at peak exercise was estimated. Across several species, [Mb] contributed ~50-70% of the total LAP to NIRS at rest in skeletal muscle. With exercise, increases in t[Hb+Mb] of up to 30% could be entirely explained by the predicted increase in microvascular hematocrit with exercise. Finally, Mb was estimated to contribute ~70% of the changes in NIRS from rest to peak exercise. PMID- 23357616 TI - Isoflurane depolarizes bronchopulmonary C neurons by inhibiting transient A-type and delayed rectifier potassium channels. AB - Inhalation of isoflurane (ISO), a widely used volatile anesthetic, can produce clinical tachypnea. In dogs, this response is reportedly mediated by bronchopulmonary C-fibers (PCFs), but the relevant mechanisms remain unclear. Activation of transient A-type potassium current (IA) channels and delayed rectifier potassium current (IK) channels hyperpolarizes neurons, and inhibition of both channels by ISO increases neural firing. Due to the presence of these channels in the cell bodies of rat PCFs, we determined whether ISO could stimulate PCFs to produce tachypnea in anesthetized rats, and, if so, whether this response resulted from ISO-induced depolarization of the pulmonary C neurons via the inhibition of IA and IK. We recorded ventilatory responses to 5% ISO exposure in anesthetized rats before and after blocking PCF conduction and the responses of pulmonary C neurons (extracellularly recorded) to ISO exposure. ISO induced (1mM) changes in pulmonary C neuron membrane potential and IA/IK were tested using the perforated patch clamp technique. We found that: (1) ISO inhalation evoked a brief tachypnea (~7s) and that this response disappeared after blocking PCF conduction; (2) the ISO significantly elevated (by 138%) the firing rate of most pulmonary C neurons (17 out of 21) in the nodose ganglion; and (3) ISO perfusion depolarized the pulmonary C neurons in the vitro and inhibited both IA and IK, and this evoked-depolarization was largely diminished after blocking both IA and IK. Our results suggest that ISO is able to stimulate PCFs to elicit tachypnea in rats, at least partly, via inhibiting IA and IK, thereby depolarizing the pulmonary C neurons. PMID- 23357617 TI - The rhythmic, transverse medullary slice preparation in respiratory neurobiology: contributions and caveats. AB - Our understanding of the sites and mechanisms underlying rhythmic breathing as well as the neuromodulatory control of respiratory rhythm, pattern, and respiratory motoneuron excitability during perinatal development has advanced significantly over the last 20 years. A major catalyst was the development in 1991 of the rhythmically-active medullary slice preparation, which provided precise mechanical and chemical control over the network as well as enhanced physical and optical access to key brainstem regions. Insights obtained in vitro have informed multiple mechanistic hypotheses. In vivo tests of these hypotheses, performed under conditions of reduced control and precision but more obvious physiological relevance, have clearly established the significance for respiratory neurobiology of the rhythmic slice preparation. We review the contributions of this preparation to current understanding/concepts in respiratory control, and outline the limitations of this approach in the context of studying rhythm and pattern generation, homeostatic control mechanisms and murine models of human genetic disorders that feature prominent breathing disturbances. PMID- 23357618 TI - Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. AB - The over-expression of voltage-gated sodium channels (VGSCs) in dorsal root ganglion (DRG) neurons following peripheral nerve injury contributes to neuropathic pain by generation of the ectopic discharges of action potentials. However, mechanisms underlying the change in VGSCs' expression are poorly understood. Our previous work has demonstrated that the pro-inflammatory cytokine TNF-alpha up-regulates VGSCs. In the present work we tested if anti-inflammatory cytokine IL-10, which had been proven to be effective for treating neuropathic pain, had the opposite effect. Western blot and immunofluorescence results showed that IL-10 receptor was localized in DRG neurons. Recombinant rat IL-10 (200 pg/ml) not only reduced the densities of TTX-sensitive and Nav1.8 currents in control DRG neurons, but also reversed the increase of the sodium currents induced by rat recombinant TNF-alpha (100 pg/ml), as revealed by patch-clamp recordings. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-alpha. Moreover, repetitive intrathecal administration of rrIL-10 for 3 days (4 times per day) attenuated mechanical allodynia in L5 spinal nerve ligation model and profoundly inhibited the excitability of DRG neurons. These results suggested that the down-regulation of the sodium channels in DRG neurons might contribute to the therapeutic effect of IL-10 on neuropathic pain. PMID- 23357619 TI - Cutaneous noradrenaline measured by microdialysis in complex regional pain syndrome during whole-body cooling and heating. AB - Complex regional pain syndrome (CRPS) is characterised by autonomic, sensory, and motor disturbances. The underlying mechanisms of the autonomic changes in CPRS are unknown. However, it has been postulated that sympathetic inhibition in the acute phase with locally reduced levels of noradrenaline is followed by an up regulation of alpha-adrenoceptors in chronic CRPS leading to denervation supersensitivity to catecholamines. This exploratory study examined the effect of cutaneous sympathetic activation and inhibition on cutaneous noradrenaline release, vascular reactivity, and pain in CRPS patients and in healthy volunteers. Seven patients and nine controls completed whole-body cooling (sympathetic activation) and heating (sympathetic inhibition) induced by a whole body thermal suit with simultaneous measurement of the skin temperature, skin blood flow, and release of dermal noradrenaline. CRPS pain and the perceived skin temperature were measured every 5 min during thermal exposure, while noradrenaline was determined from cutaneous microdialysate collected every 20 min throughout the study period. Cooling induced peripheral sympathetic activation in patients and controls with significant increases in dermal noradrenaline, vasoconstriction, and reduction in skin temperature. The main findings were that the noradrenaline response did not differ between patients and controls or between the CRPS hand and the contralateral unaffected hand, suggesting that the evoked noradrenaline release from the cutaneous sympathetic postganglionic fibres is preserved in chronic CRPS patients. PMID- 23357620 TI - Functional improvement after one- and two-eye cataract surgery in the Salisbury Eye Evaluation. AB - PURPOSE: To determine the impact that cataract and cataract surgery have on clinical measurements of vision, reading speed, objective mobility performance, and subjective visual functioning. DESIGN: Prospective, population-based study. PARTICIPANTS: A total of 1739 Salisbury Eye Evaluation (SEE) participants without previous cataract surgery with bilateral baseline best-corrected visual acuity (BCVA) of logarithm of the minimum angle of resolution (logMAR) <= 0.3 (>= 20/40) or cataract surgery between rounds 1 and 2. METHODS: Participants were categorized on the basis of cataract surgery by round 2 into no surgery, unilateral surgery, or bilateral surgery. Visual performance, mobility-based tasks, and the Activities of Daily Vision Scale (ADVS) were measured at baseline and 2 years. Mobility score was converted into a z score by subtracting the participant's time from the population baseline average and then dividing by the standard deviation. Comparisons were made between the no surgery and surgery groups using multivariate linear regression. MAIN OUTCOME MEASURES: Change in bilateral BCVA in logMAR, contrast sensitivity, reading speed in words per minute (wpm), mobility score, and ADVS. RESULTS: During the study period, 29 participants had cataract surgery on both eyes, 90 participants had unilateral surgery, and 1620 participants had no surgery. After adjusting for baseline value, demographics, depression, and mental status, the unilateral surgery group's BCVA improved 0.04 logMAR (P = 0.001) and the bilateral group's BCVA improved 0.13 compared with no surgery (P<0.001). Overall mobility declined in all groups. The unilateral group's z score decreased 0.18 more than that of the no surgery group (P = 0.02), whereas the bilateral group showed a 0.18 z score improvement compared with no surgery (P = 0.19). Change in reading speed significantly improved in the unilateral and bilateral groups compared with no surgery (12 and 31 wpm, respectively). The bilateral surgery group showed significant positive change in ADVS compared with no surgery (5 points of relative improvement; P = 0.01), whereas the unilateral group showed a 5-point relative decline (P<0.001). CONCLUSIONS: Cataract negatively affects both subjective quality of life and objective performance measures. Unilateral cataract surgery improves visual functioning, but the largest gains are found in patients who undergo second-eye cataract surgery. This finding supports second eye cataract surgery for patients with visual or functional symptoms even after successful first-eye surgery. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23357621 TI - Histologic basis of variations in retinal pigment epithelium autofluorescence in eyes with geographic atrophy. AB - PURPOSE: Lipofuscin contained in the retinal pigment epithelium (RPE) is the main source of fundus autofluorescence (FAF), the target of an imaging method useful for estimating the progression of geographic atrophy (GA) in clinical trials. To establish a cellular basis for hyperfluorescent GA border zones, histologic autofluorescence (HAF) was measured at defined stages of RPE pathologic progression. DESIGN: Experimental study. PARTICIPANTS AND CONTROLS: Ten GA donor eyes (mean age +/- standard deviation, 87.1 +/- 4.0 years) and 3 age-matched control eyes (mean age +/- standard deviation, 84.0 +/- 7.2 years) without GA. METHODS: The 10-micrometer-thick sections were divided into zones of RPE morphologic features according to an 8-point scale. Any HAF excited by 488 nm light was imaged by laser confocal microscopy. The HAF intensity summed along vertical lines perpendicular to Bruch's membrane at 0.2-MUm intervals served as a surrogate for FAF. Intensity profiles in 151 zones were normalized to grade 0 at a standard reference location in each eye. Cross-sectional area, mean, and sum autofluorescence for individual RPE cells were measured (cellular autofluorescence [CAF]). MAIN OUTCOME MEASURES: Statistically significant differences in intensity and localization of HAF and CAF at defined stages of RPE morphologic progression for GA and control eyes. RESULTS: The RPE morphologic features were most abnormal (cell rounding, sloughing, and layering; grade 2) and HAF intensity profiles were highest and most variable immediately adjacent to atrophic areas. Peaks in HAF intensity frequently were associated with vertically superimposed cells. The HAF value that optimally separated reactive RPE was 0.66 standard deviations more than the mean for uninvolved RPE and was associated with a sensitivity of 75.8% and a specificity of 76.3%. When variable cell area was accounted for, neither mean nor sum CAF differed significantly among the RPE pathologic grades. CONCLUSIONS: Areas with advanced RPE alterations are most likely to exhibit clinically recognizable patterns of elevated FAF around GA, but may not predict cells about to die, because of vertically superimposed cells and cellular fragments. These data do not support a role for lipofuscin-related cell death and call into question the rationale of treatments targeting lipofuscin. PMID- 23357622 TI - Seasonal changes in visual field sensitivity and intraocular pressure in the ocular hypertension treatment study. AB - PURPOSE: Longitudinal testing plays a key role in glaucoma management. Variability between visits hampers the ability to monitor progression. It has previously been shown that average intraocular pressure (IOP) exhibits seasonal fluctuations. This study examines whether visual field sensitivity also exhibits seasonal fluctuations and seeks to determine whether such fluctuations are correlated to seasonal IOP effects. DESIGN: Comparative case series. PARTICIPANTS: A total of 33 873 visits by 1636 participants enrolled in the Ocular Hypertension Treatment Study. Participants were split into 6 geographic zones according to the prevailing climate in their location. TESTING: At each visit, standard automated perimetry was conducted on each eye, and IOP was measured. MAIN OUTCOME MEASURES: Mixed effects regression models were formed to look for sinusoidal periodic effects on the change in perimetric mean deviation since the last visit (DeltaMD) and on IOP, both overall and within each zone. RESULTS: When all the data were included, a significant seasonal effect on DeltaMD was found with magnitude 0.06 dB, peaking in February (P < 0.001). Five of the 6 geographic zones exhibited significant seasonal effects on DeltaMD, peaking between January and April, with magnitudes ranging from 0.04 dB (P = 0.049) to 0.21 dB (P < 0.001). Zones with greater climactic variation showed larger seasonal effects on DeltaMD. All 6 zones exhibited a seasonal effect on IOP, peaking in January or February, with magnitudes ranging from 0.14 to 0.39 mmHg (P <= 0.02 in all cases). However, there was no evidence of a significant association between the magnitudes or dates of peaks of the 2 seasonal effects. CONCLUSIONS: The mean deviation was significantly higher in winter than in summer. There is no evidence of an association with seasonal IOP fluctuations. The cause of the seasonal effect on visual field sensitivity is unknown. These findings may help shed light on the glaucomatous disease process and aid efforts to reduce test-retest variability. PMID- 23357623 TI - Radiation coronary arteritis refractory to surgical and percutaneous revascularization culminating in orthotopic heart transplantation. AB - BACKGROUND: Hodgkin's lymphoma (HL) comprises of 4% of malignancies diagnosed in children from birth to 14 years of age. While overall survival rates have increased, HL survivors can be at risk of late cardiovascular complications from radiotherapy. HL survivors with a history of mediastinal RT have been found to have an increased incidence of myocardial infarction, angina, congestive heart failure, and valvular disorders compared to the general population. METHODS: A 33 year old female with a history of HL status post chemotherapy and mediastinal radiation 11 years ago became symptomatic with multivessel coronary artery disease with aggressive progression of her disease despite coronary bypass graft surgery, patch angioplasty of the left main coronary artery (LMCA) with an extracellular bioscaffold, and repeated percutaneous coronary intervention of the LMCA. She eventually underwent orthotopic heart transplant and did well postoperatively. RESULTS: Histopathological analysis of the explanted heart revealed a variety of sequelae of radiation arteritis, including thrombosis of both native vessels and arterial grafts, intimal hyperplasia and involvement of the bioscaffold in the left main coronary vasculature. The bioscaffold did not contribute significantly to the stenosis within the LMCA. CONCLUSION: Our case demonstrates an unusual indication for OHT due to severe refractory radiation induced CAD, as well the wide spectrum of the histopathologic manifestations of radiation induced arteritis. PMID- 23357624 TI - Mutations in the profilin 1 gene are not common in amyotrophic lateral sclerosis of Chinese origin. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily involving the corticospinal tract, brainstem, and anterior cells of the spinal cord. Mutations in the profilin 1 gene (PFN1) were recently described in ALS families. To investigate the spectrum and frequency of PFN1 mutations further, we sequenced all 3 exons of the PFN1 gene in 20 familial ALS index cases, 324 sporadic ALS patients, and 355 healthy control subjects. No nonsynonymous coding variants were identified. Our findings suggest that mutations in the PFN1 gene are not a common cause of ALS in the Chinese population. PMID- 23357625 TI - Hospitalized pediatric burns in North China: a 10-year epidemiologic review. AB - Retrospective surveys of all hospitalized pediatric burns under the age of 15 years were conducted in 18 hospitals from 5 provinces and municipal cities of North China between 2001 and 2010. A total of 17,770 patients were included in this study. The epidemiological characteristics of hospitalized pediatric burns and influencing factors of length of hospital stay and hospitalization cost were analyzed. In this study, children accounted for 43.57% of all hospitalized burns, with a gradually increasing trend (P=0.003). Among children hospitalized burns, the percentage of children younger than three years was 69.9%, with an upward trend (P<0.001). The ratio of male to female was 1.53:1. Scald burns accounted for 89.79% and 71.54% had burns of <10% total body surface area, with increasing trends (P<=0.001). The medians of length of hospital stay and hospitalization cost were eight days and 2469 RMB yuan respectively. The most important factors affecting length of hospital stay and hospitalization cost were burned surface area, surgery and treatment outcome. Children under three years of age, boys and children with a small area of mild scald burns should be made the focus of childhood burn prevention. Improving the medical insurance system for children is urgently needed. PMID- 23357626 TI - Apoptosis-inducing activity of the actin-depolymerizing agent aplyronine A and its side-chain derivatives. AB - Aplyronine A (1) and mycalolide B (2), which are cytotoxic actin-depolymerizing marine macrolides, were revealed to induce apoptosis in human leukemia HL60 cells and human epithelial carcinoma HeLa S(3) cells. Based on these results, actin depolymerizing compounds were expected to exhibit apoptosis-inducing activity in cancer cells. Compounds 3-6, which were synthesized based on the side-chain structure of aplyronine A, were evaluated for their actin-depolymerizing activities in vitro and cytotoxicities against HL60 cells. The growth-inhibitory activities of 3-6 were well correlated with their actin-depolymerizing activities, and derivative 6 was shown to induce the disruption of actin filaments and apoptosis in HL60 cells. These results suggested that actin depolymerizing agents 1, 2, and 6-induced apoptosis in HL60 cells may have been due to their actin-depolymerizing activity. PMID- 23357627 TI - Phosphonic analogues of glutamic acid as irreversible inhibitors of Staphylococcus aureus endoproteinase GluC: an efficient synthesis and inhibition of the human IgG degradation. AB - Endoproteinase GluC (V8 protease) is one of many virulence factors released by the Staphylococcus aureus species in vivo. The V8 protease is able to hydrolyze some serpins and all classes of mammalian immunoglobulins. The application of specific and potent inhibitors of V8 protease may lead to the development of new antibacterial agents. Herein, we present the synthesis and the inhibitory properties of novel peptidyl derivatives of a phosphonic glutamic acid analogue. One of the compounds Boc-Phe-Leu-Glu(P)(OC(6)H(4))(2) displayed an apparent second-order inhibition rate value of 8540 M(-1)s(-1). The Boc-Phe-Leu Glu(P)(OC(6)H(4))(2) compound with the highest inhibitory potency showed the ability to prevent V8-mediated human IgG proteolysis in vitro. PMID- 23357628 TI - Design and synthesis of dimethylaminomethyl-substituted curcumin derivatives/analogues: potent antitumor and antioxidant activity, improved stability and aqueous solubility compared with curcumin. AB - A series of dimethylaminomethyl-substituted curcumin derivatives/analogues were designed and synthesized. All compounds effectively inhibited HepG2, SGC-7901, A549 and HCT-116 tumor cell lines proliferation in MTT assay. Particularly, compounds 2a and 3d showed much better activity than curcumin against all of the four tumor cell lines. Antioxidant test revealed that these compounds had higher free radical scavenging activity than curcumin towards both DPPH and galvinoxyl radicals. Furthermore, the aqueous solubility and stability of the target compounds were also significantly improved compared with curcumin. PMID- 23357629 TI - Design, synthesis, characterization and anti-inflammatory evaluation of novel pyrazole amalgamated flavones. AB - A series of novel pyrazole amalgamated flavones has been designed and synthesized from 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 6. The structures of regioisomers 6 and 7 were resolved by 2D (1)H-(1)H COSY, (1)H-(13)C HSQC and (1)H (13)C HMBC experiments. The newly synthesized compounds were tested for their in vitro COX inhibition and in vivo carrageenan induced hind paw edema in rats and acetic acid induced vascular permeability in mice. Although the compounds have inhibitory profile against both COX-1 and COX-2, some of the compounds are found to be selective against COX-2, supported by inhibition of paw edema and vascular permeability. Docking studies were also carried out to determine the structural features which sway the anti-inflammatory activity of the tested compounds. The keto and phenolic -OH are major factors that are prominently involved in interaction with COX-2 active site. PMID- 23357630 TI - Inhibitory effect on NO production of triterpenes from the fruiting bodies of Ganoderma lucidum. AB - Four new lanostane triterpenes, butyl lucidenate P (1), butyl lucidenate D(2) (2), butyl lucidenate E(2) (3) and butyl lucidenate Q (4) along with 11 known compounds (5-15) were isolated from the fruiting bodies of Ganoderma lucidum. Their chemical structures were established mainly by 1D and 2D NMR techniques and mass spectrometry. Their anti-inflammatory activity was evaluated against LPS induced NO production in macrophage RAW 264.7 cells. Compounds 1, 3, 4, 9, 10 and 15 showed inhibitory potency with IC(50) values of 7.4, 6.4, 4.3, 9.4, 9.2 and 4.5 MUM, respectively. Compounds 1, 3 and 15 dose-dependently reduced the LPS induced iNOS expressions. Preincubation of cell with 1, 3 and 15 significantly suppressed LPS-induced expression of COX-2 protein. PMID- 23357631 TI - Regioselective synthesis of isoxazole-mercaptobenzimidazole hybrids and their in vivo analgesic and anti-inflammatory activity studies. AB - Regioselective synthesis of isoxazole-mercaptobenzimidazole hybrids and their efficiency in in vivo analgesic and anti-inflammatory activity was described. A comparison of structure-activity relationship for there compounds was also emphasized. PMID- 23357632 TI - Anti-malarial activity of new N-acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN) derivatives against Plasmodium falciparum. AB - Malaria is the most common of the parasitic diseases in tropical and subtropical regions. Adverse side effects of anti-malarial drugs have precluded them as a potential clinical drug. In this study, novel derivatives of N-acetyl-L-leucyl-L leucyl-L-norleucinal (ALLN) based on a variety of dipeptidyl alpha,beta unsaturated amides containing lysine as a part were synthesized and evaluated. Lower toxicity was achieved by reducing or eliminating the tendency of forming chemically reactive and toxic intermediates and metabolites. The synthesized compounds were evaluated for anti-malarial efficacy against Plasmodium falciparum and cytotoxicity in human epitheloid carcinoma cervix (HeLa cells) by estimating the therapeutic index (TI). N-Methyl amide with N'-Boc protection among them exhibited strong anti-malarial activity and N-methyl amide with N'-m-methylbenzyl amide showed excellent anti-malarial activity with much lower toxicity than the ALLN. Therefore, the two chemicals, as well as the underlying design rationale, could be useful in the discovery and development of new anti-malarial drugs. PMID- 23357633 TI - Antimycobacterial activity evaluation, time-kill kinetic and 3D-QSAR study of C (3-aminomethyl-cyclohexyl)-methylamine derivatives. AB - A series of C-(3-aminomethyl-cyclohexyl)-methylamine derivatives were synthesized and evaluated for their antitubercular activity. Some of the compounds exhibited potent activity against Mycobacterium tuberculosis H37Rv. One of the compound having t-butyl at para position of the benzene ring showed excellent activity even better than the standard drug ethambutol with MIC value 1.1 +/- 0.2 MUM. The time-kill kinetics study of two most active compounds showed rapid killing of the M. tuberculosis within 4 days. Additionally atom-based quantitative structure activity relationship (QSAR) model was developed that gave a statistically satisfying result (R(2))=0.92, Q(2)=0.75, Pearson-R=0.96 and effectively predicts the anti-tuberculosis activity of training and test set compounds. PMID- 23357634 TI - Discovery and structure-activity relationship of 1,3-cyclohexyl amide derivatives as novel mGluR5 negative allosteric modulators. AB - A novel series of trans-1,3-cyclohexyl diamides was discovered and characterized as mGluR5 negative allosteric modulators (NAMs) lacking an alkyne moiety. Conformational constraint of one of the amide bonds in the diamide template led to a spirooxazoline template. A representative compound (24d) showed good in vitro potency, high CNS penetration and, upon subcutaneous dosing, demonstrated efficacy in the mouse marble burying test, generally used as indicative of potential anxiolytic activity. PMID- 23357635 TI - Synthesis and antitubercular activity of amino alcohol fused spirochromone conjugates. AB - A series of 21 new amino alcohol fused spirochromone conjugates have been synthesized, characterized with analytical data and evaluated their antimycobacterial activity against Mycobacterium tuberculosis (virulent strain H37Rv) in vitro. Some of the compounds exerted significant inhibition, in particular, compound 4f found to be the most potent derivative exhibiting MIC=3.13 MUg/mL. PMID- 23357636 TI - Bioactive polyhydroxylated steroids from the Hainan soft coral Sinularia depressa Tixier-Durivault. AB - Two new steroids, (2beta,3beta,4alpha,5alpha,8beta)-4-methylergost-24(28)-ene 2,3,8-triol (1) and (3beta,7alpha)-24-methyl-7-hydroperoxycholest-5,24(28)-diene 3-ol (2), together with 13 known analogues (3-15) were isolated from the soft coral Sinularia depressa Tixier-Durivault. The structures of the new compounds were elucidated by detailed spectroscopic analysis and comparison with reported data. In the bioassay in vitro, compounds 3a, 4, and 14 exhibited potent PTP1B inhibitory activity, being similar as that of positive control oleanolic acid. Compound 14 also displayed a notable neuroprotective activity against both amyloid-beta(25-35)- and serum deprivation-induced injuries in SH-SY5Y cells while compound 11 showed a considerable antibacterial activity against Staphylococcus aureus. Preliminary structure-activity relationships of these steroids were discussed. PMID- 23357637 TI - Buprenorphine and norbuprenorphine quantification in human plasma by simple protein precipitation and ultra-high performance liquid chromatography tandem mass spectrometry. AB - A highly sensitive ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was developed for the quantification of buprenorphine and its major metabolite norbuprenorphine in human plasma. In order to speed up the process and decrease costs, sample preparation was performed by simple protein precipitation with acetonitrile. To the best of our knowledge, this is the first application of this extraction technique for the quantification of buprenorphine in plasma. Matrix effects were strongly reduced and selectivity increased by using an efficient chromatographic separation on a sub-2 MUm column (Acquity UPLC BEH C18 1.7 MUm, 2.1*50 mm) in 5 min with a gradient of ammonium formate 20 mM pH 3.05 and acetonitrile as mobile phase at a flow rate of 0.4 ml/min. Detection was made using a tandem quadrupole mass spectrometer operating in positive electrospray ionization mode, using multiple reaction monitoring. The procedure was fully validated according to the latest Food and Drug Administration guidelines and the Societe Francaise des Sciences et Techniques Pharmaceutiques. Very good results were obtained by using a stable isotope labeled internal standard for each analyte, to compensate for the variability due to the extraction and ionization steps. The method was very sensitive with lower limits of quantification of 0.1 ng/ml for buprenorphine and 0.25 ng/ml for norbuprenorphine. The upper limit of quantification was 250 ng/ml for both drugs. Trueness (98.4-113.7%), repeatability (1.9-7.7%), intermediate precision (2.6 7.9%) and internal standard-normalized matrix effects (94-101%) were in accordance with international recommendations. The procedure was successfully used to quantify plasma samples from patients included in a clinical pharmacogenetic study and can be transferred for routine therapeutic drug monitoring in clinical laboratories without further development. PMID- 23357638 TI - Simultaneous determination of phosphate anion and calcium cation in Plastrum testudinis by HPLC-ELSD. AB - A simple and rapid high performance liquid chromatography-evaporative light scattering detection (HPLC-ELSD) method was developed for simultaneous determination of phosphate anion and calcium cation in Plastrum testudinis. The analyte was separated on a Prevail C18 reserved-phase column (250mm*4.6mm, 5MUm) using isocratic elution at a flow rate of 0.5mL/min. The column temperature was 25 degrees C. The drift tube temperature and the nitrogen gas flow-rate of ELSD were set at 115 degrees C and 2.5L/min, respectively. This developed method was able to determine phosphate anion and calcium cation with good linearity (r(2)>0.9997), precision (RSD<1.6%) and recovery (99.52-101.94%). The newly established method was successfully applied to evaluate the contents of phosphate anion and calcium cation in six commercial samples. PMID- 23357639 TI - Near infrared spectroscopy in combination with chemometrics as a process analytical technology (PAT) tool for on-line quantitative monitoring of alcohol precipitation. AB - The application of near infrared (NIR) spectroscopy for on-line quantitative monitoring of alcohol precipitation of the Danhong injection was investigated. For the NIR measurements, two fiber optic probes designed to transmit NIR radiation through a 2mm path length flow cell were applied to collect spectra in real-time. Particle swarm optimization- (PSO-) based least square support vector machines (LS-SVM) and partial least squares (PLS) models were developed for quantitative analysis of the critical intermediate quality attributes: the soluble solid content (SSC) and concentrations of danshensu (DSS), protocatechuic aldehyde (PA), hydroxysafflor yellow A (HSYA) and salvianolic acid B (SAB). The optimal models were then used for on-line quantitative monitoring of alcohol precipitation. The results showed that the PSO-based LS-SVM with a radial basis function (RBF) kernel was slightly better than the conventional PLS method, even though both methods exhibited satisfactory fitting results and predictive abilities. In this study, successful models were built and applied on-line; these models proffer real-time data and instant feedback about alcohol precipitation. PMID- 23357640 TI - Effects of mud therapy on perceived pain and quality of life related to health in patients with knee osteoarthritis. AB - OBJECTIVE: To analyze the effects of mud therapy on perceived pain, Health Related Quality of Life (HRQL) and drug use in patients diagnosed with knee osteoarthritis. MATERIAL AND METHODS: A prospective, controlled clinical trial. The sample (n=147) was divided into an experimental group (EG) of 61 subjects (69.13 +/- 5,60 years) who received 11 consecutive sessions of peloids in the knee/s affected by the process described and a control group (CG) of 60 subjects (73.08 +/- 8,90 years) who continued routine drug treatment. The sample was assessed before and after intervention using the SF-36, Visual Analogue Scale and changes in drug use, setting a significance level of P <= .05. RESULTS: After the intervention, there were statistically significant differences (P<.05) in all parameters analyzed between EG and CG, reduced drug use in the EG versus no change in the CG. The general health, bodily pain and perceived pain are those that show major changes between the two groups. CONCLUSIONS: Mud therapy in patients diagnosed with knee osteoarthritis attains immediate effects on perceived pain and HRQOL, reducing the consumption of specific drugs. Studies are needed to evaluate the scientific evidence from the effects of such intervention. PMID- 23357641 TI - Nephronectin binds to heparan sulfate proteoglycans via its MAM domain. AB - Nephronectin is a basement membrane protein comprising five N-terminal epidermal growth factor (EGF)-like repeats, a central linker segment containing an Arg-Gly Asp (RGD) motif and a C-terminal meprin-A5 protein-receptor protein tyrosine phosphatase MU (MAM) domain. Nephronectin has been shown to interact with alpha8beta1 integrin through the central linker segment, but its interactions with other molecules remain to be elucidated. Here, we examined the binding of nephronectin to a panel of glycosaminoglycan (GAG) chains. Nephronectin bound strongly to heparin and chondroitin sulfate (CS)-E and moderately to heparan sulfate (HS), but failed to bind to CS-A, CS-C, CS-D, dermatan sulfate and hyaluronic acid. Deletion of the MAM domain severely impaired the binding of nephronectin to heparin but not CS-E, whereas deletion of the EGF-like repeats reduced its binding to CS-E but not heparin, suggesting that nephronectin interacts with CS-E and heparin through the EGF-like repeats and MAM domain, respectively. Consistent with these results, nephronectin bound to agrin and perlecan, which are heparan sulfate proteoglycans (HSPGs) in basement membranes, in HS-dependent manners. Site-directed mutagenesis of the MAM domain revealed that multiple basic amino acid residues in the putative loop regions were involved in the binding of the MAM domain to agrin. The binding of nephronectin to basement membrane HSPGs was further confirmed by in situ nephronectin overlay assays using mouse frozen tissue sections. Taken together, these findings indicate that nephronectin is capable of binding to HSPGs in basement membranes via the MAM domain, and thereby raise the possibility that interactions with basement membrane HSPGs may be involved in the deposition of nephronectin onto basement membranes. PMID- 23357642 TI - Structure-function relationships of postnatal tendon development: a parallel to healing. AB - This review highlights recent research on structure-function relationships in tendon and comments on the parallels between development and healing. The processes of tendon development and collagen fibrillogenesis are reviewed, but due to the abundance of information in this field, this work focuses primarily on characterizing the mechanical behavior of mature and developing tendon, and how the latter parallels healing tendon. The role that extracellular matrix components, mainly collagen, proteoglycans, and collagen cross-links, play in determining the mechanical behavior of tendon will be examined in this review. Specifically, collagen fiber re-alignment and collagen fibril uncrimping relate mechanical behavior to structural alterations during development and during healing. Finally, attention is paid to a number of recent efforts to augment injured tendon and how future efforts could focus on recreating the important structure-function relationships reviewed here. PMID- 23357644 TI - Genetic characterization of human respiratory syncytial virus detected in hospitalized children in the Philippines from 2008 to 2012. AB - BACKGROUND: Human respiratory syncytial virus (HRSV) is the leading cause of acute lower respiratory tract infection in infants and young children. However, molecular characteristic of HRSV is still unknown in the Philippines. OBJECTIVE: To describe the molecular epidemiology of circulating HRSV detected in the Philippines. STUDY DESIGN: From May 2008 to April 2012, nasopharyngeal swabs were collected from infants and children aged between 7 days and 14 years who were hospitalized with severe pneumonia. HRSV was detected by nested PCR targeting M2 gene, and C-terminus of the G gene was sequenced for phylogenetic analysis. RESULT: Out of total 2150 samples, 19.3% (n = 415) were positive for HRSV, and 65.0% of them (n = 270) were identified as HRSV-A and 35.0% (n = 145) as HRSV-B. There were two major HRSV outbreaks: between June 2008 and February 2009, and between June and March 2012. Majority of HRSV strains detected during the former outbreak were HRSV-A (97.5%, 203/208) whereas during the later outbreak, both HRSV-A (54/158, 34.2%) and HRSV-B (104/158, 65.8%) were detected. All HRSV-A strains were classified as genotype NA1 and all HRSV-B as genotype BA, which had 60-nucleotide duplication in secondary hypervariable region of the G gene. Among HRSV-B positive samples, there were 2 distinct clusters with unique amino acid changes and low homology in compared to other strains in BA, suggesting emergence of new variant of HRSV-B. CONCLUSION: The study provides an overview of the genetic variation in circulating HRSV viruses in the Philippines along with identification of possibly a novel variant of HRSV-B. PMID- 23357643 TI - Organizational actions of metabolic hormones. AB - Brain development is a complex and dynamic process, and many environmental factors have been found to influence the normal development of neural pathways. Cumulative evidence suggests that metabolic hormones that regulate the hypothalamic circuits that control energy homeostasis function in much the same way that sex steroids act on sexually dimorphic circuits. For example, although the effects of the adipocyte-derived hormone leptin were originally thought to be limited to the neural control of energy homeostasis in adult animals, it is now becoming increasingly clear that leptin can also determine patterns of neurogenesis, axon growth, and synaptic plasticity in the developing hypothalamus. More recent studies have also extended the role of the metabolic hormones ghrelin and insulin in various aspects of brain development. Examining how metabolic hormones control hypothalamic development will help our understanding of the developmental origin of adult metabolic diseases and, hopefully, improve our ability to predict adverse outcomes. PMID- 23357645 TI - Variant screening of the serum amyloid A1 gene and functional study of the p.Gly90Asp variant for its role in atherosclerosis. AB - OBJECTIVES: Serum amyloid A1 (SAA1) is a major acute-phase protein that is increasingly used as a reliable predictor of coronary artery disease (CAD). In this study we aim to screen the SAAI promoter and exons for genetic variants and to determine their association with CAD. In addition, we also carried out functional study on a variant of p.Gly90Asp encoded by the SAA1 gene. METHODS: Variant screening of SAA1 was performed using high resolution melting (HRM) analysis. Genetic association of p.Gly90Asp with CAD was determined in 800 CAD patients and 773 Chinese control subjects. Functional study of p.Gly90Asp was carried out using THP-1-derived macrophages and HL-60 promyelocytic leukemia cells. RESULTS: A total of 6 SNPs were identified, of which 2 were found to be novel (c.-913G > A and c.92-5T > G). The rare allele of p.Gly90Asp has a lower frequency of 0.013 in the CAD patients although this is not statistically significant. Functional studies of p.Gly90Asp revealed that the variant has decreased upregulation of key cytokines such as IL-8, MCP-1 and TNF-alpha as well as SERPINB2. CONCLUSIONS: We found the variant p.Gly90Asp SAA1 protein eliciting significantly reduced inflammatory responses in macrophages through a reduction in the secretion of inflammatory cytokines. Despite strong functional effects, the minor allele frequency is too low in the population to attain statistical significance difference between cases and controls. PMID- 23357646 TI - Impact of periodontitis on oral health-related quality of life. AB - OBJECTIVES: To investigate the impact of chronic periodontitis on oral health related quality of life (OHRQoL) using the full version of the Oral Health Impact Profile (OHIP-49) and the Oral Health Quality of Life-UK (OHQoL-UK) questionnaires. METHODS: 89 patients with chronic periodontitis and 89 age- and gender-matched patients without chronic periodontitis were recruited. OHIP-49 and OHQoL-UK were self-completed by participants and mean scores were calculated for each item, domain and the overall summary score (additive method) for each instrument in each group. RESULTS: The mean age of participants was 47 +/- 9 years, and the periodontitis patients had, on average, 33 +/- 23 sites demonstrating probing depths >= 5 mm. OHRQoL was significantly poorer in the periodontitis patients compared to the periodontally healthy patients, when assessed by either instrument. When considering OHIP-49, fourteen of the forty nine items indicated significantly poorer OHRQoL in the periodontitis group, and the overall OHIP-49 summary score was 48.6 +/- 32.0 for periodontitis patients compared to 36.8 +/- 29.8 in periodontally healthy patients (p<0.01). When considering OHQoL-UK, fifteen of the sixteen items indicated significantly poorer OHRQoL in the periodontitis group, and the overall OHQoL-UK summary score was 47.1 +/- 9.7 for periodontitis patients compared to 53.1 +/- 11.3 in periodontally healthy patients (p<0.01). Overall, those items with the greatest differences between periodontitis patients and the healthy group related to psychological concerns, halitosis, pain and aesthetics. CONCLUSION: Subjects with periodontitis report substantial functional, physical, psychological, and social OHRQoL impacts. CLINICAL SIGNIFICANCE: This study has identified that patients with chronic periodontitis report significantly poorer oral health-related quality of life (OHRQoL) than age- and gender-matched periodontally healthy patients, with significant functional, social and psychological impacts. Clinicians should be aware of the impacts that periodontitis may have on OHRQoL, including psychological concerns, halitosis, pain and aesthetics. PMID- 23357647 TI - Tooth sensitivity and efficacy of in-office bleaching in restored teeth. AB - OBJECTIVES: The aim of this clinical trial was to evaluate efficacy (BE) and tooth sensitivity (TS) of in-office bleaching with a 35% hydrogen peroxide (HP) in patients with aesthetic restorations. METHODS: Hydrogen peroxide 35% was applied in two sessions, of three 15 min applications, in 15 patients with upper anterior sound teeth (S) and 15 with aesthetic restorations (R). The colour was recorded at baseline, one week and 6 months after treatment completion. Patients recorded TS on a 0-4 scale. The BE was evaluated by two-way ANOVA and Tukey's tests (alpha=0.05). The percentage of patients with TS was evaluated by Fisher's exact test and TS intensity of treatments was compared with Mann-Whitney U-test (alpha=0.05). RESULTS: All participants experienced TS at least once during treatment. Higher TS intensity was observed in R (1.5 [1/1.75]) compared to S (0.5 [0/1.25]) during the bleaching (p<0.05). S and R demonstrated similar tooth colour enhancement compared to baseline (p<0.05) and both presented colour stability after 6 months of evaluation (p>0.05). CONCLUSIONS: The in-office bleaching with 35% HP was effective in patients with aesthetic restorations, however, a higher intensity of TS was observed during the bleaching protocol. CLINICAL RELEVANCE: In-office dental bleaching can be performed in patients with adhesive restorations promoting satisfactory results; however, it can promote higher intensity of sensitivity compared to patients with sound teeth. PMID- 23357648 TI - Acanthamoeba royreba: morphological features and in vitro cytopathic effect. AB - Observations on cultured Acanthamoeba royreba trophozoites and in vitro cytopathogenicity of this amoeba are described. In culture, amoebae were active, pleomorphic and moved on the substrate by producing endocytic structures and emitting slight cytoplasmic microprojections from the cell surface. These projections were formed by hyaline cytoplasm and they were related to motion structures such as acanthopodia and lamellipodia, in which actin provides a framework that allows rapid changes in morphology. In the cytoplasm abundant vacuoles of different size and content were seen. By means of electron microscopy, it was possible to observe the compact fibrogranular appearance of the cytoplasm, along with the main cellular organelles such as the Golgi complex, the endoplasmic reticulum, digestive vacuoles, mitochondria and contractile vacuoles. Incubation of MDCK epithelial cell monolayers with conditioned medium did not produce a significant structural damage to the monolayer, even after 24h of incubation. When the trophozoites were incubated with the target cells the monolayer exhibited a clear injury created by the amoebae, which produced focal damage. Nevertheless, the rest of the monolayer appeared to remain intact, suggesting that a contact-dependent interaction is necessary to damage the target cells. These observations demonstrate the low invasive capacity of this amoeba. PMID- 23357649 TI - Proteomic analysis of the tegument and excretory-secretory products of Dicrocoelium dendriticum (Digenea) adult worms. AB - Dicrocoeliosis, caused by Dicrocoelium dendriticum, is an important hepatic parasitosis in ruminants, whose immunological diagnosis and control remain unsatisfactory. There are very few studies on the antigens of this trematode and molecular knowledge about it is practically nil. Therefore the aim of this study was to identify the major antigenic proteins in the tegument (TG) and excretory secretory (ES) antigenic extracts of D. dendriticum. The separation conditions of the protein extracts were optimized using 2-D PAGE; the gels were stained with colloidal Coomassie or transferred to carry out immunodetection with anti Dicrocoelium dendriticum sera. The proteins of interest excised from the gels were identified by mass spectrometry (MALDI). The proteomic maps of the TG and ES extracts of D. dendriticum were defined first, detecting 332 spots in the TG and 284 in the ES, with a similar distribution in both. A quantity of 29 proteins in the excretion-secretion products and 43 in the teguments were identified first in D. dendriticum, 23 of them antigenic, involved in various processes such as: metabolism, detoxification, chaperone, transport or structural molecules. These results could help us to understand the complex parasite-host relationships, improve the diagnosis of dicroceliosis and help to produce possible vaccines to control it. PMID- 23357650 TI - Increased ratio of serum matrix metalloproteinase-9 against TIMP-1 predicts poor wound healing in diabetic foot ulcers. AB - OBJECTIVE: Little is known about serum concentrations of Matrix Metalloproteinase 9 (MMP-9), MMP-2, TIMP-1 and TIMP-2 in diabetic patients with foot ulcers. This study demonstrates their relationship with wound healing. METHODS: Ninety-four patients with diabetic foot ulcers were recruited in the study. Serum MMP-9, MMP 2, TIMP-1 and TIMP-2 were measured at the first clinic visit and the end of 4 week treatment and followed up till 12 weeks. According to the decreasing rate of ulcer healing area at the fourth week, we divided those cases into good and poor healers. Through analyses, we explore the possible relationship among those factors and degree of wound healing. RESULTS: The median level of serum MMP-9 in good healers was lower than poor healers at first visit (124.2 MUg/L vs 374.6 MUg/L, p<0.05), and after 4-week therapy it decreased 5-fold approximately. In contrast, the change in MMP-9 concentration did not reach statistical significance in poor healers. MMP-2, TIMP-1 and TIMP-2 varied slightly in both good healers and poor healers. The MMP-9/TIMP-1 ratio better reflected the healing than MMP-9 alone before therapy and after 4 week treatment (r = -0.6475 vs -0.3251, r = -0.7096 vs -0.1231, respectively). Receiver Operator Curve (ROC) showed that the cutoff for MMP-9/TIMP-1 ratio at <0.395 best predicted a reduction in wound area of 82% at the end of 4-week treatment with a sensitivity of 63.6% and a specificity of 58.6% (area under the curve 0.658, p < 0.001). CONCLUSIONS: Detecting serum MMP-9/TIMP-1 ratio on admission might be a predictor of healing and might provide a novel target for the future therapy in diabetic foot ulcers. PMID- 23357651 TI - Neuroglobin and neuronal cell survival. AB - The balance between neuronal apoptosis and survival sculpts the developing brain and has an important role in neurodegenerative diseases. Thus, the individuation of signals that could modulate the cell death machinery as well as enhance survival in neurons promises to provide multiple points of therapeutic intervention in neurodegenerative diseases. Neuroglobin (NGB), the first nerve globin identified in neuronal tissues of humans, seems to possess a protective role in the brain only after up-regulation. Here, the NGB physiological role in the control of neuronal survival is reviewed. In vitro studies suggested that cytosolic NGB could react very rapidly with cytochrome c released from mitochondria, thus interfering with the intrinsic pathway of apoptosis. Although very suggestive, these data do not explain either the role of NGB up-regulation in neuroprotection or the recently reported NGB localization into mitochondria. Recently, we identified the steroid hormone 17beta-estradiol (E2) as an endogenous modulator of NGB levels in neuroblastoma SK-N-BE cell line. Upon E2 stimulation, NGB reallocates mainly into mitochondria where the association with the mitochondrial cytochrome c occurs. Remarkably, E2 treatment before an apoptotic stimulus strongly enhances the NGB:cytochrome c association reducing cytochrome c release into the cytosol. As a consequence, a decrease of caspase-3 activation and, in turn, of the apoptotic cascade activation take place. Besides E2, other compounds have been reported to up-regulate the NGB expression highlighting the possibility to develop NGB-mediated therapeutic strategies against stroke damage and neurodegenerative diseases. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. PMID- 23357652 TI - Role of histidine 148 in stability and dynamics of a highly fluorescent GFP variant. AB - The armory of GFP mutants available to biochemists and molecular biologists is huge. Design and selection of mutants are usually driven by tailored spectroscopic properties, but some key aspects of stability, folding and dynamics of selected GFP variants still need to be elucidated. We have prepared, expressed and characterized three H148 mutants of the highly fluorescent variant GFPmut2. H148 is known to be involved in the H-bonding network surrounding the chromophore, and all the three mutants, H148G, H148R and H148K, show increased pKa values of the chromophore. Only H148G GFPmut2 (Mut2G) gave good expression and purification yields, indicating that position 148 is critical for efficient folding in vivo. The chemical denaturation of Mut2G was monitored by fluorescence emission, absorbance and far-UV circular dichroism spectroscopy. The mutation has little effect on the spectroscopic properties of the protein and on its stability in solution. However, the unfolding kinetics of the protein encapsulated in wet nanoporous silica gels, a system that allows to stabilize conformations that are poorly or only transiently populated in solution, indicate that the unfolding pathway of Mut2G is markedly different from the parent molecule. In particular, encapsulation allowed to identify an unfolding intermediate that retains a native like secondary structure despite a destructured chromophore environment. Thus, H148 is a critical residue not only for the chromophoric and photodynamic properties, but also for the correct folding of GFP, and its substitution has great impact on expression yields and stability of the mature protein. PMID- 23357653 TI - Effects of type of diet on pharmacokinetics of levothyroxine sodium oral solution. AB - The pharmacokinetics of serum total thyroxine concentration (TT4) in euthyroid dogs was studied after concomitant administration of a levothyroxine oral solution with different types of dry diet. Mixing levothyroxine with different types of dry diet did not have any effect on TT4 pharmacokinetics in the dogs (Cmax 50.6 nmol/L, tmax 4.0 h and AUC 517 nmol h/L). This finding indicates that changing from one diet to another during levothyroxine-replacement therapy should not impact therapeutic effectiveness, and should be helpful for improvement of compliance with thyroid hormone replacement therapy in dogs treated for life with this replacement therapy. PMID- 23357654 TI - [General epidemiology of nosocomial infections. Surveillance systems and programs]. AB - Infections related to the health-care system are those associated with health care practices in hospitalized patients as well as in out-patients with health care contact. Nosocomial infections affect 5% of in-patients, and carry a high morbidity, mortality and economic cost. The main types of nosocomial infections are related to invasive procedures, and include respiratory tract infection, surgical site infections, urinary tract infections, and vascular catheter bacteremia. It has been shown that the application of checklists and a bundle of measures are useful in preventing these infections. Epidemiological surveillance, defined as the gathering of information to take actions, is the basis of infection control programs. These have evolved from a global surveillance targeted at processes and indicators of nosocomial infection. The comparison of these indicators can be useful in establishing preventive measures. PMID- 23357655 TI - Alcohol-related deaths and social factors in depression mortality: a register based follow-up of depressed in-patients and antidepressant users in Finland. AB - BACKGROUND: Excess mortality of depression is established for various causes of death, but evidence is scarce on alcohol-related causes. It also remains unclear whether the magnitude of the excess varies by social factors. This study aimed to quantify the contribution of alcohol-related causes of death and to assess modifying effects of socioeconomic position, employment status, and living arrangements in the excess mortality of depression. METHODS: A 14% sample of community-dwelling Finns aged 40-64 at the end of 1997 was assessed for depression, using register data on psychiatric hospital care and antidepressant use in 1996-1997. Depressed in-patients (n=897), out-patients using antidepressants (n=13,658), and non-depressed individuals (n=217,140) were followed up for cause-specific mortality in 1998-2007, distinguishing between alcohol- and non-alcohol-related deaths, and testing for variation in the excess mortality according to baseline social factors. RESULTS: Depressed in- and out patients had significant excess mortality for suicide (age-adjusted rate ratios RR=3.77 for men and RR=6.35 for women), all accidental and violent causes (RR=3.47 and RR=4.43), and diseases (RR=1.67 and RR=1.41). Of the excess, alcohol related causes accounted for 50% among depressed men and 30% among women. Excess mortality varied little by social factors, particularly in non-alcohol-related causes. Where variation was significant, the relative excess was larger among those with higher socioeconomic position and the employed. Absolute excess was, however, larger among those with lower socioeconomic position, the unemployed, and the unpartnered. LIMITATIONS: Depression was measured indirectly by hospital and antidepressant use. CONCLUSIONS: The results highlight the major role of alcohol in depression mortality. PMID- 23357656 TI - The relation between affective temperament and resilience in depression: a controlled study. AB - BACKGROUND: The aim of this study was to investigate the presence of a relationship between affective temperament and resilience in patients with major depressive disorder (MDD) diagnosis, and to examine whether this relationship, if present, differs from healthy individuals. METHODS: In line with this purpose, 100 cases with major depressive disorder diagnosis who were in their remission period were evaluated consecutively in their regular outpatient control interviews. The control group consisted of 100 healthy individuals without any history of psychiatric admission and treatment, matched with the depressive group in terms of age and sex. Diagnostic interviews were conducted with SCID-I, affective temperament and resilience were evaluated with TEMPS-A (Evaluation of Temperament Memphis, Pisa, Paris and San Diego-Auto questionnaire) and The Resilience Scale for Adults (RSA)-Turkish version, respectively. RESULTS: We observed a strong relationship between resilience and hyperthymic temperament both in depressive and healthy individuals. There was an inverse relation between psychological resilience and irritable and anxious temperament in both groups. A negative correlation was observed between irritable temperament and family cohesion in depressive disorder group, while in healthy individuals a strong correlation was observed between family cohesion and depressive and anxious temperament, and a weak correlation between family cohesion and hyperthymic temperament. LIMITATIONS: The measurements of temperament and resilience were estimated depending on the patient's statement. CONCLUSION: There is a strong relationship between hyperthymic temperament and psychological resilience in MDD. The relationship between the type of affective temperament and the family cohesion sub-dimension of psychological resilience differs from that of healthy individuals. PMID- 23357657 TI - Internet-based behavioral activation and acceptance-based treatment for depression: a randomized controlled trial. AB - BACKGROUND: Internet-based cognitive behavior therapy for depression has been tested in several trials but there are no internet studies on behavioral activation (BA), and no studies on BA over the internet including components of acceptance and commitment therapy (ACT). The aim of this study was to develop and test the effects of internet-delivered BA combined with ACT against a waiting list control condition as a first test of the effects of treatment. METHODS: Selection took place with a computerized screening interview and a subsequent semi-structured telephone interview. A total of 80 individuals from the general public were randomized to one of two conditions. The treatment lasted for 8 weeks after which both groups were assessed. We also included a 3 month follow-up. The treatment included interactive elements online and a CD-ROM for mindfulness and acceptance exercises. In addition, written support and feedback was given by a therapist every week. RESULTS: Results at posttreatment showed a large between group effect size on the Beck Depression inventory II d=0.98 (95%CI=0.51-1.44). In the treated group 25% (10/40) reached remission defined as a BDI score <= 10 vs. 5% (2/40) in the control group. Results on secondary measures were smaller. While few dropped out from the study (N=2) at posttreatment, the average number of completed modules was M=5.1 out of the seven modules. LIMITATIONS: The study only included a waiting-list comparison and it is not possible to determine which treatment components were the most effective. CONCLUSIONS: We conclude that there is initial evidence that BA with components of ACT can be effective in reducing symptoms of depression. PMID- 23357658 TI - What does the HAMD mean? AB - Little is known about the clinical relevance of the Hamilton Rating Scale for Depression (HAMD-17) total scores. It is unclear how total scores translate into clinical severity, or what commonly used measures for response (reduction from baseline of >= 50% in the total score) and remission (total HAMD-17 score <= 7) mean from a clinical perspective. We therefore compared: (a) the percentage and absolute change in the HAMD-17 total scores with Clinical Global Impression Improvement (CGI-I); (b) the absolute and percentage change in the HAMD-17 total scores with Clinical Global Impression-Severity (CGI-S) absolute change; and (c) the percentage and absolute change in the HAMD-17 total scores with CGI-I in the subgroups of patients with <= median and > median HAMD-17 total scores at baseline. The method used was equipercentile linking of HAMD-17 and CGI ratings from 43 drug trials in patients with Major Depressive Disorder (MDD) (n = 7131). Our results confirm the validity of the commonly used measures for remission and response in MDD trials: a CGI-I score of 2 ('much improved') corresponded to a reduction from baseline of > 50% and < 60%, and a CGI-I score of 1 ('very much improved') to a reduction of > 75% and < 85%. The CGI-S score of 1 ('normal., not at all ill') corresponded to the HAMD-17 total score of < 5 and the CGI-S score of 2 ('borderline mentally ill') to the score between 6 and 8. An effect of baseline illness severity was observed. PMID- 23357659 TI - Alterations of melatonin receptors MT1 and MT2 in the hypothalamic suprachiasmatic nucleus during depression. AB - BACKGROUND: The pineal hormone melatonin regulates circadian rhythms, largely by feedback on the central biological clock of the brain, the hypothalamic suprachiasmatic nucleus (SCN). This feedback is mediated by the melatonin receptors, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). The circadian system may play a role in the pathophysiology of mood disorders, and indeed, melatonin-receptor agonists are considered a potential therapy for depression. METHOD: In order to investigate melatonin receptors in the SCN during depression, and their relationship to the major neuropeptides in the SCN, vasopressin (AVP) and vasoactive intestinal peptide (VIP), we studied the SCN in 14 depressed patients (five major depression and nine bipolar disorder) and 14 matched controls by immunocytochemistry. RESULTS: We show here that hypothalamic MT2 receptor immunoreactivity was limited to SCN, the supraoptic nucleus and paraventricular nucleus. We found that numbers of MT1-immunoreactive (MT1-ir) cells and AVP and/or VIP-ir cells were increased in the central SCN in depression, but numbers of MT2-ir cells were not altered. Moreover, the number of MT1-ir cells, but not MT2-ir cells was negatively correlated with age at onset of depression, while positively correlated with disease duration. CONCLUSION AND LIMITATIONS: Although every post-mortem study has limitations, MT1 receptors appeared specifically increased in the SCN of depressed patients, and may increase during the course of the disease. These changes may be involved in the circadian disorders and contribute to the efficacy of MT agonists or melatonin in depression. Moreover, we suggest that melatonin receptor agonists for depression should be targeted towards the MT1 receptor selectively. PMID- 23357660 TI - Abdominal relaxation during emergence from general anesthesia with propofol and remifentanil. AB - STUDY OBJECTIVE: To characterize respiratory dynamics during emergence from propofol-remifentanil anesthesia using noninvasive respiratory inductance plethysmography (RIP). DESIGN: Observational pilot study. SETTING: Operating room in a university-affiliated teaching hospital. PATIENTS: 50 ASA physical status 1, 2, and 3 patients scheduled for microdirect laryngoscopy or bronchoscopy using total intravenous anesthesia (TIVA) with high-frequency jet ventilation. INTERVENTIONS: Patients were fitted with plethysmography bands around the chest and abdomen prior to induction. Following completion of surgery in patients undergoing brief airway procedures using propofol-remifentanil general anesthesia, the anesthetic infusions were stopped and ventilation suspended until resumption of spontaneous ventilation or desaturation below 90%. During this period of apnea, abdominal and thoracic girth was assessed with noninvasive RIP. MEASUREMENTS: Cross-sectional area of the thorax and abdomen during emergence were measured. MAIN RESULTS: Useful data were obtained from 41 patients, with stable apnea lasting 404 +/- 193.1 seconds; of these, 34 exhibited a slow and significant decrease in abdominal girth over a period of 267.8 +/- 128.5 seconds. Resumption of spontaneous ventilation generally coincided with the end of this abdominal relaxation. CONCLUSION: Slow expiration is the initial step in the resumption of spontaneous ventilation during apnea induced with TIVA using propofol-remifentanil. PMID- 23357661 TI - Vascular endothelial growth factor-angiopoietin chimera with improved properties for therapeutic angiogenesis. AB - BACKGROUND: There is an unmet need for proangiogenic therapeutic molecules for the treatment of tissue ischemia in cardiovascular diseases. However, major inducers of angiogenesis such as vascular endothelial growth factor (VEGF/VEGF-A) have side effects that limit their therapeutic utility in vivo, especially at high concentrations. Angiopoietin-1 has been considered to be a blood vessel stabilization factor that can inhibit the intrinsic property of VEGF to promote vessel leakiness. In this study, we have designed and tested the angiogenic properties of chimeric molecules consisting of receptor-binding parts of VEGF and angiopoietin-1. We aimed at combining the activities of both factors into 1 molecule for easy delivery and expression in target tissues. METHODS AND RESULTS: The VEGF-angiopoietin-1 (VA1) chimeric protein bound to both VEGF receptor-2 and Tie2 and induced the activation of both receptors. Detailed analysis of VA1 versus VEGF revealed differences in the kinetics of VEGF receptor-2 activation and endocytosis, downstream kinase activation, and VE-cadherin internalization. The delivery of a VA1 transgene into mouse skeletal muscle led to increased blood flow and enhanced angiogenesis. VA1 was also very efficient in rescuing ischemic limb perfusion. However, VA1 induced less plasma protein leakage and myeloid inflammatory cell recruitment than VEGF. Furthermore, angioma-like structures associated with VEGF expression were not observed with VA1. CONCLUSIONS: The VEGF angiopoietin-1 chimera is a potent angiogenic factor that triggers a novel mode of VEGF receptor-2 activation, promoting less vessel leakiness, less tissue inflammation, and better perfusion in ischemic muscle than VEGF. These properties of VA1 make it an attractive therapeutic tool. PMID- 23357662 TI - Are serial BNP measurements useful in heart failure management? Serial natriuretic peptide measurements are useful in heart failure management. AB - To deny the fact that standard HF care has substantial opportunity for improvement is at the peril of even worse outcomes in our patients affected by the disorder. We have presented a strong rationale for the value of BNP- and NTproBNP-guided HF management. Experience gained in biomarker-guided HF trials suggests that the approach results in improvement in the quality of care without an excess of adverse events related to more aggressive management. This alone is difficult to ignore given the gaps in care that exist between RCTs and real-world practice. Beyond this fact, studies examining the strategy of biomarker-guided HF care have shown substantial improvement in outcome compared with well-managed control arms, benefits that are confirmed in meta-analysis and pooled data analyses, and justifies the imminent launch of the pivotal RCT that will lead to more widespread adoption of the approach. Compared with standard management, biomarker-guided care appears cost effective, may improve patient quality of life, and may promote reverse ventricular remodeling. Although certain subgroups such as the elderly may respond in a less vigorous manner to the approach, this may reflect the effects of age on HF therapy and how the strategy is deployed in elders rather than a weakness of the approach in older patients. A fair-minded assessment of the available data suggests that care supported by BNP/NT-proBNP guided HF treatment-as an adjunct to standard clinical acumen-is superior to standard care. The limitation of standard care strategies is evident from the suboptimal uptake and application of proven therapies documented in HF registries. Far from being a crutch to support what we should already be doing (namely, optimally evaluating and managing our patients solely with clinical means), the inclusion of NP measurement within the HF management strategy augments the quality of monitoring and treatment. Denial of the benefits of NP monitoring potentially retards advances in the care of a high-risk population of patients that continues to grow in size and importance every day. PMID- 23357663 TI - Are serial BNP measurements useful in heart failure management? Serial natriuretic peptide measurements are not useful in heart failure management: the art of medicine remains long. PMID- 23357664 TI - High-output heart failure resulting from chronic aortocaval fistula. PMID- 23357665 TI - Sporadic cardiac myxoma involving all the cardiac chambers. PMID- 23357666 TI - Cardiology patient page. Coping with trauma and stressful events as a patient with an implantable cardioverter-defibrillator. PMID- 23357667 TI - Letter by Rosner et al regarding article, "When the heart runs out of heartbeats: treatment options for refractory end-stage heart failure". PMID- 23357668 TI - Letter by Goodman and Sax regarding article, "Controlled exposure of healthy young volunteers to ozone causes cardiovascular effects". PMID- 23357669 TI - Letter by MacDonald et al regarding article, "Catheter ablation of atrial fibrillation". PMID- 23357670 TI - Potential beneficial role of sevelamer hydrochloride in diabetic retinopathy. AB - Patients with chronic kidney disease (CKD) experience co-morbid illnesses, including cardiovascular disease and retinopathy. Sevelamer hydrochloride (Renagel(r)); a non-calcium phosphate binder reduces coronary artery and aortic calcification as compared to calcium containing phosphate binders and additionally effects inflammatory biomarkers such as C-reactive protein (CRP), and lowers LDL cholesterol in patients with CKD. Since retinopathy is proven to be associated with increased coronary calcification, shared pathophysiological processes may contribute to both microvascular and macrovascular disease. We here suggest three different mechanisms of possible sevelamer's influence on the retinopathy: (1) by direct effect on the microvasculature through lowering CRP and LDL, involved in endothelial dysfunction and atherogenesis, (2) indirectly by attenuation of vascular calcification of aorta and carotid internal artery, it reduces ischaemia and improves circulation in the opthalmic artery and hence postponing retinopathy, (3) through hypertension by reducing atherosclerosis and calcification of carotid arteries, sevelamer decreases stiffness and intima-media wall thickness, therefore lowering blood pressure, which is well known to increase progression of diabetic retinopathy. So far no studies have yet been published on the direct influence of sevelamer on the retinopathy which we believe has good theoretical background. With its combined macrovascular and microvascular effect, sevelamer could potentially postpone and/or decrease retinopathy in diabetic patients with hypertension, and that are on hemodialysis or even predialysis patients. PMID- 23357671 TI - Truncated ERG proteins affect the aggressiveness of prostate cancer. AB - Prostate cancer is a significant health problem around the world. It ranks second in newly diagnosed cancers and sixth in leading causes of cancer death among men. More than half of prostate cancer cases have E twenty-six (ETS) gene fusions, which are potential diagnostic markers for prostate cancer. TMPRSS2: ERG gene fusions are the most common types of gene fusions in prostate cancer. However, the association between TMPRSS2: ERG gene fusions and the aggressiveness of prostate cancer remains elusive. Recent studies showed conflicted results. We hypothesize that some N-terminal truncated ERG proteins encoded by TMPRSS2: ERG fusion genes account for the conflict. Overexpression of full length ERG protein promotes the transcriptional activation of oncogenes and facilitates cancer progression. However some N-terminal truncated ERG proteins might inhibit the oncogenic transcriptional activation by competitive binding to ETS domain binding sites in prostate cancer. And prostate cancers that expressing truncated ERG proteins of these types might possess less aggressive features. PMID- 23357672 TI - Repercussions of occult malignancy - an etiologic basis for rheumatic disease. AB - Paraneoplastic syndromes and infection are known causes of autoimmunity, but the etiology of most autoimmune syndromes remains unknown. If the immune system can effectively fight malignant cell lines, it is likely that many potential tumors are controlled before becoming clinically apparent. This phenomenon is a potential explanation for all non-infectious auto-immunity including many rheumatic diseases. The presented discussion argues that all auto-immune disease is secondary to infection or neoplasia, and occult neoplasia is responsible for rheumatic diseases. Detecting occult neoplasia is inherently not possible, but if this theory bears truth, induced autoimmune disease could become a powerful treatment of malignancy. PMID- 23357673 TI - Stimulus pairing training for Kanji reading skills in students with developmental disabilities. AB - Japanese students with developmental disabilities often exhibit difficulties in reading, particularly in Kanji (ideogram) reading, and in acquiring the equivalence relations between pictures, written words, and sounds. Previous research suggested that one student with autism could acquire Kanji reading along with equivalence relations through stimulus pairing training. However, maintenance rates tended to be very low, possibly due to the lack of picture stimuli. In this study, we examined the acquisition and maintenance of Kanji reading skills through stimulus pairing training using corresponding pictures for six students with developmental disabilities. We prepared stimulus pairs consisting of picture stimuli that the students could name along with a corresponding Kanji character that they could not read. All students successfully acquired and maintained the Kanji reading skills through this procedure. These findings suggest that the nameability of picture stimuli in stimulus pairing training may facilitate the acquisition and maintenance of equivalence relations for reading. PMID- 23357674 TI - Adolescent idiopathic scoliosis and eating disorders: is there a relation? Results of a cross-sectional study. AB - A recent study suggests a correlation between idiopathic scoliosis in adolescence and eating disorders. However, this does not correspond with our clinical experience in the same population. The aim of this study was to verify the correlation between scoliosis and eating disorders in adolescence. A cross sectional study was designed including 187 consecutive adolescent girls with a diagnosis of idiopathic scoliosis (mean Cobb angle 26 degrees , range 11-73 degrees , age 15.2+/-2.5; 24% juveniles, 76% adolescent type) and 93 schoolgirls as controls (age 14.9+/-1.0). All of the participants answered the Italian validated questionnaire EAT-26 about eating habits in order to identify any eating disorders. Body mass index (BMI) was calculated for all participants and compared to reference data. STATISTICAL ANALYSIS: chi-square test, Student's t test, Pearson's correlation coefficient. Only 3 (1.6%; 95% CI -0.2-3.4%) participants in the scoliosis group showed EAT-26 scores suggestive for eating disorders versus 7 (7.5%; 95% CI 2.2-12.9%) in the school population (p<0.05). The BMI was slightly lower (p<0.05) for scoliosis patients (19+/-0.2) than for school girls (21+/-0.3). EAT-26 is recognized among the most valid questionnaires for eating disorders and has been widely applied in various countries. By applying this questionnaire, a lower incidence of eating disorders in female scoliosis patients was found than in the general population (using both our own controls and Italian reference values). This contrasts with some expert opinions and a recent study performed in Italy. The low BMI already reported in the literature as being typical of scoliosis participants is confirmed by our data. PMID- 23357675 TI - Comparison of the predictive validity and consistency among preference assessment procedures: a review of the literature. AB - We reviewed 14 experimental studies comparing different preference assessments for individuals with developmental disabilities that were published in peer reviewed journals between 1985 and 2012. Studies were summarized based on the following six variables: (a) the number of participants, (b) the type of disability, (c) the number and type of stimuli, (d) the average duration of administration, (e) compared procedures, and (f) results. Studies were also classified in terms of the predictive validity and consistency of the preference assessment results. The results suggest the preference assessment procedures that may produce more accurate predictions for the reinforcing effects of identified stimuli and consistent preference results. The findings are discussed in relation to the previous literature. Evidence based modifications of the most efficient preference assessment are also discussed. PMID- 23357676 TI - Chemical oxidation of aniline and N-methylaniline: a kinetic study by Raman spectroscopy. AB - For the first time, chemical oxidation of aniline and N-methylaniline with dichromate as oxidant has been studied by Raman spectroscopy with 785 nm laser beam excitation, and the suitability of this technique for kinetic study of this process was demonstrated. For both monomers used, a sigmoidal growth of the intensities for most prominent Raman bands was observed, showing a self accelerating character of this reaction. Self-acceleration appears most clearly expressed for aniline, and for the low oxidant-to-monomer molar ratio used. After reaching their maximum values, the intensities of Raman bands drop almost to zero, most probably due to increase in opacity and optical absorbance of reaction mixture. The kinetics of an increase, and the next following decrease of band intensities depend on the monomer used, and oxidant-to-monomer molar ratio. PMID- 23357677 TI - Extracellular biosynthesis of CdTe quantum dots by the fungus Fusarium oxysporum and their anti-bacterial activity. AB - The growing demand for semiconductor [quantum dots (Q-dots)] nanoparticles has fuelled significant research in developing strategies for their synthesis and characterization. They are extensively investigated by the chemical route; on the other hand, use of microbial sources for biosynthesis witnessed the highly stable, water dispersible nanoparticles formation. Here we report, for the first time, an efficient fungal-mediated synthesis of highly fluorescent CdTe quantum dots at ambient conditions by the fungus Fusarium oxysporum when reacted with a mixture of CdCl2 and TeCl4. Characterization of these biosynthesized nanoparticles was carried out by different techniques such as Ultraviolet-visible (UV-Vis) spectroscopy, Photoluminescence (PL), X-ray Diffraction (XRD), X-ray Photoelectron spectroscopy (XPS), Transmission Electron Microscopy (TEM) and Fourier Transformed Infrared Spectroscopy (FTIR) analysis. CdTe nanoparticles shows antibacterial activity against Gram positive and Gram negative bacteria. The fungal based fabrication provides an economical, green chemistry approach for production of highly fluorescent CdTe quantum dots. PMID- 23357678 TI - Identification of biomolecules by terahertz spectroscopy and fuzzy pattern recognition. AB - An approach for automatic identification of terahertz (THz) spectra of biomolecules is proposed based on principal component analysis (PCA) and fuzzy pattern recognition in this paper, and THz transmittance spectra of some typical amino acid and saccharide biomolecular samples are investigated to prove its feasibility. Firstly, PCA is applied to reduce the dimensionality of the original spectrum data and extract features of the data. Secondly, instead of the original spectrum variables, the selected principal component scores matrix is fed into the model of fuzzy pattern recognition, where a principle of fuzzy closeness based optimization is employed to identify those samples. Results demonstrate that THz spectroscopy combined with PCA and fuzzy pattern recognition can be efficiently utilized for automatic identification of biomolecules. The proposed approach provides a new effective method in the detection and identification of biomolecules using THz spectroscopy. PMID- 23357679 TI - Fluorescence of tryptophan in aqueous solution. AB - In this work, the absorption and emission spectra of Tryptophan (Trp) in aqueous solution were studied. Moreover, a hydrogen-bonded zwitterionic Trp(H2O)9 model was proposed and its ground-state and excited-state properties were investigated using the density functional theory (DFT) and the time-dependent density functional theory (TD-DFT) methods, respectively. All spectroscopic data in our experiments can be well explained by the hydrogen bond strengthening in the excited state of the model complex. The delocalization of electron density between indole moiety and neighboring H2O molecules in fluorescent state was proposed to be facilitated by the strengthened hydrogen-bond chain, and thus resulting in the large red-shift fluorescence of Trp in aqueous solution. PMID- 23357680 TI - Interaction of PARP-2 with DNA structures mimicking DNA repair intermediates and consequences on activity of base excision repair proteins. AB - Poly(ADP-ribosyl)ation is a posttranslational protein modification significant for genomic stability and cell survival in response to DNA damage. Poly(ADP ribosyl)ation is catalyzed by poly(ADP-ribose)polymerases (PARPs). Among the 17 members of the PARP family, PARP-1 and PARP-2 are described as enzymes whose catalytic activity is stimulated by some types of DNA damages. Whereas the role of PARP-1 in response to DNA damage has been widely illustrated, the contribution of another DNA-dependent PARP, PARP-2, is less documented. To find out specific DNA targets of PARP-2 we evaluated by EMSA Kd values of PARP-2-DNA complexes for several DNA structures mimicking intermediates of different DNA metabolizing processes. In addition, we tested these DNA as activators of PARP-1 and PARP-2 in poly(ADP-ribose) synthesis. Like PARP-1, PARP-2 doesn't show correlation between activation efficiency and Kd values for DNA. PARP-2 displayed the highest affinity for flap-containing DNA, but was more efficiently activated by 5' overhang DNA. Evaluating the influence of PARP-1 and PARP-2 on DNA repair synthesis catalyzed by DNA polymerase beta revealed that both PARPs inhibit DNA polymerase beta activity. However, unlike PARP-1, poly(ADP-ribosyl)ation of PARP 2 does not result in restoration of DNA synthesis efficiency. Similarly, both PARPs proteins inhibited FEN1 activity, but only activation of PARP-1, not PARP 2, could restore FEN1 activity, and only when PARP-2 was not present. Taken together, our data show that PARP-2 can directly regulate BER proteins but also can modulate the influence of PARP-1 on these BER proteins, by decreasing its poly(ADP-ribosyl)ation activity. PMID- 23357682 TI - Response. PMID- 23357681 TI - Receptors for the neuropeptides, myoinhibitory peptide and SIFamide, in control of the salivary glands of the blacklegged tick Ixodes scapularis. AB - Tick salivary glands are important organs that enable the hematophagous feeding of the tick. We previously described the innervation of the salivary gland acini types II and III by a pair of protocerebral salivary gland neurons that produce both myoinhibitory peptide (MIP) and SIFamide (Simo et al., 2009b). In this study we identified authentic receptors expressed in the salivary glands for these neuropeptides. Homology-based searches for these receptors in the Ixodes scapularis genome sequence were followed by gene cloning and functional expression of the receptors. Both receptors were activated by low nanomolar concentrations of their respective ligands. The temporal expression patterns of the two ligands and their respective receptors suggest that the SIFamide signaling system pre-exists in unfed salivary glands, while the MIP system is activated upon initiation of feeding. Immunoreactivity for the SIFamide receptor in the salivary gland was detected in acini types II and III, surrounding the acinar valve and extending to the basal region of the acinar lumen. The location of the SIFamide receptor in the salivary glands suggests three potential target cell types and their probable functions: myoepithelial cell that may function in the contraction of the acini and/or the control of the valve; large, basally located dopaminergic granular cells for regulation of paracrine dopamine; and neck cells that may be involved in the control of the acinar duct and its valve. PMID- 23357683 TI - 3q26.33-3q27.2 microdeletion: a new microdeletion syndrome? AB - We describe three unrelated patients of European descent carrying an overlapping 3q26.33-3q27.2 microdeletion who share common clinical features: neonatal hypotonia, severe feeding problems, specific facial features, abnormal dentition, recurrent upper airways infections, developmental delay and severe growth impairment. One of the patients carries a smaller deletion and presents a milder phenotype. We propose that 3q26.33-3q27.2 microdeletion may represent a novel condition caused by the haploinsufficiency of dosage sensitive genes, several of which are involved in brain development. PMID- 23357684 TI - Responses to central oxotremorine and scopolamine support the cholinergic control of male mating behavior in hamsters. AB - The responses of hamsters to intracranial injections of the cholinergic agonist oxotremorine (OXO) implicate cholinergic mechanisms in the medial preoptic area (MPOA) in the control of male mating behavior. To extend these observations, we ran three studies of responses to cholinergic drugs delivered singly or in combination to the vicinity of the MPOA. The first tested responses to OXO, confirming its ability to reduce the postejaculatory interval. The second complemented the first by examining responses to MPOA microinjections of the cholinergic antagonist scopolamine (SCO). These caused several changes revolving around intromission. These included increases in intromission frequency and ejaculation latency. They also included a change in the patterning of intromissions, marked by continuous strings without the usual separation by dismounts. The final study resembled the others in examining the effects of MPOA injections of OXO and SCO but focused on the ability of each drug to antagonize responses to the other. Most of the responses to OXO and SCO individually replicated earlier findings, though the measures examined here also permitted the description of effects on some noncopulatory sexual behaviors, specifically the male's inspection of the female. However, the most interesting results may be those suggesting asymmetry in the responses to the addition of the second drug: Whereas responses to OXO tended to be antagonized by SCO, OXO was less effective at counteracting responses to SCO. Though the explanation of this asymmetry is not completely clear, it is consistent with previous suggestions of differences in the affinities of these drugs for subtypes of muscarinic receptors. Therefore, it suggests that the cholinergic synapses and circuits controlling distinct elements of male behavior could differ in their dependence on these receptors. PMID- 23357685 TI - Increase in nitric oxide levels and mitochondrial membrane potential in platelets of untreated patients with major depression. AB - Alterations in platelet activity have been associated with the onset of major depressive disorder (MDD) and with ischemic cardiovascular events through mechanisms that remain unknown. The present study evaluated nitric oxide (NO) levels, mitochondrial membrane potential (PMMP), and P-selectin expression in platelets from 30 untreated MDD patients and 30 matched controls by flow cytometry. In addition, tryptophan and serotonin concentrations were measured in the whole blood by high performance liquid chromatography. Patients were assessed with the Mini International Neuropsychiatric Interview and the Hamilton Depression Rating Scale. The patients had not had antidepressant treatment or any other pharmacological interventions for at least 1 year. MDD patients significantly differed from controls in levels of major fluorescent platelets for NO, PMMP, and P-selectin compared with those observed in control subjects. Serotonin concentrations in MDD patients did not differ from those in controls These results demonstrate that untreated MDD patients show increased platelet activation, suggesting an alteration in the platelet function. PMID- 23357686 TI - Vimentin is a component of a complex that binds to the 5'-UTR of human heme regulated eIF2alpha kinase mRNA and regulates its translation. AB - The human heme-regulated eIF2alpha kinase, also called the human heme-regulated inhibitor (hHRI) is significantly up-regulated particularly at the level of translation during stress. In this report we show that during lead-stress, the regulation of hHRI mRNA translation is mediated through its 5'-untranslated region (UTR) that interacts with specific trans-acting factors. Further, vimentin has been identified as one of the trans-acting factors that contribute to this regulation. PMID- 23357687 TI - Reversible suicidal ideation after exposure to lacosamide. PMID- 23357688 TI - Mammary analog secretory carcinoma of salivary glands: a report of 2 cases with expression of basal/myoepithelial markers (calponin, CD10 and p63 protein). AB - Mammary analog secretory carcinoma (MASC) of salivary glands is a recently described neoplasm with favorable outcome. We describe 2 cases of MASC occurring in a 34-year-old female and a 58-year-old male, both presenting with a swelling of upper lip and right parotid gland, measuring 15 and 20mm, respectively. Without adjuvant treatment, both patients have been free of disease for 15 months and 12 months since the operation. Microscopically, both tumors were cystic and showed tubular and cystopapillary architecture. The tumor cells had round to oval nuclei and eosinophilic cytoplasm. Presence of eosinophilic material was evident within cystic spaces. Immunohistochemically, both tumors expressed cytokeratins (CK), CK7, CK8, CK18, epithelial membrane antigen, vimentin, S-100 protein, mammaglobin, and STAT5a (signal transducer and activator of transcription 5a). Interestingly, both tumors showed variable expression of basal/myoepithelial markers. In one case, we observed diffuse expression of calponin and focal expression of p63 whereas expression of CD10 was absent. In the second case, the staining of calponin was negative, but there was focal expression of both p63 and CD10. Both neoplasms harbored the ETV6-NTRK3 fusion transcript as proved by RT PCR. Although previously reported only rarely, we conclude that MASC may show expression of basal/myoepithelial markers. PMID- 23357689 TI - Pleomorphic adenoma originates from inferior nasal turbinate causing epiphora. AB - Pleomorphic adenoma is the most common benign tumor of the salivary glands. A 62 year-old female patient presented with epiphora and was suffering from breathing difficulties. With the diagnostic nasal endoscopy, a mass, originating from right inferior nasal turbinate and filling the entire nasal cavity, was seen. Originating from the inferior nasal turbinate is a very rare entity. Paranasal sinus computed tomography and magnetic resonance images revealed a mass that fills and expands the right nasal cavity. Mass was hypoechoic in B-mode ultrasonography and hypovascular in color Doppler ultrasonography, and rate of tissue stiffness was high in sonoelastography. These were helpful for the diagnosis. PMID- 23357690 TI - [Myeloproliferative neoplasms related glomerulopathy]. AB - Myeloproliferative neoplasms (MPNs, formerly called chronic myeloproliferative disorders) are clonal hematopoietic stem cell disorders characterized by the expansion of one or more of the myeloid lineages, including polymorphonuclear, erythroid, megakaryocytic, and mastocytic. The major complications of MPN are transformation into acute myeloid leukemia (occurring particularly in chronic myelogenous leukemia) and thrombotic and hemorrhagic events (most commonly observed in polycythemia vera and essential thrombocythemia). Renal involvement by MPN is infrequent. MPN-related glomerulopathy enlarges the spectrum of glomerular diseases associated with haematological neoplasms. MPN-related glomerulopathy is an under recognized late renal complication of MPN with poor prognosis. It is characterized clinically by heavy proteinuria and renal insufficiency. The histologic features of MPN-related glomerulopathy include variable degree of mesangial sclerosis and hypercellularity, segmental sclerosis, features of chronic thrombotic microangiopathy, and intracapillary hematopoietic cell infiltration. PDGF and TGFbeta likely have a crucial role in the pathogenesis of MPN-related glomerulopathy. Furthermore, aggregation of circulating hematopoietic cells within glomerular capillaries could potentially result in endothelial injury and morphologic changes resembling chronic thrombotic microangiopathy. Greater awareness of this entity is needed to define diagnosis and possible therapies. PMID- 23357691 TI - [Angiotensin converting enzyme inhibitor induced angioedema: a collateral damage?]. PMID- 23357692 TI - [Schnitzler's syndrome]. AB - Schnitzler syndrome (SS) is a rare clinical entity, which belongs to the spectrum of monoclonal gammapathy-associated systemic disorders. Its pathophysiology remains elusive, even if it is tempting to consider it as a late onset and probably acquired auto-inflammatory syndrome. SS mainly occurs in the fifth and sixth decade, and present with an urticariform rash with periodic fever and/or osteoarticular pain. Systemic inflammation and monoclonal gammapathy (overwhelmingly IgM kappa) are constant features. SS is a chronic disease, which can severely impair quality of life of the affected individuals. Many drugs have been used and proved disappointing. In the last few years, accumulating reports provided evidence for the dramatic efficacy of anakinra, which has revolutionized the management of most severe cases. The main long-term threat to these patients is to develop a lymphoproliferative disorder (mainly Waldenstrom's macroglobulinemia). The mechanisms underlying the different facets of the disease remain to be elucidated. PMID- 23357693 TI - Neurophysiological sensitivity to attentional overload in patients with psychotic disorders. AB - OBJECTIVE: Disturbances of information selection under high processing load might be a key feature predisposing to psychotic disorders. The N2pc component of the ERP is a specific measure of selective attention. It is unclear whether N2pc is altered under increased demands in patients with psychosis. METHODS: Patients with schizophrenia, with bipolar disorder (n = 20 each), and age-matched healthy controls (n = 21) had to identify two targets ("T1" and "T2") in two different simultaneous rapidly presented series of letters. We assessed the target-evoked N2pc and P3 components and the visually evoked potentials (VEPs) evoked by the rapid stream. RESULTS: T1 and T2 identification rates did not substantially differ between groups. However, T1- and T2-evoked N2pc components were reduced in both patient groups. VEPs were enlarged in response to the first stimulus of the fast series in healthy participants but not in patients. T2-evoked P3 was reduced in patients with schizophrenia only. CONCLUSIONS: Under high attentional load, neurophysiological mechanisms underlying visual selection are compromised in patients with psychosis. The lacking VEP increase to the first stimulus probably indicates deficient arousal. SIGNIFICANCE: These deficiencies of attentional selection and arousal might enhance liability to psychotic symptoms under stressful conditions. PMID- 23357694 TI - [Systematic collection and analysis of intraoperative anaesthetic-related problems]. AB - OBJECTIVE: The purpose of the study was to systematically collect and analyse the frequency, type and severity of all untoward intraoperative anaesthetic-related problems in a hospital over a 6-month period. METHODS: An observational, systematic, prospective, and cross sectional study was conducted on the events and their risk factors. The study is based on a system in which anaesthesia related data are recorded from all anaesthetic cases on a routine basis, including sedation and obstetric analgesia. The variables were demographic, procedural data, and a checklist with problem type and severity. Data were analysed using chi-square, Fisher's test, or Student's test. A P<.05 was considered statistically significant. RESULTS: The frequency of intraoperative anaesthetic-related problems was 17.2%, with 1.3 anaesthetic problems per case, being 9 times more frequent the adverse effects with low severity grade. During anaesthesia, respiratory problems occurred in 13, circulatory problems in 8, and technical problems in 2 out of every 100 procedures. The factors associated with the patient in whom the anaesthetic problem occurred were: the use of general anaesthesia, supraumbilical surgery, and a higher preoperative anaesthetic risk. CONCLUSIONS: Use of a systematic intraoperative anaesthetic-related database with a checklist of problems and severity plays an important part in quality assurance strategies. An analysis of non-fatal problems provides a basis for establishing corrective strategies before significant morbidity occurs, and by separating the surgical and anaesthesia problems. PMID- 23357695 TI - Statistical analysis of combinatorial transcriptional regulatory motifs in human intron-containing promoter sequences. AB - The combinatorial regulation is an important feature of transcriptional regulation of genes. Although a number of researches have been done, the general properties of combinatorial transcriptional regulatory elements, including their patterns and distributions, are still not well understood. Specially, the understanding for laws of transcriptional regulation involving introns is challenging. Here, we performed statistical analyses on potentially interacting motif pairs in human housekeeping genes and tissue-specific genes of some tissues. We first identified transcriptional regulatory motifs in promoter sequences, including the first introns, using a sequence-based approach which incorporates several different sequence backgrounds. And then we predicted the potentially interacting motif pairs using Hypergeometric distribution and Mann Whitney U-test. The validation of the predicted interacting motif pairs has been carried out via analyses of orthologous conservation and enrichment. The distribution characteristics of the identified motif pairs were examined using a probability model. We found that interacting motif pairs have some significant preferences in location, distance and orientation in housekeeping and tissue specific genes. The results suggest that the features of transcriptional regulation in housekeeping genes are different from the tissue-specific genes. Besides, location preferences of the motif pairs provide clues to the way of the introns participating in transcriptional regulation in different tissue-specific genes. PMID- 23357696 TI - End effects in mechanical testing of biomaterials. PMID- 23357697 TI - TGF-beta1 induces the different expressions of lysyl oxidases and matrix metalloproteinases in anterior cruciate ligament and medial collateral ligament fibroblasts after mechanical injury. AB - The anterior cruciate ligament (ACL) is known to have a poor self-healing ability. In contrast, the medial collateral ligament (MCL) can heal relatively well and restore the joint function. Transforming growth factor-beta1 (TGF-beta1) is considered to be an important chemical mediator in the wound healing of the ligaments. While the role of TGF-beta1-induced expressions of the lysyl oxidases (LOXs) and matrix metalloproteinases (MMPs), which respectively facilitate the extracellular matrix (ECM) repair and degradation, is poorly understood. In this study, we used equibiaxial stretch chamber to mimic mechanical injury of ACL and MCL fibroblasts, and aimed to determine the intrinsic differences between ACL and MCL by characterizing the differential expressions of LOXs and MMPs in response to TGF-beta1 after mechanical injury. By using semi-quantitative PCR, quantitative real-time PCR, western blot and zymography, we found TGF-beta1 induced injured MCL to express more LOXs than injured ACL (up to 1.85-fold in LOX, 2.21-fold in LOXL-1, 1.71-fold in LOXL-2, 2.52-fold in LOXL-3 and 3.32-fold in LOXL-4). Meanwhile, TGF-beta1 induced injured ACL to express more MMPs than injured MCL fibroblasts (up to 2.33-fold in MMP-1, 2.45-fold in MMP-2, 1.89-fold in MMP-3 and 1.50-fold in MMP-12). The further protein results were coincident with the gene expressions above. The different expressions of LOXs and MMPs inferred the intrinsic differences between ACL and MCL, and the intrinsic differences could help to explain their differential healing abilities. PMID- 23357698 TI - A thumb carpometacarpal joint coordinate system based on articular surface geometry. AB - The thumb carpometacarpal (CMC) joint is a saddle-shaped articulation whose in vivo kinematics can be explored more accurately with computed tomography (CT) imaging methods than with previously used skin-based marker systems. These CT based methods permit a detailed analysis of the morphology of the joint, and thus the prominent saddle geometry can be used to define a coordinate system that is inherently aligned with the primary directions of motion at the joint. The purpose of this study was to develop a CMC joint coordinate systems that is based on the computed principal directions of curvature on the trapezium and the first metacarpal. We evaluated the new coordinate system using bone surface models segmented from the CT scans of 24 healthy subjects. An analysis of sensitivity to the manual selection of articular surfaces resulted in mean orientation differences of 0.7+/-0.7 degrees and mean location differences of 0.2+/-0.1mm. Inter-subject variability, which mostly emanates from anatomical differences, was evaluated with whole bone registration and resulted in mean orientation differences of 3.1+/-2.7 degrees and mean location differences of 0.9+/-0.5mm. The proposed joint coordinate system addresses concerns of repeatability associated with bony landmark identification and provides a robust platform for describing the complex kinematics of the CMC joint. PMID- 23357699 TI - The lower extremity dexterity test as a measure of lower extremity dynamical capability. AB - The capability of the lower extremity to dynamically interact with the ground is important for skilled locomotor performance. However, there is currently no test method designed to specifically quantify this sensorimotor ability, which we refer to as lower extremity dexterity. We describe a new method to quantify lower extremity dexterity, examine its reliability (n=10), and evaluate the extent to which it is associated with lower extremity strength and anthropometry in healthy young adults (n=38). The lower extremity dexterity test (LED-test)-an adaptation of the Strength-Dexterity test for the fingers-consists of using the isolated lower extremity to compress a slender spring prone to buckling at low forces. The goal of the LED-test is to sustain the highest compression force possible. Applying higher forces makes the spring increasingly unstable, thus achieving higher compression forces represents better ability to dynamically control instability at low force levels. As such, the LED-test provides a novel way to quantify the capability of the lower extremity to regulate dynamic and unstable foot-ground interactions at submaximal forces. LED-test performance ranged between 88.6 and 119.6N, test-retest reliability was excellent (ICC(2,3)=0.94), and the minimal detectable difference was 5.5N. Performance was not correlated with strength or height (r(2)<=0.053, p>0.05), and only weakly with body mass (r(2)=0.116, p=0.04). We propose that the unique lower extremity capability quantified by the LED-test could be informative of skilled locomotor performance and injury risk. PMID- 23357700 TI - Bone creep and short and long term subsidence after cemented stem total hip arthroplasty (THA). AB - Stem-cement and cement-bone interfacial failures as well as cement fractures have been noted in cemented total hip arthroplasty (THA) as the cause of aseptic loosening. Attempts to reduce the risk of femoral component loosening include improving the stem-cement interface by various coatings, using a textured or porous coated stem surfaces or by using a tapered stem having a highly-polished surface. The latter approach, often referred to as "force-closed" femoral stem design, would theoretically result in stem stabilization subsequent to debonding and 'taper-lock'. Previous work using three-dimensional finite element analysis has shown a state of stress at the stem-cement interface indicative of 'taper lock' for the debonded stem and indicated that stem-cement interface friction and bone cement creep played a significant role in the magnitudes of stresses and subsidence of the stem. However, the previous analysis did not include the viscoelastic properties of bone, which has been hypothesized to permit additional expansion of the bone canal and allow additional stem subsidence (Lu and McKellop, 1997). The goal of this study was to investigate the effect of bone viscoelastic behavior on stem subsidence using a 3D finite element analysis. It was hypothesized that the viscoelastic behavior of bone in the hoop direction would allow expansion of the bone reducing the constraint on bone over time and permit additional stem subsidence, which may account for the discrepancies between predicted and clinical subsidence measurements. Analyses were conducted using physiological loads, 'average peak loads' and 'high peak loads' for 'normal patient' and 'active patient' (Bergmann et al., 2010) from which short and long term subsidence was predicted. Results indicated that bone creep does contribute to higher stem subsidence initially and after 10 years of simulated loading. However, it was concluded that the "constraint" upon the cement mantle is not mitigated enough to result in stem subsidence equivalent to that observed clinically. PMID- 23357701 TI - ECMO therapy after thrombotic left main occlusion bridges prolonged cardiac arrest. PMID- 23357702 TI - Where are lifesaving automated external defibrillators located and how hard is it to find them in a large urban city? AB - OBJECTIVES: Automated external defibrillators (AEDs) are lifesaving, but little is known about where they are located or how to find them. We sought to locate AEDs in high employment areas of Philadelphia and characterize the process of door-to-door surveying to identify these devices. METHODS: Block groups representing approximately the top 3rd of total primary jobs in Philadelphia were identified using the US Census Local Employment Dynamics database. All buildings within these block groups were surveyed during regular working hours over six weeks during July-August 2011. Buildings were characterized as publically accessible or inaccessible. For accessible buildings, address, location type, and AED presence were collected. Total devices, location description and prior use were gathered in locations with AEDs. Process information (total people contacted, survey duration) was collected for all buildings. RESULTS: Of 1420 buildings in 17 block groups, 949 (67%) were accessible, but most 834 (88%) did not have an AED. 283 AEDs were reported in 115 buildings (12%). 81 (29%) were validated through visualization and 68 (24%) through photo because employees often refused access. In buildings with AEDs, several employees (median 2; range 1-8) were contacted to ascertain information, which required several minutes (mean 4; range 1-55). CONCLUSIONS: Door-to-door surveying is a feasible, but time consuming method for identifying AEDs in high employment areas. Few buildings reported having AEDs and few permitted visualization, which raises concerns about AED access. To improve cardiac arrest outcomes, efforts are needed to improve the availability of AEDs, awareness of their location and access to them. PMID- 23357703 TI - Tactical and operational response to major incidents: feasibility and reliability of skills assessment using novel virtual environments. AB - OBJECTIVES: To determine feasibility and reliability of skills assessment in a multi-agency, triple-site major incident response exercise carried out in a virtual world environment. METHODS: Skills assessment was carried out across three scenarios. The pre-hospital scenario required paramedics to triage and treat casualties at the site of an explosion. Technical skills assessment forms were developed using training syllabus competencies and national guidelines identified by pre-hospital response experts. Non-technical skills were assessed using a seven-point scale previously developed for use by pre-hospital paramedics. The two in-hospital scenarios, focusing on a trauma team leader and a silver/clinical major incident co-ordinator, utilised the validated Trauma NOTECHS scale to assess five domains of performance. Technical competencies were assessed using an ATLS-style competency scale for the trauma scenario. For the silver scenario, the assessment document was developed using competencies described from a similar role description in a real-life hospital major incident plan. The technical and non-technical performance of all participants was assessed live by two experts in each of the three scenarios and inter-assessor reliability was computed. Participants also self-assessed their performance using identical proformas immediately after the scenarios were completed. Self and expert assessments were correlated (assessment cross-validation). RESULTS: Twenty three participants underwent all scenarios and assessments. Performance assessments were feasible for both experts as well as the participants. Non technical performance was generally scored higher than technical performance. Very good inter-rater reliability was obtained between expert raters across all scenarios and both technical and non-technical aspects of performance (reliability range 0.59-0.90, Ps<0.01). Significant positive correlations were found between self and expert assessment in technical skills across all three scenarios (correlation range 0.52-0.84, Ps<0.05), although no such correlations were observed in non-technical skills. CONCLUSIONS: This study establishes feasibility and reliability of virtual environment technical and non-technical skills assessment in major incident scenarios for the first time. The development for further scenarios and validated assessment scales will enable major incident planners to utilise virtual technologies for improved major incident preparation and training. PMID- 23357704 TI - AEDs in schools: lessons learned and to be learned. PMID- 23357705 TI - Challenges in the management of pleomorphic lobular carcinoma in situ of the breast. AB - BACKGROUND: Pleomorphic Lobular Carcinoma in Situ (PLCIS) is a pathological variant of Lobular Carcinoma in Situ (LCIS) with distinct features. Since first described over a decade ago there are only few papers published about this condition. METHODS: Medline and Pubmed based literature overview was done with the aim of describing the different histopathological, radiological and clinical features of this pathological entity to highlight the different clinicopathological presentations and modalities of treatment described. RESULTS: PLCIS has different biological features when compared to LCIS. It is more likely to be associated with invasive disease and the immuno-histochemical profile shows it is less likely to be ER and PR positive with higher positivity of HER2, Ki 67and p53. It has been suggested that PLCIS should be treated more aggressively than LCIS and surgically excised in similar fashion to DCIS. CONCLUSION: PLCIS is a more aggressive variant of LCIS that needs to be managed differently. Surgical excision with clear margins is advised. Further adjuvant treatments have been described in the literature with little evidence to support their use. PMID- 23357706 TI - Factors influencing the decision to offer immediate breast reconstruction after mastectomy for ductal carcinoma in situ (DCIS): the Institut Gustave Roussy Breast Cancer Study Group experience. AB - BACKGROUND: The increased rate of ductal carcinoma in situ (DCIS) is associated with a rise in indications for mastectomy and immediate breast reconstruction (IBR). The purpose of our study was to evaluate the factors affecting the indications for IBR and its modalities. STUDY DESIGN: Data concerning two hundred and thirty-eight consecutive patients with DCIS who had undergone modified radical mastectomy and a sentinel lymph node biopsy (SLNB) between 2005 and 2011 were extracted from our database. We then conducted a comparative study between patients who had undergone IBR and those who had not, to determine which factors affected the decision to offer IBR (LOE II). RESULTS: About 57.1% had IBR and 42.9% had no reconstruction. The most common reason why IBR had not been performed was that it had not been proposed by the surgeon (33.4%). Of the 136 patients offered IBR, an implant had been proposed to the majority of them (81.6%). The IBR rate was highest among women under 50 years (52.2%), and was lower among women with diabetes (0.7%) or obesity (8.8%). The choice of reconstruction was not affected by tobacco use or positive SLNB results. CONCLUSION: Factors predictive of the IBR reflect the influence of surgeon counselling and, to a lesser extent, consideration of patient comorbidities. However, there is a need to improve patient information and physician referral. PMID- 23357707 TI - Duplication of the mandible in Klippel-Feil syndrome. AB - The duplication of the mandible is an extremely rare case, which was first described by McLaughlin in 1948 as a case report of duplication of the mouth, the tongue and the mandible. Betty in 1956 and Davies in 1973 reported similar cases. The duplication of the mandible may be associated with the Klippel-Feil syndrome (KFS). A low hairline, short neck with cervical vertebral fusion and painless limitation of the head movement are the characteristic findings of this syndrome. The incidence of the syndrome varies from 1/30,000 to 1/40,000. Although autosomal recessive inheritance was suggested, no familial inheritance was found in some cases. A very rare case of mandibular duplication in association with KFS, whose duplicated mass was removed following distraction, has been reported. PMID- 23357708 TI - Effect of centrifugation and washing on adipose graft viability: a new method to improve graft efficiency. AB - BACKGROUND: Adipose tissue grafting is a promising method in the field of surgical filling. We studied the effect of centrifugation on fat grafts, and we propose an optimised protocol for the improvement of adipose tissue viability. METHODS: Adipose tissue was subjected to different centrifugations, and the volumes of interstitial liquid and oil released were measured to choose the optimal condition. Tissue from this condition was then compared to tissue obtained from two traditional techniques: strong centrifugation (commonly 3 min at 3000 rpm/900 g), and decantation, by injecting into immunodeficient mice. The cytokine interleukin-6 (IL-6) and chemokine monocyte chemotactic protein-1 (MCP 1) were assayed 24 h post-injection, and after 1 month of grafting the state of the lipografts was evaluated through macroscopic and histological analysis, with oil gap area measurement. RESULTS: Strong centrifugation (900 g, 1800 g) is deleterious for adipose tissue because it leads to until threefold more adipocyte death compared to low centrifugation (100 g, 400 g). In addition, mice injected with strong centrifuged and non-centrifuged adipose tissue have higher rates of blood IL-6 and MCP-1, compared to those grafted with soft centrifuged fat. Moreover, extensive lipid vacuoles were detectable on histological sections of the non-centrifuged lipografts, whereas lipografts from soft centrifugation contain a higher amount of connective tissue containing collagen fibres. CONCLUSION: It is necessary to wash and centrifuge adipose tissue before reinjection in order to remove infiltration liquid and associated toxic molecules, which in the long term are deleterious for the graft. However, strong centrifugation is not recommended since it leads very quickly to greater adipocyte death. Thus, soft centrifugation (400 g/1 min), preceded by washings, seems to be the most appropriate protocol for the reinjection of adipose tissue. PMID- 23357709 TI - A giant cutaneous horn on the cheek. PMID- 23357710 TI - Travel to, and use of, twenty-one Michigan trails. AB - OBJECTIVE AND METHODS: This study examined trail use among 857 trail users on 21 trails in Michigan from 2008 to 2011 using a valid and reliable intercept survey. RESULTS: Most of the 857 participants traveled to the trail from their home (92.6%), lived within 15 min of the trails (74.8%), and used active transport to travel to the trails 69.7%. The odds of active transport to the trails were greater among those who had not graduated high school (OR=3.49; 95% CI=1.02, 11.99) and high school graduates (OR=7.432; 95% CI=2.02, 27.30) compared to college graduates. Whites and adults also had greater odds of active transport than non-Whites (OR=3.160, 95% CI: 1.65, 6.05), and older adults (OR=1.75; 95% CI: 1.20, 2.54). The majority of respondents (89.7%) reported using trails for recreational purposes. A significantly greater proportion of females (73.3%) compared to males (64.7%) reported using the trail with others. CONCLUSIONS: The findings from this study might enable health and parks and recreation professionals to better promote physical activity on trails. PMID- 23357711 TI - [Prenatal diagnosis of cerebral tumors and differential diagnosis]. AB - Fetal brain tumors are rare and have different histologies. Although the definitive diagnosis relies on the histopathology of the tumor, it is useful to distinguish the tumors potentially curable from the tumors rapidly fatal after birth. Nevertheless, some intracranial masses are not tumors. We report four cases of intracerebral masses diagnosed prenatally corresponding to different histological lesions: teratoma, fetus-in-fetu, chraniopharyngioma, hemangioma. We discuss the elements of the differential diagnosis, which can be identified prenatally. PMID- 23357712 TI - Write to read: the brain's universal reading and writing network. AB - Do differences in writing systems translate into differences in the brain's reading network? Or is this network universal, relatively impervious to variation in writing systems? A new study adds intriguing evidence to these questions by showing that reading handwritten words activates a pre-motor area across writing systems. PMID- 23357713 TI - Plant proteomics: current status and future prospects. AB - As proteins represent the functional center piece of all biology, proteomics represents a field of research central to the greater plant research community. From discussions with those attending the European Proteomics Association (EuPA) 2012 meeting in Glasgow, Scotland, plant proteomics can be seen as expanding and evolving to investigate novel aspects of diverse organisms and to apply the latest technologies to plant research. Moving forward, targeted plant proteomics holds much promise in unraveling many of the complexities of plants. Highlighted are discussions on quantitative and non-quantitative plant proteomics, covalent modifications and the unique challenges of proteomics in plants. PMID- 23357714 TI - Intravenous immunoglobulin inhibits BAFF production in chronic inflammatory demyelinating polyneuropathy - a new mechanism of action? AB - Chronic-inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated disease treated with intravenous immunoglobulin (IVIg). The underlying mechanism of action remains incompletely understood. The B-cell activating factor BAFF contributes to B-cell homeostasis and (auto-)antibody production. BAFF was recently identified as one key molecule in the development of autoimmune diseases. Herein, we demonstrate that BAFF serum levels are elevated in CIDP patients. IVIg treatment resulted in a significant decrease of BAFF serum level. In vitro, IVIg inhibited BAFF in monocytes. Consequently, we identified BAFF as a new target for IVIg in CIDP treatment and provide a new, Fcgamma-receptor independent, mechanism of action for IVIg. PMID- 23357715 TI - A controlled trial of gluten-free diet in patients with irritable bowel syndrome diarrhea: effects on bowel frequency and intestinal function. AB - BACKGROUND & AIMS: Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD). METHODS: We performed a randomized controlled 4-week trial of a gluten-containing diet (GCD) or GFD in 45 patients with IBS-D; genotype analysis was performed for HLA-DQ2 and HLA-DQ8. Twenty-two patients were placed on the GCD (11 HLA-DQ2/8 negative and 11 HLA DQ2/8 positive) and 23 patients were placed on the GFD (12 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive). We measured bowel function daily, small-bowel (SB) and colonic transit, mucosal permeability (by lactulose and mannitol excretion), and cytokine production by peripheral blood mononuclear cells after exposure to gluten and rice. We collected rectosigmoid biopsy specimens from 28 patients, analyzed levels of messenger RNAs encoding tight junction proteins, and performed H&E staining and immunohistochemical analyses. Analysis of covariance models was used to compare data from the GCD and GFD groups. RESULTS: Subjects on the GCD had more bowel movements per day (P = .04); the GCD had a greater effect on bowel movements per day of HLA-DQ2/8-positive than HLA-DQ2/8-negative patients (P = .019). The GCD was associated with higher SB permeability (based on 0-2 h levels of mannitol and the lactulose:mannitol ratio); SB permeability was greater in HLA DQ2/8-positive than HLA-DQ2/8-negative patients (P = .018). No significant differences in colonic permeability were observed. Patients on the GCD had a small decrease in expression of zonula occludens 1 in SB mucosa and significant decreases in expression of zonula occludens 1, claudin-1, and occludin in rectosigmoid mucosa; the effects of the GCD on expression were significantly greater in HLA-DQ2/8-positive patients. The GCD vs the GFD had no significant effects on transit or histology. Peripheral blood mononuclear cells produced higher levels of interleukin-10, granulocyte colony-stimulating factor, and transforming growth factor-alpha in response to gluten than rice (unrelated to HLA genotype). CONCLUSIONS: Gluten alters bowel barrier functions in patients with IBS-D, particularly in HLA-DQ2/8-positive patients. These findings reveal a reversible mechanism for the disorder. Clinical trials.govNCT01094041. PMID- 23357716 TI - Islet allograft rejection in sensitized mice is refractory to control by combination therapy of immune-modulating agents. AB - Retransplantation is common in allogeneic islet transplantation, and therefore, memory responses in previously sensitized recipients present a distinct obstacle for successful islet transplantation. Given the difficulties in controlling memory responses contributing to allograft rejection, it is worth investigating the effects of new immune-modulating agents against islet allograft rejection in the sensitized recipients. In this study, we investigated immune-modulating agents including 5-azacytidine and IL-2/anti-IL-2 complex to ascertain their suppressive effects on memory responses. In suppression assays, rapamycin effectively suppressed the proliferation of memory T cells, whereas 5 azacytidine, a methylation inhibitor suppressed the survival and proliferation of memory T cells. Combination therapy of anti-CD40L, anti-OX40L, and rapamycin slightly prolonged BALB/c islet allograft survival in sensitized C57BL6 mice, and reduced intragraft infiltration of macrophages, T cells, and B cells. However, the addition of IL-2/anti-IL-2 complex, an inducer of regulatory T cells, did not exhibit additional suppression against rejection in sensitized mice. Although a combination of 5-azacytidine and rapamycin markedly suppressed islet allograft rejection in naive mice, it failed to achieve long-term graft survival even when combined with anti-CD40L and anti-OX40 in sensitized mice. In short, 5 azacytidine-based or IL-2/anti-IL-2 complex-based regimens can suppress islet allograft rejection in naive recipients, but fail to control islet allograft rejection in sensitized recipients. PMID- 23357717 TI - Prognostic value of energy loss index in asymptomatic aortic stenosis. AB - BACKGROUND: Aortic valve area index adjusted for pressure recovery (energy loss index [ELI]) has been suggested as a more accurate measure of aortic stenosis (AS) severity, but its prognostic value has not been determined in a prospective study. METHODS AND RESULTS: The relation between baseline ELI and rate of aortic valve events and combined total mortality and hospitalization for heart failure resulting from the progression of AS was assessed by multivariate Cox regression and reclassification analysis in 1563 patients with initial asymptomatic AS in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. During 4.3 years follow-up, a total of 498 aortic valve events and 181 combined total mortalities and hospitalizations for heart failure caused by the progression of AS occurred. In Cox regression analyses, 1-cm(2)/m(2) lower baseline ELI predicted a 2-fold higher risk both for aortic valve events and for combined total mortality and hospitalization for heart failure independently of baseline peak aortic jet velocity or mean aortic gradient and independently of aortic root size (all P<0.05). In reclassification analysis, ELI improved the prediction of aortic valve events by 13% (95% confidence interval, 5-19), whereas the prediction of combined total mortality and hospitalization for heart failure resulting from the progression of AS did not improve significantly. CONCLUSIONS: In asymptomatic AS patients without known atherosclerotic disease or diabetes mellitus, ELI provides independent and additional prognostic information to that derived from conventional measures of AS severity, suggesting that ELI should be measured in such patients. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00092677. PMID- 23357718 TI - 2013 ACCF/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards). PMID- 23357719 TI - Academic cheating among nursing students. AB - BACKGROUND: The purpose of the study was to investigate the magnitude and predictors of academic cheating and to understand relevant perspectives among South Korean nursing students. METHODS: Survey responses of 655 undergraduate nursing students from five institutions were analyzed. Demographics, psychological factors of an individual (perceived seriousness of cheating, ethical attitudes to cheating, neutralization behaviors, knowledge of academic integrity and policy) and contextual factors (perceived prevalence of peers' cheating, atmosphere of academic integrity, atmosphere of whistle-blowing, moral support of families and friends) were measured in relation with 11 exam-cheating and 15 assignment-cheating behaviors. Also reasons for cheating and importance of various interventions to discourage cheating were questioned. RESULTS: 50% and 78% of the students were engaged in, respectively, exam-cheating and assignment cheating behaviors. Perceived seriousness of cheating (OR=0.74, 0.64) and perceived prevalence of peers' cheating (OR=3.02, 6.66) were significant predictors for both exam-cheating and assignment cheating. A higher grade, a lack of time, a better job, and a lack of motivation were reported as a major reason for cheating. Multiple interventions were considered important to discourage cheating from different stakeholders. CONCLUSIONS: An alarming level of a cheating problem was found among South Korean nursing students, requiring immediate attention. As the nursing workforce market is becoming global, the cheating issue in nursing education should be managed under collaborative efforts of nursing faculty members around the globe. PMID- 23357721 TI - MRI findings after hyperbaric oxygen-induced seizures. AB - Hyperbaric oxygen-induced seizures are classified as generalized, tonic-clonic seizures. They are believed to cause no residual neurologic damage, although this has not been investigated in depth. We used different MRI sequences to determine whether hyperbaric oxygen-induced seizures in mice caused brain structural changes. Experimental animals were exposed to a pressure of 6 atmospheres absolute breathing oxygen, and were randomly assigned to two groups in which MRI was performed immediately after the appearance of seizures or 7 days later. Control groups were not exposed to hyperbaric oxygen. Our MRI protocols included T2*-weighted images, T2 maps, diffusion-weighted echo-planar pulse sequence, and contrast-enhanced T1-weighted images. Both the cortex and the hippocampus were analyzed. T2 values of the hippocampus and the cortex in the hyperbaric oxygen exposed groups showed a small but statistically significant decrease compared with the control groups immediately after seizures (p<0.01). One week after seizures, enhancement following contrast injection was significantly higher both in the cortex and the hippocampus in the hyperbaric oxygen-exposed groups compared with the control groups (p<0.01). Hippocampal and cortex T2 values 7 days after seizures were similar to control group values. No differences were found among the other sequences. We conclude that hyperbaric oxygen-induced seizures result in delayed injury to the blood-brain barrier. Elucidation of the mechanisms and significance of this injury will necessitate further investigation. PMID- 23357720 TI - Mislocalization of AQP4 precedes chronic seizures in the kainate model of temporal lobe epilepsy. AB - It has been suggested that loss of the astrocytic water channel aquaporin-4 (AQP4) from perivascular endfeet in sclerotic hippocampi contributes to increased seizure propensity in human mesial temporal lobe epilepsy (MTLE). Whether this loss occurs prior to or as a consequence of epilepsy development remains to be resolved. In the present study, we investigated whether the expression and distribution of AQP4 was altered prior to (i.e., in the latent phase) or after the onset of chronic epileptic seizures (i.e., in the chronic phase) in the kainate (KA) model of MTLE. Immunogold electron microscopic analysis revealed that AQP4 density in adluminal endfoot membranes was reduced in KA treated rats already in the latent phase, while the AQP4 density in the abluminal endfoot membrane was stable or slightly increased. The decrease in adluminal AQP4 immunogold labeling was accompanied by a reduction in the density of AQP4's anchoring protein alpha-syntrophin. The latent and chronic phases were associated with an upregulation of the M1 isoform of AQP4, as judged by semi-quantitative Western blot analysis. Taken together, the findings in this model suggest that a mislocalization of AQP4--reflecting a loss of astrocyte polarization--is an integral part of the epileptogenic process. PMID- 23357722 TI - Effects of anesthetic agents on seizure-induction with intra-cortical injection of convulsants. AB - RATIONALE: Studies of partial or generalized seizure pathophysiology often require the use of intact animals. Additionally, anesthesia may be required for ethical reasons or paralysis if instrumental measures require immobilization. We examined three commonly used injected anesthetic for their impact on seizures induced by three convulsant agents. METHODS: We prepared rats, under pentobarbitone anesthesia (65 mg/kg) with a catheter, electrodes and a dural window, for later non-noxious experimentation. Three to seven days later, kainic acid (1.25 MUg), picrotoxin (225 ng) or fluorocitrate (0.8 nmol) were injected intra-cortically in animals paralysed with succinylcholine, or anesthetised with pentobarbitone, urethane or fentanyl plus droperidol. We recorded EEG activity, the latencies to seizure discharges, the occurrence of spreading depressions and the presence of movements in response to the convulsants. RESULTS: Fentanyl plus droperidol was the only anesthetic agent permissive for seizure-discharges and spreading depressions. No significant differences in the time for seizure onset for fentanyl plus droperidol compared to paralyzed unanesthetised rats were seen for any of the convulsants (Student's t-test p>0.20). Movements during seizures as well as other drug-induced behaviors continued to be expressed during anesthesia. CONCLUSION: Fentanyl plus droperidol has useful properties as an anesthetic agent in studies of seizure induction with different convulsants. PMID- 23357723 TI - Ketogenic diet for infantile spasms refractory to first-line treatments: an open prospective study. AB - Ketogenic diet (KD) is an efficient treatment for refractory epilepsy including infantile spasms (IS). We evaluated the effect of a KD to treat IS as a third line treatment, after vigabatrin (VGB) and steroids. We evaluated the efficacy and the tolerability of KD in IS using the rate of seizure-free patients at 1 month. METHODS: We conducted an open study using the data from a prospective database of two French child neurology departments (Amiens & Robert Debre-Paris, France) over a three-year period. All the patients followed the KD for 6 months. The addition of an antiepileptic drug was allowed after 1 month of KD in the non seizure-free patients. RESULTS: 17 patients were treated by KD for IS. The KD was initiated at the mean age of 9.4+/-1.1 months. After 1 month with KD, 6/17 (35%) patients were seizure free while 11/17 (65%) were seizure-free after the third month. However, an additional antiepileptic drug (felbamate or topiramate) was given to all patients that were not seizure-free under KD. The KD was well tolerated. CONCLUSION: Our responder rate is similar to previous studies despite an early use (before 1-year-old) and the use of KD after VGB and steroids. The KD was well-tolerated in this population of young infants. Felbamate leads to an increase in the responder rate after the use of KD. PMID- 23357725 TI - Clinical impact of a value-based decision: a surgical case study. AB - BACKGROUND: Value is an economic utility defined by quality and cost, with the maximum benefit achieved by improving quality and reducing cost simultaneously. Health care systems are using value-based analysis to identify the best practices (BPs) that accomplish this goal. STUDY DESIGN: We chose a clinical condition, deep venous thrombophlebitis (DVT) to test this hypothesis by identifying the BPs available in the literature; determining the usual practice for DVT prophylaxis at each of 8 hospitals (ie, community, tertiary, and a university hospital) in an integrated system; measuring clinical outcomes (mortality and morbidity) for each hospital; determining cost for each treatment algorithm in each hospital; and measuring the savings opportunity if a single BP was used by all of the hospitals. RESULTS: The literature suggests that the BPs for DVT prophylaxis consist of sequential compression devices for short-stay procedures; unfractionated heparin for inpatient procedures, and low molecular weight heparin for thrombotic events. Four of the hospitals were using these BPs; the others relied on sequential compression devices and low molecular weight heparin for prophylaxis. Outcomes were identical and value-based analysis suggested a savings opportunity of nearly $4 million if a single BP was adopted. CONCLUSIONS: There were substantial variations in the type of DVT prophylaxis used by the hospitals with no difference in outcomes. A single BP increased value and resulted in savings of $1.5 million, with a savings opportunity of nearly $4 million. PMID- 23357724 TI - Completeness of American Cancer Registry Treatment Data: implications for quality of care research. AB - BACKGROUND: Evaluating and improving the quality of cancer care requires complete information on cancer stage and treatment. Hospital-based registries are a key tool in this effort, but reports in the 1990s showed that they fail to identify a major fraction of outpatient-administered treatment, including chemotherapy, endocrine therapy, and radiation. This can limit their value for evaluating patterns and quality of care. To determine the completeness of registry data in more recent years, we linked administrative claims from 2 private payers in Ohio to the National Cancer Data Base and Ohio Cancer Incidence and Surveillance System. METHODS: Incident breast and colorectal cancers among Ohio residents diagnosed in 2004-2006 were identified from linkage of the National Cancer Data Base, Ohio Cancer Incidence and Surveillance System, and payer insurance claims using ICD-9 and CPT procedure codes, and ICD-9 diagnosis codes. Linkage was accomplished using patient demographics, surgery dates, and hospital facility. Treatment found in claims and registry data were compared and assessed using the kappa statistic. RESULTS: The analytic cohort included 2,552 breast and 822 colorectal cases. Results showed high agreement for breast surgery type, and moderately high agreement for colorectal surgery type. For breast cases, the registries captured 87% of chemotherapy, 86% of radiation, and 64% of endocrine treatment in claims. For colorectal cases, the registry captured 83% of chemotherapy and 84% of radiation in claims. CONCLUSIONS: Hospital-based registries for breast and colon cancer diagnosed in 2004-2006 captured about 85% of radiation and chemotherapy data compared with claims data, a higher percentage than earlier reports. These findings provide direction and a cautionary note to those using registry data for study of patterns and quality of systemic and radiation therapy care. PMID- 23357727 TI - Comparative effectiveness of dynamic abdominal sonography for hernia vs computed tomography in the diagnosis of incisional hernia. AB - BACKGROUND: Diagnosis and characterization of incisional hernia are often established by CT, which incurs radiation exposure and substantial cost in clinical practice. The purpose of this study was to determine the comparative effectiveness of surgeon-performed Dynamic Abdominal Sonography for Hernia (DASH) vs CT for incisional hernia evaluation. STUDY DESIGN: Patients with previous abdominal operations and recent CT imaging were enrolled prospectively; patients with stomas, fistula, or soft tissue infection were excluded. In the clinic setting, DASH was performed with prerequisite training of the American College of Surgeons Ultrasound for Surgeons Basic Course. Clinical evidence of hernia, results of DASH examination, and radiologist documentation of incisional hernia were compared with the gold standard of surgeon-interpreted CT. Testing characteristics of sensitivity and specificity were compared and predictive values were calculated. Inter-rater reliability was performed by comparing DASH results in a subgroup of patients with 3 different evaluators. RESULTS: There were 181 patients enrolled, with a mean age of 54 years, and 68% were women. In patients in whom hernias were identified, the mean hernia size was 44.6 cm(2) (range 0.2 to 468.3 cm(2)). The DASH examination showed high sensitivity (98%) and specificity (88%). Hernia prevalence was 55% in this population, resulting in positive and negative predictive values of 91% and 97%, respectively. Four patients had clinically detectable hernias that were not seen on CT but were discovered with DASH. Inter-rater reliability for DASH was high, with an observed intraclass correlation coefficient of 0.79. CONCLUSIONS: The DASH examination is an accurate alternative to CT scan for diagnosing abdominal wall hernias, with additional benefits of no radiation exposure and instant bedside interpretation. The use of DASH to detect hernia recurrence can greatly facilitate long-term follow-up of hernia patients. PMID- 23357726 TI - Report of 111 consecutive patients enrolled in the International Serial Transverse Enteroplasty (STEP) Data Registry: a retrospective observational study. AB - BACKGROUND: The International Serial Transverse Enteroplasty (STEP) Data Registry is a voluntary online database created in 2004 to collect information on patients undergoing the STEP procedure. The aim of this study was to identify preoperative factors that are significantly associated with transplantation or death or attainment of enteral autonomy after STEP. STUDY DESIGN: Data were collected from September 2004 to January 2010. Univariate and multivariate logistic regression analyses were applied to determine the predictors of transplantation or death or enteral autonomy post-STEP. Time to reach full enteral nutrition was estimated using a Kaplan-Meier curve. RESULTS: Fourteen of the 111 patients in the Registry were excluded due to inadequate follow-up. Of the remaining 97 patients, 11 patients died and 5 progressed to intestinal transplantation. On multivariate analysis, higher direct bilirubin and shorter pre-STEP bowel length were independently predictive of progression to transplantation or death (p = 0.05 and p < 0.001, respectively). Of the 78 patients who were 7 days of age or older and required parenteral nutrition at the time of STEP, 37 (47%) achieved enteral autonomy after the first STEP. Longer pre-STEP bowel length was also independently associated with enteral autonomy (p = 0.002). Median time to reach enteral autonomy based on Kaplan-Meier analysis was 21 months (95% CI, 12-30). CONCLUSIONS: Overall mortality post-STEP was 11%. Pre-STEP risk factors for progressing to transplantation or death were higher direct bilirubin and shorter bowel length. Among patients who underwent STEP for short bowel syndrome, 47% attained full enteral nutrition post-STEP. Patients with longer pre-STEP bowel length were significantly more likely to achieve enteral autonomy. PMID- 23357728 TI - Measuring safety and efficiency in the operating room: development and validation of a metric for evaluating task execution in the operating room. AB - BACKGROUND: Although a number of validated tools are available for assessing nontechnical skills and teamwork in the operating room (OR), there are no tools for measuring completion of key OR tasks, which is fundamental to effective teamwork, patient safety, and OR efficiency. This study describes the development and content validation of a new tool (ie, the Metric for Evaluating Task Execution in the Operating Room) for measuring basic task completion during surgical procedures. STUDY DESIGN: The content validity of 106 OR tasks was assessed using 50 real-time observations of general surgical procedures, followed by a process of expert consensus. A panel of 15 OR experts (ie, surgeons, anesthesiologists, and OR nurses) were asked to rate all tasks observed in <70% of procedures for relevance to patient safety and OR efficiency (using scientifically accepted definitions). Tasks rated highly were retained. Those perceived less relevant were removed. A second panel of patient-safety experts refined the tool to remove duplication, ensure usability, and include novel tasks. RESULTS: Twenty-four of the original 106 tasks were observed in <70% of cases. Seven of these were rated highly by the OR experts for relevance to patient safety and efficiency and were retained in the Metric for Evaluating Task Execution in the Operating Room. Of the remaining 17, four were retained and 13 were removed by the patient-safety experts. In the final revision phase, an additional 23 tasks were removed and 10 new tasks added. The final tool consists of 80 OR tasks relating to well-established processes of care. CONCLUSIONS: The Metric for Evaluating Task Execution in the Operating Room is easy to use and can identify specific gaps in safety and/or efficiency in OR processes. Next, we should examine its links with additional measures of OR performance, for example, patient outcomes, list cancellations/delays, and nontechnical skills. PMID- 23357729 TI - Shortened night sleep impairs facial responsiveness to emotional stimuli. AB - Sleep deprivation deteriorates mood, impairs the recognition of facial expressions, and affects the ability to regulate emotions. The present study investigated the effect of partial sleep deprivation on facial responses to emotional stimuli. Thirty-three healthy undergraduates were tested twice: after a night with (i) 8h and (ii) 4h sleep. Self-reported sleepiness and sustained attention (Psychomotor Vigilance Task) were assessed. Emotional reactivity was measured with facial Electromyogram (EMG) while participants were asked to respond with either compatible or incompatible facial muscles to emotional stimuli in order to study whether partial sleep deprivation caused slower reactions mainly in response to incompatible stimuli (due to an additional effort to suppress the compatible reaction caused by decreased inhibitory control) or in response to both compatible and incompatible stimuli. Self-reported sleepiness and reaction times in a sustained attention task significantly increased after one night of partial sleep deprivation. Facial reactions to emotional stimuli were decelerated. No significant interaction between sleep restriction and compatibility of the muscle to the picture valence could be observed. Hence, volitional facial reactions in response to emotional stimuli were slower after one night of reduced sleep, but affective inhibitory control was not significantly impaired. However, slowed facial responding to emotional stimuli may affect social interaction after sleep restriction. PMID- 23357730 TI - Texture analysis of magnetic resonance images of patients with juvenile myoclonic epilepsy. AB - BACKGROUND/PURPOSE: Juvenile myoclonic epilepsy (JME) is the most frequent subsyndrome of the idiopathic generalized epilepsies, and experimental investigations support that the thalamus is a key structure in the mechanisms of JME. Texture analysis (TA) is an image processing technique which can be used to characterize images such as MRI. OBJECTIVE: The goal of this work was to investigate the thalamus of patients with JME using TA, a quantitative neuroimaging technique. METHODS: Patients and controls were submitted to MRI investigation. Images were acquired in a 2-Tesla scanner. The T1 volumetric sequence was used for thalamic segmentation and extraction of texture parameters. Twenty-four patients with a diagnosis of JME and 20 healthy volunteers were investigated. RESULTS: Texture analysis revealed differences between the right thalamus of patients and controls. CONCLUSIONS: The present investigation supports the participation of the thalamus in the disease mechanisms of JME. Texture analysis may be a useful tool in the quantitative neuroimaging investigation of the epilepsies and can be important to understand JME. PMID- 23357731 TI - Purification, characterization, and gene cloning of a cold-adapted thermolysin like protease from Halobacillus sp. SCSIO 20089. AB - Marine sediment is a distinctive habitat of cold enzyme producing bacteria. A protease producing strain Halobacillus sp. SCSIO 20089 was isolated from a marine sediment of South China Sea. Using chromatographic techniques, the extracellular protease was purified to homogeneity from the culture supernatant. The purified protease exhibited maximal activity at 30 degrees C, pH 8.0, and remained more than 20% of its activity at 0 degrees C. Its activation energy was calculated to be 34.4 kJ/mol, suggesting it is a cold-adapted protease. Based on the N-terminal amino acid sequence of the purified enzyme, full gene encoding the enzyme was obtained by combination of degenerate primer PCR and hiTAIL-PCR. The deduced amino acid sequence showed 57% and 52% identity with mesothermal and thermophilic protease in thermolysin family respectively. All these indicate the enzyme is a unique cold-active thermolysin-like protease with potential in both basic research and industrial application areas. PMID- 23357732 TI - miR-132 enhances HIV-1 replication. AB - MicroRNAs upregulated during CD4(+) T cell activation may contribute to the increased efficiency of HIV-1 replication seen following perturbation of the resting state. We have found miR-132 to be highly upregulated following CD4(+) T cell activation, and show that miR-132 potentiates viral replication in the Jurkat CD4(+) T cell line. Knockdown of MeCP2, a previously identified target of miR-132, also increases HIV-1 replication. To the best of our knowledge, miR-132 is the first miRNA reported to enhance HIV-1 replication. PMID- 23357733 TI - Human polyomaviruses in disease and cancer. AB - Today the human polyomavirus (HPyV) family consists of 10 members, BK virus (BKV) and JC virus (JCV) isolated 40 years ago and the more recently identified KI virus (KIPyV), WU virus (WUPyV), Merkel cell polyomavirus (MCPyV), HPyV6, HPyV7, trichodysplasia spinulosa virus (TSPyV), HPyV9 and MWPyV. Serological studies suggest that HPyVs subclinically infect the general population with rates ranging from 35% to 90%. However, significant disease is only observed in patients with impaired immune functions. Thus, BKV has been linked to hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation and PyV-associated nephropathy (PyVAN) after kidney transplantation; JCV to progressive multifocal leukoencephalopathy (PML) in HIV-AIDS, hematological diseases and in autoimmune diseases treated with certain lymphocyte-specific antibodies. KIPyV and WUPyV have been found in the respiratory tract, HPyV6 and 7 in the skin, and HPyV9 in serum and skin, and MWPyV in stools and skin, but so far none of these PyVs have been linked to any disease. TSPyV, on the other hand, was identified in trichodysplasia spinulosa, a rare skin disease characterized by virus-induced lytic as well as proliferative tumor-like features that is observed in immune suppressed transplant patients. In contrast to all the other HPyVs so far, MCPyV is unique in its association with a cancer, Merkel cell carcinoma, which is a rare skin cancer arising in the elderly and chronically immunosuppressed individuals. The discovery of the new HPyVs has revived interest in the Polyomaviridae and their association to human disease and cancer. In this review, we summarize knowledge about this expanding family of human pathogens. PMID- 23357734 TI - Cytoplasmic tails of bunyavirus Gn glycoproteins-Could they act as matrix protein surrogates? AB - Viruses of the family Bunyaviridae are negative-sense RNA viruses (NRVs). Unlike other NRVs bunyaviruses do not possess a matrix protein, which typically facilitates virus release from host cells and acts as an anchor between the viral membrane and its genetic core. Therefore the functions of matrix protein in bunyaviruses need to be executed by other viral proteins. In fact, the cytoplasmic tail of glycoprotein Gn (Gn-CT) of various bunyaviruses interacts with the genetic core (nucleocapsid protein and/or genomic RNA). In addition the Gn-CT of phleboviruses (a genus in the family Bunyaviridae) has been demonstrated to be essential for budding. This review brings together what is known on the role of various bunyavirus Gn-CTs in budding and assembly, and hypothesizes on their yet unrevealed functions in viral life cycle by comparing to the matrix proteins of NRVs. PMID- 23357735 TI - Systematically optimized biocompatible isotretinoin-loaded solid lipid nanoparticles (SLNs) for topical treatment of acne. AB - Isotretinoin (ITR) is a drug of choice in the treatment of all types of acne, including recalcitrant, severe and nodulocystic. The most widely employed route of its administration, i.e., oral intake, is reported to be associated with severe side-effects including teratogenecity, skin dryness and psychological disorders. Topical delivery, though advised for ITR, is marked with several hiccups like irritation, erythema and peeling of skin. The current studies, therefore, were embarked upon to develop "optimized" SLNs of ITR employing formulation by design (FbD) approach. The developed system was characterized and evaluated for skin compliance, skin transport characteristics and anti-acne potential against testosterone-induced acne in male Laca mice. The SLNs were able to transport the drug to various skin layers effectively while formed drug micro reservoirs. The nano-colloidal systems showed marked anti-acne potential and tolerability on the mouse skin vis-a-vis the marketed product. The optimized SLNs exhibited drug entrapment of 89.49+/-4.1%, while the size was found to be in the nano-range (i.e., 75.3+/-2.4 nm). The ITR formulation was found to be stable too as per ICH guidelines. The results vouch immense promise of the optimized SLNs of ITR in reducing dermal irritation and increasing the therapeutic performance, thus resulting in an efficacious and patient-compliant formulation. PMID- 23357736 TI - Doped TiO2 anodic layers of enhanced antibacterial properties. AB - Ti-6Al-4V joint replacement implants foster uncemented fixation in orthopaedic surgery. However, bacterial colonization competes with host cells and ultimately may produce implant-related difficult-to-treat infections, justifying the efforts to obtain infection-resistant materials. In a previous work, the authors demonstrated the antibacterial properties of anodic fluoride-TiO2 nanostructured layers on Ti-6Al-4V alloy. In this work, the anodizing bath has been modified in order to grow fluoride-TiO2 barrier layers (FBL). A bacterial adherence protocol, run with reference and six different clinical strains of Staphylococcus aureus and Staphylococcus epidermidis, showed a statistically significant decrease in the percentage of covered surface (p<0.0001, Kruskal-Wallis test) for FBL specimens when compared with non fluoride-containing specimens, i.e. chemically polished Ti-6Al-4V and F-free TiO2 barrier layers. The results obtained on the F barrier layers allowed discrimination between the effects of the presence of fluoride in the layer and the layer nanostructure on bacterial adhesion. PMID- 23357737 TI - Nanofibrous mats coated by homocharged biopolymer-layered silicate nanoparticles and their antitumor activity. AB - Quaternized chitosan (QC)-organic rectorite (OREC) intercalated composites based nanoparticles were immobilized on cellulose acetate nanofibrous mats by layer-by layer deposition technique via hydrogen bonds. The key design of those mats was the utilization of all negatively charged materials to reduce the quantity of nanoparticles immobilized on the fibers and then the cytotoxicity of the mats. The intercalated structure in nanoparticles was confirmed by selected area electron diffraction. The morphology and composition of NPs-assembled nanofibrous mats were studied by field emission scanning electron microscopy and X-ray photoelectron spectroscopy. The results trended to give clues as how the assembly process varied by adding OREC. MTT assay and cell culture experiments showed that NPs-assembled nanofibrous mats were commendably compatible with normal cells and could selectively kill human lung carcinoma epithelial cells. Hemolysis test indicated these mats had excellent blood compatibility. As a result, QC-OREC NPs assembled nanofibrous mats by homocharged deposition process can be considered as a novel alternative method for cancer therapy. PMID- 23357738 TI - Antibacterial microemulsion prevents sepsis and triggers healing of wound in wistar rats. AB - Microemulsions are thermodynamically stable isotropic systems comprising of oil, surfactant and water. Cinnamon oil (Cinnamomum zeylanicum) microemulsion was formulated using non-ionic surfactant Tween 20 and water. With oil to surfactant (v/v) ratio of 1:4, cinnamon oil microemulsion (CMF4) was formulated having droplet diameter of 5.79 and kinetically stable for 240 days. TEM images confirmed the spherical morphology of emulsion droplets. Surfactant concentration demonstrated a negative correlation with droplet diameter and turbidity but positive correlation with stability and viscosity. Formulated microemulsion (CMF4) was evaluated for bactericidal activity against Staphylococcus aureus by dose and time dependent killing experiment. SEM analysis suggested that microemulsion treatment resulted in alteration of permeability and surface features of bacterial cell membrane which lead to lysis and cell death. CMF4 showed no erythema for skin irritation test in wistar rats and triggered wound healing process in wistar rats. Control group without any treatment, cinnamon oil only and neomycin treated group healed in 20, 16 and 16 days, whereas cinnamon oil formulation (CMF4) treated group was healed in 14 days. PMID- 23357739 TI - Formulation, characterization and evaluation of an optimized microemulsion formulation of griseofulvin for topical application. AB - The main objective of the study was to develop a microemulsion (ME) formulation of griseofulvin for the treatment of dermatophytosis (Indian Patent Application 208/DEL/2009). The oil phase was selected on the basis of drug solubility whereas the surfactant and cosurfactant were screened on the basis of their oil solubilizing capacity as well as their efficiency to form ME from pseudo-ternary phase diagrams. The influence of surfactant and cosurfactant mass ratio (Smix) on the ME formation and its permeation through male Laca mice skin was studied. The optimized formulation (ME V) consisting of 0.2% (w/w) griseofulvin, 5% (w/w) oleic acid, 40% (w/w) Smix (1:1, Tween 80 and ethanol) possessed globule size of 12.21 nm, polydispersity index of 0.109 and zeta potential value of -0.139 mV. ME V exhibited 7, 5 and almost 3-fold higher drug permeation as compared to aqueous suspension, oily solution and conventional cream respectively. Besides this the formulation was also evaluated for drug content, pH, stability, dermatopharmacokinetics and antifungal activity against Microsporum canis using guinea pig model for dermatophytosis. Treatment of guinea pigs with ME V resulted in a complete clinical and mycological cure in 7 days. The formulation was observed to be non-sensitizing, histopathologically safe, and stable at 5+/-3 degrees C, 25+/-2 degrees C and 40+/-2 degrees C for a period of six months. PMID- 23357740 TI - The relationship between self-reported nocturnal sleep duration, daytime sleepiness and 24-h urinary albumin and protein excretion in patients with newly diagnosed type 2 diabetes. AB - AIM: In the current study the relationship between self-reported nocturnal sleep duration (NSD) and daytime sleepiness with 24-h urinary protein excretion (UPE) and 24-h urinary albumin excretion (UAE) were investigated in patients with newly diagnosed type 2 diabetes mellitus. METHODS: All patients underwent history taking, physical examination, blood pressure (BP) measurement, 12 lead electrocardiographic evaluation, routine urine analysis, biochemical analysis, 24 h urine collection to measure UAE, UPE and creatinine clearance. Self reported NSD and daytime sleepiness (using Epworth Sleepiness Scale (ESS)) were recorded for all patients. RESULTS: In total 110 patients (56 male and 54 female) were included. Self reported NSD was 7.17 +/- 1.07 h. Mean ESS score was 5.59 +/- 2.48. Stepwise linear regression of independent factors revealed that logarithmically converted 24-h UAE (as a dependent parameter) was related with clinical systolic BP (b: 0.01, p: 0.003), HbA1c (b: 0.082, p: 0.033), self reported NSD (b: -0.152, p: 0.004) and ESS score (b: 0.044, p: 0.043). Additionally, on the other hand, 24-h UPE was related with clinical systolic BP (b: 0.011, p: 0.001) and self reported NSD (b: -0.179, p<0.0001) in regression analysis. CONCLUSION: In conclusion, 24-h UAE were independently related with self reported NSD and daytime sleepiness where as 24-h UPE was related with only NSD in patients with newly diagnosed type 2 diabetic patients. PMID- 23357741 TI - The development and validation of the Portuguese risk score for detecting type 2 diabetes and impaired fasting glucose. AB - AIMS: To develop and validate a non-invasive score for detecting undiagnosed impaired fasting glucose (IFG) and type 2 diabetes (T2DM) in a Portuguese population. METHODS: We used data from 3,374 individuals aged 18-94 years from a Portuguese cross-sectional study. We developed a logistic regression model for predicting IFG/T2DM (diagnosed using fasting glucose). We externally validated the score using data from two cohorts of the EPI-Porto study, cross-sectional (n = 2,131) and data from the 5 year follow-up (n = 1,304). RESULTS: The final model included age, sex, BMI and hypertension with an area under the ROC curve of 70.1 (95%CI 68.4, 71.7). Using a cut-point which classifies 50% of the EPI-Porto cross sectional data as high-risk gave sensitivity 73.2% (95%CI 68.5%, 77.6%), specificity 55.5% (53.1%, 57.8%), positive predictive value (PPV) 27.0% (24.3%, 29.8%) and negative predictive value (NPV) 90.2% (88.3%, 92.0%) for IFG/T2DM. Using the same cut-point on the prospective data classified 45% as high-risk; sensitivity 69.1% (63.4%, 74.4%), specificity 63.3% (60.0%, 66.5%), PPV 38.0% (33.9%, 42.4%), and NPV 86.2% (83.3%, 88.8%). CONCLUSION: The Portuguese risk score can be used to identify those at high risk of both prevalent undiagnosed and incident IFG/T2DM. PMID- 23357742 TI - Sex differences in cocaine/heroin users: drug-use triggers and craving in daily life. AB - BACKGROUND: Studies of sex differences have shown that men and women with drug use disorders differ in course and outcome and in cue-induced activation of putative brain "control network" areas. We evaluated sex differences in daily functioning and subjective events related to drug use with ecological momentary assessment (EMA). METHODS: EMA data were collected from cocaine- and heroin-using outpatients (72 men; 42 women) in methadone maintenance in 2-5 randomly prompted (RP) entries per day and in participant-initiated entries for heroin or cocaine use or craving, for up to 25 weeks. Urine drug screens were conducted three times weekly. Data were analyzed via repeated-measures logistic regression, using sex as a predictor of responses. RESULTS: In RP reports, women and men reported significantly different patterns of drug-cue exposure, with women significantly more likely to report having seen cocaine or been tempted to use in the past hour. Women also had higher craving after past-hour exposure to drug cues. In reports of drug use, women, compared to men, were more likely to report that they had used more cocaine than they had meant to, tended to feel guilty more often after drug use, and to have used despite trying not to use. CONCLUSIONS: These findings provide real-time behavioral evidence that women respond differently than men to exposure to drug cues and to drug use, consistent with laboratory and brain-imaging findings. This information may be useful for development of sex specific treatment strategies. PMID- 23357744 TI - Chemical characterization of bio-oils using comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry. AB - The liquid product obtained via the biomass flash pyrolysis is commonly called bio-oil or pyrolysis oil. Bio-oils can be used as sources for chemicals or as fuels, primarily in mixtures or emulsions with fossil fuels. A detailed chemical characterization of bio-oil is necessary to determine its potential uses. Such characterization demands a powerful analytical technique such as comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC*GC-TOFMS). Limited chemical information can be obtained from conventional gas chromatography coupled mass spectrometry (GC-MS) because of the large number of compounds and coelutions. Thus, GC*GC-TOFMS was used for the individual identification of bio-oil components from two samples prepared via the flash pyrolysis of empty palm fruit bunch and pine wood chips. To the best of our knowledge, few papers have reported comprehensive two-dimensional gas chromatography (GC*GC) for bio-oil analysis. Many classes of compounds such as phenols, benzenediols, cyclopentenones, furanones, indanones and alkylpyridines were identified. Several coelutions present in the GC-MS were resolved using GC*GC-TOFMS. Many peaks were detected for the samples by GC-MS (~166 and 129), but 631 and 857 were detected by GC*GC-TOFMS, respectively. The GC*GC-TOFMS analyses indicated that the major classes of components (analytes>0.5% relative area) in the two bio-oil samples are ketones, cyclopentenones, furanones, furans, phenols, benzenediols, methoxy- and dimethoxy-phenols and sugars. In addition, esters, aldehydes and pyridines were found for sample obtained from empty palm fruit bunch, while alcohols and cyclopentanediones were found in sample prepared from pine wood chips indicating different composition profiles due to the biomass sources. The elucidation of the composition of empty fruit bunch and pine wood chips bio-oils indicates that these oils are suitable for the production of value added chemicals. The high quantity of phenol in the bio-oil of empty palm fruit bunch is of interest because phenol isolated from the bio-oil could provide an alternative to the phenol obtained from petroleum. The anhydrosugars found mainly in the bio-oil sample of pine wood chips can be isolated and fermented to produce ethanol or lipids. GC*GC-TOFMS can be used to increase the knowledge of the chemical composition of bio-oils allowing the improved usage of this attractive renewable energy source in bio-fuels. PMID- 23357745 TI - Headspace sorptive extraction for the analysis of organotin compounds using thermal desorption and gas chromatography with mass spectrometry. AB - A method based on headspace sorptive extraction (HSSE) in combination with thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS) has been developed for the simultaneous determination of six organotin compounds (OTCs), corresponding to mono- and di-substituted methyltin, butyltin and octyltin species. Several parameters affecting both the headspace extraction and thermal desorption steps were carefully optimized using multivariate designs. Analytes were derivatized by in situ ethylation with sodium tetraethylborate. The optimized method was applied to the analysis of water samples of different origins, as well as to checking the migration of the studied compounds from commercially available plastic containers to the adequate liquid simulant. Quantification was carried out against aqueous calibration curves using diphenyltin as internal standard, providing detection limits of between 1.7 and 7.0 ng(Sn) L(-1), depending on the compound, and repeatabilities lower than 10% in terms of relative standard deviation. The applicability of the method was assessed by means of recovery studies and satisfactory values for all compounds were attained. The release of OTCs from the tested packages to the liquid simulant was confirmed, concentrations as high as 2.4 MUg(Sn) L(-1) being found for dioctyltin. Even though the proposed method was developed for organotin halides, its application to an organotin ester shows its suitability for determining these compounds in migration assays. PMID- 23357743 TI - Prescription opioid mortality trends in New York City, 1990-2006: examining the emergence of an epidemic. AB - BACKGROUND: The drug overdose mortality rate tripled between 1990 and 2006; prescription opioids have driven this epidemic. We examined the period 1990-2006 to inform our understanding of how the current prescription opioid overdose epidemic emerged in urban areas. METHODS: We used data from the Office of the Chief Medical Examiner to examine changes in demographic and spatial patterns in overdose fatalities induced by prescription opioids (i.e., analgesics and methadone) in New York City (NYC) in 1990-2006, and what factors were associated with death from prescription opioids vs. heroin, historically the most prevalent form of opioid overdose in urban areas. RESULTS: Analgesic-induced overdose fatalities were the only types of overdose fatalities to increase in 1990-2006 in NYC; the fatality rate increased sevenfold from 0.39 in 1990 to 2.7 per 100,000 persons in 2006. Whites and Latinos were the only racial/ethnic groups to exhibit an increase in overdose-related mortality. Relative to heroin overdose decedents, analgesic and methadone overdose decedents were more likely to be female and to concurrently use psychotherapeutic drugs, but less likely to concurrently use alcohol or cocaine. Analgesic overdose decedents were less likely to be Black or Hispanic, while methadone overdose decedents were more likely to be Black or Hispanic in contrast to heroin overdose decedents. CONCLUSIONS: The distinct epidemiologic profiles exhibited by analgesic and methadone overdose fatalities highlight the need to define drug-specific public health prevention efforts. PMID- 23357746 TI - Robust aptamer sol-gel solid phase microextraction of very polar adenosine from human plasma. AB - Conventional solid phase microextraction (SPME) has a limited capacity to extract very polar analytes, such as adenosine. To solve this problem, aptamer conjugating sol-gel methodology was coupled with an SPME fiber. According to the authors' knowledge, this is the first reported use of aptamer SPME. The fiber of aptamer sol-gel SPME with a mesoporous structure has high porosity, large surface area, and small water contact angle. Rather than employing direct entrapment, covalent immobilization was the dominant method of aptamer loading in sol-gel. Aptamer sol-gel fiber captured a specified analyte from among the analog molecules, thereby, exhibiting an excellent selective property. Compared with commercial SPME fibers, this aptamer fiber was suitable for extracting adenosine, presenting an extraction efficiency higher than 20-fold. The values of repeatability and reproducibility expressed by relative standard deviation were low (9.4%). Interestingly, the sol-gel network enhanced the resistance of aptamer SPME to both nuclease and nonspecific proteins. Furthermore, the aptamer sol-gel fiber was applied in human plasma with LOQ 1.5 MUg/L, which is an acceptable level. This fiber also demonstrates durability and regeneration over 20-cycles without significant loss of efficiency. Given the various targets (from metal ions to biomacromolecules and cells) of aptamers, this methodology will extend the multi-domain applications of SPME. PMID- 23357747 TI - Hybrid preconcentrator/focuser module for determinations of explosive marker compounds with a micro-scale gas chromatograph. AB - This article describes the development and characterization of a partially selective preconcentrator/focuser (PCF) module for a field-portable micro-scale gas chromatograph (MUGC) designed to rapidly determine trace levels of two vapor phase markers of the explosive trinitrotoluene (TNT): 2,3-dimethyl-2,3 dinitrobutane (DMNB) and 2,4-dinitrotoluene (2,4-DNT). The PCF module has three primary components. The first is a high-volume sampler, comprising a resistively heated 6-cm long stainless steel tube packed with tandem beds of the graphitized carbons Carbopack B (C-B, 30 mg) and Carbopack Y (C-Y, 15 mg), which traps the markers but permits more volatile interferences to pass through largely unretained. The second component is a microfocuser (MUF), comprising a 4.2*9.8 mm Si chip containing a deep-reactive-ion-etched (DRIE) cavity packed with 2mg of C B, a Pyrex cap, integrated heaters, and etched fluidic channels. The third component is a commercial polymer-membrane filter used as a pre-trap to remove particles and adsorbed low volatility interferences. Markers captured in the sampler are thermally desorbed and transferred to the MUF, and then thermally desorbed/injected from the MUF into a downstream separation (micro)column and detected. Scrubbed ambient air is used as carrier gas. The adsorbent capacities, baseline temperatures, sampling and desorption flow rates, and heating profiles were optimized for each PCF module component while minimizing the analysis time. An overall transfer efficiency of 86% was achieved at marker concentrations of ~0.2-2.6 ppb. In the final configuration the PCF module requires just 60s to collect a 1-L sample (3 L/min), focus (40 mL/min), and inject the markers (3 mL/min), producing half-maximum injection peak widths of ~2 and 5 s, and preconcentration factors of 4500 and 1800, for DMNB and 2,4-DNT, respectively. PMID- 23357748 TI - Analytical method of free and conjugated neutral aroma components in tobacco by solvent extraction coupled with comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry. AB - A reliable and simple method for quantitative analysis of free and conjugated neutral aroma components (including aldehydes, ketones, alcohols, esters and alkenes) in tobacco using comprehensive two-dimensional gas chromatography-time of-flight mass spectrometry (GC * GC-TOFMS) is described. Simple solvent extraction using methyl tert-butyl ether (MTBE) ensured extraction of the neutral aroma components in their free form. The components present as conjugates were isolated using MTBE extraction following acid-catalysed hydrolysis. The GC * GC TOFMS analysis was performed to comprehensively identify different forms of neutral aroma components in tobacco. Compared with the conventional methods, our method not only simplified the process but also saved time and solvent. It also exhibited higher selectivity and sensitivity and demonstrated the following results: the limit of detection of the neutral aroma components varied from 0.006 MUg/g for 2-acetylfuran to 0.133 MUg/g for 5-(hydroxymethyl)-2-furfural, the relative standard deviations were from 0.5% to 6.8% and the recovery ranged from 82.4% to 118.2%. The optimized method was successfully employed to analyse real tobacco samples. Eighty-three neutral aroma components of interest were identified. PMID- 23357749 TI - On-line solid phase extraction-liquid chromatography-tandem mass spectrometry for the determination of 17 cytostatics and metabolites in waste, surface and ground water samples. AB - A fully automated on-line solid-phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) method has been developed for the determination of 13 cytostatics and 4 metabolites in aqueous matrices, including groundwater, surface water, and raw and treated wastewater. On-line SPE is performed by loading 5 mL of water sample at pH 2 through a PLRP-s cartridge. MS/MS is performed with an electrospray (ESI) interface operating in the positive ion mode and registering two selected reaction monitoring (SRM) transitions per compound. Quantification is carried out by the isotope dilution method using 15 different isotope-labelled compounds, specific for the target analytes, as internal standards (IS). The main advantages of the method are high sensitivity, with limits of determination in groundwater, surface water, and raw and treated wastewater below 5 ng L(-1) for all compounds except for gemcitabine (6.9-9.3 ng L(-1)), temozolomide (26-50 ng L(-1)), imatinib (80-180 ng L(-1)) and etoposide (38-65 ng L(-1)), repeatability, with relative standard deviations (RSDs) in most cases below 15%, and selectivity and reliability of results. The method is also fairly simple and fast, with an analysis time per sample (excluding the manual steps, i.e., sample filtration, pH adjustment, and addition of IS) of 40 min. Application of the method to influent wastewater samples collected daily during eight consecutive days from a wastewater treatment plant (WWTP) from Catalonia showed the presence of methotrexate, ifosfamide, capecitabine, tamoxifen and 6(alpha)-hydroxypaclitaxel but at fairly low concentrations (up to 43 ng L(-1)). PMID- 23357750 TI - Application of hydrophobic extractant in aqueous two-phase systems for selective extraction of cobalt, nickel and cadmium. AB - This work developed a new and efficient method of extracting and separating Co(II), Ni(II) and Cd(II) in aqueous two-phase systems (ATPS) composed of triblock copolymer (L64)+Na(2)C(4)H(4)O(6)+water and L64+Li(2)SO(4)+water using the hydrophobic extractant 1-nitroso-2-naphtol, which complexes the metal ions and partitions in the triblock copolymer micelles in the ATPS top phase. Metal extraction from the salt-rich phase to the copolymer - rich phase is strongly affected by the fine-tuning of the following parameters: amount of added extractant, type of electrolyte, pH, and tie-line length. Excellent separation factors (S(i,j)) between the metals were obtained at pH=3.00 (S(Co,Cd)=1550 and S(Ni,Cd)=16,700) and pH=1.00 (S(Co,Ni)=826). In the interference study, Co(II) was selectivity extracted in the top phase in the presence of Ni(II) and Cd(II) in a concentration of up to 20 times the cobalt level in the system. PMID- 23357751 TI - Determination of acidity constants by the capillary electrophoresis internal standard method. IV. Polyprotic compounds. AB - The IS-CE method is developed for pK(a) determination of polyprotic compounds. In this method, the internal standard (IS) and the polyprotic test compound are injected into the capillary electrophoresis (CE) system in buffers with appropriate pH. The pH of the buffers is not externally measured, but determined inside the capillary from the mobilities of the internal standards. Then the pK(a) values of the polyprotic compounds are obtained by fitting its mobilities to the in situ pH values. The method is faster than the classical CE method (a diprotic compound can be done in less than 15 min), and also than other methods like potentiometric and spectrophotometric titrations. The method has been successfully applied to 20 polyprotic test compounds of different chemical nature, including compounds with extreme or very close pK(a) values. PMID- 23357752 TI - Polypyrrole/sol-gel composite as a solid-phase microextraction fiber coating for the determination of organophosphorus pesticides in water and vegetable samples. AB - A novel solid-phase microextraction (SPME) fiber coated with polypyrrole/sol-gel composite was prepared through electrochemical deposition. The composite polymer coating was prepared using a three-electrode electrochemical system and directly deposited on a stainless steel wire by applying a constant potential (1.2V for 1000 s). The coating has porous surface structure, stable performance in high temperature, and good coating preparation reproducibility. The SPME composite coating was evaluated by analyzing some organophosphorus pesticides (OPPs) in water and vegetable samples followed by gas chromatography and nitrogen phosphorus detection. Different SPME parameters influencing the extraction efficiency such as coating thickness, salt concentration, stirring rate, extraction time and temperature, desorption time and desorption temperature were investigated. Under the optimized conditions, the coating showed better extraction efficiency than polypyrrole and commercial SPME fibers. The detection limits were 1.5-10 ng L(-1). Relative standard deviations for intra- and inter day precision for a single fiber were in the range of 1.1-2.9% and 2.2-4.2%, respectively. Fiber to fiber reproducibility was in the range of 6.0-10.1% (n=3). The calibration curves were linear in the concentration range from 5 to 2000 ng L(-1) (r(2)>0.9953). Finally, the developed method was applied for the analysis of cucumber, lettuce, tap and well water samples and the relative recovery was found to be in the range of 80-109%, at the optimum conditions. PMID- 23357753 TI - Electromembrane surrounded solid phase microextraction: a novel approach for efficient extraction from complicated matrices. AB - In the present work, electromembrane surrounded solid phase microextraction (EM SPME) is introduced for the first time. The organic liquid membrane, which consists of 2-nitrophenyl octyl ether (NPOE), was immobilized in the pores of a hollow fiber (HF) and the basic analytes migrated in an electrical field from aqueous sample solution through the liquid membrane and into aqueous acceptor phase and then they were adsorbed on the solid sorbent, which acts as the cathode. Effective parameters such as composition of organic liquid membrane, pH of donor and acceptor phases, applied voltage and extraction time were optimized for extraction of amitriptyline (AMI) and doxepin (DOX) as model analytes and figures of merit of the method were investigated in pure water, human plasma, and urine samples. To extract the model analytes from 24 mL neutral sample solution across organic liquid membrane and into aqueous acceptor phase, 120 V electrical potential was applied for 20 min and finally the drugs were adsorbed on a carbonaceous cathode. Regardless of high sample cleanup, which make the proposed method suitable for the analysis of drugs from complicated matrices, extraction efficiencies in the range of 3.1-11.5% and good detection limits (less than 5 ngmL(-1)) with admissible repeatability and reproducibility (intra- and inter assay precisions ranged between 4.0-8.5% and 7.5-12.2%, respectively) were obtained from different extraction media. Linearity of the method was studied in the range of 2.0-500.0 ngmL(-1) and 5.0-500.0 ngmL(-1) for AMI and DOX, respectively and coefficient of determination higher than 0.9947 were achieved. Finally, the proposed method was applied for the analysis of AMI and DOX in real samples. PMID- 23357754 TI - Hollow fiber cell fishing with high performance liquid chromatography for screening bioactive compounds from traditional Chinese medicines. AB - A novel hollow fiber cell fishing method with high performance liquid chromatography was proposed and used to screen, isolate, and analyze bioactive compounds from Traditional Chinese Medicines (TCMs). The active compounds that interact with the living cells acceptor inside the hollow fiber lumen were screened and isolated from the TCM extracts in phosphate buffer solution (pH 7.4). Subsequently, the active compounds bound to the cells were desorbed with methanol, and were analyzed using HPLC. HFCF with HPLC was introduced for the screening and analysis of lignans in Schisandra chinensis (Turcz) Baill and coumarins in Fructus Cnidii and Fructus Psoraleae. The surface properties of the hollow fibers filled with living cells were characterized. The nonspecific binding between the active centers of the hollow fibers and the bioactive compounds were investigated. The cell survival rates were determined before and after the screening. The repeatability of the method was tested. Some structures of the lignans and coumarins screened from TCMs were identified by the comparison to the retention times of the reference substances. HFCF-HPLC is a simple, fast, effective, and reliable method for the screening and analysis of bioactive compounds, and it can be extended to screen other bioactive compounds from TCMs. PMID- 23357755 TI - PARP-1 and gene regulation: progress and puzzles. AB - Poly(ADP-ribose) polymerase-1 (PARP-1), also referred to as ADP ribosyltransferase Diphtheria toxin-like 1 (ARTD1), is an abundant nuclear protein that plays key roles in a variety of nuclear processes, including the regulation of transcription. PARP-1 possesses an intrinsic enzymatic activity that catalyzes the transfer of ADP-ribose (ADPR) units from nicotinamide adenine dinucleotide (NAD(+)) onto target gene regulatory proteins, thereby modulating their activities. Although great strides have been made in the past decade in deciphering the seemingly opposing and varied roles of PARP-1 in gene regulation, many puzzles remain. In this review, we discuss the current state of understanding in this area, especially how PARP-1 interfaces with various components of gene regulatory pathways (e.g., the basal transcription machinery, DNA-binding transcription factors, coregulators, chromatin remodeling, histone modifications, and DNA methylation). In addition, we discuss some gene-specific, cell type-specific, and cell state-specific effects of PARP-1 on gene regulation, which might contribute to its biological functions. Finally, we review some of the recent progress targeting PARPs using chemical inhibitors, some of which may alter PARP-1-dependent gene regulatory programs to promote therapeutic outcomes. PMID- 23357757 TI - Reliability of principal components and discrete parameters of knee angle and moment gait waveforms in individuals with moderate knee osteoarthritis. AB - Gait measures are used to evaluate change in patients with knee osteoarthritis (OA), but reliability has not been fully established in this population. This study examined test-retest reliability of knee angle and moment gait waveform characteristics captured using discrete parameters and principal component analysis (PCA) in individuals with moderate knee OA. Participants (n=20) underwent three-dimensional gait analysis on two occasions. Motion and force data were captured using two camera banks, infrared light emitting diodes and force plate during self-selected walking. Knee angle and moment waveforms were calculated and analyzed using discrete parameters and by identifying waveform characteristics using PCA. Intraclass correlation coefficients (ICC2,k) examined test-retest reliability of discrete parameters and PCA derived scores (PC scores). ICC2,k values ranged from 0.57 to 0.93 for discrete parameters, 0.52 0.86 for knee angle PC-scores and 0.30-0.94 for the knee moment PC-scores. However, 10 of 13 discrete parameters, six of nine knee angle PC-scores and seven of nine knee moment PC-scores had ICC2,k values greater than or equal to 0.70. Discrete parameters and PC-scores from flexion angles and adduction moments had the highest ICC2,k values while adduction angles, rotation angles, and rotation moments had the lowest. Most knee angle and moment waveform characteristics demonstrated ICC2,k values that could be interpreted as acceptable. Caution should be used when examining adduction and rotation angle magnitudes and early/mid-stance rotation moment magnitudes due to lower ICC2,k values. PMID- 23357758 TI - Determinants and consequences for standing balance of spontaneous weight-bearing on the paretic side among individuals with chronic stroke. AB - Hemiparetic stroke patients commonly bear more weight on the non-paretic side which seems intuitively linked to unilateral control deficits. However, there is evidence that some post-stroke favour weighting the paretic side, which may be problematic given altered capacity of the paretic limb to contribute to the control of upright posture. This study explores the prevalence and clinical determinants of stance asymmetry, and the relationship between stance asymmetry and postural control among chronic stroke patients. Subjects (n=147; >6 months post-stroke) stood on two force plates in eyes-open and eyes-closed conditions; 59 were symmetric, 18 had paretic asymmetry (PA), and 70 had non-paretic asymmetry (NPA). Root mean square (RMS) of antero-posterior and medio-lateral centre-of-pressure under each limb and both limbs combined were compared. RMS of total medio-lateral centre-of-pressure was greater for both asymmetric groups compared with the symmetric group. PA subjects relied less on the loaded limb for control than NPA subjects and relied more on visual information for postural control than those who were symmetric. There were no differences in the characteristics of individuals between the PA and NPA groups. The loading of the paretic limb was not related to impaired postural control during stationary standing which was attributable, in part, to individuals relying on control from the non-paretic limb, in spite of lower vertical load, and a greater dependence on visual contributions. There was no evidence that greater loading on the paretic limb was related to persisting dyscontrol but may rather reflect a learned strategy. PMID- 23357759 TI - The effect of unstable sandals on instability in gait in healthy female subjects. AB - Unstable footwear generally lacks thorough peer-review published research to support concepts and marketing claims. The purpose of this study was to investigate the instability induced by four (FitFlop, Masai Barefoot Technology, Reebok Easy-Tone and Skechers Tone-Ups) commercially available unstable sandals and one stable control sandal (Earth) in walking in 15 females (mean+/-SD age was 29+/-6.7 years, mass 62.6+/-6.9kg and height 167.1+/-4.2cm). Three-dimensional motion with synchronised electromyography and kinetic data were collected. Walking speed and step length remained consistent between conditions, however double support time decreased in Masai Barefoot Technology. Centre of pressure data identified no consistent difference between the stable control and the unstable sandals, however Masai Barefoot Technology reduced the anterior posterior range of centre of pressure. Muscle activity differed significantly at the ankle in the unstable footwear. FitFlop, Reebok and Skechers increased peroneal activity during pre-swing, whereas Masai Barefoot Technology increased medial gastrocnemius and decreased tibialis anterior activity in loading response and mid-stance. The larger rocker sole of the Masai Barefoot Technology altered gait and muscle activation with regard to braking and progression in the sagittal plane. Reebok, Skechers and FitFlop, with softer, less stable foreparts increased evertor action at toe-off, having their effect in the coronal plane. The study highlighted that any instability induced by the shoes is design-specific. PMID- 23357760 TI - In vitro sensitivities of Plasmodium falciparum isolates from the China-Myanmar border to piperaquine and association with polymorphisms in candidate genes. AB - The recent reports of resistance in Plasmodium falciparum to artemisinin derivatives and their partner drugs demand intensive studies toward understanding the molecular mechanisms of resistance. In this study, we examined the in vitro susceptibility of 63 P. falciparum field isolates collected from the China Myanmar border area to chloroquine (CQ) and piperaquine (PPQ). Parasite isolates remained highly resistant to CQ, with the geometric mean 50% inhibitory concentration (IC50) of 252.7 nM and a range of 51.9 to 1,052.0 nM. In comparison, these parasites had a geometric mean IC50 of 28.4 nM for PPQ, with a fairly wide range of 5.3 to 132.0 nM, suggesting that certain parasite isolates displayed relatively high levels of resistance to PPQ. Interestingly, within the 4 years of study, the parasites exhibited a continuous decline in susceptibilities to both CQ and PPQ, and there was a significant correlation between responses to CQ and PPQ (Pearson correlation coefficient = 0.79, P < 0.0001). Consistent with the CQ-resistant phenotype, all parasites carried the pfcrt K76T mutation, and most parasites had the CVIET type that is prevalent in Southeast Asia. In contrast, pfmdr1 mutations were relatively rare, and no gene amplification was detected. Only the pfmdr1 N1042D mutation was associated with resistance to CQ. For the pfmrp1 gene, four substitutions reached relatively high prevalence of >22%, and the I876V mutation was associated with reduced sensitivity to CQ. However, we could not establish a link between PPQ responses and the polymorphisms in the three genes associated with quinoline drug resistance. PMID- 23357761 TI - Chimeric beta-defensin analogs, including the novel 3NI analog, display salt resistant antimicrobial activity and lack toxicity in human epithelial cell lines. AB - Human beta-defensins (hBDs) are crucial peptides for the innate immune response and are thus prime candidates as therapeutic agents directed against infective diseases. Based on the properties of wild-type hBD1 and hBD3 and of previously synthesized analogs (1C, 3I, and 3N), we have designed a new analog, 3NI, and investigated its potential as an antimicrobial drug. Specifically, we evaluated the antimicrobial activities of 3NI versus those of hBD1, hBD3, 1C, 3I, and 3N. Our results show that 3NI exerted greater antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, and Enterococcus faecalis than did hBD1 and hBD3, even with elevated salt concentrations. Moreover, its antiviral activity against herpes simplex virus 1 was greater than that of hBD1 and similar to that of hBD3. Subsequently, we investigated the cytotoxic effects of all peptides in three human epithelial carcinoma cell lines: A549 from lung, CaCo-2 from colon, and Capan-1 from pancreas. None of the analogs significantly reduced cell viability versus wild-type hBD1 and hBD3. They did not induce genotoxicity or cause an increase in the number of apoptotic cells. Using confocal microscopy, we also investigated the localization of the peptides during their incubation with epithelial cells and found that they were distributed on the cell surface, from which they were internalized. Finally, we show that hBD1 and hBD3 are characterized by high resistance to serum degradation. In conclusion, the new analog 3NI seems to be a promising anti-infective agent, particularly given its high salt resistance--a feature that is relevant in diseases such as cystic fibrosis. PMID- 23357762 TI - Immunoadjuvant chemotherapy of visceral leishmaniasis in hamsters using amphotericin B-encapsulated nanoemulsion template-based chitosan nanocapsules. AB - The accessible treatment options for life-threatening neglected visceral leishmaniasis (VL) disease have problems with efficacy, stability, adverse effects, and cost, making treatment a complex issue. Here we formulated nanometric amphotericin B (AmB)-encapsulated chitosan nanocapsules (CNC-AmB) using a polymer deposition technique mediated by nanoemulsion template fabrication. CNC-AmB exhibited good steric stability in vitro, where the chitosan content was found to be efficient at preventing destabilization in the presence of protein and Ca(2+). A toxicity study on the model cell line J774A and erythrocytes revealed that CNC-AmB was less toxic than commercialized AmB formulations such as Fungizone and AmBisome. The results of in vitro (macrophage amastigote system; 50% inhibitory concentration [IC(50)], 0.19 +/- 0.04 MUg AmB/ml) and in vivo (Leishmania donovani-infected hamsters; 86.1% +/- 2.08% parasite inhibition) experiments in conjunction with effective internalization by macrophages illustrated the efficacy of CNC-AmB at augmenting antileishmanial properties. Quantitative mRNA analysis by real-time PCR (RT-PCR) showed that the improved effect was synergized with the upregulation of tumor necrosis factor alpha (TNF-alpha), interleukin-12 (IL-12), and inducible nitric oxide synthase and with the downregulation of transforming growth factor beta (TGF-beta), IL-10, and IL-4. These research findings suggest that a cost-effective CNC-AmB immunoadjuvant chemotherapeutic delivery system could be a viable alternative to the current high-cost commercial lipid-based formulations. PMID- 23357763 TI - Impact of antibiotic use on carbapenem resistance in Pseudomonas aeruginosa: is there a role for antibiotic diversity? AB - In this study, we aimed to evaluate the relationship between the rates of resistance of Pseudomonas aeruginosa to carbapenems and the levels and diversity of antibiotic consumption. Data were retrospectively collected from 20 acute care hospitals across 3 regions of Switzerland between 2006 and 2010. The main outcome of the present study was the rate of resistance to carbapenems among P. aeruginosa. Putative predictors included the total antibiotic consumption and carbapenem consumption in defined daily doses per 100 bed days, the proportion of very broad-spectrum antibiotics used, and the Peterson index. The present study confirmed a correlation between carbapenem use and carbapenem resistance rates at the hospital and regional levels. The impact of diversifying the range of antibiotics used against P. aeruginosa resistance was suggested by (i) a positive correlation in multivariate analysis between the above-mentioned resistance and the proportion of consumed antibiotics having a very broad spectrum of activity (coefficient = 1.77; 95% confidence interval, 0.58 to 2.96; P < 0.01) and (ii) a negative correlation between the resistance and diversity of antibiotic use as measured by the Peterson homogeneity index (coefficient = -0.52; P < 0.05). We conclude that promoting heterogeneity plus parsimony in the use of antibiotics appears to be a valuable strategy for minimizing the spread of carbapenem resistance in P. aeruginosa in hospitals. PMID- 23357764 TI - Evaluation of the effect of a supratherapeutic dose of intravenous ceftaroline fosamil on the corrected QT interval. AB - A randomized, double-blind, placebo-controlled, 3-period crossover study was conducted in 54 healthy adults to assess the effect of ceftaroline fosamil on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using an individual correction formula (QTcIb), was determined predose and at 1, 1.25, 1.5, 2, 4, 8, 12, and 24.5 h after intravenous dosing with a supratherapeutic dose (1,500 mg) of ceftaroline fosamil, 400 mg moxifloxacin (positive control), and placebo. The pharmacokinetic profile of ceftaroline was also evaluated. At each time point following ceftaroline fosamil administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from predose baseline in QTcIb (DeltaDeltaQTcIb) was below 10 ms (maximum, 3.4 ms at 1.5 h after dosing), indicating an absence of clinically meaningful QTc increase. The lower limit of the 90% CI of DeltaDeltaQTcIb for moxifloxacin versus placebo was greater than 5 ms at 5 time points (maximum, 12.8 ms at 1 h after dosing), demonstrating assay sensitivity. There was no apparent correlation between ceftaroline plasma concentrations and DeltaDeltaQTcIb. The supratherapeutic dose of ceftaroline fosamil (1,500 mg) resulted in substantially greater systemic exposure to ceftaroline than previously observed with standard therapeutic doses. Ceftaroline fosamil was well tolerated after a single 1,500-mg intravenous dose, and no clinically meaningful abnormalities in laboratory values or vital signs were observed. PMID- 23357756 TI - Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes. AB - Poly(ADP-ribose) polymerases (PARPs) are NAD(+) dependent enzymes that were identified as DNA repair proteins, however, today it seems clear that PARPs are responsible for a plethora of biological functions. Sirtuins (SIRTs) are NAD(+) dependent deacetylase enzymes involved in the same biological processes as PARPs raising the question whether PARP and SIRT enzymes may interact with each other in physiological and pathophysiological conditions. Hereby we review the current understanding of the SIRT-PARP interplay in regard to the biochemical nature of the interaction (competition for the common NAD(+) substrate, mutual posttranslational modifications and direct transcriptional effects) and the physiological or pathophysiological consequences of the interactions (metabolic events, oxidative stress response, genomic stability and aging). Finally, we give an overview of the possibilities of pharmacological intervention to modulate PARP and SIRT enzymes either directly, or through modulating NAD(+) homeostasis. PMID- 23357765 TI - Pharmacokinetics, metabolism, and excretion of the antiviral drug arbidol in humans. AB - Arbidol is a broad-spectrum antiviral drug that is used clinically to treat influenza. In this study, the pharmacokinetics, metabolism, and excretion of arbidol were investigated in healthy male Chinese volunteers after a single oral administration of 200 mg of arbidol hydrochloride. A total of 33 arbidol metabolites were identified in human plasma, urine, and feces. The principal biotransformation pathways included sulfoxidation, dimethylamine N-demethylation, glucuronidation, and sulfate conjugation. The major drug-related component in the plasma was sulfinylarbidol (M6-1), followed by unmetabolized arbidol, N demethylsulfinylarbidol (M5), and sulfonylarbidol (M8). The exposures of M5, M6 1, and M8, as determined by the metabolite-to-parent area under the plasma concentration-time curve from 0 to t (AUC(0-t)) ratio, were 0.9 +/- 0.3, 11.5 +/- 3.6, and 0.5 +/- 0.2, respectively. In human urine, glucuronide and sulfate conjugates were detected as the major metabolites, accounting for 6.3% of the dose excreted within 0 to 96 h after drug administration. The fecal specimens mainly contained the unchanged arbidol, accounting for 32.4% of the dose. Microsomal incubation experiments demonstrated that the liver and intestines were the major organs that metabolize arbidol in humans. CYP3A4 was the major isoform involved in arbidol metabolism, whereas the other P450s and flavin-containing monooxygenases (FMOs) played minor roles. These results indicated possible drug interactions between arbidol and CYP3A4 inhibitors and inducers. Further investigations are needed to understand the importance of M6-1 in the efficacy and safety of arbidol, because of its high plasma exposure and long elimination half-life (25.0 h). PMID- 23357766 TI - A physiologically based pharmacokinetic model of rifampin in mice. AB - One problem associated with regimen-based development of antituberculosis (anti TB) drugs is the difficulty of a systematic and thorough in vivo evaluation of the large number of possible regimens that arise from consideration of multiple drugs tested together. A mathematical model capable of simulating the pharmacokinetics and pharmacodynamics of experimental combination chemotherapy of TB offers a way to mitigate this problem by extending the use of available data to investigate regimens that are not initially tested. In order to increase the available mathematical tools needed to support such a model for preclinical anti TB drug development, we constructed a preliminary whole-body physiologically based pharmacokinetic (PBPK) model of rifampin in mice, using data from the literature. Interindividual variability was approximated using Monte Carlo (MC) simulation with assigned probability distributions for the model parameters. An MC sensitivity analysis was also performed to determine correlations between model parameters and plasma concentration to inform future model development. Model predictions for rifampin concentrations in plasma, liver, kidneys, and lungs, following oral administration, were generally in agreement with published experimental data from multiple studies. Sensitive model parameters included those descriptive of oral absorption, total clearance, and partitioning of rifampin between blood and muscle. This PBPK model can serve as a starting point for the integration of rifampin pharmacokinetics in mice into a larger mathematical framework, including the immune response to Mycobacterium tuberculosis infection, and pharmacokinetic models for other anti-TB drugs. PMID- 23357767 TI - Complete sequence of the IncT-type plasmid pT-OXA-181 carrying the blaOXA-181 carbapenemase gene from Citrobacter freundii. AB - The gene encoding the carbapenemase OXA-181 (an OXA-48 variant) was identified from a Citrobacter freundii isolate coproducing NDM-1. The whole sequence of plasmid pT-OXA-181 bearing the blaOXA-181 gene was determined and revealed a 84 kb mobilizable but non-self-conjugative IncT-type plasmid. It totally differs from the 7.6-kb ColE-type and blaOXA-181-bearing plasmid recently identified in a Klebsiella pneumoniae isolate. However, in both plasmids, insertion sequence ISEcp1 might have played a role in acquisition of the blaOXA-181 gene. PMID- 23357768 TI - Pharmacokinetic and pharmacodynamic evaluation of P-873 versus Klebsiella pneumoniae in a neutropenic murine thigh infection model. AB - P-873 is a novel compound in the RX-04 pyrrolocytosine series of protein synthesis inhibitors currently under development by Rib-X Pharmaceuticals. We evaluated the pharmacodynamic and pharmacokinetic properties of this compound against Klebsiella pneumoniae using a murine neutropenic thigh infection model. P 873 demonstrated potent and rapid in vivo activity against this organism with enhanced penetration and duration of exposure in thigh tissue. PMID- 23357769 TI - Blood, tissue, and intracellular concentrations of azithromycin during and after end of therapy. AB - Although azithromycin is extensively used in the treatment of respiratory tract infections as well as skin and skin-related infections, pharmacokinetics of azithromycin in extracellular space fluid of soft tissues, i.e., one of its therapeutic target sites, are not yet fully elucidated. In this study, azithromycin concentration-time profiles in extracellular space of muscle and subcutaneous adipose tissue, but also in plasma and white blood cells, were determined at days 1 and 3 of treatment as well as 2 and 7 days after the end of treatment. Of all compartments, azithromycin concentrations were highest in white blood cells, attesting for intracellular accumulation. However, azithromycin concentrations in both soft tissues were markedly lower than in plasma both during and after treatment. Calculation of the area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MIC(90) ratios for selected pathogens suggests that azithromycin concentrations measured in the present study are subinhibitory at all time points in both soft tissues and at the large majority of observed time points in plasma. Hence, it might be speculated that azithromycin's clinical efficacy relies not only on elevated intracellular concentrations but possibly also on its known pleotropic effects, including immunomodulation and influence on bacterial virulence factors. However, prolonged subinhibitory azithromycin concentrations at the target site, as observed in the present study, might favor the emergence of bacterial resistance and should therefore be considered with concern. In conclusion, this study has added important information to the pharmacokinetic profile of the widely used antibiotic drug azithromycin and evidentiates the need for further research on its potential for induction of bacterial resistance. PMID- 23357770 TI - Target gene sequencing to define the susceptibility of Neisseria meningitidis to ciprofloxacin. AB - Meningococcal gyrA gene sequence data, MICs, and mouse infection were used to define the ciprofloxacin breakpoint for Neisseria meningitidis. Residue T91 or D95 of GyrA was altered in all meningococcal isolates with MICs of >= 0.064 MUg/ml but not among isolates with MICs of <= 0.032 MUg/ml. Experimental infection of ciprofloxacin-treated mice showed slower bacterial clearance when GyrA was altered. These data suggest a MIC of >= 0.064 MUg/ml as the ciprofloxacin breakpoint for meningococci and argue for the molecular detection of ciprofloxacin resistance. PMID- 23357771 TI - Staphylococcus aureus biofilms promote horizontal transfer of antibiotic resistance. AB - Growth as a biofilm facilitates the emergence of antibiotic resistance by mutation in Staphylococcus aureus. Here we demonstrate that biofilm growth of this species also dramatically increases horizontal transfer of plasmid-borne antibiotic resistance determinants by conjugation/mobilization and that standard laboratory practices to induce conjugation in staphylococci achieve optimal efficiency owing to the presence of a biofilm. PMID- 23357772 TI - Contribution of topoisomerase IV mutation to quinolone resistance in Mycoplasma genitalium. AB - The mechanism of quinolone resistance in Mycoplasma genitalium remains poorly understood due to difficulties with in vitro culture, especially of clinical isolates. In this study, to confirm the association between mutations in topoisomerases and antimicrobial susceptibilities to quinolones, ciprofloxacin resistant mutant strains were selected using the cultivable type strain ATCC 33530. Sequence analysis revealed that the mutant strains harbored mutations in topoisomerase IV: Gly81Cys in ParC, Pro261Thr in ParC, or Asn466Lys in ParE. The MICs of all quinolones tested against the mutant strains were 2- to 16-fold higher than those against the wild-type strain. No cross-resistance was observed with macrolides or tetracyclines. We determined the inhibitory activities of quinolones against DNA gyrase and topoisomerase IV in order to investigate the correlation between antimicrobial susceptibility and inhibitory activity against the target enzymes, considered the primary targets of quinolones. Furthermore, using enzymatic analysis, we confirmed that Gly81Cys in the ParC quinolone resistance-determining region (QRDR) contributed to quinolone resistance. This is the first study to isolate quinolone-resistant mutant strains of M. genitalium harboring substitutions in the parC or parE gene in vitro and to measure the inhibitory activities against the purified topoisomerases of M. genitalium. PMID- 23357773 TI - Pharmacodynamic variability beyond that explained by MICs. AB - Monte Carlo simulations (MCS) present a powerful tool to evaluate candidate regimens by determining the probability of target attainment. Although these assessments have traditionally incorporated variability in pharmacokinetic (PK) parameters and MICs, consideration of interstrain pharmacodynamic (PD) variability has been neglected. A population PK/PD model was developed for doripenem using murine thigh infection data based on 20 bacterial strains. PK data were fit to a linear two-compartment model with first-order input and elimination processes and an absorption lag time from a separate site (r(2) > 0.96). PK parameters were utilized to simulate free-drug profiles for various regimens in PD studies, from which the percentage of the dosing interval for which free-drug concentrations exceed the MIC of the targeted strain (%fT>MIC) was calculated. Doripenem PD was excellently described with Hill-type models (r(2) > 0.98); significant differences between mean PD estimates determined using a two-stage approach versus population analyses were not observed (P > 0.05); however, the variance in 50% effective concentration (EC50) and maximum effect (Emax) among strains was much greater using the two-stage approach. Even using the population approach, interstrain variability in EC50 (coefficient of variation expressed as a percentage [CV%] = 29.2%) and H (CV% = 46.1%) parameters was substantive, while the variability in Emax (CV% = 19.7%) was modest. This resulted in extensive variability in the range of %fT>MIC targets associated with stasis to those associated with a 2-log10 reduction in bacterial burden (CV% ~ 50%). It appears that MCS, based on the assumption that PD variability is due to MIC alone, underestimates variability and may consequently underestimate treatment failures. PMID- 23357774 TI - Synergistic effects of amiodarone and fluconazole on Candida tropicalis resistant to fluconazole. AB - There have recently been significant increases in the prevalence of systemic invasive fungal infections. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of cross-resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapies have become one of the most widely used and effective strategies to alleviate this problem. Amiodarone (AMD) is classically used for the treatment of atrial fibrillation and is the drug of choice for patients with arrhythmia. Recent studies have shown broad antifungal activity of the drug when administered in combination with fluconazole (FLC). In the present study, we induced resistance to fluconazole in six strains of Candida tropicalis and evaluated potential synergism between fluconazole and amiodarone. The evaluation of drug interaction was determined by calculating the fractional inhibitory concentration and by performing flow cytometry. We conclude that amiodarone, when administered in combination with fluconazole, exhibits activity against strains of C. tropicalis that are resistant to fluconazole, which most likely occurs via changes in the integrity of the yeast cell membrane and the generation of oxidative stress, mitochondrial dysfunction, and DNA damage that could lead to cell death by apoptosis. PMID- 23357775 TI - Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital acquired pneumonia. AB - In a previous phase 3 study, the cure rates that occurred in patients with hospital-acquired pneumonia treated with tigecycline at the approved dose were lower than those seen with patients treated with imipenem and cilastatin (imipenem/cilastatin). We hypothesized that a higher dose of tigecycline is necessary in patients with hospital-acquired pneumonia. This phase 2 study compared the safety and efficacy of two higher doses of tigecycline with imipenem/cilastatin in subjects with hospital-acquired pneumonia. Subjects with hospital-acquired pneumonia were randomized to receive one of two doses of tigecycline (150 mg followed by 75 mg every 12 h or 200 mg followed by 100 mg every 12 h) or 1 g of imipenem/cilastatin every 8 h. Empirical adjunctive therapy was administered for initial coverage of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa infection, depending on the randomization regimen. Clinical response, defined as cure, failure of treatment, or indeterminate outcome, was assessed 10 to 21 days after the last day of therapy. In the clinically evaluable population, clinical cure with tigecycline 100 mg (17/20, 85.0%) was numerically higher than with tigecycline 75 mg (16/23, 69.6%) and imipenem/cilastatin (18/24, 75.0%). No new safety signals with the high-dose tigecycline were identified. A numerically higher clinical response was observed with the 100-mg dose of tigecycline. This supports our hypothesis that a higher area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) may be necessary to achieve clinical cure in patients with hospital-acquired pneumonia. Further studies are necessary. (The ClinicalTrials.gov identifier for this clinical trial is NCT00707239.). PMID- 23357776 TI - Outbreak of NDM-1-producing Klebsiella pneumoniae in a neonatal unit in Colombia. AB - Six multiresistant, NDM-1-producing Klebsiella pneumoniae strains were recovered from an outbreak that affected six neonatal patients in a Colombian hospital. Molecular analysis showed that all of the isolates harbored the blaNDM-1, qnrA, and intI1 genes and were clonally related. Multilocus sequence typing showed that the isolates belonged to a new sequence type (ST1043) that was different from the sequence types that had previously been reported. This is the first report of NDM 1-producing isolates in South America. PMID- 23357777 TI - Evaluation of recombinant 2009 pandemic influenza A (H1N1) viruses harboring zanamivir resistance mutations in mice and ferrets. AB - Recombinant influenza A(H1N1)pdm09 wild-type (WT) and zanamivir-resistant E119G and Q136K neuraminidase mutants were generated to determine their enzymatic and replicative properties in vitro, as well as their infectivity and transmissibility in mice and ferrets. Viral titers of recombinant E119G and Q136K mutants were significantly lower than those of the WT in the first 36 h postinoculation (p.i.) in vitro. The E119G and Q136K mutations were both associated with a significant reduction of total neuraminidase (NA) activity at the cell surface of 293T cells, with relative total NA activities of 14% (P < 0.01) and 20% (P < 0.01), respectively, compared to the WT. The E119G mutation significantly reduced the affinity (8-fold increase in Km) but not the Vmax. The Q136K mutation increased the affinity (5-fold decrease in Km) with a reduction in Vmax (8% Vmax ratio versus the WT). In mice, infection with the E119G and Q136K mutants resulted in lung viral titers that were significantly lower than those of the WT on days 3 p.i. (3.4 * 10(6) +/- 0.8 * 10(6) and 2.1 * 10(7) +/- 0.4 * 10(7) PFU/ml, respectively, versus 8.8 * 10(7) +/- 1.1 * 10(7); P < 0.05) and 6 p.i. (3.0 * 10(5) +/- 0.5 * 10(5) and 8.6 * 10(5) +/- 1.4 * 10(5) PFU/ml, respectively, versus 5.8 * 10(7) +/- 0.3 * 10(7); P < 0.01). In experimentally infected ferrets, the E119G mutation rapidly reverted to the WT in donor and contact animals. The Q136K mutation was maintained in ferrets, although nasal wash viral titers from the Q136K contact group were significantly lower than those of the WT on days 3 to 5 p.i. Our results demonstrate that zanamivir resistant E119G and Q136K mutations compromise viral fitness and transmissibility in A(H1N1)pdm09 viruses. PMID- 23357778 TI - A novel mechanism underlies the hepatotoxicity of pyrazinamide. AB - Relatively little is known about the hepatotoxicity of pyrazinamide (PZA). PZA requires activation by amidase to form pyrazinoic acid (PA). Xanthine oxidase then hydroxylates PA to form 5-hydroxypyrazinoic acid (5-OH-PA). PZA can also be directly oxidized to form 5-OH-PZA. Before this study, it was unclear which metabolic pathway or PZA metabolites led to hepatotoxicity. This study determines whether PZA metabolites are responsible for PZA-induced hepatotoxicity. PZA metabolites were identified and cytotoxicity in HepG2 cells was assessed. Potential PZA and PA hepatotoxicity was then tested in rats. Urine specimens were collected from 153 tuberculosis (TB) patients, and the results were evaluated to confirm whether a correlation existed between PZA metabolite concentrations and hepatotoxicity. This led to the hypothesis that coadministration of amidase inhibitor (bis-p-nitrophenyl phosphate [BNPP]) decreases or prevents PZA- and PZA metabolite-induced hepatotoxicity in rats. PA and 5-OH-PA are more toxic than PZA. Electron microscopy showed that PZA and PA treatment of rats significantly increases aspartate transaminase (AST) and alanine aminotransferase (ALT) activity and galactose single-point (GSP) levels (P < 0.005). PA and 5-OH-PA levels are also significantly correlated with hepatotoxicity in the urine of TB patients (P < 0.005). Amidase inhibitor, BNPP, decreases PZA-induced, but not PA induced, hepatotoxicity. This is the first report of a cell line, animal, and clinical trial confirming that the metabolite 5-OH-PA is responsible for PZA induced hepatotoxicity. PMID- 23357779 TI - Feasibility and effectiveness of a population-based newborn hearing screening in an economically deprived region of Italy. AB - AIM: To describe the effectiveness of a population-based newborn hearing screening program in an economically deprived region of southern Italy. METHODS: A screening protocol was proposed for all newborns of the Campania region, starting on January, 2007. For infants identified with hearing loss, information on degree and type of hearing loss and presence of risk factors was collected. RESULTS: The infants born in the 3-year study period were 182,188. Among them, 146,026 (80%) were tested with OAE. Sensorineural hearing loss >=40dBnHL was established for 159 infants (1.1*1000). Among the NICU and WIN infants, the rate of hearing loss was respectively 9*1000 and 0.67*1000. Follow-up information was available for 111 children (70%), as 48 (30%) got care in other regions or health facilities. Most infants were fitted hearing aids by 1 month after diagnosis and 15 children (13.5%) received a cochlear implant at a mean age of 25 months (SD 10). CONCLUSIONS: Even in a setting of population poverty, a universal newborn screening program can deliver satisfactory outcomes. The coverage and the tracking system of the program need to be improved, as well as the cooperation between public and private health services. PMID- 23357780 TI - A case study of the changes in the speech-evoked auditory brainstem response associated with auditory training in children with auditory processing disorders. AB - BACKGROUND: Studies related to plasticity and learning-related phenomena have primarily focused on higher-order processes of the auditory system, such as those in the auditory cortex and limited information is available on learning- and plasticity-related processes in the auditory brainstem. DESIGN AND METHOD: A clinical electrophysiological test of speech-evoked ABR known as BioMARK has been developed to evaluate brainstem responses to speech sounds in children with language learning disorders. Fast ForWord (FFW) was used as an auditory intervention program in the current study and pre- intervention and post intervention speech-evoked ABR (BioMARK) measures were compared in 2 school-aged children with auditory processing disorders (APD). RESULTS AND CONCLUSIONS: Significant changes were noted from pre-intervention to post-intervention and reflect plasticity in the auditory brainstem's neural activity to speech stimuli. PMID- 23357781 TI - Tongue base suspension in children with cerebral palsy and obstructive sleep apnea. AB - OBJECTIVE: Children with cerebral palsy (CP) are commonly affected by obstructive sleep apnea (OSA). This study examines the efficacy of combined surgical techniques for OSA including tongue base suspension (TBS), using perioperative polysomnograms (PSG) in pediatric patients with CP. STUDY DESIGN: Case series with outcome analysis. SETTING: University based tertiary care children's hospital. METHODS: A 7-year retrospective chart review of children with CP who underwent surgical management for OSA. Surgical procedures, postoperative complications, and perioperative PSG data were examined. Only patients with both preoperative and postoperative PSG results were included in the study. Based upon procedures performed patients fell into 2 equal groups for analysis. RESULTS: Fourteen children were identified. Seven patients (mean age = 6.0 years) underwent combined adenotonsillectomy (T&A), uvulopalatopharyngoplasty (UPPP), and tongue base suspension (TBS). Another 7 patients (mean age = 6.3 years) underwent T&A and UPPP alone. Those who received TBS had a mean preoperative AHI of 27.2 compared to 6.8 in the group that did not have TBS. The AHI decreased by a mean of 16.5 in the TBS group and 5.0 in the non-TBS group. The mean oxygen saturation nadir improved in both the TBS (74.0-84.0) and non-TBS (64.8-84.6) groups. The arousal index also improved in the TBS (33.1-20.7) and non-TBS (11.0 5.8) groups. No surgical complications occurred. CONCLUSION: This study suggests that concomitant surgical approaches for OSA in children with CP are effective. Moderate to severe OSA in this population may safely benefit from the added technique of tongue base suspension. PMID- 23357782 TI - Yeast and human RNA helicases involved in ribosome biogenesis: current status and perspectives. AB - Ribosome biogenesis is a fundamental process that is conserved in eukaryotes. Although spectacular progress has been made in understanding mammalian ribosome synthesis in recent years, by far, this process has still been best characterised in the yeast Saccharomyces cerevisiae. In yeast, besides the rRNAs, the ribosomal proteins and the 75 small nucleolar RNAs, more than 250 non-ribosomal proteins, generally referred to as trans-acting factors, are involved in ribosome biogenesis. These factors include nucleases, RNA modifying enzymes, ATPases, GTPases, kinases and RNA helicases. Altogether, they likely confer speed, accuracy and directionality to the ribosome synthesis process, however, the precise functions for most of them are still largely unknown. This review summarises our current knowledge on eukaryotic RNA helicases involved in ribosome biogenesis, particularly focusing on the most recent advances with respect to the molecular roles of these enzymes and their co-factors in yeast and human cells. This article is part of a Special Issue entitled: The Biology of RNA helicases Modulation for life. PMID- 23357783 TI - Regulation of gene expression in mammalian nervous system through alternative pre mRNA splicing coupled with RNA quality control mechanisms. AB - Eukaryotic gene expression is orchestrated on a genome-wide scale through several post-transcriptional mechanisms. Of these, alternative pre-mRNA splicing expands the proteome diversity and modulates mRNA stability through downstream RNA quality control (QC) pathways including nonsense-mediated decay (NMD) of mRNAs containing premature termination codons and nuclear retention and elimination (NRE) of intron-containing transcripts. Although originally identified as mechanisms for eliminating aberrant transcripts, a growing body of evidence suggests that NMD and NRE coupled with deliberate changes in pre-mRNA splicing patterns are also used in a number of biological contexts for deterministic control of gene expression. Here we review recent studies elucidating molecular mechanisms and biological significance of these gene regulation strategies with a specific focus on their roles in nervous system development and physiology. This article is part of a Special Issue entitled 'RNA and splicing regulation in neurodegeneration'. PMID- 23357784 TI - Probing the interactions between boronic acids and cis-diol-containing biomolecules by affinity capillary electrophoresis. AB - The affinity of boronic acids to cis-diol-containing biomolecules has found wide applications in many fields, such as sensing, separation, drug delivery, and functional materials. A sound understanding of the binding interactions will greatly facilitate exquisite applications of this chemistry. Although a few analytical tools have been available for the characterization of the interactions, these techniques are associated with some apparent drawbacks, so they are only applicable to a limited range of boronic acids and cis-diol containing biomolecules. Therefore, a widely applicable method is still greatly needed. In this work, an affinity capillary electrophoresis (ACE) method was established and validated to probe the interactions between boronic acids and cis diol-containing biomolecules. The method was proven to be applicable to almost all types of cis-diol-containing biomolecules and boronic acids. Based on this method, a quantitative, comparative study on the interactions between 14 boronic acids that have important potentials for application with 5 typical monosaccharides of biological importance was carried out. The findings provided new insights into boronate affinity interactions, particularly the relationship between the binding strength with the molecular structures of the binding species. Besides, effects of pH and temperature on the binding strength were also investigated. This method exhibited several significant advantages, including (1) possibility of simultaneous study of multiple interactions, (2) low requirement on the purity of the binding species, (3) wide applicability, and (4) high accuracy and precision. PMID- 23357785 TI - Protocatechuic acid suppresses ovalbumin-induced airway inflammation in a mouse allergic asthma model. AB - Protocatechuic acid (PCA) has been isolated from the leaves of ilex chinenses and has numerous pharmacologic effects, including anti-inflammatory and antitumoral activities. This study aims to evaluate the antiasthma activity of PCA and investigate its possible molecular mechanisms. BALB/c mice were sensitized and challenged to ovalbumin (OVA).Then mice were intraperitoneally (i.p.) injected with PCA 1h before OVA challenge. We found that PCA treatment at 15 or 30 mg/kg significantly decreased OVA-induced airway hyper-responsiveness (AHR) to inhaled methacholine. Type 2 helper T cell (Th2) cytokines in bronchoalveolar lavage (BAL) fluid, such as interleukin-4 (IL-4), interleukin 5 (IL-5) and interleukin 13 (IL-13), and serum OVA-specific immunoglobulin E (IgE) levels, were also reduced by PCA. Moreover treatment with PCA markedly decreased the number of inflammatory cells in BALF and attenuated OVA-induced mRNA expression of CCl11, CCR3, Muc5ac, acidic mammalian chitinase (AMCase), chitinase 3-like protein 4 (Ym2) and E-selectin in lung tissues, lung histopathological studies showed that PCA inhibited inflammatory cell infiltration and mucus hypersecretion compared with the OVA-induced mice group. We then investigated the possible molecular mechanisms which might be implicated in PCA activity. Our results suggested that the protective effect of PCA might be mediated by the inhibition of the extracellular signal-regulated protein kinase (ERK), p38 Mitogen-activated protein kinase (MAPK) phosphorylation and the nuclear factor-kappaB (NF-kappaB) activation. PMID- 23357786 TI - CpG oligodeoxynucleotide induces apoptosis and cell cycle arrest in A20 lymphoma cells via TLR9-mediated pathways. AB - Recent studies have suggested that the anti-cancer activity of CpG oligodeoxynucleotides (CpG-ODNs) is owing to their immunomodulatory effects in tumor-bearing host. The purpose of this study is to investigate the directly cytotoxic activity of KSK-CpG, a novel CpG-ODN with an alternative CpG motif, against A20 and EL4 lymphoma cells in comparison with previously used murine CpG motif (1826-CpG). To evaluate the potential cytotoxic effects of KSK-CpG on lymphoma cells, cell viability assay, confocal microscopy, flow cytometry, DNA fragmentation, Western blotting, and reverse transcription-polymerase chain reaction (RT-PCR) analysis were used. We found that KSK-CpG induced direct cytotoxicity in A20 lymphoma cells, but not in EL4 lymphoma cells, at least in part via TLR9-mediated pathways. Apoptotic cell death was demonstrated to play an important role in CpG-ODNs-induced cytotoxicity. In addition, both mitochondrial membrane potential decrease and G1-phase arrest were involved in KSK-CpG-induced apoptosis in A20 cells. The activities of apoptotic molecules such as caspase-3, PARP, and Bax were increased, but the activation of p27 Kip1 and ERK were decreased in KSK-CpG-treated A20 cells. Furthermore, autocrine IFN-gamma partially contributed to apoptotic cell death in KSK-CpG-treated A20 cells. Collectively, our findings suggest that KSK-CpG induces apoptotic cell death in A20 lymphoma cells at least in part by inducing G1-phase arrest and autocrine IFN gamma via increasing TLR9 expression, without the need for immune system of tumor bearing host. This new understanding supports the development of TLR9-targeted therapy with CpG-ODN as a direct therapeutic agent for treating B lymphoma. PMID- 23357787 TI - Characterization of human anti-heat shock protein 60 monoclonal autoantibody Fab fragments in atherosclerosis: genetic and functional analysis. AB - Heat shock protein 60 (HSP60) is an important autoantigen in atherosclerosis. The genetic structures and pathogenic roles of anti-HSP60 autoantibodies, however, have not been well elucidated. Here, we cloned nine monoclonal IgG Fabs against human HSP60 from peripheral blood lymphocytes of atherosclerosis patients. Analysis of the variable region sequences revealed that the antibodies used diverse members of V(H) gene families with different D(H) and J(H) segments. However, in V(L), KV3-20 gene family member along with KJ1 segment was used often. Similarities between the rearranged genes and the closest germline sequences were low. The sequences of V(H) were highly mutated and V(H)-CDR3 varied greatly in length and sequences. The ratios of R/S (replacement mutation to silent mutation) were remarkably high in CDRs in all V(H) regions except one clone. Furthermore, mutations to positively charged amino acids were frequent in all V(H) and most V(L). These results suggest that the occurrence of somatic hypermutation and antigenic selection is critical, not the usage of certain V(H) gene family members or segments, in producing affinity-matured anti-HSP60 autoantibodies in atherosclerosis. However, expression of the combined germline genes of KV3-20 with KJ1 might be important for the selection by HSP60 at the early stage of B cell development. Two of these anti-HSP60 Fabs inhibited the binding and uptake of human HSP60 by murine macrophage cells. One of them also reduced the release of the pro-inflammatory mediators and inhibited the activation of NF-kappaB in HSP60-stimulated macrophages. To elucidate the functional roles of anti-HSP60 autoantibodies in atherosclerosis and the potential use of these Fabs to treat atherosclerosis, further investigation is worthy to be performed. PMID- 23357788 TI - Furanodien-6-one from Commiphora erythraea inhibits the NF-kappaB signalling and attenuates LPS-induced neuroinflammation. AB - We investigated the in vitro anti-inflammatory activity of 1(10),4-furanodien-6 one, one the most active compounds of the hexane extract of Commiphora erythraea (Ehrenb.) Engl., by exposing microglial BV-2 cells to lipopolysaccharide. We showed that furanodien-6-one pre-treatment restored cell viability and ROS to control levels while halving NO generation. Production of pro-inflammatory IL-6, IL-23, IL-17, TGF-beta, and INF-gamma, significantly induced by LPS, was also markedly reduced by furanodien-6-one treatment. We further showed that furanodien 6-one protects primary neuronal cultures against the inflammatory/toxic insults of LPS-treated BV-2 conditioned media, indicating that furanodien-6-one exerts anti-inflammatory/cytoprotective effects in neuronal cells. We then investigated whether furanodien-6-one exerts anti-inflammatory properties in an in vivo model of microglial activation. In adult mice ip-injected with LPS we found that furanodien-6-one had strong cerebral anti-inflammatory properties by inhibiting liver and brain TNFalpha as well as IL-1beta expression. Results were not unexpected since FTIR-metabolomic analyses showed that furanodien-6-one-treated mice had a reduced dissimilarity to control animals and that the response to LPS treatment was markedly modified by furanodien-6-one. In conclusion our data provide strong evidence of the anti-inflammatory properties of furanodien-6-one that could be exploited to counteract degenerative pathologies based on neuroinflammation. PMID- 23357789 TI - Characterization of a novel CRAC inhibitor that potently blocks human T cell activation and effector functions. AB - Store operated calcium entry (SOCE) downstream of T cell receptor (TCR) activation in T lymphocytes has been shown to be mediated mainly through the Calcium Release Activated Calcium (CRAC) channel. Here, we compared the effects of a novel, potent and selective CRAC current inhibitor, 2,6-Difluoro-N-{5-[4 methyl-1-(5-methyl-thiazol-2-yl)-1,2,5,6-tetrahydro-pyridin-3-yl]-pyrazin-2-yl} benzamide (RO2959), on T cell effector functions with that of a previously reported CRAC channel inhibitor, YM-58483, and a calcineurin inhibitor Cyclosporin A (CsA). Using both electrophysiological and calcium-based fluorescence measurements, we showed that RO2959 is a potent SOCE inhibitor that blocked an IP3-dependent current in CRAC-expressing RBL-2H3 cells and CHO cells stably expressing human Orai1 and Stim1, as well as SOCE in human primary CD4(+) T cells triggered by either TCR stimulation or thapsigargin treatment. Furthermore, we demonstrated that RO2959 completely inhibited cytokine production as well as T cell proliferation mediated by TCR stimulation or MLR (mixed lymphocyte reaction). Lastly, we showed by gene expression array analysis that RO2959 potently blocked TCR triggered gene expression and T cell functional pathways similar to CsA and another calcineurin inhibitor FK506. Thus, both from a functional and transcriptional level, our data provide evidence that RO2959 is a novel and selective CRAC current inhibitor that potently inhibits human T cell functions. PMID- 23357790 TI - The spatial and temporal regulation of the hormonal signal. Role of mitochondria in the formation of a protein complex required for the activation of cholesterol transport and steroids synthesis. AB - The mitochondria are critical for steroidogenesis since the ability of cholesterol to move into mitochondria to be available for cytochrome P450, CYP11A1, determines the efficacy of steroid production. Several proteins kinases, such as PKA, MEK and ERK which are essential to complete steroidogenesis, form a mitochondria-associated complex. The protein-protein interactions between kinases and key factors during the transport of cholesterol takes place in the contact sites between the two mitochondrial membranes; however, no mitochondrial targeting sequence has been described for these kinases. Here we discuss the possibility that mitochondrial reorganization may be mediating a compartmentalized cellular response. This reorganization could allow the physical interaction between the hormone-receptor complex and the enzymatic and lipidic machinery necessary for the complete steroid synthesis and release. The movement of organelles in specialized cells could impact on biological processes that include, but are not limited to, steroid synthesis. PMID- 23357791 TI - A statistical comparison of protein and carbohydrate characterisation methodology applied on sewage sludge samples. AB - Biochemical characterization of organic matter is becoming of key importance in wastewater treatment. The main objectives are to predict organic matter properties, such as granulation or flocculation, and hence treatment performance. Although standardized methods do exist for some organic molecules, such as volatile fatty acids or lipids, there are no standard methods to measure proteins and carbohydrates content, both biochemical families being the main components of sewage sludge. Consequently, the aim of the present work is to investigate the efficiency of several colorimetric methods to determine proteins and carbohydrates content as well as their compatibility with the sludge matrices. The different methods have been evaluated based on statistical criteria such as sensitivity, linearity, accuracy, rightness, and specificity using standard molecules such as Bovine Serum Albumin (BSA), glucose, cellulose and a certified reference product. The Lowry and the Dubois methods have been shown to be the best compromise for the considered criteria after having been tested on sewage sludge samples obtained from different locations in a wastewater treatment plant. In average, the measured volatile fatty acids, lipids, proteins and carbohydrates contents represented 80 +/- 7% (% volatile solids) of the organic matter. Proteins and carbohydrates represented in average 69 +/- 3%. This study underlined that the choice of a relevant methodology is of great importance for organic matter measurement. PMID- 23357792 TI - Molecular-based investigation of Cryptosporidium and Giardia from animals in water catchments in southeastern Australia. AB - There has been no large-scale systematic molecular epidemiological investigation of the waterborne protozoans, Cryptosporidium or Giardia, in southeastern Australia. Here, we explored, for the first time, the genetic composition of these genera in faecal samples from animals in nine Melbourne Water reservoir areas, collected over a period of two-years. We employed PCR-based single-strand conformation polymorphism (SSCP) and phylogenetic analyses of loci (pSSU and pgp60) in the small subunit (SSU) of ribosomal RNA and 60-kDa glycoprotein (gp60) genes to detect and characterise Cryptosporidium, and another locus (ptpi) in the triose-phosphate isomerase (tpi) gene to identify and characterise Giardia. Cryptosporidium was detected in 2.8% of the 2009 samples examined; the analysis of all amplicons defined 14 distinct sequence types for each of pSSU and pgp60, representing Cryptosporidium hominis (genotype Ib - subgenotype IbA10G2R2), Cryptosporidium parvum (genotype IIa - subgenotypes IIaA15G2R1, IIaA19G2R1, IIaA19G3R1, IIaA19G4R1, IIaA20G3R1, IIaA20G4R1, IIaA20G3R2 and IIaA21G3R1), Cryptosporidium cuniculus (genotype Vb - subgenotypes VbA22R4, VbA23R3, VbA24R3, VbA25R4 and VbA26R4), and Cryptosporidium canis, Cryptosporidium fayeri, Cryptosporidium macropodum and Cryptosporidium ubiquitum as well as six new pSSU sequence types. In addition, Giardia was identified in 3.4% of the samples; all 28 distinct ptpi sequence types defined were linked to assemblage A of Giardia duodenalis. Of all 56 sequence types characterised, eight and one have been recorded previously in Cryptosporidium and Giardia, respectively, from humans. In contrast, nothing is known about the zoonotic potential of 35 new genotypes of Cryptosporidium and Giardia recorded here for the first time. Future work aims to focus on estimating the prevalence of Cryptosporidium and Giardia genotypes in humans and a wide range of animals in Victoria and elsewhere in Australia. (Nucleotide sequences reported in this paper are available in the GenBank database under accession nos. KC282952-KC283005). PMID- 23357793 TI - Altered innate function of plasmacytoid dendritic cells restored by enzyme replacement therapy in Gaucher disease. AB - BACKGROUND: Gaucher disease (GD) is caused by an autosomal-recessive deficiency of beta-glucocerebrosidase leading to an accumulation of glucosylceramide in monocytes/macrophage lineage. We analyzed immune cells and especially the function of dendritic cells to evaluate the potential impact of glucosylceramide accumulation in these cells and its possible role in infections and malignancies usually described in this pathology. These analyses were performed for each patient without and under enzyme replacement therapy. METHODS: Seven GD patients were studied and compared with healthy volunteers. Immune cells (B cells, T cells, NK, dendritic cells), were analyzed by flow cytometry directly on whole blood. Cytokine production by blood dendritic cells was assessed after stimulation by toll-like receptor ligands. Cytokines in sera were measured using a multiplex assay. RESULTS: GD patients displayed decreased numbers of NK cells, gammadelta2 T cells and increased frequency of memory CD4(+)CD45RO(+) T cells, when compared to healthy controls. Numbers of dendritic cells (myeloid (mDC) and plasmacytoid (pDC) dendritic cells) were also decreased. We demonstrated that pDC from GD patients exhibited a decrease in IFNalpha production after TLR9 stimulation compared to controls. Importantly, enzyme replacement therapy restored pDC function. Finally, we observed an increase of IL-8 and IL-18 in GD patient sera, which were reduced under enzyme replacement therapy. CONCLUSIONS: Our data confirm that patients with GD exhibit altered numbers of innate and T lymphocytes and show for the first time that pDC from GD patients exhibit altered responsiveness to TLR9. These alterations could contribute to a decreased response to pathogens and could favor the development of malignancies. PMID- 23357794 TI - A cortical folding model incorporating stress-dependent growth explains gyral wavelengths and stress patterns in the developing brain. AB - In humans and many other mammals, the cortex (the outer layer of the brain) folds during development. The mechanics of folding are not well understood; leading explanations are either incomplete or at odds with physical measurements. We propose a mathematical model in which (i) folding is driven by tangential expansion of the cortex and (ii) deeper layers grow in response to the resulting stress. In this model the wavelength of cortical folds depends predictably on the rate of cortical growth relative to the rate of stress-induced growth. We show analytically and in simulations that faster cortical expansion leads to shorter gyral wavelengths; slower cortical expansion leads to long wavelengths or even smooth (lissencephalic) surfaces. No inner or outer (skull) constraint is needed to produce folding, but initial shape and mechanical heterogeneity influence the final shape. The proposed model predicts patterns of stress in the tissue that are consistent with experimental observations. PMID- 23357795 TI - Preparation of molecularly imprinted resin based on chitosan for chiral recognition of S-mandelic acid. AB - An enantioselective S-mandelic acid (S-MA) imprinted chitosan (SMIC) was prepared by cross-linking of chitosan using formaldehyde cross-linker, in the presence of S-MA as an imprint template molecule and 0.5% acetic acid solution as a solvent. Non-imprinted cross-linked chitosan (NIC) as control was also prepared by the same procedure in absence of template molecules. The surface morphology of both SMIC and NIC were examined by scanning electron microscope (SEM). SMIC particles were applied to determine the optimum operational condition for S-MA separation from dilute aqueous solution. In adsorption step, optimum pH and retention time were 3.5 and 60 min, while corresponding values in extraction step were 1 and 40 min, respectively. Also, the adsorption isotherms indicated that the maximum adsorption capacities of S- and R-MA on SMIC were 100 +/- 0.5 and 64 +/- 0.8 mg/g, respectively, while in the case of NIC, both R- and S-MA present the same maximum adsorption. PMID- 23357796 TI - Antioxidant activity of polysaccharide fractions extracted from Athyrium multidentatum (Doll.) Ching. AB - Crude polysaccharides were extracted from Athyrium multidentatum (Doll.) Ching (AMC) rhizome and fractionated by DEAE-Cellulose 52 ion-exchange column chromatography. Two polysaccharide fractions (F1 and F2) were obtained and had their antioxidant activities investigated employing various established in vitro systems. All fractions possessed considerable antioxidant activity. Chemical analysis suggested that F1 and F2 were neutral heteropolysaccharide in which glucose was the major component. Available data suggested that the molecular weight and sulfate content played very important roles on antioxidant activity. Our results indicated that the polysaccharides may contribute to the medicinal functions of AMC. PMID- 23357797 TI - Enzymatic production and characterization of manno-oligosaccharides from Gleditsia sinensis galactomannan gum. AB - Enzymatic hydrolysis of Gleditsia sinensis gum was performed to produce manno oligosaccharides having functional applications as dietary fiber and prebiotics. The optimum hydrolysis conditions, including enzyme loading, temperature and time, from response surface methodology were 8.1 U/g, 57.4 degrees C and 34.1 h, respectively. The yield of DP 1-5 oligosaccharides was 75.9% (29.1 g/L). The Michaelis-Menten kinetics and molecular weight distribution were determined. The obtained oligosaccharides were further separated by HPLC and SEC, and the galactose distribution of G. sinensis gum was elucidated. Results indicated that G. sinensis gum has potential to produce value-added oligosaccharides in food industries. PMID- 23357798 TI - Impact of alpha-amylase combined with hydrochloric acid hydrolysis on structure and digestion of waxy rice starch. AB - The structure and in vitro digestibility of native waxy rice starch by the combined hydrolysis of alpha-amylase and hydrochloric acid were investigated in this study. The combined hydrolysis technique generated higher hydrolysis rate and extent than the enzymatic hydrolysis. The granular appearance and chromatograph profile demonstrated that alpha-amylase and hydrochloric acid exhibited different patterns of hydrolysis. The rise in the ratio of absorbance 1047/1022cm(-1), the melting temperature range (Tc-To), and the melting enthalpy (DeltaH) were observed during the combined hydrolysis. These results suggest that alpha-amylase simultaneously cleaves the amorphous and crystalline regions, whereas the amorphous regions of starch granules are preferentially hydrolyzed during the acid hydrolysis. Furthermore, the combined hydrolysis increased rapidly digestible starch (RDS) while decreased slowly digestible starch (SDS) and resistant starch (RS), indicating that the hydrolysis mode affected the digestion property of native waxy rice starch. PMID- 23357800 TI - Aronia melanocarpa as a protector against nitration of fibrinogen. AB - Fibrinogen (Fg) also known as coagulation factor I represents about 4% of the total human plasma proteins. The main function of Fg is its involvement in last phase of blood coagulation cascade, when thrombin-induced conversion of dissolved plasma fibrinogen into an insoluble fibrin clot occurs. The reaction of fibrinogen with peroxynitrite causes both structural modifications and changes of the biological properties of this plasma glycoprotein. Recently, there is an increased interest in the screening of natural products present in fruits, vegetables and herbs for their possible antioxidative activities. Therefore, the aim of our study was to estimate the effect of extract from berries of Aronia melanocarpa against nitrative and oxidative damage induced by peroxynitrite. The extract from A. melanocarpa (0.5-50 MUg/ml) added to Fg 10 min before peroxynitrite (100 MUM) significantly inhibited both the formation of the high molecular weight protein aggregates and nitration of Fg molecule. The extract also abolished peroxynitrite-induced inhibition of fibrinogen polymerization (by 95% at 50 MUg/ml). The obtained results indicate that natural extract from berries of A. melanocarpa has protective effects against peroxynitrite-induced nitrative damage of plasma fibrinogen, and therefore may contribute in the prevention of peroxynitrite-related cardiovascular or inflammatory diseases. PMID- 23357799 TI - Enzymatically cross-linked alginic-hyaluronic acid composite hydrogels as cell delivery vehicles. AB - An injectable composite gel was developed from alginic and hyaluronic acid. The enzymatically cross-linked injectable gels were prepared via the oxidative coupling of tyramine modified sodium algiante and sodium hyaluronate in the presence of horse radish peroxidase (HRP) and hydrogen peroxide (H2O2). The composite gels were prepared by mixing equal parts of the two tyraminated polymer solutions in 10U HRP and treating with 1.0% H2O2. The properties of the alginate gels were significantly affected by the addition of hyaluronic acid. The percentage water absorption and storage modulus of the composite gels were found to be lower than the alginate gels. The alginate and composite gels showed lower protein release compared to hyaluronate gels in the absence of hyaluronidase. Even hyaluronate gels showed only approximately 10% protein release after 14 days incubation in phosphate buffer solution. ATDC-5 cells encapsulated in the injectable gels showed high cell viability. The composite gels showed the presence of enlarged spherical cells with significantly higher metabolic activity compared to cells in hyaluronic and alginic acid gels. The results suggest the potential of the composite approach to develop covalently cross-linked hydrogels with tuneable physical, mechanical, and biological properties. PMID- 23357801 TI - Does controlling for the magnitude of tonic EMG activity decrease the variability in the cVEMP measures? PMID- 23357802 TI - The effect of muscle contraction level on the cervical vestibular evoked myogenic potential (cVEMP): usefulness of amplitude normalization. AB - BACKGROUND: The cervical vestibular evoked myogenic potential (cVEMP) is a reflexive change in sternocleidomastoid (SCM) muscle contraction activity thought to be mediated by a saccular vestibulo-collic reflex. CVEMP amplitude varies with the state of the afferent (vestibular) limb of the vestibulo-collic reflex pathway, as well as with the level of SCM muscle contraction. It follows that in order for cVEMP amplitude to reflect the status of the afferent portion of the reflex pathway, muscle contraction level must be controlled. Historically, this has been accomplished by volitionally controlling muscle contraction level either with the aid of a biofeedback method, or by an a posteriori method that normalizes cVEMP amplitude by the level of muscle contraction. A posteriori normalization methods make the implicit assumption that mathematical normalization precisely removes the influence of the efferent limb of the vestibulo-collic pathway. With the cVEMP, however, we are violating basic assumptions of signal averaging: specifically, the background noise and the response are not independent. The influence of this signal-averaging violation on our ability to normalize cVEMP amplitude using a posteriori methods is not well understood. PURPOSE: The aims of this investigation were to describe the effect of muscle contraction, as measured by a prestimulus electromyogenic estimate, on cVEMP amplitude and interaural amplitude asymmetry ratio, and to evaluate the benefit of using a commonly advocated a posteriori normalization method on cVEMP amplitude and asymmetry ratio variability. RESEARCH DESIGN: Prospective, repeated measures design using a convenience sample. STUDY SAMPLE: Ten healthy adult participants between 25 and 61 yr of age. INTERVENTION: cVEMP responses to 500 Hz tone bursts (120 dB pSPL) for three conditions describing maximum, moderate, and minimal muscle contraction. DATA COLLECTION AND ANALYSIS: Mean (standard deviation) cVEMP amplitude and asymmetry ratios were calculated for each muscle contraction condition. Repeated measures analysis of variance and t-tests compared the variability in cVEMP amplitude between sides and conditions. Linear regression analyses compared asymmetry ratios. Polynomial regression analyses described the corrected and uncorrected cVEMP amplitude growth functions. RESULTS: While cVEMP amplitude increased with increased muscle contraction, the relationship was not linear or even proportionate. In the majority of cases, once muscle contraction reached a certain "threshold" level, cVEMP amplitude increased rapidly and then saturated. Normalizing cVEMP amplitudes did not remove the relationship between cVEMP amplitude and muscle contraction level. As muscle contraction increased, the normalized amplitude increased, and then decreased, corresponding with the observed amplitude saturation. Abnormal asymmetry ratios (based on values reported in the literature) were noted for four instances of uncorrected amplitude asymmetry at less than maximum muscle contraction levels. Amplitude normalization did not substantially change the number of observed asymmetry ratios. CONCLUSIONS: Because cVEMP amplitude did not typically grow proportionally with muscle contraction level, amplitude normalization did not lead to stable cVEMP amplitudes or asymmetry ratios across varying muscle contraction levels. Until we better understand the relationships between muscle contraction level, surface electromyography (EMG) estimates of muscle contraction level, and cVEMP amplitude, the application of normalization methods to correct cVEMP amplitude appears unjustified. PMID- 23357803 TI - Style preference survey: a report on the psychometric properties and a cross validation experiment. AB - BACKGROUND: Several self-report measures exist that target different aspects of outcomes for hearing aid use. Currently, no comprehensive questionnaire specifically assesses factors that may be important for differentiating outcomes pertaining to hearing aid style. PURPOSE: The goal of this work was to develop the Style Preference Survey (SPS), a questionnaire aimed at outcomes associated with hearing aid style differences. Two experiments were conducted. After initial item development, Experiment 1 was conducted to refine the items and to determine its psychometric properties. Experiment 2 was designed to cross-validate the findings from the initial experiment. RESEARCH DESIGN: An observational design was used in both experiments. STUDY SAMPLE: Participants who wore traditional, custom-fitted (TC) or open-canal (OC) style hearing aids from 3 mo to 3 yr completed the initial experiment. One-hundred and eighty-four binaural hearing aid users (120 of whom wore TC hearing aids and 64 of whom wore OC hearing aids) participated. A new sample of TC and OC users (n = 185) participated in the cross validation experiment. DATA COLLECTION AND ANALYSIS: Currently available self report measures were reviewed to identify items that might differentiate between hearing aid styles, particularly preference for OC versus TC hearing aid styles. A total of 15 items were selected and modified from available self-report measures. An additional 55 items were developed through consensus of six audiologists for the initial version of the SPS. In the first experiment, the initial SPS version was mailed to 550 veterans who met the inclusion criteria. A total of 184 completed the SPS. Approximately three weeks later, a subset of participants (n = 83) completed the SPS a second time. Basic analyses were conducted to evaluate the psychometric properties of the SPS including subscale structure, internal consistency, test-retest reliability, and responsiveness. Based on the results of Experiment 1, the SPS was revised. A cross-validation experiment was then conducted using the revised version of the SPS to confirm the subscale structure, internal consistency, and responsiveness of the questionnaire in a new sample of participants. RESULTS: The final factor analysis led to the ultimate version of the SPS, which had a total of 35 items encompassing five subscales: (1) Feedback, (2) Occlusion/Own Voice Effects, (3) Localization, (4) Fit, Comfort, and Cosmetics, and (5) Ease of Use. The internal consistency of the total SPS (Cronbach's alpha = .92) and of the subscales (each Cronbach's alpha > .75) was high. Intraclass correlations (ICCs) showed that the test-retest reliability of the total SPS (ICC = .93) and of the subscales (each ICC > .80) also was high. TC hearing aid users had significantly poorer outcomes than OC hearing aid users on 4 of the 5 subscales, suggesting that the SPS largely is responsive to factors related to style-specific differences. CONCLUSIONS: The results suggest that the SPS has good psychometric properties and is a valid and reliable measure of outcomes related to style-specific, hearing aid preference. PMID- 23357804 TI - The contribution of a frequency-compression hearing aid to contralateral cochlear implant performance. AB - BACKGROUND: Frequency-lowering signal processing in hearing aids has re-emerged as an option to improve audibility of the high frequencies by expanding the input bandwidth. Few studies have investigated the usefulness of the scheme as an option for bimodal users (i.e., combined use of a cochlear implant and a contralateral hearing aid). In this study, that question was posed. PURPOSE: The purposes of this study were (1) to determine if frequency compression was a better bimodal option than conventional amplification and (2) to determine the impact of a frequency-compression hearing aid on speech recognition abilities. RESEARCH DESIGN: There were two separate experiments in this study. The first experiment investigated the contribution of a frequency-compression hearing aid to contralateral cochlear implant (CI) performance for localization and speech perception in noise. The second experiment assessed monaural consonant and vowel perception in quiet using the frequency-compression and conventional hearing aid without the use of a contralateral CI or hearing aid. STUDY SAMPLE: Ten subjects fitted with a cochlear implant and hearing aid participated in the first experiment. Seventeen adult subjects with a cochlear implant and hearing aid or two hearing aids participated in the second experiment. To be included, subjects had to have a history of postlingual deafness, a moderate or moderate-to-severe hearing loss, and have not worn this type of frequency-lowering hearing aid previously. DATA COLLECTION AND ANALYSIS: In the first experiment, performance using the frequency-compression and conventional hearing aids was assessed on tests of sound localization, speech perception in a background of noise, and two self-report questionnaires. In the second experiment, consonant and vowel perception in quiet was assessed monaurally for the two conditions. In both experiments, subjects alternated daily between a frequency-compression and conventional hearing aid for 2 mo. The parameters of frequency compression were set individually for each subject, and audibility was measured for the frequency compression and conventional hearing aid programs by comparing estimations of the Speech Intelligibility Index (SII) using a modified algorithm (Bentler et al, 2011). In both experiments, the outcome measures were administered following the hearing aid fitting to assess performance at baseline and after 2 mo of use. RESULTS: For this group of subjects, the results revealed no significant difference between the frequency-compression and conventional hearing aid on tests of localization and consonant recognition. Spondee-in-noise and vowel perception scores were significantly higher with the conventional hearing aid compared to the frequency-compression hearing aid after 2 mo of use. CONCLUSIONS: These results suggest that, for the subjects in this study, frequency compression is not a better bimodal option than conventional amplification. In addition, speech perception may be negatively influenced by frequency compression because formant frequencies are too severely compressed and can no longer be distinguished. PMID- 23357805 TI - Validation of the Parents' Evaluation of Aural/Oral Performance of Children (PEACH) Rating Scale. AB - BACKGROUND: The Parents' Evaluation of Aural/Oral Performance of Children (PEACH) is a caregiver report questionnaire that is suitable for use with children who wear hearing aids. It is available in both a Diary format and a Rating Scale format. Following a critical review of subjective outcome evaluation tools for infants, toddlers, and preschool children (Bagatto, Moodie, Seewald et al, 2011), the Rating Scale version of the PEACH was included in a recently developed guideline for monitoring real-world auditory performance of children who have hearing loss (Bagatto, Moodie, Malandrino et al, 2011). Normative data exist only for the PEACH Diary, not the Rating Scale. PURPOSE: This article evaluates whether published normative data for the PEACH Diary (Ching and Hill, 2007) are replicated on a different sample of children using the PEACH Rating Scale. RESEARCH DESIGN: Fifty-nine children with normal hearing aged 2 mo to 83 mo and their primary caregivers participated in the study. Caregivers completed the PEACH Rating Scale for each child with normal hearing. RESULTS: Results indicated close agreement to existing normative data collected with the PEACH Diary, with no differences in scores between males and females and good internal consistency. Age-related trends published for the Diary version were replicated using the Rating Scale version, as significantly lower scores were observed for children 20 mo of age and younger compared to those older than 20 mo of age. CONCLUSIONS: The currently published norms for the PEACH Diary are valid for use with the PEACH Rating Scale with caregivers of normal hearing children. This validation work adds to the evidence base of the PEACH Rating Scale and supports its use in clinical practice. PMID- 23357806 TI - Comparison of multichannel wide dynamic range compression and ChannelFree processing in open canal hearing instruments. AB - BACKGROUND: Multichannel wide dynamic range compression (WDRC) and ChannelFree processing have similar goals yet differ significantly in terms of signal processing. Multichannel WDRC devices divide the input signal into separate frequency bands; a separate level is determined within each frequency band; and compression in each band is based on the level within each band. ChannelFree processing detects the wideband level, and gain adjustments are based on the wideband signal level and adjusted up to 20,000 times per second. Although both signal processing strategies are currently available in hearing aids, it is unclear if differences in these signal processing strategies affect the performance and/or preference of the end user. PURPOSE: The purpose of the research was to determine the effects of multichannel wide dynamic range compression and ChannelFree processing on performance and/or preference of listeners using open-canal hearing instruments. RESEARCH DESIGN: An experimental study in which subjects were exposed to a repeated measures design was utilized. STUDY SAMPLE: Fourteen adult listeners with mild sloping to moderately severe sensorineural hearing loss participated (mean age 67 yr). DATA COLLECTION AND ANALYSIS: Participants completed two 5 wk trial periods for each signal processing strategy. Probe microphone, behavioral and subjective measures were conducted unaided and aided at the end of each trial period. RESULTS: Behavioral and subjective results for both signal processing strategies were significantly better than unaided results; however, behavioral and subjective results were not significantly different between the signal processing strategies. CONCLUSIONS: Multichannel WDRC and ChannelFree processing are both effective signal processing strategies that provide significant benefit for hearing instrument users. Overall preference between the strategies may be related to the degree of hearing loss of the user, high-frequency in-situ levels, and/or acceptance of background noise. PMID- 23357807 TI - An initial-fit comparison of two generic hearing aid prescriptive methods (NAL NL2 and CAM2) to individuals having mild to moderately severe high-frequency hearing loss. AB - BACKGROUND: Johnson and Dillon (2011) provided a model-based comparison of current generic hearing aid prescriptive methods for adults with hearing loss based on the attributes of speech intelligibility, loudness, and bandwidth. PURPOSE: This study compared the National Acoustic Laboratories-Non-linear 2 (NAL NL2) and Cambridge Method for Loudness Equalization 2-High-Frequency (CAM2) prescriptive methods using adult participants with less high-frequency hearing loss than Johnson and Dillon (2011). Of study interest was quantification of prescribed audibility, speech intelligibility, and loudness. The preferences of participants for either NAL-NL2 or CAM2 and preferred deviations from prescribed settings are also reported. RESEARCH DESIGN: Using a single-blind, counter balanced, randomized design, preference judgments for the prescriptive methods with regard to sound quality of speech and music stimuli were obtained. Preferred gain adjustments from the prescription within the 4-10 kHz frequency range were also obtained from each participant. Speech intelligibility and loudness model calculations were completed on the prescribed and adjusted amplification. STUDY SAMPLE: Fourteen male Veterans, whose average age was 65 yr and whose hearing sensitivity averaged normal to borderline normal through 1000 Hz sloping to a moderately severe sensorineural loss, served as participants. DATA COLLECTION AND ANALYSIS: Following a brief listening time (~10 min), typical of an initial fitting visit, the participants made paired comparison of sound quality between the NAL-NL2 and CAM2 prescriptive settings. Participants were also asked to modify each prescription in the range of 4-10 kHz using an overall gain control and make subsequent comparisons of sound quality preference between prescriptive and adjusted settings. Participant preferences were examined with respect to quantitative analysis of loudness modeling, speech intelligibility modeling, and measured high-frequency bandwidth audibility. RESULTS: Consistent with the lack of difference in predicted speech intelligibility between the two prescriptions, sound quality preferences on the basis of clarity were split across participants while some participants did not have a discernable preference. Considering sound quality judgments of pleasantness, the majority of participants preferred the sound quality of the NAL-NL2 (8 of 14) prescription instead of the CAM2 prescription (2 of 14). Four of the 14 participants showed no preference on the basis of pleasantness for either prescription. Individual subject preferences were supported by loudness modeling that indicated NAL-NL2 was the softer of the two prescriptions and CAM2 was the louder. CAM2 did provide more audibility to the higher frequencies (5-8 kHz) than NAL-NL2. Participants turned the 4-10 kHz gain recommendation of CAM2 lower, on average, by a significant amount of 4 dB when making adjustments while no significant adjustment was made to the initial NAL-NL2 recommendation. CONCLUSIONS: NAL-NL2 prescribed gains were more often preferred at the initial fitting by the majority of participating veterans. For those patients with preference for a louder fitting than NAL-NL2, CAM2 is a good alternative. When the participant adjustment from the prescription between 4 and 10 kHz exceeded 4 dB from either NAL-NL2 (2 of 14) or CAM2 (11 of 14), the participants demonstrated a later preference for that adjustment 69% of the time. These findings are viewed as limited evidence that some individuals may have a preference for high-frequency gain that differs from the starting prescription. PMID- 23357808 TI - Sedentary and active: self-reported sitting time among marathon and half-marathon participants. AB - BACKGROUND: Emerging evidence suggests that combined physical activity (PA) and inactivity may be more important for chronic disease risk than PA alone. A highly active yet highly sedentary population is needed to study this interaction. The present purpose is to describe the sitting habits of a group of recreational runners and determine if sitting varies with reported training duration or anticipated running velocity. METHODS: Marathon and half-marathon participants completed the Multicontext Sitting Time Questionnaire and reported peak training duration, anticipated finishing time, and demographic information. Sitting time was described across 5 contexts for workdays and nonworkdays. Total sitting time was analyzed by tertiles of training duration and anticipated event running velocity. RESULTS: 218 participants took part in this study. Median reported training time was 6.5 hours per week. Median total sitting time was higher on workdays than nonworkdays (645 and 480 minutes, respectively, P < .0001). Total sitting time was not associated with training duration or anticipated event running velocity. CONCLUSIONS: These results suggest that recreational distance runners are simultaneously highly sedentary and highly active, supporting independence of sedentary behaviors and moderate- to vigorous-intensity PA. This population may provide the characteristics needed to study the joint effects of active and sedentary behaviors on health outcomes. PMID- 23357809 TI - Free-standing poly(2-vinylpyridine) foam films doped with silver nanoparticles formed at the planar liquid/liquid interface. AB - Free-standing films of poly(2-vinylpyridine) doped with Ag(+) ions were fabricated at the planar liquid/liquid interface of an aqueous solution of AgNO(3) and a chloroform solution of the polymer through adsorption of the polymer molecules, combination with Ag(+) ions, and self-assembly of the composite species. Transmission electron microscopic (TEM) investigations indicated that the films were composed of planar thin layers decorated with separated microcapsules and foam structures of conglutinated microcapsules, and no Ag nanoparticles formed in the pristine films. After UV-light irradiation and KBH(4) aqueous solution treatment, Ag nanoparticles with the average size of 3.2 nm appeared and incorporated in the polymer matrices. X-ray photoelectron spectra (XPS) and UV-vis spectra are consistent with the TEM observations. Thermogravimetric analysis (TGA) showed good thermal stability of the composite films. The silver content was estimated to be 24.0% from the TG curve, closing to the calculated value. The catalytic performance of the composite films was evaluated by using the reduction of nitro-compounds, including nitrobenzene, 4 nitrophenol, and 4-nitrobenzoic acid by KBH(4) in aqueous solutions. The results indicated that the composite films have high and durable catalytic activity. The apparent reaction constants are related to the size of the nitro-compounds, suggesting that the Ag nanoparticles were incorporated in the matrices, and the diffusion of the reactant molecules has a great influence on the catalytic reaction. PMID- 23357810 TI - Purification and use of E. coli peptide deformylase for peptide deprotection in chemoenzymatic peptide synthesis. AB - Peptide deformylases (PDFs) catalyze the removal of the formyl group from the N terminal methionine residue in nascent polypeptide chains in prokaryotes. Its deformylation activity makes PDF an attractive candidate for the biocatalytic deprotection of formylated peptides that are used in chemoenzymatic peptide synthesis. For this application it is essential to use PDF preparations that are free of contamination by peptidases that can cleave internal peptide bonds. Therefore, different purification methods were attempted and an industrially applicable purification procedure was developed based on a single anion-exchange chromatography step of an engineered PDF variant that was equipped with an anionic octaglutamate tag. The deformylation activity and stability of the engineered enzyme were similar to those of the wild-type PDF. This purification method furnished a PDF preparation with a 1500-fold decreased level of contamination by amidases and peptidases as compared to cell-free extract. It was shown that the enzyme could be used for deprotection of a formylated dipeptide that was prepared by thermolysin-mediated coupling. PMID- 23357811 TI - Characteristics and antioxidative ability of defatted rice bran extracts obtained using several extractants under subcritical conditions. AB - Defatted rice bran was treated with water, 50% (v/v) ethanol, ethanol, 50% (v/v) acetone, or acetone. The treatment temperature and time were fixed at 230 degrees C and 5 min, respectively. The treatment with 50% (v/v) acetone produced the highest yield of 0.549 g-extract/g-bran, and the extract exhibited the highest DPPH radical scavenging activity of 0.495 mmol-ascorbic acid/g-extract. The extract obtained with 50% (v/v) acetone showed the higher UV absorbance and highest amount of hydrophobic substances in the HPLC analysis than the other extracts, and it also showed the highest antioxidative ability in both the rancidity test at 105 degrees C and bulk oil system at 60 degrees C for the longest induction period of 4.9 h and 14.4 h, respectively. However, the extracts obtained using various extractants showed no effect on the oxidation rate constant of linoleic acid in the bulk oil system. PMID- 23357812 TI - Viscosity stability of O/W emulsion containing alpha-gel through an ionic-complex system. AB - Although many active ingredients are used in cosmetic products for moisturizing and whitening the skin, they are often electrolytes, and the stabilities of oil in water (O/W) type emulsion formulae containing electrolytes are generally difficult to control. To solve this problem, formulae containing an alpha crystalline phase (alpha-gel) consisting of water, higher alcohols, and anionic surfactants such as sodium N-stearoyl-N-methyl-taurate (SMT) have been developed. However, in spite of their excellent salt tolerance, these formulae have poor viscosity stability under non-electrolyte conditions, and the viscosity decreases over time. To obtain adequate viscosity stability, the required electrolyte concentration is approximately 1wt%, which is somewhat high for cosmetic applications. To replace the salts, distearyl dimethyl ammonium chloride (DSAC), a cationic surfactant, with an opposite electric charge to SMT, was used in O/W emulsion formulae, resulting in improved viscosity stability at a lower concentration than that of salts. The stabilization mechanism with DSAC was found to be different from that of salts. PMID- 23357813 TI - Generation of fluorocarbon and hydrocarbon hybrid gemini surfactants controlled by micellar miscibility. AB - Hybrid surfactants were generated through the simple mixing of fluorocarbon and hydrocarbon gemini surfactants in aqueous solutions at 25 degrees C. Disulfide exchange between the disulfide in the spacer chain occurred in the mixed micelles. However, the generation of hybrid gemini surfactants was particularly inhibited by the addition of salt. The suppression of the electrostatic repulsion between the hydrophilic headgroups led to the close packing of the hydrophobic chains in the micelles, resulting in the increased immiscibility of the fluorocarbon and hydrocarbon surfactants. On the other hand, when fluorocarbon fluorocarbon or hydrocarbon-hydrocarbon surfactants were mixed, equilibrium with a 1:2 ratio of symmetric and dissymmetric gemini surfactants was attained after incubation for 24 h. PMID- 23357814 TI - Effects of squalene/squalane on dopamine levels, antioxidant enzyme activity, and fatty acid composition in the striatum of Parkinson's disease mouse model. AB - Active oxygen has been implicated in the pathogenesis of Parkinson's disease (PD); therefore, antioxidants have attracted attention as a potential way to prevent this disease. Squalene, a natural triterpene and an intermediate in the biosynthesis of cholesterol, is known to have active oxygen scavenging activities. Squalane, synthesized by complete hydrogenation of squalene, does not have active oxygen scavenging activities. We examined the effects of oral administration of squalene or squalane on a PD mouse model, which was developed by intracerebroventricular injection of 6-hydroxydopamine (6-OHDA). Squalene administration 7 days before and 7 days after one 6-OHDA injection prevented a reduction in striatal dopamine (DA) levels, while the same administration of squalane enhanced the levels. Neither squalene nor squalane administration for 7 days changed the levels of catalase, glutathione peroxidase, or superoxide dismutase activities in the striatum. Squalane increased thiobarbituric acid reactive substances, a marker of lipid peroxidation, in the striatum. Both squalane and squalene increased the ratio of linoleic acid/linolenic acid in the striatum. These results suggest that the administration of squalene or squalane induces similar changes in the composition of fatty acids and has no effect on the activities of active oxygen scavenging enzymes in the striatum. However, squalane increases oxidative damage in the striatum and exacerbates the toxicity of 6-OHDA, while squalene prevents it. The effects of squalene or squalane treatment in this model suggest their possible uses and risks in the treatment of PD. PMID- 23357815 TI - Reaction of carboxylic acids with vinyl ethers under solvent-free conditions using molecular iodine as a catalyst. AB - The reaction of vinyl ethers with carboxylic acids using iodine as a catalyst under solvent-free conditions was investigated. The reaction of saturated carboxylic acids with vinyl ethers gave the corresponding esters. Mechanistic studies revealed the production of the adduct of the vinyl ether with the carboxylic acid, which then rearranged to form the ester. At low temperatures, the reaction of 2-(1-hydroxycyclohexyl)acetic acid (1) and butyl vinyl ether yielded a butyl ester. However, at a reaction temperature of 80 degrees C, both the esterification and the elimination of a water molecule occurred, yielding the unsaturated butyl ester butyl 2-cyclohexenylacetate. The reaction of 2 ((1S,2S,4R)-2-hydroxy-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)acetic acid (12) with butyl vinyl ether at low temperatures resulted in a mixture of four compounds. However, similar to the high-temperature (>60 degrees C) reaction of 1, the esterification was accompanied by the elimination of a water molecule to give the unsaturated butyl ester (E)-butyl 2-((1S,4R)-1,7,7 trimethylbicyclo[2.2.1]heptan-2-ylidene)acetate. While a gamma-hydrogen was abstracted to form the endo-type double bond in the reaction of 1, an alpha hydrogen was abstracted to form the exo-type double bond in the reaction of 12. PMID- 23357816 TI - Rapid synthesis of Gemini surfactants using a novel 915-MHz microwave apparatus. AB - Rapid synthesis of Gemini surfactants (C(12)-C(2)-C(12) and C(14)-C(6)-C(14)) by microwave heating is investigated. The yield of the synthesis of C(12)-C(2)-C(12) surfactant using 2.45-GHz microwaves was twice the yield obtained by the oil bath method. Moreover, the value of dielectric loss and microwave penetration depth for the sample solution suggest that the microwave frequency of 915 MHz (0.915 GHz) is preferable over the conventional frequency (2.45 GHz). A novel 915-MHz microwave organic synthesis apparatus with a closed reactor is proposed. The synthesis yields of C(12)-C(2)-C(12) obtained using the 915-MHz equipment were three to four times higher than those obtained using the conventional heating method. PMID- 23357817 TI - Physical properties of self-assembled monolayers of Mercapto Oligo (ethylene oxide) methyl ether on gold. AB - Physical properties (chemical adsorption rate, viscoelasticity, thickness, and conformation) for self-assembled monolayers (SAMs) of mercapto oligo (ethylene oxide) methyl ethers on gold were determined by quartz crystal microbalance (QCM). The values of thickness, shear viscosity and elastic shear modulus of SAMs increase with unit number of oligo (ethylene oxide) segment. However, the chemical adsorption rate determined by a Langmuir isotherm does not show such a unit number regularity. Those results suggest that difference in unit number of oligo (ethylene oxide) segment can significantly affects physical properties of SAMs. PMID- 23357818 TI - Characteristic odor components of essential oil from Scutellaria laeteviolacea. AB - The essential oils from aerial parts of Scutellaria laeteviolacea was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The characteristic odor components were also detected in the oil using gas chromatography-olfactometry (GC-O) analysis and aroma extraction dilution analysis (AEDA). As a result, 100 components (accounting for 99.11 %) of S. laeteviolacea, were identified. The major components of S. laeteviolacea oil were found to be 1-octen-3-ol (27.72 %), germacrene D (21.67 %),and beta-caryophyllene (9.18 %). The GC-O and AEDA results showed that 1-octen-3-ol, germacrene D, germacrene B, and beta-caryophyllene were the most characteristic odor components of the oil. These compounds are thought to contribute to the unique flavor of this plant. PMID- 23357819 TI - Incidental detection of pediatric achalasia cardia during gastroesophageal scintigraphy. AB - Scintigraphy is a simple technique for the demonstration of gastroesophageal reflux, and is particularly suitable in neonates and infants. The authors describe a rare case of achalasia cardia in a 3-year-old child incidentally detected as a dilated esophagus with a stricture at the lower end during a scintigraphic study. PMID- 23357820 TI - Increased FDG activity in a dermatofibroma in esophageal cancer patient. AB - PET using the radiotracer (18)F-FDG is used for staging patients with esophageal cancer. Nonmalignant conditions, mainly inflammation and some benign tumors, however, can cloud the clinical picture by taking up FDG and producing a false positive result. We report the case of a 46 year-old man with squamous cell carcinoma of the thoracic esophagus who underwent combined PET/CT and had false positive uptake in a chest wall dermatofibroma. Dermatofibroma is a benign skin lesion with a characteristic large presence of fibroblasts and macrophages. Macrophage uptake of FDG is likely responsible for the false-positive result on PET/CT. PMID- 23357821 TI - (99m)Tc-pertechnetate scintigraphy and endoscopy in assessment of caustic-induced gastric mucosal injury. AB - Endoscopy is the gold standard for evaluating caustic-induced gastric mucosal injury. Injuries >= 2b (confluent ulceration or charring) are associated with perforation and cicatrisation. Grade 1-2a injuries recover without intervention. Grade 2b and 3 injuries require observation and may need intervention. (99m)Tc pertechnetate imaging can assess gastric viability after caustic injury. We correlated (99m)Tc-pertechnetate SPECT/CT with endoscopic findings in 4 patients with increasing grades of caustic-induced gastric mucosal injury. PMID- 23357822 TI - Regions of interest-based discriminant analysis of DaTSCAN SPECT and FDG-PET for the classification of dementia. AB - PURPOSE: Neuroimaging is increasingly used to support the clinical diagnosis of patients with cognitive impairment. Dopamine transporter (DAT) imaging, such as DaTSCAN SPECT, tests the integrity of the nigrostriatal pathway, whereas FDG-PET identifies typical patterns of cortical and subcortical hypometabolism. The aim of this study was to assess the relative contribution of DAT and regional glucose metabolism imaging to the differential diagnosis. PATIENTS AND METHODS: Twenty seven subjects were investigated for neurodegenerative dementia associated with parkinsonism of variable severity by FDG-PET and DaTSCAN SPECT. They were grouped according to the clinically established diagnosis, including probable Alzheimer disease (5 subjects), corticobasal degeneration (6 subjects), Lewy body dementia (8 subjects), frontotemporal dementia (4 subjects), and Parkinson disease with dementia (4 subjects). Normalized FDG uptake and DAT uptake ratios were obtained by the BRASS software. We used a discriminant analysis with a stepwise method and a leave-one-out cross-validation. RESULTS: With the use of regional values of normalized FDG uptake, 85.2% and 55.6% of the patients were correctly classified by the discriminant analysis and the cross-validation, respectively. When DAT alone was considered, the results were 59.3% and 51.9%, whereas the combination of both DAT and normalized FDG uptake yielded 100% and 88.9% of accurate classifications. CONCLUSIONS: This automated analysis approach shows that the information provided by normalized FDG uptake and DAT is not redundant for the differential diagnosis of dementia and that taking into account both normalized FDG uptake and DAT uptake allows a better classification of individual patients. These results further support the usefulness of both modalities in the clinical workup of dementia. PMID- 23357823 TI - Intraoperative hand-held imaging gamma-camera for sentinel node detection in patients with breast cancer: feasibility evaluation and preliminary experience on 16 patients. AB - PURPOSE: This study aimed to assess the feasibility and potential usefulness of a new intraoperative portable high-resolution imaging gamma-camera for the localization of sentinel lymph node in patients with breast cancer. METHODS: Sixteen T1 to T2 breast cancer female patients were evaluated (mean age, 62 years) with preoperative lymphoscintigraphy, acquired 30 minutes after intradermal injection of 60 to 70 MBq (1.6-1.9 mCi) of (99m)Tc-nanocolloids in saline volumes of 0.1 to 0.2 mL. Surgery took place the day after (18-20 hours after tracer injection). For intraoperative sentinel lymph node localization, a traditional gamma-probe was used by the surgeon. Moreover, a portable imaging gamma-camera was used by the nuclear physician who was present in the operating room. RESULTS: The portable imaging gamma-camera showed very high spatial resolution (2.4 mm) in the 4.4 * 4.4 cm(2) FOV, with a good sensitivity of 180 cps/MBq at a Plexiglas depth of 1 cm. In 11 patients, lymphoscintigraphy, gamma probe, and imaging gamma-camera depicted the same number of radioactive lymph nodes (17 nodes; 5 of which were metastatic and detected in 6 different patients). In 6 patients, the portable imaging gamma-camera detected 1 node more than lymphoscintigraphy (in total, 5 nodes more), one of which was metastatic (the only one metastatic in that patient). CONCLUSIONS: Our preliminary results showed that a portable high-resolution hand-held imaging gamma-camera is a feasible, not time-consuming, noninvasive procedure in intraoperative sentinel node localization, offering extra confidence to the surgeon. In our hands, it was a very useful auxiliary imaging tool especially in the identification of nodes located deep in the axilla, which are difficult to detect at the preoperative lymphoscintigraphy. Additional multicenter studies involving a greater number of patients are necessary to confirm these promising data. PMID- 23357824 TI - Focused regional FDG PET/CT detects more osseous metastases than does whole-body PET/CT. AB - A patient with melanoma underwent FDG PET/CT for surveillance of metastatic disease. The whole-body PET/CT scan demonstrated a single FDG-avid lesion in the left ilium, suggestive of an osseous metastasis. Because there was no corresponding CT abnormality, biopsy was planned using PET/CT guidance. The PET/CT for biopsy guidance focused over a single pelvic bed position demonstrated at least 12 FDG-avid osseous metastases, which were not apparent on the original whole-body PET/CT. This case highlights the limitations of whole-body PET/CT in the detection of small metastases and suggests that a PET/CT focused over a specific body region can improve the sensitivity of detecting small metastases. PMID- 23357825 TI - Prognostic significance of FDG PET/CT on the follow-up of patients of differentiated thyroid carcinoma with negative I131 whole-body scan and elevated thyroglobulin levels. PMID- 23357826 TI - Homodimerization as a molecular switch between low and high efficiency PrP C cell surface delivery and neuroprotective activity. AB - PrP (C) is associated with a variety of functions, and its ability to interact with a multitude of partners, including itself, may largely explain PrP multifunctionality and the lack of consensus on the genuine physiological function of the protein in vivo. In contrast, there is a consensus in the literature that alterations in PrP (C) trafficking and intracellular retention result in neuronal degeneration. In addition, a proteolytic modification in the late secretory pathway termed the alpha-cleavage induces the secretion of PrPN1, a PrP (C) -derived metabolite with fascinating neuroprotective activity against toxic oligomeric Abeta molecules implicated in Alzheimer disease. Thus, studies focusing on understanding the regulation of PrP (C) trafficking to the cell surface and the modulation of alpha-cleavage are essential. The objective of this commentary is to highlight recent evidences that PrP (C) homodimerization stimulates trafficking of the protein to the cell surface and results in high levels of PrPN1 secretion. We also discuss a hypothetical model for these results and comment on future challenges and opportunities. PMID- 23357827 TI - Prions and lymphoid organs: solved and remaining mysteries. AB - Prion colonization of secondary lymphoid organs (SLOs) is a critical step preceding neuroinvasion in prion pathogenesis. Follicular dendritic cells (FDCs), which depend on both tumor necrosis factor receptor 1 (TNFR1) and lymphotoxin beta receptor (LTbetaR) signaling for maintenance, are thought to be the primary sites of prion accumulation in SLOs. However, prion titers in RML-infected TNFR1 (-/-) lymph nodes and rates of neuroinvasion in TNFR1 (-/-) mice remain high despite the absence of mature FDCs. Recently, we discovered that TNFR1 independent prion accumulation in lymph nodes relies on LTbetaR signaling. Loss of LTbetaR signaling in TNFR1 (-/-) lymph nodes coincided with the de differentiation of high endothelial venules (HEVs)-the primary sites of lymphocyte entry into lymph nodes. These findings suggest that HEVs are the sites through which prions initially invade lymph nodes from the bloodstream. Identification of HEVs as entry portals for prions clarifies a number of previous observations concerning peripheral prion pathogenesis. However, a number of questions still remain: What is the mechanism by which prions are taken up by HEVs? Which cells are responsible for delivering prions to lymph nodes? Are HEVs the main entry site for prions into lymph nodes or do alternative routes also exist? These questions and others are considered in this article. PMID- 23357828 TI - A closer look at prion strains: characterization and important implications. AB - Prions are infectious proteins that are responsible for transmissible spongiform encephalopathies (TSEs) and consist primarily of scrapie prion protein (PrP (Sc) ), a pathogenic isoform of the host-encoded cellular prion protein (PrP (C) ). The absence of nucleic acids as essential components of the infectious prions is the most striking feature associated to these diseases. Additionally, different prion strains have been isolated from animal diseases despite the lack of DNA or RNA molecules. Mounting evidence suggests that prion-strain-specific features segregate with different PrP (Sc) conformational and aggregation states. Strains are of practical relevance in prion diseases as they can drastically differ in many aspects, such as incubation period, PrP (Sc) biochemical profile (e.g., electrophoretic mobility and glycoform ratio) and distribution of brain lesions. Importantly, such different features are maintained after inoculation of a prion strain into genetically identical hosts and are relatively stable across serial passages. This review focuses on the characterization of prion strains and on the wide range of important implications that the study of prion strains involves. PMID- 23357829 TI - A microbial sensor for discovering structural probes of protein misfolding and aggregation. AB - In all cell types, protein homeostasis, or "proteostasis," is maintained by sophisticated quality control networks that regulate protein synthesis, folding, trafficking, aggregation, disaggregation, and degradation. In one notable example, Escherichia coli employ a proteostasis system that determines whether substrates of the twin-arginine translocation (Tat) pathway are correctly folded and thus suitable for transport across the tightly sealed cytoplasmic membrane. Herein, we review growing evidence that the Tat translocase itself discriminates folded proteins from those that are misfolded and/or aggregated, preferentially exporting only the former. Genetic suppressors that inactivate this mechanism have recently been isolated and provide direct evidence for the participation of the Tat translocase in structural proofreading of its protein substrates. We also discuss how this discriminatory "folding sensor" has been exploited for the discovery of structural probes (e.g., sequence mutations, pharmacologic chaperones, intracellular antibodies) that modulate the folding and solubility of virtually any protein-of-interest, including those associated with aggregation diseases (e.g., alpha-synuclein, amyloid-beta protein). Taken together, these studies highlight the utility of engineered bacteria for rapidly and inexpensively uncovering potent anti-aggregation factors. PMID- 23357830 TI - Silencing synapses: a route to understanding synapse degeneration in chronic neurodegenerative disease. AB - The degeneration of pre-synaptic boutons in the stratum radiatum of the dorsal hippocampus is one of earliest components of neurodegeneration in several models of murine prion disease. We recently showed that blockade of synaptic transmission by infusion of botulinum neurotoxin A (BoNT/A) into the hippocampus several weeks prior to the onset of degeneration, had no detectable impact on the extent of the synaptic degeneration. ( 1) We elaborate here on the rationale for these experiments and highlight why we believe that this negative result is interesting and important. We also discuss new observations that might provide insights into the molecular events that underlie synapse degeneration. PMID- 23357832 TI - Allelic diversity distributions of 21 new autosomal short tandem repeat loci in Chinese Ningxia Han population. PMID- 23357831 TI - Single-molecule approaches to prion protein misfolding. AB - The structural conversion of the prion protein PrP into a transmissible, misfolded form is the central element of prion disease, yet there is little consensus as to how it occurs. Key aspects of conversion into the diseased state remain unsettled, from details about the earliest stages of misfolding such as the involvement of partially- or fully-unfolded intermediates to the structure of the infectious state. Part of the difficulty in understanding the structural conversion arises from the complexity of the underlying energy landscapes. Single molecule methods provide a powerful tool for probing complex folding pathways as in prion misfolding, because they allow rare and transient events to be observed directly. We discuss recent work applying single-molecule probes to study misfolding in prion proteins, and what it has revealed about the folding dynamics of PrP that may underlie its unique behavior. We also discuss single-molecule studies probing the interactions that stabilize non-native structures within aggregates, pointing the way to future work that may help identify the microscopic events triggering pathogenic conversion. Although single-molecule approaches to misfolding are relatively young, they have a promising future in prion science. PMID- 23357833 TI - Population genetics of 17 Y-STR loci in Chinese Manchu population from Liaoning Province, Northeast China. PMID- 23357834 TI - Comparative pharmacokinetics and bioavailability of tapentadol following oral administration of immediate- and prolonged-release formulations. AB - OBJECTIVE: To evaluate the bioavailability and pharmacokinetics of orally administered tapentadol immediate release (IR) compared with tapentadol prolonged release (PR). METHODS: Three randomized, open-label, crossover studies were conducted in subjects under fasted conditions. Studies 1 and 2 determined the absolute bioavailability and pharmacokinetics of oral tapentadol IR 86 mg and tapentadol PR 86 mg, respectively, relative to a 34-mg intravenous (IV) dose of tapentadol. Study 3 determined the relative bioavailability of tapentadol PR 86 mg vs. tapentadol IR 86 mg. Pharmacokinetic parameters were calculated using non compartmental analysis and relative bioavailability using dose-adjusted, log transformed analysis of variance models for maximum concentration (Cmax) and areas under the serum concentration-time curve (AUC0-t and AUC). Adverse events (AEs), vital signs, 12-lead electrocardiograms (ECGs), and laboratory parameters were assessed. RESULTS: Absolute bioavailability was estimated to be 32% (95% confidence interval (CI), 29.4 - 34.8%; n = 24) for tapentadol IR 86 mg and 32% (95% CI, 28.0 - 35.9%; n = 18) for tapentadol PR 86 mg. Based on AUC, the relative bioavailability of tapentadol PR vs. tapentadol IR was 96% (90% CI, 87.8 - 104.4%; n = 16). Following IV administration, tapentadol had an elimination half-life of about 4 hours; in Studies 1 and 2, respectively, mean tapentadol volumes of distribution were 540 and 471 l, and mean clearance was 1,531 and 1,603 ml/min. Compared to tapentadol IR 86 mg, the prolonged-release characteristics of tapentadol PR 86 mg were evident with a lower Cmax (22.5 ng/ml vs. 64.2 ng/ml), a longer time to Cmax (5.0 h vs. 1.5 h), a higher half-value duration (HVD: 12.5 h vs. 3.6 h), and a longer mean residence time (MRT: 10.6 h vs. 6.0 h). The most common AEs reported were dizziness, headache, fatigue, nausea, somnolence, and dry mouth; most AEs were mild. No clinically relevant changes in vital signs, ECG parameters, or laboratory values were observed. CONCLUSIONS: Absolute bioavailability for both tapentadol IR and tapentadol PR was ~ 32% under fasted conditions. Extent of exposure (AUC) for tapentadol PR was very similar to tapentadol IR, whereas Cmax was lower and HVD/MRT longer for the prolonged-release formulation. Overall, the pharmacokinetic characteristics of tapentadol PR enable a twice-daily dosing regimen to be used; such a regimen is expected to improve patient compliance during chronic use. PMID- 23357835 TI - Comparative bioavailability of two moxifloxacin tablet products after single dose administration under fasting conditions in a balanced, randomized and cross-over study in healthy volunteers. AB - Moxifloxacin, a 4th generation of fluoroquinolones, is a broad spectrum antibacterial agent against respiratory tract pathogens, including Gram-positive and Gram-negative bacteria, anaerobic bacteria and atypical respiratory tract pathogens. In order to evaluate the efficacy and safety of generic moxifloxacin products, the bioequivalence of these generic products with an approved reference formulation should be demonstrated. Thus, the aim of this study was to compare the rate and extent of absorption of a new generic film coated moxifloxacin tablet product (Rapiflox(r), Atlantic Laboratories Corporation Ltd., Bangkok, Thailand) with that of a reference product (Avelox(r), Bayer Health Care AG, Leverkusen, Germany) when given as a single dose. A crossover study was performed in 20 healthy Thai volunteers. The subjects received either a 400 mg tablet of the reference or test product after overnight fasting. Blood samples were collected at pre-dose (0 hour) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 34 hours post-dose. Moxifloxacin plasma level was measured by a validated HPLC method with fluorescence detector. Pharmacokinetic parameters were calculated using a non-compartmental model. The geometric mean of maximum concentration (Cmax) of the test product was 4,069.64 ng/ml, with median time to achieve maximum concentration (tmax) at 2 hours (range 0.25 - 6.00 hours), while the geometric mean Cmax and median tmax of the reference product was 4,211.98 ng/ml and 2.00 hours (range 0.25 - 8.00 hours). Furthermore, the geometric means of AUC0-tlast and AUC0-infinity for the test product were 49,731.66 and 51,865.89 ng*h/ml while those of the reference product were 51,927.97 and 54,455.93 ng*h/ml. The geometric mean of the ratios of Test/Reference for the logtransformed Cmax, AUC0-tlast and AUC0-infinity of moxifloxacin and their 90% CIs were 96.62% (83.21 - 112.19%), 95.77% (87.07 - 105.34%) and 95.24 (86.52 - 104.85%), respectively. Therefore, it can be concluded that these two moxifloxacin tablet products were bioequivalent in healthy Thai volunteers under fasting condition. PMID- 23357836 TI - The financial impact of computer systems-based approaches to reducing repeat drug exposure in patients with known drug allergies. PMID- 23357838 TI - In vivo evaluation of drug-drug interactions linked to UGT inhibition: the effect of probenecid on dalcetrapib pharmacokinetics. AB - OBJECTIVE: To assess the effect of the UGT inhibitor probenecid on the pharmacokinetics of dalcetrapib, an investigational drug whose pharmacologically active thiol form undergoes glucuronidation (fm UGT >= 0.25). MATERIALS AND METHODS: A two-way crossover study in 20 healthy subjects. Subjects received a single 600 mg dose of dalcetrapib with or without probenecid (500 mg 4 times daily for 6 days). RESULTS: AUCinfinity and Cmax of dalcetrapib thiol were increased by 14% and 21%, respectively, by co-administration of probenecid. CONCLUSIONS: This case study illustrates the difficulty in predicting clinically relevant drug-drug interactions for UGT substrates based only on the fraction metabolized by glucuronidation. PMID- 23357837 TI - Bioequivalence assessment of a pregabalin capsule and oral solution in fasted healthy volunteers: a randomized, crossover study. AB - OBJECTIVE: To determine the oral bioavailability of a pregabalin capsule relative to a pregabalin solution. METHODS: This was an open-label, randomized, crossover study in 12 healthy volunteers. Pharmacokinetics were compared for a 100-mg capsule and a 100-mg capsule dissolved in water, administered fasted. RESULTS: Mean Cmax and AUC0-infinity for the capsule were within 2% of those for the solution (3.8 vs. 3.7 MUg/ml and 26.7 vs. 27.0 MUg*h/ml, respectively). The 90% confidence intervals for the ratios of Cmax and AUC0-infinity fell fully within 80 - 125%. CONCLUSIONS: A 100-mg pregabalin capsule is bioequivalent to a pregabalin solution (100-mg capsule dissolved in water). PMID- 23357839 TI - Changes to prothrombin international normalized ratio in patients receiving hemodialysis. AB - BACKGROUND: The clinical utility of factor Xa inhibitors (xabans) has been demonstrated, but these inhibitors are contraindicated in patients undergoing dialysis therapy. Therefore, warfarin remains the mainstay for oral anticoagulation treatment of patients receiving hemodialysis (HD). OBJECTIVE: This study investigated the changes in international normalized ratio (INR) during HD treatment of patients receiving warfarin. METHODS: Changes in INR and serum albumin levels were determined before (pre-) and after (post-) HD in six consecutive HD sessions. 30 patients (23 males, 7 females; mean age, 72 +/- 8 years) were enrolled, and a total of 180 measurements were performed. RESULTS: Post-HD INR levels were significantly decreased compared with pre-HD levels (2.07 +/- 0.52 to 1.99 +/- 0.50, p < 0.0001), while serum albumin levels were significantly increased post-HD compared with pre-HD (p < 0.0001). There was a significant negative correlation between changes in INR and serum albumin during HD (r = -0.383, p = 0.0002). CONCLUSION: INR is significantly decreased post-HD compared with pre-HD. Although the therapeutic range of INR differs according to the disease, close monitoring of the degree of anticoagulation in patients receiving warfarin is recommended to minimize the risk of thrombosis and hemorrhagic complications. PMID- 23357840 TI - Factors that contribute to clopidogrel resistance in cardiovascular disease patients: environmental and genetic approach. AB - BACKGROUND AND OBJECTIVE: Clopidogrel is a potent antiplatelet drug that reduces the risk of vascular events in patients with cardiovascular disease. However, several studies have shown that about a quarter of patients showed low or no response to clopidogrel therapy. In this study, factors that contribute to clopidogrel resistance were investigated in 270 cardiovascular disease patients from Jordan. PATIENTS AND METHODS: Clopidogrel resistance was determined through platelet aggregation analysis using the Multiplate analyzer(r). Genetic factors (CYP2C19*2 and PON1 Q192R) were examined using polymerase chain reaction restriction fragment length polymorphism analysis. RESULTS: The incidence of clopidogrel resistance among Jordanians is about 32%. Significant association between clopidogrel resistance and female gender, concomitant use of calcium channel blockers, and low HDL was found (p < 0.05). In addition, presence of CYP2C19*2 allele is strongly related to clopidogrel resistance (p < 0.001). However, lack of contribution to clipidogrel resistance was found for PON1 Q192R polymorphism, age, diabetes, hypertension, smoking and aspirin use (p > 0.05). CONCLUSION: Several factors might contribute to clopidogrel resistance including gender, concomitant use of calcium channel blockers, HDL and CYP2C19*2 polymorphism. PMID- 23357841 TI - Pharmacokinetics and safety of sirukumab following a single subcutaneous administration to healthy Japanese and Caucasian subjects. AB - OBJECTIVE: Sirukumab (CNTO 136) is a human mAb with high affinity and specificity for binding to interleukin-6. This Phase 1 study evaluated the pharmacokinetics, immunogenicity, safety, and tolerability of sirukumab following a single subcutaneous (s.c.) administration in healthy male Japanese and Caucasian subjects. METHODS: Japanese and Caucasian subjects were randomized to placebo or 25, 50, or 100 mg sirukumab. Blood samples were collected to measure serum sirukumab concentration and antibodies to sirukumab. Noncompartmental analysis and population pharmacokinetic modeling were conducted to characterize sirukumab pharmacokinetics. Adverse events were monitored at each visit. RESULTS: 25 Japanese and 24 Caucasian subjects received sirukumab and were included in the pharmacokinetic evaluation. Mean Cmax and AUC0-infinityof sirukumab increased in an approximately dose-proportional manner in both Japanese and Caucasian subjects. Median tmax was 3 -5 days after s.c. administration of sirukumab. Mean t1/2 was 15 -16 days in Japanese and 15 -18 days in Caucasian subjects. A one compartment population pharmacokinetic model adequately described sirukumab pharmacokinetics following s.c. administration. The estimated population means for CL/F, V/F, and Ka were 0.54 +/-0.03 l/day, 12.2 +/-0.55 l, and 0.77 +/-0.07 day-1, respectively. Race was not a significant covariate on CL/F or V/F. No subject was positive for antibodies to sirukumab. Adverse events were generally mild and did not appear to be dose-related or lead to study discontinuation. CONCLUSIONS: Sirukumab pharmacokinetics following subcutaneous administration was linear at doses ranging 25 -100 mg and was comparable between Japanese and Caucasian subjects. A single subcutaneous administration of 25, 50, or 100 mg sirukumab appeared to be well tolerated by both Japanese and Caucasian healthy male subjects. PMID- 23357842 TI - Diagnosing malabsorption with systemic lipid profiling: pharmacokinetics of pentadecanoic acid and triheptadecanoic acid following oral administration in healthy subjects and subjects with cystic fibrosis. AB - OBJECTIVE: A Malabsorption Blood Test (MBT) is proposed as an alternative method to the 72-hour stool and dietary collection for assessing the degree of fat malabsorption in people with pancreatic insufficiency. The MBT consists of a simultaneous oral dose of pentadecanoic acid (PA), a free fatty acid, and triheptadecanoic acid (THA), a triglyceride with three heptadecanoic (HA) saturated fatty acids requiring hydrolysis by pancreatic lipase before HA can be intestinally absorbed. The aim of this study is to demonstrate the ability of MBT to detect fat malabsorption in healthy adult subjects using the pancreatic lipase (PL) inhibitor Orlistat (Xenical(r)), and in subjects with CF and PI while on and off routine pancreatic enzyme doses. MATERIALS AND METHODS: The MBT with the PA and THA were delivered in a breakfast test meal (2.5 g PA and either 5 g or 8 g THA) to healthy adult subjects (ages 18 - 50 years, BMI 21 - 30) and to subjects with CF (> 12 years, FEV1% predicted > 40%), after a 12-hour fast and 24 hours without dairy foods. Serum levels of PA and HA were assessed by gas-liquid chromatography, from blood samples drawn prior to MBT and then hourly for 8 hours. For healthy subjects, the MBT was administered before and after Orlistat treatment, and in subjects with CF, both with subjects receiving routine pancreatic lipase treatment ("on enzyme") and also "off enzyme" treatment. Treatment groups were compared for baseline (C0) and maximum (Cmax) plasma concentrations of PA and HA over 8 hours: area under the curve (AUC) was calculated using linear trapezoid method. The ratio of HA to PA Cmax and AUC was also calculated and compared. RESULTS: For the healthy subjects (n = 15, 60% female, ages 21 - 49 years), absorption of HA was reduced 71% for Cmax (p < 0.001) and 65% for AUC (p = 0.001) after Orlistat treatment, and absorption of PA was unchanged. For subjects with CF (n = 6, 50% female, ages 13 - 19 years), absorption of HA was minimal with subjects "off enzymes" and increased significantly with subjects "on enzymes" while absorption of PA did not differ between groups. Enzyme administration resulted in increased Cmax HA/ PA ratios from 0.02 to 0.92 and from 0.05 to 0.73 in subjects with CF receiving 5.0 g and 8.0 g of THA, respectively. AUC HA/PA ratios showed similar increases. CONCLUSIONS: In this pilot and feasibility proof-of-concept study, the MBT, utilizing the relative absorption of HA to PA, two odd-chained fatty acids, responds to changes in fat absorption in healthy subjects using a lipase inhibitor and in subjects with CF while on or off enzyme therapy. The MBT holds promise to provide a more accurate, specific and acceptable alternative to the 72 hour stool collection to quantify pancreatic-based fat malabsorption in a variety of clinical and research contexts. PMID- 23357843 TI - Pharmacokinetic model incorporating mechanism-based inactivation of CYP2D6 can explain both non-linear kinetics and drug interactions of paroxetine. AB - OBJECTIVE: To develop a pharmacokinetic model able to describe the nonlinear pharmacokinetics of paroxetine (PRX) and to predict the drug-drug interaction between PRX and metoprolol under various dosage regimens. METHODS: A pharmacokinetic model of PRX incorporating mechanism-based inhibition was developed. This model was fitted to the drug concentration profiles obtained after single and repeated administrations of PRX to estimate the pharmacokinetic parameters of PRX and degradation rate constant of cytochrome P450 (CYP) 2D6. It was also fitted to the time profile of S-metoprolol after coadministration of metoprolol and PRX, and the fractional contribution of CYP2D6 to overall clearance of S-metoprolol was estimated. Using the developed model and estimated parameters, an optimal dosage regimen for metoprolol during withdrawal of PRX was simulated. RESULTS: The developed model well described the time profiles of both PRX and metoprolol concentration during concomitant administration. The estimated parameters were consistent with reported values. The nonlinear and accumulation properties of PRX could be explained by mechanism-based inhibition of CYP2D6 by PRX. Upon tapering PRX from 20 mg/ day to 10 mg/day for 14 days then 5 mg/day for 14 days until cessation, the optimal dosage regimen to resume 120 mg/day of metoprolol based on the developed model was as follows: 30 mg/day during concomitant administration, 40 mg/day for the next 14 days, 60 mg/day for the next 14 days, and finally 120 mg/day. CONCLUSIONS: The developed model enabled us to quantitatively estimate drug-drug interactions of PRX and CYP2D6 substrate drugs, and to predict optimal dosage regimens. PMID- 23357844 TI - Pharmacokinetic and tolerability of i.m. disodium clodronate 200 mg/lidocaine 1%, given twice monthly, in comparison with i.m. disodium clodronate 100 mg/lidocaine 1%, given weekly, in healthy postmenopausal female patients. AB - BACKGROUND: Clodronate is a bisphosphonate effective in the prevention and treatment of osteoporosis in postmenopausal women. Non-adherence to bisphosphonates, however, is a major issue in clinical practice. Simplifying dose regimens may increase compliance. OBJECTIVES: To assess bioequivalence between an intramuscular (i.m.) clodronate 200 mg/lidocaine 1% twice-a-month formulation and a clodronate 100 mg/lidocaine 1% weekly formulation in 32 postmenopausal women. METHODS: In this double-blind, randomized, two-way crossover study, test and reference formulations were administered in single dose, with a 2-week wash-out between administrations. The primary endpoint was clodronic acid cumulative excretion in the first 24 hours after injection (Xu0-24h). Cumulative excretion in the 72 hours post-dose (Xu0-72h) and maximum excretion rate (Ratemax) were also evaluated. Bioequivalence was assumed if the 90% confidence intervals (CIs) of the geometric means ratios of the dose-normalized parameters were within the 80.00 - 125.00% range. Local tolerability was evaluated. RESULTS: Mean Xu0-24h values were 114.03 +/-23.13 mg and 55.22 +/-9.73 mg for clodronate 200 mg and 100 mg. The 90% CIs for dose-normalized Xu0-24h, Xu0-72h and Ratemax ere 95 -110%, 94 -107% and 95 - 113%. Local tolerability of both treatments was good. The differences in pain intensity between formulations were not sigificantly different at most assessment times. Headache was the only treatment-related adverse event. CONCLUSIONS: Bioequivalence of the two formulations was confirmed in terms of dose-normalized rate and amount of clodronic acid excretion. This result, together with the favorable tolerability of the novel 200 mg formulation, suggests the possibility of reducing the number of i.m. administrations from once a-week to twice-a-month. PMID- 23357845 TI - Thrombocytopenia induced by both aspirin and clopidogrel in the same patient. AB - Aspirin and clopidogrel are used widely as antiplatelet agents due to their efficacy, safety, and tolerability. In rare cases, these agents can cause thrombotic thrombocytopenic purpura, but no report has documented severe thrombocytopenia in response to both drugs in the same patient. A 73-year old female developed severe thrombocytopenia following treatment with clopidogrel. Platelet count recovered within 6 months of drug withdrawal without additional thrombopoietic therapies. Seven months after the last dose of clopidogrel, thrombocytopenia recurred on aspirin therapy. Again, platelet count rebounded gradually and independently. This case suggests that some patients who experience thrombocytopenia in response to one antiplatelet agent may react similarly to other antiplatelet agents. PMID- 23357846 TI - Risk factors for renal impairment in patients with solid tumors or multiple myeloma treated with zoledronic acid. AB - OBJECTIVE: Using retrospective prescription analysis, this study aimed to investigate the risk factors for renal impairment among adult solid tumor and multiple myeloma patients who have received zoledronic acid injections in a teaching hospital over the last 4 years. METHODS: We examined solid tumor and multiple myeloma patients who had received at least 1 zoledronic acid injection in a teaching hospital in Seoul with at least 2,000 beds over the 4 years between January 2008 and December 2011. The injection histories and serum creatinine levels of these patients were included in the analysis. Patients who developed renal impairment subsequent to zoledronic acid injection were identified, and the risk factors were statistically analyzed. RESULTS: In only 1 case was zoledronic acid injection reduced as directed by the creatinine clearance guidelines. Four patients whose creatinine clearance was less than 30 ml/min were injected with zoledronic acid even though its use is contraindicated in this situation. Of the 338 research subjects, 26 developed renal impairment. The following were confirmed to be statistically significant (p < 0.05) risk factors for the development of renal impairment: serum creatinine (at first injection) of greater than 1.4 mg/dl, diabetes, hypertension, thalidomide prescription, multiple myeloma, and previous pamidronate usage. CONCLUSIONS: Based on the results of this study, renal monitoring is necessary following zoledronic acid injection. In addition, for patients with renal impairment risk factors, a risk-benefit analysis must be performed before zoledronic acid is administered, and it must be administered at an appropriate dose according to the level of renal function. PMID- 23357847 TI - Cognitive failure evaluation and therapy based on pharmacy practice - utilization of anti-dementia drugs and food supplements in Lithuania. AB - OBJECTIVE: To evaluate cognitive failures of patients visiting pharmacies and to study utilization of drugs for dementia therapy in Lithuania. METHODS: 153 patients completed a Cognitive Failure Questionnaire (CFQ) at pharmacy. The ATC/DDD method was used to evaluate utilization of drugs licensed for dementia treatment, including C04AE (peripheral vasodilators), N04BD (MAO inhibitors), N06D (anti-dementia drugs), N06BX (nootropics), N07C (anti-vertigo), and A11HA (plain vitamin E) preparations. RESULTS: 53 of 153 study participants (34.6%) scored over 45 CFQ points and reported cognitive failure, assessed by three factors: F1 - forgetfulness, F2 - distractibility and F3 - false triggering. All three factors correlate with age and the most significant extent has memory performance (Spearman's rank correlation coefficient (rs) F1 - rs = 0.85, p < 0.01; F3 - rs = 0.79, p < 0.01, and F2 - rs = 0.4, p < 0.01) and do not depend on gender or educational background. Total use of anti-dementia drugs and food supplements decreased from 27.08 DDD/1,000 inhabitants/day in 2006 to 26.46 DDD/1,000 inhabitants/day in 2011. Nicergoline 6.26 DDD/1,000 inhabitants/day and cinnarizine 6.16 DDD/1,000 inhabitants/ day - were the most prescribed medications in 2011. Total costs for anti-dementia drugs increased from EUR 8.91 million to EUR 11.63 million during the same period. The largest amount of EUR 3.166 million was spent on nicergoline. Older people were more likely than younger people to report using prescription drugs (rs = 0.468; p < 0.01), while younger population used more supplements (rs = -0.227; p = 0.005). CONCLUSIONS: Trend of anti-dementia drugs use in Lithuania is similar to other EU countries; however, there are some deviations from dementia treatment guidelines, particularly in terms of nicergoline and cinnarizine recommendations. PMID- 23357848 TI - Niche-less maintenance of HSCs by 2i. AB - Maintenance of hematopoietic stem cells (HSCs) in vitro has been believed to be difficult due to a lack of complete understanding of HSC quiescence maintained by the niche. Recent evidence suggests that in vitro maintenance of human and mouse long-term HSCs (LT-HSCs) is possible through dual inhibition (2i) of both GSK-3 and mTOR in the absence of cytokines, serum, or feeder cells. PMID- 23357849 TI - A proposed role for glutamine in cancer cell growth through acid resistance. PMID- 23357850 TI - Structural insight into substrate recognition by histone demethylase LSD2/KDM1b. PMID- 23357851 TI - Def defines a conserved nucleolar pathway that leads p53 to proteasome independent degradation. AB - p53 protein turnover through the ubiquitination pathway is a vital mechanism in the regulation of its transcriptional activity; however, little is known about p53 turnover through proteasome-independent pathway(s). The digestive organ expansion factor (Def) protein is essential for the development of digestive organs. In zebrafish, loss of function of def selectively upregulates the expression of p53 response genes, which raises a question as to what is the relationship between Def and p53. We report here that Def is a nucleolar protein and that loss of function of def leads to the upregulation of p53 protein, which surprisingly accumulates in the nucleoli. Our extensive studies have demonstrated that Def can mediate the degradation of p53 protein and that this process is independent of the proteasome pathway, but dependent on the activity of Calpain3, a cysteine protease. Our findings define a novel nucleolar pathway that regulates the turnover function of p53, which will advance our understanding of p53's role in organogenesis and tumorigenesis. PMID- 23357853 TI - Influence of the base curve in the performance of customized and classical progressive lenses. AB - PURPOSE: The aim of this article is to analyze the effect of the base curve on progressive power lens performance by means of the Sheedy scoring technique. We expect to find strong differences on this effect depending on the definition of lens power and on the lens optimization method. METHODS: We have used six different back side progressive lens designs. Three of them have been optimized for improving the power perceived by the user in the actual position of use. The other three have been optimized to provide prescription power when measured with a focimeter or a mapper. We have used exact ray tracing to compute both the user power maps and the focimeter power maps. We have applied the Sheedy method to these maps and analyzed the results. RESULTS: When this scoring technique is run with focimeter power maps, the performance of customized lenses is highly base curve dependent. Instead, classical lens performance is quite stable against base curve changes. On the contrary, if we run the test with user power maps, we find the opposite behavior. CONCLUSIONS: Progressive lens scoring is highly dependent on how the lens has been designed and how the lens is measured. Besides, customization of progressive lenses by real ray tracing guarantees that prescription and design parameters are preserved at the position of use regardless the base curve selected to make the lens. PMID- 23357852 TI - M98K-OPTN induces transferrin receptor degradation and RAB12-mediated autophagic death in retinal ganglion cells. AB - Mutations in the autophagy receptor OPTN/optineurin are associated with the pathogenesis of glaucoma and amyotrophic lateral sclerosis, but the underlying molecular basis is poorly understood. The OPTN variant, M98K has been described as a risk factor for normal tension glaucoma in some ethnic groups. Here, we examined the consequence of the M98K mutation in affecting cellular functions of OPTN. Overexpression of M98K-OPTN induced death of retinal ganglion cells (RGC-5 cell line), but not of other neuronal and non-neuronal cells. Enhanced levels of the autophagy marker, LC3-II, a post-translationally modified form of LC3, in M98K-OPTN-expressing cells and the inability of an LC3-binding-defective M98K variant of OPTN to induce cell death, suggested that autophagy contributes to cell death. Knockdown of Atg5 reduced M98K-induced death of RGC-5 cells, further supporting the involvement of autophagy. Overexpression of M98K-OPTN enhanced autophagosome formation and potentiated the delivery of transferrin receptor to autophagosomes for degradation resulting in reduced cellular transferrin receptor levels. Coexpression of transferrin receptor or supplementation of media with an iron donor reduced M98K-induced cell death. OPTN complexes with RAB12, a GTPase involved in vesicle trafficking, and M98K variant shows enhanced colocalization with RAB12. Knockdown of Rab12 increased transferrin receptor level and reduced M98K-induced cell death. RAB12 is present in autophagosomes and knockdown of Rab12 resulted in reduced formation of autolysosomes during starvation-induced autophagy, implicating a role for RAB12 in autophagy. These results also show that transferrin receptor degradation and autophagy play a crucial role in RGC-5 cell death induced by M98K variant of OPTN. PMID- 23357854 TI - Adult-onset cyclic esotropia: a case report. AB - PURPOSE: This case report presents the diagnosis and management of an adult patient with cyclic esotropia, a rare and poorly understood form of strabismus, that is characterized by alternating periods of manifest strabismus and orthotropia. Few cases of adult-onset cyclic strabismus have been reported. The etiology, pathogenesis, and treatment for this condition are reviewed. CASE REPORT: A 37-year-old man with high unilateral myopia and anisometropic amblyopia in his left eye developed cyclic esotropia 2 months after a scleral buckle procedure for a retinal detachment. A 48-hour cycle that consisted of a 24-hour period of orthotropia followed by a 24-hour period of constant left esotropia was present. Magnetic resonance imaging, electromyography, electroencephalography, and ocular and orbital echography were unremarkable, as was a neurological assessment that included fatigue and edrophonium testing. The patient was successfully managed with muscle surgery. CONCLUSIONS: The etiology and pathogenesis of adult-onset cyclic esotropia remain unknown. Cyclic esotropia should be considered in the differential diagnosis when an individual presents with a history of intermittent strabismus that is present some days and not others. PMID- 23357855 TI - Ocular discomfort in pterygium patients. AB - PURPOSE: To evaluate the relationship between ocular discomfort and pterygium clinical characteristics. METHODS: The ocular comfort index test was self completed by 25 men and 15 women (age [mean +/- SD], 43 +/- 11 years) with primary pterygium. Pterygium corneal area (PCA) and limbal perimeter, course and bilaterality of the lesion, visibility of episcleral vessels, conjunctival hyperemia, and exposure to dry or dusty environments were assessed. Spearman correlation and multiple linear regression were performed to evaluate the relationship between ocular discomfort and pterygium clinical characteristics. RESULTS: Ocular discomfort was inversely correlated with PCA (rho = -0.447, p < 0.01) and directly correlated with the exposure to dry or dusty environments (rho = 0.324, p < 0.05). The other studied factors did not show any significant relationship with discomfort symptoms. The linear regression analysis identified PCA as the only factor that significantly influenced ocular discomfort (R = 0.404, p < 0.01). CONCLUSIONS: The findings confirm an inverse linear relationship between ocular discomfort and PCA, providing evidence of corneal sensitivity loss in these patients. PMID- 23357856 TI - Visual impairment and myopia in Brazilian children: a population-based study. AB - PURPOSE: To determine the frequency of myopia and other causes of visual impairment (VI) in individuals aged 10 to 15 years who live in a typical Brazilian city. METHODS: Random selection of geographically based clusters was performed to obtain a sample of children aged 10 to 15 years in Gurupi City, Tocantins, Brazil. From June to August 2007, children in 12 clusters were enumerated through a door-to-door survey. All children with an uncorrected visual acuity (VA) worse than 20/32 in either eye were scheduled for ophthalmologic evaluation, including VA and ocular motility testing, cycloplegic refraction, and external, biomicroscopic, and dilated funduscopic examinations. The primary cause of VI was determined for eyes with an uncorrected VA of 20/40 or worse. RESULTS: A total of 1590 children were examined; 814 (51%) were boys and 776 (49%) were girls. The prevalence of uncorrected, presenting and best-corrected VA of 20/40 or worse in the better eye was 5.72%, 2.83%, and 0.81%, respectively. The primary cause of VI in one or both eyes was refractive error in 65 (89%) of 73 children, amblyopia in 4 (5.5%) of 73 children, retinal disorders in 3 (4.1%) of 73 children, and congenital cataracts in 1 (1.4%) of 73 children. In this population, the prevalence of VI-related myopia was 3.14%. CONCLUSIONS: The prevalence of VI among children aged 10 to 15 years in this typical Brazilian city is low and similar to other school-based studies, and most of the VI is caused by uncorrected myopia. PMID- 23357857 TI - Immunogenicity, protective efficacy and safety of a recombinant DNA vaccine encoding truncated Plasmodium yoelii sporozoite asparagine-rich protein 1 (PySAP1). AB - Although great efforts have been undertaken for the development of malaria vaccines, no completely effective malaria vaccines are available yet. Despite being clinically silent, the pre-erythrocytic stage is considered an ideal target for the development of malaria vaccines. Sporozoite asparagine-rich protein 1 (SAP1) is a sporozoite-localized protein that regulates the expression of UIS (upregulated in infectious sporozoites) genes, which are essential for the infectivity of sporozoites. In this study, a recombinant DNA vaccine encoding a predicted antigenic determinant region of Plasmodium yoelii SAP1 (PySAP1) was constructed. Immunization of mice with this DNA vaccine construct resulted in significant elevation of cytokines such as IFN-gamma, IL-2, IL-4 and IL-10, and total IgG as compared with control groups immunized with either the empty DNA vector or saline. After challenge with sporozoites, the group receiving the DNA vaccine showed delayed development of parasitemia and prolonged survival time compared with the control group. The DNA vaccine provided partial protection against P. yoelii 17XL infection, with an overall protection rate of 20%. In addition, the DNA vaccine did not show integration into the host genome. Further studies of SAP1 are needed to test whether it can be used as subunit vaccine candidate. PMID- 23357859 TI - Key issues for estimating the impact and cost-effectiveness of seasonal influenza vaccination strategies. AB - Many countries have considered or are considering modifying their seasonal influenza immunization policies. Estimating the impact of such changes requires understanding the existing clinical and economic burden of influenza, as well as the potential impact of different vaccination options. Previous studies suggest that vaccinating clinical risk groups, health care workers, children and the elderly may be cost-effective. However, challenges in such estimation include: (1) potential cases are not usually virologically tested; (2) cases have non specific symptoms and are rarely reported to surveillance systems; (3) endpoints for influenza proxies (such as influenza-like illness) need to be matched to case definitions for treatment costs, (4) disease burden estimates vary from year to year with strain transmissibility, virulence and prior immunity, (5) methods to estimate productivity losses due to influenza vary, (6) vaccine efficacy estimates from trials differ due to variation in subtype prevalence, vaccine match and case ascertainment, and (7) indirect (herd) protection from vaccination depends on setting-specific variables that are difficult to directly measure. Given the importance of knowing the impact of changes to influenza policy, such complexities need careful treatment using tools such as population-based trial designs, meta-analyses, time-series analyses and transmission dynamic models. PMID- 23357860 TI - Targeting antitumor CD4 helper T cells with universal tumor-reactive helper peptides derived from telomerase for cancer vaccine. AB - Current cancer immunotherapies predominantly rely on CD8(+) T cells to fight against tumors. However accumulative evidence showed that proinflammatory CD4(+) helper T cells are critical determinants of effective antitumor immunity. The utilization of universal tumor-reactive helper peptides from telomerase represents a powerful approach to the fully use of CD4(+) T cell-based immunotherapy. PMID- 23357858 TI - Tolerogenic vaccines for Multiple sclerosis. AB - Tolerogenic vaccines represent a new class of vaccine designed to re-establish immunological tolerance, restore immune homeostasis, and thereby reverse autoimmune disease. Tolerogenic vaccines induce long-term, antigen-specific, inhibitory memory that blocks pathogenic T cell responses via loss of effector T cells and gain of regulatory T cell function. Substantial advances have been realized in the generation of tolerogenic vaccines that inhibit experimental autoimmune encephalomyelitis in a preclinical setting, and these vaccines may be a prequel of the tolerogenic vaccines that may have therapeutic benefit in Multiple Sclerosis. The purpose here is to provide a snapshot of the current concepts and future prospects of tolerogenic vaccination for Multiple Sclerosis, along with the central challenges to clinical application. PMID- 23357861 TI - Skin microvascular morphology and hemodynamics during treatment with veno arterial extra-corporeal membrane oxygenation. AB - OBJECTIVES: To explore the potentials of microcirculatory assessments for predicting outcome of patients treated with extra corporeal membrane oxygenation for cardiogenic shock. METHODS: Eight patients with acute cardiogenic shock treated with ECMO and eight healthy controls were examined with skin vital microscopy and laser Doppler perfusion measurements. RESULTS: Three patients died on ECMO (group 1). Five patients were successfully weaned off ECMO (group 2). Four patients were discharged from hospital and one died after successful weaning from bleeding complications. Patients surviving ECMO (group 2) had microcirculatory findings comparable with healthy controls. Patients in group 1 showed major skin microvascular pathology: pericapillary bleedings (n = 1), pericapillary dark haloes (n = 2) and capillary micro thrombi (n = 1). As compared with survivors they had lower functional capillary density (FCD) (n = 3), higher heterogeneity of functional capillary density (n = 3) and significantly reduced capillary mean flow-categorical velocity (n = 2). Laser Doppler measurements in group 1 had non-significant lower laser Doppler flux values as compared with survivors and controls. CONCLUSION: Skin microvascular pathology as detected with video microscopy (pericapillary bleedings or haloes, micro-thrombi/capillaries with "no flow", low FCD with high spatial distribution heterogeneity or low mean flow-categorial velocity) seems to be associated with poor prognosis. PMID- 23357862 TI - QSPR modeling of n-octanol/air partition coefficients and liquid vapor pressures of polychlorinated dibenzo-p-dioxins. AB - The molecular geometries of 75 polychlorinated dibenzo-p-dioxins (PCDDs) were optimized using B3LYP/6-31G(*) method. The calculated structural parameters were taken as theoretical descriptors to establish two new novel QSPR models for n octanol/air partition coefficients (log K(OA)) and subcooled liquid vapor pressure (log P(L)) of PCDDs. The R(2) values of the two models are 0.983 and 0.985 respectively. Their standard deviations of prediction in modeling (SD) are 0.174 and 0.230 respectively. The results of leave-one-out (LOO) cross-validation for training set show that the two models exhibited optimum stability and good predictive power. PMID- 23357863 TI - Concentrations of polybrominated diphenyl ethers (PBDEs) in residential dust samples from Western Australia. AB - Polybrominated diphenyl ethers (PBDEs) are one of the most common types of brominated flame retardants applied to foams, plastics and textiles to prevent fires. These flame retardants are now regulated and are either banned or being voluntarily phased. However, as these chemicals are persistent humans continue to be exposed. Dust has been identified as an important source of exposure and hence residential concentrations are of interest. The aim of this paper was to determine the concentrations of PBDEs in samples of residential dust from the homes of pregnant women in Western Australia. Thirty residential dust samples were analysed for concentrations of 32 PBDE congeners. Samples were collected from urban and rural areas. PBDEs were detected in all residential dust samples with the sum of the most common PBDEs (Sigma(7) of BDEs 47, 99, 100, 153, 154, 183 and 209) ranging from 60.4 to 82400 ng g(-1) (median 571 ng g(-1)). DecaBDE makes up the highest proportion of PBDEs in residential dust, on average 66% of Sigma(32)PBDEs. We did not find a relationship between housing characteristics nor the presence of appliances and PBDE concentrations. Dust from urban areas had significantly higher concentrations of BDE-209 and Sigma(32)PBDEs than dust from rural areas of Western Australia (p values 0.01 and 0.03 respectively). PBDEs were present in residential dust in Western Australia at concentrations higher than reported previously in Australia. Further investigation of sources with a larger sample size is required to determine associations between PBDE concentrations and potential exposure sources and geographical regions. PMID- 23357864 TI - Automatic identification of activated sludge disturbances and assessment of operational parameters. AB - Activated sludge systems are prone to be affected by changes in operating conditions leading to problems such as pinpoint flocs formation, filamentous bulking, dispersed growth, and viscous bulking. These problems are often related with the floc structure and filamentous bacteria contents. In this work, a lab scale activated sludge system was operated sequentially obtaining filamentous bulking, pinpoint floc formation, viscous bulking and normal conditions. Image processing and analysis techniques were used to characterize the contents and structure of aggregated biomass and the contents of filamentous bacteria. Further principal component and decision trees analyses permitted the identification of different conditions from the collected morphological data. Furthermore, a partial least squares analysis allowed to estimate the sludge volume index and suspended solids key parameters. The obtained results show the potential of image analysis procedures, associated with chemometric techniques, in activated sludge systems monitoring. PMID- 23357865 TI - Effects of zinc oxide and titanium dioxide nanoparticles on green algae under visible, UVA, and UVB irradiations: no evidence of enhanced algal toxicity under UV pre-irradiation. AB - Some metal oxide nanoparticles are photoreactive, thus raising concerns regarding phototoxicity. This study evaluated ecotoxic effects of zinc oxide nanoparticles and titanium dioxide nanoparticles to the green algae Pseudokirchneriella subcapitata under visible, UVA, and UVB irradiation conditions. The nanoparticles were prepared in algal test medium, and the test units were pre-irradiated by UV light in a photoreactor. Algal assays were also conducted with visible, UVA or UVB lights only without nanoparticles. Algal growth was found to be inhibited as the nanoparticle concentration increased, and ZnO NPs caused destabilization of the cell membranes. We also noted that the inhibitory effects on the growth of algae were not enhanced under UV pre-irradiation conditions. This phenomenon was attributed to the photocatalytic activities of ZnO NPs and TiO2 NPs in both the visible and UV regions. The toxicity of ZnO NPs was almost entirely the consequence of the dissolved free zinc ions. This study provides us with an improved understanding of toxicity of photoreactive nanoparticles as related to the effects of visible and UV lights. PMID- 23357866 TI - Phytotoxicity and stimulatory impacts of nanosized and bulk titanium dioxide on fennel (Foeniculum vulgare Mill). AB - The objective of the this study was to compare concentrations of nanosized TiO2 at 0, 5, 20, 40, 60 and 80 mg L(-1) with bulk TiO2 for phytotoxic and stimulatory effects on fennel seed germination and early growth stage. After 14 d of seed incubation, germination percentage highly improved following exposure to 60 ppm nanosized TiO2. Similar positive effects occurred in terms of shoot dry weight and germination rate. Application of bulk TiO2 particles in 40 ppm concentration greatly decreased shoot biomass up to 50% compared to the control. Application of 40 ppm nanosized TiO2 treatment improved mean germination time by 31.8% in comparison to the untreated control. In addition, low and intermediate concentrations of nanosized TiO2 enhanced indices such as germination value, vigor index and mean daily germination. In general, there was a considerable response by fennel seed to nanosized TiO2 presenting the possibility of a new approach to overcome problems with seed germination in some plant species, particularly medicinal plants. PMID- 23357867 TI - Synthesis, characterization and the antimicrobial activity of new eco-friendly ionic liquids. AB - A green microwave-assisted procedure for the preparation of a series of 24 new 1 alkyl-3-ethylimidazolium ionic liquids with different functional groups in the alkyl chain is described. Moreover, the synthesis of a variety of ten new geminal dicationic ionic liquids is reported. Their structures were characterized by FT IR, (1)H NMR, (13)C NMR, (11)B, (19)F, (31)P, and mass spectrometry. Several ionic liquids were selected for antimicrobial activity studies, yielding very interesting and promising results. PMID- 23357868 TI - Oxidation of volatile organic vapours in air by solid potassium permanganate. AB - Volatile organic compounds (VOCs) may frequently contaminate groundwater and pose threat to human health when migrating into the unsaturated soil zone and upward to the indoor air. The kinetic of chemical oxidation has been investigated widely for dissolved VOCs in the saturated zone. But, so far there have been few studies on the use of in situ chemical oxidation (ISCO) of vapour phase contaminants. In this study, batch experiments were carried out to evaluate the oxidation of trichloroethylene (TCE), ethanol, and toluene vapours by solid potassium permanganate. Results revealed that solid potassium permanganate is able to transform the vapour of these compounds into harmless oxidation products. The degradation rates for TCE and ethanol were higher than for toluene. The degradation process was modelled using a kinetic model, linear in the gas concentration of VOC [ML(-3)] and relative surface area of potassium permanganate grains (surface area of potassium permanganate divided by gas volume) [L(-1)]. The second-order reaction rate constants for TCE, ethanol, and toluene were found to be equal to 2.0*10(-6) cm s(-1), 1.7*10(-7) cm s(-1), and 7.0*10(-8) cm s(-1), respectively. PMID- 23357869 TI - Potential effects of CRM1 inhibition in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma. The disease has no known cure, which prompts the urgent need for novel therapeutic agents. Chromosomal region maintenance 1 (CRM1) may play a role in human neoplasia and serve as a novel target of cancer treatment. This study summarizes MCL pathogenesis and determines the involvement of CRM1 in the regulation of several vital signaling pathways contributing to MCL pathogenesis, including the pathways of cell cycle progression, DNA damage response, phosphoinositide kinase-3, nuclear factor-kappaB activation, and chromosomal stability. A preclinical study is also presented to compare the CRM1 status in MCL cell lines and primary MCL cells with normal B cells, as well as the therapeutic efficiency of CRM1 inhibition in MCL in vitro and in vivo, which make these agents potential targets of novel MCL treatments. PMID- 23357870 TI - The tumor suppressor gene ARHI (DIRAS3) inhibits ovarian cancer cell migration through multiple mechanisms. AB - ARHI is an imprinted tumor suppressor gene that is downregulated in > 60% of ovarian cancers, associated with decreased progression-free survival. ARHI encodes a 26 kDa GTPase with homology to Ras. Re-expression of ARHI inhibits ovarian cancer growth, initiates autophagy and induces tumor dormancy. Recent studies have demonstrated that ARHI also plays a particularly important role in ovarian cancer cell migration. Re-expression of ARHI decreases motility of IL-6- and EGF-stimulated SKOv3 and Hey ovarian cancer cells, inhibiting both chemotaxis and haptotaxis. ARHI inhibits cell migration by binding and sequestering STAT3 in the cytoplasm, and preventing STAT3 translocation to the nucleus and localization in focal adhesion complexes. Re-expression of ARHI inhibits FAK (Y397) phosphorylation, disrupts focal adhesions and blocks FAK-mediated RhoA signaling, resulting in decreased levels of GTP-RhoA. Re-expression of ARHI disrupts formation of actin stress fibers in a FAK- and RhoA-dependent manner. Recent studies indicate that re-expression of ARHI inhibits expression of beta-1 integrin which may also contribute to inhibition of migration, adhesion and invasion. PMID- 23357871 TI - Positional bias of MHC class I restricted T-cell epitopes in viral antigens is likely due to a bias in conservation. AB - The immune system rapidly responds to intracellular infections by detecting MHC class I restricted T-cell epitopes presented on infected cells. It was originally thought that viral peptides are liberated during constitutive protein turnover, but this conflicts with the observation that viral epitopes are detected within minutes of their synthesis even when their source proteins exhibit half-lives of days. The DRiPs hypothesis proposes that epitopes derive from Defective Ribosomal Products (DRiPs), rather than degradation of mature protein products. One potential source of DRiPs is premature translation termination. If this is a major source of DRiPs, this should be reflected in positional bias towards the N terminus. By contrast, if downstream initiation is a major source of DRiPs, there should be positional bias towards the C-terminus. Here, we systematically assessed positional bias of epitopes in viral antigens, exploiting the large set of data available in the Immune Epitope Database and Analysis Resource. We show a statistically significant degree of positional skewing among epitopes; epitopes from both ends of antigens tend to be under-represented. Centric-skewing correlates with a bias towards class I binding peptides being over-represented in the middle, in parallel with a higher degree of evolutionary conservation. PMID- 23357872 TI - Methods to identify enzymes that degrade the main extracellular polysaccharide component of Staphylococcus epidermidis biofilms. AB - The production of extracellular poly-beta-1,6-N-acetyl-D-glucosamine (PNAG) by Staphylococcus epidermidis is the principal determinant of biofilm formation on indwelling medical devices. Enzymes that degrade PNAG therefore provide an attractive strategy for biofilm removal and for the manufacture of biofilm resistant coatings. Here we present methods that allow the identification of PNAG degrading enzymes with the ability to detach biofilms. Our protocol includes the preparation of soluble PNAG from S. epidermidis cultures, the incubation of soluble PNAG with candidate enzymes and assays that detect the release of N acetyl-D-glucosamine using high-pH anion-exchange chromatography (HPAEC) followed in parallel by pulsed amperometric detection (PAD) and online electrospray ionization mass spectrometry (ESI-MS). We validated our procedures using dispersin B, which is currently the only known PNAG-degrading enzyme. PMID- 23357874 TI - Oral mucosal adhesive films containing royal jelly accelerate recovery from 5 fluorouracil-induced oral mucositis. AB - Oral mucositis induced by chemotherapy or radiotherapy has an impact upon quality of-life, is dose-limiting for chemotherapy, and causes considerable morbidity. We evaluated the effect of royal jelly (RJ) on 5-fluorouracil (5-FU)-induced oral mucositis in hamsters. Oral mucositis was induced in hamsters through a combination of 5-FU treatment and mild abrasion of the cheek pouch. RJ was contained in chitosan-sodium alginate film (RJ film). Films were attached to the oral mucosa and the healing process examined by measuring the area of mucositis, myeloperoxidase (MPO) activity, microscopic aspects, and RT-PCR for detection of pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta). Furthermore, we evaluated the radical-scavenging activity of RJ and generation of keratinocyte growth factor from human periodontal ligament fibroblasts. RJ films (10%, 30%) significantly improved recovery from 5-FU-induced damage, reduced MPO activity and the production of pro-inflammatory cytokines. Additionally, RJ showed radical-scavenging activity. These data suggest that topical application of films that contain RJ had a healing effect on the severe oral mucositis induced by 5-FU and that the effect was caused by the anti-inflammatory or anti oxidative activities of RJ. PMID- 23357873 TI - Vibrio parahaemolyticus effector proteins suppress inflammasome activation by interfering with host autophagy signaling. AB - Bacterial pathogens utilize pore-forming toxins or sophisticated secretion systems to establish infection in hosts. Recognition of these toxins or secretion system by nucleotide-binding oligomerization domain leucine-rich repeat proteins (NLRs) triggers the assembly of inflammasomes, the multiprotein complexes necessary for caspase-1 activation and the maturation of inflammatory cytokines such as IL-1beta or IL-18. Here we demonstrate that both the NLRP3 and NLRC4 inflammasomes are activated by thermostable direct hemolysins (TDHs) and type III secretion system 1 (T3SS1) in response to V. parahaemolyticus infection. Furthermore, we identify T3SS1 secreted effector proteins, VopQ and VopS, which induce autophagy and the inactivation of Cdc42, respectively, to prevent mainly NLRC4 inflammasome activation. VopQ and VopS interfere with the assembly of specks in infected macrophages. These data suggest that bacterial effectors interfere with inflammasome activation and contribute to bacterial evasion from the host inflammatory responses. PMID- 23357875 TI - Differentiation-inducing factor-1 suppresses the expression of c-Myc in the human cancer cell lines. AB - Differentiation-inducing factor-1 (DIF-1), a morphogen for Dictyostelium discoideum, inhibits the proliferation of human cancer cell lines by suppressing the Wnt/beta-catenin signaling pathway. In this study, we examined the effect of DIF-1 on c-Myc, a target gene product of the Wnt/beta-catenin signaling pathway, mainly using HCT-116 colon cancer cells. DIF-1 strongly reduced the amount of c Myc protein in time- and concentration-dependent manners and reduced c-Myc mRNA expression by inhibiting promoter activity through the TCF binding sites. The effect of DIF-1 on c-Myc was also confirmed using the human cervical cell line HeLa. Pretreatment with the proteasome inhibitor MG132 or glycogen synthase kinase-3beta (GSK-3beta) inhibitors (LiCl and SB216763) attenuated the effect of DIF-1, suggesting that DIF-1 induced c-Myc protein degradation through GSK-3beta activation. Furthermore, we examined whether c-Myc was involved in the anti proliferative effect of DIF-1 using c-Myc-overexpressing cells and found that c Myc was associated with the anti-proliferative effect of this compound. These results suggest that DIF-1 inhibits c-Myc expression by inhibiting promoter activity and inducing protein degradation via GSK-3beta activation, resulting in the inhibition of cell proliferation. Since c-Myc seems to be profoundly involved in accelerated proliferation of various malignant tumors, DIF-1 may have a potential to develop into a novel anti-cancer agent. PMID- 23357876 TI - Higher risk of wheeze in female than male smokers. Results from the Swedish GA 2 LEN study. AB - BACKGROUND: Women who smoke have higher risk of lung function impairment, COPD and lung cancer than smoking men. An influence of sex hormones has been demonstrated, but the mechanisms are unclear and the associations often subject to confounding. This was a study of wheeze in relation to smoking and sex with adjustment for important confounders. METHODS: In 2008 the Global Allergy and Asthma European Network (GA(2)LEN) questionnaire was mailed to 45.000 Swedes (age 16-75 years), and 26.851 (60%) participated. "Any wheeze": any wheeze during the last 12 months. "Asthmatic wheeze": wheeze with breathlessness apart from colds. RESULTS: Any wheeze and asthmatic wheeze was reported by 17.3% and 7.1% of women, vs. 15.8% and 6.1% of men (both p<0.001). Although smoking prevalence was similar in both sexes, men had greater cumulative exposure, 16.2 pack-years vs. 12.8 in women (p<0.001). Most other exposures and characteristics associated with wheeze were significantly overrepresented in men. Adjusted for these potential confounders and pack-years, current smoking was a stronger risk factor for any wheeze in women aged <53 years, adjusted odds ratio (aOR) 1.85 (1.56-2.19) vs. 1.60 (1.30-1.96) in men. Cumulative smoke exposure and current smoking each interacted significantly with female sex, aOR 1.02 per pack-year (p<0.01) and aOR 1.28 (p = 0.04) respectively. Female compared to male current smokers also had greater risk of asthmatic wheeze, aOR 1.53 vs. 1.03, interaction aOR 1.52 (p = 0.02). These interactions were not seen in age >= 53 years. DISCUSSION: In addition to the increased risk of COPD and lung cancer female, compared to male, smokers are at greater risk of significant wheezing symptoms in younger age. This became clearer after adjustment for important confounders including cumulative smoke exposure. Estrogen has previously been shown to increase the bioactivation of several compounds in tobacco smoke, which may enhance smoke-induced airway inflammation in fertile women. PMID- 23357877 TI - Inverse relationship of food and alcohol intake to sleep measures in obesity. AB - BACKGROUND: Short sleep and weight gain are inversely related. Sleep deprivation acutely increases food intake but little is known about eating behavior in chronically sleep-deprived, obese individuals. OBJECTIVE: To characterize the relationship between sleep, food intake and alcohol consumption under free-living conditions in obese, chronically sleep-deprived individuals. DESIGN: Cross sectional study of a cohort of obese men and premenopausal women. SUBJECTS: A total of 118 obese subjects (age: 40.3+/-6.7 years; 91 females/27 males; body mass index 38.7+/-6.4 kg m(-2)). MEASUREMENTS: Energy, macronutrient, alcohol and caffeine intake assessed by 3-day food records. Sleep duration estimated by actigraphy. Respiratory disturbance index assessed by a portable device. RESULTS: SUBJECTS slept 360.7+/-50.2 min per night and had a total energy intake of 2279.1+/-689 kcal per day. Sleep duration and energy intake were inversely related (r=-0.230, P=0.015). By extrapolation, each 30-min deficit per day in sleep duration would translate to an ~83 kcal per day increase in energy intake. In addition, sleep apnea was associated with a shift from carbohydrate to fat intake. Alcohol intake in subjects consuming >3.5 g of alcohol per day (N=41) was inversely related to sleep duration (r=-0.472, P=0.002). CONCLUSIONS: Shorter sleep duration and obstructive sleep apnea are associated with higher energy, fat and alcohol intakes in obese individuals. The importance of this study relies on the population studied, obese subjects with chronic sleep deprivation. These novel findings apply to the large segment of the US population who are obese and sleep-deprived. PMID- 23357878 TI - Mechanisms underlying cancer progression caused by ezrin overexpression in tongue squamous cell carcinoma. AB - BACKGROUND: Ezrin is a member of the ezrin, radixin, and moesin family that provides a functional link between the plasma membrane and the cortical actin cytoskeleton. A correlation between ezrin overexpression and aggressive cancer behavior has been recently reported in various tumor types. However, its roles in the mechanisms underlying progression of tongue squamous cell carcinoma (SCC) are unclear. METHOD: We used human tongue SCC and noncancerous tissue microarrays to immunohistochemically analyze the ezrin expression level and its relationship with proliferative activity. The human tongue SCC cell line HSC-3 was used to determine the effects of ezrin RNA interference (RNAi) on cancer cells during MTT; wound healing and invasion assays; immunofluorescence of the actin cytoskeleton; and western blotting of E-cadherin, N-cadherin, beta-catenin, and the active and total RhoA/Rac1/cdc42. RESULTS: Ezrin was overexpressed in 46.4% of the tumors examined in human tongue SCC tissue microarrays. Ezrin expression was correlated with the Ki-67 index. Ezrin depletion by RNAi in the HSC-3 cells significantly reduced cell proliferation, migration, and invasiveness and disturbed actin reorganization during podia formation. Its effects on RhoA/Rac1/cdc42 expression were not significant, whereas it enhanced E-cadherin and beta-catenin expression and decreased N-cadherin expression. CONCLUSIONS: Ezrin is often overexpressed in primary tongue SCCs and may have an important role in their growth, migration, and invasiveness possibly via its relationship with the E-cadherin/beta-catenin complex and the cadherin switch. Thus, ezrin could be a therapeutic target in tongue SCC. PMID- 23357879 TI - Wild-Type KRAS and BRAF Could Predict Response to Cetuximab in Chinese Colorectal Cancer Patients. AB - OBJECTIVE: To analyze the relationship between KRAS, BRAF mutations and the response toCetuximab in Chinese colorectal cancer patients. METHODS: A total of273 Chinese colorectal cancer patients were evaluated for KRAS and BRAF mutations by Sanger sequencing. Among them, 59 patients with metastatic colorectal cancer (mCRC) were treated with Cetuximab in combination with chemotherapy from August 2005 to July 2009. Statistical analysis was conducted to assess the relationship between KRAS, BRAF mutations and the response or survival of 59 mCRC patients. RESULTS: KRAS and BRAF mutation rates were 38.5% (105/273) and 5.1% (14/273), respectively, and KRAS/BRAF mutations were mutually exclusive. Among 59 patients treated with Cetuximab plus chemotherapy, KRAS and BRAF mutations were identified in 11and 5 patients, respectively. The response rates and median progression-free survivals (PFS) in KRAS wild-type and mutant patients were 35.4% (17/48) vs. 9.1% (1/11) (P=0.054) and 153 days vs. 99 days (P=0.01), respectively.Also, the response rates and median PFS in BRAF wild-type and mutant patients were 37.2% (16/43) vs. 20% (1/5) (P=0.016) and 138 days vs. 90 days (P=0.036), respectively. CONCLUSION: Besides KRAS, assessing BRAF mutation should also be required to select patients eligible for Cetuximab. Further prospective evaluation in large samples should be performed to confirm these preliminary findings. PMID- 23357880 TI - Drug-Initiated, Controlled Ring-Opening Polymerization for the Synthesis of Polymer-Drug Conjugates. AB - Paclitaxel, a polyol chemotherapeutic agent, was covalently conjugated through its 2'-OH to polylactide with 100% regioselectivity via controlled polymerization of lactide mediated by paclitaxel/(BDI-II)ZnN(TMS)(2) (BDI-II = 2-((2,6 diisopropylphenyl)amino)-4-((2,6-diisopropylphenyl)imino)-2-pentene). The steric bulk of the substituents on the N-aryl groups of the BDI ligand drastically affected the regiochemistry of coordination of the metal catalysts to paclitaxel and the subsequent ring-opening polymerization of lactide. The drug-initiated, controlled polymerization of lactide was extended, again with 100% regioselectivity, to docetaxel, a chemotherapeutic agent that is even more structurally complex than paclitaxel. Regioselective incorporation of paclitaxel (or docetaxel) to other biopolymers (i.e., poly(delta-valerolactone), poly(trimethylene carbonate), and poly(epsilon-caprolactone)), was also achieved through drug/(BDI-II)ZnN(TMS)(2)-mediated controlled polymerization. These drug polylactide conjugates with precisely controlled structures are expected to be excellent building blocks for drug delivery, coating, and controlled-release applications. PMID- 23357882 TI - Innate lymphoid cells: from border protection to the initiation of inflammatory diseases. AB - Innate lymphoid cells (ILC) are a recently discovered group of innate lymphocytes found at mucosal surfaces. The transcriptional and effector programs of ILC strikingly resemble those of the various T-helper (Th) cell fates (that is, Th1, Th2, Th9, Th17, Th22). ILC are involved in protecting the mucosal borders by producing tissue protective factors. More recently, evidence has been provided that inappropriately activated ILC can be drivers of various inflammatory disorders. Here, we will highlight recent developments in our understanding of the transcriptional and developmental programs controlling ILC specification and fate decisions. We will also review the roles assigned to ILC in protecting barriers and in promoting inflammatory diseases. Finally, we will outline how the power of ILC may be harnessed for clinical application, and how interference with ILC function may be used as a new strategy to treat inflammatory diseases. PMID- 23357881 TI - Structural basis of a histone H3 lysine 4 demethylase required for stem elongation in rice. AB - Histone lysine methylation is an important epigenetic modification in regulating chromatin structure and gene expression. Histone H3 lysine 4 methylation (H3K4me), which can be in a mono-, di-, or trimethylated state, has been shown to play an important role in gene expression involved in plant developmental control and stress adaptation. However, the resetting mechanism of this epigenetic modification is not yet fully understood. In this work, we identified a JmjC domain-containing protein, JMJ703, as a histone lysine demethylase that specifically reverses all three forms of H3K4me in rice. Loss-of-function mutation of the gene affected stem elongation and plant growth, which may be related to increased expression of cytokinin oxidase genes in the mutant. Analysis of crystal structure of the catalytic core domain (c-JMJ703) of the protein revealed a general structural similarity with mammalian and yeast JMJD2 proteins that are H3K9 and H3K36 demethylases. However, several specific features were observed in the structure of c-JMJ703. Key residues that interact with cofactors Fe(II) and N-oxalylglycine and the methylated H3K4 substrate peptide were identified and were shown to be essential for the demethylase activity in vivo. Several key residues are specifically conserved in known H3K4 demethylases, suggesting that they may be involved in the specificity for H3K4 demethylation. PMID- 23357883 TI - Use of urostomy bags in the management of perioperative urine leakage after radical cystectomy. AB - BACKGROUND: Urine leakage is a common complication in patients with bladder cancer after radical cystectomy and neobladder reconstruction. OBJECTIVE: The aim of this study was to evaluate the clinical value of the use of urostomy bags in the management of urine leakage in patients with bladder cancer after radical cystectomy. METHODS: Urine leakage during the perioperative period was retrospectively analyzed in 483 patients with bladder cancer who underwent radical cystectomy from 2004 to 2010. Before 2008, all patients with urine leakages were treated by routine dressing changes (group A). After 2008, the leakages were managed with urostomy bags (group B). The perioperative quality of life (EQ-5D) and cost for urine leakage for both groups were compared in this controlled study. RESULTS: The average cost in management of preoperative urine leakage was significantly higher in group A than in group B as well as the patients with extravasations of urine or lymphoceles. Patients in group B had an overall better perioperative life quality compared with group A. In particular, the score for pain/discomfort was significantly higher in group A than in group B. CONCLUSIONS: The management of perioperative urine leakage with urostomy bags avoided constant body wetness and significantly increased the quality of life and reduced the special costs of urine leakage in patients with bladder cancer after cystectomy. IMPLICATIONS FOR PRACTICE: Early use of urostomy bag is a good choice for perioperative urine leakage in patients with bladder cancer after radical cystectomy and neobladder reconstruction. PMID- 23357884 TI - Factors relating to quality of life after esophagectomy for cancer patients in Taiwan. AB - BACKGROUND: Little is known regarding the short-term quality of life (QoL) and predictive factors for QoL after esophagectomy for cancer in Eastern countries. OBJECTIVE: The aims of this study were to assess QoL and symptoms within 1 and 6 months after surgery for esophageal cancer (EC) and to identify factors predictive of QoL within 6 months after esophagectomy in Taiwan. METHODS: A longitudinal, prospective design was used, where convenience samples of 99 patients who had undergone esophagectomy for cancer were recruited from 2 medical centers in northern Taiwan. All participants responded to a questionnaire with a QLQ-C30 (Quality of Life Questionnaire-Cancer) core and a QLQ-OES18 (esophageal module of the European Organization for Research and Treatment [EORTC] QLQ-C30) module in structured interviews at baseline and 1 and 6 months after surgery. RESULTS: The results showed significant decline in social function and global QoL; fatigue, insomnia, eating problems, reflux, and dry mouth were major problems within 6 months. Body mass index, body weight loss before surgery, activity performance status, and anastomosis site showed no significant association with the function and symptom aspect of QoL. Surgical complications, advanced cancer, neoadjuvant therapy before surgery, and tumor location other than at the EC junction had significant deleterious effects on several aspects of QoL. CONCLUSIONS: This study describes the demographics of EC and short-term changes in QoL and also the predictive impact factor for QoL after surgery for EC. IMPLICATIONS FOR PRACTICE: Knowledge of risk factors for poor postoperative QoL would be useful for health providers in detecting and prioritizing problems and treatment options in a busy clinical site. PMID- 23357885 TI - The Swedish version of the Frommelt Attitude Toward Care of the Dying scale: aspects of validity and factors influencing nurses' and nursing students' attitudes. AB - BACKGROUND: Nurses' attitudes toward caring for dying persons need to be explored. The Frommelt Attitude Toward Care of the Dying (FATCOD) scale has not previously been used in Swedish language. OBJECTIVES: The objectives of this study were to compare FATCOD scores among Swedish nurses and nursing students with those from other languages, to explore the existence of 2 subscales, and to evaluate influences of experiences on attitudes toward care of dying patients. METHODS: A descriptive, cross-sectional, and predictive design was used. The FATCOD scores of Swedish nurses from hospice, oncology, surgery clinics, and palliative home care and nursing students were compared with published scores from the United States, Israel, and Japan. Descriptive statistics, t tests, and factor and regression analyses were used. RESULTS: The sample consisted of 213 persons: 71 registered nurses, 42 enrolled nurses, and 100 nursing students. Swedish FATCOD mean scores did not differ from published means from the United States and Israel, but were significantly more positive than Japanese means. In line with Japanese studies, factor analyses yielded a 2-factor solution. Total FATCOD and subscales had low Cronbach alpha's. Hospice and palliative team nurses were more positive than oncology and surgery nurses to care for dying patients. CONCLUSIONS: Although our results suggest that the Swedish FATCOD may comprise 2 distinct scales, the total scale may be the most adequate and applicable for use in Sweden. Professional experience was associated with nurses' attitudes toward caring for dying patients. IMPLICATION FOR PRACTICE: Care culture might influence nurses' attitudes toward caring for dying patients; the benefits of education need to be explored. PMID- 23357886 TI - Comparison of the effects of a supervised exercise program and usual care in patients with colorectal cancer undergoing chemotherapy. AB - BACKGROUND: Although exercise has been addressed as a promising therapy for cancer adverse effects, few studies have evaluated the beneficial effects of exercise for colorectal cancer (CRC) patients during chemotherapy. OBJECTIVE: The purpose of this study was to compare the effects of supervised-exercise intervention with those of usual care on cardiorespiratory fitness, muscle strength, fatigue, emotional distress, sleep quality, and quality of life (QoL) in patients with CRC undergoing chemotherapy. METHODS: Patients with stage II or III CRC admitted for adjuvant chemotherapy were allocated to either a supervised exercise group that received a combined aerobic and resistance exercise program or a "usual care" control group for 12 weeks. The outcomes, QoL, muscle strength, cardiorespiratory fitness, emotional distress, physical activity, fatigue, and sleep quality, were assessed at baseline and after intervention. RESULTS: Significant interactions between intervention and time were observed for the role functioning and pain subscales of QoL and physical activity level. The time main effects were significant for the secondary outcomes: hand-grip strength, cardiorespiratory fitness, physical activity level, and physical functioning, role functioning, social functioning, fatigue, and pain subscales of QoL. CONCLUSION: Compared with usual care, the supervised exercise demonstrated larger effects than usual care on physical activity level and role functioning and pain subscales of QoL. IMPLICATIONS FOR PRACTICE: Supervised-exercise program is suggested to be incorporated as part of supportive care to promote the cardiorespiratory fitness, muscle strength, physical activity level, and QoL of patients with CRC undergoing chemotherapy. PMID- 23357887 TI - A substance use decision aid for medically at-risk adolescents: results of a randomized controlled trial for cancer-surviving adolescents. AB - BACKGROUND: Adolescent survivors of childhood cancer engage in risky behaviors. OBJECTIVE: This study tested a decision aid for cancer-surviving adolescents aimed at difficult decisions related to engaging in substance use behaviors. METHODS: This randomized controlled trial recruited 243 teen survivors at 3 cancer centers. The cognitive-behavioral skills program focused on decision making and substance use within the context of past treatment. Effects at 6 and 12 months were examined for decision making, risk motivation, and substance use behaviors using linear regression models. RESULTS: The majority of the teen cancer survivors (90%) rated the program as positive. There was an intermediate effect at 6 months for change in risk motivation for low riskers, but this effect was not sustained at 12 months. For quality decision making, there was no significant effect between treatment groups for either time point. CONCLUSIONS: The overall program effects were modest. Once teen survivors are in the program and learn what quality decision making is, their written reports indicated adjustment in their perception of their decision-making ability; thus, a more diagnostic baseline decision-making measure and a more intensive intervention are needed in the last 6 months. With 2 of 3 teen participants dealing with cognitive difficulties, the data suggest that this type of intervention will continue to be challenging, especially when 90% of their household members and 56% of their close friends model substance use. IMPLICATIONS FOR PRACTICE: This effectiveness trial using late-effects clinics provides recommendations for further program development for medically at-risk adolescents, particularly ones with cognitive difficulties. PMID- 23357888 TI - Measurement of quality of life in patients with end-stage cancer. AB - BACKGROUND: Cancer is the leading cause of death in Korean adults. A good quality of life for patients at end life can control pain and symptoms and help maintain well-being. OBJECTIVE: The aim of this study was to measure quality of life in end-stage cancer patients using the Korean version of the McMaster Quality of Life (K-MQOL). METHODS: The K-MQOL was administered to adult end-stage cancer patients from 4 Korean university hospitals. We hypothesized quality-of-life differences between participants by daily activity level, number of symptoms, and participant status (alive or not) at end of study. RESULTS: Participants' mean age was 49.2 years, and 74.5% were men. As hypothesized for discriminant validity, Pearson correlation coefficients among the K-MQOL were less than 0.4, with the exceptions of emotion (0.25-0.52) and cognition (0.33-0.51). A higher Eastern Cooperative Oncology Group Performance States Rating score was significantly associated with a lower quality of life (F = 2.840, P = 0.034). The mean score of those within 21 days of death was significantly lower than that of patients who were alive at the end of the study (t = -2.48, P = .04). Patients with a smaller number of symptoms other than pain had significantly higher quality-of-life scores than did those with more symptoms (F = 5.059, P = .004). CONCLUSIONS: The K-MQOL provided reliable and valid scores of quality of life in end-stage cancer patients. IMPLICATIONS FOR PRACTICE: Assessing end-stage cancer patients' quality of life helps to identify each patient's condition and aspects that could benefit from nursing care. We anticipate that the K-MQOL will be useful for patient assessment in clinical and community settings. PMID- 23357889 TI - The prostate cancer journey: results of an online survey of men and their partners. AB - BACKGROUND: The initial impact of treatments for men with prostate cancer is well reported in the literature. Less is known about the psychosocial needs of these men as their journey after diagnosis and treatment continues into the months and years. OBJECTIVE: The objective of this study was to examine and understand the supportive care needs of men diagnosed and treated for prostate cancer at key identifiable periods of their cancer journey. METHODS: An international Web-based survey was conducted in 2012, investigating men's prostate cancer pathways. The survey was based on substantial qualitative research and assessed for validity and reliability before piloting. To provide a unique insight into men living with prostate cancer, the views of partners were also elicited. RESULTS: Completed questionnaires were obtained from 193 men and 40 partners from 6 nations. The physical and psychosocial impact of treatment and need for support varied along the cancer journey. Fear, distress, loss, regret, anxiety, low self-esteem, depression, changes in sexuality, masculinity, and relationships were also described by both men and partners as adverse effects of the diagnosis and treatment for prostate cancer. CONCLUSIONS: Wives and partners are a key psychosocial support to men with prostate cancer. They may also provide valuable insight into men's supportive care needs that men are often unable to recognize themselves. IMPLICATIONS FOR PRACTICE: Findings suggest that wives and partners of men with prostate cancer can provide nurses and healthcare authorities with a powerful and unique resource in providing supportive care for men who are challenged by prostate cancer. PMID- 23357890 TI - Breast cancer screening practices among Hong Kong Chinese women. AB - BACKGROUND: Although the incidence rates of breast cancer have been increasing remarkably in Hong Kong over the last 2 decades, little is known on breast cancer screening practices among this group of women. OBJECTIVES: This study aimed to report breast cancer screening practices among Hong Kong Chinese women and to examine the relationship between (1) demographic factors and (2) the modified Chinese Breast Cancer Screening Beliefs Questionnaire (CBCSB) score and women's breast screening behaviors. METHODS: A descriptive and cross-sectional method was used. Both English and Chinese versions of the modified CBCSB were administered. Of 946 Hong Kong Chinese women older than 18 years and invited to participate in the study, 753 (79.6%) completed and returned the questionnaire. RESULTS: The majority of participants (70%-90%) had heard of breast self-examination (BSE), clinical breast examination (CBE), and mammograms. Only 33.3% performed a BSE monthly; 37.8% and 32.7% of women within the targeted age group had a CBE annually and had a mammogram every 2 years, respectively. Being married and part time employment were positively associated with women who performed BSE as recommended. In terms of modified CBCSB score, women who had BSE, CBE, and mammogram as recommended had significantly higher scores on the subscale attitudes to health check-up. CONCLUSION: Attitudes toward health check-up was influential in compliance with breast cancer screening practices among Chinese Australian women. IMPLICATIONS FOR PRACTICE: Effort should be focused on specific subgroups of Hong Kong Chinese women, to fully understand the barriers involved in participating in breast cancer screening practices. PMID- 23357891 TI - Words of Wisdom: re: a systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer. PMID- 23357892 TI - Words of Wisdom: re: radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. PMID- 23357893 TI - Words of Wisdom: re: is near infrared fluorescence imaging using indocyanine green dye useful in robotic partial nephrectomy: a prospective comparative study of 94 patients. PMID- 23357894 TI - Words of Wisdom: re: trends in hospital volume and operative mortality for high risk surgery. PMID- 23357895 TI - Words of Wisdom: re: testosterone replacement therapy in the setting of prostate cancer treated with radiation. PMID- 23357896 TI - Words of Wisdom: re: international variation in prostate cancer incidence and mortality rates. PMID- 23357899 TI - Visuospatial memory and neuroimaging correlates in mild cognitive impairment. AB - Spatial abilities decline in normal aging and decrease faster and earlier in Alzheimer's disease (AD), but these deficits are under investigated. The main goals of this study were to assess visuospatial memory abilities in mild cognitive impairment (MCI), in order to verify whether these tasks might be valid as the standard cognitive test to differentiate MCI individuals from normal controls and to investigate the brain structural correlates of visuospatial deficits. Twenty MCI patients and fourteen healthy elderly controls underwent an experimental visuospatial battery, which also included self-rating spatial questionnaires, and structural MRI brain imaging. Compared to healthy elderly controls, MCI patients scored significantly worse in almost all visuospatial tasks. ROC analysis showed that visuospatial tasks had an elevated discriminant power between groups (AUC >0.90). Voxel-based morphometry analysis, compared to controls, disclosed a higher level of atrophy in frontal and medio-temporal regions and a different pattern of correlation between grey matter values and visuospatial performance, with wider distributed areas of the occipital and middle temporal cortex in the map and route learning. This study indicates that visuospatial memory tests are valid tools in completing the diagnostic evaluation of MCI. PMID- 23357900 TI - Buckling the equatorial anion plane: octahedral anion distortions in ferroic perovskites and related systems resolved via neutron diffraction. AB - A framework for describing anion displacements from perfect octahedra in perovskites has been developed for use with neutron diffraction data sets. We describe the distortions as noncoplanar arrangements, or buckling, of oxygen ions in any central plane of the octahedron, ignoring the central cation. Nonplanar distortions of octahedra have been calculated for perovskite structures contained within the Inorganic Crystal Structure Database. We find that antiferroelectric materials have buckling angles larger than ~2 degrees and ferroelectric materials have buckling angles between 0 degrees and 1 degrees . The trend is found as a function of solid solution composition and temperature for common antiferroelectrics. For example, the described method resolves a structural difference between the end members PbTiO(3) and PbZrO(3), which exhibit ferroelectric and antiferroelectric responses, respectively. This technique is applicable to other structures containing anion octahedra, e.g., pyrochlores, spinels, and tungsten bronzes. PMID- 23357901 TI - Active disturbance rejection control of temperature for ultrastable optical cavities. AB - This paper describes the application of a novel active disturbance rejection control (ADRC) to the stabilization of the temperature of two ultra-stable Fabry Perot cavities. The cavities are 10 cm long and entirely made of ultralow- expansion glass. The control is based on a linear extended state observer that estimates and compensates the disturbance in the system in real time. The resulting control is inherently robust and easy to tune. A digital implementation of ADRC gives a temperature instability of 200 MUK at one day of integration time. PMID- 23357897 TI - Collagen-based wound dressings for the treatment of diabetes-related foot ulcers: a systematic review. AB - BACKGROUND: Diabetic foot ulcers are a major source of morbidity, limb loss, and mortality. A prolonged inflammatory response, extracellular matrix degradation irregularities, and increased bacteria presence have all been hypothesized as major contributing factors in the delayed healing of diabetic wounds. Collagen components such as fibroblast and keratinocytes are fundamental to the process of wound healing and skin formation. Wound dressings that contain collagen products create a biological scaffold matrix that supports the regulation of extracellular components and promotes wound healing. METHODS: A systematic review of studies reporting collagen wound dressings used in the treatment of Diabetic foot ulcers was conducted. Comprehensive searches were run in Ovid MEDLINE, PubMed, EMBASE, and ISI Web of Science to capture citations pertaining to the use of collagen wound dressings in the treatment of diabetic foot ulcers. The searches were limited to human studies reported in English. RESULTS: Using our search strategy, 26 papers were discussed, and included 13 randomized designs, twelve prospective cohorts, and one retrospective cohort, representing 2386 patients with diabetic foot ulcers. Our design was not a formal meta-analysis. In those studies where complete epithelialization, 58% of collagen-treated wounds completely healed (weighted mean 67%). Only 23% of studies reported control group healing with 29% healing (weighted mean 11%) described for controls. CONCLUSION: Collagen-based wound dressings can be an effective tool in the healing of diabetic foot wounds. The current studies show an overall increase in healing rates despite limitations in study designs. This study suggests that future works focus on biofilms and extracellular regulation, and include high risk patients. PMID- 23357898 TI - Typical cell signaling response to ionizing radiation: DNA damage and extranuclear damage. AB - To treat many types of cancer, ionizing radiation (IR) is primarily used as external-beam radiotherapy, brachytherapy, and targeted radionuclide therapy. Exposure of tumor cells to IR can induce DNA damage as well as generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) which can cause non-DNA lesions or extracellular damage like lipid perioxidation. The initial radiation-induced cell responses to DNA damage and ROS like the proteolytic processing, as well as synthesis and releasing ligands (such as growth factors, cytokines, and hormone) can cause the delayed secondary responses in irradiated and unirradiated bystander cells through paracrine and autocrine pathways. PMID- 23357903 TI - Membrane hydrophone measurement and numerical simulation of HIFU fields up to developed shock regimes. AB - For the characterization of high-intensity focused ultrasound (HIFU) fields, hydrophone measurements should be performed in water in the whole range of the radiated power; however, cavitation occurs at high output, leading to the destruction of the hydrophone. To avoid this problem, a new hydrophone with additional protective layers covering the electrodes was developed and tested in the experiments. A single-element 1-MHz focusing ultrasound source was used for detailed measurements of the acoustic field in the axial and lateral planes. Measurements were performed with a new membrane hydrophone up to the focal peak compressional and rarefactional pressures of 55.6 and of 12.8 MPa, respectively, when the shock front had already formed in the waveform. Numerical modeling for the beams of periodic waves with an initially uniform amplitude distribution was performed, based on the Khokhlov-Zabolotskaya-Kuznetsov equation. Numerical solutions were compared with the experimental data and found to be in good agreement (within 10%). The influences of the limited bandwidth and the spatial averaging effect of the hydrophone on the accurate measurements of the acoustic field parameters were also investigated. PMID- 23357902 TI - Optical fluorescent imaging to monitor temporal effects of microbubble-mediated ultrasound therapy. AB - Microbubble-mediated ultrasound therapy can noninvasively enhance drug delivery to localized regions in the body. This technique can be beneficial in cancer therapy, but currently there are limitations to tracking the therapeutic effects. The purpose of this experiment was to investigate the potential of fluorescent imaging for monitoring the temporal effects of microbubble-mediated ultrasound therapy. Mice were implanted with 2LMP breast cancer cells. The animals underwent microbubble-mediated ultrasound therapy in the presence of Cy5.5 fluorescent labeled IgG antibody (large molecule) or Cy5.5 dye (small molecule) and microbubble contrast agents. Control animals were administered fluorescent molecules only. Animals were transiently imaged in vivo at 1, 10, 30, and 60 min post therapy using a small animal optical imaging system. Tumors were excised and analyzed ex vivo. Tumors were homogenized and emulsion imaged for Cy5.5 fluorescence. Monitoring in vivo results showed significant influx of dye into the tumor (p < 0.05) using the small molecule, but not in the large molecule group (p > 0.05). However, after tumor emulsion, significantly higher dye concentration was detected in therapy group tumors for both small and large molecule groups in comparison to their control counterparts (p <0.01). This paper explores a noninvasive optical imaging method for monitoring the effects of microbubble-mediated ultrasound therapy in a cancer model. It provides temporal information following the process of increasing extravasation of molecules into target tumors. PMID- 23357905 TI - Ultrasound perfusion analysis combining bolus-tracking and burst-replenishment. AB - A new signal model and processing method for quantitative ultrasound perfusion analysis is presented, called bolus-and-burst. The method has the potential to provide absolute values of blood flow, blood volume, and mean transit time. Furthermore, it provides an estimate of the local arterial input function which characterizes the arterial tree, allowing accurate estimation of the bolus arrival time. The method combines two approaches to ultrasound perfusion analysis: bolus-tracking and burst-replenishment. A pharmacokinetic model based on the concept of arterial input functions and tissue residue functions is used to model both the bolus and replenishment parts of the recording. The pharmacokinetic model is fitted to the data using blind deconvolution. A preliminary assessment of the new perfusion-analysis method is presented on clinical recordings. PMID- 23357904 TI - Controlled cavitation to augment SWL stone comminution: mechanistic insights in vitro. AB - Stone comminution in shock wave lithotripsy (SWL) has been documented to result from mechanical stresses conferred directly to the stone, as well as the activity of cavitational microbubbles. Studies have demonstrated that the presence of this cavitation activity is crucial for stone subdivision; however, its exact role in the comminution process remains somewhat weakly defined, in part because it is difficult to isolate the cavitational component from the shock waves themselves. In this study, we further explored the importance of cavitation in SWL stone comminution through the use of histotripsy ultrasound therapy. Histotripsy was used to target model stones designed to mimic the mid-range tensile fracture strength of naturally occurring cystine calculi with controlled cavitation at strategic time points in the SWL comminution process. All SWL was applied at a peak positive pressure (p+) of 34 MPa and a peak negative pressure (p-) of 8 MPa; a shock rate of 1 Hz was used. Histotripsy pulses had a p- of 33 MPa and were applied at a pulse repetition frequency (PRF) of 100 Hz. Ten model stones were sonicated in vitro with each of five different treatment schemes: A) 10 min of SWL (600 shocks) with 0.7 s of histotripsy interleaved between successive shocks (totaling to 42 000 pulses); B) 10 min of SWL (600 shocks) followed by 10 min of histotripsy applied in 0.7-s bursts (1 burst per second, totaling to 42 000 pulses); C) 10 min of histotripsy applied in 0.7-s bursts (42 000 pulses) followed by 10 min of SWL (600 shocks); D) 10 min of SWL only (600 shocks); E) 10 min of histotripsy only, applied in 0.7-s bursts (42 000 pulses). Following sonication, debris was collected and sieved through 8-, 6-, 4-, and 2-mm filters. It was found that scheme D, SWL only, generated a broad range of fragment sizes, with an average of 14.9 +/- 24.1% of the original stone mass remaining > 8 mm. Scheme E, histotripsy only, eroded the surface of stones to tiny particulate debris that was small enough to pass through the finest filter used in this study (<2 mm), leaving behind a single primary stone piece (>8 mm) with mass 85.1 +/- 1.6% of the original following truncated sonication. The combination of SWL and histotripsy (schemes A, B, and C) resulted in a shift in the size distribution toward smaller fragments and complete elimination of debris > 8 mm. When histotripsy-controlled cavitation was applied following SWL (B), the increase in exposed stone surface area afforded by shock wave stone subdivision led to enhanced cavitation erosion. When histotripsy-controlled cavitation was applied before SWL (C), it is likely that stone surface defects induced by cavitation erosion provided sites for crack nucleation and accelerated shock wave stone subdivision. Both of these effects are likely at play in the interleaved therapy (A), although shielding of shock waves by remnant histotripsy microbubble nuclei may have limited the efficacy of this scheme. Nevertheless, these results demonstrate the important role played by cavitation in the stone comminution process, and suggest that the application of controlled cavitation at strategic time points can provide an adjunct to traditional SWL therapy. PMID- 23357906 TI - Fine mapping of tissue properties on excised samples of melanoma and skin without the need for histological staining. AB - This paper develops a novel two-frequency approach for noninvasive evaluation of cancerous tissue with optimum depth and resolution. Frequencies of about 50 MHz are used in thickly sliced tissue to detect differences of the relative attenuation (C-scan mode scanning) with relatively limited resolution. Thus, suspect zones can be identified according to a quantitative criterion. These suspect zones are then selected for preparation of thin, transversal slices from within the original thick slices. Very-high-resolution (1-MUm) visualization of cells is obtained at around 600 MHz on these transversal sections and adjacent sections are prepared for histological study in parallel. The technique's feasibility and potential are demonstrated on both normal and cancerous (melanoma) skin tissue. Isotropy of the specimens is experimentally verified to ensure that conditions were coherent for use of a 5-layer, angular spectrum model made to simulate longitudinal velocity, allowing estimation of longitudinal velocity from semiquantitative V(z) data. PMID- 23357907 TI - Noninvasive vascular elastography using plane-wave and sparse-array imaging. AB - Stroke may occur when an atherosclerotic plaque ruptures in the carotid artery. Noninvasive vascular elastography (NIVE) visualizes the strain distribution within the carotid artery, which is related to its mechanical properties that govern plaque rupture. Strain elastograms obtained from the transverse plane of the carotid artery are difficult to interpret, because strain is estimated in Cartesian coordinates. Sparsearray (SA) elastography overcomes this problem by transforming shear and normal strain to polar coordinates. However, the SA's transmit power may be too weak to produce useful elastograms in the clinical setting. Consequently, we are exploring other imaging methods to solve this potential problem. This study evaluated the quality of elastograms produced with SA imaging, plane-wave (PW) imaging, and compounded-plane-wave (CPW) imaging. We performed studies on simulated and physical vessel phantoms, and the carotid artery of a healthy volunteer. All echo imaging was performed with a linear transducer array that contained 128 elements, operating at 5 MHz. In SA imaging, 7 elements were fired during transmission, but all 128 elements were active during reception. In PW imaging, all 128 elements were active during both transmission and reception. We created CPW images by steering the acoustic beam within the range of -15 degrees to 15 degrees in increments of 5 degrees . SA radial and circumferential strain elastograms were comparable to those produced using PW and CPW imaging. Additionally, side-lobe levels incurred during SA imaging were 20 dB lower than those produced during PW imaging, and 10 dB lower than those computed using CPW imaging. Overall, SA imaging performs well in vivo; therefore, we plan to improve the technique and perform preclinical studies. PMID- 23357908 TI - Time-of-flight measurement techniques for airborne ultrasonic ranging. AB - Airborne ultrasonic ranging is used in a variety of different engineering applications for which other positional metrology techniques cannot be used, for example in closed-cell locations, when optical line of sight is limited, and when multipath effects preclude electromagnetic-based wireless systems. Although subject to fundamental physical limitations, e.g., because of the temperature dependence of acoustic velocity in air, these acoustic techniques often provide a cost-effective solution for applications in mobile robotics, structural inspection, and biomedical imaging. In this article, the different techniques and limitations of a range of airborne ultrasonic ranging approaches are reviewed, with an emphasis on the accuracy and repeatability of the measurements. Simple time-domain approaches are compared with their frequency-domain equivalents, and the use of hybrid models and biologically inspired approaches are discussed. PMID- 23357909 TI - Reliable estimation of virtual source position for SAFT imaging. AB - The synthetic aperture focusing technique (SAFT), employing a scanned focused transducer as a virtual source, is commonly used to image flaws in immersion testing. The position of a virtual source is estimated from rays emitted from the rim of a focused transducer. However, it is often found that the virtual source position cannot be uniquely determined because of severe focal spot aberration at the focal zone. Based on an analysis of the energy radiated from the focused transducer and the refracted energy varied with the incident angle of ultrasound, we propose that paraxial rays emitted from the focused transducer are the best for estimating the position of a virtual source for incorporation into SAFT. This study results also shows that by using this simple virtual source position estimation for SAFT, the axial resolution and SNR of the reconstructed image can be greatly improved. This new approach minimizes the effect of such factors as refraction at high-velocity-contrast interfaces, distance of the transducer to the couplant-specimen interface, and the focal length of a focused transducer, which may cause focal spot aberration resulting in decreased sensitivity in SAFT imaging. PMID- 23357910 TI - Electromagnetic acoustic imaging. AB - Electromagnetic acoustic imaging (EMAI) is a new imaging technique that uses long wavelength RF electromagnetic (EM) waves to induce ultrasound emission. Signal intensity and image contrast have been found to depend on spatially varying electrical conductivity of the medium in addition to conventional acoustic properties. The resultant conductivity- weighted ultrasound data may enhance the diagnostic performance of medical ultrasound in cancer and cardiovascular applications because of the known changes in conductivity of malignancy and blood filled spaces. EMAI has a potential advantage over other related imaging techniques because it combines the high resolution associated with ultrasound detection with the generation of the ultrasound signals directly related to physiologically important electrical properties of the tissues. Here, we report the theoretical development of EMAI, implementation of a dual-mode EMAI/ultrasound apparatus, and successful demonstrations of EMAI in various phantoms designed to establish feasibility of the approach for eventual medical applications. PMID- 23357911 TI - Development of a thick film PZT foil sensor for use in structural health monitoring applications. AB - Acoustic emission (AE) monitoring is a technique of growing interest in the field of nondestructive testing (NDT). The use of AE devices to monitor the health of structural components is currently limited by the cost of AE equipment, which prohibits the permanent placement of AE devices on structures for the purposes of continuous monitoring and the monitoring of areas with limited access. Micro electromechanical systems (MEMS) can provide solutions to these problems. We present the manufacture of a 4.4-MUm-thick lead zirconate titanate (PZT) film on a 110-MUm-thick titanium foil substrate for use as an AE sensor. The thick-film sensor is benchmarked against commercially available AE sensors in static and dynamic monitoring applications. The thick-film AE device is found to perform well in the detection of AE in static applications. A low signal-to-noise ratio is found to prohibit the detection of AE in a dynamic application. PMID- 23357912 TI - 250 DPI at 1000 Hz acquisition rate S0 lamb wave digitizing pen. AB - This paper presents an active stylus (X, Y) flat digitizing tablet (AST). The tablet features an acquisition rate of 1000 pts/s with 0.1 mm resolution. The cordless stylus incorporates a 1-mA low-power pulse generator. Precision is limited by diffraction to about +/-0.3 mm on a 57 x 57 mm region of a 71 x 71 x 1 mm digitizing plate. Selective generation and detection of the S(0) Lamb mode with a precessing tip is the key feature of this tablet. We first highlight the ultrasonic propagation inside the stylus tip and stability of Lamb wave generation when the stylus is inclined, rotated, and slid. Then, modeling of the limitations imposed by diffraction of a 1-MHz burst S(0) plane Lamb wave packet is carried out. The model takes into account high-order zero crossing detection as well as reflections and shear horizontal (SH) conversions of the S(0) Lamb mode at free edges of a glass plate. Reflection and transmission through an isotropic PZT bar are also calculated. Finally, localization precision by time difference of arrival (TDOA) is calculated and experimentally verified near the borders of the plate, taking into account the angular sensitivity of the precessing tip. PMID- 23357913 TI - A multiple-scale perturbation approach to mode coupling in periodic plates. AB - In this paper, guided ultrasonic wave propagation is analyzed in an elastic plate with sinusoidal surface corrugations. The corrugated area acts as a finite-length grating which corresponds to a 1-D phononic crystal (PC). The multiple-scale perturbation technique is used to derive coupled-mode equations describing the amplitudes of interacting modes. These equations are solved exactly for the two point boundary-value problem of the PC. The study involves the coupling of the incident symmetric Lamb wave S(0) to the reflected antisymmetric Lamb wave A(0). The influences of the depth of corrugation and length of the PC are studied. Theoretical results are compared with experimental measurements. PMID- 23357914 TI - Effects of air resistance on AT-cut quartz thickness-shear resonators. AB - We study theoretically the effects of air resistance on an AT-cut quartz plate thickness-shear mode resonator. Mindlin's two-dimensional equations for coupled thickness-shear and flexural motions of piezoelectric plates are employed for the crystal resonator. The equations of a Newtonian fluid and the equations of linear acoustics are used for the shear and compressive waves in the air surrounding the resonator, respectively. Solutions for free and electrically forced vibrations are obtained. The impedance of the resonator is calculated. The effects of air resistance are examined. It is found that air viscosity causes a relative frequency shift of the order of ppm. When the material quality factor of quartz Q = 10(5), the air viscosity and compressibility both have significant effects on resonator impedance. For resonators with larger aspect ratios the effects of air resistance are weaker, and the effect of air compressibility is weaker than air viscosity. PMID- 23357915 TI - Fabrication of high-power piezoelectric transformers using lead-free ceramics for application in electronic ballasts. AB - CuO is doped into (Na(0.5)K(0.5))NbO(3) (NKN) ceramics to improve the piezoelectric properties and thus obtain a piezoelectric transformer (PT) with high output power. In X-ray diffraction patterns, the diffraction angles of the CuO-doped NKN ceramics shift to lower values because of an expansion of the lattice volume, thus inducing oxygen vacancies and enhancing the mechanical quality factor. A homogeneous microstructure is obtained when NKN is subjected to CuO doping, leading to improved electrical properties. PTs with different electrode areas are fabricated using the CuO-doped NKN ceramics. Considering the efficiency, voltage gain, and temperature rise of PTs at a load resistance of 1 kOmega, PTs with an electrode with an inner diameter of 15 mm are combined with the circuit design for driving a 13-W T5 fluorescent lamp. A temperature rise of 6 degrees C and a total efficiency of 82.4% (PT and circuit) are obtained using the present PTs. PMID- 23357916 TI - Diamond-based capacitive micromachined ultrasonic transducers in immersion. AB - Diamond is a superior membrane material for capacitive micromachined ultrasonic transducers (CMUTs). By using ultrananocrystalline diamond (UNCD) membrane and plasma-activated wafer bonding technology, a single diamond-based circular CMUT is demonstrated and operated in immersion for the first time. The diamond-based CMUT, biased at 100 V, is excited with a 10-cycle burst of 36 V(p-p) sine signal at 3.5 MHz. Pressure generated on a 2-D plane coincident with the normal of the CMUT is measured using a broadband hydrophone. Peak-to-peak hydrophone voltage measurements along the scan area clearly indicate the main lobe and the side lobes, as theoretically predicted by our directivity function calculations. The peak-to-peak hydrophone voltage on the axial direction of the CMUT is found to be in agreement with our theoretical calculations in the Fraunhofer region (-45 mm =50). Quality of life in CP subjects was compared with control subjects after controlling for demographic factors, drinking history, smoking, and medical conditions. Quality of life in CP was also compared with known scores for several chronic conditions. RESULTS: Both PCS (38 [SD, 11.5] vs 52 [SD, 9.4]) and MCS (44 [SD, 11.5] vs 51 [SD, 9.2]) were significantly lower in CP compared with control subjects (P < 0.001). On multivariable analyses, compared with control subjects, a profound decrease in physical QOL (PCS 12.02 points lower) and a clinically significant decrease in mental QOL (MCS 4.24 points lower) was seen due to CP. Quality of life in CP was similar to (heart, kidney, liver, lung disease) or worse than (nonskin cancers, diabetes mellitus, hypertension, rheumatoid arthritis) other chronic conditions. CONCLUSIONS: The impact of CP on QOL appears substantial. The QOL in CP subjects appears to be worse or similar to the QOL of many other chronic conditions. PMID- 23357927 TI - Changes of Serum Trace Elements, AFP, CEA, SF, T3, T4 and IGF-II in Different Periods of Rat Liver Cancer. AB - OBJECTIVE: Based on liver cancer model built in SD rats, the contents of trace elements (Cu, Fe, Zn, Ca and Mg), AFP, CEA, SF, TH and IGF-II in serum were measured at different stages to explore the molecular changes during the rat liver cancer development. METHODS: The SD rat liver cancer model was built by using diethylnitrosamine (DENA) as the mutagen. During 16 weeks of DENA gavage, blood samples were taken in the 14th, 28th, 56th, 77th, 105th and 112th days respectively after the first day of gavage with DENA, then the contents of five trace elements (Cu, Fe, Zn, Ca and Mg), T3, T4, IGF-II, AFP, CEA and SF in serum were determined. RESULTS: During the development of the rat liver cancer, in the test group, the Cu content significantly increased in serum, while the contents of Fe, Zn and Ca significantly decreased. The content of Mg showed no significant change. AFP and CEA of the test group showed same expression level with the control group; while the content of SF was lower than that of the control group when cancerization appeared. T3 and T4 increased at the first stage and then went down, and the content of IGF-II was always high. CONCLUSION: Cu, Fe, Zn, Ca, T3, T4, SF and IGF-II are closely related to the development of liver cancer. The changes of their contents in the development of cancer could enlighten the researches on cancer pathogenesis and prevention. PMID- 23357926 TI - Fine particle, ozone exposure, and asthma/wheezing: effect modification by glutathione S-transferase P1 polymorphisms. AB - BACKGROUND: There are limited studies on the role of interaction between exposure to ambient air pollution and glutathione-S-transferase (GST) P1 on the risk of asthma/wheezing among children, which provided suggestive, but inconclusive results. METHODS: To assess the joint effect of air pollutants and GSTP1 on asthma/wheezing, we conducted a nationwide cross-sectional study of 3,825 children in Taiwan Children Health Study. The studied determinants were three GSTP1 Ile105Val (rs 1695) genotypes (Ile-Ile; Ile-Val and Val-Val) and expoure to ambient air pollutants. We used routine air-pollution monitoring data for ozone (O(3)) and particles with an aerodynamic diameter of 2.5 um or less (PM(2.5)). The effect estimates were presented as odds ratios (ORs) per interquartile changes for PM(2.5) and O(3). FINDINGS: In a two-stage hierarchical model adjusting for confounding, the risk of asthma was negatively associated with PM(2.5) (adjusted odds ratio (OR) 0.60; 95% confidence interval (CI) 0.45, 0.82) and O(3) (OR 0.74; 95% CI 0.60, 0.90) among Ile105 homozygotes, but positively associated with PM(2.5) (OR 1.52; 95% CI 1.01, 2.27) and O(3) (OR 1.19; 95% CI 0.91, 1.57) among those with at least one val105 allele (interaction p value = 0.001 and 0.03, respectively). A similar tendency of effect modification between PM(2.5) and O(3) and GSTP1 on wheezing was found. CONCLUSION: Children who carried Ile105 variant allele and exposed to PM(2.5) and O(3) may be less likely to occurrence of asthma/wheezing. PMID- 23357928 TI - Detrusor botulinum toxin A injection significantly decreased urinary tract infection in patients with traumatic spinal cord injury. AB - STUDY DESIGN: The study was designed as a single-arm clinical trial. OBJECTIVES: To investigate the effect of detrusor botulinum toxin A (BoNTA) injection on urinary tract infection (UTI) in patients with spinal cord injury (SCI). SETTING: The study was performed in a national rehabilitation research center of China. METHODS: Between September 2010 and May 2012, 41 male inpatients with neurogenic detrusor overactivity (NDO) caused by traumatic SCI, mean age 36.0+/-8.8 years, duration of SCI since inclusion 21.5+/-17.3 months, received an injection of 300 U BoNTA into detrusor. Before and 3 months after injection, each patient kept a bladder diary, underwent video-urodynamic investigation and urine culture. All UTIs occurring in the 6 months before and the 6 months after injection were recorded. RESULTS: Before injection, the mean number of UTI over 6 months was 1.39+/-1.36. After injection, the mean significantly decreased to 0.78+/-0.96 (P=0.023). The mean maximum detrusor pressure during filling decreased significantly in the patients of detrusor overactivity (n=24) compared with patients of normo-active detrusor (n=17) after injection (35.4+/-12.2 vs 20.9+/ 7.9 cmH(2)O, P=0.000), meantime, the decrease of UTI was significant in the former (1.29+/-1.21 vs 0.41+/-0.62 cmH(2)O, P=0.015) while no significant in the latter (1.46+/-1.47 vs 1.04+/-1.08, P=0.319). CONCLUSION: Detrusor BoNTA injection significantly decreased UTI in SCI patients with NDO. This effect seems to be related to the decrease of detrusor pressure. PMID- 23357929 TI - Communicating by electrolarynx with a blind tetraplegic spinal cord injury patient on mechanical ventilation in the ICU. AB - STUDY DESIGN: Single-subject case. OBJECTIVES: To describe the atypical presentation of communication with a blind tetraplegic spinal cord injury patient on a respirator using an electrolarynx. SETTING: Critical care center in Osaka, Japan. METHODS: A 53-year-old blind man with tetraplegic spinal cord injury was admitted to our center. It was difficult for him to express his desires and to communicate with others about his severe condition and other details of his care. We began to use an electrolarynx to communicate with this patient because he could move his mouth. RESULTS: With use of the electrolarynx, the patient gradually became better able to speak fluently by electrolarynx on the first day of use. The electrolarynx allowed us and his family to communicate with him. He was pleased with the improvement in communication. CONCLUSION: An electrolarynx is a useful method for communicating with blind tetraplegic spinal cord injury patients on mechanical ventilation. PMID- 23357930 TI - Total intracorporeal robotic cystectomy: are we there yet? AB - PURPOSE OF REVIEW: To provide discussion on several recently published case series describing complete intracorporeal robotic cystectomy. Are we making a complex and expensive procedure more challenging or are there patient benefits to be realized from a complete minimally invasive approach? We discuss how effective and cost-efficient a complete intracorporeal approach is, review the updates and comment on the future direction of robot-assisted radical cystectomy (RARC). RECENT FINDINGS: Several centers have recently reported a series of RARC with intracorporeal urinary diversion. Baseline demographics, complication rates and oncological outcome data were comparable to previously published open radical cystectomy series, as well as robotic cystectomy with extracorporeal urinary diversion series. In centers experienced in robotics, comparable outcomes were achieved early in the series with no significant difference in lymph node yields, positive surgical margin rates or complication rates. However, operation times and patient's length of stay (LOS) continued to improve, suggesting that aspect of the learning curve is longer than previously thought. Benefits such as decreased blood loss and reduced LOS, commonly associated with minimally invasive surgery, were seen and while costs of RARC remain prohibitive, reducing operative times and LOS will improve cost analysis. SUMMARY: RARC with totally intracorporeal urinary diversion is technically feasible with good early and intermediate-term oncological and complication rate results. High-volume centers with expertise can deliver a complete intracorporeal robotic cystectomy with no increase in the complication rates or additional costs compared to RARC with extracorporeal urinary diversion. Further long-term oncological and functional data and the results of prospective randomized controlled trials are both pending to confirm these findings. PMID- 23357931 TI - Telementoring in robotic surgery. AB - PURPOSE OF REVIEW: To provide an overview of the current concepts regarding telementoring with robotic surgery highlighting recent advances with respect to urological minimally invasive surgery (MIS). RECENT FINDINGS: As robotic surgery continues to evolve, telementoring will become a viable alternative to traditional on-site surgical proctoring. SUMMARY: MIS represents one of the most important breakthroughs in medicine over the past few decades. Newcomers to MIS need the guidance of more experienced, 'high volume' mentors to achieve the superior outcomes promised by MIS over conventional techniques.Telementoring, a subset of telemedicine, allows a surgeon at a remote site to offer intraoperative guidance via telecommunication networks. MIS lends itself well to telementoring techniques for several reasons; the primary surgeon performing MIS is working off of video images of the surgical field or images sent to a console. As such, the mentor is seeing the exact same images as the primary surgeon. In this review, we highlight many of the latest technologies in telemedicine, which are applicable to MIS and provide an overview of the pitfalls, which need to be overcome to make telementoring (and eventually telesurgery) a standard tool in the MIS arsenal. PMID- 23357932 TI - Training in percutaneous nephrolithotomy. AB - PURPOSE OF REVIEW: Training in percutaneous nephrolithotomy (PCNL) necessitates the trainee to climb the steep learning curve of this procedure sequentially. The initial steps of the process should be the acquisition of the necessary skills in a nonintimidating skills lab. We review the current scenario of the training in PCNL and advocate the means that may improve the overall patient care. RECENT FINDINGS: The training involves a comprehensive development of the trainee. Initial process starts with the cognitive skills update through conferences and observing peers do the procedure. Rapid prototyping could be useful for resident education. The benefits of three-dimensional stereolithographic biomodeling produced from computed tomography data may aid in achieving optimal access. Skills lab involving wet and dry lab reinforce the cognitive skills. The advantage of live anesthetized porcine model is it being a more realistic model and assessment tool. The specific advantage of the dry lab simulator is of repetitive tasking and easier setup feasibility. There is a lack of guideline for the lab setup and training. Funding, location, number of models installed, curriculum, a trained mentor, and instructor are the critical components that need to be planned in advance. SUMMARY: Training in PCNL starts with cognitive knowledge, reinforcement through repetitive nonpatient basic skills acquisition in wet and dry skills lab, prototyping the technique before the actual procedure, and finally supervised training under an able mentor. PMID- 23357933 TI - Percutaneous nephrolithotomy: does position matter? - prone, supine and variations. AB - PURPOSE OF REVIEW: The evolution of percutaneous renal stone surgery has recently seen an increasing number undergoing surgery in the supine position rather than just the classical prone technique. Several advantages have been proposed with the supine approach, including benefits for anaesthesia (cardiovascular and airway), the patient (reduced transfer-related injuries), and surgeon (combined retrograde and antegrade surgery, and ergonomics). As the supine technique and variations have now been practised for several years, it is timely to review whether it has been adopted universally and what factors may lead to preference for one approach over another. RECENT FINDINGS: There have been several retrospective reports, but only two prospective randomized trials published in the literature, comparing the techniques. There have also been recent attempts at establishing national and international databases for percutaneous nephrolithotomy (PCNL) surgery to try and describe the practice patterns for this surgery, and also the factors that influence the decision to adopt a particular position. Although there appear to be no clear overall benefits for one position over another, and practice is likely to remain fairly surgeon-specific, there are some cases in which the supine PCNL may be preferable (e.g. in obese patients). SUMMARY: Along with the development of centres offering this surgical technical variation, endourology training programmes will increasingly offer exposure to supine PCNL, which may then affect the global practice patterns. PMID- 23357934 TI - Laparoscopic management in stone disease. AB - PURPOSE OF REVIEW: While most renal and ureteral stones can be efficiently managed using endourologic techniques, the use of laparoscopy for the management of urolithiasis is increasing. The application of laparoscopy for stone removal will further reduce the need for open stone surgery. RECENT FINDINGS: Laparoscopic ureterolithotomy, pyelolithotomy, and anatrophic nephrolithotomy are highly successful techniques with regard to their one-session, high stone-free rates. These procedures could be considered as the preferred approaches when endourologic procedures are not available or have failed. Laparoscopic stone surgery (LSS) in patients with urinary tract anomalies offers a reliable minimally invasive procedure as an alternative to a complex endourologic technique. SUMMARY: Although laparoscopy still has a limited role in the urologist's armamentarium for the surgical management of urolithiasis, it can further reduce the need for open stone surgery in complex circumstances. LSS duplicates its open counterpart and offers a high one-session, stone-free rate in most patients with a lower morbidity and quicker convalescence. More comparative studies are needed to define the role and indications of LSS in relation to endourologic and open techniques, especially in complex circumstances. PMID- 23357935 TI - Current world literature. PMID- 23357937 TI - Visual hallucinations: charles bonnet syndrome. AB - The following is a case of Charles Bonnet syndrome in an 86-year-old woman who presented with visual hallucinations. The differential diagnosis of visual hallucinations is broad and emergency physicians should be knowledgeable of the possible etiologies. PMID- 23357938 TI - Antidermatophytic and Toxicological Evaluations of Dichloromethane-Methanol Extract, Fractions and Compounds Isolated from Coula edulis. AB - BACKGROUND: Coula edulis Bail (Olacaceae), is an evergreen tree growing to a height of 25. This study aimed at evaluating the antidermatophytic and toxicological properties of the stem bark of C. edulis extract as well as fractions and compounds isolated from it. METHODS: The plant extract was prepared by maceration in CH(2)Cl(2)-MeOH (1:1 v/v). The fractionation of this extract was done by silica gel column chromatography. Antidermatophytic activities were assayed using agar dilution method. The acute and sub-acute toxicities of oral administrations of the extract were studied in rodents. RESULTS: The crude extract of C. edulis displayed antidermatophytic activity against the tested microorganisms with highest activity against Microsporum audouinii and Trichophyton mentagrophytes. The fractionation enhanced the antidermatophytic activity in fraction F(3 )(MIC=0.62-1.25 mg/ml) compared to the crude extract (MIC=1.25-5 mg/ml). Further fractionation and purification of the fractions F(2) and F(3) gave respectively 3-O-beta-D-glucopyranoside of sitosterol (MIC=0.20 0.40 mg/ml) and a mixture of beta-sitosterol, stigmasterol and n-hexadecanoid acid (MIC=0.80 mg/ml). The median lethal doses (LD(50)) of the crude extract were 16.8 and 19.6 g/kg body weight (BW) in male and female mice, respectively. At 200 mg/kg BW(, )there was a decrease in body weight gain, food and water consumptions. Gross anatomical analysis revealed white vesicles on the liver of the rats treated with the extract at 200 mg/kg BW. This dose also induced significant (P<0.05) changes on hematological and biochemical parameters in rats after 28 days of treatment. CONCLUSION: These data suggest that the CH(2)Cl(2) MeOH (1:1 v/v) extract of C. edulis stem bark possesses antidermatophytic properties. They also show that at high doses (>= 200 mg/kg BW), the extract has significant hepatotoxic and nephrotoxic activities. PMID- 23357939 TI - A comparison of the effects of fentanyl and remifentanil on nausea, vomiting, and pain after cesarean section. AB - BACKGROUND: The effects of different opioids on postoperative nausea and vomiting (PONV) and pain have not been conclusively determined. The aim of this study was to compare the effects of fentanyl, remifentanil or fentanyl plus morphine on the incidence of PONV and pain in women subjected to cesarean section under general anesthesia. METHODS: The study was a randomized clinical trial recruiting 96 parturients with American Society of Anesthesiologists (ASA) physical status I and II. They scheduled for cesarean section under general anesthesia using sodium thiopental, succynylcholine, and isoflurane O2/N2O 50/50 mixture. After clamping the umbilical cord, the patients were given fentanyl (2 ug/kg/h), remifentanil (0.05 ug/kg/h), or fentanyl (2 ug/kg) pulse morphine (0.1 mg/kg) intravenously. Visual analog scale for pain and nausea, frequency of PONV, meperidine and metoclopramide consumption were evaluated at recovery, and 4, 8, 12 and 24 hours after the surgery. RESULTS: There was no significant difference between the three groups in terms of frequency of nausea, vomiting, and mean nausea and pain scores at any time points. None of the patients required the administration of metoclopramide. However, the mean VAS for pain in remifentanil-treated group was insignificantly more than that in fentanyl- or fentanyl plus morphine-treated group at recovery or 4 hours after the surgery. The mean mepridine consumption in remifentanil-treated group was significantly (P=0.001) more than that in fentanyl or fentanyl plus morphine-treated group in 24 hours after the surgery respectively. There was no significant difference in hemodynamic parameters of the three groups in all measurements after the surgery. CONCLUSION: The findings of this study showed that early postoperative analgesia was better with fentanyl, and postoperative meperidine consumption was significantly less with fentanyl than with remifentanil or combined fentayl and morphine. PMID- 23357940 TI - Background data for hematological and blood chemical examinations in juvenile beagles. AB - As the first step to get historical background data for physiological examinations in juvenile dogs, hematology and blood chemistry data obtained from juvenile beagle dogs (less than 3 months of age) used in the control group of toxicity studies conducted in our laboratory were summarized and compared with those obtained from adult beagle dogs (6 months of age). In the hematological examination, growth of beagle dogs was shown to be associated with increases in erythrocyte parameters and with decreases in reticulocyte and leukocyte counts. In the blood chemical examination, growth of beagle dogs was shown to be associated with increases in aspartate aminotransferase, alanine aminotransferase, and creatinine and with decreases in creatine phosphokinase, glucose, total cholesterol, and calcium. The differential leukocyte ratio showed no age relation, but the actual count showed a tendency toward decrease. Alkaline phosphatase showed a tendency to increase from 0 months of age to 3 months of age, but it decreased at 6 months of age. The present results were roughly similar to those previously reported. PMID- 23357941 TI - Comparison of the effects of cumene hydroperoxide and hydrogen peroxide on Retzius nerve cells of the leech Haemopis sanguisuga. AB - Oxidative stress and the production of reactive oxygen species are known to play a major role in neuronal cell damage, but the exact mechanisms responsible for neuronal injury and death remain uncertain. In the present study, we examined the effects of oxidative stress on spontaneous spike activity and depolarizing outward potassium current by exposing the Retzius neurons of the leech to cumene hydroperoxide (CHP) and hydrogen peroxide (H(2)O(2)), the oxidants commonly used to examine oxidative mechanisms mediating cell death. We observed that relatively low concentrations of CHP (0.25, 1, and 1.5 mM) led to a marked prolongation of spontaneous repetitive activity. The prolonged action potentials showed an initial, spike-like depolarization followed by a plateau phase. In contrast, H(2)O(2) at the same and much higher concentrations (0.25 to 5 mM) did not significantly change the duration of spontaneous spike potentials of leech Retzius nerve cells (LRNCs). In the voltage clamp experiments, calcium-activated outward potassium currents, needed for the repolarization of the action potential, were suppressed with CHP, but not with H(2)O(2). The present findings indicate that CHP is a more potent oxidant and neurotoxin than H(2)O(2) and that the effect of CHP on the electrophysiological properties of LRNCs may be due to the inhibition of the potassium channels. PMID- 23357943 TI - Cross-experimental analysis of coat color variations and morphological characteristics of the japanese wild mouse, Mus musculus. AB - There are many coat colors in the laboratory mouse, Mus musculus. On the basis of traditional genetics, there are four loci, A-D, related to coat color expressions. As shown by previous studies, Japanese wild mice have gray backs and white bellies and are assumed to carry the A(w) allele at the A (agouti) locus, which is dominant over any other alleles. However, we collected Japanese wild mice from central Honshu with black coats. To understand this black coat expression, we performed cross experiments concerning the four loci using wild caught mice and DBA/2 laboratory mice from the standpoint of traditional genetics. The offspring of the current crosses showed the wild type, the blackish type, and the intermediate type from some combinations of parents. Considering the coat colors of the offspring, we did not obtain any evidence that the Japanese wild mice always carry the A(w) allele at the A locus. Furthermore, we were not able to explain the current coat color expressions using the traditional logic with regard to the A-D loci and concluded that it is possible for another locus (loci) to be related to the coat color expressions. On the other hand, skull characteristics and external body measurements of the captured wild mice were fundamentally different from those of DBA/2 and offspring from captured wild mice and DBA/2 combinations. Thus, we concluded that the Japanese wild mice had original criteria from a morphological viewpoint. PMID- 23357942 TI - Isolated perfused rat kidney: a technical update. AB - The isolated perfused kidney is commonly utilized as a screening tool for renal clearance and metabolism, and to correlate renal drug deposition to renal function. Here, we report on several aspects of this procedure that will facilitate a higher experimental success rate and lead to a reduction in animal use. First, we investigated the utility of inulin and creatinine as commonly used markers to measure glomerular filtration rate. For inulin, in the presence of either 20 mM glucose or 4.5% dextran in the buffer, significant interference was observed using an anthrone-based colorimetric assay. These findings suggest that caution needs to be exercised when using glucose or dextran and when inulin is quantitated using this method. Under these circumstances the use of alternative methods of inulin quantitation such as fluorescently tagged inulin is preferred. Second, we optimized bovine serum albumin (BSA) and BSA/dextran compositions that are routinely recommended as oncotic agents in the perfusion buffer and found that a 4% BSA/1.67% dextran composition had the best viability of kidney biomarkers in accordance with recommended threshold parameters. These considerations will be of particular relevance to researchers utilizing the isolated perfused kidney as a screening tool to measure renal biology and drug metabolism as well as applications to investigate diabetic nephropathy. PMID- 23357944 TI - Rapid identification of Klebsiella pneumoniae, Corynebacterium kutscheri, and Streptococcus pneumoniae using triplex polymerase chain reaction in rodents. AB - Klebsiella pneumoniae, Corynebacterium kutscheri, and Streptococcus pneumoniae are important pathogens that cause respiratory infections in laboratory rodents. In this study, we used species-specific triplex PCR analysis to directly detect three common bacterial pathogens associated with respiratory diseases. Specific targets were amplified with conventional PCR using the tyrB gene from K. pneumoniae, gyrB gene from C. kutscheri, and ply gene from S. pneumoniae. Our primers were tested against purified DNA from another eleven murine bacteria to determine primer specificity. Under optimal PCR conditions, the triplex assay simultaneously yielded a 931 bp product from K. pneumoniae, a 540 bp product from C. kutscheri, and a 354 bp product from S. pneumoniae. The triplex assay detection thresholds for pure cultures were 10 pg for K. pneumoniae and S. pneumoniae, and 100 pg for C. kutscheri. All three bacteria were successfully identified in the trachea and lung of experimentally infected mice at the same time. Our triplex PCR method can be used as a useful method for detecting pathogenic bacterial infections in laboratory rodents. PMID- 23357945 TI - Current microbiological status of laboratory mice and rats in experimental facilities in Japan. AB - On the basis of our 2011 microbiological monitoring tests, we report here the current microbiological status of mice and rats housed in experimental facilities in Japan. We tested more than 14,000 mice, 6,000 serum samples, 500 fecal or cecal samples, and 200 lung samples from 3,549 mouse facilities within Japanese universities and institutes (U/I), pharmaceutical companies and contract research organizations (P/C). We also tested more than 1,500 rats, 1,600 serum samples, and 20 fecal or cecal samples from 772 U/I and P/C rat facilities. Bacterial cultures, serology, microscopy, PCR, and DNA analysis using DNA chips were performed. Staphylococcus aureus (18.8% in mouse facilities, 58.6% in rat facilities) was the most prevalent agent in both the mouse and rat facilities. The next most prevalent agents in the mouse facilities were murine norovirus (11.97%), intestinal protozoa (0.05-8.49%, from various species), Pasteurella pneumotropica (5.32%), and Helicobacter hepaticus (3.17%), while intestinal protozoa (0.74-6.84% from various species), Syphacia muris (6.20%), Pseudomonas aeruginosa (3.61%), and Pasteurella pneumotropica (3.05%) were the subsequent most prevalent agents in the rat facilities. These results suggest that the currently prevalent microbes in laboratory mice and rats in Japan are mainly opportunistic pathogens, intestinal protozoa, and microbes with low pathogenicity. PMID- 23357946 TI - Regulation of prolactin receptor gene expression in the rat choroid plexus via transcriptional activation of multiple first exons during postnatal development and lactation. AB - Prolactin (PRL) has numerous physiological functions that are mediated by its receptors in target cells. Expression of the rat PRL receptor (PRLR) gene is regulated in a tissue-specific manner via the transcriptional activation of five distinct first exons, i.e., E1(1), E1(2), E1(3), E1(4), and E1(5). In the present study, we investigated the expression profiles of these first exon variants of PRLR mRNA in the rat choroid plexus, which is considered to be a site of receptor mediated PRL transport from the blood to cerebrospinal fluid. Real-time PCR analysis revealed that E1(3)-, E1(4)-, and E1(5)-PRLR mRNA expression levels increased in the choroid plexus in male and female rats during postnatal development, with markedly higher level of E1(4)-PRLR mRNA. In female rats, the E1(4)-PRLR mRNA expression levels increased markedly during lactation compared with the diestrus state, whereas there was no increase in the E1(3)- and E1(5) PRLR mRNA levels. The E1(4)-PRLR mRNA expression pattern was similar to that of the total PRLR mRNA. The PRL plasma concentration generally correlated with the E1(4)-PRLR mRNA expression levels in both sexes. These findings suggest that PRLR gene expression in the choroid plexus is upregulated mainly via the transcriptional activation of the E1(4)-first exon. PMID- 23357947 TI - Examination of the mouse embryo by micro-CT. AB - Micro X-ray computed tomography (micro-CT) is widely used in preclinical studies of small animals. However, due to the low soft tissue contrast, segmentation of soft tissues in the micro-CT image is a challenging problem. To gain a better understanding of the macroscopic anatomy of the mouse embryo, 3 fixation methods and 3 metal stainings were examined for micro-CT using C57BL/6J mouse embryos in the present study. The examination demonstrated that 1% acetic acid/95% ethanol fixative together with zinc staining provided a high contrast micro-CT image, enabling the segmentation of soft tissues. Then, using this condition, the macroscopic embryo structure of the nude mouse was examined, revealing lack of a thymus. It appears that micro-CT with the fixation and staining condition devised in the present study could be a powerful tool in detecting the effects of various mutations at embryonic stages. PMID- 23357948 TI - Rat model of intracerebral hemorrhage permitting hematoma aspiration plus intralesional injection. AB - A combination of hematoma aspiration and local delivery of chemicals may be more effective than either therapy in intracerebral hemorrhage (ICH). The aim of the present study was to develop a rat model of hematoma aspiration plus intralesional injection after ICH. ICH was induced in adult Sprague-Dawley rats by an intrastriatal injection of bacterial collagenase IV. Hematoma aspiration was performed 3.5 h after ICH onset. Following aspiration, normal saline was injected into the lesion cavity. Hematoma aspiration with or without subsequent saline injection significantly reduced the hematoma volume, lesion volume, and perihematomal neutrophil infiltration. Hematoma aspiration plus subsequent intralesional injection is simple, feasible, and safe. This ICH model can be used to assess the effectiveness of hematoma removal plus local delivery of chemicals. PMID- 23357951 TI - Constitutively active group I mGlu receptors and PKMzeta regulate synaptic transmission in developing perirhinal cortex. AB - Synaptic transmission is essential for early development of the central nervous system. However, the mechanisms that regulate early synaptic transmission in the cerebral cortex are unclear. PKMzeta is a kinase essential for the maintenance of LTP. We show for the first time that inhibition of PKMzeta produces a profound depression of basal synaptic transmission in neonatal, but not adult, rat perirhinal cortex. This suggests that synapses in early development are in a constitutive LTP-like state. Furthermore, basal synaptic transmission in immature, but not mature, perirhinal cortex relies on persistent activity of metabotropic glutamate (mGlu) receptor, PI3Kinase and mammalian target of rapamycin (mTOR). Thus early in development, cortical synapses exist in an LTP like state maintained by tonically active mGlu receptor-, mTOR- and PKMzeta- dependent cascades. These results provide new understanding of the molecular mechanisms that control synapses during development and may aid our understanding of developmental disorders such as autism and schizophrenia. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 23357950 TI - Sequencing and de novo assembly of the western tarnished plant bug (Lygus hesperus) transcriptome. AB - BACKGROUND: Mirid plant bugs (Hemiptera: Miridae) are economically important insect pests of many crops worldwide. The western tarnished plant bug Lygus hesperus Knight is a pest of cotton, alfalfa, fruit and vegetable crops, and potentially of several emerging biofuel and natural product feedstocks in the western US. However, little is known about the underlying molecular genetics, biochemistry, or physiology of L. hesperus, including their ability to survive extreme environmental conditions. METHODOLOGY/PRINCIPAL FINDINGS: We used 454 pyrosequencing of a normalized adult cDNA library and de novo assembly to obtain an adult L. hesperus transcriptome consisting of 1,429,818 transcriptomic reads representing 36,131 transcript isoforms (isotigs) that correspond to 19,742 genes. A search of the transcriptome against deposited L. hesperus protein sequences revealed that 86 out of 87 were represented. Comparison with the non redundant database indicated that 54% of the transcriptome exhibited similarity (e-value <= 1(-5)) with known proteins. In addition, Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations, and potential Pfam domains were assigned to each transcript isoform. To gain insight into the molecular basis of the L. hesperus thermal stress response we used transcriptomic sequences to identify 52 potential heat shock protein (Hsp) homologs. A subset of these transcripts was sequence verified and their expression response to thermal stress monitored by semi-quantitative PCR. Potential homologs of Hsp70, Hsp40, and 2 small Hsps were found to be upregulated in the heat-challenged adults, suggesting a role in thermotolerance. CONCLUSIONS/SIGNIFICANCE: The L. hesperus transcriptome advances the underlying molecular understanding of this arthropod pest by significantly increasing the number of known genes, and provides the basis for further exploration and understanding of the fundamental mechanisms of abiotic stress responses. PMID- 23357949 TI - Comparative genome structure, secondary metabolite, and effector coding capacity across Cochliobolus pathogens. AB - The genomes of five Cochliobolus heterostrophus strains, two Cochliobolus sativus strains, three additional Cochliobolus species (Cochliobolus victoriae, Cochliobolus carbonum, Cochliobolus miyabeanus), and closely related Setosphaeria turcica were sequenced at the Joint Genome Institute (JGI). The datasets were used to identify SNPs between strains and species, unique genomic regions, core secondary metabolism genes, and small secreted protein (SSP) candidate effector encoding genes with a view towards pinpointing structural elements and gene content associated with specificity of these closely related fungi to different cereal hosts. Whole-genome alignment shows that three to five percent of each genome differs between strains of the same species, while a quarter of each genome differs between species. On average, SNP counts among field isolates of the same C. heterostrophus species are more than 25* higher than those between inbred lines and 50* lower than SNPs between Cochliobolus species. The suites of nonribosomal peptide synthetase (NRPS), polyketide synthase (PKS), and SSP encoding genes are astoundingly diverse among species but remarkably conserved among isolates of the same species, whether inbred or field strains, except for defining examples that map to unique genomic regions. Functional analysis of several strain-unique PKSs and NRPSs reveal a strong correlation with a role in virulence. PMID- 23357953 TI - The (pro)renin receptor / ATP6ap2 is expressed in the murine hippocampus by adult and newly generated neurons. AB - PURPOSE: The (pro)renin receptor ((P)RR) is receptor that has been shown to be involved in developmental processes. Adult neurogenesis shares many similarities with fetal and embryonic neuronal development, but is restricted to some brain areas, including the hippocampus. We therefore investigated the expression of the (P)RR within the adult hippocampal formation and investigated whether (P)PR is expressed by adult and newly generated neurons in the dentate gyrus. METHODS: (P)PR protein expressing cells in the hippocampus were analyzed using immunohistochemistry. Double-labeling with markers for adult neurogenesis was used to investigate whether newly formed cells also express (P)PR. RESULTS: (P)PR is expressed by neuronal cells with the hippocampus. (P)RR protein is expressed during different stages of adult neurogenesis within the dentate gyrus (DG). (P)RR is not expressed by Sox2 positive neuronal stem cells, but by doublecortin positive cells located both in the subgranular zone and the granular layer of the DG. CONCLUSIONS: The results indicate that (P)PR is mainly expressed by adult neurons in the hippocampus as well as in late stages of adult neurogenesis within the hippocampus. However, to clarify the involvement of this receptor in adult hippocampal neurogenesis and neuronal cell differentiation in detail, functional analyses needed to be performed. PMID- 23357952 TI - Histone H3K56 acetylation, Rad52, and non-DNA repair factors control double strand break repair choice with the sister chromatid. AB - DNA double-strand breaks (DSBs) are harmful lesions that arise mainly during replication. The choice of the sister chromatid as the preferential repair template is critical for genome integrity, but the mechanisms that guarantee this choice are unknown. Here we identify new genes with a specific role in assuring the sister chromatid as the preferred repair template. Physical analyses of sister chromatid recombination (SCR) in 28 selected mutants that increase Rad52 foci and inter-homolog recombination uncovered 8 new genes required for SCR. These include the SUMO/Ub-SUMO protease Wss1, the stress-response proteins Bud27 and Pdr10, the ADA histone acetyl-transferase complex proteins Ahc1 and Ada2, as well as the Hst3 and Hst4 histone deacetylase and the Rtt109 histone acetyl transferase genes, whose target is histone H3 Lysine 56 (H3K56). Importantly, we use mutations in H3K56 residue to A, R, and Q to reveal that H3K56 acetylation/deacetylation is critical to promote SCR as the major repair mechanism for replication-born DSBs. The same phenotype is observed for a particular class of rad52 alleles, represented by rad52-C180A, with a DSB repair defect but a spontaneous hyper-recombination phenotype. We propose that specific Rad52 residues, as well as the histone H3 acetylation/deacetylation state of chromatin and other specific factors, play an important role in identifying the sister as the choice template for the repair of replication-born DSBs. Our work demonstrates the existence of specific functions to guarantee SCR as the main repair event for replication-born DSBs that can occur by two pathways, one Rad51 dependent and the other Pol32-dependent. A dysfunction can lead to genome instability as manifested by high levels of homolog recombination and DSB accumulation. PMID- 23357954 TI - Prescription drug monitoring programs and other interventions to combat prescription opioid abuse. AB - The Center for Disease Control and Prevention (CDC) has published significant data and trends related to opioid prescription pain relievers (OPR). In 2008, 20,044 deaths were attributed to prescription drug overdose of which 14,800 (73.8%) were due to OPR, an amount greater than the number of overdose deaths from heroin and cocaine combined. The majority of these deaths were unintentional. Between 1999-2008, overdose deaths from OPR increased almost four fold. Correspondingly, sales of OPR were four times greater in 2010 than in 1999. Most significant to emergency physicians is the estimate that 39% of all opioids prescribed, administered or continued come from the emergency department (ED). We present findings from the CDC's Morbidity and Mortality Weekly Report (MMWR) with commentary on current recommendations and policies for curtailing the OPR epidemic.1. PMID- 23357956 TI - Association of elevation, urbanization and ambient temperature with obesity prevalence in the United States. AB - BACKGROUND: The macrogeographic distribution of obesity in the United States, including the association between elevation and body mass index (BMI), is largely unexplained. This study examines the relationship between obesity and elevation, ambient temperature and urbanization. METHODS AND FINDINGS: Data from a cross sectional, nationally representative sample of 422603 US adults containing BMI, behavioral (diet, physical activity, smoking) and demographic (age, sex, race/ethnicity, education, employment, income) variables from the 2011 Behavioral Risk Factor Surveillance System were merged with elevation and temperature data from WorldClim and with urbanization data from the US Department of Agriculture. There was an approximately parabolic relationship between mean annual temperature and obesity, with maximum prevalence in counties with average temperatures near 18 degrees C. Urbanization and obesity prevalence exhibited an inverse relationship (30.9% in rural or nonmetro counties, 29.2% in metro counties with <250000 people, 28.1% in counties with population from 250000 to 1 million and 26.2% in counties with >1 million). After controlling for urbanization, temperature category and behavioral and demographic factors, male and female Americans living <500 m above sea level had 5.1 (95% confidence interval (CI) 2.7 9.5) and 3.9 (95% CI 1.6-9.3) times the odds of obesity, respectively, as compared with counterparts living >= 3000 m above sea level. CONCLUSIONS: Obesity prevalence in the United States is inversely associated with elevation and urbanization, after adjusting for temperature, diet, physical activity, smoking and demographic factors. PMID- 23357955 TI - Timing of food intake predicts weight loss effectiveness. AB - BACKGROUND: There is emerging literature demonstrating a relationship between the timing of feeding and weight regulation in animals. However, whether the timing of food intake influences the success of a weight-loss diet in humans is unknown. OBJECTIVE: To evaluate the role of food timing in weight-loss effectiveness in a sample of 420 individuals who followed a 20-week weight-loss treatment. METHODS: Participants (49.5% female subjects; age (mean +/- s.d.): 42 +/- 11 years; BMI: 31.4 +/- 5.4 kg m(-2)) were grouped in early eaters and late eaters, according to the timing of the main meal (lunch in this Mediterranean population). 51% of the subjects were early eaters and 49% were late eaters (lunch time before and after 1500 hours, respectively), energy intake and expenditure, appetite hormones, CLOCK genotype, sleep duration and chronotype were studied. RESULTS: Late lunch eaters lost less weight and displayed a slower weight-loss rate during the 20 weeks of treatment than early eaters (P=0.002). Surprisingly, energy intake, dietary composition, estimated energy expenditure, appetite hormones and sleep duration was similar between both groups. Nevertheless, late eaters were more evening types, had less energetic breakfasts and skipped breakfast more frequently that early eaters (all; P<0.05). CLOCK rs4580704 single nucleotide polymorphism (SNP) associated with the timing of the main meal (P=0.015) with a higher frequency of minor allele (C) carriers among the late eaters (P=0.041). Neither sleep duration, nor CLOCK SNPs or morning/evening chronotype was independently associated with weight loss (all; P>0.05). CONCLUSIONS: Eating late may influence the success of weight-loss therapy. Novel therapeutic strategies should incorporate not only the caloric intake and macronutrient distribution - as is classically done - but also the timing of food. PMID- 23357957 TI - Effects of suboptimal or excessive gestational weight gain on childhood overweight and abdominal adiposity: results from a retrospective cohort study. AB - BACKGROUND: Defining prenatal modifiable risk factors of childhood overweight and obesity has become critical as the need of primary preventive strategies increases. OBJECTIVE: To investigate the interrelationship between inadequate or excessive gestational weight gain (GWG), according to maternal prepregnancy body mass index (BMI)-specific Institute of Medicine (IOM) recommendations, and childhood overweight and abdominal adiposity. DESIGN: In a retrospective cohort study in Germany, data of 6837 mother-child dyads were obtained from medical records, a questionnaire and by anthropometric measurements of children at school entry. Main exposure was GWG as categorized by the 2009 IOM guidelines and as a continuous variable. Outcome measures were children's overweight and abdominal adiposity defined as >= 90 th age- and sex-specific percentiles for BMI and waist circumference, respectively. RESULTS: During pregnancy, more than half of mothers (53.6%) had gained weight excessively. Among the children (mean age: 5.8 years), 10.5% were overweight and 15.1% had abdominal adiposity. A nonlinear relationship between absolute GWG and the risk of offspring overweight and abdominal adiposity was observed. An increased risk of childhood overweight was related to excessive compared with recommended GWG, after adjustment for potential confounders (odds ratio (OR): 1.57, 95% confidence interval (CI): 1.30, 1.91), but not to inadequate GWG. Similar results were obtained for the risk of childhood abdominal adiposity by excessive GWG (OR: 1.39, 95% CI: 1.19, 1.63); there was no association with inadequate GWG. Analyses stratified by maternal prepregnancy BMI category did not suggest effect modification. CONCLUSION: Exceeding the recommended BMI-specific IOM GWG ranges has an adverse impact on the risk of childhood overweight and abdominal adiposity, whereas suboptimal GWG conveys no benefit or risk, reflecting a nonlinear relationship between absolute GWG and the risk of childhood overweight and adiposity. Strategies focussing on the awareness and prevention of excessive GWG and its consequences are justified. PMID- 23357959 TI - How Type of Treatment and Presence of PTSD affect Employment, Self-regulation, and Abstinence. AB - The present study examined self-regulation, unemployment, and substance use outcomes for individuals with and without posttraumatic stress disorder (PTSD) who had transitioned from substance use treatment centers to the community. Participants, recruited from substance abuse treatment centers, were randomly assigned to an Oxford House self-help communal living environment (n = 75) or received usual aftercare (n = 75). Among these 150 individuals, 32 participants (27 women, 5 men) were diagnosed with lifetime PTSD. At a two year follow-up, individuals with PTSD in the usual aftercare condition showed significantly lower levels of self-regulation than those in the Oxford House condition with or without PTSD. These findings highlight the importance of abstinence supportive settings following substance use treatment, especially for individuals with PTSD. PMID- 23357961 TI - HER2-specific T lymphocytes kill both trastuzumab-resistant and trastuzumab sensitive breast cell lines in vitro. AB - OBJECTIVE: Although the development of trastuzumab has improved the outlook for women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the resistance to anti-HER2 therapy is a growing clinical dilemma. We aim to determine whether HER2-specific T cells generated from dendritic cells (DCs) modified with HER2 gene could effectively kill the HER2-positive breast cancer cells, especially the trastuzumab-resistant cells. METHODS: The peripheral blood mononuclear cells (PBMCs) from healthy donors, whose HLA haplotypes were compatible with the tumor cell lines, were transfected with reconstructive human adeno-association virus (rhAAV/HER2) to obtain the specific killing activities of T cells, and were evaluated by lactate dehydrogenase (LDH) releasing assay. RESULTS: Trastuzumab produced a significant inhibiting effect on SK-BR-3, the IC50 was 100ng/ml. MDA-MB-453 was resistant to trastuzumab even at a concentration of 10,000 ng/ml in vitro. HER2-specific T lymphocytes killed effectively SK-BR-3 [(69.86+/-13.41)%] and MDA-MB-453 [(78.36+/-10.68)%] at 40:1 (effector:target ratio, E:T), but had no significant cytotoxicity against HER2 negative breast cancer cell lines MDA-MB-231 or MCF-7 (less than 10%). CONCLUSION: The study showed that HER2-specific T lymphocytes generated from DCs modified by rhAAV/HER2 could kill HER2-positive breast cancer cell lines in a HER2-dependent manner, and result in significantly high inhibition rates on the intrinsic trastuzumab-resistant cell line MDA-MB-453 and the tastuzumab-sensitive cell line SK-BR-3. These results imply that this immunotherapy might be a potential treatment to HER2-positive breast cancer. PMID- 23357960 TI - Divide and conquer: functional segregation of synaptic inputs by astrocytic microdomains could alleviate paroxysmal activity following brain trauma. AB - Traumatic brain injury often leads to epileptic seizures. Among other factors, homeostatic synaptic plasticity (HSP) mediates posttraumatic epileptogenesis through unbalanced synaptic scaling, partially compensating for the trauma incurred loss of neural excitability. HSP is mediated in part by tumor necrosis factor alpha (TNFalpha), which is released locally from reactive astrocytes early after trauma in response to chronic neuronal inactivity. During this early period, TNFalpha is likely to be constrained to its glial sources; however, the contribution of glia-mediated spatially localized HSP to post-traumatic epileptogenesis remains poorly understood. We used computational model to investigate the reorganization of collective neural activity early after trauma. Trauma and synaptic scaling transformed asynchronous spiking into paroxysmal discharges. The rate of paroxysms could be reduced by functional segregation of synaptic input into astrocytic microdomains. Thus, we propose that trauma triggered reactive gliosis could exert both beneficial and deleterious effects on neural activity. PMID- 23357958 TI - Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta analysis of European origin and African American studies. AB - OBJECTIVE: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids. DESIGN AND METHODS: We conducted race/ethnic-specific meta analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800). RESULTS: After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m(-2) greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m(-2) greater for BMI (interaction P=0.0001), 0.267 cm for waist (interaction P=0.001) and 0.21 cm for hip (interaction P=0.001). No other significant interactions were observed. CONCLUSION: Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits. PMID- 23357962 TI - Quercetin vs chrysin: effect on liver histopathology in diabetic mice. AB - Effects of flavonoids quercetin and chrysin on lipid peroxidation and histopathological changes in liver of diabetic mice were studied and compared with the antioxidant and reducing ability of quercetin and chrysin and their ability to chelate Fe(2+) ions in vitro. Diabetes was induced in Swiss albino mice with a single intravenous injection of alloxan (75 mg kg(-1)). Two days after alloxan injection, flavonoid preparations (50 mg kg(-1) per day) were given intraperitoneally for 7 days in diabetic mice. The lipid peroxidation was evaluated by measuring the malondialdehyde production using the 2-thiobarbituric acid test. Administration of quercetin and chrysin to diabetic mice resulted in a significant decrease in lipid peroxidation level in liver tissue. Treatment of diabetic mice with flavonoids solutions results in decreased number of vacuolated cells and degree of vacuolization of the liver tissue. The protective role of flavonoids against the reactive oxygen species-induced damages in diabetic mice gives a hope that they may exert similar protective action in humans. PMID- 23357963 TI - Intracardiac thrombus formation induced by carbon monoxide poisoning. AB - INTRODUCTION: Carbon monoxide (CO) is one of the leading causes of poisoning; it inhibits oxygen delivery, subsequently causing ischemic changes and ultimately death by multiorgan failure. Furthermore, thromboembolic episodes due to CO poisoning have been reported. However, intracardiac thrombus formation following exposure to CO has been very rarely described. Here, a case of right atrial large thrombus formation after CO poisoning is presented. CASE PRESENTATION: A previously healthy 24-year-old woman was referred for CO poisoning. She has attempted suicide, and her initial mental status was drowsy with focal memory loss. Her initial CO fraction was 16%, and initial laboratory data showed creatinine kinase-myocardial bound of 90.6 ng/mL (upper limit 5 ng/mL) and troponin I of 1.899 ng/mL (upper limit 1.5 ng/mL). A transthoracic echocardiography was performed 24 h after the accident, revealing a 30 15 mm nodular echogenic mass in the right atrium. Anticoagulation with low-molecular weight heparin was started along with hyperbaric oxygen therapy. After 7 days of heparinization, the large thrombus in right atrium had resolved. CONCLUSION: This report describes an intracardiac thrombus formation induced by CO poisoning. Because intracardiac thrombus can result in pulmonary embolism and cerebral embolic infarction, its consideration following CO poisoning is important. PMID- 23357965 TI - Parental Divorce, Parental Religious Characteristics, and Religious Outcomes in Adulthood. AB - Parental divorce has been linked to religious outcomes in adulthood. Previous research has not adequately accounted for parental religious characteristics or subsequent family context, namely whether one's custodial parent remarries. Using pooled data from three waves of the General Social Survey, we examine the relationships among parental divorce, subsequent family structure, and religiosity in adulthood. Growing up in a single-parent family-but not a stepparent family-is positively associated with religious disaffiliation and religious switching and negatively associated with regular religious attendance. Accounting for parental religious characteristics, however, explains sizable proportions of these relationships. Accounting for parental religious affiliation and attendance, growing up with a single parent does not significantly affect religious attendance. Parental religiosity also moderates the relationship between growing up with a single parent and religious attendance: being raised in a single-parent home has a negative effect on religious attendance among adults who had two religiously involved parents. PMID- 23357964 TI - Systematic review of persistent pain and psychological outcomes following traumatic musculoskeletal injury. AB - BACKGROUND: Persistent pain and psychological distress are common after traumatic musculoskeletal injury (TMsI). Individuals sustaining a TMsI are often young, do not recover quickly, and place a large economic burden on society. OBJECTIVES: The aim of this systematic review is to determine (1) the incidence of persistent pain following TMsI, (2) the characteristics of pain, characterized by injury severity and type, and (3) risk and protective factors associated with persistent pain following TMsI. METHODS: A systematic search of electronic databases (MEDLINE((r)), PubMed((r)), Embase, and PsycINFO((r))) was conducted for prospective, interventional, or noninterventional studies measuring the incidence of pain associated with TMsI. RESULTS: The search revealed 4388 studies. Eleven studies examined persistent pain and met inclusion criteria. Pain was assessed using a validated measure of pain intensity or pain presence in six studies. Persistent pain was reported by all studies at variable time points up to 84 months postinjury, with wide variation among studies in pain intensity (ie, from mild to very severe) and pain incidence at each time point. The incidence of pain decreased over time within each study. Two studies found significant relationships between injury severity and persistent pain. Frequently cited predictive factors for persistent pain included: symptoms of anxiety and depression, patient perception that the injury was attributable to external sources (ie, they were not at fault), cognitive avoidance of distressing thoughts, alcohol consumption prior to trauma, lower educational status, being injured at work, eligibility for compensation, pain at initial assessment, and older age. CONCLUSION AND IMPLICATIONS: The evidence from the eleven studies included in this review indicates that persistent pain is prevalent up to 84 months following traumatic injury. Further research is needed to better evaluate persistent pain and other long-term posttraumatic outcomes. PMID- 23357966 TI - Histologically proven, low-grade brainstem gliomas in children: 30-year experience with long-term follow-up at Mayo Clinic. AB - INTRODUCTION: To evaluate long-term overall survival (OS), progression-free survival (PFS), and outcomes in pathologically proven brainstem low-grade gliomas (BS-LGG) in children. METHODS: The Mayo Clinic tumor registry identified 48 consecutive children (<=20 y, 52% female) with biopsy-proven BS-LGG treated at Mayo Clinic between January 1971 and December 2004. Medical records were retrospectively reviewed. For analysis, patients were censored at the time of recurrence, death, or last follow-up. RESULTS: The median age at diagnosis was 12 years with a median follow-up of 6.0 years. The majority of tumors were grade I (69%) and pathology was consistent with an astrocytoma in the majority of patients (98%). Gross total resection was obtained in 4, subtotal in 17, and 27 patients were biopsied only. Postoperative radiotherapy (RT) was used in 29 patients. Median OS for the entire group was 14.8 years with a 1-, 5-, and 10 year OS of 85%, 67% and 59%, respectively. Median PFS for the entire group was 7.3 years. Improved survival was associated with undergoing resection versus biopsy-only with 5-year OS rates of 85% and 50% (P=0.002), respectively. A high proportion of patients (42%) had diffuse tumors and 13 patients (27%) had diffuse pontine gliomas (DPGs). DPGs had an OS of 1.8 years with a worse median PFS than non-DPGs (1.8 vs. 11.1 y; P=0.009). RT was used preferentially in patients with poor prognosis such as those who had a biopsy-only procedure (19/27) and DPGs (9/13). CONCLUSIONS: OS in this single institution retrospective study in pathologically proven BS-LGG with extensive follow-up displayed favorable long term outcomes. Improved outcomes were associated with nondiffuse classification. PMID- 23357967 TI - Five-year outcomes of squamous cell carcinoma of the tonsil treated with radiotherapy. AB - PURPOSE: To retrospectively review our single institution experience of patients with tonsillar squamous cell carcinoma. MATERIAL AND METHODS: Between 1999 and 2005, a total of 79 patients were identified. Stage distribution was as follows: stages I-II, III, IVA, and IVB were in 6, 14, 43, and 16 patients, respectively. Sixty-three patients (80%) were male. Median age was 55.5 years. Treatment generally consisted of external beam radiation therapy (RT) (median dose, 70 Gy), concomitant chemotherapy (CCRT) (cisplatin 100 mg/m on days 1, 22, and 43), and neck dissection (ND), and was administered as follows: stages I/II, 6 patients received RT alone; stages III/IVA, 20, 5, and 32 patients received RT alone, CCRT, and CCRT followed by ND, respectively; stage IVB, 9 and 7 patients received CCRT and CCRT plus ND, respectively. RESULTS: After a median follow-up of 56 months (range, 12 to 122 mo), the 5-year local control (LC), regional control (RC), distant control (DC), and overall survival (OS) by stage were as follows: stage I-II 100%, 100%, 100%, 100%; stage III-IVA 98%, 96%, 95%, and 88%; stage IVB 100%, 100%, 69%, and 66%, respectively. Among stage IVB patients, DC was significantly lower (P=0.01) and a trend toward lower OS was noted (P=0.08). Long term percutaneous endoscopic gastrostomy dependence was noted in 3% of them who had received CCRT. The effect of both chemotherapy and ND on treatment outcomes was analyzed; in stage III/IVA patients treated with or without chemotherapy, LC was 97% and 100% (P=0.43); RC was 92% and 100%(P=0.27); and DC was 91% and 94% (P=0.92), respectively. In stage III/IVA, patients treated with CCRT with or without ND, RC was 100% and 88%, respectively (P=0.087). CONCLUSIONS: Primary radiotherapy with or without CCRT followed by ND provides excellent tumor control with acceptable toxicity in treating squamous cell carcinoma of the tonsil. PMID- 23357968 TI - Reirradiation for locoregionally recurrent lung cancer: outcomes in small cell and non-small cell lung carcinoma. AB - OBJECTIVES: To our knowledge this is the largest report analyzing outcomes for re irradiation (reRT) for locoregionally recurrent lung cancer, and the first to assess thoracic reRT outcomes in patients with small cell lung cancer (SCLC). METHODS: Forty-eight patients (11 SCLC, 37 non-small cell lung cancer [NSCLC]) receiving reRT to the thorax were identified; 44 (92%) received reRT by intensity modulated radiotherapy. Palliative responses, survival outcomes, and prognostic factors were analyzed. RESULTS: NSCLC patients received a median of 30 Gy in a median of 10 fractions, whereas SCLC patients received a median of 37.5 Gy in a median of 15 fractions. Median survival for the entire cohort from reRT was 4.2 months. Median survival for NSCLC patients was 5.1 months, versus 3.1 months for the SCLC patients (P=0.15). In NSCLC patients, multivariate analysis demonstrated that Karnofsky performance status>=80 and higher radiation dose were associated with improved survival following reRT, and 75% of patients with symptoms experienced palliative benefit. In SCLC, 4 patients treated with the intent of life prolongation for radiographic recurrence had a median survival of 11.7 months. However, acute toxicities and new disease symptoms limited the duration of palliative benefit in the 7 symptomatic SCLC patients to 0.5 months. CONCLUSIONS: ReRT to the thorax for locoregionally recurrent NSCLC can provide palliative benefit, and a small subset of patients may experience long-term survival. Select SCLC patients may experience meaningful survival prolongation after reRT, but reRT for patients with symptomatic recurrence and/or extrathoracic disease did not offer meaningful survival or durable symptom benefit. PMID- 23357969 TI - Impact of epidermal growth factor receptor and KRAS mutations on clinical outcome in resected non-small cell lung cancer patients. AB - OBJECTIVES: Surgery yields best results for non-small cell lung cancer (NSCLC) patients. Epidermal growth factor receptor (EGFR) and its downstream factor Kirsten rat sarcoma viral oncogene homolog (KRAS) are variably mutated in NSCLC. Such mutations predict clinical response to tyrosine kinase inhibitors. This study evaluated incidence and correlation of EGFR and KRAS mutations with clinicopathologic parameters and outcome in resected stage I to III NSCLC. METHODS: We analyzed the clinical characteristics and outcome data for 230 patients who underwent resection at our institution for stage I to III NSCLC. The tumors were assessed for both EGFR (exons 18 to 21) and KRAS (exons 2 and 3) mutations by nested polymerase chain reaction and sequenced in both sense and antisense direction. Kaplan-Meier estimates of overall survival and disease-free survival were calculated for clinical and biological variables using Cox model. RESULTS: EGFR and KRAS mutations were detected in 22 (9.6%) and 39 (16.9%) patients, respectively. In the whole population, both EGFR and KRAS mutations were significantly correlated with adenocarcinoma (ADC). Overall, EGFR mutations were more frequent in women (P<0.0001) and in nonsmokers (P<0.0001). In the ADC/BAC group, KRAS mutations were more frequent in man (P<0.02) and EGFR mutations (exon 19 deletion and L858R) demonstrated a tendency towards worse disease-free survival (P=0.056). No difference in outcome was seen between patients harboring KRAS mutations compared with KRAS wild type. CONCLUSIONS: EGFR and KRAS mutations are frequent in ADCs and are not prognostic factors for survival. EGFR mutations could be used to identify patients suitable for adjuvant treatment with targeted therapy resulting in potentially improved outcomes. PMID- 23357970 TI - Divergent management strategies for typical versus atypical carcinoid tumors of the thoracic cavity. AB - OBJECTIVES: At our institution, limited surgical techniques are reserved only for suspected typical carcinoids, and nodal dissection and multimodality therapy are frequently used for atypical carcinoids. We describe the results of these differing management strategies based on initial clinicopathologic characteristics. METHODS: Retrospective review of patients treated for thoracic carcinoid from 1995 to 2009. Information was abstracted concerning surgical and nonsurgical treatments, pathology results, and outcomes. Event-free and survival endpoints were compared. RESULTS: The median follow-up was 5.0 years (range, 0.5 to 17.4 y). Fifty-two patients underwent resection. The 5-year event-free survival for typical carcinoid patients was 88.2%. Atypical carcinoids had a tendency for nodal involvement (50% vs. 15%) and greater likelihood for disease recurrence, with a 5-year event-free survival of 50%. CONCLUSIONS: These data support the appropriateness of divergent management strategies for typical versus atypical bronchial carcinoids. We propose the following: (1) nonanatomic resection is acceptable only for peripheral typical carcinoids; (2) extended mediastinal dissection should be limited to central presentations, clinically aggressive, or atypical carcinoids; (3) atypical histology, especially with nodal involvement, is prognostic for recurrence and metastasis; (4) nonsurgical therapies only rarely achieve long-term freedom from disease. PMID- 23357971 TI - New-onset congestive heart failure with gemcitabine in ovarian and other solid cancers. AB - OBJECTIVE: To assess clinical features that may predispose individuals taking gemcitabine to new-onset congestive heart failure. METHODS: A retrospective chart review was conducted with 156 female patients, 51 with ovarian cancer and 105 with breast, lung, pancreas, and bladder cancer, all of whom had received gemcitabine. Patients with new-onset congestive heart failure were compared with patients without new-onset congestive heart failure with the use of Wilcoxon rank sum test for continuously distributed data and the Fisher exact test for proportions. RESULTS: Seven patients developed new-onset congestive heart failure (4.5%) during their treatment, which was significantly greater than that reported previously (0.76%). Patients with new-onset congestive heart failure did not differ from other patients in the study for age, weight, gravidity, parity, body mass index, and type of cancer. They also did not differ in history of myocardial infarction, hypertension, prior episodes of congestive heart failure, prior treatment with adriamycin, or use of tobacco. However, diabetes mellitus and coronary artery disease were more common, and all patients who developed new onset congestive heart failure received >17,000 mg/m of gemcitabine. The incidence of new-onset congestive heart failure in this study is significantly higher than previously reported with the use of gemcitabine. CONCLUSIONS: The single-most predictive risk factor for new-onset congestive heart failure in this cohort of patients is the receipt of a minimum dose of 17,000 mg/m. Therefore, additional follow-up may be necessary for all patients receiving >15,000 mg/m of gemcitabine to screen for potential new-onset congestive heart failure. PMID- 23357972 TI - Hypofractionated radiotherapy does not increase acute toxicity in large-breasted women: results from a prospectively collected series. AB - BACKGROUND AND PURPOSE: To compare the acute toxicity of hypofractionated whole breast radiotherapy (HypoRT) to conventionally fractionated radiotherapy (ConvRT) in large-breasted women with early stage disease. MATERIALS AND METHODS: Women with breast volume>1500 cm, body mass index>30 kg/m, or separation>25 cm treated with HypoRT or ConvRT from 2005 through 2010 were identified from a prospective database and included in the analysis. Acute toxicity was scored for each treated breast. RESULTS: Ninety-two patients were treated to 96 breasts. The median body mass index was 33 kg/m and median breast volume was 1932 cm for the ConvRT group compared with 32.4 kg/m and 1825 cm for the HypoRT group. Maximum acute skin toxicity consisted of focal moist desquamation in 26% and 11% of the ConvRT and HypoRT patients, respectively (P=0.002). Breast volume was the only patient factor significantly associated with moist desquamation on multivariable analysis (P=0.01). Among those with a breast volume >2500 cm, focal moist desquamation occurred in 40.7% (11/27) compared with 11.1% (7/63) in patients with breast volume <2500 cm (P=0.002). CONCLUSIONS: Among obese and large-breasted women, there was no increase in acute skin toxicity with the use of HypoRT. HypoRT should be considered in obese and large-breasted women when advanced planning techniques are used. PMID- 23357974 TI - Axitinib for the treatment of metastatic renal cell carcinoma: recommendations for therapy management to optimize outcomes. AB - Axitinib is a novel, oral, multitargeted tyrosine kinase inhibitor, which inhibits vascular endothelial growth factor receptors 1, 2, and 3 at subnanomolar concentrations in vitro. In the phase III clinical trial in patients with metastatic renal cell carcinoma, axitinib showed a high objective response rate, and significantly prolonged progression-free survival compared with sorafenib. Thus, it is the first drug that has proven the concept of sequencing tyrosine kinase inhibitors in second-line treatment in a phase III prospective randomized trial. Although generally well tolerated and associated with a low incidence of grade 3 or 4 toxicities, axitinib shows a distinct pattern of adverse events that require monitoring and management. The most common adverse events observed with axitinib include diarrhea, hypertension, fatigue, nausea, and vomiting. This article summarizes the most important adverse events observed and proposes recommendations for their monitoring, prevention, and treatment. The recommendations are based on the existing literature and discussion by an expert group of international physicians and nurses specialized in oncologic treatment of metastatic renal cell carcinoma, which gathered in July 2011 in London, UK. Proactive assessment and management of adverse events during axitinib therapy can minimize treatment interruptions and ensure optimal effect of treatment. PMID- 23357973 TI - Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group study, N0675. AB - OBJECTIVE: Mammalian target of rapamycin (mTOR) pathway is activated in malignant melanoma and in situ lesions as opposed to benign nevi. Inhibition of PI3K-Akt mTOR signaling is implicated in sensitization of melanoma cells to alkylating agents (temozolomide [TMZ]) and inhibition of tumor angiogenesis. METHODS: We conducted a single-arm phase II multi-institution cooperative group study to assess the antitumor activity and safety profile of the combination of TMZ and the rapamycin derivative everolimus in patients with metastatic unresectable malignant melanoma. Patients received 10 mg/d of RAD001 for 5 of 7 days (ie, 50 mg/wk) and 200 mg/m/d of TMZ for 5 days each cycle. RESULTS: Of the first 39 eligible patients, 17 were PFS-9 successes, for a predetermined threshold of 18/39 patients for a positive trial. Overall, 21 of 48 patients were progression free at 9 weeks, for an event-free survival rate of 44% (95% confidence interval, 29%-59%). The median progression-free survival was 2.4 months and the median overall survival was 8.6 months. Four patients achieved a partial response; the median duration of response was 15.1 months. No complete remissions were observed. Treatment was in general well tolerated with only 1 patient discontinuing therapy due to toxicity (hyperlipidemia). CONCLUSIONS: The combination of TMZ and RAD001 was well tolerated but failed to meet/exceed our study threshold for promising clinical activity in patients with metastatic melanoma. PMID- 23357975 TI - Pulmonary infiltrates in acute myeloid leukemia during induction treatment: how much do we know? AB - BACKGROUND: During induction treatment, acute myeloid leukemia patients may develop pulmonary infiltrates due to infectious or noninfectious etiologies. The risk association and the clinical outcome of such pulmonary infiltrates are poorly characterized in the literature. METHODS: We retrospectively reviewed 363 cases of acute myeloid leukemia patients who received induction therapy as inpatients over a period of 11 years at William Beaumont Health System. Of these 363 patients, 120 developed pulmonary infiltrates during induction therapy, those patients were divided into 2 groups based on distribution of the infiltrate presenting as localized or diffuse in nature. Data on patients characteristics, leukemia subtype, cytogenetic risk, microorganism type, white blood cell count at diagnosis, neutrophil count at the time the infiltrate was reported, response to antibiotic and/or antifungal therapy, using respiratory support, and mortality rate were retrieved through chart review. RESULTS: Thirty-three percent of patients developed pulmonary infiltrates during their induction therapy. Sixty three patients (52.5%) had a localized infiltrates and 57 patients (47.5%) had diffuse infiltrates. Of the 120 patients with pulmonary infiltrates, 48 (40%) had at least 1 pathogenic microorganism identified, and 58 (48.7%) required intubation and ventilatory support. Patients with localized pulmonary infiltrates were more likely to have positive pathogenic microorganisms (68.3% vs. 8.8%, P<0.001), to be neutropenic (96.8% vs. 21%, P<0.001), and tended to have potentially reversible infiltrates after treatment (87.3% vs. 21%, P<0.001). Whereas patients with diffuse infiltrates were more like to require intubation (78.9% vs. 21%, P<0.001), to have leukocytosis (white blood cell >100 billions/L) at diagnosis (54.4% vs. 0%, P<0.001), and had a higher mortality rate (70.2% vs. 9.5%, P<0.001). CONCLUSIONS: The radiologic patterns of pulmonary infiltrates showed specific etiological and prognostic associations. Diffuse infiltrates are an unfavorable characteristic with overall dismal outcome. PMID- 23357977 TI - The association between daily calcium intake and sarcopenia in older, non-obese Korean adults: the fourth Korea National Health and Nutrition Examination Survey (KNHANES IV) 2009. AB - Recent data suggest that variations in calcium intake may influence body weight and composition; however, the relationship between daily calcium intake and muscle mass has not been well established. The objective of this study was to assess the relationship between daily calcium intake and sarcopenia. We analyzed data for older adults (over 60 years) from the fourth Korea National Health and Nutrition Examination Survey (KNHANES) conducted in 2009. A total of 1339 Non Obese (BMI between 18.5 and 25 kg/m2), older adults (592 men and 707 women) were enrolled. Dietary variables were assessed using a nutrition survey that used a 24 hour recall method. Daily calcium intake based on the consumption of each food item was calculated. Sarcopenia was defined as an appendicular skeletal muscle mass divided by body weight less than 2 SD below the sex-specific mean for young adults. We found that daily calcium intake was negatively correlated with total body fat percentage and positively correlated with appendicular skeletal mass (p<0.001). Participants with sarcopenia appear to have significantly lower daily calcium intakes than participants without sarcopenia (p<0.001). The unadjusted prevalence of sarcopenia according to daily calcium intake tertiles were 6.3%, 4.3%, and 2.7% in tertiles 1, 2, and 3, respectively. After adjustment for age, sex, BMI, total energy intake, and lifestyle factors, compared with those in the lowest tertile of daily calcium intake, participants in the highest tertile had an odds ratio for sarcopenia of 0.295 (95% confidence interval, 0.087-0.768; p for trend = 0.014). We found that daily calcium intake, corrected for total energy intake and serum 25(OH)D status, was significantly lower in subjects with sarcopenia than in those without. Our results suggest a strong inverse association between daily calcium intake and sarcopenia in non-obese, older Korean adults. PMID- 23357976 TI - Longer HSD11B2 CA-repeat in impaired glucose tolerance and type 2 diabetes. AB - Type 2 11beta-hydroxysteroid dehydrogenase encoded by the HSD11B2 gene converts cortisol to inactive cortisone, and alteration in this enzymatic activity might affect glucose homeostasis by affecting circulating levels or tissue availability of glucocorticoids. We investigated the association of HSD11B2 variant with glucose homeostasis. Subjects with normal glucose tolerance (n=585), impaired glucose tolerance (n=202) and type 2 diabetes (n=355) were genotyped for a highly polymorphic CA-repeat polymorphism in the first intron of HSD11B2. Allele and genotype frequencies differed between normal and impaired glucose tolerance (P = 0.0014 and 0.0407, respectively; 4 degree of freedom) or type 2 diabetes (P = 0.0053 and 0.0078), with significant linear trends between the repeat length and the phenotype fraction. In normal subjects, total CA-repeat length was negatively correlated with fasting insulin and HOMA-beta. Thus, subjects having more CA repeats are susceptible to developing abnormal glucose tolerance, whereas normal subjects carrying more CA repeats appeared to have frugal characteristics in insulin secretion. PMID- 23357978 TI - Synergistic activity of bortezomib and HDACi in preclinical models of B-cell precursor acute lymphoblastic leukemia via modulation of p53, PI3K/AKT, and NF kappaB. AB - PURPOSE: Relapse of disease and subsequent resistance to established therapies remains a major challenge in the treatment of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). New therapeutic options, such as proteasome and histone deacetylase inhibitors (HDACi) with a toxicity profile differing from that of conventional cytotoxic agents, are needed for these extensively pretreated patients. EXPERIMENTAL DESIGN: Antiproliferative and proapoptotic effects of combined HDACi/proteasome inhibitor treatments were analyzed using BCP ALL monocultures, cocultures with primary mesenchymal stroma cells from patients with ALL, and xenograft mouse models. The underlying molecular mechanisms associated with combined treatment were determined by gene expression profiling and protein validation. RESULTS: We identified the proteasome inhibitor bortezomib as a promising combination partner for HDACi due to the substantial synergistic antileukemic activity in BCP-ALL cells after concomitant application. This effect was maintained or even increased in the presence of chemotherapeutic agents. The synergistic effect of combined HDACi/BTZ treatment was associated with the regulation of genes involved in cell cycle, JUN/MAPK, PI3K/AKT, p53, ubiquitin/proteasome, and NF-kappaB pathways. We observed an activation of NF kappaB after bortezomib treatment and the induction of apoptosis-related NF kappaB target genes such as TNFalphaRs after concomitant treatment, indicating a possible involvement of NF-kappaB as proapoptotic mediator. In this context, significantly lower NF-kappaB subunits gene expression was detected in leukemia cells from patients who developed a relapse during frontline chemotherapy, compared with those who relapsed after cessation of frontline therapy. CONCLUSION: These results provide a rationale for the integration of HDACi/BTZ combinations into current childhood BCP-ALL treatment protocols. PMID- 23357979 TI - A 12-gene set predicts survival benefits from adjuvant chemotherapy in non-small cell lung cancer patients. AB - PURPOSE: Prospectively identifying who will benefit from adjuvant chemotherapy (ACT) would improve clinical decisions for non-small cell lung cancer (NSCLC) patients. In this study, we aim to develop and validate a functional gene set that predicts the clinical benefits of ACT in NSCLC. EXPERIMENTAL DESIGN: An 18 hub-gene prognosis signature was developed through a systems biology approach, and its prognostic value was evaluated in six independent cohorts. The 18-hub gene set was then integrated with genome-wide functional (RNAi) data and genetic aberration data to derive a 12-gene predictive signature for ACT benefits in NSCLC. RESULTS: Using a cohort of 442 stage I to III NSCLC patients who underwent surgical resection, we identified an 18-hub-gene set that robustly predicted the prognosis of patients with adenocarcinoma in all validation datasets across four microarray platforms. The hub genes, identified through a purely data-driven approach, have significant biological implications in tumor pathogenesis, including NKX2-1, Aurora Kinase A, PRC1, CDKN3, MBIP, and RRM2. The 12-gene predictive signature was successfully validated in two independent datasets (n = 90 and 176). The predicted benefit group showed significant improvement in survival after ACT (UT Lung SPORE data: HR = 0.34, P = 0.017; JBR.10 clinical trial data: HR = 0.36, P = 0.038), whereas the predicted nonbenefit group showed no survival benefit for 2 datasets (HR = 0.80, P = 0.70; HR = 0.91, P = 0.82). CONCLUSIONS: This is the first study to integrate genetic aberration, genome-wide RNAi data, and mRNA expression data to identify a functional gene set that predicts which resectable patients with non-small cell lung cancer will have a survival benefit with ACT. PMID- 23357981 TI - Discussion: The volumetric analysis of fat graft survival in breast reconstruction. PMID- 23357982 TI - Comprehensive outcome and cost analysis of free tissue transfer for breast reconstruction: an experience with 1303 flaps. AB - BACKGROUND: Free tissue transfer is standard for postoncologic reconstruction, yet it entails a lengthy operation and significant recovery. The authors present their longitudinal experience of free tissue breast reconstructions with an emphasis on predictors of major surgical and medical complications. METHODS: The authors reviewed their prospectively maintained free flap database and identified oncologic breast reconstruction patients from 2005 to 2011. Factors associated with surgical and medical complications were identified using univariate analyses and logistic regression to determine predictors of complications. RESULTS: Complications included major immediate surgical complications [n = 34 (4.0 percent)], major delayed surgical complications [n = 54 (6.4 percent)], minor surgical complications [n = 404 (47.6 percent)], and medical complications [n = 50 (5.9 percent)]. Obesity (p = 0.034), smoking (p = 0.06), flap type (p = 0.005), and recipient vessels (p < 0.001) were associated with immediate complications. Similarly, delayed surgical complications were associated with obesity (p < 0.001), chronic obstructive pulmonary disease (p < 0.001), hypertension (p < 0.001), and prior radiation therapy (p = 0.06). Regression analysis demonstrated that flap choice (p = 0.024) was independently associated with major immediate complications, and patient comorbidities such as chronic obstructive pulmonary disease (p = 0.001) and obesity (p < 0.0001) were associated with delayed complications. Patients who developed an immediate surgical complication experienced longer hospital stays (p < 0.0001), higher operating costs (p < 0.001), and greater hospital costs (p < 0.001). CONCLUSIONS: Early major complications are related to flap selection, whereas late major complications are associated with patient comorbidities. Overall, major surgical and medical complications are associated with increased hospital length of stay and greater cost in autologous breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 23357980 TI - Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization. AB - PURPOSE: This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction. EXPERIMENTAL DESIGN: Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (>=VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim +/- cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers. RESULTS: The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% >= VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; postmobilization response rate was 96%, including 48% >= VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 * 10(6) cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation; 5 year overall survival rate was 76.4%. Grade >= 3 adverse events included thrombocytopenia (13%), hand-foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration. CONCLUSION: Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield. PMID- 23357983 TI - Micro-mechanical fractional skin rejuvenation. AB - BACKGROUND: The most commonly performed skin rejuvenation procedure, laser resurfacing, is associated with adverse events and significant expense. The authors have developed a novel device that uses micro-coring needles to remove tissue in a fractional pattern and avoid the side effects of laser therapy. The authors compare the efficacy of these needles to standard needles in a pig model. METHODS: One swine was treated with three needle types: standard hypodermic, solid hypodermic, and the authors' novel coring needles. Thirty-two 1 * 1-inch sites per flank received either 20 or 40 percent treatment coverage. Photographs were taken and punch biopsies were performed at days 0, 7, 28, 56, and 84. Biopsy specimens were evaluated for histology and collagen content. RESULTS: All treatment sites healed quickly, with no evidence of scarring or infection. Coring sites were easily identified and contained increased fibroblast activity and newly synthesized collagen. At 1 month, the papillary dermis and epidermis of the coring sites were up to 196 percent thicker compared with controls (p < 0.001). The coring sites had enhanced undulating rete ridges-consistent with regeneration. At 3 months, a pronounced increase in collagen fibers and newly organized and augmented elastic fibers was seen. Enzyme-linked immunosorbent assay confirmed an 89 percent increase in collagen content in these coring sites (p < 0.001). CONCLUSIONS: This novel approach to skin rejuvenation was found to effectively induce the microscopic and biological endpoints of skin rejuvenation. This may provide a new modality for the safe and cost-effective treatment of age related rhytides, skin laxity, photodamage, scarring, and striae. PMID- 23357984 TI - Bacteriophage therapy for Staphylococcus aureus biofilm-infected wounds: a new approach to chronic wound care. AB - BACKGROUND: Bacterial biofilms, which are critical mediators of chronic wounds, remain difficult to treat with traditional methods. Bacteriophage therapy against biofilm has not been rigorously studied in vivo. The authors evaluate the efficacy of a species-specific bacteriophage against Staphylococcus aureus biofilm-infected wounds using a validated, quantitative, rabbit ear model. METHODS: Six-millimeter dermal punch wounds in New Zealand rabbit ears were inoculated with wild-type or mutant, biofilm-deficient S. aureus. In vivo biofilm was established and maintained using procedures from our previously published wound biofilm model. Wounds were left untreated, or treated every other day with topical S. aureus-specific bacteriophage, sharp debridement, or both. Histologic wound healing and viable bacterial count measurements, and scanning electron microscopy were performed following harvest. RESULTS: Wild-type S. aureus biofilm wounds demonstrated no differences in healing or viable bacteria following bacteriophage application or sharp debridement alone. However, the combination of both treatments significantly improved all measured wound healing parameters (p < 0.05) and reduced bacteria counts (p = 0.03), which was confirmed by scanning electron microscopy. Bacteriophage treatment of biofilm-deficient S. aureus mutant wounds alone also resulted in similar trends for both endpoints (p < 0.05). CONCLUSIONS: Bacteriophages can be an effective topical therapy against S. aureus biofilm-infected wounds in the setting of a deficient (mutant) or disrupted (debridement) biofilm structure. Combination treatment aimed at disturbing the extracellular biofilm matrix, allowing for increased penetration of species-specific bacteriophages, represents a new and potentially effective approach to chronic wound care. These results establish principles for biofilm therapy that may be applied to several different clinical and surgical problems. PMID- 23357986 TI - Surface anatomy of the middle division of the facial nerve: Zuker's point. AB - BACKGROUND: The anatomy of the facial nerve and its branches has been well documented. The course of the extratemporal facial nerve, its anatomical planes, and the surface landmarks of the temporal division and marginal mandibular division are well known. However, the surface landmark of the middle division of the facial nerve has not been studied to date. METHODS: Eighteen hemifacial dissections in 10 fresh human cadavers were performed through a preauricular face lift incision. An 18-gauge needle with brilliant green dye was used to mark the nerve through the skin before dissection. The exact location of the middle division branches of the facial nerve was documented in relation to the transcutaneous marking. RESULTS: The middle division branches of the facial nerve were found to lie at a mean of 2.3 mm from the tattooed point, with a range of 0 to 6 mm. A nerve branch was found directly tattooed by the needle seven of 18 times, inferior to the tattoo five of 18 times, and superior to the tattoo six of 18 times. CONCLUSIONS: The zygomatic/buccal motor branch that innervates the zygomaticus major muscle can be reliably found at the midway point on a line drawn from the root of the helix and the lateral commissure of the mouth. This study will help guide surgeons to the middle division of the facial nerve as it applies to facial surgery. PMID- 23357985 TI - Application of poly-L-lactic acid nanosheet as a material for wound dressing. AB - The authors evaluated the efficacy of an ultrathin nanosheet consisting of poly-L lactic acid (75 nm thick) as a wound dressing material. A full-thickness skin defect was made on the backs of mice and overlapped with or without the poly-L lactic acid nanosheet. Wound healing was more rapidly improved by overlapping with the nanosheet, especially in the early healing period (at 4 to 6 days). The remaining wound area in the treatment group was significantly smaller at 4 days than in the control group. Histologically, a clear layer was observed over the granulation layer by the nanosheet therapy at 4 days. Thus, overlapping therapy with the poly-L-lactic acid nanosheet accelerated wound healing and formed a clear layer just above the granulation tissue. The poly-L-lactic acid nanosheet may have potential as a novel wound dressing to promote wound healing. PMID- 23357987 TI - Free-style puzzle flap: the concept of recycling a perforator flap. AB - Theoretically, a flap can be supplied by any perforator based on the angiosome theory. In this study, the technique of free-style perforator flap dissection was used to harvest a pedicled or free skin flap from a previous free flap for a second difficult reconstruction. The authors call this a free-style puzzle flap. For the past 3 years, the authors treated 13 patients in whom 12 pedicled free style puzzle flaps were harvested from previous redundant free flaps and recycled to reconstruct soft-tissue defects at various anatomical locations. One free style free puzzle flap was harvested from a previous anterolateral thigh flap for buccal cancer to reconstruct a foot defect. Total flap survival was attained in 12 of 13 flaps. One transferred flap failed completely. This patient had received postoperative radiotherapy after the initial cancer ablation and free anterolateral thigh flap reconstruction. Another free flap was used to close and reconstruct the wound. All the donor sites could be closed primarily. The free style puzzle flap, harvested from a previous redundant free flap and used as a perforator flap to reconstruct a new defect, has proven to be versatile and reliable. When indicated, it is an alternative donor site for further reconstruction of soft-tissue defects. PMID- 23357988 TI - An innovative cross-lip flap with a musculomucosal pedicle based on the vascular network of the lower lip. AB - The Abbe flap has been used for full-thickness defects of the upper lip with the inferior labial artery as the pedicle. Using the fine artery anatomy of the lower lip, the authors developed an innovative partial-thickness myocutaneous flap based on the vascular network of the submucosal and subcutaneous layers, which derived mainly from the horizontal labiomental artery or the vertical labiomental artery. From 2010 to 2011, this new technique was used in 33 patients with upper lip defects. The split flap was elevated from the posterior portion of the oris orbicularis muscle after the inferior labial artery was divided. All 33 cases of musculomucosal pedicle flaps were viable. The flap was perfectly symmetrical after the first-stage operation, and the operative time was reduced significantly. PMID- 23357989 TI - Early diagnosis and risk factors for lymphedema following lymph node dissection for gynecologic cancer. AB - BACKGROUND: Although early diagnosis is important for selecting an effective surgical treatment for secondary lymphedema, an efficient screening test for detecting early-stage lymphedema has not yet been established. Serial changes of lymphatic function before and after lymph node dissection and risk factors for secondary lymphedema are important indicators. METHODS: A prospective cohort observational study was conducted with 100 consecutive gynecologic cancer patients who underwent pelvic lymph node dissection. Lymphatic function was assessed by noninvasive lymphography using indocyanine green fluorescence imaging on a routine schedule. Earliest findings after lymphadenectomy and risk factors for lower leg lymphedema were investigated. RESULTS: Atypical transient dermal backflow patterns were observed in an early postoperative period in 50 cases, all of which disappeared within 3 months. Of these patterns, the splash pattern was observed in 31 patients, of which five improved to normal following a natural course. In contrast, the stardust pattern was observed in 27 patients, and none had improved with conservative therapy. Postoperative radiotherapy was a significant risk factor for the stardust pattern. CONCLUSIONS: All patients who undergo lymphadenectomy for gynecologic malignancies should be examined for secondary lower extremity lymphedema by qualitative evaluation methods on a routine schedule to determine the earliest possible diagnosis. Because the splash pattern on indocyanine green lymphography is a reversible lymphatic disorder following a natural course, surgical treatments are not recommended. The decision regarding surgical treatment can be made after observing the stardust pattern. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV. PMID- 23357990 TI - Discussion: Early diagnosis and risk factors for lymphedema following lymph node dissection for gynecologic cancer. PMID- 23357991 TI - Comparison of anterolateral thigh, lateral arm, and parascapular free flaps with regard to donor-site morbidity and aesthetic and functional outcomes. AB - BACKGROUND: The purpose of this study was to compare the morbidity and the aesthetic and functional outcomes of primarily closed donor sites of three commonly used free flaps. METHODS: Sixty patients who had undergone free flap reconstruction (20 anterolateral thigh, 20 parascapular, and 20 lateral arm flaps) were included in this study. The average follow-up time was 50 months (range, 6 to 135 months). Patients assessed subjective donor-site morbidity and satisfaction with the aesthetic and overall functional result using a self-report questionnaire. Outcome measures were the Disabilities of the Arm, Shoulder and Hand questionnaire; the Lower Extremity Functional Scale; and the Medical Outcomes Study 36-Item Short-Form Health Survey questionnaire. RESULTS: No significant differences in range of motion or in questionnaire, scale, or survey scores were detected. Sensory disorders were present in 100 percent (lateral arm), 90 percent (anterolateral thigh), and 45 percent (parascapular). No correlation to flap size was detected (187 cm for parascapular and anterolateral thigh, and 70 cm for lateral arm flaps). Postoperative complications were seromas (parascapular, n = 2), hematomas (parascapular, n = 1; lateral arm, n = 2), and dehiscence (n = 4 for each flap). Patient satisfaction with the donor site was rated 2.9 for lateral arm and anterolateral thigh flaps and 2.5 for parascapular flaps (1 = excellent, 6 = poor). Seventy percent of anterolateral thigh, 85 percent of lateral arm, and 100 percent of parascapular flap patients would choose their flap again. CONCLUSION: In terms of reducing donor-site morbidity, the parascapular flap represents a valuable alternative to the anterolateral thigh and lateral arm flaps, but side positioning and increased seroma are drawbacks. PMID- 23357992 TI - The superolateral thigh flap: cadaver and computed tomographic angiography studies with a clinical series. AB - BACKGROUND: There are few references to the reconstructive possibilities of the ascending branch of the lateral circumflex femoral artery other than the tensor fasciae latae muscle flap and the so-called muscle pedicle bone grafting technique. METHODS: An anatomical study was performed to evaluate the ascending branch of the lateral circumflex femoral artery and its contribution, through direct branches, to the iliac crest and skin. RESULTS: In nine of 20 dissections, a small branch of the ascending branch of the lateral circumflex femoral artery was found to reach the iliac crest in the space defined by the rectus femoris, gluteal muscles, and tensor fasciae latae. After emergence of the tensor fasciae latae pedicle, the ascending branch coursed through an anatomical triangular space before entering the trochanteric skin as a direct terminal branch and running for a considerable distance in a posteroinferior direction in the subcutaneous fat. This pretrochanteric triangle was defined by the tensor fasciae latae, the trochanteric insertions of the vastus lateralis and gluteus medius muscles, and the greater trochanter. CONCLUSIONS: The superolateral skin of the thigh can be transferred based on terminal branches of the ascending branch of the lateral circumflex femoral artery. Although inconstant, a small branch of the ascending branch reaches the iliac crest and might support vascularized bone transfer, although more studies are needed to define its role in composite tissue transplantation. This ascending branch might be a good alternative in pedicle or microvascular skin/fat transfer, breast reconstruction, tendocutaneous reconstructions, or composite tissue transplantation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 23357993 TI - Below-knee amputation with a vascularized fibular graft and headless compression screw. AB - Distal tibiofibular bridging (Ertl modification) in a below-knee amputation can provide an improved transmission of torque from the distal femur to the prosthesis. Without this bridge, the distal tibia and fibula are left freely rotating and translating in the soft-tissue envelope. The distal fibular segment creates a bone bridge that allows for increased distal weight bearing and more versatile prosthetic design. The purpose of this article is to describe the authors' technique for performing the Ertl modification to the below-knee amputation using a segment of vascularized fibula and a headless compression screw. PMID- 23357994 TI - Montreal Children's Hospital formula for nasoalveolar molding cleft therapy. AB - BACKGROUND: For cleft teams that use nasoalveolar molding for presurgical treatment of cleft lips, the determination of desired cleft-nasal height correction is a subjective assessment. The latter, however, is complicated by a noncleft nasal height that itself is depressed by the shifted nasal pyramid native to the deformity. The authors introduce a simple formula based on the Pythagorean theorem to estimate the corrected height of the nose as an objective guide for the endpoint of nasoalveolar molding therapy. METHODS: Nasal impressions of 20 consecutive patients with unilateral cleft lips who underwent nasoalveolar molding therapy were analyzed. Using identified landmarks on pre nasoalveolar molding impressions, the Montreal Children's Hospital formula was used to estimate the corrected height of the noncleft nostril (ideal corrected nasal height) as measured on the impressions after nasoalveolar molding therapy had verticalized the nasal pyramid. Statistical analysis was performed using the Pearson correlation test to determine the predictive value of the formula. RESULTS: Twenty patients were included in the study. Analysis demonstrated a statistically significant positive correlation (high degree) between predicted nasal heights (ideal corrected nasal height) and those measured following completion of nasoalveolar molding therapy (r = 0.760, p < 0.01). CONCLUSIONS: The Montreal Children's Hospital formula may serve as a useful tool to predict the corrected nasal height (ideal corrected nasal height) as a benchmark for cleft side nasal correction with nasoalveolar molding. The authors hope it will provide cleft teams, especially those beginning to use nasoalveolar molding, with an objective measure to guide nasoalveolar molding treatment. PMID- 23357995 TI - Discussion: Montreal children's hospital formula for nasoalveolar molding cleft therapy. PMID- 23357996 TI - Discussion: Liposuction of the arm concurrent with brachioplasty in the massive weight loss patient: is it safe? PMID- 23357997 TI - Discussion: Liposuction of the arm concurrent with brachioplasty in the massive weight loss patient: is it safe? PMID- 23357998 TI - Soft-tissue mobility of the lower face depending on positional changes and age: a three-dimensional morphometric surface analysis. AB - BACKGROUND: Reliable evaluation of the complex three-dimensional anatomy of the face has proven to be extremely difficult. Three-dimensional surface scanning technology has not yet reached widespread acceptance in clinical research in plastic surgery. This study aimed to describe two parameters that allow quantification of soft-tissue movements and to compare the surface changes of the lower face during positional changes and with increasing age. METHODS: Two groups, each with 20 voluntary female subjects aged 20 to 35 and 45 to 60 years, were examined with a three-dimensional surface scanner in both supine and sitting positions. After registration of the two surface scans, the soft-tissue mobility of the lower face was examined using two new parameters. Deformability describes the mean distance between the surfaces and stretchability describes the relative stretching of one surface when mapped onto the other. RESULTS: Both parameters show highly significant differences for tissue mobility of young versus old lower faces. The trend for the soft tissues to lose projection in the upper posterior aspect and gain projection in the lower anterior aspect increases strongly. In the older subjects, larger parts of the examined area show tissue displacements of up to 6 mm, whereas in the young faces the displacement is far less and does not exceed 4 mm. CONCLUSION: Computational analysis of the authors' experimental results using two new parameters shows a statistically significant increase of facial tissue displacement and surface stretching when comparing young and old subjects. PMID- 23357999 TI - Discussion: Soft-tissue mobility of the lower face depending on positional changes and age: a three-dimensional morphometric surface analysis. PMID- 23358000 TI - Plastic surgery and smoking: a prospective analysis of incidence, compliance, and complications. AB - BACKGROUND: Tobacco use remains a persistent risk factor in elective plastic surgery. Although nicotine is thought to increase complications, which procedures are affected and the reliability of patient-provided histories remain poorly defined. The authors sought to examine nicotine use and its impact on outcomes. METHODS: All patients in a single-surgeon practice undergoing surgery with general anesthesia during a 2-year period were enrolled. Preoperative evaluation included a thorough smoking history. All patients had urine samples taken on the day of surgery to assess for nicotine metabolites. Patients were followed for a minimum of 3 months after surgery and monitored for complications. RESULTS: Four hundred fifteen patients were enrolled. Of these, 139 (33.5 percent) stated that they had quit smoking and 39 (9.4 percent) were admitted active smokers. For the 362 patients with urine nicotine analysis available, 54 showed active smoking. Fifteen of these (4.1 percent) had denied current tobacco use. Patients stating that they had quit smoking were more likely to be deceitful than those stating they had never smoked (p < 0.001). Smokers had significantly higher overall complication rates (OR, 3.7; p < 0.001) and tissue necrosis rates (OR, 4.3; p = 0.02) and were likelier to require reoperation (OR, 3.7; p < 0.001). CONCLUSIONS: In a large cohort study examining the prevalence and impact of nicotine in the general plastic surgery population, substantial rates of deception regarding smoking status were found. Furthermore, active smoking was strongly correlated with complications. A methodologic approach to the detection and management of patients using tobacco products can help to optimize outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 23358001 TI - A report of the ASPS Task Force on regenerative medicine: opportunities for plastic surgery. AB - In 2011, the American Society of Plastic Surgeons (ASPS) created the Task Force on Regenerative Medicine to address the Society's strong interest in the emerging field of regenerative medicine, particularly cell- and tissue-based therapies applicable to plastic surgery procedures. The Task Force's U.S. Food and Drug Administration's Workgroup is informing ASPS interactions with the U.S. Food and Drug Administration's Center for Biologics Evaluation and Research. Engaging in dialogue with the agency to determine which research protocols will produce scientific data necessary to determine safety and efficacy for regenerative cellular therapies can allow research to be targeted to gather data that prove safety and efficacy of specific categories of therapies and/or products. This article reviews the regulatory backdrop of regenerative medicine, briefly reviews the history of regenerative medicine, and then looks at current research and potential future areas of research and clinical application. The historic ability of plastic surgeons to innovate and apply translational research positions the specialty of plastic surgery as a strong leader in clinical applications of regenerative medicine therapies. PMID- 23358002 TI - Discussion: A report of the ASPS Task Force on regenerative medicine: opportunities for plastic surgery. PMID- 23358003 TI - External approach for secondary rhinoplasty: advances over the past 25 years. PMID- 23358004 TI - The growing international audience for medical data: meeting the needs of the many. PMID- 23358009 TI - Microsurgical breast reconstruction for nipple-sparing mastectomy. AB - BACKGROUND: Nipple-sparing mastectomy warrants thorough preoperative evaluation to effectively achieve risk reduction, high patient satisfaction, and improved aesthetic outcome. To the authors' knowledge, this review represents the largest series of microsurgical breast reconstructions following nipple-sparing mastectomies. METHODS: All patients undergoing nipple-sparing mastectomy with microsurgical immediate breast reconstruction treated at New York University Medical Center (2007-2011) were identified. Patient demographics, breast cancer history, intraoperative details, complications, and revision operations were examined. Descriptive statistical analysis, including t test or regression analysis, was performed. RESULTS: In 51 patients, 85 free flap breast reconstructions (n = 85) were performed. The majority of flaps were performed for prophylactic indications [n = 55 (64.7 percent)], mostly through vertical incisions [n = 40 (47.0 percent)]. Donor sites included abdominally based [n = 66 (77.6 percent)], profunda artery perforator [n = 12 (14.1 percent)], transverse upper gracilis [n = 6 (7.0 percent)], and superior gluteal artery perforator [n = 1 (1.2 percent)] flaps. The most common complications were mastectomy skin flap necrosis [n = 11 (12.7 percent)] and nipple necrosis [n = 11 (12.7 percent)]. There was no correlation between mastectomy skin flap or nipple necrosis and choice of incision, mastectomy specimen weight, body mass index, or age (p > 0.05). However, smoking history was associated with nipple necrosis (p < 0.01). CONCLUSIONS: This series represents a high-volume experience with nipple-sparing mastectomy followed by immediate microsurgical reconstruction. When appropriately executed, it can deliver low complication rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23358010 TI - Surgical angiogenesis with short-term immunosuppression maintains bone viability in rabbit allogenic knee joint transplantation. AB - BACKGROUND: Vascularized composite allotransplantation has the potential for reconstruction of joint defects but requires lifelong immunosuppression, with substantial risks. This study evaluates an alternative, using surgical angiogenesis from implanted autogenous vessels to maintain viability without long term immunotherapy. METHODS: Vascularized knee joints were transplanted from Dutch Belted donors to New Zealand White rabbit recipients. Once positioned and revascularized microsurgically, a recipient-derived superficial inferior epigastric fascial flap and a saphenous arteriovenous bundle were placed within the transplanted femur and tibia, respectively, to develop a neoangiogenic, autogenous circulation. There were 10 transplants in group 1. Group 2 (n = 9) consisted of no-angiogenesis controls with ligated flaps and arteriovenous bundles. Group 3 rabbits (n = 10) were autotransplants with patent implants. Tacrolimus was used for 3 weeks to maintain nutrient flow during angiogenesis. At 16 weeks, the authors assessed bone healing, joint function, bone and cartilage mechanical properties, and histology. RESULTS: Group 1 allotransplants had more robust angiogenesis, better healing, improved mechanical properties, and better osteocyte viability than ligated controls (group 2). All three groups developed knee joint contractures and arthritic changes. Cartilage thickness and quality were poorer in allograft groups than in autotransplant controls. CONCLUSIONS: Surgical angiogenesis from implanted autogenous tissue improves bone viability, healing, and material properties in rabbit allogenic knee transplants. However, joint contractures and degenerative changes occurred in all transplants, regardless of antigenicity or blood supply. Experimental studies in a larger animal model with improved methods to maintain joint mobility are needed before the merit of living joint allotransplantation can be judged. PMID- 23358011 TI - Up-regulation of tension-related proteins in keloids: knockdown of Hsp27, alpha2beta1-integrin, and PAI-2 shows convincing reduction of extracellular matrix production. AB - BACKGROUND: Keloid disease is a fibroproliferative disorder, with an ill-defined treatment that is characterized by excessive extracellular matrix deposition. Mechanical tension promotes deposition of extracellular matrix and overexpression of tension-related proteins, which is associated with keloid disease. The aim of this study was to investigate the effect of tension-related proteins on extracellular matrix steady-state synthesis in primary keloid fibroblasts. METHODS: Keloid fibroblasts (n = 10) and normal skin (n = 4) fibroblast cultures were established from passages 0 to 3. A panel of 21 tension-related genes from microarray data were assessed at mRNA (quantitative reverse-transcriptase polymerase chain reaction) and protein (in-cell Western blotting) levels. Three genes were significantly altered in keloid tissue and fibroblasts, and their functional role was assessed using siRNA knockdown. RESULTS: Hsp27, alpha2beta1 integrin, and PAI-2 were significantly up-regulated (p < 0.05)in keloid tissue and fibroblasts compared with normal skin. Hsp27, alpha2beta1-integrin, and PAI-2 expression was inhibited by RNA interference. Both the mRNA and protein levels of Hsp27, alpha2beta1-integrin, and PAI-2 significantly decreased (p < 0.05) in keloid fibroblasts at 48 hours after transfection. After down-regulation of Hsp27, alpha2beta1-integrin, and PAI-2, the expression of intracellular extracellular matrix was significantly reduced (p < 0.05). Water-soluble tetrazolium salt-1 assay showed that transfection of Hsp27, alpha2beta1-integrin, and PAI-2 did not influence the viability/metabolic activity of keloid fibroblasts. CONCLUSIONS: This study demonstrates overexpression of key tension related proteins in keloid tissue and keloid fibroblasts. Knockdown of Hsp27, PAI 2, and alpha2beta1-integrin by RNA interference attenuates the expression of mRNA and protein levels and certain other extracellular matrix molecules. PMID- 23358012 TI - Comparison of in vivo adipogenic capabilities of two different extracellular matrix microparticle scaffolds. AB - BACKGROUND: The extracellular matrix is an essential microenvironment for cell survival activity. The adipose tissue extract microparticle scaffolds from human adipose tissue and small intestine submucosa microparticle scaffolds from porcine jejunum were prepared. Their effects on the adipogenic capabilities of human adipose-derived stem cells were compared in vivo. METHODS: A combination of physical and chemical methods was used to decellularize human fat and porcine jejunum. Expression of CD molecules on the adipose-derived stem cell surface was determined by flow cytometry. The stem cells were then cultured with the scaffold materials in vitro. The cell-scaffold complexes were implanted subcutaneously into nude mice, and samples were collected 4 and 8 weeks later. The adipogenic differentiation capabilities of adipose-derived stem cells were studied by histologic methods and real-time polymerase chain reaction. RESULTS: The authors observed high expression of CD90 and CD44; no expression of CD34, CD45, CD31, or CD106; and weak positive expression of CD49d on the extracted cells, which indicates that the cells were adipose-derived stem cells. The main constituent of the decellularized adipose tissue extract and small intestine submucosa microparticles was collagenous fiber, and the cells proliferated faster on the adipose tissue extract than on small intestine submucosa. Formation of adipocytes in the adipose tissue extract group was closer to that of normal human fat tissue compared with that of the small intestine submucosa group. CONCLUSIONS: Extracellular matrix microparticle scaffolds could promote proliferation, adhesion, and adipogenic differentiation of adipose-derived stem cells. The role of the adipose tissue extract microparticle scaffold in promoting adipogenesis was stronger and more suitable as a vector in fatty tissue engineering. PMID- 23358013 TI - Reconstructive techniques in transoral robotic surgery for head and neck cancer: a North American survey. AB - BACKGROUND: Although the use of transoral robotic surgery for tumor extirpation is expanding, little is known about national trends in the reconstruction of resultant defects. METHODS: An 18-question electronic survey was created by an expert panel of surgeons from the Department of Otolaryngology-Head and Neck Surgery and the Department of Plastic and Reconstructive Surgery at the University of Tennessee. Eligible participants were identified by the American Head and Neck Society Web site and from the Intuitive Surgical, Inc., Web site after review of surgeons trained in transoral robotic surgery techniques. RESULTS: Twenty-three of 27 preselected head and neck surgeons (85.18 percent) completed the survey. All respondents use transoral robotic surgery for head and neck tumor extirpation. The majority of the respondents [n = 17 (77.3 percent)] did not use any means of reconstruction. With respect to methods of reconstruction following transoral robotic surgery defects, the majority [n = 4 (80.0 percent)] used a free flap, a pedicled local flap [n = 3 (60.0 percent)], or a distant flap [n = 3 (60.0 percent)]. The radial forearm flap was the most commonly used free flap by all respondents. CONCLUSIONS: In general, the majority of survey respondents allow defects to heal secondarily or close primarily. Based on this survey, consensus indications for pedicled or free tissue transfer following transoral robotic surgery defects were primary head and neck tumors (stage T3 and T4a), pharyngeal defects with exposure of vital structures, and prior irradiation or chemoradiation to the operative site and neck. PMID- 23358014 TI - Discussion: Reconstructive techniques in transoral robotic surgery for head and neck cancer: a North American survey. PMID- 23358015 TI - Repair of facial scars by the free expanded deltopectoral flap. AB - BACKGROUND: Facial scars caused by burns and trauma severely affect patients' function and appearance. The expanded deltopectoral flap to local shift is the traditional method of repair, but for patients with the compulsive position after pedicle transfer, the therapeutic outcome is not satisfactory. The authors explored the surgical procedures for repairing facial scars by using the free expanded deltopectoral flap, which can reduce patient suffering and ensure a satisfactory outcome. METHODS: Eighteen patients with large facial scars underwent repair using free expanded deltopectoral flaps. After expansion, the flaps were transplanted to repair facial scars by vascular anastomosis. If the contour was not good and the pedicle was clumsy, another operation to thin the flaps was performed to perfect the repair. RESULTS: The 18 patients achieved satisfactory results. All of the flaps survived and the skin color, texture, and contour were well matched to those of the peripheral tissue. Six months postoperatively, the flaps had partially recovered sensation, and no adverse effect on facial expression was detected. One patient experienced venous congestion but the flap was successfully salvaged; another patient experienced expander exposure because of infection during saline injection. The asymmetric position of the nipples during the early phase improved gradually over time. CONCLUSION: After expansion and free transplantation, the deltopectoral flap has proved to be more effective than flaps used traditionally and will become one of the best choices for the treatment of facial scars. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 23358016 TI - Expanding the envelope: the posterior rectus sheath-liver vascular composite allotransplant. AB - BACKGROUND: Primary abdominal wall reconstruction after liver transplantation presents a challenge in patients with size mismatch, multivisceral transplants, and prior recipient abdominal surgery. The authors report their experience with a novel technique for abdominal wall reconstruction with a new vascular composite allotransplant. METHODS: Five posterior rectus sheath-liver composite vascular allotransplants were procured by a multidisciplinary team and transplanted into four patients over the course of 2 years. Liver transplantation was performed in the standard manner, and the posterior rectus sheath was inset as an inlay flap. RESULTS: Abdominal wall integrity was reestablished with vascularized fascia in all five cases. In two cases, the fascia was closed immediately at the time of initial transplantation. In three cases, the abdomen was left open for a planned second look and closed definitively when the liver appeared satisfactory. In one patient, hepatic artery thrombosis was detected 11 days after transplantation, requiring a second posterior rectus sheath-liver transplant. Skin closure was performed for all transplants in either an immediate or a delayed fashion. Reoperation requiring elevation of the posterior rectus sheath flap for a suprahepatic vena cava stenosis was performed in one patient. CONCLUSIONS: Closure of the abdominal cavity is critical to the success of liver transplantation for organ survival and overall patient morbidity and mortality. The authors describe their institutional experience with a novel method of concurrent abdominal wall reconstruction and liver transplantation using the posterior rectus sheath-liver vascular composite allotransplant in situations of size mismatch, multivisceral transplants, and compromised abdominal wall of the recipient. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 23358017 TI - Correcting the typical Apert face: combining bipartition with monobloc distraction. AB - BACKGROUND: Bipartition distraction is a novel procedure combining frontofacial bipartition and monobloc distraction. Apert syndrome and other syndromic craniofacial dysostoses are often characterized by hypertelorism, with a negative canthal axis and counterrotated orbits. Central midface hypoplasia can result in a biconcave face in both midsagittal and axial planes. Bipartition distraction can correct these facial abnormalities. METHODS: Twenty patients (19 Apert syndrome patients and one Pfeiffer syndrome patient, aged 1.6 to 21 years) underwent bipartition distraction. Severity of appearance was graded preoperatively and postoperatively as mild, moderate, or severe. Functional problems were documented by a multidisciplinary team. Central and lateral midface skeletal advancement were measured. Follow-up ranged from 15 months to 7 years. RESULTS: Bipartition distraction consistently produced more central than lateral facial advancement. Mean central advancement was 13.2 +/- 5.9 mm at sella-nasion and 11.7 +/- 5.4 mm at sella-A point. Lateral advancement was 4.7 +/- 2.8 mm. Unbending the face improved aesthetic appearance. Airway function, eye exposure, and elevated intracranial pressure were improved. Complications included six temporary cerebrospinal fluid leaks (four needing a lumbar drain), five patients with postoperative seizures, five patients requiring Rigid External Distraction frame repositioning, one palatal fistula, one velopharyngeal incompetence, five pin-site infections, one abscess under frontal bone, three cases of sepsis, nine patients with worsened strabismus, two patients with enophthalmos, one patient with partial visual field loss, and three patients who required reintubation because of aspiration. CONCLUSIONS: : Bipartition distraction is an effective procedure with which to differentially advance the central face in Apert syndrome. It improves both function and aesthetics. CLINICAL QUESTION/LEVEL OF EVIDENCE: : Therapeutic, IV. PMID- 23358018 TI - The influence of reduction mandibuloplasty history on the incidence of inferior alveolar nerve injury during sagittal split osteotomy. AB - BACKGROUND: The authors studied whether the incidence of inferior alveolar nerve injury in patients undergoing sagittal split ramus osteotomy differs in patients with a history of previous mandibular contouring surgery. METHODS: A retrospective chart review was completed on all patients who underwent orthognathic surgery, including bilateral sagittal split osteotomy and Le Fort I osteotomy, between 2009 and 2010. Patients were divided into two groups according to whether or not they had a history of mandible contouring. Patients who sustained inferior alveolar nerve injuries during orthognathic surgery were identified through an existing record of nerve-repair cases. The incidence of inferior alveolar nerve injury between groups was analyzed using the Fisher's exact test. Significance was defined as a value of p < 0.05. RESULTS: There were 168 patients (142 women and 26 men), with an average age of 25.3 years (range, 18 to 35 years). The inferior alveolar nerve injury rate in patients with a history of mandible contouring was 11.5 percent (n = 3), and that for primary sagittal split osteotomy patients was 1.6 percent (n = 5). The incidence of inferior alveolar nerve injury was significantly higher in the patients with a history of mandible contouring (p < 0.001). CONCLUSIONS: These findings suggest that patients with a history of mandibular contouring surgery had a significantly greater risk of inferior alveolar nerve injury. Surgeons should be aware of the relative change of the inferior alveolar nerve canal in patients who have undergone mandible contouring procedures and perform sagittal split ramus osteotomy with attention. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 23358019 TI - Weight reduction following abdominoplasty: a retrospective case review pilot study. AB - BACKGROUND: The question of whether or not abdominoplasty is associated with permanent weight reduction remains controversial. In coalition, should abdominoplasty be used as an adjunct for weight reduction in the overweight/obese patient? METHODS: This retrospective patient case series attempts to determine the most important factors associated with weight reduction. RESULTS: All patients undergoing abdominoplasty had weight loss beyond that of their resected pannus, with a minimum body mass index reached 11.6 +/- 1.7 weeks after surgery. Weight loss is attributed to an increase in satiety by 75 percent (n = 15) of patients. Preoperative body mass index greater than or equal to 24.5 kg/m can be used to predict long-term weight loss with a sensitivity and specificity of 92.9 percent and 83.3 percent, respectively. Patients above this threshold achieved significantly more weight loss (-4.5 +/- 1.4 percent body mass index) at 1 year compared with their lower body mass index counterparts (p = 0.014), as did those with pannus resections weighing greater than 4.5 lb (p = 0.01). CONCLUSIONS: Abdominoplasty performed on patients with a body mass index greater than 24.5 kg/m appears to be linked to sustained weight loss at 1 year. Satiety appears to be a prominent contributing factor, as does the amount of fat resected. Possible neurocrine mechanisms are discussed. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23358020 TI - Relationship of the zygomatic facial nerve to the retaining ligaments of the face: the Sub-SMAS danger zone. AB - BACKGROUND: The transition zone between cheek superficial musculoaponeurotic system (SMAS) and malar SMAS is difficult to raise because of proximity of zygomatic nerve branches. The authors attempted to clarify the three-dimensional anatomy of the retaining ligaments in relation to nerve branches in this area. METHODS: Facial dissection was performed on 22 cadaver hemifaces. The zygomatic and masseteric retaining ligaments and the zygomatic and buccal facial branches in the area of dissection were identified. Ninety-five percent confidence regions for the locations of the zygomaticus major origin and the main zygomatic retaining ligament and upper masseteric retaining ligament were created. RESULTS: The distribution, density, and size of the retaining ligaments varied. The main zygomatic and upper masseteric retaining ligaments were located at a mean distance of 44.91 +/- 9.72 mm and 46.35 +/- 8.34 mm from the tragus. An upper zygomatic branch passed between the main zygomatic and the upper masseteric retaining ligaments and was always located deep (4.07 +/- 1.29 mm) in the sub SMAS plane of dissection and passed deep under the upper third of the zygomaticus major muscle. An inferior zygomatic branch passed inferior to the upper masseteric retaining ligament or penetrated its inferior margin (54 percent of cases) and was located more superficially (1.41 +/- 0.95 mm), becoming visible just distal to the ligament. CONCLUSIONS: Despite anatomical variation, the main zygomatic and upper masseteric retaining ligaments create a safe passage in between, through which a zygomatic facial branch passes deep. The area of danger is immediately inferomedial to the upper masseteric retaining ligament, where a zygomatic branch becomes superficial and vulnerable. PMID- 23358021 TI - Intramuscular technique for gluteal augmentation: determination and quantification of muscle atrophy and implant position by computed tomographic scan. AB - BACKGROUND: New surgical techniques for gluteal augmentation have improved final results. It is estimated that more than 35,000 patients have undergone augmentation gluteoplasty using implants. The authors sought to determine and quantify the presence of muscle atrophy, and to evaluate implant positioning using the intramuscular technique. METHODS: Twenty-three female patients were selected prospectively for this study and underwent intramuscular gluteal augmentation using gluteal implants of a round or oval base. Computed tomographic scanning and three-dimensional volumetric reconstruction were used to investigate muscle atrophy and implant position, with comparison of the results between the preoperative scan and scans obtained 3, 6, and 12 months after surgery. RESULTS: Three-dimensional reconstruction and volumetric analysis showed muscular atrophy. After 12 months of follow-up, 34 gluteal muscles (17 patients) were analyzed, with 4.3 percent atrophy remaining on the right side and 2.6 percent on the left side. Twenty-three patients were studied regarding position (46 gluteal implants). All oval base implants introduced in a vertical direction (seven patients) turned to an oblique direction, following the direction of muscle fibers by 3 months after surgery. Two patients showed rotation of the implant. CONCLUSIONS: The presence of a gluteal implant caused muscle atrophy. However, it did not lead to clinical or physical limitations. It is not important whether the implants are positioned vertically or obliquely, provided that they are symmetric. The technique proved to be safe in maintaining the intramuscular position of the implant, with good satisfaction for the patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23358022 TI - Head and neck reconstruction. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Discuss the principles behind the choice of reconstructive techniques for all major head and neck regions. 2. Differentiate between the optimal choices for reconstruction of the different mandibulectomy defects. 3. List the requirements for successful reconstruction of the skull base. 4. Further study new and evolving head and neck reconstruction techniques and options. SUMMARY: Management of head and neck cancer has undergone many significant changes during the past two decades. This article gives an overview of the major areas in the head and neck, highlighting current practice and more recent trends in reconstruction choices. Further detail is given in the related videos. The five attached videos depict individual techniques of mandibular reconstruction, showing the technique of fibular dissection and osteotomy: endoscopic skull base reconstruction through a transpterygoid/lateral canthotomy approach, scalp reconstruction using a latissimus dorsi free flap and skin graft, maxillary reconstruction using the deep circumflex iliac artery iliac crest and internal oblique flap, and pharyngoesophageal reconstruction using an anterolateral thigh flap. PMID- 23358023 TI - Reepithelialization from stem cells of hair follicles of dermal graft of the scalp in acute treatment of third-degree burns: first clinical and histologic study. PMID- 23358024 TI - Reply: Reepithelialization from stem cells of hair follicles of dermal graft of the scalp in acute treatment of third-degree burns: first clinical and histologic study. PMID- 23358025 TI - Outcome comparison of endoscopic and transpalpebral decompression for treatment of frontal migraine headaches. PMID- 23358026 TI - Reply: Outcome comparison of endoscopic and transpalpebral decompression for treatment of frontal migraine headaches. PMID- 23358027 TI - The effects of acellular dermal matrix in expander-implant breast reconstruction after total skin-sparing mastectomy. PMID- 23358028 TI - Reply: The effects of acellular dermal matrix in expander-implant breast reconstruction after total skin-sparing mastectomy. PMID- 23358029 TI - The dermal bra mammaplasty: concerns regarding safety and efficacy. PMID- 23358030 TI - Reply: The dermal bra mammaplasty: concerns regarding safety and efficacy. PMID- 23358031 TI - The Rasch Model: "Litmus Test" de rigueur for rating scales? PMID- 23358032 TI - Reply: The Rasch model: "Litmus Test" de rigueur for rating scales? PMID- 23358033 TI - The inferiorly based parenchymal flap mammaplasty: the need for measurements to support claims. PMID- 23358034 TI - Reply: The inferiorly based parenchymal flap mammaplasty: the need for measurements to support claims. PMID- 23358035 TI - Pfannenstiel scar and the Jehovah's Witness patient: should you perform a DIEP breast reconstruction? PMID- 23358036 TI - Reply: Pfannenstiel scar and the Jehovah's Witness patient: should you perform a DIEP breast reconstruction? PMID- 23358037 TI - Bilateral bookend pericranial flaps. PMID- 23358038 TI - Composite facial part replantation. PMID- 23358039 TI - Bilateral blindness after filler injection. PMID- 23358040 TI - Incompatibility of betadine mixed with marcaine as an irrigant for breast implant pockets. PMID- 23358041 TI - Structured mammaplasty: a new approach for obtaining breast symmetry. PMID- 23358042 TI - Reduction mammaplasty in patients with a medialized nipple-areola complex: modification of the superomedial dermoglandular pedicle and skin pattern. PMID- 23358043 TI - Cavitation rheology as a potential method for in vivo assessment of skin biomechanics. PMID- 23358044 TI - Autologous mesenchymal stem cells as a new strategy in immunosuppressant therapy in double hand allotransplantation. PMID- 23358045 TI - Early necrotizing fasciitis or isolated subcutaneous emphysema? PMID- 23358046 TI - Free superficial palmar branch of the radial artery flap for the reconstruction of defects of the volar surface of the digits, including the pulp. PMID- 23358047 TI - Ulcerous scar soft-tissue defects in Achilles tendon and posterior heel region: anatomy and reconstruction with proximally based sural adipose-cutaneous flap. PMID- 23358048 TI - The chicken foot dorsal vessel as a high-fidelity microsurgery practice model. PMID- 23358049 TI - Comprehensive cleft center: a paradigm shift in cleft care. PMID- 23358050 TI - Orthoplastics: an evolving concept for integrated surgical care of complex limb trauma and abnormality. PMID- 23358051 TI - An objective scoring system and simple mathematical algorithm for the plastic surgery applicant to rank residency programs based on personalized preferences. PMID- 23358052 TI - Independent plastic surgery residency match rate trend. PMID- 23358053 TI - Protecting plastic surgery under the affordable care act. PMID- 23358054 TI - The use of bedside electromagnetically guided nasointestinal tube for jejunal feeding of critical ill surgical patients. AB - BACKGROUND: Gastral nutrition in critically ill surgical patients can be difficult because of gastric paresis and a large number of patients fail to reach required caloric intake. Endoscopic or radiologic placement of nasointestinal tube is frequently performed with delay and may raise the risks for critical ill patients. OBJECTIVE: Bedside placement of electromagnetically guided nasointestinal tube (EGNT) may reduce the risk of x-ray exposure, "time out of ward" and caloric deficit. METHODS: All patients in a surgical intensive care unit with need of post-pyloric feeding tube placement were identified. Data were collected from Cortrak-EGNT-System and x-ray. An analysis of placement success rate, time for tube positioning and delay of enteral feeding when EGNT failed were performed. RESULTS: 70 tubes were placed in 51 patients. After the first trial 79% were placed post-pyloric and 21% gastral. Successful postpyloric placement increased to 90% after the second trial. Placement failure occurred in 10% of all cases. In 3 patients jejunal placement was successful in modified anatomical situs after upper gastrointestinal surgery. After 20 min unsuccessful postpyloric placement, performance was stopped and declared as failure. X-ray findings correlated in 100% with Cortrak data. Time needed for placement varied from 1-20 min (mean 7.6 min). CONCLUSIONS: Bedside positioning of electromagnetically guided nasointestinal tube is safe and effective in critically ill surgical patients. Most placements succeed, even in patients after upper GI surgery. EGNT positioning is time saving and may enhance the caloric intake. PMID- 23358055 TI - Treatment of recurrent hepatocellular carcinoma confined to the liver with repeated resection and radiofrequency ablation: a single center experience. AB - BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after surgical treatment is a common problem. It can be treated by radiofrequency ablation (RFA) or repeated hepatic resection (HR). This report compares both in a retrospective, single-institution database. PATIENTS AND METHODS: A prospectively collected database was retrospectively analyzed. RFA was performed under ultrasound control using two different monopolar devices. All kinds of access were used: open surgical (n=10), percutaneous (n=13) and laparoscopic (n=4). HR was performed using an ultrasound aspiration device. Indication for a particular treatment was allocated on a case-by-case basis; the final decision was often made intraoperatively. RESULTS: Survival after RFA (median 40 months) was similar compared to that after HR (48 months, p=0.641, logRank-test). Tumor-free survival was markedly impaired after RFA (15 vs. 29 months). This difference was however not significant (p=0.07, logRank-test). Both groups were different regarding occurrence of cirrhosis, maximal tumor size, time after initial diagnosis and duration of the procedure. CONCLUSION: In this non-randomized retrospective trial, survival and disease-free survival was not significantly different when compared between patients treated by RFA and HR. There was however a tendency towards a longer tumor-free survival in the resected patients. PMID- 23358056 TI - Evaluation of metabolic syndrome related health information on internet in Indian context. AB - BACKGROUND: Metabolic Syndrome (MetS) in India is a major contributor to the global increase in CVD. Lifestyle modification programs have been effective in reducing the burden of MetS. OBJECTIVE: The Objective of our study was to evaluate the quality of MetS related health information on the internet in an Indian context. METHODOLOGY: We used a key term "metabolic syndrome" to retrieve websites from Google, Yahoo and Bing search engines by restricting pages from India during May 2012. Previously validated DISCERN tool was used by the three raters to assess 44 websites. All results have been reported as p-values. RESULTS: The most common topics that were covered in these websites included causes and risk factors of MetS (77.27%). On the contrary medication (13.64%), lab tests (11.36%), type of physical activities (6.82%), prognosis and regular check-ups (4.55%) were the least mentioned topics. The website category .org had higher average DISCERN scores as compared to others categories. CONCLUSION: Limited information was available related to treatment choices, warning signal and informed decision and hence the need exists for further research to develop evidence based health information portal for MetS in an Indian context. PMID- 23358057 TI - Perception of patients with alcohol use disorder and comorbid depression about the usefulness of supportive text messages. AB - BACKGROUND: Very little is known about the perception of patients with alcohol use disorder (AUD) and comorbid depression about the usefulness of supportive text messages. OBJECTIVE: To examine the perception of patients with AUD and comorbid depression about the usefulness of supportive text messages. METHODS: Participants (n=26) with a DSM IV diagnosis of AUD and depression and completing an in-patient dual diagnosis treatment programme had twice daily supportive text messages delivered to their mobile phones for three months as part of a randomised trial. Participants were contacted at the end of the third month to obtain their views regarding the usefulness of the supportive text messages using a semi-structured questionnaire. RESULTS: Overall, 24 out of 26 patients were contactable for feedback (92% response rate). Eighteen (75%) patients reported that the text messages always or often reminded them to remain abstinent from alcohol. Again, 20 (83%) patients reported that the intervention had played a useful role in helping to improve their mental health, in particular, in serving as a motivation for recovery and in preventing relapse. CONCLUSIONS: Patients with AUD and depression perceive that supportive text messages help them to remain abstinent from alcohol and also improve upon their mental wellbeing. PMID- 23358058 TI - Nurses' perceptions and attitudes towards new ADU technology and use. AB - BACKGROUND: The introduction of a new technology in hospitals - Automated Dispensing Units (ADUs) - aims to contribute to more secure, safe, efficient and cost effective health services. Several studies highlight the beneficial effects of similar technologies as well as their cost-savings potential but there is little literature exploring nurses' perceptions and attitudes towards technology acceptance and the impact on technology use in a healthcare unit. OBJECTIVE: This research aimed to explore nurses' perceptions and attitudes towards current technology use on their units and towards the introduction of ADU technology and use with nursing staff in two different hospitals in South-East New-Brunswick, Canada. METHODS: Semi-structured interviews were realized with the collaboration of nursing staff from two hospitals which were in urban and rural settings, prior to the introduction of ADUs in hospital wards. RESULTS: Findings in this study highlight the fact that missing medications (i.e., doses not available in cart) are inherently related to the completion of nursing staff's medication distribution routine. Missing doses cause delays in medication delivery which may increase the occurrence of medication errors. Participants described current technology use as an intricate part of their routine. The latter is mainly utilized for patient monitoring and information retrieval. Overall, interview data indicated that ADU technology introduction is positively perceived by nursing staff particularly if the technology reduces missing doses events. CONCLUSIONS: Findings in this study underscore important concerns expressed by nursing staff regarding ADU technology integration into the current medication process and its impact on time management. Pre-implementation training and technical support were identified as important factors in facilitating technology acceptance and proper technology use. PMID- 23358059 TI - HTA decision support system for sustainable business continuity management in hospitals. The case of surgical activity at the University Hospital in Florence. AB - BACKGROUND: A fundamental element of the social and safety function of a health structure is the need to guarantee continuity of clinical activity through the continuity of technology. OBJECTIVE: This paper aims to design a Decision Support System (DSS) for medical technology evaluations based on the use of Key Performance Indicators (KPI) in order to provide a multi-disciplinary valuation of a technology in a health structure. METHODS: The methodology used in planning the DSS followed the following key steps: the definition of relevant KPIs, the development of a database to calculate the KPIs, the calculation of the defined KPIs and the resulting study report. Finally, the clinical and economic validation of the system was conducted though a case study of Business Continuity applied in the operating department of the Florence University Hospital AOU Careggi in Italy. RESULTS: A web-based support system was designed for HTA in health structures. The case study enabled Business Continuity Management (BCM) to be implemented in a hospital department in relation to aspects of a single technology and the specific clinical process. Finally, an economic analysis of the procedure was carried out. CONCLUSIONS: The system is useful for decision makers in that it precisely defines which equipment to include in the BCM procedure, using a scale analysis of the specific clinical process in which the equipment is used. In addition, the economic analysis shows how the cost of the procedure is completely covered by the indirect costs which would result from the expenses incurred from a broken device, hence showing the complete auto sustainability of the methodology. PMID- 23358060 TI - A mathematical model of the mechanical link between shortening of the cardiomyocytes and systolic deformation of the left ventricular myocardium. AB - BACKGROUND: Left ventricular myocytes are arranged in a complex three-dimensional mesh. Since all myocytes contract approximately to the same degree, mechanisms must exist to enable force transfer from each of these onto the framework as a whole, despite the transmural differences in deformation strain. This process has hitherto not been clarified in detail. OBJECTIVE: To present a geometrical model that establishes a mechanical link between the three-dimensional architecture and the function of the left ventricular myocardium. METHODS: The left ventricular equator was modeled as a cylindrical tube of deformable but incompressible material, composed of virtual cardiomyocytes with known diastolic helical and transmural angles. By imposing reference circumferential, longitudinal, and torsional strains onto the model, we created a three-dimensional deformation field to calculate passive shortening of the myocyte surrogates. We tested two diastolic architectures: 1) a simple model with longitudinal myocyte surrogates in the endo- and epicardium, and circular ones in the midwall, and 2) a more accurate architecture, with progressive helical angle distribution varying from 60 degrees in the epicardium to 60 degrees in the endocardium, with or without torsion and transmural cardiomyocyte angulation. RESULTS: The simple model caused great transmural unevenness in cardiomyocyte shortening; longitudinal surrogates shortened by 15% at all depths equal to the imposed longitudinal strain, whereas circular surrogates exhibited a maximum shortening of 23.0%. The accurate model exhibited a smooth transmural distribution of cardiomyocyte shortening, with a mean (range) of 17.0 (13.2-20.8)%. Torsion caused a shortening of 17.0 (15.2 18.9)% and transmural angulation caused a shortening of 15.2 (12.4-18.2)%. Combining the effects of transmural angulation and torsion caused a change of 15.2 (13.2-16.5)%. CONCLUSION: A continuous transmural distribution of the helical angle is obligatory for smooth shortening of the cardiomyocytes, but a combination of torsional and transmural angulation changes is necessary to execute systolic mural thickening whilst keeping shortening of the cardiomyocytes within its physiological range. PMID- 23358061 TI - The role of cohabitant unusual bacterial species in infection of cardiovascular implantable electronic devices (CIED). AB - BACKGROUND: Asymptomatic bacterial colonisation of medical implants is increasingly recognised. The role of the often unusual bacteria is usually unknown however. OBJECTIVE AND METHODS: During a three-year period, patients presenting with clinically evident CIED lead endocarditis and/or pocket infections were included in a prospective database. Using 16s DNA analysis and sequencing, devices and pockets of consecutive patients with evident CIED infection were examined for the presence of bacterial species in addition to the ones grown in conventional culture in order to characterise their clinical role. RESULTS: During the study 77 of a total of 409 consecutive operations involving the explantation of a CIED were performed for clinically evident infection. 71 were included in the study and conventional extended culture and 16s DNA analysis performed and compared. In 42.3% of the patients bacteria were identified by DNA analysis in addition to the culture of the supposedly causative organisms. CONCLUSION: DNA analysis is more sensitive than conventional culture of swabs in detecting any, or indeed multiple bacterial strains in CIED infection. This may in future influence treatment strategies as e.g. the cohabitation of different strains seems common and is not reflected by classical culture results. Spread of infection along the leads was clearly demonstrated and this strongly supports the recommendation of complete removal of all CIED components in every form of CIED infection. The more unusual bacteria demonstrated here do not appear to play a significant clinical role as suspected earlier. PMID- 23358062 TI - Following Miss B's lead. AB - Opportunities for leadership abound-and we need to step up. PMID- 23358063 TI - Increasing minority representation in nursing. PMID- 23358064 TI - Identifying oneself. PMID- 23358065 TI - Infusion therapy. PMID- 23358066 TI - Maternal morbidity in the United States. PMID- 23358068 TI - Scared smokeless: graphic antismoking ads increase quitting attempts. PMID- 23358070 TI - Follow-up study links magnet status to better outcomes. AB - Better work environments for nurses seen as vital. PMID- 23358072 TI - Women's access to contraception. PMID- 23358074 TI - A long, for some too slow, health care recovery after Sandy. AB - After the disaster at four New York City hospitals. PMID- 23358083 TI - Partnering for change. AB - Nurse leaders and telemetry unit staff work together to change the way nurses conduct shift report. This is the first article in a new series on leadership, coordinated by the American Organization of Nurse Executives (AONE), highlighting how nurses are leading change efforts in hospitals. It describes work done in conjunction with the AONE's Care Innovation and Transformation initiative, which provides leadership development and educational opportunities to nurse managers and staff aimed at supporting nurses at the point of care in making changes to improve the quality and safety of patient care. PMID- 23358084 TI - Fungal meningitis outbreak. AB - How hospitals, clinics, and the public health system responded to the outbreak. PMID- 23358085 TI - Babies are still dying of SIDS. AB - OVERVIEW: The following account of a devastating, preventable death helped change licensing regulations and brought about a safer sleep environment for all infants in licensed child-care facilities in Arkansas. Coauthor Andrea Moore responded to her own personal and family tragedy with a determination to save lives by reducing risk and promoting public awareness of sudden infant death syndrome (SIDS). She teamed up with coauthor Rebecca Matthews, a community health nurse, and Rebecca's husband, pediatrician David Matthews, president of the Arkansas chapter of the American Academy of Pediatrics, to initiate a four-year public health intervention. This article provides information on SIDS, suggests ways that nurses can help educate caregivers and contribute to the prevention of SIDS, and details the progress of the team's educational initiative. PMID- 23358086 TI - Does physiotherapy improve the functional ability of patients with Parkinson's disease? PMID- 23358087 TI - Pulmonary oedema. 1912. PMID- 23358092 TI - The hardest decision. AB - Summoned from overseas, a husband and father finds a drastically altered future. PMID- 23358093 TI - Rare variations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis. PMID- 23358094 TI - WIF1 is expressed by stem cells of the human interfollicular epidermis and acts to suppress keratinocyte proliferation. PMID- 23358095 TI - Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology. AB - The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 * 10(-8)5')ECyd. The drug and metabolites of the assays and medium were determined semiquantitatively using high-performance liquid chromatography. The sensitivity of cancer and nonmalignant cell lines was clearly different against the duplex drug. A measure of 0.65 umol/l 5FdU(5'->5')ECyd, for example, reduced the growth of MKN-45 or 23132/87 gastric cancer cells from 100% on day 0 to about 50 or 20% on day 10, respectively. However, under the same conditions, the growth of the nonmalignant NHDF and CCL-241 cell lines was not markedly inhibited. The cytostatic activity of the duplex drug is based on the active metabolites in and outside the cell formed by the degradation of 5FdU(5'->5')ECyd. The sensitivity of cell lines against the duplex drug depended on its ability to metabolize the duplex drug. 5FdU(5'->5')ECyd should be more advantageous for specific and efficient polychemotherapy of gastric cancer than the corresponding equimolar mixture of 5FdU+ECyd or a standard combination regime of single drugs. PMID- 23358121 TI - Evaluation of seven noninvasive models in staging liver fibrosis in patients with chronic hepatitis B virus infection. AB - PURPOSE: Few studies have evaluated the validity of noninvasive models for the diagnosis of liver fibrosis in chronic hepatitis B (CHB) patients, with controversial results. In this study, we evaluated the ability of seven noninvasive models in staging liver fibrosis in a large cohort of CHB. METHODS: This is a retrospective study. A total of 1168 severe CHB patients with a clear diagnosis of liver fibrosis were included in this study. Data from routine laboratory tests were collected to establish noninvasive models. The stage of fibrosis was defined by the Metavir scoring system. Fibro-quotient, AST/ALT ratio, AST to PLT ratio index (APRI), cirrhosis discriminant score, age-PLT index (API), fibrosis index based on the four factors (FIB-4), and Lok's model were adapted as noninvasive models in this study. RESULTS: FIB-4 (rs=0.542), API (rs=0.427), and Lok's model (rs=0.452) showed a higher positive correlation with liver fibrosis in CHB patients than the other models. APRI, FIB-4, and Lok's model were effective in distinguishing fibrotic stage. APRI, API, FIB-4, and Lok's model were the most effective models in distinguishing significant (S1, S2) and extensive (S3, S4) fibrosis, with area under receiver-operating characteristic values of 0.721, 0.727, 0.789, and 0.712, respectively. However, only FIB-4 and Lok's model showed higher sensitivity, specificity, positive predictive value, and negative predictive value at the cutoff value of 1.433 1.858 and 0.415-0.511, respectively. CONCLUSION: FIB-4 and Lok's model are the most effective models for distinguishing significant and extensive fibrosis, whereas APRI, FIB-4, and Lok's model are suitable for staging fibrosis in CHB patients. PMID- 23358122 TI - Response Rates in National Panel Surveys. PMID- 23358124 TI - Guidelines for the use of pulse wave analysis in adults and children. PMID- 23358123 TI - Exenatide once weekly: sustained improvement in glycemic control and cardiometabolic measures through 3 years. AB - BACKGROUND: Type 2 diabetes mellitus is a progressive metabolic disease necessitating therapies with sustained efficacy and safety over time. Exenatide once weekly (ExQW), an extended-release formulation of the glucagon-like peptide 1 receptor agonist exenatide, has demonstrated improvements in glycemic and cardiometabolic measures from 30 weeks to 2 years of treatment. Here, the efficacy and safety of treatment with ExQW for 3 years are described. METHODS: Patients were initially randomized to receive either ExQW (2 mg) or exenatide twice daily for 30 weeks. Following the initial 30 weeks, all patients were treated with ExQW in an open-label extension. Analyses of primary glycemic endpoints, beta-cell function, and cardiometabolic measures were assessed for patients who completed 3 years of ExQW treatment and for the intention-to-treat population. Safety and tolerability analyses were provided for the intention-to treat population. RESULTS: Sixty-six percent of the intention-to-treat population (n = 295) completed 3 years of treatment (n = 194). At 3 years, a significant reduction in hemoglobin A(1c) (least squares mean +/- standard error) of -1.6% +/ 0.08% was observed, with 55% and 33% of patients achieving hemoglobin A(1c) targets of <7% and <=6.5%, respectively. Consistent with a sustained reduction in hemoglobin A(1c), improvements in beta-cell function were also observed. Body weight was significantly reduced by -2.3 +/- 0.6 kg. Reductions in blood pressure, total cholesterol, low-density lipoprotein cholesterol, and triglycerides were also observed. Adverse events reported most frequently during both controlled and uncontrolled periods included diarrhea, nausea, and vomiting of mostly mild intensity. The incidence of these adverse events decreased over time. Incidence of minor hypoglycemia was low and no major hypoglycemia was observed. CONCLUSION: ExQW produced clinically meaningful improvements in glycemic control that were durable through 3 years of treatment. Significant improvements in cardiometabolic measurements were also observed. ExQW was well tolerated during long-term treatment and no new adverse events were noted. TRIAL REGISTRATION: ClinicalTrials.gov NCT00308139. PMID- 23358125 TI - Immobilization method to preserve enzyme specificity in biosensors: consequences for brain glutamate detection. AB - Microelectrode biosensors are a promising technique to probe the brain interstitial fluid and estimate the extracellular concentration of neurotransmitters like glutamate. Their selectivity is largely based on maintaining high substrate specificity for the enzymes immobilized on microelectrodes. However, the effect of enzyme immobilization on substrate specificity is poorly understood. Furthermore, the accuracy of biosensor measurements for brain biological extracts has not been reliably established in comparison with conventional analytical techniques. In this study, microelectrode biosensors were prepared using different enzyme immobilization methods, including glutaraldehyde, a conventional cross-linker, and poly(ethylene glycol) diglycidyl ether (PEGDE), a milder immobilization reagent. Glutaraldehyde, but not PEGDE, significantly decreased the apparent substrate specificity of glutamate and glucose oxidase. For glutaraldehyde prepared biosensors, detection of secondary substrates by glutamate oxidase increased, resulting in a significant overestimate of glutamate levels. This effect was not observed with PEGDE-based biosensors, and when brain microdialysates were analyzed, the levels of glutamate detected by biosensors were consistent with those detected by capillary electrophoresis. In addition, basal concentrations of glutamate detected in vivo were approximately 10-fold lower than the levels detected with glutaraldehyde based biosensors (e.g., 1.2 MUM vs 16 MUM, respectively). Overall, enzyme immobilization can significantly impact substrate specificity, and PEGDE is well suited for the preparation of stable and selective biosensors. This development questions some of the previous biosensor studies aimed at detecting glutamate in the brain and opens new possibilities for specific neurotransmitter detection. PMID- 23358126 TI - State dependent valuation: the effect of deprivation on risk preferences. AB - The internal state of an organism affects its choices. Previous studies in various non-human animals have demonstrated a complex, and in some cases non monotonic, interaction between internal state and risk preferences. Our aim was to examine the systematic effects of deprivation on human decision-making across various reward types. Using both a non-parametric approach and a classical economic analysis, we asked whether the risk attitudes of human subjects towards money, food and water rewards would change as a function of their internal metabolic state. Our findings replicate some previous work suggesting that, on average, humans become more risk tolerant in their monetary decisions, as they get hungry. However, our specific approach allowed us to make two novel observations about the complex interaction between internal state and risk preferences. First, we found that the change in risk attitude induced by food deprivation is a general phenomenon, affecting attitudes towards both monetary and consumable rewards. But much more importantly, our data indicate that rather than each subject becoming more risk tolerant as previously hypothesized based on averaging across subjects, we found that as a population of human subjects becomes food deprived the heterogeneity of their risk attitudes collapses towards a fixed point. Thus subjects who show high-risk aversion while satiated shift towards moderate risk aversion when deprived but subjects who are risk tolerant become more risk averse. These findings demonstrate a more complicated interaction between internal state and risk preferences and raise some interesting implications for both day-to-day decisions and financial market structures. PMID- 23358127 TI - Treatment with carbon monoxide-releasing molecules and an HO-1 inducer enhances the effects and expression of u-opioid receptors during neuropathic pain. AB - BACKGROUND: The administration of u-opioid receptors (MOR) and delta-opioid receptors (DOR) as well as cannabinoid-2 receptor (CB2R) agonists attenuates neuropathic pain. We investigated if treatment with two carbon monoxide-releasing molecules (CORM-2 and CORM-3) or an inducible heme oxygenase inducer (cobalt protoporphyrin IX, CoPP) could modulate the local and systemic effects and expression of MOR, DOR, and CB2R during neuropathic pain. METHODS: In C57BL/6 mice, at 10 days after the chronic constriction of sciatic nerve, we evaluated the effects of the intraperitoneal administration of 10 mg/kg of CORM-2, CORM-3, or CoPP on the antiallodynic and antihyperalgesic actions of a locally or systemically administered MOR (morphine), DOR ([d-Pen(2),d-Pen(5)]-enkephalin) or CB2R ((2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone ) agonist. The effects of CORM-2 and CoPP treatments on the expression of MOR, DOR, CB2R, inducible and constitutive heme oxygenases, microglia activation marker (CD11b/c), and neuronal and inducible nitric oxide synthases were also assessed. RESULTS: Treatments with CO-RMs and CoPP reduced the mechanical and thermal hypersensitivity induced by sciatic nerve injury, increased the local, but not systemic, antinociceptive effects of morphine, and decreased those produced by DPDPE and JWH-015. Both CORM-2 and CoPP treatments enhanced MOR and inducible heme oxygenase expression, unaltered DOR and constitutive heme oxygenase expression, and decreased the overexpression of CB2R, CD11b/c, and neuronal and inducible nitric oxide synthases induced by sciatic nerve injury. CONCLUSIONS: This study shows that CO-RMs and CoPP treatments increase the local antinociceptive effects of morphine through enhancing MOR peripheral expression and inhibiting spinal microglial activation and overexpression of neuronal/inducible nitric oxide synthases. PMID- 23358128 TI - Military anesthesia trainees in WWII at the University of Wisconsin: their training, careers, and contributions. AB - The emerging medical specialty of anesthesiology experienced significant advances in the decade prior to World War II but had limited numbers of formally trained practitioners. With war looming, a subcommittee of the National Research Council, chaired by Ralph M. Waters, MD., was charged with ensuring sufficient numbers of anesthesiologists for military service. A 12-week course was developed to train military physicians at academic institutions across the country, including the Wisconsin General Hospital. A total of 17 officers were trained in Madison between September 1942 and December 1943. Notably, Virgil K. Stoelting, the future chair of anesthesiology at Indiana University, was a member of this group.A rigorous schedule of study and clinical work ensured the officers learned to administer anesthesia safely while using a variety of techniques. Their leadership and contributions in the military and after the war contributed significantly to the further growth of anesthesiology. PMID- 23358129 TI - Anomalous origin of the left pulmonary artery from the right pulmonary artery (pulmonary artery sling). PMID- 23358130 TI - Multiproject interdependencies in health systems management: a longitudinal qualitative study. AB - BACKGROUND: A health care organization often engages in the simultaneous implementation of multiple organization change initiatives. However, the degree to which these initiatives are implemented and can be enhanced based on their interdependencies is an open question. How organizations and the change initiatives they pursue might benefit from more careful examination of potential interdependencies among projects was explored in this article. PURPOSE: The aim of this study was to introduce a multiproject management conceptualization that stresses project interdependencies and suggests synergies can be found to enhance overall project and organizational performance. It examines this conceptualization in the context of a health system pursuing several major initiatives to capture insights into the nature of such interdependencies. METHODOLOGY/APPROACH: Longitudinal qualitative analysis of interviews conducted with hospital leaders attempting to manage multiple initiatives being implemented by the system's leadership team was used in this study. FINDINGS: The implementation of an electronic medical record (EMR) is empirically identified as the most central among multiple projects based on other projects dependencies on the EMR. Furthermore, concerns for data are identified most frequently as success factors across all projects. This reinforces the depiction of the EMR as a central organizational focus. PRACTICAL IMPLICATIONS: A unique perspective on multiproject management in hospitals and on EMR projects is presented. In addition, the interdependency conceptualization and its application and results provide insights into multiproject management that can help ensure that benefits of individual projects are more fully optimized or exploited in leveraging the effectiveness of other project initiatives. PMID- 23358131 TI - Service duplication within urban hospital clusters. AB - BACKGROUND: Approximately 80% of multihospital system member hospitals in U.S. urban areas are clustered with other same-system member hospitals located in the same market area. A key argument for clustering is the potential for reducing service duplication across cluster members. PURPOSE: The aim of this study is to examine the effects of characteristics of hospital clusters on service duplication within 339 hospital clusters in U.S. metropolitan statistical areas and adjacent counties in 2002. METHODOLOGY/APPROACH: Ordinary least squares regression is used to estimate the relationship between cluster characteristics in 1998 and duplicated services per cluster member in 2002. FINDINGS: Duplication is higher in hospitals clusters with higher case mix index and higher bed size range. Duplication is lower in hospital clusters with more members, for-profit ownership, and more geographic dispersion. PRACTICE IMPLICATIONS: Increases in the size of hospital clusters allow more opportunities for service rationalization. For-profit clusters may be innovators in rationalization activity, and they should be studied in this regard. Clusters with a higher case mix, lower geographic dispersion, and hub-and-spoke design (with high bed-size range) may find service reallocation less feasible. PMID- 23358132 TI - Using resource dependency theory to measure the environment in health care organizational studies: a systematic review of the literature. AB - BACKGROUND: Studies using the resource dependency theory (RDT) perspective commonly focus on one or more of the following environmental dimensions: munificence, dynamism, and complexity. To date, no one has reviewed the use of this theory in the health care management literature and there exists no consensus on how to operationalize the market environment in health care settings. PURPOSE: The purpose of this review is to examine and summarize the ways in which RDT has been applied in empirical studies of the external environments of health care organizations. In so doing, we identify gaps in the literature and examine the extent to which previous empirical findings aligned with hypothesized relationships based on RDT. METHODOLOGY: We conducted a systematic review of the peer-reviewed literature using a bibliographic search of PubMed and ABI/Inform databases. To identify all health care studies that incorporated the RDT perspective, the words "healthcare" or "health care" were searched in combination with any of the following words: resource dependency theory, uncertainty perspective, environment, munificence, dynamism, and complexity. We also performed a hand search of the reference lists of all manuscripts identified in the initial search to identify additional articles. FINDINGS: Twenty studies were included in this review. Wide variability existed in the number of variables used to measure the environment, the environmental constructs measured, and the specific variables used to operationalizethe environmental constructs. Of the 198 tests examining the relationship between environmental variables and the outcome of interest, 26.8% resulted in findings that supported the RDT-predicted hypotheses. PRACTICE IMPLICATIONS: The RDT literature is limited to studies of hospitals, nursing homes, and medical practices. There is little consensus on how to measure or operationalize the environment in these studies. No previous studies have measured the environment for other health care settings such as ambulatory surgery centers, public health departments, or assisted living facilities. PMID- 23358133 TI - Science-based and practice-based innovativeness and performance of substance abuse treatment facilities. AB - BACKGROUND: The fields of mental health and substance abuse treatment lag significantly behind other health care organizational fields in the adoption, implementation, and dissemination of evidence-based practices. Innovative organizational practices may be science based or practice based. The implementation of innovative practices requires considerable organizational resources. Whether this organizational investment actually pays off in terms of superior performance is unclear. This issue in the context of substance abuse treatment facilities (SATFs) in the United States is examined in this study. PURPOSE: The purpose of this study is to examine the influence of the use of innovative organizational practices, both science based (psychosocial interventions) and practice based, on the organizational performance of SATFs. METHODOLOGY/APPROACH: The study uses cross-sectional data on 13,513 SATFs in the United States, obtained from the National Survey of Substance Abuse Treatment Services 2009 database. FINDINGS: Multinomial logistic regression models find a positive association between the use of science-based innovations and practice based innovations and organizational performance, that is, the provision of comprehensive (core and wraparound) services. SATFs that were located in metropolitan areas, those accredited by the Commission on Accreditation of Rehabilitation Facilities and Joint Commission, that had a mixed (Substance Abuse and Mental Health) focus or were recipients of earmark funds also had higher organizational performance. PRACTICE IMPLICATIONS: The results signify that substance abuse facilities that are high innovators in terms of implementing science based and practice-based innovative practices have higher organizational performance. Organizations that have institutionalized these practices have invested considerable resources in innovation. The shown higher organizational performance provides justification for the organizational investment in innovation. PMID- 23358134 TI - Emergence of delayed behavioral effects in offspring mice exposed to low levels of mercury vapor during the lactation period. AB - This study examined the emergence of delayed behavioral effects in offspring mice exposed to low levels of mercury vapor (Hg(0)) during the lactation period. Female offspring of mice were repeatedly exposed to Hg(0) at 0.057 mg/m(3), similar to the current threshold value (TLV), for 24 hr until the 20(th) day postpartum. The behavioral effects were evaluated with locomotor activity in the open field (OPF), learning activity in the passive avoidance response (PA) and spatial learning ability in the Morris water maze (MM) at the ages of 3 and 15 months. Hg(0)-exposed mice did not differ from controls in the three behavioral measurements at 3 months of age, and no neurobehavioral effects were observed. On the other hand, the mice exhibited significantly more central locomotion in the OPF task when tested at 15 months of age, but no abnormality in other behavioral performance. Immediately after postnatal exposure, the brain mercury concentration of offspring was about 150 times that of the control, in which the concentrations were approximately 0.4 ug/g. The results indicate that mice exposed to Hg(0) at concentrations around TLV during the developing period resulted in the emergence of delayed behavioral effects at a later stage in life. PMID- 23358135 TI - Biomembrane damage caused by exposure to multi-walled carbon nanotubes. AB - Carbon nanotubes (CNTs) have potential as not only electrical materials but also biomedical devices. However, some findings have been reported indicating that the use of CNTs is accompanied by a risk of the development of certain diseases such as pulmonary fibrosis and pleura mesothelioma; and one of the reasons for this risk may be macrophage cell death. In the present study, to elucidate the mechanism of macrophage cell death by CNTs, we focused on biomembrane damage caused by multi-walled CNTs (MWCNTs). When the distribution of MWCNTs in RAW264 cells was observed under a light microscope, MWCNTs were located on the surface of the plasma membrane; and a portion of them seemed to stick into it. The acute cytotoxicity toward RAW264 cells was examined by performing the LDH cytotoxic test, and LDH release was detected after exposure to 100 ug/ml CNT. To examine the physical damage to biomembranes by CNT exposure, we conducted a calcein release assay using calcein-encapsulated liposomes. The results indicated that an increase in the permeability of the lipid bilayer was induced by MWCNTs. The present study thus demonstrated for the first time that a high concentration of MWCNTs was cytotoxic to macrophages and suggested that the direct physical perturbation of biomembranes by MWCNTs plays a role in this activity. PMID- 23358136 TI - Exposure to diesel exhaust during fetal period affects behavior and neurotransmitters in male offspring mice. AB - Exposure to ambient particulate matter (PM) has been associated with the onset of cardiovascular and respiratory diseases. Diesel exhaust particles (DEP) are major components of ambient PM. We first reported DEP in the central nervous system of offspring utilizing maternal inhalation to diesel exhaust (DE). In addition, we found that the effects of maternal exposure to DE reduced spontaneous motor activity. However, it is still unknown whether maternal exposure to DE affects higher order behavioral function. Therefore, the aim of the present study was to examine the effects of fetal exposure to DE on motor coordination, impulsive behavior and monoaminergic systems in various brain regions. The results of the rotating rod test showed that DE-exposed mice displayed decreased time on the rota rod compared to control mice. However, no changes were detected between the two groups in the hanging test. Furthermore, the cliff avoidance test revealed that DE-exposed mice spent more time in the corner and fell off an inverted glass beaker compared to control mice. High performance liquid chromatography analysis revealed that noradrenaline turnover in the cerebellum was decreased by prenatal exposure to DE, and was significantly increased in the hypothalamus. Dopamine and serotonin levels in various brain regions were also changed by prenatal exposure to DE. Our study found that prenatal exposure to DE alters motor coordination, impulsive behavior and related monoamine levels. Therefore, the present study underscores the role of behavioral changes related to monoamine in response to maternal inhalation of DE. PMID- 23358137 TI - Effect of quercetin and desferrioxamine on 6-hydroxydopamine (6-OHDA) induced neurotoxicity in striatum of rats. AB - The catecholaminergic neurotoxin 6-hydroxydopamine is used to lesion dopaminergic pathways in the experimental animal models of Parkinson's disease. The present study was aimed to evaluate the combined treatment with bioflavonoid quercetin (QN) and desferrioxamine (DFO) on 6-hydroxydopamine (6-OHDA) - induced neurotoxicity in the striatum of rats. Adult, male Sprague - Dawley rats were divided into control, sham lesion, 6-OHDA treated (300 ug, intracisternal), 6 OHDA with QN (50 mg/kg) treated, 6-OHDA with DFO (50 mg/kg) treated and 6-OHDA with QN and DFO treated groups. Striatal dopamine, protein carbonyl content (PCC), glutathione (GSH) and superoxide dismutase (SOD) were estimated. There was a significant increase (p < 0.05) in PCC and decrease in dopamine, GSH and SOD level and striatal neuronal number with 6-OHDA treatment. QN and DFO treatment significantly (p < 0.05) reduced these changes showing a significant neuronal protection. Combined treatment has a more significant effect (p < 0.05) in protecting the neurons and increasing the antioxidant enzymes in the striatum. In conclusion, an antioxidant with iron chelator treatment showed a significant neuroprotective effect against 6-hydroxydopamine (6-OHDA) by preventing dopaminergic neuronal loss and maintaining the striatal dopamine level. PMID- 23358138 TI - Effects of exposure to nanoparticle-rich or -depleted diesel exhaust on allergic pathophysiology in the murine lung. AB - Although it has been shown that exposure to diesel exhaust (DE) is linked to the induction or exacerbation of respiratory disorders, the major components responsible have not been fully identified. We examined the effects of airway exposure to nanoparticle-rich DE (NR-DE) or DE without particles on allergic pulmonary inflammation in mice. We also investigated the cellular responses to intratracheal instillation of NR-DE particles (NR-DEP). ICR mice inhaled one of four different mixtures (control air, low-concentration DE, high-concentration DE, and high-concentration DE without particles) for 8 weeks in the presence or absence of repeated intratracheal administration of ovalbumin (OVA). In a separate study, NR-DEP and/or OVA were repeatedly administrated intratracheally to mice. High-concentration NR-DE or DE without particles substantially exacerbated OVA-induced eosinophilic airway inflammation. This exacerbation was concomitant with increases in lung levels of Th2 cytokines such as interleukin (IL)-4, IL-5, and IL-13 and of chemokines such as monocyte chemotactic protein-1. Furthermore, in the presence of allergen, both DE without particles and high concentration NR-DE strongly enhanced the production and release of myeloperoxidase into the alveolar spaces. Repeated administration of NR-DEP did not substantially affect the allergic asthma. These results strongly suggest that gaseous compounds in NR-DE aggravate murine allergic airway inflammation, mainly via amplification of the Th2 response. PMID- 23358139 TI - Nanomolar concentration of triclocarban increases the vulnerability of rat thymocytes to oxidative stress. AB - It was recently reported that triclocarban was absorbed significantly from soap used during showering in human subjects and that its C(max) in their whole blood ranged from 23 nM to 530 nM. We revealed that a nanomolar concentration (300 nM) of triclocarban potentiated the cytotoxicity of 300 uM H(2)O(2) in rat thymocytes by using cytometric techniques with appropriate fluorescent probes. Although 300 nM triclocarban did not itself increase the population of dead cells (cell lethality), it facilitated the process of cell death induced by H(2)O(2), resulting in a further increase in the population of dead cells. Nanomolar concentrations (300 nM or higher) of triclocarban significantly decreased the cellular content of nonprotein thiol (glutathione), which has a protective role against oxidative stress. Triclocarban at 300 nM or higher increased the cell vulnerability to oxidative stress. The results may suggest that nanomolar concentration (300 nM or higher) of triclocarban affects some cellular functions although there is no evidence for adverse effects of triclocarban in humans at present. PMID- 23358140 TI - Molecular mechanisms underlying ochratoxin A-induced genotoxicity: global gene expression analysis suggests induction of DNA double-strand breaks and cell cycle progression. AB - Ochratoxin A (OTA) is a renal carcinogen primarily affecting the S3 segment of proximal tubules in rodents. In our previous study, we reported that OTA induces reporter gene mutations, primarily deletion mutations, in the renal outer medulla (OM), specifically in the S3 segment. In the present study, to identify genes involved in OTA-induced genotoxicity, we conducted a comparative analysis of global gene expression in the renal cortex (COR) and OM of kidneys from gpt delta rats administered OTA at a carcinogenic dose for 4 weeks. Genes associated with DNA damage and DNA damage repair, and cell cycle regulation were site specifically changed in the OM. Interestingly, genes that were deregulated in the OM possessed molecular functions such as DNA double-strand break (DSB) repair (Rad18, Brip1, and Brcc3), cell cycle progression (Cyce1, Ccna2, and Ccnb1), G(2)/M arrest in response to DNA damage (Chek1 and Wee1), and p53-associated factors (Phlda3 and Ccng1). Significant increases in the mRNA levels of many of these genes were observed in the OM using real-time RT-PCR. However, genes related to oxidative stress exhibited no differences in either the number or function of altered genes in both the OM and COR. These results suggested that OTA induced DSB and cell cycle progression at the target site. These events other than oxidative stress could trigger genotoxicity leading to OTA-induced renal tumorigenicity. PMID- 23358141 TI - Effects of acute single intranasal instillation of secondary organic aerosol on neurological and immunological biomarkers in the brain and lung of BALB/c mice. AB - Recently, we have reported that primary particles from diesel exhaust affect nervous system, immune system, and learning ability in mice. Currently, in vivo and in vitro studies have shown that secondary organic aerosol (SOA) generated from the coal-fired power plant induced adverse effects in lung and heart. However, the effect of SOA on central nervous system is still unknown. In the present study, using potential biomarkers recognized in previous studies of primary particles, we investigated the effect of acute single administration of SOA on the expression levels of various biomarkers in the brain and lung of mice. We generated the SOA by addition of ozone (O(3)) to the diesel exhaust particle (DEP). Eight-week-old male BALB/c mice were administered DEP or DEP+O(3) (SOA) (50 ug/50 ul/mouse) intranasally. Twenty-four hour after acute single exposure to SOA, olfactory bulb, hippocampus and lung from all mice were collected and mRNA expressions of neurological and immunological biomarkers were examined using real time RT-PCR analysis and histological examination. Proinflammatory cytokines, their transcription factor and neurotrophin mRNA were remarkably increased in lung of mice exposed to SOA but not in the brain. Microarray data showed that changes of the inflammatory reaction and metabolizing enzyme gene cluster were observed in the brain and lung. Our findings suggested that an acute single exposure of SOA does not affect biomarkers in the brain of normal healthy individuals. Our present results also clearly indicate that SOA induces inflammatory responses in the lung by modulating proinflammatory cytokines, transcription factor and inflammatory responsive neurotrophins. PMID- 23358142 TI - Determination of metallothionein-3 by a competitive enzyme-linked immunosorbent assay in experimental animals. AB - An easy and specific enzyme-linked immunoassay (ELISA) for the determination of metallothinein-3 (MT-3) in experimental animals for the research of heavy metal and chemical toxicity has not been reported yet. Therefore, we have developed a competitive ELISA, using a specific monoclonal antibody raised against human recombinant MT-3 (rMT-3). The epitope mapping of the antibody was conducted using mouse, rat, and human MT-3s and peptide fragments of human MT-3. MT-1/2, MT-3 knock-out (KO) mice and human brain and liver were used for the evaluation of the ELISA. A pretreatment method of the tissue homogenates was also examined. The antibody used for the ELISA had the same cross-reactivity with MT-3 in humans and experimental animals. The human MT- 3 NH(2) terminal peptide (Fr. 1-17) was the demonstrated epitope of this antibody. The reactivity of this ELISA in brain homogenate of MT-3 KO mouse was significantly low compared with the wild type and MT-1/2 KO mice. The lowest detection limit of the ELISA was 10 ng/ml and over 80% of the spiked rMT-3 was recovered in the brain homogenate. The assay linearity was intact with a 5-fold dilution in the brain homogenate. The inter- and intra assay CV was 6.5%, respectively. An effective pretreatment procedure of the tissue homogenate was also established for this MT-3 ELISA. In conclusion, this competitive ELISA is an easy and specific method for measuring the brain MT-3 level in experimental animals. PMID- 23358143 TI - Effect of thiram on avian growth plate chondrocytes in culture. AB - Thiram is a dithiocarbamate pesticide that causes tibial dyschondroplasia (TD), a growth plate defect, in poultry. Deaths of transitional zone chondrocytes appear to interrupt endochondral bone development leading to the broadening of growth plate. The mechanism of action of thiram on chondrocytes is not well understood. Since proteins play major roles in different aspects of cell's metabolism, growth, and survival, the objective of this study was to find whether thiram produces proteomic changes that could impair the development of chondrocytes. The chondrocytes, isolated from proximal tibial growth plates, were cultured with or without a sub-lethal concentration of thiram for 48 hr, and the cell proteins were extracted, and subjected to 2-D gel electrophoresis. The gel images were compared and statistically evaluated using Melanie software to identify differentially expressed protein spots. Of a total of 72 identifiable spots 3 were down-regulated and 2 up-regulated in thiram treated chondrocytes. In-gel trypsin digestion of the protein spots followed by their characterization by matrix-assisted laser desorption ionization-time-of- flight (MALDI-TOF) mass spectrometry identified 25 spots comprising of 23 proteins. Two of 3 down regulated proteins were identified as a heat shock protein 70 (HSP 70) and a GALE (UDP-galactose-4 epimerase) protein isoform I. The up-regulated proteins were Serpin H1, a protein involved in collagen metabolism and a redox sensor NmrA-like (NMRAL) family domain protein-1. Both GALE and NMRAL proteins are implicated in energy metabolism and redox regulation whereas the HSP 70 protects cells against stress, and implicated in chondrocyte hypertrophy, an important event in endochondral bone formation. The failure of chondrocyte protective mechanisms such as associated with protection against cellular stress and energy metabolism appear to be the likely cause for chondrocyte death induced by thiram. PMID- 23358144 TI - Differential mRNA expression and the uptake of methotrexate in primary MAEC and MLF cells: involvement of the Abc and Slco/Oatp transporters in alveolar epithelial cell toxicity. AB - Drug transporters play a pivotal role in the disposition and elimination of a wide variety of organic compounds across the biological membrane of the body. Recent studies have revealed that some drug transporters are involved in drug induced toxicity. We have previously reported that methotrexate (MTX)-induced cytotoxicity and apoptosis in primary mouse alveolar epithelial cells (MAEC) are more sensitive than primary mouse lung fibroblasts (MLF). In the present study, we investigated the mRNA expression of ABCs, Slco/Slc/Oatp transporters by RT-PCR and quantitative real-time PCR (qRT-PCR) techniques in mouse lung tissues and primary lung cells. The ABC transporters (Mdr1, Mrp1, 3, 4, 5, and Bcrp) and the Slco/Oatp transporters (Rfc, Oatp1a1, 1a4, 1a5, 1b2, 2a1, 2b1, 3a1, 4c1, and 5a1) were detected in mouse lung tissues, whereas some ABCs, Slcs/Oats, and Slco/Oatps transporters were not expressed in the mouse lung. Additionally, we found that some Abc transporters are expressed predominantly in MLF whereas Mrp3 and Oatp4c1 are expressed predominantly in MAEC. The transport activity of [(3)H]MTX mediated via MAEC was significantly higher than the MLF-mediated transport. When MLF was treated with MK571, accumulated [(3)H]MTX significantly increased when compared with MAEC. Thus, our results indicate that depending on the type of cells, several types of drug transporters are expressed in mouse lung tissues. Our results also suggest that MTX-induced fibrosis with cell dysfunction may be caused by the accumulation within the alveolar epithelial cells of MTX in the lung. PMID- 23358145 TI - The anti-apoptotic effect of fucoxanthin on carbon tetrachloride-induced hepatotoxicity. AB - This study evaluated the anti-apoptotic activity of fucoxanthin in carbon tetrachloride (CCl(4))-induced hepatotoxicity. An in vitro study using the 3-(4,5 dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay clearly demonstrated an attenuation of CCl(4)-induced hepatotoxicity with fucoxanthin. This effect was dose-dependent; 25 uM was more effective than 10 uM of fucoxanthin for attenuating the hepatotoxicity induced by 5 mM of CCl(4). Acute CCl(4)-hepatotoxicity in rats, with numerous cells positive for the terminal deoxynucleotidyl - transferase (TdT) -mediated deoxyuridine triphosphate digoxigenin (dUTP) nick-end labeling (TUNEL) stain were seen in the pericentral area of the hepatic lobule. Oral pretreatment of CCl(4)- injected rats with fucoxanthin significantly reduced hepatocyte apoptosis. Fucoxanthin was immunohistochemically shown to increase heme oxygenase-1 expression in the cultured liver cells of Hc cells and TRL1215 cells. By oral pretreatment of CCl(4)-injected rats with fucoxanthin, the hepatic heme oxygenase-1 protein levels were significantly increased compared to those not pretreated with fucoxanthin. Heme oxygenase-1 mRNA expression after CCl(4 )injection was higher in the CCl(4)+fucoxanthin group than in the CCl(4 )group, although the difference was not significant. The findings suggest that fucoxanthin attenuates hepatocyte apoptosis through heme oxygenase-1 induction in CCl(4)-induced acute liver injury. PMID- 23358146 TI - Induced expression of hepatic N-methyl-D-aspartate receptor 2C subunit gene during liver enlargement induced by lead nitrate, a hepatocellular mitogen. AB - We previously demonstrated the super-induced expression of the Grin2c gene encoding the N-methyl-D-aspartate receptor 2C subunit during the development of liver enlargement with hepatocellular hypertrophy induced by phenobarbital, clofibrate, or piperonyl butoxide. In the present study, we assessed whether or not Grin2c gene expression was induced during the development of chemically induced liver enlargement with hyperplasia. Male Sprague-Dawley (SD) rats, stroke prone spontaneously hypertensive rats (SHRSPs), and SHRSP's normotensive control, Wistar-Kyoto (WKY) rats, were administered lead nitrate (LN) (0.1 mmol/kg, single i.v.), a direct inducer of liver hyperplasia, and changes in the level of Grin2c mRNA in the liver were assessed by real-time RT-PCR. The level of hepatic Grin2c mRNA was significantly higher 6-48 hr after the injection in SD rats (about 30~40 and 70-fold over the control at 6~24 hr and 48 hr, respectively) and in WKY rats (about 20-fold over the control only at 12 hr), but was not significantly higher in SHRSPs. Such differences in LN-induced levels of Grin2c mRNA among SD rats, WKY rats, and SHRSPs were closely correlated with those in the previously reported increase in liver weight 48 hr after LN administration. The present findings suggest that the increase in the level of hepatic Grin2c mRNA relates to development of chemically induced liver enlargement with hyperplasia. PMID- 23358147 TI - Effects of polycyclic aromatic hydrocarbons (PAHs) on an aquatic ecosystem: acute toxicity and community-level toxic impact tests of benzo[a]pyrene using lake zooplankton community. AB - We estimated acute toxicity of benzo[a]pyrene (B[a]P) using two cladoceran species, Ceriodaphnia reticulata and Daphnia magna, and also analyzed its impact on zooplankton community throughout an exposure experiment using small-scale mesocosms. LC(50) of B[a]P for C. reticulata and D. magna was 4.3 and 4.7 ug/l, respectively. However, individuals fed with Chlorella showed higher LC(50), 6.1 ug/l for C. reticulata and 8.0 ug/l for D. magna. In the exposure experiment, we examined the impact of B[a]P on zooplankton community using conceivable concentrations in the environment (5 and 10 ug/l) using typical zooplankton community in eutrophicated systems. Despite the residence time of B[a]P in the water column was short as < 4 days, application of B[a]P induced decrease of zooplankton abundance. However, the recovery pattern was different among cladocerans and rotifers. Consequently, B[a]P showed insecticide-like impacts, suppressing cladoceran populations and inducing the dominance of rotifers particularly under high concentration (10 ug/l). Results have suggested that, even such short duration of B[a]P in the water body can have impact on zooplankton abundance and community structure. Since B[a]P easily precipitate to the bottom and rapidly disappears from the water body, careful monitoring and further assessment of the potential toxicity of polycyclic aromatic hydrocarbons are necessary. PMID- 23358148 TI - Organ-specific distribution of 7-chlorinated benz[a]anthracene and regulation of selected cytochrome P450 genes in rats. AB - We previously reported that 14-day exposure to 7-chlorinated benz[a]anthracene (7 Cl-BaA), a new environmental pollutant, selectively induced hepatic cytochrome P450 (CYP)1A2 in rats, although treatment with its parent, benz[a]anthracene (BaA), induced CYP1A1, CYP1A2, and CYP1B1. In this study, to better understand the relative contribution of chlorination to the toxicity of polycyclic aromatic hydrocarbons (PAHs), we investigated the organ-specific distributions of 7-Cl-BaA and BaA in F334 rats. After 14 days of oral administration of 7-Cl-BaA or BaA at a concentration of 1 or 10 mg/kg body weight/day, both chemicals were detected in their plasma, which was collected 24 hr after the last administration, even at the lower dosage. Dose-dependent accumulation patterns were observed in the liver, muscle, kidney, spleen, heart, and lung. The 7-Cl-BaA concentrations in the organs were higher than those of the BaA. Furthermore, at the end of the exposure, 7-Cl-BaA specifically regulated several CYP genes in the heart more so than in other organs, although these inductions were not significant in the BaA treatment. 7-Cl-BaA might also stimulate the metabolic pathways of chemicals other than AhR-mediated metabolism, which is specific to normal PAHs, because of the alterations of CYP2J4, CYP4B1, and CYP17A1 expression in rats. In conclusion, our results imply that the chlorination of PAHs may change their organ-specific distribution and consequently alter their toxicological impacts compared to their parent PAHs. PMID- 23358149 TI - Influence of injection timing on severity of cadmium-induced testicular toxicity in mice. AB - Cadmium (Cd) is one of the endocrine disrupter and is a well-known testicular toxicant. Recently, we reported that Cd-induced mortality was markedly different by injection timing. In this report, we investigated whether severity of testicular toxicity was affected by injection timing of Cd. C57BL/6J mice (male, 7 w) were received single intraperitoneal injection of CdCl(2) (4.5 mg/kg) at zeitgeber time 6 (ZT6) or ZT18; these injection timings showed highest (ZT6) or lowest (ZT18) mortality in our previous study (Miura, 2012). After one week of the injection, several parameters for testicular toxicity such as epididymal sperm motility and numbers of sperm head both in cauda epididymidis and testis were measured. At ZT6 injection group, all parameters examined were significantly reduced compared to the control group. However, very interestingly, no significant changes were observed at ZT18 injection group. We obtained similar results by another experiment in which mice were received single subcutaneous injection of CdCl(2) (4 or 6 mg/kg) followed by measuring the parameters ten days after the injection. This diurnal variation was not contradictory to the result of the lethal toxicity which we showed earlier. Therefore, our results indicate that the testicular toxicity of Cd is also influenced by the injection timing. PMID- 23358150 TI - Microarray analysis of neonatal brain exposed to cadmium during gestation and lactation. AB - DNA microarray containing 30,000 genes was used to monitor the transcriptional response of the neonatal brain after cadmium (Cd) exposure. C57BL/6J pregnant mice were exposed to Cd (10 ppm) during gestation and lactation via drinking water. In a comparison between the Cd-exposed neonatal brain and control, three genes including transferrin receptor (Tfrc) were up-regulated and one gene was down-regulated. PMID- 23358151 TI - DNA microarray analysis of hepatic gene expression in mice exposed to cadmium for 30 days. AB - Although cadmium causes hepatotoxicity, its molecular mechanism is unclear. In the present study, transcriptional responses in the liver of C57BL/6J mice given 50 ppm cadmium as a drinking water for 30 days were evaluated with DNA microarray. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were not elevated following the administration of cadmium. Cadmium increased the expressions of 2 genes and reduced those of 15 genes in the liver of mice before the leading to hepatotoxicity. PMID- 23358152 TI - Microarray analysis of 6-mercaptopurine-induced-toxicity-related genes and microRNAs in the rat placenta. AB - MicroRNAs (miRNAs) are small single-stranded RNAs of 19-25 nucleotides and are important in posttranscriptional regulation of genes. Recently, the role of miRNAs in toxicity incidence is reported to be a regulator of key-stopper of gene expression, however the detailed mechanism of miRNAs is not well known yet. 6 Mercaptopurine (6-MP), the anti-leukemic and immunosuppressive drug, produced teratogenicity and pregnancy loss. We focused on the placenta to evaluate toxicity in embryo/fetal development produced by 6-MP treatment. MiRNA expression in the placenta was analyzed by miRNA microarray. Fifteen miRNAs were upregulated on GD13 and 5 miRNAs were downregulated on GD15 in 6-MP treatment rat placentas. Some miRNAs may have functions in apoptosis (miR-195, miR-21, miR-29c and miR 34a), inflammation (miR-146b), and ischemia (miR-144 and miR-451). In the maternal plasma, expression of miR-144 was significantly reduced by 6-MP treatment when examined by real-time RT-PCR. We determined toxicity-related gene expression in the rat placenta. Gene expression analysis was carried out by DNA oligo microarray using rat placenta total RNAs. Compared between predicted targets of miRNAs and microarray data in 6-MP-treated rat placenta, expressions of hormone receptor genes (estrogen receptor 1; Esr1, progesterone receptor; Pgr, and prolactin receptor; Prlr), xanthine oxidase (Xdh), Slc38a5 and Phlda2 genes were changed. The histopathologically found increase in trophoblastic giant cells and reduced placental growth by 6-MP treatment were well correlated to these gene expressions. These data suggest that some miRNAs may link to toxicological reactions in 6-MP-induced placental toxicity. PMID- 23358153 TI - Assembly of a series of MOFs based on the 2-(m-methoxyphenyl)imidazole dicarboxylate ligand. AB - The coordination features of an imidazole dicarboxylate ligand, 2-(3 methoxyphenyl)-1H-imidazole-4,5-dicarboxylic acid (m-H(3)MOPhIDC) has been explored. Consequently, seven coordination polymers, namely [Sr(m HMOPhIDC)(H(2)O)](n) (1), [Sr(m-H(2)MOPhIDC)(2)](n) (2), [Cd(3)(m H(2)MOPhIDC)(2)(m-HMOPhIDC)(2)(H(2)O)(2)](n) (3), [Cu(m-HMOPhIDC)(phen)](n) (phen = 1,10-phenanthroline) (4), [Cd(2)(m-HMOPhIDC)(2)(phen)(2)](n) (5) [Cd(2)(m HMOPhIDC)(2)(2,2'-bipy)(2)](n) (2,2'-bipy = 2,2'-bipyridine) (6) and [Co(m HMOPhIDC)(H(2)O)(2)](n) (7) have been hydro(solvo)thermally synthesized by fine control over synthetic conditions, and structurally characterized. X-ray single crystal analyses reveal that these polymers indicate rich structural chemistry ranging from one-dimensional (4-7), two-dimensional (1 and 3) to three dimensional (2) structures, and the m-H(3)MOPhIDC ligand in these polymers can be singly deprotonated or doubly deprotonated, and coordinates to metal ions by various modes. The thermal and fluorescence properties of the complexes 1-7 have been determined as well. PMID- 23358154 TI - Another suicide using the veterinary drug T61 and distribution of drugs in the body. PMID- 23358155 TI - Sharing pain and relief: neural correlates of physicians during treatment of patients. AB - Patient-physician interactions significantly contribute to placebo effects and clinical outcomes. While the neural correlates of placebo responses have been studied in patients, the neurobiology of the clinician during treatment is unknown. This study investigated physicians' brain activations during patient physician interaction while the patient was experiencing pain, including a 'treatment', 'no-treatment' and 'control' condition. Here, we demonstrate that physicians activated brain regions previously implicated in expectancy for pain relief and increased attention during treatment of patients, including the right ventrolateral and dorsolateral prefrontal cortices. The physician's ability to take the patients' perspective correlated with increased brain activations in the rostral anterior cingulate cortex, a region that has been associated with processing of reward and subjective value. We suggest that physician treatment involves neural representations of treatment expectation, reward processing and empathy, paired with increased activation in attention-related structures. Our findings further the understanding of the neural representations associated with reciprocal interactions between clinicians and patients; a hallmark for successful treatment outcomes. PMID- 23358157 TI - DNA evidence for strong genetic stability and increasing heritability of intelligence from age 7 to 12. AB - Two genetic findings from twin research have far-reaching implications for understanding individual differences in the development of brain function as indexed by general cognitive ability (g, aka intelligence): (1) The same genes affect g throughout development, even though (2) heritability increases. It is now possible to test these hypotheses using DNA alone. From 1.7 million DNA markers and g scores at ages 7 and 12 on 2875 children, the DNA genetic correlation from age 7 to 12 was 0.73, highly similar to the genetic correlation of 0.75 estimated from 6702 pairs of twins from the same sample. DNA-estimated heritabilities increased from 0.26 at age 7 to 0.45 at age 12; twin-estimated heritabilities also increased from 0.35 to 0.48. These DNA results confirm the results of twin studies indicating strong genetic stability but increasing heritability for g, despite mean changes in brain structure and function from childhood to adolescence. PMID- 23358156 TI - Childhood intelligence is heritable, highly polygenic and associated with FNBP1L. AB - Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17,989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 * 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 * 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 * 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance. PMID- 23358161 TI - Simple solution for preventing cerebrospinal fluid loss and brain shift during multitrack deep brain stimulation surgery in the semisupine position: polyethylene glycol hydrogel dural sealant capping: rapid communication. AB - This study evaluated preliminary findings on the efficacy of polyethylene glycol (PEG) hydrogel dural sealant capping for the prevention of cerebrospinal fluid (CSF) leakage and pneumocephalus during deep brain stimulation (DBS) surgery in the semisupine position. Group A consisted of 5 patients who underwent bilateral subthalamic nucleus (STN)-DBS surgery without PEG hydrogel dural sealant capping. Group B consisted of 5 patients who underwent bilateral STN-DBS surgery with PEG hydrogel dural sealant capping. The immediate postoperative intracranial air volume was measured in all patients and compared between the 2 groups using the Welch test. Adverse effects were also examined in both groups. The intracranial air volume in Group A was 32.3 +/- 12.3 ml (range 19.1-42.5 ml), whereas that in Group B was 1.3 +/- 1.5 ml (range 0.0-3.5 ml), showing a significant difference (p < 0.005). No hemorrhage or venous air embolisms were observed in either group. The effect of brain shift was discriminated by STN recordings in Group B. These preliminary findings indicate that PEG hydrogel dural sealant capping may reduce adverse effects related to CSF leakage and brain shift during DBS surgery. PMID- 23358158 TI - Elevated serum measures of lipid peroxidation and abnormal prefrontal white matter in euthymic bipolar adults: toward peripheral biomarkers of bipolar disorder. AB - Diffusion tensor imaging (DTI) studies consistently reported abnormalities in fractional anisotropy (FA) and radial diffusivity (RD), measures of the integrity of white matter (WM), in bipolar disorder (BD), that may reflect underlying pathophysiologic processes. There is, however, a pressing need to identify peripheral measures that are related to these WM measures, to help identify easily obtainable peripheral biomarkers of BD. Given the high lipid content of axonal membranes and myelin sheaths, and that elevated serum levels of lipid peroxidation are reported in BD, these serum measures may be promising peripheral biomarkers of underlying WM abnormalities in BD. We used DTI and probabilistic tractography to compare FA and RD in ten prefrontal-centered WM tracts, 8 of which are consistently shown to have abnormal FA (and/or RD) in BD, and also examined serum lipid peroxidation (lipid hydroperoxides, LPH and 4-hydroxy-2 nonenal, 4-HNE), in 24 currently euthymic BD adults (BDE) and 19 age- and gender matched healthy adults (CONT). There was a significant effect of group upon FA in these a priori WM tracts (BDECONT: F[1,41]=10.3; P=0.003), and a significant between-group difference in LPH (BDE>CONT: t[40]=2.4; P=0.022), but not in 4-HNE. Multivariate multiple regression analyses revealed that LPH variance explained, respectively, 59 and 51% of the variance of FA and RD across all study participants. This is the first study to examine relationships between measures of WM integrity and peripheral measures of lipid peroxidation. Our findings suggest that serum LPH may be useful in the development of a clinically relevant, yet easily obtainable and inexpensive, peripheral biomarkers of BD. PMID- 23358162 TI - Behavioral performance at early (4 weeks) and later (6 months) stages in rats with unilateral medial forebrain bundle and striatal 6-hydroxydopamine lesions. AB - Our previous studies showed differences in striatal D(2) receptor functional activity between two different rat parkinsonian models, with lesions induced by 6 hydroxydopamine injection in the striatum and in the medial forebrain bundle (MFB) at both early (4 weeks) and later (6 months) stages after lesioning. The present study compared behavioral changes, including rotational movements induced by methamphetamine and bromocriptine, and the stepping test, in both models at both stages. No differences in behavioral performance were observed between the early and later stages in both striatal and MFB lesion models, whereas simultaneous D(2) receptor study showed dynamic change in D(2) receptors in MFB lesion rats. Behavioral characteristics might be controlled by comprehensive effects of the whole dopaminergic system, instead of variation in a few parameters of the dopaminergic system. More behavioral tests of different mechanisms with simultaneous molecular studies are needed for evaluation of parkinsonian animal models and the efficacy of treatments. PMID- 23358160 TI - Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci. AB - Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 * 10(-6)) and rs8057927 in CDH13 (P=1.39 * 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 * 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 * 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 * 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP * CMV)=7.3 * 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies. PMID- 23358163 TI - Correlation between the changes in ambulatory electroencephalography findings and epilepsy recurrence after medication withdrawal among the population in southern China. AB - Patients suffering from epilepsy need long-term medication. However, after the epilepsy is completely under control, the recurrence rate is high once the drug dose is reduced gradually. The present study investigated the possible correlation between the changes shown by ambulatory electroencephalography (EEG) and epilepsy recurrence after medication withdrawal, and assessed the value of ambulatory EEG findings in predicting the recurrence of epilepsy after medication withdrawal, in 265 patients from Southern China followed up for 5 years. Anticonvulsants were withdrawn until onset had been controlled thoroughly for over 3 years and ambulatory EEG detected no abnormalities. Ambulatory EEG was performed at least once per year, and findings at the first visit, during treatment, and before and after medication withdrawal were compared and analyzed. There were 47 patients with recurrent epilepsy in this study. Patients with normal ambulatory EEG findings at the first visit and during treatment had lower recurrence rate (about 8.1%) compared to patients with epileptic waves (25.0%), and patients with focal epileptic waves in the temporal, occipital, frontal, and parietal lobes, or in multiple areas was even higher. Patients with epileptic waves also showed higher clinical recurrence rate during the follow-up period. Abnormal ambulatory EEG findings are an important indicator of epileptic recurrence, and is of great value in predicting the recurrence of epilepsy after medication withdrawal. PMID- 23358164 TI - Effect of thrombin concentration on the adhesion strength and clinical application of fibrin glue-soaked sponge. AB - Fibrin glue-soaked gelatin sponge (FGGS) has been used for tissue sealing in neurosurgical practice, but too rapid clotting of fibrin glue occasionally prevents good fixation of FGGS. Dilution of thrombin may provide adequate manipulation time between mixing fibrinogen and thrombin on gelatin sponge and application into the tissue defects. The present study characterized the effect of thrombin dilution on the adhesion strength of FGGS and retrospectively assessed the clinical usage of the dilution for filling dead space or sealing arachnoid defect in 255 cases who underwent transsphenoidal surgery for the last 66 months. FGGS was prepared using three different concentrations of thrombin: 250 (standard), 50 (1:5 dilution), and 25 (1:10 dilution) units/ml, and incubated for three different periods (5, 20, and 60 seconds). FGGSs were applied over two adjacently positioned porcine skins placed on two metallic plates. The adhesion strength was evaluated by measuring maximum tensile strength during pulling out the sliding plate at a constant rate of displacement. The maximum adhesion strength was greater for FGGS with 1:10 diluted thrombin solution than for FGGS prepared with higher concentrations (p < 0.05). Adhesion strength did not decay for 20 seconds after the mixture. Only four of 255 cases (1.6%) required second reconstruction of sella floor due to the cerebrospinal fluid leakage. FGGS prepared with diluted thrombin solution can provide adequate adhesion strength for clinical use. PMID- 23358165 TI - Difference between conventional head-pin and Dispo-pin in the Sugita multipurpose head frame system. AB - Head fixation devices are commonly used in neurosurgical procedures and are considered essential tools for microneurosurgery. The Sugita multipurpose head frame system is one of such systems and has been used for more than 30 years worldwide. It is important to understand how to fix a patient's head with head pins safely, because there are no numerical parameters for head-pin screwing in the Sugita frame. Recently, the Dispo-pin has been available for disposable use as a head-pin in the Sugita frame. In contrast to the conventional head-pin, the tip of the Dispo-pin is separable from the body. Although their appearance is similar, the torque for adequate fixation is different. The relationships between torque and vertical force were analyzed. The torque of the head-pin was linearly correlated with vertical force for both types of head-pin. Different conditions caused different torque increase against a specific increase of vertical force with the conventional head-pin. In contrast, torque increase against a specific increase of vertical force with the Dispo-pin was the same regardless of the situation. The torque originates from friction between the scalp and tip of the conventional head-pin. As friction is different for each patient's condition, the torque at this part is different. The friction between the tip and body of the Dispo-pin is lower than that between the scalp and tip of the head-pin. In consequence, the torque generated from the tip of the Dispo-pin is the same in each situation. It is important to understand the difference between the Dispo pin and conventional head-pin. PMID- 23358166 TI - Retrospective analysis of operative treatment of a series of 100 patients with subdural hematoma. AB - This retrospective study of medical records, surgical protocols, patient observation cards, and imaging files of 100 patients treated for subdural hematoma analyzed the type of hematoma, patient age and sex, operative technique, neurological status, cause of injury, duration of hospital stay, mortality rate, and the number of and reasons for reoperations to determine the effects on treatment outcomes. The time between the head injury and onset of neurological symptoms was analyzed versus the type of hematoma determined from computed tomography (CT) scans. Acute hematomas accounted for 38% of the cases, with subacute hematomas representing 20%, and chronic ones accounting for 42%. In trauma patients, the mean time interval between the injury and onset of neurological symptoms was 0.38 days for acute hematomas, 13.8 days for subacute hematomas, and 23.75 days for chronic hematomas. Repeat surgery was carried out in 26% of the cases. Improvement was obtained in 44% of cases, deterioration in 20%, and no change in neurological status in 36%. Timing of the operations was between 15:00 and 23:00 in 45%, between 23:00 and 7:00 in 33%, and between 7:00 and 15:00 in 22%. The classification of hematomas based on CT presentation corresponds to the classification based on the time elapsed between injury and onset of symptoms, and appears to be appropriate and useful in everyday practice. No preceding injury was identified in 31.6% of acute hematomas, 50% of subacute hematomas, and 61.9% of chronic hematomas. Analysis of reoperations indicates that trepanation may be superior to craniotomy as primary surgery for subacute and chronic hematomas. Subdural hematoma surgeries take place at all times of the day, with most carried out outside the usual working hours. PMID- 23358167 TI - Repeated injection of contrast medium inducing dysfunction of the blood-brain barrier: case report. AB - An early 60s-year-old man suffered reversible dysfunction of the blood-brain barrier (BBB) induced by repeated injection of contrast medium during coil embolization of intracranial unruptured aneurysm. He presented with convulsion during coil embolization, and neurological symptoms of aphasia and right hemiparesis continued for 5 days, and then improved completely. All transient radiological abnormalities were limited to the territory of the left internal carotid artery, where contrast medium was injected repeatedly. Repeated computed tomography, magnetic resonance imaging, single-photon emission computed tomography, and cerebrospinal fluid test findings indicated that temporary dysfunction of the BBB might have occurred. Dysfunction of the BBB in the anterior circulation induced by contrast medium is rare. Tolerance to toxicity of contrast medium may depend on the individual patient, and repeated injection of contrast medium may cause dysfunction of the BBB, leading to toxic dysfunction directly in the brain. PMID- 23358168 TI - Recurrent trigeminal neuralgia at 20 years after surgery: case report. AB - Microvascular decompression (MVD) is now the most feasible method of treatment for trigeminal neuralgia (TN). The recurrence of symptoms is rarely encountered postoperatively. A female patient with typical right V3 distribution TN had been successfully treated by MVD at age 56 years by transposing the offending superior cerebellar artery, and she became completely pain-free postoperatively without sequelae. Twenty years after the first MVD, pain recurred on the right V2 distribution at age 76 years and she was operated on a second time to resolve the pain. Re-exploration surgery revealed that the trigeminal nerve was compressed mediocranially by the anterior inferior and posterior inferior cerebellar artery complex, which had not been close to the neural structure during the first surgery. The artery complex was successfully transpositioned to decompress the root exit zone (REZ) of the nerve and she became pain-free again. Although various causal factors likely contribute to recurrence of TN, the present case of recompression of a REZ occurred due to a newly developed offending artery which caused TN a long time after the first surgery. PMID- 23358169 TI - Trigeminal neuralgia caused by venous angioma: case report. AB - A 34-year-old female presented with trigeminal neuralgia caused by a venous malformation in the right cerebello-pontine region. Computed tomography and magnetic resonance imaging demonstrated the abnormal draining veins from the venous malformation. The dilated vessels extended around the trigeminal nerve and compressed the root entry zone. Microvascular decompression (MVD) was performed, and her trigeminal neuralgia was completely relieved without neurological deficits. The offending vessel in most cases of trigeminal neuralgia is an arterial branch. Veins may also be associated with trigeminal neuralgia. The present rare case shows that MVD may be useful for the treatment of trigeminal neuralgia associated with venous malformation. Good outcome depends on decompression of the root entry zone without injury to the vessel. Surgical injury in this region can cause severe neurological deficits. Several treatment options should be prepared for the surgery, such as MVD or rhizotomy. PMID- 23358170 TI - Histological examination of expanded polytetrafluoroethylene artificial dura mater at 14 years after craniotomy: case report. AB - Expanded polytetrafluoroethylene (ePTFE) porous material (GORE((r)) PRECLUDE((r)) Dura Substitute) does not degenerate or deteriorate in vivo, and is currently used as artificial dura mater. This material does not adhere well to the surrounding tissues, but cerebrospinal fluid leakage along the suture line has been observed in several cases. We describe a case of craniotomy for tumor resection performed 14 years after dural repair with ePTFE sheet. Histological examination of the ePTFE sheet revealed that the sheet was structurally intact, with no evidence of tissue adhesion or cellular infiltration. However, collagen deposition was observed around the suture thread. When the suture thread was removed the collagen was also removed, and the original needle hole appeared again. No significant changes were observed in the features of the ePTFE sheet even 14 years postoperatively. The formation of fibrous tissue around the needle hole was important in preventing cerebrospinal fluid leakage. PMID- 23358171 TI - Posterior disconnection in early infancy to treat intractable epilepsy with multilobar cortical dysplasia: three case report. AB - Extensive multilobar cortical dysplasias occasionally occur in children and can induce seizure onset in early infancy, causing severe epileptic encephalopathy. Surgical interventions in early infancy, such as disconnection of large parts of the brain, are challenging because of the degree of invasiveness and carry greater risks in infants compared with older children. Here we report the successful treatment of intractable epilepsy with multilobar cortical dysplasias in the posterior cortex by posterior disconnection in three infants (age 3 months). The patients showed good postoperative recovery and exhibited excellent seizure control at follow-up evaluation within a year after surgery. Developmental catch-up was also achieved and no early complications have been detected to date. Use of the posterior disconnection technique for early-stage extensive multilobar cortical dysplasias can result in good seizure control and developmental progress with little perioperative morbidity. However, the efficacy of this surgical technique needs to be verified with long-term follow up after surgery. PMID- 23358172 TI - Hanging foot switch for bipolar forceps: a device for surgeons operating in the standing position: technical note. AB - For surgeons operating in the standing position, the manipulation of foot switches involves shifting of the weight to the pivoting leg and the possible loss of contact between the switch and the foot. We solved this problem by changing the position of the switch that operates bipolar forceps. Our novel device is made of aluminum plates. The base plate features a foot strap and a height-adjustable overhang over the switch-operating foot. A commercially available disc type foot switch is attached to the underside of the overhang in upside-down position, so the switch is operable with the toe. To turn on the switch, the toe is flexed dorsally to push the switch pedal, so the action is limited to the part distal to the metatarsophalangeal joints. Our switch was used in more than 100 consecutive microsurgeries performed by surgeons operating in the standing position. The switch manipulation required no shifting of the weight and was easier and quicker than manipulation of conventionally-placed switches. The surgeons were able to change the foot position freely with the modified switch, thereby avoiding loss of contact with the switch. The modified switch placement reduced physical fatigue in the lower extremities, annoyance related to the manipulation of conventionally-placed switches, and increased the comfort of surgeons operating in the standing position. PMID- 23358173 TI - New technique of decompressive skinplasty with artificial dermis for severe brain swelling: technical note. AB - In cases of severe uncontrollable brain swelling, simple skin closure often increases intracranial pressure. This study examined the efficacy of a new technique of decompressive skinplasty to decrease intracranial pressure following decompressive craniectomy in cases of severe traumatic brain injury with uncontrollable brain swelling. In our technique, we use artificial dermis to avoid elevation of intracranial pressure. After performing decompressive craniectomy and duraplasty with artificial dura, decompressive skinplasty with artificial dermis was performed in 5 patients for whom simple skin closure caused the intracranial pressure to elevate under intracranial pressure monitoring. Artificial dermis was grafted onto the region to cover the skin defect and sutured to the skin with 4-0 nylon sutures. Two weeks after surgery, the silicone layer of the artificial dermis was removed and ointment treatment was continued until complete epithelialization was achieved. In all cases, decompressive skinplasty contributed dramatically to decreasing the intracranial pressure in patients with uncontrollable brain swelling. The technique of decompressive skinplasty with artificial dermis contributed to dramatically decreasing the intracranial pressure. More cases are required to investigate the indications for this technique. PMID- 23358174 TI - Planar geometrical analysis for design of the shortest incision to open the dura mater: technical note. AB - Quadrilateral dural window is opened with a conventional incision design, such as a pair of diagonal lines or a rectangular shape, but the total cutting length is not the shortest possible. Shorter incision length will have a lower risk of dysraphia associated with cerebrospinal fluid (CSF) liquorrhea or related CSF infection. We propose a new and effective dural incision design with the shortest cutting length for quadrilateral dural openings. We investigated the design of the dural incision using a simple planar geometrical figure. We discovered the shortest network design to connect the four vertices of the quadrilateral. The shortest network design was formed of five line segments with two three-pronged interconnections (TPIs) with the same angle of 2pi/3 between any two lines (2pi/3 TPI). In practice, first we must draw a quadrilateral W horizontally then add two equilateral triangles outside W. Using a 2pi/3-bent wire, the 2pi/3-TPIs are traced on the path connecting the outward vertices of the equilateral triangles. Using this method, we can reduce the incision length by 10% from conventional designs using a pair of diagonal lines. PMID- 23358175 TI - Enhancement of withstanding pressure of fibrin sealant by modified mixing ratio of fibrin sealant components for skull base reconstruction: technical note. AB - A method to enhance the withstanding pressure of fibrin sealant in gasket-seal closure to prevent cerebrospinal fluid (CSF) leakage after extended transsphenoidal surgery (ETSS) was investigated by adjusting the mixing ratio of the components. A plastic chamber (200 ml) was constructed with a lid made of hydroxyapatite with a hole 10 mm in diameter. The chamber could be pressurized via an opening in the side wall. The hole in the hydroxyapatite lid was covered with a Gore-Tex sheet, 15 mm in diameter. The margin of the sheet was free. Solutions A (fibrinogen 80 mg/ml) and B (thrombin 250 units/ml) of fibrin sealant were mixed in volume ratios of 1:1, 2:1, and 5:1, and applied to the Gore-Tex sheet, then water was introduced to cover the fibrin sealant. The pressure was measured at which air leakage occurred from the side of the Gore-Tex sheet. The pressure values for A/B ratios of 1:1, 2:1, and 5:1 were 117 +/- 23.8 mmH(2)O (mean +/- standard error) (n = 5), 234 +/- 38.8 mmH(2)O (n = 5), and 345 +/- 36.4 mmH(2)O (n = 5), respectively, in the acute phase (5 minutes after application of fibrin sealant). Pressures were increased after 24 hours, and that for 5:1 was the highest (373 +/- 40.4 mmH(2)O, n = 5). The use of devices such as syringes specially designed to mix solutions A and B in the ratio of 5:1 can easily enhance the preventive effect of fibrin sealant against CSF leakage in ETSS. PMID- 23358177 TI - Survivin status affects prognosis and chemosensitivity in epithelial ovarian cancer. AB - OBJECTIVE: The objective of this study was to explore the clinical significance of survivin expression in epithelial ovarian cancer (EOC) and the effect of survivin small hairpin RNA (shRNA) on survivin expression, apoptosis, and chemosensitivity in the human ovarian cancer cell line OVCAR3. METHODS: A retrospective review of 90 consecutive EOC patients with a median follow-up time of 51 months was conducted. Survivin expression was examined by immunohistochemistry. OVCAR3 cells were transfected in vitro with survivin shRNA. Survivin mRNA expression levels were detected using reverse transcription polymerase chain reaction. Flow cytometry was applied to determine survivin protein expression levels and cell apoptotic rates. The MTT method was used to examine the effects of survivin shRNA on chemosensitivity in OVCAR3 cells. RESULTS: Positive cytoplasmic expression of survivin was associated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, nonmucinous type, high grade, and recurrence. Positive survivin expression was also associated with platinum resistance (r = 0.306, P = 0.003). Statistical results indicated that FIGO stage (hazard rate = 1.649, P = 0.047) and cytoplasmic expression of survivin (hazard rate = 1.734, P = 0.010) were independent prognostic factors. Survivin mRNA and protein levels were lower in OVCAR3S (ovarian cancer cells transfected with a survivin recombinant vector) cells at 24 hours after transfection as compared with controls. The flow cytometric analysis revealed that survivin shRNA induced accumulation of cells in the G0/Gl phase, with a decrease in G2/M phase cells following 24 hours of culture as compared with a nontransfected group (P < 0.01). Furthermore, survivin shRNA increased the sensitivity of OVCAR3 cells to paclitaxel 15-fold (P < 0.05), whereas it had no significant effect on cisplatin (P > 0.05). CONCLUSIONS: In addition to FIGO stage, cytoplasmic survivin protein expression is an independent molecular marker for predicting EOC prognosis. Sequence-specific shRNA targeting survivin can effectively suppress survivin expression, enhance apoptosis, and increase the sensitivity of ovarian cancer cells to paclitaxel but not to cisplatin. PMID- 23358178 TI - Outcome and clinical management of 275 patients with advanced ovarian cancer International Federation of Obstetrics and Gynecology II to IV inside the European Ovarian Cancer Translational Research Consortium-OVCAD. AB - INTRODUCTION: The Sixth Framework Program European Union project OVCAD, "Ovarian Cancer-Diagnosis of a Silent Killer," aimed to investigate new predictors for early detection of minimal residual disease in epithelial ovarian cancer (EOC). Here we present the main pathologic, surgical, and chemotherapy characteristics of the OVCAD patient cohort. METHODS: Between February 2005 and December 2008, 5 European gynecologic cancer centers (WP2 group) enrolled prospective 275 consecutive patients with EOC into this translational study. Inclusion criteria were as follows: advanced International Federation of Obstetrics and Gynecology II to IV stage, cytoreductive surgery, platinum-based chemotherapy, and collected tumor samples. WP2 coordinated the implementation, screening, and recruiting of the patients and tumor samples into a Web-based data bank according established standard operating procedures. RESULTS: Median age at the time of diagnosis was 58 years. Most patients presented advanced high-grade EOC: International Federation of Obstetrics and Gynecology III/IV (94.5%), grade 2/3 (96%), serous histology (86.2%), ascites (76%), peritoneal carcinomatosis (67.6%), and lymph node involvement (52%). The most common surgical procedures were omentectomy (92.4%), bilateral salpingo-oophorectomy (90.9%), hysterectomy (77.3%), pelvic (69.5%) and paraaortic (66.9%) lymphadenectomy, and large (37.7%) or small bowel resection (13.4%). Patients were treated commonly with platinum-based therapy (98.2%). The macroscopic cytoreduction rate was 68.4%. After a median follow-up of 37 months, 70 patients (25.5%) developed a platinum-resistant recurrence. Biological materials such as tumor and paraffin tissue, ascites, and blood samples were collected consecutively. CONCLUSIONS: The implementation of the OVCAD cohort demonstrated the feasibility and advantages of an open, prospective, and multicenter recruitment inside a translational research study. Essential was the predefinition of all inclusion criteria, standard operating procedures, and Web-based software, which enabled the prospective patient recruitment and tissue sampling, minimizing institutional bias and variability in the quality of the biological samples. The translational concept of the OVCAD study does not conflict with the state-of-the-art surgical and chemotherapy management and guaranteed an improved outcome of patients with EOC. PMID- 23358179 TI - Preoperative leukocytosis imposes an increased risk of recurrence and death among patients with nonendometrioid endometrial carcinoma. AB - OBJECTIVE: To evaluate the impact of preoperative leukocytosis among patients with nonendometrioid endometrial carcinoma. METHODS: The medical records of all patients with nonendometrioid endometrial carcinoma who underwent surgical treatment between January 2005 and December 2010 were retrospectively reviewed. The patients were separated into 2 groups based on the presence or absence of preoperative leukocytosis (white blood cell count >= 10,000/MUL). The groups were then compared with respect to pathologic findings, progression-free survival, and overall survival. RESULTS: A total of 222 patients were identified, and preoperative leukocytosis was observed in 33 patients (14.9%). The leukocytosis group was associated with a larger mean size of the primary tumor (6.8 vs 4.6 cm, P = 0.016) and a greater percentage of patients with cervical stromal involvement (36.4% vs 20.1%, P = 0.039), adnexal involvement (42.4% vs. 22.8%, P = 0.017), and pelvic/para-aortic lymph node involvement (50% vs 27.4%, P = 0.025). On multivariate analysis, preoperative leukocytosis was independently associated with an increased risk of recurrence (hazard ratio, 2.07; 95% confidence interval, 1.12-3.84) and an increased risk of death (hazard ratio, 3.33; 95% confidence interval, 2.01-5.53). CONCLUSIONS: Among patients with nonendometrioid endometrial carcinoma, preoperative leukocytosis is independently associated with an increased risk of recurrence and death. PMID- 23358180 TI - Analysis of a continuous series of 34 young patients with early-stage cervical cancer selected for a vaginal radical trachelectomy: should "staging" conization be systematically performed before this procedure? AB - OBJECTIVE: Vaginal radical trachelectomy (VRT) is the most widely evaluated form of conservative management of young patients with early-stage (IB1) cervical cancer. Patients with nodal involvement or a tumor size greater than 2 cm are not eligible for such treatment. The aim of this study is to report the impact of a "staging" conization before VRT. METHODS: This is a retrospective study of 34 patients potentially selected for VRT for a clinical and radiologic cervical tumor less than 2 cm. Among them, 28 underwent finally a VRT (20 of them having a previous conization before this procedure) and 6 patients with macroscopic cervical cancer, confirmed by punch biopsies, "eligible" for VRT (<2 cm) had undergone "staging" conization (without further VRT) to confirm the tumor size and lymphovascular space involvement (LVSI) status. RESULTS: Six patients having "staging" conization before VRT had finally been deemed contraindications to VRT due to the presence of a histologically confirmed tumor greater than 2 cm and/or associated with multiple foci of LVSI. Among 28 patients who underwent VRT, 1 received adjuvant chemoradiation (this patient recurred and died of disease). Two patients treated with RVT (without postoperative treatment) recurred. Ten pregnancies (9 spontaneous and 1 induced) were observed in 9 patients. Among 4 patients with macroscopic "visible" tumor who do not underwent a "staging" conization before VRT, 2 recurred. Among 11 patients who underwent VRT and having LVSI, 3 recurred. CONCLUSIONS: These results suggest that if a conization is not performed initially, it should then be included among the staging procedures to select patients for VRT. PMID- 23358181 TI - Isolated mediastinal lymph node false positivity of [18F]-fluorodeoxyglucose positron emission tomography/computed tomography in patients with cervical cancer. AB - OBJECTIVE: This study aimed to evaluate the degree of mediastinal involvement in patients with cervical cancer with isolated mediastinal [F]-fluorodeoxyglucose positron emission tomography (FDG-PET) positivity as verified by histopathologic examination. METHODS: Two hundred twenty-eight patients with newly diagnosed cervical cancer and who underwent FDG-PET imaging were analyzed. Twenty-nine patients (17%) had disseminated disease detected with PET/computed tomography (CT). Only 10 patients (4%) had increased FDG uptake in mediastinal lymph nodes alone. Of the 10 patients with mediastinal disease, 2 refused surgical mediastinal lymph node biopsy and did not receive any treatment. Patients with suspected paratracheal or subcarinal lymph node metastasis detected on PET/CT underwent mediastinoscopy, and those with hilar metastasis had video-assisted mediastinal lymphadenectomy. Treatment was delivered according to final staging based on histopathologic confirmation of mediastinal lymph node involvement. RESULTS: The mean (SD) maximum standardized uptake values for primary cervical tumor and mediastinal lymph nodes were 19.7 (10.3) and 7.5 (1.6), respectively. Of 8 patients who underwent mediastinal lymph node confirmation, 6 (75%) were tumor free, demonstrating granulomatous changes, and were treated curatively. No patients had residual or recurrent disease at the primary site, and all but 1 were alive without disease. Two patients with confirmed mediastinal lymph node metastasis were treated palliatively and died between 9 and 11 months after diagnosis. CONCLUSIONS: Positron emission tomography/CT is an important tool for lymphatic staging and evaluation of distant metastases in cervical cancer. However, PET/CT should be interpreted cautiously for isolated mediastinal involvement; surgical evaluation is required for accurate staging and appropriate treatment decisions to achieve better outcomes. PMID- 23358182 TI - Weekly administration of bevacizumab, gemcitabine, and oxaliplatin in patients with recurrent and refractory ovarian cancer: a preliminary result of 19 cases. AB - OBJECTIVE: Combination therapy using gemcitabine with oxaliplatin (GEMOX) showed moderate activity in recurrent ovarian cancers. However, severe toxicities have been observed in patients who received full-dose therapy of GEMOX. On the other hand, bevacizumab enhances chemotherapeutic efficacy in various cancers. Here, we evaluated the effect of weekly low-dose administration of GEMOX in combination with bevacizumab (B-GEMOX) for patients with recurrent and refractory ovarian cancers (ROCs). METHODS: A total of 19 patients with ROC were treated with B GEMOX: 2 mg/kg of bevacizumab, 300 mg/m(2) of gemcitabine, and 30 mg/m(2) of oxaliplatin, 3 weeks on and 1 week off, q4weeks. The treatment was continued until development of severe toxicities or progressive disease. Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors and Gynecologic Cancer Intergroup criteria. RESULTS: Median number of the B-GEMOX therapy was 5 cycles. Response was observed in 4 (34%) cases by Response Evaluation Criteria in Solid Tumors, and in 2 (29%) cases by Gynecologic Cancer Intergroup criteria, resulting in overall response rate of 32%. Clinical benefit excluding progressive disease was obtained in 79% of the patients. Median progression-free survival was 4.5 months (range, 2-16+ months). Toxicities were mild and mainly consisted of hematologic, gastrointestinal, and neuropathy; however, there were no nonhematologic toxicities more than grade 1. CONCLUSIONS: Weekly administration of B-GEMOX was active for patients with ROC and showed mild toxicities. These results warrant further prospective studies for patients with ROC. PMID- 23358183 TI - Contraceptive options for women with a history of solid-organ transplantation. AB - Women of reproductive age who have received a solid-organ transplant are at risk for unplanned pregnancy. Fertility can return as soon as 1 month after transplantation, and the baseline unplanned pregnancy rate in the United States is approximately 50%. Pregnancy, although not absolutely contraindicated in this population, carries risk greater than the general population and should be timed with regard to medication regimen and organ function. The Centers for Disease Control categorizes every form of contraception as Category 2-benefits outweigh risks-in women with an uncomplicated transplantation. There is a large range of contraceptive options, varying in drug formulation, route of delivery, and discrepancy between "perfect" and "typical" use. Long-acting reversible contraceptive methods include intrauterine devices (IUDs) and subdermal implants and show great promise for women with solid-organ transplant. These methods have excellent efficacy, eliminate user error, and, in the case of IUDs, have extremely low or no systemic drug absorption. Providers have historical concerns regarding the association of IUD and infection; however, modern studies have shown their safety in both immunocompetent and immunocompromised patients. Women with a history of solid-organ transplantation can be safely offered a wide range of contraceptive options to suit their individualized needs. PMID- 23358184 TI - Breast cancer metastasis to pituitary infandibulum. AB - Metastasis from breast cancer to other parts of the body is very common, but the spread of the tumor to pituitary gland, especially to infandibulum, is a rare presentation. At the time of pituitary metastasis, a majority of the patients have clinical and radiological evidence of the disease. It seems that the posterior area of the gland is the most common site of metastasis, probably due to highly rich blood supply through the hypophyseal artery. The present report introduces a case of a 55-years-old woman presented with diabetes insipidus resulting from metastasis of the tumor to pituitary infandibulum, which is a rare site for metastasis, without significant complaint resulting from metastasis to other part of the body, or other primary diseases. Further evaluation revealed that in spite of previous reports, which metastasis usually happens in end stage of cancer, the patients had primary breast cancer. In subsequent evaluations of the case, hypofunction of adenohypophysis was also detected. PMID- 23358185 TI - NQO1 C609T polymorphism correlated to colon cancer risk in farmers from western region of Inner Mongolia. AB - OBJECTIVE: To investigate the relationship between NAD(P)H:quinone oxidoreductase 1 (NQO1) C609T polymorphism and colon cancer risk in farmers from western region of Inner Mongolia. METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to analyze NQO1 C609T polymorphism from 160 healthy controls and 76 colon cancer patients. RESULTS: Among the colon cancer patients, the incidence of NQO1 T allele (53.29%) was significantly higher than it in control group (33.75%, P<0.001). The individuals with NQO1 T allele had higher risk [2.239 (95% CI: ?1.510-3.321) times] to develop colon cancer than individuals with NQO1 C allele. The incidence of NQO1? (T/T) (34.21%) in colon cancer patients was higher than that in control group (15.62%, P<0.001). Odds ratios (OR) analysis suggested that NQO1 (T/T) and NQO1 (T/C) genotype carriers had 3.813 (95% CI: 1.836-7.920) times and 2.080 (1.026-4.219) times risk compared with wild-type NQO1 (C/C) gene carriers in developing colon cancer. Individuals with NQO1 (T/T) genotype had 2.541 (95% CI: 0.990-6.552) times, 3.713 (95% CI: 1.542-8.935) times, and 3.471 (95% CI: 1.356-8.886) times risk than individuals with NQO1 (T/C) or NQO1 (C/C) genotype in well-differentiated, moderately differentiated, and poorly-differentiated colon cancer patients, respectively. CONCLUSIONS: NQO1 gene C609T could be one of risk factors of colon cancer in farmers from western region of Inner Mongolia. PMID- 23358186 TI - Generation of an HIV resistant T-cell line by targeted "stacking" of restriction factors. AB - Restriction factors constitute a newly appreciated line of innate immune defense, blocking viral replication inside of infected cells. In contrast to these antiviral proteins, some cellular proteins, such as the CD4, CCR5, and CXCR4 cell surface receptors, facilitate HIV replication. We have used zinc finger nucleases (ZFNs) to insert a cocktail of anti-HIV restriction factors into the CCR5 locus in a T-cell reporter line, knocking out the CCR5 gene in the process. Mirroring the logic of highly active antiretroviral therapy, this strategy provides multiple parallel blocks to infection, dramatically limiting pathways for viral escape, without relying on random integration of transgenes into the genome. Because of the combination of blocks that this strategy creates, our modified T cell lines are robustly resistant to both CCR5-tropic (R5-tropic) and CXCR4 tropic (X4-tropic) HIV-1. While zinc finger nuclease-mediated CCR5 disruption alone, which mimics the strategy being used in clinical trials, confers 16-fold protection against R5-tropic HIV, it has no effect against X4-tropic virus. Rhesus TRIM5alpha, chimeric human-rhesus TRIM5alpha, APOBEC3G D128K, or Rev M10 alone targeted to CCR5 confers significantly improved resistance to infection by both variants compared with CCR5 disruption alone. The combination of three factors targeted to CCR5 blocks infection at multiple stages, providing virtually complete protection against infection by R5-tropic and X4-tropic HIV. PMID- 23358187 TI - The use of scaffold-free cell sheet technique to refine mesenchymal stromal cell based therapy for heart failure. AB - Transplantation of bone marrow-derived mesenchymal stromal cells (MSCs) is an emerging treatment for heart failure based on their secretion-mediated "paracrine effects". Feasibility of the scaffoldless cell sheet technique to enhance the outcome of cell transplantation has been reported using other cell types, though the mechanism underpinning the enhancement remains uncertain. We here investigated the role of this innovative technique to amplify the effects of MSC transplantation with a focus on the underlying factors. After coronary artery ligation in rats, syngeneic MSCs were grafted by either epicardial placement of MSC sheets generated using temperature-responsive dishes or intramyocardial (IM) injection. Markedly increased initial retention boosted the presence of donor MSCs persistently after MSC sheet placement although the donor survival was not improved. Most of the MSCs grafted by the cell sheet technique remained resided on the epicardial surface, but the epicardium quickly regressed and new vessels sprouted into the sheets, assuring the permeation of paracrine mediators from MSCs into the host myocardium. In fact, there was augmented upregulation of various paracrine effect-related genes and signaling pathways in the early phase after MSC sheet therapy. Correspondingly, more extensive paracrine effects and resultant cardiac function recovery were achieved by MSC sheet therapy. Further development of this approach towards clinical application is encouraged. PMID- 23358188 TI - SR-A and SREC-I are Kupffer and endothelial cell receptors for helper-dependent adenoviral vectors. AB - Helper-dependent adenoviral (HDAd) vectors can mediate long-term, high-level transgene expression from transduced hepatocytes with no chronic toxicity. However, a toxic acute response with potentially lethal consequences has hindered their clinical applications. Liver sinusoidal endothelial cells (LSECs) and Kupffer cells are major barriers to efficient hepatocyte transduction. Understanding the mechanisms of adenoviral vector uptake by non-parenchymal cells may allow the development of strategies aimed at overcoming these important barriers and to achieve preferential hepatocyte gene transfer with reduced toxicity. Scavenger receptors on Kupffer cells bind adenoviral particles and remove them from the circulation, thus preventing hepatocyte transduction. In the present study, we show that HDAd particles interact in vitro and in vivo with scavenger receptor-A (SR-A) and with scavenger receptor expressed on endothelial cells-I (SREC-I) and we exploited this knowledge to increase the efficiency of hepatocyte transduction by HDAd vectors in vivo through blocking of SR-A and SREC I with specific fragments antigen-binding (Fabs). PMID- 23358190 TI - Functional profiling discovers the dieldrin organochlorinated pesticide affects leucine availability in yeast. AB - Exposure to organochlorinated pesticides such as dieldrin has been linked to Parkinson's and Alzheimer's diseases, endocrine disruption, and cancer, but the cellular and molecular mechanisms of toxicity behind these effects remain largely unknown. Here we demonstrate, using a functional genomics approach in the model eukaryote Saccharomyces cerevisiae, that dieldrin alters leucine availability. This model is supported by multiple lines of congruent evidence: (1) mutants defective in amino acid signaling or transport are sensitive to dieldrin, which is reversed by the addition of exogenous leucine; (2) dieldrin sensitivity of wild-type or mutant strains is dependent upon leucine concentration in the media; (3) overexpression of proteins that increase intracellular leucine confer resistance to dieldrin; (4) leucine uptake is inhibited in the presence of dieldrin; and (5) dieldrin induces the amino acid starvation response. Additionally, we demonstrate that appropriate negative regulation of the Ras/protein kinase A pathway, along with an intact pyruvate dehydrogenase complex, is required for dieldrin tolerance. Many yeast genes described in this study have human orthologs that may modulate dieldrin toxicity in humans. PMID- 23358191 TI - Relative impact of incorporating pharmacokinetics on predicting in vivo hazard and mode of action from high-throughput in vitro toxicity assays. AB - The use of high-throughput in vitro assays has been proposed to play a significant role in the future of toxicity testing. In this study, rat hepatic metabolic clearance and plasma protein binding were measured for 59 ToxCast phase I chemicals. Computational in vitro-to-in vivo extrapolation was used to estimate the daily dose in a rat, called the oral equivalent dose, which would result in steady-state in vivo blood concentrations equivalent to the AC 50 or lowest effective concentration (LEC) across more than 600 ToxCast phase I in vitro assays. Statistical classification analysis was performed using either oral equivalent doses or unadjusted AC 50 /LEC values for the in vitro assays to predict the in vivo effects of the 59 chemicals. Adjusting the in vitro assays for pharmacokinetics did not improve the ability to predict in vivo effects as either a discrete (yes or no) response or a low effect level (LEL) on a continuous dose scale. Interestingly, a comparison of the in vitro assay with the lowest oral equivalent dose with the in vivo endpoint with the lowest LEL suggested that the lowest oral equivalent dose may provide a conservative estimate of the point of departure for a chemical in a dose-response assessment. Furthermore, comparing the oral equivalent doses for the in vitro assays with the in vivo dose range that resulted in adverse effects identified more coincident in vitro assays across chemicals than expected by chance, suggesting that the approach may also be used to identify potential molecular initiating events leading to adversity. PMID- 23358192 TI - Identification of transcription factors and coactivators affected by dibutylphthalate interactions in fetal rat testes. AB - Previous analysis of in utero dibutylphthalate (DBP)-exposed fetal rat testes indicated that DBP's antiandrogenic effects were mediated, in part, by indirect inhibition of steroidogenic factor 1 (SF1), suggesting that peroxisome proliferator-activated receptor alpha (PPARalpha) might be involved through coactivator (CREB-binding protein [CBP]) sequestration. To test this hypothesis, we have performed chromatin immunoprecipitation (ChIP) microarray analysis to assess the DNA binding of PPARalpha, SF1, CBP, and RNA polymerase II in DBP induced testicular maldevelopment target genes. Pathway analysis of expression array data in fetal rat testes examined at gestational day (GD) 15, 17, or 19 indicated that lipid metabolism genes regulated by SF1 and PPARalpha, respectively, were overrepresented, and the time dependency of changes to PPARalpha-regulated lipid metabolism genes correlated with DBP-mediated repression of SF1-regulated steroidogenesis genes. ChIP microarrays were used to investigate whether DBP-mediated repression of SF1-regulated genes was associated with changes in SF1 binding to genes involved in DBP-induced testicular maldevelopment. DBP treatment caused reductions in SF1 binding in CYP11a, StAR, and CYP17a. Follicle-stimulating hormone receptor (FSHR), regulated by SF1 but unaffected by DBP-treatment, also contained SF1-binding peaks, but DBP did not change this compared with control. GD15 and GD19 fetal testes contained PPARalpha protein-binding peaks in CYP11a, StAR, and CYP17a regulatory regions. In contrast to its repressive effect on SF1, DBP treatment caused increases in these peaks compared with control. PPARalpha-binding peaks in the FSHR promoter were not detected in GD15 samples. Hence, the repressive effect of DBP on SF1-regulated steroidogenic genes correlates with inhibition of SF1-DNA binding and increased PPARalpha-DNA binding. The data indicate that PPARalpha may act as an indirect transrepressor of SF1 on steroidogenic genes in fetal rat testes in response to DBP treatment. PMID- 23358189 TI - A comprehensive review of retinal gene therapy. AB - Blindness, although not life threatening, is a debilitating disorder for which few, if any treatments exist. Ocular gene therapies have the potential to profoundly improve the quality of life in patients with inherited retinal disease. As such, tremendous focus has been given to develop such therapies. Several factors make the eye an ideal organ for gene-replacement therapy including its accessibility, immune privilege, small size, compartmentalization, and the existence of a contralateral control. This review will provide a comprehensive summary of (i) existing gene therapy clinical trials for several genetic forms of blindness and (ii) preclinical efficacy and safety studies in a variety of animal models of retinal disease which demonstrate strong potential for clinical application. To be as comprehensive as possible, we include additional proof of concept studies using gene replacement, neurotrophic/neuroprotective, optogenetic, antiangiogenic, or antioxidative stress strategies as well as a description of the current challenges and future directions in the ocular gene therapy field to this review as a supplement. PMID- 23358195 TI - The spectrum of circulating RNA: a window into systems toxicology. AB - Adverse effects caused by therapeutic drugs are a serious and costly health concern. Despite the body's systemic responses to therapeutics, the liver is often the focus of damage and is usually the focus of studies of toxic effects due to its active roles in the metabolism of xenobiotics. It is extremely difficult, however, to assess systemic responses with currently available methods. Comprehensive cataloging of cell-free circulating RNAs using next generation sequencing technology may open a window to assess drug-associated adverse effects at the systems level. To explore this potential, we conducted an RNA profiling study using the well-characterized acetaminophen overdose mouse model on liver and plasma with microarray and next-generation sequencing platforms, respectively. After drug treatment, the levels of a number of transcripts, both endogenous and exogenous RNAs, showed significant changes in plasma, reflecting not only the classical liver injury induced by acetaminophen overdose but also damage in tissues other than the liver. The changes in exogenous RNAs also reflect alteration on dieting behavior after acetaminophen overdose. Besides reporting an extensive list of circulating RNA-based biomarker candidates, this study illustrates the possibility of using circulating RNAs to assess global effects of therapeutics. This could also lead to a new approach for a more comprehensive assessment of the efficacy and safety of therapeutics. PMID- 23358194 TI - Transcriptome alterations following developmental atrazine exposure in zebrafish are associated with disruption of neuroendocrine and reproductive system function, cell cycle, and carcinogenesis. AB - Atrazine, a herbicide commonly applied to agricultural areas and a common contaminant of potable water supplies, is implicated as an endocrine-disrupting chemical (EDC) and potential carcinogen. Studies show that EDCs can cause irreversible changes in tissue formation, decreased reproductive potential, obesity, and cancer. The U.S. Environmental Protection Agency considers an atrazine concentration of <= 3 ppb in drinking water safe for consumption. The specific adverse human health effects associated with a developmental atrazine exposure and the underlying genetic mechanisms of these effects are not well defined. In this study, zebrafish embryos were exposed to a range of atrazine concentrations to establish toxicity. Morphological, transcriptomic, and protein alterations were then assessed at 72h postfertilization following developmental atrazine exposure at 0, 0.3, 3, or 30 ppb. A significant increase in head length was observed in all three atrazine treatments. Transcriptomic profiles revealed 21, 62, and 64 genes with altered expression in the 0.3, 3, and 30 ppb atrazine treatments, respectively. Altered genes were associated with neuroendocrine and reproductive system development, function, and disease; cell cycle control; and carcinogenesis. There was a significant overlap (42 genes) between the 3 and 30 ppb differentially expressed gene lists, with two of these genes (CYP17A1 and SAMHD1) present in all three atrazine treatments. Increased transcript levels were translated to significant upregulation in protein expression. Overall, this study identifies genetic and molecular targets altered in response to a developmental atrazine exposure to further define the biological pathways and mechanisms of toxicity. PMID- 23358193 TI - Brain hemispheric differences in the neurochemical effects of lead, prenatal stress, and the combination and their amelioration by behavioral experience. AB - Brain lateralization, critical to mediation of cognitive functions and to "multitasking," is disrupted in conditions such as attention deficit disorder and schizophrenia. Both low-level lead (Pb) exposure and prenatal stress (PS) have been associated with mesocorticolimbic system-mediated executive-function cognitive and attention deficits. Mesocorticolimbic systems demonstrate significant laterality. Thus, altered brain lateralization could play a role in this behavioral toxicity. This study examined laterality of mesocorticolimbic monoamines (frontal cortex, nucleus accumbens, striatum, midbrain) and amino acids (frontal cortex) in male and female rats subjected to lifetime Pb exposure (0 or 50 ppm in drinking water), PS (restraint stress on gestational days 16-17), or the combination with and without repeated learning behavioral experience. Control males exhibited prominent laterality, particularly in midbrain and also in frontal cortex and striatum; females exhibited less laterality, and this was primarily striatal. Lateralized Pb +/- PS induced neurotransmitter changes were assessed only in males because of limited sample sizes of Pb + PS females. In males, Pb +/- PS changes occurred in left hemisphere of frontal cortex and right hemisphere of midbrain. Behavioral experience modified the laterality of Pb +/- PS-induced neurotransmitter changes in a region-dependent manner. Notably, behavioral experience eliminated Pb +/- PS neurotransmitter changes in males. These findings underscore the critical need to evaluate both sexes and brain hemispheres for the mechanistic understanding of sex-dependent differences in neuro- and behavioral toxicity. Furthermore, assessment of central nervous system mechanisms in the absence of behavioral experience, shown here for males, may constitute less relevant models of human health effects. PMID- 23358196 TI - Integrative Analysis of miRNA and inflammatory gene expression after acute particulate matter exposure. AB - MicroRNAs (miRNAs) are environmentally sensitive inhibitors of gene expression that may mediate the effects of metal-rich particulate matter (PM) and toxic metals on human individuals. Previous environmental miRNA studies have investigated a limited number of candidate miRNAs and have not yet evaluated the functional effects on gene expression. In this study, we wanted to identify PM sensitive miRNAs using microarray profiling on matched baseline and postexposure RNA from foundry workers with well-characterized exposure to metal-rich PM and to characterize miRNA relations with expression of candidate inflammatory genes. We applied microarray analysis of 847 human miRNAs and real-time PCR analysis of 18 candidate inflammatory genes on matched blood samples collected from foundry workers at baseline and after 3 days of work (postexposure). We identified differentially expressed miRNAs (fold change [FC] > 2 and p < 0.05) and correlated their expression with the inflammatory associated genes. We performed in silico network analysis in MetaCore v6.9 to characterize the biological pathways connecting miRNA-mRNA pairs. Microarray analysis identified four miRNAs that were differentially expressed in postexposure compared with baseline samples, including miR-421 (FC = 2.81, p < 0.001), miR-146a (FC = 2.62, p = 0.007), miR-29a (FC = 2.91, p < 0.001), and let-7g (FC = 2.73, p = 0.019). Using false discovery date adjustment for multiple comparisons, we found 11 miRNA-mRNA correlated pairs involving the 4 differentially expressed miRNAs and candidate inflammatory genes. In silico network analysis with MetaCore database identified biological interactions for all the 11 miRNA-mRNA pairs, which ranged from direct mRNA targeting to complex interactions with multiple intermediates. Acute PM exposure may affect gene regulation through PM-responsive miRNAs that directly or indirectly control inflammatory gene expression. PMID- 23358197 TI - Assessment of plasma prothrombotic factors in patients with Buerger's disease. AB - The pathogenesis of Buerger' disease (thrombangiitis obliterans; TAO) remains unknown, although a strong association with tobacco use has been established. Blood coagulation and fibrinolytic factors as well as selected clinical chemistry parameters have been evaluated in 37 patients with Buerger's disease. Median levels of prothrombotic factors were higher in patients with TAO than in healthy control: annexin V (P < 0.0003), factor VII (P < 0.0001), factor VIII (P < 0.0000001), factor XI (P < 0.000003), homocysteine (P < 0.014) and fibrinogen (P = 0.00007). Patients with Buerger's disease also showed higher median plasma levels of urokinase type plasminogen activator (uPA) (P < 0.000004), its receptor (uPAR) (P < 0.0008) and uPA complex with plasminogen activator inhibitor 1 (uPA PAI-1) P < 0.000006). In contrast, plasma concentrations of apolipoprotein A and folic acid were lower in patients with TAO than in control (P < 0.004 and P < 0.0006; respectively). Higher plasminogen (P < 0.05) and cholesterol (P < 0.003), as well as lower folic acid (P < .0.05) levels were noted in the smokers group than in nonsmoking patients. We found higher plasminogen (P < 0.05), factor VII (P < 0.05), total lipids (P < 0.003), cholesterol (P < 0.05) and triglycerides (P < 0.002) levels in patients requiring surgical treatment for limb-threatening ischaemia than the patients treated only conservatively. These findings suggest an important role of haemostatic risk factors in the pathogenesis of Buerger's disease, with special regard to hyperhomocysteinemia that might be aggravated by low serum folic acid level. In patients with aggressive clinical course, disturbances in serum lipids were more pronounced. Further studies are warranted to establish whether diet supplementation of folic acid as well as normalization of lipids balance might influence the clinical course of TAO. PMID- 23358198 TI - Investigation of inherited thrombophilias in patients with pulmonary embolism. AB - Inherited thrombophilias are thought to play an important role in the cause of pulmonary embolism and its recurrence. Ninety of 281 patients objectively diagnosed as pulmonary embolism between 2006 and 2009 were included in the study. The screening for thrombophilia included mutations of factor V Leiden (FVL), prothrombin (PTM) G20210A, methylene tetrahydrofolate reductase C677T-A1298C, the serum levels of antithrombin III, protein C, protein S, factor VIII and activated protein C resistance. Forty-two male (46.7%) and 48 female (53.3%) patients had a mean age of 62.6 +/- 13.4 years. Patients with common thrombophilias comprised 30% of all cases (FVL: 19.1%, PTM G20210A: 3.4%, antithrombin III deficiency: 1.1%, protein C deficiency: 5.7%, protein S deficiency: 13.6%). A significant association between recurrence of pulmonary embolism (10 patients, 12.2%) and protein S deficiency was established (P = 0.040). Serum level of protein C was also significantly lower in the subgroup of recurrent pulmonary embolism (P = 0.049). FVL and PTM mutations were high in cancer patients; the presence of inherited thrombophilia was low with risk factors of surgery and immobilization. Genetic risk factors were high in patients with pulmonary embolism. Protein C and S deficiencies may play a role in pulmonary embolism recurrence. DVT or family history of pulmonary embolism was not found to be related to inherited thrombophilias. Surgery and immobilization were thought not to have priorities for detection of genetic risk factors. The high percentages of FVL and PTM mutations in cancer patients should be considered. PMID- 23358199 TI - Increased platelet activation and inflammatory response in patients with masked hypertension. AB - Masked hypertension is associated with an increase in cardiovascular risk. Mean platelet volume (MPV), a determinant of platelet function, is a new risk factor for atherothrombosis. High-sensitive C-reactive protein (CRP) is an exquisitely sensitive systemic marker of inflammatory response. We designed this study to evaluate MPV and CRP in masked hypertensive patients and to compare those with essential hypertensive and healthy normotensive individuals. Forty-two untreated masked hypertensive patients, 53 untreated essential hypertensive patients and age-sex matched 37 normotensive healthy individuals were included in the study. Blood samples were collected and haematological parameters were measured. Plasma CRP level was measured by immunonephelometery method. The MPV was significantly higher in masked hypertensive (8.8 +/- 1.6 fl) and essential hypertensive patients (9.1 +/- 1.7 fl) than those of normotensive control individuals (7.8 +/- 0.8 fl) (P = 0.01 and P = 0.003, respectively), whereas there was no significant difference between the masked hypertensive and essential hypertensive individuals (P > 0.05). CRP levels were also significantly higher in masked hypertensive patients than in normotensives individuals (3.31 +/- 1.70, 1.98 +/- 1.56 mg/l, P < 0.001, respectively). There was a significant positive correlation between MPV and CRP levels (P < 0.001, r = 0.850) in masked hypertensive patients. Patients with masked hypertension have higher MPV and CRP values than controls. Increased MPV and CRP levels may be the possible mechanisms behind the increased cardiovascular risk in masked hypertensive patients. PMID- 23358200 TI - Hepatic coagulopathy-intricacies and challenges; a cross-sectional descriptive study of 110 patients from a superspecialty institute in North India with review of literature. AB - Hemostatic defect in chronic liver disease (CLD) is complex involving opposing factors of primary hemostasis, coagulation, and fibrinolysis. The concept of causal relationship between abnormal tests and clinical bleeding is unclear. This study was undertaken to evaluate and correlate clinical bleeding and the commonly used laboratory tests for hemostasis in CLD patients including the subgroup of acute on chronic liver failure (ACLF) patients and test the reproducibility of international normalized ratio (INR) using different reagents. This was a cross sectional descriptive study wherein clinical records and laboratory data from 110 patients (95 CLD, 15 ACLF) over a 6-month period were analysed. Variceal bleeding (33.3%) was the commonest followed by mucosal/skin bleeds (5.4%). Thrombocytopenia seen in 70.9% patients was mostly mild (48.2%) to moderate (14.5%). Prothrombin time (PT) prolongation was seen in 81.8% with significant variation in PT/INR using different reagents. Adverse outcome in the form of disseminated intravascular coagulation, septic shock or death was seen in 13.6% patients (eight ACLF and seven CLD). There was no correlation of bleeding with prolonged PT/INR, decreased platelet count and adverse clinical outcome. However, individually, there was significant but weak correlation between variceal bleeding and lower platelet count and superficial bleeding and prolonged PT. Correction of PT/INR post-fresh frozen plasma was significant but platelet count postplatelet concentrate transfusion was not. ACLF patients compared with CLD patients had greater PT prolongation and adverse outcome but no increase in bleeding. Routine tests, although globally deranged inadequately reflect haemostatic imbalance in CLD and poorly predict bleeding risk. PMID- 23358201 TI - Dosing and monitoring of enoxaparin therapy in children: experience in a tertiary care hospital. AB - Pediatric deep vein thrombosis (DVT) is an emerging problem in tertiary care hospitals, recent reviews shows a rate of 40.2/10,000 admissions. Experts affirm that enoxaparin has become in the drug of choice for DVT therapy. Despite this, there is a little information regarding the optimal dose schedule for enoxaparin therapy in children and the therapeutic guidelines for enoxaparin use in children are extrapolated from adult guidelines. Monitoring by antifactor Xa (anti-Xa) measurement and target concentrations between 0.5-1 U/ml at 4-6 h postdose are recommended. This study was designed to analyse our experience in paediatric specific dosage requirements for enoxaparin therapy. A retrospective study was performed with patients less than 16 years old, who were treated with enoxaparin for DVT and monitored by anti-Xa concentration, between January 2005 and March 2012. Demographic and clinical characteristics and outcomes were obtained. Fourteen patients were analyzed: boy/girl ratio, 8/4; median age, 3.5 months. Cerebral venous sinus thrombosis was the most common indication for therapy. All patients presented thrombosis risks factors. Dose increases were necessary only in patients less than 6 years old. Target anti-Xa concentrations were achieved in 12 (85%) patients. Children younger than 1 year required a higher dose of enoxaparin/kg (1.5-2.7 mg/kg per 12 h). Complete resolutions of DVT were registered in all cases. The mean number of dose increases was three and a median of 11 days to achieve target anti-Xa concentration. This study indicates that an initial higher enoxaparin dose may be necessary in neonates and infants, but other factors must be considered to improve management. PMID- 23358202 TI - Double heterozygous mutations Gln100Leu and His348Gln of the F7 gene in a patient with factor VII deficiency. AB - A 25-year-old Chinese woman who had a history of easy bruising was admitted to hospital due to uncontrolled epistaxis. She showed factor VII activity level of 2% and factor VII antigen level of 4% of the normal value. We detected a novel missense mutation g.8355 A>T (p.Gln100Leu) in the second epidermal growth factor like (EGF) domain and a g.11482 T>G (p.His348Gln) in the catalytic domain. Although the Gln100 residue is close to the junction of EGF-2 domain with the serine protease domain, we infer that the substitution of polar negatively charged Gln residue at the position 100 with introduction of nonpolar Leu residue may be likely to perturb proper folding, resulting in decreasing factor VII activity. PMID- 23358203 TI - I smell a rat: a case report and literature review of paradoxical thrombosis and hemorrhage in a patient with brodifacoum toxicity. AB - Brodifacoum poisoning occurs as a result of ingestion of rodenticide compounds. It acts as a superwarfarin, inhibiting vitamin K epoxide reductase, in an irreversible fashion much like warfarin but with a much longer half-life. A 48 year-old female patient reported 4 days of mild dyspnea, dry cough, bilateral popliteal fossae pain and diffuse upper abdominal pain. She had no history of liver disease or alcohol or illicit substance abuse. Initial physical examination was remarkable only for mildly pale conjunctivae and mild abdominal tenderness and pain in the left popliteal fossa. A complete blood count and complete metabolic panel were normal. Prothrombin time (PT) was above 100 s, partial thromboplastin time (PTT) was above 200 s and international normalized ratio was reported as above 12.0. Urinalysis revealed hematuria. Venous Doppler ultrasound of lower extremities demonstrated left popliteal vein thrombosis. Computed tomography scan of the abdomen demonstrated transmural hematoma, and fecal occult blood test was positive. A full anticoagulant work-up showed critical reduction of vitamin K-dependent factors II, VII, IX and X. PT and PTT corrected with mixing studies proving factor deficiency as the cause of the coagulopathy. Lupus anticoagulant studies were negative. Superwarfarin toxicity was suspected and confirmed with an anticoagulant poison panel positive for brodifacoum. The patient was hospitalized and successfully treated with fresh frozen plasma, cryoprecipitate and vitamin K. In conclusion, paradoxical thrombosis and hemorrhage should raise the suspicion for superwarfarin toxicity in the appropriate clinical setting. Further studies are required to define the management of these patients. PMID- 23358204 TI - Successful hematopoietic engraftment with gray platelets after allogeneic hematopoietic stem cell transplantation from gray platelet syndrome donor. AB - Gray platelet syndrome (GPS) is a rare inherited disorder characterized by the absence of alpha-granules and their constituents. It may be present with thrombocytopenia and bleeding tendency. Platelets have a large and gray appearance under light and electron microscope. A 19-year old female patient with her second relapse acute lymphoblastic leukemia had to be consolidated with allo hematopoietic stem cell transplantation (HSCT) after achieving remission with induction chemotherapy. The only available and one mismatch compatible donor was her brother, who was previously diagnosed as GPS. Allogeneic HSCT was performed from her brother in spite of GPS, and successful neutrophil and platelet engraftment achieved at the 12th and 42nd day of reinfusion, consecutively. The engrafted and circulating thrombocytes were large and gray and had little or no alpha-granules under electron microscope. The patient was well with no major bleeding event and increased need for thrombocyte replacement until developing bronchiolitis obliterans organizing pneumonia and respiratory distress syndrome. Thereafter death occurred. This is the first case of successful thrombocyte engraftment with documented gray thrombocyte megakaryopoiesis after allogeneic HSCT from a GPS donor. The only noteworthy issue was the slight prolongation of engraftment. PMID- 23358205 TI - Polymyalgia rheumatica: a diagnostic challenge in the elderly with haemophilia and diffuse arthropathy. AB - With the increased life expectancy and associated comorbidities in haemophilic patients, greater awareness is needed to avoid being misled by symptoms mimicking haemophilia-related conditions. Here, we discuss the case of a 77-year-old man with congenital moderate haemophilia complicated by diffuse haemophilic arthropathy. He presented with persistent pain and stiffness affecting both shoulder and pelvic girdles, unresponsive to factor VIII (FVIII) infusions. A blood test confirmed the high clinical suspicion of polymyalgia rheumatica (PMR), justifying a course of low-dose methylprednisolone that led to significant clinical and biological improvement. This is the first reported case of congenital haemophilia and PMR. We here review some elements helpful to overcome this diagnostic challenge. Adequate diagnosis and management of PMR in elderly patients with haemophilia is particularly important not only to relieve pain but also to avoid inappropriate use of clotting factor concentrates. PMID- 23358206 TI - Recurrent ischemic cerebrovascular events in a patient with type I antithrombin deficiency caused by 9788 G>A splice site mutation: a case report. AB - Type I antithrombin deficiency is an autosomal dominant disorder associated with high risk for venous thromboembolism. Data on the association between antithrombin deficiency and arterial thromboembolism are inconsistent. We report here the case of AT deficiency in a 43-year-old man free of cardiovascular risk factors who experienced venous thromboembolism and ischemic stroke followed by two transient ischemic attacks after interruption of oral anticoagulation due to colonoscopy. DNA sequencing of the antithrombin gene revealed heterozygosity for the previously reported substitution G to A at nucleotide position 9788 in intervening sequence four. To our knowledge, this report is the first to show that this genetic abnormality can be associated with recurrent cerebrovascular ischemic events. PMID- 23358207 TI - Triterpenoid saponins of Pulsatilla koreana root have inhibition effects of tumor necrosis factor-alpha secretion in lipopolysaccharide-induced RAW264.7 cells. AB - In the present study, a new oleanane-type triterpenoid saponin, pulsatilloside F (1), along with 21 known compounds (2-22), were isolated from the root of Pulsatilla koreana. Their chemical structures were elucidated by mass, (1)H-, (13)C-NMR, correlation spectroscopy (COSY), heteronuclear multiple quantum coherence (HMQC) and heteronuclear multiple bond connectivity (HMBC) spectroscopy. Anti-inflammatory effects of the compounds were evaluated in terms of inhibitory of tumor necrosis factor alpha (TNF-alpha) secretion in the lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophage cell line. Compounds 19 and 20 exhibited particularly inhibitory effects with respective IC50 values of 0.32 and 0.65 um. Compounds 1-4, 7 and 10-13 exhibited inhibitory effects with inhibition rates up to 41.55-73.76% at a concentration of 5 um, respectively. PMID- 23358208 TI - Average volume of alcohol consumed, drinking patterns, and metabolic syndrome in older Korean adults. AB - BACKGROUND: Controversial results have been reported on the relationship between alcohol intake and metabolic syndrome (MetS). We examined the association of average volume of alcohol consumed and drinking patterns with MetS and its components. METHODS: This study was conducted as a baseline survey for the Dong gu Study of adults aged 50 years or older. Drinking patterns were assessed using a structured interview, and average volume of alcohol consumed was calculated. MetS was defined according to the updated version of the National Cholesterol Education Program. RESULTS: Compared with individuals who never drank, the adjusted odds ratio (OR) for the prevalence of MetS was significantly higher in men who consumed 2.1 to 4.0 drinks/day (OR, 1.53; 95% CI, 1.17-2.00) and greater than 4.0 drinks/day (OR, 1.63; 95% CI, 1.23-2.14), whereas no significant association was observed in women. Significant dose-response relationships between average volume of alcohol consumed and all metabolic components were observed in men. A usual quantity of 5 to 6 drinks/drinking day (OR, 1.57; 95% CI, 1.19-2.09), 7 or more drinks/drinking day (OR, 1.88; 95% CI, 1.45-2.44), and binge drinking on at least 1 occasion/week (OR, 1.33; 95% CI, 1.01-1.76) were associated with a significantly higher OR for prevalence of MetS in men; however, none of these drinking patterns were associated with MetS in women. CONCLUSIONS: Unhealthy drinking patterns such as high usual quantity and binge drinking were significantly associated with MetS, suggesting that the effect of alcohol consumption on MetS should be considered in the context of drinking pattern, particularly in men. PMID- 23358209 TI - Glaucoma subtypes in Ethiopian clinic patients. AB - BACKGROUND: Until population-based data become available in Ethiopia, hospital based studies may reflect the distribution of the subtypes of glaucoma in certain parts of the country. PURPOSE: The main aim of this study was to determine the subtypes of glaucoma in Jimma University Hospital, Ethiopia. METHODS: A facility based cross-sectional study was conducted in Jimma University Hospital from April 1, 2007 to March 30, 2008. The study population consisted of 335 consecutive new and follow-up patients with glaucoma diagnosed based on strict objective criteria. RESULTS: The mean (SD) age of the study patients was 57.0 (12.7) years (range, 8 to 90 y). The male to female ratio was 2.7:1. The 2 most common subtypes of glaucoma found were exfoliation glaucoma (35.2%) and primary open angle glaucoma (32.8%). Primary angle closure glaucoma was diagnosed in 18.5% of patients. CONCLUSIONS: The finding of exfoliation glaucoma as the most common subtype of glaucoma in the present clinic-based study is interesting. Such observation has never been reported from anywhere in Africa. We recommend community-based surveys to define the real distribution of the glaucoma subtypes in Ethiopia. PMID- 23358210 TI - Recommendations for adnexal cysts: have the Society of Radiologists in Ultrasound consensus conference guidelines affected utilization of ultrasound? AB - PURPOSE: In 2009, the Society of Radiologists in Ultrasound (SRU) convened a consensus conference to discuss the management of adnexal cysts in asymptomatic women and reach consensus on when follow-up imaging was required. The purpose of this quality assurance project was to assess the impact of using the resulting guidelines in our institution during 1-month periods before and after publication of the guidelines. METHODS: We retrospectively reviewed all pelvic ultrasound reports for a 1-month period before the conference (February 2009) and 2 years later (February 2011) after publication of the SRU guidelines. Incidence of recommendations for simple cysts and classic hemorrhagic cysts 5 cm or less in premenopausal women and simple cysts less than 1 cm in postmenopausal women was compared. Fisher exact test was used to compare proportions. RESULTS: Over the time period evaluated, the number of pelvic sonograms performed in our department decreased by 27%. The overall number of cysts with recommendations for follow-up decreased from February 2009 (132 studies with recommendations for follow-up in 870 pelvic ultrasound examinations, 15%) to February 2011 (71 recommendations for follow-up in 639 examinations, 11%; P = 0.02). The percentage of premenopausal simple cysts and classic hemorrhagic cysts described as less than 5 cm where follow-up was recommended decreased from 39/48 (89%) to 2/29 (7%, P < 0.0001). CONCLUSIONS: Use of the SRU guidelines on the management of adnexal cysts has, in our practice, dramatically decreased radiologist recommendations for follow-up of benign appearing cysts. PMID- 23358212 TI - ACR Appropriateness Criteria(r) clinically suspected adnexal mass. AB - Adnexal masses are a common problem clinically and imaging-wise, and transvaginal US (TVUS) is the first-line imaging modality for assessing them in the vast majority of patients. The findings of US, however, should be correlated with the history and laboratory tests, as well as any patient symptoms. Simple cysts are uniformly benign, and most warrant no further interrogation or treatment. Complex cysts carry more significant implications, and usually engender serial ultrasound(s), with a minority of cases warranting a pelvic MRI.Morphological analysis of adnexal masses with gray-scale US can help narrow the differential diagnosis. Spectral Doppler analysis has not proven useful in most well-performed studies. However, the use of color Doppler sonography adds significant contributions to differentiating between benign and malignant masses and is recommended in all cases of complex masses. Malignant masses generally demonstrate neovascularity, with abnormal branching vessel morphology. Optimal sonographic evaluation is achieved by using a combination of gray-scale morphologic assessment and color or power Doppler imaging to detect flow within any solid areas.The ACR Appropriateness Criteria(r) are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 23358213 TI - Pearls and pitfalls in sonographic imaging of symptomatic urolithiasis in pregnancy. AB - Symptomatic urolithiasis in the pregnant patient presents a diagnostic challenge to the clinician and radiologist. The presentation can mimic multiple other disease processes, including pathology unique to the gravid patient. The objective of this article was to describe challenges in sonographic imaging of urolithiasis in pregnant patients.Ultrasonography is the imaging modality of choice in pregnant patients with suspected urolithiasis. Signs of urinary collecting system obstruction that are usually reliable in nonpregnant patients may not be reliable in pregnant patients. Normal physiological changes of pregnancy can mimic ureteral obstruction on imaging. Utilization of endovaginal scanning techniques and intrarenal resistive index determination may help improve the diagnostic accuracy of ultrasound in symptomatic patients. PMID- 23358214 TI - Sonographic evaluation of cervical lymph nodes in papillary thyroid cancer. AB - Sonography is the modality of choice for imaging cervical lymph nodes in patients with papillary thyroid cancer, both before surgery and for postoperative surveillance. Sonography is also an invaluable tool to guide fine-needle aspiration of abnormal nodes. Microcalcifications, cystic changes, abnormal morphology, and disordered vascularity are features of metastatic nodal involvement with papillary thyroid carcinoma and should be sought during surveillance scans as well as in targeting for fine-needle aspiration. PMID- 23358215 TI - Complications following vascular procedures in the upper extremities: a sonographic pictorial review. AB - The arteries of the upper extremities are increasingly utilized to gain access for angiography, percutaneous coronary interventions, endovascular therapy, and continuous hemodynamic monitoring. Hence, complications after upper-extremity arterial interventions are increasing in incidence. Similarly, the incidence of upper-extremity deep venous thrombosis is increasing as venous access is increasingly achieved with upper-extremity central line placement. Knowledge of the sonographic appearance of these complications is essential as ultrasound is often the only imaging modality used in the evaluation of suspected vascular injury. This pictorial review demonstrates the spectrum of complications observed following vascular procedures in the upper extremities, including thrombosis, hematoma, pseudoaneurysm, arteriovenous fistula, and arterial dissection. Gray scale, color, and pulsed Doppler imaging findings are described, and pertinent management issues, including endovascular and surgical therapies, are briefly discussed. PMID- 23358216 TI - To your excellent career. AB - In this issue, we offer a draft community standard for a postdoctoral career workshop that can be used as a template and resource for career development at any institution. This document addresses the issue of what can be standardized to improve the lot of postdoctoral researchers, given that this is a professional group with diverse objectives that is motivated mainly by scientific curiosity. PMID- 23358217 TI - Nurture your scientific curiosity early in your research career. AB - Uncertainty makes scientific research challenging and at the same time exciting. Whereas curiosity and passion for uncovering the unknown drive future generations of researchers, the landscape of science has changed. We investigated whether the requirements for having a successful research career are changing, and whether junior researchers are aware of these requirements. Structured discussion with peers and more experienced researchers can point the way forward to an excellent career. PMID- 23358218 TI - Loss of function of the new interferon IFN-lambda4 may confer protection from hepatitis C. AB - Attempts to elucidate the mechanism underpinning the genetic association between IFNL3, previously called IL28B, and clearance of hepatitis C virus have, by and large, been unsuccessful. A study in this issue suggests that a new gene, IFNL4, may be responsible. PMID- 23358219 TI - The burden of faulty proofreading in colon cancer. AB - Our understanding of inherited risk factors for colorectal cancer (CRC) is incomplete. A new study reports the identification of germline CRC risk variants that adversely affect the proofreading function of DNA polymerases encoded by POLE and POLD1. PMID- 23358225 TI - Crocetin administration ameliorates endotoxin-induced disseminated intravascular coagulation in rabbits. AB - Disseminated intravascular coagulation (DIC), a life-threatening secondary complication in several diseases, is characterized by large amounts of thrombin that lead to fibrin deposition and microthrombus formation throughout the microcirculation. Recent in-vitro studies suggest that crocin, crocetin or safranal, carotenoid constituents of the spice Crocus sativus L. (saffron), have antithrombotic properties, especially anti-Xa activity. The present study was designed to evaluate the effect of crocetin on thrombosis procedure using a rabbit model of bacterial endotoxin-induced DIC. Crocetin administration (3 mg/kg), 30 min before the beginning of endotoxin infusion, improved DIC-related haemostatic indices such as platelet blood counts (P<= 0.05), blood plasma fibrinogen and protein C concentration (P<= 0.05). In addition, it ameliorated DIC-associated disease and fibrin deposition in the glomeruli (P<= 0.05). These results indicate that crocetin reveals a preventive antithrombotic role in vivo and prescribe further investigation on the possibility of developing crocetin based DIC treatment modalities. PMID- 23358226 TI - PLA2 polymorphism of platelet glycoprotein IIb/IIIa but not Factor V Leiden and prothrombin G20210A polymorphisms is associated with venous thromboembolism and more recurrent events in central Iran. AB - Inherited thrombophilic gene polymorphisms have been linked to the pathogenesis of venous thromboembolism (VTE). As there are very limited data of these polymorphisms in the Iranian population, we aimed to investigate the correlation between them and VTE in central Iran. Seventy-two unrelated VTE patients and 306 healthy control individuals were recruited for the study. Genotyping from venous blood with EDTA for the factor V Leiden (FVL), prothrombin (FII) G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T and PLA2 polymorphism of platelet glycoprotein IIb/IIIa were undertaken by PCR-restriction fragment length polymorphism (PCR-RFLP). A total of 57 investigated polymorphisms with a mean of 0.79 per individual and 151 with a mean of 0.49 were found in patients and controls, respectively (P<0.001). FVL and FII G20210A were found, respectively, in 5.6 and 1.4% of the patients compared with 2.3 and 1% of the controls (P=NS). PLA2 polymorphism of GPIIb/IIIa was seen in 27.8 and 10.1% in patients and controls, respectively [odds ratio (OR), 3.4; 95% confidence interval (CI), 1.08 6.44, P<0.001]. Approximately 15.3% of VTE patients compared with 5.9% of controls had coinheritance of more than one genetic risk factor (P=0.007) and more recurrent events occurred in such patients. Patients with PLA2 polymorphism had more recurrent events than the other patients (P=0.02). Patients with more than one genetic risk factor and recurrent events were younger. The prevalence of these polymorphisms is different from some previously published data in other populations, but is consistent with some others. Higher prevalence of PLA2 polymorphism of GPIIa/IIIb in VTE patients is indicative of the impact of this polymorphism in the pathogenesis of VTE in this population. Because of the impact of coinheritance on the recurrence and the age of occurrence, such patients may need to be managed differently. PMID- 23358227 TI - Urgent minimal invasive treatment of a dental trauma in a child with Wiskott Aldrich syndrome. AB - Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia with microplatelets, eczema, recurrent infections, and predisposition to autoimmune disease and malignancy. The aim of this study is to report an urgent minimal invasive treatment of a dental trauma in a pediatric patient with WAS. The conservative management was a success and did not cause any local nor systemic complications. PMID- 23358228 TI - A hybrid likelihood model for sequence-based disease association studies. AB - In the past few years, case-control studies of common diseases have shifted their focus from single genes to whole exomes. New sequencing technologies now routinely detect hundreds of thousands of sequence variants in a single study, many of which are rare or even novel. The limitation of classical single-marker association analysis for rare variants has been a challenge in such studies. A new generation of statistical methods for case-control association studies has been developed to meet this challenge. A common approach to association analysis of rare variants is the burden-style collapsing methods to combine rare variant data within individuals across or within genes. Here, we propose a new hybrid likelihood model that combines a burden test with a test of the position distribution of variants. In extensive simulations and on empirical data from the Dallas Heart Study, the new model demonstrates consistently good power, in particular when applied to a gene set (e.g., multiple candidate genes with shared biological function or pathway), when rare variants cluster in key functional regions of a gene, and when protective variants are present. When applied to data from an ongoing sequencing study of bipolar disorder (191 cases, 107 controls), the model identifies seven gene sets with nominal p-values < 0.05, of which one MAPK signaling pathway (KEGG) reaches trend-level significance after correcting for multiple testing. PMID- 23358229 TI - Non-apoptotic toxicity of Pseudomonas aeruginosa toward murine cells. AB - Although P. aeruginosa is especially dangerous in cystic fibrosis (CF), there is no consensus as to how it kills representative cell types that are of key importance in the lung. This study concerns the acute toxicity of the sequenced strain, PAO1, toward a murine macrophage cell line (RAW 264.7). Toxicity requires brief contact with the target cell, but is then delayed for more than 12 h. None of the classical toxic effectors of this organism is required and cell death occurs without phagocytosis or acute perturbation of the actin cytoskeleton. Apoptosis is not required for toxicity toward either RAW 264.7 cells or for alveolar macrophages. Transcriptional profiling shows that encounter between PAO1 and RAW 264.7 cells elicits an early inflammatory response, followed by growth arrest. As an independent strategy to understand the mechanism of toxicity, we selected variant RAW 264.7 cells that resist PAO1. Upon exposure to P. aeruginosa, they are hyper-responsive with regard to classical inflammatory cytokine production and show transient downregulation of transcripts that are required for cell growth. They do not show obvious morphologic changes. Although they do not increase interferon transcripts, when exposed to PAO1 they dramatically upregulate a subset of the responses that are characteristic of exposure to g-interferon, including several guanylate-binding proteins. The present observations provide a novel foundation for learning how to equip cells with resistance to a complex challenge. PMID- 23358230 TI - Impact of an electronic cigarette on smoking reduction and cessation in schizophrenic smokers: a prospective 12-month pilot study. AB - BACKGROUND: Cigarette smoking is a tough addiction to break. This dependence is the most common dual diagnosis for individuals with schizophrenia. Currently three effective drugs are approved for smoking cessation: nicotine replacement therapy (NRT), varenicline and bupropion. However, some serious side effects of varenicline have been reported, including depression, suicidal thoughts, and suicide. The use of bupropion also has side effects. It should not be used by people who have epilepsy or any condition that lowers the seizure threshold, nor by people who take a specific class of drugs called monoamine oxidase inhibitors. Hence, there are pharmacodynamic reason to believe they could precipitate or exacerbate psychosis. For its capacity to deliver nicotine and provide a coping mechanism for conditioned smoking cues by replacing some of the rituals associated with smoking gestures, electronic-cigarettes may reduce nicotine withdrawal symptoms without serious side effects. Our recent work with ECs in healthy smokers not intending to quit consistently show surprisingly high success rates. We hypothesised that these positive findings could be replicated in difficult patients with schizophrenia This tool may help smokers with schizophrenia remain abstinent during their quitting attempts or to reduce cigarette consumption. Efficacy and safety of these devices in long-term smoking cessation and/or smoking reduction studies have never been investigated for this special population. METHODS: In this study we monitored possible modifications in smoking habits of 14 smokers (not intending to quit) with schizophrenia experimenting with the "Categoria" e-Cigarette with a focus on smoking reduction and smoking abstinence. Study participants were invited to attend six study visits: at baseline, week-4, week-8, week-12 week-24 and week 52. Product use, number of cigarettes smoked, carbon monoxide in exhaled breath (eCO) and positive and negative symptoms of schizophrenia levels were measured at each visit. Smoking reduction and abstinence rates were calculated. Adverse events were also reviewed. RESULTS: Sustained 50% reduction in the number of cig/day at week-52 was shown in 7/14 (50%) participants; their median of 30 cig/day decreasing significantly to 15 cig/day (p = 0.018). Sustained smoking abstinence at week-52 was observed in 2/14 (14.3%) participants. Combined sustained 50% reduction and smoking abstinence was shown in 9/14 (64.3%) participants. Nausea was observed in 2/14 (14.4%) of participants, throat irritation in 2/14 (14.4%) of participants, headache in 2/14 (14.4%) of participants , and dry cough in 4/14 (28.6%) of participants. However, these adverse events diminished substantially by week-24. Overall, one to two cartridges/day were used throughout the study. Positive and negative symptoms of schizophrenia are not increased after smoking reduction/cessation in patients using e-cigarettes. CONCLUSIONS: We have shown for the first time that the use of e-cigarette substantially decreased cigarette consumption without causing significant side effects in chronic schizophrenic patients who smoke not intending to quit. This was achieved without negative impacts on the symptoms of schizophrenia as assessed by SAPS and SANS symptoms scales. PMID- 23358231 TI - Short-term effects of gaseous pollutants and particulate matter on daily hospital admissions for cardio-cerebrovascular disease in Lanzhou: evidence from a heavily polluted city in China. AB - Panel studies show a consistent association between increase in the cardiovascular hospitalizations with air pollutants in economically developed regions, but little evidence in less developed inland areas. In this study, a time-series analysis was used to examine the specific effects of major air pollutants [particulate matter less than 10 microns in diameter (PM(10)), sulfur dioxide (SO(2)), and nitrogen dioxides (NO(2))] on daily hospital admissions for cardio-cerebrovascular diseases in Lanzhou, a heavily polluted city in China. We examined the effects of air pollutants for stratified groups by age and gender, and conducted the modifying effect of seasons on air pollutants to test the possible interaction. The significant associations were found between PM(10), SO(2) and NO(2) and cardiac disease admissions, SO(2) and NO(2) were found to be associated with the cerebrovascular disease admissions. The elderly was associated more strongly with gaseous pollutants than younger. The modifying effect of seasons on air pollutants also existed. The significant effect of gaseous pollutants (SO(2) and NO(2)) was found on daily hospital admissions even after adjustment for other pollutants except for SO(2) on cardiac diseases. In a word, this study provides the evidence for the detrimental short-term health effects of urban gaseous pollutants on cardio-cerebrovascular diseases in Lanzhou. PMID- 23358232 TI - Identifying the relationships between water quality and land cover changes in the Tseng-Wen reservoir watershed of Taiwan. AB - The effects on water quality of land use and land cover changes, which are associated with human activities and natural factors, are poorly identified. Fine resolution satellite imagery provides opportunities for land cover monitoring and assessment. The multiple satellite images after typhoon events collected from 2001 to 2010 covering land areas and land cover conditions are evaluated by the Normalized Difference Vegetation Index (NDVI). The relationship between land cover and observed water quality, such as suspended solids (SS) and nitrate nitrogens (NO(3)-N), are explored in the study area. Results show that the long term variations in water quality are explained by NDVI data in the reservoir buffer zones. Suspended solid and nitrate concentrations are related to average NDVI values on multiple spatial scales. Annual NO(3)-N concentrations are positively correlated with an average NDVI with a 1 km reservoir buffer area, and the SS after typhoon events associated with landslides are negatively correlated with the average NDVI in the entire watershed. This study provides an approach for assessing the influences of land cover on variations in water quality. PMID- 23358233 TI - Urban public health: is there a pyramid? AB - Early ecologists identified a pyramidal trophic structure in terms of number, biomass and energy transfer. In 1943, the psychologist Maslow put forward a pyramid model to describe layers of human needs. It is indicated that the pyramid principle is universally applicable in natural, humanistic and social disciplines. Here, we report that a pyramid structure also exists in urban public health (UPH). Based on 18 indicators, the UPH states of four cities (Beijing, Tokyo, New York, and London) are compared from the point of view of five aspects, namely physical health, living conditions, social security, environmental quality, and education and culture. A pyramid structure was found in each city when focusing on 2000-2009 data. The pyramid of Beijing is relatively similar to that of Tokyo, and the pyramids of New York and London are similar to each other. A general development trend in UPH is proposed and represented by different pyramid modes. As a basic conjecture, the UPH pyramid model can be verified and developed with data of more cities over a longer period, and be used to promote healthy urban development. PMID- 23358235 TI - The influence of monitoring interval on data measurement: an analysis of step counts of university students. AB - The pedometer is a widely used research tool for measuring the level and extent of physical activity (PA) within population subgroups. The sample used in this study was drawn from a population of university students to examine the influence of the monitoring interval and alternate starting days on step-count activity patterns. The study was part of a national project during 2008-2010. Eligible subjects (641) were selected from a sample of 906 university students. The students wore pedometers continuously for 7 days excluding time for sleep and personal hygiene. Steps per day were logged on record sheets by each student. Data gathering spanned an entire week, and the results were sorted by alternate starting days, by activity for an entire week, by activity for only the weekdays of the one-week monitoring interval and for the two-day weekend. The statistical analysis included ANOVA, intra-class correlation (ICC) analysis, and regression analysis. The ICC analysis suggested that monitoring starting on Monday (ICC = 0.71; 95%CI (0.61-0.79)), Tuesday (ICC = 0.67; 95%CI (0.59-0.75)) or Thursday (ICC = 0.68; 95%CI (0.55-0.79)) improved reliability. The results of regression analysis also indicated that any starting day except Sunday is satisfactory as long as a minimum of four days of monitoring are used. PMID- 23358234 TI - Ecological niche modelling of bank voles in Western Europe. AB - The bank vole (Myodes glareolus) is the natural host of Puumala virus (PUUV) in vast areas of Europe. PUUV is one of the hantaviruses which are transmitted to humans by infected rodents. PUUV causes a general mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Vector-borne and zoonotic diseases generally display clear spatial patterns due to different space dependent factors. Land cover influences disease transmission by controlling both the spatial distribution of vectors or hosts, as well as by facilitating the human contact with them. In this study the use of ecological niche modelling (ENM) for predicting the geographical distribution of bank vole population on the basis of spatial climate information is tested. The Genetic Algorithm for Rule set Prediction (GARP) is used to model the ecological niche of bank voles in Western Europe. The meteorological data, land cover types and geo-referenced points representing the locations of the bank voles (latitude/longitude) in the study area are used as the primary model input value. The predictive accuracy of the bank vole ecologic niche model was significant (training accuracy of 86%). The output of the GARP models based on the 50% subsets of points used for testing the model showed an accuracy of 75%. Compared with random models, the probability of such high predictivity was low (chi(2) tests, p < 10(-6)). As such, the GARP models were predictive and the used ecologic niche model indeed indicates the ecologic requirements of bank voles. This approach successfully identified the areas of infection risk across the study area. The result suggests that the niche modelling approach can be implemented in a next step towards the development of new tools for monitoring the bank vole's population. PMID- 23358236 TI - Inhibition of P-glycoprotein mediated multidrug resistance by stemofoline derivatives. AB - Resistance to chemotherapy in cancer patients has been correlated to the overexpression of the ATP-binding cassette (ABC) drug transporters including P glycoprotein (P-gp) that actively efflux chemotherapeutic drugs from cancer cells. We examined the multidrug resistance reversing property of stemofoline derivatives in drug-resistance human cervical carcinoma (KB-V1) and human leukemic (K562/Adr) cell lines that overexpress P-gp. Didehydrostemofoline and eleven of its derivatives were synthesized and the cytotoxicity and their effect on doxorubicin, vinblastine and paclitaxel sensitivity in drug resistant (KB-V1 and K562/Adr) and drug sensitive (KB-3-1 and K562) cell lines by a 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were determined. We found that three out of the twelve stemofoline derivatives including OH-A1, NH-B6 and NH-D6 showed commitment efficiency to increase sensitivity to doxorubicin, vinblastine and paclitaxel in KB-V1 cells and increase sensitivity to doxorubicin, and paclitaxel in K562/Adr cells whereas the effects have not been seen in their parental sensitive cancer cell lines (KB-3-1 and K562). These results indicate that stemofoline derivatives reversed P-gp mediated multidrug resistance in vitro, and thus could be developed as effective chemosensitizers to treat multidrug-resistant cancers. The molecular mechanism of modulation of P-gp would be further determined. PMID- 23358237 TI - Expression of adiponectin receptor 1 is indicative of favorable prognosis in non small cell lung carcinoma. AB - Lung cancer is a major cause of cancer-related death worldwide. It is believed that obesity-related malignancies such as breast, endometrial, colorectal, and kidney carcinomas have lower plasma level and/or tissue expression of adiponectin receptors. However, the association between adiponectin receptors and lung cancer, a non obesity-related malignancy, is still unknown. We evaluated the tissue expression of adiponectin receptor (AdipoR) 1 and AdipoR2 in 83 cases of non-small cell lung carcinoma (NSCLC) and matched non-neoplastic lung tissues by immunohistochemistry and real-time polymerase chain reaction (PCR). Clinicopathological data, including smoking history, smoker's bronchiolitis, emphysema, lymph node metastasis, and T-stage were collected and evaluated. Expression of immunohistochemically stained AdipoR1 and AdipoR2 was observed in all samples of non-neoplastic lung tissues. Both receptors showed higher mRNA expression in non-neoplastic than neoplastic tissues (p < 0.05). In NSCLC tissues, AdipoR1 immunohistochemical expression was not observed in most of patients with squamous cell carcinoma and current smoking history (31/42, p = 0.04 and 25/29, p = 0.003, respectively). Additionally, AdipoR1 mRNA expression was significantly lower in patients with lymph node metastasis (p = 0.05). Meanwhile, AdipoR2 immunohistochemical stain expression was inversely correlated with T-stage (p = 0.05) and AdipoR2 mRNA expression was significantly lower in patients with smoker's bronchiolitis (p = 0.01) and emphysema (p = 0.03). Patients with expression of AdipoR1 had longer overall survival. AdipoR2 expression was not correlated with patients' survival. In conclusion, we suggest that expression of AdipoR1 is indicative of favorable prognosis and may be used as prognostic marker in NSCLC. PMID- 23358238 TI - Dissociation of the pharmacological effects of THC by mTOR blockade. AB - The potential therapeutic benefits of cannabinoid compounds have raised interest in understanding the molecular mechanisms that underlie cannabinoid-mediated effects. We previously showed that the acute amnesic-like effects of delta9 tetrahydrocannabinol (THC) were prevented by the subchronic inhibition of the mammalian target of rapamycin (mTOR) pathway. In the present study, we assess the relevance of the mTOR pathway in other acute and chronic pharmacological effects of THC. The rapamycin derivative temsirolimus, an inhibitor of the mTOR pathway approved by the Food and Drug Administration, prevents both the anxiogenic- and the amnesic-like effects produced by acute THC. In contrast, THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception are not sensitive to the mTOR inhibition. In addition, a clear tolerance to THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception was observed after chronic treatment, but not to its anxiogenic- and amnesic-like effects. Temsirolimus pre treatment prevented the amnesic-like effects of chronic THC without affecting the downregulation of CB1 receptors (CB1R) induced by this chronic treatment. Instead, temsirolimus blockade after chronic THC cessation did not prevent the residual cognitive deficit produced by chronic THC. Using conditional knockout mice lacking CB1R in GABAergic or glutamatergic neurons, we found that GABAergic CB1Rs are mainly downregulated under chronic THC treatment conditions, and CB1 GABA-KO mice did not develop cognitive deficits after chronic THC exposure. Therefore, mTOR inhibition by temsirolimus allows the segregation of the potentially beneficial effects of cannabinoid agonists, such as the anxiolytic and antinociceptive effects, from the negative effects, such as anxiogenic- and amnesic-like responses. Altogether, these results provide new insights for targeting the endocannabinoid system in order to prevent possible side effects. PMID- 23358239 TI - Reduced presynaptic dopamine activity in adolescent dorsal striatum. AB - Adolescence coincides with symptomatic onset of several psychiatric illnesses including schizophrenia and addiction. Excess limbic dopamine activity has been implicated in these vulnerabilities. We combined molecular and dynamic indices of dopamine neurotransmission to assess dopamine function in adolescent rats in two functionally distinct striatal subregions: nucleus accumbens (NAc) and dorsal striatum (DS). In adolescents, we find an overall reduction in dopamine availability selective to the DS. Dopamine release in the DS, but not in the NAc, was less responsive to amphetamine in adolescents compared to adults. The dopamine transporter (DAT) inhibitor, nomifensine, similarly inhibited basal and amphetamine-induced dopamine release in either regions of both the age groups, suggesting that the reduced effectiveness of amphetamine is not due to differences in DAT function. Furthermore, DAT and vesicular monoamine transporter 2 expressions were similar in the DS and NAc of adolescent rats. In contrast, expression of tyrosine hydroxylase (TH) was reduced in the DS, but not in the NAc, of adolescents compared to adults. Behaviorally, adolescents were less sensitive to amphetamine but more sensitive to a TH inhibitor. These data indicate that, in contrast to the general notion that dopamine is hyperactive in adolescents, there is diminished presynaptic dopamine activity in adolescents that is selective to the DS and may result from attenuated TH activity. Given recent reports of altered dopamine activity in associative/dorsal striatum of individuals at a clinically high risk of psychosis, our data further support the idea that dorsal, as opposed to ventral, regions of the striatum are a locus of vulnerability for psychosis. PMID- 23358241 TI - Treatment of deformational plagiocephaly and torticollis using a weight distribution ring: a report of three cases. AB - Plagiocephaly, from the Greek 'plagios' (slanting) and 'kephale' (head), refers to a condition of an infant's head deformation by forces acting upon a malleable cranium. Marked plagiocephaly causes distress and stigma towards the baby and their family and has knock-on effects with craniofacial abnormalities, visual field defects and delay in motor skills, and may also cause developmental difficulties. Current treatment methods have multiple drawbacks. This small, illustrated case series presents a novel, cost-effective, practical first-line treatment using a horseshoe-shaped gel head ring to redistribute pressure, allowing uniform growth and reshaping. Our early experience suggests that this method represents an effective treatment option with promising results so far. PMID- 23358240 TI - NPY Y1 receptors differentially modulate GABAA and NMDA receptors via divergent signal-transduction pathways to reduce excitability of amygdala neurons. AB - Neuropeptide Y (NPY) administration into the basolateral amygdala (BLA) decreases anxiety-like behavior, mediated in part through the Y1 receptor (Y1R) isoform. Activation of Y1Rs results in G-protein-mediated reduction of cAMP levels, which results in reduced excitability of amygdala projection neurons. Understanding the mechanisms linking decreased cAMP levels to reduced excitability in amygdala neurons is important for identifying novel anxiolytic targets. We studied the intracellular mechanisms of activation of Y1Rs on synaptic transmission in the BLA. Activating Y1Rs by [Leu(31),Pro(34)]-NPY (L-P NPY) reduced the amplitude of evoked NMDA-mediated excitatory postsynaptic currents (eEPSCs), without affecting AMPA-mediated eEPSCs, but conversely increased the amplitude of GABAA-mediated evoked inhibitory postsynaptic currents (eIPSCs). Both effects were abolished by the Y1R antagonist, PD160170. Intracellular GDP-beta-S, or pre-treatment with either forskolin or 8Br-cAMP, eliminated the effects of L-P NPY on both NMDA- and GABAA-mediated currents. Thus, both the NMDA and GABAA effects of Y1R activation in the BLA are G-protein-mediated and cAMP-dependent. Pipette inclusion of protein kinase A (PKA) catalytic subunit blocked the effect of L-P NPY on GABAA mediated eIPSCs, but not on NMDA-mediated eEPSCs. Conversely, activating the exchange protein activated by cAMP (Epac) with 8CPT-2Me-cAMP blocked the effect of L-P NPY on NMDA-mediated eEPSCs, but not on GABAA-mediated eIPSCs. Thus, NPY regulates amygdala excitability via two signal-transduction events, with reduced PKA activity enhancing GABAA-mediated eIPSCs and Epac deactivation reducing NMDA mediated eEPSCs. This multipathway regulation of NMDA- and GABAA-mediated currents may be important for NPY plasticity and stress resilience in the amygdala. PMID- 23358242 TI - Structural basis of tubulin tyrosination by tubulin tyrosine ligase. AB - Tubulin tyrosine ligase (TTL) catalyzes the post-translational retyrosination of detyrosinated alpha-tubulin. Despite the indispensable role of TTL in cell and organism development, its molecular mechanism of action is poorly understood. By solving crystal structures of TTL in complex with tubulin, we here demonstrate that TTL binds to the alpha and beta subunits of tubulin and recognizes the curved conformation of the dimer. Biochemical and cellular assays revealed that specific tubulin dimer recognition controls the activity of the enzyme, and as a consequence, neuronal development. The TTL-tubulin structure further illustrates how the enzyme binds the functionally crucial C-terminal tail sequence of alpha tubulin and how this interaction catalyzes the tyrosination reaction. It also reveals how TTL discriminates between alpha- and beta-tubulin, and between different post-translationally modified forms of alpha-tubulin. Together, our data suggest that TTL has specifically evolved to recognize and modify tubulin, thus highlighting a fundamental role of the evolutionary conserved tubulin tyrosination cycle in regulating the microtubule cytoskeleton. PMID- 23358243 TI - Immobile myosin-II plays a scaffolding role during cytokinesis in budding yeast. AB - Core components of cytokinesis are conserved from yeast to human, but how these components are assembled into a robust machine that drives cytokinesis remains poorly understood. In this paper, we show by fluorescence recovery after photobleaching analysis that Myo1, the sole myosin-II in budding yeast, was mobile at the division site before anaphase and became immobilized shortly before cytokinesis. This immobility was independent of actin filaments or the motor domain of Myo1 but required a small region in the Myo1 tail that is thought to be involved in higher-order assembly. As expected, proteins involved in actin ring assembly (tropomyosin and formin) and membrane trafficking (myosin-V and exocyst) were dynamic during cytokinesis. Strikingly, proteins involved in septum formation (the chitin synthase Chs2) and/or its coordination with the actomyosin ring (essential light chain, IQGAP, F-BAR, etc.) displayed Myo1-dependent immobility during cytokinesis, suggesting that Myo1 plays a scaffolding role in the assembly of a cytokinesis machine. PMID- 23358244 TI - Glucose and SIRT2 reciprocally mediate the regulation of keratin 8 by lysine acetylation. AB - Lysine acetylation is an important posttranslational modification that regulates microtubules and microfilaments, but its effects on intermediate filament proteins (IFs) are unknown. We investigated the regulation of keratin 8 (K8), a type II simple epithelial IF, by lysine acetylation. K8 was basally acetylated and the highly conserved Lys-207 was a major acetylation site. K8 acetylation regulated filament organization and decreased keratin solubility. Acetylation of K8 was rapidly responsive to changes in glucose levels and was up-regulated in response to nicotinamide adenine dinucleotide (NAD) depletion and in diabetic mouse and human livers. The NAD-dependent deacetylase sirtuin 2 (SIRT2) associated with and deacetylated K8. Pharmacologic or genetic inhibition of SIRT2 decreased K8 solubility and affected filament organization. Inhibition of K8 Lys 207 acetylation resulted in site-specific phosphorylation changes of K8. Therefore, K8 acetylation at Lys-207, a highly conserved residue among type II keratins and other IFs, is up-regulated upon hyperglycemia and down-regulated by SIRT2. Keratin acetylation provides a new mechanism to regulate keratin filaments, possibly via modulating keratin phosphorylation. PMID- 23358246 TI - Yeast alpha-glucosidase inhibitory phenolic compounds isolated from Gynura medica leaf. AB - Gynura medica leaf extract contains significant amounts of flavonols and phenolic acids and exhibits powerful hypoglycemic activity against diabetic rats in vivo. However, the hypoglycemic active constituents that exist in the plant have not been fully elaborated. The purpose of this study is to isolate and elaborate the hypoglycemic activity compounds against inhibition the yeast alpha-glucosidase in vitro. Seven phenolic compounds including five flavonols and two phenolic acids were isolated from the leaf of G. medica. Their structures were identified by the extensive NMR and mass spectral analyses as: kaempferol (1), quercetin (2), kaempferol-3-O-beta-D-glucopyranoside (3), kaempferol-3-O-rutinoside (4), rutin (5), chlorogenic acid (6) and 3,5-dicaffeoylquinic acid methyl ester (7). All of the compounds except 1 and 3 were isolated for the first time from G. medica. Compounds 1-7 were also assayed for their hypoglycemic activity against yeast alpha-glucosidase in vitro. All of the compounds except 1 and 6 showed good yeast alpha-glucosidase inhibitory activity with the IC(50) values of 1.67 mg/mL, 1.46 mg/mL, 0.38 mg/mL, 0.10 mg/mL and 0.53 mg/mL, respectively. PMID- 23358245 TI - Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development. AB - Rare variants in MDGAs (MAM domain-containing glycosylphosphatidylinositol anchors), including multiple protein-truncating deletions, are linked to autism and schizophrenia, but the function of these genes is poorly understood. Here, we show that MDGA1 and MDGA2 bound to neuroligin-2 inhibitory synapse-organizing protein, also implicated in neurodevelopmental disorders. MDGA1 inhibited the synapse-promoting activity of neuroligin-2, without altering neuroligin-2 surface trafficking, by inhibiting interaction of neuroligin-2 with neurexin. MDGA binding and suppression of synaptogenic activity was selective for neuroligin-2 and not neuroligin-1 excitatory synapse organizer. Overexpression of MDGA1 in cultured rat hippocampal neurons reduced inhibitory synapse density without altering excitatory synapse density. Furthermore, RNAi-mediated knockdown of MDGA1 selectively increased inhibitory but not excitatory synapse density. These results identify MDGA1 as one of few identified negative regulators of synapse development with a unique selectivity for inhibitory synapses. These results also place MDGAs in the neurexin-neuroligin synaptic pathway implicated in neurodevelopmental disorders and support the idea that an imbalance between inhibitory and excitatory synapses may contribute to these disorders. PMID- 23358247 TI - Neurodegeneration and neuroprotection in diabetic retinopathy. AB - Diabetic retinopathy is widely considered to be a neurovascular disease. This is in contrast to its previous identity as solely a vascular disease. Early in the disease progression of diabetes, the major cells in the neuronal component of the retina consist of retinal ganglion cells and glial cells, both of which have been found to be compromised. A number of retinal function tests also indicated a functional deficit in diabetic retina, which further supports dysfunction of neuronal cells. As an endocrinological disorder, diabetes alters metabolism both systemically and locally in several body organs, including the retina. A growing body of evidences indicates increased levels of excitotoxic metabolites, including glutamate, branched chain amino acids and homocysteine in cases of diabetic retinopathy. Also present, early in the disease, are decreased levels of folic acid and vitamin-B12, which are potential metabolites capable of damaging neurons. These altered levels of metabolites are found to activate several metabolic pathways, leading to increases in oxidative stress and decreases in the level of neurotrophic factors. As a consequence, they may damage retinal neurons in diabetic patients. In this review, we have discussed those potential excitotoxic metabolites and their implications in neuronal damage. Possible therapeutic targets to protect neurons are also discussed. However, further research is needed to understand the exact molecular mechanism of neurodegeneration so that effective neuroprotection strategies can be developed. By protecting retinal neurons early in diabetic retinopathy cases, damage of retinal vessels can be protected, thereby helping to ameliorate the progression of diabetic retinopathy, a leading cause of blindness worldwide. PMID- 23358248 TI - Out of the lab and into the bathroom: evening short-term exposure to conventional light suppresses melatonin and increases alertness perception. AB - Life in 24-h society relies on the use of artificial light at night that might disrupt synchronization of the endogenous circadian timing system to the solar day. This could have a negative impact on sleep-wake patterns and psychiatric symptoms. The aim of the study was to investigate the influence of evening light emitted by domestic and work place lamps in a naturalistic setting on melatonin levels and alertness in humans. Healthy subjects (6 male, 3 female, 22-33 years) were exposed to constant dim light (<10 lx) for six evenings from 7:00 p.m. to midnight. On evenings 2 through 6, 1 h before habitual bedtime, they were also exposed to light emitted by 5 different conventional lamps for 30 min. Exposure to yellow light did not alter the increase of melatonin in saliva compared to dim light baseline during (38 +/- 27 pg/mL vs. 39 +/- 23 pg/mL) and after light exposure (39 +/- 22 pg/mL vs. 44 +/- 26 pg/mL). In contrast, lighting conditions including blue components reduced melatonin increase significantly both during (office daylight white: 25 +/- 16 pg/mL, bathroom daylight white: 24 +/- 10 pg/mL, Planon warm white: 26 +/- 14 pg/mL, hall daylight white: 22 +/- 14 pg/mL) and after light exposure (office daylight white: 25 +/- 15 pg/mL, bathroom daylight white: 23 +/- 9 pg/mL, Planon warm white: 24 +/- 13 pg/mL, hall daylight white: 22 +/- 26 pg/mL). Subjective alertness was significantly increased after exposure to three of the lighting conditions which included blue spectral components in their spectra. Evening exposure to conventional lamps in an everyday setting influences melatonin excretion and alertness perception within 30 min. PMID- 23358249 TI - Partial peptide of alpha-synuclein modified with small-molecule inhibitors specifically inhibits amyloid fibrillation of alpha-synuclein. AB - We have previously reported that pyrroloquinoline quinone (PQQ) prevents the amyloid formation of alpha-synuclein, amyloid beta(1-42) (Abeta(1-42)), and mouse prion protein. Moreover, PQQ-modified alpha-synuclein and a proteolytic fragment of the PQQ-modified alpha-synuclein are able to inhibit the amyloid formation of alpha-synuclein. Here, we identified the peptide sequences that play an important role as PQQ-modified specific peptide inhibitors of alpha-synuclein. We demonstrate that the PQQ-modified alpha-Syn(36-46) peptide, which is a partial sequence of alpha-synuclein, prevented alpha-synuclein amyloid fibril formation but did not inhibit Abeta(1-42) fibril formation. In addition, the alpha synuclein partial peptide modified with other small-molecule inhibitors, Baicalein and epigallocatechin gallate (EGCG), prevented alpha-synuclein fibril formation. Currently reported quinone amyloid inhibitors do not have selectivity toward protein molecules. Therefore, our achievements provide a novel strategy for the development of targeted specific amyloid formation inhibitors: the combination of quinone compounds with specific peptide sequence from target proteins involved in amyloid formation. PMID- 23358250 TI - The Induction of Cytokine Release in Monocytes by Electronegative Low-Density Lipoprotein (LDL) Is Related to Its Higher Ceramide Content than Native LDL. AB - Electronegative low-density lipoprotein (LDL(-)) is a minor modified LDL subfraction that is present in blood. LDL(-) promotes inflammation and is associated with the development of atherosclerosis. We previously reported that the increase of cytokine release promoted by this lipoprotein subfraction in monocytes is counteracted by high-density lipoprotein (HDL). HDL also inhibits a phospholipase C-like activity (PLC-like) intrinsic to LDL(-). The aim of this work was to assess whether the inhibition of the PLC-like activity by HDL could decrease the content of ceramide (CER) and diacylglycerol (DAG) generated in LDL( ). This knowledge would allow us to establish a relationship between these compounds and the inflammatory activity of LDL(-). LDL(-) incubated at 37 degrees C for 20 h increased its PLC-like activity and, subsequently, the amount of CER and DAG. We found that incubating LDL(-) with HDL decreased both products in LDL(-). Native LDL was modified by lipolysis with PLC or by incubation with CER-enriched or DAG-enriched liposomes. The increase of CER in native LDL significantly increased cytokine release, whereas the enrichment in DAG did not show these inflammatory properties. These data point to CER, a resultant product of the PLC-like activity, as a major determinant of the inflammatory activity induced by LDL(-) in monocytes. PMID- 23358252 TI - The Transcriptome of Brassica napus L. Roots under Waterlogging at the Seedling Stage. AB - Although rapeseed (Brassica napus L.) is known to be affected by waterlogging, the genetic basis of waterlogging tolerance by rapeseed is largely unknown. In this study, the transcriptome under 0 h and 12 h of waterlogging was assayed in the roots of ZS9, a tolerant variety, using digital gene expression (DGE). A total of 4432 differentially expressed genes were identified, indicating that the response to waterlogging in rapeseed is complicated. The assignments of the annotated genes based on GO (Gene Ontology) revealed there were more genes induced under waterlogging in "oxidation reduction", "secondary metabolism", "transcription regulation", and "translation regulation"; suggesting these four pathways are enhanced under waterlogging. Analysis of the 200 most highly expressed genes illustrated that 144 under normal conditions were down-regulated by waterlogging, while up to 191 under waterlogging were those induced in response to stress. The expression of genes involved under waterlogging is mediated by multiple levels of transcriptional, post-transcriptional, translational and post-translational regulation, including phosphorylation and protein degradation; in particular, protein degradation might be involved in the negative regulation in response to this stress. Our results provide new insight into the response to waterlogging and will help to identify important candidate genes. PMID- 23358251 TI - Maintenance of genomic stability in mouse embryonic stem cells: relevance in aging and disease. AB - Recent studies have shown that mouse embryonic stem cells (mESCs) rely on a distinctive genome caretaking network. In this review, we will discuss how mESCs functionally respond to DNA damage and describe several modifications in mESC DNA damage response, which accommodate dynamic cycling and preservation of genetic information. Subsequently, we will discuss how the transition from mESCs to adult stem/progenitor cells can be involved in the decline of tissue integrity and function in the elderly. PMID- 23358254 TI - Effects of heme oxygenase-1 upregulation on blood pressure and cardiac function in an animal model of hypertensive myocardial infarction. AB - In this study, we evaluate the effect of HO-1 upregulation on blood pressure and cardiac function in the new model of infarct spontaneous hypertensive rats (ISHR). Male spontaneous hypertensive rats (SHR) at 13 weeks (n = 40) and age matched male Wistar (WT) rats (n = 20) were divided into six groups: WT (sham + normal saline (NS)), WT (sham + Co(III) Protoporphyrin IX Chloride (CoPP)), SHR (myocardial infarction (MI) + NS), SHR (MI + CoPP), SHR (MI + CoPP + Tin Mesoporphyrin IX Dichloride (SnMP)), SHR (sham + NS); CoPP 4.5 mg/kg, SnMP 15 mg/kg, for six weeks, one/week, i.p., n = 10/group. At the sixth week, echocardiography (UCG) and hemodynamics were performed. Then, blood samples and heart tissue were collected. Copp treatment in the SHR (MI + CoPP) group lowered blood pressure, decreased infarcted area, restored cardiac function (left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), +dp/dt(max), (-dp/dt(max))/left ventricular systolic pressure (LVSP)), inhibited cardiac hypertrophy and ventricular enlargement (downregulating left ventricular end-systolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD) and heart weight/body weight (HW/BW)), lowered serum CRP, IL-6 and Glu levels and increased serum TB, NO and PGI2 levels. Western blot and immunohistochemistry showed that HO-1 expression was elevated in the SHR (MI + CoPP) group, while co-administration with SnMP suppressed the benefit functions mentioned above. In conclusion, HO-1 upregulation can lower blood pressure and improve post-infarct cardiac function in the ISHR model. These functions may be involved in the inhibition of inflammation and the ventricular remodeling process and in the amelioration of glucose metabolism and endothelial dysfunction. PMID- 23358255 TI - Effect of human flavin-containing monooxygenase 3 polymorphism on the metabolism of aurora kinase inhibitors. AB - Aurora kinases were recently identified as a potential target in anticancer therapy and, amongst their available inhibitors, Tozasertib (VX-680) and Danusertib (PHA-739358) have been indicated as possible substrates of human flavin-containing monooxygenase 3 (hFMO3). Here we report the in vitro rate of oxidation of these drugs by wild-type hFMO3 and its polymorphic variant V257M. The conversion of Tozasertib and Danusertib to their corresponding metabolites, identified by LC-MS, by the purified wild-type and V257M hFMO3 show significant differences. In the case of Tozasertib, the V257M variant shows a catalytic efficiency, expressed as k(cat)/K(m), similar to the wild-type: 0.39 +/- 0.06 min 1uM-1 for V257M compared to 0.33 +/- 0.04 min-1uM-1 for the wild type. On the other hand, in the case of Danusertib, V257M shows a 3.4* decrease in catalytic efficiency with k(cat)/K(m) values of 0.05 +/- 0.01 min-1uM-1 for V257M and 0.17 +/- 0.03 min-1uM-1 for the wild type. These data reveal how a simple V257M substitution ascribed to a single nucleotide polymorphism affects the N-oxidation of relevant anticancer drugs, with important outcome in their therapeutic effects. These findings demonstrate that codon 257 is important for activity of the hFMO3 gene and the codon change V to M has an effect on the catalytic efficiency of this enzyme. PMID- 23358257 TI - Analysis of MTHFR and MTRR Gene Polymorphisms in Iranian Ventricular Septal Defect Subjects. AB - Ventricular septal defect (VSD) is one of the most common types of congenital heart defects (CHD). There are vivid multifactorial causes for VSD in which both genetic and environmental risk factors are consequential in the development of CHD. Methionine synthase reductase (MTRR) and methylenetetrahydrofolate reductase (MTHFR) are two of the key regulatory enzymes involved in the metabolic pathway of homocysteine. Genes involved in homocysteine/folate metabolism may play an important role in CHDs. In this study; we determined the association of A66G and C524T polymorphisms of the MTRR gene and C677T polymorphism of the MTHFR gene in Iranian VSD subjects. A total of 123 children with VSDs and 125 healthy children were included in this study. Genomic DNA was extracted from the buccal cells of all the subjects. The restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method was carried out to amplify the A66G and C524T polymorphism of MTRR and C677T polymorphism of MTHFR genes digested with Hinf1, Xho1 and Nde1 enzymes, respectively. The genotype frequencies of CC, CT and TT of MTRR gene among the studied cases were 43.1%, 40.7% and 16.3%, respectively, compared to 52.8%, 43.2% and 4.0%, respectively among the controls. For the MTRR A66G gene polymorphism, the genotypes frequencies of AA, AG and GG among the cases were 33.3%, 43.9% and 22.8%, respectively, while the frequencies were 49.6%, 42.4% and 8.0%, respectively, among control subjects. The frequencies for CC and CT genotypes of the MTHFR gene were 51.2% and 48.8%, respectively, in VSD patients compared to 56.8% and 43.2% respectively, in control subjects. Apart from MTHFR C677T polymorphism, significant differences were noticed (p < 0.05) in C524T and A66G polymorphisms of the MTRR gene between cases and control subjects. PMID- 23358253 TI - Annexin-phospholipid interactions. Functional implications. AB - Annexins constitute an evolutionary conserved multigene protein superfamily characterized by their ability to interact with biological membranes in a calcium dependent manner. They are expressed by all living organisms with the exception of certain unicellular organisms. The vertebrate annexin core is composed of four (eight in annexin A6) homologous domains of around 70 amino acids, with the overall shape of a slightly bent ring surrounding a central hydrophilic pore. Calcium- and phospholipid-binding sites are located on the convex side while the N-terminus links domains I and IV on the concave side. The N-terminus region shows great variability in length and amino acid sequence and it greatly influences protein stability and specific functions of annexins. These proteins interact mainly with acidic phospholipids, such as phosphatidylserine, but differences are found regarding their affinity for lipids and calcium requirements for the interaction. Annexins are involved in a wide range of intra- and extracellular biological processes in vitro, most of them directly related with the conserved ability to bind to phospholipid bilayers: membrane trafficking, membrane-cytoskeleton anchorage, ion channel activity and regulation, as well as antiinflammatory and anticoagulant activities. However, the in vivo physiological functions of annexins are just beginning to be established. PMID- 23358256 TI - Identification and Dynamic Regulation of microRNAs Involved in Salt Stress Responses in Functional Soybean Nodules by High-Throughput Sequencing. AB - Both symbiosis between legumes and rhizobia and nitrogen fixation in functional nodules are dramatically affected by salt stress. Better understanding of the molecular mechanisms that regulate the salt tolerance of functional nodules is essential for genetic improvement of nitrogen fixation efficiency. microRNAs (miRNAs) have been implicated in stress responses in many plants and in symbiotic nitrogen fixation (SNF) in soybean. However, the dynamic regulation of miRNAs in functioning nodules during salt stress response remains unknown. We performed deep sequencing of miRNAs to understand the miRNA expression profile in normal or salt stressed-soybean mature nodules. We identified 110 known miRNAs belonging to 61 miRNA families and 128 novel miRNAs belonging to 64 miRNA families. Among them, 104 miRNAs were dramatically differentially expressed (>2-fold or detected only in one library) during salt stress. qRT-PCR analysis of eight miRNAs confirmed that these miRNAs were dynamically regulated in response to salt stress in functional soybean nodules. These data significantly increase the number of miRNAs known to be expressed in soybean nodules, and revealed for the first time a dynamic regulation of miRNAs during salt stress in functional nodules. The findings suggest great potential for miRNAs in functional soybean nodules during salt stress. PMID- 23358258 TI - Synthesis and biological evaluation of xanthine derivatives on dipeptidyl peptidase 4. AB - A series of xanthine derivatives in which a methylene was inserted at position 8 of xanthine scaffold was synthesized and evaluated as inhibitors of dipeptidyl peptidase 4 (DPP-4) for the treatment of type 2 diabetes. As the results of structure-activity relationship (SAR) study of the series, the compounds with 4 methyl-quinazoline-2-yl-methyl group at N-1 position and 2-aminoethylaminomethyl group gave better activities. Compounds H4 and H9 showed good DPP-4 inhibition and more than 100-fold selectivity over DPP-7 and DPP-8. PMID- 23358259 TI - Strain difference of oxidative metabolism of the sedative-hypnotic zaleplon by aldehyde oxidase and cytochrome P450 in vivo and in vitro in rats. AB - The in vivo and in vitro metabolism of the sedative-hypnotic agent zaleplon (ZAL) to 5-hydroxylated ZAL (5-oxo-ZAL) and N-desethylated ZAL (desethyl-ZAL) was studied in four strains of rats. Incubation of ZAL with liver microsomes afforded desethyl-ZAL via cytochrome P450-catalyzed reaction, with little strain difference. In contrast, incubation of ZAL with liver cytosol afforded 5-oxo-ZAL with marked strain differences. ZAL hydroxylase activity was well correlated with aldehyde oxidase activity in these strains. The highest level of 5-oxo-ZAL and the highest activity of aldehyde oxidase were observed in cytosol from Sea:SD rats, followed by Jcl:SD rats, while Crj:SD and WKA/Sea rats showed low levels. When ZAL was administered to Sea:SD and WKA/Sea rats, both 5-oxo-ZAL and desethyl ZAL were detected in blood as the major in vivo metabolites. However, the concentration of 5-oxo-ZAL was far higher in Sea:SD rats than in WKA/Sea rats, while that of desethyl-ZAL was far lower in Sea:SD rats. The levels of 5-oxo-ZAL in blood were closely correlated with the strain differences of cytosolic ZAL hydroxylase activity and benzaldehyde oxidase activity. Our results indicate that variability in the formation of 5-oxo-ZAL from ZAL in vivo in various strains of rats is primarily due to strain differences of hepatic aldehyde oxidase activity. PMID- 23358260 TI - Association of ABCB1 polymorphisms with the antiemetic efficacy of granisetron plus dexamethasone in breast cancer patients. AB - Resistance to antiemetic treatment with 5-hydroxytryptamine 3 receptor antagonists is a problem, with 20-30% of patients showing unsatisfactory responses. Efflux transport by P-glycoprotein, encoded by the ATP-binding cassette ABCB1 gene in the blood-brain barrier, has been the suggested resistance mechanism. We evaluated the association between the antiemetic efficacy of granisetron plus dexamethasone and ABCB1 polymorphisms 3435C>T and 2677G>T/A. Sixty-four breast cancer patients treated with doxorubicin plus cyclophosphamide were evaluated for their responses to antiemetic therapy. Genotyping of patient DNA samples for ABCB1 single nucleotide polymorphisms was performed; the genotypes were then investigated for their association with the efficacy of prophylactic antiemetics. The acute phase complete response rate was 83% in GG subjects (n = 12), and 69% (n = 35) and 41% (n = 17) in heterozygous and homozygous carriers of the 2677T/A allele, respectively (p = 0.047). The ABCB1 2677 TT genotype group showed significantly lower rates of complete control of acute emesis than the group with GG genotypes (p = 0.045). No significant association with complete response was found for 3435C>T (p = 0.190). ABCB1 polymorphisms may influence the extent of acute emesis control in granisetron treated patients, making the ABCB1 genotype a predictor of prophylactic antiemetic response. PMID- 23358261 TI - Single nucleotide polymorphisms in SULT1A1 and SULT1A2 in a Korean population. AB - SULT1A1 and SULT1A2 are encoded on the same chromatid, and exhibit a 96% amino acid similarity. To screen for genetic variants in these two closely related genes, SULT1A1 and SULT1A2 were directly sequenced in 50 healthy Koreans. A total of 30 variations were identified in SULT1A1: eight in exons, thirteen in introns, and nine in the 5'-untranslated region. With regard to SULT1A2, 21 variants were identified, comprising seven in exons, five in introns, and nine in the 5' untranslated region. Among these 51 variations, one in SULT1A1 and eight in SULT1A2 were previously unidentified, which include three coding variants (SULT1A2 R37Q, 110G>A; SULT1A2 G50S, 148G>A; SULT1A2 F286L, 3819C>A) and one null allele (SULT1A2 E217Stop, 3542G>T). Two LD blocks, major haplotype structures, and 7 haplotype-tagging SNPs were determined together for SULT1A1 and SULT1A2 as a single set. Frequencies of common functional variants were compared among ethnic groups. Since these two SULT enzymes are on the same chromatid in a parallel direction with overlapping substrate specificities, a combined analysis using LD and haplotype-tagging single-nucleotide polymorphisms (SNPs) will facilitate understanding of the variations in the sulfation reactions of a wide range of substrates, as compared with analysis of individual genes. PMID- 23358262 TI - Three-dimensional quantitative structure-activity relationship analysis of inhibitors of human and rat cytochrome P4503A enzymes. AB - Cytochrome P450 3A4 (CYP3A4) is a member of the CYP family and is an important enzyme in drug metabolism. A compound that inhibits CYP3A4 activity could also affect the pharmacokinetics of other substrates, resulting in drug-drug interactions (DDIs) that could cause side effects. Pharmacokinetic data from drug development studies in rats often determine the dosage used in human clinical trials. It is therefore useful to understand differences in metabolism in different species at an early stage in drug development. Human and rat CYP3A enzymes show different inhibition profiles with different drugs, although the mechanisms involved are not yet clear. Here we built three-dimensional quantitative structure-activity relationship (3D-QSAR) models using structure based comparative molecular field analysis (CoMFA), to predict the direct inhibitory activity of ligands for human CYP3A4 and rat CYP3A1, based on computer ligand docking. The alignment of the ligand docking poses suggested that key amino acid-ligand interactions (e.g., Thr309 in CYP3A4 and Pro310 in CYP3A1) characterized the different potencies with which the ligands inhibited CYP3A4 and CYP3A1. The 3D-QSAR models for human and rat CYP3A family inhibitors predicted the potency of inhibitors and could be useful for assessing DDIs at an early stage in drug discovery. PMID- 23358263 TI - Development of a Data Collection Instrument for Violent Patient Encounters against Healthcare Workers. AB - INTRODUCTION: Healthcare and social workers have the highest incidence of workplace violence of any industry. Assaults toward healthcare workers account for nearly half of all nonfatal injuries from occupational violence. Our goal was to develop and evaluate an instrument for prospective collection of data relevant to emergency department (ED) violence against healthcare workers. METHODS: Participants at a high-volume tertiary care center were shown 11 vignettes portraying verbal and physical assaults and responded to a survey developed by the research team and piloted by ED personnel addressing the type and severity of violence portrayed. Demographic and employment groups were compared using the independent-samples Mann-Whitney U Test. RESULTS: There were 193 participants (91 male). We found few statistical differences when comparing occupational and gender groups. Males assigned higher severity scores to acts of verbal violence versus females (mean M,F=3.08, 2.70; p<0.001). While not achieving statistical significance, subgroup analysis revealed that attending physicians rated acts of verbal violence higher than resident physicians, and nurses assigned higher severity scores to acts of sexual, verbal, and physical violence versus their physician counterparts. CONCLUSION: This survey instrument is the first tool shown to be accurate and reliable in characterizing acts of violence in the ED across all demographic and employment groups using filmed vignettes of violent acts. Gender and occupation of ED workers does not appear to play a significant role in perception of severity workplace violence. PMID- 23358264 TI - Risk factors: Vitamin D level and surgical risk. PMID- 23358265 TI - Hypertension: Treprostinil therapy for PAH. PMID- 23358266 TI - Vascular disease: Repair of infrarenal aortic aneurysm--the debate is OVER. PMID- 23358268 TI - Blood on our hands: seeing the evil in inappropriate comparators. PMID- 23358269 TI - Cataract skills: how do we judge competency? PMID- 23358270 TI - Consultant activity and the 2003 contract. PMID- 23358271 TI - Trends in consultant clinical activity and the effect of the 2003 contract. PMID- 23358267 TI - Causes and prevention of sudden cardiac death in the elderly. AB - Sudden cardiac death (SCD) is a major cause of mortality in elderly individuals owing to a high prevalence of coronary heart disease, systolic dysfunction, and congestive heart failure (CHF). Although the incidence of SCD increases with age, the proportion of cardiac deaths that are sudden decreases owing to high numbers of other cardiac causes of death in elderly individuals. Implantable cardioverter defibrillator (ICD) therapy has been demonstrated to improve survival and prevent SCD in selected patients with systolic dysfunction and CHF. However, ICD therapy in elderly patients might not be effective because of a greater rate of pulseless electrical activity underlying SCD and other competing nonarrhythmic causes of death in this population. Although under-represented in randomized trials of ICD use, elderly patients comprise a substantial proportion of the population that qualifies for and receives an ICD for primary prevention under current guidelines. Cardiac resynchronization therapy (CRT), which has been demonstrated to reduce mortality in selected populations with heart failure, is also more commonly used in this group of patients than in younger individuals. In this Review, we examine the causes of SCD in elderly individuals, and discuss the existing evidence for effectiveness of ICD therapy and CRT in this growing population. PMID- 23358273 TI - Of snarks, boojums and national drug charts. PMID- 23358272 TI - Of snarks, boojums and national drug charts. PMID- 23358274 TI - Everything is possible: personal leadership experiences. PMID- 23358275 TI - Management of operable breast cancer in older women. AB - Older women are not being given the opportunity to benefit from the improvements in both local and systemic treatment for breast cancer. Mammographic screening call/recall system ceases at age 72, making access more difficult. Knowledge about breast cancer in those aged >75 is significantly reduced in terms of understanding symptoms and personal risk but studies have shown that intervention can improve this, at least in the short term. Although older women are more likely to have estrogen receptor positive tumours, nevertheless, more than one third of women aged over 70 have grade III, aggressive breast cancers. Whenever possible, older women should be offered breast conserving therapy rather than mastectomy since this not only improves their quality of life but also reduces risk of subsequent mental health problems. Endocrine treatment alone should not be used other than in patients with severe co-morbidity and a life-expectancy of less than a year. As adjuvant treatment in those with estrogen receptor positive cancers, the choice between tamoxifen and an aromatase inhibitor will depend upon co-morbidity, side-effects and patient choice. PMID- 23358276 TI - Enhancing the h index for the objective assessment of healthcare researcher performance and impact. AB - OBJECTIVE: To investigate whether the h index (a bibliometric tool which is increasingly used to assess and appraise an individual's research performance) could be improved to better measure the academic performance and citation profile for individual healthcare researchers. DESIGN: Cohort study. SETTING: Faculty of Medicine, Imperial College London, UK. PARTICIPANTS: Publication lists from 1 January 2000 until 31 December 2009 for 501 academic healthcare researchers from the Faculty of Medicine. MAIN OUTCOME MEASURES: The h index for each researcher was calculated over a nine-year period. The citation count for each researcher was differentiated into high (h(2) upper), core (h(2) centre) and low (h(2) lower) visibility areas. Segmented regression model (sRM) was used to statistically estimate number of high visibility publications (sRM value). Validity of the h index and other proposed adjuncts were analysed against academic rank and conventional bibliometric indicators. RESULTS: Construct validity was demonstrated for h index, h(2) upper, h(2) centre, h(2) lower and sRM value (all P < 0.05). Convergent validity of the h index and sRM value was shown by significant correlations with total number of publications (r = 0.89 and 0.86 respectively, P < 0.05) and total number of citations (r = 0.96 and 0.65, respectively, P < 0.05). Significant differences in h index and sRM value existed between non-physician and physician researchers (P < 0.05). CONCLUSIONS: This study supports the construct validity of the h index as a measure of healthcare researcher academic rank. It also identifies the assessment value of our developed indices of h(2) upper, h(2) centre, h(2) lower and sRM. These can be applied in combination with the h index to provide additional objective evidence to appraise the performance and impact of an academic healthcare researcher. PMID- 23358277 TI - Comparator bias: why comparisons must address genuine uncertainties. PMID- 23358287 TI - The healthy people initiative: understanding the user's perspective. AB - OBJECTIVE: After 30 years of implementation, this study provides the first assessment of how the nation's preeminent health promotion and disease prevention initiative, Healthy People, is utilized by key stakeholders in state, local, and tribal health organizations. METHODS: Surveys of state, local, and tribal health organizations were conducted in 2005 and 2009. Respondents completed a questionnaire about their organization's awareness and the use of Healthy People 2010. RESULTS: The awareness and use of Healthy People have grown over time. However, states are 32% more likely than local organizations and more than 200% more likely than tribal organizations to use Healthy People, demonstrating a continued need for targeted outreach directed toward local, tribal, and smaller health organizations. Different stakeholders appreciate different aspects of Healthy People. Barriers to increased use of Healthy People are primarily attributed to organizations, rather than the Healthy People initiative itself. Implementation planning for Healthy People 2020 is well aligned with users' recommendations. CONCLUSIONS: The Healthy People initiative is useful to different stakeholder groups in different ways. Encouraging and assisting users to adopt a broader set of its functionalities could increase the overall utility of the initiative. PMID- 23358288 TI - African American participation in health-related research studies: indicators for effective recruitment. AB - OBJECTIVE: To elucidate factors that influence African American willingness to participate in health-related research studies. METHODS: The African American Alzheimer disease research study group at North Carolina A&T State University designed an in-person questionnaire and surveyed more than 700 African American adults on their willingness to participate in health-related research studies. The questionnaire was distributed and collected in a nonclinical setting during the years 2008 and 2009. This study was approved by the North Carolina A&T State University Institutional Review Board. RESULTS: Of the 733 valid respondents, 16% had previously participated in a health-related research study. Of these, more than 90% were willing to participate again in future research studies. Of the 614 who had never participated in a research study, more than 70% expressed willingness to participate. The majority (75%) of experienced research study participants (RSP) were older than 40 years compared with 45% of non-research study participants. Experienced research participants were also twice as likely to have a college degree compared with non-research study participants. Seventy three percent of non-research study participants were willing to participate in research studies in the future. The factors that were probable impediments to participation included lack of time and trust. Men with knowledge of the Tuskegee Syphilis Study were 50% less likely to be willing to participate compared with those who had not heard of Tuskegee Syphilis Study. CONCLUSIONS: African Americans are willing to participate in health-related research studies. Several factors such as the appropriate incentives, community trust building, outreach, and community partnership creation are necessary for engaging minority participants. Incorporating factors that target African American enrollment in research design and implementation, such as increased training of minority health ambassadors and African American researchers and public health specialists, are needed to better engage minorities across generations, in research. PMID- 23358289 TI - Comparison of 3 school-based influenza surveillance indicators: lessons learned from 2009 pandemic influenza A (H1N1)--Denver Metropolitan Region, Colorado. AB - CONTEXT: Early in the 2009 pandemic influenza A (H1N1) experience, children aged 5 to 17 years were determined to be disproportionately affected compared with recent influenza seasons. OBJECTIVE: To characterize the pandemic among school aged children, to enable timely influenza outbreak identification, and to determine which school-based influenza surveillance indicator correlated most closely with a laboratory-based standard influenza indicator (standard) and, therefore, might be most useful for future school-based influenza surveillance. DESIGN: : During the 2009-2010 school year, we monitored students using 3 different surveillance indicators: (1) all-cause absenteeism, (2) influenza-like illness (ILI)-related absenteeism, (3) and ILI-related school health office visits. Thresholds were set for each indicator to identify individual school outbreaks. Each surveillance indicator was compared with the standard, confirmed influenza cases among hospitalized patients. SETTING: Tri-County (Denver metropolitan area), Colorado. PARTICIPANTS: Prekindergarten through 12th-grade students in public schools. MAIN OUTCOME MEASURES: Correlation coefficients comparing each influenza surveillance indicator with the standard and graphs comparing weekly rates for each influenza surveillance indicator or weekly outbreak counts with the standard. RESULTS: Correlation between the surveillance indicators and the standard varied greatly. All-cause absenteeism correlated most poorly with the standard (Pearson's r = 0.33) and ILI-related health office visits correlated moderately well (r = 0.63). Influenza-like illness-related absenteeism correlated best (r = 0.92) and could be improved (r = 0.97) by shifting ILI-absenteeism data later by 1 week. Graphs of weekly rates or weekly outbreak counts also illustrated that ILI-related absenteeism correlated best with the standard. CONCLUSIONS: For influenza surveillance among school-aged children, when feasible, we recommend using ILI-related absenteeism, which correlated best and its rate peaked more than 1 week sooner than the standard. The other 2 surveillance indicators might be useful in certain situations, such as when resources are limited. PMID- 23358290 TI - Using exercises to identify Veterans Health Administration priorities for disaster response: findings from the New Madrid Earthquake training exercise. AB - Emergency managers are often charged with prioritizing the relative importance of key issues and tasks associated with disaster response. However, little work has been done to identify specific ways that the decision-making process can be improved. This exercise was conducted with 220 employees of the US Department of Veterans Affairs, who were asked to assign priority rankings to a list of possible options of the most important issues to address after a hypothetical disaster scenario impacting a Veterans Affairs Medical Center. We found that groups that were assigned to represent perspectives farther from the impacted site had less agreement in their identification of the top priorities than those assigned to the impacted facility. These findings suggest that greater geographic and administrative proximity to the impacted site may generate greater clarity and certainty about priority setting. Given the complex structure of many organizations, and the multiple levels of group decision making and coordination likely to be needed during disasters, research to better understand training needs with respect to decision making is essential to improve preparedness. Relatively simple modifications to exercises, as outlined here, could provide valuable information to better understand emergency management decision making across multiple organizational levels. PMID- 23358291 TI - Long-term effects of health factor modification in Milwaukee County. AB - We use the UCLA Health Forecasting Tool to forecast the 2011-2050 health trends in Milwaukee County. We first simulate a baseline scenario (S-1) that assumes no health behavior change, and compare this with three simulated intervention scenarios: expansion of Quitline reach to enhance smoking cessation (S-2), an increased penetration of diabetes screening (S-3) and construction of additional recreational facilities (S-4). We compared the disease-free life years (DFLY) gained from each intervention scenario by 2050 on a year-by-year and cumulative basis. Simulation results show that increasing access to recreational facilities achieves the greatest gain in DFLYs for every year from 2011 to 2050. By 2050, the cumulative DFLY gain is 22 393, 5956 and 41 396 for S-2, S-3, and S-4, respectively. The cost-effectiveness ratios for Quitline expansion, diabetes screening, and recreational facility construction are $1802, $1285, and $1322, per DFLY gained, respectively. PMID- 23358292 TI - Kansas legislators prioritize obesity but overlook nutrition and physical activity issues. AB - INTRODUCTION: State-level policymakers play an important role in the fight against obesity because of their ability to create policies that influence opportunities for physical activity and nutrition. OBJECTIVE: In 2011, we investigated how Kansas policymakers regarded obesity, nutrition, and physical activity in comparison to other issues. DESIGN: This study used a cross-sectional design. SETTING: This study was conducted in Kansas, a predominately rural and Republican Midwestern state. PARTICIPANTS: All 181 state-level policymakers in Kansas were mailed a cover letter and survey. MAIN OUTCOME MEASURES: Policymakers were asked to identify and rate the importance of issues or problems in need of attention for Kansas. The 2011 state legislative report was content analyzed and coded to match the survey. Comparisons were made by political party. RESULTS: Of the 49 policymakers who completed a survey, 37 were Republicans and 43 were elected to their position. Although obesity-related issues were rated second highest after jobs, physical activity- and nutrition-related issues were not seen as important problems; moreover, little corresponding legislation was introduced. Other key issues identified by policymakers included budget/spending/taxes, education, jobs/economy, and drug abuse, with more legislation reflecting these problems. The Democrats ranked 11 issues as more significant problems than did the Republicans: quality of public education, poverty, access to health care, lack of affordable housing, ethics in government, lack of public health training, access to healthy groceries, lack of pedestrian walkways/crosswalks/sidewalks, pedestrian safety, air pollution, and global warming (P < .05). CONCLUSIONS: There is a need to provide more public health education on the relationship between nutrition and physical activity issues and obesity for Kansas policymakers. Issues identified may be similar for other predominately rural and Republican states. PMID- 23358293 TI - Local surveillance practice evaluation in North Carolina and value of new national accreditation measures. AB - CONTEXT: Delivery of essential public health services requires collection and analysis of public health surveillance data and delivery of these data to program managers, policy makers, and the community in accessible and useable formats. Much of this work is done by local health department (LHD) staff. We define local surveillance practice as comprising data collection, handling, and dissemination. Traditional surveillance evaluation does not generally assess local surveillance practice. However, new accreditation measures capture many aspects of local surveillance practice and may be useful for assessing this practice. OBJECTIVES: To examine the collection of surveillance data in LHDs and the communication of these data to program managers and policy makers, and to describe the extent to which national accreditation measures capture local surveillance practice. DESIGN: Cross-sectional survey sampling comprises 18% of North Carolina LHDs based on a stratified random sample. SETTING: Local health departments (LHDs) in North Carolina. PARTICIPANTS: Local health department directors and nursing directors or supervisors. MAIN OUTCOME MEASURES: Local health department surveillance practices and the congruence of accreditation measures for LHDs with these practices. RESULTS: The majority of LHDs used a broad range of data sources and types and delivered surveillance data to government and community recipients. Accreditation measures captured key facets of local surveillance practice. CONCLUSIONS: Surveillance and epidemiology are performed at the local level in ways that support essential public health services. Accreditation measures may be useful in evaluating local surveillance practice. PMID- 23358294 TI - Using more activities to address health disparities: local health departments and their "top executives". AB - OBJECTIVE: Local health departments (LHDs) are expected to address health disparities. Little is known, however, about what factors influence the activities used by an LHD in addressing health disparities. The objective of this study was to examine factors such as an LHD's leader, jurisdiction, and organizational characteristics that could be considered to influence the approaches used within LHDs to address health disparities. DESIGN: We used a cross-sectional, 2-level, mixed linear model with secondary LHD data nested within states. National data were used, depicting activities conducted by LHDs. STUDY POPULATION: The sample consisted of the 2332 LHDs that responded to the National Association of County and City Health Officials's 2008 National Profile of LHDs Survey. MEASURES: The activities used by LHDs in addressing health disparities were depicted as respondents indicating that they had employed 0 to 8 types of the activities listed in the Profile Survey in relation to addressing disparities. RESULTS: Local health departments significantly vary in the number of types of activities used in addressing health disparities. Significant associations exist between more types of health disparities activities used by LHDs and LHDs having a "top executive" with more education, clinical training, and/or less than 5 years of experience as the LHD's top executive. Local health departments with a jurisdiction that is urban, with a higher percentage of black residents, with a higher percentage of Hispanic residents, with higher per capita LHD expenditures, and/or that has conducted a community health assessment in last 3 years were also significantly associated with higher numbers of types of health disparities activities used. CONCLUSIONS: Local context and the characteristics of an LHD's top executive appear to be important factors related to the activities used to address health disparities across LHDs. A focus on the competencies and development of LHD leaders may be important in promoting LHD engagement in a wider range of approaches toward reducing disparities. PMID- 23358295 TI - Siglang Buhay: nutrition and physical activity promotion in Filipino-Americans through community organizations. AB - CONTEXT: Intervening in organizations allows for targeting multiple levels of influence and greater potential for sustainability. OBJECTIVE: To evaluate an 18 month nutrition and physical activity (NPA) intervention (Siglang Buhay) conducted through culturally specific organizations. DESIGN: Site randomized trial with an active control group. SETTING: Eighteen Filipino-American social clubs in San Diego County, California. PARTICIPANTS: Members of Filipino-American social clubs randomly assigned to NPA (n = 337) or cancer education (CE; n = 336) conditions. INTERVENTION: Two to 3 members from each organization were trained to implement the interventions. The NPA focused on promoting fruit and vegetable consumption and physical activity and on decreasing dietary fat intake using health education, behavior change skills development, and organizational policy change. Cancer education focused on cancer education and cancer screening. MAIN OUTCOME MEASURES: Outcomes measured at baseline and at 18 months included 7-day self-reported physical activity and consumption of fruits and vegetables and low fat foods, as well as stage of change for these 3 behaviors. RESULTS: Longitudinal mixed-effects regression models indicated that the NPA participants showed significant increases in physical activity (B = 4.04; P < .05), adoption of a low-fat diet (OR = 3.72; P < .05), and stage of change for fruit and vegetables (B = 0.61; P < .05), dietary fat intake (B = 0.67; P < .01), and physical activity (B = 0.80; P < .01). The intervention did not lead to increases in the number of participants eating 5 servings of fruits and vegetables per day or more (OR = 2.26; P = not significant). CONCLUSIONS: Using culturally specific organizations to deliver NPA interventions was feasible and effective among Filipino-Americans. Similar multilevel approaches should be investigated in other cultures. PMID- 23358296 TI - HIV status determination among tuberculosis patients from California during 2008. AB - CONTEXT: Human immunodeficiency virus (HIV) infection complicates care and contributes to poor outcomes among tuberculosis (TB) patients. The Centers for Disease Control and Prevention recommends that providers test all TB patients for HIV. OBJECTIVE: We assessed completeness of HIV status determination among TB patients and identified key gaps in adherence. DESIGN: We conducted a retrospective review of public health charts to determine the HIV status for all TB patients reported in California during 2008. We then used logistic regression to determine the factors associated with a known (positive or negative) HIV status. A random sample of TB patients was selected for secondary review to characterize the timing of HIV status determination and the providers who had opportunity to test for HIV. SETTING: California TB programs. PARTICIPANTS: All TB patients reported from California in 2008. MAIN OUTCOME MEASURES: Proportion of patients with a known HIV status, adjusted odds ratios for having a known HIV status, proportion of patients with a known HIV status before TB diagnosis, and proportion of patients diagnosed with TB by different provider types. RESULTS: Only 1752 (66%) of 2667 TB patients had a known HIV status. Having a known HIV status was strongly associated with those aged between 15 and 44 years and being managed with any public provider involvement. Of 292 patients in the random sample, 12 patients (4%) had a known HIV status before TB diagnosis. Among the remaining 280 patients, 187 patients (67%) were diagnosed with TB by a private provider. CONCLUSIONS: The HIV status determination of TB patients was selective and not routine as recommended. Private providers can play a key role in testing for HIV at TB diagnosis. California TB programs should ensure that all TB patients have an HIV status by promulgating national recommendations, educating private providers on the benefits of testing TB patients for HIV, and monitoring completeness of HIV status determination. PMID- 23358297 TI - Influenza vaccination and its association with clinic use of evidence-based practices and individual patient characteristics, San Diego County, 2009. AB - CONTEXT: In 2008, about 40% of the US population eligible for influenza vaccine was vaccinated, which was below Healthy People 2020 goals. Little emphasis has been put on late-season vaccination efforts by medical providers. OBJECTIVE: Evaluate use of evidence-based practices (EBP) and their association with influenza vaccination for children younger than 5 years and adults aged 50 years and older. DESIGN: Patient surveys and medical clinic information were collected between January and April 2009. Influenza coverage rates and logistic regressions are used to measure associations. SETTING: Nineteen medical clinics serving children, adults, or both in San Diego County participated. PARTICIPANTS: Parents of children aged 6 months to 5 years and adults aged 50 years and over seen by a primary care provider during January through March 2009. MAIN OUTCOME: Influence of clinic EBP use on child and adult influenza vaccination status. MEASURES: Patient-reported influenza vaccination and clinic coverage rates and clinics' use of EBP and patient demographic characteristics. RESULTS: Coverage rates varied by clinic; 50% to 82% (children) and 48% to 85% (adults). Child clinics using the immunization registry, or those that were private practices or medical groups and adult clinics that used influenza vaccination clinics, provider prompts, or electronic medical records had higher coverage. Surveys from 831 children and 1038 adults documented influenza vaccination rates of 64% and 63% respectively. Receiving a reminder or having two or more visits during influenza season was positively associated with child and adult influenza vaccination. Child vaccination was associated with children younger than 2 years. Adult vaccination was associated adults aged 65 years or older, having a high-risk condition, or being female. CONCLUSIONS: Given the low use of EBP, clinics have opportunities to implement EBP appropriate for their settings and patient populations. Along with other strategies, public health departments and medical groups should encourage medical providers to implement EBP to improve influenza vaccination rates. PMID- 23358298 TI - The first 6 months: transitioning into a new position. PMID- 23358299 TI - What health officials and triathletes have in common. PMID- 23358300 TI - Administration of emergency preparedness Department of Health And Human Service funds: the experience of state and local health departments. PMID- 23358301 TI - Policy activity and policy adoption in rural, suburban, and urban local health departments. AB - Public health policy is among the most effective and cost-effective interventions in some areas of public health and is emerging as effective in others. Policy may be especially important for rural communities, where residents face serious health and economic disparities and local health departments (LHDs) lack resources to provide necessary services. Data from the 2008 National Association of County and City Health Officials National Profile of Local Health Departments were used to examine policy activity (eg, policy development; communication with policymakers) and policy adoption in a sample of 454 LHDs. Results indicate policy activity was low in some policy areas for all LHDs and lowest in all policy areas for rural departments. Policy activities had significant positive relationships with policy adoption for land use (phi = 0.31; P < .05); tobacco prevention and control (phi = 0.37; P < .05); indoor air quality (phi = 0.28; P < .05); and nutrition and physical activity (phi = 0.21; P < .05). These relationships differed for rural, suburban, and urban LHDs. Significant positive correlations were also identified between overall levels of policy activity and any policy adoption (r = 0.16-0.27; P < .05). Local health departments should increase participation in policy activity to facilitate public health policy adoption nationwide. PMID- 23358302 TI - Electronic clinical laboratory reports as a source for ascertaining and confirming chromosomal anomalies reported to the New York State Congenital Malformations Registry. AB - CONTEXT: Hospitals and physicians are required to submit case reports with confirmatory diagnosis information to the New York State Congenital Malformations Registry (CMR) on children who are born or reside in New York State and are diagnosed with major birth defects. However, the majority of the cases with chromosomal anomalies indicated in the hospital discharge files are reported to the CMR without confirmatory testing data, which are usually not available at the time of reporting. OBJECTIVE: To link the cytogenetic test reports, submitted by cytogenetic testing laboratories via Electronic Clinical Laboratory Reporting System (ECLRS), to the CMR cases in order to obtain confirmatory diagnoses and identify unreported cases with chromosomal anomalies. DESIGN: : Cytogenetic testing data, submitted by the New York State licensed laboratories, that are stored on the ECLRS Sybase server were retrieved and matched to the CMR cases. The laboratory testing results were used to confirm diagnoses of the CMR cases for matched reports and to ascertain new birth defects cases by auditing hospitals and physicians using unmatched reports with abnormal testing results. RESULTS: By the end of 2010, a total of 927 reports on 747 children were submitted to the CMR by 14 cytogenetic testing laboratories via the New York State Department of Health ECLRS. Among the 747 children reported, 398 children (53%) had abnormal test results and 412 children (55%) were matched to the CMR cases. From these laboratory reports, 151 new cases with chromosomal anomalies were identified, confirmed, and were added to the CMR. The additional cases accounted for about 7.8% of all cases with chromosomal anomalies in the CMR for the reporting years 2008-2010. CONCLUSIONS: Cytogenetic laboratory reports can serve as an important source for ascertaining and confirming chromosomal anomalies. Acquiring molecular genetics testing data directly from cytogenetic testing laboratories via ECLRS enables CMR staff to confirm diagnoses and improve the accuracy and efficiency of case reporting. PMID- 23358303 TI - Developing a multilingual questionnaire and surname list to sample Utah Pacific Islanders. AB - CONTEXT: Analyses of Utah vital records indicated that Utah Pacific Islanders had unique health problems that merited further investigation through a behavioral survey. However, statewide surveys did not reach a large enough sample of Pacific Islanders and were not administered in Samoan or Tongan. OBJECTIVE: The authors sought to complete a surveillance study of Utah Pacific Islanders. DESIGN: The authors created a surname list on the basis of names of parents who identified themselves as Pacific Islanders on Utah birth certificates. A questionnaire was developed with input of local Pacific Islanders and administered in English, Samoan, and Tongan. SETTING: Utah. PARTICIPANTS: We interviewed 605 adult Utah Pacific Islanders. RESULTS: The Utah Pacific Islander Survey (UPIS) generated estimates of health status among Utah Pacific Islanders with smaller confidence intervals than those derived from the Utah Behavioral Risk Factor Surveillance System (BRFSS), even when combining 6 years of BRFSS data. Standard errors were less than half the value of the BRFSS estimates in all cases. The UPIS estimated higher rates than the BRFSS for Pacific Islander diabetes, obesity, and male arthritis. Respondents interviewed in Samoan or Tongan had higher rates of diabetes, obesity, and high blood pressure. CONCLUSIONS: The UPIS identified significant health disparities among the Utah Pacific Islander population that warrant public health intervention, such as high rates of obesity, diabetes, and high blood pressure and low rates of preventive screening. The UPIS estimates of Utah Pacific Islander health status are more precise than those acquired by the BRFSS, establishing strong baseline data that can be used to measure the success of interventions targeting these disparities. PMID- 23358304 TI - Implementing an SMS-based intervention for persons living with human immunodeficiency virus. AB - This article describes a process evaluation conducted as part of a proof-of concept study to develop, implement, and test a text messaging program to promote medication and appointment adherence, sexual and substance use risk reduction, general health and well-being, social support, and patient involvement. The text messaging program was implemented in Chicago, Illinois, at an outpatient medical clinic that promotes the well-being of gay, lesbian, bisexual, and transgender persons. We collected and analyzed qualitative data from patients, providers, and research staff to answer the following questions: (1) What factors of the organizational context were important for implementation? (2) How are implementation policies and practices, organizational climate, and perceptions of implementation effectiveness described by intervention stakeholders? (3) What types of issues related to fidelity occurred during implementation? (4) What recommendations for improvement do stakeholders suggest? The study coordinator, providers, and the patients themselves confirmed that patients liked the messages and program overall. The program was implemented with high fidelity. The primary recommendations for improvements were to enhance confidentiality and implement strategies to lessen message fatigue. The findings from this process evaluation demonstrate the feasibility and acceptability of the intervention from the perspectives of patients, providers, and research staff. A larger-scale intervention study that incorporates these stakeholders' suggestions for improvement is warranted. PMID- 23358307 TI - Synthesis, DNA binding and antitumor evaluation of styelsamine and cystodytin analogues. AB - A series of N-14 sidechain substituted analogues of styelsamine (pyrido[4,3,2 mn]acridine) and cystodytin (pyrido[4,3,2-mn]acridin-4-one) alkaloids have been prepared and evaluated for their DNA binding affinity and antiproliferative activity towards a panel of human tumor cell lines. Overall it was found that styelsamine analogues were stronger DNA binders, with the natural products styelsamines B and D having particularly high affinity (K(app) 5.33 * 10(6) and 3.64 * 10(6) M(-1), respectively). In comparison, the cystodytin iminoquinone alkaloids showed lower affinity for DNA, but were typically just as active as styelsamine analogues at inhibiting proliferation of tumor cells in vitro. Sub panel selectivity towards non-small cell lung, melanoma and renal cancer cell lines were observed for a number of the analogues. Correlation was observed between whole cell activity and clogP, with the most potent antiproliferative activity being observed for 3-phenylpropanamide analogues 37 and 41 (NCI panel average GI(50) 0.4 MUM and 0.32 MUM, respectively) with clogP ~4.0-4.5. PMID- 23358308 TI - Characterization and in vitro culture of putative spermatogonial stem cells derived from feline testicular tissue. AB - Spermatogonial stem cells (SSCs) function to regulate the balance of self-renewal and differentiation of male gametes. SSCs have been successfully isolated and cultured in vitro in several species, but not in feline. Therefore, in this study, we aimed to culture and characterize feline SSCs. In experiment 1, testes (n=5) from different pubertal domestic cats were cryosectioned and fluorescently immunolabeled to examine the expression of SSC (GFRalpha-1), differentiated spermatogonium (c-kit) and germ cell (DDX-4) markers. In experiments 2 and 3, testicular cells were digested and subsequently cultured in vitro. The resultant presumptive SSC colonies were then collected for SSC identification (experiment 2), or further cultured in vitro on feeder cells (experiment 3). Morphology, gene expression and immunofluorescence were used to identify the SSCs. Experiment 1 demonstrated that varying types of spermatogenic cells existed and expressed different germ cell/SSC markers. A rare population of putative SSCs located at the basement membrane of the seminiferous tubules was specifically identified by co-expression of GFRalpha-1 and DDX-4. Following enzymatic digestion, grape-like colonies formed by 13-15 days of culture. These colonies expressed GFRA1 and ZBTB16, but did not express KIT. Although we successfully isolated and cultured feline SSCs in vitro, the SSCs could only be maintained for 57 days. In conclusion, this study demonstrates, for the first time, that putative SSCs from testes of pubertal domestic cats can be isolated and cultured in vitro. These cells exhibited SSC morphology and expressed SSC-specific genes. However, long term culture of these putative SSCs was compromised. PMID- 23358309 TI - Luteoprotective mechanisms of prostaglandin F2alpha stimulated by luteinizing hormone in the bovine corpus luteum. AB - Luteinizing hormone (LH) regulates several ovarian functions. However, the luteoprotective mechanisms of LH involved in the maintenance of bovine corpus luteum (CL) function are not well understood. Since prostaglandin F2alpha (PGF), PGE2 and progesterone (P4) are well documented as antiapoptotic factors in the bovine CL, we hypothesized that LH protects the CL by stimulating the local production and action of PGF, PGE2 and P4. Cultured bovine luteal cells obtained at the mid-luteal stage (days 8-12 of the estrous cycle) were treated with LH (10 ng/ml), onapristone (OP: a specific P4 receptor antagonist, 100 MUM) and indomethacin [INDO; a cyclooxygenase (COX) inhibitor, 100 MUM] for 24 h. LH with and without OP significantly increased the mRNA and protein expressions of COX-2, PGF synthase and carbonyl reductase (P<0.05) but not the mRNA and protein expressions of COX-1 and PGE synthase in bovine luteal cells. In addition, these treatments significantly increased PGF and P4 production (P<0.05) but not PGE2 production. Luteal cell viability was significantly increased by LH alone (P<0.05), but LH-increased cell viability was reduced by LH in combination with INDO as well as OP (P<0.05). The overall results suggest that LH prevents luteal cell death by stimulating luteal PGF and P4 production and supports CL function during the luteal phase in cattle. PMID- 23358311 TI - Platinum redispersion on metal oxides in low temperature fuel cells. AB - We have analyzed the aptitude of several metal oxide supports (TiO(2), SnO(2), NbO(2), ZrO(2), SiO(2), Ta(2)O(5) and Nb(2)O(5)) to redisperse platinum under electrochemical conditions pertinent to the Proton Exchange Membrane Fuel Cell (PEMFC) cathode. The redispersion on oxide supports in air has been studied in detail; however, due to different operating conditions it is not straightforward to link the chemical and the electrochemical environment. The largest differences reflect in (1) the oxidation state of the surface (the oxygen species coverage), (2) temperature and (3) the possibility of platinum dissolution at high potentials and the interference of redispersion with normal working potential of the PEMFC cathode. We have calculated the PtO(x) (x = 0, 1, 2) adsorption energies on different metal oxides' surface terminations as well as inside the metal oxides' bulk, and we have concluded that NbO(2) might be a good support for platinum redispersion at PEMFC cathodes. PMID- 23358310 TI - In vitro culture of feline embryos increases stress-induced heat shock protein 70 and apoptotic related genes. AB - Developmental competence and quality of in vitro produced embryos has been demonstrated to be lower than in vivo derived embryos. This study aimed specifically to determine the effects of in vitro culture of feline embryos using various culture densities on developmental competence and expression of stress- and apoptotic-related genes in terms of heat shock protein 70 (HSP70) and apoptotic-related (BAX and BCL-2) gene expressions. In experiment 1, we characterized the inducible form of a feline-specific HSP70 mRNA sequence, as it has not been previously reported. The primers for feline HSP70 mRNA were synthesized and tested on heat-treated cat fibroblasts. In experiment 2, feline embryos were cultured at different culture densities (embryo:culture volume; 1:1.25, 1:5 and 1:20). The developmental competence was determined along with HSP70, BAX and BCL-2 transcript abundances using quantitative RT-PCR. In vivo derived embryos were used as a control group. A partial cat HSP70 mRNA sequence (190 bp) was characterized and exhibited high nucleotide identity (93 to 96%) with other species. Cleaved embryos cultured at high density (1:1.25) developed to blastocysts at a lower rate than those generated from lower densities. Irrespective of the culture densities used, in vitro cultured blastocysts showed increased levels of HSP70 and BAX transcripts compared with in vivo counterparts. Blastocysts derived from the highest culture density (1:1.25) showed higher levels of upregulation of HSP70 and BAX transcripts than those cultured at lower culture densities (1:5 and 1:20). In conclusion, increased levels of pro apoptotic (BAX) and stress-response (HSP70) transcripts correlated with developmental incompetence of embryos cultured at high embryonic density, indicating that stress accumulated during in vitro embryo culture affected the fate for embryo development and quality. PMID- 23358312 TI - [Study of the approximate calculation of the curve of organic vapor breakthrough from a small size column of activated carbon]. PMID- 23358317 TI - Imaging: Radioactive microspheres--see and destroy. PMID- 23358318 TI - 10-year changes in upper body strength and power in elite professional rugby league players--the effect of training age, stage, and content. AB - The purpose of this investigation was to observe changes in maximal upper body strength and power across a 10-year period in professional athletes who were experienced resistance trainers. Six professional rugby league players were observed with test data reported according to 2 important training stages in their professional careers. The first stage (1996-1998) monitored the changes as the subjects strived to establish themselves as elite professionals in their sport. The remaining test data are from the latter stage (2000-2006), which is characterized by a longer competition schedule and shorter periods devoted to improving physical preparation. The changes in upper body strength, assessed by the 1 repetition maximum bench press and mean maximum power during bench press throws with various barbell resistances of 40-80 kg, were assessed by effect size (ES) and smallest worthwhile change (SWC) statistics. Large increases in strength and power of approximately 22-23% were reported across the 10-year period, however, only small changes (as determined by ES) in strength or power occurred after year 2000 till 2006. This result of only small changes in strength or power despite 6 years of intense resistance training was attributed to 3 main factors. Key among them are the possible existence of a "strength ceiling" for experienced resistance trainers, the Long-term Athlete Development model, and possibly an inappropriate volume of strength-endurance training from 2004 to 2005. The fact that an SWC in strength and power occurred in the year after the cessation of strength-endurance training suggests that training program manipulation is still an influencing factor in continuing strength and power gains in experienced resistance trainers. PMID- 23358316 TI - Safety and feasibility of targeted agent combinations in solid tumours. AB - The plethora of novel molecular-targeted agents (MTAs) has provided an opportunity to selectively target pathways involved in carcinogenesis and tumour progression. Combination strategies of MTAs are being used to inhibit multiple aberrant pathways in the hope of optimizing antitumour efficacy and to prevent development of resistance. While the selection of specific agents in a given combination has been based on biological considerations (including the role of the putative targets in cancer) and the interactions of the agents used in combination, there has been little exploration of the possible enhanced toxicity of combinations resulting from alterations in multiple signalling pathways in normal cell biology. Owing to the complex networks and crosstalk that govern normal and tumour cell proliferation, inhibiting multiple pathways with MTA combinations can result in unpredictable disturbances in normal physiology. This Review focuses on the main toxicities and the lack of tolerability of some common MTA combinations, particularly where evidence of enhanced toxicity compared to either agent alone is documented or there is development of unexpected toxicity. Toxicities caused by MTA combinations highlight the need to introduce new preclinical testing paradigms early in the drug development process for the assessment of chronic toxicities resulting from such combinations. PMID- 23358319 TI - Changes in creatine kinase and cortisol in National Collegiate Athletic Association Division I American football players during a season. AB - The purpose of this study was to track creatine kinase (CK) and serum cortisol over an American college football season starting with the preseason practice. A secondary purpose was to observe changes in basic clinical chemistries. Twenty two National Collegiate Athletic Association Division I football players (age: 20.4 +/- 1.1 years, height: 188.27 +/- 8.3 cm, weight: 115.8 +/- 29.7 kg) volunteered to participate in this study. Each of the players had participated in the summer strength and conditioning supervised program. Resting blood samples were obtained just before the start of preseason practice (T-1), 2 weeks later (T 2), and the day after game 2 (T-3), game 4 (T-4), game 6 (T-5), and game 9 (T-6) of a 12-game season. Creatine kinase, a panel of clinical chemistries, cortisol, and testosterone were assayed at each time point. No significant changes in CK concentrations were observed over the season with peak values of each range <=1,070.0 IU.L(-1), but the largest range was observed at T-6 after game 9 (119 2,834 IU.L(-1). The analysis of covariance analysis demonstrated that the number of plays in the ninth game (T-6) explained the magnitude of the changes in CK. No changes in serum cortisol concentrations were observed yet, again large variations existed with peak values of each range <=465.0 nmol.L(-1). Clinical chemistries showed various significant changes from T-1, but none were considered clinically relevant changes for any player over the time course of the study. In conclusion, the strength and conditioning program before preseason camp or the structure of summer camp practices and the in-season strength and conditioning appeared to mute muscle damage and the stress response of cortisol. Such data demonstrate that changes in muscle damage and adrenal cortical stress over the season are minimal, yet large individual variations can be observed. Management of these variables appears to be related to optimal strength and conditioning and sports medicine programs. Thus, the greater concerns for student-athlete safety in the sport of American football are related to preventing sudden death, traumatic injury, and managing concussion syndromes. PMID- 23358320 TI - Microwave-assisted improved synthesis of pyrrolo[2,3,4-kl]acridine and dihydropyrrolo[2,3,4-kl]acridine derivatives catalyzed by silica sulfuric acid. AB - An improved synthesis of multifunctionalized pyrrolo[2,3,4-kl]acridine derivatives with different substituted patterns using silica sulfuric acid (SSA) as a heterogeneous catalyst under microwave irradiation conditions was developed. The reaction could be conducted by using readily available and inexpensive substrates within short periods of 12-15 min. under microwave irradiation. Compared with the conventional methods, the remarkable advantages of this method are milder reaction conditions, operational simplicity, higher yields, short reaction times, and an environmentally friendly procedure. PMID- 23358321 TI - Diastereoselective [2+2] photocycloaddition of chiral cyclic enones with olefins in aqueous media using surfactants. AB - We conducted diastereodifferentiating [2+2] photocycloadditions of cyclo hexenones modified with a chiral 8-(p-methoxy phenyl)menthyl auxiliary with olefins in water. Although the photoreaction didn't proceed at all in pure water owing to very low solubility, the use of surfactants [sodium dodecyl sulfate (SDS) or dodecylamine hydrochloride (DAH)] and additive (organic solvent) enabled the reactions to progress with moderate to high conversions and yields. Furthermore, we synthesized a new menthol derivative substrate containing a (p octyloxy)phenyl group for enhancing hydrophobicity, and elucidated that this new substrate was found to be a suitable chiral auxiliary in this asymmetric photoreaction in aqueous system. The additive effect of organic molecules on the yield and diastereoselectivity of the photo-adducts is also discussed. PMID- 23358322 TI - Use of pyrogallol red and pyranine as probes to evaluate antioxidant capacities towards hypochlorite. AB - Hypochlorite is a strong oxidant able to induce deleterious effects in biological systems. The goal of this work was to investigate the use of PGR and PYR as probes in assays aimed at evaluating antioxidant activities towards hypochorite and apply it to plant extracts employed in Chilean folk medicine. The consumption of PGR and PYR was evaluated from the decrease in the visible absorbance and fluorescence intensity, respectively. Total phenolic content was determined by the Folin Ciocalteau assay. PGR and PYR react with hypochlorite with different kinetics, being considerably faster the consumption of PGR. Different stoichiometric values were also determined: 0.7 molecules of PGR and 0.33 molecules of PYR were bleached per each molecule of added hypochlorite. Both probes were protected by antioxidants, but the rate of PGR bleaching was too fast to perform a kinetic analysis. For PYR, the protection took place without changes in its initial consumption rate, suggesting a competition between the dye and the antioxidant for hypochlorite. Plant extracts protected PYR giving a PYR-HOCl index that follows the order: Fuchsia magellanica ~ Marrubium vulgare ~ Tagetes minuta > Chenopodium ambrosoides ~ Satureja montana > Thymus praecox. Based on both the kinetic data and the protection afforded by pure antioxidants, we selected PYR as the best probe. The proposed methodology allows evaluating an antioxidant capacity index of plant extracts related to the reactivity of the samples towards hypochlorite. PMID- 23358323 TI - Graphite-supported perchloric acid (HClO4-C): an efficient and recyclable heterogeneous catalyst for the one-pot synthesis of amidoalkyl naphthols. AB - An efficient and direct protocol for the preparation of amidoalkylnaphthols employing a multi-component, one-pot condensation reaction of 2-naphthol, aromatic aldehydes and acetamide or benzamide in the presence of graphite supported perchloric acid under solvent-free conditions is described. The thermal solvent-free procedure offers advantages such as simple work-up, shorter reaction times and higher product yields, and the catalyst exhibited remarkable reactivity and can be recycled. PMID- 23358324 TI - Production of polygalacturonases by Aspergillus section Nigri strains in a fixed bed reactor. AB - Polygalacturonases (PG) are pectinolytic enzymes that have technological, functional and biological applications in food processing, fruit ripening and plant-fungus interactions, respectively. In the present, a microtitre plate methodology was used for rapid screening of 61 isolates of fungi from Aspergillus section Nigri to assess production of endo- and exo-PG. Studies of scale-up were carried out in a fixed bed reactor operated under different parameters using the best producer strain immobilised in orange peels. Four experiments were conducted under the following conditions: the immobilised cells without aeration; immobilised cells with aeration; immobilised cells with aeration and added pectin; and free cells with aeration. The fermentation was performed for 168 h with removal of sample every 24 h. Aspergillus niger strain URM 5162 showed the highest PG production. The results obtained indicated that the maximum endo- and exo-PG activities (1.18 U . mL-1 and 4.11 U . mL-1, respectively) were obtained when the reactor was operating without aeration. The microtitre plate method is a simple way to screen fungal isolates for PG activity detection. The fixed bed reactor with orange peel support and using A. niger URM 5162 is a promising process for PG production at the industrial level. PMID- 23358325 TI - The Passiflora tripartita (Banana Passion) fruit: a source of bioactive flavonoid C-glycosides isolated by HSCCC and characterized by HPLC-DAD-ESI/MS/MS. AB - The banana passion fruit (Passiflora tripartita Breiter, Passifloraceae) known as "tumbo" is very appreciated in tropical and subtropical countries of South America. Methanolic extracts from peel and the fruit juice of P. tripartita growing in Chile were analyzed for antioxidant capacity as well as for flavonoid and phenolic content. A chromatographic method was developed for the rapid identification of the main phenolics in the samples by HPLC-DAD and HPLC-MS. The fast fingerprint analysis allowed the detection of eighteen flavonoid C glycosides and four flavonoid O-glycoside derivatives which were characterized by UV spectra and ESI-MS-MS analysis. Several of the C-glycosides detected are structurally related to the orientin derivative 4'-methoxy-luteolin-8-C (6"acetyl)-b-D-glucopyranoside (31), fully elucidated by spectroscopic methods. The antioxidant derivative 31 along with schaftoside, vicenin II, orientin and vitexin were isolated from the fruit extract by high-speed countercurrent chromatography (HSCCC). A suitable method for the preparative isolation of flavonol C-glycosides from "tumbo" extracts by HSCCC is reported. The pulp of the fruits showed good antioxidant capacity (12.89 +/- 0.02 mg/mL in the DPPH assay). The peel presented the highest content of flavonoids (56.03 +/- 4.34 mg quercetin/100 g dry weight) which is related to the highest antioxidant power (10.41 +/- 0.01 mg/mL in the DPPH assay). PMID- 23358327 TI - Chemical genetics of acetyl-CoA carboxylases. AB - Chemical genetic studies on acetyl-CoA carboxylases (ACCs), rate-limiting enzymes in long chain fatty acid biosynthesis, have greatly advanced the understanding of their biochemistry and molecular biology and promoted the use of ACCs as targets for herbicides in agriculture and for development of drugs for diabetes, obesity and cancers. In mammals, ACCs have both biotin carboxylase (BC) and carboxyltransferase (CT) activity, catalyzing carboxylation of acetyl-CoA to malonyl-CoA. Several classes of small chemicals modulate ACC activity, including cellular metabolites, natural compounds, and chemically synthesized products. This article reviews chemical genetic studies of ACCs and the use of ACCs for targeted therapy of cancers. PMID- 23358326 TI - The synthesis and evaluation of novel hydroxyl substituted chalcone analogs with in vitro anti-free radicals pharmacological activity and in vivo anti-oxidation activity in a free radical-injury Alzheimer's model. AB - Alzheimer's disease (AD) pathogenesis involves an imbalance between free radical formation and destruction. In order to obtain a novel preclinical anti-AD drug candidate, we synthesized a series of novel hydroxyl chalcone analogs which possessed anti-free radical activity, and screened their effects on scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) and OH free radicals in vitro. Compound C7, 4,2'-dihydroxy-3,5-dimethoxychalcone was found to have potent activity in these anti-free radical activity tests. Further research revealed that C7 could elevate glutathione peroxidase (GSH-PX) and super oxide dismutase (SOD) levels and lower malonaldehyde (MDA) level in vivo in the Alzheimer's model. The indication of C7's effect on AD needs further study. PMID- 23358329 TI - Effects of moxifloxacin on serum glucose concentrations in rats. AB - Moxifloxacin, a fluoroquinolone antimicrobial agent, has been reported to cause serum glucose abnormalities such as hyper- and hypoglycemia. The purpose of the present study was to investigate the effect of moxifloxacin on serum glucose concentrations in rats. Rats were intravenously injected with moxifloxacin and samples of their arterial blood were collected periodically. Serum glucose concentrations increased with moxifloxacin at 100 mg/kg, and temporal elevations were observed in serum epinephrine and histamine concentrations. On the other hand, intravenous injection of moxifloxacin at 75 mg/kg did not affect serum glucose, epinephrine, or histamine concentrations. Serum immunoreactive insulin concentrations remained unchanged by moxifloxacin both at 75 and 100 mg/kg. In conclusion, moxifloxacin can induce histamine release, leading to an increase in serum epinephrine concentrations and hyperglycemia. PMID- 23358330 TI - Reversal effect of arsenic sensitivity in human leukemia cell line K562 and K562/ADM using realgar transforming solution. AB - The success of arsenic trioxide (ATO) in treatment of acute promyelocytic leukemia (APL) attracts a great deal of attention to researchers to explore its activity of anti-leukemia. However, ATO has unavailable effect on chronic myeloid leukemia (CML), especially multidrug resistant (MDR)-CML, unless using high concentration. Realgar (As(4)S(4)) has been employed in Chinese traditional medicine for 1500 years. Research evidences confirmed realgar has similar effect on treating with APL as ATO, but the problem of large dose and long period in the CML/MDR-CML treatment still exist. By using a microbial leaching process with Acidithiobacillus ferrooxidans, we obtained realgar transforming solution (RTS) which showed significantly higher extent in inhibiting CML cell line K562 and MDR CML cell line K562/ADM, and then trigger apoptosis. Both K562 and K562/ADM showed arsenic-dose-dependent effect on RTS. Interestingly, the overexpression of MDR1 mRNA and P-glucoprotein (P-gp) in K562/ADM cells were down-regulated by RTS, where there are no obvious effects on ATO and realgar and arsenic can be subsequently accumulated in K562/ADM cells efficiently. The intracellular accumulation of arsenic in K562/ADM cells treated with RTS for 4 h was 2-fold and 16-folds higher than those treated with realgar or ATO. Meanwhile, Western blot analysis of AQP9, the main transporter of arsenic, was increased by RTS treatment particularly in K562/ADM. Thus, these results suggested that the effect from a certain arsenical or a variety of arsenicals in RTS might be a promising candidate both for treating CML/MDR-CML alone and as combinations with currently used anti-CML/MDR-CML drug, although arsenical forms in RTS are undefined. PMID- 23358328 TI - Point mutations in FimH adhesin of Crohn's disease-associated adherent-invasive Escherichia coli enhance intestinal inflammatory response. AB - Adherent-invasive Escherichia coli (AIEC) are abnormally predominant on Crohn's disease (CD) ileal mucosa. AIEC reference strain LF82 adheres to ileal enterocytes via the common type 1 pili adhesin FimH and recognizes CEACAM6 receptors abnormally expressed on CD ileal epithelial cells. The fimH genes of 45 AIEC and 47 non-AIEC strains were sequenced. The phylogenetic tree based on fimH DNA sequences indicated that AIEC strains predominantly express FimH with amino acid mutations of a recent evolutionary origin - a typical signature of pathoadaptive changes of bacterial pathogens. Point mutations in FimH, some of a unique AIEC-associated nature, confer AIEC bacteria a significantly higher ability to adhere to CEACAM-expressing T84 intestinal epithelial cells. Moreover, in the LF82 strain, the replacement of fimH(LF82) (expressing FimH with an AIEC associated mutation) with fimH(K12) (expressing FimH of commensal E. coli K12) decreased the ability of bacteria to persist and to induce severe colitis and gut inflammation in infected CEABAC10 transgenic mice expressing human CEACAM receptors. Our results highlight a mechanism of AIEC virulence evolution that involves selection of amino acid mutations in the common bacterial traits, such as FimH protein, and leads to the development of chronic inflammatory bowel disease (IBD) in a genetically susceptible host. The analysis of fimH SNPs may be a useful method to predict the potential virulence of E. coli isolated from IBD patients for diagnostic or epidemiological studies and to identify new strategies for therapeutic intervention to block the interaction between AIEC and gut mucosa in the early stages of IBD. PMID- 23358332 TI - [Lesson from great East Japan earthquake and Tsunami: what can we do?]. PMID- 23358331 TI - Capturing the elusive aromaticity of bicalicene. AB - The ring-current aromaticity of the bicalicene molecule arises, in spite of the 16 pi carbon perimeter, from strong local diatropic circulations on the two pentagonal rings, as shown by current-density maps computed at the ipsocentric RHF/6-311G** and DFT/6-311G** levels of theory. Conjugated-circuit models cannot capture this pattern of circulation as it arises from 'ionic' contributions in a valence-bond picture. Canonical molecular-orbital analysis reveals a cancellation of paratropic and diatropic frontier-orbital contributions, which explains the difficulties that Huckel-based models have in producing qualitatively correct current-density maps for this molecule. Other measures of aromaticity reflect, to different extents, the dominance of the 'tetraionic' contribution to the aromaticity of this species. PMID- 23358333 TI - [Electronic portal image device dosimetry for volumetric modulated arc therapy]. AB - Recently electronic portal image devices (EPIDs) have been widely used for quality assurance and dose verification. However there are no reports describing EPID dosimetry for Elekta volumetric modulated arc therapy (VMAT). We have investigated EPID dosimetry during VMAT delivery using a commercial software EPIDose with an Elekta Synergy linac. Dose rate dependence and the linac system sag during gantry rotation were measured. Gamma indices were calculated between measured doses using an EPID and calculation made by a treatment planning system for prostate VMAT test plans. The results were also compared to gamma indices using films and a two-dimensional detector array, MapCHECK2. The pass rates of the gamma analysis with a criterion of 3% and 2 mm for the three methods were over 96% with good consistency. Our results have showed that EPID dosimetry is feasible for Elekta VMAT. PMID- 23358334 TI - [Evaluation and examination of accuracy for the conversion factors of effective dose per dose-length product]. AB - The purpose of this paper is to reappraise the accuracy of a conversion coefficient (k) reported by International Commission on Radiological Protection Publication 102 Table A.2. The effective doses of the routine head computed tomography (CT), the routine chest CT, the perfusion CT, and the coronary CT were evaluated using the conversion coefficient (adult head: 0.021 mSv.mGy-1.cm-1, adult chest: 0.014 mSv.mGy-1.cm-1). The dose length product (DLP) used the value displayed on the console on each scanning condition. The effective doses were evaluated using a human body type phantom (Alderson Rando phantom) and thermoluminescent dosimeter (TLD) elements for comparison with the converted value. This paper reported that the effective doses evaluated from conversion coefficient became different by 0.3 mSv (17%) compared with measurements, the effective dose computed with the conversion coefficient of the adult chest may be underestimated by 45%, and the bolus-tracking which scans the narrow beams should not use a conversion coefficient. PMID- 23358335 TI - [Evaluation of over ranging in 64-slice multidetector-row computed tomography examinations for upper abdomen]. AB - 64-slice multidetector-row computed tomography (MDCT) have become widely used in recent years, but there is a possibility that a large volume of dose is radiated at the outside of the scope of scanning due to the effect of over ranging (OR). In this research, the dose volume change at the outside of the scope of scanning in the case of X-ray beam width (BW) and pitch factor (PF) is measured, and the effect of BW and PF on OR is considered. We scanned the upper abdomen of an acrylic human phantom using 64-slice multidetector-row CT in 4 conditions while changing BW and PF. We then measured the dose volume absorbed in the breasts, ovary, uterus, and the dose profile on the surface of phantom. As a result, when BW and PF are increased, the dose volume radiated at the outside of the scope of scanning increased, and the effect of OR appeared. Therefore, when BW and PF are set, X-ray radiated at the outside of the scope of scanning should also be considered. PMID- 23358336 TI - [A continuous 4-year evaluation of medical informatics education in a graduate school of health sciences using a questionnaire survey]. AB - The purpose of this study was to identify the level of awareness among undergraduate students regarding medical informatics and to ascertain whether educational training has progressed with time in the Department of Health Sciences at Hirosaki University, Japan, which is a co-medical staff training institution that conducts a 4-year university course in medical informatics. The university accepts students who have completed the 3rd grade of medical licensing tests and who have attended the medical informatics lectures for 4 years (2007 2010). The ratio of first sight terminology percentage in any given fiscal year in all the 30 terminology categories varied widely from 0% to 80%, but the trend in various categories did not vary between fiscal years. The terminology of informatics under medical technology students obtained high scores of 52.5-77.3% after attending courses, which was higher compared with students from other classes. On the other hand, student nurses and occupational therapy students obtained 0-44.2%. Each class scored a high percentage of correct answers in the medical information-related terminology. Among the radiology students who attended the classes, the percentage of correct answers in categories of "digital imaging and communication in medicine" and "picture archiving and communication system" were lower than other medical terminology categories. These results reflect the gaps in educational curriculum of 1st and 2nd grades of medical licensing tests. PMID- 23358337 TI - [Usefulness of top-hat transform processing in whole body bone scintigraphy]. AB - To assess the usefulness of top-hat transform processing in whole body bone scintigraphy, five radiological technicians interpreted both original and top-hat processed images to determine the improvement of lesion detectability and interpretation time. For the evaluation of detectability, receiver operating characteristic (ROC) analysis was performed. The area under the curve (AUC) calculated from the ROC curve was improved in all observers (from 0.786 to 0.864 in average), although no significant difference was observed. However, the interpretation time was improved significantly (from 24.5 to 16.2 s in average). Top-hat transform processing in whole body bone scintigraphy is thought to be useful for the improvement of lesion detectability and interpretation time. PMID- 23358338 TI - [Fundamental evaluation of wavelet transform based noise reduction using soft threshold method in single photon emission computed tomography image]. AB - PURPOSE: The wavelet transform is a newly developed signal-processing tool that decomposes a signal into various levels of resolution. The wavelet transform based noise reduction has the characteristics of optimally separating signal from noise, preserving the rapid rises and falls of a signal, and reconstructing a smooth signal from noise-imposed observations. The aim of this study was to evaluate the effects of applying a new noise reduction technique, the wavelet transform based noise reduction, to single photon emission computed tomography (SPECT) images. METHODS: Three experiments were performed using cylindrical phantom, line source, and hot-rod phantom, respectively. We acquired SPECT image datasets of each phantom, and reconstructed SPECT images using the wavelet transform based noise reduction with filter back projection (FBP). Images were de noised by 3 parameters of wavelet transform based noise reduction: 1st wavelet weight (WW), 2nd WW, and 3rd WW, respectively. We evaluated the variances of full width at half maximum (FWHM), coefficients of variation (%CV), and frequency domains (radius direction distribution function in the power spectrum), respectively. RESULTS: In the cylindrical phantom test, %CV was reduced from 27.92% to 15.38% using the wavelet approach. On the other hand, FWHM values showed no significant change. However, the increases of wavelet weights caused artifacts on the reconstructed images in some cases. CONCLUSIONS: The wavelet based noise reduction had the significant potential to improve SPECT image. Therefore, the wavelet method should prove to be a robust approach to improve image quantification and fidelity. PMID- 23358339 TI - [Consideration of algorithms to presume the lesion location by using X-ray images of the stomach--geometric analysis of four direction radiography for the U region]. AB - The author considered algorithms to presume the lesion location from a series of X-ray images obtained by four direction radiography without blind area for the U region of the stomach. The objects of analysis were six cases that protruding lesions were noticed in the U region. Firstly, from the length of short axis and measure of the lateral width of U region projected on the film, we presumed the length of longitudinal axis and angle between short axis and the film. Secondly, we calculated the rate of length to stomach walls from right side and left side of every image to the lateral width at the height passing through the center of the lesion. Using the lesion location calculated from these values, we presumed that the values that almost agreed between two images to be the lesion location. As the result of analysis, there were some cases that the lesion location could be presumed certainly or un-certainly, on the other hand, there were some cases that the lesion location could not be presumed. Since the form of the U region can be distorted by a change of position, or the angle between longitudinal axis and sagittal plane was changed, the error might have been made in calculation, and so it was considered that the lesion location could not be presumed. PMID- 23358340 TI - [Evaluation of prototype for additional pad packing (polystyrene ball bullet) for homogenously fat suppressed magnetic resonance imaging]. AB - PURPOSE: Homogeneity of static magnetic field (B(0)) is unstable for head and neck magnetic resonance (MR) examination; consequently, chemical shift selective fat suppression becomes inhomogeneous. There is a commercially available additional pad to attenuate the B(0) inhomogeneity, but it is expensive. It has been reported that uncooked rice can be used as a material in the pad, but it has hygienic and weight problems. We searched for a material which can replace the uncooked rice, and evaluated its performance. METHOD: After filling various materials into the cylindrical phantom, each material was evaluated by image distortion of gradient filed echo and spin echo single-shot echo planar images. A prototype additional pad was made with a material which showed less image distortion in the phantom experiment and is easily available in clinical examination. For comparison, an uncooked rice pad with the same volume was also prepared. Fat suppressed head and neck magnetic resonance imaging (MRI) of normal volunteers were visually compared when the three additional pads, including the commercial product, were used or not. RESULT: The polystyrene ball bullet (BB bullet) was adopted as a material for the additional pad. The improvement of the fat suppression in the head and neck MRI was almost the same between the three additional pads. BB bullet pad was the lightest. CONCLUSION: BB bullet can be used as a material of additional pad attenuating the B(0) inhomogeneity instead of uncooked rice. PMID- 23358342 TI - [Usefulness of low kilovoltage settings in computed tomography venography of lower limbs]. AB - It has been reported that a reduction in tube kilovoltage during computed tomography (CT) angiography results in an average reduction of the effective radiation dose. Furthermore, a lower kilovoltage has been shown as a technique dose. However, there is no fundamental data in a low-kilovoltage protocol for CT venography. Thus, the purpose of this study was to investigate contrast enhancement, image noise, and radiation exposure with lower kilovoltage on CT images scanned using phantom of lower limbs and clinical CT images. In order to grasp the effective energy in each tube voltage of the equipment used, we determined the half-value layer using aluminum attenuation coefficient. The phantom of the lower was sealed with contrast agent that was adjusted in various CT values. We scanned this phantom at 80 kVp, 100 kVp, and 120 kVp settings, and evaluated the changes in CT value. We also compared CT values, CTDIvol, contrast enhancement, and radiation exposure with 100 kVp and 120 kVp in patients with suspected pulmonary embolism or deep venous thrombosis. We found the CT value increased 30 HU with 100 kVp settings, and contrast was also improved. A reduction of radiation exposure without deterioration of image quality would be possible by lowering the kilovoltage setting in CT venography. PMID- 23358341 TI - [Initial experience of magnetic resonance imaging-guided vacuum-assisted breast biopsy]. AB - Almost all mammary lesions are detected by a mammography and an ultrasound. However, a small part of lesions cannot be shown by only a magnetic resonance imaging (MRI). MRI-guided vacuum-assisted breast biopsy is a very useful means for the pathological diagnosis of these lesions. We performed MRI-guided vacuum assisted breast biopsy to 4 patients with the lesions seen only by MRI. Biopsies were safely and easily performed using biopsy software (syngo BreVis). These biopsied specimens resulted cancer in 1, adenoma in 1 and benign lesions in 2. With an increase of the opportunity of MRI for the mammary lesions, we expect these lesions become increasingly large. We believe that MRI-guided vacuum assisted breast biopsy will be an important diagnostic modality. PMID- 23358343 TI - [Problem of spectral attenuated with inversion recovery fat suppression method with respiratory-gated]. AB - The purpose of this study was to investigate the effect of fat suppression when we use respiratory-gated spectral attenuated with inversion recovery (SPAIR) method with respiratory-gated. We experimented on phantom and in-vivo study using simulated wave of respiratory-gated SPAIR at 1.5 tesla and 3.0 tesla. As a result, the effect of fat suppression becomes wrong with longer intervals of inspiration and expiration by wave of respiratory-gated. The signal intensity also varies with each slice. This result had the same trend on phantom and in vivo study. The longitudinal magnetization of fat becomes a stable state when SPAIR pulse is shot more than once. However, the SPAIR method with respiratory gated collect signal before the longitudinal magnetization of fat to be stable state, and fat suppression effect becomes bad, because the inversion time does not match the null point of the fat. Therefore, when we use SPAIR method with respiratory-gated it always causes bad fat suppression. PMID- 23358344 TI - [Analysis of accidents for magnetically induced displacement of the large ferromagnetic material in magnetic resonance systems]. AB - To improve magnetic resonance (MR) safety, we surveyed the accidents caused by large ferromagnetic materials brought into MR systems accidentally. We sent a questionnaire to 700 Japanese medical institutions and received 405 valid responses (58%). A total of 97 accidents in 77 institutions were observed and we analyzed them regarding incidental rate, the detail situation and environmental factors. The mean accident rate of each institute was 0.7/100,000 examinations, which was widely distributed (0-25.6/100,000) depending on the institute. In this survey, relatively small institutes with less than 500 beds tend to have these accidents more frequently (p<0.01). The institutes in which daily MR examination counts are more than 10 patients have fewer accidents than those with less than 10 daily examinations. The institutes with 6-10 MR examinations daily have significantly more accidents than that with more than 10 daily MR examinations (p<0.01). The main mental factors of the accidents were considered to be "prejudice" and "carelessness" but some advocate "ignorance." Though we could not find significant reduction in the institutes that have lectures and training for MR safety, we should continue lectures and training for MR safety to reduce accidents due to "ignorance." PMID- 23358345 TI - [Comparing two groups for continuous data]. PMID- 23358346 TI - [Computer-aided diagnosis (CAD)]. PMID- 23358347 TI - [Introduction to 2D image processing]. PMID- 23358348 TI - [The roles and activities of JIRA regional committee]. PMID- 23358349 TI - [JSRT's ambitions for glocalization and transdisciplinarity]. PMID- 23358350 TI - Experiences of returning to elite alpine skiing after ACL injury and ACL reconstruction. AB - AIM: To explore the experiences of alpine skiing at the elite level after anterior cruciate ligament (ACL) injury and reconstruction. DESIGN: A qualitative approach where semi-structured interviews were conducted, and an analysis of the manifest content was performed. PARTICIPANTS: Five ski high school students, two male and three female skiers, who had suffered ACL injuries and undergone ACL reconstructions. RESULTS: Seven categories were identified. The participants described their perceived opportunities with regard to returning to alpine skiing after ACL injury and reconstruction as something positive to do with self-belief, being mentally and physically prepared, regaining confidence in their own ability, being given time and using active strategies. In contrast, perceived barriers to a return to elite alpine skiing gave rise to negative feelings, for example, fear, disheartenment, a total lack of or ambivalent confidence in their own ability and the use of passive strategies. CONCLUSION: The two male skiers returned to alpine skiing. They reported confidence in their own ability, active strategies and support on all levels, as well as enhanced physical ability. The female skiers did not return to their pre-injury level of competitive alpine skiing. They stated a lack of support on all levels, deterioration in their physical ability and two out of three reported passive strategies and no or ambivalent confidence in their own ability. The most important factors were family support, support on all levels, access to a physiotherapist and time given. PMID- 23358351 TI - Bone: cystatin C-a biomarker of hip fracture risk? PMID- 23358352 TI - Increasing incidence of thyroid cancer: controversies explored. AB - Thyroid cancer is the most common endocrine malignancy and its incidence has been increasing considerably in the past few decades. Many studies have been published providing evidence for this increase; however, why thyroid cancer incidence keeps rising is still debated and there are conflicting reports of factors leading to the increase in its incidence. In this article, Nature Reviews Endocrinology asks four experts their opinions on some of the controversies surrounding the changing trends in thyroid cancer incidence. PMID- 23358355 TI - Diabetes: IL-13 and glucose homeostasis. PMID- 23358354 TI - Growth and development: enduring effect of GH therapy in PWS. PMID- 23358353 TI - Targeting integrins to promote bone formation and repair. AB - The ageing skeleton experiences a progressive decline in the rate of bone formation, which can eventually result in osteoporosis--a common disease characterized by reduced bone mass and altered bone microarchitecture which can result in fractures. One emerging therapy involves the identification of molecules that target bone-marrow mesenchymal stromal cells (MSCs) and promote their differentiation into osteoblasts, thereby counteracting bone loss. This Review highlights the discovery that some integrins, a family of heterodimeric transmembrane proteins that can interact with matrix proteins and generate intracellular signals, can be targeted to promote homing of MSCs to bone, osteogenic differentiation and bone formation. Specifically, priming of the alpha(5)beta(1) integrin, which is required for osteoblastic differentiation of MSCs, leads to increased bone formation and improved bone repair in mice. Additionally, treatment with a peptidomimetic ligand of the alpha(4)beta(1) integrin coupled to an agent with a high affinity for bone improves the homing of MSCs to bone and promotes osteoblast differentiation and bone formation, leading to increased bone mass in osteopenic mice. Strategies that target key integrins expressed by MSCs might, therefore, translate into improved therapies for age related bone loss and possibly other disorders. PMID- 23358356 TI - Basic research: new metformin mechanism elucidated in vitro and in vivo. PMID- 23358358 TI - Paediatrics: early growth and vascular change. PMID- 23358360 TI - Paediatrics: differences in the faecal microbiota of children with beta-cell autoimmunity. PMID- 23358361 TI - Cancer: polymorphisms in detoxification genes increase HMTC risk and match tumour phenotype. PMID- 23358363 TI - Bone: vitamin D metabolites and fracture healing. PMID- 23358364 TI - Bone: zoledronic acid-interdose interval of >1 year effective? PMID- 23358366 TI - Reproductive endocrinology: macrosomia in developing countries. PMID- 23358367 TI - Design of a novel MEMS gyroscope array. AB - This paper reports a novel four degree-of-freedom (DOF) MEMS vibratory gyroscope. A MEMS gyroscope array is then presented using the novel gyroscope unit. In the design of the proposed 4-DOF MEMS vibratory gyroscope, the elements of the drive mode are set inside the whole gyroscope architecture, and the elements of sense mode are set around the drive-mode, which thus makes it possible to combine several gyroscope units into a gyroscope array through sense-modes of all the units. The complete 2-DOF vibratory structure is utilized in both the drive-mode and sense-mode of the gyroscope unit, thereby providing the desired bandwidth and inherent robustness. The gyroscope array combines several gyroscope units by using the unique detection mass, which will increase the gain of sense-mode and improve the sensitivity of the system. The simulation results demonstrate that, compared to a single gyroscope unit, the gain of gyroscope array (n = 6) is increased by about 8 dB; a 3 dB bandwidth of 100 Hz in sense-mode and 190 Hz in drive-mode are also provided. The bandwidths of both modes are highly matched with each other, providing a bandwidth of 100 Hz for the entire system, thus illustrating that it could satisfy the requirements in practical applications. PMID- 23358368 TI - Magnetic field analysis of Lorentz motors using a novel segmented magnetic equivalent circuit method. AB - A simple and accurate method based on the magnetic equivalent circuit (MEC) model is proposed in this paper to predict magnetic flux density (MFD) distribution of the air-gap in a Lorentz motor (LM). In conventional MEC methods, the permanent magnet (PM) is treated as one common source and all branches of MEC are coupled together to become a MEC network. In our proposed method, every PM flux source is divided into three sub-sections (the outer, the middle and the inner). Thus, the MEC of LM is divided correspondingly into three independent sub-loops. As the size of the middle sub-MEC is small enough, it can be treated as an ideal MEC and solved accurately. Combining with decoupled analysis of outer and inner MECs, MFD distribution in the air-gap can be approximated by a quadratic curve, and the complex calculation of reluctances in MECs can be avoided. The segmented magnetic equivalent circuit (SMEC) method is used to analyze a LM, and its effectiveness is demonstrated by comparison with FEA, conventional MEC and experimental results. PMID- 23358369 TI - Biostatistics in clinical decision making for cardiothoracic radiologists. AB - Cardiothoracic radiologists are intuitively aware of sensitivity and specificity as they pertain to diagnostic tests involving clinical information. However, many cardiothoracic radiologists are unfamiliar with odds ratios, likelihood ratios, predictive values, and receiver operating characteristic (ROC) curves, which provide more information about the performance of a test. Our article will first review the fundamental concepts of sensitivity, specificity, predictive values, and likelihood ratios. The ROC curve methodology will be covered with an emphasis on creating a look-up table, a straightforward table that communicates important information to the clinician to aid in diagnosis. The article reviews sensitivity and specificity, as well as predictive values, logistic regression, and ROC curves, using conceptual principles without unnecessary mathematical rigor. We will apply principles of sensitivity and specificity to continuous measurements by constructing ROC curves in order to tie together key ideas in diagnostic decision making. Three clinical examples are presented to illustrate these fundamental statistical concepts: predictors of pulmonary embolism in children, use of dobutamine-cardiac magnetic resonance imaging to identify impaired ventricular function in patients who have suffered a myocardial infarction, and diagnostic accuracy of 64-multidetector row computed tomography to identify occluded vessels in adult patients with suspected coronary artery disease. In addition, a glossary is provided at the end of the article with key terms important in diagnostic imaging. An understanding of the concepts presented will assist cardiothoracic radiologists in critically discerning the usefulness of diagnostic tests and how these statistics can be applied to make judgments and decisions that are essential to clinical practice. PMID- 23358370 TI - Consumption of a high-fat diet during pregnancy changes the expression of cytochrome P450 in the livers of infant male mice. AB - It has been recently reported that the consumption of a high-fat diet during pregnancy exerts various effects on fetuses and newborn mice. The purpose of this study was to determine the effects of a high-fat diet during pregnancy on the expression of cytochrome P450 (CYP) in the livers of offspring. Mouse dams were fed a high-fat diet during pregnancy from the time of conception. After their birth, the newborn mice were fed a normal diet until 12 weeks of age. In the livers of the infant male mice that consumed a high-fat diet, the protein expression of CYP3A and CYP2C was decreased, and the protein expression of CYP1A and CYP2E was increased at 6 and 12 weeks of age. However, almost no changes were observed in the CYP proteins at 6 and 12 weeks of age in the livers of the infant female mice that consumed a high-fat diet. The amount of pregnane X receptor (PXR) translocated into the nucleus was reduced in the livers of infant male mice that consumed a high-fat diet. However, there was neither an increase in tumor necrosis factor-alpha or interleukin-1beta nor a decrease in lithocholic acid. These data suggested that CYP3A and CYP2C might decrease as a result of the decrease in the amount of nuclear PXR in infant male mice that consumed a high fat diet. The results of this study suggested that the consumption of a high-fat diet by pregnant mothers may be one explanation for individual differences in pharmacokinetics. PMID- 23358371 TI - [Selenium supplementation trials for cancer prevention and the subsequent risk of type 2 diabetes mellitus: selenium and vitamin E cancer prevention trial and after]. AB - The essential trace element selenium has long been considered to exhibit cancer preventive, antidiabetic and insulin-mimetic properties. However, recent epidemiological studies have indicated that supranutritional selenium intake and high plasma selenium levels are not necessarily preventive against cancer, and are possible risk factors for developing type 2 diabetes mellitus. The results of the SELECT, Selenium and Vitamin E Cancer Prevention Trial, in which it is hypothesized that the supplementations with selenium and/or vitamin E decrease the prostate cancer incidence among healthy men in the U.S., showed that the supplementation did not prevent the development of prostate cancer and that the incidence of newly diagnosed type 2 diabetes mellitus increased among the selenium-supplemented participants. The Nutritional Prevention of Cancer (NPC) trial showed a decreased risk of prostate cancer among participants taking 200 MUg of selenium daily for 7.7 years. However, the results of the NPC trial also showed an increased risk of type 2 diabetes mellitus in the participants with plasma selenium levels in the top tertile at the start of the study. Recently, the association of serum selenium with adipocytokines, such as TNF-alpha, VCAM-1, leptin, FABP-4, and MCP-1, has been observed. Selenoprotein P has been reported to associated with adiponectin, which suggests new roles of selenoprotein P in cellular energy metabolism, possibly leading to the increased risk of type 2 diabetes mellitus and also the development of cancer. Further studies are required to elucidate the relationship between selenium and adipocytokines and the role of selenoprotein P in the development of type 2 diabetes mellitus and cancer at high levels of selenium. PMID- 23358372 TI - [Prognostic prediction of the functional capacity and effectiveness of functional improvement program of the musculoskeletal system among users of preventive care service under long-term care insurance]. AB - OBJECTIVE: The purpose of this study was to examine the effectiveness of the Functional Improvement Program of the Musculoskeletal System among users of Preventive Care Service under Long-Term Care Insurance. METHODS: A total of 3,073 subjects were analyzed. We used the prediction formula to estimate the predicted value of the Kihon Checklist after one year, and calculated the measured value minus the predicted value. The subjects were divided into two groups according to the measured value minus predicted value tertiles: the lowest and middle tertile (good-to-fair measured value) and the highest tertile (poor measured value). We used a multiple logistic regression model to calculate the odds ratio (OR) and 95% confidence interval (CI) of the good-to-fair measured values of the Kihon Checklist after one year, according to the Functional Improvement Program of the Musculoskeletal System. RESULTS: In potentially dependent elderly, the multivariate adjusted ORs (95% CI) of the good-to-fair measured values were 2.4 (1.3-4.4) for those who attended the program eight times or more in a month (vs those who attended it three times or less in a month), 1.3 (1.0-1.8) for those who engaged in strength training using machines (vs those who did not train), and 1.4 (1.0-1.9) for those who engaged in endurance training. CONCLUSIONS: In this study, among potentially dependent elderly, those who attended the program eight times or more in a month and those who engaged in strength training using machines or endurance training showed a significant improvement of their functional capacity. PMID- 23358373 TI - [Factors associated with activities of daily living (ADL) in independently living elderly persons in a community: a baseline examination of a large scale cohort study, Fujiwara-kyo study]. AB - OBJECTIVES: To investigate factors associated with activities of daily living in independently living elderly persons in a community. SUBJECTS AND METHODS: The potential subjects were 4,472 individuals aged 65 years and older who voluntarily participated in a large cohort study, the Fujiwara-kyo study. We used self administered questionnaires consisting of an activities of daily living (ADL) questionnaire with the Physical Fitness Test established by the Ministry of Education, Culture, Sports, Science and Technology (12 ADL items) to determine the index of higher-level physical independence, demographics, Geriatric Depression Scale, and so on. Mini-mental state examination, measurement of physical fitness, and blood tests were also carried out. A lower ADL level was defined as having a total score of the 12 ADL items (range, 12-36 points) that was below the first quartile of a total score for all the subjects. Factors associated with a low ADL level were examined by multiple logistic regression. RESULTS: A total of 4,198 remained as subjects for analysis. The male, female and 5-year-old groups showed significant differences in the median score of 12 ADL items between any two groups. The highest odds ratio among factors associated with lower ADL level by multiple logistic regression with mutually adjusted independent variables was 4.49 (95%CI: 2.82-7.17) in the groups of "very sharp pain" or "strong pain" during the last month. Low physical ability, self awareness of limb weakness, a BMI of over 25, low physical activity, cerebrovascular disorder, depression, low cognitive function, unable "to see normally", unable "to hear someone", "muscle, bone and joint pain" were independently associated with lower ADL level. CONCLUSION: Multiple factors are associated with lower ADL level assessed on the basis of the 12 ADL items. PMID- 23358374 TI - [Study of the dietary preferences and the social-psychological factors that affect the dietary behaviors of high school and university students]. AB - OBJECTIVES: This study was conducted to elucidate the correlation among dietary intake, dietary preferences, and social-psychological factors in the youth and to examine the factors that affect such dietary behaviors as snacking, skipping breakfast, and taking a biased nutrition. METHODS: A survey was carried out using a questionnaire with closed questions on multiple items such as dietary behaviors, psychosocial stress, dietary externalization, information and consciousness about health. The survey was conducted on 1,056 high school students and 1,323 university students in Japan. RESULTS: As a result of the factor analysis among the groups of male/female and high school/university students, relationships were found between the items of "preferences for snacking" and "snack food intakes" among all these groups. Those who like sweets and snacks tended to snack between lunch and dinner or after dinner by themselves more often than those who do not. In contrast to men, intermediate correlations were found between the item of "a meal as a diversion" and each of the items of "snack food intake," "preferences for fried foods/sauteed foods/meat dishes," and "preferences for snacking," among women who do not live alone, regardless of their being high school or university students. The item of "stress over human relationships/academic performance" was shown to have similarly weak correlations with the items of "reasons for skipping breakfast" and "nutrition intake" in the groups of male and female high school students. The less they value nutrition intake, the more they tend to be conscious of stress over human relationships/academic performance. PMID- 23358375 TI - [Determination of nicotine, tobacco-specific nitrosamine and mutagenic activity of whole tobacco in Japanese cigarettes]. AB - OBJECTIVE: To measure the nicotine and tobacco-specific nitrosamine (TSNA) contents in whole tobacco from a variety of Japanese domestic cigarette brands and to determine mutagencity. METHODS: The test cigarettes were the top ten best selling cigarette brands in Japan in 2006. The nicotine content in whole tobacco was measured by a modified version of the CORESTA Recommended method. The level of TSNA was measured by a modified version of the Health Canada method. Mutagenicity was assessed using the Salmonella typhimurium strains TA100, TA98 and YG1024 with the metabolic activation system (S9mix) by preincubation assays. RESULTS: The nicotine content in the test cigarettes averaged 15.7+/-1.2 mg/g, and was in the range between 13.7 and 17.2 mg/g. The level of TSNA averaged 1,750 ng/g, and was in the range between 931 and 2,490 ng/g. Mutagenicity was pseudopositive in several samples of the YG1024 tester strain with and without S9mix. CONCLUSION: The cigarettes brands were categorized into four groups (Ultra low, Low, Medium, and High) based on the nominal nicotine yield figures printed on the cigarette packets. The nicotine content in whole tobacco of the High group was the highest. However, the level of TSNA of the high group was the lowest. The analyses of hazardous chemical compounds in whole tobacco can contribute to the reduction and regulation of the toxicity of tobacco products. PMID- 23358376 TI - [Lead content of bones excavated from archaeological sites in Hokkaido]. AB - OBJECTIVES: The lead content of excavated bone samples from archaeological sites in Hokkaido was measured to obtain insight into the source of human lead contamination known in the historic Japanese Edo era. METHODS: Fifty-seven rib samples excavated from 11 sites of five different eras in Hokkaido were analyzed for lead (Pb), calcium (Ca), and iron (Fe) contents by ICP mass spectrometry and ICP emission spectrometry. RESULTS: The Pb/Ca ratio (mg Pb/kg Ca) was low (approximately 2.0) and constant from the Jomon (approximately 5000 BP) to the Satsumon (approximately 750 BP) eras; however, its median increased to 11 in the Modern era. This elevation of Pb/Ca ratio in the bone samples from sites of the Modern era was not considered to be due to a greater bone contamination with soil particles because of similar Fe concentrations in the bone samples from this era to those in other eras. This historic trend of Pb/Ca ratio was similar to that observed in other parts of Japan. The elevated Pb/Ca ratio in the bone samples excavated from sites in the Modern era in other parts of Japan, that is, Edo era, has been ascribed to the usage of face powder containing Pb; however, people inhabiting Hokkaido in those days, the Ainu, were not considered to have the custom of using face powder. CONCLUSIONS: Contamination source(s) other than face powder was postulated in the Modern era of both Hokkaido and other parts of Japan. PMID- 23358377 TI - [Editor's note]. PMID- 23358378 TI - Gene regulation: Enhancing the hunt for enhancers. PMID- 23358379 TI - Genotype to phenotype: lessons from model organisms for human genetics. AB - To what extent can variation in phenotypic traits such as disease risk be accurately predicted in individuals? In this Review, I highlight recent studies in model organisms that are relevant both to the challenge of accurately predicting phenotypic variation from individual genome sequences ('whole-genome reverse genetics') and for understanding why, in many cases, this may be impossible. These studies argue that only by combining genetic knowledge with in vivo measurements of biological states will it be possible to make accurate genetic predictions for individual humans. PMID- 23358381 TI - Genome evolution: The social chromosome. PMID- 23358380 TI - Sequence assembly demystified. AB - Advances in sequencing technologies and increased access to sequencing services have led to renewed interest in sequence and genome assembly. Concurrently, new applications for sequencing have emerged, including gene expression analysis, discovery of genomic variants and metagenomics, and each of these has different needs and challenges in terms of assembly. We survey the theoretical foundations that underlie modern assembly and highlight the options and practical trade-offs that need to be considered, focusing on how individual features address the needs of specific applications. We also review key software and the interplay between experimental design and efficacy of assembly. PMID- 23358383 TI - Cost comparisons and methodological heterogeneity in cost-of-illness studies: the example of colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide with over 1 million new cases diagnosed each year. Advances in treatment and survival are likely to have increased lifetime costs of managing the disease. Cost-of-illness (COI) studies are key building blocks in economic evaluations of interventions and comparative effectiveness research. We systematically reviewed and critiqued the COI literature on CRC. METHODS: We searched several databases for CRC COI studies published in English, between January 2000 and February 2011. Information was abstracted on: setting, patient population, top-down/bottom-up costing, incident/prevalent approach, payer perspective, time horizon, costs included, cost source, and per-person costs. We developed a framework to compare study methodologies and assess homogeneity/heterogeneity. RESULTS: A total of 26 papers met the inclusion criteria. There was extensive methodological heterogeneity. Studies included case-control studies based on claims/reimbursement data (10), examinations of patient charts (5), and analysis of claims data (4). Epidemiological approaches varied (prevalent, 6; incident, 8; mixed, 10; unclear, 4). Time horizons ranged from 1 year postdiagnosis to lifetime. Seventeen studies used top-down costing. Twenty-five studies included healthcare-payer direct medical costs; 2 included indirect costs; 1 considered patient costs. There was broad agreement in how studies accounted for time, but few studies described costs in sufficient detail to allow replication. In general, costs were not comparable between studies. CONCLUSIONS: Methodological heterogeneity and lack of transparency made it almost impossible to compare CRC costs between studies or over time. For COI studies to be more useful and robust there is need for clear and rigorous guidelines around methodological and reporting "best practice." PMID- 23358382 TI - Advanced glycation end-products and their receptor-mediated roles: inflammation and oxidative stress. AB - Glycation is a protein modification, which results in a change in a protein structure. Glycation is believed to be the etiology of various age-related diseases such as diabetes mellitus and Alzheimer's disease (AD). Activation of microglia and resident macrophages in the brain by glycated proteins with subsequent oxidative stress and cytokine release may be an important factor in the progression of AD. It is also suggested that interaction between an advanced glycation end product (AGE) and its receptor (RAGE) results in glial activation as well as cytokine release and reactive oxygen species release. The use of antioxidants, receptor mediated compounds and reactive oxygen species scavenging enzyme produce an opportunity to intervene with AGE-RAGE signaling pathway, and thereby to slow down the progression of aging-related diseases. PMID- 23358384 TI - Fidelity of administrative data when researching Down syndrome. AB - OBJECTIVE: To compare the fidelity of administrative data with clinical data when researching Down syndrome (DS). METHODS: From outpatient, inpatient, and emergency department administrative claims within our institution, we identified 252 patients aged 18-45 years with encounters coded for DS by the ICD9=758.0 from 2000 to 2008. We evaluated these cases for false-positive errors-cases in which DS was not actually present in clinical descriptions. Subsequently, we identified false-negative errors (cases in which DS was present without encounters coded as such) by examination of the medical records for all patients within our study frame who had one of several common DS comorbidities, including congenital heart disease, hypothyroidism, and atlantoaxial instability. RESULTS: Among the 252 people with an administrative code for DS, 53 (21%) did not have DS documented in their medical record (false-positive error). While searching for false-negative errors, 29 additional patients were discovered with DS documented in the medical record who had not been previously identified. This led to a final cohort of 228 patients with DS. The presence of a billing code for DS had moderate sensitivity (87%) and positive predictive value (79%), but high specificity (99.9%). DISCUSSION: Administrative claims misclassify a sizeable proportion of patients with DS. Judgments about quality of care on the basis of samples identified using administrative claims may not accurately reflect the experience of patients with the conditions in question. When using administrative databases to study the quality of care for patients with DS, diagnostic verification within the clinical record is advisable whenever possible. PMID- 23358385 TI - The quality of hospital care for Medicaid and private pay patients. AB - CONTEXT: Understanding Medicaid performance relative to private payers and among other states may lead to better value. DESIGN, SETTING, AND PARTICIPANTS: Hospital Quality Alliance data from 2007-2008 were used to create composite "all or-none" quality scores for nearly 900,000 nonelderly adult patients hospitalized with acute myocardial infarction (AMI), congestive heart failure (CHF), or pneumonia. MAIN OUTCOME MEASURES: Differences in the quality of care received by Medicaid compared with privately insured patients at the national and state levels. RESULTS: Nationally, 88% of Medicaid beneficiaries received all appropriate processes of care when hospitalized for AMI, compared with 73% for CHF and 77% for pneumonia. Private patients received higher quality of care than Medicaid patients, but differences were small (1.3 percentage point difference, pneumonia; 2.7, AMI; 2.9, CHF; all P<0.05). At the state level, the differences averaged <3 percentage points across all conditions, but some states (2-8 states depending on the condition) exhibited significant (P<0.05) differences of >5 percentage points in favor of private patients. Two states exhibited significantly better quality of care for their Medicaid patients in excess of 5 percentage points. Quality scores for both Medicaid and private patients varied significantly by state but were highly correlated (correlations for AMI=0.80, CHF=0.84, pneumonia=0.80; all P<0.001). CONCLUSIONS: Small national differences in quality between hospitalized Medicaid and private patients are promising, although merit close monitoring as states are forced to curb Medicaid reimbursements. Although quality for Medicaid patients varied by state, high correlations with private patients suggest that the factors driving quality have more to do with geographic factors in the delivery of hospital services than with state-established Medicaid policies. PMID- 23358387 TI - How much do physician-entrepreneurs contribute to new medical devices? AB - OBJECTIVES: As recent public and private initiatives have sought to increase the transparency of physician-industry financial relationships (including calls for restricting collaboration), it is important to understand the extent of physicians' contributions to new medical devices. We quantify the contribution of information from physician-founded startup companies to 170 premarket approval (PMA) applications filed by 4 large incumbent medical device manufacturers over the period 1978-2007. We ask: Are incumbents more likely to incorporate information from physician-founded firms than nonphysician-founded firms? METHODS: We matched the text in 4 incumbent medical device firms' PMAs (Medtronic, Johnson & Johnson, Boston Scientific, and Guidant) to the text in patent applications of 118 startup companies that received investment from these incumbents between 1978 and 2007. We use a text-matching algorithm to quantify the information contribution from physician and nonphysician-founded startups to incumbent firms' PMAs. We analyze correlates of backward citations and degree of overlap between incumbents' PMAs and startups' patents using negative binomial and tobit regressions. FINDINGS: On average, physician-founded companies account for 11% of the information in PMAs, compared with 4% from nonphysician-founded companies. Regression results show that incumbents are significantly more likely to cite physician-founded companies' patents and to incorporate them into new devices. CONCLUSIONS: Physicians are an important source of medical device innovation. The results suggest that restrictions on financial relationships between providers and industry, while potentially improving patients' trust, may result in reduced medical innovation if physicians found fewer startups or if incumbent firms reduce investments in physician-founded startups. PMID- 23358386 TI - Timeliness of abnormal screening and diagnostic mammography follow-up at facilities serving vulnerable women. AB - BACKGROUND: Whether timeliness of follow-up after abnormal mammography differs at facilities serving vulnerable populations, such as women with limited education or income, in rural areas, and racial/ethnic minorities is unknown. METHODS: We examined receipt of diagnostic evaluation after abnormal mammography using 1998 2006 Breast Cancer Surveillance Consortium-linked Medicare claims. We compared whether time to recommended breast imaging or biopsy depended on whether women attended facilities serving vulnerable populations. We characterized a facility by the proportion of mammograms performed on women with limited education or income, in rural areas, or racial/ethnic minorities. RESULTS: We analyzed 30,874 abnormal screening examinations recommended for follow-up imaging across 142 facilities and 10,049 abnormal diagnostic examinations recommended for biopsy across 114 facilities. Women at facilities serving populations with less education or more racial/ethnic minorities had lower rates of follow-up imaging (4%-5% difference, P<0.05), and women at facilities serving more rural and low income populations had lower rates of biopsy (4%-5% difference, P<0.05). Women undergoing biopsy at facilities serving vulnerable populations had longer times until biopsy than those at facilities serving nonvulnerable populations (21.6 vs. 15.6 d; 95% confidence interval for mean difference 4.1-7.7). The proportion of women receiving recommended imaging within 11 months and biopsy within 3 months varied across facilities (interquartile range, 85.5%-96.5% for imaging and 79.4% 87.3% for biopsy). CONCLUSIONS: Among Medicare recipients, follow-up rates were slightly lower at facilities serving vulnerable populations, and among those women who returned for diagnostic evaluation, time to follow-up was slightly longer at facilities that served vulnerable population. Interventions should target variability in follow-up rates across facilities, and evaluate effectiveness particularly at facilities serving vulnerable populations. PMID- 23358388 TI - The importance of nursing homes in the spread of methicillin-resistant Staphylococcus aureus (MRSA) among hospitals. AB - BACKGROUND: Hospital infection control strategies and programs may not consider control of methicillin-resistant Staphylococcus aureus (MRSA) in nursing homes in a county. METHODS: Using our Regional Healthcare Ecosystem Analyst, we augmented our existing agent-based model of all hospitals in Orange County (OC), California, by adding all nursing homes and then simulated MRSA outbreaks in various health care facilities. RESULTS: The addition of nursing homes substantially changed MRSA transmission dynamics throughout the county. The presence of nursing homes substantially potentiated the effects of hospital outbreaks on other hospitals, leading to an average 46.2% (range, 3.3%-156.1%) relative increase above and beyond the impact when only hospitals are included for an outbreak in OC's largest hospital. An outbreak in the largest hospital affected all other hospitals (average 2.1% relative prevalence increase) and the majority (~90%) of nursing homes (average 3.2% relative increase) after 6 months. An outbreak in the largest nursing home had effects on multiple OC hospitals, increasing MRSA prevalence in directly connected hospitals by an average 0.3% and in hospitals not directly connected through patient transfers by an average 0.1% after 6 months. A nursing home outbreak also had some effect on MRSA prevalence in other nursing homes. CONCLUSIONS: Nursing homes, even those not connected by direct patient transfers, may be a vital component of a hospital's infection control strategy. To achieve effective control, a hospital may want to better understand how regional nursing homes and hospitals are connected through both direct and indirect (with intervening stays at home) patient sharing. PMID- 23358389 TI - The Bayesian model on human papillomavirus vaccination in Italy lacks transparency. PMID- 23358391 TI - Ent-11alpha-Hydroxy-15-oxo-kaur-16-en-19-oic-acid Inhibits Growth of Human Lung Cancer A549 Cells by Arresting Cell Cycle and Triggering Apoptosis. AB - OBJECTIVE: To examine the apoptotic effect of ent-11alpha-hydroxy-15-oxo-kaur-16 en-19-oic-acid (5F), a compound isolated from Pteris semipinnata L (PsL), in human lung cancer A549 cells. METHODS: A549 cells were treated with 5F (0-80 MUg/ml) for different time periods. Cytotoxicity was examined using a MTT method. Cell cycle was examined using propidium iodide staining. Apoptosis was examined using Hoechst 33258 staining, enzyme-linked immunosorbent assay (ELISA) and caspase-3 activity analysis. Expression of representative apoptosis-related proteins was evaluated by Western blot analysis. Reactive oxygen species (ROS) level was measured using standard protocols. Potential interaction of 5F with cisplatin was also examined. RESULTS: 5F inhibited the proliferation of A549 cells in a concentration- and time-dependent manner. 5F increased the accumulation of cells in sub-G1 phase and arrested the cells in the G2 phase. Exposure to 5F induced morphological changes and DNA fragmentation that are characteristic of apoptosis. The expression of p21 was increased. 5F exposure also increased Bax expression, release of cytochrome c and apoptosis inducing factor (AIF), and activation of caspase-3. 5F significantly sensitized the cells to cisplatin toxicity. Interestingly, treatment with 5F did not increase ROS, but reduced ROS production induced by cisplatin. CONCLUSION: 5F could inhibit the proliferation of A549 cells by arresting the cells in G2 phase and by inducing mitochondrial-mediated apoptosis. PMID- 23358392 TI - Retraction. Enhanced cardiovascular protective effects of valsartan in high-risk hypertensive patients with left ventricular hypertrophy: sub-analysis of the KYOTO HEART study. PMID- 23358393 TI - Time patterns of adherence and long-term virological response to non-nucleoside reverse transcriptase inhibitor regimens in the Stratall ANRS 12110/ESTHER trial in Cameroon. AB - BACKGROUND: Although treatment adherence is a major challenge in sub-Saharan Africa, it is still unknown which longitudinal patterns of adherence are the most detrimental to long-term virological response to non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens. This analysis aimed to study the influence of different time patterns of adherence on virological failure after 24 months of treatment in Cameroon. METHODS: Antiretroviral therapy (ART) adherence data were collected using face-to-face questionnaires administered at months 1, 3, 6, 12, 18 and 24. Virological failure was defined as viral load >40 copies/ml at month 18 and/or 24. Two combined indicators of early adherence (months 1, 3 and 6) and adherence during the maintenance phase (months 12, 18 and 24) were designed to classify patients as always adherent during the early or maintenance phase, non-adherent at least once and having interrupted ART for >2 days at least once at any visit during either of these two phases. RESULTS: Virological failure occurred in 107 (42%) of the 254 patients included in the analysis. In the early and maintenance phases, 84% and 76%, respectively, were always adherent, 5% and 5% were non-adherent and 11% and 20% experienced >= 1 treatment interruption. Early non-adherence was independently associated with virological failure (adjusted OR 7.2 [95% CI 1.5, 34.6]), while only treatment interruptions had a significant impact on virological failure during the maintenance phase (adjusted OR 2.1 [95% CI 1.1, 4.4]). CONCLUSIONS: ART NNRTI-regimens used in sub-Saharan Africa seem to 'forgive' deviations from good adherence during the maintenance phase. Optimizing adherence in the early months of treatment remains crucial, especially in a setting of poor health care infrastructure and resources. PMID- 23358390 TI - HCV and oxidative stress in the liver. AB - Hepatitis C virus (HCV) is the etiological agent accounting for chronic liver disease in approximately 2-3% of the population worldwide. HCV infection often leads to liver fibrosis and cirrhosis, various metabolic alterations including steatosis, insulin and interferon resistance or iron overload, and development of hepatocellular carcinoma or non-Hodgkin lymphoma. Multiple molecular mechanisms that trigger the emergence and development of each of these pathogenic processes have been identified so far. One of these involves marked induction of a reactive oxygen species (ROS) in infected cells leading to oxidative stress. To date, markers of oxidative stress were observed both in chronic hepatitis C patients and in various in vitro systems, including replicons or stable cell lines expressing viral proteins. The search for ROS sources in HCV-infected cells revealed several mechanisms of ROS production and thus a number of cellular proteins have become targets for future studies. Furthermore, during last several years it has been shown that HCV modifies antioxidant defense mechanisms. The aim of this review is to summarize the present state of art in the field and to try to predict directions for future studies. PMID- 23358395 TI - Endoscopy: Tethered capsule endomicroscopy of the oesophagus--an easy pill to swallow. PMID- 23358394 TI - Helicobacter pylori infection in functional dyspepsia. AB - Functional dyspepsia is the most common reason for patients to experience chronic epigastric pain or discomfort. The causes of functional dyspepsia are multifactorial but Helicobacter pylori infection is one likely candidate. Infection with this bacterial pathogen clearly results in chronic mucosal inflammation in the stomach and duodenum, which, in turn, might lead to abnormalities in gastroduodenal motility and sensitivity. Chronic gastritis might also affect a variety of endocrine functions of the stomach including the production of the gastrointestinal hormones and neurotransmitters somatostatin, gastrin and ghrelin. Although these abnormalities might generate symptoms in some patients with functional dyspepsia, the clinical evidence needs to be critically evaluated before this hypothesis can be confirmed. A Cochrane review reported that eradication of H. pylori in these patients had a small but statistically significant long-term effect on symptom relief when compared with placebo, lasting at least 12 months after 1 week of eradication therapy. The efficacy of eradication therapy was seen in all symptom subtypes of functional dyspepsia, but was more marked in Asian than Western patients. This evidence has led to alterations in most of the major guidelines throughout the world, which now recommend H. pylori eradication in patients with functional dyspepsia if they test positive for this bacterium. PMID- 23358397 TI - Hepatitis: Long-term therapy of chronic hepatitis B reverses cirrhosis. PMID- 23358398 TI - Clostridium difficile infection: Real or fake--faecal matter does the trick for recurrent CDI. PMID- 23358399 TI - 4th international symposium on targeted radiotherapy and dosimetry (ISTARD): best ranked abstract publication. PMID- 23358396 TI - The role of psychosocial factors and psychiatric disorders in functional dyspepsia. AB - In this Review, after a brief historical introduction, we first provide an overview of epidemiological studies that demonstrate an association between functional dyspepsia and psychological traits, states or psychiatric disorders. These studies suggest an important intrinsic role for psychosocial factors and psychiatric disorders, especially anxiety and depression, in the aetiopathogenesis of functional dyspepsia, in addition to their putative influence on health-care-seeking behaviour. Second, we describe pathophysiological evidence on how psychosocial factors and psychiatric disorders might exert their role in functional dyspepsia. Novel insights from functional brain imaging studies regarding the integration of gut-brain signals, processed in homeostatic-interoceptive brain regions, with input from the exteroceptive system, the reward system and affective and cognitive circuits, help to clarify the important role of psychological processes and psychiatric morbidity. We therefore propose an integrated model of functional dyspepsia as a disorder of gut-brain signalling, supporting a biopsychosocial approach to the diagnosis and management of this disorder. PMID- 23358400 TI - Quantification of activity by alpha-camera imaging and small-scale dosimetry within ovarian carcinoma micrometastases treated with targeted alpha therapy. AB - Targeted alpha therapy (TAT) a promising treatment for small, residual, and micrometastatic diseases has questionable efficacy against malignant lesions larger than the alpha-particle range, and likely requires favorable intratumoral activity distribution. Here, we characterized and quantified the activity distribution of an alpha-particle emitter radiolabelled antibody within >100-um micrometastases in a murine ovarian carcinoma model. Nude mice bearing ovarian micrometastases were injected intra-peritoneally with 211At-MX35 (total injected activity 6 MBq, specific activity 650 MBq/mg). Animals were sacrificed at several time points, and peritoneal samples were excised and prepared for alpha-camera imaging. Spatial and temporal activity distributions within micrometastases were derived and used for small-scale dosimetry. We observed two activity distribution patterns: uniform distribution and high stable uptake (>100% IA/g at all time points) in micrometastases with no visible stromal compartment, and radial distribution (high activity on the edge and poor uptake in the core) in tumor cell lobules surrounded by fibroblasts. Activity distributions over time were characterized by a peak (140% IA/g at 4 h) in the outer tumor layer and a sharp drop beyond a depth of 50 um. Small-scale dosimetry was performed on a multi cellular micrometastasis model, using time-integrated activities derived from the experimental data. With injected activity of 400 kBq, tumors exhibiting uniform activity distribution received <25 Gy (EUD=13 Gy), whereas tumors presenting radial activity distribution received mean absorbed doses of <8 Gy (EUD=5 Gy). These results provide new insight into important aspects of TAT, and may explain why micrometastases >100 um might not be effectively treated by the examined regimen. PMID- 23358401 TI - Personalization of radioiodine treatment for Graves' disease: a prospective, randomized study with a novel method for calculating the optimal 131I-iodide activity based on target reduction of thyroid mass. AB - AIM: There is no consensus regarding the most appropriate dosimetric approach to cure Graves' disease. This study describes a personalized approach based on the desired therapy-induced volume (mass) reduction in order to define the activity of 131I-iodide to be administered, based on the MIRD approach and the radiobiological Linear Quadratic Model. METHODS: A model for calculating the "optimal" final thyroid mass has been developed and published in the past years. Based on this model, it is possible to predict the thyroid absorbed dose following administration of a certain activity as a function of desired reduction of the starting mass of the gland. A total of 147 Graves' disease patients were randomly divided into four groups based on the absorbed thyroid dose, respectively 100 Gy (Group A, N.=29), 200 Gy (Group B, N.=25), and 400 Gy (Group C, N.=29), while patients of Group D (n=64) received a 131I-iodide activity calculated based on the desired "optimal" final thyroid mass. RESULTS: At one year follow-up, 48% of patients in Group A, 64% in Group B, 97% in Group C, and 94% in Group D were cured. There was no statistical difference between cure rate in Group C versus Group D. The administered 131I-iodide activity for Group C was significantly higher than for Group D (524 +/- 201 MBq versus 386 +/- 173 MBq, P<0.001). CONCLUSION: These results demonstrate that the proposed method allows to optimize 131I-iodide therapy for Graves' disease patients on an individual basis, avoiding the administration of unjustified higher activities. PMID- 23358403 TI - Usefulness of 124I PET/CT imaging to predict absorbed doses in patients affected by metastatic thyroid cancer and treated with 131I. AB - AIM: The aim of this work was the evaluation of the usefulness of 124I PET/CT sequential scans to predict absorbed doses to metastatic thyroid cancer in patients undergoing 131I therapy. METHODS: From July 2011 until April 2012 8 patients affected by metastatic thyroid cancer were enrolled. Each patient underwent 4 PET/CT scans at 4, 24, 48, 72 h after the administration of about 74 MBq of 124I. Blood samples and whole body exposure measurements were obtained to calculate blood and red marrow doses. Activity concentrations and lesion volumes obtained from PET/CT images were used to evaluate tumour doses with MIRD formalism and spheres model. The average administered 131I therapeutic activity was 6475 MBq (range: 3700-9250 MBq). RESULTS: 124I PET/CT images showed, with a very good resolution, all 131I avid lesions detected by post therapy whole body scans. The average dose rates for blood, red marrow and lesions were respectively: 6.58E-02 +/- 1.64E-02 mGy/MBq, 5.73E-02 +/- 1.57E-02 mGy/MBq, 2.22E+01 +/- 1.62E+01 mGy/MBq. Three out of eight patients did not show any uptake of 124I in all PET/CT scans, despite high level of TSH and CT detectable lesions. Post-therapy 131I whole body scan confirmed the absence of focal iodine uptake. CONCLUSION: Negative 124I PET/CT images probably could be used as predictive of real absence of iodine avidity, avoiding all toxicity from useless 131I therapy. A higher number of patients is necessary to validate these preliminary results and a project is ongoing to compare MIRD results to voxel dosimetry based on Monte Carlo simulation. PMID- 23358402 TI - A dosimetric treatment planning strategy in radioembolization of hepatocarcinoma with 90Y glass microspheres. AB - AIM: Our goal was to limit liver toxicity and to obtain good efficacy by developing a dosimetric treatment planning strategy. While several dosimetric evaluations are reported in literature, the main problem of the safety of the treatment is rarely addressed. Our work is the first proposal of a treatment planning method for glass spheres, including both liver toxicity and efficacy issues. METHODS: Fifty-two patients (series 1) had been treated for intermediated/advanced hepatocellular carcinoma (HCC) with glass spheres, according to the Therasphere(r) prescription of 120 Gy averaged on the injected lobe. They were retrospectively evaluated with voxel dosimetry, adopting the local deposition hypothesis. Regions of interest on tumor and non tumor parenchyma were drawn to determine the parenchyma absorbed dose, averaged also on non irradiated voxels, excluding tumor voxels. The relationship between the mean non tumoral parenchyma absorbed dose D and observed liver decompensation was analyzed. RESULTS: Basal Child-Pugh strongly affected the toxicity incidence, which was 22% for A5, 57% for A6, 89% for B7 patients. Restricting the analysis to our numerically richest class (basal Child-Pugh A5 patients), D median values were significantly different between toxic (median 90 Gy) and non toxic treatments (median 58 Gy) at a Mann-Withney test, (P=0.033). Using D as a marker for toxicity, the separation of the two populations in terms of area under ROC curve was 0.75, with 95% C.I. of [0.55-0.95]. The experimental Normal Tissue Complication Probability (NTCP) curve as a function of D resulted in the following values: 0%, 14%, 40%, 67% for D interval of [0-35] Gy, [35-70] Gy, [70 105] Gy, [105-140] Gy. DISCUSSION: A limit of about 70 Gy for the mean absorbed dose to parenchyma was assumed for A5 patients, corresponding to a 14% risk of liver decompensation. This result is applicable only to our administration conditions: glass spheres after a decay interval of 3.75 days. Different safety limit (40 Gy) are published for resin spheres, characterized by higher number of particle per GBq (more uniform irradiation, bigger biological effect for the same absorbed dose). CONCLUSION: As result of this study we suggest a constraint of about 70 Gy mean absorbed dose to liver non tumoral parenchyma, corresponding to about 15% probability of radioinduced liver decompensation while still aiming at achieving an absorbed of several hundreds of Gy to lesions. PMID- 23358404 TI - Dosimetry in the therapy of metastatic differentiated thyroid cancer administering high 131I activity: the experience of Busto Arsizio Hospital (Italy). AB - AIM: The purpose of the present work was to evaluate the impact of 131I high activity therapy treatments of metastatic differentiated thyroid cancer (MDTC) in terms of feasibility, tolerance, efficacy, and the impact of dosimetry in order to optimize the process. METHODS: Seventeen MDTC patients underwent 27 treatments with 131I, with activity ranging from 6.2 GBq to 24.1 GBq. Red marrow (RM) peritherapy dosimetry was based on the Standard Operating Procedure of European Association of Nuclear Medicine (EANM SOP), while metastases dosimetry on the guidelines of Italian Association of Physicists in Medicine and Italian Association of Nuclear Medicine. In 12 cases prospective dosimetry was performed too, with the purpose of evaluating the possibility of maximizing the therapeutic activity, complying the 2 Gy red marrow (RM) dose constraint. The absorbed dose to 45 lesions was evaluated. The severity of myelotoxic effects was monitored during the follow-up. RESULTS: Treatments were generally well tolerated, also at the highest RM absorbed doses. RM absorbed doses ranged from 0.49 to 6.67 Gy, lesion doses from 1.1 Gy to 778 Gy. In case of repeated treatments on the same site, in 13 cases on a total of 15, an absorbed dose reduction was observed. RM prospective and peritherapeutic dosimetry differed somewhat: absorbed doses measured during therapy ranged from -7% to +40% with respect to provisional absorbed doses. CONCLUSION: In our experience high activity treatments were well tolerated. Prospective dosimetry needs further investigation to become sufficiently reliable in order to comply the 2 Gy constraint. Lesions became progressively less iodine-avid in case of repeated treatments, so the "first big shoot" treatment with the highest safe activity seems to be desirable to obtain the maximum efficacy. PMID- 23358405 TI - Quantitative evaluation on [90Y] DOTATOC PET and SPECT imaging by phantom acquisitions and clinical applications in locoregional and systemic treatments. AB - AIM: The aim of this paper was to compare [90Y]-PET and SPECT imaging quantification for dosimetric applications in targeted radionuclide therapy. METHODS: Imaging studies were carried out by SPECT-CT and PET equipment performing phantom tests first. [90Y]-SPECT and PET scans were compared in terms of sensitivity, minimum detectable activity concentration, recovery coefficients (RCs) and system spatial resolution (FWHM). Quantitative evaluations by PET and SPECT acquisitions were then assessed in patients who received therapeutic activity of [90Y]-DOTATOC directly injected into the surgical cavity by locoregional route in glioma treatment and by systemic route in neuroendocrine tumour patients who underwent intravenous infusion. Finally 3D-dose distributions by SPECT and PET images were obtained. RESULTS: Sensitivity was proven to be about fivefold higher for SPECT than for PET. To obtain a good-quality PET imaging, the minimum detectable activity concentration was determined to be equal to 1 MBq/mL compared with 0.05 MBq/mL that was sufficient to assess adequate SPECT imaging. RCs were 100% for volume >= 25.5 mL for PET and >= 110 mL for SPECT. FWHM was 7 mm for PET and 19 mm for SPECT scans. With regard to locoregional therapy, excellent imaging was obtained with both PET and SPECT. On the contrary, systemic administration did not permit us to obtain suitable PET imaging. PET and SPECT images were affected by considerable noise, whose influence is much more important in the quantitative evaluation of dose volume histograms rather than in the visual interpretation of images. CONCLUSION: [90Y] activity quantification is feasible by SPECT and PET imaging. For clinical applications, SPECT-CT is the best technique for visualizing the radiopharmaceuticals following systemic infusion, while both SPECT and PET scans are effective in analyzing locoregional distribution. Nevertheless PET study demonstrates the best spatial definition. PMID- 23358406 TI - Comparisons of dosimetric approaches for fractionated radioimmunotherapy of non Hodgkin lymphoma. AB - AIM: The aim of this study was to compare different dosimetric approaches on therapy naive patients enrolled in a multicentre fractionated radioimmunotherapy trial, to determine which methodological approach correlates with bone marrow toxicity. METHODS: Twenty-height non-Hodgkin lymphoma patients were treated with one or two fractions of 90Y-Ibritumomab-Tiuxetan (11.1 MBq/kg) 8 to 12 weeks apart in four different institutions. Quantitative imaging with 111In-Ibritumomab Tiuxetan (185 MBq) was performed at 0, 1, 4 and 7 days after infusion, starting two weeks before the therapeutic administration. A whole-body (WB) CT scan was also acquired prior to the 111In-Ibritumomab injection, for attenuation correction purposes and was segmented to derive patient-specific organ masses. All dosimetry processing was centralized in a single institution. The first method (M_2D) was based on geometric mean WB scans, corrected for attenuation, scatter and organs superposition. The second method (M_2.5D) was based on the computed assisted matrix inversion approach and used segmented CT scans. The third method (M_3D) used iterative reconstruction of tomographic scans, corrected for attenuation, scatter and collimator response. Absorbed doses were estimated for lungs, liver, kidneys and spleen using MIRD S values adjusted for organ masses. Bone marrow (BM) absorbed doses were evaluated according to imaging methods (3) and compared to blood-based approaches. RESULTS: For some patients, organ masses such as liver or spleen significantly differed from male/female reference masses, whereas lungs and kidneys masses were relatively constant. Except for lungs, absorbed doses estimated by M_2D were higher than those from M_2.5D and these, in turn, were higher that those calculated from M_3D (Wilcoxon P<8.6e-4). Median organ absorbed dose estimates were equivalent for both fractions except for the spleen. In fact, spleen absorbed doses for the second fraction were lower than those for the first fraction, regardless of the approach. Possible explanations are that patient spleen masses were kept constant for analysis of both fractions and/or that spleen uptake was lowered after the first fraction. Estimation of BM absorbed doses from blood sampling was unable to predict platelet toxicity, but image-based methods performed better. Additionally, for most organs, the absorbed dose delivered by the first fraction could predict that delivered by the second fraction. CONCLUSION: These results confirm that different acquisition/processing protocols will lead to statistically different absorbed doses. Additionally, image-based dosimetric approaches are needed in order to correlate absorbed dose to bone marrow toxicity. PMID- 23358407 TI - Targeted "bone-seeking" radiopharmaceuticals for palliative treatment of bone metastases: a systematic review and meta-analysis. AB - AIM: The aim of the study was to assess the state of the art of the use of bone seeking radiopharmaceuticals for palliation therapy of pain from bone metastases. METHODS: A systematic literature search was conducted about therapy with 89Sr chloride and 153Sm-EDTMP between 2001-2011. The primary outcomes were efficacy and toxicity. Descriptive and quantitative data were extracted from each study, calculating event rates and odds ratio (OR) with 95% confidence intervals (CI) for pooled analysis. Subgroup analyses were performed. RESULTS: Fifty-seven studies contributed to the systematic review. Forty-six studies used radiopharmaceuticals as a single agent, 15 investigated therapeutic combinations. Most of the studies included patients with prostate cancer. The overall efficacy of bone-seeking radiopharmaceuticals as single agents was 70%, whereas it was 74% when used in combination with other therapies. Complete response was reported in 27% of patients. Efficacy resulted to be 70% for prostate cancer and 79% for breast cancer. The overall toxicity of radiopharmaceuticals was 15%: the toxicity was 11% selecting only studies reporting on the use of radiopharmaceuticals as a single agent. No significant difference was found between bone-seeking radiopharmaceuticals and other oncological treatments regarding efficacy or toxicity. Reports of objective response outcomes suggest that bone-seeking radiopharmaceuticals have some cytotoxic activity, either alone or combination with chemotherapy. CONCLUSION: This literature analysis emphasizes multiple evidences of high efficacy and low toxicity of bone seeking radiopharmaceuticals; moreover, this therapy may have a therapeutic potential beyond simple palliation of bone pain. PMID- 23358408 TI - Is there need for radioimmunotherapy? results of a phase I/II study in patients with indolent B-cell lymphomas using lutetium-177-DOTA-rituximab. AB - AIM: The aim of the study was to explore the clinical response to 177Lutetium DOTA-rituximab (177Lu-D-R) and to determine the maximum tolerated dose (MTD) in the treatment of patients with relapsed follicular, mantle cell or other indolent lymphomas such as marginal zone lymphoma as well as to put these results into context with other therapy options for these patients. METHODS: Treatment consisted of cold rituximab (250 mg/m2) on day 1 and day 8 and 177Lu-DOTA Rituximab on day 8. Reassessment was done at week 10. Thirty-one patients (males=17, females=14, median number of pretreatments: 3) were treated in seven cohorts. Escalation of injected activity was carried out in steps of 5 mCi/m2. Dosimetry was performed in the first 20 patients. RESULTS: The MTD was found to be 45 mCi/m2. Thrombocytopenia and leukopenia were the dose-limiting toxicities. Significant anemia only occurred at dose level 7. We observed the nadir of platelets after a median of 36 days from treatment with 177Lu-D-R and a nadir of granulocytes after a median of 50 days from 177Lu-D-R treatment. Non hematological toxicity was negligible. We observed clinical responses at all dose levels and for all lymphoma entities. Some of the responses were durable; the longest follow up in complete remission is currently over eight years. CONCLUSION: The MTD of 177Lu-DOTA-Rituximab was found to be 45 mCi/m2. Non hematologic toxicity was negligible. Responses were seen in all lymphoma entities and at all dose levels tested. Further testing seems to be most promising mainly in follicular and marginal zone lymphoma in particular as the results compare well to other therapy options for these patients with regard to effectiveness, toxicity and discomfort for the patients. PMID- 23358409 TI - Super-selective hepatic arterial infusions as established technique ('ARETAIEION' Protocol) of [177Lu]DOTA-TATE in inoperable neuroendocrine liver metastases of gastro-entero-pancreatic (GEP) tumors. AB - AIM: Aim of this study was to evaluate the effectiveness of non-carrier added (n. c. a.) [177Lu]DOTA-TATE in inoperable liver metastases, positive for sst2 receptor overexpression (verified by Octreoscan and confirmed by biopsy) due to neuroendocrine gastroenteropancreatic (GEP) tumors. [177Lu]DOTA-TATE has been infused after selective catheterization of the hepatic artery, minimising in parallel the toxicity of non-target tissues. METHODS: The dose per session administered to each patient (12 cases in total) was 7400 MBq (200 mCi). Repetitions did not exceed 6-fold with treatment intervals of 5-8 weeks. Response assessment was classified according to the therapeutic benefit. Absorbed doses delivered to metastases, kidneys and red marrow were calculated according to OLINDA 1.1 program and the derived values were correlated to the Response Evaluating Criteria in Solid Tumors (RECIST). CT/MRI scans were performed as baseline before, during and after the end of treatment and monthly ultrasound images for follow-up estimation and measurements. Toxicity (World Health Organization criteria) was measured using blood and urine tests of renal, hepatic and bone marrow function. RESULTS: None of the patients resulted complete response (0.0%); partial response was assessed in 8 (66.7%), disease stabilization in 3 (25%) and progressive disease in 1(8.3%). A 14-month median survival time was estimated for all patients, so far. Eight of 12 (66.7%) showed a mean target diameter shrinkage ranging from 33% to 45%. The organ average radiation dose estimation was found as follows: a) liver tumor 20.8 mGy/MBq; b) liver 0.14 mGy/MBq; c) kidneys 0.41 mGy/MBq; d) spleen 1.4 mGy/MBq; and f) bone marrow 0.022 mGy/MBq. The average absorbed dose per session to a tumor for a spherical mass of 20 g was estimated to be 20.8 mGy/MBq, depending on the histotype of the tumor. WHO toxicity grade 2 to 3 erythro-, leuko- and thrombo cytopenia occurred in 9 (75%) cases observed about after the third session. CONCLUSION: In unresectable metastatic liver lesions positive for somatostatin receptors repeated, trans-hepatic high doses of [177Lu]DOTA-TATE resulted in a more than promising therapeutic outcome with a partial response in 75% of the treated patients. Given the loco-regional modality character of the administration technique, no nephro-toxicity has been so far observed whereas a remarkable myelotoxicity was noticed. PMID- 23358410 TI - PET in the clinical work-up of patients with spondylodiscitis: a new tool for the clinician? AB - AIM: The role of 18F-fluorodeoxyglucose-positron-emission tomography (FDG-PET) in the clinical management of patients with inflammatory diseases (e.g., chronic inflammatory diseases, fever of unknown origin, ostemyelitis, prosthesis infections) is still under investigation. The aim of the present study was to evaluate the usefulness of PET in the diagnostic work-up of patients with spondylodiscitis and to compare it with magnetic resonance imaging (MRI). METHODS: This retrospective study included 33 patients with suspected/confirmed spondylodiscitis. Two groups were created: 1) disease definition (n=24); and 2) treatment assessment (N.=16, 21 exams). Disease status was defined on the basis of data collected for symptoms, hematological parameters, imaging studies and histological findings, when available. Qualitative and semiquantitative analysis of the PET images was performed. The minimum duration of follow-up was 6 months. RESULTS: For the Disease Definition group, FDG-PET showed a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 92.9%, 50%, 72.2%, 83.3%, and 75%, respectively, and MRI showed a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100%, 50%, 76.9%, 100%, and 81.3%, respectively. For the Treatment Assessment group, FDG-PET showed a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 90%, 81.8%, 81.8%, 90%, and 85.7%, respectively, and MRI showed a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100%, 16.7%, 58.3%, 100% and 61.5%, respectively. No significant differences were observed between qualitative and semiquantitative evaluation of PET scans. CONCLUSION: PET and MRI showed similar accuracy in the diagnosis of spondylodiscitis, indicating that PET can be used when MRI is doubtful or unavailable. PET was more accurate and more specific than MRI in treatment assessment, suggesting that PET should be preferred over MRI for determining when treatment can be safely discontinued. PMID- 23358412 TI - Belling the cat--tagging live cells with quantum dots. PMID- 23358411 TI - Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome. AB - Ubiquitin-dependent proteolysis can initiate at ribosomes for myriad reasons including misfolding of a nascent chain or stalling of the ribosome during translation of mRNA. Clearance of a stalled complex is required to recycle the ribosome for future use. Here we show that the ubiquitin (Ub) pathway segregase Cdc48/p97 and its adaptors Ufd1-Npl4 participate in ribosome-associated degradation (RAD) by mediating the clearance of ubiquitinated, tRNA-linked nascent peptides from ribosomes. Through characterization of both endogenously generated and heterologous model substrates for the RAD pathway, we conclude that budding yeast Cdc48 functions downstream of the Ub ligases Ltn1 and Ubr1 to release nascent proteins from the ribosome so that they can be degraded by the proteasome. Defective RAD could contribute to the pathophysiology of human diseases caused by mutations in p97.DOI:http://dx.doi.org/10.7554/eLife.00308.001. PMID- 23358413 TI - Droplet digital PCR measurement of HER2 copy number alteration in formalin-fixed paraffin-embedded breast carcinoma tissue. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2) testing is routinely performed by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) analyses for all new cases of invasive breast carcinoma. IHC is easier to perform, but analysis can be subjective and variable. FISH offers better diagnostic accuracy and added confidence, particularly when it is used to supplement weak IHC signals, but it is more labor intensive and costly than IHC. We examined the performance of droplet digital PCR (ddPCR) as a more precise and less subjective alternative for quantifying HER2 DNA amplification. METHODS: Thirty-nine cases of invasive breast carcinoma containing >=30% tumor were classified as positive or negative for HER2 by IHC, FISH, or both. DNA templates for these cases were prepared from formalin-fixed paraffin-embedded (FFPE) tissues to determine the HER2 copy number by ddPCR. ddPCR involved emulsifying hydrolysis probe-based PCR reaction mixtures containing the ERBB2 [v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian); also known as HER2] gene and chromosome 17 centromere assays into nanoliter-sized droplets for thermal cycling and analysis. RESULTS: ddPCR distinguished, through differences in the level of HER2 amplification, the 10 HER2-positive samples from the 29 HER2-negative samples with 100% concordance to HER2 status obtained by FISH and IHC analysis. ddPCR results agreed with the FISH results for the 6 cases that were equivocal by IHC analyses, confirming 2 of these samples as positive for HER2 and the other 4 as negative. CONCLUSIONS: ddPCR can be used as a molecular-analysis tool to precisely measure copy number alterations in FFPE samples of heterogeneous breast tumor tissue. PMID- 23358414 TI - Metabolic risk factors are associated with stiffness index, reflection index and finger skin temperature in children--Physical Activity and Nutrition in Children (PANIC) study. AB - BACKGROUND: Childhood metabolic syndrome (MetS) has been found to predict adulthood MetS, type 2 diabetes and cardiovascular disease, emphasizing the early identification of children at increased risk of these diseases. Children with clustering of metabolic risk factors have been reported to have a mild arterial stiffness and endothelial dysfunction, but limited evidence is available from population-based samples of children. METHODS AND RESULTS: The associations of metabolic risk factors with arterial stiffness, tone and endothelial function were studied in 173 prepubertal children (90 girls) 6-8 years of age. MetS was assessed both by continuous MetScore and dichotomously. Stiffness index (SI), reflection index (RI) and finger skin temperature (FST) were measured before and after maximum exercise test, and percent change was calculated for RI (RI%Delta) and FST (FST%Delta). MetScore (r=0.26, P=0.001), fasting insulin (r=0.24, P=0.002), fasting triglycerides (r=0.20, P=0.009), systolic (SBP; r=0.24, P=0.002) and diastolic blood pressure (DBP; r=0.19, P=0.013) correlated with SI. MetScore (r=-0.17, P=0.024, r=0.21, P=0.006), waist circumference (r=-0.19, P=0.012, r=0.23, P=0.003) and SBP (r=-0.16, P=0.035, r=0.21, P=0.005) correlated with RI and FST. High-density lipoprotein cholesterol correlated with FST (r= 0.22, P=0.004) and FST%Delta (r=-0.24, P=0.002). RI decreased and FST increased with exercise (P<0.001). Waist circumference correlated inversely with RI%Delta in boys (r=-0.22, P=0.046) and directly with RI%Delta in girls (r=0.27, P=0.011). CONCLUSIONS: Metabolic risk factors are associated with arterial stiffness, tone and endothelial function in prepubertal children. PMID- 23358415 TI - gammaH2A-binding protein Brc1 affects centromere function in fission yeast. AB - The coordinated replication and transcription of pericentromeric repeats enable RNA interference (RNAi)-mediated transmission of pericentromeric heterochromatin in fission yeast, which is essential for the proper function of centromeres. Rad3/ATR kinase phosphorylates histone H2A on serine-128/-129 to create gammaH2A in pericentromeric heterochromatin during S phase, which recruits Brc1 through its breast cancer gene 1 protein (BRCA1) C-terminal (BRCT) domains. Brc1 prevents the collapse of stalled replication forks; however, it is unknown whether this activity influences centromere function. Here, we show that Brc1 localizes in pericentromeric heterochromatin during S phase, where it enhances Clr4/Suv39 mediated H3 lysine-9 dimethylation (H3K9me2) and gene silencing. Loss of Brc1 increases sensitivity to the microtubule-destabilizing drug thiabendazole (TBZ) and increases chromosome missegregation in the presence of TBZ. Brc1 retains significant function even when it cannot bind gammaH2A. However, elimination of the serine-121 site on histone H2A, a target of Bub1 spindle assembly checkpoint kinase, sensitizes gammaH2A-deficient and brc1Delta cells to replication stress and microtubule destabilization. Collective results suggest that Brc1-mediated stabilization of stalled replication forks is necessary for fully efficient transmission of pericentromeric heterochromatin, which is required for accurate chromosome segregation during mitosis. PMID- 23358416 TI - The piggyBac transposon displays local and distant reintegration preferences and can cause mutations at noncanonical integration sites. AB - The DNA transposon piggyBac is widely used as a tool in mammalian experimental systems for transgenesis, mutagenesis, and genome engineering. We have characterized genome-wide insertion site preferences of piggyBac by sequencing a large set of integration sites arising from transposition from two separate genomic loci and a plasmid donor in mouse embryonic stem cells. We found that piggyBac preferentially integrates locally to the excision site when mobilized from a chromosomal location and identified other nonlocal regions of the genome with elevated insertion frequencies. piggyBac insertions were associated with expressed genes and markers of open chromatin structure and were excluded from heterochromatin. At the nucleotide level, piggyBac prefers to insert into TA-rich regions within a broader GC-rich context. We also found that piggyBac can insert into sites other than its known TTAA insertion site at a low frequency (2%). Such insertions introduce mismatches that are repaired with signatures of host cell repair pathways. Transposons could be mobilized from plasmids with the observed noncanonical flanking regions, indicating that piggyBac could generate point mutations in the genome. PMID- 23358417 TI - The histone methyltransferase KMT2B is required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter. AB - KMT2B (MLL2/WBP7) is a member of the MLL subfamily of H3K4-specific histone lysine methyltransferases (KMT2) and is vital for normal embryonic development in the mouse. To gain insight into the molecular mechanism underlying KMT2B function, we focused on MagohB, which is controlled by a CpG island promoter. We show that in cells lacking Mll2-the gene encoding KMT2B-the MagohB promoter resides in inaccessible chromatin and is methylated. To dissect the molecular events leading to the establishment of silencing, we performed kinetic studies in Mll2-conditional-knockout embryonic stem cells. KMT2B depletion was followed by the loss of the active chromatin marks and progressive loss of RNA polymerase II binding with a concomitant downregulation of MagohB expression. Once the active chromatin marks were lost, the MagohB promoter was rapidly methylated. We demonstrate that in the presence of KMT2B, neither transcription elongation nor RNA polymerase II binding is required to maintain H3K4 trimethylation at the MagohB promoter and protect it from DNA methylation. Reexpression of KMT2B was sufficient to reinstate an active MagohB promoter. Our study provides a paradigm for the idea that KMT2 proteins are crucial components for establishing and maintaining the transcriptionally active and unmethylated state of CpG island promoters. PMID- 23358418 TI - Identification of a novel prenyl and palmitoyl modification at the CaaX motif of Cdc42 that regulates RhoGDI binding. AB - Membrane localization of Rho GTPases is essential for their biological functions and is dictated in part by a series of posttranslational modifications at a carboxyl-terminal CaaX motif: prenylation at cysteine, proteolysis of the aaX tripeptide, and carboxymethylation. The fidelity and variability of these CaaX processing steps are uncertain. The brain-specific splice variant of Cdc42 (bCdc42) terminates in a CCIF sequence. Here we show that brain Cdc42 undergoes two different types of posttranslational modification: classical CaaX processing or novel tandem prenylation and palmitoylation at the CCaX cysteines. In the dual lipidation pathway, bCdc42 was prenylated, but it bypassed proteolysis and carboxymethylation to undergo modification with palmitate at the second cysteine. The alternative postprenylation processing fates were conserved in the GTPases RalA and RalB and the phosphatase PRL-3, proteins terminating in a CCaX motif. The differentially modified forms of bCdc42 displayed functional differences. Prenylated and palmitoylated brain Cdc42 did not interact with RhoGDIalpha and was enriched in the plasma membrane relative to the classically processed form. The alternative processing of prenylated CCaX motif proteins by palmitoylation or by endoproteolysis and methylation expands the diversity of signaling GTPases and enables another level of regulation through reversible modification with palmitate. PMID- 23358421 TI - Long-term adherence to antiretroviral therapy in resource-limited settings: a bitter pill to swallow. AB - Adherence to antiretroviral therapy is an important predictor of long-term treatment success. Adherence can be differentiated between early adherence challenges, that are about integrating pill-taking into daily life, and long-term adherence, where patients struggle to maintain clinical connections and interrupt clinical care and medication use. In resource-limited settings, treatment interruptions may be more useful predictors of patient outcome than pill-taking alone. Interventions that are aimed at providing support to patients and their individual challenges to prevent interruptions in treatment and care may have a greater impact over time on clinically important outcomes than interventions targeted only at pill-taking behaviours. PMID- 23358419 TI - Receptor protein tyrosine phosphatase-receptor tyrosine kinase substrate screen identifies EphA2 as a target for LAR in cell migration. AB - Receptor tyrosine kinases (RTKs) exist in equilibrium between tyrosyl phosphorylated and dephosphorylated states. Despite a detailed understanding of how RTKs become tyrosyl phosphorylated, much less is known about RTK tyrosyl dephosphorylation. Receptor protein tyrosine phosphatases (RPTPs) can play essential roles in the dephosphorylation of RTKs. However, a complete understanding of the involvement of the RPTP subfamily in RTK tyrosyl dephosphorylation has not been established. In this study, we have employed a small interfering RNA (siRNA) screen to identify RPTPs in the human genome that serve as RTK phosphatases. We observed that each RPTP induced a unique fingerprint of tyrosyl phosphorylation among 42 RTKs. We identified EphA2 as a novel LAR substrate. LAR dephosphorylated EphA2 at phosphotyrosyl 930, uncoupling Nck1 from EphA2 and thereby attenuating EphA2-mediated cell migration. These results demonstrate that each RPTP exerts a unique regulatory fingerprint of RTK tyrosyl dephosphorylation and suggest a complex signaling interplay between RTKs and RPTPs. Furthermore, we observed that LAR modulates cell migration through EphA2 site-specific dephosphorylation. PMID- 23358420 TI - Large FK506-binding proteins shape the pharmacology of rapamycin. AB - The immunosuppressant and anticancer drug rapamycin works by inducing inhibitory protein complexes with the kinase mTOR, an important regulator of growth and proliferation. The obligatory accessory partner of rapamycin is believed to be FK506-binding protein 12 (FKBP12). Here we show that rapamycin complexes of larger FKBP family members can tightly bind to mTOR and potently inhibit its kinase activity. Cocrystal structures with FKBP51 and FKBP52 reveal the modified molecular binding mode of these alternative ternary complexes in detail. In cellular model systems, FKBP12 can be functionally replaced by larger FKBPs. When the rapamycin dosage is limiting, mTOR inhibition of S6K phosphorylation can be enhanced by FKBP51 overexpression in mammalian cells, whereas FKBP12 is dispensable. FKBP51 could also enable the rapamycin-induced hyperphosphorylation of Akt, which depended on higher FKBP levels than rapamycin-induced inhibition of S6K phosphorylation. These insights provide a mechanistic rationale for preferential mTOR inhibition in specific cell or tissue types by engaging specific FKBP homologs. PMID- 23358422 TI - Glomerular disease: An RCT of treatment for idiopathic membranous nephropathy. PMID- 23358423 TI - Mineral metabolism: Spironolactone and calcification. PMID- 23358425 TI - Can noninvasive imaging tools potentially predict the risk of ulceration in invasive melanomas showing blue and black colors? AB - The aim of this study was to evaluate the reflectance microscopy and histopathologic correlates of dermoscopic blue and black color (BB) in a series of melanomas. We searched our database for dermoscopic images of histopathologically diagnosed pigmented nodular melanomas (pNM), superficial spreading melanomas with a nodular component (SSM+Nod), and melanoma metastasis (METs). All cases were assessed for the presence of dermoscopic BB. Confocal microscopy findings were then compared with those of histopathology. A total of 17 BB-positive tumors including eight pNMs, five SSM+Nod, and four METs were included in the study. We identified two different dermoscopic patterns associated with black color, namely, large black blotches and irregular black dots/globules, which corresponded to two different confocal and histopathologic findings. Black blotches resulted from a total filling of the epidermis by an upward migration of melanocyte nests and pagetoid melanocytes as single cells and clusters, whereas black dots/globules also corresponded to the upward migration of melanocyte nests in the epidermis and pagetoid spread, but with sparing of intervening areas of epidermis. Interestingly, two pNM and two METs showing black color lacked any epidermal involvement and, instead, they were characterized by upward-bulging dermal masses of atypical melanocytes covered by an highly attenuated epidermis. In both cases, black color corresponded to pigment containing melanocytes in close proximity to the surface of the skin. Our study suggests that black color results not only from epidermal melanin but also from a dense dermal proliferation of pigmented melanocytes under a thinned epidermis. It seems reasonable to suggest that a bulging proliferation of dermal melanocytes beneath a thin epidermal layer could precede ulceration. As ulceration is a very significant prognostic factor, speculation arising from this study that dermoscopic black color may in some cases indicate incipient ulceration is worthy of further study. PMID- 23358424 TI - Noninsulin glucose-lowering agents for the treatment of patients on dialysis. AB - Chronic kidney disease (CKD) is a common complication of diabetes mellitus and the most common cause of end-stage renal disease (ESRD). As the worldwide prevalence of diabetes continues to increase, the number of patients with CKD will also increase. Therefore, it is essential that physicians know how to safely and effectively manage diabetes in the setting of CKD. Adequate glycaemic control in patients with diabetes is important to prevent ESRD and other complications and to decrease mortality. However, many glucose-lowering agents need to be dose adjusted or should not be used in the setting of stage 3 CKD or higher (defined as an estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m(2)), particularly in patients with stage 5 CKD (eGFR <15 ml/min/1.73 m(2)) and in those receiving dialysis. Insulin therapy is appropriate for patients undergoing dialysis; however, several orally administered glucose-lowering agents can also be used safely in these patients. In this Review, we provide an overview of the use of noninsulin glucose-lowering agents in the dialysis population. PMID- 23358426 TI - Long-term stabilization of leptomeningeal disease with whole-brain radiation therapy in a patient with metastatic melanoma treated with vemurafenib: a case report. AB - We present a patient with metastatic BRAF-mutated melanoma who achieved long-term stabilization of leptomeningeal disease (LMD) with sequential whole-brain radiation therapy and vemurafenib. A 53-year-old woman with melanoma that harbored the BRAF V600E mutation and had that metastasized to multiple lymph nodes, lungs, breast, and subcutaneous tissue had developed symptomatic LMD 16 months after starting vemurafenib treatment despite achieving a substantial response at the existing metastatic sites. Vemurafenib was discontinued for 7 days, she received whole-brain radiation therapy (30 Gy in 10 fractions), and 7 days after completing the radiation therapy, she resumed vemurafenib therapy. The neurologic symptoms improved significantly, and a cerebrospinal fluid examination revealed disappearance of melanoma cells. She remained alive with radiologically stable LMD for at least 18 months after the whole-brain radiation therapy. PMID- 23358427 TI - What are the pertinent quality-of-life issues for melanoma cancer patients? Aiming for the development of a new module to accompany the EORTC core questionnaire. AB - Melanoma is the most serious type of skin cancer. However, there is a paucity of evidence on the impact of melanoma on the quality of life (QoL) of patients. Only two clinically validated QoL instruments have been reported in the literature. The present study has identified contemporary QoL issues during a time of great change for melanoma treatment, as a precursor to an international study to develop a new melanoma-specific QoL instrument. Twenty-two melanoma patients (American Joint Committee on Cancer stages I-IV) and 10 close family members were recruited from a metropolitan tertiary referral clinical and research centre in Sydney, Australia, to participate in interview or focus group discussions. Verbatim transcripts of these recorded interviews were systematically analysed. Seventy-three issues across seven health-related QoL domains were identified. Issues across three domains featured highly; psychosocial, availability of support and information. Given the current rapid evolution of systemic therapies for melanoma, the challenges associated with treatment choices and clinical trial participation were also highlighted in this sample. Although some issues were generic in nature, experienced by many cancer patients, this study revealed that the wide range and intensity of QoL issues reported by melanoma patients are not adequately evaluated in current QoL instruments. With the increasing importance of patient reported outcome measurement, this list has been transformed into questionnaire items, in collaboration with the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Group, for testing a new melanoma specific QoL module for use with the EORTC core questionnaire (QLQ-C30). PMID- 23358428 TI - Difference of interferon-alpha and interferon-beta on melanoma growth and lymph node metastasis in mice. AB - Interferon (IFN)-alpha and IFN-beta are type I IFNs which are known to exert an antitumor effect on malignant melanoma. The aim of this study was to evaluate and compare the efficacy of IFN-alpha2b and IFN-beta1a on primary tumor growth and lymph node metastasis, and to examine the mechanisms of lymph node metastasis. The efficacy of IFN-alpha2b and IFN-beta1a was evaluated using a human melanoma xenograft model. We further examined the effect of IFNs on lymphangiogenic growth factors in human melanoma cells. IFN-beta1a showed a stronger antiproliferative and proapoptotic effect, whereas IFN-alpha2b inhibited tumor growth and lymph node metastasis through inhibition of lymphangiogenesis. Both IFN-alpha2b and IFN beta1a were effective in inhibiting lymph node metastasis compared with the control. Microvessel density decreased in tumors treated with IFN-alpha2b and IFN beta1a compared with the control, without statistical significance. Lymphatic vessel density decreased significantly only in tumors treated with IFN-alpha2b (P<0.05). Both IFN-alpha2b and IFN-beta1a decreased in-vitro and in-vivo vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 protein expression and secretory VEGF-C level in vitro. IFN-alpha2b showed an earlier and sustained effect in decreasing VEGF-C and VEGF receptor-3 protein expression and a superior effect in decreasing the secretory VEGF-C level compared with IFN-beta1a. Our investigation shows that both IFN-alpha2b and IFN-beta1a exerted different antitumor and antimetastatic effects in human melanoma xenograft. Moreover, the present findings indicate that inhibition of lymphangiogenesis is another possible antimetastatic action mechanism of IFN-alpha2b. PMID- 23358429 TI - Experimental hypoxia does not influence gene expression and protein synthesis of Eph receptors and ephrin ligands in human melanoma cells in vitro. AB - Eph receptor tyrosine kinases and their ephrin ligands are considered to play important roles in melanoma progression and metastasis. Moreover, hypoxia is known to contribute to melanoma metastasis. In this study, the influence of experimental hypoxia on the expression and synthesis of EphA2 and EphB4, and their corresponding ligands ephrinA1, ephrinA5, and ephrinB2 was studied systematically in four human melanoma cell lines in vitro. Melanoma cell monolayer and spheroid cultures were used as both extrinsic and intrinsic hypoxia models. Hypoxic conditions were confirmed by analyzing hypoxia-inducible factors 1alpha or 2alpha expression, vascular endothelial growth factor expression, and cellular uptake of [F]fluoromisonidazole. In normoxia, EphA2, EphB4, ephrinA1, ephrinA5, and ephrinB2 expression was detectable in all cell lines to varying extents. Considerable protein synthesis of EphA2 was detected in all cell lines. However, no effect of experimental hypoxia on both Eph/ephrin expression and protein synthesis was observed. This contributes critically to the debate on the hypothesis that hypoxia regulates the Eph/ephrin system in melanoma. PMID- 23358430 TI - Late downward dislocation of a balloon expandable valve into the left ventricular outflow tract following transfemoral transcatheter aortic valve implantation. PMID- 23358432 TI - Coronary vasospasm as an underlying etiology of out-of-hospital cardiac arrest. PMID- 23358431 TI - Association between J-point elevation and death from coronary artery disease--15 year follow up of the NIPPON DATA90. AB - BACKGROUND: An early repolarization pattern, characterized by an elevation of the QRS-ST junction (J-point) on 12-lead electrocardiography (ECG) is associated with cardiac and sudden death. However, little is known about the prognostic significance of J-point elevation for various disease-specific cardiovascular outcomes, including coronary artery disease (CAD). METHODS AND RESULTS: To investigate the association between the presence of J-point elevation>=0.1 mV and various disease-specific cardiovascular outcomes, we conducted a 15-year prospective study in a representative general Japanese population of 7,630 individuals (41% men, mean age 52.4 years) who participated in the National Survey of Circulatory Disorders. Cox models were used to estimate the hazard ratios (HRs) adjusted for possible confounding factors. J-point elevation was present in 264 individuals (3.5%) and was associated with an increased risk of cardiac death (adjusted HR, 2.54; 95% confidence interval [CI] 1.40-4.58; P=0.002) and death from CAD (adjusted HR, 4.66; 95% CI 2.30-9.46; P<0.001). In a subgroup analysis by age, the association between J-point elevation and cardiovascular outcomes was more remarkable in middle-aged (<60 years) than in older individuals (>=60 years) (all P for interaction<0.05). CONCLUSIONS: J-point elevation on standard 12-lead ECG was an independent predictor of cardiac death and death from CAD in a representative sample of the general Japanese population, particularly among the middle-aged. PMID- 23358433 TI - Extracellular matrix protein lumican promotes clearance and resolution of Pseudomonas aeruginosa keratitis in a mouse model. AB - Lumican is an extracellular protein that associates with CD14 on the surface of macrophages and neutrophils, and promotes CD14-TLR4 mediated response to bacterial lipopolysaccharides (LPS). Lumican-deficient (Lum(-/-)) mice and macrophages are impaired in TLR4 signals; raising the possibility that lumican may regulate host response to live bacterial infections. In a recent study we showed that invitro Lum(-/-) macrophages are impaired in phagocytosis of gram negative bacteria and in a lung infection model the Lum(-/-) mice showed poor survival. The cornea is an immune privileged barrier tissue that relies primarily on innate immunity to protect against ocular infections. Lumican is a major component of the cornea, yet its role in counteracting live bacteria in the cornea remains poorly understood. Here we investigated Pseudomonas aeruginosa infections of the cornea in Lum(-/-) mice. By flow cytometry we found that 24 hours after infection macrophage and neutrophil counts were lower in the cornea of Lum(-/-) mice compared to wild types. Infected Lum(-/-) corneas showed lower levels of the leukocyte chemoattractant CXCL1 by 24-48 hours of infection, and increased bacterial counts up to 5 days after infection, compared to Lum(+/-) mice. The pro-inflammatory cytokine TNF-alpha was comparably low 24 hours after infection, but significantly higher in the Lum(-/-) compared to Lum(+/-) infected corneas by 2-5 days after infection. Taken together, the results indicate that lumican facilitates development of an innate immune response at the earlier stages of infection and lumican deficiency leads to poor bacterial clearance and resolution of corneal inflammation at a later stage. PMID- 23358434 TI - Integration of nodal and BMP signals in the heart requires FoxH1 to create left right differences in cell migration rates that direct cardiac asymmetry. AB - Failure to properly establish the left-right (L/R) axis is a major cause of congenital heart defects in humans, but how L/R patterning of the embryo leads to asymmetric cardiac morphogenesis is still unclear. We find that asymmetric Nodal signaling on the left and Bmp signaling act in parallel to establish zebrafish cardiac laterality by modulating cell migration velocities across the L/R axis. Moreover, we demonstrate that Nodal plays the crucial role in generating asymmetry in the heart and that Bmp signaling via Bmp4 is dispensable in the presence of asymmetric Nodal signaling. In addition, we identify a previously unappreciated role for the Nodal-transcription factor FoxH1 in mediating cell responsiveness to Bmp, further linking the control of these two pathways in the heart. The interplay between these TGFbeta pathways is complex, with Nodal signaling potentially acting to limit the response to Bmp pathway activation and the dosage of Bmp signals being critical to limit migration rates. These findings have implications for understanding the complex genetic interactions that lead to congenital heart disease in humans. PMID- 23358435 TI - Thymolipoma with sebaceous differentiation: a hitherto unreported variant of thymolipoma. AB - Thymolipoma is a very rare anterior mediastinal mass of thymic origin, accounting for only 2% to 10% of all thymic neoplasm. Histologically, the tumor is usually composed of adipose tissue interspersed with thymic tissues. We report a case of a 58-year-old man who presented with a few weeks history of shortness of breath, cough, and chest pain, found to have a retrocardiac infiltrate on chest X-ray. Computed tomography scan of the chest showed a large anterior mediastinal mass. Surgical excision revealed an ovoid fatty mass, which on histological examination displayed thymic tissue intermixed with lipomatous tissue consistent with a thymolipoma. Of note was the presence of a microscopic nodule of thymic epithelial proliferation with sebaceous differentiation and focal cylindroma-like architecture. Although sebaceous tissue has been rarely reported in thymic tissue, to the best of our knowledge, this is the first case report of sebaceous differentiation in a thymolipoma. PMID- 23358436 TI - The prevalence and importance of crypt apoptosis, focal active cryptitis, and neutrophilic infiltrate of the lamina propria in colorectal adenomas. AB - Even though apoptotic bodies (ABs) are frequent in colorectal adenomas, their relevance has been covered only in a few studies. Focal active cryptitis (FAC) is a well-known manifestation of several etiologies; however, its prevalence and significance in colonic adenomas were not scrutinized. Likewise, whether the neutrophilic infiltrate of the lamina propria (LP) in colonic adenomas has a clinical or pathologic significance was not previously studied. We attempted to investigate the prevalence and importance of ABs in the cryptal epithelium and of neutrophils in the form of FAC and in the form of LP infiltrates in conventional colorectal adenomas. We conducted a retrospective review study over a 6-year period. We collected 223 conventional adenomas from 156 patients. We studied the interrelationship between these 3 histologic parameters and their potential association with other clinical and pathologic variables. Comparison controls included normal colonic mucosa, hyperplastic polyps, serrated adenomas, and flat adenomas. We found 91 (41%) adenomas to have crypt apoptosis, 40 (18%) to have FAC, and 69 (31%) to have neutrophilic infiltrate of the LP. We found ABs to be more frequent in high-grade adenomas. LP neutrophilic infiltrate was significantly associated with high-grade adenomas and in high-grade adenomas with invasive foci. In contrast, FAC was not associated with high-grade adenomas and was secondary to bowel preparations and drugs. Crypt apoptosis and LP neutrophils might have a potential prognostic value in predicting the biologic behavior of colonic adenomas. FAC in adenomas is a nonspecific finding of no prognostic significance and is related to external stimuli. PMID- 23358437 TI - Mucinous cystadenoma of the retroperitoneum. PMID- 23358438 TI - Subdural empyema presenting with seizure, confusion, and focal weakness. AB - While sinusitis is a common ailment, intracranial suppurative complications of sinusitis are rare and difficult to diagnose and treat. The morbidity and mortality of intracranial complications of sinusitis have decreased significantly since the advent of antibiotics, but diseases such as subdural empyemas and intracranial abscesses still occur, and they require prompt diagnosis, treatment, and often surgical drainage to prevent death or long-term neurologic sequelae. We present a case of an immunocompetent adolescent male with a subdural empyema who presented with seizures, confusion, and focal arm weakness after a bout of sinusitis. PMID- 23358439 TI - Analysis of factors influencing skip lymphatic metastasis in pN(2) non-small cell lung cancer. AB - OBJECTIVE: Although many clinical studies on skip lymphatic metastasis in non small cell lung cancer have been reported, the risk factors for skip lymphatic metastasis are still controversy and debatable. This study investigated, by multivariate logistic regression analysis, the clinical features of skip metastasis to mediastinal lymph nodes (N(2)) in non-small cell lung cancer (NSCLC) patients. METHODS: We collected the clinicopathological data of 256 pN(2) NSCLC patients who underwent lobectomy plus systemic lymph node dissection in Fujian Medical University Union Hospital. The cases in the present study were divided into two groups: skip metastasis (N(2) skip+) and non- skip metastasis (N(2) skip-). A retrospective analysis of clinical pathological features of two groups was performed. To determine an independent factor, multivariate logistic regression analysis was used to identify possible risk factors. RESULTS: A total of 256 pN(2)-NSCLC patients were recruited. The analysis results showed that gender, pathologic types, surgery, pleural involvement, smoking history, age, tumor stages, and differentiation were not statistical significant factors impacting on skip metastasis in pN(2)-NSCLC (P>0.05), whereas tumor size was an independent factor for skip metastasis (P=0.02). CONCLUSIONS: The rate of skip lymphatic metastasis increases in pN(2)-NSCLC patients, in accompany with an increased tumor size. PMID- 23358440 TI - Pneumothorax in a single lung patient. PMID- 23358442 TI - Sellar Chordoma Presenting as Pseudo-macroprolactinoma with Unilateral Third Cranial Nerve Palsy. AB - We described a 61-year-old female with a sellarchordoma, which presented as pseudo-macroprolactinoma with unilateral third cranial nerve palsy. Physical examination revealed that her right upper lid could not be raised by itself, right eyeball movement limited to the abduction direction, right pupil dilated to 4.5 mm with negative reaction to light, and hemianopsia in bitemporal sides. CT scanning showed a hyperdense lesion at sellar region without bone destruction. Magnetic resonance imaging (MRI) revealed the tumor was 2.3 cm*1.8 cm*2.6 cm, with iso-intensity on T1WI, hyper-intensity on T2WI and heterogeneous enhancement on contrast imaging. Endocrine examination showed her serum prolactin level increased to 1,031.49 mIU/ml. The tumor was sub-totally resected via pterional craniotomy under microscope and was histologically proven to be a chordoma. Postoperatively, she recovered uneventfully but ptosis and hemianopsia remained at the 6th month. PMID- 23358441 TI - Preconditioning with hemin decreases Plasmodium chabaudi adami parasitemia and inhibits erythropoiesis in BALB/c mice. AB - Increased susceptibility to bacterial and viral infections and dysfunctional erythropoiesis are characteristic of malaria and other hemolytic hemoglobinopathies. High concentrations of free heme are common in these conditions but little is known about the effect of heme on adaptive immunity and erythropoiesis. Herein, we investigated the impact of heme (hemin) administration on immune parameters and steady state erythropoiesis in BALB/c mice, and on parasitemia and anemia during Plasmodium chabaudi adami infection. Intra peritoneal injection of hemin (5 mg/Kg body weight) over three consecutive days decreased the numbers of splenic and bone marrow macrophages, IFN-gamma responses to CD3 stimulation and T(h)1 differentiation. Our results show that the numbers of erythroid progenitors decreased in the bone marrow and spleen of mice treated with hemin, which correlated with reduced numbers of circulating reticulocytes, without affecting hemoglobin concentrations. Although blunted IFN-gamma responses were measured in hemin-preconditioned mice, the mice developed lower parasitemia following P.c.adami infection. Importantly, anemia was exacerbated in hemin preconditioned mice with malaria despite the reduced parasitemia. Altogether, our data indicate that free heme has dual effects on malaria pathology. PMID- 23358443 TI - The flare up of catastrophic antiphospholipid syndrome: a report of an immunosuppressive withdrawal-induced case. AB - Antiphospholipid syndrome (APS) is a systemic disease that causes venous and arterial thrombosis in virtually any organ. Sometimes it is complicated into pulmonary infarction and cavitation, pulmonary hypertension, and catastrophic course with high morbidity and mortality. The present case is a 35-year-old woman with one episode of postpartum deep veins thrombosis (DVT) 12 years earlier and the second one after the second labor two years later. In spite of usual therapy for each episode of DVT, the condition had progressed into severe pulmonary hypertension. The diagnosis of primary APL syndrome was confirmed four years ago. She had been on warfarin, low dose of steroid, and azathioprine since the diagnosis of APL syndrome. After one year treatment with steroid and azathiprine the patient showed progressive well being; however, because of hyperglycemia the steroid tapered and discontinued. She had several attacks of paroxismal atrial tachycardia in the last year. On the last time, she presented with severe dyspnea, hemoptesis, and lower limbs edema. Chest radiography and Lung CT scan demonsterated the presence of lung cavitations. Because of high suspicious for fungal pulmonary infection, azathioprine was also discontinued. However, constellation renal failure, hemodynamic instability, and confusion caused the patient to succumb to death. The definite diagnosis of lung cavitations was not obtained. PMID- 23358444 TI - Synthesis, characterization and target protein binding of drug-conjugated quantum dots in vitro and in living cells. AB - Elucidation of unknown target proteins of a drug is of great importance in understanding cell biology and drug discovery. There have been extensive studies to discover and identify target proteins in the cell. Visualization of targets using drug-conjugated probes has been an important approach to gathering mechanistic information of drug action at the cellular level. As quantum dot (QD) nanocrystals have attracted much attention as a fluorescent probe in the bioimaging area, we prepared drug-conjugated QD to explore the potential of target discovery. As a model drug, we selected a well-known anticancer drug, methotrexate (MTX), which has been known to target dihydrofolate reductase (DHFR) with high affinity binding (K(d) = 0.54 nM). MTX molecules were covalently attached to amino-PEG-polymer-coated QDs. Specific interactions of MTX-conjugated QDs with DHFR were identified using agarose gel electrophoresis and fluorescence microscopy. Cellular uptake of the MTX-conjugated QDs in living CHO cells was investigated with regard to their localization and distribution pattern. MTX-QD was found to be internalized into the cells via caveolae-medicated endocytosis without significant sequestration in endosomes. A colocalization experiment of the MTX-QD conjugate with antiDHFR-TAT-QD also confirmed that MTX-QD binds to the target DHFR. This study showed the potential of the drug-QD conjugate to identify or visualize drug-target interactions in the cell, which is currently of great importance in the area of drug discovery and chemical biology. PMID- 23358445 TI - Post splenectomy fatal pulmonary embolism in a patient with moderate hemophilia a. AB - Hemophilia A is a bleeding disorder caused by defective production of factor VIII. The main concern associated with the disease is bleeding, especially after trauma and surgeries. Factor VIII replacement therapy is associated with substantial decrease of bleeding events during surgery. However, there have been a number of reports of thromboemblic events in this situation. The present report describes a case of moderate hemophilia A in which splenectomy did lead to pulmonary embolism and subsequent death.The patient was a 25-year-old man with hemophilia A admitted after a car accident and trauma to left lower chest and abdomen. He received factor VIII concentrates for replacement therapy. He was hemodynamically stable on the first day, but on the second day his hemoglobin declined and he showed signs of abdominal tenderness. He, therefore, was subjected to laparatomy and splenectomy. After the operation, he suddenly developed dyspnea and decline in blood pressure, and death afterwards. Autopsy of the patient revealed massive pulmonary thromboembolism. The symptoms and outcome of the present case indicate that although pulmonary thromboembolism in the early postoperative period in patients with hemophilia A undergoing splenectomy and receiving factor VIII concentrate for replacement is rare, it should not be assumed a far-fetched event, and prophylactic measures to prevent thromboemboly must be considered. PMID- 23358446 TI - Early routine angioplasty versus selective angioplasty after successful thrombolysis in acute ST-segment elevation myocardial infarction. AB - OBJECTIVES: The aim of this study was to evaluate the safety and feasibility of early angioplasty within 12 h and selective angioplasty 1 week later after successful thrombolysis in acute ST-segment elevation myocardial infarction. METHODS: A total of 224 patients with acute ST-segment elevation myocardial infarction who received thrombolysis with reteplase were randomly assigned to an early percutaneous coronary intervention (E-PCI) group or a selective PCI (S-PCI) group. Patients assigned to the E-PCI group received PCI within 12 h after randomization, and patients assigned to the S-PCI group received PCI 1 week later after randomization. The primary end point was a combined end point consisting of death, reinfarction, recurrent ischemia and congestive heart failure during hospitalization. The secondary end points included death, reinfarction, recurrent ischemia, and repeat PCI during 12 months of follow-up. RESULTS: The baseline clinical characteristics were well balanced between the two groups. The primary end point rate was significantly higher in the S-PCI group compared with the E PCI group (14.3 vs. 4.5%, P=0.0219). Fewer episodes of recurrent ischemia were observed in the E-PCI group compared with the S-PCI group during hospital stay (0.0 vs. 6.3%, P=0.0212). There were no significant differences in death, reinfarction, recurrent ischemia and repeat PCI between the two groups during 12 months of follow-up. CONCLUSION: For patients presenting with an ST-segment elevation myocardial infarction who could not undergo timely primary PCI, thrombolysis followed by PCI within 12 h was a preferred reperfusion strategy and associated with a significant reduction in the recurrent ischemia during hospitalization. PMID- 23358448 TI - Three-dimensional neuroepithelial culture from human embryonic stem cells and its use for quantitative conversion to retinal pigment epithelium. AB - A goal in human embryonic stem cell (hESC) research is the faithful differentiation to given cell types such as neural lineages. During embryonic development, a basement membrane surrounds the neural plate that forms a tight, apico-basolaterally polarized epithelium before closing to form a neural tube with a single lumen. Here we show that the three-dimensional epithelial cyst culture of hESCs in Matrigel combined with neural induction results in a quantitative conversion into neuroepithelial cysts containing a single lumen. Cells attain a defined neuroepithelial identity by 5 days. The neuroepithelial cysts naturally generate retinal epithelium, in part due to IGF-1/insulin signaling. We demonstrate the utility of this epithelial culture approach by achieving a quantitative production of retinal pigment epithelial (RPE) cells from hESCs within 30 days. Direct transplantation of this RPE into a rat model of retinal degeneration without any selection or expansion of the cells results in the formation of a donor-derived RPE monolayer that rescues photoreceptor cells. The cyst method for neuroepithelial differentiation of pluripotent stem cells is not only of importance for RPE generation but will also be relevant to the production of other neuronal cell types and for reconstituting complex patterning events from three-dimensional neuroepithelia. PMID- 23358447 TI - Regulation of innate immunity by extracellular nucleotides. AB - Extracellular ATP (eATP) is the most abundant among extracellular nucleotides and is commonly considered as a classical danger signal, which stimulates immune responses in the presence of tissue injury. In fact, increased nucleotide concentration in the extracellular space is generally closely associated with tissue stress or damage. However non-lytic nucleotide release may also occur in many cell types under a variety of conditions. Extracellular nucleotides are sensed by a class of plasma membrane receptors called P2 purinergic receptors (P2Rs). P2 receptors are expressed by all immunological cells and their activation elicits different responses. Extracellular ATP can act as an initiator or terminator of immune responses being able to induce different effects on immune cells depending on the pattern of P2 receptors engaged, the duration of the stimulus and its concentration in the extracellular milieu. Millimolar (high) concentrations of extracellular ATP, induce predominantly proinflammatory effects, while micromolar (low) doses exert mainly tolerogenic/immunosuppressive action. Moreover small, but significant differences in the pattern of P2 receptor expression in mice and humans confer diverse capacities of ATP in regulating the immune response. PMID- 23358449 TI - Noninvasive urine-derived cell lines derived from neurological genetic patients. AB - Many major inherited neurological disorders are characterized by early childhood onset, high lethality rate, and the absence of effective treatments. A poor understanding of the underlying mechanisms of such disorders is partly because of the scarcity of patient-specific samples. In this study, we cultured the urine sediments of such patients, aiming to explore the capacity of urine cell cultures to obtain specimens from patients suffering from rare inherited neurological diseases. We collected fresh urine from a variety of neurogenetic patients; cultured the specimens; generated different urine cell lines; and classified these cell lines through morphology, reverse transcription-PCR, and immunofluorescence. We then used these cell lines to detect the affected genes in spinal muscular atrophy and Duchenne muscular dystrophy. We successfully established cell lines from patients with spinal muscular atrophy, Duchenne muscular dystrophy, paroxysmal kinesigenic dyskinesia, and Wilson's disease. All established cell lines consisted of urinary tract epithelial cells and podocytes, and had the same gene defects as the blood specimens. Urine cell culture is thus a new, simple, and noninvasive avenue for getting patient-specific samples not only for genetic diagnosis, but also for storing the samples from patients with rare neurological inherited diseases. PMID- 23358450 TI - Salidroside promotes peripheral nerve regeneration following crush injury to the sciatic nerve in rats. AB - Salidroside (SDS), a phenylpropanoid glycoside isolated from Rhodiola rosea L., has been reported to be neuroprotective in vitro, which raises the possibility of using SDS as a neuroprotective agent after nerve injuries. In the present study, the possibly beneficial effect of SDS on promoting nerve regeneration after sciatic nerve crush injury in rats was investigated. Rats with sciatic nerve crush injury were administered intraperitoneally daily with 5 or 10 mg/kg body weight of SDS for 4 weeks. Rats that received mecobalamin or saline were considered as a positive or a negative control, respectively. Morphometric analysis of regenerated nerves and Fluoro-Gold retrograde tracing was used to evaluate axonal regeneration, whereas walking track analysis, electrophysiological assessment, and histological appearance of target muscles were carried out to evaluate the recovery of motor function. The results showed that SDS achieved functionally successful nerve regeneration in the rat sciatic nerve crush injury model, indicating that SDS holds potential as a neuroprotective agent for peripheral nerve therapies. PMID- 23358452 TI - Extended-release hydrocodone - gift or curse? AB - Hydrocodone is a semisynthetic opioid, which has been used for decades as a short acting analgesic combined with acetaminophen (or less commonly ibuprofen). Several long-acting, non-acetaminophen-containing hydrocodone formulations are undergoing trials in the US under the auspices of the US Food and Drug Administration, and may be available shortly. This article reviews some of the advantages (including drug familiarity and lack of acetaminophen toxicity) and potential disadvantages (including altered use patterns and high morphine equivalent dosing) of such a medication formulation. We also discuss the abuse potential of long-acting versus short-acting opioids in general and hydrocodone specifically, as well as the metabolism of hydrocodone. PMID- 23358453 TI - Melatonin inhibits the expression of vascular endothelial growth factor in pancreatic cancer cells. AB - OBJECTIVE: To investigate the effects of melatonin on cellular proliferation and endogenous vascular endothelial growth factor (VEGF) expression in pancreatic carcinoma cells (PANC-1). METHODS: PANC-1 cells were cultured for this study. The secreted VEGF concentration in the culture medium was determined using ELISA method, VEGF production in the tumor cells was detected by immunocytochemistry, and VEGF mRNA expression was determined by RT-PCR. RESULTS: Higher melatonin concentrations significantly inhibited cellular proliferation, with 1 mmol/L concentration exhibiting the highest inhibitory effect (P<0.01). VEGF concentrations in the cell culture supernatants and intra-cellules were all significantly reduced after melatonin (1 mmol/L) incubation (P<0.05). VEGF mRNA expression decreased markedly in a time-dependent manner during the observation period (P<0.05). CONCLUSIONS: High melatonin concentrations markedly inhibited the proliferation of pancreatic carcinoma cells. The endogenous VEGF expression was also suppressed by melatonin incubation. PMID- 23358451 TI - The scaffolding protein SYD-2/Liprin-alpha regulates the mobility and polarized distribution of dense-core vesicles in C. elegans motor neurons. AB - The polarized trafficking of axonal and dendritic components is essential for the development and maintenance of neuronal structure and function. Neuropeptide containing dense-core (DCVs) vesicles are trafficked in a polarized manner from the cell body to their sites of release; however, the molecules involved in this process are not well defined. Here we show that the scaffolding protein SYD 2/Liprin-alpha is required for the normal polarized localization of Venus-tagged neuropeptides to axons of cholinergic motor neurons in C. elegans. In syd-2 loss of function mutants, the normal polarized localization of INS-22 neuropeptide containing DCVs in motor neurons is disrupted, and DCVs accumulate in the cell body and dendrites. Time-lapse microscopy and kymograph analysis of mobile DCVs revealed that syd-2 mutants exhibit decreased numbers of DCVs moving in both anterograde and retrograde directions, and a corresponding increase in stationary DCVs in both axon commissures and dendrites. In addition, DCV run lengths and velocities were decreased in both axon commissures and dendrites of syd-2 mutants. This study shows that SYD-2 promotes bi-directional mobility of DCVs and identifies SYD-2 as a novel regulator of DCV trafficking and polarized distribution. PMID- 23358454 TI - Glucose-stimulated calcium dynamics in islets of Langerhans in acute mouse pancreas tissue slices. AB - In endocrine cells within islets of Langerhans calcium ions couple cell stimulation to hormone secretion. Since the advent of modern fluorimetry, numerous in vitro studies employing primarily isolated mouse islets have investigated the effects of various secretagogues on cytoplasmic calcium, predominantly in insulin-secreting beta cells. Due to technical limitations, insights of these studies are inherently limited to a rather small subpopulation of outermost cells. The results also seem to depend on various factors, like culture conditions and duration, and are not always easily reconcilable with findings in vivo. The main controversies regard the types of calcium oscillations, presence of calcium waves, and the level of synchronized activity. Here, we set out to combine the in situ acute mouse pancreas tissue slice preparation with noninvasive fluorescent calcium labeling and subsequent confocal laser scanning microscopy to shed new light on the existing controversies utilizing an innovative approach enabling the characterization of responses in many cells from all layers of islets. Our experiments reproducibly showed stable fast calcium oscillations on a sustained plateau rather than slow oscillations as the predominant type of response in acute tissue slices, and that calcium waves are the mechanistic substrate for synchronization of oscillations. We also found indirect evidence that even a large amplitude calcium signal was not sufficient and that metabolic activation was necessary to ensure cell synchronization upon stimulation with glucose. Our novel method helped resolve existing controversies and showed the potential to help answer important physiological questions, making it one of the methods of choice for the foreseeable future. PMID- 23358456 TI - Determination of normal range of bleeding time in rural and urban residents of Borujerd, Iran: A pilot study. AB - BACKGROUND: Bleeding time test is used to assess the function of platelets in human body. The aim of this project was thus to estimate the sample size required to determine the normal range of bleeding time (BT) in Borujerd (a city in Iran). A pilot study was designed to determine the range of normal BT in a small group of normal people. The total sample size for the next study was then calculated according to the results. METHODS: In order to determine the sample size, a total of 33 volunteers participated in this study. The normal range of BT was determined by Ivy method. Written informed consents were obtained from all participants and their clinical history was recorded. The sampling was performed once for each participant. However, the results were interpreted by two observers. The study protocol was approved by the Ethics Committee of the research center at Lorestan University of Medical Sciences (Iran). RESULTS: In this study, 33 normal participants (20 women and 13 men) were divided into four age groups of 35-44, 45-54, 55-64 and over 64 years old. Maximum and minimum BTs in men were 209 (in the age group of 35-44 years) and 150 seconds (in the age group of over 64 years), respectively. On the other hand, the corresponding values in women were 194 (in 55-64 year-old subjects) and 145 seconds (in women over 64 years of age). Considering the aforementioned results, the total sample size for the next study was determined to be 580 normal subjects by two-sample t test power analysis at a power of 0.91816. CONCLUSION: There was a significant difference between the normal range of BT in participants of Borujerd and previously recorded range in other studies. Moreover, normal BT in men decreased by aging. This study did not show any special order in increasing or decreasing BT in women. PMID- 23358455 TI - Delineating a conserved genetic cassette promoting outgrowth of body appendages. AB - The acquisition of the external genitalia allowed mammals to cope with terrestrial-specific reproductive needs for internal fertilization, and thus it represents one of the most fundamental steps in evolution towards a life on land. How genitalia evolved remains obscure, and the key to understanding this process may lie in the developmental genetics that underpins the early establishment of the genital primordium, the genital tubercle (GT). Development of the GT is similar to that of the limb, which requires precise regulation from a distal signaling epithelium. However, whether outgrowth of the GT and limbs is mediated by common instructive signals remains unknown. In this study, we used comprehensive genetic approaches to interrogate the signaling cascade involved in GT formation in comparison with limb formation. We demonstrate that the FGF ligand responsible for GT development is FGF8 expressed in the cloacal endoderm. We further showed that forced Fgf8 expression can rescue limb and GT reduction in embryos deficient in WNT signaling activity. Our studies show that the regulation of Fgf8 by the canonical WNT signaling pathway is mediated in part by the transcription factor SP8. Sp8 mutants elicit appendage defects mirroring WNT and FGF mutants, and abolishing Sp8 attenuates ectopic appendage development caused by a gain-of-function beta-catenin mutation. These observations indicate that a conserved WNT-SP8-FGF8 genetic cassette is employed by both appendages for promoting outgrowth, and suggest a deep homology shared by the limb and external genitalia. PMID- 23358457 TI - Chronic alcohol exposure renders epithelial cells vulnerable to bacterial infection. AB - Despite two centuries of reports linking alcohol consumption with enhanced susceptibility to bacterial infections and in particular gut-derived bacteria, there have been no studies or model systems to assess the impact of long-term alcohol exposure on the ability of the epithelial barrier to withstand bacterial infection. It is well established that acute alcohol exposure leads to reduction in tight and adherens junctions, which in turn leads to increases in epithelial cellular permeability to bacterial products, leading to endotoxemia and a variety of deleterious effects in both rodents and human. We hypothesized that reduced fortification at junctional structures should also reduce the epithelial barrier's capacity to maintain its integrity in the face of bacterial challenge thus rendering epithelial cells more vulnerable to infection. In this study, we established a cell-culture based model system for long-term alcohol exposure to assess the impact of chronic alcohol exposure on the ability of Caco-2 intestinal epithelial cells to withstand infection when facing pathogenic bacteria under the intact or wounded conditions. We report that daily treatment with 0.2% ethanol for two months rendered Caco-2 cells far more susceptible to wound damage and cytotoxicity caused by most but not all bacterial pathogens tested in our studies. Consistent with acute alcohol exposure, long-term ethanol exposure also adversely impacted tight junction structures, but in contrast, it did not affect the adherens junction. Finally, alcohol-treated cells partially regained their ability to withstand infection when ethanol treatment was ceased for two weeks, indicating that alcohol's deleterious effects on cells may be reversible. PMID- 23358458 TI - 'Cryptic' exons reveal some of their secrets. AB - By regulating the inclusion of 'cryptic' exons in messenger RNA in nerve cells, NOVA proteins are able to influence the abundance of the corresponding proteins. PMID- 23358459 TI - Pregnancy-related acute myocardial infarction in Japan. PMID- 23358460 TI - Post-infarction inflammation and left ventricular remodeling: a double-edged sword. AB - After myocardial infarction (MI), inflammatory cells such as neutrophils, followed by monocytes and macrophages, infiltrate and phagocytose the necrotic tissues, as well as secreting a variety of inflammatory cytokines. The vulnerable myocardium, which consists of necrotic tissue and inflammatory cells, is susceptible to wall stress, resulting in infarct expansion. Subacute cardiac rupture is an extreme form of infarct expansion, whereas ventricular aneurysm is its chronic form and a trigger for subsequent left ventricular (LV) remodeling. Although post-infarction inflammation is essential for the healing process, excessive inflammation could play an important role in the development of LV remodeling. Increase in the C-reactive protein level, which reflects myocardial inflammation, is reported to be a useful predictive marker for cardiac rupture, ventricular aneurysm and LV remodeling. In addition, an increase in peripheral monocyte count is associated with a poor outcome after MI, and an animal study has demonstrated that granulocyte/macrophage-colony stimulating factor induction causes excessive macrophage infiltration in the infarcted area and worsening of LV remodeling. Recently, it was also found that dendritic cells play an important role in controlling excessive inflammation caused by monocytes/macrophages. Thus, inflammation that develops after MI is a double-edged sword, and how to control inflammation to suppress pathological remodeling is an important issue to be considered in developing new treatment for heart failure. PMID- 23358461 TI - One in a million: a case of arm and leg pain and deformity. PMID- 23358462 TI - Weight loss and reduction in gastroesophageal reflux. A prospective population based cohort study: the HUNT study. AB - OBJECTIVES: High body mass index (BMI) is an established risk factor of gastroesophageal reflux symptoms (GERS). The aim of this study was to clarify if weight loss reduces GERS. METHODS: The study was part of the Nord-Trondelag health study (the HUNT study), a prospective population-based cohort study conducted in Nord-Trondelag County, Norway. All residents of the county from 20 years of age were invited. In 1995-1997 (HUNT 2) and 2006-2009 (HUNT 3), 58,869 and 44,997 individuals, respectively, responded to a questionnaire on heartburn and acid regurgitation. Among these, 29,610 individuals (61% response rate) participated at both times and were included in the present study. The association between weight loss and reduction of GERS was calculated using logistic regression. The analyses were stratified by antireflux medication and the results adjusted for sex, age, cigarette smoking, alcohol consumption, education, and physical exercise. RESULTS: Weight loss was dose-dependently associated with a reduction of GERS and an increased treatment success with antireflux medication. Among individuals with >3.5 units decrease in BMI, the adjusted odds ratio (OR) of loss of any (minor or severe) GERS was 1.98 (95% confidence interval (CI) 1.45-2.72) when using no or less than weekly antireflux medication, and 3.95 (95% CI 2.03-7.65) when using at least weekly antireflux medication. The corresponding ORs of loss of severe GERS was 0.90 (95% CI 0.32 2.55) and 3.11 (95% CI 1.13-8.58). CONCLUSIONS: Weight loss was dose-dependently associated with both a reduction of GERS and an increased treatment success with antireflux medication in the general population. PMID- 23358463 TI - Assessment and protection of esophageal mucosal integrity in patients with heartburn without esophagitis. AB - OBJECTIVES: Intact esophageal mucosal integrity is essential to prevent symptoms during gastroesophageal reflux events. Approximately 70% of patients with heartburn have macroscopically normal esophageal mucosa. In patients with heartburn, persistent functional impairment of esophageal mucosal barrier integrity may underlie remaining symptoms. Topical protection of a functionally vulnerable mucosa may be an attractive therapeutic strategy. We aimed to evaluate esophageal mucosal functional integrity in patients with heartburn without esophagitis, and test the feasibility of an alginate-based topical mucosal protection. METHODS: Three distal esophageal biopsies were obtained from 22 patients with heartburn symptoms, and 22 control subjects. In mini-Ussing chambers, the change in transepithelial electrical resistance (TER) of biopsies when exposed to neutral, weakly acidic, and acidic solutions was measured. The experiment was repeated in a further 10 patients after pretreatment of biopsies with sodium alginate, viscous control, or liquid control "protectant" solutions. RESULTS: Biopsy exposure to neutral solution caused no change in TER. Exposure to weakly acidic and acidic solutions caused a greater reduction in TER in patients than in controls (weakly acid -7.2% (95% confidence interval (CI) -9.9 to -4.5) vs. 3.2% (-2.2 to 8.6), P<0.05; acidic -22.8% (-31.4 to 14.1) vs. -9.4% (-17.2 to -1.6), P<0.01). Topical pretreatment with alginate but not with control solutions prevented the acid-induced decrease in TER (-1% (-5.9 to 3.9) vs. -13.5 (-24.1 to -3.0) vs. -13.2 (-21.7 to -4.8), P<0.05). CONCLUSIONS: Esophageal mucosa in patients with heartburn without esophagitis shows distinct vulnerability to acid and weakly acidic exposures. Experiments in vitro suggest that such vulnerable mucosa may be protected by application of an alginate-containing topical solution. PMID- 23358464 TI - Uterotrophic assay of percutaneous lavender oil in immature female rats. AB - The estrogenic potential of lavender oil was evaluated in a percutaneous uterotrophic bioassay in immature female rats. Four groups of 10 immature female rats each were randomly selected on postpartum day (PPD) 16. During the 3-day treatment period (PPDs 19-21), the immature rats were separated from the dams, caged in groups of 5 in a litter box for 6 hours, and administered the vehicle control article (corn oil) or lavender oil at 20 or 100 mg/kg per day. All dosages were administered as a 5 mL/kg volume in a Hilltop Chamber (25 mm diameter; absorbent material removed) placed on the shaved back of each immature rat, and secured with micropore tape and Vetrap. A positive control group was gavaged twice daily with 2.5 MUg/kg per day of 17alpha-ethinyl estradiol. Daily observations included viability, clinical signs, body weights, and body weight gains. All rats were euthanized 24 hours after the third and final treatment, the uteri and ovaries were removed, and the paired ovaries and wet and blotted uterine weights were recorded. No unscheduled deaths occurred. No skin reactions were observed. Both dosages of lavender oil significantly reduced body weight gains after the third day of treatment, but terminal body weights and mean absolute and relative uterine weights did not differ significantly from vehicle control values. Positive controls showed significant increases in body weight and increased mean absolute and relative uterine weights as expected. Based on these data, lavender oil, at dosages of 20 or 100 mg/kg, was not active in the rat uterotrophic assay and gave no evidence of estrogenic activity. PMID- 23358465 TI - Effect of Trastuzumab on Notch-1 Signaling Pathway in Breast Cancer SK-BR3 Cells. AB - OBJECTIVE: To investigate the effects and mechanisms of trastuzumab on Notch-1 pathway in breast cancer cells, recognizing the significance of Notch-1 signaling pathway in trastuzumab resistance. METHODS: Immunocytochemistry staining and Western blotting were employed to justify the expression of Notch-1 protein in HER2-overexpressing SK-BR3 cells and HER2-non-overexpressing breast cancer MDA-MB 231 cells. Western blotting and reverse transcription PCR (RT-PCR) were used to detect the activated Notch-1 and Notch-1 target gene HES-1 mRNA expression after SK-BR3 cells were treated with trastuzumab. Double immunofluorescence staining and co-immunoprecipitation were used to analyze the relationship of Notch-1 and HER2 proteins. RESULTS: The level of Notch-1 nuclear localization and activated Notch-1 proteins in HER2-overexpressing cells were significantly lower than in HER2-non-overexpressing cells (P<0.01), and the expressions of activated Notch-1 and HES-1 mRNA were obviously increased after trastuzumab treatment (P<0.05), but HER2 expression did not change significantly for trastuzumab treating (P>0.05). Moreover, Notch-1 was discovered to co-localize and interact with HER2 in SK-BR3 cells. CONCLUSION: Overexpression of HER2 decreased Notch-1 activity by the formation of a HER2-Notch1 complex, and trastuzumab can restore the activity of Notch-1 signaling pathway, which could be associated with cell resistance to trastuzumab. PMID- 23358466 TI - Poly(amino acid) functionalized maghemite and gold nanoparticles. AB - Bimodal MRI/OI imaging probes are of great interest in nanomedicine. Although many organic polymers have been studied thoroughly for in vivo applications, reports on the use of poly(amino acid)s as coating polymers are scarce. In this paper, poly-(d-glutamic acid, d-lysine) (PGL) has been used for coating maghemite and gold nanoparticles. An advantage of this flexible and biocompatible polymer is that, once anchored to the nanoparticle surface, dangling lysine amino groups are available for the incorporation of new functionalities. As an example, Alexa Fluor derivatives have been attached to PGL-coated maghemite nanoparticles to obtain magnetic/fluorescent materials. These dual-property materials could be used as bimodal MRI/OI probes for in vivo imaging. PMID- 23358467 TI - Prognostic impact of Fas-associated death domain, a key component in death receptor signaling, is dependent on the presence of lymph node metastasis in head and neck squamous cell carcinoma. AB - FAS-associated death domain (FADD) is a key adaptor protein that bridges a death receptor (e.g., death receptor 5; DR5) to caspase-8 to form the death-inducing signaling complex during apoptosis. The expression and prognostic impact of FADD in head and neck squamous cell carcinoma (HNSCC) have not been well studied. This study focuses on detecting FADD expression and analyzing its prognostic impact in primary and metastatic HNSCCs. We found a significant increase in FADD expression in primary tumors with lymph node metastasis (LNM) in comparison with primary tumors with no LNM. This increase was significantly less in the matched LNM tissues. Both univariate and multivariable analyses indicated that lower FADD expression was significantly associated with better disease-free survival and overall survival in HNSCC patients with LNM although FADD expression did not significantly affect survival of HNSCC patients without LNM . When combined with DR5 or caspase-8 expression, patients with LNM expressing both low FADD and DR5 or both low FADD and caspase-8 had significantly better prognosis than those expressing both high FADD and DR5 or both high FADD and caspase-8. However, the expression of both low FADD and caspase-8 was significantly linked to worse overall survival compared with both high FADD and caspase-8 expression in HNSCC patients without LNM. Hence, we suggest that FADD alone or together with DR5 and caspase-8 participates in metastatic process of HNSCC. PMID- 23358468 TI - Mechanisms of resistance to EGFR targeted therapies. AB - EGFR is a validated therapeutic target in many human cancers. EGFR targeted therapies are in widespread clinical use in patients with non-small cell lung cancer and other tumor types. Despite the clinical success of EGFR targeted therapy, resistance to treatment is a significant barrier to the optimized use of EGFR inhibitors to cure patients with lung and other cancers. Here, we review established and emerging mechanisms of resistance to EGFR targeted therapy and highlight strategies that could overcome treatment resistance and therefore enhance clinical outcomes. PMID- 23358469 TI - Novel Hsp90 inhibitor NVP-AUY922 radiosensitizes prostate cancer cells. AB - Outcomes for poor-risk localized prostate cancers treated with radiation are still insufficient. Targeting the "non-oncogene" addiction or stress response machinery is an appealing strategy for cancer therapeutics. Heat-shock-protein-90 (Hsp90), an integral member of this machinery, is a molecular chaperone required for energy-driven stabilization and selective degradation of misfolded "client" proteins, that is commonly overexpressed in tumor cells. Hsp90 client proteins include critical components of pathways implicated in prostate cancer cell survival and radioresistance, such as androgen receptor signaling and the PI3K Akt-mTOR pathway. We examined the effects of a novel non-geldanamycin Hsp90 inhibitor, AUY922, combined with radiation (RT) on two prostate cancer cell lines, Myc-CaP and PC3, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, gamma-H2AX foci kinetics and client protein expression in pathways important for prostate cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined treatment (RT-AUY922) on the PI3K-Akt-mTOR and AR pathways in a hind-flank tumor graft model. We observed that AUY922 caused supra-additive radiosensitization in both cell lines at low nanomolar doses with enhancement ratios between 1.4-1.7 (p < 0.01). RT-AUY922 increased apoptotic cell death compared with either therapy alone, induced G 2-M arrest and produced marked changes in client protein expression. These results were confirmed in vivo, where RT-AUY922 combination therapy produced supra additive tumor growth delay compared with either therapy by itself in Myc-CaP and PC3 tumor grafts (both p < 0.0001). Our data suggest that combined RT-AUY922 therapy exhibits promising activity against prostate cancer cells, which should be investigated in clinical studies. PMID- 23358470 TI - Lenalidomide in combination with gemcitabine as first-line treatment for patients with metastatic carcinoma of the pancreas: a Sarah Cannon Research Institute phase II trial. AB - OBJECTIVES: To evaluate the 6-mo overall survival, safety and tolerability of lenalidomide in combination with standard gemcitabine as first-line treatment for patients with metastatic pancreatic cancer. METHODS: Eligibility included: previously untreated metastatic adenocarcinoma of the pancreas with metastases incurable by surgery/radiation therapy; ECOG PS 0-2; adequate organ function; prophylactic anticoagulation for venous thromboembolic events (VTEs). Patients received lenalidomide 25 mg PO (days 1-21) and gemcitabine 1,000 mg/m ( 2) IV (days 1, 8 and 15) each 28-day cycle, with response evaluations every eight weeks. RESULTS: Between 5/2009-4/2010, 72 patients (median age 64 years; 68% male; 42% ECOG PS 0) were enrolled in this multicenter, community-based study. Six-month OS was 37% (95% CI 26-48%). Median PFS and OS were 2.3 (95% CI 1.9-3.5) and 4.7 (95% CI 3.4-5.7) months, respectively. Eight partial responses (11%) were documented. Thirty-nine patients (54%) experienced thrombocytopenia (2 patients, 3% grade 4). Hematologic toxicities resulted in dose modifications for the majority of patients. Twenty patients (28%) developed VTEs during treatment. CONCLUSIONS: The observed 6-month OS (37%) of lenalidomide with gemcitabine does not suggest improvement compared with historical results with gemcitabine alone. Toxicities and dose modifications likely limited dose intensity. Further development of this regimen in pancreas cancer is not recommended. PMID- 23358471 TI - In vivo metabolism of tryptophan in meningiomas is mediated by indoleamine 2,3 dioxygenase 1. AB - Expression and activity of indoleamine 2,3-dioxygenase (IDO), the first and rate limiting step of the kynurenine pathway of tryptophan catabolism, can enable tumor cells to effectively evade the host's immune response. The potential role of this system was investigated in meningiomas. Surgical specimens from 22 patients with meningiomas were used for cellular, immunological and molecular techniques (immunofluorescence, western blotting, RT-PCR and biochemical assay of enzyme activity) to investigate the expression and activity of IDO. In addition, PET imaging was obtained preoperatively in 10 patients using the tracer alpha-[ ( 11) C]methyl-L-tryptophan (AMT) which interrogates the uptake and metabolism of tryptophan. Strong AMT accumulation was noted in all meningiomas by PET imaging indicating in vivo tryptophan uptake. Freshly-resected meningiomas expressed both LAT1, the tryptophan transporter system and IDO, demonstrating an active kynurenine pathway. Dissociated meningioma cells lost IDO expression. Following exposure to interferon-gamma (IFNgamma), IDO expression was reinduced and could be blocked by a selective IDO1 inhibitor. IDO activity may represent an element of local self-protection by meningiomas and could be targeted by emerging IDO1 inhibitors. PMID- 23358472 TI - Stearoyl gemcitabine nanoparticles overcome obesity-induced cancer cell resistance to gemcitabine in a mouse postmenopausal breast cancer model. AB - Obesity is associated with increased breast tumor aggressiveness and decreased response to multiple modalities of therapy in postmenopausal women. Delivering cancer chemotherapeutic drugs using nanoparticles has evolved as a promising approach to improve the efficacy of anticancer agents. However, the application of nanoparticles in cancer chemotherapy in the context of obesity has not been studied before. The nucleoside analog gemcitabine is widely used in solid tumor therapy. Previously, we developed a novel stearoyl gemcitabine solid-lipid nanoparticle formulation (GemC18-NPs) and showed that the GemC18-NPs are significantly more effective than gemcitabine in controlling tumor growth in mouse models. In the present study, using ovariectomized diet-induced obese female C57BL/6 mice with orthotopically transplanted MMTV-Wnt-1 mammary tumors as a model of postmenopausal obesity and breast cancer, we discovered that obesity induces tumor cell resistance to gemcitabine. Furthermore, our GemC18-NPs can overcome the obesity-related resistance to gemcitabine chemotherapy. These findings have important clinical implications for cancer chemotherapies involving gemcitabine or other nucleoside analogs in the context of obesity. PMID- 23358474 TI - Metabolic reprogramming of the immune response in the tumor microenvironment. AB - A Division of Cancer Biology, NCI sponsored workshop, Metabolic Reprogramming of the Immune Response in the Tumor Microenvironment, was held October 2nd in Bethesda, MD. The purpose of the workshop was to bring together cancer cell biologists and immunologists to explore the mechanistic relationships between the metabolic pathways used by cancer cells and anti-tumor immune cells and how this information could be used to improve cancer immunotherapy. At the conclusion of the workshop a general discussion focused on defining the major challenges and opportunities concerning the impact of metabolism on anti-tumor immunity and cancer immunotherapy as well as what tools, technologies, resources or community efforts are required to accelerate research in this area. Overall, future studies need to consider how cancer cell metabolic pathways differ from activated lymphocytes in order to define a therapeutic window for cancer therapy. Further, studies aimed at reprogramming the metabolic qualities of T cells with the goal of improving immunotherapy were considered a promising avenue. PMID- 23358473 TI - Therapeutic strategies targeting cancer stem cells. AB - Increasing studies have demonstrated a small proportion of cancer stem cells (CSCs) exist in the cancer cell population. CSCs have powerful self-renewal capacity and tumor-initiating ability and are resistant to chemotherapy and radiation. Conventional anticancer therapies kill the rapidly proliferating bulk cancer cells but spare the relatively quiescent CSCs, which cause cancer recurrence. So it is necessary to develop therapeutic strategies acting specifically on CSCs. In recent years, studies have shown that therapeutic agents such as metformin, salinomycin, DECA-14, rapamycin, oncostatin M (OSM), some natural compounds, oncolytic viruses, microRNAs, cell signaling pathway inhibitors, TNF-related apoptosis inducing ligand (TRAIL), interferon (IFN), telomerase inhibitors, all-trans retinoic acid (ATRA) and monoclonal antibodies can suppress the self-renewal of CSCs in vitro and in vivo. A combination of these agents and conventional chemotherapy drugs can significantly inhibit tumor growth, metastasis and recurrence. These strategies targeting CSCs may bring new hopes to cancer therapy. PMID- 23358476 TI - Mammaglobin peptide as a novel biomarker for breast cancer detection. AB - Among the different types of tests used for cancer diagnosis, molecular tests have been increrasingly incorporated because of their ability to detect either expression or functional changes in the molecules associated with the disease. Mammaglobin is a protein found in mammary tissue and can be detected in serum. This protein has been proposed as a biomarker to diagnose breast cancer, given that patients exhibit an increased amount of the protein in serum and tumor tissue, in comparison to healthy individuals. The ELISA test was used in the present study to detect mammaglobin in blood samples from 51 breast cancer patients and 51 control individuals. Antibodies against mamaglobin were generated in rabbits by using the following synthetic peptides: A (amino acids 13 to 21), B (amino acids 31 to 39), C (amino acids 56 to 64) and a D peptide, corresponding to the protein isoform without three amino acids (59, 60 and 61 amino acids) from peptide C. All peptides were immunogenic and allowed generation of antibodies that were able to discriminate patients from controls. The best results were obtained for antiserum B, achieving the best sensitivity (86.3%) and specificity (96%). PMID- 23358475 TI - PKC signaling in glioblastoma. AB - Glioblastoma Multiforme (GBM) is the most aggressive brain tumor characterized by intratumoral heterogeneity at cytopathological, genomic and transcriptional levels. Despite the efforts to develop new therapeutic strategies the median survival of GBM patients is 12-14 months. Results from large-scale gene expression profile studies confirmed that the genetic alterations in GBM affect pathways controlling cell cycle progression, cellular proliferation and survival and invasion ability, which may explain the difficulty to treat GBM patients. One of the signaling pathways that contribute to the aggressive behavior of glioma cells is the protein kinase C (PKC) pathway. PKC is a family of serine/threonine specific protein kinases organized into three groups according the activating domains. Due to the variability of actions controlled by PKC isoforms, its contribution to the development of GBM is poorly understood. This review intends to highlight the contribution of PKC isoforms to proliferation, survival and invasive ability of glioma cells. PMID- 23358478 TI - Myocardial radionuclide imaging in patients with hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy is defined as a primary and familial cardiac disorder characterized by heterogeneous expression, unique pathophysiology and considerable diversity in clinical presentation. Clinical diagnosis was mainly based on the performance of ECG. In addition, cardiovascular MRI or ECG plays an important role in the diagnosis. Nevertheless, myocardial radionuclide imaging, which could provide detailed information on myocardial perfusion, metabolism and neurological function, is a valuable method for exploring the inter-relationship between the morphological, pathophysiological and functional changes in hypertrophic cardiomyopathy. It is also helpful in evaluating the effect of transcoronary ethanol septal ablation and prognosis in patients with hypertrophic cardiomyopathy, which suggests that it is an important imaging method in the comprehensive evaluation of hypertrophic cardiomyopathy. PMID- 23358477 TI - The translocator protein (TSPO) ligand PK11195 induces apoptosis and cell cycle arrest and sensitizes to chemotherapy treatment in pre- and post-relapse neuroblastoma cell lines. AB - High-risk neuroblastoma (NB) has a poor prognosis. Even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal, and new treatments are needed. Translocator protein 18kDa (TSPO) ligands have been studied as potential new therapeutic agents in many cancers, but not in NB. We studied the effects of TSPO ligands on cell proliferation, cell cycle progression and apoptosis using paired cell lines derived from the same patient at the time of initial surgery and again after development of progressive disease or relapse post-chemotherapy. We found that TSPO expression was significantly increased 2- to 10-fold in post-relapse cell lines compared with pre-treatment lines derived from the same individual. Subsequently, these cell lines were treated with the specific TSPO ligand 1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195) (0-160uM) as a single agent, with cytotoxic chemotherapy agents alone (carboplatin, etoposide or melphalan), or with combinations of PK11195 and chemotherapy drugs. We found that PK11195 inhibited proliferation in a dose dependent manner, induced apoptosis and caused G 1/S cell cycle arrest in all tested NB cell lines at micromolar concentrations. In addition, PK11195 significantly decreased mRNA expression of the chemotherapy resistance efflux pumps ABCA3, ABCB1 and ABCC1 in two post-relapse NB cell lines. We also found that pre-treatment with PK11195 sensitized these cell lines to treatment with cytotoxic chemotherapy agents. These results suggest that PK11195 alone or in combination with standard chemotherapeutic drugs warrants further study for the treatment of neuroblastoma. PMID- 23358481 TI - Movement disorders: Advancing our understanding of dystonias--genetic studies reveal TUBB4 mutation in patients with dystonia type 4. PMID- 23358480 TI - Surgical resection of malignant gliomas-role in optimizing patient outcome. AB - Malignant gliomas represent one of the most devastating human diseases. Primary treatment of these tumours involves surgery to achieve tumour debulking, followed by a multimodal regimen of radiotherapy and chemotherapy. Survival time in patients with malignant glioma has modestly increased in recent years owing to advances in surgical and intraoperative imaging techniques, as well as the systematic implementation of randomized trial-based protocols and biomarker-based stratification of patients. The role and importance of several clinical and molecular factors-such as age, Karnofsky score, and genetic and epigenetic status that have predictive value with regard to postsurgical outcome has also been identified. By contrast, the effect of the extent of glioma resection on patient outcome has received little attention, with an 'all or nothing' approach to tumour removal still taken in surgical practice. Recent studies, however, reveal that maximal possible cytoreduction without incurring neurological deficits has critical prognostic value for patient outcome and survival. Here, we evaluate state-of-the-art surgical procedures that are used in management of malignant glioma, with a focus on assessment criteria and value of tumour reduction. We highlight key surgical factors that enable optimization of adjuvant treatment to enhance patient quality of life and improve life expectancy. PMID- 23358483 TI - Citicoline in stroke and TBI clinical trials. PMID- 23358486 TI - Multiple sclerosis: reprogramming the immune repertoire with alemtuzumab in MS. AB - Results from two phase III trials show the potency of alemtuzumab-a T-cell and B cell depleting antibody-in reducing clinical and paraclinical measures of disease activity in relapsing-remitting multiple sclerosis. The effects of this immunotherapeutic agent highlight the relevance of T lymphocytes in the early pathogenesis of disease. PMID- 23358487 TI - Patient reported outcome measures could help transform healthcare. AB - Routine use of patient reported outcome measures (PROMs) has the potential to help transform healthcare, SAYS NICK BLACK: . Not only can PROMs help patients and clinicians make better decisions, but they can also enable comparisons of providers' performances to stimulate improvements in services. PMID- 23358489 TI - Doctors are unaware of "fantastic opportunities" offered by personal health budgets, says health department. PMID- 23358490 TI - Medical regulator urges doctors to prescribe generic drugs. PMID- 23358491 TI - Clinical networks are effective, work in patients' interests, and shouldn't be disbanded. PMID- 23358488 TI - Efficacy and safety of dual blockade of the renin-angiotensin system: meta analysis of randomised trials. AB - OBJECTIVE: To compare the long term efficacy and adverse events of dual blockade of the renin-angiotensin system with monotherapy. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, and the Cochrane central register of controlled trials, January 1990 to August 2012. STUDY SELECTION: Randomised controlled trials comparing dual blockers of the renin-angiotensin system with monotherapy, reporting data on either long term efficacy (>= 1 year) or safety events (>= 4 weeks), and with a sample size of at least 50. Analysis was stratified by trials with patients with heart failure versus patients without heart failure. RESULTS: 33 randomised controlled trials with 68,405 patients (mean age 61 years, 71% men) and mean duration of 52 weeks were included. Dual blockade of the renin-angiotensin system was not associated with any significant benefit for all cause mortality (relative risk 0.97, 95% confidence interval 0.89 to 1.06) and cardiovascular mortality (0.96, 0.88 to 1.05) compared with monotherapy. Compared with monotherapy, dual therapy was associated with an 18% reduction in admissions to hospital for heart failure (0.82, 0.74 to 0.92). However, compared with monotherapy, dual therapy was associated with a 55% increase in the risk of hyperkalaemia (P<0.001), a 66% increase in the risk of hypotension (P<0.001), a 41% increase in the risk of renal failure (P=0.01), and a 27% increase in the risk of withdrawal owing to adverse events (P<0.001). Efficacy and safety results were consistent in cohorts with and without heart failure when dual therapy was compared with monotherapy except for all cause mortality, which was higher in the cohort without heart failure (P=0.04 v P=0.15), and renal failure was significantly higher in the cohort with heart failure (P<0.001 v P=0.79). CONCLUSION: Although dual blockade of the renin angiotensin system may have seemingly beneficial effects on certain surrogate endpoints, it failed to reduce mortality and was associated with an excessive risk of adverse events such as hyperkalaemia, hypotension, and renal failure compared with monotherapy. The risk to benefit ratio argues against the use of dual therapy. PMID- 23358492 TI - Catholic hospitals in Germany are told they must treat victims of sexual assault. PMID- 23358493 TI - NHS chief tells politicians to embrace hospital closures to improve services for patients. PMID- 23358494 TI - Skin conductance reflects drug-induced changes in blood levels of cortisol, adrenaline and noradrenaline in dogs. AB - To verify availability of skin conductance (SC) as an indicator for the sympathetic nervous system (SNS) activity in dogs, the changes in SC and blood levels of stress-related hormones induced by drugs were compared. SC and cortisol, adrenaline and noradrenaline levels were measured in 5 dogs on 4 occasions with or without drug-induced sedation at 7-day intervals (no treatment, intramuscular medetomidine 0.01 mg/kg, intramuscular acepromazine 0.1 mg/kg and intravenous fentanyl 0.02 mg/kg). The fentanyl treatment produced significantly higher levels of SC and plasma cortisol and adrenaline compared with the other 3 treatments. The plasma noradrenaline level also tended to be higher following the fentanyl treatment. These results indicate that SC may reflect changes in the SNS activities in dogs. PMID- 23358495 TI - Identification and antimicrobial susceptibility of enterococci isolated from dogs and cats subjected to differing antibiotic pressures. AB - The purpose of the present study was to determine the prevalence of antibiotic resistant enterococci in dogs and cats subjected to differing antibiotic pressures, and the prevalence of vancomycin resistance genes in isolates from these animals. Enterococci were isolated from fecal samples of 65 healthy dogs and 29 healthy cats brought to animal hospitals, from rectal swabs of 73 puppies and 15 kittens from five breeders and two pet shops, and from fecal samples of 20 dogs and 9 cats that were treated with antibiotics in Nippon Veterinary and Life Science University Animal Medical Center. The rates of resistance to ampicillin among isolates from the kitten-puppy group and healthy dog-cat group were 6.8 and 4.3%, respectively. In contrast, the rates of resistance to ampicillin in enterococci from the treatment group under antibiotic pressure were 37.5%. There was a significant difference between the antibiotic-treated group and the untreated group (P<0.01). Similarly, in the treatment group, the rate of resistance to enrofloxacin was extremely high (75.0%). In comparison, in the healthy group and kitten-puppy group, the rates of resistance to enrofloxacin were 23.4 and 12.1%, respectively. Among these groups, a significant difference was also observed in the apparent resistance rates (P<0.01). Vancomycin-resistant enterococci (VRE) harboring vanA or vanB were not detected in any groups. Therefore, contamination of VRE in dogs and cats is still considered to be minimal in Japan. PMID- 23358496 TI - Anatomical study on the diaphyseal nutrient foramen of the femur and tibia of the German shepherd dog. AB - To provide anatomical data on the nutrient foramen (NF), the authors observed the number, site and its index (SI), position, diameter and penetrating direction of the nutrient canal (NC) in the femur and tibia of German shepherd dogs. The femur often had more than two NF on the caudal surface with 30.0 to 86.7% of SI. The proximal NF of the femur was regarded to be the major NF, because it was present in most dogs and had the largest diameter. The tibia always had only one NF with 23.2 to 38.3% of SI on the lateral border. Their direction of the NC followed Berard's rule with the exception of the proximal NF of the femur. These results describe the anatomical condition of the NF and NC in the dog. PMID- 23358497 TI - Cytotoxicity and expression of genes involved in the cellular stress response and apoptosis in mammalian fibroblast exposed to cotton cellulose nanofibers. AB - Cellulose nanofibers (CNF) have mechanical properties that make them very attractive for applications in the construction of polymeric matrices, drug delivery and tissue engineering. However, little is known about their impact on mammalian cells. The objective of this study was to evaluate the cytotoxicity of CNF and their effect on gene expression of fibroblasts cultured in vitro. The morphology of CNF was analyzed by transmission electron microscopy and the surface charge by Zeta potential. Cell viability was analyzed by flow cytometry assay and gene expression of biomarkers focused on cell stress response such as Heat shock protein 70.1 (HSP70.1) and Peroxiredoxin 1 (PRDX1) and apoptosis as B cell leukemia (BCL-2) and BCL-2 associated X protein (BAX) by RT-PCR assay. Low concentrations of CNF (0.02-100 MUg ml(-1)) did not cause cell death; however, at concentrations above 200 MUg ml(-1), the nanofibers significantly decreased cell viability (86.41 +/- 5.37%). The exposure to high concentrations of CNF (2000 and 5000 MUg ml(-1)) resulted in increased HSP70.1, PRDX1 and BAX gene expression. The current study concludes that, under the conditions tested, high concentrations (2000 and 5000 MUg ml(-1)) of CNF cause decreased cell viability and affect the expression of stress- and apoptosis-associated molecular markers. PMID- 23358498 TI - Structural heterogeneity in familial Alzheimer's disease mutants of amyloid-beta peptides. AB - Alzheimer's disease is a neurodegenerative disorder characterized by progressive deposition of amyloid-beta (Abeta) peptides in brain parenchyma and cerebral blood vessels. Several pathogenic familial mutations of Abeta peptides have been identified that exhibit enhanced neurotoxicity and aggregative ability. However, knowledge of the structural characteristics of those Abeta mutants is still limited. Here, we report multiple all-atom molecular dynamics simulations of the wild-type 42-residue Abeta peptide (Abeta42) and its Flemish (A21G), Arctic (E22G), Dutch (E22Q), Italian (E22K), and Iowa (D23N) familial mutants in explicit water. After validating our simulations by comparison with available experimental data, we examined common/different features in the secondary and tertiary structures of the wild-type and five familial mutants of Abeta42. We found that Abeta42 peptides display quite heterogeneous secondary and tertiary structure ensembles. Such structural heterogeneity in the monomeric state would facilitate interconversions between various secondary structures during the formation of a beta-sheet-rich amyloid fibril, and may also serve as a structural basis of the amyloid polymorphism. PMID- 23358499 TI - Influence of admixture components on CYP2C9*2 allele frequency in eight indigenous populations from Northwest Mexico. AB - We previously documented the lowest frequency of CYP2C9*2 in Mexican indigenous Tepehuanos followed by Mestizos and Mexican-Americans populations, suggesting a negative correlation between the CYP2C9*2 frequency and the degree of Asian ancestry in indigenous Americans. We determined the influence of ethnic admixture components on the CYP2C9 allele distribution in 505 Amerindian from eight indigenous populations through genotyping CYP2C9*2, *3 and *6 alleles by real time PCR and molecular evaluation of ancestry. The frequencies for CYP2C9*2 were 0.026 in Seris and 0.057 in Mayos, being higher than in Asians (P<0.001). CYP2C9*3 was found in Tarahumaras (0.104), Mayos (0.091), Tepehuanos (0.075), Guarijios (0.067), Huicholes (0.033) and Coras (0.037), with East Asians having lower frequencies than the former three groups (P<0.001). CYP2C9*6 was not found. The frequency of CYP2C9*2 was lower in Amerindians than in European populations, and higher than their Asian ancestors. The presence of this allele in ethnic groups in Mexico can be explained by European admixture. PMID- 23358501 TI - Kienbock's Disease in a Child. AB - Kienbock's disease, which is an idiopathic osteonecrosis and collapse of the lunate bone, is an uncommon disease in children. This report describes a case of an 11-year-old girl, who presented with avascular necrosis of lunate bone confirmed by radiographic and magnetic resonance imaging evidence. After a short period of casting, the case was fully recovered within one year. The signal change was confirmed by magnetic resonance imaging, and the deformity of lunate that was demonstrated by avascular necrosis. The patient wore a long arm cast for six weeks, and after one year radiographic pattern was normalized. PMID- 23358500 TI - Variation in the alpha 5 nicotinic acetylcholine receptor subunit gene predicts cigarette smoking intensity as a function of nicotine content. AB - A single-nucleotide polymorphism (SNP) in the alpha5 nicotinic acetylcholine receptor subunit gene, rs16969968, has been repeatedly associated with both smoking and respiratory health phenotypes. However, there remains considerable debate as to whether associations with lung cancer are mediated through effects on smoking behavior. Preclinical studies suggest that alpha5 receptor subunit expression and function may have a direct role in nicotine titration during self administration. The present study investigated the association of CHRNA5 polymorphisms and smoking topography in 66 smokers asked to smoke four nicotine containing (nicotine yield=0.60 mg) and four placebo (nicotine yield <0.05 mg) cigarettes, during separate experimental sessions. Genotype at rs16969968 predicted nicotine titration, with homozygotes for the major allele (G:G) displaying significantly reduced puff volume in response to nicotine, whereas minor allele carriers (A:G or A:A) produced equivalent puff volumes for placebo and nicotine cigarettes. The present results suggest that puff volume may be a more powerful objective phenotype of smoking behavior than self-reported cigarettes per day and nicotine dependence. Further, these results suggest that the association between rs16969968 and lung cancer may be mediated by the quantity of smoke inhaled. PMID- 23358502 TI - Deletion of Synechocystis sp. PCC 6803 leader peptidase LepB1 affects photosynthetic complexes and respiration. AB - The cyanobacterium Synechocystis sp. PCC 6803 possesses two leader peptidases, LepB1 (Sll0716) and LepB2 (Slr1377), responsible for the processing of signal peptide-containing proteins. Deletion of the gene for LepB1 results in an inability to grow photoautotrophically and an extreme light sensitivity. Here we show, using a combination of Blue Native/SDS-PAGE, Western blotting and iTRAQ analysis, that lack of LepB1 strongly affects the cell's ability to accumulate wild-type levels of both photosystem I (PSI) and cytochrome (Cyt) b6f complexes. The impaired assembly of PSI and Cyt b6f is considered to be caused by the no or slow processing of the integral subunits PsaF and Cyt f respectively. In particular, PsaF, one of the PSI subunits, was found incorporated into PSI in its unprocessed form, which could influence the assembly and/or stability of PSI. In contrast to these results, we found the amount of assembled photosystem II (PSII) unchanged, despite a slower processing of PsbO. Thus, imbalance in the ratios of PSI and Cyt b6f to photosystem II leads to an imbalanced photosynthetic electron flow up- and down-stream of the plastoquinone pool, resulting in the observed light sensitivity of the mutant. We conclude that LepB1 is the natural leader peptidase for PsaF, PsbO, and Cyt f. The maturation of PsbO and Cyt f can be partially performed by LepB2, whereas PsaF processing is completely dependent on LepB1. iTRAQ analysis also revealed a number of indirect effects accompanying the mutation, primarily a strong induction of the CydAB oxidase as well as a significant decrease in phycobiliproteins and chlorophyll/heme biosynthesis enzymes. PMID- 23358503 TI - Phosphotyrosine signaling proteins that drive oncogenesis tend to be highly interconnected. AB - Mutation and overexpression of receptor tyrosine kinases or the proteins they regulate serve as oncogenic drivers in diverse cancers. To better understand receptor tyrosine kinase signaling and its link to oncogenesis, we used protein microarrays to systematically and quantitatively measure interactions between virtually every SH2 or PTB domain encoded in the human genome and all known sites of tyrosine phosphorylation on 40 receptor tyrosine kinases and on most of the SH2 and PTB domain-containing adaptor proteins. We found that adaptor proteins, like RTKs, have many high affinity bindings sites for other adaptor proteins. In addition, proteins that drive cancer, including both receptors and adaptor proteins, tend to be much more highly interconnected via networks of SH2 and PTB domain-mediated interactions than nononcogenic proteins. Our results suggest that network topological properties such as connectivity can be used to prioritize new drug targets in this well-studied family of signaling proteins. PMID- 23358504 TI - Integrated proteomics identified novel activation of dynein IC2-GR-COX-1 signaling in neurofibromatosis type I (NF1) disease model cells. AB - Neurofibromatosis type 1 (NF1) tumor suppressor gene product, neurofibromin, functions in part as a Ras-GAP, and though its loss is implicated in the neuronal abnormality of NF1 patients, its precise cellular function remains unclear. To study the molecular mechanism of NF1 pathogenesis, we prepared NF1 gene knockdown (KD) PC12 cells, as a NF1 disease model, and analyzed their molecular (gene and protein) expression profiles with a unique integrated proteomics approach, comprising iTRAQ, 2D-DIGE, and DNA microarrays, using an integrated protein and gene expression analysis chart (iPEACH). In NF1-KD PC12 cells showing abnormal neuronal differentiation after NGF treatment, of 3198 molecules quantitatively identified and listed in iPEACH, 97 molecules continuously up- or down-regulated over time were extracted. Pathway and network analysis further revealed overrepresentation of calcium signaling and transcriptional regulation by glucocorticoid receptor (GR) in the up-regulated protein set, whereas nerve system development was overrepresented in the down-regulated protein set. The novel up-regulated network we discovered, "dynein IC2-GR-COX-1 signaling," was then examined in NF1-KD cells. Validation studies confirmed that NF1 knockdown induces altered splicing and phosphorylation patterns of dynein IC2 isomers, up regulation and accumulation of nuclear GR, and increased COX-1 expression in NGF treated cells. Moreover, the neurite retraction phenotype observed in NF1-KD cells was significantly recovered by knockdown of the dynein IC2-C isoform and COX-1. In addition, dynein IC2 siRNA significantly inhibited nuclear translocation and accumulation of GR and up-regulation of COX-1 expression. These results suggest that dynein IC2 up-regulates GR nuclear translocation and accumulation, and subsequently causes increased COX-1 expression, in this NF1 disease model. Our integrated proteomics strategy, which combines multiple approaches, demonstrates that NF1-related neural abnormalities are, in part, caused by up-regulation of dynein IC2-GR-COX-1 signaling, which may be a novel therapeutic target for NF1. PMID- 23358506 TI - Autoimmunity: Will worms cure rheumatoid arthritis? PMID- 23358505 TI - Argonaute2 regulates the pancreatic beta-cell secretome. AB - Argonaute2 (Ago2) is an established component of the microRNA-induced silencing complex. Similar to miR-375 loss-of-function studies, inhibition of Ago2 in the pancreatic beta-cell resulted in enhanced insulin release underlining the relationship between these two genes. Moreover, as the most abundant microRNA in pancreatic endocrine cells, miR-375 was also observed to be enriched in Ago2 associated complexes. Both Ago2 and miR-375 regulate the pancreatic beta-cell secretome, and by using quantitative mass spectrometry, we identified the enhanced release of a set of proteins or secretion "signatures " in response to a glucose stimulus using the murine beta-cell line MIN6. In addition, the loss of Ago2 resulted in the increased expression of miR-375 target genes, including gephyrin and ywhaz. These targets positively contribute to exocytosis indicating they may mediate the functional role of both miR-375 and Ago proteins in the pancreatic beta-cell by influencing the secretory pathway. This study specifically addresses the role of Ago2 in the systemic release of proteins from beta-cells and highlights the contribution of the microRNA pathway to the function of this cell type. PMID- 23358508 TI - Regenerative medicine: Adhesive-hydrogel composite developed to repair damaged cartilage. PMID- 23358509 TI - Therapy: Bisphosphonates for early complex regional pain syndrome. PMID- 23358513 TI - Serological survey to determine the occurrence of malignant catarrhal fever infection in the Japanese small ruminant population from northern districts. AB - Ovine herpesvirus 2 (OvHV-2) causes sheep-associated malignant catarrhal fever (SA-MCF), and is responsible for economic losses in cattle and other susceptible species around the world. A survey of 154 serum samples from 14 flocks in 3 Japanese prefectures (Hokkaido, Aomori and Iwate) was undertaken between 2007 and 2008 to test for antibodies to OvHV-2. OvHV-2 was present in 56 sheep and 2 goats, with 37.66% of samples having a positive reaction using a serum neutralization test. The immune reaction reported in goats could result from Caprine herpesvirus-2. These results indicate that sheep are reservoirs for OvHV 2 in the field in Japan, and they might transmit the virus to susceptible cattle and wild fauna. PMID- 23358514 TI - Effects of exposure to clothianidin on the reproductive system of male quails. AB - Clothianidin (CTD) is a neonicotinoid developed in the 1990s as an insecticide having selective toxicity, but it was later found to cause reproductive abnormalities in rats through oxidative stress. There is an attempt to preserve endangered animals, including the Japanese crested ibis, in Japan. However, there is a concern that neonicotinoid affects the reproduction of this bird, since it is used in its habitat. CTD toxicity in the birds is poorly understood, so we investigated whether or not the daily oral administration of CTD has any deleterious effects on the reproductive functions of mature male quails as experimental animals. The animals were randomly divided into four groups of 6 or 7 quails each, treated orally with 0, 0.02, 1 or 50 mg CTD/kg body weight (Control, CTD0.02, CTD1 and CTD50). After that the males bred with untreated females to estimate the egg weights, and rates of fertilization and normal development, the testes, liver and spleen were examined histologically. Vacuolization and the number of germ cells having fragmented DNA in seminiferous tubules, and the number and size of vacuoles in hepatocytes increased dose dependently. There were no significant differences in egg weights and fertilization rates between the groups, but some eggs of the CTD1 and CTD50 groups failed to develop, and embryonic length decreased dose-dependently. Thus, it was found that CTD affected the reproduction of the male quail through the fragmentation of germ cells and the inhibition or delay of embryonic development. PMID- 23358515 TI - Regulatory T-cells in chronic lymphocytic leukemia: actor or innocent bystander? AB - Regulatory T (Treg) cells are now under extensive investigation in chronic lymphocytic leukemia (CLL). This small subset of T-cells has been, in fact, considered to be involved in the pathogenesis and progression of CLL. However, whether Treg dysregulation in CLL plays a key role or it rather represents a simple epiphenomenon is still matter of debate. In the former case, Treg cells could be appealing for targeting therapies. Finally, Treg cells have also been proposed as a prognostic indicator of the disease clinical course. PMID- 23358516 TI - Size dependent competition between second harmonic generation and two-photon luminescence observed in gold nanoparticles. AB - We investigate systematically the competition between the second harmonic generation (SHG) and two-photon-induced luminescence (TPL) that are simultaneously present in Au nanoparticles excited by using a femtosecond (fs) laser. For a large-sized (length ~ 800 nm, diameter ~ 200 nm) Au nanorod, the SHG appears to be much stronger than the TPL. However, the situation is completely reversed when the Au nanorod is fragmented into many Au nanoparticles by the fs laser. In sharp contrast, only the TPL is observed in small-sized (length ~ 40 nm, diameter ~ 10 nm) Au nanorods. When a number of the small-sized Au nanorods are optically trapped and fused into a large-sized Au cluster by focused fs laser light, the strong TPL is reduced while the weak SHG increases significantly. In both cases, the morphology change is characterized by scanning electron microscope. In addition, the modification of the scattering and absorption cross sections due to the morphology change is calculated by using the discrete dipole approximation method. It is revealed that SHG is dominant in the case when the scattering is much larger than the absorption. When the absorption becomes comparable to or larger than the scattering, the TPL increases dramatically and will eventually become dominant. Since the relative strengths of scattering and absorption depend strongly on the size of the Au nanoparticles, the competition between SHG and TPL is found to be size dependent. PMID- 23358518 TI - Prostate cancer: Timing is everything for docetaxel therapy. PMID- 23358519 TI - Infectious disease: Chlamydia-induced infertility. PMID- 23358520 TI - Paediatrics: In it for the long-haul--caring for patients treated for hypospadias. PMID- 23358521 TI - Inverse opal structured alpha-Fe2O3 on graphene thin films: enhanced photo assisted water splitting. AB - A graphene interlayer was successfully inserted into inverse opaline hematite (alpha-Fe(2)O(3)) photoanodes for solar water splitting using the template assisted electrodeposition method. Finding the optimal thermal annealing temperature is crucial for the successful attainment of the inverse opaline hematite nanostructure on a graphene thin film. This is because an appropriate temperature is required to convert pre-deposited Fe(0) into hematite with optimum crystalline structure and to simultaneously remove the soft polystyrene template without thermal degradation of the graphene film on a transparent conductive substrate. Different from the conventional strategies based on graphene semiconductor systems, this novel mechanism has been proposed whereby the graphene interlayer can act as both an electron transfer layer and an electrolyte blocking barrier, by which it not only reduces the charge recombination at the substrate-electrolyte interface but also helps electron transportation from alpha Fe(2)O(3) to the substrate of the photoanode. Therefore, both photocurrent density and incident photon-to-current efficiency (IPCE) have been remarkably improved, which are several times higher than those of the pure inverse opaline hematite photoanode. PMID- 23358523 TI - Fine needle aspiration-induced vascular proliferation of the thyroid: A report of two cases. PMID- 23358522 TI - Diabetic patients with and without peripheral neuropathy reveal different hip and ankle biomechanical strategies during stair descent. AB - BACKGROUND: The progression of diabetes and the challenge of daily tasks may result in changes in biomechanical strategies. Descending stairs is a common task that patients have to deal with, however it still has not been properly studied in this population. OBJECTIVES: We describe and compare the net joint moments and kinematics of the lower limbs in diabetic individuals with and without peripheral neuropathy and healthy controls during stair descent. METHOD: Forty-two adults were assessed: control group (13), diabetic group (14), and neuropathic diabetic group (15). The flexor and extensor net moment peaks and joint angles of the hip, knee, and ankle were described and compared in terms of effect size and ANOVAs (p<0.05). RESULTS: Both diabetic groups presented greater dorsiflexion [large effect size] and a smaller hip extensor moment [large effect size] in the weight acceptance phase. In the propulsion phase, diabetics with and without neuropathy showed a greater hip flexor moment [large effect size] and smaller ankle extension [large effect size]. CONCLUSION: Diabetic patients, even without neuropathy, revealed poor eccentric control in the weight acceptance phase, and in the propulsion phase, they showed a different hip strategy, where they chose to take the leg off the ground using more flexion torque at the hip instead of using a proper ankle extension function. PMID- 23358524 TI - Graphene transparent electrode for enhanced optical power and thermal stability in GaN light-emitting diodes. AB - We report an improvement of the optical power and thermal stability of GaN LEDs using a chemically doped graphene transparent conducting layer (TCL) and a low resistance contact structure. In order to obtain low contact resistance between the TCL and p-GaN surface, a patterned graphene TCL with Cr/Au electrodes is suggested. A bi-layer patterning method of a graphene TCL was utilized to prevent the graphene from peeling off the p-GaN surface. To improve the work function and the sheet resistance of graphene, CVD (chemical vapor deposition) graphene was doped by a chemical treatment using a HNO(3) solution. The effect of the contact resistance on the power degradation of LEDs at a high injection current level was investigated. In addition, the enhancement of the optical power via an increase in the current spreading and a decrease in the potential barrier of the graphene TCL was investigated. PMID- 23358525 TI - Simple accurate approximations for the optical properties of metallic nanospheres and nanoshells. AB - This work aims to provide simple and accurate closed-form approximations to predict the scattering and absorption spectra of metallic nanospheres and nanoshells supporting localised surface plasmon resonances. Particular attention is given to the validity and accuracy of these expressions in the range of nanoparticle sizes relevant to plasmonics, typically limited to around 100 nm in diameter. Using recent results on the rigorous radiative correction of electrostatic solutions, we propose a new set of long-wavelength polarizability approximations for both nanospheres and nanoshells. The improvement offered by these expressions is demonstrated with direct comparisons to other approximations previously obtained in the literature, and their absolute accuracy is tested against the exact Mie theory. PMID- 23358526 TI - Kangaroo mother care revisited. PMID- 23358527 TI - Ion doping of graphene for high-efficiency heterojunction solar cells. AB - We demonstrated the p-type chemical doping by chlorine and nitrate anions to enhance the Schottky junction in the solar cell. Nitrate ions were found to be more effective for reducing the sheet resistance and enlarging the work function of graphene for effective charge separation and transport, and the efficiency was increased to 9.2% by a factor of 1.68 under AM 1.5 illumination. PMID- 23358528 TI - Gut hormones, appetite suppression and cachexia in patients with pulmonary TB. AB - BACKGROUND: Cachexia is a hallmark of pulmonary tuberculosis and is associated with poor prognosis. A better understanding of the mechanisms behind such weight loss could reveal targets for therapeutic intervention. The role of appetite regulatory hormones in tuberculosis is unknown. METHODS AND FINDINGS: 41 subjects with newly-diagnosed pulmonary TB (cases) were compared to 82 healthy controls. We measured appetite, body mass index (BMI), % body fat (BF), plasma peptide YY (PYY), leptin, ghrelin, and resistin for all subjects. Measurements were taken at baseline for controls and at treatment days 0, 30, and 60 for cases. Baseline appetite, BMI, and BF were lower in cases than in controls and improved during treatment. PYY, ghrelin, and resistin were significantly elevated in cases and fell during treatment. Leptin was lower in cases and rose with treatment. Appetite was inversely related to PYY in cases. High pre-treatment PYY predicted reduced gains in appetite and BF. PYY was the strongest independent predictor of appetite in cases across all time points. CONCLUSIONS: Appetite-regulatory hormones are altered in TB patients. As hormones normalize during treatment, appetite is restored and nutritional status improves. High baseline PYY is an indicator of poor prognosis for improvement in appetite and nutrition during treatment. Wasting in TB patients may partly be mediated by upregulation of PYY with resulting appetite suppression. PMID- 23358529 TI - Postpartum hypercalcemia secondary to a neuroendocrine tumor of pancreas; a case report and review of literature. AB - Parathyroid hormone-related protein producing pancreatic neuroendocrine tumors have been infrequently reported. Herein, we report a case of an Iranian woman who had such a tumor during pregnancy, and gave birth to a female neonate with esophago-tracheal fistula and imperforated anus. Hypercalcemia was diagnosed at postpartum because of elevated serum calcium levels in the neonate and neurologic deterioration of the mother. Extensive literature review revealed 42 cases with pancreatic neuroendocrine tumors and hypercalcaemia. The clinical and laboratory findings of such patients are reviewed in this manuscript. PMID- 23358531 TI - Solution-processed soldering of carbon nanotubes for flexible electronics. AB - We report a simple lithography-free, solution-based method of soldering of carbon nanotubes with Ohmic contacts, by taking specific examples of multi-walled carbon nanotubes (MWNTs). This is achieved by self-assembling a monolayer of soldering precursor, Pd(2+) anchored to 1,10 decanedithiol, onto which MWNTs could be aligned across the gap electrodes via solvent evaporation. The nanosoldering was realized by thermal/electrical activation or by both in sequence. Electrical activation and the following step of washing ensure selective retention of MWNTs spanning across the gap electrodes. The soldered joints were robust enough to sustain strain caused during the bending of flexible substrates as well as during ultrasonication. The estimated temperature generated at the MWNT-Au interface using an electro-thermal model is ~150 degrees C, suggesting Joule heating as the primary mechanism of electrical activation. Further, the specific contact resistance is estimated from the transmission line model. PMID- 23358532 TI - NHS could save L1bn by adopting green strategies used in kidney units. PMID- 23358533 TI - Improving antimicrobial stewardship and surveillance: the Chennai Declaration. PMID- 23358534 TI - HFEA and HTA will not now be axed. PMID- 23358535 TI - An efficient Au-catalyzed synthesis of isomukonidine, clausine L, mukonidine, glycosinine, mukonal, and clausine V from propadienyl methyl ether. AB - Naturally occurring carbazole alkaloids such as isomukonidine, clausine L, mukonidine, glycosinine, mukonal, and clausine V have been synthesized through a gold-catalyzed cyclization reaction of 1-(indol-2-yl)-2-methoxy-2,3-allenols, which are readily available from indolecarbaldehydes and methoxypropadiene. Compared to the reported procedures, our approach is general, atom economic, highly selective, and the starting materials are easily available. PMID- 23358537 TI - In Situ Biotreatment of TBA with Recirculation/Oxygenation. AB - The potential for in situ biodegradation of tert-butyl alcohol (TBA) by creation of aerobic conditions in the subsurface with recirculating well pairs was investigated in two field studies conducted at Vandenberg Air Force Base (VAFB). In the first experiment, a single recirculating well pair with bromide tracer and oxygen amendment successfully delivered oxygen to the subsurface for 42 days. TBA concentrations were reduced from approximately 500 MUg/L to below the detection limit within the treatment zone and the treated water was detected in a monitoring transect several meters downgradient. In the second experiment, a site calibrated model was used to design a double recirculating well pair with oxygen amendment, which successfully delivered oxygen to the subsurface for 291 days and also decreased TBA concentrations to below the detection limit. Methylibium petroleiphilum strain PM1, a known TBA-degrading bacterium, was detectable at the study site but addition of oxygen had little impact on the already low baseline population densities, suggesting that there was not enough carbon within the groundwater plume to support significant new growth in the PM1 population. Given favorable hydrogeologic and geochemical conditions, the use of recirculating well pairs to introduce dissolved oxygen into the subsurface is a viable method to stimulate in situ biodegradation of TBA or other aerobically-degradable aquifer contaminants. PMID- 23358538 TI - In-plane organization of silicon nanocrystals embedded in SiO2 thin films. AB - Nanofabrication of buried structures with dimensions below 5 nm and with controlled 3D-positioning at the nanoscale was attempted to open new routes to future nanodevices where single nanostructures could be systematically interfaced. A typical example is ultralow-energy ion beam synthesis where already the depth positioning of embedded arrays of silicon nanocrystals can be finely controlled with nanometric precision. In this study, we investigated for the first time the control of the in-plane organization of the nanocrystals using a legitimate patterning option for microelectronic industries, self-assembled block copolymer. The compatibility with the ultralow-energy ion beam synthesis process of polymeric nanoporous films used as mask was demonstrated together with the capability to control in 3D the organization of Si nanocrystals. The resulting nano-organization consists in a hexagonal array of 20 nm wide nanovolumes containing on average 8 nanocrystals embedded at a controlled depth within a silica matrix. PMID- 23358536 TI - The pharmacokinetic-pharmacodynamic model of azithromycin for lipopolysaccharide induced depressive-like behavior in mice. AB - A mechanism-based model was developed to describe the time course of lipopolysaccharide-induced depressive-like behavior and azithromycin pharmacodynamics in mice. The lipopolysaccharide-induced disease progression was monitored by lipopolysaccharide, proinflammatory cytokines, and kynrenine concentration in plasma. The depressive-like behavior was investigated by forced swimming test and tail suspension test. Azithromycin was selected to inhibit the surge of proinflammatory cytokines induced by lipopolysaccharide. Disease progression model and azithromycin pharmacodynamics were constructed from transduction and indirect response models. A delay in the onset of increased proinflammatory cytokines, kynrenine, and behavior test compared to lipopolysaccharide was successfully characterized by series transduction models. The inhibition of azithromycin on proinflammatory cytokines was described by an indirect response model. After lipopolysaccharide challenging, the proinflammatory cytokines, kynrenine and behavior tests would peak approximately at 3, 12, and 24 h respectively, and then the time courses slowly declined toward a baseline state after peak response. During azithromycin administration, the peak levels of proinflammatory cytokines, kynrenine and behavior indexes decreased. Model parameters indicated that azithromycin significantly inhibited the proinflammatory cytokines level in plasma and improved the depressive-like behavior induced by inflammation. The integrated model for disease progression and drug intervention captures turnovers of proinflammatory cytokines, kynrenine and the behavior results in the different time phases and conditions. PMID- 23358540 TI - Adding risk factors for potentially resistant pathogens, increasing antibiotic pressure and risk creating the "untreatable bacteria": time to change direction. PMID- 23358539 TI - Potentially resistant microorganisms in intubated patients with hospital-acquired pneumonia: the interaction of ecology, shock and risk factors. AB - PURPOSE: As per 2005 American Thoracic Society and Infectious Disease Society of America (ATS/IDSA) guidelines for managing hospital-acquired pneumonia, patients with early-onset pneumonia and without risk factors do not need to be treated for potentially resistant microorganisms (PRM). METHODS: This was a secondary analysis of a prospective, observational, cohort, multicentre study conducted in 27 ICUs from nine European countries. RESULTS: From a total of 689 patients with nosocomial pneumonia who required mechanical ventilation, 485 patients with confirmed etiology and antibiotic susceptibility were further analysed. Of these patients, 152 (31.3 %) were allocated to group 1 with early-onset pneumonia and no risk factors for PRM acquisition, and 333 (68.7 %) were classified into group 2 with early-onset pneumonia with risk factors for PRM or late-onset pneumonia. Group 2 patients were older and had more chronic renal failure and more severe illness (SAPS II score, 44.6 +/- 16.5 vs. 47.4 +/- 17.8, p = 0.04) than group 1 patients. Trauma patients were more frequent and surgical patients less frequent in group 1 than in group 2 (p < 0.01). In group 1, 77 patients (50.7 %) had PRM in spite of the absence of classic risk factors recognised by the current guidelines. A logistic regression analysis identified that presence of severe sepsis/septic shock (OR = 3.7, 95 % CI 1.5-8.9) and pneumonia developed in centres with greater than 25 % prevalence of PRM (OR = 11.3, 95 % CI 2.1-59.3) were independently associated with PRM in group 1 patients. CONCLUSIONS: In patients admitted to ICUs with a prevalence of PRM greater than 25 % or with severe sepsis/septic shock, empiric therapy for group 1 nosocomial pneumonia requiring mechanical ventilation should also include agents likely to be effective for PRM pathogens. PMID- 23358543 TI - An unprecedented dynamic porous metal-organic framework assembled from fivefold interlocked closed nanotubes with selective gas adsorption behaviors. AB - An unprecedented 3D dynamic porous metal-organic framework assembled from fivefold interlocked closed nanotubes has been constructed, which exhibits highly selective adsorption of CO(2) over N(2) and H(2), as well as stepwise and hysteretic behaviors. PMID- 23358544 TI - Silver nanoparticles embedded in cyclodextrin-silicate composite and their applications in Hg(II) ion and nitrobenzene sensing. AB - Different synthetic routes were described to prepare silver (Ag) nanoparticles (NPs) embedded in an amine functionalized silicate sol-gel matrix (TPDT) by employing different combination of reagents such as silicate sol-gel (TPDT), beta cyclodextrin (CD)-TPDT, TPDT-surfactant (BDAC), CD-TPDT-BDAC and CD-TPDT BDAC/ascorbic acid (AA). The spectral and colorimetric detection of Hg(II) ions were carried out using the Ag NPs which showed a significant blue shift in the surface plasmon resonance (SPR) band upon the addition of Hg(II) ions. It was found that the addition of optimum level of Hg(II) ions into the Ag NPs completely quenched the SPR band and deformed the shape of the Ag NPs due to the formation of anisotropic Ag amalgam crystals (AgHg). The selective detection of Hg(II) ions using the Ag NPs in the presence of other environmentally relevant metal ions by spectral and colorimetric methods was also reported. Furthermore, the prepared Ag nanostructure modified electrodes were employed for the electrocatalytic reduction and sensing of nitrobenzene. PMID- 23358541 TI - Long-term mortality and quality of life after septic shock: a follow-up observational study. AB - PURPOSE: In septic shock, short-term outcomes are frequently reported, while long term outcomes are not. The aim of this study was to evaluate mortality and health related quality of life (HRQOL) in survivors 6 months after an episode of septic shock. METHODS: This single-centre observational study was conducted in an intensive care unit in a university hospital. All patients with septic shock were included. Mortality was assessed 6 months after the onset of septic shock, and a comparison between patients who survived and those who died was performed. HRQOL was assessed using the MOS SF-36 questionnaire prior to hospital admission (baseline) and at 6 months in survivors. HRQOL at baseline and at 6 months were compared to the general French population, and HRQOL at baseline was compared to 6-month HRQOL. RESULTS: Ninety-six patients were included. Six-month mortality was 45%. Survivors were significantly younger, had significantly lower lactate levels and SAPS II scores, required less renal support, received less frequent administration of corticosteroids, and had a longer length of hospital stay. At baseline (n = 39) and 6 months (n = 46), all of the components of the SF-36 questionnaire were significantly lower than those in the general population. Compared to baseline (n = 23), the Physical Component Score (CS) improved significantly at 6 months, the Mental CS did not differ. CONCLUSIONS: Mortality 6 months after septic shock was high. HRQOL at baseline was impaired when compared to that of the general population. Although improvements were noted at 6 months, HRQOL remained lower than that in the general population. PMID- 23358545 TI - Facile template-free synthesis and visible-light driven photocatalytic performances of dendritic CdS hierarchical structures. AB - In this paper, large scale hierarchical CdS dendrites are synthesized via a facile and effective hydrothermal route. The morphologies, microstructures and photocatalytic properties of the as-synthesized products are investigated in detail. Individual CdS dendrites consist of a long central trunk with secondary and tertiary sharp branches, which preferentially grow in a parallel direction with a definite angle to the trunk. A possible growth mechanism for CdS dendrites is proposed based on the experimental results and phenomena. Photocatalytic tests reveal that eosin red can be degraded nearly completely (over 95%) after visible light irradiation of 100 min. In addition, Congo red and methylene blue aqueous solution degradation experiments are also conducted under the same conditions, revealing versatile potential applications of such dendritic structures for wastewater purification. PMID- 23358546 TI - Direct patterning of high density sub-15 nm gold dot arrays using ultrahigh contrast electron beam lithography process on positive tone resist. AB - Ultrahigh density nanostructure arrays with controlled size and position have promised a variety of potential applications. However, their practical realization is often hindered by the amount of resources required for large-scale fabrication. Using an ultrahigh contrast electron beam lithography process, we show ultrahigh resolution and high aspect ratio patterning capability which can be done at an exposure dose lower than 100 MUC cm(-2). In particular, the high aspect ratio of dot arrays on 110 nm thick resist is confirmed by a standard lift off process of 20 nm thick gold nanodots at sub-15 nm feature size and 40 nm pitch. The smallest gold nanodot size from our experiment is 11 nm. PMID- 23358547 TI - Perivascular epithelioid cell tumor of male pelvic cavity: a case report and literature review. AB - Perivascular epithelioid cell tumors (PEComas) are a family of rare mesenchymal neoplasms. The PEComas, composed of epithelioid and spindle cells, have the same cellular and immunohistochemical features but are found in different visceral and soft tissue sites. Here, we report the histological and immunohistochemical features of one case of PEComa restricted in the pelvic visceral peritoneum of a male patient. The patient was treated with radical surgery, and was well and on follow-up visits without tumor recurrence. PMID- 23358550 TI - Evaluation of the effect of glucosamine administration on biomarkers of cartilage and bone metabolism in bicycle racers. AB - In the present study, the effect of glucosamine administration (1.5 or 3 g/day) on cartilage and bone metabolism was investigated in bicycle racers, using cartilage- and bone-specific biomarkers, including C-terminal cross-linked telopeptides of type II collagen (CTX-II), C-terminal propeptides of type II procollagen (CPII), N-terminal telopeptides of bone-specific type I collagen (NTx) and bone alkaline phosphatase (BAP). The results indicate that CPII (a marker of type II collagen synthesis) was not substantially changed, however, CTX II (a marker of type II degradation) was reduced by glucosamine administration, particularly at a dose of 3 g/day. Consistent with these observations, the ratio of CTX-II/CPII was reduced by glucosamine administration and the effect of glucosamine was dose-dependent. By contrast, the levels of NTx (a bone resorption marker) and BAP (a bone formation marker) were not altered by glucosamine administration. A previous study by this group reported that glucosamine exerts a chondroprotective action in soccer players by preventing type II collagen degradation but maintaining type II collagen synthesis. Together these observations indicate that glucosamine may exert a chondroprotective action by preventing type II collagen degradation in athletes of various sports, including soccer players and bicycle racers. PMID- 23358551 TI - Suppression of the coffee-ring effect by self-assembling graphene oxide and monolayer titania. AB - The in situ self-assembly of two types of typical two-dimensional (2D) nanomaterials (i.e., graphene oxide (GO) and monolayer titania (TO)) is realized using a simple drop-casting method. Within the as-prepared hybrid films, the GO and TO nanosheets arrange alternately into a lamellar structure. Notably, the hybridization of GO and TO suppresses the formation of coffee-rings when drop cast, which is attributed to the strong interactions between the GO and TO nanosheets. Finally, the mechanism for the in situ hybridization of these two types of nanosheets into heterogeneous lamellar films and the suppression of the coffee-ring effect are discussed. These results demonstrate the potential applications of drop-cast hybrid films for high-quality membrane deposition from liquid phases. PMID- 23358553 TI - Tanshinone IIA inhibits the growth of pancreatic cancer BxPC-3 cells by decreasing protein expression of TCTP, MCL-1 and Bcl-xL. AB - Pancreatic cancer remains a challenging disease worldwide. Tanshinone IIA (Tan IIA) is one of the active constituents of Danshen (Radix Salviae miltiorrhizae). Tan-IIA has been hypothesized to inhibit numerous human cancer cells by various molecular mechanisms. However, the efficacy and molecular mechanism of Tan-IIA action in pancreatic cancer has not been well studied. In the present study, the cytotoxicity of Tan-IIA in human pancreatic cancer BxPC-3 cells was evaluated by MTT assay. Cell cycle analysis of BxPC-3 cells treated with Tan-IIA was performed by flow cytometry (FACS). Protein expression levels of TCTP, Mcl-1, Bcl-xL, Bax and Caspase-3 in BxPC-3 cells were measured by western blot analysis. The results revealed that Tan-IIA inhibited BxPC-3 cells in a time- and dose-dependent manner. FACS analysis demonstrated that Tan-IIA increases the rate of sub-G1 phase. BxPC-3 cells treated with Tan-IIA were identified to upregulate protein expression of Bax and Caspase-3 and downregulate expression of TCTP, Mcl-1 and Bcl-xL. These results indicate that Tan-IIA may inhibit BxPC-3 human pancreatic cancer cells through the induction of apoptosis by decreasing protein expression of TCTP, Mcl-1 and Bcl-xL and increasing Bax expression in vitro. The chemotherapeutic potential of Tan-IIA for human pancreatic cancer warrants further study. PMID- 23358554 TI - Enantioselective trapping of phosphoramidate ammonium ylides with imino esters for synthesis of 2,3-diaminosuccinic acid derivatives. AB - A highly enantioselective trapping of protic phosphoramidate ammonium ylides with alpha-imino esters is reported. The intriguing Rh2(OAc)4 and chiral Bronsted acid co-catalyzed three-component Mannich-type reaction of a diazo compound, a phosphoramidate, and an alpha-imino ester provides a rapid and efficient access to 2,3-diaminosuccinic acid derivatives with a high level control of diastereo- and enantioselectivity. PMID- 23358555 TI - Quantification of blood flow in internal cerebral artery by optical flow method on digital subtraction angiography in comparison with time-of-flight magnetic resonance angiography. AB - OBJECTIVE: This study compared data on the blood flow velocity in the internal carotid artery, which was obtained using the optical flow method (OFM) with digital subtraction angiography (DSA) and the time-of-flight (TOF) technique using magnetic resonance angiography (MRA). MATERIALS AND METHODS: Images were obtained from 12 cerebrovascular patients who underwent both brain DSA and MRA imaging. The OFM was applied on the DSA images to determine the average blood flow velocity. The calculated results were compared with the values obtained from the TOF-MRA data. A linear fit was performed on the data and Bland-Altman plots were analyzed. RESULTS: The blood flow velocity was closely associated with vascular diseases. Color-coding of the OFM measurements were superimposed on to the DSA images, which quantitatively illustrated the relative flow in the vessels. The average blood flow velocity was calculated using OFM and DSA, which demonstrated a high correlation with the MRA measurements in the anterior posterior (AP) view (R = 0.71). In contrast, the average blood flow velocity was low in the lateral view (R = 0.28). The consistency between the high and low blood velocity in the AP view was better compared to the lateral view. The blood flow velocity distribution in the AP view was statistically closer to the MRA measurement compared to the lateral view. CONCLUSIONS: This study evaluated the correlation of blood flow measured using DSA and TOF-MRA in a small heterogeneous group of patients with cerebrovascular lesions. OFM with DSA imaging reveals hemodynamic information and TOF-MRA. PMID- 23358558 TI - Diagnostic dilemma: Saccular aneurysm or pseudoaneurysm of the ascending aorta with dissection above level of leaflets. AB - BACKGROUND: In true aneurysm, the wall of aneurysm is composed of the normal histological components of aorta. A false aneurysm (pseudoaneurysm) represents a rupture which does not contain the normal histological components of aorta. It is a fibrous peel that has formed from a small perforation of aorta. We describe an unusual presentation that has signs which some of them are only manifested in true aneurysm and some others only in pseudoaneurysm. CASE REPORT: An 85-year-old man underwent elective coronary angiography for chest pain work-up. Our evaluation by invasive angiography and CT angiography showed aortic dissection. In surgery we found that dissection flap was composed of some parts of intima and media layers. These signs leaded to confusing symptoms. Localized bulging of ascending aorta had continued to brachiocephalic artery (transverse arch involvement). Dissection flap was composed of some part of intima and media layers. It was a strange case, it was not solely a perivascular hematoma and it did not have all three layers of aorta wall. Partial aorta replacement was performed. The operation and recovery was uneventful. CONCLUSION: This unusual presentation of disease has not been mentioned in literatures. Our experience can help to manage similar cases. This case was the first unusual presentation of its type. PMID- 23358556 TI - Genetic variation in the interleukin-28B gene is associated with spontaneous clearance and progression of hepatitis C virus in Moroccan patients. AB - BACKGROUND: Genetic variation in the IL28B gene has been strongly associated with treatment outcomes, spontaneous clearance and progression of the hepatitis C virus infection (HCV). The aim of the present study was to investigate the role of polymorphisms at this locus with progression and outcome of HCV infection in a Moroccan population. METHODS: We analyzed a cohort of 438 individuals among them 232 patients with persistent HCV infection, of whom 115 patients had mild chronic hepatitis and 117 had advanced liver disease (cirrhosis and hepatocellular carcinoma), 68 individuals who had naturally cleared HCV and 138 healthy subjects. The IL28B SNPs rs12979860 and rs8099917 were genotyped using a TaqMan 5' allelic discrimination assay. RESULTS: The protective rs12979860-C and rs8099917-T alleles were more common in subjects with spontaneous clearance (77.9% vs 55.2%; p = 0.00001 and 95.6% vs 83.2%; p = 0.0025, respectively). Individuals with clearance were 4.69 (95% CI, 1.99-11.07) times more likely to have the C/C genotype for rs12979860 polymorphism (p = 0.0017) and 3.55 (95% CI, 0.19-66.89) times more likely to have the T/T genotype at rs8099917. Patients with advanced liver disease carried the rs12979860-T/T genotype more frequently than patients with mild chronic hepatitis C (OR = 1.89; 95% CI, 0.99-3.61; p = 0.0532) and this risk was even more pronounced when we compared them with healthy controls (OR = 4.27; 95% CI, 2.08-8.76; p = 0.0005). The rs8099917-G allele was also associated with advanced liver disease (OR = 2.34; 95% CI, 1.40-3.93; p = 0.0100). CONCLUSIONS: In the Moroccan population, polymorphisms near the IL28B gene play a role both in spontaneous clearance and progression of HCV infection. PMID- 23358559 TI - Novel multifunctional titania-silica-lanthanum phosphate nanocomposite coatings through an all aqueous sol-gel process. AB - A novel nanocomposite coating containing titania, silica and lanthanum phosphate prepared through an all aqueous sol-gel route exhibits excellent self-cleaning ability arising from the synergistic effect of the constituents in the nanocomposite. A highly stable titania-silica-lanthanum phosphate nanocomposite sol having particle size in the range of 30-50 nm has been synthesized starting from a titanyl sulphate precursor, which was further used for the development of photocatalytically active composite coatings on glass. The coatings prepared by the dip coating technique as well as the nanocomposite powders are heat treated and characterized further for their morphology and multifunctionality. The nanocomposite containing 1.5 wt% LaPO4 has shown a surface area as high as 138 m(2) g(-1) and a methylene blue degradation efficiency of 94% in two hours of UV exposure. The composite coating has shown very good homogeneity evidenced by transparency as high as 99.5% and low wetting behaviour. The present novel approach for energy conserving, aqueous derived, self-cleaning coatings may be suitable for large scale industrial applications. PMID- 23358557 TI - The human functional brain network demonstrates structural and dynamical resilience to targeted attack. AB - In recent years, the field of network science has enabled researchers to represent the highly complex interactions in the brain in an approachable yet quantitative manner. One exciting finding since the advent of brain network research was that the brain network can withstand extensive damage, even to highly connected regions. However, these highly connected nodes may not be the most critical regions of the brain network, and it is unclear how the network dynamics are impacted by removal of these key nodes. This work seeks to further investigate the resilience of the human functional brain network. Network attack experiments were conducted on voxel-wise functional brain networks and region-of interest (ROI) networks of 5 healthy volunteers. Networks were attacked at key nodes using several criteria for assessing node importance, and the impact on network structure and dynamics was evaluated. The findings presented here echo previous findings that the functional human brain network is highly resilient to targeted attacks, both in terms of network structure and dynamics. PMID- 23358560 TI - Strong passivation effects on the properties of an InAs surface quantum dot hybrid structure. AB - We report on an InAs quantum dot (QD) hybrid structure with a top surface QD layer coupled to two buried QD layers that is highly sensitive to surface passivation. After 180 min of passivation, the photoluminescence (PL) peak of the surface QDs shifts from 1545 to 1275 nm while its intensity decreases by one order of magnitude. Time-resolved PL reveals a significant decrease of carrier tunneling between the QD layers because of the surface state modification by chemical treatment. A simple model with rate equations is used to explain the observed optical performance. Our results show that the optical performance of this hybrid structure is very sensitive to the surface environment, making it a potential candidate for sensing applications. PMID- 23358561 TI - A cohort study on psychosocial adjustment and psychopathology in adolescents and young adults with congenital heart disease. AB - OBJECTIVES: Our purpose was to study psychosocial adjustment and psychiatric morbidity of adolescents and young adults with congenital heart disease (CHD). DESIGN: All assessment measures were obtained on a single occasion. Clinical data was obtained through the patient's clinical records. SETTING: A teaching and tertiary care facility in Porto, Portugal. PARTICIPANTS: We evaluated 110 CHD patients (62 male) aged from 12 to 26 years (mean=18.00+/-3.617), 58 cyanotic. All assessment measures were obtained on a single occasion in a tertiary hospital. Demographic information and clinical history were collected. PRIMARY AND SECONDARY OUTCOME MEASURES: Questionnaires regarded topics such as social support, family educational style, self-image and physical limitations, a standardised psychiatric interview Schedule for Affective Disorders and Schizophrenia-Lifetime version (SADS-L), and a self-report questionnaire on psychosocial adjustment, youth self-report or adult self-report. One of the relatives completed an observational version of the same questionnaire (child behaviour checklist (CBCL) or ABCL (adult behaviour checklist)). RESULTS: We found a 21.8% lifetime prevalence of psychopathology, 31.3%, in females, 14.5% in males, showing a somewhat increased proneness in CHD patients. Females also showed worse psychosocial adjustment, with more somatic complaints (u=260 000; p=0.011), anxiety/depression (u=984 000; p=0.002), aggressive behaviour (u=920 500; p=0.001), attention problems (u=1123 500; p=0.027), thought problems (u=1069 500; p=0.010), internalisation (u=869 000; p=0.0) and externalisation (u=1163 000; p=0.05). Patients with severe CHD (u=939 000; p=0.03) and surgical repair (u=719 000; p=0.037) showed worse psychosocial adjustment. Those with poor social support showed more withdrawal (u=557 500; p=0.0) and social problems (u=748 500; p=0.023), and patients with unsatisfactory school performance revealed more anxiety/depression (u=916 000; p=0.02) and attention problems (u=861 500; p=0.007). CONCLUSIONS: CHD males with good social support and good academic performance have a better psychosocial adjustment. PMID- 23358562 TI - EGFR status in oral squamous cell carcinoma: comparing immunohistochemistry, FISH and CISH detection in a case series study. AB - OBJECTIVES: To compare the immunohistochemistry (IHC) expression of epidermal growth factor receptor (EGFR) in oral squamous cell carcinomas (OSCC) with the gene amplification evaluated by fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization (CISH) and their association with clinicopathological parameters. Additionally, we tested the sensibility and specificity of CISH in comparison with FISH. DESIGN: Case series study SETTING: Oral surgery and pathology department in a school of dentistry. PARTICIPANTS: 52 patients with histopathological diagnosis of OSCC. METHODS: Tumour tissue samples from 52 patients with OSCC were evaluated by IHC, FISH and CISH using tissue microarray technology. Clinicopathological data from all patients were collected. RESULTS: EGFR+ rates were 53.8% (28/52) by IHC, 5.8% (3/52) by CISH and 15.4% (8/52) by FISH. Amplification detected by CISH and FISH with IHC negative occurred in 3.8% (2/52), and one case (1.9%) showed amplification detected by CISH and FISH and protein overexpression concomitantly. There were 9.6% FISH+ cases with IHC and CISH negative rates and 6/8 (75%) FISH+ and also EGFR+ cases; however, an association between protein expression and gene amplification was not found for both techniques. IHC and FISH rates were not associated with clinicopathological features. CISH+ rates were associated with T3-T4 status. Compared with FISH assay, CISH reached a sensitivity of 37.5% and specificity of 100%. CONCLUSIONS: There is no association between EGFR expression and gene amplification in OSCC when the IHC is driven to external epitopes of the protein. Although CISH demonstrates specificity, technical problems may influence sensibility when compared with FISH. PMID- 23358563 TI - Disparities in fatal and non-fatal injuries between Irish travellers and the Irish general population are similar to those of other indigenous minorities: a cross-sectional population-based comparative study. AB - OBJECTIVES: To assess recent disparities in fatal and non-fatal injury between travellers and the general population in Ireland. DESIGN: A cross-sectional population-based comparative study. SETTING: Republic of Ireland. PARTICIPANTS: Population census and retrospective mortality data were collected from 7042 traveller families, travellers being those identified by themselves and others as members of the traveller community. Retrospective injury incidence was estimated from a survey of a random sample of travellers in private households, aged 15 years or over (702 men and 961 women). Comparable general population data were obtained from official statistical reports, while retrospective incidence was estimated from the Survey of Lifestyle, Attitude and Nutrition 2002, a random sample of 5992 adults in private households aged 18 years or over. OUTCOME MEASURES: Potential Years of Life Lost (PYLL), Standardised Mortality Ratios (SMR), Standardised Incidence Ratios (SIR) and Case Fatality Ratios (CFR). RESULTS: Injury accounted for 36% of PYLL among travellers, compared with 13% in the general population. travellers were more likely to die of unintentional injury than the general population (SMR=454 (95% CI 279 to 690) in men and 460 (95% CI 177 to 905) in women), with a similar pattern for intentional injury (SMR=637 (95% CI 367 to 993) in men and 464 (95% CI 107 to 1204 in women). They had a lower incidence of unintentional injury but those aged 65 years or over were about twice as likely to report an injury. Travellers had a higher incidence of intentional injuries (SIR=181 (95% CI 116 to 269) in men and 268 (95% CI 187 to 373) in women). Injury CFR were consistently higher among travellers. CONCLUSIONS: Irish travellers continue to bear a disproportionate burden of injury, which calls for scaling up injury prevention efforts in this group. Prevention and further research should focus on suicide, alcohol misuse and elderly injury among Irish travellers. PMID- 23358564 TI - Effectiveness and cost-effectiveness of a novel, group self-management course for adults with chronic musculoskeletal pain: study protocol for a multicentre, randomised controlled trial (COPERS). AB - INTRODUCTION: Chronic musculoskeletal pain is a common condition that often responds poorly to treatment. Self-management courses have been advocated as a non-drug pain management technique, although evidence for their effectiveness is equivocal. We designed and piloted a self-management course based on evidence for effectiveness for specific course components and characteristics. METHODS/ANALYSIS: COPERS (coping with persistent pain, effectiveness research into self-management) is a pragmatic randomised controlled trial testing the effectiveness and cost-effectiveness of an intensive, group, cognitive behavioural-based, theoretically informed and manualised self-management course for chronic pain patients against a control of best usual care: a pain education booklet and a relaxation CD. The course lasts for 15 h, spread over 3 days, with a -2 h follow-up session 2 weeks later. We aim to recruit 685 participants with chronic musculoskeletal pain from primary, intermediate and secondary care services in two UK regions. The study is powered to show a standardised mean difference of 0.3 in the primary outcome, pain-related disability. Secondary outcomes include generic health-related quality of life, healthcare utilisation, pain self-efficacy, coping, depression, anxiety and social engagement. Outcomes are measured at 6 and 12 months postrandomisation. Pain self-efficacy is measured at 3 months to assess whether change mediates clinical effect. ETHICS/DISSEMINATION: Ethics approval was given by Cambridgeshire Ethics 11/EE/046. This trial will provide robust data on the effectiveness and cost effectiveness of an evidence-based, group self-management programme for chronic musculoskeletal pain. The published outcomes will help to inform future policy and practice around such self-management courses, both nationally and internationally. TRIAL REGISTRATION: ISRCTN24426731. PMID- 23358566 TI - Epigenetic inactivation of ADAMTS9 via promoter methylation in multiple myeloma. AB - A disintegrin-like and metalloprotease with thrombospondin type I motifs (ADAMTS) are a family of 19 secreted mammalian metalloproteases. ADAMTS9 was reported to be a novel tumor suppressor gene and is downregulated in various types of human cancer due to hypermethylation of promoter CpG islands. In the present study, the silencing mechanism of the ADAMTS9 gene was analyzed in the multiple myeloma (MM) cell lines, KM3 and RPMI-8226. Control and MM samples were obtained by conventional bone marrow (BM) biopsy of normal and MM adult BM, respectively. RT PCR revealed a high expression of the ADAMTS9 gene in normal samples and RPMI 8226 cells while marked gene silencing of ADAMTS9 was observed in MM patients and KM3 cells. Promoter methylation of ADAMTS9 was detected in the KM3 cell line and 66% (37/56) MM patients by methylation-specific PCR. In addition, the DNA demethylating agent, 5-aza-2'-deoxycytidine and trichostatin A restored ADAMTS9 expression by suppressing promoter methylation in KM3 cells. Ectopic expression of ADAMTS9 in ADAMTS9-silenced MM cells was found to significantly suppress cell colony formation and proliferation. In the present study, DNA methylation was found to play a key role in ADAMTS9 gene silencing and the biological behavior of myeloma cells. The results demonstrate that ADAMTS9 silencing by methylation may be a novel tumor marker for MM and the applicability of demethylating agents in the treatment of MM. PMID- 23358567 TI - MoS2-MWCNT hybrids as a superior anode in lithium-ion batteries. AB - Molybdenum disulfide (MoS(2))-multiwalled carbon nanotube (MWCNT) hybrids have been prepared by simple dry grinding. Excellent initial charge capacity (1214 mA h g(-1)) and ~85% retention after 60 discharge-charge cycles at different current densities (100-500 mA g(-1)) make MoS(2)-MWCNT (1 : 1) hybrids a superior anode in Li-ion batteries. PMID- 23358568 TI - Formation of a dimeric host-guest complex via binding between a dicationic ionic liquid and a pyrogallol[4]arene macrocycle. AB - The crystal structure of a cocrystal comprising a complex of a bis(imidazolium) ionic liquid hosted by pyrogallol[4]arene (PgC) macrocycles is reported. Introduction of the dicationic species yields complexation by two PgC macrocycles, the resulting bilayer structure formed from alternately arranged dimeric host-guest complexes. PMID- 23358569 TI - The secondary phosphite selenide, CpFe(CO)2P(Se)(O(i)Pr)2, as an organometalloligand in heterometallic M-Se-P-Fe(Cp)-type complexes [M = Cr(0), W(0), Pd(II), Pt(II), Au(I)]. AB - The neutral metalloligand [CpFe(CO)2P(Se)(O(i)Pr)2] (Cp = eta(5)-C5H5), which contains the rare secondary phosphite selenide moiety, reacts with different metal complex precursors to form six new heterobimetallic complexes containing M Se-P-Fe(Cp) bond connectivity. The complexes [M(CO)5{CpFe(CO)2P(Se)(O(i)Pr)2}] (M = Cr, 1; M = W, 2), [MCl2{CpFe(CO)2P(Se)(O(i)Pr)2}2] (M = Pd, 3; M = Pt, 4), [Au4Cl4{CpFe(CO)2P(Se)(O(i)Pr)2}2], 5, and [AuI{CpFe(CO)2P(Se)(O(i)Pr)2}], 6, are all heterometallic, neutral, dinuclear (1, 2, 6), trinuclear (3, 4), and hexanuclear (5) complexes. The complexes were all prepared from straightforward substitution reactions (1-5) or as an adduct, 6. All new complexes were characterized by (1)H, (31)P, (77)Se NMR, infrared spectroscopy, elemental analysis and single crystal X-ray diffraction. PMID- 23358570 TI - Radial vibration of free anisotropic nanoparticles based on nonlocal continuum mechanics. AB - Radial vibration of spherical nanoparticles made of materials with anisotropic elasticity is theoretically investigated using nonlocal continuum mechanics. The anisotropic elastic model is reformulated using the nonlocal differential constitutive relations of Eringen. The nonlocal differential equation of radial motion is derived in terms of radial displacement. Cubic, hexagonal, trigonal and tetragonal symmetries of the elasticity are discussed. The suggested model is justified by a good agreement between the results given by the present model and available experimental data. Furthermore, the model is used to elucidate the effect of small scale on the vibration of several nanoparticles. Our results show that the small scale is essential for the radial vibration of the nanoparticles when the nanoparticle radius is smaller than 1.5 nm. PMID- 23358571 TI - Metal-free dehydrogenation of amine-boranes by an N-heterocyclic carbene. AB - The dehydrogenation of primary and secondary amine-boranes (RNH(2).BH(3) and R(2)NH.BH(3); R = alkyl groups) was studied using the bulky N-heterocyclic carbene IPr (IPr = [(HCNDipp)C:]; Dipp = 2,6-(i)Pr(2)C(6)H(3)) as a stoichiometric dehydrogenation agent. In the case of primary amine-boranes, carbene-bound adducts IPr.BH(2)-NH(R)-BH(3) were obtained in place of the desired polymers [RNH-BH(2)](n). The secondary amine-borane (i)Pr(2)NH.BH(3) participated in dehydrogenation chemistry with IPr to afford the aminoborane [(i)Pr(2)N=BH(2)] and the dihydroaminal IPrH(2) as products. Attempts to induce H(2) elimination from the arylamine-borane DippNH(2).BH(3) yielded a reaction mixture containing the known species IPr.BH(2)NHDipp, IPr.BH(2)NH(Dipp)-BH(3), free DippNH(2) and IPrH(2). The new hindered aryl-amine borane adduct Ar*NH(2).BH(3) [Ar* = 2,6 (Ph(2)CH)(2)-4-MeC(6)H(2)] underwent a reaction with IPr to give IPr.BH(3) and free Ar*NH(2), consistent with the presence of a weaker N-B dative bond in Ar*NH(2).BH(3) relative to its less hindered amine-borane analogues. PMID- 23358572 TI - Dynamic pH mapping in microfluidic devices by integrating adaptive coatings based on polyaniline with colorimetric imaging techniques. AB - In this paper we present a microfluidic device that has integrated pH optical sensing capabilities based on polyaniline. The optical properties of polyaniline coatings change in response to the pH of the solution that is flushed inside the microchannel offering the possibility of monitoring pH in continuous flow over a wide pH range throughout the entire channel length. This work also features an innovative detection system for spatial localisation of chemical pH gradients along microfluidic channels through the use of a low cost optical device. Specifically, the use of a microfluidic channel coated with polyaniline is shown to respond colorimetrically to pH and that effect is detected by the detection system, even when pH gradients are induced within the channel. This study explores the capability of detecting this gradient by means of imaging techniques and the mapping of the camera's response to its corresponding pH after a successful calibration process. The provision of an inherently responsive channel means that changes in the pH of a sample moving through the system can be detected dynamically using digital imaging along the entire channel length in real time, without the need to add reagents to the sample. This approach is generic and can be applied to other chemically responsive coatings immobilised on microchannels. PMID- 23358573 TI - Liposuction. PMID- 23358574 TI - Immunosuppression induced by apoptosis of mixed lymphocyte culture is associated with p53. AB - A lymphocyte inhibition model was created using a co-culture of donor and host lymphocytes, resulting in apoptosis of the latter, and subsequently, inducing immune tolerance. This method may be used to resolve the immune rejection problem prior to organ transplantation. Using mixed lymphocyte culture (MLC) and/or addition of anti-anti-IL-2 neutralizing monoclonal antibody, we successfully developed a lymphocyte inhibition model in vitro. In this model, the apoptosis of recipient lymphocytes co-cultured with donor lymphocytes was observed by Wright Giemsa stain, electron microscopy imaging and flow cytometry. The growth and proliferation of mixed lymphocytes were detected by XTT and BrdU assays. Cell viability was determined using CCK-8 cell viability assay. The activity of the recipient lymphocytes was very high when stimulated by antigens alone [PMLC+D2 (Bm) group] but markedly lowered by anti-anti-IL-2 neutralizing monoclonal antibody [PMLC+D2 (Bm)+anti-IL-2 group]. The suppression of recipient lymphocyte activity was due to apoptosis mediated by p53 and caspase-3, and the optimal ratio of donor and recipient lymphocytes for apoptosis was explored. With the exception of the control group, the ratio of apoptotic cells was highest in the PMLC+D2 (Bm)+anti-IL-2 group and lowest in the PMLC+D2 (Bm) group. Blockade of IL 2 with anti-IL-2 neutralizing antibody resulted in an increased number of apoptotic lymphocytes in our experiment, which suggested that IL-2 inhibits the apoptosis of lymphocytes. These data suggest that IL-2 is involved in MLC-induced apoptosis of recipient lymphocytes, and that apoptosis may be associated with p53 and caspase-3 pathways. PMID- 23358575 TI - Glenoid and humeral head bone loss in traumatic anterior glenohumeral instability: a systematic review. AB - PURPOSE: The aim of this systematic review is to analyze outcomes of surgical procedures for glenoid and/or humeral bony defects, performed singularly or in combination, in patients with traumatic anterior glenohumeral instability. A secondary aim is to establish in clinical settings which percentage of glenoid or humeral bone loss needs to be treated with a bony procedure to avoid recurrence of dislocation. METHODS: A systematic review of the literature according to the PRISMA guidelines was performed. A comprehensive search of PubMed, Medline, CINAHL, Cochrane, Embase and Google Scholar databases using various combinations of the keywords "shoulder", "instability", "dislocation", "bone loss", "bony bankart", "osseous glenoid defects", "glenoid bone grafting", "Latarjet", "glenoid", "humeral head", "surgery", "glenohumeral", "Hill Sachs", "Remplissage", over the years 1966-2012 was performed. RESULTS: Twenty-seven articles, describing patients with glenoid bony defect, humeral bony defect or both in the setting of traumatic anterior glenohumeral instability, were included. A total of 1,816 shoulders in 1,801 patients were included, with a median age at surgery of 27.1 years, ranging from 12 to 75 years. Patients were assessed at a median follow-up period of 2.8 years (ranging from 6 months to 28.2 years). The overall recurrence of redislocation occurred in 117 (6.5 %) shoulders. The redislocation event occurred in 40 of 553 (7.2 %) shoulders with glenoid bony defect, in 30 of 225 (13.3 %) shoulders with humeral bony defect and in 63 of 1,009 (6.3 %) shoulders with both glenoid and humeral involvement. CONCLUSION: Even though the general principle of recognizing and treating glenoid and humeral bone defects in patients with traumatic anterior glenohumeral instability is widely accepted, few studies are available to date to accurately establish which bone defects should be treated with bone procedures and the exact percentage of bone loss leading to higher risk of redislocation in clinical settings. PMID- 23358576 TI - The unhappy total knee arthroplasty (TKA) patient: higher WOMAC and lower KSS in depressed patients prior and after TKA. AB - PURPOSE: Patient-based and psychological factors do influence outcome in patients undergoing total knee arthroplasty (TKA). The purpose was to investigate if preoperative psychological factors influence the subjective and objective outcomes 6 weeks, 4 months and 1 year after TKA. Our hypothesis was that there is a significant influence of psychological factors on clinical outcome scores before and after TKA. METHODS: A prospective, longitudinal, single-cohort study investigating the correlation of depression, control beliefs, anxiety and a variety of other psychological factors with outcomes of patients undergoing TKA was performed. A total of 104 consecutive patients were investigated preoperatively using the Beck's depression inventory, the State-Trait Anxiety Index, the questionnaire for assessment of control beliefs and the SCL-90R inventory. The Knee Society Clinical Rating System (KSS) and the WOMAC were used. Analysis of TKA position was performed on radiographs according to Ewald et al. Correlation of psychological variables with outcomes was performed (p < .05). RESULTS: Self-efficacy did not influence clinical scores. More depressed patients showed higher pre- and postoperative WOMAC scores, but no difference in amelioration. KSS scores were not influenced. Patients with higher State and Trait Anxiety Indexes had higher WOMAC and lower KSS scores before and after the operation, but most significant correlations were <0.3. Several SCL-90 dimensions had significant correlations with pre- and postoperative clinical scores, but not with their amelioration. The SCL-90 subscore for somatization and the overall SCL 90 significantly correlated with the WOMAC, KSS before and after TKA. CONCLUSIONS: Depression, anxiety, a tendency to somatize and psychological distress were identified as significant predictors for poorer clinical outcomes before and/or after TKA. Standardized preoperative screening and subsequent treatment should become part of the preoperative work-up in orthopaedic practice. LEVEL OF EVIDENCE: Prognostic prospective, Level I. PMID- 23358577 TI - Enhanced luminescence of Ag nanoclusters via surface modification. AB - In this work we present a detailed study on the influence of surface modifications for luminescent silver (Ag) clusters. Ag clusters (25 atoms) capped with dihydrolipoic acid show a distinct absorbance spectrum with several sharp transitions, and relative broad deep red luminescence with a quantum yield of 5% combined with a remarkably long luminescence lifetime of ~3 MUs at room temperature. Both pH and the presence of coordinating ligands influence the absorbance spectra and fluorescence intensity. A strong increase in luminescence intensity up to 45% quantum yield could be induced by coordination with PEG ligands. CONCLUSION: the surface coordination of the Ag clusters strongly influences the optical properties. PMID- 23358579 TI - The "dermal cage": a modification of the inferior pedicle breast reduction. AB - In spite of more recent techniques for breast reduction, the inferior pedicle technique has proven to be enduring and still a very popular option in the plastic surgeon's armamentarium despite certain shortcomings. This technique is especially important for treating large breasts with a long sternal notch-to nipple distance. The modifications we describe in this article overcome some of the main drawbacks of the standard inferior pedicle technique and make the procedure particularly effective when used on appropriately selected patients. This is achieved principally by the creation of a strong, durable, and internalized "dermal cage" that remains fixed to the chest wall in the upper part, as well as on both sides, to support the majority of the remaining breast tissue. This serves several purposes, including narrowing the breast thereby giving good projection and reduction of the N-IMF length of the inferior pedicle. Through suspension and fixation of the inferior pedicle to the chest wall, one can mitigate the effects of gravity on the inferior pedicle. The benefits of this include reduced tension on the T junction, thereby reducing the incidence of wound dehiscence in the immediate postoperative period, while reduction of tension on the nipple-areola complex reduces "bottoming" out over the long term. This process has been the main shortcoming of the inferior pedicle technique to date. The technique was used on 26 patients over a 7-year period with a mean long term follow-up of 41 months. The results demonstrate the short- and long-term effectiveness of our own particular combination of modifications to previously described techniques and modifications of the inferior pedicle breast reduction. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23358580 TI - A novel approach to structural facial volume replacement. AB - Improved understanding of the anatomy and physiology of the aging face has laid the foundation for adopting an earlier and more comprehensive approach to facial rejuvenation, shifting the focus from individual wrinkle treatment and lift procedures to a holistic paradigm that considers the entire face and its structural framework. This article presents an overview of a comprehensive method to address facial aging. The key components to the reported strategy for improving facial cosmesis include, in addition to augmentation of volume loss, protection with sunscreens and antioxidants; promotion of epidermal cell turnover with techniques such as superficial chemical peels; microlaser peels and microdermabrasion; collagen stimulation and remodeling via light, ultrasound, or radiofrequency (RF)-based methods; and muscle control with botulinum toxin. For the treatment of wrinkles and for the augmentation of pan-facial dermal lipoatrophy, several types of fillers and volumizers including hyaluronic acid (HA), autologous fat, and calcium hydroxylapatite (CaHA) or injectable poly-L lactic acid (PLLA) are available. A novel bimodal, trivector technique to restore structural facial volume loss that combines supraperiosteal depot injections of volume-depleted fat pads and dermal/subcutaneous injections for panfacial lipoatrophy with PLLA is presented. The combination of treatments with fillers; toxins; light-, sound-, and RF-based technologies; and surgical procedures may help to forestall the facial aging process and provide more natural results than are possible with any of these techniques alone. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23358582 TI - Metal-bound halogen atoms in crystal engineering. AB - In this viewpoint article we discuss an early contribution from Brammer and Orpen et al., which highlights the very rich supramolecular behaviour of halogen atoms. Their findings appear even more timely when viewed in light of the recently proposed IUPAC definition of the halogen bond. PMID- 23358581 TI - Lowering revision rates in medial pedicle breast reduction by the selective addition of "inverted-T" technique. AB - BACKGROUND: The superomedial pedicle vertical-scar breast reduction is an effective technique, but high revision rates have been reported. The purpose of this study is to determine if revision rates can be lowered by the rational use of an inverted-T technique in a subset of patients who undergo superomedial pedicle reduction. METHODS: Records were reviewed of 127 breast reductions performed between 2002 and 2011. Group 1 (2002-2007) consisted of 51 patients who underwent a superomedial pedicle vertical-scar reduction. Four of these patients (8%) required a subsequent revision. Based on this, indications were adopted where vertical-scar reductions were performed in patients with proposed nipple position to inframammary fold (PNP-IMF) distances of less than 22 cm, with the remainder undergoing reduction with a superomedial pedicle and inverted-T skin resection pattern. In Group 2 (2008-2011), there were 41 vertical reductions and 35 "hybrid" reductions. Age, BMI, preoperative medical conditions, and reduction size did not differ significantly between the two groups. RESULTS: Nine patients in Group 1 (18%) experienced one or more minor complications, as did 12 patients in Group 2 (16%), (p=0.62). There were four revisions in Group 1 (8%) and none in Group 2 (p<0.001). Mean operative time was 177 min in Group 1 compared to 136 min in Group 2 (p<0.001). CONCLUSIONS: Breast reduction employing a superomedial pedicle can be used effectively in a wide range of patients. Revision rates can be reduced by employing an inverted-T skin resection in patients with a long PNP IMF distance, while not significantly increasing complication rates or operative time. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23358583 TI - A new bone-anchored hearing implant: short-term retrospective data on implant survival and subjective benefit. AB - This report provides the first short-term follow-up data on the Ponto bone anchored hearing implant from our tertiary referral centre. Thirty-one consecutive patients with a mean age of 51 years who received the implant between October 2010 and December 2011 were included retrospectively in this study. Implant loss, skin reactions around the implant (according to Holgers' grading system), revision surgery, and abutment replacements were retrospectively gathered from the patients' files as objective outcome measures. To obtain information on subjective patient satisfaction, the Glasgow Benefit Inventory (GBI) was used. The mean follow-up period was 16.9 months (range 12.1-25.2 months). One implant was lost. Over a total of 94 follow-up visits, 21 skin reactions were observed in 16 patients: Holgers grade 1 (slight redness, no need for treatment) in 18.1 % of the visits,and grade 2 (redness and moist, needing conservative treatment) in 4.3 % of the visits. Four 6-mm abutments (12.9 %) were replaced for a 9-mm abutment during the follow-up period, of which one (3.2 %) was in combination with revision surgery. In one patient keloid formation around the implant was observed. The GBI revealed a moderate subjective benefit. The short-term results with these percutaneous implants demonstrate a clinically stable implant with a low percentage of skin reactions that require treatment. Long-term, prospective follow-up data are needed to draw firmer conclusions. PMID- 23358584 TI - Cochlear implantation in a child with posttraumatic single-sided deafness. AB - Cochlear implantation has become a standard therapy for children with bilateral profound hearing loss, resulting in substantial and sustainable benefits for the development of expressive and receptive and expressive language skills and cognition. During the last few years, audiologic and otologic criteria for cochlear implantation have been expanded. Recently, patients with profound single sided deafness with or without tinnitus have received cochlear implants despite normal to near-normal hearing on the contralateral side. This indication, however, has thus far been restricted to adult patients. Although it is known that unilateral hearing has an impact on social-emotional development in children, otologic surgeons have been reluctant to treat children with single sided deafness with a cochlear implant. We report here on a case of successful cochlear implantation in an 8-year-old boy with acute single-sided deafness due to a lateral skull-base fracture, after an MRI showed signs of imminent fibrosis of the inner ear with possible prevention of cochlear implantation at a later stage. There was normal hearing in the contralateral ear. The child showed rapid development of speech discrimination in the implanted ear, improvements in sound localization and speech perception in noise, and a high degree of patient satisfaction. This experience may encourage using this therapeutic approach in children with chronic profound single-sided deafness. PMID- 23358585 TI - The effects of lycopene on cisplatin-induced ototoxicity. AB - To investigate the potential preventive effect of lycopene in cisplatin-related ototoxicity. Thirty-five healthy 3-3.5-month adult female Sprague-Dawley rats were randomly divided into three groups and treated as follows: Group 1 (n = 10), received no cisplatin or lycopene. Both group 2 (n = 10) and; Group 3 (n = 15) received a single dose of 12 mg/kg cisplatin intraperitoneally. Lycopene was administered via gavage feeding in group 2 for 15 days. Prior to any medication administration, the baseline distortion product emissions were obtained in three groups. The animals were tested again at 15th day. The resulting distortion product otoacoustic emissions (DPOAE) were evaluated at 1.5, 2, 3, 4, 5, 6, 7, 8, 10, and 12 kHz. On day 0, prior to any medications, the initial DPOAEs measurement results gave similar values in the three groups (p > 0.05). In group 2 and 3, statistically significant differences were recorded for all frequencies between day 0 and day 15 values (p < 0.05). Lycopene group demonstrated significantly higher DP-grams except for 1.5 kHz frequency when compared to cisplatin group (p < 0.05). There was a statistically significant difference in basal and mid turn external ciliated cells number (p < 0.05), but there was no statistically significant difference in apical turn between three groups (p > 0.05). Stria vascularis changes were statistically significant between the groups, and the median score for stria vascularis injury was significantly greater in group 3 than in group 2 (p < 0.05). The median scores for spiral ganglion cells changes were significantly greater in group 3 than in group 2 (p < 0.05). The analyses of the results revealed statistically significant differences between two groups (p < 0.05), suggesting lycopene's possible protective effect against cisplatin ototoxicity. The present study revealed that administration of lycopene may demonstrate a protective role against cisplatin-induced ototoxicity in rats. PMID- 23358587 TI - Severe Neck Pain with Fever: Is it Meningitis? AB - A 58-year-old male patient presented to the emergency department with complaints of severe neck pain. He admitted to drug use but denied using intravenous (IV) drugs. On exam, he had a fever of 100.7 degrees F, positive Kernig's sign, and normal neurologic exam. The patient was suspected to have bacterial meningitis and was started on IV antibiotics. The next day the patient developed decreased hand grip. Magnetic resonance imaging of the spine the next day showed a soft tissue mass impinging on the spinal canal. The patient was subsequently taken to the operating room where the epidural abscess was drained. PMID- 23358586 TI - The presence of CD209 expressing dendritic cells correlates with biofilm positivity in chronic rhinosinusitis with nasal polyposis. AB - Biofilm-positive cases of chronic rhinosinusitis with nasal polyposis (CRSwNP) may form a separate clinical entity, which is characterized by high recurrence rates and resistance against different therapeutic strategies. This can be explained by a special immunologic phenotype. Biofilm existence has been supposed to correlate with increased amount of dendritic cells that are responsible for antigen presentation in CRSwNP. A total of 20 patients with CRSwNP undergoing endoscopic sinus surgery (ESS) were analyzed. The negative control group consisted of ten patients undergoing septoplasty without CRSwNP. Three series of individual nasal polyps and control specimens were processed to hematoxylin-eosin (HE) and Gram staining and to CD209-specific immunofluorescent assay, respectively. Biofilm was detected in 13 of 20 patients (65 %) with CRSwNP and in none of the ten negative controls. The subepithelial layer of biofilm-positive nasal polyps displayed a statistically significant (p < 0.001) increase in the numbers of CD209-expressing dendritic cells compared to biofilm-negative specimens. It was found that biofilm detectability showed strong correlation to the architecture of respiratory mucosa and to the dominant inflammatory cell type of the subepithelial layer. Persisting bacterial biofilms may affect the type of antigen presentation and consecutive immune reactions in the subepithelial layer of nasal mucosa. This phenomenon may result in different inflammatory pathways with specific cytokine profile compared to biofilm-negative cases. Co-existence of bacterial biofilms and dominant pattern of dendritic cells suggest a biofilm associated immunologic phenotype in CRSwNP. This can explain the mucosal changes, functional disorders and therapy resistance featuring CRSwNP. PMID- 23358588 TI - The Assessment of Reliability and Validity of Persian Version of the Endometriosis Health Profile (EHP-30). AB - BACKGROUND: The Endometriosis Health Profile-30 (EHP-30) is a disease-specific questionnaire to measure the health-related quality of life in patients with endometriosis. The aim of this study was to evaluate the validity and reliability of the Persian version of Endometriosis Health Profile (EHP-30) in women with endometriosis referring to three Gynecology Clinics in Tehran, Iran. METHODS: One hundred women (20 to 50 years old) with surgically confirmed endometriosis recruited from three outpatient Gynecology Clinics affiliated to the Iran University of Medical Sciences. All 100 patients were asked to complete EHP-30 questionnaire while referring to the Clinics. The findings were analyzed using descriptive statistics, internal reliability consistency, construct validity (using short form-36, which had already been validated in Iran), factor analysis (with principle component analysis method), and item total correlation to assess the validity and reliability of the questionnaire. RESULTS: The internal consistency reliability of the questionnaire was high (Cronbach's alpha ranged between 0.80 and 0.93 for core, and 0.78 and 0.90 for modular parts). All items were loaded on their own factors except item 17 (feeling aggressive or violent) and item 18 (feeling unwell), which were loaded on pain and social support domains, respectively. Construct validity of EHP-30, established by using SF-36, indicates good correlations in several similar scales of these two questionnaires. CONCLUSION: The findings of the study demonstrate that Persian version of EHP-30 is a valid and reliable measure to assess the quality of life in women with endometriosis. PMID- 23358590 TI - Gallbladder Metastasis of Non-small Cell Lung Cancer Presenting as Acute Cholecystitis. AB - Although non-small cell lung cancer (NSCLC) can metastasize to almost any organ, metastasis to the gallbladder with significant clinical manifestation is relatively rare. Here, we report a case of gallbladder metastasis of NSCLC presenting as acute cholecystitis. A 79-year-old man presented with pain in the right upper quadrant and fever. A computed tomography (CT) scan of the chest and abdomen showed a cavitary mass in the right lower lobe of the lung and irregular wall thickening of the gallbladder. Open cholecystectomy and needle biopsy of the lung mass were performed. Histological examination of the gallbladder revealed a moderately-differentiated squamous cell carcinoma displaying the same morphology as the lung mass assessed by needle biopsy. Subsequent immunohistochemical examination of the gallbladder and lung tissue showed that the tumor cells were positive for P63 but negative for cytokeratin 7, cytokeratin 20 and thyroid transcription factor-1. A second primary tumor of the gallbladder was excluded by immunohistochemical methods, and the final pathological diagnosis was gallbladder metastasis of NSCLC. Although the incidence is extremely rare, acute cholecystitis can occur in association with lung cancer metastasis to the gallbladder. PMID- 23358591 TI - Metal free and selective activation of one C-F bond in a bound CF3 group. AB - The first metal free selective C-F bond activation of a CF(3) group was observed with N-heterocyclic silylenes [PhC(NtBu)(2)SiCl] (1) and [CH{(C=CH(2))(CMe)(2,6 iPr(2)C(6)H(3)N)(2)}Si] (2) with PhN=C(CF(3))(2). The reaction proceeds in a 1 : 1 molar ratio to yield the mono C-F bond activated products 3 and 4 with each containing a CF(2) group. Both the reactions proceed through an unprecedented selective activation of one of the C-F bonds rather than forming the [1+2] cycloaddition product containing the three-membered SiNC rings. PMID- 23358592 TI - Sulodexide may alleviate neointimal hyperplasia by inhibiting angiopoietin-2 in an arteriovenous fistula model. AB - The present study was undertaken to confirm whether sulodexide aleviates neointimal hyperplasia by regulating angiopoietin/Tie in a rat femoral arteriovenous fistula (AVF) model. Sprague Dawley rats were divided into four groups: sham, model, treatment and treatment control. An arteriovenous shunt model was created in the model and treatment groups. Sulodexide was subcutaneously administered (10 mg/kg/day) 6 times per week for 8 weeks in the treatment and treatment control groups. Histology and immunofluorescence were analyzed and the protein expression of angiopoietin-1, angiopoietin-2, Tie-2, p ERK and total-ERK were tested by ELISA and/or western blotting after 8 weeks. HE staining revealed that sulodexide was able to partially alleviate intimal hyperplasia of remodeled veins in the AVF model. Additionally, sulodexide was able to decrease angiopoietin-2 and Tie-2 expression while increasing angiopoietin-1 expression in AVF tissue. Sulodexide was also able to decrease ERK phosphorylation which was increased in the model. Serum levels of soluble Tie-2 (sTie-2) were also significantly decreased by sulodexide compared with the model. Immunofluorescent analysis also confirmed that sulodexide was able to decrease angiopoietin-2 expression, possibly partially by inhibiting endothelial cell proliferation. Sulodexide may alleviate venous intimal hyperplasia by regulating the angiopoietin/Tie system, which may play a significant role in assisting remodeled veins to cope with their new biomechanical environment, but whether the angiopoietin/Tie system is beneficial or not requires further study. PMID- 23358589 TI - Gene mutations and molecularly targeted therapies in acute myeloid leukemia. AB - Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period of time. However, over the last 30 years fine tuning of therapeutics have increased the rates of remission and cure. Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3, JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in clinical development. For loss-of function gene mutations, which are mostly biomarkers of favorable prognosis, combined therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products, proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their biological functions and clinical significance and present small molecule compounds in clinical development, which are expected to have a role in treating AML subtypes with characteristic molecular alterations. PMID- 23358594 TI - Observation of vocal fold and pharyngeal paralysis after carotid endarterectomy using a magnifying laryngoscope. AB - BACKGROUND: Injury to the vagus nerve or one of its branches during carotid endarterectomy (CEA) can result in vocal fold paralysis (VFP), but the exact mechanisms and site of injury responsible for VFP after CEA are unclear. The aim of this study was to identify the site of nerve injury in patients with VFP after CEA using magnifying laryngoscopy. METHODS: We performed 96 consecutive CEA procedures in 87 patients over 5 years. After 56 CEA procedures, we examined vocal fold movements with a flexible nasolaryngoscope and detected VFP in 5 of 40 cases (9 %). At 6-8 weeks after CEA, these five patients also underwent magnifying laryngoscopy at another institution by a specialist in vocalization. RESULTS: We confirmed ipsilateral VFP and pharyngeal paralysis in three patients. The other two patients recovered from their nerve injuries spontaneously before the magnifying examination. CONCLUSIONS: VFP and pharyngeal paralysis were caused by damage to the recurrent laryngeal and pharyngeal nerves. Therefore, the probable site of nerve injury during CEA was near the inferior vagal ganglion of the vagus nerve trunk in our three patients. PMID- 23358595 TI - Single port laparoscopic totally extraperitoneal hernioplasty: a comparative study of short-term outcome with conventional laparoscopic totally extraperitoneal hernioplasty. AB - BACKGROUND: Recently, single port laparoscopic surgery has begun to develop as an extension of minimally invasive surgery, but there have been only a few reports of single port laparoscopic totally extraperitoneal (SPLTEP) hernioplasty. In addition, there are few comparative studies with conventional laparoscopic totally extraperitoneal (CLTEP) hernioplasty. The aim of the present study was to report our experience with SPLTEP hernioplasty and to compare short-term outcomes for SPLTEP hernioplasty with CLTEP hernioplasty. METHODS: Data were prospectively collected for all patients undergoing SPLTEP hernioplasty for inguinal hernia at Incheon St. Mary's Hospital, Incheon, Korea. Data for the SPLTEP group (n = 76 patients enrolled between June 2010 and May 2011) were compared retrospectively with data for the CLTEP group (n = 93 patients enrolled between June 2009 and May 2010). RESULTS: There were no significant differences in patient demographics. This study showed no significant difference in terms of operative time between the two groups (SPLTEP group 54.0 min vs. CLTEP group 47.8 min; p = 0.07). There were no conversions to conventional TEP hernioplasty or transabdominal preperitoneal hernioplasty or open surgery in SPLTEP hernioplasty. Morbidity rates were 7.9 % (n = 6) in the SPLTEP group and 10.8 % (n = 10) in the CLTEP group, and the difference was not significant. CONCLUSIONS: Single port laparoscopic totally extraperitoneal hernioplasty is technically feasible and the short-term operative outcome is comparable to that of CLTEP hernioplasty. Future large-scale prospective controlled studies and long-term analysis are needed to establish the cosmetic outcomes, quality of life, long-term recurrence rate, and long-term complication rate of SPLTEP hernioplasty. PMID- 23358596 TI - Real time radiation dosimeters based on vertically aligned multiwall carbon nanotubes and graphene. AB - Measurements of the absorbed dose and quality assurance programs play an important role in radiotherapy. Ionization chambers (CIs) are considered the most important dosimeters for their high accuracy, practicality and reliability, allowing absolute dose measurements. However, they have a relative large physical size, which limits their spatial resolution, and require a high bias voltage to achieve an acceptable collection of charges, excluding their use for in vivo dosimetry. In this paper, we propose new real time radiation detectors with electrodes based on graphene or vertically aligned multiwall carbon nanotubes (MWCNTs). We have investigated their charge collection efficiency and compared their performance with electrodes made of a conventional material. Moreover, in order to highlight the effect of nanocarbons, reference radiation detectors were also tested. The proposed dosimeters display an excellent linear response to dose and collect more charge than reference ones at a standard bias voltage, permitting the construction of miniaturized CIs. Moreover, an MWCNT based CI gives the best charge collection efficiency and it enables working also to lower bias voltages and zero volts, allowing in vivo applications. Graphene based CIs show better performance with respect to reference dosimeters at a standard bias voltage. However, at decreasing bias voltage the charge collection efficiency becomes worse if compared to a reference detector, likely due to graphene's semiconducting behavior. PMID- 23358597 TI - Assessment of environmental public exposure from a hypothetical nuclear accident for Unit-1 Bushehr nuclear power plant. AB - Unit-1 of the Bushehr nuclear power plant (BNPP-1) is a VVER-type reactor with 1,000-MWe power constructed near Bushehr city at the coast of the Persian Gulf, Iran. The reactor has been recently operational to near its full power. The radiological impact of nuclear power plant (NPP) accidents is of public concern, and the assessment of radiological consequences of any hypothetical nuclear accident on public exposure is vital. The hypothetical accident scenario considered in this paper is a design-basis accident, that is, a primary coolant leakage to the secondary circuit. This scenario was selected in order to compare and verify the results obtained in the present paper with those reported in the Final Safety Analysis Report (FSAR 2007) of the BNPP-1 and to develop a well proven methodology that can be used to study other and more severe hypothetical accident scenarios for this reactor. In the present study, the version 2.01 of the PC COSYMA code was applied. In the early phase of the accidental releases, effective doses (from external and internal exposures) as well as individual and collective doses (due to the late phase of accidental releases) were evaluated. The surrounding area of the BNPP-1 within a radius of 80 km was subdivided into seven concentric rings and 16 sectors, and distribution of population and agricultural products was calculated for this grid. The results show that during the first year following the modeled hypothetical accident, the effective doses do not exceed the limit of 5 mSv, for the considered distances from the BNPP-1. The results obtained in this study are in good agreement with those in the FSAR 2007 report. The agreement obtained is in light of many inherent uncertainties and variables existing in the two modeling procedures applied and proves that the methodology applied here can also be used to model other severe hypothetical accident scenarios of the BNPP-1 such as a small and large break in the reactor coolant system as well as beyond design-basis accidents. Such scenarios are planned to be studied in the near future, for this reactor. PMID- 23358598 TI - Bomb-pulse 14C analysis combined with 13C and 15N measurements in blood serum from residents of Malmo, Sweden. AB - The (14)C content of 60 human blood serum samples from residents of Malmo (Sweden) in 1978, obtained from a biobank, has been measured to estimate the accuracy of (14)C bomb-pulse dating. The difference between the date estimated using the Calibomb software and sampling date varied between -3 +/- 0.4 and +0.2 +/- 0.5 years. The average age deviation of all samples was -1.5 +/- 0.7 years, with the delay between production and consumption of foodstuffs being probably the dominating cause. The potential influence of food habits on the (14)C date has been evaluated using stable isotope delta(13)C and delta(15)N analysis and information about the dietary habits of the investigated individuals. Although the group consisting of lacto-ovo vegetarians and vegans (pooled group) was not completely separated from the omnivores in a stable isotopic trophic level diagram, this analysis proved to add valuable information on probable dietary habits. The age deviation of the sampling date from the respective Calibomb date was found strongly correlated with the delta(13)C values, probably due to influence from marine diet components. For the omnivore individuals, there were indications of seasonal effects on delta(13)C and the age deviation. No significant correlation was found between the age deviation and the delta(15)N values of any dietary group. No influence of sex or year of birth was found on neither the (14)C nor the delta(13)C and delta(15)N values of the serum samples. The data were also divided into two groups (omnivores and pooled group), based on the level of delta(15)N in the samples. The consumption of high delta(15)N-valued fish and birds can be responsible for this clustering. PMID- 23358599 TI - Heterocoupling of 2-naphthols enabled by a copper-N-heterocyclic carbene complex. AB - The reactivity of a Cu catalyst for oxidative coupling is modulated by a small molecule additive, diethyl malonate, that slows over-oxidation of 2-naphthols. Efficient heterocoupling between electron-rich and electron-poor 2-naphthols/2 naphthylamines affords C(1)-symmetric BINOLs with yields ranging from 35-98%. PMID- 23358600 TI - Survival of pig-to-rhesus corneal xenografts prolonged by prior donor bone marrow transplantation. AB - The aim of the present study was to explore the survival of pig-rhesus corneal xenografts following donor bone marrow transplantation (BMT). Wuzhishan pigs were used as donors and rhesus monkeys as recipients for corneal xenotransplantation. Twelve rhesus monkeys were divided into two groups. Group 1 received intravenous injection of cyclophosphamide (CP) followed by pig bone marrow cell transplantation, while group 2 was used as a control and only received intravenous CP injection. All xenografts were evaluated using a slit-lamp microscope. The immunological status of the recipients following transplantation, including the formation of chimerism, mixed lymphocyte reaction (MLR) and immunoglobulin and complement in the serum, was analyzed. Two rhesus monkeys in each group were sacrificed for corneal histopathology examination. The mean survival time was 36.0+/-4.7 days in group 1 and 17.7+/-3.2 days in group 2. The mean chimerism percentage in group 1 at week 1 was 5.20+/-1.02%, but decreased with time and was <1% after week 3. MLR demonstrated that immune reactivity to donor spleen cells in group 1 was decreased following surgery. Immunoglobulin and complement levels in the serum revealed a decreasing trend. Histopathological examination demonstrated that the corneal xenografts in group 1 had minimal inflammatory cell infiltration and no eosinophil infiltration. Survival of corneal xenografts may be prolonged by prior BMT, suggesting that immune reactivity to donors is suppressed, and is highly dependent on chimerism formation. PMID- 23358602 TI - Contralesional motor deficits after unilateral stroke reflect hemisphere-specific control mechanisms. AB - We have proposed a model of motor lateralization, in which the left and right hemispheres are specialized for different aspects of motor control: the left hemisphere for predicting and accounting for limb dynamics and the right hemisphere for stabilizing limb position through impedance control mechanisms. Our previous studies, demonstrating different motor deficits in the ipsilesional arm of stroke patients with left or right hemisphere damage, provided a critical test of our model. However, motor deficits after stroke are most prominent on the contralesional side. Post-stroke rehabilitation has also, naturally, focused on improving contralesional arm impairment and function. Understanding whether contralesional motor deficits differ depending on the hemisphere of damage is, therefore, of vital importance for assessing the impact of brain damage on function and also for designing rehabilitation interventions specific to laterality of damage. We, therefore, asked whether motor deficits in the contralesional arm of unilateral stroke patients reflect hemisphere-dependent control mechanisms. Because our model of lateralization predicts that contralesional deficits will differ depending on the hemisphere of damage, this study also served as an essential assessment of our model. Stroke patients with mild to moderate hemiparesis in either the left or right arm because of contralateral stroke and healthy control subjects performed targeted multi-joint reaching movements in different directions. As predicted, our results indicated a double dissociation; although left hemisphere damage was associated with greater errors in trajectory curvature and movement direction, errors in movement extent were greatest after right hemisphere damage. Thus, our results provide the first demonstration of hemisphere specific motor control deficits in the contralesional arm of stroke patients. Our results also suggest that it is critical to consider the differential deficits induced by right or left hemisphere lesions to enhance post-stroke rehabilitation interventions. PMID- 23358601 TI - Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer's disease. AB - The factors driving clinical heterogeneity in Alzheimer's disease are not well understood. This study assessed the relationship between amyloid deposition, glucose metabolism and clinical phenotype in Alzheimer's disease, and investigated how these relate to the involvement of functional networks. The study included 17 patients with early-onset Alzheimer's disease (age at onset <65 years), 12 patients with logopenic variant primary progressive aphasia and 13 patients with posterior cortical atrophy [whole Alzheimer's disease group: age = 61.5 years (standard deviation 6.5 years), 55% male]. Thirty healthy control subjects [age = 70.8 (3.3) years, 47% male] were also included. Subjects underwent positron emission tomography with (11)C-labelled Pittsburgh compound B and (18)F-labelled fluorodeoxyglucose. All patients met National Institute on Ageing-Alzheimer's Association criteria for probable Alzheimer's disease and showed evidence of amyloid deposition on (11)C-labelled Pittsburgh compound B positron emission tomography. We hypothesized that hypometabolism patterns would differ across variants, reflecting involvement of specific functional networks, whereas amyloid patterns would be diffuse and similar across variants. We tested these hypotheses using three complimentary approaches: (i) mass-univariate voxel wise group comparison of (18)F-labelled fluorodeoxyglucose and (11)C-labelled Pittsburgh compound B; (ii) generation of covariance maps across all subjects with Alzheimer's disease from seed regions of interest specifically atrophied in each variant, and comparison of these maps to functional network templates; and (iii) extraction of (11)C-labelled Pittsburgh compound B and (18)F-labelled fluorodeoxyglucose values from functional network templates. Alzheimer's disease clinical groups showed syndrome-specific (18)F-labelled fluorodeoxyglucose patterns, with greater parieto-occipital involvement in posterior cortical atrophy, and asymmetric involvement of left temporoparietal regions in logopenic variant primary progressive aphasia. In contrast, all Alzheimer's disease variants showed diffuse patterns of (11)C-labelled Pittsburgh compound B binding, with posterior cortical atrophy additionally showing elevated uptake in occipital cortex compared with early-onset Alzheimer's disease. The seed region of interest covariance analysis revealed distinct (18)F-labelled fluorodeoxyglucose correlation patterns that greatly overlapped with the right executive-control network for the early-onset Alzheimer's disease region of interest, the left language network for the logopenic variant primary progressive aphasia region of interest, and the higher visual network for the posterior cortical atrophy region of interest. In contrast, (11)C-labelled Pittsburgh compound B covariance maps for each region of interest were diffuse. Finally, (18)F-labelled fluorodeoxyglucose was similarly reduced in all Alzheimer's disease variants in the dorsal and left ventral default mode network, whereas significant differences were found in the right ventral default mode, right executive-control (both lower in early-onset Alzheimer's disease and posterior cortical atrophy than logopenic variant primary progressive aphasia) and higher-order visual network (lower in posterior cortical atrophy than in early-onset Alzheimer's disease and logopenic variant primary progressive aphasia), with a trend towards lower (18)F-labelled fluorodeoxyglucose also found in the left language network in logopenic variant primary progressive aphasia. There were no differences in (11)C-labelled Pittsburgh compound B binding between syndromes in any of the networks. Our data suggest that Alzheimer's disease syndromes are associated with degeneration of specific functional networks, and that fibrillar amyloid-beta deposition explains at most a small amount of the clinico-anatomic heterogeneity in Alzheimer's disease. PMID- 23358605 TI - Endovascular treatment of diabetic foot in a selected population of patients with below-the-knee disease: is the angiosome model effective? AB - PURPOSE: To evaluate the efficacy of percutaneous transluminal angioplasty (PTA) in a selected population of diabetic patients with below-the-knee (BTK) disease and to analyze the reliability of the angiosome model. METHODS: We made a retrospective analysis of the results of PTA performed in 201 diabetic patients with BTK-only disease treated at our institute from January 2005 to December 2011. We evaluated the postoperative technical success, and at 1, 6, and 12 months' follow-up, we assessed the rates and values of partial and complete ulcer healing, restenosis, major and minor amputation, limb salvage, and percutaneous oximetry (TcPO2) (Student's t test). We used the angiosome model to compare different clinicolaboratory outcomes in patients treated by direct revascularization (DR) from patients treated with indirect revascularization (IR) technique by Student's t test and the chi(2) test. RESULTS: At a mean +/- standard deviation follow-up of 17.5 +/- 12 months, we observed a mortality rate of 3.5 %, a major amputation rate of 9.4 %, and a limb salvage rate of 87 % with a statistically significant increase of TcPO2 values at follow-up compared to baseline (p < 0.05). In 34 patients, treatment was performed with the IR technique and in 167 by DR; in both groups, there was a statistically significant increase of TcPO2 values at follow-up compared to baseline (p < 0.05), without statistically significant differences in therapeutic efficacy. CONCLUSION: PTA of the BTK-only disease is a safe and effective option. The DR technique is the first treatment option; we believe, however, that IR is similarly effective, with good results over time. PMID- 23358603 TI - Corticospinal tract degeneration associated with TDP-43 type C pathology and semantic dementia. AB - Four subtypes of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions have been described (types A-D). Of these four subtypes, motor neuron disease is more commonly associated with type B pathology, but has also been reported with type A pathology. We have noted, however, the unusual occurrence of cases of type C pathology having corticospinal tract degeneration. We aimed to assess the severity of corticospinal tract degeneration in a large cohort of cases with type C (n = 31). Pathological analysis included semi-quantitation of myelin loss of fibres of the corticospinal tract and associated macrophage burden, as well as axonal loss, at the level of the medullary pyramids. We also assessed for motor cortex degeneration and fibre loss of the medial lemniscus/olivocerebellar tract. All cases were subdivided into three groups based on the degree of corticospinal tract degeneration: (i) no corticospinal tract degeneration; (ii) equivocal corticospinal tract degeneration; and (iii) moderate to very severe corticospinal tract degeneration. Clinical, genetic, pathological and imaging comparisons were performed across groups. Eight cases had no corticospinal tract degeneration, and 14 cases had equivocal to mild corticospinal tract degeneration. Nine cases, however, had moderate to very severe corticospinal tract degeneration with myelin and axonal loss. In these nine cases, there was degeneration of the motor cortex without lower motor neuron degeneration or involvement of other brainstem tracts. These cases most commonly presented as semantic dementia, and they had longer disease duration (mean: 15.3 years) compared with the other two groups (10.8 and 9.9 years; P = 0.03). After adjusting for disease duration, severity of corticospinal tract degeneration remained significantly different across groups. Only one case, without corticospinal tract degeneration, was found to have a hexanucleotide repeat expansion in the C9ORF72 gene. All three groups were associated with anterior temporal lobe atrophy on MRI; however, the cases with moderate to severe corticospinal tract degeneration showed right-sided temporal lobe asymmetry and greater involvement of the right temporal lobe and superior motor cortices than the other groups. In contrast, the cases with no or equivocal corticospinal tract degeneration were more likely to show left-sided temporal lobe asymmetry. For comparison, the corticospinal tract was assessed in 86 type A and B cases, and only two cases showed evidence of corticospinal tract degeneration without lower motor neuron degeneration. These findings confirm that there exists a unique association between frontotemporal lobar degeneration with type C pathology and corticospinal tract degeneration, with this entity showing a predilection to involve the right temporal lobe. PMID- 23358606 TI - Branching and capping determine the force-velocity relationships of branching actin networks. AB - A branching actin network is the major engine that drives cell motility. A measure of the effectiveness of an engine is the velocity the engine is able to produce at a given resistance-the force-velocity relationship. Concave force velocity relationships consist of a force-insensitive region, indicative of an adaptive response. In contrast, convex force-velocity relationships would reflect a passive response. Even in in vitro experiments, branching actin networks can exhibit both concave and convex force-velocity curves. However, the exact mechanism that can explain both force-velocity curves is not yet known. We carried out an agent-based stochastic simulation to explore such a mechanism. We discovered an emergent behavior of a branching actin network: Upon resistance, it remodels itself by increasing the number of filaments growing in contact with the load. The remodeling is favored by branching events and limited by capping. The force-velocity relationship hinges on the relative time-scale between the intrinsic kinetics of the branching actin network and the loading. Shortly after encountering resistance (~seconds), the force-velocity relationship of the actin network is always convex, as it does not have enough time to remodel itself. A concave force-velocity relationship requires network remodeling at longer time scales (~tens of seconds to minutes) and the faster branching event relative to capping. Furthermore, our model explains the observed hysteresis in the force velocity relationship of actin networks. Our model thus establishes a unified mechanism that can account for both convex and concave force-velocity relationships observed in branching actin networks. PMID- 23358607 TI - Serotonin-norepinephrine reuptake inhibitor therapy in late-life depression is associated with increased marker of bone resorption. AB - Antidepressants are associated with bone loss and fractures in older adults. We treated depressed older adults with an antidepressant and examined its effects on bone turnover by comparing blood samples before and after treatment. Bone resorption increased after antidepressant treatment, which may increase fracture risk. INTRODUCTION: Antidepressants have been associated with increased bone loss and fractures in older adults in observational studies, but the mechanism is unclear. We examined the effects of a serotonin-norepinephrine reuptake inhibitor, venlafaxine, on biomarkers of bone turnover in a prospective treatment study of late-life depression. METHODS: Seventy-six individuals aged 60 years and older with current major depressive disorder received a 12-week course of venlafaxine XR 150-300 mg daily. We measured serum C-terminal cross-linking telopeptide of type I collagen (beta-CTX) and N-terminal propeptide of type I procollagen (P1NP), measures of bone resorption and formation, respectively, before and after treatment. We then analyzed the change in beta-CTX and P1NP within each participant. Venlafaxine levels were measured at the end of the study. We assessed depression severity at baseline and remission status after treatment. RESULTS: After 12 weeks of venlafaxine, beta-CTX increased significantly, whereas P1NP did not significantly change. The increase in beta CTX was significant only in participants whose depression did not remit (increase by 10 % in non-remitters vs. 4 % in remitters). Change in beta-CTX was not correlated with serum levels of venlafaxine or norvenlafaxine. CONCLUSION: Our findings suggest that the primary effect of serotonergic antidepressants is to increase bone resorption. However, such an increase in bone resorption seemed to depend on whether or not participants' depression remitted. Our results are in agreement with prior observational studies reporting increased bone loss in older adults taking serotonergic antidepressants. These negative effects on bone homeostasis could potentially contribute to increased fracture risk in older adults. PMID- 23358610 TI - Paraganglioma with unusual presentation in parotid gland: A diagnostic dilemma in fine needle aspiration. AB - Paragangliomas (PGLs) are uncommon tumors. Although PGLs are known to occur in the head and neck region, especially the carotid body, middle ear, and larynx, involvement of the parotid glands has not been reported. In this article, we report the fine needle aspiration features of tumor in an unusual location, presenting as a parotid gland mass, submitted to pathology for initial diagnosis. The clinical presentation, cytomorphology, and the immunohistochemical features for the diagnosis are described. To our knowledge, this is the first case of paraganglioma of the parotid gland reported in the literature. PMID- 23358608 TI - Serum extracellular secreted antagonists of the canonical Wnt/beta-catenin signaling pathway in patients with Cushing's syndrome. AB - Patients with endogenous hypercortisolism have higher sclerostin, but do not differ in Dickkopf 1 (Dkk1) or secreted frizzled-related protein 1 (SFRP1) levels as compared to healthy control. INTRODUCTION: Endogenous Cushing's syndrome (CS), usually affecting young and otherwise healthy patients, is a good model to validate the effects of supraphysiological levels of glucocorticoids in humans. This study evaluates circulating levels of extracellular antagonists of the Wnt/beta-catenin signaling pathway (sclerostin, Dkk1, SFRP1) in patients with CS versus healthy individuals. METHODS: Forty patients with clinically and biochemically evident CS and 40 sex-, age-, and body mass index-matched healthy subjects provided fasting serum samples for sclerostin, SFRP1 and Dkk1, along with bone turnover markers. RESULTS: Patients with CS had higher sclerostin levels (34.5 (30.3-37.1) pmol/L) versus healthy individuals (29.9 (24.3-36.8) pmol/L) (p = 0.032). Differences in sclerostin were due to the lack of lower sclerostin values rather than an increase in protein levels above the upper limits of the healthy control. The odds of sclerostin levels being higher than 30 pmol/L were greater in patients with CS as compared with the odds in healthy subjects (odds ratio = 3.81 95 % confidence interval 1.45-10.02) (p = 0.01). It coexisted with suppressed bone formation and unchanged bone resorption markers. Dkk1, SFRP1 did not differ from the control group. CONCLUSIONS: Of all the tested proteins (sclerostin, Dkk1, SFRP1), only sclerostin showed a significant difference when contrasting CS with healthy subjects. Hypercortisolism might prevent the down-regulation of sclerostin. Targeting sclerostin seems to be a promising therapeutic approach to treating osteoporosis in patients with CS. PMID- 23358611 TI - First diastereoselective [3 + 2] cycloaddition reaction of diethyl isocyanomethylphosphonate and maleimides. AB - Bicyclic alpha-iminophosphonates were prepared via the first diastereoselective silver catalyzed [3 + 2] cycloaddition reaction of diethyl isocyanomethylphosphonate and diversely N-substituted maleimides. The reduction of the resulting imine by catalytic hydrogenation led to cyclic alpha aminophosphonates, which are alpha-aminoester surrogates. The relative stereochemistry of the adducts was confirmed by X-ray crystallographic analysis of . The diastereoselectivity of the cycloaddition reaction was rationalised by theoretical studies. PMID- 23358613 TI - Novel cyclovirus discovered in the Florida woods cockroach Eurycotis floridana (Walker). AB - A novel cyclovirus (proposed genus "Cyclovirus", family Circoviridae) was discovered in a specimen of Eurycotis floridana (Walker), also known as the Florida woods cockroach or palmetto bug, collected from Tarpon Springs, Florida. The Florida woods cockroach-associated cyclovirus GS140 (FWCasCyV-GS140) was obtained through a degenerate PCR assay and showed 64 % genome-wide pairwise identity to a cyclovirus identified in bat feces. This finding supports recent reports suggesting that Circoviridae members, traditionally thought to only infect vertebrates, are present within insect populations. PMID- 23358612 TI - Virus nomenclature below the species level: a standardized nomenclature for laboratory animal-adapted strains and variants of viruses assigned to the family Filoviridae. PMID- 23358614 TI - The complete nucleotide sequence of sweet potato C6 virus: a carlavirus lacking a cysteine-rich protein. AB - The complete nucleotide sequence of a sweet potato virus, first identified two decades ago as virus "C-6", was determined in this study. Sequence similarity and phylogenetic analysis clearly place it as a member of a distinct species within the genus Carlavirus, family Betaflexiviridae. Its genome structure was typical for that of other carlaviruses except that the ORF for the cysteine-rich protein was replaced by an ORF encoding a predicted protein with no similarity to any known protein. PMID- 23358615 TI - Changes of plasma vWF level in response to the improvement of air quality: an observation of 114 healthy young adults. AB - Plasma von Willebrand factor (vWF) is an important factor involving in hemostasis and various cardiovascular diseases. Air pollution is related to many respiratory and cardiovascular diseases. During the Olympic Games Beijing 2008 period (August 8 to September 17, 2008) when air quality in Beijing improved greatly, we studied the relationship between plasma vWF level and the factors of air pollution index (API), ABO blood group, and polymorphisms in vWF gene in healthy young adults. We recruited 114 healthy medical students. In a period of more than 4 months around the period of Olympic Games Beijing 2008, six blood samples at stages 1 and 2 (before Olympic Games), stages 3 and 4 (during Olympic Games), and stages 5 and 6 (after Olympic Games) were taken from every participant for the measurement of plasma vWF level and genotyping of three SNPs (rs7954855, rs7965413, and rs216311) in vWF gene. Daily air pollution index near their living places was obtained from the officially published data. The average API began to decrease from stage 2, reached to nadir in stages 3 and 4, and increased but was still lower in stages 5 and 6. Plasma vWF decreased during the experimental period in all participants. The average plasma vWF decreased from stage 2 and remained lower in stages 3-6. vWF level varied greatly among the participants (from 30 to 170 %) but decreased proportionately when we analyzed their levels individually. Participants with O blood type had lower plasma vWF level than those with A, B, and AB blood types. Those with the SNP in vWF gene causing homozygous threonine at codon 1381 had lower plasma vWF level than those with homozygous alanine or heterozygous alanine/threonine. In the 114 normal individuals, the average plasma vWF level decreased during the period of Olympic Games Beijing 2008 when air quality improved greatly. This suggests that control of air pollution may be useful to prevent some diseases such as cardiovascular diseases. PMID- 23358616 TI - Autologous stem cell transplantation with busulfan, cyclophosphamide, and etoposide as an intensifying frontline treatment in patients with peripheral T cell lymphomas: a multicenter retrospective trial. AB - The effectiveness of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) as a frontline treatment in peripheral T cell lymphomas (PTCLs) is still unclear. We retrospectively investigated the clinical outcomes of HDT/ASCT as an intensifying frontline treatment in 31 patients with newly diagnosed PTCLs. The conditioning regimen of HDT/ASCT consisted of busulfan, cyclophosphamide, and etoposide (BuCyE). At diagnosis, five (16.1 %) patients were classified as high risk according to the prognostic index for PTCL (PIT). The disease status of the patients before HDT/ASCT consisted of 23 patients (74.2 %) with complete response (CR) and eight patients (25.8 %) with partial response (PR). Six (75 %) out of eight patients with PR at pretransplantation were improved in terms of the response to CR after HDT/ASCT. At a median follow-up of 32.4 months, the 3-year probability of overall survival (OS) and progression-free survival (PFS) was 64.5 +/- 8.6 %. Transplant-related mortality occurred in three patients (9.7 %), due to septic shock, hemorrhage, and delayed pneumonia, respectively. Bone marrow involvement of PTCL at diagnosis was a poor prognostic factor for OS. In conclusion, frontline HDT/ASCT with a conditioning regimen of BuCyE may be an effective and tolerable intensifying therapeutic option to improve outcomes in patients with PTCLs. PMID- 23358619 TI - [Meconium-stained amniotic fluid and maternal and neonatal factors associated]. AB - OBJECTIVE: To identify the frequency and maternal and neonatal factors associated with meconium-stained amniotic fluid at birth. METHODS: Cross-sectional study carried out with 2,441 births at an in-hospital birth center in the city of Sao Paulo (Southeastern Brazil) in March and April, 2005. The association between meconium-stained amniotic fluid and the independent variables (maternal age, parity, previous c-section or not, gestational age, obstetric history, oxytocin use in the labor, cervical dilation at admission, mode of current delivery, newborn weight, Apgar score at the 1st and 5th minute) was expressed as prevalence ratio (PR). RESULTS: Meconium-stained amniotic fluid was verified in 11.9% of the births; 68.2% of these were normal births and 38.8% c-sections. Meconium was associated with: primiparity (PR=1.49, 95%CI 1.29; 1.73), gestational age >= 41 weeks (PR = 5.05, 95%CI 1.93;13.25), oxytocin in labor (PR = 1.83, 95%CI 1.60; 2.10), c- section (PR = 2.65, 95%CI 2.17; 3.24) and Apgar scores < 7 at the 5th minute (PR = 2.96, 95%CI 2,94;2,99). Neonatal mortality was 1.6/1,000 live births. Meconium-stained amniotic fluid was found in 50% of neonatal deaths and it was associated with higher rates of surgical deliveries. CONCLUSIONS: Oxytocin use, worse conditions of the newborn after the delivery and increased c-section rates were factors associated with meconium-stained amniotic fluid. Routine use of oxytocin in the intrapartum period could be evaluated due to its association with meconium-stained amniotic fluid. PMID- 23358618 TI - [Burnout Syndrome: population-based study on public servants]. AB - OBJECTIVE: To identify predictors of burnout syndrome among workers in the public sector. METHODS: Cross-sectional study with a representative sample consisting of 879 municipal civil servants in a city of the metropolitan region of Porto Alegre, Southern Brazil. In order to measure the demographic variables and related characteristics of work we used a questionnaire developed for this purpose.The perception of the work environment was measured by the Work Atmosphere Scale. The Maslach Burnout Inventory was used to assess burnout syndrome. Three multiple stepwise linear regression tests were performed, in which each dimension of the syndrome was considered outcome while the other variables were estimated as predictors, adjusted for gender and age. RESULTS: The variables related to perceptions of work environment were the ones which most contributed to the occurrence of burnout. Perceiving work as stressful and the presence of people who negatively affect the work environment contributed to the explanatory model of the three dimensions. There were nine variables which comprised a predictive model which explained 43% of Emotional Exhaustion. The variable 'perceives how stressful the job appeared to be' had the highest explanatory power. In Despersonalization, eight variables comprised 25% of the model and, once again, 'perceives how stressful the job appeared to be' was the variable with the highest explanatory power. 'Low Professional Fulfillment' revealed a set of variables with an explanatory power of 20%; a working environment considered to be good showed a higher weighting, showing it to be inversely associated. CONCLUSIONS: Public servants' perceptions of their work environment play an important role as a predictor of burnout. Viewing work as stressful and the presence of people who negatively affect the environment proved to be the elements of greatest importance. PMID- 23358617 TI - High response rate and improved exercise capacity and quality of life with a new regimen of darbepoetin alfa with or without filgrastim in lower-risk myelodysplastic syndromes: a phase II study by the GFM. AB - Darbepoetin (DAR), with or without granulocyte colony-stimulating factor (G-CSF), has proved effective in treating anemia in patients with lower-risk myelodysplastic syndrome (MDS), but its effects on quality of life (QoL) and exercise functioning are less well established. In this phase II study (no. NCT00443339), lower-risk MDS patients with anemia and endogenous erythropoietin (EPO) level <500 IU/L received DAR 500 MUg once every 2 weeks for 12 weeks, with G-CSF added at week 12 in non-responders. Physical performance was assessed with the 6-min walking test and, for fit patients, maximal oxygen consumption (VO2max). QoL was evaluated using SF-36 and FACT-An tests. In 99 patients, erythroid response rate according to IWG 2006 criteria was 48 and 56 % at 12 and 24 weeks, respectively. Addition of G-CSF rescued 22 % of non-responders. In 48 % of the responders, interval between darbepoetin injections could be increased for maintenance treatment. Serum EPO level was the only independent predictive factor of response at 12 weeks, and its most discriminant cutoff value was 100 IU/L. QoL and VO2max showed improvement over time in responders, compared with non responders. With a median follow-up of 52 months, median response duration was not reached, and 3-year cumulative incidence of acute myeloid leukemia and overall survival (OS) was 14.5 and 70 %, respectively. Baseline transfusion dependence, International Prognostic Score System (IPSS), and Revised IPSS accurately predicted OS from treatment onset. Tolerance of darbepoetin was good. In conclusion, this regimen of darbepoetin every 2 weeks yielded high response rates and prolonged response duration. Objective improvement in exercise testing and in patient-reported QoL confirms the clinical relevance of anemia correction with erythropoiesis-stimulating agents. PMID- 23358620 TI - [Trends in the epidemic of Aids cases in Southern Brazil from 1986 to 2008]. AB - OBJECTIVE: To describe trends in the incidence of Aids cases according to age and gender from 1986 to 2008. METHODS: Analyses of Aids trends according to age group and to gender was carried out Londrina, Southern Brazil. The timeframe was divided into two periods (1986-1995 and 1996-2008). Of the polynomial models, it was the first-degree polynomial model which best explained the Aids epidemic within the two periods. The incidence rate of Aids among men who have sex with other men (MSM), injecting drug users (IDU), heterosexual men and women was calculated. RESULTS: During the first period, from 1986 to 1995, there was an increase in the incidence of Aids in almost all age groups and the epidemic spread across both sexes (p < 0.001), although this was more marked in men aged 14-39. The second period (1996-2008) did not show a positive or negative statistical increase, indicating that the epidemic had stabilized. A significant fall in the rate for the male 14 to 29 age group was found, with increases of 0.88 and 0.87 for the first and second period respectively. Cases in women aged 50 and over showed a marked increase (p = 0.019). The IDU and MSM groups predominated as the categories with the most exposure, with MSM taking over from IDU in the last three years of the study. From 2000 onwards, incidences in females aged 15 to 49 overtook that of heterosexual men. CONCLUSIONS: The study showed a decrease in incidence in the younger age groups and stabilization in the other age groups. There is a need for different approaches in order to reach groups with several characteristics due to the increase in the proportion of women and MSM within the exposure categories. PMID- 23358621 TI - [Leprosy-related disabilities after release from multidrug treatment: prevalence and spatial distribution]. AB - OBJECTIVE: To estimate the frequency of people with leprosy-related physical disabilities after release from multidrug treatment and to analyze their spatial distribution. METHODS: Descriptive cross-sectional study with 232 leprosy patients treated between 1998 and 2006. Physical disabilities were assessed using the World Health Organization disability grading and the eye-hand-foot (EHF) sum score. The residential address of patients and rehabilitation centers were geocoded. It was estimated the overall frequency of physical disability and frequency by disability grade (grade 0, grade 1, and grade 2) according to the WHO disability grading taking into consideration clinical and sociodemographic variables in the descriptive analysis. Student's t-test, chi-square test (chi2), and Fisher's test were used as appropriate at a 5% significance level. RESULTS: Of the patients studied, 51.6% were female, mean age 54 years old (SD 15.7), 30.5% had less than 2 years of formal education, 43.5% were employed, and 26.9% were retired. Borderline leprosy was the most prevalent form of leprosy (39.9%). A total of 32% of these patients had disabilities according to the WHO disability grading and the EHF score. Disabilities increased with age (p = 0.029), they were more common in patients with multibacillary leprosy (p = 0.005) and poor self rated physical health (p < 0.001). Those who required prevention/rehabilitation care traveled on average 5.5 km to the rehabilitation center. People with physical disabilities lived scattered across the city but they were mostly concentrated in the most densely populated and socioeconomically deprived area. CONCLUSIONS: There is a high frequency of people with leprosy-related disabilities after release from multidrug therapy. Prevention and rehabilitation actions should target uneducated and older patients, those who had multibacillary forms of leprosy and poor self-rated physical health. The travel distance to rehabilitation centers calls for reorganization of local care networks. PMID- 23358622 TI - [Hospital readmissions related to drug interactions: a retrospective study in a hospital setting]. AB - OBJECTIVE: To examine the relationship between potential drug interactions and hospital readmissions. METHODS: Retrospective study with 1,487 adult patients (> 18 years old) admitted to a general hospital in the city of Vitoria da Conquista, Northeastern Brazil, from January to December 2007. Data were collected from Hospital Admission Authorization (AIH) forms in the Brazilian National Health System Hospital Database (SIH/SUS). Probabilistic linkage was used to combine multiple AIH forms from the same admission into a single record and to identify readmissions. Information on prescriptions was manually added to the SIH/SUS records. Logistic regression was used to quantitatively assess the impact of drug interactions on hospital readmissions. Cox regression was performed to test the impact of this variable on time to first readmission. RESULTS: A total of 99 readmissions (7% of all patients) were identified. Potential drug interactions were found in 35% of all prescriptions evaluated. Patients with potential drug interactions in a prior admission were more likely to be readmitted. The adjusted odds ratio indicated a 2.4-fold increase in odds of being readmitted; and the adjusted hazard ratio showed that this risk was increased by 79% in patients with potential drug interactions (p < 0.01). CONCLUSIONS: The study results suggest an association between prior drug interactions and increased risk of readmission. Health professionals should be aware of potential hazard of certain drug combinations and closely monitor high-risk patients such as elderly patients and those with renal impairment. PMID- 23358623 TI - Human endogenous retrovirus-H insertion screening. AB - Endogenous retroviruses (ERVs) and ERV-like sequences comprise 8% of the human genome. We aimed to analyze genome integration polymorphisms of human endogenous retrovirus (HERV)-H by the inter-retrotransposon amplified polymorphism (IRAP) technique using the sequences of LTR7A (450 bp), LTR7B (445 bp) and LTR7C (471 bp). Blood samples from 20 individuals (10 females and 10 males) of diverse ethnic origins were used for the determination of integration variations at the genomic level. Isolated genomic DNA was screened using 3 pairs of primers corresponding to LTR regions of the HERV-H gene. We observed insertion polymorphism patterns between 0-87% in all subjects. The findings obtained contribute to our understanding of the effects of HERV-H on variations within the human genome. PMID- 23358624 TI - Ideomotor apraxia in agrammatic and logopenic variants of primary progressive aphasia. AB - There are few studies examining praxis in subjects with primary progressive aphasia. The aim of this study was to examine the pattern and severity of ideomotor apraxia in subjects with logopenic and agrammatic variants of primary progressive aphasia and to determine if the presence of ideomotor apraxia correlated with specific neuroanatomical structural abnormalities. Subjects with primary progressive aphasia were prospectively recruited and classified according to published criteria. Using the apraxia subtest of the Western Aphasia Battery, pattern and severity of ideomotor apraxia was examined in all subjects diagnosed with agrammatic and logopenic variants of primary progressive aphasia. The study included 47 subjects, 21 diagnosed with agrammatic variant of primary progressive aphasia and 26 with logopenic variant primary progressive aphasia. Subjects with agrammatic aphasia were older at onset than the logopenic variant (67.2 vs. 61.7 years, p = 0.02), but there was no difference in illness duration prior to evaluation. Those with logopenic aphasia showed more cognitive impairment on the Mini-Mental Status Examination (agrammatic = 26.7/30, logopenic = 22/30, p = 0.002), and a trend for more severe language impairment as measured by the Western Aphasia Battery-Aphasia Quotient (agrammatic = 82.3, logopenic = 75.2, p = 0.11). Strong correlations were found between Western Aphasia Battery-Aphasia Quotient and total apraxia, instrumental apraxia, and complex apraxia, while average to modest correlations were seen with upper limb apraxia and facial apraxia. After adjusting for age, mental status performance, and Western Aphasia Battery-Aphasia Quotient score, those with agrammatic aphasia had a higher degree of total apraxia (p = 0.004), facial apraxia (p = 0.03), instrumental apraxia (p = 0.0006), and complex apraxia (p = 0.0006) than those with logopenic aphasia. The agrammatic variant of primary progressive aphasia was associated with greater praxis deficits but less cognitive impairment than the logopenic variant. The presence of ideomotor apraxia was associated with grey matter loss in the left lateral premotor cortex with extension into the motor cortex. These findings suggest that although some affected areas in the agrammatic and logopenic variants of primary progressive aphasia overlap, there exists an area that is more affected in the agrammatic variant than the logopenic variant that accounts for the greater association of agrammatic aphasia with ideomotor apraxia. PMID- 23358625 TI - Adult-onset leukodystrophies from respiratory chain disorders: do they exist? AB - Respiratory chain disorders (RCDs) have been included in the differential diagnosis of adult-onset leukodystrophies. Here, we first report a 32-year-old female with an atypical, adult-onset, non-syndromic RCD due to a mitochondrial DNA deletion and manifesting as complicated ataxia. A 'leukodystrophic' pattern was found on brain MRI, but it was neither isolated nor predominant because of the presence of overt basal ganglia and infratentorial lesions, which led us to the proper diagnosis. Subsequently, we evaluated our series of patients with RCDs in order to verify whether a 'leukodystrophic' pattern with little or no involvement of deep grey structures and brainstem may be found in adult-onset RCDs, as reported in children. Among 52 patients with adult-onset RCDs, no case with a 'leukodystrophic' pattern was found, apart from three cases with a classical phenotype of mitochondrial neurogastrointestinal encephalopathy. In addition, no case of RCDs was found among six cases of adult-onset leukodystrophy of unknown origin and at least one feature suggestive of mitochondrial disease. The review of the literature was in agreement with these findings. Thus, we provide evidence that, unlike in children, RCDs should not be included in the differential diagnosis of adult-onset leukodystrophies, except when there are additional MRI findings or clinical features which unequivocally point towards a mitochondrial disorder. PMID- 23358626 TI - Differential diagnostic yield of lumbar puncture in investigation of suspected subarachnoid haemorrhage: a retrospective study. AB - The diagnostic algorithm of computerized tomography (CT) and lumbar puncture (LP) for suspected subarachnoid haemorrhage (SAH) has lately been challenged by the advancement of radiological techniques, such as higher resolution offered by newer generation CT-scanners and increased availability of CT-angiography. A purely radiological workup of suspected SAH offers great advantages for both patients and the health care system, but the risks of abandoning LP in this setting are not well investigated. We have characterized the differential diagnostic yield of LP in the investigation of suspected SAH by a retrospective study. From the hospital laboratory database, we analyzed the medical records of all patients who had undergone CSF-analysis in search of subarachnoid bleeding during 2009-2011. A total of 453 patients were included. In 14 patients (3%) the LP resulted in an alternative diagnosis, the most common being aseptic meningitis. Two patients (0.5%) received treatment for herpes meningitis. Five patients (1%) with subarachnoid haemorrhages were identified. Among these, the four patients presenting with thunderclap headache had non-aneurysmal bleedings and did not require surgical intervention. We conclude that the differential diagnostic yield of LP in investigation of suspected SAH is low, which indicates that alternative diagnoses is not a reason to keep LP in the workup when a purely radiological strategy has been validated. However, algorithms should be developed to increase the recognition of aseptic meningitis. One hundred and fifty-three patients (34%) were admitted to undergo LP, which estimates the number of hospital beds that might be made available by a radiological diagnostic algorithm. PMID- 23358627 TI - A novel tool to prevent endotracheal tube compression in cleft palate surgery. PMID- 23358629 TI - Views of recently first-certified US child neurologists on their residency training. AB - We surveyed child neurologists first certified in "Neurology with Special Qualification in Child Neurology" by the American Board of Psychiatry and Neurology (ABPN) between 2001 and 2010 using a 24-item questionnaire. Respondents (n = 204, 54% response rate) were between the ages of 30 and 59 years (54% male), and 68% completed adult neurology training in a 10- to 12-month, primarily inpatient block. Sixty-two percent of the sample completed subspecialty fellowship training and 82% currently reported practicing within a hospital or hospital-based/owned clinic. Current practice data showed just 3% provide general neurology services to adults. A majority reported using adult neurology residency training "less than weekly" and believed the ideal model for residency training in diagnosis and management of both common and rare neurologic conditions would involve less time in adult neurology and more time (mean 6 months) in child neurology, most prominently in genetics and developmental and behavioral areas. PMID- 23358628 TI - Microstructural abnormalities in language and limbic pathways in orphanage-reared children: a diffusion tensor imaging study. AB - This study utilized diffusion tensor imaging fiber tractography to examine the miscrostructural integrity of limbic and paralimbic white matter tracts in 36 children (age M = 124 months) with histories of early deprivation, raised from birth in orphanages and subsequently adopted into the United States, compared to 16 age-matched typically developing children. We found increased mean diffusivity bilaterally in the arcuate fasciculus and increased mean diffusivity and reduced fractional anisotropy bilaterally in the uncinate fasciculus and cingulum in children with early deprivation. Microstructural integrity of the left arcuate fasciculus and right cingulum was related to language and behavioral functioning, respectively. White matter abnormalities were also associated with length of deprivation and time in the adoptive home. Our findings suggest that white matter pathways, connecting limbic and paralimbic brain regions is abnormal in children with histories of early deprivation, with some pathways appearing more susceptible to early deprivation than others. PMID- 23358630 TI - A pediatric case of severe pandysautonomia responsive to plasmapheresis. AB - We describe a 13-year-old female with abrupt onset urinary retention progressing rapidly to pandysautonomia with symptoms of postural orthostatic tachycardia syndrome, gastroparesis, anhidrosis, pupillary dysfunction, and abdominal pain. Pandysautonomia has been reported frequently in adults, but is less commonly described in children. Autonomic nervous system dysfunction usually has a self limiting course with gradual near-complete or complete recovery. Most patients with pure pandysautonomia produce an antibody targeted against the ganglionic nicotinic acetylcholine receptor and titers have been shown to correlate with symptom severity. The clinical presentation described in this report is consistent with a progressive form of acute autoimmune autonomic neuropathy, but she was initially seronegative for known autoantibodies. She responded promptly to plasmapheresis. This case report emphasizes the importance of recognizing features of autonomic nervous system dysfunction and discusses the medical evaluation and treatment options for pediatric patients based on symptom severity. PMID- 23358631 TI - Heat stroke in an infant with hypohidrotic ectodermal dysplasia: brain magnetic resonance imaging findings. AB - We describe the magnetic resonance imaging findings of a 4 month old infant with hypohidrotic ectodermal dysplasia who developed heat stroke. Magnetic resonance imaging of the brain revealed signal alteration with restricted diffusion in the splenium of corpus callosum, cerebral peduncles and cerebellar dentate nuclei. PMID- 23358632 TI - Bladder bulge: unifying old and new sonographic bladder wall abnormalities in ureterolithiasis. PMID- 23358633 TI - Role of CEACAM1 and CEACAM20 in an in vitro model of prostate morphogenesis. AB - CEACAM20, a novel member of the CEACAM1 gene family with expression limited to the lumen of small intestine, testes, and prostate, is co-expressed with CEACAM1 in adult prostate tissue and down-regulated to the same extent as CEACAM1 in prostate cancer. Since prostate cancer often involves loss of epithelial lumen formation, we hypothesized that CEACAM20 and CEACAM1 play important roles in lumen formation of normal prostate epithelium. When prostate cells were grown on Matrigel as a source of extracellular matrix (ECM), they differentiated into acinar structures with single tubules and well-defined lumina closely resembling embryonic prostate organoids. Confocal microscopic analysis revealed restriction of CEACAM20 to acini and CEACAM1 to tubule structures, respectively. Inhibition of CEACAM1 with antibodies or soluble CEACAM1 or antisense oligonucleotides inhibited tubule formation by over 50% while the remaining tubules were stunted. Inhibition of CEACAM20 with antisense oligonucleotides completely inhibited tubule formation and stunted the growth of acini. We conclude that CEACAM20 and CEACAM1 not only mark the lumina of adult prostate tissue but also play a critical role in the vitro generation of prostate organoids. PMID- 23358634 TI - Surveillance of Japanese encephalitis virus infection in mosquitoes in Vietnam from 2006 to 2008. AB - Japanese encephalitis virus (JEV) infection in mosquitoes was monitored in Vietnam from 2006 to 2008. A total of 15,225 mosquitoes, identified as 26 species in five genera were collected and 12,621 were grouped into 447 pools for examination of JEV infection by assays for cytopathic effects in C6/36 cells and by RT-PCR to detect flavivirus RNA. Three JEV strains were isolated from Culex tritaeniorhynchus Giles collected in northern and southern Vietnam and two JEV strains were isolated from Culex vishnui Theobald collected in the highlands of Vietnam. Genetic and phylogenetic analyses, based on complete E gene nucleotide sequences, revealed that the five JEV strains were classified into the genotype I group and six amino acid differences were found in these five strains. These results indicated that multiple JEV genotype I populations are circulating countrywide in Vietnam, transmitted by bites of their Cx. tritaeniorhynchus and Cx. vishnui. PMID- 23358635 TI - Isolation and molecular characterization of Leptospira interrogans and Leptospira borgpetersenii isolates from the urban rat populations of Kuala Lumpur, Malaysia. AB - Rats are considered the principal maintenance hosts of Leptospira. The objectives of this study were isolation and identification of Leptospira serovars circulating among urban rat populations in Kuala Lumpur. Three hundred urban rats (73% Rattus rattus and 27% R. norvegicus) from three different sites were trapped. Twenty cultures were positive for Leptospira using dark-field microscopy. R. rattus was the dominant carrier (70%). Polymerase chain reaction (PCR) confirmed that all isolates were pathogenic Leptospira species. Two Leptospira serogroups, Javanica and Bataviae, were identified using microscopic agglutination test (MAT). Pulsed-field gel electrophoresis (PFGE) identified two serovars in the urban rat populations: L. borgpetersenii serovar Javanica (85%) and L. interrogans serovar Bataviae (15%). We conclude that these two serovars are the major serovars circulating among the urban rat populations in Kuala Lumpur. Despite the low infection rate reported, the high pathogenicity of these serovars raises concern of public health risks caused by rodent transmission of leptospirosis. PMID- 23358636 TI - Pathogenesis of Modoc virus (Flaviviridae; Flavivirus) in persistently infected hamsters. AB - The long-term persistence of Modoc virus (MODV) infection was investigated in a hamster model. Golden hamsters (Mesocricetus auratus) were infected by subcutaneous inoculation with MODV, in which fatal encephalitis developed in 12.5% (2 of 16). Surviving hamsters shed infectious MODV in their urine during the first five months after infection, and infectious MODV was recovered by co cultivation of kidney tissue up to eight months after infection. There were no histopathologic changes observed in the kidneys despite detection of viral antigen for 250 days after infection. Mild inflammation and neuronal degeneration in the central nervous system were the primary lesions observed during early infection. These findings confirm previous reports of persistent flavivirus infection in animals and suggest a mechanism for the maintenance of MODV in nature. PMID- 23358637 TI - Bacillus thuringiensis var. israelensis misting for control of Aedes in cryptic ground containers in north Queensland, Australia. AB - In Australia, dengue is not endemic, although the vector mosquito Aedes aegypti is established in far north Queensland (FNQ). Aedes albopictus has recently invaded the Torres Strait region, but is not established on mainland Australia. To maintain dengue-free, public health departments in FNQ closely monitor introduced dengue infections and confine outbreaks through rigorous vector control responses. To safeguard mainland Australia from Ae. albopictus establishment, pre-emptive strategies are required to reduce its breeding in difficult to access habitats. We compare the residual efficacy of VectoBac WDG, Bacillus thuringiensis var. israelensis (Bti) formulation, as a residual treatment when misted across a typical FNQ bushland using a backpack mister (Stihl SR 420 Mist Blower) at two dose rates up to 16 m. Semi-field condition results, over 16 weeks, indicate that Bti provided high mortality rates (> 80%) sustained for 11 weeks. Mist application penetrated 16 m of dense bushland without efficacy decline over distance. PMID- 23358638 TI - Endemic (murine) typhus in returned travelers from Asia, a case series: clues to early diagnosis and comparison with dengue. PMID- 23358639 TI - Prevalence of asymptomatic parasitemia and gametocytemia among HIV-infected Ugandan children randomized to receive different antiretroviral therapies. AB - In a recent randomized controlled trial, the use of protease inhibitor (PI)-based antiretroviral therapy (ART) was associated with a significantly lower incidence of malaria compared with non-nucleoside reverse transcriptase inhibitor-based ART in a cohort of human immunodeficiency virus-infected Ugandan children living in an area of high malaria transmission intensity. In this report, we compared the prevalence of asymptomatic parasitemia and gametocytemia using data from the same cohort. The prevalence of asymptomatic parasitemia did not differ between the two ART treatment arms. The PI-based arm was associated with a lower risk of gametocytemia at the time of diagnosis of malaria (6.6% versus 14.5%, P = 0.03) and during the 28 days after malaria diagnosis (3.4% versus 6.5%, P = 0.04). Thus, in addition to decreasing the incidence of malaria, the use of PI-based ART may lower transmission, as a result of a decrease in gametocytemia, in areas of high malaria transmission intensity. PMID- 23358641 TI - Origin of the St. Elizabeth strain of Plasmodium vivax. AB - The St. Elizabeth strain of Plasmodium vivax originated in the South Carolina State Hospital instead of the St. Elizabeth Hospital in Washington, DC. PMID- 23358640 TI - Inter-relationships of cardinal features and outcomes of symptomatic pediatric Plasmodium falciparum MALARIA in 1,933 children in Kampala, Uganda. AB - Malaria remains a challenging diagnosis with variable clinical presentation and a wide spectrum of disease severity. Using a structured case report form, we prospectively assessed 1,933 children at Mulago Hospital in Kampala, Uganda with acute Plasmodium falciparum malaria. Children with uncomplicated malaria significantly differed from those with severe disease for 17 features. Among 855 children with severe disease, the case-fatality rate increased as the number of severity features increased. Logistic regression identified five factors independently associated with death: cerebral malaria, hypoxia, severe thrombocytopenia, leukocytosis, and lactic acidosis. Cluster analysis identified two groups: one combining anemia, splenomegaly, and leukocytosis; and a second group centered on death, severe thrombocytopenia, and lactic acidosis, which included cerebral malaria, hypoxia, hypoglycemia, and hyper-parasitemia. Our report updates previous clinical descriptions of severe malaria, quantifies significant clinical and laboratory inter-relationships, and will assist clinicians treating malaria and those planning or assessing future research (NCT00707200) (www.clinicaltrials.gov). PMID- 23358642 TI - Escherichia coli pathotypes in Pakistan from consecutive floods in 2010 and 2011. AB - This study compares Escherichia coli pathotypes circulating among children in Pakistan during the floods of 2010 and 2011 and from sporadic cases outside flood affected areas. Using multiplex polymerase chain reaction 115 of 205 stool samples (56.29%) were positive for diarrheagenic E. coli from specimens taken during the floods compared with 50 of 400 (12.5%) stool samples being positive for sporadic cases. The E. coli pathotypes were categorized as Enteropathogenic E. coli 33 (28.69%) and 13 (26%), Enterotoxigenic E. coli 29 (25.21%) and 15 (30%), Enteroaggregative E. coli 21 (18.2%) and 18 (36%), Enterohemorrhagic E. coli 5 (4.34%) and 1 (2%) from flood and sporadic cases, respectively. Furthermore, patients co-infected with more than one pathotype were 26 (22.60%) and 3 (6%) from flood and sporadic cases, respectively. The study shows an unexpectedly high rate of isolation of E. coli pathotypes suggesting Pakistan as an endemic region that requires active surveillance particularly during flood periods. PMID- 23358643 TI - Estimation of the impact of a Japanese encephalitis immunization program with live, attenuated SA 14-14-2 vaccine in Nepal. AB - Wider availability of the live, attenuated SA 14-14-2 Japanese encephalitis (JE) vaccine has facilitated introduction or expansion of immunization programs in many countries. However, information on their impact is limited. In 2006, Nepal launched a JE immunization program, and by 2009, mass campaigns had been implemented in 23 districts. To describe the impact, we analyzed surveillance data from 2004 to 2009 on laboratory-confirmed JE and clinical acute encephalitis syndrome (AES) cases. The post-campaign JE incidence rate of 1.3 per 100,000 population was 72% lower than expected if no campaigns had occurred, and an estimated 891 JE cases were prevented. In addition, AES incidence was 58% lower, with an estimated 2,787 AES cases prevented, suggesting that three times as many disease cases may have been prevented than indicated by the laboratory-confirmed JE cases alone. These results provide useful information on preventable JE disease burden and the potential value of JE immunization programs. PMID- 23358645 TI - The PPARgamma agonist pioglitazone crosses the blood-brain barrier and reduces tumor growth in a human xenograft model. AB - PURPOSE: The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor family, represents a target in glioma therapy due to its antineoplastic effects in vitro on human glioma cell lines. We investigate the antineoplastic effects of the PPARgamma agonist pioglitazone (pio) in a human glioma xenograft model to define the minimal required dose to induce antineoplastic effects. Additionally, we assess the ability of pio to cross the blood-brain barrier by measuring brain parenchymal concentration after oral administration. METHODS: Human LN-229 cells were injected into the striatum of Balb/cJHanHsd-Prkdc-scid mice. Tumor volumes, invasion, proliferation and parenchymal pio concentrations were measured in this xenograft model after continuous intracerebral drug administration through an osmotic pump or after oral administration. RESULTS: Continuous intracerebral or oral administration of pio reduced tumor volumes, invasion, and proliferation in vivo. To achieve a significant antineoplastic effect, pio needed to be dosed at 240 PPM in the oral group and >1 MUM when delivered intracerebrally. After oral pio administration, the drug reached >1 nM levels in brain parenchyma. CONCLUSIONS: These data indicate that pioglitazone crosses the blood-brain barrier and has antineoplastic effects in this glioma xenograft model and may be of potential use in treatment of malignant gliomas. PMID- 23358646 TI - Cu-catalyzed in situ generation of thiol using xanthate as a thiol surrogate for the one-pot synthesis of benzothiazoles and benzothiophenes. AB - A new copper-catalyzed in situ generation of aryl thiolates strategy was successfully developed for the one-pot synthesis of substituted benzothiazoles from 2-iodoanilides using xanthate as a thiol precursor. A wide range of 2 iodoanilides with both electron-releasing and electron-withdrawing groups produced the corresponding benzothiazoles in good yields. Further, this one-pot protocol was successfully utilized for the synthesis of a potent antitumor agent 2-(3,4-dimethoxyphenyl)-5-fluorobenzo[d]thiazole (PMX 610). Finally, the copper catalyzed in situ generation of aryl thiolates strategy was successfully applied for the domino synthesis of substituted benzothiophenes from o-haloalkynyl benzenes using xanthate as a thiol precursor. PMID- 23358644 TI - Non-typhoidal Salmonella gastroenteritis at a diarrheal hospital in Dhaka, Bangladesh, 1996-2011. AB - Data on non-typhoidal Salmonella (NTS) infection in South Asia are limited. We used data gathered prospectively from 1996 to 2011 as part of a hospital surveillance system in Dhaka, Bangladesh, to identify diarrheal patients with NTS isolated from stool. NTS was isolated in 1.3% (468 of 37,439) of diarrheal patients; 47% of total cases of NTS were in children < 5 years of age, although older adults (>= 60 years) had the highest isolation rates. NTS isolation peaked in the monsoon months of July and August. Over the study period, rates of multidrug resistance decreased, whereas rates of decreased susceptibility to ciprofloxacin increased. Compared with control patients, NTS patients were older and wealthier; however, no differences in type of housing or exposure to animals were found. NTS patients had increased inflammatory cells in stool and required more fluid resuscitation. PMID- 23358647 TI - Is the family physician an accomplice in the development of the 'primary care gap'? The importance of high quality real-life primary care respiratory research. PMID- 23358648 TI - The role of primary care as part of the multidisciplinary team (MDT) in the management of lung cancer: the "Dream MDT" report - new guidance from the UK Lung Cancer Coalition. PMID- 23358649 TI - Effects of waterlogging on amyloplasts and programmed cell death in endosperm cells of Triticum aestivum L. AB - The effects of waterlogging on amyloplasts and programmed cell death (PCD) in endosperm cells in Chinese wheat (Triticum aestivum L.; cv: Hua mai 8) are here discussed. Four water treatments were established from anthesis to maturity: they were 3 days of waterlogging treatment (DWT), 7 DWT, 12 DWT, and moderate water supply (the control). Lugol staining and scanning electron microscopy showed decreases in the number of amyloplasts and partially filled circular cavities under the waterlogging treatments. These resulted in serious deformities in the endosperm cells. Evans blue staining analysis and terminal deoxynucleotidyl transferase-mediated fluorescein deoxyuridine triphosphate nick-end labeling assays indicated that the PCD progression of endosperm cells occurred earlier under waterlogging treatments than in the control, so did the internucleosomal DNA fragmentation, which accompanies PCD in endosperm cells. Electron transmission microscopy analysis showed similar results. Under waterlogging treatments, the following PCD characteristics appeared earlier and were more pronounced than in normal endosperm cells: chromatin condensation, degradation of the nuclear envelope, swelling, and degradation of the mitochondrial cristae. Our study concluded that under waterlogging conditions, the number of amyloplasts tended to decrease and PCD was likely to appear ahead of time. PMID- 23358650 TI - First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. AB - RNA interference (RNAi) is a potent and specific mechanism for regulating gene expression. Harnessing RNAi to silence genes involved in disease holds promise for the development of a new class of therapeutics. Delivery is key to realizing the potential of RNAi, and lipid nanoparticles (LNP) have proved effective in delivery of siRNAs to the liver and to tumors in animals. To examine the activity and safety of LNP-formulated siRNAs in humans, we initiated a trial of ALN-VSP, an LNP formulation of siRNAs targeting VEGF and kinesin spindle protein (KSP), in patients with cancer. Here, we show detection of drug in tumor biopsies, siRNA mediated mRNA cleavage in the liver, pharmacodynamics suggestive of target downregulation, and antitumor activity, including complete regression of liver metastases in endometrial cancer. In addition, we show that biweekly intravenous administration of ALN-VSP was safe and well tolerated. These data provide proof of-concept for RNAi therapeutics in humans and form the basis for further development in cancer. SIGNIFICANCE: The fi ndings in this report show safety, pharmacokinetics, RNAi mechanism of action, and clinical activity with a novel fi rst-in-class LNP-formulated RNAi therapeutic in patients with cancer. The ability to harness RNAi to facilitate specifi c multitargeting, as well as increase the number of druggable targets, has important implications for future drug development in oncology. PMID- 23358653 TI - Solvent dependent reductive defluorination of aliphatic C-F bonds employing Sm(HMDS)2. AB - Sm(HMDS)(2) in n-hexane mediates fast cleavage of primary, secondary and tertiary alkyl fluorides in good to excellent yields. In n-hexane Sm(HMDS)(2) exhibits uniquely enhanced reductive ability towards the C-F bond compared to when using THF as solvent. PMID- 23358654 TI - Therapeutic potential of EGCG on acute renal damage in a rat model of obstructive nephropathy. AB - As a major active component in green tea, (-)-epigallocatechin 3-O-gallate (EGCG) has many anti-oxidative activities. This study investigated whether intraperitoneal administration of EGCG was capable of suppressing oxidative stress in rats with unilateral ureteral obstruction (UUO) and probed the potential mechanisms involved. In total, 150 adult male rats were randomly divided into 5 groups (n=30 each): the control group (group N); the unilateral ureteral obstruction (UUO) group (group C), where the unilateral ureter was ligated resulting in an obstructive nephropathy model; and the EGCG group (group T), following unilateral ureteral ligation, rats were intraperitoneally injected with EGCG at a dosage of 2.5 (T1), 5 (T2) and 10 mg/kg/day (T3). Each group of rats was sacrificed 72 h after surgery. We evaluated the effects of EGCG on the reactive oxygen species (ROS), reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione in the renal tissue of rats. Immunohistochemistry and western blot analysis were applied to detect nuclear factor erythoid-derived 2 related factor 2 (Nrf2) and gamma-glutamylcysteine synthetase (gamma-GCS) protein expression. Real-time PCR was performed to detect the mRNA levels of Nrf2 and gamma-GCS. Changes in renal ultrastructure were also observed using electron microscopy. There was no significant difference in GSH, and compared with group N, ROS, GSSG and total GSH levels were much higher in the T groups (p<0.01), while much lower than those of group C (p<0.01). Protein levels of Nrf2 and gamma GCS and the mRNA levels of Nrf2 and gamma-GCS notably increased in EGCG-treated rats (all p<0.05). Furthermore, electron microscopy showed that renal ultrastructure was improved in the treatment groups. Our findings suggest that, resulting from suppression of oxidative stress influenced by free radicals, EGCG exerts a protective effect on rats with obstructive nephropathy, and this anti oxidative effect may be partly induced by activating the Nrf2 signaling pathway. PMID- 23358651 TI - RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. AB - Non-small cell lung cancer (NSCLC) often expresses mutant KRAS together with tumor-associated mutations of the CDKN2A locus, which are associated with aggressive, therapy-resistant tumors. Here, we unravel specific requirements for the maintenance of NSCLC that carries this genotype. We establish that the extracellular signal-regulated kinase (ERK)/RHOA/focal adhesion kinase (FAK) network is deregulated in high-grade lung tumors. Suppression of RHOA or FAK induces cell death selectively in mutant KRAS;INK4A/ARF-deficient lung cancer cells. Furthermore, pharmacologic inhibition of FAK caused tumor regression specifically in the high-grade lung cancer that developed in mutant Kras;Cdkn2a null mice. These findings provide a rationale for the rapid implementation of genotype-specific targeted therapies using FAK inhibitors in patients with cancer. SIGNIFICANCE: Targeted therapies are effective for only a small fraction of patients with cancer. We report that FAK inhibitors exert potent antitumor effects in NSCLCs that express mutant KRAS in association with INK4A/ARF deficiency. These results reveal a novel genotype-specific vulnerability of cancer cells that can be exploited for therapeutic purposes. PMID- 23358655 TI - Clinical correlates to the goniodysgensis among juvenile-onset primary open-angle glaucoma patients. AB - OBJECTIVES: To evaluate gonioscopic features and relate them to clinical characteristics in eyes with juvenile-onset primary open-angle glaucoma (JOAG). METHODS: Goniophotographs of unrelated JOAG patients, presenting between 10-40 years of age, were evaluated and compared with 60 healthy subjects in the same age group. Age of onset, family history of glaucoma, highest untreated IOP and visual field defect (mean deviation) were analyzed and correlated with the gonioscopic features among JOAG patients. RESULTS: Of 126 patients included in the study, 44 (34 %) had a normal open angle (group 1), while 82 (66 %) had developmental anomalies (group 2). Developmental anomalies of the angle were classified as: high iris insertion with or without prominent iris processes (n=42), a featureless angle (n=30), and those with prominent iris processes alone (n=10). There was no difference in age of onset (group 1, 30.5 +/- 7 years and group 2, 26.3 +/- 9.6 years) (p=0.07) or the untreated IOP at presentation (group 1; 36 +/- 12.5 mmHg and group 2, 38.8 +/- 12.3 mmHg; p=0.37) between the groups. However, those with angle anomalies presented with a greater visual field defect (MD -23.5 +/- 10.5 vs -14.8 +/- 13 dB; p=0.02) compared to those with normal appearing angle. CONCLUSIONS: While two thirds of JOAG patients present with developmental anomalies of the angle, one third have normal appearing angles. High insertion of the iris is the most common form of gonio dysgenesis observed. Those with angle dysgenesis are more likely to present with severe disease. PMID- 23358656 TI - Descemet's stripping automated endothelial keratoplasty in abnormal anterior segment: scleral indentation technique to enhance donor adherence. AB - BACKGROUND: To describe a scleral indentation technique to enhance donor adherence in Descemet's stripping and automated endothelial keratoplasty (DSAEK) in patients with abnormal anterior segment. METHODS: In patients with visual potential, we performed transscleral fixation of a foldable intraocular lens (IOL) and DSAEK. In patients only for pain relief, we performed DSAEK without IOL implantation. During air tamponade, we injected only a medium air bubble instead of big bubble into anterior chamber and used scleral indentation technique as an aid. The position of the grafts was checked by the slit lamp and anterior segment optical coherence tomography (AS-OCT). RESULTS: Five eyes of five patients of aphakic bullous keratopathy (ABK) or pseudophakic bullous keratopathy (PBK) with anterior chamber IOL (AC IOL) were included in this non-comparative interventional case series. The grafts attached well in all patients without any graft dislocation intraoperatively and during the follow-up period. There was no pupillary block or peripheral anterior synechiae postoperatively. CONCLUSIONS: Scleral indentation technique with or without transscleral fixation of a foldable IOL in DSAEK can facilitate the air tamponade and enhance the donor adherence in certain anterior segment abnormities. PMID- 23358657 TI - Synthesis of MoS2 nanosheet-graphene nanosheet hybrid materials for stable lithium storage. AB - A facile method to synthesize a MoS(2) nanosheet-graphene nanosheet hybrid has been developed via the combination of a lithiation-assisted exfoliation process and a hydrazine monohydrate vapour reduction technique. The as-obtained nanosheet nanosheet hybrid is more robust and exhibits much improved cycle life (>700), which make it an efficient morphological solution to the stable lithium storage problem of nanomaterials. PMID- 23358658 TI - The changes of cerebral morphology related to aging in Taiwanese population. AB - A cross-sectional study with the 3-dimensional (3D) MRI reconstruction technique was conducted to investigate cerebral complexity changes related to age differences in native Taiwanese population. In our sample of 85 participants aged between 25 and 81, age was associated with gradual ventricular expansion. A nonlinear quadratic relationship between white matter volume and age was found overall in the brain. Widespread age-related reduction in white matter was detected from late adulthood onwards. However, no significant age-related changes in the cortex and whole brain volume were determined throughout adulthood. These findings provided information in describing brain structural complexity, which might in the future serve as an objective diagnostic index or as a predictive parameter for neurological diseases. Our method then may be used for cross cultural longitudinal studies to evaluate the effect of disease, environment and aging on the brain. PMID- 23358659 TI - Initial rate kinetic studies show an unexpected influence of para-substituents on the catalytic behaviour of manganese complexes of TMTACN in the epoxidation of styrenes with H2O2. AB - Investigations into the efficacy of a range of enantiomerically pure BINOL additives in the epoxidation of styrene substrates with a number of manganese catalysts prepared from the ligand 1,4,7-trimethyl-1,4,7-triazacyclononane, TMTACN, using hydrogen peroxide as the oxidant have revealed that there are fundamental differences in reactivity between apparently similar systems. Whilst no asymmetric induction was obtained in the styrene oxide products formed, the data obtained from initial rate kinetic studies appear to be consistent with a number of different catalytically active species operating, the nature of which are profoundly affected by the starting materials used. PMID- 23358660 TI - Recommended adult immunization schedule: United States, 2013*. PMID- 23358661 TI - Epoxidation of alkenes through oxygen activation over a bifunctional CuO/Al2O3 catalyst. AB - The epoxidation of alkenes was carried out over a CuO/Al(2)O(3) catalyst using cumene as an oxygen carrier, through a one-pot reaction, giving high conversion and selectivity with different substrates. Trans-beta-methylstyrene gave the corresponding epoxide in 95% yield after 3 h. PMID- 23358662 TI - Scaling up alcohol intervention among youth and experiments of naturalistic settings. PMID- 23358663 TI - Organizational and psychosocial risk factors for carpal tunnel syndrome: a cross sectional study of French workers. AB - PURPOSE: The aim of the study was to examine the organizational and psychosocial risk factors for carpal tunnel syndrome (CTS) in workers exposed to various levels of work-related constraints, with a special focus on factors related to the work organization. METHODS: From 3,710 workers, representative of a French region's working population, trained occupational physicians diagnosed a total of 156 cases of CTS between 2002 and 2005. Diagnoses were established by standardized physical examination, while personal factors and work exposure were assessed by self-administered questionnaires. Statistical associations between CTS and personal and work-related factors were analyzed for each gender using logistic regression modeling. RESULTS: Among the factors related to work organization, working with temporary workers was associated with CTS for women (OR = 1.99, 95 % CI 1.23-3.25), but not for men. Task rotation during the job (OR = 2.45 95 % CI 1.41-4.24) and work pace dependent on quantified targets (OR = 1.93 95 % CI 1.08-3.46) were associated with CTS only for men. The work-related psychosocial factors highlighted by the logistic modeling were high psychological demand for women (OR = 1.90, 95 % CI 1.17-3.09) and low skill discretion (OR = 1.77, 95 % CI 1.01-3.11) for men. CONCLUSION: This study has identified some psychosocial factors and factors related to work organization associated with clinically diagnosed and symptom-only cases of CTS as well as personal and biomechanical factors. However, due to the cross-sectional design of the study, no causal conclusion could be drawn and longitudinal studies are necessary to confirm these results. PMID- 23358664 TI - HER2-targeted hybrid peptide that blocks HER2 tyrosine kinase disintegrates cancer cell membrane and inhibits tumor growth in vivo. AB - HER2 is a transmembrane oncoprotein encoded by the HER2/neu gene and is overexpressed in approximately 20% to 30% of breast cancers. We have recently designed a novel class of drug, the hybrid peptide, which is chemically synthesized and is composed of a target-binding peptide and a lytic peptide containing cationic-rich amino acid components that disintegrate the cell membrane, leading to cancer cell death via membrane lysis. In this study, we designed a HER2-binding peptide linked to this novel lytic peptide, which we termed the HER2-lytic hybrid peptide and assessed the cytotoxic activity of this hybrid peptide in vitro and in vivo. The HER2-lytic hybrid peptide showed high cytotoxic activity against all ovarian and breast cancer cell lines, even trastuzumab- and/or lapatinib-resistant cells, but not against normal cells. Competition assays using anti-HER2 antibody and knockdown of this receptor by siRNA confirmed the specificity of the HER2-lytic hybrid peptide. In addition, it was shown that the HER2-lytic hybrid peptide can disintegrate the cancer cell membrane of HER2-overexpressing SK-BR-3 cancer cells in only 5 minutes, but not normal cells, and block HER2 signaling. Intravenous administration of the HER2 lytic peptide in the athymic mouse implanted with BT-474 and MDA-MB-453 cells significantly inhibited tumor progression. The HER2-lytic hybrid peptide was effective even in breast cancer cell lines that are resistant to trastuzumab and/or lapatinib in vitro and in vivo. Therefore, this hybrid peptide may provide a potent treatment option for patients with cancer. PMID- 23358666 TI - Cationic lipophosphoramidates with two disulfide motifs: synthesis, behaviour in reductive media and gene transfection activity. AB - Lipophosphoramidates have previously been identified as efficient vectors for gene delivery. The incorporation of functional groups that respond to a physiological stimulus is hypothesised to further improve the efficacy of this type of vector and eventually reduce its cytotoxicity. In the present work, we report the effects of the incorporation of two disulfide motifs into the hydrophobic domain, close to the phosphoramidate group. Three cationic vectors possessing such a red/ox sensitive function were synthesised. The capability of one of them (5b) to compact DNA is reported jointly with its ability to release that DNA in the presence of a reducing agent. Finally, compound 5b was tested as a vector for gene delivery into human cells in vitro and its cytotoxicity was also evaluated. PMID- 23358665 TI - Biological characterization of TAK-901, an investigational, novel, multitargeted Aurora B kinase inhibitor. AB - Protein kinases Aurora A, B, and C play essential roles during mitosis and cell division, are frequently elevated in cancer, and represent attractive targets for therapeutic intervention. TAK-901 is an investigational, multitargeted Aurora B kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype. TAK-901 exhibited time-dependent, tight-binding inhibition of Aurora B, but not Aurora A. Consistent with Aurora B inhibition, TAK-901 suppressed cellular histone H3 phosphorylation and induced polyploidy. In various human cancer cell lines, TAK-901 inhibited cell proliferation with effective concentration values from 40 to 500 nmol/L. Examination of a broad panel of kinases in biochemical assays revealed inhibition of multiple kinases. However, TAK-901 potently inhibited only a few kinases other than Aurora B in intact cells, including FLT3 and FGFR2. In rodent xenografts, TAK-901 exhibited potent activity against multiple human solid tumor types, and complete regression was observed in the ovarian cancer A2780 model. TAK-901 also displayed potent activity against several leukemia models. In vivo biomarker studies showed that TAK-901 induced pharmacodynamic responses consistent with Aurora B inhibition and correlating with retention of TAK-901 in tumor tissue. These preclinical data highlight the therapeutic potential of TAK-901, which has entered phase I clinical trials in patients within a diverse range of cancers. PMID- 23358667 TI - Comparison of the bacterial communities in anaerobic, anoxic, and oxic chambers of a pilot A(2)O process using pyrosequencing analysis. AB - A(2)O process is a sequential wastewater treatment process that uses anaerobic, anoxic, and oxic chambers for nitrogen and phosphorus removal. In this study, the bacterial communities among these chambers were compared, and the diversity of the bacteria involved in nitrogen and phosphorus removal was surveyed. A pilot scale A(2)O process (50 m(3) day(-1)) was operated for more than 6 months, and bacterial 16S rRNA gene diversity was analyzed using pyrosequencing. A total of 7,447 bacterial sequence reads were obtained from anaerobic (1,546), anoxic (2,158), and oxic (3,743) chambers. Even though there were differences in the atmospheric condition and functionality, no prominent differences could be found in the bacterial community of the three chambers of the pilot A(2)O process. All sequence reads, which were taxonomically analyzed using the Eztaxon-e database, were assigned into 638 approved or tentative genera. Among them, about 72.2 % of the taxa were contained in the phyla Proteobacteria and Bacteroidetes. Phosphate accumulating bacteria, Candidatus Accumulibacter phosphatis, and two other Accumulibacter were found to constitute 3.1 % of the identified genera. Ammonia oxidizing bacteria, Nitrosomonas oligotropha, and four other phylotypes in the same family, Nitrosomonadaceae, constituted 0.2 and 0.9 %, respectively. Nitrite oxidizing bacteria, Nitrospira defluvii, and other three phylotypes in the same family, Nitrospiraceae, constituted 2.5 and 0.1 %, respectively. In addition, Dokdonella and a phylotype of the phylum Chloroflexi, function in nitrogen and/or phosphate removal of which have not been reported in the A(2)O process, constituted the first and third composition among genera at 4.3 and 3.8 %, respectively. PMID- 23358668 TI - The secretion of an intrinsically disordered protein with different secretion signals in Bacillus subtilis. AB - In this study, a naturally unsecretory intrinsically disordered domain of nucleoskeletal-like protein (Nsp) was attempted to be secreted with different types of secretion signals in Bacillus subtilis. The results showed that Nsp can be secreted efficiently by all selected Sec-type signal peptides. Nsp was successfully exported when fused to Tat-type signal peptides but less efficient than Sec-type. The fusion protein with the non-classical extracellular proteins can be detected in the cell and extracellular milieu. This study further demonstrated that the mature protein plays an important role in protein secretion. Moreover, these results indicated that Nsp could be a useful tool to understand the individual roles of mature proteins and signal peptide in protein secretion, to evaluate the effect of conformation of mature proteins on their export pathway when coupled with Tat-type signal peptide, and to seek the signal of non-classical secretory proteins. PMID- 23358671 TI - The internal medicine reporting milestones and the next accreditation system. PMID- 23358672 TI - Primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery for patients with advanced ovarian cancer. AB - OBJECTIVES: To compare the survival and perioperative morbidity between primary debulking surgery (PDS) and neoadjuvant chemotherapy followed by interval debulking surgery (NAC/IDS) in treating patients with advanced epithelial ovarian cancer (EOC). METHODS: We retrospectively reviewed 67 patients with stage IIIC or IV EOC treated at Peking University Cancer Hospital from January 2006 to June 2009. Wherein, 37 and 30 patients underwent PDS and NAC/IDS, respectively. RESULTS: No difference in overall survival (OS) or progression-free survival (PFS) was observed between NAC/IDS group and PDS group (OS: 41.2 vs. 39.1 months, P=0.23; PFS: 27.1 vs. 24.3 months, P=0.37). The optimal debulking rate was 60% in the NAC/IDS group, which was significantly higher than that in the PDS group (32.4%) (P=0.024). The NAC/IDS group had significantly less intraoperative estimated blood loss and transfusion, lower nasogastric intubation rate, and earlier ambulation and recovery of intestinal function than the PDS group (P<0.05). CONCLUSIONS: NAC/IDS is less invasive than PDS, and offers the advantages regarding optimal cytoreduction rate, intraoperative blood loss, and postoperative recovery, without significantly impairing the survival compared with PDS in treating patients with stage IIIC or IV EOC. Therefore, NAC/IDS may be a valuable treatment alternative for EOC patients. PMID- 23358673 TI - Simultaneous chromatography and electrophoresis: two-dimensional planar separations. AB - Single-dimension separations are routinely coupled in series to achieve two dimensional separations, yet little has been done to simultaneously exploit multiple dimensions during separation. In this work, simultaneous chromatography and electrophoresis is introduced and evaluated for its potential to achieve two dimensional separations. In simultaneous chromatography and electrophoresis, chromatography occurs via capillary action while an orthogonal electric field concurrently promotes electrophoresis in a second dimension. A novel apparatus with a dual solvent reservoir was designed to apply the concurrent electric field. Various compounds were used to characterize the apparatus and technique, i.e., vitamins, amino acids, and dyes. Improved separation is reported with equivalent analysis times in comparison to planar chromatography alone. The feasibility of simultaneously employing chromatography and electrophoresis in two dimensions is discussed. PMID- 23358674 TI - Capillary electrophoretic study of the synergistic biological effects of alkaloids from Chelidonium majus L. in normal and cancer cells. AB - In this study, the synergistic biological action of five celandine alkaloids in normal and cancer cells was investigated by capillary electrophoresis with light emitting diode-induced native fluorescence detection. The specific capacity of each alkaloid to penetrate into the cells was estimated by monitoring alkaloid concentration decreases in the cell medium during incubation with murine fibroblast NIH/3T3, mouse melanoma B16F10, and human breast cancer MCF7 cell lines. Mixtures of isoquinoline alkaloids containing protopine, chelidonine, sanguinarine, allocryptopine, and stylopine were applied to cell cultures for 20 and 40 min, and the content of alkaloids in the cell media was measured by capillary electrophoresis (CE). CE separation of isoquinoline alkaloids was performed in 30 mM phosphate buffer (pH 2.5). As these alkaloids have native fluorescence, they were directly detected using the commercially available UV light-emitting diode without troublesome fluorescent derivatization. The results showed a differential ability of celandine alkaloids to penetrate into the normal and cancer cell interior, which was inversely proportional to their cytotoxic activity. While the most effective transport of celandine alkaloids from the cell medium to the cell interior was observed for normal murine fibroblast NIH/3T3 cells (about 55% of total content), cytotoxicity tests demonstrated selective and profound apoptotic effects of a five-alkaloid combination in the mouse melanoma B16F10 cell line. PMID- 23358669 TI - Heterologous gln/asn-rich proteins impede the propagation of yeast prions by altering chaperone availability. AB - Prions are self-propagating conformations of proteins that can cause heritable phenotypic traits. Most yeast prions contain glutamine (Q)/asparagine (N)-rich domains that facilitate the accumulation of the protein into amyloid-like aggregates. Efficient transmission of these infectious aggregates to daughter cells requires that chaperones, including Hsp104 and Sis1, continually sever the aggregates into smaller "seeds." We previously identified 11 proteins with Q/N rich domains that, when overproduced, facilitate the de novo aggregation of the Sup35 protein into the [PSI(+)] prion state. Here, we show that overexpression of many of the same 11 Q/N-rich proteins can also destabilize pre-existing [PSI(+)] or [URE3] prions. We explore in detail the events leading to the loss (curing) of [PSI(+)] by the overexpression of one of these proteins, the Q/N-rich domain of Pin4, which causes Sup35 aggregates to increase in size and decrease in transmissibility to daughter cells. We show that the Pin4 Q/N-rich domain sequesters Hsp104 and Sis1 chaperones away from the diffuse cytoplasmic pool. Thus, a mechanism by which heterologous Q/N-rich proteins impair prion propagation appears to be the loss of cytoplasmic Hsp104 and Sis1 available to sever [PSI(+)]. PMID- 23358675 TI - Comparative study of recent wide-pore materials of different stationary phase morphology, applied for the reversed-phase analysis of recombinant monoclonal antibodies. AB - Various recent wide-pore reversed-phase stationary phases were studied for the analysis of intact monoclonal antibodies (mAbs) of 150 kDa and their fragments possessing sizes between 25 and 50 kDa. Different types of column technology were evaluated, namely, a prototype silica-based inorganic monolith containing mesopores of ~250 A and macropores of ~ 1.1 MUm, a column packed with 3.6 MUm wide-pore core-shell particles possessing a wide pore size distribution with an average around 200 A and a column packed with fully porous 1.7 MUm particles having pore size of ~300 A. The performance of these wide-pore materials was compared with that of a poly(styrene-divinyl benzene) organic monolithic column, with a macropore size of approximately 1 MUm but without mesopores (stagnant pores). A systematic investigation was carried out using model IgG1 and IgG2 mAbs, namely rituximab, panitumumab, and bevacizumab. Firstly, the recoveries of intact and reduced mAbs were compared on the two monolithic phases, and it appeared that adsorption was less pronounced on the organic monolith, probably due to the difference in chemistry (C18 versus phenyl) and the absence of mesopores (stagnant zones). Secondly, the kinetic performance was investigated in gradient elution mode for all columns. For this purpose, peak capacities per meter as well as peak capacities per time unit and per pressure unit (PPT) were calculated at various flow rates, to compare performance of columns with different dimensions. In terms of peak capacity per meter, the core-shell 3.6 MUm and fully porous 1.7 MUm columns outperformed the two monolithic phases, at a temperature of 60 degrees C. However, when considering the PPT values, the core shell 3.6 MUm column remained the best phase while the prototype silica-based monoliths became very interesting, mostly due to a very high permeability compared with the organic monolith. Therefore, these core-shell and silica-based monolith provided the fastest achievable separation. Finally, at the maximal working temperature of each column, the core-shell 3.6 MUm column was far better than the other one, because it is the only one stable up to 90 degrees C. Lastly, the loading capacity was also measured on these four different phases. It appeared that the organic monolith was the less interesting and rapidly overloaded, due to the absence of mesopores. On the other hand, the loading capacity of prototype silica-based monolith was indeed reasonable. PMID- 23358676 TI - Role of occlusion in masseter muscle acetylcholine receptor clustering. AB - Nicotinic acetylcholine receptor (nAChR) clustering is a key event in the synaptogenesis of the neuromuscular junction (NMJ) for the efficient transmission of neural signals from motor neurons to skeletal muscle. The microphthalmic mouse (mi/mi) with a mutation in the mitf gene cannot perform occlusion, because its teeth do not erupt. The present study attempted to elucidate the contribution of occlusion to the clustering of nAChR in the NMJ of the masseter, with mi/mi as a model system. In mice at 1 week of age, no significant change in the fragmentation or volume of the nAChR cluster was observed in either the masseter or gastrocnemius between breast-fed +/+ and mi/mi. In mice at 4 and 12 weeks of age, after the occlusion emerged in the +/+, excessive fragmentation and volume decline in the nAChR cluster were observed in the masseter of mi/mi fed a powdered diet compared with +/+ fed a pellet or powdered diet, whereas, in the gastrocnemius, no such differences were observed between the 2 strains. These results indicate abnormal formation of the nAChR cluster in the NMJ of the masseter of mi/mi, suggesting that occlusion is essential for the normal progress of nAChR clustering in the NMJ of the masseter. PMID- 23358677 TI - The role of osteocytes in bone resorption during orthodontic tooth movement. AB - We investigated the roles of osteocytes in osteoclastic bone resorption during orthodontic tooth movement using the transgenic mice in which osteocytes can be specifically ablated. Because these transgenic mice express the receptor for diphtheria toxin on the cell surfaces of osteocytes, the injection of diphtheria toxin can ablate their osteocytes in vivo. Injection of diphtheria toxin into the transgenic mice significantly increased the number of ablated osteocytes in alveolar bone compared with that in wild-type mice with or without diphtheria toxin injection. Increased numbers of ablated osteocytes were observed from day 4 to day 12 after the injection in alveolar bones as well as in cortical bone of the tibiae. We applied the orthodontic force 4 days after the injection of diphtheria toxin, and the distance of tooth movement on day 12 was significantly smaller in transgenic mice than that in control mice. The numbers of osteoclasts and the quantity of eroded bone surface at the compression site were significantly reduced in the transgenic mice injected with diphtheria toxin than in control mice. These results provide in vivo demonstration of osteocyte involvement in osteoclastic bone resorption during orthodontic tooth movement. PMID- 23358678 TI - The biology of TMJ growth modification: a review. AB - Several studies have indicated a positive response of the temporomandibular joint (TMJ) to mandibular advancement, while others have reported that TMJ adaptive responses are non-existent and negligible. Controversy continues to grow over the precise nature of skeletal changes that occur during mandibular growth modification, due to an apparent lack of tissue markers required to substantiate the precise mechanism by which this is occurring. However, evidence suggests that orthopedic forces clinically modify the growth of the mandible. To further our knowledge about the effect of orthopedic treatment on the TMJ, it is necessary that we understand the biologic basis behind the various tissues involved in the TMJ's normal growth and maturation. The importance of this knowledge is to consider the potential association between TMJ remodeling and mandibular repositioning under orthopedic loading. Considerable histologic and biochemical research has been performed to provide basic information about the nature of skeletal growth modification in response to mandibular advancement. In this review, the relevant histochemical evidence and various theories regarding TMJ growth modification are discussed. Furthermore, different regulatory growth factors and tissue markers, which are used for cellular and molecular evaluation of the TMJ during its adaptive response to biomechanical forces, are underlined. PMID- 23358679 TI - The association of sport performance with ACE and ACTN3 genetic polymorphisms: a systematic review and meta-analysis. AB - BACKGROUND: Genetic polymorphism is suggested to be associated with human physical performance. The angiotensin I-converting enzyme insertion/deletion (ACE I/D) polymorphism and the alpha-actinin-3 gene (ACTN3) R577X polymorphism have been most widely studied for such association analysis. However, the findings are frequently heterogeneous. We aim to summarize the associations of ACE I/D and ACTN3 R577X with sport performance by means of meta-analysis. METHODS: We systematically reviewed and quantitatively summarized published studies, until October 31, 2012, on relationship between ACE/ACTN3 genetic polymorphisms and sports performance, respectively. RESULTS: A total of 366 articles on ACE and 88 articles on ACTN3 were achieved by literature search. A significant association was found for ACE II genotype compared to D allele carriage (DD+ID) with increased possibility of physical performance (OR, 1.23; 95% CI, 1.05-1.45). With respect to sport discipline, the II genotype was found to be associated with performance in endurance athletes (OR, 1.35; 95% CI, 1.17-1.55). On the other hand, no significant association was observed for ACTN3 RR genotype as compared to X allele carriage (XX+RX) (OR, 1.03; 95% CI, 0.92-1.15). However, when restricted the analyses to power events, a significant association was observed (OR, 1.21; 95% CI, 1.03-1.42). CONCLUSION: Our results provide more solid evidence for the associations between ACE II genotype and endurance events and between ACTN3 R allele and power events. The findings suggest that the genetic profiles might influence human physical performance. PMID- 23358680 TI - Impact of attending physician workload on patient care: a survey of hospitalists. PMID- 23358681 TI - Measuring frequency domain granger causality for multiple blocks of interacting time series. AB - In the past years, several frequency-domain causality measures based on vector autoregressive time series modeling have been suggested to assess directional connectivity in neural systems. The most followed approaches are based on representing the considered set of multiple time series as a realization of two or three vector-valued processes, yielding the so-called Geweke linear feedback measures, or as a realization of multiple scalar-valued processes, yielding popular measures like the directed coherence (DC) and the partial DC (PDC). In the present study, these two approaches are unified and generalized by proposing novel frequency-domain causality measures which extend the existing measures to the analysis of multiple blocks of time series. Specifically, the block DC (bDC) and block PDC (bPDC) extend DC and PDC to vector-valued processes, while their logarithmic counterparts, denoted as multivariate total feedback [Formula: see text] and direct feedback [Formula: see text], represent into a full multivariate framework the Geweke's measures. Theoretical analysis of the proposed measures shows that they: (i) possess desirable properties of causality measures; (ii) are able to reflect either direct causality (bPDC, [Formula: see text] or total (direct + indirect) causality (bDC, [Formula: see text] between time series blocks; (iii) reduce to the DC and PDC measures for scalar-valued processes, and to the Geweke's measures for pairs of processes; (iv) are able to capture internal dependencies between the scalar constituents of the analyzed vector processes. Numerical analysis showed that the proposed measures can be efficiently estimated from short time series, allow to represent in an objective, compact way the information derived from the causal analysis of several pairs of time series, and may detect frequency domain causality more accurately than existing measures. The proposed measures find their natural application in the evaluation of directional interactions in neurophysiological settings where several brain activity signals are simultaneously recorded from multiple regions of interest. PMID- 23358682 TI - pH dependent multifunctional and multiply-configurable logic gate systems based on small molecule G-quadruplex DNA recognition. AB - A variety of logic operations such as XNOR, NOR, AND, NAND, NOT have been designed with pH as an external modulator by choosing thiazole orange (TO) and a c-kit2 promoter quadruplex as two inputs and fluorescence signals of pyridyl bis indole amide (PBIA) and TO as two outputs. PMID- 23358683 TI - A new approach to inhibit human beta-tryptase by protein surface binding of four armed peptide ligands with two different sets of arms. AB - A series of six new tetravalent ligands (1-6) with two different sets of arms bind to the surface of beta-tryptase, a tetrameric enzyme with an A(2)B(2) arrangement of its four monomers and two different binding sites on its protein surface (as suggested by a docking study). Besides proteinogenic amino acids also the guanidiniocarbonyl pyrrole cation (abbreviated as GCP), as an artificial arginine analog, was introduced into the arms of the ligands to investigate its influence on protein surface binding and enzyme inhibition. Furthermore, four ligands (7-10) with four identical arms also containing the GCP group were additionally synthesized to study the influence of the GCP moiety on the inhibition properties compared to related ligands previously identified by us in earlier work. The best ligand from this new series (RWKG)(2)(GCP-LFG)(2) (6) indeed contains the artificial GCP group and with a K(i)-value of 67 nM is two orders of magnitude more efficient than the analogous ligand (RWKG)(2)(RLFG)(2) (1) derived solely from proteinogenic amino acids. Hence, four-armed ligands with two different arms are indeed efficient inhibitors for beta-tryptase and the artificial GCP group can improve the binding affinity of this type of ligand to the protein, demonstrating the advantage of tailor-made binding motifs to increase affinity. PMID- 23358684 TI - ST6Gal-I protein expression is upregulated in human epithelial tumors and correlates with stem cell markers in normal tissues and colon cancer cell lines. AB - The ST6Gal-I sialyltransferase adds an alpha2-6-linked sialic acid to the N glycans of certain receptors. ST6Gal-I mRNA has been reported to be upregulated in human cancer, but a prior lack of antibodies has limited immunochemical analysis of the ST6Gal-I protein. Here, we show upregulated ST6Gal-I protein in several epithelial cancers, including many colon carcinomas. In normal colon, ST6Gal-I localized selectively to the base of crypts, where stem/progenitor cells are found, and the tissue staining patterns were similar to the established stem cell marker ALDH1. Similarly, ST6Gal-I expression was restricted to basal epidermal layers in skin, another stem/progenitor cell compartment. ST6Gal-I was highly expressed in induced pluripotent stem (iPS) cells, with no detectable expression in the fibroblasts from which iPS cells were derived. On the basis of these observations, we investigated further an association of ST6Gal-I with cancer stem cells (CSC). Selection of irinotecan resistance in colon carcinoma cells led to a greater proportion of CSCs compared with parental cells, as measured by the CSC markers CD133 and ALDH1 activity (Aldefluor). These chemoresistant cells exhibited a corresponding upregulation of ST6Gal-I expression. Conversely, short hairpin RNA (shRNA)-mediated attenuation of ST6Gal I in colon carcinoma cells with elevated endogenous expression decreased the number of CD133/ALDH1-positive cells present in the cell population. Collectively, our results suggest that ST6Gal-I promotes tumorigenesis and may serve as a regulator of the stem cell phenotype in both normal and cancer cell populations. PMID- 23358685 TI - Targeting the deregulated spliceosome core machinery in cancer cells triggers mTOR blockade and autophagy. AB - The spliceosome is a large ribonucleoprotein complex that guides pre-mRNA splicing in eukaryotic cells. Here, we determine whether the spliceosome could constitute an attractive therapeutic target in cancer. Analysis of gene expression arrays from lung, breast, and ovarian cancers datasets revealed that several genes encoding components of the core spliceosome composed of a heteroheptameric Sm complex were overexpressed in malignant disease as compared with benign lesions and could also define a subset of highly aggressive breast cancers. siRNA-mediated depletion of SmE (SNRPE) or SmD1 (SNRPD1) led to a marked reduction of cell viability in breast, lung, and melanoma cancer cell lines, whereas it had little effect on the survival of the nonmalignant MCF-10A breast epithelial cells. SNRPE or SNRPD1 depletion did not lead to apoptotic cell death but autophagy, another form of cell death. Indeed, induction of autophagy was revealed by cytoplasmic accumulation of autophagic vacuoles and by an increase in both LC3 (MAP1LC3A) protein conversion and the amount of acidic autophagic vacuoles. Knockdown of SNRPE dramatically decreased mTOR mRNA and protein levels and was accompanied by a deregulation of the mTOR pathway, which, in part, explains the SNRPE-dependent induction of autophagy. These findings provide a rational to develop new therapeutic agents targeting spliceosome core components in oncology. PMID- 23358688 TI - User preferences in a carrageenan-based vaginal drug delivery system. AB - Topical microbicides are a promising solution to address the global threat of HIV and other sexually transmitted infections. To be successful, a microbicide not only needs to be biologically functional but also highly acceptable to users. User acceptability of microbicides can be incorporated early in the product formulation and design process. Previous qualitative research revealed women had strong preferences regarding product shape, while preferences related to size and firmness were less clear. Here, we explored the effect of size and firmness on the acceptability of semisolid ovoid microbicide prototypes intended for vaginal use. Sexually active women (n = 74) were randomized to one of two conditions: with and without applicator. Nine different prototypes were evaluated; they were formulated to low, medium and high firmness using mixtures of kappa and iota carrageenan and potassium chloride. Three sizes were produced at each firmness level. Women manipulated all nine prototypes, rating them for perceived effectiveness, imagined ease-of-insertion and willingness-to-try on visual analog scales. The influence of size and firmness on these three outcome measures were assessed using ANOVA and response surface models. Results indicated size and firmness both influenced the outcome measures, but firmness was more influential than size. Also, the specific effects of size and firmness depended strongly on presence or absence of an applicator. Generally, women in the without applicator condition wanted a larger, firmer product. Collectively, these data suggest efforts to rationally design of microbicides for enhanced user acceptability must consider factors like size and firmness. Also, the decision to include or forego an applicator should be addressed early in the design process, as it strongly influences other design decisions. PMID- 23358687 TI - Is the simultaneously integrated boost (SIB) technique for early breast cancer ready to be adopted for routine adjuvant radiotherapy? Statement of the German and the Austrian Societies of Radiooncology (DEGRO/OGRO). PMID- 23358686 TI - Inhibition of protein kinase CK2 reduces Cyp24a1 expression and enhances 1,25 dihydroxyvitamin D(3) antitumor activity in human prostate cancer cells. AB - Vitamin D has broad range of physiological functions and antitumor effects. 24 Hydroxylase, encoded by the CYP24A1 gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D(3). Inhibition of CYP24A1 enhances 1,25D(3) antitumor activity. To isolate regulators of CYP24A1 expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with CYP24A1 promoter driving luciferase expression to screen a small molecular library for compounds that inhibit CYP24A1 promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz inhibits CYP24A1 promoter activity induced by 1,25D(3) in prostate cancer cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz-treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D(3)-induced CYP24A1 mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D(3)-mediated target gene expression. Finally, inhibition of CK2 by TBBz or CK2 siRNA significantly enhances 1,25D(3)-mediated antiproliferative effect in vitro and in vivo in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25D(3) and CK2 inhibitor enhances 1,25D(3)-mediated antitumor effect. PMID- 23358689 TI - Molecular evidence for the intermolecular S...S interaction in the surface molecular packing motifs of a fused thiophene derivative. AB - A microscopic investigation of the molecular packing structures of a fused thiophene derivative reveals the important role of intermolecular S...S interaction in directing the 2D self-assembly. Thermal annealing of the assembly results in the irreversible phase transition to a new structure with different molecular trimeric packing motifs. PMID- 23358690 TI - Early palliative care in advanced lung cancer: a qualitative study. AB - BACKGROUND Early ambulatory palliative care (PC) is an emerging practice, and its key elements have not been defined. We conducted a qualitative analysis of data from a randomized controlled trial that demonstrated improved quality of life, mood, and survival in patients with newly diagnosed metastatic non-small cell lung cancer who received early PC integrated with standard oncologic care vs standard oncologic care alone. Our objectives were to (1) identify key elements of early PC clinic visits, (2) explore the timing of key elements, and (3) compare the content of PC and oncologic visit notes at the critical time points of clinical deterioration and radiographic disease progression. METHODS We randomly selected 20 patients who received early PC and survived within 4 periods: less than 3 months (n = 5), 3 to 6 months (n = 5), 6 to 12 months (n = 5), and 12 to 24 months (n = 5). We performed content analysis on PC and oncologic visit notes from the electronic health records of these patients. RESULTS Addressing symptoms and coping were the most prevalent components of the PC clinic visits. Initial visits focused on building relationships and rapport with patients and their families and on illness understanding, including prognostic awareness. Discussions about resuscitation preferences and hospice predominantly occurred during later visits. Comparing PC and oncologic care visits around critical time points, both included discussions about symptoms and illness status; however, PC visits emphasized psychosocial elements, such as coping, whereas oncologic care visits focused on cancer treatment and management of medical complications. CONCLUSIONS Early PC clinic visits emphasize managing symptoms, strengthening coping, and cultivating illness understanding and prognostic awareness in a responsive and time-sensitive model. During critical clinical time points, PC and oncologic care visits have distinct features that suggest a key role for PC involvement and enable oncologists to focus on cancer treatment and managing medical complications. PMID- 23358692 TI - Recent applications of arene diazonium salts in organic synthesis. AB - Arene diazonium salts are common, easily prepared and highly useful intermediates in organic synthesis due to their rich reactivity and diverse transformations. In this review, recent advances involving arene diazonium salts as starting materials or active intermediates for various synthetically useful applications are summarized. PMID- 23358691 TI - Is survivin expression prognostic or predictive in malignant pleural mesothelioma? AB - Malignant pleural mesothelioma is an incurable cancer strongly associated with asbestos exposure and characterised by poor response to treatment. The inhibitor of-apoptosis protein family member survivin is involved in apoptosis and proliferation and is expressed in cancer cells only. The aims of the present study were to elucidate whether survivin expression is associated with tumour cell apoptosis and proliferation and to assess the prognostic and predictive value of survivin expression in malignant pleural mesothelioma. Archival pleural mesothelioma tissue samples from 101 patients were immunohistochemically analysed for nuclear expression of survivin, for proliferation with the use of Ki-67 as marker and for apoptosis using active caspase-3 as a marker. Staining results and clinical data were included in a survival analysis. Survivin was highly expressed in tumour cell nuclei in all samples and this correlated positively with both apoptosis and proliferation, but did not have a significant prognostic value. We found significantly higher survivin expression in patients who responded to chemotherapy compared to patients with progressive disease. Survivin expression might contribute to treatment response prediction, but survivin expression in malignant pleural mesothelioma did not have prognostic significance. PMID- 23358693 TI - Transjugular Intrahepatic Portosystemic Shunt (TIPS) Migration to the Heart Diagnosed by Emergency Department Ultrasound. AB - A 57-year-old man presented to our emergency department with altered mental status. He had a past medical history significant for cirrhosis and previous placement of a transjugular intrahepatic portosystemic shunt (TIPS). On cardiac auscultation, a new heart murmur and an unexpected degree of cardiac ectopy were noted. On the 12-lead electrocardiogram, the patient was noted to have multiple premature atrial contractions, corroborating the irregular heart rhythm on physical exam. A focused bedside emergency ultrasound of the heart was then performed. This exam revealed an apparent foreign body in the right atrium. It appeared as if the patient's TIPS had migrated from the heart into the right atrium. This case, as well as the literature describing this unusual complication of TIPS placement, is reviewed in this case report. PMID- 23358695 TI - Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment related neuroendocrine prostate cancer. AB - Neuroendocrine prostate cancer (NEPC), also referred to as anaplastic prostate cancer, is a lethal tumor that most commonly arises in late stages of prostate adenocarcinoma (PCA) with predilection to metastasize to visceral organs. In the current study, we explore for evidence that Aurora kinase A (AURKA) and N-myc (MYCN) gene abnormalities are harbingers of treatment-related NEPC (t-NEPC). We studied primary prostate tissue from 15 hormone naive PCAs, 51 castration resistant prostate cancers, and 15 metastatic tumors from 72 patients at different stages of disease progression to t-NEPC, some with multiple specimens. Histologic evaluation, immunohistochemistry, and fluorescence in situ hybridization were performed and correlated with clinical variables. AURKA amplification was identified in overall 65% of PCAs (hormone naive and treated) from patients that developed t-NEPC and in 86% of metastases. Concurrent amplification of MYCN was present in 70% of primary PCAs, 69% of treated PCAs, and 83% of metastases. In contrast, in an unselected PCA cohort, AURKA and MYCN amplifications were identified in only 5% of 169 cases. When metastatic t-NEPC was compared to primary PCA from the same patients, there was 100% concordance of ERG rearrangement, 100% concordance of AURKA amplification, and 60% concordance of MYCN amplification. In tumors with mixed features, there was also 100% concordance of ERG rearrangement and 94% concordance of AURKA and MYCN co amplification between areas of NEPC and adenocarcinoma. AURKA and MYCN amplifications may be prognostic and predictive biomarkers, as they are harbingers of tumors at risk of progressing to t-NEPC after hormonal therapy. PMID- 23358694 TI - The effect of modes of delivery on infants' feeding practices. AB - Breast feeding has a great impact on the infant morbidity and mortality. According to Pakistan Demographic and Health survey (PDHS) infant mortality rate is 78 deaths per 1,000 live births. World Health Organization recommends that exclusive breast feeding for six months can decrease infant mortality rate by one third. The objective of the study was to find out how the mode of delivery had impact on the practice of breast feeding. Data were collected for 2500 consecutive patients during a period of two years, and it was seen that maternal initiative to breast feed was low and problems with lactation were much more in cases delivering their babies via cesarean sections than those delivering theirs by normal delivery. Vaginal and cesarean section deliveries took place in 54% and 46% of the case, respectively. Thirty percent of the women studied felt that they had no problems regarding breastfeeding, but 70% of them had some sort of problems with breastfeeding their babies. When the women were matched for the mode of delivery, 58% of women who had breastfeeding problems belonged to the cesarean delivery group and 42% of complaining mothers were from women with normal delivery. The relative risk of having problems with breastfeeding for women subjected to cesarean was 1.38 and the odds ratio was 0.61. The findings of the present study indicate that more in depth counseling sessions are required for women undergoing operative delivery to improve breast feeding among them. PMID- 23358696 TI - The role of potassium channel activation in celecoxib-induced analgesic action. AB - BACKGROUND AND PURPOSE: Celecoxib (CXB) is a widely prescribed COX-2 inhibitor used clinically to treat pain and inflammation. Recently, COX-2 independent mechanisms have been described to be the targets of CXB. For instance, ion channels such as the voltage-gated sodium channel, L-type calcium channel, Kv2.1, Kv1.5, Kv4.3 and HERG potassium channel were all reported to be inhibited by CXB. Our recent study revealed that CXB is a potent activator of Kv7/M channels. M currents expressed in dorsal root ganglia play an important role in nociception. Our study was aimed at establishing the role of COX-2 independent M current activation in the analgesic action of CXB. METHODS AND RESULTS: We compared the effects of CXB and its two structural analogues, unmethylated CXB (UMC) and 2,5 dimethyl-CXB (DMC), on Kv7/M currents and pain behavior in animal models. UMC is a more potent inhibitor of COX-2 than CXB while DMC has no COX-2 inhibiting activity. We found that CXB, UMC and DMC concentration-dependently activated Kv7.2/7.3 channels expressed in HEK293 cells and the M-type current in dorsal root ganglia neurons, negatively shifted I-V curve of Kv7.2/7.3 channels, with a potency and efficiency inverse to their COX-2 inhibitory potential. Furthermore, CXB, UMC and DMC greatly reduced inflammatory pain behavior induced by bradykinin, mechanical pain behavior induced by stimulation with von Frey filaments and thermal pain behavior in the Hargreaves test. CXB and DMC also significantly attenuated hyperalgesia in chronic constriction injury neuropathic pain. CONCLUSION: CXB, DMC and UMC are openers of Kv7/M K(+) channels with effects independent of COX-2 inhibition. The analgesic effects of CXBs on pain behaviors, especially those of DMC, suggest that activation of Kv7/M K(+) channels may play an important role in the analgesic action of CXB. This study strengthens the notion that Kv7/M K(+) channels are a potential target for pain treatment. PMID- 23358697 TI - Development of a respite care program for caregivers of pediatric oncology patients and their siblings. AB - Children with chronic health care needs, including those with cancer, require complex care under direct caregiver supervision. This intensive care management may result in increased stress and psychological distress for the caregiver and family. Respite care services are needed in providing alleviation of caregiver stress among families of children with complex health care needs. This report describes the feasibility of a pilot hospital-based respite care program for caregivers of pediatric oncology patients and their siblings and development of a permanent, expanded service to include both inpatient and outpatient units under the supervision of hospital volunteer services. During the feasibility pilot, 39 respite care requests were made by caregivers for care of patients, with 67% of these requests for care of infants and toddlers. The respite care providers were hospital volunteers. Reasons for the caregiver respite care request included a need to leave the hospital for running an errand, eating a meal, taking a mental break, or talking with the medical team. At the completion of the pilot, caregivers and staff were surveyed and expressed a strong desire for continuation of the service. The success of the pilot led to the implementation of a formal respite care program, Helping Hands, which provides services 7 days a week for inpatients, outpatients, and their siblings. Although this respite care service is specific to children with cancer, the program model is feasible within most pediatric care facilities. PMID- 23358698 TI - Synthesis and characterization of a luminescent and fully rigid tetrakisimidazolium macrocycle. AB - A fully rigid tetrakisimidazolium macrocycle was synthesized in good yield for the first time through direct [2+2] cyclization. The structure was characterized by NMRs, MS and X-ray diffraction analysis. This cationic, fluorescent macrocycle with four hydrogen bond donors pointing inward the large and rigid cavity may serve as an anion receptor, a fluorescent material and a building block for supramolecular assembly. PMID- 23358699 TI - Sinus of Valsalva aneurysm: An uncommon presentation. AB - BACKGROUND: Sinus of Valsalva aneurysm (SVA) may be congenital or acquired. They could mimic ventricular tumor symptoms and cause signs and symptoms of ventricular outflow tract obstruction. They may also involve the conduction system and cause palpitations or syncopal episodes. Both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) serve as quick, noninvasive methods to provide information on size and location of aneurysmal dilatation and cardiac chamber involvement. These methods can identify any associated anomalies or complications. This study presents a patient with unruptured SVA. CASE REPORT: A 46-year-old man, who had been suffering from nonspecific symptoms such as exercise intolerance and weakness for a few months, referred to our clinic in Isfahan (Iran). In TTE, a large mass was observed in the right ventricle. SVA was suspected after meticulous probing. This diagnosis was confirmed by TEE and computed tomography angiography. At open heart surgery, an SVA with a lot of clots it was removed. CONCLUSION: SVA must be kept in mind when a tumor-like mass is observed in the right ventricle. Detailed evaluation would thus be necessary to rule out SVA and to prevent wrong diagnosis and treatment that can sometimes be catastrophic. PMID- 23358701 TI - Equilibria and stability of a class of positive feedback loops. AB - Positive feedback loops are common regulatory elements in metabolic and protein signalling pathways. The length of such feedback loops determines stability and sensitivity to network perturbations. Here we provide a mathematical analysis of arbitrary length positive feedback loops with protein production and degradation. These loops serve as an abstraction of typical regulation patterns in protein signalling pathways. We first perform a steady state analysis and, independently of the chain length, identify exactly two steady states that represent either biological activity or inactivity. We thereby provide two formulas for the steady state protein concentrations as a function of feedback length, strength of feedback, as well as protein production and degradation rates. Using a control theory approach, analysing the frequency response of the linearisation of the system and exploiting the Small Gain Theorem, we provide conditions for local stability for both steady states. Our results demonstrate that, under some parameter relationships, once a biological meaningful on steady state arises, it is stable, while the off steady state, where all proteins are inactive, becomes unstable. We apply our results to a three-tier feedback of caspase activation in apoptosis and demonstrate how an intermediary protein in such a loop may be used as a signal amplifier within the cascade. Our results provide a rigorous mathematical analysis of positive feedback chains of arbitrary length, thereby relating pathway structure and stability. PMID- 23358702 TI - A virus responds instantly to the presence of the vector on the host and forms transmission morphs. AB - Many plant and animal viruses are spread by insect vectors. Cauliflower mosaic virus (CaMV) is aphid-transmitted, with the virus being taken up from specialized transmission bodies (TB) formed within infected plant cells. However, the precise events during TB-mediated virus acquisition by aphids are unknown. Here, we show that TBs react instantly to the presence of the vector by ultra-rapid and reversible redistribution of their key components onto microtubules throughout the cell. Enhancing or inhibiting this TB reaction pharmacologically or by using a mutant virus enhanced or inhibited transmission, respectively, confirming its requirement for efficient virus-acquisition. Our results suggest that CaMV can perceive aphid vectors, either directly or indirectly by sharing the host perception. This novel concept in virology, where viruses respond directly or via the host to the outside world, opens new research horizons, that is, investigating the impact of 'perceptive behaviors' on other steps of the infection cycle.DOI:http://dx.doi.org/10.7554/eLife.00183.001. PMID- 23358703 TI - Protein Microarrays for Quantitative Detection of PAI-1 in Serum. AB - OBJECTIVE: Plasminogen activator inhibitor-1 (PAI-1), one crucial component of the plasminogen activator system, is a major player in the pathogenesis of many vascular diseases as well as in cancer. High levels of PAI-1 in breast cancer tissue are associated with poor prognosis. The aim of this study is to evaluate rigorously the potential of serum PAI-1 concentration functioning as a general screening test in diagnostic or prognostic assays. METHODS: A protein-microarray based sandwich fluorescence immunoassay (FIA) was developed to detect PAI-1 in serum. Several conditions of this microarray-based FIA were optimized to establish an efficacious method. Serum specimens of 84 healthy women and 285 women with breast cancer were analyzed using the optimized FIA microarray. RESULTS: The median serum PAI-1 level of breast cancer patients was higher than that of healthy women (109.7 ng/ml vs. 63.4 ng/ml). Analysis of covariance revealed that PAI-1 levels of the two groups were significantly different (P<0.001) when controlling for an age effect on PAI-1 levels. However, PAI-1 values in TNM stage I-IV patients respectively were not significantly different from each other. CONCLUSION: This microarray-based sandwich FIA holds potential for quantitative analysis of tumor markers such as PAI-1. PMID- 23358700 TI - Important miRs of pathways in different tumor types. AB - We computationally determined miRs that are significantly connected to molecular pathways by utilizing gene expression profiles in different cancer types such as glioblastomas, ovarian and breast cancers. Specifically, we assumed that the knowledge of physical interactions between miRs and genes indicated subsets of important miRs (IM) that significantly contributed to the regression of pathway specific enrichment scores. Despite the different nature of the considered cancer types, we found strongly overlapping sets of IMs. Furthermore, IMs that were important for many pathways were enriched with literature-curated cancer and differentially expressed miRs. Such sets of IMs also coincided well with clusters of miRs that were experimentally indicated in numerous other cancer types. In particular, we focused on an overlapping set of 99 overall important miRs (OIM) that were found in glioblastomas, ovarian and breast cancers simultaneously. Notably, we observed that interactions between OIMs and leading edge genes of differentially expressed pathways were characterized by considerable changes in their expression correlations. Such gains/losses of miR and gene expression correlation indicated miR/gene pairs that may play a causal role in the underlying cancers. PMID- 23358704 TI - Overexpression of Gli1 in cancer interstitial tissues predicts early relapse after radical operation of breast cancer. AB - OBJECTIVE: To investigate whether Gli1 expression is important in relapse after radical operation of breast cancer. METHODS: Using immunohistochemistry, Gli1 expression was analyzed in human primary breast cancer (n=284) and paracancerous tissues (n=20), and also in local lymph nodes (n=28) and metastatic lymph nodes (n=28). RESULTS: Initial analysis of Gli1 expression in a small cohort of 20 breast tumors and their paracancerous tissues showed a tendency towards Gli1 overexpression in breast cancer tissues (P<0.001). Further, Gli1 expression in 284 breast cancer tissue samples was analyzed and a significant correlation was found between increased expression of nuclear Gli1 and unfavorable recurrence free survival (RFS) (P<0.05). The nuclear expression of Gli1 in metastatic lymph nodes following relapse after radical operation was much higher than that in the local lymph nodes of primary carcinoma (P<0.05). Most interestingly, the expression of Gli1 was much higher in the interstitial tissues of the relapsed group than of the non-relapsed group (P<0.001). CONCLUSIONS: Breast cancer shows a high prevalence of Gli1 expression, which is significantly correlated with aggressive features and unfavorable RFS. Nuclear Gli1 overexpression, especially in the interstitial tissues, signified early relapse after radical operation of breast cancer. PMID- 23358705 TI - Performance of coralline hydroxyapatite in sinus floor augmentation: a retrospective study. AB - OBJECTIVE: The purpose of this study is to retrospectively explore the utilization of coralline hydroxyapatite in maxillary sinus augmentation. METHOD: One hundred and eighteen cases of sinus lift with coralline hydroxyapatite (CHA) were included in this study. In detail, simultaneous implantation was conducted in 78 patients (174 implants) and delayed implantation was done in 40 cases (82 implants) around 6 months after bone transplantation. The clinical features and X ray radiographs after operation were analyzed to evaluate osseointegration procedures according to a planned medical follow-up. In the delayed group, around 6 months, a bone biopsy was taken just during implant placement in order to evaluate the new formed bone from a histological and histomorphometrical point of view. A further 6 months later, abutment connection was performed, and the patients received prosthetic restoration of the missing teeth. RESULT: Clinically, the incisions healed well. No abnormal reactions were found during follow-up period. All the 174 simultaneous implants were successful after 1-5 years of medical review; Out of 82 delayed implants, 3 were found to be loose. Histologically, all the specimens showed signs of active remodeling, and all the tissues had a large amount of osteocyte at sixth month after sinus augmentation. New bone formed dramatically. Radiologically, the density of CHA gradually reduced since the beginning of the third month, and CHA may be completely resolved at about fifth year. CONCLUSION: CHA is proven an ideal bone graft material for its reliable clinical results and favorable histocompatibility in the treatment of sinus atrophy or other kinds of insufficient bone volume in this region. Moreover, CHA's signal application can achieve desired clinical effect. CLINICAL RELEVANCE: This study shows the clinic application of CHA in maxillary sinus augmentation. Compared with popular mixture of autogenous bone and grafting materials, our results show CHA's signal application can achieve ideal osseointegration interface and satisfying clinic effect. PMID- 23358706 TI - Metacognition of agency: proximal action and distal outcome. AB - The cues contributing to people's metacognitions of agency were investigated in two experiments in which people played a computer game that involved trying to "touch", via a mouse moving a cursor, downward scrolling X's (Experiment 1), or trying to "explode" the downward scrolling X's (Experiment 2). Both experiments varied (a) proximal action-related information by either introducing or not introducing Turbulence into the mouse controls and (b) distal outcome-related information such that touched X's "exploded" either 100 or 75 % of the time. Both variables affected people's judgments of agency (JOAs), but the effect was different. First, the decrement in feelings of agency was greater with the proximal variable than with distal variable. Second, while the proximal variable always had a large direct effect on JOAs, even taking judgments of performance (JOPs) into account, JOPs completely accounted for the effect of the distal variable in Experiment 1, where the instructions were just to touch the X's. And even in Experiment 2, in which the instructions were to explode the X's, the direct effect of the distal variable on JOAs was small. These data indicate that these two cues exhibit different psychological profiles. The proximal action related information is a diagnostic cue to agency indicating the match between one's own intentions and actions. Internal monitoring of intentions is necessary and so the self is implicated. However, distal outcome can be largely monitored using information external to the agent, and so-while it is used by people to make agency judgments-it is a non-diagnostic cue. PMID- 23358707 TI - Specific insect-virus interactions are responsible for variation in competency of different Thrips tabaci isolines to transmit different Tomato Spotted Wilt Virus isolates. AB - Local adaptation between sympatric host and parasite populations driven by vector genetics appears to be a factor that influences dynamics of disease epidemics and evolution of insect-vectored viruses. Although T. tabaci is the primary vector of Tomato spotted wilt virus (TSWV) in some areas of the world, it is not an important vector of this economically important plant virus in many areas where it occurs. Previous studies suggest that genetic variation of thrips populations, virus isolates, or both are important factors underlying the localized importance of this species as a vector of TSWV. This study was undertaken to quantify variation in transmissibility of TSWV isolates by T. tabaci, in the ability of T. tabaci to transmit isolates of TSWV, and to examine the possibility that genetic interactions and local adaptation contribute to the localized nature of this species as a vector of TSWV. Isofemale lines of Thrips tabaci from multiple locations were tested for their ability to transmit multiple TSWV isolates collected at the same and different locations as the thrips. Results revealed that the probability of an isofemale line transmitting TSWV varied among virus isolates, and the probability of an isolate being transmitted varied among isofemale lines. These results indicate that the interaction of T. tabaci and TSWV isolate genetic determinants underlie successful transmission of TSWV by T. tabaci. Further analysis revealed sympatric vector-virus pairing resulted in higher transmission than allopatric pairing, which suggests that local adaptation is occurring between T. tabaci and TSWV isolates. PMID- 23358708 TI - Inflammatory responses to hepatitis B virus vaccine in healthy term infants. AB - Hepatitis B virus (HBV) infection continues to be a serious global health problem. During the course of HBV vaccination, we observed C-reactive protein (CRP) elevation in term infants without sepsis. Therefore, we prospectively studied interleukin-6 (IL-6) and CRP responses to HBV immunization. In 70 healthy term infants without signs and symptoms of sepsis and sepsis risk factors, IL-6, CRP, and white blood cell count levels were determined before and 24 h after immunization. Significant increases in CRP levels were seen 24 h after vaccination (p < 0.001). Although CRP levels of 22 infants at second evaluation were above the cutoff level for sepsis (4.82 mg/L), they had no clinical signs and symptoms of sepsis. After 48-72 h, CRP levels of these infants returned to normal levels with no blood culture positivity. CONCLUSION: our study showed that HBV vaccine is responsible for CRP elevation in term infants after vaccination at birth. To the best of our knowledge, this is the first study evaluating CRP response to HBV vaccine at birth in term infants. We suggest that this response should be considered in differentiation of early neonatal sepsis to avoid unnecessary antibiotic use. PMID- 23358709 TI - Hyperexcretion of homocitrulline in a Malaysian patient with lysinuric protein intolerance. AB - Lysinuric protein intolerance (LPI; MIM 222700) is an inherited aminoaciduria with an autosomal recessive mode of inheritance. Biochemically, affected patients present with increased excretion of the cationic amino acids: lysine, arginine, and ornithine. We report the first case of LPI diagnosed in Malaysia presented with excessive excretion of homocitrulline. The patient was a 4-year-old male who presented with delayed milestones, recurrent diarrhea, and severe failure to thrive. He developed hyperammonemic coma following a forced protein-rich diet. Plasma amino acid analysis showed increased glutamine, alanine, and citrulline but decreased lysine, arginine and ornithine. Urine amino acids showed a marked excretion of lysine and ornithine together with a large peak of unknown metabolite which was subsequently identified as homocitrulline by tandem mass spectrometry. Molecular analysis confirmed a previously unreported homozygous mutation at exon 1 (235 G > A, p.Gly79Arg) in the SLC7A7 gene. This report demonstrates a novel mutation in the SLC7A7 gene in this rare inborn error of diamino acid metabolism. It also highlights the importance of early and efficient treatment of infections and dehydration in these patients. CONCLUSION: The diagnosis of LPI is usually not suspected by clinical findings alone, and specific laboratory investigations and molecular analysis are important to get a definitive diagnosis. PMID- 23358712 TI - [Plantar ulcer in a multimorbid patient]. PMID- 23358713 TI - Thyroid evaluation in a patient with thyrotoxicosis with bedside ultrasound. PMID- 23358711 TI - Urinary microRNA profiling in the nephropathy of type 1 diabetes. AB - BACKGROUND: Patients with Type 1 Diabetes (T1D) are particularly vulnerable to development of Diabetic nephropathy (DN) leading to End Stage Renal Disease. Hence a better understanding of the factors affecting kidney disease progression in T1D is urgently needed. In recent years microRNAs have emerged as important post-transcriptional regulators of gene expression in many different health conditions. We hypothesized that urinary microRNA profile of patients will differ in the different stages of diabetic renal disease. METHODS AND FINDINGS: We studied urine microRNA profiles with qPCR in 40 T1D with >20 year follow up 10 who never developed renal disease (N) matched against 10 patients who went on to develop overt nephropathy (DN), 10 patients with intermittent microalbuminuria (IMA) matched against 10 patients with persistent (PMA) microalbuminuria. A Bayesian procedure was used to normalize and convert raw signals to expression ratios. We applied formal statistical techniques to translate fold changes to profiles of microRNA targets which were then used to make inferences about biological pathways in the Gene Ontology and REACTOME structured vocabularies. A total of 27 microRNAs were found to be present at significantly different levels in different stages of untreated nephropathy. These microRNAs mapped to overlapping pathways pertaining to growth factor signaling and renal fibrosis known to be targeted in diabetic kidney disease. CONCLUSIONS: Urinary microRNA profiles differ across the different stages of diabetic nephropathy. Previous work using experimental, clinical chemistry or biopsy samples has demonstrated differential expression of many of these microRNAs in a variety of chronic renal conditions and diabetes. Combining expression ratios of microRNAs with formal inferences about their predicted mRNA targets and associated biological pathways may yield useful markers for early diagnosis and risk stratification of DN in T1D by inferring the alteration of renal molecular processes. PMID- 23358714 TI - Patient preferences for deactivation of implantable cardioverter-defibrillators. PMID- 23358715 TI - Repeated treatment with high dose cyclophosphamide for severe autoimmune diseases. AB - High dose cyclophosphamide (HiCY) without stem cell rescue has been shown to induce remissions in patients with severe autoimmune disorders (SADS). However, up to 80% of these patients ultimately relapse. Here we review the outcomes of seven patients treated with two cycles and one patient treated with three cycles of HiCY. The diseases re-treated were scleroderma, multiple sclerosis, three patients with severe aplastic anemia (SAA), and three patients with myasthenia gravis (MG). All but two patients with SAA had received standard immunomodulatory therapy for their disease up front and had been refractory. All patients had complete hematologic recovery. Overall survival in this cohort was 100%. All patients relapsed after the initial cycle but event free survival thereafter was 93.3%. All are still in remission except two MG patients, one of whom relapsed after a severe GI infection requiring hospitalization, and the other relapsed 3 years after the second treatment and she did not respond to the third treatment. This shows that HiCY can be safely re-administered in patients with SAA and refractory SADS. The quality and duration of second remissions appears to be equal or superior to the first remission. PMID- 23358716 TI - Quantitative p retreatment VOI analysis of liver metastases. (99m)Tc-MAA SPECT/CT and FDG PET/CT in relation with treatment response to SIRT. AB - Using quantitive VOI analysis, the percentage (99m)Tc-MAA uptake and SUVmax and mean values of liver metastases obtained prior to SIRT were related to treatment response using both a lesion-based and clinical dichotomous approach. Based on the VOI % of (99m)Tc-MAA activity, the estimated (90)Y-microspheres activity/cc (MBq/cc) was calculated from the effective dose injected. Baseline VOI FDG PET SUVmean and max values and estimated MBq/cc values were related to treatment response using a lesion-based approach (% change in SUVmean >= 50%) and a clinical dichotomous approach. Fifteen treatment sessions were analyzed (13 patients). Using the lesion-based approach (12 treatment sessions) 40 lesions responded and 37 did not. SUVmax and mean values proved significantly different between non-responding and responding lesions; 18.6 (SD 10.8) versus 13.5 (SD 8.4 ) for SUVmax (p = 0.02) and 11.4 (SD 3.8) versus 6.3 (SD 4.5) for SUVmean (p = 0.002). Using the clinical dichotomous approach (15 treatment sessions / 11 responding), 91 lesions were analyzed; 57 responded. VOI volumes and estimated (90)Y-loaded glass microspheres activity (MBq/cc) did not differ between responders and non responders; 24 cc (SD 27) versus 21 cc (SD 21 cc) (p = 0.4) and 1.95 MBq/cc (SD 1.1 MBq/cc) versus 1.90 MB/cc (SD 2.7 MBq/cc) (p = 0.92). On the contrary, SUVmax and mean values proved significantly different between responders and non-responders; 23.7 (SD 9.8) versus 9.4 (SD 3.8 ) for SUVmax (p = 0.0001) and 13.1 (SD 8.1) versus 4.9 (SD 1.4) for SUVmean. CONCLUSION: These findings suggest that in patients presenting with high baseline SUVmax and mean values, the administration of higher activities or alternatively, other potentially more useful treatment options might be considered. PMID- 23358717 TI - Sonographic consensual pupillary reflex. AB - Patients suffering from severe orbital trauma are at risk for numerous complications, including orbital compartment syndromes. This can result in an afferent pupillary defect, which must be evaluated for on physical examination. Unfortunately, these at-risk patients are often challenging to examine properly due to surrounding edema. Point-of-care ultrasonography can be used as an adjunct to the standard examination in this situation. PMID- 23358718 TI - Field-modified multiple slow relaxations in a metamagnet composed of cobalt(II) chains with mixed azide and tetrazolate bridges. AB - The title heterobridge system exhibits the coexistence of AF ordering, SCM derived multi-relaxation dynamics, field-induced metamagnetism and field-induced spin-glass-like dynamics. PMID- 23358719 TI - Detection of circulating tumor cells in different stages of prostate cancer. AB - PURPOSE: To explore circulating tumor cell (CTCs) counts in different stages of prostate cancer (PC) in association with tumor burden, metastatic pattern and conventional serum biomarkers. Overall survival (OS) analyses were conducted with respect to optimized CTC cutoff levels. METHODS: Circulating tumor cell counts were assessed in healthy controls (n = 15) as well as in locally advanced high risk (LAPC, n = 20), metastatic castration resistant (mCRPC, n = 40) and taxane refractory (mTRPC, n = 15) PC patients. CTCs were detected using the CellSearch System. RESULTS: In metastatic PC (mPC), CTC counts were significantly increased compared to LAPC (p < 0.001). In LAPC, CTCs were at control level (p = 0.66). Patients with both bone and visceral lesions revealed the highest median CTC count (p = 0.004), whereas patients with sole soft tissue metastases displayed CTC counts comparable to controls (p = 0.16). No correlation was observed between CTC counts and osseous tumor burden assessed by bone lesion count (p = 0.54) or bone scan index (p = 0.81). CTC counts revealed a positive correlation with alkaline phosphatase (p < 0.001) and lactate dehydrogenase (p < 0.001) as well as a negative association with hemoglobin (p = 0.004) and PSA-doubling time (p = 0.01). Kaplan-Meier analyses demonstrated a cohort adjusted cutoff level of 3 CTCs with a shorter OS in case of >=3 CTCs compared to <3 CTCs (p = 0.001), a cutoff level applicable in mCRPC (p = 0.003) but not in mTRPC patients (p = 0.054). CONCLUSIONS: Circulating tumor cell counts are applicable as a prognostic molecular marker, especially in mCRPC patients harboring bone metastases with or without visceral metastases. For clinical practice, mPC patients with elevated CTC counts in combination with short PSA-DT, high alkaline phosphatase and lactate dehydrogenase levels as well as low hemoglobin levels are at high risk of disease progression and limited OS. PMID- 23358722 TI - Effects of dietary supplementation with ghee, hydrogenated oil, or olive oil on lipid profile and fatty streak formation in rabbits. AB - BACKGROUND: Coronary heart disease is the leading cause of mortality worldwide. A high-fat diet, rich in saturated fatty acids and low in polyunsaturated fatty acids, is said to be an important cause of atherosclerosis and cardiovascular diseases. METHODS: In this experimental study, 40 male rabbits were randomly assigned to eight groups of five to receive normal diet, hypercholesterolemic diet, normal diet plus ghee, normal diet plus olive oil, normal diet plus hydrogenated oil, hypercholesterolemic diet plus ghee, hypercholesterolemic diet plus olive oil, and hypercholesterolemic diet plus hydrogenated oil. They received rabbit chow for a period of 12 weeks. At the start and end of the study, fasting blood samples were taken from all animals to measure biochemical factors including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), fasting blood sugar (FBS), and C-reactive protein (CRP). Moreover, aorta, left and right coronary arteries were dissected at the end of the study to investigate fatty streak formation (FSF). Data was analyzed in SPSS at a significance level of 0.05. RESULTS: In rabbits under normal diet, ghee significantly increased TC, LDL, and HDL compared to the beginning (P < 0.01) and also to the other two types of fat (P < 0.05). Moreover, normal diet plus olive oil significantly enhanced FSF in left coronary arteries and aorta compared to normal diet plus ghee. In groups receiving hypercholesterolemic diets, ghee significantly increased HDL and CRP (P < 0.05) and significantly decreased FBS (P < 0.01). The hypecholesterolemic diet plus olive oil significantly increased HDL (P < 0.01). Supplementation of hypecholesterolemic diet with ghee significantly increased HDL and FBS in comparison with hydrogenated oil. Significant increase of FBS was also detected with the use of ghee compared to olive oil. Ghee also significantly reduced FSF in left and right coronary arteries compared to olive oil. FSF in left coronary arteries was significantly lower in the hypecholesterolemic diet plus ghee group compared to the hypecholesterolemic diet plus hydrogenated oil group. CONCLUSION: According to the achieved results, future clinical trial studies and investigation of other risk factors such as inflammatory factors are required. PMID- 23358720 TI - Relevance of cellular and serum carbonic anhydrase IX in primary breast cancer. AB - BACKGROUND: Carbonic anhydrase IX (CAIX) is involved in pH homeostasis, growth and survival of tumor cells. Besides the membranous form of CAIX, a soluble form is detectable in serum (s-CAIX). Overexpression of CAIX in tumors offers the opportunity for therapeutic strategies such as CAIX targeting antibodies. The aim of this study was to examine the relationships of CAIX mRNA expression and s-CAIX levels with clinicopathological parameters and survival of patients with primary breast cancer. METHODS: Tumor tissue of 169 primary breast cancer patients was analyzed for RNA expression by microarray analysis (Affymetrix HG-U133A). Concentration of s-CAIX was determined by ELISA in blood samples of 140 patients. RESULTS: In tumor tissue, CAIX mRNA signal intensities (MAS5 values) ranged from 34 to 2,513. Higher CAIX expression was associated with younger age (=50 years p = 0.040), negative hormone receptors (estrogen receptor p = 0.004; progesterone receptor p = 0.022) and positive nodal status (p = 0.001) as well as with shorter disease-free survival (p = 0.031). Concentrations of s-CAIX ranged from 56 to 1,500 pg/ml. There was no correlation between s-CAIX and CAIX mRNA levels as well as clinicopathological characteristics or outcome. CONCLUSION: In contrast to reported immunohistochemical studies, we performed RNA-based tissue analyses of CAIX expression and, for the first time, analyzed CAIX serum levels in primary breast cancer. The correlations between CAIX RNA expression and prognostic factors and patient outcome support a biologic role of CAIX in early breast cancer. A role of s-CAIX in primary breast cancer is not supported by our findings. PMID- 23358721 TI - Adiponectin receptor expression in gastric carcinoma: implications in tumor development and progression. AB - PURPOSE: Adiponectin, an adipocyte-secreted endogenous insulin sensitizer, appears to play an important role in progression of several malignancies. Expression of adiponectin receptors--AdipoR1 and AdipoR2--has been documented in gastric cancer (GC) cell lines, but its role in GCs is still controversial. We investigated expression level of 2 adiponectin receptors and correlated their expression with prognosis in GC patients. METHODS: We immunohistochemically evaluated AdipoR1 and AdipoR2 expression in 59 non-neoplastic gastric mucosas, 48 gastric adenomas, 250 GCs, and 58 lymph nodes involved by metastatic GC and assessed its association with clinicopathologic characteristics. RESULTS: Expression rates of both receptors increased stepwise in non-neoplastic gastric mucosa, gastric adenoma, intestinal-type GC, and metastatic GC (p < 0.001). AdipoR1 and AdipoR2 expression was observed in 85 (34.0 %) and 118 (47.2 %) GC cases, respectively. Expression rates were higher in intestinal-type GC than in diffuse-type GC (p < 0.001 and 0.016, respectively). AdipoR1 and AdipoR2 expression was more frequent in advanced GC than in early GC (p < 0.001, each) and was associated with lymphatic invasion (p = 0.046 and 0.001, respectively). AdipoR2 expression was associated with poor overall and disease-free survival (p = 0.001 and 0.007, respectively). AdipoR1 expression was associated with poor disease-free survival for intestinal-type GC patients (p = 0.046). In multivariate analysis, AdipoR2 was an independent prognostic factor for intestinal-type GC (p = 0.017). CONCLUSIONS: Adiponectin receptor expression is related to GC development and progression, especially intestinal-type GC. Thus, adiponectin receptor expression can serve as a prognostic marker in GC patients. PMID- 23358723 TI - Dynamic large-scale chromosomal rearrangements fuel rapid adaptation in yeast populations. AB - Large-scale genome rearrangements have been observed in cells adapting to various selective conditions during laboratory evolution experiments. However, it remains unclear whether these types of mutations can be stably maintained in populations and how they impact the evolutionary trajectories. Here we show that chromosomal rearrangements contribute to extremely high copper tolerance in a set of natural yeast strains isolated from Evolution Canyon (EC), Israel. The chromosomal rearrangements in EC strains result in segmental duplications in chromosomes 7 and 8, which increase the copy number of genes involved in copper regulation, including the crucial transcriptional activator CUP2 and the metallothionein CUP1. The copy number of CUP2 is correlated with the level of copper tolerance, indicating that increasing dosages of a single transcriptional activator by chromosomal rearrangements has a profound effect on a regulatory pathway. By gene expression analysis and functional assays, we identified three previously unknown downstream targets of CUP2: PHO84, SCM4, and CIN2, all of which contributed to copper tolerance in EC strains. Finally, we conducted an evolution experiment to examine how cells maintained these changes in a fluctuating environment. Interestingly, the rearranged chromosomes were reverted back to the wild-type configuration at a high frequency and the recovered chromosome became fixed in less selective conditions. Our results suggest that transposon-mediated chromosomal rearrangements can be highly dynamic and can serve as a reversible mechanism during early stages of adaptive evolution. PMID- 23358724 TI - Palliative care: an approach for all internists: comment on "Early palliative care in advanced lung cancer: a qualitative study". PMID- 23358725 TI - Loss and retention of RNA interference in fungi and parasites. PMID- 23358726 TI - Metformin therapy decreases hyperandrogenism and ovarian volume in women with polycystic ovary syndrome. AB - BACKGROUND: It is well known that there is a close relationship between elevated androgen plasma levels and the ultrasound findings of stromal hypertrophy in polycystic ovary syndrome (PCOS). The objective of this study was to investigate the effects metformin on the hyperandrogenism and ovarian volume in PCOS. METHODS: The study is an unrandomized clinical trial with before-after design. Twenty eight patients with infertility (male or female factor) meeting the Rotterdam ESHRE/ASRM criteria for PCOS were studied during the 2008-2009. The anthropometric characteristics of the patients, mean bilateral ovarian volume, and morphology by trans vaginal sonography as well as the plasma levels of leutinizing hormone, follicle stimulating hormone, estradiol, testosterone, 17 alpha-hydroxyprogesterone, and dehydroepianderosterone sulfate were obtained before and after treatment with metformin (500 mg three times a day) for three months. Paired t, Pearson's Correlation Coefficient, or Partial Correlation test was used to analyze the findings. RESULTS: The patients had a mean age of 25.67 years. A significant reduction in mean ovarian volume (11.70+/-4.31 ml vs 8.27+/ 3.71 ml P=0.001), body mass index (BMI, 28.11+/-4.55 kg/m(2) vs 26.84+/-4.55 kg/m(2) P=0.000) and serum androgen levels was seen after three months of treatment with metformin. There was positive correlations between the ovarian volume and serum testosterone level (r=0.589, P=0.001) or BMI (r=0.663, P=0.000). CONCLUSION: Metformin therapy may lead to a reduction in ovarian volume. It is likely that the reduction of ovarian volume reflect a decrease in the mass of androgen producing tissues. TRIAL REGISTRATION NUMBER: IRCT138903244176N1. PMID- 23358727 TI - [Herpes zoster after varicella-zoster vaccination]. AB - A five-year-old girl, vaccinated against varicella-zoster virus (VZV) presented with clinical symptoms of herpes zoster in the 6th cervical dermatome. A VZV direct immune-fluorescence assay was negative three times but additional genotypical analysis showed a VZV strain genotype 2 (Oka vaccine strain). Therefore the diagnosis of a breakthrough varicella disease with the vaccine strain was established. An immunodeficiency was ruled out and the patient responded well to the initiated therapy. This case demonstrates that a negative VZV direct immunofluorescence assay does not exclude an infection with the vaccine strain. PMID- 23358730 TI - Cell sorting analysis of geographically separated hypersaline environments. AB - Biogeography of microbial populations remains to be poorly understood, and a novel technique of single cell sorting promises a new level of resolution for microbial diversity studies. Using single cell sorting, we compared saturated NaCl brine environments (32-35 %) of the South Bay Salt Works in Chula Vista in California (USA) and Santa Pola saltern near Alicante (Spain). Although some overlap in community composition was detected, both samples were significantly different and included previously undiscovered 16S rRNA sequences. The community from Chula Vista saltern had a large bacterial fraction, which consisted of diverse Bacteroidetes and Proteobacteria. In contrast, Archaea dominated Santa Pola's community and its bacterial fraction consisted of the previously known Salinibacter lineages. The recently reported group of halophilic Archaea, Nanohaloarchaea, was detected at both sites. We demonstrate that cell sorting is a useful technique for analysis of halophilic microbial communities, and is capable of identifying yet unknown or divergent lineages. Furthermore, we argue that observed differences in community composition reflect restricted dispersal between sites, a likely mechanism for diversification of halophilic microorganisms. PMID- 23358731 TI - Thermal effects on microbial composition and microbiologically induced corrosion and mineral precipitation affecting operation of a geothermal plant in a deep saline aquifer. AB - The microbial diversity of a deep saline aquifer used for geothermal heat storage in the North German Basin was investigated. Genetic fingerprinting analyses revealed distinct microbial communities in fluids produced from the cold and warm side of the aquifer. Direct cell counting and quantification of 16S rRNA genes and dissimilatory sulfite reductase (dsrA) genes by real-time PCR proved different population sizes in fluids, showing higher abundance of bacteria and sulfate reducing bacteria (SRB) in cold fluids compared with warm fluids. The operation-dependent temperature increase at the warm well probably enhanced organic matter availability, favoring the growth of fermentative bacteria and SRB in the topside facility after the reduction of fluid temperature. In the cold well, SRB predominated and probably accounted for corrosion damage to the submersible well pump and iron sulfide precipitates in the near wellbore area and topside facility filters. This corresponded to lower sulfate content in fluids produced from the cold well as well as higher content of hydrogen gas that was probably released from corrosion, and maybe favored growth of hydrogenotrophic SRB. This study reflects the high influence of microbial populations for geothermal plant operation, because microbiologically induced precipitative and corrosive processes adversely affect plant reliability. PMID- 23358729 TI - Integral role of PTP1B in adiponectin-mediated inhibition of oncogenic actions of leptin in breast carcinogenesis. AB - The molecular effects of obesity are mediated by alterations in the levels of adipocytokines. High leptin level associated with obese state is a major cause of breast cancer progression and metastasis, whereas adiponectin is considered a "guardian angel adipocytokine" for its protective role against various obesity related pathogenesis including breast cancer. In the present study, investigating the role of adiponectin as a potential inhibitor of leptin, we show that adiponectin treatment inhibits leptin-induced clonogenicity and anchorage independent growth. Leptin-stimulated migration and invasion of breast cancer cells is also effectively inhibited by adiponectin. Analyses of the underlying molecular mechanisms reveal that adiponectin suppresses activation of two canonical signaling molecules of leptin signaling axis: extracellular signal regulated kinase (ERK) and Akt. Pretreatment of breast cancer cells with adiponectin protects against leptin-induced activation of ERK and Akt. Adiponectin increases expression and activity of the physiological inhibitor of leptin signaling, protein tyrosine phosphatase 1B (PTP1B), which is found to be integral to leptin-antagonist function of adiponectin. Inhibition of PTP1B blocks adiponectin-mediated inhibition of leptin-induced breast cancer growth. Our in vivo studies show that adenovirus-mediated adiponectin treatment substantially reduces leptin-induced mammary tumorigenesis in nude mice. Exploring therapeutic strategies, we demonstrate that treatment of breast cancer cells with rosiglitazone results in increased adiponectin expression and inhibition of migration and invasion. Rosiglitazone treatment also inhibits leptin-induced growth of breast cancer cells. Taken together, these data show that adiponectin treatment can inhibit the oncogenic actions of leptin through blocking its downstream signaling molecules and raising adiponectin levels could be a rational therapeutic strategy for breast carcinoma in obese patients with high leptin levels. PMID- 23358733 TI - Evaluation of circulating endothelial biomarkers in familial Mediterranean fever. AB - The aim of this was to evaluate some of the vascular biomarkers and cytokines related with atherosclerosis in regularly treated and attack-free familial Mediterranean fever (FMF) patients. Forty (21 males [M] and 19 females [F], 31 [15-58] years) FMF patients and eighteen healthy controls (11 M and 7 F, 35.5 [19 46] years) with no known cardiovascular (CV) risk factors were included. All patients were receiving regular colchicine treatment, and examinations were performed during attack-free periods. Serum samples were used for the determination of high-sensitive C-reactive protein (hs-CRP), tissue factor (TF), tissue plasminogen activator (t-PA), osteoprotegerin (OPG), interleukin-6 (IL-6), IL-17, and IL-23. Plasma samples were used for the determination of asymmetric dimethylarginine (ADMA) and thrombomodulin (TM). Age, sex distribution, waist circumference, body mass index, smoking status, and serum lipids were similar between the patients and controls (P > 0.05). The concentrations of (hs-CRP) and IL-17 were significantly higher in FMF patients compared with controls (P < 0.05). On the other hand, IL-6 and IL-23 levels were not different between the groups (P > 0.05). ADMA, OPG, and TM concentrations were significantly lower in the patients' group compared to those of controls (P < 0.05). However, vWF, TF, and t-PA levels were similar between the groups (P > 0.05). FMF patients receiving regular colchicine therapy during inactive disease state had significantly lower levels of vascular injury parameters. PMID- 23358734 TI - Characterisation of full-length mitochondrial copies and partial nuclear copies (numts) of the cytochrome b and cytochrome c oxidase subunit I genes of Toxoplasma gondii, Neospora caninum, Hammondia heydorni and Hammondia triffittae (Apicomplexa: Sarcocystidae). AB - Genomic DNA was extracted from three oocyst isolates of Hammondia triffittae from foxes and two oocyst isolates of Hammondia heydorni from dogs, as well as from cell culture-derived tachyzoites of Toxoplasma gondii (RH strain) and Neospora caninum (NC-Liverpool strain), and examined by PCR with primers targeting the cytochrome b (cytb) and the cytochrome c oxidase subunit I (cox1) genes in order to characterise both genes and, if possible, the remainder of the mitochondrial genome of these species. Several primers were designed and used in various combinations to amplify regions within and between both genes and to determine gene order. When certain forward primers targeting cytb were used in combination with certain reverse primers targeting cox1, two overlapping sequences were obtained for each species and isolate studied, which showed that a full-length copy of cytb was followed 36-37 bp downstream by a full-length copy of cox1, and these sequences are believed to represent the true mitochondrial genes and the gene order in the mitochondrial genome of the four species examined. The cytb of T. gondii, N. caninum, H. heydorni and H. triffittae comprised a total of 1,080 bp (359 amino acids) and used ATG and TAA as start and stop codon, respectively. The cox1 of these species also used TAA as stop codon, whereas the most likely start codon was ATG, resulting in a gene comprising 1,491 bp (496 amino acids). Pair-wise sequence comparisons based on either cytb or cox1 clearly separated T. gondii from N. caninum and both of these species from the two Hammondia species, whereas the latter two species were 100 % identical at cytb and shared 99.3 % identity at cox1. Phylogenetic analyses using the maximum-likelihood method confirmed these findings and placed T. gondii in a clade separate from the three other species and all four Toxoplasmatinae in a sister clade to Eimeria spp. PCR with other primers and/or primer pairs than those used to obtain the full-length mitochondrial genes yielded several types of about 1-1.5 kb long sequences, which comprised stretches of the primer-targeted genes at both ends and an intervening non-coding sequence of various length and composition. Thus, portions of cytb could be found both upstream and downstream from portions of cox1 and portions of the same gene could be found adjacent to each other (cytb->cox1; cox1->cytb; cytb >cytb; cox1->cox1). Sequence comparisons revealed that some of these gene fragments were truncated genes, whereas others included the putative start or stop codon of the full-length mitochondrial genes. From the nature of the gene fragments and/or their flanking sequences, they are assumed to be located on the chromosomes of the nuclear genome and to represent nuclear mitochondrial DNA segments (numts) or pseudogenes. In the four species examined, there were no nucleotide differences between the full-length mitochondrial copies of cytb and cox1 and their various incomplete nuclear counterparts. With a few exceptions, identical numt types and closely similar flanking sequences were obtained for all four species, which would indicate that the original transfer of these mitochondrial genes to the nuclear genome and/or the majority of any subsequent rearrangements of these gene fragments within the nuclear genome happened before the four species diverged. Yet, there were species-specific differences in the nucleotide composition of the nuclear gene fragments, identical to the differences in the mitochondrial genes, which would indicate that the incomplete nuclear copies of cytb and cox1 have been continuously updated during evolution to conform to their mitochondrial parent genes. The PCR-based findings of numts were further supported by Basic Local Alignment Search Tool (BLAST) searches against genome sequences of T. gondii and N. caninum using the concatenated mitochondrial cytb/cox1 sequences as queries. These searches revealed the presence of numerous numts of eighth distinct types in both species, with each one having a fixed starting and end point with respect to the nucleotide positions in the full-length mitochondrial genes. Four numt types were completely homologous between both species, whereas four other types differed with respect to their end point and/or the absence/presence of a 96-bp deletion. Each starting and end point was associated with a unique 100-200-bp long flanking sequence, which further revealed the presence of numts. For both species, the numt types and their various arrangements with respect to each other were identical or similar to those obtained by PCR in all four species examined. None of the identified numts covered a full-length gene, but together, the various numts covered the entire mitochondrial cytb and cox1 genes in an overlapping manner. In addition, they were fairly closely spaced on the chromosomes, and these features may explain why the nuclear copies were preferentially amplified to the exclusion of the true mitochondrial genes with most primers and primer pairs used in the present study. The possibility of a similar high prevalence of numts occurring in the nuclear genome of dinoflagellates is discussed. PMID- 23358735 TI - Evidence for bacteria-independent hatching of Trichuris muris eggs. AB - Hatching of infective larvae from embryonated eggs in the intestine is an essential first step in Trichuris infections. There are three isolates of the murine parasitic nematode Trichuris muris: E, E-J (the E isolate maintained in Japan), and S. Incubation of T. muris embryonated eggs with the intestinal bacteria Escherichia coli and Staphylococcus aureus induced in vitro hatching of the eggs, but Enterococcus faecalis failed to induce hatching. Bacteria-induced in vitro hatching of embryonated eggs occurred in the E and E-J isolates, whereas the S isolate was unresponsive to bacteria. T. muris worms recovered from infected mice showed no significant difference between the E-J and S isolates in their infectivity to susceptible B10.BR mice (P>0.05). In vivo hatching of embryonated eggs occurred at 30 min post-infection in the upper and lower halves of the small intestine of ddY mice infected with the E-J or S isolates, and on average, 65% of embryonated eggs recovered from the upper half of the small intestine were hatched in both the E-J and S isolates. In comparison with Enterococcus, the bacteria E. coli and S. aureus represent relatively minor components of the flora of the upper half of the small intestine of mice. These observations point to the possibility that bacteria-independent hatching might also occur in vivo, at least for the S isolate, and imply the existence of a very different system of induction of hatching in vivo. PMID- 23358736 TI - Application of praziquantel in schistosomiasis japonica control strategies in China. AB - Schistosomiasis remains a major public health problem with an estimated 200 million people infected in the world, and in China, schistosomiasis japonica is endemic in the south part of the country. In 1960s, before praziquantel was developed, there were about seven million patients. Praziquantel has a high efficacy against Schistosoma, few and transient side effects, simple administration and competitive cost, and is equally suited for both individual and large-scale treatment. Praziquantel has been widely used in the morbidity control, transmission control, and prevention of schistosomiasis japonica in China since 1980s. The schemes of praziquantel chemotherapy include the diagnostic selective chemotherapy, extensive chemotherapy, mass chemotherapy, stratified chemotherapy, phased chemotherapy, etc. Chemotherapy alone or combined with other control measure, such as Oncomelania snail control, health education, safety water supply, and so on, has achieved a great success, and there are only 0.33 million infected people now. This paper reviews the application of praziquantel in the schistosomiasis japonica control strategies in China so as to provide the rich experiences for reference of health workers of other countries where schistosomiasis is endemic. PMID- 23358737 TI - Indigenous Dirofilaria immitis in Bangladesh. AB - Dirofilaria immitis is a parasite of domestic and wild canids and felids in tropical, subtropical and temperate regions throughout the world. The canine heartworm (D. immitis) is the causative agent of canine and feline cardiopulmonary dirofilariasis. This parasite is known to cause a zoonotic disease, namely human pulmonary dirofilariasis. D. immitis is known to be endemic in several South and Southeast Asian countries (e.g. India and Malaysia), but there has previously been no information about the presence of this pathogen in Bangladesh. We present a case of canine dirofilariasis caused by D. immitis in rural southeastern Bangladesh. A male filaroid nematode (95 mm in length and 1.94 mm in width) was identified in the heart of a dog. Species classification was performed by microscopy and molecular tools. Sequence analysis revealed a 100 % identity within the mitochondrial cytochrome c oxidase I (CO1) gene to two Chinese and one Australian D. immitis samples. Usually, dogs stay outside overnight with a high risk to get infected with D. immitis via nocturnal mosquito vectors, which may lead to high prevalences of this pathogen in the canine population and thus increase the risk of human infections with this neglected parasitic disease. PMID- 23358738 TI - Fracture morphology and fracture management. PMID- 23358739 TI - Associations of genetic polymorphisms in the renin-angiotensin system with central aortic and ambulatory blood pressure in type 2 diabetic patients. AB - Patients with type 2 diabetes (T2D) are at high risk of developing hypertension and related cardiovascular disease. The renin-angiotensin system (RAS) plays a central role in regulation of blood pressure (BP). Accordingly, each component of this system represents a potential candidate in the etiology of hypertension. This study investigated the impact of polymorphisms within the RAS on ambulatory and central BP in T2D subjects. A cohort of 761 subjects (55-65 years) with T2D was studied. Ambulatory and central BP were measured, and ACE I/D genotype, angiotensinogen M235T, renin rs6693954 and ATR1-A1166C polymorphisms were analyzed. Women carrying the AA-genotype had lower 24-hour and day-time systolic and diastolic BP (p<0.05), and lower night-time and central diastolic BP (p<0.05), compared to T allele carriers. In men, the AA-genotype was instead associated with higher central diastolic BP (p=0.018) and higher augmentation index (p=0.016). Further, the associations between the renin rs6693954 SNP and diastolic BP were strongly gender dependent (p<=0.001). In T2D patients, there is a gender-dependent association of the renin rs6693954 SNP with central and ambulatory BP. Women carrying the renin rs6693954 AA-genotype may be protected against the higher BP seen in men with the same genotype. PMID- 23358740 TI - Defibrillators, deactivation, decisions, and dying. PMID- 23358741 TI - Assessment of XAF1 as A Biomarker to Differentiate Hepatocellular Carcinoma from Nonneoplastic Liver Tissues. AB - OBJECTIVE: XIAP-associated factor 1 (XAF1) expression has been shown to be related with apoptosis in hepatocellular carcinoma (HCC). However, the correlation of XAF1 expression with HCC tumor grade has not been intensively assessed. XIAP-associated factor-1 (XAF1) is an important apoptosis inducer in human HCC. The aim of this study is to determine the correlation between XAF1 expression and HCC histopathological grades. METHODS: The mRNA levels of XAF1 in 24 paired HCC-nonneoplastic specimens were quantified by real-time reverse transcription PCR (RT-PCR). Protein levels of XAF1 in 110 paired HCC-noncancer tissues were investigated by immunostaining specimens on a tissue microarray (TMA). Correlations between XAF1 mRNA levels or protein expression and clinicopathological features were assessed by statistical analysis. RESULTS: Both XAF1 mRNA and protein were significantly under-expressed in HCC tissues compared to their non-neoplastic counterparts. No significant relationship was found between XAF1 mRNA or protein expression and histological tumor grade. CONCLUSION: All these data suggest that XAF1 is a potential biomarker for differentiating HCC with noncancerous tissues. PMID- 23358742 TI - Dinitroamino benzene derivatives: a class new potential high energy density compounds. AB - Dinitroamino benzene derivatives are designed and studied in detail with quantum chemistry method. The molecular theory density, heats of formation, bond dissociation energies, impact sensitive and detonation performance are investigated at DFT-B3LYP/6-311G** level. The results of detonation performance indicated most of the compounds have better detonation velocity and pressure than RDX and HMX. The N-N bond can be regard as the trigger bond in explosive reaction, and the bond dissociation energies of trigger bond are almost not affected by the position and number of substituent group. The impact sensitive are calculated by two different theory methods. It is found that the compounds, which can become candidates of high energy materials, have smaller H50 values than RDX and HMX. It is hoped that this work can provide some basis information for further theory and experiment studies of benzene derivatives. PMID- 23358745 TI - [Pain management in palliative care. Current aspects of medicinal therapy]. AB - Palliative care patients do not only suffer from cancer pain but also from painful muscle spasticity due to multiple sclerosis, amyotrophic lateral sclerosis, after stroke or due to dementia if damage of the pyramidal motor system is present. Centrally active muscle relaxants can be helpful also when used as coanalgesics for cancer pain. In addition to opioids other coanalgesics, such as tricyclic antidepressants or serotonin/noradrenalin reuptake inhibitors as well as anticonvulsants (sodium channel and calcium channel blockers) can be helpful if neuropathic cancer pain is present. Idiopathic Parkinsonism or multiple system atrophy leads more to a painful rigor and pain control should be supported here by optimal adjustment of L-DOPA or DOPA agonist therapy. However, pain treatment should always address the psychological, social and spiritual demands of the patient. PMID- 23358744 TI - [Acute myeloid leukemia. Genetic diagnostics and molecular therapy]. AB - Acute myeloid leukemia (AML) is a genetically heterogeneous disease. The genetic diagnostics have become an essential component in the initial work-up for disease classification, prognostication and prediction. More and more promising molecular targeted therapeutics are becoming available. A prerequisite for individualized treatment strategies is a fast pretherapeutic molecular screening including the fusion genes PML-RARA, RUNX1-RUNX1T1 and CBFB-MYH11 as well as mutations in the genes NPM1, FLT3 and CEBPA. Promising new therapeutic approaches include the combination of all- trans retinoic acid and arsentrioxid in acute promyelocytic leukemia, the combination of intensive chemotherapy with KIT inhibitors in core-binding factor AML and FLT3 inhibitors in AML with FLT3 mutation, as well as gemtuzumab ozogamicin therapy in patients with low and intermediate cytogenetic risk profiles. With the advent of the next generation sequencing technologies it is expected that new therapeutic targets will be identified. These insights will lead to a further individualization of AML therapy. PMID- 23358746 TI - Autocrine and paracrine interactions and neuroprotection in glaucoma. AB - Retinal ganglion cells represent the output neurons of the retina. They are responsible for integrating electrical signals that originate with the photoreceptors and, via their axons that comprise the optic nerve, transmit that information to higher visual centers of the brain. The retinal ganglion cells reside on the inner surface of the retina and their axons course across the inner surface to exit at the back of the eye through a region known as the optic nerve head. Within this region, initiation of the degenerative processes associated with glaucoma are thought to occur, leading to degeneration of not only the optic nerve but also the retinal ganglion cells themselves. Studies aimed at understanding the mechanisms behind glaucoma have identified diverse cellular components and molecular events that occur in response to nerve injury. The challenge to date has been to identify and promote pro-survival events while suppressing those that support further degradation and loss of vision. Complicating this process is the fact that the cells and molecules involved can play multiple roles. An understanding of the players and their complex relationships is central to the development of a successful treatment strategy. PMID- 23358748 TI - Take with a grain of salt. PMID- 23358749 TI - Commentary. PMID- 23358747 TI - ACTH promotes chondrogenic nodule formation and induces transient elevations in intracellular calcium in rat bone marrow cell cultures via MC2-R signaling. AB - Adrenocorticotropic hormone (ACTH) is among several melanocortin peptide hormones that are derived from proopiomelanocortin (POMC). ACTH has been found to enhance osteogenesis and chondrogenesis. We show that, in the presence of dexamethasone, ACTH dose-dependently increases chondrogenic nodule formation in bone marrow stromal cells (BMSC) from the Wistar Kyoto (WKY) rat. The nodules consist in condensed cells highly expressing alkaline phosphatase, Sox9 and type II collagen transcripts and a proteoglycan-rich matrix. Immunoblot analysis of crude membrane fractions has shown that these cells express three melanocortin receptors (MC-R), namely MC2-R, MC3-R and MC5-R and the melanocortin 2-receptor accessory protein (MRAP). To determine which of these receptors mediate ACTH-induced effects, we have used MC-R-specific peptides and the known agonist profiles of the receptors. Neither alpha-MSH, a strong agonist of MC5-R, nor gamma2-MSH, a strong agonist of MC3-R, duplicates ACTH effects in rat BMSC. In addition, calcium flux has been examined as a mechanism for ACTH action at the MC2-R. Consistent with MC2-R and MRAP expression patterns in the BMSC cultures, ACTH-induced transient increases in intracellular calcium are increased with dexamethasone treatment. Neither alpha-MSH nor gamma2-MSH affects calcium flux. Dexamethasone increases MC2-R and MRAP expression and POMC peptide expression and cleavage increasing the production of the lipolytic beta-lipotropic hormone product. Therefore, the effects of ACTH in rat BMSC enriched for mesenchymal progenitors are consistent with an MC2-R signaling mechanism, with dexamethasone being capable of regulating components of the melanocortin system in these cells. PMID- 23358750 TI - Commentary. PMID- 23358751 TI - Data submission and quality in microarray-based microRNA profiling. AB - BACKGROUND: Public sharing of scientific data has assumed greater importance in the omics era. Transparency is necessary for confirmation and validation, and multiple examiners aid in extracting maximal value from large data sets. Accordingly, database submission and provision of the Minimum Information About a Microarray Experiment (MIAME)(3) are required by most journals as a prerequisite for review or acceptance. METHODS: In this study, the level of data submission and MIAME compliance was reviewed for 127 articles that included microarray-based microRNA (miRNA) profiling and were published from July 2011 through April 2012 in the journals that published the largest number of such articles--PLOS ONE, the Journal of Biological Chemistry, Blood, and Oncogene--along with articles from 9 other journals, including Clinical Chemistry, that published smaller numbers of array-based articles. RESULTS: Overall, data submission was reported at publication for <40% of all articles, and almost 75% of articles were MIAME noncompliant. On average, articles that included full data submission scored significantly higher on a quality metric than articles with limited or no data submission, and studies with adequate description of methods disproportionately included larger numbers of experimental repeats. Finally, for several articles that were not MIAME compliant, data reanalysis revealed less than complete support for the published conclusions, in 1 case leading to retraction. CONCLUSIONS: These findings buttress the hypothesis that reluctance to share data is associated with low study quality and suggest that most miRNA array investigations are underpowered and/or potentially compromised by a lack of appropriate reporting and data submission. PMID- 23358752 TI - Is this pathological? PMID- 23358755 TI - Technology and emotions: the futurists. PMID- 23358756 TI - [Scientific output on nutrition in the scope of Primary Health Care in Brazil: a review of the literature]. AB - Nutrition campaigns in Primary Health Care (PHC) play an important role in health promotion and the prevention and treatment of injuries. The scope of this paper is to chart and evaluate the scientific output of nutrition in Brazilian PHC. A search and review of the literature and papers was conducted on the PubMed and Lilacs databases, using key words related to PHC and nutrition. The studies were restricted to Brazil with the professionals or population assisted by PHC in the Brazilian Unified Health System and published prior to March 2011. The references in the selected articles were also consulted in order to identify additional studies. From the total of papers located, 68 were eligible and a further 49 were identified in the references lists, such that a total of 117 papers were analyzed. The studies reviewed were mostly original articles, using quantitative methodology, carried out by Sao Paulo University in that state and published from 2002 to 2011. The main issues were diagnosis seeking the evaluation of nutritional status involving children. The output in this field is growing, although there is a need to redirect the scope of future studies to a focus on intervention models and program evaluation. PMID- 23358757 TI - [Methods of analysis of food and nutritional security programs: an experience in Brazil]. AB - The development of methods that enable analysis of programs and public policies is a key point for their objectives to be attained. This study presents a Brazilian experience of analysis of two food and nutritional security programs in cities in Brazil's northeast region, namely the National Program for Vitamin A Supplementation, and monitoring health conditions of those included in the Family Allowance Program. The methodological stages included the definition of programs to be analyzed, data collection locations, the population participating in the research, collection procedures and data analysis. The methodology used made it possible to ascertain the perception of the different social actors involved in the operationalization of these programs, proving to be an important tool for the insertion of these actors, not only as objects of analysis, but also mainly as subjects of self-evaluation. PMID- 23358758 TI - [The non perception of obesity can be an obstacle to the role of mothers in taking care of their children]. AB - The goal of this study is to review articles in the scientific literature investigating the role of mothers, fathers and relatives in the treatment of obesity of their children. A search for original articles was conducted in the BIREME (BVS), PUBMED (MEDLINE) and Scielo platforms from 2004 to 2010, using the key words "the role of parents" and "childhood obesity," "the role of parents" and "child obesity treatment," "the mother's role" and "childhood obesity," "the mothers role" and "child obesity treatment." Twenty papers were selected and divided into two thematic categories. It was revealed that there are implications of the role of family, namely the father or mother, on the obesity of children, and more specifically related to the role of mothers. The conclusion drawn is that the role of parents and relatives is fundamental in promoting healthy behavior and lifestyles. Distorted maternal perception leads to excess weight being perceived as normal and this may prejudice treatment of child obesity. Acknowledging that the children are overweight most probably promotes greater acceptance of the need for treatment, in addition to being the necessary impetus for seeking professional assistance. PMID- 23358759 TI - [Profile of the rice and beans food option when eating away from home at a buffet by-weight restaurant]. AB - The scope of this cross-sectional study was to describe the prevalence and factors associated with the choice of rice and beans (CRB) among diners in a buffet-by-weight restaurant. Data on anthropometric, socio-demographic and behavioral characteristics as well as weight and photographic record of the dishes chosen by the diner were collected. The representative sample consisted of 675 luncheon diners, aged between 16 and 81. A subsample of 396 diners was analyzed, consisted of two groups: CRB and non-CRB. The Chi-square test verified the representativeness of the subsample in relation to the total sample. The Wald test, the chi-square test and the Poisson regression with robust variance examined the associations between the CRB and the data collected. Rice and beans were not chosen by 38.4% of diners. The conclusion drawn is that the CRB can still be considered the norm among Brazilians and more frequent among men. The choice of not opting for the CRB appears to be associated with less healthy eating habits and increased risk of overweight/obesity. PMID- 23358760 TI - [Educational nutritional intervention as an effective tool for changing eating habits and body weight among those who practice physical activities]. AB - The scope of this study was to evaluate the effectiveness of two methods of educational nutritional intervention together with women who practice regular physical activities by fostering the adoption of healthy eating habits. The study population consisted of 52 women aged between 19 and 59 who frequented the Academia da Cidade Program in Aracaju in the State of Sergipe. The study was a randomized comparison of two intervention groups and was of the pre-test/post test variety. The educational activities were based on two protocols - one less intensive (P1 Group) and one more intensive (P2 Group) - over a period of two months. The variables analyzed were nutritional knowledge, anthropometric measurements and changes in eating habits. The changes identified were improvement in eating habits and reduction in weight and Body Mass Index for the P2 group. The modifications identified referred mainly to increased consumption of fruit and vegetables, reduction of fat in cooking, reduction in the volume of food eaten per meal and increased meal frequency. In relation to nutritional knowledge, only 2 of the 12 questions showed significant changes. The most intensive method proved effective in changing dietary habits leading to weight loss. PMID- 23358761 TI - [Healthy eating, schooling and being overweight among low-income women]. AB - The scope of this study was to analyze the factors associated with the prevalence of being overweight and obesity in a population of low-income adult women living in a metropolitan region and its association with socioeconomic, demographic, reproductive and lifestyle variables, highlighting the importance of healthy eating. A population-based, cross-sectional study was conducted with a random sample of 758 women aged 20 or older living in Campos Eliseos - Duque de Caxias - State of Rio de Janeiro. Bivariate and multivariate hierarchical regression was used to identify factors associated with overweight and obesity. A prevalence of 23% of obesity was found, and a prevalence of 56% of being overweight and obesity combined. An inverse association was found between years of study, being overweight and obesity. Most of the women reported having a healthy diet (73.6%) that increased positively with income, education and age. Failure to consume vegetables weekly was associated with being overweight and not having a healthy diet was associated with obesity. The results of this study demonstrate that even in low-income populations, a higher level of education has an impact on prevention of this problem and in food choices. PMID- 23358762 TI - [Social network, social support and feeding habits of infants in their fourth month of life]. AB - The scope of this study was to investigate the association between the social network, social support and the feeding habits of infants in their fourth month of life. A cross-sectional study was conducted among 294 children selected at 4 Primary Health Care Units in Rio de Janeiro/ Brazil. A 24-hour dietary recall was applied to the mothers to evaluate the feeding habits. Questions related to the number of people upon whom the woman can rely were asked as well as their participation in social activities to measure the social network. The scale in the Medical Outcomes Study was used to measure social support. The analysis was based on multinomial logistic regression models. Most of the infants (84%) received breast milk, but only 16% were exclusively breastfed. Children whose mothers had a small number of relatives to rely on and with low social support were more likely to be bottle-fed rather than exclusively breastfed. The need to integrate members of the social network of the woman during pre-natal care, birth and the after birth period should be encouraged, in such a way that social support can serve the mother's requirements, contributing to exclusive breastfeeding. PMID- 23358763 TI - [Assessment of the diets of elderly people in a city in Sao Paulo state: application of the Healthy Eating Index]. AB - The scope of this paper was to evaluate the quality of the diet of the elderly in the city of Avare, Sao Paulo state, using the Healthy Eating Index (HEI). A cross sectional population-based study was conducted by home interviews. The sample consisted of 73 individuals, randomly selected among elderly people from the public health system in the city. Food consumption was measured by 3 24-hour recalls. The HEI adapted to the Brazilian population was applied for evaluation purposes. It is believed that this study is the first in Brazil to apply the HEI using 3 surveys of the 24-hour recall type among the elderly population. This methodology was chosen because, as described in the literature, a single day does not accurately reflect the usual intake of an individual due to the high interpersonal variance in consumption. It was found that 32.9% of elderly people were on a poor quality diet, 60.3% needed adjustments and 6.8% had a good quality diet. The conclusion that can be drawn is that the elderly population studied need to improve their diet, which emphasizes the importance of policies geared to encouraging healthy eating in old age. PMID- 23358764 TI - [Consumption of fruit and vegetables associated with the metabolic syndrome and its components in an adult population sample]. AB - Metabolic Syndrome (MS) increases the risk of cardiovascular events and the recommended intake of fruits and vegetables (FV) is related to its prevention. The scope of this study is to associate the intake of FV and its relation to MS and its components in an adult population sample. A prospective cross-sectional study was conducted with 636 adults in the period between 2004 and 2008. Anthropometric, clinical, dietary and biochemical profiles were recorded for all participants. MS was classified by the NCEP ATP-III, modified for glucose >100 mg/dl. Logistic regression was used to determine the odds ratio (OR) between the consumption of FV with MS and its components, and the level of significance adopted was 5%. The intake of fruit had protective effects against obesity (OR: 0.77, CI: 0.38-0.93), hypertriglyceridemia (OR: 0.76, CI: 0.35-0.96) and presence of MS (OR: 0.78, CI: 0.39-0.96), and proper intake of FV showed a protective effect for the presence of MS (OR: 0.79, CI: 0.41-0.95). Vegetable intake did not show protective effects / risk for the presence of MS and its components. The conclusion drawn is that the recommended intake of FV revealed a protective effect against MS and recommended intake of fruit had a protective effect not only for MS but also for its components. PMID- 23358765 TI - [Prevalence and factors associated with the consumption of fruit and vegetables by adolescents in public schools in Caruaru, Pernambuco state]. AB - This is a cross-sectional school-based study that evaluated the prevalence and associated factors of the daily intake of fruit and vegetables by adolescents at public schools in Caruaru, Pernambuco. Poisson regression with a hierarchical model, including sociodemographic variables in the first hierarchical level, behavioral variables in the second and diet-related variables in the third was used to assess the factors associated with fruit and vegetable intake. The results showed that of the 600 adolescents interviewed, 10% reported never eating fruit and 30.7% mentioned not eating vegetables. Prevalence of fruit intake was 32.9% and vegetables 29.0%. Only 6.5% reported eating both kinds of food daily. Merely the daily vegetable intake showed a significant difference according to sex (higher among girls). Daily fruit intake was 63% higher among adolescents living in urban areas. Not consuming alcohol was associated with higher fruit intake, though not to vegetable intake. Daily intake of fruits and vegetables was 2.4 times higher among adolescents who consumed rice and beans daily. Daily fruit and vegetable intake among adolescents in Caruaru is below the recommendations, and was associated with gender, residence area, consumption of alcoholic beverages and consumption of rice and beans. PMID- 23358766 TI - [Nutritional profile of the Xukuru-Kariri indigenous people in the state of Minas Gerais in accordance with different anthropometric and body composition indicators]. AB - The scope of this study was to evaluate the nutritional profile of indigenous Xukuru-Kariri villagers in the state of Minas Gerais between seven and seventy eight years of age in accordance with the different anthropometric and body composition indicator. The measurements were: weight, height, waist circumference (WC) and body fat percentage (BF%). The sensitivity and specificity of anthropometric indices were calculated with a confidence interval of 95% and positive predictive value (PPV) and negative predictive value (NPV). A total of 58 individuals was evaluated, of which 56.9% (n =33) were male and 43.1% (n =25) were female. Specificity was greater than sensitivity in all indices. It was seen that 29% of individuals were classified as having excess body fat as assessed by BMI and hand-to-hand bioimpedance and 50% of subjects had high body fat in relation to BMI and WC. Studies need to be conducted with different ethnic groups in order to construct indicators for specific nutritional guidance of indigenous health services. PMID- 23358767 TI - [Basal metabolism during pregnancy: a systematic review]. AB - Gestational energy expenditure (EE) is the basis for nutritional counseling and body weight control. The objective of this study was to systematically review the behavior of the basal metabolic rate (BMR), the major component of EE, during non gemelar pregnancy of healthy women. Based on the inclusion criteria, 37 articles were identified (24 cohort and 13 cross-sectional studies). Increases in BMR (between 8% and 35%) were observed in most cohort studies and it was related to the duration of follow-up and nutritional status. In the cross-sectionals, the increase in BMR varied from 8% to 28% close to delivery in comparison with the first trimester or post-partum. Lack of information on maternal age, loss of follow-up and short duration of follow-up during the pregnancy were serious limitations in the identified studies. In conclusion, BMR increases during pregnancy, and the increase is more intense after the second trimester. The most reliable data come from the few cohort studies that initiated before pregnancy. PMID- 23358768 TI - [Factors associated with the use of supplements among newborns in communal wards in Rio de Janeiro, 2009]. AB - The scope of this study was to estimate the prevalence of the use of supplements among newborns and analyze the factors associated with their use. A cross sectional study was conducted in 2009 with a representative sample of 687 mothers interviewed in 15 communal wards in hospitals of the Unified Health System in the city of Rio de Janeiro. Prevalence ratios (PR) of supplement use were obtained by Poisson Regression with robust variance, using a hierarchical model. The prevalence of supplement use was 49.8%. Factors associated with supplement use were: being submitted to the rapid HIV test (PR = 1.37; CI95%:1.18-1.58); cesarean delivery (PR = 1.57; CI95%:1.38-1.79); not being helped to breastfeed in the delivery room (PR = 1.60; CI95%:1.29-1.99); mother-child separation (PR = 1.24; CI95%:1.05-1.46); pacifier use (PR = 1.31; CI95%:1.08-1.58); maternal or neonatal interventions (PR = 1.56; CI95%:1.34-1.82); BFH certification (PR = 0.52; CI95%:0.44-0.61); and not receiving help to breastfeed in the communal ward (PR = 0.78; CI95%:0.66-0.92). Supplements to breast milk are being widely used. Hospital routines should be reviewed, so that exclusive breastfeeding becomes the norm. PMID- 23358769 TI - [Dentistry and supplementary health: regulatory framework, health promotion policies and quality of care]. AB - Based on the regulatory framework and an overview of dentistry in supplementary health, this paper discusses the specifics of the dental sector with respect to health promotion policies and quality of health care services proposed by the National Supplementary Health Agency (ANS). The State's activities in supplementary health are based on law 9.656/98, which defines the relations between operators, products and their beneficiaries, and law 9.961/2000, which created the ANS. Concomitantly there was a great increase in dentistry in the private health plan market, because of changes in the practices of the profession. This required the need to know the logic of the organization of the services regarding the assistance provided and the model of care. The ANS develops measures to encourage operators to implement health promotion programs, striving for an integral care model. At the same time, it promotes the qualification policy of supplementary health care, with emphasis on the scope of care, though in dentistry the focus of evaluation is still individual and fragmented care. Indeed, the great challenge of dentistry is making it a public health policy, accessible to all, and the qualification of dental care in supplementary health. PMID- 23358770 TI - [Technical quality and satisfaction related to full conventional dentures]. AB - Tooth loss is highly prevalent in Brazil, especially among the elderly, where more than three million need bimaxillary dentures. The federal government instituted Specialized Dental Care Centers (SDCC) to remedy this situation. The scope of this study was to evaluate one attribute of these Centers, namely the provision of full conventional dentures (FCD) from the perspective of quality and satisfaction related to this product. A cross-sectional study was conducted with 149 individuals fitted with such dentures in SDCC of Rio Grande do Norte between 2007 and 2009. Data were obtained by questionnaire and clinical examination of FCD regarding its retention, stability, aesthetics, and fixation. From the 233 dentures evaluated, 52.7% of upper FCD and 9.5% of lower FCD were technically satisfactory. With respect to the association between technical quality and satisfaction, the chi-square test indicated that upper FCDs were technically adequate (p = 0.041), particularly in terms of retention (p = 0.002) and stability (p = 0.000) and were associated with patient satisfaction. Thus, the FCD satisfied the users, despite the technical defects. However, this satisfaction may come from the fitting itself rather than its functionality. PMID- 23358771 TI - [Inequalities in the distribution of dental caries in Brazil: a bioethical approach]. AB - The scope of this paper was to analyze the problem of dental caries as a public health issue of epidemiological relevance. It is a case study based on documentary analysis of national epidemiological surveys on oral health in the years 1986, 2003 and 2010, with the Bioethics of Protection as an analytical support. The surveys revealed inequalities between population groups; and such inequalities were analyzed with respect to the reduction of the disease in the younger population, access to oral health care, and tooth loss, which is the worst outcome for tooth decay. The good results presented in the surveys have not reached the whole population; data have shown inequalities regarding family income and Brazilian region. It was also found that from 2003 government interventions in protective actions such as the adoption of criteria of equity in the allocation of health resources and inclusion of vulnerable population have contributed to a reduction in caries. Nevertheless, it is considered necessary update oral health care models by using Epidemiology as a structuring tool, and an interface with socially responsible protective bioethics, since regional differences continued to be marked in the analysis. PMID- 23358772 TI - [Oral health in the family health strategy in a regional management territory of the state of Piaui]. AB - The objective of this cross-sectional study was to assess the professional profile of dental-surgeons (DS) who work in the Family Health Strategy (FHS), and on the basis of this reflect upon aspects of the development of dental actions in primary health care in municipalities of a health region of the state of Piaui (Brazil) The study covered the nineteen municipalities of the region. The sample consisted of 111 dentists and data was collected using a questionnaire from August to December 2008. An Excel O database was created for the statistical analysis. The dentists were predominantly female, aged 20-39 years, with one to five years of professional experience. Most of them are specialists in a clinical field of dentistry and make home care visits. However, these visits are infrequent and without a health team and they rarely meet with the health team to compare notes. The results indicate that the problems that were detected are likely to be the same in other regions of the country. The lack of an interdisciplinary professional approach among DS is an issue to be properly addressed when examining the role of dentistry and its potentially unquestionable participation in the family health strategy. PMID- 23358773 TI - [Evaluation of the tuberculosis program in Sapucaia do Sul, state of Rio Grande do Sul: indicators, 2000-2008]. AB - The scope of this study was to describe the trends of tuberculosis indicators in relation to their prevalence, incidence and the case outcome percentages (cure, abandonment of treatment or death) for the patients who entered in the Program in Sapucaia do Sul, state of Rio Grande do Sul, between 2000 and 2008. An ecological analysis of the incidence was conducted and the gross frequency rates and respective confidence intervals of 95% were presented. The rate estimates were verified by means of average annual percent change as well as the mobile averages every three years. The prevalence rate was 64.3 and the incidence rate was 58.0 per 100.000 inhabitants. Analysis of the indicators did not reveal statistically significant differences between the annual rates or in the mobile averages during the period. The outcomes were below the targets proposed by the World Health Organization, what compromises control of the disease, as it is not proving possible to interrupt the chain of transmission. PMID- 23358774 TI - [Association of knowledge about STD and level of schooling among conscripts upon enlistment in the Brazilian Army, Brazil, 2007]. AB - The scope of this study was to describe knowledge of military conscripts about STD in relation to level of schooling upon enlistment in the Brazilian Army. A self-administered questionnaire with demographic and clinical aspects, forms of transmission, sexual behavior and access to STD information was applied in a national sample in 2007. Variables associated with low schooling were: being 19 20 years old [OR=1.2(95%CI:1.18-1.32)]; saying that STD can be transmitted by: eating contaminated food [OR=2.2(95%CI:1,96-2.55)]; bathing in rivers/beaches [OR=1.5(95%CI:1.27-1.88)]; mosquito bites [OR=1.5(95%CI:1.38-1.65)]; sexual intercourse <=14 years old [OR=1.4 (95%CI:1.33-1.55)]. Variables inversely associated with low schooling were: being white [OR=0.9 (95%CI:0.82-0.91)]; stating that STD can be transmitted by: sharing syringes/needles [OR=0.7(95%CI: 0.62-0.78)]; mother-to-child transmission [OR=0.6(95%CI:0.58-0.69)]; having used a condom in the last sexual intercourse [OR=0.8(95%CI:0.71-0.85)]; being MSM [OR=0.7(95% CI: 0.60-0.92)]; knowing that sex without condoms increases risk of transmission [OR=0.4 (95%CI:0,37-0,51)]. Given the association of low schooling with less knowledge about STD, educational policies geared to this population are needed because they are more vulnerable. PMID- 23358775 TI - [Incidence and risk factors for congenital syphilis in Belo Horizonte, Minas Gerais, 2001-2008]. AB - Congenital syphilis continues to be a public health problem in Brazil. The scope of this study is to describe the trends in the incidence of congenital syphilis in Belo Horizonte between 2001 and 2008 and determine risk factors associated with disease diagnosis. Data on cases of congenital syphilis and on the population of live births were obtained from the National Notifiable Diseases Information System (SINAN) and from the National Live Birth Information System (SINASC), respectively. Multivariate logistic regression analysis used the population of live births as the reference group to identify independent risk factors for congenital syphilis. The annual incidence of congenital syphilis revealed a rising trend from 0.9 to 1.6 cases per 1,000 live births between 2001 and 2008. Independent risk factors for congenital syphilis included: maternal schooling <8 years (OR: 1,3; 95% CI: 1,2-1,4); black or mixed maternal race (2,1; 1,5-2,8) and lack of antenatal care (11,4; 8,5-15,4). The strong association between the lack of antenatal care and congenital syphilis indicates that universalization of antenatal care is critical for the control of congenital syphilis. The effective control of the disease in Brazil will depend on actions to reduce social inequities in health. PMID- 23358776 TI - [A Colombian institutional response to Colombian children infected with HIV/AIDS]. AB - Children with HIV/AIDS is a social issue,the approach to which transcends the health sector. The normative, political, institutional and service sector responses have specificities related to children. A proposed approach is based on the following points: health care, nutrition, education, family-socioeconomic status, psychosocial repercussions, protection, housing, stigmatization and discrimination. Based on these guidelines,a survey was conducted of an institutional responseapplying the Bioecological Model of Human Development. Life of children in the institution is described and analyzed. A group of 31 children and 30 adults participated in this ethnographic study. The institutional response concerning health, nutrition, education and basic care, is satisfactory. The main weaknesses identified were nondisclosure of the diagnosis, stigmatization and discrimination, institutionalization validation, psychoemotional repercussions and stigmatization management, and the research budget. The children acknowledge that the institution satisfies their basic-needs and disapprove of some stigmatizing and coercive practices. The reintegration of the children with their families is recommended as a future strategy based on evidence that shows it has better bio-psychosocial results and lower costs. PMID- 23358777 TI - [Allies of A. Aegypti: factors contributing to the occurrence of dengue according to social representations of professionals of family health teams]. AB - Historically, health policies and actions to combat dengue have been based on vector control and field activities, while neglecting health education activities. Establishing the social representations of family health unit professionals about the factors that contribute to the sustained level of the occurrence rates of dengue is the scope of this research, in order to contribute to improved communication between health professionals and citizens, seeking to control the disease. A qualitative study was conducted with family health strategy professionals in six selected cities, with data tabulated by the Collective Subject Discourse technique. The results showed four discourses about the issues that were raised by the question of what caused the incidence of dengue. The conclusion drawn is that the professionals attribute the major share of responsibility for the incidence of dengue to the population, but also note the lack of structure and organization of services as well as perceiving difficulties for changes in observed behavior to occur with the resources available. PMID- 23358778 TI - [What does health have to do with community radio?: an analysis of an experience in Nova Friburgo - State of Rio de Janeiro]. AB - The field of Communication and Health in Brazil has been developing and getting stronger after each National Health Conference (NHC). In the final report of the XII NHC, in 2003, there was clear recognition that community radio is an instrument for the dissemination and treatment of issues related to the Brazilian Unified Health System (SUS). This study seeks to analyze the relationships that are established between health professionals, listeners/users and popular communicators as a means of understanding the nexus between a radio program on health and the imaginations of the listeners. A qualitative methodological approach was used of ethnographic and media audience methodologies. The field was a radio program about health, Bloco Mulher Saude, broadcast by the Radio Comunidade FM 104,9 in Nova Friburgo, State of Rio de Janeiro. The discussions were divided into analytical categories. The conclusion drawn is that community communication can be a cultural and political mediator for the expression of the demands of the community on health; the predominant medical jargon is maintained and reproduced by the physicians when participating on radio; community communication can contribute to the creation of strategies that broaden the social control of SUS. PMID- 23358779 TI - [Emotion and soma (dis)connected in magazine pages: the thematic categories of the prescriptive discourse on phenomena of life and illness]. AB - Magazines sold on newsstands have become self-help texts, and the study of the topics covered makes it possible to understand how the discourses are constructed, how they become repositories used to give meaning to life. In the case of magazines that deal with the sphere of health, prescribing methods of treatment, prevention and even healthy lifestyles, the studies allow us to understand the meanings of discourses about body and health. In some articles, the emphasis that sometimes highlights the physical aspect is accompanied by the inclusion of mental aspects. This fact gave rise to this study, which seeks to clarify how this mind-body connection is conceptualized and prescribed in these pages. Six articles of a Brazilian health magazine published between August 2005 and February 2006 were analyzed regarding the content of the texts as well as graphic and textual features. The way this media format operates was considered significant, and when associated with the themes: self-diagnosis, the place of emotion, the prescriptions and causality reinforce healthy lifestyles. Readers must learn to self-diagnose and control their emotions, considered to be juxtaposed to the physical emotions. The articles outline a field of health in which the mind-body split deepens and extends, establishing the medicalization of society. PMID- 23358780 TI - [Perceptions of day care center teachers about daily practices of infant feeding: the impact of training]. AB - This article stresses the importance of the qualification of professionals involved in the feeding of children in daycare centers, such that they offer adequate food and programs are developed in order to foster healthy food habits in infants from birth. Thus, the scope of this paper was to evaluate the impact of a training program for these daycare teachers in their perceptions and practices in infant feeding. A qualitative approach was used to evaluate the impact of training, with the application of the focus group technique. Sixteen groups were created, eight of which were daycare centers with training and eight without training, the average number of participants being 6 to 11 per institution aged between 19 and 66. The discourse of the teachers who took part in the training program is replete with signs of small changes, or at least with the recognition that it is indeed necessary and possible to promote change. The importance of organizing and conducting training programs for the nutritional education of teachers in day care centers is emphasized, with the continuous supervision of the effects of the qualification as a strategy for infant health. PMID- 23358781 TI - [Evaluation of medication advertising broadcast on radio stations]. AB - The scope of this paper was to evaluate advertising for medication broadcast on radio stations in Natal, State of Rio Grande do Norte, Brazil, from April to September 2008 and from April to September 2010. The advertising was recorded and transcribed in order to conduct legal analysis and content analysis based on the precepts of Laurence Bardin. Both the advertising recorded during the first stage (regulated by RDC 102/00) and the second stage (regulated by RDC 96/08) contained some form of legal violation. Content analysis detected practically the same violations in both stages, namely the lack of information regarding adverse effects of the medication, appeal to consumption, exaggeration of efficiency/effectiveness and abusive exploitation of illness. Despite the inclusion of more modern and restrictive legislation, radio advertising continues to violate the law blatantly, committing abuse and disrespecting the population's entitlement to good health. The study reveals the need for medication advertising to be dealt with in a broader context, in other words to be treated as a public health concern. It must take into consideration the socio-historical scenario in which it evolved, since the legislation alone is insufficient to combat abuse committed to the detriment of public health. PMID- 23358782 TI - [Social participation and health promotion: a case study in the region of Paranapiacaba and Parque Andreense]. AB - Community participation is considered a key condition for communities to assume control of their health within the scope of health promotion. This study sought to identify and analyze the perceptions of residents of the watershed areas of Santo Andre/Sao Paulo with respect to the actions of health education and environmental education developed by the public authorities of the city, and how the local community participates in these processes. Data collection was conducted via structured and semi-structured interviews with civil servants and local residents. The methodology of content analysis proposed by Bardin was used for data interpretation. The main results showed that the health measures developed in the region studied are still predominantly viewed from the standpoint of prevention and not as an educational process able to support and achieve some of the goals of health promotion, such as the development of personal skills and support for community action. Data analysis showed the importance of intersectorial activity and conducting emancipatory educational measures as a key factor for participative procedures and the empowerment of the population. PMID- 23358784 TI - Managed problem solving for antiretroviral therapy adherence: a randomized trial. AB - BACKGROUND: Adherence to antiretroviral therapy is critical to successful treatment of human immunodeficiency virus (HIV). Few interventions have been demonstrated to improve both adherence and virologic outcomes. We sought to determine whether an intervention derived from problem solving theory, Managed Problem Solving (MAPS), would improve antiretroviral outcomes. METHODS: We conducted a randomized investigator blind trial of MAPS compared with usual care in HIV-1 infected individuals at 3 HIV clinics in Philadelphia, Pennsylvania. Eligible patients had plasma HIV-1 viral loads greater than 1000 copies/mL and were initiating or changing therapy. Managed Problem Solving consists of 4 in person and 12 telephone-based meetings with a trained interventionist, then monthly follow-up calls for a year. Primary outcome was medication adherence measured using electronic monitors, summarized as fraction of doses taken quarterly over 1 year. Secondary outcome was undetectable HIV viral load over 1 year. We assessed 218 for eligibility, with 190 eligible and 180 enrolled, 91 randomized to MAPS and 89 to usual care. Fifty-six participants were lost to follow-up: 33 in the MAPS group and 23 in usual care group. RESULTS: In primary intention-to-treat analyses, the odds of being in a higher adherence category was 1.78 (95% CI,1.07-2.96) times greater for MAPS than usual care. In secondary analyses, the odds of an undetectable viral load was 1.48 (95% CI, 0.94-2.31) times greater for MAPS than usual care. In as-treated analyses, the effect of MAPS was stronger for both outcomes. There was neither a difference by prior treatment status nor change in effect over time. CONCLUSIONS: Managed Problem Solving is an effective antiretroviral adherence intervention over the first year with a new regimen. It was equally effective at improving adherence in treatment experienced and naive patients and did not lose effect over time. Implementation of MAPS should be strongly considered where resources are available. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00130273. PMID- 23358787 TI - Pathologic features and clinical outcome of central neurocytoma: analysis of 15 cases. AB - OBJECTIVE: To get better recognition of central neurocytoma and diminish misdiagnosis. METHODS: A retrospective review identified 15 cases of central neurocytoma. All cases of central neurocytoma were analyzed for their clinical symptoms, pathologic changes, immunohistochemical staining, prognosis and differential diagnosis. Clinical follow up was performed. RESULTS: There were 8 males and 7 females aged 10-64 years (median 32.93 years). The most common presenting symptoms were those related to increased intracranial pressure (ICP), including headache (100%), papilledema (93%) and vomiting (80%). All tumors were located in the ventricular system. The tumors were composed of uniform cells with round nuclei and a fine chromatin pattern, and in some areas, small cells with perinuclear halo could be seen. In particular, the anuclear areas may have a fine fibrillary matrix (neuropil). Nuclear atypia and vascular proliferation appeared in two cases, respectively. Focal necrosis could be seen in one case. Immunohistochemical findings included expression of synaptophysin (15/15), neuron specific enolase (12/15) and glial fibrillary acidic protein (GFAP) (3/15). MIB-1 proliferation index ranged from 0.8-12.5%, and was more than 2% in 3 of 15 cases assessed. Follow-up information of 11 patients was available. CONCLUSIONS: Central neurocytoma has a favorable prognosis in general, but in some cases, the clinical course could be aggressive. Increase of GFAP positivity, proliferation index and vascular proliferation might suggest a more malignant process. PMID- 23358786 TI - A lower degree of PBMC L1 methylation is associated with excess body weight and higher HOMA-IR in the presence of lower concentrations of plasma folate. AB - BACKGROUND: Identification of associations between global DNA methylation and excess body weight (EBW) and related diseases and their modifying factors are an unmet research need that may lead to decreasing DNA methylation-associated disease risks in humans. The purpose of the current study was to evaluate the following; 1) Association between the degree of peripheral blood mononuclear cell (PBMC) L1 methylation and folate, and indicators of EBW, 2) Association between the degree of PBMC L1 methylation and folate, and insulin resistance (IR) as indicated by a higher homeostasis model assessment (HOMA-IR). METHODS: The study population consisted of 470 child-bearing age women diagnosed with abnormal pap. The degree of PBMC L1 methylation was assessed by pyrosequencing. Logistic regression models specified indicators of EBW (body mass index-BMI, body fat-BF and waist circumference-WC) or HOMA-IR as dependent variables and the degree of PBMC L1 methylation and circulating concentrations of folate as the independent predictor of primary interest. RESULTS: Women with a lower degree of PBMC L1 methylation and lower plasma folate concentrations were significantly more likely to have higher BMI, % BF or WC (OR = 2.49, 95% CI:1.41-4.47, P = 0.002; OR = 2.49, 95% CI:1.40-4.51, P = 0.002 and OR = 1.98, 95% = 1.14-3.48 P = 0.0145, respectively) and higher HOMA-IR (OR = 1.78, 95% CI:1.02-3.13, P = 0.041). CONCLUSION: Our results demonstrated that a lower degree of PBMC L1 methylation is associated with excess body weight and higher HOMA-IR, especially in the presence of lower concentrations of plasma folate. PMID- 23358788 TI - Risk taking in first and second generation Afro-Caribbean adolescents: an emerging challenge for school nurses. AB - School nurses are well positioned to address risk-taking behaviors for adolescents in their care. The purpose of this mixed-method exploratory study was to explore risk taking in Afro-Caribbean adolescents in South Florida, comparing first- to second-generation adolescents. Quantitative and qualitative data were collected from an immigrant group using the adolescent risk-taking instrument to evaluate risk-taking attitudes, behaviors, and self-described riskiest activities. One-hundred and six adolescents participated; 44% were first generation Afro-Caribbean. Data analysis included analysis of variance, frequencies, and content analysis. There were no differences in risk-taking attitudes; smaller percentages of first generation Afro-Caribbean adolescents reported sexual activity, substance use, and violence. Over one third of the sample, regardless of generational status, reported alcohol use, but did not note alcohol or other health-compromising behaviors as "riskiest" activities. It is important to better understand Afro-Caribbean adolescents' perspectives about risky behaviors, and school-based venues offer the best promise for reaching these adolescents. PMID- 23358789 TI - Can we predict the clinical outcome of patients with bladder trauma? PMID- 23358790 TI - Salvage radical prostatectomy as management of locally recurrent prostate cancer: outcomes and complications. AB - PURPOSE: Management of prostate cancer following radiation therapy remains challenging, especially for younger men or those with life expectancy greater than 10 years. We outline the efficacy, safety and adequacy of radical prostatectomy for the treatment of radiorecurrent localized prostate cancer. METHODS: A systematic review was performed in September 2012 searching MEDLINE articles from 1980 to 2012 on salvage radical prostatectomy. We excluded unpublished data and non-English-language articles. RESULTS: The ideal candidate for salvage radical prostatectomy (SRP) has a life expectancy greater than 10 years, a PSA < 10 ng/ml and whose initial clinical staging was T1 or T2. A prostate biopsy and imaging studies to rule out metastatic disease should be performed prior to SRP. Salvage RP has a high complication rate, but this appears to be decreasing over time. Urinary continence rates range from 36 to 81%, whereas erectile function following SRP was generally poor with less than 30% of men regaining adequate erectile function. Men with good erectile function prior to SRP fared better than those with pre-operative erectile dysfunction. Biochemical recurrence-free probability at 5 years ranged from 37 to 55% and the estimated cancer-specific survival at 10 years ranged from 70 to 83%. Minimally invasive SRP is feasible and early outcomes suggest that this approach is not inferior to open surgery. CONCLUSION: SRP offers a potentially curative option with proven long-term disease-free survival in appropriately selected patients. Given the morbidity of this procedure, judicious patient selection and referral to providers experienced with salvage surgery may optimize patient outcomes. PMID- 23358791 TI - Increasing prevalence of ciprofloxacin resistance in extended-spectrum-beta lactamase-producing Escherichia coli urinary isolates. AB - PURPOSE: To describe the incidence and drug susceptibility profiles of uropathogenic extended-spectrum-beta-lactamase-producing Escherichia coli (ESBL EC) during a 10-year period and to identify differences in resistance patterns between urological and non-urological ESBL-EC isolates. METHODS: Retrospective analysis of 191,564 urine samples obtained during 2001 to 2010 at the University Hospital Basel, Switzerland. The computerized database of the Clinical Microbiology Laboratory and the Division of Infectious Diseases and Hospital Epidemiology was used to identify ESBL-EC positive urine samples. ESBL-EC isolates were stratified according their origin into two groups: Urology and non Urology isolates. RESULTS: The rate of ESBL-EC positive urine samples increased significantly during the study period (3 in 2001 compared to 55 in 2010, p < 0.05). The most active agents were imipenem, meropenem, and fosfomycin (100%), followed by amikacin (99.1%) and nitrofurantoin (84%). The least active substances were ampicillin-clavulanate (20%), sulfamethoxazole (28%), and ciprofloxacin (29.6%). ESBL-EC isolates from urological and non-urological patients showed similar susceptibility profiles. However, ESBL-EC isolates from urological patients were significantly less susceptible to ciprofloxacin compared to non-urological isolates (14.7 vs. 32.7%, p < 0.05). CONCLUSIONS: The rate of urinary ESBL-EC isolates is increasing. Their susceptibility to nitrofurantoin, fosfomycin, and carbapenems is excellent, whereas ampicillin-clavulanate, sulfamethoxazole, and ciprofloxacin demonstrate only low susceptibility. In particular, the use of ciprofloxacin should be strictly avoided in urologic patients with suspicion for an ESBL-EC urinary tract infection as well as routine antibiotic prophylaxis prior to urological interventions if not explicit indicated by current international guidelines or local resistance patterns. PMID- 23358793 TI - Surgical resection for esophageal cancer synchronously or metachronously associated with head and neck cancer. AB - BACKGROUND: Esophageal cancer is frequently associated with head and neck cancer, and esophagectomy is usually difficult in such a case. The purpose of this study was to clarify the clinical significance of esophagectomy for patients with esophageal cancer associated either synchronously or metachronously with head and neck cancer. METHODS: The clinical outcomes of surgical resections for esophageal cancer were compared between 26 patients with head and neck cancer (double cancer group) and 176 without head and neck cancer (control group). RESULTS: Staged operations were performed in 5 patients in the double cancer group, while microvascular anastomosis as well as a muscle flap was added for 3 and 4 patients, respectively. The mortality and morbidity of the double cancer group were 0 and 35 %, respectively, which were not significantly different from those of the control group (3 and 31 %, respectively). There were no significant differences in overall survival in the double cancer and control groups, which had 5-year survival rates of 59 and 49 %, respectively. CONCLUSIONS: Esophagectomy can be an effective treatment when techniques are adopted that are appropriate for each case, such as staged operations, muscular flaps, and microvascular anastomosis, even in patients with double cancers of the esophagus and the head and neck. PMID- 23358792 TI - Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers. AB - BACKGROUND: Despite regular surveillance colonoscopy, the metachronous colorectal cancer risk for mismatch repair (MMR) gene mutation carriers after segmental resection for colon cancer is high and total or subtotal colectomy is the preferred option. However, if the index cancer is in the rectum, management decisions are complicated by considerations of impaired bowel function. We aimed to estimate the risk of metachronous colon cancer for MMR gene mutation carriers who underwent a proctectomy for index rectal cancer. METHODS: This retrospective cohort study comprised 79 carriers of germline mutation in a MMR gene (18 MLH1, 55 MSH2, 4 MSH6, and 2 PMS2) from the Colon Cancer Family Registry who had had a proctectomy for index rectal cancer. Cumulative risks of metachronous colon cancer were calculated using the Kaplan-Meier method. RESULTS: During median 9 years (range 1-32 years) of observation since the first diagnosis of rectal cancer, 21 carriers (27 %) were diagnosed with metachronous colon cancer (incidence 24.25, 95 % confidence interval [CI] 15.81-37.19 per 1,000 person years). Cumulative risk of metachronous colon cancer was 19 % (95 % CI 9-31 %) at 10 years, 47 (95 % CI 31-68 %) at 20 years, and 69 % (95 % CI 45-89 %) at 30 years after surgical resection. The frequency of surveillance colonoscopy was 1 colonoscopy per 1.16 years (95 % CI 1.01-1.31 years). The AJCC stages of the metachronous cancers, where available, were 72 % stage I, 22 % stage II, and 6 % stage III. CONCLUSIONS: Given the high metachronous colon cancer risk for MMR gene mutation carriers diagnosed with an index rectal cancer, proctocolectomy may need to be considered. PMID- 23358794 TI - Breast cancer prevention knowledge, attitudes, and behaviors among college women and mother-daughter communication. AB - Although breast cancer prevention targets mostly women ages 40 and older, little is known about breast cancer prevention for young women and mother's advice. The purpose of this study was to examine breast cancer prevention knowledge, attitudes, and behaviors among college women and mother-daughter communication. Hispanic and non-Hispanic students at a southwestern university completed a breast cancer prevention survey with items for mother's advice, breast self awareness and risk reduction knowledge, self-efficacy, susceptibility, family history, provider breast self-exam (BSE) recommendation, peer norms, BSE practice, and demographics. An openended item was also used to elicit types of mother's advice. Logistic regression was used to assess predictors for receiving mother's advice for breast cancer prevention and BSE practice. Self-reported data using a survey were obtained from 546 college women with a mean age of 23.3 (SD = 7.75). Nearly 36 % received mothers' advice and 55 % conducted BSE. Predictors for receiving mother's advice were age, self-efficacy, and family history of breast cancer. Predictors for BSE practice were mother's advice, age, self efficacy, and provider BSE recommendation. Family history of breast cancer and knowledge were not significant predictors for BSE practice. Findings support the need for clinicians, community health educators, and mothers to provide breast cancer prevention education targeting college women. PMID- 23358795 TI - Linking the evolution of habitat choice to ecosystem functioning: direct and indirect effects of pond-reproducing fire salamanders on aquatic-terrestrial subsidies. AB - Shifts in life history traits and in the behaviour of species can potentially alter ecosystem functioning. The reproduction of the central European fire salamander (Salamandra salamandra), which usually deposits its larvae in first order streams, in small pool and pond-like habitats, is an example of a recent local adaptation in this species. Here we aimed to quantify the direct and indirect effects of the predatory larvae on the aquatic food webs in the ponds and on the flux of matter between the ponds and adjacent terrestrial habitats. Our estimates are based on biomass data of the present pond fauna as well as on the analysis of stomach content data, growth rates and population dynamics of the salamander larvae in pond habitats. By their deposition of larvae in early spring, female fire salamanders import between 0.07 and 2.86 g dry mass m(-2) larval biomass into the ponds. Due to high mortality rates in the larval phase and the relatively small size at metamorphosis of the pond-adapted salamanders compared to stream-adapted ones, the biomass export of the metamorphosed salamanders clearly falls below the initial biomass import. Catastrophic events such as high water temperatures and low oxygen levels may even occasionally result in mass mortalities of salamander larvae and thus in a net 100 % import of the salamander biomass into the pond food webs. Indirect effects further accelerate this net import of matter into the aquatic habitat, e.g. the feeding of salamanders on aquatic insect larvae with the emergence of terrestrial adults thus preventing export-and on terrestrial organisms that fall on the water surface (supporting import). This study demonstrates that the adaptation of salamanders to pond reproduction can alter food web linkages across ecosystem boundaries by enhancing the flux of materials and energy from terrestrial (i.e. forest) to the aquatic (i.e. pond) habitat. PMID- 23358796 TI - The value in the evidence: teaching residents to "choose wisely". AB - The Accreditation Council for Graduate Medical Education mandates that training physicians "incorporate considerations of cost awareness" into practice. However, medical education has traditionally avoided addressing costs, and most residency programs currently lack curricula to fulfill this requirement. With the recent widespread emphasis on unsustainable costs, inefficiencies, and waste in healthcare, the need to appropriately train physicians in this domain is increasingly apparent. In this article, we describe the implementation of a resident-led, case-based cost awareness curriculum for medicine residents at the University of California, San Francisco, sharing our keys to success and defining guiding principles. PMID- 23358798 TI - Mathematical model of growth factor driven haptotaxis and proliferation in a tissue engineering scaffold. AB - Motivated by experimental work (Miller et al. in Biomaterials 27(10):2213-2221, 2006, 32(11):2775-2785, 2011) we investigate the effect of growth factor driven haptotaxis and proliferation in a perfusion tissue engineering bioreactor, in which nutrient-rich culture medium is perfused through a 2D porous scaffold impregnated with growth factor and seeded with cells. We model these processes on the timescale of cell proliferation, which typically is of the order of days. While a quantitative representation of these phenomena requires more experimental data than is yet available, qualitative agreement with preliminary experimental studies (Miller et al. in Biomaterials 27(10):2213-2221, 2006) is obtained, and appears promising. The ultimate goal of such modeling is to ascertain initial conditions (growth factor distribution, initial cell seeding, etc.) that will lead to a final desired outcome. PMID- 23358799 TI - Modeling secondary messenger pathways in neurovascular coupling. AB - Neurovascular coupling is the well-documented link between neural stimulation and constriction or dilation of the surrounding vasculature. Glial cells mediate this response via their unique anatomy, which connects neurons to arterioles. It is believed that calcium transients and the release of secondary messengers by these cells influence the vascular response. We present a model of intracellular calcium dynamics in an astrocyte (glial cell) and show that stable oscillatory behaviour is possible under certain conditions. We then couple this to a novel model for the relationship between calcium concentration and the production of vasoactive secondary messengers through a fatty-acid intermediate. The two secondary messengers modelled are epoxyeicosatrienoic and 20 hydroxyeicosatetraenoic acids (EET and 20-HETE, respectively). These secondary messengers are produced on different time scales, and we show how this supports the observation that the vasculature dilates rapidly in response to neural stimulation, before returning to baseline levels on a slower time scale. PMID- 23358800 TI - Relationship of 14-3-3zeta (zeta), HIF-1alpha, and VEGF expression in human brain gliomas. AB - Accumulating evidence suggests that tissue hypoxia and apoptosis play important roles in the malignant progression of brain tumors. We investigated the relationship of 14-3-3zeta (an apoptosis-related protein), HIF-1alpha, and VEGF immunohistochemistry, and evaluated the prognostic value of their expression in human brain gliomas. A semiquantitative analysis of the immunoreactivity scores (IRSs) of the 14-3-3zeta, HIF-1alpha, and VEGF proteins was performed in 27 patients with various grades of gliomas. The IRS of 14-3-3zeta increased with tumor grade, with grade IV gliomas having the highest score (P < 0.05). Similar results were found for the IRSs of HIF-1alpha and VEGF (P < 0.05). A significant positive correlation was found between the IRSs of 14-3-3zeta and HIF-1alpha, 14 3-3zeta and VEGF, and HIF-1alpha and VEGF (P < 0.001 for all). The survival time of HIF-1alpha in grade III and grade IV glioma patients with low IRSs (0-6) was significantly longer than that in such glioma patients with high IRSs (8-12) (P < 0.05). These data indicate that 14-3-3zeta, HIF-1alpha, and VEGF are involved in the same cascade of the malignant progression of gliomas. Further studies will elucidate their detailed role in the malignant progression of glioma, and will contribute to the development of a new treatment strategy for this lethal disease. PMID- 23358801 TI - Modeling and in vitro experimental validation for kinetics of the colonoscope in colonoscopy. AB - Colonoscopy is the most sensitive and specific means for detection of colon cancers and polyps. To make colonoscopy more effective several problems must be overcome including: pain associated with the procedure, the risk of perforation, and incomplete intubation colonoscopy. Technically, these problems are the result of loop formation during colonoscopy. Although, several solutions such as modifying the stiffness of the colonoscope, using an overtube and developing image-guided instruments have been introduced to resolve the looping problem, the results of these systems are not completely satisfactory. A new paradigm to overcome loop formation is proposed that is doctor-assistive colonoscopy. In this approach, the endoscopists performance is enhanced by providing using a kinetic model that provides information such as the shape of the scope, direction of the colon and forces exerted within certain sections. It is expected that with the help of this model, the endoscopist would be able to adjust the manipulation to avoid loop formation. In the present studies, the kinetic model is developed and validated using an ex vivo colonoscopy test-bed with a comprehensive kinematic and kinetic data collection. The model utilizes an established colon model based on animal tissue with position tracking sensors, contact force sensors for the intraluminal portion of the scope and a Colonoscopy Force Monitor for the external insertion tube. PMID- 23358802 TI - An in vitro study on the deposition of micrometer-sized particles in the extrathoracic airways of adults during tidal oral breathing. AB - Deposition of particles in the aerodynamic diameter range of 0.5-6.7 MUm was measured in nine replicas of the extrathoracic airways of adults with four sinusoidal patterns and oral breathing. The four chosen breathing patterns are typical of those occurring during natural resting breathing and during nebulization therapy. Additionally, deposition of micrometer-sized particles in the "Alberta Idealized Adult Throat," which was previously found useful in simulating the average deposition of particles during inhalation of constant flow rates, was measured during inhalation of the four sinusoidal patterns in this study. To reduce intersubject scatter in developing predictive correlations, the non-dimensional Reynolds (Re) and Stokes (Stk) numbers are used with the square root of the average cross sectional area of the oral airways as the characteristic diameter being found to reduce intersubject variability to the highest extent. Our best fit to the deposition data is given by eta = [1 - 1/(1.51 x 10(5)(Stk(3.03)Re(0.25)) + 1)] x 100. Moreover, the "Alberta Idealized Adult Throat" is found to mimic average deposition, given in past in vivo studies, in the upper airways of adults during natural tidal breathing. PMID- 23358803 TI - Ultrasound diagnosis of urethral calculi. PMID- 23358804 TI - Juvenile morphology: a clue to the origins of the most mysterious of mysticetes? AB - The origin of the pygmy right whale (Caperea marginata) has long been one of the most vexing conundrums of marine mammal evolution. The extremely disparate skeletal structure of Caperea and a patchy fossil record have left morphology and molecules at odds: whereas most morphological analyses ally Caperea with right whales (Balaenidae), most molecular studies instead suggest a close relationship with rorquals (Balaenopteridae) and grey whales (Eschrichtiidae). The morphological evidence supporting a Caperea-balaenid clade consists of several shared features of the skull and mandible, as traditionally observed in adult individuals. Here, we show that at least two of these features, the ascending process of the maxilla and the coronoid process, arise from substantially different precursors early during ontogeny and therefore likely do not represent genuine synapomorphies. Both of these juvenile morphologies have adult counterparts in the fossil record, thus indicating that the ontogenetic variation in the living species may be a genuine reflection of differing ancestral states. This new evidence contradicts previous morphological hypotheses on the origins of Caperea and may help to reconcile morphological and molecular evidence. PMID- 23358805 TI - The influence of body movements on children's perception of music with an ambiguous expressive character. AB - The theory of embodied music cognition states that the perception and cognition of music is firmly, although not exclusively, linked to action patterns associated with that music. In this regard, the focus lies mostly on how music promotes certain action tendencies (i.e., dance, entrainment, etc.). Only recently, studies have started to devote attention to the reciprocal effects that people's body movements may exert on how people perceive certain aspects of music and sound (e.g., pitch, meter, musical preference, etc.). The present study positions itself in this line of research. The central research question is whether expressive body movements, which are systematically paired with music, can modulate children's perception of musical expressiveness. We present a behavioral experiment in which different groups of children (7-8 years, N = 46) either repetitively performed a happy or a sad choreography in response to expressively ambiguous music or merely listened to that music. The results of our study show indeed that children's perception of musical expressiveness is modulated in accordance with the expressive character of the dance choreography performed to the music. This finding supports theories that claim a strong connection between action and perception, although further research is needed to uncover the details of this connection. PMID- 23358806 TI - Mast Cells in Adjacent Normal Colon Mucosa rather than Those in Invasive Margin are Related to Progression of Colon Cancer. AB - OBJECTIVE: Mast cells (MC) reside in the mucosa of the digestive tract as the first line against bacteria and toxins. Clinical evidence has implied that the infiltration of mast cells in colorectal cancers is related to malignant phenotypes and a poor prognosis. This study compared the role of mast cells in adjacent normal colon mucosa and in the invasive margin during the progression of colon cancer. METHODS: Specimens were obtained from 39 patients with colon adenomas and 155 patients with colon cancers treated at the Sun Yat-sen University Cancer Center between January 1999 and July 2004. The density of mast cells was scored by an immunohistochemical assay. The pattern of mast cell distribution and its relationship with clinicopathologic parameters and 5-year survival were analyzed. RESULTS: The majority of mast cells were located in the adjacent normal colon mucosa, followed by the invasive margin and least in the cancer stroma. Mast cell count in adjacent normal colon mucosa (MCC(adjacent)) was associated with pathologic classification, distant metastases and hepatic metastases, although it was not a prognostic factor. In contrast, mast cell count in the invasive margin (MCC(invasive)) was associated with neither the clinicopathlogic parameters nor overall survival. CONCLUSION: Mast cells in the adjacent normal colon mucosa were related to the progression of colon cancer, suggesting that mast cells might modulate tumor progression via a long-distance mechanism. PMID- 23358807 TI - Examination of Veterans Affairs disability compensation as a disincentive for employment in a population-based sample of Veterans under age 65. AB - PURPOSE: Concerns that disability benefits may create disincentives for employment may be especially relevant for young American military veterans, particularly veterans of the recent wars in Iraq and Afghanistan who are facing a current economic recession and turning in large numbers to the Department of Veterans Affairs (VA) for disability compensation. This study describes the rate of employment and VA disability compensation among a nationally representative sample of veterans under the age of 65 and examines the association between levels of VA disability compensation and employment, adjusting for sociodemographics and health status. METHODS: Data on a total of 4,787 veterans from the 2010 National Survey of Veterans were analyzed using multinomial logistic regressions to compare employed veterans with two groups that were not employed. RESULTS: Two-thirds of veterans under the age of 65 were employed, although only 36 % of veterans with a VA service-connected disability rating of 50 % or higher were employed. Veterans who received no VA disability compensation or who were service-connected 50 % or more were more likely to be unemployed and not looking for employment than veterans who were not service-connected or were service-connected less than 50 %, suggesting high but not all levels of VA disability compensation create disincentives for employment. Results were similar when analyses were limited to veterans who served in Iraq and Afghanistan. CONCLUSIONS: Education and vocational rehabilitation interventions, as well as economic work incentives, may be needed to maximize employment among veterans with disabilities. PMID- 23358808 TI - Cross-cultural adaptation of the Work Role Functioning Questionnaire to Spanish spoken in Spain. AB - PURPOSE: The Work Role Functioning Questionnaire (WRFQ) is a tool developed in the United States to measure work disability and assess the perceived impact of health problems on worker ability to perform jobs. We translated and adapted the WRFQ to Spanish spoken in Spain and assessed preservation of its psychometric properties. METHODS: Cross-cultural adaptation of the WRFQ was performed following a systematic 5-step procedure: (1) direct translation, (2) synthesis, (3) back-translation, (4) consolidation by an expert committee and (5) pre-test. Psychometric properties were evaluated by administering the questionnaire to 40 patients with different cultural levels and health problems. Applicability, usability, readability and integrity of the WRFQ were assessed, together with its validity and reliability. RESULTS: Questionnaire translation, back translation and consolidation were carried out without relevant difficulties. Idiomatic issues requiring reformulation were found in the instructions, response options and in 2 items. Participants appreciated the applicability, usability, readability and integrity of the questionnaire. The results indicated good face and content validity. Internal consistency was satisfactory for all subscales (Cronbach's alpha between 0.88 and 0.96), except for social demands (Cronbach's alpha = 0.56). Test-retest reliability showed good stability, with intraclass correlation coefficients between 0.77 and 0.93 for all subscales. Construct validity was considered preserved based on the comparison of median scores for each patient group and subscale. CONCLUSIONS: Our results indicate the cross cultural adaptation of the WRFQ to Spanish was satisfactory and preserved its psychometric properties, except for the subscale of social demands, whose internal consistency should be interpreted with caution. PMID- 23358809 TI - Effectiveness of a coordinated and tailored return-to-work intervention for sickness absence beneficiaries with mental health problems. AB - PURPOSE: Sickness absence and exclusion from the labour market due to mental health problems (MHPs) is a growing concern in many countries. Knowledge about effective return-to-work (RTW) intervention models is still limited, but a multidisciplinary, coordinated and tailored approach has shown promising results in the context of musculoskeletal disorders. The purpose of this study was to assess the effectiveness of this approach as implemented among sickness absence beneficiaries with MHPs. METHODS: In a quasi-randomised, controlled trial, we assessed the intervention's effect in terms of time to RTW and labour market status after 1 year. We used two different analytical strategies to compare time to RTW between participants receiving the intervention (n = 88) and those receiving conventional case management (n = 80): (1) a traditional multivariable regression analysis controlling for measured confounding, and (2) an instrumental variable (IV) analysis controlling for unmeasured confounding. RESULTS: The two analytical approaches provided similar results in terms of a longer time to RTW among recipients of the intervention (HR = 0.50; 95 % CI 0.34-0.75), although the estimate provided by the IV-analysis was non-significant (HR = 0.70; 95 % CI 0.23 2.12). After 1 year, more recipients of the intervention than of conventional case management were receiving sickness absence benefits (p = 0.031). CONCLUSION: The intervention delayed RTW compared to conventional case management, after accounting for measured confounding. The delayed RTW may be due to either implementation or program failure, or both. It may also reflect the complexity of retaining employees with mental health problems in the workplace. PMID- 23358810 TI - Lifetime HIV antiretroviral therapy adherence intervention: timing is everything: comment on "Managed problem solving for antiretroviral therapy adherence". PMID- 23358811 TI - Effect of fermentation inhibitors in the presence and absence of activated charcoal on the growth of Saccharomyces cerevisiae. AB - The acidic hydrolysis of biomass generates numerous inhibitors of fermentation, which adversely affect cell growth and metabolism. The goal of the present study was to determine the effects of fermentation inhibitors on growth and glucose consumption by Saccharomyces cerevisiae. We also conducted in situ adsorption during cell cultivation in synthetic broth containing fermentation inhibitors. In order to evaluate the effect of in situ adsorption on cell growth, five inhibitors, namely 5-hydroxymethylfurfural, levulinic acid, furfural, formic acid, and acetic acid, were introduced into synthetic broth. The existence of fermentation inhibitors during cell culture adversely affects cell growth and sugar consumption. Furfural, formic acid, and acetic acid were the most potent inhibitors in our culture system. The in situ adsorption of inhibitors by the addition of activated charcoal to the synthetic broth increased cell growth and sugar consumption. Our results indicate that detoxification of fermentation media by in situ adsorption may be useful for enhancing biofuel production. PMID- 23358812 TI - Construction of non-invasively constitutive expression vectors using a metagenome derived promoter for soluble expression of proteins. AB - Expression of soluble and functional proteins has been one of the critical challenges to many aspects of synthetic biology, metabolic and protein engineering. Among the current methods for expression of target proteins, constitutive expression systems offer several advantages over inducible systems, which require a chemical or physical inducer. In a previous study, a G196 DNA fragment containing constitutive promoters was mined from the soil metagenome and evaluated for the expression of target proteins in the functional and soluble state. In this study, we further improved this system by constructing a series of constitutive expression vectors, pCEM (using the CEM promoter trimmed from G196), pCEMT (incorporating rrnB T1 and T2 terminator into the downstream region of MCS in pCEM) and pRCEMT (grafting the cis-acting region of pCEMT into a low-copy number plasmid). Subsequently, genes encoding GFPuv, esterase 1767 and beta glucosidase were subcloned into the resulting vectors, and their expression level and solubility were compared with those of IPTG-inducible vector systems pQE30 and pTrc99A. The extent of homogeneity and the ratio of the soluble fraction in the pRCEMT vector were relatively higher, without any delay of growth rate, than that of the pQE30 or pTrc99A. These results indicate that new expression vectors with moderate constitutive function could more easily lead to a homogenous population of cells expressing target proteins than those with conventionally inducible promoters. PMID- 23358813 TI - Clinical and CT imaging features of pancreatic acinar cell carcinoma. AB - PURPOSE: This study was undertaken to analyse the clinical characteristics and computed tomography (CT) imaging features of patients with pancreatic acinar cell carcinoma and to clarify characteristic imaging features. MATERIALS AND METHODS: Clinical and CT imaging records of ten patients with pancreatic acinar cell carcinoma (three women and seven men; mean age, 58 years) examined using multidetector CT scanners were retrospectively studied. CT features emphasised included lesion location, size, shape, margin, solid or cystic component, density and enhancement. Imaging results were correlated with intraoperative surgical and pathological results. RESULTS: Lesions were distributed throughout the pancreatic head (n=3), body (n=3), tail (n=2) and both body and tail (n=2). The average diameter was 6.1 cm, varying from 2.3 cm to 15.8 cm. The tumours were round or oval (n=7) or lobular (n=3). Seven tumours appeared as enhanced solid pancreatic masses, with the large masses having hypodense areas; three had >75 % cystic component; seven (70%), including four solid and three cystic masses, had well circumscribed or partially well-defined thin, enhanced encapsulation. After contrast injection, the masses presented heterogeneous enhancement. CONCLUSIONS: Acinar cell carcinoma should always be considered when a large pancreatic mass with typical imaging is found in solid masses with variably sized central cystic areas or cystic masses. PMID- 23358814 TI - Neoadjuvant oxaliplatin and 5-fluorouracil with concurrent radiotherapy in patients with locally advanced rectal cancer: a single-institution experience. AB - PURPOSE: The aim of this study was to evaluate the rate of pathological response (PR), disease control and safety of neoadjuvant chemotherapy using oxaliplatin (OX) and 5-fluorouracil (5-FU) with concurrent radiotherapy for treating locally advanced rectal cancer. MATERIALS AND METHODS: Between November 2002 and December 2010, 90 patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy (CRT) were retrospectively analysed. All patients underwent preoperative radiotherapy (45 Gy in 1.8-Gy fractions) with concurrent OX (80 mg/m(2) i.v., day 1) and a 120-h continuous infusion of 5-FU (1,000 mg/m(2) per day). Surgery was performed within 6 weeks after completion of CRT treatment. RESULTS: Complete pathological response was obtained in six patients (6.7%), and 39 (43.3%) had their disease downstaged. The median follow-up period was 4.7 years (6 months to 9 years). Local recurrence occurred in two patients (2.2%), one of whom developed also liver metastases. Distant metastases not associated with local relapse occurred in 23 (25.6%) patients. Overall (OS) and disease-free (DFS) survival were 62.9% and 52.8%, respectively. CRT was well tolerated, with only one grade 3 (1.2%) haematological toxicity (neutropaenia). CONCLUSIONS: Neoadjuvant systemic chemotherapy based on OX and 5-UC associated with radiotherapy is well tolerated, with good results in terms of pathological response, disease control and survival, in rectal cancer patients. PMID- 23358815 TI - Virtual autopsy using multislice computed tomography in forensic medical diagnosis of drowning. AB - PURPOSE: This study evaluated the usefulness of multidetector computed tomography (MDCT) in the postmortem diagnosis of death by drowning in fresh water by measuring the difference of blood density within the cardiac chambers. MATERIALS AND METHODS: Twenty-two corpses including six cases of fresh-water drowning (group A) and 16 deaths by other causes (group B), among which were also different forms of mechanical asphyxia other than drowning, underwent MDCT and conventional autopsy. Blood density within the right and left heart chambers, the aorta and the pulmonary trunk was measured and values compared between groups and within each group between heart chambers. RESULTS: Blood density in all cardiac chambers was lower in group A than in group B. The difference was statistically significant within the left atrium and ventricle and was significantly lower in the left than in the right heart chambers in group A only. CONCLUSIONS: MDCT, together with conventional autopsy, may contribute to the diagnosis of drowning, by measuring blood density in the heart chambers. PMID- 23358816 TI - Multidetector CT Dentascan evaluation of bone regeneration obtained with deproteinised bovine graft in residual cavity after mandibular cyst enucleation. AB - PURPOSE: This study compared spontaneous bone healing and regeneration obtained with deproteinised bovine graft in residual cavities after mandibular cyst enucleation using computed tomography (CT) Dentascan. MATERIALS AND METHODS: Eighty patients with a radiological diagnosis of mandibular cyst underwent surgical enucleation. Patients were divided into a control group (spontaneous healing, 40 patients) and a test group (deproteinised bovine graft, 40 patients). All patients underwent follow-up CT Dentascan 12 months after the procedure. For each residual cavity, apical-coronal and mesial-distal distance, average pixel intensity and volume were calculated and results compared between two groups using the t test. RESULTS: The control group showed mean volume, apical-coronal and mesial-distal distance of 703.2 +/- 185.3 mm(3), 28.6 +/- 9.4 mm and 25 +/- 2.84 mm, respectively. In the test group, values were 738.2 +/- 189.2 mm(3), 27.5 +/- 3.6 mm and 25.3 +/- 2.97 mm, respectively. There was no statistically significant difference between groups. Average pixel intensity was 1,102.8 +/- 124.3 in the test group and 624.9 +/- 133.3 in the control group, with a significant difference between groups (p<0.0001). CONCLUSIONS: The significantly higher average pixel intensity observed in the test group demonstrates the cavalue of treatment with biomaterials to obtain earlier bone regeneration. PMID- 23358818 TI - The PROCAINA (PROstate CAncer INdication Attitudes) Project (Part I): a survey among Italian radiation oncologists on postoperative radiotherapy in prostate cancer. AB - PURPOSE: Radiotherapy (RT) has an established role in the postoperative treatment of prostate cancer patients with extracapsular extension, positive surgical margins or a detectable post-operative prostate-specific antigen (PSA). Despite the large number of patients treated with postoperative RT, some issues about optimal technique, doses, volumes, timing and association with androgen deprivation are still subject of debate. The aim of this survey was to determine the patterns of choice of Italian radiation oncologists in two different clinical cases of postoperative prostate cancer patients. STUDY DESIGN: During the 2010 National Congress of the Italian Association of Radiation Oncology (AIRO), four clinical cases were presented to the attending radiation oncologists. Two of them were cases of postoperative prostate cancer, differing in T stage of the primary tumour according to the TNM classification, preoperative staging procedures, preoperative PSA (iPSA), Gleason score of biopsies and definitive pathological specimen after surgery and postoperative PSA. For each clinical case, the radiation oncologists were asked to: (a) give indication to new pre-treatment procedures for staging; b) give indication to postoperative treatment; (c) to define specifically, where indicated, the total dose, type of fractionation, treatment volumes, type of technique, type of image-guided setup control; (d) indicate whether adjuvant hormonal therapy should be prescribed; (e) define criteria that mostly influenced the prescription. A descriptive statistical analysis was then performed. RESULTS: A total of 300 questionnaires were distributed amongst radiation oncologists attending the congress; 128 were completed and considered for this analysis (41%). Some important differences were shown in prescribing and performing postoperative radiotherapy, and some significant differences with international guidelines and data available from the literature were also reviewed and discussed. CONCLUSIONS: Despite the results of clinical trials, significant differences still exist among Italian radiation oncologists in deciding postoperative treatment in prostate cancer patients. These patients probably deserve a more uniform approach based on updated, detailed and evidence-based recommendations. PMID- 23358817 TI - Rationale, design and methods of CTCA-PRORECAD (Computed Tomography Coronary Angiography Prognostic Registry for Coronary Artery Disease): a multicentre and multivendor registry. AB - PURPOSE: This study was done to assess the prognostic value of computed tomography coronary angiography (CTCA) in a large multicentre population of patients with suspected coronary artery disease (CAD) and, in particular, its incremental value compared with traditional methods for risk stratification. MATERIALS AND METHODS: This is a retrospective observational study that began in January 2003 conducted on patients with suspected CAD assessed with CTCA on the basis of symptoms (chest pain, dyspnoea) and/or abnormal or equivocal stress test and/or a high cardiovascular risk profile. The participating centres will provide data obtained with CTCA performed with 16-slice or higher equipment. Exclusion criteria are renal insufficiency, allergy to iodinated contrast material, pregnancy and previous myocardial infarction or revascularisation (percutaneous coronary intervention and/or coronary artery bypass graft). All patients are stratified by means of clinical assessment and/or data retrieved from a clinical database. Risk factors considered are hypertension, dyslipidaemia, diabetes mellitus, smoking, family history and obesity. Symptoms are classified as absent, typical chest pain, atypical chest pain and dyspnoea. Primary endpoints are death, major adverse cardiovascular events (cardiac death, unstable angina requiring hospitalisation, acute myocardial infarction) and shifting of cardiovascular risk category on the basis of coronary plaque burden. The secondary endpoint is coronary revascularisation. Telephone interviews and/or clinical databases are used for the follow-up. The study will be conducted on a population >1,000 patients. CONCLUSIONS: The information collected from the Prognostic Registry for Coronary Artery Disease (PRORECAD) will provide insight into the prognostic value of CTCA in addition to demographic and clinical features. The results will allow for better use and interpretation of CTCA for prognostic purposes. PMID- 23358820 TI - Definitely NOT Just another Hernia. PMID- 23358819 TI - Single-step multimodal locoregional treatment for unresectable hepatocellular carcinoma: balloon-occluded percutaneous radiofrequency thermal ablation (BO-RFA) plus transcatheter arterial chemoembolization (TACE). AB - PURPOSE: This study was undertaken to evaluate the feasibility, safety and efficacy of a new combined single-step therapy in patients with unresectable multinodular unilobar hepatocellular carcinoma (HCC), with at least one lesion >3 cm, with balloon-occluded radiofrequency ablation (BO-RFA) plus transcatheter arterial chemoembolization (TACE) of the main lesion and TACE of the other lesions. The second purpose of our study was to compare the initial effects in terms of tumour necrosis of this new combined therapy with those obtained in a matched population treated with TACE alone in a singlestep treatment in our centre in the previous year. METHODS AND MATERIALS: This pilot study was approved by the institutional review board, and informed consent was obtained from all patients. Ten consecutive patients with multinodular (two to six nodules) unilobar unresectable HCC and with a main target lesion >3 cm (range, 3.5-6 cm) not suitable for curative therapy were enrolled in our single-centre multidisciplinary pilot study. The schedule consisted of percutaneous RFA (single 3-cm monopolar needle insertion) of the target lesion during occlusion of the hepatic artery supplying the tumour, followed by selective TACE, plus lobar TACE for other lesions (450-mg carboplatin and lipiodol plus temporary embolisation with SPONGOSTAN). Adverse events and intra- and periprocedural complications were clinically assessed. Early local efficacy was evaluated on 1-month follow-up multiphasic computed tomography (CT) on the basis of the Modified Response Evaluation Criteria in Solid Tumors (m-RECIST). A separate evaluation of target lesions in terms of enhancement, necrotic diameter and presence and distribution of lipiodol uptake was also performed. RESULTS: No major complications occurred. Overall technical success, defined as complete devascularisation of all nodules during the arterial phase, was achieved in seven of 10 patients, with three cases of partial response (persistence of small hypervascular nodules). When considering only target lesions, technical success was obtained in all patients, with a nonenhancing area corresponding in shape to the previously identified HCC (necrotic diameter, 3.5-5 cm) and with circumferential peripheral lipiodol uptake (safety margin) of at least 0.5 cm (0.5-1.3cm). CONCLUSIONS: TACE and BO-RFA, plus TACE in a singlestep approach seems to be a safe and effective combined therapy for treating advanced, unresectable HCC lesions, allowing a high rate of complete local response to be achieved in large lesions also. PMID- 23358821 TI - Lewis acid catalysis of phosphoryl transfer from a copper(II)-NTP complex in a kinase ribozyme. AB - The chemical strategies used by ribozymes to enhance reaction rates are revealed in part from their metal ion and pH requirements. We find that kinase ribozyme K28(1-77)C, in contrast with previously characterized kinase ribozymes, requires Cu(2+) for optimal catalysis of thiophosphoryl transfer from GTPgammaS. Phosphoryl transfer from GTP is greatly reduced in the absence of Cu(2+), indicating a specific catalytic role independent of any potential interactions with the GTPgammaS thiophosphoryl group. In-line probing and ATPgammaS competition both argue against direct Cu(2+) binding by RNA; rather, these data establish that Cu(2+) enters the active site within a Cu(2+)*GTPgammaS or Cu(2+)*GTP chelation complex, and that Cu(2+)*nucleobase interactions further enforce Cu(2+) selectivity and position the metal ion for Lewis acid catalysis. Replacing Mg(2+) with [Co(NH3)6](3+) significantly reduced product yield, but not kobs, indicating that the role of inner-sphere Mg(2+) coordination is structural rather than catalytic. Replacing Mg(2+) with alkaline earths of increasing ionic radii (Ca(2+), Sr(2+) and Ba(2+)) gave lower yields and approximately linear rates of product accumulation. Finally, we observe that reaction rates increased with pH in log-linear fashion with an apparent pKa = 8.0 +/- 0.1, indicating deprotonation in the rate-limiting step. PMID- 23358823 TI - Probing the activity of diguanylate cyclases and c-di-GMP phosphodiesterases in real-time by CD spectroscopy. AB - Bacteria react to adverse environmental stimuli by clustering into organized communities called biofilms. A remarkably sophisticated control system based on the dinucleotide 3'-5' cyclic diguanylic acid (c-di-GMP) is involved in deciding whether to form or abandon biofilms. The ability of c-di-GMP to form self intercalated dimers is also thought to play a role in this complex regulation. A great advantage in the quest of elucidating the catalytic properties of the enzymes involved in c-di-GMP turnover (diguanylate cyclases and phosphodiesterases) would come from the availability of an experimental approach for in vitro quantification of c-di-GMP in real-time. Here, we show that c-di-GMP can be detected and quantified by circular dichroism (CD) spectroscopy in the low micromolar range. The method is based on the selective ability of manganese ions to induce formation of the intercalated dimer of the c-di-GMP dinucleotide in solution, which displays an intense sigmoidal CD spectrum in the near-ultraviolet region. This characteristic spectrum originates from the stacking interaction of the four mutually intercalated guanines, as it is absent in the other cyclic dinucleotide 3'-5' cyclic adenilic acid (c-di-AMP). Thus, near-ultraviolet CD can be used to effectively quantify in real-time the activity of diguanylate cyclases and phosphodiesterases in solution. PMID- 23358824 TI - Fast and accurate read mapping with approximate seeds and multiple backtracking. AB - We present Masai, a read mapper representing the state-of-the-art in terms of speed and accuracy. Our tool is an order of magnitude faster than RazerS 3 and mrFAST, 2-4 times faster and more accurate than Bowtie 2 and BWA. The novelties of our read mapper are filtration with approximate seeds and a method for multiple backtracking. Approximate seeds, compared with exact seeds, increase filtration specificity while preserving sensitivity. Multiple backtracking amortizes the cost of searching a large set of seeds by taking advantage of the repetitiveness of next-generation sequencing data. Combined together, these two methods significantly speed up approximate search on genomic data sets. Masai is implemented in C++ using the SeqAn library. The source code is distributed under the BSD license and binaries for Linux, Mac OS X and Windows can be freely downloaded from http://www.seqan.de/projects/masai. PMID- 23358822 TI - Genome-wide localization of exosome components to active promoters and chromatin insulators in Drosophila. AB - Chromatin insulators are functionally conserved DNA-protein complexes situated throughout the genome that organize independent transcriptional domains. Previous work implicated RNA as an important cofactor in chromatin insulator activity, although the precise mechanisms are not yet understood. Here we identify the exosome, the highly conserved major cellular 3' to 5' RNA degradation machinery, as a physical interactor of CP190-dependent chromatin insulator complexes in Drosophila. Genome-wide profiling of exosome by ChIP-seq in two different embryonic cell lines reveals extensive and specific overlap with the CP190, BEAF 32 and CTCF insulator proteins. Colocalization occurs mainly at promoters but also boundary elements such as Mcp, Fab-8, scs and scs', which overlaps with a promoter. Surprisingly, exosome associates primarily with promoters but not gene bodies of active genes, arguing against simple cotranscriptional recruitment to RNA substrates. Similar to insulator proteins, exosome is also significantly enriched at divergently transcribed promoters. Directed ChIP of exosome in cell lines depleted of insulator proteins shows that CTCF is required specifically for exosome association at Mcp and Fab-8 but not other sites, suggesting that alternate mechanisms must also contribute to exosome chromatin recruitment. Taken together, our results reveal a novel positive relationship between exosome and chromatin insulators throughout the genome. PMID- 23358825 TI - The Epstein-Barr virus nuclear antigen-1 reprograms transcription by mimicry of high mobility group A proteins. AB - Viral proteins reprogram their host cells by hijacking regulatory components of protein networks. Here we describe a novel property of the Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA1) that may underlie the capacity of the virus to promote a global remodeling of chromatin architecture and cellular transcription. We found that the expression of EBNA1 in transfected human and mouse cells is associated with decreased prevalence of heterochromatin foci, enhanced accessibility of cellular DNA to micrococcal nuclease digestion and decreased average length of nucleosome repeats, suggesting de-protection of the nucleosome linker regions. This is a direct effect of EBNA1 because targeting the viral protein to heterochromatin promotes large-scale chromatin decondensation with slow kinetics and independent of the recruitment of adenosine triphosphate dependent chromatin remodelers. The remodeling function is mediated by a bipartite Gly-Arg rich domain of EBNA1 that resembles the AT-hook of High Mobility Group A (HMGA) architectural transcription factors. Similar to HMGAs, EBNA1 is highly mobile in interphase nuclei and promotes the mobility of linker histone H1, which counteracts chromatin condensation and alters the transcription of numerous cellular genes. Thus, by regulating chromatin compaction, EBNA1 may reset cellular transcription during infection and prime the infected cells for malignant transformation. PMID- 23358827 TI - Can cardiac rehabilitation programs improve functional capacity and left ventricular diastolic function in patients with mechanical reperfusion after ST elevation myocardial infarction?: A double-blind clinical trial. AB - BACKGROUND: Current guidelines recommend cardiac rehabilitation programs (CRP) as a means to improve functional status of patients after coronary revascularization. However, research supporting this recommendation has been limited and positive effects of CRP on diastolic function are controversial. The aim of this study was to examine the effects of an 8-week CRP on left ventricular diastolic function. METHODS: This randomized, clinical trial included 29 men with ST elevation myocardial infarction (MI) who had received reperfusion therapy, i.e. coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). They were randomized to a training group (n = 15; mean age: 54.2 +/- 9.04 years old) and a control group (n = 14; mean age: 51.71 +/- 6.98 years old). Patients in the training group performed an 8-week CRP with an intensity of 60 85% of maximum heart rate. Exercise sessions lasted 60-90 minutes and were held three times a week. At the start and end of the study, all patients performed symptom-limited exercise test based on Naughton treadmill protocol. Pulsed-wave Doppler echocardiography was also used to determine peak velocity of early (E) and late (A) waves, E/A ratios, and the deceleration time of E (DT). RESULTS: Left ventricular diastolic indices (E, A, E/A ratio, DT) did not change significantly after the CRP. Compared to baseline, patients in the training group had significant improvements in functional capacity (8.30 +/- 1.30 vs. 9.7 +/- 1.7) and maximum heart rate (118.50 +/- 24.48 vs. 126.85 +/- 22.75). Moreover, resting heart rate of the training group was significantly better than the control group at the end of the study (75.36 +/- 7.94 vs. 79.80 +/- 7.67; P < 0.001). CONCLUSION: An 8-week CRP in post-MI patients revascularized with PCI or CABG led to improved exercise capacity. However, the CRP failed to enhance diastolic function. PMID- 23358826 TI - Identification of a novel human mitochondrial endo-/exonuclease Ddk1/c20orf72 necessary for maintenance of proper 7S DNA levels. AB - Although the human mitochondrial genome has been investigated for several decades, the proteins responsible for its replication and expression, especially nucleolytic enzymes, are poorly described. Here, we characterized a novel putative PD-(D/E)XK nuclease encoded by the human C20orf72 gene named Ddk1 for its predicted catalytic residues. We show that Ddk1 is a mitochondrially localized metal-dependent DNase lacking detectable ribonuclease activity. Ddk1 degrades DNA mainly in a 3'-5' direction with a strong preference for single stranded DNA. Interestingly, Ddk1 requires free ends for its activity and does not degrade circular substrates. In addition, when a chimeric RNA-DNA substrate is provided, Ddk1 can slide over the RNA fragment and digest DNA endonucleolytically. Although the levels of the mitochondrial DNA are unchanged on RNAi-mediated depletion of Ddk1, the mitochondrial single-stranded DNA molecule (7S DNA) accumulates. On the other hand, overexperssion of Ddk1 decreases the levels of 7S DNA, suggesting an important role of the protein in 7S DNA regulation. We propose a structural model of Ddk1 and discuss its similarity to other PD-(D/E)XK superfamily members. PMID- 23358828 TI - Suppression of STAT5A and STAT5B chronic myeloid leukemia cells via siRNA and antisense-oligonucleotide applications with the induction of apoptosis. AB - Signal transducers and activators of transcription (STAT) proteins function in the JAK/STAT signaling pathway and are activated by phosphorylation. As a result of this signaling event, they affect many cellular processes including cell growth, proliferation, differentiation, and survival. Increases in the expressions of STAT5A and STAT5B play a remarkable role in the development of leukemia in which leukemic cells gain uncontrolled proliferation and angiogenesis ability. At the same time, these cells acquire ability to escape from apoptosis and host immune system. In this study, we aimed to suppress STAT-5A and -5B genes in K562 CML cells by siRNA transfection and antisense oligonucleotides (ODN) targeting and then to evaluate apoptosis rate. Finally, we compared the transfection efficiencies of these approaches. Quantitative RT-PCR and Western blot results indicated that STAT expressions were downregulated at both mRNA and protein levels following siRNA transfection. However, electroporation mediated ODN transfection could only provide limited suppression rates at mRNA and protein levels. Moreover, it was displayed that apoptosis were significantly induced in siRNA treated leukemic cells as compared to ODN treated cells. As a conclusion, siRNA applications were found to be more effective in terms of gene silencing when compared to ODN treatment based on the higher apoptosis and mRNA suppression rates. siRNA application could be a new and alternative curative method as a supporting therapy in CML patients. PMID- 23358830 TI - [Predictors for presence of residual tumor in follow-up transurethral resection of bladder tumors: single center results]. AB - BACKGROUND: European Association of Urology (EAU) guidelines recommend a follow up transurethral resection of bladder tumors (reTUR-B) for intermediate and high risk non-muscle invasive bladder cancer (NMIBC) 2-6 weeks after the initial resection. The purpose of this study was to find parameters which indicate the presence of residual tumor in reTUR-B and to evaluate the prognostic value. PATIENTS AND METHODS: The data from all patients treated with TUR-B between January 2005 and December 2008 were retrospectively evaluated. The residual tumor rate was correlated with age, sex, staging, grading, risk group, multifocality and surgeon's level of training. RESULTS: A total number of 555 TUR-B operations were carried out and 179 patients received reTUR-B according to the EAU guidelines. Age (p=0.8), sex (p=0.7), initial staging (p=0.2), initial grading (p=0.3) and surgeon's level of training (p=0.7) did not have an impact on the rate of residual tumor in reTUR-B. Tumors categorized as high risk according to the EAU risk score in initial TUR-B (p<0.01) and multifocality (p=0.01) were associated with significantly higher rates of residual tumor. CONCLUSIONS: A reTUR-B is strongly indicated in high risk bladder tumors as well as multifocal tumors showing a significantly increased residual tumor rate. Other clinical parameters showed no prognostic value for the existence of residual tumor in reTUR-B. PMID- 23358829 TI - New-onset systemic lupus erythematosus during pregnancy. AB - Few studies have been published focusing on the clinical features of new-onset systemic lupus erythematosus (SLE) during pregnancy. This study examined the clinical characteristics of SLE during pregnancy or puerperium. The clinical characteristics and serological parameters of 48 patients with onset of SLE during pregnancy were retrospectively compared with those of age-matched new onset SLE patients who were diagnosed in a period of more than 12 months without pregnancy (n = 65) and age-matched preeclampsia patients (n = 48). SLE tended to occur during the first and second trimesters (33 and 42 %, respectively). Lupus nephritis (LN) and severe thrombocytopenia were more commonly seen in new-onset SLE during pregnancy than in patients without pregnancy (68.8 vs 35.4 % and 25 vs 9.2 %, respectively, p < 0.05). However, pregnant patients had lower frequency of fever, arthritis, arthralgia, alopecia, oral ulcer, and hypocomplementemia than the nonpregnant controls (p < 0.05). Compared to LN patients without pregnancy (n = 23), LN patients with pregnancy (n = 33) had more prominent proteinuria and nephrotic syndrome (p < 0.05). On the other hand, when compared to patients with preeclampsia, patients with new-onset SLE during pregnancy had early onset of symptoms during gestation and were characterized by presence of fever, malar lesion, autoantibodies, hypocomplementemia, hyperuricemia, active urinary sediment, and multi-organ involvement. In conclusion, patients with their first onset of lupus during pregnancy generally have more severe disease with higher prevalence of renal and platelet involvement. PMID- 23358831 TI - [Siliconchiptechnology-based MMP-7 analysis in urine: an option for preoperative identification of lymph node metastasis in bladder cancer]. AB - BACKGROUND: Early detection of metastases in muscle-invasive bladder cancer is crucial. Current imaging techniques provide only limited sensitivity for the detection of low volume metastases. Molecular markers and new rapid analysis techniques are therefore needed to improve metastasis detection sensitivity. High urinary matrix metalloproteinase 7 (MMP 7) levels were previously shown to be correlated with the presence of lymph node metastases. In the present study we applied a new innovative antibody-based electrical biochip technology for the quantitative detection of urinary MMP 7. MATERIALS AND METHODS: Preoperative urine samples were acquired from 30 bladder cancer patients (15xN0 and 15xN1-2) who underwent cystectomy because of muscle-invasive bladder cancer. In addition, urine samples of 15 age-matched healthy individuals were also collected. The MMP 7 analyses were performed using electrical biochip technology and a standard ELISA technique in parallel. RESULTS: Urinary MMP 7 concentrations measured by biochip technology were significantly higher in patients with metastatic bladder cancer compared to those with organ-confined cancer. The sensitivity for the detection of lymph node metastases was over 70 % using the biochip technology. CONCLUSIONS: These results confirm MMP 7 as a promising metastasis marker in bladder cancer. The new electrical biochip technology provides a rapid and reliable quantitative method for measurement of protein markers in urine. PMID- 23358832 TI - [Bladder cancer in focus: update 2012 of the German Bladder Cancer Association]. AB - The German Bladder Cancer Association (DFBK) invited its members to the 3rd annual meeting 2012 in Hannover 4 years after the official founding. The meeting was directed to discuss the progress of ongoing and newly initiated projects and collaborations. In this article we will introduce current research activities and collaborations of the DFBK and would like to invite interested researchers to join this national interdisciplinary research association. The aim of the DFBK is to initiate interdisciplinary collaboration and to support scientific discussions among its members. For further information please visit our website at www.forschungsverbund-blasenkarzinom.de. PMID- 23358833 TI - [Trends in inpatient treatment in ophthalmology in Germany]. AB - BACKGROUND: Over the last decade inpatient treatment has been reduced in favor of outpatient care or markedly shortened inpatient stays in most organ-specific surgical specialties such as ophthalmology in Germany. METHODS: Data from the federal statistics agency on the international classification of disease (ICD), diagnosis-related groups (DRG) and performed operations and procedures from 2000 to 2010 as well as data from the Institute for Reimbursements of Hospitals (InEK) on average costs per DRG in every German DRG (G-DRG) version from 2004 to 2010 were analyzed for ophthalmology. RESULTS: From 2000 to 2010, the number of cases with a main ophthalmological diagnosis decreased (-19 %), which was mostly due to a reduction in the number of cataract inpatients (-56 %). All subspecialties such as glaucoma (+82 %) and retina (+68 %) with the exception of primary strabismus diagnoses (-15 %) gained in number of cases. Inpatient cataract surgery was the most common surgery in 2004 but numbers decreased to 2010 (-9 %). The most often performed inpatient procedure was vitreoretinal surgery in 2007 and 2010 (increase 2004-2010 + 46 %). Average hospital stay decreased between 2005 and 2010 from 3.9 to 3.4 days and the average cost per case increased by 3.6 % overall and by 13.4 % for surgical cases. CONCLUSION: Ophthalmic healthcare provided as inpatient services decreased with a trend towards more complex cases being treated as inpatients from 2000 to 2010. PMID- 23358836 TI - Social desirability bias in self-rated presenteeism among resident physicians. PMID- 23358837 TI - Social desirability bias in self-rated presenteeism among resident physicians- reply. PMID- 23358838 TI - Correcting the record on dietary supplement regulation. PMID- 23358839 TI - Correcting the record on dietary supplement regulation--reply. PMID- 23358840 TI - Computed tomography in the emergency department setting. PMID- 23358841 TI - Computed tomography in the emergency department setting--reply. PMID- 23358842 TI - Moderate exercise for improvement in 6-minute walk test performance in stable coronary heart disease. PMID- 23358843 TI - Moderate exercise for improvement in 6-minute walk test performance in stable coronary heart disease--reply. PMID- 23358844 TI - Clinical feasibility of inferior right hepatic vein-preserving trisegmentectomy 5, 7, and 8 (with video). AB - BACKGROUND AND AIM: Hepatic resection involves not only complete removal of tumors but also preservation of optimal liver function after surgery. This study introduces the technique of inferior right hepatic vein (IRHV)-preserving trisegmentectomy 5, 7, and 8 and evaluates its clinical feasibility. METHODS: Between January 2008 and December 2011, four patients underwent this procedure. Postoperative outcomes and interim results were evaluated. RESULTS: The median estimated volumes of the left lobe only and the left lobe plus preserved parenchyma relative to the total estimated liver volume were 22.8 % (range, 21.1 24.2 %) and 43.6 % (range, 38.0-47.5 %), respectively. The median total operating time and blood loss were 349 min (range, 348-417 min) and 650 ml (range, 300 1,700 ml), respectively. One patient developed the postoperative complication of bile leakage. The median hospital stay was 14.5 days (range, 14-50 days). Median follow-up was 23.5 months (range, 6-70 months), and two patients developed recurrence. One patient died of disease progression, and the other three patients were alive at the last follow-up. CONCLUSION: Based on our experience, IRHV preserving trisegmentectomy 5, 7, and 8 is a safe and feasible procedure. This technique could be an option for curative resection minimizing postoperative deterioration of liver function without preoperative portal vein embolization in patients with a reliable IRHV. PMID- 23358845 TI - Surgical outcomes after gastric electric stimulator placement for refractory gastroparesis. AB - BACKGROUND: Gastric electric stimulation (GES) is used for refractory gastroparesis symptoms. Although symptomatic improvement has been reported with GES, few studies describe the need for additional surgery after placement. Our goal was to evaluate the outcomes of a large series of GES at a single institution. METHODS: A retrospective review was performed for patients undergoing Enterra GES (Medtronic, Inc.) placement for refractory gastroparesis from October 2000 to October 2011. The main outcome measures were the need/indications for additional procedures and symptom improvement. RESULTS: A total of 266 patients had a GES implanted; 233 had complete records and were included in the analysis. Fifty-eight percent (n = 135) required an additional procedure after GES placement. Nutrition access (45 patients requiring 77 procedures) and subcutaneous pocket issues (n = 21) were the most common indications for subsequent procedures. Twelve percent (n = 29) had the GES explanted, mainly for continued gastroparetic symptoms (n = 11), mechanical issues (n = 9), or infection (n = 4). Ninety patients had subsequent hospitalizations, mainly for gastroparetic flares. Mortality during the follow-up period was 2.1 %. BMI was predictive of additional surgical procedure: when overweight, the risk of pocket revision increased 4.45 times (OR = 4.452). Of 74 most recent patients with prospective long-term outcome data, 70 % reported improved symptoms of pain, bloating, and nausea. CONCLUSIONS: Although most patients reported symptomatic improvement after GES implantation, there is often a need for additional surgical procedures as well as associated complications after GES placement. Additional procedures were most frequent for surgical nutrition and subcutaneous pocket issues; pocket revisions were more frequent in obese patients. From our results, we amended our practice to add a jejunostomy tube in malnourished patients and suture the stimulator to the subcutaneous pocket fascia. Further studies will determine if these changes reduce the rate of complications and additional procedures after GES placement. PMID- 23358846 TI - Laparoscopic versus open splenectomy and esophagogastric devascularization for bleeding varices or severe hypersplenism: a comparative study. AB - BACKGROUND: The safety and feasibility of laparoscopic splenectomy and esophagogastric devascularization are still uncertain. The aim of this study was to compare our results for laparoscopic splenectomy and esophagogastric devascularization with those for open splenectomy and esophagogastric devascularization. MATERIALS AND METHODS: From January 2008 to December 2011, 153 patients were diagnosed with portal hypertension and serious gastroesophageal varices in our institute, among which, 107 patients also had repeated upper gastrointestinal bleeding and 85 had severe hypersplenism. Eighty patients chose laparoscopic splenectomy and esophagogastric devascularization and 73 patients underwent the open procedure. Results and outcomes were compared retrospectively. RESULTS: Nine patients underwent conversion to laparotomy in the laparoscopic group. We compared the laparoscopic group (80 patients) and the open group (73 patients). Operating times and the frequencies of blood transfusions were similar. Blood loss was less (P = 0.044), the passing of flatus was earlier (P = 0.041), and hospital stays were shorter (P = 0.028) in the laparoscopic group. Portal vein system thrombosis after laparoscopy was more frequent (P = 0.012) but the rates of main trunk occlusion were similar between the two groups. Pleural effusion after laparoscopy was less (P = 0.021) and, apart from this, there was no difference in other morbidities between the two groups. During a postoperative follow-up period of 2 to 50 months in 80 patients of the laparoscopic group vs. 73 patients of the open group, the incidence of esophagogastric variceal rebleeding, encephalopathy, and secondary liver cancer showed no significant differences. And the mortality rates for each of the groups were not different. CONCLUSIONS: The short-term effects of laparoscopic splenectomy and esophagogastric devascularization were better than those for open surgery, and the medium-term effects were similar between these two surgical approaches. Prospective randomized studies with a greater number of cases are needed to confirm the role of laparoscopy in splenectomy and esophagogastric devascularization. PMID- 23358847 TI - Colonic endolumenal stenting devices and elective surgery versus emergency subtotal/total colectomy in the management of malignant obstructed left colon carcinoma. AB - BACKGROUND: Traditionally, left-sided acute bowel obstruction is treated by a staged procedure because immediate resection and anastomosis in a massive distended and unprepared colon carries a high complication rate. Total abdominal colectomy is a one-stage procedure that will remove synchronous proximal neoplasms, reduce the risk of subsequent metachronous tumor, and avoid stoma. Colorectal stents are being used for palliation and as a bridge to surgery in obstructing colorectal carcinoma, making elective surgery straightforward, enabling easily mobilization and resection of the colon with a possible trend toward reduction in postoperative complication rates compared to emergency surgery. The purpose of this work was to compare the procedures of endoscopic stenting followed by elective colectomy versus total abdominal colectomy and ileorectal anastomosis in the management of acute obstructed carcinoma of the left colon as regards feasibility, safety, and clinical outcomes METHODS: From January 2009 through May 2012, 60 patients were randomized to either emergency stenting followed by elective resection (ESER group) or total abdominal colectomy and ileorectal anastomosis (TACIR group). RESULTS: Twenty nine patients (96.7 %) had successful stenting and underwent elective surgery 7-10 days later (ESER group). Postoperative complications were encountered in four patients in the ESER group compared to 15 patients in the TACIR group (p = 0.012). Anastomotic leakage was encountered in one patient (3.3 %) in the TACIR group. There were no operative mortalities in the present study. Within the first three postoperative months, the TACIR group patients had significantly more frequent bowel motions per day compared to the ESER group patients although (p = 0.013). In both study groups, the follow-up duration ranged from 6 to 40 months with a median of 18 months. Recurrent disease was encountered in five patients (17.2 %) in the ESER group compared to four patients (13.3 %) in the TACIR group (p = 0.228). CONCLUSION: Both techniques are feasible, safe, and produce comparable oncological outcomes. However, endoscopic stenting followed by elective resection was associated with significantly less postoperative complications and bowel motions per day. PMID- 23358849 TI - Polymorphism in the HASPB repeat region of East African Leishmania donovani strains. AB - BACKGROUND/OBJECTIVES: Visceral leishmaniasis (VL) caused by Leishmania donovani is a major health problem in Ethiopia. Parasites in disparate regions are transmitted by different vectors, and cluster in distinctive genotypes. Recently isolated strains from VL and HIV-VL co-infected patients in north and south Ethiopia were characterized as part of a longitudinal study on VL transmission. METHODOLOGY/PRINCIPAL FINDINGS: Sixty-three L. donovani strains were examined by polymerase chain reaction (PCR) targeting three regions: internal transcribed spacer 1 (ITS1), cysteine protease B (cpb), and HASPB (k26). ITS1- and cpb--PCR identified these strains as L. donovani. Interestingly, the k26--PCR amplicon size varied depending on the patient's geographic origin. Most strains from northwestern Ethiopia (36/40) produced a 290 bp product with a minority (4/40) giving a 410 bp amplicon. All of the latter strains were isolated from patients with HIV-VL co-infections, while the former group contained both VL and HIV-VL co infected patients. Almost all the strains (20/23) from southwestern Ethiopia produced a 450 bp amplicon with smaller products (290 or 360 bp) only observed for three strains. Sudanese strains produced amplicons identical (290 bp) to those found in northwestern Ethiopia; while Kenyan strains gave larger PCR products (500 and 650 bp). High-resolution melt (HRM) analysis distinguished the different PCR products. Sequence analysis showed that the k26 repeat region in L. donovani is comprised of polymorphic 13 and 14 amino acid motifs. The 13 amino acid peptide motifs, prevalent in L. donovani, are rare in L. infantum. The number and order of the repeats in L. donovani varies between geographic regions. CONCLUSIONS/SIGNIFICANCE: HASPB repeat region (k26) shows considerable polymorphism among L. donovani strains from different regions in East Africa. This should be taken into account when designing diagnostic assays and vaccines based on this antigen. PMID- 23358848 TI - Memory T cells in latent Mycobacterium tuberculosis infection are directed against three antigenic islands and largely contained in a CXCR3+CCR6+ Th1 subset. AB - An understanding of the immunological footprint of Mycobacterium tuberculosis (MTB) CD4 T cell recognition is still incomplete. Here we report that human Th1 cells specific for MTB are largely contained in a CXCR3(+)CCR6(+) memory subset and highly focused on three broadly immunodominant antigenic islands, all related to bacterial secretion systems. Our results refute the notion that secreted antigens act as a decoy, since both secreted proteins and proteins comprising the secretion system itself are targeted by a fully functional T cell response. In addition, several novel T cell antigens were identified which can be of potential diagnostic use, or as vaccine antigens. These results underline the power of a truly unbiased, genome-wide, analysis of CD4 MTB recognition based on the combined use of epitope predictions, high throughput ELISPOT, and T cell libraries using PBMCs from individuals latently infected with MTB. PMID- 23358850 TI - Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma. AB - In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations. PMID- 23358851 TI - Basal stem cells contribute to squamous cell carcinomas in the oral cavity. AB - The cells of origin of oral cavity squamous cell carcinoma (OCSCC) are unknown. We used a cell lineage tracing approach (adult K14-CreER(TAM); ROSA26 mice transiently treated with tamoxifen) to identify and track normal epithelial stem cells (SCs) in mouse tongues by X-gal staining and to determine if these cells become neoplastically transformed by treatment with a carcinogen, 4 nitroquinoline 1-oxide (4-NQO). Here, we show that in normal tongue epithelia, X gal(+) cells formed thin columns throughout the entire epithelium 12 weeks after tamoxifen treatment, indicating that the basal layer contains long-lived SCs that produce progeny by asymmetric division to maintain homeostasis. Carcinogen treatment results in a ~10-fold reduction in the total number of X-gal(+) clonal cell populations and horizontal expansion of X-gal(+) clonal cell columns, a pattern consistent with symmetric division of some SCs. Finally, X-gal(+) SCs are present in papillomas and invasive OCSCCs, and these long-lived X-gal(+) SCs are the cells of origin of these tumors. Moreover, the resulting 4-NQO-induced tumors are multiclonal. These findings provide insights into the identity of the initiating cells of oral cancer. PMID- 23358853 TI - Telomere crisis in kidney epithelial cells promotes the acquisition of a microRNA signature retrieved in aggressive renal cell carcinomas. AB - Telomere shortening is a major source of chromosome instability (CIN) at early stages during carcinogenesis. However, the mechanisms through which telomere driven CIN (T-CIN) contributes to the acquisition of tumor phenotypes remain uncharacterized. We discovered that human epithelial kidney cells undergoing T CIN display massive microRNA (miR) expression changes that are not related to local losses or gains. This widespread miR deregulation encompasses a miR-200 dependent epithelial-to-mesenchymal transition (EMT) that confers to immortalized pre-tumoral cells phenotypic traits of metastatic potential. Remarkably, a miR signature of these cells, comprising a downregulation of miRs with conserved expression in kidney, was retrieved in poorly differentiated aggressive renal cell carcinomas. Our results reveal an unanticipated connection between telomere crisis and the activation of the EMT program that occurs at pre-invasive stages of epithelial cancers, through mechanisms that involve miR deregulation. Thus, this study provides a new rational into how telomere instability contributes to the acquisition of the malignant phenotype. PMID- 23358852 TI - Wnt/beta-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1alpha signaling. AB - Epithelial-mesenchymal transition (EMT) is a critical process for tumor invasion and metastasis. Hypoxia may induce EMT, and upregulated beta-catenin expression has been found in various tumors. In this study, we investigate the role of beta catenin in hypoxia-induced EMT in hepatocellular carcinoma (HCC). Induction of EMT in HCC cell lines by hypoxia was confirmed by altered morphology, expression change of EMT-associated markers and enhanced invasion capacity. We showed that hypoxia-induced EMT could be enhanced by addition of recombinant Wnt3a while it was repressed by beta-catenin small interfering RNA. An interaction between beta catenin and hypoxia-induced factor-1alpha (hif-1alpha) was found, and an underlying competition for beta-catenin between hif-1alpha and T-cell factor-4 was implied. Notably, increased hif-1alpha activity was accompanied with more significant EMT features. We also showed that the pro-EMT effect of beta-catenin in hypoxia was deprived in the absence of hif-1alpha. Moreover, beta-catenin was found to be responsible for the maintenance of viability and proliferation for tumor cells undergoing hypoxia. We further showed a correlation between hif 1alpha and beta-catenin expression, and corresponding expression of EMT associated markers in human HCC tissues. Our results suggest that Wnt/beta catenin signaling enhances hypoxia-induced EMT in HCC by increasing the EMT associated activity of hif-1alpha and preventing tumor cell death. PMID- 23358854 TI - Progression of genotype-specific oral cancer leads to senescence of cancer associated fibroblasts and is mediated by oxidative stress and TGF-beta. AB - Keratinocyte senescence acts as a barrier to tumor progression but appears to be lost in late pre-malignancy to yield genetically unstable oral squamous cell carcinomas (GU-OSCC); a subset of OSCC possessing wild-type p53 and are genetically stable (GS-OSCC). In this study, fibroblasts from GU-OSCC were senescent relative to fibroblasts from GS-OSCC, epithelial dysplastic tissues or normal oral mucosa, as demonstrated by increased senescence-associated beta galactosidase (SA beta-Gal) activity and overexpression of p16(INK4A). Keratinocytes from GU-OSCC produced high levels of reactive oxygen species (ROS) and this was associated with an increase in the production of transforming growth factor-beta1 (TGF-beta1) and TGF-beta2 in stromal fibroblasts. Treatment of normal fibroblasts with keratinocyte conditioned media (CM) from GU-OSCC, but not GS-OSCC or dysplastic keratinocytes with dysfunctional p53, induced fibroblast senescence. This phenomenon was inhibited by antioxidants and anti-TGF-beta antibodies. Fibroblast activation by TGF-beta1 preceded cellular senescence and was associated with increased ROS levels; antioxidants inhibited this reaction. Senescent fibroblasts derived from GU-OSCC or normal fibroblasts treated with CM from GU-OSCC or hydrogen peroxide, but not non-senescent fibroblasts derived from GS-OSCC, promoted invasion of keratinocytes in vitro. Epithelial invasion was stimulated by fibroblast activation and amplified further by fibroblast senescence. The data demonstrate that malignant keratinocytes from GU-OSCC, but not their pre-malignant counterparts, produce high levels of ROS, which, in turn, increase TGF-beta1 expression and induce fibroblast activation and senescence in a p5-independent manner. Fibroblasts from GU-OSCC were particularly susceptible to oxidative DNA damage because of high levels of ROS production, downregulation of antioxidant genes and upregulation of pro-oxidant genes. The results demonstrate the functional diversity of cancer-associated fibroblasts and show that malignant keratinocytes from GU-OSCC reinforce their malignant behavior by inducing fibroblast activation and senescence through ROS and TGF-beta-dependent mechanisms. PMID- 23358855 TI - Perceptions of human attractiveness comprising face and voice cues. AB - In human mate choice, sexually dimorphic faces and voices comprise hormone mediated cues that purportedly develop as an indicator of mate quality or the ability to compete with same-sex rivals. If preferences for faces communicate the same biologically relevant information as do voices, then ratings of these cues should correlate. Sixty participants (30 male and 30 female) rated a series of opposite-sex faces, voices, and faces together with voices for attractiveness in a repeated measures computer-based experiment. The effects of face and voice attractiveness on face-voice compound stimuli were analyzed using a multilevel model. Faces contributed proportionally more than voices to ratings of face-voice compound attractiveness. Faces and voices positively and independently contributed to the attractiveness of male compound stimuli although there was no significant correlation between their rated attractiveness. A positive interaction and correlation between attractiveness was shown for faces and voices in relation to the attractiveness of female compound stimuli. Rather than providing a better estimate of a single characteristic, male faces and voices may instead communicate independent information that, in turn, provides a female with a better assessment of overall mate quality. Conversely, female faces and voices together provide males with a more accurate assessment of a single dimension of mate quality. PMID- 23358856 TI - Gender nonconformity, perceived stigmatization, and psychological well-being in Dutch sexual minority youth and young adults: a mediation analysis. AB - Dutch sexual minority youth and young adults (106 females and 86 males, 16-24 years old) were assessed to establish whether there was a relation between gender nonconformity and psychological well-being and whether this relation was mediated by perceived experiences of stigmatization due to perceived or actual sexual orientation and moderated by biological sex. The participants were recruited via announcements on Dutch LGBTQ-oriented community websites and then linked to a protected online questionnaire. The questionnaire was used to measure gender nonconformity, perceived experiences of stigmatization, and psychological well being. Gender nonconformity was found to predict lower levels of psychological well-being and the mediation analysis confirmed that lower levels of psychological well-being were related to the perceived experiences of stigmatization. This mediation was not moderated by biological sex. These findings show that both research and interventions should pay more attention to gender nonconformity among young people in order to create a more positive climate for young sexual minority members. PMID- 23358857 TI - Circumcision and HIV infection among men who have sex with men in Britain: the insertive sexual role. AB - The objective was to examine the association between circumcision status and self reported HIV infection among men who have sex with men (MSM) in Britain who predominantly or exclusively engaged in insertive anal intercourse. In 2007-2008, a convenience sample of MSM living in Britain was recruited through websites, in sexual health clinics, bars, clubs, and other venues. Men completed an online survey which included questions on circumcision status, HIV testing, HIV status, sexual risk behavior, and sexual role for anal sex. The analysis was restricted to 1,521 white British MSM who reported unprotected anal intercourse in the previous 3 months and who said they only or mostly took the insertive role during anal sex. Of these men, 254 (16.7 %) were circumcised. Among men who had had a previous HIV test (n = 1,097), self-reported HIV seropositivity was 8.6 % for circumcised men (17/197) and 8.9 % for uncircumcised men (80/900) (unadjusted odds ratio [OR], 0.97; 95 % confidence interval [95 % CI], 0.56, 1.67). In a multivariable logistic model adjusted for known risk factors for HIV infection, there was no evidence of an association between HIV seropositivity and circumcision status (adjusted OR, 0.79; 95 % CI, 0.43, 1.44), even among the 400 MSM who engaged exclusively in insertive anal sex (adjusted OR, 0.84; 95 % CI, 0.25, 2.81). Our study provides further evidence that circumcision is unlikely to be an effective strategy for HIV prevention among MSM in Britain. PMID- 23358858 TI - The malleability of mate selection in speed-dating events. AB - This study examined to what extent individual mate selectivity could be explained by characteristics of the mating market. Specifically, we hypothesized that females' selectivity would be more malleable, or context-dependent, than males' mate selectivity (cf. Baumeister, 2000; Gangestad & Simpson, 2000). In a series of 22 speed-dating events in which 546 adults aged 22-42 years participated, we investigated whether the proportion of available potential mates (i.e., male female ratio), which sex rotated during the speed-date event (i.e., approached the other sex), and mate qualities of same-sex competitors affected individuals' selectivity, as indexed by the proportion of no's given during the speed-dating events. Results from multilevel analyses demonstrated that, as hypothesized, event characteristics explained mate selectivity only for females. Specifically, women with a lower facial attractiveness and more deviant body mass index (BMI) values were overall less selective, but this trend was only present in speed dating events characterized by higher intrasex competition--when females rotated or when other females in the event were more attractive or had healthier BMI. The findings partially support the idea of "erotic plasticity" in females, demonstrating that females' mate selectivity is more malleable and dependent on context than males' mate selectivity. PMID- 23358859 TI - Staring at the cold sun: blue light regulation is distributed within the genus Acinetobacter. AB - We previously showed that the opportunistic nosocomial pathogen Acinetobacter baumannii is able to sense and respond to light via BlsA, a BLUF (Blue-Light sensing Using FAD)-domain photoreceptor protein. Here, we extend our previous studies showing that light regulation is not restricted to A. baumannii, but rather widespread within the genus Acinetobacter. First, we found that blue light modulates motility and biofilm formation in many species of the genus, including members of the Acinetobacter calcoaceticus-A. baumannii complex. In many of these species blue light acts as a key factor guiding the decision between motility or sessility at 24 degrees C, whereas in A. baumannii, light inhibits both motility and biofilm formation. We also show that light regulation of motility occurred not only at 24 degrees C but also at 37 degrees C in non-A. baumannii species, contrasting the situation of A. baumannii which only shows photoregulation at 24 degrees C. Second, we show that Acinetobacter baylyi (strain ADP1) BLUF photoreceptors can functionally replace in vivo the A. baumannii 17978 BlsA protein and that the pathways leading to biofilm formation are inversely regulated at 24 degrees C between these two microorganisms. Finally, we found the presence of predicted genes coding BLUF-containing proteins in all Acinetobacter sequenced genomes, even though the copy number is variable among them. Phylogenetic analysis suggests a common origin for all BLUF domains present in members of this genus, and could distinguish well-differentiated clusters that group together BLUF homologs from different species, a situation particularly clear for members of the ACB complex. Despite a role played by these BLUF domain containing proteins in the photoregulation observed in the members of the genus Acinetobacter is a likely scenario given our findings in A. baumannii and A. baylyi, further research will contribute to confirm this possibility. PMID- 23358860 TI - Further analysis of the Crouzon mouse: effects of the FGFR2(C342Y) mutation are cranial bone-dependent. AB - Crouzon syndrome is a debilitating congenital disorder involving abnormal craniofacial skeletal development caused by mutations in fibroblast growth factor receptor-2 (FGFR2). Phenotypic expression in humans exhibits an autosomal dominant pattern that commonly involves premature fusion of the coronal suture (craniosynostosis) and severe midface hypoplasia. To further investigate the biologic mechanisms by which the Crouzon syndrome-associated FGFR2(C342Y) mutation leads to abnormal craniofacial skeletal development, we created congenic BALB/c FGFR2(C342Y/+) mice. Here, we show that BALB/c FGFR2(C342Y/+) mice have a consistent craniofacial phenotype including partial fusion of the coronal and lambdoid sutures, intersphenoidal synchondrosis, and multiple facial bones, with minimal fusion of other craniofacial sutures. This phenotype is similar to the classic and less severe form of Crouzon syndrome that involves significant midface hypoplasia with limited craniosynostosis. Linear and morphometric analyses demonstrate that FGFR2(C342Y/+) mice on the BALB/c genetic background differ significantly in form and shape from their wild-type littermates and that in this genetic background the FGFR2(C342Y) mutation preferentially affects some craniofacial bones and sutures over others. Analysis of cranial bone cells indicates that the FGFR2(C342Y) mutation promotes aberrant osteoblast differentiation and increased apoptosis that is more severe in frontal than parietal bone cells. Additionally, FGFR2(C342Y/+) frontal, but not parietal, bones exhibit significantly diminished bone volume and density compared to wild type mice. These results confirm that FGFR2-associated craniosynostosis occurs in association with diminished cranial bone tissue and may provide a potential biologic explanation for the clinical finding of phenotype consistency that exists between many Crouzon syndrome patients. PMID- 23358861 TI - Targeted linkage map densification to improve cell wall related QTL detection and interpretation in maize. AB - Several QTLs for cell wall degradability and lignin content were previously detected in the F288 * F271 maize RIL progeny, including a set of major QTLs located in bin 6.06. Unexpectedly, allelic sequencing of genes located around the bin 6.06 QTL positions revealed a monomorphous region, suggesting that these QTLs were likely "ghost" QTLs. Refining the positions of all QTLs detected in this population was thus considered, based on a linkage map densification in most important QTL regions, and in several large still unmarked regions. Re-analysis of data with an improved genetic map (173 markers instead of 108) showed that ghost QTLs located in bin 6.06 were then fractionated over two QTL positions located upstream and downstream of the monomorphic region. The area located upstream of bin 6.06 position carried the major QTLs, which explained from 37 to 59 % of the phenotypic variation for per se values and extended on only 6 cM, corresponding to a physical distance of 2.2 Mbp. Among the 92 genes present in the corresponding area of the B73 maize reference genome, nine could putatively be considered as involved in the formation of the secondary cell wall [bHLH, FKBP, laccase, fasciclin, zinc finger C2H2-type and C3HC4-type (two genes), NF YB, and WRKY]. In addition, based on the currently improved genetic map, eight QTLs were detected in bin 4.09, while only one QTL was highlighted in the initial investigation. Moreover, significant epistatic interaction effects were shown for all traits between these QTLs located in bin 4.09 and the major QTLs located in bin 6.05. Three genes related to secondary cell wall assembly (ZmMYB42, COV1 like, PAL-like) underlay QTL support intervals in this newly identified bin 4.09 region. The current investigations, even if they were based only on one RIL progeny, illustrated the interest of a targeted marker mapping on a genetic map to improve QTL position. PMID- 23358862 TI - Development and characterization of a compensating wheat-Thinopyrum intermedium Robertsonian translocation with Sr44 resistance to stem rust (Ug99). AB - The emergence of the highly virulent Ug99 race complex of the stem rust fungus (Puccinia graminis Pers. f. sp. tritici Eriks. and Henn.) threatens wheat (Triticum aestivum L.) production worldwide. One of the effective genes against the Ug99 race complex is Sr44, which was derived from Thinopyrum intermedium (Host) Barkworth and D.R. Dewey and mapped to the short arm of 7J (designated 7J#1S) present in the noncompensating T7DS-7J#1L?7J#1S translocation. Noncompensating wheat-alien translocations are known to cause genomic duplications and deficiencies leading to poor agronomic performance, precluding their direct use in wheat improvement. The present study was initiated to produce compensating wheat-Th. intermedium Robertsonian translocations with Sr44 resistance. One compensating RobT was identified consisting of the wheat 7DL arm translocated to the Th. intermedium 7J#1S arm resulting in T7DL?7J#1S. The T7DL?7J#1S stock was designated as TA5657. The 7DL?7J#1S stock carries Sr44 and has resistance to the Ug99 race complex. This compensating RobT with Sr44 resistance may be useful in wheat improvement. In addition, we identified an unnamed stem rust resistance gene located on the 7J#1L arm that confers resistance not only to Ug99, but also to race TRTTF, which is virulent to Sr44. However, the action of the second gene can be modified by the presence of suppressors in the recipient wheat cultivars. PMID- 23358865 TI - "My religion picked my birth control": the influence of religion on contraceptive use. AB - This research investigates the influence of religious preference and practice on the use of contraception. Much of earlier research examines the level of religiosity on sexual activity. This research extends this reasoning by suggesting that peer group effects create a willingness to mask the level of sexuality through the use of contraception. While it is understood that certain religions, that is, Catholicism does not condone the use of contraceptives, this research finds that Catholics are more likely to use certain methods of contraception than other religious groups. With data on contraceptive use from the Center for Disease Control's Family Growth Survey, a likelihood probability model is employed to investigate the impact religious affiliation on contraception use. Findings suggest a preference for methods that ensure non pregnancy while preventing feelings of shame and condemnation in their religious communities. PMID- 23358864 TI - Plasma reactive oxygen metabolites and non-enzymatic antioxidant capacity are not affected by an acute increase of metabolic rate in zebra finches. AB - Understanding the sources of variation in oxidative stress level is a challenging issue due to the implications of oxidative stress for late age diseases, longevity and life-history trade-offs. Reactive oxygen species that cause oxidative stress are mostly a by-product of energy metabolism and it is therefore often assumed that oxidative stress is proportional to energy consumption. In mammals, an increased metabolic rate induced by cold exposure generally increases oxidative stress. However, compared to mammals, birds generate fewer free radicals per ATP produced and hence it is not obvious that, in birds, a cold induced increase of metabolic rate increase oxidative stress. We tested whether cold-induced increase in metabolic rate increased oxidative stress in zebra finches by exposing individuals to cold and warm overnight temperatures. We registered metabolic rate and plasma levels of non-enzymatic antioxidants and reactive oxygen metabolites (ROMs), a measure of oxidative damage. Metabolic rate was on average 88 % higher in cold compared to warm temperature, with females being stronger affected than males. However, temperature had no effect on plasma antioxidants or our measure of oxidative damage. Middle-age birds had higher levels of plasma antioxidants than younger and older birds, but age was unrelated to ROMs. Birds showed repeatability of plasma ROMs across temperatures but not of non-enzymatic antioxidants. In contrast to similar studies in mammals, our results do not show evidence of increased oxidative stress in plasma after an acute cold-induced increase of metabolic rate but research in more bird species is needed to assess the generality of this pattern. PMID- 23358867 TI - Establishing primary cell cultures from Branchiostoma belcheri Japanese. PMID- 23358866 TI - Embryo-luteal cells co-culture: an in vitro model to evaluate steroidogenic and prostanoid bovine early embryo-maternal interactions. AB - The role of progesterone (P(4)) and prostaglandins (PGs) in bovine early embryonic development and embryo-maternal crosstalk is almost unknown. Here, the in vitro steroidogenic (P(4)) and prostanoid (PGE(2) and PGF(2alpha)) interactions between bovine embryos and luteal cells (LC) were evaluated. In two experiments, embryos (n = 1.900) were either co-cultured with LC or cultured alone, from days 2 to 7 (day 0 = in vitro insemination). LC were also cultured alone, and medium was used as a control, all groups being cultured either with or without oil overlay of culture medium. Oil overlay of culture medium significantly decreased the amount of P(4), but not of PGE(2) and PGF(2alpha) measured in culture medium. Embryos and LC had transcripts of genes coding for enzymes of the PGs (PTGS2, PGES, and PGFS) and P(4) (StAR, P450scc, and 3beta HSD) synthesis pathways, and produced P(4), PGF(2alpha), and PGE(2) into culture medium. Co-culture with LC exerted an embryotrophic effect, significantly increasing blastocyst yield and quality. This indicates a possible direct effect of LC in early embryo development. Embryos did not exert a luteotrophic effect upon LC. This may indicate that early embryos (until day 7) probably do not exert influence in LC main function. It is suggested that production of P(4), PGE(2), and PGF(2alpha) by early embryos may be associated to autocrine signaling leading to events in development and to paracrine signaling in the endometrium leading to local uterine receptivity. PMID- 23358868 TI - Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy. AB - OBJECTIVE: To report first experiences with interleukin 6 receptor inhibition in therapy-resistant neuromyelitis optica (NMO). DESIGN: Retrospective case series. SETTING: Neurology department at a tertiary referral center. PATIENTS: Patients with an aggressive course of NMO switched to tocilizumab after failure of anti CD20 therapy. MAIN OUTCOME MEASURES: Annualized relapse rate and disability progression measured by the Expanded Disability Status Scale. RESULTS: We report 3 female patients with a median age of 39 years (range, 26-40 years) and aquaporin 4-positive NMO. All patients had been treated with different immunosuppressive and immunomodulating agents, followed by 1 to 3 cycles of rituximab. Despite complete CD20-cell depletion during rituximab therapy, the median annualized relapse rate was 3.0 (range, 2.3-3.0) and the median Expanded Disability Status Scale score increased from 5.0 (range, 4.5-7.0) to 6.5 (range, 5.0-7.0). After the switch to tocilizumab (median duration of therapy, 18 months), the median annualized relapse rate decreased to 0.6 (range, 0-1.3). A total of 2 relapses occurred; however, they were mild and there were no changes in clinical disability. CONCLUSIONS: Interleukin 6 receptor-blocking therapy can be effective in therapy-resistant cases of NMO. Larger controlled studies are needed to confirm the efficacy of tocilizumab. PMID- 23358869 TI - Annular subacute cutaneous lupus erythematosus lesions and polymyositis onset in a patient with primary Sjogren's syndrome: how should this unusual association be classified? AB - Classification of the wide variety of autoimmune diseases that can occur before or after the onset of Sjogren's syndrome (SS) is currently debated within the conventional SS criteria or as primary SS (pSS) developing autoimmune disease or as 'associated-overlap' with other systemic autoimmune diseases. There is also debate on whether or not to consider annular polycyclic subacute cutaneous lupus erythematosus (SCLE) and annular erythema associated with Sjogren's syndrome (AESS) as a spectrum linked to Ro-SSA and/or La-SSB auto-antibodies (SSA/SSB auto ab). We present the case of a 55-year-old female patient, with pSS positive for SSA and SSB auto-ab, who developed chronic relapsing polymyositis and atypical annular non-polycyclic SCLE lesions resembling AESS, which seemed to suggest a common spectrum. While a chronic-progressive polymyositis may be generally accepted as a relatively rare myositis complicating pSS, interpretation of annular lesions of non-systemic SCLE in SS patients might actually be underestimated as pSS skin manifestation likely related to SSA/SSB auto-ab. PMID- 23358870 TI - Periodic lateralized epileptiform discharges (PLEDs) in cerebral lupus correlated with white-matter lesions in brain MRI and reduced cerebral blood flow in SPECT. AB - This is a case report on an uncommon correlation between periodic lateralized epileptiform discharges (PLEDs) and white-matter lesions in cerebral lupus, and with a reduced cerebral blood flow (CBF) in single-photon emission computed tomography (SPECT). A 47-year-old woman with a long-term history of systemic lupus erythematosus (SLE) presented with a seizure followed by frontal lobe dysfunction clinically. An electroencephalogram (EEG) showed bilateral independent PLEDs in the frontal region. A magnetic resonance image of the brain showed white-matter changes in the frontal periventricular region. Cerebral angiogram did not reveal any evidence of vasculitis. A cerebral SPECT with tracer injected during the EEG showing PLEDs showed a reduction in CBF in the frontal regions. Clinical recovery was observed with intravenous immunoglobulin. This case shows that PLEDs can be seen with white-matter changes in SLE. PMID- 23358871 TI - The reliability, validity and responsiveness of the Thai version of Systemic Lupus Erythematosus Quality of Life (SLEQOL-TH) instrument. AB - OBJECTIVES: The English version of the Systemic Lupus Erythematosus Quality of Life Questionnaire (SLEQOL) is a validated disease-specific quality of life instrument. The aim of this study was to evaluate the psychometric properties of the Thai version of the SLEQOL (SLEQOL-TH). METHODS: Two independent translators translated the SLEQOL into Thai. The back translation of this version was performed by two other independent translators. The final version, SLEQOL-TH, was completed after resolving the discrepancies revealed by the back translation. One hundred and nine patients with SLE were enrolled to test the reliability, construct validity, floor and ceiling effects, and sensitivity to the changes of the SLEQOL-TH at six months. The differential item functioning (DIF) between the Thai and English versions was analyzed using the partial gamma. RESULTS: The internal consistency of the SLEQOL-TH was satisfactory with the overall Cronbach's alpha of 0.86. The test-retest reliability of the SLEQOL-TH was acceptable with the intra-class correlation coefficient of 0.86. Low correlations between the SLEQOL-TH and SLEDAI were observed. The total score of the SLEQOL-TH was moderately responsive to changes in quality of life, with a standardized response mean of 0.50. When comparing the SLEQOL-TH from Thai SLE patients with the original SLEQOL version obtained from Singapore SLE patients, 11 out of 40 items showed a moderate to large DIF. CONCLUSIONS: The SLEQOL-TH has acceptable psychometric properties and shows construct validity. In comparison with the English version of SLEQOL, there are some items that showed DIF. The applicability of the SLEQOL-TH in real-life clinical practice and clinical trials needs to be determined. PMID- 23358872 TI - The HECTD3 E3 ubiquitin ligase suppresses cisplatin-induced apoptosis via stabilizing MALT1. AB - Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3) is an E3 ubiquitin ligase with unknown functions. Here, we show that HECTD3 confers cancer cell resistance to cisplatin. To understand the molecular mechanisms, we performed a yeast two-hybrid analysis and identified mucosa associated lymphoid tissue 1 (MALT1) as an HECTD3-interacting protein. HECTD3 promotes MALT1 ubiquitination with nondegradative polyubiquitin chains by direct interacting with the MALT1 through its N-terminal destruction of cyclin domain. HECTD3 does not target MALT1 for degradation but stabilize it. HECTD3 depletion dramatically decreases the levels of MALT1 in MCF7 and HeLa cells treated with cisplatin, which is correlated to an increase in apoptosis. Knockdown of MALT1 likewise increases cisplatin-induced apoptosis in these cancer cells. However, HECTD3 over-expression leads to a decreased cisplatin-induced apoptosis, whereas overexpression of MALT1 partially rescues HECTD3 depletion-induced apoptosis. These findings suggest that HECTD3 promotes cell survival through stabilizing MALT1. Our data have important implications in cancer therapy by providing novel molecular targets. PMID- 23358874 TI - Characterization of cell seeding and specific capture of B cells in microbubble well arrays. AB - Development of micro-well array systems for use in high-throughput screening of rare cells requires a detailed understanding of the factors that impact the specific capture of cells in wells and the distribution statistics of the number of cells deposited into wells. In this study we investigate the development of microbubble (MB) well array technology for sorting antigen-specific B-cells. Using Poisson statistics we delineate the important role that the fractional area of MB well opening and the cell seeding density have on determining cell seeding distribution in wells. The unique architecture of the MB well hinders captured cells from escaping the well and provides a unique microenvironmental niche that enables media changes as needed for extended cell culture. Using cell lines and primary B and T cells isolated from human peripheral blood we demonstrate the use of affinity capture agents coated in the MB wells to enrich for the selective capture of B cells. Important differences were noted in the efficacy of bovine serum albumin to block the nonspecific adsorption of primary cells relative to cell lines as well as the efficacy of the capture coatings using mixed primary B and T cells samples. These results emphasize the importance of using primary cells in technology development and suggest the need to utilize B cell capture agents that are insensitive to cell activation. PMID- 23358873 TI - Microfluidics and cancer: are we there yet? AB - More than two decades ago, microfluidics began to show its impact in biological research. Since then, the field of microfluidics has evolving rapidly. Cancer is one of the leading causes of death worldwide. Microfluidics holds great promise in cancer diagnosis and also serves as an emerging tool for understanding cancer biology. Microfluidics can be valuable for cancer investigation due to its high sensitivity, high throughput, less material-consumption, low cost, and enhanced spatio-temporal control. The physical laws on microscale offer an advantage enabling the control of physics, biology, chemistry and physiology at cellular level. Furthermore, microfluidic based platforms are portable and can be easily designed for point-of-care diagnostics. Developing and applying the state of the art microfluidic technologies to address the unmet challenges in cancer can expand the horizons of not only fundamental biology but also the management of disease and patient care. Despite the various microfluidic technologies available in the field, few have been tested clinically, which can be attributed to the various challenges existing in bridging the gap between the emerging technology and real world applications. We present a review of role of microfluidics in cancer research, including the history, recent advances and future directions to explore where the field stand currently in addressing complex clinical challenges and future of it. This review identifies four critical areas in cancer research, in which microfluidics can change the current paradigm. These include cancer cell isolation, molecular diagnostics, tumor biology and high-throughput screening for therapeutics. In addition, some of our lab's current research is presented in the corresponding sections. PMID- 23358875 TI - A metabolomic study on the effect of intravascular laser blood irradiation on type 2 diabetic patients. AB - Intravenous laser blood irradiation (ILBI) is widely applied in the treatment of different pathologies including diabetes mellitus. The aim of this study is to evaluate the effects of ILBI on the metabolites of blood in diabetic type 2 patients using metabolomics. We compared blood samples of nine diabetic type 2 patients, using metabolomics, before and after ILBI with blue light laser. The results showed significant decrease in glucose, glucose 6 phosphate, dehydroascorbic acid, R-3-hydroxybutyric acid, L-histidine, and L-alanine and significant increase in L-arginine level in blood and blood sugar in the patients have reduced significantly (p < 0.05). This study clearly demonstrated a significant positive effect of ILBI on metabolites of blood in diabetic type 2 patients. These findings support the therapeutic potential of ILBI in diabetic patients. PMID- 23358876 TI - Accelerated decline in renal function after acute myocardial infarction in patients with high low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol ratio. AB - High low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol (L/H) ratio is associated with progressions of coronary arteriosclerosis and chronic kidney disease. On the other hand, renal function markedly declined after acute myocardial infarction (AMI). The aims of the present study were (1) to identify what type of patients with AMI would have high L/H ratio at follow-up and (2) to evaluate whether decline in renal function after AMI had accelerated or not in patients with high L/H ratio. The 190 eligible AMI patients who underwent primary percutaneous coronary intervention (PCI) and received atorvastatin (10 mg) were divided into one of two groups according to the L/H ratio at 6-month follow-up: L/H >2 group (n = 81) or L/H <=2 group (n = 109). The characteristics on admission in the two groups were examined. Furthermore, changes in serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) during 1- and 6-month follow-up were compared between the two groups. L/H >2 group were significantly younger and had greater body mass index (BMI) and worse lipid profile on admission compared with L/H <=2 group. Percentage increase in sCr and percentage decrease in eGFR during 1-month follow-up in L/H >2 group tended to be greater than in L/H <=2 group, and those during 6-month follow-up were significantly greater (16.5 +/- 2.77 vs. 9.79 +/- 2.23 %, p = 0.03 and 11.8 +/- 1.93 vs. 2.75 +/- 3.85 %, p = 0.04, respectively). In AMI patients undergoing primary PCI, those who were young and had large BMI and poor lipid profile on admission were likely to have a high L/H ratio at follow-up despite statin therapy. In addition, the decline in renal function after AMI had significantly accelerated in patients with high L/H ratio. PMID- 23358877 TI - Quantitative 3-T diffusion tensor imaging in detecting optic nerve degeneration in patients with glaucoma: association with retinal nerve fiber layer thickness and clinical severity. AB - INTRODUCTION: To investigate the association of quantitative 3-T diffusion tensor imaging (DTI) with retinal nerve fiber layer (RNFL) thickness measured by optical coherence tomography (OCT) and clinical severity in detecting optic nerve degeneration in patients with primary closed-angle glaucoma. METHODS: Twenty three patients (42 eyes; 9 men, 14 women) with primary closed-angle glaucoma and 20 healthy controls were enrolled in this study. Both DTI and OCT were performed on the optic nerves of all subjects. The mean diffusivity (MD), fractional anisotropy (FA), and eigenvalue maps were obtained for quantitative analysis. RNFL thickness and quantitative electrophysiology were also performed on all subjects. The association of quantitative DTI with RNFL thickness and glaucoma stage was analyzed. RESULTS: Compared with control nerves, the FA, lambda[parallel], and lambda[perpendicular] values, and RNFL thickness in affected nerves decreased, while MD increased in patients with primary glaucoma (p < 0.05). There was a significant correlation between FA, MD, lambda[parallel], and lambda[perpendicular] and the mean RNFL thickness (P < 0.01). The mean FA and lambda[perpendicular] values derived with DT MR imaging correlated well with glaucoma stage (P < 0.05), but the mean MD and lambda[parallel] values did not correlate with glaucoma stage (P > 0.05). CONCLUSION: DTI measurement could detect abnormality of the optic nerve in patients with glaucoma and may serve as a biomarker of disease severity. PMID- 23358878 TI - Neuroform stent-assisted treatment of intracranial aneurysms: long-term follow-up study of aneurysm recurrence and in-stent stenosis rates. AB - INTRODUCTION: Our purpose was to analyze the long-term evolution of wide neck cerebral aneurysms treated with stent assistance. METHODS: Data of consecutive patients treated with the Neuroform stent over 9 years were retrospectively analyzed with emphasis on periprocedural complications, aneurysm occlusion grade evolution, and in-stent stenosis rates. RESULTS: Altogether, 113 patients with 117 unruptured and ruptured aneurysms were subject of analysis. Mean aneurysm size was 9.4 mm, and mean neck size was 4.7 mm. Procedural thromboembolic and hemorrhagic complications affected eight (6.8%) and four cases (3.4%), respectively. Immediate complete occlusion and occlusion with residual neck was achieved in 85% of cases, which at the first follow-up of 6 months, changed to 77 and 76 % at 36 months. Aneurysms >=10 mm showed a higher tendency of recurrence. During the overall follow-up time ranging from 1 to 9 years, an in-stent stenosis of >=50 % was observed only in three cases, all of them being asymptomatic. CONCLUSIONS: Stent-assisted coiling of wide neck aneurysms provided stable occlusion over the long-term follow-up, with very low and silent in-stent stenosis rates. Some incompletely occluded aneurysms showed a tendency of progressive occlusion; however, this was counterbalanced by the regrowth of others. PMID- 23358879 TI - Clinical and laboratory features of viral hepatitis A in children. AB - Recent outbreaks of viral hepatitis A in non-endemic European countries and the potential outbreak risk in susceptible populations has led us to evaluate the clinical characteristics of children hospitalised with hepatitis A. Retrospective study included 118 children (68 boys and 50 girls) with the mean age of 8.5 years hospitalised at Hospital Na Bulovce in Prague from June 2008 to June 2009. The clinical course was symptomatic icteric in 57 (48.3 %) children, symptomatic anicteric in 23 (19.5 %), subclinical in 22 (18.6 %) and asymptomatic inapparent in 16 (13.6 %). The relapse of the disease occurred in three patients. There were no cases of fulminant hepatitis. The most frequent symptoms included jaundice (57 cases), abdominal pain/discomfort (38), vomiting (38), dark urine (37), subfebrility (29) and fever (25). Hepatic injury markers were substantially elevated in icteric patients, but moderate elevations were identified in anicteric and subclinical cases as well. Lower white blood cell and lymphocyte counts were independently associated with symptomatic and more severe clinical course. Active immunisation was provided to 22 patients, and as a post-exposure prophylaxis to 19 of them. The clinical course and laboratory parameters in vaccinated children were not significantly different from non-vaccinated children. The clinical course of hepatitis A was largely self-limiting and benign. Asymptomatic infections are frequent, representing risk for disease spread; however, they are associated with elevations of hepatic injury markers. The inclusion of significant proportion of asymptomatic cases that were identified and investigated only because of active epidemiological surveillance in the outbreak focus represents the particular asset of this study. PMID- 23358880 TI - Nail biting; etiology, consequences and management. AB - Nail biting (NB) is a common, but unresolved, problem in psychiatry, psychology, medicine and dentistry. While it seems that NB is a simple behavior that can be stopped easily, many of the children with NB have already tried to stop it, but they have not been successful. The frustrations due to failed attempt involve others such as parents and siblings. The present review aims at providing an overview of prevalence, co-morbidities, education and counseling, and management for NB. Overall, the reviewed literatures suggest that co-morbidities of psychiatric disorders and other stereotypic behaviors in clinical sample of children with NB is more than 80%, and more than half of the parents suffer from psychiatric disorders mainly depression. Treatment of NB, however, is not as easy as it seems. The management of NB is much more complicated than just focusing on stopping it. Nail biting cannot be managed without considering its co morbidities, antecedents and consequences. It might be concluded form the reviewed literature that children with NB, parents, siblings, and teachers should be educated about what to do and what not to do about NB. Punishment is not effective. Moreover, clinical randomized controlled trials are required to make available evidence-based behavioral and pharmacologic treatment protocols. PMID- 23358881 TI - Prognostic Value of Promoter Hypermethylation of Retinoic Acid Receptor Beta (RARB) and CDKN2 (p16/MTS1) in Prostate Cancer. AB - OBJECTIVE: The molecular mechanism of prostate cancer is poorly understood. The aim of the study was to investigate the prevalence and prognostic value of promoter hypermethylation of retinoic acid receptor beta (RARB) and p16 among benign prostatic hyperplasia (BPH) and prostate cancer patients. METHODS: In this case-control study, 63 patients were included in three groups; 21 with BPH as the control group, 21 with prostate cancer and good prognostic factors (based on prostate-specific antigen, Gleason score and stage) as good prognosis group, and 21 with prostate cancer and poor prognostic features as poor prognosis group. The prostate biopsy specimen of each individual was examined for hypermethylation of RARB and p16 promoters by methylation specific PCR (MSPCR). RESULTS: Seven (33.3%) patients with good prognosis and 15 (71.4%) patients with poor prognosis were positive for RARB methylation, which were significantly higher than controls (P<0.0001). p16 promoter methylation was shown in 19.0% and 47.6% patients with good and poor prognosis, respectively. The RARB and p16 promoter methylation in the poor prognosis group was significantly higher than that in the good prognosis group (P =0.02 for RARB and P<0.0001 for p16). CONCLUSION: Hypermethylation of RARB and p16 promoters may predict prognosis in prostate cancer. PMID- 23358882 TI - Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin induced diabetes in a mouse model. AB - AIMS/HYPOTHESIS: Cardiotrophin 1 (CT-1) is a recently described cytokine originally isolated from the heart where it has been shown to play an important role in apoptotic protection of cardiomyocytes and heart hypertrophy. Its beneficial properties have also been described in other organs such as liver and neuromuscular tissue. In the present study, we investigated whether CT-1 can confer protection against pro-apoptotic stimuli in pancreatic beta cells, and its role in insulin secretion and diabetes development. METHODS: The effects of CT-1 on apoptosis and function were studied using MIN6B1 cells and freshly isolated murine pancreatic islets. The impact on the development of diabetes was evaluated in Ct1-null (Ct1 (-/-)) mice (the gene Ct1 is also known as Ctf1) using two streptozotocin (STZ)-induced models of diabetes. RESULTS: CT-1 has a protective effect in MIN6B1 cells and murine islets under the pro-apoptotic stimulus of serum deprivation, which correlates with the expression of B cell lymphoma-extra large, or following exposure to a mixture of cytokines. In addition, CT-1 enhances glucose-stimulated insulin secretion in MIN6B1 cells and this was repressed by inhibitors of phospholipase C. Furthermore, Ct1 (-/-) mice were more prone to develop diabetes, and their glucose tolerance test showed impaired plasma glucose clearance which correlated with decreased pancreatic insulin secretion. CONCLUSIONS/INTERPRETATION: The results obtained from both in vitro and in vivo experiments show that CT-1 improves beta cell function and survival, and protects mice against STZ-induced diabetes. PMID- 23358883 TI - Function of Ikaros as a tumor suppressor in B cell acute lymphoblastic leukemia. AB - The Ikaros transcription factor is crucial for many aspects of hematopoiesis. Loss of function mutations in IKZF1, the gene encoding Ikaros, have been implicated in adult and pediatric B cell acute lymphoblastic leukemia (B-ALL). These mutations result in haploinsufficiency of the Ikaros gene in approximately half of the cases. The remaining cases contain more severe or compound mutations that lead to the generation of dominant-negative proteins or complete loss of function. All IKZF1 mutations are associated with a poor prognosis. Here we review the current genetic, clinical and mechanistic evidence for the role of Ikaros as a tumor suppressor in B-ALL. PMID- 23358885 TI - Expression of Gli1 in the hedgehog signaling pathway and breast cancer recurrence. PMID- 23358884 TI - Cardiac disease associated with increased risk of nonamnestic cognitive impairment: stronger effect on women. AB - OBJECTIVE: To investigate the association of cardiac disease with amnestic and nonamnestic mild cognitive impairment (aMCI and naMCI, respectively). Nonamnestic mild cognitive impairment, a putative precursor of vascular and other non Alzheimer dementias, is hypothesized to have a vascular etiology. DESIGN: A prospective, population-based, cohort study with a median 4.0 years of follow-up. SETTING: Olmsted County, Minnesota. PARTICIPANTS: A total of 2719 participants were evaluated at baseline and every 15 months using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing. A diagnosis of normal cognition, MCI, or dementia was made by consensus. Cardiac disease at baseline was assessed from the participant's medical records. MAIN OUTCOME MEASURES: Incident MCI, aMCI, or naMCI. RESULTS: Of 1450 participants without MCI or dementia at baseline, 366 developed MCI. Cardiac disease was associated with an increased risk of naMCI (hazard ratio, 1.77 [95% CI, 1.16-2.72]). However, the association varied by sex (P = .02 for interaction). Cardiac disease was associated with an increased risk of naMCI (hazard ratio, 3.07 [95% CI, 1.58 5.99]) for women but not for men (hazard ratio, 1.16 [95% CI, 0.68-1.99]). Cardiac disease was not associated with any type of MCI or with aMCI. CONCLUSIONS: Cardiac disease is an independent risk factor for naMCI; within-sex comparisons showed a stronger association for women. Prevention and management of cardiac disease and vascular risk factors may reduce the risk of naMCI. PMID- 23358886 TI - A novel dictionary based computer vision method for the detection of cell nuclei. AB - Cell nuclei detection in fluorescent microscopic images is an important and time consuming task in a wide range of biological applications. Blur, clutter, bleed through and partial occlusion of nuclei make individual nuclei detection a challenging task for automated image analysis. This paper proposes a novel and robust detection method based on the active contour framework. Improvement over conventional approaches is achieved by exploiting prior knowledge of the nucleus shape in order to better detect individual nuclei. This prior knowledge is defined using a dictionary based approach which can be formulated as the optimization of a convex energy function. The proposed method shows accurate detection results for dense clusters of nuclei, for example, an F-measure (a measure for detection accuracy) of 0.96 for the detection of cell nuclei in peripheral blood mononuclear cells, compared to an F-measure of 0.90 achieved by state-of-the-art nuclei detection methods. PMID- 23358887 TI - The interplay between interpersonal stress and psychological intimate partner violence over time for young at-risk couples. AB - The substantial number of young people in romantic relationships that involve intimate partner violence, a situation deleterious to physical and mental health, has resulted in increased attention to understanding the links between risk factors and course of violence. The current study examined couples' interpersonal stress related to not liking partners' friends and not getting along with parents as contextual factors associated with couples' psychological partner violence and determined whether and when couples' friend and parent stress increased the likelihood of couples' psychological partner violence. A linear latent growth curve modeling approach was used with multiwave measures of psychological partner violence, friend stress, parent stress, and relationship satisfaction obtained from 196 men at risk for delinquency and their women partners over a 12-year period. At the initial assessment, on average, the men were age 21.5 years and the women were age 21 years. Findings indicated that couples experiencing high levels of friend and parent stress were more likely to engage in high levels of psychological partner violence and that increases in couples' friend stress predicted increases in couples' partner violence over time, even when accounting for the couples' relationship satisfaction, marital status, children in the home, and financial strain. Interactive effects were at play when the couples were in their early 20s, with couples being most at risk for increases in psychological partner violence if they experienced both high friend stress and low relationship satisfaction. Couples' friend stress had the greatest effect on psychological partner violence when the couples were in their early to mid 20s when levels of friend stress were high. As the couples reached their 30s, low relationship satisfaction became the leading predictor of couples' psychological partner violence. PMID- 23358888 TI - Adolescent caffeine consumption and self-reported violence and conduct disorder. AB - Caffeine is the most widely used psychoactive substance in the world and currently the only one legally available to children and adolescents. The sale and use of caffeinated beverages has increased markedly among adolescents during the last decade. However, research on caffeine use and behaviors among adolescents is scarce. We investigate the relationship between adolescent caffeine use and self-reported violent behaviors and conduct disorders in a population-based cross-sectional sample of 3,747 10th grade students (15-16 years of age, 50.2 % girls) who were enrolled in the Icelandic national education system during February 2012. Through a series of multiple regression models, while controlling for background factors, Attention Deficit Hyperactivity Disorder symptoms and current medication and peer delinquency, and including measures on substance use, our findings show robust additive explanatory power of caffeine for both violent behaviors and conduct disorders. In addition, the association of caffeine to the outcomes is significantly stronger for girls than boys for both violent behaviors and conduct disorders. Future studies are needed to examine to what extent, if at all, these relationships are causal. Indication of causal connections between caffeine consumption and negative outcomes such as those reported here would call into question the acceptability of current policies concerning the availability of caffeine to adolescents and the targeting of adolescence in the marketing of caffeine products. PMID- 23358891 TI - Pulmonary hypertension, hemoptysis and an echocardiographic finding of a ventricular septal defect. PMID- 23358890 TI - Bcl-2-enhanced efficacy of microtubule-targeting chemotherapy through Bim overexpression: implications for cancer treatment. AB - Bcl-2 is commonly overexpressed in tumors, where it is often associated with unfavorable outcome. However, it has also been linked to a favorable sensitivity to microtubule-targeting agents (MTAs). We show that Bcl-2-overexpressing lung and breast cancer cells were more sensitive to both paclitaxel and vinorelbine. Bcl-2 over-expression also significantly potentiated in vivo efficacy of paclitaxel, in terms of tumor volume decrease and survival benefits, in models of nude mice bearing lung cancer xenografts. To further investigate this favorable effect of Bcl-2, a genomic approach was taken. It revealed that Bcl-2 overexpression induced up-regulation of the proapoptotic protein Bim in lung cancer cells and that, conversely, Bcl-2 silencing decreased Bim expression level. A gene regulation study implicated the transcription factor Forkhead box containing protein, class O3a in Bim up-regulation. Lastly, we show that Bim was responsible for MTA-triggered lung cancer cell death through a dynamin-related protein 1-mediated mitochondrial fragmentation. The Bcl-2-governed Bim induction evidence offers for the first time an explanation for the favorable higher sensitivity to treatment shown by Bcl-2-overexpressing cells. We suggest that Bim could be a powerful predictive factor for tumor response to MTA chemotherapy. Our data also give new insight into some failures in the efficacy of therapies targeted against Bcl-2. PMID- 23358889 TI - IFITM proteins restrict viral membrane hemifusion. AB - The interferon-inducible transmembrane (IFITM) protein family represents a new class of cellular restriction factors that block early stages of viral replication; the underlying mechanism is currently not known. Here we provide evidence that IFITM proteins restrict membrane fusion induced by representatives of all three classes of viral membrane fusion proteins. IFITM1 profoundly suppressed syncytia formation and cell-cell fusion induced by almost all viral fusion proteins examined; IFITM2 and IFITM3 also strongly inhibited their fusion, with efficiency somewhat dependent on cell types. Furthermore, treatment of cells with IFN also markedly inhibited viral membrane fusion and entry. By using the Jaagsiekte sheep retrovirus envelope and influenza A virus hemagglutinin as models for study, we showed that IFITM-mediated restriction on membrane fusion is not at the steps of receptor- and/or low pH-mediated triggering; instead, the creation of hemifusion was essentially blocked by IFITMs. Chlorpromazine (CPZ), a chemical known to promote the transition from hemifusion to full fusion, was unable to rescue the IFITM-mediated restriction on fusion. In contrast, oleic acid (OA), a lipid analog that generates negative spontaneous curvature and thereby promotes hemifusion, virtually overcame the restriction. To explore the possible effect of IFITM proteins on membrane molecular order and fluidity, we performed fluorescence labeling with Laurdan, in conjunction with two-photon laser scanning and fluorescence-lifetime imaging microscopy (FLIM). We observed that the generalized polarizations (GPs) and fluorescence lifetimes of cell membranes expressing IFITM proteins were greatly enhanced, indicating higher molecularly ordered and less fluidized membranes. Collectively, our data demonstrated that IFITM proteins suppress viral membrane fusion before the creation of hemifusion, and suggested that they may do so by reducing membrane fluidity and conferring a positive spontaneous curvature in the outer leaflets of cell membranes. Our study provides novel insight into the understanding of how IFITM protein family restricts viral membrane fusion and infection. PMID- 23358892 TI - Bacterial colonization of host cells in the absence of cholesterol. AB - Reports implicating important roles for cholesterol and cholesterol-rich lipid rafts in host-pathogen interactions have largely employed sterol sequestering agents and biosynthesis inhibitors. Because the pleiotropic effects of these compounds can complicate experimental interpretation, we developed a new model system to investigate cholesterol requirements in pathogen infection utilizing DHCR24(-/-) mouse embryonic fibroblasts (MEFs). DHCR24(-/-) MEFs lack the Delta24 sterol reductase required for the final enzymatic step in cholesterol biosynthesis, and consequently accumulate desmosterol into cellular membranes. Defective lipid raft function by DHCR24(-/-) MEFs adapted to growth in cholesterol-free medium was confirmed by showing deficient uptake of cholera toxin B and impaired signaling by epidermal growth factor. Infection in the absence of cholesterol was then investigated for three intracellular bacterial pathogens: Coxiella burnetii, Salmonella enterica serovar Typhimurium, and Chlamydia trachomatis. Invasion by S. Typhimurium and C. trachomatis was unaltered in DHCR24(-/-) MEFs. In contrast, C. burnetii entry was significantly decreased in -cholesterol MEFs, and also in +cholesterol MEFs when lipid raft associated alpha(V)beta(3) integrin was blocked, suggesting a role for lipid rafts in C. burnetii uptake. Once internalized, all three pathogens established their respective vacuolar niches and replicated normally. However, the C. burnetii-occupied vacuole within DHCR24(-/-) MEFs lacked the CD63-positive material and multilamellar membranes typical of vacuoles formed in wild type cells, indicating cholesterol functions in trafficking of multivesicular bodies to the pathogen vacuole. These data demonstrate that cholesterol is not essential for invasion and intracellular replication by S. Typhimurium and C. trachomatis, but plays a role in C. burnetii-host cell interactions. PMID- 23358893 TI - Members of 3-O-Sulfotransferases (3-OST) Family: A Valuable Tool from Zebrafish to Humans for Understanding Herpes Simplex Virus Entry. AB - The journey of many viruses to infect cells begins when the virus first binds to cell surface heparan sulfate (HS). The initial step of cell attachment or binding during herpes simplex virus type-1 (HSV-1) entry is mediated by envelope glycoprotein B (gB) and C (gC). The binding is followed by fusion between virus envelope and cell membrane during which HSV-1 glycoprotein D (gD) interacts with a modified form of HS know as 3-O-sulfated heparan sulfate (3-OS HS). The rare modification of 3-O-sulfation on HS chain is governed by enzymes known as 3-O sulfotransferase (3-OST). Currently, there are seven isoforms of human 3-OSTs that have been identified, and with the exception of 3-OST-1, all other 3-OST isoforms allow HSV-1 entry and spread. Recently, the product of the zebrafish (ZF)-encoded 3-OST-3 was also recognized as a gD receptor, which mediates HSV-1 entry and cell-cell fusion similar to human 3-OST-3. Interestingly, the ZF system expresses multiple isoforms of 3-OST which could be very useful for studying the involvement of HS and 3-OS HS in virus tropism and virus-induced inflammation. In addition, therapeutic targeting of 3-OST generated HS is likely to bring about novel interventions against HSV-1. In this review we have taken a closer look at the potential of both human and ZF encoded 3-OSTs as valuable tools in HSV entry and inflammation studies. PMID- 23358894 TI - Fibroblast growth factor 21: a novel metabolic regulator from pharmacology to physiology. AB - Fibroblast growth factor 21 (FGF21) is a member of the fibroblast growth factor family. It actually functions as endocrine hormones but does not regulate cell growth and differentiation. It is demonstrated that FGF21 acts on multiple tissue to coordinate carbohydrate and lipid metabolism, including enhancing insulin sensitivity, decreasing triglyceride concentrations, causing weight loss, ameliorating obesity-associated hyperglycemia and hyperlipidemia. Moreover, FGF21 also plays important roles in some physiological processes, such as fasting and feeding, growth hormone axis and thermogenic function of brown adipose tissue. Clinical relevance of FGF21 in humans is still unclear, and the basis and consequences of increased FGF21 in metabolic disease remain to be determined. Both the pharmacological actions and physiological roles make FGF21 attractive drug candidates for treating metabolic disease, but some questions remain to be answered. This article concentrates on recent advances in our understanding of FGF21. PMID- 23358895 TI - Association of SIPA1 545 C > T polymorphism with survival in Chinese women with metastatic breast cancer. AB - It has been demonstrated that single nucleotide polymorphisms (SNPs) of SIPA1 (signal-induced proliferation associated gene 1) are associated with metastatic efficiency in both human and rodents. The purpose of this study was to determine whether SIPA1 545 C > T polymorphism was associated with overall survival in patients with metastatic breast cancer. In this study, SIPA1 545 C > T polymorphism was detected in 185 metastatic breast cancer patients using polymerase chain reaction-restriction fragment length polymorphism assay (PCR RFLP). Survival curves for patients with SIPA1 545 C > T polymorphism was compared using the Kaplan-Meier method with log-rank tests. We found that SIPA1 545 C > T polymorphism was significantly associated with survival in 185 patients with metastatic breast cancer. Patients with SIPA1 545 T/T genotype had a significantly worse overall survival (OS) than did patients with C/T or C/C genotype (50.0% vs. 62.9%, P = 0.042). Moreover, in multivariate analysis, as compared with the C/C or C/T genotype, the T/T genotype remained an independent unfavorable prognostic marker of OS in this cohort (hazard ratio [HR] = 2.16; 95% CI = 1.12-4.15; P = 0.022). Our findings indicate that metastatic breast cancer patients with SIPA1 545 T/T genotype have a poorer survival compared to patients with C/C or C/T genotype. PMID- 23358897 TI - An uncommon case of abdominal pain: superior mesenteric artery syndrome. AB - Superior mesenteric artery (SMA) syndrome is a rare cause of abdominal pain, nausea and vomiting that may be undiagnosed in patients presenting to the emergency department (ED). We report a 54-year-old male presenting to a community ED with abdominal pain and the subsequent radiographic findings.The patient's computed tomgraphy (CT) of the abdomen and pelvis demonstrates many of the hallmark findings consistent with SMA syndrome, including; compression of the duodenum between the abdominal aorta and superior mesenteric artery resulting in intestinal obstruction, dilation of the left renal vein, and gastric distension. Patients diagnosed with SMA syndrome have a characteristically short distance between the superior mesenteric artery and the aorta (usually 2-8 mm) in contrast to healthy patients (10-34 mm). Our patient's aortomesenteric distance was measured to be approximately 4 mm. Furthermore, the measured angle between the superior mesenteric artery and the aorta is reduced in patients with SMA syndrome from a normal range of 28 degrees -65 degrees to a measurement between 6 degrees -22 degrees . Our patient's aortomesenteric angle was difficult to measure secondary to poor sagittal reconstructions, but appears to be approximately 30 degrees . Following radiographic evidence suggesting SMA syndrome together with our patient's constellation of presenting symptoms, a diagnosis of SMA syndrome was made and the patient was admitted to the general surgery service. However, our patient decided to leave against medical advice owing to improvement of his symptoms following the emptying of two liters of gastric contents via nasogastric tube evacuation. PMID- 23358896 TI - Comprehensive analysis of DNA methylation in head and neck squamous cell carcinoma indicates differences by survival and clinicopathologic characteristics. AB - Head and neck squamous cell carcinoma (HNSCC) is the eighth most commonly diagnosed cancer in the United States. The risk of developing HNSCC increases with exposure to tobacco, alcohol and infection with human papilloma virus (HPV). HPV-associated HNSCCs have a distinct risk profile and improved prognosis compared to cancers associated with tobacco and alcohol exposure. Epigenetic changes are an important mechanism in carcinogenic progression, but how these changes differ between viral- and chemical-induced cancers remains unknown. CpG methylation at 1505 CpG sites across 807 genes in 68 well-annotated HNSCC tumor samples from the University of Michigan Head and Neck SPORE patient population were quantified using the Illumina Goldengate Methylation Cancer Panel. Unsupervised hierarchical clustering based on methylation identified 6 distinct tumor clusters, which significantly differed by age, HPV status, and three year survival. Weighted linear modeling was used to identify differentially methylated genes based on epidemiological characteristics. Consistent with previous in vitro findings by our group, methylation of sites in the CCNA1 promoter was found to be higher in HPV(+) tumors, which was validated in an additional sample set of 128 tumors. After adjusting for cancer site, stage, age, gender, alcohol consumption, and smoking status, HPV status was found to be a significant predictor for DNA methylation at an additional 11 genes, including CASP8 and SYBL1. These findings provide insight into the epigenetic regulation of viral vs. chemical carcinogenesis and could provide novel targets for development of individualized therapeutic and prevention regimens based on environmental exposures. PMID- 23358898 TI - Effects of occupational exposure to lead on left ventricular echocardio graphic variables. AB - BACKGROUND: Lead contamination can affect many body organs including the heart. This study assessed a number of echocardiographic indices to clarify the effects of lead on cardiac function among battery factory workers who are in constant exposure to lead. METHODS: In a cross-sectional study, 142 male battery factory workers who had been exposed to lead for at least 1 year were evaluated. The subjects aged 25-55 years old and were excluded if they had hypertension, diabetes, or cardiovascular diseases. Demographic characteristics, professional profile, lead exposure, history of respiratory diseases, drugs intake, and lifestyle information of the participants were collected. Height, weight and blood pressure measurements were then performed. Blood tests were also ordered to determine blood lead levels. The subjects finally underwent M-mode and Doppler echocardiography. Linear regression analysis was used to establish the effects of lead on the target indices. All statistical analyses were conducted in SPSS18. RESULTS: The mean age and mean duration of lead exposure of the subjects were 41.78 +/- 13.58 and 23.54 +/- 14.44 years, respectively. The mean blood lead level was 7.59 +/- 2.75 ug/dl. Left ventricular hypertrophy was detected in 12% of the participants. Blood lead levels were not significantly related with echocardiographic indices in the crude model or after adjustments for age alone or for age and other risk factors. CONCLUSION: Blood lead levels of our participants were below standard values. In addition, no significant relation was found between left ventricular function indices and blood lead levels. The absence of such relations could have been caused by the exclusion of individuals with hypertension or cardiovascular diseases. Structural modifications in battery factories following legislations in Iran might have been responsible for low blood lead levels among the subjects. PMID- 23358899 TI - Impact of frequent hemodialysis on anemia management: results from the Frequent Hemodialysis Network (FHN) Trials. AB - BACKGROUND: The extent to which anemia management is facilitated by more frequent hemodialysis (HD) is controversial. We hypothesized as a preselected outcome that patients receiving HD six times (6*) compared with three times (3*) per week would require lower doses of erythropoietin-stimulating agents (ESA) and/or achieve higher blood hemoglobin (Hb) concentrations. METHODS: Subjects enrolled in the Frequent Hemodialysis Network (FHN) daily and nocturnal trials were studied. As the primary outcome for anemia, the dose of ESAs was recorded at 4 month intervals and the monthly dose of intravenous iron (IV Fe) was reported. Serum iron, transferrin saturation and ferritin were measured at baseline and then at 4-month intervals, whereas Hb concentration was measured monthly. RESULTS: There was no significant treatment effect in the 6* versus 3* treatment groups on logESA dose or the ratio of log of ESA dose to Hb concentration in either trial. In the daily trial, Hb concentrations increased significantly in the 6* versus 3* group, at Month 12 compared with baseline (0.3 g/dL; 95% CI: 0.05-0.58, P<0.021), but both groups had Hb concentrations in the usual target range. In the daily trial, the weekly logESA dose and the logESA dose to Hb concentration ratio tended to decline more in the 6* versus 3* group. This trend was not observed in the nocturnal trial. IV Fe doses were significantly lower in the 6* compared with the 3* group by Month 12 in the nocturnal trial, but not different in the daily trial. CONCLUSIONS: In the FHN Daily and Nocturnal Trials, more frequent HD did not have a significant or clinically important effect on anemia management. PMID- 23358900 TI - On measuring miRNAs after transient transfection of mimics or antisense inhibitors. AB - The ability to alter microRNA (miRNA) abundance is crucial for studying miRNA function. To achieve this there is widespread use of both exogenous double stranded miRNA mimics for transient over-expression, and single stranded antisense RNAs (antimiRs) for miRNA inhibition. The success of these manipulations is often assessed using qPCR, but this does not accurately report the level of functional miRNA. Here, we draw attention to this discrepancy, which is overlooked in many published reports. We measured the functionality of exogenous miRNA by comparing the total level of transfected miRNA in whole cell extracts to the level of miRNA bound to Argonaute following transfection and show that the supraphysiological levels of transfected miRNA frequently seen using qPCR do not represent the functional levels, because the majority of transfected RNA that is detected is vesicular and not accessible for loading into Argonaute as functionally active miRNAs. In the case of microRNA inhibition by transient transfection with antisense inhibitors, there is also the potential for discrepancy, because following cell lysis the abundant inhibitor levels from cellular vesicles can directly interfere with the PCR reaction used to measure miRNA level. PMID- 23358901 TI - Clinicopathological Significance of Mucin 2 Immuno-histochemical Expression in Colorectal Cancer: A Meta-Analysis. AB - OBJECTIVE: To evaluate the association between mucin 2 (MUC2) expression and clinicopathological characters of colorectal cancer. METHODS: A literature search was performed on December 31, 2010 according to defined selection criteria. We evaluated the correlation between MUC2 (detected by immunohistochemistry) and clinicopathological characters of colorectal cancer. According to the tumor histological type, differentiation, location and TNM staging of colorectal carcinoma, we divided the clinicopathological characteristics into different subgroups. Fixed and random effects models were applied for estimation of the summarized risk ratios (RRs) and 95% confidence intervals (CIs) in different subgroups. Finally, forest plots and funnel plots were created to allow for visual comparison of the results or the effect of publication bias. RESULTS: According with the inclusive criteria, fourteen studies (n=1,558) were eligible for the meta-analysis. We observed a trend towards a correlation of MUC2 higher positivity in mucinous than non-mucinous carcinoma (RR, 2.10; 95% CI, 1.30-3.40; P=0.002) and less positivity in distal than proximal colon (RR, 0.74; 95% CI, 0.64-0.85; P=0.000). There was no statistically significance for the association between MUC2 expression and differentiation or TNM staging of colorectal cancer, but MUC2 overexpression tended to be associated with the presence of T stage tumor (RR, 1.17; P=0.052). CONCLUSION: MUC2 overexpression was associated with the mucinous and proximal colorectal cancer. PMID- 23358902 TI - Cadmium exposure and the risk of breast cancer in Japanese women. AB - Non-occupational exposure to cadmium has been suspected to be a risk factor for breast cancer. The present study examined the association between urinary cadmium level and the risk of breast cancer in a case-control study among Japanese women. Cases were 153 women newly diagnosed and histologically confirmed with breast cancer at a general hospital in Gifu, Japan. A total of 431 controls individually matched to cases by age, menopausal status, and the period of urine sampling were selected from those who attended a breast cancer mass screening at this hospital. Urinary cadmium levels were measured using spot urine samples. Spot urine samples were collected from cases after surgery but before any cancer therapy. For controls, spot urine samples were obtained at the date of the screening visit. Information on known or suggested breast cancer risk factors was obtained by a self-administered questionnaire. The odds ratios (ORs) and 95 % confidence intervals (CIs) of breast cancer according to the tertile of the creatinine adjusted cadmium level were calculated using conditional logistic regression models. Women in the highest tertile of the creatinine-adjusted cadmium level (>2.620 MUg/g) had significantly elevated OR of breast cancer relative to those in the lowest tertile (<1.674 MUg/g) after controlling for covariates [OR = 6.05, (95 % CI 2.90, 12.62)]. The trend of increase in risk with increasing cadmium level was also statistically significant [OR = 1.67, (95 % CI 1.39, 2.01) for every 1.0 MUg/g increase in urinary cadmium level, P-trend <0.01]. These data suggested that exposure to cadmium was associated with a risk of breast cancer in Japanese women. PMID- 23358903 TI - Molecularly targeted therapies for metastatic triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) refers to a heterogeneous group of tumors that do not express the estrogen/progesterone-receptor (ER/PR), and human epidermal growth factor receptor-2 (HER2). TNBC is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapy regimens. There have been significant improvements in the outcome of other subtypes of breast cancer, including ER positive/HER2 overexpressed tumors, attributed to the addition of targeted therapy, including hormonal agents and trastuzumab. However, no specific targeted agents are currently available for the treatment of TNBC. This review aims to collate and describe the most recent data on targeted therapies that have demonstrated efficacy in the management of metastatic TNBC. Targeted agents that have been investigated in the treatment of metastatic TNBC include inhibitors of poly(ADP-ribose) polymerase, angiogenesis, mammalian target of rapamycin, epidermal growth factor receptor, HDAC, Jak2, and Src. Several of these agents have shown considerable promise. PMID- 23358904 TI - Changes in adherence to statins and subsequent lipid profiles during and following breast cancer treatment. AB - Breast cancer tends to arise in older women who are also burdened with comorbidities such as cardiovascular disease (CVD). Increasing numbers of breast cancer survivors and an aging population warrant a better understanding of CVD management and adherence to preventive therapies. We estimated adherence to statins and therapeutic goal lipid values during the year before breast cancer diagnosis or baseline, treatment period, and in subsequent years of clinical management among breast cancer survivors. We sampled women from an existing cohort of 4,221 women diagnosed with incident early stage (I, II) invasive breast cancer from 1990 to 2008 and enrolled in a large integrated group practice health plan. Among prevalent statin users (N = 1,393), medication adherence and persistence were measured by medication possession ratio (MPR), % adherent (MPR < 0.80), and discontinuation rates. Laboratory data on LDL and HDL were obtained for the coinciding periods. Mean MPR for statin use (0.78 vs. 0.68; P < 0.001) and proportion adherent (67.0 vs. 51.9 %; P < 0.001) declined from baseline to the treatment period. Mean LDL (143 mg/dL baseline vs. 150 mg/dL treatment period; P < 0.001) and proportion not at LDL goal (60.1 vs. 70.8 %; P < 0.001) coincided with decreases in adherence. During treatment, non-adherent statin users had the highest mean LDL (160.4 mg/dL) and proportion not at goal LDL (91.8 %) overall. Adherence did not return to baseline in subsequent years following treatment although LDL levels did. HDL did not differ by periods of interest or adherence levels. Adherence to statins in this population was poor, particularly in the treatment period, and lagged in returning to baseline. Understanding the influence of life events such as cancer diagnosis and treatment on management of comorbidities and adherence to preventive therapies are important to the growing population of breast cancer survivors. PMID- 23358906 TI - Expert's comment concerning grand rounds case entitled "solid variant of aneurysmal bone cyst on the cervical spine of a child: case report, differential diagnosis, and treatment rationale" (by Christos Karampalis, Robert Lenthall, and Bronek Boszczyk). PMID- 23358905 TI - Answer to the letter to the editor of A. Gardner concerning "Loss of apical vertebral derotation in adolescent idiopathic scoliosis: 2-year follow-up using multi-planar reconstruction computed tomography" (by G. Cui, K. Watanabe, Y. Nishiwaki, N. Hosogane, T. Tsuji, K. Ishii, M. Nakamura, Y. Toyama, K. Chiba, M. Matsumoto; Eur spine j (2012) Jun;21(6):1111-20. doi:10.1007/s00586-012-2633-0). PMID- 23358907 TI - New concepts in scoliosis treatment. PMID- 23358908 TI - Longitudinal study of the neurodevelopmental characteristics of treated and untreated nonsyndromic craniosynostosis in infancy. AB - PURPOSE: Nonsyndromic craniosynostosis (NSC) are a group of congenital disorders sharing premature fusion of one or more of the cranial sutures that restricts and distorts growth of the skull and underlying brain. This study examined the neurodevelopmental sequelae of NSC both prior to and following reconstructive cranial surgery. METHODS: Sixty-four consecutive referrals with mixed forms of untreated NSC aged 4 to 16 months (M = 8.9, SD = 2.9) comprised the pre-operative cohort. Forty-four of these patients aged 6 to 32 months (M = 21.2, SD = 4.5) underwent post-operative developmental evaluation. Neurodevelopmental function was assessed with the mental (Mental Development Index) and motor (Psychomotor Development Index) scales of the Bayley Scales of Infant Development-2nd edition. RESULTS: Children with untreated NSC displayed significantly lower mental (M = 97.5) and motor (M = 87.7) scores than normative expectations, with the distribution of scores also differing significantly from the normative distribution. Post-operatively, children continued to display significantly lower mental (M = 89.5) and motor (M = 88.0) abilities, with mental abilities falling significantly lower than pre-operative levels. An increased prevalence of severe motor delay was found, and no child displayed accelerated development. Subgroup comparisons revealed no differences in mental or motor skills between the primary diagnostic subtypes (sagittal and metopic synostosis) both prior to and following corrective surgery. CONCLUSIONS: NSC is associated with an increased incidence of developmental delay in both treated and untreated conditions. Timing of surgery appears unrelated to developmental outcome. PMID- 23358909 TI - Embryonal tumor with abundant neuropil and true rosettes: an autopsy case-based update and review of the literature. AB - INTRODUCTION: Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a rare subtype of primitive neuroectodermal tumors first reported in 2000. It is rare among the group of embryonal central nervous system tumors with approximately 50 reported cases. ETANTR has been suggested to be a separate entity among this group of tumors. CASE REPORT: Herein, we present only the second autopsy case of ETANTR, which occurred in a 17-month-old boy, and was located in the brainstem. The tumor was inoperable, and despite chemotherapy, the child died 3 months after initial hospitalization. A brain only autopsy was performed. DISCUSSION: Neuropathological and neuroimaging examinations suggest ETANTR grew by expansion rather than invasion distorting anatomical structures of the posterior fossa. We suggest that the characteristic histopathological picture of the tumor is the result of multifocal and dispersed germinative activity surrounded by mature neuropil-like areas. CONCLUSION: ETANTR is a pediatric tumor occurring in children under 4 with a significantly poor prognosis with more cases and research required to characterize this rare embryonal tumor. PMID- 23358910 TI - Iodine deficiency: a probable cause of neural tube defect. AB - INTRODUCTION: Iodine deficiency is the most devastating event in developing brain in the fetus and neonate. Iodine is absolutely necessary on the myelination, neuronal differentiation, and formation of neural processes, synaptogenesis, and neuronal migration by thyroidal hormones throughout pregnancy and shortly after birth. Neural tube defects (NTD) form after third and fourth gestational weeks and their etiologies are multifactorial. CASE REPORT: We herein present a male newborn with iodine deficiency and thoracic neuroenteric cyst bound to a myelomeningocele via a pedinculi. We hypothesize that iodine deficiency may be a cause of NTD, and iodine supplementation in preconception and pregnancy may prevent NTD. PMID- 23358911 TI - Identification and characterization of an extracellular alkaline phosphatase in the marine diatom Phaeodactylum tricornutum. AB - In phosphorus-deficient conditions, Phaeodactylum tricornutum releases an alkaline phosphatase (PtAPase) to the medium that is readily detectable by activity staining. Nucleic acid and amino acid sequence of this alkaline phosphatase (APase) was identified by performing proteomic analysis and database searches. Sequence alignment suggests that PtAPase belongs to the PhoA family, and it possesses key residues at the Escherichia coli PhoA active site. Quantitative PCR results indicate that the induction of APase mRNA transcription is very sensitive to phosphorus availability and population growth. The molecular mass of native PtAPase (148 kDa) determined by gel filtration chromatography indicates that PtAPase, like most PhoA, is homodimeric. Zn and Mg ions are essential cofactors for most PhoA enzymes; however, PtAPase activity did not require Zn ions. In fact, 5 mM Zn2+, Mo2+, Co2+, Cd2+, or Cu2+ inhibited its enzymatic activity, whereas 5 mM Mn2+, Mg2+, or Ca2+ enhanced its enzymatic activity. The responses of PtAPase to divalent metal ions were different from those of most PhoAs, but were similar to the PhoA in a marine bacterium, Cobetia marina. Phylogenetic analysis shows that homologs of PhoA are also present in other diatom species, and that they clustered in a unique branch away from other PhoA members. PtAPase may represent a novel class of PhoA that helps diatoms to survive in the ocean. Quantification of the PtAPase mRNA may help monitor the physiological condition of diatoms in natural environments and artificial bioreactors. PMID- 23358912 TI - Abnormal circumferential strain is present in young Duchenne muscular dystrophy patients. AB - Advances in management of non-cardiac issues in Duchenne muscular dystrophy (DMD) have improved such that DMD-associated cardiac disease has become the leading cause of death for such patients. Cardiac dysfunction measured by standard transthoracic echocardiographic methods, e.g., fractional shortening (FS) and ejection fraction (EF), is rarely present during the first decade of life. The current study used transthoracic echocardiogram (TTE) to assess strain (epsilon), an indicator of regional ventricular function, in young DMD patients. A retrospective review of the TTE database was performed. TTE results from DMD patients <8 years (n = 63) performed during 2009 to 2010 were compared with TTE results from an unaffected control group (n = 61). Feature tracking analysis software was used to measure total circumferential strain (epsilon cc) as well as segmental epsilon cc based on the American Society of Echocardiography 16-segment model. Although there were no differences in FS, the absolute value for left ventricular (LV) epsilon cc at the mid-chamber level was decreased in DMD (-21.7 % +/- 3.8 % vs. -19.8 % +/- 4.2 %, p < 0.01; unaffected vs. DMD). Segmental epsilon(cc) was similarly affected in the anteroseptal segment (-23.0 % +/- 6.1 % vs. -18.9 % +/- 7.0 %, p = 0.001; controls vs. DMD), the inferior segment (-20.7 % +/- 5.16 % vs. -17.7 % +/- 6.1 %, p = 0.003; controls vs. DMD), and the inferolateral segment (-18.3 % +/- 6.2 % vs. -15.9 % +/- 6.7 %, p = 0.04; controls vs. DMD). In the present study we demonstrate both total and segmental LV epsilon cc (anteroseptal, inferior, and inferolateral segments) abnormalities at the mid-chamber level in a large group of young DMD patients with normal FS. These novel findings substantiate that the disease process is present and results in abnormal myocardial function before standard measures detect global dysfunction. PMID- 23358913 TI - Rheumatic severe mitral stenosis with complete heart block. AB - Rheumatic fever presenting with complete heart block is very rare and usually transient. We describe a child with chronic severe rheumatic mitral stenosis with persistent complete heart block with interesting echocardiographic findings. PMID- 23358914 TI - Detection and identification of globally distributed mycobacterial fish pathogens in some ornamental fish in India. AB - Mycobacteriosis is a progressive disease of a wide range of wild and captive, marine and freshwater fish species. Conventional detection of fish Mycobacteria is based on histopathology, culture, and biochemical characteristics. The present study analyzed the occurrence of Mycobacteria in clinically ill ornamental fish of different species, from different places of India. In first group, 60 fish were examined for presence of granulomatous inflammation and acid-fast bacteria. Thirty-eight (63.34 %) fish were positive for granulomatous inflammations. Presences of acid-fast bacteria were detected in 27 (45 %) fish having granulomatous inflammation and in two (3.33 %) fish without granulomatous inflammation. In total, AFB were found in 29 (48.34 %) of the 60 fish examined. In second group, 20 fish having granulomatous inflammation, 12 (60 %) samples were positive using Ziehl-Neelsen (Z-N) staining and 11 (55 %) of them were culture positive. Eight (40 %) samples were Z-N negative but two (10 %) of them were culture positive. In total, 13 (65 %) of the 20 examined fish were culture positive. On the basis of biochemical tests and 16S rRNA sequencing, 13 isolates were identified: five as Mycobacterium fortuitum, five as Mycobacterium gordonae, and three as Mycobacterium chelonae. In comparison of two decontamination methods, 2 % HCl treatment was better than 4 % NaOH treatment. Mycobacteria recovery from decontaminated samples was significantly high on Lowenstein-Jensen medium compared to Middlebrook 7H11 agar and Stonebrink (SB) media. The disease is transmissible from fish to fish and also from fish to human, so the significance of Mycobacteria in ornamental fish should not be overlooked. PMID- 23358915 TI - No evidence of efficacy or evidence of no efficacy. PMID- 23358916 TI - Estimating improvement in prediction with matched case-control designs. AB - When an existing risk prediction model is not sufficiently predictive, additional variables are sought for inclusion in the model. This paper addresses study designs to evaluate the improvement in prediction performance that is gained by adding a new predictor to a risk prediction model. We consider studies that measure the new predictor in a case-control subset of the study cohort, a practice that is common in biomarker research. We ask if matching controls to cases in regards to baseline predictors improves efficiency. A variety of measures of prediction performance are studied. We find through simulation studies that matching improves the efficiency with which most measures are estimated, but can reduce efficiency for some. Efficiency gains are less when more controls per case are included in the study. A method that models the distribution of the new predictor in controls appears to improve estimation efficiency considerably. PMID- 23358917 TI - Primary pediatric cardiac malignancies: the SEER experience. AB - PURPOSE: Pediatric cardiac malignancies are exceedingly rare. We sought to examine demographics, presentation, and outcomes for this pathology. METHODS: The SEER registry from 1973 to 2008 was queried for all patients <20 years of age with cardiac malignancies. RESULTS: A total of 25 pediatric patients were identified with primary cardiac malignancies, with age-adjusted incidence of 0.00686 per 100,000 United States population. Median age at diagnosis was 10 years. The majority of patients were adolescent (n = 13, 52 %), Caucasian (n = 17, 68 %) and males (n = 14, 56 %). The most common histology was soft tissue sarcoma (n = 10, 40%), followed by non-Hodgkin lymphoma and teratoma (both n = 3, 12 %). Six patients presented with distant disease. More than half of patients (n = 16, 64 %) underwent surgical resection, while four patients (16 %) underwent radiation. The mean survival time for the cohort was 47 +/- 67 months, with 14 (56 %) patients dying over the study period. Lymphomas had significantly longer survival than other malignancies (108 +/- 66 vs. 36 +/- 66, p = 0.03), while lack of surgical treatment was associated with worse survival (p = 0.016). CONCLUSIONS: Primary malignant cardiac tumors are exceedingly rare in pediatric patients. They are most commonly soft tissue sarcomas and lymphomas demonstrated longer survival. PMID- 23358919 TI - Assessment of myocardial viability in patients with acute myocardial infarction by two-dimensional speckle tracking echocardiography combined with low-dose dobutamine stress echocardiography. AB - It is clinically important to determine the myocardial viability of regional wall motion abnormality segments in patients with acute myocardial infarction (AMI). The purpose of this study was to ascertain the ability and value of a combination of speckle tracking echocardiography (STE) and low dose dobutamine stress echocardiography (LDDSE) for the evaluation of viable myocardium in patients with AMI. Forty-two hospitalized patients with AMI and left ventricular systolic dysfunction (left ventricular ejection fraction <50%) were underwent STE in conjunction with LDDSE and dual isotope simultaneous acquisition single photon emission computed tomography (DISA-SPECT). Percutaneous coronary intervention (PCI) was performed subsequently in all patients. STE was used to measure radial, circumferential, and longitudinal end-systolic strain and peak systolic strain rate. The movement of each segment was observed by routine echocardiography 1, 3, and 6 months after PCI, and its improvement over time was the criterion of viable myocardium. The sensitivity, specificity and accuracy of DISA-SPECT for the assessment of viable myocardium were 83.6, 74.4, and 80.7%, respectively. Among the radial, circumferential, and longitudinal strain and strain rate parameters, only longitudinal strain (LS) and longitudinal strain rate (LSr) at rest and LDDSE emerged as independent predictors of viable myocardium, When combining LS and LSr at LDDSE, the sensitivity, specificity and accuracy for the assessment of viable myocardium rose to 89.8, 90.2 and 89.9%, respectively. The sensitivity of STE in conjunction with LDDSE was similar to DISA-SPECT for detecting viable myocardium in patients with AMI, but the specificity and accuracy of STE performed with LDDSE were higher than DISA-SPECT. PMID- 23358918 TI - Association of inflammatory markers with the morphology and extent of coronary plaque as evaluated by 64-slice multidetector computed tomography in patients with stable coronary artery disease. AB - We evaluated the association between inflammatory markers and coronary artery plaque assessed by 64-slice multidetector computed tomography. Coronary computed tomography angiography was performed in patients with chest discomfort suggestive of coronary artery disease (CAD). Individuals with an acute coronary syndrome were excluded from the study. Coronary plaque morphology, the number of artery segments exhibiting plaque, and the number of vessels with >50% stenosis were evaluated. Plasma levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), plasminogen activator inhibitor-1, and vascular endothelial growth factor were measured. Among the 178 patients studied (age 65 +/- 10 years; 70% men), 125 were diagnosed with CAD. Hs-CRP and IL-6 concentrations were significantly higher in patients with CAD than in patients without (2.73 +/- 4.7 vs. 1.32 +/- 2.6 mg/L, P = 0.018, and 3.06 +/- 3.3 vs. 2.19 +/- 2.4 pg/mL, P = 0.036). The IL-6 level was high in patients with predominantly calcified plaque, and was significantly higher in patients with 4-9 plaque segments than in those with no or 1-3 plaque segments (4.07 +/- 5.3 vs. 2.19 +/- 2.4 pg/mL and 2.43 +/- 2.0 pg/mL, respectively, P = 0.025). The number of stenotic vessels was not significantly related to inflammatory markers. Multivariate logistic analysis revealed that plasma levels of hs-CRP but not IL-6 were associated with the presence of coronary plaque with calcification (OR 3.37, P = 0.026). This study supports the usefulness of inflammatory markers for the evaluation of coronary plaque in patients with stable CAD. PMID- 23358921 TI - Optimizing bone surveys performed for suspected non-accidental trauma with attention to maximizing diagnostic yield while minimizing radiation exposure: utility of pelvic and lateral radiographs. AB - BACKGROUND: Skeletal surveys for non-accidental trauma (NAT) include lateral spinal and pelvic views, which have a significant radiation dose. OBJECTIVE: To determine whether pelvic and lateral spinal radiographs should routinely be performed during initial bone surveys for suspected NAT. MATERIALS AND METHODS: The radiology database was queried for the period May 2005 to May 2011 using CPT codes for skeletal surveys for suspected NAT. Studies performed for skeletal dysplasia and follow-up surveys were excluded. Initial skeletal surveys were reviewed to identify fractures present, including those identified only on lateral spinal and/or pelvic radiographs. Clinical information and MR imaging was reviewed for the single patient with vertebral compression deformities. RESULTS: Of the 530 children, 223 (42.1%) had rib and extremity fractures suspicious for NAT. No fractures were identified solely on pelvic radiographs. Only one child (<0.2%) had vertebral compression deformities identified on a lateral spinal radiograph. This infant had rib and extremity fractures and was clinically paraplegic. MR imaging confirmed the vertebral body fractures. CONCLUSION: Since no fractures were identified solely on pelvic radiographs and on lateral spinal radiographs in children without evidence of NAT, nor in nearly all with evidence of NAT, inclusion of these views in the initial evaluation of children for suspected NAT may not be warranted. PMID- 23358920 TI - Myocardial dysfunction and chronic heart failure in patients with long-lasting type 1 diabetes: a 7-year prospective cohort study. AB - The aim of the study is to evaluate the prevalence and incidence of myocardial dysfunction (MD) and heart failure (HF) in long-lasting (>=10 years) type 1 diabetes without cardiovascular disorders or with hypertension or coronary heart disease (CHD). The study included 1,685 patients with type 1 diabetes (mean baseline age, 51 years; diabetes duration, 36 years). In all patients, echocardiography was performed, NT-proBNP levels were measured, and clinical symptoms were evaluated. A 7-year follow-up was conducted to monitor systolic and diastolic manifestations of MD and HF. At the end of the follow-up period, the prevalence of HF in the entire group was 3.7 %, and the incidence was 0.02 % per year. The prevalence of MD was 14.5 % and the incidence -0.1 % per year. MD and HF were observed only in hypertensive or CHD patients. At baseline, subjects with diastolic HF constituted 85 % of the HF population and those with systolic HF the remaining 15 %. Baseline HF predictors included age, diabetes duration, HbA1c levels, CHD, systolic blood pressure >140 mmHg, and GFR <60 mL/min/1.73 m(2). In patients with type 1 diabetes, MD and HF occurred only when diabetes coexisted with cardiovascular disorders affecting myocardial function. The prevalence and incidence of HF in patients with hypertension and CHD were relatively low. While the cause of this observation remains uncertain, it could probably be explained, at least partially, by the cardioprotective effect of concomitant treatment. PMID- 23358922 TI - Chemical imaging of drug delivery systems with structured surfaces-a combined analytical approach of confocal raman microscopy and optical profilometry. AB - Confocal Raman microscopy is an analytical technique with a steadily increasing impact in the field of pharmaceutics as the instrumental setup allows for nondestructive visualization of component distribution within drug delivery systems. Here, the attention is mainly focused on classic solid carrier systems like tablets, pellets, or extrudates. Due to the opacity of these systems, Raman analysis is restricted either to exterior surfaces or cross sections. As Raman spectra are only recorded from one focal plane at a time, the sample is usually altered to create a smooth and even surface. However, this manipulation can lead to misinterpretation of the analytical results. Here, we present a trendsetting approach to overcome these analytical pitfalls with a combination of confocal Raman microscopy and optical profilometry. By acquiring a topography profile of the sample area of interest prior to Raman spectroscopy, the profile height information allowed to level the focal plane to the sample surface for each spectrum acquisition. We first demonstrated the basic principle of this complementary approach in a case study using a tilted silica wafer. In a second step, we successfully adapted the two techniques to investigate an extrudate and a lyophilisate as two exemplary solid drug carrier systems. Component distribution analysis with the novel analytical approach was neither hampered by the curvature of the cylindrical extrudate nor the highly structured surface of the lyophilisate. Therefore, the combined analytical approach bears a great potential to be implemented in diversified fields of pharmaceutical sciences. PMID- 23358923 TI - Institute of Medicine report on fitness measures and health outcomes in youth. PMID- 23358924 TI - NPY modulates miR-30a-5p and BDNF in opposite direction in an in vitro model of Alzheimer disease: a possible role in neuroprotection? AB - Using in vitro models of Alzheimer's disease (AD), we found that the toxic effects of amyloid beta 25-35 (Abeta(25-35)) on the neurotrophin brain-derived neurotrophic factor (BDNF) were counteracted by pre-incubation with neuropeptide Y (NPY), a neuropeptide expressed within the central nervous system. Nonetheless, the mechanism of action of NPY on BDNF neuronal production in the presence of Abeta is not known. BDNF expression might be directly regulated by microRNA (miRs), small non-coding DNA fragments that regulate the expression of target genes. Thus, there is the possibility that miRs alterations are present in AD affected neurons and that NPY influences miR expression. To test this hypothesis, we exposed NPY-pretreated primary rat cortical neurons to Abeta(25-35) and measured miR-30a-5p (a member of the miR-30a family involved in BDNF tuning expression) and BDNF mRNA and protein expression after 24 and 48 h. Our results demonstrated that pre-treatment with NPY decreased miR-30a-5p expression and increased BDNF mRNA and protein expression at 24 and 48 h of incubation with Abeta. Therefore, this study demonstrates that NPY modulates BDNF and its regulating microRNA miR-30a-5p in opposite direction with a mechanism that possibly contributes to the neuroprotective effect of NPY in rat cortical neurons exposed to Abeta. PMID- 23358927 TI - Some Comments on "the Knowledge, Attitude and Behavior of HIV/AIDS Patients' Family toward Their Patients before and after Counseling". PMID- 23358925 TI - Identification of porcine glycogen synthase kinase 3alpha (GSK-3alpha) gene and its association with carcass traits. AB - GSK-3 plays an important role on numerous cellular processes involved in the regulation of embryonic development, protein synthesis, glycogen metabolism, inflammatory, mitosis and apoptosis. In this study, we obtained the cDNA and promoter sequences of the porcine GSK-3alpha gene, analyzed its genomic organization and mapped it to SSC6q12 through comparative mapping method. Moreover, the qRT-PCR analysis revealed that porcine GSK-3alpha gene was widely expressed in many tissues, and a high expression level was observed in the brain and spleen. In addition, seven single-nucleotide polymorphisms were detected in the promoter region of porcine GSK-3alpha gene. Association analysis revealed that the GSK-3alpha Hin1I and MspI polymorphisms both had significant associations (p < 0.05) with loin muscle area, average backfat thickness, thorax waist fat thickness, and buttock fat thickness. These results provide useful information for further investigation on the function of porcine GSK-3alpha gene. PMID- 23358926 TI - TNF receptor-associated factor 6 regulates proliferation, apoptosis, and invasion of glioma cells. AB - Tumor necrosis factor receptor-associated factor 6 (TRAF6), which plays an important role in inflammation and immune response, is an essential adaptor protein for the NF-kappaB (nuclear factor kappaB) signaling pathway. Recent studies have shown that TRAF6 played an important role in tumorigenesis and invasion by suppressing NF-kappaB activation. However, up to now, the biologic role of TRAF6 in glioma has still remained unknown. To address the expression of TRAF6 in glioma cells, four glioma cell lines (U251, U-87MG, LN-18, and U373) and a non-cancerous human glial cell line SVG p12 were used to explore the protein expression of TRAF6 by Western blot. Our results indicated that TRAF6 expression was upregulated in human glioma cell lines, especially in metastatic cell lines. To investigate the role of TRAF6 in cell proliferation, apoptosis, invasion, and migration of glioma, we generated human glioma U-87MG cell lines in which TRAF6 was either overexpressed or depleted. Subsequently, the effects of TRAF6 on cell viability, cell cycle distribution, apoptosis, invasion, and migration in U-87MG cells were determined with 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) assay, flow cytometry analysis, transwell invasion assay, and wound healing assay. The results showed that knockdown of TRAF6 could decrease cell viability, suppress cell proliferation, invasion and migration, and promote cell apoptosis, whereas overexpression of TRAF6 displayed the opposite effects. In addition, the effects of TRAF6 on the expression of phosphor-NF-kappaB (p-p65), cyclin D1, caspase 3, and MMP-9 were also probed. Knockdown of TRAF6 could lower the expression of p-p65, cyclin D1, and MMP-9, and raise the expression of caspase 3. All these results suggested that TRAF6 might be involved in the potentiation of growth, proliferation, invasion, and migration of U-87MG cell, as well as inhibition of apoptosis of U-87MG cell by abrogating activation of NF kappaB. PMID- 23358928 TI - Resveratrol protects HUVECs from oxidized-LDL induced oxidative damage by autophagy upregulation via the AMPK/SIRT1 pathway. AB - PURPOSE: Resveratrol could induce basal autophagy through the activation of sirtuin. In this study, we investigated the effect of resveratrol on oxidative injury of human umbilical endothelial vein cells (HUVECs) induced by oxidized low density lipoprotein (ox-LDL) and the role of autophagy in this effect. METHODS: HUVECs were exposed to 100 mg/L ox-LDL for 24 h to cause oxidative injury. The effect of different concentrations of resveratrol on oxidative damage in HUVECs treated with ox-LDL was evaluated by MTT assay and superoxide dismutase (SOD) activity test. The autophagic level in different groups was measured by the protein expression of microtubule-associated protein 1 light chain 3 (LC3) and sequestosome 1 (SQSTM1/P62). Autophagosomes were observed under electron microscope and fluorescence microscope (by MDC staining). The expression of silencing information regulator1 (Sirt1) and AMP activated protein kinasealpha1 (AMPK) was investigated by Western blot. Autophagy inhibitor 3-methyladenine (3 MA) and Sirt1 inhibitor 6-Chloro-2,3,4,9-tetrahydro-1H-Carbazole-1-carboxamide (EX527) were used to confirm the role of autophagy in this effect of resveratrol and the pathway involved. RESULTS: Resveratrol reversed the decreases in cell viability (72.9 +/- 1.7 % of the control group) and SOD activity (14.37 +/- 0.21 U/ml) caused by ox-LDL at 83.4 +/- 1.4 % of the control group and 16.41 +/- 0.27 U/ml respectively. This effect accompanied by upregulation of autophagy and increased protein expression of Sirt1 and AMPK phosphorylation on threonine 172 (p-AMPK). Both 3-MA and EX527 abolished the protective effect of resveratrol in cell viability, at 80.4 +/- 2.7 % and 73.9 +/- 1.1 % of the control group respectively. 3-MA inhibited autophagy activation without any change of Sirt1 expression at both the mRNA and protein level. EX527 suppressed the expression of Sirt1 and diminished the upregulation of autophagy. Addition of 3-MA or EX527 could not affect the protein level of p-AMPK. CONCLUSION: Resveratrol protected HUVECs from oxidative damage caused by ox-LDL. This effect was mediated by Sirt1 dependent autophagy via the AMPK/ Sirt1 pathway. PMID- 23358929 TI - Escalated radiation dose alone vs. concurrent chemoradiation for locally advanced and unresectable rectal cancers: results from phase II randomized study. AB - PURPOSE: This trial was undertaken to compare the rates of resectability between patients treated with neoadjuvant concurrent chemoradiation vs. boosted radiotherapy alone. MATERIALS AND METHODS: Patients with clinically unresectable rectal cancer were randomized to receive external beam radiation therapy (EBRT) to pelvis (45 Gy) with concurrent oral Capecitabine (CRT group; Arm 1) or EBRT to pelvis (45 Gy) alone followed by 20 Gy dose of localized radiotherapy boost to the primary tumor site (RT with boost group, Arm 2). All patients were assessed for resectability after 6 weeks by clinical examination and by CT scan and those deemed resectable underwent surgery. RESULTS: A total of 90 patients were randomized, 46 to Arm 1 and 44 to Arm 2. Eighty seven patients (44 in Arm 1 and 41 in Arm 2) completed the prescribed treatment protocol. Overall resectability rate was low in both the groups; R0 resection was achieved in 20 (43 %) patients in Arm 1 vs. 15 (34 %) in Arm 2. Adverse factors that significantly affected the resectability rate in both the groups were extension of tumor to pelvic bones and signet ring cell pathology. Complete pathological response was seen in 7 and 11 %, respectively. There was greater morbidity such as wound infection and delayed wound healing in Arm 2 (16 vs. 40 %; p = 0.03). CONCLUSION: Escalated radiation dose without chemotherapy does not achieve higher complete (R0) tumor resectability in locally advanced inoperable rectal cancers, compared to concurrent chemoradiation. PMID- 23358930 TI - Results of endovascular treatment of middle cerebral artery aneurysms after first giving consideration to clipping. AB - BACKGROUND: Middle cerebral artery (MCA) aneurysms are among the more challenging aneurysms for endovascular treatment. We report a contemporary 5-year experience with endovascular therapy for MCA aneurysms at a high-volume neurovascular center. METHODS: Review of prospectively maintained intracranial aneurysm database. RESULTS: Between 2005 and 2009, 148 patients underwent treatment of 149 MCA aneurysms at our hospital, of which 33 patients with 34 aneurysms underwent endovascular therapy. Among these 33 patients, 14 presented with subarachnoid hemorrhage. Eleven patients were treated with stent-assisted coiling, 1 with balloon-assisted coiling, and the remainder with coiling alone. Three patients required repeat endovascular treatment. There were 7 periprocedural complications, including intraprocedural aneurysm rupture resulting in death in 2 patients. Two patients died at later dates from remote aneurysm rehemorrhage. Average follow-up of remaining patients was 17.1 months radiographically, and 20.3 months clinically. Average modified Rankin scale (mRS) score at last follow up was 2.09, with 17 patients with mRS 0/1 and 5 patients with mRS 2. Fifteen patients showed evidence of radiographic residual at last follow up: 13 were simple neck residuals. Unruptured status and saccular aneurysms were associated with mRS 0/1 outcome (each p < 0.05). CONCLUSIONS: At our hospital, MCA aneurysms are being treated with endovascular techniques, but in a minority of patients. Despite the rate of residual neck remnants, few retreatments were necessary and few rehemorrhages occurred. The periprocedural complication rate was not insignificant; therefore, in more recent years and at present, most MCA aneurysms are considered for clipping first at our center. PMID- 23358931 TI - In silico peptide-binding predictions of passerine MHC class I reveal similarities across distantly related species, suggesting convergence on the level of protein function. AB - The major histocompatibility complex (MHC) genes are the most polymorphic genes found in the vertebrate genome, and they encode proteins that play an essential role in the adaptive immune response. Many songbirds (passerines) have been shown to have a large number of transcribed MHC class I genes compared to most mammals. To elucidate the reason for this large number of genes, we compared 14 MHC class I alleles (alpha1-alpha3 domains), from great reed warbler, house sparrow and tree sparrow, via phylogenetic analysis, homology modelling and in silico peptide binding predictions to investigate their functional and genetic relationships. We found more pronounced clustering of the MHC class I allomorphs (allele specific proteins) in regards to their function (peptide-binding specificities) compared to their genetic relationships (amino acid sequences), indicating that the high number of alleles is of functional significance. The MHC class I allomorphs from house sparrow and tree sparrow, species that diverged 10 million years ago (MYA), had overlapping peptide-binding specificities, and these similarities across species were also confirmed in phylogenetic analyses based on amino acid sequences. Notably, there were also overlapping peptide-binding specificities in the allomorphs from house sparrow and great reed warbler, although these species diverged 30 MYA. This overlap was not found in a tree based on amino acid sequences. Our interpretation is that convergent evolution on the level of the protein function, possibly driven by selection from shared pathogens, has resulted in allomorphs with similar peptide-binding repertoires, although trans species evolution in combination with gene conversion cannot be ruled out. PMID- 23358932 TI - FCGR3A-158 polymorphism influences the biological response to infliximab in Crohn's disease through affecting the ADCC activity. AB - An association between FCGR3A-158 V/F polymorphism and biological responses to infliximab has been reported in Crohn's disease (CD) in Western countries. However, little is known about the mechanism by which gene polymorphism affects the responses to infliximab. The aims of this study were to confirm the association in Japanese CD patients and to reveal the effect of gene polymorphism on biological responses to infliximab. Japanese CD patients were examined retrospectively at weeks 8 and 30. Clinical and biological responses were assessed by the Crohn's disease activity index and C-reactive protein levels, respectively. The infliximab-binding affinity of natural killer (NK) cells from FCGR3A-158 V/V, V/F and F/F donors was examined. Infliximab-mediated antibody dependent cell-mediated cytotoxicity (ADCC) activities were also determined using transmembrane TNF-alpha-expressing Jurkat T cells as target cells and peripheral blood mononuclear cells (PBMCs) from V/V, V/F and F/F donors as effector cells. Biological responses at week 8 were statistically higher in V/V patients, whereas no significant differences were observed in either clinical responses at weeks 8 and 30 or biological responses at week 30 among the three genotypes. NK cells and PBMCs from V/V patients also showed higher infliximab-binding affinity and infliximab-mediated ADCC activity, respectively. Our results suggest that FCGR3A 158 polymorphism is a predicting factor of biological responses to infliximab in the early phases. FCGR3A-158 polymorphism was also found to affect the infliximab binding affinity of NK cells and infliximab-mediated ADCC activity in vitro, suggesting that an effect on ADCC activity influences biological responses to infliximab in CD patients. PMID- 23358933 TI - MHC class II association study in eight breeds of dog with hypoadrenocorticism. AB - Canine hypoadrenocorticism is an endocrine disorder characterised by inadequate secretion of steroid hormones from the adrenal glands. Pathology results from immune-mediated destruction of the adrenal cortex, which is similar to that seen in the human Addison's disease. Both the canine and human diseases have similar clinical presentation, with the diagnosis based on performing a dynamic adrenocorticotropic hormone stimulation test. MHC class II has previously been associated with the human and canine diseases. In the current study, we conducted an MHC class II association study in eight breeds of dog with diagnoses of hypoadrenocorticism. We demonstrated significant differences in dog leukocyte antigen (DLA) haplotype frequencies in six of these breeds: Cocker spaniel, Springer spaniel, Labrador, West Highland white terrier (WHWT), Bearded collie, and Standard poodle. In the Springer spaniel, the DLA-DRB1*015:01--DQA1*006:01- DQB1*023:01 haplotype was significantly associated with disease risk (p = 0.014, odds ratio (OR) = 5.14) and showed a similar trend in the Cocker spaniel. This haplotype is related to one associated with hypoadrenocorticism in the Nova Scotia duck tolling retriever. Similar haplotypes shared between breeds were demonstrated, with DLA-DRB1*001:01--DQA1*001:01--DQB1*002:01 more prevalent in both affected Labrador (p = 0.0002, OR = 3.06) and WHWT (p = 0.01, OR = 2.11). Other haplotypes that have not previously been associated with the disease were identified. The inter-breed differences in DLA haplotypes associated with susceptibility to canine hypoadrenocorticism could represent divergent aetiologies. This could have implications for clinical diagnosis and future comparative studies. Alternatively, it may suggest that the gene of interest is closely linked to the MHC. PMID- 23358934 TI - Thermally triggered mucoadhesive in situ gel of loratadine: beta-cyclodextrin complex for nasal delivery. AB - The aim of the present study was to increase the solubility of an anti-allergic drug loratadine by making its inclusion complex with beta-cyclodextrin and to develop it's thermally triggered mucoadhesive in situ nasal gel so as to overcome first-pass effect and consequently enhance its bioavailability. A total of eight formulations were prepared by cold method and optimized by 2(3) full factorial design. Independent variables (concentration of poloxamer 407, concentration of carbopol 934 P, and pure drug or its inclusion complex) were optimized in order to achieve desired gelling temperature with sufficient mucoadhesive strength and maximum permeation across experimental nasal membrane. The design was validated by extra design checkpoint formulation (F9) and Pareto charts were used to help eliminate terms that did not have a statistically significant effect. The response surface plots and possible interactions between independent variables were analyzed using Design Expert Software 8.0.2 (Stat Ease, Inc., USA). Faster drug permeation with zero-order kinetics and target flux was achieved with formulation containing drug: beta-cyclodextrin complex rather than those made with free drug. The optimized formulation (F8) with a gelling temperature of 28.6+/-0.47 degrees C and highest mucoadhesive strength of 7,676.0+/-0.97 dyn/cm2 displayed 97.74+/-0.87% cumulative drug permeation at 6 h. It was stable for over 3 months and histological examination revealed no remarkable damage to the nasal tissue. PMID- 23358937 TI - The alpha band of the resting electroencephalogram under pulsed and continuous radio frequency exposures. AB - The effect of GSM-like electromagnetic fields with the resting electroencephalogram (EEG) alpha band activity was investigated in a double-blind cross-over experimental paradigm, testing the hypothesis that pulsed but not continuous radio frequency (RF) exposure would affect alpha activity, and the hypothesis that GSM-like pulsed low frequency fields would affect alpha. Seventy two healthy volunteers attended a single recording session where the eyes open resting EEG activity was recorded. Four exposure intervals were presented (sham, pulsed modulated RF, continuous RF, and pulsed low frequency) in a counterbalanced order where each exposure lasted for 20 min. Compared to sham, a suppression of the global alpha band activity was observed under the pulsed modulated RF exposure, and this did not differ from the continuous RF exposure. No effect was seen in the extremely low frequency condition. That there was an effect of pulsed RF that did not differ significantly from continuous RF exposure does not support the hypothesis that "pulsed" RF is required to produce EEG effects. The results support the view that alpha is altered by RF electromagnetic fields, but suggest that the pulsing nature of the fields is not essential for this effect to occur. PMID- 23358936 TI - Interlaboratory comparison of IDH mutation detection. AB - Isocitrate dehydrogenase (IDH) mutational testing is becoming increasingly important. For this, robust and reliable assays are needed. We tested the variation of results between six laboratories of testing for IDH mutations. Each laboratory received five unstained slides from 31 formalin-fixed paraffin embedded (FFPE) glioma samples, and followed its own standard IDH diagnostic routine. All laboratories used immunohistochemistry (IHC) with an antibody against the most frequent IDH1 mutation (R132H) as a first step. Three laboratories then sequenced only IHC negative cases while the others sequenced all cases. Based on the overall analysis, 13 samples from 11 tumors had an R132H mutation and one tumor showed an R132G mutation. Results of IHC for IDH1 R132H mutations in all six laboratories were completely in agreement, and identified all R132H mutations. Upon sequencing the results of two laboratories deviated from those of the others. After a review of the entire diagnostic process, on repeat (blinded) testing one laboratory was completely in agreement with the overall result. A change in technique did only partially improve the results in the other laboratory. IHC for the IDH1 R132H mutation is very reliable and consistent across laboratories. IDH sequencing procedures yielded inconsistent results in 2 out of 6 laboratories. Quality assurance is pivotal before IDH testing is made part of clinical management of patients. PMID- 23358935 TI - Pharmacologic treatment of pediatric headaches: a meta-analysis. AB - OBJECTIVE To assess the effectiveness of prophylactic headache treatment in children and adolescents. DATA SOURCES PubMed, EMBASE, Cochrane Database of Clinical Trials, and bibliography of retrieved articles through August 11, 2012. STUDY SELECTION Randomized trials of headache treatment among children and adolescents (<18 years old). INTERVENTION Any placebo-controlled trial or comparisons between 2 or more active medications. MAIN OUTCOME MEASURE Number of headaches per month. RESULTS Among 21 included trials, there were 13 placebo controlled and 10 active comparator trials (2 also included placebo). Twenty trials focused on episodic migraines and 1 on chronic daily headaches. Drugs more effective than placebo for episodic migraines (<15 headaches per month) included topiramate (difference in headaches per month, -0.71; 95% CI, -1.19 to -0.24) and trazodone (-0.60; 95% CI, -1.09 to -0.11). Ineffective drugs included clonidine, flunarizine, pizotifen, propranolol, and valproate. A single trial of fluoxetine for chronic daily headaches found it ineffective. Patients given placebo experienced a significant (P = .03) decline in headaches, from 5.6 (95% CI, 4.52 6.77; Q = 8.14 [Cochran Q is a measure of the heterogeneity of the included studies]) to 2.9 headaches per month (95% CI, 1.66-4.08; Q = 4.72). Among the 10 active comparator trials, flunarizine was more effective than piracetam (difference in headaches per month, -2.20; 95% CI, -3.93 to -0.47) but no better than aspirin, dihydroergotamine, or propranolol. Propranolol was compared with valproate as well as behavioral treatment, and 2 studies compared different doses of topiramate; none of these trials showed significant differences. CONCLUSIONS Topiramate and trazodone have limited evidence supporting efficacy for episodic migraines. Placebo was effective in reducing headaches. Other commonly used drugs have no evidence supporting their use in children and adolescents. More research is needed. PMID- 23358938 TI - The use of a bone-anchored device as a hard-wired conduit for transmitting EMG signals from implanted muscle electrodes. AB - The use of a bone-anchored device to transmit electrical signals from internalized muscle electrodes was studied in a sheep model. The bone-anchored device was used as a conduit for the passage of a wire connecting an internal epimysial electrode to an external signal-recording device. The bone-anchored device was inserted into an intact tibia and the electrode attached to the adjacent M. peroneus tertius. "Physiological" signals with low signal-to-noise ratios were successfully obtained over a 12-week period by walking the sheep on a treadmill. Reliable transmission of multiple muscle signals across the skin barrier is essential for providing intuitive, biomimetic upper limb prostheses. This technology has the potential to provide a better functional and reliable solution for upper limb amputee rehabilitation: attachment and control. PMID- 23358939 TI - Development of surrogate spinal cords for the evaluation of electrode arrays used in intraspinal implants. AB - We report the development of a surrogate spinal cord for evaluating the mechanical suitability of electrode arrays for intraspinal implants. The mechanical and interfacial properties of candidate materials (including silicone elastomers and gelatin hydrogels) for the surrogate cord were tested. The elastic modulus was characterized using dynamic mechanical analysis, and compared with values of actual human spinal cords from the literature. Forces required to indent the surrogate cords to specified depths were measured to obtain values under static conditions. Importantly, to quantify surface properties in addition to mechanical properties normally considered, interfacial frictional forces were measured by pulling a needle out of each cord at a controlled rate. The measured forces were then compared to those obtained from rat spinal cords. Formaldehyde crosslinked gelatin, 12 wt% in water, was identified as the most suitable material for the construction of surrogate spinal cords. To demonstrate the utility of surrogate spinal cords in evaluating the behavior of various electrode arrays, cords were implanted with two types of intraspinal electrode arrays (one made of individual microwires and another of microwires anchored with a solid base), and cord deformation under elongation was evaluated. The results demonstrate that the surrogate model simulates the mechanical and interfacial properties of the spinal cord, and enables in vitro screening of intraspinal implants. PMID- 23358940 TI - Ultrasound probe and needle-guide calibration for robotic ultrasound scanning and needle targeting. AB - Image-to-robot registration is a typical step for robotic image-guided interventions. If the imaging device uses a portable imaging probe that is held by a robot, this registration is constant and has been commonly named probe calibration. The same applies to probes tracked by a position measurement device. We report a calibration method for 2-D ultrasound probes using robotic manipulation and a planar calibration rig. Moreover, a needle guide that is attached to the probe is also calibrated for ultrasound-guided needle targeting. The method is applied to a transrectal ultrasound (TRUS) probe for robot-assisted prostate biopsy. Validation experiments include TRUS-guided needle targeting accuracy tests. This paper outlines the entire process from the calibration to image-guided targeting. Freehand TRUS-guided prostate biopsy is the primary method of diagnosing prostate cancer, with over 1.2 million procedures performed annually in the U.S. alone. However, freehand biopsy is a highly challenging procedure with subjective quality control. As such, biopsy devices are emerging to assist the physician. Here, we present a method that uses robotic TRUS manipulation. A 2-D TRUS probe is supported by a 4-degree-of-freedom robot. The robot performs ultrasound scanning, enabling 3-D reconstructions. Based on the images, the robot orients a needle guide on target for biopsy. The biopsy is acquired manually through the guide. In vitro tests showed that the 3-D images were geometrically accurate, and an image-based needle targeting accuracy was 1.55 mm. These validate the probe calibration presented and the overall robotic system for needle targeting. Targeting accuracy is sufficient for targeting small, clinically significant prostatic cancer lesions, but actual in vivo targeting will include additional error components that will have to be determined. PMID- 23358941 TI - A fully constrained optimization method for time-resolved multispectral fluorescence lifetime imaging microscopy data unmixing. AB - This paper presents a new unmixing methodology of multispectral fluorescence lifetime imaging microscopy (m-FLIM) data, in which the spectrum is defined as the combination of time-domain fluorescence decays at multiple emission wavelengths. The method is based on a quadratic constrained optimization (CO) algorithm that provides a closed-form solution under equality and inequality restrictions. In this paper, it is assumed that the time-resolved fluorescence spectrum profiles of the constituent components are linearly independent and known a priori. For comparison purposes, the standard least squares (LS) solution and two constrained versions nonnegativity constrained least squares (NCLS) and fully constrained least squares (FCLS) (Heinz and Chang, 2001) are also tested. Their performance was evaluated by using synthetic simulations, as well as imaged samples from fluorescent dyes and ex vivo tissue. In all the synthetic evaluations, the CO obtained the best accuracy in the estimations of the proportional contributions. CO could achieve an improvement ranging between 41% and 59% in the relative error compared to LS, NCLS, and FCLS at different signal to-noise ratios. A liquid mixture of fluorescent dyes was also prepared and imaged in order to provide a controlled scenario with real data, where CO and FCLS obtained the best performance. The CO and FCLS were also tested with 20 ex vivo samples of human coronary arteries, where the expected concentrations are qualitatively known. A certainty measure was employed to assess the confidence in the estimations made by each algorithm. The experiments confirmed a better performance of CO, since this method is optimal with respect to equality and inequality restrictions in the linear unmixing formulation. Thus, the evaluation showed that CO achieves an accurate characterization of the samples. Furthermore, CO is a computational efficient alternative to estimate the abundance of components in m-FLIM data, since a global optimal solution is always guaranteed in a closed form. PMID- 23358942 TI - Reduction of the linear reflex gain explained from the M1-M2 refractory period. AB - Linear system identification methods combined with neuromechanical modeling enable the quantification of reflex gains from recorded joint angular perturbation, torque, and/or electromyography (EMG). However, the stretch reflex response as recorded by EMG consists of multiple consecutive activation volleys (M1 and M2 responses) separated by a period of reduced activity and is nonlinearly related to joint perturbation. The goal of this study is to assess to what extent linear assumptions hold when quantifying these reflexive responses. Series of ramp-and-hold angular perturbations with fixed velocity but different ramp durations (and, therefore, different amplitudes) were applied to the wrist joint of seven healthy volunteers. Evoked EMG responses were compared to the reflex response estimated from a common linear reflex model relating EMG to perturbation velocity. Model fits described the measured EMG responses best when the perturbation and M1 response durations were equivalent. With increasing perturbation duration, i.e., amplitude, EMG response increased but reflex gain decreased due to the inert period after M1, which is believed to be related to alignment of the refractory period of the motoneurons. For angular joint perturbations exceeding the M1 duration (coinciding with 2 ( degrees ) of wrist joint rotation in this study), reflex gain variation may be largely explained from a shortcoming of the linear model in describing the nonlinear reflex response, and in particular the period of low reflexive activity after M1. PMID- 23358943 TI - An experimental vestibular neural prosthesis: design and preliminary results with rhesus monkeys stimulated with modulated pulses. AB - A vestibular neural prosthesis was designed on the basis of a cochlear implant for treatment of Meniere's disease and other vestibular disorders. Computer control software was developed to generate patterned pulse stimuli for exploring optimal parameters to activate the vestibular nerve. Two rhesus monkeys were implanted with the prototype vestibular prosthesis and they were behaviorally evaluated post implantation surgery. Horizontal and vertical eye movement responses to patterned electrical pulse stimulations were collected on both monkeys. Pulse amplitude modulated (PAM) and pulse rate modulated (PRM) trains were applied to the lateral canal of each implanted animal. Robust slow-phase nystagmus responses following the PAM or PRM modulation pattern were observed in both implanted monkeys in the direction consistent with the activation of the implanted canal. Both PAM and PRM pulse trains can elicit a significant amount of in-phase modulated eye velocity changes and they could potentially be used for efficiently coding head rotational signals in future vestibular neural prostheses. PMID- 23358944 TI - Angular momentum during unexpected multidirectional perturbations delivered while walking. AB - This study investigated the hypothesis that the coupled contribution of all body segments to the whole-body response during both walking and managing unexpected perturbations is characterized by similar features which do not depend on the laterality (i.e., right versus left sides), but can be influenced by the direction (e.g., north, east, south, etc.) of the perturbation. The whole-body angular momentum was estimated as summation of segmental angular momenta, while 15 young adults managed ten unexpected unilateral perturbations during walking. Then, the Principal component analysis was used to extract primitive features describing intersegment coordination. Results showed that intersegment coupling was similar even though the reactive response to the perturbations elicited more consistent motor schemes across body segments than during walking, especially in the frontal plane. The direction of the perturbation significantly affected angular momentum regulation documenting the attitude of the central nervous system to interpret multiple sensory inputs in order to produce context-dependent reactive responses. With respect to the side, results highlighted anisotropic features of the elicited motor schemes that seemed to depend on subjects' dominance. Finally, results confirm that the coordination of upper and lower body segments is synergistically achieved strengthening the hypothesis that it may result from common neural pathways. PMID- 23358945 TI - Closed-loop control of renal perfusion pressure in physiological experiments. AB - This paper presents the design, experimental modeling, and control of a pump driven renal perfusion pressure (RPP)-regulatory system to implement precise and relatively fast RPP regulation in rats. The mechatronic system is a simple, low cost, and reliable device to automate the RPP regulation process based on flow mediated occlusion. Hence, the regulated signal is the RPP measured in the left femoral artery of the rat, and the manipulated variable is the voltage applied to a dc motor that controls the occlusion of the aorta. The control system is implemented in a PC through the LabView software, and a data acquisition board NI USB-6210. A simple first-order linear system is proposed to approximate the dynamics in the experiment. The parameters of the model are chosen to minimize the error between the predicted and experimental output averaged from eight input/output datasets at different RPP operating conditions. A closed-loop servocontrol system based on a pole-placement PD controller plus dead-zone compensation was proposed for this purpose. First, the feedback structure was validated in simulation by considering parameter uncertainty, and constant and time-varying references. Several experimental tests were also conducted to validate in real time the closed-loop performance for stepwise and fast switching references, and the results show the effectiveness of the proposed automatic system to regulate the RPP in the rat, in a precise, accurate (mean error less than 2 mmHg) and relatively fast mode (10-15 s of response time). PMID- 23358946 TI - Microwave stethoscope: development and benchmarking of a vital signs sensor using computer-controlled phantoms and human studies. AB - This paper describes a new microwave-based method and associated measurement system for monitoring multiple vital signs (VS) as well as the changes in lung water content. The measurement procedure utilizes a single microwave sensor for reflection coefficient measurements, hence the name "microwave stethoscope (MiSt)," as opposed to the two-sensor transmission method previously proposed by the authors. To compensate for the reduced sensitivity due to reflection coefficient measurements, an improved microwave sensor design with enhanced matching to the skin and broadband operation, as well as an advanced digital signal processing algorithm are used in developing the MiSt. Results from phantom experiments and human clinical trials are described. The results clearly demonstrate that MiSt provides reliable monitoring of multiple VS such as the respiration rate, heart rate, and the changes in lung water content through a single microwave measurement. In addition, information such as heart waveforms that correlates well with electrocardiogram is observed from these microwave measurements. Details of the broadband sensor design, experimental procedure, DSP algorithms used for VS extraction, and obtained results are presented and discussed. PMID- 23358948 TI - Surgical robot system for single-port surgery with novel joint mechanism. AB - Single-port surgery is a new surgical method performed by inserting several surgical tools and a laparoscope through an umbilical incision. Compared with conventional laparoscopic surgery, the smaller incision in this procedure produces a lower amount of trauma, which leads to shorter hospitalization. However, with the current laparoscopic tools and surgical robots, the surgeon must overcome several difficulties, such as a limited range of motion and collisions between the surgical instruments and the laparoscope. This paper proposes a new surgical robot system for single-port surgery that uses a novel joint mechanism. The proposed joint mechanism is suitable for surgical instruments with multiple degrees of freedom (DOF). Thus, it can prevent hysteresis of the joint and achieve more accurate motion with a large force. A 6 DOF surgical instrument with this joint mechanism can avoid collisions between surgical tools or arms and approach the surgical target more easily than a conventional straight surgical tool. The external arm with 2-DOF passive joints can extend the workspace of the system during surgery. Preliminary tests and validations were performed with a prototype of the system. PMID- 23358947 TI - An approach to rapid calculation of temperature change in tissue using spatial filters to approximate effects of thermal conduction. AB - We present an approach to performing rapid calculations of temperature within tissue by interleaving, at regular time intervals, 1) an analytical solution to the Pennes (or other desired) bioheat equation excluding the term for thermal conduction and 2) application of a spatial filter to approximate the effects of thermal conduction. Here, the basic approach is presented with attention to filter design. The method is applied to a few different cases relevant to magnetic resonance imaging, and results are compared to those from a full finite difference (FD) implementation of the Pennes bioheat equation. It is seen that results of the proposed method are in reasonable agreement with those of the FD approach, with about 15% difference in the calculated maximum temperature increase, but are calculated in a fraction of the time, requiring less than 2% of the calculation time for the FD approach in the cases evaluated. PMID- 23358949 TI - Magnetic fluid hyperthermia modeling based on phantom measurements and realistic breast model. AB - Magnetic fluid hyperthermia (MFH) is a minimally invasive procedure that destroys cancer cells. It is based on a superparamagnetic heat phenomenon and consists in feeding a ferrofluid into a tumor, and then applying an external electromagnetic field, which leads to apoptosis. The strength of the magnetic field, optimal dose of the ferrofluid, the volume of the tumor and the safety standards have to be taken into consideration when MFH treatment is planned. In this study, we have presented the novel complementary investigation based both on the experiments and numerical methodology connected with female breast cancer. We have conducted experiments on simplified female breast phantoms with numerical analysis and then we transferred the results on an anatomically-like breast model. PMID- 23358950 TI - Influence of running stride frequency in heart rate variability analysis during treadmill exercise testing. AB - The analysis and interpretation of heart rate variability (HRV) during exercise is challenging not only because of the nonstationary nature of exercise, the time varying mean heart rate, and the fact that respiratory frequency exceeds 0.4 Hz, but there are also other factors, such as the component centered at the pedaling frequency observed in maximal cycling tests, which may confuse the interpretation of HRV analysis. The objectives of this study are to test the hypothesis that a component centered at the running stride frequency (SF) appears in the HRV of subjects during maximal treadmill exercise testing, and to study its influence in the interpretation of the low-frequency (LF) and high-frequency (HF) components of HRV during exercise. The HRV of 23 subjects during maximal treadmill exercise testing is analyzed. The instantaneous power of different HRV components is computed from the smoothed pseudo-Wigner-Ville distribution of the modulating signal assumed to carry information from the autonomic nervous system, which is estimated based on the time-varying integral pulse frequency modulation model. Besides the LF and HF components, the appearance is revealed of a component centered at the running SF as well as its aliases. The power associated with the SF component and its aliases represents 22+/-7% (median+/-median absolute deviation) of the total HRV power in all the subjects. Normalized LF power decreases as the exercise intensity increases, while normalized HF power increases. The power associated with the SF does not change significantly with exercise intensity. Consideration of the running SF component and its aliases is very important in HRV analysis since stride frequency aliases may overlap with LF and HF components. PMID- 23358952 TI - Glial heterotopia of the middle ear and Eustachian tube in children. PMID- 23358951 TI - Evaluation of superficial musculoaponeurotic system flap and fat graft outcomes for benign and malignant parotid disease. AB - OBJECTIVE: (1) To evaluate the effectiveness of the superficial musculoaponeurotic system (SMAS) flap and free fat graft in reconstructing the parotidectomy defect. (2) To evaluate the long-term viability of the free fat graft following parotidectomy for benign and malignant disease, including in the postradiation setting. STUDY DESIGN: Prospective study of consecutive patients. SETTING: Academic tertiary care medical center. Subjects and Methods Thirty-one consecutive patients underwent parotidectomy with SMAS flap and free fat graft reconstruction from 2006 to 2012. Data were compiled through a manual chart review. RESULTS: Twenty-three of the 31 total patients had benign disease, including pleomorphic adenoma, oncocytoma, and Warthin tumor. The 8 remaining patients (9 parotidectomies) underwent surgery for malignant disease, followed by postoperative radiation. The average age was 56 years (range, 16-84 years). The mean follow-up was 22.5 months. Satisfactory volumetric symmetry was achieved in all procedures for benign and malignant disease. Magnetic resonance imaging confirmed long-term fat graft viability in the postradiation setting. There was 1 case of Frey syndrome and no cases of unexpected, permanent facial nerve weakness among the patients. CONCLUSION: The combined technique of SMAS flap and free fat graft is effective for immediate reconstruction of the parotidectomy defect with minimal morbidity and low complication rates. This study demonstrates long-term viability of the free fat graft even in the setting of postoperative radiation. PMID- 23358953 TI - Endolaryngeal hookwire electrodes for intraoperative recurrent laryngeal nerve monitoring during pediatric thyroid surgery. AB - OBJECTIVE: To describe the senior author's surgical technique and discuss his experience with endolaryngeal hookwire electrodes for intraoperative, recurrent laryngeal nerve monitoring during pediatric thyroid surgery. STUDY DESIGN: Consecutive case series. SETTING: Tertiary-care, academic, children's hospital. SUBJECTS AND METHODS: A consecutive case series review of pediatric patients (age <16 years) who underwent thyroid surgery with intraoperative, endolaryngeal hookwire recurrent laryngeal nerve monitoring. Nerve injury was defined as vocal cord dysfunction present >12 months postoperatively. RESULTS: Seventeen patients were identified. There were 5 males and 12 females, and the average age was 11.7 years (range, 4-15 years). Nineteen procedures were performed--4 hemithyroidectomies, 2 completion thyroidectomies, and 13 total thyroidectomies- with 32 nerves at risk. One patient had a recurrent laryngeal nerve injury with a nerve paresis that persisted longer than 12 months postoperatively, making our recurrent laryngeal nerve injury rate 3.1% (1/32). Fortunately, the nerve eventually recovered to normal function. CONCLUSION: Thyroid nodules and surgery in children consist of higher rates of malignancy and potentially higher risks for recurrent laryngeal nerve complications. Our injury rate was 3.1%. Intraoperative recurrent laryngeal nerve monitoring with endolaryngeal hookwire electrodes in pediatric thyroid surgery may be helpful in nerve identification and is very sensitive. This technique can be used in situations in which endotracheal tubes with surface electrodes cannot be accommodated by the smaller size of the pediatric airway. PMID- 23358954 TI - White mass in the middle ear cavity behind an intact tympanic membrane. PMID- 23358955 TI - Single-stage excision of localized head and neck venous malformations using preoperative glue embolization. AB - OBJECTIVE: Describe single-stage removal of head and neck venous malformations using percutaneous embolization with n-butyl cyanoacrylate (n-BCA) glue prior to surgical resection. STUDY DESIGN: Case series with chart review. SETTING: Tertiary-care pediatric hospital. SUBJECTS AND RESULTS: A total of 169 venous malformations were identified between 2000 and 2012, and 102 (60.1%) were in the head and neck. Thirty-five of 102 (34.3%) were observed, 56 of 102 (54.9%) had invasive therapy, and 11 of 102 (10.8%) underwent n-BCA embolization and surgery ("GES procedure"). The median age of the glue embolization and surgery cohort was 14 years (range, 6-19), and 7 of 11 (63.6%) were female. Treated venous malformations involved the oral cavity/tongue (4/11; 36.4%) and parotid/face (7/11; 63.6%). During facial lesion excision, intraoperative facial nerve monitoring was used. All surgical sites (11/11) were closed primarily. No patient in this cohort had any posttreatment nerve deficits, dysarthria, and dysphagia or lesion persistence. CONCLUSIONS: Localized venous malformations can be treated with preoperative percutaneous embolization with n-BCA glue followed by surgical excision. This technique, with selective motor nerve monitoring, appears safe and allows for complete venous malformation removal with limited nerve dissection, to allow maximal tissue and functional preservation. PMID- 23358956 TI - Simple and safe exposure of the sigmoid sinus with presigmoid approaches. AB - Although entire exposure of the sigmoid sinus has been recognized as a complicated procedure in presigmoid approaches, we developed a new technique to expose the sigmoid sinus quite safely and simply without tough bone work. This study aims to demonstrate our technique in detail and present the effect of the procedure. Between January 2004 and December 2010, 77 patients underwent operations via presigmoid approaches in our institute. In all cases, the sigmoid sinus was completely exposed with our new surgical technique. The key step to expose the sigmoid sinus in our technique is dissection of the sinus from the overlying inner cortical bone in an antegrade direction from the junction of the transverse-sigmoid sinus to the jugular bulb using a bone dissector, avoiding meticulous bone drilling. We retrospectively examined a surgical video of all cases and determined the operative time required to entirely expose the sigmoid sinus from the transverse-sigmoid junction to the jugular bulb. In all 77 cases, the sigmoid sinuses were safely exposed with our new technique, and there was no episode of sinus injury. The operative time required to expose the sigmoid sinus ranged from 9.4 to 28.2 min (mean, 14.5 min). Standard drilling techniques took 32.3 min (range, 18.4-46.6 min) in last 20 cases before adoption of new technique. The new technique significantly shortened the surgical time to expose the sigmoid sinus (p < 0.01, Welch's t test). Our new technique is very useful for safely and simply exposing the sigmoid sinus, especially for standard neurosurgeons. PMID- 23358957 TI - Model-driven harmonic parameterization of the cortical surface: HIP-HOP. AB - In the context of inter subject brain surface matching, we present a parameterization of the cortical surface constrained by a model of cortical organization. The parameterization is defined via an harmonic mapping of each hemisphere surface to a rectangular planar domain that integrates a representation of the model. As opposed to previous landmark-based registration methods we do not match folds between individuals but instead optimize the fit between cortical sulci and specific iso-coordinate axis in the model. This strategy overcomes some limitation to sulcus-based registration techniques such as topological variability in sulcal landmarks across subjects. Experiments on 62 subjects with manually traced sulci are presented and compared with the result of the Freesurfer software. The evaluation involves a measure of dispersion of sulci with both angular and area distortions. We show that the model-based strategy can lead to a natural, efficient and very fast (less than 5 min per hemisphere) method for defining inter subjects correspondences. We discuss how this approach also reduces the problems inherent to anatomically defined landmarks and open the way to the investigation of cortical organization through the notion of orientation and alignment of structures across the cortex. PMID- 23358958 TI - Long-term bone health in glucocorticoid-treated children with rheumatic diseases. AB - Glucocorticoids (GC) are a standard treatment for pediatric rheumatic disease. Recent literature highlights skeletal vulnerability in children with rheumatic illness, including vertebral and peripheral fractures and reductions in bone mineral density in longitudinal follow-up. Annual vertebral fracture incidence of 4-6 % in those recently diagnosed and prevalence of 7-28 % in those several years post diagnosis have been reported. The fractures are often asymptomatic, often thoracic in location, and usually of mild, anterior wedge morphology. Diseases with more systemic involvement and severe inflammation (SLE, JDM) seem to be at higher risk. Neither BMD nor GC dose are ideal predictors for risk of fractures. These children also seem to have an increased incidence of long-bone fractures, particularly in the forearm and wrist; in the scant literature, long-bone fractures are not predictive of vertebral fractures. Bone mass accrual is typically suboptimum across time, although the use of potent steroid-sparing anti inflammatory agents may counteract the effects of GC and active disease. Vitamin D insufficiency warrants ongoing monitoring. Additional targeted studies are justified to increase understanding of bone health risks in this population. PMID- 23358959 TI - Comparison of contamination of femoral heads and pre-processed bone chips during hip revision arthroplasty. AB - With bone impaction grafting, cancellous bone chips made from allograft femoral heads are impacted in a bone defect, which introduces an additional source of infection. The potential benefit of the use of pre-processed bone chips was investigated by comparing the bacterial contamination of bone chips prepared intraoperatively with the bacterial contamination of pre-processed bone chips at different stages in the surgical procedure. To investigate baseline contamination of the bone grafts, specimens were collected during 88 procedures before actual use or preparation of the bone chips: in 44 procedures intraoperatively prepared chips were used (Group A) and in the other 44 procedures pre-processed bone chips were used (Group B). In 64 of these procedures (32 using locally prepared bone chips and 32 using pre-processed bone chips) specimens were also collected later in the procedure to investigate contamination after use and preparation of the bone chips. In total, 8 procedures had one or more positive specimen(s) (12.5 %). Contamination rates were not significantly different between bone chips prepared at the operating theatre and pre-processed bone chips. In conclusion, there was no difference in bacterial contamination between bone chips prepared from whole femoral heads in the operating room and pre-processed bone chips, and therefore, both types of bone allografts are comparable with respect to risk of infection. PMID- 23358960 TI - Correlation between blink reflex abnormalities and magnetic resonance imaging findings in patients with multiple sclerosis. AB - This study investigates the correlation between brain magnetic resonance imaging findings and blink reflex abnormalities in patients with relapsing remitting multiple sclerosis. Twenty-six patients and 17 healthy subjects were included in this study. Blink reflex test (BRT) results were obtained using right and left stimulations; thus, 52 BRT results were recorded for the patient group, and 34 BRT results were recorded for the control group. The magnetic resonance imaging (MRI) findings were classified based on the existence of brainstem lesions (hyperintense lesion on T2 weighted (W) and fast fluid-attenuated inversion recovery MRI or contrast-enhancing lesion on T1W MRI). Correlation analysis was performed for the BRT and MRI findings. The percentage of individuals with abnormal BRT results (including R1 latency, ipsilateral R2 latency, and contralateral R2 latency) was significantly higher in the patient group as compared to the control group (p values: 0.015, 0.001, and 0.002, respectively). Correlation analysis revealed significant correlations between contralateral R2 latency abnormalities and brainstem lesions (p value: 0.011). Our results showed significant correlation correlations between contralateral R2 latency abnormalities and brainstem lesions and these results may be explained the effects of multiple demyelinating lesions of the brain stem of patients with relapsing remitting multiple sclerosis. PMID- 23358961 TI - Isolated third nerve palsy caused by dural fistula of the cavernous sinus. PMID- 23358962 TI - Treatment of NMO relapse in the elderly: rituximab when plasma exchange fails? PMID- 23358963 TI - Salivary alpha-amylase: a new non-invasive biomarker for assessment of pain perception in epileptic children. AB - The aim of this study was to evaluate pain perception in epileptic children during an invasive procedure as the collection of venous blood through salivary alpha-amylase (sAA) activity determination, and to compare it with that of healthy children. In the study 23 children, 12 with epilepsy and 11 healthy controls were enrolled. From all children of both groups, one sample of saliva was collected through a non-invasive device, 15 min before (t 0), during (t 1), and 15 min later (t 2) blood withdrawal, and sAA activity was then determined through a kinetic-colorimetric assay. A statistically significant difference (p < 0.001) was found at t 2 between the sAA activity in the two groups, suggesting that epileptic children have an increased sensitization to pain, while at t 0 the difference was at the limit of statistical significance and at t 1 no statistically significant difference was found indicating that in both groups the venipuncture equally induced a state of stress. Our data suggest that sAA activity could represent a new objective and non-invasive biomarker for the assessment of pain perception in epileptic children. PMID- 23358964 TI - Prevalence of Parkinson's disease in a rural village of coastal Ecuador. A two phase door-to-door survey. AB - Occupational exposure to toxic solvents increases the odds for having Parkinson's disease (PD). We performed a door-to-door survey to assess PD prevalence in Atahualpa, a rural village of coastal Ecuador where more than 50 % of men work as carpenters, being in contact with toxic solvents under poor safety settings. During Phase I, rural doctors screened all Atahualpa residents aged >=40 years with a questionnaire directed to identify those with PD. In Phase II, neurologists evaluated individuals who screened as suspected cases of PD, as well as a random sample of negative individuals to assess possible false negative cases. As a result, the census yielded 642 Atahualpa residents aged >=40 years. An affirmative response to the questionnaire was obtained in seven persons. Neurological examination confirmed the diagnosis of PD in two of them (both carpenters). Examination of 14 non-suspected individuals disclosed no further PD patients. Prevalence of PD in Atahualpa residents aged >=40 years was 312 per 100,000 which increased to 671 per 100,000 when only people aged >=60 years was considered. Job-specific prevalence was 1,470 per 100,000 in carpenters. In conclusions, PD prevalence in Atahualpa is similar to that reported from other regions. However, we noted an increase in PD prevalence when only carpenters were considered. Unsafe occupational exposure to toxic substances may counterbalance the apparently lower risk of PD in the non-industrialized world. PMID- 23358965 TI - Solitary sclerosis: progressive myelopathy from solitary demyelinating lesion. A new entity? PMID- 23358967 TI - Outpatient therapy for fever and neutropenia is safe but implementation is the key. PMID- 23358966 TI - Postinduction dexamethasone and individualized dosing of Escherichia Coli L asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana Farber Cancer Institute ALL Consortium Protocol 00-01. AB - PURPOSE: We assessed the toxicity and efficacy of dexamethasone and a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Patients achieving complete remission (CR) on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 were eligible for random assignment to 1) dexamethasone or prednisone, administered as 5-day pulses, every 3 weeks, and 2) weekly EC-Asnase, administered as a 25,000 IU/m(2) fixed dose (FD) or individualized dose (ID) starting at 12,500-IU/m(2), adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations. RESULTS: Between 2000 and 2004, 492 evaluable patients (ages 1 to 18 years) enrolled; 473 patients (96%) achieved CR. Four hundred eight patients (86%) participated in the corticosteroid randomization and 384 patients (81%) in the EC-Asnase randomization. With 4.9 years of median follow-up, dexamethasone was associated with superior 5-year event-free survival (EFS; 90% v 81% for prednisone; P = .01) but higher rates of infection (P = .03) and, in older children, higher cumulative incidence of osteonecrosis (P = .02) and fracture (P = .06). ID EC-Asnase had superior 5-year EFS (90% v 82% for FD; P = .04), but did not reduce the frequency of asparaginase-related toxicity. Multivariable analysis identified both dexamethasone and ID EC-Asnase as independent predictors of favorable EFS. CONCLUSION: There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL. PMID- 23358968 TI - Angiosarcoma arising within a long-standing cystic lesion of the adrenal gland: a case report. PMID- 23358969 TI - Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy. AB - PURPOSE: This study aimed to establish an effective prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) after partial hepatectomy. PATIENTS AND METHODS: The nomogram was based on a retrospectively study on 367 patients who underwent partial hepatectomy for ICC at the Eastern Hepatobiliary Surgery Hospital from 2002 to 2007. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve and compared with five currently used staging systems on ICC. The results were validated using bootstrap resampling and a prospective study on 82 patients operated on from 2007 to 2008 at the same institution. RESULTS: On multivariate analysis of the primary cohort, independent factors for survival were serum carcinoembryonic antigen, CA 19-9, tumor diameter and number, vascular invasion, lymph node metastasis, direct invasion, and local extrahepatic metastasis, which were all selected into the nomogram. The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.74 (95% CI, 0.71 to 0.77), which was statistically higher than the C-index values of the following systems: American Joint Committee on Cancer (AJCC) seventh edition (0.65), AJCC sixth edition (0.65), Nathan (0.64), Liver Cancer Study Group of Japan (0.64), and Okabayashi (0.67; P < .001 for all). It was also higher (0.74) in predicting survival for the mass-forming type of ICC (P < .001). In the validation cohort, the nomogram discrimination was superior to the five other staging systems (C-index: 0.75 v 0.60 to 0.63; P < .001 for all). CONCLUSION: The proposed nomogram resulted in more-accurate prognostic prediction for patients with ICC after partial hepatectomy. PMID- 23358970 TI - Bevacizumab plus temozolomide: a novel treatment option for advanced neuroendocrine tumors? PMID- 23358971 TI - Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. AB - PURPOSE: In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss. PATIENTS AND METHODS: We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease-free survival, incidence of contralateral new primary breast cancer, and safety. RESULTS: In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease-free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms. CONCLUSION: This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor-positive breast cancer. PMID- 23358972 TI - Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. AB - PURPOSE: This double-blind, phase III study aimed to demonstrate that sunitinib plus FOLFIRI (fluorouracil, leucovorin, and irinotecan) was superior to placebo plus FOLFIRI in previously untreated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI and either sunitinib (37.5 mg per day) or placebo (4 weeks on treatment, followed by 2 weeks off [schedule 4/2]) until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, safety, and patient-reported outcomes. The correlation between genotype and clinical outcomes was also analyzed. RESULTS: In all, 768 patients were randomly assigned to sunitinib plus FOLFIRI (n = 386) or placebo plus FOLFIRI (n = 382). Following a second prespecified interim analysis, the study was stopped because of potential futility of sunitinib plus FOLFIRI. Final results are reported. The PFS hazard ratio was 1.095 (95% CI, 0.892 to 1.344; one-sided stratified log-rank P = .807), indicating a lack of superiority for sunitinib plus FOLFIRI. Median PFS for the sunitinib arm was 7.8 months (95% CI, 7.1 to 8.4 months) versus 8.4 months (95% CI, 7.6 to 9.2 months) for the placebo arm. Sunitinib plus FOLFIRI was associated with more grade >= 3 adverse events and laboratory abnormalities than placebo (especially diarrhea, stomatitis/oral syndromes, fatigue, hand-foot syndrome, neutropenia, thrombocytopenia, anemia, and febrile neutropenia). More deaths as a result of toxicity (12 v four) and significantly more dose delays, dose reductions, and treatment discontinuations occurred in the sunitinib arm. CONCLUSION: Sunitinib 37.5 mg per day (schedule 4/2) plus FOLFIRI is not superior to FOLFIRI alone and has a poorer safety profile. This combination regimen is not recommended for previously untreated mCRC. PMID- 23358973 TI - Two-year randomized controlled prospective trial converting treatment of stable renal transplant recipients with cutaneous invasive squamous cell carcinomas to sirolimus. AB - PURPOSE: In light of the significant morbidity and mortality of cutaneous invasive squamous cell carcinomas (SCCs) in renal transplant recipients, we investigated whether conversion to sirolimus-based immunosuppression from standard immunosuppression could diminish the recurrence rate of these skin cancers. PATIENTS AND METHODS: In a 2-year randomized controlled trial, 155 renal transplant recipients with at least one biopsy-confirmed SCC were stratified according to age (< 55 v >= 55 years) and number of previous SCCs (one to nine v >= 10) and randomly assigned to conversion to sirolimus (n = 74) or continuation of their original immunosuppression (n = 81). Development of a new SCC within 2 years after random assignment was the primary end point. RESULTS: After 2 years of follow-up, the risk reduction of new SCCs in the multivariable analysis was not significant, with a hazard ratio (HR) of 0.76 (95% CI, 0.48 to 1.2; P = .255), compared with a non-sirolimus-based regimen. After the first year, there was a significant 50% risk reduction, with an HR of 0.50 (95% CI, 0.28 to 0.90; P = .021) for all patients together and an HR of 0.11 (95% CI, 0.01 to 0.94; P = .044) for patients with only one previous SCC. The tumor burden of SCC was reduced during the 2-year follow-up period in those receiving sirolimus (0.82 v 1.38 per year; HR, 0.51; 95% CI, 0.32 to 0.82; P = .006) if adjusted for the number of previous SCCs and age. Twenty-nine patients stopped taking sirolimus because of various adverse events. CONCLUSION: Conversion to sirolimus-based immunosuppression failed to show a benefit in terms of SCC-free survival at 2 years. PMID- 23358975 TI - Specificity of problem-solving skills training in mothers of children newly diagnosed with cancer: results of a multisite randomized clinical trial. AB - PURPOSE: Diagnosis of cancer in a child can be extremely stressful for parents. Bright IDEAS, a problem-solving skills training (PSST) intervention, has been shown to decrease negative affectivity (anxiety, depression, post-traumatic stress symptoms) in mothers of newly diagnosed patients. This study was designed to determine the specificity of PSST by examining its direct and indirect (eg, social support) effects compared with a nondirective support (NDS) intervention. PATIENTS AND METHODS: This randomized clinical trial included 309 English- or Spanish-speaking mothers of children diagnosed 2 to 16 weeks before recruitment. Participants completed assessments prerandomization (T1), immediately postintervention (T2), and at 3-month follow-up (T3). Both PSST and NDS consisted of eight weekly 1-hour individual sessions. Outcomes included measures of problem solving skill and negative affectivity. RESULTS: There were no significant between-group differences at baseline (T1). Except for level of problem-solving skill, which was directly taught in the PSST arm, outcome measures improved equally in both groups immediately postintervention (T2). However, at the 3-month follow-up (T3), mothers in the PSST group continued to show significant improvements in mood, anxiety, and post-traumatic stress; mothers in the NDS group showed no further significant gains. CONCLUSION: PSST is an effective and specific intervention whose beneficial effects continue to grow after the intervention ends. In contrast, NDS is an effective intervention while it is being administered, but its benefits plateau when active support is removed. Therefore, teaching coping skills at diagnosis has the potential to facilitate family resilience over the entire course of treatment. PMID- 23358976 TI - Biomarker-directed therapy of squamous carcinomas of the head and neck: targeting PI3K/PTEN/mTOR pathway. PMID- 23358977 TI - Surgical site spread of skeletal diffuse large B-cell lymphoma. PMID- 23358978 TI - What is the optimal endocrine therapy for postmenopausal women with hormone receptor-positive early breast cancer? AB - A 56-year-old postmenopausal woman with a recent diagnosis of breast cancer was referred to discuss adjuvant therapy. Annual screening mammogram demonstrated a suspicious mass in the left breast. Ultrasound-guided core needle biopsy revealed an infiltrating ductal carcinoma that was estrogen receptor (ER) positive and progesterone receptor (PR) negative and lacked amplification of human epidermal growth factor receptor 2 (HER2; ie, HER2 negative). She underwent excision and sentinel node evaluation. Pathology demonstrated a 1.9-cm grade 2 invasive cancer without lymphatic vascular invasion; clean margins were obtained, and both sentinel nodes were free of cancer. The 21-gene recurrence score was 16. She has a body mass index (BMI) of 28.5 but is otherwise healthy; levothyroxine is the only prescription medication she takes. She experienced vaginal spotting 2 years earlier because of an endometrial polyp, which was resected. She exercises regularly and takes a calcium supplement with vitamin D. Bone density study performed 6 months earlier was normal other than mild osteopenia in the femoral neck (T score, -1.3). Radiation therapy is planned. PMID- 23358974 TI - Role of ubiquitin ligases and the proteasome in oncogenesis: novel targets for anticancer therapies. AB - The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS. PMID- 23358979 TI - To target or not to target, that is the question. PMID- 23358980 TI - Pulmonary fibrosis after pegylated liposomal Doxorubicin in a patient with uterine papillary serous carcinoma. PMID- 23358981 TI - Cytochrome P17 inhibition with ketoconazole as treatment for advanced granulosa cell ovarian tumor. PMID- 23358982 TI - Activating germline R776H mutation in the epidermal growth factor receptor associated with lung cancer with squamous differentiation. PMID- 23358984 TI - Evaluation of treatment benefit in Journal of Clinical Oncology. PMID- 23358985 TI - Sex differences in the return-to-work process of cancer survivors 2 years after diagnosis: results from a large French population-based sample. AB - PURPOSE: To investigate the effects of clinical, sociodemographic, and occupational factors on time to return to work (RTW) during the 2 years after cancer diagnosis and to analyze whether sex differences exist. PATIENTS AND METHODS: This study was based on a French national cross-sectional survey involving 4,270 cancer survivors. Time to RTW was estimated through the duration of sick leave of 801 cancer survivors younger than 58 years who were employed during the 2-year survey. Multivariate analysis of the RTW after sick leave was performed using a Weibull accelerated failure time model. RESULTS: We found some sex differences in the RTW process. Older men returned to work more slowly than older women (P = .013), whereas married men returned to work much faster than married women (P = .019). Duration dependence was also sex-specific. In men, the time spent on sick leave was independent of the probability of returning to work, whereas in women, this duration dependence was positive (P < .001). For both men and women, clinical factors including chemotherapy, adverse effects, and cancer severity were found to delay RTW (P = .035, P = .001, and P < .001, respectively). Survivors investing most strongly in their personal lives also delayed their RTW (P = .006), as did those with a permanent work contract (P = .042). The factor found to accelerate RTW was a higher educational level (P = .014). CONCLUSION: The RTW process 2 years after cancer diagnosis differed between men and women. A better knowledge of this process should help the national implementation of more cost-effective strategies for managing the RTW of cancer survivors. PMID- 23358983 TI - Oral antibiotics for fever in low-risk neutropenic patients with cancer: a double blind, randomized, multicenter trial comparing single daily moxifloxacin with twice daily ciprofloxacin plus amoxicillin/clavulanic acid combination therapy- EORTC infectious diseases group trial XV. AB - PURPOSE: This double-blind, multicenter trial compared the efficacy and safety of a single daily oral dose of moxifloxacin with oral combination therapy in low risk febrile neutropenic patients with cancer. PATIENTS AND METHODS: Inclusion criteria were cancer, febrile neutropenia, low risk of complications as predicted by a Multinational Association for Supportive Care in Cancer (MASCC) score > 20, ability to swallow, and <= one single intravenous dose of empiric antibiotic therapy before study drug treatment initiation. Early discharge was encouraged when a set of predefined criteria was met. Patients received either moxifloxacin (400 mg once daily) monotherapy or oral ciprofloxacin (750 mg twice daily) plus amoxicillin/clavulanic acid (1,000 mg twice daily). The trial was designed to show equivalence of the two drug regimens in terms of therapy success, defined as defervescence and improvement in clinical status during study drug treatment (< 10% difference). RESULTS: Among the 333 patients evaluated in an intention-to treat analysis, therapy success was observed in 80% of the patients administered moxifloxacin and in 82% of the patients administered combination therapy (95% CI for the difference, -10% to 8%, consistent with equivalence). Minor differences in tolerability, safety, and reasons for failure were observed. More than 50% of the patients in the two arms were discharged on protocol therapy, with 5% readmissions among those in either arm. Survival was similar (99%) in both arms. CONCLUSION: Monotherapy with once daily oral moxifloxacin is efficacious and safe in low-risk febrile neutropenic patients identified with the help of the MASCC scoring system, discharged early, and observed as outpatients. PMID- 23358986 TI - Rational follow-up after curative cancer resection. PMID- 23358987 TI - Brainstem ganglioglioma successfully treated with vemurafenib. PMID- 23358988 TI - Inflammatory myofibroblastic tumor of the colon. PMID- 23358989 TI - Metformin and breast cancer risk. PMID- 23358990 TI - Bevacizumab and subtype-adapted chemotherapy backbone in neuroendocrine tumors. PMID- 23358991 TI - Front-loaded smear microscopy for the diagnosis of pulmonary TB in Tripoli, Libya. AB - BACKGROUND: Diagnosis of pulmonary TB by conventional smear microscopy requires patient attendance on 2 consecutive days. We investigated whether collecting sputum on-the-spot for smear microscopy on the day the patient presented was as sensitive and specific for diagnosis as the conventional spot-morning-spot scheme. METHOD: We enrolled 412 adults who presented between January 2009 and October 2010 at the National Centre for TB Control in Tripoli, Libya, with cough of >2 weeks' duration, into a cross-sectional survey collecting four sputum specimens: on-the-spot and Xspot on Day 1; morning and on-the-spot on Day 2. RESULTS: 97 (24%) of 401 culture results were culture positive. Spot-Xspot and spot-morning smear microscopy had, respectively, 65% and 66% sensitivity and 97% and 96% specificity (p > 0.5). Spot-Xspot-morning and Spot-morning-spot smear microscopy had, respectively, 67% and 66% sensitivity and 96% and 96% specificity (p > 0.5). CONCLUSION: For the diagnosis of pulmonary TB, the sensitivity and specificity of front-loaded (same-day) smear microscopy is similar to that of the standard smear microscopy scheme. PMID- 23358998 TI - Pseudomonas: a promising biocatalyst for the bioconversion of terpenes. AB - The Pseudomonas genus is one of the most diverse and ecologically significant groups of known bacteria, and it includes species that have been isolated worldwide in all types of environments. The bacteria from this genus are characterized by an elevated metabolic versatility, which is due to the presence of a complex enzymatic system. Investigations since the early 1960s have demonstrated their potential as biocatalysts for the production of industrially relevant and value-added flavor compounds from terpenes. Although terpenes are often removed from essential oils as undesirable components, its synthetic oxy functionalized derivatives have broad applications in flavors/fragrances and pharmaceutical industries. Hence, biotransformation appears to be an effective tool for the structural modification of terpene hydrocarbons and terpenoids to synthesize novel and high-valued compounds. This review highlights the potential of Pseudomonas spp. as biocatalysts for the bioconversion of terpenes and summarizes the presently known bioflavors that are obtained from these processes. PMID- 23358997 TI - Ecological characteristics of anaerobic ammonia oxidizing bacteria. AB - Anaerobic ammonium oxidation (anammox) is the microbial conversion of ammonium and nitrite to dinitrogen gas. The functional microbes of anammox reaction are anammox bacteria, which were discovered in a wastewater treatment system for nitrogen removal. Anammox bacteria are prevalent in anoxic ecosystems and play an important role in both biological nitrogen cycle and nitrogen pollution control. In this paper, we reviewed the investigation on ecological characteristics of anammox bacteria, and tried to figure out their complicated intraspecies and interspecies relationships. As for intraspecies relationship, we focused on the quorum sensing system, a cell density-dependent phenomenon. As for interspecies relationship, we focused on the synergism and competition of anammox bacteria with other microorganisms for substrate and space. Finally, we discussed the great influence of environmental factors (e.g., dissolved oxygen, organic matters) on the constitution, structure and function of anammox bacteria community. PMID- 23358999 TI - Directed evolution of phloroglucinol synthase PhlD with increased stability for phloroglucinol production. AB - Phloroglucinol synthase PhlD is a type III polyketide synthase capable of directly converting three molecules of malonyl-CoA to an industrially important chemical--phloroglucinol (1, 3, 5-trihydroxylbenzene). Although this enzymatic process provides an attractive biosynthetic route to phloroglucinol, the low productivity of PhlD limits its further practical application. Here we used protein engineering coupled with in situ product removal to improve the productivity of phoroglucinol biosynthesis in recombinant Escherichia coli. Specifically, directed evolution was used to obtain a series of thermostable PhlD mutants with the best one showing over 24-fold longer half-life of thermal inactivation than the wild-type enzyme at 37 degrees C. When introduced into a malonyl-CoA overproducing E. coli strain, one of the mutants showed 30% improvement in phloroglucinol productivity compared to the wild-type enzyme in a shake-flask study and the final phloroglucinol concentration reached 2.35 g/L with 25% of theoretical yield. A continuous product extraction strategy was designed to remove the toxic phloroglucinol product from the cell media, which further increased the titer of phloroglucinol to 3.65 g/L, which is the highest phloroglucinol titer ever reported to date. PMID- 23359000 TI - A novel cell modification method used in biotransformation of glycerol to 3-HPA by Lactobacillus reuteri. AB - The aim of the present study was to develop a new cell modification method to facilitate the cell separation from broth. In order to reduce the transfer limitation of substrate and product caused by general immobilization methods in the following biotransformation of glycerol, the carboxyl-functioned superparamagnetic nanoparticle (MNP) was directly attached to the surface of Lactobacillus reuteri for 3-hydroxypropionealdehyde producing. The modification process could be finished in several minutes by just adding MNP fluid into the bulk fermentation broth. The modified cells could be rapidly separated from the solution with the aid of magnetic field. The interaction between cell and MNP was shown by electron microscopy. The efficiency of the cells attached by MNPs for transformation of various concentrations of glycerol (100-400 mM) was studied at various temperatures (25-40 degrees C) and pH levels (5.8-7.5) with different cell concentrations (7.5-30 g/L). The 3- hydroxypropionealdehyde (HPA)/glycerol molar conversion under optimal condition (30 degrees C and pH 7) reached 70 %. The inactive modified cell could be reactivated easily by fresh medium and recovered the ability of glycerol conversion. MNPS distributing on cell surface had little adverse effect on cell activity. The modification method simplified the two-step production of 3-HPA by resting L. reuteri. The method of MNPs attached to cell surface is totally different from the traditional immobilization method in which the cell is attached to or entrapped in big carrier. The results obtained in this study showed that carboxyl-functioned MNP could be directly used as cell modification particle and realized cell recycle with the aid of magnetic field in bioprocess. PMID- 23359002 TI - Migraine therapeutics in adolescents: a systematic analysis and historic perspectives of triptan trials in adolescents. AB - OBJECTIVES To conduct a systematic review and analysis of trial data submitted to the US Food and Drug Administration (FDA) to identify possible causes for the failure of pediatric trials of triptans for treatment of migraines. DATA SOURCE The FDA website for drug information and published literature. STUDY SELECTION All pediatric efficacy and pharmacokinetics trial data of drugs used for abortive treatment of migraine submitted to the FDA from January 1, 1999, through December 31, 2011. MAIN OUTCOME MEASURES Patient demographic baseline characteristics, inclusion and exclusion criteria, trial designs, efficacy end points, and pharmacokinetic profiles were analyzed and compared across drug products. RESULTS We analyzed data for sumatriptan succinate nasal spray and zolmitriptan, eletriptan hydrobromide, almotriptan malate, and rizatriptan benzoate tablets. Seven efficacy trials had a randomized, double-blinded, placebo-controlled, parallel-group trial design. In 4 trials, patients were required to have a history of migraine attacks lasting at least 4 hours. High response rates for placebo were observed in all trials, with pain relief at 2 hours ranging from 53% to 57.5%. Nonrandomization of patients with an early placebo response design was used in the rizatriptan trial in 2011. Compared with the rizatriptan trial conducted in 1999, the 2011 rizatriptan trial reduced the placebo response rate by 6% for headache freedom at the 2-hour posttreatment end point owing to study design. The pharmacokinetic profiles between adolescents and adults were statistically similar. CONCLUSIONS High placebo response rates are consistent across all trials and may represent the principal challenge in pediatric trials of drugs for abortive treatment of migraine. Enrichment with selection of subjects with long-lasting migraine attacks is not sufficient to overcome high placebo response rates. Another enrichment strategy, the nonrandomization of patients with an early placebo response, successfully reduces the high placebo response rate for rizatriptan and is a trial design that should be considered for future pediatric trials of abortive migraine therapeutics. PMID- 23359003 TI - Cigarette smoke exposure in utero and impact on neurological development: a knockdown of the expression of Hox-genes? PMID- 23359004 TI - Molecular mechanisms of central leptin resistance in obesity. AB - The rapidly increasing prevalence of obesity confers a huge health burden globally. The hypothalamus plays a central role in the regulation of energy homeostasis by integrating multiple metabolic signals from peripheral organs and modulating feeding behavior and energy metabolism. Leptin, a key appetite regulating hormone derived from the white adipose tissue, primarily acts on hypothalamic neurons to activate catabolic pathway and inhibit anabolic pathway, which can result in anorexia and weight reduction. Despite striking obesity resulting from leptin deficiency, treatment with this hormone in human obesity has been unsuccessful due to leptin resistance. In this review, we describe recent researches extending our understanding of obesity-associated hypothalamic leptin resistance. PMID- 23359006 TI - Intravenous epoprostenol treatment of patients with connective tissue disease and pulmonary arterial hypertension at a single center. AB - OBJECTIVE: To assess the efficacy of epoprostenol treatment in Japanese patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD). METHODS: Sixteen patients with PAH-CTD treated with continuous intravenous epoprostenol at a single center between 2000 and 2009 were enrolled. Baseline characteristics, short-term and long-term outcomes, predictors of mortality, and safety profiles were evaluated. For survival analysis, 16 controls were selected who matched the underlying CTD, World Health Organization functional class, and use of PAH drugs, except for epoprostenol. RESULTS: Six patients had systemic lupus erythematosus, five had mixed CTD, four had systemic sclerosis, and one had primary Sjogren's syndrome. The mean pulmonary arterial pressure (mPAP), cardiac index (CI), pulmonary vascular resistance, and functional class were significantly improved during the first 6 months of epoprostenol treatment. Cumulative survival rates at 1, 2, and 3 years in epoprostenol-treated patients were 69, 69, and 55%, respectively, and were significantly better than those of the controls. Functional class, CI at baseline, and reduction of mPAP at 6 months were identified as predictors of survival. Adverse events, including flushing and catheter-related infection, were frequent, but all patients tolerated the treatment. CONCLUSION: Based on the improvements in both short-term and long-term outcomes among our patient cohort, epoprostenol is an effective treatment for CTD patients with advanced PAH. PMID- 23359007 TI - Young male patient diagnosed with cutaneous polyarteritis nodosa successfully treated with etanercept. AB - Cutaneous polyarteritis nodosa (CPAN) is a form of necrotizing vasculitis of small and medium-sized arteries. It is limited to the skin and has a recurrent and chronic course, possibly associated with fever, arthralgia, myalgia and neuropathy, but without visceral involvement. We report the clinical case of a 7 year-old male patient with CPAN refractory to treatment with high doses of corticoids and cyclophosphamide, who was successfully treated with the TNF-alpha (tumor necrosis factor-alpha) inhibitor, etanercept, in monotherapy. PMID- 23359008 TI - Involvement of valgus hindfoot deformity in hallux valgus deformity in rheumatoid arthritis. AB - The involvement of valgus hindfoot deformity in hallux valgus deformity was confirmed in a rheumatoid arthritis case with a destructive valgus hindfoot deformity. Correction of severe valgus, calcaneal lateral offset, and pronated foot deformity instantly normalized hallux valgus deformities postoperatively. Thus, careful hindfoot status evaluation is important when assessing forefoot deformity, including hallux valgus, in rheumatoid arthritis cases. PMID- 23359009 TI - Use of multi-parameter flow cytometry as tool to monitor the impact of formic acid on Saccharomyces carlsbergensis batch ethanol fermentations. AB - The use of lignocellulosic materials as substrate for bioethanol production is considered a cost-effective approach to make the biofuel production process economically sustainable. However, lignocellulosic hydrolysis releases toxic compounds such as weak acids which inhibit microorganism growth and ethanol production. In order to understand the physiological response of Saccharomyces carlsbergensis when fermenting glucose in the presence of formic acid (HF), the yeast growth was monitored by multi-parameter flow cytometry. Cytoplasmic membrane potential decreased as the HF concentration increased and as the yeast culture reached the stationary phase. However, the proportion of cells with permeabilized membrane did not increase with the HF concentration increase. The accumulation of reactive oxygen species was also monitored. Control and fermentations at low HF concentrations (<1 g/L) resulted in a high proportion of highly oxidized cells at the stationary phase. The multi-parameter flow cytometry approach proved to be a useful tool to monitor the physiological stress response of S. carlsbergensis growth and ethanol production in the presence of HF, an inhibitor present in lignocellulosic hydrolysates. The information here obtained at near real time can be used to enhance second-generation bioethanol production process efficiency. PMID- 23359010 TI - Pretreatment of chicken feather waste for improved biogas production. AB - This study deals with the utilization of chicken feather waste as a substrate for anaerobic digestion and improving biogas production by degradation of the compact structure of the feather keratin. In order to increase the digestibility of the feather, different pretreatments were investigated, including thermal pretreatment at 120 degrees C for 10 min, enzymatic hydrolysis with an alkaline endopeptidase [0.53-2.66 mL/g volatile solids (VS) feathers] for 0, 2, or 24 h at 55 degrees C, as well as a combination of these pretreatments. The effects of the treatments were then evaluated by anaerobic batch digestion assays at 55 degrees C. The enzymatic pretreatment increased the methane yield to 0.40 Nm(3)/kg VS(added), which is 122 % improvement compared to the yield of the untreated feathers. The other treatment conditions were less effective, increasing the methane yield by 11-50 %. The long-term effects of anaerobic digestion of feathers were examined by co-digestion of the feather with organic fraction of municipal solid waste performed with and without the addition of enzyme. When enzyme was added together with the feed, CH(4) yield of 0.485 Nm(3)/kg VS(-1) d(-1) was achieved together with a stable reactor performance, while in the control reactor, a decrease in methane production, together with accumulation of undegraded feather, was observed. PMID- 23359011 TI - Biodegradation of phenol by the yeast Candida tropicalis: an investigation by NMR spectroscopy. AB - The process of phenol biodegradation by the yeast Candida tropicalis NCIM 3556 in aqueous medium was studied by (1)H, (13)C, and DOSY NMR techniques. Samples at regular intervals were centrifuged to separate the cells, and (1)H spectral data were collected at 400 MHz. Though a gradual decrease in the concentration of phenol was observed, after an incubation period of ~8 h, formation of any intermediate products could not be detected. Experiments carried out with uniformly (13)C-labeled phenol also failed to detect formation of any carboxylic acid intermediates during degradation. The studies indicated that the phenol was completely degraded to carbon dioxide and water in approximately 20 h. Self diffusion coefficient measurements showed that the lifetime of phenol in the bound form is too small to impart any change in its diffusion behavior and the intermediates formed are converted to carbon dioxide and water at a very fast rate. PMID- 23359012 TI - Reduction of TMS induced artifacts in EEG using principal component analysis. AB - Co-registration of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) is a new, promising method for assessing cortical excitability and connectivity. Using this technique, a TMS evoked potential (TEP) can be induced and registered with the EEG. However, the TEP contains an early, short lasting artifact due to the magnetic pulse, and a second artifact, which depends on the location of stimulation and can last up to 40 ms. Different causes for this second artifact have been suggested in literature. In this study, we used principal component analysis (PCA) to suppress both the first and second artifact in TMS-EEG data. Single pulse TMS was applied at the motor and visual cortex in 18 healthy subjects. PCA using singular value decomposition was applied on single trials to suppress the artifactual components. A large artifact suppression was realized after the removal of the first five PCA components, thereby revealing early TEP peaks, with only a small suppression of later TEP components. The spatial distribution of the second artifact suggests that it is caused by electrode movement due to activation of the temporal musculature. In conclusion, we showed that PCA can be used to reduce TMS-induced artifacts in EEG, thereby revealing components of the TMS evoked potential. PMID- 23359013 TI - Large interrelated clusters of repetitive elements (REs) and RE arrays predominantly represent reference mouse chromosome Y. AB - The vast majority of the mouse and human genomes consist of repetitive elements (REs), while protein-coding sequences occupy only ~3 %. It has been reported that the Y chromosomes of both species are highly populated with REs although at present, their complete sequences are not available in any public database. The recent update of the mouse genome database (Build 38.1) from the National Center for Biotechnology Information (NCBI) indicates that mouse chromosome Y is ~92 Mb in size, which is substantially larger than the ~16 Mb reported previously (Build 37.2). In this study, we examined how REs are arranged in mouse chromosome Y (Build 38.1) using REMiner-II, a RE mining program. A combination of diverse REs and RE arrays formed large clusters (up to ~28 Mb in size) and most of them were directly or inversely related. Interestingly, the RE population of human chromosome Y (NCBI Build 37.2-current) was less dense, and the RE/RE array clusters were not evident in comparison to mouse chromosome Y. The annotated gene loci were distributed in five different regions and most of them were surrounded by unique RE arrays. In particular, tandem RE arrays were embedded into the introns of two adjacent gene loci. The findings from this study indicate that the large and interrelated clusters of REs and RE arrays predominantly represent the unique organizational pattern of mouse chromosome Y. The potential interactions among the clusters, which are populated with various interrelated REs and RE arrays, may play a role in the structural configuration and function of mouse chromosome Y. PMID- 23359015 TI - [Creativity in cannabis-users and in drug addicts in maintenance treatment and in rehabilitation]. AB - The main aim of this study was to investigate potential differences between different groups of drug addicts (patients in maintenance treatment, n = 14; patients in rehabilitation, n = 12) and Cannabis-Users (n = 13), along with a healthy control group (n = 18), with respect to verbal and figural creativity and general cognitive ability. Participants worked on different measures for the assessment of different facets of creativity, intelligence and experienced psychiatric symptoms. The results indicated that patients in maintenance and, to some extent Cannabis-Users scored higher regarding verbal creativity than patients in rehabilitation. With respect to figural creativity we observed no differences between the experimental groups. Concerning the Big Five personality traits, patients in maintenance treatment scored highest on Neuroticism while on a purely descriptive level Cannabis-Users achieved the highest scores with respect to openness to experience and extraversion. PMID- 23359014 TI - Cranberry proanthocyanidins improve intestinal sIgA during elemental enteral nutrition. AB - BACKGROUND: Elemental enteral nutrition (EEN) decreases gut-associated lymphoid tissue (GALT) function, including fewer Peyer's patch lymphocytes and lower levels of the tissue T helper 2 (Th2) cytokines and mucosal transport protein polymeric immunoglobulin receptor (pIgR), leading to lower luminal secretory immunoglobulin A (sIgA) levels. Since we recently demonstrated that cranberry proanthocyanidins (PACs) maintain the Th2 cytokine interleukin (IL)-4 when added to EEN, we hypothesized the addition of PACs to EEN would normalize other GALT parameters and maintain luminal levels of sIgA. METHODS: Institute of Cancer Research mice were randomized (12/group) to receive chow, EEN, or EEN + PACs (100 mg/kg body weight) for 5 days, starting 2 days after intragastric cannulation. Ileum tissue was collected to measure IL-4 by enzyme-linked immunosorbent assay, pIgR by Western blot, and phosphorylated STAT-6 by microarray. Intestinal wash fluid was collected to measure sIgA by Western blot. RESULTS: Compared with chow, EEN significantly decreased tissue IL-4, phosphorylated STAT-6, and pIgR. The addition of PACs to EEN prevented these alterations. Compared with chow, EEN resulted in significantly lower levels of luminal sIgA. The addition of PACs to EEN increased luminal sIgA levels compared with EEN alone. CONCLUSIONS: This study suggests the addition of PACs to EEN may support GALT function and maintain intestinal sIgA levels compared with EEN administration alone. PMID- 23359016 TI - Bruton's tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. AB - In chronic lymphocytic leukemia (CLL) signals from the B cell receptor (BCR) play a major role in disease development and progression. In this light, new therapies that specifically target signaling molecules downstream of the BCR continue to be developed. While first studies on the selective small molecule inhibitor of Bruton's tyrosine kinase (Btk), Ibrutinib (PCI-32765), demonstrated that Btk inhibition sensitizes CLL cells to apoptosis and alters their migratory behavior, these studies however did not address whether Btk-mediated signaling is involved in the process of CLL leukemogenesis. To investigate the requirement of Btk signaling for CLL development, we modulated Btk expression in the IgH.ETMU CLL mouse model, which is based on sporadic expression of the simian oncovirus SV40 T antigen in mature B cells. To this end, we crossed IgH.ETMU mice on a Btk deficient background or introduced a human Btk transgene (CD19-hBtk). Here we show that Btk deficiency fully abrogates CLL formation in IgH.ETMU mice, and that leukemias formed in Btk haplo-insufficient mice selectively expressed the wild type Btk allele on their active X chromosome. Conversely, Btk overexpression accelerated CLL onset, increased mortality, and was associated with selection of non-stereotypical BCRs into CLL clones. Taken together, these data show that Btk expression represents an absolute prerequisite for CLL development and that Btk mediated signaling enhances leukemogenesis in mice. We therefore conclude that in CLL Btk expression levels set the threshold for malignant transformation. PMID- 23359018 TI - Disability pension due to musculoskeletal diagnoses: importance of work-related factors in a prospective cohort study of Finnish twins. AB - OBJECTIVES: The aim of this study was to investigate the impact of work-related risk factors for future disability pension (DP) due to musculoskeletal diagnoses and for a subgroup of these, namely, DP due to osteoarthritis. METHODS: For this prospective study of 16,028 Finnish twins born in 1911-1957 and employed at baseline, a postal questionnaire collected information in 1975 on work-related factors; follow-up data on DP was gathered through register linkages up to 2004. A series of proportional hazards (Cox) regression models were used to analyze the associations between work-related factors and the incidence of DP. RESULTS: During the 30-year follow-up, 1297 participants (8%) were granted DP due to musculoskeletal diagnoses, 376 of which were due to osteoarthritis. High stress of daily activities, monotonous work, physical workload (namely work including lifting and carrying or physically heavy work), several workplace changes, and unemployment displayed a strong association with DP due to musculoskeletal diagnoses that was not affected by familial factors, including genetics and shared environment. Additionally, standing work increased the risk for DP due to osteoarthritis. CONCLUSIONS: Uninfluenced by family background or other confounding factors, several work-related factors were identified as being strong and direct risk factors for DP due to musculoskeletal diagnoses. PMID- 23359019 TI - Interspecific hybridization between Tigridia pavonia and T. augusta through ovary slice culture. AB - Tigridia pavonia is the most popular species in the Tigridia genus, and is currently marketed in Europe, Asia, and Australia as a landscape plant. Although it is native to Mexico, there are no breeding programs for it. In this study, we attempted to increase its flower color spectrum and growth habit by interspecific hybridization with T. augusta. Interspecific hybrids between T. pavonia and T. augusta were successfully obtained for the first time using the cut-style pollination and ovary slice culture techniques. On the contrary, no hybrids were obtained from a reciprocal cross. At three, four, and five days after pollination (DAP) ovaries were sliced and cultured on Murashige and Skoog medium without growth regulators and ammonium nitrate, but were supplemented with 6% sucrose, 50 mg/L yeast extract, and 0.25% Gelrite. After 80 days of culture initiation, the germination of only 10 embryos was observed in ovary slices cultured at three DAP. After transfer to identical fresh medium, six hybrid embryos developed into seedlings. All obtained hybrid seedlings were transplanted successfully to soil, and grew normally. The progenies investigated were identified as true hybrids based on randomly amplified polymorphic DNA analysis. PMID- 23359020 TI - Allelic frequencies and statistical data obtained from 15 STR loci in a population of the Goias State. AB - Due to the miscegenation of the Brazilian population, the central region of Brazil was colonized by internal migration of individuals from different origins, who contributed to the genetic diversity existing in this population. The purpose of this study was to estimate population parameters based on the allele frequencies for 15 polymorphic autosomal short-tandem repeat (STR) loci present in the population of the State of Goias in the central region of Brazil, and to compare the results with those of others from different Brazilian populations. DNA was obtained from a sample of 986 unrelated individuals by a commercial reagent kit and was quantified by spectrometry for later amplification in the thermocycler. These loci, commonly used in forensics and paternity testing, reflected Hardy-Weinberg equilibrium in this population. The D18S51 and Penta E loci had the highest number of alleles, while the observed heterozygosity reached the highest rates in FGA (0.920), D7S820 (0.870), and vWA (0.867) markers. Genetic diversity reached the highest levels in Penta E (0.906), Penta D (0.873), and D18S51 (0.860) markers, and the investigated forensic parameters showed high average values, with 93% power of discrimination, polymorphism information content of 78%, gene diversity of 79%, and observed heterozygosity of 79%. Similar to the other populations of Brazil, the population of the Midwest is derived from the admixture of 3 main parental groups: Amerindian, European, particularly Portuguese, and Africans from sub-Saharan Africa. In this context, the overall distribution of allele frequencies in the STR markers of various Brazilian populations is quite similar to the data obtained in this study. PMID- 23359017 TI - Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death. AB - Sound perception requires functional hair cell mechanotransduction (MET) machinery, including the MET channels and tip-link proteins. Prior work showed that uptake of ototoxic aminoglycosides (AG) into hair cells requires functional MET channels. In this study, we examined whether tip-link proteins, including Cadherin 23 (Cdh23), regulate AG entry into hair cells. Using time-lapse microscopy on cochlear explants, we found rapid uptake of gentamicin-conjugated Texas Red (GTTR) into hair cells from three-day-old Cdh23(+/+) and Cdh23(v2J/+) mice, but failed to detect GTTR uptake in Cdh23(v2J/v2J) hair cells. Pre treatment of wildtype cochleae with the calcium chelator 1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA) to disrupt tip-links also effectively reduced GTTR uptake into hair cells. Both Cdh23(v2J/v2J) and BAPTA-treated hair cells were protected from degeneration caused by gentamicin. Six hours after BAPTA treatment, GTTR uptake remained reduced in comparison to controls; by 24 hours, drug uptake was comparable between untreated and BAPTA-treated hair cells, which again became susceptible to cell death induced by gentamicin. Together, these results provide genetic and pharmacologic evidence that tip-links are required for AG uptake and toxicity in hair cells. Because tip-links can spontaneously regenerate, their temporary breakage offers a limited time window when hair cells are protected from AG toxicity. PMID- 23359021 TI - Assessment of BCL2/J(H) translocation in healthy individuals exposed to low level radiation of 137CsCl in Goiania, Goias, Brazil. AB - Healthy radio-exposed individuals who received low levels of Cesium-137 radiation during the accident that occurred in Goiania in 1987, their families and controls were tested for the detection of t(14;18)-rearranged B cells in peripheral blood by using a highly sensitive, real-time quantitative PCR method. The chromosomal translocation t(14;18)(q32;q21) is characteristic of follicular lymphoma and is a frequent abnormality observed in other types of non-Hodgkin's lymphoma. This translocation leads to constitutive activation of the BCL2 oncogene by the enhancers of the immunoglobulin heavy-chain locus. In healthy individuals, the same translocation may also be found in a small fraction of peripheral blood lymphocytes, and positive cells might serve as an indicator for environmental exposure to carcinogens and possibly correlate with the cumulative risk of developing t(14;18)- positive non-Hodgkin's lymphoma. Twenty healthy radio-exposed individuals, 10 relatives and 10 non-exposed healthy individuals were tested for the detection of this translocation. Only 1 non-exposed individual was positive for the chromosomal translocation, and healthy radio exposed individuals presented lower levels of cells bearing the BCL2/J(H) rearrangement when compared to the levels of the patients with follicular lymphoma before treatment. However, evaluation of more cells would be required to confirm the total absence of circulating cells bearing BCL2/J(H) rearrangement. PMID- 23359022 TI - Genes expressed in cotton (Gossypium hirsutum) buds isolated with a subtractive library. AB - A subtractive cDNA library from cotton buds was constructed to prospect for differentially expressed genes related to early bud development. A library was constructed and 768 cDNA sequences were obtained, comprising 168 clusters, with 126 contigs and 42 singlets. Both the Gossypium as well as Arabidopsis databases were utilized for the in silico analysis, since some genes identified in cotton have not yet been studied for functionality, although they have homology with genes from other species. The transcriptome revealed a large number of transcripts, some of them with unknown function, and others related to pollen development, pollen tubes, ovules, and fibers at different stages. The most populated contig was identified as fiber from 0-10 days after anthesis, with 12 reads. The success and novelty rates generated from the library were 67 and 51%, respectively. The information obtained here will provide a framework for research on functional cotton genomics. PMID- 23359023 TI - Amplifiability of mitochondrial, microsatellite and amelogenin DNA loci from fecal samples of red brocket deer Mazama americana (Cetartiodactyla, Cervidae). AB - We tried to amplify mitochondrial, microsatellite and amelogenin loci in DNA from fecal samples of a wild Mazama americana population. Fifty-two deer fecal samples were collected from a 600-ha seasonal semideciduous forest fragment in a subtropical region of Brazil (21 degrees 20'S, 47 degrees 17'W), with the help of a detection dog; then, stored in ethanol and georeferenced. Among these samples 16 were classified as "fresh" and 36 as "non-fresh". DNA was extracted using the QIAamp((r)) DNA Stool Mini Kit. Mitochondrial loci were amplified in 49 of the 52 samples. Five microsatellite loci were amplified by PCR; success in amplification varied according to locus size and sample age. Successful amplifications were achieved in 10/16 of the fresh and in 13/36 of the non-fresh samples; a negative correlation (R = -0.82) was found between successful amplification and locus size. Amplification of the amelogenin locus was successful in 22 of the 52 samples. The difficulty of amplifying nuclear loci in DNA samples extracted from feces collected in the field was evident. Some methodological improvements, including collecting fresh samples, selecting primers for shorter loci and quantifying the extracted DNA by real-time PCR, are suggested to increase amplification success in future studies. PMID- 23359024 TI - Lack of mutations of G4.5 in three families from China with noncompaction of the ventricular myocardium. AB - To find the underlying cause of noncompaction of the ventricular myocardium (NVM), three Chinese families with probands who presented this problem were studied. After the family members were evaluated by echocardiography, the gene G4.5 (taffazin) was scanned by sequencing. Although X-linked inheritance could not be ruled out, NVM were thought to have a vague rule of inheritance in our data from 8 patients and 28 family members. We also did not identify any mutations in G4.5 in all samples. Our data suggest that other genes are responsible for the familial form of this disease. PMID- 23359025 TI - Association study between Y-chromosome haplogroups and susceptibility to spermatogenic impairment in Han People from southwest China. AB - The non-recombining portion of the Y-chromosome contains numerous polymorphisms; therefore, it is now the most informative haplotyping system with wide-ranging applications. Idiopathic azoospermia and oligospermia are among the most important causes of male infertility. Different haplogroups may have different genetic backgrounds, which may be either susceptible or unsusceptible to idiopathic azoospermia or oligospermia. This study investigated the possible association between Y-chromosome haplogroup distribution and susceptibility to spermatogenic impairment. Peripheral blood was collected from 193 men with normozoospermia, 193 men with idiopathic azoospermia and 105 men with idiopathic oligospermia. All of the subjects underwent karyotyping, azoospermia factor (AZF) deletion analysis by 15 AZF-specific sequence-tagged sites and Y chromosome haplotype analysis by 17 binary markers. Excluding men with AZF deletions and abnormal karyotypes, the remainder of these 3 groups was named Group i, Group ii, and Group iii, respectively. The comparisons of 17 Y haplogroup distributions between Group i and Group ii, Group iii or Group ii + iii were performed with the SPSS V.18.0 software. Significantly different Y haplogroup distributions were observed between Group i and Group ii in N1* (P = 0.002), between Group i and Group iii in F*, K*, P*, and O3* (P = 0.002, 0.001, 0.004, and 0.007, respectively), and between Group i and Group ii + iii in K*, N1* and O3* (P = 0.008, 0.012, and 0.009, respectively). These results suggest that Y-chromosome haplogroups play a role in spermatogenic impairment. PMID- 23359026 TI - The genetic variant rs401681C/T is associated with the risk of non-small cell lung cancer in a Chinese mainland population. AB - Although lung cancer (LC) is a highly environmentally associated disease, genetic factors are also thought to play a role in this disease. In recent years, genome wide association studies have identified various susceptible genetic regions for LC. Herein, we used high-resolution melting analysis to genotype 2 significant single nucleotide polymorphisms previously reported in Caucasians, that is, rs401681 at 5p15.33 and rs8034191 at 15q25, in a case-control study with 492 LC cases and 486 cancer-free controls in a Chinese population. We found that the rs401681C/T allele in the TERT-CLPTM1L gene was associated with the risk of non small cell lung cancer [NSCLC; P = 0.012, odds ratio (OR) = 1.29, 95% confidence interval (95%CI) = 1.09-1.50], but was not associated with the risk of small cell lung cancer (P = 0.571, OR = 1.15, 95%CI = 0.82-1.47). However, no significant association was found between rs8034191T/C and LC risk. These results suggest that genetic variants in the TERT-CLPTM1L gene may predispose individuals to be susceptible to LC, particularly NSCLC, in the Chinese population. PMID- 23359027 TI - Meta-analysis demonstrates lack of association between the ACE gene I/D polymorphism and obstructive sleep apnea-hypopnea syndrome occurrence and severity. AB - Published data on a possible association between the angiotensin-converting enzyme (ACE) gene I/D polymorphism and obstructive sleep apnea-hypopnea syndrome (OSAHS) occurrence and its severity risk are inconclusive. We performed a meta analysis of case-control studies published in English or Chinese. Thirteen studies, totaling 1361 cases and 1373 controls, were investigated for association of the ACE I/D polymorphism with OSAHS. We also made a study of ACE I/D with OSAHS severity risk, including 879 mild/moderate OSAHS patients and 357 severe OSAHS patients. A random-effects model was used, irrespective of between-study heterogeneity. Study quality was assessed in duplicate. Overall, the ACE I/D polymorphism was not significantly associated with an increase in OSAHS risk [odds ratio (OR) = 1.21; 95% confidence interval (95%CI) = 0.88-1.65; P = 0.24]. In subgroup analysis by ethnicity, comparison of alleles I with D demonstrated a 58% (nonsignificantly) increased risk for OSAHS in Chinese (OR = 1.58; 95%CI = 0.92-2.70; P = 0.09). We also found that there was no significant association between ACE I/D and OSAHS severity risk. No publication biases were observed. This meta-analysis suggests that there is no significantly increased risk for OSAHS occurrence or severity associated with the ACE I/D polymorphism. PMID- 23359028 TI - Molecular cloning and characterization of the pseudorabies virus US1 gene. AB - Using polymerase chain reaction, a 1050-bp sequence of the US1 gene was amplified from the pseudorabies virus (PRV) Becker strain genome; identification of the US1 gene was confirmed by further cloning and sequencing. Bioinformatics analysis indicated that the PRV US1 gene encodes a putative polypeptide with 349 amino acids. The encoded protein, designated PICP22, had a conserved Herpes_IE68 domain, which was found to be closely related with the herpes virus immediate early regulatory protein family and is highly conserved among the counterparts encoded by Herpes_IE68 genes. Multiple nucleic acid sequence and amino acid sequence alignments suggested that the product of PRV US1 has a relatively higher homology with ICP22-like proteins of genus Varicellovirus than with those of other genera of Alphaherpesvirinae. In addition, phylogenetic analysis showed that PRV US1 has a close evolutionary relationship with members of the genus Varicellovirus, especially Equid herpes virus 1 (EHV-1), EHV-4 and EHV-9. Antigen prediction indicated that several potential B-cell epitopes are located in PICP22. Also, subcellular localization analysis demonstrated that PICP22 is predominantly located in the cytoplasm, suggesting that it might function as a cytoplasmic-targeted protein. PMID- 23359029 TI - Genetic diversity in the germplasm of tropical maize landraces determined using molecular markers. AB - Maize landraces derived from tropical germplasm represent an important source of genetic variability, which is currently poorly understood and under-exploited by Brazilian crop breeding programs. The aims of our study were to a) estimate the genetic diversity across 48 varieties of maize landraces cultivated at different locations in the States of Rio Grande do Sul (RS) and Parana (PR) by means of random amplified polymorphic DNA (RAPD), simple sequence repeat (SSR), and amplified fragment length polymorphism (AFLP) markers; b) cluster these varieties based on their genetic similarity estimates, and c) establish possible correlations between genetic similarity and germplasm collection sites. Maize landrace accessions were genotyped through the 30 RAPD, 47 SSR, and 25 combinations of AFLP primers. The results revealed high levels of variability across landraces within and between collection sites. AFLP analysis resulted in amplification of 762 polymorphic fragments and a polymorphic index of 40.3%, followed by RAPD with 335 fragments (81.9%) and SSR with 105 fragments (78.3%). The genetic similarity estimates of the investigated landraces ranged from 41 (SSR) to 74% (AFLP), and the amplitudes of these indices were notably similar between RAPD and SSR, as well as between AFLP and joint analysis. Regarding the RAPD and AFLP dendrograms, groups comprising accessions from RS prevailed, whereas SSR comprised varieties from both collection sites. Groups exclusive to RS or PR support the hypothesis that divergence between groups is possible owing to the fixation of regional adaptation alleles and to spatial barriers hindering genetic flow between locations. PMID- 23359030 TI - Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients. AB - OBJECTIVE: The activation of hedgehog (HH) pathway is implicated in the development of human malignancies including hepatocellular carcinoma (HCC). However, the clinical impact of HH activation in HCC patients is still unclear. This study was conducted to confirm whether the expression of HH pathway components was associated with HCC progression and clinical outcome. METHODS: This study was a sample-expanded and prolonged follow up of one of our previous studies. It included 46 HCC patients who underwent surgical treatment from 2002 to 2005. The expression of sonic HH (SHH), patched-1 (PTCH1), smoothened (SMOH) and glioma-associated oncogene-1 (GLI1) genes in tumor and adjacent normal tissues extracted from the patients were examined by reverse transcription polymerase chain reaction (RT-PCR) to explore the relationship between these genes and the clinical prognosis of HCC. RESULTS: The expression levels of SHH, PTCH1, SMOH and GLI1 in HCC tissues were 60.87%, 50.00%, 32.61% and 54.35%, respectively. The expression levels of SHH-related molecules were relatively intense in cancer tissue, but insignificantly correlated with any clinicopathological factors of tumor. Transcriptional factor GLI1 was the only molecule associated with poor prognosis among the HCC patients. The expression of GLI1 gene in tumor tissues was significantly related with disease-free survival (DFS) (P=0.042) and overall survival (OS) (P=0.030). The simultaneous expression of GLI1 in tumor and adjacent normal liver tissues correlated with DFS (P<0.029) and OS (P<0.025). CONCLUSIONS: HH signaling activation is an important event in the development of human HCC. The expression of GLI1 in SHH pathway is possibly involved in HCC progression, which may be a useful prognostic indicator of HCC. PMID- 23359031 TI - A medication assessment tool to evaluate adherence to medication guideline in asthmatic children. AB - OBJECTIVE: Asthma is one of the commonest causes of morbidity and mortality in childhood. The goals of the present study were to design a valid medication assessment tool for evaluating the quality of medication use according to recommendations of updated asthma guidelines for children aged from 5 to 12 years, and to quantify adherence to guideline recommendations. SETTING: Two primary care settings in Scotland, UK. METHODS: Recommendations related to the long-term management of asthmatic children in the British Thoracic Society/Scottish Intercollegiate Guidelines Network and Global Initiative for Asthma guidelines were identified and corresponding criteria were created. These criteria were incorporated to generate an assessment tool named MAT ASTHMA-PAED. Two phases of field-testing were undertaken and the tool was also subject to examination by a focus group of specialist practitioners. Thereafter, MAT ASTHMA PAED was modified accordingly. MAIN OUTCOME MEASURE: Applicability and adherence to each criterion and overall adherence to the MAT ASTHMA-PAED. RESULTS: The MAT ASTHMA-PAED field-testing was undertaken in two primary care practices in Scotland, United Kingdom and 77 asthmatic children were recruited. Results of the pilot study field-testing showed a high overall adherence of 70.0 % (95 % CI: 58.7-81.3 %) to the guidelines. Low adherence (<50 %) was seen for 4 criteria, whereas 8 criteria were considered high-adherence criteria (>70 %). The final MAT ASTHMA-PAED comprised of 25 criteria was produced based on the results of field testing and the opinions from the focus group. CONCLUSION: Although high utility of MAT ASTHMA-PAED criteria was found, there were gaps in the implementation of certain recommendations, particularly in relation to demonstrated satisfactory technique of inhaler. Moreover, further studies assessing the use of oral steroids and exercise-induced asthma, and wider implementation of MAT ASTHMA-PAED are required. PMID- 23359032 TI - Bilayer properties of giant magnetic liposomes formed by cationic pyridine amphiphile and probed by active deformation under magnetic forces. AB - We synthesize giant magnetic liposomes by a reverse-phase evaporation method (REV) using a new self-assembling Cationic Pyridine Amphiphile (CPA) derived from 1,4-dihydropyridine as liposome-forming agent and a magnetic ferrofluid based on gamma-Fe(2)O(3) nanoparticles. Having in view the potential interest of CPA in targeted transport by magnetic forces, the mechanical elastic properties of such bilayers are here directly investigated in vesicles loaded with magnetic nanoparticles. Bending elastic modulus K(b) ~ 0.2 to 5k(B)T and pre-stress tau ~ 3.2 to 12.10(-6) erg/cm(2) are deduced from the under-field deformations of the giant magnetic liposomes. The obtained K(b) values are discussed in terms of A. Wurgers's theory. PMID- 23359033 TI - Protective effects of mangiferin in subchronic developmental lead-exposed rats. AB - Lead is a ubiquitous environmental and industrial pollutant. Exposure to excessive amounts of lead is especially harmful to the central nervous systems of infants and young children, and oxidative stress has been reported as a major mechanism of lead-induced toxicity. To evaluate the ameliorative potential of antioxidant mangiferin (MGN) on lead-induced toxicity, Morris water maze test, determination of blood and bone lead concentration, determination of antioxidant status in plasma, as well as observation of ultrastructural changes in the hippocampus were carried out. In the present study, under a transmission electron microscope, ameliorated morphological damages in the hippocampus were observed in MGN-treated groups. Blood and bone lead concentration in MGN-treated groups lowered to some extent (p < 0.05, p < 0.01). The activities of antioxidant enzymes, glutathione (GSH) content, and the GSH/oxidized glutathione ratio in MGN treated groups were increased, respectively. Further studies are needed to establish whether the observed differences were a direct cause of mangiferin on lead-induced toxicity or not. This study might provide clues for the treatment of lead-induced toxicity. PMID- 23359034 TI - Computed tomography of the cervical spine: comparison of image quality between a standard-dose and a low-dose protocol using filtered back-projection and iterative reconstruction. AB - OBJECTIVE: To compare image quality of a standard-dose (SD) and a low-dose (LD) cervical spine CT protocol using filtered back-projection (FBP) and iterative reconstruction (IR). MATERIALS AND METHODS: Forty patients investigated by cervical spine CT were prospectively randomised into two groups: SD (120 kVp, 275 mAs) and LD (120 kVp, 150 mAs), both applying automatic tube current modulation. Data were reconstructed using both FBP and sinogram-affirmed IR. Image noise, signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were measured. Two radiologists independently and blindly assessed the following anatomical structures at C3-C4 and C6-C7 levels, using a four-point scale: intervertebral disc, content of neural foramina and dural sac, ligaments, soft tissues and vertebrae. They subsequently rated overall image quality using a ten-point scale. RESULTS: For both protocols and at each disc level, IR significantly decreased image noise and increased SNR and CNR, compared with FBP. SNR and CNR were statistically equivalent in LD-IR and SD-FBP protocols. Regardless of the dose and disc level, the qualitative scores with IR compared with FBP, and with LD-IR compared with SD-FBP, were significantly higher or not statistically different for intervertebral discs, neural foramina and ligaments, while significantly lower or not statistically different for soft tissues and vertebrae. The overall image quality scores were significantly higher with IR compared with FBP, and with LD-IR compared with SD-FBP. CONCLUSION: LD-IR cervical spine CT provides better image quality for intervertebral discs, neural foramina and ligaments, and worse image quality for soft tissues and vertebrae, compared with SD-FBP, while reducing radiation dose by approximately 40 %. PMID- 23359036 TI - Authors' reply to Godman and Gustafsson: "A new reimbursement system for innovative pharmaceuticals combining value-based and free market pricing". PMID- 23359035 TI - Arthroscopic treatment for cuff tear: strength recovery at 12 months of follow up. AB - The rotator cuff tear is one of the most frequent musculoskeletal disorders, but the real incidence is not clearly known because it's usually asymptomatic, even if it's more common in patients with shoulder pain (36%). The prevalence of the complete tear among general population is estimated approximately around 20.7% and it is more usual with the increasing of the age. The aim of this study is to evaluate a group of patients with any size of full-thickness cuff tear treated by arthroscopic technique, comparing the clinical and functional recovery (isokinetic, isotonic and isometric strength) with the un-operated side. Between October 2009 and June 2011, 74 patients, mean age 59 (20-72) years old, underwent arthroscopic treatment for rotator cuff tear. Forty-two patients were finally included in the study, 20 men and 22 women, mean age of 55 (20-68) years old. The mean follow-up was 12 months (6-23 months). The strength of each patient's shoulder, both operated and un-operated, was evaluated using isokinetic, isotonic and isometric tests (BIODEX Medical System). The functional outcome showed no significant differences between operated and un-operated shoulder, confirmed by Constant-Murley score and DASH score. The isokinetic, isotonic and isometric tests are valid support to clinical evaluation in order to obtain an objective data on shoulder recovery. PMID- 23359037 TI - Handling ability of gaseous microemboli of two pediatric arterial filters in a simulated CPB model. AB - OBJECTIVE: The purpose of this experiment was to compare the Sorin KIDS D131 and the Terumo Capiox AF02 pediatric arterial filters in a simulated CPB procedure to determine which filter is the better for clinical use. METHODS: The experimental circuit was primed with an 800 ml combination of lactated Ringer's solution and human blood (hematocrit (Hct) 30%). The two filters were tested under flow rates of 500, 1000, and 1500 ml/min at room temperature and their purge lines opened and closed as 5cc of air was injected into the circuit. RESULTS: As the flow rates increased, the number of gaseous microemboli (GME) being returned to the pseudo patient increased for both of the pediatric arterial filters. Having an open purge line increased the number of GME removed from the CPB circuit, caused less of a pressure drop than when closed and increased the total hemodynamic energy loss than when closed. Both of the filters performed and reacted similarly in decreasing GME, hemodynamic energy loss and pressure drop. The only minor difference was that the Capiox AF02 had slightly less stolen blood flow (109.5 +/ 1.7 ml/min at 500 ml/min, 114.7 +/- 1.1 ml/min at 1000 ml/min and 105.8 +/- 4.2 ml/min at 1500ml/min) from the open purge line than the KIDS D131 (119.5 +/- 2.5 ml/min at 500 ml/min, 128.3 +/- 1.0 ml/min at 1000 ml/min and 126.3 +/- 3.1 ml/min at 1500 ml/min). CONCLUSION: Our study confirmed that both the Sorin KIDS D131 and the Terumo Capiox AF02 were equivalent in their ability to remove significant numbers of GME, the amount of pressure drop and the total hemodynamic energy loss across the arterial filters at the various flow rates. An arterial filter is not an option, but a necessity for removing microemboli delivered to the patient. PMID- 23359038 TI - Glossitis secondary to vitamin B12 deficiency anemia. PMID- 23359041 TI - Roll, roll, roll me away. PMID- 23359039 TI - Glucose-responsive insulin and glucagon delivery (dual-hormone artificial pancreas) in adults with type 1 diabetes: a randomized crossover controlled trial. AB - BACKGROUND: Most patients with type 1 diabetes do not achieve their glycemic targets. We aimed to assess the efficacy of glucose-responsive insulin and glucagon closed-loop delivery for controlling glucose levels in adults with type 1 diabetes. METHODS: We conducted a randomized crossover trial involving 15 adults with type 1 diabetes, comparing standard insulin-pump therapy with dual hormone, closed-loop delivery. Patients were admitted twice to a clinical research facility and received, in random order, both treatments. Each 15-hour visit (from 1600 to 0700) included an evening exercise session, followed by a medium-sized meal, a bedtime snack and an overnight stay. During visits that involved closed-loop delivery, basal insulin and glucagon miniboluses were delivered according to recommendations based on glucose sensor readings and a predictive dosing algorithm at 10-minute intervals. During visits involving standard insulin-pump therapy (control visits), patients used conventional treatment. RESULTS: Dual-hormone closed-loop delivery increased the percentage of time for which patients' plasma glucose levels were in the target range (median 70.7% [interquartile range (IQR) 46.1%-88.4%] for closed-loop delivery v. 57.3% [IQR 25.2%-71.8%] for control, p = 0.003) and decreased the percentage of time for which plasma glucose levels were in the low range (bottom of target range [< 4.0 mmol/L], 0.0% [IQR 0.0%-3.0%] for closed-loop delivery v. 10.2% [IQR 0.0% 13.0%] for control, p = 0.01; hypoglycemia threshold [< 3.3 mmol/L], 0.0% [IQR 0.0%-0.0%] for closed-loop delivery v. 2.8% [IQR 0.0%-5.9%] for control, p = 0.006). Eight participants (53%) had at least 1 hypoglycemic event (plasma glucose < 3.0 mmol/L) during standard treatment, compared with just 1 participant (7%) during closed-loop treatment (p = 0.02). INTERPRETATION: Dual-hormone, closed-loop delivery guided by advanced algorithms improved short-term glucose control and reduced the risk of hypoglycemia in a group of 15 adults with type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01297946. PMID- 23359042 TI - Treatment of constipation in older people. PMID- 23359043 TI - The future of care for type 1 diabetes. PMID- 23359044 TI - The trend toward self-diagnosis. PMID- 23359045 TI - Promoting change in medical practice. PMID- 23359046 TI - A clearer picture of physician income. PMID- 23359047 TI - Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors. AB - BACKGROUND: Clinical trials are commonly done without blinded outcome assessors despite the risk of bias. We wanted to evaluate the effect of nonblinded outcome assessment on estimated effects in randomized clinical trials with outcomes that involved subjective measurement scales. METHODS: We conducted a systematic review of randomized clinical trials with both blinded and nonblinded assessment of the same measurement scale outcome. We searched PubMed, EMBASE, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, HighWire Press and Google Scholar for relevant studies. Two investigators agreed on the inclusion of trials and the outcome scale. For each trial, we calculated the difference in effect size (i.e., standardized mean difference between nonblinded and blinded assessments). A difference in effect size of less than 0 suggested that nonblinded assessors generated more optimistic estimates of effect. We pooled the differences in effect size using inverse variance random-effects meta-analysis and used metaregression to identify potential reasons for variation. RESULTS: We included 24 trials in our review. The main meta-analysis included 16 trials (involving 2854 patients) with subjective outcomes. The estimated treatment effect was more beneficial when based on nonblinded assessors (pooled difference in effect size 0.23 [95% confidence interval (CI) -0.40 to -0.06]). In relative terms, nonblinded assessors exaggerated the pooled effect size by 68% (95% CI 14% to 230%). Heterogeneity was moderate (I(2) = 46%, p = 0.02) and unexplained by metaregression. INTERPRETATION: We provide empirical evidence for observer bias in randomized clinical trials with subjective measurement scale outcomes. A failure to blind assessors of outcomes in such trials results in a high risk of substantial bias. PMID- 23359048 TI - When doctors' fees become a political football. PMID- 23359049 TI - Survival after lumpectomy and mastectomy for early stage invasive breast cancer: the effect of age and hormone receptor status. AB - BACKGROUND: Randomized clinical trials (RCT) have demonstrated equivalent survival for breast-conserving therapy with radiation (BCT) and mastectomy for early-stage breast cancer. A large, population-based series of women who underwent BCT or mastectomy was studied to observe whether outcomes of RCT were achieved in the general population, and whether survival differed by surgery type when stratified by age and hormone receptor (HR) status. METHODS: Information was obtained regarding all women diagnosed in the state of California with stage I or II breast cancer between 1990 and 2004, who were treated with either BCT or mastectomy and followed for vital status through December 2009. Cox proportional hazards modeling was used to compare overall survival (OS) and disease-specific survival (DSS) between BCT and mastectomy groups. Analyses were stratified by age group (< 50 years and >= 50 years) and tumor HR status. RESULTS: A total of 112,154 women fulfilled eligibility criteria. Women undergoing BCT had improved OS and DSS compared with women with mastectomy (adjusted hazard ratio for OS entire cohort = 0.81, 95% confidence interval [CI] = 0.80-0.83). The DSS benefit with BCT compared with mastectomy was greater among women age >= 50 with HR positive disease (hazard ratio = 0.86, 95% CI = 0.82-0.91) than among women age < 50 with HR-negative disease (hazard ratio = 0.88, 95% CI = 0.79-0.98); however, this trend was seen among all subgroups analyzed. CONCLUSIONS: Among patients with early stage breast cancer, BCT was associated with improved DSS. These data provide confidence that BCT remains an effective alternative to mastectomy for early stage disease regardless of age or HR status. PMID- 23359051 TI - Peer influence and physical activity behavior in young children: an experimental study. AB - BACKGROUND: There is evidence that the presence of a friend increases physical activity behavior in school-aged children (>= 8 years old) and in young adolescents. Little is known about the developmental trajectory of the effects of peer influences on children's physical activity. Therefore, we sought to test the effect of the presence versus absence of a friend on physical activity in young children (<= 6 years old). METHODS: Physical activity was assessed, via accelerometery, in 3- to 6-year-old children, during 2 social conditions: alone and in the presence of a friend. During each condition, children were taken to a gymnasium and had free access to physical and sedentary activities for 30 minutes. In one condition children were tested alone (solo play), whereas in the other they were tested in the presence of a friend who had access to the same activities. RESULTS: Children exhibited 54% greater (P < .02) average accelerometer counts during the friend condition (mean = 2629, SD = 1080 or 5.7 METs) than during the solo play condition (mean = 1707, SD = 1009 or 4.5 METs). CONCLUSIONS: The presence of a friend contributes to increased physical activity behavior in young children. PMID- 23359050 TI - FLT3 mutations in early T-cell precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors. AB - Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has been identified as high-risk subgroup of acute T-lymphoblastic leukemia (T-ALL) with a high rate of FLT3-mutations in adults. To unravel the underlying pathomechanisms and the clinical course we assessed molecular alterations and clinical characteristics in a large cohort of ETP-ALL (n = 68) in comparison to non-ETP T-ALL adult patients. Interestingly, we found a high rate of FLT3-mutations in ETP-ALL samples (n = 24, 35%). Furthermore, FLT3 mutated ETP-ALL was characterized by a specific immunophenotype (CD2+/CD5-/CD13+/CD33-), a distinct gene expression pattern (aberrant expression of IGFBP7, WT1, GATA3) and mutational status (absence of NOTCH1 mutations and a low frequency, 21%, of clonal TCR rearrangements). The observed low GATA3 expression and high WT1 expression in combination with lack of NOTCH1 mutations and a low rate of TCR rearrangements point to a leukemic transformation at the pluripotent prothymocyte stage in FLT3 mutated ETP-ALL. The clinical outcome in ETP-ALL patients was poor, but encouraging in those patients with allogeneic stem cell transplantation (3-year OS: 74%). To further explore the efficacy of targeted therapies, we demonstrate that T-ALL cell lines transfected with FLT3 expression constructs were particularly sensitive to tyrosine kinase inhibitors. In conclusion, FLT3 mutated ETP-ALL defines a molecular distinct stem cell like leukemic subtype. These data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic stem cell transplantation for this high risk subgroup. PMID- 23359052 TI - Charge versus sequence for nuclear/nucleolar localization of plant ribosomal proteins. AB - Ribosomal subunit assembly in the nucleolus is dependent on efficient targeting of ribosomal proteins (RPs) from the cytoplasm into the nucleus and nucleolus. Nuclear/nucleolar localization of a protein is generally mediated by one or more specific stretches of basic amino acids-nuclear/nucleolar localization signals (NLSs/NoLSs). Arabidopsis thaliana RPL23aA has eight putative NLSs/NoLSs (pNLSs/NoLSs). Here we mutated all eight NLS/NoLSs individually and in groups and showed, via transient expression in tobacco cells that nucleolar localization of RPL23aA was disrupted by mutation of various combinations of five or more pNLSs/NoLSs. Mutation of all eight pNLSs/NoLSs, a 50 % reduction in total basic charge of RPL23aA, resulted in a complete disruption of nucleolar localization, however, the protein can still localize to the nucleus. As no individual or specific combination of NoLSs was absolutely required for nucleolar localization, we suggest that nucleolar localization/retention of RPL23aA is dependent on the overall basic charge. In addition to the optimal basic charge conferred by these NoLSs, nucleolar localization/retention of RPL23aA also required a C-terminal putative 26S rRNA binding site. In contrast, in the RPs RPS8A and RPL15A, mutation of just two and three N-terminal pNLSs, respectively, disrupted both nuclear and nucleolar localization of these two RPs, indicating differential signal requirements for nuclear and nucleolar localization of the three Arabidopsis RPs RPL23aA, RPL15A and RPS8A. PMID- 23359054 TI - Construction of suppressor of cytokine signaling 2 (SOCS2) adenoviral overexpression vector and its impact on growth-hormone-induced lipolysis in swine primary adipocytes. AB - We investigated the effect of overexpression suppressor of cytokine signaling 2 (SOCS2) on lipolysis in swine primary adipocytes (pAd) induced by growth hormone (GH). We constructed pAd-SOCS2 adenoviral overexpression vectors to infect HEK293 cells for virus packaging and propagation. Cultured swine primary adipocytes were infected with virus particles; after 48 h the infected adipocytes were treated with 500 ng GH/mL in the growth medium. Lipometabolism-related gene expressions were detected at 0, 0.25, 0.5, 1, 2, and 4 h, by measuring mRNA and protein levels. The pAd-SOCS2 overexpression vector was successfully constructed and the concentration of titrated virus was 1.2 x 10(9) PFU/mL. We found that virus infection significantly increased SOCS2 mRNA and protein levels in swine primary adipocytes. Overexpression of SOCS2 significantly inhibited the increase in fatty acid synthase, adipose triglyceride lipase mRNA, and protein expression at 0.5 h. However, after 0.5 h, this inhibition was not significant. We concluded that overexpression of SOCS2 inhibited the increase in lipolysis induced by GH in swine primary adipocytes; this could provide a basis for studies of lipometabolism. PMID- 23359053 TI - Whole-genome duplications contributed to the expansion of cytochrome b5 genes in Paramecium tetraurelia. AB - Cytochrome b5 (cyt b5) genes encode ubiquitous electron transport hemoproteins found in animals, plants, fungi, and purple bacteria. However, little is known about their evolutionary history in genomes so far. Here, we conducted an extensive genome-wide survey of cyt b5 genes in 20 representative model species and identified 310 of these genes. Both the absolute number and relative proportion of cyt b5 genes in Paramecium tetraurelia were significantly higher than those in other genomes. Our data also showed that whole-genome duplications (WGDs), especially the recent WGD, contributed to the species-specific expansion of cyt b5 genes in the Paramecium genome. Furthermore, 24 cyt b5 genes were identified as the minimal number of ancestral cyt b5 in the ancestral Paramecium genome, which is also the largest number of these genes encountered in an organism. These results suggest that an excess of cyt b5 genes were selectively retained in this species even before the three WGDs took place. Although more cyt b5 genes were retained in P. tetraurelia than in other genomes, more cyt b5 losses were also observed in the P. tetraurelia genome, suggesting that the balance of gene retention and loss maintained an optimum dosage of cyt b5 genes. PMID- 23359056 TI - Phenotypic and molecular characterization of a tomato (Solanum lycopersicum L.) F2 population segregation for improving shelf life. AB - Breeding for better quality fruits is a major focus for tomatoes, which are continuously subjected to post-harvest losses. Several methods have been used to improve the fruit shelf life of tomatoes, including the use of ripening gene mutants of Solanum lycopersicum. We developed extended shelf-life tomato hybrids with better quality fruits using ripening mutants. Nine tomato crosses were developed using 3 fruit ripening gene mutants of S. lycopersicum [alcobaca (alc), non-ripening, and ripening inhibitor] and 3 agronomically superior Indian cultivars ('Sankranti', 'Vaibhav', and 'Pusaruby') with short shelf life. The hybrid progenies developed from alc x 'Vaibhav' had the highest extended shelf life (up to 40 days) compared with that of other varieties and hybrids. Further, the F(2) progenies of alc x 'Vaibhav' were evaluated for fruit quality traits and yield parameters. A wide range of genetic variability was observed in shelf life (5-106 days) and fruit firmness (0.55-10.65 lbs/cm(2)). The potential polymorphic simple sequence repeat markers underlying shelf life traits were identified in an F(2) mapping population. The marker association with fruit quality traits and yield was confirmed with single-marker analysis and composite interval mapping. The genetic parameters analyzed in the parents and F(1) and F(2) populations indicated that the cross between the cultivar 'Vaibhav' and ripening gene mutant alc yielded fruit with long shelf life and good quality. PMID- 23359055 TI - Characterization and comparison of EST-SSR and TRAP markers for genetic analysis of the Japanese persimmon Diospyros kaki. AB - We developed and characterized expressed sequence tags (ESTs)-simple sequence repeats (SSRs) and targeted region amplified polymorphism (TRAP) markers to examine genetic relationships in the persimmon genus Diospyros gene pool. In total, we characterized 14 EST-SSR primer pairs and 36 TRAP primer combinations, which were amplified across 20 germplasms of 4 species in the genus Diospyros. We used various genetic parameters, including effective multiplex ratio (EMR), diversity index (DI), and marker index (MI), to test the utility of these markers. TRAP markers gave higher EMR (24.85) but lower DI (0.33), compared to EST-SSRs (EMR = 3.65, DI = 0.34). TRAP gave a very high MI (8.08), which was about 8 times than the MI of EST-SSR (1.25). These markers were utilized for phylogenetic inference of 20 genotypes of Diospyros kaki Thunb. and allied species, with a result that all kaki genotypes clustered closely and 3 allied species formed an independent group. These markers could be further exploited for large-scale genetic relationship inference. PMID- 23359057 TI - Change in heritability estimates due to half-sib family selection in the maize variety Pahari. AB - This research was carried out at the Agriculture Research Farm, Khyber Pakhtunkhwa Agricultural University, Peshawar, and the Cereal Crops Research Institute, Pirsabak, Nowshera, during 2009 and 2010. Half-sib families (HS) derived from the maize variety Pahari in spring crop seasons 2009 and 2010 were developed at the Cereal Crops Research Institute. All HS families were detasseled well before pollen shedding. At maturity, each family was harvested and shelled separately. During the summer crop of seasons 2009 and 2010, these HS families were evaluated in 12 x 12 and 11 x 11 partially balanced lattice square arrangements at the Khyber Pakhtunkhwa Agricultural University, Peshawar, for various flowering and yield traits, respectively. The data on days to mid silking, anthesis, anthesis-silking interval, 100-grain weight, and grain yield were recorded. The results revealed significant differences among families for all traits in both cycles. High heritability (0.88) was observed for days to mid silking in cycle 0 (C0), while moderate heritability (0.42) was recorded for 100 grain weight in C1. The selection differential was quite reasonable and varied according to the traits of interest. The observed response for grain yield in C0 (815.74 kg/ha) was greater than the expected response (681.76 kg/ha). PMID- 23359058 TI - Meta-analysis demonstrates association of XRCC1 genetic polymorphism Arg399Gln with esophageal cancer risk in the Chinese population. AB - We made a meta-analysis of the association between X-ray cross-complementing gene 1 (XRCC1) genetic polymorphism Arg399Gln and esophageal cancer (EC) risk. Statistical analysis was performed with the Review Manager version 4.2.8 software program and STATA version 11.0. We selected 16 case-control studies for this meta analysis, including 3591 EC cases and 5752 controls. Overall, the Gln399 allele was not associated with EC risk, compared with the Arg399 allele in the populations included in the analysis. However, stratified analysis revealed that the Gln399 allele was associated with increased EC risk among the Chinese population in a recessive model [odds ratio (OR) = 1.42; 95% confidence interval (95%CI) = 1.07-1.90; P = 0.02 for heterogeneity] and by homozygote contrast (OR = 1.43; 95%CI = 1.05-1.96; P = 0.02 for heterogeneity), particularly for the tumor histology of squamous cell carcinoma (OR = 1.46; 95%CI = 1.10-1.95 for the recessive model and OR = 1.42; 95%CI = 1.03-1.95 for the homozygote contrast). We conclude that the XRCC1 Arg399Gln polymorphism has potential as a biomarker for EC susceptibility in the Chinese population, particularly for squamous cell carcinoma. PMID- 23359059 TI - Characterization and description of a multiple sex chromosome system in Potamotrygon motoro (Chondrichthyes, Myliobatiformes) from the Parana River, Argentina. AB - The Potamotrygonidae family represents the only freshwater group of specialized elasmobranchs and is composed of 4 genera: Plesiotrygon, Paratrygon, Potamotrygon, and Heliotrygon. Individuals of Potamotrygon motoro were collected from the Parana River at Ituzaingo (Province of Corrientes) in Argentina. Mitotic preparations were obtained using direct techniques and lymphocyte cultures. Chromosomes were studied with conventional Giemsa, C-band and nucleolus organizer region stainings. The diploid number and karyotype formulae were 2n = 66 with 33 homomorphic pairs (14M + 16SM + 22ST + 14A) in females and 2n = 65 with 31 homomorphic pairs plus 3 heteromorphic chromosomes (13M + 15SM + 23ST + 14A) in males. Heterochromatin was distributed at the pericentromeric regions of almost all chromosomes and in the telomeric and interstitial positions of some chromosomes. nucleolus organizer regions were multiple and located at telomeric regions. Because of the clear karyotype differences between the 2 sexes and the presence of 3 unpaired chromosomes in males, it is possible to suggest the occurrence of a multiple sex chromosome system, with male heterogamety (X1X1X2X2/X1X2Y). Further cytogenetic studies are required to develop a hypothesis about the origin of the multiple sex chromosome system in P. motoro. PMID- 23359060 TI - Linkage and mapping analyses of the normal marking gene +P in the silkworm (Bombyx mori) using SSR markers. AB - In the silkworm, Bombyx mori, normal markings are mainly controlled by the +P gene, which is located on the second chromosome. Due to a lack of crossing over in females, reciprocal backcrossed F1 (BC1) progenies were used for linkage analysis and mapping of the +P gene based on an SSR linkage map using silkworm strains P50 and H9, which are normal marking and sex-limited marking, respectively. The +P gene was found to be linked to 3 SSR markers. Using a reciprocal BC1M cross, we constructed a linkage map of 22.5 cM, with +P mapped at 11.3 cM and the nearest SSR marker S0206 at a distance of 3.0 cM. Based on a fine genome map of domesticated silkworms, Kaikoblast analysis showed that the physical distance between the nearest markers (containing the +P gene) is 995 kb. Further analysis showed that BGIBMGA009689, BGIBMGA009688, and BGIBMGA009687 are closer to +P, and that BGIBMGA009689 is closest to +P, with a physical distance of 19.1 kb. PMID- 23359061 TI - Loop-tail phenotype in heterozygous mice and neural tube defects in homozygous mice result from a nonsense mutation in the Vangl2 gene. AB - N-ethyl-N-nitrosourea (ENU) is a powerful point mutagen that can generate random mutations. It has been used to generate mouse mutations to produce phenotypic models of human disease. Neural tube defects (NTD) are common birth defects in which the brain and/or spinal cord can be exposed; however, the mechanisms of these defects are poorly understood. Craniorachischisis is one type of NTD that bears a close resemblance to the phenotype of the loop-tail (Lp) mouse. Here we describe a C57BL/6J Lp mouse generated by ENU-induced mutagenesis. The mutation was mapped to the Vangl2 gene on chromosome 1, near markers D1Mit113 and D1Mit149. Sequence analysis of Vangl2 heterozygotes (Vangl2(m1Yzcm)/+) revealed a C/T transition mutation that resulted in substitution of a glutamine codon for a stop (nonsense) codon at position 449. The Vangl2 protein is involved in epithelium planar cell polarity. The predicted truncated protein would lack the PDZ-domain binding motif involved in protein-protein interaction; therefore, Vangl2(m1Yzcm) may be a loss-of-function mutant. Morphological and histological examination of homozygous mouse embryos revealed a neural tube closure defect that leads to craniorachischisis. This Vangl2(m1Yzcm) mouse represents a valuable model for the study of NTDs in humans. PMID- 23359062 TI - A novel mathematical model of activation and sensitization of platelets subjected to dynamic stress histories. AB - Blood recirculating devices, such as ventricular assist devices and prosthetic heart valves, are burdened by thromboembolic complications requiring complex and lifelong anticoagulant therapy with its inherent hemorrhagic risks. Pathologic flow patterns occurring in such devices chronically activate platelets, and the optimization of their thrombogenic performance requires the development of flow induced platelet activation models. However, existing models are based on empirical correlations using the well-established power law paradigm of constant levels of shear stress during certain exposure times as factors for mechanical platelet activation. These models are limited by their range of application and do not account for other relevant phenomena, such as loading rate dependence and platelet sensitization to high stress conditions, which characterize the dynamic flow conditions in devices. These limitations were addressed by developing a new class of phenomenological stress-induced platelet activation models that specifies the rate of platelet activation as a function of the entire stress history and results in a differential equation that can be directly integrated to calculate the cumulative levels of activation. The proposed model reverts to the power law under constant shear stress conditions and is able to describe experimental results in response to a diverse range of highly dynamic stress conditions found in blood recirculating devices. The model was tested in vitro under emulated device flow conditions and correlates well with experimental results. This new model provides a reliable and robust mathematical tool that can be incorporated into computational fluid dynamic studies in order to optimize design, with the goal of improving the thrombogenic performance of blood recirculating devices. PMID- 23359063 TI - Hormesis phenomena under Cd stress in a hyperaccumulator--Lonicera japonica Thunb. AB - A hydroponic experiment was carried out to investigate possible hormetic response induced by cadmium (Cd) in a potential hyperaccumulator-Lonicera japonica Thunb. The results showed that Cd at low concentrations induced a significant increase in plant growth, leaf water content and content of photosynthetic pigments in L. japonica, but decreased them at high concentrations, displayed inverted U-shaped dose response curves, confirming a typical biphasic hormetic response. The U shaped dose response curves were displayed in malondialdehyde (MDA) and electrolyte leakage in leaves at low doses of Cd, indicating reduce oxidative stress and toxic effect. The increase of superoxide dismutase (SOD) and catalase (CAT) activities was observed along with the increased Cd concentration, indicative of increase in anti-oxidative capacity that ensures redox homeostasis is maintained. After 28 days exposure to 10 mg L(-1) Cd, stem and leaf Cd concentrations reached 502.96 +/- 28.90 and 103.22 +/- 5.62 mg kg(-1) DW, respectively and the plant had high bioaccumulation coefficient (BC) and translocation factor (TF'). Moreover, the maximum TF value was found at 2.5 mg L( 1) Cd treatment, implying that low Cd treatment improved the ability to transfer Cd from medium via roots to aerial structures. Taking together, L. japonica could be considered as a new plant to investigate the underlying mechanisms of hormesis and Cd tolerance. Our results suggest that hormetic effects should be taken into consideration in phytoremediation of Cd-contaminated soil. PMID- 23359065 TI - Influence of myocardial region of interest definition on quantitative analysis of planar 123I-mIBG images. AB - PURPOSE: In planar (123)I-mIBG myocardial imaging, definition of the heart region of interest (ROI) is a critical step in quantifying uptake. The present study evaluated the impact of changes in heart ROI size on quantitative results in subjects with good and poor uptake. METHODS: Reference irregular whole-heart and square upper mediastinum ROIs were defined visually on 531 planar (123)I-mIBG images. Based on the reference heart ROI, an automated program created two other ROIs: one larger (+1 pixel) and one smaller (-1 pixel), the stated numbers representing the spacing intervals between each epicardial boundary pixel. Two additional smaller ROIs (-2 and -3 pixels) were drawn for the 100 images (19 %) with a heart/mediastinum (H/M) ratio <=1.30. The number of pixels, the counts per pixel, and the H/M ratio for each heart ROI were calculated and compared to that in the reference ROI. Washout rate and changes as a function of ROI size were also calculated for 110 subjects who had both early and late images. RESULTS: The mean changes in heart ROI size ranged from +19.0 % for the +1 pixel to -44.4 % for the -3 pixels ROI. For the +1 and -1 pixel ROIs, mean relative counts per pixel changes were -1.2 % and +0.7 %, respectively, with corresponding ranges of change in the H/M ratio of -0.12 to +0.05 and -0.05 to +0.11. For scans with H/M ratio <=1.30, mean relative counts per pixel changes were 0, 0, -0.7 %, and -1.4 % for the four ROIs, with range of change in the H/M ratio from -0.13 to +0.05. Mean washout rates were almost identical for the reference ROIs (45.0 %) and the +1 pixel and -1 pixel heart ROIs (44.9 % and 45.1 %, respectively). CONCLUSION: Significant changes in the size of the best visually defined heart ROI produce minimal, clinically inconsequential changes in the H/M ratio and washout rate, even in subjects with significantly reduced myocardial uptake of (123)I-mIBG. PMID- 23359064 TI - The implication of vitamin D and autoimmunity: a comprehensive review. AB - Historically, vitamin D has been associated with the regulation of bone metabolism. However, increasing evidence demonstrates a strong association between vitamin D signaling and many biological processes that regulate immune responses. The discovery of the vitamin D receptor in multiple immune cell lineages, such as monocytes, dendritic cells, and activated T cells credits vitamin D with a novel role in modulating immunological functions and its subsequent role in the development or prevention of autoimmune diseases. In this review we, discuss five major areas in vitamin D biology of high immunological significance: (1) the metabolism of vitamin D; (2) the significance of vitamin D receptor polymorphisms in autoimmune diseases, such as multiple sclerosis, type 1 diabetes mellitus, and systemic lupus erythematosus; (3) vitamin D receptor transcriptional regulation of immune cell lineages, including Th1, Th17, Th2, regulatory T, and natural killer T cells; (4) the prevalence of vitamin D insufficiency/deficiency in patients with multiple sclerosis, type 1 diabetes mellitus, and systemic lupus erythematosus; and finally, (5) the therapeutic effects of vitamin D supplementation on disease severity and progression. PMID- 23359066 TI - Effect of pioglitazone versus metformin on cardiovascular risk markers in type 2 diabetes. AB - INTRODUCTION: Besides its critical role in metabolic homeostasis, peroxisome proliferator-activated receptor (PPAR)-gamma modulates several cellular responses involved in atherothrombosis. This multicenter, double-blind, randomized study investigated the effects of two oral hypoglycemic agents on markers of inflammation, platelet activation, thrombogenesis, and oxidative stress in patients with type 2 diabetes. METHODS AND RESULTS: The primary objective of this study was to evaluate the effect on C-reactive protein (CRP) after a 16-week treatment period with either pioglitazone or metformin. Additionally, markers of vascular inflammatory response, platelet activation, thrombogenesis, oxidative stress, glucose, and lipid metabolism, as well as liver function, were measured. In total, 50 patients completed the study. Pioglitazone-treated patients were found to have statistically significantly larger decreases in mean CRP levels ( 0.4 mg/dL) compared to those treated with metformin (-0.2 mg/dL) (P=0.04), as well as greater reductions in levels of mean fasting plasma glucose (-27 vs. -9 mg/dL; P=0.01), serum insulin (-2 vs. -1.9 mU/L; P=0.014), homeostatic model assessment (HOMA) (-1.2 vs. -0.9; P=0.015), and E-selectin (-12.4 vs. +3.4 MUg/mL; P=0.01). Mean glycated hemoglobin (HbA1c) levels decreased in both treatment groups from baseline to week 16 (-0.4% in the pioglitazone group, -0.2% in the metformin group; P=0.36). Pioglitazone treatment was also found to be associated with a statistically significant increase in total cholesterol levels (+10 mg/dL in the pioglitazone arm, -3 mg/dL in the metformin arm; P=0.05) and a decrease in liver enzyme levels. CONCLUSIONS: The favorable changes in markers of systemic and vascular inflammatory response with pioglitazone suggest that it may positively influence the atherothrombotic process in type 2 diabetes. PMID- 23359067 TI - Pharmacokinetic and pharmacodynamic properties of a new long-acting granulocyte colony-stimulating factor (HM10460A) in healthy volunteers. AB - BACKGROUND: HM10460A is a newly developed recombinant human granulocyte colony stimulating factor with long-lasting characteristics. This factor is expected to be used for chemotherapy-related neutropenic conditions. OBJECTIVE: The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of HM10460A following subcutaneous administration to healthy Korean subjects. METHODS: A randomized, double-blind, placebo-controlled, escalating single-dose study was conducted in 40 healthy Korean subjects. The subjects were allocated to single-dose groups of 5, 15, 45, 135 or 350 MUg/kg, or placebo. Serial blood samples for pharmacokinetic/pharmacodynamic analyses were collected up to 22 days, and urine samples for pharmacokinetic analysis were collected up to 3 days after subcutaneous administration of HM10460A. The serum and urine concentrations were analyzed by enzyme-linked immunosorbent assay. RESULTS: Most of the serum concentrations in the 5 and 15 MUg/kg dosing groups were below the lower limit of quantification (LLOQ). The median times to the peak concentration (T(max)) of HM10460A in the 45, 135, and 350 MUg/kg dosing groups were 8.0, 14.0, and 24.0 h, respectively. The mean +/- standard deviation values of the dose-normalized maximum concentration (C(max)) and dose-normalized area under the concentration time curve (AUC(last)) for the 45, 135, and 350 MUg/kg dosing groups were 14.13 +/- 6.37, 66.19 +/- 38.71, and 34.65 +/- 19.69 MUg/L/mg, respectively, and 265.0 +/- 124.1, 2144 +/- 1232, and 1386 +/- 701.2 MUg h/L/mg, respectively. The concentrations of HM10460A in the urine were below the LLOQ in all of the subjects. In all of the dosing groups, the area under the effect-time curve (AUEC(last)) of both the absolute neutrophil count (ANC) and the CD34(+) cell count increased as the dose increased. CONCLUSION: HM10460A showed dose-dependent pharmacokinetic characteristics, and the systemic exposure of HM10460A was positively correlated with the ANC and CD34(+) cell counts. PMID- 23359071 TI - Sestrins: novel antioxidant and AMPK-modulating functions regulated by exercise? AB - Oxidative stress results from damage to tissues caused by free radicals and is increased by exercise. Peroxiredoxins (PRXs) maintain the cellular reducing environment by scavenging intracellular hydrogen peroxide. It has been recently noted that physical exercise has a positive effect on the PRX system, exerting a protective effect against oxidative stress-induced damage. However, other compounds, such as sestrins (SESNs), a stress-inducible protein family with antioxidant properties, should also be considered in the function of PRXs. SESNs are clearly involved in the regeneration process of PRXs and therefore may also be modulated by physical exercise. In addition, SESNs are clearly involved in TOR, AMPK, p53, FoxO, and PRXs signaling pathways. The aforementioned pathways are implicated in aging processes by inducing an increased resistance to subsequent stress, thus delaying age-related changes, such as sarcopenia and frailty, and consequently promoting longevity. Likewise, exercise also modulates these pathways. In fact, exercise is one of the most important recommended strategies to prevent sarcopenia and frailty, increase longevity, and improve health in the elderly. Loss of SESNs can cause several chronic pathologies, such as fat accumulation, mitochondrial dysfunction, cardiac arrhythmia, and/or muscle degeneration. Accordingly, physical inactivity leads to accumulation of visceral fat and consequently the activation of a network of inflammatory pathways, which promote development of insulin resistance, atherosclerosis, neurodegeneration, and tumor growth. To date, the SESNs-exercise relationship has not been explored. However, this emerging family of stress proteins may be part of the redox-based adaptive response to exercise. PMID- 23359068 TI - Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies. AB - Many human monoclonal antibodies that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian autoantigens. Indeed, the generation of neutralizing antibodies to the 2F5 and 4E10 epitopes of HIV-1 gp41 in man may be proscribed by immune tolerance because mice expressing the V(H) and V(L) regions of 2F5 have a block in B cell development that is characteristic of central tolerance. This developmental blockade implies the presence of tolerizing autoantigens that are mimicked by the membrane-proximal external region of HIV-1 gp41. We identify human kynureninase (KYNU) and splicing factor 3b subunit 3 (SF3B3) as the primary conserved, vertebrate self-antigens recognized by the 2F5 and 4E10 antibodies, respectively. 2F5 binds the H4 domain of KYNU which contains the complete 2F5 linear epitope (ELDKWA). 4E10 recognizes an epitope of SF3B3 that is strongly dependent on hydrophobic interactions. Opossums carry a rare KYNU H4 domain that abolishes 2F5 binding, but they retain the SF3B3 4E10 epitope. Immunization of opossums with HIV-1 gp140 induced extraordinary titers of serum antibody to the 2F5 ELDKWA epitope but little or nothing to the 4E10 determinant. Identification of structural motifs shared by vertebrates and HIV-1 provides direct evidence that immunological tolerance can impair humoral responses to HIV-1. PMID- 23359070 TI - Notch pathway activation targets AML-initiating cell homeostasis and differentiation. AB - Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia. PMID- 23359069 TI - Notch activation inhibits AML growth and survival: a potential therapeutic approach. AB - Although aberrant Notch activation contributes to leukemogenesis in T cells, its role in acute myelogenous leukemia (AML) remains unclear. Here, we report that human AML samples have robust expression of Notch receptors; however, Notch receptor activation and expression of downstream Notch targets are remarkably low, suggesting that Notch is present but not constitutively activated in human AML. The functional role of these Notch receptors in AML is not known. Induced activation through any of the Notch receptors (Notch1-4), or through the Notch target Hairy/Enhancer of Split 1 (HES1), consistently leads to AML growth arrest and caspase-dependent apoptosis, which are associated with B cell lymphoma 2 (BCL2) loss and enhanced p53/p21 expression. These effects were dependent on the HES1 repressor domain and were rescued through reexpression of BCL2. Importantly, activated Notch1, Notch2, and HES1 all led to inhibited AML growth in vivo, and Notch inhibition via dnMAML enhanced proliferation in vivo, thus revealing the physiological inhibition of AML growth in vivo in response to Notch signaling. As a novel therapeutic approach, we used a Notch agonist peptide that led to significant apoptosis in AML patient samples. In conclusion, we report consistent Notch-mediated growth arrest and apoptosis in human AML, and propose the development of Notch agonists as a potential therapeutic approach in AML. PMID- 23359073 TI - [Neurocognitive screening in substance addicts: the Montreal Cognitive Assessment]. AB - INTRODUCTION: The detection of neurocognitive disorders in addicts would allow subjects with functional impairment to be assigned to cognitive rehabilitation programmes. The Montreal Cognitive Assessment (MoCA) is a screening test that can be a valuable aid with this kind of patient. AIMS: To use the MoCA with a sample of subjects with addictions who are receiving treatment and to compare the results with the criteria proposed for the general population, mild cognitive impairment and early dementias. It also intends to examine the concurrent validity with global execution tests and the relationship with socio-demographic variables and others related to addiction. PATIENTS AND METHODS: The MoCA and the Allen Cognitive Level Screen-5 (ACLS-5) test were administered to a sample of 79 patients with addiction who were beginning treatment in a specific centre. RESULTS: Only 29.1% of the participants presented normal performance in terms of the criteria proposed by the authors. The others achieved scores below the cut off point, many of them displaying an alarmingly low score, even when compared with criteria for mild cognitive impairment and early dementias. The MoCA showed concurrent validity with the ACLS-5 and correlation with academic level, but not with variables related to addiction. CONCLUSIONS: The MoCA is a test that is quick and simple to administer and correct. It allows the detection of subjects with extremely low cognitive performance that require neuropsychological and occupational interventions for cognitive rehabilitation, which increases treatment compliance and the benefits to be gained from other interventions with important cognitive demands, such as relapse prevention psychotherapy. PMID- 23359072 TI - Evaluation of active living every day in adults with arthritis. AB - BACKGROUND: Adults with arthritis can benefit from participation in physical activity and may be assisted by organized programs. The purpose of this study was to evaluate the effectiveness of a 20-week behavioral lifestyle intervention, Active Living Every Day (ALED), for improvements in primary outcomes (physical activity levels, aerobic endurance, function, symptoms). METHODS: A 20-week randomized controlled community trial was conducted in 354 adults. Outcomes were assessed at baseline and 20 weeks in the intervention and wait-list control groups. The intervention group was also assessed at 6 and 12 months. Mean outcomes were determined by multilevel regression models in the intervention and control groups at follow-up points. RESULTS: At 20 weeks, the intervention group significantly increased participation in physical activity, and improved aerobic endurance, and select measures of function while pain, fatigue and stiffness remained status quo. In the intervention group, significant improvements in physical activity at 20 weeks were maintained at 6 and 12 months, and stiffness decreased. CONCLUSIONS: ALED appears to improve participation in physical activity, aerobic endurance, and function without exacerbating disease symptoms in adults with arthritis. PMID- 23359074 TI - [Carotid angioplasty in stenosis following radiotherapy: a review of 12 cases]. AB - INTRODUCTION: Carotid stenosis is a complication of cervical radiotherapy. In these cases carotid angioplasty has been considered as the elective revascularisation treatment. Yet, the indication to treat is under discussion due to the high rate of restenosis and the scarcity of studies conducted on the long term development. AIMS: To report on a series of patients with carotid stenosis following radiotherapy who were treated by means of angioplasty, the aim being to analyse their long- and short-term development. PATIENTS AND METHODS: Of a series of 426 patients with carotid stenosis treated by endovascular means, 12 of them (2.8%) had previously received radiotherapy in the neck. All of them were submitted to a clinical and imaging follow-up. Data were collected concerning the rate of complications during the first four weeks and in the long term, as well as the rate of restenosis in the follow-up. RESULTS: The mean interval between radiotherapy and the detection of stenosis was 14.7 years. Ten patients (83.3%) were symptomatic. No complications occurred during the first four weeks following the angioplasty. The mean follow-up time was 45.09 months: 16.7% of patients presented a stroke, 8.3% suffered acute myocardial infarction and 33.3% died (16.6% due to cancer). At least six patients (50%) were diagnosed with restenosis, all equal to or greater than 50% and none of them were symptomatic. CONCLUSIONS: Carotid angioplasty is a safe, effective technique in stenosis following radiotherapy, with few short-term complications. The rate of carotid restenosis is high. The main cause of death is cancer. PMID- 23359075 TI - [Triptans in clinical practice: effectiveness, tolerance and patient's satisfaction with medication (TRIPRACLI study)]. AB - INTRODUCTION AND AIMS: This study was aimed determining the effectiveness, tolerance and satisfaction of patients with migraine as regards different triptans, according to the characteristics of their attacks. At the same time it sought to establish a predictive model that can be used to recommend one or another, depending on those characteristics. PATIENTS AND METHODS: Retrospective observation-based study conducted in headache units in a number of different centres. Patients included in the study were those with migraine who used the same triptan to treat their attacks. Data concerning preference, effectiveness, speed and tolerance were analysed. RESULTS: The analysis included 160 patients (88 females), with a mean age of 42.92 years. The most commonly used triptans were eletriptan, almotriptan and rizatriptan. Both patients and doctors reported a high degree of satisfaction (88% and 65%) with the triptan that was used. In the surveys on preference, patients preferred their current triptan to the previous one (83%) or to non-specific drugs. The overall score on a visual analogue scale was above 7 for all the triptans, without any differences from one to another. On analysing the use of a particular triptan depending on the characteristics of the attacks, no statistically significant differences were found. CONCLUSIONS: In this selected group of patients, triptans are a treatment that patients claim to be very satisfied with. Although there are no overall differences in the scores among different triptans, the fact that certain triptans are used more by patients after previous experiences with others suggests that they are more effective. We did not find any parameter that predicts the use of a particular triptan. PMID- 23359077 TI - [Presurgical endovascular treatment of symptomatic carotid stenosis caused by a meningioma of the planum sphenoidale]. AB - INTRODUCTION: Cerebral infarction is a very rare presenting symptom of a meningioma. This form of clinical onset poses the challenge of treating ischaemic events before dealing with the tumour surgically. CASE REPORT: A 48-year-old woman from Georgia who visited due to loss of strength in the right-hand side of the body, intense headache and self-limiting episodes of forgetting her own language. Computerised axial tomography scans of her head revealed a left frontal expansive process and hypodense lesions in the left caudate nucleus. The patient underwent an unfavourable progression, with episodes of neurological deterioration and hemiparesis of the right-hand side and aphasia, which alternated with periods of improvement. Magnetic resonance imaging and an angiographic study revealed tumour occlusion of the left middle cerebral artery, secondary to a clinoidal meningioma. Treatment involved endovascular recanalisation of the middle cerebral artery and later surgical removal of the meningioma. CONCLUSIONS: Endovascular treatment by means of angioplasty, prior to the surgical excision of the tumour, is a technique that enables the incidence of ischaemic events to be diminished. PMID- 23359076 TI - [Medication-related oculogyric crises: a description of four cases and a review of the literature]. AB - INTRODUCTION: Oculogyric crises are considered to be a form of focal dystonia and can be observed as reactions to pharmaceuticals. The signs and symptoms may be confused with epileptic crises. AIMS: To describe the clinical features and progress of patients with pharmaceutical-related oculogyric crises and to carry out a review of the topic. CASE REPORTS: We conducted a retrospective, descriptive study of four patients evaluated in the neurology service due to oculogyric crises. The patients had been diagnosed with an associated conduct disorder requiring treatment with antipsychotic drugs. The episodes of oculogyric crises did not correlate with the findings in the electroencephalogram. They responded well to the reduction in dosage or to withdrawal of the apparent causing agent. CONCLUSIONS: The clinical picture does not present only in patients treated with antipsychotics but is also linked with other pharmaceuticals that are frequently used in daily paediatric practice. When oculogyric crises are the reason for visiting, differential diagnoses must be taken into account in order to avoid unnecessary studies and to carry out an appropriate therapeutic management. PMID- 23359078 TI - [Clinico-pathological and molecular aspects of diagnostic and prognostic value in gliomas]. AB - INTRODUCTION: Diffuse infiltrative gliomas, the most common primary brain tumours, account for almost 80% of malignant brain tumours. 60-70% of gliomas are astrocytic and over 80% of these tumours is considered high grade malignancy (grade III and IV) according to current World Health Organization classification. Infiltrating gliomas include diffuse astrocytomas, oligodendrogliomas and oligoastrocytomas. AIM: To review the clinical and histological features of cerebral gliomas, and molecular alterations that add relevant information for novel approaches in diagnosis, prognosis and treatment. DEVELOPMENT: The current gold standard diagnosis of these tumours relies on histopathological classification, which provides a grading of malignancy as a predictor of biological behaviour. However emerging molecular abnormalities have been discovered in the last years and these molecular changes are playing an increasingly prominent role as predictive biomarkers or in the development of diagnostic and prognostic. Now the neuropathologist is in crossroads between pathology and molecular biology and he plays a significant role in implementation of treatments and/or clinical trials. CONCLUSIONS: The study of proteomics and molecular biomarkers should complement the histopathological analysis and sometimes allows to determine direct or indirect predictive factors as well as the study of affected pathways which may become selective therapeutic targets. PMID- 23359080 TI - [Left-sided hemiparesis in a diabetic patient: chronic granulomatous encephalitis due to Acanthamoeba]. PMID- 23359081 TI - [Efficacy of lacosamide in the treatment of neuropathic pain]. PMID- 23359082 TI - [Simultaneous myasthenia gravis and Guillain-Barre syndrome: the first case reported in Spain]. PMID- 23359083 TI - [Deep brain stimulation in Parkinson's disease]. PMID- 23359084 TI - Functional food quality of Curcuma caesia, Curcuma zedoaria and Curcuma aeruginosa endemic to Northeastern India. AB - Curcuma spp. (Zingiberaceae) is one of the significant ingredients in food and traditional medicines. The current study was to investigate health-benefits of the rhizomes of endemic Curcuma caesia, Curcuma zedoaria and Curcuma aeruginosa using in vitro antioxidant, antiinflammatory and human tumor cell proliferation inhibitory activities. Among these, C. caesia (black turmeric) showed the best overall biological activities based on [3-(4, 5-dimethylthiazole-2-yl)-2,5 diphenyltetrazolium bromide] (MTT) and lipid peroxidation (LPO), cyclooxygenase (COX-1 and -2) enzymes, and tumor cell growth inhibitory assays. The hexane and methanolic extracts of C. caesia (CCH and CCM) showed LPO inhibition by 31 and 43 %, and COX-2 enzyme by 29 and 38 %, respectively, at 100 MUg/ml. Eleven terpenoids were isolated and identified. The MTT antioxidant assay revealed that the extracts of three Curcuma spp. at 250 MUg/ml and isolates at 5 MUg/ml demonstrated activity comparable to positive controls vitamin C and t-butyl hydroquinone (TBHQ) at 25 MUg/ml. The extracts inhibited LPO by 40 % at 250 MUg/ml whereas pure isolates 1-11 by about 20 %. The extracts and isolates inhibited COX-1 and -2 enzymes between the ranges of 3-56 and 5-30 %, respectively. The in vitro biological activity exhibited by the extracts and isolates of C. caesia rhizome further supported its use in traditional medicine. PMID- 23359085 TI - Estimated glycemic index and dietary fiber content of cookies elaborated with extruded wheat bran. AB - The increasing demand for high-fiber products has favored the design of numerous bakery products rich in fiber such as bread, cookies, and cakes. The objective of this study was to evaluate the dietary fiber and estimated glycemic index of cookies containing extruded wheat bran. Wheat bran was subjected to extrusion process under three temperature profiles: TP1;(60, 75, 85 and 100 degrees C), TP2;(60, 80, 100 and 120 degrees C), and TP3;(60, 80, 110 and 140 degrees C) and three moisture contents: (15, 23, and 31 %). Cookies were elaborated using extruded wheat bran (30 %), separated into two fractions (coarse and fine). The dietary fiber content of cookies elaborated with extruded wheat bran was higher than the controls; C0 (100 % wheat flour) and C1 (30 % of no extruded bran coarse fraction) and C2 (30 % of no extruded bran fine fraction). The higher values of dietary fiber were observed on cookies from treatments 5 (TP1, 31 % moisture content and coarse fraction) and 11 (TP2, 31 % moisture content and coarse fraction). The estimated glycemic index of cookies ranged from 68.54 to 80.16. The dietary fiber content of cookies was increased and the lowest glycemic index corresponded to the cookies elaborated with extruded wheat bran. Cookie made with the treatment 11 had a better dietary fiber content and lower estimated glycemic index. PMID- 23359086 TI - Self-affirmation underlies Facebook use. AB - Social network sites, such as Facebook, have acquired an unprecedented following, yet it is unknown what makes them so attractive to users. Here we propose that these sites' popularity can be understood through the fulfillment of ego needs. We use self-affirmation theory to hypothesize why and when people spend time on their online profiles. Study 1 shows that Facebook profiles are self-affirming in the sense of satisfying users' need for self-worth and self-integrity. Study 2 shows that Facebook users gravitate toward their online profiles after receiving a blow to the ego, in an unconscious effort to repair their perceptions of self worth. In addition to illuminating some of the psychological factors that underlie Facebook use, the results provide an important extension to self affirmation theory by clarifying how self-affirmation operates in people's everyday environments. PMID- 23359088 TI - Increased prevalence of tumour infiltrating immune cells in oropharyngeal tumours in comparison to other subsites: relationship to peripheral immunity. AB - BACKGROUND: The nature of the tumour microenvironment immune response in head and neck cancer patients has an important role in tumour development and metastasis, but it is unknown if this differs between cancer subsites or whether it is related to the peripheral immune response. METHODS: Immune cells (CD4, CD8, Foxp3) in head and neck squamous cell carcinoma tissue (HNSCC; n = 66), detected by immunohistochemistry, have been correlated with tumour subsite and immune cells in the peripheral circulation (CD4(+)CD25(High)Foxp3(+) Treg and CD4(+) T cells), identified using flow cytometry. RESULTS: Oropharyngeal tumours had a greater number of infiltrating immune cells in both tumour and stroma compared with other subsites, but no difference was observed in the circulating levels. Immune cells in the stroma were positively related to those in the tumour with consistently higher levels in stroma. A strong relationship was found between the number of CD4(+) and Foxp3(+) cells but not between the number of CD8(+) and Foxp3(+) cells in the tumour. The number of Foxp3(+) cells within the tumour was positively correlated with the percentage of circulating CD4(+)CD25(High) cells positive for Foxp3. Late stage laryngeal tumours showed a higher number of Foxp3(+) lymphocytes compared with early stage malignancies, and oropharyngeal tumours had more CD4(+) cells in node negative tumours compared with node positive ones. CONCLUSION: The level of immune cell infiltration in head and neck squamous cell carcinoma appears to be subsite dependent residing primarily in the stroma and is likely to be dependent on the peripheral immune response. PMID- 23359087 TI - CD39 is highly involved in mediating the suppression activity of tumor infiltrating CD8+ T regulatory lymphocytes. AB - CD39 is an ectoenzyme, present on different immune cell subsets, which mediates immunosuppressive functions catalyzing ATP degradation. It is not known whether CD39 is expressed and implicated in the activity of CD8+ regulatory T lymphocytes (Treg). In this study, CD39 expression and function was analyzed in both CD8+ and CD4+CD25(hi) Treg from the peripheral blood of healthy donors as well as from tumor specimens. CD39 was found expressed by both CD8+ (from the majority of healthy donors and tumor patients) and CD4+CD25(hi) Treg, and CD39 expression correlated with suppression activity mediated by CD8+ Treg. Importantly, CD39 counteraction remarkably inhibited the suppression activity of CD8+ Treg (both from peripheral blood and tumor microenvironment) suggesting that CD39-mediated inhibition constitutes a prevalent hallmark of their function. Collectively, these findings, unveiling a new mechanism of action for CD8+ Treg, provide new knowledge on intratumoral molecular pathways related to tumor immune escape, which could be exploited in the future for designing new biological tools for anticancer immune intervention. PMID- 23359089 TI - Automatic classification of left ventricular regional wall motion abnormalities in echocardiography images using nonrigid image registration. AB - Identification and classification of left ventricular (LV) regional wall motion (RWM) abnormalities on echocardiograms has fundamental clinical importance for various cardiovascular disease assessments especially in ischemia. In clinical practice, this evaluation is still performed visually which is highly dependent on training and experience of the echocardiographers and therefore suffers from significant interobserver and intraobserver variability. This paper presents a new automatic technique, based on nonrigid image registration for classifying the RWM of LV in a three-point scale. In this algorithm, we register all images of one cycle of heart to a reference image (end-diastolic image) using a hierarchical parametric model. This model is based on an affine transformation for modeling the global LV motion and a B-spline free-form deformation transformation for modeling the local LV deformation. We consider image registration as a multiresolution optimization problem. Finally, a new regional quantitative index based on resultant parameters of the hierarchical transformation model is proposed for classifying RWM in a three-point scale. The results obtained by our method are quantitatively evaluated to those obtained by two experienced echocardiographers visually as gold standard on ten healthy volunteers and 14 patients (two apical views) and resulted in an absolute agreement of 83 % and a relative agreement of 99 %. Therefore, this diagnostic system can be used as a useful tool as well as reference visual assessment to classify RWM abnormalities in clinical evaluation. PMID- 23359090 TI - An interactive RADIANCE toolkit for customizable CT dose monitoring and reporting. AB - The need for tools to monitor imaging-related radiation has grown dramatically in recent years. RADIANCE, a freely available open-source dose-monitoring tool, was developed in response to the need for an informatics solution in this realm. A number of open-source as well as commercial solutions have since been developed to enable radiology practices to monitor radiation dose parameters for modalities ranging from computed tomography to radiography to fluoroscopy. However, it is not sufficient to simply collect this data; it is equally important to be able to review it in the appropriate context. Most of the currently available dose monitoring solutions have some type of reporting capability, such as a real-time dashboard or a static report. Previous versions of RADIANCE have included a real time dashboard with pre-set screens that plot effective dose estimates according to different criteria, as well as monthly scorecards to summarize dose estimates for individuals within a radiology practice. In this work, we present the RADIANCE toolkit, a customizable reporting solution that allows users to generate reports of interest to them, summarizing a variety of metrics that can be grouped according to useful parameters. The output of the toolkit can be used for real time dose monitoring or scheduled reporting, such as to a quality assurance committee. Making dose parameter data more accessible and more meaningful to the user promotes dose reduction efforts such as regular protocol review and optimization, and ultimately improves patient care by decreasing unnecessary radiation exposure. PMID- 23359091 TI - Digital pathology consultations-a new era in digital imaging, challenges and practical applications. AB - Digital pathology has grown dramatically in the last 10 years and has created opportunities to not only support the triaging of difficult cases among specialists within an organization, but also enable remote pathology consultations with external organizations across the world. This study investigated one organization's need for a vendor agnostic Digital Pathology Consultation workflow solution that overcomes the challenges associated with the transfer of large studies across a local area network or across the Internet. The organization investigated is a large multifacility healthcare organization that consists of 20 hospitals spread across a wide geographical area. The organization has one of the largest academic pathology departments in the USA, with more than 100 diagnostic anatomic pathologists. This organization developed a set of web based tools to support the workflow of digital pathology consultations and allow the viewing of whole slide images. The challenges and practical implementations of two different use cases are addressed: the occasional end user (professional or patient) requesting a second opinion and the external laboratory or hospital looking for an established consultative relationship with a large volume of cases. The solution presented in this study addresses the challenges associated with the distribution of large images and the lack of established imaging standards, while providing for a convenient and secure portal for pathologist report entry and distribution. PMID- 23359092 TI - Prognostic Factors for Survival of Stage IB Upper Lobe Non-small Cell Lung Cancer Patients: A Retrospective Study in Shanghai, China. AB - OBJECTIVE: To identify clinical and pathologic factors that were associated with the survival of stage IB upper lobe non-small cell lung cancer (NSCLC) patients. METHODS: A retrospective study of 147 subjects who had undergone curative resection for stage IB upper lobe NSCLC was performed. Patients who had received any adjuvant or neo-adjuvant chemotherapy were excluded. Survival function curves were estimated using the Kaplan-Meier procedure. Crude and adjusted hazard ratios (HRs) of potential prognostic factors were estimated using Cox proportional hazards models. RESULTS: Five factors, including age, tumor size, histologic grade of differentiation, number of removed superior mediastinal lymph node stations and presence of visceral pleura invasion, were significantly and independently associated with mortality risk. Adjusted HRs were 2.6 [95% confidence interval (95% CI): 1.1-6.5] and 4.6 (95% CI: 1.9-11) for those aged 58 68 years and those >68 years, respectively, relative to those aged <58 years. HRs for those with poorly and moderately differentiated tumors were 6.4 (95% CI: 2.3 18) and 1.4 (95% CI: 0.7-2.8), respectively. HRs for those with tumor size 3.1-5 cm and >5 cm (vs<=3.0 cm) were 2.3 (95% CI: 1.1-4.9) and 4.3 (95% CI: 1.9-10), respectively. The presence of visceral pleura invasion also increased the risk of mortality (HR=4.0, 95% CI: 1.3-12). CONCLUSION: Advanced age, larger tumor size, poorly differentiated histology, smaller number of removed superior mediastinal lymph node stations, and presence of visceral pleura invasion were associated with poor survival of surgically treated stage IB upper lobe NSCLC patients. PMID- 23359094 TI - Application of sequential leaching, risk indices and multivariate statistics to evaluate heavy metal contamination of estuarine sediments: Dhamara Estuary, East Coast of India. AB - In the present study, concentration of some selected trace metals (Fe, Mn, Ni, Co, Pb, Zn, Cu, Cr and Cd) are measured in Brahmani, Baitarani river complex along with Dhamara estuary and its near shore. Chemical partitioning has been made to establish association of metals into different geochemical phases. The exchangeable fraction is having high environmental risk among non-lithogeneous phases due to greater potential for mobility into pore water. The metals with highest bio-availability being Cd, Zn and Cr. The metals like Mn, Zn, Cd and Cu represent an appreciable portion in carbonate phase. Fe-Mn oxides act as efficient scavenger for most of the metals playing a prime role in controlling their fate and transport. Among non-lithogeneous phases apart from reducible, Cr showed a significant enrichment in organic phase. Risk assessment code values indicate that all metals except Fe fall under medium-risk zone. In estuarine zone Cd, Zn, Pb and Cr are released to 32.43, 26.10, 21.81 and 20 %, respectively, indicating their significant bio-availability pose high ecological risk. A quantitative approach has been made through the use of different risk indices like enrichment factor, geo-accumulation index and pollution load index. Factor analysis indicates that in riverine zone, Fe-Mn oxides/hydroxides seem to play an important role in scavenging metals, in estuarine zone, organic precipitation and adsorption to the fine silt and clay particles while in coastal zone, co precipitation with Fe could be the mechanism for the same. Canonical discriminant function indicates that it is highly successful in discriminating the groups as predicted. PMID- 23359096 TI - Combined associations of sitting time and physical activity with obesity in young adults. AB - BACKGROUND: We investigated associations of total sedentary behavior (SB) and objectively-measured and self-reported physical activity (PA) with obesity. METHODS: Data from 1662 adults (26-36 years) included daily steps, self-reported PA, sitting, and waist circumference. SB and PA were dichotomized at the median, then 2 variables created (SB/self-reported PA; SB/objectively-measured PA) each with 4 categories: low SB/high PA (reference group), high SB/high PA, low SB/low PA, high SB/low PA. RESULTS: Overall, high SB/low PA was associated with 95 -168% increased obesity odds. Associations were stronger and more consistent for steps than self-reported PA for men (OR 2.68, 95% CI 1.36-5.32 and OR 1.95, 95% CI 1.01 3.79, respectively) and women (OR 2.66, 95% CI 1.58-4.49 and OR 2.00, 95% CI 1.21 3.31, respectively). Among men, obesity was higher when daily steps were low, irrespective of sitting (low SB/low steps OR 2.07, 95% CI 1.03-4.17; high SB/low steps OR 2.68, 95% CI 1.36-5.32). CONCLUSIONS: High sitting and low activity increased obesity odds among adults. Irrespective of sitting, men with low step counts had increased odds of obesity. The findings highlight the importance of engaging in physical activity and limiting sitting. PMID- 23359093 TI - The contribution of systematic approaches to characterizing the proteins and functions of the endoplasmic reticulum. AB - The endoplasmic reticulum (ER) is a complex organelle responsible for a range of functions including protein folding and secretion, lipid biosynthesis, and ion homeostasis. Despite its central and essential roles in eukaryotic cells during development, growth, and disease, many ER proteins are poorly characterized. Moreover, the range of biochemical reactions that occur within the ER membranes, let alone how these different activities are coordinated, is not yet defined. In recent years, focused studies on specific ER functions have been complemented by systematic approaches and innovative technologies for high-throughput analysis of the location, levels, and biological impact of given components. This article focuses on the recent progress of these efforts, largely pioneered in the budding yeast Saccharomyces cerevisiae, and also addresses how future systematic studies can be geared to uncover the "dark matter" of uncharted ER functions. PMID- 23359095 TI - Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. Rationale for development and current status. AB - Orexin A and orexin B are hypothalamic neuropeptides initially identified as endogenous ligands for two orphan G-protein coupled receptors (GPCRs). They play critical roles in the maintenance of wakefulness by regulating function of monoaminergic and cholinergic neurons that are implicated in the regulation of wakefulness. Loss of orexin neurons in humans is associated with narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy, further suggesting the particular importance of orexin in the maintenance of the wakefulness state. These findings have encouraged pharmaceutical companies to develop drugs targeting orexin receptors as novel medications of sleep disorders, such as narcolepsy and insomnia. Indeed, phase III clinical trials were completed last year of suvorexant, a non-selective (dual) antagonist for orexin receptors, for the treatment of primary insomnia, and demonstrate promising results. The New Drug Application (NDA) for suvorexant has been submitted to the US FDA. Thus, the discovery of a critical role played by the orexin system in the regulation of sleep/wakefulness has opened the door of a new era for sleep medicine. PMID- 23359098 TI - Radiological validation of a fluoroscopic guided technique for femoral implant positioning during hip resurfacing. AB - PURPOSE: The positioning of the femoral cup in hip resurfacing is essential for the survival of the implant. We described a technique in 2005 to position the femoral cup guided by fluoroscopy independent of the approach performed. The main objectives were to study the positioning of the femoral components of the implant and the accuracy of the technique. METHODS: Between 2003 and 2011 we conducted a prospective study of 160 consecutive hip resurfacings all operated with this fluoroscopic-guided technique. Three independent observers performed a radiographic analysis at the pre-operative planning stage and on postoperative radiographs using OsiriX software. The statistical analysis was based on comparison of two groups by Student's t test. RESULTS: The entire implant was positioned in valgus, with an average of 7.816 degrees valgus (p <0.001). All implants were positioned in neutral or anteverted with a mean of 1.98 degrees (p <0.001). The risk of malpositioning on the antero-posterior plane was less than 1.41 degrees with p <0.019. The risk of profile positioning error was lower than 0.80 degrees with p <0.047. CONCLUSION: This study validates a technique of femoral implant positioning for resurfacing. It is simple, precise and independent of the approach performed. PMID- 23359097 TI - The Swiss cohort of elderly patients with venous thromboembolism (SWITCO65+): rationale and methodology. AB - Venous thromboembolism (VTE) is common and has a high impact on morbidity, mortality, and costs of care. Although most of the patients with VTE are aged >=65 years, there is little data about the medical outcomes in the elderly with VTE. The Swiss Cohort of Elderly Patients with VTE (SWITCO65+) is a prospective multicenter cohort study of in- and outpatients aged >=65 years with acute VTE from all five Swiss university and four high-volume non-university hospitals. The goal is to examine which clinical and biological factors and processes of care drive short- and long-term medical outcomes, health-related quality of life, and medical resource utilization in elderly patients with acute VTE. The cohort also includes a large biobank with biological material from each participant. From September 2009 to March 2012, 1,863 elderly patients with VTE were screened and 1003 (53.8%) were enrolled in the cohort. Overall, 51.7% of patients were aged >=75 years and 52.7% were men. By October 16, 2012, after an average follow-up time of 512 days, 799 (79.7%) patients were still actively participating. SWITCO65+ is a unique opportunity to study short- and long-term outcomes in elderly patients with VTE. The Steering Committee encourages national and international collaborative research projects related to SWITCO65+, including sharing anonymized data and biological samples. PMID- 23359099 TI - Biomechanical testing of a new plate system for the distal humerus compared to two well-established implants. AB - PURPOSE: A biomechanical study was performed to test the hypothesis that a new anatomically preformed, thinner, soft-tissue protecting plate system for distal humeral fractures (Tifix(r)-hybridplate [HP]) would show comparable results in the quasi-static and dynamic testings compared to two conventional implants: The 3.5-mm reconstruction plate (RP) providing primary stability with normal bone mineral density (BMD), and a multidirectional locking plate (Tifix((r))-plate [P]) which can be used with poor bone quality. METHODS: The Tifix((r))-HP was developed by the working group. The biomechanical testing was performed on a C2 fracture-model in 24 synthetic humeri. Three groups, each with eight bone-implant constructs, were analysed in quasi-static and dynamic tests. RESULTS: The quasi static measurements showed that under extension loading both locking plates (Tifix((r))-P, Tifix((r))-HP) were significantly stiffer than the reconstruction plate, and that the Tifix((r))-HP had a significantly lower stiffness than the two other implants under flexion loading. In the dynamic tests the Tifix((r))-P allowed significantly less fracture motion compared to the Tifix((r))-HP and the reconstruction plate. In an osteopaenic bone model locking plates failed only under much higher dynamic force than the reconstruction plate. The reconstruction plate and the Tifix((r))-P always failed through screw loosening, whereas the newly developed Tifix((r))-HP showed screw loosening in only one third of cases. CONCLUSION: The hypothesis that the newly designed plate system showed comparable results in the quasi-static and dynamic tests compared to the conventional implants with a significantly lower implant volume and thickness was confirmed. PMID- 23359100 TI - Is etoricoxib effective in preventing heterotopic ossification after primary total hip arthroplasty? AB - PURPOSE: Heterotopic ossification is a common complication after total hip arthroplasty. Non-steroidal anti-inflammatory drugs (NSAIDs) are known to prevent heterotopic ossifications effectively, however gastrointestinal complaints are reported frequently. In this study, we investigated whether etoricoxib, a selective cyclo-oxygenase-2 (COX-2) inhibitor that produces fewer gastrointestinal side effects, is an effective alternative for the prevention of heterotopic ossification. METHODS: We investigated the effectiveness of oral etoricoxib 90 mg for seven days in a prospective two-stage study design for phase 2 clinical trials in a small sample of patients (n = 42). A cemented primary total hip arthroplasty was implanted for osteoarthritis. Six months after surgery, heterotopic ossification was determined on anteroposterior pelvic radiographs using the Brooker classification. RESULTS: No heterotopic ossification was found in 62 % of the patients that took etoricoxib; 31 % of the patients had Brooker grade 1 and 7 % Brooker grade 2 ossification. CONCLUSIONS: Etoricoxib seems effective in preventing heterotopic ossification after total hip arthroplasty. This finding further supports the use of COX-2 inhibitors for the prevention of heterotopic ossification following total hip arthroplasty. PMID- 23359101 TI - Reply to comment on Irena Krusche-Mandl et al. Crossed pinning in paediatric supracondylar humerus fractures: a retrospective cohort analysis. PMID- 23359102 TI - From the mouths of babes: dental caries in infants and children and the intensification of agriculture in mainland Southeast Asia. AB - Many bioarchaeological studies have established a link between increased dental caries prevalence and the intensification of agriculture. However, research in Southeast Asia challenges the global application of this theory. Although often overlooked, dental health of infants and children can provide a sensitive source of information concerning health and subsistence change. This article investigates the prevalence and location of caries in the dentition of infants and children (less than 15 years of age) from eight prehistoric mainland Southeast Asian sites collectively spanning the Neolithic to late Iron Age, during which time rice agriculture became an increasingly important subsistence mode. Caries prevalence varied among the sites but there was no correlation with chronological change. The absence of evidence of a decline in dental health over time can be attributed to the relative noncariogenicity of rice and retention of broad-spectrum subsistence strategies. No differences in caries type indicating differences in dental health were found between the sites, apart from the Iron Age site of Muang Sema. There was a higher prevalence of caries in the deciduous dentition than the permanent dentition, likely due to a cariogenic weaning diet and the higher sensitivity of deciduous teeth to decay. The level of caries in the permanent dentition suggests an increased reliance on less cariogenic foods during childhood, including rice. The absence of a temporal decline in dental health of infants and children strengthens the argument that the relationship between caries and agricultural intensification in Southeast Asia was more complex than the general model suggests. PMID- 23359103 TI - Trabecular meshwork depigmentation in Vogt-Koyanagi-Harada disease. AB - PURPOSE: Since some patients develop depigmentation of the trabecular meshwork in the course of Vogt-Koyanagi-Harada (VKH) disease, we examined the incidence of trabecular depigmentation and its correlation with other ocular findings and systemic symptoms. METHODS: We retrospectively reviewed the clinical charts of 53 Japanese patients diagnosed with VKH disease. The scores of trabecular and limbal pigmentation of all patients were recorded. We then examined the correlation between trabecular pigmentation and the presence of sunset glow fundus or skin lesions. RESULTS: Trabecular pigmentation was significantly lower in the patients with sunset glow fundus than in those without it (P = 0.022), whereas limbal pigmentation showed no significance. However, there were no significant differences in trabecular and limbal pigmentation between the patients with and those without skin lesions. Furthermore, there was no correlation between trabecular and limbal pigmentation. CONCLUSIONS: Depigmentation of the trabecular meshwork develops in some patients in the course of VKH disease. This depigmentation is significantly correlated with sunset glow fundus, but not with limbal depigmentation or skin lesions. PMID- 23359104 TI - Priority setting and patient adaptation to disability and illness: outcomes of a qualitative study. AB - The study examined the question of who should make decisions for a National Health Scheme about the allocation of health resources when the health states of beneficiaries could change because of adaptation. Eight semi-structured small group discussions were conducted. Following focus group theory, interviews commenced with general questions followed by transition questions and ended with a 'focus' or 'key' question. Participants were presented with several scenarios in which patients adapted to their health states. They were then asked their views about the appropriate role of the public, patients and health professionals in making social judgements of quality of life. After discussion and debate, all groups were asked the key question: 'In light of adaptation, who should evaluate quality of life for the purpose of setting priorities in the allocation of health care?' In all groups participants presented strong arguments for and against decision making by patients, the public and health professionals. However, most groups thought a representative body which included a range of perspectives should make the relevant judgements. This is at odds with the recommendations in most national pharmaceutical guidelines. The main conclusion of the paper is that health economists and other researchers should explore the possibility of adopting a deliberative, consensus-based approach to evaluating health-related quality of life when such judgements are to be used to inform priority setting in a public system. PMID- 23359105 TI - A community survey on neighborhood violence, park use, and physical activity among urban youth. AB - BACKGROUND: Neighborhoods can be an important feature of the built environment influencing physical activity; however, neighborhood poverty and violence may pose significant barriers for youth physical activity. We conducted a community survey of 107 households with youth 3-12 years of age in select neighborhoods of the city of Newark, New Jersey, a highly impoverished and racially/ethnically segregated city of the United States. RESULTS: The majority of sampled households did not have access to a park, and nearly 60% of youth were not engaged in a team or organized physical activity program. Hearing gunshots and seeing drug deals in the neighborhood were reported by 74% and 56%, respectively, of study participants. In adjusted regression models, a 1-unit increase in self-reported neighborhood safety was associated with perceptions that parks were safe for youth to use (OR = 1.7, CI = 1.3, 2.3) and increased odds of youth using parks (OR = 1.3, CI = 1.0, 1.6). Self-reported neighborhood violence was marginally associated with lower levels of Metabolic Equivalent (MET)-min/week of moderate PA (beta = -54.25, P = .05). CONCLUSION: To ensure national goals of increased physical activity and use of outdoor spaces, addressing the neighborhood contexts under which the most vulnerable of our youth live will be required. PMID- 23359106 TI - The Tanapoxvirus 142R Protein is a Serine-Threonine Kinase that Phosphorylates the Tumor Suppressor p53. AB - To effectively respond to viral infections, mammals rely on the innate and adaptive immune systems. Additionally, host cellular responses, such as apoptosis also play a vital role in the host defense mechanisms. To accomplish a successful replicative strategy in vivo, animal viruses have evolved a variety of molecular mechanisms that interfere with host responses. Poxviruses in particular, represents a prime example of where animal viruses encode a wide variety of proteins necessary for replication and subversion of the host's immune and single cell responses. Several proteins that inhibit host immmunomodulatory cytokines and apoptosis of infected cells have been characterized in vaccinia virus (VV). Here, we describe the identification of a protein encoded by the tanapox virus genome (142R open reading frame) that is orthologous to the B1R protein from VV. We demonstrate that like B1R, TPV142R encodes a serine threonine kinase that can phosphorylate the tumor suppressor p53 and therefore has the potential for inhibiting apoptosis of infected cells. PMID- 23359107 TI - Local ethanol injection for the treatment of deltoid parathyroid cell hyperplasia. AB - Secondary hyperparathyroidism (SHPT) is a serious complication in dialysis patients and is routinely managed with medical therapy. Refractory disease is usually treated either surgically or by local ethanol injection into the parathyroid glands. Total parathyroidectomy with deltoid implant can be successful; however, recurrent, resistant disease is not uncommon. Local ethanol injection was applied to the deltoid autoimplant of a patient with recurrent, resistant SHPT, which had not been resolved with surgical treatment. Serum intact parathyroid hormone (iPTH) levels subsequently decreased from 1,400 to 219 pg/dl and remained stable for the next 6 months. To our knowledge, this procedure has not been previously described in the literature. Local injection of ethanol may represent an interesting alternative to surgery for the treatment of deltoid parathyroid cell hyperplasia in patients in which surgical treatment is not an option. PMID- 23359108 TI - Increase in non-contrast computerized tomography scans of the head following popular media stories about head injury. AB - INTRODUCTION: On March 18, 2009, actress Natasha Richardson died after a head injury. It is possible that the rate of patients presenting with mild head injury and receiving computed tomographies (CTs) may have been influenced by the Richardson event. We hypothesized that there was a statistically significant increase in the rate of census-adjusted head CTs performed for mild trauma after March 16, 2009, compared to prior to this date. METHODS: We included all with a non-contrast head CT performed from the emergency department (ED) between March 1 and April 15, 2009, for minor trauma. The primary outcome was the census-adjusted rate of head CTs per time (# of head CTs/census). We compared the census adjusted rate for the 2 weeks prior to 2 weeks after the accident. To document media dissemination we searched Lexis-Nexis for news stories mentioning "Richardson." RESULTS: In the 2 weeks prior to March 16, 2009, the census-adjusted rate was 0.81% (95% CI 0.54-1.16) and there were no stories. The first media reports appeared on March 16, 2009, (n = 19) and quickly doubled (n = 40, n = 43) over the subsequent 2 days. The rate of CTs nearly doubled during the 2 weeks post accident 1.46% (1.10-1.91%). This absolute increase in rate percentage was statistically significant. (0.65%; 0.17 to 1.14%). CONCLUSION: The percentage of all ED patients seen with mild trauma tested with head CT almost doubled when comparing the pre-Richardson accident vs. post time periods. There was an increase in media reports of the accident that occurred rapidly after the event and peaked on day 3. PMID- 23359109 TI - Marital satisfaction and physical health: evidence for an orchid effect. AB - Marital distress and conflict are linked to poor physical health. Here, we used behavior genetic modeling to determine the etiology of this association. Biometric moderation models were used to estimate gene-by-environment interaction in the presence of gene-environment correlation between marital satisfaction and self-reported health. Using a sample of 347 married twin pairs from the Midlife in the United States study, we found that genetic influences on the variation in self-reported health were greatest at both high (h (2) = .30) and low (h (2) = .38) levels of marital satisfaction, with the lowest levels of heritability estimated for participants at the average level of marital satisfaction (h (2) = .10). These findings are evidence of the orchid effect: the idea that genetic influences on a phenotype such as physical health are enhanced in nonnormative both unusually positive and unusually negative-environmental contexts. PMID- 23359111 TI - Molecular mechanisms underlying the antitumor activity of 3-aminopropanamide irreversible inhibitors of the epidermal growth factor receptor in non-small cell lung cancer. AB - Overcoming the emergence of acquired resistance to clinically approved epidermal growth factor receptor (EGFR) inhibitors is a major challenge in the treatment of advanced non-small cell lung cancer (NSCLC). The aim of this study was to investigate the effects of a series of novel compounds affecting viability of NSCLC NCI-H1975 cells (carrying the EGFR T790M mutation). The inhibition of the autophosphorylation of EGFR occurred at nanomolar concentrations and both UPR1282 and UPR1268 caused a significant induction of apoptosis. Targeting of EGFR and downstream pathways was confirmed by a peptide substrate array, which highlighted the inhibition of other kinases involved in NSCLC cell aggressive behavior. Accordingly, the drugs inhibited migration (about 30% vs. control), which could be, in part, explained also by the increase of E-cadherin expression. Additionally, we observed a contraction of the volume of H1975 spheroids, associated with the reduction of the cancer stem-like cell hallmark CD133. The activity of UPR1282 was retained in H1975 xenograft models where it determined tumor shrinkage (P < .05) and resulted well tolerated compared to canertinib. Of note, the kinase activity profile of UPR1282 on xenograft tumor tissues showed overlapping results with respect to the activity in H1975 cells, unraveling the inhibition of kinases involved in pivotal proliferation and invasive signaling pathways. In conclusion, UPR1282 and UPR1268 are effective against various processes involved in malignancy transformation and progression and may be promising compounds for the future treatment of gefitinib-resistant NSCLCs. PMID- 23359113 TI - The coronary collateral circulation revisited. PMID- 23359112 TI - Dickkopf-1 as a novel predictor is associated with risk stratification by GRACE risk scores for predictive value in patients with acute coronary syndrome: a retrospective research. AB - OBJECTIVE: Dickkopf-1 (DKK-1), a major regulator of the Wnt pathway, plays an important role in cardiovascular disease. However, no study has evaluated the association of DKK-1 and acute coronary syndrome (ACS). We investigated this association and whether the Global Registry of Acute Coronary Events (GRACE) hospital-discharge risk score predicting major adverse cardiac events (MACE) can be improved by adding the DKK-1 value. METHODS: We enrolled 291 patients (46 with ST-segment elevation myocardial infarction [STEMI] and 245 with non-ST elevated ACS [NSTE-ACS]) who were divided into groups by tertiles of baseline plasma DKK-1 level measured by ELISA. The GRACE risk score was calculated and predictive value alone and together with DKK-1 and/or high-sensitivity C-reactive protein (hs-CRP) level were assessed, respectively. RESULTS: Compared with patients with NSTE-ACS, those with STEMI had higher plasma DKK-1 level at baseline (P = 0.006). Plasma DKK-1 level was correlated with hs-CRP level (r = 0.295, P<0.001) and was greater with high than intermediate or low GRACE scores (P = 0.002 and P<0.001, respectively). We found 44 (15.1%) MACEs during a median 2-year follow-up. DKK-1 levels were higher for patients with than without events (P<0.001). The rate of MACE increased with increasing DKK-1 level (P<0.001). The area under the receiver operating characteristic curve for GRACE score with MACE was 0.524 and improved to 0.791 with the addition of hs-CRP level, 0.775 with the addition of DKK-1 level and 0.847 with both values added. CONCLUSIONS: DKK-1 is an independent predictor of long-term MACE of patients with ACS. The long-term predictive ability of post-discharge GRACE score may be enhanced by adding DKK-1 level. PMID- 23359110 TI - Epigenetics and psychostimulant addiction. AB - Chronic drug exposure alters gene expression in the brain and produces long-term changes in neural networks that underlie compulsive drug taking and seeking. Exactly how drug-induced changes in synaptic plasticity and subsequent gene expression are translated into persistent neuroadaptations remains unclear. Emerging evidence suggests that complex drug-induced neuroadaptations in the brain are mediated by highly synchronized and dynamic patterns of gene regulation. Recently, it has become clear that epigenetic mechanisms contribute to drug-induced structural, synaptic, and behavioral plasticity by regulating expression of gene networks. Here we review how alterations in histone modifications, DNA methylation, and microRNAs regulate gene expression and contribute to psychostimulant addiction with a focus on the epigenetic mechanisms that regulate brain-derived neurotrophic factor (BDNF) expression following chronic cocaine exposure. Identifying epigenetic signatures that define psychostimulant addiction may lead to novel, efficacious treatments for drug craving and relapse. PMID- 23359114 TI - Can the infusion of isotonic fluids or vasopressors prevent hemodynamic changes in cardiac surgery patients? AB - BACKGROUND: A common problem in cardiac surgery patients is decreased central venous pressure (CVP) and systemic blood pressure during transfer from operation room to intensive care unit (ICU). Since these reductions may lead to dangerous complications, this study aimed to evaluate the effects of vasopressors and isotonic fluids on hemodynamic status of cardiac surgery patients during their transfer to ICU. METHODS: This randomized single-blind clinical trial was conducted in Chamran Hospital (Isfahan, Iran). A total number of 75 consecutive patients undergoing planned first-time coronary artery bypass grafting entered our study. Systolic blood pressure (SBP), diastolic blood pressure (DBP), CVP, and pulse rate (PR) were recorded at 5 to 10 minutes before leaving operating room and immediately after hospitalization in the ICU. Subjects in the first group received 7 cc/kg intravenous normal saline (as an isotonic fluid) within 5 10 minutes. The second group received 10 mg ephedrine before being transferred to the ICU. RESULTS: The mean age of participants was 61.0 +/- 3.6 years. No significant change in PR was detected in normal saline group (P > 0.05). No significant differences were found in two groups in SBP before and after hospitalization in the ICU (P > 0.05). DBP and CVP had statistically significant reductions in both groups after hospitalization in the ICU (P < 0.001). The mean CVP was also reduced significantly (10.7 +/- 2.9 vs. 8.2 +/- 3.4; P < 0.001). CONCLUSION: Significant reductions in mean values of DBP and CVP occur during cardiac surgery and after arrival to the ICU. These reductions cannot be prevented by administration of vasopressors, such as ephedrine, or infusion of isotonic fluids, such as normal saline. Further studies are required to assess whether more fluids, other types of fluids, or other drugs can stop this phenomenon. PMID- 23359115 TI - CTHRC1 is associated with peritoneal carcinomatosis in colorectal cancer: a new predictor for prognosis. AB - Colorectal cancer (CRC) patients with peritoneal carcinomatosis (PC) have a poor prognosis. Over the last decade, increasing evidence has suggested that the Collagen Triple Helix Repeat Containing 1 (CTHRC1) gene is involved in cancer progression and invasion. In this study, we investigated the expression of CTHRC1 in CRC and its potential as a prognostic factor for CRC patients with PC. Microarray analysis of four fresh paired samples showed that the expression of CTHRC1 in peritoneal metastases was higher than that in the corresponding primary tumor. These results were validated using semi-quantitative reverse transcription and polymerase chain reaction. Finally, immunohistochemical analysis showed that CTHRC1 was increased in the peritoneal metastasis group (n = 30) and the primary cancer with peritoneal metastasis group (n = 57) compared to the primary cancer without peritoneal metastasis group (n = 54), both P < 0.001. Cox proportional hazards model analysis showed that high CTHRC1 expression was associated with poor survival (HR = 2.754, P < 0.001, 95 % CI 1.731-4.383). Overall, the results of our study suggest that increased expression of CTHRC1 is associated with PC in CRC patients and could predict poor outcome in CRC patients. PMID- 23359117 TI - Current trends in the management of difficult urinary catheterizations. AB - Routine urinary catheter placement may cause trauma and poses a risk of infection. Male catheterization, in particular, can be difficult, especially in patients with enlarged prostate glands or other potentially obstructive conditions in the lower urinary tract. Solutions to problematic urinary catheterization are not well known and when difficult catheterization occurs, the risk of failed catheterization and concomitant complications increase. Repeated and unsuccessful attempts at urinary catheterization induce stress and pain for the patient, injury to the urethra, potential urethral stricture requiring surgical reconstruction, and problematic subsequent catheterization. Improper insertion of catheters also can significantly increase healthcare costs due to added days of hospitalization, increased interventions, and increased complexity of follow-up evaluations. Improved techniques for catheter placement are essential for all healthcare personnel involved in the management of the patient with acute urinary retention, including attending emergency physicians who often are the first physicians to encounter such patients. Best practice methods for blind catheter placement are summarized in this review. In addition, for progressive clinical practice, an algorithm for the management of difficult urinary catheterizations that incorporates technology enabling direct visualization of the urethra during catheter insertion is presented. This algorithm will aid healthcare personnel in decision making and has the potential to improve quality of care of patients. PMID- 23359118 TI - Carvedilol for preventing recurrent variceal bleeding: waiting for convincing evidence. PMID- 23359116 TI - Glomerular endothelial cell injury and damage precedes that of podocytes in adriamycin-induced nephropathy. AB - The role of podocytes in the development and progression of glomerular disease has been extensively investigated in the past decade. However, the importance of glomerular endothelial cells in the pathogenesis of proteinuria and glomerulosclerosis has been largely ignored. Recent studies have demonstrated that endothelial nitric oxide synthatase (eNOS) deficiency exacerbates renal injury in anti-GBM and remnant kidney models and accelerates diabetic kidney damage. Increasing evidence also demonstrates the importance of the glomerular endothelium in preventing proteinuria. We hypothesize that endothelial dysfunction can initiate and promote the development and progression of glomerulopathy. Administration of adriamycin (ADR) to C57BL/6 mice, normally an ADR resistant strain, with an eNOS deficiency induced overt proteinuria, severe glomerulosclerosis, interstitial fibrosis and inflammation. We also examined glomerular endothelial cell and podocyte injury in ADR-induced nephropathy in Balb/c mice, an ADR susceptible strain, by immunostaining, TUNEL and Western blotting. Interestingly, down-regulation of eNOS and the appearance of apoptotic glomerular endothelial cells occurred as early as 24 hours after ADR injection, whilst synaptopodin, a functional podocyte marker, was reduced 7 days after ADR injection and coincided with a significant increase in the number of apoptotic podocytes. Furthermore, conditioned media from mouse microvascular endothelial cells over-expressing GFP-eNOS protected podocytes from TNF-alpha-induced loss of synaptopodin. In conclusion, our study demonstrated that endothelial dysfunction and damage precedes podocyte injury in ADR-induced nephropathy. Glomerular endothelial cells may protect podocytes from inflammatory insult. Understanding the role of glomerular endothelial dysfunction in the development of kidney disease will facilitate in the design of novel strategies to treat kidney disease. PMID- 23359119 TI - Internet video telephony allows speech reading by deaf individuals and improves speech perception by cochlear implant users. AB - OBJECTIVE: To analyze speech reading through Internet video calls by profoundly hearing-impaired individuals and cochlear implant (CI) users. METHODS: Speech reading skills of 14 deaf adults and 21 CI users were assessed using the Hochmair Schulz Moser (HSM) sentence test. We presented video simulations using different video resolutions (1280 * 720, 640 * 480, 320 * 240, 160 * 120 px), frame rates (30, 20, 10, 7, 5 frames per second (fps)), speech velocities (three different speakers), webcameras (Logitech Pro9000, C600 and C500) and image/sound delays (0 500 ms). All video simulations were presented with and without sound and in two screen sizes. Additionally, scores for live SkypeTM video connection and live face-to-face communication were assessed. RESULTS: Higher frame rate (>7 fps), higher camera resolution (>640 * 480 px) and shorter picture/sound delay (<100 ms) were associated with increased speech perception scores. Scores were strongly dependent on the speaker but were not influenced by physical properties of the camera optics or the full screen mode. There is a significant median gain of +8.5%pts (p = 0.009) in speech perception for all 21 CI-users if visual cues are additionally shown. CI users with poor open set speech perception scores (n = 11) showed the greatest benefit under combined audio-visual presentation (median speech perception +11.8%pts, p = 0.032). CONCLUSION: Webcameras have the potential to improve telecommunication of hearing-impaired individuals. PMID- 23359121 TI - Agrochemicals in field margins--assessing the impacts of herbicides, insecticides, and fertilizer on the common buttercup (Ranunculus acris). AB - The effects of herbicide, insecticide, and fertilizer inputs on the common buttercup Ranunculus acris in field margins were studied in an experimental field study. The test design allowed us to investigate the single and combined effects of repeated herbicide, insecticide, and fertilizer applications in successive growing seasons. To assess the effects of the agrochemical applications on R. acris, plant community assessments were carried out and a photodocumentation of the flowering intensity was performed over two years. In addition, the authors conducted a monitoring survey of R. acris in field margins in the proximity of the study site. In the field experiment, R. acris plant density decreased significantly with treatments including fertilizer. The herbicide caused a sublethal effect by reducing flower intensity by 85%. In the long run, both effects will result in a decline of R. acris and lead to shifts in plant communities in field margins. This was confirmed by the monitoring survey, where R. acris could hardly be observed in field margins directly adjacent to cereal fields, whereas in margins next to meadows the species was recorded frequently. Besides the implications for the plants, the sublethal effects may also affect many flower-visiting insects. The results indicate that the current risk assessment for nontarget plants is insufficiently protective for wild plant species in field margins and that consideration of sublethal effects is crucial to preserve biodiversity in agricultural landscapes. PMID- 23359120 TI - Expression of G-protein-coupled receptor kinase 6 (GRK6) after acute spinal cord injury in adult rat. AB - Spinal cord injury frequently results in permanent loss of neurological function. It includes many complex molecular and biochemical mechanisms. G-protein-coupled receptor kinase 6 (GRK6) is an intracellular kinase that regulates the sensitivity of certain G-protein-coupled receptors. Some studies reported GRK2 and GRK5 modulate the NFkappaB pathway in macrophages. Additionally, GRK2 is referred to as regulating activation of spinal cord microglia and GRK6 expression is significantly elevated in most brain regions in the MPTP-lesioned parkinsonian monkeys. However, the expression and function of GRK6 in nervous system lesion and repair are not well understood. In this study, we performed an acute spinal cord injury (SCI) model in adult rats. Western blot analysis showed the expression of GRK6 was upregulated significantly at protein level in spinal cord after SCI. Immunohistochemistry and immunofluorescence revealed wide expression of GRK6 in the normal spinal cord. After injury, GRK6 expression was increased predominantly in microglia, which expressed F4/80 (marker of macrophages and activated microglia) strongly. To understand whether GRK6 played a role in microglia activation, we applied lipopolysaccharide (LPS) to induce microglia activation in vitro. Western blot analysis demonstrated up-regulation in GRK6 protein expression after LPS stimulation was time- and dose-dependent and that up regulation in F4/80 expression was concomitant with GRK6. These data suggested that GRK6 might be involved in the pathophysiology of SCI. PMID- 23359123 TI - How to motivate childcare workers to engage preschoolers in physical activity. AB - BACKGROUND: Data available indicate that numerous childcare workers are not strongly motivated to engage children aged 3-5 in physical activity. Using the theory of planned behavior as the main theoretical framework, this study has 2 objectives: to identify the determinants of the intention of childcare workers to engage preschoolers in physical activity and to identify the variables that could be used to develop an intervention to motivate childcare workers to support preschoolers' physical activity. METHODS: 174 childcare workers from 60 childcare centers selected at random in 2 regions of Quebec completed a self-administered questionnaire assessing the constructs of the theory of planned behavior as well as past behavior, descriptive norm and moral norm. RESULTS: Moral norm, perceived behavioral control and subjective norm explained 85% of the variance in intention to engage the children in physical activity. CONCLUSIONS: To motivate childcare workers, it is necessary that they perceive that directors, children's parents and coworkers approve of their involvement in children's physical activity. In addition, their ability to overcome perceived barriers (lack of time, loaded schedule, inclement weather) should be developed. Access to a large outdoor yard might also help motivate childcare workers. PMID- 23359122 TI - Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms. AB - The effects of standard adenosine receptor (AR) agonists and antagonists on the proliferation of human T lymphocytes, unstimulated and phytohemagglutinin stimulated human peripheral blood lymphocytes (PBL), and Jurkat T cells were investigated. Real-time PCR measurements confirmed the presence of all four AR subtypes on the investigated cells, although at different expression levels. A2A ARs were predominantly expressed in PBL and further upregulated upon stimulation, while malignant Jurkat T cells showed high expression levels of A1, A2A, and A2B ARs. Cell proliferation was measured by [(3)H]-thymidine incorporation assays. Several ligands, including the subtype-selective agonists CPA (A1), BAY60-6583 (A2B), and IB-MECA (A3), and the antagonists PSB-36 (A1), MSX-2 (A2A), and PSB-10 (A3) significantly inhibited cell proliferation at micromolar concentrations, which were about three orders of magnitude higher than their AR affinities. In contrast, further investigated AR ligands, including the agonists NECA (nonselective) and CGS21680 (A2A), and the antagonists preladenant (SCH-420814, A2A), PSB-1115 (A2B), and PSB-603 (A2B) showed no or only minor effects on lymphocyte proliferation. The anti-proliferative effects of the AR agonists could not be blocked by the corresponding antagonists. The non-selective AR antagonist caffeine stimulated phytohemagglutinin-activated PBL with an EC50 value of 104 MUM. This is the first study to compare a complete set of commonly used AR ligands for all subtypes on lymphocyte proliferation. Our results strongly suggest that these compounds induce an inhibition of lymphocyte proliferation and cell death through AR-independent mechanisms. PMID- 23359124 TI - Sexual dimorphism in the olfactory system of a solitary and a eusocial bee species. AB - Sexually dimorphic sensory systems are common in Hymenoptera and are considered to result from sex-specific selection pressures. An extreme example of sensory dimorphism is found in the solitary bee tribe Eucerini. Males of long-horned bees bear antennae that exceed body length. This study investigated the pronounced sexual dimorphism of the peripheral olfactory system and its representation in higher brain centers of the species Eucera berlandi. Eucera males have elongated antennae, with 10 times more pore plates and three times more olfactory receptor neurons than females. The male antennal lobe (AL) comprises fewer glomeruli than the female AL (~100 vs. ~130), of which four are male-specific macroglomeruli. No sex differences were found in the relative volume of the mushroom bodies, a higher order neuropil essential for learning and memory in Hymenoptera. Compared with the Western honeybee, the degree of sexual dimorphism in Eucera is more pronounced at the periphery. In contrast, sex differences in glomerular numbers are higher in the eusocial honeybee and a sexual dimorphism of the relative investment in mushroom body tissue is observed only in Apis. The observed differences between the eusocial and the solitary bee species may reflect differences in male-specific behavioral traits and associated selection pressures, which are discussed in brief. PMID- 23359125 TI - Increased understanding of the biochemistry and biosynthesis of MUC2 and other gel-forming mucins through the recombinant expression of their protein domains. AB - The gel-forming mucins are large and heavily O-glycosylated proteins which build up mucus gels. The recombinant production of full-length gel-forming mucins has not been possible to date. In order to study mucin biosynthesis and biochemistry, we and others have taken the alternative approach of constructing different recombinant proteins consisting of one or several domains of these large proteins and expressing them separately in different cell lines. Using this approach, we have determined that MUC2, the intestinal gel-forming mucin, dimerizes via its C terminal cysteine-knot domain and also trimerizes via one of the N-terminal von Willebrand D domains. Both of these interactions are disulfide bond mediated. Via this assembly, a molecular network is built by which the mucus gel is formed. Here we discuss not only the functional understanding obtained from studies of the recombinant proteins, but also highlight the difficulties encountered when these proteins were produced recombinantly. We often found an accumulation of the proteins in the ER and consequently no secretion. This was especially apparent when the cysteine-rich domains of the N- and C-terminal parts of the mucins were expressed. Other proteins that we constructed were either not secreted or not expressed at all. Despite these problems, the knowledge of mucin biosynthesis and assembly has advanced considerably through the studies of these recombinant proteins. PMID- 23359126 TI - Protein bodies in nature and biotechnology. AB - Protein bodies are natural structures containing protein aggregates that exist in many organisms ranging from bacteria to mammals and plants. In bacteria they are often a phenomenon associated to over-expression of heterologous proteins. In mammals the so called Russell bodies indicate an accumulation of mutated immune globulins. In plants the protein bodies play a major role as protein storage organelle in seeds. Besides these natural cases, protein bodies can also be artificially induced primarily using self-assembling peptides. Frequently plant derived proteins such as prolamins or their derivatives are used. In some cases the help of an endoplasmatic retention signal is needed to create artificial protein bodies. The biotechnological application of protein bodies offers novel solutions such as the simplification of downstream processing in protein manufacture, the utilisation as particle for immunisation as vaccines or as carrier free self immobilised enzyme particle for many industrial catalytic processes. PMID- 23359127 TI - Anti-digoxin Fab variants generated by phage display. AB - Digoxin is a pharmaceutical used in the control of cardiac dysfunction. Its therapeutic window is narrow, with effect dosage very close to the toxic dosage. To counteract the toxic effect, polyclonal Fab fragments are commercially available. Our study is based on a monoclonal anti-digoxin antibody, which would provide a product with a specific potency and more precise dosage for the detoxification of patients under digoxin treatment. Phage display technology was used to select variants with high affinity. From an anti-digoxin hybridoma, RNA was extracted for subsequent cDNA synthesis. Specific primers were used for the LC and Fd amplifications, then cloned sequentially in a phagemid vector (pComb3X) for the combinatorial Fab library construction. Clones were selected for their ability to bind to digoxin-BSA. The presence of light and heavy chains was checked, randomly selected clones then sequenced and induced to produce soluble Fabs, and subsequently analyzed for anti-digoxin expression. Out of ten clones randomly chosen, six resulted positive expression of the product. The sequencing of these revealed two identical clones and one presenting a pseudogene in the LC. Four clones presenting variations in the framework1 showed binding to digoxin-BSA by ELISA and western blotting. The specific binding was further confirmed by Biacore((r)), which allowed ranking of the clones. The development of these clones allowed the selection of variants with higher affinity than the original version. PMID- 23359128 TI - Diphtheria Toxin/Human B-Cell Activating Factor Fusion Protein Kills Human Acute Lymphoblastic Leukemia BALL-1 Cells: An Experimental Study. AB - OBJECTIVE: This study aimed to express a fusion protein of diphtheria toxin and human B cell-activating factor (DT388sBAFF) in Escherichia coli (E. coli) and investigate its activity in human B-lineage acute lymphoblastic leukemia 1 cells (BALL-1). METHODS: A fragment of DT388sBAFF fusion gene was separated from plasmid pUC57-DT388sBAFF digested with Nde I and Xho I, and inserted into the expression vector pcold II digested with the same enzymes. Recombinants were screened by the colony polymerase chain reaction (PCR) and restriction map. The recombinant expression vector was transformed into BL21 and its expression was induced by isopropyl beta-D-1-thiogalactopyranoside (IPTG). The recombinant protein was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot, and then purified by Ni(2+)-NTA affinity chromatography. The expression level of B cell-activating factor receptor (BAFF-R) on BALL-1 cells was assessed by real-time PCR. The receptor binding capacity of recombinant protein was determined by cell fluorescent assay. The specific cytotoxicity of recombinant protein on BALL-1 cells was detected by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The expression level of recombinant protein was 50% of total bacterial proteins in E. coli, and the recombinant protein could bind to BAFF-R-positive BALL-1 cells and thereby produce a cytotoxic effect on the cells. CONCLUSION: The fusion protein expression vector DT388sBAFF was successfully constructed and the recombinant protein with selective cytotoxicity against BALL-1 cells was obtained, providing foundation for further study of the therapy of human B lineage acute lymphoblastic leukemia. PMID- 23359129 TI - Childhood suicide attempts with acetaminophen in Denmark: characteristics, social behaviour, trends and risk factors. AB - AIMS: To explore: (1) The relationship between children admitted to our paediatric department as a result of suicide attempts with acetaminophen and their parents and friends. (2) The extent to which the children had attempted to speak to their parents about their problems before their suicide attempts. (3) The frequency of self-mutilation among children with suicidal behaviour. (4) The purposes and reasons for childhood suicide attempts. METHODS: A retrospective case-control study based on medical records and in-hospital child psychiatric assessments at the Paediatric Department, Hillerod Hospital, Denmark, 2006-2011. STUDY GROUP: 107 children, 11 to 15 years old. CONTROL GROUP: 59 age- and gender matched children. RESULTS: 43.5% experienced a dissociated parental relationship characterized by the inability to speak to their parents about any problems, compared with 2% in the control group. There was a significant association between a dissociated parental relationship and 'the feeling of not being heard' (p = 0.004), the discovery of the suicide attempt (p = 0.008), the reasons for the suicide attempt (p = 0.006), academic school problems (p = 0.03), and the child's relationships with friends (p = 0.02). Prior to their suicide attempts, 41.5% of the children had attempted to speak to their parents about their problems but felt that they were not heard. There was a significant association among 'the feeling of not being heard' and the purpose of the suicide attempt (p = 0.002) and self-mutilation (p = 0.002). Forty percent mutilated themselves repeatedly. CONCLUSIONS: A consistently impaired parent-child relationship, 'the feeling of not being heard', and self-mutilation are identifiable early risk factors that require increased concern and attention among professionals who work with children. PMID- 23359130 TI - Notch2 signaling and undifferentiated liver cancers: evidence of hepatic stem/progenitor cell origin. PMID- 23359131 TI - Lower limb activity in the Cis-Baikal: entheseal changes among middle Holocene Siberian foragers. AB - Lower limb entheseal changes are evaluated in order to reconstruct activity levels and more fully understand cultural and behavioral variation among the middle Holocene (ca. 9,000-3,000 years BP) foragers of Siberia's Cis-Baikal region. The four cemetery samples examined span a period of diachronic change characterized by an 800- to 1,000-year discontinuity in the use of formal cemeteries in the region. Two of the cemetery samples represent the early Neolithic Kitoi culture, dating from 8,000 to 7,000/6800 cal. BP; the other two represent the late Neolithic-early Bronze Age Isakovo-Serovo-Glazkovo (ISG) cultural complex, dating from 6,000/5,800 to 4,000 cal. BP. Findings suggest a dynamic pattern of cultural variability in the Cis-Baikal, with spatial distribution (i.e., site location within particular microregions) appearing to be just as important a factor as cultural/temporal affiliation in explaining intersample differences in entheseal morphology. In addition, intrasample comparisons reveal increasing sexual disparity with advancing age at death, emphasizing the influence of sex-related activities on lower limb entheseal changes. Finally, results from the separate fibrous and fibrocartilaginous datasets appear to be largely congruous, implying that activity patterns in the Cis-Baikal may have similar effects on the morphology of both types of entheses. PMID- 23359132 TI - Decisional answer tree analysis of exudative age-related macular degeneration treatment outcomes. AB - The use of intravitreal ranibizumab in exudative age-related macular degeneration (eAMD) has become commonplace. We aim to investigate the early predictors of this treatment outcome. Seventy-one treatment-naive eyes of 71 patients with eAMD of all lesion subtypes who received intravitreal ranibizumab treatment and completed 12 months of follow-up were included. All patients were loaded with three injections of ranibizumab at monthly intervals. Further injections were given if clinically indicated based on logMAR best-corrected visual acuity (BCVA) and optical coherence tomography findings. Casenotes of eligible patients were reviewed retrospectively. The main outcome measure was logMAR BCVA change at month 12. The mean number of injections given over 12 months was 5.4 +/- 1.9. A total of 88.7 % of the patients achieved visual stabilisation (loss of <15 letters) and 15.0 % achieved visual improvement (gain of >=15 letters). The mean letter change at 12 months was +0.3 letters. Regression analysis showed that baseline BCVA and letter change at month 3 predicted visual acuity outcome at month 12 (baseline BCVA: t = 6.97, p < 0.001; letter change: t = 5.84, p < 0.01) but age, gender and eAMD in the fellow eye were not predictive. Finally, a decisional answer tree model demonstrated that letter change at month 3 was a strong predictor of visual outcome at month 12 with an overall accuracy of 69 %. We found that letter change from baseline at month 3 was strongly predictive of visual outcome at month 12. PMID- 23359133 TI - Fluffy white iris precipitates in Fuchs uveitis: a new sign for an old disease. AB - To describe particular iris precipitates in a series of five eyes from six patients with Fuchs uveitis (FU). Iris precipitates were noted by four independent examiners during routine physical examination of the angle by gonioscopy with Goldmann's three-mirror lens in patients with FU. The result was confirmed by examination, using the same method, of five other consecutive patients with FU and compared to 10 normal control eyes from five healthy individuals. Other causes of anterior uveitis were excluded. There were no iris precipitates in the healthy eyes. In eyes with FU, there were fluffy white iris precipitates, not visible by full-face examination or by classic slit-lamp examination. They were similar to keratic precipitates described in FU: starry, blurry and transparent with a tendency towards the white. Situated on the surface of the iris, they were visible only with the particular diffusion of the light from the gonioscopy's glass on the darkly pigmented iris of patients from North Africa. Fluffy white iris precipitates, seen in FU patients, appear to represent an additional clinical sign and may improve our diagnostic accuracy in this disease. Its visibility requires a specific technique during clinical examination. The validity of this new clinical sign based on this fact is yet to be determined. PMID- 23359134 TI - The use of Densiron-68TM as a perioperative surgical tool. AB - Agents such as Densiron-68TM, with specific gravity slightly greater than that of water (1.06 g/cm(3)), have been developed to tamponade the inferior retina following retinal detachment repair procedures. The minimal force that would result from the sinking of such an agent in balanced saline solution is not considered sufficient to permit the use of Densiron-68TM as a surgical tool to displace subretinal fluid and stabilise the retina perioperatively. We report five cases where Densiron-68TM was instilled directly into a saline-filled eye with an unstable retinal detachment. The detachment was reduced and the Densiron 68TM left in situ. Four cases involved giant retinal tears and the fifth an inferior retinal detachment with no breaks identified. The injection of Densiron 68TM as a single manoeuvre to flatten the retina and to simultaneously provide postoperative tamponade was successfully used in these five patients. Six months after removal of Densiron-68TM the retina remained flat in all five cases. This previously unfamiliar technique provides an additional surgical option to gain control in cases of complicated retinal detachment with a mobile retina, especially if inferior tamponade is required. PMID- 23359135 TI - Effect propagation in a toxicokinetic/toxicodynamic model explains delayed effects on the growth of unicellular green algae Scenedesmus vacuolatus. AB - Ecotoxicological standard tests assess toxic effects by exposing an organism to high concentrations over defined periods of time. To evaluate toxicity under field conditions such as fluctuating and pulsed exposures, process-based toxicokinetic/toxicodynamic (TK/TD) models may be used for extrapolation from the existing evidence. A TK/TD model was developed that simulates the effect on growth of the green algae Scenedesmus vacuolatus continuously exposed to the model chemicals norflurazon, triclosan, and N-phenyl-2-naphthylamine. A pharmacological time-response model describing the effects of anticancer treatments on cancer cell growth was adapted and modified to model the affected growth of synchronized algae cells. The TK/TD model simulates the temporal effect course by linking the ambient concentration of a chemical to the observable adverse effect via an internal concentration and a sequence of biological events in the organism. The parameters of the toxicodynamic model are related to the growth characteristics of algae cells, a no effect concentration, the chemical efficacy as well as the ability of recovery and repair, and the delay during damage propagation. The TK/TD model fits well to the observed algae growth. The effect propagation through cumulative cell damage explained the observed delayed responses better than just the toxicokinetics. The TK/TD model could facilitate the link between several effect levels within damage propagation, which prospectively may be helpful to model adverse outcome pathways and time-dependent mixture effects. PMID- 23359136 TI - Light-intensity physical activity is associated with insulin resistance in elderly Japanese women independent of moderate-to vigorous-intensity physical activity. AB - BACKGROUND: It is unclear whether light physical activity is beneficially associated with insulin resistance, similar to moderate and/or vigorous physical activity. This cross-sectional study was performed to determine the relationship between the amount of light physical activity, as determined with a triaxial accelerometer, and insulin resistance. METHODS: A total of 807 healthy men and women participated in this study. Physical activity was measured using a triaxial accelerometer worn for 28 days and summarized as light intensity (1.1-2.9 METs) or moderate to vigorous intensity (>= 3.0 METs). Insulin resistance was evaluated by HOMA_R (FPG [mg/dL] * IRI [MUU/mL]/405). RESULTS: The daily time spent in light physical activity was inversely associated with HOMA_R (r = -0.173, P < 0.05). After adjustment for confounders, the association between light physical activity and HOMA_R remained statistically significant (beta = -0.119, P < .05). Light physical activity remained significantly associated with HOMA_R following further adjustment for moderate to vigorous intensity activity (beta = -0.125, P < .05). Similar results were observed when light physical activity was modeled as quartiles, especially in elderly women. CONCLUSIONS: These cross-sectional data suggest that light-intensity physical activity is beneficially associated with insulin resistance in elderly Japanese women. PMID- 23359137 TI - Basal leptin regulates amino acid uptake in polarized Caco-2 cells. AB - Leptin is secreted by gastric mucosa and is able to reach the intestinal lumen where its receptors are located in the apical membrane of the enterocytes. We have previously demonstrated that apical leptin inhibits sugar and amino acids uptake in vitro and glucose absorption in vivo. Since leptin receptors are also expressed in the basolateral membrane of the enterocytes, the aim of the present work was to investigate whether leptin acting from the basolateral side could also regulate amino acid uptake. Tritiated Gln and beta-Ala were used to measure uptake into Caco-2 cells grown on filters, in the presence of basal leptin at short incubation times (5 and 30 min) and after 6 h of preincubation with the hormone. In order to compare apical and basal leptin effect, Gln and beta-Ala uptake was measured in the presence of leptin acting from the apical membrane also in cells grown on filters. Basal leptin (8 mM) inhibited by ~15-30% the uptake of 0.1 mM Gln and 1 mM beta-Ala quickly, after 5 min exposure, and the effect was maintained after long preincubation periods. Apical leptin had the same effect. Moreover, the inhibition was rapidly and completely reversed when leptin was removed from the apical or basolateral medium. These results extend our previous findings and contribute to the vision of leptin as an important hormonal signal for the regulation of intestinal absorption of nutrients. PMID- 23359138 TI - Periosteal versus true cross-sectional geometry: a comparison along humeral, femoral, and tibial diaphyses. AB - Cross-sectional geometric (CSG) properties of human long bone diaphyses are typically calculated from both periosteal and endosteal contours. Though quantification of both is desirable, periosteal contours alone have provided accurate predictions of CSG properties at the midshaft in previous studies. The relationship between CSG properties calculated from external contours and "true" (endosteal and periosteal) CSG properties, however, has yet to be examined along the whole diaphysis. Cross-sectional computed tomography scans were taken from 21 locations along humeral, femoral, and tibial diaphyses in 20 adults from a late prehistoric central Illinois Valley cemetery. Mechanical properties calculated from images with (a) artificially filled medullary cavities ("solid") and (b) true unaltered cross-sections were compared at each section location using least squares regression. Results indicate that, in this sample, polar second moments of area (J), polar section moduli (Z(p) ), and cross-sectional shape (I(max) /I(min) ) calculated from periosteal contours correspond strongly with those calculated from cross-sections that include the medullary cavity. Correlations are high throughout most of the humeral diaphysis and throughout large portions of femoral and tibial diaphyses (R(2) = 0.855-0.998, all P < 0.001, %SEE <= 8.0, %PE <= 5.0), the major exception being the proximal quarter of the tibial diaphysis for J and Z(p). The main source of error was identified as variation in %CA. Results reveal that CSG properties quantified from periosteal contours provide comparable results to (and are likely to detect the same differences among individuals as) true CSG properties along large portions of long bone diaphyses. PMID- 23359139 TI - Imbalance of desmoplastic stromal cell numbers drives aggressive cancer processes. AB - Epithelial tissues have sparse stroma, in contrast to their corresponding tumours. The effect of cancer cells on stromal cells is well recognized. Increasingly, stromal components, such as endothelial and immune cells, are considered indispensable for cancer progression. The role of desmoplastic stroma, in contrast, is poorly understood. Targeting such cellular components within the tumour is attractive. Recent evidence strongly points towards a dynamic stromal cell participation in cancer progression that impacts patient prognosis. The role of specific desmoplastic stromal cells, such as stellate cells and myofibroblasts in pancreatic, oesophageal and skin cancers, was studied in bio-engineered, physiomimetic organotypic cultures and by regression analysis. For pancreatic cancer, the maximal effect on increasing cancer cell proliferation and invasion, as well as decreasing cancer cell apoptosis, occurs when stromal (pancreatic stellate cells) cells constitute the majority of the cellular population (maximal effect at a stromal cell proportion of 0.66-0.83), accompanied by change in expression of key molecules such as E-cadherin and beta-catenin. Gene-expression microarrays, across three tumour types, indicate that stromal cells consistently and significantly alter global cancer cell functions such as cell cycle, cell cell signalling, cell movement, cell death and inflammatory response. However, these changes are mediated through cancer type-specific alteration of expression, with very few common targets across tumour types. As highlighted by these in vitro data, the reciprocal relationship of E-cadherin and polymeric immunoglobulin receptor (PIGR) expression in cancer cells could be shown, in vivo, to be dependent on the stromal content of human pancreatic cancer. These studies demonstrate that context-specific cancer-stroma crosstalk requires to be precisely defined for effective therapeutic targeting. These data may be relevant to non-malignant processes where epithelial cells interact with stromal cells, such as chronic inflammatory and fibrotic conditions. PMID- 23359141 TI - The effects of simvastatin on the serum concentrations of thyroid stimulating hormone and free thyroxine in hypothyroid patients treated with levothyroxine. AB - BACKGROUND: Statins, such as simvastatin, are the drugs of choice for the treatment of hypercholesterolemia. On the other hand hypercholesterolmia can occur in hypothyroid patients, who receive levothyroxine. There are few clinical case reports in regards to drug interaction between levothyroxine and lovastatin or simvastatin, indicating decreased levothyroxine effects. This study aimed at determining possible interaction between simvastatin and levothyroxine in hypothyroid patients by assessing serum levels of thyroid stimulating hormone (TSH) and free thyroxine (FT4), the two important laboratory indices for levothyroxine therapy. METHODS: In a cross sectional study, 41 eligible hypothyroid patients receiving levothyroxine (50-150 ug/d) were selected. Blood samples were taken before and after three months of simultaneous treatment with simvastatin (20 mg/d) and levothyroxine to determine the serum levels of TSH and FT4. RESULTS: There was no significant difference between the serum levels of TSH (P=0.77) or FT4 (P=0.76) before and after three months of simultaneous treatment. Also, there was no aggravation or initiation of any sign or symptom of hypothyroidism in the patients during the study period. CONCLUSION: Considering that FT(4) and TSH are the most reliable indicators for the levothyroxine treatment, the findings of the present study suggest that there may not be any significant interaction between simvastatin and levothyroxine. PMID- 23359140 TI - On the origin and destination of cancer stem cells: a conceptual evaluation. AB - Despite remaining uncertainties and ongoing research it is possible to draw up a model for the role of (cancer) stem cells in both the initiation and progression of cancer towards metastasis. The cancer stem cell of origin and the cancer stem cell are, despite phenotypic similarities, genotypically different entities. Given the right circumstances provided by a combination of genomic changes and biochemical and physical interactions with its microenvironment, an epithelial cancer cell may undergo a phenotypic epithelial mesenchymal transition (EMT) towards a cancer stem cell. This transition conveys upon the cell crucial stem cell-like abilities which facilitate migration into the blood circulation as an individual circulating tumor cell, survive there, and subsequently seed into organ tissue where, once more in close interaction with its microenvironment, the process of clonal self renewal may start, leading to a metastatic tumor. Both in the primary tumor as well as in the metastatic tumor, partial differentiation of the cancer stem cell progeny leads to phenotypic heterogeneity. Throughout this complex process of cancer metastasis similarities with the way stem cells function during embryonic development, including the signaling pathways that mediate these functions, are evident. Deeper insight in the EMT process, plasticity of the resulting cancer stem cells, and the role of cancer stem cells in the metastatic process is expected to lead to novel anti-metastatic cancer therapies. Emerging human in vitro cancer models in the form of "organ-on-a-chip" may contribute valuable novel research tools to achieve this aim. PMID- 23359142 TI - Reply: To PMID 22334567. PMID- 23359143 TI - Comparison of questionnaires used for the evaluation of patients with chronic pelvic pain. AB - AIMS: Comparison of questionnaires for the evaluation of symptoms and QoL in patients with CPPS. METHODS: The MPQ-DLV, PDI, NIH-CPSI, ICSI, and PUF, were compared for: pain, bladder complaints, and for QoL. RESULTS: The studied group N = 26 (male: 16; female: 10) showed a good distribution in gender for the age (MW U: P = 0.6) and BMI (MW-U: P = 0.5). The intraclass correlation (ICC) for pain intensity of MPQ-NWC and MPQ-PRIT was 0.55. The ICC's, for other different pain intensity scores were mostly <0.25 (global = 0.23). For bladder complaints a positive global score (ICC = 0.64) was shown, with the score for NIH-CPSI and ICSI > 0.77. The ICC for NIH-CPSI and PUF-SS was the lowest (=0.48). The QoL showed a global bad correlation (ICC <= 0.27) with MPQ-DLV-QoL/PDI, PDI/ICPI, PDI/PUF-BS and ICPI/PUF-BS scoring >0.5. CONCLUSION: When the most used questionnaires for QoL assessment in patients with CPPS are compared, very different results can be found. This indicates that results from one questionnaire cannot be used for overall conclusions concerning pain intensity and QoL. For bladder symptoms the results seem to correspond better. To develop one generally accepted questionnaire would facilitate the interpretation and comparison of data in this condition. PMID- 23359144 TI - Sluggish cognitive tempo in psychiatrically hospitalized children: factor structure and relations to internalizing symptoms, social problems, and observed behavioral dysregulation. AB - As research examining sluggish cognitive tempo (SCT) advances, it is important to examine the structure and validity of SCT in a variety of samples, including samples of children who are clinically-distressed but not referred specifically for attention-deficit/hyperactivity disorder (ADHD). The present study used a large sample of psychiatrically hospitalized children (N = 680; 73 % male; 66 % African American) between the ages of 6 and 12 to examine the latent structure of SCT, ADHD, oppositional defiant disorder (ODD), depression, and anxiety using confirmatory factor analysis (CFA). Results of the CFA analyses demonstrated that SCT is distinct from these other dimensions of child psychopathology, including ADHD inattention, depression, and anxiety. Regression analyses indicated that SCT symptoms were positively associated with depression and, to a lesser degree, anxiety. SCT symptoms were also positively associated with children's general social problems, whereas SCT symptoms were negatively associated with an observational measure of behavioral dysregulation (i.e., frequency of time-outs received as a part of a manualized behavior modification program). These associations were significant above and beyond relevant child demographic variables (i.e., age, sex, race), children's other mental health symptoms (i.e., ADHD, ODD, depression, anxiety symptoms), and, for all relations except child anxiety, parents' own anxiety and depression symptoms. PMID- 23359146 TI - Identification and analysis of precursors to invasive pancreatic cancer. AB - Precursor lesions of pancreatic cancer have been recognized about a century ago. The development of a consistent reproducible nomenclature and classification system for these lesions has been a major advance in the study of these noninvasive precursors. Pancreatic intraepithelial neoplasia (PanIN) as microscopic precursor lesions can be distinguished from mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMN) that are cystic and can often be recognized on imaging. Since precursor lesions harbor the unique chance to treat a patient before a fatal pancreatic cancer can arise a molecular characterization is essential to understand the biology and to find diagnostic and therapeutic targets to fight this disease of near uniform lethality. In order to study precursor lesions on a molecular level a meticulous isolation of the neoplastic cells is inevitable. We present the salient histopathologic and molecular features of precursor lesions of pancreatic cancer as well as methods that have proved to be useful within experimental studies. PMID- 23359145 TI - The association between sluggish cognitive tempo and academic functioning in youth with attention-deficit/hyperactivity disorder (ADHD). AB - The purpose of the study was to evaluate the relation between Sluggish Cognitive Tempo (SCT) and academic functioning in a sample of 52 adolescents (40 males, 12 females) with Attention-Deficit/Hyperactivity Disorder (ADHD; M age = 13.75). This study builds on prior work by utilizing an empirically-based and psychometrically validated measure of SCT, collecting ratings of SCT from both parents and teachers, and examining associations with multiple domains of academic functioning from both the parent and teacher perspective as well as grade point average (GPA). Both SCT and DSM-IV symptoms of inattention were significantly correlated with domains of academic functioning. Multiple regression analyses demonstrated that the parent-rated SCT Slow subscale predicted overall academic functioning, organizational skills impairment, and homework problems above and beyond ADHD symptoms and child and demographic characteristics known to be associated with academics, including intelligence, academic achievement, and family income. The teacher-rated SCT Low Initiation/Persistence subscale also predicted homework problems and was the only SCT variable to predict school grades above and beyond ADHD symptoms and relevant covariates. Both the SCT Slow and Low Initiation/Persistence subscales include items related to youth seeming apathetic, unmotivated, and lacking initiative, behaviors that are strongly related to ADHD symptoms of inattention but not currently captured by the DSM-IV. Implications of these findings towards supporting the external validity of the SCT construct are discussed along with potential implications for intervention. PMID- 23359147 TI - Tissue microarrays: construction and use. AB - Tissue microarrays (TMAs) enable high-throughput tissue analysis by selecting a large number of -paraffin-embedded donor tissue block cores and transferring these tissue cores into a positionally encoded array in the recipient TMA block. Once TMAs are constructed, a variety of analysis may be performed on the arrays including histochemical, immunohistochemical, or immunofluorescent staining, and in situ hybridization for DNA or RNA. TMAs offer a cost-effective method for performing parallel analysis of a large number of tissue samples. In this chapter we outline the method of TMA construction with an emphasis on providing useful information in the analysis of a variety of pancreatic neoplasms, including pancreatic adenocarcinomas and pre-invasive lesions. The technique of TMA construction in this chapter is restricted to the use of formalin-fixed paraffin embedded tissue. PMID- 23359148 TI - Immunohistochemistry of pancreatic neoplasia. AB - Immunohistochemistry (IHC) is a valuable tool to visualize the distribution and localization of specific cellular components within morphologically preserved tissue sections or cell preparations. It combines the histologic morphology of tissues for detecting the actual antigen distribution, specificity of antibody antigen interaction for optimal detection, and sensitivity of immunochemical methods for assessing the amount of antigen in tissues. It is routinely used clinically to diagnose type (benign or malignant), stage, and grade of cancer using specific tumor markers. The application of IHC ranges from disease diagnosis and prognosis to drug development and analysis of the pathobiological roles of various molecular players during disease development. Due to better availability of highly specific antibodies and optimal methodologies for performing immunohistochemical studies, IHC is being used at an expanding rate to understand pancreatic tumor biology as well as to study the fate of various molecular markers during the initiation, progression, and metastasis of pancreatic neoplasia. Herein, we describe the detailed protocol for IHC analyses of pancreatic intraepithelial neoplasia in tissues and fine needle aspirates from both human and mouse samples. PMID- 23359149 TI - A method for conducting highly sensitive microRNA in situ hybridization and immunohistochemical analysis in pancreatic cancer. AB - Profiling experiments in whole tissue biopsies have linked altered expression of microRNAs (miRNAs) to different types of cancer, including pancreatic ductal adenocarcinoma (PDAC). Emerging evidence indicates that altered miRNA expression can occur in different cellular compartments (cancer and non-cancer cells) in tumor lesions, and thus it is important to ascertain which specific cell type expresses a particulars miRNA in PDAC tissues. Here, we describe a highly sensitive fluorescence-based ISH method to visualize miRNA accumulation within individual cells in formalin-fixed paraffin-embedded (FFPE) tissue sections using 5' and 3' terminally fluorescein-labeled locked nucleic acid (LNA)-modified probes. We describe a multicolor ISH/IHC method based on sequential rounds of horseradish peroxidase (HRP)-mediated tyramide signal amplification (TSA) reactions with different in-house synthesized fluorochrome-conjugated substrates that enable co-detection of miRNAs, abundant noncoding RNAs and protein markers for signal quantification, and cell type co-localization studies in FFPE pancreatic tissue sections from clinical specimens and mouse models of PDAC. PMID- 23359150 TI - Optimal molecular profiling of tissue and tissue components: defining the best processing and microdissection methods for biomedical applications. AB - Isolation of well-preserved pure cell populations is a prerequisite for sound studies of the molecular basis of any tissue-based biological phenomenon. This updated chapter reviews current methods for obtaining anatomically specific signals from molecules isolated from tissues, a basic requirement for productive linking of phenotype and genotype. The quality of samples isolated from tissue and used for molecular analysis is often glossed over or omitted from publications, making interpretation and replication of data difficult or impossible. Fortunately, recently developed techniques allow life scientists to better document and control the quality of samples used for a given assay, creating a foundation for improvement in this area. Tissue processing for molecular studies usually involves some or all of the following steps: tissue collection, gross dissection/identification, fixation, processing/embedding, storage/archiving, sectioning, staining, microdissection/annotation, and pure analyte labeling/identification and quantification. We provide a detailed comparison of some current tissue microdissection technologies and provide detailed example protocols for tissue component handling upstream and downstream from microdissection. We also discuss some of the physical and chemical issues related to optimal tissue processing and include methods specific to cytology specimens. We encourage each laboratory to use these as a starting point for optimization of their overall process of moving from collected tissue to high quality, appropriately anatomically tagged scientific results. Improvement in this area will significantly increase life science quality and productivity. The chapter is divided into introduction, materials, protocols, and notes subheadings. Because many protocols are covered in each of these sections, information relating to a single protocol is not contiguous. To get the greatest benefit from this chapter, readers are advised to read through the entire chapter first, identify protocols appropriate to their laboratory for each step in their workflow, and then reread entries in each section pertaining to each of these single protocols. PMID- 23359151 TI - Considerations for sequencing analyses of pancreatic cancer progression and metastasis. AB - Sequencing analyses have been invaluable in identifying the genes associated with pancreatic -carcinogenesis. However, whereas gene discovery related to carcinogenesis can be fairly straightforward, there are several additional aspects of experimental design that need to be considered when performing genetic analyses of metastatic disease. This chapter aims to review these issues and provide examples of the types of data generated. PMID- 23359153 TI - Quantitative real-time PCR expression analysis of peripheral blood mononuclear cells in pancreatic cancer patients. AB - The ability of peripheral blood mononuclear cells (PBMCs) to act as a surrogate window into the presence and physiologic effects of pancreatic cancer is becoming increasingly apparent. In this chapter, we describe the techniques for isolation, lysis, RNA extraction, cDNA synthesis, and Q-RT PCR analysis of PBMCs as well as reasonable alternatives and the advantages and disadvantages of each. We further discuss the noteworthy considerations necessary for successful isolation and conversion of the high-quality PBMC RNA required to acquire interpretable and reproducible results for PBMC genetic expression analysis. PMID- 23359152 TI - DNA methylation analysis in human cancer. AB - The functional impact of aberrant DNA methylation and the widespread alterations in DNA methylation in cancer development have led to the development of a variety of methods to characterize the DNA methylation patterns. This chapter critiques and describes the major approaches to analyzing DNA methylation. PMID- 23359154 TI - Development of a cytokine-modified allogeneic whole cell pancreatic cancer vaccine. AB - Management of patients with pancreatic cancer is a multidisciplinary approach that presents enormous challenges to the clinician. Overall 5-year survival for all patients remains <3%. Symptoms of early pancreas cancer are nonspecific. As such, only a fraction of patients are candidates for surgery. While surgical resection provides the only curative option, most patients will develop tumor recurrence and die of their disease. To date, the clinical benefits of chemotherapy and radiation therapy have been important but have led to modest improvements. Tumor vaccines have the potential to specifically target the needle of pancreas cancer cells amidst the haystack of normal tissue. The discovery of pancreas tumor-specific antigens and the subsequent ability to harness this technology has become an area of intense interest for tumor immunologists and clinicians alike. Without knowledge of specific antigen targets, the whole tumor cell represents the best source of immunizing antigens. This chapter will focus on the development of whole tumor cell vaccine strategies for pancreas cancer. PMID- 23359155 TI - The prevention and genetics of pancreatic cancer: a programmatic approach. AB - Pancreatic cancer (PC) is typically a fatal disease due to its rapid growth and the lack of early diagnostic -techniques. Because approximately 10% of PCs are attributable to a hereditary susceptibility, identifying and studying patients with a family history of PC or known genetic predisposition to PC can improve the prevention, diagnosis, and treatment of PC. A skilled team of study investigators, physicians, genetic counselors, and data managers must work with patients and families to confidentially store and organize data from PC patients and high-risk patients. This data, collected in conjunction with patients' tissue and blood specimens, will contribute to the understanding of the biology, etiology, and epidemiology of PC, and can ultimately improve screening and management for patients with an underlying hereditary predisposition to PC. PMID- 23359156 TI - Development of orthotopic pancreatic tumor mouse models. AB - Genetically engineered mouse models of pancreatic cancer that recapitulate human pancreatic tumorigenesis have been established. However, the cost associated with generating and housing these mice can be -prohibitive. Tumor latency and progression to invasive diseases in these models are also highly variable. Xenograft mouse models of human pancreatic cancer including heterotopic and orthotopic have been widely used in preclinical studies for their comparatively low cost and rapid, predictable tumor growth. Of the two, orthotopic tumor mouse models are preferred because they offer tissue site-specific pathology, allow studies of metastasis, and are generally deemed more clinically relevant. Here we describe the procedures of implanting cancer cell lines to generate orthotopic mouse models for pancreatic cancer. PMID- 23359157 TI - Evaluating dietary compounds in pancreatic cancer modeling systems. AB - With the establishment of outstanding rodent models of pancreatic neoplasia and cancer, there are now systems available for evaluating the role diet, dietary supplements, and/or therapeutic compounds (which can be delivered in the diet) play in disease suppression. Several outstanding reports, which demonstrate clear inhibition or regression of pancreatic tumors following dietary manipulations, represent a noticeable advancement in the field by allowing for the contribution of diet and natural and synthetic compounds to be identified. The real goal is to provide support for translational components that will provide true chemoprevention to individuals at higher risk for developing pancreatic cancer. In addition, administration of molecules with proven efficacy in an in vivo system will screen likely candidates for future clinical trials. Despite this growing enthusiasm, it is important to note that the mere one-to-one translation of findings in rodent models to clinical outcomes is highly unlikely. Thus, careful consideration must be made to correlate findings in rodents with those in human cells with full disclosure of the subtle but often critical differences between animal models and humans. Additional concern should also be placed on the approaches employed to establish dietary components with real potential in the clinic. This chapter is focused on procedures that provide a systematic design for evaluating dietary compounds in cell culture and animal models to highlight which ones might have the greatest potential in people. The general format for this text is a stepwise use of fairly well-known approaches covered briefly but annotated with certain considerations for dietary studies. These methods include administration of a compound or a diet, measuring the cellular and molecular effects (histology, proliferation, apoptosis, RNA and protein expression, and signaling pathways), measuring the level of certain metabolites, and assessing the stability of active compounds. Though this chapter is divided into in vitro and in vivo sections, it is not an implication as to the order of experiments but an endorsement for utilizing human cells to complement work in a rodent modeling system. The notion that cell culture can provide the basis for further in vivo work is an attractive starting point, though the lack of a response in a single cell type should not necessarily prevent diet studies in rodents. The advantage of cell culture over animal models is the human origin of these cells and the ease and directness of manipulating a single cell type (particularly when exploring mechanism of action in that cell). Of course, the full effect of a diet, diet supplement, or therapeutic can only be wholly appreciated in an intact living organism with similar anatomical and physiological relevance. Thus, both approaches are considered in this chapter as each can provide unique strengths to determining the effectiveness of various dietary compounds or supplements on pancreatic neoplasia and cancer. PMID- 23359158 TI - Quantification of murine pancreatic tumors by high-resolution ultrasound. AB - Ultrasonography is a powerful imaging modality that enables noninvasive, real time visualization of abdominal organs and tissues. This technology may be adapted for use in mice through the utilization of higher frequency transducers, allowing for extremely high-resolution imaging of the mouse pancreas. This technique is particularly well suited to pancreas imaging due to the ultrasonographic properties of the normal mouse pancreas, easily accessible imaging planes for the head and tail of the mouse pancreas, and the comparative difficulty in imaging the mouse pancreas with other technologies. A suite of measurement tools is available to characterize the normal and diseased states of tissues. Of particular utility for cancer applications is the ability to use tomography to construct a 3D tumor volume, enabling longitudinal imaging studies to track tumor development, or response to therapies. Here, we describe a detailed method for performing high-resolution ultrasound to detect and measure pancreatic lesions in a genetically engineered mouse model of pancreatic ductal using the VisualSonics Vevo2100 High Resolution Ultrasound System. The method includes preparation of the animal for imaging, 2D and 3D image acquisition, and post-acquisition analysis of tumor volumes. The combined procedure has been utilized extensively by our group and others for the preclinical evaluation of novel therapeutic agents in the treatment of pancreatic ductal adenocarcinoma (Olive et al., Science 324:1457-1461, 2009; Cook et al., Methods Enzymol 439:73 85, 2008; Singh et al., Nat Biotechnol 28:585-593, 2010; Beatty et al., Science 331:1612-1616, 2011). PMID- 23359159 TI - Microdissection and culture of murine pancreatic ductal epithelial cells. AB - Given the complexity of morphological presentation and variability in clinical outcomes observed in -epithelial cancers, it is important to understand how genomic perturbations and resultant molecular aberrations lead to acquisition of tumorigenic phenotypes. Complex 3D epithelial culture systems provide investigators with the ability to propagate and manipulate primary cells in an appropriate physical setting in order to deconstruct the contribution of a given genetic lesion(s) to the process of cellular transformation. Pancreatic ductal epithelial cells (PDEC) can give rise to pancreatic intraepithelial neoplasia precursor lesions that precede pancreatic ductal adenocarcinoma (PDA). In this chapter, we describe a series of methods for derivation and culture of primary PDEC, which can be used to elucidate the mechanistic contribution of oncogenic insults to the initiation and progression of pancreatic tumorigenesis. PMID- 23359160 TI - Sphere-forming assays for assessment of benign and malignant pancreatic stem cells. AB - Sphere-forming assays are an in vitro technique to assay both normal and neoplastic cells for clonogenic growth potential. Currently, the identification of adult progenitors in the pancreas remains an area of intense investigation. The use of sphere-forming assays provides a critical step to identify new cell types in the pancreas that are capable of clonogenic growth and differentiation. In the field of cancer biology, cancer stem cells have been defined functionally by two major criteria: their ability to undergo self-renewal and their ability to produce differentiated progeny, two conditions which satisfy the criteria of stem cells. Here we briefly review both the capabilities of pancreatosphere and pancreatic tumorsphere assays, discuss important caveats regarding their use, and provide detailed protocols for the assay of both normal and neoplastic cells. PMID- 23359161 TI - Analysis of transplanted bone marrow-derived cells in chronic pancreatitis. AB - Pancreatic cancer is a uniformly lethal disease characterized by a strong stromal reaction called desmoplasia. Organ fibrosis is also a feature of chronic pancreatitis a known risk factor for pancreatic cancer. Here we describe a transplantation approach to investigate bone marrow-derived cells in murine models of chronic pancreatitis and pancreatic cancer. PMID- 23359162 TI - Analysis of the potential for pancreatic cancer metastasis in vitro and in vivo. AB - Pancreatic cancer remains a challenging disease, with an overall 5-year survival rate below 5%, the main reason being that it has an extremely high potential for invasion and metastasis. This potential may contribute to the fact that in more than three fourths of patients diagnosed with pancreatic cancer, it has already spread locally and to distant organs, precluding curative resection. Therefore, improved understanding of the mechanisms underlying pancreatic cancer metastasis is urgently needed. In this chapter, we describe our approaches to determining the metastatic potential of pancreatic cancer cells. Specifically, we report the details of these approaches, including in vitro assays of migration, invasion, adhesion, and angiogenesis and in vivo models of liver and lung metastasis and angiogenesis. PMID- 23359163 TI - The use of fluorescent probes in the study of reactive oxygen species in pancreatic cancer cells. AB - The use of fluorescent probes can be an easy and quick method to analyze whether or not reactive oxygen species (ROS) are involved in a particular cellular process or the result of a particular drug treatment. ROS activate a variety of cell signaling and death pathways including apoptosis and necrosis (Raha and Robinson. Am J Med Gen 106:62-70, 2001). Here we describe a number of different probes, their specificities, advantages and limitations, as well as useful techniques important for their use. PMID- 23359164 TI - Analysis of tumor-associated mucin glycotopes by Western transfer methods. AB - In mucins, glycosylation is complex and the most predominant posttranslational modification. Since mucins exhibit differential glycosylation pattern under physiological and pathological conditions, analysis of mucin glycans is important for understanding their specific functions during pathological conditions like cancer. Given the complexity of mucin glycans, several sophisticated analytical tools such as HPLC, mass spectrometry, and lectin sandwich assays are employed for glyco-analysis of mucins. However the specialized expertise and instrumentation required for such analysis are beyond the reach of an average cancer biology laboratory. We described in this chapter the utility of the simple electrophoresis/immunoblotting method to examine the mucin glycan epitopes, using specific antibodies and lectins. PMID- 23359165 TI - Evaluating tumor angiogenesis. AB - The evaluation of tumor angiogenesis in pancreatic cancers involves determining the status of tumor vasculature and hypoxia in the tumor. Describing the nature and extent of tumor angiogenesis involves evaluating the expression of endothelial and perivascular cells within the tumor, and the expression of angiogenesis-related genes in tumor vasculature. Here we describe the methodology for assessment of tumor vasculature in murine mouse models of cancer. Specifically, we provide methodology for the evaluation of tumor hypoxia, tumor vessel perfusion, and chromogenic and fluorescent immunohistochemistry applied to tumor vascular analysis. PMID- 23359166 TI - Pooled shRNA screenings: experimental approach. AB - RNA interference (RNAi) has emerged as a powerful genetic strategy to functionally interrogate the entire genome by loss-of-function studies. In the last years, several arrayed shRNA libraries that can silence almost all the human genome have been developed. The generation of new and more efficient shRNA plasmids has allowed performing genetic screens in a pooled fashion and provides the opportunity to investigate the entire genome finding relevant genes to any biological process. In this chapter, the pipeline and methods to perform a pooled shRNA screen are discussed. PMID- 23359167 TI - Pooled shRNA screenings: computational analysis. AB - Genome-wide RNA interference screening has emerged as a powerful tool for functional genomic studies of disease-related phenotypes and the discovery of molecular therapeutic targets for human diseases. Commercial short hairpin RNA (shRNA) libraries are commonly used in this area, and state-of-the-art technologies including microarray and next-generation sequencing have emerged as powerful methods to analyze shRNA-triggered phenotypes. However, computational analysis of this complex data remains challenging due to noise and small sample size from such large-scaled experiments. In this chapter we discuss the pipelines and statistical methods of processing, quality assessment, and post-analysis for both microarray- and sequencing-based screening data. PMID- 23359168 TI - Author response to: Sleep and beverage drinking among Thai college students. PMID- 23359169 TI - Strategies for developing and delivering a parental physical activity intervention: answers to the what and how. AB - BACKGROUND: Parents are at risk for physical inactivity; however, few studies have designed physical activity (PA) interventions specifically applied to individuals with young children. To ensure the effectiveness of interventions, it may be useful to first elicit the needs from the target population and incorporate salient strategies identified to the design and delivery of a resultant intervention. We aimed to explore strategies for what to include in and how to best deliver a program designed to increase parental PA. METHODS: Twelve parents (6 mothers, 6 fathers) of children younger than 5 years participated in focus group discussions exploring strategies for an intervention program designed to increase parental PA. RESULTS: A range of themes such as Focus on the Children and Flexible Life/Family Plans imbedded in strategies such as persuasion and information, problem-solving, skill building, and environmental approaches were identified. In addition, a range of strategies for how to best deliver a parental PA intervention evidenced in emerging themes such as Diverse and Brief and Individualized Approach was discussed. CONCLUSIONS: Future research should continue to adopt a ground up, community-based approach to the development and implementation of interventions for this at-risk group to ensure sustained involvement in regular PA. PMID- 23359170 TI - Radiotherapy alone versus radiochemotherapy in patients with stage IIIA adenocarcinoma (ADC) of the lung. AB - PURPOSE: To evaluate the outcome of radiotherapy (RT) versus radiochemotherapy (RT-CHT) in patients with locally advanced (stage III) inoperable adenocarcinoma of the lung. PATIENTS AND METHODS: 146 patients with these characteristics were among 600 patients enrolled into five prospective trials and were treated with either hyperfractionated (Hfx) RT (64.8 and 69.6 Gy using 1.2 Gy bid) alone (n = 33) or with Hfx RT (64.8 and 69.6 Gy using 1.2 Gy bid and 67.6 Gy using 1.3 Gy bid) and concurrent carboplatin-etoposide or paclitaxel-carboplatin (n = 113). RESULTS: The median times and 5-year overall survival (OS), local progression free survival (LPFS) and the distant metastasis-free survival (DMFS) rates for all 146 patients were 17, 20 and 20 months, respectively, and 15, 26 and 33, respectively. RT-CHT was superior to RT alone in terms of both OS (MST 19 vs. 12 months, respectively, 5-year OS 18 vs. 6 %, respectively; p = 0.003) and LPFS (MTLP 21 vs. 15 months, respectively, 5-year LPFS 28 vs. 0 %; p = 0.06), but not the DMFS (p = 0.43). In all 146 patients, the most frequent acute high-grade toxicity was esophageal, bronchopulmonary and hematological (each 12 %), while the most frequent late high-grade toxicity was bronchopulmonary (4 %) and esophageal (3 %). RT-CHT caused significantly more frequent acute high-grade (>3) esophageal (15 %), and hematological (15 %), while late high-grade toxicity was similar between RT and RT-CHT groups of patients. CONCLUSION: RT-CHT achieved excellent results (MST 19 months, 5-year survival 18 %) in this patient population accompanied with low toxicity, comparing favorably to results of other similar studies. PMID- 23359171 TI - An update on molecularly targeted therapies in second- and third-line treatment in non-small cell lung cancer: focus on EGFR inhibitors and anti-angiogenic agents. AB - Docetaxel, pemetrexed and epidermal growth factor receptor tyrosine kinase inhibitors (gefitinib and erlotinib) are recommended second-line therapy for advanced non-small cell lung cancer (NSCLC) patients with disease progression. Although erlotinib is the only recommended third-line therapy, several drugs are being used in the clinic. Recent studies have focused on combining targeted agents with approved therapies, including broad-spectrum multikinase inhibitors targeting multiple ErbB Family receptors and multitargeted anti-angiogenic agents targeting the vascular endothelial growth factor receptor, platelet-derived growth factor receptor and fibroblast growth factor receptor pathways. Here, we review targeted therapies that are being evaluated in second- and third-line settings in NSCLC, including the ErbB Family Blocker afatinib (BIBW 2992), multityrosine kinase inhibitors (pelitinib [EKB-56]), neratinib [HKI-272], canertinib [CI-1033], lapatinib [GW-572016], dacomitinib [PF-299804]) and multitargeted anti-angiogenic agents (vandetanib [ZD6474], sunitinib [SU11248], sorafenib [BAY43-9006], nintedanib [BIBF1120], axitinib [AG-013736], cediranib [AZD2171], motesanib [AMG 706], linifanib [ABT869] and pazopanib [GW786034]). PMID- 23359172 TI - The clinical implication of tumoral Gal-1 expression in laryngeal squamous cell carcinomas. AB - PURPOSE: To explore the expression of tumoral Gal-1 in association with clinical parameters and outcome in a large population with laryngeal squamous cell carcinomas (LSCCs). METHODS: A total of 187 patients with LSCC were retrospectively enrolled. Immunohistochemistry was performed to evaluate the tumoral expression of Gal-1, apoptosis-related proteins and the density of tumor infiltrating lymphocytes (TILs) in tumor tissues before any intervene. Survival curves were estimated by the Kaplan-Meier method, and differences in survival between groups were determined using the log-rank test. Prognostic effects were evaluated by Cox regression analysis. RESULTS: A total of 102 carcinomas (54.5 %) were identified as high Gal-1 expression, and 85 carcinomas (45.5 %) as low expression. Tumoral Gal-1 expression was not significantly related with clinical stage and histology differentiation. No correlation of Gal-1 expression with apoptosis-related protein was identified. Instead, Gal-1 status was correlated positively with the ratio of FOXP3(+)/CD8(+) TILs (P = 0.024). In multivariate regression analysis, advanced clinical stage and the presence of metastases were identified as the independent predictors for poor survival in entire cohort. Especially, the statistical correlation between the Gal-1 expression and prognosis was particularly due to the late-stage tumors (P < 0.05). CONCLUSION: Current results represent valuable advancements in Gal-1 research and provided further support for using Gal-1 as a diagnostic biomarker and immunotherapeutic target for LSCC. PMID- 23359173 TI - The expression of Nek7, FoxM1, and Plk1 in gallbladder cancer and their relationships to clinicopathologic features and survival. AB - PURPOSE: Gallbladder carcinoma (GC) is generally considered as a relatively rare malignancy with poor prognosis. In order to guide clinicians in selecting suitable treatment for GC patients, reliable markers predictive of poor clinical outcome are desirable. This study analyzed the expression of Polo-like kinase 1 (Plk1), Nima related kinases 7 (Nek7) and Forkhead box M1 (FoxM1) in GC tissues and their relationship to clinicopathologic features and survival. METHODS: We immunohistochemically investigated the 76 specimens of gallbladder carcinoma, pericarcinoma and normal tissues using Nek7, FoxM1 and Plk1 antibodies and analyzed the overall survival time of these 76 patients. RESULTS: There were significant correlations between the high level expression of Nek7, FoxM1 and Plk1 and the tumor differentiation, Nevin staging and metastasis. The high level expression of Nek7, FoxM1 and Plk1 was significantly associated with shorter overall survival time in univariate analysis (log-rank test), also identified as an independent prognostic factor in multivariate analysis. CONCLUSION: Nek7, FoxM1 and Plk1 were significantly associated with certain clinicopathologic indices in GC. Evaluation of Nek7, FoxM1 and Plk1 expression may be an important factor in identifying a group of poor GC prognosis. PMID- 23359174 TI - Lung adenocarcinoma in the era of targeted therapies: histological classification, sample prioritization, and predictive biomarkers. AB - The arrival of targeted therapies has presented both a conceptual and a practical challenge in the treatment of patients with advanced non-small cell lung carcinomas (NSCLCs). The relationship of these treatments with specific histologies and predictive biomarkers has made the handling of biopsies the key factor for success. In this study, we highlight the balance between precise histological diagnosis and the practice of conducting multiple predictive assays simultaneously. This can only be achieved where there is a commitment to multidisciplinary working by the tumor board to ensure that a sensible protocol is applied. This proposal for prioritizing samples includes both recent technological advances and the some of the latest discoveries in the molecular classification of NSCLCs. PMID- 23359175 TI - Do comorbidity influences acute toxicity and outcome in elderly patients with endometrial cancer treated by adjuvant radiotherapy plus brachytherapy? AB - PURPOSE: To correlate comorbidity and acute radiation toxicity in elderly patients treated with adjuvant external beam radiotherapy (EBRT) plus brachytherapy-high dose rate (HDR-BRT) for endometrial cancer (EC). METHODS: Endometrial cancer patients over 65 were treated and evaluated for comorbidity assessment with ACE-27 and Charlson comorbidity index (CCI). EBRT total dose was 45-50.4 Gy (1.8 Gy/day). The vault vagina boost of dose was performed by HDR-BRT with 2/3 fractions with a total dose of 10-15 Gy. RESULTS: From 2008 to 2011, 35 patients were analyzed. Eighteen patients (51.43 %) had not ACE-27 comorbidity; while 27 patients (77.14 %) had CCI lower than three. During treatment, acute toxicity was mild and not influenced by the comorbidity score. Two-year Progression Free and Overall Survival were 69 and 80 %. ACE-27 and CCI did not affect progression-free survival (p = 0.51, p = 0.3) and OS (p = 0.26, p = 0.5). CONCLUSION: External beam radiotherapy plus BRT-HDR are well tolerated in EC elderly with good performance status and low comorbidity profile. PMID- 23359176 TI - Prognostic factors for acute toxicity in prostate cancer patients treated with high-dose hypofractionated radiotherapy. AB - PURPOSE: To prospectively study acute genitourinary (GU) and gastrointestinal (GI) toxicity during hypofractionated radiotherapy. PATIENTS AND MATERIALS: One hundred and seventy-one consecutive men with cT1-T3cN0cM0 prostate cancer were treated at 2.6 Gy/fraction to a total dose of 67.6 for low risk (EQD2 = 79 Gy) and 70.2 Gy for intermediate-high risk (EQD2 = 82 Gy) over 5.2-5.4 weeks (alpha/beta 1.5). Acute toxicity was scored according to RTOG/EORTC toxicity extended criteria after completing a 22-item questionnaire (basal, weekly, at 6 months). RESULTS: Minimum and median follow-up were 36 and 54.2 months, respectively. GU toxicity grades 0, 1, 2 and 3 were found in 30.4, 37, 32 and 0.6 % of patients, respectively. The figures for grades 0, 1, 2 and 3 GI toxicity were 66, 24, 10 and 0 %. The highest degree of acute reactions was reached at 4-5 weeks. At 6 months, 15 % of patients had GU toxicity (11 % grade 1, 4 % grade 2) and 5.8 % GI toxicity (5.3 % grade 1, 0.5 % grade 2). Multivariate analysis shows that bladder volume receiving >=65 Gy (V 65) is associated with an increased risk of GU complications (p = 0.017, HR = 1.143, 95 % CI = 1.025-1.276), while history of TURP is linked to lower risk (p = 0.002, HR = 0.310, 95 % CI 0.004-0.370). Mean rectal dose (p = 0.013, HR = 1.089, 95 % CI 1.018-1.116) and total dose (p = 0.019, HR = 0.734, 95 % CI 0.567-0.950) are significantly related to GI toxicity. CONCLUSIONS: This 5-week dose-escalation hypofractionated radiotherapy schedule that uses 3D-conformal radiotherapy without IGRT has resulted in <1 % grade 3 acute complications. Our study suggests that reducing the mean rectal dose and the bladder V 65 helps prevent acute toxicity. TURP before radiotherapy was associated with lower acute GU toxicity. PMID- 23359177 TI - Unsuspected gallbladder carcinoma discovered during or after cholecystectomy: focus on appropriate radical re-resection according to the T-stage. AB - BACKGROUND: The long-term survival of patients with unsuspected gallbladder carcinoma (UGC) and the role of radical re-resection for this disease remain unclear. METHODS: A retrospective study was carried out on 38 UGC patients. The time-to-event data were demonstrated by Kaplan-Meier curves. Comparing survival curves of two groups using the log-rank test. RESULTS: The overall incidence of UGC in patients underwent cholecystectomy in our hospital was 0.18 % (25 of 14,073). Distribution according to actual pT-stage (the UICC) was: pT1a: n = 3; pT1b: n = 11; pT2: n = 4; pT3: n = 12; pT4: n = 8. The preoperative diagnosis included a high rate of acute biliary tract inflammation (24 of 38, 63.2 %). Compared with other gallbladder carcinoma patients, UGC group had significantly higher proportion of early stages (pT1) (36.8 %, 14 of 38 cases) (p < 0.01), and better prognosis. The comparison of radical re-resection versus simple cholecystectomy showed a significant benefit in overall survival for the pT3 group (22.0 +/- 5.48 vs. 5.0 +/- 0.9 months; p = 0.02). There are median survival differences between the two subgroups of patients with pT1b tumors whether received re-resection or not. Median survival was 62.0 months and 24.0 +/- 8.5 months, respectively, though the differences are not statistically significant (p = 0.131). CONCLUSION: Radical re-resection is strongly recommended for patients with pT1b-stage cancer. The reoperation should be performed as soon as possible, preferably within 10 days after the initial operation. PMID- 23359178 TI - Cisplatin plus oral vinorelbine as first-line treatment for advanced non-small cell lung cancer: a prospective study confirming that the day-8 hemogram is unnecessary. AB - INTRODUCTION: Cisplatin plus oral vinorelbine, one of the standard treatments for metastatic non-small-cell lung cancer (NSCLC), is associated with a high rate of neutropenia, and a hemogram is performed on day 8. We analyzed the oncologists' opinions and the result of the hemogram on day 8 to address the question of whether this hemogram could be avoided. MATERIALS AND METHODS: Fifty-eight chemotherapy-naive, advanced NSCLC patients were included. Each received intravenous doses of 75 mg/m(2) cisplatin on day 1 plus oral vinorelbine [60 mg/m(2) in the first cycle (80 mg/m(2) in subsequent cycles) on days 1 and 8], every 3 weeks, for a maximum of six cycles. RESULTS: Out of 257 cycles analyzed, oral vinorelbine was administered on day 8 in 214 (83.2 %) and the dose was canceled in 6 cycles (2.3 %) due to hematological toxicity. On analyzing the patients to whom chemotherapy had been administered on day 8, based on medical opinion without the doctor knowing the hemogram result, we found that the cycle had been administered with a hemogram showing fewer than 1,500 * 10(6) neutrophils in only 3 of the 185 evaluable cycles [event rate of 1.6 %, with confidence interval 95 % = (0.34-4.67 %)]. CONCLUSION: The hemogram on day 8 can be avoided and oral vinorelbine administered in relative safety in patients with good performance status, when confirmed by the clinician's perception, thereby making this regimen more comfortable for the patient. This is the first prospective study to examine this issue. PMID- 23359179 TI - Phase II trial of sequential subcutaneous interleukin-2 plus interferon alpha followed by sorafenib in renal cell carcinoma (RCC). AB - PURPOSE: Immunotherapy (IL-2 and INF-alpha) was the treatment of choice for advanced renal cell carcinoma (RCC) until antiangiogenic therapy with tyrosin kinase inhibitors was developed in the early 2000s. This clinical trial explored the efficacy and toxicity of sequential treatment of IL-2 plus INF-alpha followed by sorafenib. METHODS: Eligibility criteria included measurable, non-resectable, histologically confirmed predominantly clear cell RCC, no prior systemic treatment, and ECOG PS 0-2. The treatment regimen was a 6-week cycle of subcutaneous IL-2 at 9 * 10(6) IU on days 1-6 of weeks 1, 2, 4 and 5 plus s.c. INF-alpha at 6 * 10(6) IU on days 1, 3 and 5 of weeks 1-6. Responders received 6 additional weeks of this regimen. All patients received oral sorafenib (400 mg bid) after immunotherapy until disease progression. The primary endpoint was progression-free survival. RESULTS: Forty-one patients were enrolled, median age 57 years. ECOG was 0/1 in 17/20 patients, 35 patients had prior nephrectomy and 18 patients pure clear cell cancer. Median PFS was 7.4 months (95 % CI 6.5-13.1) and OS was 16.6 months (95 % CI not reached). In 36 patients evaluable for response, ORR was 44.4 % and control rate was 94.4 %. Most adverse events (AEs) were Grade 1 or 2 toxicities (84.7 %). During immunotherapy the most common AEs were pyrexia (82.9 %), asthenia (56.1 %) and anorexia (46.3 %), whereas during sorafenib were diarrhoea (48.8 %) and hand-foot syndrome (46.3 %). CONCLUSIONS: A sequential regimen of IL-2 and INF-alpha followed by sorafenib showed effectiveness and manageable toxicity in patients with advanced RCC. PMID- 23359180 TI - Clinical target volume definition for glioblastoma radiotherapy planning: magnetic resonance imaging and computed tomography. AB - PURPOSE: To assess the differences between the target delineation using computed tomography (CT) and imaging fusion CT/magnetic resonance imaging (MRI) for the radiotherapy planning of glioblastoma. METHODS: One hundred-twenty gross tumor volume and clinical target volume on CT and MRI (GTVCT/CTVCT, GTVMRI/CTVMRI, respectively) were contoured and evaluated. The treatments planning (total dose 60 Gy) based on CTVCT were analysed in terms of percentage of CTVCT and CTVMRI receiving 95 % of the prescribed dose (V95-CTVCT, V95-CTVMRI). RESULTS: GTVs and CTVs contoured on MRI were significantly larger than those delineated on CT (p = 0.0003, p = 0.0006, respectively). Nighty-two percent of CTVCT was coincident with the CTVMRI and 8 % was normal tissue; 20 % of CTVMRI, considered as tumor volume, was not included on CTVCT. The V95-CTVMRI was significantly lower than the V95-CTVCT (p = 0.0005). CONCLUSIONS: In the delineation of glioblastoma target volume, fusion CT/MRI was preferred. The CT only is insufficient for the CTV dose coverage. PMID- 23359181 TI - Panitumumab and irinotecan every 3 weeks is an active and convenient regimen for second-line treatment of patients with wild-type K-RAS metastatic colorectal cancer. AB - PURPOSE: To evaluate the efficacy and safety profile of the combination of panitumumab and irinotecan every 3 weeks in a phase II trial as second-line treatment in patients with advanced wild-type (WT) K-RAS colorectal cancer (CRC). METHODS: Fifty-three patients received 9 mg/kg of panitumumab followed by 350 mg/m(2) of irinotecan every 21 days until disease progression, unacceptable toxicity or consent withdrawal. RESULTS: Median age of patients included was 67 years. All patients had previously received 5-fluorouracil, 84 % oxaliplatin and 8 % irinotecan as first-line treatment. Patients received a median of five infusions of panitumumab and irinotecan. On an intention-to-treat analysis, 12 patients (23 %) achieved partial responses and 22 patients (41 %) achieved disease stabilization. Median progression-free survival and overall survival were 4.5 and 15.1 months, respectively. The most frequent treatment-related severe toxicities per patient were diarrhoea (35.8 %), followed by skin rash (32.1 %), asthenia (18.9 %) and neutropenia (13.2 %). A significant association between clinical response and incidence and grade of skin toxicity was observed (p = 0.0032). CONCLUSION: This study shows that the administration of panitumumab plus irinotecan every 3 weeks is safe, active and feasible as second-line treatment in patients with advanced WT K-RAS CRC. PMID- 23359182 TI - Carnosol, radiation and melanoma: a translational possibility. AB - PURPOSE: To compare the genoprotective and radioprotective effect of carnosol (COL) against damage induced by ionizing radiation with similar effects produced by different antioxidant compounds. METHODS: The genoprotective effect was studied by means of the micronucleus test for antimutagenic activity in which the reduction in the frequency of micronuclei was evaluated in cytokinesis-blocked cells of human lymphocytes. The radioprotective effects were studied by cell viability test (MTT) in PNT2 (normal prostate) and B16F10 (melanoma) cell lines when they were administered before exposure to different X-ray doses (4, 6, 8, 10 and 0 Gy). RESULTS: Carnosol shows a significant genoprotective capacity (p < 0.001) against radiation with a protection factor of 50 %, and a dose-reduction factor of 4.3. Cell survival obtained with COL administered before exposure to 10 Gy of X-rays showed a protection factor of 55.1 %, eliminating 39 % of radiation induced cell death in normal epithelial cells of prostate (PNT2) (p < 0.001). However, in the melanoma cell lines (B16F10) assayed, COL acted not as a radioprotector, but as a sensitizing agent increasing the cellular death by 34 % (p < 0.01) and producing an enhancement ratio of 2.12. CONCLUSIONS: Carnosol may be developed as a radioprotective agent in the non-tumoral cells. However, in the B10F16 melanoma cells, melanogenesis is activated by COL leading to redistribution of the enzymatic balances of glutathione and cysteine-lyase production, which could compromise the intracellular redox defence system. This effect appears as an increase in the capacity of ionizing radiation-induced damage, and thus exhibits a paradoxical protective effect of COL on melanoma cells. PMID- 23359183 TI - Beam angle selection for intensity-modulated radiotherapy (IMRT) treatment of unresectable pancreatic cancer: are noncoplanar beam angles necessary? AB - BACKGROUND AND PURPOSE: External beam radiation therapy with concurrent chemotherapy (CRT) is widely used for the treatment of unresectable pancreatic cancer. Noncoplanar (NCP) 3D conformal radiotherapy (3DCRT) and coplanar (CP) IMRT have been reported to lower the radiation dose to organs at risk (OARs). The purpose of this article is to examine the utility of noncoplanar beam angles in IMRT for the management of pancreatic cancer. MATERIALS AND METHODS: Sixteen patients who were treated with CRT for unresectable adenocarcinoma of the pancreatic head or neck were re-planned using CP and NCP beams in 3DCRT and IMRT with the Varian Eclipse treatment planning system. RESULTS: Compared to CP IMRT, NCP IMRT had similar target coverage with slightly increased maximum point dose, 5,799 versus 5,775 cGy (p = 0.008). NCP IMRT resulted in lower mean kidney dose, 787 versus 1,210 cGy (p < 0.0001) and higher mean liver dose, 1,208 versus 1,061 cGy (p < 0.0001). Also, NCP IMRT resulted in similar mean stomach dose, 1,257 versus 1,248 cGy (p = 0.86) but slightly higher mean small bowel dose, 981 versus 866 cGy (p < 0.0001). CONCLUSIONS: The NCP IMRT was able to significantly decrease bilateral kidney dose, but did not improve other dose-volume criteria. The use of NCP beam angles is preferred only in patients with risk factors for treatment-related kidney dysfunction. PMID- 23359184 TI - Resveratrol induces apoptosis of pancreatic cancers cells by inhibiting miR-21 regulation of BCL-2 expression. AB - OBJECTIVE: Resveratrol is an edible polyphenolic phytoalexin present in different plant species and plays important role in inhibiting proliferation and inducing apoptosis of pancreatic cancer cells. In this paper, the mechanism of resveratrol on PANC-1, CFPAC-1 and MIA Paca-2 cells apoptosis was examined. METHODS: We first evaluated the effect of resveratrol on viability of PANC-1, CFPAC-1 and MIA Paca 2 cells using MTT assay. Next, we performed real-time PCR to assess the effect of resveratrol on miR-21 expression. We also used Western blot to measure BCL-2 protein levels after down-regulation of miR-21 expression. Finally, we evaluated the effect of miR-21 on resveratrol-induced anti-tumor activity using miR-21 mimic. RESULTS: Resveratrol induced a significant inhibition of PANC-1, CFPAC-1 and MIA Paca-2 cells viability in a dose-dependent manner. Resveratrol also decreased the expression of miR-21. Besides, down-regulation of miR-21 expression can inhibit BCL-2 expression in PANC-1, CFPAC-1 and MIA Paca-2 cells. Over expression of miR-21 expression can reverse down-regulation of BCL-2 expression and apoptosis induced by resveratrol. CONCLUSIONS: In this study, we demonstrated that the effect of resveratrol on apoptosis is due to inhibiting miR-21 regulation of BCL-2 expression. PMID- 23359186 TI - Clinical research in individual information of celiac artery CT imaging and gastric cancer surgery. AB - OBJECTIVE: The objective of this study is to acquire CT images of the celiac artery by 64-multi-slice spiral CT angiography (64-MSCTA) in gastric cancer patients to facilitate gastric cancer surgery. METHODS: Preoperative 64-MSCTA was performed to observe the origin, course and anatomical variations of the celiac artery and vascular calcifications in 102 gastric cancer patients. RESULTS: (1) The celiac trunk mostly arose at the level between the 12th thoracic vertebra and the 1st lumbar vertebra; the mean inferior angle with the abdominal aorta was 63.5 degrees (14 degrees -159 degrees ), the mean length was 36.29 mm (5.80 73.58 mm), and its course showed many styles. (2) Of 102 gastric cancer patients, 34 patients (33.33 %) were observed with celiac artery variations of whom there were 27 patients with anatomical variations of the hepatic artery, 3 patients with anatomical variation of the left gastric artery and 1 patient with anatomical variation of the splenic artery; in 1 patient, the celiac trunk and the superior mesenteric artery originated from a common trunk. In other cases, it was observed with another variation. (3) The abdominal aortic calcified plaque was observed in 48 patients (47.1 %), and among them, 34 patients were more than 60 years old, and the existence of the abdominal aortic calcified plaque was related to age, significantly (P < 0.01). CONCLUSIONS: The 64-MSCTA largely improves our understanding of the origin, course and anatomical variations of the celiac artery and vascular calcifications in individual patient with gastric cancer. It is recommended that the 64-MSCTA of the celiac artery should be classified as a routine preoperative procedure in gastric cancer patients. PMID- 23359185 TI - Selections of appropriate regimen of high-dose chemotherapy combined with adoptive cellular therapy with dendritic and cytokine-induced killer cells improved progression-free and overall survival in patients with metastatic breast cancer: reargument of such contentious therapeutic preferences. AB - BACKGROUND: We hypothesized that combination of dendritic cell (DC) with autologous cytokine-induced killer (CIK) immunotherapy in setting of high-dose chemotherapy (HDC) would be effective for selected metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: Our previous work showed thiotepa could eradicate breast cancer stem cells. From 2004 to 2009, 79 patients received standard dose chemotherapy (SDC) of 75 mg/m(2) docetaxel and 75 mg/m(2) thiotepa versus 87 patients of HDC + DC/CIK: 120 mg/m(2) docetaxel to mobilize peripheral CD34(+) progenitor cells, a sequence of HDC (120 mg/m(2) docetaxel, plus 175 mg/m(2) thiotepa) + DC/CIK, with or without 400 mg/m(2) carboplatin depending upon bone marrow function. The endpoints were response rates (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: Compared with SDC, PFS and OS were improved in HDC + DC/CIK (median PFS 10.2 vs. 3.7 months, P < 0.001; median OS 33.1 vs. 15.2 months, P < 0.001). Patients of pre-menopausal, HDC as first line treatment after metastasis, or with visceral metastasis showed prolonged PFS and OS. SDC group also achieved the similar response as previous reports. CONCLUSION: Our study demonstrated the novel combination of HDC with DC/CIK to be an effective choice for the selected MBC population, in which choosing appropriate chemo regimens played important roles, and also specific HDC regimen plus DC/CIK immunotherapy showed the clinical benefits compared with chemotherapy alone. PMID- 23359189 TI - Serum vaspin may be a good indicator of fibrosis in chronic hepatitis C and is not altered by antiviral therapy. AB - Vaspin was found to modulate insulin resistance (IR) and to inhibit proinflammatory and profibrogenic agents. The aim of the study was to evaluate vaspin serum concentration prior to and after antiviral treatment and to assess its relationship with morphological alterations, IR and response to antiviral therapy. The study encompassed 75 non-obese, non-diabetic chronic hepatitis C (CHC) patients, 30 of whom underwent antiviral treatment. Serum vaspin levels decreased in CHC patients and was positively associated with fibrosis stage (r = 0.44, p = 0.001). Serum vaspin was significantly higher in patients with septal fibrosis/cirrhosis or periportal fibrosis compared to those with portal fibrosis or without fibrosis (F3-4 vs. F2 vs. F1 vs. F0, p = 0.012). A marked increase in the serum vaspin level occurred in patients with periportal or more advanced fibrosis (F0-1 vs. F2-4, p < 0.001). Serum vaspin levels were also positively related to steatosis grade (r = 0.32, p = 0.03). Antiviral therapy did not change serum vaspin levels, irrespective of its efficiency. Our study showed that the serum vaspin level is decreased in CHC patients with non-advanced fibrosis, but the virus seems to have no direct effect on this finding. Progressive fibrosis is associated with rise of the vaspin level and this adipokine may serve as a predictor of advanced liver fibrosis. PMID- 23359187 TI - Radiosensitization by gold nanoparticles. AB - Recent years brought increasing use of gold nano particles (GNP) as a model platform for interaction of irradiation and GNPs aiming radiosensitization. Endocytosis seems to be one of the major pathways for cellular uptake of GNPs. Internalization mechanism of GNPs is likely receptor-mediated endocytosis, influenced by GNP size, shape, its coating and surface charging. Many showed that DNA damage can occur as a consequence of metal-enhanced production of low energy electrons, Auger electrons and alike. Kilovoltage radiotherapy (RT) carries significantly higher dose enhancement factor (DEF) that is observed with megavoltage irradiations, the latter usually been at the order of 1.1-1.2. Higher gold concentrations seem to carry higher risk of toxicity, while with lower concentrations the DEF can be reduced. Adding a chemotherapeutic agent could increase level of enhancement. Clinical trials are eagerly awaited with a promise of gaining more knowledge deemed necessary for more successful transition to widespread clinical practice. PMID- 23359190 TI - Impact of COX-2, IL-1beta, TNF-alpha, IL-4 and IL-10 on the process of carcinogenesis in the large bowel. AB - In recent years there have been many intensive studies on the molecular mechanisms involving the carcinogenesis of colorectal cancer (CRC). An inflammatory process and genetics play the key role in neoplasia of CRC. Currently, there are two known pathways of CRC carcinogenesis, such as the adenoma and the serrated adenoma, which are referred to as "classic" and "alternative", respectively. Among all the components of the inflammatory process, the proinflammatory and anti-inflammatory cytokines play a major role as a factor influencing the process of malignant transformation. In our study we focused on key inflammatory factors such as cytokines interleukin (IL)-10, IL 1beta, IL-4, tumor necrosis factor alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) in adenomas, serrated adenomas, hyperplastic polyps, adenocarcinomas and normal mucosa. Our study confirmed the hypothesis that inflammation has a major effect on carcinogenesis of CRC. Our studies also showed the difference in carcinogenesis of CRC. It showed a greater effect of the inflammatory process in carcinogenesis of CRC by a "serrated" (alternative) way as compared to the classic way. In a serrated way all the inflammatory factors had a higher expression. It might suggest that effectiveness of cancer prevention with the use of NSAIDs has a greater impact in patients whose tumors were formed in an alternative way. Additionally, it also showed that the inflammatory process has no influence on the final form of cancer. PMID- 23359188 TI - CUG-binding protein 1 (CUGBP1) expression and prognosis of non-small cell lung cancer. AB - BACKGROUND AND AIMS: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. As CUGBP1 may also play a great role in tumor genesis and deterioration, the purpose of this study was to detect the expression of CUGBP1 mRNA and CUGBP1 and assess the prognostic significance of CUGBP1 in NSCLC. METHODS: Expression of CUGBP1 mRNA and CUGBP was detected by Semi-quantitative PCR and Immunohistochemistry, respectively, from 57 NSCLC patients. The percentage of CUGBP1 mRNA and CUGBP1 expression was correlated with clinical characteristics using chi (2) test. The prognostic significance was assessed by univariate and multivariate analyses in the Cox hazard model. RESULTS: The expression of CUGBP1 mRNA and CUGBP1 was over-expressed in cancer group and was correlated with TNM stage and Differentiation. By both univariate and multivariate survival analyses, CUGBP1 expression (P = 0.0074, HR = 3.701, 95 % CI 1.420-9.648), TNM-stage (HR = 4.043, 95 % CI 2.098-7.794) and age (HR = 3.207, 95 % CI 1.544-6.664) were noted to be independent indicators of a shorter postsurgical survival. CONCLUSIONS: The expression of CUGBP1 independently predicted a shorter postsurgical survival in NSCLC. PMID- 23359191 TI - Expression of ER/PR/HER2, basal markers and adhesion molecules in primary breast cancer and in lymph nodes metastases: a comparative immunohistochemical analysis. AB - The immunophenotypic differences between primary and metastatic tumour cells could influence patient's treatment or/and the results of selected diagnostic procedures. That prompted us to investigate potential differences between primary tumours and corresponding synchronous lymph node metastases in the T ? 1/N+/M0 breast cancer patients. The investigated group consisted of 108 patients with invasive ductal breast cancer, who underwent radical surgery. The expression of ER, PR, HER2 as well as CK5/6, P-cadherin, EGFR and Ep-CAM was assessed immunohistochemically. Our data suggest that ER, PR, HER2, EGFR and CK5/6 are expressed conservatively, with some minor changes between primary tumour and simultaneous lymph node metastases. On the contrary, Ep-CAM and P-cadherin immunoreactivity in primary and metastatic cells varied significantly. This variation might exclude Ep-CAM and P-cadherin as potential diagnostic or therapeutic targets. PMID- 23359192 TI - Microvascular density and mast cells in benign and malignant pheochromocytomas. AB - Pheochromocytomas, uncommon adrenal tumors, have an uncertain behavior. Recently, PASS criteria were proposed for differentiating between benign and malignant cases. These are not perfect, however. The aim of the study was to investigate angiogenesis and mast cell density in context of the clinical behavior and morphologic characteristics of pheochromocytomas. Mean intratumoral chymase positive cell count was 14.50 for malignant, 15.73 for benign cases; mean subcapsular chymase positive cell count was 12.50 for malignant, 11.27 for benign cases. Mean intratumoral tryptase positive cell count was 17.50 for malignant and 17.91 for benign cases; mean subcapsular tryptase positive cell count was 15.25 for malignant and 15.73 for benign cases. Mean intratumoral CD31 positive vessel count was 46.98 for malignant and 51.02 for benign cases; mean subcapsular CD31 positive vessel count was 44.86 for malignant and 39.81 for benign cases. Mean intratumoral CD105 positive vessel count was 37.84 for malignant and 35.95 for benign cases; mean subcapsular CD105 positive vessel count was 26.36 for malignant and 22.03 for benign cases. The differences between benign and malignant cases were not significant. All the vascular counts were correlated with mast cells counts. PASS index was inversely correlated with mast cell counts. PMID- 23359193 TI - Effects of nitric oxide synthase inhibitor (L-NAME) on cytopathologic changes due to cholestasis in hepatic cells of adult male rats. AB - Obstructive cholestasis is associated with overproduction of endogenous opioids, nitric oxide (NO) and cytokines in the blood stream. Nitro-L-arginine methyl ester (L-NAME) administration decreases the NO serum level and it is able to reduce related complications. The aim of this research is to survey the effects of the NO inhibitor on complications relating to cholestasis in liver cells and intrahepatic biliary ducts. We used five groups of animals: control, sham operated (surgical control), bile duct ligated (BDL) group, BDL and normal saline infused group, and BDL with L-NAME administrated group. After 3 weeks all animals were killed, histopathology of liver cells and intrahepatic biliary ducts were evaluated by hematoxylin-eosin (HE), PAS (periodic acid-Schiff) and trichrome staining. The status of inflammation and fibrosis was evaluated by the modified Knodell score system. Microscopic study of different groups showed that the necro-inflammatory score in the control group was 0.36, it was 1 in the sham operated group and it raised to 15.2 in the cholestatic group. After administration of L-NAME it had a meaningful decrease to 7, but in the saline treated group, the score was 16. L-NAME with the mentioned dose was capable of decreasing the serum nitric oxide level, although it is able to decrease the unfavorable complications of cholestatic jaundice. PMID- 23359194 TI - Allicin has significant effect on autoimmune anti-islet cell antibodies in type 1 diabetic rats. AB - The research purpose was to experimentally investigate the effect of allicin administration on the levels of main type 1 diabetes (IDDM) autoantibodies which are anti-islet cell antibodies (ICA) with an attempt to find a relation between this immunological effect and histological and/or biochemical findings. We have evaluated, with the help of ELISA kits, the levels of ICA and serum insulin in male Sprague-Dawley rats with Streptozotocin-induced IDDM in addition to pancreatic histological findings. The four groups (6 rats each) under study received or not different intraperitoneal doses of allicin for a period of 30 days. Daily intraperitoneal administration of allicin (either at as low dose of 8 mg/kg or high dose of 16 mg/kg) for up to 30 days to type 1 diabetic rats effectively reduces levels of anti-islet cell antibodies and in addition, reduced the level of insulin due to damaged Langerhans islet cell was significantly increased in the serum due to a repairing tissue process in pancreatic tissues. These experimental results suggest that allicin treatment has a therapeutic protective effect against autoimmune reactions occurring in IDDM. The data may provide new strategies for using allicin to be recommended as an excellent candidate in the clinical management, control, and prevention of IDDM. PMID- 23359195 TI - Evaluation of serum concentrations of vascular endothelial growth factor (VEGF) in breast cancer patients. AB - The aim of the study was to assess the value of vascular endothelial growth factor (VEGF) measurements in breast cancer patients with respect to recognized clinicopathological prognostic factors. The study was conducted in 87 women with histologically confirmed breast cancer who underwent surgical treatment and 37 healthy women. Vascular endothelial growth factor concentration levels in the blood samples of patients were correlated with the size of the primary tumor, lymph nodes in the armpit, cancer stage, histological type, grading, multifocality, status of estrogen and progesterone receptors and HER-2 protein expression. Statistical analysis did not show any correlation between concentrations of VEGF and any of the selected parameters. The comparison of VEGF concentrations showed a slightly raised level of VEGF in women with the disease as opposed to the healthy subjects but the differences were not statistically significant (p = 0.472). Similar results were obtained for marker CEA (p = 0.09), while the level of Ca 15-3 in both groups differed significantly (p < 0.001) reaching higher values in the patients with diagnosed breast cancer. Vascular endothelial growth factor concentrations in breast cancer patients do not correlate with recognized clinicopathological prognostic factors and CEA and Ca 15-3 markers, which does not preclude the potential role of VEGF as an independent prognostic factor. PMID- 23359196 TI - Rare association of polyneuropathy and Crohn's disease: a clinicopathological study of 4 cases. AB - The purpose of this study is to investigate the clinical, electrophysiological and pathological features of neuropathy in patients with Crohn's disease. Biopsies were selected from over 700 sural nerve biopsies. The diagnosis of Crohn's disease was based on established clinicopathological criteria. Complete laboratory, clinical, electrophysiological and pathological studies were performed in all cases. Nerve biopsies of 4 patients were diagnosed as neuropathy and Crohn's disease. Distal symmetrical sensorimotor polyneuropathy was the pattern of neuropathy. The pathological features were mixed, demyelination with predominant axonal degeneration and a varying pattern of myelinated fiber loss. There were no vasculitic changes found. We conclude that patients with Crohn's disease are complicated frequently with polyneuropathy, and as remission depends on immunosuppressive therapy, it is important to recognise it in the early stage. The diagnosis of polyneuropathy is based on clinical and electrophysiological studies, but precise histology, immunohistochemistry and morphometric studies of the peripheral nerve biopsy may be decisive in establishing the diagnosis. PMID- 23359197 TI - CD34+ fibroblast-like cells in the interstitial infiltrates in glomerulonephritis - an immunohistochemical observation. AB - CD34 cells in the interstitial infiltrates in glomerulonephritis (GN) could be the turning point between regenerative processes and interstitial fibrosis. The aim of our study was to assess the presence of CD34+ cells in the interstitial infiltrates in GN. A cross-sectional study of 33 patients with glomerulonephritis, mean age: 43.3 +/-11.31 years, 20 male and 13 female, was conducted. Conventional stains, as well as immunohistochemistry for the CD34 antigen were employed on kidney biopsies. Strength of immunohistochemical reaction was assessed semi-quantitatively. Regarding the percentage of cases with CD34+ cells in the interstitial infiltrates out of 33 patients: cells of interstitial infiltrates were 27.3% positive. The percentage of cases showing CD34+ cells at the level of interstitial infiltrates was: 44.4% in FSGS, 14.3% in membranoproliferative GN, 28.6% in membranous nephropathy, 20% in mesangial proliferative GN, 0% in minimal change disease, and 50% in crescentic GN. With the exception of minimal change disease, CD34+ cells were found in the interstitial infiltrates in all histopathological forms of GN. Some of these cells were spindle-shaped fibroblast-like cells. As inflammation in the tubulointerstitial compartment either resolves or proceeds to fibrosis, aims at reversing this process will benefit from analyses of the interstitial infiltrates harboring CD34+ cells. PMID- 23359198 TI - Expression of Ki-67 (MIB-1) and GLUT-1 proteins in non-advanced prostatic cancer. AB - The expression of Ki-67 (MIB-1) and glucose transporter-1 (GLUT-1) were evaluated in patients with clinically localized prostate cancer (PC) who had undergone radical prostatectomy with curative intent. 140 low advanced PC specimens were studied. Protein expression was assessed immunohistochemically on tumour sections and expressed as a labelling index, i.e. the percentage of positively stained cells. In the case of Ki-67 nuclear staining and in the case of GLUT-1 membrane and cytoplasmic staining was considered as positive. The patients' mean age was 62.9 +/-6.2 years. There were 13 (9.3%) at pTNM stage 1, 78 (55.7%) at stage 2, 40 (28.6%) at stage 3 and 9 (6.4%) at stage 4, respectively. 75 (53.6%) tumours were well differentiated (Gleason score <=6), 52 (37.1%) moderately differentiated (Gleason score of 7) and 13 (9.3%) poorly differentiated (Gleason score 8-10). The mean pre-operative serum PSA was 9.9 +/- SE 0.5 ng/ml, and the mean LI was equal to 8.1 +/-0.6% and 29.7 +/-2.0%, for MIB-1 and GLUT-1, respectively. Increase of pathological tumor volume and tumor grade was associated with statistically significant growth of PSA (p < 0.011) and MIB-1LI (p < 0.003), however, for GLUT-1 LI the relation was not significant. Ki-67 expression was correlated with PSA levels (p = 0.013) and GLUT-1 scores (p = 0.04). In PC, an increase in the proliferation rate (higher MIB-1LI) in higher pTNM stages and tumour grades may point to Ki-67 as a good marker of biological aggressiveness useful in selecting patients for more aggressive treatment. A correlation between proliferation and GLUT-1 score may be the evidence of active glycolytic metabolism in hypoxic regions. PMID- 23359199 TI - Association between MDM2 SNP309 polymorphism and endometrial cancer risk in Polish women. AB - The prognostic value of the MDM2 gene amplification/expression in many types of cancer remains unclear. Polymorphisms in the promoter region of the MDM2 gene have been shown to alter the protein expression and thus, may play a role in carcinogenesis. The aim of the present study was to evaluate the association between the risk of endometrial cancer and SNP309 polymorphisms in the MDM2 gene. The genotype analysis of SNP309 MDM2 gene polymorphisms in 152 endometrial cancer patients and 100 controls of cancer-free subjects, in the Polish population, was performed using the PCR-based restriction fragment length polymorphism (PCR-RFLP). In the presented study, an association between MDM2 SNP309 polymorphisms and the incidence of endometrial cancer was identified. Our results obtained for the SNP309 polymorphisms of the MDM2 gene indicated that both the G/G genotype and the G allele are strongly associated with endometrial cancer. We did not observe any relationship between gene polymorphism and endometrial cancer progression assessed by FIGO grade. This is the first study linking single nucleotide polymorphisms of the MDM2 gene with endometrial cancer incidence in the population of Polish women. The results support the hypothesis that the SNP309 polymorphism of the MDM2 gene may be associated with the incidence of endometrial cancer in the female population. PMID- 23359200 TI - Carcinoma breast metastasis to the suprarenal gland: an unusual presentation. PMID- 23359201 TI - Expression of p21 is dependent on or independent of p53 in carcinoma ex pleomorphic adenoma (undifferentiated and adenocarcinoma types). AB - Our study is aimed to characterize alteration in the immunohistochemical expression of p21 and p53 in normal tissue of the salivary gland surrounding carcinoma arising in pleomorphic adenoma, and the tumor cells of carcinoma arising in pleomorphic adenoma as well as to identify whether the induction of expression p21 is dependent on or independent of p53 in carcinoma arising in pleomorphic adenoma. A selected series of 27 cases of carcinoma ex pleomorphic adenoma (undifferentiated and adenocarcinoma types) was examined. The results showed that p21 and p53 expression was negative in the most components of normal tissue of the salivary gland surrounding carcinoma arising in pleomorphic adenoma. p21 was strongly expressed in carcinoma cells in 9 (33.3%) cases out of 27. p53 was strongly expressed in carcinoma cells in 10 (37%) cases out of 27. Also a co-expression of p21 and p53 showed negative nuclear staining in 9 cases, while 8 cases expressed positive staining. p21 expressed negative nuclear staining in 4 cases but p53 expressed positive staining in the same cases. p21 expressed positive nuclear staining in 6 cases but p53 expressed negative nuclear staining in the same cases. Our data suggest that inactivation of p53 and p21 may play an important role in the evolution of carcinoma ex pleomorphic adenoma. Also p21 behaves as dependent on or independent of p53 in carcinoma arising in pleomorphic adenoma. PMID- 23359202 TI - Antitumor actions of human mast cells. PMID- 23359204 TI - Goblet cell carcinoid of the vermiform appendix - a case report. AB - Goblet cell carcinoid (GCC) is a rare neuroendocrine tumor of the vermiform appendix with uncertain clinical behavior. It was first described by Gagne and Subbuswamy in 1969 and 1974, respectively. The tumor occurs almost exclusively in the vermiform appendix. We present a case of a 60-year-old female, who was referred to the Bielanski Hospital with signs and symptoms of acute appendicitis. Microscopic examination of the appendix showed features of acute appendicitis, however scattered groups of cells with clear cytoplasm as well as strands of single cells with no evidence of atypia were seen. The patient underwent a right hemicolectomy due to the diagnosis of GCC. PMID- 23359205 TI - Gene copy-number polymorphism caused by retrotransposition in humans. AB - The era of whole-genome sequencing has revealed that gene copy-number changes caused by duplication and deletion events have important evolutionary, functional, and phenotypic consequences. Recent studies have therefore focused on revealing the extent of variation in copy-number within natural populations of humans and other species. These studies have found a large number of copy-number variants (CNVs) in humans, many of which have been shown to have clinical or evolutionary importance. For the most part, these studies have failed to detect an important class of gene copy-number polymorphism: gene duplications caused by retrotransposition, which result in a new intron-less copy of the parental gene being inserted into a random location in the genome. Here we describe a computational approach leveraging next-generation sequence data to detect gene copy-number variants caused by retrotransposition (retroCNVs), and we report the first genome-wide analysis of these variants in humans. We find that retroCNVs account for a substantial fraction of gene copy-number differences between any two individuals. Moreover, we show that these variants may often result in expressed chimeric transcripts, underscoring their potential for the evolution of novel gene functions. By locating the insertion sites of these duplicates, we are able to show that retroCNVs have had an important role in recent human adaptation, and we also uncover evidence that positive selection may currently be driving multiple retroCNVs toward fixation. Together these findings imply that retroCNVs are an especially important class of polymorphism, and that future studies of copy-number variation should search for these variants in order to illuminate their potential evolutionary and functional relevance. PMID- 23359206 TI - Timing of hepatectomy in resectable synchronous colorectal liver metastases (SCRLM): Simultaneous or delayed? AB - The optimal surgical strategy for treatment of patients with synchronous colorectal liver metastases (SCLRM) remains controversial. We conducted a systematic review and meta-analysis of all observational studies to define the safety and efficacy of simultaneous versus delayed resection of the colon and liver. A search for all major databases and relevant journals from inception to April 2012 without restriction on languages or regions was performed. Outcome measures were the primary parameters of postoperative survival, complication, and mortality, as well as other parameters of blood loss, operative time, and length of hospitalization. The test of heterogeneity was performed with the Q statistic. A total of 2,880 patients were included in the meta-analysis. Long-term oncological pooled estimates of overall survival (hazard ratio [HR]: 0.96; 95% confidence interval [CI]: 0.81-1.14; P = 0.64; I(2) = 0) and recurrence-free survival (HR: 1.04; 95% CI: 0.76-1.43; P = 0.79; I(2) = 53%) all showed similar outcomes for both simultaneous and delayed resections. A lower incidence of postoperative complication was attributed to the simultaneous group as opposed to that in the delayed group (modified relative ratio [RR] = 0.77; 95% CI: 0.67 0.89; P = 0.0002; I(2) = 10%), whereas in terms of mortality within the postoperative 60 days no statistical difference was detected (RR = 1.12; 95% CI: 0.61-2.08; P = 0.71; I(2) = 32%). Finally, selection criteria were recommended for SCRLM patients suitable for a simultaneous resection. CONCLUSION: Simultaneous resection is as efficient as a delayed procedure for long-term survival. There is evidence that in SCRLM patients simultaneous resection is an acceptable and safe option with carefully selected conditions. Due to the inherent limitations of the present study, future randomized controlled trials will be useful to confirm this conclusion. (HEPATOLOGY 2013;57:2346-2357). PMID- 23359208 TI - Anacardic acid (6-pentadecylsalicylic acid) induces apoptosis of prostate cancer cells through inhibition of androgen receptor and activation of p53 signaling. AB - Anacardic acid (AA) is a mixture of 2-hydroxy-6-alkylbenzoic acid homologs. It is widely regarded as a non-specific histone acetyltransferase inhibitor of p300. The effects and the mechanisms of AA in LNCaP cells (prostate cancer cells) remain unknown. To investigate the effect of AA on LNCaP cells, we had carried out several experiments and found that AA inhibits LNCaP cell proliferation, induces G1/S cell cycle arrest and apoptosis of LNCaP cell. The mechanisms via which AA acts on LNCaP cells may be due to the following aspects. First, AA can regulate p300 transcription and protein level except for its mechanisms regulating function of p300 through post-translational modification in LNCaP cells. Second, AA can activate p53 through increasing the phosphorylation of p53 on Ser15 in LNCaP cells. AA can selectively activate p21 (target genes of p53). Third, AA can down-regulates androgen receptor (AR) through supressing p300. Our study suggests that AA has multiple anti-tumor activities in LNCaP cells and warrants further investigation. PMID- 23359207 TI - Regulation of HGF expression by DeltaEGFR-mediated c-Met activation in glioblastoma cells. AB - The hepatocyte growth factor receptor (c-Met) and a constitutively active mutant of the epidermal growth factor receptor (DeltaEGFR/EGFRvIII) are frequently overexpressed in glioblastoma (GBM) and promote tumorigenesis. The mechanisms underlying elevated hepatocyte growth factor (HGF) production in GBM are not understood. We found higher, coordinated mRNA expression levels of HGF and c-Met in mesenchymal (Mes) GBMs, a subtype associated with poor treatment response and shorter overall survival. In an HGF/c-Met-dependent GBM cell line, HGF expression declined upon silencing of c-Met using RNAi or by inhibiting its activity with SU11274. Silencing c-Met decreased anchorage-independent colony formation and increased the survival of mice bearing intracranial GBM xenografts. Consistent with these findings, c-Met activation by DeltaEGFR also elevated HGF expression, and the inhibition of DeltaEGFR with AG1478 reduced HGF levels. Interestingly, c Met expression was required for DeltaEGFR-mediated HGF production, anchorage independent growth, and in vivo tumorigenicity, suggesting that these pathways are coupled. Using an unbiased mass spectrometry-based screen, we show that signal transducer and activator of transcription 3 (STAT3) Y705 is a downstream target of c-Met signaling. Suppression of STAT3 phosphorylation with WP1193 reduced HGF expression in DeltaEGFR-expressing GBM cells, whereas constitutively active STAT3 partially rescued HGF expression and colony formation in c-Met knockdown cells expressing DeltaEGFR. These results suggest that the c-Met/HGF signaling axis is enhanced by DeltaEGFR through increased STAT3-dependent HGF expression and that targeting c-Met in Mes GBMs may be an important strategy for therapy. PMID- 23359209 TI - Opportunities for promoting youth physical activity: an examination of youth summer camps. AB - BACKGROUND: Youth summer camp programs have the potential to provide opportunities for physical activity, but little to no research has been conducted to determine activity levels of campers. This study aimed to examine physical activity occurring in day and resident summer camps and how activity levels differed in these camps based upon demographic characteristics. METHODS: Pedometer data were collected during hours of camp operation from 150 day campers and 114 resident campers between the ages of 8 and 12 years old. Independent t tests were used to compare physical activity by sex, race, and Body Mass Index. RESULTS: Campers at day camps averaged 11,916 steps per camp day, while resident campers averaged 19,699 steps per camp day. Day campers averaged 1586 steps per hour over 7.5 hour days and resident campers averaged 1515 steps per hour over 13 hour days. Male sex, Caucasian race, and normal Body Mass Index were significant correlates of more physical activity. CONCLUSIONS: Youth summer camps demonstrate the potential to provide ample opportunities for physical activity during the summer months. Traditional demographic disparities persisted in camps, but the structure of camp programs should allow for changes to increase physical activity for all participants. PMID- 23359210 TI - Culture modifies expectations of kinship and sex-biased dispersal patterns: a case study of patrilineality and patrilocality in tribal Yemen. AB - Studies of the impact of post-marital residence patterns on the distribution of genetic variation within populations have returned conflicting results. These studies have generally examined genetic diversity within and between groups with different post-marriage residence patterns. Here, we directly examine Y chromosome microsatellite variation in individuals carrying a chromosome in the same Y haplogroup. We analyze Y chromosome data from two samples of Yemeni males: a sample representing the entire country and a sample from a large highland village. Our results support a normative patrilocality in highland Yemeni tribal populations, but also suggest that patrilocality is violated often enough to break down the expected correlation of genetic and geographic distance. We propose that a great deal of variation in male dispersal distance distributions is subsumed under the "patrilocal" label and that few human societies are likely to realize the idealized male dispersal distribution expected under strict patrilocality. In addition, we found almost no specific correspondence between social kinship and genetic patriline at the level of the clan (large, extended patrilineal kinship group) within a large, highland Yemeni village. We discuss ethnographic accounts that offer several cultural practices that explain exceptions to patrilocality and means by which social kinship and genetic patriline may become disentangled. PMID- 23359211 TI - Fentanyl-associated fatalities among illicit drug users in Wayne County, Michigan (July 2005-May 2006). AB - BACKGROUND: During the summer of 2005, multiple cities in the United States began to report outbreaks of fentanyl-associated fatalities among illicit drug users. The objectives of this study were to (1) determine if an outbreak of fentanyl associated fatalities occurred in mid-2005 to mid-2006 and (2) to examine trends and compare features of fentanyl-contaminated heroin-associated fatalities (FHFs) with non-fentanyl, heroin-associated fatalities (NFHFs) among illicit drug users. METHODS: Baseline prevalence of fentanyl- and heroin-associated deaths was estimated from January to May 2005 based on recorded cause of death (determined by the medical examiner (ME)) using the Wayne County, MI, USA toxicology database. The database was then queried for both FHFs and NFHFs between July 1, 2005 and May 12, 2006. A FHF was defined as having fentanyl or norfentanyl (metabolite) detected in any postmortem biological sample and either (1) detection of heroin or its metabolite (6-acetylmorphine) and/or cocaine or its metabolite (benzoylecgonine) in a postmortem biological specimen or (2) confirmation of fentanyl abuse as the cause of death by the ME or a medical history available sufficient enough to exclude prescription fentanyl or other therapeutic opioid use. A NFHF was defined as detection of heroin, 6 acetylmorphine (heroin metabolite) or morphine in any postmortem biological specimen, heroin overdose listed as the cause of death by the ME, and absence of fentanyl detection on postmortem laboratory testing. Information was systematically collected, trended for each group and then compared between the two groups with regard to demographic, exposure, autopsy, and toxicology data. Logistic regression was performed using SAS v 9.1 examining the effects of age, gender, and marital status with fentanyl group status. RESULTS: Monthly prevalence of fentanyl-associated fatalities among illicit drug users increased from an average of two in early 2005 to a peak of 24 in May, 2006. In total, 101 FHFs and 90 NFHFs were analyzed. The median age of decedents was 46 and 45 years for the fentanyl and non-fentanyl groups, respectively. Fentanyl-contaminated heroin-associated fatalities (FHFs) were more likely to be female (p = 0.003). Women aged over 44 years (OR = 4.67;95 % CI = 1.29-16.96) and divorced/widowed women (OR = 14.18;95 % CI = 1.59-127.01) were more likely to be FHFs when compared to women aged less than 44 years and single, respectively. A significant interaction occurred between gender and age, and gender and marital status. Most FHFs had central (heart) blood samples available for fentanyl testing (n = 96; 95 %): fentanyl was detected in most (n = 91; 95 %). Of these, close to half had no detectable heroin (or 6-acetylmorphine) concentrations (n = 37; 40.7 %). About half of these samples had detectable cocaine concentrations (n = 20; 54 %). Median fentanyl concentration in central blood samples was 0.02 MUg/ml (n = 91, range <0.002-0.051 MUg/ml) and 0.02 MUg/ml (n = 32, range <0.004-0.069 MUg/ml) in peripheral blood samples. The geometric mean of the ratio of central to peripheral values was 2.10 (median C/P = 1.75). At autopsy, pulmonary edema was the most frequently encountered finding for both groups (77 %). CONCLUSION: Illicit drugs may contain undeclared ingredients that may increase the likelihood of fatality in users. Gender differences in fentanyl-related mortality may be modified by age and/or marital status. These findings may help inform public health and prevention activities if fatalities associated with fentanyl contaminated illicit drugs reoccur. PMID- 23359212 TI - Towards a naturalistic brain-machine interface: hybrid torque and position control allows generalization to novel dynamics. AB - Realization of reaching and grasping movements by a paralytic person or an amputee would greatly facilitate her/his activities of daily living. Towards this goal, control of a computer cursor or robotic arm using neural signals has been demonstrated in rodents, non-human primates and humans. This technology is commonly referred to as a Brain-Machine Interface (BMI) and is achieved by predictions of kinematic parameters, e.g. position or velocity. However, execution of natural movements, such as swinging baseball bats of different weights at the same speed, requires advanced planning for necessary context specific forces in addition to kinematic control. Here we show, for the first time, the control of a virtual arm with representative inertial parameters using real-time neural control of torques in non-human primates (M. radiata). We found that neural control of torques leads to ballistic, possibly more naturalistic movements than position control alone, and that adding the influence of position in a hybrid torque-position control changes the feedforward behavior of these BMI movements. In addition, this level of control was achievable utilizing the neural recordings from either contralateral or ipsilateral M1. We also observed changed behavior of hybrid torque-position control under novel external dynamic environments that was comparable to natural movements. Our results demonstrate that inclusion of torque control to drive a neuroprosthetic device gives the user a more direct handle on the movement execution, especially when dealing with novel or changing dynamic environments. We anticipate our results to be a starting point of more sophisticated algorithms for sensorimotor neuroprostheses, eliminating the need of fully automatic kinematic-to-dynamic transformations as currently used by traditional kinematic-based decoders. Thus, we propose that direct control of torques, or other force related variables, should allow for more natural neuroprosthetic movements by the user. PMID- 23359213 TI - Maintenance Therapy for NSCLC: Consensus and Controversy. AB - Nowadays, advanced non-small cell lung cancer (NSCLC) is still an incurable disease. However, recent researches on maintenance therapy have led to considerable progress. Recently, pemetrexed and erlotinib have been approved for maintenance chemotherapy by both the U.S. Food and Drug Administration and European Medicines Agency. However, there are not adequate data to support the maintenance therapy as the standard treatment for advanced NSCLC and there has been no conclusive predictor of who will get benefit from maintenance chemotherapy and what type of maintenance, continuation or switch, is preferred. This article reviews the main studies on maintenance therapy of advanced NSCLC and discusses the results available to date. PMID- 23359214 TI - Comparison of brachial artery vasoreactivity in elite power athletes and age matched controls. AB - Elite endurance athletes typically have larger arteries contributing to greater skeletal muscle blood flow, oxygen and nutrient delivery and improved physical performance. Few studies have examined structural and functional properties of arteries in power athletes. PURPOSE: To compare the size and vasoreactivity of the brachial artery of elite power athletes to age-matched controls. It was hypothesized brachial artery diameters of athletes would be larger, have less vasodilation in response to cuff occlusion, but more constriction after a cold pressor test than age-matched controls. METHODS: Eight elite power athletes (age = 23 +/- 2 years) and ten controls (age = 22 +/- 1 yrs) were studied. High resolution ultrasonography was used to assess brachial artery diameters at rest and following 5 minutes of forearm occlusion (Brachial Artery Flow Mediated Dilation = BAFMD) and a cold pressor test (CPT). Basic fitness measures included a handgrip test and 3-minute step test. RESULTS: Brachial arteries of athletes were larger (Athletes 5.39 +/- 1.51 vs. CONTROLS: 3.73 +/- 0.71 mm, p<0.05), had greater vasodilatory (BAFMD%: Athletes: 8.21 +/- 1.78 vs. CONTROLS: 5.69 +/- 1.56%) and constrictor (CPT %: Athletes: -2.95 +/- 1.07 vs. CONTROLS: -1.20 +/- 0.48%) responses, compared to controls. Vascular operating range (VOR = Peak dilation+Peak Constriction) was also greater in athletes (VOR: Athletes: 0.55 +/- 0.15 vs. CONTROLS: 0.25 +/- 0.18 mm, p<0.05). Athletes had superior handgrip strength (Athletes: 55.92 +/- 17.06 vs. CONTROLS: 36.77 +/- 17.06 kg, p<0.05) but similar heart rate responses at peak (Athletes: 123 +/- 16 vs. CONTROLS: 130 +/- 25 bpm, p>0.05) and 1 minute recovery (Athletes: 88 +/- 21 vs. CONTROLS: 98 +/- 26 bpm, p>0.05) following the step test. CONCLUSION: Elite power athletes have larger brachial arteries, and greater vasoreactivity (greater vasodilatory and constrictor responses) than age-matched controls, contributing to a significantly greater VOR. These data extend the existence of an 'athlete's artery' as previously shown for elite endurance athletes to elite power athletes, and presents a hypothetical explanation for the functional significance of the 'power athlete's artery'. PMID- 23359215 TI - Factors Affecting Candidate Placement on an Emergency Medicine Residency Program's Rank Order List. AB - INTRODUCTION: Several factors influence the final placement of a medical student candidate on an emergency medicine (EM) residency program's rank order list, including EM grade, standardized letter of recommendation, medical school class rank, and US Medical License Examination (USMLE) scores. We sought to determine the correlation of these parameters with a candidate's final rank on a residency program's rank order list. METHODS: We used a retrospective cohort design to examine 129 candidate packets from an EM residency program. Class ranks were assessed according to the instructions provided by the students' medical schools. EM grades were scored from 1 (honors) to 5 (fail). Global assessments noted on the standardized letter of recommendation (SLOR) were scored from 1 (outstanding) to 4 (good). USMLE scores were reported as the candidate's 3-digit scores. Spearman's rank correlation coefficient was used to analyze data. RESULTS: Electronic Residency Application Service packets for 127/129 (98.4%) candidates were examined. The following parameters correlated positively with a candidate's final placement on the rank order list: EM grade, rho = 0.379, P < 0.001; global assessment, rho = 0.332, P < 0.001; and class rank, rho = 0.234, P = 0.035. We found a negative correlation between final placement on the rank order list with both USMLE step 1 scores, rho = -0.253, P=0.006; and USMLE step 2 scores, rho = 0.348, P = 0.004. CONCLUSION: Higher scores on EM rotations, medical school class ranks, and SLOR global assessments correlated with higher placements on a rank order list, whereas candidates with higher USMLE scores had lower placements on a rank order list. However, none of the parameters examined correlated strongly with ultimate position of a candidate on the rank list, which underscores that other factors may influence a candidate's final ranking. PMID- 23359216 TI - Effects of gradual exposure to carbon dioxide gas on the blood pressure status of workers in coal mines of Kerman province, Iran. AB - BACKGROUND: The present study was conducted to investigate the probable changes in blood pressure of workers in coal mines. METHODS: In this study 91 workers, who worked in forwarding, preparation and exploitation units of coal mines and were in direct contact with carbon dioxide gas (from fireworks), have been selected as the case group, and 70 workers, who did not have direct contact with this gas, from other units were selected as the control group by simple random sampling method. The inclusion criteria were over 10 years of work experience and the age range of 30 to 45 years. The blood pressure values and their classification were determined based on the Seventh Report of the Joint National Committee on Prevention of Hypertension. Statistical analysis was performed using t-test. RESULTS: The results of this study showed that mean systolic and diastolic blood pressures in the case group were significantly lower than the control group (P < 0.001). CONCLUSION: The mean diastolic blood pressure of workers in coal mines is less than other people due to the CO2 gas. A greater control of the existing gas in mines by relevant factors is required. Necessary medical care and support measures should also be considered. PMID- 23359217 TI - Changing concepts and findings on autism. AB - New research findings provide major challenges regarding our understanding of the concept of autism. These are critically discussed in relation to research relevant to classification, genetics, environmental risk factors, gene environment interplay, animal models, biomarkers, clinical features, neuropathology, pharmacotherapy, behavioral treatments, and functioning in adult life. It is concluded that, although there have been major research advances; there is a need for a reconceptualization and an avoidance of claims that go beyond the evidence. PMID- 23359219 TI - Move to Improve: How Knee Osteoarthritis Patients Can Use Exercise to Enhance Quality of Life. AB - Symptomatic knee osteoarthritis (OA) is a prevalent chronic degenerative disease that is associated with impaired quality of life and physical functioning. Although there is no cure for knee OA, regular exercise participation consistently results in improvements in quality of life, physical function, and knee OA symptoms. Findings from contemporary randomized controlled trials also demonstrate that lifestyle interventions involving modification of exercise and dietary behaviors yield superior improvements in relevant quality of life outcomes relative to either intervention alone. PMID- 23359218 TI - Fine tuning inflammation at the front door: macrophage complement receptor 3 mediates phagocytosis and immune suppression for Francisella tularensis. AB - Complement receptor 3 (CR3, CD11b/CD18) is a major macrophage phagocytic receptor. The biochemical pathways through which CR3 regulates immunologic responses have not been fully characterized. Francisella tularensis is a remarkably infectious, facultative intracellular pathogen of macrophages that causes tularemia. Early evasion of the host immune response contributes to the virulence of F. tularensis and CR3 is an important receptor for its phagocytosis. Here we confirm that efficient attachment and uptake of the highly virulent Type A F. tularensis spp. tularensis strain Schu S4 by human monocyte-derived macrophages (hMDMs) requires complement C3 opsonization and CR3. However, despite a>40-fold increase in uptake following C3 opsonization, Schu S4 induces limited pro-inflammatory cytokine production compared with non-opsonized Schu S4 and the low virulent F. novicida. This suggests that engagement of CR3 by opsonized Schu S4 contributes specifically to the immune suppression during and shortly following phagocytosis which we demonstrate by CD11b siRNA knockdown in hMDMs. This immune suppression is concomitant with early inhibition of ERK1/2, p38 MAPK and NF-kappaB activation. Furthermore, TLR2 siRNA knockdown shows that pro inflammatory cytokine production and MAPK activation in response to non-opsonized Schu S4 depends on TLR2 signaling providing evidence that CR3-TLR2 crosstalk mediates immune suppression for opsonized Schu S4. Deletion of the CD11b cytoplasmic tail reverses the CR3-mediated decrease in ERK and p38 activation during opsonized Schu-S4 infection. The CR3-mediated signaling pathway involved in this immune suppression includes Lyn kinase and Akt activation, and increased MKP-1, which limits TLR2-mediated pro-inflammatory responses. These data indicate that while the highly virulent F. tularensis uses CR3 for efficient uptake, optimal engagement of this receptor down-regulates TLR2-dependent pro inflammatory responses by inhibiting MAPK activation through outside-in signaling. CR3-linked immune suppression is an important mechanism involved in the pathogenesis of F. tularensis infection. PMID- 23359220 TI - Nocturia and overnight polysomnography in Parkinson disease. AB - AIM: Characterize clinical factors related to nocturia and sleep disruption in Parkinson disease (PD) using polysomnography (PSG). METHODS: Sixty-three PD patients were recruited regardless of sleep or voiding complaints from a university-based movement disorders clinic for a 48 hr inpatient PSG protocol. Nocturia frequency and bother related to urinary symptoms were assessed using the International Prostate Symptom Score (IPSS) and were corroborated by measurements of PSG-defined sleep made immediately preceding and subsequent to each in-lab voiding episode. PSG measures included whole-night total sleep time (TST), sleep efficiency (SE), apnea/hypopnea index (AHI), and time to PSG-defined sleep following nocturia episodes. Differences between groups were assessed using Mantel-Haenszel chi-square, t-tests, or Wilcoxon signed rank tests. Linear regression was used to assess factors associated with reported nocturia frequency. RESULTS: Sixty patients completed the IPSS. Thirty-seven (61%) reported at least two nocturia episodes nightly; those individuals demonstrated lower PSG-defined SE (P = 0.01) and TST (P = 0.02) than patients with 0-1 episodes. Participants reporting 2-3 episodes of nocturia with high bother on the IPSS (n = 12) demonstrated lower whole-night TST (280.5 +/- 116.1 min vs. 372.5 +/- 58.7 min, P = 0.03) and worse SE (59.2 +/- 22.7% vs. 75.9 +/- 11.2%, P = 0.04) when compared to participants with 2-3 episodes of nocturia with low bother (n = 13). CONCLUSIONS: These results verify objectively that PD patients with nocturia have poor sleep. Furthermore, among individuals with comparable levels of reported nocturia, higher bother is associated with poorer sleep as defined on PSG. Neurourol. Urodynam. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. PMID- 23359221 TI - Influence of array interspacing on the force required for successful microneedle skin penetration: theoretical and practical approaches. AB - Insertion behaviour of microneedle (MN) arrays depends upon the mechanical properties of the skin and, MN geometry and distribution in an array. In addressing this issue, this paper studies MN array insertion mechanism into skin and provides a simple quantitative basis to relate the insertion force with distance between two MNs. The presented framework is based on drawing an analogy between a beam on an elastic foundation and mechanism of needle insertion, where insertion force is separated into different components. A theoretical analysis indicates that insertion force decreases as interspacing increases. For a specified skin type, insertion force decreased from 0.029 to 0.028 N/MN when interspacing at MN tip was increased from 50 MUm (350 MUm at MN base) to 150 MUm (450 MUm at MN base). However, dependence of insertion force seems to decrease as the interspacing is increased beyond 150 MUm. To assess the validity of the proposed model, a series of experiments was carried out to determine the force required for skin insertion of MN. Experiments performed at insertion speed of 0.5 and 1.0 mm/s yielded insertion force values of 0.030 and 0.0216 N, respectively, for 30 MUm interspacing at MN base (330 MUm interspacing at tip) and 0.028 and 0.0214 N, respectively, for 600 MUm interspacing at MN base (900 MUm interspacing at tip). Results from theoretical analysis and finite element modelling agree well with experimental results, which show MN interspacing only begins to affect insertion force at low interspacing (<150 MUm interspacing at MN base). This model provides a framework for optimising MN devices, and should aid development of suitable application method and determination of force for reliable insertion into skin. PMID- 23359222 TI - Titanium elastic nail - Complications in the treatment of paediatric diaphyseal fracture of femur [corrected]. AB - BACKGROUND: Femoral shaft fracture is the most common major paediatric orthopaedic. For generations traction and casting was the standard treatment for all femoral shaft fractures in children. Over the past two decades the advantages of fixation and rapid mobilisation have been increasingly recognised. METHODS: A prospective study was conducted in five private hospitals in the district of Bankura, West Bengal over a period of two years (April 2010 to March 2012) on 70 patients with closed shaft femur fractures between 6- 14 years age of either sex. The aim was to find out the short term complications of titanium elastic nailing in diaphyseal fracture of femur in children and compare the findings of this study with pre- existing studies in this field. RESULTS: In our study the most common complication was pain at nail entry site (60%). 5.71% had local inflammatory reaction due to nails. Superficial infection occurred in 2.85%. At the end of 1 year, 2.85% had limb length discripancies. Proximal migration occurred in 2.85%. 2.85% encountered acute reactive synovitis, 5.71% developed angulation of fracture site and 2.85% developed per operative breakage of nail. CONCLUSION: The treatment of paediatric shaft femur fracture has been drastically changed over the last two decades to internal fixation by elastically stable intra- medullary nail (ESIN). In our study, we encountered only a few complications most of them being minor. Most of the complications were surgical technique related and were seen at the initial phase of the learning curve. PMID- 23359224 TI - Detection of A2142C, A2142G, and A2143G Mutations in 23s rRNA Gene Conferring Resistance to Clarithromycin among Helicobacter pylori Isolates in Kerman, Iran. AB - BACKGROUND: Clarithromycin resistance in Helicbacter pylori has been found to be associated with point mutations in 23s rRNA gene leads to reduced affinity of the antibiotic to its ribosomal target or changing the site of methylation. The aim of this study was to determine the most important point mutations in 23s rRNA gene in H. pylori that are closely related to clarithromycin resistance among such isolates. METHODS: Sixty three H. pylori isolates, obtained from gastric biopsy speciemens in Kerman, Iran, were used to evaluate their susceptibility to clarithromycin by disk diffusion test, and to detect the most common point mutations in 23s rRNA gene associated with clarithromycin resistance by Polymerase chain reaction-amplification and restriction fragment length polymorphism (PCR-RFLP) and 3'-mismatch PCR. RESULTS: 31.7% of the H. pylori isolates were resistant to clarithromycin, and each of the resistant isolate had at least one of the most common point mutations in 23s rRNA gene associated with calrithromycin resistance. CONCLUSION: According to our results three common point mutation in 23s rRNA gene in H. pylori are closely related to clarithromycin resistance. There was an absolute relation between 23s rRNA gene point mutations and clarithromycin resistance in this study. Helicbacter pylori resistance to clarithromycin can cause failure in the eradications of the bacteria. The resistance of the bacteria is expanding in most parts of the world including Iran. PMID- 23359223 TI - 15N, 13C and 1H resonance assignments and secondary structure determination of a variable heavy domain of a heavy chain antibody. AB - Heavy chain antibodies differ in structure to conventional antibodies lacking both the light chain and the first heavy chain constant domain (CH1). Characteristics of the antigen-binding variable heavy domain of the heavy chain antibody (VHH) including the smaller size, high solubility and stability make them an attractive alternative to more traditional antibody fragments for detailed NMR-based structural analysis. Here we report essentially complete backbone and side chain (15)N, (13)C and (1)H assignments for a free VHH. Analysis of the backbone chemical shift data obtained indicates that the VHH is comprised predominantly of beta-sheets corresponding to nearly 60% of the protein backbone. PMID- 23359225 TI - Individualized Chemotherapy in Advanced NSCLC Patients Based on mRNA Levels of BRCA1 and RRM1. AB - OBJECTIVE: Experimental evidence suggests that the overexpression of breast cancer-specific tumor suppressor protein 1 (BRCA1) gene enhances sensitivity to docetaxel and resistance to cisplatin and ribonucleotide reductase M1 (RRM1) gene overexpression enhances resistance to gemcitabine. To further examine the effect of BRCA1 and RRM1 mRNA levels on outcome in advanced non-small cell lung cancer (NSCLC), we performed this non-randomized phase II clinical trial which tested the hypothesis that customized therapy would confer improved outcome over non customized therapy. METHODS: RNA was isolated from fresh tumor tissue. Patients received chemotherapy regimen based on their BRCA1 and RRM1 mRNA levels: both low cisplatin plus gemcitabine (GP); both high-vinorelbine plus cisplatin (NP); BRCA1 low and RRM1 high-cisplatin plus docetaxel (TP); BRCA1 high and RRM1 low vinorelbine plus gemcitabine (GN). RESULTS: From Dec 2005 to Nov 2008, 94 metastatic and locally advanced NSCLC patients from our institute were enrolled in this study. The median age was 58 years old. Among them, 21 patients received GP, 30 patients received TP and 43 patients received NP chemotherapy. GP group had a higher response rate, and longer median time to progression (TTP) and median overall survival (OS) time than the other 2 groups. The response rates in the GP, TP and NP groups were 42.9%, 36.7% and 27.9%, respectively (P=0.568). The median TTP was 5.6, 5.0, 4.8 months (P=0.975), respectively, and the median OS time was 12.5, 11.0, 9.7 months (P=0.808), respectively. CONCLUSION: Chemotherapy customized according to BRCA1 and RRM1 expression levels is associated with higher response rate and longer TTP and OS time in the GP group. This suggests that BRCA1 and RRM1 mRNA levels could be used as biomarkers in individual therapy in NSCLC. PMID- 23359226 TI - Crosstalk between thyroid hormone receptor and liver X receptor in the regulation of selective Alzheimer's disease indicator-1 gene expression. AB - Selective Alzheimer's disease (AD) indicator 1 (Seladin-1) has been identified as a gene down-regulated in the degenerated lesions of AD brain. Up-regulation of Seladin-1 reduces the accumulation of beta-amyloid and neuronal death. Thyroid hormone (TH) exerts an important effect on the development and maintenance of central nervous systems. In the current study, we demonstrated that Seladin-1 gene and protein expression in the forebrain was increased in thyrotoxic mice compared with that of euthyroid mice. However, unexpectedly, no significant decrease in the gene and protein expression was observed in hypothyroid mice. Interestingly, an agonist of liver X receptor (LXR), TO901317 (TO) administration in vivo increased Seladin-1 gene and protein expression in the mouse forebrain only in a hypothyroid state and in the presence of mutant TR-beta, suggesting that LXR-alpha would compensate for TR-beta function to maintain Seladin-1 gene expression in hypothyroidism and resistance to TH. TH activated the mouse Seladin 1 gene promoter (-1936/+21 bp) and site 2 including canonical TH response element (TRE) half-site in the region between -159 and -154 bp is responsible for the positive regulation. RXR-alpha/TR-beta heterodimerization was identified on site 2 by gel-shift assay, and chromatin immunoprecipitation assay revealed the recruitment of TR-beta to site 2 and the recruitment was increased upon TH administration. On the other hand, LXR-alpha utilizes a distinct region from site 2 (-120 to -102 bp) to activate the mouse Seladin-1 gene promoter. Taking these findings together, we concluded that TH up-regulates Seladin-1 gene expression at the transcriptional level and LXR-alpha maintains the gene expression. PMID- 23359227 TI - The Role of chemokine receptor CXCR4 in breast cancer metastasis. AB - Breast cancer is one of the leading causes of cancer related deaths worldwide. Breast cancer-related mortality is associated with the development of metastatic potential of primary tumor lesions. The chemokine receptor CXCR4 has been found to be a prognostic marker in various types of cancer, including breast cancer. Recent advances in the field of cancer biology has pointed to the critical role that CXCR4 receptor and its ligand CXCL12 play in the metastasis of various types of cancer, including breast cancer. Breast tumors preferentially metastasize to the lung, bones and lymph nodes, all of which represent organs that secrete high levels of CXCL12. CXCL12 acts as a chemoattractant that drives CXCR4-positive primary tumor cells towards secondary metastatic sites leading to the onset of metastatic lesions. Since its discovery in 2001, the CXCR4 field has progressed at a very fast rate and further studies have pointed to the role of CXCR4 in dissemination of tumor cells from primary sites, transendothelial migration of tumor cells as well as the trafficking and homing of cancer stem cells. This review summarizes the information that has been obtained over the years regarding the role of CXCL12-CXCR4 signaling in breast cancer, discusses its potential application to the development of new therapeutic tools for breast cancer control, and elucidates the potential therapeutic challenges which lie ahead and the future directions that this field can take for the improvement of prognosis in breast cancer patients. PMID- 23359228 TI - Psammaplin A inhibits hepatitis C virus NS3 helicase. AB - Hepatitis C virus (HCV) is the causative agent of hepatitis C, a chronic infectious disease that can lead to development of hepatocellular carcinoma. The NS3 nucleoside triphosphatase (NTPase)/helicase has an essential role in HCV replication, and is therefore an attractive target for direct-acting antiviral strategies. In this study, we employed high-throughput screening using a photo induced electron transfer (PET) system to identify an inhibitor of NS3 helicase from marine organism extracts. We successfully identified psammaplin A as a novel NS3 inhibitor. The dose-response relationship clearly demonstrates the inhibition of NS3 RNA helicase and ATPase activities by psammaplin A, with IC50 values of 17 and 32 MUM, respectively. Psammaplin A has no influence on the apparent Km value (0.4 mM) of NS3 ATPase activity, and acts as a non-competitive inhibitor. Additionally, it inhibits the binding of NS3 to single-stranded RNA in a dose dependent manner. Furthermore, psammaplin A shows an inhibitory effect on viral replication, with EC50 values of 6.1 and 6.3 MUM in subgenomic replicon cells derived from genotypes 1b and 2a, respectively. We postulate that psammaplin A is a potential anti-viral agent through the inhibition of ATPase, RNA binding and helicase activities of NS3. PMID- 23359229 TI - Flavonoids from Millettia nitida var. hirsutissima with their anticoagulative activities and inhibitory effects on NO production. AB - Two new compounds, (2R)-7,3'-dihydroxy-6,4'-methoxyflavan (1) and (3R)-7,4' dihydroxy-2'-methoxyisoflavan (2), along with 12 known flavonoids (3-14), were isolated from the vine stems of Millettia nitida var. hirsutissima. The structures of the isolated compounds were elucidated based on spectroscopic analyses and comparison of literature data. All of the isolates were evaluated for their effects on in-vitro anticoagulative assay and on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated RAW264.7 macrophages. As a result, all compounds showed weak antiplatelet aggregation activities and compounds 4, 5, 7, 8 and 9 demonstrated antithrombin activity with a good dose effect relationship from 5 to 100 MUg mL-1 in rabbit plasma. Compounds 8, 9, 10 and 14 exhibited inhibitory effects on LPS-induced NO production in RAW264.7 macrophages with IC50 values of 4.79 +/- 0.20, 8.23 +/- 0.35, 5.23 +/- 0.11 and 6.30 +/- 0.30 MUg mL-1, respectively. PMID- 23359230 TI - Impact of oral versus intravenous ibuprofen on neurodevelopmental outcome: a randomized controlled parallel study. AB - OBJECTIVE: Although neurodevelopmental outcomes related to the management of patent ductus arteriosus with intravenous indomethacin and ibuprofen are known, little data on the long-term effects of oral ibuprofen can be found in the literature. METHOD: A follow-up study of 99 infants with birth weight <= 1,500 g and gestational age <= 32 weeks who received either oral or intravenous ibuprofen for patent ductus arteriosus was conducted to assess at 18 to 24 months (corrected age), abnormal neurological, neurosensory, and cognitive impairment were defined as follows:neurological outcomes included moderate/severe cerebral palsy, neurosensory outcomes included bilateral hearing loss and blindness in either eye, and cognitive impairment included mental developmental index score < 70. RESULTS: The 18- to 24-month (corrected age) long-term outcomes of 30 subjects who received oral ibuprofen were compared with 27 subjects who received intravenous ibuprofen by certified and experienced examiners who were blind to the definitions of the groups. The results revealed that the long-term outcomes of the treatment regimens did not significantly differ. CONCLUSIONS: Preterm infants who were treated with oral ibuprofen for patent ductus arteriosus had similar neurological, neurosensory, and cognitive outcomes to patients who received intravenous ibuprofen at 2 years of age. PMID- 23359231 TI - Maternal and neonatal nurse perceived value of kangaroo mother care and maternal care partnership in the neonatal intensive care unit. AB - BACKGROUND: Kangaroo Mother Care (KMC) enhances infant and maternal well-being and requires maternal-care partnerships (MCP) for implementation. OBJECTIVE: To examine maternal and neonatal nurse provider perspectives on the value of KMC and MCP. STUDY DESIGN: Prospective cohort design of neonatal nurses and mothers of preterm infants self-report anonymous questionnaire. Analyses of categorical independent variables and continuous variables were calculated. RESULTS: In all, 82.3% of nurses (42) and 100% (143) of mothers participated in the survey. compared with 18% of nurses, 63% of mothers believed "KMC should be provided daily" and 90% of mothers compared with 40% of nurses strongly believed "mothers should be partners in care." In addition, 61% of nonwhite mothers identified that "KMC was not something they were told they could do for their infant" compared with 39% of white mothers. Nonwhite and foreign-born nurses were 2.8 and 3.1 times more likely to encourage MCP and KMC. CONCLUSION: Mothers held strong positive perceptions of KMC and MCP value compared with nurses. Nonwhite mothers perceived they received less education and access to KMC. Barriers to KMC and MCP exist among nurses, though less in nonwhite, foreign-born, and/or nurses with their own children, identifying important provider educational opportunities to improve maternal KMC access in the NICU. PMID- 23359232 TI - The impact of medically indicated and spontaneous preterm birth among hypertensive women. AB - OBJECTIVE: To (1) describe the frequency of spontaneous preterm birth (SPTB) and medically indicated preterm birth (PTB) among women with chronic hypertension (CHTN) and (2) to evaluate differences in neonatal outcomes according to SPTB or medically indicated PTB. STUDY DESIGN: Retrospective analysis of a previously conducted multicenter randomized trial. Deliveries were categorized as SPTB or medically indicated and stratified by gestational ages (<37 weeks, 34 to 366/7 weeks, 30 to 336/7 weeks, < 30 weeks). Rates of neonatal intensive care unit admission, composite respiratory morbidity, perinatal mortality, and small for gestational age (SGA) were evaluated. RESULTS: Of 765 women, 32.2% (n = 246) delivered at < 37 weeks, of which 10.5% (n = 80) were SPTB and 21.6% (n = 166) were medically indicated. Fifty-nine percent of PTBs occurred in the late preterm period (n = 146). SGA was significantly more frequent among those with medically indicated PTB at < 30 weeks (p = 0.03). There were no other differences in adverse neonatal outcomes between medically indicated versus SPTB at any gestational age (p > 0.05). CONCLUSION: Nearly one-third of women with CHTN delivered preterm. The majority of PTBs were medically indicated and late preterm, but approximately one-third were due to SPTB. PMID- 23359233 TI - High rate of preterm birth in pregnancies complicated by rheumatoid arthritis. AB - OBJECTIVE: To describe the outcomes of pregnancies complicated by rheumatoid arthritis (RA) and to estimate potential associations between disease characteristics and pregnancy outcomes. STUDY DESIGN: We reviewed all pregnancies complicated by RA delivered at our institution from June 2001 through June 2009. Fisher exact tests were used to calculate odds ratios. Univariable regression was performed using STATA 10.1 (StataCorp, College Station, TX). A p value of <= 0.05 was considered statistically significant. RESULTS: Forty-six pregnancies in 40 women were reviewed. Sixty percent of pregnancies had evidence of disease flare and 28% delivered prior to 37 weeks. We did not identify associations between preterm birth and active disease at conception or during pregnancy. In univariate analysis, discontinuation of medication because of pregnancy was associated with a significantly earlier gestational age at delivery (362/7 versus 383/7 weeks, p = 0.022). CONCLUSION: Women with RA may be at higher risk for preterm delivery. PMID- 23359234 TI - Changes in care associated with the introduction of a postpartum hemorrhage patient safety program. AB - OBJECTIVE: To determine whether the introduction of a postpartum hemorrhage (PPH) patient safety program was associated with changes in patient care or outcomes. STUDY DESIGN: A multipronged patient safety program regarding PPH was instituted at a tertiary care maternity hospital. Patient care and outcomes were assessed for 6 months prior to (period A) and 6 months after (period B) program institution. RESULTS: In all, 278 and 341 women were diagnosed with PPH during periods A and B, respectively. Women who had a PPH after the program were more likely to receive more than one dose of prostaglandin F2 alpha (24% versus 9%, p = 0.01) and more than one type of uterotonic (34% versus 25%, p = 0.02) and to have a B-lynch suture placed (9.4% versus 4.7%, p = 0.03). The frequency of blood transfusion, hysterectomy, and intensive care unit admission were similar between periods. CONCLUSION: Introduction of a PPH safety program resulted in several indications of a more quickly escalated response. PMID- 23359235 TI - Association of inhibitors of gastric acid secretion and higher incidence of necrotizing enterocolitis in preterm very low-birth-weight infants. AB - BACKGROUND: Inhibitors of gastric acid (IGA) are used for upper gastrointestinal bleeding or gastroesophageal reflux in preterm infants. The resultant increase in gastric pH may enhance the growth of pathogens and increase the risk of necrotizing enterocolitis (NEC). Our systematic review examined the association between IGA and NEC in preterm infants. METHODS: Standard methodology of systematic reviews was followed. PubMed, Embase, Cochrane, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched in August 2012. RESULTS: One case-control and one prospective cohort study (n = 11,346), both evaluating H2-blockers as IGA, were included. Meta-analysis showed a significant association between NEC and IGA (odds ratio [OR]: 1.78, 95% confidence interval [CI]: 1.4, 2.27, p < 0.00001). The prospective cohort study found higher incidence of infection (sepsis, pneumonia, urinary tract infection) with IGA (37.4% versus 9.8%, OR: 5.5, 95% CI: 2.9 to 10.4, p < 0.001). CONCLUSIONS: Exposure to H2 receptor antagonists may be associated with increased risk of NEC and infections in preterm infants. PMID- 23359236 TI - A randomized controlled trial of plastic drape for prevention of hypothermia during umbilical catheterization. AB - OBJECTIVE: To determine the efficacy of polyethylene plastic draping in preventing hypothermia during umbilical catheterization. METHODS: A randomized controlled trial was conducted in newborns who required umbilical catheterization. A sterile polyethylene plastic sheet covering the procedural field was used in the plastic group, and a sterile conventional cotton drape was used in the control group. RESULTS: Sixty infants were enrolled and randomly assigned to the plastic group (n = 30) and control group (n = 30). There were no significant differences in the baseline demographic data. The use of plastic drapes was associated with a higher rectal temperature compared with the control group. Incidence of hypothermia at the end of procedure were 20% and 50% in the plastic group and control group, respectively (p = 0.03). CONCLUSION: Polyethylene plastic draping was superior to conventional cloth draping in maintaining rectal temperature and preventing hypothermia during umbilical catheterization. PMID- 23359237 TI - Randomized controlled trial of the effect of 30% versus 80% fraction of inspired oxygen on cesarean delivery surgical site infection. AB - OBJECTIVE: To determine if supplemental perioperative oxygen will reduce surgical site infection (SSI) following cesarean delivery. METHODS: This is a randomized, controlled trial evaluating SSI following either 30% or 80% fraction of inspired oxygen (FIO2) during and 2 hours after cesarean delivery. Anesthesia providers administered FIO2 via a high-flow oxygen blender. Subjects, surgeons, and wound evaluation teams were blinded. Serial wound evaluations were performed. Data were analyzed using logistic regression models, Fisher exact test, and t test. RESULTS: In all, 179 women were randomized, and 160 subjects were included in the analysis. There were 12/83 (14.5%) SSIs in the control group versus 10/77 (13.0%) in the investigational group (p = 0.82). Caucasian race, increased body mass index, and longer operative time were identified as significant risk factors for infection (p = 0.026, odds ratio 0.283; p = 0.05, odds ratio = 1.058; p = 0.037, odds ratio = 1.038, respectively). CONCLUSION: Perioperative oxygenation with 80% Fio2 is not effective in reducing SSI following cesarean delivery. PMID- 23359238 TI - A clinical approach to intrahepatic cholestasis of pregnancy. AB - Intrahepatic cholestasis of pregnancy (ICP) has a varying prevalence worldwide. The etiology behind this disease remains not fully understood with multiple factors influencing its development including genetic variations, dietary factors, hormonal changes, and environmental influences. Presenting mainly during the third trimester with generalized itching and resolving spontaneously postpartum, this condition is still associated with fetal morbidity and mortality. The diagnosis is based on clinical presentation in association with biochemical abnormalities. Elevation in total bile acid levels is the most frequent laboratory abnormality and seems to be the most important for gauging further management of the disease. The most appropriate gestational age for the delivery of women with ICP is yet to be determined. In this review we discuss the epidemiology, clinical features, diagnosis, etiology, and management of ICP, trying to shed light on some controversial aspects of the disease. PMID- 23359239 TI - Noninvasive molecular sexing: an evaluation and validation of the SRY- and amelogenin-based method in three new lemur species. AB - Many lemur species are arboreal, elusive, and/or nocturnal and are consequently difficult to approach, observe and catch. In addition, most of them are endangered. For these reasons, non-invasive sampling is especially useful in primates including lemurs. A key issue in conservation and ecological studies is to identify the sex of the sampled individuals to investigate sex-biased dispersal, parentage, social organization and population sex ratio. Several molecular tests of sex are available in apes and monkeys, but only a handful of them work in the lemuriform clade. Among these tests, the coamplification of the SRY gene with the amelogenin X gene using strepsirhine-specific X primers seems particularly promising, but the reliability and validity of this sexing test have not been properly assessed yet. In this study, we (i) show that this molecular sexing test works on three additional lemur species (Microcebus tavaratra, Propithecus coronatus and P. verreauxi) from two previously untested genera and one previously untested family, suggesting that these markers are likely to be universal among lemurs and other strepsirrhines; (ii) provide the first evidence that this PCR-based sexing test works on degraded DNA obtained from noninvasive samples; (iii) validate the approach using a large number of known-sex individuals and a multiple-tubes approach, and show that mismatches between the field sex and the final molecular consensus sex occur in less than 10% of all the samples and that most of these mismatches were likely linked to incorrect sex determinations in the field rather than genotyping errors. PMID- 23359240 TI - The role of magnetic resonance imaging in assessing residual disease and pathologic complete response in breast cancer patients receiving neoadjuvant chemotherapy: a systematic review. AB - OBJECTIVES: This systematic review aimed to assess the role of magnetic resonance imaging (MRI) in evaluating residual disease extent and the ability to detect pathologic complete response (pCR) after neoadjuvant chemotherapy for invasive breast cancer. METHODS: PubMed, the Cochrane Library, MEDLINE, and Embase databases were searched for relevant studies published until 1 July 2012. After primary selection, two reviewers independently assessed the content of each eligible study using a standardised extraction form and pre-defined inclusion and exclusion criteria. RESULTS: A total of 35 eligible studies were selected. Correlation coefficients of residual tumour size assessed by MRI and pathology were good, with a median value of 0.698. Reported sensitivity, specificity, positive predictive value and negative predictive value for predicting pCR with MRI ranged from 25 to 100 %, 50-97 %, 47-73 % and 71-100 %, respectively. Both overestimation and underestimation were observed. MRI proved more accurate in determining residual disease than physical examination, mammography and ultrasound. Diagnostic accuracy of MRI after neoadjuvant chemotherapy could be influenced by treatment regimen and breast cancer subtype. CONCLUSIONS: Breast MRI accuracy for assessing residual disease after neoadjuvant chemotherapy is good and surpasses other diagnostic means. However, both overestimation and underestimation of residual disease extent could be observed. MAIN MESSAGES: * Breast MRI accuracy for assessing residual disease is good and surpasses other diagnostic means. * Correlation coefficients of residual tumour size assessed by MRI and pathology were considered good. * However, both overestimation and underestimation of residual disease were observed. * Diagnostic accuracy of MRI seems to be affected by treatment regimen and breast cancer subtype. PMID- 23359241 TI - Functional characteristics of macrophages in patients with acute liver failure. PMID- 23359242 TI - Polar solvents decrease the viscosity of high concentration IgG1 solutions through hydrophobic solvation and interaction: formulation and biocompatibility considerations. AB - Low-volume protein dosage forms for subcutaneous injection pose unique challenges to the pharmaceutical scientist. Indeed, high protein concentrations are often required to achieve acceptable bioavailability and efficacy for many indications. Furthermore, high solution viscosities are often observed with formulations containing protein concentrations well above 150 mg/mL. In this work, we explored the use of polar solvents for reducing solution viscosity of high concentration protein formulations intended for subcutaneous injection. An immunoglobulin, IgG1, was used in this study. The thermodynamic preferential interaction parameter (Gamma23 ) measured by differential scanning calorimetry, as well as Fourier transform infrared, Raman, and second-derivative UV spectroscopy, were used to characterize the effects of polar solvents on protein structure and to reveal important mechanistic insight regarding the nature of the protein-solvent interaction. Finally, the hemolytic potential and postdose toxicity in rats were determined to further investigate the feasibility of using these cosolvents for subcutaneous pharmaceutical formulations. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1182-1193, 2013. PMID- 23359243 TI - Dual involvements of cyclooxygenase and nitric oxide synthase expressions in ketamine-induced ulcerative cystitis in rat bladder. AB - AIMS: The aims of the present study were to investigate voiding patterns, tissue constituents and the expressions of cyclooxygenase-2 (COX-2) and nitric oxide synthase (NOS) involved in ketamine-induced ulcerative cystitis in rat urinary bladder. METHODS: Thirty Sprague-Dawley rats were distributed into three groups which received saline or ketamine (25 mg/kg/day) for a period of 14 and 28 days. In each group, cystometry was performed weekly and the concentration of ketamine and its metabolites (norketamine) was assayed. Paraffin-embedded sections were stained with Masson's trichrome stain, and ketamine-induced morphological changes were examined. Western blot analyses were carried out to examine the expressions of COX-2 and different NOS isoforms in bladder tissues. Immunofluorescence study was done to evaluate the expressions of COX-2 and macrophage infiltration (stained with ED-1 macrophage cell surface antigen) within the bladder. RESULTS: Ketamine treatment resulted in bladder hyperactivity and the non-voiding contractions were significantly increased. The urine concentrations of ketamine and norketamine were much higher in ketamine-treated group. Moreover, ulcerated urothelium and mononuclear cell infiltration were noted in ketamine-treated group. These alterations in urodynamic functions and tissue constituents were accompanied by increases in the expression of COX-2. Two NOS isoforms (iNOS and eNOS) were also overexpressed, but no significant change was observed for nNOS. COX-2 positive stained cells were significantly increased. Meanwhile, increased amounts of ED-1 positive stained macrophages were present and most of COX-2 expressed cells were co-stained with ED-1 in the early stage of ketamine treatment. CONCLUSIONS: Ketamine treatment affected bladder tissues by enhancing interstitial fibrosis and accelerating macrophages infiltration. Ketamine also initiated the up-regulations of COX-2 and iNOS and eNOS expressions. These up regulated enzymes might play an important role in contributing to ketamine induced alterations in micturition patterns and ulcerative cystitis. PMID- 23359244 TI - Impact of subject head motion on quantitative brain (15)O PET and its correction by image-based registration algorithm. AB - OBJECTIVE: Subject head motion during sequential (15)O positron emission tomography (PET) scans can result in artifacts in cerebral blood flow (CBF) and oxygen metabolism maps. However, to our knowledge, there are no systematic studies examining this issue. Herein, we investigated the effect of head motion on quantification of CBF and oxygen metabolism, and proposed an image-based motion correction method dedicated to (15)O PET study, correcting for transmission-emission mismatch and inter-scan mismatch of emission scans. METHODS: We analyzed (15)O PET data for patients with major arterial steno occlusive disease (n = 130) to determine the occurrence frequency of head motion during (15)O PET examination. Image-based motion correction without and with realignment between transmission and emission scans, termed simple and 2-step method, respectively, was applied to the cases that showed severe inter-scan motion. RESULTS: Severe inter-scan motion (>3 mm translation or >5 degrees rotation) was observed in 27 of 520 adjacent scan pairs (5.2 %). In these cases, unrealistic values of oxygen extraction fraction (OEF) or cerebrovascular reactivity (CVR) were observed without motion correction. Motion correction eliminated these artifacts. The volume-of-interest (VOI) analysis demonstrated that the motion correction changed the OEF on the middle cerebral artery territory by 17.3 % at maximum. The inter-scan motion also affected CBV, CMRO2 and CBF, which were improved by the motion correction. A difference of VOI values between the simple and 2-step method was also observed. CONCLUSIONS: These data suggest that image-based motion correction is useful for accurate measurement of CBF and oxygen metabolism by (15)O PET. PMID- 23359245 TI - The effects of GATA-1 and NF-E2 deficiency on bone biomechanical, biochemical, and mineral properties. AB - Mice deficient in GATA-1 or NF-E2, transcription factors required for normal megakaryocyte (MK) development, have increased numbers of MKs, reduced numbers of platelets, and a striking high bone mass phenotype. Here, we show the bone geometry, microarchitecture, biomechanical, biochemical, and mineral properties from these mutant mice. We found that the outer geometry of the mutant bones was similar to controls, but that both mutants had a striking increase in total bone area (up to a 35% increase) and trabecular bone area (up to a 19% increase). Interestingly, only the NF-E2 deficient mice had a significant increase in cortical bone area (21%) and cortical thickness (27%), which is consistent with the increase in bone mineral density (BMD) seen only in the NF-E2 deficient femurs. Both mutant femurs exhibited significant increases in several biomechanical properties including peak load (up to a 32% increase) and stiffness (up to a 13% increase). Importantly, the data also demonstrate differences between the two mutant mice. GATA-1 deficient femurs break in a ductile manner, whereas NF-E2 deficient femurs are brittle in nature. To better understand these differences, we examined the mineral properties of these bones. Although none of the parameters measured were different between the NF-E2 deficient and control mice, an increase in calcium (21%) and an increase in the mineral/matrix ratio (32%) was observed in GATA-1 deficient mice. These findings appear to contradict biomechanical findings, suggesting the need for further research into the mechanisms by which GATA-1 and NF-E2 deficiency alter the material properties of bone. PMID- 23359246 TI - Children's enjoyment of play during school lunchtime breaks: an examination of intraday and interday reliability. AB - BACKGROUND: Enjoyment and play during school lunchtime are correlated with children's physical activity. Despite this, there is an absence of studies reporting children's enjoyment of play during school lunchtime breaks. The purpose of this study was to examine the intraday and interday reliability of children's enjoyment of school lunchtime play. METHODS: Surveys used to assess children's enjoyment of lunchtime play were distributed to and completed by 197 children (112 males, 85 females), aged 8-12 years attending an elementary school in Victoria, Australia. Children completed the surveys during class before lunch (expected enjoyment) and after lunch (actual enjoyment) for 5 days. The intra- and interday enjoyment of school lunchtime play reliability were determined using a weighted kappa. RESULTS: Intraday kappa values ranged from fair (0.31) to substantial (0.75) within each of the 5 days (median kappa = 0.41). In comparison, "expected" (0.09-0.40; median 0.30) and "actual" (0.05-0.46; median 0.28) interday enjoyment of lunchtime play displayed low reliability. CONCLUSIONS: Children's enjoyment of lunchtime play appears to be more consistent within days than across days. The findings suggest that assessment of children's enjoyment of lunchtime play once on a single day would be representative of a particular day but not necessarily that particular school week. PMID- 23359247 TI - Caspase signalling pathways in human spermatogenesis. AB - PURPOSE: Little is known about the apoptotic mechanisms involved in abnormal spermatogenesis. In order to describe the significance of apoptosis in azoospermia, testicular tissue from abnormal spermatogenesis was analysed. METHODS: Testicular treatment biopsies were obtained from 27 men. Five presented oligozoospermia, 9 obstructive azoospermia (4 congenital bilateral absence of the vas deferens; 5 secondary azoospermia) and 13 non-obstructive azoospermia (5 hypospermatogenis; 3 maturation arrest; 5 Sertoli-cell-only syndrome). Immunohistochemical staining was performed for active caspases-3, -8 and -9. The presence of active caspases in Sertoli cells and germ cells was analyzed using stereological tools. RESULTS: Increased active caspase-3 was found in Sertoli cell-only syndrome. No significant differences were found in maturation arrest. In hypospermatogenesis, primary spermatocytes were the germ cells with higher active caspases. Oligozoospermia and secondary obstruction showed significant differences among germ cells for the presence of all active caspases. In oligozoospermia, spermatogonia presented significant increased active caspase-9 in relation to active caspase-8. In primary obstruction and hypospermatogenesis, germ cells presented significant increased active caspases-3 and -9. CONCLUSIONS: Results suggest that increased active caspase-3 might be involved in Sertoli-cell only syndrome etiology. In cases of hypospermatogenesis, intrinsic lesions at the meiotic stage seem to be related to the pathology. In secondary obstruction apoptosis is suggested to be initiated due to extrinsic and intrinsic lesions, whereas in primary obstruction only the intrinsic apoptotic pathway seems to be present. Finally, in oligozoospermic patients spermatogonia death by mitochondrial damage additionally to meiosis malfunctioning, might be on the origin of the decreased sperm output. PMID- 23359249 TI - Characterizing crystal disorder of trospium chloride: a comprehensive,(13) C CP/MAS NMR, DSC, FTIR, and XRPD study. AB - Analysis of C cross-polarization magic angle spinning (CP/MAS) nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and X-ray powder diffraction data of trospium chloride (TCl) products crystallized from different mixtures of water-ethanol [phi(EtOH) = 0.5 1.0] at various temperatures (0 degrees C, 20 degrees C) and initial concentrations (saturated solution, 30%-50% excess of solvent) revealed extensive structural variability of TCl. Although (13) C CP/MAS NMR spectra indicated broad variety of structural phases arising from molecular disorder, temperature modulated DSC identified presence of two distinct components in the products. FTIR spectra revealed alterations in the hydrogen bonding network (ionic hydrogen bond formation), whereas the X-ray diffraction reflected unchanged unit cell parameters. These results were explained by a two-component character of TCl products in which a dominant polymorphic form is accompanied by partly separated nanocrystalline domains of a secondary phase that does not provide clear Bragg reflections. These phases slightly differ in the degree of molecular disorder, in the quality of crystal lattice and hydrogen bonding network. It is also demonstrated that, for the quality control of such complex products, (13) C CP/MAS NMR spectroscopy combined with factor analysis (FA) can satisfactorily be used for categorizing the individual samples: FA of (13) C CP/MAS NMR spectra found clear relationships between the extent of molecular disorder and crystallization conditions. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1235-1248, 2013. PMID- 23359250 TI - Selective hepatic insulin resistance in a murine model heterozygous for a mitochondrial trifunctional protein defect. AB - Earlier reports suggest a link between mitochondrial dysfunction and development of hepatic insulin resistance. Here we used a murine model heterozygous (HET) for a mitochondrial trifunctional protein (MTP) gene defect to determine if a primary defect in mitochondrial long-chain fatty acid oxidation disrupts hepatic insulin action. Hyperinsulinemic-euglycemic clamps and signaling studies were performed for assessment of whole-body and hepatic insulin resistance/signaling. In addition, hepatic fatty acid oxidation and hepatic insulin action were assessed in vitro using primary hepatocytes isolated from HET and wildtype (WT) mice. In both hepatic mitochondria and isolated primary hepatocytes, heterozygosity of MTP caused an ~50% reduction in mitochondrial fatty acid oxidation, a significantly impaired glucose disposal during the insulin clamp, and a markedly lower insulin stimulated suppression of hepatic glucose production. HET mice also exhibited impaired insulin signaling, with increased hepatic phosphorylation of IRS2 (ser731) and reduced Akt phosphorylation (ser473) in both hepatic tissue and isolated primary hepatocytes. Assessment of insulin-stimulated FOXO1/phospho FOXO1 protein content and PEPCK/G6Pase messenger RNA (mRNA) expression did not reveal differences between HET and WT mice. However, insulin-induced phosphorylation of GSK3beta was significantly blunted in HET mice. Hepatic insulin resistance was associated with an increased methylation status of the catalytic subunit of protein phosphatase 2A (PP2A-C), but was not associated with differences in hepatic diacylglycerol content, activated protein kinase C-epsilon (PKC-epsilon), inhibitor kappaB kinase beta (IKK-beta), c-Jun N-terminal kinase (JNK), or phospho-JNK protein contents. Surprisingly, hepatic ceramides were significantly lower in the HET mice compared with WT. CONCLUSION: A primary defect in mitochondrial fatty acid beta-oxidation causes hepatic insulin resistance selective to hepatic glycogen metabolism that is associated with elevated methylated PP2A-C, but independent of other mechanisms commonly considered responsible for insulin resistance. (HEPATOLOGY 2013;). PMID- 23359251 TI - Turkish adaptation of the short form of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ-12): a validation and reliability study. AB - AIM: The purpose of this methodological study is to evaluate the reliability and validity of a Turkish adaptation of the short form of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ-12) used in assessing sexuality function in women with POP/UI. METHODS: The PISQ-12 was translated into Turkish; the adaptation of the PISQ-12 to Turkish language was performed via back-translation, the content validity of the questionnaire was conducted by experts in the field, test-retest reliability was examined with 40 women with UI and/or POP. PISQ-12 was administered to 120 women with pelvic floor dysfunction. The reliability and validity of the PISQ-12 were analyzed. Evaluation of the data was performed using Content Validity Index (CVI), Cronbach's alpha, test-retest reliability, item total correlation, and confirmatory factor analysis. RESULTS: CVI of the Turkish PISQ-12 was found 1.00 (% 100). Item-total correlations were between 0.42 and 0.68 (P < 0.001). The PISQ 12 had an adequate and high internal consistency (Cronbach's alpha = 0.74) as well as a high test-retest reliability (Pearson correlation coefficient, r = 0.961; P < 0.001). Factor analysis results revealed strong construct validity. CONCLUSION: The Turkish version of the PISQ-12 is a reliable, consistent and valid instrument to assess sexual function in women with urinary incontinence and/or pelvic organ prolapse. It is also a comprehensive and easily applicable instrument which as a treatment outcome or research tool in clinical practices. PMID- 23359253 TI - Genetic evidence for spatio-temporal changes in the dispersal patterns of two sympatric African colobine monkeys. AB - Western black-and-white colobus and Temmink's red colobus are two forest dependent African primates with similar ecological requirements, often found in sympatry. Their most striking difference lies in their social system: black-and white colobus live in small groups with mainly male-mediated dispersal but where females can also disperse, whereas red colobus live in larger groups with males described as philopatric. To investigate whether genetic evidence supports the reported patterns of dispersal based on observational data, we examined eight black-and-white and six red colobus social groups from Cantanhez National Park, Guinea-Bissau. Microsatellite markers revealed a lack of sex-biased dispersal for black-and-white colobus. Gene flow, mainly mediated by females, better explained the genetic patterns found in red colobus, with some evidence for less extensive male dispersal. In contrast to the microsatellite data, low mitochondrial diversity for the black-and-white colobus suggests that historical and/or long range male-mediated gene flow might have been favored. In red colobus, the co existence of three divergent mitochondrial haplogroups suggests that the Cantanhez population contains a secondary contact zone between divergent lineages that evolved in allopatry. Female-biased dispersal in this species may be a major factor contributing to the colonization by such differentiated mitochondrial lineages in the region. Overall, we find evidence for a spatio-temporal change in the dispersal patterns of the colobus monkeys of Cantanhez, with mitochondrial DNA indicating dispersal by mainly a single sex and microsatellite data suggesting that recently both sexes appear to be dispersing within the population. PMID- 23359254 TI - The relationship between physical activity and care-seeking behavior among employed adults. AB - BACKGROUND: Physical activity is regarded an important health behavior. Routine doctor visits, dentist visits, and willingness to seek phone advice from a nurse are considered important care-seeking behaviors (ie, behaviors that reflect the way in which people seek and access health care delivery resources available to them). Employers promote physical activity as well as care-seeking behavior to protect and promote health, optimize productivity, and manage health care costs. The purpose of this study was to investigate the association between physical activity and 3 care-seeking behaviors among a sample of 5500 employed adults. METHODS: Data were obtained from employee health assessments. Logistic regression was used to test the relationship between physical activity and care-seeking behavior. RESULTS: Physical activity was positively associated with all 3 measures of care-seeking behavior: doctor visits (P < .001), dentist visits (P < .001), and willingness to seek phone advice from a nurse (P < .05). For individuals reporting chronic conditions, physical activity was negatively associated with doctor visits for the condition (P < .05) and positively associated with self-perceived health (P < .001). CONCLUSIONS: Physical activity is associated with important care-seeking behaviors for employees with and without chronic conditions. PMID- 23359252 TI - beta1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c Jun amino terminal kinase 1. AB - This study was carried out to dissect the mechanism by which beta1 integrins promote resistance to radiation. For this purpose, we conditionally ablated beta1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of beta1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to beta1 , AIIB2, in a xenograft model. The role of beta1 integrins and of a beta1 downstream target, c Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that beta1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, beta1 integrins are shown here to suppress activation of JNK1 and, consequently apoptosis, in response to irradiation. Downregulation of JNK1 is necessary to preserve the effect of beta1 on resistance to radiation in vitro and in vivo. Finally, given the established crosstalk between beta1 integrins and type1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate beta1 integrin levels. We report that IGF-IR regulates the expression of beta1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that beta1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation. PMID- 23359255 TI - Generating anatomical models of the heart and the aorta from medical images for personalized physiological simulations. AB - The anatomy and motion of the heart and the aorta are essential for patient specific simulations of cardiac electrophysiology, wall mechanics and hemodynamics. Within the European integrated project euHeart, algorithms have been developed that allow to efficiently generate patient-specific anatomical models from medical images from multiple imaging modalities. These models, for instance, account for myocardial deformation, cardiac wall motion, and patient specific tissue information like myocardial scar location. Furthermore, integration of algorithms for anatomy extraction and physiological simulations has been brought forward. Physiological simulations are linked closer to anatomical models by encoding tissue properties, like the muscle fibers, into segmentation meshes. Biophysical constraints are also utilized in combination with image analysis to assess tissue properties. Both examples show directions of how physiological simulations could provide new challenges and stimuli for image analysis research in the future. PMID- 23359256 TI - Non-parametric and integrated framework for segmenting and counting neuroblastic cells within neuroblastoma tumor images. AB - Neuroblastoma is a malignant tumor and a cancer in childhood that derives from the neural crest. The number of neuroblastic cells within the tumor provides significant prognostic information for pathologists. An enormous number of neuroblastic cells makes the process of counting tedious and error-prone. We propose a user interaction-independent framework that segments cellular regions, splits the overlapping cells and counts the total number of single neuroblastic cells. Our novel segmentation algorithm regards an image as a feature space constructed by joint spatial-intensity features of color pixels. It clusters the pixels within the feature space using mean-shift and then partitions the image into multiple tiles. We propose a novel color analysis approach to select the tiles with similar intensity to the cellular regions. The selected tiles contain a mixture of single and overlapping cells. We therefore also propose a cell counting method to analyse morphology of the cells and discriminate between overlapping and single cells. Ultimately, we apply watershed to split overlapping cells. The results have been evaluated by a pathologist. Our segmentation algorithm was compared against adaptive thresholding. Our cell counting algorithm was compared with two state of the art algorithms. The overall cell counting accuracy of the system is 87.65 %. PMID- 23359259 TI - The hedgehog pathway in breast cancer. PMID- 23359258 TI - Dynamic finite size effects in spiking neural networks. AB - We investigate the dynamics of a deterministic finite-sized network of synaptically coupled spiking neurons and present a formalism for computing the network statistics in a perturbative expansion. The small parameter for the expansion is the inverse number of neurons in the network. The network dynamics are fully characterized by a neuron population density that obeys a conservation law analogous to the Klimontovich equation in the kinetic theory of plasmas. The Klimontovich equation does not possess well-behaved solutions but can be recast in terms of a coupled system of well-behaved moment equations, known as a moment hierarchy. The moment hierarchy is impossible to solve but in the mean field limit of an infinite number of neurons, it reduces to a single well-behaved conservation law for the mean neuron density. For a large but finite system, the moment hierarchy can be truncated perturbatively with the inverse system size as a small parameter but the resulting set of reduced moment equations that are still very difficult to solve. However, the entire moment hierarchy can also be re-expressed in terms of a functional probability distribution of the neuron density. The moments can then be computed perturbatively using methods from statistical field theory. Here we derive the complete mean field theory and the lowest order second moment corrections for physiologically relevant quantities. Although we focus on finite-size corrections, our method can be used to compute perturbative expansions in any parameter. PMID- 23359257 TI - A NMR guided approach for CsrA-RNA crystallization. AB - Structure determination of protein-nucleic acid complexes remains a challenging task. Here we present a simple method for generating crystals of a CsrA-nucleic acid complex, guided entirely by results from nuclear magnetic resonances spectroscopy (NMR) spectroscopy. Using a construct that lacks thirteen non essential C-terminal residues, efficient binding to DNA could be demonstrated. One CsrA dimer interacts with two DNA oligonucleotides, similar to previous findings with RNA. Furthermore, the NMR study of the CsrA-DNA complex was the basis for successfully homing in on conditions that were suitable for obtaining crystals of the CsrA-DNA complex. Our results may be useful for those cases where RNA in protein-nucleic acid complexes may be replaced by DNA. PMID- 23359260 TI - [Who's afraid of the bad wolf?]. PMID- 23359261 TI - [Immediate manuscript submission via the Internet]. PMID- 23359262 TI - [Health effects of aircraft noise: current evidence]. PMID- 23359264 TI - CD8+ tumor-infiltrating T cells are trapped in the tumor-dendritic cell network. AB - Chemotherapy enhances the antitumor adaptive immune T cell response, but the immunosuppressive tumor environment often dominates, resulting in cancer relapse. Antigen-presenting cells such as tumor-associated macrophages (TAMs) and tumor dendritic cells (TuDCs) are the main protagonists of tumor-infiltrating lymphocyte (TIL) immunosuppression. TAMs have been widely investigated and are associated with poor prognosis, but the immunosuppressive activity of TuDCs is less well understood. We performed two-photon imaging of the tumor tissue to examine the spatiotemporal interactions between TILs and TuDCs after chemotherapy. In a strongly immunosuppressive murine tumor model, cyclophosphamide-mediated chemotherapy transiently enhanced the antitumor activity of adoptively transferred ovalbumin-specific CD8(+) T cell receptor transgenic T cells (OTI) but barely affected TuDC compartment within the tumor. Time lapse imaging of living tumor tissue showed that TuDCs are organized as a mesh with dynamic interconnections. Once infiltrated into the tumor parenchyma, OTI T cells make antigen-specific and long-lasting contacts with TuDCs. Extensive analysis of TIL infiltration on histologic section revealed that after chemotherapy the majority of OTI T cells interact with TuDCs and that infiltration is restricted to TuDC-rich areas. We propose that the TuDC network exerts antigen-dependent unproductive retention that trap T cells and limit their antitumor effectiveness. PMID- 23359265 TI - Comparison of nevirapine plasma concentrations between lead-in and steady-state periods in Chinese HIV-infected patients. AB - OBJECTIVES: To investigate the potential of nevirapine 200 mg once-daily regimen and evaluate the influence of patient characteristics on nevirapine concentrations. METHODS: This was a prospective, multicentre cohort study with 532 HIV-infected patients receiving nevirapine as a part of their initial antiretroviral therapy. Plasma samples were collected at trough or peak time at the end of week 2 (lead-in period) and week 4, 12, 24, 36, and 48 (steady-state period), and nevirapine concentrations were determined using a validated HPLC method. Potential influencing factors associated with nevirapine concentrations were evaluated using univariate and multivariate logistic regression. RESULTS: A total of 2348 nevirapine plasma concentrations were collected, including 1510 trough and 838 peak values. The median nevirapine trough and peak concentration during the lead-in period were 4.26 ug/mL (IQR 3.05-5.61) and 5.07 ug/mL (IQR 3.92-6.44) respectively, which both exceeded the recommended thresholds of nevirapine plasma concentrations. Baseline hepatic function had a moderate effect on median nevirapine trough concentrations at week 2 (4.25 ug/mL v.s. 4.86 ug/mL, for ALT <1.5 * ULN and >= 1.5 * ULN, respectively, P = 0.045). No significant difference was observed in median nevirapine trough concentration between lead-in and steady-state periods in patients with baseline ALT and AST level >= 1.5 * ULN (P = 0.171, P = 0.769), which was different from the patients with ALT/AST level <1.5ULN. The median trough concentrations were significantly higher in HIV/HCV co infected patients than those without HCV at week 48 (8.16 ug/mL v.s. 6.15 ug/mL, P = 0.004). CONCLUSIONS: The 200 mg once-daily regimen of nevirapine might be comparable to twice-daily in plasma pharmacokinetics in Chinese population. Hepatic function prior to nevirapine treatment and HIV/HCV coinfection were significantly associated with nevirapine concentrations. PMID- 23359267 TI - Multicenter clinical study for evaluation of efficacy and safety of transdermal fentanyl matrix patch in treatment of moderate to severe cancer pain in 474 chinese cancer patients. AB - OBJECTIVE: Although a new matrix formulation fentanyl has been used throughout the world for cancer pain management, few data about its efficacy and clinical outcomes associated with its use in Chinese patients have been obtained. This study aimed to assess the efficacy and safety of the new system in Chinese patients with moderate to severe cancer pain. METHODS: A total of 474 patients with moderate to severe cancer pain were enrolled in this study and were treated with the new transdermal fentanyl matrix patch (TDF) up to 2 weeks. All the patients were asked to record pain intensity, side effects, quality of life (QOL), adherence and global satisfaction. The initial dose of fentanyl was 25 MUg/h titrated with opioid or according to National Comprehensive Cancer Network (NCCN) guidelines. Transdermal fentanyl was changed every three days. RESULTS: After 2 weeks. The mean pain intensity of the 459 evaluated patients decreased significantly from 5.63+/-1.26 to 2.03+/-1.46 (P<0.0001). The total remission rate was 91.29%, of which moderate remission rate 53.16%, obvious remission rate 25.49% and complete remission rate 12.64%. The rate of adverse events was 33.75%, 18.78% of which were moderate and 3.80% were severe. The most frequent adverse events were constipation and nausea. No fatal events were observed. The quality of life was remarkably improved after the treatment (P<0.0001). CONCLUSION: The new TDF is effective and safe in treating patients with moderate to severe cancer pain, and can significantly improve the quality of life. PMID- 23359268 TI - An investigation into the effect of spray drying temperature and atomizing conditions on miscibility, physical stability, and performance of naproxen-PVP K 25 solid dispersions. AB - The present study investigates the effect of changing spray drying temperature (40 degrees C-120 degrees C) and/or atomizing airflow rate (AR; 5-15 L/min) on the phase structure, physical stability, and performance of spray-dried naproxen polyvinylpyrrolidone (PVP) K 25 amorphous solid dispersions. The modulated differential scanning calorimetry, attenuated total internal reflectance-Fourier transform infrared, and powder X-ray diffractometry (pXRD) studies revealed that higher inlet temperature (IT) or atomization airflow leads to the formation of amorphous-phase-separated dispersions with higher strongly H-bonded and free PVP fractions, whereas that prepared with the lowest IT was more homogeneous. The dispersion prepared with the lowest atomization AR showed trace crystallinity. Upon exposure to 75% relative humidity (RH) for 3 weeks, the phase-separated dispersions generated by spray drying at higher temperature or higher atomization airflow retained relatively higher amorphous drug fraction compared with those prepared at slow evaporation conditions. The humidity-controlled pXRD analysis at 98% RH showed that the dispersion prepared with highest atomization AR displayed the slowest kinetics of recrystallization. The molecular-level changes occurring during recrystallization at 98% RH was elucidated by spectroscopic monitoring at the same humidity. The rate and extent of the drug dissolution was the highest for dispersions prepared at the highest atomizing AR and the lowest for that prepared with the slowest atomizing condition. PMID- 23359266 TI - The battle between rotavirus and its host for control of the interferon signaling pathway. AB - Viral pathogens must overcome innate antiviral responses to replicate successfully in the host organism. Some of the mechanisms viruses use to interfere with antiviral responses in the infected cell include preventing detection of viral components, perturbing the function of transcription factors that initiate antiviral responses, and inhibiting downstream signal transduction. RNA viruses with small genomes and limited coding space often express multifunctional proteins that modulate several aspects of the normal host response to infection. One such virus, rotavirus, is an important pediatric pathogen that causes severe gastroenteritis, leading to ~450,000 deaths globally each year. In this review, we discuss the nature of the innate antiviral responses triggered by rotavirus infection and the viral mechanisms for inhibiting these responses. PMID- 23359270 TI - Asterixis as a presentation of cerebellar ischemic stroke. AB - Asterixis is not yet considered a common neurological sign of cerebellum infarction, and the pathogenic mechanism for asterixis remains elusive. We report a 58-year-old male with moderate hypertension who presented to our emergency department for acute headache in both cervical and occipital regions of the left side. About 2 hours later the patient developed ipsilateral asterixis in the upper left limb; 3 days later the asterixis disappeared. Magnetic resonance imaging of the brain disclosed cerebellar infarctions at the left superior cerebellar artery. In conclusion, we observed that a transitory asterixis associated with ipsilateral headache can be an initial clinical manifestation of ipsilateral cerebellar infarctions in the superior cerebellar artery area. PMID- 23359269 TI - Lexical processing in deaf readers: an FMRI investigation of reading proficiency. AB - Individuals with significant hearing loss often fail to attain competency in reading orthographic scripts which encode the sound properties of spoken language. Nevertheless, some profoundly deaf individuals do learn to read at age appropriate levels. The question of what differentiates proficient deaf readers from less-proficient readers is poorly understood but topical, as efforts to develop appropriate and effective interventions are needed. This study uses functional magnetic resonance imaging (fMRI) to examine brain activation in deaf readers (N = 21), comparing proficient (N = 11) and less proficient (N = 10) readers' performance in a widely used test of implicit reading. Proficient deaf readers activated left inferior frontal gyrus and left middle and superior temporal gyrus in a pattern that is consistent with regions reported in hearing readers. In contrast, the less-proficient readers exhibited a pattern of response characterized by inferior and middle frontal lobe activation (right>left) which bears some similarity to areas reported in studies of logographic reading, raising the possibility that these individuals are using a qualitatively different mode of orthographic processing than is traditionally observed in hearing individuals reading sound-based scripts. The evaluation of proficient and less-proficient readers points to different modes of processing printed English words. Importantly, these preliminary findings allow us to begin to establish the impact of linguistic and educational factors on the neural systems that underlie reading achievement in profoundly deaf individuals. PMID- 23359271 TI - T-cell immunoglobulin- and mucin-domain-containing molecule 3 gene polymorphisms and prognosis of non-small-cell lung cancer. AB - Lung cancer is the leading cause of death worldwide. Non-small-cell lung cancer (NSCLC) accounts for most of these cases. T-cell immunoglobulin- and mucin-domain containing molecule 3 (TIM-3) has been established as a negative regulatory molecule and plays a critical role in immune tolerance. Studies have shown that polymorphisms in TIM-3 gene can be associated with various diseases. The aim of this study was to investigate whether polymorphisms in the TIM-3 gene were associated with susceptibility to NSCLC. Three polymorphisms in TIM-3 gene ( 1516G/T, -574G/T, and +4259T/G) were identified by polymerase chain reaction restriction fragment length polymorphism in 432 NSCLC patients and 466 healthy controls. Results showed that frequencies of TIM-3 +4259TG genotype for cases and controls were 10.9 and 4.1 %, respectively; subjects carrying the +4259TG genotype had a 2.81-fold increased risk of NSCLC compared to the wild-type genotype (P < 0.0001). The TIM-3 -1516G/T and -574G/T polymorphisms did not show any correlation with NSCLC. In addition, when analyzing the survival time of NSCLC patients with TIM-3 +4259T/G polymorphism, cases with +4259TG genotype had significantly shorter survival time compared to the wild-type patients (15.2 months vs. 26.7 months, P = 0.007). These results suggested polymorphism in TIM-3 gene is associated with increased susceptibility to NSCLC and could be used as prognostic factor for this malignancy. PMID- 23359272 TI - The curcumin analog DM-1 induces apoptotic cell death in melanoma. AB - The main difficulty in the successful treatment of metastatic melanoma is that this type of cancer is known to be resistant to chemotherapy. Chemotherapy remains the treatment of choice, and dacarbazine (DTIC) is the best standard treatment. The DM-1 compound is a curcumin analog that possesses several curcumin characteristics, such as antiproliferative, antitumor, and antimetastatic properties. The objective of this study was to evaluate the signaling pathways involved in melanoma cell death after treatment with DM-1 compared to the standard agent for melanoma treatment, DTIC. Cell death was evaluated by flow cytometry for annexin V and iodide propide, cleaved caspase 8, and TNF-R1 expression. Hoechst 33342 staining was evaluated by fluorescent microscopy; lipid peroxidation and cell viability (MTT) were evaluated by colorimetric assays. The antiproliferative effects of the drugs were evaluated by flow cytometry for cyclin D1 and Ki67 expression. Mice bearing B16F10 melanoma were treated with DTIC, DM-1, or both therapies. DM-1 induced significant apoptosis as indicated by the presence of cleaved caspase 8 and an increase in TNF-R1 expression in melanoma cells. Furthermore, DM-1 had antiproliferative effects in this the same cell line. DTIC caused cell death primarily by necrosis, and a smaller melanoma cell population underwent apoptosis. DTIC induced oxidative stress and several physiological changes in normal melanocytes, whereas DM-1 did not significantly affect the normal cells. DM-1 antitumor therapy in vivo showed tumor burden decrease with DM-1 monotherapy or in combination with DTIC, besides survival rate increase. Altogether, these data confirm DM-1 as a chemotherapeutic agent with effective tumor control properties and a lower incidence of side effects in normal cells compared to DTIC. PMID- 23359273 TI - Long noncoding RNA: an emerging paradigm of cancer research. AB - Recent studies have demonstrated the importance of non-protein coding part of human genome in carcinogenesis and metastasis. Among numerous kinds of non protein coding RNAs, long noncoding RNAs (lncRNAs) play a key regulatory role in cancer biology. LncRNAs are dysregulated in different kinds of cancer and the expression levels of certain lncRNAs are associated with recurrence, metastasis, and prognosis of cancer. It is also proved that overexpression of certain lncRNAs, behaving like oncogenes, can promote matrix invasion of cancer cells and tumor growth. In this review, we focus our attention on lncRNAs those have been validated in human cancer tissues to suggest reasonable strategies for future research. We introduce an update view of lncRNA, extract cancer-related lncRNAs from literature, and describe the known functions and possible underlying molecular mechanisms of some well investigated lncRNAs (MALAT1, HOX antisense intergenic RNA, and highly upregulated in hepatocellular cancer), as well as their current and potential future application in cancer diagnosis (PCA3) and treatment (H19). PMID- 23359274 TI - Methylenetetrahydrofolate reductase gene polymorphisms association with the risk of follicular lymphoma: a meta-analysis. AB - To date, case-control studies on the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and follicular lymphoma have provided controversial results. To clarify the effect of MTHFR polymorphisms on the risk of follicular lymphoma, a meta-analysis of all case control studies was performed. The fixed effects and random effects model showed that the C677T polymorphism was associated with a risk of follicular lymphoma among Caucasian populations, and A1298C polymorphism was associated with a risk of follicular lymphoma among Asian populations. Our pooled data suggest evidence for a major role of MTHFR polymorphisms in the carcinogenesis of follicular lymphoma. PMID- 23359275 TI - Fluorouracil selectively enriches stem-like cells in the lung adenocarcinoma cell line SPC. AB - Most adult stem cells are in the G0 or quiescent phase of the cell cycle and account for only a small percentage of the cells in the tissue. Thus, isolation of stem cells from tissues for further study represents a major challenge. This study sought to enrich cancer stem cells and explore cancer stem-like cell clones using 5-fluorouracil (5-FU) in the lung adenocarcinoma cell line, SPC. Proliferation inhibition was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assays, according to which half maximal inhibitory concentration values were calculated. Expression levels of stem cell markers after treatment with 5-FU were examined using immunofluorescence and Western blotting. Additionally, side population (SP) cells were sorted using FACS. Properties of SP cells were evaluated by using Transwell, colony-forming assays, and tumor formation experiments. 5-FU greatly inhibits proliferation, especially of cells in S phase. SP cells possess greater invasive potential, higher clone forming potential, and greater tumor-forming ability than non-SP cells. Treatment with 5-FU enriches the SP cells with stem cell properties in human lung adenocarcinoma cell lines. PMID- 23359276 TI - Hepatitis B testing and access to care among racial and ethnic minorities in selected communities across the United States, 2009-2010. AB - Hepatitis B virus (HBV) infection is widely prevalent among racial and ethnic minorities in the United States; however, few data have been available regarding HBV testing and referral to care for these populations. Using survey data collected in 2009-2010 from the Racial and Ethnic Approaches to Community Health (REACH) across the U.S., we assessed rates and determinants of hepatitis B testing and access to care in 28 minority communities in the U.S. Of 53,896 respondents, 21,129 (39.2%) reported having been tested for hepatitis B. Of the 1,235 who reported testing positive, 411 (33.3%) reported currently receiving specialty care. After controlling for demographic and socioeconomic characteristics, the likelihood of having been tested for hepatitis B and receiving care if infected was higher among males, non-English speaking persons, and those having health insurance compared to their counterparts. Compared to college graduates, respondents without a college education were less likely to get tested for hepatitis B. CONCLUSION: These data indicate that more than half of racial/ethnic minority persons in these communities had not been tested for hepatitis B, and only about one-half of those who tested positive had ever received treatment. More state and federal efforts are needed to screen racial/ethnic minorities, especially foreign-born persons, for HBV and link those with infection to care. PMID- 23359277 TI - Consultation on the Libyan health systems: towards patient-centred services. AB - The extra demand imposed upon the Libyan health services during and after the Libyan revolution in 2011 led the ailing health systems to collapse. To start the planning process to re-engineer the health sector, the Libyan Ministry of Health in collaboration with the World Health Organisation (WHO) and other international experts in the field sponsored the National Health Systems Conference in Tripoli, Libya, between the 26th and the 30th of August 2012. The aim of this conference was to study how health systems function at the international arena and to facilitate a consultative process between 500 Libyan health experts in order to identify the problems within the Libyan health system and propose potential solutions. The scientific programme adopted the WHO health care system framework and used its six system building blocks: i) Health Governance; ii) Health Care Finance; iii) Health Service Delivery; iv) Human Resources for Health; v) Pharmaceuticals and Health Technology; and vi) Health Information System. The experts used a structured approach starting with clarifying the concepts, evaluating the current status of that health system block in Libya, thereby identifying the strengths, weaknesses, and major deficiencies. This article summarises the 500 health expert recommendations that seized the opportunity to map a modern health systems to take the Libyan health sector into the 21st century. PMID- 23359278 TI - Changes in serum lipid profile of obese or overweight children and adolescents following a lifestyle modification course. AB - BACKGROUND: Considering rapid global increase in children obesity and high prevalence of dyslipidemia in obese and overweight children, this study aimed to evaluate the effect of an educational course on changes of lipid profile in children. METHODS: This non-pharmacological clinical trial study was performed on 4-18 year-old children attending outpatient clinics of Isfahan Endocrine and Metabolism Research Center (Iran). Anthropometric measurements were conducted for all children. Fasting blood samples were taken from right hand of the participants at the first laboratory visit. Biochemical tests including measurement of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were also carried out. Children took part in one educational session in which they were taught about ways and benefits of having regular physical activity once a day and having healthy foods. All children were followed up for about four months and anthropometrics and biochemical tests were repeated. Data was analyzed using SPSS16. RESULTS: A total number of 412 children (245 girls and 167 boys) were divided into four age groups of under 6, 6-9, 10-13, and 14-18 years old. Baseline anthropometric measures were significantly higher in boys. However, there was no difference between boys and girls in baseline lipid profile. Children's body mass index (BMI) z-score increased in all age groups except for 14-18 year-old boys. In boys older than 10 years, there were significant reductions in LDL-C and TC. In girls over 10 years of age, there was a significant increase in HDL-C. Although anthropometric measurements did not change in children (except for 14-18 year-old-boys), there was a significant reduction in children's lipid profile after the study. CONCLUSION: Our study showed that although one session of interventional education had no significant effects on children's anthropometric measurements, it could change their lipid profile. Moreover, the intervention was more effective on improving lipid profile in children over 10 years of age. Therefore, effective interventional strategies must be invented and implemented on children based on their age group. PMID- 23359279 TI - On optimizing therapies, Orai, and ORNs. PMID- 23359280 TI - A Ca2+- and PKC-driven regulatory network in airway smooth muscle. PMID- 23359282 TI - Mechanism of sodium channel NaV1.9 potentiation by G-protein signaling. AB - Tetrodotoxin (TTX)-resistant voltage-gated Na (Na(V)) channels have been implicated in nociception. In particular, Na(V)1.9 contributes to expression of persistent Na current in small diameter, nociceptive sensory neurons in dorsal root ganglia and is required for inflammatory pain sensation. Using ND7/23 cells stably expressing human Na(V)1.9, we elucidated the biophysical mechanisms responsible for potentiation of channel activity by G-protein signaling to better understand the response to inflammatory mediators. Heterologous Na(V)1.9 expression evoked TTX-resistant Na current with peak activation at -40 mV with extensive overlap in voltage dependence of activation and inactivation. Inactivation kinetics were slow and incomplete, giving rise to large persistent Na currents. Single-channel recording demonstrated long openings and correspondingly high open probability (P(o)) accounting for the large persistent current amplitude. Channels exposed to intracellular GTPgammaS, a proxy for G protein signaling, exhibited twofold greater current density, slowing of inactivation, and a depolarizing shift in voltage dependence of inactivation but no change in activation voltage dependence. At the single-channel level, intracellular GTPgammaS had no effect on single-channel amplitude but caused an increased mean open time and greater P(o) compared with recordings made in the absence of GTPgammaS. We conclude that G-protein activation potentiates human Na(V)1.9 activity by increasing channel open probability and mean open time, causing the larger peak and persistent current, respectively. Our results advance our understanding about the mechanism of Na(V)1.9 potentiation by G-protein signaling during inflammation and provide a cellular platform useful for the discovery of Na(V)1.9 modulators with potential utility in treating inflammatory pain. PMID- 23359281 TI - Ca2+ oscillations, Ca2+ sensitization, and contraction activated by protein kinase C in small airway smooth muscle. AB - Protein kinase C (PKC) has been implicated in the regulation of smooth muscle cell (SMC) contraction and may contribute to airway hyperresponsiveness. Here, we combined optical and biochemical analyses of mouse lung slices to determine the effects of PKC activation on Ca(2+) signaling, Ca(2+) sensitivity, protein phosphorylation, and contraction in SMCs of small intrapulmonary airways. We found that 10 uM phorbol-12-myristate-13-acetate or 1 uM phorbol 12,13-dibutyrate induced repetitive, unsynchronized, and transient contractions of the SMCs lining the airway lumen. These contractions were associated with low frequency Ca(2+) oscillations in airway SMCs that resulted from Ca(2+) influx through L-type voltage-gated Ca(2+) channels and the subsequent release of Ca(2+) from intracellular stores through ryanodine receptors. Phorbol ester stimulation of lung slices in which SMC intracellular Ca(2+) concentration ([Ca(2+)](i)) was "clamped" at a high concentration induced strong airway contraction, indicating that PKC mediated sensitization of the contractile response to [Ca(2+)](i). This Ca(2+) sensitization was accompanied by phosphorylation of both the PKC potentiated PP1 inhibitory protein of 17 kD (CPI-17) and the regulatory myosin light chain. Thrombin, like the phorbol esters, induced a strong Ca(2+) sensitization that was inhibited by the PKC inhibitor GF-109203X and also potentiated airway contraction to membrane depolarization with KCl. In conclusion, we suggest that PKC activation in small airways leads to both the generation of Ca(2+) oscillations and strong Ca(2+) sensitization; agents associated with airway inflammation, such as thrombin, may activate this pathway to sensitize airway smooth muscle to agonists that cause membrane depolarization and Ca(2+) entry and induce airway hyperresponsiveness. PMID- 23359283 TI - Opening the shaker K+ channel with hanatoxin. AB - Voltage-activated ion channels open and close in response to changes in membrane voltage, a property that is fundamental to the roles of these channels in electrical signaling. Protein toxins from venomous organisms commonly target the S1-S4 voltage-sensing domains in these channels and modify their gating properties. Studies on the interaction of hanatoxin with the Kv2.1 channel show that this tarantula toxin interacts with the S1-S4 domain and inhibits opening by stabilizing a closed state. Here we investigated the interaction of hanatoxin with the Shaker Kv channel, a voltage-activated channel that has been extensively studied with biophysical approaches. In contrast to what is observed in the Kv2.1 channel, we find that hanatoxin shifts the conductance-voltage relation to negative voltages, making it easier to open the channel with membrane depolarization. Although these actions of the toxin are subtle in the wild-type channel, strengthening the toxin-channel interaction with mutations in the S3b helix of the S1-S4 domain enhances toxin affinity and causes large shifts in the conductance-voltage relationship. Using a range of previously characterized mutants of the Shaker Kv channel, we find that hanatoxin stabilizes an activated conformation of the voltage sensors, in addition to promoting opening through an effect on the final opening transition. Chimeras in which S3b-S4 paddle motifs are transferred between Kv2.1 and Shaker Kv channels, as well as experiments with the related tarantula toxin GxTx-1E, lead us to conclude that the actions of tarantula toxins are not simply a product of where they bind to the channel, but that fine structural details of the toxin-channel interface determine whether a toxin is an inhibitor or opener. PMID- 23359284 TI - Interaction between residues in the Mg2+-binding site regulates BK channel activation. AB - As a unique member of the voltage-gated potassium channel family, a large conductance, voltage- and Ca(2+)-activated K(+) (BK) channel has a large cytosolic domain that serves as the Ca(2+) sensor, in addition to a membrane spanning domain that contains the voltage-sensing (VSD) and pore-gate domains. The conformational changes of the cytosolic domain induced by Ca(2+) binding and the conformational changes of the VSD induced by membrane voltage changes trigger the opening of the pore-gate domain. Although some structural information of these individual functional domains is available, how the interactions among these domains, especially the noncovalent interactions, control the dynamic gating process of BK channels is still not clear. Previous studies discovered that intracellular Mg(2+) binds to an interdomain binding site consisting of D99 and N172 from the membrane-spanning domain and E374 and E399 from the cytosolic domain. The bound Mg(2+) at this narrow interdomain interface activates the BK channel through an electrostatic interaction with a positively charged residue in the VSD. In this study, we investigated the potential interdomain interactions between the Mg(2+)-coordination residues and their effects on channel gating. By introducing different charges to these residues, we discovered a native interdomain interaction between D99 and E374 that can affect BK channel activation. To understand the underlying mechanism of the interdomain interactions between the Mg(2+)-coordination residues, we introduced artificial electrostatic interactions between residues 172 and 399 from two different domains. We found that the interdomain interactions between these two positions not only alter the local conformations near the Mg(2+)-binding site but also change distant conformations including the pore-gate domain, thereby affecting the voltage- and Ca(2+)-dependent activation of the BK channel. These results illustrate the importance of interdomain interactions to the allosteric gating mechanisms of BK channels. PMID- 23359285 TI - Convective washout reduces the antidiarrheal efficacy of enterocyte surface targeted antisecretory drugs. AB - Secretory diarrheas such as cholera are a major cause of morbidity and mortality in developing countries. We previously introduced the concept of antisecretory therapy for diarrhea using chloride channel inhibitors targeting the cystic fibrosis transmembrane conductance regulator channel pore on the extracellular surface of enterocytes. However, a concern with this strategy is that rapid fluid secretion could cause convective drug washout that would limit the efficacy of extracellularly targeted inhibitors. Here, we developed a convection-diffusion model of washout in an anatomically accurate three-dimensional model of human intestine comprising cylindrical crypts and villi secreting fluid into a central lumen. Input parameters included initial lumen flow and inhibitor concentration, inhibitor dissociation constant (K(d)), crypt/villus secretion, and inhibitor diffusion. We modeled both membrane-impermeant and permeable inhibitors. The model predicted greatly reduced inhibitor efficacy for high crypt fluid secretion as occurs in cholera. We conclude that the antisecretory efficacy of an orally administered membrane-impermeant, surface-targeted inhibitor requires both (a) high inhibitor affinity (low nanomolar K(d)) to obtain sufficiently high luminal inhibitor concentration (>100-fold K(d)), and (b) sustained high luminal inhibitor concentration or slow inhibitor dissociation compared with oral administration frequency. Efficacy of a surface-targeted permeable inhibitor delivered from the blood requires high inhibitor permeability and blood concentration (relative to K(d)). PMID- 23359286 TI - Effects of PFM rehabilitation on PFM function and morphology in older women. AB - AIMS: The purpose of this study was to examine the effect of a pelvic floor muscle (PFM) rehabilitation program on incontinence symptoms, PFM function, and morphology in older women with SUI. METHODS: Women 60 years old and older with at least weekly episodes of SUI were recruited. Participants were evaluated before and after a 12-week group PFM rehabilitation intervention. The evaluations included 3-day bladder diaries, symptom, and quality of life questionnaires, PFM function testing with dynamometry (force) and electromyography (activation) during seven tasks: rest, PFM maximum voluntary contraction (MVC), straining, rapid-repeated PFM contractions, a 60 sec sustained PFM contraction, a single cough and three repeated coughs, and sagittal MRI recorded at rest, during PFM MVCs and during straining to assess PFM morphology. RESULTS: Seventeen women (68.9 +/- 5.5 years) participated. Following the intervention the frequency of urine leakage decreased and disease-specific quality of life improved significantly. PFM function improved significantly: the participants were able to perform more rapid-repeated PFM contractions; they activated their PFMs sooner when coughing and they were better able to maintain a PFM contraction between repeated coughs. Pelvic organ support improved significantly: the anorectal angle was decreased and the urethrovescial junction was higher at rest, during contraction and while straining. CONCLUSIONS: This study indicated that improvements in urine leakage were produced along with improvements in PFM co ordination (demonstrated by the increased number of rapid PFM contractions and the earlier PFM activation when coughing), motor-control, pelvic organ support. PMID- 23359287 TI - Coordination strategies used in stone knapping. AB - Stone tool-use and manufacture is seen as an important skill during the evolution of our species and recently there has been increased interest in the understanding of perceptual-motor abilities underlying this skill. This study provides further information with respect to the motor strategies used during stone knapping. Kinematics of the striking arm were recorded in expert and novice knappers while producing flakes of two different sizes. Using Uncontrolled Manifold Analysis, the results showed that knappers structure joint angle movements such that the hammer trajectory variability is minimized across trials, with experts displaying significantly smaller variability compared with novices. Principal component analysis further revealed that a single component captures the complexity of the strike and that the strike is governed by movements of the elbow and the wrist. Analysis of movement velocities indicated that both groups adjusted movement velocities according to flake size although experts used smaller hammer, wrist, and elbow velocities in both flake conditions compared with novices. The results suggest that while the gross striking movement is easy to replicate for a novice knapper, it requires prolonged training before a knapper becomes attuned to the finer details necessary for controlled flaking. PMID- 23359289 TI - Neurofibromatosis in a 16 Year old. PMID- 23359288 TI - Obesity-driven inflammation and cancer risk: role of myeloid derived suppressor cells and alternately activated macrophages. AB - During carcinogenesis, tumors induce dysfunctional development of hematopoietic cells. Myeloid lineage cells, in the form of myeloid derived suppressor cells (MDSCs) and alternatively polarized M2 macrophages, influence almost all types of cancers by regulating diverse facets of immunosuppression, angiogenesis, cell proliferation, growth and metastasis. One-third of Americans are obese, and accumulating evidence suggests that obesity is a risk factor for various cancers. However, the relationship between these immune players and obesity are not well described. In this review, we evaluate potential mechanisms through which different aspects of obesity, namely insulin resistance, increased estrogen, adiposity and low grade chronic inflammation from adipose tissue macrophages, may coalesce to promote MDSC induction and M2 macrophage polarization, thereby facilitating cancer development. Detailed understanding of the interplay between obesity and myeloid mediated immunosuppression may provide novel avenues for therapeutic targeting, with the goal to reduce the challenge obesity presents towards gains made in cancer outcomes. PMID- 23359290 TI - Evolution of the tissue selective estrogen complex (TSEC). AB - Estrogens mediate gene transcription and signaling of numerous cellular processes in a variety of tissues, including the bone, breast, and endometrium, through binding and activation of estrogen receptors (ERs). Estrogen-mediated ER agonist activity has shown benefit in conditions related to estrogen deficiency in women; however, these effects have been associated with stimulation of breast and uterine tissues. Due to the complexity of ER signaling, selective estrogen receptor modulators (SERMs) can exhibit ER agonist or antagonist activity depending on the target tissue. A newer approach to menopausal therapy, the tissue selective estrogen complex (TSEC), pairs a SERM with one or more estrogens with the goal of maintaining the benefits of estrogens without the stimulatory effects on the breast and uterus. Preclinically, different TSECs have been associated with distinct gene expression profiles compared with each other and with their individual SERM/estrogen components. Studies in cultured breast cancer cells and animal models have demonstrated a lack of estrogen-induced stimulation with TSECs in the mammary gland and endometrium. In the breast, biochemical analyses indicate that degradation of the ER is an important mechanism by which TSECs exert their antagonistic effects. TSECs have also shown positive effects similar to estrogens in other tissue types, including bone and the central nervous system, although mechanisms underlying these activities are less clear. Overall, preclinical studies have shown that estrogens, SERMs, and TSECs each exert distinct and tissue specific molecular and pharmacologic effects. PMID- 23359291 TI - Phylogenetic Comparison of Influenza Virus Isolates from Three Medical Centers in Tehran with the Vaccine Strains during 2008-2009. AB - BACKGROUND: Influenza virus is a major infectious pathogen of the respiratory system causing a high degree of morbidity and mortality annually. The worldwide vaccines are decided and produced annually by World Health Organization and licensed companies based on the samples collected from all over the world. The aim of this study was to determine phylogenecity and heterogenecity of the circulating influenza isolates during 2008-2009 outbreaks in Tehran, compare them with the vaccine strains that were recommended by WHO for the same period. METHODS: Nasopharyngeal swabs (n=142) were collected from patients with influenza and influenza-like illness. Typing and subtyping of the isolates were performed using multiplex RT-PCR and phylogenetic analysis was carried out for hemagglutinin genes of the isolates. RESULTS: Fifty out of 142 samples were positive for influenza A virus, and no influenza B virus was detected. Phylogenetic analyses revealed that the A/H1N1 isolates were related closely to A/Brisbane/59/2007, and the A/H3N2 isolates were close to A/Brisbane/10/2007 vaccine strains. CONCLUSION: The findings of the present study demonstrate that the A/H1N1 was the predominant subtype of human influenza virus among the patients studied in Tehran during 2008-2009 winter seasons. In addition, some amino acid variation was found in Tehran/2008/H1N1 isolates from the 2008-2009 vaccine strain, but the H3N2 isolates showed higher genetic resemblance to the vaccine strain. PMID- 23359292 TI - Reduction of CAII Expression in Gastric Cancer: Correlation with Invasion and Metastasis. AB - OBJECTIVE: Human carbonic anhydrases II (CAII) gene plays an important role in different cancer. However, its relevance to gastric cancer (GC) remains unclear. In the present study, we aimed to investigate the expression of CAII in GC and explore its correlation with some clinicopathologic characteristics of GC. METHODS: The expression of CAII in 20 specimens of normal gastric mucosa, 38 specimens of intraepithelial neoplasia and 112 specimens of gastric carcinoma were detected by immunohistochemical techniques. Survival in GC with CAII expression was studied. RESULTS: The positive rate of CAII protein in normal gastric mucosa was significantly higher than that in intraepithelial neoplasia and gastric carcinoma (100% vs. 63.16% and 28.57%, P<0.001). The positive rate of CAII protein was significantly higher in gastric carcinoma at early stages than that at advanced stages (70.0% vs. 19.57%, P<0.001). The positive rate of CAII protein was significantly lower in gastric carcinoma with lymph node metastases than that without lymph node metastases (10.81% vs. 37.33%, P<0.05). Furthermore, the positive rate of CAII protein was significantly lower in poorly differentiated gastric carcinoma than in moderately- or well-differentiated gastric carcinoma (15.94% vs. 31.03% or 60.00%, P<0.05). Moreover, CAII expression was not related with sex, age and tumor size. The patients with CAII positive tumors showed a better survival rate than those with CAII-negative tumors (P=0.024, log-rank test). CONCLUSION: CAII expression was related with stages and lymph node metastases in gastric carcinoma. The reduction of CAII expression in GC might promote tumor cell motility and contribute to tumor growth and metastasis. PMID- 23359293 TI - [Incisional hernias after median laparotomy. A concept for anatomic reconstruction of the abdominal wall]. AB - The abdominal wall is a complex system of fibres and has its function in stabilisation of the lower back and pressure build-up for coughing and evacuation of the bowels. In case of incicional hernias after median laparotomy, which occur in 10-20%, reconstruction is a great challange for the surgeon. As methods of repair doubling of fascias, implantation of mesh grafts and muscle transfers have been described. In the following article we present a concept for anatomic and functional restoration of the abdominal wall in a selected patient population. Besides an exact surgical technique, the patient's compliance for weight reduction, special work-out and wearing a bodice pre- and postoperatively is essential for a good result. PMID- 23359295 TI - Vitamin D: metabolism, molecular mechanisms, and mutations to malignancies. AB - The potential protective effects of vitamin D against cutaneous carcinogenesis are still poorly understood. The inhibition, by vitamin D, of various cancers in in vitro and in vivo models has triggered detailed investigation of vitamin D effects on neoplastic behavior. Recent studies highlight that such neoplastic features as the tumor microenvironment, angiogenesis, DNA mutagenesis, and apoptosis are all connected to vitamin D metabolic pathways. This review discusses these connections. Vitamin D modulation of the cell cycle, DNA repair and apoptosis via its receptors (VDRs) may have a suppressive effect on skin cancer as some studies suggest. The regulation of multiple tumor signaling pathways by vitamin D may have an implication in cutaneous carcinogenesis and tumor progression to malignancy. PMID- 23359296 TI - Active commuting and sociodemographic factors among university students in Spain. AB - BACKGROUND: Commuting to university represents an opportunity to incorporate physical activity (walking or biking) into students' daily routines. There are few studies that analyze patterns of transport in university populations. This cross-sectional study estimated energy expenditure from active commuting to university (ACU) and examined sociodemographic differences in findings. METHODS: The sample included 518 students with a mean age of 22.4 years (59.7% female) from 2 urban universities in Valencia, Spain. Time spent in each mode of transport to university and sociodemographic factors was assessed by self-report. RESULTS: Nearly 35% of the students reported walking or biking as their main mode of transport. ACU (min/wk) were highest for walkers (168) and cyclists (137) and lowest for motorbike riders (0.0) and car drivers (16). Public transport users, younger students, low socioeconomic status students, and those living <= 2 km from the university had higher energy expenditure from active commuting than comparison groups. Biking was highest among those living 2-5 km from the university. CONCLUSIONS: Our findings suggest that active commuting and public transit use generated substantial weekly energy expenditure, contributed to meeting physical activity recommendations, and may aid in obesity prevention. PMID- 23359294 TI - Only missense mutations affecting the DNA binding domain of p53 influence outcomes in patients with breast carcinoma. AB - The presence of a TP53 gene mutation can influence tumour response to some treatments, especially in breast cancer. In this study, we analysed p53 mRNA expression, LOH at 17p13 and TP53 mutations from exons 2 to 11 in 206 patients with breast carcinoma and correlated the results with disease-free and overall survival. The observed mutations were classified according to their type and location in the three protein domains (transactivation domain, DNA binding domain, oligomerization domain) and correlated with disease-free and overall survival. In our population, neither p53 mRNA expression nor LOH correlated with outcome. Concerning TP53 mutations, 27% of tumours were mutated (53/197) and the presence of a mutation in the TP53 gene was associated with worse overall survival (p = 0.0026) but not with disease-free survival (p = 0.0697), with median survival of 80 months and 78 months, respectively. When alterations were segregated into mutation categories and locations, and related to survival, tumours harbouring mutations other than missense mutations in the DNA binding domain of P53 had the same survival profiles as wild-type tumours. Concerning missense mutations in the DNA binding domain, median disease-free and overall survival was 23 months and 35 months, respectively (p = 0.0021 and p<0.0001, respectively), compared with 78 and 80 months in mutated tumours overall. This work shows that disease-free and overall survival in patients with a frameshift mutation of TP53 or missense mutation in the oligomerization domain are the same as those in wild-type TP53 patients. PMID- 23359298 TI - Molecular epidemiology of Echovirus 30 in Fujian, China between 2001 and 2011. AB - Echovirus 30 (E-30) was responsible for an outbreak of aseptic meningitis between April 1 and June 2, 2011 in Fujian Province, China. A molecular epidemiology study of 115 E-30 strains was performed to characterize the genetic features of the etiologic agent of the 2011 aseptic meningitis outbreak. The phylogenetic trees of the complete VP1 gene (876 bp) from 74 of 115 isolates and 50 reference sequences were analyzed. Three lineages (E-30_h, i, and j) were detected that had co-circulated in Fujian in the last decade, of which E-30_j was new. The other 72 Fujian strains and 16 representative strains from other provinces of China all belong to E-30_h and E-30_i. Two distinct E-30 clusters including virus isolates obtained during adult surveillance were associated with the 2011 outbreak and differed from Fujian isolates prior to 2011, suggesting that the viruses may vary and adult infections play an important role in viral transmission. Thus, the multiple lineages of E-30 in Fujian and variant viruses enhanced transmissibility, which may be related to the epidemic activity of E-30. PMID- 23359300 TI - Prognostic implications of tumor extent in early-stage diffuse large B-cell lymphoma. AB - Therapeutic strategies for early-stage diffuse large B-cell lymphoma (DLBCL) are often influenced by tumor extent, but the prognostic value of this parameter is rarely defined. Here, a retrospective analysis was performed to define the impact of tumor extent on survival of patients with early-stage DLBCL. Eighty-six patients with stage II DLBCL, diagnosed from 2000-2007, were categorized into localized (n = 55, 64 %) and disseminated groups (n = 31, 36 %) based on tumor extent at time of diagnosis. Treatment modalities, chemotherapy regimen and number of chemotherapy cycles were the same between groups. With a median follow up of 7.6 years (range 2.1-12.1 years), overall 5-year event-free survival (EFS) and overall survival (OS) were 70.6 and 76.5 %, respectively. EFS (P = 1.00) and OS (P = 0.20) did not differ between the two groups. Older age (>60 years) was significantly associated with poor EFS (P = 0.01) and OS (P = 0.04). High-risk patients as rated by stage-modified international prognostic index (IPI) had inferior EFS (P = 0.04) and OS (P = 0.06) compared with the intermediate-risk group. These results indicate that tumor extent has no prognostic value in patients with early-stage DLBCL. Consistent with previous studies, age and stage modified IPI were useful prognostic indices for these patients. PMID- 23359301 TI - IL-6-positive classical Hodgkin's lymphoma co-occurring with plasma cell type of Castleman's disease: report of a case. AB - We present a case of classical Hodgkin's lymphoma (HL) co-occurring with histological features of Castleman's disease (CD). A 25-year-old man presented with left supraclavicular and axillary lymph node swelling and mediastinal mass. Using an initial biopsy specimen from left axillary lymph node, a tentative diagnosis of multicentric CD of plasma cell type was made. The serum level of interleukin-6 (IL-6) was elevated. The patient was treated with immunosuppressive therapy containing tocilizumab (TCZ). Shrinkage of mediastinal mass and axillary lymph nodes was seen; however, swelling of his left axillary lymph nodes reemerged, even after therapy with TCZ. A second left axillary lymph node biopsy was performed and a diagnosis of nodular sclerosis of classical HL without histologic features of CD was made. The initial biopsy specimen was re-examined, and scattered CD30+ Hodgkin/Reed-Sternberg cells were found in the interfollicular area. Interestingly, Hodgkin/Reed-Sternberg cells and surrounding reactive cells in both lymph nodes were stained with anti-IL-6 antibody. We emphasize that biopsy specimens with HL involvement may also have histologic features reminiscent of those seen in CD. To our knowledge, this is the first report to provide a detailed description of this pathology, including a survey of IL-6 and clinical course upon treatment with TCZ. PMID- 23359299 TI - Gene mutations of acute myeloid leukemia in the genome era. AB - Ten years ago, gene mutations found in acute myeloid leukemia (AML) were conceptually grouped into class I mutation, which causes constitutive activation of intracellular signals that contribute to the growth and survival, and class II mutation, which blocks differentiation and/or enhance self-renewal by altered transcription factors. A cooperative model between two classes of mutations has been suggested by murine experiments and partly supported by epidemiological findings. In the last 5 years, comprehensive genomic analysis proceeded to find new gene mutations, which are found in the epigenome-associated enzymes and the molecules never noticed so far. These new mutations apparently increase the complexity and heterogeneity of AML. Although a long list of gene mutations might have been compiled, the entire picture of molecular pathogenesis in AML remains to be elucidated because gene rearrangement, gene copy number, DNA methylation and expression profiles are not fully studied in conjunction with gene mutations. Comprehensive genome research will deepen the understanding of AML to promote the development of new classification and treatment. This review focuses on gene mutations that were recently discovered by genome sequencing. PMID- 23359302 TI - Successful treatment of a pregnant woman with Philadelphia chromosome-positive acute lymphoblastic leukemia. AB - The management of acute leukemia during pregnancy is challenging. Delays in treatment for acute leukemia can adversely affect maternal prognosis, but chemotherapy during pregnancy may induce severe adverse effects on the fetus. Here, we report a case of a pregnant woman with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) who underwent remission induction therapy and successfully delivered a live infant after chemotherapy. The case is a 36 year-old woman diagnosed with Ph(+)ALL in the 27th week of pregnancy. She underwent remission induction therapy including daunorubicin, vincristine, cyclophosphamide, and prednisolone. Imatinib was not used in the induction therapy. She delivered the infant after one course of chemotherapy. The infant and the patient are both alive now, without any major complications. PMID- 23359303 TI - Clonal lymphoproliferation of T cell large granular lymphocytes with pleomorphic nuclei following mantle cell lymphoma. PMID- 23359304 TI - Clinical progression of multiple myeloma presenting as parotid gland plasmacytoma. PMID- 23359305 TI - Silibinin inhibits ultraviolet B radiation-induced DNA-damage and apoptosis by enhancing interleukin-12 expression in JB6 cells and SKH-1 hairless mouse skin. AB - Recent studies have demonstrated silibinin efficacy against ultraviolet B (UVB) induced skin carcinogenesis via different mechanisms in cell lines and animal models; however, its role in regulating interleukin-12 (IL-12), an immunomodulatory cytokine that reduces UVB-induced DNA damage and apoptosis, is not known. Here, we report that UVB irradiation causes caspase 3 and PARP cleavage and apoptosis, and addition of recombinant IL-12 or silibinin immediately after UVB significantly protects UVB-induced apoptosis in JB6 cells. IL-12 antibody-mediated blocking of IL-12 activity compromised the protective effects of both IL-12 and silibinin. Both silibinin and IL-12 also accelerated the repair of UVB-caused cyclobutane-pyrimidine dimers (CPDs) in JB6 cells. Additional studies confirmed that indeed silibinin causes a significant increase in IL-12 levels in UVB-irradiated JB6 cells as well as in mouse skin epidermis, and that similar to cell-culture findings, silibinin topical application immediately after UVB exposure causes a strong protection against UVB-induced TUNEL positive cells in epidermis possibly through a significantly accelerated repair of UVB-caused CPDs. Together, these findings for the first time provide an important insight regarding the pharmacological mechanism wherein silibinin induces endogenous IL-12 in its efficacy against UVB-caused skin damages. In view of the fact that an enhanced endogenous IL-12 level could effectively remove UVB caused DNA damage and associated skin cancer, our findings suggest that the use of silibinin in UVB-damaged human skin would also be a practical and translational strategy to manage solar radiation-caused skin damages as well as skin cancer. PMID- 23359306 TI - The potential role of HMGB1 release in peritoneal dialysis-related peritonitis. AB - High mobility group box 1 (HMGB1), a DNA-binding nuclear protein, has been implicated as an endogenous danger signal in the pathogenesis of infection diseases. However, the potential role and source of HMGB1 in the peritoneal dialysis (PD) effluence of patients with peritonitis are unknown. First, to evaluate HMDB1 levels in peritoneal dialysis effluence (PDE), a total of 61 PD patients were enrolled in this study, including 42 patients with peritonitis and 19 without peritonitis. Demographic characteristics, symptoms, physical examination findings and laboratory parameters were recorded. HMGB1 levels in PDE were determined by Western blot and ELISA. The concentrations of TNF-alpha and IL 6 in PDE were quantified by ELISA. By animal model, inhibition of HMGB1 with glycyrrhizin was performed to determine the effects of HMGB1 in LPS-induced mice peritonitis. In vitro, a human peritoneal mesothelial cell line (HMrSV5) was stimulated with lipopolysaccharide (LPS), HMGB1 extracellular content in the culture media and intracellular distribution in various cellular fractions were analyzed by Western blot or immunofluorescence. The results showed that the levels of HMGB1 in PDE were higher in patients with peritonitis than those in controls, and gradually declined during the period of effective antibiotic treatments. Furthermore, the levels of HMGB1 in PDE were positively correlated with white blood cells (WBCs) count, TNF-alpha and IL-6 levels. However, pretreatment with glycyrrhizin attenuated LPS-induced acute peritoneal inflammation and dysfunction in mice. In cultured HMrSV5 cells, LPS actively induced HMGB1 nuclear-cytoplasmic translocation and release in a time and dose dependent fashion. Moreover, cytosolic HMGB1 was located in lysosomes and secreted via a lysosome-mediated secretory pathway following LPS stimulation. Our study demonstrates that elevated HMGB1 levels in PDE during PD-related peritonitis, at least partially, from peritoneal mesothelial cells, which may be involved in the process of PD-related peritonitis and play a critical role in acute peritoneal dysfunction. PMID- 23359307 TI - Analysis of the surgical learning curve using the cumulative sum (CUSUM) method. AB - AIMS: The concept of the "learning curve" is a term that has become increasingly prevalent in medical literature. Using a unique Female Urology fellowship program running over the last 3 years, we set out to better define the learning process for mid-urethral slings. METHODS: We examined surgical outcomes for six urology trainees who participated in the 6-month program from 2006 to 2011. We identified all retropubic mid-urethral sling procedures they had performed. Demographics included age, BMI, and smoking status. Outcomes focused on complication rates, as well as a subjective patient assessment. Analysis was by the cumulative sum method. RESULTS: Six trainees performed 187 retropubic slings during their fellowships. Mean age was 54 (SD +/- 12.7), mean BMI was 29.5 (SD +/- 5.5). One hundred sixty-five (88%) patients only underwent a mid-urethral tape with 22 (12%) undergoing a concomitant procedure. There were 5 cases of bladder perforation, 1 case of urethral injury, 25 cases of voiding dysfunction, and 8 cases of mesh exposure. One hundred sixty-seven out of 180 patients reported a cure or improvement. All complications occurred in the first 4 months of training. CUSUM analysis of voiding dysfunction showed that four out of six trainees did not reach the expected incidence of voiding dysfunction within the completed fellowship. Bladder perforation showed a similar trend. CONCLUSION: CUSUM analysis is an underused tool for the analysis of surgical competence. The learning curve for retropubic sling surgery is variable and may be longer than is often acknowledged. We suggest the focus of surgical training should move away from absolute numbers to look at training in an individualized manner. PMID- 23359308 TI - The psychopharmacology of agitation: consensus statement of the American association for emergency psychiatry project BETA psychopharmacology workgroup. PMID- 23359309 TI - Brief report: differences in multijoint symptomatic osteoarthritis phenotypes by race and sex: the Johnston County Osteoarthritis Project. AB - OBJECTIVE: To determine differences in the phenotypes (patterns) of multiple joint symptomatic osteoarthritis (OA) involvement by race and sex. METHODS: A cross-sectional analysis of symptomatic OA phenotypes was performed in a community-based cohort, comprising subjects for whom data were collected from 4 sites of symptomatic OA involvement (the hands, knees, hips, and lumbosacral [LS] spine) at a single visit (2003-2010). Mutually exclusive phenotypes describing all combinations of these 4 sites were compared by race and by sex, using Fisher's exact tests. For those phenotypes occurring in >40 subjects, logistic regression was performed, with adjustments for race, sex, age, and body mass index (BMI), and interactions of race and sex were assessed. RESULTS: The sample included 1,650 participants, of whom 36% were men and 32% were African American. The mean age of the subjects was 66 years, and the mean BMI was 31 kg/m(2). Overall, in this sample, 13% of subjects had symptomatic hand OA, 25% had symptomatic knee OA, 11% had symptomatic hip OA, and 28% had symptomatic LS spine OA. African Americans, as compared with Caucasians, were less likely to have involvement of symptomatic OA in the hand only, or in some combination of the hand and other sites, but were more likely to have involvement of the knee only. Men, as compared to women, were less likely to have involvement of the hand only, but were more likely to have involvement of the LS spine only. CONCLUSION: There are differences in the phenotypes of multiple-joint symptomatic OA involvement by race and by sex that may influence the definitions of multiple-joint, or generalized, OA. PMID- 23359310 TI - Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. AB - OBJECTIVE: To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue. METHODS: Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain. RESULTS: When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported. CONCLUSION: The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel group randomized controlled trials are needed to fully determine the efficacy of the medication. PMID- 23359313 TI - Referral and receipt of treatment for hepatocellular carcinoma in United States veterans: effect of patient and nonpatient factors. AB - The delivery of treatment for hepatocellular carcinoma (HCC) could be influenced by the place of HCC diagnosis (hospitalization versus outpatient), subspecialty referral following diagnosis, as well as physician and facility factors. We conducted a study to examine the effect of patient and nonpatient factors on the place of HCC diagnosis, referral, and treatment in Veterans Administration (VA) hospitals in the United States. Using the VA Hepatitis C Clinical Case Registry, we identified hepatitis C virus (HCV)-infected patients who developed HCC during 1998-2006. All cases were verified and staged according to Barcelona Clinic Liver Cancer (BCLC) criteria. The main outcomes were place of HCC diagnosis, being seen by a surgeon or oncologist, and treatment. We examined factors related to these outcomes using hierarchical logistic regression. These factors included HCC stage, HCC surveillance, physician specialty, and facility factors, in addition to risk factors, comorbidity, and liver disease indicators. Approximately 37.2% of the 1,296 patients with HCC were diagnosed during hospitalization, 31.0% were seen by a surgeon or oncologist, and 34.3% received treatment. Being seen by a surgeon or oncologist was associated with surveillance (adjusted odds ratio [aOR] = 1.47; 95% CI: 1.20-1.80) and varied by geography (1.74;1.09-2.77). Seeing a surgeon or oncologist was predictive of treatment (aOR = 1.43; 95% CI: 1.24 1.66). There was a significant increase in treatment among patients who received surveillance (aOR = 1.37; 95% CI: 1.02-1.71), were seen by gastroenterology (1.65;1.21-2.24), or were diagnosed at a transplant facility (1.48;1.15-1.90). CONCLUSION: Approximately 40% of patients were diagnosed during hospitalization. Most patients were not seen by a surgeon or oncologist for treatment evaluation and only 34% received treatment. Only receipt of HCC surveillance was associated with increased likelihood of outpatient diagnosis, being seen by a surgeon or oncologist, and treatment. PMID- 23359314 TI - [Inflammatory salivary gland diseases]. PMID- 23359315 TI - Cardioprotective effect of ghrelin in cardiopulmonary bypass involves a reduction in inflammatory response. AB - BACKGROUND: Ghrelin has been reported to protect the cardiovascular system; however, the cardioprotective effect of ghrelin against cardiopulmonary bypass (CPB) induced myocardial injury are unclear. In this study, the protective effect of ghrelin on CPB induced myocardial injury and the underlying mechanisms were investigated. METHODS AND RESULTS: Adult male rats were subjected to CPB and randomly to receive vehicle (n = 8), ghrelin (n = 8), ghrelin plus [D-Lys3]-GHRP 6, a GHSR-1a inhibitor (n = 8), or ghrelin plus wortmannin, a phosphoinositide 3' kinase (PI3K) inhibitor (n = 8). In vitro study was performed on cultured cardiomyocytes subjected to simulated cardiopulmonary bypass (SCPB). Ghrelin attenuated the inflammatory response, as evidenced by reduced induction of TNF alpha, IL-6 and myocardial myeloperoxidase activity and concurrent reduction in apoptosis, oxidative stress, and levels of myocardial injury markers following CPB. Moreover, ghrelin significantly increased cardiac function after CPB. In cultured cardiomyocytes subjected to simulated CPB, ghrelin increased cell viability and decreased the percentage of apoptotic myocytes. Inhibition of ghrelin downstream signaling blocked the cardioprotective effects both in vivo and vitro. CONCLUSIONS: Ghrelin could provide an effective approach to the attenuation of CPB induced myocardial injury. The cardioprotective effects elicited by ghrelin may contribute to the inhibition of inflammatory response through the Akt-activated pathway. PMID- 23359316 TI - Inverse relationship between physical activity and arterial stiffness in adults with hypertension. AB - BACKGROUND: Physical activity has beneficial effects on arterial stiffness among healthy adults. There is a lack of data on this relationship in adults with hypertension. The majority of studies which have examined physical activity and arterial stiffness have used subjective measures of activity. The aim of this study was to investigate the relationship between objectively measured habitual physical activity and arterial stiffness in individuals with newly diagnosed essential hypertension. METHODS: Adults attending an outpatient hypertension clinic were recruited into this cross sectional study. Physical activity was measured using a triaxial accelerometer. Pulse wave velocity (PWV) and augmentation index (AIx) were measured using applanation tonometry. Participant's full lipid profile and glucose were determined through the collection of a fasting blood sample. RESULTS: Fifty-three adults [51(14) years, 26 male] participated, 16 of whom had the metabolic syndrome. Inactivity was positively correlated with PWV (r = .53, P < .001) and AIx (r = .48, P < .001). There were significant inverse associations between habitual physical activity of all intensities and both AIx and PWV. In stepwise regression, after adjusting for potential confounders, physical activity was a significant predictor of AIx and PWV. CONCLUSION: Habitual physical activity of all intensities is associated with reduced arterial stiffness among adults with hypertension. PMID- 23359317 TI - The role of tumor suppressor p15Ink4b in the regulation of hematopoietic progenitor cell fate. AB - Epigenetic silencing of the tumor suppressor gene p15Ink4b (CDKN2B) is a frequent event in blood disorders like acute myeloid leukemia and myelodysplastic syndromes. The molecular function of p15Ink4b in hematopoietic differentiation still remains to be elucidated. Our previous study demonstrated that loss of p15Ink4b in mice results in skewing of the differentiation pattern of the common myeloid progenitor towards the myeloid lineage. Here, we investigated a function of p15Ink4b tumor suppressor gene in driving erythroid lineage commitment in hematopoietic progenitors. It was found that p15Ink4b is expressed more highly in committed megakaryocyte-erythroid progenitors than granulocyte-macrophage progenitors. More importantly, mice lacking p15Ink4b have lower numbers of primitive red cell progenitors and a severely impaired response to 5-fluorouracil and phenylhydrazine-induced hematopoietic stress. Introduction of p15Ink4b into multipotential progenitors produced changes at the molecular level, including activation of mitogen-activated protein kinase?extracellular signal-regulated kinase (MEK/ERK) signaling, increase GATA-1, erythropoietin receptor (EpoR) and decrease Pu1, GATA-2 expression. These changes rendered cells more permissive to erythroid commitment and less permissive to myeloid commitment, as demonstrated by an increase in early burst-forming unit-erythroid formation with concomitant decrease in myeloid colonies. Our results indicate that p15Ink4b functions in hematopoiesis, by maintaining proper lineage commitment of progenitors and assisting in rapid red blood cells replenishment following stress. PMID- 23359318 TI - Multidimensional scaling. AB - The concept of similarity, or a sense of 'sameness' among things, is pivotal to theories in the cognitive sciences and beyond. Similarity, however, is a difficult thing to measure. Multidimensional scaling (MDS) is a tool by which researchers can obtain quantitative estimates of similarity among groups of items. More formally, MDS refers to a set of statistical techniques that are used to reduce the complexity of a data set, permitting visual appreciation of the underlying relational structures contained therein. The current paper provides an overview of MDS. We discuss key aspects of performing this technique, such as methods that can be used to collect similarity estimates, analytic techniques for treating proximity data, and various concerns regarding interpretation of the MDS output. MDS analyses of two novel data sets are also included, highlighting in step-by-step fashion how MDS is performed, and key issues that may arise during analysis. WIREs Cogn Sci 2013, 4:93-103. doi: 10.1002/wcs.1203 This article is categorized under: Psychology > Perception and Psychophysics. PMID- 23359319 TI - Genome-wide association study identifies loci at ATF7IP and KLK2 associated with percentage of circulating free PSA. AB - BACKGROUND: Percentage of free-to-total prostate-specific antigen (%fPSA) is an independent predictor of risk for prostate cancer among men with modestly elevated level of total PSA (tPSA) in blood. Physiological and pathological factors have been shown to influence the %fPSA value and diagnostic accuracy. MATERIALS/METHODS: To evaluate genetic determinants of %fPSA, we conducted a genome-wide association study of serum %fPSA by genotyping 642,584 single nucleotide polymorphisms (SNPs) in 3192 men of European ancestry, each with a tPSA level of 2.5 to 10 ng/ml, that were recruited in the REduction by DUtasteride of Prostate Cancer Events study. Single nucleotide polymorphisms (SNPs) with P < 10(-5) were further evaluated among the controls of a population based case-control study in Sweden (2899 prostate cancer cases and 1722 male controls), including 464 controls having tPSA levels of 2.5 to 10 ng/ml. RESULTS: We identified two loci that were associated with %fPSA at a genome-wide significance level (P <5 x 10(-8)). The first associated SNP was rs3213764 (P = 6.45 x 10(-10)), a nonsynonymous variant (K530R) in the ATF7IP gene at 12p13. This variant was also nominally associated with tPSA (P = .015). The second locus was rs1354774 (P = 1.25 x 10(-12)), near KLK2 at 19q13, which was not associated with tPSA levels, and is separate from the rs17632542 locus at KLK3 that was previously associated with tPSA levels and prostate cancer risk. Neither rs3213764 nor rs1354774 was associated with prostate cancer risk or aggressiveness. CONCLUSIONS: These findings demonstrate that genetic variants at ATF7IP and KLK2 contribute to the variance of %fPSA. PMID- 23359320 TI - Adhesion of Neisseria meningitidis to dermal vessels leads to local vascular damage and purpura in a humanized mouse model. AB - Septic shock caused by Neisseria meningitidis is typically rapidly evolving and often fatal despite antibiotic therapy. Further understanding of the mechanisms underlying the disease is necessary to reduce fatality rates. Postmortem samples from the characteristic purpuric rashes of the infection show bacterial aggregates in close association with microvessel endothelium but the species specificity of N. meningitidis has previously hindered the development of an in vivo model to study the role of adhesion on disease progression. Here we introduced human dermal microvessels into SCID/Beige mice by xenografting human skin. Bacteria injected intravenously exclusively associated with the human vessel endothelium in the skin graft. Infection was accompanied by a potent inflammatory response with the secretion of human inflammatory cytokines and recruitment of inflammatory cells. Importantly, infection also led to local vascular damage with hemostasis, thrombosis, vascular leakage and finally purpura in the grafted skin, replicating the clinical presentation for the first time in an animal model. The adhesive properties of the type IV pili of N. meningitidis were found to be the main mediator of association with the dermal microvessels in vivo. Bacterial mutants with altered type IV pili function also did not trigger inflammation or lead to vascular damage. This work demonstrates that local type IV pili mediated adhesion of N. meningitidis to the vascular wall, as opposed to circulating bacteria, determines vascular dysfunction in meningococcemia. PMID- 23359321 TI - Report of incidence and mortality in china cancer registries, 2008. AB - OBJECTIVE: Annual cancer incidence and mortality in 2008 were provided by National Central Cancer Registry in China, which data were collected from population-based cancer registries in 2011. METHODS: There were 56 registries submitted their data in 2008. After checking and evaluating the data quality, total 41 registries' data were accepted and pooled for analysis. Incidence and mortality rates by area (urban or rural areas) were assessed, as well as the age- and sex-specific rates, age-standardized rates, proportions and cumulative rate. RESULTS: The coverage population of the 41 registries was 66,138,784 with 52,158,495 in urban areas and 13,980,289 in rural areas. There were 197,833 new cancer cases and 122,136 deaths in cancer with mortality to incidence ratio of 0.62. The morphological verified rate was 69.33%, and 2.23% of cases were identified by death certificate only. The crude cancer incidence rate in all areas was 299.12/100,000 (330.16/100,000 in male and 267.56/100,000 in female) and the age-standardized incidence rates by Chinese standard population (ASIRC) and world standard population (ASIRW) were 148.75/100,000 and 194.99/100,000, respectively. The cumulative incidence rate (0-74 years old) was of 22.27%. The crude incidence rate in urban areas was higher than that in rural areas. However, after adjusted by age, the incidence rate in urban was lower than that in rural. The crude cancer mortality was 184.67/100,000 (228.14/100,000 in male and 140.48/100,000 in female), and the age-standardized mortality rates by Chinese standard population (ASMRC) and by world population were 84.36/100,000 and 114.32/100,000, respectively. The cumulative mortality rate (0-74 years old) was of 12.89%. Age-adjusted mortality rates in urban areas were lower than that in rural areas. The most common cancer sites were lung, stomach, colon-rectum, liver, esophagus, pancreas, brain, lymphoma, breast and cervix which accounted for 75% of all cancer incidence. Lung cancer was the leading cause of cancer death, followed by gastric cancer, liver cancer, esophageal cancer, colorectal cancer and pancreas cancer, which accounted for 80% of all cancer deaths. The cancer spectrum varied by areas and sex in rural areas, cancers from digestive system were more common, such as esophageal cancer, gastric cancer and liver cancer, while incidence rates of lung cancer and colorectal cancer were much higher in urban areas. In addition, breast cancer was the most common cancer in urban women followed by liver cancer, gastric cancer and colorectal cancer. CONCLUSION: Lung cancer, gastric cancer, colorectal cancer, liver cancer, esophageal cancer and female breast cancer contributed to the increased incidence of cancer, which should be paid more attention to in further national cancer prevention and control program. Different cancer control strategies should be carried out due to the varied cancer spectrum in different groups. PMID- 23359322 TI - Endothelial cell leptin receptor mutant mice have hyperleptinemia and reduced tissue uptake. AB - Hyperleptinemia is usually associated with obesity and leptin resistance. Endothelial cell leptin receptor knockout (ELKO) mice without a signaling membrane-bound leptin receptor in endothelia, however, have profound hyperleptinemia without signs of leptin resistance. Leptin mRNA in adipose tissue was unchanged. To test the hypothesis that the ELKO mutation results in delayed degradation and slowed excretion, we determined the kinetics of leptin transfer in groups of ELKO and wildtype mice after intravenous bolus injection of (125) I leptin and the reference substance (131) I-albumin. The degradation pattern of (125) I-leptin in serum and brain homogenates at different time points between 10 and 60 min was measured by HPLC and acid precipitation. Although ELKO mice had reduced uptake of (125) I-leptin uptake by the brain and several peripheral organs, leptin was more stable in blood and tissue. There was no change in the rate of renal excretion. ELISA showed that serum soluble leptin receptor, known to antagonize leptin transport, had a 400-fold increase, probably contributing to the hyperleptinemia and reduced tissue uptake. Thus, the ELKO mutation unexpectedly increased the stability of leptin but suppressed its tissue uptake. These changes probably contribute to the known partial resistance of the ELKO mice to diet-induced obesity. PMID- 23359323 TI - Norovirus infection in children admitted to hospital for acute gastroenteritis in Belem, Para, Northern Brazil. AB - Noroviruses are the leading cause of epidemic, non-bacterial outbreaks of acute gastroenteritis, and are also a major cause of sporadic acute gastroenteritis in infants. The aim of the present study was to identify norovirus infections in children not infected by rotavirus admitted to hospital for acute gastroenteritis in Belem. A total of 348 fecal specimens were obtained from children with diarrhea aged less than 5 years, all of whom had tested negative for rotavirus, between May 2008 and April 2010. Fecal samples were screened for norovirus antigen using enzyme-immunoassay (EIA). Specimens were subjected to reverse transcription polymerase chain reaction (RT-PCR) using the primers Mon432/434 Mon431/433 for detection of the GI and GII norovirus strains, respectively. Based on both methods, the overall norovirus positivity rate was 36.5% (127/348). Of the 169 samples collected in the first year, 44.4% (n = 75) tested positive for norovirus using both methods, 35.5% (n = 60) by EIA and 40.8% (n = 69) by RT-PCR. Using RT-PCR as a reference standard, a sensitivity of 78.3%, specificity of 94%, and agreement of 87.6% were recorded. Genome sequencing was obtained for 22 (31.9%) of the 69 positive samples, of which 90.9% (20/22) were genotype GII.4d and 9.1% (2/22) were genotype GII.b. Norovirus infection was most frequent in children under 2 years of age (41.5%-115/277). The peak incidence (62.1%) of norovirus-related acute gastroenteritis in these patients (not infected by rotavirus) was observed in February 2010. These findings emphasize the importance of norovirus as a cause of severe acute gastroenteritis among children in Belem, Para, Northern Brazil. PMID- 23359324 TI - Physiological impact of CTO recanalization assessed by coronary pressure measurement: a case report. AB - In this case report, physiological changes of myocardial perfusion in the collateral recipient right coronary artery (RCA) and the collateral donor left anterior descending artery (LAD) with an intermediate lesion were assessed using intracoronary pressure measurement, before and after revascularization of chronic total occlusion (CTO). A 44-year-old male was referred for a catheter examination due to silent myocardial ischemia. An invasive coronary angiogram revealed diffuse narrowing of the RCA with focal occlusive segments in addition to intermediate stenosis in the LAD. A well developed collateral channel from the LAD to the RCA was also confirmed. Fractional flow reserve (FFRmyo) of the LAD before opening the RCA was 0.81. After successful revascularization of the RCA, FFRmyo of the LAD and the RCA were measured with and without an RCA balloon occlusion. Because collateral fractional flow reserve (FFRcoll) of the RCA could be regarded as FFRmyo before revascularization, FFRmyo of the RCA increased from 0.67 to 0.90, meaning a 23% increase of maximum flow by intervention. Interestingly, improvement of FFRmyo of the LAD from 0.81 to 0.93 was also observed, which means a 12% increase of maximum flow. Coronary steal in the LAD was reconfirmed by dramatic worsening of FFRmyo from 0.93 to 0.77 by an RCA balloon occlusion. This phenomenon may be explained by an immediate recruitment of collateral channels. This case clearly demonstrated that CTO opening improves perfusion in not only myocardium supplied by the CTO vessel, but also in that which is supplied by a contralateral collateral donor artery. PMID- 23359326 TI - A novel interaction between hScrib and PP1gamma downregulates ERK signaling and suppresses oncogene-induced cell transformation. AB - Previous studies have shown that the cell polarity regulator hScrib interacts with, and consequently controls, the ERK signaling pathway. This interaction occurs through two well-conserved Kinase Interacting Motifs, which allow hScrib to bind ERK1 directly, resulting in a reduction in the levels of phospho-ERK. This suggests that hScrib might recruit a phosphatase to regulate this signaling pathway. Using a proteomic approach we now show that Protein Phosphatase 1gamma (PP1gamma) is a major interacting partner of hScrib. This interaction is direct and occurs through a conserved PP1gamma interaction motif on the hScrib protein, and this interaction appears to be required for hScrib's ability to downregulate ERK phosphorylation. In addition, hScrib also controls the pattern of PP1gamma localization, where loss of hScrib enhances the nuclear translocation of PP1gamma. Furthermore, we also show that the ability of hScrib to interact with PP1gamma is important for the ability of hScrib to suppress oncogene-induced transformation of primary rodent cells. Taken together, these results demonstrate that hScrib acts as a scaffold to integrate the control of the PP1gamma and ERK signaling pathways and explains how disruption of hScrib localisation can contribute towards the development of human malignancy. PMID- 23359328 TI - Reply: To PMID 22532296. PMID- 23359327 TI - Multipeak fat-corrected complex R2* relaxometry: theory, optimization, and clinical validation. AB - PURPOSE: To develop R2* mapping techniques corrected for confounding factors and optimized for noise performance. THEORY AND METHODS: Conventional R2* mapping is affected by two key confounding factors: noise-related bias and the presence of fat in tissue. Noise floor effects introduce bias in magnitude-based reconstructions, particularly at high R2* values. The presence of fat, if uncorrected, introduces severe protocol-dependent bias. In this work, the bias/noise properties of different R2* mapping reconstructions (magnitude- and complex-fitting, fat-uncorrected, and fat-corrected) are characterized using Cramer-Rao Bound analysis, simulations, and in vivo data. A framework for optimizing the choice of echo times is provided. Finally, the robustness of liver R2* mapping in the presence of fat is evaluated in 28 subjects. RESULTS: Fat corrected R2* mapping removes fat-related bias without noise penalty over a wide range of R2* values. Complex nonlinear least-squares fitted and fat-corrected R2* reconstructions that account for the spectral complexity of fat provide robust R2* estimates with low bias and optimized noise performance over a wide range of echo times combinations and R2* values. CONCLUSION: The use of complex fitting and fat-correction improves the robustness, noise performance, and accuracy of R2* measurements, and are necessary to establish R2* as quantitative imaging biomarker in the liver. PMID- 23359330 TI - Efficient production of transgenic mice by intracytoplasmic injection of streptolysin-O-treated spermatozoa. AB - Many methods for efficient production of transgenic animals for biomedical research have been developed. Despite great improvements in transgenesis rates resulting from the use of intracytoplasmic sperm injection (ICSI), the ICSI-based sperm-mediated gene-transfer (iSMGT) technique is still not optimal in terms of sperm permeabilization efficiency and subsequent development. Here, we demonstrate that streptolysin-O (SLO) can efficiently permeabilize mouse spermatozoa, leading to improved developmental competence and high transgenesis rates in iSMGT embryos and pups. In particular, the most efficient production of iSMGT-transgenic embryos resulted from pretreatment with 5 U/ml SLO for 30 min and co-incubation with 1.0 ng/ul of an EGFP expression vector. By incubating spermatozoa with Cy-3-labelled DNA, we found that fluorescence intensity was prominently detected in the head region of SLO-treated spermatozoa. In addition, blastocyst development rate and blastomere survival were greatly improved by iSMGT using SLO-treated spermatozoa (iSMGT-SLO) as compared to freeze-thawed spermatozoa. Consistent with this, a high proportion of transgenic offspring was obtained by iSMGT-SLO after transfer into foster mothers, reaching 10.6% of the number of oocytes used (42.3% among pups). Together with successful germline transmission of transgenes in all founders analyzed, our data strongly suggest that SLO makes spermatozoa amenable to exogenous DNA uptake, and that the iSMGT SLO technique is an efficient method for production of transgenic animals for biomedical research. PMID- 23359329 TI - Combination chemotherapy with paclitaxel, cisplatin and fluorouracil for patients with advanced and metastatic gastric or esophagogastric junction adenocarcinoma: a multicenter prospective study. AB - OBJECTIVE: To evaluate the efficacy and toxicity of the combination regimen of paclitaxel, cisplatin and 5-FU (PCF) as first-line or second-line therapy in patients with advanced gastric and esophagogastric junction (EGJ) adenocarcinoma in China. METHODS: The patients were treated with paclitaxel 150 mg/m(2) on d1; fractionated cisplatin 15 mg/m(2) and continuous infusion 5-FU 600 mg/(m(2).d) intravenously on d1-d5 of a 21-d cycle until disease progression or unacceptable toxicities. RESULTS: Seventy-five patients have been enrolled, among which, 41 received PCF regimen as the first-line therapy (group A) and 34 received the regimen as the second-line therapy (group B) with the median age of 59 years old and Karnofsky performance status (KPS) score >=80. Toxicities were analyzed in all 75 patients. Seventy-one patients were evaluable for efficacy. The median overall survival (mOS) was 12.0 months (95% CI: 7.9-16.2 months) in group A and 7.3 months (95% CI: 4.3-10.3 months) in group B, respectively. The median progression-free survival (mPFS) was 5.7 months (95% CI: 4.1-7.2 months) and 5.0 months (95% CI: 3.1-6.9 months), respectively. The response rate (CR+PR) was 40% (16/40; 95% CI: 24.9-56.7%) in group A and 22.6% (7/31; 95% CI: 9.6-41.1%) in group B. Major grade 3 or 4 adverse events include neutropenia (41.3%), febrile neutropenia (9.3%), nausea/anorexia (10.7%), and vomiting (5.3%). There was no treatment-related death. CONCLUSIONS: The combination chemotherapy with PCF is active and tolerable as first-line and second-line therapy in Chinese patients with advanced gastric and EGJ adenocarcinoma. The response and survival of PCF are same as those of DCF, but the tolerance is much better. PMID- 23359331 TI - Reactivation of occult hepatitis B virus infection following cytotoxic lymphoma therapy in an anti-HBc negative patient. AB - Screening hepatitis B virus (HBV) surface antigen (HBsAg) and HBV core antibody (anti-HBc) is recommended prior to cytotoxic or immunosuppressive therapy. This case describes an anti-HBc negative, DNA positive occult HBV infection in a 71 year-old Caucasian male following rituximab-based treatment for follicular lymphoma. Pre-screening serology indicated negative HBsAg and anti-HBc. However, following sequential treatment cycles the patient developed weak HBsAg with a low HBV DNA load (<1,000 IU/ml), but remained anti-HBc negative. The DNA load peaked 5 months later (>1 * 10(6) IU/ml) and he was subsequently treated with Tenofovir. Currently the patient remains anti-HBc negative, and is anti-HBe negative, anti-HBs negative, HBeAg positive. No clinical or biochemical evidence of hepatitis has occurred. Sequencing and phylogenetic analysis identified the HBV genosubtype as D4, most probably acquired some years ago during a stay in Papua New Guinea, in spite of prior hepatitis B vaccination. Four amino acid substitutions were detected within the HBsAg loop yet none in the core protein. This case questions the dependability of anti-HBc testing and highlights the role of HBV DNA testing prior to and throughout cytotoxic or immunosuppressive regimes. As this case exemplifies, vaccination protects against clinical infection but may not exclude seronegative occult infection with the possibility of reactivation. PMID- 23359332 TI - The value of reporting decreased or absent fetal movements by mothers in predicting the pregnancy outcome. PMID- 23359333 TI - A bisazobenzene crosslinker that isomerizes with visible light. AB - BACKGROUND: Large conformational and functional changes of azobenzene-modified biomolecules require longer azobenzene derivatives that undergo large end-to-end distance changes upon photoisomerization. In addition, isomerization that occurs with visible rather than UV irradiation is preferred for biological applications. RESULTS: We report the synthesis and characterization of a new crosslinker in which a central piperazine unit links two azobenzene chromophores. Molecular modeling indicates that this crosslinker can undergo a large change in end-to-end distance upon trans,trans to cis,cis isomerization. Photochemical characterization indicates that it does isomerize with visible light (violet to blue wavelengths). However, the thermal relaxation rate of this crosslinker is rather high (tau(1/2) ~ 1 s in aqueous buffer at neutral pH) so that it is difficult to produce large fractions of the cis,cis-species without very bright light sources. CONCLUSION: While cis-lifetimes may be longer when the crosslinker is attached to a biomolecule, it appears the para-piperazine unit may be best suited for applications where rapid thermal relaxation is required. PMID- 23359334 TI - Mutational and expressional analyses of PTEN gene in colorectal cancer from Northern India. AB - The PTEN is a tumor-suppressor gene located on chromosome 10q23.3 and established to play key role in the varied types of cancer. To elucidate the possible effect of mutations and inactivation of PTEN gene on the occurrence and development of colorectal cancer (CRC), 223 cancer specimens were selected to probe PTEN gene mutations through the micro dissection of the genome. Polymerase chain reaction single-strand conformation polymorphism and DNA sequencing methods were applied for mutations while protein expression was evaluated by immunohistochemistry. Mutations in exons 7 and 8 of PTEN were observed in 12.5% and PTEN loss of expression was identified in 48% in CRC. In exon 7, we found the insertion of "G" resulted into the change at codon 218 from TGC to GTC leading to change in the reading frame starting downward from Cystein to Valine. In addition, the insertion of "A" in the same exon at codon 213 resulted into the change of codon CCT to CCA, which cause silent mutation. In exon 8, however, "A" is replaced by C at codon 282, but both encodes for Glycine. Statistically significant loss of PTEN expression was observed in cancerous tissue when compared with the adjacent control (P < 0.05). Furthermore, weak PTEN expression in CRC tissues were significantly associated with tumor size, depth of invasion, lymphatic invasion, lymph node metastasis, grade of differentiation, and TNM stage (P < 0.05). Our results suggested that PTEN gene mutation and loss of PTEN expression may provide valuable prognostic information to aid treatment strategies for CRC patients. PMID- 23359335 TI - Determination of chitin content in fungal cell wall: an alternative flow cytometric method. AB - The conventional methods used to evaluate chitin content in fungi, such as biochemical assessment of glucosamine release after acid hydrolysis or epifluorescence microscopy, are low throughput, laborious, time-consuming, and cannot evaluate a large number of cells. We developed a flow cytometric assay, efficient, and fast, based on Calcofluor White staining to measure chitin content in yeast cells. A staining index was defined, its value was directly related to chitin amount and taking into consideration the different levels of autofluorecence. Twenty-two Candida spp. and four Cryptococcus neoformans clinical isolates with distinct susceptibility profiles to caspofungin were evaluated. Candida albicans clinical isolate SC5314, and isogenic strains with deletions in chitin synthase 3 (chs3Delta/chs3Delta) and genes encoding predicted GlycosylPhosphatidylInositol (GPI)-anchored proteins (pga31Delta/Delta and pga62Delta/Delta), were used as controls. As expected, the wild-type strain displayed a significant higher chitin content (P < 0.001) than chs3Delta/chs3Delta and pga31Delta/Delta especially in the presence of caspofungin. Ca. parapsilosis, Ca. tropicalis, and Ca. albicans showed higher cell wall chitin content. Although no relationship between chitin content and antifungal drug susceptibility phenotype was found, an association was established between the paradoxical growth effect in the presence of high caspofungin concentrations and the chitin content. This novel flow cytometry protocol revealed to be a simple and reliable assay to estimate cell wall chitin content of fungi. PMID- 23359336 TI - Electrocardiogram changes in Thyrotoxic Periodic Paralysis. AB - Thyrotoxic periodic paralysis (TPP) attacks are characterized as recurrent, transient episodes of muscle weakness that range from mild weakness to complete flaccid paralysis. Episodes of weakness are accompanied by hypokalemia, which left untreated can lead to life-threatening arrhythmias (6). In this case study, we followed a patient's potassium levels analyzing how they correlate with electrocardiogram changes seen while treating his hypokalemia and ultimately his paralysis. PMID- 23359337 TI - Association of ethnicity with antipsychotic dosage using STRUCTURE analysis. AB - Several studies have examined whether ethnicity as an independent factor can influence the individual's dosage of antipsychotics. However, there has been inconsistency in the results of these studies, particularly between white and non white populations. This retrospective study tests the hypothesis of different dosing of antipsychotics in white Europeans vs. non-white Europeans considering both the self-reported ethnicity and the geographical ancestry calculated using 196 DNA markers.We collected self-reported ethnicity and DNA samples from 209 schizophrenia patients. We tested the association between self-reported and genetically-determined ethnicity with the chlorpromazine equivalent dose of each antipsychotic prescribed at the time of the assessment.We did not find any significant difference between self-reported white European -ethnicity and chlorpromazine equivalent doses (p=0.972). Furthermore, when we considered the geographical ancestry determined by the 196 SNPs, we could not find any correlation between the European ancestry and chlorpromazine equivalent dose.Our preliminary analysis shows that there is no evidence that different ethnic groups receive different dose of antipsychotics. PMID- 23359338 TI - Bispectral index monitoring and seizure quality optimization in electroconvulsive therapy. AB - In ECT, the relative timing of seizure induction and anesthesia may critically impact on seizure quality when anesthetic agents with anticonvulsive properties such as barbiturates or propofol are used. Measuring the depth of anesthesia by bispectral index (BIS) monitoring and thereby identifying the optimal moment for seizure induction might enhance seizure quality.Seizures from 869 individual ECT sessions with thiopental anesthetic from 118 patients were examined in this retrospective study. The associations of the BIS value at the moment of seizure induction with 7 established seizure parameters and with a novel model of seizure quality were tested by regression analyses.BIS value at induction correlated positively with seizure duration, central inhibition, coherence and maximal heart rate, but not with midictal amplitude. Higher seizure quality was related with a higher BIS value at the moment of seizure induction.The BIS value at seizure induction serves as an independent predictor of seizure quality, influencing most other established markers. BIS monitoring appears as a simple tool to identify the optimal moment for seizure induction. PMID- 23359339 TI - Withdrawal and discontinuation phenomena associated with tranylcypromine: a systematic review. AB - Tranylcypromine (TCP) is an effective antidepressant with a complex pharmacological profile and a relevant risk of abuse and dependence. Withdrawal phenomena (WP, in the case of TCP-abuse/dependence) or discontinuation phenomena (DP, in the case of absent TCP-abuse/dependence) subsequent to abrupt termination of TCP are a potentially severe clinical syndrome. We conducted a systematic review of all previously published WP/DP cases following abrupt termination of TCP in order to identify typical clinical presentations and risk factors of WP/DP and frequency of TCP abuse or dependence within these patients. By searching the Medline and Scopus databases we identified n=25 cases (cohort WP: n=18, cohort DP: n=7). Delirium was found in n=13 patients (cohort WP: 10/55.6%; cohort DP: 3/42.9%), n=6 demonstrated WP/DP without delirium (WP: 6/33.3%; DP: 0/0%) and n=5 rapid relapse in depression (WP: 1/5.6%; DP: 4/57.1%). Mean time until development of WP/DP was 1.9 (WP) and 2.2 (DP) days. Mean duration of WP/DP was 5.7 (WP) and 11.3 (DP) days. All patients of cohort WP were described to feature TCP-abuse/dependence. Patients with delirium were on average older (41.8 years vs. 37.8 years) and featured higher mean prescribed (71.0 mg vs. 38.3 mg) and actually taken daily TCP dosages (285.8 mg vs. 187.7 mg). In conclusion, even termination of lower daily dosages of TCP may result in delirium. Thrombocytopenia features diagnostic value in patients with deliria of unknown etiology. TCP should be administered with great care, especially in dependence prone patients.. PMID- 23359340 TI - The small GTPase Rif is dispensable for platelet filopodia generation in mice. AB - BACKGROUND: Formation of filopodia and other shape change events are vital for platelet hemostatic function. The mechanisms regulating filopodia formation by platelets are incompletely understood however. In particular the small GTPase responsible for initiating filopodia formation by platelets remains elusive. The canonical pathway involving Cdc42 is not essential for filopodia formation in mouse platelets. The small GTPase Rif (RhoF) provides an alternative route to filopodia generation in other cell types and is expressed in both human and mouse platelets. HYPOTHESIS/OBJECTIVE: We hypothesized that Rif might be responsible for generating filopodia by platelets and generated a novel knockout mouse model to investigate the functional role of Rif in platelets. METHODOLOGY/PRINCIPAL FINDINGS: Constitutive RhoF(-/-) mice are viable and have normal platelet, leukocyte and erythrocyte counts and indices. RhoF(-/-) platelets form filopodia and spread normally on various agonist surfaces in static conditions and under arterial shear. In addition, RhoF(-/-) platelets have normal actin dynamics, are able to activate and aggregate normally and secrete from alpha and dense granules in response to collagen related peptide and thrombin stimulation. CONCLUSIONS: The small GTPase Rif does not appear to be critical for platelet function in mice. Functional overlap between Rif and other small GTPases may be responsible for the non-essential role of Rif in platelets. PMID- 23359341 TI - Convergence and divergence in the evolution of the APOBEC3G-Vif interaction reveal ancient origins of simian immunodeficiency viruses. AB - Naturally circulating lentiviruses are abundant in African primate species today, yet their origins and history of transmitting between hosts remain obscure. As a means to better understand the age of primate lentiviruses, we analyzed primate genomes for signatures of lentivirus-driven evolution. Specifically, we studied the adaptive evolution of host restriction factor APOBEC3G (A3G) in Old World Monkey (OWM) species. We find recurrent mutation of A3G in multiple primate lineages at sites that determine susceptibility to antagonism by the lentiviral accessory protein Vif. Using a broad panel of SIV Vif isolates, we demonstrate that natural variation in OWM A3G confers resistance to Vif-mediated degradation, suggesting that adaptive variants of the host factor were selected upon exposure to pathogenic lentiviruses at least 5-6 million years ago (MYA). Furthermore, in members of the divergent Colobinae subfamily of OWM, a multi-residue insertion event in A3G that arose at least 12 MYA blocks the activity of Vif, suggesting an even more ancient origin of SIV. Moreover, analysis of the lentiviruses associated with Colobinae monkeys reveal that the interface of the A3G-Vif interaction has shifted and given rise to a second genetic conflict. Our analysis of virus-driven evolution describes an ancient yet ongoing genetic conflict between simian primates and lentiviruses on a million-year time scale. PMID- 23359342 TI - Systemic effects of Wnt signaling. AB - Wnt signaling plays a key role in several physiological and pathological aspects. Even if Wnt signal was first described more than 20 years ago, its role in systemic effects, such as angiogenesis and vascular disorders, bone biology, autoimmune diseases, neurological diseases, and neoplastic disorders, was only recently emerged through the use of animal and in vitro models. Moreover, Wnt signaling inhibitors, such as DKK-1, may be advantageously considered targets for the treatment of several diseases, including osteoporosis, vascular diseases, inflammatory diseases, neurological diseases, and cancer. Nevertheless, further studies are required to provide a complete understanding of this complex signaling pathway, and especially of its role in human diseases, considering the possible advantageous effects of Wnt signaling inhibitors on the progression of disease conditions. PMID- 23359343 TI - Inhibitory Effects of 5-Aza-2'-Deoxycytidine and Trichostatin A in Combination with p53-Expressing Adenovirus on Human Laryngocarcinoma Cells. AB - OBJECTIVE: To investigate the effects of 5-Aza-2'-deoxycytidine (5-Aza-Cdr) and trichostatin A (TSA) combined with p53-expressing adenovirus (Ad-p53) on Hep-2 cell line in vivo and in vitro, in order to explore its possibility in biological treatment of laryngocarcinoma. METHODS: Effects of 5-Aza-Cdr and TSA in combination with Ad-p53 on Hep-2 cell line in vivo were determined by Cell Counting Kit-8 (CCK-8) assay. The effect of drug combination was calculated by Jin's formula. Effects on the cell line in vitro were investigated by establishing the nude mice model. RESULTS: 5-Aza-Cdr and TSA showed inhibitory effects on the proliferation of Hep-2 cells in dose- and time-dependent manner. Ad-p53 can inhibit the growth of Hep-2 cells in vivo and in vitro. However, the combination of epigenetic reagents (5-Aza-Cdr/TSA) and Ad-p53 was less effective than individual use of Ad-p53. 5-Aza-Cdr and Ad-p53 inhibited the growth of transplanted tumors and reduced the volume of tumors, and the tumor volume of Ad p53 group was significantly smaller than that of the control group (P<0.05). CONCLUSION: Both epigenetic reagents (5-Aza-Cdr/TSA) and Ad-p53 can suppress cell proliferation on Hep-2 in vivo and in vitro and there may be some antagonistic mechanism between Ad-p53 and epigenetic reagents (5-Aza-Cdr/ TSA). PMID- 23359344 TI - Tabalumab in rheumatoid arthritis patients with an inadequate response to methotrexate and naive to biologic therapy: a phase II, randomized, placebo controlled trial. AB - OBJECTIVE: Tabalumab, a fully human IgG4 monoclonal antibody, neutralizes soluble and membrane-bound BAFF. The aim of this study was to examine the tolerability and efficacy of tabalumab in patients with active rheumatoid arthritis receiving methotrexate. METHODS: In this randomized, double-blind, placebo-controlled, parallel, multiple-dose study, patients who were naive to biologic therapy received infusions of tabalumab (30, 60, or 160 mg) or placebo at weeks 0, 3, and 6 in combination with methotrexate and were evaluated for 24 weeks. The primary efficacy end point was the percentage of patients meeting American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16. RESULTS: At week 16, the percentages of patients achieving an ACR20 response in the 30-mg (57.6%), 60-mg (67.6%), and 160-mg (51.5%) groups were significantly greater than the percentage of patients achieving an ACR20 response in the placebo group (29.4%; P<0.05). There were initial transient increases from baseline in the frequency of CD20+ and IgD+/CD27- B cells, followed by reductions, although B cells were not completely depleted. Also, the frequency of IgD-/CD27+ B cells increased in all tabalumab groups compared with the placebo group and returned toward baseline levels by the end of the study. The incidence of adverse events was similar across all treatment groups; no deaths occurred. Serum IgM levels decreased significantly in all tabalumab groups combined compared with the placebo group. There were no significant decreases in serum IgG or IgA levels in the tabalumab groups compared with the placebo group. CONCLUSION: Tabalumab treatment significantly reduces the signs and symptoms of rheumatoid arthritis and has a safety profile similar to that seen with placebo treatment. PMID- 23359345 TI - Ibuprofen inhibits colitis-induced overexpression of tumor-related Rac1b. AB - The serrated pathway to colorectal tumor formation involves oncogenic mutations in the BRAF gene, which are sufficient for initiation of hyperplastic growth but not for tumor progression. A previous analysis of colorectal tumors revealed that overexpression of splice variant Rac1b occurs in around 80% of tumors with mutant BRAF and both events proved to cooperate in tumor cell survival. Here, we provide evidence for increased expression of Rac1b in patients with inflamed human colonic mucosa as well as following experimentally induced colitis in mice. The increase of Rac1b in the mouse model was specifically prevented by the nonsteroidal anti-inflammatory drug ibuprofen, which also inhibited Rac1b expression in cultured HT29 colorectal tumor cells through a cyclooxygenase inhibition.independent mechanism. Accordingly, the presence of ibuprofen led to a reduction of HT29 cell survival in vitro and inhibited Rac1b-dependent tumor growth of HT29 xenografts. Together, our results suggest that stromal cues, namely, inflammation, can trigger changes in Rac1b expression in the colon and identify ibuprofen as a highly specific and efficient inhibitor of Rac1b overexpression in colorectal tumors. Our data suggest that the use of ibuprofen may be beneficial in the treatment of patients with serrated colorectal tumors or with inflammatory colon syndromes. PMID- 23359346 TI - Comparative analysis of circulating endothelial progenitor cells in age-related macular degeneration patients using automated rare cell analysis (ARCA) and fluorescence activated cell sorting (FACS). AB - BACKGROUND: Patients with age-related macular degeneration (ARMD) begin with non neovascular (NNV) phenotypes usually associated with good vision. Approximately 20% of NNV-ARMD patients will convert to vision debilitating neovascular (NV) ARMD, but precise timing of this event is unknown. Developing a clinical test predicting impending conversion to NV-ARMD is necessary to prevent vision loss. Endothelial progenitor cells (EPCs), defined as CD34(+)VEGR2(+) using traditional fluorescence activated cell sorting (FACS), are rare cell populations known to be elevated in patients with NV-ARMD compared to NNV-ARMD. FACS has high inter observer variability and subjectivity when measuring rare cell populations precluding development into a diagnostic test. We hypothesized that automated rare cell analysis (ARCA), a validated and FDA-approved technology for reproducible rare cell identification, can enumerate EPCs in ARMD patients more reliably. This pilot study serves as the first step in developing methods for reproducibly predicting ARMD phenotype conversion. METHODS: We obtained peripheral venous blood samples in 23 subjects with NNV-ARMD or treatment naive NV-ARMD. Strict criteria were used to exclude subjects with known angiogenic diseases to minimize confounding results. Blood samples were analyzed in masked fashion in two separate laboratories. EPCs were independently enumerated using ARCA and FACS within 24 hours of blood sample collection, and p<0.2 was considered indicative of a trend for this proof of concept study, while statistical significance was established at 0.05. RESULTS: We measured levels of CD34(+)VEGFR2(+) EPCs suggestive of a trend with higher values in patients with NV compared to NNV-ARMD (p = 0.17) using ARCA. Interestingly, CD34(+)VEGR2(+) EPC analysis using FACS did not produce similar results (p = 0.94). CONCLUSIONS: CD34(+)VEGR2(+) may have predictive value for EPC enumeration in future ARCA studies. EPC measurements in a small sample size were suggestive of a trend in ARMD using ARCA but not FACS. ARCA could be a helpful tool for developing a predictive test for ARMD phenotype conversion. PMID- 23359347 TI - Patterns of distribution of the helminth parasites of freshwater fishes of Mexico. AB - In order to draw patterns in helminth parasite composition and species richness in Mexican freshwater fishes we analyse a presence-absence matrix representing every species of adult helminth parasites of freshwater fishes from 23 Mexican hydrological basins. We examine the distributional patterns of the helminth parasites with regard to the main hydrological basins of the country, and in doing so we identify areas of high diversity and point out the biotic similarities and differences among drainage basins. Our dataset allows us to evaluate the relationships among drainage basins in terms of helminth diversity. This paper shows that the helminth fauna of freshwater fishes of Mexico can characterise hydrological basins the same way as fish families do, and that the basins of south-eastern Mexico are home to a rich, predominantly Neotropical, helminth fauna whereas the basins of the Mexican Highland Plateau and the Nearctic area of Mexico harbour a less diverse Nearctic fauna, following the same pattern of distribution of their fish host families. The composition of the helminth fauna of each particular basin depends on the structure of the fish community rather than on the limnological characteristics and geographical position of the basin itself. This work shows distance decay of similarity and a clear linkage between host and parasite distributions. PMID- 23359348 TI - Self-reported and objective physical activity in postgastric bypass surgery, obese and lean adults: association with body composition and cardiorespiratory fitness. AB - BACKGROUND: This study aimed to 1) describe physical activity (PA) in 15 post gastric bypass surgery (GB), 16 obese (Ob), and 14 lean (L) participants (mean +/ se: age = 37.1 +/- 1.6, 30.8 +/- 1.9, 32.7 +/- 2.3 yrs.; BMI = 29.7 +/- 1.2, 38.2 +/- 0.8, 22.9 +/- 0.5 kg/m2, respectively); and 2) test associations between PA, body composition, and cardiorespiratory fitness (VO2max). METHODS: Participants completed a PA questionnaire after wearing accelerometers from 5-7 days. Body composition was determined with DEXA and CT scans, and VO2max with open circuit spirometry. ANOVA was used to detect differences between groups, and linear regressions to evaluate associations between PA (self-reported, accelerometer), body composition, and VO2max. RESULTS: Self-reported moderate to vigorous PA (MVPA) in GB, Ob, and L participants was 497.7 +/- 215.9, 988.6 +/- 230.8, and 770.7 +/- 249.3 min/week, respectively (P = .51); accelerometer MVPA was 185.9 +/- 41.7, 132.3 +/- 51.1, and 322.2 +/- 51.1 min/week, respectively (P = .03); and steps/day were 6647 +/- 141, 6603 +/- 377, and 9591 +/- 377, respectively (P = .03). Ob showed a marginally higher difference between self report and accelerometer MVPA (P = .06). Accelerometer-MVPA and steps/day were inversely associated with percent fat (r = -0.53, -0.46), and abdominal fat (r = 0.36, -0.40), and directly associated with VO2max (r = .36). CONCLUSIONS: PA was similar between GB and Ob participants, and both were less active than L. Higher MVPA was associated with higher VO2max and lower body fat. PMID- 23359349 TI - Direct transformation of amorphous silicon carbide into graphene under low temperature and ambient pressure. AB - A large-scale availability of the graphene is critical to the successful application of graphene-based electronic devices. The growth of epitaxial graphene (EG) on insulating silicon carbide (SiC) surfaces has opened a new promising route for large-scale high-quality graphene production. However, two key obstacles to epitaxial growth are extremely high requirements for almost perfectly ordered crystal SiC and harsh process conditions. Here, we report that the amorphous SiC (a-Si(1-x)C(x)) nano-shell (nano-film) can be directly transformed into graphene by using chlorination method under very mild reaction conditions of relative low temperature (800 degrees C) and the ambient pressure in chlorine (Cl(2)) atmosphere. Therefore, our finding, the direct transformation of a-Si(1-x)C(x) into graphene under much milder condition, will open a door to apply this new method to the large-scale production of graphene at low costs. PMID- 23359350 TI - Frequency-domain optical coherence tomography assessment of unprotected left main coronary artery disease-a comparison with intravascular ultrasound. AB - OBJECTIVES: To investigate safety and feasibility of imaging unprotected left main (ULM) using frequency-domain optical coherence tomography (FD-OCT) compared with intravascular ultrasound (IVUS). BACKGROUND: IVUS has been used to assess and guide percutaneous coronary intervention (PCI) of ULM disease. FD-OCT offers 10-fold higher axial resolution than IVUS and its high-speed image acquisition obviates the need for proximal balloon occlusion. METHODS: We prospectively enrolled 35 consecutive patients with ULM disease. FD-OCT and IVUS assessments were attempted pre- and post-PCI and compared in regards to safety, ability to image the region of interest (ROI), number of pullbacks, volume of contrast and ability to detect malapposition, dissection, and thrombus. RESULTS: Patients were followed for 1 year when FD-OCT imaging was repeated. FD-OCT required more repeated pullbacks to image the ROI compared to IVUS. Mean lumen and stent areas were similar between FD-OCT and IVUS (11.24 +/- 2.66 vs. 10.85 +/- 2.47 mm(2) , P = 0.13 and 10.44 +/- 2.33 vs. 10.49 +/- 2.32 mm(2) , P = 0.82, respectively), whereas imaged stent length was shorter with FD-OCT. Malapposition areas and volumes were larger and more edge dissections were detected by FD-OCT. There were no clinical adverse events and no complications associated with FD-OCT at baseline and 1-year follow-up. All dissections were healed, whereas stent malapposition was still detected at follow-up. CONCLUSIONS: FD-OCT assessment of ULM is feasible and safe. Direct comparisons with IVUS reveal that FD-OCT achieved imaging completeness less often, whereas it was more sensitive in detecting malapposition and edge dissections, and similar to IVUS in the assessment of lumen and stent dimensions. PMID- 23359351 TI - Quality of life in cancer patients with pain in beijing. AB - OBJECTIVE: To investigate the quality of life (QOL) of cancer pain patients in Beijing, and explore the effect of cancer pain control on patients' QOL. METHODS: Self-developed demographic questionnaire, numeric rating scale and SF-36 questionnaire were used together among 643 cancer pain patients in 28 Grade 2nd to 3rd general hospitals and 2 Grade 3rd cancer hospitals. RESULTS: The SF-36 eight dimensions scores ranged from 31.75 to 57.22 in these cancer pain patients. The t test and Wilcoxon rank sum test were used to compare the QOL between pain controlled (PC) group and pain uncontrolled (PUC) group, and the results showed that patients in PC group had the higher QOL scores in 6 areas of SF-36 (P<0.05). Binary logistic regression results found that pain management satisfaction scores (P<0.001), family average personal monthly income (P=0.029), current receiving chemotherapy (P=0.009) and cancer stage (P<0.001) were the predictors to cancer pain controlled results. CONCLUSION: Cancer patients with pain in Beijing had poor QOL. Pain control will improve the QOL of cancer pain patients. PMID- 23359352 TI - Hypofractionated palliative radiotherapy for advanced head and neck cancer: the IHF2SQ regimen. AB - BACKGROUND: Standard treatment for unresectable advanced head and neck squamous cell carcinoma is chemoradiotherapy, which can be toxic, particularly among patients with coexisting medical conditions. We report our experience with the hypofractionated radiotherapy regimen Irradiation HypoFractionnee 2 Seances Quotidiennes (IHF2SQ). METHODS: We retrospectively reviewed 78 patients treated with the IHF2SQ regimen. Radiotherapy was administrated as 2 fractions of 3 Gy per day (days 1 and 3), during the first, third, fifth, and seventh week of treatment with concurrent platinum-based chemotherapy. RESULTS: Tolerance was excellent. Forty-one patients had complete or partial response. Median overall survival (OS) was 12.9 months and median progression-free survival (PFS) was 10.3 months. One-year OS, specific survival (SS), and PFS were 58%, 71%, 51.5%, respectively. Independent predictive factors increasing the PFS were response to chemoradiotherapy, male sex, and laryngeal tumor location. CONCLUSIONS: This regimen is an alternative to conventional chemoradiotherapy with good response rates and acceptable toxicity for selected patients. PMID- 23359353 TI - Predictors of poor outcome in patients w ith autoimmune hepatitis: a population based study. AB - Autoimmune hepatitis (AIH) can lead to cirrhosis, hepatic failure, and death. We aimed to identify predictors of advanced liver fibrosis at presentation, predictors of incomplete response to initial immunosuppression, and predictors of poor liver-related outcomes in the population-based AIH cohort from Canterbury, New Zealand. Cases diagnosed after 1980 that fulfilled standard diagnostic criteria were included. Cases were censored at death or liver transplantation and had a median follow-up of 9 years. Analyses were performed with Cox proportional hazards regression and logistic binary regression. The times to event outcomes were summarized using Kaplan-Meier curves. A total of 133 AIH patients were included. Predictors for advanced liver fibrosis at diagnosis were age at presentation of <=20 years or >60 years (P = 0.02), serum albumin <36 g/L (P < 0.01), platelet <150 U/L (P < 0.01), and International Normalized Ratio (INR) >1.2 (P < 0.01). The only independent predictor for incomplete normalization of alanine aminotransferase (ALT) at 6 months was age at presentation <=20 years. Independent predictors of poor liver-related outcomes were incomplete normalization of ALT at 6 months (P < 0.01), serum albumin <36 g/L (P < 0.01), and age at presentation of <=20 years or >60 years (P = 0.01). Kaplan-Meier estimates showed that 10-year adverse liver event-free survival was 80% for age at presentation <=20 years and >60 years, and 93% and 100% for age at presentation between 21-40 years and 41-60 years, respectively. CONCLUSION: Incomplete normalization of ALT at 6 months, low serum albumin concentration at diagnosis, and age at presentation of <=20 years or >60 years were significant independent predictors of liver-related death or requirement for liver transplantation. Histological cirrhosis at diagnosis was not associated with poor prognosis and did not influence the response to initial immunosuppressive treatment. (HEPATOLOGY 2013;57:2399-2406). PMID- 23359354 TI - Spectral information for detection of acoustic time to arrival. AB - The exponential increase of intensity for an approaching sound source provides salient information for a listener to make judgments of time to arrival (TTA). Specifically, a listener will experience a greater rate of increasing intensity for higher than for lower frequencies during a sound source's approach. To examine the relative importance of this spectral information, listeners were asked to make judgments about the arrival times of nine 1-octave-band sound sources (the bands were consecutive, nonoverlapping single octaves, ranging from 40-80 Hz to ~10-20 kHz). As is typical in TTA tasks, listeners tended to underestimate the arrival time of the approaching sound source. In naturally occurring and independently manipulated amplification curves, bands with center frequencies between 120 and 250 Hz caused the least underestimation, and bands with center frequencies between 2000 and 7500 Hz caused the most underestimation. This spectral influence appears to be related to the greater perceived urgency of higher-frequency sounds. PMID- 23359355 TI - Resource demands of object tracking and differential allocation of the resource. AB - The attentional processes for tracking moving objects may be largely hemisphere specific. Indeed, in our first two experiments the maximum object speed (speed limit) for tracking targets in one visual hemifield (left or right) was not significantly affected by a requirement to track additional targets in the other hemifield. When the additional targets instead occupied the same hemifield as the original targets, the speed limit was reduced. At slow target speeds, however, adding a second target to the same hemifield had little effect. At high target speeds, the cost of adding a same-hemifield second target was approximately as large as would occur if observers could only track one of the targets. This shows that performance with a fast-moving target is very sensitive to the amount of resource allocated. In a third experiment, we investigated whether the resources for tracking can be distributed unequally between two targets. The speed limit for a given target was higher if the second target was slow rather than fast, suggesting that more resource was allocated to the faster of the two targets. This finding was statistically significant only for targets presented in the same hemifield, consistent with the theory of independent resources in the two hemifields. Some limited evidence was also found for resource sharing across hemifields, suggesting that attentional tracking resources may not be entirely hemifield-specific. Together, these experiments indicate that the largely hemisphere-specific tracking resource can be differentially allocated to faster targets. PMID- 23359356 TI - Inhibition of atypical protein kinase Ciota induces apoptosis through autophagic degradation of beta-catenin in esophageal cancer cells. AB - Atypical protein kinase Ciota (PKCiota) has been identified as an oncoprotein in esophageal squamous cell carcinomas. However, the mechanisms underlying the role of PKCiota in this disease remain unclear. In the present work, we found that inhibition of PKCiota expression by RNAi induced apoptosis via the down regulation of beta-catenin in esophageal cancer cells. Furthermore, we found that PKCiota regulated beta-catenin in an autophagy dependent way. Since down regulation of beta-catenin induced by knockdown of PKCiota could be rescued by autophagy inhibition; knockdown of PKCiota activated autophagy and promoted the recruitment of beta-catenin into autophagosome. These results suggested that PKCiota positively regulated beta-catenin through negatively regulated autophagy and depletion of PKCiota promoted apoptosis via autophagic degradation of beta catenin in esophageal cancer cells. These data provide new insights into PKCiota signaling in human cancer. PMID- 23359357 TI - Diffusion-weighted 3D multislab echo planar imaging for high signal-to-noise ratio efficiency and isotropic image resolution. AB - PURPOSE: To acquire isotropic high-resolution, signal-to-noise ratio (SNR) efficient, 3D encoded diffusion-weighted MRI data. METHODS: Multiple Fourier encoded slabs were combined into one full volume, using a generalized autocalibrating partially parallel acquisitions (GRAPPA) accelerated diffusion weighted 3D multislab echo planar imaging (EPI) sequence with 2D phase navigation and in-plane motion correction. RESULTS: Reconstructed data with 1.5-mm(3) nominal resolution is presented and shown under the influence of motion and with variable slab thicknesses. The SNR efficiency between diffusion-weighted 3D multislab EPI and DW 2D ss-EPI is compared. Finally, a 1.3-mm(3) full brain scan with 45 diffusion directions is presented. CONCLUSIONS: Diffusion-weighted 3D multislab EPI has been presented as an alternative sequence for high-resolution and high-SNR full brain coverage diffusion studies. Compared with the gold standard 2D diffusion-weighted single-shot Echo Planar Imaging, the SNR efficiency is significantly higher. PMID- 23359358 TI - Evaluation of current eligibility criteria for bariatric surgery: diabetes prevention and risk factor changes in the Swedish obese subjects (SOS) study. AB - OBJECTIVE: Patients with a BMI <35 kg/m(2) and patients with a BMI between 35 and 40 kg/m(2) without comorbidities are noneligible by current eligibility criteria for bariatric surgery. We used Swedish obese subjects (SOS) to explore long-term outcomes in noneligible versus eligible patients. RESEARCH DESIGN AND METHODS: The SOS study involved 2,010 obese patients who underwent bariatric surgery (68% vertical-banded gastroplasty, 19% banding, and 13% gastric bypass) and 2,037 contemporaneously matched obese controls receiving usual care. At inclusion, the participant age was 37-60 years and BMI was >=34 kg/m(2) in men and >=38 kg/m(2) in women. The effect of surgery was assessed in patients that do (n = 3,814) and do not (n = 233) meet current eligibility criteria. The date of analysis was 1 January 2012. The follow-up time was up to 20 years, with a median of 10 years. RESULTS: Cardiovascular risk factors were significantly improved both in noneligible and eligible individuals after 10 years of follow-up. Surgery reduced the diabetes incidence in both the noneligible (adjusted hazard ratio 0.33 [95% CI 0.13-0.82], P = 0.017) and eligible (0.27 [0.22-0.33], P < 0.001) groups. We could not detect a difference in the effect of surgery between the groups (adjusted interaction P value = 0.713). CONCLUSIONS: Bariatric surgery drastically reduced the incidence of type 2 diabetes both in noneligible and eligible patients and improved cardiovascular risk factors in both groups. Our results show that strict BMI cutoffs are of limited use for bariatric surgery prioritization if the aim is to prevent diabetes and improve cardiovascular risk factors. PMID- 23359359 TI - Predicting clinical outcomes and response to thrombolysis in acute stroke patients with diabetes. AB - OBJECTIVE: Few tools are available to evaluate clinical outcomes and response to thrombolysis (tPA) in stroke patients with diabetes. We explored how the iScore (www.sorcan.ca/iscore), a validated risk score, predicts clinical outcomes in stroke patients with and without diabetes. RESEARCH DESIGN AND METHODS: We applied the iScore to stroke patients presenting to stroke centers participating in the Registry of the Canadian Stroke Network. Main outcomes included favorable outcome, defined as a modified Rankin scale (mRS) 0-2 at discharge, and intracerebral hemorrhage (ICH) after tPA. RESULTS: Among 12,686 patients with an acute ischemic stroke, 3,228 (25.5%) had diabetes. Among patients receiving tPA (n = 1,689), those with diabetes had a lower rate of a favorable outcome compared with their counterparts (24.3 vs. 31.1%; RR 0.90 [95% CI 0.82-0.98]). The risk of ICH was not significantly different in patients with or without diabetes (for any type 12.6 vs. 12.5%, RR 1.01 [0.72-1.40]; for symptomatic ICH 7.5 vs. 6.8%, RR 1.11 [0.70-1.72]). The regression analysis revealed a decline in the probability of a favorable outcome after tPA with increments in the iScore (P value for iScore * tPA interaction <0.001). There was no difference in the response to tPA predicted by the iScore between stroke patients with and without diabetes (P value = 0.07). CONCLUSIONS: Stroke patients with diabetes have poorer outcomes compared with patients without diabetes, which is not explained by ICH. The iScore similarly predicts response to tPA between stroke patients with and without diabetes. PMID- 23359360 TI - Renal glucose handling: impact of chronic kidney disease and sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes. AB - OBJECTIVE: Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, stimulates glycosuria and lowers glycemia in patients with type 2 diabetes (T2DM). The objective of this study was to assess the pharmacodynamics of ipragliflozin in T2DM patients with impaired renal function. RESEARCH DESIGN AND METHODS: Glycosuria was measured before and after a single ipragliflozin dose in 8 nondiabetic subjects and 57 T2DM patients (age 62 +/- 9 years, fasting glucose 133 +/- 39 mg/dL, mean +/- SD) with normal renal function (assessed as the estimated glomerular filtration rate [eGFR]) (eGFR1 >=90 mL . min(-1) . 1.73 m( 2)), mild (eGFR2 >=60 to <90), moderate (eGFR3 >=30 to <60), or severe reduction in eGFR (eGFR4 <=15 to <30). RESULTS: Ipragliflozin significantly increased urinary glucose excretion in each eGFR class (P < 0.0001). However, ipragliflozin induced glycosuria declined (median [IQR]) across eGFR class (from 46 mg/min [33] in eGFR1 to 8 mg/min [7] in eGFR4, P < 0.001). Ipragliflozin-induced fractional glucose excretion (excretion/filtration) was 39% [27] in the T2DM patients (pooled data), similar to that of the nondiabetic subjects (37% [17], P = ns). In bivariate analysis of the pooled data, ipragliflozin-induced glycosuria was directly related to eGFR and fasting glucose (P < 0.0001 for both, r(2) = 0.55), predicting a decrement in 24-h glycosuria of 15 g for each 20 mL/min decline in eGFR and an increase of 7 g for each 10 mg/dL increase in glucose above fasting normoglycemia. CONCLUSIONS: In T2DM patients, ipragliflozin increases glycosuria in direct, linear proportion to GFR and degree of hyperglycemia, such that its amount can be reliably predicted in the individual patient. Although absolute glycosuria decreases with declining GFR, the efficiency of ipragliflozin action (fractional glucose excretion) is maintained in patients with severe renal impairment. PMID- 23359361 TI - Effects of a D-xylose preload with or without sitagliptin on gastric emptying, glucagon-like peptide-1, and postprandial glycemia in type 2 diabetes. AB - OBJECTIVE: Macronutrient "preloads" can reduce postprandial glycemia by slowing gastric emptying and stimulating glucagon-like peptide-1 (GLP-1) secretion. An ideal preload would entail minimal additional energy intake and might be optimized by concurrent inhibition of dipeptidyl peptidase-4 (DPP-4). We evaluated the effects of a low-energy D-xylose preload, with or without sitagliptin, on gastric emptying, plasma intact GLP-1 concentrations, and postprandial glycemia in type 2 diabetes. RESEARCH DESIGN AND METHODS: Twelve type 2 diabetic patients were studied on four occasions each. After 100 mg sitagliptin (S) or placebo (P) and an overnight fast, patients consumed a preload drink containing either 50 g D-xylose (X) or 80 mg sucralose (control [C]), followed after 40 min by a mashed potato meal labeled with (13)C-octanoate. Blood was sampled at intervals. Gastric emptying was determined. RESULTS: Both peak blood glucose and the amplitude of glycemic excursion were lower after PX and SC than PC (P < 0.01 for each) and were lowest after SX (P < 0.05 for each), while overall blood glucose was lower after SX than PC (P < 0.05). The postprandial insulin-to-glucose ratio was attenuated (P < 0.05) and gastric emptying was slower (P < 0.01) after D-xylose, without any effect of sitagliptin. Plasma GLP-1 concentrations were higher after D-xylose than control only before the meal (P < 0.05) but were sustained postprandially when combined with sitagliptin (P < 0.05). CONCLUSIONS: In type 2 diabetes, acute administration of a D-xylose preload reduces postprandial glycemia and enhances the effect of a DPP-4 inhibitor. PMID- 23359362 TI - Four-year analysis of cardiovascular disease risk factors, depression symptoms, and antidepressant medicine use in the Look AHEAD (Action for Health in Diabetes) clinical trial of weight loss in diabetes. AB - OBJECTIVE: To study the association of depressive symptoms or antidepressant medicine (ADM) use with subsequent cardiovascular disease (CVD) risk factor status in the Look AHEAD (Action for Health in Diabetes) trial of weight loss in type 2 diabetes. RESEARCH DESIGN AND METHODS: Participants (n = 5,145; age [mean +/- SD] 58.7 +/- 6.8 years; BMI 35.8 +/- 5.8 kg/m(2)) in two study arms (intensive lifestyle [ILI], diabetes support and education [DSE]) completed the Beck Depression Inventory (BDI), reported ADM use, and were assessed for CVD risk factors at baseline and annually for 4 years. Risk factor-positive status was defined as current smoking, obesity, HbA1c >7.0% or insulin use, and blood pressure or cholesterol not at levels recommended by expert consensus panel or medicine to achieve recommended levels. Generalized estimating equations assessed within-study arm relationships of elevated BDI score (>=11) or ADM use with subsequent year CVD risk status, controlled for demographic variables, CVD history, diabetes duration, and prior CVD risk status. RESULTS: Prior year elevated BDI was associated with subsequent CVD risk factor-positive status for the DSE arm (A1C [odds ratio 1.30 (95% CI 1.09-1.56)]; total cholesterol [0.80 (0.65-1.00)]; i.e., protective from high total cholesterol) and the ILI arm (HDL [1.40 (1.12-1.75)], triglyceride [1.28 (1.00-1.64)]). Prior year ADM use predicted subsequent elevated CVD risk status for the DSE arm (HDL [1.24 (1.03 1.50)], total cholesterol [1.28 (1.05-1.57)], current smoking [1.73 (1.04-2.88)]) and for the ILI arm (A1C [1.25 (1.08-1.46)], HDL [1.32 (1.11-1.58)], triglycerides [1.75 (1.43-2.14)], systolic blood pressure [1.39 (1.11-1.74)], and obesity [1.46 (1.22-2.18)]). CONCLUSIONS: Aggressive monitoring of CVD risk in diabetic patients with depressive symptoms or who are treated with ADM may be warranted. PMID- 23359363 TI - GLP-1 action and glucose tolerance in subjects with remission of type 2 diabetes after gastric bypass surgery. AB - OBJECTIVE: Glucagon like peptide-1 (GLP-1) has been suggested as a major factor for the improved glucose tolerance ensuing after Roux-en-Y gastric bypass (RYGBP) surgery. We examined the effect of blocking endogenous GLP-1 action on glucose tolerance in subjects with sustained remission of type 2 diabetes mellitus (T2DM) present before RYGBP. RESEARCH DESIGN AND METHODS: Blood glucose, insulin, C peptide, glucagon, GLP-1, and glucose-dependent insulinotropic peptide levels were measured after a meal challenge with either exendin-(9-39) (a GLP-1r antagonist) or saline infusion in eight subjects with sustained remission of T2DM after RYGBP and seven healthy controls. RESULTS: Infusion of exendin-(9-39) resulted in marginal deterioration of the 2-h plasma glucose after meal intake in RYGBP subjects [saline 78.4 +/- 15.1 mg/dL compared with exendin-(9-39) 116.5 +/- 22.3 mg/dL; P < 0.001]. Furthermore, glucose response to meal intake was similarly enlarged in the two study groups [percent change in the area under the curve of glucose exendin-(9-39) infusion versus saline infusion: controls 10.84 +/- 8.8% versus RYGBP 9.94 +/- 8.4%; P = 0.884]. In the RYGBP group, the blockade of the enlarged GLP-1 response to meal intake resulted in reduced insulin (P = 0.001) and C-peptide (P < 0.001), but no change in glucagon (P = 0.258) responses. CONCLUSIONS: The limited deterioration of glucose tolerance on blockade of GLP-1 action in our study suggests the resolution of T2DM after RYGBP may be explained by mechanisms beyond enhancement of GLP-1 action. PMID- 23359365 TI - Multi-parametric phospho-flow cytometry: a crucial tool for T lymphocyte signaling studies. AB - Tools such as protein immunoblotting have proven benefits for investigating T lymphocyte signaling but have several drawbacks such as the number of cells required and the difficulty of distinguishing subset-specific differences without expensive and invasive cell sorting. Recent advances in immunology and the identification of T lymphocyte sub-populations making up only a very small fraction of the total population highlight the importance of studying signaling in those small subsets in a feasible, cost-effective, high-throughput manner. To this end, we have developed a simplified protocol to study both intracellular phosphorylation patterns of important signal transduction molecules concomitantly with T cell surface marker expression. A multi-parametric analysis may allow the quantification of the phosphorylation of up to five signaling molecules in CD4 and CD8 T lymphocytes and their naive, central memory, effector memory, and TEMRA subsets. This enables precise identification of subset-specific signaling and alterations of signaling pathways in physiological and pathological situations. The importance of such detailed analysis is discussed. PMID- 23359364 TI - Rapid detection of aneuploidies on a benchtop sequencing platform. AB - OBJECTIVE: To report a novel method of rapidly detecting fetal aneuploidies for spontaneous abortion using ultra-low whole genome sequencing data on a benchtop sequencing platform. METHOD: Fetal chorionic villus samples were collected from 40 cases of spontaneous abortion with 22 different types of aneuploidy. Genomic DNA of each sample was extracted and sequenced on Illumina MiSeq platform. Unique reads of different read lengths were generated and analyzed using a z-score test. RESULTS: The entire test was finished in 48 hours. An average of 102 k unique reads was obtained for each sample, and all 40 different aneuploidy samples were correctly identified with a z-score of >=3 or <= -3. No false positives or false negatives were observed. Further analysis demonstrated that read length and sequencing type (Paired-end or Single-end) significantly affects the efficiency of sex chromosomal aneuploidy detection. Paired-end 50 bp reads displayed the highest mapping rate and is recommended for future large-scale clinical settings. CONCLUSION: Ultra-low whole genome sequencing can rapidly detect aneuploidy of chromosomes in spontaneous abortion samples in less than 48 hours and therefore can serve as an alternative option to current aneuploidy detection methods for aborted tissues. PMID- 23359366 TI - Vive la difference. PMID- 23359368 TI - Gendered innovation in cardiovascular science: implementation of sex and gender into clinical and biomedical research. PMID- 23359370 TI - Physical activity in high school physical education: impact of lesson context and class gender composition. AB - BACKGROUND: Physical education (PE) is recommended as a source for physical activity (PA) and learning generalizable PA skills. Few studies have objectively examined high school PE, specifically its delivery, including PA, lesson contexts, and class gender composition. METHODS: We used the System for Observing Fitness Instruction Time (SOFIT) to assess PA during 6 lesson contexts in 47 boys only, 54 girls-only, and 63 coed lessons from 7 high schools. MANOVA assessed differences based on class gender composition. RESULTS: Actual lesson length was 27.7 min, only 65% of the scheduled length of class periods. Students engaged in moderate-vigorous PA (MVPA) 54% of the time, with boys being more active than girls. Game play was the most dominant context (47%), and little time was allocated to knowledge and skill development. Class size, lesson length, PA, and lesson contexts all differed by class gender composition (P < .001). CONCLUSIONS: Many differences in the conduct of high school PE are related to class gender composition. Boys accumulated more MVPA than girls. When held, PE lessons contributed about 25% of recommended daily PA minutes; improvements could be made by increasing allocations to fitness and skill practice and reducing transition and management time. Teacher professional development is warranted. PMID- 23359369 TI - TGFbeta-induced PI 3 kinase-dependent Mnk-1 activation is necessary for Ser-209 phosphorylation of eIF4E and mesangial cell hypertrophy. AB - Transforming growth factorbeta (TGFbeta)-induced canonical signal transduction is involved in glomerular mesangial cell hypertrophy; however, the role played by the noncanonical TGFbeta signaling remains largely unexplored. TGFbeta time dependently stimulated eIF4E phosphorylation at Ser-209 concomitant with enhanced phosphorylation of Erk1/2 (extracellular signal regulated kinase1/2) and MEK (mitogen-activated and extracellular signal-regulated kinase kinase) in mesangial cells. Inhibition of Erk1/2 by MEK inhibitor or by expression of dominant negative Erk2 blocked eIF4E phosphorylation, resulting in attenuation of TGFbeta induced protein synthesis and mesangial cell hypertrophy. Expression of constitutively active (CA) MEK was sufficient to induce protein synthesis and hypertrophy similar to those induced by TGFbeta. Pharmacological or dominant negative inhibition of phosphatidylinositol (PI) 3 kinase decreased MEK/Erk1/2 phosphorylation leading to suppression of eIF4E phosphorylation. Inducible phosphorylation of eIF4E at Ser-209 is mediated by Mnk-1 (mitogen-activated protein kinase signal-integrating kinase-1). Both PI 3 kinase and Erk1/2 promoted phosphorylation of Mnk-1 in response to TGFbeta. Dominant negative Mnk-1 significantly inhibited TGFbeta-stimulated protein synthesis and hypertrophy. Interestingly, inhibition of mTORC1 activity, which blocks dissociation of eIF4E 4EBP-1 complex, decreased TGFbeta-stimulated phosphorylation of eIF4E without any effect on Mnk-1 phosphorylation. Furthermore, mutant eIF4E S209D, which mimics phosphorylated eIF4E, promoted protein synthesis and hypertrophy similar to TGFbeta. These results were confirmed using phosphorylation deficient mutant of eIF4E. Together our results highlight a significant role of dissociation of 4EBP 1-eIF4E complex for Mnk-1-mediated phosphorylation of eIF4E. Moreover, we conclude that TGFbeta-induced noncanonical signaling circuit involving PI 3 kinase-dependent Mnk-1-mediated phosphorylation of eIF4E at Ser-209 is required to facilitate mesangial cell hypertrophy. PMID- 23359371 TI - Head-to-head comparison of sirolimus-eluting stent versus bare metal stent evaluation of the coronary endothelial dysfunction in the same patient presenting with multiple coronary artery lesions: the CREDENTIAL study. AB - OBJECTIVES: To assess the endothelial dysfunction (ED) after bare metal stents (BMS) and sirolimus eluting stents (SES) implantation in the same patient, overcoming the confounding role of individual variables. BACKGROUND: SES reduce restenosis rate compared to BMS but causes more ED. ED is a potentially unsafe phenomenon, since it is the first step in the cascade of atherosclerosis. Studies showing more pronounced ED with drug eluting stents than BMS involved different series of patients, making the comparison difficult because endothelial function (EF) is responsive to many risk factors. METHODS: we designed a prospective comparison of 6 months post-deployment EF of SES versus BMS implanted in the same patient, but in different coronary segments. Forty-eight lesions were randomly assigned on a 1:1 allocation using block sizing of 4 according to a computer generated sequence (SAS System, Version 9.1) basis to treatment with SES or BMS. The EF was evaluated by measuring vessel diameter variation in the stented segment, before and after selective intracoronary infusion of acetylcholine (iiAch). RESULTS: In eligible patients, the relative magnitudes of major vasoconstriction were 2.6, 2.9, 4.6, and 3.1 at 5 mm proximal and 5, 10 and 20 mm distal to the stent edge. Overall, a 3.5-fold major distal vasoconstriction after iiAch of SES vs. BMS was calculated. CONCLUSIONS: in the same patients, but treating different coronary segments, SES implantation induces a higher rate of vasoconstriction compared to BMS. The increased vasoconstriction after iiAch is an indicator of ED. PMID- 23359372 TI - Be careful who you kiss. PMID- 23359375 TI - Clinical assessment of noninvasive intracranial pressure absolute value measurement method. PMID- 23359373 TI - Adjunctive behaviors are operants. AB - Adjunctive behaviors such as schedule-induced polydipsia are said to be induced by periodic delivery of incentives, but not reinforced by them. That standard treatment assumes that contingency is necessary for conditioning and that delay of reinforcement gradients are very steep. The arguments and evidence for this position are reviewed and rejected. In their place, data are presented that imply different gradients for different classes of responses. Proximity between response and reinforcer, rather than contingency or contiguity, is offered as a key principle of association. These conceptions organize a wide variety of observations and provide the rudiments for a more general theory of conditioning. PMID- 23359374 TI - Criteria for the diagnosis of corticobasal degeneration. AB - Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset >= 50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed. PMID- 23359376 TI - Clinical Reasoning: a girl presenting with stiffness episodes during sleep, cafe au-lait spots, and flecked retina. AB - A 4-year-old girl who had been born of normal pregnancy and delivery and had an unremarkable family or personal history was referred to a neuropsychiatric department because of the appearance of peculiar nocturnal episodes. Parents described that their child abruptly became stiff during sleep. These episodes usually ranged from 20 to 40 seconds, and after that the child continued to sleep. Initially she presented 1 episode per week, but there was a progressive increase in frequency up to 3 to 4 times per night. The child never presented similar episodes while awake. Her examination revealed some cafe-au-lait spots, congenital microcephaly (3rd centile) and low stature for the age (10th centile). She did not present any neurologic deficit, but she failed to develop an age appropriate speech, with a delay in the main language milestones. PMID- 23359377 TI - Emerging subspecialties in neurology: deep brain stimulation and electrical neuro network modulation. AB - Deep brain stimulation (DBS) is a surgical therapy that involves the delivery of an electrical current to one or more brain targets. This technology has been rapidly expanding to address movement, neuropsychiatric, and other disorders. The evolution of DBS has created a niche for neurologists, both in the operating room and in the clinic. Since DBS is not always deep, not always brain, and not always simply stimulation, a more accurate term for this field may be electrical neuro network modulation (ENM). Fellowships will likely in future years evolve their scope to include other technologies, and other nervous system regions beyond typical DBS therapy. PMID- 23359378 TI - Residency Training: the role of neurocritical care in resident education. AB - Neurology is traditionally recognized as primarily an outpatient or consultative specialty, usually attracting candidates whose main focus may not necessarily be the management of complex critically ill patients or the performance of invasive procedures. However, the advent of modern mechanical ventilation and, more recently, effective therapies for the treatment of acute ischemic stroke and other neurologic catastrophes is bringing about a paradigm shift, with neurologists increasingly assuming a more aggressive attitude and rapid response to frequently disabling and often fatal pathologies. PMID- 23359379 TI - Teaching NeuroImages: intermittent symptomatic occlusion of the vertebral artery caused by a cervical osteophyte. AB - A 77-year-old man presented with 2 episodes of waking up with symptoms of vertebrobasilar ischemia (figure, A and B) within 6 months. A CT angiogram showed narrowing of the right vertebral artery due to extrinsic compression by an osteophyte of the superior articular process of the fourth cervical vertebra, compromising the foramen transversarium (figure, C and D). Dynamic angiography demonstrated intermittent vascular occlusion associated with head turning (figure, E-G). After recurrence, surgical decompression of the vertebral artery was performed. Extrinsic compressions of the vertebral artery is rare.(1) The most frequent signs are those of vertebrobasilar insufficiency. Surgical treatment has been proposed when conservative management fails.(1). PMID- 23359380 TI - Teaching Video NeuroImages: myokymia and nerve hyperexcitability as components of Morvan syndrome due to malignant thymoma. AB - A 50-year-old woman with a history of metastatic malignant thymoma presented with diffuse neuropathic pain involving the extremities and torso prior to chemotherapy and radiation. She also developed episodic diarrhea, diaphoresis, fevers, insomnia, and encephalopathy. Examination revealed rippling muscles (video on the Neurology(r) Web site at www.neurology.org). Prolonged afterdischarges were noted in motor nerve studies, suggestive for nerve hyperexcitability (figures 1 and 2). Electromyography (approximately 8 years after mediastinal radiation) revealed fasciculations, doublets, triplets, and myokymic discharges. Elevated serum antibodies for voltage-gated potassium channel (0.30 nmol/L, normal <0.02) and striational muscle (1:30,720, normal <1:60) were suggestive of paraneoplastic Morvan syndrome, which includes all of the features noted in our case.(1,2) The CNS features of Morvan syndrome differentiate it from Isaac syndrome, which is most often due to an autoimmune etiology. A substantial proportion of Morvan syndrome cases are paraneoplastic, the majority of which are due to thymomas.(1). PMID- 23359381 TI - Subarachnoid hemorrhage. AB - Subarachnoid hemorrhage (SAH) can result from the rupture of an intracranial aneurysm-a weakened, dilated area of a blood vessel in the brain that is prone to burst. SAH can be devastating. Approximately 1 in 6 patients dies at the time of the bleeding. Those who initially survive can die after early rebleeding or have major complications. The complications of SAH include strokes from delayed spasm of blood vessels in the brain even after the aneurysm that caused the hemorrhage is treated. Most of the research on SAH has been focused on this early phase. Less is known about what happens longer term to those patients who survive SAH. PMID- 23359382 TI - Flu-like illness among workers at a soy processing plant. PMID- 23359383 TI - Identification of differentially expressed genes relevant to corm formation in Sagittaria trifolia. AB - Sagittaria trifolia is a good model of wetland plants to elucidate the formation of corm. However, few studies have been conducted to uncover the complexity of gene expression involved in corm formation. In this study, high-throughput tag sequencing based on Solexa Genome Analyzer Platform was applied to monitor the changes in gene expression with three libraries of differentially expressed genes (DEGs) (C1 library: stolon stage, C2 library: initial swelling stage and C3 library: swelling stage) during corm formation in Sagittaria trifolia. Approximately 6.0 million tags were sequenced, and 5854021, 5983454, and 5761079 clean tags including 138319, 116804, and 101739 distinct tags were obtained after removal of low quality tags from each library, respectively. About 46% distinct tags were unambiguous tags mapping to the reference genes, and 33% were unambiguous tag-mapped genes. Totally, 20575, 19807, and 18438 were annotated in C1, C2, and C3 libraries, respectively, after mapping their functions in existing databases. In addition, we found that profiling of gene expression in C1/C2 and C2/C3 libraries were different among most of the selected 20 DEGs. Most DEGs in C1/C2 libraries were relevant to hormone synthesis and response; energy metabolism and stress response, while most of the genes in C2/C3 libraries were involved in carbohydrate metabolism. All up-regulated transcriptional factors and 16 important genes relevant to corm formation in three libraries were also identified. To further analyze the expression of 9 genes, from the results of tag sequencing, qRT-PCR was applied. In summary, this study provides a comprehensive understanding of gene expression, during the formation of corm in Sagittaria trifolia. PMID- 23359384 TI - Roles of phosphorylated JNK in esophageal squamous cell carcinomas of Kazakh ethnic. AB - The c-Jun NH2 -terminal kinase (JNK) signal pathway has been implicated in the growth, cellular proliferation, and apoptosis in many kinds of carcinomas. However, the role of JNK in the development of esophageal squamous cell carcinomas (ESCCs) is unknown. To investigate the role of JNK in ESCC, in vitro, esophageal cancer cell line Eca109 was pretreated using SP600125, JNK specific inhibitor, then was subjected to MTT assay to examine cellular proliferation, flow cytometric analysis to detect apoptosis and cell cycle, and wound healing assay to evaluate cell migration. Meanwhile, the mRNA and protein expression of JNK in Eca109 cells pretreated with SP600125 were examined by real-time quantitative reverse transcription PCR (qRT-PCR) and Western blotting, respectively. In vivo, 12 paired of fresh ESCC and normal adjacent tissues (NAT) from Kazakh patients were used to validate the expression of JNK by qRT-PCR and Western blotting. Furthermore, to reconfirm the expression trend of activation JNK (p-JNK), enlarged 72 paired of Kazakh's ESCC and NAT were subjected to immunohistochemistry. Our results showed that the suppression of p-JNK could lead to apoptosis and reduce proliferation in Eca109 cells. However, there was an elevated expression of p-JNK protein in NAT compared with ESCC tissues, and there was significant difference between p-JNK expression and pathological differentiation (P < 0.05) in Kazakh populations. Together, all the data we obtained in the present study indicated that the p-JNK MAPK pathway was involved in pathogenesis of Kazakh's ESCC, and played a different roles in carcinogenesis and development of Kazakh's ESCC. PMID- 23359385 TI - In vitro study on newly designed biodegradable Fe-X composites (X = W, CNT) prepared by spark plasma sintering. AB - Early in vivo animal test on pure iron coronary stent had proved that it is a promising candidate material as biodegradable metal, despite a faster degradation rate and uniform degradation mode is expected. In this work, Fe-X (X= W, CNT) composites were prepared from powders of pure iron and the additive secondary phase X using the spark plasma sintering (SPS) method, aiming to obtain a higher corrosion rate and a more uniform corrosion mode in physiological environment. The microstructures, mechanical properties, corrosion behaviors, and in vitro biocompatibility of these Fe-X composites were investigated. It was found that the additives were uniformly distributed in the iron matrix and relatively high dense Fe-X composite bulk samples were obtained after sintering by SPS. Both the yield strength and ultimate compressive strength increased when compared with that of as-cast pure iron. The corrosion mode of Fe-X composites turned out to be uniform corrosion instead of localized corrosion. Electrochemical measurements and immersion tests indicated that the addition of W and CNT could increase the corrosion rate of the iron matrix. From the results of cytotoxicity evaluation, it was found that all the Fe-X composites extracts induced no obvious cytotoxicity to L929 cells and ECV304 cells whereas significantly decreased cell viabilities of VSMC cells. The hemocompatibility tests showed that all the hemolysis percentage of Fe-X composites were less than 5%, and no sign of thrombogenicity was observed. It might be concluded that Fe composited with suitable second phase can exhibit higher strength, faster degradation rate, and uniform degradation mode than those of pure iron and are promising candidates for future development of new degradable metallic stents. PMID- 23359386 TI - Lung morphometry using hyperpolarized (129) Xe apparent diffusion coefficient anisotropy in chronic obstructive pulmonary disease. AB - PURPOSE: The goal of this work was to investigate lung morphological changes associated with chronic obstructive pulmonary disease (COPD) using hyperpolarized (129) Xe diffusion-weighted MRI. METHODS: Hyperpolarized (129) Xe MRI was performed at three different nonzero diffusion sensitizations (b-value = 12, 20, and 30 s/cm(2) ) in the lungs of four subjects with COPD and four healthy volunteers. The image signal intensities were fit as a function of b-value to obtain anisotropic diffusion coefficient maps for all subjects. The image signal intensities were also fit to a morphological model allowing extraction of length scales associated with the terminal airways: external radius (R), internal radius (r), mean airspace chord length (Lm ), and depth of alveolar sleeve (h). RESULTS: Longitudinal (DL ) and transverse (DT ) anisotropic diffusion coefficients were both significantly increased (both P= 0.004) in the COPD subjects (0.102 +/- 0.02 cm(2) /s and 0.072 +/- 0.02 cm(2) /s, respectively) compared with the healthy subjects (0.083 +/- 0.011 cm(2) /s and 0.046 +/- 0.017 cm(2) /s, respectively). Significant morphological differences were observed between the COPD subjects and healthy volunteers, specifically decreases in h (68 +/- 36 um vs. 95 +/- 710 um, respectively, P = 0.019) and increases in Lm (352 +/- 57 um vs. 253 +/- 37 um, respectively, P = 0.002) consistent with values obtained previously using hyperpolarized (3) He MRI in similar subjects. CONCLUSIONS: Diffusion-weighted hyperpolarized (129) Xe MRI is a promising technique for mapping changes in human lung morphology and may be useful for early detection of emphysema associated with COPD. PMID- 23359387 TI - System for Observing Staff Promotion of Activity and Nutrition (SOSPAN). AB - BACKGROUND: Frontline-staff are critical to achieving policies related to child physical activity and nutrition (PAaN) in out-of-school-time programs (OSTP). Recent policies call upon staff to demonstrate behaviors related to PAaN. Currently, no instrument exists to measure these behaviors. This study fills the gap between policy mandates and staff behaviors by describing the development of the System for Observing Staff Promotion of Activity and Nutrition (SOSPAN) in OSTP. METHODS: SOSPAN items were aligned with existing OSTP policies. Reliability and validity data of SOSPAN were collected across 8 OSTP: 4 summer day camps and 4 afterschool programs. Validity of SOSPAN staff behaviors/management of PA was established using the percent of children active measured concurrently via direct observation. RESULTS: A total of 6437 scans were performed. Interrater percent agreement ranged from 74%-99% across PAaN behaviors. Children's activity was associated with staff facilitative behaviors/management, such as playing with the children and providing 2 or more activities for children to choose, while prohibitive behaviors/management, such as waiting in line were related to increased sedentary behavior. Staff nutrition behaviors were observed in less than 0.6% of scans. CONCLUSION: SOSPAN is a reliable and valid tool to assess staff behaviors/management of PAaN in OSTPs. PMID- 23359388 TI - Molecular biomarkers as potential targets for therapeutic strategies in human testicular germ cell tumors: an overview. AB - Testicular germ cell tumors (TGCTs), the most common malignancy in males between 15 and 34 years of age and the most frequent cause of death from solid tumors in this age group. TGCTs can be subdivided into seminoma and non-seminoma germ cell tumors (NSGCTs), including embryonal cell carcinoma, choriocarcinoma, yolk sac tumor, and teratoma. Seminomas and NSGCTs do not only present distinctive clinical features, but they also show significant differences as far as therapy and prognosis are concerned. Seminomas are highly sensitive to both radiation and chemotherapy, with a good prognosis, non-seminomas are sensitive to platinum based combination chemotherapy and are less susceptible to radiation, with the exception of teratomas. The different therapeutic outcome might be explained by inherent properties of the cells from which testicular neoplasia originate. The unique treatment sensitivity of TGCTs is unexplained so far, but it is likely to be related to intrinsic molecular characteristics of the PGCs/gonocytes, from which these tumors originate. Many discovered bio-markers including OCT3/4, SOX2, SOX17, HMGA1, HMGA2, PATZ1, GPR30, Aurora B, estrogen receptor beta, and others have given further advantages to discriminate between histological subgroups. In addition, therapeutic approaches for the treatment of TGCTs have been proposed: humanized antibodies against receptors/surface molecules on cancer cells, inhibitors of serine-threonine, and tyrosine kinases, and others. The mini-review will be an overview on the molecular alterations identified in TGCTs and on novel targeted antineoplastic strategies that might help to treat chemotherapy resistant TGCTs. PMID- 23359389 TI - Improved peri-operative risk stratification in non-cardiac surgery: going beyond established clinical scores. PMID- 23359390 TI - Women treated with second-generation zotarolimus-eluting resolute stents and everolimus-eluting xience V stents: insights from the gender-stratified, randomized, controlled TWENTE trial. AB - BACKGROUND: Women are underrepresented in clinical research, and few data are available from randomized head-to-head comparisons of second-generation drug eluting stents (DES) in female patients. Aim of this study was to assess safety and efficacy of two second-generation DES in women. In TWENTE-a prospective, randomized, comparative DES trial-"real-world" patients were stratified for gender before randomization for Resolute or Xience V stents. METHODS: Target vessel failure (TVF; cardiac death, target vessel-related myocardial infarction, and clinically indicated target vessel revascularization) after 1 year was the predefined endpoint. RESULTS: Among 1,391 patients, 382 (27.5%) women were randomized to Resolute (n = 192) and Xience V (n = 190). Baseline and procedural characteristics were similar for females in both study arms, except for smaller vessel and stent diameters in Resolute-treated lesions. After 1 year, TVF (8.9 vs. 8.4%; adjusted odds ratio [OR]: 0.95, 95% confidence interval [CI]: 0.41 2.20, P = 0.91) and a patient-oriented composite endpoint (13.0 vs. 12.1%, P = 0.79) did not differ significantly between women in both arms. Women were older than men (P < 0.01) and had more often diabetes mellitus (26.4 vs. 19.8%, P = 0.01) and hypertension (63.6 vs. 52.5%, P < 0.01), but there was no significant gender difference in TVF (adjusted OR: 1.18, 95% CI: 0.73-1.92, P = 0.50). CONCLUSIONS: This gender-stratified TWENTE trial analysis resulted in no significant difference in safety and efficacy outcomes between Resolute- and Xience V-treated females. PMID- 23359391 TI - Association between anti-TNF-alpha therapy and interstitial lung disease. AB - BACKGROUND: Anti-tumor necrosis factor-alpha (TNF-alpha) agents have been hypothesized to increase the risk of interstitial lung disease (ILD), including its most severe manifestation, pulmonary fibrosis. METHODS: We conducted a cohort study among autoimmune disease patients who were members of Kaiser Permanente Northern California, 1998-2007. We obtained therapies from pharmacy data and diagnoses of ILD from review of X-ray and computed tomography reports. We compared new users of anti-TNF-alpha agents to new users of non-biologic therapies using Cox proportional hazards analysis to adjust for baseline propensity scores and time-varying use of glucocorticoids. We also made head-to head comparisons between anti-TNF-alpha agents. RESULTS: Among the 8417 persons included in the analysis, 38 (0.4%) received a diagnostic code for ILD by the end of follow-up, including 23 of 4200 (0.5%) who used anti-TNF-alpha during study follow-up, and 15 of 5423 (0.3%) who used only non-biologic therapies. The age standardized and gender-standardized incidence rate of ILD, per 100 person-years, was 0.21 [95% confidence interval (CI) 0-0.43] for rheumatoid arthritis and appreciably lower for other autoimmune diseases. Compared with the use of non biologic therapies, use of anti-TNF-alpha therapy was not associated with a diagnosis of ILD among patients with rheumatoid arthritis (adjusted hazard ratio, 1.03; 95%CI 0.51-2.07), nor did head-to-head comparisons across anti-TNF-alpha agents suggest important differences in risk, although the number of cases available for analysis was limited. CONCLUSION: The study provides evidence that compared with non-biologic therapies, anti-TNF-alpha therapy does not increase the occurrence of ILD among patients with autoimmune diseases and informs research design of future safety studies of ILD. PMID- 23359392 TI - Apigenin inhibits TGF-beta-induced VEGF expression in human prostate carcinoma cells via a Smad2/3- and Src-dependent mechanism. AB - Cancer progression relies on establishment of the blood supply necessary for tumor growth and ultimately metastasis. Prostate cancer mortality is primarily attributed to development of metastases rather than primary, organ-confined disease. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis in prostate tissue. Our previous studies have demonstrated that the chemopreventive bioflavonoid apigenin inhibited hypoxia-induced elevation of VEGF production at low oxygen conditions characteristic for solid tumors. Low oxygen (hypoxia) and transforming growth factor-beta (TGF-beta) are two major factors responsible for increased VEGF secretion. In the present study, experiments were performed to investigate the inhibitory effect of apigenin on TGF-beta-induced VEGF production and the mechanisms underlying this action. Our results demonstrate that VEGF expression is induced by TGF-beta1 in human prostate cancer PC3-M and LNCaP C4-2B cells, and treatment with apigenin markedly decreased VEGF production. Additionally, apigenin inhibited TGF-beta1-induced phosphorylation and nuclear translocation of Smad2 and Smad3. Further experiments demonstrated that specific transient knockdown of Smad2 or Smad3 blunted apigenin's effect on VEGF expression. We also found that apigenin inhibited Src, FAK, and Akt phosphorylation in PC3-M and LNCaP C4-2B cells. Furthermore, constitutively active Src reversed the inhibitory effect of apigenin on VEGF expression and Smad2/3 phosphorylation. Taken together, our results suggest that apigenin inhibits prostate carcinogenesis by modulating TGF-beta-activated pathways linked to cancer progression and metastases, in particular the Smad2/3 and Src/FAK/Akt pathways. These findings provide new insights into molecular pathways targeted by apigenin, and reveal a novel molecular mechanism underlying the antiangiogenic potential of apigenin. PMID- 23359394 TI - Purple urine bag syndrome. PMID- 23359393 TI - Effect of occupational exposure to aflatoxins on some liver tumor markers in textile workers. AB - BACKGROUND: In a study of textile workers, the effects of occupational exposure to cotton dust-with possible exposure to aflatoxin-on levels of some liver tumor biomarkers were explored. METHODS: The study included 58 textile workers and 64 controls. Skin prick tests, urinary Aflatoxin M1 (AFM1) and the tumor biomarkers (alpha-fetoprotein (AFP), alpha-L-fucosidase (AFU), insulin-like growth factors (IGF-1) were measured. RESULTS: Positive reactants to Aspergillus niger, Aspergillus flavus, and cotton dust were significantly higher in pre-spinning (14.3%, 28.6%, and 28.6%, respectively) and spinning workers (25.0%, 33.3%, and 25.0%, respectively) compared to controls (4.7%, 7.8%, and 3.1%, respectively). Urinary AFM1 was significantly higher in the pre-spinning, spinning, and weaving groups compared to controls (554.2 +/- 346.2 pg/ml, 459.1 +/- 781.6 pg/ml, 296.5 +/- 336.5 pg/ml and 68.5 +/- 136.8 pg/ml, respectively). We found a highly significant increase in levels of serum AFU in textile workers, compared to the control group. CONCLUSION: Exposure to fungi had a significant effect on AFM1 measurements and tumor biomarkers, especially in allergic textile workers (with the exception of the arginase biomarker), though results were generally within normal limits. PMID- 23359395 TI - Low back pain among textile workers: a cross-sectional study. AB - BACKGROUND: Low back pain (LBP) is one of the most prevalent occupational health problems in industrialized countries. Little is known about the epidemiology of LBP in developing countries. AIMS: To determine the prevalence of LBP among Nepalese textile workers and to investigate the influence of exposure to mechanical and other factors on LBP reporting. METHODS: Interviewers completed questionnaires with study subjects, and work-related mechanical exposures were measured by self-completed questionnaires. Associations of LBP with mechanical factors and somatic symptoms were determined by logistic regression and reported as odds ratios (ORs) with 95% confidence intervals (CI). RESULTS: Nine hundred and thirty-eight workers took part, a participation rate of 92%. The 1 month period prevalence of LBP was 35% (n = 324), being higher in females than males (45% versus 28%; P < 0.001). Several work-related mechanical factors were associated with increased odds of reporting LBP: lifting heavy weights with one hand (OR 1.7; 95% CI 1.1-2.8), pushing weights (OR 1.6; 95% CI 1.2-2.3 and pulling weights (OR 1.6; 95% CI 1.1-2.1). No association was found with working posture. Strong associations were found for reporting one (OR 2.4; 95% CI 1.7 3.4) or two somatic symptoms (OR 2.7; 95% CI 1.4-5.1). On multivariable analysis, reporting of somatic symptoms (OR 2.8; 95% CI 1.5-5.4), female gender (OR 2.2; 95% CI 1.5-3.1) and increasing age were significantly associated with increased risk of reporting LBP (OR 1.7; 95% CI 1.2-2.5), but no associations were found with mechanical factors. CONCLUSIONS: This study suggests that mechanical load may not be the leading cause of LBP and adds to evidence that psychological factors play an important role in LBP in non-industrialized countries. PMID- 23359396 TI - High density Lipoprotein; What to Measure: Quality or Quantity? PMID- 23359397 TI - The EIUS unicompartmental knee design: early failure in elderly patients. AB - This report presents the results of 34 unicompartmental knee replacements in 28 elderly patients. The mean age of patients at the time of index surgery was 78.7 years. All cases were performed by a single surgeon over a 16-month period. In all cases, the EIUS Unicompartmental Knee System (Stryker, Mahwah, NJ) was used. The surgeon was technically experienced at implanting EIUS knee prostheses prior to the start of this study.Knees were evaluated by Knee Society Score through 5 years, and patients were followed up by phone interviews for a minimum period of 8 years. With revision as the end point, the 5-year failure rate was 14.7% (n = 5), and the mean time to failure was 25.6 months (range: 4 to 44 months).At 8 years follow-up, 3 patients (4 knees) died for reasons unrelated to the knee implant, and 2 patients (4 knees) were lost to follow-up. Three knees in 3 patients were revised at 5.75 years, 7.0 years, and 8.0 years, respectively. The majority of knees that did not experience early failure remained pain and symptom free at minimum 8 years follow-up.We suspect the early failures were more likely due to a combination of the design characteristics and instrumentation of the EIUS prosthesis than surgical technique. PMID- 23359398 TI - Single-use instrumentation, cutting blocks, and trials decrease contamination during total knee arthroplasty: a prospective comparison of navigated and nonnavigated cases. AB - The purpose of this prospective controlled trial was to determine whether decrease in contamination could be achieved in nonnavigated and navigated total knee arthroplasties by replacing traditional saws, cutting blocks, and trials with specialized saws and single-use cutting blocks and trials. Various tray wrapping metrics during total knee arthroplasty were measured in 400 procedures performed by 8 different surgeons at 6 institutions. Instrumentation contamination was determined by counting the number of tray sterility indicators, pans, and instruments that were compromised. The results show that a decrease in contamination was evident in 57% (nonnavigated) and 32% (navigated) fewer compromises of tray sterility indicators, pans, and instruments. Single-use instruments show promising benefits, but further study is needed to confirm safety and efficacy before they can be widely adopted. The authors believe that the use of single-use instruments, cutting guides, and trial implants for total knee arthroplasty will play an increasing role in decreasing operating room contamination and potential deep infections. PMID- 23359399 TI - Obesity and operative time in primary total joint arthroplasty. AB - Obesity has been associated with osteoarthritis and increased morbidity and mortality. Most joint arthroplasty patients have a high body mass index (BMI). Some surgeons are reluctant to operate on obese patients due to technical difficulties and the anticipated higher complication rate. The purpose of this prospective study was to determine whether obesity is associated with longer operative times. We attended 100 consecutive primary total joint arthroplasties. Patients were divided into four groups depending on their BMI: the normal group (BMI: 18 to 24.9 kg/m2), the overweight group (BMI: 25 to 29.9 kg/m2), the obese group (BMI: 30 to 39.9 kg/m2), and the morbidly obese group (BMI >= 40 kg/m2). Anesthesia type and time, duration of surgery, time needed for scrubbing, draping, and transferring the patient to the operating table were all documented. The mean operative time for total hip arthroplasty (THA) was significantly increased in morbidly obese patients (R2 = 0.197, p = 0.003). The mean scrubbing time for total knee arthroplasty varied with BMI (p = 0.028). Time to administer spinal anesthesia was significantly increased in morbidly obese patients (R2 = 0.1466, p = 0.018). Morbid obesity is associated with a significant increase in the time needed to administer spinal anesthesia and the overall time needed to perform a THA. PMID- 23359401 TI - Improvement of adhesive strength of segmented polyurethane on Ti-29Nb-13Ta-4.6Zr alloy through H2O2 treatment for biomedical applications. AB - The number of hydroxyl groups on a Ti-29Nb-13Ta-4.6Zr (TNTZ) alloy surface was controlled through H2O2 treatment for further improvement of the adhesive strength and durability against water of TNTZ/silane layers (SILs)/segmented polyurethane (SPU) composites. The effect of the terminal functional groups on the adhesive strength of SPU on TNTZ, and the adhesiveness of SPU on TNTZ against water was investigated. Three types of silane-coupling agents were used to bind TNTZ and SPU: methacryloxypropyltrimethoxysilane (gamma-MPTS), aminopropyltriethoxysilane (APS), and mercaptopropyltrimethoxysilane (gamma-MPS). The adhesive strength of each composite was evaluated by shear bonding tests. The number of hydroxyl groups increases with an increase in treatment time at a H2O2 concentration of 5% (v/v). On the other hand, an increase from 5% (v/v) to 30% (v/v) in H2O2 concentration leads to a decrease in the number of hydroxyl groups on the TNTZ surface because at higher H2O2 concentrations, the reaction that consumes the hydroxyl groups is dominant. The shear bonding strength is doubled compared with the untreated TNTZ/SIL/SPU interface. Although the shear bonding strength decreases after immersion in water for 30 days when APS and gamma-MPS are used, TNTZ/gamma-MPTS/SPU composites exhibit good durability to water and maintain an equivalent shear bonding strength before immersion in water. PMID- 23359400 TI - Trehalose maintains bioactivity and promotes sustained release of BMP-2 from lyophilized CDHA scaffolds for enhanced osteogenesis in vitro and in vivo. AB - Calcium phosphate (Ca-P) scaffolds have been widely employed as a supportive matrix and delivery system for bone tissue engineering. Previous studies using osteoinductive growth factors loaded Ca-P scaffolds via passive adsorption often experience issues associated with easy inactivation and uncontrolled release. In present study, a new delivery system was fabricated using bone morphogenetic protein-2 (BMP-2) loaded calcium-deficient hydroxyapatite (CDHA) scaffold by lyophilization with addition of trehalose. The in vitro osteogenesis effects of this formulation were compared with lyophilized BMP-2/CDHA construct without trehalose and absorbed BMP-2/CDHA constructs with or without trehalose. The release characteristics and alkaline phosphatase (ALP) activity analyses showed that addition of trehalose could sufficiently protect BMP-2 bioactivity during lyophilization and achieve sustained BMP-2 release from lyophilized CDHA construct in vitro and in vivo. However, absorbed BMP-2/CDHA constructs with or without trehalose showed similar BMP-2 bioactivity and presented a burst release. Quantitative real-time PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) demonstrated that lyophilized BMP-2/CDHA construct with trehalose (lyo tre-BMP-2) promoted osteogenic differentiation of bone marrow stromal cells (bMSCs) significantly and this formulation could preserve over 70% protein bioactivity after 5 weeks storage at 25 degrees C. Micro-computed tomography, histological and fluorescent labeling analyses further demonstrated that lyo-tre BMP-2 formulation combined with bMSCs led to the most percentage of new bone volume (38.79% +/- 5.32%) and area (40.71% +/- 7.14%) as well as the most percentage of fluorochrome stained bone area (alizarin red S: 2.64% +/- 0.44%, calcein: 6.08% +/- 1.37%) and mineral apposition rate (4.13 +/- 0.62 um/day) in critical-sized rat cranial defects healing. Biomechanical tests also indicated the maximum stiffness (118.17 +/- 15.02 Mpa) and load of fracture (144.67 +/- 16.13 N). These results lay a potential framework for future study by using trehalose to preserve growth factor bioactivity and optimize release profile of Ca-P based delivery system for enhanced bone regeneration. PMID- 23359403 TI - In vitro cytocompatibility assessment of amorphous carbon structures using neuroblastoma and Schwann cells. AB - The development of scaffolds for neural tissue engineering application requires an understanding of cell adhesion, proliferation, and migration of neuronal cells. Considering the potential application of carbon as scaffold materials and the lack of understanding of compatibility of amorphous carbon with neuronal cells, the carbon-based materials in the forms of carbon films and continuous electrospun carbon nanofibers having average diameter of ~200 nm are being investigated with or without ultraviolet (UV) and oxy-plasma (OP) treatments for cytocompatibility property using mouse Neuroblastoma (N2a) and rat Schwann cells (RT4-D6P2T). The use of Raman spectroscopy in combination with Fourier transform infrared (FTIR) and X-ray diffraction establishes the amorphous nature and surface-bonding characteristics of the studied carbon materials. Although both UV and OP treatments make carbon surfaces more hydrophilic, the cell viability of N2a cells is statistically more significant on OP treated fibers/films compared to UV fiber/film substrates after 4 days in culture. The electrospun carbon fibrous substrate provides the physical guidance to the cultured Schwann cells. Overall, the experimental results of this study demonstrate that the electrospun amorphous carbon nanofibrous scaffolds can be used as a suitable biomaterial substrate for supporting cell adhesion and proliferation of neuronal cells in the context of their applications as artificial nerve implants. PMID- 23359402 TI - Reliability of two clinically relevant fiber pathways reconstructed with constrained spherical deconvolution. AB - The single diffusion tensor model is inadequate for the reconstruction of fiber pathways in brain regions with multiple fiber orientations. To overcome this limitation, constrained spherical deconvolution has been proposed. A high reliability of constrained spherical deconvolution is, however, a pre-requisite for its use in clinical applications. Reliability of reconstructed fiber pathways can be assessed in terms of architectural (addressing their spatial configuration) and microstructural (addressing diffusion-derived measures along the fibers) reproducibility. We assess the reliability for two clinically relevant fiber pathways: the corticospinal tract and arcuate fasciculus. The fiber pathways were reconstructed using constrained spherical deconvolution in 11 healthy subjects who were scanned on three occasions. Coefficients of variations of diffusion-derived measures were used to assess the microstructural reproducibility. Image correlation and fiber overlap were used to assess the architectural reproducibility. The mean correlation between sessions was 72% for both the corticospinal tract and arcuate fasciculus. The mean overlap between sessions was 63% for the corticospinal tract and 58% for the arcuate fasciculus. Coefficients of variations of diffusion-derived measures showed very low variation (all measures <3.1%). These results are comparable with reliability results based on the diffusion tensor model, which is commonly used in clinical settings. The reliability results found here are, therefore, promising to further investigate the use of constrained spherical deconvolution in clinical practice. PMID- 23359404 TI - Safe lists for medications in pregnancy: inadequate evidence base and inconsistent guidance from Web-based information, 2011. AB - PURPOSE: Medication use during pregnancy is common and increasing. Women are also increasingly getting healthcare information from sources other than their physicians. METHODS: This report summarizes an environmental scan that identified 25 active Internet sites that list medications reported to be safe for use in pregnancy and highlights the inadequate evidence base and inconsistent guidance provided by these sites. RESULTS: These lists included 245 different products, of which 103 unique components had been previously evaluated in terms of fetal risk by the Teratogen Information System (TERIS), a resource that assesses risk of birth defects after exposure under usual conditions by consensus of clinical teratology experts. For 43 (42%) of the 103 components that were listed as 'safe' on one or more of the Internet sites surveyed, the TERIS experts were unable to determine the fetal risk based on published scientific literature. For 40 (93%) of these 43, either no data were available to assess human fetal risk or the available data were limited. CONCLUSIONS: Women who see a medication on one of these 'safe' lists would be led to believe that there is no increased risk of birth defects resulting from exposure. Thus, women are being reassured that fetal exposure to these medications is safe even though a sufficient evidence base to determine the relative safety or risk does not exist. PMID- 23359405 TI - RB1 in cancer: different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis. AB - Loss of RB1 gene is considered either a causal or an accelerating event in retinoblastoma. A variety of mechanisms inactivates RB1 gene, including intragenic mutations, loss of expression by methylation and chromosomal deletions, with effects which are species-and cell type-specific. RB1 deletion can even lead to aneuploidy thus greatly increasing cancer risk. The RB1gene is part of a larger gene family that includes RBL1 and RBL2, each of the three encoding structurally related proteins indicated as pRb, p107, and p130, respectively. The great interest in these genes and proteins springs from their ability to slow down neoplastic growth. pRb can associate with various proteins by which it can regulate a great number of cellular activities. In particular, its association with the E2F transcription factor family allows the control of the main pRb functions, while the loss of these interactions greatly enhances cancer development. As RB1 gene, also pRb can be functionally inactivated through disparate mechanisms which are often tissue specific and dependent on the scenario of the involved tumor suppressors and oncogenes. The critical role of the context is complicated by the different functions played by the RB proteins and the E2F family members. In this review, we want to emphasize the importance of the mechanisms of RB1/pRb inactivation in inducing cancer cell development. The review is divided in three chapters describing in succession the mechanisms of RB1 inactivation in cancer cells, the alterations of pRb pathway in tumorigenesis and the RB protein and E2F family in cancer. PMID- 23359406 TI - Analysis of the health and environmental status of sterilizers in hospital waste management: a case study of hospitals in Tehran. AB - According to the first article of the waste management rule ratified in 2004, healthcare facilities are responsible for sterilizing their own infectious wastes. Nowadays non-incineration techniques are preferred internationally owing to toxic emissions caused by incinerators. Surveys have been conducted in Iran, resulting in ratification of an executive code by the Iranian Board of Ministers, which imposed a ban on incinerators; furthermore, it emphasized, instead, the use of sterilizers. The main objective of this research was evaluating the present status of these facilities to figure out which ones have less effect on the community, personnel and on the environment. A questionnaire was used to collect the data. The results showed that biological tests had not been conducted for most of the sterilizers. As biological testing is the most important factor in assessing autoclave accuracy, a comprehensive program should be initiated to perform these tests to improve functioning of the sterilizers so that the best treating process can be achieved. PMID- 23359407 TI - Unexpected crystal and domain structures and properties in compositionally graded PbZr(1-x)Ti(x)O3 thin films. AB - Synthesis of compositionally graded versions of PbZr(1-x)Ti(x)O3 thin films results in unprecedented strains (as large as ~4.5 * 10(5) m(-1)) and correspondingly unexpected crystal structures, ferroelectric domain structures, and properties. This includes the observation of built-in electric fields in films as large as 200 kV/cm. Compositional and strain gradients could represent a new direction of strain-control of materials. PMID- 23359408 TI - Upper limb tendinitis and entrapment neuropathy in coal miners. AB - BACKGROUND: It is well-known that work-related upper limb musculoskeletal disorders, particularly tendinitis and nerve entrapment, remain a difficult and costly problem in industrialized countries. The aim of this study was to evaluate tendinitis and entrapment neuropathy of the upper limb of Turkish coal miners. METHODS: Eighty coal miners and 43 age-matched clerical workers were included in the study. The evaluation procedures included collection of personal and clinical data, physical examination and bilateral electrodiagnostic testing. Subjects were examined to diagnose tendinitis and nerve entrapment of the upper limb. Bilateral median and ulnar nerves conduction tests were performed on all subjects. Data were collected between August 2011 and December 2011. RESULTS: There were 33 subjects with lateral epicondylitis, 10 with medial epicondylitis, and 22 with De Quervain's disease among the coal miners. There were seven subjects with lateral epicondylitis, eight with medial epicondylitis, and four with De Quervain's disease in the control group. The two groups significantly differed in the prevalences of lateral epicondylitis and De Quervain's disease (P = 0.024 and P =0.029, respectively). Sixteen subjects in the coal miners and 12 subjects in the controls had carpal tunnel syndrome (P = 0.66). Thirty-seven subjects in the coal miners had ulnar neuropathy of the elbow (UNE), while four subjects in the controls had UNE; this difference was statistically significant (P < 0.001). CONCLUSION: Lateral epicondylitis, De Quervain disease, and ulnar neuropathy are common work-related upper limb disorders among coal miners. PMID- 23359409 TI - Generation of knock-in mice that express nuclear enhanced green fluorescent protein and tamoxifen-inducible Cre recombinase in the notochord from Foxa2 and T loci. AB - The node and the notochord are important embryonic signaling centers that control embryonic pattern formation. Notochord progenitor cells present in the node and later in the posterior end of the notochord move anteriorly to generate the notochord. To understand the dynamics of cell movement during notochord development and the molecular mechanisms controlling this event, analyses of cell movements using time-lapse imaging and conditional manipulation of gene activities are required. To achieve this goal, we generated two knock-in mouse lines that simultaneously express nuclear enhanced green fluorescent protein (EGFP) and tamoxifen-inducible Cre, CreER(T2) , from two notochord gene loci, Foxa2 and T (Brachury). In Foxa2(nEGFP-CreERT2/+) and T(nEGFP-CreERT2/+) embryos, nuclei of the Foxa2 or T-expressing cells, which include the node, notochord, and endoderm (Foxa2) or wide range of posterior mesoderm (T), were labeled with EGFP at intensities that can be used for live imaging. Cre activity was also induced in cells expressing Foxa2 and T 1 day after tamoxifen administration. These mice are expected to be useful tools for analyzing the mechanisms of notochord development. PMID- 23359410 TI - Improved MRI R2 * relaxometry of iron-loaded liver with noise correction. AB - Accurate and reproducible MRI R2 * relaxometry for tissue iron quantification is important in managing transfusion-dependent patients. MRI data are often acquired using array coils and reconstructed by the root-sum-square algorithm, and as such, measured signals follow the noncentral chi distribution. In this study, two noise-corrected models were proposed for the liver R2 * quantification: fitting the signal to the first moment and fitting the squared signal to the second moment in the presence of the noncentral chi noise. These two models were compared with the widely implemented offset and truncation models on both simulation and in vivo data. The results demonstrated that the "slow decay component" of the liver R2 * was mainly caused by the noise. The offset model considerably overestimated R2 * values by incorrectly adding a constant to account for the slow decay component. The truncation model generally produced accurate R2 * measurements by only fitting the initial data well above the noise level to remove the major source of errors, but underestimated very high R2 * values due to the sequence limit of obtaining very short echo time images. Both the first and second-moment noise-corrected models constantly produced accurate and precise R2 * measurements by correctly addressing the noise problem. PMID- 23359411 TI - Activation and promotion of adipose stem cells by tumour necrosis factor-alpha preconditioning for bone regeneration. AB - There is a major medical need for developing novel and effective approaches for repairing non-union and critical-sized bone defects. Although the mechanisms remain to be determined, it is known that inflammation plays a crucial role in initiating bone repair and regeneration. This study investigated the effect of short-term (3 days) preconditioning with tumor necrosis factor-alpha (TNF-alpha) on proliferation, mobilization, and differentiation of adipose tissue-derived mesenchymal stem cells (ASCs). We demonstrated that TNF-alpha pre-conditioning increased proliferation, mobilization, and osteogenic differentiation of ASCs and up-regulated bone morphogenetic protein-2 (BMP-2) protein level. BMP-2 silencing by siRNA partially inhibited osteogenic differentiation of ASCs induced by TNF alpha; BMP-2 pre-conditioning also significantly increased osteogenic differentiation of ASCs but the effects were significantly smaller than those observed for TNF-alpha preconditioning. Furthermore, TNF-alpha treatment promoted extracellular-signal-regulated kinases(Erk)1/2 and p38 mitogen-activated protein kinase (MAPK) signaling pathways, but only Erk1/2 inhibition reduced the BMP-2 levels and osteogenic differentiation induced by TNF-alpha preconditioning. Together, these results support the hypothesis that inflammation contributes to bone regeneration by promoting proliferation, mobilization, and osteogenic differentiation of ASCs; 3 days of TNF-alpha preconditioning, mimicking the short boost of inflammation normally occurring after bone injury, might serve as a feasible approach for directing stem cells into osteogenic differentiation. PMID- 23359412 TI - Psychiatric manifestations, personality traits and health-related quality of life in cancer of unknown primary site. AB - OBJECTIVE: Psychiatric manifestations and personality traits are known to influence cancer patients. We aimed to assess psychological distress symptoms, psychosocial factors and health-related quality of life (HRQoL) in cancer of unknown primary site (CUP) and to test whether these parameters differ between CUP and Metastatic (MKPC) or Non-Metastatic Known Primary Cancers (N-MKPC) after controlling for demographics and clinical variables. METHODS: In this cross sectional study, we recruited 50 CUP, 264 N-MKPC and 52 MKPC participants. We assessed depressive symptoms (Center for Epidemiologic Studies-Depression [CES D]), psychological distress symptoms (Symptom Distress Checklist-90 Revised), sense of coherence (SOC), ego defense mechanisms (Life Style Index) and HRQoL (World Health Organization Quality of Life Instrument, Short Form). RESULTS: The prevalence of clinically significant depressive symptoms (CES-D >= 23) was 40.0% in CUP, 28.8% in MKPC and 23.5% N-MKPC (p=0.037). Multivariate logistic regression analysis showed that N-MKPC patients were 5 times less likely (p=0.028) and MKPC patients 3.3 times less likely (p=0.05) to be assessed with probable depression compared with CUP patients after controlling for the major demographic and clinical variables studied. CUP patients presented also higher levels of somatization, anxiety and depressive symptoms; they also had more impaired Physical (p=0.005), Mental (p=0.041) and Social Relations (p=0.044) HRQoL, along with lower scores on SOC and intellectualization defense and higher scores on repression defense, compared with MKPC and N-MKPC patients. CONCLUSIONS: These findings suggest that psychiatric manifestations are frequent in CUP, and the patients' resources to cope with the burden of their illness are limited. Attention to CUP patients' psychological distress and coping resources and capacities may enable oncologists to identify and manage modifiable aspects of HRQoL. PMID- 23359413 TI - Transplantation of inbred adipose-derived stromal cells in rats with plasma gel containing fragmin/protamine microparticles and FGF-2. AB - Fragmin/protamine microparticles (F/P MPs) have been used as a cell carrier for adipose-derived stromal cells (IR-ASCs) in inbred male Fisher 344 rats, and for preservation and controlled-release of fibroblast growth factor (FGF)-2 and various cytokines in inbred rat plasma (IRP)-DMEM (Dulbecco's modified Eagle's medium) gel. In this study, we investigated the capability of an IRP-DMEM gel containing F/P MPs and/or FGF-2, as a three-dimensional (3D)-culture, to expand IR-ASCs. We found that IR-ASCs grow faster under 3D-culture conditions in low IRP (3%)-DMEM gel containing F/P MPs and FGF-2 without any animal serum than those under 2D-culture in low inbred rat serum (3%)-DMEM with F/P MPs and FGF-2. About 0.3 mL of IR-ASCs (about 4,000,000 cells mL-1) grown in IRP (6%)-DMEM gel containing F/P MPs and FGF-2 disappeared 8 days after subcutaneous injection in rats, suggesting that they are rapidly biodegradable. The number of large (diameter >=200 MUm or containing >=100 erythrocytes), medium (diameter = 20-200 MUm or containing 10-100 erythrocytes) and small (diameter <=20 MUm or containing 1-10 erythrocytes) capillaries after injection with IR-ASCs in an IRP-DMEM gel containing both F/P MPs and FGF-2, as well as the thickness of tissue granulation per microphotograph at the injected site, was significantly higher than those after injection with IR-ASCs in an IRP-DMEM gel containing either FGF-2 or F/P MPs. Thus, IRP-DMEM gel containing F/P MPs and FGF-2 are useful and safe IR-ASC carriers that facilitate cell proliferation, vascularization, and tissue granulation locally at injection sites. PMID- 23359414 TI - Fabrication of crosslinked carboxymethylchitosan microspheres and their incorporation into composite scaffolds for enhanced bone regeneration. AB - Carboxymethylchitosan (CMCS) microspheres were prepared by the carboxymethylation of chitosan (CS) beads using monochloroacetic acid. The CMCS microspheres were crosslinked using two different methods: the amine-amine crosslinker genipin and carbodiimide chemistry, yielding Gen-X CMCS and X-CMCS beads, respectively. The Gen-X CMCS beads were found to have poor degradation and drug release profiles. The X-CMCS microspheres displayed good potential for use in tissue engineering applications in which degradation and local drug delivery are desired. The X-CMCS beads displayed enzymatic degradation of 82.7 +/- 1.2% in 100 MUg/mL lysozyme after 1 month. An extended release of rhBMP-2 for at least 45 days was also observed with the X-CMCS microspheres. Scaffolds were formed by fusing beads together, and the X-CMCS beads were successfully incorporated into composite X CMCS/CS scaffolds. The composite scaffolds had increased degradation of 14.5 +/- 6.6% compared to 0.5 +/- 0.4% for CS-only scaffolds, and the X-CMCS/CS scaffolds released more rhBMP-2 at all timepoints. The composite scaffolds also supported the attachment and proliferation of SAOS-2 cells. The addition of X-CMCS beads resulted in fabrication of scaffolds with improved properties for use in bone tissue engineering. PMID- 23359415 TI - Repair of rheumatic mitral valve regurgitation: how far can we go? PMID- 23359416 TI - Should aortic arch replacement be performed during initial surgery for aortic root aneurysm in patients with Marfan syndrome? AB - OBJECTIVES: The aim of this study was to investigate whether total arch replacement (TAR) during initial surgery for root aneurysm should be routinely performed in patients with Marfan syndrome (MFS). METHODS: Retrospective analysis of 94 consecutive MFS patients fulfilling Ghent criteria who underwent 148 aortic surgeries and were followed at this institution during the past 16 years. RESULTS: The mean follow-up interval was 8.8 +/- 7 years. Initial presentation was acute aortic dissection (AAD) in 35% of patients (76% Type A and 24% Type B) and aneurysmal disease in 65%. TAR was performed in 8% of patients during initial surgery for AAD (otherwise a hemi-arch replacement was performed) and 1.6% in elective root repair. Secondary TAR had to be performed in only 3% of patients without, but in 33% following AAD (33% Type A and 33% Type B; P = 0.0001). Thirty day, 6-month, 1-year and overall mortalities were 3.2, 5.3, 6.4 and 11.7%, respectively. Operative and 30-day mortalities in secondary aortic arch replacement were zero. Secondary TAR after AAD did not increase the need for the replacement of the entire thoracoabdominal aorta during follow-up compared with patients without secondary TAR (37 vs 40%, P = 1.0). CONCLUSIONS: MFS patients undergoing elective root repair have small risk of reinterventions on the aortic arch, and primary prophylactic replacement does not seem to be justified. In patients with AAD, the need for reinterventions is precipitated by the dissection itself and not by limiting the procedure to the hemi-arch replacement in the emergency setting. Limiting surgery to the aortic root, ascending aorta and proximal aortic arch is associated with low mortality in MFS patients presenting with AAD. PMID- 23359417 TI - Liquid-crystalline elastomer-nanoparticle hybrids with reversible switch of magnetic memory. AB - A stimuli-responsive material is synthesized that combines the actuation potential of liquid-crystalline elastomers with the anisotropic magnetic properties of ellipsoidal iron oxide nanoparticles. The resulting nanocomposite exhibits unique shape-memory features with magnetic information, which can be reversibly stored and erased via parameters typical of soft materials, such as high deformations, low stresses, and liquid-crystalline smectic-isotropic transition temperatures. PMID- 23359418 TI - Improving memory after environmental context change: a strategy of "preinstatement". AB - A change in environmental context between study and test can produce detrimental effects on memory. For instance, when a change in the environment occurs after an event, memory for the event declines. However, the negative effects of context change can be eliminated when participants are provided with contextual cues. Here, we report that, as predicted by the Lehman-Malmberg model (Lehman & Malmberg Journal of Experimental Psychology: Learning, Memory, and Cognition 35(4):970, 2009, Psychological Review, 2012), participants can overcome a change in the environment by recalling the future test environment while studying, a strategy referred to as preinstatement. PMID- 23359419 TI - Parts function as perceptual organizational entities in infancy. AB - Both objects and parts function as organizational entities in adult perception. Prior research has indicated that objects affect organization early in life: Infants grouped elements located within object boundaries and segregated them from those located on different objects. Here, we examined whether parts also induce grouping in infancy. Five- and 6.5-month-olds were habituated to two-part objects containing element pairs. In a subsequent test, infants treated groupings of elements that crossed part boundaries as novel, in comparison with groupings that had shared a common part during habituation. In contrast, the same arrangement of elements failed to elicit evidence of grouping in control conditions in which the elements were not surrounded by closed part boundaries. Thus, infants grouped and segregated elements on the basis of part structure. Part-based processing is a key aspect of many theories of perception. The present research adds to this literature by indicating that parts function as organizational entities early in life. PMID- 23359420 TI - What is learning? On the nature and merits of a functional definition of learning. AB - Learning has been defined functionally as changes in behavior that result from experience or mechanistically as changes in the organism that result from experience. Both types of definitions are problematic. We define learning as ontogenetic adaptation-that is, as changes in the behavior of an organism that result from regularities in the environment of the organism. This functional definition not only solves the problems of other definitions, but also has important advantages for cognitive learning research. PMID- 23359421 TI - Coverage and effectiveness of Kyasanur forest disease (KFD) vaccine in Karnataka, South India, 2005-10. AB - BACKGROUND: Kyasanur forest disease (KFD), a tick-borne viral disease with hemorrhagic manifestations, is localised in five districts of Karnataka state, India. Annual rounds of vaccination using formalin inactivated tissue-culture vaccine have been conducted in the region since 1990. Two doses of vaccine are administered to individuals aged 7-65 years at an interval of one month followed by periodic boosters after 6-9 months. In spite of high effectiveness of the vaccine reported in earlier studies, KFD cases among vaccinated individuals have been recently reported. We analysed KFD vaccination and case surveillance data from 2005 to 2010. METHODOLOGY/PRINCIPAL FINDINGS: We calculated KFD incidence among vaccinated and unvaccinated populations and computed the relative risk and vaccine effectiveness. During 2005-2010, a total of 343,256 individuals were eligible for KFD vaccination (details of vaccination for 2008 were not available). Of these, 52% did not receive any vaccine while 36% had received two doses and a booster. Of the 168 laboratory-confirmed KFD cases reported during this 5-year period, 134 (80%) were unvaccinated, nine each had received one and two doses respectively while 16 had received a booster during the pre transmission season. The relative risks of disease following one, two and booster doses of vaccine were 1.06 (95% CI = 0.54-2.1), 0.38 (95% CI = 0.19-0.74) and 0.17 (95% CI = 0.10-0.29) respectively. The effectiveness of the vaccine was 62.4% (95% CI = 26.1-80.8) among those who received two doses and 82.9% (95% CI = 71.3-89.8) for those who received two doses followed by a booster dose as compared to the unvaccinated individuals. CONCLUSIONS: Coverage of KFD vaccine in the study area was low. Observed effectiveness of the KFD vaccine was lower as compared to the earlier reports, especially after a single dose administration. Systematic efforts are needed to increase the vaccine coverage and identify the reasons for lower effectiveness of the vaccine in the region. PMID- 23359422 TI - Conditional and domain-specific inactivation of the Tsc2 gene in neural progenitor cells. AB - Tuberous sclerosis complex (TSC) is a genetic disease characterized by multiorgan benign tumors as well as neurological manifestations. Epilepsy and autism are two of the more prevalent neurological complications and are usually severe. TSC is caused by mutations in either the TSC1 (encodes hamartin) or the TSC2 (encodes tuberin) genes with TSC2 mutations being associated with worse outcomes. Tuberin contains a highly conserved GTPase-activating protein (GAP) domain that indirectly inhibits mammalian target of rapamycin complex 1 (mTORC1). mTORC1 dysregulation is currently thought to cause much of the pathogenesis in TSC but mTORC1-independent mechanisms may also contribute. We generated a novel conditional allele of Tsc2 by flanking exons 36 and 37 with loxP sites. Mice homozygous for this knock-in Tsc2 allele are viable and fertile with normal appearing growth and development. Exposure to Cre recombinase then creates an in frame deletion involving critical residues of the GAP domain. Homozygous conditional mutant mice generated using Emx1(Cre) have increased cortical mTORC1 signaling, severe developmental brain anomalies, seizures, and die within 3 weeks. We found that the normal levels of the mutant Tsc2 mRNA, though GAP deficient tuberin protein, appear unstable and rapidly degraded. This novel animal model will allow further study of tuberin function including the requirement of the GAP domain for protein stability. PMID- 23359423 TI - Stress-mediated alterations in chromatin architecture correlate with down regulation of a gene encoding 60S rpL32 in rice. AB - Several ribosomal proteins are down-regulated at the translational, post transcriptional and transcriptional level in response to abiotic stress, resulting in retardation of growth and productivity in various plants. However, transcriptional mechanisms associated with the stress-mediated down-regulation of such genes have not been well studied. Recently, we reported salt-responsive transcriptional down-regulation of a gene encoding 60S ribosomal protein L32, rpL32_8.1, in rice. In the present work, chromatin remodeling mechanisms associated with down-regulation of this gene under salt stress have been studied. The data obtained from the sodium bisulfite sequencing of a genomic region containing portions of the promoter and 5'-untranslated region of rpL32_8.1 exclude a role for DNA methylation in this down-regulation event. Fine mapping of the first nucleosome after the transcription start site (TSS) revealed its occupancy over the TSS to a greater extent under salt stress than that observed in a controlled environment, possibly causing a hindrance to transcription initiation during its down-regulation. Using chromatin immunoprecipitation, it was observed that histone modifications that are generally associated with highly active genes were markedly reduced under stress conditions at the 5' end region of this gene under salt stress. By applying a modified chromatin conformation capture (mCCC) technique, promoter-terminator interaction was detected for this gene under control conditions. The efficiency of this interaction was diminished under salt stress. This work indicates that the stress-responsive transcriptional down-regulation of rpL32_8.1 is accompanied by alterations in nucleosome positioning, histone modification and gene looping, but not DNA methylation. PMID- 23359424 TI - An atypical bHLH transcription factor regulates early xylem development downstream of auxin. AB - The vascular system in plants, which comprises xylem, phloem and vascular stem cells, originates from provascular cells and forms a continuous network throughout the plant body. Although various aspects of vascular development have been extensively studied, the early process of vascular development remains largely unknown. LONESOME HIGHWAY (LHW), which encodes an atypical basic helix loop-helix (bHLH) transcription factor, plays an essential role in establishing vascular cells. Here, we report the analysis of LHW homologs in relation to vascular development. Three LHW homologs, LONESOME HIGHWAY LIKE 1-3 (LHL1-LHL3), were preferentially expressed in the plant vasculature. Genetic analysis indicated that, although the LHL3 loss-of-function mutant showed no obvious phenotype, the lhw lhl3 double mutant displayed more severe phenotypic defects in the vasculature of the cotyledons and roots than the lhw single mutant. Only one xylem vessel was formed at the metaxylem position in lhw lhl3 roots, whereas the lhw root formed one protoxylem and one or two metaxylem vessels. Conversely, overexpression of LHL3 enhanced xylem development in the roots. Moreover, N-1 naphthylphthalamic acid caused ectopic LHL3 expression in accordance with induced auxin maximum. These results suggest that LHL3 plays a positive role in xylem differentiation downstream of auxin. PMID- 23359425 TI - The Saccharomyces cerevisiae enolase-related regions encode proteins that are active enolases. AB - In addition to two genes (ENO1 and ENO2) known to code for enolase (EC4.2.1.11), the Saccharomyces cerevisiae genome contains three enolase-related regions (ERR1, ERR2 and ERR3) which could potentially encode proteins with enolase function. Here, we show that products of these genes (Err2p and Err3p) have secondary and quaternary structures similar to those of yeast enolase (Eno1p). In addition, Err2p and Err3p can convert 2-phosphoglycerate to phosphoenolpyruvate, with kinetic parameters similar to those of Eno1p, suggesting that these proteins could function as enolases in vivo. To address this possibility, we overexpressed the ERR2 and ERR3 genes individually in a double-null yeast strain lacking ENO1 and ENO2, and showed that either ERR2 or ERR3 could complement the growth defect in this strain when cells are grown in medium with glucose as the carbon source. Taken together, these data suggest that the ERR genes in Saccharomyces cerevisiae encode a protein that could function in glycolysis as enolase. The presence of these enolase-related regions in Saccharomyces cerevisiae and their absence in other related yeasts suggests that these genes may play some unique role in Saccharomyces cerevisiae. Further experiments will be required to determine whether these functions are related to glycolysis or other cellular processes. PMID- 23359426 TI - Long-term muscle-derived cell culture: multipotency and susceptibility to cell death stimuli. AB - Improvement in the yield of adult organism stem cells, and the ability to manage their differentiation and survival potential are the major goals in their application in regenerative medicine and in the adult stem cell research. We have demonstrated that adult rabbit muscle-derived cell lines with an unlimited proliferative potential in vitro can differentiate into myogenic, osteogenic, adipogenic and neurogenic lineages. Studies of cell survival in vitro showed that differentiated cells, except neurogenic ones, are more resistant to apoptosis inducers compared to proliferating cells. Resistance to death signals correlated with the level of protein kinase AKT phosphorylation. Skeletal muscle-derived cell lines can be multipurpose tools in therapy. Enhanced resistance of differentiated cells to certain types of damage shows their potential for long term survival and maintenance in an organism. This article was published online on 29 January 2013. An error was subsequently identified. This notice is included in the online and print versions to indicate that both have been corrected 6 March 2013. PMID- 23359427 TI - Nrf1 is time-dependently expressed and distributed in the distinct cell types after trauma to skeletal muscles in rats. AB - Our goal was to elucidate the dynamic expression and distribution of the nuclear factor erythroid-derived factor 2-related factor 1 (Nrf1) by immunohistochemistry, Western blotting, and real-time PCR during wound healing of contused skeletal muscle in rats. An animal model of skeletal muscle contusion was established in 40 Sprague-Dawley male healthy rats. Samples were taken at 6 h, 12 h, 1 day, 3 days, 5 days, 7 days, 10 days, and 14 days post-injury, respectively (5 rats in each posttraumatic interval). 5 rats were employed as control. A weak immunoreactivity of Nrf1 was observed in the sarcoplasm and nuclei of normal myofibers in control rats. Prominent immunostaining for Nrf1 was seen in a large number of polymorphonuclear cells, round-shaped mononuclear cells and spindle-shaped fibroblastic cells, and regenerated multinucleated myotubes in the injured tissue. Subsequently, neutrophils, macrophages and myofibroblasts were identified as expressing Nrf1 by double immunofluorescent procedures. By real-time PCR analysis, Nrf1 expression was up-regulated and peaked at inflammatory phase. The expression tendency was also confirmed by Western blot. In conclusion, Nrf1 is time-dependently expressed in certain cell types, such as neutrophils, macrophages, myofibroblasts and regenerated multinucleated myotubes, suggesting that Nrf1 may modulate oxidative stress response and regeneration after trauma to skeletal muscles. PMID- 23359429 TI - Highly efficient production of the Alzheimer's gamma-secretase integral membrane protease complex by a multi-gene stable integration approach. AB - Inefficient production of membrane-embedded multi-protein complexes by conventional methods has largely prevented the generation of high-resolution structural information and the performance of high-throughput drug discovery screens for this class of proteins. Not exempt from this rule is gamma-secretase, an intramembrane-cleaving protease complex regulating a multitude of signaling pathways and biological processes by influencing gene transcription. gamma Secretase is also implicated in the pathogenesis of Alzheimer's disease and several types of cancer. As an additional challenge, the reconstitution of the protease complex in its active form requires an intricate assembly and maturation process, including a highly regulated endoproteolytic processing of its catalytic component. In this article we report the application of a transposon-mediated multigene stable integration technology to produce active gamma-secretase in mammalian cells in amounts adequate for crystallization studies and drug screening. Our strategy is expected to help elucidate the molecular mechanisms of intramembrane proteolysis. It is further expected to be widely used for the production of other multi-protein complexes for applications in structural biology and drug development. PMID- 23359428 TI - TNFalpha induces expression of HIF-1alpha mRNA and protein but inhibits hypoxic stimulation of HIF-1 transcriptional activity in airway smooth muscle cells. AB - Airway smooth muscle cells (ASMCs) participate in tissue remodeling characteristic of airway inflammatory diseases like asthma. Inflammation and hypoxia pathways are often interconnected and the regulatory subunit of the hypoxia inducible factor, HIF-1alpha, has been recently shown to be induced by cytokines. Here we investigate the effect of individual or combined treatment of ASMCs with the inflammatory mediator TNFalpha and/or hypoxia on the expression of HIF-1alpha, HIF-1 targets and inflammation markers. TNFalpha enhances HIF-1alpha protein and mRNA levels, under both normoxia and hypoxia. TNFalpha-mediated induction of HIF-1alpha gene transcription is repressed by inhibition of the NF kappaB pathway. Despite the up-regulation of HIF-1alpha protein, the transcription of HIF-1 target genes remains low in the presence of TNFalpha at normoxia and is even reduced at hypoxia. We show that the reduction in HIF-1 transcriptional activity by TNFalpha is due to inhibition of the interaction of HIF-1alpha with ARNT and subsequent blocking of its binding to HREs. Comparison between hypoxia and TNFalpha for their effects on the expression of inflammatory markers shows significant differences: hypoxia up-regulates the expression of IL 6, but not RANTES or ICAM, and reduces the induction of VCAM by TNFalpha. Finally, ex vivo treatment of rabbit trachea strips with TNFalpha increases HIF 1alpha protein levels, but reduces the expression of HIF-1 targets under hypoxia. Overall, TNFalpha induces HIF-1alpha mRNA synthesis via an NF-kappaB dependent pathway but inhibits binding of HIF-1alpha to ARNT and DNA, while hypoxia and TNFalpha have distinct effects on ASMC inflammatory gene expression. PMID- 23359430 TI - Preliminary validation of self-assessment tool to measure imatinib adherence in patients with chronic myeloid leukemia. AB - STUDY OBJECTIVES: To develop and validate a self-assessment adherence tool for imatinib in patients with chronic myeloid leukemia (CML), and to correlate the use of this tool with response to treatment and adverse effects. DESIGN: Retrospective cohort study. SETTING: Regional cancer center in France. PATIENTS: Forty-six patients with chronic phase CML treated with imatinib for 6 months or longer as of July 1, 2009. MEASUREMENTS AND MAIN RESULTS: We developed a self assessment questionnaire consisting of 10 questions to identify patients who were nonadherent to their cancer treatment. Each answer was worth 1 point, resulting in a possible maximum score of 10. The questionnaire was validated in patients receiving imatinib, using an objective adherence evaluation: a patient's score on the self-assessment questionnaire was correlated with prescription refills, expressed as a medication possession ratio. A score of less than 8 was associated with a positive predictive value of 0.83 to have a medication possession ratio below 90%. With use of this questionnaire, half of the patients receiving imatinib would be identified as being nonadherent (sensitivity 0.5). Few adherent patients would be falsely identified as nonadherent, as the questionnaire's specificity was 0.97. CONCLUSION: This self-assessment questionnaire was validated for the first time in patients receiving imatinib for CML treatment. It provides a simple practical tool for health care professionals to assess patient adherence during their routine clinical practice and to propose targeted interventions for those identified as possibly nonadherent. PMID- 23359432 TI - Nonadhesive, silica nanoparticles-based brush-coated contact lens cases- compromising between ease of cleaning and microbial transmission to contact lenses. AB - Surface properties of lens cases are determinant for their cleanability and for microbial transmission from lens cases to contact lenses (CLs). PEG-polymer-brush coatings are known to decrease microbial adhesion more than other surface coatings. Here, we applied a robust, silica nanoparticles-based brush-coating to polypropylene cases to evaluate their ease of cleaning and probability of bacterial transmission to CLs. Adhesion forces of nine bacterial strains (Pseudomonas, Staphylococci, and Serratia) to rigid CLs, polypropylene, and silica nanoparticles-based brush-coated polypropylene were measured using atomic force-microscopy and subjected to Weibull analyses to yield bacterial transmission probabilities. Biofilms of each strain were grown in coated and uncoated cases and rinsed with a NaCl or antimicrobial lens care solution. Residual, viable organisms were quantified. Bacterial adhesion forces of all strains were significantly, up to tenfold smaller on brush-coated than on uncoated polypropylene. This yielded, higher transmission probabilities to a CL, but mild-rinsing yielded 10-100 fold higher removal of bacteria from brush-coated than from polypropylene cases. Moreover, due to weak adhesion forces, bacteria on brush-coated cases were two-to-three fold more susceptible to an antimicrobial lens care solution than on polypropylene cases. Therewith, the design of lens case surfaces is a compromise between ease of cleaning and transmission probability to CLs. PMID- 23359431 TI - Crevice corrosion of biomedical alloys: a novel method of assessing the effects of bone cement and its chemistry. AB - In this study, five commercially available poly(methyl methacrylate) PMMA bone cements were tested to investigate the effects of antibiotics on the severity of crevice corrosion. Bone cements with varying chemistry were also tested. A test method was developed in part reference to ASTM F746-04. Cylindrical specimens were fitted with a bone cement tapered collar, creating consistent crevice conditions. Crevice corrosion was then studied using potentiodynamic polarization techniques in 0.9% NaCl solution (pH7.4) at 37 degrees C. Surface analyses using a light microscope and scanning electron microscopy were also conducted to investigate the surface morphology after accelerated electrochemical testing. Initial testing of commercially available bone cements indicated that different PMMA bone cements can affect the initiation and propagation mechanism of crevice corrosion. Further studies, utilising electrochemical and mass spectroscopy techniques, have identified that the addition of radiopaque agent and antibiotics affect the initiation mechanisms of 316L stainless steel, whilst significantly increasing the extent of propagation in CoCrMo alloys. PMID- 23359433 TI - Analysis of regional timelines to set up a global phase III clinical trial in breast cancer: the adjuvant lapatinib and/or trastuzumab treatment optimization experience. AB - PURPOSE: This study measured the time taken for setting up the different facets of adjuvant lapatinib and/or trastuzumab treatment optimization (ALTTO), an nternational phase III study being conducted in 44 participating countries. METHODS: Time to regulatory authority (RA) approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were prospectively collected in the ALTTO study. Analyses were conducted by grouping countries into either geographic regions or economic classes as per the World Bank's criteria. RESULTS: South America had a significantly longer time to RA approval (median: 236 days, range: 21-257 days) than Europe (median: 52 days, range: 0-151 days), North America (median: 26 days, range: 22-30 days), and Asia-Pacific (median: 62 days, range: 37-75 days). Upper-middle economies had longer times to RA approval (median: 123 days, range: 21-257 days) than high income (median: 47 days, range: 0-112 days) and lower-middle income economies (median: 57 days, range: 37-62 days). No significant difference was observed for time to EC/IRB approval across the studied regions (median: 59 days, range 0-174 days). Overall, the median time from EC/IRB approval to first recruited patient was 169 days (range: 26-412 days). CONCLUSION: This study highlights the long time intervals required to activate a global phase III trial. Collaborative research groups, pharmaceutical industry sponsors, and regulatory authorities should analyze the current system and enter into dialogue for optimizing local policies. This would enable faster access of patients to innovative therapies and enhance the efficiency of clinical research. PMID- 23359434 TI - Incidence of second neoplasm in childhood cancer survivors treated with GH: an analysis of GeNeSIS and HypoCCS. AB - OBJECTIVE: Childhood cancer survivors are commonly treated with GH for GH deficiency that develops either as a result of primary malignancy or its treatment. One study--the Childhood Cancer Survivor Study (CCSS)--demonstrated increased risk of second neoplasm (SN) in GH-treated childhood cancer survivors compared with non-GH treated, after adjusting for key risk factors. We assessed the incidence of SN in GH-treated childhood cancer survivors in outpatient observational studies of GH replacement. DESIGN: Retrospective analysis of two prospective cohort studies that collected data on safety of GH replacement as prescribed in clinical practice. METHODS: Childhood cancer survivors enrolled in Eli Lilly and Company's pediatric (Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS)) and adult (Hypopituitary Control and Complications Study (HypoCCS)) observational studies of GH treatment were assessed for incidence of SN. RESULTS: The percentage of childhood cancer survivors treated with GH who developed a SN was 3.8% in pediatric GeNeSIS participants and 6.0% in adult HypoCCS participants. The estimated cumulative incidence of SN at 5 years of follow-up in these studies was 6.2 and 4.8% respectively. CONCLUSIONS: The incidence of SN in GeNeSIS and HypoCCS GH-treated participants is similar to the published literature and is thus consistent with increased risk of SN in childhood cancer survivors treated with GH. As follow-up times were relatively short (<3 years), longer observation is recommended. Nevertheless, clinicians should be alerted to the possibility of increased risk of SN in childhood cancer survivors treated with GH and continue chronic surveillance. PMID- 23359435 TI - Crosslinking using rapid thermal processing for the fabrication of efficient solution-processed phosphorescent organic light-emitting diodes. AB - Copolymers with a triscarbazole hole-transport group and an oxetane or benzocyclobutene crosslinkable group can be readily thermally crosslinked on timescales of 30 min or less, with rapid thermal processing (RTP) being highly effective for this purpose. Devices with RTP-crosslinked hole-transport layers and spin-coated emissive layers exhibit high external quantum efficiencies of up to 15%. PMID- 23359436 TI - Glycerol administration before endurance exercise: metabolism, urinary glycerol excretion and effects on doping-relevant blood parameters. AB - Glycerol is prohibited as a masking agent by the World Anti-Doping Agency and a urinary threshold has recently been recommended. However, little is known about urinary glycerol excretion after exercise, when (1) exogenous glycerol is metabolized increasingly and (2) endogenous glycerol levels are elevated. The purpose of the placebo-controlled cross-over study was to determine the effects of pre-exercise glycerol administration on glycerol metabolism, urinary excretion, and selected blood parameters. After administration of glycerol (G; 1.0 g/kg body weight (BW) + 25 ml fluid/kg BW) or placebo (P; 25 ml fluid/kg), 14 cyclists exercised 90 min at 60% VO2max . Samples were taken at 0 h (before administration), 2.5 h (before exercise), 4 h (after exercise) and 6.5 h and additional urine samples were collected until 24 h. Exercise increased endogenous plasma glycerol (0.51 +/- 0.21 mmol/l) but peak concentrations were much higher in G (2.5 h: 15.6 +/- 7.8 mmol/l). Urinary glycerol increased rapidly (58,428 +/- 71,084 ug/ml after 2.5 h) and was significantly higher than in P until 13.6 +/- 0.9 h (p < 0.01). In comparison with placebo administration, G caused significantly greater changes in plasma volume and haemoglobin concentrations after 2.5 h. BW and urine production were significantly different between P and G after 2.5 h and post-exercise. Despite exercise-induced increases in endogenous glycerol in the control group, urinary excretion remained well below the previously recommended threshold. In addition, exercise-related glycerol degradation did not appear to negatively affect the detection of exogenously administered glycerol. PMID- 23359437 TI - Quality control of mitochondria during aging: is there a good and a bad side of mitochondrial dynamics? AB - Maintenance of functional mitochondria is essential in order to prevent degenerative processes leading to disease and aging. Mitochondrial dynamics plays a crucial role in ensuring mitochondrial quality but may also generate and spread molecular damage through a population of mitochondria. Computational simulations suggest that this dynamics is advantageous when mitochondria are not or only marginally damaged. In contrast, at a higher degree of damage, mitochondrial dynamics may be disadvantageous. Deceleration of fusion-fission cycles could be one way to adapt to this situation and to delay a further decline in mitochondrial quality. However, this adaptive response makes the mitochondrial network more vulnerable to additional molecular damage. The "mitochondrial infectious damage adaptation" (MIDA) model explains a number of inconsistent and counterintuitive data such as the "clonal expansion" of mutant mitochondrial DNA. We propose that mitochondrial dynamics is a double-edged sword and suggest ways to test this experimentally. PMID- 23359438 TI - Bamboo-dominated forests of the southwest Amazon: detection, spatial extent, life cycle length and flowering waves. AB - We map the extent, infer the life-cycle length and describe spatial and temporal patterns of flowering of sarmentose bamboos (Guadua spp) in upland forests of the southwest Amazon. We first examine the spectra and the spectral separation of forests with different bamboo life stages. False-color composites from orbital sensors going back to 1975 are capable of distinguishing life stages. These woody bamboos flower produce massive quantities of seeds and then die. Life stage is synchronized, forming a single cohort within each population. Bamboo dominates at least 161,500 km(2) of forest, coincident with an area of recent or ongoing tectonic uplift, rapid mechanical erosion and poorly drained soils rich in exchangeable cations. Each bamboo population is confined to a single spatially continuous patch or to a core patch with small outliers. Using spatial congruence between pairs of mature-stage maps from different years, we estimate an average life cycle of 27-28 y. It is now possible to predict exactly where and approximately when new bamboo mortality events will occur. We also map 74 bamboo populations that flowered between 2001 and 2008 over the entire domain of bamboo dominated forest. Population size averaged 330 km(2). Flowering events of these populations are temporally and/or spatially separated, restricting or preventing gene exchange. Nonetheless, adjacent populations flower closer in time than expected by chance, forming flowering waves. This may be a consequence of allochronic divergence from fewer ancestral populations and suggests a long history of widespread bamboo in the southwest Amazon. PMID- 23359441 TI - Emotion and the moral lives of adolescents: vagaries and complexities in the emotional experience of doing harm. AB - Far from being unthinking energies or irrational impulses that control or push people around, emotions are intricately connected to the way people perceive, understand, and think about the world. As such, emotions are also an inextricable part of people's moral lives. As people go about making moral judgments and decisions, they do not merely apply abstract principles in a detached manner. Their emotions--their loves and sympathies, angers and fears, grief and sadness, guilt and shame--are inseparable from how they make sense of and evaluate their own and others' actions, the way things are, and the ways things ought to be. While this is not to say that emotions have a privileged role in morality, it does mean that emotions cannot be reasonably sidelined from the study of people's moral lives. Thus, an important part of formulating a theory of moral development is to articulate a framework for capturing children's relevant emotional experiences in the context of morally laden events. Such a framework should also help us understand how these sometimes turbulent or bewildering experiences inform, enrich, and change children's thinking about what is right and wrong and about themselves as moral agents. This article considers the research on the relation between emotion and moral thinking, offers a perspective that aims to broaden and elaborate our understanding of the connections between emotion and morality in adolescence, and sets a new agenda for research on this topic. PMID- 23359442 TI - Adolescents' emotions and reasoning in contexts of moral conflict and social exclusion. AB - This article explores how adolescents feel and think about contexts of moral conflict and social exclusion. We asked twelve-year-old adolescents how they would feel about intentionally harming another peer, omitting a prosocial duty, and excluding another peer. We then asked them to explain the reasoning behind their feelings and report on levels of sympathy. In all contexts, adolescents anticipated a variety of negative emotions for reasons of fairness and empathy. However, more feelings of guilt were reported in contexts of intentional harm than in other contexts. Adolescents with high levels of sympathy reported more guilt, for reasons of fairness and empathy, than adolescents with low levels of sympathy. These findings provide a window into adolescents' emotions and reasoning regarding moral and social issues. PMID- 23359444 TI - Linking moral emotion attributions with behavior: why "(un)happy victimizers" and "(un)happy moralists" act the way they feel. AB - This article addresses the question of why the emotions children and adolescents anticipate in the context of hypothetical scenarios have been repeatedly found to predict actual (im)moral behavior. It argues that a common motivational account of this relationship is insufficient. Instead, three links are proposed that connect cognitive representations of emotional experiences related to future (im)moral actions with decision making and action. Accordingly, it is argued that moral emotion attributions can represent a dominant desire (link 1), outcome expectancies (link 2), or an emotional response to anticipated (in)consistencies of the self (link 3). These three links exemplify different forms of moral agency that emerge in the course of children's and adolescents' development. PMID- 23359443 TI - Moral judgments and emotions: adolescents' evaluations in intergroup social exclusion contexts. AB - This article examines children's moral judgments and emotional evaluations in the context of social exclusion. As they age, children and adolescents face increasingly complex situations in which group membership and allegiance are in opposition with morally relevant decisions, such as the exclusion of an individual from a group. While adolescents are often characterized as being conformists to group norms, research demonstrates that their judgments about fairness, justice, and rights can supersede negative or exclusive norms espoused by groups. Additionally, young people's emotional evaluations of members who do not conform to a group norm are in concert with these fairness judgments. Implications for social and moral development will be discussed in the context of empirical findings. PMID- 23359445 TI - Behaving badly or goodly: is it because I feel guilty, shameful, or sympathetic? Or is it a matter of what I think? AB - The article provides a brief review of theory and research on the roles of guilt, shame, and sympathy in predicting moral behaviors. Two models are presented and contrasted. The guilt-based model proposes that guilt and shame jointly predict prosocial and aggressive behaviors. In contrast, the sympathy-based model suggests that perspective taking and sympathy are linked to such behaviors. In both models, prosocial moral reasoning is proposed as a possible mediator in these relations. Results from a study of college students suggest support for both models. Moreover, there is evidence that prosocial moral reasoning mediates the relations between these moral emotions and moral behaviors. The implications for the need to incorporate moral emotions and cognitions into existing models of morality are discussed and emphasized. PMID- 23359446 TI - Adolescents' perceptions of institutional fairness: relations with moral reasoning, emotions, and behavior. AB - This article addresses how low-income urban adolescents view the fairness of different aspects of American society, including how wealth is distributed, the nature of legal constraints, and overall social opportunities and legitimacy. This research emerged from efforts to understand the moral and emotional nature of some adolescents' aggressive tendencies. Recently it has become clearer that aggression can serve many purposes and that, for some adolescents, aggression is a coherent though problematic response to larger familial, neighborhood, and institutional forces. Consequently, the authors focus on the connections between low-income adolescents' perceptions of institutional and interpersonal fairness, certain aggressive tendencies, and related emotion judgments. At the same time, relatively little is known about how low-income adolescents as a group perceive the fairness of wealth distribution and other broad aspects of American society. Consequently, a second important goal is to examine these adolescents' normative beliefs about institutional fairness at a time of growing financial and educational inequalities in the United States. PMID- 23359447 TI - Mindfulness for adolescents: a promising approach to supporting emotion regulation and preventing risky behavior. AB - This article reviews the contextual and neuropsychological challenges of the adolescent period with particular attention to the role that universal prevention can play in moderating the harmful effects of stress. The centrality of emotion regulation skills to long-term health and wellness suggests their importance in prevention and intervention efforts for youth. Mindfulness has been shown to be an effective means of reducing stress and improving emotion balance in research with adults, although research on mindfulness with adolescents is limited. The authors present available data and describe one potentially effective program for adolescent mindfulness: Learning to BREATHE. PMID- 23359448 TI - PLGA/PEG-hydrogel composite scaffolds with controllable mechanical properties. AB - Biodegradable polymer scaffolds have great potential for regenerative medicine applications such as the repair of musculoskeletal tissues. Here, we describe the development of scaffolds that blend hydrogel components with thermoplastic materials, combining the unique properties of both components to create mouldable formulations. This study focuses on the structural and mechanical properties of the composite scaffolds, produced by combining temperature-sensitive poly(DL lactic acid-co-glycolic acid) (PLGA)/poly(ethylene glycol) (PEG) particles with a hydrogel component [Pluronic F127, fibrin or hyaluronic acid (HyA)]. The composite formulations solidified over time at 37 degrees C, with a significant increase (p <= 0.05) in compressive strength observed from 15 min to 2 h at this temperature. The maximum compressive strength was 1.2 MPa for PLGA/PEG-Pluronic F127 scaffolds, 2.4 MPa for PLGA/PEG-HyA scaffolds and 0.6 MPa for PLGA/PEG fibrin scaffolds. Porosity for each of the PLGA/PEG-hydrogel formulations tested was between 50 and 51%. This study illustrates the ability to combine this thermoplastic PLGA/PEG system with hydrogels to fabricate composite scaffolds, and demonstrates that altering the particle to hydrogel ratio produces scaffolds with varying mechanical properties. PMID- 23359449 TI - Characterization of porous polymethylmethacrylate space maintainers for craniofacial reconstruction. AB - Porous polymethylmethacrylate (PMMA) has been used as an alloplastic bone substitute in the craniofacial complex, showing integration with the surrounding soft and hard tissue. This study investigated the physicochemical properties of curing and cured mixtures of a PMMA-based bone cement and a carboxymethylcellulose (CMC) gel porogen. Four formulations yielding porous PMMA of varied porosity were examined; specifically, two groups containing 30% (w/w) CMC gel in the mixture using a 7% (w/v) or 9% (w/v) stock CMC gel (30-7 and 30-9, respectively) and two groups containing 40% (w/w) CMC gel (40-7 and 40-9). An additional group comprising solid PMMA without CMC was investigated. The incorporation of the CMC gel into the PMMA bone cement during polymerization decreased the setting time from 608 +/- 12 s for the solid PMMA to 427 +/- 10 s for the 40-9 group, and decreased the maximum temperature from 81 +/- 4 degrees C for the solid PMMA to 38 +/- 2 degrees C for the 40-9 group. The porous PMMA groups exhibited reduced compressive strength and bending modulus and strength relative to the solid PMMA. All the porous PMMA formulations released more unconverted methylmethacrylate (MMA) monomer and N,N-dimethyl-p-toluidine (DMT) from cured specimens and less MMA and DMT from curing specimens than the solid PMMA. The data suggest that the physicochemical properties of the porous PMMA formulations are appropriate for their application in craniofacial space maintenance. PMID- 23359450 TI - Pigment epithelium-derived factor delays cellular senescence of human mesenchymal stem cells in vitro by reducing oxidative stress. AB - Mesenchymal stem cells (MSCs) are multipotent progenitor cells that represent a promising approach in the field of regenerative medicine; however, this potential diminishes with senescence. Pigment epithelium-derived factor (PEDF) gives some protection by reducing oxidative stress, which is known to accelerate cellular senescence. Thus we hypothesized that PEDF could delay senescence during MSC expansion by reducing oxidative stress. Proliferation and differentiation potentials, oxidative stress, senescence and p53/p16 expressions have been examined. In MSCs cultured under normoxic conditions treated with PEDF, proliferative lifespan in vitro was significantly increased compared with control group not given PEDF, with ~10 additional population doublings (PD) occurring before terminal growth arrest. Most of the MSCs cultured under normoxic conditions ceased to proliferate after 20-28 PD, while few senescent cells were found in the hypoxic, PEDF-hypoxic and PEDF-normoxic cultures; this was associated with downregulation of p53 and p16 expression and decreased oxidative stress. PEDF also preserved differentiation potentials of MSCs compared with the control group. Thus PEDF suppression of oxidative stress delays cellular senescence and allows greater expansion of MSCs. PMID- 23359451 TI - Circulating tumor cells (CTCs) in breast cancer: a diagnostic tool for prognosis and molecular analysis. AB - Metastatic breast cancer (MBC) is characterized by a combination of tumor growth, proliferation and metastatic progression and is typically managed with palliative intent. The benefit of standard systemic therapies is relatively limited and the disease is considered incurable suggesting the need to investigate the biological drivers of the various phases of the metastatic process in order to improve the selection of molecularly driven therapies. The detection, enumeration and molecular analysis of circulating tumor cells (CTCs) provide an intriguing opportunity to advance this knowledge. CTCs enumerated by the Food and Drugs Administration-cleared CellSearch((r)) system are an independent prognostic factor of progression-free survival (PFS) and overall survival (OS) in MBC patients. Several published papers demonstrated the poor prognosis for MBC patients that presented basal CTC count >=5 in 7.5 mL of blood. Therefore, the enumeration of CTCs during treatment for MBC provides a tool with the ability to predict progression of disease earlier than standard timing of anatomical assessment using conventional radiological tests. During the metastatic process cancer cells exhibit morphological and phenotypic plasticity undergoing epithelial-mesenchymal transition (EMT). This important phenomenon is associated with down regulation of epithelial marker (e.g., EpCAM) with potential limitations in the applicability of current CTCs enrichment methods. Such observations translated in a number of investigations aimed at improving our capabilities to enumerate and perform molecular characterization of CTCs. Theoretically, the phenotypic analysis of CTCs can represent a "liquid" biopsy of breast tumor that is able to identify a new potential target against the metastatic disease and advanced the development and monitoring of personalized therapies. PMID- 23359452 TI - Hepatocellular carcinoma with blood supply from parasitized omental artery: angiographic appearance and chemoembolization. AB - OBJECTIVE: To analyze angiographic appearance of hepatocellular carcinoma (HCC) with blood supply from parasitized omental artery (POA), and evaluate the technical feasibility, safety and therapeutic efficacy of chemo-embolization via the POAs. METHODS: A total of 1,221 HCC patients who had undergone chemoembolization procedures were evaluated retrospectively. The evaluated indexes included the incidence rate of POAs, success rate of superselective catheterization, post-reaction after chemoembolization, and the cumulative survival rates. RESULTS: Totally 1,221 HCC patients had undergone 3,639 chemoembolization procedures, and 32 patients with POAs were enrolled, with 97 POAs found in 76 angiography procedures, giving an incidence rate of 2.09%. POA was observed mostly at the right lobe and left medial lobe except the segment II, and 62 POAs underwent superselective catheterization with microcatheter, giving a success rate of 63.9%. The angiographic appearance was: (1) hypertrophic POAs participating in tumor staining (n=28); (2) stiff and distorted POA (n=11), displaced due to tumor's oppression (n=8); and (3) defective tumor staining close to either gastrocolic omentum distribution or liver capsule (n=7). In 19 patients, chemoembolization via POAs was performed successfully (A group), while the remaining 13 patients failed (B group). Except 1 acute edema pancreatitis case, no serious complication was recorded. The cumulative survival rates of 6-, 12-, 18- and 24-month were 78.9%, 47.4%, 31.6% and 21.1% respectively for A group; correspondingly, 61.5%, 30.8%, 15.4% and 7.7%% for B group, in which 2 patients died of ruptured HCC. CONCLUSION: Chemoembolization with microcatheter via POAs is a relatively safe, feasible and valuable method. PMID- 23359453 TI - First evidence of prothymosin alpha localization in the acrosome of mammalian male gametes. AB - Prothymosin alpha (PTMA) is a highly acidic intrinsically unstructured protein. Its expression in male gonads is evolutionary conserved; in rat testis it is specifically localized in the cytoplasm of post-meiotic germ cells, in association with the developing acrosome system. In the present paper we investigated on PTMA localization inside the head of mammalian spermatozoa (SPZ). We chose a confocal approach to ascertain whether PTMA is expressed in the acrosome or in the perinuclear theca, two regions that are tightly linked and partially overlapped in the mature haploid cells. The obtained results showed that PTMA is specifically localized in the acrosome of rat epididymal SPZ; the same experimental approach evidenced, for the first time, PTMA presence in human ejaculated SPZ. A Western blot analysis on protein extracts from human sperm head fractions confirmed the confocal data and demonstrated that the peptide is specifically associated with the inner acrosomal membrane fraction. Finally, when the acrosome reaction was induced in vitro by progesterone treatment on both rat and human sperm, PTMA signal was retained in the apical region of reacted SPZ. In conclusion, this study confirms the conservation of PTMA distribution in vertebrate male gametes and strongly supports a role for this polypeptide in their physiology. PMID- 23359454 TI - Comparative efficacy of oral nucleoside or nucleotide analog monotherapy used in chronic hepatitis B: a mixed-treatment comparison meta-analysis. AB - STUDY OBJECTIVE: To compare the efficacy of nucleoside or nucleotide analog monotherapy for the treatment of chronic hepatitis virus B (HBV) with adefovir dipivoxil, entecavir, lamivudine, telbivudine, and tenofovir disoproxil fumarate. DESIGN: Mixed-treatment comparison meta-analysis of nine randomized controlled clinical trials. PATIENTS: A total of 3972 adults with a diagnosis of chronic hepatitis B. MEASUREMENTS AND MAIN RESULTS: A systematic review was conducted to search for randomized clinical trials that evaluated the efficacy of nucleoside or nucleotide analogs used as monotherapy. The evaluated outcomes were reduction of HBV DNA levels, normalization of alanine aminotransferase levels, and seroconversion of hepatitis B e antigen (HBeAg). A mixed-treatment comparison was conducted to compare the odds ratios among the treatments and to rank the therapies to determine the optimal treatment option. Tenofovir had the best results among the nucleoside or nucleotide analogs for the three evaluated efficacy outcomes in both HBeAg-positive and -negative patients. CONCLUSION: Tenofovir has the highest probability of reducing HBV DNA, normalizing alanine aminotransferase levels and inducing HBeAg seroconversion after 1 year of treatment. An efficacy comparison of therapies is an important tool to guide clinicians in selecting the optimal treatment option. PMID- 23359455 TI - Induced effect of Na(+) on ganoderic acid biosynthesis in static liquid culture of Ganoderma lucidum via calcineurin signal transduction. AB - Na(+)/Ca(2+) exchange is important to cell physiology and metabolism, but its role in the secondary metabolite biosynthesis by fungi is yet unclear. In this work, in static liquid cultures of Ganoderma lucidum, which is an efficient process for hyper-production of anti-tumor ganoderic acids (GAs), it was interestingly found that Na(+) addition could enhance the GAs production, but K(+) did not. Further investigation by intracellular Ca(2+) imaging and using a calcineurin inhibitor (i.e., cyclosporin A) revealed that addition of Na(+) led to the influx of Ca(2+) from culture broth to the cells and calcineurin signals were also triggered. Addition of 100 mM Na(+) at the beginning of the static liquid cultivation, in which the addition dosage and timing were optimized, resulted in 2.8-fold improvement of total GAs production. Quantitative gene transcription analysis indicated that the expression levels of the genes of Ca(2+) sensors and GA biosynthesis were upregulated with Na(+) induction while downregulated by using the calcineurin inhibitor, implying that higher GA production might result from higher expression of those genes. This work not only provided a simple and efficient induction strategy by Na(+) addition for the improved GAs production but also suggested the regulation mechanism of Na(+) on the GA biosynthesis through calcineurin signaling transduction. PMID- 23359456 TI - Well-defined multibranched gold with surface plasmon resonance in near-infrared region from seeding growth approach using gyroid block copolymer template. AB - Well-defined multibranched gold (Au) in polymers, both as bulk or continuous thin films, can be fabricated by using a nanoporous polymer with gyroid nanochannels as a template. The nanoporous polymer template is obtained from the self-assembly of a degradable block copolymer, polystyrene-b-poly (L-lactide) (PS-PLLA), followed by the hydrolysis of PLLA blocks. Templated seeding growth approach can be conducted to create precisely controlled nanostructured Au giving remarkable surface plasmon resonance (SPR) in (branched Au with uniform distribution in PS matrix) near-infrared (NIR) region. Controlled growth conditions allow the fabrication of three-dimensionally ordered nanoporous Au particles that possess NIR SPR. Double gyroid Au with dual networks in the PS matrix is obtained after completing the seeding growth at which the NIR SPR diminishes resulting from the reduction in the density of nanostructured edge. PMID- 23359457 TI - Non-invasively derived respiratory severity score and oxygenation index in ventilated newborn infants. AB - OBJECTIVE: To evaluate the association between the respiratory severity score (RSS) and oxygenation index (OI) in intubated, mechanically ventilated, newborn infants. STUDY DESIGN: In a retrospective cohort study (December 2006 to June 2010) medical records of all infants who were admitted to our neonatal intensive care unit (NICU) and required invasive mechanical ventilation were reviewed for patients' demographics, ventilator settings, and arterial blood gas (ABG). RESULTS: During the study period 2,332 infants were admitted to our NICU, and 425 infants were intubated and had an ABG with a gestational age of 30.5 +/- 4.9 weeks and a birth weight of 1,635 +/- 923 g (mean +/- standard deviation). There was a strong association between RSS and OI in infants with oxygen saturation (SaO2 ) between 88% and 94% (R2 = 0.982, n = 101; P < 0.001). CONCLUSION: In intubated newborn infants, there is a strong association between RSS and OI at SaO2 between 88% and 94%. PMID- 23359458 TI - Cloning and characterization of canine prostate-specific membrane antigen. AB - BACKGROUND: Prostate-specific membrane antigen (PSMA) is a promising biomarker in the diagnosis of prostate cancer and a potential target for antibody-based therapeutic strategies. We isolated the canine PSMA cDNA and investigated the cellular and biochemical characteristics of the recombinant protein as a potential target for animal preclinical studies of antibody based-therapies. METHODS: Canine PSMA cDNA was isolated by PCR, cloned into expression vectors and transfected into COS-1 and MDCK cells. The biosynthesis and glycosylation of the recombinant protein were investigated in pulse-chase experiments, the cellular localization by confocal laser microscopy, the mode of association of PSMA with the membrane with solubilization in different detergents and its quaternary structure in sucrose-density gradients. RESULTS: Canine PSMA shows 91% amino acid homology to human PSMA, whereby the major difference is a longer cytoplasmic tail of canine PSMA compared to its human counterpart. Canine PSMA is trafficked efficiently along the secretory pathway, undergoes homodimerization when it acquires complex glycosylated mature form. It associates with detergent-resistant membranes, which act as platforms along its intracellular trafficking. Confocal analysis revealed canine PSMA at the cell surface, Golgi, and the endoplasmic reticulum. A similar distribution is revealed for human PSMA, yet with reduced cell surface levels. CONCLUSIONS: The cloning, expression, biosynthesis, processing and localization of canine PSMA in mammalian cells is described. We demonstrate that canine PSMA reveals similar characteristics to human PSMA rendering this protein useful as a translational model for investigations of prostate cancer as well as a suitable antigen for targeted therapy studies in dogs. PMID- 23359459 TI - Impairment of neutrophil reactivity to elastin peptides in COPD. AB - RATIONALE: Neutrophils play an important role in the inflammatory process associated with chronic obstructive pulmonary disease (COPD). Lung-infiltrating neutrophils secrete elastinolytic proteases that participate in elastin breakdown and the formation of elastin peptides (EPs). OBJECTIVES: We hypothesized that circulating neutrophil-associated immune response may be modulated by EPs during COPD. METHODS: Neutrophils obtained from patients with either stable or exacerbated COPD and controls were cultured with or without EPs. Cell chemotaxis was analysed by the Boyden method and cytokine expression was analysed by ELISA and real-time reverse transcriptase PCR. Bacterial phagocytosis and killing of ingested bacteria were evaluated after incubation with Pseudomonas aeruginosa. Reactive oxygen species (ROS) measurement and elastin receptor expression were determined by flow cytometry. RESULTS: Chemotactic activity of neutrophils from patients with COPD towards the VGVAPG EP was reduced compared with controls. VGVAPG increased proinflammatory cytokine synthesis and bacterial load, but reduced ROS production in neutrophils from controls and from patients with stable COPD. Patients with exacerbated COPD were unresponsive to VGVAPG treatment. These findings were associated with a decreased or almost complete loss of S-Gal elastin receptor expression in neutrophils from patients with stable or exacerbated COPD, respectively. CONCLUSIONS: The study demonstrates that the response of neutrophils from patients with COPD to VGVAPG varied according to COPD phase and critical level of S-Gal expression. S-Gal downregulation could result from a feedback mechanism induced by high levels of EPs. PMID- 23359460 TI - Female adolescent craniofacial growth spurts: real or fiction? AB - The purpose of the study is to determine whether the various aspects of the craniofacial complex exhibit female adolescent growth spurts. Multilevel polynomial models were used to estimate the growth curves of a mixed-longitudinal sample of 111 untreated females 10-15 years of age. To evaluate the horizontal and vertical movements of the individual landmarks relative to stable structures, the tracings were superimposed on the natural reference structures in the anterior cranial base. The horizontal and vertical growth changes of four landmarks and the changes of three traditional linear measurements were evaluated. Posterior nasal spine (PNS) moved posteriorly at a constant rate of approximately 0.12mm/year. Five measures showed changes in growth velocity (i.e. quadratic growth curves) but not adolescent growth spurts, including the anterior movements of anterior nasal spine (ANS) and pogonion (Pg), the inferior movements of gonion (Go), and the increases in ANS-PNS and condylion to pogonion (Co-Pg). Five measurements, including the inferior movements of ANS, PNS and Pg, the posterior movements of Go, and the increases of Go-Pg exhibited adolescent growth spurts. Peak growth velocities were attained between 11.4 and 12.8 years of age, approximately 0.7-1.4 years earlier in the maxilla than mandible. While the vertical aspects of craniofacial growth exhibit distinct female adolescent growth spurts, with peak rates occurring earlier in the maxilla than mandible, most horizontal aspects of craniofacial growth do not exhibit an adolescent spurt. PMID- 23359461 TI - Apropos "evaluation of serological diagnostic tests for typhoid Fever in papua new Guinea using a composite reference standard". PMID- 23359462 TI - Reply to 'apropos "evaluation of serological diagnostic tests for typhoid Fever in papua new Guinea using a composite reference standard"'. PMID- 23359464 TI - The effect of PCL-TCP scaffold loaded with mesenchymal stem cells on vertical bone augmentation in dog mandible: a preliminary report. AB - Polycaprolactone-tricalcium phosphate (PCL-TCP), a new composite scaffold, has been shown to facilitate early revascularization and speed up bone regeneration process. The objective of this study was to evaluate the effect of PCL-TCP seeded with mesenchymal stem cells (MSCs) on healing of the vertical bone critical sized defect in dog's mandible. Bone marrow aspirate from dog humerous was cultured and the stemness of the cells was examined by differentiation staining methods and flow cytometric analysis. Third passage subculture cells (5 * 105 cells) were loaded on 20 * 10 * 10 mm3 and incubated for 48 h. The presence of MSCs in the pores was evaluated by scanning electron microscope. Bilateral mandibular premolar teeth were extracted in four dogs and the buccal and lingual bone plates were reduced to make a vertical defect. Cell-loaded scaffolds were fixed in right side and left side received pure PCL-TCP scaffolds as a control side defects. Histomorphometric analysis after 8 weeks of the scaffold implantation showed higher amount of lamellar bone in the test side (48.63%) than control side (17.27%) (p < 0.05).The results suggest that PCL-TCP may be an appropriate scaffold for loading MSCs in bone regeneration. PMID- 23359465 TI - Isolated bladder exstrophy associated with a de novo 0.9 Mb microduplication on chromosome 19p13.12. AB - BACKGROUND: The exstrophy-epispadias complex (BEEC) is a urogenital birth defect of varying severity. The causes of the BEEC are likely to be heterogeneous, with individual environmental or genetic risk factors still being largely unknown. In this study, we aimed to identify de novo causative copy number variations (CNVs) that contribute to the BEEC. METHODS: Array-based molecular karyotyping was performed to screen 110 individuals with BEEC. Promising CNVs were tested for de novo occurrence by investigating parental DNAs. Genes located in regions of rearrangements were prioritized through expression analysis in mice to be sequenced in the complete cohort, to identify high-penetrance mutations involving small sequence changes. RESULTS: A de novo 0.9 Mb microduplication involving chromosomal region 19p13.12 was identified in a single patient. This region harbors 20 validated RefSeq genes, and in situ hybridization data showed specific expression of the Wiz gene in regions surrounding the cloaca and the rectum between GD 9.5 and 13.5. Sanger sequencing of the complete cohort did not reveal any pathogenic alterations affecting the coding region of WIZ. CONCLUSIONS: The present study suggests chromosomal region 19p13.12 as possibly involved in the development of CBE, but further studies are needed to prove a causal relation. The spatiotemporal expression patterns determined for the genes encompassed suggest a role for Wiz in the development of the phenotype. Our mutation screening, however, could not confirm that WIZ mutations are a frequent cause of CBE, although rare mutations might be detectable in larger patient samples. 19p13.12, microduplication, bladder exstrophy-epispadias complex, array-based molecular karyotyping, in situ hybridization analysis, copy number variations, WIZ gene. PMID- 23359466 TI - Mutation of Hof1 PEST motif phosphorylation sites leads to retention of Hof1 at the bud neck and a decrease in the rate of myosin contraction. AB - Regulation of actomyosin ring contraction is important for the coordination of cytokinesis with mitosis. Hof1, a member of the Pombe Cdc15 homology (PCH) family of proteins, is required for efficient cytokinesis in budding yeast. Phosphorylation of Hof1 depends on the mitotic exit network (MEN), and its degradation at the end of mitosis depends on its PEST motif and interaction with the E3 ligase Grr1. To test the hypothesis that targeted destruction of Hof1 temporally couples mitotic exit with contraction of the actomyosin ring, we mutated the Hof1 PEST motif to prevent phosphorylation and subsequent degradation. These mutations increased the amount of Hof1 at the bud neck during cytokinesis, resulted in smaller bud neck diameter, and slowed the rate of myosin contraction. However, Hof1 PEST motif phosphorylation site mutants did not have cytokinesis defects, indicating that regulation of Hof1 levels does not control the onset of actomyosin ring contraction as predicted. PMID- 23359467 TI - The effects of acute tryptophan depletion on impulsivity and mood in adolescents engaging in non-suicidal self-injury. AB - OBJECTIVE: Non-suicidal self-injury (NSSI) is associated with impaired emotion regulation and impulsivity. Low serotonin (5-hydroxytryptamine) function is associated with NSSI, impaired emotion regulation and impulsivity. We investigated the effects of experimentally lowered 5-hydroxytryptamine activity, via acute tryptophan depletion (ATD), on impulsive action, reflection impulsivity and mood in female adolescents engaging in NSSI. METHODS: Thirty-two female adolescents engaging in NSSI participated in a parallel group ATD study. Following ATD, impulsive action was assessed using the Continuous Performance Test, Identical Pairs Version. Reflection impulsivity was assessed using the Matching Familiar Figures Test. Mood-lowering was examined using the Profile of Mood States. RESULTS: Following ATD, the participants showed an impulsive response style (as reflected in their low beta) and increased attentional capacity (as reflected in their elevated d'). ATD did not affect reflection impulsivity or mood. CONCLUSIONS: Acute tryptophan depletion caused an impulsive response style and increased attentional capacity. Importantly, the findings suggest that low serotonin function is a vulnerability among female adolescents for engaging in NSSI when in emotional distress. PMID- 23359468 TI - BIS impulsivity and acute nicotine exposure are associated with discounting global consequences in the Harvard game. AB - OBJECTIVE: The Barratt Impulsivity Scale (BIS) provides a transdiagnostic marker for a number of psychiatric conditions and drug abuse, but the precise psychological trait(s) tapped by this questionnaire remain obscure. METHOD: To address this, 51 smokers completed in counterbalanced order the BIS, a delay discounting task and a Harvard game that measured choice between a response that yielded a high immediate monetary payoff but decreased opportunity to earn money overall (local choice) versus a response that yielded a lower immediate payoff but afforded a greater opportunity to earn overall (global choice). RESULTS: Individual level of BIS impulsivity and self-elected smoking prior to the study were independently associated with increased preference for the local over the global choice in the Harvard game, but not delay discounting. CONCLUSIONS: BIS impulsivity and acute nicotine exposure reflect a bias in the governance of choice by immediate reward contingencies over global consequences, consistent with contemporary dual-process instrumental learning theories. PMID- 23359469 TI - Yokukansan in the treatment of behavioral and psychological symptoms of dementia: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVES: There is currently no meta-analysis of the efficacy and tolerability of Yokukansan in the treatment of behavioral and psychological symptoms of dementia. METHOD: We used information obtained from the PubMed and Cochrane Library databases until October 2012. We conducted a systematic review and meta analysis of individual patient data from randomized controlled trials comparing Yokukansan with usual care (UC, i.e., controls). Standardized mean difference and weighted mean difference were calculated. All studies used the Neuropsychiatric Inventory (NPI) for the evaluation of behavioral and psychological symptoms of dementia. RESULTS: Four relevant studies (total n = 236) were identified. Yokukansan was superior to UC in the reduction of total NPI scores (p = 0.0009, weighted mean difference = -7.20, I(2) = 0%). In addition, Yokukansan was more efficacious in reducing scores on the NPI subscale (delusions, hallucinations, and agitation/aggression) than UC (p < 0.00001-0.0009). Yokukansan treatment also improved activities of daily living scores compared with UC (p = 0.04, standardized mean difference = -0.32, I(2) = 0%). Mini-mental state examination scores did not differ between the Yokukansan and UC treatment groups. Yokukansan was not different from UC regarding discontinuation due to any cause. CONCLUSION: Our results suggest that Yokukansan has a beneficial effect on NPI and on ADL scores and that Yokukansan seems to be a well-tolerated treatment. PMID- 23359471 TI - Wear measurement of highly cross-linked UHMWPE using a 7Be tracer implantation technique. AB - The very low wear rates achieved with the current highly cross-linked ultrahigh molecular weight polyethylenes (UHMWPE) used in joint prostheses have proven to be difficult to measure accurately by gravimetry. Tracer methods are therefore being explored. The purpose of this study was to perform a proof-of-concept experiment on the use of the radioactive tracer beryllium-7 ((7)Be) for the determination of in vitro wear in a highly cross-linked orthopedic UHMWPE. Three cross-linked and four conventional UHMWPE pins made from compression-molded GUR 1050, were activated with 10(9) to 10(10) (7)Be nuclei using a new implantation setup that produced a homogenous distribution of implanted nuclei up to 8.5 MUm below the surface. The pins were tested for wear in a six-station pin-on-flat apparatus for up to 7.1 million cycles (178 km). A Germanium gamma detector was employed to determine activity loss of the UHMWPE pins at preset intervals during the wear test. The wear of the cross-linked UHMWPE pins was readily detected and estimated to be 17 +/- 3 MUg per million cycles. The conventional-to-cross-linked ratio of the wear rates was 13.1 +/- 0.8, in the expected range for these materials. Oxidative degradation damage from implantation was negligible; however, a weak dependence of wear on implantation dose was observed limiting the number of radioactive tracer atoms that can be introduced. Future applications of this tracer technology may include the analysis of location-specific wear, such as loss of material in the post or backside of a tibial insert. PMID- 23359472 TI - Myocardin and microRNA-1 modulate bladder activity through connexin 43 expression during post-natal development. AB - Overactive bladder (OAB) is a pervasive clinical problem involving alterations in both neurogenic and myogenic activity. While there has been some progress in understanding neurogenic inputs to OAB, the mechanisms controlling myogenic bladder activity are unclear. We report the involvement of myocardin (MYOCD) and microRNA-1 (miR-1) in the regulation of connexin 43 (GJA1), a major gap junction in bladder smooth muscle, and the collective role of these molecules during post natal bladder development. Wild-type (WT) mouse bladders showed normal development from early post-natal to adult including increases in bladder capacity and maintenance of normal sensitivity to cholinergic agents concurrent with down-regulation of MYOCD and several smooth muscle cell (SMC) contractile genes. Myocardin heterozygous-knockout mice exhibited reduced expression of Myocd mRNA and several SMC contractile genes concurrent with bladder SMC hypersensitivity that was mediated by gap junctions. In both cultured rat bladder SMC and in vivo bladders, MYOCD down-regulated GJA1 expression through miR-1 up regulation. Interestingly, adult myocardin heterozygous-knockout mice showed normal increases in bladder and body weight but lower bladder capacity compared to WT mice. These results suggest that MYOCD down-regulates GJA1 expression via miR-1 up-regulation, thereby contributing to maintenance of normal sensitivity and development of bladder capacity. PMID- 23359473 TI - Impact of serum vascular endothelial growth factor on prognosis in patients with unresectable hepatocellular carcinoma after transarterial chemoembolization. AB - OBJECTIVE: To investigate the expression level of serum vascular endothelial growth factor (VEGF) in patients with unresectable hepatocellular carcinoma (HCC) and its relationship with the clinicopathological characteristics, and to assess the impact of serum VEGF as a predictive factor for HCC prognosis during transarterial chemoembolization (TACE) treatments. METHODS: Serum VEGF levels were measured using enzyme-linked immunosorbent assay (ELISA) in 60 random patients who underwent TACE or transarterial infusion (TAI) for unresectable HCC between May and September 2008 and 12 healthy volunteers were also involved in this study to serve as control. All patients' clinicopathological features were retrospectively analyzed. Serum VEGF levels were correlated with clinicopathological features of the HCC patients. The patients' survival rates were analyzed with Kaplan-Meier survival curves and compared by the log-rank test. The prognostic significance of serum VEGF levels and factors related to survival rate were evaluated by univariate and multivariate analysis. RESULTS: The median serum VEGF level in the HCC patients was 285 pg/ml (range 14-1,207 pg/ml), significantly higher than that of healthy controls (P=0.021). The serum VEGF levels were significantly correlated with platelet counts (r=0.396, P=0.002) but not other clinicopathological features. Patients with serum VEGF level >285 pg/ml had worse overall survival compared with those with serum VEGF level <285 pg/ml (P=0.002). By multivariate analysis, the serum VEGF level was a significant prognostic factor. CONCLUSION: High serum VEGF levels may predict poor prognosis of HCC after TACE. This study highlights the importance of tumor biomarker as a prognostic predictor in TACE therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features. PMID- 23359475 TI - Pharmacologic therapy for nonalcoholic fatty liver disease in adults. AB - Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides in hepatocytes in the absence of excessive alcohol intake, ranging in severity from simple steatosis to nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis can ultimately progress to cirrhosis and hepatocellular carcinoma. NAFLD is associated with cardiometabolic risk factors and is the most common chronic liver disease among adults in the Western Hemisphere. Although simple steatosis is generally considered a self-limiting disease, evidence suggests an increased risk of cardiovascular disease, and, less conclusively, mortality, among individuals with NAFLD and/or NASH. The current standard of care for the treatment of patients with NAFLD focuses on lifestyle interventions, particularly diet and exercise. There is a lack of consensus regarding the most effective and appropriate pharmacologic therapy. A PubMed search was conducted using the medical subject heading terms "fatty liver" and "steatohepatitis." This review focuses on the current pharmacologic options available for treating adults with NAFLD and/or NASH. Continued investigation of drugs or combinations that improve NAFLD progression is crucial. Clinicians, particularly pharmacists, must take an active role in identification and appropriate selection of pharmacotherapy for NAFLD. PMID- 23359474 TI - Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. AB - Environmental compounds are known to promote epigenetic transgenerational inheritance of adult onset disease in subsequent generations (F1-F3) following ancestral exposure during fetal gonadal sex determination. The current study was designed to determine if a mixture of plastic derived endocrine disruptor compounds bisphenol-A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP) at two different doses promoted epigenetic transgenerational inheritance of adult onset disease and associated DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to either the "plastics" or "lower dose plastics" mixture during embryonic days 8 to 14 of gonadal sex determination and the incidence of adult onset disease was evaluated in F1 and F3 generation rats. There were significant increases in the incidence of total disease/abnormalities in F1 and F3 generation male and female animals from plastics lineages. Pubertal abnormalities, testis disease, obesity, and ovarian disease (primary ovarian insufficiency and polycystic ovaries) were increased in the F3 generation animals. Kidney and prostate disease were only observed in the direct fetally exposed F1 generation plastic lineage animals. Analysis of the plastics lineage F3 generation sperm epigenome previously identified 197 differential DNA methylation regions (DMR) in gene promoters, termed epimutations. A number of these transgenerational DMR form a unique direct connection gene network and have previously been shown to correlate with the pathologies identified. Observations demonstrate that a mixture of plastic derived compounds, BPA and phthalates, can promote epigenetic transgenerational inheritance of adult onset disease. The sperm DMR provide potential epigenetic biomarkers for transgenerational disease and/or ancestral environmental exposures. PMID- 23359477 TI - Does limiting oral contrast decrease emergency department length of stay? AB - INTRODUCTION: The purpose of this study was to examine the impact on emergency department (ED) length of stay (LOS) of a new protocol for intravenous (IV) contrast only abdominal/pelvic computed tomography (ABCT) compared to historical controls. METHODS: This was a retrospective case-controlled study performed at a single academic medical center. Patients >= 18 undergoing ABCT imaging for non traumatic abdominal pain were included in the study. We compared ED LOS between historical controls undergoing ABCT imaging with PO/IV contrast and study patients undergoing an IV-contrast-only protocol. Imaging indications were the same for both groups and included patients with clinical suspicion for appendicitis, diverticulitis, small bowel obstruction, or perforation. We identified all patients from the hospital's electronic storehouse (imaging code, ordering department, imaging times), and we abstracted ED LOS and disposition from electronic medical records. RESULTS: Two hundred and eleven patients who underwent PO/IV ABCT prep were compared to 184 patients undergoing IV-contrast only ABCT prep. ED LOS was shorter for patients imaged with the IV-contrast only protocol (4:35 hrs vs. 6:39 hrs, p < 0.0001). CONCLUSION: Implementation of an IV contrast only ABCT prep for select ED patients presenting for evaluation of acute abdominal pain significantly decreased ED LOS. PMID- 23359478 TI - Refractory otitis media: an unusual presentation of childhood granulomatosis with polyangiitis. AB - Childhood granulomatosis with polyangiitis (cGPA), previously known as Wegener's granulomatosis, is a rare, potentially fatal necrotizing vasculitis, the symptoms of which overlap with infection. We present a 16-year-old girl who, following 6 months of treatment for persistent middle ear effusion with progressive sensorineural hearing loss, developed rapidly progressing pneumonia, with pleural effusion, and multiple cavitatory lung lesions. Investigations demonstrated high titer c-ANCA and nasal septal biopsy confirmed the diagnosis of cGPA. This case highlights the difficulty in diagnosing cGPA and the potentially life-threatening consequences of failing to do so. PMID- 23359479 TI - Identification of transcription factors associated with castration-resistance: is the serum responsive factor a potential therapeutic target? AB - BACKGROUND: Advanced prostate cancer is treated by hormone ablation therapy. However, despite an initial response, the majority of men relapse to develop castration-resistant disease for which there are no effective treatments. We have previously shown that manipulating individual proteins has only minor alterations on the resistant phenotype so we hypothesize that targeting the central transcription factors (TFs) would represent a better therapeutic approach. METHODS: We have undertaken a transcriptomic analysis of gene expression differences between the androgen-dependent LNCaP parental cells and its castration-resistant Abl and Hof sublines, revealing 1,660 genes associated with castration-resistance. Using effective bioinformatic techniques, these transcriptomic data were integrated with TF binding sites resulting in a list of TFs associated with the differential gene expression observed. RESULTS: Following validation of the gene-chip results, the serum response factor (SRF) was chosen for clinical validation and functional analysis due to its recent association with prostate cancer progression. SRF immunoreactivity in prostate tumor samples was shown for the first time to be associated with castration-resistance. SRF inhibition by siRNA and the small molecule inhibitor CCG-1423 resulted in decreased proliferation. CONCLUSION: SRF is a key TF by which resistant cells survive with depleted levels of androgens representing a target for therapeutic manipulation. PMID- 23359480 TI - Remote delivery of hydroxyl radicals via secondary chemistry of a nonthermal plasma effluent. AB - Electron paramagnetic resonance spectroscopy is used to observe hydroxyl radicals produced by an atmospheric pressure nonthermal plasma device at distances greater than 1 m from the discharge. The plasma device is an indirect treatment setup with closed loop airflow and hydrogen peroxide additives that is effective in deactivating bacteria on time scales of seconds. The generation of the detected hydroxyl radicals is shown to occur in secondary chemical processes near the point of delivery of the plasma treated air stream. The production of hydroxyl radicals is correlated with humidity of the air stream and ability to lyse bacterial membranes. The overall mechanisms of bacteria inactivation are found to be a combinatorial effect of effluent species. The results indicate the feasibility of selective plasma induced free radical delivery for biomedical applications even in the case of short-lived species like the hydroxyl radical. PMID- 23359481 TI - Acetylcholinesterase activity, cohabitation with floricultural workers, and blood pressure in Ecuadorian children. AB - BACKGROUND: Acetylcholinesterase (AChE) inhibitors are commonly used pesticides that can effect hemodynamic changes through increased cholinergic stimulation. Children of agricultural workers are likely to have paraoccupational exposures to pesticides, but the potential physiological impact of such exposures is unclear. OBJECTIVES: We investigated whether secondary pesticide exposures were associated with blood pressure and heart rate among children living in agricultural Ecuadorian communities. METHODS: This cross-sectional study included 271 children 4-9 years of age [51% cohabited with one or more flower plantation workers (mean duration, 5.2 years)]. Erythrocyte AChE activity was measured using the EQM Test mate system. Linear regression models were used to estimate associations of systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate with AChE activity, living with flower workers, duration of cohabitation with a flower worker, number of flower workers in the child's home, and number of practices that might increase children's exposure to pesticides. RESULTS: Mean (+/- SD) AChE activity was 3.14 +/- 0.49 U/mL. A 1-U/mL decrease in AChE activity was associated with a 2.86-mmHg decrease in SBP (95% CI: -5.20, -0.53) and a 2.89 mmHg decrease in DBP (95% CI: -5.00, -0.78), after adjustment for potential confounders. Children living with flower workers had lower SBP (-1.72 mmHg; 95% CI: -3.53, 0.08) than other children, and practices that might increase exposure also were associated with lower SBP. No significant associations were found between exposures and heart rate. CONCLUSIONS: Our findings suggest that subclinical secondary exposures to pesticides may affect vascular reactivity in children. Additional research is needed to confirm these findings. PMID- 23359482 TI - Antiproliferative effects of pomegranate extract in MCF-7 breast cancer cells are associated with reduced DNA repair gene expression and induction of double strand breaks. AB - Pomegranate extract (PE) inhibits the proliferation of breast cancer cells and stimulates apoptosis in MCF-7 breast cancer cells. While PE is a potent antioxidant, the present studies were conducted to examine the mechanisms of action of PE beyond antioxidation by studying cellular and molecular mechanisms underlying breast tumorigenesis. PE inhibited cell growth by inducing cell cycle arrest in G2 /M followed by the induction of apoptosis. In contrast, antioxidants N-acetylcysteine and Trolox did not affect cell growth at doses containing equivalent antioxidant capacity as PE, suggesting that growth inhibition by PE cannot solely be attributed to its high antioxidant potential. DNA microarray analysis revealed that PE downregulated genes associated with mitosis, chromosome organization, RNA processing, DNA replication and DNA repair, and upregulated genes involved in regulation of apoptosis and cell proliferation. Both microarray and quantitative RT-PCR indicated that PE downregulated important genes involved in DNA double strand break (DSB) repair by homologous recombination (HR), such as MRE11, RAD50, NBS1, RAD51, BRCA1, BRCA2, and BRCC3. Downregulation of HR genes correlated with increased levels of their predicted microRNAs (miRNAs), miR-183 (predicted target RAD50) and miR-24 (predicted target BRCA1), suggesting that PE may regulate miRNAs involved in DNA repair processes. Further, PE treatment increased the frequency of DSBs. These data suggest that PE downregulates HR which sensitizes cells to DSBs, growth inhibition and apoptosis. Because HR represents a novel target for cancer therapy, downregulation of HR by PE may be exploited for sensitization of tumors to anticancer drugs. PMID- 23359483 TI - Preparation of a novel anorganic bovine bone xenograft with enhanced bioactivity and osteoconductivity. AB - A novel anorganic bovine bone xenograft with enhanced bioactivity and osteoconductivity was prepared by an ion substitution method using sodium hypochlorite. Bovine bone granules were defatted, washed, and then soaked in sodium hypochlorite solution at room temperature. Subsequently, the granules were dried and then heat-treated at 1000 degrees C with sodium hypochlorite. As a control, bovine bone granules were prepared with the same conditions but without sodium hypochlorite treatment. Phase, functional group, and elemental analyses by XRD, FTIR, and EPMA showed that the granules heat-treated without and with sodium hypochlorite were pure hydroxyapatite and sodium-chlorine-bearing hydroxyapatite, respectively. After soaking in simulated body fluid (SBF) for 1 week, low crystalline hydroxyl carbonate apatite fully covered the surface of sodium chlorine-bearing hydroxyapatite, whereas it formed little on the hydroxyapatite surface. After soaking in SBF and deionized water, ICP-AES and IC analyses showed that the dissolutions of calcium, sodium, chlorine, and hydroxyl ions from sodium chlorine-bearing hydroxyapatite notably increased compared with those from hydroxyapatite. This resultantly increased the ionic activity product of apatite in SBF and induced new formation of low crystalline hydroxyl carbonate apatite. The cytotoxicity test by BCA assay showed that there were no statistically significant differences between hydroxyapatite and sodium-chlorine-bearing hydroxyapatite. In addition, sodium-chlorine-bearing hydroxyapatite showed better osteoconductivity in the calvarial defects of New Zealand white rabbits within 4 weeks compared with that of hydroxyapatite. The results suggest that this novel anorganic bovine bone xenograft possesses encouraging potential for use as a bone grafting material due to better bioactivity and osteoconductivity than hydroxyapatite. PMID- 23359484 TI - Comparison of bare metal and statin-coated coils on rates of intra-aneurysmal tissue organization in a rat model of aneurysm. AB - Endovascular treatment of intracranial aneurysms with detachable coils has been accepted widely. Problems of coil compaction, recanalization and rare endothelialization at the aneurysm orifice are not yet solved. We investigated the efficacy of a simvastatin coating applied without any additional matrix to coils to accelerate thrombus organization in the cavity in a rat model of aneurysm. Twelve metal coils coated with simvastatin and 12 bare coils were inserted into the ligated external carotid arterial (ECA) sacs of rats. The ECA sacs were removed 2 or 4 weeks after the coils were implanted and examined by histology and immunohistochemical assay. The organized areas in the ECA sacs in the simvastatin group (73.6 +/- 19.4%, 2 wk; 83.4 +/- 11.1%, 4 wk) was significantly higher p = 0.003, 2 wk; p = 0.0004, 4 wk than the bare metal group at 2 and 4 weeks (20.5 +/- 10.7%, 2 wk, p < 0.003; 37.4 +/- 20.6%, 4 wk, p < 0.0004). Organized tissues that formed around the coils coated with simvastatin were characterized by an accumulation of cells positive for alphaSMA and collagen connective matrix. Tissues also were accompanied by marked formation of endothelium at the orifice of the ECA sac. We suggest that coating coils with simvastatin effectively accelerated organization within the aneurysms and endothelialization over the coil. PMID- 23359485 TI - Osteogenic potential of Sr-doped calcium phosphate hollow spheres in vitro and in vivo. AB - Treatment of osteoporotic fractures with conventional surgical methods is associated with a high rate of complications. Intense search for new treatment options includes development of specific biomaterials aimed to be part of the surgical armamentarium. Strontium doped calcium phosphate spheres (SrCPS) is a new material that might be of interest due to the influence on osteoclast and osteoblast activity. In the present study, we successfully constructed hollow spherical SrCPS particles with a diameter of ~700 nm and shell thickness of ~150 nm. The Sr content was about 20 wt %. Cell viability and cytotoxicity were investigated in vitro with concentrations from 0 to 1000 MUg/mL of SrCPS in medium extract in a day chase study. The in vivo biocompatibility was tested in a delayed bone-healing model in a rat vertebral defect by histology, MUCT, and nanoSPECT. The SrCPS showed no toxicity in vitro with comparable cell number in all concentrations. Increased metabolism was seen in the cell viability study in cells exposed to 400 and 600 MUg/mL. SPECT showed good biocompatibility with no local adverse effects and an increased osteoblast activity as compared to adjacent vertebra. SrCPS implantation induced bone formation and resulted in complete resorption and defect consolidation. PMID- 23359487 TI - Three polymorphic Cd(II) coordination polymers obtained from the solution and mechanochemical reactions of 3-cyanopentane-2,4-dione with Cd(II) acetate. AB - We previously reported that monomeric and polymeric metal complexes are obtained from solution and mechanochemical reactions of 3-cyano-pentane-2,4-dione (CNacacH) with 3d metal acetates (M = Mn(II), Fe(II), Co(II), Ni(II), Cu(II), and Zn(II)). A common feature found in all complexes was that their structural base is trans-[M(CNacac)(2)]. Here, we report that the reactions of CNacacH with Cd(II) acetate in the solution and solid states afford different coordination polymers composed of trans-[Cd(CNacac)(2)] and cis-[Cd(CNacac)(2)] units, respectively. From a methanol solution containing CNacacH (L) and Cd(OAc)(2)?2 H(2)O (M), a coordination polymer (Cd-1) in which trans-[Cd(CNacac)(2)] units are three-dimensionally linked was obtained. In contrast, two different coordination polymers, Cd-2 and Cd-3, were obtained from mechanochemical reactions of CNacacH with Cd(OAc)(2)?2 H(2)O at M/L ratios of 1:1 and 1:2, respectively. In Cd-2, cis [Cd(CNacac)(2)] units are two-dimensionally linked, whereas the units are linked three-dimensionally in Cd-3. Furthermore, Cd-1 and Cd-2 converted to Cd-3 by applying an annealing treatment and grinding with a small amount of liquid, respectively, in spite of the polymeric structures. These phenomena, 1) different structures are formed from solution and mechanochemical reactions, 2) two polymorphs are formed depending on the M/L ratio, and 3) structural transformation of resulting polymeric structures, indicate the usability of mechanochemical method in the syntheses of coordination polymers as well as the peculiar structural flexibility of cadmium-CNacac polymers. PMID- 23359486 TI - SIRT1 silencing confers neuroprotection through IGF-1 pathway activation. AB - The following study demonstrated that, in in vitro differentiated neurons, SIRT1 silencing induced an increase of IGF-1 protein expression and secretion and of IGF-1R protein levels which, in turn, prolonged neuronal cell survival in presence of an apoptotic insult. On the contrary, SIRT1 overexpression increased cell death. In particular, IGF-1 and IGF-1R expression levels were negatively regulated by SIRT1. In SIRT1 silenced cells, the increase in IGF-1 and IGF-1R expression was associated to an increase in AKT and ERK1/2 phosphorylation. Moreover, neuronal differentiation was reduced in SIRT1 overexpressing cells and increased in SIRT1 silenced cells. We conclude that SIRT1 silenced neurons appear more committed to differentiation and more resistant to cell death through the activation of IGF-1 survival pathway. PMID- 23359488 TI - gamma-Aminobutyric acid-rho expression in ependymal glial cells of the mouse cerebellum. AB - The ependymal glial cells (EGCs) from the periventricular zone of the cerebellum were studied to determine their distribution and the functional properties of their gamma-aminobutyric acid type A (GABA(A) ) receptors. EGCs were identified by the presence of ciliated structures on their ventricular surface and their expression of glial fibrillary acidic protein (GFAP). Interestingly, diverse cell types, including neurons, astrocytes, and other types of glia, were identified in the subventricular zone by their current profiles. Electron microscopy showed ciliated cells and myelinated axons in this zone, but we found no collateral connections to suggest the presence of functional synapses. GABA-mediated currents were recorded from EGCs in cerebellar slices from postnatal days 13 to 35 (PN13-PN35). These currents were blocked by TPMPA (a highly specific GABA(A) rho subunit antagonist) and bicuculline (a selective antagonist for classic GABA(A) receptors). Pentobarbital failed to modulate GABA(A)-mediated currents despite the expression of GABAalpha1 and GABAgamma2 subunits. In situ hybridization, RT-PCR, and immunofluorescence studies confirmed GABArho1 expression in EGCs of the cerebellum. We conclude that cerebellar EGCs express GABArho1, which is functionally involved in GABA(A) receptor-mediated responses that are unique among glial cells of the brain. PMID- 23359489 TI - TNF-238 polymorphism may predict bronchopulmonary dysplasia among preterm infants in the Egyptian population. AB - Bronchopulmonary dysplasia (BPD) remains as a major and increasing burden in Egypt. RATIONALE: To determine whether alleles of TNFalpha-238G > A affect the risk of BPD or the severity of BPD in preterm infants in Egypt. STUDY DESIGN: We prospectively genotyped 220 premature neonates (birth weight <1,500 g and gestational age 26-32 weeks) for the -238 polymorphism, and assessed the clinical risk factors for BPD in our study populations. Infants with BPD were mechanically ventilated. RESULTS: Infants who developed BPD (n = 120) had a younger gestational age (31.0 +/- 2.1 weeks vs. 34.3 +/- 1.5 weeks) and lower birth weight (1,490 +/- 360 g vs. 1,880 +/- 520 g) than infants who did not develop BPD (n = 100). Results of antenatal steroid supplementation, surfactant therapy, or sepsis might affect the genetic modulation of BPD. The -238G > A polymorphism was associated with a twofold risk of BPD (OR = 2.86; 95% confidence interval, 1.35 3.83). Despite the dominance of the G allele in the Egyptian population, the 238A allele was more common among infants with BPD (23%) than among infants without BPD (15%). The A allele occurred less often in infants with mild BPD (9%) than in infants with severe (39%) or moderate (52%). The AA genotype occurred in 15% of cases but in none of the controls. CONCLUSION: The TNFalpha -238G > A polymorphism-particularly the presence of an A allele-should be evaluated as a biomarker to predict the clinical outcome of preterm infants with BPD in Egypt. Even the presence of one copy of this mutant allele appears to be sufficient to influence the severity of disease. PMID- 23359490 TI - Effects of short elastin-like peptides on filamentous particles and their transition behavior. AB - While elastin-like polypeptides and peptides (ELPs) have been used for various stimulus-responsive applications, details of their switching remain unclear. We therefore constructed a novel series of filamentous phage particles displaying a high surface density of short ELPs. The surface display of ELPs did not disrupt either particle shape or dimensions, and the resulting ELP-phage particles were colloidally stable over several weeks. However, in spite of a saturating surface density, macroscopic aggregation of ELP-phages cannot be triggered in water. To investigate the underlying mechanisms we examined conformational changes in the secondary structure of the phage proteins by circular dichroism and tryptophan fluorescence, which indicate partial protein unfolding in ELP-phage particles. To gain further insight into the ELP itself, analogous "free" ELP peptides were synthesized and characterized. Circular dichroism of these peptides shows the onset of beta-type conformations with increasing temperature, consistent with the accepted view of the microscopic transition that underlies the inverse phase behavior of ELPs. Increased guest residue hydrophobicity was found to depress the microscopic transition temperature of the peptides, also consistent with a previously proposed intramolecular hydrogen-bonding mechanism. Importantly, our results indicate that although the nanoscale presentation state can suppress macroscopic aggregation of ELPs, microscopic transitions of the ELP can still occur. Given the growing use of ELPs within supra-molecular scaffolds, such effects are important design considerations for future applications. PMID- 23359491 TI - JUMP-C: a randomized trial of mericitabine plus pegylated interferon alpha 2a/ribavirin for 24 weeks in treatment-naive HCV genotype 1/4 patients. AB - Mericitabine is a selective nucleoside analog inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, with activity across all HCV genotypes. Treatment-naive patients infected with HCV genotype 1 or 4 were randomized to 24 weeks of double-blind treatment with either mericitabine 1,000 mg (N = 81) or placebo (N = 85) twice-daily (BID) in combination with pegylated interferon alpha 2a (Peg-IFNalpha-2a)/ribavirin (RBV). Patients randomized to mericitabine with HCV RNA <15 IU/mL from week 4 to 22 (extended rapid virologic response; eRVR) stopped all treatment at week 24; all other patients continued Peg-IFNalpha 2a/RBV to complete 48 weeks of treatment. The primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <15 IU/mL after 24 weeks of treatment free follow-up). SVR was achieved in 56.8% (95% confidence interval [CI]: 45.9 67.0) of mericitabine-treated patients and 36.5% (95% CI: 27.0-47.1) of placebo treated patients (Delta = 20.3%; 95% CI 5.5-35.2). SVR rates were higher in mericitabine- than placebo-treated patients when subdivided by IL28B genotype (CC, 77.8% versus 56.0%; non-CC, 44.1% versus 16.2%) and hepatic fibrosis (noncirrhotic, 63.3% versus 41.9%; cirrhotic, 38.1% versus 21.7%). Overall relapse rates were 27.7% and 32.0% in mericitabine- and placebo-treated patients, respectively. No evidence of NS5B S282T-variant virus or phenotypic resistance to mericitabine was observed in the one patient who experienced partial response. No S282T variants were detected in any baseline samples. The safety profile of mericitabine was similar to that of, and fewer patients in the mericitabine than in the placebo group discontinued treatment for safety reasons. CONCLUSION: A 24 week response-guided combination regimen of mericitabine 1,000 mg BID plus Peg IFNalpha-2a/RBV is well tolerated and more effective than a standard 48-week course of Peg-IFNalpha-2a/RBV. PMID- 23359492 TI - Efficacy of post exposure administration of doxycycline in a murine model of inhalational melioidosis. AB - Burkholderia pseudomallei is the causative agent of melioidosis. Treatment of melioidosis is suboptimal and developing improved melioidosis therapies requires animal models. In this report, we exposed male BALB/c mice to various amounts of aerosolized B. pseudomallei 1026b to determine lethality. After establishing a median lethal dose (LD(50)) of 2,772 colony forming units (cfu)/animal, we tested the ability of doxycycline administered 6 hours after exposure to a uniformly lethal dose of ~20 LD(50) to prevent death and eliminate bacteria from the lung and spleens. Tissue bacterial burdens were examined by PCR analysis. We found that 100% of mice treated with doxycycline survived and B. pseudomallei DNA was not amplified from the lungs or spleens of most surviving mice. We conclude the BALB/c mouse is a useful model of melioidosis. Furthermore, the data generated in this mouse model indicate that doxycycline is likely to be effective in post exposure prophylaxis of melioidosis. PMID- 23359493 TI - Effect of fabrication and processing technology on the biodegradability of magnesium nanocomposites. AB - Magnesium and its alloys have gained significant attention recently as potential alternatives for biodegradable materials due to their unique biodegradability, biocompatibility, and mechanical properties. However, magnesium alloys tend to have high corrosion rates in biological liquids, thus presenting a potential problem if a magnesium implant/device needs to maintain mechanical integrity for a sufficient period under practical physiological conditions. In this study, hydroxyapatite nanoparticles were used to form magnesium based metal matrix nanocomposites (MMNC) through two processes: friction stir processing (FSP) and a two-state nanoprocessing (TSnP) combining liquid state ultrasonic processing and solid state FSP. In addition, laser surface melting (LSM) was carried out for further surface treatment. In vitro immersion tests indicated that the corrosion rate of MMNC decreased by 52% compared with pure Mg through FSP. Potentiodynamic polarization tests showed that the corrosion current of MMNC decreased by 71% and 30%, respectively, by TSnP and LSM when compared with pure Mg or untreated counterparts. This study suggests that fabrication of MMNC and further processing through FSP and LSM can robustly enhance the corrosion resistance of magnesium, which will boost its potential for biological applications. PMID- 23359494 TI - Effects of different sterilization techniques and varying anodized TiO2 nanotube dimensions on bacteria growth. AB - Infection of titanium (Ti)-based orthopedic implants is a growing problem due to the ability of bacteria to develop a resistance to today's antibiotics. As an attempt to develop a new strategy to combat bacteria functions, Ti was anodized in the present study to possess different diameters of nanotubes. It is reported here for the first time that Ti anodized to possess 20 nm tubes then followed by heat treatment to remove fluorine deposited from the HF anodization electrolyte solution significantly reduced both S. aureus and S. epidermidis growth compared to unanodized Ti controls. It was further found that the sterilization method used for both anodized nanotubular Ti and conventional Ti played an important role in the degree of bacteria growth on these substrates. Overall, UV light and ethanol sterilized samples decreased bacteria growth, while autoclaving resulted in the highest amount of bacteria growth. In summary, this study indicated that through a simple and inexpensive process, Ti can be anodized to possess 20 nm tubes that no matter how sterilized (UV light, ethanol soaking, or autoclaving) reduces bacteria growth and, thus, shows great promise as an antibacterial implant material. PMID- 23359495 TI - Interleukin-32 expression is associated with a poorer prognosis in head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) represent the sixth most common malignancy diagnosed worldwide. Patient's survival is low due the high frequency of tumor recurrence. Inflammation promotes carcinogenesis as well as the formation of metastasis. Indeed, proinflammatory mediators are known to stimulate the expression of specific transcription factors such as Snai1 and to increase the ability of tumor cells to migrate into distant organs. The atypical interleukin-32 (IL32) was mainly described to exacerbate inflammatory responses in rheumatoid arthritis and inflammatory bowel diseases. IL32 is expressed in various cancers but its role in HNSCC physiology is still unexplored. Here, we analyzed the expression of IL32 and its implication on HNSCC aggressiveness. We showed that patients with tumor expressing high amounts of IL32 exhibit decreased disease-free periods (20.5 mo vs. 41 mo, P = 0.0041) and overall survival (P = 0.0359) in comparison with individuals with weak IL32 tumor expression. This overexpression was negatively correlated with gender (P = 0.0292) and p53 expression (P = 0.0307). In addition, in vitro data linked IL32 expression to metastasis formation since IL32 inhibition decreased Snai1 expression and tumor cell migration in a Boyden chamber assay. Our data provide new insight into the role of IL32 in HNSCC aggressiveness. PMID- 23359496 TI - Kidins220/ARMS associates with B-Raf and the TCR, promoting sustained Erk signaling in T cells. AB - The activation kinetics of MAPK Erk are critical for T cell development and activation. In particular, sustained Erk signaling is required for T cell activation and effector functions, such as IL-2 production. Although Raf-1 triggers transient Erk activation, B-Raf is implicated in sustained Erk signaling after TCR stimulation. In this study, we show that B-Raf is dephosphorylated on its inhibitory serine 365 upon TCR triggering. However, it is unknown how B-Raf activation is coupled to the TCR. Using mass spectrometry, we identified protein kinase D-interacting substrate of 220 kDa (Kidins220)/ankyrin repeat-rich membrane spanning protein, mammalian target of rapamycin, Rictor, Dock2, and GM130 as novel B-Raf interaction partners. We focused on Kidins220, a protein that has been studied in neuronal cells and found that it associated with the pre TCR, alphabetaTCR, and gammadeltaTCR. Upon prolonged TCR stimulation, the Kidins220-TCR interaction was reduced, as demonstrated by immunoprecipitation and proximity ligation assays. We show that Kidins220 is required for TCR-induced sustained, but not transient, Erk activation. Consequently, induction of the immediate early gene products and transcription factors c-Fos and Erg-1 was blocked, and upregulation of the activation markers CD69, IL-2, and IFN-gamma was reduced. Further, Kidins220 was required for optimal calcium signaling. In conclusion, we describe Kidins220 as a novel TCR-interacting protein that couples B-Raf to the TCR. Kidins220 is mandatory for sustained Erk signaling; thus, it is crucial for TCR-mediated T cell activation. PMID- 23359497 TI - Prostaglandin E2 potentiates mesenchymal stem cell-induced IL-10+IFN-gamma+CD4+ regulatory T cells to control transplant arteriosclerosis. AB - Mesenchymal stem cells (MSCs) are known for their immunomodulatory functions. We previously demonstrated that bone marrow-derived MSCs effectively control transplant arteriosclerosis (TA) by enhancing IL-10(+) and IFN-gamma(+) cells. The objective of this study is to elucidate the mechanism by which MSCs induce IL 10(+)IFN-gamma(+)CD4(+) regulatory T type 1 (T(R)1)-like cells. In an MLR system using porcine PBMCs, MSC-induced IL-10(+)IFN-gamma(+)CD4(+) cells, which confer resistance to allogeneic proliferation in an IL-10-dependent manner, resemble T(R)1-like cells. Both cyclooxygenase-derived PGE(2) and IDO help to induce T(R)1 like cells by MSCs. MSCs constitutively secrete PGE(2), which is augmented in allogeneic reactions. However, T(R)1-like cells were deficient in PGE(2) and 4 fold less potent than were MSCs in suppressing MLR. PGE(2) mimetic supplements can enhance the immunosuppressive potency of T(R)1-like cells. In a porcine model of allogeneic femoral arterial transplantation, MSC-induced T(R)1-like cells combined with PGE(2), but not either alone, significantly reduced TA at the end of 6 wk (percentage of luminal area stenosis: T(R)1-like cells + PGE(2): 11 +/- 10%; PGE(2) alone: 93 +/- 8.7%; T(R)1-like cells alone: 88 +/- 2.4% versus untreated 94 +/- 0.9%, p < 0.001). These findings indicate that PGE(2) helps MSC induced IL-10(+)IFN-gamma(+)CD4(+) T(R)1-like cells inhibit TA. PGE(2) combined with MSC-induced T(R)1-like cells represents a new approach for achieving immune tolerance. PMID- 23359498 TI - Two rare disease-associated Tyk2 variants are catalytically impaired but signaling competent. AB - Tyk2 belongs to the Janus protein tyrosine kinase family and is involved in signaling of immunoregulatory cytokines (type I and III IFNs, IL-6, IL-10, and IL 12 families) via its interaction with shared receptor subunits. Depending on the receptor complex, Tyk2 is coactivated with either Jak1 or Jak2, but a detailed molecular characterization of the interplay between the two enzymes is missing. In human populations, the Tyk2 gene presents high levels of genetic diversity with >100 nonsynonymous variants being detected. In this study, we characterized two rare Tyk2 variants, I684S and P1104A, which have been associated with susceptibility to autoimmune disease. Specifically, we measured their in vitro catalytic activity and their ability to mediate Stat activation in fibroblasts and genotyped B cell lines. Both variants were found to be catalytically impaired but rescued signaling in response to IFN-alpha/beta, IL-6, and IL-10. These data, coupled with functional study of an engineered Jak1 P1084A, support a model of nonhierarchical activation of Janus kinases in which one catalytically competent Jak is sufficient for signaling provided that its partner behaves as proper scaffold, even if inactive. Through the analysis of IFN-alpha and IFN-gamma signaling in cells with different Jak1 P1084A levels, we also illustrate a context in which a hypomorphic Jak can hamper signaling in a cytokine-specific manner. Given the multitude of Tyk2-activating cytokines, the cell context dependent requirement for Tyk2 and the catalytic defect of the two disease associated variants studied in this paper, we predict that these alleles are functionally significant in complex immune disorders. PMID- 23359499 TI - Computational identification of antigen-binding antibody fragments. AB - Determining which parts of the Ab are essential for Ag recognition and binding is crucial for understanding B cell-mediated immunity. Identification of fragments of Abs that maintain specificity to the Ag will also allow for the development of improved Ab-based therapy and diagnostics. In this article, we show that structural analysis of Ab-Ag complexes reveals which fragments of the Ab may bind the Ag on their own. In particular, it is possible to predict whether a given CDR is likely to bind the Ag as a peptide by analyzing the energetic contribution of each CDR to Ag binding and by assessing to what extent the interaction between that CDR and the Ag depends on other CDRs. To demonstrate this, we analyzed five Ab-Ag complexes and predicted for each of them which of the CDRs may bind the Ag on its own as a peptide. We then show that these predictions are in agreement with our experimental analysis and with previously published experimental results. These findings promote our understanding of the modular nature of Ab-Ag interactions and lay the foundation for the rational design of active CDR-derived peptides. PMID- 23359501 TI - Porcine gammadelta T lymphocytes can be categorized into two functionally and developmentally distinct subsets according to expression of CD2 and level of TCR. AB - Porcine gammadelta T cells have two levels of TCRgammadelta expression. Whereas TCRgammadelta(med) cells are mostly CD2(+)CD8(-) and CD2(+)CD8(+), TCRgammadelta(hi) cells are highly enriched for CD2(-)CD8(-). This distribution is independent of bacterial colonization and it is already established in the thymus prior to export of gammadelta cells to the periphery. Sorting and cultivation experiments revealed that CD2(-)CD8(-) gammadelta cells are unable to acquire CD2 and CD8, whereas CD2(+) subsets can gain or loose CD8. There is also differential susceptibility for proliferation between CD2(+) and CD2(-) gammadelta cells. Although CD2(-)CD8(-) almost do not proliferate, proliferation of CD2(+)CD8(-) and CD2(+)CD8(+) is substantial. Population of CD2(-) gammadelta cells is also absent in CD1(+) immature thymocytes. Additionally, subpopulations of CD2(+) and CD2(-) gammadelta cells in the thymus differ in expression of auxiliary surface molecules such as CD25, CD45RA/RC, and MHC class II. Moreover, TCRgammadelta(hi) cells can generate TCRgammadelta(med) cells but never the opposite. The only exception is the thymus, where a few TCRgammadelta(med) cells can be induced to TCRgammadelta(hi) but only under IL-2 influence. The repertoire of TCRdelta is polyclonal in all subsets, indicating that there is the same extent of diversification and equal capability of immune responses. Results collectively indicate that CD2 expression determines two lineages of gammadelta cells that differ in many aspects. Because CD2(-) gammadelta cells are missing in the blood of humans and mice but are obvious in other members of gammadelta-high species such as ruminants and birds, our findings support the idea that circulating CD2(-) gammadelta T cells are a specific lineage. PMID- 23359500 TI - Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation. AB - IL-17C is a functionally distinct member of the IL-17 family that binds IL-17 receptor E/A to promote innate defense in epithelial cells and regulate Th17 cell differentiation. We demonstrate that IL-17C (not IL-17A) is the most abundant IL 17 isoform in lesional psoriasis skin (1058 versus 8 pg/ml; p < 0.006) and localizes to keratinocytes (KCs), endothelial cells (ECs), and leukocytes. ECs stimulated with IL-17C produce increased TNF-alpha and KCs stimulated with IL 17C/TNF-alpha produce similar inflammatory gene response patterns as those elicited by IL-17A/TNF-alpha, including increases in IL-17C, TNF-alpha, IL-8, IL 1alpha/beta, IL-1F5, IL-1F9, IL-6, IL-19, CCL20, S100A7/A8/A9, DEFB4, lipocalin 2, and peptidase inhibitor 3 (p < 0.05), indicating a positive proinflammatory feedback loop between the epidermis and ECs. Psoriasis patients treated with etanercept rapidly decrease cutaneous IL-17C levels, suggesting IL-17C/TNF-alpha mediated inflammatory signaling is critical for psoriasis pathogenesis. Mice genetically engineered to overexpress IL-17C in KCs develop well-demarcated areas of erythematous, flakey involved skin adjacent to areas of normal-appearing uninvolved skin despite increased IL-17C expression in both areas (p < 0.05). Uninvolved skin displays increased angiogenesis and elevated S100A8/A9 expression (p < 0.05) but no epidermal hyperplasia, whereas involved skin exhibits robust epidermal hyperplasia, increased angiogenesis and leukocyte infiltration, and upregulated TNF-alpha, IL-1alpha/beta, IL-17A/F, IL-23p19, vascular endothelial growth factor, IL-6, and CCL20 (p < 0.05), suggesting that IL-17C, when coupled with other proinflammatory signals, initiates the development of psoriasiform dermatitis. This skin phenotype was significantly improved following 8 wk of TNF alpha inhibition. These findings identify a role for IL-17C in skin inflammation and suggest a pathogenic function for the elevated IL-17C observed in lesional psoriasis skin. PMID- 23359502 TI - IL-2 produced by CD8+ immune T cells can augment their IFN-gamma production independently from their proliferation in the secondary response to an intracellular pathogen. AB - Chronic infection with Toxoplasma gondii induces a potent resistance against reinfection, and IFN-gamma production by CD8(+) T cells is crucial for the protective immunity. However, the molecular mechanisms that regulate the secondary response remain to be elucidated. In the current study, we examined the role of IL-2 in IFN-gamma production by CD8(+) immune T cells in their secondary responses using T. gondii-specific CD8(+) T cell hybridomas and splenic CD8(+) immune T cells from chronically infected mice. The majority (92%) of CD8(+) T cell hybridomas produced large amounts of IFN-gamma only when a low amount (0.5 ng/ml) of exogenous IL-2 was provided in combination with T. gondii Ags. Inhibition of cell proliferation by mitomycin C did not affect the enhancing effect of IL-2 on the IFN-gamma production, and significant increases in transcription factor T-bet expression were associated with the IL-2-mediated IFN gamma amplification. Splenic CD8(+) immune T cells produced similar low levels of IL-2 in the secondary response to T. gondii, and a blocking of IL-2 signaling by anti-IL-2Ralpha Ab or inhibitors of JAK1 and JAK3 significantly reduced IFN-gamma production of the T cells. This IL-2-mediated upregulation of IFN-gamma production was observed in mitomycin C-treated CD8(+) immune T cells, thus independent from their cell division. Therefore, endogenous IL-2 produced by CD8(+) immune T cells can play an important autocrine-enhancing role on their IFN gamma production in the secondary responses to T. gondii, suggesting an importance of induction of CD8(+) immune T cells with an appropriate IL-2 production for vaccine development. PMID- 23359504 TI - Helios+ and Helios- cells coexist within the natural FOXP3+ T regulatory cell subset in humans. AB - FOXP3-expressing T regulatory cells (Tregs) can be divided into two distinct subsets: naturally occurring Tregs (nTregs) that develop in the thymus, and induced Tregs (iTregs) that differentiate in peripheral tissues upon exposure to Ag in a tolerogenic environment. Recently it has been proposed that expression of Helios, an Ikaros family transcription factor, may specifically identify nTregs, allowing specific tracking of Tregs from different origins in health and disease. Surprisingly, we found that Helios(-) cells can be readily identified within naive (CD45RA(+)CD31(+)CCR7(+)CD62L(+)) FOXP3(+) Tregs, a finding inconsistent with the notion that lack of Helios expression identifies Ag-experienced iTregs that should express memory markers. To investigate the phenotype and function of naive Helios(+) and Helios(-) Tregs within the nTreg population, we isolated single-cell clones from each subset. We found that both Helios(+) and Helios(-) nTreg clones have a similar suppressive capacity, as well as expression of FOXP3 and cell surface proteins, including CD39 and CTLA-4. Helios(-) nTregs, however, produced significantly more CCL3 and IFN-gamma compared with Helios(+) nTregs. Despite increased cytokine/chemokine production, Helios(-) FOXP3(+) nTreg clones were demethylated at the FOXP3 Treg-specific demethylated region, indicative of Treg lineage stability. When cultured under Th1-polarizing conditions, Helios(+) and Helios(-) nTreg clones had an equal ability to produce IFN-gamma. Collectively, these data show that a lack of Helios expression does not exclusively identify human iTregs, and, to our knowledge, the data provide the first evidence for the coexistence of Helios(+) and Helios(-) nTregs in human peripheral blood. PMID- 23359503 TI - Usage of sphingosine kinase isoforms in mast cells is species and/or cell type determined. AB - FcepsilonRI engagement in mast cells (MCs) induces the activation of two distinct sphingosine kinase isoforms (SphK1 and SphK2) to produce sphingosine-1-phosphate, a mediator essential for MC responses. Whereas embryonic-derived SphK2-null MCs showed impaired responses to Ag, RNA silencing studies on other MC types indicated a dominant role for SphK1. Given the known functional heterogeneity of MCs, we explored whether the reported differences in SphK1 or SphK2 usage could be reflective of phenotypic differences between MC populations. Using lentiviral based short hairpin RNA to silence SphK1 or SphK2, we found that SphK2 is required for murine MC degranulation, calcium mobilization, and cytokine and leukotriene production, irrespective of the tissue from which the MC progenitors were derived, the stage of MC granule maturity, or the conditions used for differentiation. This finding was consistent with the lack of a full allergic response in SphK2-null mice challenged to undergo passive cutaneous anaphylaxis. A redundant role for both SphKs was uncovered, however, in chemotaxis toward Ag in all MC types tested and in TNF-alpha production in certain MC types. In contrast, human MC responses were dependent only on SphK1, associating with a more robust expression of this isoform and a more varied representation of SphK variants relative to murine MCs. The findings show that the function of SphK1 and SphK2 can be interchangeable in MCs; however, an important determinant of SphK isoform usage is the species of origin and an influencing factor, the tissue from which MCs may be derived and/or their differentiation state. PMID- 23359506 TI - Butyrophilin-like 2 modulates B7 costimulation to induce Foxp3 expression and regulatory T cell development in mature T cells. AB - Naive T cell activation involves at least two signals from an APC, one through the TCR via interaction with peptide-MHC complexes and a second through ligation of CD28 with B7 ligands. Following activation, T cells upregulate a host of other membrane-bound costimulatory molecules that can either promote or inhibit further T cell maturation and proliferation. In some cases, it is necessary to attenuate T cell activation to prevent deleterious inflammation, and inhibitory members of the B7/butyrophilin family of ligands have evolved to balance the strong stimuli the activating B7 ligands confer. Human genetic association and in vitro studies have implicated one such ligand, BTNL2, in controlling inflammation at mucosal surfaces. In this study, we show that recombinant mouse BTNL2 modifies B7/CD28 signaling to promote expression of Foxp3, a transcription factor necessary for regulatory T cell (Treg) development and function. BTNL2 blocks Akt-mediated inactivation of Foxo1, a transcription factor necessary for Foxp3 expression. Immunophenotyping and gene profiling reveal that BTNL2-induced Treg share many properties with natural Treg, and in vivo they suppress enteritis induced by mouse effector T cells. These findings describe a mechanism by which environmental Ag-specific Tregs may be induced by APC expressing specific modulators of costimulatory signals. PMID- 23359505 TI - Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model. AB - The antitumor effects of paclitaxel are generally attributed to the suppression of microtubule dynamics resulting in defects in cell division. New data demonstrated that in ultralow noncytotoxic concentrations, paclitaxel modulated in immune cells in vitro the activity of small Rho GTPases, the key regulators of intracellular actin dynamics. However, the immunomodulatory properties of paclitaxel in vivo have not been evaluated. In this study, using the ret transgenic murine melanoma model, which mimics human cutaneous melanoma, we tested effects of ultralow noncytotoxic dose paclitaxel on functions of myeloid derived suppressor cells (MDSCs), chronic inflammatory mediators, and T cell activities in the tumor microenvironment in vivo. Administration of paclitaxel significantly decreased accumulation and immunosuppressive activities of tumor infiltrating MDSCs without alterations of the bone marrow hematopoiesis. This was associated with the inhibition of p38 MAPK activity, TNF-alpha and production, and S100A9 expression in MDSCs. The production of mediators of chronic inflammation in the tumor milieu also was diminished. Importantly, reduced tumor burden and increased animal survival upon paclitaxel application was mediated by the restoration of CD8 T cell effector functions. We suggest that the ability of paclitaxel in a noncytotoxic dose to block the immunosuppressive potential of MDSCs in vivo represents a new therapeutic strategy to downregulate immunosuppression and chronic inflammation in the tumor microenvironment for enhancing the efficacy of concomitant anticancer therapies. PMID- 23359507 TI - FcalphaRI-mediated inhibition of IL-12 production and priming by IFN-gamma of human monocytes and dendritic cells. AB - We showed that IgA induces IL-10 in monocytes and dendritic cells. Because reciprocal inhibition exists between IL-10 and IL-12, we explored whether IgA could regulate this other immunoregulatory cytokine. In human monocytes and monocyte-derived dendritic cells preincubated with IFN-gamma before stimulation by LPS, suppression of p40 and IL-12p70 production was observed upon IgA treatment during IFN-gamma priming. Washout experiments and inhibition of IFN gamma-induced CXCL10 (IP-10) and FcgammaRI (CD64) indicated that inhibition by IgA occurred at both the LPS and IFN-gamma levels. Inhibition was not affected by blockade of IL-10 or MAPK but involved FcalphaRI/CD89-mediated suppression of STAT1 phosphorylation. These data indicate that FcalphaRI ligation on human monocytes and dendritic cells inhibits IL-12 expression and type 1 activation by interfering with STAT1 activation. PMID- 23359508 TI - Peripheral blood NK cells from breast cancer patients are tumor-induced composite subsets. AB - Human NK lymphocytes are involved in antitumor immunity. The therapeutic potential of this population against cancers has stimulated their study and led to the discovery of several NK cell subsets, each of which is endowed with different immunoregulatory functions. We have previously reported that NK cell functions are profoundly altered in advanced breast cancer patients. In this study, we show that these tumor-mediated alterations also variably affect NK cell subsets. We found that in addition to the known human CD56(dim)CD16(+), CD56(bright)CD16(-), and CD56(-)CD16(+) NK cell subsets, two additional subsets, namely the CD56(bright)CD16(+) and CD56(dim)CD16(-) subsets, were increased in the peripheral blood of patients with advanced invasive breast cancers. These subsets corresponded to the main two subsets found at the tumor site. The extensive phenotype of these subsets revealed an "a la carte" pattern of expression for the various NK receptors, functional molecules, adhesion molecules, and chemokine receptors, depending on the subset. We next compared these subsets to known NK cell populations endowed with specific phenotypic characteristics, but also with functional properties. Our data show that advanced breast cancer patients have an increased proportion of more immature and noncytotoxic NK cell subsets in their peripheral blood, which might account for at least part of the low cytotoxic functions observed in these patients. They reveal a major heterogeneity and plasticity of the NK cell compartment, which are both tightly linked to the microenvironment. The identification of NK cell subsets endowed with particular functional capabilities might help monitor residual antitumor NK cell-mediated responses in breast cancer patients. PMID- 23359510 TI - Encapsulation-induced remarkable stability of a hydrogen-bonded heterocapsule. AB - Remarkably enhanced stability of the self-assembled hydrogen-bonded heterocapsule 1?2 by the encapsulation of 1,4-bis(1-propynyl)benzene 3 a was found with Ka =1.14*10(9) M(-1) in CDCl3 and Ka2 =1.59*10(8) M(-2) in CD3 OD/CDCl3 (10 % v/v) at 298 K. The formation of 3 a@(1?2) was enthalpically driven (DeltaH degrees <0 and DeltaS degrees <0) and there was a unique inflection point in the correlation between DeltaH degrees versus DeltaS degrees as a function of polar solvent content. The ab initio calculations revealed that favorable guest-capsule dispersion and electrostatic interactions between the acetylenic parts (triple bonds) of 3 a and the aromatic inner space of 1?2, as well as less structural deformation of 1?2 upon encapsulation of 3 a, play important roles in the remarkable stability of 3 a@(1?2). PMID- 23359511 TI - Comparative lung function performance of stroke survivors and age-matched and sex matched controls. AB - BACKGROUND AND PURPOSE: Reduced endurance and excessive fatigue in stroke survivors (SS) during exercise may be linked to impairment of lung function and breathing mechanics, but little is known about lung function of SS. The purpose of this study is to determine lung function (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], FEV1 /FVC ratio and peak expiratory flow [PEF]) and influence of anthropometrics on lung function in SS compared with healthy controls (CG). METHODS: In this case-control, cross-sectional study, we recruited 70 participants (42 males, 28 females), comprising 35 SS and 35 CG (range 34-73 years). Anthropometrics were measured using standard instruments and procedure. Chest excursion was measured at the axilla, xiphoid and lower costal levels. Lung function indices were measured using a micro-computerized spirometer. Ethical approval was obtained from the Ethics and Research Committee of Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria. RESULTS/FINDINGS: Compared with the CG, the SS had significantly lower values for FEV1 (1.99 +/- 0.66 vs. 2.36 +/- 0.45 L, p = 0.004), FVC (2.55 +/- 0.70 vs. 2.90 +/- 0.54 L, p = 0.014), PEF (3.88 +/- 1.38 vs. 5.24 +/- 1.30 L second(-1) , p = 0.001) and chest excursion (3.0 +/- 0.71 vs. 3.5 +/- 0.91 cm, p = 0.018). Correlations between chest excursion, FEV1 , FVC and PEF were not significant (p > 0.05). DISCUSSION: The weakness of respiratory muscles associated with stroke may have contributed to decreases in lung function observed. There was a significant reduction in chest excursion of SS compared with CG. Chest excursion has been used as an indicator of respiratory muscle function because the range of motion of the thorax serves the respiration. Movements of the thorax influence the content of the thorax cavity, leading to alterations in lung volumes. IMPLICATIONS FOR PHYSIOTHERAPY PRACTICE: Stroke survivors have lower lung function when compared with CG; this has implications for clinicians in stroke rehabilitation, underscoring the importance for inclusion of interventions to improve lung function. PMID- 23359512 TI - Influence of surface features of hydroxyapatite on the adsorption of proteins relevant to bone regeneration. AB - Protein-surface interaction may determine the success or failure of an implanted device. Not much attention have been paid to the specific surface parametes of hydroxyapatite (OHAp) that modulates and determines the formation and potential activity of the layer of proteins that is first formed when the material get in contact with the host tissue. the influence of specific surface area (SSA), crystallite size (CS) and particle size (PS) of OHAp on the adsorption of proteins relevant for bone regeneration is evaluated in this article. OHAp have been prepared by a wet chemical reaction of Ca(OH)2 with H3PO4. One set of reactions included poly acrylic acid in the reactant solution to modify the properties of the powder. Fibrinogen (Fg) Fraction I, type I: from Human plasma, (67% Protein), and Fibronectin (Fn) from Human plasma were selected to perform the adsorption experiments. The analysis of protein adsorption was carried out by UV/Vis spectrometry. A lower SSA and a different aspect ratio are obtained when the acrylic acid is included in the reaction badge. The deconvolution of the amide I band on the Raman spectra of free and adsorbed proteins reveals that the interaction apatite-protein happens through the carboxylate groups of the proteins. The combined analysis of CS, SSA and PS should be considered on the design of OHAp materials intended to interact with proteins. PMID- 23359513 TI - RKIP: much more than Raf kinase inhibitory protein. AB - From its discovery as a phosphatidylethanolamine-binding protein in bovine brain to its designation as a physiological inhibitor of Raf kinase protein, RKIP has emerged as a critical molecule for maintaining subdued, well-orchestrated cellular responses to stimuli. The disruption of RKIP in a wide range of pathologies, including cancer, Alzheimer's disease, and pancreatitis, makes it an exciting target for individualized therapy and disease-specific interventions. This review attempts to highlight recent advances in the RKIP field underscoring its potential role as a master modulator of many pivotal intracellular signaling cascades that control cellular growth, motility, apoptosis, genomic integrity, and therapeutic resistance. Specific biological and functional niches are highlighted to focus future research towards an enhanced understanding of the multiple roles of RKIP in health and disease. PMID- 23359509 TI - Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid. AB - The liver has long been described as immunosuppressive, although the mechanisms underlying this phenomenon are incompletely understood. Hepatic stellate cells (HSCs), a population of liver nonparenchymal cells, are potent producers of the regulatory T cell (Treg)-polarizing molecules TGF-beta1 and all-trans retinoic acid, particularly during states of inflammation. HSCs are activated during hepatitis C virus infection and may therefore play a role in the enrichment of Tregs during infection. We hypothesized that Ag presentation in the context of HSC activation will induce naive T cells to differentiate into Foxp3(+) Tregs. To test this hypothesis, we investigated the molecular interactions between murine HSCs, dendritic cells, and naive CD4(+) T cells. We found that HSCs alone do not present Ag to naive CD4(+) T cells, but in the presence of dendritic cells and TGF-beta1, preferentially induce functional Tregs. This Treg induction was associated with retinoid metabolism by HSCs and was dependent on all-trans retinoic acid. Thus, we conclude that HSCs preferentially generate Foxp3(+) Tregs and, therefore, may play a role in the tolerogenic nature of the liver. PMID- 23359514 TI - Increase of extracellular glutamate concentration increases its oxidation and diminishes glucose oxidation in isolated mouse hippocampus: reversible by TFB TBOA. AB - Glutamate concentration at the synaptic level must be kept low in order to prevent excitotoxicity. Astrocytes play a key role in brain energetics, and also astrocytic glutamate transporters are responsible for the vast majority of glutamate uptake in CNS. Experiments with primary astrocytic cultures suggest that increased influx of glutamate cotransported with sodium at astrocytes favors its flux to the tricarboxylic acid cycle instead of the glutamate-glutamine cycle. Although metabolic coupling can be considered an emergent field of research with important recent discoveries, some basic aspects of glutamate metabolism still have not been characterized in brain tissue. Therefore, the aim of this study was to investigate whether the presence of extracellular glutamate is able to modulate the use of glutamate and glucose as energetic substrates. For this purpose, isolated hippocampi of mice were incubated with radiolabeled substrates, and CO2 radioactivity and extracellular lactate were measured. Our results point to a diminished oxidation of glucose with increasing extracellular glutamate concentration, glutamate presumably being the fuel, and might suggest that oxidation of glutamate could buffer excitotoxic conditions by high glutamate concentrations. In addition, these findings were reversed when glutamate uptake by astrocytes was impaired by the presence of (3S)-3-[[3-[[4 (trifluoromethyl)benzoyl]amino]phenyl]methoxy]-L-aspartic acid (TFB-TBOA). Taken together, our findings argue against the lactate shuttle theory, because glutamate did not cause any detectable increase in extracellular lactate content (or, presumably, in glycolysis), because the glutamate is being used as fuel instead of going to glutamine and back to neurons. PMID- 23359515 TI - Duplication in CHIT1 gene and the risk for Aspergillus lung disease in CF patients. AB - BACKGROUND: Aspergillus often persists in the respiratory tract of patients with Cystic Fibrosis (CF) and may cause allergic broncho-pulmonary aspergillosis (ABPA). Chitinases are enzymes that digest the chitin polymer. Plants use chitinase as a defense mechanism against fungi. Chitotriosidase (CHIT1) is the major chitinase in human airways. Variation in the coding region with 24-bp duplication allele results in reduced CHIT1 activity. Recently, CHIT1 duplication heterozygocity was found in 6/6 patients with severe asthma and fungal sensitization (SAFS). AIM: Our aim was to evaluate the link between CHIT1 duplication in CF patients and the predisposition to Allergic broncho-pulmonary mycosis (ABPM) or persistent Aspergillus positive sputum (APS). PATIENTS AND METHODS: CHIT1 duplication was assessed in three CF groups. Group 1: patients who had neither ABPM nor APS in the past (control group). Group 2: patients with persistent APS (>=2/year), without ABPA. Group 3: patients with current or past ABPM. RESULTS: Forty patients with CF were included in the analysis, CHIT1 duplication heterozygocity was found in 3/6 (50%) of the patients in the ABPM group, 3/12 (25%) in the APS group, and 7/22 (31.8%) in the control group (P > 0.05). Eleven patients carried W1282X mutation, 90.9% were negative for CHIT1 duplication, five of them were homozygous for W1282X; none of them had CHIT1 duplication or ABPM. CONCLUSIONS: CHIT1 duplication is not found in all CF patients with ABPM in contrast to patients with SAFS. These results suggest that CHIT1 duplication cannot be the sole explanation for Aspergillus positive sputum in CF patients. PMID- 23359516 TI - Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment naive patients with chronic genotype 1 HCV: SILEN-C1 trial. AB - Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor with pharmacokinetic properties supportive of once-daily (QD) dosing. Four hundred and twenty-nine HCV genotype (GT)-1 treatment-naive patients without cirrhosis were randomized 1:1:2:2 to receive 24 weeks of pegylated interferon alfa-2a and ribavirin (PegIFN/RBV) in combination with placebo, faldaprevir 120 mg QD with 3 days of PegIFN/RBV lead-in (LI), 240 mg QD with LI, or 240 mg QD without LI, followed by an additional 24 weeks of PegIFN/RBV. Patients in the 240 mg QD groups achieving maintained rapid virologic response (mRVR; viral load [VL] <25 IU/mL at week 4 and undetectable at weeks 8-20) were rerandomized to cease all treatment at week 24 or continue receiving PegIFN/RBV up to week 48. VL was measured by Roche TaqMan. Sustained virologic response (SVR) rates were 56%, 72%, 72%, and 84% in the placebo, faldaprevir 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD groups. Ninety-two percent of mRVR patients treated with faldaprevir 240 mg QD achieved SVR, irrespective of PegIFN/RBV treatment duration. Eighty-two percent of GT-1a patients who received faldaprevir 240 mg QD achieved SVR versus 47% with placebo. Mild gastrointestinal disorders, jaundice resulting from isolated unconjugated hyperbilirubinemia, and rash or photosensitivity were more common in the active groups than with placebo. Discontinuations resulting from adverse events occurred in 4%, 11%, and 5% of patients treated with 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD of faldaprevir versus 1% with placebo. CONCLUSION: Faldaprevir QD with PegIFN/RBV achieved consistently high SVR rates with acceptable tolerability and safety at all dose levels. The 120 and 240 mg QD doses are currently undergoing phase 3 evaluation. (HEPATOLOGY 2013;57:2143 2154). PMID- 23359517 TI - The osteopontin-c splice junction is important for anchorage-independent growth. AB - The secreted molecule osteopontin (OPN) is important for metastasis by various cancers. While the full-length form, OPN-a, is also present in healthy tissues, human breast tumors generate a shorter splice form, OPN-c, which has only been found in cancers. OPN-c is more potent than OPN-a in supporting anchorage independence and may be critical for metastasis. Here we analyze the structural requirements for OPN-c function. An antibody specific to the splice junction neutralizes the OPN-c effects. A short peptide covering the sequence around the splice junction inhibits, whereas a long peptide mimics the effects of OPN-c. Site-directed mutagenesis identifies the distal, but not the proximal phosphorylation sites upstream and downstream of the splice junction as important for function. The interposed amino acids are also important as their mutation to alanines leads to a loss of OPN-c effects. We find that small peptides and specific antibodies can neutralize the anchorage-independence enhancing functions of OPN-c. This implies potential for future therapeutic approaches. PMID- 23359518 TI - Evaluation of the flexural strength of dual-cure composite resin cements. AB - The aim of this study was to evaluate of flexural strength of some adhesive resin cements. Three dual-cure composite resin cements (Nexus 3; Variolink II, Panavia F) were prepared. The manufacturer's mixing directions for the cements were followed. Adhesive resin cement was mixed, placed in the rectangular portion of the mold. Fifteen specimens were prepared for each cements. The cements were light-activated with light lamp for 40 s on both and top and bottom surfaces. The each cement specimens were divided into three groups according to time of storage and stored in distilled water for 24 h, 15, and 30 days. Total 45 specimens were stored at 37 degrees C (98.6 0F) in distilled water for 24 h, 15, and 30 days prior to tests. The flexural strength was tested with a universal testing machine at a crosshead speed of 0.5 mm/min (0.02 in.) The maximum load was recorded as MPa. The results were analyzed by Analysis of Variance and Duncan test. The Panavia F resin cements content Bisphenol A was showed the highest flexural strength (80.80 MPa) (11.71 ksi) for 24 h. The lowest flexural strength was observed in Nexus 3 (51.00 MPa) (7.39 ksi). It was found significant interaction of material and time (p < 0.05). The types of cement and time of storage was statistically significant on the flexural strengths (p < 0.001). PMID- 23359519 TI - Novel pluronic-chitosan micelle as an ocular delivery system. AB - Pluronic micelles were prepared for ophthalmic delivery by incorporation of ethyl acetate as a dispersion agent and their surfaces were modified by chitosan to improve their bioavailability. The micelles disperse well in the solution and have a core-shell like structure with a particle size ranging from 93 to 181 nm for drug unloaded, 123-232 nm for drug-loaded, and a zeta potential between 6.1 and 9.2 mV, indicating very suitable use as ophthalmic carrier. The in vitro serum stability tests indicate the particle size of the micelles was very stable during the serum absorption. The turbidity test reveals that the prepared micelles were very stable under phosphate buffered saline environment, which can prevent the blurred vision. The loading efficiency of metipranolol in micelles can be as high as 83%. Finally, the in vitro and in vivo studies indicate the pluronic micelles modified by chitosan have sustained release behavior and good pharmacological response. As the results, the pluroic-chitosan micelles system provides a potential opportunity in decreasing frequency of administration and improving patient compliance for ocular drug delivery. PMID- 23359520 TI - Pycnogenol(r) supplementation improves health risk factors in subjects with metabolic syndrome. AB - This open, controlled study evaluated the effects of 6 month supplementation with Pycnogenol(r) maritime pine bark extract on health risk factors in subjects with metabolic syndrome. Pycnogenol(r) was used with the aim of improving risk factors associated with metabolic syndrome, central obesity, elevated triglycerides (TG), low HDL cholesterol, high blood pressure and fasting blood glucose. Sixty-four subjects (range 45-55 years) presenting with all five risk factors of metabolic syndrome were included, and Pycnogenol(r) was administered for 6 months. A group of 66 equivalent subjects were followed up as controls. In the 6-month study Pycnogenol(r) supplementation 150 mg/day decreased waist circumference, TG levels, blood pressure and increased the HDL cholesterol levels in subjects. Pycnogenol lowered fasting glucose from baseline 123 +/- 8.6 mg/dl to 106.4 +/- 5.3 after 3 months and to 105.3 +/- 2.5 at the end of the study (p < 0.05 vs controls). Men's waist circumference decreased with Pycnogenol from 106.2 +/- 2.2 cm to 98.8 +/- 2.3 cm and to 98.3 +/- 2.1 after 3 and 6 months. Women's waist decreased from 90.9 +/- 1.6 cm to 84.6 +/- 2.1 cm and to 83.6 +/- 2.2 cm after 3 and 6 months. Both genders waist circumference reduction was significant as compared to controls at both time points. In addition, plasma free radicals decrease in the Pycnogenol group was more effective than in the control group ( 34.6%; p < 0.05). In conclusion, this study indicates a role for Pycnogenol(r) for improving health risk factors in subjects with metabolic syndrome. PMID- 23359521 TI - The effects of nanostructured hydroxyapatite coating on the biodegradation and cytocompatibility of magnesium implants. AB - Magnesium (Mg) alloys, a novel class of degradable, metallic biomaterials, have attracted growing interest as a promising alternative for medical implant and device applications due to their advantageous mechanical and biological properties. Although its biodegradability is an attractive property, rapid degradation of Mg in the physiological environments imposes a major obstacle that limits the translation of Mg-based implants to clinical applications. Therefore, the objective of this study was to develop a nanostructured hydroxyapatite (nHA) coating on polished Mg substrates to mediate the rapid degradation of Mg while improving its integration with bone tissue for orthopedic applications. The nHA coatings were deposited on polished Mg using the patented transonic particle acceleration (Spire Biomedical) process. Surface morphology, elemental compositions, and crystal structures were characterized using scanning electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffraction (XRD) analysis, respectively. The degradation of nHA-coated and non-coated Mg samples was investigated by incubating the samples in phosphate buffered saline and revised simulated body fluid, under standard cell culture conditions. Rat bone marrow stromal cells (BMSCs) were harvested and cultured with nHA-coated and non coated Mg samples to determine cytocompatibility. The degradation results suggested that the nHA coatings decreased Mg degradation. Improved BMSC adhesion was observed on the surfaces of the nHA-coated and non-coated Mg samples, in comparison with the cells on the culture plate surrounding the Mg samples. In conclusion, nHA coatings showed promise for improving the biodegradation and cytocompatibility properties of Mg-based orthopedic implants and should be further studied. PMID- 23359523 TI - Human Ng2+ adipose stem cells loaded in vivo on a new crosslinked hyaluronic acid Lys scaffold fabricate a skeletal muscle tissue. AB - Mesenchymal stem cell (MSC) therapy holds promise for treating diseases and tissue repair. Regeneration of skeletal muscle tissue that is lost during pathological muscle degeneration or after injuries is sustained by the production of new myofibers. Human Adipose stem cells (ASCs) have been reported to regenerate muscle fibers and reconstitute the pericytic cell pool after myogenic differentiation in vitro. Our aim was to evaluate the differentiation potential of constructs made from a new cross-linked hyaluronic acid (XHA) scaffold on which different sorted subpopulations of ASCs were loaded. Thirty days after engraftment in mice, we found that NG2(+) ASCs underwent a complete myogenic differentiation, fabricating a human skeletal muscle tissue, while NG2(-) ASCs merely formed a human adipose tissue. Myogenic differentiation was confirmed by the expression of MyoD, MF20, laminin, and lamin A/C by immunofluorescence and/or RT-PCR. In contrast, adipose differentiation was confirmed by the expression of adiponectin, Glut-4, and PPAR-gamma. Both tissues formed expressed Class I HLA, confirming their human origin and excluding any contamination by murine cells. In conclusion, our study provides novel evidence that NG2(+) ASCs loaded on XHA scaffolds are able to fabricate a human skeletal muscle tissue in vivo without the need of a myogenic pre-differentiation step in vitro. We emphasize the translational significance of our findings for human skeletal muscle regeneration. PMID- 23359524 TI - TATES: efficient multivariate genotype-phenotype analysis for genome-wide association studies. AB - To date, the genome-wide association study (GWAS) is the primary tool to identify genetic variants that cause phenotypic variation. As GWAS analyses are generally univariate in nature, multivariate phenotypic information is usually reduced to a single composite score. This practice often results in loss of statistical power to detect causal variants. Multivariate genotype-phenotype methods do exist but attain maximal power only in special circumstances. Here, we present a new multivariate method that we refer to as TATES (Trait-based Association Test that uses Extended Simes procedure), inspired by the GATES procedure proposed by Li et al (2011). For each component of a multivariate trait, TATES combines p-values obtained in standard univariate GWAS to acquire one trait-based p-value, while correcting for correlations between components. Extensive simulations, probing a wide variety of genotype-phenotype models, show that TATES's false positive rate is correct, and that TATES's statistical power to detect causal variants explaining 0.5% of the variance can be 2.5-9 times higher than the power of univariate tests based on composite scores and 1.5-2 times higher than the power of the standard MANOVA. Unlike other multivariate methods, TATES detects both genetic variants that are common to multiple phenotypes and genetic variants that are specific to a single phenotype, i.e. TATES provides a more complete view of the genetic architecture of complex traits. As the actual causal genotype phenotype model is usually unknown and probably phenotypically and genetically complex, TATES, available as an open source program, constitutes a powerful new multivariate strategy that allows researchers to identify novel causal variants, while the complexity of traits is no longer a limiting factor. PMID- 23359525 TI - Novel cationic quinazolin-4(3H)-one conjugated fullerene nanoparticles as antimycobacterial and antimicrobial agents. AB - A series of novel cationic fullerene derivatives bearing a substituted-quinazolin 4(3H)-one moiety as a side arm were synthesized using the 1,3-dipolar cycloaddition reaction of C60 with azomethine ylides generated from the corresponding Schiff bases of substituted quinazolinones. The synthesized compounds 5a-f were characterized by elemental analysis, FT-IR, 1H NMR, 13C NMR, and ESI-MS and screened for their antibacterial activity against Mycobacterium tuberculosis (H37RV) and antimicrobial activity against selected Gram-positive (Staphylococcus aureus and S. pyogenes) and Gram-negative (Pseudomonas aeruginosa, Klebsiella pneumonia and Escherichia coli) bacterial and fungal strains (Candida albicans, Aspergillus clavatus, and A. niger), respectively. All the compounds exhibited significant activity, with the most effective compounds having MIC values and zones of inhibition comparable to those of standard drugs. PMID- 23359526 TI - Transgenic overexpression of 14-3-3 zeta protects hippocampus against endoplasmic reticulum stress and status epilepticus in vivo. AB - 14-3-3 proteins are ubiquitous molecular chaperones that are abundantly expressed in the brain where they regulate cell functions including metabolism, the cell cycle and apoptosis. Brain levels of several 14-3-3 isoforms are altered in diseases of the nervous system, including epilepsy. The 14-3-3 zeta (zeta) isoform has been linked to endoplasmic reticulum (ER) function in neurons, with reduced levels provoking ER stress and increasing vulnerability to excitotoxic injury. Here we report that transgenic overexpression of 14-3-3zeta in mice results in selective changes to the unfolded protein response pathway in the hippocampus, including down-regulation of glucose-regulated proteins 78 and 94, activating transcription factors 4 and 6, and Xbp1 splicing. No differences were found between wild-type mice and transgenic mice for levels of other 14-3-3 isoforms or various other 14-3-3 binding proteins. 14-3-3zeta overexpressing mice were potently protected against cell death caused by intracerebroventricular injection of the ER stressor tunicamycin. 14-3-3zeta overexpressing mice were also potently protected against neuronal death caused by prolonged seizures. These studies demonstrate that increased 14-3-3zeta levels protect against ER stress and seizure-damage despite down-regulation of the unfolded protein response. Delivery of 14-3-3zeta may protect against pathologic changes resulting from prolonged or repeated seizures or where injuries provoke ER stress. PMID- 23359527 TI - Colistin inhalation monotherapy for ventilator-associated pneumonia of Acinetobacter baumannii in prematurity. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) caused by Acinetobacter baumannii is increasing. It has a high mortality rate but experience in using inhaled colistin as monotherapy for VAP in children, especially pre-term infants, is limited. This study presents experiences using aerosolized colistin as monotherapy for VAP due to A. baumannii infection in pre-term infants. METHODS: Eight pre-term infants (gestational age 25-36 weeks) admitted to the neonatal intensive care unit (NICU) of Kaohsiung Chang Gung Memorial Hospital in Taiwan from January 2006 to December 2010 who received inhaled colistin as monotherapy for VAP due to A. baumannii infection were retrospectively evaluated. Of the isolated microorganisms, five were multi-drug resistant strains of A. baumannii (MDR-AB) but all were sensitive to colistin. All patients received inhaled colistin at a dose of 1,000,000 IU (33.4 mg) twice daily for an average of 9.1 days (range, 4-22 days). RESULTS: All pre-term infants were cured, with A. baumannii eradicated from airway secretions. There were no clinical or laboratory adverse events related to colistin use. CONCLUSIONS: Aerosolized colistin may be used as monotherapy for VAP due to A. baumannii infection in pre-term infants. A larger controlled study is warranted to corroborate the findings. PMID- 23359528 TI - Porous TiO2 surface formed on nickel-titanium alloy by plasma electrolytic oxidation: a prospective polymer-free reservoir for drug eluting stent applications. AB - In this study, a porous oxide layer was formed on the surface of nickel-titanium alloy (NiTi) by plasma electrolytic oxidation (PEO) with the aim to produce a polymer-free drug carrier for drug eluting stent (DES) applications. The oxidation was performed galvanostatically in concentrated phosphoric acid electrolyte at low temperature. It was found that the response of NiTi substrate during the PEO process was different from that of bulk Ti, since the presence of large amount of Ni delayed the initial formation of a compact oxide layer that is essential for the PEO to take place. Under optimized PEO conditions, the resultant surface showed porosity, pore density and oxide layer thickness of 14.11%, 2.40 * 105 pores/mm2 and 0.8 MUm, respectively. It was additionally noted that surface roughness after PEO did not significantly increase as compared with that of original NiTi substrate and the EDS analyses revealed a decrease in Ni/Ti ratio on the surface after PEO. The cross-section morphology showed no discontinuity between the PEO layer and the NiTi substrate. Furthermore, wettability and surface free energy of the NiTi substrate increased significantly after PEO treatment. The PEO process could be successfully translated to NiTi stent configuration proving for the first time its feasibility for such a medical device and offering potential for development of alternative, polymer-free drug carriers for NiTi DES. PMID- 23359529 TI - Density-controlled synthesis of uniform ZnO nanowires: wide-range tunability and growth regime transition. PMID- 23359530 TI - Modulation of human osteoblasts by metal surface chemistry. AB - The use of metal implants in dental and orthopedic surgery is continuously expanding and highly successful. While today longevity and load-bearing capacity of the implants fulfill the expectations of the patients, acceleration of osseointegration would be of particular benefit to shorten the period of convalescence. To further clarify the options to accelerate the kinetics of osseointegration, within this study, the osteogenic properties of structurally identical surfaces with different metal coatings were investigated. To assess the development and function of primary human osteoblasts on metal surfaces, cell viability, differentiation, and gene expression were determined. Titanium surfaces were used as positive, and surfaces coated with gold were used as negative controls. Little differences in the cellular parameters tested for were found when the cells were grown on titanium discs sputter coated with titanium, zirconium, niobium, tantalum, gold, and chromium. Cell number, activity of cell layer-associated alkaline phosphatase (ALP), and levels of transcripts encoding COL1A1 and BGLAP did not vary significantly in dependence of the surface chemistry. Treatment of the cell cultures with 1,25(OH)2 D3 /Dex, however, significantly increased ALP activity and BGLAP messenger RNA levels. The data demonstrate that the metal layer coated onto the titanium discs exerted little modulatory effects on cell behavior. It is suggested that the microenvironment regulated by the peri-implant tissues is more effective in regulating the tissue response than is the material of the implant itself. PMID- 23359531 TI - Subclavian artery pseudoaneurysm complicating central venous catheterization: endovascular treatment with Amplatzer Vascular Plug 4 and covered stent. AB - Central venous catheterization is a routine vascular access procedure; however, it may be associated with life-threatening complications such as arterial puncture, leading to pseudoaneurysm formation. We report a case of a 41-year-old female that developed an iatrogenic left subclavian pseudoaneurysm complicating the attempt of left internal jugular vein cannulation for temporary hemodialysis therapy. The patient underwent urgent endovascular treatment with deployment of covered stent into the left subclavian artery (SCA) after embolization of the origin of the left internal mammary artery with Amplatzer Vascular Plug 4. The patient's recovery was unremarkable. Follow-up till 24 months reveals total exclusion of the pseudoaneurysm of the left SCA with patency of the distal branches. PMID- 23359532 TI - Enhancement of adriamycin cytotoxicity by sodium butyrate involves hTERT downmodulation-mediated apoptosis in human uterine cancer cells. AB - Activation of telomerase is a key element in oncogenesis and resistance to apoptosis for many cancers. Some histone deacetylase inhibitors (HDACi) or chemotheraputic agents have been reported to downregulate the expression of human telomerase reverse transcriptase (hTERT). However, whether hTERT is involved in cell death of uterine cancer cells induced by combination of HDACi with chemotheraputic regents remain unknown. The present study shows that combining sodium butyrate (NaBu) and adriamycin (ADR) inhibits proliferation of uterine cancer cell lines in a concentration and time-dependent manner. Growth inhibition was accompanied by caspase-dependent apoptosis with reduced telomerase activity and decreased hTERT mRNA expression. Ectopic wild type (WT)-hTERT suppressed the apoptosis induced by NaBu/ADR treatment, while knockdown of hTERT sensitized uterine cancer cells to ADR. Moreover, the addition of NaBu significantly enhanced ADR cytotoxicity for the primary uterine cancer cells with high hTERT expression. These data indicate that downregulation of hTERT is an important part of the mechanism by which NaBu enhances ADR-induced apoptosis, and suggests that combining NaBu and ADR may be effective in treating uterine tumor with high telomerase activity. PMID- 23359534 TI - Bronchopulmonary dysplasia: clinical grading in relation to ventilation/perfusion mismatch measured by single photon emission computed tomography. AB - Bronchopulmonary dysplasia (BPD) is a significant cause of morbidity in the preterm population. Clinical severity grading based on the need for supplemental oxygen and/or need for positive airway pressure at 36 weeks postmenstrual age does not yield reproducible predictive values for later pulmonary morbidity. Single photon emission computed tomography (SPECT) was used to measure the distribution of lung ventilation (V) and perfusion (Q) in 30 BPD preterm infants at a median age of 37 weeks postmenstrual age. The V and Q were traced with 5 MBq Technegas and Technetium-labeled albumin macro aggregates, respectively, and the V/Q match-mismatch was used to quantify the extent of lung function impairment. The latter was then compared with the clinical severity grading at 36 weeks, and time spent on mechanical ventilation, continuous positive airway pressure (CPAP) and supplemental oxygen. Of those with mild and moderate BPD 3/9 and 3/11 patients, respectively, showed significant V/Q mismatches. By contrast, 4/10 patients with severe BPD showed a satisfactory V/Q matching distribution. An unsatisfactory V/Q match was not correlated with time spent on supplemental oxygen or CPAP, but was significantly negatively correlated with time spent on mechanical ventilation. SPECT provides unique additional information about regional lung function. The results suggest that the current clinical severity grading can be improved and/or complemented with SPECT. PMID- 23359533 TI - Interferon-gamma promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) beta2. AB - Systemic sclerosis (SSc) is a complex disease characterized by vascular alterations, activation of the immune system and tissue fibrosis. Previous studies have implicated activation of the interferon pathways in the pathogenesis of SSc. The goal of this study was to determine whether interferon type I and/or type II could play a pathogenic role in SSc vasculopathy. Human dermal microvascular endothelial cells (HDMVECs) and fibroblasts were obtained from foreskins of healthy newborns. The RT Profiler PCR Array System was utilized to screen for EndoMT genes. Treatment with IFN-alpha or IFN-gamma downregulated Fli1 and VE-cadherin. In contrast, IFN-alpha and IFN-gamma exerted opposite effects on the expression of alpha-SMA, CTGF, ET-1, and TGFbeta2, with IFN-alpha downregulating and IFN-gamma upregulating this set of genes. Blockade of TGFbeta signaling normalized IFN-gamma-mediated changes in Fli1, VE-cadherin, CTGF, and ET-1 levels, whereas upregulation of alpha-SMA and TGFbeta2 was not affected. Bosentan treatment was more effective than TGFbeta blockade in reversing the actions of IFN-gamma, including downregulation of alpha-SMA and TGFbeta2, suggesting that activation of the ET-1 pathway plays a main role in the IFN-gamma responses in HDMECs. IFN-gamma induced expression of selected genes related to endothelial-to-mesenchymal transition (EndoMT), including Snail1, FN1, PAI1, TWIST1, STAT3, RGS2, and components of the WNT pathway. The effect of IFN-gamma on EndoMT was mediated via TGFbeta2 and ET-1 signaling pathways. This study demonstrates distinct effects of IFN-alpha and IFN-gamma on the biology of vascular endothelial cells. IFN-gamma may contribute to abnormal vascular remodeling and fibrogenesis in SSc, partially via induction of EndoMT. PMID- 23359535 TI - A case of CTO treated with minimum use of contrast media. AB - The retrograde approach is a novel technique for improving the success rate of guidewire passage through chronic total occlusion (CTO). In addition, this technique, especially when intravascular ultrasound-guided reverse controlled antegrade and retrograde subintimal tracking is employed, may help the operator to save on the contrast media used. In the case reported here, only 10 ml of contrast media was used in percutaneous coronary intervention for CTO. PMID- 23359536 TI - In vitro response of preosteoblastic MG63 cells on Ni-free Ti shape memory substrates. AB - Ni-free Ti alloys are a potential strategy to overcome the risk of Ni-adverse reactions and rigidity mismatch for implant materials. Here, we report the biological behavior induced for two promising candidate alloys--Ti19.1Nb8.8Zr (M(S) temperature of 46 degrees C and elastic modulus of 74 GPa) and Ti41.2Nb6.1Zr (elastic modulus of 67 GPa)--on cultured MG63 cells, as well as their physical and chemical properties. Contact angle results revealed the hydrophobic character of the former alloy (59.02 degrees +/- 2.35 degrees ) attributed to the presence of the martensitic phase, while the latter one presented a hydrophilic response (67.77 degrees +/- 2.78 degrees ). Results showed also that the cell adhesion response (after 4 and 8 h of incubation) in both substrates was not statistically different to that obtained in the cp Ti as control material. These surfaces induced well spread cell morphology with cytoplasmic extension like filopodia of up to 100 MUm even at short culture times and presented an uninterrupted proliferation after longer incubation times (9 days). A decrement in the proliferation rate was appreciated from the Ti19.1Nb8.8Zr surface at that time, which was attributed to an earlier activation of the cell differentiation stage, as confirmed by the twofold increment of alkaline phosphatase activity. The results also evidenced that the presence of a 2 nm thick layer of amorphous Nb2O5, which was detected on both alloys, has a significant effect on cell behavior favoring the cell adhesion and morphology response of the new alloys studied. PMID- 23359537 TI - Grasp detection from human ECoG during natural reach-to-grasp movements. AB - Various movement parameters of grasping movements, like velocity or type of the grasp, have been successfully decoded from neural activity. However, the question of movement event detection from brain activity, that is, decoding the time at which an event occurred (e.g. movement onset), has been addressed less often. Yet, this may be a topic of key importance, as a brain-machine interface (BMI) that controls a grasping prosthesis could be realized by detecting the time of grasp, together with an optional decoding of which type of grasp to apply. We, therefore, studied the detection of time of grasps from human ECoG recordings during a sequence of natural and continuous reach-to-grasp movements. Using signals recorded from the motor cortex, a detector based on regularized linear discriminant analysis was able to retrieve the time-point of grasp with high reliability and only few false detections. Best performance was achieved using a combination of signal components from time and frequency domains. Sensitivity, measured by the amount of correct detections, and specificity, represented by the amount of false detections, depended strongly on the imposed restrictions on temporal precision of detection and on the delay between event detection and the time the event occurred. Including neural data from after the event into the decoding analysis, slightly increased accuracy, however, reasonable performance could also be obtained when grasping events were detected 125 ms in advance. In summary, our results provide a good basis for using detection of grasping movements from ECoG to control a grasping prosthesis. PMID- 23359538 TI - Tailor-made micro-object optical sensor based on mesoporous pellets for visual monitoring and removal of toxic metal ions from aqueous media. AB - Methods for the continuous monitoring and removal of ultra-trace levels of toxic inorganic species (e.g., mercury, copper, and cadmium ions) from aqueous media such as drinking water and biological fluids are essential. In this paper, the design and engineering of a simple, pH-dependent, micro-object optical sensor is described based on mesoporous aluminosilica pellets with an adsorbed dressing receptor (a porphyrinic chelating ligand). This tailor-made optical sensor permits ultra-fast (<= 60 s), specific, pH-dependent visualization and removal of Cu(2+) , Cd(2+) , and Hg(2+) at sub-picomolar concentrations (~10(-11) mol dm(-3) ) from aqueous media, including drinking water and a suspension of red blood cells. The acidic active acid sites of the pellets consist of heteroatoms arranged around uniformly shaped pores in 3D nanoscale gyroidal mesostructures densely coated with the chelating ligand. The sensor can be used in batch mode, as well as in a flow-through system in which sampling, target ion recognition and removal, and analysis are integrated in a highly automated and efficient manner. Because the pellets exhibit long-term stability, reproducibility, and versatility over a number of analysis/regeneration cycles, they can be expected to be useful for the fabrication of inexpensive sensor devices for naked-eye detection of toxic pollutants. PMID- 23359539 TI - Effect of crosslinking on the mechanical properties of mineralized and non mineralized collagen fibers. AB - Problems associated with current bone substitutes led to an increased interest in tissue engineered surrogates with properties similar to natural bones. Commonly used materials lack the ultimate mechanical properties. In this study, we examined the influence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) as a crosslinking agent on the strength of collagen fibers. Collagen fibers are crosslinked with EDC, or EDC/N-hydroxysulfosuccinimide (Sulfo NHS) in water or EDC in acetone. After which fibers are mineralized using calcium chloride and potassium phosphate. The mechanical properties of the treated fibers are measured using tensile testing. In addition, the effect of crosslinking on cellular behavior was tested by culturing bone marrow mesenchymal stem cells (BMMSCs) on modified fibers. We found that the mechanical properties of non mineralized and mineralized collagen fibers are significantly affected by the crosslinking method. The tensile strength of single fibers is greatly improved by crosslinking with EDC in acetone. BMMSCs were found to attach and spread well on modified fibers confirming biocompatibility. PMID- 23359540 TI - Family history is a predictor for appendicitis in adults in the emergency department. AB - INTRODUCTION: A family history of appendicitis has been reported to increase the likelihood of the diagnosis in children and in a retrospective study of adults. We compare positive family history with the diagnosis of acute appendicitis in a prospective sample of adults. METHODS: We conducted a prospective observational study of a convenience sample of 428 patients. We compared patients with surgically proven appendicitis to a group without appendicitis. The latter were further grouped by their presenting symptoms: those presenting with a chief complaint of abdominal pain and those with other chief complaints. Participants answered questions regarding their family history of appendicitis. Family history was then compared for the appendicitis group versus the nonappendicitis group as a whole, and then versus the subgroup of patients without appendicitis but with abdominal pain. The primary analysis was a chi(2) test of proportions and the calculation of odds ratio (OR) for the relationship between final diagnosis of appendicitis and family history. RESULTS: Of 428 patients enrolled, 116 had appendicitis. Of those with other diagnoses, 158 had abdominal pain and 154 had other complaints. Of all patients with appendicitis, 37.9% (confidence interval [Cl] = 29.1-46.8) had positive family history. Of those without appendicitis, 23.7% (Cl = 19.0-28.4) had positive family history. In the subgroup without appendicitis but with abdominal pain, 25.9% (Cl = 19.1-32.8) had positive family history. Both comparisons were significant (P = 0.003; OR = 1.97; 95% Cl = 1.2 3.1; and P=0.034; OR = 1.74; 95% Cl = 1.04-2.9, respectively). By multivariate logistic regression analysis across the full sample, family history was a significant independent predictor (P = 0.011; OR = 1.883) of appendicitis. CONCLUSION: Adults presenting to the emergency department with a known family history of appendicitis are more likely to have this disease than those without. PMID- 23359541 TI - Spinal posture in the sagittal plane is associated with future dependence in activities of daily living: a community-based cohort study of older adults in Japan. AB - BACKGROUND: Accumulated evidence shows how important spinal posture is for aged populations in maintaining independence in everyday life. However, the cross sectional designs of most previous studies prevent elucidation of the relationship between spinal posture and future dependence in activities of daily living (ADL). We tried to clarify the association by measuring spinal posture noninvasively in a community-based prospective cohort study of older adults, paying particular attention to thoracic curvature, lumbar curvature, sacral hip angle, and inclination to determine which parameter is most strongly associated with dependence in ADL. METHODS: Spinal posture was evaluated in 804 participants (338 men, 466 women, age range: 65-94 years) who were independent in ADL at baseline. We defined dependence in ADL as admission to a nursing home or need of home assistance. During the 4.5-year follow-up period, 126 (15.7%) participants became dependent in ADL. The relationship between the spinal posture parameters and outcome was assessed by dividing the participants into sex-specific quartiles of the parameters. RESULTS: Only inclination (angle subtended between the vertical and a line joining C7 to the sacrum) was associated with outcome, although lumbar curvature also showed a marginal association. The age- and sex adjusted odds ratio for a 1 unit increase in the quartiles of inclination was 1.79 (confidence interval: 1.44, 2.23). After mutual adjustment for the 4 parameters, statistical significance for inclination still remained, with no substantial changes in the association estimates. CONCLUSIONS: This study indicates that spinal inclination is associated with future dependence in ADL among older adults. PMID- 23359542 TI - The optimal management for patients. PMID- 23359543 TI - Staged total percutaneous treatment of aortic valve pathology and mitral regurgitation: institutional experience. AB - OBJECTIVES: To summarize our single Institution experience with staged total percutaneous management of aorto-mitral pathology. BACKGROUND: Percutaneous treatment of aortic valve stenosis (AVS) and mitral valve regurgitation (MVR) has been recently proposed for patients at high surgical risk. METHODS: Data concerning consecutive patients undergoing percutaneous transcatheter AV implantation (TAVI) followed by MV repair with MitraClip(r) were prospectively collected and analyzed. RESULTS: From January 2010 to February 2012 a total of 254 patients were referred to undergo TAVI in our Institution. Seventeen (6.7%) had preoperative severe MVR that remained unchanged after TAVI. Due to exacerbation of symptoms 12 patients were subsequently submitted to MV repair with the MitraClip(r) device. Mean age was 79 years (72-86 years), median Ambler score was 30.1 (17.2-42.6) and EuroSCORE 22.3 (10.2-48.6). Procedural success rate was 100%. Postprocedural hospitalization was 7.1 +/- 2.7 and 4.6 +/- 0.9 days after TAVI and MV repair, respectively. Six months follow-up echocardiography confirms improvement in LV-EF (37.2 +/- 9.9 vs. 43.5 +/- 10.7, P < 0.0001). No patient presents MVR exceeding grade I(+) or prosthetic aortic insufficiency > I grade and all patients experienced an improvement in functional status. CONCLUSIONS: Percutaneous treatment of AVS and MVR is feasible and safe. A tailored approach should be considered to treat firstly the AVS and subsequently the MVR when severe MV dysfunction and symptoms persist. Short-term durability of this combined percutaneous approach seems encouraging and justifies the economical burden to treat patients that have no other option. PMID- 23359545 TI - The effectiveness of cabergoline for the prevention of ovarian hyperstimulation syndrome. AB - Type 2 receptors for vascular endothelial growth factor are believed to be involved in the pathophysiology of ovarian hyperstimulation syndrome (OHSS). The objective of this study was to examine the preventive effects of cabergoline on OHSS and its complications. The study is a non randomized clinical trial conducted in 2006-2008 on 75 patients, which were at risk of OHSS and underwent assisted reproductive techniques. The diagnosis and severity of OHSS were determined using standard criteria. The study included an intervention and a control group. The intervention group comprised of 50 women at risk of OHSS, who were treated with cabergoline (1 mg every other day for 8 days) commencing from the day of ovum pick up. The control group comprised of 25 historical cases, which were similar to the case group. The latter group did not receive cabergoline, and their OHSS, if occurred, were managed conservatively after hospital admission. The rates of OHSS, baseline characteristics, ovarian stimulation parameters, and pregnancy occurrence were compared. There was no significant difference between baseline characteristics or ovarian stimulation parameters form the two groups. The incidence of OHSS in the cabergoline-treated group, was significantly (P=0.01) lower than that in the control group (12% vs 36%). Embryo freezing was significantly (P=0.001) lower in the control group, but cycle cancellation was significantly (0.03) lower in the cabergoline group. The findings of the study indicate that cabergoline reduces the incidence of OHSS, and is not associated with adverse effects on pregnancy. PMID- 23359544 TI - Genetic and functional modularity of Hox activities in the specification of limb innervating motor neurons. AB - A critical step in the assembly of the neural circuits that control tetrapod locomotion is the specification of the lateral motor column (LMC), a diverse motor neuron population targeting limb musculature. Hox6 paralog group genes have been implicated as key determinants of LMC fate at forelimb levels of the spinal cord, through their ability to promote expression of the LMC-restricted genes Foxp1 and Raldh2 and to suppress thoracic fates through exclusion of Hoxc9. The specific roles and mechanisms of Hox6 gene function in LMC neurons, however, are not known. We show that Hox6 genes are critical for diverse facets of LMC identity and define motifs required for their in vivo specificities. Although Hox6 genes are necessary for generating the appropriate number of LMC neurons, they are not absolutely required for the induction of forelimb LMC molecular determinants. In the absence of Hox6 activity, LMC identity appears to be preserved through a diverse array of Hox5-Hox8 paralogs, which are sufficient to reprogram thoracic motor neurons to an LMC fate. In contrast to the apparently permissive Hox inputs to early LMC gene programs, individual Hox genes, such as Hoxc6, have specific roles in promoting motor neuron pool diversity within the LMC. Dissection of motifs required for Hox in vivo specificities reveals that either cross-repressive interactions or cooperativity with Pbx cofactors are sufficient to induce LMC identity, with the N-terminus capable of promoting columnar, but not pool, identity when transferred to a heterologous homeodomain. These results indicate that Hox proteins orchestrate diverse aspects of cell fate specification through both the convergent regulation of gene programs regulated by many paralogs and also more restricted actions encoded through specificity determinants in the N-terminus. PMID- 23359547 TI - Robotics - The answer to the Achilles' heel of VATS pulmonary resection. PMID- 23359546 TI - Root canal hydrophobization by dentinal silanization: improvement of silicon based endodontic treatment tightness. AB - A new strategy to improve silicon-based endodontic treatment tightness by dentine hydrophobization is presented in this work: root dentine was silanized to obtain a hydrophobic dentine-sealer interface that limits fluid penetration. This strategy was based on the grafting of aliphatic carbon chains on the dentine through a silanization with the silane end groups [octadecyltrichlorosilane (OTS) and octadecyltriethoxysilane]. Dentine surface was previously pretreated, applying ethylenediaminetetraacetic acid and sodium hypochlorite, to expose hydroxyl groups of collagen for the silane grafting. Collagen fibers exposure after pretreatment was visible with scanning electron microscopy, and Fourier transform infrared (FTIR) spectroscopy showed their correct exposition for the silanization (amide I and II, with 1630, 1580, and 1538 cm-1 peaks corresponding to the vibration of C=O and C--N bonds). The grafting of aliphatic carbon chains was confirmed by FTIR (peaks at 2952 and 2923 cm-1 corresponding to the stretching of C--H bonds) and by the increasing of the water contact angle. The most efficient hydrophobization was obtained with OTS in ethyl acetate, with a water contact angle turning from 51 degrees to 109 degrees . Gas and liquid permeability tests showed an increased seal tightness after silanization: the mean gas and water flows dropped from 2.02 * 10-8 to 1.62 * 10-8 mol s-1 and from 10.8 * 10-3 to 5.4 * 10-3 uL min-1, respectively. These results show clear evidences to turn hydrophilic dentine surface into a hydrophobic surface that may improve endodontic sealing. PMID- 23359548 TI - Polymeric nanoparticles with sequential and multiple FRET cascade mechanisms for multicolor and multiplexed imaging. AB - The ability to map multiple biomarkers at the same time has far-reaching biomedical and diagnostic applications. Here, a series of biocompatible poly(D,L lactic-co-glycolic acid) and polyethylene glycol particles for multicolor and multiplexed imaging are reported. More than 30 particle formulations that exhibit distinct emission signatures (ranging from the visible to NIR wavelength region) are designed and synthesized. These particles are encapsulated with combinations of carbocyanine-based fluorophores DiO, Dil, DiD, and DiR, and are characterized as <100 nm in size and brighter than commercial quantum dots. A particle formulation is identified that simultaneously emits fluorescence at three different wavelengths upon a single excitation at 485 nm via sequential and multiple FRET cascade events for multicolor imaging. Three other particles that display maximum fluorescence intensities at 570, 672, or 777 nm for multiplexed imaging are also identified. These particles are individually conjugated with specific (Herceptin or IgG2A11 antibody) or nonspecific (heptaarginine) ligands for targeting and, thus, could be applied to differentiate different cancer cells from a cell mixture according to the expressions of cell-surface human epidermal growth factor receptor 2 and the receptor for advanced glycation endproducts. Using an animal model subcutaneously implanted with the particles, it is further demonstrated that the developed platform could be useful for in vivo multiplexed imaging. PMID- 23359549 TI - Repression of osteoblast maturation by ERRalpha accounts for bone loss induced by estrogen deficiency. AB - ERRalpha is an orphan member of the nuclear receptor family, the complete inactivation of which confers resistance to bone loss induced by ageing and estrogen withdrawal to female mice in correlation with increased bone formation in vivo. Furthermore ERRalpha negatively regulates the commitment of mesenchymal cells to the osteoblast lineage ex vivo as well as later steps of osteoblast maturation. We searched to determine whether the activities of ERRalpha on osteoblast maturation are responsible for one or both types of in vivo induced bone loss. To this end we have generated conditional knock out mice in which the receptor is normally present during early osteoblast differentiation but inactivated upon osteoblast maturation. Bone ageing in these animals was similar to that observed for control animals. In contrast conditional ERRalphaKO mice were completely resistant to bone loss induced by ovariectomy. We conclude that the late (maturation), but not early (commitment), negative effects of ERRalpha on the osteoblast lineage contribute to the reduced bone mineral density observed upon estrogen deficiency. PMID- 23359550 TI - Cytotoxicity, in vitro models and preliminary in vivo study of dual physical and chemical gels for endovascular embolization of cerebral aneurysms. AB - We report the evaluation of dual-gelling poly(N-isopropylacrylamide)-based polymer systems as embolic agents for intracranial aneurysms. These hydrogels undergo gelation physically via temperature-responsiveness of poly(NIPAAm) and chemically through a Michael-addition reaction between thiol and vinyl functional groups on the copolymers. Cytotoxicity studies were performed for biocompatibility of the hydrogels. In vitro glass models were utilized to assess injectability and embolization using the gelling systems and an in vivo swine model was used as proof-of-concept for catheter delivery, injection, and occlusion properties of the hydrogels. Rheology creep tests were conducted for determination of viscoelastic behavior, and degradation of the hydrogels was also investigated. Live/dead and proliferation assays indicated good biocompatibility of the hydrogels. In vitro and in vivo assessment demonstrated that the hydrogels were easily delivered via catheters into the aneurysms. Slight recanalization was observed in vivo, with some adhesion of the gels to the balloon catheter seen in vitro. The materials show creep deformation occurring with time; however, the hydrogels did not degrade over the course of 1.5 year. With the possibility to engineer hydrogels bottom-up for particular applications, these studies show properties that need to be optimized for dual-gelling polymer systems to serve as liquid-to-solid embolic agents for aneurysm treatment. PMID- 23359551 TI - Functional capacity during exercise in very-low-birth-weight premature children. AB - OBJECTIVES: The functional capacity of children born prematurely with very-low birth weight was compared with that of children born at full-term using the six minute walk test (6MWT) and the ten-minutes shuttle walk test (10MSWT). The factors affecting walking distance were analyzed. METHODS: A cross-sectional study was conducted with two groups of children aged 6-9 years, matched by sex and age. One group included children born before 37 weeks of gestation weighing <1,500 g and the second group included children born at term. Both groups were submitted to the 6MWT and 10MWST, performed on the same day with an interval of 20 min between tests and the sequence of the tests was randomized, by sealed envelope technique. Physiological parameters were measured at the beginning and end of each test. The walking distance and factors affecting the walking distance were analyzed. RESULTS: Thirty-seven children born prematurely and 37 born at term were studied. The premature children walked shorter distances in the 6MWT (480.9 +/- 80.5 m vs. 518.3 +/- 51.8 m, P = 0.010) than term children, and both groups walked similar distances in the 10MSWT (391.5 +/- 99.0 m vs. 406.1 +/- 79.2 m, P = 0.487). By multiple linear regression analysis, adjusted for confounders, walking distance was associated with height (OR: 3.6) and oxygen dependency at 28 days (OR: -67.7) in the 6MWT (P < 0.001) and with height (OR: 4.9) and oxygen dependency at 28 days (OR: -91.0) in the 10MSWT (P < 0.001). CONCLUSION: In conclusion, this study suggests that children born prematurely with very low birth weight, especially those who had bronchopulmonary dysplasia present limited functional capacity during exercise. PMID- 23359553 TI - Prediction of mechanical properties of multilayer gradient hydroxyapatite reinforced poly(vinyl alcohol) gel biomaterial. AB - Functional graded materials provided us one new concept for artificial articular cartilage design with graded component and graded structure. In this article, a novel functional material design was proposed by functionalizing hydroxyapatite (HA) particles in poly(vinyl alcohol) (PVA) hydrogel. The goal of the present study was to fabricate a multilayer gradient HA/PVA gel biocomposites through layer-by-layer casting method combining with freeze/thaw cycle technology and establish a mechanical model to predict the compressive mechanical properties of multilayer gradient gel biocomposites. The results showed that the compressive strength of the multilayer gradient gel biocomposites increased with the rise of HA content, but it presented decreasing trend with the rise of interlayer gradient concentration of HA particles. Furthermore, the compressive strength of multilayer gradient biocomposites would be approximately predicted by the established mechanical model. The maximum error between theoretical compressive strength predicted by the model and the experimental strength is less than 7%. On the other hand, the compressive mechanical properties of multilayer gradient composites could be designed and controlled by the mechanical model as established in this study. PMID- 23359552 TI - Physicochemical changes in phosphorylase kinase induced by its cationic activator Mg(2+). AB - For over four decades free Mg(2+) ions, that is, those in excess of MgATP, have been reported to affect a wide variety of properties of phosphorylase kinase (PhK), including its affinity for other molecules, proteolysis, chemical crosslinking, phosphorylation, binding to certain monoclonal antibodies, and activity, which is stimulated. Additionally, for over three decades Mg(2+) has been known to act synergistically with Ca(2+) , another divalent activator of PhK, to affect even more properties of the enzyme. During all of this time, however, no study has been performed to determine the overall effects of free Mg(2+) ions on the physical properties of PhK, even though the effects of Ca(2+) ions on PhK's properties are well documented. In this study, changes in the physicochemical properties of PhK induced by Mg(2+) under nonactivating (pH 6.8) and activating (pH 8.2) conditions were investigated by circular dichroism spectroscopy, zeta potential analyses, dynamic light scattering, second derivative UV absorption, negative stain electron microscopy, and differential chemical crosslinking. The effects of the activator Mg(2+) on some of the properties of PhK measured by these techniques were found to be quite different at the two pH values, and displayed both differences and similarities with the effects previously reported to be induced by the activator Ca(2+) (Liu et al., Protein Sci 2008;17:2111-2119). The similarities may reflect the fact that both cations are activators, and foremost among their similarities is the dramatically less negative zeta potential induced by their binding to PhK. PMID- 23359554 TI - Impact of advanced age on the safety and effectiveness of paclitaxel-eluting stent implantation in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: The HORIZONS-AMI trial. AB - OBJECTIVES: To assess the impact of age on safety and efficacy of paclitaxel eluting stent (PES) implantation during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The benefits of paclitaxel-eluting stent (PES) implantation during primary PCI were confirmed by the long-term results of the HORIZONS-AMI trial. Whether the effects of PES are independent of age has not been reported. METHODS: Data on 3,006 patients from the HORIZONS-AMI study randomized in a 3:1 ratio to PES or bare-metal stent (BMS) in whom at least one stent was implanted were assessed. There were 2,302 (76.6%) patients <70, and 704 patients >=70 years of age. RESULTS: At 3 years, among older patients a trend toward lower risk of major adverse cardiac events (MACE; death from any cause, stroke, reinfarction and unplanned revascularization for ischemia) related to PES use was observed (PES vs. BMS: 18.0% vs. 21.3%; P = 0.07). There was also a trend for reduction of MACE related to PES in older patients (26.4% vs. 33.1%; P = 0.09). Both, patients <70 and >=70 years of age treated with PES were at lower risk for ischemic target vessel revascularization. However, a higher risk of major bleeding in elderly patients treated with PES was observed (P = 0.02 for interaction between age group and PES effects). No interaction between age and stent type in terms of the risk of other clinical end points, including all-cause death, was confirmed. CONCLUSIONS: For STEMI patients undergoing primary PCI, the implantation of PES as compared with BMS reduced ischemic TVR, and this effect was independent of age. PMID- 23359555 TI - Electrochemical synthesis of transparent, amorphous, C60-rich, photoactive, and low-doped film with an interconnected structure. PMID- 23359556 TI - Osteoblastic cellular responses on ionically crosslinked chitosan tripolyphosphate fibrous 3-D mesh scaffolds. AB - Tripolyphosphate (TPP) crosslinked chitosan (CH)-based fibrous matrices have potential as bioactive scaffolds for bone tissue engineering. This study describes mechanical, biomineralization, and in vitro bone cell growth and differentiation properties of CH-TPP (chitosan-tripolyphosphate) fibrous scaffolds and compared with that of uncrosslinked CH one. The hydrated CH-TPP scaffolds were viscoelastic in nature and their compressive strength was ~2.9 MPa, which is greater than recent polymer experimental bone scaffolds. This improvement in mechanical properties of CH-TPP scaffold may be beneficial toward cancellous bone graft application. Furthermore, CH-TPP fibers supported in vitro biomineralization with phosphate as nucleation site; however, no significant difference in biomineralization morphology was observed with uncrosslinked CH fibers. Interestingly, a significant improvement in cellular responses (>33% increase in cell number based on DNA quantification) was observed when osteoblast like cells were cultured on the CH-TPP scaffolds than that of CH scaffolds without phosphate group. Enhanced osteoblastic differentiation of MG63 cells on CH-TPP scaffolds was also evidenced. Altogether, the results show that the CH-TPP fibrous scaffolds are encouraging for bone tissue engineering. PMID- 23359557 TI - Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: VI. Executive summary. AB - Acute pulmonary exacerbations (APE) are well-described complications of cystic fibrosis (CF) and are associated with progressive morbidity and mortality. Despite aggressive management with two or more intravenous anti-pseudomonal agents, approximately 25% of exacerbations will result in a loss of lung function. The aim of this review is to provide an overview of the classes of intravenous anti-pseudomonal antibiotics, the findings of anti-pseudomonal antibiotic utilization surveys, the current antibiotic dosing recommendations from the U.S. and Europe, and the pharmacokinetic (PK) and pharmacodynamic (PD) differences between CF and non-CF individuals. Anti-pseudomonal antibiotic classes include beta-lactams, aminoglycosides, fluoroquinolones, and colistimethate sodium. Recent surveys of antibiotic utilization in CF Foundation accredited care centers have shown that a large number of centers are not following recommended dosing strategies despite published recommendations in the U.S. and Europe. The recommended doses for anti-pseudomonal antibiotics may be higher than FDA-approved doses due to PK and PD differences. As a large portion of CF patients will not regain their lung function following an APE, it seems possible that currently available anti-pseudomonal agents are being used sub optimally. As new anti-pseudomonal agents are not currently available, we suggest the need to optimize antibiotic dosing and dosing regimens used to treat pulmonary exacerbations in an effort to improve outcomes for CF patients infected with Pseudomonas aeruginosa. PMID- 23359558 TI - In silico study of human aquaporin AQP11 and AQP12 channels. AB - AQP11 and AQP12 are the most distantly related paralogs of the aquaporin family in human. They share indeed a low sequence similarity with other aquaporins and exhibit a modified N-terminal NPA signature motif. Furthermore, they have an anomalous subcellular localization. The AQP11 and AQP12 biological role remains to be fully clarified and their ability to allow transport of water is still debated. We have built accurate 3D-models for AQP11 and AQP12 and comprehensively compared their sequence and structure to other known aquaporins. In order to investigate whether they appear compatible or not with water permeability, we especially focused on the amino acid composition and electrostatics of their channels, keeping the structure of the low-water efficiency AQP0 as a reference system. Our analysis points out a possible alternative ar/R site and shows that these aquaporins feature unique residues at key pore-lining positions that make the shape, composition and electrostatics of their channel peculiar. Such residues can represent pivotal hints to study and explain the AQP11 and AQP12 biological and molecular function. PMID- 23359559 TI - Bomb Pulse Biology. AB - The past decade has seen an explosion in use of the (14)C bomb-pulse to do fundamental cell biology. Studies in the 1960's used decay counting to measure tissue turnover when the atmospheric (14)C/C concentration was changing rapidly. Today bulk tissue measurements are of marginal interest since most of the carbon in the tissue resides in proteins, lipids and carbohydrates that turn over rapidly. Specific cell types with specialized functions are the focus of cell turnover investigations. Tissue samples need to be fresh or frozen. Fixed or preserved samples contain petroleum-derived carbon that has not been successfully removed. Cell or nuclear surface markers are used to sort specific cell types, typically by fluorescence-activated cell sorting (FACS). Specific biomolecules need to be isolated with high purity and accelerator mass spectrometry (AMS) measurements must accommodate samples that generally contain less than 40 micrograms of carbon. Furthermore, all separations must not add carbon to the sample. Independent means such as UV absorbance must be used to confirm molecule purity. Approaches for separating specific proteins and DNA and combating contamination of undesired molecules are described. PMID- 23359560 TI - A molecular beacon-based signal-off surface-enhanced Raman scattering strategy for highly sensitive, reproducible, and multiplexed DNA detection. PMID- 23359561 TI - Self-activated mesh device using shape memory alloy for periosteal expansion osteogenesis. AB - The present study evaluated the use of this self-activated shape memory alloy (SMA) device, with a focus on its effects in the region under the periosteum. Twelve Japanese white rabbits were used in this study. The device was inserted under the periosteum at the forehead. In the experimental group, the device was pushed, bent, and attached to the bone surface and fixed with a titanium screw. In control group, the device was only inserted under the periosteum. After 14 days, the screw was removed and the mesh was activated in the experimental group. Rabbits were sacrificed 5 and 8 weeks after the operation and newly formed bone was histologically and radiographically evaluated. The quantitative data by the area and the occupation of newly formed bone indicated that the experimental group had a higher volume of new bone than the control group at each consolidation period. Histologically, some newly formed bone was observed and most of the subperiosteal space underneath the device was filled with fibrous tissue, and a thin layer of immature bone was observed in the control group. In the experimental group, multiple dome-shaped bones, outlined by thin and scattered trabeculae, were clearly observed under the SMA mesh device. The use of self-activated devices for the periosteal expansion technique may make it possible to avoid donor site morbidity, trans-skin activation rods, any bone cutting procedure, and the following intermittent activation procedure. PMID- 23359563 TI - The Medtronic Melody(r) transcatheter pulmonary valve implanted at 24-mm diameter -it works. AB - OBJECTIVES: We report the Melody valve implanted and/or expanded to 24-mm diameter. BACKGROUND: The Medtronic Melody valve has been implanted up to 22 mm in the pulmonary position for over a decade. METHODS: A retrospective chart review was performed on 82 patients who underwent Melody valve implant. Technical implant method, pre- and postimplant echocardiographic findings, and initial follow-up were reviewed. RESULTS: Between 04/2008 and 12/2011, 13 Melody valves were successfully implanted in 11 patients, median age 35 years (range 16-61 years), in the pulmonary (bioprosthetic valve, right ventricle to pulmonary artery conduit, native valve) position (n = 9), tricuspid position (bioprosthetic valve n = 3), and aortic position (bioprosthetic valve n = 1). Ten valves were delivered on a 24-mm balloon in balloon catheter and three were implanted using a 22-mm Ensemble balloon delivery system, followed by postdilation using a 24-mm * 2-cm Atlas balloon catheter. Postimplant, the median peak systolic gradient across the pulmonary valve was 7 mm Hg and median gradient across the tricuspid valve was 3 mm Hg. There was no change in gradient across the Melody valve in the aortic position where valve prosthesis-patient mismatch was present. Postimplant intracardiac echocardiography demonstrated none or mild valve regurgitation. No more than mild regurgitation was noted at a median follow-up of 9.5 months. CONCLUSIONS: The Melody valve can be implanted at 24 mm in the stenotic/regurgitant bioprosthetic pulmonary, tricuspid, and aortic valve, dysfunctional right ventricle to pulmonary artery conduit, and the native right ventricular outflow tract, whereas the valve remains competent with only mild regurgitation. PMID- 23359562 TI - The autoimmunity risk variant LYP-W620 cooperates with CSK in the regulation of TCR signaling. AB - The protein tyrosine phosphatase LYP, a key regulator of TCR signaling, presents a single nucleotide polymorphism, C1858T, associated with several autoimmune diseases such as type I diabetes, rheumatoid arthritis, and lupus. This polymorphism changes an R by a W in the P1 Pro rich motif of LYP, which binds to CSK SH3 domain, another negative regulator of TCR signaling. Based on the analysis of the mouse homologue, Pep, it was proposed that LYP and CSK bind constitutively to inhibit LCK and subsequently TCR signaling. The detailed study of LYP/CSK interaction, here presented, showed that LYP/CSK interaction was inducible upon TCR stimulation, and involved LYP P1 and P2 motifs, and CSK SH3 and SH2 domains. Abrogating LYP/CSK interaction did not preclude the regulation of TCR signaling by these proteins. PMID- 23359564 TI - Functional evaluation of a novel vitreous substitute using polyethylene glycol sols injected into a foldable capsular vitreous body. AB - Polyethylene glycol (PEG) is a short-term (41 days) potential vitreous substitute and is too short for an ideal vitreous substitute. Previously, a foldable capsular vitreous body (FCVB) was designed to mimic vitreous function. The aim of this study is to evaluate whether PEG injected into FCVB can serve as a long-term vitreous substitute. In vitro study, a concentration of 5% (w/v) PEG sols showed natural-like mechanical and optical properties in terms of pH, density, light transmittance, refractive index, interfacial tension, viscosity, rheology, and cytotoxicity. Then in vivo tests, 30 rabbits received standard pars plana vitrectomy, of which 12 eyes were implanted with PEG injected into FCVB, nine eyes were injected with PEG sols alone, and nine others were injected with balance salt solution as control. A clinical evaluation of the anterior segment, fundus, and intraocular pressure was measured pre- and postoperatively up to 180 days, which showed that FCVBs had good retina supporting function, except for a higher incidence of cataracts. Gross pathology, hematoxylin and eosin, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining analysis also showed that FCVBs had good biocompatibility, and that all quadrants of the capsular wall fitted well with the retina. This study demonstrated that PEG injected into FCVB can serve as a long-term vitreous substitute and has potential clinical use. PMID- 23359565 TI - Endothelial NOS gene Glu298Asp polymorphism in preterm neonates with respiratory distress syndrome. AB - RATIONALE: Respiratory Distress Syndrome (RDS) due to prematurity is one of the most important causes of morbidity and mortality in Neonatal Intensive Care Units. According to few studies in recent years, endothelial nitric oxide synthase (eNOS) gene polymorphisms are found to be partially responsible for liability to RDS. The purpose of this study was to determine the association between eNOS gene polymorphism and RDS in preterm neonates. PATIENTS AND METHODS: The patient group consisted of 152 premature neonates born before 37 weeks of gestation and diagnosed as RDS. The control group consisted of 125 premature neonates born before 37 weeks of gestation, but was not diagnosed as RDS. Genomic DNA from patients and controls was analyzed by polymerase chain reaction. RESULTS: It was found that Glu/Glu, Glu/Asp, and Asp/Asp genotype frequencies of the eNOS gene polymorphism were 35.2%, 59.2%, and 5.6% of the control group, and 32.9%, 65.1%, and 2.0% of the patient group, respectively (P > 0.05). However, significant increases in Glu/Glu genotype and Glu allele frequencies were noted in the RDS groups when the preterm neonates were divided into two groups (24-30 weeks and 31-36 weeks) by gestational age. Additionally, Glu/Asp genotype and Asp allele were markedly less frequent among the RDS groups (P < 0.05). Asp allele frequency in boys and Glu allele frequency in girls were significantly high in RDS group (P < 0.05). CONCLUSIONS: These data suggest that there were significant gestational age-related differences between RDS and control groups in terms of Glu298Asp polymorphism. Therefore, RDS seems to develop with alterations in eNOS Glu298Asp genotype frequencies in the Turkish population. PMID- 23359566 TI - HLA Class I Expressions on Peripheral Blood Mononuclear Cells in Colorectal Cancer Patients. AB - OBJECTIVE: To investigate the expression change of human leukocyte antigen (HLA) class I on human peripheral blood mononuclear cells (PBMCs) at both mRNA and protein levels, and to evaluate its roles in the development of colorectal cancer (CRC). METHODS: In the present study, 50 patients with CRC, 35 patients with benign colorectal lesion and 42 healthy volunteers were enrolled. Expression levels of HLA class I mRNA and protein were determined using real-time quantitative reverse transcription PCR (RT-PCR) and flow cytometry analysis, respectively. RESULTS: The expression levels of HLA class I mRNA and proteins were not influenced by age and gender. The relative ratios of HLA class I mRNA were 0.99+/-0.27 in healthy controls, 0.76+/-0.19 in benign patients, and 0.48+/ 0.21 in CRC patients. Mean fluorescence intensities of HLA class I were 145.58+/ 38.14 in healthy controls, 102.05+/-35.98 in benign patients and 87.44+/-34.01 in CRC patients. HLA class I on PBMCs was significantly down-regulated at both mRNA and protein levels in patients with stage III and IV CRC. CRC patients with lymph node metastasis also showed a decreased HLA class I expression at protein level. CONCLUSION: HLA class I expressions on PBMCs are associated with staging of CRC and lymph node metastasis. Monitoring the expression of HLA class I on PBMCs may provide useful information for diagnosis and metastasis judgement of CRC. PMID- 23359567 TI - Cell viabilities and biodegradation rates of DNA/protamine complexes with two different molecular weights of DNA. AB - Two types of DNA/protamine complexes were prepared from protamine sulfate and 7000 base pair (bp) DNA or original DNA to investigate the effect of the molecular weight of DNA on zeta potential, cell viability, flowability, soft tissue response, and biodegradation rate. The 7000 bp DNA/protamine complex had a negative charge while the original DNA/protamine complex had a positive charge. The cell viabilities (90.4-106.8%) of these complexes were close to each other. The 7000 bp DNA/protamine complex became a softer dough than that of the original DNA/complex when both were kneaded with water. In vivo, the original DNA/protamine complex showed a milder tissue response. The original DNA/protamine complex almost disappeared 30 days after implantation. The 7000 bp DNA/complex disappeared approximately 2 weeks after implantation and areas where samples were implanted became empty. Thereafter, the empty space was gradually replaced by new soft tissues. The original DNA/protamine complex showed low intercalation and groove binding ratios of daunorubicin hydrochloride. Results indicate that high DNA condensation by cationic protamine protected the penetration of degradation enzymes into these complexes. It was found that a high molecular weight of DNA reduced the biodegradation rate and flowability. This study suggests that DNA/protamine complexes could be candidates for biomaterials that control biodegradation rates and flowability. PMID- 23359568 TI - Synergistic effect of thrombus aspiration and abciximab in primary percutaneous coronary intervention. AB - BACKGROUND: Previous studies failed to assess the individual prognostic role of thrombus aspiration (TA) or abciximab in primary percutaneous coronary intervention (pPCI), due their prevalent combined use. METHODS AND RESULTS: A total of 644 consecutive ST-segment elevation myocardial infarction patients treated with pPCI were included in this retrospective registry from January 2006 to December 2008. Patients were divided in: (a) Group 1, with conventional pPCI; (b) Group 2, with pPCI and abciximab; (c) Group 3, with pPCI and TA; (d) Group 4, with pPCI and abciximab plus TA. Primary end point was the composite of major adverse cardiovascular events (MACEs, defined as overall mortality, myocardial infarction, target vessel revascularization, and major bleedings) at 1 year. Baseline clinical and angiographic characteristics were not different among the groups, with the exception of a younger age in group 4. The two groups of patients treated with TA (group 3 and 4) received more frequently direct stenting (P < 0.001 vs. group 1 for both), presented higher rate of end-procedural TIMI flow grade 3 (P < 0.001 vs. group 1 for both), and lower rate of no-reflow (P = 0.016 and P < 0.001 vs. group 1, respectively). Patients of group 2 presented a borderline nonsignificant trend toward higher rate of end-procedural TIMI flow grade 3 (P = 0.083 vs. group 1). MACEs at 1 year were 43 (29%) in group 1 versus 25 (22%) in group 2 versus 24 (19%) in group 3 versus 32 (13%) in group 4 (log rank P = 0.001). At the multivariate Cox regression analysis, combined TA plus abciximab in group 4 [hazard ratio (HR): 0.48, confidence interval (CI) 95% 0.28 0.84, P = 0.01] and a higher left ventricular ejection fraction (HR: 0.97, CI 95% 0.95-0.98, P < 0.001) were significantly associated with lower MACE rate. CONCLUSIONS: The combination of pharmacologic and mechanic antithrombotic treatment during pPCI was associated with better 1-year clinical outcome. PMID- 23359569 TI - Motor and sensory neuropathy due to myelin infolding and paranodal damage in a transgenic mouse model of Charcot-Marie-Tooth disease type 1C. AB - Charcot-Marie-Tooth disease type 1C (CMT1C) is a dominantly inherited motor and sensory neuropathy. Despite human genetic evidence linking missense mutations in SIMPLE to CMT1C, the in vivo role of CMT1C-linked SIMPLE mutations remains undetermined. To investigate the molecular mechanism underlying CMT1C pathogenesis, we generated transgenic mice expressing either wild-type or CMT1C linked W116G human SIMPLE. Mice expressing mutant, but not wild type, SIMPLE develop a late-onset motor and sensory neuropathy that recapitulates key clinical features of CMT1C disease. SIMPLE mutant mice exhibit motor and sensory behavioral impairments accompanied by decreased motor and sensory nerve conduction velocity and reduced compound muscle action potential amplitude. This neuropathy phenotype is associated with focally infolded myelin loops that protrude into the axons at paranodal regions and near Schmidt-Lanterman incisures of peripheral nerves. We find that myelin infolding is often linked to constricted axons with signs of impaired axonal transport and to paranodal defects and abnormal organization of the node of Ranvier. Our findings support that SIMPLE mutation disrupts myelin homeostasis and causes peripheral neuropathy via a combination of toxic gain-of-function and dominant-negative mechanisms. The results from this study suggest that myelin infolding and paranodal damage may represent pathogenic precursors preceding demyelination and axonal degeneration in CMT1C patients. PMID- 23359571 TI - European perspective of ecosystem services and related policies. AB - In this article, we focus on the importance of terrestrial ecosystems and the services they provide. European Union policies, contributing to the conservation and maintenance of ecosystem services in Europe are discussed and their current impacts briefly reviewed in the light of the main challenges that European ecosystems might face in the near future. PMID- 23359570 TI - Missense mutations in beta-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker-Warburg syndrome. AB - Several known or putative glycosyltransferases are required for the synthesis of laminin-binding glycans on alpha-dystroglycan (alphaDG), including POMT1, POMT2, POMGnT1, LARGE, Fukutin, FKRP, ISPD and GTDC2. Mutations in these glycosyltransferase genes result in defective alphaDG glycosylation and reduced ligand binding by alphaDG causing a clinically heterogeneous group of congenital muscular dystrophies, commonly referred to as dystroglycanopathies. The most severe clinical form, Walker-Warburg syndrome (WWS), is characterized by congenital muscular dystrophy and severe neurological and ophthalmological defects. Here, we report two homozygous missense mutations in the beta-1,3-N acetylglucosaminyltransferase 1 (B3GNT1) gene in a family affected with WWS. Functional studies confirmed the pathogenicity of the mutations. First, expression of wild-type but not mutant B3GNT1 in human prostate cancer (PC3) cells led to increased levels of alphaDG glycosylation. Second, morpholino knockdown of the zebrafish b3gnt1 orthologue caused characteristic muscular defects and reduced alphaDG glycosylation. These functional studies identify an important role of B3GNT1 in the synthesis of the uncharacterized laminin-binding glycan of alphaDG and implicate B3GNT1 as a novel causative gene for WWS. PMID- 23359573 TI - Recommended childhood and adolescent immunization schedule--United States, 2013. PMID- 23359572 TI - Isolation and characterization of antibody fragments selective for specific protein morphologies from nanogram antigen samples. AB - We developed atomic force microscope (AFM)-based protocols that enable isolation and characterization of antibody-based reagents that selectively bind target protein variants using low nanogram amounts or less of unpurified starting material. We isolated single-chain antibody fragments (scFvs) that specifically recognize an oligomeric beta-amyloid (Abeta) species correlated with Alzheimer's disease (AD) using only a few nanograms of an enriched but not purified sample obtained from human AD brain tissue. We used several subtractive panning steps to remove all phage binding nondesired antigens and then used a single positive panning step using minimal antigen. We also used AFM to characterize the specificity of the isolated clones, again using minimal material, selecting the C6 scFv based on expression levels. We show that C6 selectively binds cell and brain-derived oligomeric Abeta. The protocols described are readily adapted to isolating antibody-based reagents against other antigenic targets with limited availability. PMID- 23359574 TI - Management of newly diagnosed type 2 Diabetes Mellitus (T2DM) in children and adolescents. AB - Over the past 3 decades, the prevalence of childhood obesity has increased dramatically in North America, ushering in a variety of health problems, including type 2 diabetes mellitus (T2DM), which previously was not typically seen until much later in life. The rapid emergence of childhood T2DM poses challenges to many physicians who find themselves generally ill-equipped to treat adult diseases encountered in children. This clinical practice guideline was developed to provide evidence-based recommendations on managing 10- to 18-year old patients in whom T2DM has been diagnosed. The American Academy of Pediatrics (AAP) convened a Subcommittee on Management of T2DM in Children and Adolescents with the support of the American Diabetes Association, the Pediatric Endocrine Society, the American Academy of Family Physicians, and the Academy of Nutrition and Dietetics (formerly the American Dietetic Association). These groups collaborated to develop an evidence report that served as a major source of information for these practice guideline recommendations. The guideline emphasizes the use of management modalities that have been shown to affect clinical outcomes in this pediatric population. Recommendations are made for situations in which either insulin or metformin is the preferred first-line treatment of children and adolescents with T2DM. The recommendations suggest integrating lifestyle modifications (ie, diet and exercise) in concert with medication rather than as an isolated initial treatment approach. Guidelines for frequency of monitoring hemoglobin A1c (HbA1c) and finger-stick blood glucose (BG) concentrations are presented. Decisions were made on the basis of a systematic grading of the quality of evidence and strength of recommendation. The clinical practice guideline underwent peer review before it was approved by the AAP. This clinical practice guideline is not intended to replace clinical judgment or establish a protocol for the care of all children with T2DM, and its recommendations may not provide the only appropriate approach to the management of children with T2DM. Providers should consult experts trained in the care of children and adolescents with T2DM when treatment goals are not met or when therapy with insulin is initiated. The AAP acknowledges that some primary care clinicians may not be confident of their ability to successfully treat T2DM in a child because of the child's age, coexisting conditions, and/or other concerns. At any point at which a clinician feels he or she is not adequately trained or is uncertain about treatment, a referral to a pediatric medical subspecialist should be made. If a diagnosis of T2DM is made by a pediatric medical subspecialist, the primary care clinician should develop a comanagement strategy with the subspecialist to ensure that the child continues to receive appropriate care consistent with a medical home model in which the pediatrician partners with parents to ensure that all health needs are met. PMID- 23359575 TI - Nine-year follow-up of a home-visitation program: a randomized trial. AB - OBJECTIVE: To evaluate the extent to which a home-visitation program (Early Start) had benefits for child abuse, child behavior, and parental- and family level benefits to the 9-year follow-up. METHODS: A randomized controlled trial in which 220 families receiving Early Start were contrasted with a control series of 223 families not receiving the program. Families were enrolled in the program for up to 5 years. Outcomes were assessed at 6 months, annually from 1 year to 6 years, and at 9 years after trial entry. RESULTS: Comparisons between the Early Start and control series showed that families in the Early Start program showed significant (P < .05) benefits in reduced risk of hospital attendance for unintentional injury, lower risk of parent-reported harsh punishment, lower levels of physical punishment, higher parenting competence scores, and more positive child behavioral adjustment scores. Effect sizes (Cohen's "d") ranged from 0.13 to 0.29 (median = 0.25). There were no significant differences (all P values > .05) between the Early Start and control series on a range of measures of parental behavior and family outcomes, including maternal depression, parental substance use, intimate partner violence, adverse economic outcomes, and life stress. CONCLUSIONS: The Early Start program was associated with small to moderate benefits in a range of areas relating to child abuse, physical punishment, child behavior, and parenting competence. There was little evidence to suggest that the Early Start program had benefits that extended to the level of parents or family overall. PMID- 23359577 TI - Infant feeding and transmission of human immunodeficiency virus in the United States. AB - Physicians caring for infants born to women infected with HIV are likely to be involved in providing guidance to HIV-infected mothers on appropriate infant feeding practices. It is critical that physicians are aware of the HIV transmission risk from human milk and the current recommendations for feeding HIV exposed infants in the United States. Because the only intervention to completely prevent HIV transmission via human milk is not to breastfeed, in the United States, where clean water and affordable replacement feeding are available, the American Academy of Pediatrics recommends that HIV-infected mothers not breastfeed their infants, regardless of maternal viral load and antiretroviral therapy. PMID- 23359576 TI - Guidance on management of asymptomatic neonates born to women with active genital herpes lesions. AB - Herpes simplex virus (HSV) infection of the neonate is uncommon, but genital herpes infections in adults are very common. Thus, although treating an infant with neonatal herpes is a relatively rare occurrence, managing infants potentially exposed to HSV at the time of delivery occurs more frequently. The risk of transmitting HSV to an infant during delivery is determined in part by the mother's previous immunity to HSV. Women with primary genital HSV infections who are shedding HSV at delivery are 10 to 30 times more likely to transmit the virus to their newborn infants than are women with recurrent HSV infection who are shedding virus at delivery. With the availability of commercial serological tests that reliably can distinguish type-specific HSV antibodies, it is now possible to determine the type of maternal infection and, thus, further refine management of infants delivered to women who have active genital HSV lesions. The management algorithm presented herein uses both serological and virological studies to determine the risk of HSV transmission to the neonate who is delivered to a mother with active herpetic genital lesions and tailors management accordingly. The algorithm does not address the approach to asymptomatic neonates delivered to women with a history of genital herpes but no active lesions at delivery. PMID- 23359578 TI - Symptoms and otoscopic signs in bilateral and unilateral acute otitis media. AB - OBJECTIVE: Bilateral acute otitis media (AOM) is considered more severe than unilateral AOM, and several guidelines recommend more active treatment and/or follow-up of bilateral AOM. We studied whether bilateral AOM is a clinically more severe illness than unilateral AOM by comparing symptoms and otoscopic signs between bilateral and unilateral AOM. METHODS: Two hundred thirty-two children aged 6 to 35 months diagnosed with AOM were eligible. We surveyed the symptoms with a structured questionnaire and recorded the otoscopic signs systematically. RESULTS: Ninety-eight children had bilateral and 134 children unilateral AOM. Children with bilateral AOM were more often <24 months than children with unilateral AOM (87% vs 75%; P = .032). Fever (>=38 degrees C) occurred in 54% and 36% (P = .006) and severe conjunctivitis in 16% and 44% (P = .047) of children with bilateral and unilateral AOM, respectively. In 15 other symptoms, we found no overall differences even when adjusted with age. We observed the following severe otoscopic signs in the bilateral and unilateral AOM group, respectively: moderate/marked bulging of tympanic membrane (63% and 40%; P = .001), purulent effusion (89% and 71%; P = .001), bulla formation (11% and 10%; P = .707), and hemorrhagic redness of tympanic membrane (7% and 10%; P = .386). CONCLUSIONS: Bilateral AOM seems to be a clinically only slightly more severe illness than unilateral AOM. Therefore, when assessing AOM severity, bilaterality should not be used as a determining criterion; instead, the child's symptomatic condition together with otoscopic signs should also be taken into consideration. PMID- 23359579 TI - Validation of rapid neurodevelopmental assessment for 2- to 5-year-old children in Bangladesh. AB - OBJECTIVE: Validate a tool to determine neurodevelopmental impairments (NDIs) in >2- to 5-year-old children in a country with limited child development expertise. METHODS: Rapid Neurodevelopmental Assessment (RNDA) is a tool designed to detect functional status and NDIs across multiple neurodevelopmental domains. Validity was determined in 77 children enrolled by door-to-door sampling in Dhaka and who were administered the RNDA by 1 of 6 testers (4 developmental therapists, 2 special education teachers) and simultaneously administered a test of adaptive behavior (AB; Independent Behavior Assessment Scale) and intelligence quotient (IQ) tests (Bayley Scales of Infant Development II, Stanford Binet Intelligence Scale, Wechsler Preschool and Primary Scales of Intelligence) by psychologists. RESULTS: Interrater reliability ranged from good to excellent. There were significant differences in AB in mean percentile scores on the Independent Behavior Assessment Scale for motor (P = .0001), socialization (P = .001), communication (P = .001), and full-scale (P = .001) scores in children with >=1 NDI ("any NDI") versus no NDI. Significant differences in those with versus those without "any NDI" were found on IQ scores. Sensitivity and specificity for "significant difficulties" (defined as AB z-scores < -2 SDs and/or IQ <70) and "mild difficulties included" (AB z-scores < -1SD and/or IQ <85) were 90% and 60% and 80% and 76%, respectively. CONCLUSIONS: The RNDA validity results are promising for use by child care professionals in field and clinical settings, but the tool needs further replication and refinement for assessment of specific impairments of vision, hearing, and seizures. PMID- 23359580 TI - Physician advice to adolescents about drinking and other health behaviors. AB - BACKGROUND: This report assessed the proportion of US 10th graders (average age, 16) who saw a physician in the past year and were asked and given advice about their drinking. We hypothesized that advice would vary by whether students were asked about drinking and their drinking, bingeing, and drunkenness frequency. METHODS: A nationally representative sample of 10th graders in 2010 (N = 2519) were asked their past 30-day frequency of drinking, bingeing, and intoxication and whether, during their last medical examination, their drinking was explored and they received advice about alcohol's risks and reducing or stopping. RESULTS: In the past month, 36% reported drinking, 28% reported bingeing, and 23% reported drunkenness (11%, 5%, and 7%, respectively, 6 or more times). In the past year, 82% saw a doctor. Of that group, 54% were asked about drinking, 40% were advised about related harms, and 17% were advised to reduce or stop. Proportions seeing a doctor and asked about drinking were similar across drinking patterns. Respondents asked about drinking were more often advised to reduce or stop. Frequent drinkers, bingers, and those drunk were more often advised to reduce or stop. Nonetheless, only 25% of them received that advice from physicians. In comparison, 36% of frequent smokers, 27% of frequent marijuana users, and 42% of frequent other drug users were advised to reduce or quit those behaviors. CONCLUSIONS: Efforts are warranted to increase the proportion of physicians who follow professional guidelines to screen and counsel adolescents about unhealthy alcohol use and other behaviors that pose health risks. PMID- 23359581 TI - Surfactant administration via thin catheter during spontaneous breathing: randomized controlled trial. AB - BACKGROUND: The primary aim of this randomized study was to describe the feasibility of early administration of surfactant via a thin catheter during spontaneous breathing (Take Care) and compare early mechanical ventilation (MV) requirement with the InSurE (Intubate, Surfactant, Extubate) procedure. METHODS: Preterm infants, who were <32 weeks and stabilized with nasal continuous positive airway pressure (nCPAP) in the delivery room, were randomized to receive early surfactant treatment either by the Take Care or InSurE technique. Tracheal instillation of 100 mg/kg poractant alpha via 5-F catheter during spontaneous breathing under nCPAP was performed in the intervention group. In the InSurE procedure, infants were intubated, received positive pressure ventilation for 30 seconds after surfactant instillation, and placed on nCPAP immediately. RESULTS: One hundred infants in each group were analyzed. The MV requirement in the first 72 hours of life was significantly lower in the Take Care group when compared with the InSurE group (30% vs 45%, P = .02, odds ratio -0.52, 95% confidence interval -0.94 to -0.29). Mean duration of both nCPAP and MV were significantly shorter in the Take Care group (P values .006 and .002, respectively). Bronchopulmonary dysplasia rate was significantly lower among the infants treated with the Take Care technique (relative risk -0.27, 95% confidence interval -0.1 to -0.72) CONCLUSIONS: The Take Care technique is feasible for the treatment of respiratory distress syndrome in infants with very low birth weight. It significantly reduces both the need and duration of MV, and thus the bronchopulmonary dysplasia rate in preterm infants. PMID- 23359582 TI - Parental leave for residents and pediatric training programs. AB - The American Academy of Pediatrics (AAP) is committed to the development of rational, equitable, and effective parental leave policies that are sensitive to the needs of pediatric residents, families, and developing infants and that enable parents to spend adequate and good-quality time with their young children. It is important for each residency program to have a policy for parental leave that is written, that is accessible to residents, and that clearly delineates program practices regarding parental leave. At a minimum, a parental leave policy for residents and fellows should conform legally with the Family Medical Leave Act as well as with respective state laws and should meet institutional requirements of the Accreditation Council for Graduate Medical Education for accredited programs. Policies should be well formulated and communicated in a culturally sensitive manner. The AAP advocates for extension of benefits consistent with the Family Medical Leave Act to all residents and interns beginning at the time that pediatric residency training begins. The AAP recommends that regardless of gender, residents who become parents should be guaranteed 6 to 8 weeks, at a minimum, of parental leave with pay after the infant's birth. In addition, in conformance with federal law, the resident should be allowed to extend the leave time when necessary by using paid vacation time or leave without pay. Coparenting, adopting, or fostering of a child should entitle the resident, regardless of gender, to the same amount of paid leave (6-8 weeks) as a person who takes maternity/paternity leave. Flexibility, creativity, and advanced planning are necessary to arrange schedules that optimize resident education and experience, cultivate equity in sharing workloads, and protect pregnant residents from overly strenuous work experiences at critical times of their pregnancies. PMID- 23359583 TI - Prehypertension and hypertension in community-based pediatric practice. AB - OBJECTIVE: To examine the prevalence of prehypertension and hypertension among children receiving well-child care in community-based practices. METHODS: Children aged 3 to 17 years with measurements of height, weight, and blood pressure (BP) obtained at an initial (index) well-child visit between July 2007 and December 2009 were included in this retrospective cohort study across 3 large, integrated health care delivery systems. Index BP classification was based on the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents: normal BP, <90th percentile; prehypertension, 90th to 94th percentile; hypertension, 3 BP measurements >=95th percentile (index and 2 subsequent consecutive visits). RESULTS: The cohort included 199 513 children (24.3% aged 3-5 years, 34.5% aged 6-11 years, and 41.2% aged 12-17 years) with substantial racial/ethnic diversity (35.9% white, 7.8% black, 17.6% Hispanic, 11.7% Asian/Pacific Islander, and 27.0% other/unknown race). At the index visit, 81.9% of participants were normotensive, 12.7% had prehypertension, and 5.4% had a BP in the hypertension range (>=95th percentile). Of the 10 848 children with an index hypertensive BP level, 3.8% of those with a follow-up BP measurement had confirmed hypertension (estimated 0.3% prevalence). Increasing age and BMI were significantly associated with prehypertension and confirmed hypertension (P < .001 for trend). Among racial/ethnic groups, blacks and Asians had the highest prevalence of hypertension. CONCLUSIONS: The prevalence of hypertension in this community-based study is lower than previously reported from school-based studies. With the size and diversity of this cohort, these results suggest the prevalence of hypertension in children may actually be lower than previously reported. PMID- 23359584 TI - Management of type 2 diabetes mellitus in children and adolescents. AB - OBJECTIVE: Over the last 3 decades, the prevalence of childhood obesity has increased dramatically in North America, ushering in a variety of health problems, including type 2 diabetes mellitus (T2DM), which previously was not typically seen until much later in life. This technical report describes, in detail, the procedures undertaken to develop the recommendations given in the accompanying clinical practice guideline, "Management of Type 2 Diabetes Mellitus in Children and Adolescents," and provides in-depth information about the rationale for the recommendations and the studies used to make the clinical practice guideline's recommendations. METHODS: A primary literature search was conducted relating to the treatment of T2DM in children and adolescents, and a secondary literature search was conducted relating to the screening and treatment of T2DM's comorbidities in children and adolescents. Inclusion criteria were prospectively and unanimously agreed on by members of the committee. An article was eligible for inclusion if it addressed treatment (primary search) or 1 of 4 comorbidities (secondary search) of T2DM, was published in 1990 or later, was written in English, and included an abstract. Only primary research inquiries were considered; review articles were considered if they included primary data or opinion. The research population had to constitute children and/or adolescents with an existing diagnosis of T2DM; studies of adult patients were considered if at least 10% of the study population was younger than 35 years. All retrieved titles, abstracts, and articles were reviewed by the consulting epidemiologist. RESULTS: Thousands of articles were retrieved and considered in both searches on the basis of the aforementioned criteria. From those, in the primary search, 199 abstracts were identified for possible inclusion, 58 of which were retained for systematic review. Five of these studies were classified as grade A studies, 1 as grade B, 20 as grade C, and 32 as grade D. Articles regarding treatment of T2DM selected for inclusion were divided into 4 major subcategories on the basis of type of treatment being discussed: (1) medical treatments (32 studies); (2) nonmedical treatments (9 studies); (3) provider behaviors (8 studies); and (4) social issues (9 studies). From the secondary search, an additional 336 abstracts relating to comorbidities were identified for possible inclusion, of which 26 were retained for systematic review. These articles included the following: 1 systematic review of literature regarding comorbidities of T2DM in adolescents; 5 expert opinions presenting global recommendations not based on evidence; 5 cohort studies reporting natural history of disease and comorbidities; 3 with specific attention to comorbidity patterns in specific ethnic groups (case-control, cohort, and clinical report using adult literature); 3 reporting an association between microalbuminuria and retinopathy (2 case-control, 1 cohort); 3 reporting the prevalence of nephropathy (cohort); 1 reporting peripheral vascular disease (case series); 2 discussing retinopathy (1 case-control, 1 position statement); and 3 addressing hyperlipidemia (American Heart Association position statement on cardiovascular risks; American Diabetes Association consensus statement; case series). A breakdown of grade of recommendation shows no grade A studies, 10 grade B studies, 6 grade C studies, and 10 grade D studies. With regard to screening and treatment recommendations for comorbidities, data in children are scarce, and the available literature is conflicting. Therapeutic recommendations for hypertension, dyslipidemia, retinopathy, microalbuminuria, and depression were summarized from expert guideline documents and are presented in detail in the guideline. The references are provided, but the committee did not independently assess the supporting evidence. Screening tools are provided in the Supplemental Information. PMID- 23359585 TI - Exposure to alcohol advertisements and teenage alcohol-related problems. AB - OBJECTIVE: This study used prospective data to test the hypothesis that exposure to alcohol advertising contributes to an increase in underage drinking and that an increase in underage drinking then leads to problems associated with drinking alcohol. METHODS: A total of 3890 students were surveyed once per year across 4 years from the 7th through the 10th grades. Assessments included several measures of exposure to alcohol advertising, alcohol use, problems related to alcohol use, and a range of covariates, such as age, drinking by peers, drinking by close adults, playing sports, general TV watching, acculturation, parents' jobs, and parents' education. RESULTS: Structural equation modeling of alcohol consumption showed that exposure to alcohol ads and/or liking of those ads in seventh grade were predictive of the latent growth factors for alcohol use (past 30 days and past 6 months) after controlling for covariates. In addition, there was a significant total effect for boys and a significant mediated effect for girls of exposure to alcohol ads and liking of those ads in 7th grade through latent growth factors for alcohol use on alcohol-related problems in 10th grade. CONCLUSIONS: Younger adolescents appear to be susceptible to the persuasive messages contained in alcohol commercials broadcast on TV, which sometimes results in a positive affective reaction to the ads. Alcohol ad exposure and the affective reaction to those ads influence some youth to drink more and experience drinking-related problems later in adolescence. PMID- 23359586 TI - Quantitative brain electrical activity in the initial screening of mild traumatic brain injuries. AB - INTRODUCTION: The incidence of emergency department (ED) visits for Traumatic Brain Injury (TBI) in the United States exceeds 1,000,000 cases/year with the vast majority classified as mild (mTBI). Using existing computed tomography (CT) decision rules for selecting patients to be referred for CT, such as the New Orleans Criteria (NOC), approximately 70% of those scanned are found to have a negative CT. This study investigates the use of quantified brain electrical activity to assess its possible role in the initial screening of ED mTBI patients as compared to NOC. METHODS: We studied 119 patients who reported to the ED with mTBI and received a CT. Using a hand-held electroencephalogram (EEG) acquisition device, we collected data from frontal leads to determine the likelihood of a positive CT. The brain electrical activity was processed off-line to generate an index (TBI-Index, biomarker). This index was previously derived using an independent population, and the value found to be sensitive for significant brain dysfunction in TBI patients. We compared this performance of the TBI-Index to the NOC for accuracy in prediction of positive CT findings. RESULTS: Both the brain electrical activity TBI-Index and the NOC had sensitivities, at 94.7% and 92.1% respectively. The specificity of the TBI-Index was more than twice that of NOC, 49.4% and 23.5% respectively. The positive predictive value, negative predictive value and the positive likelihood ratio were better with the TBI-Index. When either the TBI-Index or the NOC are positive (combining both indices) the sensitivity to detect a positive CT increases to 97%. CONCLUSION: The hand-held EEG device with a limited frontal montage is applicable to the ED environment and its performance was superior to that obtained using the New Orleans criteria. This study suggests a possible role for an index of brain function based on EEG to aid in the acute assessment of mTBI patients. PMID- 23359587 TI - In vivo biological responses to silk proteins functionalized with bone sialoprotein. AB - Recombinant 6mer + BSP protein, combining six repeats of the consensus sequence for Nephila clavipes dragline (6mer) and bone sialoprotein sequence (BSP), shows good support for cell viability and induces the nucleation of hydroxyapatite and tricalcium phosphate during osteoblast in vitro culture. The present study is conducted to characterize this bioengineered protein-based biomaterial further for in vivo behavior related to biocompatibility. 6mer + BSP protein films are implanted in subcutaneous pouches in the back of mice and responses are evaluated by flow cytometry and histology. The results show no major differences between the inflammatory responses induced by 6mer + BSP films and the responses observed for the controls. Thus, this new chimeric protein could represent an alternative for bone regeneration applications. PMID- 23359588 TI - Biocompatibility studies and characterization of poly(3-hydroxybutyrate-co-3 hydroxyhexanoate)/polycaprolactone blends. AB - Poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) is a biocompatible and bioresorbable copolymer that has generated research interest as a bone scaffold material. However, its brittleness and degradation characteristics can be improved upon. We hypothesized that blending with medical-grade polycaprolactone (PCL) can improve degradation and mechanical characteristics. Here, we report the development of solvent-blended PHBHHx/PCL for application as a potential biomaterial for tissue engineering. Enhanced yield strength, yield strain and Young's modulus occurred at 30/70 blend when compared with PHBHHx and PCL. Polarized light microscopy demonstrated PHBHHx and PCL to exist as morphologically and optically distinct phases and, together with thermal analyses, revealed immiscibility. Hydrophilicity improved with the addition of PCL. Accelerated hydrolytic studies suggested predictable behavior of PHBHHx/PCL. Notably, 30/70 blend exhibited similar degradation behavior to PCL in terms of changes in crystallinity, molecular weight, morphology, and mass loss. Finally, human fetal mesenchymal stem cells (hfMSCs) were evaluated on PHBHHx/PCL using live/dead assay and results suggested encouraging hfMSC adhesion and proliferative capacity, with near-confluence occurring in PHBHHx and 30/70 blend after 5 days. Taken together, these are encouraging results for the further development of PHBHHx/PCL as a potential biomaterial for tissue engineering. PMID- 23359589 TI - Stent angioplasty to relieve left pulmonary artery obstruction caused by patent ductus arteriosus device occlusion: bipartisan teamwork by two interventional devices. AB - A 7-month-old patient in congestive heart failure due to a moderate sized patent ductus arteriosus (PDA) underwent uncomplicated implantation of an Amplatzer Ductal Occluder (ADO1). Two months after percutaneous device PDA closure, left pulmonary artery (LPA) stenosis was discovered. Rather than spontaneous improvement as reported in previous cases, our patient's LPA stenosis progressed in severity 7 months after ADO1 placement. A catheterization demonstrated a 32 mm Hg peak gradient from her main pulmonary artery to her LPA. She underwent successful stent angioplasty of her LPA with an excellent result and preserved PDA closure. This case demonstrates that stent angioplasty is a feasible an effective method of relieving LPA obstruction caused by a PDA occluder device. Additionally, despite slight deflection by the stent, the ADO1 device continued to provide complete ductal closure. Stent angioplasty should be considered in patients who have LPA stenosis caused by ADO1 occluder device that does not improve over time. PMID- 23359590 TI - The Toll-like receptor 9 ligand, CpG oligodeoxynucleotide, attenuates cardiac dysfunction in polymicrobial sepsis, involving activation of both phosphoinositide 3 kinase/Akt and extracellular-signal-related kinase signaling. AB - BACKGROUND: Toll-like receptors (TLRs) play a role in the pathophysiology of sepsis and multiple organ failure. This study examined the effect of CpG oligodeoxynucleotide (CpG-ODN), the TLR9 ligand, on polymicrobial sepsis-induced cardiac dysfunction. METHODS: Male C57BL/6 mice were treated with CpG-ODN, control CpG-ODN (control-ODN), or inhibitory CpG-ODN (iCpG-ODN) 1 hour prior to cecal ligation and puncture (CLP)-induced sepsis. Mice that underwent sham surgery served as sham controls. Cardiac function was examined by echocardiography before and 6 hours after CLP. RESULTS: Cardiac function was significantly decreased 6 hours after CLP. CpG-ODN prevented CLP-induced cardiac dysfunction, as evidenced by maintenance of the ejection fraction and fractional shortening. Control-ODN or iCpG-ODN did not alter CLP-induced cardiac dysfunction. CpG-ODN significantly attenuated CLP-induced myocardial apoptosis and increased myocardial Akt and extracellular-signal-related kinase (ERK) phosphorylation levels following CLP. In vitro experiments demonstrated that CpG ODN promotes an association between TLR9 and Ras, resulting in Akt and ERK phosphorylation. Inhibition of phosphoinositide 3-kinase (PI3K) by Ly294002 or inhibition of ERK by U0126 in vivo abolished CpG-ODN attenuation of CLP-induced cardiac dysfunction. CONCLUSIONS: CpG-ODN prevents CLP-induced cardiac dysfunction, in part through activation of PI3K/Akt and ERK signaling. Modulation of TLR9 could be an effective approach for treatment of cardiovascular dysfunction in patients with sepsis or septic shock. PMID- 23359591 TI - Role of interleukin 6 in innate immunity to Mycobacterium tuberculosis infection. AB - BACKGROUND: Mycobacterium tuberculosis can grow in the hostile intracellular environment of macrophages by actively evading macrophage-associated antibacterial activities. The stress response factor SigH contributes to this process by modulating beta-chemokine and interleukin 6 (Il6) expression. Hence, Il6 is of critical importance for acquired immunity against M. tuberculosis infection. Here, we attempted to better characterize the role of Il6 in the immune response to M. tuberculosis infection. METHODS: A small interfering RNA based approach was used to silence expression of the Il6 transcript in host macrophages infected with a wild-type strain of M. tuberculosis or an attenuated mutant strain of M. tuberculosis (Mtb:Delta-sigH). The outcome was measured by the analysis of bacterial burden and transcriptome-wide analysis of host gene expression. Transcriptome results were confirmed via quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Wild type and Mtb:Delta-sigH infection of host macrophages in which Il6 had been silenced resulted in increased expression of interferon-inducible genes, especially those involved in type I interferon signaling. The expression of Ly-6 genes was significantly higher in cells infected with Mtb:Delta-sigH, compared with those infected with the wild-type strain (P < .05). CONCLUSIONS: M. tuberculosis regulates host Il6 production to inhibit type I interferon signaling and, consequently, disease progression. Mtb:Delta-sigH is associated with delayed activation of macrophages, compared with the wild-type strain, and with delayed inflammatory stimuli as consequence. These findings have important implications for improving understanding of the mechanisms behind M. tuberculosis virulence and pathogenesis and provide an initial road map to further investigate the mechanisms that may account for the deleterious effects of type I interferons in M. tuberculosis infection. PMID- 23359593 TI - Depolymerization of cytokeratin intermediate filaments facilitates intracellular infection of HeLa cells by Bartonella henselae. AB - Bartonella henselae is capable of invading epithelial and endothelial cells by modulating the function of actin-dependent cytoskeleton proteins. Although understanding of the pathogenesis has been increased by the development of an in vitro infection model involving endothelial cells, little is known about the mechanism of interaction between B. henselae and epithelial cells. This study aims to identify the binding candidates of B. henselae in epithelial cells and explores their effect on B. henselae infection. Pull-down assays and mass spectrometry analysis confirmed that some of the binding proteins (keratin 14, keratin 6, and F-actin) are cytoskeleton associated. B. henselae infection significantly induces the expression of the cytokeratin genes. Chemical disruption of the keratin network by using ethylene glycol tetraacetic acid promotes the intracellular persistence of B. henselae in HeLa cells. However, cytochalasin B and phalloidin treatment inhibits B. henselae invasion. Immunofluorescent staining demonstrates that B. henselae infection induces an F actin-dependent rearrangement of the cytoskeleton. However, we demonstrated via immunofluorescent staining and whole-mount cell electron microscopy that keratin intermediate filaments are depolymerized by B. henselae. The results indicate that B. henselae achieves an intracellular persistence in epithelial cells through the depolymerization of cytokeratin intermediate filaments that are protective against B. henselae invasion. PMID- 23359592 TI - Intestinal epithelial restitution after TcdB challenge and recovery from Clostridium difficile infection in mice with alanyl-glutamine treatment. AB - BACKGROUND: Clostridium difficile is an anaerobic bacterium that causes antibiotic-associated diarrhea. It produces toxin A and toxin B (TcdB), which cause injury to the gut epithelium. Glutamine is a fundamental fuel for enterocytes, maintaining intestinal mucosal health. Alanyl-glutamine (AQ) is a highly soluble dipeptide derivative of glutamine. We studied whether administration of AQ ameliorates the effects of TcdB in the intestinal cells and improves the outcome of C. difficile infection in mice. METHODS: WST-1 proliferation and cell-wounding-migration assays were assessed in IEC-6 cells exposed to TcdB, with or without AQ. Apoptosis and necrosis were assessed using Annexin V and flow cytometry. C57BL/6 mice were infected with VPI 10463 and treated with either vancomycin, AQ, or vancomycin with AQ. Intestinal tissues were collected for histopathologic analysis, apoptosis staining, and determination of myeloperoxidase activity. RESULTS: AQ increased proliferation in intestinal cells exposed to TcdB, improved migration at 24 and 48 hours, and reduced apoptosis in intestinal cells challenged with TcdB. Infected mice treated with vancomycin and AQ had better survival and histopathologic findings than mice treated with vancomycin alone. CONCLUSIONS: AQ may reduce intestinal mucosal injury in C. difficile-infected mice by partially reversing the effects of TcdB on enterocyte proliferation, migration, and apoptosis, thereby improving survival from C. difficile infection. PMID- 23359594 TI - Introduction: past, present, and future care of individuals with XXY. PMID- 23359595 TI - Is it all the X: familial learning dysfunction and the impact of behavioral aspects of the phenotypic presentation of XXY? AB - The behavioral phenotype of children with XXY has not been extensively studied until recently and this research has been confounded by insufficient study populations and ascertainment biases. The aim of the study was to expand the behavioral aspect of the XXY phenotype as well as investigate the role of existing familial learning disabilities (FLD) on behavioral problems. Behavioral phenotype of XXY includes social anxiety, ADHD, social communication, and atypical peer interactions. The Child Behavior Checklist (CBCL), Social Responsiveness Scale (SRS), and Gilliam Autism Rating Scale (GARS) were completed by the parents of 54 boys with XXY who had not received hormonal replacement prior to participation. Our findings suggest fewer behavioral deficits and lower severity in the general 47,XXY population than previously published and found significant differences between the groups with a positive FLD on the behavioral assessments. Findings demonstrate that boys with FLD exhibit an increased incidence and severity of behavioral problems. Our study expands on the findings of Samango-Sprouse et al. [Samango-Sprouse et al. (2012b) J Intellect Disabil Res] and the significant influence that FLD has on not only neurodevelopment, but also behavioral deficits. Our study suggests that part of the XXY phenotypic profile may be modulated by FLD. Further study is underway to examine the interaction between the many salient factors effecting behavioral and neurodevelopmental progression in XXY and variant forms. (c) 2013 Wiley Periodicals, Inc. PMID- 23359596 TI - Musculoskeletal anomalies in a large cohort of boys with 49, XXXXY. AB - 49, XXXXY is a rare aneuploidy and variant of Klinefelter syndrome, occurring in 1 per 80,000-100,000 live births. We present a cohort of 40 affected males, focusing on musculoskeletal problems. Subjects were participants in an annual 49er family support group meeting. Children were examined in a multidisciplinary clinic by a pediatric neurologist and geneticist, a pediatric orthopedist, a neurodevelopmentalist, and two physical therapists. The patient data were collected from this clinic from 2004 to 2012. All patients were required to have karyotypes that confirmed the presence of XXXXY. There was a high prevalence of musculoskeletal disorders, particularly hypotonia (34 patients [85%]), radioulnar synostosis (30 [75%]), pes planus (26 [65%]), asymmetric hip rotation (27 [67.5%]), and clinodactyly (24 [60%]). Other, less common lower-extremity disorders, included, 5 patients (12.5%) with unilateral club foot, 5 boys (12.5%) with pes cavus, 10 patients (25%) genu valgum and 2 children with genu varus (5%). To our knowledge, this is the first large cohort of boys with 49, XXXXY that focuses on musculoskeletal disorders. There was an increased incidence of hypotonia, clubfoot, avascular necrosis of the femoral head, radioulnar synostosis, and pes planus compared to the normative population. Boys with 49, XXXXY would benefit from multidisciplinary evaluations, particularly from pediatric orthopedists, physical therapists, neurologists, and geneticists for appropriate medical care. PMID- 23359597 TI - Prenatal diagnosis and 47,XXY. AB - In this contribution, we consider detection of 47,XXY by a variety of available methods. These include traditional invasive procedures, screening with maternal serum analytes and fetal ultrasound, and most recently cell-free fetal DNA. Since its introduction in the late 1960s, prenatal genetic diagnosis has evolved greatly. Serendipitious detection of 47,XXY was not infrequent when prenatal genetic diagnosis routinely involved testing by the invasive procedures CVS and amniocentesis. In 2013 this is much less common and relatively few pregnancies in the U.S. and Europe are tested without prior screening protocols, traditionally maternal serum analyte and fetal ultrasound (NT). These protocols are not designed to identify 47,XXY or other X-chromosome aneuploides and with screening by analysis of cell-free DNA in maternal blood, this situation may or may not be altered. Increased numbers of cases could be detected if intake increases and vendors offer information on 47,XXY. A further consideration is that ability of array CGH to detect microdeletions or microduplications below resolution of a karyotype could make return to direct testing using an invasive procedure attractive. PMID- 23359599 TI - PEG-modified macroporous poly(glycidyl methacrylate) and poly(2-hydroxyethyl methacrylate) microspheres to reduce non-specific protein adsorption. AB - To minimize non-specific protein adsorption on macroporous poly(glycidyl methacrylate) and poly(2-hydroxyethyl methacrylate) microspheres containing amino and/or carboxyl groups, the microspheres are coated with alpha,omega-bis-carboxy poly(ethylene glycol) and amino-terminated poly(ethylene glycol-co-propylene glycol) or alpha-methoxy-omega-amino poly(ethylene glycol). Adsorption of bovine serum albumin (BSA), gamma-globulin, (125) I-BSA, pepsin, and chymotrypsin on neat and PEGylated microspheres is determined by UV-VIS spectroscopy of supernatants and eluates or by measurement of radioactivity in an ionization chamber. Neat and PEGylated microspheres adsorb 0.8-70% and 0.02-44% of protein, respectively. PMID- 23359598 TI - Optimizing microalgal production in raceway systems. AB - The industrial exploitation of microalgae is characterized by the production of high-value compounds. Optimization of the performance of microalgae culture systems is essential to render the process economically viable. For raceway systems, the optimization based on optimal control theory is rather challenging, because the process is by essence periodically forced and, as a consequence, optimization must be carried out in a periodic framework. In this article, we propose a simple operational criterion for raceway systems that when integrated in a strategy of closed-loop control allows attaining biomass productivities very near to the theoretical maximal productivities. The strategy developed was tested numerically using a mathematical model of microalgae growth in raceways. The model takes into account the temporal variation of the environmental variables temperature and light intensity and their influence on microalgae growth. PMID- 23359600 TI - Effects of density of anisotropic microstamped silica thin films on guided bone tissue regeneration--in vitro study. AB - The growing demand for better implant aesthetics has led to increased research on the development of all-ceramic dental implants. The use of microtextured coatings with enhanced properties has been presented as a viable way to improve tissue integrability of all-ceramic implants. The aim of this study was to evaluate the effects of different densities of anisotropic microtextured silica thin films, which served as a model coating, on the behavior of human osteoblast-like cells. The differential responses of human osteoblast-like cells to anisotropic silica microtextures with varying densities, produced via a combination of sol-gel and soft lithography processing, were evaluated in terms of alignment, elongation (using fluorescence microscopy), overall cellular activity, and the expression/activity levels of alkaline phosphatase (ALP). Statistical analysis was conducted using one-way ANOVA/Tukey HSD post hoc test. The thin films were thoroughly characterized via scanning electron microscopy/energy dispersive spectroscopy, Fourier transform infrared, and contact angle measurements. Thin film characterization revealed increased nanoscale roughness and reduced wettability on the micropatterned surfaces. Cell culture experiments indicated that the microtextures induced cell alignment, elongation, and guided colonization on the surface. Cells cultured on denser micropatterns exhibited increased metabolic activity (t = 14-21 days). The early expression/activity levels of ALP released into the medium were found to be significantly higher only on the least dense micropattern. These results suggest the possibility that microstructured silica thin films could be used to guide and enhance peri-implant cell/tissue responses, potentially improving tissue integration for metallic and all-ceramic dental implants. PMID- 23359602 TI - The secrets of secretion, trafficking and death. PMID- 23359601 TI - Spontaneous synchronization of arm motion between Japanese macaques. AB - Humans show spontaneous synchronization of movements during social interactions; this coordination has been shown to facilitate smooth communication. Although human studies exploring spontaneous synchronization are increasing in number, little is known about this phenomenon in other species. In this study, we examined spontaneous behavioural synchronization between monkeys in a laboratory setting. Synchronization was quantified by changes in button-pressing behaviour while pairs of monkeys were facing one another. Synchronization between the monkeys was duly observed and it was participant-partner dependent. Further tests confirmed that the speed of button pressing changed to harmonic or sub-harmonic levels in relation to the partner's speed. In addition, the visual information from the partner induced a higher degree of synchronization than auditory information. This study establishes advanced tasks for testing social coordination in monkeys, and illustrates ways in which monkeys coordinate their actions to establish synchronization. PMID- 23359607 TI - Genome-wide analysis of miRNA signature differentially expressed in doxorubicin resistant and parental human hepatocellular carcinoma cell lines. AB - Chemotherapy regiments have been widely used in the treatment of a variety of human malignancies including hepatocellular carcinoma (HCC). A major cause of failure in chemotherapy is drug resistance of cancer cells. Resistance to doxorubicin (DOX) is a common and representative obstacle to treat cancer effectively. Individual microRNA (miRNA) has been introduced in the evolution of DOX resistance in HCC in recent studies. However, a global and systematic assessment of the miRNA expression profiles contributing to DOX resistance is still lacking. In the present study, we applied high-throughput Illumina sequencing to comprehensively characterize miRNA expression profiles in both human HCC cell line (HepG2) and its DOX-resistant counterpart (HepG2/DOX). A total of 269 known miRNAs were significantly differentially expressed, of which 23 were up-regulated and 246 were down-regulated in HepG2/DOX cells, indicating that part of them might be involved in the development of DOX resistance. In addition, we have identified 9 and 13 novel miRNAs up- and down-expressed significantly in HepG2/DOX cells, respectively. miRNA profiling was then validated by quantitative real-time PCR for selected miRNAs, including 22 known miRNAs and 6 novel miRNAs. Furthermore, we predicted the putative target genes for the deregulated miRNAs in the samples. Function annotation implied that these selected miRNAs affected many target genes mainly involved in MAPK signaling pathway. This study provides us a general description of miRNA expression profiling, which is helpful to find potential miRNAs for adjunct treatment to overcome DOX resistance in future HCC chemotherapy. PMID- 23359608 TI - Comparison of ceramic-on-metal and metal-on-metal hip prostheses under adverse conditions. AB - Ceramic-on-metal (COM) hip replacements, where the head is BIOLOX(r) Delta ceramic and the liner is CoCrMo alloy, have demonstrated reduced wear under standard simulator conditions compared to metal-on-metal (MOM) bearings. COM hips are now being used clinically around the world. MOM hip resurfacings have raised concerns regarding poor clinical performance and increased in vivo wear was associated with steeply inclined acetabular components and translationally malpositioned components. The aim of this study was to compare the wear rates of MOM and COM total hip prostheses under adverse edge-loading conditions in a hip simulator test. COM and MOM 36 mm hip prostheses were tested in a hip simulator, with liners mounted to provide a clinical inclination angle of 55 degrees . A simplified gait cycle and microseparation conditions were applied for two million cycles in 25% new born calf serum. The overall mean volumetric wear rate of COM bearings under adverse conditions was 0.36 +/- 0.55 mm3/million cycles; this was significantly less than MOM wear (1.32 +/- 0.91 mm3/million cycles). Under these adverse conditions; the contact zone on the head intersects the rim of the cup causing substantially elevated contact stresses, disrupting the protective boundary and mixed lubrication regime causing changes in types and severity of wear mechanisms. In COM bearings, the harder head does not become damaged when there is lubricant starvation and wear does not accelerate. In conclusion, COM bearings showed reduced wear compared to MOM bearings under standard and adverse clinically relevant simulator conditions and COM bearings may provide an advantage over MOM bearings under edge-loading conditions clinically. PMID- 23359609 TI - Display of Clostridium cellulovorans xylose isomerase on the cell surface of Saccharomyces cerevisiae and its direct application to xylose fermentation. AB - Xylose isomerase (XI) is a key enzyme in the conversion of D-xylose, which is a major component of lignocellulosic biomass, to D-xylulose. Genomic analysis of the bacterium Clostridium cellulovorans revealed the presence of XI-related genes. In this study, XI derived from C. cellulovorans was produced and displayed using the yeast cell-surface display system, and the xylose assimilation and fermentation properties of this XI-displaying yeast were examined. XI-displaying yeast grew well in medium containing xylose as the sole carbon source and directly produced ethanol from xylose under anaerobic conditions. PMID- 23359610 TI - Susceptibility of L-FABP-/- mice to oxidative stress in early-stage alcoholic liver. AB - Chronic ethanol consumption is a prominent cause of liver disease worldwide. Dysregulation of an important lipid uptake and trafficking gene, liver-fatty acid binding protein (L-FABP), may contribute to alterations in lipid homeostasis during early-stage alcoholic liver. We have reported the detrimental effects of ethanol on the expression of L-FABP and hypothesize this may deleteriously impact metabolic networks regulating fatty acids. Male wild-type (WT) and L-FABP(-/-) mice were fed a modified Lieber-DeCarli liquid diet for six weeks. To assess the response to chronic ethanol ingestion, standard biochemical indicators for alcoholic liver disease (ALD) and oxidative stress were measured. Ethanol ingestion resulted in attenuation of hepatic triglyceride accumulation and elevation of cholesterol in L-FABP(-/-) mice. Lipidomics analysis validated multiple alterations in hepatic lipids resulting from ethanol treatment. Increased immunohistochemical staining for the reactive aldehydes 4 hydroxynonenal and malondialdehyde were observed in WT mice ingesting ethanol; however, L-FABP(-/-) mice displayed prominent protein adducts in liver sections evaluated from pair-fed and ethanol-fed mice. Likewise, alterations in glutathione, thiobarbituric acid reactive substances (TBARS), 8-isoprostanes, and protein carbonyl content all indicated L-FABP(-/-) mice exhibit high sustained oxidative stress in the liver. These data establish that L-FABP is an indirect antioxidant protein essential for sequestering FFA and that its impairment could contribute to in the pathogenesis of ALD. PMID- 23359611 TI - The association between cultural orientation and drinking behaviors among university students in Wuhan, China. AB - OBJECTIVES: This study examines the association between cultural orientation and drinking behaviors among university students. Cultural orientation is the measure of how the cultural values of individuals living in their own society are influenced by cultural values introduced from the outside. METHODS: In 2011, a cross-sectional survey collected data from 1279 university students from six universities in central China. Participants used a likert scale to rank a series of statements reflecting cultural values from the previously validated Chinese Cultural Orientation Scale and answered questions about their drinking behaviors and socio-demographic characteristics. RESULTS: Statistically significant differences in cultural orientation were observed for gender, hometown and type of university attendance. Traditional-oriented students were more likely to be occasional drinkers or nondrinkers, while marginal-oriented students, bicultural oriented students and western-oriented students were more likely to be regular drinkers. Bicultural orientation (OR = 1.80, P<0.05) and marginal orientation (OR = 1.64, P<0.05) increased the likelihood of the student being regular drinking, compared to students with traditional orientations. Males (OR = 4.40, P<0.05) had a higher likelihood of regular drinking than females, graduate students (OR = 2.59, P<0.05) had a higher likelihood of regular drinking than undergraduates, students from urban areas (OR = 1.79, P<0.05) had a higher likelihood of regular drinking than those from towns/rural areas, and students attending key universities (OR = 0.48, P<0.05) had a lower likelihood of regular drinking than those attending general universities. CONCLUSIONS: Cultural orientation influences drinking behaviors. Traditional cultural orientation was associated with less drinking while western cultural orientation, marginal cultural orientation and bicultural orientation were associated with more drinking. The role of gender, hometown and university attendance is partially moderated through the influence of cultural orientation. The relationship between a traditional cultural orientation and alcohol drinking suggests that traditional Chinese cultural values should be examined for their role in possibly reducing alcohol related risks through education and policy initiatives. PMID- 23359612 TI - Depth-sensitive Raman spectroscopy combined with optical coherence tomography for layered tissue analysis. AB - Complete characterization of a layered tissue requires probing both the biochemical and the morphological information from its different layers at various depths. We report the development of a combined Raman spectroscopy (RS) and optical coherence tomography (OCT) system that is capable of measuring depth sensitive Raman signal from the tissue layers imaged by the OCT. The sample arm of a real-time time-domain OCT system was modified to allow for co-alignment of the OCT with the Raman probe beam. The depth sensitivity of Raman was obtained by incorporating confocal Raman configuration that minimized out-of-focus Raman scattered light. The system was first validated using a layered phantom prepared by depositing a thin layer of paraffin over acetaminophen. A good correlation was observed between the OCT images and the Raman signal. The system was also used to record OCT and Raman images of a resected mucosal tissue sample. While OCT image showed the presence of epithelial and stromal layers, Raman spectra measured from these layers confirmed the biochemical difference between the two. PMID- 23359613 TI - Continuous rhamnolipid production using denitrifying Pseudomonas aeruginosa cells in hollow-fiber bioreactor. AB - Rhamnolipids are high-value effective biosurfactants produced by Pseudomonas aeruginosa. Large-scale production of rhamnolipids is still challenging especially under free-cell aerobic conditions in which the highly foaming nature of the culture broth reduces the productivity of the process. Immobilized systems relying on oxygen as electron acceptor have been previously investigated but oxygen transfer limitation presents difficulties for continuous rhamnolipid production. A coupled system using immobilized cells and nitrate instead of oxygen as electron acceptor taking advantage of the ability of P. aeruginosa to perform nitrate respiration was evaluated. This denitrification-based immobilized approach based on a hollow-fiber setup eliminated the transfer limitation problems and was found suitable for continuous rhamnolipid production in a period longer than 1,500 h. It completely eliminated the foaming difficulties related to aerobic systems with a comparable specific productivity of 0.017 g/(g dry cells) h and allowed easy recovery of rhamnolipids from the cell-free medium. PMID- 23359614 TI - Parkin differently regulates presenilin-1 and presenilin-2 functions by direct control of their promoter transcription. AB - We previously established that besides its canonical function as E3-ubiquitin ligase, parkin also behaves as a transcriptional repressor of p53. Here we show that parkin differently modulates presenilin-1 and presenilin-2 expression and functions at transcriptional level. Thus, parkin enhances/reduces the protein expression, promoter activity and mRNA levels of presenilin-1 and presenilin-2, respectively, in cells and in vivo. This parkin-associated function is independent of its ubiquitin-ligase activity and remains unrelated to its capacity to repress p53. Accordingly, physical interaction of endogenous or overexpressed parkin with presenilins promoters is demonstrated by chromatin immunoprecipitation assays (ChIP). Furthermore, we identify a consensus sequence, the deletion of which abolishes parkin-dependent modulation of presenilins-1/2 and p53 promoter activities. Interestingly, electrophoretic mobility shift assays (EMSA) revealed a physical interaction between this consensus sequence and wild type but not mutated parkin. Finally, we demonstrate that the RING1-IBR-RING2 domain of parkin harbors parkin's potential to modulate presenilins promoters. This transcriptional control impacts on presenilins-associated phenotypes, since parkin increases presenilin-1-associated gamma-secretase activity and reduces presenilin-2-linked caspase-3 activation. Overall, our data delineate a promoter responsive element targeted by parkin that drives differential regulation of presenilin-1 and presenilin-2 transcription with functional consequences for gamma-secretase activity and cell death. PMID- 23359615 TI - Swimming capability and swimming behavior of juvenile acipenser schrenckii. AB - Acipenser schrenckii, the Amur Sturgeon, was a commercially valuable fish species inhabiting the Amur (Heilongjiang) River but populations have rapidly declined in recent years. Dams impede A. schrenckii spawning migration and wild populations were critically endangered. Building fishways helped maintain fish populations but data on swimming performance and behavior was crucial for fishway design. To obtain such data on A. schrenckii, a laboratory study of juvenile A. schrenckii (n = 18, body mass = 32.7 +/- 1.2 g, body length = 18.8 +/- 0.3 cm) was conducted using a stepped velocity test carried out in a fish respirometer equipped with a high-speed video camera at 20 degrees C. Results indicate: (1) The counter current swimming capability of A. schrenckii was low with critical swimming speed of 1.96 +/- 0.10 BL/sec. (2) When a linear function was fitted to the data, oxygen consumption, as a function of swimming speed, was determined to be MO2 = 337.29 + 128.10U (R(2) = 0.971, P < 0.001) and the power value (1.0) of U indicated high swimming efficiency. (3) Excess post-exercise oxygen cost was 48.44 mgO2 /kg and indicated excellent fatigue recovery. (4) Cost of transport decreased slowly with increased swimming speed. (5) Increased swimming speed led to increases in the tail beat frequency and stride length. This investigation contributed to the basic science of fish swimming behavior and provided data required for the design of fishways. Innovative methods have allowed cultivation of the species in the Yangtze River and, if effective fishways could be incorporated into the design of future hydropower projects on the Amur River, it would contribute to conservation of wild populations of A. schrenckii. The information provided here contributes to the international effort to save this critically endangered species. J. Exp. Zool. 319A:149-155, 2013. (c) 2013 Wiley Periodicals, Inc. PMID- 23359617 TI - Persistent hiccups as a rare presenting symptom of pulmonary embolism. AB - Pulmonary embolism (PE) is a life-threatening condition that may present as dyspnea, chest pain, cough or hemoptysis, but often occurs without symptoms. It is not typically associated with hiccups. Hiccups are generally self-limiting benign contractions of the diaphragm that may be associated with medications or food but may also be symptomatic of serious disease when persistent. We report 3 cases of PE presenting as persistent hiccups. PMID- 23359616 TI - Pattern of regional cortical thinning associated with cognitive deterioration in Parkinson's disease. AB - BACKGROUND: Dementia is a frequent and devastating complication in Parkinson's disease (PD). There is an intensive search for biomarkers that may predict the progression from normal cognition (PD-NC) to dementia (PDD) in PD. Mild cognitive impairment in PD (PD-MCI) seems to represent a transitional state between PD-NC and PDD. Few studies have explored the structural changes that differentiate PD NC from PD-MCI and PDD patients. OBJECTIVES AND METHODS: We aimed to analyze changes in cortical thickness on 3.0T Magnetic Resonance Imaging (MRI) across stages of cognitive decline in a prospective sample of PD-NC (n = 26), PD-MCI (n = 26) and PDD (n = 20) patients, compared to a group of healthy subjects (HC) (n = 18). Cortical thickness measurements were made using the automatic software Freesurfer. RESULTS: In a sample of 72 PD patients, a pattern of linear and progressive cortical thinning was observed between cognitive groups in cortical areas functionally specialized in declarative memory (entorhinal cortex, anterior temporal pole), semantic knowledge (parahippocampus, fusiform gyrus), and visuoperceptive integration (banks of the superior temporal sulcus, lingual gyrus, cuneus and precuneus). Positive correlation was observed between confrontation naming and thinning in the fusiform gyrus, parahippocampal gyrus and anterior temporal pole; clock copy with thinning of the precuneus, parahippocampal and lingual gyrus; and delayed memory with thinning of the bilateral anteromedial temporal cortex. CONCLUSIONS: The pattern of regional decreased cortical thickness that relates to cognitive deterioration is present in PD-MCI patients, involving areas that play a central role in the storage of prior experiences, integration of external perceptions, and semantic processing. PMID- 23359618 TI - Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-kappaB/HIF-1alpha signaling pathway. AB - Lipopolysaccharide (LPS) is involved in a variety of inflammatory disorders. Under stress conditions, endoplasmic reticulum (ER) loses the homeostasis in its functions, which is defined as ER stress. Little is known how ER stress is implicated in LPS-induced lung inflammation. In this study, effects of inhibition of ER stress on LPS-induced lung inflammation and transcriptional regulation were examined. An ER stress regulator, 4-phenylbutyrate (PBA) reduced LPS-induced increases of various ER stress markers in the lung. Furthermore, inhibition of ER stress reduced the LPS-induced lung inflammation. Moreover, LPS-induced increases of NF-kappaB and HIF-1alpha activity were lowered by inhibition of ER stress. These results suggest that inhibition of ER stress ameliorates LPS-induced lung inflammation through modulation of NF-kappaB/IkappaB and HIF-1alpha signaling pathway. PMID- 23359620 TI - Simulating the effect of slab features on vapor intrusion of crack entry. AB - In vapor intrusion screening models, a most widely employed assumption in simulating the entry of contaminant into a building is that of a crack in the building foundation slab. Some modelers employed a perimeter crack hypothesis while others chose not to identify the crack type. However, few studies have systematically investigated the influence on vapor intrusion predictions of slab crack features, such as the shape and distribution of slab cracks and related to this overall building foundation footprint size. In this paper, predictions from a three-dimensional model of vapor intrusion are used to compare the contaminant mass flow rates into buildings with different foundation slab crack features. The simulations show that the contaminant mass flow rate into the building does not change much for different assumed slab crack shapes and locations, and the foundation footprint size does not play a significant role in determining contaminant mass flow rate through a unit area of crack. Moreover, the simulation helped reveal the distribution of subslab contaminant soil vapor concentration beneath the foundation, and the results suggest that in most cases involving no biodegradation, the variation in subslab concentration should not exceed an order of magnitude, and is often significantly less than this. PMID- 23359619 TI - T cell post-transcriptional miRNA-mRNA interaction networks identify targets associated with susceptibility/resistance to collagen-induced arthritis. AB - BACKGROUND: Due to recent studies indicating that the deregulation of microRNAs (miRNAs) in T cells contributes to increased severity of rheumatoid arthritis, we hypothesized that deregulated miRNAs may interact with key mRNA targets controlling the function or differentiation of these cells in this disease. METHODOLOGY/PRINCIPAL FINDINGS: To test our hypothesis, we used microarrays to survey, for the first time, the expression of all known mouse miRNAs in parallel with genome-wide mRNAs in thymocytes and naive and activated peripheral CD3(+) T cells from two mouse strains the DBA-1/J strain (MHC-H2q), which is susceptible to collagen induced arthritis (CIA), and the DBA-2/J strain (MHC-H2d), which is resistant. Hierarchical clustering of data showed the several T cell miRNAs and mRNAs differentially expressed between the mouse strains in different stages of immunization with collagen. Bayesian statistics using the GenMir(++) algorithm allowed reconstruction of post-transcriptional miRNA-mRNA interaction networks for target prediction. We revealed the participation of miR-500, miR-202-3p and miR-30b*, which established interactions with at least one of the following mRNAs: Rorc, Fas, Fasl, Il-10 and Foxo3. Among the interactions that were validated by calculating the minimal free-energy of base pairing between the miRNA and the 3'UTR of the mRNA target and luciferase assay, we highlight the interaction of miR-30b*-Rorc mRNA because the mRNA encodes a protein implicated in pro-inflammatory Th17 cell differentiation (Rorgammat). FACS analysis revealed that Rorgammat protein levels and Th17 cell counts were comparatively reduced in the DBA-2/J strain. CONCLUSIONS/SIGNIFICANCE: This result showed that the miRNAs and mRNAs identified in this study represent new candidates regulating T cell function and controlling susceptibility and resistance to CIA. PMID- 23359621 TI - High-risk endometrial cancer may be benefit from adjuvant radiotherapy plus chemotherapy. AB - OBJECTIVE: To present patterns of practice and outcomes in the adjuvant treatment of intermediate- and high-risk endometrial cancer. METHODS: Retrospective data on 224 women with intermediate-risk and high-risk endometrial cancer from 1999 to 2006 were reviewed. All patients underwent surgical staging. Patterns of adjuvant treatment, consisting of pelvic radiotherapy, chemotherapy, and radiotherapy plus chemotherapy, were assessed. The 3- and 5-year disease-specific survival (DSS) rates were calculated using the Kaplan-Meier method. RESULTS: The difference in 5 year DSS rate was statistically significant between adjuvant group and non adjuvant group (80.65% vs. 63.80%, P=0.040). In 110 high-risk patients who underwent adjuvant treatment, both 5-year DSS rate and recurrent rate were significantly different in combined radiotherapy and chemotherapy group compared with radiotherapy alone and chemotherapy alone groups (DSS rate, P=0.049; recurrent rate, P=0.047). In 83 intermediate-risk women who underwent adjuvant treatment, there was no significant difference in 5-year DSS rate and recurrence rate among the combined radiotherapy and chemotherapy, radiotherapy alone and chemotherapy alone groups (DSS rate, P=0.776; recurrent rate, P=0.937). CONCLUSIONS: Adjuvant radiotherapy plus chemotherapy is associated with a higher 5-year DSS rate and lower recurrence rate compared with radiotherapy alone and chemotherapy alone in high-risk endometrial cancer patients. Patients with intermediate-risk endometrial cancer may be not likely to benefit from adjuvant combined radiotherapy and chemotherapy. PMID- 23359623 TI - The effectiveness of modified vertical dome division technique in reducing nasal tip projection in rhinoplasty. AB - BACKGROUND: The technique of vertical dome division or tip defining, involves incising the lateral crura and vestibular skin at or lateral to the dome or tip defining point. The incision divides the lower lateral cartilage into a lateral segment and a medial segment, which are advanced anteriorly and sutured together to increase tip projection. The present study aimed at assessing a new vertical dome division, which is a modified version of vertical dome technique to decrease nasal tip projection, and increase or decrease nasal tip rotation and other tip deformities. METHODS: The medical files of patients undergone rhinoplasty from 2003 to 2008 were retrospectively analyzed. The files were selected from a computerized rhinoplasty database of patients, who had been operated using a modified vertical dome technique and followed-up for one year or more after the surgery. RESULTS: A total of 3756 patients were operated. Complications related to the nasal tip such as bossae, bifidity, persistent tip projection or tip asymmetry was seen in 81 patients (2.1%). Revisions for tip-related problems were performed in 42 patients (1.1%). CONCLUSIONS: The findings suggest that the modified vertical dome technique is an effective method for nasal tip deprojection and narrowing via an open approach. The length of follow-up and the large sample size support effectiveness of the technique. PMID- 23359622 TI - A single multilocus sequence typing (MLST) scheme for seven pathogenic Leptospira species. AB - BACKGROUND: The available Leptospira multilocus sequence typing (MLST) scheme supported by a MLST website is limited to L. interrogans and L. kirschneri. Our aim was to broaden the utility of this scheme to incorporate a total of seven pathogenic species. METHODOLOGY AND FINDINGS: We modified the existing scheme by replacing one of the seven MLST loci (fadD was changed to caiB), as the former gene did not appear to be present in some pathogenic species. Comparison of the original and modified schemes using data for L. interrogans and L. kirschneri demonstrated that the discriminatory power of the two schemes was not significantly different. The modified scheme was used to further characterize 325 isolates (L. alexanderi [n = 5], L. borgpetersenii [n = 34], L. interrogans [n = 222], L. kirschneri [n = 29], L. noguchii [n = 9], L. santarosai [n = 10], and L. weilii [n = 16]). Phylogenetic analysis using concatenated sequences of the 7 loci demonstrated that each species corresponded to a discrete clade, and that no strains were misclassified at the species level. Comparison between genotype and serovar was possible for 254 isolates. Of the 31 sequence types (STs) represented by at least two isolates, 18 STs included isolates assigned to two or three different serovars. Conversely, 14 serovars were identified that contained between 2 to 10 different STs. New observations were made on the global phylogeography of Leptospira spp., and the utility of MLST in making associations between human disease and specific maintenance hosts was demonstrated. CONCLUSION: The new MLST scheme, supported by an updated MLST website, allows the characterization and species assignment of isolates of the seven major pathogenic species associated with leptospirosis. PMID- 23359624 TI - Comparison of Prehospital Glucose with or without IV Thiamine. AB - INTRODUCTION: Loading of thiamine prior to glucose administration during hypoglycemia to prevent Wernicke's encephalopathy is routine in the prehospital setting. To date no study has looked at the validity of this therapy. METHODS: We evaluated a retrospective cohort of 242 patients who received intravenous glucose for hypoglycemia comparing those who received thiamine supplementation versus those who did not. Study endpoints were heart rate, blood pressure, Glasgow Coma Scale (GCS), reentry into the 911 system, and emergency department (ED) discharge rates. RESULTS: There were no significant differences between the thiamine, and without-thiamine groups. All patients were discharged neurologically intact or were alert and oriented when refusing transport to the hospital. None of the 242 patients re-called 911 within the immediate 24-hour period or returned to the ED. CONCLUSION: To our knowledge this is the first study in the literature which evaluated the use of thiamine with glucose to prevent Wernicke's encephalopathy in the prehospital setting. We found that routine administration of thiamine with glucose did not result in differences in respiratory rate, systolic blood pressure, GCS or ED hospital discharge rates. Until further research is done to validate our results emergency medical services leadership should consider whether the routine use of thiamine in the prehospital setting is appropriate for their system. PMID- 23359625 TI - The effect of Heparin-VEGF multilayer on the biocompatibility of decellularized aortic valve with platelet and endothelial progenitor cells. AB - The application of polyelectrolyte multilayer films is a new, versatile approach to surface modification of decellularized tissue, which has the potential to greatly enhance the functionality of engineered tissue constructs derived from decellularized organs. In the present study, we test the hypothesis that Heparin- vascular endothelial growth factor (VEGF) multilayer film can not only act as an antithrombotic coating reagent, but also induce proliferation of endothelial progenitor cells (EPCs) on the decellularized aortic heart valve. SEM demonstrated the adhesion and geometric deformation of platelets. The quantitative assay of platelet activation was determined by measuring the production of soluble P-selectin. Binding and subsequent release of heparin and VEGF from valve leaflets were assessed qualitatively by laser confocal scanning microscopy and quantitatively by ELISA methods. Human blood derived EPCs were cultured and the adhesion and growth of EPCs on the surface modified valvular scaffolds were assessed. The results showed that Heparin-VEGF multilayer film improved decellularized valve haemocompatibility with respect to a substantial reduction of platelet adhesion. Release of VEGF from the decellularized heart valve leaflets at physiological conditions was sustained over 5 days. In vitro biological tests demonstrated that EPCs achieved better adhesion, proliferation and migration on the coatings with Heparin-VEGF multilayer film. Combined, these results indicate that Heparin-VEGF multilayer film could be used to cover the decellularized porcine aortic valve to decrease platelet adhesion while exhibiting excellent EPCs biocompatibility. PMID- 23359626 TI - Genome analysis and phylogenetic relatedness of Gallibacterium anatis strains from poultry. AB - Peritonitis is the major disease problem of laying hens in commercial table egg and parent stock operations. Despite its importance, the etiology and pathogenesis of this disease have not been completely clarified. Although avian pathogenic Escherichia coli (APEC) isolates have been incriminated as the causative agent of laying hen peritonitis, Gallibacterium anatis are frequently isolated from peritonitis lesions. Despite recent studies suggesting a role for G. anatis in the pathogenesis of peritonitis, little is known about the organism's virulence mechanisms, genomic composition and population dynamics. Here, we compared the genome sequences of three G. anatis isolates in an effort to understand its virulence mechanisms and identify novel antigenic traits. A multilocus sequence typing method was also established for G. anatis and used to characterize the genotypic relatedness of 71 isolates from commercial laying hens in Iowa and 18 international reference isolates. Genomic comparisons suggest that G. anatis is a highly diverse bacterial species, with some strains possessing previously described and potential virulence factors, but with a core genome containing several antigenic candidates. Multilocus sequence typing effectively distinguished 82 sequence types and several clonal complexes of G. anatis, and some clones seemed to predominate among G. anatis populations from commercial layers in Iowa. Biofilm formation and resistance to antimicrobial agents was also observed in several clades. Overall, the genomic diversity of G. anatis suggests that multiple lineages exist with differing pathogenic potential towards birds. PMID- 23359627 TI - Can common functional gene variants affect visual discrimination in metacontrast masking? AB - Mechanisms of visual perception should be robustly fast and provide veridical information about environmental objects in order to facilitate survival and successful coping. Because species-specific brain mechanisms for fast vision must have evolved under heavy pressure for efficiency, it has been held that different human individuals see the physical world in the same way and produce psychophysical functions of visual discrimination that are qualitatively the same. For many years, this assumption has been implicitly accepted in vision research studying extremely fast, basic visual processes, including studies of visual masking. However, in recent studies of metacontrast masking surprisingly robust individual differences in the qualitative aspects of subjects' performance have been found. As the basic species-specific visual functions very likely are based on universal brain mechanisms of vision, these differences probably are the outcome of variability in ontogenetic development (i.e., formation of idiosyncrasic skills of perception). Such developmental differences can be brought about by variants of genes that are differentially expressed in the course of CNS development. The objective of this study was to assess whether visual discrimination in metacontrast masking is related to three widely studied genetic polymorphisms implicated in brain function and used here as independent variables. The findings suggest no main effects of BDNF Val66Met, NRG1/rs6994992, or 5-HTTLPR polymorphisms on metacontrast performance, but several notable interactions of genetic variables with gender, stage of the sequence of experimental trials, perceptual strategies, and target/mask shape congruence were found. Thus, basic behavioral functions of fast vision may be influenced by common genetic variability. Also, when left uncontrolled, genetic factors may seriously confound variables in vision research using masking, obscure clear theoretical interpretation, lead to unexplicable inter-regional differences and create problems of replicability of formerly successful experiments. PMID- 23359628 TI - Cancer incidence and mortality in china, 2007. AB - OBJECTIVE: Cancer incidence and mortality data collected from population-based cancer registries were analyzed to present the overall cancer statistics in Chinese registration areas by age, sex and geographic area in 2007. METHODS: In 2010, 48 cancer registries reported cancer incidence and mortality data of 2007 to National Central Cancer Registry of China. Of them, 38 registries' data met the national criteria. Incidence and mortality were calculated by cancer sites, age, gender, and area. Age-standardized rates were described by China and World population. RESULTS: The crude incidence rate for all cancers was 276.16/100,000 (305.22/100,000 for male and 246.46/100,000 for female; 284.71/100,000 in urban and 251.07/100,000 in rural). Age-standardized incidence rates by China and World population were 145.39/100,000 and 189.46/100,000 respectively. The crude mortality rate for all cancers was 177.09/100,000 (219.15/100,000 for male and 134.10/100,000 for female; 173.55/100,000 in urban and 187.49/100,000 in rural). Age-standardized mortality rates by China and World population were 86.06/100,000 and 116.46/100,000, respectively. The top 10 most frequently common cancer sites were the lung, stomach, colon and rectum, liver, breast, esophagus, pancreas, bladder, brain and lymphoma, accounting for 76.12% of the total cancer cases. The top 10 causes of cancer death were cancers of the lung, liver, stomach, esophagus, colon and rectum, pancreas, breast, leukemia, brain and lymphoma, accounting for 84.37% of the total cancer deaths. CONCLUSION: Cancer remains a major disease threatening people's health in China. Prevention and control should be enhanced, especially for the main cancers. PMID- 23359629 TI - A new genus of aplodontid rodent (Mammalia, Rodentia) from the late Oligocene of northern Junggar Basin, China. AB - A new genus and species of aplodontid rodent, Proansomys dureensis, from the late Oligocene of the northern Junggar Basin of China is described. The new genus is referred to as Ansomyinae because the ectoloph on the upper cheek teeth, although not fully crested, has attained the same characteristic bucket-handle-shaped configuration as other members of the subfamily. It represents the earliest record of the subfamily yet discovered in Asia and is more plesiomorphic than species of the genus Ansomys in having a partly crested ectoloph, a lower degree of lophodonty, and less complex tooth basins (lacking accessory lophules). Proansomys has transitional features between Prosciurus and Ansomys, suggesting that the Ansomyinae derived from a group of aplodontids related to Prosciurus, as did other advanced aplodontid rodents. This provides new light on the paleobiogeography of the Ansomyinae. PMID- 23359631 TI - "Challenging the Pathophysiologic Connection between Subdural Hematoma, Retinal Hemorrhage, and Shaken Baby Syndrome". PMID- 23359630 TI - An intact brachyury function is necessary to prevent spurious axial development in Xenopus laevis. AB - We have previously shown that the member of the HES family hairy2 induces the ectopic expression of dorsal markers when it is overexpressed in the ventral side of Xenopus embryos. Intriguingly, hairy2 represses the mesoderm transcription factor brachyury (bra) throughout its domain in the marginal zone. Here we show that in early gastrula, bra and hairy2 are expressed in complementary domains. Overexpression of bra repressed hairy2. Interference of bra function with a dominant-negative construct expanded the hairy2 domain and, like hairy2 overexpression, promoted ectopic expression of dorsal axial markers in the ventral side and induced secondary axes without head and notochord. Hairy2 depletion rescued the ectopic dorsal development induced by interference of bra function. We concluded that an intact bra function is necessary to exclude hairy2 expression from the non-organiser field, to impede the ectopic specification of dorsal axial fates and the appearance of incomplete secondary axes. This evidence supports a previously unrecognised role for bra in maintaining the dorsal fates inhibited in the ventral marginal zone, preventing the appearance of trunk duplications. PMID- 23359633 TI - Effectiveness of the KEEP Foster Parent Intervention during an Implementation Trial. AB - Externalizing behavior problems are highly prevalent among children in foster care, placing them at risk for placement disruptions and later personal and social maladjustment. The KEEP foster parent intervention was designed to equip foster parents and relative caregivers with the parenting skills necessary for managing challenging behavior problems. In prior research, the KEEP intervention was found to be effective in reducing child behavior problems. In the current study, the KEEP foster parent intervention was implemented in San Diego County during a three-year trial. The intervention was delivered by paraprofessionals employed by a local community agency (Social Advocates for Youth, San Diego) to 181 foster parent and relative caregivers of boys and girls between the ages of 5 and 12. The control group from an earlier effectiveness study of the KEEP intervention that was also conducted in San Diego County was utilized as a historical comparison group. Regression analyses were used to examine the effects of the intervention on reducing levels of child behavior problems at treatment termination. Consistent with the findings from the previous KEEP effectiveness study, the intervention was found to be effective in reducing child behavior problems when delivered by a community agency. Furthermore, the KEEP intervention was found to be effective in reducing child behavior problems among children displaying various levels of initial behavior problems. PMID- 23359632 TI - A rationally designed nitrogen-rich metal-organic framework and its exceptionally high CO(2) and H(2) uptake capability. AB - On the way towards a sustainable low-carbon future, the design and construction of chemical or physical adsorbents for CO(2) capture and clean energy storage are vital technology. The incorporation of accessible nitrogen-donor sites into the pore walls of porous adsorbents can dramatically affect the CO(2) uptake capacity and selectivity on account of the dipole-quadrupole interactions between the polarizable CO(2) molecule and the accessible nitrogen site. In the present work, a nitrogen-rich rth-type metal-organic framework (MOF) was constructed based on rational design and careful synthesis. The MOF presents exceptionally high uptake capacity not only for CO(2) but also for H(2), which is attributed to favorable interactions between the gas molecules and the nitrogen-rich triazole units of the MOF proved by both experimental measurements and theoretical molecular simulations. PMID- 23359634 TI - Evolution of viral RNA in a Chinese patient to interferon/ribavirin therapy for hepatitis C. AB - OBJECTIVE: The combination of interferon (IFN) and ribavirin (RBV) is the standard therapy for hepatitis C virus (HCV) infection. HCV genotype 2a has proved more amenable to the therapy, but its efficacy is yet limited. This study aimed to investigate the mechanism of the poor response in a case of HCV genotype 2a infection. METHODS: We analyzed dynamic change of HCV RNA from a patient, infected with HCV genotype 2a, showing a poor virological response to IFN/RBV as judged 12 weeks after initiation of the therapy by HCV clone sequencing. Then we constructed subgenomic Japanese fulminant hepatitis-1 (JFH1) replicon and different chimeric replicons with humanized Gaussia luciferase gene. The chimeric replicons were derived from subgenomic JFH1 replicon, in which the NS5A region was replaced by the patient's sequence from the pre/post-treatment, and the chimeric replicons' susceptibility to IFN were evaluated by relative Gausia Luciferase activity. RESULTS: The pretreatment HCV sequences appeared almost uniform, and the quasispecies variation was further more simplified after 12 weeks of therapy. Besides, the quasispecies variation seemed to be more diversified in the NS5A, relatively, a region crucial for IFN response, and each of chimeric replicons exhibited distinct response to IFN. CONCLUSIONS: During the course of the chronic infection, HCV population seems to be adapted to the patient's immunological system, and further to be selected by combination of IFN/RBV therapy, indicating quasispecies may completely eliminated by addition of other drugs with targets different from those of IFN. In addition, each different response of chimeric replicon to IFN is most likely related to amino acid changes in or near the IFN-sensitivity determining region (ISDR) of NS5A during chronic infection and IFN/RBV therapy. PMID- 23359635 TI - Non-hodgkin lymphoma in a child with schimke immuno-osseous dysplasia. AB - Schimke immuno-osseous dysplasia is a rare autosomal recessive multisystem disorder characterized by steroid-resistant nephrotic syndrome, immunodeficiency, and spondyloepiphyseal dysplasia. Mutations in SWI/SNF2 related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) gene are responsible for the disease. The present report describes, for the first time, a Schimke immuno-osseous dysplasia child with SMARCAL1 missense mutation (R561H) and manifestations of intussusception secondary to Epstein-Barr virus negative non-Hodgkin lymphoma, who expired due to septicemia following chemotherapy. The report emphasizes the necessity of more limited immunosuppressive protocols in Schimke immuno-osseous dysplasia patients with lymphoproliferative disorders. PMID- 23359637 TI - Factors influencing emergency department preference for access to healthcare. AB - INTRODUCTION: African-Americans are more likely than Caucasians to access healthcare through the emergency department (ED); however, the reasons behind this pattern are unclear. The objective is to investigate the effect of race, insurance, socioeconomic status, and perceived health on the preference for ED use. METHODS: This is a prospective study at a tertiary care ED from June to July 2009. Patients were surveyed to capture demographics, healthcare utilization, and baseline health status. The primary outcome of interest was patient-reported routine place of healthcare. Other outcomes included frequency of ED visits in the previous 6 months, barriers to primary care and patient perception of health using select questions from the Medical Outcomes Study Short Form 36 (SF-36). RESULTS: Two hundred and ninety-two patients completed the survey of whom 58% were African-American and 44% were uninsured. African-Americans were equally likely to report 3 or more visits to the ED, but more likely to state a preference for the ED for their usual place of care (24% vs. 13%, p < 0.01). No significant differences between groups were found for barriers to primary care, including insurance. African-Americans less often reported comorbidities or hospitalization within the previous 6 months (23% vs. 34%, p = 0.04). On logistic regression modeling, African-Americans were more than 2 times as likely to select the ED as their usual place of healthcare (OR 2.24, 95% CI 1.22 - 4.08). CONCLUSION: African-Americans, independent of health insurance, are more likely than Caucasians to designate the ED as their routine place of healthcare. PMID- 23359636 TI - An EAV-HP insertion in 5' Flanking region of SLCO1B3 causes blue eggshell in the chicken. AB - The genetic determination of eggshell coloration has not been determined in birds. Here we report that the blue eggshell is caused by an EAV-HP insertion that promotes the expression of SLCO1B3 gene in the uterus (shell gland) of the oviduct in chicken. In this study, the genetic map location of the blue eggshell gene was refined by linkage analysis in an F(2) chicken population, and four candidate genes within the refined interval were subsequently tested for their expression levels in the shell gland of the uterus from blue-shelled and non-blue shelled hens. SLCO1B3 gene was found to be the only one expressed in the uterus of blue-shelled hens but not in that of non-blue-shelled hens. Results from a pyrosequencing analysis showed that only the allele of SLCO1B3 from blue-shelled chickens was expressed in the uterus of heterozygous hens (O*LC/O*N). SLCO1B3 gene belongs to the organic anion transporting polypeptide (OATP) family; and the OATPs, functioning as membrane transporters, have been reported for the transportation of amphipathic organic compounds, including bile salt in mammals. We subsequently resequenced the whole genomic region of SLCO1B3 and discovered an EAV-HP insertion in the 5' flanking region of SLCO1B3. The EAV-HP insertion was found closely associated with blue eggshell phenotype following complete Mendelian segregation. In situ hybridization also demonstrated that the blue eggshell is associated with ectopic expression of SLCO1B3 in shell glands of uterus. Our finding strongly suggests that the EAV-HP insertion is the causative mutation for the blue eggshell phenotype. The insertion was also found in another Chinese blue-shelled breed and an American blue-shelled breed. In addition, we found that the insertion site in the blue-shelled chickens from Araucana is different from that in Chinese breeds, which implied independent integration events in the blue-shelled chickens from the two continents, providing a parallel evolutionary example at the molecular level. PMID- 23359638 TI - Global priority conservation areas in the face of 21st century climate change. AB - In an era when global biodiversity is increasingly impacted by rapidly changing climate, efforts to conserve global biodiversity may be compromised if we do not consider the uneven distribution of climate-induced threats. Here, via a novel application of an aggregate Regional Climate Change Index (RCCI) that combines changes in mean annual temperature and precipitation with changes in their interannual variability, we assess multi-dimensional climate changes across the "Global 200" ecoregions - a set of priority ecoregions designed to "achieve the goal of saving a broad diversity of the Earth's ecosystems" - over the 21(st) century. Using an ensemble of 62 climate scenarios, our analyses show that, between 1991-2010 and 2081-2100, 96% of the ecoregions considered will be likely (more than 66% probability) to face moderate-to-pronounced climate changes, when compared to the magnitudes of change during the past five decades. Ecoregions at high northern latitudes are projected to experience most pronounced climate change, followed by those in the Mediterranean Basin, Amazon Basin, East Africa, and South Asia. Relatively modest RCCI signals are expected over ecoregions in Northwest South America, West Africa, and Southeast Asia, yet with considerable uncertainties. Although not indicative of climate-change impacts per se, the RCCI based assessment can help policy-makers gain a quantitative and comprehensive overview of the unevenly distributed climate risks across the G200 ecoregions. Whether due to significant climate change signals or large uncertainties, the ecoregions highlighted in the assessment deserve special attention in more detailed impact assessments to inform effective conservation strategies under future climate change. PMID- 23359640 TI - Malignant hemangioendothelioma of occipital bone. AB - Epithelioidhemangioendothelioma is a rare vascular tumor of bone, and rarely these lesions can present as unique and extremely aggressive tumor. We report a case of highly aggressive epithelioidhemangioendothelioma and discuss the imaging findings. CT brain plain study revealed a poorly-defined, mixed density expansile and lytic lesion involving the occipital bone with extension to the left side with poorly defined trabecula formation. There was significant but irregular enhancement after intravenous administration of contrast material and also marked bone destruction. Microscopic examination of the fine needle aspiration cytology showed a tumor composed of vascular channels lined by plump endothelial cells, which had enlarged hyperchromatic nuclei. In view of the extensive infiltration the patient was submitted for the radiotherapy. PMID- 23359639 TI - DPP4 deficiency exerts protective effect against H2O2 induced oxidative stress in isolated cardiomyocytes. AB - Apart from the antihyperglycemic effects, DPP4 inhibitors and GLP-1 molecules are involved in the preservation of cardiac functions. We have demonstrated that DPP4 deficient rats possess resistance to endotoxemia and ischemia/reperfusion stress. However, whether the decrease of DPP4 activity simply augmented the GLP-1 signaling or that such decrease resulted in a change of cellular function remain unclear. Accordingly, we investigated the responses of H(2)O(2)-induced oxidative stress in adult wild-type and DPP4-deficient rats isolated cardiomyocytes. The coadministration of GLP-1 or DPP4 inhibitor was also performed to define the mechanisms. Cell viability, ROS concentration, catalase activity, glucose uptake, prosurvival, proapoptotic signaling, and contractile function were examined after cells exposed to H(2)O(2). DPP4-deficient cardiomyocytes were found to be resistant to H(2)O(2)-induced cell death via activating AKT signaling, enhancing glucose uptake, preserving catalase activity, diminishing ROS level and proapoptotic signaling. GLP-1 concentration-dependently improved cell viability in wild-type cardiomyocyte against ROS stress, and the ceiling response concentration (200 nM) was chosen for studies. GLP-1 was shown to decrease H(2)O(2)-induced cell death by its receptor-dependent AKT pathway in wild-type cardiomyocytes, but failed to cause further activation of AKT in DPP4-deficient cardiomyocytes. Acute treatment of DPP4 inhibitor only augmented the protective effect of low dose GLP-1, but failed to alter fuel utilization or ameliorate cell viability in wild-type cardiomyocytes after H(2)O(2) exposure. The improvement of cell viability after H(2)O(2) exposure was correlated with the alleviation of cellular contractile dysfunction in both DPP4-deficient and GLP-1 treated wild type cardiomyocytes. These findings demonstrated that GLP-1 receptor-dependent pathway is important and exert protective effect in wild-type cardiomyocyte. Long term loss of DPP4 activity increased the capability against ROS stress, which was more than GLP-1 dependent pathway. PMID- 23359641 TI - ACTN3 allele frequency in humans covaries with global latitudinal gradient. AB - A premature stop codon in ACTN3 resulting in alpha-actinin-3 deficiency (the ACTN3 577XX genotype) is common in humans and reduces strength, muscle mass, and fast-twitch fiber diameter, but increases the metabolic efficiency of skeletal muscle. Linkage disequilibrium data suggest that the ACTN3 R577X allele has undergone positive selection during human evolution. The allele has been hypothesized to be adaptive in environments with scarce resources where efficient muscle metabolism would be selected. Here we test this hypothesis by using recently developed comparative methods that account for evolutionary relatedness and gene flow among populations. We find evidence that the ACTN3 577XX genotype evolved in association with the global latitudinal gradient. Our results suggest that environmental variables related to latitudinal variation, such as species richness and mean annual temperature, may have influenced the adaptive evolution of ACTN3 577XX during recent human history. PMID- 23359642 TI - Does targeted education of emergency physicians improve their comfort level in treating psychiatric patients? AB - INTRODUCTION: We determined if targeted education of emergency physicians (EPs) regarding the treatment of mental illness will improve their comfort level in treating psychiatric patients boarding in the emergency department (ED) awaiting admission. METHODS: We performed a pilot study examining whether an educational intervention would change an EP's comfort level in treating psychiatric boarder patients (PBPs). We identified a set of psychiatric emergencies that typically require admission or treatment beyond the scope of practice of emergency medicine. Diagnoses included major depression, schizophrenia, schizoaffective disorder, bipolar affective disorder, general anxiety disorder, suicidal ideation, and criminal behavior. We designed equivalent surveys to be used before and after an educational intervention. Each survey consisted of 10 scenarios of typical psychiatric patients. EPs were asked to rate their comfort levels in treating the described patients on a visual analogue scale. We calculated summary scores for the non intervention survey group (NINT) and intervention survey group (INT) and compared them using Student's t-test. RESULTS: Seventy-nine percent (33/42) of eligible participants completed the pre-intervention survey (21 attendings, 12 residents) and comprised the NINT group. Fifty-five percent (23/42) completed the post-intervention survey (16 attendings, 7 residents) comprising the INT group. A comparison of summary scores between 'NINT' and 'INT' groups showed a highly significant improvement in comfort levels with treating the patients described in the scenarios (P = 0.003). Improvements were noted on separate analysis for faculty (P = 0.039) and for residents (P = 0.012). Results of a sensitivity analysis excluding one highly significant scenario showed decreased, but still important differences between the NINT and INT groups for all participants and for residents, but not for faculty (all: P = 0.05; faculty: P = 0.25; residents: P = 0.03). CONCLUSION: This pilot study suggests that the comfort level of EPs, when asked to treat PBPs, may be improved with education. We believe our data support further study of this idea and of whether an improved comfort level will translate to a willingness to treat. PMID- 23359643 TI - Correlation of Minimum Inhibitory Concentration Breakpoints and Methicillin Resistance Gene Carriage in Clinical Isolates of Staphylococcus epidermidis. AB - Staphylococcus epidermidis is the most important member of coagulase negative staphylococci responsible for community and hospital acquired infections. Most clinical isolates of S. epidermidis are resistant to methicillin making these infections difficult to treat. In this study, correlation of methicillin resistance phenotype was compared with methicillin resistance (mecA) gene carriage in 55 clinical isolates of S. epidermidis. Susceptibility was measured by disc diffusion using methicillin discs, and minimum inhibitory concentrations (MIC) were measured using broth microdilution. Methicillin resistance gene (MecA gene) carriage was detected by specific primers and PCR. Disc susceptibility results showed 90.9% resistance to methicillin. Considering a MIC of 4 ug/ml, 78.1% of the isolates were methicillin resistant, 76.36% of which carried the mecA gene. On the other hand, when a breakpoint of 0.5 ug/ml was used, 89.09% were methicillin resistant, of which 93.75% were mecA positive. There was a better correlation between MIC of 0.5 ug/ml with disc diffusion results and mecA gene carriage. The findings suggest that despite the usefulness of molecular methods for rapid diagnosis of virulence genes, gene carriage does not necessarily account for virulence phenotype. Ultimately, gene expression, which is controlled by the environment, would determine the outcome. PMID- 23359645 TI - Limitations of widely used high-risk human papillomavirus laboratory-developed testing in cervical cancer screening. PMID- 23359644 TI - Sex-specific signaling in the blood-brain barrier is required for male courtship in Drosophila. AB - Soluble circulating proteins play an important role in the regulation of mating behavior in Drosophila melanogaster. However, how these factors signal through the blood-brain barrier (bbb) to interact with the sex-specific brain circuits that control courtship is unknown. Here we show that male identity of the blood brain barrier is necessary and that male-specific factors in the bbb are physiologically required for normal male courtship behavior. Feminization of the bbb of adult males significantly reduces male courtship. We show that the bbb specific G-protein coupled receptor moody and bbb-specific Go signaling in adult males are necessary for normal courtship. These data identify sex-specific factors and signaling processes in the bbb as important regulators of male mating behavior. PMID- 23359646 TI - Evaluation of treatment response for breast cancer: are we entering the era of "biological complete remission"? AB - Breast cancer is one of the most common malignancies in women. The post-operative recurrence and metastasis are the leading causes of breast cancer-related mortality. In this study, we tried to explore the role of circulating tumor cell (CTC) detection combination PET/CT technology evaluating the prognosis and treatment response of patients with breast cancer; meanwhile, we attempted to assess the concept of "biological complete remission" (bCR) in this regard. A 56 year-old patient with breast cancer (T(2)N(1)M(1), stage IV left breast cancer, with metastasis to axillary lymph nodes and lungs) received 6 cycles of salvage treatment with albumin-bound paclitaxel plus capecitabine and trastuzumab. Then, she underwent CTC detection and PET/CT for efficacy evaluation. CTC detection combination PET/CT is useful for the evaluation of the biological efficacy of therapies for breast cancer. The bCR of the patient appeared earlier than the conventional clinical imaging complete remission and promised the histological (pathological) complete remission. The integrated application of the concepts including bCR, imageological CR, and histological CR can achieve the early and accurate assessment of biological therapeutic reponse and prognosis of breast cancer. PMID- 23359648 TI - Nedaplatin/Gemcitabine Versus Carboplatin/Gemcitabine in Treatment of Advanced Non-small Cell Lung Cancer: A Randomized Clinical Trial. AB - OBJECTIVE: To evaluate the efficacy and safety of nedaplatin/gemcitabine (NG) and carboplatin/gemcitabine (CG) in the management of untreated advanced non-small cell lung cancer (NSCLC). METHODS: Sixty-two patients with previously untreated advanced NSCLC were recruited between June 2006 and November 2007. Subjects were randomly assigned to the NG arm (n=30) and the CG arm (n=32). Only patients (24 and 25 in the NG and CG arms, respectively) who completed >=2 chemotherapy cycles were included in the data analysis. The primary outcome measure was the objective response rate (ORR). The secondary outcome measures included progression-free survival (PFS), overall survival (OS) and adverse events. RESULTS: There were no statistically significant differences in the efficacy measures (ORR, P=0.305; median PFS, P=0.198; median OS, P=0.961) or in the major adverse events (grade 3/4 neutropenia, P=0.666; grade 3/4 anemia, P=0.263; grade 3/4 thrombocytopenia, P=0.212) between the two treatment arms. However, there was a trend towards higher ORR (37.5% vs. 24.0%), longer PFS (6.0 vs. 5.0 months), and less adverse events in the NG arm. CONCLUSION: NG regimen seems to be superior over CG regimen for advance NSCLS, but further investigation is needed to validate this superiority. PMID- 23359647 TI - A pathogen type III effector with a novel E3 ubiquitin ligase architecture. AB - Type III effectors are virulence factors of Gram-negative bacterial pathogens delivered directly into host cells by the type III secretion nanomachine where they manipulate host cell processes such as the innate immunity and gene expression. Here, we show that the novel type III effector XopL from the model plant pathogen Xanthomonas campestris pv. vesicatoria exhibits E3 ubiquitin ligase activity in vitro and in planta, induces plant cell death and subverts plant immunity. E3 ligase activity is associated with the C-terminal region of XopL, which specifically interacts with plant E2 ubiquitin conjugating enzymes and mediates formation of predominantly K11-linked polyubiquitin chains. The crystal structure of the XopL C-terminal domain revealed a single domain with a novel fold, termed XL-box, not present in any previously characterized E3 ligase. Mutation of amino acids in the central cavity of the XL-box disrupts E3 ligase activity and prevents XopL-induced plant cell death. The lack of cysteine residues in the XL-box suggests the absence of thioester-linked ubiquitin-E3 ligase intermediates and a non-catalytic mechanism for XopL-mediated ubiquitination. The crystal structure of the N-terminal region of XopL confirmed the presence of a leucine-rich repeat (LRR) domain, which may serve as a protein protein interaction module for ubiquitination target recognition. While the E3 ligase activity is required to provoke plant cell death, suppression of PAMP responses solely depends on the N-terminal LRR domain. Taken together, the unique structural fold of the E3 ubiquitin ligase domain within the Xanthomonas XopL is unprecedented and highlights the variation in bacterial pathogen effectors mimicking this eukaryote-specific activity. PMID- 23359649 TI - Photostable fluorescent organic dots with aggregation-induced emission (AIE dots) for noninvasive long-term cell tracing. AB - Long-term noninvasive cell tracing by fluorescent probes is of great importance to life science and biomedical engineering. For example, understanding genesis, development, invasion and metastasis of cancerous cells and monitoring tissue regeneration after stem cell transplantation require continual tracing of the biological processes by cytocompatible fluorescent probes over a long period of time. In this work, we successfully developed organic far-red/near-infrared dots with aggregation-induced emission (AIE dots) and demonstrated their utilities as long-term cell trackers. The high emission efficiency, large absorptivity, excellent biocompatibility, and strong photobleaching resistance of the AIE dots functionalized by cell penetrating peptides derived from transactivator of transcription proteins ensured outstanding long-term noninvasive in vitro and in vivo cell tracing. The organic AIE dots outperform their counterparts of inorganic quantum dots, opening a new avenue in the development of fluorescent probes for following biological processes such as carcinogenesis. PMID- 23359650 TI - How Frequently are "Classic" Drug-Seeking Behaviors Used by Drug-Seeking Patients in the Emergency Department? AB - INTRODUCTION: Drug-seeking behavior (DSB) in the emergency department (ED) is a very common problem, yet there has been little quantitative study to date of such behavior. The goal of this study was to assess the frequency with which drug seeking patients in the ED use classic drug seeking behaviors to obtain prescription medication. METHODS: We performed a retrospective chart review on patients in an ED case management program for DSB. We reviewed all visits by patients in the program that occurred during a 1-year period, and recorded the frequency of the following behaviors: complaining of headache, complaining of back pain, complaining of dental pain, requesting medication by name, requesting a refill of medication, reporting medications as having been lost or stolen, reporting 10/10 pain, reporting greater than 10/10 pain, reporting being out of medication, and requesting medication parenterally. These behaviors were chosen because they are described as "classic" for DSB in the existing literature. RESULTS: We studied 178 patients from the case management program, who made 2,486 visits in 1 year. The frequency of each behavior was: headache 21.7%, back pain 20.8%, dental pain 1.8%, medication by name 15.2%, requesting refill 7.0%, lost or stolen medication 0.6%, pain 10/10 29.1%, pain greater than 10/10 1.8%, out of medication 9.5%, and requesting parenteral medication 4.3%. Patients averaged 1.1 behaviors per visit. CONCLUSION: Drug-seeking patients appear to exhibit "classically" described drug-seeking behaviors with only low to moderate frequency. Reliance on historical features may be inadequate when trying to assess whether or not a patient is drug-seeking. PMID- 23359651 TI - Synthesis of water-soluble poly(alpha-hydroxy acids) from living ring-opening polymerization of O-benzyl-L-serine carboxyanhydrides. AB - O-benzyl-L-serine carboxyanhydrides were synthesized via diazotization of O benzyl-L-serine with sodium nitrite in aqueous sulfuric acid solution followed by cyclization of the resulting serine-based alpha-hydroxy acid with phosgene. Degradable, water-soluble poly(alpha-hydroxy acids) bearing pendant hydroxyl groups were readily prepared under mild conditions via ring-opening polymerization of O-benzyl-L-serine carboxyanhydrides followed by removal of the benzyl group and showed excellent cell compatibility, suggesting their potential being used as novel materials in constructing drug delivery systems and as hydrogel scaffolds for tissue engineering applications. PMID- 23359653 TI - Adie's Tonic Pupil. PMID- 23359652 TI - SB225002 promotes mitotic catastrophe in chemo-sensitive and -resistant ovarian cancer cells independent of p53 status in vitro. AB - Recent evidence indicates that CXCR2 signaling is crucial for cancer progression, and its antagonist SB225002 induces apoptosis in Wilms' tumor cells. Here, we investigated the effect of SB225002 on cell cycle progression and apoptosis induction in vitro, using CDDP-sensitive and -resistant OVCA cell lines with different p53 status (wild type, mutant or null). Adenovirus infection of wild type p53 or transfection of p53 siRNA was used to over-express or knock-down p53. Cell cycle and apoptosis were determined by flow cytometry or Hoechst staining and observation of nuclear morphology. Our data demonstrated that SB225002 induced apoptosis in both wild-type and p53-deficient ovarian cancer (OVCA) cells through alternative mechanisms. SB225002 promoted mitotic catastrophe, as evidenced by the accumulation of mitotic cells with spindle abnormalities, chromosome mis-segregation, multi-polar cell division, multiple nuclei, aneuploidy/polyploidy and subsequent extensive apoptosis. SB225002-induced mitotic catastrophe appeared to be mediated by down-regulation of checkpoint kinase Chk1 and Cdk1-cyclin B activation. In cells expressing wild-type p53 (OV2008 and C13*), SB225002 increased total and phospho-Ser p53 levels, and p53 knock-down decreased SB225002-induced apoptosis, without affecting premature mitosis. These results suggest that SB225002 induces p53-dependent apoptosis, and provokes mitotic catastrophe in p53-independent manner in p53 wild-type cells. Reconstitution with wild-type P53 in P53-null SKOV3 cell attenuated SB225002 induced mitotic catastrophe, suggesting p53 prevented mitotic catastrophe induced by SB225002 in p53-deficient OVCA cells. Finally, the effect of SB225002 could not be prevented by pretreatment with CXCR2 ligand or its neutralizing antibody. The present studies demonstrate for the first time that SB225002 has dual actions in OVCA cells, inducing classic apoptosis through p53 activation and provoking mitotic catastrophe in both p53 wild-type and deficient cells by Chk1 inhibition and Cdk activation. These findings raise the possibility of SB225002 as a new candidate molecule for OVCA therapy independent of the p53 status. PMID- 23359654 TI - A comparison of 4- and 24-hour urine samples for the diagnosis of proteinuria in pregnancy. AB - BACKGROUND: Preeclampsia is a serious complication of pregnancy, and it is vital to diagnosis the condition as early as possible. Proteinuria is an important symptom of preeclampsia, and repeated urine analysis to screen for the condition is part of the standard antenatal care. The purpose of this study was to determine the correlation between 4- and 24-hour urine total protein values to examine whether the 4-hour urine samples could be used for the diagnosis of proteinuria in hypertensive disorders of pregnancy. METHODS: A cross-sectional study was performed on 110 pregnant (after gestational week 20 of pregnancy) patients who were hypertensive (blood pressure >=140/90 mmHg) and had proteinuria as defined by positive urinary protein of at least 1+ in dipstick. Patients' urine samples were collected over 24 hours; the first 4 hours were collected separately from the next 20-hours. Patients, who did not collect the 24-hour urine, were excluded from the study. One hundred patients met the criteria, and were included in the study. The urine volume, total protein and creatinine levels of 4- and 24-hours samples were measured. The correlation between 4-hour and 24 hour samples was examined using Pearson correlation test. RESULTS: Of the 100 patients, 42 had no proteinuria, 44 had mild proteinuria, and 14 had severe proteinuria. The urine protein values of 4-hour samples correlated with those of the 24-hours samples for patients with mild and severe forms of the disease (P<0.001, r=0.86). CONCLUSION: This study showed there was a correlation between 4-hour and 24-hour urine proteins. The finding indicates that a random 4-hour sample might be used for the initial assessment of proteinuria. PMID- 23359655 TI - Morphine- and buprenorphine-induced analgesia and antihyperalgesia in a human inflammatory pain model: a double-blind, randomized, placebo-controlled, five-arm crossover study. AB - PURPOSE: Opioid therapy is associated with the development of tolerance and paradoxically increased sensitivity to pain. It has been suggested that buprenorphine is associated with a higher antihyperalgesia/analgesia ratio than MU-opioid receptor agonists. The primary outcome of this study was therefore to investigate relative differences in antihyperalgesia and analgesia effects between morphine and buprenorphine in an inflammatory pain model in volunteers. The secondary outcome was to examine the relationship between pain sensitivity and opioid-induced effects on analgesia, antihyperalgesia, and descending pain modulation. SUBJECTS AND METHODS: Twenty-eight healthy subjects were included. The study was a double-blind, randomized, placebo-controlled, five-arm crossover study with a multimodal (electrical, mechanical, and thermal stimuli) testing technique. After baseline assessments, intravenous infusions of morphine (10/20 mg), buprenorphine (0.3/0.6 mg), or placebo (normal saline) were administered over a 210-minute period, during which a cold pressor test, heat injury (47 degrees C, 7 minutes, 12.5 cm(2)), and the first postburn assessment were done. After completion of the drug infusions, two additional postburn assessments were done. The subjects were monitored during each 8-hour session by an anesthesiologist. RESULTS: For nearly all tested variables, significant dose dependent analgesic effects were demonstrated. The median antihyperalgesia/analgesia ratio (secondary hyperalgesia/heat injury relative to placebo) for low-dose morphine was 0.01 (interquartile range: -6.2; 9.9), 0.00 ( 2.4; 2.1) for high-dose morphine, 0.03 (-1.8; 2.1) for low-dose buprenorphine, and 0.00 (-3.2; 1.1) for high-dose buprenorphine (P > 0.466). There were no significant differences in opioid responses between high and low pain-sensitive subjects (P > 0.286). High-dose buprenorphine, compared to placebo, was associated with a significantly enhanced action of the descending inhibitory pain control system (P = 0.004). CONCLUSION: The present study, using multimodal testing technique, could not demonstrate any significant differences between morphine and buprenorphine in the profiles of antihyperalgesia and analgesia. Only high-dose buprenorphine was associated with a significant effect on the descending inhibitory pain control system. PMID- 23359658 TI - Barriers to clinical translation with diagnostic drugs. AB - Radioactive imaging agents, like diagnostic drugs generally, undergo a drug development process that parallels that of therapeutic agents, with similar development times but substantially lower development costs and substantially smaller postapproval markets. Although rapid advances in genetic and expression profiling are furthering the development of expensive pharmacotherapies targeted to small patient populations, the commercial development of imaging agents for small patient populations is blocked by the limited revenues available with current per-dose pricing and the relatively small numbers of imaging procedures that would be performed. A wide-ranging discussion on the best approaches to allow new diagnostic imaging agents to become part of the health-care system, and benefit the patient, is needed. PMID- 23359657 TI - Assessment of cellular proliferation in tumors by PET using 18F-ISO-1. AB - This first study in humans was designed to evaluate the safety and dosimetry of a cellular proliferative marker, N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H) yl)butyl)-2-(2-(18)F-fluoroethoxy)-5-methylbenzamide ((18)F-ISO-1), and evaluate the feasibility of imaging tumor proliferation by PET in patients with newly diagnosed malignant neoplasms. METHODS: Patients with biopsy-proven lymphoma, breast cancer, or head and neck cancer underwent (18)F-ISO-1 PET. Tumor (18)F-ISO 1 uptake was assessed semiquantitatively by maximum standardized uptake value, ratios of tumor to normal tissue and tumor to muscle, and relative distribution volume ratio. The PET results were correlated with tumor Ki-67 and mitotic index, from in vitro assays of the tumor tissue. The biodistribution of (18)F-ISO-1 and human dosimetry were evaluated. RESULTS: Thirty patients with primary breast cancer (n = 13), head and neck cancer (n = 10), and lymphoma (n = 7) were evaluated. In the entire group, tumor maximum standardized uptake value and tumor to-muscle ratio correlated significantly with Ki-67 (tau = 0.27, P = 0.04, and tau = 0.38, P = 0.003, respectively), but no significant correlation was observed between Ki-67 and tumor-to-normal-tissue ratio (tau = 0.07, P = 0.56) or distribution volume ratio (tau = 0.26, P = 0.14). On the basis of whole-body PET data, the gallbladder is the dose-limiting organ, with an average radiation dose of 0.091 mGy/MBq. The whole-body and effective doses were 0.012 mGy/MBq and 0.016 mSv/MBq, respectively. No adverse effects of (18)F-ISO-1 were encountered. CONCLUSION: The presence of a significant correlation between (18)F-ISO-1 and Ki 67 makes this agent promising for evaluation of the proliferative status of solid tumors. The relatively small absorbed doses to normal organs allow for the safe administration of up to 550 MBq, which is sufficient for PET imaging in clinical trials. PMID- 23359656 TI - Sequencing of Pax6 loci from the elephant shark reveals a family of Pax6 genes in vertebrate genomes, forged by ancient duplications and divergences. AB - Pax6 is a developmental control gene essential for eye development throughout the animal kingdom. In addition, Pax6 plays key roles in other parts of the CNS, olfactory system, and pancreas. In mammals a single Pax6 gene encoding multiple isoforms delivers these pleiotropic functions. Here we provide evidence that the genomes of many other vertebrate species contain multiple Pax6 loci. We sequenced Pax6-containing BACs from the cartilaginous elephant shark (Callorhinchus milii) and found two distinct Pax6 loci. Pax6.1 is highly similar to mammalian Pax6, while Pax6.2 encodes a paired-less Pax6. Using synteny relationships, we identify homologs of this novel paired-less Pax6.2 gene in lizard and in frog, as well as in zebrafish and in other teleosts. In zebrafish two full-length Pax6 duplicates were known previously, originating from the fish-specific genome duplication (FSGD) and expressed in divergent patterns due to paralog-specific loss of cis elements. We show that teleosts other than zebrafish also maintain duplicate full length Pax6 loci, but differences in gene and regulatory domain structure suggest that these Pax6 paralogs originate from a more ancient duplication event and are hence renamed as Pax6.3. Sequence comparisons between mammalian and elephant shark Pax6.1 loci highlight the presence of short- and long-range conserved noncoding elements (CNEs). Functional analysis demonstrates the ancient role of long-range enhancers for Pax6 transcription. We show that the paired-less Pax6.2 ortholog in zebrafish is expressed specifically in the developing retina. Transgenic analysis of elephant shark and zebrafish Pax6.2 CNEs with homology to the mouse NRE/Palpha internal promoter revealed highly specific retinal expression. Finally, morpholino depletion of zebrafish Pax6.2 resulted in a "small eye" phenotype, supporting a role in retinal development. In summary, our study reveals that the pleiotropic functions of Pax6 in vertebrates are served by a divergent family of Pax6 genes, forged by ancient duplication events and by independent, lineage-specific gene losses. PMID- 23359659 TI - Modeling cyclosporine A inhibition of the distribution of a P-glycoprotein PET ligand, 11C-verapamil, into the maternal brain and fetal liver of the pregnant nonhuman primate: impact of tissue blood flow and site of inhibition. AB - Through PET imaging, our laboratory has studied the dynamic biodistribution of (11)C-verapamil, a P-gp substrate, in the nonhuman primate Macaca nemestrina. To gain detailed insight into the kinetics of verapamil transport across the blood brain barrier (BBB) and the blood-placental barrier (BPB), we analyzed these dynamic biodistribution data by compartmental modeling. METHODS: Thirteen pregnant macaques (gestational age, 71-159 d; term, ~172 d) underwent PET imaging with (11)C-verapamil before and during infusion (6, 12, or 24 mg/kg/h) of cyclosporine A (CsA, a P-glycoprotein [P-gp] inhibitor). Dynamic (11)C-verapamil brain or fetal liver (reporter of placental P-gp function) activity was assessed by a 1- or 2-tissue-compartment model. RESULTS: The 1-tissue-compartment model best explained the observed brain and fetal liver distribution of (11)C radioactivity. When P-gp was completely inhibited, the brain and fetal liver distribution clearance (K1) approximated tissue blood flow (Q); that is, extraction ratio (K1/Q) was approximately 1, indicating that in the absence of P gp function, the distribution of (11)C-verapamil radioactivity into these compartments is limited by blood flow. The potency of CsA to inhibit P-gp was tissue-independent (maternal BBB half-maximal inhibitory concentration [IC50], 5.67 +/- 1.07 MUM, vs. BPB IC50, 7.63 +/- 3.16 MUM). CONCLUSION: We propose that on deliberate or inadvertent P-gp inhibition, the upper boundary of increase in human brain (or fetal) distribution of lipophilic drugs such as verapamil will be limited by tissue blood flow. This finding provides a means to predict the magnitude of P-gp-based drug interactions at the BBB and BPB when only the baseline distribution of the drug (i.e., in the absence of P-gp inhibition) across these barriers is available through PET. Our data suggest that P-gp-based drug interactions at the human BBB and BPB can be clinically significant, particularly for those P-gp substrate drugs for which P-gp plays a significant role in excluding the drug from these privileged compartments. PMID- 23359660 TI - EANM/SNMMI guideline for 18F-FDG use in inflammation and infection. PMID- 23359661 TI - Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association. AB - Positron emission tomography (PET) of brain amyloid beta is a technology that is becoming more available, but its clinical utility in medical practice requires careful definition. To provide guidance to dementia care practitioners, patients, and caregivers, the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened the Amyloid Imaging Taskforce (AIT). The AIT considered a broad range of specific clinical scenarios in which amyloid PET could potentially be used appropriately. Peer-reviewed, published literature was searched to ascertain available evidence relevant to these scenarios, and the AIT developed a consensus of expert opinion. Although empirical evidence of impact on clinical outcomes is not yet available, a set of specific appropriate use criteria (AUC) were agreed on that define the types of patients and clinical circumstances in which amyloid PET could be used. Both appropriate and inappropriate uses were considered and formulated, and are reported and discussed here. Because both dementia care and amyloid PET technology are in active development, these AUC will require periodic reassessment. Future research directions are also outlined, including diagnostic utility and patient-centered outcomes. PMID- 23359662 TI - Vasopressin V(1A) receptors mediate the increase in gastric mucosal oxygenation during hypercapnia. AB - Hypercapnia (HC) improves systemic oxygen delivery (DO2) and microvascular hemoglobin oxygenation of the mucosa (MUHbO2). Simultaneously, HC increases plasma levels of vasopressin. Although vasopressin is generally regarded a potent vasoconstrictor particularly in the splanchnic region, its effects on splanchnic microcirculation during HC is unclear. The aim of this study was to evaluate the role of endogenous vasopressin on gastric mucosal oxygenation and hemodynamic variables during physiological (normocapnia) and hypercapnic conditions. Five dogs were repeatedly anesthetized to study the effect of vasopressin V(1A) receptor blockade ([Pmp1,Tyr(Me)2]-Arg8-Vasopressin, 35 MUg/kg) on hemodynamic variables and MUHbO2 during normocapnia or HC (end-tidal CO2 70 mmHg). In a control group, animals were subjected to HC alone. MUHbO2 was measured by reflectance spectrophotometry, systemic DO2 was calculated from intermittent blood gas analysis, and cardiac output was measured by transpulmonary thermodilution. Data are presented as mean+/-s.e.m. for n=5 animals. During HC alone, DO2 increased from 12+/-1 to 16+/-1 ml/kg per min and MUHbO2 from 70+/-4 to 80+/-2%. By contrast, additional vasopressin V(1A) receptor blockade abolished the increase in MUHbO2 (80+/-2 vs. 69+/-2%) without altering the increase in DO2 (16+/-1 vs. 19+/-2 ml/kg per min). Vasopressin V1A receptor blockade (VB) during normocapnia neither affected DO2 (13+/-1 vs. 14+/-1 ml/kg per min) nor MUHbO2 (75+/-3 vs. 71+/-5%). Vasopressin V(1A) receptor blockade abolished the increase in MUHbO2 during HC independent of DO2. Thus, in contrast to its generally vasoconstrictive properties, the vasopressin V1A receptors seem to mediate the increase in gastric microcirculatory mucosal oxygenation induced by acute HC. PMID- 23359663 TI - Assembly of the transmembrane domain of E. coli PhoQ histidine kinase: implications for signal transduction from molecular simulations. AB - The PhoQP two-component system is a signaling complex essential for bacterial virulence and cationic antimicrobial peptide resistance. PhoQ is the histidine kinase chemoreceptor of this tandem machine and assembles in a homodimer conformation spanning the bacterial inner membrane. Currently, a full understanding of the PhoQ signal transduction is hindered by the lack of a complete atomistic structure. In this study, an atomistic model of the key transmembrane (TM) domain is assembled by using molecular simulations, guided by experimental cross-linking data. The formation of a polar pocket involving Asn202 in the lumen of the tetrameric TM bundle is crucial for the assembly and solvation of the domain. Moreover, a concerted displacement of the TM helices at the periplasmic side is found to modulate a rotation at the cytoplasmic end, supporting the transduction of the chemical signal through a combination of scissoring and rotational movement of the TM helices. PMID- 23359666 TI - Coverage gap in maternal and child health services in India: assessing trends and regional deprivation during 1992-2006. AB - BACKGROUND: Increasing the coverage of key maternal, newborn and child health interventions is essential, if India has to attain Millennium Development Goals 4 and 5. This study assesses the coverage gap in maternal and child health services across states in India during 1992-2006 emphasizing the rural-urban disparities. Additionally, association between the coverage gap and under-5 mortality rate across states are illustrated. METHODS: The three waves of National Family Health Survey (NFHS) conducted during 1992-1993 (NFHS-1), 1998-1999 (NFHS-2) and 2005 2006 (NFHS-3) were used to construct a composite index of coverage gap in four areas of health-care interventions: family planning, maternal and newborn care, immunization and treatment of sick children. RESULTS: The central, eastern and northeastern regions of India reported a higher coverage gap in maternal and child health care services during 1992-2006, while the rural-urban difference in the coverage gap has increased in Gujarat, Haryana, Rajasthan and Kerala over the period. The analysis also shows a significant positive relationship between the coverage gap index and under-five mortality rate across states. CONCLUSION: Region or area-specific focus in order to increase the coverage of maternal and child health care services in India should be the priority of the policy-makers and programme executors. PMID- 23359665 TI - A novel macrolide solithromycin exerts superior anti-inflammatory effect via NF kappaB inhibition. AB - Macrolides are reported to reduce exacerbation of chronic inflammatory respiratory disease, such as chronic obstructive pulmonary disease (COPD), and also show anti-inflammatory effects in vitro and in vivo. However the anti inflammatory efficacies of current macrolides are relatively weak. Here we found that a novel macrolide/fluoroketolide solithromycin (CEM-101) showed superior anti-inflammatory effects to macrolides in current clinical use. The effects of solithromycin (SOL) on lipopolysaccharide-induced TNFalpha (tumor necrosis factor alpha) and/or CXCL8 (C-X-C motif chemokine ligand 8; interleukin-8) release, phorbol 12-myristate 13-acetate-induced MMP9 (matrix metalloproteinase 9) activity and NF-kappaB (nuclear factor-kappaB) activity under conditions of oxidative stress have been evaluated and compared with the effects of erythromycin, clarithromycin, azithromycin, and telithromycin in macrophage-like PMA-differentiated U937 cells and peripheral blood mononuclear cells (PBMC) obtained from COPD patients. We also examined effect of SOL on cigarette smoke induced airway inflammation in mice. SOL exerted superior inhibitory effects on TNFalpha/CXCL8 production and MMP9 activity in monocytic U937 cells. In addition, SOL suppressed TNFalpha release and MMP9 activity in PBMC from COPD patients at 10 uM, which is 10 times more potent than the other macrolides tested. Activated NF-kappaB by oxidative stress was completely reversed by SOL. SOL also inhibited cigarette smoke-induced neutrophilia and pro-MMP9 production in vivo, although erythromycin did not inhibit them. Thus, SOL showed better anti-inflammatory profiles compared with macrolides currently used in the clinic and may be a promising anti-inflammatory and antimicrobial macrolide for the treatment of COPD in future. PMID- 23359664 TI - Motivational Enhancement System for Adherence (MESA): pilot randomized trial of a brief computer-delivered prevention intervention for youth initiating antiretroviral treatment. AB - OBJECTIVE: To pilot test a two-session computer-delivered motivational intervention to facilitate adherence among youth with HIV newly prescribed antiretroviral treatment (ART). METHODS: Youth (N = 76) newly prescribed ART were recruited from 8 sites, and were randomized to the intervention or an active nutrition and physical activity control. Primary outcomes were HIV-1 viral load at baseline, 3 months, and 6 months, and self-reported adherence at 3 and 6 months. RESULTS: Satisfaction ratings were high. Effect sizes suggested that the intervention group showed a greater drop than controls in viral load from baseline to 6 months (Cohen's d = 0.39 at 3 months; d = 0.19 at 6 months), and had greater percent undetectable by 6 months (d = 0.28). Effects sizes were medium to large for 7-day and weekend adherence. CONCLUSIONS: A brief computer delivered motivational intervention showed promise for youth starting ART and is ready to be tested in a full-scale clinical trial. PMID- 23359667 TI - Fibre type-specific change in FXYD1 phosphorylation during acute intense exercise in humans. AB - The aim of the present study was to examine fibre type-specific Na(+)-K(+) pump subunit expression and exercise-induced alterations in phospholemman (FXYD1) phosphorylation in humans. Segments of human skeletal muscle fibres were dissected and fibre typed, and protein expression was determined by Western blotting. The protein expression of the Na(+)-K(+) pump alpha2 isoform was lower in type I than in type II fibres (0.63 +/- 0.04 a.u. vs. 1.00 +/- 0.07 a.u., P < 0.001), while protein expression of the Na(+)-K(+) pump alpha1 and beta1 isoforms was not different. Protein expression of the ATP-dependent potassium channel Kir6.2 was higher in type I compared with type II fibres. In both type I (P < 0.01) and type II fibres (P < 0.001) the AB_FXYD1 signal was lower after exercise compared with rest, indicating an increase in unspecific FXYD1 phosphorylation. The FXYD1 serine 68 phosphorylation was higher (P < 0.001) after exercise compared with rest in type II fibres (1.90 +/- 0.25 vs. 1.00 +/- 0.08) and not changed in type I fibres. Total FXYD1 was not expressed in a fibre type-specific manner. Expression of phosphofructokinase was lower (P < 0.001) in type I than in type II fibres, whereas citrate synthase and 3-hydroxyacyl-CoA dehydrogenase were more abundant (P < 0.001) in type I fibres. In conclusion, FXYD1 phosphorylation at serine 68 increased after an acute bout of intense exercise in human type II fibres, while AB_FXYD1 signal intensity was lower in both type I and type II fibres, indicating fibre type-specific differences in FXYD1 phosphorylation on serine 63, serine 68 and threonine 69. This, together with the observation of a higher abundance of the Na(+)-K(+) pump alpha2 isoform protein in type II fibres, is likely to have importance for the exercise-induced human Na(+)-K(+) pump activity in the different fibre types. PMID- 23359668 TI - Functional significance of synaptic terminal size in glutamatergic sensory pathways in thalamus and cortex. AB - Glutamatergic pathways are a major information-carrying and -processing network of inputs in the brain. There is considerable evidence suggesting that glutamatergic pathways do not represent a homogeneous group and that they can be segregated into at least two broad categories. Class 1 glutamatergic inputs, which are suggested to be the main information carriers, are characterized by a number of unique synaptic and anatomical features, such as the large synaptic boutons with which they often terminate. On the other hand, Class 2 inputs, which are thought to play a modulatory role, are associated, amongst other features, with exclusively small terminal boutons. Here we summarize and briefly discuss these two classes of glutamatergic input and how their unique features, including their terminal bouton size and anatomy, are related to their suggested function. PMID- 23359669 TI - STIM2 drives Ca2+ oscillations through store-operated Ca2+ entry caused by mild store depletion. AB - Abstract Agonist-induced Ca(2+) oscillations in many cell types are triggered by Ca(2+) release from intracellular stores and driven by store-operated Ca(2+) entry. Stromal cell-interaction molecule (STIM) 1 and STIM2 serve as endoplasmic reticulum Ca(2+) sensors that, upon store depletion, activate Ca(2+) release activated Ca(2+) channels (Orai1-3, CRACM1-3) in the plasma membrane. However, their relative roles in agonist-mediated Ca(2+) oscillations remain ambiguous. Here we report that while both STIM1 and STIM2 contribute to store-refilling during Ca(2+) oscillations in mast cells (RBL), T cells (Jurkat) and human embryonic kidney (HEK293) cells, they do so dependent on the level of store depletion. Molecular silencing of STIM2 by siRNA or inhibition by G418 suppresses store-operated Ca(2+) entry and agonist-mediated Ca(2+) oscillations at low levels of store depletion, without interfering with STIM1-mediated signals induced by full store depletion. Thus, STIM2 is preferentially activated by low level physiological agonist concentrations that cause mild reductions in endoplasmic reticulum Ca(2+) levels. We conclude that with increasing agonist concentrations, store-operated Ca(2+) entry is mediated initially by endogenous STIM2 and incrementally by STIM1, enabling differential modulation of Ca(2+) entry over a range of agonist concentrations and levels of store depletion. PMID- 23359670 TI - The essential role of peripheral respiratory chemoreceptor inputs in maintaining breathing revealed when CO2 stimulation of central chemoreceptors is diminished. AB - Central sleep apnoea is a condition characterized by oscillations between apnoea and hyperpnoea during sleep. Studies in sleeping dogs suggest that withdrawal of peripheral chemoreceptor (carotid body) activation following transient ventilatory overshoots plays an essential role in causing apnoea, raising the possibility that sustaining carotid body activity during ventilatory overshoots may prevent apnoea. To test whether sustained peripheral chemoreceptor activation is sufficient to drive breathing, even in the absence of central chemoreceptor stimulation and vagal feedback, we used a vagotomized, decerebrate dual-perfused in situ rat preparation in which the central and peripheral chemoreceptors are independently and artificially perfused with gas-equilibrated medium. At varying levels of carotid body stimulation (CB PO2/PCO2: 40/60, 100/40, 200/15, 500/15 Torr), we decreased the brainstem perfusate PCO2 in 5 Torr steps while recording phrenic nerve activity to determine the central apnoeic thresholds. The central apnoeic thresholds decreased with increased carotid body stimulation. When the carotid bodies were strongly stimulated (CB 40/60), the apnoeic threshold was 3.6 +/- 1.4 Torr PCO2 (mean +/- SEM, n = 7). Stimulating carotid body afferent activity with either hypercapnia (60 Torr PCO2) or the neuropeptide pituitary adenylate cyclase-activating peptide restored phrenic activity during central apnoea. We conclude that peripheral stimulation shifts the central apnoeic threshold to very hypocapnic levels that would likely increase the CO2 reserve and have a protective effect on breathing. These data demonstrate that peripheral respiratory chemoreceptors are sufficient to stave off central apnoeas when the brainstem is perfused with low to no CO2. PMID- 23359672 TI - Calcium-dependent regulation of climbing fibre synapse elimination during postnatal cerebellar development. AB - Functional neural circuit formation during postnatal development involves massive elimination of early-formed redundant synapses and strengthening of necessary synaptic connections. In the cerebellum, one-to-one connection from a climbing fibre (CF) to a Purkinje cell (PC) is established through four distinct phases: (1) strengthening of a single CF among multiple CFs in each PC at postnatal age P3-P7 days, (2) translocation of a single strengthened CF to PC dendrites from around P9, (3) early-phase (P7 to around P11) and (4) late-phase (around P12-P17) elimination of weak CF synapses from PC somata. Mice with PC-selective deletion of the P/Q-type voltage-dependent Ca(2+) channel (VDCC) exhibit severe defects in strengthening of single CFs, dendritic translocation of single CFs and CF elimination from P7. In contrast, mice with a mutation of a single allele for the GABA synthesizing enzyme GAD67 show selective impairment of CF elimination from P10. Electrophysiological and Ca(2+) imaging data suggest that GABAA receptor mediated inhibition onto PC somata from putative basket cells influences CF induced Ca(2+) transients and regulates elimination of redundant CF synapses from PC somata at P10-P16. Thus, regulation of Ca(2+) influx to PCs through VDCCs is crucial for the four phases of CF synapse elimination during postnatal development. PMID- 23359671 TI - Endogenous activation of presynaptic NMDA receptors enhances glutamate release from the primary afferents in the spinal dorsal horn in a rat model of neuropathic pain. AB - Activation of N-methyl-D-aspartate (NMDA) receptors (NMDARs) is a crucial mechanism underlying the development and maintenance of pain. Traditionally, the role of NMDARs in the pathogenesis of pain is ascribed to their activation and signalling cascades in postsynaptic neurons. In this study, we determined if presynaptic NMDARs in the primary afferent central terminals play a role in synaptic plasticity of the spinal first sensory synapse in a rat model of neuropathic pain induced by spinal nerve ligation. Excitatory postsynaptic currents (EPSCs) were recorded from superficial dorsal horn neurons of spinal slices taken from young adult rats. We showed that increased glutamate release from the primary afferents contributed to the enhanced amplitudes of EPSCs evoked by input from the primary afferents in neuropathic rats. Endogenous activation of presynaptic NMDARs increased glutamate release from the primary afferents in neuropathic rats. Presynaptic NMDARs in neuropathic rats were mainly composed of NR2B receptors. The action of presynaptic NMDARs in neuropathic rats was enhanced by exogenous D-serine and/or NMDA and dependent on activation of protein kinase C. In contrast, glutamate release from the primary afferents in sham-operated rats was not regulated by presynaptic NMDARs. We demonstrated that the lack of NMDAR-mediated regulation of glutamate release in sham-operated rats was not attributable to low extracellular levels of the NMDAR agonist and/or coagonist (D serine), but rather was due to the insufficient function and/or number of presynaptic NMDARs. This was supported by an increase of NR2B receptor protein expression in both the dorsal root ganglion and spinal dorsal horn ipsilateral to the injury site in neuropathic rats. Hence, suppression of the presynaptic NMDAR activity in the primary sensory afferents is an effective approach to attenuate the enhanced glutamatergic response in the spinal first sensory synapse induced by peripheral nerve injury, and presynaptic NMDARs might be a novel target for the development of analgesics. PMID- 23359673 TI - Genetic ablation of aquaporin-2 in the mouse connecting tubules results in defective renal water handling. AB - Body water balance is regulated via the water channel aquaporin-2 (AQP2), which is expressed in the renal connecting tubule (CNT) and collecting duct (CD). The relative roles of AQP2 in the CNT and CD are not fully understood. To study the role of AQP2 in the CNT we generated a mouse model with CNT-specific AQP2 deletion (AQP2-CNT-knockout (KO)). Confocal laser scanning microscopy and immunogold electron microscopy demonstrated an absence of AQP2 in the CNT of AQP2 CNT-KO mice. Twenty-four hour urine output was significantly increased (KO: 3.0 +/- 0.3 ml (20 g body weight (BW))(-1); wild-type (WT): 1.9 +/- 0.3 ml (20 g BW)( 1)) and urine osmolality decreased (KO: 1179 +/- 107 mosmol kg(-1); WT: 1790 +/- 146 mosmol kg(-1)) in AQP2-CNT-KO mice compared with controls. After 24 h water restriction, urine osmolality was still significantly lower in AQP2-CNT-KO mice (KO: 2087 +/- 169 mosmol kg(-1); WT: 2678 +/- 144 mosmol kg(-1)). A significant difference in urine osmolality between groups before desmopressin (dDAVP) (KO: 873 +/- 129 mosmol kg(-1); WT: 1387 +/- 163 mosmol kg(-1)) was not apparent 2 h after injection, with urine osmolality increased significantly in both groups (KO: 2944 +/- 41 mosmol kg(-1); WT: 3133 +/- 66 mosmol kg(-1)). Cortical kidney fractions from AQP2-CNT-KO mice had significantly reduced AQP2, with no compensatory changes in sodium potassium chloride cotransporter (NKCC2), AQP3 or AQP4. Lithium chloride treatment increased urine volume and decreased osmolality in both WT and AQP2-CNT-KO mice. After 8 days of treatment, the AQP2-CNT-KO mice still had a significantly higher urine volume and lower urine osmolality, suggesting that the CNT does not play a significant role in the pathology of lithium-induced nephrogenic diabetes insipidus. Our studies indicate that the CNT plays a role in regulating body water balance under basal conditions, but not for maximal concentration of the urine during antidiuresis. PMID- 23359674 TI - Gastrin-releasing peptide acts via postsynaptic BB2 receptors to modulate inward rectifier K+ and TRPV1-like conductances in rat paraventricular thalamic neurons. AB - Gastrin-releasing peptide (GRP) is a bombesin-like peptide with a widespread distribution in mammalian CNS, where it has a role in food intake, circadian rhythm generation, fear memory, itch sensation and sexual behaviour. While it has been established that GRP predominantly excites neurons, details of the membrane mechanism involved in this action remain largely undefined. We used perforated patch clamp recording in acute brain slice preparations to investigate GRP affected receptors and ionic conductances in neurons of the rat paraventricular thalamic nucleus (PVT). PVT is a component of the midline and intralaminar thalamus that participates in arousal, motivational drives and stress responses, and exhibits a prominence of GRP-like immunoreactive fibres. Exposure of PVT neurons to low nanomolar concentrations of GRP induced sustained TTX-resistant membrane depolarizations that could trigger rhythmic burst discharges or tonic firing. Membrane current analyses in voltage clamp revealed an underlying postsynaptic bombesin type 2 receptor-mediated inward current that resulted from the simultaneous suppression of a Ba(2+)-sensitive inward rectifier K(+) conductance and activation of a non-selective cation conductance with biophysical and pharmacological properties reminiscent of transient receptor potential vanilloid (TRPV) 1. A role for a TRPV1-like conductance was further implied by a significant suppressant influence of a TRPV1 antagonist on GRP-induced membrane depolarization and rhythmic burst or tonic firing. The results provide a detailed picture of the receptor and ionic conductances that are involved in GRP's excitatory action in midline thalamus. PMID- 23359675 TI - Leaf-wax n-alkanes record the plant-water environment at leaf flush. AB - Leaf-wax n-alkanes (2)H/(1)H ratios are widely used as a proxy in climate reconstruction. Although the broad nature of the relationship between n-alkanes delta(2)H values and climate is appreciated, the quantitative details of the proxy remain elusive. To examine these details under natural environmental conditions, we studied a riparian broadleaf angiosperm species, Populus angustifolia, growing on water with a constant delta(2)H value and monitored the delta(2)H values of leaf-wax n-alkanes and of stem, leaf, stream, and atmospheric waters throughout the entire growing season. Here we found the delta(2)H values of leaf-wax n-alkanes recorded only a 2-wk period during leaf flush and did not vary for the 19 weeks thereafter when leaves remained active. We found delta(2)H values of leaf-wax n-alkanes of P. angustifolia record conditions earlier in the season rather than fully integrating the entire growing season. Using these data, we modeled precipitation delta(2)H values during the time of wax synthesis. We observed that the isotope ratios of this precipitation generally were (2)H enriched compared with mean annual precipitation. This model provides a mechanistic basis of the often-observed (2)H-enrichment from the expected fractionation values in studies of broadleaf angiosperm leaf-wax delta(2)H. In addition, these findings may have implications for the spatial and temporal uses of n-alkane delta(2)H values in paleoapplications; when both plant community and growth form are known, this study allows the isolation of the precipitation dynamics of individual periods of the growing season. PMID- 23359676 TI - Human Tim-Tipin complex affects the biochemical properties of the replicative DNA helicase and DNA polymerases. AB - Tim (Timeless) and Tipin (Tim-interacting protein) form a stable heterodimeric complex that influences checkpoint responses and replication fork progression. We report that the Tim-Tipin complex interacts with essential replication fork proteins and affects their biochemical properties. The Tim-Tipin complex, reconstituted and purified using the baculovirus expression system, interacts directly with Mcm complexes and inhibits the single-stranded DNA-dependent ATPase activities of the Mcm2-7 and Mcm4/6/7 complexes, the DNA unwinding activity of the Mcm4/6/7 complex, and the DNA unwinding and ATPase activity of Cdc45-Mcm2-7 GINS complex, the presumed replicative DNA helicase in eukaryotes. Although stable interactions between Tim-Tipin and DNA polymerases (pols) were not observed in immunoprecipitation experiments with purified proteins, Tim was shown to interact with DNA pols alpha, delta, and epsilon in cells. Furthermore, the Tim-Tipin complex significantly stimulated the pol activities of DNA pols alpha, delta, and epsilon in vitro. The effects of Tim-Tipin on the catalytic activities of the Mcm complexes and DNA pols are mediated by the Tim protein alone, and distinct regions of the Tim protein are responsible for the inhibition of Mcm complex activities and stimulation of DNA pols. These results suggest that the Tim-Tipin complex might play a role in coupling DNA unwinding and DNA synthesis by directly affecting the catalytic activities of replication fork proteins. PMID- 23359677 TI - Dorsolateral prefrontal and orbitofrontal cortex interactions during self-control of cigarette craving. AB - Drug-related cues induce craving, which may perpetuate drug use or trigger relapse in addicted individuals. Craving is also under the influence of other factors in daily life, such as drug availability and self-control. Neuroimaging studies using drug cue paradigms have shown frontal lobe involvement in this contextual influence on cue reactivity, but have not clarified how and which frontal area accounts for this phenomenon. We explored frontal lobe contributions to cue-induced drug craving under different intertemporal drug availability conditions by combining transcranial magnetic stimulation and functional magnetic resonance imaging in smokers. We hypothesized that the dorsolateral prefrontal cortex (DLPFC) regulates craving during changes in intertemporal availability. Subjective craving was greater when cigarettes were immediately available, and this effect was eliminated by transiently inactivating the DLPFC with transcranial magnetic stimulation. Functional magnetic resonance imaging demonstrated that the signal most proportional to subjective craving was located in the medial orbitofrontal cortex across all contexts, whereas the DLPFC most strongly encoded intertemporal availability information. The craving-related signal in the medial orbitofrontal cortex was attenuated by inactivation of the DLPFC, particularly when cigarettes were immediately available. Inactivation of the DLPFC also reduced craving-related signals in the anterior cingulate and ventral striatum, areas implicated in transforming value signals into action. These findings indicate that DLPFC builds up value signals based on knowledge of drug availability, and support a model wherein aberrant circuitry linking dorsolateral prefrontal and orbitofrontal cortices may underlie addiction. PMID- 23359678 TI - Iron induces bimodal population development by Escherichia coli. AB - Bacterial biofilm formation is a complex developmental process involving cellular differentiation and the formation of intricate 3D structures. Here we demonstrate that exposure to ferric chloride triggers rugose biofilm formation by the uropathogenic Escherichia coli strain UTI89 and by enteric bacteria Citrobacter koseri and Salmonella enterica serovar typhimurium. Two unique and separable cellular populations emerge in iron-triggered, rugose biofilms. Bacteria at the air-biofilm interface express high levels of the biofilm regulator csgD, the cellulose activator adrA, and the curli subunit operon csgBAC. Bacteria in the interior of rugose biofilms express low levels of csgD and undetectable levels of matrix components curli and cellulose. Iron activation of rugose biofilms is linked to oxidative stress. Superoxide generation, either through addition of phenazine methosulfate or by deletion of sodA and sodB, stimulates rugose biofilm formation in the absence of high iron. Additionally, overexpression of Mn superoxide dismutase, which can mitigate iron-derived reactive oxygen stress, decreases biofilm formation in a WT strain upon iron exposure. Not only does reactive oxygen stress promote rugose biofilm formation, but bacteria in the rugose biofilms display increased resistance to H(2)O(2) toxicity. Altogether, we demonstrate that iron and superoxide stress trigger rugose biofilm formation in UTI89. Rugose biofilm development involves the elaboration of two distinct bacterial populations and increased resistance to oxidative stress. PMID- 23359679 TI - WISP2 regulates preadipocyte commitment and PPARgamma activation by BMP4. AB - Inability to recruit new adipose cells following weight gain leads to inappropriate enlargement of existing cells (hypertrophic obesity) associated with inflammation and a dysfunctional adipose tissue. We found increased expression of WNT1 inducible signaling pathway protein 2 (WISP2) and other markers of WNT activation in human abdominal s.c. adipose tissue characterized by hypertrophic obesity combined with increased visceral fat accumulation and insulin resistance. WISP2 activation in the s.c. adipose tissue, but not in visceral fat, identified the metabolic syndrome in equally obese individuals. WISP2 is a novel adipokine, highly expressed and secreted by adipose precursor cells. Knocking down WISP2 induced spontaneous differentiation of 3T3-L1 and human preadipocytes and allowed NIH 3T3 fibroblasts to become committed to the adipose lineage by bone morphogenetic protein 4 (BMP4). WISP2 forms a cytosolic complex with the peroxisome proliferator-activated receptor gamma (PPARgamma) transcriptional activator zinc finger protein 423 (Zfp423), and this complex is dissociated by BMP4 in a SMAD-dependent manner, thereby allowing Zfp423 to enter the nucleus, activate PPARgamma, and commit the cells to the adipose lineage. The importance of intracellular Wisp2 protein for BMP4-induced adipogenic commitment and PPARgamma activation was verified by expressing a mutant Wisp2 protein lacking the endoplasmic reticulum signal and secretion sequence. Secreted Wnt/Wisp2 also inhibits differentiation and PPARgamma activation, albeit not through Zfp423 nuclear translocation. Thus adipogenic commitment and differentiation is regulated by the cross-talk between BMP4 and canonical WNT signaling and where WISP2 plays a key role. Furthermore, they link WISP2 with hypertrophic obesity and the metabolic syndrome. PMID- 23359680 TI - Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. AB - Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific de-ubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1(GLU7ALA)), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1(GLU7ALA), compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1(GLU7ALA) relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system. PMID- 23359681 TI - Direct chemical evidence for sphingolipid domains in the plasma membranes of fibroblasts. AB - Sphingolipids play important roles in plasma membrane structure and cell signaling. However, their lateral distribution in the plasma membrane is poorly understood. Here we quantitatively analyzed the sphingolipid organization on the entire dorsal surface of intact cells by mapping the distribution of (15)N enriched ions from metabolically labeled (15)N-sphingolipids in the plasma membrane, using high-resolution imaging mass spectrometry. Many types of control experiments (internal, positive, negative, and fixation temperature), along with parallel experiments involving the imaging of fluorescent sphingolipids--both in living cells and during fixation of living cells--exclude potential artifacts. Micrometer-scale sphingolipid patches consisting of numerous (15)N-sphingolipid microdomains with mean diameters of ~200 nm are always present in the plasma membrane. Depletion of 30% of the cellular cholesterol did not eliminate the sphingolipid domains, but did reduce their abundance and long-range organization in the plasma membrane. In contrast, disruption of the cytoskeleton eliminated the sphingolipid domains. These results indicate that these sphingolipid assemblages are not lipid rafts and are instead a distinctly different type of sphingolipid-enriched plasma membrane domain that depends upon cortical actin. PMID- 23359682 TI - Activity-based probes for rhomboid proteases discovered in a mass spectrometry based assay. AB - Rhomboid proteases are evolutionary conserved intramembrane serine proteases. Because of their emerging role in many important biological pathways, rhomboids are potential drug targets. Unfortunately, few chemical tools are available for their study. Here, we describe a mass spectrometry-based assay to measure rhomboid substrate cleavage and inhibition. We have identified isocoumarin inhibitors and developed activity-based probes for rhomboid proteases. The probes can distinguish between active and inactive rhomboids due to covalent, reversible binding of the active-site serine and stable modification of a histidine residue. Finally, the structure of an isocoumarin-based inhibitor with Escherichia coli rhomboid GlpG uncovers an unusual mode of binding at the active site and suggests that the interactions between the 3-substituent on the isocoumarin inhibitor and hydrophobic residues on the protease reflect S' subsite binding. Overall, these probes represent valuable tools for rhomboid study, and the structural insights may facilitate future inhibitor design. PMID- 23359683 TI - A random world is a fair world. PMID- 23359684 TI - Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. AB - Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. We analyzed the mutational landscape of USC by whole-exome sequencing of 57 cancers, most of which were matched to normal DNA from the same patients. The distribution of the number of protein-altering somatic mutations revealed that 52 USC tumors had fewer than 100 (median 36), whereas 5 had more than 3,000 somatic mutations. The mutations in these latter tumors showed hallmarks of defects in DNA mismatch repair. Among the remainder, we found a significantly increased burden of mutation in 14 genes. In addition to well-known cancer genes (i.e., TP53, PIK3CA, PPP2R1A, KRAS, FBXW7), there were frequent mutations in CHD4/Mi2b, a member of the NuRD-chromatin-remodeling complex, and TAF1, an element of the core TFIID transcriptional machinery. Additionally, somatic copy-number variation was found to play an important role in USC, with 13 copy-number gains and 12 copy-number losses that occurred more often than expected by chance. In addition to loss of TP53, we found frequent deletion of a small segment of chromosome 19 containing MBD3, also a member of the NuRD chromatin-modification complex, and frequent amplification of chromosome segments containing PIK3CA, ERBB2 (an upstream activator of PIK3CA), and CCNE1 (a target of FBXW7-mediated ubiquitination). These findings identify frequent mutation of DNA damage, chromatin remodeling, cell cycle, and cell proliferation pathways in USC and suggest potential targets for treatment of this lethal variant of endometrial cancer. PMID- 23359685 TI - Hsp70/Hsp90 chaperone machinery is involved in the assembly of the purinosome. AB - The de novo biosynthesis of purines is carried out by a highly conserved metabolic pathway that includes several validated targets for anticancer, immunosuppressant, and anti-inflammatory chemotherapeutics. The six enzymes in humans that catalyze the 10 chemical steps from phosphoribosylpyrophosphate to inosine monophosphate were recently shown to associate into a dynamic multiprotein complex called the purinosome. Here, we demonstrate that heat shock protein 90 (Hsp90), heat shock protein 70 (Hsp70), and several cochaperones functionally colocalize with this protein complex. Knockdown of expression levels of the identified cochaperones leads to disruption of purinosomes. In addition, small molecule inhibitors of Hsp90 and Hsp70 reversibly disrupt purinosomes and are shown to have a synergistic effect with methotrexate, an anticancer agent that targets purine biosynthesis. These data implicate the Hsp90/Hsp70 chaperone machinery in the assembly of the purinosome and provide a strategy for the development of improved anticancer therapies that disrupt purine biosynthesis. PMID- 23359686 TI - Role for the obesity-related FTO gene in the cellular sensing of amino acids. AB - SNPs in the first intron of FTO (fat mass and obesity associated) are strongly associated with human obesity. While it is not yet formally established that this effect is mediated through the actions of the FTO protein itself, loss of function mutations in FTO or its murine homologue Fto result in severe growth retardation, and mice globally overexpressing FTO are obese. The mechanisms through which FTO influences growth and body composition are unknown. We describe a role for FTO in the coupling of amino acid levels to mammalian target of rapamycin complex 1 signaling. These findings suggest that FTO may influence body composition through playing a role in cellular nutrient sensing. PMID- 23359687 TI - Stick-slip friction and wear of articular joints. AB - Stick-slip friction was observed in articular cartilage under certain loading and sliding conditions and systematically studied. Using the Surface Forces Apparatus, we show that stick-slip friction can induce permanent morphological changes (a change in the roughness indicative of wear/damage) in cartilage surfaces, even under mild loading and sliding conditions. The different load and speed regimes can be represented by friction maps--separating regimes of smooth and stick-slip sliding; damage generally occurs within the stick-slip regimes. Prolonged exposure of cartilage surfaces to stick-slip sliding resulted in a significant increase of surface roughness, indicative of severe morphological changes of the cartilage superficial zone. To further investigate the factors that are conducive to stick-slip and wear, we selectively digested essential components of cartilage: type II collagen, hyaluronic acid (HA), and glycosaminoglycans (GAGs). Compared with the normal cartilage, HA and GAG digestions modified the stick-slip behavior and increased surface roughness (wear) during sliding, whereas collagen digestion decreased the surface roughness. Importantly, friction forces increased up to 2, 10, and 5 times after HA, GAGs, and collagen digestion, respectively. Also, each digestion altered the friction map in different ways. Our results show that (i) wear is not directly related to the friction coefficient but (ii) more directly related to stick-slip sliding, even when present at small amplitudes, and that (iii) the different molecular components of joints work synergistically to prevent wear. Our results also suggest potential noninvasive diagnostic tools for sensing stick-slip in joints. PMID- 23359688 TI - DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge. AB - We have previously shown that macaques vaccinated with DNA vectors expressing SIVmac239 antigens developed potent immune responses able to reduce viremia upon high-dose SIVmac251 challenge. To further improve vaccine-induced immunity and protection, we combined the SIVmac239 DNA vaccine with protein immunization using inactivated SIVmac239 viral particles as protein source. Twenty-six weeks after the last vaccination, the animals were challenged intrarectally at weekly intervals with a titrated dose of the heterologous SIVsmE660. Two of DNA-protein coimmunized macaques did not become infected after 14 challenges, but all controls were infected by 11 challenges. Vaccinated macaques showed modest protection from SIVsmE660 acquisition compared with naive controls (P = 0.050; stratified for TRIM5alpha genotype). Vaccinees had significantly lower peak (1.6 log, P = 0.0048) and chronic phase viremia (P = 0.044), with 73% of the vaccinees suppressing viral replication to levels below assay detection during the 40-wk follow-up. Vaccine-induced immune responses associated significantly with virus control: binding antibody titers and the presence of rectal IgG to SIVsmE660 Env correlated with delayed SIVsmE660 acquisition; SIV-specific cytotoxic T cells, prechallenge CD4(+) effector memory, and postchallenge CD8(+) transitional memory cells correlated with control of viremia. Thus, SIVmac239 DNA and protein-based vaccine protocols were able to achieve high, persistent, broad, and effective cellular and humoral immune responses able to delay heterologous SIVsmE660 infection and to provide long-term control of viremia. These studies support a role of DNA and protein-based vaccines for development of an efficacious HIV/AIDS vaccine. PMID- 23359689 TI - Tryptophan at the transmembrane-cytosolic junction modulates thrombopoietin receptor dimerization and activation. AB - Dimerization of single-pass membrane receptors is essential for activation. In the human thrombopoietin receptor (TpoR), a unique amphipathic RWQFP motif separates the transmembrane (TM) and intracellular domains. Using a combination of mutagenesis, spectroscopy, and biochemical assays, we show that W515 of this motif impairs dimerization of the upstream TpoR TM helix. TpoR is unusual in that a specific residue is required for this inhibitory function, which prevents receptor self-activation. Mutations as diverse as W515K and W515L cause oncogenic activation of TpoR and lead to human myeloproliferative neoplasms. Two lines of evidence support a general mechanism in which W515 at the intracellular juxtamembrane boundary inhibits dimerization of the TpoR TM helix by increasing the helix tilt angle relative to the membrane bilayer normal, which prevents the formation of stabilizing TM dimer contacts. First, measurements using polarized infrared spectroscopy show that the isolated TM domain of the active W515K mutant has a helix tilt angle closer to the bilayer normal than that of the wild-type receptor. Second, we identify second-site R514W and Q516W mutations that reverse dimerization and tilt angle changes induced by the W515K and W515L mutations. The second-site mutations prevent constitutive activation of TpoR W515K/L, while preserving ligand-induced signaling. The ability of tryptophan to influence the angle and dimerization of the TM helix in wild-type TpoR and in the second-site revertants is likely associated with its strong preference to be buried in the headgroup region of membrane bilayers. PMID- 23359690 TI - Assembly and mechanism of a group II ECF transporter. AB - Energy-coupling factor (ECF) transporters are a recently discovered family of primary active transporters for micronutrients and vitamins, such as biotin, thiamine, and riboflavin. Found exclusively in archaea and bacteria, including the human pathogens Listeria, Streptococcus, and Staphylococcus, ECF transporters may be the only means of vitamin acquisition in these organisms. The subunit composition of ECF transporters is similar to that of ATP binding cassette (ABC) importers, whereby both systems share two homologous ATPase subunits (A and A'), a high affinity substrate-binding subunit (S), and a transmembrane coupling subunit (T). However, the S subunit of ECF transporters is an integral membrane protein, and the transmembrane coupling subunits do not share an obvious sequence homology between the two transporter families. Moreover, the subunit stoichiometry of ECF transporters is controversial, and the detailed molecular interactions between subunits and the conformational changes during substrate translocation are unknown. We have characterized the ECF transporters from Thermotoga maritima and Streptococcus thermophilus. Our data suggests a subunit stoichiometry of 2S:2T:1A:1A' and that S subunits for different substrates can be incorporated into the same transporter complex simultaneously. In the first crystal structure of the A-A' heterodimer, each subunit contains a novel motif called the Q-helix that plays a key role in subunit coupling with the T subunits. Taken together, these findings suggest a mechanism for coupling ATP binding and hydrolysis to transmembrane transport by ECF transporters. PMID- 23359691 TI - Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control. AB - Peptide drugs are an exciting class of pharmaceuticals increasingly used for the treatment of a variety of diseases; however, their main drawback is a short half life, which dictates multiple and frequent injections and an undesirable "peak and-valley" pharmacokinetic profile, which can cause undesirable side-effects. Synthetic prolonged release formulations can provide extended release of biologically active native peptide, but their synthetic nature can be an obstacle to production and utilization. Motivated by these limitations, we have developed a new and entirely genetically encoded peptide delivery system--Protease Operated Depots (PODs)--to provide sustained and tunable release of a peptide drug from an injectable s.c. depot. We demonstrate proof-of-concept of PODs, by fusion of protease cleavable oligomers of glucagon-like peptide-1, a type-2 diabetes drug, and a thermally responsive, depot-forming elastin-like-polypeptide that undergoes a thermally triggered inverse phase transition below body temperature, thereby forming an injectable depot. We constructed synthetic genes for glucagon-like peptide-1 PODs and demonstrated their high-yield expression in Escherichia coli and facile purification by a nonchromatographic scheme we had previously developed. Remarkably, a single injection of glucagon-like peptide-1 PODs was able to reduce blood glucose levels in mice for up to 5 d, 120 times longer than an injection of the native peptide drug. These findings demonstrate that PODs provide the first genetically encoded alternative to synthetic peptide encapsulation schemes for sustained delivery of peptide therapeutics. PMID- 23359692 TI - Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist. AB - Gastrin releasing-peptide (GRP) is a potent growth factor in many malignancies. Benign prostatic hyperplasia (BPH) is a progressive age-related proliferation of glandular and stromal tissues; various growth factors and inflammatory processes are involved in its pathogenesis. We have demonstrated that potent antagonists of GRP inhibit growth of experimental human tumors including prostate cancer, but their effect on models of BPH has not been studied. Here, we evaluated the effects of GRP antagonist RC-3940-II on viability and cell volume of BPH-1 human prostate epithelial cells and WPMY-1 prostate stromal cells in vitro, and in testosterone-induced BPH in Wistar rats in vivo. RC-3940-II inhibited the proliferation of BPH-1 and WPMY-1 cells in a dose-dependent manner and reduced prostatic cell volume in vitro. Shrinkage of prostates was observed after 6 wk of treatment with RC-3940-II: a 15.9% decline with 25 MUg/d; and a 18.4% reduction with 50 MUg/d (P < 0.05 for all). Significant reduction in levels of proliferating cell nuclear antigen, NF-kappabeta/p50, cyclooxygenase-2, and androgen receptor was also seen. Analysis of transcript levels of genes related to growth, inflammatory processes, and signal transduction showed significant changes in the expression of more than 90 genes (P < 0.05). In conclusion, GRP antagonists reduce volume of human prostatic cells and lower prostate weight in experimental BPH through direct inhibitory effects on prostatic GRP receptors. GRP antagonists should be considered for further development as therapy for BPH. PMID- 23359694 TI - Membrane invaginations facilitate reversible water flux driving tunable iridescence in a dynamic biophotonic system. AB - Squids have used their tunable iridescence for camouflage and communication for millions of years; materials scientists have more recently looked to them for inspiration to develop new "biologically inspired" adaptive optics. Iridocyte cells produce iridescence through constructive interference of light with intracellular Bragg reflectors. The cell's dynamic control over the apparent lattice constant and dielectric contrast of these multilayer stacks yields the corresponding optical control of brightness and color across the visible spectrum. Here, we resolve remaining uncertainties in iridocyte cell structure and determine how this unusual morphology enables the cell's tunable reflectance. We show that the plasma membrane periodically invaginates deep into the iridocyte to form a potential Bragg reflector consisting of an array of narrow, parallel channels that segregate the resulting high refractive index, cytoplasmic protein containing lamellae from the low-index channels that are continuous with the extracellular space. In response to control by a neurotransmitter, the iridocytes reversibly imbibe or expel water commensurate with changes in reflection intensity and wavelength. These results allow us to propose a comprehensive mechanism of adaptive iridescence in these cells from stimulation to color production. Applications of these findings may contribute to the development of unique classes of tunable photonic materials. PMID- 23359693 TI - Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 3 kinase and phosphoinositide-dependent kinase-1. AB - The Hippo signaling pathway inhibits cell growth and regulates organ size through a kinase cascade that leads to the phosphorylation and nuclear exclusion of the growth-promoting transcriptional coactivator Yes-associated protein (YAP)/Yorkie. It mediates contact inhibition of cell growth downstream of cadherin adhesion molecules and other cell surface proteins. Contact inhibition is often antagonized by mitogenic growth factor signaling. We report an important mechanism for this antagonism, inhibition of Hippo pathway signaling by mitogenic growth factors. EGF treatment of immortalized mammary cells triggers the rapid translocation of YAP into the nucleus along with YAP dephosphorylation, both of which depend on Lats, the terminal kinase in the Hippo pathway. A small-molecule inhibitor screen of downstream effector pathways shows that EGF receptor inhibits the Hippo pathway through activation of PI3-kinase (PI3K) and phosphoinositide dependent kinase (PDK1), but independent of AKT activity. The PI3K-PDK1 pathway also mediates YAP nuclear translocation downstream of lysophosphatidic acid and serum as a result of constitutive oncogenic activation of PI3K. PDK1 associates with the core Hippo pathway-kinase complex through the scaffold protein Salvador. The entire Hippo core complex dissociates in response to EGF signaling in a PI3K PDK1-dependent manner, leading to inactivation of Lats, dephosphorylation of YAP, and YAP nuclear accumulation and transcriptional activation of its target gene, CTGF. These findings show that an important activity of mitogenic signaling pathways is to inactivate the growth-inhibitory Hippo pathway and provide a mechanism for antagonism between contact inhibition and growth factor action. PMID- 23359695 TI - First molar eruption, weaning, and life history in living wild chimpanzees. AB - Understanding dental development in chimpanzees, our closest living relatives, is of fundamental importance for reconstructing the evolution of human development. Most early hominin species are believed to show rapid ape-like patterns of development, implying that a prolonged modern human childhood evolved quite recently. However, chimpanzee developmental standards are uncertain because they have never been based on living wild individuals. Furthermore, although it is well established that first molar tooth emergence (movement into the mouth) is correlated with the scheduling of growth and reproduction across primates broadly, its precise relation to solid food consumption, nursing behavior, or maternal life history is unknown. To address these concerns we conducted a photographic study of subadult chimpanzees (Pan troglodytes schweinfurthii) in Kanyawara, Kibale National Park, Uganda. Five healthy infants emerged their lower first molars (M1s) by or before 3.3 y of age, nearly identical to captive chimpanzee mean ages (~3.2 y, n = 53). First molar emergence in these chimpanzees does not directly or consistently predict the introduction of solid foods, resumption of maternal estrous cycling, cessation of nursing, or maternal interbirth intervals. Kanyawara chimpanzees showed adult patterns of solid food consumption by the time M1 reached functional occlusion, spent a greater amount of time on the nipple while M1 was erupting than in the preceding year, and continued to suckle during the following year. Estimates of M1 emergence age in australopiths are remarkably similar to the Kanyawara chimpanzees, and recent reconstructions of their life histories should be reconsidered in light of these findings. PMID- 23359696 TI - Shp2 plays a crucial role in cell structural orientation and force polarity in response to matrix rigidity. AB - Cells can sense and respond to physical properties of their surrounding extracellular matrix. We have demonstrated here that tyrosine phosphatase Shp2 plays an essential role in the response of mouse embryonic fibroblasts to matrix rigidity. On rigid surfaces, large focal adhesions (FAs) and anisotropically oriented stress fibers are formed, whereas cells plated on compliant substrates form numerous small FAs and radially oriented stress fibers. As a result, traction force is increased and organized to promote cell spreading and elongation on rigid substrates. Shp2-deficient cells do not exhibit the stiffness dependent increase in FA size and polarized stress fibers nor the intracellular tension and cell shape change. These results indicate the involvement of Shp2 in regulating the FAs and the cytoskeleton for force maintenance and organization. The defect of FA maturation in Shp2-deficient cells was rescued by expressing Y722F Rho-associated protein kinase II (ROCKII), suggesting that ROCKII is the molecular target of Shp2 in FAs for the FA maturation. Thus, Shp2 serves as a key mediator in FAs for the regulation of structural organization and force orientation of mouse embyonic fibroblasts in determining their mechanical polarity in response to matrix rigidity. PMID- 23359698 TI - Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. AB - Over the last two decades, we have extensively studied the genetics of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CAH) and have performed 8,290 DNA analyses of the CYP21A2 gene on members of 4,857 families at risk for CAH--the largest cohort of CAH patients reported to date. Of the families studied, 1,507 had at least one member affected with one of three known forms of CAH, namely salt wasting, simple virilizing, or nonclassical CAH. Here, we report the genotype and phenotype of each affected patient, as well as the ethnic group and country of origin for each patient. We showed that 21 of 45 genotypes yielded a phenotypic correlation in our patient cohort. In particular, contrary to what is generally reported in the literature, we found that certain mutations, for example, the P30L, I2G, and I172N mutations, yielded different CAH phenotypes. In salt wasting and nonclassical CAH, a phenotype can be attributed to a genotype; however, in simple virilizing CAH, we observe wide phenotypic variability, particularly with the exon 4 I172N mutation. Finally, there was a high frequency of homozygous I2G and V281L mutations in Middle Eastern and Ashkenazi Jewish populations, respectively. By identifying the predominant phenotype for a given genotype, these findings should assist physicians in prenatal diagnosis and genetic counseling of parents who are at risk for having a child with CAH. PMID- 23359697 TI - IKs channels open slowly because KCNE1 accessory subunits slow the movement of S4 voltage sensors in KCNQ1 pore-forming subunits. AB - Human I(Ks) channels activate slowly with the onset of cardiac action potentials to repolarize the myocardium. I(Ks) channels are composed of KCNQ1 (Q1) pore forming subunits that carry S4 voltage-sensor segments and KCNE1 (E1) accessory subunits. Together, Q1 and E1 subunits recapitulate the conductive and kinetic properties of I(Ks). How E1 modulates Q1 has been unclear. Investigators have variously posited that E1 slows the movement of S4 segments, slows opening and closing of the conduction pore, or modifies both aspects of electromechanical coupling. Here, we show that Q1 gating current can be resolved in the absence of E1, but not in its presence, consistent with slowed movement of the voltage sensor. E1 was directly demonstrated to slow S4 movement with a fluorescent probe on the Q1 voltage sensor. Direct correlation of the kinetics of S4 motion and ionic current indicated that slowing of sensor movement by E1 was both necessary and sufficient to determine the slow-activation time course of I(Ks). PMID- 23359699 TI - Arachidonoyl-phosphatidylcholine oscillates during the cell cycle and counteracts proliferation by suppressing Akt membrane binding. AB - The activity of protein kinase B (Akt)--a major kinase promoting cell proliferation and survival--oscillates during the cell cycle. To investigate whether membrane phospholipids may regulate Akt phosphorylation and thus activity, we monitored the lipid profile of nocodazole-synchronized mouse NIH 3T3 fibroblasts during the cell cycle by liquid chromatography electrospray ionization tandem mass spectrometry (LC-MS/MS). The proportion of sn-2 arachidonoyl-phosphatidylcholine (20:4-PC) inversely correlated with Akt activity. Increasing the cellular ratio of 20:4-PC by supplementation of 20:4-PC to the cell culture medium diminished Akt [serine (Ser)473] phosphorylation. Saturated and monounsaturated phosphatidylcholines, used as control had no effect; 20:4-PC reduced cell proliferation relative to controls, interfered with S-phase transition, and suppressed Akt downstream signaling and cyclin expression like LY294002, which is a specific inhibitor of the phosphatidylinositol-3 kinase/Akt pathway. Additive effects of 20:4-PC and LY294002 were not observed, underlining the critical role of Akt for 20:4-PC signaling; 20:4-PC suppressed Akt membrane translocation as shown by immunofluorescence microscopy but left the concentration of the anchor lipid phosphatidylinositol-3,4,5-trisphosphate unchanged. An in vitro binding assay suggests that 20:4-PC attenuates the interaction of Akt with its membrane binding site. We conclude that 20:4-PC oscillates during the cell cycle and delays cell cycle progression by inhibiting Akt membrane binding. PMID- 23359701 TI - Observability of complex systems. AB - A quantitative description of a complex system is inherently limited by our ability to estimate the system's internal state from experimentally accessible outputs. Although the simultaneous measurement of all internal variables, like all metabolite concentrations in a cell, offers a complete description of a system's state, in practice experimental access is limited to only a subset of variables, or sensors. A system is called observable if we can reconstruct the system's complete internal state from its outputs. Here, we adopt a graphical approach derived from the dynamical laws that govern a system to determine the sensors that are necessary to reconstruct the full internal state of a complex system. We apply this approach to biochemical reaction systems, finding that the identified sensors are not only necessary but also sufficient for observability. The developed approach can also identify the optimal sensors for target or partial observability, helping us reconstruct selected state variables from appropriately chosen outputs, a prerequisite for optimal biomarker design. Given the fundamental role observability plays in complex systems, these results offer avenues to systematically explore the dynamics of a wide range of natural, technological and socioeconomic systems. PMID- 23359700 TI - Possible incipient sympatric ecological speciation in blind mole rats (Spalax). AB - Sympatric speciation has been controversial since it was first proposed as a mode of speciation. Subterranean blind mole rats (Spalacidae) are considered to speciate allopatrically or peripatrically. Here, we report a possible incipient sympatric adaptive ecological speciation in Spalax galili (2n = 52). The study microsite (0.04 km(2)) is sharply subdivided geologically, edaphically, and ecologically into abutting barrier-free ecologies divergent in rock, soil, and vegetation types. The Pleistocene Alma basalt abuts the Cretaceous Senonian Kerem Ben Zimra chalk. Only 28% of 112 plant species were shared between the soils. We examined mitochondrial DNA in the control region and ATP6 in 28 mole rats from basalt and in 14 from chalk habitats. We also sequenced the complete mtDNA (16,423 bp) of four animals, two from each soil type. Remarkably, the frequency of all major haplotype clusters (HC) was highly soil-biased. HCI and HCII are chalk biased. HC-III was abundant in basalt (36%) but absent in chalk; HC-IV was prevalent in basalt (46.5%) but was low (20%) in chalk. Up to 40% of the mtDNA diversity was edaphically dependent, suggesting constrained gene flow. We identified a homologous recombinant mtDNA in the basalt/chalk studied area. Phenotypically significant divergences differentiate the two populations, inhabiting different soils, in adaptive oxygen consumption and in the amount of outside-nest activity. This identification of a possible incipient sympatric adaptive ecological speciation caused by natural selection indirectly refutes the allopatric alternative. Sympatric ecological speciation may be more prevalent in nature because of abundant and sharply abutting divergent ecologies. PMID- 23359702 TI - Second act: Drug repurposing gets a boost as academic researchers join the search for novel uses of existing drugs. PMID- 23359704 TI - Science interminable: Blame Ben? PMID- 23359703 TI - Involvement of Toso in activation of monocytes, macrophages, and granulocytes. AB - Rapid activation of immune responses is necessary for antibacterial defense, but excessive immune activation can result in life-threatening septic shock. Understanding how these processes are balanced may provide novel therapeutic potential in treating inflammatory disease. Fc receptors are crucial for innate immune activation. However, the role of the putative Fc receptor for IgM, known as Toso/Faim3, has to this point been unclear. In this study, we generated Toso deficient mice and used them to uncover a critical regulatory function of Toso in innate immune activation. Development of innate immune cells was intact in the absence of Toso, but Toso-deficient neutrophils exhibited more reactive oxygen species production and reduced phagocytosis of pathogens compared with controls. Cytokine production was also decreased in Toso(-/-) mice compared with WT animals, rendering them resistant to septic shock induced by lipopolysaccharide. However, Toso(-/-) mice also displayed limited cytokine production after infection with the bacterium Listeria monocytogenes that was correlated with elevated presence of Listeria throughout the body. Accordingly, Toso(-/-) mice succumbed to infections of L. monocytogenes, whereas WT mice successfully eliminated the infection. Taken together, our data reveal Toso to be a unique regulator of innate immune responses during bacterial infection and septic shock. PMID- 23359705 TI - Catalytic consequences of open and closed grafted Al(III)-calix[4]arene complexes for hydride and oxo transfer reactions. AB - An approach for the control and understanding of supported molecular catalysts is demonstrated with the design and synthesis of open and closed variants of a grafted Lewis acid active site, consisting of Al(III)-calix[4]arene complexes on the surface of silica. The calixarene acts as a molecular template that enforces open and closed resting-state coordination geometries surrounding the metal active sites, due to its lower-rim substituents as well as site isolation by virtue of its steric bulk. These sites are characterized and used to elucidate mechanistic details and connectivity requirements for reactions involving hydride and oxo transfer. The consequence of controlling open versus closed configurations of the grafted Lewis acid site is demonstrated by the complete lack of observed activity of the closed site for Meerwein-Ponndorf-Verley (MPV) reduction; whereas, the open variant of this catalyst has an MPV reduction activity that is virtually identical to previously reported soluble molecular Al(III)-calix[4]arene catalysts. In contrast, for olefin epoxidation using tert butyl-hydroperoxide as oxidant, the open and closed catalysts exhibit similar activity. This observation suggests that for olefin epoxidation catalysis using Lewis acids as catalyst and organic hydroperoxide as oxidant, covalent binding of the hydroperoxide is not required, and instead dative coordination to the Lewis acid center is sufficient for catalytic oxo transfer. This latter result is supported by density functional theory calculations of the transition state for olefin epoxidation catalysis, using molecular analogs of the open and closed catalysts. PMID- 23359706 TI - Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. AB - Mutations in the cytochrome p450 (CYP)21A2 gene, which encodes the enzyme steroid 21-hydroxylase, cause the majority of cases in congenital adrenal hyperplasia, an autosomal recessive disorder. To date, more than 100 CYP21A2 mutations have been reported. These mutations can be associated either with severe salt-wasting or simple virilizing phenotypes or with milder nonclassical phenotypes. Not all CYP21A2 mutations have, however, been characterized biochemically, and the clinical consequences of these mutations remain unknown. Using the crystal structure of its bovine homolog as a template, we have constructed a humanized model of CYP21A2 to provide comprehensive structural explanations for the clinical manifestations caused by each of the known disease-causing missense mutations in CYP21A2. Mutations that affect membrane anchoring, disrupt heme and/or substrate binding, or impair stability of CYP21A2 cause complete loss of function and salt-wasting disease. In contrast, mutations altering the transmembrane region or conserved hydrophobic patches cause up to a 98% reduction in enzyme activity and simple virilizing disease. Mild nonclassical disease can result from interference in oxidoreductase interactions, salt-bridge and hydrogen bonding networks, and nonconserved hydrophobic clusters. A simple in silico evaluation of previously uncharacterized gene mutations could, thus, potentially help predict the often diverse phenotypes of a monogenic disorder. PMID- 23359707 TI - The steady-state mosaic of disturbance and succession across an old-growth Central Amazon forest landscape. AB - Old-growth forest ecosystems comprise a mosaic of patches in different successional stages, with the fraction of the landscape in any particular state relatively constant over large temporal and spatial scales. The size distribution and return frequency of disturbance events, and subsequent recovery processes, determine to a large extent the spatial scale over which this old-growth steady state develops. Here, we characterize this mosaic for a Central Amazon forest by integrating field plot data, remote sensing disturbance probability distribution functions, and individual-based simulation modeling. Results demonstrate that a steady state of patches of varying successional age occurs over a relatively large spatial scale, with important implications for detecting temporal trends on plots that sample a small fraction of the landscape. Long highly significant stochastic runs averaging 1.0 Mg biomass?ha(-1)?y(-1) were often punctuated by episodic disturbance events, resulting in a sawtooth time series of hectare-scale tree biomass. To maximize the detection of temporal trends for this Central Amazon site (e.g., driven by CO2 fertilization), plots larger than 10 ha would provide the greatest sensitivity. A model-based analysis of fractional mortality across all gap sizes demonstrated that 9.1-16.9% of tree mortality was missing from plot-based approaches, underscoring the need to combine plot and remote sensing methods for estimating net landscape carbon balance. Old-growth tropical forests can exhibit complex large-scale structure driven by disturbance and recovery cycles, with ecosystem and community attributes of hectare-scale plots exhibiting continuous dynamic departures from a steady-state condition. PMID- 23359708 TI - Molecular basis of antibiotic multiresistance transfer in Staphylococcus aureus. AB - Multidrug-resistant Staphylococcus aureus infections pose a significant threat to human health. Antibiotic resistance is most commonly propagated by conjugative plasmids like pLW1043, the first vancomycin-resistant S. aureus vector identified in humans. We present the molecular basis for resistance transmission by the nicking enzyme in S. aureus (NES), which is essential for conjugative transfer. NES initiates and terminates the transfer of plasmids that variously confer resistance to a range of drugs, including vancomycin, gentamicin, and mupirocin. The NES N-terminal relaxase-DNA complex crystal structure reveals unique protein DNA contacts essential in vitro and for conjugation in S. aureus. Using this structural information, we designed a DNA minor groove-targeted polyamide that inhibits NES with low micromolar efficacy. The crystal structure of the 341 residue C-terminal region outlines a unique architecture; in vitro and cell-based studies further establish that it is essential for conjugation and regulates the activity of the N-terminal relaxase. This conclusion is supported by a small angle X-ray scattering structure of a full-length, 665-residue NES-DNA complex. Together, these data reveal the structural basis for antibiotic multiresistance acquisition by S. aureus and suggest novel strategies for therapeutic intervention. PMID- 23359709 TI - Water-controlled wealth of nations. AB - Population growth is in general constrained by food production, which in turn depends on the access to water resources. At a country level, some populations use more water than they control because of their ability to import food and the virtual water required for its production. Here, we investigate the dependence of demographic growth on available water resources for exporting and importing nations. By quantifying the carrying capacity of nations on the basis of calculations of the virtual water available through the food trade network, we point to the existence of a global water unbalance. We suggest that current export rates will not be maintained and consequently we question the long-term sustainability of the food trade system as a whole. Water-rich regions are likely to soon reduce the amount of virtual water they export, thus leaving import dependent regions without enough water to sustain their populations. We also investigate the potential impact of possible scenarios that might mitigate these effects through (i) cooperative interactions among nations whereby water-rich countries maintain a tiny fraction of their food production available for export, (ii) changes in consumption patterns, and (iii) a positive feedback between demographic growth and technological innovations. We find that these strategies may indeed reduce the vulnerability of water-controlled societies. PMID- 23359710 TI - Evolution of resistance to satyrization through reproductive character displacement in populations of invasive dengue vectors. AB - Recently, the highly invasive Asian tiger mosquito, Aedes albopictus, rapidly displaced resident populations of the yellow fever mosquito, Aedes aegypti in the southeastern United States and in Bermuda. Although multiple mechanisms of competitive displacement have been hypothesized, recent evidence of cross insemination between these species in nature and the sterilizing effects of male accessory gland products asymmetrically favoring A. albopictus in interspecific matings support a role for satyrization (a form of reproductive interference) to explain the rapid displacements. Because of the drastic reproductive loss of A. aegypti females satyrized by A. albopictus males, we predicted selection for prezygotic isolation in populations of A. aegypti sympatric with A. albopictus. Exposures in cages demonstrated that female A. aegypti from populations in Florida sympatric with A. albopictus for the past 20 y were significantly less likely than nearby allopatric populations to mate with heterospecific males. Cross-inseminations of A. albopictus females by A. aegypti males were significantly less common, supporting the one-way direction of displacements observed in nature. Our results indicate rapid sexual selection leading to reproductive character displacement and the potential for satyr-resistant A. aegypti to recover from competitive displacements. These results have implications for increased risks of dengue transmission where these vector species meet worldwide. PMID- 23359712 TI - Microbiome of the upper troposphere: species composition and prevalence, effects of tropical storms, and atmospheric implications. AB - The composition and prevalence of microorganisms in the middle-to-upper troposphere (8-15 km altitude) and their role in aerosol-cloud-precipitation interactions represent important, unresolved questions for biological and atmospheric science. In particular, airborne microorganisms above the oceans remain essentially uncharacterized, as most work to date is restricted to samples taken near the Earth's surface. Here we report on the microbiome of low- and high altitude air masses sampled onboard the National Aeronautics and Space Administration DC-8 platform during the 2010 Genesis and Rapid Intensification Processes campaign in the Caribbean Sea. The samples were collected in cloudy and cloud-free air masses before, during, and after two major tropical hurricanes, Earl and Karl. Quantitative PCR and microscopy revealed that viable bacterial cells represented on average around 20% of the total particles in the 0.25- to 1 MUm diameter range and were at least an order of magnitude more abundant than fungal cells, suggesting that bacteria represent an important and underestimated fraction of micrometer-sized atmospheric aerosols. The samples from the two hurricanes were characterized by significantly different bacterial communities, revealing that hurricanes aerosolize a large amount of new cells. Nonetheless, 17 bacterial taxa, including taxa that are known to use C1-C4 carbon compounds present in the atmosphere, were found in all samples, indicating that these organisms possess traits that allow survival in the troposphere. The findings presented here suggest that the microbiome is a dynamic and underappreciated aspect of the upper troposphere with potentially important impacts on the hydrological cycle, clouds, and climate. PMID- 23359711 TI - Cell-permeable probe for identification and imaging of sialidases. AB - Alkyne-hinged 3-fluorosialyl fluoride (DFSA) containing an alkyne group was shown to be a mechanism-based target-specific irreversible inhibitor of sialidases. The ester-protected analog DFSA (PDFSA) is a membrane-permeable precursor of DFSA designed to be used in living cells, and it was shown to form covalent adducts with virus, bacteria, and human sialidases. The fluorosialyl-enzyme adduct can be ligated with an azide-annexed biotin via click reaction and detected by the streptavidin-specific reporting signals. Liquid chromatography-mass spectrometry/mass spectrometry analysis on the tryptic peptide fragments indicates that the 3-fluorosialyl moiety modifies tyrosine residues of the sialidases. DFSA was used to demonstrate influenza infection and the diagnosis of the viral susceptibility to the anti-influenza drug oseltamivir acid, whereas PDFSA was used for in situ imaging of the changes of sialidase activity in live cells. PMID- 23359714 TI - The characteristics and chronology of the earliest Acheulean at Konso, Ethiopia. AB - The Acheulean technological tradition, characterized by a large (>10 cm) flake based component, represents a significant technological advance over the Oldowan. Although stone tool assemblages attributed to the Acheulean have been reported from as early as circa 1.6-1.75 Ma, the characteristics of these earliest occurrences and comparisons with later assemblages have not been reported in detail. Here, we provide a newly established chronometric calibration for the Acheulean assemblages of the Konso Formation, southern Ethiopia, which span the time period ~1.75 to <1.0 Ma. The earliest Konso Acheulean is chronologically indistinguishable from the assemblage recently published as the world's earliest with an age of ~1.75 Ma at Kokiselei, west of Lake Turkana, Kenya. This Konso assemblage is characterized by a combination of large picks and crude bifaces/unifaces made predominantly on large flake blanks. An increase in the number of flake scars was observed within the Konso Formation handaxe assemblages through time, but this was less so with picks. The Konso evidence suggests that both picks and handaxes were essential components of the Acheulean from its initial stages and that the two probably differed in function. The temporal refinement seen, especially in the handaxe forms at Konso, implies enhanced function through time, perhaps in processing carcasses with long and stable cutting edges. The documentation of the earliest Acheulean at ~1.75 Ma in both northern Kenya and southern Ethiopia suggests that behavioral novelties were being established in a regional scale at that time, paralleling the emergence of Homo erectus-like hominid morphology. PMID- 23359713 TI - Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins. AB - The epigenetic regulator Bmi1 controls proliferation in many organs. Reexpression of cell cycle proteins such as cyclin-dependent kinases (CDKs) is a hallmark of neuronal apoptosis in neurodegenerative diseases. Here we address the potential role of Bmi1 as a key regulator of cell cycle proteins during neuronal apoptosis. We show that several cell cycle proteins are expressed in different models of retinal degeneration and required in the Rd1 photoreceptor death process. Deleting E2f1, a downstream target of CDKs, provided temporary protection in Rd1 mice. Most importantly, genetic ablation of Bmi1 provided extensive photoreceptor survival and improvement of retinal function in Rd1 mice, mediated by a decrease in cell cycle markers and regulators independent of p16(Ink4a) and p19(Arf). These data reveal that Bmi1 controls the cell cycle-related death process, highlighting this pathway as a promising therapeutic target for neuroprotection in retinal dystrophies. PMID- 23359715 TI - S-nitrosylation of HDAC2 regulates the expression of the chromatin-remodeling factor Brm during radial neuron migration. AB - Dynamic epigenetic modifications play a key role in mediating the expression of genes required for neuronal development. We previously identified nitric oxide (NO) as a signaling molecule that mediates S-nitrosylation of histone deacetylase 2 (HDAC2) and epigenetic changes in neurons. Here, we show that HDAC2 nitrosylation regulates neuronal radial migration during cortical development. Bead-array analysis performed in the developing cortex revealed that brahma (Brm), a subunit of the ATP-dependent chromatin-remodeling complex BRG/brahma associated factor, is one of the genes regulated by S-nitrosylation of HDAC2. In the cortex, expression of a mutant form of HDAC2 that cannot be nitrosylated dramatically inhibits Brm expression. Our study identifies NO and HDAC2 nitrosylation as part of a signaling pathway that regulates cortical development and the expression of Brm in neurons. PMID- 23359717 TI - Genomic dosage effects on heterosis in triploid maize. AB - The genetic basis of hybrid vigor or heterosis has been debated for more than a century. A popular hypothesis to explain this phenomenon is that there are different slightly deleterious recessive homozygous alleles in the two parents and that these alleles are complemented in the hybrid so that the biomass and fertility exceed both parents. To address the complementation hypothesis in a direct manner, heterosis was examined in diploid inbreds and reciprocal hybrids and compared with matched triploid inbred derivatives and two types of triploid hybrids that differ in the number of genomes from the different parents. Complementation of recessive mutations would occur equally in the two types of triploid hybrids predicting that, if this complementation were the sole basis of the heterotic response, the two types of triploid hybrids would be equivalent for hybrid vigor. However, the reciprocal diploid hybrids were similar for six of nine measured traits, but the two types of triploid hybrids differed significantly for eight of the same traits. Importantly, the triploid hybrids differed in the level of high-parent heterosis relative to the derived triploid inbreds. Also, the differences observed between the reciprocal triploid hybrids correlated strongly with differences observed between the inbreds, either at the diploid or triploid level, in a manner explicable by genome dosage rather than parent of origin effects. The findings of this study suggest that a major component of heterosis is a mechanism that is modulated by dosage-sensitive factors that involves allelic diversity across the genome. PMID- 23359719 TI - Multiple skin metastases of malignant melanoma. PMID- 23359718 TI - Engineering fluorescent protein substrates for the AAA+ Lon protease. AB - AAA+ proteases, such as Escherichia coli Lon, recognize protein substrates by binding to specific peptide degrons and then unfold and translocate the protein into an internal degradation chamber for proteolysis. For some AAA+ proteases, attaching specific degrons to the N- or C-terminus of green fluorescent protein (GFP) generates useful substrates, whose unfolding and degradation can be monitored by loss of fluorescence, but Lon fails to degrade appropriately tagged GFP variants at a significant rate. Here, we demonstrate that Lon catalyzes robust unfolding and degradation of circularly permuted variants of GFP with a beta20 degron appended to the N terminus or a sul20 degron appended to the C terminus. Lon degradation of non-permuted GFP-sul20 is very slow, in part because the enzyme cannot efficiently extract the degron-proximal C-terminal beta-strand to initiate denaturation. The circularly permuted GFP substrates described here allow convenient high-throughput assays of the kinetics of Lon degradation in vitro and also permit assays of Lon proteolysis in vivo. PMID- 23359720 TI - Fatal haemorrhage following endobronchial ultrasound-transbronchial needle aspiration: an unfortunate first. PMID- 23359721 TI - Restless legs syndrome is underdiagnosed in the US Renal Data System. PMID- 23359722 TI - Sloughing esophageal mucosa. PMID- 23359726 TI - AARC Clinical Practice Guideline. Surfactant replacement therapy: 2013. AB - We searched the MEDLINE, CINAHL, and Cochrane Library databases for English language randomized controlled trials, systematic reviews, and articles investigating surfactant replacement therapy published between January 1990 and July 2012. By inspection of titles, references having no relevance to the clinical practice guideline were eliminated. The update of this clinical practice guideline is based on 253 clinical trials and systematic reviews, and 12 articles investigating surfactant replacement therapy. The following recommendations are made following the Grading of Recommendations Assessment, Development, and Evaluation scoring system: 1: Administration of surfactant replacement therapy is strongly recommended in a clinical setting where properly trained personnel and equipment for intubation and resuscitation are readily available. 2: Prophylactic surfactant administration is recommended for neonatal respiratory distress syndrome (RDS) in which surfactant deficiency is suspected. 3: Rescue or therapeutic administration of surfactant after the initiation of mechanical ventilation in infants with clinically confirmed RDS is strongly recommended. 4: A multiple surfactant dose strategy is recommended over a single dose strategy. 5: Natural exogenous surfactant preparations are recommended over laboratory derived synthetic suspensions at this time. 6: We suggest that aerosolized delivery of surfactant not be utilized at this time. PMID- 23359727 TI - Noninvasive carbon monoxide detection: insufficient evidence for broad clinical use. PMID- 23359716 TI - Long prereproductive selection and divergence by depth in a Caribbean candelabrum coral. AB - Long-lived corals, the foundation of modern reefs, often follow ecological gradients, so that populations or sister species segregate by habitat. Adaptive divergence maintains sympatric congeners after secondary contact or may even generate species by natural selection in the face of gene flow. Such ecological divergence, initially between alternative phenotypes within populations, may be aided by immigrant inviability, especially when a long period separates larval dispersal and the onset of reproduction, during which selection can sort lineages to match different habitats. Here, we evaluate the strength of one ecological factor (depth) to isolate populations by comparing the genes and morphologies of pairs of depth-segregated populations of the candelabrum coral Eunicea flexuosa across the Caribbean. Eunicea is endemic to the Caribbean and all sister species co-occur. Eunicea flexuosa is widespread both geographically and across reef habitats. Our genetic analysis revealed two depth-segregated lineages. Field survivorship data, combined with estimates of selection coefficients based on transplant experiments, suggest that selection is strong enough to segregate these two lineages. Genetic exchange between the Shallow and Deep lineages occurred either immediately after divergence or the two have diverged with gene flow. Migration occurs asymmetrically from the Shallow to Deep lineage. Limited recruitment to reproductive age, even under weak annual selection advantage, is sufficient to generate habitat segregation because of the cumulative prolonged prereproductive selection. Ecological factors associated with depth can act as filters generating strong barriers to gene flow, altering morphologies, and contributing to the potential for speciation in the sea. PMID- 23359728 TI - Additional evidence to support the use of noninvasive ventilation in asthma exacerbation. PMID- 23359729 TI - Incomplete network for survivors of catastrophic illness after release from ICUs. PMID- 23359730 TI - Expiratory reserve volume maneuver may be the preferred method for some patients during spirometry testing. PMID- 23359731 TI - Successful use of extracorporeal membrane oxygenation in a hematopoietic stem cell transplant patient with idiopathic pneumonia syndrome. AB - We report the case of an adult patient with idiopathic pneumonia syndrome following allogeneic hematopoietic stem cell transplantation, which was successfully managed with venovenous extracorporeal membrane oxygenation (ECMO) and immunosuppressive therapy. A 30-year-old man with precursor B cell acute lymphocytic leukemia had received chemotherapy 10 years previously, with complete remission. He underwent allogeneic hematopoietic stem cell transplantation 4 months prior to enrollment, owing to leukemia relapse. One hundred thirty days post-transplant the patient developed shortness of breath, nonproductive cough, and low-grade fever for 1 week. He subsequently developed acute hypercapnic and hypoxic respiratory failure that was unresponsive to conventional medical therapy. He was successfully managed with venovenous ECMO for 19 days, with complete resolution of his respiratory symptoms. Thus, judicious use of ECMO as a bridge before steroid and other conventional therapy take effect in patients with isolated respiratory failure appears justified. PMID- 23359732 TI - Could energy-intensive industries be powered by carbon-free electricity? AB - While the main thrust of the Discussion Meeting Issue on 'Material efficiency: providing material services with less material production' was to explore ways in which society's net demand for materials could be reduced, this review examines the possibility of converting industrial energy demand to electricity, and switching to clean electricity sources. This review quantifies the scale of infrastructure required in the UK, focusing on wind and nuclear power as the clean electricity sources, and sets these requirements in the context of the decarbonization of the whole energy system using wind, biomass, solar power in deserts and nuclear options. The transition of industry to a clean low-carbon electricity supply, although technically possible with several different technologies, would have very significant infrastructure requirements. PMID- 23359733 TI - Resource convergence and resource power: towards new concepts for material efficiency. AB - Material efficiency is not a panacea, but it lies at the intersection of many problems of global sustainability. Reducing the usage of a single material in a value chain may require ingenuity and wide cooperation, but conceptually it is not a problem. When the problem stretches to several resources in changing circumstances, we have to understand the linkages between resources and the power, and the influence of each resource in decision-making in different settings. In this paper, we concisely go from the time dimension to a very short history of resource thinking, and then introduce our resource convergence concept. Using text mining on a sample of articles linking different resources, we show in a 'visual literature review' how resource convergence emerges from unrelated texts. To demonstrate one new method under the resource convergence umbrella, we use a case example with our Resource Power Index method. In our opinion, mastering complexity will be the key to solving the challenges we are facing, and mastering resource convergence and translating it into material efficiency is one of the central problems. What we show in this paper is a core framework and some details of the direction we see as worth pursuing. PMID- 23359734 TI - Material efficiency: rare and critical metals. AB - In the last few decades, progress in electronics, especially, has resulted in important new uses for a number of geologically rare metals, some of which were mere curiosities in the past. Most of them are not mined for their own sake (gold, the platinum group metals and the rare Earth elements are exceptions) but are found mainly in the ores of the major industrial metals, such as aluminium, copper, zinc and nickel. We call these major metals 'attractors' and the rare accompanying metals 'hitch-hikers'. The key implication is that rising prices do not necessarily call forth greater output because that would normally require greater output of the attractor metal. We trace the geological relationships and the functional uses of these metals. Some of these metals appear to be irreplaceable in the sense that there are no known substitutes for them in their current functional uses. Recycling is going to be increasingly important, notwithstanding a number of barriers. PMID- 23359735 TI - Material efficiency: from top-down steering to tailor-made governance. AB - Material efficiency is one of the major challenges facing our society in the twenty-first century. Research can help to understand how we can make the transition towards a material-efficient society. This study focuses on the role of the government in such transition processes. Use is made of literature in the field of public administration and innovation literature, particularly transition management. On the basis of three Dutch examples (plastics, e-waste and bio energy), the complex system change towards a material-efficient society will be reflected upon. These case studies underline the need for a tailor-made governance approach instead of a top-down government approach to enhance material efficiency in practice. The role of the government is not restricted to formulating policies and then leaving it up to other actors to implement these policies. Instead, it is a continuous interplay between the different actors during the whole implementation process. As such, the government's role is to steer the development in the desired direction and orchestrate the process from beginning to end. In order to govern with a better compass, scientifically underpinned guiding principles and indicators are needed. This is a challenge for researchers both in public administration and in transition management. PMID- 23359736 TI - Intermediate inputs and economic productivity. AB - Many models of economic growth exclude materials, energy and other intermediate inputs from the production function. Growing environmental pressures and resource prices suggest that this may be increasingly inappropriate. This paper explores the relationship between intermediate input intensity, productivity and national accounts using a panel dataset of manufacturing subsectors in the USA over 47 years. The first contribution is to identify sectoral production functions that incorporate intermediate inputs, while allowing for heterogeneity in both technology and productivity. The second contribution is that the paper finds a negative correlation between intermediate input intensity and total factor productivity (TFP)--sectors that are less intensive in their use of intermediate inputs have higher productivity. This finding is replicated at the firm level. We propose tentative hypotheses to explain this association, but testing and further disaggregation of intermediate inputs is left for further work. Further work could also explore more directly the relationship between material inputs and economic growth--given the high proportion of materials in intermediate inputs, the results in this paper are suggestive of further work on material efficiency. Depending upon the nature of the mechanism linking a reduction in intermediate input intensity to an increase in TFP, the implications could be significant. A third contribution is to suggest that an empirical bias in productivity, as measured in national accounts, may arise due to the exclusion of intermediate inputs. Current conventions of measuring productivity in national accounts may overstate the productivity of resource-intensive sectors relative to other sectors. PMID- 23359737 TI - A low carbon economy and society. AB - This paper examines various aspects of moving from high carbon economies and societies to a cluster of low carbon systems. First, some historical material is considered from the Second World War and the 1970s, periods with some lessons for the contemporary 'powering down' of whole societies. Second, analysis is provided of some green shoots of a powering down of existing systems identifiable in the contemporary developed world. Third, analysis is provided of the array of systems, social practices and innovations that would have to develop in order to effect powering down on a sufficient scale and within an appropriate time period. Most examples are drawn from transport and mobility. Finally, the paper demonstrates just why developing new systems is so hard, especially as this must involve a transformed cluster of systems. The forces that make a new cluster unlikely are exceptionally powerful and make this a very difficult but not impossible outcome. PMID- 23359738 TI - Policy for material efficiency--sustainable taxation as a departure from the throwaway society. AB - The present economy is not sustainable with regard to its per capita material consumption. A dematerialization of the economy of industrialized countries can be achieved by a change in course, from an industrial economy built on throughput to a circular economy built on stock optimization, decoupling wealth and welfare from resource consumption while creating more work. The business models of a circular economy have been known since the mid-1970s and are now applied in a number of industrial sectors. This paper argues that a simple and convincing lever could accelerate the shift to a circular economy, and that this lever is the shift to a tax system based on the principles of sustainability: not taxing renewable resources including human labour--work--but taxing non-renewable resources instead is a powerful lever. Taxing materials and energies will promote low-carbon and low-resource solutions and a move towards a 'circular' regional economy as opposed to the 'linear' global economy requiring fuel-based transport for goods throughput. In addition to substantial improvements in material and energy efficiency, regional job creation and national greenhouse gas emission reductions, such a change will foster all activities based on 'caring', such as maintaining cultural heritage and natural wealth, health services, knowledge and know-how. PMID- 23359739 TI - Energy and the English Industrial Revolution. AB - Societies before the Industrial Revolution were dependent on the annual cycle of plant photosynthesis for both heat and mechanical energy. The quantity of energy available each year was therefore limited, and economic growth was necessarily constrained. In the Industrial Revolution, energy usage increased massively and output rose accordingly. The energy source continued to be plant photosynthesis, but accumulated over a geological age in the form of coal. This poses a problem for the future. Fossil fuels are a depleting stock, whereas in pre-industrial time the energy source, though limited, was renewed each year. PMID- 23359740 TI - 'Visionary rather than practical': craft, art and material efficiency. AB - Emotional responses to materials and manufactured objects have a long history but provoked vivid writing during the design reform debates of the nineteenth century and were carried forward into the twentieth century. In particular, nineteenth century anxieties about plasticity and about composite materials are still with us. Wood continues to represent sustainability, 'truth to materials', emotional durability and an assumed reassuring contact between material, tools and maker. By contrast, the facture offered by new media, in the form of self-replicating rapid prototyping machines, appears disembodied while also offering the possibility of homesteader-making. The desirability of recycling and up-cycling is currently central to our emotional responses to materials, with the world's waste dumps becoming sites of horrified fascination and inspiration. Symbolic moves in the direction of autarchy and reverse engineering by artists and designers register doubts about sustainability and seek to uncover the hidden impact of individual materials. This survey of historic and current attitudes towards materials and making processes by makers, artists and designers sheds light on anxieties familiar to us all, concerning technological development, authentic experience, agency, a sense of selfhood and the often bruising experience of modernity itself. PMID- 23359741 TI - Material efficiency in Dutch packaging policy. AB - Packaging materials are one of the largest contributors to municipal solid waste generation. In this paper, we evaluate the material impacts of packaging policy in The Netherlands, focusing on the role of material efficiency (or waste prevention). Since 1991, five different policies have been implemented to reduce the environmental impact of packaging. The analysis shows that Dutch packaging policies helped to reduce the total packaging volume until 1999. After 2000, packaging consumption increased more rapidly than the baseline, suggesting that policy measures were not effective. Generally, we see limited attention to material efficiency to reduce packaging material use. For this purpose, we tried to gain more insight in recent activities on material efficiency, by building a database of packaging prevention initiatives. We identified 131 alterations to packaging implemented in the period 2005-2010, of which weight reduction was the predominant approach. More appropriate packaging policy is needed to increase the effectiveness of policies, with special attention to material efficiency. PMID- 23359742 TI - Transitions to material efficiency in the UK steel economy. AB - Steel production is energy intensive so already has achieved impressive levels of energy efficiency. If the emissions associated with steel must be reduced in line with the requirements of the UK Climate Change Act, demand for new steel must be reduced. The strategies of 'material efficiency' aim to achieve such a reduction, while delivering the same final services. To meet the emissions targets set into UK law, UK consumption of steel must be reduced to 30 per cent of present levels by 2050. Previous work has revealed six strategies that could contribute to this target, and this paper presents an approximate analysis of the required transition. A macro-economic analysis of steel in the UK shows that while the steel industry is relatively small, the construction and manufacturing sectors are large, and it would be politically unacceptable to pursue options that lead to a major contraction in other sectors. Alternative business models are therefore required, and these are explored through four representative products- one for each final sector with particular emphasis given to options for reducing product weight, and extending product life. Preliminary evidence on the triggers that would lead to customers preferring these options is presented and organized in order to predict required policy measures. The estimated analysis of transitions explored in this paper is used to define target questions for future research in the area. PMID- 23359743 TI - Material efficiency in a multi-material world. AB - Material efficiency--using less of a material to make a product or supply a service--is gaining attention as a means for accomplishing important environmental goals. The ultimate goal of material efficiency is not to use less physical material but to reduce the impacts associated with its use. This article examines the concept and definition of material efficiency and argues that for it to be an effective strategy it must confront the challenges of operating in a multi-material world, providing guidance when materials are used together and when they compete. A series of conceptions of material efficiency are described, starting with mass-based formulations and expanding to consider multiple resources in the supply chain of a single material, and then to multiple resources in the supply chains of multiple materials used together, and further to multiple environmental impacts. The conception of material efficiency is further broadened by considering material choice, exploring the technical and economic effects both of using less material and of materials competition. Finally, this entire materials-based techno-economic system is considered with respect to the impact of complex policies and political forces. The overall goal here is to show how the concept of material efficiency when faced with more expansive--and yet directly relevant--definitional boundaries is forced to confront analytical challenges that are both familiar and difficult in life cycle assessment and product-based approaches. PMID- 23359744 TI - The energy required to produce materials: constraints on energy-intensity improvements, parameters of demand. AB - In this paper, we review the energy requirements to make materials on a global scale by focusing on the five construction materials that dominate energy used in material production: steel, cement, paper, plastics and aluminium. We then estimate the possibility of reducing absolute material production energy by half, while doubling production from the present to 2050. The goal therefore is a 75 per cent reduction in energy intensity. Four technology-based strategies are investigated, regardless of cost: (i) widespread application of best available technology (BAT), (ii) BAT to cutting-edge technologies, (iii) aggressive recycling and finally, and (iv) significant improvements in recycling technologies. Taken together, these aggressive strategies could produce impressive gains, of the order of a 50-56 per cent reduction in energy intensity, but this is still short of our goal of a 75 per cent reduction. Ultimately, we face fundamental thermodynamic as well as practical constraints on our ability to improve the energy intensity of material production. A strategy to reduce demand by providing material services with less material (called 'material efficiency') is outlined as an approach to solving this dilemma. PMID- 23359745 TI - Energy and materials conservation: applying pioneering research and techniques to current non-energy materials conservation issues. AB - The research of the Energy Research Group (ERG) at the University of Illinois at Urbana-Champaign through the 1970s and early 1980s has recurring bouts of popularity. That research traced the flow of various energy types from nature to the final product or service, using modified economic input-output analysis. That information allowed for a comparison of alternative uses of products and services that delivered the same demand. The goal of the study was to identify the energy conserving potential of the alternatives. Interest in that research has risen and fallen with the price of energy through three cycles now, with the current interest also encompassing materials conservation. Although the specific numerical results of this work are dated, the process by which the analysis was conducted creates, at least, a suggestion for future analysis in the arena of materials research. A review of the ERG history, including techniques pioneered for investigating the potential for energy conservation and some of the ancillary lessons learned along the way, may be of some use to those working on issues of materials conservation today. In the coming years, the most relevant research will include assessment of the socio-economic-ecological impact of technological materials conservation policies. PMID- 23359746 TI - Material efficiency: providing material services with less material production. AB - Material efficiency, as discussed in this Meeting Issue, entails the pursuit of the technical strategies, business models, consumer preferences and policy instruments that would lead to a substantial reduction in the production of high volume energy-intensive materials required to deliver human well-being. This paper, which introduces a Discussion Meeting Issue on the topic of material efficiency, aims to give an overview of current thinking on the topic, spanning environmental, engineering, economics, sociology and policy issues. The motivations for material efficiency include reducing energy demand, reducing the emissions and other environmental impacts of industry, and increasing national resource security. There are many technical strategies that might bring it about, and these could mainly be implemented today if preferred by customers or producers. However, current economic structures favour the substitution of material for labour, and consumer preferences for material consumption appear to continue even beyond the point at which increased consumption provides any increase in well-being. Therefore, policy will be required to stimulate material efficiency. A theoretically ideal policy measure, such as a carbon price, would internalize the externality of emissions associated with material production, and thus motivate change directly. However, implementation of such a measure has proved elusive, and instead the adjustment of existing government purchasing policies or existing regulations-- for instance to do with building design, planning or vehicle standards--is likely to have a more immediate effect. PMID- 23359747 TI - Functional and Developmental Analysis of CD4(+)CD25(+) Regulatory T Cells under the Influence of Streptococcal M Protein in Rheumatic Heart Disease. AB - The purpose of this study was to determine the role of streptococcal M protein in naturally-occurring CD4(+)CD25(+) regulatory T cells (nTregs) function and development in rheumatic heart disease in Iraqi patients. Streptococcus pyogenes was isolated for subsequent M protein extraction. Also, peripheral blood nTregs and CD4(+) T cells were isolated by using Magnetic Cell Separation System. Tissue culture for isolated cells was performed in the presence and absence of M protein. Cell count was performed, and tumor necrosis factor alpha (TNF-alpha) and interleukin-4 (IL-4) were determined in culture supernatant using ELISA system. There was a significant positive correlation (P<0.01) between the number of proliferated nTregs and CD4(+) T cells in the presence as well as the absence of streptococcal M protein. Moreover, there was a significant negative correlation between the mean number of nTregs and CD4(+) T cells in mixed culture system in the absence of M protein (r=-0.995). There was also a positive, but not significant (P>0.05), association (r=0.353) between the mean number of nTregs and CD4(+) T cells in the presence of M protein. The M protein stimulated CD4(+) T cells to produce IL-4 in very little amount (<4 pg/ml) in all samples. Compared to the production of IL4, TNF-alpha was produced in higher concentrations in the culture supernatants. The findings of the study indicate that streptococcal M protein has an important role in increasing the proliferation of D4(+)CD25(+)regulatory T cells and CD4(+) T cells. However, CD4(+)CD25(+) regulatory T cells have lower suppressive activity against CD4(+) T cells in the presence of M protein. PMID- 23359748 TI - The authors' reply. PMID- 23359749 TI - Cerebral venous-sinus thrombosis: a case series analysis. AB - BACKGROUND: Cerebral venous-sinus thrombosis is an uncommon form but important cause of stroke, especially in young-aged women. METHODS: We performed a retrospective descriptive-analytical study in which 124 patients with cerebral venous-sinus thrombosis, who referred to Nemazee Hospital, Shiraz University of Medical Sciences from January 2000 to March 2008, were included, and their demographic, etiologic, radiological and prognostic characteristics were evaluated. RESULTS: The patients' mean age was 34.01+/-10.25. Eighty seven (70.16%) were women and 37 (29.83%) were men. The most frequent clinical manifestations were headache, papilledema and seizures. Fifty seven (65.51%) women took oral contraceptive pills. Twenty of 57 women (35.08%) took the pill longer than one month to be able to fast in Ramadan or perform the Hajj ceremonies. In the mean time they developed cerebral venous-sinus thrombosis. Superior sagital sinus, with or without lateral sinuses, was the most involved area (70.96%). High mortality and morbidity rates (14.51% and 35.48%, respectively) were found in patients. Poor prognostic factors at the time of admission were stupor and coma (P=0.001) and evidence of hemorrhage in primary CT scan (P=0.005). CONCLUSION: Taking oral contraceptive pills was a main factor associated with cerebral venous-sinus thrombosis. Clinical manifestations, prognostic factors, common involved sinuses and image findings of this study were similar to those of other studies. Health care policy makers should design a plan to warn susceptible women of the risk of cerebral venous-sinus thrombosis, and to educate them the ways to prevent it. PMID- 23359750 TI - Effect of different treatment regimen with dexamethasone and acetylcysteine on corneal wound healing in rabbits. AB - BACKGROUND: The effect of corticosteroid therapy on corneal wound healing is controversial. The objective of this study was to evaluate the effects of combination therapy with dexamethasone and acetylcysteine at different times and durations on experimentally-induced corneal wounds and haze in rabbits. METHODS: Eighteen adult New Zealand white rabbits were divided into three groups of six each. Under anesthesia corneal wounds were created surgically in the center of all eyes. The right eyes of rabbits in group 1 were treated topically with acetylcysteine and dexamethasone immediately after surgery, those in group 2 were treated with acetylcysteine from day 1 and with acetylcysteine and dexamethasone from day 8, and those in group 3 were treated with acetylcysteine from day 1 and with acetylcysteine and dexamethasone from day 15. The left eyes were assigned as controls and were treated with normal saline. All eyes were treated six times a day for 28 days. Corneal wounds were measured by fluorescein staining every day. RESULTS: The combination of acetylcysteine and dexamethasone in group 1 significantly increased mean healing time, but did not change that in groups 2 and 3. Clinical and histopathologic examinations revealed that one month after the ulceration in groups 1 corneal haze was greater in treated than in the control eyes. Moreover, there was no significant difference between the control and treated eyes of group 1, 2, or 3 in terms of corneal haze at two or three months after the ulceration. CONCLUSIONS: The findings of the present study show that the association of 3% concentration of NAC and 0.1% concentration of dexamethasone immediately after corneal ulceration can delay corneal wound healing, and consequently produce more corneal haze. Thus, the use of 0.1% concentration of dexamethasone should be delayed at least until the completion of the epithelial defects. PMID- 23359751 TI - Hepatocellular tumors: immunohistochemical analyses for classification and prognostication. AB - Following the classification of hepatocellular nodules by the International Working Party in 1995 and further elaboration by the International Consensus Group for Hepatocellular Neoplasia in 2009, entities under the spectrum of hepatocellular nodules have been better characterized. Research work hence has been done to answer questions such as distinguishing high-grade dysplastic nodules from early hepatocellular carcinoma (HCC), delineating the tumor cell origin of HCC, identifying its prognostic markers, and subtyping hepatocellular adenomas. As a result, a copious amount of data at immunohistochemical and molecular levels has emerged. A panel of immunohistochemical markers including glypican-3, heat shock protein 70 and glutamine synthetase has been found to be of use in the diagnosis of small, well differentiated hepatocellular tumors and particularly of HCC. The use of liver fatty acid binding protein (L-FABP), beta catenin, glutamine synthetase, serum amyloid protein and C-reactive protein is found to be helpful in the subtyping of hepatocellular adenomas. The role of tissue biomarkers for prognostication in HCC and the use of biomarkers in subclassifying HCC based on tumor cell origin are also discussed. PMID- 23359752 TI - Dosimetry Comparison between Volumetric Modulated Arc Therapy with Rapid Arcand Fixed Field Dynamic IMRT for Local-Regionally Advanced Nasopharyngeal Carcinoma. AB - OBJECTIVE: A dosimetric study was performed to evaluate the performance of volumetric modulated arc radiotherapy with RapidArc on locally advanced nasopharyngeal carcinoma (NPC). METHODS: The CT scan data sets of 20 patients of locally advanced NPC were selected randomly. The plans were managed using volumetric modulated arc with RapidArc and fixed nine-field coplanar dynamic intensity-modulated radiotherapy (IMRT) for these patients. The dosimetry of the planning target volumes (PTV), the organs at risk (OARs) and the healthy tissue were evaluated. The dose prescription was set to 70 Gy to the primary tumor and 60 Gy to the clinical target volumes (CTV) in 33 fractions. Each fraction applied daily, five fractions per week. The monitor unit (MU) values and the delivery time were scored to evaluate the expected treatment efficiency. RESULTS: Both techniques had reached clinical treatment's requirement. The mean dose (Dmean), maximum dose (Dmax) and minimum dose (Dmin) in RapidArc and fixed field IMRT for PTV were 68.4+/-0.6 Gy, 74.8+/-0.9 Gy and 56.8+/-1.1 Gy; and 67.6+/-0.6 Gy, 73.8+/-0.4 Gy and 57.5+/-0.6 Gy (P<0.05), respectively. Homogeneity index was 78.85+/-1.29 in RapidArc and 80.34+/-0.54 (P<0.05) in IMRT. The conformity index (CI: 95%) was 0.78+/-0.01 for both techniques (P>0.05). Compared to IMRT, RapidArc allowed a reduction of Dmean to the brain stem, mandible and optic nerves of 14.1% (P<0.05), 5.6% (P<0.05) and 12.2% (P<0.05), respectively. For the healthy tissue and the whole absorbed dose, Dmean of RapidArc was reduced by 3.6% (P<0.05), and 3.7% (P<0.05), respectively. The Dmean to the parotids, the spinal cord and the lens had no statistical difference among them. The mean MU values of RapidArc and IMRT were 550 and 1,379. The mean treatment time of RapidArc and IMRT was 165 s and 447 s. Compared to IMRT, the delivery time and the MU values of RapidArc were reduced by 63% and 60%, respectively. CONCLUSION: For locally advanced NPC, both RapidArc and IMRT reached the clinic requirement. The target volume coverage was similar for the different techniques. The RapidArc technique showed some improvements in OARs and other tissue sparing while using reduced MUs and delivery time. PMID- 23359753 TI - Detection and Clinical Significance of DLC1 Gene Methylation in Serum DNA from Colorectal Cancer Patients. AB - OBJECTIVE: Deleted in liver cancer 1 (DLC1) is a new candidate tumor suppressor gene, whose down-regulation or even silence will result from promoter hypermethylation in various human cancers including colorectal cancer (CRC). The aim of this study is toevaluate the diagnostic role of DLC1gene methylationin the serum DNA from CRC patients. METHODS: This study enrolled 85 CRC patients and 45 patients with benign colorectal diseases. Methylation-specific polymerase chain reaction (MSP) was used to determine the promoter methylation status of DLC1 gene in serum DNA. The combination of DLC1 methylation and conventional tumor markers was further analyzed. RESULTS: Hypermethylation of DLC1 was detected in 42.4% (36/85) of CRC serums, while seldom in the benign controls(8.9%, 4/45) (P<0.001). The aberrant DLC1 methylation in serum DNA was not associated with patients' clinicopathological features and elevated CEA/CA19-9 levels. Furthermore, the combinational analysis of CEA, CA19-9 and DLC1 methylation showed a higher sensitivity and no reduced diagnostic specificity than CEA and CA19-9 combination for CRC diagnosis. CONCLUSION: The serum DLC1 methylation may be a promising biomarker for the early detection of CRC, which will further increase the diagnostic efficiency in combination with CEA and CA19-9. PMID- 23359754 TI - Radiofrequency ablation for postoperative recurrences of intrahepatic cholangiocarcinoma. AB - OBJECTIVE: Most recurrent intrahepatic cholangiocarcinoma (RICC) lost the opportunity of radical resection while most nonsurgical management failed to prolong patients' survival. The efficacy and safety of radiofrequency ablation (RFA) as a local treatment for recurrent hepatocellular carcinoma have been confirmed by many clinical studies. The purpose of this study was to evaluate the efficacy, long-term survival and complications of RFA for RICC. METHODS: A total of 12 patients with 19 RICCs after radical resection were included in this study. The tumors were 1.9-6.8 cm at the maximum diameter (median, 3.2+/-1.6 cm). All patients were treated with ultrasound guided RFA. There were two RFA approaches including percutaneous and open. RESULTS: A total of 18 RFA treatment sessions were performed. Ablation was successful (evaluated by 1-month CT after the initial RFA procedure) in 18 (94.7%) of 19 tumors. By a median follow-up period of 29.9 months after RFA, 5 patients received repeated RFA because of intrahepatic lesion recurrence. The median local recurrence-free survival period and median event-free survival period after RFA were 21.0 months and 13.0 months, respectively. The median overall survival was 30 months, and the 1- and 3-year survival rates were 87.5% and 37.5%, respectively. The complication rate was 5.6% (1/18 sessions). The only one major complication was pleural effusion requiring thoracentesis. CONCLUSION: This study showed RFA may effectively and safely manage RICC with 3-year survival of 37.5%. It provides a treatment option for these RICC patients who lost chance for surgery. PMID- 23359755 TI - Expression and Distribution Characteristics of Human Ortholog of Mammalian Enabled (hMena) in Glioma. AB - OBJECTIVE: To investigate the utility of hMena, a family of enabled/vasodilator stimulated phosphoprotein (Ena/VASP), we sought to characterize the expression profile and distribution characteristics of hMena in a large panel of glioma samples and determine whether hMena expression levels might correlate with the pathological grade of glioma. METHODS: Sixty-five specimens of glioma with different pathological grades and five control brain tissues were collected. In 6 of the 21 glioblastoma patients, multi-specimens were obtained respectively from the main tumor mass, the junction zone between the tumor and the normal tissue, and adjacent brain tissue 1.5 cm away from the tumor boundary under assistance of neuronavigation system during the operation. Immunohistochemistry was used to detect the expression and distribution characteristics of hMena. hMena expression was analyzed by Western blot in 20 specimens. RESULTS: The hMena expression was negative in control brain tissue but positive in different grades of glioma. The expression rate of hMena was positively correlated with the increasing grade of the World Health Orgnization (WHO) classification (r(s)=0.682, P=0.000). hMena was located in cytoplasm. Positive cells only distributed around the vessels within the tumor mass in low grade glioma, while in high grade glioma, these cells were able to be detected not only in the tumor but also in the boundary zone and adjacent brain parenchyma. In the tumor mass, hMena expressed highly and diffusedly. In the junction zone, hMena positive cells formed radiolitic pattern around the vessels. In adjacent brain parenchyma, single positive cell was scattered. hMena expression was markedly elevated in Grade III and IV glioma compared with Grade II and I. CONCLUSION: Our data suggested that the expression of hMena is closely related to malignant grade of glioma. hMena can label the migrating cells, and indicate the migrating path of glioma cells from the tumor to adjacent tissue along with the vascular basement membranes and tracts of white matter. PMID- 23359757 TI - Attributable causes of breast cancer and ovarian cancer in china: reproductive factors, oral contraceptives and hormone replacement therapy. AB - OBJECTIVE: To provide an evidence-based, consistent assessment of the burden of breast cancer attributable to reproductive factors (RFs, including nulliparity, mean number of children, age at first birth and breastfeeding), use of oral contraceptives (OCs, restricted to the age group of 15-49 years), and hormone replacement therapy (HRT), as well as of the burden of ovarian cancer attributable to the mean number of children in China in 2005. METHODS: We derived the prevalence of these risk factors and the relative risk of breast and ovarian cancer from national surveys or large-scale studies conducted in China. In the case of RFs, we compared the exposure distributions in 2001 and counterfactual exposure. RESULTS: Exposure of RFs in 2001 was found to account for 6.74% of breast cancer, corresponding to 9,617 cases and 2,769 deaths, and for 2.78% of ovarian cancer (711 cases, 294 deaths). The decrease in mean number of children alone was responsible for 1.47% of breast cancer and 2.78% of ovarian cancer. The prevalence of OC use was 1.74% and the population attributable fraction (PAF) of breast cancer was 0.71%, corresponding to 310 cases and 90 deaths. The PAF of breast cancer due to HRT was 0.31%, resulting in 297 cases and 85 deaths. CONCLUSION: RFs changes in China contributed to a sizable fraction of breast and ovarian cancer incidence and mortality, whereas HRT and OCs accounted for relatively low incidence of breast cancer in China. PMID- 23359758 TI - Value of c-Met for Predicting Progression of Precancerous Gastric Lesions in Rural Chinese Population. AB - OBJECTIVE: To investigate the value of c-Met in predicting progression of precancerous gastric lesions. METHODS: A population-based study was conducted to detect the overexpression of c-Met by immunohisto- chemical analysis in 124 subjects with precancerous gastric lesions. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated for the association of c-Met overexpression with the risk of advanced gastric lesions. RESULTS: The positive rates of c-Met were 55.7% in intestinal metaplasia (IM) and 64.8% in dysplasia (DYS), respectively. Stratified analysis indicated that the proportion of c-Met overexpression was 71.4% for IM progressive group, significantly higher than that for IM persistent group (40.0%, P<0.05). Compared to the IM persistent group, unconditional logistic regression showed that OR of c-Met overexpression for the IM progressive group was 7.416 (95% CI: 2.084-26.398). CONCLUSION: c-Met plays an important role in gastric carcinogenesis. Detection of c-Met is of value in predicting progression of precancerous gastric lesions from IM to DYS. PMID- 23359759 TI - Caveolin-1, E-cadherin and beta-catenin in Gastric Carcinoma, Precancerous Tissues and Chronic Non-atrophic Gastritis. AB - OBJECTIVE: To investigate the expressions of caveolin-1, E-cadherin and beta catenin in gastric carcinoma, precancerous gastric and chronic non-atrophic gastritis tissues, and evaluate the correlation of these expressions with the development of gastric cancer. METHODS: The expressions of caveolin-1, E-cadherin and beta-catenin were detected by biotin-streptavidin- peroxidase (SP) immunohistochemistry on 58 gastric cancer tissues, 40 precancerous gastric tissues and 42 chronic non-atrophic gastritis tissues. The correlation between the expressions of caveolin-1, E-cadherin and beta-catenin, and the clinicopathologic parameters of gastric cancer was analyzed retrospectively. RESULTS: The positive rates of caveolin-1 and E-cadherin expressions in gastric carcinoma were significantly lower than precancerous gastric and chronic non atrophic gastritis tissues (P<0.01). An abnormal rate of beta-catenin expression in gastric carcinoma was higher than precancerous gastric and chronic non atrophic gastritis tissues (P<0.01). Moreover, low expressions of caveolin-1, E cadherin and beta-catenin correlated with tumor size, depth of invasion, lymph node metastasis and TNM stage (P<0.05). The positive rates of caveolin-1 and E cadherin expressions decreased (P<0.01), while an abnormal rate of beta-catenin expression increased inversely, with the degree of atypical hyperplasia (P<0.01). Caveolin-1 expression correlated positively with E-cadherin (r=0.41, P<0.05). Caveolin-1 (r=-0.36, P<0.05) and E-cadherin (r=-0.45, P<0.05) expressions negatively correlated with abnormal beta-catenin expression. CONCLUSION: These results suggested that dysregulated expressions of caveolin-1, E-cadherin and beta-catenin correlated with the development of gastric cancer and its biological behavior. PMID- 23359760 TI - Single-nucleotide polymorphism associations for colorectal cancer in southern chinese population. AB - OBJECTIVE: Genome-wide association studies (GWAS) have identified 11 loci that influence the risk of developing colorectal cancer (CRC). Given that these studies were conducted in European Caucasian populations, it is not clear whether the results are relevant for populations with different ethnicities. The aim of this study was to examine these associations in a southern Chinese population. METHODS: Eleven single-nucleotide polymorphisms (SNPs), rs12701937, rs16892766, rs7014346, rs6983267, rs719725, rs10795668, rs3802842, rs4444235, rs9929218, rs10411210, and rs961253, were genotyped in 229 CRC patients and 267 controls using the MassArray SNP genotyping system. RESULTS: Evidence of an association with CRC was found for four of the 11 loci. The strongest associations were with rs4444235 and rs961253, with significant odds ratios close to those reported in previous GWAS. Among these four loci, rs719725 and rs4444235 were significantly associated with female gender, rs3802842, rs961253, and rs4444235 with early disease onset, and rs3802842 with later disease onset. However, no associations with CRC risk were detected for six other loci (rs9929218, rs10411210, rs12701937, rs7014346, rs6983267, and rs10795668), and one SNP, rs16892766, was not polymorphic in any of the study participants. CONCLUSION: The rs4444235 and rs961253 loci are strongly associated with the risk of CRC in southern Chinese. PMID- 23359761 TI - Role of contrast enhanced ultrasound in radiofrequency ablation of metastatic liver carcinoma. AB - OBJECTIVE: To investigate the application of contrast enhanced ultrasound (CEUS) in planning and guiding for radiofrequency ablation (RFA) for metastatic liver carcinoma (MLC). METHODS: One hundred and thirty-five patients with clinically and pathologically diagnosed MLC (from gastrointestinal tumors) were included in the present study, and 104 of them had received CEUS prior to RFA to assess the number, size, shape, infiltration, location and enhancing features of the lesions. Among the 104 patients, 21 (20.1%) were excluded from RFA treatment due to too many lesions or large infiltrative range based on CEUS. The remaining 83 patients with 147 lesions underwent RFA (group A). During the same period, other 31 patients with 102 lesions serving as control group were treated based on findings of conventional ultrasound without contrast (group B). The patients underwent follow-up enhanced CT at the 1st month, and then every 3-6 months after RFA. The tumor was considered as early necrosis if no contrast enhancement was detected in the treated area on the CT scan at the 1st month. RESULTS: In group A, 72 of 147 MLC lesions (48.9%) showed increased sizes on CEUS. Among them, 48 lesions (66.6%) appeared enlarged in arterial phase, and 24 (33.3%) showed enlarged hypoechoic area in parenchymal phase. CEUS showed total 61 additional lesions in 35 patients (42.1%) (ranged from 8 to 15 mm) compared with conventional ultrasound (US), and 42 (68.8%) of them were visualized in parenchymal phase only. There were total 208 lesions in group A underwent RFA with CEUS planning, and the tumor necrosis rate was 94.2% (196/208). In this group, local recurrence was found in 16 lesions (7.7%) during 3-42 months' following up, and new metastases were seen in 30 cases (36.1%). For group B, the tumor necrosis rate was 86.3% (88/102), local recurrence in 17 lesions (16.7%), and new metastases in 13 cases (41.9%). Tumor early necrosis and recurrence rates were significantly different between the two groups (P=0.018, P=0.016, respectively). CONCLUSION: CEUS played an important role in RFA for liver metastases by candidate selecting and therapy planning, which helped to improve the outcome of the treatment. PMID- 23359762 TI - Use of Radioiodinated Peptide Arg-Arg-Leu Targeted to Neovasculari- zation as well as Tumor Cells in Molecular Tumor Imaging. AB - OBJECTIVE: To explore a tumor peptide imaging agent Arginine-Arginine-Leucine (Tyr-Cys-Gly-Gly-Arg-Arg- Leu-Gly-Gly-Cys, tripeptide RRL [tRRL]) that targeted to tumor cells and tumor-derived endothelial cells (TDECs) and primarily investigate the possible relationship between tRRL and vascular endothelial growth factor receptor 2 (VEGFR-2). METHODS: The tRRL sequence motif was identified as a tumor molecular marker specifically binding to TDECs. Tyrosine was conjugated to the amino terminal of RRL (Cys-Gly-Gly-Arg-Arg-Leu-Gly-Gly-Cys) for labeling with radionuclide iodine-131 ((131)I-tRRL). The uptake ability and molecular binding of tRRL to tumor cells and angiogenic endothelium were studied using flow cytometry and radioactivity counter in vitro. Whether VEGFR-2 is the binging site of tRRL was investigated. Biodistribution and single-photon emission computed tomography (SPECT) imaging of (131)I-tRRL were used to evaluate the effectiveness of this new imaging agent to visualize varied tumor xenografts in nude mice. RESULTS: In vitro cellular uptake experiments revealed that tRRL could not only adhere to tumor angiogenic endothelial cells but also largely accumulate in malignant tumor cells. VEGFR-2, which is highly expressed on TDECs, was probably not the solely binding ligand for tRRL targeted to tumor angiogenic endothelium. (131)I-tRRL mainly accumulated in tumors in vivo, not other organs at 24 h after injection. SPECT imaging with (131)I-tRRL clearly visualized tumors in nude mice, especially at 24 h. CONCLUSION: Radioiodinated tRRL offers a noninvasive nuclear imaging method for functional molecular imaging of tumors targeted to neovascularization, and may be a promising candidate for tumor radioimmunotherapeutic carrier. PMID- 23359763 TI - Combined detection of serum matrix metalloproteinase 9, acetyl heparinase and cathepsin L in diagnosis of ovarian cancer. AB - OBJECTIVE: To investigate the clinic values of combining test of serum matrix metalloproteinase 9 (MMP-9), acetyl heparinase (Hpa) and Cathepsin L (CL) in diagnosis of ovarian cancer. METHODS: Serum levels of MMP-9, Hpa and CL were detected in a total of 418 cases, including 217 cases with ovarian malignant tumor, 100 cases with ovarian benign tumor and 101 healthy controls, by using enzyme-linked immunosorbent assay (ELISA). Their correlation with clinicopathologic feature of ovarian malignant tumor was analyzed and their diagnosis performance was evaluated by receiver operating characteristic (ROC). The combined diagnosis model was established by logistic regression analysis. RESULTS: The serum levels of MMP-9, Hpa and CL were significantly higher in patients with ovarian malignant tumor than in benign tumor and healthy control, the serum levels of CL and Hpa were higher in epithelial cancer than in non epithelial tumor, and MMP-9, Hpa and CL were elevated in low grade and advanced stage compared to high grade and early stage. The sensitivity for diagnosis of ovarian malignant tumor from high to low was CL, Hpa and MMP-9, and the specificity was MMP-9, CL and Hpa. The united diagnosis model was established and showed the sensitivity and specificity of combined detection were 84.6% and 82.1%, respectively, which were significantly higher than a single tumor marker. CONCLUSION: Serum MMP-9, Hpa and CL were correlated with ovarian malignant tumor and the combined detection of which may be valuable for clinical diagnosis of ovarian malignant tumor. PMID- 23359764 TI - JAK2 V617F, MPL W515L and JAK2 Exon 12 Mutations in Chinese Patients with Primary Myelofibrosis. AB - OBJECTIVE: JAK2 V617F, MPL W515L and JAK2 exon 12 mutations are novel acquired mutations that induce constitutive cytokine-independent activation of the JAK STAT pathway in myeloproliferative disorders (MPD). The discovery of these mutations provides novel mechanism for activation of signal transduction in hematopoietic malignancies. This research was to investigate their prevalence in Chinese patients with primary myelofibrosis (PMF). METHODS: We introduced allele specific PCR (AS-PCR) combined with sequence analysis to simultaneously screen JAK2 V617F, MPL W515L and JAK2 exon 12 mutations in 30 patients with PMF. RESULTS: Fifteen PMF patients (50.0%) carried JAK2 V617F mutation, and only two JAK2 V617F-negative patients (6.7%) harbored MPL W515L mutation. None had JAK2 exon 12 mutations. Furthermore, these three mutations were not detected in 50 healthy controls. CONCLUSION: MPL W515L and JAK2 V617F mutations existed in PMF patients but JAK2 exon 12 mutations not. JAK2 V617F and MPL W515L and mutations might contribute to the primary molecular pathogenesis in patients with PMF. PMID- 23359765 TI - Lymph node metastases and prognosis in penile cancer. AB - Lymph node status is a key prognostic factor in penile squamous cell carcinoma. Recently, growing evidence indicates a multimodality approach consisting of neoadjuvant chemotherapy followed by consolidation surgery improves the outcome of locally advanced penile cancer. Thus, accurate estimation of survival probability in node-positive penile cancer is critical for treatment decision making, counseling of patients and follow-up scheduling. This article reviewed evolving developments in assessing the risk for cancer progression based on lymph node related variables, such as the number of metastatic lymph nodes, bilateral lymph node metastases, the ratio of positive lymph nodes, extracapsular extension of metastatic lymph nodes, pelvic lymph node metastases, metastatic deposit in sentinel lymph nodes and N stage in TNM classification. Controversial issues surrounding the prognostic value of these nodal related predictors were also discussed. PMID- 23359766 TI - Expressions of Osteopontin (OPN), alphanubeta3 and Pim-1 Associated with Poor Prognosis in Non-small Cell Lung Cancer (NSCLC). AB - OBJECTIVE: To examine the expressions of osteopontin (OPN), (alpha) (nu) (beta) (3) and Pim-1 in non-small cell lung cancer (NSCLC), and investigate their potential pathogenic roles in the development of NSCLC. METHODS: Immunohistochemistry was used to examine the expressions of OPN, (alpha) (nu) (beta) (3) and Pim-1 in cohort (136 cases) of NSCLC samples and their adjacent normal lung tissue specimens. Statistical analysis was performed to evaluate the relationships among expressions of OPN, (alpha) (nu) (beta) (3) and Pim-1 and their associations with patients clinico- pathological parameters. RESULTS: The expressions of OPN and Pim-1 were predominantly observed in cytoplasm. The expression of (alpha) (nu) (beta) (3) was mostly detected in cytoplasm and/or membrane. In NSCLC samples, the positive rates of OPN, (alpha) (nu) (beta) (3) and Pim-1 expressions were 68.4% (93/136), 77.2% (105/136) and 57.4% (78/136), respectively. In normal lung tissues, in contrast, the positive rates of OPN, (alpha) (nu) (beta) (3) and Pim-1 were 24.0% (12/50), 26.0% (13/50) and 16.0% (8/50), respectively. There were significant differences of the positive expression rates of OPN, (alpha) (nu) (beta) (3) and Pim-1 between NSCLCs samples and normal lung tissues (P<0.01). In addition, the positive expression of OPN, (alpha) (nu) (beta) (3) and Pim-1 in NSCLCs samples was significantly associated with increased pathological grade, lymph node metastasis and advanced clinical stage (P<0.01), and they were independent of other clinicopathological parameters (P>0.05). Furthermore, a significantly positive correlation between the expression of OPN and (alpha) (nu) (beta) (3) (r=0.38, P<0.01), OPN and Pim-1 (r=0.37, P<0.01), or (alpha) (nu) (beta) (3) and Pim-1 (r=0.20, P<0.05) was evaluated in our NSCLC cohort. CONCLUSION: OPN, (alpha) (nu) (beta) (3) and Pim-1 proteins are frequently overexpressed in NSCLC, and they may play important roles in the development and/or progression of NSCLC. PMID- 23359768 TI - Antiproliferative effects of zinc-citrate compound on hormone refractory prostate cancer. AB - OBJECTIVE: To investigate the antiproliferative effects of zinc-citrate compound on hormone refractory prostate cancer (HRPC). METHODS: HRPC cell line (DU145) and normal prostate cell line (RWPE-1) were treated with zinc, citrate and zinc citrate compound at different time intervals and concentrations to investigate the effect of zinc-citrate compound. Mitochondrial (m)-aconitase activity was determined using aconitase assay. DNA laddering analysis was performed to investigate apoptosis of DU145 cells. Molecular mechanism of apoptosis was investigated by Western blot analysis of P53, P21(waf1), Bcl-2, Bcl-xL and Bax, and also caspase-3 activity analysis. RESULTS: Treatment with zinc-citrate compound resulted in a time- and dose-dependent decrease in cell number of DU145 cells in comparison with RWPE-1. M-aconitase activity was significantly decreased. DNA laddering analysis indicated apoptosis of DU145 cells. Zinc citrate compound increased the expression of P21(waf1) and P53, and reduced the expression of Bcl-2 and Bcl-xL proteins but induced the expression of Bax protein. Zinc-citrate compound induced apoptosis of DU145 cells by activation of the caspase-3 pathway. CONCLUSION: Zinc-citrate compound can induce apoptotic cell death in DU145, by caspase-3 activation through up-regulation of apoptotic proteins and down-regulation of antiapoptotic proteins. PMID- 23359767 TI - Glycogen Synthase Kinase 3beta Inhibitor (2'Z,3'E)-6-Bromo-indirubin- 3'-Oxime Enhances Drug Resistance to 5-Fluorouracil Chemotherapy in Colon Cancer Cells. AB - OBJECTIVE: To explore the effects and mechanism of glycogen synthase kinase 3beta (GSK-3beta) inhibitor (2'Z,3'E)-6-bromo-indirubin-3'-oxime (BIO) on drug resistance in colon cancer cells. METHODS: The colon cancer SW480 and SW620 cells were treated with BIO, 5-fluorouracil (5-FU) and BIO/5-FU, separately. Cell cycle distribution, apoptosis level and efflux ability of rhodamine 123 (Rh123) were detected by flow cytometry. The protein expressions of P-glycoprotein (P-gp), multidrug resistance protein 2 (MRP2), thymidylate synthase (TS), beta-catenin, E2F-1 and Bcl-2 were detected by Western blot. beta-catenin and P-gp were stained with double immunofluorescence and observed under a confocal microscope. RESULTS: BIO up-regulated beta-catenin, P-gp, MRP2 and TS, enhanced the efflux ability of Rh123, decreased Bcl-2 protein and gave the opposite effect to E2F-1 protein in SW480 and SW620 cells. Furthermore, BIO significantly inhibited cell apoptosis, increased S and G(2)/M phase cells, and reduced the cell apoptosis induced by 5 FU in SW480 cells, whereas the effects were slight or not obvious in SW620 cells. CONCLUSION: GSK-3beta was involved in drug resistance regulation, and activation of beta-catenin and inhibition of E2F-1 may be the most responsible for the enhancement of 5-FU chemotherapy resistance induced by GSK-3beta inhibitor BIO in colon cancer. PMID- 23359770 TI - Short hairpin RNA-mediated MDR1 gene silencing increases apoptosis of human ovarian cancer cell line A2780/Taxol. AB - OBJECTIVE: Recurrent ovarian cancer is often resistant to drugs such as paclitaxel. Short hairpin RNA (shRNA) targeting MDR1, a gene involved in the process of drug resistance, may be a promising strategy to overcome drug resistance. METHODS: Construction and identification of eukaryotic expression plasmid of shRNA targeting on MDR1 gene. The plasmid was transiently transfected into human ovarian cancer cell line A2780/Taxol. Apoptosis was determined by flow cytometry using annexin V-FITC/PI double labeling. Expression of MDR1 mRNA was detected by quantitative polymerase chain reaction (qPCR) and P-glycoprotein expression was detected using Western blot. RESULTS: The IC50 of paclitaxel in MDR1shRNA-transfected group was significantly reduced (1.986+/-0.153) MUmol/ml as compared with that in negative control (5.246+/-0.107) MUmol/ml and empty vector transfected group (5.212+/-0.075) MUmol/ml (P<0.05). The percent of the relative reverse sensitivity to paclitaxel on A2780/Taxol cells was 67.1%, and the apoptotic rate was significantly increased [(6.977+/-0.333)%] compared with control [(1.637+/-0.111)%] and empty vector-transfected group [(1.663+/-0.114)%] (P<0.05). Expressions of MDR1 mRNA and P-glycoprotein were significantly reduced compared with control (P<0.05). CONCLUSION: The present study demonstrated that the eukaryotic expression plasmid of shRNA targeting on MDR1 inhibited the expression of MDR1 effectively, thus enhance the sensitivity of A2780/Taxol cells to paclitaxel. PMID- 23359769 TI - Overexpression and immunosuppressive functions of transforming growth factor 1, vascular endothelial growth factor and interleukin-10 in epithelial ovarian cancer. AB - OBJECTIVE: Transforming growth factor-1 (TGF-beta1), vascular endothelial growth factor (VEGF), and interleukin-10 (IL-10) may be critical cytokines in the microenvironment of a tumor, playing roles in immune suppression. This study was conducted to elucidate the roles and immunosuppressive functions of these cytokines in epithelial ovarian cancer (EOC). METHODS: The expression levels of TGF-beta1, VEGF and IL-10 in malignant tissue were evaluated by immune- histochemistry and compared with corresponding borderline, benign, and tumor-free tissues. Moreover, relationships among the levels of these cytokines and correlations between expression and the prognosis of EOC were analyzed by Pearson rank correlations and multi-factor Logistic regression. The roles of TGF-beta1, VEGF, and IL-10 in the immunosuppressive microenvironment of ovarian cancer were studied through dendritic cell (DC) maturation and CD4+CD25+FoxP3+ Treg generation in vitro experiments. RESULTS: TGF-beta1, VEGF, and IL-10 were expressed in 100%, 74.69%, and 54.96% of EOC patients, respectively. TGF-beta1 was an independent prognostic factor for EOC. IL-10 was significantly co expressed with VEGF. In vitro, VEGF and TGF-beta1 strongly interfered with DC maturation and consequently led to immature DCs, which secreted high levels of IL 10 that accumulated around the tumor site. TGF-beta1 and IL-10 induced Treg generation without antigen presentation in DCs. CONCLUSIONS: TGF-beta1, VEGF and IL-10 play important roles in EOC and can lead to frequent immune evasion events. PMID- 23359771 TI - Effects of anastrozole combined with Shuganjiangu decoction on osteoblast-like cell proliferation, differentiation and OPG/RANKL mRNA expression. AB - OBJECTIVE: To investigate the effects of anastrozole combined with Shuganjiangu decoction on osteoblast-like cells. METHODS: Human osteoblast-like cells MG-63 were cultured and divided into four groups: control, anastrozole, Shuganjiangu decoction (SGJGD), and anastrozole combined with SGJGD. Cell proliferation was investigated by MTT assay. Alkaline phosphatase (ALP) and osteocalcin, the indicators of cell differentiation, were evaluated by p-nitrophenyl- phosphate method and radioimmunoassay, respectively. Gene expressions of ALP, osteocalcin, osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) were examined by real-time PCR. RESULTS: As evidenced by MTT assay, cell proliferation of MG-63 was inhibited by anastrozole, but stimulated with treatment of SGJGD alone and combined with anastrozole (P<0.01). Compared with control group, ALP activity was increased by the treatment of SGJGD alone and combined with anastrozole (P<0.01). Also, osteocalcin secretion was enhanced with the treatment of SGJGD single and combination with anastrozole (P<0.05). In the real-time PCR assay, gene expressions of ALP and osteocalcinwere significantly increased (P<0.01 for ALP, P<0.05 for osteocalcin) by the treatment of SGJGD and anastrozole combined with SGJGD, but the expression of RANKL was decreased (P<0.05). Moreover, anastrozole combined with SGJGD upregulated gene expression of OPG (P<0.01). CONCLUSION: SGJGD may alleviate the injury effects of anastrozole on MG-63 cells through adjusting bone formation and resorption indicators. PMID- 23359772 TI - Carcinoma of Colon: a rare cause of fever of unknown origin. AB - Fever of unknown origin (FUO) was originally defined as a body temperature greater than 38.3 degrees C on several occasions longer than 3 weeks, with a diagnosis that remains unclear after 7 days of obligatory investigation. Only a few types of solid tumors have been associated with FUO. We described 2 patients who had recurrent fever but no other specific gastrointestinal symptoms where carcinoma of the colon was the only identifiable cause. In the first case, a mass arising from the sigmoid colon was found without any nodal metastasis, and the fever was resolved after three days of the surgical resection. In the second case, advanced adenocarcinoma was found in the ascending colon together with liver cirrhosis. Although it was not possible to surgically remove this tumor, prolonged fever in the patient was most likely due to the carcinoma. These cases indicate that clinicians should consider carcinoma of the colon in the differential diagnosis of patients with FUO. PMID- 23359773 TI - Extraskeletal osteosarcoma of penis: a case report. AB - Extraskeletal osteosarcoma (EOS) is rare and commonly arises in the retroperitoneum, limbs, head and neck. There is no significant difference between EOS and other malignant tumors in soft tissue. Localized pain and swelling are the common presenting symptoms. Clinical diagnosis of EOS is difficult, imaging techniques may be helpful and careful, and the histopathological analysis is necessary. The common histological variants of EOS include: osteoblastoma, chondroblastoma, and fibroblastoma, and other unusual subtypes were reported occasionally. It should be distinguished with myositis ossificans, malignant mesenchymoma, giant cell tumor and parosteal osteosarcoma. We present an EOS arising in the penis. The primary site and histological category of the tumor were extremely rare. We hope the case will be helpful to the recognition of clinical signs, iconography and histopathology of EOS. PMID- 23359774 TI - XPC Polymorphism Increases Risk of Digestive System Cancers: Current Evidence from A Meta-Analysis. AB - OBJECTIVE: Xeroderma pigmentosum complementation group C (XPC) participates in the initial recognition of DNA damage during nucleotide excision repair process in global genomic repair. Our meta-analysis was performed to evaluate the association between three polymorphisms (Lys939Gln, PAT+/- and Ala499Val) of XPC gene and risk of digestive system cancers. METHODS: All the relevant case-control studies published to April 2011 were identified through searching PubMed. Digestive system cancer risk with the three polymorphisms was estimated for each study by odds ratio (OR) with its 95% confidence interval (95% CI). RESULTS: We found an increased overall risk for digestive system cancers in all three models of Lys939Gln A>C (AC/CC vs. AA: OR, 1.20; 95% CI, 1.11-1.30; CC vs. AC/AA: OR, 1.24; 95% CI, 1.11-1.39; CC vs. AA: OR, 1.36; 95% CI, 1.21-1.53). When stratified by ethnicity, results remained significant in Asian population (AC/CC vs. AA: OR, 1.18; 95% CI, 1.02-1.37; CC vs. AC/AA: OR, 1.32; 95% CI, 1.1-1.51; CC vs. AA: OR, 1.35; 95% CI, 1.08-1.70), but not for Caucasians. However for Ala499Val C>T, a significant protective effect of T allele was only observed in the dominant model. Otherwise, no significant results were observed for PAT+/-. CONCLUSION: XPC Lys939Gln A>C polymorphism may play an important role in digestive system cancer susceptibility. PMID- 23359775 TI - Dys-psychological Stress Effect on Expressions of P53 and NFkappaBp65 in Human Ovarian Carcinoma In Vivo. AB - OBJECTIVE: To investigate the dys-psychological stress effect on the growth of subcutaneous xenotransplanted tumor in nude mice bearing human epithelium ovarian carcinoma, and the influence on P53 and NFkappaBp65 expressions. METHODS: The subcutaneous tumor xenografts were established by implanting human epithelium ovarian carcinoma tissues into nude mice and the dys-psychological stress model was established with restraint. The mice were randomized into the following four treatment groups with each group six mice respectively: tumor group (group A), normal saline intraperitoneal injection; tumor with stress group (group B), normal saline intraperitoneal injection; tumor therapy group (group C), cisplatin intraperitoneal injection; and tumor therapy with stress group (group D), cisplatin intraperitoneal injection. The expressions of P53 and NFkappaBp65 in tumor tissues were determined by Western blotting. RESULTS: The expressions of P53 and NFkappaBp65 in each restraint group were enhanced compared with the control groups (P<0.05). CONCLUSION: The dys-psychological stress may induce the high expressions of P53 and NFkappaBp65 proteins and further promote tumor growth. PMID- 23359776 TI - CPT-11 Chemotherapy Rescued A Patient with Atypical Sclerosing Epithelioid Fibrosarcoma from Emergent Condition. AB - Sclerosing epithelioid fibrosarcoma (SEF) is a rare and poorly defined variant of fibrosarcoma, but generally insensitive to chemotherapy and progresses with poor prognosis. We report the marvelous effect of irinotecan hydrochloride (CPT-11) chemotherapy in rescuing a patient with atypical SEF from emergent condition, who underwent recurrences after several treatment methods. Small dose of CPT-11 was administered to the patient, with which, the size of superficial mass (cervical lymph node) gradually decreased observed by the naked eyes in 5 days. X-ray and CT image proved a marked reduction in the size of the tumor. CPT-11 is valuable for the treatment of this aggressive sarcoma. In condition of emergency caused by sarcoma oppression, administering a tolerable small dose of topoisomerase I inhibiting drug could be a beneficial choice. PMID- 23359777 TI - NRS2002 assesses nutritional status of leukemia patients undergoing hematopoietic stem cell transplantation. AB - OBJECTIVE: To discuss whether nutritional risk screening 2002 (NRS2002) is appropriate for nutritional risk screening for leukemia patients before and after hematopoietic stem cell transplantation (HSCT), and whether there are risk differences in other conditions, such as age, gender and matching degree; to find the methods and indicators of nutritional risk screening for these patients before and after HSCT, in order to give timely intervention to guarantee the successful completion of the entire transplantation process. METHODS: Nutritional risk of 99 leukemia patients was screened with NRS2002 before and after HSCT. The (chi) (2) test was applied to compare the risk differences between groups such as age, gender and matching degree, while the differences of other enumeration data, such as recent (1-3 months) weight loss, reduced food intake within one week and BMI, were compared by continuity correction. RESULTS: Of the 99 leukemia patients, 22 cases (22.2%) had nutritional risk before HSCT, while all patients had nutritional risk after HSCT; there is no significant difference in nutritional risk between male and female, and patients of less than 30 years old, not-full matched, recent (1-3 months) weight loss, reduced food intake within a week or BMI <18.5 were more likely to have nutritional risk; and 77 cases (77.8%) had weight loss, among which 49 patients (63.6%) had more than 5% weight loss within one month. CONCLUSIONS: This study showed that leukemia patients should receive the nutritional risk screening conventionally before and after HSCT, and NRS2002 was only appropriate for nutritional risk screening before HSCT. More attention should be paid to the patients less than 30 years old or not-full matched. Weight change was one of the important nutritional indicators for patients after HSCT. PMID- 23359778 TI - The efficacy of the inhalation of an aerosolized Group A streptococcal preparation in the treatment of lung cancer. AB - OBJECTIVE: To observe the efficacy of the inhalation of an aerosolized group A streptococcal (GAS) preparation in treating orthotopic lung cancer in mouse models and assess the feasibility, safety, and effectiveness of this administration mode for lung cancer. METHODS: Lewis lung carcinoma (LLC) cell strains were administered via intrathoracic injection to establish orthotopic lung cancer mouse models. After the tumor-bearing models were successfully established, as confirmed by computed tomography, the mice were administered by inhalation with an aerosolized GAS preparation (GAS group) or aerosolized normal saline (control group). The anti-tumor effect of the aerosolized GAS preparation was evaluated histologically; meanwhile, the survival and quality of life were compared between these two groups. RESULTS: The aerosolized GAS preparation showed remarkably anti-tumor effect, causing the necrosis of the orthotopic lung cancer cells in tumor-bearing mice. Furthermore, mice in the GAS group had significantly better quality of life and longer survival than those in control group. CONCLUSIONS: The inhalation of aerosolized GAS preparation may be a feasible, safe and effective solution for lung cancer. PMID- 23359779 TI - Proton therapy for hepatocellular carcinoma. AB - Proton radiotherapy has seen an increasing role in the treatment of hepatocellular carcinoma (HCC). Historically, external beam radiotherapy has played a very limited role in HCC due to a high incidence of toxicity to surrounding normal structures. The ability to deliver a high dose of radiation to the tumor is a key factor in improving outcomes in HCC. Advances in photon radiotherapy have improved dose conformity and allowed dose escalation to the tumor. However, despite these advances there is still a large volume of normal liver that receives a considerable radiation dose during treatment. Proton beams do not have an exit dose along the beam path once they enter the body. The inherent physical attributes of proton radiotherapy offer a way to maximize tumor control via dose escalation while avoiding excessive radiation to the remaining liver, thus increasing biological effectiveness. In this review we discuss the physical attributes and rationale for proton radiotherapy in HCC. We also review recent literature regarding clinical outcomes of using proton radiotherapy for the treatment of HCC. PMID- 23359781 TI - Comparing the renal safety of isoosmolar versus low-osmolar contrast medium by renal biomarkers N-acetyl-beta-D-glucosaminidase and endothelin. AB - Iodixanol and iopamidol are commonly used contrast agents in coronary angiography. We evaluated the nephrotoxic effects of both contrast media in relation to renal biomarkers. A total of 38 low-risk patients who underwent coronary angiography were enrolled. Patients were randomized to receive either low-osmolar nonionic monomer or isoosmolar nonionic dimer contrast medium. N Acetyl-beta-d-glucosaminidase (NAG), endothelin, blood urea nitrogen, and urine and serum creatinine (SCr) levels were measured before the procedure (T0), at 6 hours (T6), and at 1 year after the procedure. Plasma endothelin, urine NAG/creatinine, and SCr were higher; accordingly, the urine creatinine values were lower in both the groups when comparing T0 versus T6. The groups were similar with each other when comparing T0 and T6 values. Both the contrast agents may be safely used at a low volume for coronary angiography in low-risk patients. Endothelin and NAG are sensitive to acute renal changes in function. There is a need for further prospective investigations with more patients. PMID- 23359780 TI - The induction of the apoptosis of cancer cell by sonodynamic therapy: a review. AB - Ultrasound can be used not only in the examination, but also in the therapy, especially in the therapy of cancer, which has got effect in the treatment. Sonodynamic therapy is an experimental cancer therapy which uses ultrasound to enhance the cytotoxic effects of drugs known as sonosensitizers. It has been tested in vitro and in vivo. The ultrasound could penetrate the tissue and cell under some of conditions which directly changes the cell membranes permeability, thereby allowing the delivery of exogenous molecules into the cells in some degree. Ultrasound could inhibit the proliferation or induce the apoptosis of the cancer cell in vitro or in vivo. Recent research indicated low frequency and low intensity ultrasound could induce cells apoptosis, and which could be strengthened by sonodynamic sensitivities, microbubbles, chemotherapeutic drugs and so on. Most kinds of ultrasound suppressed the proliferation of cancer cell through inducing the apoptosis of cancer cell. The mechanism of apoptosis is not clear. In this review, we will focus on and discuss the mechanisms of the induction of the apoptosis of cancer cell by ultrasound. PMID- 23359782 TI - Efficacy and safety of triple antiplatelet therapy in obese patients undergoing stent implantation. AB - We evaluated the impact of triple antiplatelet therapy on platelet reactivity, reducing cardiovascular events and the safety in obese patients undergoing coronary stenting. Obese patients (n = 428) undergoing coronary stenting were randomly assigned to 2 groups: standard dual group (clopidogrel plus aspirin, n = 215) and triple group (n = 213); adjunctive cilostazol was added to the dual group treatment. Platelet reactivity was assessed at baseline and at 1-year follow-up by conventional aggregometry. Major adverse cardiovascular events, stent thrombosis, target lesion revascularization (TLR), target vessel revascularization, and bleeding events were analyzed after 1-year follow-up. At 1 year follow-up after stenting, major adverse cardiac events including death, myocardial infarction, and ischemic-driven TLR were lower in the triple group than the dual group. Major bleeding was similar in both the groups. In obese patients undergoing percutaneous coronary intervention, triple antiplatelet therapy was superior to dual antiplatelet therapy in decreasing thrombotic events in 12-month cardiac events, mainly driven by a decrease in the incidence of clopidogrel resistance. PMID- 23359783 TI - Carotid Intima Media Thickness and its Association With Total Bilirubin Levels in Patients With Coronary Artery Ectasia. AB - Atherosclerosis plays an important role in the etiopathogenesis of coronary artery ectasia (CAE). The relationship between total bilirubin (TBil) and carotid intima media thickness (cIMT) in patients with CAE has not been fully investigated. Hence, we evaluated the relationship between TBil levels and cIMT in 142 consecutive eligible patients with CAE, newly diagnosed coronary artery disease (CAD), and normal coronary arteries. There were no significant differences in TBil (P = .772) and cIMT (P = .791) between the CAE and CAD groups. Bilirubin levels were significantly lower in both CAE and CAD groups compared to the controls (P < .01). The cIMT was significantly higher in both CAE and CAD groups compared to control participants (P < .01). A negative correlation between cIMT and TBil was found in all the groups (P < .01, r = .354). We show for the first time that patients with CAE and CAD have lower TBil and greater cIMT compared to controls with normal coronary angiograms. PMID- 23359784 TI - Coronary lesions complexity in patients with stable coronary artery disease. PMID- 23359785 TI - Pseudomembranous colitis within radiotherapy field following concurrent chemoradiation therapy: a case report. AB - Development of nonantibiotic-associated pseudomembranous colitis has been reported in patients receiving chemotherapy. Herein, we report a case of a 70 year-old man with diabetes mellitus and hypertension who received concurrent chemoradiation therapy after surgery for stage III pT3N1M0 rectal cancer. After completion of the therapy, the patient presented with a 2-week history of intermittent watery diarrhea (seven to nine times per day). However, the patient was afebrile and laboratory examination revealed no evidence of leukocytosis. Computed tomography disclosed inflammation of the sigmoid colon, infiltrative changes around the anastomotic site, and edematous changes straddling the serosal surface. Colonoscopic examination revealed multiple whitish patches within the radiation field, a finding suggestive of pseudomembranous colitis. No concomitant antibiotics were used during the period of concurrent chemoradiation therapy. Empirical oral metronidazole (500 mg every 8 hours) was administrated for 2 weeks. At the end of this treatment, stool culture was negative for Clostridium difficile. Physicians should be aware of the potential for the development of pseudomembranous colitis following concurrent chemoradiation therapy. PMID- 23359786 TI - Acromegaly: the disease, its impact on patients, and managing the burden of long term treatment. AB - Acromegaly is a rare disease most often caused by the prolonged secretion of excess growth hormone from a pituitary adenoma. The disease is associated with multiple significant comorbidities and increased mortality. The delay to diagnosis is often long. This may be because of low disease awareness among health care professionals, the insidious onset of differentiating features, and because patients are likely to present with complaints typical of other conditions more frequently seen in primary care. Early identification of acromegaly facilitates prompt treatment initiation and may minimize the permanent effects of excess growth hormone. The primary treatment for many patients will be pituitary surgery, although not all patients will be eligible for surgery or achieve a surgical cure. If biochemical control is not achieved following surgery, other treatment options include medical therapy and radiation therapy. Improved biochemical control may only alleviate rather than reverse the associated comorbidities. Thus, lifelong monitoring of patient health is needed, with particular attention to the management of cardiovascular risk factors. It is additionally important to consider the impact of both disease and treatment on patients' quality of life and minimize that impact where possible, but particularly for chronic therapies. For the majority of patients, chronic therapy is likely to include somatostatin analog injections. In some circumstances, it may be possible to extend the dosing interval of the analog once good biochemical control is achieved. Additional convenience may be gained from the possibility of self-/partner administration of treatment or administration of treatment by a health care professional at home. Overall, it is clear that the care of patients with acromegaly requires a highly coordinated approach involving numerous specialties (eg, endocrinology, surgery, cardiology). Further, patients' needs must be at the core of management and every effort must be made to improve health care experiences and minimize treatment burdens. PMID- 23359787 TI - Validity of the coding for intensive care admission, mechanical ventilation, and acute dialysis in the Danish National Patient Registry: a short report. AB - BACKGROUND: Large health care databases provide a cost-effective data source for observational research in the intensive care unit (ICU) if the coding is valid. The aim of this study was to investigate the accuracy of the recorded coding of ICU admission, mechanical ventilation, and acute dialysis in the population-based Danish National Patient Registry (DNPR). METHODS: We conducted the study in the North Denmark Region, including seven ICUs. From the DNPR we selected a total of 150 patients with an ICU admission by the following criteria: (1) 50 patients randomly selected among all patients registered with an ICU admission code, (2) 50 patients with an ICU admission code and a concomitant code for mechanical ventilation, and (3) 50 patients with an ICU admission code and a concomitant code for acute dialysis. Using the medical records as gold standard we estimated the positive predictive value (PPV) for each of the three procedure codes. RESULTS: We located 147 (98%) of the 150 medical records. Of these 147 patients, 141 (95.9%; 95% confidence interval [CI]: 91.8-98.3) had a confirmed ICU admission according to their medical records. Among patients, who were selected only on the coding for ICU admission, the PPV for ICU admission was 87.2% (95% CI: 75.6-94.5). For the mechanical ventilation code, the PPV was 100% (95% CI: 95.1-100). Forty-nine of 50 patients with the coding for acute dialysis received this treatment, corresponding to a PPV of 98.0% (95% CI: 91.0-99.8). CONCLUSION: We found a high PPV for the coding of ICU admission and even higher PPVs for mechanical ventilation, and acute dialysis in the DNPR. The DNPR is a valuable data source for observational studies of ICU patients. PMID- 23359788 TI - IUD discontinuation rates, switching behavior, and user satisfaction: findings from a retrospective analysis of a mobile outreach service program in Pakistan. AB - BACKGROUND: In Pakistan, the uptake rate for the intrauterine device (IUD) is very low at 2.5%. The most popular modern contraceptive methods in Pakistan are female sterilization and use of condoms. The Marie Stopes Society established its mobile outreach service delivery program with the aim of increasing use of modern quality contraceptive services, including the long-term reversible IUD, by women living in hard-to-reach areas. The present study attempts to assess IUD discontinuation rates and associated factors, including switching behavior and level of satisfaction with this type of service delivery. METHODS: Using a cross sectional approach, we contacted 681 women who had received an IUD from the Marie Stopes Society mobile outreach program during July and August 2009. Successful interviews were conducted with 639 of these women using a structured questionnaire. The data were analyzed with Stata 11.2 using simple descriptive Chi-square and Cox proportional techniques. RESULTS: Analysis revealed that 19.4% (95% confidence interval 16.3-22.5) of the women discontinued use of their IUD at 10 months and, of these women, the majority (69.4%) cited side effects as the main reason for discontinuation. Other factors, such as geographical catchment province, age of the woman, history of contraceptive use before IUD insertion, and side effects following insertion of the device, were found to be significantly associated with IUD. Amongst the women who had their IUD removed, 56.5% did not switch to any other contraceptive method, while 36.3% switched to either short-term or traditional methods, such as withdrawal, rhythm, and folk methods. Degree of satisfaction with the device was also significantly associated with discontinuation. CONCLUSION: Early discontinuation and not switching to another contraceptive method increases the risk of unplanned pregnancy. Health care workers should be trained in managing clients' concerns about the IUD to prevent discontinuation and providing counseling services for clients to select an alternative contraceptive method if they decide to discontinue. PMID- 23359789 TI - WNT5A-NFAT signaling mediates resistance to apoptosis in pancreatic cancer. AB - INTRODUCTION: WNT5A belongs to the Wnt family of secreted signaling molecules. Using transcriptional profiling, we previously identified WNT5A as target of the antiapoptotic transcription factor CUX1 and demonstrated high expression levels in pancreatic cancer. However, the impact of WNT5A on drug resistance and the signaling pathways employed by WNT5A remain to be elucidated. OBJECTIVES: This project aims to decipher the impact of WNT5A on resistance to apoptosis and the signaling pathways employed by WNT5A in pancreatic cancer. METHODS: The impact of WNT5A and its downstream effectors on tumor growth and drug resistance was studied in vitro and in xenograft models in vivo. Tissue microarrays of pancreatic cancer specimens were employed for immunohistochemical studies. RESULTS: Knockdown of WNT5A results in a significant increase in drug-induced apoptosis. In contrast, overexpression of WNT5A or addition of recombinant WNT5A mediates resistance to apoptosis in vitro. In our attempt to identify downstream effectors of WNT5A, we identified the transcription factor nuclear factor of activated T cells c2 (NFATc2) as transcriptional target of WNT5A signaling. NFATc2 confers a strong antiapoptotic phenotype mediating at least in part the effects of WNT5A on drug resistance and tumor cell survival. In vivo, WNT5A expression leads to resistance to gemcitabine-induced apoptosis in a xenograft model, which is paralleled by up-regulation of NFATc2. Both WNT5A and NFATc2 proteins are highly expressed in human pancreatic cancer tissues and their expression levels correlated significantly. CONCLUSION: We identified the WNT5A NFATc2 axis as important mediator of drug resistance in pancreatic cancer. PMID- 23359790 TI - Comparative interrater reliability of Asian Stroke Disability Scale, modified Rankin Scale and Barthel Index in patients with brain infarction. AB - BACKGROUND: This study tried to develop an Asian Stroke Disability Scale (ASDS) and compared its interrater reliability with modified Rankin Scale (mRS) and Barthel Index (BI). METHODS: Three items including self-care, mobility, and daily activities were selected as variables for development of the ASDS. The variables were provisionally graded on a 2- to 4-point scale based on the importance of each item. Each of the variables was categorized into 3 categories. Afterward, 125 rater-patient assessments for each scale (mRS, BI, and ASDS) were performed on 25 stroke patients by 5 raters. For categorization of functional impairment as minor or major, the scores of mRS, BI and ASDS were categorized as <= 2 and > 2, < 90 and >= 90, and < 3 and >= 3, respectively.125 rater-patient assessments for each of the mRS, BI, and ASDS were performed on 25 stroke patients by five raters. RESULTS: The quantitative variability of BI, mRS, and ASDS scores was not significant (P = 0.379; P = 0.780; and P = 0.835, respectively). Interrater variability of mRS, BI, and ASDS scores based on qualitative categorization was not significant (P = 1.000; P = 0.978; and P = 0.901, respectively). Paired interrater variability of mRS, BI, and ASDS scores based on qualitative categorization was not significant (P > 0.05). CONCLUSION: The ASDS is easy to use, requires less than 1 minute to complete and is as valid as mRS and BI in assessment of functional impairment of patients with stroke. PMID- 23359791 TI - Chest pain units: A necessity or only a name to encourage patients. AB - BACKGROUND: Acute chest pain is a common symptom among patients presenting to emergency wards. Identification and admission of patients with real acute coronary syndrome and preventing the hospitalization of people with false diagnosis of coronary syndrome are the most important tasks in emergency wards. The purpose of this study was to investigate the usefulness of designing a special chest pain unit in emergency department of Imam Khomeini Hospital (Ahvaz, Iran). METHODS: The patients with markers of ongoing cardiac ischemia underwent selective coronary angiography. The chest pain unit protocol was applied to selected patients with no definite evidence of acute coronary syndrome or alternative pathology. The protocol consisted of twelve hours of observation and serial 12-lead electrocardiography, transthoracic echocardiography, and biochemical testing followed by an exercise treadmill test. We compared the number of patients who were discharged after work up, discharged themselves against medical advice, admitted at coronary care unit (CCU), underwent invasive procedures or died between 2007 and 2010. RESULTS: During 2010, 43% of patients were discharged after evaluation in the chest pain unit. In 2007 however, 26% were discharged following traditional assessments. The admission rate increased from 23% in 2007 to 36% in 2010. The percentage of patients who discharged themselves against medical advice decreased from 37% in 2007 to 14% in 2010. There was not a statistically significant difference between mortality rates in 2007 and 2010. CONCLUSION: Providing a special chest pain unit in emergency ward in our condition is helpful. It reduces unnecessary admissions and improves patient satisfaction. PMID- 23359792 TI - An accurate method for the qualitative detection and quantification of mycobacterial promoter activity. AB - The present study was designed to determine the half-life of gfp(m) (2+) mRNA, which encodes mycobacterial codon-optimised highly fluorescent GFP(m) (2+) protein, and to find out whether mycobacterial promoter activity can be quantitated more accurately using the mRNA levels of the reporter gene, gfp(m) (2+), than the fluorescence intensity of the GFP(m) (2+) protein. Quantitative PCR of gfp(m) (2+) mRNA in the pulse-chased samples of the rifampicin-treated Mycobacterium smeg-matis/gfpm(2+) transformant showed the half-life of gfp(m) (2+) mRNA to be 4.081 min. The levels of the gfp(m) (2+) mRNA and the fluorescence intensity of the GFP(m) (2+) protein, which were expressed by the promoters of Mycobacterium tuberculosis cell division gene, ftsZ (MtftsZ), were determined using quantitative PCR and fluorescence spectrophotometry, respectively. The data revealed that quantification of mycobacterial promoter activity by determining the gfp(m) (2+) mRNA levels is more accurate and statistically significant than the measurement of GFP(m) (2+) fluorescence intensity, especially for weak promoters. PMID- 23359793 TI - Correction: A beta-Lactamase based reporter system for ESX dependent protein translocation in mycobacteria. PMID- 23359794 TI - Quercetin induces hepatic lipid omega-oxidation and lowers serum lipid levels in mice. AB - Elevated circulating lipid levels are known risk factors for cardiovascular diseases (CVD). In order to examine the effects of quercetin on lipid metabolism, mice received a mild-high-fat diet without (control) or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and (1)H nuclear magnetic resonance were used to quantitatively measure serum lipid profiles. Whole genome microarray analysis of liver tissue was used to identify possible mechanisms underlying altered circulating lipid levels. Body weight, energy intake and hepatic lipid accumulation did not differ significantly between the quercetin and the control group. In serum of quercetin-fed mice, triglycerides (TG) were decreased with 14% (p<0.001) and total poly unsaturated fatty acids (PUFA) were increased with 13% (p<0.01). Palmitic acid, oleic acid, and linoleic acid were all decreased by 9-15% (p<0.05) in quercetin-fed mice. Both palmitic acid and oleic acid can be oxidized by omega (omega)-oxidation. Gene expression profiling showed that quercetin increased hepatic lipid metabolism, especially omega oxidation. At the gene level, this was reflected by the up-regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450s) and the transcription factor constitutive androstane receptor (Car; official symbol Nr1i3) were also up-regulated in the quercetin-fed mice. We conclude that quercetin intake increased hepatic lipid omega-oxidation and lowered corresponding circulating lipid levels, which may contribute to potential beneficial effects on CVD. PMID- 23359795 TI - Fluorescence in situ hybridization and immunohistochemistry as diagnostic methods for ALK positive non-small cell lung cancer patients. AB - BACKGROUND: Anaplastic Lymphoma Kinase (ALK) positivity represents a novel molecular target in a subset of Non-Small Cell Lung Cancers (NSCLC). We explore Fluorescence in situ Hybridization (FISH) and Immunohistochemistry (IHC) as diagnostic methods for ALK positive patients and to describe its prevalence and outcomes in a population of NSCLC patients. METHODS: NSCLC patients previously screened for Epidermal Growth Factor Receptor (EGFR) at our institution were selected. ALK positive patients were identified by FISH and the value of IHC (D5F3) was explored. RESULTS: ninety-nine patients were identified. Median age was 61.5 years (range 35-83), all were caucasians, eighty percent were adenocarcinomas, fifty-one percent were male and thirty-eight percent were current smokers. Seven (7.1%) patients were ALK positive by FISH, thirteen (13.1%) were EGFR mutant, and 65 (65.6%) were negative/Wild Type (WT) for both ALK and EGFR. ALK positivity and EGFR mutations were mutually exclusive. ALK positive patients tend to be younger than EGFR mutated or wt patients. ALK positive patients were predominantly never smokers (71.4%) and adenocarcinoma (71.4%). ALK positive and EGFR mutant patients have a better outcome than negative/WT. All patients with ALK FISH negative tumours were negative for ALK IHC. Out of 6 patients positive for ALK FISH with more tissue available, 5 were positive for ALK IHC and 1 negative. CONCLUSIONS: ALK positive patients represent 7.1% of a population of selected NSCLC. ALK positive patients have different clinical features and a better outcome than EGFR WT and ALK negative patients. IHC is a promising method for detecting ALK positive NSCLC patients. PMID- 23359796 TI - Adjuvant chemotherapy for elderly patients with gastric cancer after D2 gastrectomy. AB - BACKGROUND: A phase III clinical trial has already shown the survival benefits of postoperative chemotherapy in gastric cancer. However, there are limited published data concerning the elderly. This study aims to investigate the use of adjuvant chemotherapy for gastric cancer after D2 gastrectomy among the elderly and identify its impact on survival. METHODS: We retrospectively reviewed 360 patients who had undergone D2 gastrectomy, aged 65 years or older, with non metastatic gastric cancer in a single institution. We analyzed the predictors and survival benefits of adjuvant chemotherapy use in the elderly. Further, we analyzed the survival benefits of adjuvant chemotherapy by dividing the patients into groups according to disease stages and chemotherapeutic regimens. RESULTS: Among the 360 patients, only 34.7% of patients received adjuvant chemotherapy. Age, tumor location, lymph node involvement and tumor invasion were associated with the receipt of adjuvant chemotherapy. Adjuvant chemotherapy improved the overall survival for non-metastatic elderly patients (HR 0.60, 95%CI 0.42-0.83, P = 0.003). Significant survival benefits were found with adjuvant chemotherapy in stage III patients (HR 0.67, 95%CI 0.47-0.97, P = 0.033), but not in stage I patients or in stage II patients (HR 0.52, 95%CI 0.21-1.30 P = 0.161). Compared to adjuvant chemotherapy without platinum, no significant survival benefits were observed with platinum-containing chemotherapy (HR 0.84, 95%CI 0.49-1.45, P = 0.530). Besides adjuvant chemotherapy, other independent prognostic factors of survival included tumor location, tumor size, histologic grade, depth of tumor invasion, and lymph node status. CONCLUSIONS: This study demonstrated the survival benefits of adjuvant fluoropyrimidine-based chemotherapy among the elderly patients with non-metastatic gastric cancer after D2 gastrectomy. However, due to the limitations of this study, further well-designed prospective studies with large populations are needed to confirm these findings and identify the patients that can tolerate and benefit from adjuvant chemotherapy. PMID- 23359797 TI - High frequency targeted mutagenesis using engineered endonucleases and DNA-end processing enzymes. AB - Targeting DNA double-strand breaks is a powerful strategy for gene inactivation applications. Without the use of a repair plasmid, targeted mutagenesis can be achieved through Non-Homologous End joining (NHEJ) pathways. However, many of the DNA breaks produced by engineered nucleases may be subject to precise re-ligation without loss of genetic information and thus are likely to be unproductive. In this study, we combined engineered endonucleases and DNA-end processing enzymes to increase the efficiency of targeted mutagenesis, providing a robust and efficient method to (i) greatly improve targeted mutagenesis frequency up to 30 fold, and; (ii) control the nature of mutagenic events using meganucleases in conjunction with DNA-end processing enzymes in human primary cells. PMID- 23359798 TI - A role for the membrane in regulating Chlamydomonas flagellar length. AB - Flagellar assembly requires coordination between the assembly of axonemal proteins and the assembly of the flagellar membrane and membrane proteins. Fully grown steady-state Chlamydomonas flagella release flagellar vesicles from their tips and failure to resupply membrane should affect flagellar length. To study vesicle release, plasma and flagellar membrane surface proteins were vectorially pulse-labeled and flagella and vesicles were analyzed for biotinylated proteins. Based on the quantity of biotinylated proteins in purified vesicles, steady-state flagella appeared to shed a minimum of 16% of their surface membrane per hour, equivalent to a complete flagellar membrane being released every 6 hrs or less. Brefeldin-A destroyed Chlamydomonas Golgi, inhibited the secretory pathway, inhibited flagellar regeneration, and induced full-length flagella to disassemble within 6 hrs, consistent with flagellar disassembly being induced by a failure to resupply membrane. In contrast to membrane lipids, a pool of biotinylatable membrane proteins was identified that was sufficient to resupply flagella as they released vesicles for 6 hrs in the absence of protein synthesis and to support one and nearly two regenerations of flagella following amputation. These studies reveal the importance of the secretory pathway to assemble and maintain full length flagella. PMID- 23359799 TI - Predicting insect migration density and speed in the daytime convective boundary layer. AB - Insect migration needs to be quantified if spatial and temporal patterns in populations are to be resolved. Yet so little ecology is understood above the flight boundary layer (i.e. >10 m) where in north-west Europe an estimated 3 billion insects km(-1) month(-1) comprising pests, beneficial insects and other species that contribute to biodiversity use the atmosphere to migrate. Consequently, we elucidate meteorological mechanisms principally related to wind speed and temperature that drive variation in daytime aerial density and insect displacements speeds with increasing altitude (150-1200 m above ground level). We derived average aerial densities and displacement speeds of 1.7 million insects in the daytime convective atmospheric boundary layer using vertical-looking entomological radars. We first studied patterns of insect aerial densities and displacements speeds over a decade and linked these with average temperatures and wind velocities from a numerical weather prediction model. Generalized linear mixed models showed that average insect densities decline with increasing wind speed and increase with increasing temperatures and that the relationship between displacement speed and density was negative. We then sought to derive how general these patterns were over space using a paired site approach in which the relationship between sites was examined using simple linear regression. Both average speeds and densities were predicted remotely from a site over 100 km away, although insect densities were much noisier due to local 'spiking'. By late morning and afternoon when insects are migrating in a well-developed convective atmosphere at high altitude, they become much more difficult to predict remotely than during the early morning and at lower altitudes. Overall, our findings suggest that predicting migrating insects at altitude at distances of ~ 100 km is promising, but additional radars are needed to parameterise spatial covariance. PMID- 23359800 TI - Stomatal control and leaf thermal and hydraulic capacitances under rapid environmental fluctuations. AB - Leaves within a canopy may experience rapid and extreme fluctuations in ambient conditions. A shaded leaf, for example, may become exposed to an order of magnitude increase in solar radiation within a few seconds, due to sunflecks or canopy motions. Considering typical time scales for stomatal adjustments, (2 to 60 minutes), the gap between these two time scales raised the question whether leaves rely on their hydraulic and thermal capacitances for passive protection from hydraulic failure or over-heating until stomata have adjusted. We employed a physically based model to systematically study effects of short-term fluctuations in irradiance on leaf temperatures and transpiration rates. Considering typical amplitudes and time scales of such fluctuations, the importance of leaf heat and water capacities for avoiding damaging leaf temperatures and hydraulic failure were investigated. The results suggest that common leaf heat capacities are not sufficient to protect a non-transpiring leaf from over-heating during sunflecks of several minutes duration whereas transpirative cooling provides effective protection. A comparison of the simulated time scales for heat damage in the absence of evaporative cooling with observed stomatal response times suggested that stomata must be already open before arrival of a sunfleck to avoid over heating to critical leaf temperatures. This is consistent with measured stomatal conductances in shaded leaves and has implications for water use efficiency of deep canopy leaves and vulnerability to heat damage during drought. Our results also suggest that typical leaf water contents could sustain several minutes of evaporative cooling during a sunfleck without increasing the xylem water supply and thus risking embolism. We thus submit that shaded leaves rely on hydraulic capacitance and evaporative cooling to avoid over-heating and hydraulic failure during exposure to typical sunflecks, whereas thermal capacitance provides limited protection for very short sunflecks (tens of seconds). PMID- 23359802 TI - A new technique for analysing interacting factors affecting biodiversity patterns: crossed-DPCoA. AB - We developed an approach for analysing the effects of two crossed factors A and B on the functional, taxonomic or phylogenetic composition of communities. The methodology, known as crossed-DPCoA, defines a space where species, communities and the levels of the two factors are organised as a set of points. In this space, the Euclidean distance between two species-specific points is a measure of the (functional, taxonomic or phylogenetic) dissimilarity. The communities are positioned at the centroid of their constitutive species; and the levels of two factors at the centroid of the communities associated with them. We develop two versions for crossed-DPCoA, the first one moves the levels of factor B to the centre of the space and analyses the axes of highest variance in the coordinates of the levels of factor A. It is related to previous ordination approaches such as partial canonical correspondence analysis and partial non-symmetrical correspondence analysis. The second version projects all points on the orthogonal complement of the space generated by the principal axes of factor B. This second version should be preferred when there is an a priori suspicion that factor A and B are associated. We apply the two versions of crossed-DPCoA to analyse the phylogenetic composition of Central European and Mediterranean bird communities. Applying crossed-DPCoA on bird communities supports the hypothesis that allopatric speciation processes during the Quaternary occurred in open and patchily distributed landscapes, while the lack of geographic barriers to dispersal among forest habitats may explain the homogeneity of forest bird communities over the whole western Palaearctic. Generalizing several ordination analyses commonly used in ecology, crossed-DPCoA provides an approach for analysing the effects of crossed factors on functional, taxonomic and phylogenetic diversity, environmental and geographic structure of species niches, and more broadly the role of genetics on population structures. PMID- 23359801 TI - Determination of vascular dementia brain in distinct frequency bands with whole brain functional connectivity patterns. AB - Recent studies have shown that multivariate pattern analysis (MVPA) can be useful for distinguishing brain disorders into categories. Such analyses can substantially enrich and facilitate clinical diagnoses. Using MPVA methods, whole brain functional networks, especially those derived using different frequency windows, can be applied to detect brain states. We constructed whole brain functional networks for groups of vascular dementia (VaD) patients and controls using resting state BOLD-fMRI (rsfMRI) data from three frequency bands - slow-5 (0.01 ~ 0.027 Hz), slow-4 (0.027~0.073 Hz), and whole-band (0.01 ~ 0.073 Hz). Then we used the support vector machine (SVM), a type of MVPA classifier, to determine the patterns of functional connectivity. Our results showed that the brain functional networks derived from rsfMRI data (19 VaD patients and 20 controls) in these three frequency bands appear to reflect neurobiological changes in VaD patients. Such differences could be used to differentiate the brain states of VaD patients from those of healthy individuals. We also found that the functional connectivity patterns of the human brain in the three frequency bands differed, as did their ability to differentiate brain states. Specifically, the ability of the functional connectivity pattern to differentiate VaD brains from healthy ones was more efficient in the slow-5 (0.01 ~ 0.027 Hz) band than in the other two frequency bands. Our findings suggest that the MVPA approach could be used to detect abnormalities in the functional connectivity of VaD patients in distinct frequency bands. Identifying such abnormalities may contribute to our understanding of the pathogenesis of VaD. PMID- 23359803 TI - Progesterone alleviates neural behavioral deficits and demyelination with reduced degeneration of oligodendroglial cells in cuprizone-induced mice. AB - Demyelination occurs widely in neurodegenerative diseases. Progesterone has neuroprotective effects, is known to reduce the clinical scores and the inflammatory response. Progesterone also promotes remyelination in experimental autoimmune encephalomyelitis and cuprizone-induced demyelinating brain. However, it still remains unclear whether progesterone can alleviate neural behavioral deficits and demyelination with degeneration of oligodendroglial cells in cuprizone-induced mice. In this study, mice were fed with 0.2% cuprizone to induce demyelination, and treated with progesterone to test its potential protective effect on neural behavioral deficits, demyelination and degeneration of oligodendroglial cells. Our results showed noticeable alleviation of neural behavioral deficits following progesterone treatment as assessed by changes in average body weight, and activity during the open field and Rota-rod tests when compared with the vehicle treated cuprizone group. Progesterone treatment alleviated demyelination as shown by Luxol fast blue staining, MBP immunohistochemical staining, and electron microscopy. There was an obvious decrease in TUNEL and Caspase-3-positive apoptotic cells, and an increase in the number of oligodendroglial cells staining positive for PDGFRalpha, Olig2, Sox10 and CC-1 antibody in the brains of cuprizone-induced mice after progesterone administration. These results indicate that progesterone can alleviate neural behavioral deficits and demyelination against oligodendroglial cell degeneration in cuprizone-induced mice. PMID- 23359804 TI - Molecular markers in sex hormone pathway genes associated with the efficacy of androgen-deprivation therapy for prostate cancer. AB - Although most advanced prostate cancer patients respond to androgen-deprivation therapy (ADT), the efficacy is widely variable. We investigated whether the host genetic variations in sex hormone pathway genes are associated with the efficacy of ADT. A cohort of 645 patients with advanced prostate cancer treated with ADT was genotyped for 18 polymorphisms across 12 key genes involved in androgen and estrogen metabolism. We found that after adjusting for known risk factors in multivariate Cox regression models, AKR1C3 rs12529 and AR-CAG repeat length remained significantly associated with prostate cancer-specific mortality (PCSM) after ADT (P <= 0.041). Furthermore, individuals carrying two unfavorable genotypes at these loci presented a 13.7-fold increased risk of PCSM compared with individuals carrying zero (P<0.001). Our results identify two candidate molecular markers in key genes of androgen and estrogen pathways associated with PCSM after ADT, establishing the role of pharmacogenomics in this therapy. PMID- 23359805 TI - Both serum apolipoprotein B and the apolipoprotein B/apolipoprotein A-I ratio are associated with carotid intima-media thickness. AB - BACKGROUND: Previous studies indicated that apolipoprotein measurements predicted cardiovascular disease (CVD) risk; however, associations between apolipoproteins and carotid intima-media thickness (CIMT) were less explored. METHODOLOGY AND PRINCIPAL FINDINGS: The cross-sectional study included 6069 participants aged 40 years or older with NGT from Shanghai, China. Serum fasting traditional lipids (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high density lipoprotein cholesterol [HDL-C] and triglycerides [TG]), apoA-I and apoB were assessed. A high-resolution B-mode ultrasonography was performed to measure CIMT. We found CIMT increased progressively across the quartiles of serum apoB (p for trend <0.0001). In logistic regression, concentrations of apoB (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.18-1.36), TC (OR 1.23, 95% CI 1.14 1.32), LDL-C (OR 1.25, 95% CI 1.16-1.34) and TG (OR 1.11, 95% CI 1.04-1.20) were significantly related to elevated CIMT after adjusted for age and sex. Meanwhile, the apoB/apoA-I ratio (OR 1.25, 95% CI 1.17-1.34) related to elevated CIMT. ApoB (OR 1.23, 95% CI 1.00-1.51) and the apoB/apoA-I ratio (OR 1.19, 95% CI 1.04-1.36) remained significantly associated with elevated CIMT, after adjusted for the traditional CVD risk factors including traditional lipids. CONCLUSIONS AND SIGNIFICANCE: There were significant associations between serum apoB, the apoB/apoA-I ratio and elevated CIMT. Serum apoB and the apoB/apoA-I ratio might be independent predictors of early atherosclerosis in NGT. PMID- 23359806 TI - Geochemical and visual indicators of hydrothermal fluid flow through a sediment hosted volcanic ridge in the Central Bransfield Basin (Antarctica). AB - In the austral summer of 2011 we undertook an investigation of three volcanic highs in the Central Bransfield Basin, Antarctica, in search of hydrothermal activity and associated fauna to assess changes since previous surveys and to evaluate the extent of hydrothermalism in this basin. At Hook Ridge, a submarine volcanic edifice at the eastern end of the basin, anomalies in water column redox potential (E(h)) were detected close to the seafloor, unaccompanied by temperature or turbidity anomalies, indicating low-temperature hydrothermal discharge. Seepage was manifested as shimmering water emanating from the sediment and from mineralised structures on the seafloor; recognisable vent endemic fauna were not observed. Pore fluids extracted from Hook Ridge sediment were depleted in chloride, sulfate and magnesium by up to 8% relative to seawater, enriched in lithium, boron and calcium, and had a distinct strontium isotope composition ((87)Sr/(86)Sr = 0.708776 at core base) compared with modern seawater ((87)Sr/(86)Sr ~ 0.70918), indicating advection of hydrothermal fluid through sediment at this site. Biogeochemical zonation of redox active species implies significant moderation of the hydrothermal fluid with in situ diagenetic processes. At Middle Sister, the central ridge of the Three Sisters complex located about 100 km southwest of Hook Ridge, small water column E(h) anomalies were detected but visual observations of the seafloor and pore fluid profiles provided no evidence of active hydrothermal circulation. At The Axe, located about 50 km southwest of Three Sisters, no water column anomalies in E(h), temperature or turbidity were detected. These observations demonstrate that the temperature anomalies observed in previous surveys are episodic features, and suggest that hydrothermal circulation in the Bransfield Strait is ephemeral in nature and therefore may not support vent biota. PMID- 23359807 TI - High doses of romiplostim induce proliferation and reduce proplatelet formation by human megakaryocytes. AB - BACKGROUND: Romiplostim (AMG531) is a Thrombopoietin (TPO) receptor agonist with no homology with the endogenous TPO that has been used to treat patients affected by immune thrombocytopenia (ITP). Despite the use of TPO mimetics in the clinical practice, the mechanisms underlying their impact on megakaryocyte function is still unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this project we took advantage of an in vitro human model, that we have established in our laboratory for long time to study megakaryocyte development from human cord blood-derived progenitor cells, and we demonstrated that increasing doses of AMG531 (100 to 2000 ng/mL) determine a progressive increase of megakaryocyte proliferation with a parallel decrease in megakaryocyte ploidy and capacity of extending proplatelets. Most importantly, these differences in megakaryocyte function seemed to be correlated to modulation of AKT phosphorylation. CONCLUSIONS/SIGNIFICANCE: Overall our results shed new light on the mechanisms and on the relevance of dosage related to AMG531 impact on megakaryocyte function. PMID- 23359808 TI - Household risk factors for colonization with multidrug-resistant Staphylococcus aureus isolates. AB - Antimicrobial resistance, particularly in pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), limits treatment options and increases healthcare costs. To understand patient risk factors, including household and animal contact, potentially associated with colonization with multidrug-resistant MRSA isolates, we performed a prospective study of case patients colonized with MRSA on admission to a rural tertiary care hospital. Patients were interviewed and antimicrobial resistance patterns were tested among isolates from admitted patients colonized with MRSA in 2009-10. Prevalence of resistance was compared by case-patient risk factors and length-of-stay outcome among 88 MRSA case patients. Results were compared to NHANES 2003-04. Overall prevalence of multidrug resistance (non-susceptibility to >= four antimicrobial classes) in MRSA nasal isolates was high (73%) and was associated with a 1.5-day increase in subsequent length of stay (p = 0.008). History of hospitalization within the past six months, but not antimicrobial use in the same time period, was associated with resistance patterns. Within a subset of working-age case patients without recent history of hospitalization, animal contact was potentially associated with multidrug resistance. History of hospitalization, older age, and small household size were associated with multidrug resistance in NHANES data. In conclusion, recent hospitalization of case patients was predictive of antimicrobial resistance in MRSA isolates, but novel risk factors associated with the household may be emerging in CA-MRSA case patients. Understanding drivers of antimicrobial resistance in MRSA isolates is important to hospital infection control efforts, relevant to patient outcomes and to indicators of the economic burden of antimicrobial resistance. PMID- 23359809 TI - Shifting evaluation windows: predictable forward primes with long SOAs eliminate the impact of backward primes. AB - Recent work suggests that people evaluate target stimuli within short and flexible time periods called evaluation windows. Stimuli that briefly precede a target (forward primes) or briefly succeed a target (backward primes) are often included in the target's evaluation. In this article, the authors propose that predictable forward primes act as "go" signals that prepare target processing, such that earlier forward primes pull the evaluation windows forward in time. Earlier forward primes may thus reduce the impact of backward primes. This shifting evaluation windows hypothesis was tested in two experiments using an evaluative decision task with predictable (vs. unpredictable) forward and backward primes. As expected, a longer time interval between a predictable forward prime and a target eliminated backward priming. In contrast, the time interval between an unpredictable forward primes and a target had no effects on backward priming. These findings suggest that predictable features of dynamic stimuli can shape target extraction by determining which information is included (or excluded) in rapid evaluation processes. PMID- 23359810 TI - Spindle shaped human mesenchymal stem/stromal cells from amniotic fluid promote neovascularization. AB - Human amniotic fluid obtained at amniocentesis, when cultured, generates at least two morphologically distinct mesenchymal stem/stromal cell (MSC) subsets. Of these, the spindle shaped amniotic fluid MSCs (SS-AF-MSCs) contain multipotent cells with enhanced adipogenic, osteogenic and chondrogenic capacity. Here, we demonstrate, for the first time, the capacity of these SS-AF-MSCs to support neovascularization by umbilical cord blood (UCB) endothelial colony forming cell (ECFC) derived cells in both in vitro and in vivo models. Interestingly, although the kinetics of vascular tubule formation in vitro were similar when the supporting SS-AF-MSCs were compared with the best vasculogenic supportive batches of bone marrow MSCs (BMSCs) or human dermal fibroblasts (hDFs), SS-AF-MSCs supported vascular tubule formation in vivo more effectively than BMSCs. In NOD/SCID mice, the human vessels inosculated with murine vessels demonstrating their functionality. Proteome profiler array analyses revealed both common and distinct secretion profiles of angiogenic factors by the SS-AF-MSCs as opposed to the hDFs and BMSCs. Thus, SS-AF-MSCs, which are considered to be less mature developmentally than adult BMSCs, and intermediate between adult and embryonic stem cells in their potentiality, have the additional and very interesting potential of supporting increased neovascularisation, further enhancing their promise as vehicles for tissue repair and regeneration. PMID- 23359811 TI - Obsessive compulsive personality disorder and Parkinson's disease. AB - OBJECTIVES: To evaluate the frequency of personality disorders in Parkinson's disease (PD) patients and in a group of healthy controls. METHODS: Patients affected by PD diagnosed according to the United Kingdom Parkinson's disease Society Brain Bank diagnostic criteria and a group of healthy controls were enrolled in the study. PD patients with cognitive impairment were excluded from the study. Structured Clinical Interview for Personality Disorders-II (SCID-II) has been performed to evaluate the presence of personality disorders. Presence of personality disorders, diagnosed according to the DSM-IV, was confirmed by a psychiatric interview. Clinical and pharmacological data were also recorded using a standardized questionnaire. RESULTS: 100 PD patients (57 men; mean age 59.0 +/- 10.2 years) and 100 healthy subjects (52 men; mean age 58.1 +/- 11.4 years) were enrolled in the study. The most common personality disorder was the obsessive compulsive personality disorder diagnosed in 40 PD patients and in 10 controls subjects (p-value<0.0001) followed by the depressive personality disorder recorded in 14 PD patients and 4 control subjects (p-value 0.02). Obsessive compulsive personality disorder was also found in 8 out of 16 de novo PD patients with a short disease duration. CONCLUSION: PD patients presented a high frequency of obsessive-compulsive personality disorder that does not seem to be related with both disease duration and dopaminergic therapy. PMID- 23359812 TI - Pancreatic tumors and immature immunosuppressive myeloid cells in blood and spleen: role of inhibitory co-stimulatory molecules PDL1 and CTLA4. An in vivo and in vitro study. AB - BACKGROUND: Blood and spleen expansion of immature myeloid cells (IMCs) might compromise the immune response to cancer. We studied in vivo circulating and splenic T lymphocyte and IMC subsets in patients with benign and malignant pancreatic diseases. We ascertained in vitro whether pancreatic adenocarcinoma (PDAC)-associated IMC subsets are induced by tumor-derived soluble factors and whether they are immunosuppressive focusing on the inhibitory co-stimulatory molecules PDL1 and CTLA4. METHODOLOGY AND PRINCIPAL FINDINGS: 103 pancreatic and/or splenic surgical patients were enrolled including 52 PDAC, 10 borderline and 10 neuroendocrine tumors (NETs). Lymphocytes and IMCs were analysed by flow cytometry in blood, in spleen and in three PDAC cell conditioned (CM) or non conditioned PBMC. PDL1 and CTLA4 were studied in 30 splenic samples, in control and conditioned PBMC. IMCs were FACS sorted and co-coltured with allogenic T lymphocytes. In PDAC a reduction was found in circulating CD8(+) lymphocytes (p = 0.004) and dendritic cells (p = 0.01), which were reduced in vitro by one PDAC CM (Capan1; p = 0.03). Blood myeloid derived suppressive cells (MDSCs) CD33(+)CD14( )HLA-DR(-) were increased in PDAC (p = 0.022) and were induced in vitro by BxPC3 CM. Splenic dendritic cells had a higher PDL1 expression (p = 0.007), while CD33(+)CD14(+)HLA-DR(-) IMCs had a lower CTLA4 expression (p = 0.029) in PDAC patients. In vitro S100A8/A9 complex, one of the possible inflammatory mediators of immune suppression in PDAC, induced PDL1 (p = 0.018) and reduced CTLA4 expression (p = 0.028) among IMCs. IMCs not expressing CTLA4 were demonstrated to be immune suppressive. CONCLUSION: In PDAC circulating dendritic and cytotoxic T cells are reduced, while MDSCs are increased and this might favour tumoral growth and progression. The reduced CTLA4 expression found among splenic IMCs of PDAC patients was demonstrated to characterize an immune suppressive phenotype and to be consequent to the direct exposure of myeloid cells to pancreatic cancer derived products, S100A8/A9 complex in particular. PMID- 23359813 TI - Potential of the virion-associated peptidoglycan hydrolase HydH5 and its derivative fusion proteins in milk biopreservation. AB - Bacteriophage lytic enzymes have recently attracted considerable interest as novel antimicrobials against Gram-positive bacteria. In this work, antimicrobial activity in milk of HydH5 [a virion-associated peptidoglycan hydrolase (VAPGH) encoded by the Staphylococcus aureus bacteriophage vB_SauS-phiIPLA88], and three different fusion proteins created between HydH5 and lysostaphin has been assessed. The lytic activity of the five proteins (HydH5, HydH5Lyso, HydH5SH3b, CHAPSH3b and lysostaphin) was confirmed using commercial whole extended shelf life milk (ESL) in challenge assays with 10(4) CFU/mL of the strain S. aureus Sa9. HydH5, HydH5Lyso and HydH5SH3b (3.5 uM) kept the staphylococcal viable counts below the control cultures for 6 h at 37 degrees C. The effect is apparent just 15 minutes after the addition of the lytic enzyme. Of note, lysostaphin and CHAPSH3b showed the highest staphylolytic protection as they were able to eradicate the initial staphylococcal challenge immediately or 15 min after addition, respectively, at lower concentration (1 uM) at 37 degrees C. CHAPSH3b showed the same antistaphyloccal effect at room temperature (1.65 uM). No re growth was observed for the remainder of the experiment (up to 6 h). CHAPSH3b activity (1.65 uM) was also assayed in raw (whole and skim) and pasteurized (whole and skim) milk. Pasteurization of milk clearly enhanced CHAPSH3b staphylolytic activity in both whole and skim milk at both temperatures. This effect was most dramatic at room temperature as this protein was able to reduce S. aureus viable counts to undetectable levels immediately after addition with no re-growth detected for the duration of the experiment (360 min). Furthermore, CHAPSH3b protein is known to be heat tolerant and retained some lytic activity after pasteurization treatment and after storage at 4 degrees C for 3 days. These results might facilitate the use of the peptidoglycan hydrolase HydH5 and its derivative fusions, particularly CHAPSH3b, as biocontrol agents for controlling undesirable bacteria in dairy products. PMID- 23359814 TI - A novel mechanism of formaldehyde neurotoxicity: inhibition of hydrogen sulfide generation by promoting overproduction of nitric oxide. AB - BACKGROUND: Formaldehyde (FA) induces neurotoxicity by overproduction of intracellular reactive oxygen species (ROS). Increasing studies have shown that hydrogen sulfide (H(2)S), an endogenous gastransmitter, protects nerve cells against oxidative stress by its antioxidant effect. It has been shown that overproduction of nitric oxide (NO) inhibits the activity of cystathionine-beta synthase (CBS), the predominant H(2)S-generating enzyme in the central nervous system. OBJECTIVE: We hypothesize that FA-caused neurotoxicity involves the deficiency of this endogenous protective antioxidant gas, which results from excessive generation of NO. The aim of this study is to evaluate whether FA disturbs H(2)S synthesis in PC12 cells, and whether this disturbance is associated with overproduction of NO. PRINCIPAL FINDINGS: We showed that exposure of PC12 cells to FA causes reduction of viability, inhibition of CBS expression, decrease of endogenous H(2)S production, and NO production. CBS silencing deteriorates FA-induced decreases in endogenous H(2)S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells; while ADMA, a specific inhibitor of NOS significantly attenuates FA-induced decreases in endogenous H(2)S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells. CONCLUSION/SIGNIFICANCE: Our data indicate that FA induces neurotoxicity by inhibiting the generation of H(2)S through excess of NO and suggest that strategies to manipulate endogenous H(2)S could open a suitable novel therapeutic avenue for FA-induced neurotoxicity. PMID- 23359815 TI - Robust internal elastic lamina fenestration in skeletal muscle arteries. AB - Holes within the internal elastic lamina (IEL) of blood vessels are sites of fenestration allowing for passage of diffusible vasoactive substances and interface of endothelial cell membrane projections with underlying vascular smooth muscle. Endothelial projections are sites of dynamic Ca(2+) events leading to endothelium dependent hyperpolarization (EDH)-mediated relaxations and the activity of these events increase as vessel diameter decreases. We tested the hypothesis that IEL fenestration is greater in distal vs. proximal arteries in skeletal muscle, and is unlike other vascular beds (mesentery). We also determined ion channel protein composition within the endothelium of intramuscular and non-intramuscular skeletal muscle arteries. Popliteal arteries, subsequent gastrocnemius feed arteries, and first and second order intramuscular arterioles from rat hindlimb were isolated, cut longitudinally, fixed, and imaged using confocal microscopy. Quantitative analysis revealed a significantly larger total fenestration area in second and first order arterioles vs. feed and popliteal arteries (58% and 16% vs. 5% and 3%; N = 10 images/artery), due to a noticeably greater average size of holes (9.5 and 3.9 um(2) vs 1.5 and 1.9 um(2)). Next, we investigated via immunolabeling procedures whether proteins involved in EDH often embedded in endothelial cell projections were disparate between arterial segments. Specific proteins involved in EDH, such as inositol trisphosphate receptors, small and intermediate conductance Ca(2+)-activated K(+) channels, and the canonical (C) transient receptor potential (TRP) channel TRPC3 were present in both popliteal and first order intramuscular arterioles. However due to larger IEL fenestration in first order arterioles, a larger spanning area of EDH proteins is observed proximal to the smooth muscle cell plasma membrane. These observations highlight the robust area of fenestration within intramuscular arterioles and indicate that the anatomical architecture and endothelial cell hyperpolarizing apparatus for distinct vasodilatory signaling is potentially present. PMID- 23359816 TI - Transgenic fluorescent Plasmodium cynomolgi liver stages enable live imaging and purification of Malaria hypnozoite-forms. AB - A major challenge for strategies to combat the human malaria parasite Plasmodium vivax is the presence of hypnozoites in the liver. These dormant forms can cause renewed clinical disease after reactivation through unknown mechanisms. The closely related non-human primate malaria P. cynomolgi is a frequently used model for studying hypnozoite-induced relapses. Here we report the generation of the first transgenic P. cynomolgi parasites that stably express fluorescent markers in liver stages by transfection with novel DNA-constructs containing a P. cynomolgi centromere. Analysis of fluorescent liver stages in culture identified, in addition to developing liver-schizonts, uninucleate persisting parasites that were atovaquone resistant but primaquine sensitive, features associated with hypnozoites. We demonstrate that these hypnozoite-forms could be isolated by fluorescence-activated cell sorting. The fluorescently-tagged parasites in combination with FACS-purification open new avenues for a wide range of studies for analysing hypnozoite biology and reactivation. PMID- 23359817 TI - HIPdb: a database of experimentally validated HIV inhibiting peptides. AB - BACKGROUND: Besides antiretroviral drugs, peptides have also demonstrated potential to inhibit the Human immunodeficiency virus (HIV). For example, T20 has been discovered to effectively block the HIV entry and was approved by the FDA as a novel anti-HIV peptide (AHP). We have collated all experimental information on AHPs at a single platform. DESCRIPTIONS: HIPdb is a manually curated database of experimentally verified HIV inhibiting peptides targeting various steps or proteins involved in the life cycle of HIV e.g. fusion, integration, reverse transcription etc. This database provides experimental information of 981 peptides. These are of varying length obtained from natural as well as synthetic sources and tested on different cell lines. Important fields included are peptide sequence, length, source, target, cell line, inhibition/IC(50), assay and reference. The database provides user friendly browse, search, sort and filter options. It also contains useful services like BLAST and 'Map' for alignment with user provided sequences. In addition, predicted structure and physicochemical properties of the peptides are also included. CONCLUSION: HIPdb database is freely available at http://crdd.osdd.net/servers/hipdb. Comprehensive information of this database will be helpful in selecting/designing effective anti-HIV peptides. Thus it may prove a useful resource to researchers for peptide based therapeutics development. PMID- 23359818 TI - Sensorimotor recalibration depends on attribution of sensory prediction errors to internal causes. AB - Sensorimotor learning critically depends on error signals. Learning usually tries to minimise these error signals to guarantee optimal performance. Errors can, however, have both internal causes, resulting from one's sensorimotor system, and external causes, resulting from external disturbances. Does learning take into account the perceived cause of error information? Here, we investigated the recalibration of internal predictions about the sensory consequences of one's actions. Since these predictions underlie the distinction of self- and externally produced sensory events, we assumed them to be recalibrated only by prediction errors attributed to internal causes. When subjects were confronted with experimentally induced visual prediction errors about their pointing movements in virtual reality, they recalibrated the predicted visual consequences of their movements. Recalibration was not proportional to the externally generated prediction error, but correlated with the error component which subjects attributed to internal causes. We also revealed adaptation in subjects' motor performance which reflected their recalibrated sensory predictions. Thus, causal attribution of error information is essential for sensorimotor learning. PMID- 23359819 TI - Identification of single nucleotide polymorphisms regulating peripheral blood mRNA expression with genome-wide significance: an eQTL study in the Japanese population. AB - Several recent studies have reported that expression quantitative trait loci (eQTLs) may affect gene expression in a cell-dependent manner. In the current study, a genome-wide eQTL analysis was performed in whole blood samples collected from 76 Japanese subjects. RNA microarray analysis was performed for 3 independent sample groups that were genotyped in a genome-wide scan. The correlations between the genotypes of 534,404 autosomal single nucleotide polymorphisms (SNPs) and the expression levels of 30,465 probes were examined for each sample group. The SNP-probe pairs with combined correlation coefficients of all 3 sample groups corresponding to P<3.1 * 10(-12) (i.e., Bonferroni-corrected P<0.05) were considered significant. SNP-probe pairs with a high likelihood of cross-hybridization and SNP-in-probe effects were excluded to avoid false positive results. We identified 102 cis-acting and 5 trans-acting eQTL regions. The cis-eQTL regions were widely distributed both upstream and downstream of the gene, as well as within the gene. The eQTL SNPs identified were examined for their influence on the expression levels in lymphoblastoid cell lines by using a public database. The results showed that genetic variants affecting expression levels in whole blood may have different effects on gene expression in lymphoblastoid cell lines. Further studies are required to clarify how SNPs function in affecting the expression levels in whole blood as well as in other tissues. PMID- 23359820 TI - N-cadherin dependent collective cell invasion of prostate cancer cells is regulated by the N-terminus of alpha-catenin. AB - Cancer cell invasion is the critical first step of metastasis, yet, little is known about how cancer cells invade and initiate metastasis in a complex extracellular matrix. Using a cell line from bone metastasis of prostate cancer (PC3), we analyzed how prostate cancer cells migrate in a physiologically relevant 3D Matrigel. We found that PC3 cells migrated more efficiently as multi cellular clusters than isolated single cells, suggesting that the presence of cell-cell adhesion improves 3D cell migration. Perturbation of N-cadherin function by transfection of either the N-cadherin cytoplasmic domain or shRNA specific to N-cadherin abolished collective cell migration. Interestingly, PC3 cells do not express alpha-catenin, an actin binding protein in the cadherin complex. When the full-length alpha-catenin was re-introduced, the phenotype of PC3 cells reverted back to a more epithelial phenotype with a decreased cell migration rate in 3D Matrigel. Interestingly, we found that the N-terminal half of alpha-catenin was sufficient to suppress invasive phenotype. Taken together, these data suggest that the formation of N-cadherin junctions promotes 3D cell migration of prostate cancer cells, and this is partly due to an aberrant regulation of the N-cadherin complex in the absence of alpha-catenin. PMID- 23359821 TI - Conditional knockout of integrin alpha2beta1 in murine megakaryocytes leads to reduced mean platelet volume. AB - We have engineered a transgenic mouse on a C57BL/6 background that bears a floxed Itga2 gene. The crossing of this mouse strain to transgenic mice expressing Cre recombinase driven by the megakaryocyte (MK)-specific Pf4 promoter permits the conditional knockout of Itga2 in the MK/platelet lineage. Mice lacking MK alpha2beta1 develop normally, are fertile, and like their systemic alpha2beta1 knockout counterparts, exhibit defective adhesion to and aggregation induced by soluble type I collagen and a delayed onset to low dose fibrillar collagen induced aggregation, results consistent with blockade or loss of platelet alpha2beta1. At the same time, we observed a significant reduction in mean platelet volume, which is consistent with the reported role of alpha2beta1 in MK maturation and proplatelet formation in vivo. This transgenic mouse strain bearing a floxed Itga2 gene will prove valuable to distinguish in vivo the temporal and spatial contributions of alpha2 integrin in selected cell types. PMID- 23359822 TI - Deep sequencing of maize small RNAs reveals a diverse set of microRNA in dry and imbibed seeds. AB - Seed germination plays a pivotal role during the life cycle of plants. As dry seeds imbibe water, the resumption of energy metabolism and cellular repair occur and miRNA-mediated gene expression regulation is involved in the reactivation events. This research was aimed at understanding the role of miRNA in the molecular control during seed imbibition process. Small RNA libraries constructed from dry and imbibed maize seed embryos were sequenced using the Illumina platform. Twenty-four conserved miRNA families were identified in both libraries. Sixteen of them showed significant expression differences between dry and imbibed seeds. Twelve miRNA families, miR156, miR159, miR164, miR166, miR167, miR168, miR169, miR172, miR319, miR393, miR394 and miR397, were significantly down regulated; while four families, miR398, miR408, miR528 and miR529, were significantly up-regulated in imbibed seeds compared to that in dry seeds. Furthermore, putative novel maize miRNAs and their target genes were predicted. Target gene GO analysis was performed for novel miRNAs that were sequenced more than 50 times in the normalized libraries. The result showed that carbohydrate catabolic related genes were specifically enriched in the dry seed, while in imbibed seed target gene enrichment covered a broad range of functional categories including genes in amino acid biosynthesis, isomerase activity, ligase activity and others. The sequencing results were partially validated by quantitative RT-PCR for both conserved and novel miRNAs and the predicted target genes. Our data suggested that diverse and complex miRNAs are involved in the seed imbibition process. That miRNA are involved in plant hormone regulation may play important roles during the dry-imbibed seed transition. PMID- 23359823 TI - Insertion/deletion polymorphisms in the promoter region of BRM contribute to risk of hepatocellular carcinoma in Chinese populations. AB - BACKGROUND: BRM (Brahma homologue) is well known for its critical role in tumor suppression and cancer development. Genetic variations in the promoter region of BRM have been suggested to be associated with loss of BRM expression and lung cancer risk. To the authors' knowledge, no study on the role of BRM genetic polymorphisms in hepatocellular carcinoma (HCC) risk has been performed. METHODOLOGY/PRINCIPAL FINDINGS: In two independent case-control studies containing 796 HCC cases and 806 cancer-free individuals, we genotyped two putative functional insertion/deletion (indel) polymorphisms [BRM-1321 (rs3832613) and BRM-741 (rs34480940)] within promoter region of BRM in Chinese populations using a PCR-based method. Real-time RT-PCR analysis was used to explore the genotype-phenotype correlation between these polymorphisms and BRM expression in both tissue samples and HCC cell lines. Logistic regression analysis showed that compared to BRM-1321del/del genotype, the ins/del and ins/ins variant genotypes had an increased HCC risk [adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.19-1.82; adjusted OR = 2.55, 95% CI = 1.75 3.72, respectively]. No significant association between BRM-741 and HCC incidence was observed. However, stratification analysis revealed a significant association between ins/ins genotype of BRM-741 and increased HCC susceptibility in smokers (adjusted OR = 2.07, 95% CI = 1.33-3.22). Quantitative PCR analyses demonstrated that the genotypes of BRM-1321 and the corresponding haplotypes were significantly correlated with BRM expression in vivo. Compared with ins/ins genotype, subjects carrying ins/del and del/del genotype had 2.30 and 4.99 fold higher BRM expression in HCC tissue samples, respectively. Similar trends were observed in western blot analysis at protein level. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that BRM promoter polymorphism (BRM-1321) could regulate BRM expression and may serve as a potential marker for genetic susceptibility to HCC. PMID- 23359824 TI - O'nyong nyong virus molecular determinants of unique vector specificity reside in non-structural protein 3. AB - O'nyong nyong virus (ONNV) and Chikungunya virus (CHIKV) are two closely related alphaviruses with very different infection patterns in the mosquito, Anopheles gambiae. ONNV is the only alphavirus transmitted by anopheline mosquitoes, but specific molecular determinants of infection of this unique vector specificity remain unidentified. Fifteen distinct chimeric viruses were constructed to evaluate both structural and non-structural regions of the genome and infection patterns were determined through artificial infectious feeds in An. gambiae with each of these chimeras. Only one region, non-structural protein 3 (nsP3), was sufficient to up-regulate infection to rates similar to those seen with parental ONNV. When ONNV non-structural protein 3 (nsP3) replaced nsP3 from CHIKV virus in one of the chimeric viruses, infection rates in An. gambiae went from 0% to 63.5%. No other single gene or viral region addition was able to restore infection rates. Thus, we have shown that a non-structural genome element involved in viral replication is a major element involved in ONNV's unique vector specificity. PMID- 23359825 TI - Typhoid Fever and its association with environmental factors in the Dhaka Metropolitan Area of Bangladesh: a spatial and time-series approach. AB - Typhoid fever is a major cause of death worldwide with a major part of the disease burden in developing regions such as the Indian sub-continent. Bangladesh is part of this highly endemic region, yet little is known about the spatial and temporal distribution of the disease at a regional scale. This research used a Geographic Information System to explore, spatially and temporally, the prevalence of typhoid in Dhaka Metropolitan Area (DMA) of Bangladesh over the period 2005-9. This paper provides the first study of the spatio-temporal epidemiology of typhoid for this region. The aims of the study were: (i) to analyse the epidemiology of cases from 2005 to 2009; (ii) to identify spatial patterns of infection based on two spatial hypotheses; and (iii) to determine the hydro-climatological factors associated with typhoid prevalence. Case occurrences data were collected from 11 major hospitals in DMA, geocoded to census tract level, and used in a spatio-temporal analysis with a range of demographic, environmental and meteorological variables. Analyses revealed distinct seasonality as well as age and gender differences, with males and very young children being disproportionately infected. The male-female ratio of typhoid cases was found to be 1.36, and the median age of the cases was 14 years. Typhoid incidence was higher in male population than female (chi(2) = 5.88, p<0.05). The age-specific incidence rate was highest for the 0-4 years age group (277 cases), followed by the 60+ years age group (51 cases), then there were 45 cases for 15 17 years, 37 cases for 18-34 years, 34 cases for 35-39 years and 11 cases for 10 14 years per 100,000 people. Monsoon months had the highest disease occurrences (44.62%) followed by the pre-monsoon (30.54%) and post-monsoon (24.85%) season. The Student's t test revealed that there is no significant difference on the occurrence of typhoid between urban and rural environments (p>0.05). A statistically significant inverse association was found between typhoid incidence and distance to major waterbodies. Spatial pattern analysis showed that there was a significant clustering of typhoid distribution in the study area. Moran's I was highest (0.879; p<0.01) in 2008 and lowest (0.075; p<0.05) in 2009. Incidence rates were found to form three large, multi-centred, spatial clusters with no significant difference between urban and rural rates. Temporally, typhoid incidence was seen to increase with temperature, rainfall and river level at time lags ranging from three to five weeks. For example, for a 0.1 metre rise in river levels, the number of typhoid cases increased by 4.6% (95% CI: 2.4-2.8) above the threshold of 4.0 metres (95% CI: 2.4-4.3). On the other hand, with a 1 degrees C rise in temperature, the number of typhoid cases could increase by 14.2% (95% CI: 4.4-25.0). PMID- 23359826 TI - The urine circulating cathodic antigen (CCA) dipstick: a valid substitute for microscopy for mapping and point-of-care diagnosis of intestinal schistosomiasis. AB - BACKGROUND: The World Health Organization now recommends the provision of praziquantel treatment to preschool-aged children infected with schistosomiasis. For intestinal schistosomiasis the current operational field diagnostic standard is examination of a thick Kato-Katz smear by microscopy prepared from a single stool specimen, and although pragmatic, this methodology has well-known shortcomings. Here, as a potential alternative, the performance of the urine circulating cathodic antigen (CCA) dipstick test was assessed in terms of disease mapping and point-of-care diagnosis for intestinal schistosomiasis in preschool aged children. Our manuscript reports on findings at baseline and at the end of a one-year longitudinal treatment study. METHODOLOGY/PRINCIPAL FINDINGS: A total of 925 children (mean age 2.8 years) were initially recruited from six lakeshore villages representative of high, moderate and low levels of disease transmission. At baseline, all children were tested for intestinal schistosomiasis by microscopic examination of duplicate Kato-Katz smears prepared from a single stool faecal, by antigen detection with the urine CCA dipstick test and by serology with a commercially available ELISA test (as 'gold-standard') that measures host antibody titres to soluble egg antigens. As a point-of-care diagnosis, the urine CCA dipstick test achieved sensitivity and specificity values ranging from 52.5-63.2% and 57.7-75.6%, respectively, with faecal microscopy achieving very high specificities (>87%) but sensitivities as low as 16.7% in the low transmission setting. CONCLUSION/SIGNIFICANCE: The urine CCA test was shown to be more effective than faecal microscopy especially in lower transmission settings. The diagnostic performance of this test was not significantly impacted by treatment history or co-infections with other intestinal helminths. PMID- 23359827 TI - Towards rational use of antibiotics for suspected secondary infections in Buruli ulcer patients. AB - BACKGROUND: The emerging disease Buruli ulcer is treated with streptomycin and rifampicin and surgery if necessary. Frequently other antibiotics are used during treatment. METHODS/PRINCIPAL FINDINGS: Information on prescribing behavior of antibiotics for suspected secondary infections and for prophylactic use was collected retrospectively. Of 185 patients that started treatment for Buruli ulcer in different centers in Ghana and Benin 51 were admitted. Forty of these 51 admitted patients (78%) received at least one course of antibiotics other than streptomycin and rifampicin during their hospital stay. The median number (IQR) of antibiotic courses for admitted patients was 2 (1, 5). Only twelve patients received antibiotics for a suspected secondary infection, all other courses were prescribed as prophylaxis of secondary infections extended till 10 days on average after excision, debridement or skin grafting. Antibiotic regimens varied considerably per indication. In another group of BU patients in two centers in Benin, superficial wound cultures were performed. These cultures from superficial swabs represented bacteria to be expected from a chronic wound, but 13 of the 34 (38%) S. aureus were MRSA. CONCLUSIONS/SIGNIFICANCE: A guide for rational antibiotic treatment for suspected secondary infections or prophylaxis is needed. Adherence to the guideline proposed in this article may reduce and tailor antibiotic use other than streptomycin and rifampicin in Buruli ulcer patients. It may save costs, reduce toxicity and limit development of further antimicrobial resistance. This topic should be included in general protocols on the management of Buruli ulcer. PMID- 23359828 TI - Implementation of a national reference laboratory for Buruli ulcer disease in Togo. AB - BACKGROUND: In a previous study PCR analysis of clinical samples from suspected cases of Buruli ulcer disease (BUD) from Togo and external quality assurance (EQA) for local microscopy were conducted at an external reference laboratory in Germany. The relatively poor performance of local microscopy as well as effort and time associated with shipment of PCR samples necessitated the implementation of stringent EQA measures and availability of local laboratory capacity. This study describes the approach to implementation of a national BUD reference laboratory in Togo. METHODOLOGY: Large scale outreach activities accompanied by regular training programs for health care professionals were conducted in the regions "Maritime" and "Central," standard operating procedures defined all processes in participating laboratories (regional, national and external reference laboratories) as well as the interaction between laboratories and partners in the field. Microscopy was conducted at regional level and slides were subjected to EQA at national and external reference laboratories. For PCR analysis, sample pairs were collected and subjected to a dry-reagent-based IS2404 PCR (DRB-PCR) at national level and standard IS2404 PCR followed by IS2404 qPCR analysis of negative samples at the external reference laboratory. PRINCIPAL FINDINGS: The inter-laboratory concordance rates for microscopy ranged from 89% to 94%; overall, microscopy confirmed 50% of all suspected BUD cases. The inter laboratory concordance rate for PCR was 96% with an overall PCR case confirmation rate of 78%. Compared to a previous study, the rate of BUD patients with non ulcerative lesions increased from 37% to 50%, the mean duration of disease before clinical diagnosis decreased significantly from 182.6 to 82.1 days among patients with ulcerative lesions, and the percentage of category III lesions decreased from 30.3% to 19.2%. CONCLUSIONS: High inter-laboratory concordance rates as well as case confirmation rates of 50% (microscopy), 71% (PCR at national level), and 78% (including qPCR confirmation at external reference laboratory) suggest high standards of BUD diagnostics. The increase of non-ulcerative lesions, as well as the decrease in diagnostic delay and category III lesions, prove the effect of comprehensive EQA and training measures involving also procedures outside the laboratory. PMID- 23359829 TI - The use of bivariate spatial modeling of questionnaire and parasitology data to predict the distribution of Schistosoma haematobium in Coastal Kenya. AB - BACKGROUND: Questionnaires of reported blood in urine (BIU) distributed through the existing school system provide a rapid and reliable method to classify schools according to the prevalence of Schistosoma haematobium, thereby helping in the targeting of schistosomiasis control. However, not all schools return questionnaires and it is unclear whether treatment is warranted in such schools. This study investigates the use of bivariate spatial modelling of available and multiple data sources to predict the prevalence of S. haematobium at every school along the Kenyan coast. METHODOLOGY: Data from a questionnaire survey conducted by the Kenya Ministry of Education in Coast Province in 2009 were combined with available parasitological and environmental data in a Bayesian bivariate spatial model. This modeled the relationship between BIU data and environmental covariates, as well as the relationship between BIU and S. haematobium infection prevalence, to predict S. haematobium infection prevalence at all schools in the study region. Validation procedures were implemented to assess the predictive accuracy of endemicity classification. PRINCIPAL FINDINGS: The prevalence of BIU was negatively correlated with distance to nearest river and there was considerable residual spatial correlation at small (~15 km) spatial scales. There was a predictable relationship between the prevalence of reported BIU and S. haematobium infection. The final model exhibited excellent sensitivity (0.94) but moderate specificity (0.69) in identifying low (<10%) prevalence schools, and had poor performance in differentiating between moderate and high prevalence schools (sensitivity 0.5, specificity 1). CONCLUSIONS: Schistosomiasis is highly focal and there is a need to target treatment on a school-by-school basis. The use of bivariate spatial modelling can supplement questionnaire data to identify schools requiring mass treatment, but is unable to distinguish between moderate and high prevalence schools. PMID- 23359830 TI - Increasing incidence of Plasmodium knowlesi malaria following control of P. falciparum and P. vivax Malaria in Sabah, Malaysia. AB - BACKGROUND: The simian parasite Plasmodium knowlesi is a common cause of human malaria in Malaysian Borneo and threatens the prospect of malaria elimination. However, little is known about the emergence of P. knowlesi, particularly in Sabah. We reviewed Sabah Department of Health records to investigate the trend of each malaria species over time. METHODS: Reporting of microscopy-diagnosed malaria cases in Sabah is mandatory. We reviewed all available Department of Health malaria notification records from 1992-2011. Notifications of P. malariae and P. knowlesi were considered as a single group due to microscopic near identity. RESULTS: From 1992-2011 total malaria notifications decreased dramatically, with P. falciparum peaking at 33,153 in 1994 and decreasing 55-fold to 605 in 2011, and P. vivax peaking at 15,857 in 1995 and decreasing 25-fold to 628 in 2011. Notifications of P. malariae/P. knowlesi also demonstrated a peak in the mid-1990s (614 in 1994) before decreasing to ~ 100/year in the late 1990s/early 2000s. However, P. malariae/P. knowlesi notifications increased >10 fold between 2004 (n = 59) and 2011 (n = 703). In 1992 P. falciparum, P. vivax and P. malariae/P. knowlesi monoinfections accounted for 70%, 24% and 1% respectively of malaria notifications, compared to 30%, 31% and 35% in 2011. The increase in P. malariae/P. knowlesi notifications occurred state-wide, appearing to have begun in the southwest and progressed north-easterly. CONCLUSIONS: A significant recent increase has occurred in P. knowlesi notifications following reduced transmission of the human Plasmodium species, and this trend threatens malaria elimination. Determination of transmission dynamics and risk factors for knowlesi malaria is required to guide measures to control this rising incidence. PMID- 23359831 TI - Value of mandatory screening studies in emergency department patients cleared for psychiatric admission. AB - INTRODUCTION: Laboratory and radiographic studies are often required by psychiatric services prior to admitting emergency patients who are otherwise deemed medically stable. Such testing may represent an unnecessary expense that prolongs emergency department stays without significantly improving care. This study determines the prevalence of such testing and how often it leads to changes in care. METHODS: We prospectively tracked laboratory testing among psychiatric patients presenting to the emergency departments of two academic tertiary care facilities. For each visit we determined whether laboratory or radiographic studies were ordered, and whether the examination was conducted at the request of the emergency physician as part of a medical screening examination or requested by the psychiatry service. We then determined if this testing changed patient disposition. RESULTS: Our study enrolled 598 patients. Of these, emergency physicians ordered testing as a part of medical screening on 155 patients (25.9%). We found the psychiatry service ordered laboratory or radiographic studies for 191 of 434 patients (44.0%) who emergency physicians determined did not require ancillary testing for medical clearance. Of these 191 patients, only one (0.5%; 95% Confidence Interval: 0.01% - 2.9%) had an abnormal result that led to a change in disposition. Total Medicare reimbursement rates for the additional ancillary testing in this study was $37,682. CONCLUSION: Ancillary testing beyond what is required for medical clearance of psychiatric emergency patients rarely alters care. Policies that require panels of testing prior to psychiatric admission are costly and appear to be unnecessary. PMID- 23359832 TI - Urine collection in the emergency department: what really happens in there? AB - INTRODUCTION: In women with suspected urinary tract infection (UTI), a non contaminated voided specimen is considered important for valid urinalysis and culture results. We assess whether midstream parted-labia catch (MSPC) instructions were provided by nurses, understood, and performed correctly, according to the patient. METHODS: We conducted a cross-sectional survey of English- and Spanish-speaking female patients submitting voided urine samples for urinalysis for suspected UTI. The survey was conducted in a public teaching hospital emergency department (ED) from June to December 2010, beginning 2 months after development and dissemination of a nursing MSPC instructions protocol. Research assistants administered the survey within 2 hours of urine collection. Nurses were unaware of the study purpose. RESULTS: Of 129 patients approached, 74 (57%) consented and were included in the analysis. Median age was 35; 44% were Latino. Regarding instructions from nurses, patients reported the following: 45 (61%; 95% CI 50-72%) received any instructions; of whom 37 (82%; 95% CI 71-93%) understood them completely. Sixteen (36%; 95% CI 22-51%) were instructed to collect midstream; and 7 (16%; 95% CI 6-29%) to part the labia. Regardless of receiving or understanding instructions, 33 (45%; 95% CI 33-57%) reported actually collecting midstream, and 11 (15%, 95% CI 8-25%) parting the labia. CONCLUSION: In this ED, instructions for MSPC urine collection frequently were not given, despite a nursing protocol, and patients rarely performed the essential steps. An evidence-based approach to urine testing in the ED that considers urine collection technique, is needed. PMID- 23359833 TI - How long are patients willing to wait in the emergency department before leaving without being seen? AB - INTRODUCTION: Our goal was to evaluate patients' threshold for waiting in an emergency department (ED) waiting room before leaving without being seen (LWBS). We analyzed whether willingness to wait was influenced by perceived illness severity, age, race, triage acuity level, or insurance status. METHODS: We conducted this survey-based study from March to July 2010 at an urban academic medical center. After triage, patients were given a multiple-choice questionnaire, designed to ascertain how long they would wait for medical care. We collected data including age, gender, race, insurance status, and triage acuity level. We looked at the association between willingness to wait and these variables, using stratified analysis and logistic regression. RESULTS: Of the 375 patients who were approached, 340 (91%) participated. One hundred seventy-one (51%) were willing to wait up to 2 hours before leaving, 58 (17%) would wait 2 to 8 hours, and 110 (32%) would wait indefinitely. No association was found between willingness to wait and race, gender, insurance status, or perceived symptom severity. Patients willing to wait >2 hours tended to be older than 25, have higher acuity, and prefer the study site ED. CONCLUSION: Many patients have a defined, limited period that they are willing to wait for emergency care. In our study, 50% of patients were willing to wait up to 2 hours before leaving the ED without being seen. This result suggests that efforts to reduce the percentage of patients who LWBS must factor in time limits. PMID- 23359834 TI - Takayasu's Arteritis - An Unusual Cause of Stroke in a Young Patient. AB - We describe the case of a 28-year-old-male with no significant medical history who presented with right-sided hemiparesis, bruits over the carotid and subclavian arteries and an elevated erythrocyte sedimentation rate. Imaging studies revealed a middle cerebral artery thrombus and inflammatory changes of the carotid and subclavian arteries and aorta. The diagnosis of Takayasu's arteritis was made and the patient was started on steroids and immunomodulators with good clinical response. PMID- 23359835 TI - Unusual presentation of toxoplasma gondii encephalitis. AB - We report a case of altered mental status secondary to acute Toxoplasma Gondii encephalitis. The patient had no medical or surgical history and presented with acute onset of lethargy with no clear precipitant. A physical exam revealed no focal neurological deficits and a subsequent medical workup revealed multiple intracranial lesions with a biopsy confirming the diagnosis of Toxoplasma Gondii encephalitis in the setting of newly diagnosed human immunodeficiency virus (HIV). A literature review revealed that this is a unique case of toxoplasmic encephalopathy in the United States in a previously undiagnosed HIV positive patient presenting to an emergency department. PMID- 23359836 TI - Chief complaint: right hip pain. PMID- 23359837 TI - Left upper quadrant abdominal pain. AB - We present a case of acute appendicitis from mobile cecum presenting with left upper quadrant abdominal pain. PMID- 23359838 TI - What's Eating Your Wishbone? Sternoclavicular Septic Arthritis with Osteomyelitis. PMID- 23359839 TI - Grade III or Grade IV Hypertensive Retinopathy with Severely Elevated Blood Pressure. AB - INTRODUCTION: Hypertensive retinopathy describes a spectrum of retinal changes in patients with elevated blood pressure (BP). It is unknown why some patients are more likely to develop acute ocular end-organ damage than others with similar BP. We examined risk factors for grade III/IV hypertensive retinopathy among patients with hypertensive urgency in the emergency department (ED) and compared healthcare utilization and mortality between patients with and without grade III/IV hypertensive retinopathy. METHODS: A preplanned subanalysis of patients who presented to a university hospital ED with diastolic BP >= 120 mmHg and who enrolled in the Fundus Photography versus Ophthalmoscopy Trial Outcomes in the ED study was performed. Bilateral nonmydriatic ocular fundus photographs, vital signs, and demographics were obtained at presentation. Past medical history, laboratory values, healthcare utilization, and mortality were ascertained from medical record review at least 8 months after initial ED visit. RESULTS: Twenty one patients with diastolic BP >= 120 mmHg, 7 of whom (33%) had grade III/IV hypertensive retinopathy, were included. Patients with retinopathy were significantly younger than those without (median 33 vs 50 years, P= 0.02). Mean arterial pressure (165 vs 163 mmHg) was essentially equal in the 2 groups. Patients with retinopathy had substantially increased but nonsignificant rates of ED revisit (57% vs 29%, P = 0.35) and hospital admission after ED discharge (43% vs 14%, P = 0.28). One of the patients with retinopathy died, but none without. CONCLUSION: Younger patients may be at higher risk for grade III/IV hypertensive retinopathy among patients with hypertensive urgency. Chronic compensatory mechanisms may have not yet developed in these younger patients. Alternatively, older patients with retinopathy may be underrepresented secondary to increased mortality among these patients at a younger age (survivorship bias). Further research is needed to validate these preliminary findings. PMID- 23359840 TI - Holiday plants with toxic misconceptions. AB - Several plants are used for their decorative effect during winter holidays. This review explores the toxic reputation and proposed management for exposures to several of those, namely poinsettia (Euphorbia pulcherrima), English holly (Ilex aquifolium), American holly (Ilex opaca), bittersweet (Solanum dulcamara), Jerusalem cherry (Solanum pseudocapsicum), American mistletoe (Phoradendron serotinum), and European mistletoe (Viscum album). PMID- 23359841 TI - Unusual Skin lesion. PMID- 23359842 TI - Primary epithelioid sarcoma of the scalp complicated by humoral hypercalcemia of malignancy. PMID- 23359843 TI - Neostigmine to relieve a suspected colonic pseudo-obstruction in a burn patient: a case-based review of the literature. AB - OBJECTIVE: Neostigmine is one of the treatment options for colonic pseudo obstruction in the medical patient. However, experience in using neostigmine for this indication in burn patients has not been reported in the literature. We will present a case of a woman who developed colonic pseudo-obstruction during her hospital stay. When conservative management failed, neostigmine was administered with no adverse effects and resolution of the pseudo-obstruction. We will review the literature regarding the pathophysiology and treatment options for acute colonic pseudo-obstruction in burn patients. METHODS: A 27-year-old woman with 35% total body surface area deep-partial and full-thickness flame burns. On hospital day 17, she developed a nonobstructive ileus. She failed conservative medical therapy. After consultation with colleagues in trauma surgery and a review of the literature (MeSH/PubMed/NLM), the decision was made to try neostigmine therapy rather than a surgical/procedural option such as colonoscopy. RESULTS: The patient was moved to the intensive care unit and 2 mg of neostigmine was administered intravenously over 4 minutes. After 30 minutes, all abdominal examination findings had returned to baseline. No significant adverse effects were noted, and she did not redevelop abdominal distension afterward. CONCLUSION: This case report provides an alternative treatment modality in which neostigmine was used successfully in a burn patient after conservative medical treatment had failed. The authors believe that neostigmine may be a viable alternative to decompressive colonoscopy in burn patients for whom mechanical obstruction is properly excluded. PMID- 23359844 TI - Reverse abdominoplasty: a practical option for oncological trunk reconstruction. AB - OBJECTIVES: Following radical oncological resection, full-thickness upper central trunk defects present a significant challenge. Common reconstructive options include pedicled flaps, such as pectoralis major, rectus abdominis, and latissimus dorsi. In complex cases, free tissue transfer may be required. Reverse abdominoplasty, although initially described for cosmetic body contouring, can be used to reconstruct upper central trunk defects following radical tumour ablation. We present 4 such applications in the management of advanced or recurrent malignancies and review the relative indications for this approach. METHODS: Four consecutive cases (2004-2010) were reviewed with respect to indication, operative procedure, and complications. RESULTS: There were no cases of complete flap loss. One patient underwent revision for marginal flap necrosis while another developed local recurrence, requiring re-excision and reconstruction with flap advancement. CONCLUSIONS: Where pedicled flaps are unavailable or insufficient, adjacent abdominal tissue can be recruited into chest wall defects, avoiding microsurgical free tissue transfer. The authors feel that the reverse abdominoplasty is currently underused in this context and offers an excellent alternative in complex cases where other reconstructive options are unavailable, or where comorbidities preclude free-tissue transfer. The technique is versatile, simple to perform and affords an acceptable cosmetic outcome, yet is not widely reported in the literature. It has particular merit in cases with a high chance of disease recurrence, in the management of recurrent breast cancer, and in patients with multiple comorbidities. The reverse abdominoplasty should therefore be considered when evaluating patients for oncological trunk reconstruction. PMID- 23359845 TI - CASE REPORT Successful Breast Reconstruction in a Patient With Epidermolysis Bullosa. AB - OBJECTIVES: Epidermolysis bullosa is a rare skin disorder characterized by blister formation in response to minor trauma as well as extracutaneous manifestations. Details of the surgical history and technical considerations for performing breast reconstruction in a patient with epidermolysis bullosa are discussed. METHOD: The history and details of breast reconstruction in a patient with epidermolysis bullosa are reported. RESULT: A 56-year-old patient with junctional epidermolysis bullosa developed left breast cancer, which was initially treated with lumpectomy. Two years later, a completion total mastectomy was performed for recurrent disease with immediate 2-stage implant-based reconstruction. Nipple reconstruction was completed using a skate flap technique with full-thickness skin graft harvested from the groin region. No blistering, infection, or wound dehiscence was observed. CONCLUSIONS: Successful immediate implant breast reconstruction is feasible in patients with epidermolysis bullosa. Reconstructive decision-making should be individualized based on the extent and severity of the skin disease. PMID- 23359846 TI - Dupuytren's Contracture. PMID- 23359847 TI - Nasal reconstruction after Basal cell excision. PMID- 23359848 TI - Abdominal wall reconstruction. PMID- 23359849 TI - Superficial acral fibromyxoma of the thumb. PMID- 23359850 TI - Palmar contracture. PMID- 23359851 TI - Axillary hidradenitis. PMID- 23359852 TI - Fracture of the base of the first metacarpal bone. PMID- 23359853 TI - Carpal tunnel syndrome. PMID- 23359854 TI - Penetrating injury to the upper extremity. PMID- 23359855 TI - Metamorphosis of mesothelial cells with active horizontal motility in tissue culture. AB - Mesothelial cells, which have diverse roles in physiology and pathology, constitute the mesothelium along with connective tissue and the basement membrane; the mesothelium serves to shield the somatic cavities. After mesothelial injury, mesothelial cells undergo tissue recovery. However, the mechanism of mesothelial regeneration remains poorly understood. In this study, we used confocal time-lapse microscopy to demonstrate that transformed mesothelial cells (MeT5A) and mouse peritoneal mesothelial cells can randomly migrate between cells in cell culture and in ex vivo tissue culture, respectively. Moreover, peritoneal mesothelial cells changed their morphology from a flattened shape to a cuboidal one prior to the migration. Conversely, MDCKII epithelial cells forming tight cell-cell contacts with one another do not alter the arrangement of adjacent cells during movement. Our evidence complements the current hypotheses of mesothelial regeneration and suggests that certain types of differentiated mesothelial cells undergo morphological changes before initiating migration to repair injured sites. PMID- 23359856 TI - Parasitic amorphous on single-domain crystal: structural observations of silicate glass-ceramics. AB - Glass-ceramics (GCs) are materials obtained from the crystallisation of functional phases in glass, and have a structure that the crystallised phase embedded in the glass matrix. Glass-forming oxides are commonly added to the functional phases to improve the stability of precursor glass; however, the issue of glass-ceramics permitting the presence of residual phases resulting from addition is required to be clarified. To elucidate this issue, we prepared 'perfectly surface-crystallised' GC consisting of fresnoite-type Sr(2)TiSi(2)O(8) from a non-stoichiometric glass and performed texture/morphology observations. Numerous SiO(2)-rich binodal-like nanospheres (~10 nm) were parasitic on the fresnoite single-crystal domains. The parasitic texture is considered to form via the following process: (i) binodal-type phase separation into stoichiometric fresnoite (crystalline matrix) and SiO(2)-rich phases (amorphous nanoparticles) and (ii) single-domain formation by surface crystallisation in the matrix. Furthermore, in terms of texture, the resulting GC differs from the GCs reported to date, i.e., inverse GC. PMID- 23359857 TI - A reinvestigation of the reference frame of the tilt-adaptation aftereffect. AB - The tilt-adaptation aftereffect (TAE) is the phenomenon that prolonged perception of a tilted 'adapter' stimulus affects the perceived tilt of a subsequent 'tester' stimulus. Although it is clear that TAE is strongest when adapter and tester are presented at the same location, the reference frame of the effect is debated. Some authors have reported that TAE is spatiotopic (world centred): It occurs when adapter and tester are presented at the same display location, even when this corresponds to different retinal locations. Others have reported that TAE is exclusively retinotopic (eye centred): It occurs only when adapter and tester are presented at the same retinal location, even when this corresponds to different display locations. Because this issue is crucial for models of transsaccadic perception, we reinvestigated the reference frame of TAE. We report that TAE is exclusively retinotopic, supporting the notion that there is no transsaccadic integration of low-level visual information. PMID- 23359858 TI - Changing the responses of cortical neurons from sub- to suprathreshold using single spikes in vivo. AB - Action Potential (APs) patterns of sensory cortex neurons encode a variety of stimulus features, but how can a neuron change the feature to which it responds? Here, we show that in vivo a spike-timing-dependent plasticity (STDP) protocol consisting of pairing a postsynaptic AP with visually driven presynaptic inputs modifies a neurons' AP-response in a bidirectional way that depends on the relative AP-timing during pairing. Whereas postsynaptic APs repeatedly following presynaptic activation can convert subthreshold into suprathreshold responses, APs repeatedly preceding presynaptic activation reduce AP responses to visual stimulation. These changes were paralleled by restructuring of the neurons response to surround stimulus locations and membrane-potential time-course. Computational simulations could reproduce the observed subthreshold voltage changes only when presynaptic temporal jitter was included. Together this shows that STDP rules can modify output patterns of sensory neurons and the timing of single-APs plays a crucial role in sensory coding and plasticity.DOI:http://dx.doi.org/10.7554/eLife.00012.001. PMID- 23359860 TI - Strong inter-population cooperation leads to partner intermixing in microbial communities. AB - Patterns of spatial positioning of individuals within microbial communities are often critical to community function. However, understanding patterning in natural communities is hampered by the multitude of cell-cell and cell environment interactions as well as environmental variability. Here, through simulations and experiments on communities in defined environments, we examined how ecological interactions between two distinct partners impacted community patterning. We found that in strong cooperation with spatially localized large fitness benefits to both partners, a unique pattern is generated: partners spatially intermixed by appearing successively on top of each other, insensitive to initial conditions and interaction dynamics. Intermixing was experimentally observed in two obligatory cooperative systems: an engineered yeast community cooperating through metabolite-exchanges and a methane-producing community cooperating through redox-coupling. Even in simulated communities consisting of several species, most of the strongly-cooperating pairs appeared intermixed. Thus, when ecological interactions are the major patterning force, strong cooperation leads to partner intermixing.DOI:http://dx.doi.org/10.7554/eLife.00230.001. PMID- 23359861 TI - Crossing oceans. AB - Eve Marder explains why all scientists should spend time living and working in a foreign country. PMID- 23359859 TI - NOVA-dependent regulation of cryptic NMD exons controls synaptic protein levels after seizure. AB - The neuronal RNA binding protein NOVA regulates splicing, shuttles to the cytoplasm, and co-localizes with target transcripts in dendrites, suggesting links between splicing and local translation. Here we identified >200 transcripts showing NOVA-dependent changes in abundance, but, surprisingly, HITS-CLIP revealed NOVA binds these RNAs in introns rather than 3' UTRs. This led us to discover NOVA-regulated splicing of cryptic exons within these introns. These exons triggered nonsense mediated decay (NMD), as UPF1 and protein synthesis were required for NOVA's effect on RNA levels. Their regulation was dynamic and physiologically relevant. The NMD exons were regulated by seizures, which also induced changes in Nova subcellular localization and mediated large changes in synaptic proteins, including proteins implicated in familial epilepsy. Moreover, Nova haploinsufficient mice had spontaneous epilepsy. The data reveal a hidden means of dynamic RNA regulation linking electrical activity to splicing and protein output, and of mediating homeostatic excitation/inhibition balance in neurons.DOI:http://dx.doi.org/10.7554/eLife.00178.001. PMID- 23359862 TI - How to train a neuron. AB - A cellular learning rule known as spike-timing-dependent plasticity can form, reshape and erase the response preferences of visual cortex neurons. PMID- 23359864 TI - Role of heparan sulfatases in ovarian and breast cancer. AB - Endosulfatases HSulf-1 and -2 (also referred to as Sulf1 and -2) represent a family of enzymes that modulate heparin binding growth factor signaling. Heparan sulfatase 1 (HSulf-1) and heparan sulfatase 2 (HSulf-2) are two important 6-O endosulfatases which remove or edit 6-O sulfate residues of N-glucosamine present on highly sulfated HS. Alteration of heparan sulfatases have been identified in the context of several cancer types. Many cancer types either exhibit increased or decreased HSulfs expression at the transcript levels. Specifically, HSulf-1 was found to be downregulated in early-stage ovarian tumors, hepatocellular carcinoma, and metastatic breast cancer patients. HSulf-2 was found to be upregulated in ductal carcinoma in situ and invasive ductal carcinoma, whereas limited information is present about HSulf-2 expression in different stages of ovarian cancers. Here, we review the important role of these sulfatases play in ovarian and breast cancers in terms of tumorigenesis such as angiogenesis, chemoresistance, apoptosis, growth factor signaling, hypoxia and metastasis. These recent discoveries have added significant understanding about these sulfate editing enzymes. PMID- 23359863 TI - Life after death: targeting high mobility group box 1 in emergent cancer therapies. AB - High mobility group box 1 (HMGB1), an evolutionarily highly conserved and abundant nuclear protein also has roles within the cytoplasm and as an extracellular damage-associated molecular pattern (DAMP) molecule. Extracellular HMGB1 is the prototypic endogenous 'danger signal' that triggers inflammation and immunity. Recent findings suggest that posttranslational modifications dictate the cellular localization and secretion of HMGB1. HMGB1 is actively secreted from immune cells and stressed cancer cells, or passively released from necrotic cells. During cancer development or administration of therapeutic agents including chemotherapy, radiation, epigenetic drugs, oncolytic viruses, or immunotherapy, the released HMGB1 may either promote or limit cancer growth, depending on the state of progression and vascularization of the tumor. Extracellular HMGB1 enhances autophagy and promotes persistence of surviving cancer cells following initial activation. When oxidized, it chronically suppresses the immune system to promote cancer growth and progression, thereby enhancing resistance to cancer therapeutics. In its reduced form, it can facilitate and elicit innate and adaptive anti-tumor immunity, recruiting and activating immune cells, in conjunction with cytotoxic agents, particularly in early transplantable tumor models. We hypothesize that HMGB1 also functions as an epigenetic modifier, mainly through regulation of NF-kB-dependent signaling pathways, to modulate the behavior of surviving cancer cells as well as the immune cells found within the tumor microenvironment. This has significant implications for developing novel cancer therapeutics. PMID- 23359865 TI - LXR, prostate cancer and cholesterol: the Good, the Bad and the Ugly. AB - Cholesterol is a fundamental molecule for life. Located in the cell membrane, this sterol participates to the cell signaling of growth factors. Inside the cell it can be converted in hormones such as androgens or modulate the immune response. Such important functions could not be solely dependent of external supply by diet hence de novo synthesis could occur from acetate in almost all mammalian cells. If a deficiency in cholesterol sourcing leads to development troubles, overstocking has been associated to various diseases such as atherosclerosis and cancers. Cholesterol homeostasis should thus be tightly regulated at the uptake, de novo synthesis, storage and export processes. Various transcription factors have been described these last years as important to regulate cholesterol levels. Besides, synthetic molecules have been developed for many years to modulate cholesterol synthesis, such as statins. Many articles have associated prostate cancer, whose incidence is constantly increasing, to cholesterol disequilibrium. Targeting cholesterol could thus be a new pharmacological hit to counteract the initiation, development and/or progression of prostate cancer. Among the transcription factors regulating cholesterol homeostasis, the nuclear receptors Liver X Receptors (LXRs) control cholesterol uptake and export. Targeting the LXRs offers a new field of investigation to treat cancer. This review highlights the molecular relationships among LXRs, prostate cancer and cholesterol and why LXRs have good chance to be targeted one day in this tumor. LXRs, prostate cancer and cholesterol, more than a "Menage a trois", The Good, the Bad and the Ugly. PMID- 23359866 TI - Morphologic and other clinicopathologic features of endometrial clear cell carcinoma: a comprehensive analysis of 50 rigorously classified cases. AB - Clear cell carcinoma of the endometrium (CCC) is an uncommon histotype whose analyses have generally been hampered by its rarity and issues of interobserver diagnostic variability. In this study, we analyzed the clinicopathologic features of 50 CCCs that were assembled from multiple institutions and which we considered to be morphologically unambiguous after a rigorous review process for diagnostic accuracy. Forty-four (88%) of the 50 CCC cases showed an admixture of the classic architectural patterns (glandular, papillary, solid and cystic in decreasing order of prevalence). Mitotic indices were variable but were generally low: 60% of cases had a mitotic index of 3 or lower. The predominant cell type lining glands and papillae was invariably hobnail and/or cuboidal. Stratification of nuclei (greater than 3 cells) or columnar cells on glands and papillae were uncommon and never diffusely present. 82% of cases showed an admixture of polygonal cells with clear and eosinophilic cytoplasm; only clear cells were present in 4% and only eosinophilic cells were present in 10%. Hobnail cells were common, being identifiable in 86% of cases, and being diffuse in 60%. Only 2 cases had a predominance of nuclear grade 3 cells. Psammoma, hyaline and targetoid bodies were identified in 32%, 52% and 20% of cases respectively. Clear cell endometrial intraepithelial carcinoma was identified in 41.7% of cases with evaluable background endometrium. The 5-year progression free survival (PFS) for the entire cohort was 61%, and was 88%, 75%, 22% and 28.6% for stages I to IV respectively. On univariate analyses, age >65 years, advanced FIGO stage, and the presence of any lymph node metastases were associated with reduced PFS (p=0.02, 0.002, and 0.002 respectively). On multivariate analyses, the only variable associated with reduced PFS was age >65 years. The 5-year overall survival (OS) for the entire cohort was 78%, and was 94%, 87.5%, 66.7%, and 42.8% for stages I to IV respectively. On univariate analyses, the following factors were associated with reduced OS: age >65 years (p=0.04), advanced FIGO stage (p=0.003), distant metastases (p=0.003), myometrial invasion >30% (p=0.01), a mitotic index >4 (p=0.014), and a specific architectural pattern (at least 10% of the tumor composed of solid masses or individual infiltrating tumor cells, p=0.02). On multivariate analyses, only age >65 years and advanced stage were associated with reduced OS (p=0.023 and 0.022 respectively). In summary, endometrial CCC has a wide morphologic spectrum that is detailed and illustrated herein, but also has core cytoarchitectural features that are of high diagnostic utility. Morphologically unambiguous CCC apparently have patient outcomes that are more favorable than has previously been reported, indicating that ambiguous tumors should be classified separately. The existence of morphologically ambiguous clear cell rich carcinomas that do not fit the conventional histotypic groupings, is a likely reflection of the biologic complexity of endometrial carcinomas in general; these cases should be reported descriptively, and studied separately from conventional CCC. PMID- 23359868 TI - Adolescent tobacco use and its determinants: evidence from Global Youth Tobacco Survey, Bangladesh 2007. AB - Adolescent tobacco use (ATU) is on the rise worldwide and the problem is particularly severe in developing countries. Based on nationally representative data, this study aims to investigate the association between ATU and its possible correlates for Bangladesh, where the prevalence rate of ATU is high. The data set is extracted from the Global Youth Tobacco Survey for Bangladesh conducted in 2007. The survey collected information from a total of 3113 students from 52 schools, with a response rate of 100% at the school level, while a response rate of 88.9% was achieved from the students. Students covered in the survey were in grades 7, 8, 9, and 10, with age ranging from 11 to 17 years. The prevalence rate of ATU at the time of the survey was 8.4%, while 35.6% of the students had used at least a type of tobacco products before. Logistic regressions were used to obtain the odds ratios (ORs) in favor of ATU for each of the possible determinants and the confidence intervals (CIs) of these ratios. Use of tobacco among friends (OR = 3.46; CI = 2.37-5.05), the experience of seeing others smoking at home (OR = 2.10; CI = 1.36-3.22) or other places (OR = 1.6; CI = 1.02 2.57), receiving pocket money (OR = 7.6; CI = 4.59-13.28), receiving free tobacco from vendors (OR = 2.3; CI = 1.44-3.78), and exposure to advertisements and promotions of tobacco products (OR = 1.83; CI = 1.23-2.79) were associated with a higher likelihood of ATU. Increased awareness of health hazards of tobacco use through education in schools helped mitigate the problem of ATU. The findings of this study have ramifications for tobacco control prevention strategies in Bangladesh. PMID- 23359867 TI - SUMO modification of menin. AB - Menin acts as contextual a tumor suppressor and a tumor promoter, partly via epigenetic regulation of gene transcription. While menin is phosphorylated, it remains unclear whether wild type menin has other post-translational modifications. Here, we report that menin is SUMOylated by SUMO1 in vivo and in vitro, and the SUMOylation is reduced by a SUMO protease. Lysine 591 of menin was covalently modified by SUMO1 and K591R mutation in menin blocked SUMOylation of the C-terminal part of menin in transfected cells. Full-length menin with K591 mutation was still SUMOylated in vivo, suggesting the existence of multiple SUMOylation sites. Menin K591R mutant or menin-SUMO fusion protein still retains the ability to regulate cell proliferation and the expression of the examined menin target genes. PMID- 23359870 TI - Electrochemical fabrication of electroactive ordered mesoporous electrode. AB - A novel and simple method for the electrochemical modification of ordered mesoporous silica is described. A well-organized thin film of amine functionalized ordered mesoporous silica has been deposited electrochemically on the electrode surface. The resulting amine-functionalized electrodes were then subjected to post-functionalization with catechol moieties through electrochemical generation of reactive o-quinone followed by covalent bonding to the anchored amine groups inside the mesoporous channels of silica to afford the corresponding modified electrodes bearing aminocatechol electroactive groups. This simply obtained nanoporous modified electrode with adequate loading of electroactive groups shows very good electrochemical responses. PMID- 23359869 TI - The role of parental, school, and peer factors in adolescent bullying involvement: results from the Turkish HBSC 2005/2006 study. AB - The aim of this study was to explore the relationships between involvement in bullying behaviors and school, family, and peer factors. Health Behavior in School Age Children survey questionnaire was used. Of the students surveyed, 20% were both bully and victim, 11% were bully, and 21% were victim. Being male, poor parental support, and poor monitoring by the father were found to be risk factors for being both bully and victim. Poor academic achievement, having peers at different ages, poor quality of friendship, poor communication with parents, and not being isolated by peers were found to be risk factors for being bully. Not liking school, feeling pressured by school work, poor quality of friendship, poor monitoring by the father, close bonding with mother, and poor status of the peer group were found to be risk factors for being victim. These findings highlight the importance that bullying intervention programs should include country specific and culture-specific influences for success. PMID- 23359871 TI - A highly sensitive and selective aptasensor based on graphene oxide fluorescence resonance energy transfer for the rapid determination of oncoprotein PDGF-BB. AB - Oncoprotein platelet derived growth factor-BB (PDGF-BB) is one of the most critical growth factors that regulates tumor growth and division. In this work, a highly sensitive and selective fluorescence resonance energy transfer (FRET) aptasensor for PDGF-BB detection based on the assembly of dye-labeled aptamer and graphene oxide (GO) is developed for the first time. Due to the non-covalent assembly between aptamer and GO, fluorescence quenching of the dye takes place because of FRET. In the presence of PDGF-BB, the binding between aptamer and PDGF BB will disturb the interaction between aptamer and GO, and release the dye labeled aptamer from the GO surface, resulting in restoration of the fluorophore fluorescence. Because of the high fluorescence quenching efficiency, unique structure, and electronic properties of GO, the GO aptasensor exhibits extraordinarily high sensitivity. We also demonstrate that two highly related molecular variants of PDGF (AA, AB) can be distinguished from PDGF-BB, which indicates the aptasensor has excellent selectivity. Such an aptasensor opens a rapid, selective and sensitive route for the detection of PDGF-BB and provides a promising strategy for other cancer-related proteins detections. PMID- 23359872 TI - Interictal cortical hyperresponsiveness in migraine is directly related to the presence of aura. AB - OBJECTIVE: The objective of this study was to compare the interictal cortical response to a visual stimulus between migraine with aura (MWA), migraine without aura (MwoA), and control subjects. METHODS: In a prospective case-control study, blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) was used to assess the response to a visual stimulus and arterial spin labeled perfusion MR to determine resting cerebral blood flow. A standardized questionnaire was used to assess interictal visual discomfort. RESULTS: Seventy five subjects (25 MWA, 25 MwoA, and 25 controls) were studied. BOLD fMRI response to visual stimulation within primary visual cortex was greater in MWA (3.09 +/- 0.15%) compared to MwoA (2.36 +/- 0.13%, P = 0.0008) and control subjects (2.47 +/- 0.11%, P = 0.002); responses were also greater in the lateral geniculate nuclei in MWA. No difference was found between MwoA and control groups. Whole brain analysis showed that increased activation in MWA was confined to the occipital pole. Regional resting cerebral blood flow did not differ between groups. MWA and MwoA subjects had significantly greater levels of interictal visual discomfort compared to controls ( P = 0.008 and P = 0.005, respectively), but this did not correlate with BOLD response. CONCLUSIONS: Despite similar interictal symptoms of visual discomfort, only MWA subjects have cortical hyperresponsiveness to visual stimulus, suggesting a direct connection between cortical hyperresponsiveness and aura itself. PMID- 23359873 TI - Brainstem activation in cluster headache: an adaptive behavioural response? AB - INTRODUCTION: The functional neuroimaging of headache patients has revolutionized our understanding of the pathophysiology of primary headaches, providing unique insights into these syndromes. Indeed, functional neuroimaging studies have shown the activation of specific brain structures, the brainstem in migraine and posterior hypothalamus in cluster headache (CH), as well as in other trigeminal autonomic cephalalgias. We describe the functional neuroimaging findings in a patient suffering from CH headache, investigated with functional magnetic resonance imaging (fMRI) during typical pain attacks. MATERIAL AND METHODS: Two typical, consecutive CH attacks were investigated by two fMRI imaging sessions on the same day. Both fMRI scans were performed at rest, during the CH attacks and the pain-free state induced by subcutaneous administration of sumatriptan. RESULTS: Significant activation of the bilateral red nucleus, ventral pons and trigeminal root entry zone ipsilaterally to the pain side was detected during the pain state, in addition to the hypothalamic region ipsilaterally to the pain side. CONCLUSION: Being that such structures are mainly involved in motor function and reactive behaviour, their activation, in our hypothesis, may be linked to pain avoidance and may well represent a defence reaction in cluster headache, which is characterised by a "fight-or-flight" type behavioural pattern during pain attacks. PMID- 23359874 TI - Ictal epileptic headache: terms do matter in clinical practice! reply to Cianchetti et al. PMID- 23359876 TI - Oncolytic viruses successfully delivered intravenously. PMID- 23359875 TI - Bayesian adaptive phase II screening design for combination trials. AB - BACKGROUND: Trials of combination therapies for the treatment of cancer are playing an increasingly important role in the battle against this disease. To more efficiently handle the large number of combination therapies that must be tested, we propose a novel Bayesian phase II adaptive screening design to simultaneously select among possible treatment combinations involving multiple agents. METHODS: Our design is based on formulating the selection procedure as a Bayesian hypothesis testing problem in which the superiority of each treatment combination is equated to a single hypothesis. During the trial conduct, we use the current values of the posterior probabilities of all hypotheses to adaptively allocate patients to treatment combinations. RESULTS: Simulation studies show that the proposed design substantially outperforms the conventional multiarm balanced factorial trial design. The proposed design yields a significantly higher probability for selecting the best treatment while allocating substantially more patients to efficacious treatments. LIMITATIONS: The proposed design is most appropriate for the trials combining multiple agents and screening out the efficacious combination to be further investigated. CONCLUSIONS: The proposed Bayesian adaptive phase II screening design substantially outperformed the conventional complete factorial design. Our design allocates more patients to better treatments while providing higher power to identify the best treatment at the end of the trial. PMID- 23359877 TI - Study: shingles vaccine safe for patients on immune-suppressing drugs. PMID- 23359878 TI - Pfizer's men B vaccine shows promise in phase 2. PMID- 23359879 TI - Biovest initiates formal regulatory approval process for BiovaxID in Europe. PMID- 23359880 TI - Authors' response. PMID- 23359881 TI - Authors' response. PMID- 23359883 TI - [Frederic Dubas (1952-2012)]. PMID- 23359884 TI - [Frederic Dubas]. PMID- 23359888 TI - Contemporary treatment of low risk stage I non-seminomatous germ cell testicular tumors: a survey of the Society of Urologic Oncology. PMID- 23359890 TI - US-led economic sanctions strangle Iran's drug supply. PMID- 23359889 TI - Lipoma of the pancreas. PMID- 23359891 TI - Costa Rican couples await court-ordered IVF legalisation. PMID- 23359892 TI - Humanitarian crisis worsens as fighting escalates in Sudan. PMID- 23359893 TI - Profile: The King's College London unit tackling eating disorders. PMID- 23359894 TI - Anatomist and embryo: a portrait sculpture. PMID- 23359895 TI - Is social anxiety disorder the appropriate definition? PMID- 23359896 TI - Intermetamorphosis syndrome in a patient with paranoid schizophrenia. PMID- 23359897 TI - An example as to the role of literary works in psychiatry training: detail from Mrs. Dalloway--Septimus Warren Smith, shrapnel, and schizophrenia. PMID- 23359898 TI - Author's reply: To PMID 23043362. PMID- 23359900 TI - Health care reform: new year's resolutions. PMID- 23359899 TI - A survey of California nursing programs: admission and accommodation policies for students with disabilities. AB - A survey study was conducted to investigate the admission and accommodation policies of nursing programs for students with disabilities. Surveys were sent to 130 Board of Registered Nursing-approved nursing programs throughout California. Sixty-five (50%) of the surveys were returned and completed. Of the major findings of the study, learning disabilities were the most common type of disability reported. Testing time accommodations and a quiet environment were the most frequently requested and received accommodations. Seventy-two percent of nursing programs reported they have encountered students with disabilities who do not self-disclose or ask for accommodations. Most accommodations requested and received by students were classroom related. Few students with physical disabilities were reported as enrolled in nursing programs, possibly suggesting that prospective students with physical disabilities may not meet the physical requirements for nursing programs. Other reasons for underenrollment of students with disabilities should be explored, as well as reasons for nondisclosure. PMID- 23359901 TI - Look beyond the health care arena. PMID- 23359902 TI - HIV transmission may be prevented by intravaginal tenofovir ring. PMID- 23359903 TI - Superoxide dismutase, thermal respiratory acclimation, and growth in an earthworm, Eisenia foetida. AB - The superoxide dismutase activity units/mg protein were determined for earthworms (Eisenia foetida) acclimated at 15 degrees , 22.5 degrees and 30 degrees C. Worms acclimated at 15 degrees gave a value of SOD units significantly lower than those acclimated at 30 degrees . Those at 22.5 degrees gave an intermediate value. SOD activity units of the anterior, mid and posterior regions showed no indication of the classical U-shaped axial gradient of respiration. SOD levels increased as O2uptake increased, though to a lesser extent, indicating that SOD levels are somehow tied to metabolic rate even if not in a one to one relationship. The increased ratio of SOD/specific metabolic rate of 15 degrees compared to 30 degrees acclimates implies that at 15 degrees worms have more protection against the superoxide radical and thus would be expected to survive longer. PMID- 23359904 TI - Bringing veterinary medicine to the fore: founder of U.S. organized veterinary medicine was also its most outspoken critic. PMID- 23359905 TI - Comments on "research indicates breed misidentification currently exists as a "disease". PMID- 23359906 TI - Caregiver placebo effects. PMID- 23359907 TI - Ongoing performance improvement process. PMID- 23359908 TI - 2013 payment policy and coding changes affecting surgical practice. PMID- 23359909 TI - 2012 state legislative wrap-up. PMID- 23359910 TI - 2011-2012: a year of reaffirming the College's past and anticipating the needs of the future. PMID- 23359911 TI - Bulletin provides coverage of the dedication and inauguration of Murphy Memorial. 1926. PMID- 23359912 TI - The importance of surgical workforce maps. PMID- 23359913 TI - College leaders answer the question, "Why is rural surgery an important issue now"? PMID- 23359914 TI - Is medicine still a good profession? Reflections of a retired surgeon. PMID- 23359916 TI - Using simulation to achieve high reliability. PMID- 23359915 TI - Borderline resectable pancreatic cancer: pushing the technical limits of surgery. PMID- 23359917 TI - Annual report 2012: more than 70 percent. PMID- 23359918 TI - New York health care leaders review data-driven approach to quality surgical care. PMID- 23359919 TI - [Effects of light quality on the seed germination of main tree species in a secondary forest ecosystem of Northeast China]. AB - This paper explored the effects of light quality on the seed germination of five dominant tree species (Larix kaempferi, Phellodendron amurense, Acer mono, Fraxinus mandshurica, and Pinus koraiensis) in a secondary forest ecosystem of Northeast China, based on the experiments with the seeds of the five tree species in laboratory and those of the P. koraiensis and L. kaempferi in the field. Four treatments of different light quality were designed in laboratory (taking dark as the control), and three treatments of R/FR (the ratio of red light and far red light intensity) were installed in the field. The laboratory experiment showed that light quality had less effect on the seed germination of L. kaempferi, but the seed germination rates of the other four tree species were significantly different under the treatments of different light quality. P. amurense had the highest seed germination rate under white light, whereas A. mono, F. mandshurica, and P. koraiensis had the highest one under the alternative irradiation with red light and far red light (R-FR-R). In consistence with the results in laboratory, the seed germination rate of P. koraiensis in the field decreased with decreasing R/FR ratio, while that of L. kaempferi was less affected. Under natural condition, the R-FR-R fluctuated with the activity of sun-fleck, and the seed germination patterns of A. mono, F. mandshurica, and P. koraiensis could be the adaptation to the sun-fleck environment in forest stand. The germination of large seeds was significantly affected by light quality. PMID- 23359920 TI - [Relationships between soil moisture and needle-fall in Masson pine forests in acid rain region of Chongqing, Southwest China]. AB - From March 2009 to November 2011, an investigation was conducted on the spatiotemporal variation of soil moisture and its effects on the needle-fall in Masson pine (Pinus massoniana) forests in acid rain region of Chongqing, Southeast China, with the corresponding soil moisture thresholds determined. No matter the annual precipitation was abundant, normal or less than average, the seasonal variation of soil moisture in the forests could be obviously divided into four periods, i.e., sufficient (before May), descending (from June to July), drought (from August to September), and recovering (from October to November). With increasing soil depth, the soil moisture content increased after an initial decrease, but the difference of the soil moisture content among different soil layers decreased with decreasing annual precipitation. The amount of monthly needle-fall in the forests in growth season was significantly correlated with the water storage in root zone (0-60 cm soil layer), especially in the main root zone (20-50 cm soil layer). Soil field capacity (or capillary porosity) and 82% of field capacity (or 80% of capillary porosity) were the main soil moisture thresholds affecting the litter-fall. It was suggested that in acid rain region, Masson pine forest was easily to suffer from water deficit stress, especially in dry-summer period. The water deficit stress, together with already existed acid rain stress, would further threaten the health of the Masson forest. PMID- 23359921 TI - [Content and distribution of active components in cultivated and wild Taxus chinensis var. mairei plants]. AB - Taxus chinensis var. mairei is an endemic and endangered plant species in China. The resources of T. chinensis var. mairei have been excessively exploited due to its anti-cancer potential, accordingly, the extant T. chinensis var. mairei population is decreasing. In this paper, ultrasonic extraction and HPLC were adopted to determine the contents of active components paclitaxel, 7-xylosyltaxol and cephalomannine in cultivated and wild T. chinensis var. mairei plants, with the content distribution of these components in different parts of the plants having grown for different years and at different slope aspects investigated. There existed obvious differences in the contents of these active components between cultivated and wild T. chinensis var. mairei plants. The paclitaxel content in the wild plants was about 0.78 times more than that in the cultivated plants, whereas the 7-xylosyltaxol and cephalomannine contents were slishtly higher in the cultivated plants. The differences in the three active components contents between different parts and tree canopies of the plants were notable, being higher in barks and upper tree canopies. Four-year old plants had comparatively higher contents of paclitaxel, 7-xylosyltaxol and cephalomannine (0.08, 0.91 and 0.32 mg x g(-1), respectively), and the plants growing at sunny slope had higher contents of the three active components, with significant differences in the paclitaxel and 7-xylosyltaxol contents and unapparent difference in the cephalomannine content of the plants at shady slope. It was suggested that the accumulation of the three active components in T. chinensis var. mairei plants were closely related to the sunshine conditions. To appropriately increase the sunshine during the artificial cultivation of T. chinensis var. mairei would be beneficial to the accumulation of the three active components in T. chinensis var. mairei plants. PMID- 23359922 TI - [Effects of cutting on the dominant and subdominant plant species in a Stipa krylovii steppe of Inner Mongolia]. AB - Based on the long-term cutting experiment, this paper analyzed the responses of the aboveground biomass of five dominant and subdominant plant species and the community stability in a Stipa krylovii steppe of Inner Mongolia to various cutting height. Cutting with a stubble height of > 10 cm had slight effects on the aboveground biomass of the five species. Cutting with a stubble height of 10 cm benefited the growth of Artemisia frigida but made against the growth of Stipa krylovii. Cleistogenes squarrosa at the stubble height of 2 cm performed best, and Carex korshinskyi at the stubble height of 5 cm contributed most to the community, with the biomass positively correlated with the cutting years. Potentilla acaulis growth was detrimentally affected at the stubble heights of 2 and 15 cm. Overall, perennial species with higher plant height and stronger competitive ability were more tolerant to disturbances, and a minimum cutting height of 10 cm should be applied to maintain a high stability of the steppe ecosystem. PMID- 23359923 TI - [Ecological adaptability of leaf epidermis of erosion-resistant plants in hilly gully area of Loess Plateau, Northwest China]. AB - By the temporary slide method of leaf epidermis, an observation was made on the morphological characteristics of the leaf epidermis of six erosion-resistant plant species in different soil erosion environments (gully, inter-gully, and inter-gully artificial Robinia pseudoacacia forest land) in hilly-gully area of Loess Plateau. Compared with those in the gully, the stomata aperture, stomata density, stomata index, stomata apparatus length/width plasticity, stomata apparatus area plasticity, epidermal hair density, and epidermal cell density of the leaf upper and lower epidermis of the plants in the inter-gully were 93.8% and 90.4%, 66.8% and 76.6%, 17.9% and 9.8%, 36.4% and 47.1%, 42.3% and 43.9%, 199.4% and 98.2%, and 46.5% and 50.1% higher, respectively; while in the inter gully artificial R. pseudoacacia forest land, the same morphological indices of the leaf upper and lower epidermis of the plants were 66.7% and 106.7%, 20.5% and 45.8%, 11.9% and 11.9%, 37.9% and 41.3%, 19.8% and 21.2%, 113.1% and 52.2%, and 10.8% and 28.1% higher than those in the gully, respectively. The epidermal hair length and epidermal cell area of the leaf upper and lower epidermis of the plants in the inter-gully were 58.8% and 29.7%, and 40.3% and 37.0% lower than those in the gully, and the same morphological indices of the leaf upper and lower epidermis of the plants in the intergully artificial R. pseudoacacia forest land were respectively 25.0% and 23.6%, and 22.2% and 19.2% lower than those in the gully, respectively. The results suggested that the erosion-resistant plants in the study area were able to adapt to various soil erosion environments by increasing their leaf stomata aperture, stomata density, stomata index, stomata apparatus length/width plasticity, stomata apparatus area plasticity, epidermal hair density, and epidermal cell density, and by reducing their epidermal hair length and epidermal cell area. PMID- 23359924 TI - [Inhibitory effect of DMPP on soil nitrification as affected by soil moisture content, pH and organic matter]. AB - A laboratory incubation test with meadow brown soil was conducted to study the inhibitory effect of 3,4-dimethylpyrazole phosphate (DMPP) on soil nitrification as affected by soil moisture content (40%, 60% and 80% of the maximum field capacity), pH (4, 7 and 10), and organic matter (retained and removal). With the decrease of soil moisture content, the degradation of DMPP in soil tended to slow down, and the oxidation of soil NH4+ was more inhibited. At pH 10, more DMPP was remained in soil, and had the greatest inhibitory effect; at pH 7 and pH 4, the DMPP was lesser remained, with a smaller inhibitory effect. The removal of organic matter prolonged the remaining time of DMPP in soil, and decreased the apparent soil nitrification rate significantly. PMID- 23359925 TI - [Effects of land use type and incubation temperature on soil nitrogen transformation and greenhouse gas emission]. AB - A laboratory experiment with the soil samples collected from China and Canada was conducted to study the effects of land use type (forestland vs. grassland) and incubation temperature (10 degrees C vs. 15 degrees C) on the soil nitrification, nitrogen mineralization, and N2O and CO2 emissions under aerobic condition. As compared with forestland soils, grassland soils had higher nitrification rate and N2O emission, with the highest nitrification rate in China grassland soil. At 10 and 15 degrees C, the average net nitrification rate of China grassland soil was 2.10 and 2.86 mg N x kg(-1) x d(-1) and the cumulative N2O emission in 15 incubation days was 10.2 and 15.4 microg N2O-N x kg(-1), respectively. Soil pH was the main factor affecting the nitrification rate and N2O emission, and there existed significant positive correlations between the soil pH and the nitrification rate and N2O emission. Forestland soils had higher nitrogen mineralization rate and CO2 emission than grassland soils, and China forestland soil had the highest nitrogen mineralization rate, with the average net mineralization rate at 10 and 15 degrees C being 3.08 and 2.87 mg N x kg(-1) x d( 1), respectively. The CO2 emission was the highest in Canada forestland soil, and the cumulative CO2 emission in 15 incubation days at 10 and 15 degrees C was 314 and 370 mg CO2-C x kg(-1), respectively. The soil organic carbon and soluble organic carbon contents had significant positive correlations with the soil nitrogen mineralization rate and CO2 emission, respectively, whereas the increasing soil temperature promoted the nitrification in grassland soils and the N2O emission from forestland soils and grassland soils. The same pronounced effects of increasing temperature were also found on the CO2 emission from forestland soils. PMID- 23359926 TI - [Effects of land use type on spatiotemporal distribution of soil nutrients in Dianchi watershed, Yunnan Province of Southwest China]. AB - Surface soil samples were monthly collected from six land use types (abandoned greenhouse field, forest land, sloped farmland, table land, flat vegetable land and greenhouse field) in Dianchi watershed of Yunnan to determine the soil pH and the contents of soil organic matter (OM), total nitrogen (TN), and total phosphorus (TP), aimed to understand the effects of different land use types on the spatiotemporal distribution of the soil nutrients. The soil pH, SOM, TN and TP, contents, and soil C/N differed significantly with soil land use types. The soil pH was in the order of abandoned greenhouse field > flat vegetable land > greenhouse field > table land > sloped farmland > forest land; the OM content was in the sequence of abandoned greenhouse field > flat vegetable land > greenhouse field > sloped farmland > forest land > table land; the TN content was in the order of greenhouse field > flat vegetable land > abandoned greenhouse field > sloped farmland > table land > forest land; the TP content was in the order of flat vegetable field > greenhouse field > abandoned greenhouse field > sloped farmland > table land > forest land; and the C/N ratio was in the sequence of forest land > sloped farmland > flat vegetable plot > table land > abandoned greenhouse field > greenhouse field. The OM, TN and TP contents were affected by fertilization, irrigation, field cultivation and season. All the test parameters had the highest values in rainy season, which could be related to the local top dressing habits. There were significant positive correlations among the TN, TP and OM under all the land use types. In greenhouse field and abandoned greenhouse field, due to the severe human disturbances, the soil pH and OM, TN and TP contents were obviously higher than those in forestland and table land. PMID- 23359927 TI - [Chemical properties and enzyme activities of rhizosphere and non-rhizosphere soils under six Chinese herbal medicines on Mt. Taibai of Qinling Mountains, Northwest China]. AB - This paper studied the chemical properties and enzyme activities of rhizosphere and non-rhizosphere soils in different habitats of six Chinese herbal medicines, including Pyrola decorata, Cephalotaxus fortunei, Polygonatum odoratum, Potentilla glabra, Polygonum viviparum, and Potentilla fruticosa, on the Mt. Taibai of Qinling Mountains. In the rhizosphere soils of the herbs, the contents of soil organic matter, total nitrogen, available nitrogen, and available phosphorus and the soil cation exchange capacity (CEC) were higher, presenting an obvious rhizosphere aggregation, and the soil enzyme activities also showed an overall stronger characteristics, compared with those in non-rhizosphere soils. The soil organic matter, total nitrogen, and total phosphorus contents in the rhizosphere soils had significant positive correlations with soil neutral phosphatase activity, and the soil CEC had significant positive correlations with the activities of soil neutral phosphatase and acid phosphatase. In the non rhizosphere soils, the soil organic matter and total nitrogen contents had significant positive correlations with the activities of soil urease, catalase and neutral phosphatase, and the soil CEC showed a significant positive correlation with the activities of soil urease, catalase, neutral phosphatase and acid phosphatase. The comprehensive fertility level of the rhizosphere soils was higher than that of the non-rhizosphere soils, and the rhizosphere and non rhizosphere soils of P. fruticosa, P. viviparum, and P. glabra had higher comprehensive fertility level than those of P. decorata, P. odoratum and C. fortunei. In the evaluation of the fertility levels of rhizosphere and non rhizosphere soils under the six Chinese herbal medicines, soil organic matter content and CEC played important roles, and soil neutral phosphatase could be the preferred soil enzyme indicator. PMID- 23359928 TI - [Effects of applying endophytic fungi on the soil biological characteristics and enzyme activities under continuously cropped peanut]. AB - A pot experiment was conducted to investigate the effects of applying endophytic fungi Phomopsis liquidambari strain B3, Phomopsis sp. strain NJ4.1, and Ceratobasidum stevensii strain B6 on the soil biological characteristics and enzyme activities under continuously cropped peanut at its different growth stages. Compared with the control, applying B3 increased the peanut yield significantly by 19.8%, and applying NJ4.1, B3 and B6 increased the peanut nodule number significantly by 20.4%, 29.3% and 27.6%, respectively. In the three treatments of applying endophytic fungi, the average population of soil bacteria and actinomycetes in the whole growth period of peanut was higher than that of the control, and the soil microbial biomass carbon was significantly greater at germination and seedling stages. The soil microbial biomass nitrogen increased at germination stage, but decreased at flowering stage. The DGGE analysis indicated that at flowering stage, the soil bacteria and fungi in treatment B3 had the largest band number and diversity. From germination stage to maturing stage, the three treatments of applying endophytic fungi had higher activities of soil invertase and catalase than the control, but less difference in soil urease activity. It was suggested that applying endophytic fungi could improve the peanut continuous cropping soil environment, and applying B3 had the best effect. PMID- 23359929 TI - [Effects of applying sewage sludge on chemical form distribution and bioavailability of heavy metals in soil]. AB - A pot experiment was conducted to study the effects of applying sewage sludge on the chemical form distribution of heavy metals (Cd, Pb, Cu and Zn) in soil and the transfer and accumulation of the heavy metals in soil-plant (ryegrass) system. With the application of sewage sludge, the contents of bioavailable Cd and Zn in soil increased significantly but that of bioavailable Pb in soil had a significant decrease, and the content of residual form Pb in soil increased by 33.3% -74.5%, compared with CK. When the application rate of sewage sludge was 50% (M/M) of soil, the contents of exchangeable and reducible Cu in soil only occupied 0.7% and 0.2% of the total Cu respectively. The application of sewage sludge promoted the Cd, Cu and Zn absorption while inhibited the Pb absorption by ryegrass. Multiple linear regression analysis showed that the Cd, Zn and Cu contents in ryegrass were positively correlated with the reducible Cd and Zn and oxidizable Cu contents in soil, respectively, and Pb content in ryegrass was highly correlated with the soil exchangeable and oxidizable Pb contents. After planting ryegrass, the oxidizable Cd and Cu in rhizosphere soil were transformed into exchangeable Cd and residual form Cu, respectively, the exchangeable and reducible Zn transformed into oxidizable Zn, whereas the bioavailability of Pb was less affected. PMID- 23359930 TI - [Degradation and bioaccumulation characteristics of ciprofloxacin in soil vegetable system]. AB - A pot experiment was conducted to investigate the effects of applying ciprofloxacin (CIP) on the growth of flowering Chinese cabbage (Brassica campestris), radish (Raphanus sativus), tomato (Solanum lycopersicum) and long bean (Vigna unguiculata), the bioaccumation of CIP in the vegetables, and the degradation of the antibiotics in soil. The results showed that applying 5, 30 and 75 mg x kg(-1) of CIP had no significant effects on the plant biomass of flowering Chinese cabbage, tomato and long bean, but the high concentration of CIP (> or = 30 mg x kg(-1)) inhibited the radish growth significantly. The degradation of CIP in soil was fast at beginning, but slowed down gradually since then. The DT50 and DT90 of CIP in long bean soil were 18.3-43.9 d and 260-738 d, respectively. The CIP could be absorbed by the roots of all the four vegetables and allocated to their aboveground parts, and the CIP residues in the vegetables in creased with the concentration of CIP in soil. The CIP concentration in flowering Chinese cabbage roots was higher than that in the cabbage aboveground parts, that in radish showed a higher concentration in aboveground parts than in roots, and the CIP concentration in tomato and long bean was in the same order of root > stem > leaf. PMID- 23359931 TI - [Characteristics of soil microbial biomass carbon and soil water soluble organic carbon in the process of natural restoration of Karst forest]. AB - By the method of taking space instead of time, an incubation test was conducted to study the characteristics of soil microbial biomass carbon and water soluble organic carbon in the process of natural restoration of Karst forest in Maolan Nature Reserve, Guizhou Province of Southwest China. The soil microbial biomass carbon content and soil basal respiration decreased with increasing soil depth but increased with the process of the natural restoration, soil microbial quotient increased with increasing soil depth and with the process of restoration, and soil water soluble organic carbon content decreased with increasing soil depth. In the process of the natural restoration, surface soil water soluble organic carbon content increased, while sublayer soil water soluble organic carbon content decreased after an initial increase. The ratio of soil water soluble organic carbon to total soil organic carbon increased with increasing soil depth but decreased with the process of restoration. Soil quality increased with the process of restoration. Also, the quality and quantity of soil organic carbon increased with the process of restoration, in which, soil microbial biomass carbon content had the greatest change, while soil water soluble organic carbon content had less change. PMID- 23359932 TI - [Effects of revegetation on organic carbon storage in deep soils in hilly Loess Plateau region of Northwest China]. AB - Taking the Robinia pseudoacacia woodlands, Caragana korshinskii shrublands, and abandoned croplands with different years of revegetation in the hilly Loess Plateau region of Northwest China as test objects, this paper studied the profile distribution and accumulation dynamics of organic carbon storage in deep soil (100-400 cm), with those in 0-100 cm soil profile as the control. In 0-100 cm soil profile, the organic carbon storage decreased significantly with the increase of soil depth; while in deep soil, the organic carbon storage had a slight fluctuation. The total organic carbon storage in 100-400 cm soil profile was considerably high, accounting for approximately 60% of that in 0-400 cm soil profile. The organic carbon storage in 80-100 cm soil layer had a significant linear correlation with that in 100-200 and 200-400 cm soil layers, and among the organic carbon storages in the five layers in 0-100 cm soil profile, the organic carbon storage in 80-100 cm soil layer had the strongest correlation with that in 100-400 cm soil profile, being able to be used to estimate the organic carbon storage in deep soil in this region. The organic carbon storage in 0-20 cm soil layer in the three types of revegetation lands was significantly higher than that in slope croplands, but the organic carbon storage in deep soil had no significant difference among the land use types. The organic carbon storage in deep soil increased with the increasing years of revegetation. In R. pseudoacacia woodlands and C. korshinskii shrub lands, the average increasing rate of the organic carbon storage in 100-400 cm soil layer was 0.14 and 0.19 t x hm(-2) x a( 1), respectively, which was comparable to that in the 0-100 cm soil layer in C. korshinskii shrublands. It was suggested that in the estimation of the soil carbon sequestration effect of revegetation in hilly Loess Plateau region, the organic carbon accumulation in deep soil should be taken into consideration. Otherwise, the effect of revegetation on soil carbon sequestration would be significantly underestimated. PMID- 23359933 TI - [Allelopathic effects of Streptomyces sp. 6803 on plants]. AB - Streptomyces can produce an overwhelming majority of known antibiotics and several biologically active compounds, but whether Streptomyces can display allelopathic effects on higher plants is largely unknown. In this study, seven actinomyces strains isolated from soils showed inhibitory effect on plant seedlings growth, among which, Streptomyces sp. 6803 had strong capability in inhibiting the seedlings growth of Brassica campestris and Echinochloa crusgalli in both solid and liquid cultures. The dilute solution (x 5) of fermented broth inhibited the seedlings growth of B. campestris and E. crusgalli by 60.7% and 61.3%, respectively. Based on the morphological and physiological-biochemical characteristics and 16S rRNA sequencing, Streptomyces sp. 6803 was identified as Streptomyces arenae, with the 16S rRNA sequence identity being 99.28%. Ultraviolet radiation and diethyl sulfate (DES) were used to produce mutants to enhance the allelopathic potential of this strain. After 80 and 100 seconds of ultraviolet radiation, the dilute solution (x10) of fermented broth of obtained mutants UV8024 and UV100-2 showed 37.5% and 38.1% higher inhibition effect on the root growth of B. campestris seedlings, respectively, compared with the control. The mutant D507 obtained through 1% DES treatment for 50 min showed 29.8% higher inhibition effect on the root growth of B. campestris seedlings. This study showed that Streptomyces sp. 6803 had allelopathic effect on higher plants, and it was possible to enhance the allelopathic potential of the strain via mutation breeding. PMID- 23359934 TI - [Effects of different sowing dates and low-light stress at heading stage on the physiological characteristics and grain yield of hybrid rice]. AB - Hybrid rice Chuanxiang 9838 with medium shade-endurance was taken as the test material to investigate the effects of different sowing dates and low-light stress at heading stage on the flag leaf photosynthetic rate (P(n)), osmotic regulators, antioxidant enzyme activities and the grain yield of hybrid rice. Sowing date and low-light stress at heading stage had significant effects on the flag leaf P(n) and antioxidant enzyme activities and plant dry matter accumulation at heading stage and the grain yield. With the delay of sowing date, the whole period of rice growth and development shortened notably, and the grain yield decreased to different degrees. Compared with the control, shortterm slight low-light stress (20% shading) at heading stage could relieve the harms from high temperature and strong light, and further, relieve the decrease of flag leaf P(n) and plant dry matter accumulation at heading stage, adjust the flag leaf antioxidant enzyme activities, and moderately improve the seed setting rate. However, short-term medium low-light stress (40% shading) and serious low-light stress (60% shading) were not beneficial to the rice growth. Correlation analysis indicated that the flag leaf P(n), malondialdehyde (MDA) content, and superoxide dismutase (SOD) were more sensitive to the sowing date and low-light stress at heading stage, and there existed a highly significant positive correlation between the flag leaf P(n) at initial heading stage (1-5 d) and the plant dry matter accumulation at late heading stage and grain yield. PMID- 23359935 TI - [Effects of irrigation time on the growth and water- and fertilizer use efficiencies of winter wheat]. AB - A field experiment was conducted to study the effects of irrigation time before wintering (November 10th, November 25th, and December 10th) and in spring (March 5th, re-greening stage; and April 5th, jointing stage) on the growth, dry matter translocation, water use efficiency (WUE), and fertilizer use efficiency (FUE) of winter wheat after returning corn straw into soil. The irrigation time before wintering mainly affected the wheat population size before wintering and at jointing stage, whereas the irrigation time in spring mainly affected the spike number, grain yield, dry matter translocation, WUE, and FUE. The effects of irrigation time before wintering to the yield formation of winter wheat were closely related to the irrigation time in spring. When the irrigation time in spring was at re-greening stage, the earlier the irrigation time before wintering, the larger the spike number and the higher the grain yield; when the irrigation time in spring was at jointing stage, the delay of the irrigation time before wintering made the spike number and grain yield decreased after an initial increase, the kernel number per plant increased, while the 1000-kernel mass was less affected. The WUE, nutrition uptake, and FUE all decreased with the delay of the irrigation time before wintering, but increased with the delay of the irrigation time in spring. Therefore, under the conditions of returning corn straw into soil and sowing when the soil had enough moisture, to properly advance the irrigation time before wintering could make the soil more compacted, promote the tillering and increase the population size before winter, and in combining the increased irrigation at jointing stage, could control the invalid tillering in early spring, increase the spiking rate, obtain stable kernel mass, and thus, increase the WUE and FUE, realizing water-saving and high efficiency for winter wheat cultivation. PMID- 23359936 TI - [Effects of irrigation mode and N application rate on cotton field fertilizer N use efficiency and N losses]. AB - A field experiment was conducted to study the effects of different irrigation modes (drip irrigation and furrow irrigation) and different N application rates (0, 240, 360 and 480 kg N x hm(-2)) on the fertilizer N use efficiency and N losses in a cotton field in Xinjiang, Northwest China. The main N cycling pathways, such as the N uptake by cotton plant, NO3(-)-N residual in soil, NH3 volatilization, NO3(-)-N leaching, and nitrification-denitrification, were quantitatively monitored. Compared with furrow irrigation, drip irrigation increased the seed cotton yield, plant N uptake, and fertilizer N use efficiency significantly. The NO3(-)-N residual in soil was significantly greater under furrow irrigation than under drip irrigation. With the application of fertilizer N, the N loss from NH3 volatilization under drip irrigation occupied 0.06% -0.14% of applied N, and was significantly greater than that under furrow irrigation. The N loss from NO3(-)-N leaching under drip irrigation and furrow irrigation was 4.4% and 8.8% of the applied N, respectively. Compared with furrow irrigation, drip irrigation could significantly decrease the NO3(-)-N leakage rate in leakage water. The nitrification-dinetrification loss under drip irrigation and furrow irrigation was 17.9% and 16.8% of the applied N, respectively. It was suggested that NO3(-)-N leaching and nitrification-denitrification were the main N losses in the cotton fields of Xinjiang. PMID- 23359937 TI - [Fate and balance of bulk blending controlled release fertilizer nitrogen under continuous cropping of mustard]. AB - Under the conditions of applying water soluble fertilizer and its bulk blending with controlled release fertilizer (BB-CRF), and by using micro-lysimeter, this paper quantitatively studied the nitrogen (N) uptake by mustard, the soil N losses from N2O emission, leaching and others, and the N residual in soil in three rotations of continuously cropped mustard. In the treatment of BB-CRF with 25% of controlled release nitrogen, the N uptake by mustard increased with rotations, and the yield by the end of the experiment was significantly higher than that in the treatment of water soluble fertilizer. The cumulated N2O emission loss and the N leaching loss were obviously higher in treatment water soluble fertilizer than in treatment BB-CRF. NO3(-)-N was the primary form of N in the leachate. In relative to water soluble fertilizer, BB-CRF altered the fates of fertilizer nitrogen, i.e., the N uptake by mustard and the N residual in soil increased by 75.4% and 76.0%, and the N leaching loss and other apparent N losses decreased by 27.1% and 66.3%, respectively. The application of BB-CRF could be an effective way to reduce the various losses of fertilizer N while increase the fertilizer N use efficiency, and the controlled release fertilizer is the environmentally friendly fertilizer with the property of high N use efficiency. PMID- 23359938 TI - [Effects of nitrogen deposition on leaf physiological and ecological characteristics of Lindera aggregata seedlings]. AB - From June 2010 to July 2011, a pot experiment was conducted to explore the effects of nitrogen deposition on the leaf physiological and ecological characteristics of Lindera aggregate seedlings. Three levels of NH4NO3, i. e., low-N (2 g x m(-2) x a(-1)), medium-N (8 g x m(-2) x a(-1)), and high-N (32 g x m(-2) x a(-1)) , were added to simulate nitrogen deposition, and the seedling leaf photosynthesis, relative chlorophyll content, chlorophyll fluorescence parameters, membrane lipid peroxidation, and antioxidant enzyme activities were determined. After one-year treatment, the daily mean values of the net photosynthetic rate (P)n)) and the maximum net photosynthetic rate (P(n max)) at low, medium and high levels of NH4 NO3 addition were 47.0%, 117.8% and 41.2%, and 82.6%, 191.3% and 152.2% higher than those of the control (no NH4 NO3 addition), respectively, with the highest values at medium level of NH4NO3 addition. The intercellular CO2 concentration, daily mean stomatal conductance, light saturation point, and apparent quantum yield in the three treatments of NH4NO3 addition were all higher than those of the control, and the dark respiration rate was the highest in treatment high-N. The relative chlorophyll content was the highest in treatment medium-N, followed by in treatment high-N, and had no significant difference between treatment low-N and the control. The chlorophyll fluorescence parameters varied with the levels of NH4NO3 addition. The PS II primary chemical efficiency (F(v)/F(m)) and PS II potential activity (F(v)/F(o)) were the lowest in treatment high-N, the superoxide dismutase activity was higher in nitrogen addition treatments than in the control, and the peroxidase activity, malonydialdehyde content, and membrane permeability were the highest in treatment high-N. All the results suggested that nitrogen deposition enhanced the photosynthetic ability of L. aggregata seedlings, with the most obvious effects in treatment medium-N, and altered the other physiological traits of the seedlings to different degrees. PMID- 23359939 TI - [Simulation model for the crop development stages in sunflower-potato intercropping]. AB - Potato-sunflower intercropping is a prevailing cropping system in the agricultural and pastoral ecotone in China. To precisely simulate the crop phenology in the intercropping system is of significance for the assessment and optimization of intercropping systems. In this paper, the simulation model for the development stages of sunflower and potato in monoculture and intercropping was established, based on the crop's physiological development time, and validated with the field experimental data from 2010 to 2011. A good fitness was observed between the simulated and observed values of the crop's development stages. The root mean square error (RMSE) of the development stages from sowing to emergence, emergence to flowering, flowering to mature, and from sowing to mature was 1.2, 2.9, 2.4 and 2.6 d, respectively, with the prediction error lower than 5%. The model was strong on mechanistic, explanation and adaptability, and could be applied as a good tool in the researches of crop growth and development. PMID- 23359940 TI - [Seedling index of Salvia miltiorrhiza and its simulation model]. AB - Through the correlation analysis on the quantitative traits and their ratios of Salvia miltiorrhiza seedlings and seedling quality, a series of representative indices reflecting the seedling quality of the plant species were determined, and the seedling index suitable to the S. miltiorrhiza seedlings was ascertained by correlation degree analysis. Meanwhile, based on the relationships between the seedling index and the air temperature, solar radiation and air humidity, a simulation model for the seedling index of S. miltiorrhiza was established. The experimental data of different test plots and planting dates were used to validate the model. The results showed that the root diameter, stem diameter, crown dry mass, root dry mass, and plant dry mass had significant positive relationships with the other traits, and could be used as the indicators of the seedling's health. The seedling index of S. miltiorrhiza could be calculated by (stem diameter/root diameter + root dry mass/crown dry mass) x plant dry mass. The stem diameter, root dry mass, crown dry mass and plant dry mass had higher correlations with the seedling index, and thus, the seedling index determined by these indicators could better reflect the seedling's quality. The coefficient of determination (R2) between the predicted and measured values based on 1:1 line was 0.95, and the root mean squared error (RMSE) was 0.15, indicating that the model established in this study could precisely reflect the quantitative relationships between the seedling index of S. miltiorrhiza and the environmental factors. PMID- 23359941 TI - [Thermal resources and maize temperature suitability in Northeast China under climate change]. AB - This paper analyzed the spatiotemporal patterns of thermal resources and of temperature suitability of maize at its different growth stages in Northeast China, based on the 1951-2100 daily mean and minimum air temperature from RegCM3. In 1951-2100, the thermal resources in Northeast China had an obvious persistent increase, the first day of temperature > or = 10 degrees C continued to be advanced, and the north boundary line in the zone of the first date of temperature > or = 10 degrees C before April 25th moved eastward and northward. In 2071-2100, the first date in some areas of Liaoning Province would advance to March 26th, and the areas with active accumulated temperature > or = 10 degrees C more than 3000 degrees C x d, the length of growth season, and the areas suitable for late-maturing maize planting in Northeast China would increase persistently. In the region, the mean annual temperature in 2011-2100 would be 3.34 degrees C higher than that in 1981-2010. In 1951-2100, there was and would be an increasing temperature suitability of maize at its sowing-heading stage. In 1951-2040, the maize temperature suitability at heading-maturing stage and in whole growth season was and would be higher in Liaoning Province than in Heilongjiang Province; in 2041-2100, the maize temperature suitability at heading-maturing stage and in whole growth season would decrease gradually in Liaoning Province but increase gradually in east Jilin Province and Heilongjiang Province. PMID- 23359942 TI - [Sowing date of corn in semiarid region of Jilin Province, Northeast China in adapting to climate change]. AB - Under the background of global climate change, the climate in semiarid region of west Jilin Province changed greatly, producing a profound impact on the corn production in this region. In this study, the corn seeds were under three treatments (accelerating germination at 10 and 25 degrees C, and dry seeds), and a field experiment with early sowing and traditional sowing was conducted in 2008 to investigate the effects of early sowing these seeds on the seedling emergence, growth, and yield, and compare the effects of early sowing and traditional sowing dates on the corn production and yield. In 1961-2010, the first day of the growth season of corn in semiarid region of west Jilin Province was advanced, the air temperature increased significantly, and the precipitation displayed a decreasing trend. At present, the corn sowing date in this region could be advanced to 11th, April. Accelerating germination at 10 degrees C, directly sowing dry seeds, and bed-irrigation sowing all benefited the seedling emergence and cold resistance of early-sown seeds, and the corn plant height and leaf area under early sowing were significantly higher, with the yield increased by 35% - 48%, compared with those under traditional sowing. PMID- 23359943 TI - [Risk assessment and regionalization of maize drought disasters in Sichuan Basin, Southeast China]. AB - Based on the information of maize yield, phonological period, and related weather data, four models (those of climatic drought risk, crop drought risk, yield loss risk, and drought resistant capability) applicable for the assessment of maize drought risk in Sichuan Basin and the corresponding index systems were established, and a comprehensive model for assessing the maize drought disasters in the Basin was constructed, with the comprehensive index for the risk regionalization of the maize drought disasters determined. The values of the indices for assessing the maize drought risk in the Basin differed obviously with different regions, but showed similarity in some areas. The Sichuan Basin was divided into three regions, with high, medium and low maize drought risk, respectively. The region with high risk was mainly in the most areas of northwest basin, the middle basin, and parts of the south basin of Sichuan, the region with medium risk was in the north basin and some parts of the south basin, and the region with low risk was in the northeast and southwest basin, and parts of the southeast basin. PMID- 23359944 TI - [Correlative analysis of the diversity patterns of regional surface water, NDVI and thermal environment]. AB - Taking Zhengzhou City, the capital of Henan Province in Central China, as the study area, and by using the theories and methodologies of diversity, a discreteness evaluation on the regional surface water, normalized difference vegetation index (NDVI), and land surface temperature (LST) distribution was conducted in a 2 km x 2 km grid scale. Both the NDVI and the LST were divided into 4 levels, their spatial distribution diversity indices were calculated, and their connections were explored. The results showed that it was of operability and practical significance to use the theories and methodologies of diversity in the discreteness evaluation of the spatial distribution of regional thermal environment. There was a higher overlap of location between the distributions of surface water and the lowest temperature region, and the high vegetation coverage was often accompanied by low land surface temperature. In 1988-2009, the discreteness of the surface water distribution in the City had an obvious decreasing trend. The discreteness of the surface water distribution had a close correlation with the discreteness of the temperature region distribution, while the discreteness of the NDVI classification distribution had a more complicated correlation with the discreteness of the temperature region distribution. Therefore, more environmental factors were needed to be included for a better evaluation. PMID- 23359945 TI - [Variation trends of the vegetations in distribution region of Amur tiger based on MODIS NDVI]. AB - By using the averaged 250 m MODIS NDVI data in growth seasons of 2000-2010 and the approach of ordinary linear regression, this paper analyzed the variation trends of the vegetations in the distribution region of Amur tiger (Panthera tigris altaica), the Far East region of Russia and the eastern part of Northeast China, as well as the relationships between these variation trends and the anthropogenic activities. In 2000 - 2010, the areas with significantly decreased NDVI were sparsely distributed and accounted for 9.6% of the total, while the areas with significantly increased NDVI were mainly concentrated in the central part of northern Russia Far East Region and only accounted for 0.5% of the total. The percentage of the areas with significantly decreased NDVI in the distribution region of Amur tiger was slightly higher than that in the whole study region. The areas with significantly decreased NDVI were mainly distributed in the places of low elevation, gentle slope, and close to roads/railroads. The number of the pixels with significantly decreased NDVI increased with the increase of the nearest distance to residential locations first, and then decreased gradually. The significant decrease of the NDVI was closely related to the anthropogenic activities, and thus, to adopt effective measures to reduce human disturbances could control the vegetation degradation, and further, provide sustainable basis for the protection of Amur tiger and the conservation of the biodiversity in the studied region. PMID- 23359946 TI - [Driving forces of carbon emission from energy consumption in China old industrial cities: a case study of Shenyang City, Northeast China]. AB - To quantitatively analyze the effects of anthropogenic factors on regional environmental quality is a hot topic in the field of sustainable development research. Taking the typical old industrial city Shenyang in Northeast China as a case, and by using the IPCC method for calculating carbon emission from energy consumption, this paper estimated the carbon emission from energy consumption in the city in 1978-2009, and a time series analysis on the anthropogenic factors driving this carbon emission was made by the STIRPAT model based upon Kaya equation and ridge regression. In 1978-2009, the carbon emission in the city had a slow increase first, slow decrease then, and a rapid increase thereafter. The total carbon emission in 2009 was 4.6 times of that in 1978. Population growth was the main factor driving the growth of the emission, and there existed an equal-proportional variation between the population growth and the carbon emission growth. Urbanization was another main driving factor followed by population growth, and the per capita GDP was positively correlated with the carbon emission. Kuznets curve did not exist for the relationship between economic development and carbon emission in Shenyang. Energy source intensity reduction (representing technology improvement) was the main factor driving the reduction of the total carbon emission. PMID- 23359947 TI - [Analysis on barriers of urban sustainable development based on DEMATEL: a case of Shenyang City]. AB - To scientifically identify the key barriers which the urban sustainable development is facing and to analyze the interrelationships among the barriers are of significance to promote urban sustainable development. Through literature review, site investigation and structural interview, 21 factors affecting the Shenyang City's sustainable development were recognized, and based on questionnaire survey and statistics analysis, 12 main factors were screened. Further, by employing decision-making and trial evaluation laboratory (DEMATEL) method, the interrelationships among these factors were analyzed. The key factors affecting the Shenyang's sustainable development included the lack of leaders' attention, the economy-oriented governmental performance evaluation system, the lower public awareness on sustainable development, and the lack of academic understanding on regional eco-carrying capacity and related key projects. It was suggested that the local government should pay more attention on sustainable development, increase propaganda activities, reform governmental performance evaluation system, establish a reward-punishment system for promoting sustainable development and an effective monitoring mechanism, and enhance the implementation of related regulations, the local enterprises should establish research and development funds to support the researches of key technologies and introduce key projects, and general publics should improve their awareness on sustainable development and actively participate in related activities. PMID- 23359948 TI - [Ecological effects of wheat-oilseed rape intercropping combined with methyl salicylate release on Sitobion avenae and its main natural enemies]. AB - In order to explore the effects of wheat-oilseed rape intercropping in combining with methyl salicylate (MeSA) release on Sitobion avenae and its main natural enemies, a field experiment was conducted at the Tai'an Experimental Station of Shandong Agricultural University in East China from October 2008 to June 2010 to study the temporal dynamics of S. avenae and its main natural enemies as well as the ecological control effect on the aphid. In the plots of intercropping combined with MeSA release, the S. avenae apterae population reached a peak about 12 d in advance of the control, but the peak value was significantly lower than that of the control. The average annual number of S. avenae apterae per 100 wheat tillers decreased in the order of wheat monoculture > wheat-oilseed rape intercropping > MeSA release > wheat-oilseed rape intercropping combined with MeSA release. Moreover, the total number of ladybeetles was the highest in the plots of intercropping combined with MeSA release. The population densities of aphid parasitoids reached a peak about 10 d in advance of the control, which could play a significant role in controlling S. avenae at the filling stage of wheat. Taking the biological control index (BCI) as a quantitative indicator, and with the ladybeetles and parasitoids as the dominant control factors in fields, it was observed that wheat-oilseed rape intercropping combined with MeSA release could suppress the population increase of S. avenae apterae effectively from the heading to filling stages of wheat. PMID- 23359949 TI - [Effects of different years of planting Pennisetum sp. on the plant- and insect diversity in Pennisetum sp. communities]. AB - This paper studied the effects of 1-, 2- and 3 years of planting Pennisetum sp. on the plant- and insect diversity in the Pennisetum sp. communities, taking the barren mountain land without planting Pennisetum sp. as the control (CK). Compared with CK, the plant species richness in Pennisetum sp. communities with different years of planting was lower, but the coverage was higher. The coverage in the Pennisetum sp. community having been planted for 3 years was the highest, up to 91.6%, and 75.8% higher than the CK. The insect species richness in the Pennisetum sp. communities having been planted for 1, 2 and 3 years was 3.6, 5.3 and 5.6 times of the CK, respectively. The plant- and insect diversity indices, including Simpson index, Shannon index, evenness, Brillouin index, and McIntosh index for the Pennisetum sp. communities with different years of planting were significantly higher than the CK, which indicated that the growth of Pennisetum sp. could affect the plant- and insect diversity. With the increasing year of planting, the plant- and insect diversity in Pennisetum sp. communities tended to be stable. PMID- 23359950 TI - [Combined toxicity of copper and cadmium to cladoceran Moina marocopa]. AB - In this paper, the 48 h LC50 values of Cu2+, Cd2+ and CU(2+)+Cd2+ (CU2+:Cd2+ = 1:1) to Moina macrocopa were determined by acute toxicity tests, and the effects of different concentrations of Cu2+, Cd2+ and Cu(2+)+Cd2+ on the life table demography of M. macrocopa were studied by life table demography. The 48 h LC50 of Cu2+, Cd2+ and Cu(2+)+Cd2+ to M. macrocopa was 0.106, 0.117 and 0.212 mg x L( 1), respectively, and the acute toxicity of Cu(2+)+Cd2+ mixture to M. macrocopa showed an antagonistic effect. Cu2+ had no significant effects on the life expectancy at hatching, gross reproductive rate, net reproductive rate, generation time, and intrinsic rate of population increase of M. macrocopa, whereas Cd2+ and Cu(2+)+Cd2+ had significant effects on the life expectancy at hatching, gross reproductive rate, net reproductive rate and generation time, but no significant effects on the intrinsic rate of population increase of M. macrocopa. Compared with the control, the 0.004 and 0.005 mg x L(-1) of Cd2+ and the 0.006-0.010 mg x L(-1) of Cu(2+)+Cd2+ decreased the life expectancy at hatching and the gross reproductive rate of M. macrocopa significantly, and the 0.004 and 0.005 mg x L(-1) of Cd2+ and the 0.008-0.010 mg x L(-1) of Cu(2+)+Cd2+ reduced the net reproductive rate and the generation time of M. macrocopa significantly. The chronic toxicity of Cu(2+)+Cd2+ mixture to M. macrocopa showed a synergistic effect. There existed significant dose-effect relationships between the concentrations of Cd2+ and Cu(2+)+Cd2+ and the life expectancy at hatching, gross reproductive rate, net reproductive rate, and generation time of M. macrocopa. PMID- 23359951 TI - [Annual dynamics of cladocera community structure in Backshore Wetland of Expo Garden, Shanghai]. AB - The Backshore Wetland of Expo Garden, Shanghai was one of the key parts of the World Expo construction project in 2010. From September 2009 to August 2010, a monthly investigation was conducted to understand the spatiotemporal dynamics of cladocera community structure (including species composition and standing crop) and related main affecting factors in the Backshore Wetland. A total of 36 cladocera species in 13 genera of 5 families were identified through the year. There were 12 dominant species, mainly Chydorus sphaericus, C. ovalis, Diaphanosoma leuchtenbergianum, and Sida crystalline. The mean annual abundance and biomass of the cladocera were 5.7 ind x L(-1) and 0.3559 mg x L(-1), respectively, and the annual dynamics of the standing crop showed bimodal, with the main peak in April and July, and the second peak in July and May, respectively. The Shannon index, Pielou index, and Margelf index were high in summer and autumn, but low in winter and spring. The canonical correspondence analysis (CCA) showed that water temperature, pH, dissolved oxygen, and nitrite nitrogen were the main factors affecting the community structure of cladocera in the Backshore Wetland. PMID- 23359952 TI - [Land layout for lake tourism based on ecological restraint]. AB - To avoid the decrease and deterioration of lake wetlands and the other ecological issues such as lake water pollution that were caused by the unreasonable exploration of lake tourism, a land layout for the tourism development of Liangzi Lake with the priority of ecological security pattern was proposed, based on the minimal cumulative resistance model and by using GIS technology. The study area was divided into four ecological function zones, i. e., core protection zone, ecological buffer zone, ecotone zone, and human activity zone. The core protection zone was the landscape region of ecological source. In the protection zone, new tourism land was forbidden to be increased, and some of the existing fundamental tourism facilities should be removed while some of them should be upgraded. The ecological buffer zone was the landscape region with resistance value ranged from 0 to 4562. In the buffer zone, expansion of tourism land should be forbidden, the existing tourism land should be downsized, and human activities should be isolated from ecological source by converting the human environment to the natural environment as far as possible. The ecotone zone was the landscape region with resistance value ranged from 4562 to 30797. In this zone, the existing tourism land was distributed in patches, tourism land could be expanded properly, and the lake forestry ecological tourism should be developed widely. The human activity zone was the landscape region with resistance value ranged from 30797 to 97334, which would be the key area for the land layout of lake tourism. It was suggested that the land layout for tourism with the priority of landscape ecological security pattern would be the best choice for the lake sustainable development. PMID- 23359953 TI - [Structure and function of Lidao artificial reef ecosystem in Rongcheng of Shandong Province, East China: an evaluation based on Ecopath model]. AB - Based on the annual investigation data of biological resources in Lidao artificial reef zone in 2009, an Ecopath model of the Lidao artificial reef ecosystem was constructed to analyze the energy flow pattern and the system attributes of the ecosystem. The model was consisted of 19 functional groups, basically covering the main processes of the energy flow in the Lidao artificial reef ecosystem. The functional groups were divided according to the relationships of the corresponding positions between appeared fishes and artificial reefs, and the planktonic heterotrophic bacteria were included into the model as a functional group. The fishes appeared in the investigation zone were divided into seven functional groups, and the trophic levels of the functional groups varied from 1.00 to 3.72. The type I fishes had the highest trophic level. The total system throughput was estimated to be 10786.68 t x km(-2) x a(-1), 27% of which flowed to detritus, and 17% flowed out the ecosystem in the forms of fishing and sediment. The total net primary productivity of the system was 4131.97 t x km(-2) x a(-1) and the total energy transfer efficiency was 10.5%. The proportion of the total flow originated from detritus was 39%, and that from primary producers was 61%, indicating that the energy flow was dominated by food web rather than detritus. The ratio of total primary productivity to total respiration of the system was 1.84, the connectivity index was 0.20, and the Finn's cycling index and the mean path length of the energy flow were 4.5% and 2.62, respectively. This study showed that the Lidao artificial reef ecosystem had a relatively low maturity and stability, was at a developing stage, and had weak resistance against outside interference. The ecological environment and the output of fisheries in the artificial reef zone would have inter-annual fluctuations, and thus, the eco-environment restoration of the artificial reef ecosystem could only be realized by the sustainable maintaining of the ecosystem. PMID- 23359954 TI - [Effects of environmental factors on catch distribution of stow net Pseudosciaena polyactis and Lophius litulon in southern Yellow Sea in spring]. AB - Stow net fishery is one of the important fishing methods in southern Yellow Sea. Based on the 2006-2009 data from the stow net fishery resources survey in the southern Yellow Sea in spring, and by using the generalized linear model (GLM) and generalized additive model (GAM), this paper quantitatively analyzed the relationships between the catch distribution of Pseudosciaena polyactis and Lophius litulon and the environmental factors such as year, position, water depth, and sea surface temperature (SST). Compared with GLM model, GAM model could better explain the relationships between the spatiotemporal distribution of the catch per unit effort (CPUE) of P. polyactis and P. litulon and the environmental factors. There was a significant negative correlation between the CPUE of the two fish species. The P. polyactis' CPUE showed a decreasing trend from north to south along the latitude direction, being smaller especially around the Yangtze River estuary, and the L. litulon' s CPUE was also smaller near the Yangtze River estuary. The CPUE of the two species showed a significant correlation with the SST. The calculated optimal scale of the SST for L. polyactis and P. litulon was 9-11 degrees C and 9-14 degrees C, respectively. PMID- 23359955 TI - [Effects of water temperature, salinity and pH on sex differentiation of Oreochromis niloticus]. AB - By using Box-Behnken design and response surface methodology, this paper studied the effects of three major environmental factors, i. e., water temperature (20-36 degrees C), salinity (0-16), and pH (5.5-8.5), on the sex differentiation of GIFT strain Nile tilapia (Oreochromis niloticus). It was observed that water temperature had highly significant linear and quadratic effects on the sex differentiation, water salinity and pH had non-significant linear and quadratic effects, and the two-factor interactions of the three factors were not significant. The analysis with response surface methodology showed that the male rate of the GIFT tilapia increased with increasing water temperature, and at water temperature 36 degrees C, salinity 8, and pH 8.5, the male rate reached the maximum (80%). A model equation about the relationships of the male rate with the three major environmental factors was established, and after eliminating the related non-significant factors, an optimal model equation about the relationship between the male rate and water temperature was attained, which could predict the variation of the GIFT tilapia male rate. PMID- 23359956 TI - [Selenium cycling and transformation in paddy field and selenium nutrition of rice: a review]. AB - Due to the alternate variation of soil redox potential and the particularity of soil components in paddy field, the selenium (Se) cycling and transformation in paddy soil are obviously different from those in upland soil, and can affect the Se availability in soil and the Se absorption and accumulation by rice. To deeply understand the Se cycling and transformation in paddy soil and the Se absorption and accumulation by rice is of great importance in studying the transformation of soil inorganic Se to organic Se. This paper summarized the researches on the cycling mechanisms and form transformation of Se in paddy soil and the metabolic mechanisms and absorption characteristics of Se by rice, and discussed the present status and development trend of the studies on the Se transformation in soil-rice system and the Se translocation in rice plant, which could provide references for the study of soil Se availability and the cultivation of Se enriched rice. PMID- 23359957 TI - [Staged strategy of plants in response to drought stress]. AB - Drought is one of the most important abiotic factors limiting plant growth, development and survival. Due to global warming, the drought episodes in the future will become more frequent and severe. Therefore, the plant responses to drought stress, especially the drought-resistant mechanisms, have been a focus of the studies. This paper summarized the plant growth and physiological responses to drought stress, and proposed a staged response strategy of plants for the adaptation to natural drought stress. Overall, from drought initiation to drought induced death, plants experienced five stress stages with increasing drought intensity, i. e., drought initiation-mild drought-moderate drought-severe drought extreme drought, and the plant responsive and adaptive process in this whole event could be acute response-active adaptation to mild and severe drought stresses-passive adaptation to extreme drought stress. The essential function of the plant drought-resistant mechanisms varied with drought stress stages. Some key scientific problems and research directions about the staged response characteristics of plants to drought stress needed to be solved urgently in the future were pointed out. PMID- 23359958 TI - [Dynamic observation, simulation and application of soil CO2 concentration: a review]. AB - Soil CO2 concentration is the consequences of biological activities in above- and below-ground, and its fluctuation may significantly affect the future atmospheric CO2 concentration and the projected climate change. This paper reviewed the methodologies for measuring the soil CO2 concentration in situ as well as their advantages and disadvantages, analyzed the variation patterns and controlling factors of soil CO2 concentration across the temporal (diurnal, several days, seasonal and inter-annual) and spatial (soil profile, site and landscape) scales, introduced the primary empirical and mechanical models for estimating and predicting soil CO2 concentration, and summarized the applications and constraints of soil CO2 concentration gradient in determining soil respiration. Four research priorities were proposed, i. e., to develop new techniques for collecting and determining the soil CO2 in severe soil conditions (e. g., flooding, lithoso and others), to approach the responses of soil CO2 concentration to weather change and related regulation mechanisms, to strengthen the researches on the spatial heterogeneity of soil CO2 concentration, and to expand the applications of soil CO2 concentration gradient in the measurement of tropical-subtropical soil respiration. PMID- 23359959 TI - [Applications of soil metaproteomics in soil pollution assessment: a review]. AB - Soil microbial indicator is one of the important biological indicators in evaluating the extent of soil contamination. In recent years, with the development of molecular biology, many studies have focused on the ecological functions of soil microorganisms by using metagenomics, metatranscriptome and metaproteomics. Relative to metagenomics and metatranscriptome, soil metaproteomics aims to investigate the spatial and temporal changes of the proteins extracted from soil as well as the functional components of soil microbial genomic expression products, which is more conclusive to explore the ecological functions of soil microbes and their roles in soil pollutants transportation and transformation. Therefore, soil metaproteomics has great potential in soil pollution assessment. Currently, soil metaproteomics is still at its infancy stage, while soil protein extraction method is one of the key factors restraining the potential application of soil metaproteomics. In this paper, the advantages and disadvantage of soil metaproteomics in soil pollution assessment were reviewed, with the focus on the comparison of different soil protein extraction methods. In combining with case studies, the feasibility and limits of soil proteins as an indicator for soil pollution assessment were analyzed. In addition, the future research perspectives on the development of soil metaproteomics were discussed. PMID- 23359960 TI - [An explanation of lightspots on 2012 universal definition of myocardial infarction]. PMID- 23359961 TI - [The current state of acupoint-acupuncture effects and discussion on its laws]. AB - To make an induction and conclusion on related literatures on acupoint acupuncture effects published at home and abroad in recent years. The important links and laws influencing the acupuncture effects were analyzed from the following 3 aspects: the specificity of acupoints, the stimulatory methods of acupoints, and acupuncture dose-effect relationship, thus providing possible clues for studies on acupoint-acupuncture effect, and enriching the theoretical bases for acupoint-acupuncture effect study. PMID- 23359962 TI - [Acupoint and therapeutic efficacy of acupuncture-moxibustion]. AB - The close relationship between acupoint and therapeutic efficacy of acupuncture moxibustion is the basis for acupuncture-moxibustion to achieve the treatment effect. Crucial factors that affect the efficacy of acupuncture-moxibustion therapy should include the features and compatibility of acupoints, acquirement for needling response, reinforcing-reducing needling methods, stimulation methods and intensity, and so on. How to make good use of acupoint to enhance the clinical efficacy of acupuncture-moxibustion is one of the key and urgent scientific problems in the field of acupuncture-moxibustion. In this paper the relationship between acupoint and therapeutic efficacy of acupuncture moxibustion, as well as its current research state were elucidated. Pondering and prospective on how to carry out researches to improve the clinical efficacy of acupuncture-moxibustion were also undertaken. PMID- 23359963 TI - [Conversion and transformation: the historical destiny of Chinese medicine and Western medicine classics]. AB - Chinese medicine (CM) and Western Medicine (WM) show different traces in the inheritance and innovation. The great distinguished physicians in the history of CM and WM, and eternal classic works have experienced similar fates in the river of the history, but they have manifested the same origins and different branches. In this paper, I hold that it is understandable that CM classics and WM classics have experienced different historical destinies from different disciplinary attributes. Their methodological origins could be found from different ideological and cultural bases. They construct necessary tension of mutual reference and bridging from future development of a medical community. PMID- 23359964 TI - [Consensus on diagnosis and treatment of cholecystitis by Chinese medicine (Hainan 2011)]. PMID- 23359965 TI - [Clinical observation of warm needling therapy for treating knee osteoarthritis of different Chinese medical syndrome types]. AB - OBJECTIVE: To observe the difference in the therapeutic efficacy of warm needling therapy on knee osteoarthritis (KOA) patients of different Chinese medical syndrome types. METHODS: Totally 197 KOA outpatients [including wind-cold-damp retention syndrome (50 cases, 61 knees), yang deficiency cold coagulation syndrome (48 cases, 58 knees), stagnation of blood stasis syndrome (49 cases, 63 knees), and insufficiency of Shen-essence syndrome (50 cases, 66 knees)] were treated with warm needling therapy, 10 days as one therapeutic course, 3 courses in total. The symptom score and changes of clinical efficacy were assessed. The contents of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) in the synovial fluid were determined before and after treatment. RESULTS: The symptom scores and the clinical efficacy were improved in all syndrome groups after treatment (P < 0.05), with the best effects shown in the yang deficiency cold coagulation syndrome (P < 0.05) and the worst effects shown in the stagnation of blood stasis syndrome (P < 0.05). The contents of IL 1, IL-6, and TNF-alpha in the synovial fluid decreased after treatment in all syndrome groups (P < 0.05), with the best effects shown in the yang deficiency cold coagulation syndrome (P < 0.05). CONCLUSION: Warm needling therapy had favorable therapeutic effects on KOA patients of wind-cold-damp retention syndrome, yang deficiency cold coagulation syndrome, and insufficiency of Shen essence syndrome, with the best effects shown on KOA patients of yang deficiency cold coagulation syndrome. PMID- 23359966 TI - [External application of compound Tripterygium wilfordii decreased the activity of rheumatoid arthritis]. AB - OBJECTIVE: To explore the therapeutic efficacy of external application of Compound Tripterygium wilfordii (CTW) for treating rheumatoid arthritis (RA) on the basis of treatment by integrative medicine. METHODS: Totally 67 active RA patients of damp-heat stagnation syndrome were randomly assigned to the external application group (35 cases) and the placebo group (32 cases). The reaction standard by American College of Rheumatology and Disease Activity Score (DAS) were taken as the indices for therapeutic assessment. A randomized controlled, single blind clinical trial was performed for 4 weeks, with a 3-month follow-up. The statistical analyses were performed using intention to treat analysis set (ITT). RESULTS: After treatment the rate of reaching ACR20 was 34.3% and 12.5% in the external application group and the placebo group respectively. The mean for the average drop of DAS28 ratings was 1.07 in the external application group and 0.40 in the placebo group, showing statistical difference (P < 0.05, P < 0.01). As for the safety, there was no effect on the menstruation in the external application group. Only mild skin allergy occurred in 2 cases of the external application group, but they were alleviated after drug withdrawal. CONCLUSIONS: External application of CTW could control the condition of RA and reduce the disease activity of RA. It had better safety. PMID- 23359967 TI - [Effects of all-trans retinoic acid and compound huangdai tablet sequential maintenance treatment on the long-term efficacy of acute promyelocytic leukemia patients]. AB - OBJECTIVE: To compare the difference in the long-term efficacy between all-trans retinoic acid (ATRA) combined Compound Huangdai Tablet and ATRA combined methotrexate (MTX) and 6-mercaptopurine (6MP) as the sequential maintenance treatment of acute promyelocytic leukemia (APL) patients. METHODS: Totally 83 APL patients in the molecular remission (PML/RARalpha negative) were randomly assigned to two groups, the treatment group (45 cases) and the control group (38 cases) after they were induced to the complete remission (CR) by ATRA combined chemotherapy, and treated by sequential chemotherapy as the consolidated treatment for 3 therapeutic courses. Those in the treatment group were sequentially treated with ATRA and Compound Huangdai Tablet as maintenance therapy, while those in the control group were treated with ATRA and MTX + 6MP as maintenance therapy. After a long-term follow-up (2003 -2011), the long-term therapeutic efficacy and adverse reactions were compared between the two therapeutic regimens. RESULTS: The 5-year relapse-free survival (RFS) rate was 84.4% +/- 5.4% in the treatment group and 63.2% +/- 7.8% in the control group, showing statistical difference between the two groups (P < 0.05). The 5-year overall survival rate (OSR) was 86.7% +/- 5. 1% in the treatment group and 78.7% +/- 6.7% in the control group, showing no statistical difference between the two groups (P > 0.05). There was no statistical difference in the adverse reaction between the two groups (P > 0.05). CONCLUSION: The application of ATRA and Compound Huangdai Tablet as maintenance therapy could elevate the long-term RFS rate of APL patients. PMID- 23359968 TI - [Clinical observation on the safety and efficacy of ursodeoxycholic acid and fuzheng huayu capsule in the treatment of primary biliary cirrhosis]. AB - OBJECTIVE: To observe the clinical efficacy of ursodeoxycholic acid (UDCA) and Fuzheng Huayu Capsule (FHC) in the treatment of primary biliary cirrhosis (PBC). METHODS: Eighty PBC patients were randomly assigned to two groups, the treatment group and the control group, 40 in each group. Patients in the treatment group took UDCA and FHC, while those in the control group were treated with UDCA alone. The treatment course was 48 weeks for both groups. The clinical symptoms and signs, liver function indices (ALT, AST, ALP, GGT, ALB, TBIL, and TBA), hepatic fibrosis indices (HA, LN, IV-CL, and PIIIP), immunologic indices (IgG, IgM, and autoimmune antibodies), changes of portal hemodynamics, and adverse reactions were observed before treatment, as well as at week 4, 12, 24, and 48 after treatment. RESULTS: After treatment the skin itching and fatigue were significantly improved in the treatment group, showing statistical difference when compared with the control group (P < 0.05, P < 0.01). After treatment the levels of ALT, AST, ALP, GGT, TBIL, and TBA obviously decreased in the two groups. They were lower in the treatment group than in the control group at the same time point (P < 0.05). The decrement was the largest at week 4. Besides, at week 48 after treatment the ALB level was improved in the treatment group (P < 0.05). The levels of HA and PIIIP obviously decreased at week 4, 12, and 24, the levels of LN and IV-C obviously decreased at week 4 and 12, the decrement of the hepatic fibrosis indices at week 4 were more obvious in the treatment group. But the levels of HA and PIIIP were lower than the pre-treatment levels at week 12 in the control group. The immunologic indices such as IgM and IgG were improved in the two groups, with better results obtained in the treatment group (P < 0.05, P < 0.01). In the treatment group ANA turned negative in 1 patient and AMA turned negative in 2 patients. After 48 weeks of treatment, the spleen was retracted, the inner diameters of the portal vein (PV) and the splenic vein (SV) were significantly reduced, and the blood flow velocity in the PV and SV increased in the treatment group (P < 0.01). At week 24 and 48, 33 patients (82.5%) and 26 patients (90.0%) in the treatment group had complete relief, better than those of the control group [22 cases (55.0%) and 28 cases (70.0%)]. No obvious adverse reaction was found in the two groups during the treatment course. CONCLUSIONS: The combination therapy of UDCA and FHC was effective and safe in anti fibrosis and improving the liver functions of PBC patients. It was safe and better than the application of UDCA alone. It was advocated to be combined use for a long term. It might improve the long-term efficacy. PMID- 23359969 TI - [Effects of suxiao jiuxin pill on patients with acute coronary syndrome undergoing early percutaneous coronary intervention]. AB - OBJECTIVE: To investigate the intervention effects of Suxiao Jiuxin Pill (SJP) on patients with acute coronary syndrome (ACS) undergoing early percutaneous coronary intervention (PCI). METHODS: Sixty ACS patients were randomly assigned to the treatment group (treated by SJP and Western medicine) and the control group (treated by Western medicine alone), 30 in each group. Coronary arteriography and early PCI were performed in all patients. The effects of SJP on the blood flow rate, the collateral artery patency, and perioperative myocardial infarction incidence were observed. RESULTS: The coronary blood flow rate was better in the treatment group than in the control group either pre- or post-PCI. [pre-PCI thrombolysis in myocardial infarction (TIMI) level III: 16/30 vs 11/30, P < 0.01; post-PCI TIMI level III: 14/14 vs 13/19, P < 0.05)]. In patients with ITMI level 0 - I , more patients in the treatment group had collateral artery protective function than those in the control group (5/6 vs 3/13, P < 0.05). The incidence of perioperative myocardial infarction was obviously lower in the treatment group than in the control group (8/30 vs 15/30, P < 0.05). CONCLUSION: SJP could improve the pre- and post-PCI coronary artery flow rate, increase the collateral artery patency, and reduce the incidence of perioperative myocardial infarction of ACS patients. PMID- 23359970 TI - [Treatment of thirty primary hypothyroidism patients by fuzheng fujia mixture ]. AB - OBJECTIVE: To observe the clinical efficacy of treating primary hypothyroidism by Fuzheng Fujia Mixture (FFM) with formula composing principles of warming and tonifying Pi and Shen, and eliminating blood stasis and removing turbid substances. METHODS: Totally 60 patients with primary hypothyroidism were randomly assigned to the treated group and the control group, 30 in each group. All were treated by Levothyroxine Sodium Tablet (LST) as routines. Those in the treated group took FFM additionally, 3 times daily, one month as 1 therapeutic course. The therapeutic efficacy was assessed after three therapeutic courses. RESULTS: After treatment the symptom scores were significantly reduced in the two groups (P < 0.05). The decrement was larger in the treated group than in the control group (P < 0.05). The dose of LST was significantly lower in the treated group than in the control group (P < 0.05). The blood lipids levels were significantly reduced in the two groups after treatment (P < 0.05). The decrement was significantly larger in the treated group than in the control group (P < 0.05). CONCLUSION: FFM could obviously improve the symptoms of hypothyroidism patients, reduce the replacement dose of thyroid hormone, and lower the blood lipids levels. PMID- 23359971 TI - [Comparative study on Chinese medical syndrome typing and treatment combined different surgical methods for treating clomiphene-resistant polycystic ovary syndrome]. AB - OBJECTIVE: To observe the therapeutic efficacy of Chinese medical syndrome typing and treatment combined cold needle puncture drainage operation or unipolar electrocoagulation drilling technique under laparoscope for treating clomiphene resistant polycystic ovary syndrome (PCOS). METHODS: Forty infertility patients with clomiphene-resistant PCOS were assigned to two groups using stratified random sampling method according to age, infertility time, and body mass index, 20 in each group. Patients in Group A were treated with Chinese medical syndrome typing and treatment combined cold needle puncture drainage operation, while those in Group B were treated with Chinese medical syndrome typing and treatment combined unipolar electrocoagulation drilling technique. After operation Chinese herbal treatment was administered to all patients according to syndrome typing. The serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), androgen (T), estradiol (E2), and prolactin (PRL) were determined before and after operation. The ovulation was monitored. The pregnancy rate and the pregnancy outcomes were recorded after operation. RESULTS: There was no statistical difference in the 3-month spontaneous ovulation rate or the 1-year pregnancy rate (P > 0.05). The levels of LH, T, and PRL were significantly lower after operation than before operation in the two groups (P < 0.05). The menstruation and ovulation were obviously improved after operation. The total ovulation rate was 95% (19/20) in Group A. Successful pregnancy occurred in 15 cases of Group A. Ovarian hyperstimulation syndrome (OHSS) occurred in 1 case of Group A. The total ovulation rate was 90% (18/20) in Group B. Successful pregnancy occurred in 13 cases of Group B. Hypovaria occurred in 1 case of Group B. Luteinized unruptured follicle (LUFS) occurred in 2 cases of Group A and 1 case of Group B. CONCLUSIONS: Chinese medical syndrome typing and treatment combined cold needle puncture drainage operation or unipolar electrocoagulation drilling technique could effectively promote the ovulation. The two methods showed similar therapeutic effects. PMID- 23359972 TI - [Study on correlated proteins in the urine of chronic renal failure patients of Chinese medicine damp syndrome based on SELDI-TOF-MS technique]. AB - OBJECTIVE: To investigate the protein markers in the urine of chronic renal failure (CRF) patients of Chinese medicine damp syndrome (CMDS) based on surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS) technique. METHODS: The urine was sampled from 90 CRF patients of CMDS and 60 CRF patients of non-CMDS. Then the proteomics of the urine was studied by H4 gene chip. The chips were scanned and analyzed using PBS II (a protein chip reader). RESULTS: (1) Totally 25 differential protein peaks were identified in the e/m range of 1 000-20 000 of the protein atlas of the two groups (P < 0.01). (2) The urine protein predictive model of CFR patients of CMDS was established after bioinformatic analysis. Totally 4 biomarkers consisting of M/Z 8 654.96, M/Z 2 081.65, M/Z 18 667.3, and M/Z 2 242.14 were obtained, which could better classify the samples of CMDS and those of non-CMDS. Its accuracy rate was 84.7%, the sensitivity was 92.2%, and the specificity was 73.3%. (3) Between the CMDS group and the non-CMDS group, 7 kinds of proteins in the urine were possibly identified by SwissProt Database. CONCLUSIONS: This study had primarily screened the protein markers in the urine of CRF patients of CMDS, and established the predictive model. The protein markers in the urine were identified by database, thus providing certain experimental evidence for clinical typing of CRF patients of CMDS. PMID- 23359973 TI - [Study on the scores of blood stasis syndrome of acute ischemic stroke and its correlation with TOAST subtypes]. AB - OBJECTIVE To compare the differences in the scores of blood stasis syndrome (BSS) in three subtypes of acute ischemic stroke (AIS) based on modified Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria, and to explore the influencing factors of BSS. METHODS: Patients with AIS were classified by modified TOAST criteria. The BSS score was determined in 418 patients of atherosclerosis thrombosis (AT), cardioembolism (CE), and small artery disease (SAD) subtypes. The BSS scores were compared in the three subtypes. Univariate analysis and multivariable Logistic analysis were carried out to analyze the influencing factors of BSS. RESULTS: As for the BSS score, CE (120.08 +/- 14.91) > AT (79.56 +/- 11.43) > SAD (37.88 +/- 8.32), and there was statistical difference among different subtypes (P < 0.01). Univariate analysis indicated that age, heart disease, carotid stenosis, NIHSS, GCS, and multiple infarction positions had significant effects on BSS. Multiple Logistic regression analysis suggested that age (OR: 1.71, 95% CII: 1.13-2.74, P = 0.034), heart disease (OR: 2.05,95% CI: 1.52-4.15, P = 0.000), carotid stenosis (OR: 2.74, 95% CI: 1.65-4.55, P = 0.007), and multiple infarction positions (OR: 3.46, 95% CI: 2.16-6.62, P = 0.005) were independent influencing factors of BSS. CONCLUSIONS: Different TOAST subtypes of BSS had different BSS scores, which was helpful to indicate the reasons for BSS. Age, heart disease, carotid stenosis, and multiple infarction positions were independent influencing factors of BSS. PMID- 23359975 TI - [Transcriptomics study of the transcriptional response of the spinal dorsal horn to electroacupuncture stimulation with different frequencies]. AB - OBJECTIVE: To explore the effects of low-and high-frequency electroacupuncture (EA) on the gene expression profiles in rat spinal dorsal horn (DH) under the physiological state, thus providing the information to find out the differences of different EA frequencies induced effects. METHODS: Using cDNA microarray, the changes of the gene expressions in the DH were detected and compared between 2 Hz EA and 100 Hz EA at bilateral Zusanli (ST36) and Sanyinjiao (SP6). The differentially expressed genes were identified. The EASE scores were used to comprehensively analyze the gene functions (by Gene Ontology) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. RESULTS: (1) After EA stimulation 1 150 genes/expressed sequence tags (ESTs) were differentially expressed by 2 Hz EA, while 1 270 genes/ESTs were differentially expressed by 100 Hz EA. (2) Both 2 Hz and 100 Hz EA could induce the modulation of the same 516 genes/ESTs in the same direction, which was correlated with neural signal transmission. (3) The differentially expressed genes regulated specifically by 2 Hz were correlated with neural plasticity. (4) The differentially expressed genes regulated specifically by 100 Hz were correlated with stress and immunoregulation. CONCLUSIONS: Either low-or high-frequency EA could extensively regulate the spinal cord information processing. The low-frequency EA participated more in the regulation of neural plasticity, while high-frequency EA had more significant effects on stress and immunoregulation. PMID- 23359974 TI - [Correlation between neurotransmitters and neurosteroids and premenstrual syndrome patients of Gan-yang ascending syndrome and Gan-qi stagnation syndrome]. AB - OBJECTIVE: To explore the pathogenesis of premenstrual syndrome (PMS), and the correlation between anger and depression and PMS of Gan-yang ascending syndrome (GYAS) and Gan-qi stagnation syndrome (GQSS) by detecting the neuro-reproductive hormones of PMS patients of GYAS and GOSS, thus providing theoretical reliance for diagnostic standards for clinical normative PMS. METHODS: Using techniques such as HPLC, HPLC-MC, ELISA, and radioimmunoassay (RIA), levels of serum sex hormones (follicle stimulating hormone, luteinizing hormone, estradiol, progesterone, testosterone, and prolactin), plasma neurotransmitters (gamma aminobutyric acid, beta-endorphin, glutamic acid, dopamine, 5-HT, adrenaline, and noradrenaline), neurosteroids (allopregnanolone, pregnenolone, and dehydroepiandrosterone) in the follicular phase and the luteal phase of PMS patients of GYAS (30 cases) and GQSS (30 cases) were detected, and compared with the healthy control group (30 cases). RESULTS: There was no statistical difference in either index of the follicular phase among the 3 groups. Compared with the healthy control group, the testosterone level in PMS patients of GYAS in the luteal phase showed increasing tendency (P > 0.05). The levels of dopamine and 5-HT of PMS patients of GYAS in the luteal phase were higher and the gamma aminobutyric acid level was lower than those of the healthy control group (all P < 0.05). The levels of adrenaline and noradrenaline of PMS patients of GYAS and GQSS in the luteal phase were higher than those of the healthy control group (all P < 0.05). The levels of allopregnanolone and pregnenolone of PMS patients of GYAS and GQSS in the luteal phase were lower, and the dehydroepiandrosterone level was higher than those of the healthy control group (all P < 0.05). The ratios of dehydroepiandrosterone/allopregnanolone and dehydroepiandrosterone/pregnenolone of PMS patients of GYAS and GQSS in the luteal phase were higher than those of the healthy control group (P < 0.05). CONCLUSION: The decreased levels of pregnenolone and allopregnanolone, increased dehydroepiandrosterone levels, and increased ratios of dehydroepiandrosterone/allopregnanolone and dehydroepiandrosterone/pregnenolone might be one of biological factors for anger and depression in PMS patients of GYAS and GQSS. PMID- 23359976 TI - [Effects of the renal blood flow at different levels by transcutaneous electrical acupoint stimulation combined general anesthesia induced controlled hypotension]. AB - OBJECTIVE: To observe the intervention of transcutaneous electrical acupoint stimulation (TEAS) on the renal blood flow at different levels of mean arterial pressure (MAP) in controlled hypotension. METHODS: Forty-two male beagle dogs were randomly divided into seven groups, i. e., the general anesthesia group, the 50% controlled group, the 40% controlled group, the 30% controlled group, the 50% experimental group, the 40% experimental group, and the 30% experimental group, 6 in each group. Beagles in the general anesthesia group were not treated with controlled hypotension, and the target MAP was achieved in those of the rest groups and maintained for 60 min. In the experimental groups, TEAS was applied to bilateral Hegu (LI4), Zusanli (ST36), Sanyinjiao (SP6), and Quchi (LI11) at 2/100 Hz with the stimulation strength of (4 +/- 1) mA starting from the stability of their physiological conditions to 60 min of maintaining the target MAP level. The changes of the renal blood flow were monitored at different time points using laser Doppler. RESULTS: From starting pressure control to the target MAP level, the renal blood flow was significantly lower in the 30% controlled group than in the general anesthesia group and the basic level of the same group (P < 0.05), while there was no obvious change in the 30% experimental group. In maintaining the blood pressure, the renal blood flow was significantly lower in the 50% controlled group, the 40% controlled group, the 30% controlled group, and the 30% experimental group than in the general anesthesia group (P < 0.05), while there was no obvious change in the 50% experimental group or the 40% experimental group. By the end of blood pressure recovery, the renal blood flow restored to the basic level in the 50% controlled group, the 50% experimental group, and the 40% experimental group (P > 0.05), while it was not restored to the basic level in the 40% controlled group, the 30% controlled group, and the 30% experimental group (P < 0.05). CONCLUSION: TEAS combined general anesthesia in controlled hypotension could effectively improve the renal blood flow, thus protecting the kidney. PMID- 23359977 TI - [Effects of shugan jianpi recipe on the ion transport of diarrhea predominant irritable bowel syndrome rat colon mucosa induced by 5-HT]. AB - OBJECTIVE: To investigate the mechanism of Shugan Jianpi Recipe (SJR) on the ion transportation of diarrhea predominant irritable bowel syndrome (IBS-D) colon mucosa induced by 5-HT. METHODS: Totally 36 male SD rats were randomly divided into three groups, i. e., the normal group, the model group, and the SJR group, 12 in each group. IBS-D Rat model was induced by intracolonic instillation of acetic acid and restraint stress. After successful modeling, normal saline was given to rats in the normal group and the model group, while SJR was given to those in the SJR group by gastrogavage for 14 days. The short circuit current (lsc) technology was used to measure 5-HT induced lsc changes of the colon mucosa under the actions of drugs and specific blocking agents. RESULTS: There was no difference in basal current (BC), the potential difference (PD), and transmembrane resistance (TR) of the distal colon among the 3 groups (all P > 0.05). The 5-HT induced short circuit current change (delta lsc) was lower in the model group than in the normal group (P < 0.05), and it was higher in the SJR group than in the model group (P < 0.05). When 4,4'-diisothiocyanato-stilbene 2,2'-disulfonic acid (DIDS, 500 micromol/L), an Ca(+)-dependent Cl- channel blocker, was added from the epiphragm of the colonic mucosa, the 5-HT induced delta lsc was lower in the model group than in the normal group (P < 0.05), and it was higher in the SJR group than in the model group (P < 0.05). When Na+ was substituted in the epiphragm solution (Na+ free) or amiloride (100 micromol/L) was added from the epiphragm of the colonic mucosa, an epithelial Na+ channel blocker, the 5-HT induced delta lsc was lower in the model group than in the normal group (P < 0.05), and it was higher in the SJR group than in the model group (P < 0.05). CONCLUSIONS: SJR could affect the transmembrane electrolyte transportation of IBS-D rat induced by 5-HT through regulating the secretion of Cl- and HCO3-. The effects might be achieved by the coordination of apical Cl- channel CFTR, basolateral Na(+)-K+ ATPase, sodium-potassium-chloride cotransporter, sodium-bicarbonate cotransporter, Cl-/HCO3- exchanger, as well as K+ channel. PMID- 23359978 TI - [The cytotoxicity of indirubin derivative PHII-7 against human breast cancer MCF 7 cells and its mechanisms]. AB - OBJECTIVE: To observe the cytotoxicity of indirubin derivative PHII-7 against human breast cancer MCF-7 cells and to study its primary mechanisms. METHODS: The proliferation of MCF-7 cells was detected using MTT colorimetry. Annexin V/PI double staining was applied to detect the apoptosis rate of MCF-7 cells. The distribution of cell cycles was detected using PI staining and flow cytometry (FCM). The levels of reactive oxygen species (ROS) in MCF-7 cells were detected by DCFH-DA staining. The mRNA and protein levels of c-fos were detected using RT PCR and Westem blot analysis. RESULTS: PHII-7 at different concentrations inhibited the proliferation of MCF-7 cells in a concentration-dependent manner, with the inhibitory rate ranging from 43.13% to 90.90% (P < 0.05). The inhibition was strengthened along with increased concentrations. PHII-7 at different concentrations could induce the apoptosis of MCF-7 cells. The early apoptosis rate was 1.43% +/- 0.02%, 9.14% +/- 0.36%, and 45.79% +/- 8.46%, respectively with the action of 1.25, 2.50, and 5.00 micromol/L PHII-7, respectively, showing dose-dependent manner. FCM analysis found that the proportion of MCF-7 cells in the G0/G1 phase and the S phase decreased after treatment with PHII-7, and the ratio of MCF-7 cells in the G2/M phase obviously increased (P < 0.01). The intra cellular ROS level was significantly elevated 2 h after pretreatment with PHII-7. The levels of the protooncogene c-fos mRNA and protein were down-regulated in a dose-dependent manner after action of PHII-7. CONCLUSIONS: PHII-7 exerted obvious in vitro cytotoxic effects on MCF-7 cells. Its mechanisms might be associated with arresting the cell cycle, regulating the redox equilibrium, and down regulating the expression of the protooncogene. PMID- 23359979 TI - [Effects of ru'ai shuhou recipe on the matrix metalloproteinases and the inhibitive factors in the recurrence and metastasis of HER2 positive breast cancer]. AB - OBJECTIVE: To observe the anti-tumor recurrent and metastatic efficacy of Ru'ai Shuhou Recipe (RSR) on HER2 positive breast cancer, to evaluate the effects of RSR on the expressions of matrix metalloproteinases (MMPs) and the tissue inhibitor of metalloproteinases (TIMPs) in the recurrence and metastasis of HER2 positive breast cancer, thus revealing its anti-tumor recurrent and metastatic mechanisms. METHODS: Selected were 30-week-old HER2/neu transgenic spontaneous breast cancer mice FVB/neu. The primary tumor resection was carried out. After surgery they were randomly divided into the blank control group, the RSR group, the Herceptin group, and the combination group (RSR + Herceptin group). The treatment lasted for 4 months. The inhibition rate of the recurrent tumor volume and the inhibition rate of the lung metastasis were evaluated. The expressions of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase (TIMP-1), and TIMP-2 in the recurrent tumor tissue were detected using Western blot. RESULTS: By the end of the treatment the average recurrent tumor volume was 11.11 +/- 8.71 cm3 in the blank control group and 5.56 +/- 5.55 cm3 of the RSR group, showing statistical difference between the two groups (P = 0.037). The average lung metastatic nodule was 16 in the blank control group and 10 in the RSR group. The inhibition rate of lung metastasis was 37. 85% in the RSR group, but with no statistical significance. The expression level of activated MMP-2 in the RSR group was down-regulated when compared with the blank control group, the Herceptin group, and the combination group (P < 0.05). The expression of MMP-9 of the RSR group, the Herceptin group, and the combination group was significantly down-regulated when compared with the blank control group (P < 0.05). The expression of MMP-9 of the RSR group and the combination group was further down-regulated when compared with the Herceptin group (P < 0.05). The expressions of both TIMP-1 and TIMP-2 of the RSR group, the Herceptin group, and the combination group were all up-regulated when compared with the blank control group (P < 0.05). The increased expression of TIMP-1 was more significantly in the RSR group and the combination group when compared with the Herceptin group (P < 0.05). It was higher in the combination group than in the RSR group (P < 0.05). CONCLUSIONS: RSR could inhibit the tumor recurrence of FVB/neu mice. It could reduce the degradation of extracellular matrix and increase the protective effects of extracellular matrix. It might achieve its anti-tumor effect through effecting the invasive and metastatic capabilities of breast tumor cells. PMID- 23359980 TI - [Effects of danzhi jiangtang Capsule combined exercise on pancreatic oxidative stress and islet beta-cell function in diabetic rats]. AB - OBJECTIVE: To explore the effects of Danzhi Jiangtang Capsule (DJC) and exercise on islet beta-cell function index (HOMA-% beta), blood glucose, and oxidative stress of diabetic rats. METHODS: A diabetic rat model was established using low dose streptozotocin and high fat forage in 60 male Wistar rats. The effects of exercise, DJC, and DJC combined exercise on the serum levels of fasting blood glucose (FBG), fasting insulin (FINS), triglyceride (TG), total cholesterol (TC), as well as the activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and malondialdehyde (MDA) in the pancreatic tissue were observed. The HOMA-%beta was also calculated. The main factors that affecting HOMA-%beta were explored using multi-factor regression analysis. RESULTS: Compared with model group, the levels of FBG, TG, TC, and pancreatic MDA were significantly reduced after intervention of exercise or DJC (P < 0.05, P < 0.01), while HOMA-% beta obviously increased (P < 0.01). The pancreatic GSH-Px activity significantly increased in the exercise group (P < 0.01). Exercise and DJC had synergistic effects on FBG, TG, HOMA-% beta, pancreatic SOD, and GSH-Px activities (P < 0.05). There was a negative and linear regression correlation between FBG and pancreatic SOD and GSHPx activities. HOMA-%beta was negatively correlated with FBG, TG, TC, and pancreatic MDA content, and positively correlated with SOD and GSH-Px activities. Besides, there was a linear regression correlation between HOMA-%beta and FBG. CONCLUSION: Exercise and DJC played synergistic effects, could improve the glucose and lipid metabolisms and enhance antioxidant activities, thus relieving the injury of pancreatic beta cells. PMID- 23359981 TI - [Effects of ginsenoside Rb1 on the oxidative stress in the skeletal muscles of rats with postoperative fatigue syndrome]. AB - OBJECTIVE: To observe the effects of ginsenoside Rb1 (GRb1) on the oxidative stress in the skeletal muscles of rats with postoperative fatigue syndrome (POFS) and to study its anti-fatigue mechanisms. METHODS: The POFS model was established using resection of 70% of mid-small intestine. Ninety-six Sprague-Dawley (SD) rats were screened using grasping test. The rats were randomly divided into the control group, the model group, and the GRb1 treated group (at 10 mg/kg) by the body weight. The maximum grip strength of rats was detected on the 1st, 3rd, 7th, and 10th day after operation, respectively. The contents of malondialdehyde (MDA), the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) were detected. RESULTS: Compared with the model group, the maximum grip strength was obviously enhanced on the postoperative day 7 and 10 (P < 0. 05), the MDA content obviously decreased on the postoperative day 3 and 7 (P < 0.05), the SOD activity obviously increased in the GRb1 treated group (P < 0.05). There was no obvious change in the activities of CAT and GSH-PX among the three groups at each time point (P > 0.05). CONCLUSION: GRb1 could reduce the oxidative stress injury in the skeletal muscles, improve the activities of antioxidant enzymes, and enhance the functions of the skeletal muscles in POFS rats, which may be important reasons for fighting against POFS. PMID- 23359982 TI - [Effects of intrathecal injection of ginsenoside Rg1 on the level of glutamate transporter in the arthritis rats with chronic morphine tolerance]. AB - OBJECTIVE: To investigate the effects of intrathecal injection of ginsenoside Rg1 at different doses on the changes of the behavior and the expressions of excitatory amino-acid transporter 1 (EAAT1), i. e., glutamate-aspartate transporter (GLAST) in the spinal dorsal horn of the arthritis rats with chronic morphine tolerance, and further to explore its mechanisms for morphine tolerance. METHODS: After successful intrathecal injection, an adjuvant arthritis model was established in 36 healthy male SD rats. They were randomly divided into 6 groups, 6 in each group. They were intrathecally injected with 10 microL normal saline (Group NS), 10 microg morphine (Group M), 10 microg morphine + 50 microg ginsenoside Rg1 (Group MG50), 10 microg morphine +100 microg ginsenoside Rg1 (Group MG100), 10 microg morphine + 200 microg ginsenoside Rg1 (Group MG200), and 100 microg ginsenoside Rg1 (Group G100), respectively. The normal saline and morphine were intrathecally injected twice daily, while ginsenoside Rg1 at different doses was intrathecally injected once daily, for 7 successive days. Fifty percent mechanical paw withdrawal threshold (PWT) was dynamically detected to evaluate their behaviors. The rats were sacrificed on day 7 after medication. The L3-L5 segment of the spinal cord was isolated for determining the expression of GLAST in the spinal dorsal horn using immunofluorescence staining. RESULTS: The PWT of Group M was significantly higher than that of Group NS on the 1st and 3rd day after medication (P < 0.05). But it was gradually shortened along with the increasing days of medication. There was no statistical difference between Group M and Group NS on the 7th day (P > 0.05), indicating the formation of morphine tolerance. The PWT of Group MG100 also showed a decreasing tendency, but obviously slower than that of Group M (P < 0.05). The PWT of Group G100 was higher than that of Group NS (P < 0.05). Compared with Group NS, the expression of GLAST in the spinal dorsal horn of rats in Group M was down-regulated (P < 0.01). Compared with Group M, the expression of GLAST in the spinal dorsal horn of rats in Group MG100 and Group G100 was up-regulated (P < 0.05). CONCLUSIONS: Single application of ginsenoside Rg1 showed mild antinociceptive effect in adjuvant-induced arthritis rats. Intrathecal injection of 100 microg ginsenoside Rg1 could attenuate the formation of morphine tolerance. Its mechanisms might be correlated with up-regulating of the expression of GLAST. PMID- 23359983 TI - [Effects of xinfeng capsule on the cardiac function and the myocardial ultrastructure in rats with adjuvant arthritis]. AB - OBJECTIVE: To observe the effects of Xinfeng Capsule (XC) on the cardiac function and the myocardial ultrastructure in rats with adjuvant arthritis (AA). METHODS: Sixty rats were randomly divided into the normal control group, the model group, the methotrexate (MTX) treated group, the Tripterygium Glycosides Tablet (TGT) treated group, and the XC treated group, 12 in each group. Except those in the normal control group, rats in the rest groups were induced to establish the AA model by intradermally injecting Freund's complete adjuvant into their right paws. The medication was started from the 19th day. Normal saline was administered to rats in the normal control group and the model group. MTX, TGT, and XC was respectively administered to rats in the MTX, TGT, and XC groups. The medication lasted for 30 days. The swelling degree of voix pedis, arthritis index (AI), the heart function, serum levels of cytokines, and the myocardial ultrastructure were observed. RESULTS: (1) Compared with the normal control group, the swelling degree of voix pedis and AI significantly increased (P < 0.01), the body weight significantly decreased (P < 0.05) in the model group and the other 3 treated groups. (2) Compared with the model group, the heart index (HI), left ventricular systolic pressure (LVSP), and left ventricular end diastolic pressure (LVEDP) significantly decreased (P < 0.05, P < 0.01), the maximum rate of left ventricular pressure of development or decline (+/- dp/dt(max)) significantly increased (P < 0.05, P < 0.01). Compared with the MTX treated group, the LVSP and LVEDP significantly decreased (P < 0.05), and +/- dp/dtmax significantly increased (P < 0.05). (3) Compared with the model group, TNF-alpha, brain natriuretic peptide (BNP), and IL-17 significantly decreased (P < 0.05, P < 0.01); IL-10, CD4+, CD4+ CDA25+ significantly increased (P < 0.05, P < 0.01). Compared with the MTX treated group, IL-17 significantly decreased (P < 0.05), CD4+ CD25+ expression significantly increased in the XC group (P < 0.05). (4) Transmission electron microscopy showed that myocardial ultrastructure was basically contact in the XC treated group, approaching to that of the normal control group. CONCLUSIONS: Decreased cardiac function and damaged myocardial ultrastructure existed in AA rats. XFC could ameliorate the swelling degree of voix pedis and AI, as well as improve the heart function. Its mechanisms might be correlated with down-regulating serum levels of inflammatory factors, up regulating the expressions of anti-inflammation factors, thus improving the myocardial ultrastructure and protecting injured myocardial cells. PMID- 23359984 TI - [Effects and mechanisms of zuogulyin on the ovarian NO production in peri menopausal rats]. AB - OBJECTIVE: To study the effects and mechanisms of Zuoguiyin (ZGY) on the ovarian nitric oxide (NO) production in peri-menopausal rats. METHODS: The peri menopausal model rats were respectively administered with low (13.78 g/kg), middle (20.67 g/kg), and high (31.00 g/kg) dose ZGY, and nilestriol for 8 weeks. Normal saline was given by gastrogavage to rats in the model group and the young control group (as the control group). The ovarian NO content and the activity of total nitric oxide synthase (NOS) were detected using nitrate reductase method and chemical colorimetry respectively. The mRNA and protein expressions of inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS) were detected using RT-PCR and immunohistochemical assay. RESULTS: (1) Compared with that in the control group, the ovarian NO content and the activity of total NOS in peri-menopausal rats were significantly lower (P < 0.01). Middle and high dose ZGY could obviously up-regulate them (P < 0.01, P < 0.05). (2) The three kinds of NOS expression levels in perimenopausal rats were obviously lower when compared with those of the control group (P < 0.01). Middle dose ZGY could significantly promote all the three kinds of NOS expression levels of pre-senile rats (P < 0.01). High dose ZGY could up-regulate the expressions of iNOS and eNOS, while low dose ZGY could only enhance the iNOS expression (P < 0.01). CONCLUSIONS: The down-regulated expressions of eNOS, iNOS, and nNOS in local ovaries resulted in decreased NOS activity and NO production, which were closely correlated with damaged microcirculatory vascular functions of ovaries in peri-menopausal rats. ZGY could protect rats' ovarian microcirculation by up-regulating the expressions of eNOS, iNOS, and nNOS, and enhancing the ovarian NOS activity and NO production. PMID- 23359985 TI - [Effects of zhuyun recipe on the endometrial receptivity in mice with blastocyst implantation dysfunction and ovulation stimulation]. AB - OBJECTIVE: To study the effects and underlying mechanisms of Zhuyun Recipe (ZR) on the endometrial receptivity in ovarian stimulation (OS) and blastocyst implantation dysfunction (BID) mice. METHODS: Totally 200 normal female Kunming mice were randomly divided into 6 groups, i. e., the control group (Group A), the OS group (Group B), the OS + ZR group (Group C), the BID group (Group D), the BID + ZR group (Group E), and the ZR group (Group F). The pregnant mare's serum gonadotrophin (PMSG) and human chorionic gonadotrophin (HCG) were intraperitoneally injected to mice in Group B. Mifepristone was subcutaneously injected to mice in Group D at 9:00 am on the 4th gestation day. Corresponding medications were given to mice in Group C, E, and F at 1.5 mL/100 g by gastrogavage at 8:00 am from the first to the 4th gestation day. Eight uterus samples were collected at 9:00 pm on the 4th gestation day and fixed. The expression levels of leukemia inhibitory factor (LIF) and integrin beta3 were detected using immunohistochemical assay. The pregnant mice were sacrificed at 9:30 pm on the 8th gestation day, and their uterus were taken out. The number of blastocysts was counted. RESULTS: Compared with Group A, the pregnant rate was 6.67% (1/15 cases) in Group B and 18.75% (3/16 cases) in Group D, the mean OD value of LIF was 0. 18 +/- 0.02 in Group B and 0.23 +/- 0.02 in Group D, and the mean OD value of integrin beta3 was 0.20 +/- 0.05 in Group B and 0.19 +/- 0. 02 in Group D, showing statistical difference (P < 0.01). The pregnant rate was 54.55% (12/22 cases) in Group C and 65. 22% (15/23 cases) in Group E, the mean OD value of LIF was 0.37 +/- 0. 09 in Group C and 0.39 +/- 0.02 in Group E, and the mean OD value of integrin beta3 was 0.34 +/- 0.04 in Group C and 0.38 +/- 0.08 in Group E, showing statistical difference when compared with those of Group B and Group D respectively (P < 0.05). CONCLUSIONS: OS and BID had negative effects on the endometrial receptivity and hindered the blastocyst implantation. ZR could improve the uterine receptivity and elevate the pregnant rate by up-regulating the expressions of endometrial LIF and integrin beta3. PMID- 23359986 TI - [Research of luyuan capsule leachate on the in vitro maturation of dendritic cells of adult peripheral blood]. AB - OBJECTIVE: To investigate the effect of Luyuan Capsule (LYC) leachate on the proliferation and maturation of dendritic cells (DCs) of adult peripheral blood. METHODS: Totally 100 mL peripheral blood was collected from 4 healthy males. The peripheral blood mononuclear cells were isolated using density gradient centrifugation. The precursor DCs were obtained using wall adherent culture. The immature DCs with recombinant human GM-CSF (rhGM-CSF) and recombinant human IL-4 (rhlL-4) added were harvested for 7 days to get immature DCs. The immature DCs cultured with 1% LYC leachate for two days were taken as the experimental group, while the immature DCs cultured with 20 ng/mL recombinant human TNF-alpha (rhTNF alpha) for two days were taken as the control group. The morphology of DCs was observed by inverted phase contrast microscope, and the cell proliferation was detected by cell counting. The DCs specific marker CD83 was analyzed using flow cytometry. RESULTS: The proliferation capacities of DCs were improved in the experimental group. More and longer dendritic protrusions and possess were shown on the surface of DCs in the experimental group than in the control group. The CD83 expressions was obviously higher in the experimental group (84.1% +/- 0.3%) than in the control group (58.7% +/- 0.2%), showing statistical difference (P < 0.05). CONCLUSION: 1% LYC leachate could promote the maturation and proliferation of peripheral blood DCs, stronger than that of 20 ng/mL rhTNF-alpha. PMID- 23359987 TI - [Study on microRNA and Chinese medicine syndromes of coronary artery disease]. AB - MicroRNA (miRNA) is single-stranded small non-coding RNA, which binds to the 3'untranslated region of the target mRNAs and negatively regulates the expression of the target mRNAs by translational inhibition or miRNA cleavage. miRNA plays an important role in regulating the occurrence and progression of coronary artery disease (CAD), and could be potential biomarkers and treatment targets of CAD. The syndrome typing is the superiority and feature for treating CAD by Chinese medicine (CM). To master the space-time qualitation and quantitation is the key step in improving the clinical efficacy of treating CAD. The specificity and sequence of miRNA are very similar to the dynamic space-time features of syndromes. Besides, miRNA is closely correlated with CAD. Therefore, by using miRNA microarray and bioinformatics to build CM syndrome correlated miRNA regulating networks, miRNA can be introduced to study the CM syndromes of CAD, thus providing a new angle to elucidate the essence of CM syndrome of CAD at the post-transcriptional level. PMID- 23359988 TI - [On the loss and transmission of cultural image in translating Chinese medicine formulae names]. PMID- 23359989 TI - [The overview of chronic allograft nephropathy treated by integrative medicine]. PMID- 23359990 TI - [The current state and prospect of Chinese medical researches on endometriosis related infertility]. PMID- 23359991 TI - In-vitro shoot regeneration via caulogenesis in fern, Pteris vittata L. AB - An attempt was made to standardize the protocol for the shoot regeneration via caulogenesis in Pteris vittata L. employing leaf primordium explants. Calli were induced on Murashige and Skoog's (MS) and Parkers and Thompson's (P and T) media supplemented with different combinations of 2, 4-dichlorophenoxyaceticacid (2, 4 D), 6-benzylaminopurine (BAP), alpha-naphthalene acetic acid (NAA) and Indole-3 acetic acid (IAA). A combination of full strength MS medium with 2, 4-D (2.26 microM) and BAP (2.22 microM) was found to be ideal for profuse callusing (80%) against other combinations. More shoot differentiation (2.8 +/- 0.06) was achieved from the calli on one-fourth strength of P and T media fortified with BAP (4.44 microM) and NAA (2.68 microM) when compared to other combinations but statistically not significant. PMID- 23359992 TI - Evaluation of potable groundwater quality in some villages of Adilabad in Andhra Pradesh, India. AB - Reconnaissance hydrochemical survey was conducted in some villages of Adilabad district, Andhra Pradesh to assess the quality of groundwater, which is mainly used for drinking purpose. The study consists of the determination of physico chemical properties, trace metals, heavy metals and rare earth elements in water samples. The data showed the variation of the investigated parameters in samples as follows: pH 6.92 to 8.32, EC 192 to 2706 microS cm(-1), TDS 129.18 to 1813.02 ppm. The pH of the waters was within the permissible limits whereas EC and TDS were above the permissible limits of World Health Organization (WHO). Total 27 elements (Li, Be, B, Na, Mg, Al, Si, K, Ca, V, Cr, Mn, Fe, Ni, Co, Cu, Zn, As, Se, Rb, Sr, Mo, Ag, Cd, Sb, Ba and Pb) were analyzed using Inductively Coupled Plasma-Mass Spectrometer (ICP-MS). The concentration of elements in water samples ranged between 0.063 to 0.611 mg l(-1) for B, 11.273 to 392 mg l(-)1 for Na, 5.871 to 77.475 mg l(-1) for Mg, 0.035 to 1.905 mg l(-1) for Al, 0.752 to 227.893 mg l(-1) for K, 11.556 to 121.655 mg l(-1) for Ca and 0.076 to 0.669 mg l(-1) for Fe respectively. The concentrations of Na, Mg, Al, K, Ca, and Fe exceeded the permissible limits of WHO and BIS guidelines for drinking water quality. In the present study, Bhimavaram, Kazipalli, Kannepalli and Chennur areas of the Adilabad are especially prone to geogenic contamination. Overall water quality was found unsatisfactory for drinking purposes. PMID- 23359993 TI - Effect of sodium nitroprusside on morphological characters under chilling stress in chickpea (Cicer arietinum L.). AB - An experiment was conducted with chilling tolerant (IC-424234) and sensitive (PBG 1) chickpea (Cicer arietinum L.) genotypes to study the effect of sodium nitroprusside (SNP)- nitric oxide donor applied as foliar spray of 150 and 300 microM concentrations at 45 DAS (vegetative stage), 85 DAS (flowering stage) and 125 DAS (post flowering stage). Both the concentrations of SNP (150 and 300 microM) resulted in significant increase in all the morphological characters viz. plant height, number of leaves plant1, leaf area plant(-1) and leaf area index (LAI) over the control at all the stages, though lower concentration (150 microM) was more effective. Chilling sensitive (CS) genotype PBG-1 responded more effectively to SNP treatment. Electrolyte leakage percentage was effectively reduced by SNP treatments in both the genotypes at low temperature (15 DAA). Chilling sensitive genotype PBG-1 treated with SNP (150 microM) recorded significantly higher yield contributing characters viz. number of pods plant1, number of seeds pod(-1), seed yield plant1(g), pod setting percentage (%), 100 seed weight (g) and yield (kg ha(-1)) over the chilling tolerant (IC-424234) PMID- 23359994 TI - Identification of DNA damage in marine fish Therapon jarbua by comet assay technique. AB - The marine fish Therapon jarbua was exposed to acute concentration of mercuric chloride (HgCl2). In static acute toxicity bioassays at 24, 48, 72 and 96 hr LC50 values were estimated for each concentrations such as control, 2, 1, 0.5, 0.25 and 0.125 ppm, respectively. DNAdamage (single-strand break) was also studied in gill, kidney and blood tissues at single-cell levels in the specimens exposed to different acute doses of HgCl2, by applying single-cell electrophoresis (comet assay). Dose-dependent responses were observed in DNA damage in all tissues. A comparison of DNA damage in all tissue at two concentration namely, 0.125 and 0.25 ppm indicated that the gill cells (maximum damage as 249.3 and 289.7 AU) were more sensitive to the heavy metal exposure than kidney (maximum 225.17 AU) and blood cells (maximum 200.3 AU). This study explored the utility of the comet assay for in vivo laboratory studies using fish for screening the genotoxic potential for various agents. PMID- 23359995 TI - Distribution of enteric bacteria in the sediments of Parangipettai and Cuddalore coast of India. AB - Distribution of major groups of enteric bacteria viz., Escherichia coli, Shigella spp., Salmonella spp., Vibrio parahaemolyticus and Vibrio cholerae was studied in the sediment samples collected from different depths of 5, 15, 25 and 35 m in Parangipettai and Cuddalore coast during March, 2009 to February, 2010. Among the bacterial population in Parangipettai, V parahaemolyticus was found to be maximum with an occurrence of 55% followed by Shigella spp. (15%), V cholerae (12%), Salmonella spp. (12%) and E. coli (6%). In Cuddalore, as an oddity, Vibrio cholerae emerged as dominant species with an incidence of 60% of the total. V parahaemolyticus came next in the order with an incidence of 14%, followed by E. coli (11%), Shigella spp. (8%) and Salmonella spp. (7%). Similarly, monsoon and premonsoon seasons registered higher bacterial populations in both the regions. When the depth wise results were viewed, 5 and 15 m depths showed maximum (V parahaemolyticus 3.7 x 10 CFU g(-1) in Parangipettai; V cholera--8.6 x 10 CFU g( 1) in Cuddalore) bacterial population compared to subsequent depths. Cluster and MDS also showed distinct spatial and seasonal variations of bacterial populations in both the regions. Biota-Environment (BIO-ENV) method revealed the combinations of temperature, salinity and TOC as the best match influencing bacterial population. PMID- 23359996 TI - Effects of five earthworm species on some physico-chemical properties of soil. AB - An incubation experiment was conducted to study the changes that occur in organic carbon content, phosphorous and potassium availability and other soil properties with ingestion of soil mixed with rubber leaf litter and cow dung by five earthworm species viz. Pontoscolex corethrurus, Drawida assamensis, Drawida papillifer papillifer, Eutyphoeus comillahnus and Metaphire houlletiof rubber plantation in Tripura (India). Due to earthworm activity organic C (1.56-1.63%) and available P (14.71-27.60 mg 100 g(-1)) and K (43.50-49.0 mg 100 g(-1)) content of the soil increased significantly (p < 0.05) in most of the earthworm species studied. M. houlleti and D. papillifer papillifer had the highest P (27.60 mg 100 g ) and K (49.0 mg 100 g ) mobilization capacity, respectively. Earthworms, irrespective of the species, increased the pH (7.05-7.17) and electrical conductivity (663-1383 microS cm(-1)) of the soil significantly (p < 0.05). PMID- 23359997 TI - Biodegradation of anionic surfactant, sodium dodecyl sulphate by Pseudomonas aeruginosa MTCC 10311. AB - The anionic surfactant sodium dodecyl sulphate (SDS), the core components of detergent and cosmetic product formulations, contributes significantly to the pollution profile of sewage and wastewater of all kinds. In this study, 44 SDS degrading strains were isolated by soil enrichment methods and the utilization efficiency was assessed by methylene blue active substances (MBAS) assay and High performance liquid chromatography (HPLC) method. Isolate S2 which showed maximum degradation was identified as Pseudomonas aeruginosa MTCC 10311 based on phenotypic features and 16 S rDNA typing. The isolate was found to harbor plasmid within the size range of 9-10 kb. The cured derivative of SDS degrading Pseudomonas aeruginosa was obtained at a frequency of 10.7% by incubation with ethidium bromide (500 mg ml(-1) at 40 degrees C. 96% of SDS degradation occurred at 1500 ppm level within 48 hr of incubation, whereas higher concentration of SDS (10000 ppm) showed only 20% degradation. The optimum temperature and pH was 30 degrees C and 7.5, respectively. The additional supplementation of carbon and nitrogen source increased the degradation capacity from 93 to 95% and 90 to 96% respectively within 36 hrs of incubation. PMID- 23359998 TI - In vivo interactions of entomopathogenic fungi, Beauveria spp. and Metarhizium anisopliae with selected opportunistic soil fungi of sugarcane ecosystem. AB - In the present study, the interactions of entomopathogenic fungi viz., Beauveria bassiana, Beauveria brongniartii and Metarhizium anisopliae among themselves and three other opportunistic soil fungi from the sugarcane ecosystem namely, Fusarium saachari, Aspergillus sp. and Penecillium sp. were assayed in vivo against Galleria mellonella larvae. The tested fungi were co-applied on IV instar G. mellonella @ 1 x 10(7) ml(-1), in combinations of two, at the interval of 24 hrs either preceding or succeeding each otherto assess their efficacy and sporulation rates. Results showed that often mortality rates did not correspond to the spore harvest of the mortality agent and presence of other fungus may be antagonistic. The efficacy of B. bassiana (90%) and B. brongniartii (100%) was not enhanced further but was negatively affected in most combinations with other fungi. In case of M. anisopliae compatibility was higher, resulting in higher mortality by application of B. bassiana before (100%) or after (83.3%) M. anisopliae than when it was applied alone (70%). During sporulation, B. bassiana faced the most intense competition from M. anisopliae (2.75 x 10(6) larva(-1)) and enhancement due to F sacchari irrespective of sequence of application. In case of B. brongniartii, sporulation was lowest in the combination of B. brongniartiipreceding M. anisopliae (1.83 x10(6) larva(-1)) and B. brongniartii succeeding B. bassiana (1.58 x 10(6) larva(-1)). Of all fungi tested, except F sacchari (65.33 x 10(6) larva(-1)) all the other species affected sporulation of M. ansiopliae with the least in treatment of B. bassiana application following M. anisopliae. Similar kind of interaction was observed during sporulation of soil fungi when combined with entomopathogenic fungi, though individually they could not cause mortality of larvae. PMID- 23359999 TI - Environmental monitoring of adulterated gasoline with kerosene and their assessment at exhaust level. AB - Fuel adulteration increases the emission of total hydrocarbons, carbon monoxide, nitrogen oxides and respirable particulate matter, and thus adds to air pollution. The study examined the effects of mixing of different percentage of kerosene with petrol on the motorized rickshaw exhausts in terms of volatile organic compounds (benzene, toluene, xylene and ethyl benzene) and total suspended particulate matter (SPM). The personal sampler was used for sampling, and gas chromatography-mass spectrometry for quantification of compounds. Concentration of volatile organic compounds significantly decreased (p < 0.001) along with the increase in fraction of kerosene in petrol. The level of benzene in exhausts while, using petrol (100%) was significantly higher (p < 0.001) than that of three combinations used in this study (75% petrol + 25% kerosene, 50% petrol + 50% kerosene and 25% petrol + 75% kerosene). Similar trend was observed for toluene, xylene and ethyl benzene also. The mean concentration of benzene, toluene, xylene and ethyl benzene were 31.34,160.93, 10.07 and 5.58 microg m(-3) in pure petrol, while 12.30, 51.41,4.89 and 3.16 microg m(-3) for fuel combination 75% petrol + 25% kerosene. The observed levels of benzene, toluene, xylene and ethyl benzene were 9.12, 41.04, 4.33 and 2.91 microg m(-3) for fuel mixture having 50% petrol with 50% kerosene and levels were 8.36, 20.05, 3.82 and 2.95 microg m(-3) were for 25% petrol with 75% kerosene fuel combination. The levels of suspended particulate matter (SPM) increased along with the increase in fraction of kerosene in petrol. The data generated is useful to understand the common volatile organic compounds trend with the increasing fraction of kerosene in petrol. PMID- 23360000 TI - Morphological changes in the gills of Heteropneustes fossilis (Bloch) exposed to coal mining effluent water. AB - Ultrastructural changes in the gills of cat fish Heteropneustes fossilis exposed to coal mining effluent water collected from Rymbai river in Jaintia hills, Meghalaya, India was investigated under scanning electron microscopy (SEM). The pH of effluent water in the river was significantly low (2.5-3.0) due to coal mining activity in the adjacent areas. The dissolved oxygen (DO) was 7.7 mg l(-1) and conductivity 0.93 mS. Morphological changes like dissociation of the epithelium (E) of branchial arches and gill filaments, hypertrophy and disorientation in the array of lamellae were observed in the treated fish, leading to fish death. The primary and secondary gill lamellae (PL and SL) exhibited fusion, distortion and loss of alignment. Some of the gill rackers showed necrosis at certain places. The morphological features of the gills as revealed through SEM were highly deteriorated when compared to control. PMID- 23360001 TI - Seasonal variations and biodiversity of zooplankton in Harsool-Savangi dam, Aurangabad, India. AB - The present study concerns seasonal variations, correlation coefficient and biodiversity indices of zooplanktons during January-December, 2008 in the Harsool Savangi dam, Aurangabad, India. A total of 25 genera were recorded of which 10 were Rotifers, 8 Cladocerons, 5 Copepods and 2 Ostracods. Present study revealed maximum percentage wise compositions of Rotifers at north site were 58.28%, Cladocerons at south site were 29.78%, Copepods at east site were 16.59% and Ostracods at south site were 4.20%, respectively. Minimum percentage wise compositions Rotifers at south site were 51.54%, Cladocerons at west site were 26.71%, Copepods at north site were 11.03% and Ostracods at north site were 1.36%, respectively. Margalefs index (R1) and Menhinick index (R2) values (3.58 and 0.87) were found to be the highest at south site and lowest at (3.16 and 0.56) north site. Simpson's index (I) values (0.43) were found to be the highest at north site and lowest (0.37) at south site. Shannon-Weiner index (H') values (1.06) were found to be the highest at south site and lowest values (0.94) at north site. Maximum species evenness was recorded at south site while minimum species evenness was recorded at north site. Maximum population density of Rotifers, Cladocerons, Copepods and Ostracods (799, 350, 163 and 18) were recorded at north site in summer and minimum (58, 35, 22 and 13) were recorded at south site in monsoon, respectively. PMID- 23360002 TI - Effect of fluoride pollution on genetic diversity of a medicinal tree, Syzygium cumini. AB - Syzygium cumini Linn. (Myrtaceae) is a medicinal tree (Jamun) used worldwide in treatment of diabetes. However, no molecular data is available on genetic polymorphism and its relationship, if any with fluoride pollution. In the present study, the genetic variability of two populations of S. cumini growing in fluoride rich soils and normal soils located in Rajasthan and Haryana regions of India, respectively was determined using random amplified polymorphic DNA (RAPD) markers. Different measures of diversity in Rajasthan populations: Shannon's index of phenotypic diversity (I) = 0.440; Nei's genetic diversity (h) = 0.292; effective number of alleles per locus (Ne) = 1.497; total species diversity (Hsp) = 0.307 and within population diversity (Hpop) = 0.158 showed high diversity in comparison to Haryana populations. Thus, it seems that Rajasthan population responds with increased genetic variation resulting possibly from new mutation that affect allele frequencies as a consequence of adaptation to contaminated environment. This may imply that the increased diversity levels may act as a buffer to combat fluoride stress. Cluster analysis and principal component analysis (PCA) results showed mixing between the populations. PMID- 23360003 TI - Impact of coal mining on soil characteristics around Ib river coalfield, Orissa, India. AB - The present article deals with soil analysis around five opencast coal projects of Ib river coalfield during pre-monsoon (March), monsoon (July) and post monsoon (November) periods of successive three years (i.e., 2006, 2007 and 2008). Sampling of soil has been done from the vertical surface of the overburden at successive depths of 0-5 ft, 5-10 ft and at 10-15 ft. The different physical (soil texture, soil moisture, particle density, bulk density and porosity) and chemical (pH, organic carbon, nitrogen, phosphorus and potassium) parameters have been analysed. The soil textures of the study area are found to be loamy sand to loam, loam to silty loam and clay loam to silty clay loam in the depth of 0-5 ft, 5-10 ftand at 10-15 ft, respectively. The moisture content (7.297 at 0-5ft, 5.25 at 5-10 ft and 4.134% at 10-15 ft) and porosity (43.994 at 0-5 ft, 40.682 at 5-10 ft and 35.85% at 10-15 ft) of the soil in the study area decreased gradually from the surface to greater depth. However, the particle density (2.639 at 0-5 ft, 3.11 at 5-10 ft and 3.523 g cc(-1) at 10-15 ft) and the bulk density (1.478 at 0 5ft, 1.839 at 5-10 ft and 2.269 g cc(-1) at 10-15 ft) in this region increased from surface to the deeper region of the soil. The organic carbon (1.367 at 0-5 ft, 0.9 at 5-10 ft and 0.396 kg ha(-1) at 10-15 ft), nitrogen (2.845 at 0-5 ft, 1.059 at 5-10 ft and 0.48 kg ha(-1) at 10-15 ft) and phosphorus level (1.11 at 0 5 ft, 0.715 at 5-10 ft and 0.679 kg ha(-1) at 10-15 ft) of the soil decreased with increasing depth of the soil. However, the content of potassium (2.636 at 0 5 ft, 4.374 at 5-10 ft and 5.82 kg ha(-1) at 10-15 ft) increased gradually from the surface to the greater depth. Analysis of variance is computed to infer the variation in the concentration of parameters in different open cast coal projects and in various depths of the study area. PMID- 23360004 TI - Analysis of heavy metals in dying wetland Pallikaranai, Tamil Nadu, India. AB - Pallikaranai wetland has high ecological significance as it has been a home for other associated biodiversities. This wetland is highly polluted due to the rapid industrialization, urbanization and dumping of solid waste. The water quality of the Pallikaranai wetland has been studied with reference to toxic metals. The metals analyzed include lead, chromium, iron, copper, nickel, zinc and cadmium. The heavy metal analysis in surface waters were in the following range; Cd: BDL- 0.019 mg l(-1), Fe: BDL--1.52 mg l(-1), Cu: BDL--0.02 mg l(-1), Ni: BDL-0.60 mg l(-1), Pb: 0.03-1.13 mg l(-1), Zn: 0.002-0.14 mg l(-1) and Cr: 0.10-1.52 mg l(-1) respectively. The dominance of various heavy metals in the surface water of the Pallikaranai wetland followed the sequence: Pb > Cr > Fe > Ni > Zn > Cd > Cu. The quality of water has deterioted due to the various anthropogenic activities. Most of the metal ions were in higherconcentration compared to the standards. It has been observed that the quality of the surface water is not safe for aquatic and domestic life, hence necessary management actions should be taken to control the quality of the surface water. PMID- 23360005 TI - Analysis of lactate and malate dehydrogenase enzyme profiles of selected major carps of wetland of Calcutta. AB - The East Calcutta Wetland (ECW), a Ramsar site in India, acts as the only sink for both city sewages as well as effluents from the surrounding small-scale industries and is alarmingly polluted with heavy metals. The three best edible major carp species rohu (Labeo rohita,), catla (Catla catla,) and mrigala (Cirrhinus mrigala) were undertaken to monitor lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) by cellulose acetate electrophoresis (CAE) to assess the effects of pollutants, if any. Crude tissue extracts were prepared from brain, eye, heart, skeletal muscle and kidney tissue respectively from each type of fish. No differences were not found in MDH of catla from both sites for all tissues analyzed in this study. Rohu also showed similar mobility for all tissues except for heart tissue which was distinctly different in fishes from ECW site than that of its counterpart from non ECW site. On the other hand, MDH of two tissues of mrigala, eye and muscle respectively showed different migration patterns. LDH profiles for all tissues of three fish species from both the sites were consistently similar, only the expression levels of muscle LDH of mrigala and kidney LDH of rohu varied little. PMID- 23360006 TI - Correlation of total heterotrophic bacterial load in relation with hydrographical features of Pazhayakayal estuary, Tuticorin, India. AB - An investigation was made on total heterotrophic bacterial (THB) load in relation with hydrographical features of Pazhayakayal estuary, Tuticorin, from July 2009 to June 2010. The watertemperature (25 to 32 degrees C), pH (7 to 10), and salinity (0 per thousand to 35.7 per thousand) were maximum during summer season (April-June) and minimum during monsoon season (October-December). The dissolved oxygen (DO) varied from 0.2 to 9.95 mg l(-1). The THB load was high (42.0 x 10( 7) cfu m(-1)) during monsoon season and low (1.2 x 10(-7) cfu ml(-1)) during summer. The correlation was insignificant between temperature, pH and THB load, however THB load was negatively correlated with salinity. Almost in all the stations (I-VI), THB load were found to be maximum (40.0 x 10(-7), 36.0 x 10(-7), 30.0 x 10(-7), 36x10(-7), 42.0 x 10 x 10(-7) and 29.6 x 10(-7) cfu ml(-1)) during monsoon season might be due to the bulk rainfall and freshwater input. PMID- 23360007 TI - Studies on antimicrobial efficacy of medicinal tuberous shrub Talinum cuneifolium. AB - Talinum cuneifolium (Vahl.) Willd. an erect shrub with subterranian tuber (Portulacaceae) is endowed with wide range of pharmacological activities. The antimicrobial efficacy of the plant is evaluated against three bacteria and two fungal species by disc diffusion method. Preliminary phytochemical screening was carried out among hexane, ethylacetate, methanolic extracts of leaf and roottuber for different potent chemicals. The leaf methanolic extract of T cuneifolium showed maximum effect on the growth of Proteus (25.8 mm) followed by Bacillus (24.62 mm) and E. coli (19.42 mm). The tuberous methanolic extract of T cuneifolium showed maximum effect on growth of Proteus (28.15 mm) followed by Bacillus (26.88 mm) and E. coli (24.51 mm). The Gram-positive bacterial strains (Bacillus) were more susceptible to the extractions of T cuneifolium as compared to Gram-negative bacteria (E. coli, Pseudomonas aeruginosa, Proteus vulgaris and Klebsiella pneumoneia). The antifungal activity of selected plant leaf and root tubers exhibit pronounced activity against Candida albicans rather than Aspergillus niger. These studies showed that the methanolic extracts of T cuneifolium plant parts were certainly much better and powerful. This may be due to the better solubility of the action components in organic solvent. PMID- 23360008 TI - Studies on genetic divergence among Indian varieties of a spice herb, Coriandrum sativum. AB - Coriander (Coriandrum sativum L.) is an annual spice herb that belongs to umbel family Apiaceae with diversified uses. We investigated the extent of variability among 22 Indian varieties of coriander using phenotypic and genetic markers. Multilocus genotyping by nine RAPD primers detected an average of intraspecific variations amounting to 66.18% polymorphism in banding patterns. Analysis of molecular variance indicated that a greater proportion of total genetic variation exists within population (98%) rather than among populations (2%). Higher values of Nei's gene diversity (h) and Shannon Information Index (i) and genetic distance analysis validate wider genetic diversity among Indian coriander varieties. Besides total internal transcribed spacer (ITS) length variations and single nucleotide polymorphisms, insertions/deletions (INDELS) were detected at seven sites in ITS-1 region. Multiple sequence alignment of 12 sequenced varieties revealed cent per cent identities of 5.8S gene region (162 bp) that validates its conserved nature. Multiple sequence alignment of ITS-1 region may be of phylogenetic significance in distinguishing and cataloguing of coriander germplasm. The representative sequences of each subgroup and all distinct varieties of RAPD clusters have been submitted to NCBI database and assigned Gen Accession numbers HQ 377194-377205. The measures of relative genetic distances among the varieties of coriander did not completely correlate the geographical places of their development. Eventually, the knowledge of their genetic relationships and DNA bar coding will be of significance. PMID- 23360009 TI - Floristic diversity of regenerated tree species in Dipterocarp forests in Western Ghats of Karnataka, India. AB - The research was focused on exploring the structure, diversity and form of regeneration process of the Dipterocarp forests in Western Ghats in relation to environmental factors. Eight populations in the distribution range of Dipterocarp forests were selected. In each population 32 plots of 2mx2m were laid down randomly. Atotal of 1243 seedlings < or = 10 cm dbh (diameter at breast height) belonging to 99 species and 48 families were recorded. The number of regenerated tree species was found to be high in the populations of Mudigere (40), Sakleshpura (40) and Makuta (39), which are characterized by favorable locality factors and lower disturbances. The highest similarity index in species composition was recorded between the populations of Sampaje in Kodagu district and Gundya in Dakshina Kannada (60%) whereas the lowest similarity index was observed between the population of Sringeri in Chikmagalore and Sampaje (53%) and Gundya and Makuta (35%) in Kodagu district. Dipterocarpus indicus was found to be dominant among the regenerated tree species in all the sites studied except Gundy and Sampaje. The frequencies of regeneration classes (seedlings, saplings, poles and adult trees) were shaped as inverse J curve indicating the normal regeneration pattern under the present disturbance. The average disturbance of litter collection, grazing, fire, weeds and canopy opening were significant among different populations (p < or = 0.05). Negative correlation was observed between disturbance and species richness, number of individuals and density. PMID- 23360010 TI - Effect of a non steroidal tamoxifen on the gonad and sex differentiation in Nile tilapia, Oreochromis niloticus. AB - The effect of different doses of anti-estrogenic chemical was studied in a cichlid Oreochromis niloticus on mortality, growth, sexual development and sex differentiation. Percent mortality (5, 10 and 10) appeared to be dose-dependent. All groups of tamoxifen (TA) treated fishes exhibited significant growth as compared to the controlled fishes. Immature fishes treated with TA at 200 microg l(-1), showed lower gonado-somatic-index (GSI) (male 0.137; female 0.118) than control group (male 0.138; female 0.122) of fishes. Ovarian and testicular differentiation was adjudged by the appearance of the ovarian cavity (ovary) and the efferent (sperm) duct (testis), respectively. Sex and sexual maturity of individual fishes were determined using standard histological method. Tamoxifen treatment to the fry (yolk sac absorbed stage) of Oreochromis niloticus in the dose of 200 microg l(-1) for 60 days produced 90% males and 1% intersex population. Results suggested masculinizing action of tamoxifen reversing the sex of genetic female tilapia. PMID- 23360011 TI - Evaluation of the estrogenic effects of bisphenol-A on male freshwater prawn Macrobrachium asperulum. AB - Bisphenol-A(BPA), a known endocrine-disrupting chemical that is distributed world wide, is extensively employed in industry, dentistry and consumer household products. This study was conducted to explore the estrogenic effects of BA on the male freshwater prawn, Macrobrachium asperulum, by examining the daily survival rate, molting frequency, hepatosomatic index (HSI), and levels of vitellogenin like protein. Results revealed that BPAcan elicitthe expression of vitellogenin like protein (0.09 and 0.09 microg P x (mg protein))-1), respectively) in male organisms exposed to 0.1 and 1 ng l(-1) BPA at day 7. Moreover, prawns were perceived to be sensitive to estrogenic compounds. Hence, it can be concluded that M. asperulum can be used as a species for biomonitoring, and levels of vitellogenin-like protein in males are a useful biomarker for detecting estrogenic contaminations. PMID- 23360012 TI - Effect of some plant growth regulators on lindane and alpha-endosulfan toxicity to Brassica chinensis. AB - The effect of indolebutyric acid (IBA) and gibberellic acid (GA3), to alleviate the organochlorine phytotoxicity were studied in Brassica chinensis. Presence of organochlorine decreased Brassica chinensis seedlings growth in contaminated alkaline soil. One mg l(-1) IBA could enhance 14 and 26% shoot and root length of B. chinensis seedlings grown at 40 mg kg(-1) lindane contaminated soil, respectively. Ten mg l(-1) IBA also increased 80 and 40% root fresh weight of seedling grown in 40 mg kg(-1) lindane and alpha-endosulfan contaminated soils, respectively. However, IBAhad no effect on shoot and root length of seedlings grown in endosulfan contaminated soil. On the other hand, 10 mg l(-1) GA3 only increased 80% of shoot and root fresh weigh of B. chinensisin 40 mg kg(-1) endosulfan contaminated soil. External auxin addition could increase B. chinensis growth in lindane more than endosulfan contaminated soil. External gibberellin was less effective than external auxin to increase B. chinensis growth in organochlorine contaminated soil. There is possibility that auxin could decrease organochlorine phytotoxicity in plants and hence can be useful for organochlorine phytoremediation. PMID- 23360013 TI - Determination of incoming solar radiation in major tree species in Turkey. AB - Light requirements and spatial distribution of major forest tree species in Turkey hasn't been analyzed yet. Continuous surface solar radiation data, especially at mountainous-forested areas, are needed to put forward this relationship between forest tree species and solar radiation. To achieve this, GIS-based modeling of solar radiation is one of the methods used in rangelands to estimate continuous surface solar radiation. Therefore, mean monthly and annual total global solar radiation maps of whole Turkey were computed spatially using GRASS GIS software "r.sun" model under clear-sky (cloudless) conditions. 147498 pure forest stand point-based data were used in the study for calculating mean global solar radiation values of all the major forest tree species of Turkey. Beech had the lowest annual mean total global solar radiation value of 1654.87 kWh m(-2), whereas juniper had the highest value of 1928.89 kWh m(-2). The rank order of tree species according to the mean monthly and annual total global solar radiation values, using a confidence level of p < 0.05, was as follows: Beech < Spruce < Fir species < Oak species < Scotch pine < Red pine < Cedar < Juniper. The monthly and annual solar radiation values of sites and light requirements of forest trees ranked similarly. PMID- 23360014 TI - Appearance and characteristics of major phytoplankton species based on long-term monitoring datasets in southern sea of Korea. AB - To understand the mechanism of phytoplankton bloom forming, we investigated the relationship between several species and water quality factors using long-term monitoring datasets from 1996 to 2003. The seven sites at this study were classified into four groups by phytoplankton species or water quality datasets and the species for phytoplankton bloom forming seems to be mainly influenced by the water quality or surrounding water conditions. E. gymnastica and P. minimum were observed for the longest time period from April to September, and C. polykrikoides shortest time period from summer to autumn. E. gymnastica was observed across the widest temperature range (14-27 degrees C), and C. polykrikoides narrowest temperature range (20-28 degrees C). Chaetoceros spp. was observed over the narrowest salinity range (22-33 ppt), and E. gymnastica, P. minimum, H. akashiwo wide salinity range (14-34 ppt). The main reasons for the formation of Chaetoceros spp. and S. costatum blooms seems to be fresh water input through forest and fields by heavy rainfall events. Thalassiosira spp. seems to grow well in conditions of fresh water input and/or in eutrophicated areas with salinities >20 ppt and water temperatures > 17 degrees C. C. furca seems to grow well in sea areas that are affected by inflows of domestic and industrial wastewater and by inflows of freshwater with domestic and industrial wastewater, rather than only freshwater input, after May when water temperatures are higher than 18 degrees C. E. gymnastica, H. akashiwo, P. minimum, and P. triestinum seem to grow well in eutrophicated sea areas where nutrient levels are high and where domestic and industrial wastewater flow are abundant. C. polykrikoides blooms seem to be due to suitable seawater input from off sea areas, and freshwater after heavy rainfall that has high nitrogen concentration. PMID- 23360015 TI - Studies on water quality and pathogenic bacteria in coastal water Langkawi, Malaysia. AB - A study on physico-chemical parameters and pathogenic bacterial community was carried out at the coastal waters of Pulau Tuba island, Langkawi. The physico chemical parameters such as temperature (27.43-28.88 degrees C), dissolved oxygen (3.79-6.49 mg l(-1)), pH (7.72-8.20), salinity (33.10-33.96 ppt), total dissolved solids (32.27-32.77 g l(-1)) and specific conductivity (49.83-51.63 mS cm(-1)) were observed. Station 3 and station 4 showed highest amount of nitrates (26.93 and 14.61 microg at N l(-1)) than station 1 (2.04 microg at N l(-1)) and station 2 (4.18 microg at N l(-1)). The highest concentration (12.4 +/- microg l(-1)) of chlorophyll a was observed in station 4 in October 2005. High phosphorus content (561 microg P l(-1)) was found in the station 2. Thirteen bacterial isolates were successfully identified using API 20E system. The highest amount of bacteria was observed at Station 4 (3400 CFU ml(-1)) and the lowest numberwas at Station 2 (890 CFU ml(-1)). Out of identified 13 Gram-negative bacterial isolates dominant species were Aeromonas hydrophila, Klebsiella oxytoca, Pseudomonas baumannii, Vibrio vulnificus, Proteus mirabilis, Providencia alcalifaciens and Serratia liquefaciens. Apart from this, oil biodegrading Pseudomonas putida were also identified. The study reveals the existing status of water quality is still conducive and the reasonably diverse with Gram-negative bacteria along the Pulau Tuba Langkawi. PMID- 23360016 TI - Cardiac health and lifestyle--a window of opportunity. PMID- 23360017 TI - Epidemic of myocardial infarction in Indian subcontinent. PMID- 23360018 TI - Assessment of prognostic factors for locally advanced breast cancer. AB - In spite of apparent improvement in outcome in locally advanced breast cancer, the prognosis remains dismal in many patients. The aim of this study was to define prognostic subgroups within this heterogeneous entity. The prospective follow-up study was carried out for a period of three and half years involving patients attending the radiotherapy department of Burdwan Medical College and Hospital. Forty-five patients with clinical stages IIIA and IIIB breast cancer were treated with neoadjuvant chemotherapy followed by mastectomy, radiotherapy and completion of chemotherapy with an objective to assess the 2 years disease free and overall survival and to find out the correlates of prognosis. On follow up disease-free survival and overall survival at 2 years were noted to be 60% and 80% respectively. Patients with age more than 45 years, earlier stage, less than 4 positive axillary nodes, tumour size less than 8 cm, oestrogen receptor positive and Her-2-neu negative status and lesser number of chemotherapy cycles required before surgery had better outcome though not statistically significant. Thus it can be concluded that the above mentioned prognostic variables are strong predictors of treatment outcome in locally advanced breast cancer though further studies with larger sample size are required to establish their statistical significance. PMID- 23360019 TI - How do school girls deal with dysmenorrhoea? AB - To estimate the prevalence of primary dysmenorrhoea among the school girls, to determine its impact on their routine life and to ascertain the practices adopted by them for management of primary dysmenorrhoea, a cross-sectional study was conducted in two schools of Chandigarh, India. Two hundred twenty-four school girls in the standard VIII to X of the selected schools, who had attained menarche, were included in the study. A modified menstrual distress questionnaire was used to score the severity of dysmenorrhoea and its impact on their life. Visual analogue scale for pain was used to measure pain during menstruation. Analysis was done by percentage, mean and standard deviation. Prevalence of dysmenorrhoea was 59.82%. Sickness absenteeism due to dysmenorrhoea was reported in 25.8% girls. According to visual analogue scale for pain scoring, 52.3% had moderate pain and 25% cases had severe pain. Menstrual distress questionnaire scores showed mood swings, irritability, difficulty in concentrating, poor school performances were common problems; 8.6% of the study population went for physicians' consultation, 15.6% took painkillers, 12.5% used hot water bottles, 3.1% practised exercise, 26.6% practised dietary modifications for reducing pain. Most of the cases were partially or completely relieved by these measures. Dysmenorrhoea is rapidly developing as a public health problem with its high prevalence, the degree of discomfort felt by the sufferer as well as the reduction in their quality of life. School based counselling of the suffering girls can be useful for empowering them with different options for managing their menstrual pain. PMID- 23360020 TI - Catheter-based renal denervation for refractory hypertension: a review of the literature. PMID- 23360021 TI - Management of atrial fibrillation. PMID- 23360022 TI - Hypertension. PMID- 23360023 TI - Point of care for gestational diabetes mellitus--a community-based study. AB - Universal screening for gestational diabetes mellitus (GDM) is advocated in Indian women as they have the highest frequency of GDM, among South Asian population. For this the diagnostic procedure has to be simple, economical and evidence based. Hence, this study was undertaken to compare the point-of-care measuring capillary blood glucose (CBG) by glucometer and venous plasma glucose (VPG) estimated in the laboratory and to suggest the feasible diagnostic tool. Consecutive pregnant women in the third trimester were included in this study with the approval of the institutional ethical committee. They were given 75 g oral glucose in the fasting state. After 2 hours, CBG was measured by finger prick using one touch select simple glucometer and venous blood was drawn to estimate VPG in the laboratory by GOD- POD method. The diagnosis of GDM was based on 2 hours plasma glucose > or = 7.8 mmol/l. Among a cohort of 500 pregnant women, 32 (6.4%) were diagnosed as GDM in their first visit. The CBG value at 2 hours plasma glucose > or = 7.8 mmol/l had a sensitivity of 93.8% and specificity of 97.4% with a false positive and false negative of 2.6% and 6.2%, respectively. The area under the receiver operating characteristic curve of CBG was 0.993. CBG value at 2 hours plasma glucose > or = 7.8 mmol/l may be recommended for the diagnosis of GDM in healthcare centres where laboratory technology is not available. PMID- 23360024 TI - Role of protein rich maternal diet in infantile colic. AB - Infantile colic in exclusively breastfed infant is very common. The mother in this situation gets panickyand under stress. This is very common emergency in paediatric hospital. Infantile colic is characterised by paroxysms of uncontrollable crying in an otherwise healthy and well fed infants younger than three months of age, more specifically infantile colic is defined as cry exceeding 180 minutes per 24 hours on 3 days in the week in first 3 months of life. The incidence of infantile colic is 5 to 19% in different studies. The mothers' description of this condition is that the breastfed baby who has been apparently alright in the day, frowns, his face becomes red, draws up his legs, screams, continues to cry for about 2 to 20 minutes and then attack ends suddenly. Episodes of cry are usually clustered in the late evening and early morning hours, which may cause significant disruption of family interactions. To find out the any supportive cause for infantile colic pertaining to maternal diet, we have conducted a study, where 110 crying infants were examined who happened to attend paediatric department over a period of one year. In this study it was found that more infants (50%) were in the age group >2-3 months, then >1-2 months (39.09%). Most of the patients happened to attend in casualty hours (5PM-9 AM) than in OPD hours (9 AM - 5 PM). Most cases (30.9%) took pulses in last 48 hours, followed by buffalo milk (20%). Most mothers (n=34) took pulses in diet in last 48 hours. It can be concluded that protein rich diet in one of the factor causing infantile colic. PMID- 23360026 TI - Tuberculosis is still a scourge of mankind--why? AB - This article focuses on issues and challenges regarding why tuberculosis (TB) remains as horrible scourge to mankind even today that too in the era of nanotechnology. It tries to evoke a uniform consciousness among treating doctorsboth at government and private levels to follow a uniform diagnostic algorithm and treatment protocols which is very much readily available under Revised National Tuberculosis Control Programme (RNTCP) Directly Observed Treatment Short course (DOTS) throughout our nation. Even today TB is the singlemost major infectious killer disease which claims 2 deaths in every 3 minutes in India which has one-fifth of global TB burden. The challenges faced are highlighted here like issues of uniformity in treatment, multidrug resistant TB (MDR TB), extensive drug resistant TB (XDR TB), HIV-TB coinfection, diabetes and TB, etc. In spite of nationwide coverage of RNTCP DOTS, every practitioner is not strictly or willfully following the guidelines prescribed. If the guidelines are maintained one hundred per cent with full involvement of Indian Medical Association/Indian Academy of Pediatrics and various other medical organisations then the author can confidently feels that the day is not far to combat and contain the horrible scourge. Time has come that every medical practitioner should take an oath to evolve a uniform consciousness to adhere to the guidelines prescribed under RNTCP DOTS which may prevent the future generation to succumb to the horrible scourge of TB. Shall we? PMID- 23360025 TI - Use of fasciocutaneous flap for open-type III B tibial fractures--clinical experience and analysis. AB - Full thickness soft tissue defect over tibia is a big problem. Between December 2004 and July 2006, 20 patients of open Gustilo type IIIB tibial fractures were treated with fasciocutaneous flap after initial external fixation and control of infection done as evidenced by negative culture sensitivity test. The flap was chosen from the area between superior flexion crease of the calf at the popliteal fossa to the junction of the middle and inferior thirds of the posterior calf. The delay in flap surgery was mostly due to associated infection. Good results with satisfactory union were achieved in 85% cases. Infection occurred in 2 cases (10%). Marginal and full thickness necroses in this series were seen with sural flap; 2 cases (10%) developed partial necrosis of flap which was managed by skin graft and 1 (5%) developed full thickness necrosis. Fasciocutaneous flap helps in fracture union, control of infection and improves the functional outcome. PMID- 23360027 TI - Percutaneous transluminal coronary angioplasty in a patient in cardiogenic shock due to recent anterior wall MI with history of prior inferior wall MI 15 days back. AB - Extensive damage of the myocardium following an acute myocardial infarction usually causes cardiogenic shock. A 66-year-old male patient was treated successfully by primary percutaneous transluminal coronary angioplasty (PTCA) following an acute anterior wall myocardial infarction with prior moderate LV systolic dysfunction and developing cardiogenic shock with intra-aortic balloon counterpulsation (IABP), ventilator support and support with four inotropic drugs in full dosage. PMID- 23360028 TI - A patient with recurrent attacks of drowsiness and lethargy--a diagnosis not to be missed. AB - Polyglandular auto-immune syndromes are uncommon constellation of organ specific auto-immune diseases, characterised by the existence of two or more endocrinopathies. Polyglandular autoimmune type II syndrome also known as Schmidt's syndrome is more common, comprising Addison's disease, auto-immune thyroid disease, type 1 diabetes mellitus and/or hypogonadism, pernicious anaemia, coeliac disease, vitiligo, hypophysitis, etc. Here a case of a 56-year old man is reported with a prior history of hypothyroidism who presented with adrenal crisis. Further laboratory investigations revealed primary auto-immune hypothyroidism, primary adrenal insufficiency, hypogonadism and he was diagnosed as a case of polyglandular auto-immune type II syndrome or Schmidt's syndrome. Early recognition of the syndrome and replacement therapy can be life saving, particularly when there is adrenal or thyroid insufficiency. PMID- 23360030 TI - Large post-traumatic ciliary staphyloma--a simple, safe and successful management. AB - Surgical management of scleral staphylomas is challenging and is usually associated with poor visual outcome. A middle aged lady developed a large post traumatic scleral staphyloma following injury with a cow's horn. She sought treatment for poor vision and cosmetic blemish. She was satisfactorily managed by surface diathermy and closure of defect with partial thickness rotational scleral autografts and her corrected visual improvement was 6/12. PMID- 23360029 TI - Giant mass conjunctival rhinosporidiosis causing severe mechanical ectropion. AB - Rhinosporidiosis is a granulomatous disease of the mucous membrane caused by Rhinosporidium seeberi, an organism of uncertain taxonomic position, most probably a fungus. It usually infects mucous membrane of the nose and nasopharynx but may infect mucous membrane of all other parts even the skin. Inoculation of the eye and related structures are grouped as oculosporidiosis. In this case of a 50 years old male agriculturist from remote village had complaints of a mass protruding out from the palpebral fissure since last one year. It was gradually increasing in size and shape. There was recurrent redness, watering and discharge. This mass caused dragging of lower lid to produce mechanical ectropion. On examination there was a pedunculated polypoidal broad based conjunctival mass originated from inferior bulbar conjunctiva. It is chemosed with the evidence of necrosis and old haemorrhagic spot, engorged conjunctival vessel and in the exposed pert there is keratinisation. Conjunctival rhinosporidosis has predilection for agriculture workers so that contact with contaminated soil may be the causative factor. The only effective treatment is radical surgical excision followed by thermal and chemical coagulation, nevertheless relapse is the rule rather the exception. No such medical treatment has proved to be effective. Griseofulvin and amphotericin have been used without success. PMID- 23360031 TI - Castleman's disease--a rare disease with varying presentation. AB - Castleman's disease is a relatively rare immunoproliferative disease primarily involving the lymph nodes. It occurs in two forms- unicentric and multicentric. Though it is a benign disorder the multicentric form can be difficult to treat and can have a poor prognosis. The treatment is often delayed as its differential diagnosis includes several common diseases including lymphoma, benign and malignant lymph node mass, thymoma, rheumatoid nodules. It is at times associated with pemphigus vulgaris as a paraneoplastic syndrome as has occurred in one of the cases. This makes the diagnosis even more difficult as the patients generally undergo a prolonged treatment initially for the associated condition without significant improvement. Three such cases were encountered in the last three years, all of which occurred in relatively young patients and caused great diagnostic dilemma. They responded well to treatment and are currently doing well in follow-up. This disease though rare should be considered in the differential diagnosis of lymphoma, reactive nodular hyperplasia, malignant lymph node enlargement. It is also important to rule out this disease in the diagnosis of treatment-refractory cases of pemphigus vulgaris. PMID- 23360032 TI - Bilateral temporalis muscle hypertrophy--two case reports. AB - Isolated idiopathic bilateral temporalis muscle hypertrophy is a very rare clinical entity. It can change the facial appearance that manifests itself as a morphopsychological conflict for the subject, which is termed as 'Minotaur syndrome' in the medical literature. Here one such case is reported. The second patient sought medical attention for fear of malignancy. PMID- 23360033 TI - Liraglutide in type 2 diabetes mellitus. AB - Liraglutide (victoza, Novo Nordisk A/S) is human GLP-1 analogue developed by recombinant DNA technology. It is indicated along with diet and exercise in management of type 2 diabetes (T2DM) in adults. Liraglutide has been made available in India recently. Present review evaluates the efficacy and safety of liraglutide in T2DM and its comparison with other incretin based therapies. Liraglutide has been evaluated as monotherapy, in combination with one, two and three oral antidiabetic drugs similarly to routine clinical practice. These studies reported greater improvement in glycaemic control with liraglutide compared with comparators. Evaluation up to 2 years revealed sustained improvement in glycaemic control with liraglutide use. Liraglutide was well tolerated except for mild to moderate gastro-intestinal adverse events, which declined after continuation of therapy. Low risk of hypoglycaemia was reported with liraglutide therapy. Greater efficacy than other incretin based therapies was noted with liraglutide. Liraglutide has an important place in the management of T2DM. Apart from glycaemic control it also provides some important non glycaemic benefits in terms of improving beta-cell function, weight reduction, and reduction in systolic blood pressure thereby overcoming the present therapeutic gap. PMID- 23360034 TI - Indian Medical Association and Unicef: Prevention and treatment of childhood diarrhea. Diarrhea prevention and control need for integrated approaches. PMID- 23360035 TI - Environment and human health. PMID- 23360036 TI - Swine flu (H1N1 influenza): awareness profile of visitors of swine flu screening booths in Belgaum city, Karnataka. AB - The 2009 flu pandemic was a global outbreak of a new strain of H1N1 influenza virus often referred colloquially as "swine flu". The objectives of the study were: (1) To know the sociodemographic and awareness profile of visitors attending swine flu screening booths. (2) To reveal sources of information. The present cross-sectional study was undertaken among the visitors (18 years and above) attending swine flu screening booths organised within the Belgaum city during Ganesh festival from 28-08-2009 to 03-09-2009 by interviewing them using predesigned, pretested structured questionnaire on swine flu. The data was collected and analysed using SPSS software programme for windows (version 16). Chi-square test was applied. Out of 206 visitors, 132 (64.1%) were males and 107 (51.9%) were in the age group of 30-49 years; 183 (88.8%) had heard about swine flu. More than a third of the visitors (38.3%) disclosed that there was a vaccine to prevent swine flu. Majority responded that it could be transmitted by being in close proximity to pigs (49.0%) and by eating pork (51.5%). Newspaper/magazine (64.6%), television (61.7%), and public posters/pamphlets (44.2%) were common sources of information. The present study revealed that doctors/public health workers have played little role in creating awareness in the community. The improved communication between doctors and the community would help to spread correct information about the disease and the role that the community can play in controlling the spread of the disease. PMID- 23360037 TI - Reproductive tract infection and health seeking behaviour of eligible couples--an appraisal. AB - A community-based cross-sectional study was conducted in Paschim Midnapur district of West Bengal during March 2009 to August 2009 to find out the prevalence of reproductive tract infection and the health seeking behaviour. The respondents were 2000 currently married women (15-49 years age group) selected by stratified multistage random sampling. House to house visit and data collection by interview technique was done by faculty members of community medicine of Calcutta National Medical College and other medical colleges through predesigned and pretested schedule. The prevalence of reproductive tract infection was 11.7%, which was higher in 30-35 years age group (19.4%). Reproductive tract infection was indirectly proportional to literacy status. Prevalence of reproductive tract infection was significantly higher among those who did not use sanitary napkin / clean sun-dried domestic clothes. The occurrence of reproductive tract infection was lower who used to practise barrier method of contraception. Majority of symptomatic females complained about vaginal discharge (29.2%). Information, education, communication regarding small family norms, reproductive hygiene and contraceptive practice to be enhanced in the community through intervention (interpersonal communication and mass media) in future to reduce the reproductive tract infection morbidities. PMID- 23360038 TI - Measurement of first ray of foot with reference to hallux valgus. AB - A study was carried out on 58 healthy volunteers. None of the volunteeres had any foot complaints. This was done to study Indian feet, as foot is an important part of human anatomy and its certain deformities eg, hallux valgus, can be very disabling. We have studied anatomical angles between 1st and 2nd rays of foot eg, angle of hallux valgus and angle of slant of distal facet of medial cuneiform and have shown significant correlation between them and development of hallux valgus. The coefficient of correlation (r) calculated between these two angles is significant, showing that this angle influences the angle of hallux valgus and hence development of hallux valgus. These are anatomical angles and indicate shapes of medial cuneiform and 1st metatarsal. Hence these seem to be inherited, making the feet anatomically predisposed to develop hallux valgus. This view is supported by Gray's Anatomy. The extrinsic factors such as narrow toes, closed, footwear worn for an extended period do increase the angle of hallux valgus. So, in predisposed feet, this is one of the extrinsic factor which can lead to development of hallux valgus. On studying these two angles, orthopaedicians should be on alert and should advise such individuals on wearing foot- friendly foot-wear. PMID- 23360040 TI - Primary percutaneous coronary intervention versus pharmaco-invasive strategy. PMID- 23360039 TI - Three years audit of the emergency patients in the department of ENT of a rural medical college. AB - Surgical audit is a systematic, critical analysis of the quality of surgical care provided, with the aims of improving quality of care, continuing education for surgeons, and guiding appropriate use of health resources. Emergency service is an integral part of any discipline of clinical medicine and it is considered as an indicator of quality of healthcare system. A three years record based, retrospective, cross-sectional study was carried out in the department of ear, nose and throat (ENT) of Midnapore Medical College, Paschim Medinipur,West Bengal to identify the total attendance of various emergency patients, diagnosis made thereafter, the mode of interference and outcome and the potential problems in the quality of care provided to the community. A total of 9051 patients had been admitted/attended in the ENT emergency from January 2008 to December 2010 who were included in this audit. Detailed statistical analysis of the data showed male: female (2.38:1) with the peak in the first decade of life. Majority of the patients were from Medinipur sadar (58.43%). The total otological cases were maximum (42.41%) in comparison to nose (28.98%) and throat (28.60%). The most common ear emergencies were earache due to impacted wax, acute suppurative otitis media, foreign body ear and the trauma/injury. Chronic suppurative otitis media with complications were the least. Amongst the sinonasal emergency, the most common aetiology was the epistaxis and foreign body nose in children. The different types of foreign body impaction in the throat and the inflammatory condition of throat or the inspiratory stridor due to upper airway obstruction were the main emergency situation recorded. Some cases were fatal. The overall mortality was 0.44%. PMID- 23360041 TI - Application of amniotic membrane transplantation in cases of symblepharon. AB - Injuries to the eye causing ocular surface damage may develop symblepharon as a complication in which palpebral conjunctiva got adhered to the bulbar conjunctiva or cornea. Removal of adhesions is must for ocular surface reconstruction but chances of recurrence are more in simple removal. A study was done among 10 eyes of 10 patients to see the efficacy, safety and outcome of symblepharon excision with amniotic membrane transplantation. All the patients were operated by a single surgeon with standard technique and all of them were followed up for 6 months. All eyes exhibit a stable, intact corneal epithelial surface and healthy conjunctival growth without developing recurrent erosion or persistent epithelial defect. Visual improvement was seen in 60% of cases. Eighty per cent patients showed symptomatic relief. All eyes exhibited decreased vascularisation and inflammation at final follow-up. Thus, amniotic membrane transplantation is very effective in ocular surface reconstruction in cases of symblepharon and limbal stem cell deficiency. PMID- 23360042 TI - Cell block cytology in pleural effusion. AB - Cell blocks prepared from residual tissue fluid can be used as adjuncts to smear for establishing a more definitive cytopathological diagnosis. It can be useful for categorisation also. Improved ethanol formalin fixative is used which offers excellent cytomorphologic features corresponding closely to cell in Papanicolaou stained smears. The technique is simple, safe, cost effective and reproducible even in resource limited rural areas. In this study among a total of 60 cases of suspected malignant pleural effusion, 56 were confirmed to be of malignant aetiology by all modalities. Only cell block preparation diagnosed 46 cases. Other modalities of diagnosis like bronchoscopy, broncho-alveolar lavage fluid study, fine needle aspiration cytology also have a great role in diagnosis. Twenty-two cases were diagnosed by Papanicolaou stain smear. So cell block preparation have more effective role in definitive diagnosis. It can be useful for better diagnosis in cases of poorly differentiated malignant neoplasms by immunocytochemistry. PMID- 23360043 TI - Study of mutated p53 protein by immunohistochemistry in urothelial neoplasm of urinary bladder. AB - It is difficult to predict which urothelial neoplasm would subsequently recur or progress to muscle invasive tumours or produce metastasis.The aim and objective of the study were to evaluate the scope of immunohistochemical expression of p53 in human urothelial neoplasms with regard to grade, stage and outcome of the patients. Eighteen consecutive patients were taken and urothelial tumour samples were obtained from transurethral resection or surgical excision. Histopathological examinations were performed and the grading was done according to the WHO/ISUP consensus classification of urothelial neoplasms. Immunohistochemical staining for p53 was performed on formalin fixed paraffin embedded tissue sections with appropriate positive and negative control. It was found 3 patients with papillary urothelial neoplasm of low malignant potential (PUNLMP), 5 cases of papillary low grade urothelial carcinoma, 10 patients with papillary high grade urothelial carcinoma including 2 cases of invasive urothelial carcinoma. All three PUNLMP cases showed negative results. Four out of 5 low grade papillary urothelial carcinoma had nuclear p53 accumulation, while all of the 10 papillary high grade carcinoma had high p53 index. The finding of negative p53 staining in PUNLMPs and high p53 index in high grade papillary urothelial carcinomas and invasive carcinomas support the notion that mutation of p53 gene might be unrelated to the development of urothelial neoplasms but definitely play a crucial role in progression of the malignancy. PMID- 23360044 TI - Foreign bodies in bronchus--2 years experience at IPGME&R, Kolkata. AB - Foreign body in the bronchus is one of the life saving emergency in the ENT department. Most patients of foreign body bronchus are kids. Common presentation is respiratory distress or noisy respiration of sudden onset. Proper clinical examination and suspicion needed for proper diagnosis. In this report, 52 cases of foreign body bronchus were included. All patients underwent straight x-ray chest after taking proper history and while aroused suspicion. All of them received antibiotic and steroid. Foreign body was removed by rigid bronchoscope, flexible bronchoscope and by rigid telescope along with rigid bronchoscope. Most foreign bodies lodged in the left bronchus. Only one patient had died in the process for anaesthetic hazards. PMID- 23360045 TI - Herpes zoster: mistaken for radiculopathy and back pain. AB - Herpes zoster should be considered as one of the differential diagnosis in acute pain of short duration on one side of the body with or without skin lesions. Pain, a prodromal manifestation of herpes zoster may be mistaken for various disease conditions, leading to hasty unwise investigation, therapy. and surgical interventions. There is a need to identify prodrome and skin eruptions of herpes zoster, so that early antiviral therapy can be started in elderly patients who are at higher risk of developing postherpetic neuralgia. PMID- 23360046 TI - Primary non-Hodgkin's lymphoma of breast with scalp involvement in follow-up--an uncommon presentation. AB - Primary non-Hodgkin's lymphoma of the breast is a rare tumour accounting for 0.04 to 0.5% of all malignant breast tumours. The aim of this case presentation is to report such rare entity with an uncommon presentation. A 48-year female presented with rapidly growing firm mass in right breast (upper outer quadrant) and fine needle aspiration cytology (FNAC) was performed for clinical suspicion of breast carcinoma. Cytological examination of smears showed large cells arranged discretely, though occasional small clusters were also seen. The cells had high nuclear-cytoplasm (N-C) ratio and prominent nucleoli. Based on cytomorphology, differential diagnoses of high grade non-Hodgkin's lymphoma and poorly differentiated carcinoma was made. A tru-cut biopsy was suggested for confirmation. Histologic examination revealed diffuse large cells (monomorphic type) with prominent nucleoli.The tumour cells were reactive for CD45, CD20, and negative for cytokeratin, CD30, CD3 and CD5. A histopathologic diagnosis of non Hodgkin's lymphoma of diffuse large B cell lymphoma type was confirmed. The patient was treated with combined chemotherapy and radiotherapy. After one year, the patient developed a swelling in the scalp and proved to be diffuse large B cell lymphoma by tru-cut biopsy. Now, the patient was treated with chemotherapy alone. Two-year follow-up of the case was uneventful. Since FNAC is initial diagnostic tool for breast lesions, a differential diagnosis of breast lymphoma should always be kept in mind, especially in poorly differentiated malignant tumours. Such cases need to be confirmed by histopathology and immunohistochemistry. PMID- 23360047 TI - Tuberculosis of the gall bladder clinically mimicking carcinoma--a case report. AB - Gall bladder tuberculosis is very rare and curable but, sometimes can be confused with the clinical diagnosis like carcinoma. A 32-year-old male presented with acute pain in right abdomen for one month and fever off and on for two months. CT scan (whole abdomen) showed features suggestive of lymphadenopathy although peroperatively no significant lymph node could be identified but there were multiple white patches on gastrohepatic ligament and neck of gall bladder probably which were identified as lymph nodes on scanning. On the basis of peroperative findings clinician diagnosed it as a case of carcinoma gall bladder and was subjected to cholecystectomy. On histopathological examination it turned out to be tuberculosis gall bladder. Therefore tuberculosis of gall bladder can mimic carcinoma clinically. PMID- 23360048 TI - Gastro-intestinal stromal tumour--a case report. AB - Gastro-intestinal stromal tumours are rare tumours of the gastro-intestinal tract. Among non-epithelial tumours of gastro-intestinal tract, gastro-intestinal stromal tumours are the commonest but as they are not extensively documented, they are underestimated, poorly understood and inadequately treated for various reasons, particularly at peripheral centres in India. The gravity of the problem increases further as these tumours respond poorly to conventional cytotoxic chemotherapy and radiation therapy. Here a case of gastro-intestinal stromal tumour is reported. The patient was a 35-year-old male who was admitted with evidence of subacute intestinal obstruction. The haematological and biochemical tests showed moderate anaemia, raised serum aminotransferase aspartate (AST, SGOT) and mild hypoproteinaemia. Laparatomy revealed a jejunal tumour which was resected. The routine histopathological examination revealed a spindle cell tumour suggestive of gastro-intestinal stromal tumour -intermediate risk group. Immunohistochemical study showed strong positivity for c-kit confirming the diagnosis of gastro-intestinal stromal tumour. The patient was then referred to oncology centre for further management. PMID- 23360049 TI - Schmidt syndrome--a rare polyendocrinopathy. AB - Polyglandular auto-immune syndromes are rare entity. It is characterised by immune, dysfunction affecting two or more endocrine glands as well as certain non endocrine organs. Diagnosing such cases could be challenging and misleading too. Early recognition and treatment of such cases can stand between the life and death of a patient. Here a case of Schmidtsyndrome (polyglandular auto-immune syndrome type II) is reported, where timely treatment was life saving. PMID- 23360050 TI - Medicaid expansions--will they or won't they? PMID- 23360051 TI - 5 ways to reduce risk related to personal health information. PMID- 23360052 TI - Preparing for ACA-driven Medicare cuts. AB - To prepare for Medicare payment cuts, hospitals may opt to: Limit Medicare volume, Reduce people expenses, Improve operational efficiency, Follow the government's road map for success. PMID- 23360053 TI - Population health management: a "start small" strategy. AB - Catholic Health Initiatives (CHI) is piloting population health management for a test population that comprises CHI employees and their families. CHI is using a medical home model to coordinate care. The system anticipates a reduction in its employee healthcare costs of 10 to 14 percent. PMID- 23360054 TI - The risks and rewards of setting physician compensation internally. AB - To establish physician compensation internally, finance leaders should: Educate decision makers on basic regulatory guidance and valuation theory. Determine fair market value. Consider using a compensation calculator. PMID- 23360055 TI - Fiscal strategy in an era of reform. AB - In a reform environment, hospitals and health systems should be able to control rather than simply understand-their costs. Senior managers and line managers throughout a healthcare organization should be solidly behind-and deeply involved in-the organization's cost-control efforts. Physicians also should be heavily engaged in cost control, as they are the only ones who can both establish clinical pathways and monitor their colleagues' use of them. PMID- 23360056 TI - SCOTUS and the voters have spoken: where do we go from here? AB - Innovative ways in which hospitals are preparing for an era of reform include: Developing virtual-care models that enhance access to care, Entering into joint arrangements with other health systems to form accountable care organizations, Working internally to improve value, enhance customer satisfaction, and reduce costs, Promoting the use of standard clinical protocols for certain procedures, Investing in initiatives designed to reduce readmissions. PMID- 23360057 TI - Jeffrey C Brenner: on driving down the cost of care. PMID- 23360058 TI - Financing your strategic plan: finding the right tool for the right job. AB - Financing options available through the private sector and government agencies can fund facility renovations or new construction. To upgrade IT, hospital leaders have three major financing options: purchase, use cloud-based services for a fee, or lease. Hospital leaders may finance physician integration like other capital projects, but there are risks to diverting dollars from buildings. PMID- 23360059 TI - Community benefit: beyond health fairs and form 990. AB - Hospitals that are committed to a population health strategy should take five steps to address the strategic, cultural, technical, and structural challenges involved in such an effort: Adopt wellness as a strategic priority for the hospital. Challenge those responsible for community health to become more actively involved in actually improving the health of the population the hospital serves. Adopt a wellness philosophy and demonstrate to the community that the organization is committed to that philosophy. Leverage limited charitable resources by collaborating and partnering with community stakeholders. Integrate the agenda, policies, procedures, and systems of clinical care management, quality, and population health functions. PMID- 23360060 TI - What you should know about restrictive covenants in health care. AB - In recent years, many states have shown a greater inclination to enforce restrictive covenant provisions in contracts involving healthcare organizations and their employees, physicians, or other contacting parties. In general, an enforceable restrictive covenant is one that is deemed to have been reasonably drafted to do no more than to protect the company's legitimate business interest. Key areas of concern in health care that often fall under the protection of restrictive covenants include patient referral sources and relationships with patients. PMID- 23360061 TI - Preparing for ICD-10: a system's opportunity to integrate. AB - To prepare for ICD-10 implementation, Seattle-based UW Medicine: Conducted an impact assessment and a feasibility study, Built teams, selected leaders, and created a clear organizational structure, Collaborated with project teams that had similar goals, including those implementing computerized provider order entry, Developed physician education to drive compliance. PMID- 23360062 TI - The rising transparency tide. PMID- 23360063 TI - Addressing healthcare complexity. PMID- 23360064 TI - Winds of change. PMID- 23360065 TI - Solving the rural healthcare revenue conundrum. PMID- 23360066 TI - Correspondence of fatty acid and drug binding sites on human serum albumin: a two dimensional nuclear magnetic resonance study. AB - The ability of human serum albumin (HSA) to bind fatty acids (FA) in multiple sites has been revealed by many studies. Here we detect and characterize nine individual binding sites by two-dimensional (2D) nuclear magnetic resonance (NMR) spectroscopy of 18-[(13)C]-oleic acid (OA) complexed with HSA. We characterize site-specific FA binding by addition of (i) different FA molar ratios (from 1:1 to 4:1 OA:HSA) to observe the order of filling and occupancy of binding sites; (ii) methyl-beta-cyclodextrin, as a FA acceptor, to observe the dissociation of FA; and (iii) drugs (with known binding sites in the crystal structure) to reveal the correspondence of three NMR peaks with sites in the crystal structure. At 1:1 and 2:1 OA:HSA ratios, three sites were shown to fill sequentially. These high affinity sites were well resolved from additional sites (one medium-affinity and five low-affinity) observed at 3:1 and 4:1 OA:HSA ratios. Methyl-beta cyclodextrin extracted OA from individual sites in the reverse order of filling. FA bound in three low-affinity sites were displaced by drugs shown to bind in crystalline HSA to FA sites 7 and 3 (Sudlow's drug sites I and II, respectively) and FA site 6. With this strategy, 2D NMR spectral analysis permits site-specific characterization of the binding of drugs and FA and provides a sensitive probe of the mutual effects of FA and ligand binding. PMID- 23360067 TI - Mechanisms of PI3Kbeta-selective inhibition revealed by reciprocal mutagenesis. AB - The p110beta isoform of PI3 kinase (PI3Kbeta) has been implicated in pathological disorders such as thrombosis and cancer and a number of PI3Kbeta-selective inhibitors have recently progressed into clinical studies. Although crystallography studies identify a binding site conformation favored by the inhibitors, no specific interaction explains the observed selectivity. Using site directed mutagenesis we have identified a specific tyrosine residue of the binding site Y778 that dictates the ability of the PI3Kbeta isoform to bind these inhibitors. When mutated to isoleucine, PI3Kbeta has reduced ability to present a specific cryptic binding site into which a range of reported PI3Kbeta inhibitors can bind, and conversely when tyrosine is introduced into the same position in PI3Kalpha, the same inhibitors gain potency. The results provide a cogent explanation for the selectivity profiles displayed by these PI3K inhibitors and maybe others as well. PMID- 23360068 TI - Bacteriostatic effect of sequential hydrodynamic and ultrasound-induced stress. AB - AIMS: To elucidate the mechanism of action of a nonchemical microbial control technology employing coupled hydrodynamic and ultrasound-induced stress. METHODS & RESULTS: The effects of a laboratory model system using a commercial nonchemical device on Pseudomonas putida revealed growth and respiration were inhibited without a loss of viability from the treated population. Damage to cell membranes was evident using fluorescent microscopy and a reporter strain containing lux genes fused with a membrane damage stress-response promoter. Other reporter strains also indicated the possible involvement of DNA and protein repair systems. A consequence of treatment was a reduced ability to form biofilms. CONCLUSIONS: The nonchemical device caused a biostatic effect on treated cells induced by sublethal damage to several cellular systems, including cell membranes. SIGNIFICANCE AND IMPACT OF THE STUDY: The study demonstrates that biostasis can be an effective mechanism for microbial control in some industrial systems and provides insight into understanding and applying this device and other nonchemical microbial control technologies to real-world problems of microbial contamination. PMID- 23360069 TI - A review of vapor intrusion models. AB - A complete vapor intrusion (VI) model, describing vapor entry of volatile organic chemicals (VOCs) into buildings located on contaminated sites, generally consists of two main parts: one part describing vapor transport in the soil and the other describing its entry into the building. Modeling the soil vapor transport part involves either analytically or numerically solving the equations of vapor advection and diffusion in the subsurface. Contaminant biodegradation must often also be included in this simulation, and can increase the difficulty of obtaining a solution, especially when explicitly considering coupled oxygen transport and consumption. The models of contaminant building entry pathway are often coupled to calculations of indoor air contaminant concentration, and both are influenced by building construction and operational features. The description of entry pathway involves consideration of building foundation characteristics, while calculation of indoor air contaminant levels requires characterization of building enclosed space and air exchange within this. This review summarizes existing VI models, and discusses the limits of current screening tools commonly used in this field. PMID- 23360070 TI - Hydrophobic interaction drives surface-assisted epitaxial assembly of amyloid like peptides. AB - The molecular mechanism of epitaxial fibril formation has been investigated for GAV-9 (NH(3)(+)-VGGAVVAGV-CONH(2)), an amyloid-like peptide extracted from a consensus sequence of amyloidogenic proteins, which assembles with very different morphologies, "upright" on mica and "flat" on the highly oriented pyrolytic graphite (HOPG). Our all-atom molecular dynamics simulations reveal that the strong electrostatic interaction induces the "upright" conformation on mica, whereas the hydrophobic interaction favors the "flat" conformation on HOPG. We also show that the epitaxial pattern on mica is ensured by the lattice matching between the anisotropic binding sites of the basal substrate and the molecular dimension of GAV-9, accompanied with a long-range order of well-defined beta strands. Furthermore, the binding free energy surfaces indicate that the longitudinal assembly growth is predominantly driven by the hydrophobic interaction along the longer crystallographic unit cell direction of mica. These findings provide a molecular basis for the surface-assisted molecular assembly, which might also be useful for the design of de novo nanodevices. PMID- 23360071 TI - Conformational analysis and intramolecular interactions in aminofluorobenzoic acids. AB - Some aminofluorobenzoic acids were studied to evaluate the power of the F...HO hydrogen bond and other interactions as driving forces of the conformational isomerism of these compounds. Despite the occurrence of this hydrogen bond in the 2-fluorinated derivatives, as well as attractive O/F nonbonding interactions and NH...O?C hydrogen bond, the O/O repulsion dictates the orientation of the carboxyl group. Unlike 2-fluorophenol, which is reported to not experience a F...HO hydrogen bond, 2-fluorobenzoic acid derivatives were calculated to exhibit such interaction, but it could not be monitored experimentally by means of F/H(O) coupling constant, because of the low solubility of these compounds in nonpolar solvents, the acidity of the carboxyl hydrogen, the small population of some conformers capable of exhibiting hydrogen bond, and the solute self-association in solution, which make their conformational equilibrium different from that in gas phase. PMID- 23360072 TI - Case study of the Swiss flora for prior phytochemical and biological investigations. AB - Estimates in the literature as to what extent the world's higher plant species have been studied chemically or for bioactivity are contradictory and range from 0.5% to >12%. In this survey, a model to make credible estimates of the extent of their study is proposed and is exemplified by applying it in a case study of plants native to Switzerland. Using a widely available database (SciFinder Scholar), 454 535 literature references for the 2677 native Swiss plant species were retrieved. It was determined that 55% of these species have been investigated phytochemically and 28% for biological activity. The influence of factors such as commonness, growth form, habitat, medicinal use, and reported toxicity on the extent to which different plant groups have been studied is analyzed. The predictive value of random sampling of subsets of plants is compared to the study of the entire Swiss flora, to show that a credible estimate of the extent of prior studies can be achieved with just 5% of these species. PMID- 23360073 TI - Polymorphic Alu insertions in human populations of Bosnia and Herzegovina. AB - BACKGROUND: From a demographic and genetic perspective, Bosnia and Herzegovina is interwoven with a number of differentially isolated local populations of indigenous people with different population and religious backgrounds. AIM: In order to estimate their genetic structure, this study investigated the frequencies of 10 Alu polymorphic loci in 10 regional populations distributed across Bosnia and Herzegovina. Genetic differentiation among the three major population groups in Bosnia and Herzegovina was estimated. SUBJECTS AND METHODS: DNA from 506 unrelated individuals was extracted from buccal swabs using the salting-out extraction method. Each DNA sample was PCR-amplified using locus specific primers. RESULTS: Gene diversity values showed similarity in all analysed populations and ranged from 0.305-0.328. FST values for all loci showed that most variability is found within populations. Overall FST for all loci and AMOVA indicated that most variability was detected within populations. CONCLUSION: Results of this study are in agreement with the previous studies, indicating that the three populations in Bosnia and Herzegovina have the same genetic background. There is no significant differentiation among regional populations, pointing to absence of geographic influence. The Bosnian population is clearly located within the European gene pool. PMID- 23360074 TI - Variety-based variation in the antimutagenic potential of various vegetables and lack of its correlation with their antioxidant capacity. AB - As mutation causes many life-threatening diseases including cancer, a diet enriched with specific vegetables having potential to reduce mutagenesis possesses immense significance. In this study, 41 commonly used vegetables from diverse botanical taxa were evaluated and compared for their relative antimutagenic potential using standard assays [Escherichia coli RNA polymerase beta (rpoB)-based Rif(S) -> Rif(R) assay and Ames test] against known mutagens (UV, gamma radiation, 4-nitroquinoline-N-oxide and ethylmethanesulphonate). Significant differences in antimutagenicity were observed even among the cultivars within the same species, as well as at other phylogenetic levels such as genus or family. The effect of cooking in terms of boiling (aquathermal treatment), on the antimutagenicity of these vegetables, was also investigated. In majority of the cases, aquathermal treatment did not affect the antimutagenic potential. The antimutagenicity of these vegetables was not found to correlate well with their antioxidant properties. PMID- 23360075 TI - Quantification of the effect of conformational restriction on supramolecular effective molarities. AB - The association constants for a family of 96 closely related zinc porphyrin pyridine ligand complexes have been measured in two different solvents, toluene and 1,1,2,2-tetrachloroethane (TCE). The zinc porphyrin receptors are equipped with phenol side arms, which can form intramolecular H-bonds with ester or amide side arms on the pyridine ligands. These association constants were used to construct 64 chemical double mutant cycles, which measure the free energy contributions of intramolecular H-bonding interactions to the overall stability of the complexes. Measurement of association constants for the corresponding intermolecular H-bonding interactions allowed determination of the effective molarities (EM) for the intramolecular interactions. Comparison of ligands that feature amide H-bond acceptors and ester H-bonds at identical sites on the ligand framework show that the values of EM are practically identical. Similarly, the values of EM are practically identical in toluene and in TCE. However, comparison of two ligand series that differ by one degree of torsional freedom shows that the values of EM for the flexible ligands are an order of magnitude lower than for the corresponding rigid ligands. This observation holds for a range of different supramolecular architectures with different degrees of receptor-ligand complementarity and suggests that in general the cost of freezing a rotor in supramolecular complexes is of the order of 5 kJ/mol. PMID- 23360076 TI - On-chip assessment of the protein-release profile from 3D hydrogel arrays. AB - As the formation of healthy tissue and the treatment of several diseases are often dependent on an effective and prolonged action of bioactive agents, the delivery of molecules for therapeutic or induction purposes in a tissue is a common procedure. The correct administration of those agents is often dependent on tailored delivery mechanisms from hydrogel or polymeric matrixes. To the best of our knowledge, methods for the high-throughput monitoring of bioactive agent delivery are nonexistent. The methods for the in vitro monitoring of molecule release are expensive and laborious. As a simple alternative to these methods, we propose the imprinting of superhydrophobic biomimetic surfaces with ring-shaped transparent spots with concentric superhydrophobic millimetric regions to be used as bioactive agent release study platforms. We designed an array where polymeric precursors mixed with a growth-factor model protein labeled with a fluorescent tag could be dispensed in the concentric highly repellent regions and cross linked afterward, generating a polymeric protein-loaded sphere. The ring-shaped region was then filled with a physiological-like fluid that covered the polymeric sphere. The acquisition of sequential images of each spot over time using microscopy methods allowed one to easily monitor the protein release by image based fluorescence quantification. As the platform is easily adaptable and amenable for future automation in order to mimic standardized organ dynamics, we concluded that the device shows applicability for rapid and efficient in vitro bioactive agent release studies. PMID- 23360077 TI - Examining factors related to accelerated long-term forgetting in epilepsy using ambulatory EEG monitoring. AB - PURPOSE: Some patients with epilepsy demonstrate normal memory when this is tested at relatively short intervals (e.g., 30 min), but substantial loss over longer delay periods (e.g., days or weeks) when compared to healthy control subjects. This pattern of "accelerated long-term forgetting" (ALF) affects the everyday lives of patients, yet goes undetected by standard neuropsychological memory tests, and its pathophysiologic basis is poorly understood. By testing memory over a period of concurrent ambulatory electroencephalography (EEG), the current study aimed to investigate possible factors contributing to ALF. METHODS: Thirty-nine patients diagnosed with epilepsy or probable epilepsy underwent 5 days of continuous ambulatory EEG: 18 had normal EEG studies, 10 had focal epileptic discharges, 5 had generalized epileptic discharges, and 6 had one or more seizures. Fifteen matched healthy control subjects also participated, but did not undergo EEG. Subjects were taught 13-item word and design lists to criterion, and recall was tested at 30 min, 24 h, and 4 days. Subjects also completed questionnaires pertaining to everyday memory and mood. KEY FINDINGS: Group analyses (excluding patients who experienced seizures during monitoring) indicated that patients who experienced generalized discharges during the 24-h to 4-day delay intervals showed higher rates of forgetting for nonverbal information. Those with focal discharges showed ALF between 30 min and 4 days for verbal information, whereas those with normal EEGs over the 4 days recording had no evidence of ALF. Surprisingly, mood and epilepsy variables (such as duration of disease or number of anticonvulsant medications) showed no significant correlation with ALF. Although no aspect of nighttime sleep architecture was found to be related to recall after the first 24 h, daytime naps were associated with better retention. Self-report of everyday memory functioning was related to recall at longer delays, but not at 30 min. SIGNIFICANCE: The present findings indicated that ALF in epilepsy is associated with subclinical discharges rather than antiepileptic drugs (AEDs), mood or sleep disturbance. Measures of longer term recall can reveal correlations with subjective everyday memory complaints that are not evident when recall is only tested at a standard (30 min) delay interval. These findings have the potential to improve treatment strategies for patients who complain of memory difficulties. PMID- 23360078 TI - An exploration of student experiences of using biology podcasts in nursing training. AB - BACKGROUND: Students regard biological science as one of the most difficult components of the nursing curriculum. However, a good understanding of this area is essential for effective nursing practice. The aim of this study was to explore nursing students' perceptions of the usefulness of supplementary biology podcasts for their learning. METHODS: Biological science podcasts (n=9) were made available to first-year nursing students (n=189) as supplementary learning tools. On completion of their first year, students were asked to complete a survey which investigated the frequency of their podcast use, reasons for use and their perception of the usefulness of podcasts as a learning tool. 153 of these students participated in the survey study (80.9%). Two focus groups were conducted with students (n=6) to gain a detailed understanding of student experiences of the usefulness of the podcasts for their learning. RESULTS: Survey data demonstrated that most students (71%) accessed at least one podcast. The majority of students who reported accessing podcasts agreed that they were useful as learning tools (83%), revision aids (83%) and that they helped promote understanding of course materials (72%). Focus group participants discussed how they found podcasts especially useful in terms of revision. Students valued being able to repeatedly access the lecture materials, and appreciated having access to podcasts from a range of lecturers. Focus group members discussed the benefits of live recordings, in terms of valuing the information gleaned from questions asked during the lecture sessions, although there were concerns about the level of background noise in live recordings. Lack of awareness of the availability of podcasts was an issue raised by participants in both the survey component and the focus groups and this negatively impacted on podcast use. CONCLUSIONS: Nursing students found the availability of biology podcasts helpful for their learning. Successful implementation of these tools to support learning requires teaching staff to understand and promote the importance of these tools. PMID- 23360079 TI - Effects of alpha lipoic acid and its R+ enantiomer supplemented to hyperbaric oxygen therapy on interleukin-6, TNF-alpha and EGF production in chronic leg wound healing. AB - CONTEXT: Lipoic acid (LA) and hyperbaric oxygenation therapy (HBOT) improve chronic wound healing. OBJECTIVE: We compared the effects of LA or its enantiomer R-(+)-lipoic acid (RLA) on wound healing. MATERIALS AND METHODS: Groups LA + HBOT (L), RLA + HBOT (R) and placebo + HBOT (P). Lesion areas measured before treatment and on 20th and 40th day. The biopsies and plasma were harvested before treatment and on 7th and 14th (measurements of VEGF, vascular endothelial growth factor; EGF, epidermal growth factor, TNF-alpha and IL-6). RESULTS: Ulcers improved more on RLA. In both L and R groups, EGF and VEFG increased in time. RLA decreased IL-6 on T7 and T14, which did not happen with LA. TNF-alpha levels decreased on T14 in both LA and RLA. DISCUSSION: The improved wound healing is associated with increased EGF and VEGF and reduced plasma TNF-alpha and IL-6. CONCLUSION: RLA may be more effective than LA in improving chronic wound healing in patients undergoing HBO therapy. PMID- 23360080 TI - Generation of an artificial ring chromosome in Arabidopsis by Cre/LoxP-mediated recombination. AB - A eukaryotic chromosome consists of a centromere, two telomeres and a number of replication origins, and 'artificial chromosomes' may be created in yeast and mammals when these three elements are artificially joined and introduced into cells. Plant artificial chromosomes (PACs) have been suggested as new vectors for the development of new crops and as tools for basic research on chromosomes. However, indisputable PAC formation has not yet been confirmed. Here, we present a method for generating PACs in the model plant Arabidopsis thaliana using the Cre/LoxP and Activator/Dissociation element systems. The successfully generated PAC, designated AtARC1 (A. thaliana artificial ring chromosome 1), originated from a centromeric edge of the long arm of chromosome 2, but its size (2.85 Mb) is much smaller than that of the original chromosome (26.3 Mb). Although AtARC1 contains only a short centromere domain consisting of 180 bp repeats approximately 250 kb in length, compared with the 3 Mb domain on the original chromosome 2, centromere-specific histone H3 (HTR12) was detected on the centromeric region. This result supported the observed stability of the PAC during mitosis in the absence of selection, and transmission of the PAC to the next generation through meiosis. Because AtARC1 contains a unique LoxP site driven by the CaMV 35S promoter, it is possible to introduce a selectable marker and desired transgenes into AtARC1 at the LoxP site using Cre recombinase. Therefore, AtARC1 meets the criteria for a PAC and is a promising vector. PMID- 23360081 TI - Oscillation and recoil of single and consecutively printed droplets. AB - In this study, the recoil and oscillation of single and consecutively printed drops on substrates of different wettabilities are examined using a high speed camera. The results show that, for a droplet impact on a dry surface at Weber number ~ O (1), both inertia and capillary effects are important in the initial spreading regime before the droplet starts to oscillate. For a substrate of higher wettability, drop oscillation decays faster due to a stronger viscous dissipation over a longer oscillation path parallel to the substrate. It is also found that when a drop impacts on a sessile drop sitting on a hydrophobic substrate, the combined drop recoil twice resulted from the coalescence of the two drops, whereas no recoil is observed for the impact of a single drop on a dry surface under the same condition. Furthermore, a single-degree-of-freedom vibration model for the height oscillation of single and combined drops on a hydrophobic substrate is established. For the condition considered, the model predictions match well with the experiments. The results also show the extent to which the increase in the liquid viscosity facilitates oscillation damping and the quantitative extension of the oscillation time of a combined drop compared to a single drop. PMID- 23360082 TI - Electronic structure of individual hybrid colloid particles studied by near-edge X-ray absorption fine structure (NEXAFS) spectroscopy in the X-ray microscope. AB - The electronic structure of individual hybrid particles was studied by nanoscale near-edge X-ray absorption spectromicroscopy. The colloidal particles consist of a solid polystyrene core and a cross-linked poly-N-(isopropylacrylamide) shell with embedded crystalline titanium dioxide (TiO(2)) nanoparticles (d = 6 +/- 3 nm). The TiO(2) particles are generated in the carrier network by a sol-gel process at room temperature. The hybrid particles were imaged with photon energy steps of 0.1 eV in their hydrated environment with a cryo transmission X-ray microscope (TXM) at the Ti L(2,3)-edge. By analyzing the image stacks, the obtained near-edge X-ray absorption fine structure (NEXAFS) spectra of our individual hybrid particles show clearly that our synthesis generates TiO(2) in the anastase phase. Additionally, our spectromicroscopy method permits the determination of the density distribution of TiO(2) in single carrier particles. Therefore, NEXAFS spectroscopy combined with TXM presents a unique method to get in-depth insight into the electronic structure of hybrid materials. PMID- 23360083 TI - Audit of complications in post-operative epidural analgesia and adherence to acute pain service protocols at an Indian cancer center. AB - An audit of epidural anesthesia in an Indian teaching hospital is described. The authors reviewed Acute Pain Service (APS) documentation of epidural anesthesia and outcomes form the procedure over a 6-month period. Variances from established protocols were noted and reasons for these variances are discussed. PMID- 23360084 TI - Modulation of esophageal afferent pathways by 5-HT3 receptor inhibition. AB - BACKGROUND: The study aims were to investigate whether neural pathways involving 5-HT3 receptors mediate: (i) distension-induced upper esophageal sphincter (UES) relaxation reflex, (ii) esophageal sensitivity to acid and electrical stimuli, and (iii) viserosomatic sensitization following acid exposure. METHODS: In Study I, in a double-blind crossover trial (n = 9) esophageal sensory and pain thresholds to electrical stimulation were measured in the esophagus, midsternum, and the foot, before subjects were randomized to receive either Ondansetron (8 mg i.v.) or NaCl (0.9% w/v). HCl (0.15 mol L(-1)) was then infused into distal esophagus and electrical thresholds were reassessed. Following electrical sensory threshold testing, subjects received a second esophageal infusion of HCl to evaluate esophageal sensitivity to acid. In Study II (N = 10), frequencies of distension-induced UES relaxation responses were scored before and after treatment with Ondansetron and NaCl in a double-blind crossover trial. KEY RESULTS: In Study I, ondansetron had no effect on esophageal sensitivity to HCl or acid-induced sensitization. However, blockade of 5-HT3 receptors did reduce midsternum somatic pain thresholds. Sixty minutes after esophageal acid exposure, pain thresholds were significantly lower in the ondansetron arm (mean Delta-1.36 +/- 0.4 mA) when compared with NaCl (mean Delta-0.14 +/- 0.58 mA) (P < 0.05). In Study II, 5-HT3 receptor blockade had no significant effect on UES relaxation reflex. CONCLUSIONS & INFERENCES: This study does not support the hypothesis that in health, 5-HT3 receptors play a significant role in esophago-UES distention induced relaxation reflex and esophageal sensitivity to acid or electrical stimulation. It does provide new evidence for involvement of 5-HT3 receptors in viscerosomatic sensitization. PMID- 23360085 TI - Clinical progress in the two years following a course of exclusive enteral nutrition in 109 paediatric patients with Crohn's disease. AB - BACKGROUND: Exclusive enteral nutrition (EEN) is an effective first line treatment for active paediatric Crohn's disease (CD). AIM: To examine the effect of EEN on short- and long-term clinical outcome together with anthropometric measurements. METHODS: Retrospective case-note review in newly diagnosed CD (<16 years) who completed 8 weeks of EEN. Demographics, anthropometry, disease characteristics and inflammatory markers were collected at EEN initiation and at 1, 2, 6, 12 & 24 months post treatment initiation. EEN response was determined by a patient global assessment. RESULTS: One hundred and nine patients were included (Males 68; Median age: 11.2 years). After 8 weeks EEN, 65 were in remission, 32 improved and 12 had no improvement. By 4 weeks, mean weight/BMI z-score (s.d.) increased (P < 0.02) and between 4 and 8 weeks (P < 0.05). Baseline inflammatory markers all improved significantly by week 4 (albumin, CRP and platelets; all P < 0.01) and ESR (P < 0.00001). 63/109(58%) relapsed during follow-up. 44/63(70%) patients completed a second course of EEN with similar response rate, but lower weight gain (3.3 vs. 5.1 kg, P < 0.05). Height z-score did not change significantly over the 24 months. Introduction of azathioprine within 6 months of diagnosis did not improve height outcomes at 24 months. CONCLUSIONS: Weight and BMI z-score improved with EEN and changes are sustained to 2 years, but height z score did not. Seventy per cent of patients who relapsed during 2-year follow-up managed a 2nd course of EEN. The optimal therapeutic strategies for length of EEN course and to improve linear growth are awaited. PMID- 23360086 TI - The New England Research Institutes, Inc. (NERI) Nocturia Advisory Conference 2012: focus on outcomes of therapy. AB - A consensus statement published in 2011 summarised current research, clinical approaches, and treatment options for nocturia. Since that time, new research has refined our understanding of nocturia in clinically important ways and new evidence has been presented on the efficacy and outcomes of several treatment methods for this underreported, infrequently recognised, and undertreated problem in adults. This paper provides updated guidance to clinicians in light of recent advances in the field. PMID- 23360088 TI - Two-step recrystallization of water in concentrated aqueous solution of poly(ethylene glycol). AB - Crystallization behavior of water in a concentrated aqueous solution of poly(ethylene glycol) (PEG) with a water content of 37.5 wt % was investigated by temperature variable mid-infrared (mid-IR) spectroscopy in a temperature range of 298-170 K. The mid-IR spectrum of water at 298 K showed that a large water cluster was not formed and that most of the water molecules were associated with the PEG chain. Ice formation, however, occurred as found in previous studies by differential scanning calorimetory. Ice formations were grouped into three types: crystallization at 231 K during cooling, that at 198 K during heating, and that at 210 K during heating. The latter two were just recrystallization. These ice formations were the direct transition from hydration species to ice without condensation regardless of crystallization or recrystallization. This means that the recrystallized water in the present system was not generated from low-density amorphous solid water. At a low cooling rate, nearly complete crystallization at 231 K during cooling and no recrystallization were observed. At a high cooling rate, no crystallization and two-step recrystallization at 198 and 210 K were observed. The former and latter recrystallizations were found to be generated from water associated with the PEG chains with ttg (the sequence -O-CH(2)-CH(2)-O having a trans (t) conformation about the -C-O- bond and a gauche (g) conformation about the -C-C- bond) and random conformations, respectively. These results indicate that recrystallizable water does not have a single specific water structure. PMID- 23360087 TI - Thyroid follicle formation and thyroglobulin expression in multipotent endodermal stem cells. AB - OBJECTIVE: The aim of this study was to assess the impact of transcriptional induction on thyroid follicular cell (TFC) differentiation from endodermally matured embryonic stem (ES) cells. The thyroid transcription factors-NKx2 homeobox 1 (NKx2-1, formerly called TTF-1) and Paired box gene 8 (Pax8)-are known to associate biochemically and synergistically in the activation of thyroid functional genes including the sodium/iodide symporter (NIS), thyrotropin (TSH) receptor (TSHR), thyroglobulin (Tg), and thyroid peroxidase (TPO) genes. In this study, we investigated the ability of ectopically expressed Pax8 and NKx2-1 to further the induction and differentiation of murine ES cells into potential TFCs. METHODS: ES cells were stably transfected with either the Pax8 gene, the NKx2-1 gene, or both genes to study the induction of NIS, TSHR, Tg, and TPO genes as assessed using both quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and protein expression. The derived cells were cultured with or without the presence of activin A to allow their differentiation into multipotent endodermal cells. RESULTS: The four thyroid-specific genes NIS, TSHR, Tg, and TPO were all significantly activated by expressing both transcription factors within the same ES cell. In contrast, significant but much lower transcriptional activity of the TSHR, Tg, and TPO genes was detected in cells expressing just NKx2-1, and only the NIS and TSHR genes responded to Pax8 alone. No Tg protein expression could be detected prior to their development into endodermal derivatives. However, after further differentiation of postembryoid body ES cells with activin A and TSH into endodermal cell lines, those cells with dual transfection of Pax8 and NKx2-1 demonstrated greatly enhanced expression of the NIS, TSHR, Tg, and TPO genes to such a degree that it was similar to that found in control thyroid cells. Furthermore, these same cells formed three-dimensional neofollicles in vitro and expressed Tg protein, but these phenomena were absent from lines expressing only Pax8 or NKx2-1. CONCLUSION: These findings provide further evidence that co-expression of Pax8 and NKx2-1 in murine ES cells may induce the differentiation of thyroid-specific gene expression within endodermally differentiated ES cells and commit them to form three-dimensional neofollicular structures. PMID- 23360090 TI - An interactive human carbonic anhydrase-II (hCA-II) receptor--pharmacophore molecular model & anti-convulsant activity of the designed and synthesized 5 amino-1,3,4-thiadiazole-2-thiol conjugated imine derivatives. AB - New imines, derived from aromatic aldehyde, chalcones and 5-amino-1,3,4 thiadiazole-2-thiol exhibited promising anti-convulsant activity which is explained through chemo-biological interactions at receptor site producing the inhibition of human Carbonic Anhydrase-II enzyme (hCA-II) through the proposed pharmacophore model at molecular levels as basis for pharmacological activity. The compounds 5-{1-(4-Chlorophenyl)-3-[4-(methoxy-phenyl)-prop-2-en-1 ylidene]amino}-1,3,4-thiadiazole-2-thiol (2b), 5-{[1-(4-chloro-phenyl)]-3-[4 (dimethyl-amino-phenyl)-prop-2-en-1-ylidene]amino}-1,3,4-thiadiazole-2-thiol (2c) and 5-{[1-(4-chloro-phenyl)]-3-[(4-amino-phenyl)-prop-2-en-1-ylidene]amino}-1,3,4 thiadiazole-2-thiol (2f) showed 100% activity in comparison with standard Acetazolamide, a known anti-convulsant drug. The compounds 2c, 2f also passed the Rotarod and Ethanol Potentiation tests which further confirmed them to be safe in motor coordination activity and safe from generating neurological toxicity. PMID- 23360089 TI - Risk and clinical-outcome indicators of delirium in an emergency department intermediate care unit (EDIMCU): an observational prospective study. AB - BACKGROUND: Identification of delirium in emergency departments (ED) is often underestimated; within EDs, studies on delirium assessment and relation with patient outcome in Intermediate Care Units (IMCU) appear missing in European hospital settings. Here we aimed to determine delirium prevalence in an EDIMCU (Hospital de Braga, Braga, Portugal) and assessed routine biochemical parameters that might be delirium indicators. METHODS: The study was prospective and observational. Sedation level was assessed via the Richmond Agitation-Sedation Scale and delirium status by the Confusion Assessment Method for the ICU. Information collected included age and gender, admission type, Charlson Comorbidity Index combined condition score (Charlson score), systemic inflammatory response syndrome criteria (SIRS), biochemical parameters (blood concentration of urea nitrogen, creatinine, hemoglobin, sodium and potassium, arterial blood gases, and other parameters as needed depending on clinical diagnosis) and EDIMCU length of stay (LOS). Statistical analyses were performed as appropriate to determine if baseline features differed between the 'Delirium' and 'No Delirium' groups. Multivariate logistic regression was performed to assess the effect of delirium on the 1-month outcome. RESULTS: Inclusion and exclusion criteria were met in 283 patients; 238 were evaluated at 1-month for outcome follow-up after EDIMCU discharge ("good" recovery without complications requiring hospitalization or institutionalization; "poor" institutionalization in permanent care-units/assisted-living or death). Delirium was diagnosed in 20.1% patients and was significantly associated with longer EDIMCU LOS. At admission, Delirium patients were significantly older and had significantly higher blood urea, creatinine and osmolarity levels and significantly lower hemoglobin levels, when compared with No Delirium patients. Delirium was an independent predictor of increased EDIMCU LOS (odds ratio 3.65, 95% CI 1.97-6.75) and poor outcome at 1 month after discharge (odds ratio 3.51, CI 1.84-6.70), adjusted for age, gender, admission type, presence of SIRS criteria, Charlson score and osmolarity at admission. CONCLUSIONS: In an EDIMCU setting, delirium was associated with longer LOS and poor outcome at 1-month post-discharge. Altogether, findings support the need for delirium screening and management in emergency settings. PMID- 23360092 TI - Coincidence of total anomalous pulmonary venous drainage to the superior vena cava, common atrium, and single ventricle: a very rare condition. AB - Single ventricle defects, including inflow emptying into 1 ventricle, occur at an incidence of 0.05-0.1 per 10,000 live births. The association of total anomalous pulmonary venous drainage (TAPVD) with single ventricle defects is a risk factor for poor outcome. Conversely, common atrium, a rare congenital anomaly, is an endocardial cushion defect. We present a rare case of an unoperated patient with coincidence of a single ventricle defect, TAPVD with direct drainage from the pulmonary veins into the superior vena cava, and common atrium. To the best of our knowledge, such a case has not been previously reported in the literature. PMID- 23360093 TI - Association study of STAT4 polymorphisms and type 1 diabetes in Northeastern Chinese Han population. AB - Type 1 diabetes (T1D) is an organ-specific, T-cell-mediated disease resulting from the selective destruction of pancreatic beta cells. The signal transducer and activator of transcription 4 (STAT4) gene is one of the most interesting genes for the pathogenesis of autoimmune diseases, including T1D. In this study, a case-control study was conducted in a Han population in northeastern China comparing the genotypes of T1D patients to healthy controls for the presence of two single-nucleotide polymorphisms (SNPs) in the STAT4 gene. The study population comprised of 410 T1D patients and 407 healthy individuals. Two SNPs (rs7574865 and rs3024866) of STAT4 were genotyped with Multiplex SNaPShot method. Data were analyzed with spss 13.0 to determine if a statistical association existed between these genotypes and T1D. One of the two SNPs (rs7574865) was strongly associated with T1D in Northeastern Chinese population compared to healthy controls (P < 0.05), whereas the other tested SNP (rs3024866) demonstrated no significant relationship. In conclusion, the STAT4 gene may play an important role in facilitating susceptibility to T1D in this Han Chinese population. PMID- 23360094 TI - Comparison of musculoskeletal anatomic relationships, determined by magnetic resonance imaging, in postpubertal female patients with and without classic bladder exstrophy. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Several studies in the paediatric literature have characterized the pelvic musculoskeletal anatomy of infants and children with bladder exstrophy using MRI and three-dimensional CT. The pelvic floor anatomy of female patients with bladder exstrophy who have undergone somatic growth and puberty is less well described. This study uses MRI to characterize comprehensively the pelvic anatomy of postpubertal females with classic bladder exstrophy by measuring 15 pelvic floor variables previously described in younger children with bladder exstrophy. OBJECTIVE: To characterize pelvic musculoskeletal anatomy in postpubertal females with classic bladder exstrophy, and to compare this with females without bladder exstrophy. PATIENTS AND METHODS: The authors reviewed the medical records of all females in our institutional review board-approved bladder exstrophy database of 1078 patients and identified those with classic bladder exstrophy who underwent pelvic magnetic resonance imaging (MRI) after the age of 12 years. Indications for MRI included haematuria, adnexal lesion, perineal fistula, non-pelvic cancer staging, abdominal wall hernia and vaginal stenosis. Age- and race-matched female patients without exstrophy who underwent MRI evaluation for similar indications were included for comparison. The MRI protocol included axial, sagittal and coronal T1 and/or T2-weighted imaging. RESULTS: The study included 30 patients with a median (range) age of 22.5 (12-55) years at time of MRI. Ten patients had bladder exstrophy while 20 control patients did not. A smaller percentage of levator ani was located in the anterior compartment of the pelvis in patients with bladder exstrophy compared with controls. The iliac wing angle, puborectalis angle, ileococcygeous angle, levator ani width, symphyseal diastasis, erectile body diastasis, posterior bladder neck distance and posterior anal distance was greater in patients with bladder exstrophy than in those without. The ischial angle and obturator internus angle were narrower in patients with bladder exstrophy than in those without, and there was no significant difference between levator ani surface area, sacral anal angle, sacral bladder neck angle and bladder neck erectile body distance between the two patient groups. CONCLUSIONS: In postpubertal females with bladder exstrophy, significant deviations from normal pelvimetry exist, including posterior location of the majority of the levator ani muscle, a wider ileococcygeous angle and a wider symphyseal diastasis. These differences are similar to those described in previous comparisons of younger children with bladder exstrophy and control children. PMID- 23360095 TI - A chemical complementation approach reveals genes and interactions of flavonoids with other pathways. AB - In addition to the classical functions of flavonoids in the response to biotic/abiotic stress conditions, these phenolic compounds have been implicated in the modulation of various developmental processes. These findings suggest that flavonoids are more integral components of the plant signaling machinery than traditionally recognized. To understand how flux through the flavonoid pathway affects plant cellular processes, we used wild-type and chalcone isomerase mutant (transparent testa 5, tt5) seedlings grown under anthocyanin inductive conditions, in the presence or absence of the flavonoid intermediate naringenin, the product of the chalcone isomerase enzyme. Because flavonoid biosynthetic genes are expressed under anthocyanin inductive conditions regardless of whether anthocyanins are formed or not, this system provides an excellent opportunity to specifically investigate the molecular changes associated with increased flux through the flavonoid pathway. By assessing genome-wide mRNA accumulation changes in naringenin-treated and untreated tt5 and wild-type seedlings, we identified a flavonoid-responsive gene set associated with cellular trafficking, stress responses and cellular signaling. Jasmonate biosynthetic genes were highly represented among the signaling pathways induced by increased flux through the flavonoid pathway. In contrast to studies showing a role for flavonoids in the control of auxin transport, no effect on auxin-responsive genes was observed. Taken together, our data suggest that Arabidopsis can sense flavonoids as a signal for multiple fundamental cellular processes. PMID- 23360097 TI - Phenolic profile and antioxidant capacity of the principal apples produced in Brazil. AB - This study evaluated the phenols of the Gala, Fuji and Golden Delicious varieties, which make up 95% of Brazilian production. The phenolic profiles (whole fruit) were determined by high pressure liquid chromatography, total phenols were determined using the Folin-Ciocalteau method and antioxidant capacity by the FRAP method (whole fruit, skin, pulp and centre). The Golden Delicious had the highest phenol content (408 mg/fruit) compared to Fuji (194 mg/fruit) and Gala (162 mg/fruit), and the antioxidant capacity of the Golden Delicious was 2.5 and 3.6 times higher than that found in the Fuji and Gala, respectively. The phenolic profile for the three varieties showed 5 caffeoylquinic acid, ( - )-epicatechin, procyanidin B2 and phloridzin as major components with procyanidins as the predominant class and quercetin as the minority. The consumption of apple pulp may provide 48-78% of the antioxidant capacity; however, if the peel is ingested, it may increase to 79-89%. The type of apple variety and the parts ingested are factors that must be taken into consideration in consumption. PMID- 23360096 TI - Resting energy expenditure at 3 months of age following neonatal surgery for congenital heart disease. AB - OBJECTIVE: Infants with Congenital Heart Disease (CHD) often exhibit growth failure. This can affect anthropometric and neurodevelopmental outcomes well into childhood. To determine the resting energy expenditure (REE), body composition, and growth in infants with CHD at 3 months of age, with the secondary aim to identify predictors of REE as compared with healthy infants. DESIGN AND METHODS: This descriptive study is a subanalysis of a prospective study investigating predictors of growth in postoperative infants with CHD compared with healthy infants. Growth measurements, REE, and body composition were obtained in all infants. Analysis included chi-square for association between categorical variables, t-tests, ANOVA and ANCOVA. Outcome measures included the REE as determined by indirect calorimetry, anthropometric z-scores and body composition at 3 months of age. SETTING: Participants were recruited from the Cardiac Intensive Care Unit of a large, urban, pediatric cardiac center and pediatric primary care practices. RESULTS: The analysis included 93 infants, 44 (47%) with CHD. Of the infants with CHD, 39% had single ventricle (SV) physiology. There was no difference in REE related to cardiac physiology between infants with CHD and healthy infants or between infants with SV and biventricular (BV) physiology. Anthropometric z-scores for weight (-1.1 +/- 1.1, P < 0.001), length (-0.7 +/- 1.1, P < 0.05), and head circumference (-0.6 +/- 1.2, P < 0.001) were lower in infants with CHD at 3 months of age. The percentage of body fat (%FAT) in postoperative infants with SV (24% +/- 6, P = 0.02) and BV (23% +/- 5, P < 0.001) physiology were lower than in healthy infants (27% +/- 5), with no difference in REE. CONCLUSION: At 3 months of age, there was no difference in REE between postsurgical infants with CHD and healthy infants. Infants with CHD had lower growth z-scores and %FAT. These data demonstrate decreased %FAT contributed to growth failure in the infants with CHD. PMID- 23360098 TI - Oxygen-reducing biocathodes operating with passive oxygen transfer in microbial fuel cells. AB - Oxygen-reducing biocathodes previously developed for microbial fuel cells (MFCs) have required energy-intensive aeration of the catholyte. To avoid the need for aeration, the ability of biocathodes to function with passive oxygen transfer was examined here using air cathode MFCs. Two-chamber, air cathode MFCs with biocathodes produced a maximum power density of 554 +/- 0 mW/m(2), which was comparable to that obtained with a Pt cathode (576 +/- 16 mW/m(2)), and 38 times higher than that produced without a catalyst (14 +/- 3 mW/m(2)). The maximum current density with biocathodes in this air-cathode MFC was 1.0 A/m(2), compared to 0.49 A/m(2) originally produced in a two-chamber MFC with an aqueous cathode (with cathode chamber aeration). Single-chamber, air-cathode MFCs with the same biocathodes initially produced higher voltages than those with Pt cathodes, but after several cycles the catalytic activity of the biocathodes was lost. This change in cathode performance resulted from direct exposure of the cathodes to solutions containing high concentrations of organic matter in the single-chamber configuration. Biocathode performance was not impaired in two-chamber designs where the cathode was kept separated from the anode solution. These results demonstrate that direct-air biocathodes can work very well, but only under conditions that minimize heterotrophic growth of microorganisms on the cathodes. PMID- 23360099 TI - The dynamics of singlet fission in crystalline tetracene and covalent analogs. AB - Singlet fission (SF) is a spin-allowed process in which an excited singlet state spontaneously splits into a pair of triplet excitons. This relaxation pathway is of interest as a mechanism for increasing the efficiency of photovoltaic solar cells, since ionization of the triplets could produce two charge carriers per absorbed photon. In this Account, we summarize our recent work on trying to understand how SF occurs using both covalent and noncovalent assemblies of tetracene. We first give a brief overview of the SF process and discuss why tetracene, where the singlet and triplet pair energies are nearly degenerate, is a particularly useful molecule for studying this process. Then we describe our experiments, beginning with the study of phenylene-linked tetracene dimers as covalent analogs for the crystal form, where SF is known to be very efficient. We found that only 2-3% of the initially excited singlets underwent SF in these dimers. These results motivated us to study crystalline tetracene in more detail. Transient absorption and photoluminescence experiments on polycrystalline thin films provided evidence for a delocalized singlet exciton that decays with a complicated temperature-dependence, but we were unable to unambiguously identify the signature of the triplet pair formed by SF. Then, using ultrathin single crystals, we observed quantum beats in the delayed fluorescence arising from recombination of spin-coherent triplet pairs. Analyzing these quantum beats revealed that SF proceeds through a direct one-step process occurring within 200 ps at room temperature. The product of this reaction is a pair of unperturbed triplets that have negligible interaction with each other. Looking at the overall SF process in tetracene, remaining issues that need to be clarified include the role of exciton diffusion, the temperature dependence of the SF rate, and how to use insights gained from the solid-state studies to generate design principles for high-efficiency covalent systems. Our experiments provide a good illustration of why the polyacenes, and tetracene in particular, play an important role as systems for the study of SF. PMID- 23360100 TI - Vasopressin modulates neural responses during human reactive aggression. AB - The neuropeptide arginine vasopressin (AVP) is known to modulate aggressive behavior in mammals, but the neural mechanisms underlying this modulation are not clear yet. In the present study, we administered 20 IU AVP nasally in a randomized, placebo-controlled, double-blind manner to 36 healthy men using a between-subjects design. After drug administration, participants performed a competitive reaction time task (Taylor Aggression Paradigm, TAP) to elicit reactive aggressive behavior while functional magnetic resonance imaging was recorded. Under AVP treatment, we found increased activations in the right superior temporal sulcus in the decision phase during trials in which participants could get punished after losing the reaction time competition. At the behavioral level, no differences could be found between AVP treatment and placebo condition. The lack of AVP-related behavioral effects is discussed in terms of the general aggression model (GAM). PMID- 23360101 TI - Emerging executive skills in very preterm children at 2 years corrected age: a composite assessment. AB - Executive Function (EF) deficits have previously been identified in preterm children. However, only recently have emerging executive functions been studied in preschool children who were born preterm without major brain damage. Our study provides a broad assessment of EFs in 72 extremely preterm births (gestational age < 34 weeks and birth weight < 2500 g) and 73 full-term children, born between 2006 and 2008, at 24 months of corrected age. Three factors were extracted from the EF administered measures: working memory, cognitive flexibility, and impulsivity control. Only cognitive flexibility was found to discriminate preterm children from controls. PMID- 23360102 TI - Vagus nerve stimulation: from epilepsy to the cholinergic anti-inflammatory pathway. AB - BACKGROUND: The brain and the gut communicate bidirectionally through the autonomic nervous system (ANS). The vagus nerve (VN), a major component of the ANS, plays a key role in the neuro-endocrine-immune axis to maintain homeostasia through its afferents (through the activation of the hypothalamic pituitary adrenal axis and the central ANS) and through its efferents (i.e. the cholinergic anti-inflammatory pathway; CAP). The CAP has an anti-TNF effect both through the release of acetylcholine at the distal VN acting on macrophages and through the connection of the VN with the spleen through the splenic sympathetic nerve. Vagus nerve stimulation (VNS) of vagal afferents at high frequency (20-30 Hz) is used for the treatment of drug-resistant epilepsy and depression. Low-frequency (5 Hz) VNS of vagal efferents activates the CAP for an anti-inflammatory effect that is as an anti-TNF therapy in inflammatory diseases were TNF is a key cytokine as represented by experimental sepsis, postoperative ileus, burn-induced intestinal barrier injury, colitis. However, both vagal afferents and efferents are activated by VNS. PURPOSE: The objective of this review was to explore the following: (i) the supporting evidence for the importance of VNS in epilepsy (and depression) and its mechanisms of action, (ii) the anti-inflammatory characteristics of the VN, (iii) the experimental evidence that VNS impact on inflammatory disorders focusing on the digestive tract, and (iv) how VNS could potentially be harnessed therapeutically in human inflammatory disorders such as inflammatory bowel diseases, irritable bowel syndrome, postoperative ileus, rheumatoid arthritis as an anti-inflammatory therapy. PMID- 23360103 TI - Calculating two-dimensional spectra with the mixed quantum-classical Ehrenfest method. AB - We present a mixed quantum-classical simulation approach to calculate two dimensional spectra of coupled two-level electronic model systems. We include the change in potential energy of the classical system due to transitions in the quantum system using the Ehrenfest method. We study how this feedback of the quantum system on the classical system influences the shape of two-dimensional spectra. We show that the feedback leads to the expected Stokes shift of the energy levels in the quantum system. This subsequently leads to changes in the population transfer between quantum sites, which in turn influence the intensities of the peaks in two-dimensional spectra. The obtained spectra are compared with spectra calculated using the Hierarchical Equations of Motion method which is exact. While the spectra match perfectly for short waiting times, clear differences are found for longer waiting times. This is attributed to a violation of detailed balance between the quantum states in the Ehrenfest method. The energy of the total quantum-classical system however does obey a Boltzmann distribution, when coupled to a stochastic heat bath. PMID- 23360104 TI - Bioactive sesterterpenoids from a Korean sponge Monanchora sp. AB - Chemical investigation of a Korean marine sponge, Monanchora sp., yielded nine new sesterterpenoids (1-9) along with phorbaketals A-C (10-12). The planar structures were established on the basis of NMR and MS analysis, and the absolute configurations of 1-9 were defined using the modified Mosher's method and CD spectroscopic data analysis. Compounds 1-8, designated as phorbaketals D-K, possess a spiroketal-modified benzopyran moiety such as phorbaketal A, and their structural variations are due to oxidation and/or reduction of the tricyclic core or the side chain. Compound 9, designated as phorbin A, has a monocyclic structure and is proposed to be a possible biogenetic precursor of the phorbaketals. Compounds 1-9 were evaluated for cytotoxicity against four human cancer cell lines (A498, ACHN, MIA-paca, and PANC-1), and a few of them were found to exhibit cytotoxic activity. PMID- 23360106 TI - Assortative mating in mixed swarms of the mosquito Anopheles gambiae s.s. M and S molecular forms, in Burkina Faso, West Africa. AB - The molecular form composition of Anopheles gambiae Giles s.s. (Diptera: Culicidae) mating swarms and the associated mating pairs (copulae) were investigated during two rainy seasons (July to October, 2005 and July to November, 2006) in the villages of Soumousso and Vallee du Kou (VK7). Although the habitats of these villages differ markedly, sympatric populations of M and S molecular forms of An. gambiae s.s. occur in both places periodically. The main aim was to assess the degree to which these molecular forms mate assortatively. In Soumousso, a wooded savannah habitat, the majority of swarm samples consisted of only S-form males (21/28), although a few M-form males were found in mixed M- and S-form swarms. In VK7, a rice growing area, the majority of swarm samples consisted of only M-form males (38/62), until October and November 2006, when there were nearly as many mixed-form as single-form swarms. Overall, ~60% of M- and S-form swarms were temporally or spatially segregated; the two forms were effectively prevented from encountering each other. Of the remaining 40% of swarms, however, only about half were single-form and the rest were mixed-form. Of the 33 copulae collected from mixed-form swarms, only four were mixed-form pairs, significantly fewer than expected by random pairing between forms (chi(2) = 10.34, d.f. = 2, P < 0.01). Finally, all specimens of inseminated females were of the same form as the sperm contained within their spermatheca (n = 91), even for the four mixed-form copulae. These findings indicate that assortative mating occurs within mixed-form swarms, mediated most probably by close-range mate recognition cues. PMID- 23360105 TI - A population-based experimental model for protein evolution: effects of mutation rate and selection stringency on evolutionary outcomes. AB - Protein evolution is a critical component of organismal evolution and a valuable method for the generation of useful molecules in the laboratory. Few studies, however, have experimentally characterized how fundamental parameters influence protein evolution outcomes over long evolutionary trajectories or multiple replicates. In this work, we applied phage-assisted continuous evolution (PACE) as an experimental platform to study evolving protein populations over hundreds of rounds of evolution. We varied evolutionary conditions as T7 RNA polymerase evolved to recognize the T3 promoter DNA sequence and characterized how specific combinations of both mutation rate and selection stringency reproducibly result in different evolutionary outcomes. We observed significant and dramatic increases in the activity of the evolved RNA polymerase variants on the desired target promoter after selection for 96 h, confirming positive selection occurred under all conditions. We used high-throughput sequencing to quantitatively define convergent genetic solutions, including mutational "signatures" and nonsignature mutations that map to specific regions of protein sequence. These findings illuminate key determinants of evolutionary outcomes, inform the design of future protein evolution experiments, and demonstrate the value of PACE as a method for studying protein evolution. PMID- 23360107 TI - Sequencing of the novel HLA-B*49:24 and HLA-DRB1*03:64 alleles. AB - HLA-B*49:24 shows one nucleotide difference regarding B*49:10 at codon 12 (ATG>GTG). DRB1*03:64 differs from DRB1*03:01:01 in one amino acid residue at position 59, E>Q. PMID- 23360108 TI - Need for intensive care for neonates born between 29 and 34 weeks inclusive gestation. AB - AIMS: To identify the proportion of preterm infants needing neonatal intensive care (NIC) between 29 and 34 weeks gestation. To identify any associated risk factors. METHODS: This population-based study identified all babies, born without congenital abnormalities, between 29 and 34 weeks gestation inclusive. A 21-month period ending September 2009 was used. The need for NIC was defined using specific cardiorespiratory and nutritional criteria. The use of continuous positive airway pressure alone was not included as a need for NIC. Data were extracted from a neonatal clinical database and individual medical records. RESULTS: Complete data were available from 707 out of 709 eligible infants born in the study period. The percentage of infants requiring cardiorespiratory support varied from 39 to 2.7% at 29 and 34 weeks, respectively. If nutritional criteria were included, this increased to 77% at 29 weeks and 7.2% at 34 weeks. Multivariate analysis determined that gestational age and delivery by Caesarean section increased the need for intensive care (P-value <0.01). Antenatal steroids, gender, underlying maternal medical conditions, being small for gestational age or twin pregnancy had no statistically significant impact. CONCLUSIONS: This study supports the National Health and Medical Research Council Guidelines of in-utero transfer at <33 weeks gestation. Gestational age and delivery by Caesarean section remain major indicators for the need for NIC. In special care nurseries that have the capability and expertise to use nasal continuous positive airway pressure, the main indication for NIC is for nutritional support. PMID- 23360109 TI - Modulation of cytochrome P450 enzymes in response to continuous or intermittent high-fat diet in pigs. AB - 1. To date, no information has been available on the modulation of cytochrome P450 enzymes (CYPs) following the administration of a hyperlipidemic diet in pigs. 2. We investigated the potential modulation of xenobiotic-metabolizing CYPs in liver, heart and duodenum of pigs subjected to a high-fat/high-cholesterol diet for 2 months continuously (C-HFD) or on alternate weeks (A-HFD). 3. The administration of the high-fat diet resulted in considerably increased plasma cholesterol levels although the animals were still able to manage the lipid overload efficiently, and no sign of effective tissue inflammation occurred in livers. Plasma lipid profile and liver histology indicated a better adaptive response of the A-HFD pigs compared to the C-HFD group. We showed a post transcriptional induction of hepatic CYP2E1 activity in C-HFD pigs and a transcriptional induction of hepatic CYP3As - especially in the A-HFD group. No further CYP modulation was observed in either liver or extra-hepatic tissues. 4. In conclusion, the administration of a high-fat diet in pigs resulted in limited effects on the drug metabolism system. The better adaptive response of A-HFD pigs compared to C-HFD pigs is a very interesting observation since the intermittent administration of the diet reflects the mode of human behavior more closely. PMID- 23360110 TI - In situ X-ray study of the structural evolution of gold nano-domains by spray deposition on thin conductive P3HT films. AB - Gold (Au) nanoparticles are deposited from aqueous solution onto one of the most used conductive polymers, namely poly(3-hexylthiophene) (P3HT), using airbrush deposition. We report on the structure formation and packing of the Au nanoparticles after a 5 s spray cycle. In situ grazing incidence small-angle X ray scattering (GISAXS) measurements with 20 ms time resolution allow a real-time observation of the emergence and evolution of the microstructure during a spray cycle and subsequent solvent evaporation. The results reveal multistage nanoscale ordering of the Au nanoparticles during the spray cycle. Further ex situ atomic force microscopy measurements of the sprayed films showed the formation of Au monolayer islands on top of the polymer film. Our study suggests that the solvent substrate interaction as well as solvent evaporation kinetics are important factors that need to be taken into consideration in order to grow a compact uniform monolayer film for the fabrication of ultrathin films using airbrush deposition. PMID- 23360112 TI - Serum receptor activator of nuclear factor kappaB ligand (RANKL) levels predict biochemical recurrence in patients undergoing radical prostatectomy. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There is increasing evidence that the receptor activator of nuclear factor kappaB ligand (RANKL) pathway not only contributes to the development of bone metastases, but also influences tumour biology in earlier stages of cancer. The study shows that preoperative serum levels of RANKL and its inhibitor osteoprotegerin (OPG) have a prognostic impact in patients undergoing radical prostatectomy for clinically localized prostate cancer. Both high levels of RANKL and a higher RANKL/OPG ratio are independent predictors of early biochemical recurrence in these patients. OBJECTIVE: To assess the prognostic impact of proteins of the receptor activator of nuclear factor kappaB (RANKL) pathway in serum samples from patients undergoing radical prostatectomy. PATIENTS AND METHODS: We retrospectively determined soluble RANKL (sRANKL) and osteoprotegerin (OPG) by ELISA in serum samples of 178 patients undergoing radical prostatectomy between 2004 and 2006. Clinical and patient follow-up data were analysed using the Wilcoxon-Mann-Whitney test, the Kaplan-Maier method, and single variable or multifactorial Cox proportional hazards analysis. RESULTS: Higher serum sRANKL levels (P = 0.01), lower serum OPG levels (P = 0.01) and a higher sRANKL/OPG ratio (P = 0.004) were significant risk factors for biochemical recurrence (BCR). In multifactorial analysis, adjusted for the common risk factors for BCR, sRANKL and sRANKL/OPG ratio were confirmed as independent prognostic factors. Neither sRANKL nor OPG showed a clear association with histopathological factors such as pT stage, pN Gleason score or resection margin status, nor were they associated with prostate specific antigen level. CONCLUSIONS: Greater activity of the RANKL pathway in the serum of patients with prostate cancer undergoing radical prostatectomy is a risk factor for BCR. The RANKL pathway seems to contribute to the biological behaviour of prostate cancer even at the organ-confined stage of the disease. PMID- 23360113 TI - Role of transition metals in UV-B-induced damage to bacteria. AB - The purpose of this study was to explore the possible link between metals and UV B-induced damage in bacteria. The effect of growth in the presence of enhanced concentrations of different transition metals (Co, Cu, Fe, Mn and Zn) on the UV-B sensitivity of a set of bacterial isolates was explored in terms of survival, activity and oxidative stress biomarkers (ROS generation, damage to DNA, lipid and proteins and activity of antioxidant enzymes). Metal amendment, particularly Fe, Cu and Mn, enhanced bacterial inactivation during irradiation by up to 35.8%. Amendment with Fe increased ROS generation during irradiation by 1.2-13.3%, DNA damage by 10.8-37.4% and lipid oxidative damage by 9.6-68.7%. Lipid damage during irradiation also increased after incubation with Cu and Co by up to 66.8% and 56.5% respectively. Mn amendment decreased protein carbonylation during irradiation by up to 44.2%. These results suggest a role of Fe, Co, Cu and Mn in UV-B-induced bacterial inactivation and the importance of metal homeostasis to limit the detrimental effects of ROS generated during irradiation. PMID- 23360111 TI - Targeting the RAS oncogene. AB - INTRODUCTION: The Ras proteins (K-Ras, N-Ras, and H-Ras) are GTPases that function as molecular switches for a variety of critical cellular activities and their function is tightly and temporally regulated in normal cells. Oncogenic mutations in the RAS genes, which create constitutively-active Ras proteins, can result in uncontrolled proliferation or survival in tumor cells. AREAS COVERED: The paper discusses three therapeutic approaches targeting the Ras pathway in cancer: i) Ras itself, ii) Ras downstream pathways, and iii) synthetic lethality. The most adopted approach is targeting Ras downstream signaling, and specifically the PI3K-AKT-mTOR and Raf-MEK pathways, as they are frequently major oncogenic drivers in cancers with high Ras signaling. Although direct targeting of Ras has not been successful clinically, newer approaches being investigated in preclinical studies, such as RNA interference-based and synthetic lethal approaches, promise great potential for clinical application. EXPERT OPINION: The challenges of current and emerging therapeutics include the lack of "tumor specificity" and their limitation to those cancers which are "dependent" on aberrant Ras signaling for survival. While the newer approaches have the potential to overcome these limitations, they also highlight the importance of robust preclinical studies and bidirectional translational research for successful clinical development of Ras-related targeted therapies. PMID- 23360114 TI - The glycaemic and C-peptide responses of foods rich in dietary fibre from oat, buckwheat and lingonberry. AB - Dietary fibre has a beneficial effect on metabolic syndrome, e.g. by influencing the absorption of glucose. The source and structure of fibre affect the glucose response. In this study, the glycaemic and insulinaemic response to oat bread, oat bread with lingonberry fibre, oat-buckwheat bread and buckwheat porridge were tested in a small-scale clinical study (KHSHP E514/09). Nine healthy volunteers consumed test foods after overnight fasting. Serum glucose and C-peptide levels were determined by colorimetric and ELISA methods, respectively, from samples taken at seven time points during 120 min. The mean glycaemic and C-peptide indexes (C-pepIs) were 32 and 100 for oat bread, 47 and 119 for oat-lingonberry fibre bread, 58 and 105 for oat-buckwheat bread and 71 and 77 for buckwheat porridge. Similar to rye, buckwheat porridge having a relatively high glycaemic index (GI) tended to have a low C-pepI. Buckwheat and lingonberry fibres provide new alternatives for low GI foods. PMID- 23360115 TI - Several synthetic progestins with different potencies adversely affect reproduction of fish. AB - Synthetic progestins are widely used as a component in both contraceptives and in hormone replacement therapy (HRT), both on their own and in combination with EE2. Their presence in the environment is now established in wastewater effluent and river water and this has led to concerns regarding their potential effects on aquatic organisms living in these waters. We carried out in vivo experiments to determine the potencies of four different synthetic progestins on the reproductive capabilities of the fathead minnow (Pimephales promelas). We then performed a series of in vitro assays to try and determine the reason for the effects seen in the in vivo experiments. In the first experiment, fathead minnow exposed to a single concentration of 100 ng/L of either Levonorgestrel or Gestodene stopped spawning almost completely. The same nominal concentration of Desogestrel and Drospirenone did not affect reproduction (21 d NOECs of 100 ng/L). The second experiment investigated two progestins of different potency: Gestodene at 1, 10, and 100 ng/L and Desogestrel at 100 ng/L, 1 MUg/L, and 10 MUg/L. Gestodene concentrations as low as 1 ng/L had significant effects on reproduction over 21 d, whereas concentrations of Desogestrel at or above 1 MUg/L were required to significantly reduce egg production. The synthetic progestins also masculinized the female fish in a concentration-dependent manner. Results from yeast-based in vitro assays demonstrated that the progestins are all strongly androgenic, thereby explaining the masculinization effects. The results strongly suggest that synthetic progestins merit serious consideration as environmental pollutants. PMID- 23360116 TI - Treatment of airway compromise due to laryngeal venous malformations: our experience of four patients. PMID- 23360117 TI - Host iron redistribution as a risk factor for incident tuberculosis in HIV infection: an 11-year retrospective cohort study. AB - BACKGROUND: Identifying people at higher risk of developing tuberculosis with human immunodeficiency virus (HIV) infection may improve clinical management of co-infections. Iron influences tuberculosis (TB) pathogenesis, but understanding the exact mechanisms of how and timing of when iron is involved remains challenging since biological samples are rarely available from the disease susceptibility period due to the difficulty in predicting in who and when, if ever, TB will develop. The objective of this research was to determine how host iron status measured at HIV diagnosis and genotypes related to host iron metabolism were associated with incident TB. METHODS: Archived clinical data, plasma and DNA were analyzed from 1139 adult participants in a large HIV-1, HIV-2 and dual seroprevalent cohort based at the Medical Research Council Laboratories in The Gambia. Incident pulmonary and/or extrapulmonary TB diagnoses a minimum of 28 days after HIV diagnosis were independently re-confirmed using available evidence (n=152). Multiple host iron status biomarkers, Haptoglobin and solute carrier family 11, member 1 (SLC11A1) genotypes were modeled to characterize how indicators of host iron metabolism were associated with TB susceptibility. RESULTS: Hemoglobin (incidence rate ratio, IRR=0.88, 95% CI=0.79-0.98), plasma transferrin (IRR=0.53, 0.33-0.84) and ferritin (IRR=1.26, 1.05-1.51) were significantly associated with TB after adjusting for TB susceptibility factors. While genotype associations were not statistically significant, SLC11A1 associations replicated similar directions as reported in HIV-seronegative meta analyses. CONCLUSIONS: Evidence of host iron redistribution at HIV diagnosis was associated with incident TB, and genetic influences on iron homeostasis may be involved. Low hemoglobin was associated with subsequent diagnosis of TB, but when considered in combination with additional iron status biomarkers, the collective findings point to a mechanism whereby anemia and iron redistribution are likely due to viral and/or bacteria-driven processes and the host immune response to infection. As a result, iron supplementation may not be efficacious or safe under these circumstances. Clinical and nutritional management of HIV and Mycobacterium tuberculosis co-infected individuals, especially in regions where food insecurity and malnutrition co-exist, may be further improved when the iron-related TB risk factors identified here are better understood and managed to favor host rather than pathogen outcomes. PMID- 23360118 TI - Assessing the regioselectivity of OleD-catalyzed glycosylation with a diverse set of acceptors. AB - To explore the acceptor regioselectivity of OleD-catalyzed glucosylation, the products of OleD-catalyzed reactions with six structurally diverse acceptors flavones- (daidzein), isoflavones (flavopiridol), stilbenes (resveratrol), indole alkaloids (10-hydroxycamptothecin), and steroids (2-methoxyestradiol)-were determined. This study highlights the first synthesis of flavopiridol and 2 methoxyestradiol glucosides and confirms the ability of OleD to glucosylate both aromatic and aliphatic nucleophiles. In all cases, molecular dynamics simulations were consistent with the determined product distribution and suggest the potential to develop a virtual screening model to identify additional OleD substrates. PMID- 23360119 TI - Health system reform and safe abortion: a case study of Mongolia. AB - Unsafe abortion serves as a marker of global inequity as it is concentrated in the developing world where the poorest and most vulnerable women live. While liberalisation of abortion law is essential to the reduction of unsafe abortion, a number of challenges exist beyond this important step. This paper investigates how popular health system reforms consonant with neoliberal agendas can challenge access to safe abortion. We use Mongolia, a country that has liberalised abortion law, yet, limited access to safe abortion, as a case study. Mongolia embraced market reforms in 1990 and subsequently reformed its health system. We document how common reforms in the areas of finance and regulation can compromise the safety of abortions as they foster challenges that include inconsistencies in service delivery that further foment health inequities, adoption of reproductive health programmes that are incompatible with the local sociocultural context, unregulated growth of the private sector and poor enforcement of standards and technical guidelines for safe abortion. We then discuss how this case study suggests the conversations that reproductive health policy-makers must have with those engineering health sector reform to ensure access to safe abortion in a liberalised environment. PMID- 23360121 TI - Gas transport across hyperthin membranes. AB - The use of organic polymeric membranes to separate gaseous mixtures provides an attractive alternative to other methods such as selective adsorption and cryogenic distillation. The primary advantages of membrane-based separations are their relative energy efficiency and lower costs. Because the flux of a gas across a membrane is inversely proportional to the membrane's thickness, this method relies on fabricating membranes that are as thin as possible. However, as researchers have tried to produce "hyperthin" membranes (less than 100 nm), these membranes often form defects and lose their permeation selectivity. In this Account, we review some of the progress in our laboratories at Lehigh University to create hyperthin membranes with high permeation selectivities. We focus special attention on gaseous permeants that are relevant for the production of clean energy (H2 and CO2 formed from CH4) and the reduction of global warming (CO2 and N2, the major components of flue gas). Our studies make extensive use of Langmuir-Blodgett (LB) methods and porous surfactants derived from calix[6]arenes. We specially designed each surfactant to form cohesive monolayers and multilayers, and we introduced a "gluing" technique, where we cross-link porous surfactants containing quaternary ammonium groups ionically with polymeric counterions. Using ellipsometry, atomic force microscopy, X-ray photoelectron spectroscopy, monolayer isotherm, surface viscosity, and permeation measurements, we have characterized these hyperthin films. While molecular sieving appears to make a significant contribution to the permeation selectivity of some of these membranes, solution-diffusion pathways predominate. We also describe initial studies in which we formed hyperthin films from poly(ethylene glycol)-based polyelectrolytes using layer-by-layer deposition (LbL) methods. We have found remarkably high H2/CO2 and CO2/N2 permeation selectivities with these LB- and LbL based hyperthin membranes. These results suggest that such materials may lead the way to materials that researchers can exploit to purify hydrogen produced from CH4 and to capture CO2 from flue gas. PMID- 23360120 TI - Platelet serotonin transporter and 5-HT2A receptor binding in adolescents with eating disorders. AB - The pathogenetic involvement of the serotonergic system in eating disorders is an established finding. Conclusions from platelet studies are based on results from investigations of subjects with a mean age of 20 years or more. The aim was to investigate whether previous findings in adults are valid also for adolescents who are examined within a relatively short interval after the onset of the eating disorder. [(3)H]paroxetine binding to the platelet serotonin transporter and [(3)H]lysergic acid diethylamide ([(3)H]LSD) binding to the 5-HT2A receptor was studied in 15 female adolescents with eating disorders (11 with anorexia nervosa and 4 with clearly anorectic eating behaviour not fulfilling the criteria for anorexia nervosa) and 32 controls. The patients revealed a higher density of serotonin transporters and a lower density of 5-HT2A receptors compared with healthy controls of the same age (775 +/- 165 vs. 614 +/- 111 fmol/mg protein (p = 0.003) for [(3)H]paroxetine binding and 215 +/- 59 vs. 314 +/- 151 fmol/mg protein (p = 0.005) for [(3)H]LSD binding). The findings of increased density of platelet serotonin transporters and reduced density of 5-HT2A receptors differ from previous results in older patients. The lower patient age and the short duration of disease in the present study, possibly in conjunction with variations in stress-related psychological and biological factors, may have caused these differences. Although the present findings contradict prevailing evidence, they add further information concerning the nature of serotonergic involvement in eating disorders and indicate that demographic and course-related factors might influence the regulation of the serotonin system in these disorders. PMID- 23360122 TI - Classification of normal and abnormal colonic motility based on cross correlations of pancolonic manometry data. AB - BACKGROUND: Manual analysis of data acquired from manometric studies of colonic motility is laborious, subject to laboratory bias and not specific enough to differentiate all patients from control subjects. Utilizing a cross-correlation technique, we have developed an automated analysis technique that can reliably differentiate the motor patterns of patients with slow transit constipation (STC) from those recorded in healthy controls. METHODS: Pancolonic manometric data were recorded from 17 patients with STC and 14 healthy controls. The automated analysis involved calculation of an indicator value derived from cross correlations calculated between adjacent recording sites in a manometric trace. The automated technique was conducted on blinded real data sets (observed) and then to determine the likelihood of positive indicator values occurring by chance, the channel number within each individual data set were randomized (expected) and reanalyzed. KEY RESULTS: In controls, the observed indicator value (3.2 +/- 1.4) was significantly greater than that predicted by chance (0.8 +/- 1.5; P < 0.0001). In patients, the observed indicator value (-2.7 +/- 1.8) did not differ from that predicted by chance (-3.5 +/- 1.6; P = 0.1). The indicator value for controls differed significantly from that of patients (P < 0.0001), with all individual patients falling outside of the range of indicator values for controls. CONCLUSIONS & INFERENCES: Automated analysis of colonic manometry data using cross-correlation separated all patients from controls. This automated technique indicates that the contractile motor patterns in STC patients differ from those recorded in healthy controls. The analytical technique may represent a means for defining subtypes of constipation. PMID- 23360123 TI - PACCRETA: clinical situations at high risk of placenta ACCRETA/percreta: impact of diagnostic methods and management on maternal morbidity. AB - BACKGROUND: No population-based study has assessed the prevalence of placenta accreta, the predictive value of prenatal diagnostic examinations, the maternal morbidity associated with its management, or its psychological effects. Moreover, the technical resources necessary for the safest delivery of women at risk have not been clearly identified. OBJECTIVES: The primary objectives are to identify individual risk factors, as well as factors associated with types of management and with the healthcare facilities for postpartum hemorrhage. Secondary objectives are to (i) determine the prevalence of placenta accreta among women at risk; (ii) assess the predictive value of ultrasound and MRI for the diagnosis of placenta accreta in this population; (iii) evaluate psychological impact and physical complications; and (iv) report maternal physical complications during the year after delivery. DESIGN: Population-based prospective observational study of pregnant women with a placenta inserted at a uterine scar. SETTING: A total of 182 centers in eight French regions, with 270 000 deliveries annually. METHODS: We expect to include 620 women at risk of placenta accreta in two years, of whom approximately 120 (20%) will have placenta accreta. MAIN OUTCOME MEASURES: The primary outcome measure is severe maternal hemorrhage; secondary outcome measures are maternal morbidity and deaths, predictive value of ultrasound and MRI, and psychological evaluations at 6 and 12 months. CONCLUSION: This study will be the first prospective population-based study to include women at risk of placenta accreta and to investigate incidence, prenatal detection, type of management, morbidity and maternal psychological consequences. PMID- 23360124 TI - Microarray Glycoprofiling of CA125 improves differential diagnosis of ovarian cancer. AB - The CA125 biomarker assay plays an important role in the diagnosis and management of primary invasive epithelial ovarian/tubal cancer (iEOC). However, a fundamental problem with CA125 is that it is not cancer-specific and may be elevated in benign gynecological conditions such as benign ovarian neoplasms and endometriosis. Aberrant O-glycosylation is an inherent and specific property of cancer cells and could potentially aid in differentiating cancer from these benign conditions, thereby improving specificity of the assay. We report on the development of a novel microarray-based platform for profiling specific aberrant glycoforms, such as Neu5Acalpha2,6GalNAc (STn) and GalNAc (Tn), present on CA125 (MUC16) and CA15-3 (MUC1). In a blinded cohort study of patients with an elevated CA125 levels (30-500 kU/L) and a pelvic mass from the UK Ovarian Cancer Population Study (UKOPS), we measured STn-CA125, ST-CA125 and STn-CA15-3. The combined glycoform profile was able to distinguish benign ovarian neoplasms from invasive epithelial ovarian/tubule cancer (iEOCs) with a specificity of 61.1% at 90% sensitivity. The findings suggest that microarray glycoprofiling could improve differential diagnosis and significantly reduce the number of patients elected for further testing. The approach warrants further investigation in other cancers. PMID- 23360125 TI - The structure and spectroscopy of cyanate and bicarbonate ions. Astrophysical implications. AB - Cyanate and bicarbonate are two ions that play active roles in many fields of physics and chemistry, including biological sciences and astrochemistry. We present here a comprehensive study of these species covering a range of phases and methodologies. We have performed theoretical calculations on the isolated ions and their hydrates with one to four water molecules, and in clusters with 15 water molecules. The predicted infrared spectra are compared with observed spectra from experiments where liquid droplets of their solutions are frozen at 14 K on a substrate, to mimic some astrophysical conditions. Crystals of cyanate and bicarbonate sodium and potassium salts are also studied experimental and theoretically. As well, the spontaneous decomposition of cyanate into bicarbonate is documented from the spectra of an aged solution. Finally, the possible astrophysical observation of bicarbonate in water-containing particles is discussed. PMID- 23360126 TI - Photochemical degradation of the plant growth regulator 2-(1-naphthyl) acetamide in aqueous solution upon UV irradiation. AB - The photochemical degradation of 2-(1-naphthyl) acetamide (NAD) in aqueous solution using simulated sunlight excitation as well as UV light within the 254 300 nm range was investigated to obtain an insight into the transformation mechanism that could occur under environmental conditions. Several photoproducts were identified using HPLC/MS/MS techniques. The degradation quantum yield was found to be independent of the excitation wavelength, but showed a dependence of oxygen concentration. This increased by a factor of approximately 3 from aerated to oxygen-free solutions. There is a clear involvement of both triplet and singlet excited states in NAD photoreactivity. The participation of singlet oxygen as a significant route in NAD degradation was ruled out by comparison with the behavior using Rose Bengal as a photosensitizer. A mechanistic pathway implying hydroxylation process through NAD radical cation species as well as an oxidation reaction by molecular oxygen is proposed. The photochemical behavior of NAD appears to mainly involve the aromatic moieties without any participation of the amide side chain. Toxicity tests clearly show that the generated primary photoproducts are responsible for a significant increase in the toxicity. However, upon prolonged irradiation this toxicity tends to decrease. PMID- 23360127 TI - SEREX: a promising approach for identification of thyroid cancer serological biomarkers. PMID- 23360128 TI - Early childhood-onset restless legs syndrome: symptoms and effect of oral iron treatment. AB - AIM: To describe symptoms of restless legs syndrome (RLS) in early childhood and the effect of oral iron treatment. METHODS: A study population comprising 22 children, 15 males and seven females referred for paediatric evaluation because of sleep disturbances. Presence of RLS was evaluated using the International RLS Study Group consensus criteria of RLS. In case of ferritin level below 50 ng/mL, oral iron treatment was initiated. Fourteen were examined by polysomnography as well, and periodic limb movement index during sleep (PLMSI) was calculated. Relief of symptoms was recorded by the parents and correlated with ferritin levels and PLMSI. RESULTS: Median age at onset of symptoms was 7.5 months (0-40 months). The most striking single symptom was awakening after 1-3 h of sleep followed by screaming, crying, kicking or hitting the legs. Oral iron supplementation had a positive ferritin-concentration-dependent clinical effect. A relation between high PLMSI and low ferritin levels was demonstrated. CONCLUSION: Symptoms of RLS may start as early as the first year of life, are accompanied by low ferritin levels and a high PLMSI and can be ameliorated by iron supplementation. An increased awareness and knowledge of RLS in early childhood are warranted. PMID- 23360129 TI - Metabolite profiles of epimedin B in rats by ultraperformance liquid chromatography/quadrupole-time-of-flight mass spectrometry. AB - In this work, the metabolite profiles of epimedin B in rat feces, bile, urine, and plasma were qualitatively investigated, and the possible metabolic pathways of epimedin B were subsequently proposed. After oral administration of epimedin B at a single dose of 80 mg/kg, rat biological samples were collected and pretreated by protein precipitation. Then, these pretreated samples were injected into an Acquity ultraperformance liquid chromatography BEH C18 column with mobile phase consisting of 0.1% formic acid-water and 0.1% formic acid-acetonitrile and detected by ultraperformance liquid chromatography/quadrupole-time-of-flight mass spectrometry. In all, 43 metabolites were identified in the biosamples. Of these, 13, including F5, F7, F16-F18, D5-D7, D9, N5, N7, M1, and M3, were to our knowledge reported for the first time. The results indicated that epimedin B was metabolized via desugarization, dehydrogenation, hydrogenation, hydroxylation, demethylation, glucuronidation, and glycosylation pathways in vivo. Specific hydrolysis of 7-O-glucosides in the gut lumen and glucuronic acid conjugation in the liver were considered as the main physiologic processes of epimedin B. This study revealed the possible metabolite profiles of epimedin B in rats. PMID- 23360130 TI - Tsw gene-based resistance is triggered by a functional RNA silencing suppressor protein of the Tomato spotted wilt virus. AB - As a result of contradictory reports, the avirulence (Avr) determinant that triggers Tsw gene-based resistance in Capsicum annuum against the Tomato spotted wilt virus (TSWV) is still unresolved. Here, the N and NSs genes of resistance inducing (RI) and resistance-breaking (RB) isolates were cloned and transiently expressed in resistant Capsicum plants to determine the identity of the Avr protein. It was shown that the NSs(RI) protein triggered a hypersensitive response (HR) in Tsw-containing Capsicum plants, but not in susceptible Capsicum, whereas no HR was discerned after expression of the N(RI) (/) (RB) protein, or when NSs(RB) was expressed. Although NSs(RI) was able to suppress the silencing of a functional green fluorescence protein (GFP) construct during Agrobacterium tumefaciens transient assays on Nicotiana benthamiana, NSs(RB) had lost this capacity. The observation that RB isolates suppressed local GFP silencing during an infection indicated a recovery of RNA silencing suppressor activity for the NSs protein or the presence of another RNA interference (RNAi) suppressor. The role of NSs as RNA silencing suppressor and Avr determinant is discussed in the light of a putative interplay between RNAi and the natural Tsw resistance gene. PMID- 23360131 TI - Dietary anhydrous milk fat naturally enriched with conjugated linoleic acid and vaccenic acid modify cardiovascular risk biomarkers in spontaneously hypertensive rats. AB - Saturated and trans fatty acids have been associated with the risk to develop cardiovascular diseases. However, health-promoting effects are associated with consumption of anhydrous milk fat (AMF) and ruminant trans fatty acids, such as conjugated linoleic acid (CLA) and vaccenic acid (VA) contained in the lipid fraction of milk and dairy products. The purpose of this study was to evaluate the effect of AMF naturally enriched with CLA and VA in spontaneously hypertensive rats (SHR), using sterculic oil to inhibit the conversion of VA into CLA. The administration of AMF to SHR during 7 weeks exerted beneficial effects on cardiovascular risk biomarkers (reduction of insulin, blood lipids, increase of adiponectin). When sterculic oil was included, some parameters were further ameliorated (reduction of insulin, increase of adiponectin). Sterculic oil alone reduced body weight and adiposity, and improved blood pressure, adiponectin and triglyceride levels. PMID- 23360132 TI - Vascular calcification on plain radiographs is associated with carotid intima media thickness, malnutrition and cardiovascular events in dialysis patients: a prospective observational study. AB - BACKGROUND: Vascular calcification (VC) and carotid intima media thickness (CIMT) are strongly associated with cardiovascular (CV) disease. We hypothesized that significant VC on plain radiographs is associated with CIMT and CV events in dialysis patients. In addition, we evaluated risk factors for VC progression on plain radiographs in dialysis patients. METHODS: In this 2-year observational, prospective study, 67 dialysis patients were included. We checked plain radiographs at baseline and after 2 years. Laboratory tests and malnutrition score were obtained at baseline, after 12 months, and after 24 months. RESULTS: The mean age of patients was 56.3 +/- 10.3 years and duration of dialysis was 41.3 +/- 34.5 months. The prevalence of significant VC was 61.2% and the prevalence of carotid artery atheromatous plaques was 55.6%. Mean CIMT, malnutrition scores, CRP level and prevalence of carotid atheromatous plaques were significantly higher in patients with significant VC. Serum albumin and total iron binding capacity were significantly lower in patients with significant VC compared to patients without significant VC. During a mean observational period of 22 months, patients without significant VC showed lower CV events by the Kaplan-Meyer method (p = 0.010). Progression of VC was found in 35.7% among 56 patients followed up. Hemoglobin after 24 months was an independent factor for progression of VC (Exp(B) = 0.344, 95% Confidence Interval = 0.13 - 0.96, p = 0.034). CONCLUSIONS: Significant VC on plain radiograph was associated with CIMT, malnutrition, inflammation, and CV events in dialysis patients. Conditions which increase hemoglobin level may retard progression of VC in dialysis patients. PMID- 23360133 TI - Audiologic evaluation of Meniere's disease patients one day and one week after intratympanic application of gadolinium contrast agent: our experience in sixty five patients. PMID- 23360134 TI - Mineralization behavior of fluorine in perfluorooctanesulfonate (PFOS) during thermal treatment of lime-conditioned sludge. AB - The fate and transport of the fluorine in perfluorooctanesulfonate (PFOS) during the thermal treatment of lime-conditioned sludge were observed using both qualitative and quantitative X-ray diffraction techniques. Two main fluorine mineralization mechanisms leading to the substantial formation of CaF2 and Ca5(PO4)3F phases were observed. They had a close relationship with the thermal treatment condition and the PFOS content of the sludge. At low temperatures (300 600 degrees C), CaF2 dominated in the product and increases in treatment time and temperature generally enhanced the fluorine transformation. However, at higher temperatures (700-900 degrees C), increases in treatment time and temperature had a negative effect on the overall efficiency of the fluorine crystallization. The results suggest that in the high temperature environment there were greater losses of gaseous products such as HF and SiF4 in the transformation of CaF2 to Ca5(PO4)3F, the hydrolysis of CaF2, and the reaction with SiO2. The quantitative analysis also showed that when treating sludge with low PFOS content at high temperatures, the formation of Ca5(PO4)3F may be the primary mechanism for the mineralization of the fluorine in PFOS. The overall results clearly indicate the variations in the fate and transport of fluorine in PFOS when the sludge is subject to different PFOS contents and treatment types, such as heat drying or incineration. PMID- 23360135 TI - Lipophilic efficiency: the most important efficiency metric in medicinal chemistry. PMID- 23360136 TI - New agents to treat lung infection in cystic fibrosis: a big enough leap? PMID- 23360137 TI - Memory restored in Alzheimer's disease brain cells: the compound AC253, originally designed to target diabetes, appears to restore memory. PMID- 23360138 TI - Osteopromotive activity of a novel pyrazole carboxamide derivative. AB - AIMS: To investigate the effect of 1-(4-(tert-butyl)benzyl)-N-(4-methoxyphenyl)-3 phenyl-1H-pyrazole-5-carboxamide (Pyr-C) on the proliferation and osteogenic differentiation of MC3T3-E1 cells. MATERIALS & METHODS: MTT and BrdU incorporation assay were used to determine cell survival and proliferation. The gene expression levels of osteogenic markers were determined using real-time PCR and ALP activity was detected. Western-blot analysis was used to determine the protein expression of BSP and OPN. The long-term effect of Pyr-C on mineralization deposition was measured by Alizarin Red Staining. RESULTS: Pyr-C inhibited cell proliferation and increased ALP activity. Gene expression of ALP, BSP, OCN, Runx2, and Osterix was up-regulated in Pyr-C-induced group. Pyr-C increased the protein expression of BSP at day 7, 14 and 21, and OPN at day 14, 21 and 28. Meanwhile, Pyr-C enhanced the mineral deposition. CONCLUSION: Pyr-C inhibits proliferation and stimulates osteogenic differentiation of MC3T3-E1 cells. PMID- 23360139 TI - Synthesis, DNA binding, hemolysis assays and anticancer studies of copper(II), nickel(II) and iron(III) complexes of a pyrazoline-based ligand. AB - BACKGROUND: Over the last few decades, metal-based drugs, particularly cisplatin and its analogs have been used for the treatment of various cancers. Currently, scientists are developing other metal complexes as anticancer agents to eliminate the toxicity associated with platinum drugs. RESULTS: Claisen-Schmidt condensation was used to synthesize the pyrazoline-based ligand; (5-(4 chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide), followed by the synthesis of its complexes with copper(II), nickel(II) and iron(III) metal ions. DNA binding and in silico studies indicated quite good binding with DNA; requirements for good anticancer drugs. CONCLUSION: DNA binding constants for ligand, copper, nickel and iron complexes were 1.42 * 10(4), 3.16 * 10(4), 5.82 * 10(5) and 6.72 * 10(5) M(-1), respectively, indicating strong binding with DNA. All the reported compounds were slightly hemolytic towards rabbit red blood corpuscles and exhibited moderate activities against MCF-7 cancer cell lines. PMID- 23360140 TI - Nonhuman targets in allergic lung conditions. AB - Existing therapies for allergic asthma are far from perfect: the global prevalence of disease increases despite them and they are poorly effective in dealing with the exacerbations that account for hospitalization and asthma deaths. Commercially, there are pressures on these existing medicines too--a growing threat from generics and reluctance by payers to reimburse for increasingly marginal improvements in medicines with precedented mechanisms. Experience shows that attempts to devise selective small-molecule interventions directed at the myriad of downstream effector pathways has not been a fertile ground for the development of effective new medicines. An alternative strategy, exploiting breakthroughs in understanding the molecular basis of allergenicity and the key role of innate immune mechanisms in asthma, is to direct new approaches to the disease triggers themselves: allergens. This raises interesting possibilities for anti-Lipinski drug design (extracellular nonhuman targets, inhaled delivery) and creates unprecedented pharmacological opportunities in the therapeutic area. PMID- 23360141 TI - Post SELECT: selenium on trial. AB - Selenium is an essential trace element for humans and other animals that is required in very small amounts for proper growth and functioning. Several selenium compounds have shown promise as cancer chemopreventive and chemotherapeutic agents. However, the negative outcome of the SELECT trial to some extent dampened the enthusiasm of selenium-related drug development. A look at the selenium compounds, their diverse mechanism of action, bioavailability and efficacy based on chemical structure, however, suggests that failure of SELECT that used selenomethionine supplement to prevent prostate cancer was not a failure of selenium compounds as a whole. This is certainly true in regard to therapeutic applications of selenium compounds. This article puts these arguments in perspective, and based on the literature reports, especially several newly developed selenium compounds, emphasizes the importance of selenium in the development of chemopreventive and particularly chemotherapeutic drugs for cancer in near future. PMID- 23360142 TI - CO and CO-releasing molecules in medicinal chemistry. AB - Since the discovery that CO acts as a cytoprotective and homeostatic molecule, increasing research efforts have been devoted to the exploitation of its therapeutic effects. Both endogenous and exogenous CO improves experimental lung, vascular and cardiac injuries and protects against several inflammatory states. The technology is now in place to bring CO to clinical applications, but the use of the gaseous molecule poses several problems. The challenges associated with the clinical implementation of the gas have in part been answered by the development of CO-releasing molecules (CO-RMs). As stable solid forms of CO, these molecules represent an alternative to the administration of carbon monoxide (orally or by injection). In this article, we present insights into the biochemical action of CO and discuss the efficacy of CO and CO-RMs in preclinical disease models. Recent advances in the CO-RMs field are critically addressed. PMID- 23360143 TI - Therapeutic potential of targeting lipid aldehydes and lipoxidation end-products in the treatment of ocular disease. AB - Lipoxidation reactions and the subsequent accumulation of advanced lipoxidation end products (ALEs) have been implicated in the pathogenesis of many of the leading causes of visual impairment. Here, we begin by outlining some of the major lipid aldehydes produced through lipoxidation reactions, the ALEs formed upon their reaction with proteins, and the endogenous aldehyde metabolizing enzymes involved in protecting cells against lipoxidation mediated damage. Discussions are subsequently focused on the clinical and experimental evidence supporting the contribution of lipid aldehydes and ALEs in the development of ocular diseases. From these discussions, it is clear that inhibition of lipoxidation reactions and ALE formation could represent a new therapeutic avenue for the treatment of a broad range of ocular disorders. Current and emerging pharmacological strategies to prevent or neutralize the effects of lipid aldehydes and ALEs are therefore considered, with particular emphasis on the potential of these drugs for treatment of diseases of the eye. PMID- 23360147 TI - Concealing surface topography by attachment of nanometer-thick film. AB - Concealing of surface topology of substrates by decal-like attachment of nanomembrane is demonstrated. The nanomembrane attachment provides a flat surface on various substrates, including porous substrates, and the surface property such as wettability was changed to that of the nanomembrane. The monitoring of drying process revealed that a nanomembrane with certain thickness tolerates their flexural deflection during the procedure. Moreover, the supporting position of nanomembranes as well as the physical properties of nanomembranes strongly affected the degree of deflection. The decal-like attachment of nanomembranes shown here is potentially a powerful method for creating a new functional surface that is independent of the topological and chemical properties of the original substrate. PMID- 23360144 TI - Cytochrome P450-activated prodrugs. AB - A prodrug is a compound that has negligible, or lower, activity against a specified pharmacological target than one of its major metabolites. Prodrugs can be used to improve drug delivery or pharmacokinetics, to decrease toxicity, or to target the drug to specific cells or tissues. Ester and phosphate hydrolysis are widely used in prodrug design because of their simplicity, but such approaches are relatively ineffective for targeting drugs to specific sites. The activation of prodrugs by the cytochrome P450 system provides a highly versatile approach to prodrug design that is particularly adaptable for targeting drug activation to the liver, to tumors or to hypoxic tissues. PMID- 23360148 TI - Immunisation coverage in children with cerebral palsy compared with the general population. AB - AIM: To compare immunisation coverage of a cerebral palsy (CP) cohort with the known general population vaccination coverage statistics. METHODS: A cohort of children with CP aged less than 7 years was extracted from the Victorian Cerebral Palsy Register. The vaccination status of these children was compared with the general population using the Australian Childhood Immunisation Register (ACIR). Details that were audited included overall 'up-to-date' status of immunisations and individual vaccines missed. RESULTS: The CP cohort consisted of 449 children. Eighty-six or 19.2% (95% confidence intervals 15.6-23.1%) of these children were not 'up to date' (NUTD) with the Australian immunisation schedule at the time of the ACIR data link (13 March 2009). This NUTD result is well above the general population percentage (range 6.4-8%). This group was divided into subgroups based on age, with all groups having significantly lower rates of immunisation, varying from 100% NUTD in the youngest subgroup to 18.6% in the oldest subgroup. The most common vaccine NUTD was MMR (measles, mumps and rubella), followed by polio and DTaP (diphtheria-tetanus-acellular pertussis). CONCLUSION: This study demonstrates that children with CP are at high risk of incomplete and delayed immunisation, a significant problem given the increased health-care needs of this patient group and their increased vulnerability to the complications of vaccine preventable diseases. PMID- 23360149 TI - Shoe cleat position during cycling and its effect on subsequent running performance in triathletes. AB - Research with cyclists suggests a decreased load on the lower limbs by placing the shoe cleat more posteriorly, which may benefit subsequent running in a triathlon. This study investigated the effect of shoe cleat position during cycling on subsequent running. Following bike-run training sessions with both aft and traditional cleat positions, 13 well-trained triathletes completed a 30 min simulated draft-legal triathlon cycling leg, followed by a maximal 5 km run on two occasions, once with aft-placed and once with traditionally placed cleats. Oxygen consumption, breath frequency, heart rate, cadence and power output were measured during cycling, while heart rate, contact time, 200 m lap time and total time were measured during running. Cardiovascular measures did not differ between aft and traditional cleat placement during the cycling protocol. The 5 km run time was similar for aft and traditional cleat placement, at 1084 +/- 80 s and 1072 +/- 64 s, respectively, as was contact time during km 1 and 5, and heart rate and running speed for km 5 for the two cleat positions. Running speed during km 1 was 2.1% +/- 1.8 faster (P < 0.05) for the traditional cleat placement. There are no beneficial effects of an aft cleat position on subsequent running in a short distance triathlon. PMID- 23360150 TI - Characterization of a cervical spinal cord hemicontusion injury in mice using the infinite horizon impactor. AB - The majority of clinical spinal cord injuries (SCIs) are contusive and occur at the cervical level of the spinal cord. Most scientists and clinicians agree that the preclinical evaluation of novel candidate treatments should include testing in a cervical SCI contusion model. Because mice are increasingly used because of the availability of genetically engineered lines, we characterized a novel cervical hemicontusion injury in mice using the Infinite Horizon Spinal Cord Impactor (Precisions Systems & Instrumentation, Lexington, KY). In the current study, C57BL/6 mice received a hemicontusion injury of 75 kilodynes with or without dwell time in an attempt to elicit a sustained moderate-to-severe motor deficit. Hemicontusion injuries without dwell time resulted in sustained deficits of the affected forepaw, as revealed by a 3-fold decrease in usage during rearing, a ~50% reduction in grooming scores, and retrieval of significantly fewer pellets on the Montoya staircase test. Only minor transient deficits were observed in grasping force. CatWalk analysis revealed reduced paw-print size and swing speed of the affected forelimb. Added dwell time of 15 or 30 sec significantly worsened behavioral outcome, and mice demonstrated minimal ability of grasping, paw usage, and overground locomotion. Besides worsening of behavioral deficits, added dwell time also reduced residual white and gray matter at the epicenter and rostral-caudal to the injury, including on the contralateral side of the spinal cord. Taken together, we developed and characterized a new hemicontusion SCI model in mice that produces sufficient and sustained impairments in gross and skilled forelimb function and produced primarily unilateral functional deficits. PMID- 23360151 TI - Factors influencing admission and outcomes in gastroparesis. AB - BACKGROUND: Current data suggest that gastroparesis is associated with an increased mortality, with reported rates ranging from 4% to nearly 40%. Considering this variability, the goal of this study was to determine mortality rates and risk factors for adverse outcomes in gastroparesis. METHODS: Using the diagnosis code for gastroparesis, admission rates, duration of hospitalizations, discharge status, and inpatient mortality were determined for emergency department encounters and admissions compiled in the Nationwide Emergency Department Sample and Nationwide Inpatient Sample of the Agency for Healthcare Research and Quality. Comorbid conditions, procedural evaluations, age cohort, and gender distribution were examined as potential risk factors. KEY RESULTS: More than 50% of the emergency encounters for gastroparesis resulted in admission with age, cardiovascular, renal, and infectious disorders, but not diabetes mellitus being associated with higher admission rates. Inpatient mortality was 1.2 +/- 0.1%, was not negatively affected by diabetes mellitus as comorbidity, and increased with coexisting infections and with more aggressive therapy. Discharge status was similarly affected by comorbidities, treatment complications, and more aggressive therapy. CONCLUSIONS & INFERENCES: These results demonstrate that gastroparesis does not come with a high mortality risk, with most deaths being due to comorbid conditions. Although gastrostomies and/or nutritional support were used in only a minority of admissions, the associated increase in morbidity and mortality highlights the need to carefully select the right candidates for such interventions and to discuss the common occurrence of adverse outcomes with patients. PMID- 23360152 TI - Preterm birth trends in Greece, 1980-2008: a rising concern. AB - OBJECTIVE: To identify preterm birth trends in Greece. DESIGN: Retrospective epidemiological study. SETTING: Women giving birth in Greece from 1980 to 2008. POPULATION: Live births beyond the 24th gestational week. METHODS: Data acquisition from the Hellenic Vital Statistics records. Statistical analysis of preterm birth rate among neonates estimated for each year. MAIN OUTCOME MEASURES: Total number of births and preterm births, as well as rate of preterm birth by gestational week. Stillbirth rates by gestational age. RESULTS: 3 218 463 births occurred during the period under study, 151 594 (4.7%) of which were preterm. A steep rise in preterm births was noted during the final years of the study, reaching 9.6% in 2008. This was mainly due to the "late preterm" sub-group (34(+0) -36(+6) gestational weeks). The rates of stillbirth fell in a constant way regardless of the maturity index. CONCLUSIONS: Although preterm birth etiology is multifactorial, the selective rise in the "late preterm" group possibly was due to an increase in medical reasons necessitating a preterm delivery, changes in obstetric practice, or both. Further studies are needed to estimate the precise effect of each contributing factor. PMID- 23360153 TI - Separating smoking-related diseases using NMR-based metabolomics of exhaled breath condensate. AB - Nuclear magnetic resonance (NMR)-based metabolomics separates exhaled breath condensate (EBC) profiles of patients affected by pulmonary disease from those of healthy subjects. Here we show the discriminatory ability of NMR-based metabolomics in separating patients exposed to the same risk factor, namely, smoking habit in smoking-related diseases. Fifty duplicated EBC samples from a cohort of current smokers without chronic obstructive pulmonary disease (COPD, henceforth HS), COPD smokers, and subjects with established pulmonary Langerhans cell histiocytosis (PLCH) were analyzed by means of NMR spectroscopy followed by principal component analysis (PCA) and projection to latent structures discriminant analysis (PLS-DA). Clusterization of EBC spectra was disease specific. COPD and PLCH samples present a profile different from that of HS, showing acetate increase and 1-methylimidazole reduction. An inverse behavior of 2-propanol and isobutyrate characterized COPD with respect to PLCH (high/low in COPD, low/high in PLCH). Both the 2-component and the 3-component PLS-DA models showed a 96% cross-validated accuracy, presenting R(2) and Q(2) values in the ranges of 0.97-0.87 and 0.91-0.78, respectively, and R(2) = 0.87 and Q(2) = 0.78, indicating that data variation is well explained by each model (R(2)), with a good predictivity (Q(2)). NMR spectra of EBC discriminate COPD and PLCH patients from HS and between them, with well-defined metabolic profiles for each class. The specificity of EBC profiles suggests that disease itself drives metabolic separation overwhelming the "common background" due to smoking habit. EBC-NMR investigation offers a powerful tool for assessing the evolution of airway diseases even in the presence of a strong common factor. PMID- 23360154 TI - In this issue: Immunology of the eye--inside and out. PMID- 23360157 TI - Mechanisms of immune privilege in the posterior eye. AB - Immune privilege protects vital organs and their functions from the destructive interference of inflammation. Because the eye is easily accessible for surgical manipulation and for assessing and imaging the outcomes, the eye has been a major tissue for the study of immune privilege. Here, we focus on the immune regulatory mechanisms in the posterior eye, in part, because loss of immune privilege may contribute to development of certain retinal diseases in the aging population. We begin with a background in immune privilege and then focus on the select regulatory mechanisms that have been studied in the posterior eye. The review includes a description of the immunosuppressive environment, regulatory surface molecules expressed by cells in the eye, types of cells that participate in immune regulation and finally, discusses animal models of retinal laser injury in the context of mechanisms that overcome immune privilege. PMID- 23360155 TI - Host defense at the ocular surface. AB - Microbial infections of the cornea frequently cause painful, blinding and debilitating disease that is often difficult to treat and may require corneal transplantation. In addition, sterile corneal infiltrates that are associated with contact lens wear cause pain, visual impairment and photophobia. In this article, we review the role of Toll-Like Receptors (TLR) in bacterial keratitis and sterile corneal infiltrates, and describe the role of MD-2 regulation in LPS responsiveness by corneal epithelial cells. We conclude that both live bacteria and bacterial products activate Toll-Like Receptors in the cornea, which leads to chemokine production and neutrophil recruitment to the corneal stroma. While neutrophils are essential for bacterial killing, they also cause tissue damage that results in loss of corneal clarity. These disparate outcomes, therefore, represent a spectrum of disease severity based on this pathway, and further indicate that targeting the TLR pathway is a feasible approach to treating inflammation caused by live bacteria and microbial products. Further, as the P. aeruginosa type III secretion system (T3SS) also plays a critical role in disease pathogenesis by inducing neutrophil apoptosis and facilitating bacterial growth in the cornea, T3SS exotoxins are additional targets for therapy for P. aeruginosa keratitis. PMID- 23360156 TI - Dry eye as a mucosal autoimmune disease. AB - Dry eye is a common ocular surface inflammatory disease that significantly affects quality of life. Dysfunction of the lacrimal function unit (LFU) alters tear composition and breaks ocular surface homeostasis, facilitating chronic inflammation and tissue damage. Accordingly, the most effective treatments to date are geared towards reducing inflammation and restoring normal tear film. The pathogenic role of CD4+ T cells is well known, and the field is rapidly realizing the complexity of other innate and adaptive immune factors involved in the development and progression of disease. The data support the hypothesis that dry eye is a localized autoimmune disease originating from an imbalance in the protective immunoregulatory and proinflammatory pathways of the ocular surface. PMID- 23360158 TI - Corneal transplantation and immune privilege. AB - Corneal transplants have been successfully performed in human subjects for over 100 years and enjoy an immune privilege that is unrivaled in the field of transplantation. Immune privilege is defined as the reduced incidence and tempo in the immune rejection of corneal allografts compared to other categories of organ allografts performed under the same conditions. Skin allografts transplanted across various MHC or minor histocompatibility barriers undergo rejection in approximately 100% of the hosts. By contrast, orthotopic corneal allografts experience long-term survival in 50% to >90% of the hosts, depending on the histocompatibility barriers that confront the host. The capacity of corneal allografts to evade immune rejection is attributable to multiple anatomical, physiological and immunoregulatory conditions that conspire to prevent the induction and expression of alloimmunity. PMID- 23360159 TI - Innate immune signals in autoimmune and autoinflammatory uveitis. AB - Although traditionally the adaptive immune system has been viewed as the essential contributor to autoimmune diseases, the evidence implicating the innate immune system has grown considerably in recent years. Several multisystem inflammatory diseases affect the uvea and occur as a result of a mutation in a gene coding for a component of the innate immune system. Diseases associated with uveitis such as ankylosing spondylitis, sarcoidosis, Behcet's disease and inflammatory bowel disease can best be conceptually understood by hypotheses that consider microbial infection and innate immunity as contributing factors. PMID- 23360160 TI - Uveitis in mouse and man. AB - Uveitis is underappreciated as a sight-threatening cause of blindness. There are two broad causative classes of uveitis: infectious and non-infectious. Non infectious uveitis is considered a prototypical autoimmune disorder based mainly on data from experimental models in the mouse. Several different experimental models exist that reflect the different types of uveitis in man (anterior, intermediate, and posterior uveitis). These models have demonstrated that uveitis is predominantly a Th1/Th17 mediated disease, although innate immune cells play a significant role both in induction of disease and in tissue damage. Most experimental models of uveitis rely on activation of the innate immune system by use of adjuvants that activate a range of pathogen recognition receptors (PRRs). This begs the question of the underlying role of initial and/or persistent infection, including latent infection, in immune-mediated uveitis in which active infection cannot be demonstrated. This further raises the possibility of pathogenic mechanisms such as antigenic cross-reactivity and molecular mimicry. Alternatively, residual/latent antigen from infectious agents may act as "endogenous" adjuvants for induction of immune reactions to damaged/altered self antigen, suggesting a commonality in pathogenesis for both infectious and non infectious uveitis in man. PMID- 23360161 TI - The immunological basis of degenerative diseases of the eye. AB - It has become clear that disorders that were once considered "degenerative" have complex mechanisms, with many having been shown to have immune mediation as part of the disease process. These include arteriosclerotic heart disease and Alzheimer's disease. Indeed, several ocular disorders that once fell into the "degenerative" category meet this criterion as well. Immune mediation has been shown to be a part of many of the most common ocular disorders, and not just that of uveitis, or ocular inflammatory disease. PMID- 23360162 TI - Variability of memory B cell markers in a cohort of common variable immune deficiency patients over 6 months. AB - Common Variable Immunodeficiency Disorder (CVID) is a complex disorder that predisposes patients to recurrent and severe infections. Immunophenotypic classification schemes were developed to categorize patients with CVID into phenotypic and prognostic groups based on different memory B cell subsets. Whether the B cell subset analysis is stable over time has not been investigated. B cell phenotyping in patients with CVID (n = 15) and sex- and age-matched controls (n = 26) were carried out according to the three B cell classifications. Patients with CVID were evaluated monthly over 6 months. Controls were assessed once during the study. We scored how often each patient was assigned to the same group within each classification. The Freiburg classification assigned patients to the same group at a rate of 73% and the Paris classification at 88%. The EUROclass classification of smB- versus smB+ was at 90%. The two subclassifications [(smB-21low or smB-21norm) and transitional B] were at 87% and 97%, respectively. The level of naive B cells measured in all patients with CVID during the 6-month evaluation was the most stable B cell subset. We conclude that all classifications systems show considerable variability, but the EUROclass classification was the most reliable scheme for our 15 CVID and 26 healthy cohorts. Our results indicate that phenotypic classifications within CVID will be difficult while there is variability of commonly used assays. PMID- 23360163 TI - Variability in UVB radiation in Beijing, China. AB - The variation characteristics of Ultraviolet-B (UVB; 280-315 nm) radiation over Beijing were explored using measured data that were collected in Beijing from November 2010 to October 2011. Seasonal variations in UVB radiation and influence of ozone and clearness index on the ratio of UVB to broadband solar radiation (G) were investigated. The annual value of UVB radiation in Beijing is 6.37 MJ m(-2), and monthly average value ranges from 4.96 to 28.37 kJ m(-2) d(-1). The maximum daily total UVB radiation ranges from 6.55 kJ m(-2) d(-1) in November to 54.22 kJ m(-2) d(-1) in July. The monthly minimum of daily total UVB radiation varies from 0.5 kJ m(-2) d(-1) in February to 11.52 kJ m(-2) d(-1) in July. The monthly average of the ratio of UVB radiation to G ranges from 0.007 to 0.017%, with an annual average value of 0.012%. The variation in slant ozone column causes annual cycle of the ratio UVB radiation to G, with maximum value in summer. In addition, clouds have a greater effect on G than UVB radiation. Thus, the ratio increases by more than 17% when the atmospheric conditions change from clear to cloudy. PMID- 23360164 TI - Hyperemesis gravidarum and risks of placental dysfunction disorders: a population based cohort study. AB - OBJECTIVE: To study whether pregnancies complicated by hyperemesis gravidarum in the first (<12 weeks) or second (12-21 weeks) trimester are associated with placental dysfunction disorders. DESIGN: Population-based cohort study. SETTING: Sweden. POPULATION: All pregnancies in the Swedish Medical Birth Register estimated to have started on 1 January 1997 or later and ended in a single birth on 31 December 2009 or earlier (n = 1 156 050). METHODS: Odds ratios with 95% confidence intervals were estimated for placental dysfunction disorders in women with an inpatient diagnosis of hyperemesis gravidarum, using women without inpatient diagnosis of hyperemesis gravidarum as reference. Risks were adjusted for maternal age, parity, body mass index, height, smoking, cohabitation with the infant's father, infant's sex, mother's country of birth, education, presence of hyperthyreosis, pregestational diabetes mellitus, chronic hypertension and year of infant birth. MAIN OUTCOME MEASURES: Placental dysfunction disorders, i.e. pre eclampsia, placental abruption, stillbirth and small for gestational age (SGA). RESULTS: Women with hyperemesis gravidarum in the first trimester had only a slightly increased risk of pre-eclampsia. Women with hyperemesis gravidarum with first admission in the second trimester had a more than doubled risk of preterm (<37 weeks) pre-eclampsia, a threefold increased risk of placental abruption and a 39% increased risk of an SGA birth (adjusted odds ratios [95% confidence intervals] were: 2.09 [1.38-3.16], 3.07 [1.88-5.00] and 1.39 [1.06-1.83], respectively). CONCLUSIONS: There is an association between hyperemesis gravidarum and placental dysfunction disorders, which is especially strong for women with hyperemesis gravidarum in the second trimester. PMID- 23360165 TI - Imidazoline-1 receptor ligands as apoptotic agents: pharmacophore modeling and virtual docking study. AB - The group of imidazoline-1 receptors (I(1)-IR) agonists encompasses drugs are currently used in treatment of high blood pressure and hyperglycemia. The I(1)-IR protein structures have not been determined yet, but Nischarin protein that binds numerous imidazoline ligands inducing initiation of various cell-signaling cascades, including apoptosis, is identified as strong I(1)-IR candidate. In this study we examined apoptotic activity of rilmenidine (potent I(1)-IR agonist), moxonidine (moderate I(1)-IR agonist), and efaroxan (I(1)-IR partial agonist) on cancer cell line (K562) expressing Nischarin. The Nischarine domains mapping was performed by use of the Informational Spectrum Method (ISM). The 3D-Quantitative Structure-Activity Relationship (3D-QSAR) and virtual docking studies of 29 I(1) IR ligands (agonists, partial agonists, and antagonists) were carried out on I(1) IR receptors binding affinities. The 3D-QSAR study defined 3D-pharmacophore models for I(1)-IR agonistic and I(1)-IR antagonistic activity and created regression model for prediction of I(1)-IR activity of novel compounds. The 3D QSAR models were applied for design and evaluation of novel I(1)-IR agonists and I(1)-IR antagonists. The most promising I(1)-IR ligands with enhanced activities than parent compounds were proposed for synthesis. The results of 3D-QSAR, ISM, and virtual docking studies were in perfect agreement and allowed precise definition of binding mode of I(1)-IR agonists (Arg 758, Arg 866, Val 981, and Glu 1057) and significantly different binding modes of I(1)-IR antagonists or partial I(1)-IR agonists. The performed theoretical study provides reliable system for evaluation of I(1)-IR agonistic and I(1)-IR antagonistic activity of novel I(1)-IR ligands, as drug candidates with anticancer activities. PMID- 23360166 TI - Effects of selenium-enriched probiotics on heat shock protein mRNA levels in piglet under heat stress conditions. AB - The effects of selenium-enriched probiotics (SP) on tissue selenium (Se) deposition, glutathione peroxidase-1 (GPx1) activity and mRNA level, and heat shock protein (Hsp) mRNA levels of piglets under heat stress conditions were investigated. A total of 48 crossbred ([Landrace * Yorkshire] * Duroc) piglets were randomly divided into 4 groups and fed a basal diet (Con, 0.16 mg Se/kg) or basal diets with added probiotics (P, 0.16 mg Se/kg), sodium selenite (SS, 0.46 mg Se/kg), or SP (0.46 mg Se/kg), respectively, for 42 days. Three piglets were randomly selected from each group for blood sample collection at days 0, 14, 28, and 42 and for liver, kidney, and spleen sample collection at day 42. The results showed that P, SS, and SP could significantly down-regulate the average mRNA levels of Hsp70 (17.3, 23.7, and 40.1%) and Hsp27 (22.4, 24.4, and 44.7%) of the tissues, respectively (P < 0.05), whereas SS and SP could significantly elevate Se concentration, GPx1 activity and mRNA level (P < 0.05). The maximal effects of these parameters were observed in SP. It was concluded that SP is a feasible dietary supplementation of piglets under heat stress conditions during the summer season. PMID- 23360167 TI - Mercury exposure is associated with negative effects on turtle reproduction. AB - Mercury (Hg), a ubiquitous and highly toxic bioaccumulative contaminant, can maternally transfer and elicit deleterious effects on adult reproduction and offspring phenotype in fish, amphibians, and birds. However, the effects of Hg on reproduction remain largely unstudied in reptiles. We evaluated the consequences of maternally transferred Hg on a long-lived aquatic omnivore, the common snapping turtle (Chelydra serpentina). We collected eggs and tissues from gravid female turtles along a broad Hg contamination gradient in a river in central Virginia. We incubated eggs in the laboratory, quantified embryonic mortality, infertility, and hatching success of each clutch, and assessed all hatchlings and dead embryos for gross morphological malformations. As predicted, Hg concentrations in eggs were strongly and positively correlated with Hg levels in female tissues. We found that Hg in eggs was negatively correlated with hatching success, and this effect was driven by both increased egg infertility and embryonic mortality. In comparison to previous effect-based studies on other amniotes, our findings suggest that C. serpentina may be more resilient to Hg exposure and perhaps better suited for long-term monitoring of bioavailability of Hg than as indicators of adverse effects. PMID- 23360168 TI - Help bring back the celebration of life: a community-based participatory study of rural Aboriginal women's maternity experiences and outcomes. AB - BACKGROUND: Despite clear evidence regarding how social determinants of health and structural inequities shape health, Aboriginal women's birth outcomes are not adequately understood as arising from the historical, economic and social circumstances of their lives. The purpose of this study was to understand rural Aboriginal women's experiences of maternity care and factors shaping those experiences. METHODS: Aboriginal women from the Nuxalk, Haida and 'Namgis First Nations and academics from the University of British Columbia in nursing, medicine and counselling psychology used ethnographic methods within a participatory action research framework. We interviewed over 100 women, and involved additional community members through interviews and community meetings. Data were analyzed within each community and across communities. RESULTS: Most participants described distressing experiences during pregnancy and birthing as they grappled with diminishing local maternity care choices, racism and challenging economic circumstances. Rural Aboriginal women's birthing experiences are shaped by the intersections among rural circumstances, the effects of historical and ongoing colonization, and concurrent efforts toward self determination and more vibrant cultures and communities. CONCLUSION: Women's experiences and birth outcomes could be significantly improved if health care providers learned about and accounted for Aboriginal people's varied encounters with historical and ongoing colonization that unequivocally shapes health and health care. Practitioners who better understand Aboriginal women's birth outcomes in context can better care in every interaction, particularly by enhancing women's power, choice, and control over their experiences. Efforts to improve maternity care that account for the social and historical production of health inequities are crucial. PMID- 23360170 TI - Dissemination of antimicrobial-resistant clones of Salmonella enterica among domestic animals, wild animals, and humans. AB - Non-typhoidal salmonellosis is an important zoonotic disease caused by Salmonella enterica. This work focuses on the identification of Salmonella enterica clonal strains which, presenting a wide distribution potential, express resistance determinants that compromise effectiveness of the antimicrobial therapy. The screening was performed on 506 Salmonella enterica isolates from animals and humans, which were characterized by serovar and phage typing, genome macrorestriction and pulsed-field gel electrophoresis, and detection of phenotypic and genotypic traits for antimicrobial resistance. A Salmonella Enteritidis strain with strong quinolone resistance is spread on three host environments carrying one of the four variants found for the GyrA protein: (1) Asp87Tyr, the major polymorphism found in 39 Salmonella isolates from human origin and six from poultry; (2) Ser83Phe, with four isolates from human origin and one from white stork (Ciconia ciconia); and (3) Asp87Asn or (4) Asp87Gly, with two isolates each from human origins. Several Salmonella Typhimurium strains that presented int1 elements and the classically associated pentaresistance (ACSSuT) phenotype were found distributed between two host environments: domestic animals and humans, domestics and wild animals, or wild fauna plus humans. This study points out the importance of monitoring gut microbiota and its antimicrobial resistance from wildlife, in parallel to livestock animals and humans, especially for animal species that are in close contact with people. PMID- 23360169 TI - Association between putative functional variants in the PSMB9 gene and risk of melanoma--re-analysis of published melanoma genome-wide association studies. AB - To mine possibly hidden causal single-nucleotide polymorphisms (SNPs) of melanoma, we investigated the association of SNPs in 76 M/G1 transition genes with melanoma risk using our published genome-wide association study (GWAS) data set with 1804 melanoma cases and 1026 cancer-free controls. We found multiple SNPs with P < 0.01 and performed validation studies for 18 putative functional SNPs in PSMB9 in two other GWAS data sets. Two SNPs (rs1351383 and rs2127675) were associated with melanoma risk in the GenoMEL data set (P = 0.013 and 0.004, respectively), but failed in validation using the Australian data set. Genotype phenotype analysis revealed these two SNPs were significantly correlated with mRNA expression level of PSMB9. Further experiments revealed that SNP rs2071480, which is in high LD with rs1351383 and rs2127675, may have a weak effect on the promoter activity of PSMB9. Taken together, our data suggested that functional variants in PSMB9 may contribute to melanoma susceptibility. PMID- 23360171 TI - An outbreak of Salmonella Typhimurium phage type 42 associated with the consumption of raw flour. AB - A cluster of salmonellosis cases caused by Salmonella Typhimurium phage type 42 (STM42) emerged in New Zealand in October 2008. STM42 isolates from a wheat-based poultry feed raw material (broll; i.e., product containing wheat flour and particles of grain) had been identified in the 2 months prior to this cluster. Initial investigations indicated that eating uncooked baking mixture was associated with illness. A case-control study was conducted to test the hypothesis that there was an association between STM42 cases and consumption of raw flour or other baking ingredients. Salmonella isolates from human and non human sources were compared using pulsed-field gel electrophoresis (PFGE) and multiple-locus variable number tandem repeat analysis (MLVA). Environmental investigations included testing flour and other baking ingredients from case homes, unopened bags of flour purchased from retail stores, and inspection of an implicated flour mill. A case-control study of 39 cases and 66 controls found cases had 4.5 times the odds of consuming uncooked baking mixture as controls (95% confidence interval [CI] 1.6-12.5, p-value 0.001). Examination of individual baking ingredients found that, after adjusting for eggs, flour had an odds ratio (OR) of 5.7 (95% CI 1.1-29.1, p-value 0.035). After adjusting for flour, eggs had an OR of 0.8 (95% CI 0.2-3.4, p-value 0.762). PFGE patterns were identical for all STM42 isolates tested; however, MLVA distinguished isolates that were epidemiologically linked to the cluster. STM42 was recovered from flour taken from four cases' homes, two unopened packs purchased from retail stores and packs from three batches of retrieved (recalled) product. This outbreak was associated with the consumption of uncooked baking mixture containing flour contaminated with STM42. The implicated flour mill initiated a voluntary withdrawal from sale of all batches of flour thought to be contaminated. Media releases informed the public about implicated flour brands and the risks of consuming uncooked baking mixture. PMID- 23360172 TI - Ngati and healthy: translating diabetes prevention evidence into community action. AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a major health issue in New Zealand Maori. Clinical trials have demonstrated potential for the prevention of T2DM, but whether community public health programmes aiming to prevent diabetes are effective is untested. OBJECTIVE: To describe the planning and design of an intervention aiming to translate T2DM prevention clinical trial evidence into a community-wide population health intervention in a high risk predominantly Maori community. APPROACH: Community concerns about the diabetes burden were heard by the local diabetes nurse, herself a tribal member, and discussed with a locally raised academic. Project planning ensued. The intervention and its evaluation were designed using a participatory community development model. The planned intervention had three components: community-wide health promotion initiatives conveying healthy lifestyle messages, community education and monitoring for identified high-risk individuals and their extended families, and a structural strategy aimed at adapting local environments to support lifestyle changes. The evaluation plan involved interrupted time series surveys coupled with formative and process evaluations rather than a randomised control trial design. DISCUSSION: Consulting communities, validating community concerns and prioritising cultural and ethical issues were key steps. Time spent developing good relationships amongst the health provider and academic research team members at the outset proved invaluable, as the team were united in addressing the project planning and implementation challenges, such as funding obstacles that arose because of our ethically and culturally appropriate non-randomised control trial evaluation design. The pre-intervention survey demonstrated high rates of diabetes (13%), insulin resistance (33%) and risk factors, and provided evidence for positive, as opposed to negative, lifestyle intervention messages. CONCLUSION: Community-wide lifestyle interventions have the potential to reduce rates of type 2 diabetes and other chronic diseases in high-risk communities, but require a high level of commitment from the health sector and buy-in from the community. Adequate commitment, leadership, planning and resources are essential. PMID- 23360173 TI - Clinical utility of a panfungal polymerase chain reaction assay for invasive fungal diseases in patients with haematologic disorders. AB - OBJECTIVES: Invasive fungal diseases (IFDs) are life-threatening events in patients with haematologic disorders, and the spectrum of the aetiological pathogens continues to expand. This study aimed to evaluate the clinical utility of a panfungal polymerase chain reaction (PCR) assay for the management of IFDs in such patients. METHODS: We prospectively analysed 273 consecutive blood samples from 64 risk episodes in 51 patients with haematologic disorders at high risk for IFD who were treated at our hospital between April 2007 and October 2010. RESULTS: PCR-positive results were obtained in 18 of 64 risk episodes (35.3%). IFD was documented in 14 episodes (21.9%, 9 probable IFDs and 5 possible IFDs) according to the revised criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group. PCR was positive in all of these 14 episodes, and in 4 of the 50 episodes with no IFD category. Sensitivity, specificity, positive predictive value, and negative predictive value of our assay were 100%, 92%, 78% and 100% respectively. A considerable number of fungi (44.4%) that are less common than Aspergillus and Candida species were positive by PCR. Molecular diagnoses of Cunninghamella species, Aspergillus ustus, Fusarium species, Scedosporium apiospermum, Rhodotorula species and Rhizopus species were beneficial in selecting suitable treatments. CONCLUSIONS: Our panfungal PCR approach allows for the highly sensitive and specific detection and identification of a wide spectrum of fungal pathogens, which provides indispensable information for managing IFDs, especially refractory or breakthrough IFDs during antifungal therapy in high-risk patients with haematologic disorders. PMID- 23360174 TI - More than cell dust: microparticles isolated from cerebrospinal fluid of brain injured patients are messengers carrying mRNAs, miRNAs, and proteins. AB - Microparticles are cell-derived, membrane-sheathed structures that are believed to shuttle proteins, mRNA, and miRNA to specific local or remote target cells. To date best described in blood, we now show that cerebrospinal fluid (CSF) contains similar structures that can deliver RNAs and proteins to target cells. These are, in particular, molecules associated with neuronal RNA granules and miRNAs known to regulate neuronal processes. Small RNA molecules constituted 50% of the shuttled ribonucleic acid. Using microarray analysis, we identified 81 mature miRNA molecules in CSF microparticles. Microparticles from brain injured patients were more abundant than in non-injured subjects and contained distinct genetic information suggesting that they play a role in the adaptive response to injury. Notably, miR-9 and miR-451 were differentially packed into CSF microparticles derived from patients versus non-injured subjects. We confirmed the transfer of genetic material from CSF microparticles to adult neuronal stem cells in vitro and a subsequent microRNA-specific repression of distinct genes. This first indication of a regulated transport of functional genetic material in human CSF may facilitate the diagnosis and analysis of cerebral modulation in an otherwise inaccessible organ. PMID- 23360176 TI - Fluid-fluid transitions at bulk supercritical conditions. AB - We use three different polymer solvent mixture models to theoretically determine the existence of capillary-induced phase separation in simple pores under supercritical bulk conditions. These models undergo bulk demixing, due to quite different mechanisms, yet readily display supercritical transitions without the use of esoteric interactions in the capillary. The theoretical method used to analyze these systems is density functional theory. We find that capillary demixing is not reliant on the presence of a pure surface transition but may occur in the absence of the latter. This is shown by considering cases where the surface enhancement factor is too weak to cause demixing at a single surface or else the bulk conditions are supercritical to both bulk and surface transitions. This phenomenon may prove useful in applications involving adsorption from mixtures into porous particles. PMID- 23360177 TI - Impact on healthcare resource usage and costs among Medicaid-insured schizophrenia patients after initiation of treatment with long-acting injectable antipsychotics. AB - OBJECTIVE: This study compared healthcare resource usage and costs before and after initiating LAI antipsychotics among Medicaid-insured schizophrenia patients. METHODS: Schizophrenia patients >=13 years of age initiating LAI antipsychotics were identified from the Thomson Reuters MarketScan(r) Research Medicaid database between 7/1/2005 and 6/30/2010. Patients were required to have 6 months of continuous medical/prescription drug coverage prior to LAI initiation (baseline period) and during a variable follow-up period. Annualized healthcare resource usage and costs for the baseline and follow-up periods were determined and compared. RESULTS: Among 5694 eligible patients, 55% were male and 45% were female, and the majority of the population was between the ages of 18-55 (86%). The study population had low general comorbidity, as assessed by the Charlson Comorbidity Index (CCI). Diabetes (17%) and chronic pulmonary disease (14%) were the most prevalent comorbidities. In comparison to the baseline period, during the follow-up period (mean duration = 25.7 months) the mean number of hospitalizations, all cause (1.52 +/- 2.41 vs 0.70 +/- 1.61, p < 0.001) and schizophrenia-related (1.21 +/- 2.04 vs 0.57 +/- 1.41, p < 0.001) declined as well as hospital lengths of stay (all cause: 14.77 +/- 28.61 vs 5.75 +/- 16.26 days, p < 0.001; schizophrenia-related: 12.39 +/- 25.86 vs 4.67 +/- 13.54 days, p < 0.001). As a result, annualized hospital payments were much lower (all cause: $16,249 +/- $36,404 vs $7380 +/- $21,087, p < 0.001; schizophrenia-related: $13,388 +/- $31,614 vs $5645 +/- $15,767, p < 0.001). LIMITATIONS: This study attempted to minimize the impact of differences in patient characteristics by having patients serve as their own controls in the before vs after comparison, however one still may not be able to account for all confounders in this non randomized study population. CONCLUSION: For patients with schizophrenia who initiate LAI antipsychotic therapy, there is an improvement in disease management based on fewer hospitalizations for relapses, which is also associated with a marked reduction in healthcare costs. PMID- 23360178 TI - Esophageal chemical clearance is impaired in gastro-esophageal reflux disease--a 24-h impedance-pH monitoring assessment. AB - BACKGROUND: Impedance-pH monitoring allows assessment of retrograde and antegrade intra-esophageal movement of fluids and gas. Reflux is followed by volume clearance and chemical clearance, elicited by secondary and swallow-induced peristalsis, respectively. We aimed to assess whether chemical clearance is impaired in gastro-esophageal reflux disease (GERD). METHODS: Blinded retrospective review of impedance-pH tracings from patients with erosive reflux disease (ERD) and non-erosive reflux disease (NERD), and from proton pump inhibitor (PPI)-refractory patients before and after laparoscopic fundoplication. The number of refluxes followed within 30 s by swallow-induced peristaltic waves was divided by the number of total refluxes to obtain a parameter representing chemical clearance namely the postreflux swallow-induced peristaltic wave (PSPW) index. KEY RESULTS: The PSPW index was significantly lower in 31 ERD (15%) and in 44 NERD (33%) off-PPI patients than in 30 controls (75%), as well as in 18 ERD (16%) and in 48 NERD (31%) on-PPI patients than in 26 on-PPI functional heartburn (FH) cases (67%) (P < 0.05 for all comparisons). In 29 PPI-refractory patients, the median PSPW index was unaltered by otherwise effective antireflux surgery (20% postoperatively, 21% preoperatively). The overall sensitivity, specificity, positive, and negative predictive values of the PSPW index in identifying GERD patients were 97%, 89%, 96%, and 93%. CONCLUSIONS & INFERENCES: Impairment of chemical clearance is a primary pathophysiological mechanism specific to GERD: it is unaffected by medical/surgical therapy, is not found in FH, and is more pronounced in ERD than in NERD. Using the PSPW index could improve the diagnostic efficacy of impedance-pH monitoring. PMID- 23360179 TI - Acute responses of biomechanical parameters to different sizes of hand paddles in front-crawl stroke. AB - This study investigated the acute effects of different sizes of paddles on the force-time curve during tethered swimming and swimming velocity in front-crawl stroke. Fourteen male swimmers (20.0 +/- 3.7 years; 100-m best time: 53.70 +/- 0.87 s) performed two 10-s maximal efforts in tethered swimming to obtain peak force, average force, impulse, rate of force development, stroke duration and time to peak force. Swimming velocity, stroke rate and stroke length were obtained from two 25-m maximal swims. Both tests were repeated in five conditions: free swimming, wearing small (280 cm (2) ), medium (352 cm (2) ), large (462 cm (2) ) and extra-large (552 cm (2) ) hand paddles. Compared to free swimming, paddles provided significant increases of peak force (medium: 11.5%, large: 16.7%, extra-large: 21.7%), impulse (medium: 15.2%, large: 22.4%, extra large: 30.9%), average force (medium: 5.1%, large: 7.5%), rate of force development (extra-large: 11.3%), stroke duration (medium: 9.3%, large: 11.8%, extra-large: 18.5%), time to peak force (medium: 11.1%, large: 15.9%, extra large: 22.1%), swimming velocity (medium: 2.2%, large: 3.2%, extra-large: 3.7%) and stroke length (medium: 9.0%, large: 9.0%, extra-large: 14.8%), while stroke rate decreased (medium: -6.2%, large: -5.5%, extra-large: -9.5%). It is concluded that medium, large and extra-large paddles influence the force-time curve and change swimming velocity, suggesting these sizes may be useful for force development in water. PMID- 23360180 TI - Combined effects of Ag nanoparticles and oxygen plasma treatment on PLGA morphological, chemical, and antibacterial properties. AB - The purpose of this study is to investigate the combined effects of oxygen plasma treatments and silver nanoparticles (Ag) on PLGA in order to modulate the surface antimicrobial properties through tunable bacteria adhesion mechanisms. PLGA nanocomposite films, produced by solvent casting with 1 wt % and 7 wt % of Ag nanoparticles were investigated. The PLGA and PLGA/Ag nanocomposite surfaces were treated with oxygen plasma. Surface properties of PLGA were investigated by field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), static contact angle (CA), and high resolution X-ray photoelectron spectroscopy (XPS). Antibacterial tests were performed using an Escherichia coli RB (a Gram negative) and Staphylococcus aureus 8325-4 (a Gram positive). The PLGA surface becomes hydrophilic after the oxygen treatment and its roughness increases with the treatment time. The surface treatment and the Ag nanoparticle introduction have a dominant influence on the bacteria adhesion and growth. Oxygen-treated PLGA/Ag systems promote higher reduction of the bacteria viability in comparison to the untreated samples and neat PLGA. The combination of Ag nanoparticles with the oxygen plasma treatment opens new perspectives for the studied biodegradable systems in biomedical applications. PMID- 23360181 TI - Physiological adaptation of the Rhodococcus jostii RHA1 membrane proteome to steroids as growth substrates. AB - Rhodococcus jostii RHA1 is a catabolically versatile soil actinomycete that can utilize a wide range of organic compounds as growth substrates including steroids. To globally assess the adaptation of the protein composition in the membrane fraction to steroids, the membrane proteomes of RHA1 grown on each of cholesterol and cholate were compared to pyruvate-grown cells using gel-free SIMPLE-MudPIT technology. Label-free quantification by spectral counting revealed 59 significantly regulated proteins, many of them present only during growth on steroids. Cholesterol and cholate induced distinct sets of steroid-degrading enzymes encoded by paralogous gene clusters, consistent with transcriptomic studies. CamM and CamABCD, two systems that take up cholate metabolites, were found exclusively in cholate-grown cells. Similarly, 9 of the 10 Mce4 proteins of the cholesterol uptake system were found uniquely in cholesterol-grown cells. Bioinformatic tools were used to construct a model of Mce4 transporter within the RHA1 cell envelope. Finally, comparison of the membrane and cytoplasm proteomes indicated that several steroid-degrading enzymes are membrane-associated. The implications for the degradation of steroids by actinomycetes, including cholesterol by the pathogen Mycobacterium tuberculosis , are discussed. PMID- 23360182 TI - Sleep deprivation alters gene expression and antioxidant enzyme activity in mice splenocytes. AB - Cellular defence against the formation of reactive oxygen species (ROS) involves a number of mechanisms in which antioxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD) play an important role. The relation between sleep deprivation and oxidative stress has not yet been completely elucidated. Although some authors did not find evidence of this relationship, others found alterations in some oxidative stress markers in response to sleep deprivation. Thus, the objective of this study was to identify changes induced by sleep deprivation in the activity and gene expression of antioxidant enzymes in mice splenocytes, ideally corroborating a better understanding of the observed effects related to sleep deprivation, which could be triggered by oxidative imbalance. Splenocytes from mice sleep deprived for 72 h showed no significant difference in CAT and CuZnSOD gene expression compared with normal sleep mice. However, sleep-deprived mice did show higher MnSOD gene expression than the control group. Concerning enzymatic activity, CuZnSOD and MnSOD significantly increased after sleep deprivation, despite the expression in CuZnSOD remained unchanged. Moreover, CAT activity was significantly lower after sleep deprivation. The data suggest that the antioxidant system is triggered by sleep deprivation, which in turn could influence the splenocytes homoeostasis, thus interfering in physiological responses. PMID- 23360184 TI - Protective effects of carboxyfullerene in irradiated cells and BALB/c mice. AB - It has been reported that carboxyfullerene (C3) exhibits a strong free radical scavenging capacity, which plays a critical role in radiation damage. We hypothesized that C3 is an effective radioprotective agent. In this study, we demonstrated that C3 effectively scavenged hydroxyl radical in a cell-free Fenton system and that C3 showed no obvious toxicity for cultured cells. Different concentrations (100-400 mg/L) of C3 pretreatment effectively protected AHH-1 cells from radiation-induced apoptosis, by about 2-folds, while only 100 mg/L of C3 reduced the apoptosis rate of human intestinal crypt epithelial cells (HIECs). C3 also alleviated DNA damage detected using comet assay at 0, 4, and 8 h after irradiation. It was found that 75% of mice were protected from 7.2 Gy gamma irradiation-induced death when 100 mg/kg of C3 was administered prior to irradiation, but no change was observed for the survival time of mice which died. We also found that C3 attenuated radiation-mediated decreases in endogenous antioxidants such as SOD and GSH and reduced the level of MDA. In conclusion, these data showed that C3 effectively protected cells and mice from radiation injury, thus indicating the potential of C3 as a safe and effective radioprotectant. PMID- 23360185 TI - Anaerobic conversion of chlorobenzene and benzene to CH4 and CO2 in bioaugmented microcosms. AB - Chlorobenzene is a widespread groundwater contaminant found at many industrial sites. Reductive dechlorination of chlorobenzene requires input of electron donor and results in problematic accumulation of benzene, which is more toxic than chlorobenzene. We hypothesized that coupling a culture capable of reductive dechlorination of chlorobenzene to benzene with a second benzene-degrading methanogenic culture would completely detoxify chlorobenzene. To this end, active chlorobenzene-dechlorinating microcosms that were producing benzene were inoculated with a previously described enriched methanogenic benzene-degrading consortium. The combination resulted in the transformation of chlorobenzene via benzene to the nontoxic degradation products, CO2 and CH4. Sustainable degradation of chlorobenzene and benzene was observed in the microcosms and was further confirmed by shifts in the carbon isotopic ratios of chlorobenzene and benzene during degradation. Moreover, we could show that benzene derived electrons fueled chlorobenzene dechlorination removing the need to provide exogenous electron donor. The results have promising implications for sustainable bioremediation of sites contaminated with chlorinated benzenes and benzene. PMID- 23360175 TI - Initial assessment of the pathogenic mechanisms of the recently identified Alzheimer risk Loci. AB - Recent genome wide association studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long established APOE, as loci for Alzheimer's disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology. Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer's disease. PMID- 23360183 TI - International migration and caesarean birth: a systematic review and meta analysis. AB - BACKGROUND: Perinatal health disparities including disparities in caesarean births have been observed between migrant and non-migrant women and some literature suggests that non-medical factors may be implicated. A systematic review was conducted to determine if migrants in Western industrialized countries consistently have different rates of caesarean than receiving-country-born women and to identify the reasons that explain these differences. METHODS: Reports were identified by searching 12 literature databases (from inception to January 2012; no language limits) and the web, by bibliographic citation hand-searches and through key informants. Studies that compared caesarean rates between international migrants and non-migrants living in industrialized countries and that did not have a 'fatal flaw' according to the US Preventative Services Task Force criteria were included. Studies were summarized, analyzed descriptively and where possible, meta-analyzed. RESULTS: Seventy-six studies met inclusion criteria. Caesarean rates between migrants and non-migrants differed in 69% of studies. Meta-analyses revealed consistently higher overall caesarean rates for Sub-Saharan African, Somali and South Asian women; higher emergency rates for North African/West Asian and Latin American women; and lower overall rates for Eastern European and Vietnamese women. Evidence to explain the consistently different rates was limited. Frequently postulated risk factors for caesarean included: language/communication barriers, low SES, poor maternal health, GDM/high BMI, feto-pelvic disproportion, and inadequate prenatal care. Suggested protective factors included: a healthy immigrant effect, preference for a vaginal birth, a healthier lifestyle, younger mothers and the use of fewer interventions during childbirth. CONCLUSION: Certain groups of international migrants consistently have different caesarean rates than receiving-country-born women. There is insufficient evidence to explain the observed differences. PMID- 23360186 TI - Glyoxalase 1 enzyme activity in erythrocytes and Ala111Glu polymorphism in type 1 diabetes patients. AB - AIMS/HYPOTHESIS: The enzyme glyoxalase 1 (GLO1) can inactivate the glycoxidation product methylglyoxal that is thought to be an important contributor to the pathogenesis of vascular complications in diabetes. We aimed to study erythrocyte GLO1 activity and whether the Ala111Glu GLO1 gene polymorphism affected GLO1 activity. METHODS: Fasting erythrocyte GLO1 activity was measured spectrophotometrically. The A111G gene polymorphism, assessed in DNA from leucocytes was analyzed in patients with type 1-diabetes and normal kidney function and compared with a control group. RESULTS: Sixty-one patients with type 1-diabetes duration of 26.1 (10.7) years, mean (SD) with a HbA1c of 7.8 (0.9)%, 61.7 (9.9) mmol/mol and normal glomerular filtration rate were compared with 62 age- and sex-matched healthy controls. GLO1 activity was 0.206 (0.183-0.231) median (25-75% percentiles) U/mg Hb in the control group vs. 0.192 (0.165-0.224) in the diabetes group, (p = 0.149). In the diabetes group GLO1 correlated with HbA1c (r = 0.33, p < 0.01) and oxidized glutathione (GSSG) (r = - 0.34, p < 0.01) and in the control group with GSH (r = 0.37, p < 0.005) and fasting glucose (r = 0.26, p < 0.04). In a multiple regression analysis with GLO1 activity as the dependent variable, including the Ala111Glu polymorphism, the significant independent variables were log GSSG (beta - 0.318, p = 0.02) and HbA1c (beta 0.285, p = 0.041) in the diabetes group and log GSH, (beta 0.407, p = 0.004) in the control group. CONCLUSIONS/INTERPRETATION: Erythrocyte glyoxalase 1 activity did not differ between patients with type 1-diabetes and controls. The Ala111Glu glyoxalase gene polymorphism did not have an effect on glyoxalase 1 activity in either group. PMID- 23360187 TI - Bone disease in patients with haemophilia. What is true? PMID- 23360188 TI - Theoretical study of firefly luciferin pKa values--relative absorption intensity in aqueous solutions. AB - Ground-state vibrational analyses of firefly luciferin and its conjugate acids and bases are performed. The Gibbs free energies obtained from these analyses are used to estimate pKa values for phenolic hydroxy and carboxy groups and the N H(+) bond in the N-protonated thiazoline or benzothiazole ring of firefly luciferin. The theoretical pKa values are corrected using the experimental values. The concentrations of these chemical species in solutions with different pH values are estimated from their corrected pKa values, and the pH dependence of their relative absorption intensities is elucidated. With the results obtained we assign the experimental spectra unequivocally. Especially, the small peak near 400 nm at pH 1-2 in experimental absorption spectra is clarified to be due to the excitation of carboxylate anion with N-protonated thiazoline ring of firefly luciferin. Our results show that the pKa values of chemical species, which are contained in the aqueous solutions, are effective to assign experimental absorption spectra. PMID- 23360189 TI - BRAF mutation testing algorithm for vemurafenib treatment in melanoma: recommendations from an expert panel. AB - The incidence of melanoma has increased rapidly over the past 30 years, and the disease is now the sixth most common cancer among men and women in the U.K. Many patients are diagnosed with or develop metastatic disease, and survival is substantially reduced in these patients. Mutations in the BRAF gene have been identified as key drivers of melanoma cells and are found in around 50% of cutaneous melanomas. Vemurafenib (Zelboraf((r)) ; Roche Molecular Systems Inc., Pleasanton, CA, U.S.A.) is the first licensed inhibitor of mutated BRAF, and offers a new first-line option for patients with unresectable or metastatic melanoma who harbour BRAF mutations. Vemurafenib was developed in conjunction with a companion diagnostic, the cobas((r)) 4800 BRAF V600 Mutation Test. The purpose of this paper is to make evidence-based recommendations to facilitate the implementation of BRAF mutation testing and targeted therapy in patients with metastatic melanoma in the U.K. The recommendations are the result of a meeting of an expert panel and have been reviewed by melanoma specialists and representatives of the National Cancer Research Network Clinical Study Group on behalf of the wider melanoma community. This article is intended to be a starting point for practical advice and recommendations, which will no doubt be updated as we gain further experience in personalizing therapy for patients with melanoma. PMID- 23360190 TI - Sequential analysis of masseter activity patterns during chewing in healthy males. AB - The present study examined sequential changes in masseter activity patterns observed during chewing of four different agar samples in eight healthy young males. Two parameters, T(50) and D(50), were specifically used for evaluation of the activity patterns of individual bursts. Statistical significances were detected in regression coefficients (21.9% of 32 trials) and Spearman's rank correlation coefficients (28.1%) between the calculated T(50) values and chewing cycles, whereas no significant differences among the four agar samples were found. Three (I-III) types of activity patterns of masseter bursts during chewing sequences were classified by the D(50) values, which were derived from the T(50) values. The three types physiologically corresponded to incrementing (Type I), decrementing (Type III) and mixed discharge patterns (Type II). The classification of activity patterns suggested the usefulness of D(50) values in the sequential analysis of masseter activity patterns. PMID- 23360191 TI - Surface density mapping of natural tissue by a scanning haptic microscope (SHM). AB - To expand the performance capacity of the scanning haptic microscope (SHM) beyond surface mapping microscopy of elastic modulus or topography, surface density mapping of a natural tissue was performed by applying a measurement theory of SHM, in which a frequency change occurs upon contact of the sample surface with the SHM sensor - a microtactile sensor (MTS) that vibrates at a pre-determined constant oscillation frequency. This change was mainly stiffness-dependent at a low oscillation frequency and density-dependent at a high oscillation frequency. Two paragon examples with extremely different densities but similar macroscopic elastic moduli in the range of natural soft tissues were selected: one was agar hydrogels and the other silicon organogels with extremely low (less than 25 mg/cm(3)) and high densities (ca. 1300 mg/cm(3)), respectively. Measurements were performed in saline solution near the second-order resonance frequency, which led to the elastic modulus, and near the third-order resonance frequency. There was little difference in the frequency changes between the two resonance frequencies in agar gels. In contrast, in silicone gels, a large frequency change by MTS contact was observed near the third-order resonance frequency, indicating that the frequency change near the third-order resonance frequency reflected changes in both density and elastic modulus. Therefore, a density image of the canine aortic wall was subsequently obtained by subtracting the image observed near the second-order resonance frequency from that near the third-order resonance frequency. The elastin-rich region had a higher density than the collagen-rich region. PMID- 23360192 TI - Material selection indices for design of surgical instruments with long tubular shafts. AB - In any medical device design process, material selection plays an important role. For devices which sustain mechanical loading, strength and stiffness requirements can be significant drivers of the design. This paper examines the specific case of minimally invasive surgical instruments, including robotic instruments, having long, tubular shafts. Material properties-based selection indices are derived for achieving high performance of these devices in terms of strength and stiffness, and the use of these indices for informing the medical device design problem is illustrated. PMID- 23360193 TI - Remote eye tracking assesses age dependence processing of coherent motion in typically-developing children. AB - The aim of this study was to quantify processing of different types of coherent motion in terms of ocular motor response times in a group of normally-developing children (age 0-12+ years old) using remote eye tracking. Motion coherence was applied in three different types of Random Dot Kinematograms (RDKs): vertical (RDK1) and diagonal (RDK2) motion and expansion (RDK3). Orienting eye movements were quantified using the Reaction Time to the first Fixation (RTF). The children were divided into two groups: the "youngest group" between 0-3+ years and the "oldest group" between 4-12+ years old. The results showed that RTF was significantly prolonged in the "youngest group" compared to the "oldest group" for each RDK. In the "oldest group", RTF was significantly affected by the type of RDK shown. The presented results suggest that, based on ocular motor responses, age-dependence of processing different types of coherent motion may be revealed. PMID- 23360194 TI - ECG feature extraction using principal component analysis for studying the effect of diabetes. AB - The condition of cardiac health is given by Electrocardiogram (ECG). ECG analysis is one of the most important aspects of research in the field of Biomedical and healthcare. The precision in the identification of various parameters in ECG is of great importance. Many algorithms have been developed in the last few years for this purpose. Since diabetes is the major chronic illness prevailing today, recently there has been increasing interest in the study of the relationship between diabetes and cardiac health. This paper presents an algorithm based on Principal Component Analysis (PCA) for 12 lead ECG feature extraction and the estimation of diabetes-related ECG parameters. The data used for our purpose is acquired by XBio Aqulyser unit from TMI systems. The baseline wander is removed from the acquired data using the FFT approach and the signal is de-noised using wavelet transform and then the PCA method is employed to extract the R-wave. The other waves are then extracted using the window method. Later, using these primary features, the diabetes mellitus (DM)-related features like corrected QT interval (QTc), QT dispersion (QTd), P wave dispersion (PD) and ST depression (STd) are estimated. This study has taken 25 diabetic patients data for study. PMID- 23360195 TI - A MEMS accelerometer-based real-time motion-sensing module for urological diagnosis and treatment. AB - This paper reports a real-time motion-sensing module, which is realized by incorporating multiple MEMS accelerometers into a standard Foley catheter, for assisting diagnosis and treatment of stressed urinary incontinence. The accelerometers measure the orientations of the catheter at multiple points, so the shape of the urethra and movement of the bladder neck can be tracked in real time. An algorithm for extracting tilting, position and shape information from 3 axis MEMS accelerometers has been developed. The model of measurement errors for both static and dynamic testing is also established. The experimental results indicate that the module tracks the movement of the Foley catheter successfully in a real-time environment and the absolute error for static measurement is no more than 1.1 degrees within the operation range. PMID- 23360196 TI - Novel parameters for evaluating severity of sleep disordered breathing and for supporting diagnosis of sleep apnea-hypopnea syndrome. AB - Sleep apnea-hypopnea syndrome (SAHS) is a complex public health problem causing increased risk of cardiovascular diseases. Traditionally, evaluation of the severity of the disease is based on Apnea-Hypopnea Index (AHI). It is defined as the average number of apnea and hypopnea events per hour during sleep. However, e.g. the total duration and the morphology of the recorded events are not considered when evaluating the severity of the disease. This is surprising, as increasing the length of apnea and hypopnea events will most likely lead to longer and deeper oxygen desaturation events. Obviously, this is physiologically more stressful and may have more severe health consequences than shorter and shallower desaturation events. Paradoxically, the lengthening of apnea and hypopnea events may even lead to a decrease in AHI and oxygen desaturation index (ODI). This raises the question of whether additional information is needed besides AHI and ODI for the evaluation of the severity of SAHS and its potential cardiovascular consequences. In the present paper, several novel parameters are introduced to bring additional information for evaluation of the severity of SAHS. Besides the number of events per hour, that AHI and ODI takes into account, the duration of the breathing cessations and the morphology of the oxygen desaturation events are considered as important factors that may influence the daytime fatigue and also the related cardiovascular problems. In this study diagnostic ambulatory polygraphy recordings of 19 male patients were retrospectively analysed. Importantly, the novel parameters showed significant variation amongst patients with similar AHI. For example, the correlation between AHI and the Obstruction severity-parameter was only moderate (r(2)=0.604, p<0.001). This suggests that patients with similar AHI may exhibit significantly different cardiovascular stress related to the disease. It is suggested that the present novel parameters might provide additional information over the currently used parameters and support the evaluation of the severity of SAHS. PMID- 23360197 TI - Rationale, design and clinical performance of the mechanical response tissue analyser: a non-invasive technology for measurement of long bone bending stiffness. AB - Prediction of osteoporotic fractures is currently an imperfect science and new tools are desperately needed to identify at-risk patients at an earlier stage in the disease process. The mechanical response tissue analyser (MRTA) is a novel, non-invasive, radiation-free device that measures the bending stiffness of long bones in vivo, an indicator of a bone's ability to resist deformation under a given load and a strong predictor of long bone structural integrity and strength. Bone bending stiffness measured with the MRTA has been consistently shown to be a stronger predictor of post-mortem and ex vivo bone breaking strength compared to bone mineral measured with dual-energy X-ray absorptiometry. Bone bending stiffness measured with MRTA also decreases with advanced age and disease states and increases with chronic physical activity, independent of bone mineral changes. The MRTA measures different parameters than DXA (bone quality vs bone mineral content and density) and may be a more robust tool for identifying those at risk for fracture. Research initiatives focused on improving long-term repeatability and optimizing the signal-to-noise ratio of the measurement are currently underway to further advance the clinical usefulness of this technology. PMID- 23360198 TI - Radiofrequency ablation technique in the treatment of liver tumours: review and future issues. AB - Thermal ablation is increasingly being used for treatment of liver tumours. Among the techniques of thermal ablation, radiofrequency ablation (RF) is undoubtedly being used most frequently because of its advantages, such as morbidity and mortality rates, effective tumour ablation, as well as being less time-consuming. This paper presents the state of the art of RF ablation technique. This includes the theoretical development, experimental study and clinical application of the radiofrequency ablation technique. First, it introduces the principle of this technique. Second, it shows the development of this technique and valuable achievements. These achievements include the device, strategy of operation and extension to other diseases. Third, it concludes future issues to be addressed in order to further advance this technique. PMID- 23360202 TI - Antifungal activities of metabolites produced by a termite-associated Streptomyces canus BYB02. AB - Two main antifungal metabolites resistomycin and tetracenomycin D were isolated and purified from a termite-associated Streptomyces canus BYB02 by column chromatography. The structures of isolated compounds were determined on the basis of extensive spectroscopic analysis. Resistomycin possessed strong activities against mycelial growth of Valsa mali (IC(50) = 1.1 MUg/mL) and Magnaporthe grisea (IC(50) = 3.8 MUg/mL), which were comparable to those of referenced cycloheximide, with IC(50) values of 2.3 and 0.3 MUg/mL, respectively. A further spore germination test showed that resistomycin exhibited potent reduction in spore germination for M. grisea , with an IC(50) value of 5.55 MUg/mL. Finally, the in vivo antifungal activity experiment showed that resistomycin possessed significant preventive efficacy against rice blast, which was more potent than that of referenced carbendazim, with control efficacies of 66.8 and 58.7%, respectively. The present results suggest that resistomycin has potential to be used as a fungicide. PMID- 23360201 TI - Inflammatory consequences in a rodent model of mild traumatic brain injury. AB - Mild traumatic brain injury (mTBI), particularly mild "blast type" injuries resulting from improvised exploding devices and many sport-caused injuries to the brain, result in long-term impairment of cognition and behavior. Our central hypothesis is that there are inflammatory consequences to mTBI that persist over time and, in part, are responsible for resultant pathogenesis and clinical outcomes. We used an adaptation (1 atmosphere pressure) of a well-characterized moderate-to-severe brain lateral fluid percussion (LFP) brain injury rat model. Our mild LFP injury resulted in acute increases in interleukin-1alpha/beta and tumor necrosis factor alpha levels, macrophage/microglial and astrocytic activation, evidence of heightened cellular stress, and blood-brain barrier (BBB) dysfunction that were evident as early as 3-6 h postinjury. Both glial activation and BBB dysfunction persisted for 18 days postinjury. PMID- 23360203 TI - The mere presence of a goalkeeper affects the accuracy of penalty kicks. AB - The keeper-independent strategy, in which a football penalty kicker selects a target location in advance and ignores the goalkeeper's actions during the run up, has been suggested to be the preferable strategy for taking a penalty kick. The current in-field experiment investigated the question of whether the goalkeeper can indeed be ignored. Ten intermediate-level football players were instructed to adopt a goalkeeper-independent strategy and to perform penalty kicks directed at one of two targets located in the upper corners of the goal under three conditions: without a goalkeeper, in the presence of a goalkeeper (who tried to save the ball), and in the presence of a goalkeeper who was informed by the penalty kickers where they intended to direct the ball. The mere presence of a goalkeeper impaired shot accuracy. The shots were more centralised, that is, biased toward the goalkeeper. The effects were enhanced for the condition in which the penalty kicker knew the goalkeeper was knowledgeable about ball direction. The findings were consistent with the response activation model that holds that aiming at a target can be biased toward salient visual non targets. The implications for adopting and practising goalkeeper-independent strategies are discussed. PMID- 23360204 TI - Efficient singlet-singlet energy transfer in a novel host-guest assembly composed of an organic cavitand, aromatic molecules, and a clay nanosheet. AB - A supramolecular host-guest assembly composed of a cationic organic cavitand (host), neutral aromatic molecules (guests), and an anionic clay nanosheet has been prepared and demonstrated that in this arrangement efficient singlet-singlet energy transfer could take place. The novelty of this system is the use of a cationic organic cavitand that enabled neutral organic molecules to be placed on an anionic saponite nanosheet. Efficient singlet-singlet energy transfer between neutral pyrene and 2-acetylanthracene enclosed within a cationic organic cavitand (octa amine) arranged on a saponite nanosheet was demonstrated through steady state and time-resolved emission studies. The high efficiency was realized from the suppression of aggregation, segregation, and self-fluorescence quenching. We believe that the studies presented here using a novel supramolecular assembly have expanded the types of molecules that could serve as candidates for efficient energy-transfer systems, such as in an artificial light-harvesting system. PMID- 23360205 TI - Distension-evoked motility analysis in human esophagus. AB - BACKGROUND: The major function of the esophagus is to transport food from the mouth to the stomach by peristaltic muscle action. However, only few techniques exist for detailed evaluation of motor activity of the esophagus in vivo. The aim of this study is to use distension combined with manometry and impedance planimetry [pressure-cross-sectional area (P-CSA) recordings] to assess esophageal peristaltic motor function in terms of the mechanical energy output, and to examine the change in the motor activity of the esophagus in response to butylscopolamine, an anticholinergic drug known to impair the smooth muscle contraction in the gastrointestinal tract. METHODS: The probe with CSA measurements was positioned 7 cm above the lower esophageal sphincter in 16 healthy volunteers before and during butylscopolamine administration. Distension evoked esophageal peristalsis was analyzed using P-CSA data during distension up to pressures of 5 kPa. The P-CSA, work output (area of the tension-CSA curves), and propulsive tension were analyzed. KEY RESULTS: The wave-like peristalsis resulted in P-CSA loops consisting of relaxation and contraction phases. The work increased with the distension pressure (from 1311 +/- 198 to 16 330 +/- 1845 MUJ before butylscopolamine vs from 2615 +/- 756 to 11 404 +/- 1335 MUJ during butylscopolamine administration), and propulsive tension increased from 18.7 +/- 1.9 to 88.5 +/- 5.5 N m(-1) before the drug and from 23.1 +/- 3.9 to 79.5 +/- 3.3 N m(-1) during butylscopolamine administration). Significantly, lower values were found during butylscopolamine administration compared with the distension before using the drug (P < 0.01). CONCLUSIONS & INFERENCES: Esophageal muscle properties during peristalsis can be assessed in vivo in terms of mechanical energy output parameters. Butylscopolamine impaired muscle contraction which could be detected as altered contraction parameters. The analysis can be further used as an adjunct tool of the combined manometry and impedance planimetry recordings to derive advanced esophageal motor function parameters for studying the physiological and pathophysiological mechanical consequences of esophageal contractions. PMID- 23360206 TI - Rhodium- and iridium-catalyzed dehydrogenative cyclization through double C-H bond cleavages to produce fluorene derivatives. AB - The rhodium-catalyzed cyclization of a series of 2,2-diarylalkanoic acids in the presence of copper acetate as an oxidant smoothly proceeded through double C-H bond cleavages and subsequent decarboxylation to produce the corresponding fluorene derivatives. The direct cyclization of triarylmethanols also took place efficiently by using an iridium catalyst in place of the rhodium, while the hydroxy function was still intact. PMID- 23360207 TI - Variants in melanocortin 1 receptor gene contribute to risk of melanoma--a direct sequencing analysis in a Texas population. PMID- 23360208 TI - Larvicidal activity and click synthesis of 2-alkoxyl-2-(1,2,3-triazole-1- yl)acetamide library. AB - Heterogeneous copper-in-charcoal-catalyzed click synthesis in 96-well polypropylene filter plates is an efficient method for the rapid generation of sufficient pure 2-alkoxyl-2-(1,2,3-triazole-1-yl) acetamide derivatives library by simple filtration, which directly assay the products for larvicidal activity against mosquitoes. In this procedure, copper nanoparticles on charcoal were arrayed into each well on a 96-well plate, reagents were delivered using a pipette gun, and a constant temperature shaker bath was used to complete the click reaction in 24-72 hours under temperature-controlled conditions. The results of bioassays indicated that the target compounds possessed excellent larvacidal activities against mosquitoes. In particular, the larvacidal activities against mosquitoes of compounds 8[2,3] and 8[7,1] at 2 ug.mL-1 were 100% and 73% respectively. PMID- 23360209 TI - KF/Clinoptilolite: an efficient promoter for the synthesis of thioethers. AB - Potassium fluoride impregnated on natural zeolite as a new solid base system effectively catalyzes the coupling of thiophenols with electron-deficient fluoro , chloro- and bromo-arenes in DMSO. This versatile and efficient solid base has been demonstrated to afford the corresponding desired products in good to excellent yields. This procedure provides a convenient, efficient and practical method for the preparation of diaryl thioethers. PMID- 23360211 TI - Macroporous silk fibroin cryogels. AB - Silk fibroin cryogels with remarkable properties were obtained from frozen fibroin solutions (4.2-12.6%) at subzero temperatures between -5 and -22 degrees C. This was achieved by the addition of ethylene glycol diglycidyl ether (EGDE) into the cryogelation system. EGDE triggers the conformational transition of fibroin from random coil to beta-sheet structure and hence fibroin gelation. One of the unique features of fibroin cryogels is their elasticity that allows them to resist complete compression without any crack development, during which water inside the cryogel is removed. The compressed cryogel immediately swells during unloading to recover its original shape. The scaffolds obtained by freeze-drying of the cryogels consist of regular, interconnected pores of diameters ranging from 50 to 10 MUm that could be regulated by the synthesis parameters. The mechanical compressive strength and the modulus of the scaffolds increase with decreasing pore diameter, that is, with decreasing gelation temperature or, with increasing fibroin or EGDE concentrations in the feed. The scaffolds produced at 12.6% fibroin exhibit a very high compressive modulus (50 MPa) making them good candidates as bone scaffold materials. PMID- 23360210 TI - The mitochondrial genome and a 60-kb nuclear DNA segment from Naegleria fowleri, the causative agent of primary amoebic meningoencephalitis. AB - Naegleria fowleri is a unicellular eukaryote causing primary amoebic meningoencephalitis, a neuropathic disease killing 99% of those infected, usually within 7-14 days. Naegleria fowleri is found globally in regions including the US and Australia. The genome of the related nonpathogenic species Naegleria gruberi has been sequenced, but the genetic basis for N. fowleri pathogenicity is unclear. To generate such insight, we sequenced and assembled the mitochondrial genome and a 60-kb segment of nuclear genome from N. fowleri. The mitochondrial genome is highly similar to its counterpart in N. gruberi in gene complement and organization, while distinct lack of synteny is observed for the nuclear segments. Even in this short (60-kb) segment, we identified examples of potential factors for pathogenesis, including ten novel N. fowleri-specific genes. We also identified a homolog of cathepsin B; proteases proposed to be involved in the pathogenesis of diverse eukaryotic pathogens, including N. fowleri. Finally, we demonstrate a likely case of horizontal gene transfer between N. fowleri and two unrelated amoebae, one of which causes granulomatous amoebic encephalitis. This initial look into the N. fowleri nuclear genome has revealed several examples of potential pathogenesis factors, improving our understanding of a neglected pathogen of increasing global importance. PMID- 23360212 TI - The biotic ligand model can successfully predict the uptake of a trivalent ion by a unicellular alga below pH 6.50 but not above: possible role of hydroxo-species. AB - In many reported cases, the biotic ligand model (BLM) has been shown to predict the bioavailability of divalent metals toward aquatic biota successfully. However, studies on the bioavailability of nonessential trivalent metals, including aluminum (Al), are relatively scarce. In the present study, short-term scandium (Sc) internalization fluxes (Jint) were measured in Chlamydomonas reinhardtii in order to explore the applicability of the BLM to trivalent metals. Scandium was selected for its chemical similarities with Al and for its convenient radio-isotope (Sc-46). Apparent affinity constants of Sc(3+) with membrane transport sites (KSc-Rcell app) were surprisingly high, ranging from 10(8.08) M(-1) to 10(13.95) M(-1) over the pH range from 4.50 to 7.90. The competition of H(+) for binding with Sc(3+) transport sites explained this trend within the pH range of 4.50 to 6.00, but not from pH 6.50-7.90. In this latter pH range, predicted fluxes were smaller than observed fluxes and this divergence increased with pH, from a factor of 4 to approximately 1000. Above pH 6.50, the calculated supply of Sc(3+) to the biointerface by physical diffusion of the free Sc(3+) ion and by the dissociation of its hydroxo-complexes (ScOH(2+), Sc(OH)2(+) and Sc(OH)3) was insufficient to support the high observed internalization fluxes. We speculate that this failure of the BLM could be due to the transmembrane transport of undissociated Sc hydroxo-complexes. Scandium uptake could be modeled reasonably well using a simple semiempirical equation considering equal contributions from Sc(3+), ScOH(2+), Sc(OH)2(+), and Sc(OH)3 and no H(+) competition. Our work highlights the importance of studying the possible role of hydroxo-species in trace metal uptake. PMID- 23360214 TI - Effects of rotational and continuous grazing on herbage quality, feed intake and performance of sheep on a semi-arid grassland steppe. AB - Compared to continuous grazing (CG), rotational grazing (RG) increases herbage production and thereby the resilience of grasslands to intensive grazing. Results on feed intake and animal performance, however, are contradictory. Hence, the objective of the study was to determine the effects of RG and CG on herbage mass, digestibility of ingested organic matter (dOM), organic matter intake (OMI) and live weight gain (LWG) of sheep in the Inner Mongolian steppe, China. During June September 2005-2008, two 2-ha plots were used for each grazing system. In RG, plots were divided into four 0.5-ha paddocks that were grazed for 10 days each at a moderate stocking rate. Instead, CG sheep grazed the whole plots throughout the entire grazing season. At the beginning of every month, dOM was estimated from faecal crude protein concentration. Faeces excretion was determined using titanium dioxide in six sheep per plot. The animals were weighed every month to determine their LWG. Across the years, herbage mass did not differ between systems (p = 0.820). However, dOM, OMI and LWG were lower in RG than in CG (p <= 0.005). Thus, our study showed that RG does not improve herbage growth, feed intake and performance of sheep and suggests that stocking rates rather than management system determine the ecological sustainability of pastoral livestock systems in semi-arid environments. PMID- 23360213 TI - Radiosensitizing effect of intratumoral interleukin-12 gene electrotransfer in murine sarcoma. AB - BACKGROUND: Interleukin-12 (IL-12) based radiosensitization is an effective way of tumor treatment. Local cytokine production, without systemic shedding, might provide clinical benefit in radiation treatment of sarcomas. Therefore, the aim was to stimulate intratumoral IL-12 production by gene electrotransfer of plasmid coding for mouse IL-12 (mIL-12) into the tumors, in order to explore its radiosensitizing effect after single or multiple intratumoral gene electrotransfer. METHODS: Solid SA-1 fibrosarcoma tumors, on the back of A/J mice, were treated intratumorally by mIL-12 gene electrotransfer and 24 h later irradiated with a single dose. Treatment effectiveness was measured by tumor growth delay and local tumor control assay (TCD(50) assay). With respect to therapeutic index, skin reaction in the radiation field was scored. The tumor and serum concentrations of cytokines mIL-12 and mouse interferon gamma (mIFNgamma) were measured. Besides single, also multiple intratumoral mIL-12 gene electrotransfer before and after tumor irradiation was evaluated. RESULTS: Single intratumoral mIL-12 gene electrotransfer resulted in increased intratumoral but not serum mIL-12 and mIFNgamma concentrations, and had good antitumor (7.1% tumor cures) and radiosensitizing effect (21.4% tumor cures). Combined treatment resulted in the radiation dose-modifying factor of 2.16. Multiple mIL-12 gene electrotransfer had an even more pronounced antitumor (50% tumor cures) and radiosensitizing (86.7% tumor cures) effect. CONCLUSIONS: Single or multiple intratumoral mIL-12 gene electrotransfer resulted in increased intratumoral mIL 12 and mIFNgamma cytokine level, and may provide an efficient treatment modality for soft tissue sarcoma as single or adjuvant therapy to tumor irradiation. PMID- 23360215 TI - Exploring a new frontier in cancer treatment: targeting the ubiquitin and ubiquitin-like activating enzymes. AB - The labeling of proteins with small ubiquitin (Ub) and ubiquitin-like (Ubl) modifiers regulates a plethora of activities within the cell, such as protein recycling, cell cycle modifications, and protein translocation. These processes are often overactive in diseased cells, leading to unregulated cell growth and disease progression. Therefore, in systems where Ub/Ubl protein labeling is dysregulated, the development of drugs to selectively and potently disrupt Ub/Ubl protein labeling offers a targeted molecular approach for sensitizing these diseased cells. This Perspective outlines the progress that has been made in the context of inhibitor development for targeting Ub/Ubl pathways. PMID- 23360216 TI - Involvement of extracellular signal regulated kinases in traumatic brain injury induced depression in rodents. AB - Traumatic brain injury (TBI) is the most common cause of death and acquired disability among children and young adults in the developed countries. In clinical studies, the incidence of depression is high after TBI, and the mechanisms behind TBI-induced depression remain unclear. In the present study, we subjected rats to a moderate fluid percussion into the closed cranial cavity to induce TBI. After 3 days of recovery, injured rats were given a forced swim test (FST) and novelty-suppressed feeding tests. We found that TBI rats exhibited increased duration of immobility and longer latency to begin chewing food in a new environment compared with sham-operated rats. Western blot analysis showed that TBI led to a decrease in the phosphorylated levels of extracellular signal regulated kinases (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK). Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), significantly reduced the duration of immobility when administered once per day for 14 days. Consistent with behavioral tests, fluoxetine treatment reversed TBI-induced decrease in p-ERK1/2 and p-p38 MAPK levels. Pre-treatment with a selective tryptophan hydroxylase inhibitor para-chlorophenylalanine (PCPA) blocked the antidepressant effect of fluoxetine. PCPA also prevented the effect of fluoxetine on ERK1/2 phosphorylation without affecting p38 MAPK phosphorylation. Pre treatment with ERK inhibitor SL327 but not p38 MAPK inhibitor SB203580 prevented the antidepressant effect of fluoxetine. These results suggest that ERK1/2 plays a critical role in TBI-induced depression. PMID- 23360218 TI - Prediction of eye irritation potential of liquid and granular laundry detergent formulas using the bovine corneal opacity and permeability (BCOP) assay. AB - Evaluation of eye irritation potential is a routine part of consumer product testing. Increasingly, companies are using in vitro methods to perform these assessments. We have used the bovine corneal opacity and permeability (BCOP) assay for the prediction of eye irritation of liquid and granular laundry detergent formulas. The BCOP assay was selected because it can distinguish between moderate and severe irritants as required to evaluate these classes of formulations. Corneas were maintained in short-term culture and the exposure conditions were optimized using marketed product upper-end benchmark formulas for each product class. The primary endpoint was the loss of epithelium as measured by the change in permeability of the cornea to fluorescein and was complemented by histological evaluation of depth of injury. The opacity endpoint was not used, as the surfactants in these products do not induce opacity in proportion to the depth of injury induced. Liquid laundry detergents were diluted to 25% and exposed to the corneas for 20 min while the granular detergents were diluted to 10% and exposed for 30 min. These conditions were selected for each product type to induce OD490 values in the midrange (between 0.5 and 0.6 absorbance units) and so increased or decreased irritation potential in the test formulas could readily be observed. Seventeen liquid and eleven granular laundry detergents were tested and the OD490 values ranged from 0.278 to 2.193 for the liquid detergents and 0.267 to 0.856 for the granular detergents. Histological changes in the epithelium and stroma were consistent with the OD490 values. These data suggest that the OD490 provides an effective measure of epithelial cell loss (degree of cell lysis) and thus irritation potential for these surfactant-based formulas. The upper-end benchmark set a known upper range for acceptable irritation for the product class. Those formulas inducing lower OD490 values may be considered to fall within the acceptable range while those inducing greater OD490 values should receive further evaluation and perhaps reformulation. PMID- 23360217 TI - Associations between medication use and functional gastrointestinal disorders: a population-based study. AB - BACKGROUND: Functional GI syndromes are known to be very prevalent, but this may be linked to unrecognized medications use. We aimed to estimate the prevalence of PPI, antidepressant, and narcotic use in the general population, and to evaluate the association between each medication and functional GI syndromes adjusting for potential confounders. METHODS: In 2008 and 2009, newly revised versions of a validated bowel disease questionnaire were mailed to a community-based cohort (total mailed = 8006) of Olmsted County, MN residents; 3831 returned the questionnaire (response rate = 48.0%). Medication usage, specifically PPIs, narcotics, and antidepressants in the last year, was elicited via three separate questions on the questionnaire. The association between each medication and GI symptom complexes was assessed using multiple variable logistic regression models. KEY RESULTS: A total of 3515 of the respondents (92%) had complete data (mean age: 61 +/- 15; 54% female). The overall proportion reporting PPI use was 20% (95% CI: 19, 22), narcotic use 12% (95% CI: 11, 13), and antidepressant use 15% (95% CI: 14, 16). PPI use was significantly associated with IBS status (OR = 1.4, 95% CI 1.1, 1.7) as well as with GERD (OR = 3.5, 95% CI 2.7, 4.4) and dyspepsia (OR = 2.0, 95% CI 1.5, 2.7). The association of PPI use with IBS was not explained by coexistent GERD or dyspepsia. Antidepressant use was significantly associated only with bloating (OR = 1.6, 1.1, 2.2). CONCLUSIONS & INFERENCES: Some medications that may alter intestinal transit or bowel flora are commonly utilized by the general population, and PPI use appears to be linked to IBS. PMID- 23360219 TI - Photophysical properties and electronic structure of bacteriochlorin-chalcones with extended near-infrared absorption. AB - Synthetic bacteriochlorins enable systematic tailoring of substituents about the bacteriochlorin chromophore and thereby provide insights concerning the native bacteriochlorophylls of bacterial photosynthesis. Nine free-base bacteriochlorins (eight prepared previously and one prepared here) have been examined that bear diverse substituents at the 13- or 3,13-positions. The substituents include chalcone (3-phenylprop-2-en-1-onyl) derivatives with groups attached to the phenyl moiety, a "reverse chalcone" (3-phenyl-3-oxo-1-enyl), and extended chalcones (5-phenylpenta-2,4-dien-1-onyl, retinylidenonyl). The spectral and photophysical properties (taus, Phif, Phi(ic), Phi(isc), tauT, k(f), k(ic), k(isc)) of the bacteriochlorins have been characterized. The bacteriochlorins absorb strongly in the 780-800 nm region and have fluorescence quantum yields (Phif) in the range 0.05-0.11 in toluene and dimethylsulfoxide. Light-induced electron promotions between orbitals with predominantly substituent or macrocycle character or both may give rise to some net macrocycle <-> substituent charge transfer character in the lowest and higher singlet excited states as indicated by density functional theory (DFT) and time-dependent DFT calculations. Such calculations indicated significant participation of molecular orbitals beyond those (HOMO - 1 to LUMO + 1) in the Gouterman four-orbital model. Taken together, the studies provide insight into the fundamental properties of bacteriochlorins and illustrate designs for tuning the spectral and photophysical features of these near-infrared-absorbing tetrapyrrole chromophores. PMID- 23360220 TI - A 5- to 6-year radiological evaluation of titanium plasma sprayed/sandblasted and acid-etched implants: results from private practice. AB - OBJECTIVES: This study aimed to determine bone level changes after 5-6 years of follow-up for a large group of one-stage dental implants consecutively placed in private practice. Potential confounding factors influencing crestal bone loss (CBL) were also assessed. MATERIALS AND METHODS: A total of 378 transmucosal Straumann implants in 174 patients were examined radiographically. Half of the study population (189 implants) had a titanium plasma sprayed (TPS) surface, and the other half (189 implants) were sandblasted and acid-etched (SLA). Mean CBL was measured from 5 to 6 years post-operative radiographs on the basis of known implant landmarks. Correlations of increased CBL with various independent variables were also investigated. Statistical analyses were performed using generalized estimating equations. RESULTS: Radiographic measurements showed a CBL <= 1.5 mm for 65% of studied implants. A CBL > 1.5 mm was found for 28% of implants, while 7% of implants had a CBL >= 3 mm. Three factors significantly influenced CBL (P < 0.05): implant surface texture (TPS > SLA), smoking status (smokers > non-smokers), and implant location (anterior > posterior). CONCLUSIONS: CBL was <=1.5 mm after 5-6 years for the majority of followed implants. For implants with a CBL > 1.5 mm, statistically significant correlations were found for TPS surface type, anterior jaw locations, and smoking. Implant length did not influence CBL. PMID- 23360221 TI - Enantioselective synthesis of (+)-malbrancheamide B. AB - The asymmetric total synthesis of the chlorinated [2.2.2]-diazabicyclic indole alkaloid (+)-malbrancheamide B is reported. Key to the synthesis is a domino reaction sequence that employs an aldol condensation, alkene isomerization, and intramolecular Diels-Alder cycloaddition. Diastereofacial selection between the azadiene stereofaces is enforced with a chiral aminal auxiliary. A formal 7-step (longest linear route) synthesis of (+/-)-malbrancheamide B is also reported. PMID- 23360222 TI - Aggregation behavior and antimicrobial activity of ester-functionalized imidazolium- and pyridinium-based ionic liquids in aqueous solution. AB - Two series of long chain imidazolium- and pyridinium-based ionic liquids containing an ester functional group in the alkyl side chain, 3-methyl-1 alkyloxycarbonylmethylimidazolium bromides (C(n)EMeImBr) and 1 alkyloxycarbonylmethylpyridinium bromides (C(n)EPyrBr), were synthesized and their thermal stability, aggregation behavior in aqueous medium, and antimicrobial activity investigated. The introduction of an ester group decreased the thermal stability of the functionalized ILs compared to simple alkyl chain containing ILs (1-alkyl-3-methylimidazolium bromides and 1-alkylpyridinium bromides). Tensiometry, conductimetry, and spectrofluorimetry were applied to study the self-aggregation of the amphiphilic ILs in aqueous solution. The ILs investigated displayed surface activity and the characteristic chain length dependence of the micellization process of surfactants. As compared to simple alkyl chain containing ILs bearing the same hydrocarbon chain, ester functionalized ILs possess higher adsorption efficiency (pC(20)) and significantly lower critical micelle concentration (cmc) and surface tension at the cmc (gamma(cmc)), indicating that the incorporation of an ester group promotes adsorption at the air/water interface and micelle formation. The antimicrobial activity was evaluated against Gram-negative and Gram-positive bacteria and fungi. ILs containing more than eight carbon atoms in the alkyl chain showed antimicrobial activity. Their efficiency as antimicrobial agents increased with the hydrophobicity of the amphiphilic cation being the C(12) homologous the most active compounds. The incorporation of an ester group particularly increased the biological activity against fungi. PMID- 23360223 TI - Human epidermal growth factor receptor 2 protein overexpression and gene amplification in extramammary Paget disease. AB - BACKGROUND: Several recent studies have reported on the overexpression of human epidermal growth factor receptor (HER)2 in extramammary Paget disease (EMPD). However, there are only a few cases in which both overexpression and gene amplification of HER2 have been examined. OBJECTIVES: To evaluate the overexpression and gene amplification of HER2 using a standardized method with a large number of cases of EMPD. METHODS: Immunohistochemically, the overexpression of the HER2 protein was examined in 104 cases of EMPD, including 31 intraepithelial cases and 73 invasive cases (35 superficially invasive and 38 deeply invasive). When the HER2 protein was overexpressed or potentially overexpressed, further analysis of amplification of the gene encoding HER2, ERBB2, was undertaken using fluorescence in situ hybridization. RESULTS: The HER2 protein was overexpressed in 16 cases (15%) in total, and in 13 of 73 cases (18%) of invasive EMPD. The ERBB2 gene was amplified in all cases with a HER2 score of 3+. A HER2 score of 3+ or 2+, and ERBB2 amplification were significantly more frequent in the cases of deeply invasive EMPD than in intraepithelial/superficially invasive EMPD (24% vs. 6%/3%, P=0.012) and were correlated with a larger number of lymph-node metastases (P=0.047). Log-rank tests for survival curves showed that lymph-node metastasis and ERBB2 amplification were significant prognostic factors (P=0.0001 and P=0.043, respectively). However, by a multivariate analysis, only lymph-node status was a significant indicator of Paget-disease-specific survival (P=0.0001). CONCLUSIONS: A subset of EMPD, both intraepithelial and invasive, showed HER2 overexpression and gene amplification. These HER2 alterations were correlated with biologically aggressive EMPDs, i.e. those with deep invasion and lymph-node metastasis. Clinical trials of HER2-targeted therapy are awaited for improvement of the prognosis of patients with aggressive EMPD. PMID- 23360224 TI - Gene-guided gefitinib switch maintenance therapy for patients with advanced EGFR mutation-positive non-small cell lung cancer: an economic analysis. AB - BACKGROUND: Maintenance therapy with gefitinib notably improves survival in patients with advanced non-small cell lung cancer (NSCLC) and EGFR mutation positive tumors, but the economic impact of this practice is unclear. METHODS: A decision-analytic model was developed to simulate 21-day patient transitions in a 10-year time horizon. The clinical data were primarily obtained from the results of a pivotal phase III trial that assessed gefitinib maintenance treatment in patients with advanced NSCLC. The cost data were derived from the perspective of the Chinese health care system. The primary outcome was the incremental cost effectiveness ratio (ICER) at a willingness-to-pay (WTP) threshold of 3 times the per capita GDP of China. Sensitivity analyses were used to explore the impact of uncertainty regarding the results. The impact of the gefitinib patient assistance program (GPAP) was evaluated. RESULTS: After EGFR genotyping, gefitinib maintenance treatment for advanced NSCLC with EGFR mutations increased the life expectancy by 0.74 years and 0.46 QALYs compared with routine follow-up at an additional cost of $26,149.90 USD ($7,178.20 with the GPAP). The ICER for gefitinib maintenance was $57,066.40 and $15,664.80 per QALY gained (at a 3% discount rate) without and with the GPAP, respectively. The utility of progression free survival, the hazard ratio of progression-free survival for gefitinib treatment and the cost of gefitinib per dose were the three factors that had the greatest influence on the results. CONCLUSIONS: These results indicate that gene-guided maintenance therapy with gefitinib with the GPAP might be a cost-effective treatment option. PMID- 23360225 TI - Estimation of data-specific constitutive exons with RNA-Seq data. AB - BACKGROUND: RNA-Seq has the potential to answer many diverse and interesting questions about the inner workings of cells. Estimating changes in the overall transcription of a gene is not straightforward. Changes in overall gene transcription can easily be confounded with changes in exon usage which alter the lengths of transcripts produced by a gene. Measuring the expression of constitutive exons--xons which are consistently conserved after splicing--ffers an unbiased estimation of the overall transcription of a gene. RESULTS: We propose a clustering-based method, exClust, for estimating the exons that are consistently conserved after splicing in a given data set. These are considered as the exons which are "constitutive" in this data. The method utilises information from both annotation and the dataset of interest. The method is implemented in an openly available R function package, sydSeq. CONCLUSION: When used on two real datasets exClust includes more than three times as many reads as the standard UI method, and improves concordance with qRT-PCR data. When compared to other methods, our method is shown to produce robust estimates of overall gene transcription. PMID- 23360226 TI - Analysing gait using a force-measuring walkway: intrasession repeatability in healthy children and adolescents. AB - The goal of this study was to determine the repeatability of gait parameters measured by a force plate gait analysis system (Leonardo Mechanograph((r)) GW) in healthy children. Nineteen healthy children and adolescents (age range: 7-17 years) walked at a self-selected speed on an 11-m-long walkway. Vertical ground reaction forces were measured in the central 6 m of the walkway. Each participant performed three blocks of three trials while walking barefoot and three blocks of three trials while wearing shoes. There were no differences between trials within each condition. All force and spatiotemporal parameters had intraclass correlation coefficients above 0.87 and coefficients of variation in the order of 1-6%. In this group of healthy children and adolescents, gait analysis with a force plate system produced repeatable intra-day results. PMID- 23360227 TI - Effect of erythrocyte aggregation on spatiotemporal variations in cell-free layer formation near on arteriolar bifurcation. AB - OBJECTIVE: To investigate how red blood cell aggregation could modulate the spatial variations in cell-free layer formation in the vicinity of an arteriolar bifurcation. METHODS: Visualization of blood flow was performed in upstream and downstream vessels of arteriolar bifurcations in the rat cremaster muscles under reduced flow conditions before and after induction of red blood cell aggregation to both physiological normal- and pathological hyperlevels seen in humans. RESULTS: Large asymmetries of layer widths on opposite sides of the downstream vessel were attenuated along the vessel and this effect could be prominently enhanced by the hyperaggregation due to a higher formation rate of the layer which was greater on one side than the other of the vessel. The proportion of downstream layer formation constituted by the smaller downstream vessel generally increased with a thicker layer width at the wall of the upstream vessel adjacent it. A greater tendency of the layer formation in the smaller downstream vessel was found under the hyperaggregating condition than normal-aggregating and nonaggregating conditions. CONCLUSION: Red blood cell aggregation could attenuate the asymmetry in cell-free layer formation on opposite sides of the downstream vessel, but enhances the heterogeneity of the layer formation between downstream vessels. PMID- 23360228 TI - Preparation of a molecularly imprinted soft contact lens as a new ocular drug delivery system for dorzolamide. AB - In the present work a series of imprinted (MIPs) and non-imprinted (NIPs) hydrogels were prepared using 2-hydroxyethyl methacrylate (HEMA) as a backbone monomer, ethylene glycol dimethacrylate (EGDMA) as a cross-linker monomer, methacrylic acid (MAA) as a functional monomer and dorzolamide (DZD) as the template molecule. Different concentrations of MAA (0, 100, 200, 400 mM) were used for preparation of NIPs. Two DZD: MAA molar ratios (1:8 and 1:4) and 400 mM MAA were also applied in imprinting process. The hydrogels (0.4 mm thickness) were synthesized by thermal polymerization at 50 degrees C in 24h in a polypropylene mould. Then, the swelling and binding properties of hydrogels were evaluated in water. Their loading and releasing properties were also studied in NaCl 0.9% and artificial lachrymal fluid. The results showed that using MAA as co monomer and applying molecular imprinting technique increased loading capacity of hydrogels. The optimized imprinted hydrogel (MIP1:4), prepared with 400 mM MAA and DZD: MAA molar ratio of 1:4, had the highest affinity for DZD and the greatest ability to control the release process in aqueous media. Our data indicated that the use of suitable co-monomer and applying a molecular imprinting technique had important influence on loading and releasing properties of hydrogels. PMID- 23360229 TI - Altered neuronal density and neurotransmitter expression in the ganglionated region of Ednrb null mice: implications for Hirschsprung's disease. AB - BACKGROUND: Hirschsprung's disease (HSCR) is a congenital condition in which enteric ganglia, formed from neural crest cells (NCC), are absent from the terminal bowel. Dysmotility and constipation are common features of HSCR that persist following surgical intervention. This persistence suggests that the portion of the colon that remains postoperatively is not able to support normal bowel function. To elucidate the defects that underlie this condition, we utilized a murine model of HSCR. METHODS: Mice with NCC-specific deletion of Ednrb were used to measure the neuronal density and neurotransmitter expression in ganglia. KEY RESULTS: At the site located proximal to the aganglionic region of P21 Ednrb null mice, the neuronal density is significantly decreased and the expression of neurotransmitters is altered compared with het animals. The ganglia in this colonic region are smaller and more isolated while the size of neuronal cell bodies is increased. The percentage of neurons expressing neuronal nNOS and VIP is significantly increased in Ednrb nulls. Conversely, the percentage of choline acetyltransferase (ChAT) expressing neurons is decreased, while Substance P is unchanged between the two genotypes. These changes are limited to the colon and are not detected in the ileum. CONCLUSIONS & INFERENCES: We demonstrate changes in neuronal density and alterations in the balance of expression of neurotransmitters in the colon proximal to the aganglionic region in Ednrb null mice. The reduced neuronal density and complementary changes in nNOS and ChAT expression may account for the dysmotility seen in HSCR. PMID- 23360230 TI - Surface-enhanced Raman scattering dye-labeled Au nanoparticles for triplexed detection of leukemia and lymphoma cells and SERS flow cytometry. AB - The labeling of cell surface receptors by fluorescent markers is an established method for the identification of cell phenotype in both research and clinical settings. Fluorescence dye labeling has inherent constraints, most notably the upper limit of labels per cell that may be probed using a single excitation source, in addition to a physical limit to the number of broad emission spectra that can be distinctly collected within the visible wavelength region. SERS labeling has the potential to mitigate these shortfalls. Herein, antibody targeted, PEG-coated surface-enhanced Raman scattering (SERS) Au nanoparticles are used simultaneously to label three cell surface markers of interest on malignant B cells from the LY10 lymphoma cell line. The SERS probes were characterized by multiple methods to confirm their monodispersity and functionalization with both PEG and monoclonal antibodies. The specificity of the particles' cell labeling was demonstrated on both primary chronic lymphocytic leukemia and LY10 cells using SERS from cell suspensions and confocal Raman mapping, respectively. Fluorescence flow cytometry was employed to confirm the binding of SERS probes to LY10 over large cell populations, and the particles' SERS was collected directly from labeled cells using a commercial flow cytometer. To the best of our knowledge, this is the first demonstration of SERS flow cytometry from cells tagged with targeted SERS probes. PMID- 23360231 TI - Construction of cucurbit[7]uril based tubular nanochannels incorporating associated [CdCl4]2- and lanthanide ions. AB - There is intensive interest in the design of tubular channels because of their novel structures and various applications in a variety of research fields. Herein, we present a series of coordination-driven Q[7]-derived organic nanochannels using an anion-induced strategy under different acid concentrations. An advantage of this approach is that the tubular channels not only retain the original character of the parent macrocyclic receptors but also provide deep hydrophobic cavities possessing guest binding sites. Importantly, this study also emphasizes the efficiency of the macrocyclic receptors in providing a tubular hydrophobic cavity by directly stacking on top of one another with the anion fixed and by acid control. The resulting combination of hydrogen bonding, C H...Cl, and ion-dipole interactions helps to stabilize these supramolecular architectures. Such systems are both tunable and versatile and allow for interconvertibility in the construction of nanochannels based on these macrocyclic receptors. PMID- 23360232 TI - Surface-modified HK:siRNA nanoplexes with enhanced pharmacokinetics and tumor growth inhibition. AB - We characterized in this study the pharmacokinetics and antitumor efficacy of histidine-lysine (HK):siRNA nanoplexes modified with PEG and a cyclic RGD (cRGD) ligand targeting alphavbeta3 and alphavbeta5 integrins. With noninvasive imaging, systemically administered surface-modified HK:siRNA nanoplexes showed nearly 4 fold greater blood levels, 40% higher accumulation in tumor tissue, and 60% lower luciferase activity than unmodified HK:siRNA nanoplexes. We then determined whether the surface-modified HK:siRNA nanoplex carrier was more effective in reducing MDA-MB-435 tumor growth with an siRNA targeting Raf-1. Repeated systemic administration of the selected surface modified HK:siRNA nanoplexes targeting Raf 1 showed 35% greater inhibition of tumor growth than unmodified HK:siRNA nanoplexes and 60% greater inhibition of tumor growth than untreated mice. The improved blood pharmacokinetic results and tumor localization observed with the integrin-targeting surface modification of HK:siRNA nanoplexes correlated with greater tumor growth inhibition. This investigation reveals that through control of targeting ligand surface display in association with a steric PEG layer, modified HK: siRNA nanoplexes show promise to advance RNAi therapeutics in oncology and potentially other critical diseases. PMID- 23360233 TI - alpha-Glucosidase inhibitors via green pathway: biotransformation for bicoumarins catalyzed by Momordica charantia peroxidase. AB - Peroxidase extracted from Momordica charantia catalyzed the H(2)O(2)-dependent oxidative coupling of 7-hydroxy-4-methylcoumarin to form four new dimers (1-4) and two known ones (5, 6). The structures, including the absolute configurations of axially chiral compounds, were unambiguously characterized by NMR spectroscopy, online HPLC-CD, and a variety of computational methods. Bioactive experiments demonstrated that compounds 1 and 2 had significant inhibitory effects on yeast alpha-glucosidase, much better than the controls. Noncompetitive binding mode was found by the graphical analysis of steady-state inhibition data. The mechanism of enzymatic inhibition confirmed in some depth that the inhibitors altered the secondary structure of alpha-glucosidase by decreasing the alpha helix and increasing the beta-sheet content. In summary, bicoumarins 1 and 2 might be exploited as the lead compounds for further research of antidiabetic agents, and this research provided a "green" method to synthesize compounds with the chiral biaryl axis generally calling for multistep reactions in organic chemistry. PMID- 23360234 TI - Side scatter intensity is highly heterogeneous in undifferentiated pluripotent stem cells and predicts clonogenic self-renewal. AB - In culture, human pluripotent stem cells (PSCs) are phenotypically (for instance, the SSEA3 expression level) and functionally (capacity to survive after single cell dissociation) heterogeneous. We report here that the side scatter (SSC) signal measured by flow cytometry, a variable correlated with membrane irregularity and cell granularity, is very high in PSCs, even higher than in blood polymorphonuclear cells, and markedly heterogeneous. Moreover, SSC intensity rapidly and strongly decreases upon PSC differentiation into any of the three germ layers. PSCs with high SSC (HSSC cells) or low SSC (LSSC cells) values both express pluripotency markers, but HSSC cells are characterized by more frequent simultaneous expression of the membrane pluripotency factors SSEA3, SSEA4, TRA-1-81, TRA-1-60, and CD24 and by a higher mitochondrial content. Functionally, HSSC cells are more likely to generate colonies upon single-cell passage than LSSC cells. SSC monitoring might provide a simple, but robust and rapid method to estimate pluripotency variations in culture and unveils a new phenotypic and functional heterogeneity in PSCs. PMID- 23360235 TI - Hypothermia and pharmacological regimens that prevent overexpression and overactivity of the extracellular calcium-sensing receptor protect neurons against traumatic brain injury. AB - Traumatic brain injury (TBI) leads to acute functional deficit in the brain. Molecular events underlying TBI remain unclear. In mouse brains, we found controlled cortical impact (CCI) injury induced overexpression of the extracellular calcium-sensing receptor (CaSR), which is known to stimulate neuronal activity and accumulation of intracellular Ca(2+) and concurrent down regulation of type B or metabotropic GABA receptor 1 (GABA-B-R1), a prominent inhibitory pathway in the brain. These changes in protein expression preceded and were closely associated with the loss of brain tissue, as indicated by the increased size of cortical cavity at impact sites, and the development of motor deficit, as indicated by the increased frequency of right-biased swing and turn in the CCI mice. Mild hypothermia, an established practice of neuroprotection for brain ischemia, partially but significantly blunted all of the above effects of CCI. Administration of CaSR antagonist NPS89636 mimicked hypothermia to reduce loss of brain tissue and motor functions in the CCI mice. These data together support the concept that CaSR overexpression and overactivity play a causal role in potentiating TBI potentially by stimulating excitatory neuronal responses and by interfering with inhibitory GABA-B-R signaling and that the CaSR could be a novel target for neuroprotection against TBI. PMID- 23360236 TI - Selectivity switch in the catalytic functionalization of nonprotected carbohydrates: selective synthesis in the presence of anomeric and structurally similar carbohydrates under mild conditions. AB - A catalytic process for the chemo- and regioselective functionalization of nonprotected carbohydrates has been developed. This novel process allows selective thiocarbonylation, acylation, and sulfonylation of a particular hydroxy group in a particular carbohydrate in the simultaneous presence of structurally similar carbohydrates such as anomers. In addition, the chemoselectivity can be switched by regulating only the length of the alkyl chain in the organotin catalyst. PMID- 23360238 TI - Mechanistic studies of the oxygen evolution reaction mediated by a nickel-borate thin film electrocatalyst. AB - A critical determinant of solar-driven water splitting efficiency is the kinetic profile of the O2 evolving catalyst (OEC). We now report the kinetic profiles of water splitting by a self-assembled nickel-borate (NiBi) OEC. Mechanistic studies of anodized films of NiBi exhibit the low Tafel slope of 2.3 * RT/2F (30 mV/decade at 25 degrees C). This Tafel slope together with an inverse third order rate dependence on H(+) activity establishes NiBi as an ideal catalyst to be used in the construction of photoelectrochemical devices for water splitting. In contrast, nonanodized NiBi films display significantly poorer activity relative to their anodized congeners that we attribute to a more sluggish electron transfer from the catalyst resting state. Borate is shown to play two ostensibly antagonistic roles in OEC activity: as a promulgator of catalyst activity by enabling proton-coupled electron transfer (PCET) and as an inhibitor in its role as an adsorbate of active sites. By defining the nature of the PCET pre-equilibrium that occurs during turnover, trends in catalyst activity may be completely reversed at intermediate pH as compared to those at pH extremes. These results highlight the critical role of PCET pre-equilibria in catalyst self assembly and turnover, and accordingly suggest a reassessment in how OEC activities of different catalysts are compared and rationalized. PMID- 23360237 TI - Ability of preoperative 3.0-Tesla magnetic resonance imaging to predict the absence of side-specific extracapsular extension of prostate cancer. AB - OBJECTIVE: Recent studies have shown an improvement in prostate cancer diagnosis with the use of 3.0-Tesla magnetic resonance imaging. We retrospectively assessed the ability of this imaging technique to predict side-specific extracapsular extension of prostate cancer. METHODS: From October 2007 to August 2011, prostatectomy was carried out in 396 patients after preoperative 3.0-Tesla magnetic resonance imaging. Among these, 132 (primary sample) and 134 patients (validation sample) underwent 12-core prostate biopsy at the National Cancer Center Hospital of Tokyo, Japan, and at other institutions, respectively. In the primary dataset, univariate and multivariate analyses were carried out to predict side-specific extracapsular extension using variables determined preoperatively, including 3.0-Tesla magnetic resonance imaging findings (T2-weighted and diffusion-weighted imaging). A prediction model was then constructed and applied to the validation study sample. RESULTS: Multivariate analysis identified four significant independent predictors (P < 0.05), including a biopsy Gleason score of >=8, positive 3.0-Tesla diffusion-weighted magnetic resonance imaging findings, >=2 positive biopsy cores on each side and a maximum percentage of positive cores >=31% on each side. The negative predictive value was 93.9% in the combination model with these four predictors, meanwhile the positive predictive value was 33.8%. Good reproducibility of these four significant predictors and the combination model was observed in the validation study sample. CONCLUSIONS: The side-specific extracapsular extension prediction by the biopsy Gleason score and factors associated with tumor location, including a positive 3.0-Tesla diffusion-weighted magnetic resonance imaging finding, have a high negative predictive value, but a low positive predictive value. PMID- 23360239 TI - A novel class of oral direct renin inhibitors: highly potent 3,5-disubstituted piperidines bearing a tricyclic p3-p1 pharmacophore. AB - A small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S3-S1 pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P3(sp)-tethered tricyclic P3-P1 pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model. PMID- 23360240 TI - Early amniotic membrane transplantation for toxic keratopathy secondary to topical proparacaine abuse: a report of seven cases. AB - PURPOSE: The aim of this study is to evaluate the effect of early amniotic membrane transplantation (AMT) in patients with topical proparacaine-related toxic keratopathy. MATERIALS AND METHODS: Between 2008 and 2011, eight eyes of seven patients with toxic keratopathy related to 0.5% proparacaine abuse underwent early AMT (within 1 to 5 days following the diagnosis). Clinical findings and treatment outcomes of these cases were evaluated retrospectively. RESULTS: The median time of topical anesthetic abuse until admission to our clinic was 28 (10-112) days. One case was referred due to achanthamoeba keratitis; two cases due to intractable corneal ulcer and melting. At initial examination, visual acuities varied between hand motions and 0.4 (in decimal notation). Biomicroscopic evaluation at presentation revealed epithelial defects, corneal ulcers, stromal ring infiltrate, stromal edema and corneal melting with varying degrees. At third month after AMT, the visual acuities varied between hand motions and 0.9, and all the patients had corneal stromal opacities with varying densities. One patient, who did not respond to medical and surgical treatment and developed secondary infections that invaded intraocular structures, underwent evisceration. CONCLUSION: Topical anesthetic abuse can lead to serious ocular complications. After proper diagnosis, the first step of treatment is the cessation of drug abuse. In addition to medical treatment, early AMT has an advantage of early pain relief and consequential elimination of the need for topical anesthetic instillation. PMID- 23360241 TI - Development of colon specific microspheres of flurbiprofen for inflammatory bowel disease. AB - In the present investigation chitosan microspheres loaded with flurbiprofen (FLB) were prepared by oil/oil emulsification method for colon specific drug delivery. FLB was entrapped in chitosan microspheres, following coating with Eudragit S-100 utilizing the benefits of pH dependent solubility of Eudragit S-100, so as to prevent the premature release of FLB in upper GIT. Different batches of FLB microspheres were prepared by varying FLB: chitosan ratio (1:1 to 1:4). The effect of chitosan concentration on size, entrapment efficiency, percent drug loading and degree of swelling was evaluated. DSC studies revealed the dispersion of FLB in the matrix of chitosan microspheres. SEM analysis indicated the nearly smooth surface and spherical shape of the prepared microspheres. X-ray diffract gram of FLB microspheres showed less intense peaks as compared to free FLB. In vitro release studies of uncoated FLB- chitosan microspheres showed burst release in initial 4 h, while Eudragit S-100 coated microspheres prevented the premature release of FLB and showed controlled release for 12 h following Higuchi model, thus suitable for colon specific drug delivery. PMID- 23360242 TI - Growth of Salmonella enterica in foliar pesticide solutions and its survival during field production and postharvest handling of fresh market tomato. AB - AIMS: To evaluate in vitro the growth kinetics of Salmonella enterica in pesticide solutions labelled for fresh market tomato and the effect of ag chemical application with contaminated water to tomatoes during field production. METHODS AND RESULTS: The capacity of pesticide formulations in the survival of S. enterica was evaluated in vitro and on tomato surfaces during field production. Most pesticides had ability to maintain the growth of Salmonella, however, specific pesticides can also support its growth, which was also dependent on the water composition and temperature to which pesticide solutions were held. Salmonella applied to field grown tomatoes through pesticide application was able to survive up to 15 days in up to 80% of the collected samples, even more postharvest washing with sodium hypochlorite was insufficient to completely mitigate the presence of Salmonella on tomato surfaces. CONCLUSIONS: This study provides further evidence that pesticides may support the growth of Salmonella, if introduced with source water and may elevate risk during foliar contact application beyond that of the water source alone. SIGNIFICANCE AND IMPACT OF STUDY: The study points out the importance of the microbiological quality of foliar contact water as a critical point to prevent contamination of fruits and vegetables from early stages of field production. PMID- 23360243 TI - Comparison of phacotrabeculectomy versus phacocanaloplasty in the treatment of patients with concomitant cataract and glaucoma. AB - BACKGROUND: Cataract and glaucoma are both common comorbidities among older patients. Combining glaucoma surgery with minimal invasive phacoemulsification (phaco) is a considerable option to treat both conditions at the same time, although the combination with filtration surgery can produce a strong inflammatory response. Combined non-penetrating procedures like canaloplasty have shown to reduce intraocular pressure (IOP) comparable to trabeculectomy without the risk of serious bleb-related complications. The purpose of this retrospective study was to compare the outcomes of phacotrabeculectomy and phacocanaloplasty. METHODS: Thirty-nine eyes with concomitant cataract and glaucoma who underwent phacotrabeculectomy (n=20; 51.3%) or phacocanaloplasty (n=19; 48.7%) were included into this trial on reduction of IOP, use of medication, success rate, incidence of complications and postsurgical interventions. Complete success was defined as IOP reduction by 30% or more and to 21 mmHg or less (definition 1a) or IOP to less than 18 mmHg (definition 2a) without glaucoma medication. RESULTS: Over a 12-month follow-up, baseline IOP significantly decreased from 30.0 +/- 5.3 mmHg with a mean of 2.5 +/- 1.2 glaucoma medications to 11.7 +/- 3.5 mmHg with a mean of 0.2 +/- 0.4 medications in eyes with phacotrabeculectomy (P< .0001). Eyes with phacocanaloplasty had a preoperative IOP of 28.3 +/- 4.1 mmHg and were on 2.8 +/- 1.1 IOP-lowering drugs. At 12 months, IOP significantly decreased to 12.6 +/- 2.1 mmHg and less glaucoma medications were necessary (mean 1.0 +/- 1.5 topical medications; P< .05). 15 patients (78.9%) with phacotrabeculectomy and 9 patients (60.0%) in the phacocanaloplasty group showed complete success according to definition 1 and 2 after 1 year (P= .276). Postsurgical complications were seen in 7 patients (36.8%) of the phacocanaloplasty group which included intraoperative macroperforation of the trabeculo-Descemet membrane (5.3%), hyphema (21.1%) and bleb formation (10.5%). Although more complications were observed in the phacotrabeculectomy group, no statistically significant difference was found. CONCLUSIONS: Phacocanaloplasty offers a new alternative to phacotrabeculectomy for treatment of concomitant glaucoma and cataract, although phacotrabeculectomy yielded in better results in terms of IOP maintained without glaucoma medications. PMID- 23360245 TI - National survey focusing on the crucial information needs of intensive care charge nurses and intensivists: same goal, different demands. AB - BACKGROUND: Although information technology adequately supports clinical care in many intensive care units (ICUs), it provides much poorer support for the managerial information needed to coordinate multi-professional care. To gain a general view of the most crucial multi-professional information needs of ICU shift leaders a national survey was conducted, focusing on the information needs of charge nurses and intensivists. METHODS: Based on our previous observation study an online survey was developed, containing 122 information need statements related to the decision-making of ICU shift leaders. Information need statements were divided into six dimensions: patient admission, organisation and management of work, allocation of staff and material resources, special treatments, and patient discharge. This survey involved all ICU shift leaders (n = 738) who worked in any of the 17 highest level ICUs for adults in university hospitals in Finland during the autumn of 2009. Both charge nurses' and intensivists' crucial information needs for care coordination were evaluated. RESULTS: Two hundred and fifty-seven (50%) charge nurses and 96 (43%) intensivists responded to the survey. The consistency of the survey was found to be good (Cronbach's alpha scores between .87-.97, with a total explanatory power of 64.53%). Altogether, 57 crucial information needs for care coordination were found; 22 of which were shared between shift leaders. The most crucial of these information needs were related to organisation and management, patient admission, and allocation of staff resources. The associations between working experience, or shift leader acting frequencies, and crucial information needs were not statistically significant. However, a statistically significant difference was found between the number of ICU beds and the ICU experience of charge nurses with information needs, under the dimension of organisation and management of work. The information needs of charge nurses and intensivists differed. Charge nurses' information needs related to care coordination, were more varied, and concerned issues at a unit level, whereas intensivists focused on direct patient care. CONCLUSIONS: The reliability and validity of our survey was found to be good. Our study findings show that care coordination at an ICU is a collaborative process among ICU shift leaders with multiprofessional information needs related to organisation and management, patient admission, and allocation of staff resources. Study findings can be used to identify the most crucial information needs of ICU shift leaders when new information technology is developed to support managerial decision-making during care coordination. PMID- 23360246 TI - Development of solid dispersion systems of dapivirine to enhance its solubility. AB - Dapivirine, formerly known as TMC 120, is a poorly-water soluble anti-HIV drug, currently being developed as a vaginal microbicide. The clinical use of this drug has been limited due to its poor solubility. The aim of this study was to design solid dispersion systems of Dapivirine to improve its solubility. Solid dispersions were prepared by solvent and fusion methods. Dapivirine release from the solid dispersion system was determined by conducting in-vitro dissolution studies. The physicochemical characteristics of the drug and its formulation were studied using Differential Scanning Calorimetry (DSC), powder X-ray Diffraction (XRD), Fourier-transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). A significant improvement in drug dissolution rate was observed with the solid dispersion systems. XRD, SEM and DSC results indicated the transformation of pure Dapivirine which exists in crystalline form into an amorphous form in selected solid dispersion formulations. FTIR and HPLC analysis confirmed the absence of drug-excipient interactions. Solid dispersion systems can be used to improve the dissolution rate of Dapivirine. This improvement could be attributed to the reduction or absence of drug crystallinity, existence of drug particles in an amorphous form and improved wettability of the drug. PMID- 23360244 TI - Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease. AB - Acute kidney injury (AKI) is a major burden on health systems and may arise from multiple initiating insults, including ischaemia-reperfusion injury, cardiovascular surgery, radiocontrast administration and sepsis. Similarly, the incidence and prevalence of chronic kidney disease (CKD) continues to increase, with significant morbidity and mortality. Moreover, an increasing number of AKI patients survive to develop CKD and end-stage renal disease. Although the mechanisms for the development of AKI and progression to CKD remain poorly understood, initial impairment of oxygen balance likely constitutes a common pathway, causing renal tissue hypoxia and ATP starvation that, in turn, induce extracellular matrix production, collagen deposition and fibrosis. Thus, possible future strategies for one or both conditions may involve dopamine, loop diuretics, atrial natriuretic peptide and inhibitors of inducible nitric oxide synthase, substances that target kidney oxygen consumption and regulators of renal oxygenation, such as nitric oxide and heme oxygenase-1. PMID- 23360247 TI - Microbubbles and their applications in pharmaceutical targeting. AB - Microbubbles are small spherical gas filled bubbles in the size range of 1-10 microns. Their external coat is made of polymers or phospholipids. In combination with ultrasound, they have been explored as contrast agents for ultrasound and also carriers for drug and gene delivery. In response to ultrasound of lower mechanical index, microbubbles oscillate and vibrate to give a distinct signal in ultrasound imaging. At a higher mechanical index, these microbubbles rupture and break to deliver the drugs or genes enclosed in them or attached to their surface. The behaviour of microbubbles in response to ultrasound is a characteristic of the properties of microbubbles like its shell composition, shell thickness and the density and compressibility of the enclosed gas. Microbubbles have various applications in diagnostic imaging like echocardiography, and imaging of cancer cells, inflammed cells etc. They are also used as a medium for drug and gene delivery. Microbubbles can be further modified by binding specific ligands to their surface which specifically attach to certain cells so that selective action of the microbubbles can be seen at that location of cells. PMID- 23360248 TI - Development, optimization and in vitro-in vivo evaluation of pioglitazone- loaded jackfruit seed starch-alginate beads. AB - The present investigation describes development and optimization of pioglitazone loaded jackfruit seed starch (JFSS)-alginate beads by ionotropic-gelation using 3(2) factorial design. The effect of polymer-blend ratio and CaCl2 concentration on the drug encapsulation efficiency (DEE, %), and cumulative drug release after 10 hours (R10h, %) was optimized. The DEE (%) of these beads were 64.80 +/- 1.92 to 94.07 +/- 3.82 % with sustained in vitro drug release of 64.+/- 1.83 to 92.66 +/- 4.54 % over 10 hours. The in vitro drug release from these beads followed controlled-release pattern with super case-II transport. Particle size range of these beads was 0.77 +/- 0.04 to 1.24 +/- 0.09 mm. The beads were also characterized by SEM and FTIR. The swelling of these beads was influenced by pH of the test medium. The optimized pioglitazone-loaded JFSS-alginate beads showed significant hypoglycemic effect in alloxan-induced diabetic rats over prolonged period after oral administration. PMID- 23360249 TI - Parallel nanometric 3D tracking of intracellular gold nanorods using multifocal two-photon microscopy. AB - We report a novel technique for long-term parallel three dimensional (3D) tracking of gold nanorods in live cells with nanometer resolution. Gold nanorods feature a strong plasmon-enhanced two-photon luminescence, can be easily functionalized, and have been shown to be nontoxic. These properties make gold nanorods very suitable for in vivo two-photon luminescence microscopy. By rapid multifocal scanning, we combine the advantages of 3D molecular tracking methods using wide-field imaging with the advantages of two-photon microscopy. Isolated gold nanorods can be localized with a resolution of 4 nm in the xy-plane and 8 nm in the z-direction. The polarization-dependence of the two-photon luminescence signal can be used to resolve the angular orientation, even when two gold nanorods are separated by less than the diffraction limit. Individual nanorods in live U2OS cells could be followed in 3 dimensions for over 30 min, with a photon noise limited accuracy, and a time resolution of 50 ms in 2D and 500 ms in 3D. PMID- 23360251 TI - Prevention of allergic rhinitis by aldose reductase inhibition in a murine model. AB - BACKGROUND: Allergic rhinitis, one of the most common atopic diseases, is known to be elicited by Th2 cytokine-mediated inflammatory response. We have shown earlier that a polyol pathway enzyme aldose reductase (AR) regulates airway inflammation; however its role in allergic rhinitis is not known. We have investigated the role of AR in mediating pathological symptoms associated with allergic rhinitis in mice. METHODS: The wild-type (WT) mice treated without or with AR inhibitor and AR knock out (AR(-/-)) mice were sensitized by two intraperitoneal injections of ragweed pollen extract (RWE) with adjuvant alum on days 0 and 4 followed by challenge on day 11 and/or 18 and 25. The allergic rhinitis symptoms were assessed by monitoring the nasal scratch, mast cell degranulation and release of tryptase in nasal lavage, infiltration of inflammatory cells, production of inflammatory cytokines and nasal epithelium remodeling. RESULTS: Sensitization and challenge of mice with RWE produced robust and reproducible pathological symptoms of allergic rhinitis as compared to control mice. AR inhibitor, fidarestat administered mice showed markedly reduced early phase response to allergen exposure such as nasal scratches, mast cells degranulation and release of tryptase in the nasal passage as well as late phase response such as inflammatory cell infiltration and release of Th2 type cytokines and nasal epithelial remodeling. Further, prevention of these events in AR(-/-)) mice suggests the role of AR in the mediation of allergic rhinitis. CONCLUSION: These results indicate an important role of AR in the mediation of RWE-induced allergic rhinitis in mice and prevention by AR inhibitor, fidarestat offers a novel therapeutic approach to ameliorate allergic rhinitis. PMID- 23360252 TI - Intravenous immunoglobulin therapy in dermatology: an update. AB - Intravenous immunoglobulin (IVIG) is a fractioned blood product consisting of IgG antibodies which was first used in antibody deficiency disorders. It is increasingly being used for several inflammatory and autoimmune conditions. IVIG can also be used in a wide range of dermatological diseases which are difficult to treat including autoimmune bullous skin diseases and toxic epidermal necrolysis. The use of IVIG in dermatological disorders is discussed in this article. PMID- 23360253 TI - Polka-dotted vesicles: lipid bilayer dynamics and cross-linking effects. AB - We have investigated the effects of cross-linking perturbations on lipid phase domain coalescence. Our model system explores cross-linking in the fluid disordered phase of two-phase vesicles. Here, we quantify the vesicle population shift from the expected predominance of two-domain, two-phase configuration to a multidomain vesicle majority. We have found that the increase in multidomain vesicles is a distinct outcome from the cross-linking of biotinylated lipids and avidin. Analysis of our cross-linking data suggests that avidin forms clusters on the surface of the fluid-disordered domains, resulting in a large immobile fraction and restricted diffusion. In cellular membranes, receptor concentrations are similar to our experimental model, and we expect similar cluster formations, leading to nonideal mixing and lateral heterogeneity. We have induced and quantified a global response by cross-linking only a small percentage of lipids in our system, similar to receptor-ligand interactions on the cell membrane. Common activities, such as ligand-receptor coupling, contribute to lateral heterogeneity and membrane protein clustering, adding to cell membrane complexity. Fundamental studies into subtle shifts such as cross-linking events, which induce global cellular response, are pertinent to understanding membrane activities and effects of external stimuli. PMID- 23360255 TI - Editorial (hot topic:modulation of cholinergic system activity in neuronal and non-neuronal tissues: therapeutic implications). PMID- 23360254 TI - Mechanistic analysis of multi-omics datasets to generate kinetic parameters for constraint-based metabolic models. AB - BACKGROUND: Constraint-based modeling uses mass balances, flux capacity, and reaction directionality constraints to predict fluxes through metabolism. Although transcriptional regulation and thermodynamic constraints have been integrated into constraint-based modeling, kinetic rate laws have not been extensively used. RESULTS: In this study, an in vivo kinetic parameter estimation problem was formulated and solved using multi-omic data sets for Escherichia coli. To narrow the confidence intervals for kinetic parameters, a series of kinetic model simplifications were made, resulting in fewer kinetic parameters than the full kinetic model. These new parameter values are able to account for flux and concentration data from 20 different experimental conditions used in our training dataset. Concentration estimates from the simplified kinetic model were within one standard deviation for 92.7% of the 790 experimental measurements in the training set. Gibbs free energy changes of reaction were calculated to identify reactions that were often operating close to or far from equilibrium. In addition, enzymes whose activities were positively or negatively influenced by metabolite concentrations were also identified. The kinetic model was then used to calculate the maximum and minimum possible flux values for individual reactions from independent metabolite and enzyme concentration data that were not used to estimate parameter values. Incorporating these kinetically-derived flux limits into the constraint-based metabolic model improved predictions for uptake and secretion rates and intracellular fluxes in constraint-based models of central metabolism. CONCLUSIONS: This study has produced a method for in vivo kinetic parameter estimation and identified strategies and outcomes of kinetic model simplification. We also have illustrated how kinetic constraints can be used to improve constraint-based model predictions for intracellular fluxes and biomass yield and identify potential metabolic limitations through the integrated analysis of multi-omics datasets. PMID- 23360256 TI - Synthesis of the Alzheimer drug Posiphen into its primary metabolic products (+) N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their inhibition of amyloid precursor protein, alpha-Synuclein synthesis, interleukin 1beta release, and cholinergic action. AB - A major pathological hallmark of Alzheimer disease (AD) is the appearance in the brain of senile plaques that are primarily composed of aggregated forms of beta amyloid peptide (Abeta) that derive from amyloid precursor protein (APP). Posiphen (1) tartrate is an experimental AD drug in current clinical trials that reduces Abeta levels by lowering the rate of APP synthesis without toxicity. To support the clinical development of Posiphen (1) and elucidate its efficacy, its three major metabolic products, (+)-N1-norPosiphen (15), (+)-N8-norPosiphen (17) and (+)-N1, N8-bisnorPosiphen (11), were required in high chemical and optical purity. The efficient transformation of Posiphen (1) into these metabolic products, 15, 17 and 11, is described. The biological activity of these metabolites together with Posiphen (1) and its enantiomer, the AD drug candidate (-)-phenserine (2), was assessed against APP,alpha-synuclein and classical cholinergic targets. All the compounds potently inhibited the generation of APP and alpha-synuclein in neuronal cultures. In contrast, metabolites 11 and 15, and (-)-phenserine (2) but not Posiphen (1) or 17, possessed acetyl cholinesterase inhibitory action and no compounds bound either nicotinic or muscarinic receptors. As Posiphen (1) lowered CSF markers of inflammation in a recent clinical trial, the actions of 1 and 2 on proinflammatory cytokine interleukin (IL)-1beta release human peripheral blood mononuclear cells was evaluated, and found to be potently inhibited by both agents. PMID- 23360258 TI - MicroRNA: novel modulators of the cholinergic anti-inflammatory pathway. AB - MicroRNAs (miRNAs) have emerged as key gene regulators controlling the expression of many target mRNAs. The nervous system harbors highest number of miRNAs expressed in a spatially and temporally controlled manner. Neural miRNAs have been accredited with diverse roles like regulation of neural differentiation, synaptogenesis, inflammation, memory and cognition. Their aberrant expression and/or function has been linked to various neurodegenerative, neuroinflammatory and stress related disorders. Recent evidence indicates that miRNAs are essential to the fine tuning of the immune responses. Besides controlling the maturation, proliferation and differentiation of myeloid and lymphoid lineages they participate directly by modulating the signaling pathways through the Toll-like receptors and thus the cytokine response. The miRNAs commuting between the nervous and immune systems and affecting the neuro-immune dialogue are emerging. PMID- 23360257 TI - Molecular interaction study of N1-p-fluorobenzyl-cymserine with TNF-alpha , p38 kinase and JNK kinase. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disease distinguished by progressive memory loss and cognitive decline. It is accompanied by classical neuropathological changes, including cerebral deposits of amyloid- beta peptide (Abeta) containing senile plaques, neurofibrillary tangles (NFTs) of phosphorylated tau (p-tau), and clusters of activated glial cells. Postmortem studies strongly support a critical role for neuroinflammation in the pathogenesis of AD, with activated microglia and reactive astrocytes surrounding senile plaques and NFTs. These are accompanied by an elevated expression of inflammatory mediators that further drives Abeta and p-tau generation. Although epidemiological and experimental studies suggested that long-term use of non steroidal anti-inflammatory drugs (NSAIDs) may lessen AD risk by mitigating inflammatory responses, primary NSAID treatment trials of AD have not proved successful. Elevated systemic butyrylcholinesterase (BuChE) levels have been considered a marker of low-grade systemic inflammation, and BuChE levels are reported elevated in AD brain. Recent research indicates that selective brain inhibition of BuChE elevates acetylcholine (ACh) and augments cognition in rodents free of the characteristic undesirable actions of acetylcholinesterase- inhibitors (AChE-Is). Hence, centrally active BuChE-selective-inhibitors, cymserine analogs, have been developed to test the hypothesis that BuChE-Is would be efficacious and better tolerated than AChE-Is in AD. The focus of the current study was to undertake an in-silico evaluation of an agent to assess its potential to halt the self-propagating interaction between inflammation,Abeta and p-tau generation. Molecular docking studies were performed between the novel BuChE-I, N1-p-fluorobenzyl-cymserine (FBC) and inflammatory targets to evaluate the potential of FBC as an inhibitor of p38, JNK kinases and TNF-alpha with respect to putative binding free energy and IC50 values. Our in-silico studies support the ability of FBC to bind these targets in a manner supportive of anti inflammatory action that is subject to molecular dynamics and physiochemical studies for auxiliary confirmation. PMID- 23360259 TI - Cholinergic drugs as therapeutic tools in inflammatory diseases: participation of neuronal and non-neuronal cholinergic systems. AB - Acetylcholine (ACh) is synthesized by choline acetyltransferase (ChAT) from acetylcoenzime A and choline. This reaction occurs not only in pre-ganglionic fibers of the autonomic nervous system and post-ganglionic parasympathetic nervous fibers but also in non neuronal cells. This knowledge led to expand the role of ACh as a neurotransmitter and to consider it as a "cytotransmitter" and also to evaluate the existence of a non-neuronal cholinergic system comprising ACh, ChAT, acetylcholinesterase, and the nicotinic and muscarinic ACh receptors, outside the nervous system. This review analyzes the participation of cholinergic system in inflammation and discusses the role of different muscarinic and nicotinic drugs that are being used to treat skin inflammatory disorders, asthma, and chronic obstructive pulmonary disease as well as, intestinal inflammation and systemic inflammatory diseases, among others, to assess the potential application of these compounds as therapeutic tools. PMID- 23360260 TI - Brain white matter microstructure is associated with susceptibility to motion induced nausea. AB - Nausea is associated with significant morbidity, and there is a wide range in the propensity of individuals to experience nausea. The neural basis of the heterogeneity in nausea susceptibility is poorly understood. Our previous functional magnetic resonance imaging (fMRI) study in healthy adults showed that a visual motion stimulus caused activation in the right MT+/V5 area, and that increased sensation of nausea due to this stimulus was associated with increased activation in the right anterior insula. For the current study, we hypothesized that individual differences in visual motion-induced nausea are due to microstructural differences in the inferior fronto-occipital fasciculus (IFOF), the white matter tract connecting the right visual motion processing area (MT+/V5) and right anterior insula. To test this hypothesis, we acquired diffusion tensor imaging data from 30 healthy adults who were subsequently dichotomized into high and low nausea susceptibility groups based on the Motion Sickness Susceptibility Scale. We quantified diffusion along the IFOF for each subject based on axial diffusivity (AD); radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA), and evaluated between-group differences in these diffusion metrics. Subjects with high susceptibility to nausea rated significantly (P < 0.001) higher nausea intensity to visual motion stimuli and had significantly (P < 0.05) lower AD and MD along the right IFOF compared to subjects with low susceptibility to nausea. This result suggests that differences in white matter microstructure within tracts connecting visual motion and nausea-processing brain areas may contribute to nausea susceptibility or may have resulted from an increased history of nausea episodes. PMID- 23360261 TI - A fibrinogen concentrate Haemocomplettan (Riastap) or a Factor XIII concentrate Fibrogammin combined with a mini dose of tranexamic acid can reverse the fibrin instability to fibrinolysis induced by thrombin- or FXa-inhibitor. AB - To assess whether Haemocomplettan((r)) (fibrinogen concentrate) or Fibrogammin((r)) (Factor XIII concentrate) can be used to manage bleeding complications of antithrombotic treatment, we examined a normal plasma pool spiked with AR-H067637 (thrombin inhibitor) or rivaroxaban (activated factor X inhibitor), to which one of the concentrates was added. Fibrin network permeability (Ks), images of Scanning Electron Microscopy (SEM) and Clot Lysis Time (CLT) were examined. Both inhibitors increased the Ks levels, which could be fully or partly reversed by Haemocomplettan((r)) or Fibrogammin((r)) respectively. However, these modified clots with tightened network remained non resistant to fibrinolysis, shown as unaffected CLT. Tranexamic acid at a very low concentration (0.4 mg/ml) aided the two concentrates to stabilize the clots, where the prolongation of CLT was more pronounced for a lower dose than a higher dose of Haemocomplettan((r)) while Fibrogammin((r)) brought the greatest delay to CLT out of all additions. These observations were partly supported by SEM images, displaying alterations of fibrin fibre arrangement known to influence fibirinolysis. The in vitro data suggest that Haemocomplettan((r)) or Fibrogammin((r)) given in combination with a mini dose of tranexamic acid may slow down the natural clearance of fibrin clot by plasmin and thus prevent patients from haemorrhagic complications during antithrombotic therapy. PMID- 23360262 TI - FRET based ratio-metric sensing of hyaluronidase in synthetic urine as a biomarker for bladder and prostate cancer. AB - Elevated hyaluronidase levels are found in the urine of bladder and prostate cancer patients. Therefore, HA-ase is regarded as an important biomarker for the detection of these cancers. In this report, we use a FRET based ratiometric sensing approach to detect the level of HA-ase in synthetic urine. For this, we have used a HA-FRET probe (hyaluronan) labeled with fluorescein as a donor and rhodamine as an acceptor. We monitor the digestion of our HA-FRET probe with different concentrations of HA-ase in synthetic urine via fluorescence emission. The extent to which FRET is released depends on the concentration of HA-ase. Our fluorescence intensity results are also supported with time resolved fluorescence decay data. This assay can be used to develop a non-invasive technique for the detection of bladder and/or prostate cancer progression. PMID- 23360263 TI - Advancement in infection control of opportunistic pathogen (Aspergillus spp.): adjunctive agents. AB - There is continuous emergence of resistant strains which leads to urgent need to discover new antifungal agents. The investigation of adjunctive agents for antifungal activity might help to optimize the therapy for Invasive Aspergillosis (IA). The chelating agents Ethylenediamine Tetraacetic Acid (EDTA) & Disodium salt of EDTA (DiEDTA) as adjunct to antifungal drugs have been investigated against 8 pathogenic isolates of Aspergillus spp. The MIC (Minimum Inhibitory Concentration) found by DDA (Disc Diffusion Assay) is 7.50-15.0 MUg/disc; by MDA (Microbroth Dilution Assay) is 30.0-49.13 MUg/ml & SGIA (Spore germination Inhibition Assay) is 30.0-49.13 MUg/ml. Moreover, these agents did not show any toxicity up to a concentration of 312.5 MUg/ml. The antifungal activity is also confirmed by another method i.e time kill curve analysis. While these agents were ten times less active than gold standard drug (Amphotericin B; AmpB) but eight times less toxic than AmpB. This leads to preliminary investigation of in vitro combination of chelating agents with antifungal drugs (Polyenes & Azoles) by DDA. These combinations showed a significant increase in zone of inhibition in contrast to single drug used. This preliminary work with chelating agents suggest that EDTA as an enhancing agent with antifungal properties in combination with antifungal drugs can be used in pharmaceutical preparations. Further investigation is in progress. PMID- 23360264 TI - Physical and structural stability of the monoclonal antibody, trastuzumab (Herceptin(r)), intravenous solutions. AB - A major limitation of biological therapeutics is their propensity for degradation particularly in aqueous solutions hence resulting in their short shelf-life. In this study, the stability of trastuzumab (Herceptin(r)) intravenous (i.v.) solutions, an IgG1 monoclonal antibody (mAb), indicated for the treatment of HER2 positive breast cancer, stored under refrigerated conditions, was evaluated over 28 days. No change in visual appearance or average particle size was observed. The pH values of the trastuzumab i.v. solutions remained stable over time. Interestingly, no change in trastuzumab monomer concentration was observed throughout the 28-day study, as determined by SEC-HPLC. SDSPAGE showed only a monomer band corresponding to the molecular weight of trastuzumab. Circular dichroism spectra obtained following 28-day storage demonstrated integrity of the secondary structural conformation of trastuzumab. Results from this study show that trastuzumab i.v. solutions remain physically and structurally stable on storage at 2-8 degrees C for 28 days. These findings suggest that trastuzumab in solution may not be as sensitive to degradation as expected for a mAb and therefore may have important implications in extending trastuzumab shelf life for clinical use and reducing associated healthcare cost. PMID- 23360265 TI - Recombinant Salmonella vaccination technology and its application to human bacterial pathogens. AB - Salmonella enterica is a Gram-negative intracellular bacterial pathogen which causes salmonellosis in humans and animals. During the past several decades, extensive studies have shown that the attenuated Salmonella vaccine vector is an optimal vehicle for delivering passenger antigens to mucosal sites to induce humoral, cellular, and mucosal immunity. This immunity leads to protection against challenges with the wild-type pathogens from which the passenger antigens were derived. A myriad of studies have demonstrated that using attenuated Salmonella vaccines for recombinant multivalent vaccine construction has multiple advantages. In this review, we summarize these advantages and further evaluate the Salmonella-based vaccines against five bacterial diseases. Four of these are Gram-negative pathogens- Escherichia coli, Helicobacter pylori, Shigella dysenteriae, and Yersinia pestis-and one is a mycobacterial pathogen, Mycobacterium tuberculosis. Apart from H. pylori, the Salmonella-based vaccines against the other four pathogens exhibit excellent performance in safety, immunogenicity, and protection. These properties qualify them to be as a new generation of vaccines for preventing infections from bacterial pathogens. PMID- 23360266 TI - Cytochrome P450 2C19 polymorphism and antiplatelet therapy. Who should really be genotyped? AB - CYP2C19 is one of the principal enzymes involved in the metabolism of clopidogrel. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function. A loss-of-function allele, CYP2C19*2, is associated with an increased risk of major adverse cardiovascular events, particularly stent thrombosis, in patients with acute coronary syndromes who are receiving clopidogrel, especially among those undergoing percutaneous coronary intervention. Newer, more potent P2Y12 inhibitors like prasugrel and ticagrelor have been introduced recently in the daily clinical practice with better cardiovascular outcome in these patients. The purpose of this review article is to provide information regarding the clinical use of CYP2C19 genotyping in patients requiring antiplatelet therapy. PMID- 23360267 TI - Role of descending aminergic pathways in the development of locomotion. AB - The development of locomotor function in terrestrial higher vertebrates takes place during both the embryonic period and the first days (or weeks, depending on the species) of postnatal life. It relies on the maturation of different elements such as musculoskeletal system, sensory systems, network connectivity, and neuronal intrinsic properties. This maturation results from the interplay between genetic determinants and activity dependent processes. Numerous studies have shown that aminergic (serotonin, noradrenaline, dopamine) projections to the spinal cord could contribute to the maturation of locomotor networks. In this review we will describe the development of aminergic projections in the spinal cord of higher terrestrial vertebrates, and we will review literature describing the trophic role played by these pathways on different parameters of locomotor function. PMID- 23360268 TI - The control of male sexual responses. AB - Male sexual responses are reflexes mediated by the spinal cord and modulated by neural circuitries involving both the peripheral and central nervous system. While the brain interact with the reflexes to allow perception of sexual sensations and to exert excitatory or inhibitory influences, penile reflexes can occur despite complete transections of the spinal cord, as demonstrated by the reviewed animal studies on spinalization and human studies on spinal cord injury. Neurophysiological and neuropharmacological substrates of the male sexual responses will be discussed in this review, starting with the spinal mediation of erection and its underlying mechanism with nitric oxide (NO), followed by the description of the ejaculation process, its neural mediation and its coordination by the spinal generator of ejaculation (SGE), followed by the occurrence of climax as a multisegmental sympathetic reflex discharge. Brain modulation of these reflexes will be discussed through neurophysiological evidence involving structures such as the medial preoptic area of hypothalamus (MPOA), the paraventricular nucleus (PVN), the periaqueductal gray (PAG), and the nucleus para-gigantocellularis (nPGI), and through neuropharmacological evidence involving neurotransmitters such as serotonin (5-HT), dopamine and oxytocin. The pharmacological developments based on these mechanisms to treat male sexual dysfunctions will complete this review, including phosphodiesterase (PDE-5) inhibitors and intracavernous injections (ICI) for the treatment of erectile dysfunctions (ED), selective serotonin reuptake inhibitor (SSRI) for the treatment of premature ejaculation, and cholinesterase inhibitors as well as alpha adrenergic drugs for the treatment of anejaculation and retrograde ejaculation. Evidence from spinal cord injured studies will be highlighted upon each step. PMID- 23360269 TI - Control and role of plateau potential properties in the spinal cord. AB - In this review we will first give a historical account of how the discovery of persistent inward currents (PICs) and plateau potentials changed the understanding of the operation and function of the "final common path", i.e. the motoneurons themselves. A major function of voltage-dependent PICs is to serve as an adjustable amplifier of classical synaptic inputs. The complex control of this, and other intrinsic properties, certainly adjusts the performance of the motoneurons to the needs of the behavioral settings. It has emerged that supraspinal facilitation, mainly by monoaminergic projections, is a prerequisite for the normal function of the PIC channels. When these pathways are interrupted following a spinal lesion the "gain" of the transmission across the motoneurons is reduced and this is likely to be an important explanation for the spinal shock. However, after a few weeks the "plateau properties" of the motoneurons return - now without descending monoaminergic control. This plasticity after spinal lesion is likely to contribute to the hyperreflexia (spasticity) seen after spinal lesions. We then review the current knowledge on PICs in other spinal (inter-)neurons. The monoaminergic systems seem to play a pivotal role in activating the spinal network generating the rhythm and basic motor pattern of locomotion and scratch - the spinal "central pattern generators" (CPGs). We give a short historical background of this research with a special emphasis on the importance of the descending monoaminergic systems. PMID- 23360270 TI - Modulation of the intrinsic properties of motoneurons by serotonin. AB - Serotonin (5-HT) is one of the main transmitters in the nervous system. Serotonergic neurons in the raphe nuclei in the brainstem innervate most parts of the central nervous system including motoneurons in the spinal cord and brainstem. This review will focus on the modulatory role that 5-HT exerts on motoneurons and its physiological consequences. The somato-dendritic compartments of motoneurons are densely innervated by serotonergic synaptic boutons and several receptors are expressed in the membrane of motoneurons including 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C and 5-HT5A. The activation of serotonergic receptors induces a general increase of the excitability of motoneurons through the modulation of several classes of ion channels. 5-HT depolarizes motoneurons towards the threshold for action potentials by inhibiting leak conductances and promoting a hyperpolarization activated cationic current. At the same time, 5-HT increases the firing frequency by inhibiting the small Ca2+ activated K+ conductance (SK) responsible for the medium afterhyperpolarization (AHP) following action potentials. 5-HT also promotes persistent inward currents mediated by voltage sensitive Ca2+ and Na+ conductances, producing a sustained depolarization and an amplification of synaptic inputs. Under pathological conditions, such as after a spinal cord injury, the promotion of persistent inward currents by serotonin and/or the overexpression of autoactive serotonergic receptors may contribute to motoneuronal excitability, muscle spasms and spasticity and hence, impairment of stereotyped motor behaviors such as locomotion, ejaculation and micturition. PMID- 23360271 TI - How do glial cells contribute to motor control? AB - For many years, glial cells from the central nervous system have been considered as support cells involved in the homeostasis of the brain. However, a series of key-findings obtained during the past two decades has put light on unexpected roles for glia and it is getting more and more admitted that glia play an active role in several physiological functions. The discovery that a bidirectional communication takes place between astrocytes (the star shaped glial cell of the brain) and neurons, was a major breakthrough in the field of synaptic physiology. Astrocytes express receptors that get activated by neurotransmitters during synaptic transmission. In turn they release other transmitters - called gliotransmitters - that bind to neuronal receptors and modulate synaptic transmission. This feedback, which led to the concept of the tripartite synapse, has been reported with various transmitters including glutamate, ATP, GABA or serine. In the present review we will focus on astrocytes and review the evidence suggesting and demonstrating their role in motor control. Rhythmic motor behaviors such as locomotion, swimming or chewing are generated by networks of neurons termed central pattern generators (CPG). These networks are highly flexible and adjust the frequency of their output to the external environment. In the case of respiration, the CPG reacts when changes in the pH of the blood occur. The chemosensory control of breathing is ensured by astrocytes, which react to variation of the blood pH by releasing ATP on neurons that in turn adapt the frequency of respiration. In the spinal cord, diverse transmitters such as ATP, adenosine or endocannabinoids modulate the CPG responsible for locomotion. A growing body of evidence suggests that glial cells release some of these molecules. These data suggest that astrocytes play an essential role in motor control and we believe that a range of studies will confirm this view in the near future. PMID- 23360272 TI - Rho as a target to promote repair: translation to clinical studies with cethrin. AB - Spinal cord injury (SCI) often results in permanent paralysis because there is little spontaneous repair. Neuronal injury in the central nervous system (CNS) causes breakage of axonal connections, release of myelin, inflammation and cell death at the lesion site. Many factors contribute to the failure of spontaneous repair after SCI, including the presence of growth inhibitory proteins in myelin, the inflammatory environment of the injured CNS, and the resulting signaling cascades that result in over-activation of Rho, a signaling switch in neurons and axons. In this review, we provide a general overview of growth inhibition in the CNS, and show evidence that most growth inhibitory proteins signal through a common intracellular pathway. Rho is a convergent signal for growth inhibition, and also for signaling some of the secondary consequences of inflammation after SCI. We review the preclinical evidence that targeting Rho is an effective way to stimulate axon regeneration and functional recovery in preclinical animal models. In the last part of the review, we describe the creation of Cethrin, a new investigational drug, and summarize the results of the Phase I/IIa clinical study to examine the safety, tolerability and efficacy of Cethrin in patients with acute SCI. We conclude with some insight for future clinical studies. PMID- 23360273 TI - Neuropeptide/Receptor expression and plasticity in micturition pathways. AB - Several motor behaviors such as locomotion, respiration, sexual function, and micturition are generated by rhythmic and stereotyped motor patterns of activity. In most cases, these functions are primarily controlled by signals and neuronal commands that originate from the brainstem and spinal cord. Defined as the storage and periodic elimination of urine, micturition requires a complex neural control system that coordinates the activities of a variety of effector organs including the smooth muscle of the urinary bladder and the smooth and striated muscle of the urethral sphincters. The lower urinary tract (LUT) reflex mechanisms, organized at the level of the lumbosacral spinal cord, are modulated predominantly by supraspinal controls. These LUT mechanisms include: (1) storage reflexes organized at the spinal level; (2) elimination reflexes organized at a supraspinal site in the pons; and (3) spinal storage reflexes modulated by inputs from the rostral pons. Precise coordination of the reciprocal functions of the urinary bladder and urethra and complex neural organization are required for normal function. Numerous neuropeptide/receptor systems are expressed in central and peripheral nervous system pathways that regulate the LUT and expression can also be found in both neural and non-neural (e.g., urothelium) components. Neuropeptides have tissue-specific distributions and functions in the LUT and exhibit neuroplastic changes in expression and function with LUT dysfunction with neural injury, inflammation, stress and disease. LUT dysfunction with abnormal voiding including urinary urgency, increased voiding frequency, nocturia, urinary incontinence, urinary retention, continence, detrusor dysynergia and/or pain may reflect a change in the balance of neuropeptides in central and peripheral bladder reflex pathways. LUT neuropeptide/receptor systems in LUT pathways may thus represent potential targets for therapeutic intervention. PMID- 23360274 TI - Pharmacological approaches to chronic spinal cord injury. AB - Although research on neural tissue repair has made enormous progress in recent years, spinal cord injury remains a devastating condition for which there is still no cure. In fact, recent estimates of prevalence in the United States reveal that spinal cord injury has undergone a five-fold increase in the last decades. Though, it has become the second most common neurological problem in North America after Alzheimer's disease. Despite modern trauma units and intensive care treatments, spinal cord injury remains associated with several comorbid conditions and unbearable health care costs. Regular administration of a plethora of symptomatic drug treatments aimed at controlling related-secondary complications and life-threatening problems in chronic spinal cord-injured patients has recently been reported. This article provides a thorough overview of the main drug classes and products currently used or in development for chronic spinal cord injury. Special attention is paid to a novel class of drug treatment designed to provide a holistic solution for several chronic complications and diseases related with spinal cord injury. There is clear evidence showing that new class can elicit 'on-demand' episodes of rhythmic and stereotyped walking activity in previously completely paraplegic animals and may consequently constitute a simple therapy against several physical inactivity-related comorbid problems. Understanding further pharmacological approaches to chronic spinal cord injury may improve both life expectancy and overall quality of life while reducing unsustainable cost increases associated with this debilitation condition. PMID- 23360275 TI - A valuable animal model of spinal cord injury to study motor dysfunctions, comorbid conditions, and aging associated diseases. AB - Most animal models of contused, compressed or transected spinal cord injury (SCI) require a laminectomy to be performed. However, despite advantages and disadvantages associated with each of these models, the laminectomy itself is generally associated with significant problems including longer surgery and anaesthesia (related post-operative complications), neuropathic pain, spinal instabilities, deformities, lordosis, and biomechanical problems, etc. This review provides an overview of findings obtained mainly from our laboratory that are associated with the development and characterization of a novel murine model of spinal cord transection that does not require a laminectomy. A number of studies successfully conducted with this model provided strong evidence that it constitutes a simple, reliable and reproducible transection model of complete paraplegia which is particularly useful for studies on large cohorts of wild-type or mutant animals - e.g., drug screening studies in vivo or studies aimed at characterizing neuronal and non-neuronal adaptive changes post-trauma. It is highly suitable also for studies aimed at identifying and developing new pharmacological treatments against aging associated comorbid problems and specific SCI-related dysfunctions (e.g., stereotyped motor behaviours such as locomotion, sexual response, defecation and micturition) largely related with 'command centers' located in lumbosacral areas of the spinal cord. PMID- 23360276 TI - The multifunctional mesencephalic locomotor region. AB - In 1966, Shik, Severin and Orlovskii discovered that electrical stimulation of a region at the junction between the midbrain and hindbrain elicited controlled walking and running in the cat. The region was named Mesencephalic Locomotor Region (MLR). Since then, this locomotor center was shown to control locomotion in various vertebrate species, including the lamprey, salamander, stingray, rat, guinea-pig, rabbit or monkey. In human subjects asked to imagine they are walking, there is an increased activity in brainstem nuclei corresponding to the MLR (i.e. pedunculopontine, cuneiform and subcuneiform nuclei). Clinicians are now stimulating (deep brain stimulation) structures considered to be part of the MLR to alleviate locomotor symptoms of patients with Parkinson's disease. However, the anatomical constituents of the MLR still remain a matter of debate, especially relative to the pedunculopontine, cuneiform and subcuneiform nuclei. Furthermore, recent studies in lampreys have revealed that the MLR is more complex than a simple relay in a serial descending pathway activating the spinal locomotor circuits. It has multiple functions. Our goal is to review the current knowledge relative to the anatomical constituents of the MLR, and its physiological role, from lamprey to man. We will discuss these results in the context of the recent clinical studies involving stimulation of the MLR in patients with Parkinson's disease. PMID- 23360277 TI - Sex, stress and their influence on respiratory regulation. AB - Much like locomotion or micturition, respiration is a rhythmic and stereotyped motor pattern controlled mainly by non-cortical structures including a complex circuit in the brainstem. Because tight regulation of lung ventilation is essential from the beginning of life, it has been presumed that the neural system regulating breathing is fixed, following a genetically predetermined developmental pattern. Here, we review evidence indicating that early life exposure to a non-systemic stress in the form of neonatal maternal separation (NMS) is sufficient to exert sex-specific consequences on the developmental trajectory of this vital homeostatic system that persist well into full maturity. At adulthood, male rats subjected to NMS are hypertensive and show an abnormally high hypoxic chemoreflex that correlates positively with respiratory instability during sleep. The effects are not observed in females. Investigation of the mechanisms this respiratory phenotype have highlighted the importance of 1) neuroendocrine influences on respiratory regulation and 2) stress-related imbalance between inhibitory (GABAergic) and excitatory (glutamatergic) modulation of the neural elements regulating breathing. These results provide new and valuable insight into the origins of respiratory disorders related to neural control dysfunction such as sleep disordered breathing. PMID- 23360278 TI - Extrasynaptic GABA(A) receptors in the brainstem and spinal cord: structure and function. AB - gamma-aminobutyric acid (GABA) plays many of its key roles in embryonic development and functioning of the central nervous system (CNS) by acting on ligand gated chloride-permeable channels known as GABAA receptors (GABAAR). Classically, GABAARmediated synaptic communication is tailored to allow rapid and precise transmission of information to synchronize the activity of large populations of cells to generate and maintain neuronal networks oscillations. An alternative type of inhibition mediated by GABAA receptors, initially described about 25 years ago, is characterized by a tonic activation of receptors that react to ambient extracellular GABA. The receptors that mediate this action are wide-spread throughout the nerve cells but are located distant from the sites of GABA release, and therefore they have been called extrasynaptic GABAA receptors. The molecular nature of the extrasynaptic GABAA receptors and the tonic inhibitory current they generate have been characterized in many brain structures, and due to its relevance in controlling neuron excitability they have become attractive pharmacological targets for a variety of neurological disorders such as schizophrenia, epilepsy and Parkinson disease. In the spinal cord, early studies have implicated these receptors in anesthesia, chronic pain, motor control, and locomotion. This review highlights past and present developments in the field of extrasynaptic GABAA receptors and emphasizes their subunit containing distribution and physiological role in the spinal cord. PMID- 23360279 TI - Activity-dependent synaptic plasticity and metaplasticity in spinal motor networks. AB - Throughout life, neuronal network properties are modulated according to both external and internal stimuli. These adaptive capabilities of the central nervous system (CNS) have been generically termed "plasticity". One prominent form of CNS plasticity is the capability of synapses to change their strength. Synaptic strength is not a constant value but depends at each moment on the synapse's past activity. These changes in transmission efficacy are called activity-dependent synaptic plasticity (ADSP) and result in an increase (potentiation) or a decrease (depression) in synaptic strength. The ability of synapses to express one type of ADSP can change as a function of previous plasticity and previous activation of synapses. This plasticity of synaptic plasticity has been termed metaplasticity. ADSP and metaplasticity are now regarded as essential mechanisms for normal information processing in neuronal networks. Rhythmic activities such as locomotion are generated by rhythmically active central neuronal networks called central pattern generators (CPGs) that possess the intrinsic ability to generate rhythmic and organized activity in the absence of sensory inputs. The CPG activity arises from a complex dynamic interaction between synaptic transmission, intrinsic membrane properties and neuromodulatory inputs. A growing body of evidence suggests that the spinal cord matches the plastic and metaplastic properties found in other parts of the CNS, both under normal conditions and after spinal cord injury. Here, findings describing ADSP and its neuromodulation in vertebrate sensorimotor networks are reviewed, followed by a discussion of the potential role of ADSP and neuromodulation in the physiology and pathophysiology of motor circuit assembly. PMID- 23360280 TI - Role of neurotrophins in spinal plasticity and locomotion. AB - Synaptic transmission through descending motor pathways to lumbar motoneurons and then to leg muscles is essential for walking in humans and rats. Spinal cord injury (SCI), even when incomplete, results in diminished transmission to motoneurons and very limited recovery of motor function. Neurotrophins have emerged as essential molecules known to promote cell survival and support anatomical reorganization in damaged spinal cord. This review will summarize the evidence implicating the role of neurotrophins in synaptic plasticity in both undamaged and damaged spinal cord, with special emphasis on the potential for neurotrophins to strengthen synaptic connections to motoneurons in support of the application of neurotrophins for recovery of locomotor function after SCI. An important consideration related to therapeutic use of neurotrophins is the successful delivery of these molecules. Prolonged delivery of neurotrophins to the spinal cord of adult mammals has recently become possible through advances in biotechnology. Fibroblasts engineered to secrete neurotrophins and gene transfer of neurotrophins via recombinant viral vectors are among the most promising therapeutic transgene delivery systems for safe and effective neurotrophin delivery. Administration of neurotrophins to the spinal cord using these delivery systems was found to enhance both anatomical and synaptic plasticity and improve functional recovery after SCI. The findings summarized here indicate that neurotrophins have translational research potential for SCI repair, most likely as an essential component of combination therapy. PMID- 23360281 TI - Pharmacology and biochemistry of stereotyped motor behaviors. PMID- 23360283 TI - Altered transporter-mediated neocortical GABA release in Rasmussen encephalitis. AB - To learn whether epileptic seizures in Rasmussen encephalitis (RE) may be promoted by insufficient gamma-aminobutyric acid (GABA) release. (3) H-GABA was released from neocortical synaptosomes through transporter reversal following intrasynaptosomal Na(+) accumulation by veratridine that prevents inactivation of Na(+) channels. Tissues of three RE patients were compared with those of nine non RE. In RE, the release was markedly reduced. In non-RE, the extracellular Ca(2+) concentration ([Ca(2+) ]e ) was inversely related to the amount of release. In RE, the percental decline of additional release upon Cae 2+ withdrawal was linked with the presurgical duration of epilepsy. Permanent opening of Na(+) channels by veratridine resembles maximal frequency of action potentials corresponding to epileptic seizures. These are preceded by a fall in [Ca(2+) ]e . Zero [Ca(2+) ]e increased release through the Na(+) /Ca(2+) exchanger additionally elevating intrasynaptosomal Na(+) . This enhanced GABA release probably reflects an antiseizure mechanism. In RE, the additional release gets lost over epilepsy duration. PMID- 23360282 TI - Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with an enhanced risk for cardiovascular and other inflammatory diseases. Chronic low-level inflammation has been suggested as a potential mechanism linking these conditions. METHODS: We investigated plasma cytokine levels as well as spontaneous and lipopolysaccharide (LPS)-stimulated cytokine production by peripheral blood mononuclear cells (PBMCs) in a group of 35 severely traumatized PTSD patients compared to 25 healthy controls. RESULTS: Spontaneous production of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha by isolated PBMCs was significantly higher in the PTSD compared to the control group and even correlated with PTSD symptom severity within the PTSD group. In contrast, circulating plasma levels of pro- and anti-inflammatory cytokines such as IL-6, IL-8, IL-10, TNF-alpha, or monocyte chemotactic protein (MCP)-1 were not significantly altered in PTSD patients compared to healthy controls. CONCLUSIONS: Our findings indicate that PBMCs of PTSD patients are already pre-activated in vivo, providing further evidence for low-grade inflammation in PTSD. This might possibly represent one psychobiological pathway from PTSD to poor physical health. PMID- 23360284 TI - Novel antitumor indolizino[6,7-b]indoles with multiple modes of action: DNA cross linking and topoisomerase I and II inhibition. AB - A series of bis(hydroxymethyl)indolizino[6,7-b]indoles and their bis(alkylcarbamates) were synthesized for antitumor studies. These agents were designed as hybrid molecules of beta-carboline (topoisomerase inhibition moiety) and bis(hydroxymethyl)pyrrole (DNA cross-linking moiety). The preliminary antitumor studies indicated that these agents exhibited significant cytotoxicity against a variety of human tumor cells in vitro. Treatment of human breast carcinoma MX-1 xenograft-bearing nude mice with compounds 18b and 28c achieved more than 99% tumor remission. We also observed that 18a displayed potent therapeutic efficacy against human lung adenocarcinoma A549 and colon cancer HT 29 xenografts. These results revealed that compound 18a was more potent than irinotecan against HT-29 cells and was as potent as irinotecan against A549 cells in xenograft models. Furthermore, we demonstrated that these derivatives possess multiple modes of action, such as induction of DNA cross-linking, inhibition of topoisomerase I and II, and cell-cycle arrest at the S-phase. PMID- 23360285 TI - Degradation of rhodamine B/phenol mixtures in water by sun-like excitation of a Bi2 WO6-TiO2 photocatalyst. AB - Bi2 WO6 and Bi2 WO6-TiO2 (5% molar Ti) nano-heterostructures were synthesized by a hydrothermal method. The properties of the synthesized catalysts were characterized, having high photoactivity for Rhodamine B degradation under sun like illumination, explained by a synergetic mechanism previously proposed through UV and visible induced processes, in which the photosensitization effect of Rhodamine B is considered. We now report that using Phenol, a molecule which does not lead the photosensitization process, the photoactivity decreased considerably, thus emphasizing how important is the model molecule selected as degradation substrate for evaluating the photoactivity. The photocatalytic properties of the synthesized catalysts have been evaluated by exposing a mixture of Rhodamine B and Phenol in water, to different illumination conditions. It can be confirmed that the photoinduced mechanism via the photosensitization of Rhodamine B is a key factor responsible for the increase on the photocatalytic activity showed by the Bi2 WO6-TiO2 compound and that the degradation mechanism of Rhodamine B is not changed by the simultaneous presence of other transparent substrate as Phenol. PMID- 23360286 TI - Lean on me: an exploratory study of the spousal support received by physicians. AB - This paper uses interview data from physicians and their spouses to describe the types of spousal support physicians receive when coping with work-related stress and to explore whether they vary by occupational similarity, gender, and parental status. The physicians described receiving different types of spousal support: emotional, informational, and instrumental. Male physicians in this study often reported receiving emotional support from their spouse, consistent with the support gap hypothesis in the literature. An unexpected finding is that from the responses of the physicians' spouses, the husbands often reported offering emotional support to their physician spouse. Physicians who shared similar occupational and work experiences with their spouse (i.e. married to another physician) reported receiving informational support from their spouse, consistent with the theory of homophily. Finally, the findings also suggested that once physicians have children, their wives often reported providing instrumental support by being primarily responsible for childcare and housework. An interesting finding of this study is the discrepancy between the physicians and their spouses in their perceptions of support. PMID- 23360287 TI - The fractal dimension approach in posture: a comparison between Down and Prader Willi syndrome patients. AB - The suitability of new dynamic system analysis was investigated to compare postural control in Prader-Willi syndrome (PWS) and Down syndrome (DS) patients. Time-domain, frequency-domain parameters and fractal dimension (FD) of centre of pressure (CoP) were computed in maintaining normal standing on a force platform in 20 DS and 13 PWS patients, compared to 26 obese (obese control group, OCG) and 20 healthy individuals (healthy control group, HCG). DS and PWS showed greater displacements along both directions and longer sway path (SP) parameter than HCG and OCG, with statistical differences between PWS and DS for anteroposterior displacement and SP. DS used higher frequency strategy when compared to PWS, OCG and HCG. Both DS and PWS were characterised by greater values of FD than OCG and HCG, with higher values in DS. The analyses in frequency domain and of the dynamic nature of CoP suggest that DS patients are characterised by a more complex and irregular signal than PWS patients. PMID- 23360288 TI - Mitochondria in cancer stem cells: a target for therapy. AB - Complete knowledge about the evolution of the carcinogenic process has to include cancer stem cells (CSCs), which are essential to understand tumor occurrence, recurrence, and also its reduction rate after radio- and/or chemotherapeutic treatments. Understanding CSCs physiology and metabolism may be crucial for the development of novel effective therapies. Therefore, being mitochondria an undeniable target for cancer therapy and a central hub in metabolism and cell and death decisions, it is essential to take this organelle into account and explore its actions and involvements in the context of CSCs physiology. In this review, we focus on recent patents and discoveries about mitochondrial bioenergetics and physiology of CSCs. A full understanding of the role of mitochondrial activity in CSCs and the creation of new strategies, methods and discoveries to support actual treatments with novel ones are of pivotal importance in order to ultimately eradicate cancer. PMID- 23360289 TI - Quantitative fate of chlorogenic acid during enzymatic browning of potato juice. AB - The quantitative fate of chlorogenic acid (ChA) during enzymatic browning of potato juice was investigated. Potato juice was prepared in water without the use of any antibrowning agent (OX treatment). As a control, a potato juice was prepared in the presence of NaHSO(3) (S control). To study the composition of phenolic compounds in potato in their native states, also a potato extract was made with 50% (v/v) methanol containing 0.5% (v/v) acetic acid (MeOH control). Water-soluble low molecular weight fractions (LMWFs) and high molecular weight fractions (HMWFs) from S and OX extracts were obtained by ultrafiltration and dialysis, respectively. Pellets obtained after the OX treatment and the S and MeOH controls were also analyzed for ChA content. Whereas in the S-LMWF all ChA was converted to sulfonic acid adducts, no free ChA was found in the OX-LMWF, indicating its high reactivity upon enzymatic browning. Analysis of protein in the HMWFs showed a higher content of "reacted" ChA in OX (49.8 +/- 7.1 mg ChA/100 g potato DW) than in S (14.4 +/- 1.5 mg ChA/100 g potato DW), as evidenced by quinic acid release upon alkaline hydrolysis. The presence of quinic acid in S HMWF was unexpected, but a mass balance incorporating the ChA content of LMWF, HMWF, and pellet for the three extractions suggested that ChA might have been attached to polymeric material, soluble in the aqueous environment of S but not in that of MeOH. Size exclusion chromatography, combined with proteolysis, revealed that ChA reacted with patatin and protease inhibitors to produce brown soluble complexes. PMID- 23360290 TI - A new family of lanthanide borate halides with unusual coordination and a new neodymium-containing cationic framework. AB - The reactions of Ln(2)O(3)/CeO(2)/Pr(6)O(11) (Ln = La-Nd, Sm), molten boric acid, and concentrated HBr or HI result in the formation of La[B(7)O(10)(OH)(3)(H(2)O)Br], Ln[B(6)O(9)(OH)(2)(H(2)O)(2)Br].0.5H(2)O (Ln = Ce, Pr), Nd(2)[B(12)O(17.5)(OH)(5)(H(2)O)(4)Br(1.5)]Br(0.5).H(2)O (NdBOBr), Sm(4)[B(18)O(25)(OH)(13)Br(3)], and Ln[B(7)O(11)(OH)(H(2)O)(3)I] (Ln = La-Nd, Sm). The lanthanide(III) centers in these compounds are found with 9-coordinate hula hoop or 10-coordinate capped triangular cupola geometries, where there are six approximately coplanar oxygen donors provided by the polyborate sheet. The sheets are formed into three-dimensional frameworks via BO(3) triangles that are roughly perpendicular to the layers. Additionally, a new cationic framework, NdBOBr, has been isolated. NdBOBr is unusual in that not only is it a cationic framework, but it is also the first trivalent f-element borate to have terminal halides bound exclusively to the base site of the hula hoop. The Ln[B(7)O(11)(OH)(H(2)O)(3)I] (Ln = La-Nd, Sm) structures require two corner shared BO(3) units in order to tether the layers together because of the large size of the capping iodine atom. PMID- 23360292 TI - Reactions of buffers in cyanogen bromide-induced ligations. AB - Rapid, template-directed ligation reactions between a phosphate-terminated oligonucleotide and an unphosphorylated reaction partner may be induced by cyanogen bromide (BrCN). Frequently, however, the reaction is low yielding, and even a large excess of the condensing agent can fail to induce quantitative conversions. In this study, we used BrCN to induce chemical primer extension reactions. Here, we report that buffers containing hydroxyl groups react with short oligodeoxynucleotides in the presence of BrCN. One stable adduct between HEPBS buffer and cytosine was characterized by mass spectrometry and NMR after HPLC purification, indicating that a side reaction occurred at this nucleobase. Further, a first example of a primer extension reaction between an unmodified oligodeoxynucleotide as primer and dGMP is reported. Together, our results shed light on the potency, as well as the drawbacks of BrCN as a highly reactive condensing reagent for the ligation of unmodified nucleic acids. PMID- 23360291 TI - Synthesis of biotinylated c-di-gmp and c-di-amp using click conjugation. AB - The biotinylated c-di-GMP and c-di-AMP conjugates 10a/b were synthesized by a straightforward set of procedures from standard, commercially available phosphoramidites. Their availability should allow isolation and characterization of new protein and RNA receptors for these key bacterial signaling molecules. PMID- 23360293 TI - Synthesis of bis-acyclonucleoside analogues bearing benzothienyl-1,2,4-Triazol-3 Yl-disulfide under conventional and microwave methods. AB - The oxidation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol (1) with a solution of iodine and potassium iodide at room temperature afforded [5-(3 chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-yl]disulfide (2). In contrast, when the reaction mixture was heated or irradiated by MW, an unexpected additional product was obtained and identified as 3-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4 triazole (3); the ratio of products was 3:1. The preferred conformer of 2 was deduced from the theoretical calculation. The alkylation of compounds 2 and 3 with epichlorohydrin and hydroxyalkylating agents gave the corresponding N,N-bis- and N-acyclonucleosides analogues 8-15. PMID- 23360294 TI - In vitro stimulation of oxidative stress by hypoxanthine in blood of rats: prevention by vitamins e plus C and allopurinol. AB - We herein investigated the in vitro effect of hypoxanthine on the activities of antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) in erythrocytes, as well as on thiobarbituric acid reactive substances (TBA-RS), in the plasma of rats. Results showed that hypoxanthine, when added to the incubation medium, enhanced CAT (10.0 MUM), GSH Px and SOD (8.5 MUM and 10.0 MUM) activities in erythrocytes of 15-day-old rats, reduced CAT activity (10.0 MUM) and enhanced GSH-Px activity (10.0 MUM) in erythrocytes of 30-day-old rats, reduced CAT activity (10.0 MUM) and enhanced GSH Px activity (8.5 MUM and 10.0 MUM) in erythrocytes of 60-day-old rats, as compared to controls. In addition, hypoxanthine (10.0 MUM) enhanced TBA-RS levels in the plasma of 30- and 60-day old rats. Furthermore, we also tested the influence of allopurinol, trolox, and ascorbic acid on the effects elicited by hypoxanthine on the antioxidant enzymes and TBA-RS. Allopurinol and/or administration of antioxidants prevented most alterations caused by hypoxanthine in the oxidative stress parameters evaluated. Findings suggest that hypoxanthine alters antioxidant defenses and induces lipid peroxidation in the blood of rats; however, in the presence of allopurinol and antioxidants, some of these alterations in oxidative stress caused are prevented. Data indicate that, in humans, antioxidant administration might serve as a potential adjuvant therapy for ameliorating the damage caused by hypoxanthine. PMID- 23360295 TI - Effects of polymer end-group chemistry and order of deposition on controlled protein delivery from layer-by-layer assembly. AB - Layer-by-layer (LBL) assembly is an attractive platform for controlled release of biologics given its mild fabrication process and versatility in coating substrates of any shape. Proteins can be incorporated into LBL coatings by sequentially depositing oppositely charged polyelectrolytes, which self-assemble into nanoscale films on medical devices or tissue engineering scaffolds. However, previously reported LBL platforms often require the use of a few hundred layers to avoid burst release, which hinders their broad translation due to the lengthy fabrication process, cost, and batch-to-batch variability. Here we report a biodegradable LBL platform composed of only 10 layers with tunable protein release kinetics, which is an order of magnitude less than previously reported LBL platforms. We performed a combinatorial study to examine the effects of polymer chemistry and order of deposition of poly(beta-amino) esters on protein release kinetics under 81 LBL assembly conditions. Using the optimal "polyelectrolyte couples" for constructing the LBL film, basic fibroblast growth factor (bFGF) was released gradually over 14 days with retained biological activity to stimulate cell proliferation. The method reported herein is applicable for coating various substrates including metals, polymers, and ceramics and may be used for a broad range of biomedical and tissue engineering applications. PMID- 23360297 TI - High production of poly(3-hydroxybutyrate) from a wild Bacillus megaterium Bolivian strain. AB - AIM: Taking into account that a novel strain of Bacillus megaterium was isolated from Uyuni salt lake (Bolivia) in a previous work, the objectives of this new study were to determine the maximal Poly-3-hydroxybutyrate production potential of B. megaterium strain uyuni S29 in an industrial conventional media, the possibility that the strain accumulates different types of polyhydroxyalkanoates, the cellular morphology during the biosynthesis process and the characterization of the produced biopolymers. METHODS AND RESULTS: The micro-organism was first tested in a 3-L bioreactor obtaining a high specific growth rate of 1.64 h(-1). A second fed-batch experiment was carried out in shaking flasks, reaching up to 70% PHB of cell dry mass. The biosynthesized polymers were extracted by two different extraction procedures and characterized. The results showed that all of them were PHB with thermal properties different to the conventional PHB. The micrographs taken by TEM show the different cell morphology during the fermentation process. CONCLUSIONS: In this previous study, the strain not only grew properly in the industrial conditions proposed without spore formation, but also produced and accumulated a large content of PHB, never reached before for its genus. Therefore, if the culture conditions can be optimized, the biopolymer production could be increased. SIGNIFICANCE AND IMPACT OF THE STUDY: The impact of the study has related to the area of the biomaterials and their production. The study provides new data related to the high production of PHB from the wild novel strain B. megaterium uyuni S29, the highest polymer accumulation for the genus Bacillus without spores formation. PMID- 23360298 TI - Layer-by-layer templated assembly of silica at the nanoscale. AB - Bioinspired bottom-up assembly and layer-by-layer (LbL) construction of inorganic materials from lithographically defined organic templates enables the fabrication of nanostructured systems under mild temperature and pH conditions. Such processes open the door to low-impact manufacturing and facile recycling of hybrid materials for energy, biology, and information technologies. Here, templated LbL assembly of silica was achieved using a combination of electron beam lithography, chemical lift-off, and aqueous solution chemistry. Nanopatterns of lines, honeycomb-lattices, and dot arrays were defined in polymer resist using electron beam lithography. Following development, exposed areas of silicon were functionalized with a vapor deposited amine-silane monolayer. Silicic acid solutions of varying pH and salt content were reacted with the patterned organic amine-functional templates. Vapor treatment and solution reaction could be repeated, allowing LbL deposition. Conditions for the silicic acid deposition had a strong effect on thickness of each layer, and the morphology of the amorphous silica formed. "Defects" in the arrays of silica nanostructures were minor and do not affect the overall organization of the layers. The bioinspired method described here facilitates the bottom-up assembly of inorganic nanostructures defined in three dimensions and provides a path, via LbL processing, for the construction of layered hybrid materials under mild conditions. PMID- 23360299 TI - From yellow to black: dramatic changes between cerium(IV) and plutonium(IV) molybdates. AB - Hydrothermal reactions of CeCl(3) and PuCl(3) with MoO(3) and Cs(2)CO(3) yield surprisingly different results. Ce(3)Mo(6)O(24)(H(2)O)(4) crystallizes as bright yellow plates (space group C2/c, a = 12.7337(7) A, b = 22.1309(16) A, c = 7.8392(4) A, beta = 96.591(4) degrees , V = 2194.6(2) A(3)), whereas CsPu(3)Mo(6)O(24)(H(2)O) crystallizes as semiconducting black-red plates (space group C2/c, a = 12.633(5) A, b = 21.770(8) A, c = 7.743(7) A, beta = 96.218(2) degrees , V = 2117(2) A(3)). The topologies of the two compounds are similar, with channel structures built from disordered Mo(VI) square pyramids and (RE)O(8) square antiprisms (RE = Ce(IV), Pu(IV)). However, the Pu(IV) compound contains Cs(+) in its channels, while the channels in Ce(3)Mo(6)O(24)(H(2)O)(4) contain water molecules. Disorder and an ambiguous oxidation state of Mo lead to the formula CsPu(3)Mo(6)O(24)(H(2)O), where one Mo site is Mo(V) and the rest are Mo(VI). X-ray absorption near-edge structure (XANES) experiments were performed to investigate the source of the black color of CsPu(3)Mo(6)O(24)(H(2)O). These experiments revealed Pu to be tetravalent, while the strong pre-edge absorption from the distorted molybdate anions leaves the oxidation state ambiguous between Mo(V) and Mo(VI). PMID- 23360296 TI - Mammary stem cell research in veterinary science: an update. AB - The mammary gland is an organ with a remarkable regenerative capacity that can undergo multiple cycles of proliferation, lactation, and involution. Growing evidence suggests that these changes are driven by the coordinated division and differentiation of mammary stem cell populations (MaSC). Whereas information regarding MaSC and their role in comparative mammary gland physiology is readily available in human and mice, such information remains scarce in most veterinary mammal species such as cows, horses, sheep, goats, pigs, and dogs. We believe that a better knowledge on the MaSC in these species will not only help to gain more insights into mammary gland (patho) physiology in veterinary medicine, but will also be of value for human medicine. Therefore, this review summarizes the current knowledge on stem cell isolation and characterization in different mammals of veterinary importance. PMID- 23360300 TI - Tonic phase of a generalized convulsive seizure is an independent predictor of postictal generalized EEG suppression. AB - PURPOSE: To determine the incidence, duration, risk factors for, and clinical correlates of postictal generalized electroencephalography (EEG) suppression (PGES), and to further delineate the significance of PGES in the pathogenesis of sudden unexpected death in epilepsy (SUDEP). METHODS: We retrospectively reviewed the video-EEG studies of 109 consecutive patients with 151 generalized convulsive seizures (GCS) during video-EEG monitoring. We determined the incidence, duration, and clinical correlates of PGES. We also investigated whether factors such as age, sex, seizure type, total seizure duration, and duration of tonic and clonic phases influenced PGES. KEY FINDINGS: PGES was observed in 64 (58.7%) of 109 patients and in 98 (64.9%) of 151 GCS. Average duration of PGES was 42.4 +/- 19.1 s. Statistical analysis showed that patients with PGES had no difference in age, gender, total seizure duration, total convulsive duration, clonic phase, seizure type, and seizure termination, as compared to those without PGES. However, tonic phase was significantly prolonged in patients with PGES than in those without PGES (p = 0.00086). A 1 s increase in tonic phase duration was associated with a 0.06 increase in log odds of PGES (odds ratio = 1.1, p = 0.00055). Clinically, 95.3% patients were unresponsive or immobile during PGES, whereas only 26.7% patients without PGES were unresponsive or immobile immediately after seizure termination. SIGNIFICANCE: PGES is a common EEG pattern of GCS. Tonic phase of GCS is an independent predictor of PGES, which is well correlated with postictal unresponsiveness or immobile, and may play a significant role in the mechanism of SUDEP. PMID- 23360302 TI - Beneficial function of cell division cycle 2 activity in astrocytes on axonal regeneration after spinal cord injury. AB - Migrating activity of reactive astrocytes induced after spinal cord injury (SCI) controls glial scar formation by limiting inflammatory responses around the injury area, and, therefore, can be beneficial for regenerative responses of spinal axons. Recently, we found that cell division cycle 2 (cdc2) activity in primary astrocytes facilitated neurite outgrowth of co-cultured neurons. Here, we investigated the effects of cdc2 activity on regenerative processes in vivo after SCI. Administration of the cdc2 inhibitor purvalanol A restricted compaction of the injury cavity and astrocyte infiltration into the cavity. After SCI, regenerative responses of anterogradely labeled corticospinal tract (CST) axons were attenuated by purvalanol A treatment. Using the polymeric tube that was implanted into the spinal cord as a nerve guide conduit, we found that purvalanol A treatments reduced astrocyte migration into the tube graft and, in parallel, retarded the extension of spinal axons into the tube. These results suggest that astrocytes with cdc2 activity may play a permissive role in mediating regrowth of spinal axons after lesion. PMID- 23360301 TI - The influence of habitats on female mobility in Central and Western Africa inferred from human mitochondrial variation. AB - BACKGROUND: When studying the genetic structure of human populations, the role of cultural factors may be difficult to ascertain due to a lack of formal models. Linguistic diversity is a typical example of such a situation. Patrilocality, on the other hand, can be integrated into a biological framework, allowing the formulation of explicit working hypotheses. The present study is based on the assumption that patrilocal traditions make the hypervariable region I of the mtDNA a valuable tool for the exploration of migratory dynamics, offering the opportunity to explore the relationships between genetic and linguistic diversity. We studied 85 Niger-Congo-speaking patrilocal populations that cover regions from Senegal to Central African Republic. A total of 4175 individuals were included in the study. RESULTS: By combining a multivariate analysis aimed at investigating the population genetic structure, with a Bayesian approach used to test models and extent of migration, we were able to detect a stepping-stone migration model as the best descriptor of gene flow across the region, with the main discontinuities corresponding to forested areas. CONCLUSIONS: Our analyses highlight an aspect of the influence of habitat variation on human genetic diversity that has yet to be understood. Rather than depending simply on geographic linear distances, patterns of female genetic variation vary substantially between savannah and rainforest environments. Our findings may be explained by the effects of recent gene flow constrained by environmental factors, which superimposes on a background shaped by pre-agricultural peopling. PMID- 23360304 TI - Expression and functional role of beta3 -adrenoceptors in the human ureter. AB - OBJECTIVES: To investigate the presence of beta-adrenoceptor subtypes in the human ureter, and to examine whether beta(3) -adrenoceptors modulate relaxation of the human ureter. METHODS: Expression of messenger ribonucleic acid of beta adrenoceptors in the human ureter was determined by reverse transcription polymerase chain reaction, and distribution of beta-adrenoceptors was examined by immunohistochemistry. In functional studies, the relaxant effects of isoproterenol, procaterol, TRK-380, salbutamol and BRL 37344 on KCl-induced contraction of the human ureter were evaluated, and the inhibitory effects of isoproterenol, procaterol and TRK-380 on electrical field stimulation-induced contractions were determined. RESULTS: Expression of beta(1) -, beta(2) - and beta(3) -adrenoceptor messenger ribonucleic acid in the human ureter was confirmed by reverse transcription polymerase chain reaction. Positive staining for beta(1) -, beta(2) - and beta(3) -adrenoceptor was identified not only in smooth muscle, but also in the urothelium of the human ureter. All beta adrenoceptor agonists decreased the tone of KCl-induced contractions of the human ureter with a rank order of relaxant effects of isoproterenol > procaterol > TRK 380 > salbutamol > BRL 37344. Furthermore, isoproterenol, procaterol and TRK-380 significantly decreased the amplitude of electrical field stimulation-induced contractions with a rank order of inhibitory effects of isoproterenol > procaterol > TRK-380. CONCLUSIONS: Human ureteral relaxation is mediated by both beta(2) - and beta(3) -adrenoceptor stimulation. beta(3) -Adrenoceptor agonists have the potential to relax the human ureter, and their clinical application in the treatment of ureteral stones is expected. PMID- 23360303 TI - The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib. AB - Interactions between the Bruton tyrosine kinase (BTK) inhibitor PCI-32765 and the proteasome inhibitor (bortezomib) were examined in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells, including those highly resistant to bortezomib. Co-administration of PCI-32765/bortezomib synergistically increased mitochondrial injury and apoptosis in germinal centre- or activated B-cell-like DLBCL cells and in MCL cells. These events were accompanied by marked AKT and nuclear factor (NF)-kappaB (NFKB1) inactivation, down-regulation of Mcl-1 (MCL1), Bcl-xL (BCL2L1), and XIAP, and enhanced DNA damage (e.g., gammaH2A.X formation) and endoplasmic reticulum (ER) stress. Similar interactions were observed in highly bortezomib-resistant DLBCL and MCL cells, and in primary DLBCL cells. In contrast, PCI-32765/bortezomib regimens displayed minimal toxicity toward normal CD34(+) bone marrow cells. Transfection of DLBCL cells with a constitutively active AKT construct attenuated AKT inactivation and significantly diminished cell death, whereas expression of an NF-kappaB "super-repressor" (IkappaBalphaser34/36 ) increased both PCI-32765 and bortezomib lethality. Moreover, cells in which the ER stress response was disabled by a dominant negative eIF2alpha construct were resistant to this regimen. Finally, combined exposure to PCI-32765 and bortezomib resulted in more pronounced and sustained reactive oxygen species (ROS) generation, and ROS scavengers significantly diminished lethality. Given promising early clinical results for PCI-32765 in DLBCL and MCL, a strategy combining BTK/proteasome inhibitor warrants attention in these malignancies. PMID- 23360305 TI - Factors of accepting pain management decision support systems by nurse anesthetists. AB - BACKGROUND: Pain management is a critical but complex issue for the relief of acute pain, particularly for postoperative pain and severe pain in cancer patients. It also plays important roles in promoting quality of care. The introduction of pain management decision support systems (PM-DSS) is considered a potential solution for addressing the complex problems encountered in pain management. This study aims to investigate factors affecting acceptance of PM-DSS from a nurse anesthetist perspective. METHODS: A questionnaire survey was conducted to collect data from nurse anesthetists in a case hospital. A total of 113 questionnaires were distributed, and 101 complete copies were returned, indicating a valid response rate of 89.3%. Collected data were analyzed by structure equation modeling using the partial least square tool. RESULTS: The results show that perceived information quality (gamma=.451, p<.001), computer self-efficacy (gamma=.315, p<.01), and organizational structure (gamma=.210, p<.05), both significantly impact nurse anesthetists' perceived usefulness of PM DSS. Information quality (gamma=.267, p<.05) significantly impacts nurse anesthetists' perceptions of PM-DSS ease of use. Furthermore, both perceived ease of use (beta=.436, p<.001, R(2)=.487) and perceived usefulness (beta=.443, p<.001, R(2)=.646) significantly affected nurse anesthetists' PM-DSS acceptance (R2=.640). Thus, the critical role of information quality in the development of clinical decision support system is demonstrated. CONCLUSIONS: The findings of this study enable hospital managers to understand the important considerations for nurse anesthetists in accepting PM-DSS, particularly for the issues related to the improvement of information quality, perceived usefulness and perceived ease of use of the system. In addition, the results also provide useful suggestions for designers and implementers of PM-DSS in improving system development. PMID- 23360306 TI - Rotational mobility of single molecules affects localization accuracy in super resolution fluorescence microscopy. AB - The asymmetric nature of single-molecule (SM) dipole emission patterns limits the accuracy of position determination in localization-based super-resolution fluorescence microscopy. The degree of mislocalization depends highly on the rotational mobility of SMs; only for SMs rotating within a cone half angle alpha > 60 degrees can mislocalization errors be bounded to <=10 nm. Simulations demonstrate how low or high rotational mobility can cause resolution degradation or distortion in super-resolution reconstructions. PMID- 23360307 TI - Piezotronic effect on the sensitivity and signal level of Schottky contacted proactive micro/nanowire nanosensors. AB - We demonstrated the first piezoelectric effect on the performance of a pH sensor using an MSM back-to-back Schottky contacted ZnO micro/nanowire device. When the device is subjected to an external strain, a piezopotential is created in the micro/nanowire, which tunes the effective heights of the Schottky barriers at the local contacts, consequently increasing the sensitivity and signal level of the sensors. Furthermore, the strain-produced piezopotential along the ZnO micro/nanowire will lead to a nonuniform distribution of the target molecules near the micro/nanowire surface owing to electrostatic interaction, which will make the sensor proactive to detect the target molecules even at extremely low overall concentration, which naturally improves the sensitivity and lowers the detection limit. A theoretical model is proposed to explain the observed performance of the sensor using the energy band diagram. This prototype device offers a new concept for designing supersensitive and fast-response micro/nanowire sensors by introducing an external strain and piezotronic effect, which may have great applications in building sensors with fast response and reset time, high selectivity, high sensitivity, and good signal-to-noise ratio for chemical, biochemical, and gas sensing. PMID- 23360308 TI - Diagnostic accuracy of urine-based kits for detection of Helicobacter pylori antibody in children. AB - BACKGROUND: Rapid urine-HpAb is reported to be a reliable test of Helicobacter pylori infection in adults, but there are no data on the application of the test in children. The aim of this study was to evaluate the accuracy of a urine-based enzyme-linked immunosorbent assay (urine-HpELISA) and immunochromatography (rapid urine-HpAb) kit for anti-H. pylori immunoglobulin G antibody in children. We compared its sensitivity and specificity in reference to the (13) C-urea-breath test (UBT) and H. pylori stool antigen test (HpSA). METHODS: In total, 101 Japanese children without significant upper-abdominal symptoms were included (mean age, 7.1 years; range 2-15 years). Their sensitivity and specificity were evaluated in reference to the UBT and HpSA. RESULTS: Thirty-seven children were judged H. pylori-positive and 64 negative by the UBT and HpSA. No discrepancy in the results was observed between UBT and HpSA. Urine-HpELISA showed 91.9% sensitivity and 96.9% specificity with an accuracy of 95.0%. Rapid urine-HpAb showed 78.4% sensitivity and 100% specificity with an accuracy of 92.1%. Seven false negative results for rapid urine-HpAb were from children aged younger than 10 years, and their antibody titers of urine-HpELISA were lower than true positives. CONCLUSIONS: For the diagnosis of H. pylori infection in Japanese children, both tests are non-invasive, inexpensive, reliable and easy-to-perform methods giving satisfactory accuracy, although the sensitivity of the rapid urine HpAb kit was inferior to that of the urine-HpELISA kit, especially in children aged younger than 10 years, showing relatively low titer of H. pylori antibody. PMID- 23360309 TI - Synthesis and in vitro antimalarial testing of neocryptolepines: SAR study for improved activity by introduction and modifications of side chains at C2 and C11 on indolo[2,3-b]quinolines. AB - To obtain a high antimalarial activity with neocryptolepine derivatives, modifying and changing the side chains at the C11 position with varying the substituents of an electron-withdrawing or electron-donating nature at the C2 position for a SAR study were executed. Installation of alkylamino and omega aminoalkylamino groups at the C11 position of the neocryptolepine core was successful. For further variation, the aminoalkylamino substituents were transformed into the corresponding acyclic or cyclic carbamides or thiocarbamides. These side chain modified neocryptolepine derivatives were tested for antimalarial activity against CQR (K1) and CQS (NF54) of Plasmodium falciparum in vitro and for cytotoxicity toward mammalian L6 cells. Among the tested compounds, the compound 17f showed an IC50 of 2.2 nM for CQS (NF54) and a selectivity index of 1400, and 17i showed an IC50 of 2.2 nM for CQR (K1), a selectivity index of 1243, and a resistance index of 0.5. PMID- 23360311 TI - How has the flu virus infected the Web? 2010 influenza and vaccine information available on the Internet. AB - BACKGROUND: The 2009-10 influenza pandemic was a major public health concern. Vaccination was recommended by the health authorities, but compliance was not optimal and perception of the presumed associated risks was high among the public. The Internet is increasingly being used as a source of health information and advice. The aim of the study was to investigate the characteristics of websites providing information about flu vaccine and the quality of the information provided. METHODS: Website selection was performed in autumn 2010 by entering eight keywords in two of the most commonly used search engines (Google.com and Yahoo.com). The first three result pages were analysed for each search, giving a total of 480 occurrences. Page rank was evaluated to assess visibility. Websites based on Web 2.0 philosophy, websites merely displaying popular news/articles and single files were excluded from the subsequent analysis. We analysed the selected websites (using WHO criteria) as well as the information provided, using a codebook for pro/neutral websites and a qualitative approach for the adverse ones. RESULTS: Of the 89 websites selected, 54 dealt with seasonal vaccination, three with anti-H1N1 vaccination and 32 with both. Rank analysis showed that only classic websites (ones not falling in any other category) and one social network were provided on the first pages by Yahoo; 21 classic websites, six displaying popular news/articles and one blog by Google. Analysis of the selected websites revealed that the majority of them (88.8%) had a positive/neutral attitude to flu vaccination. Pro/neutral websites distinguished themselves from the adverse ones by some revealing features like greater transparency, credibility and privacy protection. CONCLUSIONS: We found that the majority of the websites providing information on flu vaccination were pro/neutral and gave sufficient information. We suggest that antivaccinationist information may have been spread by a different route, such as via Web 2.0 tools, which may be more prone to the dissemination of "viral" information. The page ranking analysis revealed the crucial role of search engines regarding access to information on the Internet. PMID- 23360310 TI - Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. AB - Replicative cellular senescence is an important tumor suppression mechanism and also contributes to aging. Progression of both cancer and aging include significant epigenetic components, but the chromatin changes that take place during cellular senescence are not known. We used formaldehyde assisted isolation of regulatory elements (FAIRE) to map genome-wide chromatin conformations. In contrast to growing cells, whose genomes are rich with features of both open and closed chromatin, FAIRE profiles of senescent cells are significantly smoothened. This is due to FAIRE signal loss in promoters and enhancers of active genes, and FAIRE signal gain in heterochromatic gene-poor regions. Chromatin of major retrotransposon classes, Alu, SVA and L1, becomes relatively more open in senescent cells, affecting most strongly the evolutionarily recent elements, and leads to an increase in their transcription and ultimately transposition. Constitutive heterochromatin in centromeric and peri-centromeric regions also becomes relatively more open, and the transcription of satellite sequences increases. The peripheral heterochromatic compartment (PHC) becomes less prominent, and centromere structure becomes notably enlarged. These epigenetic changes progress slowly after the onset of senescence, with some, such as mobilization of retrotransposable elements becoming prominent only at late times. Many of these changes have also been noted in cancer cells. PMID- 23360312 TI - Laser therapy in metabolic syndrome-related kidney injury. AB - Metabolic syndrome is characterized by hyperglycemia, hypertension, dyslipidemia and obesity. Diabetes and hypertension are the main causes of chronic end-stage kidney disease in humans. Chronic kidney disease is characterized by kidney inflammation and eventual development of kidney fibrosis. Low-level laser (or light) therapy (LLLT) can be used to relieve pain associated with some inflammatory diseases due to photochemical effects. Despite the known contribution of inflammation to metabolic syndrome and kidney disease, there is scarce information on the potential therapeutic use of LLLT in renal disease. The aim of this randomized, placebo-controlled study was to test the hypothesis that LLLT could modulate chronic kidney injury. Rats with nephropathy, hypertension, hyperlipidemia and type II diabetes (strain ZSF1) were subjected to three different conditions of LLLT or sham treatment for 8 weeks, and then sacrificed 10 weeks later. The main findings of this study are that the LLLT-treated rats had lower blood pressure after treatment and a better preserved glomerular filtration rate with less interstitial fibrosis upon euthanasia at the end of follow-up. This initial proof-of-concept study suggests that LLLT may modulate chronic kidney disease progression, providing a painless, noninvasive, therapeutic strategy, which should be further evaluated. PMID- 23360313 TI - Motivators to participation in medical trials: the application of social and personal categorization. AB - The Health Belief Model provides a framework to understand motivators for volunteering for medical research. Motivators can take the form of social and personal benefits. In this systematic review of review articles, we contrast motivators of participation in actual cancer trials to those in actual HIV vaccine trials. We retrieved eight review articles from 2000 to 2012 examining motivators to participation in actual cancer trials. Personal benefits were most often psychological in nature, such as "coping with symptoms." Social benefits included "advancing research," "helping other cancer patients," and "for their family." While specific motivators vary between considerations - cancer research and HIV vaccine trials, these motivators fall into similar categories at similar frequencies. For example, personal/psychological benefits are common in each. Participant recruitment must be mindful of these categories of motivators for both cancer and HIV vaccine research. PMID- 23360314 TI - Population structure of Tor tor inferred from mitochondrial gene cytochrome b. AB - Tor tor, commonly called as Tor mahseer, is a high-valued food and game fish endemic to trans-Himalayan region. Mitochondrial cytochrome b (cyt b) gene region of 967 bp was used to estimate the population structure of T. tor. Three populations of T. tor were collected from Narmada (Hosangabad), Ken (Madla), and Parbati river (Sheopur) in Madhya Pradesh, India. The sequence analysis revealed that the nucleotide diversity (pi) was low, ranging from 0.000 to 0.0150. Haplotype diversity (h) ranged from 0.000 to 1.000. The analysis of molecular variance analysis indicated significant genetic divergence among the three populations of T. tor. Neighboring-joining tree also showed that all individuals from three populations clustered into three distinct clades. The data generated by cyt b marker revealed interesting insight about population structure of T. tor, which would serve as baseline data for conservation and management of mahseer fishery. PMID- 23360315 TI - Long-term exercising video-endoscopic examination of the upper airway following laryngoplasty surgery: a prospective cross-sectional study of 41 horses. AB - REASONS FOR PERFORMING STUDY: To investigate upper respiratory tract function in horses, previously undergoing laryngoplasty (LP), using exercising video endoscopy. OBJECTIVES: To evaluate arytenoid abduction and stability, diagnose any concurrent upper airway problems, and correlate these with the owners' perception of success. METHODS: Horses undergoing LP during a 6-year period at one hospital were initially included. Those available for re-examination were exercised for a duration and intensity considered maximal for their discipline using an over-ground endoscope. Resting and exercising laryngeal and pharyngeal videos were analysed blindly. Multivariable analysis was used to test associations between resting and exercising endoscopic variables, and also between endoscopic variables and owner questionnaire findings. RESULTS: Forty-one horses were included and 78% had a form of upper airway collapse at exercise, with 41% having complex forms, despite 93% of owners reporting the surgery to have been beneficial. Horses with poor abduction (grades 4 or 5/5) were 6 times more likely to make respiratory noise compared with those with good (grades 2 or 3/5) abduction (P = 0.020; 95% confidence interval [CI] 1.3-27.0), and those not having a ventriculectomy were 4.9 times more likely to produce respiratory noise post operatively (P = 0.048; 95% CI 1.0-23.9). Palatal dysfunction was observed in 24% of horses at rest, and 56% at exercise, with the diagnosis at rest and exercise significantly associated (P = 0.001). Increasing severity of pharyngeal lymphoid hyperplasia (prevalence 61%) was significantly associated with increasing arytenoid abduction (P = 0.01). Thirty-four per cent of horses had aryepiglottic fold collapse and 22% of horses had vocal fold collapse. CONCLUSIONS: Many horses that had previously had LP were diagnosed with upper airway abnormalities, despite the procedure being considered as beneficial by most owners. POTENTIAL RELEVANCE: When investigating cases of ongoing respiratory noise or poor performance following LP, exercising endoscopy must be considered. Continued respiratory noise may be associated with poor arytenoid abduction and not performing concurrent ventriculectomy. PMID- 23360316 TI - Fast pouch emptying, delayed small intestinal transit, and exaggerated gut hormone responses after Roux-en-Y gastric bypass. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) causes extensive changes in gastrointestinal anatomy and leads to reduced appetite and large weight loss, which partly is due to an exaggerated release of anorexigenic gut hormones. METHODS: To examine whether the altered passage of foods through the gastrointestinal tract after RYGB could be responsible for the changes in gut hormone release, we studied gastrointestinal motility with a scintigraphic technique as well as the secretion of the gut hormones glucagon-like peptide (GLP)-1 and peptide YY3-36 (PYY3-36 ) in 17 patients>1 year after RYGB and in nine healthy control subjects. KEY RESULTS: At meal completion, a smaller fraction of liquid and solid radiolabeled marker was retained in the pouch of RYGB patients than in the stomach of control subjects (P = 0.002 and P < 0.001, respectively). Accordingly, pouch emptying in patients was faster than gastric emptying in control subjects (P < 0.001 and P = 0.004, respectively liquid and solid markers). For the solid marker, small intestinal transit was slower in patients than control subjects (P = 0.034). Colonic transit rate did not differ between the groups. GLP-1 and PYY3-36 secretion was increased in patients compared to control subjects and fast pouch emptying of the liquid marker was associated with high gut hormone secretion. CONCLUSIONS & INFERENCES: After RYGB, the bulk of foods pass without hindrance into the small intestine, while the small intestinal transit is prolonged. The rapid exposure of the gut epithelium contributes to the exaggerated release of GLP-1 and PYY3-36 after RYGB. PMID- 23360317 TI - Strecker-type degradation of phenylalanine initiated by 4-oxo-2-alkenals in comparison to that initiated by 2,4-alkadienals, 4,5-epoxy-2-alkenals, or 4 hydroxy-2-nonenal. AB - The conversion of phenylalanine to phenylacetaldehyde as a consequence of its reaction with 4-oxo-2-alkenals was studied both to characterize the reaction pathway and to compare the reactivities and kinetic constants of oxoalkenals with those of other lipid oxidation products: 2,4-alkadienals, 4,5-epoxy-2-alkenals, and 4-hydroxy-2-nonenal. Oxoalkenals produced the Strecker aldehyde through imine formation, which was then decarboxylated and hydrolyzed. In the course of the reaction the lipid was converted into an unsaturated hydroxylamine that eventually cycled to 2-alkylpyrrole. The Ea of phenylacetaldehyde formation in the presence of oxoalkenals was 55-64 kJ/mol. This Ea was similar to the Ea determined for the other tertiary lipid oxidation products assayed (58-67 kJ/mol), but higher than the Ea determined for alkadienals (28-38 kJ/mol). However, this difference in Ea only correlated with the amount of phenylacetaldehyde produced at 37 degrees C. At higher temperatures, 4-oxo-2 nonenal was the lipid-derived carbonyl compound that produced the highest amount of the Strecker aldehyde, therefore pointing to this oxoalkenal as the most efficient Strecker aldehyde forming compound derived from lipids. For this reason, oxoalkenals should be expected to play a significant role in reactions in which Strecker aldehydes are recognized intermediates, as occurs in the formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). PMID- 23360318 TI - Reticulocyte hemoglobin content and iron deficiency: a retrospective study in adults. AB - AIM: To evaluate the reticulocyte hemoglobin content (CHr) in a total of 260 adult patients having anemia of chronic disease (ACD), iron deficiency anemia, and chronic renal failure (CRF) who enrolled at the King Khalid University Hospital (Riyadh, Saudi Arabia). RESULTS: Results from this study showed that there was a significant correlation between the CHr and hematological parameters, like hemoglobin, hematocrit, mean cell volume, mean cell hemoglobin, and red blood cell distribution. In addition, a significant correlation was seen between the CHr and biochemical parameters for iron status like serum iron, transferrin saturation, and total iron-binding capacity. CONCLUSIONS: The CHr, together with a complete blood count, may provide an alternative to the traditional hematological or biochemical panels for the diagnosis of absolute iron deficiency and functional iron deficiency in the case of ACD and the anemia associated with CRF. PMID- 23360319 TI - Arg399Gln polymorphism of X-ray repair cross-complementing group 1 gene is associated with angiographically documented coronary artery disease in South Indian type 2 diabetic patients. AB - AIMS: DNA damage resulting from oxidative stress contributes significantly to the development and progression of atherosclerosis in type 2 diabetic (T2DM) individuals, thereby implicating polymorphisms in DNA repair genes in the modulation of DNA repair efficiency. Based on this premise, we explored the association between X-ray repair cross-complementing group 1 (XRCC1) gene Arg399Gln polymorphism, coronary artery disease (CAD), and myocardial infarction (MI) in type 2 diabetic patients. We screened 283 T2DM patients, inclusive of 160 with angiographically defined CAD, 73 with MI, 89 without MI, and 121 T2DM individuals with no evidence of CAD for XRCC1 Arg399Gln polymorphism. RESULTS: There appeared to be a significant difference in the distribution of genotype and allele frequencies of XRCC1 Arg399Gln polymorphism between T2DM groups with and without CAD (p=0.03), albeit no significant association with MI was observed (p=0.055). A further analysis revealed that the frequencies of the Arg/Gln, Gln/Gln genotypes and 399Gln allele were considerably higher in patients with triple vessel disease (TVD) as compared with those with the single and double vessel disease (p=0.03), thereby associating this polymorphism with severity of CAD in T2DM individuals. Multiple logistic regression analysis revealed a significant and independent association of XRCC1 Arg399Gln polymorphism and other putative risk factors with CAD/TVD in T2DM individuals. CONCLUSIONS: These findings reveal a significant association between XRCC1 gene Arg399Gln polymorphism, CAD/TVD, and coincident putative risk factors in T2DM individuals in the South Indian population. PMID- 23360321 TI - Photodynamic effect of 5-aminolevulinic acid-loaded nanoparticles on bladder cancer cells: a preliminary investigation. AB - OBJECTIVE: The aim of this study was to assess the photodynamic effect of nanoparticles loaded with a photosensitizing nanomedicine, 5-aminolevulinic acid (5-ALA), on T24 bladder cancer cells in vitro. MATERIAL AND METHODS: The nanoprecipitation technique was successfully used to prepare the drug-loaded polymeric nanoparticles. The drug loading rate and the drug loading efficiency were determined by ultraviolet spectrophotometry. The size and morphology of nanoparticles were detected using dynamic light scattering (DLS) and transmission electron microscopy. Cytotoxicity to T24 bladder cancer cells was assessed by coincubating 5-ALA-loaded nanoparticles of different concentrations with T24 bladder cancer cells. The cell growth inhibitory rate was measured after irradiation by a 650 nm wavelength diode laser. RESULTS: The drug loading rate of 5-ALA-loaded nanoparticles was 7% with a loading efficiency of 85%. The T24 cell growth inhibitory rates after incubation with 5.0, 10.0, 25.0 and 50.0 MUg/ml 5 ALA-loaded nanoparticles were 73.19%, 79.95%, 83.86% and 89.74%, respectively, which demonstrated significantly higher cytotoxicity than those in the empty nanoparticle groups and 5-ALA free drug groups (p < 0.05). CONCLUSIONS: 5-ALA loaded nanoparticles were successfully prepared and had a significantly enhanced photodynamic tumoricidal effect on bladder cancer cells in vitro. PMID- 23360322 TI - Electronic structure of one-electron-oxidized form of the methylcobalamin cofactor: spin density distribution and pseudo-Jahn-teller effect. AB - The electronic and structural properties of the one-electron-oxidized form of methylcobalamin (MeCbl) cofactor have been investigated using density functional theory (DFT) and CASSCF/MC-XQDPT2 calculations. We applied two types of functionals (hybrid and GGA) which produced quite different results in terms of spin density profiles: the B3LYP description was consistent with Co(III) and the pi-cation corrin radical while the BP86 result was more in line with the Co(IV) oxidation state. A closer inspection of both outcomes indicates that the oxidized species have a mixed pi-cation corrin radical and Co(III)/Co(IV) character. This mixed character was further supported by high-level ab initio CASSCF/MC-XQDPT2 calculations, which reveal the strong mixing of the electronic states due to nondynamical correlation effects. The near degeneracy, which takes place between the ground and first excited state, was consistent with the presence of a pseudo Jahn-Teller (pJT) effect in the oxidized form of MeCbl. In addition, the DFT based investigation of the structurally related porphyrin complexes gives a description consistent with corrin-based analogues and reveals that the corrin species have more Co(IV) character. The most important finding of the present study, regardless of the type of functional used, was the significant lowering of dissociation energy (~35%), which might be due to the partial depopulation of the Co-C sigma orbital upon removal of an electron. PMID- 23360320 TI - A platelet-mimetic paradigm for metastasis-targeted nanomedicine platforms. AB - There is compelling evidence that, beyond their traditional role in hemostasis and thrombosis, platelets play a significant role in mediating hematologic mechanisms of tumor metastasis by directly and indirectly interacting with pro metastatic cancer cells. With this rationale, we hypothesized that platelets can be an effective paradigm to develop nanomedicine platforms that utilize platelet mimetic interaction mechanisms for targeted diagnosis and therapy of metastatic cancer cells. Here we report on our investigation of the development of nanoconstructs that interact with metastatic cancer cells via platelet-mimetic heteromultivalent ligand-receptor pathways. For our studies, pro-metastatic human breast cancer cell line MDA-MB-231 was studied for its surface expression of platelet-interactive receptors, in comparison to another low-metastatic human breast cancer cell line, MCF-7. Certain platelet-interactive receptors were found to be significantly overexpressed on the MDA-MB-231 cells, and these cells showed significantly enhanced binding interactions with active platelets compared to MCF 7 cells. Based upon these observations, two specific receptor interactions were selected, and corresponding ligands were engineered onto the surface of liposomes as model nanoconstructs, to enable platelet-mimetic binding to the cancer cells. Our model platelet-mimetic liposomal constructs showed enhanced targeting and attachment of MDA-MB-231 cells compared to the MCF-7 cells. These results demonstrate the promise of utilizing platelet-mimetic constructs in modifying nanovehicle constructs for metastasis-targeted drug as well as modifying surfaces for ex-vivo cell enrichment diagnostic technologies. PMID- 23360323 TI - Purification and characterization of a thermolysin like protease from Thermoactinomyces thalpophilus MCMB-380. AB - The extracellular thermolysin like protease (TLP) was purified and characterized from Thermoactinomyces thalpophilus MCMB-380 (Genbank Accession No. EF397000). The enzyme was purified to homogeneity by successive ultra filtration steps using 50 kDa and 10 kDa membrane filters followed by anion exchange chromatography. The molecular mass and isoelectric point of the enzyme were found to be 34.4 kDa and 9.5, respectively. The proteolytic activity was inhibited by EDTA and the enzyme required Ca2+ to show the full activity as well as thermostability. The T50 of the enzyme at 80 degrees C was 1 h and the activation energy was estimated to be 11.02 Kcal / mol. Atomic absorption spectrophotometric analysis revealed the presence of Zn2+ ion in the protein core indicating that it is a metalloprotease. This protease has commercial potential in catalyzing the condensation reaction of two amino acids for production of the dipeptide aspartame, an artificial sweetener. The one hour time-frame is significantly faster than that of the enzyme thermolysin from Bacillus thermoproteolyticus. Moreover the TLP was stable at 80 degrees C for one hour which makes it industrially robust. The Zn2+ ion in the T. thalpophilus protease appears to be necessary for maintaining the active conformation of the enzyme molecule. PMID- 23360324 TI - Spatial ordering of colloids in a drying aqueous polymer droplet. AB - We explore the role of polymer chains on deposition of colloidal particles at solid surfaces from drying aqueous drops and show that the kinetics of phase separation of colloids and polymers can be explained by spinodal decomposition of binary systems. Concentrations of polymer solutions and polymer chain lengths were varied to understand the aggregation dynamics of colloidal particles via a polymer bridging mechanism. We show that when polymer concentration in the droplet is increased, particles spatially order upon drying due to a combination of the phase separation of highly bridged particles and the Marangoni flow effect. The demonstrated effect of particle-adsorbing, water-soluble polymers on the coffee-ring formation opens up new ways of creating highly ordered, long range patterned surfaces using a facile, template-free approach. PMID- 23360325 TI - Identification and functional analysis of fructosyl amino acid-binding protein from Gram-positive bacterium Arthrobacter sp. AB - AIM: Fructosyl amino acid-binding protein (FABP) is a substrate-binding protein (SBP), which recognizes fructosyl amino acids (FAs) as its ligands. Although FABP has been shown as a molecular recognition tool of biosensing for glycated proteins, the availability of FABP is still limited and no FABP was reported from Gram-positive bacteria. In this study, a novel FABP from Gram-positive bacteria, Arthrobacter spp., was reported. METHOD AND RESULTS: BLAST analysis revealed that FABP homologues exist in some of Arthrobacter species genomes. An FABP homologue cloned from Arthrobacter sp. FV1-1, FvcA, contained a putative lipoprotein signal sequence, suggesting that it is a lipoprotein anchored to the bacterial cytoplasmic membrane, which is a typical characteristic for SBPs from Gram positive bacteria. In contrast, FvcA also exhibits high amino acid sequence similarity to a known Gram-negative bacterial FABP, which exists as a free periplasmic protein. FvcA, without the N-terminal anchoring region, was then recombinantly produced as soluble protein and was found to exhibit Nalpha-FA specific binding activity by intrinsic fluorescent measurement. CONCLUSION: This study identified a novel FABP from a Gram-positive bacterium, Arthrobacter sp., which exhibited Nalpha-FA-specific binding ability. This is the first report concerning an FABP from a Gram-positive bacterium, suggesting that FABP-dependent FA catabolism system is also present in Gram-positive bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: The novel FABP exhibits the ability to specifically bind to Nalpha-FA with a high affinity. This selectivity is beneficial for applying FABP in HbA1c sensing. The successful preparation of water-soluble, functionally expressed Gram-negative bacterial FABP may make way for future applications for a variety of SBPs from Gram-positive bacteria employing the same expression strategy. The results obtained here enhance our understanding of bacterial FA catabolism and contribute to the improved development of FABP as Nalpha-FA sensing molecules. PMID- 23360327 TI - How "hollow" are hollow nanoparticles? AB - Diamond anvil cell (DAC), synchrotron X-ray diffraction (XRD), and small-angle X ray scattering (SAXS) techniques are used to probe the composition inside hollow gamma-Fe(3)O(4) nanoparticles (NPs). SAXS experiments on 5.2, 13.3, and 13.8 nm hollow-shell gamma-Fe(3)O(4) NPs, and 6 nm core/14.8 nm hollow-shell Au/Fe(3)O(4) NPs, reveal the significantly high (higher than solvent) electron density of the void inside the hollow shell. In high-pressure DAC experiments using Ne as pressure-transmitting medium, formation of nanocrystalline Ne inside hollow NPs is not detected by XRD, indicating that the oxide shell is impenetrable. Also, FTIR analysis on solutions of hollow-shell gamma-Fe(3)O(4) NPs fragmented upon refluxing shows no evidence of organic molecules from the void inside, excluding the possibility that organic molecules get through the iron oxide shell during synthesis. High-pressure DAC experiments on Au/Fe(3)O(4) core/hollow-shell NPs show good transmittance of the external pressure to the gold core, indicating the presence of the pressure-transmitting medium in the gap between the core and the hollow shell. Overall, our data reveal the presence of most likely small fragments of iron and/or iron oxide in the void of the hollow NPs. The iron oxide shell seems to be non-porous and impenetrable by gases and liquids. PMID- 23360326 TI - Comprehensive phylogenetic analysis of all species of swordtails and platies (Pisces: Genus Xiphophorus) uncovers a hybrid origin of a swordtail fish, Xiphophorus monticolus, and demonstrates that the sexually selected sword originated in the ancestral lineage of the genus, but was lost again secondarily. AB - BACKGROUND: Males in some species of the genus Xiphophorus, small freshwater fishes from Meso-America, have an extended caudal fin, or sword - hence their common name "swordtails". Longer swords are preferred by females from both sworded and - surprisingly also, non-sworded (platyfish) species that belong to the same genus. Swordtails have been studied widely as models in research on sexual selection. Specifically, the pre-existing bias hypothesis was interpreted to best explain the observed bias of females in presumed ancestral lineages of swordless species that show a preference for assumed derived males with swords over their conspecific swordless males. However, many of the phylogenetic relationships within this genus still remained unresolved. Here we construct a comprehensive molecular phylogeny of all 26 known Xiphophorus species, including the four recently described species (X. kallmani, X. mayae, X. mixei and X. monticolus). We use two mitochondrial and six new nuclear markers in an effort to increase the understanding of the evolutionary relationships among the species in this genus. Based on the phylogeny, the evolutionary history and character state evolution of the sword was reconstructed and found to have originated in the common ancestral lineage of the genus Xiphophorus and that it was lost again secondarily. RESULTS: We estimated the evolutionary relationships among all known species of the genus Xiphophorus based on the largest set of DNA markers so far. The phylogeny indicates that one of the newly described swordtail species, Xiphophorus monticolus, is likely to have arisen through hybridization since it is placed with the southern platyfish in the mitochondrial phylogeny, but with the southern swordtails in the nuclear phylogeny. Such discordance between these two types of markers is a strong indication for a hybrid origin. Additionally, by using a maximum likelihood approach the possession of the sexually selected sword trait is shown to be the most likely ancestral state for the genus Xiphophorus. Further, we provide a well supported estimation of the phylogenetic relationships between the previously unresolved northern swordtail groups. CONCLUSIONS: This comprehensive molecular phylogeny of the entire genus Xiphophorus provides evidence that a second swordtail species, X. monticolus, arose through hybridization. Previously, we demonstrated that X. clemenciae, another southern swordtail species, arose via hybridization. These findings highlight the potential key role of hybridization in the evolution of this genus and suggest the need for further investigations into how hybridization contributes to speciation more generally. PMID- 23360328 TI - Probing the distribution of water molecules hydrating lipid membranes with ultrafast Forster vibrational energy transfer. AB - We determine the relative positioning of water molecules in 1,2-dioleoyl-sn glycero-3-phosphocholine (DOPC) membranes by measuring the rate of vibrational resonant (Forster) energy transfer between the water hydroxyl stretch vibrations. The rate of Forster energy transfer is strongly distance dependent and thus gives detailed information on the relative positioning of the water molecules. We determine the rate of intermolecular Forster energy by measuring the anisotropy dynamics of excited O-D stretch vibrations of HDO and D(2)O molecules with polarization-resolved femtosecond mid-infrared spectroscopy. We study the dynamics for deuterium fractions between 0.1 and 1 and for hydration levels between 2 and 12 water molecules per DOPC lipid molecule. We find that most of the water molecules hydrating the membrane are contained in nanoclusters and have an average intermolecular distance of 3.4 A. The density of these nanoclusters increases with increasing hydration level of the DOPC membranes. PMID- 23360329 TI - Editorial comment from Dr Funahashi to intravesical drug delivery for dysfunctional bladder. PMID- 23360330 TI - Observations of carbon nanotube oxidation in an aberration-corrected environmental transmission electron microscope. AB - We report the first direct study on the oxidation of carbon nanotubes at the resolution of an aberration-corrected environmental transmission electron microscope (ETEM), as we locate and identify changes in the same nanotubes as they undergo oxidation at increasing temperatures in situ in the ETEM. Contrary to earlier reports that CNT oxidation initiates at the end of the tube and proceeds along its length, our findings show that only the outside graphene layer is being removed and, on occasion, the interior inner wall is oxidized, presumably due to oxygen infiltrating into the hollow nanotube through an open end or breaks in the tube. We believe that this work provides the foundation for a greater scientific understanding of the mechanism underlying the nanotube oxidation process, as well as guidelines to manipulate the nanotubes' structure or prevent their oxidation. PMID- 23360331 TI - Reduced expression of MIR409-3p in primary immune thrombocytopenia. AB - Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease with many immune dysfunctions. MicroRNAs (miRNAs) are a class of non-coding RNAs that post transcriptionally regulate gene expression by messenger RNA degradation or translational repression. Accumulating evidence has demonstrated that miRNAs play a vital role in the regulation of immunological functions and prevention of autoimmunity. However, whether miRNAs are involved in the pathogenesis of ITP is still unknown. To illustrate the role of miRNAs in ITP, the expression profile of miRNAs from peripheral blood mononuclear cells (PBMCs) in ITP patients was investigated by miRNA microarray, and further validated by TaqMan real-time polymerase chain reaction. MIR409-3p expression was decreased in PBMCs of active ITP patients, but this recovered after effective therapy. IFNG was identified and validated as one of the targeted genes of MIR409-3p by bioinformatic prediction and reporter gene analysis. In addition, we found DGCR8 transcript was down regulated in ITP patients and positively correlated with MIR409-3p. Thus, in ITP patients, decreased DGCR8 leads to down-regulation of MIR409-3p, which in turn results in up-regulation of IFNG (IFN-gamma). PMID- 23360333 TI - Epitaxial silicon dots self-assembled on aluminum nitride/Si (111). AB - Si nanoscale dots are synthesized on AlN/Si(111) by molecular beam epitaxy. A dot density of 2.2 * 10(11) cm(-2) with a mean radius of 5.6 +/- 2.8 nm is obtained in Volmer-Weber growth mode. A double Si coverage leads to a decrease in dot density and increase in dot size. The dot orientations are [11[overline]0](Si) (or [1[overline]10](Si))//[112[overline]0](AlN) and (111)(Si)//(0001)(AlN), which are similar (or identical) to the orientation of AlN relative to the Si substrate. PMID- 23360334 TI - Label-free real-time detection of DNA methylation based on quartz crystal microbalance measurement. AB - DNA methylation plays an important role in the regulation of gene transcription, chromatin compaction, genome imprinting, and X-chromosome inactivation. DNA methyltransferase is considered a potential target for anticancer drug design. It is important to locate aberrantly methylated sequences on the human genome that are linked to specific diseases and to discover new low-toxic methylation inhibitors for medical treatments. We developed a DNA methylation detection method using a quartz crystal microbalance (QCM). We applied this method to assay genes p16 and GALR2 in two cell lines. Methylation of p16 was detected in both HT29 and HepG2 cell lines, whereas methylation of GALR2 was detected only in the HT29 cell line. We also used this method to evaluate the effect of 5-aza-2' deoxycytidine (decitabine), a methyltransferase inhibitor used in clinical treatment. We found methylation of genes p16 and GALR2 to be strongly inhibited. The results show that this method is sensitive to DNA methylation and is fit for evaluation of methyltransferase inhibitors. PMID- 23360332 TI - A mixed methods descriptive investigation of readiness to change in rural hospitals participating in a tele-critical care intervention. AB - BACKGROUND: Telemedicine technology can improve care to patients in rural and medically underserved communities yet adoption has been slow. The objective of this study was to study organizational readiness to participate in an academic community hospital partnership including clinician education and telemedicine outreach focused on sepsis and trauma care in underserved, rural hospitals. METHODS: This is a multi-method, observational case study. Participants included staff from 4 participating rural South Carolina hospitals. Using a readiness-for change model, we evaluated 5 general domains and the related factors or topics of organizational context via key informant interviews (n=23) with hospital leadership and staff, compared these to data from hospital staff surveys (n=86) and triangulated data with investigators' observational reports. Survey items were grouped into 4 categories (based on content and fit with conceptual model) and scored, allowing regression analyses for inferential comparisons to assess factors related to receptivity toward the telemedicine innovation. RESULTS: General agreement existed on the need for the intervention and feasibility of implementation. Previous experience with a telemedicine program appeared pivotal to enthusiasm. Perception of need, task demands and resource need explained nearly 50% of variation in receptivity. Little correlation emerged with hospital or ED leadership culture and support. However qualitative data and investigator observations about communication and differing support among disciplines and between staff and leadership could be important to actual implementation. CONCLUSIONS: A mixed methods approach proved useful in assessing organizational readiness for change in small organizations. Further research on variable operational definitions, potential influential factors, appropriate and feasible methods and valid instruments for such research are needed. PMID- 23360335 TI - Leadership development: see the need. PMID- 23360336 TI - Taking the plunge: things to consider when making the decision to provide a national conference. AB - This column describes factors and beginning steps that members of a provider unit should consider when making a decision to undertake a national conference. PMID- 23360337 TI - Strategies to improve delirium recognition in hospitalized older adults. AB - As 24-hour caregivers, nurses' detection of delirium is critical to physician diagnosis because of the waxing and waning of delirium-related clinical features. However, nurses fail to accurately interpret delirium-related clinical features more than 30% of the time. PMID- 23360338 TI - Teaching the business of health care. AB - This column identifies teaching modalities for assessing economic value, creating strategic plans, supporting implementation of cost-saving initiatives, and constantly evaluating. PMID- 23360340 TI - Hip fractures and pain following proton therapy for management of prostate cancer. AB - BACKGROUND: Proton therapy (PT) for prostate cancer reduces rectal and bladder dose, but increases dose to the femoral necks. We assessed the risk of hip fracture and pain in men treated with PT for prostate cancer. MATERIAL AND METHODS: From 2006 to 2008, 382 men were treated for prostate cancer and evaluated at six-month intervals after PT for toxicities at University of Florida Proton Therapy Institute (UFPTI). The WHO Fracture Risk Assessment Tool (FRAX) generated annual hip-fracture risk for the cohort. The WHO FRAX tool was utilized to generate the expected number of patients with hip fractures and the observed to-expected ratio; confidence intervals and p-value were generated with the mid-P exact test. Univariate analysis of hip pain as a function of several prognostic factors was accomplished with Fisher's exact test. RESULTS: Median follow-up was four years (range, 0.1-5.5 years). Per FRAX, 3.02 patients were expected to develop a hip fracture without PT. Three PT patients actually developed fractures for a rate of 0.21 fractures per 100 person-years of follow-up. There was an observed-expected ratio of 0.99 (p-value not significant). Forty-eight patients (13%) reported new pain in the hip during follow-up; three required prescription analgesics. CONCLUSION: PT for prostate cancer did not increase hip-fractures in the first four years after PT compared to expected rates in untreated men. PMID- 23360341 TI - Concordance of MRI lesions and EEG focal slowing in children with nonsyndromic epilepsy. AB - PURPOSE: To investigate the significance of electroencephalography (EEG) focal slowing in children with epilepsy and to determine the correlation between focal slowing and focal lesions on brain magnetic resonance imaging (MRI). METHODS: We reviewed 5,149 EEG and 22,543 MRI reports for children who visited our institution from 2000 to 2010. Patients with nonsyndromic epilepsy (n = 253) were divided into groups with: focal slowing without any interictal epileptiform discharge (IED) (group 1); focal IEDs without focal slowing (group 2); focal slowing and focal IED (group 3); and normal findings (group 4). Focal slowing and MRI lesions were categorized by location, side, and depth. KEY FINDINGS: We found MRI abnormalities in 59% of subjects in group 1, 56% in group 2, 74% in group 3, and 27% in group 4 (p < 0.0001). Cortical malformation (CM) was the most common pathology in groups with focal slowing. Focal slowing often correlated with the laterality of the MRI lesion (61-70%), but the location was concordant in only 40%. The associated lesions rarely were exclusively confined to the centrum semiovale (18%). SIGNIFICANCE: Focal slowing in children with epilepsy is highly associated with focal structural lesions on MRI, most commonly CM, and usually involves multiple layers. Focal slowing, as well as focal interictal epileptiform activity, is an important and useful EEG indicator of a brain structural abnormality in children with nonsyndromic epilepsy. PMID- 23360342 TI - What is the value of L-carnitine level determination for carnitine supplementation in hemodialysis patients? PMID- 23360343 TI - Severe adverse effects related to dermal exposure to a glyphosate-surfactant herbicide. AB - This is a case of severe chemical burns following prolonged accidental exposure to a glyphosate-surfactant herbicide. The patient developed local swelling, bullae and exuding wounds. Neurological impairment followed affecting finger flexion and sensation with reduced nerve conduction. Imaging revealed oedema of the soft tissue and juxta-articular osteopenia, and a causal relationship to exposure is suggested. PMID- 23360344 TI - Risk assessment of methanol poisoning in outbreaks not applicable to isolated cases. PMID- 23360345 TI - Fluorescence spectroscopy of the retina from scrapie-infected mice. AB - Recently, we have proposed that the fluorescence spectra of sheep retina can be well correlated with the presence or absence of scrapie. Scrapie is the most widespread TSE (transmissible spongiform encephalopathy) affecting sheep and goats worldwide. Mice eyes have been previously reported as a model system to study age-related accumulation of lipofuscin, which has been investigated by monitoring the increasing fluorescence with age covering its entire life span. The current work aims at developing mice retina as a convenient model system to diagnose scrapie and other fatal TSE diseases in animals such as sheep and cows. The objective of the research reported here was to determine whether the spectral features are conserved between two different species namely mice and sheep, and whether an appropriate small animal model system could be identified for diagnosis of scrapie based on the fluorescence intensity in retina. The results were consistent with the previous reports on fluorescence studies of healthy and scrapie-infected retina of sheep. The fluorescence from the retinas of scrapie infected sheep was significantly more intense and showed more heterogeneity than that from the retinas of uninfected mice. Although the structural characteristics of fluorescence spectra of scrapie-infected sheep and mice eyes are slightly different, more importantly, murine retinas reflect the enhancement of fluorescence intensity upon infecting the mice with scrapie, which is consistent with the observations in sheep eyes. PMID- 23360347 TI - Parental thoughts and actions regarding their child's first febrile seizure. AB - BACKGROUND: Little is known about what parents think and how they act when their child experiences febrile seizure (FS). This study therefore surveyed parents of 78 children who had experienced a first FS regarding their thoughts and actions. METHODS: The questionnaire was divided into three parts: details of the child and their family; medical management of the child before reaching hospital; and parental thoughts and actions when the child experienced convulsions. RESULTS: Parents without prior knowledge of FS showed a higher rate of thinking that FS were harmful than parents with prior knowledge (P < 0.03). Parents with prior knowledge were aware that their child was having an FS at a higher rate than parents without prior knowledge (P < 0.001). Moreover, parents without prior knowledge managed the convulsions less appropriately than parents with prior knowledge (P < 0.03). CONCLUSIONS: Parental fears that the death of their child was imminent and the misperception of FS as a serious, life-threatening condition indicate a lack of knowledge regarding FS. Organizing parental support groups and effective educational intervention programs for parents should be given priority in the care of children with FS. PMID- 23360346 TI - Association between perceived insufficient sleep, frequent mental distress, obesity and chronic diseases among US adults, 2009 behavioral risk factor surveillance system. AB - BACKGROUND: Although evidence suggests that poor sleep is associated with chronic disease, little research has been conducted to assess the relationships between insufficient sleep, frequent mental distress (FMD >=14 days during the past 30 days), obesity, and chronic disease including diabetes mellitus, coronary heart disease, stroke, high blood pressure, asthma, and arthritis. METHODS: Data from 375,653 US adults aged >= 18 years in the 2009 Behavioral Risk Factor Surveillance System were used to assess the relationships between insufficient sleep and chronic disease. The relationships were further examined using a multivariate logistic regression model after controlling for age, sex, race/ethnicity, education, and potential mediators (FMD and obesity). RESULTS: The overall prevalence of insufficient sleep during the past 30 days was 10.4% for all 30 days, 17.0% for 14-29 days, 42.0% for 1-13 days, and 30.6% for zero day. The positive relationships between insufficient sleep and each of the six chronic disease were significant (p < 0.0001) after adjustment for covariates and were modestly attenuated but not fully explained by FMD. The relationships between insufficient sleep and both diabetes and high blood pressure were also modestly attenuated but not fully explained by obesity. CONCLUSIONS: Assessment of sleep quantity and quality and additional efforts to encourage optimal sleep and sleep health should be considered in routine medical examinations. Ongoing research designed to test treatments for obesity, mental distress, or various chronic diseases should also consider assessing the impact of these treatments on sleep health. PMID- 23360348 TI - Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kalpha. AB - PI3Kalpha has been identified as an oncogene in human tumors. By use of rational drug design, a targeted covalent inhibitor 3 (CNX-1351) was created that potently and specifically inhibits PI3Kalpha. We demonstrate, using mass spectrometry and X-ray crystallography, that the selective inhibitor covalently modifies PI3Kalpha on cysteine 862 (C862), an amino acid unique to the alpha isoform, and that PI3Kbeta, -gamma, and -delta are not covalently modified. 3 is able to potently (EC(50) < 100 nM) and specifically inhibit signaling in PI3Kalpha-dependent cancer cell lines, and this leads to a potent antiproliferative effect (GI(50) < 100 nM). A covalent probe, 8 (CNX-1220), which selectively bonds to PI3Kalpha, was used to investigate the duration of occupancy of 3 with PI3Kalpha in vivo. This is the first report of a PI3Kalpha-selective inhibitor, and these data demonstrate the biological impact of selectively targeting PI3Kalpha. PMID- 23360349 TI - Preventable maternal mortality in Morocco: the role of hospitals. AB - OBJECTIVE: In 2009, the Ministry of Health of Morocco launched a national confidential enquiry around maternal deaths based on the newly implemented routine maternal death surveillance system (MDSS). The objective of this paper is to show the importance of substandard care among the factors associated with maternal deaths. METHODS: The Moroccan National Expert Committee (NEC) organised an audit of maternal deaths identified by the MDSS to determine the medical cause, the preventability of the deaths and the type of substandard care involved. RESULTS: Three hundred and three cases of maternal deaths were analysed for the year 2009. Direct causes accounted for 80.8%. 75.9% were considered avoidable by the NEC. The three main factors were insufficient follow-up of care in 45.6% of cases, inadequate treatment in 43.9% and delay in seeking care in 41.3%. The auditors found that 54.3% of all maternal deaths could have been avoided if appropriate action had been taken at the health facilities. CONCLUSION: The audit of maternal deaths in Morocco enabled a better understanding of the circumstances contributing to maternal deaths and pinpointed that more than half of maternal deaths were associated with substandard care in hospitals. PMID- 23360351 TI - Heterogeneity of six children and their mothers with mitochondrial DNA 3243 A>G mutation. AB - To study the clinical, biochemical, and genetic heterogeneity of six Chinese patients and their mothers with the 3243 A>G mutation, six patients (ranging from 5 to 11 years) were hospitalized. All the mothers were healthy. Mitochondrial respiratory chain enzyme activities were determined by spectrophotometry. Mitochondrial gene was analyzed in all patients. Six core pedigrees were investigated. Two patients had mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome and one had Leigh syndrome. The common initial symptoms were headache, vomiting, blurred vision, and epilepsy. m.3243A>G mutation was detected in all patients and their mothers. The mutation loads ranged from 43.6% to 58% and those of their mothers ranged from 14.1% to 28.6%. Varied respiratory chain deficiencies were observed in all patients and two mothers. m.3243A>G mutation can result in a wide spectrum of respiratory chain complex deficiencies. Mitochondrial DNA mutation detected in blood may be likely to transmit to offspring, and the mutation load may increase. PMID- 23360350 TI - Direct head-to-head comparison of cationic liposome-mediated gene delivery to mesenchymal stem/stromal cells of different human sources: a comprehensive study. AB - Nonviral gene delivery to human mesenchymal stem/stromal cells (MSC) can be considered a very promising strategy to improve their intrinsic features, amplifying the therapeutic potential of these cells for clinical applications. In this work, we performed a comprehensive comparison of liposome-mediated gene transfer efficiencies to MSC derived from different human sources-bone marrow (BM MSC), adipose tissue-derived cells (ASC), and umbilical cord matrix (UCM MSC). The results obtained using a green fluorescent protein (GFP)-encoding plasmid indicated that MSC isolated from BM and UCM are more amenable to genetic modification when compared to ASC as they exhibited superior levels of viable, GFP(+) cells 48 hr post-transfection, 58 +/- 7.1% and 54 +/- 3.8%, respectively, versus 33 +/- 4.7%. For all cell sources, high cell recoveries (~50%) and viabilities (>85%) were achieved, and the transgene expression was maintained for 10 days. Levels of plasmid DNA uptake, as well as kinetics of transgene expression and cellular division, were also determined. Importantly, modified cells were found to retain their characteristic immunophenotypic profile and multilineage differentiation capacity. By using the lipofection protocol optimized herein, we were able to maximize transfection efficiencies to human MSC (maximum of 74% total GFP(+) cells) and show that lipofection is a promising transfection strategy for MSC genetic modification, especially when a transient expression of a therapeutic gene is required. Importantly, we also clearly demonstrated that intrinsic features of MSC from different sources should be taken into consideration when developing and optimizing strategies for MSC engineering with a therapeutic gene. PMID- 23360352 TI - An investigation of the relationship between hindlimb lameness and saddle slip. AB - REASONS FOR PERFORMING STUDY: We have observed saddle slip consistently to one side because of a crooked rider, an ill-fitting saddle, asymmetry in a horse's thoracolumbar shape and lameness. Currently, there are no objective data to permit assessment of the relative importance of each factor. OBJECTIVES: To document the frequency of occurrence of saddle slip in horses with hindlimb lameness compared with other horses. To describe the effect of lameness characteristics and grade, the abolition of lameness by diagnostic analgesia, breed, size, thoracolumbar shape and symmetry and the rider's weight. METHODS: One hundred and twenty-eight horses were assessed prospectively, and lameness and saddle slip were assigned a grade before and after diagnostic analgesia. The thoracolumbar shape and symmetry were measured objectively. In 3 horses, the force distribution and magnitude underneath the saddle were measured before and after diagnostic analgesia. RESULTS: The saddle consistently slipped to one side in 38 of 71 horses (54%) with hindlimb lameness, compared with one of 26 horses (4%) with forelimb lameness, none of 20 (0%) with back pain and/or sacroiliac joint region pain and none of 11 sound horses (0%). The association between saddle slip and hindlimb lameness was significant (Spearman's rank correlation coefficient, rho = 0.548, P<0.001). Diagnostic analgesia abolishing the hindlimb lameness eliminated the saddle slip in 37 of 38 horses (97%). In 2 horses, the saddle continued to slip after resolution of lameness; one horse had bilateral forelimb lameness and the other horse had concurrent hindlimb and forelimb lameness. The saddle of both these horses was asymmetrically flocked. The saddle slipped to the side of the lamer hindlimb in most horses (32 of 37 [86%]). No horse with saddle slip had significant left-right asymmetry of the back at 4 predetermined sites. CONCLUSIONS AND CLINICAL RELEVANCE: Hindlimb lameness is an important factor in inducing saddle slip. Saddle slip may be an indicator of the presence of hindlimb lameness. PMID- 23360353 TI - The effect of July admission on inpatient outcomes following spinal surgery. AB - OBJECT: The presence of a "July effect," where the influx of new residents and fellows at teaching hospitals every July may negatively affect patient care and outcomes, is widely debated. The authors used the Nationwide Inpatient Sample (NIS) to identify all cases of spinal surgery and examine outcomes among patients who underwent surgery in July compared with those who underwent surgery in other months. METHODS: Spinal surgery hospitalizations from 2001 to 2008 were identified in the NIS by extracting relevant ICD-9 codes. Rates of in-hospital mortality, discharge to a long-term care facility, and postoperative complications were compared between admission months and between teaching and nonteaching hospitals using the Wilcoxon rank-sum test, Fisher exact test, and multivariate regression analysis. RESULTS: Compared with patients admitted in other months, patients who were admitted to teaching hospitals in July for spinal surgery showed a similar likelihood of in-hospital mortality (OR 0.94 [95% CI 0.78-1.11], p = 0.46), reaction to implanted device/instrumentation (OR 0.88 [95% CI 0.77-1.02], p = 0.09), and postoperative wound dehiscence (OR 1.12 [95% CI 0.94-1.33], p = 0.25). A significantly higher likelihood of discharge to a long term care facility (OR 1.03 [95% CI 1.00-1.07], p = 0.0467) and postoperative infection (OR 1.11 [95% CI 1.05-1.17], p = 0.0341) was observed in teaching hospitals in July compared with other months; however, incidence rates were similar regardless of admission month. Higher-risk patients (Charlson score >= 2) admitted to teaching hospitals in July had a similar likelihood of all outcomes regardless of admission month. CONCLUSIONS: This study of nationwide hospitalizations demonstrates that the influx of new residents and fellows in July has a negligible effect on periprocedural outcomes following spinal surgery. PMID- 23360355 TI - Editorial comment from Dr Saito and Dr Shimizu to intravesical drug delivery for dysfunctional bladder. PMID- 23360354 TI - Diversification and reproductive isolation: cryptic species in the only New World high-duty cycle bat, Pteronotus parnellii. AB - BACKGROUND: Molecular techniques are increasingly employed to recognize the presence of cryptic species, even among commonly observed taxa. Previous studies have demonstrated that bats using high-duty cycle echolocation may be more likely to speciate quickly. Pteronotus parnellii is a widespread Neotropical bat and the only New World species to use high-duty cycle echolocation, a trait otherwise restricted to Old World taxa. Here we analyze morphological and acoustic variation and genetic divergence at the mitochondrial COI gene, the 7th intron region of the y-linked Dby gene and the nuclear recombination-activating gene 2, and provide extensive evidence that P. parnellii is actually a cryptic species complex. RESULTS: Central American populations form a single species while three additional species exist in northern South America: one in Venezuela, Trinidad and western Guyana and two occupying sympatric ranges in Guyana and Suriname. Reproductive isolation appears nearly complete (only one potential hybrid individual found). The complex likely arose within the last ~6 million years with all taxa diverging quickly within the last ~1-2 million years, following a pattern consistent with the geological history of Central and northern South America. Significant variation in cranial measures and forearm length exists between three of the four groups, although no individual morphological character can discriminate these in the field. Acoustic analysis reveals small differences (5-10 kHz) in echolocation calls between allopatric cryptic taxa that are unlikely to provide access to different prey resources but are consistent with divergence by drift in allopatric species or through selection for social recognition. CONCLUSIONS: This unique approach, considering morphological, acoustic and multi-locus genetic information inherited maternally, paternally and bi-parentally, provides strong support to conclusions about the cessation of gene flow and degree of reproductive isolation of these cryptic species. PMID- 23360356 TI - Complexation and extraction of trivalent actinides and lanthanides by triazinylpyridine N-donor ligands. PMID- 23360357 TI - Transient JAK2 V617F mutation in an aplastic anaemia patient with a paroxysmal nocturnal haemoglobinuria clone. PMID- 23360358 TI - On-surface azide-alkyne cycloaddition on Cu(111): does it "click" in ultrahigh vacuum? AB - Using scanning tunneling microscopy, we demonstrate that the 1,3-dipolar cycloaddition between a terminal alkyne and an azide can be performed under solvent-free ultrahigh vacuum conditions with reactants adsorbed on a Cu(111) surface. XPS shows significant degradation of the azide upon adsorption, which is found to be the limiting factor for the reaction. PMID- 23360359 TI - Coenzyme Q10 supplementation and diastolic heart functions in hemodialysis patients: a randomized double-blind placebo-controlled trial. AB - Coenzyme Q10 (CoQ10) supplementation has been shown to improve diastolic heart function in various patient cohorts. Systolic and diastolic dysfunctions are common in patients with end-stage renal disease. Favorable effects of CoQ10 on cardiac functions are yet to be seen in hemodialysis patients. We aimed to evaluate effect of CoQ10 supplementation on diastolic function in a cohort of maintenance hemodialysis patients. This was a prospective, double-blind, placebo controlled, crossover study in which all patients received placebo and oral CoQ10 200 mg/d during the 8 weeks in each phase, with a 4-week washout period. Participants underwent conventional and tissue Doppler echocardiography before and after each study phase. Parameters characterizing left ventricle diastolic function and other standard echocardiographic measurements were recorded. Twenty eight patients were randomized, but 22 patients completed study protocol. Intraventricular septum (IVS) thickness and left ventricle mass were significantly decreased in CoQ10 group (P = 0.03 and P = 0.01, respectively). Myocardial peak systolic and early diastolic velocities derived from IVS were significantly increased (P = 0.048 and P = 0.04, respectively). Isovolumetric relaxation time and E/Em ratio calculated for IVS also significantly reduced in CoQ10 group (p = 0.02 and p = 0.04, respectively). There was no significant difference in any of the studied echocardiographic parameters in placebo group. The results of this study showed that CoQ10 supplementation did not significantly improved diastolic heart functions compared with placebo in maintenance hemodialysis patients. PMID- 23360360 TI - Falling through the cracks: a qualitative study of HIV risks among women who use drugs and alcohol in Northeast India. AB - BACKGROUND: HIV risks for women who inject drugs and those who engage in sex work are well documented. Women who are dependent on non-injecting drugs and alcohol are also likely to have increased vulnerability to HIV infection, but until they actually inject drugs or engage in sex work, are unlikely to come to the attention of HIV prevention programs. METHODS: We undertook a qualitative study involving nine focus group discussions (FGDs) and 27 key informant interviews to investigate the context of female drug and alcohol use in two high HIV prevalence states of India (Manipur and Nagaland) and to describe their HIV risks. The FGD and interview transcripts were thematically analyzed RESULTS: The women were relatively young (mean age 31 years in Manipur and 28 years in Nagaland), but 64% in Manipur and 35% in Nagaland were widowed or divorced. Both heroin and alcohol were commonly used by the women from Manipur, while alcohol was primarily used by the women from Nagaland, especially in the context of 'booze joints' (illicit bars). Reasons for drug and alcohol use included: to avoid symptoms of withdrawal, to suppress emotional pain, to overcome the shame of sex work, pleasure, and widowhood. HIV vulnerability was clearly described, not only in relation to injecting drug use and sex work, but also alcohol consumption. CONCLUSIONS: The contribution of alcohol use to the HIV vulnerability of women is not currently considered when HIV prevention programs are being designed and implemented leaving a group of high-risk women uncovered by much needed services such as treatment for a range of health problems including alcohol dependence. PMID- 23360361 TI - Vesicles composed of fatty acid and N-[3-(dimethylamino)propyl]-octadecanamide: effect of fatty acid chain length on physicochemical properties of vesicles. AB - BACKGROUND AND OBJECTIVES: Vesicles, recently claimed as drug delivery carriers, were prepared by taking advantage of an electrostatic interaction between the carboxylic groups of fatty acids (FAs) and the amino groups of N-[3 (Dimethylamino)propyl]-Octadecanamide (DMAPODA). The study is to find out the effect of FAs' chain length on physicochemical properties of vesicles. METHODS: Decanoic acid (DA), myristic acid (MA), stearic acid (SA) and behenic acid (BA) were used as FAs. Vesicles composed of them and DMAPODA were studied about formation on microscope, calorimetric analysis, size and zeta potential. RESULTS: On microphotographs, all of FAs could form vesicles when mixed with DMAPODA in an equi-molar ratio. However, DA/DMAPODA vesicles were disintegrated during the homogenization. Due to the asymmetry of DA/DMAPODA associate, it seems to hardly form a stable and well-packed bilayer. On thermograms, the vesicles exhibited one strong peak, indicating that FAs can be homogeneously mixed with the cationic amphiphile. The sizes of the four kinds of vesicles suspended in an aqueous solution (final pH 7.5) were in the same order (hundreds of nanometer) on microphotographs. But, on a light scattering machine, the mean size of MA/DMAPODA vesicle was measured to be much greater than those of the other vesicles, possibly because of the low absolute value of the zeta potential. In addition, the medium pH value had a significant effect on the size of BA/DMAPODA vesicle possibly because the zeta potential was strongly dependent on the pH value. CONCLUSION: FAs' chain length would affect the physicochemical properties of vesicles composed of them and DMAPODA. PMID- 23360362 TI - Default mode network connectivity indicates episodic memory capacity in mesial temporal lobe epilepsy. AB - PURPOSE: The clinical relevance of resting state functional connectivity in neurologic disorders, including mesial temporal lobe epilepsy (mTLE), remains unclear. This study investigated how connectivity in the default mode network changes with unilateral damage to one of its nodes, the hippocampus (HC), and how such connectivity can be exploited clinically to characterize memory deficits and indicate postsurgical memory change. METHODS: Functional magnetic resonance imaging (fMRI) resting state scans and neuropsychological memory assessments (Warrington Recognition Tests for Words and Faces) were performed on 19 healthy controls, 20 patients with right mTLE, and 18 patients with left mTLE. In addition, postsurgical fMRI resting state and memory change (postsurgical memory performance-presurgical memory performance) data were available for half of these patients. KEY FINDINGS: Patients with mTLE showed reduced connectivity from the posterior cingulate cortex (PCC) to the epileptogenic HC and increased PCC connectivity to the contralateral HC. Stronger PCC connectivity to the epileptogenic HC was associated with better presurgical memory and with greater postsurgical memory decline. Stronger PCC connectivity to the contralateral HC was associated with less postsurgical memory decline. Following surgery, PCC connectivity to the remaining HC increased from presurgical values and showed enhanced correlation with postsurgical memory function. It is notable that this index was superior to others (hippocampal volume, preoperative memory scores) in explaining variance in memory change following surgery. SIGNIFICANCE: Our results demonstrate the striking clinical significance of the brain's intrinsic connectivity in evaluating cognitive capacity and indicating the potential of postsurgical cognitive morbidity in patients with mTLE. PMID- 23360363 TI - Characterization of markers of botanical origin and other compounds extracted from unifloral honeys. AB - The possibility of tracing the botanical and geographical origin of products such as honey has become more important because of market globalization. As a consequence, numerous analytical methods have been applied to the determination of honey authenticity. The scope of the present work is to chromatographically purify and characterize 23 compounds from organic extracts of unifloral (chestnut, linden, orange, acacia, eucalyptus, honeydew) and polyfloral honeys. Of these compounds, 17 were identified as specific markers and were used for botanical discrimination in a previous study based on multivariate statistical analysis of proton nuclear magnetic resonance ((1)H NMR) data. Together with the botanical markers, 6 other substances were isolated and characterized using NMR and mass spectrometry. These phytochemicals belong to several classes, that is, terpenes, organic acids, flavonoids, and others. For the first time, a diacylglyceryl ether and 5 other compounds present in different types of honey were identified and characterized. PMID- 23360364 TI - Control of surface energy of silicon oxynitride films. AB - Microstructure and chemical composition determine the wetting property of solid surfaces. To achieve hydrophobicity or hydrophilicity, recent efforts have mostly focused on designed patterns and sophisticated surface modification. Here we show the fabrication of a dense amorphous silicon oxynitride (SiON) film by simple annealing of perhydropolysilazane (PHPS), which experiences significant and abrupt transition in surface energy as a function of temperature. The polar component of surface energy, derived from contact angle measurements, exhibits an increase of 20-40 times in an annealing temperature window of ~100 degrees C, which leads to a 5-fold increase of its total surface energy. On the basis of the chemical analyses, we propose a compositional gradient in the film. Due to this gradient, the hydrophilic SiON film, for instance, can be used as the bond coat material in a double-layer environmental barrier coating system with outstanding oxidation resistant properties. PMID- 23360365 TI - Electrochemically induced far-infrared difference spectroscopy on metalloproteins using advanced synchrotron technology. AB - New information on a protein's structure, intra- and intermolecular hydrogen bonds, or metal-ligand bond properties can be unraveled in the far-infrared (far IR)-terahertz-domain (600-3 cm(-1) or 18-0.1 THz). In this study, we compare the performances of thermal sources with synchrotron far-IR to record reaction induced Fourier transform infrared (FT-IR) difference signals with proteins in solution. Using the model protein Cu-azurin placed in a short path length electrochemical cell adapted for transmission spectroscopy in vacuum-purged optics, we show that minute spectral shifts induced by metal isotope labeling or temperature changes are detected using the far-IR beamline AILES of the synchrotron SOLEIL. On one hand, these data allow us to identify modes involving Cu-ligand vibrations and pave the way for the analysis of metal sites or metal redox states of proteins not amenable to resonance Raman spectroscopy. On another hand, small band shifts or changes in band intensity upon temperature modifications show that far-IR difference spectroscopy allows one to extract from a complex background hydrogen-bonding signatures directly relevant to the protein function. For Cu-azurin, a temperature-sensitive IR mode involving Cu(II)-His vibrations points to the role of a hydrogen bond between a Cu histidine ligand and the water solvent in tuning the Cu(II)-histidine bond properties. Furthermore, these experimental data support the possible role of a His117-water interaction in electron-transfer activity of Cu-azurin proposed by theoretical studies. PMID- 23360366 TI - Amyloid fiber formation by synthetic peptides derived from the sequence of the protein CsgA of Escherichia coli. AB - We characterized the formation of amyloid fibers by two peptides derived from the CsgA sequence: R5 (133- 151) corresponding to the whole repeating unit R5 and a truncated form of this peptide called R5T (134-143). In the presence of either of the two peptides: an increase in the fluorescence intensity of Thioflavin T was observed; a shift of the absorbance of Congo red was measured; spontaneous formation of amyloid fibers was observed by polarized light as well asatomic force microscopy imaging. Large-size aggregates were observed with R5 while R5T formed fagots of individualized fibers. The infrared spectroscopy analysis revealed the presence of a greater number of intermolecular bonds for R5. In conclusion, a 10 aminoacids peptide derived from the R5 sequence was sufficient for the spontaneous formation of amyloid fibrils but not to form large-size aggregates of fibers. PMID- 23360367 TI - Intrathecal apelin-13 produced different actions in formalin test and tail-flick test in mice. AB - Apelin was identified as natural ligand for APJ, a G protein-coupled receptor. APJ is expressed in spinal cord and dorsal root ganglion. This study was designed to investigate the effects and mechanisms of intrathecally (i.t.) administered apelin-13 on nociceptive response in formalin test and tail-flick test. In formalin test, i.t. injection of apelin-13 (0.3-3 nmol/mouse) had no effect on the nociceptive response in either acute phase (0-10 min) or interphase (10-20 min), but significantly produced hyperalgesic effect in late phase (20-30 min) at the dose of 3 nmol/mouse. The APJ receptor antagonist apelin-13(F13A) and GABAA receptor antagonist bicuculline methiodide, but not opioid receptor antagonist naloxone, significantly blocked the hyperalgesia caused by apelin-13 in late phase, indicating that i.t. apelin-13- induced hyperalgesia was mediated by APJ and GABAA receptor, rather than opioid receptor. However, in tail-flick test, i.t. injected apelin-13 (1 and 3 nmol/mouse) induced a significant antinociceptive effect, which was significantly antagonized by apelin-13(F13A) and naloxone, suggesting APJ and opioid receptor were involved in the antinociception of spinal apelin-13. PMID- 23360368 TI - Synthesis, structural characterization, and electrical properties of new oxygen deficient tetragonal tungsten bronzes Ba2NdTi(2+x)Nb(3-x)O(15-x/2). AB - Oxygen-deficient tetragonal tungsten bronzes ceramics with general formula Ba(2)NdTi(2+x)Nb(3-x)O(15-x/2) (0 <= x <= 1) have been prepared by low temperature solvothermal synthesis with final firing of ceramics at 1100-1300 degrees C in air. Rietveld refinement of X-ray powder diffraction (XRD) and neutron powder diffraction (ND) data at room temperature of Ba(2)NdTi(3)Nb(2)O(14.5) shows that Ba and Nd are ordered on the 15-coordinate and 12-coordinate sites, respectively, Ti and Nb are disordered nonrandomly over the two octahedral sites, and oxygen vacancies locate preferentially in the coordination sphere of Nd and Ti/Nb(2) atoms. Variable frequency impedance measurements show that samples are poor electronic conductors with activation energies ~0.8-1.7 eV, conductivities ~1 * 10(-5) S cm(-1) at ~725 degrees C and with some evidence of oxide ion conduction at high x values. Composition dependence of the dielectric properties shows a transition from classic ferroelectric behavior with Ba(2)NdTi(2)Nb(3)O(15) to a relaxor-like behavior with Ba(2)NdTi(3)Nb(2)O(14.5). At intermediate compositions, both a first-order phase transition and relaxor-like behavior are observed. PMID- 23360369 TI - Synthesis and structure-activity relationships of N-methyl-5,6,7 trimethoxylindoles as novel antimitotic and vascular disrupting agents. AB - Several new series of 5,6,7-trimethoxyindole derivatives were synthesized and their structure-activity relationships (SARs) were studied. Some of these compounds exhibited strong antiproliferative activities in the submicromolar range. N-Methyl-5,6,7-trimethoxylindoles 21 and 31 displayed the highest antiproliferative activities, with IC50 values ranging from 22 to 125 nM in four human cancer cell lines and activated human umbilical vein endothelial cells (HUVECs). In addition to vascular disrupting activity verified by in vitro assays, compounds 21 and 31 displayed much higher selectivity for activated HUVECs versus quiescent HUVECs than those of colchicine and combretastatinA-4. The polymerization of cancer cell tubulin was inhibited and the cell cycle was arrested in the G2/M phase after treatment with 21 and 31. It was showed that 21 disrupted tumor vasculature by use of in vivo assay. Our results suggest that these two new compounds we synthesized may become the promising leads for the development of vascular disrupting agents. PMID- 23360370 TI - Lithium transport through nanosized amorphous silicon layers. AB - Lithium migration in nanostructured electrode materials is important for an understanding and improvement of high energy density lithium batteries. An approach to measure lithium transport through nanometer thin layers of relevant electrochemical materials is presented using amorphous silicon as a model system. A multilayer consisting of a repetition of five [(6)LiNbO3(15 nm)/Si (10 nm)/(nat)LiNbO3 (15 nm)/Si (10 nm)] units is used for analysis, where LiNbO3 is a Li tracer reservoir. It is shown that the change of the relative (6)Li/(7)Li isotope fraction in the LiNbO3 layers by lithium diffusion through the nanosized silicon layers can be monitored nondestructively by neutron reflectometry. The results can be used to calculate transport parameters. PMID- 23360371 TI - Effect of hospital volume on the mortality of congenital diaphragmatic hernia in Japan. AB - BACKGROUND: During the last decade, new supportive modalities and new therapeutic strategies to treat congenital diaphragmatic hernia (CDH) have been introduced. In Japan, the large number of hospitals prevents centralizing infants with CDH in tertiary centers. The aim of this study was to evaluate the correlations between the number of CDH patients, survival rates, and the current strategies employed to treat CDH at the individual hospitals. METHODS: Eighty-three hospitals with 674 CDH cases were analyzed using questionnaires. We classified the hospitals into three groups according to the number of CDH patients treated: Group 1 (G1; more than 21 patients), Group 2 (G2; 11-20 patients), and Group 3 (G3; fewer than 10 patients). RESULTS: The median number of CDH patients in G1, G2, and G3 were 28, 14, and 4, respectively. The overall survival rate was 74.5%. When only the isolated CDH cases with a prenatal diagnosis were included, the overall survival rate was 79.3%. The survival rate of isolated CDH cases with a prenatal diagnosis was significantly higher in G1 than that in G2 or G3 (87.2% vs 75.2% vs 74.3%; P < 0.001). There were no differences in perinatal therapeutic strategies among the three groups. CONCLUSIONS: We concluded that it might therefore be important to centralize infants with CDH, especially those with isolated CDH with a prenatal diagnosis, to tertiary centers in Japan in order to improve the survival rates. PMID- 23360372 TI - Nasal cutaneous infection in a healthy boy caused by Fusarium moniliforme. AB - A healthy 10-year-old Chinese boy developed verrucous plaques on the nose. The fungus was identified as Fusarium moniliforme via culture of biopsy fragments. The patient had normal immune status and was successfully treated with oral itraconazole (100 mg/day) for 2 months and application of oral itraconazole and topical sertaconazole nitrate cream. Fusarium is a ubiquitous hyalohyphomycete isolated from food that is also widespread in the environment and is present at all latitudes. Infections due to this mold may be disseminated or localized. Fusarium species have been known to colonize the cornea, nails, and burn eschars in otherwise healthy patients. Cutaneous and disseminated infections have been reported mostly in immunocompromised hosts. Here we describe an unusual case of localized infection caused by Fusarium moniliforme in an otherwise healthy child, with significant improvement after 2 months of oral itraconazole and topical sertaconazole nitrate cream therapy. PMID- 23360374 TI - Zwitter-wettability and antifogging coatings with frost-resisting capabilities. AB - Antifogging coatings with hydrophilic or even superhydrophilic wetting behavior have received significant attention due to their ability to reduce light scattering by film-like condensation. However, under aggressive fogging conditions, these surfaces may exhibit frost formation or excess and nonuniform water condensation, which results in poor optical performance of the coating. In this paper, we show that a zwitter-wettable surface, a surface that has the ability to rapidly absorb molecular water from the environment while simultaneously appearing hydrophobic when probed with water droplets, can be prepared by using hydrogen-bonding-assisted layer-by-layer (LbL) assembly of poly(vinyl alcohol) (PVA) and poly(acrylic acid) (PAA). An additional step of functionalizing the nano-blended PVA/PAA multilayer with poly(ethylene glycol methyl ether) (PEG) segments produced a significantly enhanced antifog and frost resistant behavior. The addition of the PEG segments was needed to further increase the nonfreezing water capacity of the multilayer film. The desirable high-optical quality of these thin films arises from the nanoscale control of the macromolecular complexation process that is afforded by the LbL processing scheme. An experimental protocol that not only allows for the exploration of a variety of aggressive antifogging challenges but also enables quantitative analysis of the antifogging performance via real-time monitoring of transmission levels as well as image distortion is also described. PMID- 23360373 TI - Disparities in attendance at diabetes self-management education programs after diagnosis in Ontario, Canada: a cohort study. AB - BACKGROUND: Patients newly-diagnosed with diabetes require self-management education to help them understand and manage the disease. The goals of the study were to determine the frequency of diabetes self-management education program utilization by newly-diagnosed patients, and to evaluate whether there were any demographic or clinical disparities in utilization. METHODS: Using population level health care data, all 46,553 adults who were diagnosed with any type of non gestational diabetes in Ontario, Canada between January and June 2006 were identified. They were linked with a diabetes self-management education program registry to identify those who attended within 6 months of diagnosis. The demographic and clinical characteristics of attendees and non-attendees were compared. RESULTS: A total of 9,568 (20.6%) patients attended a diabetes self management education program within 6 months of diagnosis. Younger age, increasing socioeconomic status, and the absence of mental health conditions or other medical comorbidity were associated with attendance. Patients living in rural areas, where access to physicians may be limited, were markedly more likely to attend. Recent immigrants were 40% less likely to attend self-management education programs than longer-term immigrants or nonimmigrants. CONCLUSION: Only one in five newly-diagnosed diabetes patients attended a diabetes self-management education program. Demographic and clinical disparities in utilization persisted despite a publicly-funded health care system where patients could access these services without direct charges. Primary care providers and education programs must ensure that more newly-diagnosed diabetes patients receive self-management education, particularly those who are older, poorer, sicker, or recent immigrants. PMID- 23360375 TI - Extensive genomic characterization of a set of near-isogenic lines for heterotic QTL in maize (Zea mays L.). AB - BACKGROUND: Despite the crucial role that heterosis has played in crop improvement, its genetic and molecular bases are still elusive. Several types of structured populations were used to discover the genetic architecture underlying complex phenotypes, and several QTL related to heterosis were detected. However, such analyses generally lacked the statistical power required for the detailed characterization of individual QTL. Currently, QTL introgression into near isogenic materials is considered the most effective strategy to this end, despite such materials inevitably contain a variable, unknown and undesired proportion of non-isogenic genome.An introgression program based on residual heterozygous lines allowed us to develop five pairs of maize (Zea mays L.) near-isogenic lines (NILs) suitable for the fine characterization of three major heterotic QTL previously detected. Here we describe the results of the detailed genomic characterization of these NILs that we undertook to establish their genotypic structure, to verify the presence of the expected genotypes within target QTL regions, and to determine the extent and location of residual non-isogenic genomic regions. RESULTS: The SNP genotyping approach allowed us to determine the parent-of-origin allele for 14,937 polymorphic SNPs and to describe in detail the genotypic structure of all NILs. The correct introgression was confirmed for all target QTL in the respective NIL and several non-isogenic regions were detected genome-wide. Possible linkage drag effects associated to the specific introgressed regions were observed. The extent and position of other non-isogenic regions varied among NIL pairs, probably deriving from random segregating sections still present at the separation of lineages within pairs. CONCLUSIONS: The results of this work strongly suggest that the actual isogenicity and the genotypic architecture of near-isogenic materials should be monitored both during the introgression procedure and on the final materials as a paramount requisite for a successful mendelization of target QTL. The information here gathered on the genotypic structure of NILs will be integrated in future experimental programs aimed at the fine mapping and isolation of major heterotic QTL, a crucial step towards the understanding of the molecular bases of heterosis in maize. PMID- 23360376 TI - Editorial comment to interleukin-6 levels in female rats with protamine sulfate induced chronic cystitis treated with hyaluronic acid. PMID- 23360377 TI - Vector production in an academic environment: a tool to assess production costs. AB - Generating gene and cell therapy products under good manufacturing practices is a complex process. When determining the cost of these products, researchers must consider the large number of supplies used for manufacturing and the personnel and facility costs to generate vector and maintain a cleanroom facility. To facilitate cost estimates, the Indiana University Vector Production Facility teamed with the Indiana University Kelley School of Business to develop a costing tool that, in turn, provides pricing. The tool is designed in Microsoft Excel and is customizable to meet the needs of other core facilities. It is available from the National Gene Vector Biorepository. The tool allows cost determinations using three different costing methods and was developed in an effort to meet the A21 circular requirements for U.S. core facilities performing work for federally funded projects. The costing tool analysis reveals that the cost of vector production does not have a linear relationship with batch size. For example, increasing the production from 9 to18 liters of a retroviral vector product increases total costs a modest 1.2-fold rather than doubling in total cost. The analysis discussed in this article will help core facilities and investigators plan a cost-effective strategy for gene and cell therapy production. PMID- 23360378 TI - Quantum dots as templates for self-assembly of photoswitchable polymers: small, dual-color nanoparticles capable of facile photomodulation. AB - A photomodulatable amphiphilic polymer has been synthesized with a backbone of poly[isobutylene-alt-maleic anhydride] and pendant dodecyl alkyl chains, Lucifer Yellow (LY) fluorescent probes, and diheteroarylethenes photochromic (PC) groups. The latter serve as reversible UV-activated FRET acceptors for the LY donors. We characterized the spectral and switching properties of the polymer in an organic solvent (CHCl(3)). In an aqueous medium the polymer forms polymersomes, constituting fluorescence probes ~75 nm in diameter. Self-assembly of the polymer on the surface of a quantum dot (QD) serving as a template creates a dual-color photoswitchable nanoparticle (psNP) with improved properties due to the increase in polymer density and efficiency of PC photoconversion. The psNP exhibits a second QD red emission band that functions as an internal standard requiring only a single excitation wavelength, and is much reduced in size (<20 nm diameter) compared to the polymersomes. The QD template also greatly increases the depth of modulation by photochromic FRET of the LY emission monitored by both steady-state and time-resolved (lifetime) fluorescence (from 20%->70%, and from 12%->55%, respectively). PMID- 23360380 TI - Bifunctional ruthenium(II) hydride complexes with pendant strong Lewis acid moieties: structure, dynamics, and cooperativity. AB - The synthesis of a novel class of bifunctional ruthenium hydride complexes incorporating Lewis acidic BR(2) moieties is reported. Determination of the molecular structures in the solid state and in solution provided evidence for tunable interaction between the two functionalities. Cooperative effects on the reactivity of the complexes were demonstrated including the activation of small Lewis basic molecules by reversible anchoring at the boron center. PMID- 23360381 TI - The complete mitochondrial genome of Liobagrus kingi (Teleostei, Siluriformes: Amblycipitidae). AB - Liobagrus kingi is endemic to southwest China and listed as endangered species (IUCN 2012). Genetic diversity is necessary for conservation issue. In studying this, the complete mitochondrial genome sequence of L. kingi has been obtained with PCR, which contains 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a non-coding control region with the total length of 16,483 bp. The gene arrangement and composition are similar to that of other vertebrates. Most of the genes are encoded on heavy strand, except for eight tRNA and ND6 genes. Just like most other vertebrates, the against bias of G has a universality in different statistical results. The complete mitochondrial genome sequence of L. kingi would contribute to better understand population genetics and protect its genetic diversity. PMID- 23360382 TI - Patients with a history of spine surgery or spinal injury may have a higher chance of intrathecal catheter granuloma formation. AB - BACKGROUND GOALS: Intrathecal drug delivery is an effective method to treat intractable pain. However, intrathecal catheter tip granuloma (ICTG) is a devastating complication of intrathecal drug delivery systems. It typically occurs in the thoracic region; particularly, in patients receiving high doses or high concentrations of intrathecal drug infusions. MATERIALS AND METHODS: The PUBMED/MEDLINE and Cochrane databases were also systematically searched for all reports on ICTG published in any language. The key words included "intrathecal," "granuloma," and "spine surgery," and all related publications between the earliest available date (the first granuloma-related chronic complication of intrathecal infusion reported in PUBMED/MEDLINE in 1996) and June (week 1) of 2012 were searched. This case report is unique because it describes the formation of an intrathecal granuloma in the lumbar region of a patient who received a low dose intrathecal infusion. RESULTS AND CONCLUSION: Cerebrospinal fluid flow dynamics within the spinal canal along with the physical, chemical, and immunological properties of intrathecal medications have been suggested to be responsible for the growth of inflammatory mass lesions at the tips of intrathecal drug delivery catheters. Our literature review supports the possible role of certain factors, specifically previous spine surgery or spinal injury, in granuloma formation. The rate of development of ICTG appears to be higher in patients who have had previous spine surgery or spinal injury (68%) than in a general cohort of patients (48%), with an intrathecal pump. Therefore patients with a history of spine surgery or injury may be at increased risk of ICTG when receiving chronic intrathecal analgesia. PMID- 23360383 TI - Arthropod intermediate hosts of Abbreviata antarctica (Nematoda: Physalopteridae) in Australia. AB - This study examines potential arthropod intermediate hosts for the nematode Abbreviata antarctica. Five species of arthropod (tropical native cricket Teleogryllus oceanicus; native roach Drymoplaneta communis; native termite Nasutitermes exitiosus; and 2 introduced species, the East African roach Naupheta cinerea and the Asian cricket Acheta domesticus) were fed feces from a skink, Tiliqua rugosa, containing embryonated eggs of A. antarctica . The insects were dissected at 4 intervals (1 day, 4 days, 8-16 days, and 25-26 days). Viable third stage larvae were recovered from cysts on the external wall of the midgut and hindgut of 62.5% nymphal and adult T. oceanicus crickets at 25-26 days post infection and from a single nymphal A. domesticus cricket. No roaches contained eggs or first-stage larvae after 48 hr, and neither eggs nor larvae were found in termites. PMID- 23360384 TI - Sinusoidal endothelial cells are damaged and display enhanced autophagy in myelodysplastic syndromes. PMID- 23360385 TI - Temporal changes in concentrations of lipids and apolipoprotein B among adults with diagnosed and undiagnosed diabetes, prediabetes, and normoglycemia: findings from the National Health and Nutrition Examination Survey 1988-1991 to 2005-2008. AB - BACKGROUND: Diabetes is characterized by profound lipid abnormalities. The objective of this study was to examine changes in concentrations of lipids and apolipoprotein B among participants stratified by glycemic status (diabetes, undiagnosed diabetes, prediabetes, and normoglycemia) in the United States from 1988-1991 to 2005-2008. METHODS: We used data from 3202 participants aged >=20 years from the National Health and Nutrition Examination Survey (NHANES) III (1988-1991) and 3949 participants aged >=20 years from NHANES 2005-2008. RESULTS: Among participants of all four groups, unadjusted and adjusted mean concentrations of total cholesterol, low-density lipoprotein cholesterol, non high-density lipoprotein cholesterol, and apolipoprotein B, but not triglycerides, decreased significantly. Among participants with prediabetes and normoglycemia, unadjusted and adjusted mean concentrations of high-density lipoprotein cholesterol increased significantly. Adjusted mean log-transformed concentrations of triglycerides decreased in adults with undiagnosed diabetes and prediabetes. During 2005-2008, unadjusted concentrations of apolipoprotein B >=80 mg/dl were observed in 72.8% of participants with diagnosed diabetes, 87.9% of participants with undiagnosed diabetes, 86.6% of participants with prediabetes, and 77.2% of participants with normoglycemia. The unadjusted use of cholesterol lowering medications rose rapidly, especially among participants with diabetes (from ~1% to ~49%, P <0.001). The use of fenofibrate, gemfibrozil, and niacin rose significantly only among adults with diagnosed diabetes (from ~2% to ~8%, P = 0.011). CONCLUSION: Lipid profiles of adults with diabetes improved during the approximately 16-year study period. Nevertheless, large percentages of adults continue to have elevated concentrations of apolipoprotein B. PMID- 23360387 TI - Agropyrenol, a phytotoxic fungal metabolite, and its derivatives: a structure activity relationship study. AB - Agropyrenol is a phytotoxic substituted salicylic aldehyde produced in liquid culture by Ascochyta agropyrina var. nana , a potential mycoherbicide proposed for the control of the perennial weed Elytrigia repens. In this study, six derivatives obtained by chemical modifications of the toxin were assayed for phytotoxic, antimicrobial, and zootoxic activities, and the structure-activity relationships were examined. Each compound was tested on non-host weedy and agrarian plants, fungi, Gram-positive and Gram-negative bacteria, and brine shrimp larvae. The results provide insights into the structure-activity relationships of agropyrenol. Both the double bond and the diol system of the 3,4 dihydroxypentenyl side chain as well as the aldehyde group at C-1 of the phenolic ring of agropyrenol proved to be important for the phytotoxicity. The lesser polar 3',4'-O,O'-isopropylidene of agropyrenol also showed significant zootoxic and slight antimicrobial activities. This finding could be useful in devising new natural herbicides for practical application in agriculture. PMID- 23360388 TI - Sinus node dysfunction: an adverse effect of lacosamide. AB - Lacosamide, a recently introduced antiepileptic drug, acts by enhancing the slow inactivation of voltage-dependent sodium channels. Cardiac conduction disturbances, namely atrial fibrillation and atrioventricular block, have been reported in patients with epilepsy. We report a patient with drug-resistant focal epilepsy who developed asymptomatic sinus node dysfunction following lacosamide use, which resolved on stopping lacosamide. This is the first report of sinus node dysfunction associated with lacosamide therapy. PMID- 23360386 TI - The genetics of human obesity. AB - It has long been known that there is a genetic component to obesity, and that characterizing this underlying factor would likely offer the possibility of better intervention in the future. Monogenic obesity has proved to be relatively straightforward, with a combination of linkage analysis and mouse models facilitating the identification of multiple genes. In contrast, genome-wide association studies have successfully revealed a variety of genetic loci associated with the more common form of obesity, allowing for very strong consensus on the underlying genetic architecture of the phenotype for the first time. Although a number of significant findings have been made, it appears that very little of the apparent heritability of body mass index has actually been explained to date. New approaches for data analyses and advances in technology will be required to uncover the elusive missing heritability, and to aid in the identification of the key causative genetic underpinnings of obesity. PMID- 23360389 TI - Rapid antibiotic susceptibility testing in a microfluidic pH sensor. AB - For appropriate selection of antibiotics in the treatment of pathogen infection, rapid antibiotic susceptibility testing (AST) is urgently needed in clinical practice. This study reports the utilization of a microfluidic pH sensor for monitoring bacterial growth rate in culture media spiked with different kinds of antibiotics. The microfluidic pH sensor was fabricated by integration of pH sensitive chitosan hydrogel with poly(dimethylsiloxane) (PDMS) microfluidic channels. For facilitating the reflectometric interference spectroscopic measurements, the chitosan hydrogel was coated on an electrochemically etched porous silicon chip, which was used as the substrate of the microfluidic channel. Real-time observation of the pH change in the microchannel can be realized by Fourier transform reflectometric interference spectroscopy (FT-RIFS), in which the effective optical thickness (EOT) was selected as the optical signal for indicating the reversible swelling process of chitosan hydrogel stimulated by pH change. With this microfluidic pH sensor, we demonstrate that confinement of bacterial cells in a nanoliter size channel allows rapid accumulation of metabolic products and eliminates the need for long-time preincubation, thus reducing the whole detection time. On the basis of this technology, the whole bacterial growth curve can be obtained in less than 2 h, and consequently rapid AST can be realized. Compared with conventional methods, the AST data acquired from the bacterial growth curve can provide more detailed information for studying the antimicrobial behavior of antibiotics during different stages. Furthermore, the new technology also provides a convenient method for rapid minimal inhibition concentration (MIC) determination of individual antibiotics or the combinations of antibiotics against human pathogens that will find application in clinical and point-of-care medicine. PMID- 23360390 TI - Phosphorylation regulates TRPV1 association with beta-arrestin-2. AB - Post-translational modifications in TRPV1 (transient receptor potential vanilloid 1) play a critical role in channel activity. Phosphorylation of serine/threonine residues within the N- and C-termini of TRPV1 are implicated in receptor sensitization and activation. Conversely, TRPV1 desensitization occurs via a calcium-dependent mechanism and leads to receptor de-phosphorylation. Importantly, we recently demonstrated that TRPV1 association with beta-arrestin-2 is critical to receptor desensitization via its ability to scaffold the phosphodiesterase PDE4D5 to the receptor, regulating TRPV1 phosphorylation. In the present study, we demonstrate that phosphorylation of TRPV1 and beta-arrestin 2 regulates this association at the membrane. Under serum-free media conditions, we observed a significant decrease in TRPV1 and beta-arrestin-2 association in transfected CHO (Chinese-hamster ovary) cells. Pharmacological activation of the kinases PKA (protein kinase A) and PKC (protein kinase C) led to a robust increase in TRPV1 and beta-arrestin-2 association, whereas inhibition of PKA and PKC decreased association. Previously, we identified potential PKA residues (Ser(116), Thr(370)) in the N-terminus of TRPV1 modulated by beta-arrestin-2. In the present study we reveal that the phosphorylation status of Thr(370) dictates the beta-arrestin-2 and TRPV1 association. Furthermore, we demonstrate that CK2 (casein kinase 2)-mediated phosphorylation of beta-arrestin-2 at Thr(382) is critical for its association with TRPV1. Taken together, the findings of the present study suggest that phosphorylation controls the association of TRPV1 with beta-arrestin-2. PMID- 23360391 TI - Brief report: Comparison of continuous glucose monitoring and finger-prick blood glucose levels in hospitalized patients administered basal-bolus insulin. AB - BACKGROUND: Previous studies have assessed the efficacy of basal-bolus insulin (BBI) in hospitalized patients by measuring four finger-prick blood glucose levels (BGLs) per day. The aim of this study was to investigate whether this BGL monitoring regimen provides an accurate reflection of glycemia in hospitalized patients administered BBI. We hypothesized that, as three of four readings are preprandial, finger-prick BGLs would underestimate the mean glucose concentration. SUBJECTS AND METHODS: Twenty-six consecutive consenting subjects with type 1 (n=3) or type 2 (n=23) diabetes mellitus admitted to the hospital and administered insulin glargine once daily and rapid-acting insulin before meals underwent continuous glucose monitoring for up to 72 h. Finger-prick BGLs were performed before each main meal (0700, 1200, and 1700 h) and at 2100 h. RESULTS: Mean daily glucose concentration was not significantly different when assessed by continuous glucose monitoring and finger-prick BGLs (9.6+/-2.4 vs. 9.6+/-2.7 mmol/L, P=0.84). A Bland-Altman plot revealed some variability but no bias between the two methods of measurement of glucose concentration. There were 88 postprandial hyperglycemic excursions recorded on continuous glucose monitoring; 61 (69%) were identified by finger-prick BGL monitoring. There were 10 glucose excursions <4 mmol/L during continuous glucose monitoring; only one was detected by finger-prick BGL monitoring. CONCLUSIONS: Traditional finger-prick BGL monitoring provides a reasonable approximation of mean daily glucose concentration in the majority of hospitalized patients receiving BBI but underestimates the prevalence of postprandial hyperglycemia and hypoglycemia. PMID- 23360392 TI - Elucidation of the molecular interaction between cisplatin and flavonol(s) and their effect on DNA binding. AB - Combination therapy of cisplatin with flavonols is a promising treatment for increasing the efficacy of cisplatin when combating cancer. However, little is known about the molecular interactions between cisplatin and flavonols. The data herein helps to elucidate this interaction. Spectrophotometric data in the UV visible range indicates that hydroxyl groups on the B-ring of flavonols are essential for reactivity with cisplatin. The use of a quartz crystal microbalance with dissipation monitoring approach clearly supports the critical role played by B-ring hydroxyls in their interactions with a cisplatin-bound double-stranded DNA surface; an increase in the number of hydroxyl groups on the B-ring of flavonols parallels the increase in their reaction rates with cisplatin and correlates well with their reported effects on leukemia cell apoptosis efficacy. This study underscores the importance of B-ring hydroxyls in cisplatin's toxicity and may be used to better understand and improve combination therapies of flavonols with cisplatin. PMID- 23360393 TI - Reactivity of a mononuclear iridium(I) species bearing a terminal phosphido fragment embedded in a triphosphorus ligand. AB - The first example of an iridium(I) species bearing a terminal phosphido (PR(2)( )) ligand is reported. This stable compound shows well-behaved reactivity toward various electrophiles, owing to its exposed phosphorus lone pair, allowing reversible protonation, selective alkylation, isolation of a phosphidoborane of iridium, and generation of a phosphido-bridged iridium(I)-gold(I) dinuclear species. PMID- 23360394 TI - Revealing the interfacial self-assembly pathway of large-scale, highly-ordered, nanoparticle/polymer monolayer arrays at an air/water interface. AB - The pathway of interfacial self-assembly of large-scale, highly ordered 2D nanoparticle/polymer monolayer or bilayer arrays from a toluene solution at an air/water interface was investigated using grazing-incidence small-angle scattering at a synchrotron source. Interfacial-assembly of the ordered nanoparticle/polymer array was found to occur through two stages: formation of an incipient randomly close-packed interfacial monolayer followed by compression of the monolayer to form a close-packed lattice driven by solvent evaporation from the polymer. Because the nanoparticles are hydrophobic, they localize exclusively to the polymer-air interface during self-assembly, creating a through thickness asymmetric film as confirmed by X-ray reflectivity. The interfacial self-assembly approach can be extended to form binary NP/polymer arrays. It is anticipated that by understanding the interfacial self-assembly pathway, this simple evaporative procedure could be conducted as a continuous process amenable to large area nanoparticle-based manufacturing needed for emerging energy technologies. PMID- 23360395 TI - Major characteristics of Staphylococcus aureus colonizing Jordanian infants. AB - BACKGROUND: Colonization of infants with methicillin-resistant Staphylococcus aureus (MRSA) carries specific toxin genes. In particular, Panton-Valentine leukocidin (PVL) are a risk factor for subsequent infection during hospitalization. This prospective study investigated important epidemiological characteristics of Staphylococcus aureus colonizing the nares and intestines of Jordanian infants. METHODS: A total of 860 nasal and stool specimens were obtained from each of the 430 infants admitted to the neonatal intensive care unit or referred to outpatient clinics of Jordan University Hospital. All specimens were cultured to recover S. aureus, all isolates were tested for antimicrobial susceptibility and the MRSA strains for presence of specific toxin genes and SCCmec using polymerase chain reaction. RESULTS: Eighty of the 430 (18.6%) infants were colonized with S. aureus, of these, 27 (6.3%) harbored the organism in both the nose and intestine. The frequency of S. aureus nasal and intestinal carriage in outpatient infants compared to inpatients admitted to the neonatal intensive care unit was significantly higher (27.3% vs 2.8%) and (17.1% vs 2.3%), respectively. MRSA accounted for 57/107 (53.3%) of all isolates, and of these 16/57 (28%) were PVL-positive and carried SCCmec type IV, except one, which was type III. All nasal and intestinal MRSA carried at least one toxin gene (tst, eta, seb), but few carried two toxin genes. CONCLUSION: This study demonstrates that S. aureus strains are more frequently colonizing Jordanian outpatient infants than inpatients and all MRSA strains carried 1-3 clinically important staphylococcal toxin genes. Further studies are needed to investigate the role of these toxins in hospitalized infants. PMID- 23360396 TI - Psoriasis from a prosthesis: unusual Koebner phenomenon in a girl with autoamputation of the leg. AB - An 8-year-old girl showed psoriatic lesions confined to her autoamputated left thigh. She was wearing an above-the-knee prosthesis that induced plaque psoriasis by koebnerization. Rapid clinical remission was achieved using tacrolimus 0.03% ointment. PMID- 23360397 TI - Fertility desire and intention of people living with HIV/AIDS in Tanzania: a call for restructuring care and treatment services. AB - BACKGROUND: Scaling up of antiretroviral therapy (ART) is currently underway in sub-Saharan Africa including, Tanzania, increasing survival of people living with HIV/AIDS (PLWHA). Programmes pay little attention to PLWHA's reproductive health needs. Information on fertility desire and intention would assist in the integration of sexual and reproductive health in routine care and treatment clinics. METHODS: A cross-sectional study of all PLWHA aged 15-49 residing in Kahe ward in rural Kilimanjaro Tanzania was conducted. Participants were recruited from the community and a local counselling centre located in the ward. Data on socio-demographic, medical and reproductive characteristics were collected through face-to-face interviews. Data were entered and analysed using STATA statistical software. RESULTS: A total of 410 PLWHA with a mean age of 34.2 and constituting 264 (64.4%) females participated. Fifty-one per cent reported to be married/cohabiting, 73.9% lived with their partners and 60.5% were sexually active. The rate of unprotected sex was 69.0% with 12.5% of women reporting to be pregnant at the time of the survey. Further biological children were desired by 37.1% of the participants and lifetime fertility intention was 2.4 children. Increased fertility desire was associated with living and having sex with a partner, HIV disclosure, good perceived health status and CD4 count >=200 cells for both sexes. Reduced desire was associated with havingmore than 2 children among females, divorce or separation, and having a child with the current partner among both males and females. CONCLUSION: Fertility desire and intention of PLWHA was substantially high though lower than that of the general population in Tanzania. Practice of unprotected sexual intercourse with higher pregnancy rate was observed. Fertility desire was determined by individual perceived health and socio-family related factors. With increasing ART coverage and subsequent improved quality of life of PLWHA, these findings underscore the importance of integrating reproductive health services in the routine care and treatment of HIV/AIDS worldwide. The results also highlight a group of PLWHA with potentially high desire for children who need to be targeted during care. PMID- 23360398 TI - Induction of aberrant vascular growth, but not of normal angiogenesis, by cell based expression of different doses of human and mouse VEGF is species-dependent. AB - Therapeutic angiogenesis by vascular endothelial growth factor (VEGF) gene delivery is an attractive approach to treat ischemia. VEGF remains localized around each producing cell in vivo, and overexpression of mouse VEGF(164) (mVEGF(164)) induces normal or aberrant angiogenesis, depending strictly on its dose in the microenvironment in vivo. However, the dose-dependent effects of the clinically relevant factor, human VEGF(165) (hVEGF(165)), are unknown. Here we exploited a highly controlled gene delivery platform, based on clonal populations of transduced myoblasts overexpressing specific VEGF levels, to rigorously compare the in vivo dose-dependent effects of hVEGF(165) and mVEGF(164) in skeletal muscle of severe combined immune deficient (SCID) mice. While low levels of both factors efficiently induced similar amounts of normal angiogenesis, only high levels of mVEGF(164) caused widespread angioma-like structures, whereas equivalent or even higher levels of hVEGF(165) induced exclusively normal and mature capillaries. Expression levels were confirmed both in vitro and in vivo by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). However, in vitro experiments showed that hVEGF(165) was significantly more effective in activating VEGF receptor signaling in human endothelial cells than mVEGF(164), while the opposite was true in murine endothelial cells. In conclusion, we found that, even though hVEGF is similarly efficient to the syngenic mVEGF in inducing angiogenesis at lower doses in a widely adopted and convenient mouse preclinical model, species-dependent differences in the relative activation of the respective receptors may specifically mask the toxic effects of high doses of the human factor. PMID- 23360399 TI - miR-296-3p, miR-298-5p and their downstream networks are causally involved in the higher resistance of mammalian pancreatic alpha cells to cytokine-induced apoptosis as compared to beta cells. AB - BACKGROUND: The molecular bases of mammalian pancreatic alpha cells higher resistance than beta to proinflammatory cytokines are very poorly defined. MicroRNAs are master regulators of cell networks, but only scanty data are available on their transcriptome in these cells and its alterations in diabetes mellitus. RESULTS: Through high-throughput real-time PCR, we analyzed the steady state microRNA transcriptome of murine pancreatic alpha (alphaTC1-6) and beta (betaTC1) cells: their comparison demonstrated significant differences. We also characterized the alterations of alphaTC1-6 cells microRNA transcriptome after treatment with proinflammatory cytokines. We focused our study on two microRNAs, miR-296-3p and miR-298-5p, which were: (1) specifically expressed at steady state in alphaTC1-6, but not in betaTC1 or INS-1 cells; (2) significantly downregulated in alphaTC1-6 cells after treatment with cytokines in comparison to untreated controls. These microRNAs share more targets than expected by chance and were co expressed in alphaTC1-6 during a 6-48 h time course treatment with cytokines. The genes encoding them are physically clustered in the murine and human genome. By exploiting specific microRNA mimics, we demonstrated that experimental upregulation of miR-296-3p and miR-298-5p raised the propensity to apoptosis of transfected and cytokine-treated alphaTC1-6 cells with respect to alphaTC1-6 cells, treated with cytokines after transfection with scramble molecules. Both microRNAs control the expression of IGF1Rbeta, its downstream targets phospho-IRS 1 and phospho-ERK, and TNFalpha. Our computational analysis suggests that MAFB (a transcription factor exclusively expressed in pancreatic alpha cells within adult rodent islets of Langerhans) controls the expression of miR-296-3p and miR-298 5p. CONCLUSIONS: Altogether, high-throughput microRNA profiling, functional analysis with synthetic mimics and molecular characterization of modulated pathways strongly suggest that specific downregulation of miR-296-3p and miR-298 5p, coupled to upregulation of their targets as IGF1Rbeta and TNFalpha, is a major determinant of mammalian pancreatic alpha cells resistance to apoptosis induction by cytokines. PMID- 23360400 TI - Inhibition of tau filament formation by conformational modulation. AB - Antiaggregation drugs play an important role in therapeutic approaches for Alzheimer's disease. Although a large number of small molecules that inhibit the aggregation of the tau protein have been identified, little is known about their mode of action. Here, we reveal the mechanism and the nature of tau species that are generated by interaction of tau with the organic compound pthalocyanine tetrasulfonate (PcTS). We demonstrate that PcTS interferes with tau filament formation by targeting the protein into soluble oligomers. A combination of NMR spectroscopy, electron paramagnetic resonance, and small-angle X-ray scattering reveals that the soluble tau oligomers contain a dynamic, noncooperatively stabilized core with a diameter of 30-40 nm that is distinct from the core of tau filaments. Our results suggest that specific modulation of the conformation of tau is a viable strategy for reduction of pathogenic tau deposits. PMID- 23360402 TI - Biomphalaria straminea and Biomphalaria glabrata (Mollusca: Planorbidae) as new intermediate hosts of the fish eyefluke Austrodiplostomum compactum (Trematoda: Diplostomidae) in Brazil. AB - Austrodiplostomum compactum has been involved in cases of ocular diplostomiasis in several species of fish in Brazil, but the molluscan intermediate hosts of the parasite remain unknown. In the present study, malacological surveys were carried out at Pampulha Reservoir, Belo Horizonte, Minas Gerais, Brazil, between January 2009 and July 2012. A total of 16,119 specimens of Biomphalaria spp. were collected and examined, of which 68/14,948 specimens (0.45%) of Biomphalaria straminea and 6/541 (1.11%) of Biomphalaria glabrata were found harboring a strigeid cercariae. Groups of 5 specimens of Cyprinius carpio were experimentally infected with these cercariae (100 larvae/fish), and metacercariae were recovered from the eyes of the fish, 65 days after infection, with a mean intensity of infection of 10.4 (8-13) metacercariae/fish. Morphological study on cercariae and metacercariae identified them as A. compactum . This is the first record of cercariae of A. compactum in Brazil, and B. straminea and B. glabrata as new intermediate hosts for the parasite. PMID- 23360401 TI - Motor cortex electrical stimulation promotes axon outgrowth to brain stem and spinal targets that control the forelimb impaired by unilateral corticospinal injury. AB - We previously showed that electrical stimulation of motor cortex (M1) after unilateral pyramidotomy in the rat increased corticospinal tract (CST) axon length, strengthened spinal connections, and restored forelimb function. Here, we tested: (i) if M1 stimulation only increases spinal axon length or if it also promotes connections to brain stem forelimb control centers, especially magnocellular red nucleus; and (ii) if stimulation-induced increase in axon length depends on whether pyramidotomy denervated the structure. After unilateral pyramidotomy, we electrically stimulated the forelimb area of intact M1, to activate the intact CST and other corticofugal pathways, for 10 days. We anterogradely labeled stimulated M1 and measured axon length using stereology. Stimulation increased axon length in both the spinal cord and magnocellular red nucleus, even though the spinal cord is denervated by pyramidotomy and the red nucleus is not. Stimulation also promoted outgrowth in the cuneate and parvocellular red nuclei. In the spinal cord, electrical stimulation caused increased axon length ipsilateral, but not contralateral, to stimulation. Thus, stimulation promoted outgrowth preferentially to the sparsely corticospinal innervated and impaired side. Outgrowth resulted in greater axon density in the ipsilateral dorsal horn and intermediate zone, resembling the contralateral termination pattern. Importantly, as in spinal cord, increase in axon length in brain stem also was preferentially directed towards areas less densely innervated by the stimulated system. Thus, M1 electrical stimulation promotes increases in corticofugal axon length to multiple M1 targets. We propose the axon length change was driven by competition into an adaptive pattern resembling lost connections. PMID- 23360403 TI - What are functional ionic liquids for the absorption of acidic gases? AB - As a kind of novel and efficient material, ionic liquids (ILs) are used for capture of acidic gases including SO2 and CO2 from flue gas. Due to very low content of acidic gases in flue gas, it is important to find functional ILs to absorb the acidic gases. However, up to now, there is no criterion to distinguish if the ILs are functional or not before use, which greatly influences the design of functional ILs. In this work, a series of ILs were synthesized and used to determine functional or normal ILs for the capture of acidic gases. It has been found that the pKa of organic acids forming the anion of ILs can be used to differentiate functional ILs from normal ILs for the capture of acidic gases from flue gas. If the pKa of an organic acid is larger than that of sulfurous acid (or carbonic acid), the ILs formed by the organic acid can be called functional ILs for SO2 (or CO2) capture, and it can have a high absorption capacity of SO2 (or CO2) with low SO2 (or CO2) concentrations. If not, the IL is just a normal IL. The pKa of organic acids can also be used to explain the absorption mechanism and guide the synthesis of functional ILs. PMID- 23360404 TI - The effect of fibrinogen, collagen type I, and fibronectin on mesenchymal stem cell growth and differentiation into osteoblasts. AB - We have shown that human mesenchymal stem cells (hMSCs) have the potential to differentiate into bone when seeded within three-dimensional (3-D) fibrin constructs. Proteins endogenous to the fibrin construct and those secreted by cells in the 3-D constructs provide cues that can promote differentiation of hMSCs along with mechanical support for cell growth and migration. In this study, we decided to take a step back and examine the effect different extracellular matrix (ECM) proteins--fibrinogen, fibronectin, and collagen type I--had on hMSC osteogenic differentiation on two-dimensional (2-D) monolayer cultures. Briefly, 24-well tissue culture plates pre-coated with either fibrinogen (10 mg/mL), fibronectin (10 MUg/mL), or collagen type I (1 mg/mL) were seeded with 25,000 cells/well and cultured in normal growth medium or in osteogenic induction medium. At days 1, 7, 14, 21, and 30, cultures were assessed for cell growth using alamarBlue((r)) and osteogenic indicators using alkaline phosphatase and Von Kossa staining. The results show that collagen type I stained positive for calcium deposition the greatest by day 30 in both osteogenic medium and standard culture medium. However, fibrinogen had the greatest staining in osteogenic medium at day 21 and fibronectin was the only substrate to promote calcium deposition in standard culture medium at day 21. These results suggest that the osteogenic differentiation of hMSCs is influenced by both culturing conditions and substrate and that together they have a synergistic effect. By knowing the effect ECM proteins in 3-D fibrin construct have on promoting osteogenic differentiation of hMSCs, the fabrication of complex, biomimetic models designed to manipulate hMSC differentiation toward an osteoblastic lineage will be improved. PMID- 23360405 TI - Home and Community Based Services (HCBS) waivers: a nationwide study of the states. AB - In fiscal year (FY) 2009, the Medicaid program funded over 75% of all publicly funded long-term supports and services (LTSS) for individuals with intellectual and developmental disabilities (IDD) in the United States ( Braddock et al., 2011 ). The majority of spending was attributed to the Home and Community Based Services (HCBS) Waiver program. In FY 2009, federal-state spending for the HCBS Waiver program reached over $25.1 billion and constituted almost half of total funding across the nation that year ( Braddock et al., 2011 ). Considerable effort has been spent investigating Medicaid program expenditures, however, due in part to the unique and state-specific nature of HCBS programs, national-level analysis on the types of services offered to individuals with IDD has not been available. A full understanding of the supports available through the Medicaid program is critical as the United States considers strategies for economic recovery among competing state and federal budget priorities. This article presents the results of an analysis of 88 Medicaid HCBS Section 1915(c) waiver applications for individuals with intellectual and developmental disabilities in 41 states and the District of Columbia. It analyzes IDD data and trends close to the real time intent of states and empowers advocates in presenting timely solutions to real-time issues. PMID- 23360406 TI - A friendships and dating program for adults with intellectual and developmental disabilities: a formative evaluation. AB - Meaningful relationships with others are often elusive for people with intellectual and developmental disabilities, but no less desired for their full inclusion and participation in society. It is well documented that people with disabilities are victims of interpersonal violence at higher rates than peers without disabilities. This article presents a formative evaluation of the Friendships and Dating Program (FDP). The FDP was designed to teach the social skills needed to develop healthy, meaningful relationships and to prevent violence in dating and partnered relationships. Thirty-one adults were recruited by 5 community agencies in Alaska to participate. The results showed the size of the participants' social networks increased and the number of incidents of interpersonal violence was reduced for participants who completed the FDP, and outcomes were maintained 10 weeks later. PMID- 23360407 TI - Feasibility of eight physical fitness tests in 1,050 older adults with intellectual disability: results of the healthy ageing with intellectual disabilities study. AB - Although physical fitness is relevant for well-being and health, knowledge on the feasibility of instruments to measure physical fitness in older adults with intellectual disability (ID) is lacking. As part of the study Healthy Ageing with Intellectual Disabilities with 1,050 older clients with ID in three Dutch care services, the feasibility of 8 physical fitness tests was expressed in completion rates: box and block test, response time test, Berg balance scale, walking speed, grip strength, 30-s chair stand, 10-m incremental shuttle walking test, and the extended modified back saver sit and reach test. All tests had moderate to good feasibility in all subgroups, except for the participants with profound ID (all tests), severe ID (response time test and Berg balance scale), and wheelchair users (all tests that involve the legs). We conclude that the 8 tests are feasible to measure physical fitness in most older adults with ID. PMID- 23360408 TI - Congregational participation and supports for children and adults with disabilities: parent perceptions. AB - Although religion and spirituality have received relatively limited attention in the literature addressing people with disabilities, each is strongly associated with a host of positive outcomes, including enhanced quality of life. One way to participate in religious activities and enhance spirituality is to participate in a faith community. In this article, we report findings from a survey of 416 parents exploring the ways in which they and their children with disabilities participated in their congregations and examining factors associated with participation and inclusion in those communities. Consistent with findings from general social surveys, the majority of parents indicated their faith was important to them and many-along with their sons or daughters with disabilities participated in congregational activities. Although parents reported their sons and daughters with disabilities participated in somewhat fewer types of activities than they did, this involvement occurred most often in activities involving peers without disabilities. However, parents generally were not satisfied with the level of supports provided by faith communities, and they highly valued a welcoming and supportive attitude by the community. We discuss implications for extending inclusive efforts into congregational contexts and suggest future research directions. PMID- 23360409 TI - Family caregivers' perspectives on barriers and facilitators of cervical and breast cancer screening for women with intellectual disability. AB - Women with intellectual disability do not receive cervical and breast cancer screening at the same number as women without disabilities. Numerous barriers to receipt of screening have been reported by individuals with intellectual disability, paid caregivers, nurses, and other medical professionals. This study utilized semi-structured qualitative interviews to assess barriers to care from the perspective of female familial caregivers (n = 32). Caregivers reported a number of barriers to care including not knowing or not believing the exam was needed for their family member and discomfort during exams. Caregivers also described enablers to screening. The most common response to what enabled the woman with an intellectual disability to receive the exam was preparation prior to the exam. A significant portion of the sample of family caregivers lacked knowledge about the need for cervical and breast cancer screening by women with intellectual disability. Policy recommendations are discussed. PMID- 23360410 TI - Intellectual disability and space: critical narratives of exclusion. AB - The language of intellectual disability is rife with spatial terms. Students labeled with intellectual disability are "placed in" special education where they may be "self-contained," "segregated," "excluded," or "included." Conversations ensue about where to seat them, next to whom, and at what distance from the teacher and other students. In this article, critical spatial studies and critical narratives are used to illustrate the ways in which power and exclusion constitute intellectual disability. PMID- 23360412 TI - Bioactivation of the nasal toxicant 2,6-dichlorobenzonitrile: an assessment of metabolic activity in human nasal mucosa and identification of indicators of exposure and potential toxicity. AB - The herbicide 2,6-dichlorobenzonitrile (DCBN) is a potent nasal toxicant in rodents; however, it is not known whether DCBN causes similar nasal toxicity in humans. The tissue-selective toxicity of DCBN in mouse nasal mucosa is largely dependent on target tissue bioactivation by CYP2A5. The human orthologues of CYP2A5, CYP2A6 and CYP2A13, are both expressed in nasal mucosa and are capable of activating DCBN. In this study, we directly determined the ability of human nasal mucosa to bioactivate DCBN. We also tested the suitability of a glutathione conjugate of DCBN (GS-DCBN) or its derivatives as biomarkers of DCBN exposure and nasal toxicity in mouse models. We found that human fetal nasal mucosa microsomes catalyze the formation of GS-DCBN, with a Km value comparable to that of adult mouse nasal mucosa microsomes. The activity of the human nasal mucosa microsomes was inhibited by 8-methoxypsoralen, a known CYP2A inhibitor. GS-DCBN and its metabolites were detected in the nasal mucosa and nasal-wash fluid obtained from DCBN-treated mice, in amounts that increased with escalations in DCBN dose, and they were all still detectable at 24 h after a DCBN treatment (at 10 mg/kg). Further studies in Cyp2a5-null mice indicated that GS-DCBN and its metabolites in nasal-wash fluid were generated in the nasal mucosa, rather than in other organs. Thus, our data indicate for the first time that the human nasal mucosa is capable of bioactivating DCBN and that GS-DCBN and its metabolites in nasal-wash fluid may collectively serve as indicators of DCBN exposure and potential nasal toxicity in humans. PMID- 23360413 TI - Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. AB - Pregnancy is a state where pharmacokinetic changes are more pronounced and more rapid than during any other period of life. The consequences of such changes can be far reaching, not least in the management of epilepsy where the risks with uncontrolled seizures during pregnancy need to be balanced against potential teratogenic effects of antiepileptic drugs (AEDs). This article aims to review the literature on gestational effects on the pharmacokinetics of older and newer generation AEDs and discuss the implications for the treatment of epilepsy in women during pregnancy. Pregnancy can affect the pharmacokinetics of AEDs at any level from absorption, distribution, metabolism, to elimination. The effect varies depending on the type of AED. The most pronounced decline in serum concentrations is seen for AEDs that are eliminated by glucuronidation (UGT), in particular lamotrigine where the effect may be profound. Serum concentrations of AEDs that are cleared mainly through the kidneys, for example, levetiracetam, can also decline significantly. Some AEDs, such as carbamazepine seem to be affected only marginally by pregnancy. Data on pharmacokinetics during pregnancy are lacking completely for some of the newer generation AEDs: pregabalin, lacosamide, retigabine, and eslicarbazepine acetate. Where data are available, the effects of pregnancy on serum concentrations seem to vary considerably individually and are thus difficult to predict. Although large-scale systematic studies of the clinical relevance of the pharmacokinetic alterations are lacking, prospective and retrospective case series have reported an association between declining serum concentrations and deterioration in seizures control. The usefulness of routine monitoring of AED serum concentrations in pregnancy and of dose adjustments based on falling levels, are discussed in this review. We suggest that monitoring could be important, in particular when women have been titrated to the lowest effective AED dose and serum concentration before pregnancy, and when that individual optimal concentration can be used as reference. PMID- 23360414 TI - Treatment for neuropathic pain in patients with cancer: comparative analysis of recommendations in national clinical practice guidelines from European countries. AB - INTRODUCTION: Neuropathic pain is a common symptom, present in 39% of the patients with cancer pain. Treating this type of pain is challenging, as this patient group is often frail and has comorbidities which increase the risk of side events and hence influences their quality of life. Clinical practice guidelines (CPGs) can be helpful for clinicians, especially when scientific evidence is uncertain or weak. In this study, we focused on the quality of the review of the literature used in treatment recommendations in the selected European CPGs. METHODS: In a previous study, 9 CPGs from European countries that contained at least one paragraph on treatment for neuropathic pain in cancer were included. Recommendations with their grade (according SIGN 55 classification) and supporting literature (first author, patients' population, year and type of publication) were compared between CPGs. RESULTS: In all CPGs, amitriptylin was mentioned as the drug of first choice. Six guidelines proposed also gabapentinoids. Only 30 of the 163 citations (18%) were based on studies in patients with cancer. Seven CPGs did not argue the indirect evidence due to extrapolation of study results from non-cancer to patients with cancer. CONCLUSION: The majority of guideline development groups extrapolated their results from non-cancer publications to formulate recommendations. Consequently, these guidelines fail to address important issues such as altered kinetics and side effect profiles in these patients. We recommend creating specific recommendations by an international expert group for the treatment for neuropathic pain in patients with cancer supported by targeted research in patients with cancer. PMID- 23360415 TI - Analysis of resistant starches in rat cecal contents using Fourier transform infrared photoacoustic spectroscopy. AB - Fourier transform infrared photoacoustic spectroscopy (FTIR-PAS) qualitatively and quantitatively measured resistant starch (RS) in rat cecal contents. Fisher 344 rats were fed diets of 55% (w/w, dry basis) starch for 8 weeks. Cecal contents were collected from sacrificed rats. A corn starch control was compared against three RS diets. The RS diets were high-amylose corn starch (HA7), HA7 chemically modified with octenyl succinic anhydride, and stearic-acid-complexed HA7 starch. To calibrate the FTIR-PAS analysis, samples from each diet were analyzed using an enzymatic assay. A partial least-squares cross-validation plot generated from the enzymatic assay and FTIR-PAS spectral results for starch fit the ideal curve with a R(2) of 0.997. A principal component analysis plot of components 1 and 2 showed that spectra from diets clustered significantly from each other. This study clearly showed that FTIR-PAS can accurately quantify starch content and identify the form of starch in complex matrices. PMID- 23360416 TI - Evaluation of absolute hardness: a new approach. AB - By taking the energy to be a Morse-like function of the number of electrons, E(N) = alpha{1 - e(-beta(N-delta))}(2) - kappa, the electronic chemical potential and global hardness values for a set of atoms and some molecules are calculated from the accurate definitions of these two concepts and using the hybrid B3LYP functional and 6-311++G** basis set. By a comparison between the obtained hardnesses and the corresponding experimental values, it is found that the proposed model yields better values for hardnesses with respect to those that are obtained from the other frequently used methods. It is claimed that the difference between the calculated and experimental hardness values may arise from the approximate equation used for the evaluation of experimental hardnesses. Both of the calculated and experimental molecular hardnesses are used to investigate the change of hardness during the course of some exothermic reactions according to the maximum hardness principle (MHP). It is shown that the obtained hardnesses of reactions from the calculated hardnesses (Deltaeta(calc)) are more successful in predicting the directions of these reactions than those that are evaluated from the experimental hardnesses (Deltaeta(exp)). PMID- 23360417 TI - Dynamite analysis by Raman spectroscopy as a unique analytical tool. AB - Apart from powerful explosives, dynamites are complex samples with an intricate analysis. These mixtures of compounds of diverse chemical nature present a challenge to the analyst, and as a result, several analytical techniques need to be applied currently for their analysis. Taking into account that presently there are almost no methods for dynamite analysis in the literature, it is crucial to develop analytical methods that could be applied for the analysis of these samples. This study introduces the use of Raman spectroscopy to analyze dynamites. Two different dynamites made up of ethylene glycol dinitrate and ammonium nitrate, among other minor components, were analyzed by Raman spectroscopy. First, confocal Raman spectroscopy allowed the identification of different components easily distinguished by eye (ammonium nitrate, ethylene glycol dinitrate, and sawdust). Then, Raman mapping was used to show the distribution of the main components throughout the dynamite mass. Finally, several minor components were identified after flocculation (nitrocellulose) or precipitation (sawdust, CaCO3, and flour). The results obtained demonstrate the huge potential of this technique for the analysis of such a complex and tricky sample. PMID- 23360418 TI - Transcriptional profiling of Brazilian Saccharomyces cerevisiae strains selected for semi-continuous fermentation of sugarcane must. AB - Brazil played a pioneering role in the global establishment of the sugarcane bioethanol industry. The bioethanol fermentation process currently used in Brazil is unique due to the acid wash and recycling of yeast cells. Two, industrially adopted, wild yeast strains, CAT-1 and PE-2, have become the most widely used in Brazil. How these strains respond to the unique fermentation process is poorly understood. The improved performance of CAT-1 and PE-2 is hypothesised to be related to enhanced stress tolerance. This study presents a genome-wide analysis of the CAT-1 and PE-2 transcriptomes during a small-scale fermentation process that mimicked the industrial conditions. The common and unique transcriptional responses of the two strains to the Brazilian fermentation process were identified. Environmental stress response genes were up-regulated postfermenter feeding, demonstrating the impact of the prior acid wash and high glucose environment. Cell wall and oxidative stress tolerance were subsequently demonstrated to be enhanced for the industrial strains. Conversely, numerous genes involved in protein synthesis were down-regulated at the end of fermentation revealing the later impact of ethanol-induced stress. Subsequently, the industrial strains demonstrated a greater tolerance of ethanol and the disruption of endoplasmic reticulum homoeostasis. This increased ethanol tolerance was finally correlated with an increased unfolded protein response and increased HAC1 splicing. PMID- 23360419 TI - Pharmacodynamic and pharmacokinetic evaluation of coadministration of lacosamide and an oral contraceptive (levonorgestrel plus ethinylestradiol) in healthy female volunteers. AB - PURPOSE: To determine whether the antiepileptic drug lacosamide affects the pharmacokinetics or pharmacodynamics of a combined oral contraceptive (OC; ethinylestradiol 0.03 mg plus levonorgestrel 0.15 mg). METHODS: This was an open label trial in healthy female volunteers. Eligible women entered cycle 1 of the trial on the first day of menstruation. Cycle 1 was a medication-free, run-in phase of approximately 28 days to confirm that normal ovulation occurred. Volunteers with confirmed ovulation entered the subsequent cycle and started taking OCs. After establishing ovulation suppression (defined as progesterone serum concentration <5.1 nm on day 21 of the menstrual cycle) in volunteers taking the OCs in cycle 2, lacosamide 400 mg/day was administered concomitantly in the subsequent cycle (cycle 3). The pharmacokinetic parameters of area under the concentration-time curve (AUC), maximum steady-state plasma drug concentration (Cmax ), and time to maximum concentration (tmax ) were measured for the OC components and lacosamide. KEY FINDINGS: A total of 37 volunteers completed cycle 1, and 32 completed cycle 2. In each of the 31 volunteers who completed the trial (through cycle 3), pharmacodynamic assessment showed progesterone serum concentration was <5.1 nm on day 21 of cycle 2, when the OC was administered alone, and on day 21 of cycle 3, when lacosamide was administered concomitantly. The AUC of ethinylestradiol alone versus together with lacosamide was 1,067 +/- 404 versus 1,173 +/- 330 pg h/ml. Corresponding values of Cmax were 116.9 +/- 48.8 versus 135.7 +/- 28.6 pg/ml. For levonorgestrel, the AUC alone was 74.2 +/- 21.4 versus 80.9 +/- 18.5 ng h/ml with lacosamide. Corresponding values of Cmax were 6.7 +/- 1.9 versus 7.4 +/- 1.5 ng/ml. The AUC and Cmax point estimates and almost all 90% confidence intervals (except for Cmax of ethinylestradiol) for ethinylestradiol and levonorgestrel (with and without lacosamide) were within the conventional bioequivalence range, and no relevant changes in tmax were observed for ethinylestradiol (1.5 +/- 0.6 h alone vs. 1.4 +/- 0.7 h with lacosamide) or for levonorgestrel (1.5 +/- 1.0 h alone vs. 1.1 +/- 0.6 h with lacosamide). Lacosamide pharmacokinetics were consistent with those observed in previous studies of lacosamide alone, with values for AUC of 113.5 +/- 20.7 MUg h/ml, Cmax of 13.8 +/- 2.2 MUg/ml, and tmax of 1.1 +/- 0.4 h. SIGNIFICANCE: Lacosamide and an OC containing ethinylestradiol and levonorgestrel have low potential for drug-drug interaction; therefore, coadministration of the two drugs is unlikely to result in contraceptive failure or loss of seizure control. PMID- 23360421 TI - Novel adaptor protein Shf interacts with ALK receptor and negatively regulates its downstream signals in neuroblastoma. AB - Our neuroblastoma cDNA project previously identified Src homology 2 domain containing F (Shf) as one of the genes expressed at high levels in favorable neuroblastoma. Shf is an adaptor protein containing four putative tyrosine phosphorylation sites and an SH2 domain. In this study, we found that Shf interacted with anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase in neuroblastoma. Real-time PCR analysis showed that Shf mRNA is highly expressed in non-metastatic neuroblastomas compared to metastatic tumor samples (P < 0.030, n = 106). Interestingly, patients showing high ALK and low Shf mRNA expressions showed poor prognosis, whereas low ALK and high Shf expressions were related to better prognosis (P < 0.023, n = 38). Overexpression of ALK and siRNA mediated knockdown of Shf yielded similar results, such as an increase in cellular growth and phosphorylation of ALK, in addition to Erk1/2 and signal transducer and activator of transcription 3 (STAT3) that are downstream signals of the ALK-initiated phospho-transduction pathway. Knockdown of Shf also increased the cellular mobility and invasive capability of neuroblastoma cells. These results suggest that Shf interacts with ALK and negatively regulates the ALK-initiated signal transduction pathway in neuroblastoma. We thus propose that Shf inhibits phospho-transduction signals mediated by ALK, which is one of the major key players on neuroblastoma development, resulting in better prognosis of the tumor. PMID- 23360423 TI - Enhancing CaP biomimetic growth on TiO2 cuboids nanoparticles via highly reactive facets. AB - Pure decahedral anatase TiO(2) particles with high content of reactive {001} facets were obtained from titanium(IV) tetrachloride (TiCl(4)) using a microemulsions droplet system at specific conditions as chemical microreactor. The product was systematically characterized by X-ray diffraction, field-emission scanning and transmission electron microscopy (FE-SEM, TEM), N(2) adsorption desorption isotherms, FT-IR and UV-vis spectroscopy, and photoluminescence studies. The obtained cuboids around 90 nm in size have a uniform and dense surface morphology with a BET specific surface area of 11.91 m(2) g(-1) and a band gap energy (3.18 eV) slightly inferior to the anatase dominated by the less reactive {101} surface (3.20 eV). The presence of reactive facets on titania anatase favors the biomimetic growth of amorphous tricalcium phosphate after the first day of immersion in simulated human plasma. The results presented here can facilitate and improve the integration of anchored implants and enhance the biological responses to the soft tissues. PMID- 23360422 TI - Pathogenesis of type 1 diabetes: lessons from natural history studies of high risk individuals. AB - Type 1 diabetes (T1D) is an autoimmune disease characterized by known genetic risk factors with T cell-mediated infiltration and destruction of the beta cells within pancreatic islets. Autoantibodies are the most significant preclinical marker of T1D, and birth cohort studies have provided important insights into the natural history of autoimmunity and T1D. While HLA remains the strongest genetic risk factor, a number of novel gene variants associated with T1D have been found through genome-wide studies, some of which have been linked to suspected environmental risk factors. Multiple environmental factors that have been suggested to play a role in the development of T1D await confirmation. Current risk-stratification models for T1D take into account genetic risk factors and autoantibodies. In the future, metabolic profiles, epigenetics, as well as environmental risk factors may be included in such models. PMID- 23360424 TI - Computerized decision support systems in primary care for type 2 diabetes patients only improve patients' outcomes when combined with feedback on performance and case management: a systematic review. AB - PURPOSE: Computerized decision support systems (CDSSs) are often part of a multifaceted intervention to improve diabetes care. We reviewed the effects of CDSSs alone or in combination with other supportive tools in primary care for type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A systematic literature search was conducted for January 1990-July 2011 in PubMed, Embase, and the Cochrane Database and by consulting reference lists. Randomized controlled trials (RCTs) in general practice were selected if the interventions consisted of a CDSS alone or combined with a reminder system and/or feedback on performance and/or case management. The intervention had to be compared with usual care. Two pairs of reviewers independently abstracted all available data. The data were categorized by process of care and patient outcome measures. RESULTS: Twenty RCTs met inclusion criteria. In 14 studies a CDSS was combined with another intervention. Two studies were left out of the analysis because of low quality. Four studies with a CDSS alone and four studies with a CDSS and reminders showed improvements of the process of care. CDSS with feedback on performance with or without reminders improved the process of care (one study) and patient outcome (two studies). CDSS with case management improved patient outcome (two studies). CDSS with reminders, feedback on performance, and case management improved both patient outcome and the process of care (two studies). CONCLUSIONS: CDSSs used by healthcare providers in primary T2DM care are effective in improving the process of care; adding feedback on performance and/or case management may also improve patient outcome. PMID- 23360425 TI - Understanding and controlling nanoporosity formation for improving the stability of bimetallic fuel cell catalysts. AB - Nanoporosity is a frequently reported phenomenon in bimetallic particle ensembles used as electrocatalysts for the oxygen reduction reaction (ORR) in fuel cells. It is generally considered a favorable characteristic, because it increases the catalytically active surface area. However, the effect of nanoporosity on the intrinsic activity and stability of a nanoparticle electrocatalyst has remained unclear. Here, we present a facile atmosphere-controlled acid leaching technique to control the formation of nanoporosity in Pt-Ni bimetallic nanoparticles. By statistical analysis of particle size, composition, nanoporosity, and atomic scale core-shell fine structures before and after electrochemical stability test, we uncover that nanoporosity formation in particles larger than ca. 10 nm is intrinsically tied to a drastic dissolution of Ni and, as a result of this, a rapid drop in intrinsic catalytic activity during ORR testing, translating into severe catalyst performance degradation. In contrast, O2-free acid leaching enabled the suppression of nanoporosity resulting in more solid core-shell particle architectures with thin Pt-enriched shells; surprisingly, such particles maintained high intrinsic activity and improved catalytic durability under otherwise identical ORR tests. On the basis of these findings, we suggest that catalytic stability could further improve by controlling the particle size below ca. 10 nm to avoid nanoporosity. Our findings provide an explanation for the degradation of bimetallic particle ensembles and show an easy to implement pathway toward more durable fuel cell cathode catalysts. PMID- 23360428 TI - Necrotic carpal tunnel syndrome in a child. AB - Median nerve entrapment at the wrist level causes carpal tunnel syndrome (CTS). Although frequent in adults, CTS is a rare entity in children. Bouvier described an exceptional necrotic variant in 1979 in which skin, nail, and bone lesions are typical. We report the case of a 10-year-old child with necrotic CTS secondary to trauma. To our knowledge, this is the first case reported in a child. PMID- 23360426 TI - The role of interferon-beta in the treatment of multiple sclerosis and experimental autoimmune encephalomyelitis - in the perspective of inflammasomes. AB - Inflammasomes in innate immune cells mediate the induction of inflammation by sensing microbes and pathogen-associated/damage-associated molecular patterns. Inflammasomes are also known to be involved in the development of some human and animal autoimmune diseases. The Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is currently the most fully characterized inflammasome, although a limited number of studies have demonstrated its role in demyelinating autoimmune diseases in the central nervous system of humans and animals. Currently, the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), is known to be induced by the NLRP3 inflammasome through enhanced recruitment of inflammatory immune cells in the central nervous system. On the other hand, interferon-beta (IFNbeta), a first line drug to treat MS, inhibits NLRP3 inflammasome activation, and ameliorates EAE. The NLRP3 inflammasome is indeed a factor capable of inducing EAE, but it is dispensable when EAE is induced by aggressive disease induction regimens. In such NLRP3 inflammasome-independent EAE, IFN-beta treatment is generally not effective. This might therefore be one mechanism that leads to occasional failures of IFN-beta treatment in EAE, and possibly, in MS as well. In the current review, we discuss inflammasomes and autoimmunity; in particular, the impact of the NLRP3 inflammasome on MS/EAE, and on IFN-beta therapy. PMID- 23360427 TI - High-density lipoprotein of patients with type 2 diabetes mellitus upregulates cyclooxgenase-2 expression and prostacyclin I-2 release in endothelial cells: relationship with HDL-associated sphingosine-1-phosphate. AB - BACKGROUND: Dysfunctional high-density lipoprotein (HDL) may have pro inflammatory effects on the endothelial cells,which causes atherosclerosis in type 2 diabetes mellitus (T2DM). HDL is a major carrier of sphingosine-1 phosphate (S1P) in plasma while S1P exhibits multiple biological activities. However, potential role of HDL and S1P in T2DM remains unexplored. We hypothesized that diabetic HDL with higher contents of S1P exerts beneficial effects on the vascular system. METHODS: Subjects with T2DM with or without proved large arteries atherosclerosis and normal controls (n=15 for each group) were recruited in the present study. HDL was isolated from the subjects by ultracentrifugation. The levels of HDL-associated S1P were determined by UPLC MS/MS. The protective function of diabetic HDL and S1P was evaluated by measuring cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release by human umbilical vein endothelial cells (HUVECs) using western blot and enzyme-linked immunosorbent assay (ELISA), respectively. RESULTS: The S1P levels in isolated HDL were significantly increased in T2DM subjects compared with controls (235.6 +/- 13.4 vs 195.0 +/- 6.4 ng/mg, P< 0.05). The diabetic HDL exerted greater protective effects on inducing COX-2 expression and PGI-2 release by HUVECs than those of control HDL (p < 0.05, p < 0.01, respectively). Pertussis toxin, a common inhibitor of G-couple protein receptors, and VPC 23019, an antagonist of S1P receptor 1 and 3 significantly attenuated HDL-induced COX-2 expression and PGI-2 release. CONCLUSIONS: Diabetic HDL carries higher level of S1P compared with normal HDL, which has the potential to contribute to protective effects on endothelial cells by inducing COX-2 expression and PGI-2 release. These findings provide a new insight of S1P function in T2DM patients, possibly leading to a new therapeutic target. PMID- 23360429 TI - Burden of childhood diseases and malnutrition in a semi-urban slum in southern India. AB - BACKGROUND: India has seen rapid unorganized urbanization in the past few decades. However, the burden of childhood diseases and malnutrition in such populations is difficult to quantify. The morbidity experience of children living in semi-urban slums of a southern Indian city is described. METHODS: A total of 176 children were recruited pre-weaning from four geographically adjacent, semi urban slums located in the western outskirts of Vellore, Tamil Nadu for a study on water safety and enteric infections and received either bottled or municipal drinking water based on their area of residence. Children were visited weekly at home and had anthropometry measured monthly until their second birthday. RESULTS: A total of 3932 episodes of illness were recorded during the follow-up period, resulting in an incidence of 12.5 illnesses/child-year, with more illness during infancy than in the second year of life. Respiratory, mostly upper respiratory infections, and gastrointestinal illnesses were most common. Approximately one third of children were stunted at two years of age, and two-thirds had at least one episode of growth failure during the two years of follow up. No differences in morbidity were seen between children who received bottled and municipal water. CONCLUSIONS: Our study found a high burden of childhood diseases and malnutrition among urban slum dwellers in southern India. Frequent illnesses may adversely impact children's health and development, besides placing an additional burden on families who need to seek healthcare and find resources to manage illness. PMID- 23360430 TI - Bisphenol A activates the Nrf1/2-antioxidant response element pathway in HEK 293 cells. AB - Bisphenol A (BPA) is used in the production of polycarbonate plastics and epoxy resins for baby bottles, liners of canned food, and many other consumer products. Previously, BPA has been shown to reduce the activity of several antioxidant enzymes, which may contribute to oxidative stress. However, the underlying mechanism of the BPA-mediated effect upon antioxidant enzyme activity is unknown. Antioxidant and phase II metabolizing enzymes protect cells from oxidative stress and are transcriptionally activated by Nrf1 and Nrf2 factors through their cis regulatory antioxidant response elements (AREs). In this work, we have assessed the effect of BPA on the Nrf1/2-ARE pathway in cultured human embryonic kidney (HEK) 293 cells. Surprisingly, glutathione and reactive oxygen species (ROS) assays revealed that BPA application created a more reduced intracellular environment in cultured HEK 293 cells. Furthermore, BPA increased the transactivation activity of ectopic Nrf1 and Nrf2 and increased the expression of ARE-target genes ho-1 and nqo1 at high (100-200 MUM) BPA concentrations only. Our study suggests that BPA activates the Nrf1/2-ARE pathway at high (>10 MUM) micromolar concentrations. PMID- 23360431 TI - Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 12. Structure-activity relationships associated with 4-fluoro-6-azaindole derivatives leading to the identification of 1-(4-benzoylpiperazin-1-yl)-2-(4-fluoro-7 [1,2,3]triazol-1-yl-1h-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-585248). AB - A series of highly potent HIV-1 attachment inhibitors with 4-fluoro-6-azaindole core heterocycles that target the viral envelope protein gp120 has been prepared. Substitution in the 7-position of the azaindole core with amides (12a,b), C linked heterocycles (12c-l), and N-linked heterocycles (12m-u) provided compounds with subnanomolar potency in a pseudotype infectivity assay and good pharmacokinetic profiles in vivo. A predictive model was developed from the initial SAR in which the potency of the analogues correlated with the ability of the substituent in the 7-position of the azaindole to adopt a coplanar conformation by either forming internal hydrogen bonds or avoiding repulsive substitution patterns. 1-(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-[1,2,3]triazol-1 yl-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-585248, 12m) exhibited much improved in vitro potency and pharmacokinetic properties than the previous clinical candidate BMS-488043 (1). The predicted low clearance in humans, modest protein binding, and good potency in the presence of 40% human serum for 12m led to its selection for human clinical studies. PMID- 23360432 TI - Heart rate turbulence in patients with metabolic syndrome. AB - BACKGROUND: Metabolic syndrome is a cluster of risk factors leading to cardiometabolic diseases. The association between metabolic syndrome and cardiovascular disease (CVD) has been evaluated previously, but none of those studies looked at cardiac autonomic functions in these patients. The aim of the present study was to investigate the effect of metabolic syndrome on heart rate turbulence, which plays an important role in the development of CVD. METHODS: Thirty-seven patients (17 females and 20 males) were included in the metabolic syndrome group and 37 subjects (19 females and 18 males) were included in the control group. Heart rate turbulence (HRT) indices [turbulence onset (TO) and turbulence slope (TS)] were calculated from 24-hr ambulatory electocardiographic recordings. RESULTS: At least one of the TO or TS values were within the abnormal range in 62% of the patients within the metabolic syndrome group. In the control group, at least one of the TO or TS values were within the abnormal range in 27% of the subjects. CONCLUSIONS: Our study results indicate that cardiac autonomic function is impaired even in the absence of overt cardiac disease in patients with metabolic syndrome. Further studies are needed to elucidate the prognostic significance and clinical implications of impaired autonomic functions in patients with metabolic syndrome. PMID- 23360433 TI - Serum uric acid predicts both current and future components of the metabolic syndrome. AB - BACKGROUND: Uric acid (UA) is known to be associated with excess adiposity and insulin resistance. Our aim was to investigate the relationship between UA and the factors associated with the metabolic syndrome and type 2 diabetes mellitus (T2DM), both initially and longitudinally. METHODS: Serum UA was assessed as a potential determinant of concurrent blood pressure, serum lipids, glucose regulation measured via an oral glucose tolerance test (OGTT), acute insulin response (AIR), and insulin action (M) measured with hyperinsulinemic-euglycemic clamps in 245 participants (72% Native American, 56% male). UA was also assessed as a predictor of the above variables in 60 participants with follow-up data available (median follow-up time=11.2 years [interquartile range (IQR)=8.1, 13.6 years]. The impact of UA on the risk of T2DM was determined as 36 of the 245 participants developed T2DM after the baseline visit. RESULTS: UA was negatively associated with both concurrent and future M, such that for every 1 mg/dL increase in serum UA, M decreased 7.6% (P<0.001) and future M decreased 6.3% (P=0.02). However, UA was not associated with AIR (P=0.7). UA concentrations were a predictor of T2DM [hazard risk ratio (HRR)=1.5; P=0.02]. UA was positively associated with both concurrent blood pressure and lipids and also predicted future increases in blood pressure and total cholesterol. CONCLUSIONS: Not only did UA associate with concomitant insulin action, blood pressure, and lipids, it also predicted future declines in insulin action and T2DM. UA is a potential target for preventing decreases in insulin sensitivity and rises in blood pressure and cholesterol. PMID- 23360434 TI - Genetic and environmental associations between C-reactive protein and components of the metabolic syndrome. AB - BACKGROUND: Metabolic syndrome has been suggested to have an association with C reactive protein (CRP), a biomarker of cardiovascular disease risk. Given that genetic factors influence both metabolic syndrome and CRP, it seems necessary to examine the association with consideration of genetic influence. METHODS: We conducted a cross-sectional study and a co-twin-control study in 2555 Korean adults composed of twins and their family members. For the co-twin-control study, 113 pairs of monozygotic twins who were discordant in regard to CRP level (>0.5 mg/L) were selected. Cross-trait additive genetic correlation between CRP and metabolic syndrome and the risk for having higher CRP level associated with components of metabolic syndrome were estimated. RESULTS: With increasing CRP level, the prevalence of metabolic syndrome increased linearly. Among components of metabolic syndrome, high-density lipoprotein cholesterol (HDL-C) was inversely associated with CRP, whereas other components were positively associated. Most of the components of metabolic syndrome except for HDL-C had a significant genetic correlation with CRP, with the highest correlation for obesity indices. A co-twin control study that allows full control of genetic influence showed that only obesity was significantly associated with higher CRP levels: Odds ratios (95% confidence intervals) were 1.23 (1.04,1.46) for 1 kg/m(2) increase in body mass index and 1.12 (1.03,1.22) for 1% increased in total body fat, respectively. CONCLUSIONS: Although genetic influence played a significant role in the associations between CRP and most metabolic syndrome components, environmental influence that may be modifiable also contributed to the association, especially to the associations between the obesity indices and CRP. PMID- 23360435 TI - Photoinitiated electron transfer in zinc porphyrin-perylenediimide cruciforms and their self-assembled oligomers. AB - Two X-shaped, cruciform electron donor(2)-acceptor-acceptor'(2) (D(2)-A-A'(2)) molecules, 1 and 2, in which D = zinc 5-phenyl-10,15,20-tripentylporphyrin (ZnTPnP) or zinc 5,10,15,20-tetraphenylporphyrin (ZnTPP), respectively, A = pyromellitimide (PI), and A' = perylene-3,4:9,10-bis(dicarboximide) (PDI), were prepared to study self-assembly motifs that promote photoinitiated charge separation followed by electron and hole transport through pi-stacked donors and acceptors. PDI secondary electron acceptors were chosen because of their propensity to form self-ordered, pi-stacked assemblies in solution, while the ZnTPnP and ZnTPP donors were selected to test the effect of peripheral substituent steric interactions on the pi-stacking characteristics of the cruciforms. Small- and wide-angle X-ray scattering measurements in toluene solution reveal that 1 assembles into a pi-stacked structure having an average of 5 +/- 1 molecules, when [1] =/~ 10(-5) M, while 2 remains monomeric. Photoexcitation of the pi-stacked structure of 1 results in formation of ZnTPnP(*+)-PI-PDI(*-) in tau(CS1) = 0.3 ps, which is nearly 100-fold faster than the formation of ZnTPnP(*+)-PI(*-) in a model system lacking the PDI acceptor. The data are consistent with a self-assembled structure for 1 in which the majority of the intermolecular interactions have the ZnTPnP donor of one monomer cofacially pi-stacked with the PDI acceptor of a neighboring monomer in a crisscrossed fashion. In contrast, 2 remains monomeric in toluene, so that photoexcitation of ZnTPP results in the charge separation reaction sequence: (1*)ZnTPP-PI-PDI -> ZnTPP(*+)-PI(*-)-PDI -> ZnTPP(*+)-PI-PDI(*-), where tau(CS1) = 33 ps and tau(CS2) = 239 ps. The perpendicular orientation of ZnTPnP and ZnTPP relative to PDI in 1 and 2 is designed to decrease the porphyrin-PDI distance without greatly decreasing the overall number of bonds linking them. This serves to decrease the Coulomb energy penalty required to produce D(*+)-PI-PDI(*-) relative to the corresponding linear D-PI-PDI array, while retaining the weak electronic coupling necessary to achieve long-lived charge separation, as evidenced by tau(CR) = 24 ns for ZnTPP(*+)-PI-PDI(*-). PMID- 23360436 TI - Zc3h12c inhibits vascular inflammation by repressing NF-kappaB activation and pro inflammatory gene expression in endothelial cells. AB - Endothelial activation characterized by the expression of multiple chemokines and adhesive molecules is a critical initial step of vascular inflammation, which results in recruitment of leucocytes into the sub-endothelial layer of the vascular wall and triggers vascular inflammatory diseases such as atherosclerosis. Although inhibiting endothelial inflammation has already been well recognized as a therapeutic strategy in vascular inflammatory diseases, the therapeutic targets are still elusive. In the present study we found that Zc3h12c (zinc finger CCCH-type-containing 12C), a recently discovered CCCH zinc finger containing protein, significantly inhibited the endothelial cell inflammatory response in vitro. Overexpression of Zc3h12c significantly attenuated TNFalpha (tumour necrosis factor alpha)-induced expression of chemokines and adhesive molecules, and thus reduced monocyte adherence to HUVECs (human umbilical vein endothelial cells). Conversely, siRNA (small interfering RNA)-mediated knockdown of Zc3h12c increased the TNFalpha-induced expression of chemokines and adhesive molecules in HUVECs. Furthermore, forced expression of Zc3h12c decreased TNFalpha induced IKKalpha/beta [IkappaB (inhibitor of nuclear factor kappaB) kinase alpha/beta], IkappaBalpha phosphorylation and p65 nuclear translocation, suggesting that Zc3h12c exerted its anti-inflammatory function probably by suppressing the NF-kappaB (nuclear factor kappaB) pathway. Thus Zc3h12c is an endogenous inhibitor of TNFalpha-induced inflammatory signalling in HUVECs and might be a therapeutic target in vascular inflammatory diseases. PMID- 23360438 TI - Reduction of carbon dioxide promoted by a dinuclear tantalum tetrahydride complex. AB - The reaction of 1 equiv of carbon dioxide with the dinuclear tetrahydride complex ([NPN]Ta)(2)(MU-H)(4) [where NPN = PhP(CH(2)SiMe(2)NPh)(2)] results in the formation of ([NPN]Ta)(2)(MU-OCH(2)O)(MU-H)(2) via a combination of migratory insertion and reductive elimination. The identity of the ditantalum complex containing a methylene diolate fragment was confirmed by single-crystal X-ray analysis, NMR analysis, and isotopic labeling studies. Density functional theory calculations were performed to provide information on the structure of the initial adduct formed and likely transition states and intermediates for the process. PMID- 23360437 TI - Deep sequencing uncovers commonality in small RNA profiles between transgene induced and naturally occurring RNA silencing of chalcone synthase-A gene in petunia. AB - BACKGROUND: Introduction of a transgene that transcribes RNA homologous to an endogenous gene in the plant genome can induce silencing of both genes, a phenomenon termed cosuppression. Cosuppression was first discovered in transgenic petunia plants transformed with the CHS-A gene encoding chalcone synthase, in which nonpigmented sectors in flowers or completely white flowers are produced. Some of the flower-color patterns observed in transgenic petunias having CHS-A cosuppression resemble those in existing nontransgenic varieties. Although the mechanism by which white sectors are generated in nontransgenic petunia is known to be due to RNA silencing of the CHS-A gene as in cosuppression, whether the same trigger(s) and/or pattern of RNA degradation are involved in these phenomena has not been known. Here, we addressed this question using deep-sequencing and bioinformatic analyses of small RNAs. RESULTS: We analyzed short interfering RNAs (siRNAs) produced in nonpigmented sectors of petal tissues in transgenic petunia plants that have CHS-A cosuppression and a nontransgenic petunia variety Red Star, that has naturally occurring CHS-A RNA silencing. In both silencing systems, 21-nt and 22-nt siRNAs were the most and the second-most abundant size classes, respectively. CHS-A siRNA production was confined to exon 2, indicating that RNA degradation through the RNA silencing pathway occurred in this exon. Common siRNAs were detected in cosuppression and naturally occurring RNA silencing, and their ranks based on the number of siRNAs in these plants were correlated with each other. Noticeably, highly abundant siRNAs were common in these systems. Phased siRNAs were detected in multiple phases at multiple sites, and some of the ends of the regions that produced phased siRNAs were conserved. CONCLUSIONS: The features of siRNA production found to be common to cosuppression and naturally occurring silencing of the CHS-A gene indicate mechanistic similarities between these silencing systems especially in the biosynthetic processes of siRNAs including cleavage of CHS-A transcripts and subsequent production of secondary siRNAs in exon 2. The data also suggest that these events occurred at multiple sites, which can be a feature of these silencing phenomena. PMID- 23360439 TI - Accessing long-lived nuclear spin order by isotope-induced symmetry breaking. AB - Nuclear singlet states are nonmagnetic states of nuclear spin-1/2 pairs that may exhibit lifetimes much slower than the relaxation of the component spins in isolation. This feature makes them attractive vehicles for conveying nuclear hyperpolarization in NMR spectroscopy and magnetic resonance imaging experiments and for reducing signal losses in other NMR experiments caused by undesirably fast nuclear spin relaxation. Here we show access to (13)C(2) singlet states in a symmetrical oxalate molecule by substituting one or more (16)O nuclei by the stable nonmagnetic isotope (18)O. The singlet relaxation time of the (13)C(2) pair in [1-(18)O,(13)C(2)]-oxalate is 2-3 times longer than the spin-lattice relaxation time T(1). PMID- 23360441 TI - The effect of IGF-I on anatomically shaped tissue-engineered menisci. AB - This study investigates the effect of insulin-like growth factor (IGF)-I on the development of anatomically-shaped alginate menisci seeded with meniscal fibrochondrocytes. To accomplish this, bovine meniscal fibrochondrocytes were seeded into 2% w/v alginate, crosslinked with calcium sulfate, and injected into anatomical molds derived from microcomputed tomography scans. The meniscal constructs were then cultured for up to 4 weeks with or without 100 ng/mL IGF-I supplemented in the media. Histological, immunohistological, biochemical, and mechanical analyses were performed to characterize tissue development, accumulation and localization of extracellular matrix, and mechanical properties. After 4 weeks of culture, IGF-I treatment significantly improved mechanical and biochemical properties, while maintaining DNA content, with a 26-fold increase in glycosaminoglycan (GAG) content and 10-fold increase in collagen content compared to 0-week controls, and a 3-fold increase in the equilibrium modulus at 2 weeks compared to controls. IGF-I-treated menisci had ~60% of the GAG content of native tissue and the compressive equilibrium modulus matched native properties by 2 weeks of culture. Further, IGF-I-treated menisci developed a distinct surface layer similar to native tissue with elongated cells and collagen fibers aligned parallel to the surface, the presence of types I and II collagen, and accumulation of lubricin. This study demonstrates that IGF-I treatment can greatly increase the mechanical and biochemical properties of engineered tissues and aid in the development of a distinct surface zone similar to the superficial zone of native menisci. PMID- 23360442 TI - Radioluminescent gold nanocages with controlled radioactivity for real-time in vivo imaging. AB - Cerenkov luminescence imaging based on light emission from the decay of radionuclides has recently drawn great interest in molecular imaging. In this paper, we report for the first time the Cerenkov luminescence phenomenon of (198)Au isotope, as well as a facile route to the preparation of radioluminescent Au nanocages without additional radiolabeling or dye conjugation. The specific radioactivity of the Au nanocages could be easily and precisely controlled by varying the concentration of H(198)AuCl(4) precursor used for the galvanic replacement reaction. The direct incorporation of (198)Au atoms into the structure of Au nanocages enabled the ability of accurate analysis and real-time imaging in vivo. Furthermore, under biological conditions the radioactive Au nanocages were shown to emit light with wavelengths in the visible and near infrared regions, enabling luminescence imaging of the whole mice in vivo, as well as the organs ex vivo. When combined with their favorable scattering and absorption properties in the near-infrared region, the radioactive Au nanocages can serve as a new platform for multimodality imaging and will have a significant impact on both small animal and clinical imaging. PMID- 23360443 TI - Safety of posaconazole. AB - INTRODUCTION: The increasing number of invasive fungal infections (IFI) among immunocompromised hosts is a significant clinical issue. Diagnosis of IFI, choosing among the available antifungal drugs, and the high morbidity/mortality associated with IFI pose clinical challenges for healthcare providers. Besides efficacy, a thorough knowledge of the pharmacokinetics, drug-drug interactions and safety profile of the antifungal drugs is critical for appropriate drug selection. Among the commonly used triazoles, the recently released posaconazole is relatively less well investigated in terms of its safety. With expanding clinical use of posaconazole, the present review examines the safety of the drug and its propensity for drug-drug interaction. AREAS COVERED: This paper mainly discusses the safety profile of posaconazole, its adverse effects and drug-drug interaction. EXPERT OPINION: Posaconazole is generally safe and well tolerated. Lack of an intravenous formulation and unpredictable bioavailability of the suspension form are significant factors limiting the widespread use of posaconazole. PMID- 23360440 TI - Multifunctional gold nanoparticles for diagnosis and therapy of disease. AB - Gold nanoparticles (AuNPs) have a number of physical properties that make them appealing for medical applications. For example, the attenuation of X-rays by gold nanoparticles has led to their use in computed tomography imaging and as adjuvants for radiotherapy. AuNPs have numerous other applications in imaging, therapy and diagnostic systems. The advanced state of synthetic chemistry of gold nanoparticles offers precise control over physicochemical and optical properties. Furthermore gold cores are inert and are considered to be biocompatible and nontoxic. The surface of gold nanoparticles can easily be modified for a specific application, and ligands for targeting, drugs or biocompatible coatings can be introduced. AuNPs can be incorporated into larger structures such as polymeric nanoparticles or liposomes that deliver large payloads for enhanced diagnostic applications, efficiently encapsulate drugs for concurrent therapy or add additional imaging labels. This array of features has led to the aforementioned applications in biomedical fields, but more recently in approaches where multifunctional gold nanoparticles are used for multiple methods, such as concurrent diagnosis and therapy, so-called theranostics. This review covers basic principles and recent findings in gold nanoparticle applications for imaging, therapy and diagnostics, with a focus on reports of multifunctional AuNPs. PMID- 23360444 TI - Word-finding difficulties confound performance on verbal cognitive measures in adults with intractable left temporal lobe epilepsy. AB - This study sought to determine if word-finding difficulties (WFDs), which are common in adults with dominant temporal lobe epilepsy (TLE), are related to performance on verbal cognitive measures, including memory. One hundred six individuals with left TLE and pathologically confirmed mesial temporal sclerosis completed comprehensive preoperative neuropsychological evaluations. Patients were divided into two groups based on the degree of benefit received from phonemic cueing on a confrontation naming task. Cognitive performance was then compared between patients with greater and fewer WFDs. Patients with greater WFDs demonstrated poorer performance on many verbal cognitive measures compared to those with fewer WFDs. In contrast, there were no significant differences between groups on any of the nonverbal cognitive measures. Chi-square analyses indicated that below average verbal memory performance occurred at a significantly higher rate for patients with greater WFDs (42-46%) as compared to patients with fewer WFDs (18-24%). Results showed that WFDs confound performance on verbal cognitive measures in adult patients with left TLE, particularly on measures with high demands for lexical retrieval. This suggests that when patients have word retrieval difficulties, measures of verbal memory and verbal intelligence may be underestimated and potentially lead to misinterpretation of test performance and misinformation regarding risk of declines after surgical resection. PMID- 23360445 TI - Mood-congruent bias and attention shifts in the different episodes of bipolar disorder. AB - An "affective" go/no-go task was used in the different episodes of bipolar patients (euthymic, depressed, and manic) to examine (1) the presence of a mood congruent attentional bias; and (2) the patients' ability to inhibit and invert associations between stimuli and responses through blocks. A group of healthy individuals served as controls. Results revealed a mood-congruent attentional bias: patients in the manic episode processed positive information faster, whereas those in the depressive episode processed negative information faster. In contrast, neither euthymic patients nor healthy individuals showed any mood congruent biases. Furthermore, there was a shift cost across blocks for healthy individuals, but not for the patients. This may reflect a general impairment at selecting relevant information (e.g., in terms of disability to inhibit and invert associations between stimuli and responses) in bipolar participants, regardless of their episode. This state/trait dissociation in an episodic and chronic disorder such as bipolar disorder is important for its appropriate characterisation. PMID- 23360446 TI - Cross-sensitization between cocaine and acute restraint stress is associated with sensitized dopamine but not glutamate release in the nucleus accumbens. AB - Repeated administration of psychostimulant drugs or stress can elicit a sensitized response to the stimulating and reinforcing properties of the drug. Here we explore the mechanisms in the nucleus accumbens (NAc) whereby an acute restraint stress augments the acute locomotor response to cocaine. This was accomplished by a combination of behavioral pharmacology, microdialysis measures of extracellular dopamine and glutamate, and Western blotting for GluR1 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor (AMPAR). A single exposure to restraint stress 3 weeks before testing revealed that enduring locomotor sensitization to cocaine was paralleled by an increase in extracellular dopamine in the core, but not the shell subcompartment, of the NAc. Wistar rats pre-exposed to acute stress showed increased basal levels of glutamate in the core, but the increase in glutamate by acute cocaine was blunted. The alterations in extracellular glutamate seem to be relevant, as blocking AMPAR by 6-cyano-7-nitroquinoxaline-2,3-dione microinjection into the core prevented both the behavioral cross-sensitization and the augmented increase in cocaine-induced extracellular dopamine. Further implicating glutamate, the locomotor response to AMPAR stimulation in the core was potentiated, but not in the shell of pre-stressed animals, and this was accompanied by an increase in NAc GluR1 surface expression. This study provides evidence that the long-term expression of restraint stress-induced behavioral cross-sensitization to cocaine recapitulates some mechanisms thought to underpin the sensitization induced by daily cocaine administration, and shows that long-term neurobiological changes induced in the NAc by acute stress are consequential in the expression of cross sensitization to cocaine. PMID- 23360447 TI - Monascus-fermented yellow pigments monascin and ankaflavin showed antiobesity effect via the suppression of differentiation and lipogenesis in obese rats fed a high-fat diet. AB - Monascus-fermented monascin and ankaflavin are found to strongly inhibit differentiation and lipogenesis and stimulate lipolysis effects in a 3T3-L1 preadipocyte model, but the in vivo regulation mechanism is unclear. This study uses obese rats caused by a high-fat diet to examine the effects of daily monascin and ankaflavin feeding (8 weeks) on antiobesity effects and modulation of differentiation, lipogenesis, and lipid absorption. The results show that monascin and ankaflavin had a significant antiobesity effect, which should result from the modulation of monascin and ankaflavin on the inhibition of differentiation by inhibiting CCAT/enhancer-binding protein beta (C/EBPbeta) expression (36.4% and 48.3%) and its downstream peroxisome proliferator-activated receptor gamma (PPARgamma) (55.6% and 64.5%) and CCAT/enhancer-binding protein alpha (C/EBPalpha) expressions (25.2% and 33.2%) and the inhibition of lipogenesis by increasing lipase activity (14.0% and 10.7%) and decreasing heparin releasable lipoprotein lipase (HR-LPL) activity (34.8% and 30.5%). Furthermore, monascin and ankaflavin are the first agents found to suppress Niemann-Pick C1 Like 1 (NPC1L1) protein expression (73.6% and 26.1%) associated with small intestine tissue lipid absorption. Importantly, monascin and ankaflavin are not like monacolin K, which increases creatine phosphokinase (CPK) activity, known as a rhabdomyolysis indicator. PMID- 23360449 TI - Organoselenium compounds modulate extracellular redox by induction of extracellular cysteine and cell surface thioredoxin reductase. AB - The effect of selenium compounds on extracellular redox modulating capacity was studied in murine macrophage RAW 264.7 cells and differentiated human THP-1 monocytes. The arylselenium compounds benzeneselenol (PhSeH), dibenzyl diselenide (DBDSe), diphenyl diselenide (DPDSe), and ebselen were capable of inducing extracellular cysteine accumulation via a cystine- and glucose-dependent process. Extracellular cysteine production was dose-dependently inhibited by glutamate, an inhibitor of cystine/glutamate antiporter (Xc(-) transporter), supporting the involvement of Xc(-) transporter for cystine uptake in the above process. These arylselenium compounds also induced cellular thioredoxin reductase (TrxR) expression, particularly at the exofacial surface of cells. TrxR1 knockdown using small interfering RNA attenuated TrxR increases and cysteine efflux induced in cells by DPDSe. Sodium selenite (Na2SeO3), selenomethionine (SeMet), seleno-l cystine (SeCySS), and Se-methylselenocysteine (MeSeCys) did not have these effects on macrophages under the same treatment conditions. The effects of organoselenium compounds on extracellular redox may contribute to the known, but inadequately understood, biological effects of selenium compounds. PMID- 23360450 TI - Gold nanorods carrying paclitaxel for photothermal-chemotherapy of cancer. AB - Nanotechnology-based photothermal therapy has emerged as a promising treatment for cancer during the past decade. However, heterogeneous laser heating and limited light penetration can lead to incomplete tumor cell eradication. Here, we developed a method to overcome these limitations by combining chemotherapy with photothermal therapy using paclitaxel-loaded gold nanorods. Paclitaxel was loaded to gold nanorods with high density (2.0 * 10(4) paclitaxel per gold nanorod) via nonspecific adsorption, followed by stabilization with poly(ethylene glycol) linked with 11-mercaptoundecanoic acid. Paclitaxel was entrapped in the hydrophobic pocket of the polymeric monolayer on the surface of gold nanorods, which allows direct cellular delivery of the hydrophobic drugs via the lipophilic plasma membrane. Highly efficient drug release was demonstrated in a cell membrane mimicking two-phase solution. Combined photothermal therapy and chemotherapy with the paclitaxel-loaded gold nanorods was shown to be highly effective in killing head and neck cancer cells and lung cancer cells, superior to photothermal therapy or chemotherapy alone due to a synergistic effect. The paclitaxel-gold nanorod enabled photothermal chemotherapy has the potential of preventing tumor reoccurrence and metastasis and may have an important impact on the treatment of head and neck cancer and other malignancies in the clinic. PMID- 23360448 TI - Development of kappa opioid receptor antagonists. AB - kappa opioid receptors (KORs) belong to the G-protein-coupled class of receptors (GPCRs). They are activated by the endogenous opioid peptide dynorphin (DYN) and expressed at particularly high levels within brain areas implicated in modulation of motivation, emotion, and cognitive function. Chronic activation of KORs in animal models has maladaptive effects including increases in behaviors that reflect depression, the propensity to engage in drug-seeking behavior, and drug craving. The fact that KOR activation has such a profound influence on behaviors often triggered by stress has led to interest in selective KOR antagonists as potential therapeutic agents. This Perspective provides a description of preclinical research conducted in the development of several different classes of selective KOR antagonists, a summary of the clinical studies conducted thus far, and recommendations for the type of work needed in the future to determine if these agents would be useful as pharmacotherapies for neuropsychiatric illness. PMID- 23360452 TI - Mass transfer and adsorption equilibrium for low volatility alkanes in BPL activated carbon. AB - The structure of a molecule and its concentration can strongly influence diffusional properties for transport in nanoporous materials. We study mass transfer of alkanes in BPL activated carbon using the concentration-swing frequency response method, which can easily discriminate among mass transfer mechanisms. We measure concentration-dependent diffusion rates for n-hexane, n octane, n-decane, 2,7-dimethyloctane, and cyclodecane, which have different carbon numbers and geometries: straight chain, branched chain, and cyclic. Micropore diffusion is determined to be the controlling mass transfer resistance except at low relative saturation for n-decane, where an external mass transfer resistance also becomes important, showing that the controlling mass transfer mechanism can change with system concentration. Micropore diffusion coefficients are found to be strongly concentration dependent. Adsorption isotherm slopes obtained from measured isotherms, the concentration-swing frequency response method, and a predictive method show reasonably good agreement. PMID- 23360451 TI - Physiologic and metabolic characterization of a new marine isolate (BM39) of Pantoea sp. producing high levels of exopolysaccharide. AB - BACKGROUND: Marine environments are the widest fonts of biodiversity representing a resource of both unexploited or unknown microorganisms and new substances having potential applications. Among microbial products, exopolysaccharides (EPS) have many physiological functions and practical applications. Since EPS production by many bacteria is too scarce for practical use and only few species are known for their high levels of production, the search of new high EPS producers is of paramount importance. Many marine bacteria, that produce EPS to cope with strong environmental stress, could be potentially exploited at the industrial level. RESULTS: A novel bacterium, strain BM39, previously isolated from sediments collected in the Tyrrhenian Sea, was selected for its production of very high levels of EPS. BM39 was affiliated to Pantoea sp. (Enterobacteriaceae) by 16S rRNA gene sequencing and biochemical tests. According to the phylogenetic tree, this strain, being quite far from the closest known Pantoea species (96% identity with P. agglomerans and P. ananatis) could belong to a new species. EPS production was fast (maximum of ca. 21 g/L in 24 h on glucose medium) and mainly obtained during the exponential growth. Preliminary characterization, carried out by thin layer and gel filtration chromatography, showed that the EPS, being a glucose homopolymer with MW of ca. 830 kDa, appeared to be different from those of other bacteria of same genus. The bacterium showed a typical slightly halophilic behavior growing optimally at NaCl 40 0/00 (growing range 0-100 0/00). Flow cytometry studies indicated that good cell survival was maintained for 24 h at 120 0/00. Survival decreased dramatically with the increase of salinity being only 1 h at 280 0/00. The biochemical characterization, carried out with the Biolog system, showed that MB39 had a rather limited metabolic capacity. Its ability, rather lower than that of P. agglomerans, was almost only confined to the metabolization of simple sugars and their derivatives. Few alcohols, organic acids and nitrogen compounds were partially used too. CONCLUSIONS: Strain BM39, probably belonging to a new species, due to its remarkable EPS production, comparable to those of known industrial bacterial producers, could be suggested as a new microorganism for industrial applications. PMID- 23360453 TI - An overview of information giving in fertility clinics. AB - Information giving is a key aspect of the provision of high-quality patient centred health care, resulting in patients who are well-informed, better adjusted to their circumstances and are compliant with their treatment. Fertility patients generally appear to be satisfied with the information they are given but a significant minority are not. Giving information to infertile patients is complicated by the nature of their condition, desire for a child and complexity of treatment options. Patients need detailed, well-timed information to support difficult decision-making, such as when to end treatment. The experiences of some individual patients and particular sub-groups in receiving and understanding information suggest that the quality of information or the way it is communicated could be improved. It is suggested that this may be achieved by reviewing the format and timing of the information provided, ensuring adequate staff training and facilitating flexibility in clinic organisation. PMID- 23360454 TI - Differential expression of natural killer cell activating receptors in blood versus bone marrow in patients with monoclonal gammopathy. AB - In monoclonal gammopathies (MG) and multiple myeloma (MM), normal natural cytotoxicity receptors (NCR) expression (NCR1/NKp46, NCR2/NKp44, NCR3/NKp30) is observed in natural killer (NK) cells. Nonetheless, except in plasma cell leukemia, few tumor plasmocytes are present in PB, while NK studies have been performed on peripheral blood (PB). For this reason we focused our attention on NK from bone marrow (BM). Our study demonstrates that the down-regulation of NCR3/NKp30 is only detectable in NK from BM but not in PB, and shows a drastic decrease of both NKG2D and CD244/2B4/p38 expression in NK from BM in comparison with PB. In conclusion, our data more precisely describe the mechanism of immune escape of MG/MM from innate immunity since we show a drastic down regulation of 3 major activating NK receptors (NCR3/NKp30, NKG2D and CD244/2B4/p38) at the site of tumor, i.e BM, that was undetectable in PB. Further studies regarding immune regulatory drugs in MG/MM will imperiously require the assessment of immune cell status not only in PB but also in BM to obtain more relevant data regarding anti tumor efficacy. PMID- 23360455 TI - Stevens-Johnson Syndrome associated with mogamulizumab treatment of adult T-cell leukemia / lymphoma. AB - We report an adult T-cell leukemia/lymphoma patient suffering from Stevens Johnson Syndrome (SJS) during mogamulizumab (humanized anti-CCR4 monoclonal antibody) treatment. There was a durable significant reduction of the CD4(+) CD25(high) FOXP3(+) regulatory T (Treg) cell subset in the patient's PBMC, and the affected inflamed skin almost completely lacked FOXP3-positive cells. This implies an association between reduction of the Treg subset by mogamulizimab and occurrence of SJS. The present case should contribute not only to our understanding of human pathology resulting from therapeutic depletion of Treg cells, but also alert us to the possibility of immune-related severe adverse events such as SJS when using mogamulizumab. We are currently conducting a clinical trial of mogamulizumab for CCR4-negative solid cancers (UMIN000010050), specifically aiming to deplete Treg cells. PMID- 23360456 TI - NPC1 in human white adipose tissue and obesity. AB - BACKGROUND: Genetic studies have implicated the NPC1 gene (Niemann Pick type C1) in susceptibility to obesity. METHODS: To assess the potential function of NPC1 in obesity, we determined its expression in abdominal white adipose tissue (WAT) in relation to obesity. NPC1 mRNA was measured by RT-qPCR in lean and obese individuals, paired samples of subcutaneous (sc) and omental (om) WAT, before and after weight loss, in isolated adipocytes and intact adipose pieces, and in primary adipocyte cultures during adipocyte differentiation. NPC1 protein was examined in isolated adipocytes. RESULTS: NPC1 mRNA was significantly increased in obese individuals in scWAT and omWAT and downregulated by weight loss. NPC1 mRNA was enriched in isolated fat cells of WAT, in scWAT versus omWAT but not modified during adipocyte differentiation. NPC1 protein mirrored expression of mRNA in lean and obese individuals. CONCLUSIONS: NPC1 is highly expressed in human WAT adipocytes with increased levels in obese. These results suggest that NPC1 may play a role in adipocyte processes underlying obesity. PMID- 23360457 TI - Biological nitrogen fixation in the context of global change. AB - The intensive application of fertilizers during agricultural practices has led to an unprecedented perturbation of the nitrogen cycle, illustrated by the growing accumulation of nitrates in soils and waters and of nitrogen oxides in the atmosphere. Besides increasing use efficiency of current N fertilizers, priority should be given to value the process of biological nitrogen fixation (BNF) through more sustainable technologies that reduce the undesired effects of chemical N fertilization of agricultural crops. Wider legume adoption, supported by coordinated legume breeding and inoculation programs are approaches at hand. Also available are biofertilizers based on microbes that help to reduce the needs of N fertilization in important crops like cereals. Engineering the capacity to fix nitrogen in cereals, either by themselves or in symbiosis with nitrogen fixing microbes, are attractive future options that, nevertheless, require more intensive and internationally coordinated research efforts. Although nitrogen fixing plants may be less productive, at some point, agriculture must significantly reduce the use of warming (chemically synthesized) N and give priority to BNF if it is to sustain both food production and environmental health for a continuously growing human population. PMID- 23360458 TI - Modification of Tobacco rattle virus RNA1 to serve as a VIGS vector reveals that the 29K movement protein is an RNA silencing suppressor of the virus. AB - Tobacco rattle virus (TRV) has a bipartite, positive-sense single-stranded RNA genome and is widely used for virus-induced gene silencing (VIGS) in plants. RNA1 of TRV that lacks the gene for the cysteine-rich 16K silencing-suppression protein infects plants systemically in the absence of RNA2. Here, we attempted to engineer RNA1 for use as a VIGS vector by inserting heterologous gene fragments to replace 16K. The RNA1 vector systemically silenced the phytoene desaturase (PDS) gene, although less efficiently than when the original VIGS vector system was used, which consists of wild-type RNA1 and engineered RNA2 carrying the heterologous gene. Infectious RNA1 mutants with a dysfunctional 16K suppressed silencing and enhanced transgene expression in green fluorescent protein transgenic Nicotiana benthamiana following inoculation by agroinfiltration, unlike mutants that also lacked 29K, a movement protein (MP) gene. The 30K MP gene of Tobacco mosaic virus complemented in cis the movement defect but not the silencing suppression functions of TRV 29K. Silencing suppression by 29K occurred in the context of RNA1 replication but not in an agroinfiltration assay which tested 29K alone for suppression of sense-mediated silencing. Both 29K and 16K were needed to avoid necrotic symptoms in RNA1-infected N. benthamiana. The results shed new light on virulence factors of TRV. PMID- 23360459 TI - Genomic segments RNA1 and RNA2 of Prunus necrotic ringspot virus codetermine viral pathogenicity to adapt to alternating natural Prunus hosts. AB - Prunus necrotic ringspot virus (PNRSV) affects Prunus fruit production worldwide. To date, numerous PNRSV isolates with diverse pathological properties have been documented. To study the pathogenicity of PNRSV, which directly or indirectly determines the economic losses of infected fruit trees, we have recently sequenced the complete genome of peach isolate Pch12 and cherry isolate Chr3, belonging to the pathogenically aggressive PV32 group and mild PV96 group, respectively. Here, we constructed the Chr3- and Pch12-derived full-length cDNA clones that were infectious in the experimental host cucumber and their respective natural Prunus hosts. Pch12-derived clones induced much more severe symptoms than Chr3 in cucumber, and the pathogenicity discrepancy between Chr3 and Pch12 was associated with virus accumulation. By reassortment of genomic segments, swapping of partial genomic segments, and site-directed mutagenesis, we identified the 3' terminal nucleotide sequence (1C region) in RNA1 and amino acid K at residue 279 in RNA2-encoded P2 as the severe virulence determinants in Pch12. Gain-of-function experiments demonstrated that both the 1C region and K279 of Pch12 were required for severe virulence and high levels of viral accumulation. Our results suggest that PNRSV RNA1 and RNA2 codetermine viral pathogenicity to adapt to alternating natural Prunus hosts, likely through mediating viral accumulation. PMID- 23360460 TI - Unexpected phytostimulatory behavior for Escherichia coli and Agrobacterium tumefaciens model strains. AB - Plant-beneficial effects of bacteria are often underestimated, especially for well-studied strains associated with pathogenicity or originating from other environments. We assessed the impact of seed inoculation with the emblematic bacterial models Agrobacterium tumefaciens C58 (plasmid-cured) or Escherichia coli K-12 on maize seedlings in nonsterile soil. Compared with the noninoculated control, root biomass (with A. tumefaciens or E. coli) and shoot biomass (with A. tumefaciens) were enhanced at 10 days for 'PR37Y15' but not 'DK315', as found with the phytostimulator Azospirillum brasilense UAP-154 (positive control). In roots as well as in shoots, Agrobacterium tumefaciens and E. coli triggered similar (in PR37Y15) or different (in DK315) changes in the high-performance liquid chromatography profiles of secondary metabolites (especially benzoxazinoids), distinct from those of Azospirillum brasilense UAP-154. Genome sequence analysis revealed homologs of nitrite reductase genes nirK and nirBD and siderophore synthesis genes for Agrobacterium tumefaciens, as well as homologs of nitrite reductase genes nirBD and phosphatase genes phoA and appA in E. coli, whose contribution to phytostimulation will require experimental assessment. In conclusion, the two emblematic bacterial models had a systemic impact on maize secondary metabolism and resulted in unexpected phytostimulation of seedlings in the Azospirillum sp.-responsive cultivar. PMID- 23360461 TI - Circadian misalignment, reward-related brain function, and adolescent alcohol involvement. AB - BACKGROUND: Developmental changes in sleep and circadian rhythms that occur during adolescence may contribute to reward-related brain dysfunction, and consequently increase the risk of alcohol use disorders (AUDs). METHODS: This review (i) describes marked changes in circadian rhythms, reward-related behavior and brain function, and alcohol involvement that occur during adolescence, (ii) offers evidence that these parallel developmental changes are associated, and (iii) posits a conceptual model by which misalignment between sleep-wake timing and endogenous circadian timing may increase the risk of adolescent AUDs by altering reward-related brain function. RESULTS: The timing of sleep shifts later throughout adolescence, in part due to developmental changes in endogenous circadian rhythms, which tend to become more delayed. This tendency for delayed sleep and circadian rhythms is at odds with early school start times during secondary education, leading to misalignment between many adolescents' sleep-wake schedules and their internal circadian timing. Circadian misalignment is associated with increased alcohol use and other risk-taking behaviors, as well as sleep loss and sleep disturbance. Growing evidence indicates that circadian rhythms modulate the reward system, suggesting that circadian misalignment may impact adolescent alcohol involvement by altering reward-related brain function. Neurocognitive function is also subject to sleep and circadian influence, and thus circadian misalignment may also impair inhibitory control and other cognitive processes relevant to alcohol use. Specifically, circadian misalignment may further exacerbate the cortical-subcortical imbalance within the reward circuit, an imbalance thought to explain increased risk-taking and sensation seeking during adolescence. Adolescent alcohol use is highly contextualized, however, and thus studies testing this model will also need to consider factors that may influence both circadian misalignment and alcohol use. CONCLUSIONS: This review highlights growing evidence supporting a path by which circadian misalignment may disrupt reward mechanisms, which may in turn accelerate the transition from alcohol use to AUDs in vulnerable adolescents. PMID- 23360462 TI - Clinical manifestations of pediatric psoriasis: results of a multicenter study in the United States. AB - The clinical features of pediatric psoriasis warrant further attention. A national study was conducted to determine the prevalence of scalp and nail involvement and a history of guttate psoriasis at onset according to age, sex, and disease severity. One hundred eighty-one children ages 5 to 17 years with plaque psoriasis were enrolled in a multicenter, cross-sectional study. Subjects and guardians were asked about a history of scalp and nail involvement and whether the initial presentation was guttate. Peak psoriasis severity was assessed and defined historically as mild psoriasis (MP) or severe psoriasis (SP) according to the Physician's Global Assessment and body surface area measures. One hundred forty-three (79.0%) subjects reported a history of scalp involvement, and 71 (39.2%) described a history of nail involvement. Boys were less likely than girls to report a history of scalp involvement (odds ratio [OR] = 0.40, 95% confidence interval [CI] = 0.19-0.84) but more likely to have had nail involvement (OR = 3.01, 95% CI = 1.62-5.60). Scalp and nail involvement was not related to psoriasis severity. In contrast, subjects with SP (35.9%) more often reported a history of guttate lesions than did those with MP (21.8%) (p = .02). Antecedent streptococcal infection was more common in children with guttate than those with plaque psoriasis at onset (p = .02) but did not correlate with severity. Sex-related differences in scalp and nail involvement suggest koebnerization. Preceding streptococcal infection predicts guttate morphology but not severity, and initial guttate morphology is associated with eventual greater severity of disease. More aggressive monitoring and management should be considered for guttate psoriasis, given its later association with more severe disease. PMID- 23360464 TI - Colloidal aggregates of Pd nanoparticles supported by larch arabinogalactan. AB - Palladium nanoparticles (PdNPs) are used in catalysis, hydrogen storage, biomedicine, and so on. Arranging the self-assembly of PdNPs within colloidal aggregates is desirable for improving their consumer properties. Stable widely dispersed colloidal aggregates of larch arabinogalactan (LARB) containing nanosized (5-nm) PdNPs were obtained by reducing Pd ions in alkaline solutions of LARB. Centrifugation resulted in a set of LARB-PdNP colloids ranging from 60 to 240 nm. The colloids were studied by static light scattering (SLS) and dynamic light scattering (DLS). The SLS data presented as Kratki plots correspond to a particle scattering factor of linear rather than branched chains. The fractal dimension of the LARB-PdNP colloids was found by SLS to be d = 1.96, which is between the values for diffusion- and reaction-limited aggregation. This result is ascribed to the aggregate's internal motion, which is evident from the power law exponent of the dependence of the DLS relaxation rate on the scattering vector, ~ q(alpha) with alpha = 2.24. The structure-sensitive ratio of the radius of gyration to the hydrodynamic radius was found to vary within the interval of 0.8 <= R(g)/R(h) <= 1.2 corresponding, to the spherical form of LARB PdNP colloids. A spiderweblike PdNP distribution pattern was observed by transmission electron microscopy. Insertion of PdNPs did not affect the fractal dimension, the power-law exponent alpha, or the architecture of the pristine LARB aggregates in water. The red shift of the surface plasmon extinction observed with increasing LARB-PdNP colloidal size indicates the collective optical response of the PdNP ensemble in the colloid. PMID- 23360463 TI - Is walking to school associated with improved metabolic health? AB - BACKGROUND: Active commuting to/from school is an important source of physical activity that has been declining over the past years. Although it is an affordable and simple way of increasing physical activity levels it is still unclear whether it has enough potential to improve health. Therefore, the aim of this cross sectional study was to examine the relationship between active commuting to/from school and metabolic risk factors in 10 to 12 year old children. METHODS: Participants were 229 adolescents, selected through consecutive sampling, (121 girls) with mean age of 11.65 (+/-0.73) years old from Porto, Portugal. Means of transport to/from school was accessed by asking: "How do you usually travel to school?" and "How do you usually travel from school?". Active commuting was considered if children reported at least one of the trips (to or from school) by active means. Total physical activity was obtained with Actigraph accelerometer for 7 consecutive days. Lipid profile measurements were conducted with Cholestech LDX(r) analyser. Waist circumference and blood pressure were measured by standard methods. The criteria for metabolic syndrome defined by International Diabetes Federation for children and adolescents were used. RESULTS: Adjusted binary logistic regression analysis suggested that walkers have higher odds to have a better waist circumference (OR = 2.64, 95% CI = 1.63-6.01) and better high density lipoprotein cholesterol (OR = 2.14, 95% CI = 1.01-4.52) profiles than non-active commuters, independent of moderate-to-vigorous physical activity. No associations were found for other metabolic risk factors. CONCLUSIONS: Exertions to increase and maintain walking to school may be particularly relevant as it is likely to have a positive impact on children's health and eventually decrease metabolic and cardiovascular diseases. PMID- 23360465 TI - Selective cell death by photochemically induced pH imbalance in cancer cells. AB - Singlet oxygen sensitized photodynamic therapy (PDT) relies on the concentration of oxygen in the tissue to be treated. Most cancer lesions, however, have poor vasculature and, as a result, are hypoxic, significantly hindering PDT efficacies. An oxygen-independent PDT method may circumvent this limitation. To address this, we prepared sulfonium salts that produced a pH drop within HCT 116 cells via the generation of a photoacid within the cytosol. This process was driven by one- or two-photon absorption (1PA or 2PA) of the endocytosed photoacid generators (PAGs). One of these PAGs, which had a significantly lower dark cytotoxicity and was more efficient in generating a photoacid, effectively induced necrotic cell death in the HCT 116 cells. The data suggest that PAGs may be an attractive alternative PDT modality to selectively induce cell death in oxygen-deprived tissue such as tumors. PMID- 23360466 TI - Variable magnetic interactions between S = 1/2 cation radical salts of functionalizable electron-rich dithiolene and diselenolene Cp2Mo complexes. AB - A series of Cp(2)Mo(dithiolene) and Cp(2)Mo(diselenolene) complexes containing N alkyl-1,3-thiazoline-2-thione-4,5-dithiolate ligand (R-thiazdt, R = Me, Et, CH(2)CH(2)OH) and N-alkyl-1,3-thiazoline-2-thione-4,5-diselenolate ligand (R thiazds, R = Me, Et) have been synthesized. These heteroleptic molybdenum complexes have been characterized by electrochemistry, spectroelectrochemistry, and single crystal X-ray diffraction. They act as very good electron donor complexes with a first oxidation potential 200 mV lower than in the prototypical Cp(2)Mo(dmit) complex and exhibit almost planar MoS(2)C(2) (or MoSe(2)C(2)) metallacycles. All five complexes formed charge transfer salts with a weak (TCNQ) and a strong acceptor (TCNQF(4)), affording ten different charge-transfer salts, all with 1:1 stoichiometry. Crystal structure determinations show that the S/Se substitution in the metallacycle systematically affords isostructural salts, while the Cp(2)Mo(R-thiazdt) complexes with R equals ethyl or CH(2)CH(2)OH can adopt different structures, depending on the involvement of the hydroxyl group into intra- or intermolecular hydrogen bonding interactions. Magnetic susceptibility data of the salts are correlated with their structural organization, demonstrating that a face-to-face organization of the Me-thiazdt (or Me-thiazds) ligand favors a strong antiferromagnetic interaction, while the bulkier R = Et or R = CH(2)CH(2)OH substituents can completely suppress such intermolecular interactions, with the added contribution of hydrogen bonding to the solid state organization. PMID- 23360467 TI - Genetically encoded copper(I) reporters with improved response for use in imaging. AB - Copper represents one of the most important biological metal ions due to its role as a catalytic cofactor in a multitude of proteins. However, an excess of copper is highly toxic. Thus, copper is heavily regulated, and copper homeostasis is controlled by many metalloregulatory proteins in various organisms. Here we report a genetically encoded copper(I) probe capable of monitoring copper fluctuations inside living cells. We insert the copper regulatory protein Ace1 into a yellow fluorescent protein, which selectively binds copper(I) and generates improved copper(I) probes. PMID- 23360468 TI - The ICP22 protein selectively modifies the transcription of different kinetic classes of pseudorabies virus genes. AB - BACKGROUND: Pseudorabies virus (PRV), an alpha-herpesvirus of swine, is a widely used model organism in investigations of the molecular pathomechanisms of the herpesviruses. This work is the continuation of our earlier studies, in which we investigated the effect of the abrogation of gene function on the viral transcriptome by knocking out PRV genes playing roles in the coordination of global gene expression of the virus. In this study, we deleted the us1 gene encoding the ICP22, an important viral regulatory protein, and analyzed the changes in the expression of other PRV genes. RESULTS: A multi-timepoint real time RT-PCR technique was applied to evaluate the impact of deletion of the PRV us1 gene on the overall transcription kinetics of viral genes. The mutation proved to exert a differential effect on the distinct kinetic classes of PRV genes at the various stages of lytic infection. In the us1 gene-deleted virus, all the kinetic classes of the genes were significantly down-regulated in the first hour of infection. After 2 to 6 h of infection, the late genes were severely suppressed, whereas the early genes were unaffected. In the late stage of infection, the early genes were selectively up-regulated. In the mutant virus, the transcription of the ie180 gene, the major coordinator of PRV gene expression, correlated closely with the transcription of other viral genes, a situation which was not found in the wild-type (wt) virus. A 4-h delay was observed in the commencement of DNA replication in the mutant virus as compared with the wt virus. The rate of transcription from a gene normalized to the relative copy number of the viral genome was observed to decline drastically following the initiation of DNA replication in both the wt and mutant backgrounds. Finally, the switch between the expressions of the early and late genes was demonstrated not to be controlled by DNA replication, as is widely believed, since the switch preceded the DNA replication. CONCLUSIONS: Our results show a strong dependence of PRV gene expression on the presence of functional us1 gene. ICP22 is shown to exert a differential effect on the distinct kinetic classes of PRV genes and to disrupt the close correlation between the transcription kinetics of ie180 and other PRV transcripts. Furthermore, DNA replication exerts a severe constraint on the viral transcription. PMID- 23360470 TI - PXR/CYP3A4-humanized mice for studying drug-drug interactions involving intestinal P-glycoprotein. AB - Rodent models are less suitable for predicting drug-drug interactions at the level of the human intestinal mucosa, especially when nuclear receptors such as pregnane X receptor (PXR) are involved. Recently, a transgenic mouse model, expressing both human PXR and CYP3A4, was developed and shown to be a better predictor of CYP3A4 induction by xenobiotics in humans as compared to wild-type mice. In the present study, we tested the hypothesis that this mouse model can also predict PXR-mediated induction of intestinal P-gp in humans. By use of the in situ intestinal perfusion technique with mesenteric blood sampling, the effect of oral rifampicin treatment on intestinal permeability for the HIV protease inhibitor darunavir, a dual CYP3A4/P-gp substrate, was investigated. Rifampicin treatment lowered the intestinal permeability for darunavir by 50% compared to that in nontreated mice. The P-gp inhibitor GF120918 increased the permeability for darunavir by 400% in rifampicin-treated mice, whereas this was only 56% in mice that were not treated, thus indicating P-gp induction by rifampicin. The nonspecific P450 inhibitor aminobenzotriazole (100 MUM) did not affect the permeability for darunavir. Quantitative Western blot analysis of the intestinal tissue showed that rifampicin treatment induced intestinal P-gp levels 4-fold, while CYP3A4 levels remained unchanged. Oral co-administration of rifampicin with the phytochemical sulforaphane for 3 days increased the permeability for darunavir by 50% compared to that with rifampicin treatment alone. These data show that PXR/CYP3A4-humanized mice can be used to study the inducing effects of xenobiotics on intestinal P-gp. PMID- 23360469 TI - Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. AB - PURPOSE: To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS), and benign familial infantile seizures (BFIS). METHODS: Families with at least two first-degree relatives affected by focal seizures starting within the first year of life and normal development before seizure onset were included. Families were classified as BFNS when all family members experienced neonatal seizures, BFNIS when the onset of seizures in family members was between 1 and 4 months of age or showed both neonatal and infantile seizures, and BFIS when the onset of seizures was after 4 months of age in all family members. SCN2A, KCNQ2, KCNQ3, PPRT2 point mutations were analyzed by direct sequencing of amplified genomic DNA. Genomic deletions involving KCNQ2 and KCNQ3 were analyzed by multiple dependent probe amplification method. KEY FINDINGS: A total of 46 families including 165 affected members were collected. Eight families were classified as BFNS, 9 as BFNIS, and 29 as BFIS. Genetic analysis led to the identification of 41 mutations, 14 affecting KCNQ2, 1 affecting KCNQ3, 5 affecting SCN2A, and 21 affecting PRRT2. The detection rate of mutations in the entire cohort was 89%. In BFNS, mutations specifically involve KCNQ2. In BFNIS two genes are involved (KCNQ2, six families; SCN2A, two families). BFIS families are the most genetically heterogeneous, with all four genes involved, although about 70% of them carry a PRRT2 mutation. SIGNIFICANCE: Our data highlight the important role of KCNQ2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures during follow up is associated with KCNQ2 mutations and may represent a predictive factor. In addition, we showed that KCNQ3 mutations might be also involved in families with infantile seizures. Taken together our data indicate an important role of K channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN2A mutation in a family with infantile seizures with onset between 6 and 8 months provides further confirmation that this gene is not specifically associated with BFNIS and is also involved in families with a delayed age of onset. Our data indicate that PRRT2 mutations are clustered in families with BFIS. Paroxysmal kinesigenic dyskinesia emerges as a distinctive feature of PRRT2 families, although uncommon in our series. We showed that the age of onset of seizures is significantly correlated with underlying genetics, as about 90% of the typical BFNS families are linked to KCNQ2 compared to only 3% of the BFIS families, for which PRRT2 represents the major gene. PMID- 23360471 TI - Dual effect of platelet lysate on human articular cartilage: a maintenance of chondrogenic potential and a transient proinflammatory activity followed by an inflammation resolution. AB - Platelet-rich plasma (PRP), a cocktail of platelet growth factors and bioactive proteins, has been proposed as a therapeutic agent to restore damaged articular cartilage. We report the biological effect of the platelet lysate (PL), a PRP derivative, on primary human articular chondrocytes cultured under both physiological and inflammatory conditions. When added to the culture medium, PL induced a strong mitogenic response in the chondrocytes. The in vitro expanded cell population maintained a chondrogenic redifferentiation potential as revealed by micromass culture in vitro and ectopic cartilage formation in vivo. Further, in chondrocytes cultured in the presence of the proinflammatory cytokine interleukin-1alpha (IL-1alpha), the PL induced a drastic enhancement of the synthesis of the cytokines IL-6 and IL-8 and of neutrophil-gelatinase associated lipocalin, a lipocalin expressed during chondrocyte differentiation and inflammation. These events were mediated by the p38 MAP kinase and NF-kappaB pathways. We observed that inflammatory stimuli activated phospo-MAP kinase activated protein kinase 2, a direct target of p38. The proinflammatory effect of the PL was a transient phenomenon; after an initial upregulation, we observed significant reduction of the NF-kappaB activity together with the repression of the inflammatory enzyme cyclooxygenase-2. Moreover, the medium of chondrocytes cultured in the simultaneous presence of PL and IL-1alpha, showed a significant enhancement of the chemoattractant activity versus untreated chondrocytes. Our findings support the concept that the platelet products have a direct beneficial effect on articular chondrocytes and could drive in sequence a transient activation and the resolution of the inflammatory process, thus providing a rational for their use as therapeutic agents in cartilage inflammation and damage. PMID- 23360472 TI - Identification and characterization of rhizosphere fungal strain MF-91 antagonistic to rice blast and sheath blight pathogens. AB - AIM: To examine the inhibition effects of rhizosphere fungal strain MF-91 on the rice blast pathogen Magnaporthe grisea and sheath blight pathogen Rhizoctonia solani. METHODS AND RESULTS: Rhizosphere fungal strain MF-91 and its metabolites suppressed the in vitro mycelial growth of R. solani. The inhibitory effect of the metabolites was affected by incubation temperature, lighting time, initial pH and incubation time of rhizosphere fungal strain MF-91. The in vitro mycelial growth of M. grisea was insignificantly inhibited by rhizosphere fungal strain MF 91 and its metabolites. The metabolites of rhizosphere fungal strain MF-91 significantly inhibited the conidial germination and appressorium formation of M. grisea. Moreover, the metabolites reduced the disease index of rice sheath blight by 35.02% in a greenhouse and 57.81% in a field as well as reduced the disease index of rice blast by 66.07% in a field. Rhizosphere fungal strain MF-91 was identified as Chaetomium aureum based on the morphological observation, the analysis of 18S ribosomal DNA internal transcribed spacer sequence and its physiological characteristics, such as the optimal medium, temperature and initial pH for mycelial growth and sporulation production. CONCLUSIONS: Rhizosphere fungus C. aureum is effective in the biocontrolling of rice blast pathogen M. grisea and sheath blight pathogen R. solani both in in vitro and in vivo conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first to show that rhizosphere fungus C. aureum is a potential fungicide against rice blast and sheath blight pathogens. PMID- 23360473 TI - Gold-catalyzed intramolecular hydroamination of o-alkynylbenzyl carbamates: a route to chiral fluorinated isoindoline and isoquinoline derivatives. AB - Enantiomerically pure fluorinated isoindoline and dihydroisoquinoline scaffolds have been prepared through a diastereoselective addition of fluorinated nucleophiles to Ellman's N-(tert-butanesulfinyl)imines followed by a sequence of Sonogashira cross-coupling/gold(I)-catalyzed cycloisomerization of the corresponding carbamate. A more favored 5-exo-dig mechanism was observed mainly due to an electronic effect of the fluorinated group. PMID- 23360474 TI - Weight-adjusted versus fixed dose of linezolid for Chinese healthy volunteers of higher and lower body weight: a Phase I pharmacokinetic and pharmacodynamic study. AB - OBJECTIVES: The objective was to evaluate the pharmacokinetic and pharmacodynamic properties of a single intravenous fixed dose compared with a weight-adjusted dose of linezolid. METHODS: A Phase I, comparative clinical trial was conducted involving 20 healthy male Chinese volunteers, assigned into low weight (LW) (50 kg < weight <= 55 kg) and high weight (HW) (>= 80 kg) groups. All subjects were administrated single dose of linezolid (600 mg/30 min) and, after 72 h washout period, another single-dose (10 mg/kg/30 min). Plasma linezolid concentrations were measured by liquid chromatography-tandem mass spectrometry. A Monte Carlo simulation was used to evaluate the probability of pharmacodynamic target attainment (PTA). RESULTS: With 600 mg dose, plasma concentrations in LW group were much higher than that in HW group. A persistent serum inhibitory activity was observed in LW group; the inhibitory activity was lower in HW group. The PTA in HW group was lower than in LW group. For 10 mg/kg dose, both HW and LW groups had similar plasma concentrations. The HW and LW groups had similar serum inhibitory effects. The PTA in HW and LW groups also showed no difference. CONCLUSIONS: Our findings suggest that a weight-adjusted, 10 mg/kg regimen of linezolid may be more appropriate than fixed dosing for patients of different body weight. PMID- 23360475 TI - Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents. AB - The natural product tryptanthrin (1a) represents a potential lead for new tuberculosis (TB) drugs since tryptanthrin and its synthetic analogues possess potent in vitro activity against Mycobacterium tuberculosis (Mtb). However, in spite of their in vitro activity, none of these agents have been shown to be efficacious in vivo against animal models of TB. Described herein are syntheses of new tryptanthrin analogues together with a systematic investigation of their in vitro antitubercular activity and ADME properties followed by pharmacokinetic characterization in rodents for the most promising compounds. Those with the best potency and oral bioavailability were progressed to evaluations of efficacy against acute murine TB. The work aimed to prove the concept that this compound class can limit growth of Mtb during infection as well as to establish the SAR for in vitro activity against Mtb and the range of in vitro ADME parameters for this class of natural products. Novel C-11-deoxy (5b) and A-ring-saturated (6) tryptanthrin analogues were discovered that maintained activity against Mtb and showed improved solubility compared to tryptanthrin as well as evidence of oral bioavailability in rodents. However, neither 5b nor 6 demonstrated efficacy against acute murine TB following administration at doses up to 400 mg/kg daily for 4 weeks. Although 5b and 6 failed to inhibit replication or kill Mtb in vivo, they illuminate a path to new structural variations of the tryptanthrin scaffold that may maximize the potential of this class of compounds against TB. PMID- 23360476 TI - Glycosaminoglycans are functional ligands for receptor for advanced glycation end products in tumors. AB - Glycosaminoglycans, including chondroitin sulfate (CS), dermatan sulfate, and heparan sulfate, attached to proteoglycans at the surface of tumor cells play key roles in malignant transformation and metastasis. A Lewis lung carcinoma (LLC) derived tumor cell line with high metastatic potential shows a higher proportion of E disaccharide units, d-glucuronic acid-GalNAc(4,6-O-disulfate), in CS chains than LLC cells with low metastatic potential, suggesting that E units in the CS chains contribute to the metastatic potential. In fact, the metastasis of LLC to mouse lungs is drastically inhibited by preadministration of CS-E or a phage display antibody specific for CS-E. However, the molecular mechanism underlying the pulmonary metastasis involving CS chains remained to be elucidated. Recently, receptor for advanced glycation end-products (RAGE), which is predominantly expressed in the lung, was identified as a functional receptor for CS chains containing E units. RAGE strongly interacted with not only CS-E but also heparan sulfate in vitro. The interaction with CS-E required a decasaccharide length and a cluster of basic amino acids. Intriguingly, antibody against RAGE robustly inhibited the pulmonary metastasis of not only LLC but also B16 melanoma cells, which also colonize mouse lungs after injection into a tail vein. Thus, CS chains containing E units are involved in the metastatic process, and RAGE is a critical receptor for glycosaminoglycan chains expressed at the tumor cell surface. Hence, RAGE and glycosaminoglycans are potential targets of drugs for pulmonary metastasis and a number of other pathological conditions involving RAGE in the pathogenetic mechanism. PMID- 23360477 TI - Optimal temperature range of a plastic species, Drosophila simulans. AB - 1. When a species experiences a new climate, it can adapt in two main ways: become genetically adapted to the new temperature, or adopt a plastic approach that allows it to survive at a range of temperatures. 2. The constraint on fitness for genetically adapted populations that are exposed to a new temperature has been well studied, but the range of optimal temperatures and their effect on fitness has never been examined across the worldwide distribution of a plastic species. 3. Here, we determined the optimum temperature range of 11 populations of the phenotypically plastic species Drosophila simulans. We measured the influence of temperature on eggs, larvae and adults at six temperatures that span the natural range the flies experience during their primary breeding season. We found no correlation between optimum temperature and native temperature, an effect that is not likely due to laboratory maintenance, suggesting that the species has not locally adapted to temperature. 4. We also found that this species had equal survival and reproductive success at most of the temperatures and life stages that we tested, regardless of the native temperature where the flies originated. 5. Thus, this genetically plastic species has an optimum fitness at a surprisingly wide range of temperatures, and is the first example of a cosmopolitan species exhibiting this large amount of plasticity across its sampling distribution. PMID- 23360478 TI - Endocytosis and intracellular dissociation rates of human insulin-insulin receptor complexes by quantum dots in living cells. AB - Insulin signaling is involved in glucose metabolism, cellular growth, and differentiation. Its function is altered in diabetes and many cancer types. Insulin binding to insulin receptor (IR) triggers diverse signaling pathways. However, signal transduction by IR is not mediated exclusively at the cell surface. Activated ligand-receptor complexes are internalized into endosomes from which the IR recruits adapters acting on substrates that are distinct from those accessible at the membrane. We report the biotinylation of human-recombinant insulin (rhIns) specifically at the position 29 of the B chain. We combined visible fluorescent proteins fused to IR and biotinylated rhIns conjugated with streptavidin-quantum dots to perform extended, quantitative experiments in real time. Modified rhIns bound to the IR and conjugated with the quantum dots was internalized with a rate constant (k) of 0.009 min(-1). Dissociation of insulin IR complex in endocytosed vesicles occurred with k = 0.006 min(-1). PMID- 23360479 TI - High effective coverage of vector control interventions in children after achieving low malaria transmission in Zanzibar, Tanzania. AB - BACKGROUND: Formerly a high malaria transmission area, Zanzibar is now targeting malaria elimination. A major challenge is to avoid resurgence of malaria, the success of which includes maintaining high effective coverage of vector control interventions such as bed nets and indoor residual spraying (IRS). In this study, caretakers' continued use of preventive measures for their children is evaluated, following a sharp reduction in malaria transmission. METHODS: A cross-sectional community-based survey was conducted in June 2009 in North A and Micheweni districts in Zanzibar. Households were randomly selected using two-stage cluster sampling. Interviews were conducted with 560 caretakers of under-five-year old children, who were asked about perceptions on the malaria situation, vector control, household assets, and intention for continued use of vector control as malaria burden further decreases. RESULTS: Effective coverage of vector control interventions for under-five children remains high, although most caretakers (65%; 363/560) did not perceive malaria as presently being a major health issue. Seventy percent (447/643) of the under-five children slept under a long-lasting insecticidal net (LLIN) and 94% (607/643) were living in houses targeted with IRS. In total, 98% (628/643) of the children were covered by at least one of the vector control interventions. Seasonal bed-net use for children was reported by 25% (125/508) of caretakers of children who used bed nets. A high proportion of caretakers (95%; 500/524) stated that they intended to continue using preventive measures for their under-five children as malaria burden further reduces. Malaria risk perceptions and different perceptions of vector control were not found to be significantly associated with LLIN effective coverage. CONCLUSIONS: While the majority of caretakers felt that malaria had been reduced in Zanzibar, effective coverage of vector control interventions remained high. Caretakers appreciated the interventions and recognized the value of sustaining their use. Thus, sustaining high effective coverage of vector control interventions, which is crucial for reaching malaria elimination in Zanzibar, can be achieved by maintaining effective delivery of these interventions. PMID- 23360480 TI - Atrial remodeling in newly diagnosed drug-naive hypertensive subjects. AB - BACKGROUND: Systemic hypertension is a major risk factor for heart disease and stroke. Data regarding temporal relationship of left atrial (LA) remodeling to onset of hypertension are sparse. We aimed to quantitate LA structural and functional remodeling in newly diagnosed hypertensive patients. METHOD: We prospectively identified 380 patients with newly diagnosed systemic hypertension naive to drug therapy, and 380 age-matched control subjects without any history or evidence of hypertension. History or evidence of prior cardiovascular events, congenital or valvular heart disease, and renal dysfunction were exclusion criteria. Prevalence of LA enlargement, LA mechanical dysfunction expressed in total emptying fraction, left ventricular (LV) diastolic dysfunction, LV hypertrophy, and their interrelationships were assessed. RESULTS: Of the 380 newly diagnosed hypertensive patients, 285 (75%) had LA enlargement, 308 (81%) had LA mechanical dysfunction, and 19 (5%) had LVH. Diastolic dysfunction was present in 334 (88%) of the patients. Compared to the controls, the hypertensive group had larger maximal, minimal, and pre-A LA volumes (all P < 0.001). Total and active LA emptying fraction were significantly reduced (both P < 0.001). Total LA emptying fraction was strongly associated with systolic blood pressure [per 10 mmHg, HR 0.94 (0.89-0.98); P < 0.001], with stepwise decrease in LA emptying fraction of 6%, 10%, and 16% from the lowest (141-150 mmHg) to the top tertile of systolic blood pressure (>160 mmHg). CONCLUSION: In this drug-naive cohort with newly diagnosed hypertension, LA structural and functional remodeling, and LV diastolic dysfunction were common findings prior to initiation of drug treatment. LVH was uncommon. Impairment of LA mechanical function was evident even in the mildly hypertensive subgroup. PMID- 23360482 TI - Ultraviolet laser induced hydrogen transfer reaction: study of the first step of MALDI in-source decay mass spectrometry. AB - The early mechanisms of matrix-assisted laser desorption/ionization in-source decay (MALDI-ISD) are described herein. MALDI-ISD is initiated by the hydrogen transfer from excited matrix molecules to the carbonyl oxygen of the peptide backbone, which is followed by a radical-induced cleavage, producing the c'/z* fragment pair. As expected, the use of 2,5-DHB or 1,5-DAN was efficient to induce MALDI-ISD, and the strongest intensity of MALDI-ISD fragments was observed when laser shots were performed on matrix crystals. In contrast, the hydrogen radical transfer reaction was suppressed by using ionic liquid and amorphous structure of 2,5-DHB and 1,5-DAN mixture as a matrix. Our results suggest that the hydrogen transfer occurs on the matrix crystal during the dissipation of the laser energy and before desorption, following ISD fragments formed in the MALDI plume. PMID- 23360481 TI - Estrogen-related receptor beta deletion modulates whole-body energy balance via estrogen-related receptor gamma and attenuates neuropeptide Y gene expression. AB - Estrogen-related receptors (ERRs) alpha, beta and gamma are orphan nuclear hormone receptors with no known ligands. Little is known concerning the role of ERRbeta in energy homeostasis, as complete ERRbeta-null mice die mid-gestation. We generated two viable conditional ERRbeta-null mouse models to address its metabolic function. Whole-body deletion of ERRbeta in Sox2-Cre:ERRbeta(lox/lox) mice resulted in major alterations in body composition, metabolic rate, meal patterns and voluntary physical activity levels. Nestin-Cre:ERRbeta(lox/lox) mice exhibited decreased expression of ERRbeta in hindbrain neurons, the predominant site of expression, decreased neuropeptide Y (NPY) gene expression in the hindbrain, increased lean body mass, insulin sensitivity, increased energy expenditure, decreased satiety and decreased time between meals. In the absence of ERRbeta, increased ERRgamma signaling decreased satiety and the duration of time between meals, similar to meal patterns observed for both the Sox2 Cre:ERRbeta(lox/lox) and Nestin-Cre:ERRbeta(lox/lox) strains of mice. Central and/or peripheral ERRgamma signaling may modulate these phenotypes by decreasing NPY gene expression. Overall, the relative expression ratio between ERRbeta and ERRgamma may be important in modulating ingestive behavior, specifically satiety, gene expression, as well as whole-body energy balance. PMID- 23360483 TI - Emotional intelligence competencies provide a developmental curriculum for medical training. AB - Since healthcare faces challenges of access, quality, and cost, effective leadership for healthcare is needed. This need is especially acute among physicians, whose demanding training focuses on scientific and clinical skills, eclipsing attention to leadership development. Among the competencies needed by leaders, emotional intelligence (EI) - defined as the ability to understand and manage oneself and to understand others and manage relationships - has been shown to differentiate between great and average leaders. In this context, teaching EI as part of the medical training curriculum is recommended. Furthermore, because physicians' developmental needs evolve over the course of prolonged training, specific components of EI (e.g., teambuilding, empathy, and negotiation) should be taught at various phases of medical training. Consistent with the concept of a spiral curriculum, such EI competencies should be revisited iteratively throughout training, with differing emphasis and increasing sophistication to meet evolving needs. For example, teamwork training is needed early in undergraduate medical curricula to prompt collaborative learning. Teamwork training is also needed during residency, when physicians participate with differing roles on patient care teams. Training in EI should also extend beyond graduate medical training to confer the skills needed by clinicians and by faculty in academic medical centers. PMID- 23360484 TI - Stages and transitions in medical education around the world: clarifying structures and terminology. AB - BACKGROUND: In a world that increasingly serves the international exchange of information on medical training, many students, physicians and educators encounter numerous variations in curricula, degrees, point of licensing and terminology. AIMS: The aim of this study was to shed some light for those trying to compare medical training formats across countries. METHODS: We surveyed a sample of key informants from 40 countries. Survey questions included: structure of medical education, moment that unrestricted practice is allowed, various options after general medical licensing, nomenclature of degrees granted and relevant terminology related to the medical education system. In addition, we searched the literature for description of country-specific information. RESULTS: Based on the results, we described the six models of current medical training around the world, supplemented with a list of degrees granted after medical school and an explanation of frequently used terminology. CONCLUSIONS: The results of this questionnaire study lead to the conclusion that while there are many differences between countries, there appear to be six dominant models. The models vary in structure and length of medical training, point of full registration and degrees that are granted. PMID- 23360485 TI - Career choices of the United Kingdom medical graduates of 2005, 2008 and 2009: questionnaire surveys. AB - OBJECTIVES: To compare specialty choices of the UK medical graduates of 2005, 2008 and 2009, one year after graduation, with those of graduates from previous years and with the distribution of senior medical practitioners working in England. METHOD: Postal questionnaire surveys. RESULTS: The proportion of graduates giving more than one specialty choice rose in the most recent cohorts. Among men, choices for surgical careers fell from 37% of 2005 graduates to 25% of 2008 and 2009 graduates. The percentages who specified anaesthetics, general practice and obstetrics and gynaecology rose. Among women, general practice and surgery were unchanged in popularity, but increasing percentages specified paediatrics, anaesthetics and obstetrics and gynaecology. Choices for psychiatry and emergency medicine showed no trend. General practice was substantially under represented, and hospital surgical and medical specialties were over-represented, in choices when compared to the distribution of senior National Health Service doctors. CONCLUSION: More current graduates consider two or more specialties than did their predecessors, which may reflect an increase in uncertainty about obtaining a post in their favoured specialty. The specialty preferences expressed by newly qualified doctors, notably the shortfall in numbers choosing general practice, remain inconsistent with future service needs. PMID- 23360486 TI - Interprofessional clinical training improves self-efficacy of health care students. AB - BACKGROUND: Interprofessional collaboration potentially enhances patient safety and satisfaction, and reduces tensions and conflicts among health professionals. However, health professionals often lack sufficient knowledge of other professional roles and competences to engage in interprofessional teamwork. The aim of this study was to assess the impact of an interprofessional training programme on students' perceived self-efficacy. METHODS: A quasi-experimental study with an intervention group (239 students) and a control group (405 students). The intervention was an interprofessional clinical study (ICS) unit including students from nursing, medicine, physiotherapy, occupational therapy, laboratory technology and radiography. Data on students' perceived self-efficacy were collected through web-based questionnaires. Aspects of self-efficacy measured were: (1) collaboration with other professions in planning goals and actions for patients; (2) collaboration with other professions for rehabilitation; (3) identifying the functions of other professions and (4) assessing and describing patients' needs and problems. RESULTS: All scores of perceived self-efficacy for the ICS group improved over time although one score change was non-significant (p = 0.08). After adjustment for baseline differences and the score change for the control group, the ICS group's self-efficacy score gain remained statistically significant. CONCLUSION: The study showed that interprofessional training improved students' perception of self-efficacy more than traditional clinical training. PMID- 23360487 TI - Script concordance testing: from theory to practice: AMEE guide no. 75. AB - The script concordance test (SCT) is used in health professions education to assess a specific facet of clinical reasoning competence: the ability to interpret medical information under conditions of uncertainty. Grounded in established theoretical models of knowledge organization and clinical reasoning, the SCT has three key design features: (1) respondents are faced with ill-defined clinical situations and must choose between several realistic options; (2) the response format reflects the way information is processed in challenging problem solving situations; and (3) scoring takes into account the variability of responses of experts to clinical situations. SCT scores are meant to reflect how closely respondents' ability to interpret clinical data compares with that of experienced clinicians in a given knowledge domain. A substantial body of research supports the SCT's construct validity, reliability, and feasibility across a variety of health science disciplines, and across the spectrum of health professions education from pre-clinical training to continuing professional development. In practice, its performance as an assessment tool depends on careful item development and diligent panel selection. This guide, intended as a primer for the uninitiated in SCT, will cover the basic tenets, theoretical underpinnings, and construction principles governing script concordance testing. PMID- 23360488 TI - Genetically modified adipose tissue-derived stem/stromal cells, using simian immunodeficiency virus-based lentiviral vectors, in the treatment of hemophilia B. AB - Hemophilia is an X-linked bleeding disorder, and patients with hemophilia are deficient in a biologically active coagulation factor. This study was designed to combine the efficiency of lentiviral vector transduction techniques with murine adipose tissue-derived stem/stromal cells (mADSCs) as a new method to produce secreted human coagulation factor IX (hFIX) and to treat hemophilia B. mADSCs were transduced with simian immunodeficiency virus (SIV)-hFIX lentiviral vector at multiplicities of infection (MOIs) from 1 to 60, and the most effective dose was at an MOI of 10, as determined by hFIX production. hFIX protein secretion persisted over the 28-day experimental period. Cell sheets composed of lentiviral vector-transduced mADSCs were engineered to further enhance the usefulness of these cells for future therapeutic applications in transplantation modalities. These experiments demonstrated that genetically transduced ADSCs may become a valuable cell source for establishing cell-based gene therapies for plasma protein deficiencies, such as hemophilia. PMID- 23360489 TI - Sorting nexin 2-mediated membrane trafficking of c-Met contributes to sensitivity of molecular-targeted drugs. AB - The sorting nexin (SNX) family is a diverse group of cytoplasmic and membrane associated proteins that are involved in membrane-trafficking steps within the endocytotic network. SNX1 and SNX2 are components of the mammalian retromer complex and they also play critical roles in the membrane trafficking of growth factor receptors including epidermal growth factor receptor (EGFR) and c-Met. The human lung cancer cell lines, which harbor activating mutations in the kinase domain of EGFR gene, are sensitive to EGFR-targeted drugs gefitinib or erlotinib. However, a lung cancer cell line harboring gene amplification of c-Met is sensitive to the c-Met-targeted drug SU11274 but not to EGFR-targeted drugs. C Met overexpression is identified as one of the bypass mechanisms for acquired resistance to EGFR-targeted drugs. Here we show that the siRNA-mediated knockdown of SNX2 decreases the cell-surface localization of c-Met, but not that of EGFR, resulting in lysosomal degradation of the c-Met protein. SNX2 specifically interacts with c-Met and treatment with lysosomal inhibitors almost completely annihilates downregulation of c-Met protein by SNX2 knockdown. Therefore, silencing of SNX2 markedly alters sensitivity to anticancer drugs targeted to c Met (SU11274) and EGFR (gefitinib and erlotinib) through promotion of compensatory activation of the EGFR pathway in lung cancer cells. These findings suggest that development of drugs targeting SNX2 could be useful in overcoming drug resistance to EGFR-targeted drugs in lung cancer cells harboring c-Met gene amplification. PMID- 23360490 TI - The relation between social sharing and the duration of emotional experience. AB - People often socially share their emotions to regulate them. Two-mode theory of social sharing states that cognitive sharing will contribute to emotional recovery, whereas socio-affective sharing will only temporarily alleviate emotional distress. Previous studies supporting this theory, measured emotional recovery in terms of residual emotional intensity. Until now, another important time-dynamic aspect of emotions, emotion duration, has been largely ignored. In two experience sampling studies we addressed this gap. In Study 1, participants reported on the duration of anger, fear, and sadness episodes; additionally time varying information on the occurrence and mode of sharing was collected. This study revealed that sharing led to a shortening in emotion duration, in particular when it was socio-affective in nature. In Study 2 we investigated whether this result could be interpreted in terms of our measure of duration primarily reflecting emotional relief rather than recovery. In this study, the same method as in Study 1 was used; additionally, residual emotional intensity was measured three days after emotion onset. Study 2 largely replicated the findings from Study 1. Furthermore, duration appeared to be empirically distinct from residual intensity. Finally, no relation between sharing and residual intensity was found, even when considering the sharing mode. PMID- 23360492 TI - Slow photoelectron spectroscopy of 3-hydroxyisoquinoline. AB - We studied the single photon ionization of gas phase 3-hydroxyisoquinoline by means of VUV synchrotron radiation coupled to a velocity map imaging electron/ion coincidence spectrometer. Near the ionization thresholds of 3 hydroxyisoquinoline, the photoionization is found to occur mainly via a direct process. The spectra are assigned with the help of theoretical calculations on the equilibrium geometries, electronic states patterns, harmonic and anharmonic wavenumbers of the lactim and lactam forms of 3-hydroxyisoquinoline and their cations. The slow photoelectron spectrum (SPES) of this lactim is dominated by vibrational transitions to the X state of the cation. In addition, several weaker and complex bands are observed, corresponding to the population of the vibrational bands (pure or combination) of the A electronically excited state of the cation. The adiabatic ionization energy of 3-hydroxyisoquinoline and the lowest electronic state energetics of the lactim and lactam cationic forms are determined. PMID- 23360491 TI - Is the processing of affective prosody influenced by spatial attention? An ERP study. AB - BACKGROUND: The present study asked whether the processing of affective prosody is modulated by spatial attention. Pseudo-words with a neutral, happy, threatening, and fearful prosody were presented at two spatial positions. Participants attended to one position in order to detect infrequent targets. Emotional prosody was task irrelevant. The electro-encephalogram (EEG) was recorded to assess processing differences as a function of spatial attention and emotional valence. RESULTS: Event-related potentials (ERPs) differed as a function of emotional prosody both when attended and when unattended. While emotional prosody effects interacted with effects of spatial attention at early processing levels (< 200 ms), these effects were additive at later processing stages (> 200 ms). CONCLUSIONS: Emotional prosody, therefore, seems to be partially processed outside the focus of spatial attention. Whereas at early sensory processing stages spatial attention modulates the degree of emotional voice processing as a function of emotional valence, emotional prosody is processed outside of the focus of spatial attention at later processing stages. PMID- 23360493 TI - Structural and functional variation in soil fungal communities associated with litter bags containing maize leaf. AB - Soil fungi are key players in the degradation of recalcitrant organic matter in terrestrial ecosystems. To examine the organisms and genes responsible for complex organic matter degradation in soil, we tracked changes in fungal community composition and expressed genes in soil adjacent to mesh bags containing maize leaves undergoing decomposition. Using high-throughput sequencing approaches, changes in fungal community composition were determined by targeting 18S rRNA gene sequences, whereas community gene expression was examined via a metatranscriptomic approach. The majority of the 93 000 partial 18S rRNA gene sequences generated, were affiliated with the Ascomycota and Basidiomycota. Fungal diversity was at least 224 operational taxonomic units at the 97% similarity cutoff level. During litter degradation, the relative proportion of Basidiomycota increased, with a decrease in Ascomycota : Basidiomycota ratios over time. The most commonly detected decomposition-associated fungi included Agaricomycetes and Tremellales as well as unclassified Mucoromycotina. The majority of protein families found in the metatranscriptomic data were affiliated to fungal groups described to degrade plant-derived cellulose, such as Mucoraceae, Chaetomiaceae, Sordariaceae, Sebacinaceae, Tremellaceae, Psathyrellaceae and Schizophyllaceae. The combination of high-throughput rRNA gene-based and metatranscriptomic approaches provided perspectives into the organisms and genes involved in complex organic matter in soil. PMID- 23360494 TI - A fluorescent organic nanotube assembled from novel p-phenylene ethynylene-based dicationic amphiphiles. AB - Novel pi-extended conjugated amphiphiles composed of a hydrophilic section of two quaternary ammonium groups and p-phenylene ethynylene with adjustable alkyl chain hydrophobic section were prepared by a multistep synthesis. These dicationic amphiphiles showed good water solubility and formed a tubular assembly in water. The evidence for the nanotubular comes from direct optical and TEM observations. A strong pi-pi stacking interaction between neighboring molecules, as evidenced by the red-shift and self-quenching in fluorescence, is proposed for the self assembly. At the same time, dehydration of the bromide led to strong counterion condensation in headgroups, which resulted in the small curvature structure of the nanotubes. A bilayer lamellar structural model for the organic nanotube is proposed, and a reasonable structural model based on the experimental XRD pattern, as well as cell constants, is proposed. PMID- 23360495 TI - Dietary supplementation with long-chain monounsaturated fatty acids attenuates obesity-related metabolic dysfunction and increases expression of PPAR gamma in adipose tissue in type 2 diabetic KK-Ay mice. AB - The objective of present study was to examine the effect of long-chain monounsaturated fatty acids (LC-MUFAs) with chain lengths longer than 18 (i.e., C20:1 and C22:1 isomers combined) on obesity-related metabolic dysfunction and its molecular mechanisms. Type-2 diabetic KK-Ay mice (n = 20) were randomly assigned to the 7% soybean oil-diet group (control group) and 4% LC-MUFA concentrate-supplemented-diet group (LC-MUFA group). At 8 weeks on the diet, the results showed that plasma, liver and adipose tissue levels of C20:1 and C22:1 isomers increased significantly with LC-MUFA treatment. Supplementation with LC MUFAs markedly reduced white fat pad weight as well as adipocyte size in the mice. The levels of plasma free fatty acids, insulin, and leptin concentration in the obese diabetic mice of the LC-MUFA group were also decreased as compared with the mice in the soybean oil-diet control group. Dietary LC-MUFAs significantly increased the mRNA expression of peroxisome proliferator-activated receptor gamma (Pparg), lipoprotein lipase (Lpl), fatty acid transport protein (Fatp), fatty acid translocase/CD36 (Cd36), as well as mRNA expression of genes involved in lipid oxidation such as carnitine palmitoyltransferase-1A (Cpt1a) and citrate synthase (Cs), and decreased the mRNA expression of inflammatory marker serum amyloid A 3 (Saa3) in the adipose tissues of diabetic mice. The results suggest that LC-MUFAs may ameliorate obesity-related metabolic dysfunction partly through increased expression of Pparg as well as its target genes, and decreased inflammatory marker expression in white adipose tissue. PMID- 23360496 TI - Follicular thyroid cancer incidence patterns in the United States, 1980-2009. AB - BACKGROUND: The increases in thyroid cancer overall and in the predominant papillary type have been well documented, but trends for follicular thyroid cancer, a less common but more aggressive variant, have not been as well characterized. In this study, we determined the incidence patterns for follicular thyroid cancer and compared trends between the follicular and papillary thyroid cancers in the United States. METHODS: We used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program to examine incidence in the United States during 1980-2009, stratified by demographic and tumor characteristics. Incidence rates (IR) were calculated, relative risks were expressed as incidence rate ratios (IRR), and temporal trends were expressed as percentage changes and plotted. RESULTS: Overall we observed a modest increase in age-adjusted follicular thyroid cancer rates among women (31.89%) and men (35.88%). Rates increased most dramatically for regional stage tumors compared to localized tumors in women, whereas the rates for all tumor sizes rose. These findings reveal increases in more aggressive tumors in women in addition to small and localized tumors. The trends for males were different from those among females. Among males, the largest increase was observed for regional and smaller size tumors. The papillary-to-follicular IRR overall was 7.07 [95% confidence interval 6.91-7.24], which varied from 7.37 among Whites to 3.86 among Blacks (SEER race/ethnicity categories), and increased significantly from 3.98 during 1980-1984 to 9.88 during 2005-2009. CONCLUSION: The different trends for follicular and papillary types of thyroid cancer illustrate that thyroid cancer is a heterogeneous disease. Our results do not support the hypothesis that increasing thyroid cancer rates are largely due to improvements in detection, and suggest the importance of evaluating thyroid cancer types separately in future studies. PMID- 23360498 TI - A review of the nature and effectiveness of nutrition interventions in adult males--a guide for intervention strategies. AB - BACKGROUND: Energy excess, low fruit and vegetable intake and other suboptimal dietary habits contribute to an increased poor health and the burden of disease in males. However the best way to engage males into nutrition programs remains unclear. This review provides a critical evaluation of the nature and effectiveness of nutrition interventions that target the adult male population. METHODS: A search for full-text publications was conducted using The Cochrane Library; Web of Science; SCOPUS; MEDLINE and CINAHL. Studies were included if 1) published from January 1990 to August 2011 and 2) male only studies (>=18 years) or 3) where males contributed to >90% of the active cohort. A study must have described, (i) a significant change (p<0.05) over time in an objective measure of body weight, expressed in kilograms (kg) OR Body Mass Index (BMI) OR (ii) at least one significant change (p<0.05) in a dietary intake measure to qualify as effective. To identify emerging patterns within the research a descriptive process was used. RESULTS: Nine studies were included. Sample sizes ranged from 53 to 5042 male participants, with study durations ranging from 12 weeks to 24 months. Overlap was seen with eight of the nine studies including a weight management component whilst six studies focused on achieving changes in dietary intake patterns relating to modifications of fruit, vegetable, dairy and total fat intakes and three studies primarily focused on achieving weight loss through caloric restriction. Intervention effectiveness was identified for seven of the nine studies. Five studies reported significant positive changes in weight (kg) and/or BMI (kg/m2) changes (p<=0.05). Four studies had effective interventions (p<0.05) targeting determinants of dietary intake and dietary behaviours and/or nutritional intake.Intervention features, which appeared to be associated with better outcomes, include the delivery of quantitative information on diet and the use of self-monitoring and tailored feedback. CONCLUSION: Uncertainty remains as to the features of successful nutrition interventions for males due to limited details provided for nutrition intervention protocols, variability in mode of delivery and comparisons between delivery modes as well as content of information provided to participants between studies. This review offers knowledge to guide researchers in making informed decisions on how to best utilise resources in interventions to engage adult males while highlighting the need for improved reporting of intervention protocols. PMID- 23360497 TI - Gene expression alterations in bipolar disorder postmortem brains. AB - OBJECTIVES: Bipolar disorder (BD) is a mental illness of unknown neuropathology and has several genetic associations. Antipsychotics are effective for the treatment of acute mania, psychosis, or mixed states in individuals with BD. We aimed to identify gene transcripts differentially expressed in postmortem brains from antipsychotics-exposed individuals with BD (hereafter the 'exposed' group), non-exposed individuals with BD (hereafter the 'non-exposed' group), and controls. METHODS: We quantified the abundance of gene transcripts in postmortem brains from seven exposed individuals, seven non-exposed individuals, and 12 controls with the Affymetrix U133P2 GeneChip microarrays and technologies. We applied a q-value of <=0.005 to identify statistically significant transcripts with mean abundance differences between the exposed, non-exposed and control groups. RESULTS: We identified 2191 unique genes with significantly altered expression levels in non-exposed brains compared to those in the control and exposed groups. The expression levels of these genes were not significantly different between exposed brains and controls, suggesting a normalization effect of antipsychotics on the expression of these genes. Gene ontology (GO) enrichment analysis showed significant (Bonferroni p <= 0.05) clustering of subgroups of the 2191 genes under many GO terms; notably, the protein products of genes enriched are critical to the function of synapses, affecting, for example, intracellular trafficking and synaptic vesicle biogenesis, transport, release and recycling, as well as organization and stabilization of the node of Ranvier. CONCLUSIONS: These results support a hypothesis of synaptic and intercellular communication impairment in BD. The apparent normalization of expression patterns with exposure to antipsychotic medication may represent a physiological process that relates both to etiology and improvement patterns of the disorder. PMID- 23360499 TI - Spirosilane derivatives as fluoride sensors. AB - Spirosilane derivatives have been investigated as fluoride sensors. The reactions between these compounds and different fluoride sources, which resulted in structural alterations, have been monitored and quantified by UV and fluorescence spectroscopy. The high selectivity of these probes for fluoride ions has been demonstrated in either organic or aqueous media. PMID- 23360500 TI - Structure of a glycomimetic ligand in the carbohydrate recognition domain of C type lectin DC-SIGN. Structural requirements for selectivity and ligand design. AB - In genital mucosa, different fates are described for HIV according to the subtype of dendritic cells (DCs) involved in its recognition. This notably depends on the C-type lectin receptor, langerin or DC-SIGN, involved in gp120 interaction. Langerin blocks HIV transmission by its internalization in specific organelles of Langerhans cells. On the contrary, DC-SIGN enhances HIV trans-infection of T lymphocytes. Thus, approaches aiming to inhibit DC-SIGN, without blocking langerin, represent attractive anti-HIV strategies. We previously demonstrated that dendrons bearing multiple copies of glycomimetic compounds were able to block DC-SIGN-dependent HIV infection in cervical explant models. Optimization of such ligand requires detailed characterization of its binding mode. In the present work, we determined the first high-resolution structure of a glycomimetic/DC-SIGN complex by X-ray crystallography. This glycomimetic, pseudo 1,2-mannobioside, shares shape and conformational properties with Manalpha1-2Man, its natural counterpart. However, it uses the binding epitope previously described for Lewis X, a ligand specific for DC-SIGN among the C-type lectin family. Thus, selectivity gain for DC-SIGN versus langerin is observed with pseudo-1,2-mannobioside as shown by surface plasmon resonance analysis. In parallel, ligand binding was also analyzed by TR-NOESY and STD NMR experiments, combined with the CORCEMA-ST protocol. These studies demonstrate that the complex, defined by X-ray crystallography, represents the unique binding mode of this ligand as opposed to the several binding orientations described for the natural ligand. This exclusive binding mode and its selective interaction properties position this glycomimetic as a good lead compound for rational improvement based on a structurally driven approach. PMID- 23360501 TI - The early toad gets the worm: cane toads at an invasion front benefit from higher prey availability. AB - In biological invasions, rates of range expansion tend to accelerate through time. What kind of benefits to more rapidly dispersing organisms might impose natural selection for faster rates of dispersal, and hence the evolution of range edge acceleration? We can answer that question by comparing fitness-relevant ecological traits of individuals at the invasion front compared with conspecifics in the same area a few years post-invasion. In tropical Australia, the rate of invasion by cane toads (Rhinella marina) has increased substantially over recent decades, due to shifts in heritable traits. Our data on field-collected cane toads at a recently invaded site in the Australian wet-dry tropics span a 5-year period beginning with toad arrival. Compared with conspecifics that we monitored in the same sites post-invasion, toads in the invasion vanguard exhibited higher feeding rates, larger energy stores, better body condition and faster growth. Three processes may have contributed to this pattern: (i) higher prey availability at the front (perhaps due to reduced competition from conspecifics); (ii) the lack of viability-reducing parasites and pathogens in invasion-front toads; and (iii) distinctive (active, fast-growing) phenotypes of the invasion front toads. Nutritional benefits to individuals in the invasion vanguard (whether because of higher prey availability, or lower pathogen levels) thus may have conferred a selective advantage to accelerated dispersal in this system. PMID- 23360502 TI - The long and tortuous history of the discovery of testosterone and its clinical application. AB - INTRODUCTION: The testis importance in homeostasis was recognized for millennia, but a consistent interest in exploring their endocrine function only goes back to about a century. AIM: The aim of this study is to provide a succinct perspective of the events leading to the discovery of testosterone, the mind-boggling early attempts at therapy and today's situation. METHOD: The literature was reviewed with searches in OvidSP Medline, PubMed, and Google Scholar under the headings of testosterone/androgens history. Due to the explosion of reports between the late 19th and early 20th centuries, a manual review of the collection of the period's journals at the university's library was performed. Pertinent books were consulted for specific biographical details. RESULTS: There is a robust body of literature dealing with testicular function for the period starting in the late 1800s. It is illustrative to learn the painful efforts of many well-intentioned and honest scientists with more conviction and determination than knowledge. Among them, unfortunately, a number of charlatans and profiteers tainted the concept of hypogonadism and its treatment with repercussions lasting until this day. The discovery and synthesis of testosterone represent the effort of brilliant minds (two Nobel Prizes) in various countries and frequently working for the pharmaceutical industry. Shortly after testosterone became available, controversy arose about its application, use, abuse, and potential detrimental effects. Over the decades, the hullabaloo about hypogonadism and its treatment has focused on a variety of issues ranging from absurd efficacy claims to solid studies and from doubts of its existence to convincing proof of a detrimental age associated deficit in testosterone production. CONCLUSIONS: The history of testosterone discovery, synthesis, and introduction into the therapeutic armamentarium is an outstanding example of human curiosity, ingenuity, greed, and skepticism. Despite the vast progress in the field, many issues remain unresolved, but thoughtful science augurs well for its future. PMID- 23360503 TI - Aminopurine derivatives as putative SopE inhibitors. AB - Abstract Salmonella outer protein E, SopE, is a virulence factor that is secreted from gram-negative Salmonella enterica, which is pathogenic to humans and is responsible for gastroenteritis and typhoid fever. SopE targets the Rho GTPase family proteins of the host cell and manipulates them by mimicking GTPase regulatory protein guanine nucleotide exchange factor. The aim of this work is the investigation of novel inhibitors against SopE. Structure-based pharmacophore modeling was used to identify structural features that would be important for SopE recognition. Glide fragment library was used for four-point pharmacophore hypothesis development. Small-molecule database screening was performed based on a 3D similarity to the best pharmacophore hypothesis. Binding affinity of filtered database molecules to SopE was predicted quantitatively by molecular docking and scoring using Glide software. Top scoring hits were further analyzed and five molecules were proposed as potent and selective SopE inhibitors. Four out of five proposed molecules were found to be aminopurine derivatives. PMID- 23360504 TI - Enhanced transfection efficiency of poly(N,N-dimethylaminoethyl methacrylate) based deposition transfection by combination with tris(hydroxymethyl)aminomethane. AB - We have developed a substrate-mediated transfection method called "deposition transfection technology" using a poly(N,N-dimethylaminoethylmethacrylate) (PDMAEMA) homopolymer with both thermoresponsive and cationic characteristics. In this study, we enhanced deposition transfection efficiency by using tris(hydroxymethyl)aminomethane (Tris buffer) as a pH adjuster for transfection solution composed of PDMAEMA and plasmid DNA (pDNA). PDMAEMA with a molecular weight of 9.7 * 10(4) g mol(-1) was synthesized by photoinduced radical polymerization. The pH of PDMAEMA solution was increased gradually in the range from 8 to 11 by the addition of Tris, and then the solubility of PDMAEMA was significantly decreased and the dissolution time was extended from 15 to 40 min at Tris/PDMAEMA ratio of 1 and higher. On the other hand, while the polyion complexes (polyplexes) were formed by mixing PDMAEMA with luciferase-encoding plasmid DNA even under an excess amount of Tris at Tris/PDMAEMA ratio of 8, the binding affinity between PDMAEMA and pDNA was decreased with increasing Tris at Tris/PDMAEMA ratio of 2 and higher. When HeLa cells, smooth muscle cells, and cardiac fibroblasts were transfected by the deposition method using polyplex solution containing various amounts of Tris, the transgene expression dramatically increased at a Tris/PDMAEMA ratio of 2 in all cell types, which were more than 150-fold in HeLa cells, 40-fold in smooth muscle cells, and 30-fold in cardiac fibroblasts compared to those in the Tris-free condition. In addition, the enhanced transgene expression by Tris was sustained for over 10 days post transfection as well as that observed in Tris-free condition. Thus, deposition transfection efficiency can be dramatically enhanced by using Tris buffer as a pH adjuster for polyplex solution. PMID- 23360505 TI - In vitro and in vivo evaluation of three metronidazole topical products. AB - Two 1% and one 0.75% metronidazole cream products were approved as bioequivalent products. These products were evaluated for their in vivo cutaneous penetration characteristics by dermatopharmacokinetic (DPK) and dermal microdialysis (DMD) sampling methodologies. The same three products were also evaluated for their rheological and in vitro drug release (IVR) properties. Structural differences were observed in the resulting flow curves. However, similar IVR profiles were obtained for the two topical semisolid dosage forms containing 1% metronidazole. For the lower strength product, a higher IVR rate was associated with the lower DPK profile. All three products exhibited similar values of area under the curve when investigated by DMD. This in vitro evaluation corroborated the divergent penetration characteristics found using in vivo methodologies. PMID- 23360506 TI - Evaluation of the cytotoxic effect and antibacterial, antifungal, and antiviral activities of Hypericum triquetrifolium Turra essential oils from Tunisia. AB - BACKGROUND: A number of bio-active secondary metabolites have been identified and reported for several Hypericum species. Many studies have reported the potential use of the plant extracts against several pathogens. However, Hypericum triquetrifolium is one of the least studied species for its antimicrobial activity. The aim of the present study was to evaluate the cytotoxic effect of the essential oils of Hypericum triquetrifolium as well as their antimicrobial potential against coxsakievirus B3 and a range of bacterial and fungal strains. METHODS: The essential oils of Hypericum triquetrifolium harvested from five different Tunisian localities (Fondouk DJedid, Bou Arada, Bahra, Fernana and Dhrea Ben Jouder) were evaluated for their antimicrobial activities by micro broth dilution methods against bacterial and fungal strains. In addition, the cytotoxic effect and the antiviral activity of these oils were carried out using Vero cell lines and coxsakievirus B3. RESULTS: The results showed a good antibacterial activities against a wide range of bacterial strains, MIC values ranging between 0.39-12.50 mg/ml and MBC values between 1.56-25.0 mg/ml. In addition, the essential oils showed promising antifungal activity with MIC values ranging between 0.39 MUg/mL and 12.50 MUg/mL; MFC values ranged between 3.12 MUg/mL and 25.00 MUg/mL; a significant anticandidal activity was noted (MIC values comprised between 0.39 MUg/mL and 12.50 MUg/mL). Although their low cytotoxic effect (CC50 ranged between 0.58 mg/mL and 12.00 mg/mL), the essential oils did not show antiviral activity against coxsakievirus B3. CONCLUSION: The essential oils obtained from Hypericum triquetrifolium can be used as antimicrobial agents and could be safe at non cytotoxic doses. As shown for the tested essential oils, comparative analysis need to be undertaken to better characterize also the antimicrobial activities of Hypericum triquetrifolium extracts with different solvents as well as their purified fractions and their pure secondary metabolites. PMID- 23360508 TI - Community perceptions on malaria and care-seeking practices in endemic Indian settings: policy implications for the malaria control programme. AB - BACKGROUND: The focus of India's National Malaria Programme witnessed a paradigm shift recently from health facility to community-based approaches. The current thrust is on diagnosing and treating malaria by community health workers and prevention through free provision of long-lasting insecticidal nets. However, appropriate community awareness and practice are inevitable for the effectiveness of such efforts. In this context, the study assessed community perceptions and practice on malaria and similar febrile illnesses. This evidence base is intended to direct the roll-out of the new strategies and improve community acceptance and utilization of services. METHODS: A qualitative study involving 26 focus group discussions and 40 key informant interviews was conducted in two districts of Odisha State in India. The key points of discussion were centred on community perceptions and practice regarding malaria prevention and treatment. Thematic analysis of data was performed. RESULTS: The 272 respondents consisted of 50% females, three-quarter scheduled tribe community and 30% students. A half of them were literates. Malaria was reported to be the most common disease in their settings with multiple modes of transmission by the FGD participants. Adoption of prevention methods was seasonal with perceived mosquito density. The reported use of bed nets was low and the utilization was determined by seasonality, affordability, intoxication and alternate uses of nets. Although respondents were aware of malaria-related symptoms, care-seeking from traditional healers and unqualified providers was prevalent. The respondents expressed lack of trust in the community health workers due to frequent drug stock-outs. The major determinants of health care seeking were socio-cultural beliefs, age, gender, faith in the service provider, proximity, poverty, and perceived effectiveness of available services. CONCLUSION: Apart from the socio-cultural and behavioural factors, the availability of acceptable care can modulate the community perceptions and practices on malaria management. The current community awareness on symptoms of malaria and prevention is fair, yet the prevention and treatment practices are not optimal. Promoting active community involvement and ownership in malaria control and management through strengthening community based organizations would be relevant. Further, timely availability of drugs and commodities at the community level can improve their confidence in the public health system. PMID- 23360507 TI - Manganese toxicity in the central nervous system: the glutamine/glutamate-gamma aminobutyric acid cycle. AB - Manganese (Mn) is an essential trace element that is required for maintaining proper function and regulation of numerous biochemical and cellular reactions. Despite its essentiality, at excessive levels Mn is toxic to the central nervous system (CNS). Increased accumulation of Mn in specific brain regions, such as the substantia nigra, globus pallidus and striatum, triggers neurotoxicity resulting in a neurological brain disorder, termed manganism. Mn has been also implicated in the pathophysiology of several other neurodegenerative diseases. Its toxicity is associated with disruption of the glutamine (Gln)/glutamate (Glu)-gamma aminobutyric acid (GABA) cycle (GGC) between astrocytes and neurons, thus leading to changes in Glu-ergic and/or GABAergic transmission and Gln metabolism. Here we discuss the common mechanisms underlying Mn-induced neurotoxicity and their relationship to CNS pathology and GGC impairment. PMID- 23360509 TI - Relationship of multidirectional myocardial strain with radial thickening and ejection fraction and impact of left ventricular hypertrophy: a study in a community-based cohort. AB - BACKGROUND: Left ventricular (LV) systolic strain provides additional prognostic value to LV ejection fraction (LVEF) and wall motion analysis. However, the relationship between myocardial multidirectional strain and LVEF, and the effect of LV hypertrophy on this relationship, are not completely understood especially in unselected populations. METHODS: LV global longitudinal (epsilonL ) and circumferential (epsilonC ) systolic strain analysis was performed by two dimensional speckle tracking echocardiography in 215 participants from a community-based study. LV radial wall thickening was measured as global radial strain (epsilonR ), and LVEF was assessed by biplane Simpson's method. RESULTS: epsilonR was significantly associated with epsilonC (beta = -0.56, P < 0.01) and with epsilonL (beta = -0.18, P < 0.01). The contribution of epsilonL to epsilonR was especially evident in subjects with lower epsilonC and in presence of LV hypertrophy (beta = -0.30, P < 0.01). epsilonL and epsilonC were significantly associated with LVEF (beta = -0.36 and beta = -0.49, both P < 0.01) independent of LV mass and other confounders, and their interaction significantly improved the prediction of LVEF (R(2) -change = 0.14) but not of epsilonR (R(2) -change = 0.002). CONCLUSIONS: epsilonR is mainly related to epsilonC with a smaller contribution of epsilonL , which becomes especially evident in subjects with lower epsilonC and in presence of LV hypertrophy. Therefore, radial thickening may not detect subclinical LV longitudinal function reduction in normal ventricles and when epsilonC is preserved. While a reduction in epsilonL has a limited impact on epsilonR , it exerts a greater effect on global LVEF, therefore for a more accurate LVEF prediction both epsilonL and epsilonC need to be considered. PMID- 23360511 TI - Lateral cis-1,3,5,7-tetraazadecalin podands and their complexes: synthesis, structure, and strong binding with Pb(II) and other heavy metal ions. AB - The chemistry and complexation behavior of diaminal podands based on cis-1,3,5,7 tetraazadecalin (cis-TAD) were elaborated, reassessed, and extended. The synthesis of 2,6-bis(hydroxymethylene)-cis-TAD (9) and 2,6-bis(alpha,alpha' dimethyl-beta- hydroxyethyl)-cis-TAD (10) as well as of suitably substituted 2,6 diaryl-cis-TAD podands is laid out. For the latter, the effect of electron donating or withdrawing substituents on the benzaldehyde reagents was examined while 9 and 10 were probed and showed considerable propensity for heavy metal-ion chelation. The [Cd(II).(9)] and [Pb(II).(9)] complexes stood out indeed, and their structure and properties show a particularly interesting 5-amino-1,3 diazane chelation type and strong ligand-ion binding mode, with intramolecular donor exchange in solution, all strongly influenced by the anomeric effect in the ligand. PMID- 23360512 TI - Spectroscopic and theoretical investigations of UF and UF+. AB - Laser induced fluorescence and resonantly enhanced multiphoton ionization spectra were recorded for UF in the 18,000-20,000 cm(-1) range. Rotationally resolved data were obtained, and the analysis of a band at 18624 cm(-1) yielded a ground state rotational constant of 0.2348 cm(-1). The electronic ground state was clearly identified as |Omega| = 4.5, confirming the theoretically predicted U(+)(5f(3)7s(2))F(-) configuration. Dispersed fluorescence spectra revealed low lying electronic states that are assigned as |Omega| = 3.5 (435 cm(-1)) and 2.5 (650 cm(-1)). Two-color photoionization spectroscopy was used to study UF(+). The ground state and fifteen electronically excited states have been characterized. The ground state was found to be |Omega| = 4, as it is for the isoelectronic molecule UO, and with vibrational constants of omegae = 649.92 and omegaexe = 1.83 cm(-1). The patterns of electronically excited states observed for UF(+), with |Omega| values ranging from 0 to 6, were qualitatively consistent with the predictions of a ligand field theory model developed for UO. The experimental data for both UF and UF(+) were reasonably well reproduced by CASSCF/CASPT2 electronic structure calculations that included spin-orbit coupling. PMID- 23360510 TI - Gene expression profiling of early intervertebral disc degeneration reveals a down-regulation of canonical Wnt signaling and caveolin-1 expression: implications for development of regenerative strategies. AB - INTRODUCTION: Early degeneration of the intervertebral disc (IVD) involves a change in cellular differentiation from notochordal cells (NCs) in the nucleus pulposus (NP) to chondrocyte-like cells (CLCs). The purpose of this study was to investigate the gene expression profiles involved in this process using NP tissue from non-chondrodystrophic and chondrodystrophic dogs, a species with naturally occurring IVD degeneration. METHODS: Dual channel DNA microarrays were used to compare 1) healthy NP tissue containing only NCs (NC-rich), 2) NP tissue with a mixed population of NCs and CLCs (Mixed), and 3) NP tissue containing solely CLCs (CLC-rich) in both non-chondrodystrophic and chondrodystrophic dogs. Based on previous reports and the findings of the microarray analyses, canonical Wnt signaling was further evaluated using qPCR of relevant Wnt target genes. We hypothesized that caveolin-1, a regulator of Wnt signaling that showed significant changes in gene expression in the microarray analyses, played a significant role in early IVD degeneration. Caveolin-1 expression was investigated in IVD tissue sections and in cultured NCs. To investigate the significance of Caveolin-1 in IVD health and degeneration, the NP of 3-month-old Caveolin-1 knock-out mice was histopathologically evaluated and compared with the NP of wild-type mice of the same age. RESULTS: Early IVD degeneration involved significant changes in numerous pathways, including Wnt/beta-catenin signaling. With regard to Wnt/beta-catenin signaling, axin2 gene expression was significantly higher in chondrodystrophic dogs compared with non chondrodystrophic dogs. IVD degeneration involved significant down-regulation of axin2 gene expression. IVD degeneration involved significant down-regulation in Caveolin-1 gene and protein expression. NCs showed abundant caveolin-1 expression in vivo and in vitro, whereas CLCs did not. The NP of wild-type mice was rich in viable NCs, whereas the NP of Caveolin-1 knock-out mice contained chondroid-like matrix with mainly apoptotic, small, rounded cells. CONCLUSIONS: Early IVD degeneration involves down-regulation of canonical Wnt signaling and Caveolin-1 expression, which appears to be essential to the physiology and preservation of NCs. Therefore, Caveolin-1 may be regarded an exciting target for developing strategies for IVD regeneration. PMID- 23360513 TI - pi-Conjugated nickel bis(dithiolene) complex nanosheet. AB - A pi-conjugated nanosheet comprising planar nickel bis(dithiolene) complexes was synthesized by a bottom-up method. A liquid-liquid interfacial reaction using benzenehexathiol in the organic phase and nickel(II) acetate in the aqueous phase produced a semiconducting bulk material with a thickness of several micrometers. Powder X-ray diffraction analysis revealed that the crystalline portion of the bulk material comprised a staggered stack of nanosheets. A single-layer nanosheet was successfully realized using a gas-liquid interfacial reaction. Atomic force microscopy and scanning tunneling microscopy confirmed that the pi-conjugated nanosheet was single-layered. Modulation of the oxidation state of the nanosheet was possible using chemical redox reactions. PMID- 23360515 TI - Water's structure around hydrophobic solutes and the iceberg model. AB - The structure of water in the hydration shells of small hydrophobic solutes was investigated through molecular dynamics. The results show that a subset of water molecules in the first hydration shell of a nonpolar solute have a significantly enhanced tetrahedrality and a slightly larger number of hydrogen bonds, relative to the molecules in water at room temperature, consistent with the experimentally observed negative excess entropy and increased heat capacity of hydrophobic solutions at room temperature. This ordering results from the rearrangement of a small number of water molecules near the nonpolar solutes that occupy one to two vertices of the enhanced water tetrahedra. Although this structuring is not nearly like that often associated with a literal interpretation of the term "iceberg" in the Frank and Evans iceberg model, it does support a moderate interpretation of this model. Thus, the tetrahedral orientational order of this ensemble of water molecules is comparable to that of liquid water at ~10 degrees C, although not accompanied by the small contraction of the O-O distance observed in cold water. Further, we show that the structural changes of water in the vicinity of small nonpolar solutes cannot be inferred from the water radial distribution functions, explaining why this increased ordering is not observed through neutron diffraction experiments. The present results restore a molecular view where the slower translational and reorientational dynamics of water near hydrophobic groups has a structural equivalent resembling water at low temperatures. PMID- 23360516 TI - Roles and mechanisms of cellular senescence in regulation of tissue homeostasis. AB - Cellular senescence is the state of irreversible cell cycle arrest that can be induced by a variety of potentially oncogenic stimuli and has therefore long been considered to suppress tumorigenesis, acting as a guardian of homeostasis. However, surprisingly, emerging evidence reveals that senescent cells also promote secretion of a series of inflammatory cytokines, chemokines, growth factors and matrix remodeling factors, which alter the local tissue environment and contribute to chronic inflammation and cancer. This newly identified senescence phenotype, termed the senescence-associated secretory phenotype (SASP) or the senescence-messaging secretome (SMS), is induced by DNA damage that promotes the induction of cellular senescence. All of these senescence-associated secreting factors are involved in homeostatic disorders such as cancer. Therefore, it is quite possible that accumulation of senescent cells during the aging process in vivo might contribute to age-related increases in homeostatic disorders. In this review, current knowledge of the molecular and cellular biology of cellular senescence is introduced, focusing on its positive and negative roles in controlling tissue homeostasis in vivo. PMID- 23360514 TI - Efficient clinical scale gene modification via zinc finger nuclease-targeted disruption of the HIV co-receptor CCR5. AB - Since HIV requires CD4 and a co-receptor, most commonly C-C chemokine receptor 5 (CCR5), for cellular entry, targeting CCR5 expression is an attractive approach for therapy of HIV infection. Treatment of CD4(+) T cells with zinc-finger protein nucleases (ZFNs) specifically disrupting chemokine receptor CCR5 coding sequences induces resistance to HIV infection in vitro and in vivo. A chimeric Ad5/F35 adenoviral vector encoding CCR5-ZFNs permitted efficient delivery and transient expression following anti-CD3/anti-CD28 costimulation of T lymphocytes. We present data showing CD3/CD28 costimulation substantially improved transduction efficiency over reported methods for Ad5/F35 transduction of T lymphocytes. Modifications to the laboratory scale process, incorporating clinically compatible reagents and methods, resulted in a robust ex vivo manufacturing process capable of generating >10(10) CCR5 gene-edited CD4+ T cells from healthy and HIV+ donors. CD4+ T-cell phenotype, cytokine production, and repertoire were comparable between ZFN-modified and control cells. Following consultation with regulatory authorities, we conducted in vivo toxicity studies that showed no detectable ZFN-specific toxicity or T-cell transformation. Based on these findings, we initiated a clinical trial testing the safety and feasibility of CCR5 gene-edited CD4+ T-cell transfer in study subjects with HIV-1 infection. PMID- 23360517 TI - Involvement of tryptophan hydroxylase 2 gene polymorphisms in susceptibility to tic disorder in Chinese Han population. AB - BACKGROUND: Tryptophan hydroxylase-2 (TPH2) is a potential candidate gene for screening tic disorder (TD). METHODS: A case-control study was performed to examine the association between the TPH2 gene and TD. The Sequenom(r) Mass ARRAY iPLEX GOLD System was used to genotype two single nucleotide polymorphisms (SNPs) of the TPH2 gene in 149 TD children and in 125 normal controls. RESULTS: For rs4565946, individuals with the TT genotype showed a significantly higher risk of TD than those with TC plus CC genotypes [odds ratio (OR) =3.077, 95% confidence interval (CI): 1.273-7.437; P = 0.009], as did male TD children with the TT genotype (OR = 3.228, 95% CI: 1.153-9.040; P = 0.020). The G allele of rs4570625 was significantly more frequent in TD children with higher levels of tic symptoms (Yale Global Tic Severity Scale, YGTSS) than those in controls among the male children (OR = 1.684, 95%: 1.097-2.583; P = 0.017]. TD children with severe tic symptoms had significantly higher frequencies of rs4546946 TT genotype than did normal controls in boys (OR = 3.292, 95% CI: 1.139-9.513; P = 0.022). We also found that genotype distributions of both SNPs were different between the Asian and European populations. CONCLUSIONS: Our results indicated that the TT genotype of rs4565946 is a potential genetic risk factor for TD, and the allele G of rs4570625 might be associated with the severity of tic symptoms in boys. These polymorphisms might be susceptibility loci for TD in the Chinese Han population. Because of the confounding of co-existing attention deficit hyperactivity disorder (ADHD),these findings need to be confirmed by studies in much larger samples. PMID- 23360518 TI - Synchronous intrathyroid metastasis from undifferentiated endometrial sarcoma. PMID- 23360519 TI - Fecal microbial communities of healthy adult dogs fed raw meat-based diets with or without inulin or yeast cell wall extracts as assessed by 454 pyrosequencing. AB - Our objective was to determine the effects of feeding raw meat-based diets with or without inulin or yeast cell wall extract (YCW) on fecal microbial communities of dogs using 454 pyrosequencing. Six healthy female adult beagles (5.5 +/- 0.5 years; 8.5 +/- 0.5 kg) were randomly assigned to six test diets using a Latin square design: (1) beef control; (2) beef + 1.4% inulin; (3) beef + 1.4% YCW; (4) chicken control; (5) chicken + 1.4% inulin; and (6) chicken + 1.4% YCW. Following 14 days of adaptation, fresh fecal samples were collected on day 15 or day 16 of each period. Fecal genomic DNA was extracted and used to create 16S rRNA gene amplicons, which were subjected to 454 pyrosequencing and qPCR. Predominant fecal bacterial phyla included Fusobacteria, Firmicutes, Bacteroidetes, and Proteobacteria. Beef-based diets increased (P < 0.05) Escherichia, but decreased (P < 0.05) Anaerobiospirillum vs. chicken-based diets. Inulin decreased (P < 0.05) Enterobacteriaceae. Inulin increased (P < 0.05) Megamonas vs. control. Inulin also decreased (P < 0.05) Escherichia vs. YCW. qPCR data showed that YCW increased (P < 0.05) Bifidobacterium vs. inulin and control and inulin increased (P < 0.05) Lactobacillus vs. YCW. Although a few changes in fecal microbiota were observed with inulin or YCW consumption, a strong prebiotic effect was not observed. PMID- 23360520 TI - Potential-dependent adsorption/desorption behavior of perfluorosulfonated ionomer on a gold electrode surface studied by cyclic voltammetry, electrochemical quartz microbalance, and electrochemical atomic force microscopy. AB - Potential-dependent adsorption/desorption behavior of perfluorosulfonated ionomer (PFSI) on a gold electrode was investigated by cyclic voltammetry (CV), electrochemical quartz crystal microbalance (EQCM), and electrochemical atomic force microscopy (EC-AFM) in a Nafion (i.e., PFSI) dispersed aqueous solution without any other electrolyte. It was found that PFSI serves as an electrolyte and that electrochemical measurements can be performed in this solution without any significant IR drop. PFSI molecules were adsorbed on the Au surface in the lying-down configuration in the potential range between 0 and 0.45 V, the amount of adsorbed PFSI increased when the potential was made more positive than 0.75 V, and the adsorbed PFSI fully desorbed from the surface at potentials more positive than 1.4 V where gold oxide was formed. Once the gold oxide had been reduced, PFSI readsorbed on the surface, albeit slowly. PFSI desorbed from the surface as the potential was made more negative than 0 V. These processes took place reversibly. PMID- 23360521 TI - Ligerin, an antiproliferative chlorinated sesquiterpenoid from a marine-derived Penicillium strain. AB - A new chlorinated sesquiterpenoid analogue of fumagillin, ligerin (1), was isolated from a marine-derived strain of Penicillium, belonging to the subgenus Penicillium, along with the known compounds penicillic acid (2), orcinol, and orsellinic acid. Chemical structures were established by an interpretation of spectroscopic data including IR, UV, and HRESIMS, together with analyses of 1D and 2D NMR spectra and X-ray analysis for the determination of the absolute configuration. Ligerin (1) displayed strong inhibitory activity against an osteosarcoma cell line. This is the first report of the isolation of a fumagillin analogue from a marine-derived Penicillium strain. PMID- 23360522 TI - Mechanistic heteroaggregation of gold nanoparticles in a wide range of solution chemistry. AB - Heteroaggregation behavior of gold nanospheres (AuNS) in presence of pluronic acid (PA) modified single-walled carbon nanotubes (PA-SWNTs) was systematically studied for a wide range of mono- and divalent (NaCl and CaCl(2)) electrolyte conditions. Homoaggregation rates of AuNS were also determined to delineate heteroaggregation mechanisms. Time resolved dynamic light scattering (DLS) was employed to monitor aggregation. The homoaggregation of AuNS showed classical Derjaguin-Landau-Verwey-Overbeek (DLVO) type behavior with defined reaction limited (RLCA) and diffusion limited (DLCA) aggregation regimes. PA-SWNTs homoaggregation on the one hand showed no response with electrolyte increase. AuNS heteroaggregation rates on the other hand, showed regime dependent response. At low electrolyte or RLCA regime, AuNS heteroaggregation showed significantly slower rates, compared to its homoaggregation behavior; whereas enhanced heteroaggregation was observed for DLCA regime. The key mechanisms of heteroaggregation of AuNS are identified as obstruction to collision at RLCA regime and facilitating enhanced attachment at DLCA regime manifested by the presence of PA-SWNTs. Presence of Suwannee River humic acid (SRHA) showed aggregation enhancement for both homo- and hetero-systems, in presence of divalent Ca(2+) ions. Bridging between SRHA molecules is identified as the key mechanism for increased aggregation rate. The findings of this study are relevant particularly to coexistence of engineered nanomaterials. The strategy of using nonaggregating PA-SWNTs is a novel experimental strategy that can be adopted elsewhere to further the heteroaggregation studies for a wider set of particles and surface coatings. PMID- 23360523 TI - Copper-catalyzed asymmetric conjugate addition of alkenyl- and alkylalanes to alpha,beta-unsaturated lactams. AB - Alkenyl and alkyl groups have been successfully introduced to six-membered alpha,beta-unsaturated lactams via a copper-catalyzed asymmetric 1,4-addition of the corresponding alanes. Moderate to good yields and good to excellent enantioselectivities are achieved by using a combination of the very cheap copper(II) naphthenate and a readily available phosphine amine ligand. The creation of an all-carbon quaternary stereogenic center, via Michael addition to a trisubstituted conjugated lactam, is also disclosed for the first time. PMID- 23360524 TI - Extracellular matrix-associated gene expression in adult sensory neuron populations cultured on a laminin substrate. AB - BACKGROUND: In our previous investigations of the role of the extracellular matrix (ECM) in promoting neurite growth we have observed that a permissive laminin (LN) substrate stimulates differential growth responses in subpopulations of mature dorsal root ganglion (DRG) neurons. DRG neurons expressing Trk and p75 receptors grow neurites on a LN substrate in the absence of neurotrophins, while isolectin B4-binding neurons (IB4+) do not display significant growth under the same conditions. We set out to determine whether there was an expression signature of the LN-induced neurite growth phenotype. Using a lectin binding protocol IB4+ neurons were isolated from dissociated DRG neurons, creating two groups - IB4+ and IB4-. A small-scale microarray approach was employed to screen the expression of a panel of ECM-associated genes following dissociation (t=0) and after 24 hr culture on LN (t=24LN). This was followed by qRT-PCR and immunocytochemistry of selected genes. RESULTS: The microarray screen showed that 36 of the 144 genes on the arrays were consistently expressed by the neurons. The array analyses showed that six genes had lower expression in the IB4+ neurons compared to the IB4- cells at t=0 (CTSH, Icam1, Itgbeta1, Lamb1, Plat, Spp1), and one gene was expressed at higher levels in the IB4+ cells (Plaur). qRT-PCR was carried out as an independent assessment of the array results. There were discrepancies between the two methods, with qRT-PCR confirming the differences in Lamb1, Plat and Plaur, and showing decreased expression of AdamTs1, FN, and Icam in the IB4+ cells at t=0. After 24 hr culture on LN, there were no significant differences detected by qRT-PCR between the IB4+ and IB4- cells. However, both groups showed upregulation of Itgbeta1 and Plaur after 24 hr on LN, the IB4+ group also had increased Plat, and the IB4- cells showed decreased Lamb1, Icam1 and AdamTs1. Further, the array screen also detected a number of genes (not subjected to qRT-PCR) expressed similarly by both populations in relatively high levels but not detectably influenced by time in culture (Bsg, Cst3, Ctsb, Ctsd, Ctsl, Mmp14, Mmp19, Sparc. We carried out immunohistochemistry to confirm expression of proteins encoded by a number of these genes. CONCLUSIONS: Our results show that 1B4+ and IB4- neurons differ in the expression of several genes that are associated with responsiveness to the ECM prior to culturing (AdamTs1, FN, Icam1, Lamb1, Plat, Plaur). The data suggest that the genes expressed at higher levels in the IB4- neurons could contribute to the initial growth response of these cells in a permissive environment and could also represent a common injury response that subsequently promotes axon regeneration. The differential expression of several extracellular matrix molecules (FN, Lamb1, Icam) may suggest that the IB4- neurons are capable of maintaining /secreting their local extracellular environment which could aid in the regenerative process. Overall, these data provide new information on potential targets that could be manipulated to enhance axonal regeneration in the mature nervous system. PMID- 23360525 TI - Periodontal disease and gene-expression levels of metalloendopeptidases in human buccal mucosal epithelium. AB - BACKGROUND AND OBJECTIVE: Endopeptidases, such as neutral endopeptidase (NEP), endothelin-converting enzyme-1 (ECE-1) and a disintegrin and metalloprotease 17 (ADAM17), are believed to have various important roles in oral mucosal and epidermal tissue for the regulation of defensive biological responses in the oral cavity, and their expression and activity are influenced by various factors, including oral diseases. However, knowledge concerning these endopeptidases in the oral cavity has been minimal until now. This study focused on three metalloendopeptidases - NEP, ECE-1 and ADAM17 - in the oral buccal mucosal epithelium of patients with periodontal diseases and investigated the relationship between their gene-expression levels and periodontal disease. MATERIAL AND METHODS: The levels of expression of NEP, ECE-1 and ADAM17 mRNAs in tissue samples collected from the oral buccal mucosal epithelium of 61 patients were investigated by relative quantification using real-time RT-PCR analysis. information on oral and systemic health was obtained from the clinical record of each patient. RESULTS: Among the three groups, classified based on the diagnosis of periodontal diseases (healthy/gingivitis, early periodontitis and moderate/advanced periodontitis), the relative expression level of NEP mRNA was significantly increased in the early periodontitis group and in the moderate/advanced periodontitis group compared with that in the healthy/gingivitis group. Moreover, the relative expression levels of ECE1 and ADAM17 mRNAs were significantly increased in the moderate/advanced periodontitis group compared with those in the healthy/gingivitis group. The correlation coefficients between the mean relative expression levels of NEP and ECE1 mRNAs, NEP and ADAM17 mRNAs, and ECE1 and ADAM17 mRNAs were r = 0.758, r = 0.707 and r = 0.934, respectively (p < 0.001). Furthermore, among the oral-related factors, there was a significant correlation between the number of sites with probing pocket depths of more than 4 mm and of more than 6 mm and the relative expression levels of NEP, ECE1 and ADAM17 mRNAs. In stepwise logistic regression models, high relative expression levels of ECE1 and ADAM17 mRNAs were significantly associated with moderate/advanced periodontitis. CONCLUSION: The present study suggests that the severity of periodontal disease may be associated with the expression of metalloendopeptidase genes, including NEP, ECE1 and ADAM17, in the buccal mucosal epithelium. PMID- 23360526 TI - A CD19/Fc fusion protein for detection of anti-CD19 chimeric antigen receptors. AB - BACKGROUND: Chimeric Antigen Receptors (CARs) consist of the antigen-recognition portion of a monoclonal antibody fused to an intracellular signaling domain capable of activating T-cells. CARs displayed on the surface of transduced cells perform non-MHC-restricted antigen recognition and activating intracellular signaling pathways for induction of target cytolysis, cytokine secretion and proliferation. Clinical trials are in progress assessing the use of mature T lymphocytes transduced with CARs targeting CD19 antigen to treat B-lineage malignancies. CD19 is an attractive target for immunotherapy because of its consistent and specific expression in most of the stages of maturation and malignancies of B-lymphocyte origin, but not on hematopoietic stem cells. Antibodies against the extracellular domain of the CAR molecule (anti-Fab, Fc or idiotype) have been used for detection of CAR expression in research and clinical samples by flow cytometry, but may need development for each construct and present significant background in samples from xenograft models. METHODS: A specific reagent for the detection of anti-CD19 CAR expression was developed, a fusion protein consisting of human CD19 extracellular domains and the Fc region of human IgG1 (CD19sIg). Genes encoding CD19sIg fusion proteins were constructed by fusing either exons 1 to 3 (CD19sIg1-3) or exons 1 to 4 (CD19sIg1-4) of the human CD19 cDNA to a human IgG1Fc fragment. These fusion proteins are intended to work in similar fashion as the MHC Tetramers used for identification of antigen specific T-cells, and may also have other applications in studies of activation of anti-CD19 CAR bearing cells. The CD19sIg proteins were produced from 293 T cells by stable lentiviral vector transduction and purification from culture medium. RESULTS: ELISA assays using several different monoclonal antibodies to CD19 demonstrated dose-related specific binding by the fusion molecule CD19sIg1 4, but no binding by CD19sIg1-3. Conjugation of the CD19sIg1-4 fusion protein to Alexa Fluor 488 allowed specific and sensitive staining of anti-CD19 CAR-bearing cells for flow cytometry assays, detecting as low as 0.5% of CAR-modified primary cells with minimal background staining. CONCLUSIONS: This fusion molecule is a sensitive reagent for detection of anti-CD19 CAR derived from any monoclonal antibody present in CAR-modified T-cells. PMID- 23360528 TI - Randomized, blinded study to assess the effect of povidone-iodine on the groin wound of patients undergoing primary varicose vein surgery. AB - BACKGROUND: The aim of this study was to assess the effect of povidone-iodine on the groin wounds of patients undergoing primary varicose vein surgery. METHODS: This is a prospective, randomized, blinded, controlled study on patients undergoing primary saphenofemoral ligation. Patients were randomized to a povidone-iodine (Betadine; Pfizer, West Ryde, Australia)-soaked surgical gauze placed in the open wound or a saline-soaked gauze placed in the wound. Patients were then followed up weekly for 6 weeks to observe for signs of wound infection. RESULTS: Sixty-eight legs in 49 patients were recruited. Thirty-seven groin wounds were randomized to saline and 32 to Betadine. There was a reduced incidence of groin wound infections in those randomized to Betadine (3 versus 1), but this was not statistically significant (P = 0.4). CONCLUSION: Although there may be a trend towards a lower wound infection rate when povidone-iodine is use in surgical wounds, this is not significant for varicose vein surgery. PMID- 23360527 TI - Dynamic DNA assemblies mediated by binding-induced DNA strand displacement. AB - Dynamic DNA assemblies, including catalytic DNA circuits, DNA nanomachines, molecular translators, and reconfigurable nanostructures, have shown promising potential to regulate cell functions, deliver therapeutic reagents, and amplify detection signals for molecular diagnostics and imaging. However, such applications of dynamic DNA assembly systems have been limited to nucleic acids and a few small molecules, due to the limited approaches to trigger the DNA assemblies. Herein, we describe a binding-induced DNA strand displacement strategy that can convert protein binding to the release of a predesigned output DNA at room temperature with high conversion efficiency and low background. This strategy allows us to construct dynamic DNA assembly systems that are able to respond to specific protein binding, opening an opportunity to initiate dynamic DNA assembly by proteins. PMID- 23360529 TI - Is gender responsible for everything? The relationship between sex and right ventricular remodeling in metabolic syndrome. AB - BACKGROUND: The aim of this study was to examine the impact of metabolic syndrome (MS) on right ventricular (RV) remodeling in different genders. METHODS: The study included 341 subjects (216 subjects with MS and 125 controls). MS was defined by the presence of >= 3 ATP-NCEP-III criteria. All subjects underwent complete two-dimensional echocardiography. RESULTS: RV structure, diastolic, and global function were significantly impaired in MS subjects, in both genders. The multiple regression analysis of MS parameters showed that systolic blood pressure (BP) and waist circumference were independently associated with RV wall thickness in women, whereas the only independent predictor in men was systolic BP. The multivariate logistic regression analysis revealed that increased BP, impaired fasting glucose, and dyslipidemia were a combination of MS risk factors related with RV hypertrophy solely in women. Increased systolic BP, impaired fasting glucose, and abdominal obesity were independently associated with tricuspid E/e' in women, whereas increased systolic BP was the only independent predictor in men. Impaired fasting glucose, abdominal obesity, and dyslipidemia were a combination of MS criteria, which was independently associated with RV diastolic dysfunction only in women. CONCLUSIONS: Different parameters of MS are responsible for RV remodeling in women and men. The metabolic parameters of MS are more important for RV remodeling in women. PMID- 23360531 TI - Complete genome sequence and biological characterization of Moroccan pepper virus (MPV) and reclassification of Lettuce necrotic stunt virus as MPV. AB - Moroccan pepper virus (MPV) and Lettuce necrotic stunt virus (LNSV) have been steadily increasing in prevalence in central Asia and western North America, respectively, over the past decade. Recent sequence analysis of LNSV demonstrated a close relationship between the coat proteins of LNSV and MPV. To determine the full extent of the relationship between LNSV and MPV, the genomes of three MPV isolates were sequenced and compared with that of LNSV. Sequence analysis demonstrated that genomic nucleotide sequences as well as virus-encoded proteins of the three MPV isolates and LNSV shared 97% or greater identity. A full-length clone of a California LNSV isolate was developed and virus derived from infectious transcripts was used to evaluate host plant reactions under controlled conditions. Symptoms of LNSV matched those described previously for MPV on most of a select series of host plants, although some differences were observed. Collectively, these molecular and biological results demonstrate that LNSV should be classified as MPV within the family Tombusviridae, genus Tombusvirus, and confirm the presence of MPV in North America. PMID- 23360530 TI - Avian haemosporidian persistence and co-infection in great tits at the individual level. AB - BACKGROUND: Many studies have tracked the distribution and persistence of avian haemosporidian communities across space and time at the population level, but few studies have investigated these aspects of infection at the individual level over time. Important aspects of parasite infection at the individual level can be missed if only trends at the population level are studied. This study aimed to determine how persistent Haemosporida are in great tit individuals recaptured over several years, whether parasitaemia differed by parasite lineage (mitochondrial cytochrome b haplotype) and how co-infection (i.e. concurrent infection with multiple genera of parasites) affects parasitaemia and body mass. METHODS: Parasite prevalence was determined by polymerase chain reaction (PCR), quantitative PCR were used to assess parasitaemia and sequencing was employed to determine the identity of the lineages using the MalAvi database. RESULTS: Haemosporidian prevalence was high over sampled years with 98% of 55 recaptured individuals showing infection in at least one year of capture. Eighty-two percent of all positive individuals suffered co-infection, with an overall haemosporidian lineage diversity of seventeen. Plasmodium and Haemoproteus parasites were found to be highly persistent, with lineages from these genera consistently found in individuals across years and with no differences in individual parasitaemia being recorded at subsequent captures. Conversely, Leucocytozoon parasites showed higher turnover with regard to lineage changes or transitions in infection status (infected vs non-infected) across years. Parasitaemia was found to be lineage specific and there was no relationship between Plasmodium parasitaemia or host body condition and the presence of Leucocytozoon parasites. CONCLUSIONS: The findings of this study suggest that different genera of haemosporidian parasites interact differently with their host and other co-infecting parasites, influencing parasite persistence most likely through inter-parasite competition or host-parasite immune interactions. Even-though co-infections do not seem to result in increased virulence (higher parasitaemia or poorer host body condition), further investigation into infection potential of these parasites, both individually and as co-infections, is necessary. PMID- 23360532 TI - Nonhost resistance of Arabidopsis thaliana against Alternaria alternata involves both pre- and postinvasive defenses but is collapsed by AAL-toxin in the absence of LOH2. AB - The tomato pathotype of Alternaria alternata causes Alternaria stem canker on tomato depending upon the production of the host-specific AAL-toxin. Host defense mechanisms to A. alternata, however, are largely unknown. Here, we elucidate some of the mechanisms of nonhost resistance to A. alternata using Arabidopsis mutants. Wild-type Arabidopsis showed either no symptoms or a hypersensitive reaction (HR) when inoculated with both strains of AAL-toxin-producing and non producing A. alternata. Yet, when these Arabidopsis penetration (pen) mutants, pen2 and pen3, were challenged with both strains of A. alternata, fungal penetration was possible. However, further fungal development and conidiation were limited on these pen mutants by postinvasion defense with HR-like cell death. Meanwhile, only AAL-toxin-producing A. alternata could invade lag one homologue (loh)2 mutants, which have a defect in the AAL-toxin resistance gene, subsequently allowing the fungus to complete its life cycle. Thus, the nonhost resistance of Arabidopsis thaliana to A. alternata consists of multilayered defense systems that include pre-invasion resistance via PEN2 and PEN3 and postinvasion resistance. However, our study also indicates that the pathogen is able to completely overcome the multilayered nonhost resistance if the plant is sensitive to the AAL-toxin, which is an effector of the toxin-dependent necrotrophic pathogen A. alternata. PMID- 23360533 TI - Multiple Ceratocystis smalleyi infections associated with reduced stem water transport in bitternut hickory. AB - Hundreds of cankers caused by Ceratocystis smalleyi are associated with hickory bark beetle-attacked bitternut hickory exhibiting rapid crown decline in the north-central and northeastern United States. Discolored sapwood colonized by the fungus commonly underlies the cankers. Field studies were conducted to test the hypothesis that C. smalleyi infections cause vascular system dysfunction in infected trees. Fifty C. smalleyi inoculations made at 1.8 to 3.8 m in height on stems of healthy bitternut hickory trees (13 to 28 cm in diameter at 1.4 m in height) resulted in extensive canker formation and sapwood discoloration 12 to 14 months after treatment compared with water-inoculated and noninoculated controls. Sap flow velocity (midday) was significantly lower in the infected trees compared with that in the controls. Sap flow velocity also was inversely correlated with the proportion of bark area with cankered tissues and with tylose abundance in the youngest two growth rings. Tylose formation in current-year vessels associated with C. smalleyi infections is likely responsible for much of the water transport disruption. It is hypothesized that multiple stem infections of C. smalleyi and the resulting xylem dysfunction contribute to crown wilt development in bitternut hickory exhibiting rapid crown decline. PMID- 23360536 TI - Abdominal accommodation induced by meal ingestion: differential responses to gastric and colonic volume loads. AB - BACKGROUND: Using an experimental model of colonic gas infusion, we previously showed that the abdominal walls adapt to its content by an active phenomenon of abdominal accommodation. We now hypothesized that abdominal accommodation is a physiological phenomenon, and aimed to confirm that it can be induced by ingestion of a meal; a secondary aim was to determine whether the response to gut filling is region-specific. METHODS: In healthy subjects (n = 24) a nutrient test meal was administered until tolerated at a rate of 50 mL min(-1). Electromyographic (EMG) activity of the anterior wall (upper and lower rectus, external and internal oblique) was measured via four pairs of surface electrodes, and EMG activity of the diaphragm via intraluminal electrodes on an esophageal tube. To address the secondary aim, the response to gastric filling was compared with that induced by colonic filling (1440 mL 30 min(-1) anal gas infusion; n = 8). KEY RESULTS: Participants tolerated 927 +/- 66 mL of meal (450-1500 mL). Meal ingestion induced progressive diaphragmatic relaxation (EMG reduction by 16 +/- 2%; P < 0.01) and selective contraction of the upper abdominal wall (24 +/- 2% increase in activity of the upper rectus and external oblique; P < 0.01 for both), with no significant changes in the lower rectus (4 +/- 2%) or internal oblique (5 +/- 3%). Colonic gas infusion induced a similar response, but with an overall contraction of the anterior wall. CONCLUSIONS & INFERENCES: Meal ingestion induces a metered and region-specific response of the abdominal walls to accommodate the volume load. Abnormal abdominal accommodation could be involved in postprandial bloating. PMID- 23360535 TI - Mammographic density and risk of breast cancer according to tumor characteristics and mode of detection: a Spanish population-based case-control study. AB - INTRODUCTION: It is not clear whether high mammographic density (MD) is equally associated with all subtypes of breast cancer (BC). We investigated the association between MD and subsequent BC, considering invasiveness, means of detection, pathologic subtype, and the time elapsed since mammographic exploration and BC diagnosis. METHODS: BC cases occurring in the population of women who attended screening from 1997 through 2004 in Navarre, a Spanish region with a fully consolidated screening program, were identified via record linkage with the Navarre Cancer Registry (n = 1,172). Information was extracted from the records of their first attendance at screening in that period. For each case, we randomly selected four controls, matched by screening round, year of birth, and place of residence. Cases were classified according to invasiveness (ductal carcinoma in situ (DCIS) versus invasive tumors), pathologic subtype (considering hormonal receptors and HER2), and type of diagnosis (screen-detected versus interval cases). MD was evaluated by a single, experienced radiologist by using a semiquantitative scale. Data on BC risk factors were obtained by the screening program in the corresponding round. The association between MD and tumor subtype was assessed by using conditional logistic regression. RESULTS: MD was clearly associated with subsequent BC. The odds ratio (OR) for the highest MD category (MD >75%) compared with the reference category (MD <10%) was similar for DCIS (OR = 3.47; 95% CI = 1.46 to 8.27) and invasive tumors (OR = 2.95; 95% CI = 2.01 to 4.35). The excess risk was particularly high for interval cases (OR = 7.72; 95% CI = 4.02 to 14.81) in comparison with screened detected tumors (OR = 2.17; 95% CI = 1.40 to 3.36). Sensitivity analyses excluding interval cases diagnosed in the first year after MD assessment or immediately after an early recall to screening yielded similar results. No differences were seen regarding pathologic subtypes. The excess risk associated with MD persisted for at least 7 to 8 years after mammographic exploration. CONCLUSIONS: Our results confirm that MD is an important risk factor for all types of breast cancer. High breast density strongly increases the risk of developing an interval tumor, and this excess risk is not completely explained by a possible masking effect. PMID- 23360534 TI - Expression profiling of 21 biomolecules in locally advanced nasopharyngeal carcinomas of Caucasian patients. AB - BACKGROUND: Since scarce data exist on the pathogenesis of nasopharyngeal carcinoma in Caucasian patients, we attempted to elucidate the responsible molecular pathways in this patient population. METHODS: Formalin-fixed paraffin embedded tumor tissue samples from 107 patients, diagnosed with locally-advanced nasopharyngeal carcinoma and treated with chemotherapy or chemo-radiotherapy, were analyzed by immunohistochemistry for the expression of the following proteins: E-cadherin, P-cadherin, Fascin-1, Cyclin D1, COX-2, EGFR, VEGF-A, VEGF C, VEGFR-2, VEGFR-3, ERCC1, p53, p63, Ki67, MAPT, phospho-p44/42MAPK, PTEN, phospho-AKT, phospho-mTOR, and phospho-GSK-3beta. EBER status was assessed by in situ hybridization. The majority of the cases were included in tissue microarray. All stains were performed and assessed centrally by two pathologists. The median follow-up time was 76.8 (42.3 - 99.2) months. RESULTS: Biomolecules expressed in >90% of cases were: p53, COX-2, P-cadherin, EBER, phospho-GSK-3beta, and Fascin 1. WHO II+III tumors were more frequently EBER & PTEN positive and VEGF-A negative. Advanced age was significantly associated with positive phospho-GSK 3beta and ERCC1 expression; male gender with positive phospho-AKT and phospho p44/42MAPK; and worse performance status (1 or 2) with negative Ki67, ERCC1, PTEN, and phospho-mTOR expression. Earlier disease stage was closely associated with p63, MAPT, PTEN, and Cyclin D1 positivity. Univariate Cox regression analysis highlighted Cyclin D1 as a negative prognostic factor for disease-free survival (p=0.034) and EBER as a positive one for overall survival (p=0.048). In multivariate analysis, advanced age and stage, poor performance status, and positive ERCC1 emerged as predictors of worse disease-free and overall survival, as opposed to positive phospho-mTOR. Clustering analysis defined two protein expression groups being predictive of better overall survival (p=0.043). CONCLUSIONS: Our study is the first to examine the activation and interaction of established biomolecules and signaling pathways in Caucasian NPC patients in an effort to reveal new therapeutic targets. PMID- 23360537 TI - A nonribosomal peptide synthetase-derived iron(III) complex from the pathogenic fungus Aspergillus fumigatus. AB - Small molecules (SMs) play central roles as virulence factors of pathogenic fungi and bacteria; however, genomic analyses suggest that the majority of microbial SMs have remained uncharacterized. Based on microarray analysis followed by comparative metabolomics of overexpression/knockout mutants, we identified a tryptophan-derived iron(III)-complex, hexadehydro-astechrome (HAS), as the major product of the cryptic has nonribosomal peptide synthetase (NRPS) gene cluster in the human pathogen Aspergillus fumigatus. Activation of the has cluster created a highly virulent A. fumigatus strain that increased mortality of infected mice. Comparative metabolomics of different mutant strains allowed to propose a pathway for HAS biosynthesis and further revealed cross-talk with another NRPS pathway producing the anticancer fumitremorgins. PMID- 23360538 TI - SANS, infrared, and 7Li and 23Na NMR studies on phase separation of alkali halide acetonitrile-water mixtures by cooling. AB - Phase separation of alkali halide (MX) (M = Li+, Na+, and K+ and X = Cl- and Br-) acetonitrile (AN)-water mixtures by cooling has been investigated at the molecular level. The phase diagram obtained for the MX-AN-H2O ternary systems showed that the temperatures of phase separation for the mixtures with MCl are higher than those with MBr. The phase-separation temperatures of the mixtures with MCl and MBr are higher in the sequence of NaX > KX > LiX, although the magnitude of the hydration enthalpies for the alkali metal ions is larger in the sequence of Li+ > Na+ > K+. To elucidate the reasons for the sequence of phase separation on the meso- and microscopic scales, small-angle neutron scattering (SANS), infrared (IR), and 7Li and 23Na NMR measurements have been conducted on MX-AN-water mixtures with lowering temperature. The results of SANS and IR experiments showed that the mechanism of phase separation of the mixtures by cooling is the same among all of the mixtures but did not clearly reveal the reasons for the phase separation sequence. In contrast, the spin-lattice relaxation rates and the chemical shifts of 7Li and 23Na NMR for the mixtures suggested the different solvation structure of Li+ and Na+ in the mixtures. In conclusion, the solvation of acetonitrile molecules for Li+ and the formation of Li+-X- contact ion pairs in the mixtures cause the weakest effect of LiX on phase separation of the mixtures by cooling among the alkali metal ions. PMID- 23360539 TI - WordPerfect Office X6 software review. PMID- 23360540 TI - Outcomes and patterns of care of patients with locally advanced oropharyngeal carcinoma treated in the early 21st century. AB - BACKGROUND: We performed this study to assess outcomes of patients with oropharyngeal cancer treated with modern therapy approaches. METHODS: Demographics, treatments and outcomes of patients diagnosed with Stage 3- 4B squamous carcinoma of the oropharynx, between 2000-2007 were tabulated and analyzed. RESULTS: The cohort consisted of 1046 patients. The 5-year actuarial overall survival, recurrence-free survival and local-regional control rates for the entire cohort were 78%, 77% and 87% respectively. More advanced disease, increasing T-stage and smoking were associated with higher rates of local regional recurrence and poorer survival. CONCLUSIONS: Patients with locally advanced oropharyngeal cancer have a relatively high survival rate. Patients' demographics and primary tumor volume were very influential on these favorable outcomes. In particular, patients with small primary tumors did very well even when treatment was not intensified with the addition of chemotherapy. PMID- 23360541 TI - Neutral polymeric micelles for RNA delivery. AB - RNA interference (RNAi) drugs have significant therapeutic potential, but delivery systems with appropriate efficacy and toxicity profiles are still needed. Here, we describe a neutral, ampholytic polymeric delivery system based on conjugatable diblock polymer micelles. The diblock copolymer contains a hydrophilic poly[N-(2-hydroxypropyl)methacrylamide-co-N-(2-(pyridin-2 yldisulfanyl)ethyl)methacrylamide) (poly[HPMA-co-PDSMA]) segment to promote aqueous stability and facilitate thiol-disulfide exchange reactions and a second ampholytic block composed of propylacrylic acid (PAA), dimethylaminoethyl methacrylate (DMAEMA), and butyl methacrylate (BMA). The poly[(HPMA-co-PDSMA)-b (PAA-co-DMAEMA-co-BMA)] was synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization with an overall molecular weight of 22 000 g/mol and a PDI of 1.88. Dynamic light scattering and fluorescence measurements indicated that the diblock copolymers self-assemble under aqueous conditions to form polymeric micelles with a hydrodynamic radius and critical micelle concentration of 25 nm and 25 MUg/mL, respectively. Red blood cell hemolysis experiments show that the neutral hydrophilic micelles have potent membrane destabilizing activity at endosomal pH values. Thiolated siRNA targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was directly conjugated to the polymeric micelles via thiol exchange reactions with the pyridal disulfide groups present in the micelle corona. Maximum silencing activity in HeLa cells was observed at a 1:10 molar ratio of siRNA to polymer following a 48 h incubation period. Under these conditions 90% mRNA knockdown and 65% protein knockdown at 48 h was achieved with negligible toxicity. In contrast the polymeric micelles lacking a pH-responsive endosomalytic segment demonstrated negligible mRNA and protein knockdown under these conditions. The potent mRNA knockdown and excellent biocompatibility of the neutral siRNA conjugates demonstrate the potential utility of this carrier design for delivering therapeutic siRNA drugs. PMID- 23360542 TI - Berberine protects human renal proximal tubular cells from hypoxia/reoxygenation injury via inhibiting endoplasmic reticulum and mitochondrial stress pathways. AB - BACKGROUND: Ischemia/reperfusion injury plays a crucial role in renal transplantation, and represents a significant risk factor for acute renal failure and delayed graft function. The pathophysiological contribution of endoplasmic reticulum and mitochondria stress to ischemia/reperfusion injury has also been highlighted. Berberine (BBR) has been showed to attenuate ischemia/reperfusion injury by inhibiting oxidative stress. The study was carried out to investigate whether the pretreatment of BBR could reduce hypoxia/reoxygenation (H/R)-induced injury by inhibiting mitochondria stress and endoplasmic reticulum stress pathways. METHODS: The cultured human renal proximal tubular cell line HK-2 cells were exposed to 24 h hypoxia (5% CO2, 1% O2, 94% N2) followed by 3 h reoxygenation (5% CO2, 21% O2, 74% N2). And BBR was added to the culture medium 2h prior to the treatment. Then the cell viability, oxidative stress level, morphological change of apoptosis and apoptotic rate were determined. In addition, Western blot analysis was performed to identify the expression of apoptotic pathway parameters, including Bcl-2, Bax and cytochrome C involved in mitochondrial-dependent pathway and ER stress hallmarks such as glucose-regulated protein 78 and CCAAT/enhancer binding protein homologous protein. RESULTS: H/R produced dramatic injuries in HK-2 cells. The cell viability and the oxidative stress level in group H/R was significantly decreased. The classical morphological change of apoptosis was found, while the apoptotic rate and the expression of proteins involved in mitochondrial stress and endoplasmic reticulum stress pathways increased (p<0.05). Administration of BBR significantly inhibited these H/R induced changes (p<0.05). CONCLUSION: This study revealed that BBR pretreatment serves a protective role against H/R induced apoptosis of human renal proximal tubular cells, and the mechanism is related to suppression of mitochondrial stress and endoplasmic reticulum stress pathways. PMID- 23360544 TI - Hyaluronidase contributes to early inflammatory events induced by electrotransfer in mouse skeletal muscle. AB - Electrotransfer of genes is one of the preferred strategies used to deliver plasmid DNA into skeletal muscle. In our experience, the combination of hyaluronidase (HYA) with electrotransfer (ET) of DNA vaccine enhances transfection of muscular fibers and increases expression of the encoded antigen. However, the contribution of HYA to the inflammatory reaction induced by ET, and its role in supporting ET adjuvancy, has never been investigated. We analyzed the events occurring in the first 2 weeks after electrotransfer to mouse muscle in the presence of HYA, to verify whether HYA contributes to the local inflammatory response induced by ET. Our results demonstrate that HYA amplifies the ET effect in terms of inflammatory cell recruitment enhancing the early release of interleukin (IL)-1beta, tumor necrosis factor-alpha, and IL-6 cytokines. In contrast, HYA does not induce helper T cell type 1 and 2 cytokine production, confirming that the DNA vaccine is indispensable to induce mediators of antigen specific immune responses. We observed inflammatory cell migration in the muscle treated with HYA plus ET in a time window between days 4 and 7 after cytokine induction. These observations are important in the choice of prime-boost intervals for optimizing ET-based DNA vaccination protocols. Because HYA contributes to vaccine spread and enhances the proinflammatory effect of ET in muscle we strongly support the use of HYA to potentiate DNA vaccine efficacy. PMID- 23360545 TI - Comparative surface thermodynamic analysis of new fluid phase formation between a sphere and a flat plate. AB - This paper investigates the behavior of confined fluid in the gap between a sphere and a flat plate by examining the curve of free energy of the system versus size of the new phase. Four possible situations corresponding to new phase formation out of confined liquid or vapor at pressures above or below the saturation pressure are studied. Using surface thermodynamics, the feasible shape of the meniscus (concave/convex), the possibility of phase transition, as well as the number and the nature (unstable/stable) of equilibrium states have been determined for each of these four situations. The effects of equilibrium contact angle, separation distance of confinement surfaces, and sphere size have been studied. We show that the number and nature of equilibrium states, along with the effect of different parameters in these four possible situations, can be well described under two categories of new phase formation with (a) concave or (b) convex meniscus. Our results reveal that in the sphere-plate gap, stable coexistence of the liquid and vapor phases is only possible when the meniscus is concave (which corresponds to either capillary condensation or capillary evaporation), and when the sphere and plate are separated by a distance less than a critical amount (where that critical amount is always less than the Kelvin radius). With convex menisci, no stable coexistence of liquid and vapor phase is possible. PMID- 23360543 TI - Asperterpenoid A, a new sesterterpenoid as an inhibitor of Mycobacterium tuberculosis protein tyrosine phosphatase B from the culture of Aspergillus sp. 16-5c. AB - Asperterpenoid A (1), a novel sesterterpenoid with a new carbon skeleton, has been isolated from a mangrove endophytic fungus Aspergillus sp. 16-5c. Its structure was characterized by extensive spectroscopic methods, and the absolute configuration was determined by single crystal X-ray diffraction analysis. Asperterpenoid A (1) exhibited strong inhibitory activity against Mycobacterium tuberculosis protein tyrosine phosphatase B (mPTPB) with an IC(50) value of 2.2 MUM. PMID- 23360546 TI - Epigenetic modification contributes to the expression divergence of three TaEXPA1 homoeologs in hexaploid wheat (Triticum aestivum). AB - Common wheat is a hexaploid species with most of the genes present as triplicate homoeologs. Expression divergences of homoeologs are frequently observed in wheat, as well as in other polyploid plants. However, the mechanisms underlying this phenomenon are poorly understood. Expansin genes play important roles in the regulation of cell size, as well as organ size. We found that all three TaEXPA1 homoeologs were silenced in seedling roots. In seedling leaves, TaEXPA1-A and TaEXPA1-D were expressed, but TaEXPA1-B was silenced. Further analysis revealed that silencing of TaEXPA1-B in leaves occurred after the formation of the hexaploid. Chromatin immunoprecipitation assays revealed that the transcriptional silencing of three TaEXPA1 homoeologs in roots was correlated with an increased level of H3K9 dimethylation and decreased levels of H3K4 trimethylation and H3K9 acetylation. Reactivation of TaEXPA1-A and TaEXPA1-D expression in leaves was correlated with increased levels of H3K4 trimethylation and H3K9 acetylation, and decreased levels of H3K9 dimethylation in their promoters, respectively. Moreover, a higher level of cytosine methylation was detected in the promoter region of TaEXPA1-B, which may contribute to its silencing in leaves. We demonstrated that epigenetic modifications contribute to the expression divergence of three TaEXPA1 homoeologs during wheat development. PMID- 23360548 TI - Toward large-scale energy harvesting by a nanoparticle-enhanced triboelectric nanogenerator. AB - This article describes a simple, cost-effective, and scalable approach to fabricate a triboelectric nanogenerator (NG) with ultrahigh electric output. Triggered by commonly available ambient mechanical energy such as human footfalls, a NG with size smaller than a human palm can generate maximum short circuit current of 2 mA, delivering instantaneous power output of 1.2 W to external load. The power output corresponds to an area power density of 313 W/m(2) and a volume power density of 54,268 W/m(3) at an open-circuit voltage of ~1200 V. An energy conversion efficiency of 14.9% has been achieved. The power was capable of instantaneously lighting up as many as 600 multicolor commercial LED bulbs. The record high power output for the NG is attributed to optimized structure, proper materials selection and nanoscale surface modification. This work demonstrated the practicability of using NG to harvest large-scale mechanical energy, such as footsteps, rolling wheels, wind power, and ocean waves. PMID- 23360547 TI - Food venue choice, consumer food environment, but not food venue availability within daily travel patterns are associated with dietary intake among adults, Lexington Kentucky 2011. AB - OBJECTIVE: The retail food environment may be one important determinant of dietary intake. However, limited research focuses on individuals' food shopping behavior and activity within the retail food environment. This study's aims were to determine the association between six various dietary indicators and 1) food venue availability; 2) food venue choice and frequency; and 3) availability of healthy food within food venue. METHODS: In Fall, 2011, a cross-sectional survey was conducted among adults (n=121) age 18 years and over in Lexington, Kentucky. Participants wore a global position system (GPS) data logger for 3-days (2 weekdays and 1 weekend day) to track their daily activity space, which was used to assess food activity space. They completed a survey to assess demographics, food shopping behaviors, and dietary outcomes. Food store audits were conducted using the Nutrition Environment Measurement Survey-Store Rudd (NEMS-S) in stores where respondents reported purchasing food (n=22). Multivariate logistic regression was used to examine associations between six dietary variables with food venue availability within activity space; food venue choice; frequency of shopping; and availability of food within food venue. RESULTS: 1) Food venue availability within activity space - no significant associations. 2) Food Venue Choice - Shopping at farmers' markets or specialty grocery stores reported higher odds of consuming fruits and vegetables (OR 1.60 95% CI [1.21, 2.79]). Frequency of shopping - Shopping at a farmers' markets and specialty stores at least once a week reported higher odds of consumption of fruits and vegetables (OR 1.55 95% CI [1.08, 2.23]). Yet, shopping frequently at a super market had higher odds of consuming sugar-sweetened beverages (OR 1.39 95% CI [1.03, 1.86]). 3) Availability of food within store - those who shop in supermarkets with high availability of healthy food has lower odds of consuming sugar-sweetened beverages (OR 0.65 95% CI [0.14, 0.83]). CONCLUSION: Interventions aimed at improving fruit and vegetable intake need to consider where individuals' purchase food and the availability within stores as a behavioral and environmental strategy. PMID- 23360549 TI - In vitro and mechanistic studies of an antiamyloidogenic self-assembled cyclic D,L-alpha-peptide architecture. AB - Misfolding of the Abeta protein and its subsequent aggregation into toxic oligomers are related to Alzheimer's disease. Although peptides of various sequences can self-assemble into amyloid structures, these structures share common three-dimensional features that may promote their cross-reaction. Given the significant similarities between amyloids and the architecture of self assembled cyclic D,L-alpha-peptide, we hypothesized that the latter may bind and stabilize a nontoxic form of Abeta, thereby preventing its aggregation into toxic forms. By screening a focused library of six-residue cyclic D,L-alpha-peptides and optimizing the activity of a lead peptide, we found one cyclic D,L-alpha peptide (CP-2) that interacts strongly with Abeta and inhibits its aggregation. In transmission electron microscopy, optimized thioflavin T and cell survival assays, CP-2 inhibits the formation of Abeta aggregates, entirely disassembles preformed aggregated and fibrillar Abeta, and protects rat pheochromocytoma PC12 cells from Abeta toxicity, without inducing any toxicity by itself. Using various immunoassays, circular dichroism spectroscopy, photoinduced cross-linking of unmodified proteins (PICUP) combined with SDS/PAGE, and NMR, we probed the mechanisms underlying CP-2's antiamyloidogenic activity. NMR spectroscopy indicates that CP-2 interacts with Abeta through its self-assembled conformation and induces weak secondary structure in Abeta. Upon coincubation, CP-2 changes the aggregation pathway of Abeta and alters its oligomer distribution by stabilizing small oligomers (1-3 mers). Our results support studies suggesting that toxic early oligomeric states of Abeta may be composed of antiparallel beta peptide structures and that the interaction of Abeta with CP-2 promotes formation of more benign parallel beta-structures. Further studies will show whether these kinds of abiotic cyclic D,L-alpha-peptides are also beneficial as an intervention in related in vivo models. PMID- 23360550 TI - Age-related changes in frequency of mind-wandering and task-related interferences during memory encoding and their impact on retrieval. AB - During the performance of cognitive tasks such as memory encoding, attention can become decoupled from the external environment and instead focused on internal thoughts related to the appraisal of the current task (task-related interferences; TRI), or personal thoughts unrelated to the task at hand (mind wandering; MW). However, the association between the frequency of these thoughts experienced at encoding and retrieval accuracy in young and older adults remains poorly understood. In this study young and older adults encoded lists of words using one of two encoding tasks: judging whether words are man-made/natural (objective task), or whether they are pleasant/neutral (subjective task). We measured the frequency of TRI and MW at encoding, and related them to retrieval accuracy in both age groups. We found that encoding task influenced the type of internal thoughts experienced by young, but not older, adults: young exhibited greater MW in the subjective vs the objective task, and greater TRI in the objective vs subjective encoding task. Second, across both tasks we found marked age-related decreases in both MW and TRI at encoding, and frequency of these thoughts negatively impacted memory retrieval in young adults only. We discuss these findings in relation to current theories of ageing, attention and memory. PMID- 23360551 TI - Molecular recognition of complex-type biantennary N-glycans by protein receptors: a three-dimensional view on epitope selection by NMR. AB - The current surge in defining glycobiomarkers by applying lectins rekindles interest in definition of the sugar-binding sites of lectins at high resolution. Natural complex-type N-glycans can present more than one potential binding motif, posing the question of the actual mode of interaction when interpreting, for example, lectin array data. By strategically combining N-glycan preparation with saturation-transfer difference NMR and modeling, we illustrate that epitope recognition depends on the structural context of both the sugar and the lectin (here, wheat germ agglutinin and a single hevein domain) and cannot always be predicted from simplified model systems studied in the solid state. We also monitor branch-end substitutions by this strategy and describe a three dimensional structure that accounts for the accommodation of the alpha2,6 sialylated terminus of a biantennary N-glycan by viscumin. In addition, we provide a structural explanation for the role of terminal alpha2,6-sialylation in precluding the interaction of natural N-glycans with lectin from Maackia amurensis . The approach described is thus capable of pinpointing lectin-binding motifs in natural N-glycans and providing detailed structural explanations for lectin selectivity. PMID- 23360552 TI - Prediction of reference phosphorus concentrations in Swedish lakes. AB - The relationship between total phosphorus (TP) and chemical, climatic, morphological, and geographic variables was examined for over a thousand reference lakes across Sweden. A significant relationship was found between TP and both absorbance of irradiance (at 420 nm, filtered) and altitude for all lakes. These two variables alone, however, were not able to adequately predict TP concentrations in naturally turbid lakes. A natural particulate matter factor (PM(n)) was developed as part of this study to incorporate the effect of natural suspended matter on lake phosphorus concentration. Variability in TP concentration was well explained with the addition of PM(n) to the model (R(2) = 0.71) even though conditions external and internal to the lakes varied greatly. The ability of the three parameter model to identify culturally eutrophic systems was then successfully tested using a data set of lakes with known anthropogenic phosphorus loads. Thus, the model allows for estimation of reference TP concentration and by extension can be used to identify when a reference concentration has been exceeded due to anthropogenic phosphorus loading. The model output also provides a realistic end point to which phosphorus concentrations should be reduced to achieve a natural trophic state in both clear water and naturally turbid lakes. PMID- 23360553 TI - Targeted search for actinomycetes from nearshore and deep-sea marine sediments. AB - Sediment samples collected off the coast of San Diego were analyzed for actinomycete diversity using culture-independent techniques. Eight new operational taxonomic units (OTUs) in the Streptomycetaceae were identified as well as new diversity within previously cultured marine OTUs. Sequences belonging to the marine actinomycete genus Salinispora were also detected, despite the fact that this genus has only been reported from more tropical environments. Independent analyses of marine sediments from the Canary Basin (3814 m) and the South Pacific Gyre (5126 and 5699 m) also revealed Salinispora sequences providing further support for the occurrence of this genus in deep-sea sediments. Efforts to culture Salinispora spp. from these samples have yet to be successful. This is the first report of Salinispora spp. from marine sediments > 1100 m and suggests that the distribution of this genus is broader than previously believed. PMID- 23360554 TI - Incidence and outcomes of ruptured abdominal aortic aneurysms in rural and urban Australia. AB - BACKGROUND: Rural and regional populations suffer higher rates of preventable disease and all-cause mortality than urban areas, with rural areas of the USA experiencing double the rate of ruptured abdominal aortic aneurysms (AAAs). We investigated the incidence and outcomes of ruptured AAAs in an Australian rural and regional setting, and compared these with those of an urban population. METHODS: We undertook a retrospective analysis of all patients suffering AAA rupture in New South Wales (NSW) from 2009/2010 to 2010/2011. Variables included rates of rupture, mortality and intensive care admission. Urban and rural regional areas were stratified according to NSW Health Local Health Districts, and comparisons between the two groups were performed. RESULTS: Ruptured AAAs had an incidence of 4.1/100 000, with males twice as likely to suffer AAA rupture (P = 0.009), but females 88% more likely to die from rupture (P = 0.001). There was no significant difference between AAA rupture rates (5.0 versus 3.4 per 100 000; P = 0.054) nor case-fatality rates (41.22% versus 40.94%; P = 0.087) in rural regional and urban populations. Patients in urban areas had a longer hospital stay (5 days versus 1 day, P = 0.001), were more likely to be admitted to intensive care unit (29.4% versus 19.9%, P = 0.001) and were less likely to be transferred to another hospital (19% versus 32%, P = 0.001). CONCLUSIONS: AAA ruptures remain a significant public health burden. Rural and regional areas suffer disproportionately, which may be improved by implementation of AAA screening and funding for rural and regional hospitals to sustain adequate surgical and intensive care facilities. PMID- 23360556 TI - Improvements in logistics could increase survival after out-of-hospital cardiac arrest in Sweden. AB - OBJECTIVES: In a review based on estimations and assumptions, to report the estimated number of survivors after out-of-hospital cardiac arrest (OHCA) in whom cardiopulmonary resuscitation (CPR) was started and to speculate about possible future improvements in Sweden. DESIGN: An observational study. SETTING: All ambulance organisations in Sweden. SUBJECTS: Patients included in the Swedish Cardiac Arrest Registry who suffered an OHCA between January 1, 2008 and December 31, 2010. Approximately 80% of OHCA cases in Sweden in which CPR was started are included. INTERVENTIONS: None RESULTS: In 11 005 patients, the 1-month survival rate was 9.4%. There are approximately 5000 OHCA cases annually in which CPR is started and 30-day survival is achieved in up to 500 patients yearly (6 per 100 000 inhabitants). Based on findings on survival in relation to the time to calling for the Emergency Medical Service (EMS) and the start of CPR and defibrillation, it was estimated that, if the delay from collapse to (i) calling EMS, (ii) the start of CPR, and (iii) the time to defibrillation were reduced to <2 min, <2 min, and <8 min, respectively, 300-400 additional lives could be saved. CONCLUSION: Based on findings relating to the delay to calling for the EMS and the start of CPR and defibrillation, we speculate that 300-400 additional OHCA patients yearly (4 per 100 000 inhabitants) could be saved in Sweden. PMID- 23360555 TI - Pro/con debate: should PaCO2 be tightly controlled in all patients with acute brain injuries? AB - You are the attending intensivist in a neurointensive care unit caring for a woman five days post-rupture of a cerebral aneurysm (World Federation of Neurological Surgeons Grade 4 and Fisher Grade 3). She is intubated for airway protection and mild hypoxemia related to an aspiration event at the time of aneurysm rupture, but is breathing spontaneously on the ventilator. Your patient is spontaneously hyperventilating with high tidal volumes despite minimal support and has developed significant hypocapnia. She has not yet developed the acute respiratory distress syndrome. You debate whether to tightly control her partial pressure of arterial carbon dioxide, weighing the known risks of acute hypocapnia in other forms of brain injury against the potential loss of clinical neuromonitoring associated with deep sedation and neuromuscular blockade in this patient who is at high risk of delayed ischemia from vasospasm. You are also aware of the potential implications of tidal volume control if this patient were to develop the acute respiratory distress syndrome and the effect of permissive hypercapnia on her intracranial pressure. In this paper we provide a detailed and balanced examination of the issues pertaining to this clinical scenario, including suggestions for clinical management of ventilation, sedation and neuromonitoring. Until more definitive clinical trial evidence is available to guide practice, clinicians are forced to carefully weigh the potential benefits of tight carbon dioxide control against the potential risks in each individual patient based on the clinical issues at hand. PMID- 23360557 TI - High efficacy of CpG-ODN, cetuximab and cisplatin combination for very advanced ovarian xenograft tumors. AB - BACKGROUND: To mimic clinical treatment situations in advanced human ovarian disease, we tested the efficacy of CpG-oligodeoxynucleotides (CpG-ODN), synthetic DNA sequences recognized by Toll-like receptor 9 and able to induce innate/adaptive immune responses, in combination with other possible therapeutic reagents in ovarian carcinoma ascites-bearing athymic mice. METHODS: Mice injected i.p. with IGROV-1 ovarian cancer cells were treated at different stages of ascites progression for 4 weeks with CpG-ODN, alone or in combination with Bevacizumab, Polyinosinic:Polycytidylic acid (Poly(I):Poly(C)), Gefitinib, Cetuximab and Cisplatin. Median survival time (MST) was calculated for each group. IGROV-1 cells treated or not with Cetuximab were assayed for antibody dependent cellular cytotoxicity by 51Cr-release assay, and for macrophage antibody-dependent cell-mediated phagocytosis by flow cytometry. RESULTS: In mice treated when ascitic fluid began to accumulate, CpG-ODN combined with Bevacizumab, Poly(I):Poly(C) or Gefitinib did not significantly increase MST as compared with that using CpG-ODN alone, whereas MST in mice treated with CpG-ODN plus Cetuximab was significantly increased (>103 days for combination vs 62 days for CpG alone; P = 0.0008), with 4/8 mice alive at the end of the experiment. In experiments in mice showing increased abdominal volume and body weight (27.9 +/- 0.8 g after vs 23 +/- 1.1 g before tumor cell injection), treatment with Cisplatin in addition to CpG-ODN/Cetuximab led to significantly increased MST (105.5 days; P = 0.001), with all mice still alive at 85 days, over that using CpG-ODN/Cetuximab (66 days), Cetuximab/Cisplatin (18.5 days), Cisplatin (23 days) or saline (16 days). At a very advanced stage of disease (body weight: 31.4 +/- 0.9 g), when more than half of control mice had to be sacrificed 6 days after starting treatments, the triple-combination therapy still increased MST (45 days; P = 0.0089) vs controls. CONCLUSIONS: CpG-ODN combination therapies that enhance the immune response in the tumor microenvironment and concomitantly target tumor cells are highly efficacious even in experimental advanced malignancies. Although differences in the distribution of TLR9 in mice and humans and the enrichment of this receptor on innate immune cells of athymic mice must be considered, our results indicate a promising strategy to treat ovarian cancer patients with bulky ascites. PMID- 23360558 TI - Characterization of heat shock protein 70 gene from Haemonchus contortus and its expression and promoter analysis in Caenorhabditis elegans. AB - Haemonchus contortus infections in small ruminants are of major economic importance worldwide. Heat shock proteins (HSPs) are a family of molecular chaperones that play important roles in the process of invasion and survival of nematodes. Although HSP70 has been identified in several parasitic nematodes, little is known of its distribution and function in Haemonchus contortus. The aims of this study were to characterize HSP70 from Haemonchus contortus (designed as Hc-hsp70), express Hc-hsp70 and analyse the promoter activity in Caenorhabditis elegans. Bioinformatic analysis revealed that the open reading frame of the Hc-hsp70 cDNA encodes a 646-amino acid peptide, which is highly conserved in comparison to HSP70 in other nematodes. Phylogenetic analysis indicated that H. contortus is closely related to Caenorhabditis. The 5'-flanking region promoted green fluorescence protein (GFP) expression in the intestine in all larval stages and adult with 2 expression patterns in C. elegans. Expression of Hc-hsp70 mRNA transcripts in C. elegans increased following 2, 4, 6 h of heat shock and peaked at 4 h. However, its expression induced down-regulation of hsp-1 of C. elegans. These results suggest that the H. contortus hsp70 might have a similar function to that of C. elegans hsp-1. PMID- 23360560 TI - Iron-catalyzed benzannulation reactions of 2-alkylbenzaldehydes and alkynes leading to naphthalene derivatives. AB - An efficient and practical method for the synthesis of naphthalene derivatives via Fe(III)-catalyzed benzannulation of 2-(2-oxoethyl)-benzaldehydes and alkynes has been developed. The system holds the advantages of cheap catalysts, wide substrate scope, and mild reaction conditions. PMID- 23360559 TI - Hodgkin's lymphoma emerging radiation treatment techniques: trade-offs between late radio-induced toxicities and secondary malignant neoplasms. AB - BACKGROUND: Purpose of this study is to explore the trade-offs between radio induced toxicities and second malignant neoplasm (SMN) induction risk of different emerging radiotherapy techniques for Hodgkin's lymphoma (HL) through a comprehensive dosimetric analysis on a representative clinical model. METHODS: Three different planning target volume (PTVi) scenarios of a female patient with supradiaphragmatic HL were used as models for the purpose of this study. Five treatment radiation techniques were simulated: an anterior-posterior parallel opposed (AP-PA), a forward intensity modulated (FIMRT), an inverse intensity modulated (IMRT), a Tomotherapy (TOMO), a proton (PRO) technique. A radiation dose of 30 Gy or CGE was prescribed. Dose-volume histograms of PTVs and organs-at risk (OARs) were calculated and related to available dose-volume constraints. SMN risk for breasts, thyroid, and lungs was estimated through the Organ Equivalent Dose model considering cell repopulation and inhomogeneous organ doses. RESULTS: With similar level of PTVi coverage, IMRT, TOMO and PRO plans generally reduced the OARs' dose and accordingly the related radio-induced toxicities. However, only TOMO and PRO plans were compliant with all constraints in all scenarios. For the IMRT and TOMO plans an increased risk of development of breast, and lung SMN compared with AP-PA and FIMRT techniques was estimated. Only PRO plans seemed to reduce the risk of predicted SMN compared with AP-PA technique. CONCLUSIONS: Our model-based study supports the use of advanced RT techniques to successfully spare OARs and to reduce the risk of radio-induced toxicities in HL patients. However, the estimated increase of SMNs' risk inherent to TOMO and IMRT techniques should be carefully considered in the evaluation of a risk-adapted therapeutic strategy. PMID- 23360561 TI - Telephone survey of service-user experiences of a telephone-based mental health triage service. AB - The participation of service users in all aspects of mental health service delivery including policy development, service planning and evaluation is increasingly an expectation of contemporary mental health care. Although there are a growing number of publications reporting service-user perspectives in the evaluation of mental health services, little attention has been paid to the views of service users about mental health triage services. The purpose of the study reported here was to examine service-users' (consumers and informal carers) experiences of a telephone-based mental health triage service. Using a framework developed from the World Health Organisation's elements of responsiveness, we conducted structured telephone interviews with service users who had contacted a telephone-based mental health triage service in regional Victoria, Australia. The main findings of the study were that consumers experienced more difficulty than carers in accessing the service and that, although most participants were satisfied, only a minority reported being involved in decision-making. Further work is needed to improve accessibility of mental health triage services and to investigate barriers to consumer self-referral. Professional development and practice support systems should be established to support mental health triage nurses in the development of collaborative, consumer-focused care. PMID- 23360562 TI - Social determinants of health on glycemic control in pediatric type 1 diabetes. AB - OBJECTIVE: To evaluate the relationship between the social determinants of health (SDH) and glycemic control in a large pediatric type 1 diabetes (T1D) population. STUDY DESIGN: Deprivation Indices (DI) were used to ascertain population-level measures of socioeconomic status, family structure, and ethnicity in patients with T1D followed at The Hospital for Sick Children August 2010-2011 (n = 854). DI quintile scores were determined for individual patients based on de-identified postal codes, and linked to mean patient A1Cs as a measure of glycemic control. We compared mean A1C between the most and least deprived DI quintiles. Associations were estimated controlling for age and sex, and repeated for insulin pump use. RESULTS: The T1D population evaluated in this study was most concentrated in the least and most deprived quintiles of the Material DI. A1C levels were highest in patients with the greatest degree of deprivation (fifth vs first quintile) on the Material DI (9.2% vs 8.3%, P < .0001), Social DI (9.1% vs 8.3%, P < .0001), and Ethnic Concentration Index (8.9% vs 8.4%, P = .03). These relationships between measures of the SDH and A1C were not evident for patients on insulin pumps. On regression analysis, higher A1C was predicted by older age, female sex, not using pump therapy, and being in the most deprived quintile for Material and Social Deprivation, but not Ethnic Concentration. CONCLUSIONS: Measures of the SDH comprising Material and Social Deprivation were significantly associated with suboptimal glycemic control in our pediatric T1D cohort. Use of insulin pump therapy also predicted A1C and may have a moderating effect on these relationships. PMID- 23360563 TI - Nonsteroidal anti-inflammatory drugs are an important cause of acute kidney injury in children. AB - OBJECTIVE: To characterize nonsteroidal anti-inflammatory drug (NSAID)-associated acute kidney injury (AKI) in children. STUDY DESIGN: We conducted a retrospective chart review of children diagnosed with AKI through the use of International Classification of Diseases, Ninth Revision diagnosis code 584.5 or 584.9 from January 1999 to June 2010. Medical records were reviewed to confirm the diagnosis of AKI and to quantify NSAID administration. Pediatric RIFLE criteria were used to codify AKI. Patients were not classified as having NSAID-associated AKI if they had a diagnosis explaining AKI or comorbid clinical conditions predisposing to AKI development. RESULTS: Patients (N=1015) were identified through International Classification of Diseases, Ninth Revision screening. Twenty-one children had clinical, laboratory, and radiographic studies suggesting NSAID associated acute tubular necrosis and 6 had findings suggesting NSAID-associated acute interstitial nephritis, representing 2.7% (27 of 1015) of the total cohort with AKI and 6.6% when excluding complex patients with multifactorial AKI. Children with NSAID-associated AKI had a median (range) age of 14.7 years (0.5 17.7 years); 4 patients (15%) were <5 years old. Fifteen of 20 children (75%) for whom dosing data were available received NSAIDs within recommended dosing limits. Patients<5 years old were more likely to require dialysis (100% vs 0%, P<.001), intensive care unit admission (75% vs 9%, P=.013), and a longer length of stay (median 10 vs 7 days, P=.037). CONCLUSIONS: NSAID-associated AKI accounted for 2.7% of AKI in this pediatric population. AKI typically occurred after the administration of correctly dosed NSAIDs. Young children with NSAID-associated AKI may have increased disease severity. PMID- 23360564 TI - Bilateral external ophthalmoplegia in biotin-responsive basal ganglia disease. PMID- 23360566 TI - Is this (still) a man's world? AB - During the past 50 years, the participation of women in medicine has increased dramatically. However, this encouraging influx has not been accompanied by equality for male and female faculty in terms of rank attainment, leadership roles and salaries. There is considerable evidence that women are still under represented in the higher echelons of academic medicine, either as heads of departments, authors of scientific papers or members of editorial boards. Participation in medical congresses is another important measure of medical achievement; this manuscript comments on the female representation in four of the largest international meetings in the field of intensive care medicine (ICM). It notes the scarcity of female faculty members and proposes several explanations for this phenomenon. The notable under-representation of women in the ICM congresses suggests the existence of a 'glass ceiling' in the field of intensive care medicine, a specialty that, up until today, hasn't been considered as traditionally 'male'. PMID- 23360565 TI - Growth and body composition of uninfected children exposed to human immunodeficiency virus: comparison with a contemporary cohort and United States National Standards. AB - OBJECTIVE: To compare growth and body composition of uninfected children exposed to HIV with a contemporary HIV-unexposed group and to US references. STUDY DESIGN: Uninfected children exposed to HIV under 2 years were enrolled into a longitudinal observational study and unexposed children under 2 years of age in a cross-sectional evaluation. Weights, lengths, head circumferences, skinfold thicknesses, and arm and thigh circumferences were measured and adjusted for age using Centers for Disease Control and National Health and Nutrition Examination Survey standards. Uninfected children exposed to HIV were compared with an unexposed nearest-neighbor matched comparison group. Uninfected children exposed to HIV were compared by age to Centers for Disease Control standards for growth measures and National Health and Nutrition Examination Survey standards for body composition. RESULTS: One hundred eleven uninfected children exposed to HIV and 82 children not exposed to HIV were evaluated. For the matched comparison for both groups, the mean age was 10 months, 59% were male, and 73% were African American. No statistical differences were found in anthropometric measurements between uninfected children who were or were not exposed to HIV. Uninfected children exposed to HIV were smaller than US standards at birth with mean (SD) weight-for-age and weight-for-length z-scores of -0.39 (1.06); P = .002 and -0.35 (1.04); P = .005, respectively. Over the first 2 years of life, there was a trend toward increasing weight-for-age z-score, length-for-age z-score, and weight-for length z-score in uninfected children exposed to HIV. Subscapular and triceps skinfolds among uninfected children exposed to HIV were lower than national standards and there was a trend that mid-upper arm circumference decreased over time. CONCLUSIONS: Growth and body composition of uninfected children who were or were not exposed to HIV were similar. Uninfected children exposed to HIV weigh less at birth and show a pattern of slightly accelerated growth in the first 2 years of life. Uninfected children exposed to HIV had less subcutaneous fat and decreasing mid-upper arm circumference over time when compared with US standards. PMID- 23360567 TI - A rechargeable Li-O2 battery using a lithium nitrate/N,N-dimethylacetamide electrolyte. AB - A major challenge in the development of rechargeable Li-O(2) batteries is the identification of electrolyte materials that are stable in the operating environment of the O(2) electrode. Straight-chain alkyl amides are one of the few classes of polar, aprotic solvents that resist chemical degradation in the O(2) electrode, but these solvents do not form a stable solid-electrolyte interphase (SEI) on the Li anode. The lack of a persistent SEI leads to rapid and sustained solvent decomposition in the presence of Li metal. In this work, we demonstrate for the first time successful cycling of a Li anode in the presence of the solvent, N,N-dimethylacetamide (DMA), by employing a salt, lithium nitrate (LiNO(3)), that stabilizes the SEI. A Li-O(2) cell containing this electrolyte composition is shown to cycle for more than 2000 h (>80 cycles) at a current density of 0.1 mA/cm(2) with a consistent charging profile, good capacity retention, and O(2) detected as the primary gaseous product formed during charging. The discovery of an electrolyte system that is compatible with both electrodes in a Li-O(2) cell may eliminate the need for protecting the anode with a ceramic membrane. PMID- 23360569 TI - Influence of bacterial communities based on 454-pyrosequencing on the survival of Escherichia coli O157:H7 in soils. AB - Shiga toxin-producing Escherichia coli O157:H7 has been implicated in many foodborne illnesses. In this study, survival of E. coli O157:H7 in 32 soils from California (CA) and Arizona (AZ) was investigated. Our goal was to correlate the survival time of E. coli O157:H7 in soils with 16S rRNA pyrosequencing based bacterial community composition. Kohonen self-organizing map of survival and associated soil chemical, physical and biological variables using artificial neural network analysis showed that survival of E. coli O157:H7 in soils was negatively correlated with salinity (EC), but positively correlated with total nitrogen (TN) and water soluble organic carbon (WSOC). Bacterial diversity as determined by the Shannon diversity index had no significant (P = 0.635) effect on ttd, but individual bacterial phyla had different effects. The survival of E. coli O157:H7 was positively correlated with the abundances of Actinobacteria (P < 0.001) and Acidobacteria (P < 0.05), and negatively correlated with those of Proteobacteria and Bacteroidetes (P < 0.05). Our data showed that specific groups of bacteria correlate with the persistence of E. coli O157:H7 in soils thus opening new ways to study the influence of certain bacterial phyla on persistence of this pathogen and other related pathogens in complex environments. PMID- 23360568 TI - Antioxidant enzymes activities in obese Tunisian children. AB - BACKGROUND: The oxidant stress, expected to increase in obese adults, has an important role in the pathogenesis of many diseases. It results when free radical formation is greatly increased or protective antioxidant mechanisms are compromised. The main objective of this study is to evaluate the antioxidant response to obesity-related stress in healthy children. METHODS: A hundred and six healthy children (54 obese and 52 controls), aged 6-12 years old, participated in this study. The collected data included anthropometric measures, blood pressure, fasting glucose, total cholesterol, triglycerides and enzymatic antioxidants (Superoxide dismutase: SOD, Catalase: CAT and Glutathione peroxidase: GPx). RESULTS: The first step antioxidant response, estimated by the SOD activity, was significantly higher in obese children compared with normal weight controls (p < 0.05). Mean activities of anti-radical GPx and CAT enzymes were not affected by the BMI increase. Although, total cholesterol levels were statistically higher in the obese group, there was no significant association with the SOD activity. CONCLUSIONS: The obesity-related increase of the oxidant stress can be observed even in the childhood period. In addition to the complications of an increased BMI, obesity itself can be considered as an independent risk factor of free radical production resulting in an increased antioxidant response. PMID- 23360570 TI - Establishment of the cumulative margin of exposure for a group of polychlorinated biphenyl (PCB) congeners using an improved approach that accounts for both variability and uncertainty. AB - In this study, the cumulative margin of exposure (MOE) was estimated for a group of polychlorinated biphenyls (PCBs) based on reduction of hepatic retinoids as a mode-of-action relevant toxicological endpoint. The MOE was defined as the ratio between a reference dose, derived using the benchmark dose (BMD) approach, and the estimated human dietary PCB exposure. A distribution for the cumulative MOE was established, taking into account inter- and intra-individual variability as well as uncertainty in data measurements. The cumulative MOE reflected mainly the MOE for PCB 126; other PCB congeners had little contribution to the cumulative exposure and MOE. The median of the 0.1st percentile for the cumulative MOE was about 20 for women; depending on the percentile, cumulative MOE was 2-4 times higher for men compared to women. Furthermore, a relative potency factor (RPF) based approach was compared to an RPF-free approach for estimating the cumulative MOE. The RPF-free approach more completely accounts for variability and uncertainty but is more data intensive than the RPF-based approach, which can be more easily implemented in practice and allows for a use of historical data on RPFs. Consideration of the discussed approaches may contribute to improving cumulative health risk assessments. PMID- 23360571 TI - Surgical excision with left atrial reconstruction of a primary functioning retrocardiac paraganglioma. AB - About 2% of all paragangliomas are located in the chest, and a few have been described to be found in the heart. Primary cardiac paragangliomas are extremely uncommon tumors and surgical experience with this neoplasm is limited. Treatment strategies described in the literature have included simple excision, excision with reconstruction, autotransplantation after excision of the tumor and even orthotopic cardiac transplantation, depending on the extent of disease. A primary retrocardiac paraganglioma catecholamine-productive was identified in an asymptomatic 49-year old female associated to familial pheochromocytoma paraganglioma syndrome caused by germline mutation of the gen which codifies for the subunit B of succinate dehydrogenase enzyme (SDHB). The neoplasm was surgically excised from the posterior surface of the left atrium via median sternotomy using cardiopulmonary bypass. Direct ligation of feeding vessels of the tumor along with left atrial reinforcement using a pericardial patch was performed. The post-operative course was uneventful, with normalization of catecholamine secretion and no recurrence at three-month follow-up. We review the current literature about this exceptional cardiac tumor, pathophysiological conditions and options for surgical management. PMID- 23360573 TI - Aspect ratio dependence of auger recombination and carrier multiplication in PbSe nanorods. AB - Nanomaterials with efficient carrier multiplication (CM), that is, generation of multiple electron-hole pairs by single photons, have been the object of intense scientific interest as potential enablers of high efficiency generation-III photovoltaics. In this work, we explore nanocrystal shape control as a means for enhancing CM. Specifically, we investigate the influence of aspect ratio (rho) of PbSe nanorods (NRs) on both CM and the inverse of this process, Auger recombination. We observe that Auger lifetimes in NRs increase with increasing particle volume and for a fixed cross-sectional size follow a linear dependence on the NR length. For a given band gap energy, the CM efficiency in NRs shows a significant dependence on aspect ratio and exhibits a maximum at rho ~ 6-7 for which the multiexciton yields are a factor of ca. 2 higher than those in quantum dots with a similar bandgap energy. To rationalize our experimental observations, we analyze the influence of dimensionality on both CM and non-CM energy-loss mechanisms and offer possible explanations for the seemingly divergent effects the transition from zero- to one-dimensional confinement has on the closely related processes of Auger recombination and CM. PMID- 23360572 TI - Roles of histone hypoacetylation in LAT expression on T cells and Th2 polarization in allergic asthma. AB - BACKGROUND: Linker for activation of T cells (LAT), a transmembrane adaptor protein, plays a role in T cell and mast cell function, while it remains unclear how histone modifications mediate LAT expression in allergic asthma. The present study aimed at understanding alterations of lymphocyte LAT in patients with asthma and potential mechanisms by which histone modulation may be involved in. METHOD: The expression of LAT mRNA was checked by Quantitative real-time PCR and histone hypoacetylation on LAT promoter was detected by Chromatin Immunoprecipitation. RESULTS: Our results demonstrated that the expression of LAT mRNA in peripheral blood T cells from patients with asthma decreased, as compared to healthy controls. Peripheral blood T cells were treated with pCMV-myc-LAT, pCMV-myc or LAT-siRNA plasmid. Over-expression of LAT mRNA and decrease of Th2 cytokine production were noted, which could be prevented by the inhibition of LAT. The further investigation of the role of histone was performed in an asthma model induced by allergen. Histone hypoacetylation on LAT promoter could inhibit LAT expression and enhanced Th2 differentiation, while trichostatin A, a histone deacetylase inhibitor, promoted LAT expression and inhibited Th2 cytokine production. CONCLUSION: Our results indicate that histone hypoacetylation may regulate LAT expression on T cells and modify Th2 polarization in allergic asthma. PMID- 23360574 TI - Over-time changes of Helicobacter pylori infection rate in patients with inflammatory bowel disease. PMID- 23360575 TI - Hypothesis: Increased consumption of emulsifiers as an explanation for the rising incidence of Crohn's disease. AB - Crohn's disease (CD) incidence has increased over the past fifty years but the explanation is unclear. CD can be brought into remission by liquid enteral feeding, but the mechanism for this response is unknown. We suggest that consumption of emulsifiers in processed foods may promote CD by increasing bacterial translocation. This is supported by evidence that (i) geographical variation in CD correlates with emulsifier consumption as does the increasing incidence of CD in Japan; (ii) although CD incidence also correlates with fat consumption, the response to enteral feeding is not affected by the fat content of the feed and (iii) very small concentrations of the emulsifier polysorbate 80 enhance bacterial translocation across intestinal epithelia. Undigested emulsifiers may increase bacterial translocation, particularly in the small intestine where the mucus layer is discontinuous. The hypothesis should be testable by trials of enteral feeding with/without emulsifiers. PMID- 23360576 TI - Validation of the Violence Risk Screening-10 instrument among clients discharged from a psychiatric hospital in Beijing. AB - The Violence Risk Screening-10 is one of the few instruments available for evaluating violence risk in mental health clients during and after hospitalization. This prospective study examined the applicability of this brief instrument with a sample of 289 clients in the 6 months after discharge from a general psychiatric hospital in Beijing. During the research period, 24 of the 289 clients demonstrated aggression. The receiver-operator characteristic curve yielded an area under the curve of 0.62. At the cut-off point of 4.5, its sensitivity/specificity was 79.2%/33.3%, and the corresponding positive/negative predictive value was 9.9%/94.5%. The predictive accuracy of this instrument was lower compared with the results of the original study, and was also less accurate than when it was administered while the clients were in the hospital. While promising in its utility for use beyond the hospital, it deserves further modification prior to its wide use across culturally-diverse China. PMID- 23360578 TI - Methods for primary concentration of viruses from water samples: a review and meta-analysis of recent studies. AB - Since the beginning of environmental virology in the mid-twentieth century, a key challenge to scientists in the environmental field has been how to collect, isolate and detect pathogenic viruses from water that is used for drinking and/or recreational purposes. Early studies investigated different types of membrane filters, with more sophisticated technologies being developed more recently. The purpose of this study was to look at the current state of the science of methods for the concentration of viruses from water. Several technologies were reviewed, and associated data were included in a meta-analysis which showed that electronegative filters, electropositive filters and ultrafilters are comparable in performance and that significant differences in recovery are due to virus type rather than filter type, water matrix or sample volume. This information is useful, as it will help to determine which method(s) should be used, particularly if there is a specific viral type being targeted for a particular study. In addition, it will be helpful when sampling different environmental water matrices and/or when budget allowance must be taken into consideration. Taken together, this will be useful in performing viral occurrence studies, which ultimately can help ensure safer water for both humans and the environment. PMID- 23360579 TI - High-active anatase TiO2 nanosheets exposed with 95% {100} facets toward efficient H2 evolution and CO2 photoreduction. AB - We succeed in preparation of anatase TiO2 single crystals with marked photocatalytic activity via a facile and effective method. This TiO2 is composed of TiO2 ultrathin nanosheets (2 nm in thickness) with 95% of exposed {100} facet, which is considered to be the active facet for photocatalytic reaction. This percentage (95%) is the highest among previously reported {100} facet exposed anatase TiO2. More importantly, due to this high ratio, our developed TiO2 nanosheets showed marked photocatalytic activity, about 5 times higher activity in both H2 evolution and CO2 reduction than the reference sample, TiO2 cuboids with 53% of exposed {100} facet. For the TiO2 nanosheets, both the higher percentage of exposed {100} facets and larger surface area can offer more surface active sites in the photocatalytic reaction. On the other hand, the superior electronic band structure which results from the higher percentage of {100} facet is also beneficial for the higher activity. This study exemplifies that the facet engineering of semiconductors is one of the most effective strategies to achieve advanced properties over photofunctional materials for solar energy conversion. PMID- 23360580 TI - Still a man's world, but why? AB - Women are generally under-represented in many academic medical settings. Through a brief commentary on this issue, the present article discusses possible explanations for this under-representation as well as potential solutions. Issues examined include women in leadership positions, attrition out of academic medicine, salary imbalance between men and women, potential bias among both genders, and the need for cultural change. We believe this is an extremely important issue of which we all need to be aware and hope that articles such as this will aid in starting a crucial conversation about gender issues in academic medicine. PMID- 23360581 TI - Spiritual and religious beliefs as risk factors for the onset of major depression: an international cohort study. AB - BACKGROUND: Several studies have reported weak associations between religious or spiritual belief and psychological health. However, most have been cross sectional surveys in the U.S.A., limiting inference about generalizability. An international longitudinal study of incidence of major depression gave us the opportunity to investigate this relationship further. METHOD: Data were collected in a prospective cohort study of adult general practice attendees across seven countries. Participants were followed at 6 and 12 months. Spiritual and religious beliefs were assessed using a standardized questionnaire, and DSM-IV diagnosis of major depression was made using the Composite International Diagnostic Interview (CIDI). Logistic regression was used to estimate incidence rates and odds ratios (ORs), after multiple imputation of missing data. RESULTS: The analyses included 8318 attendees. Of participants reporting a spiritual understanding of life at baseline, 10.5% had an episode of depression in the following year compared to 10.3% of religious participants and 7.0% of the secular group (p<0.001). However, the findings varied significantly across countries, with the difference being significant only in the U.K., where spiritual participants were nearly three times more likely to experience an episode of depression than the secular group [OR 2.73, 95% confidence interval (CI) 1.59-4.68]. The strength of belief also had an effect, with participants with strong belief having twice the risk of participants with weak belief. There was no evidence of religion acting as a buffer to prevent depression after a serious life event. CONCLUSIONS: These results do not support the notion that religious and spiritual life views enhance psychological well-being. PMID- 23360582 TI - Highly enantioselective synthesis of cyclopropylamine derivatives via Ru(II) pheox-catalyzed direct asymmetric cyclopropanation of vinylcarbamates. AB - The Ru(II)-Pheox-catalyzed asymmetric cyclopropanation of vinylcarbamates with diazoesters resulted in the corresponding cyclopropylamine derivatives in high yield and excellent diastereoselectivity (up to 96:4) and enantioselectivity (up to 99% ee). PMID- 23360583 TI - Passive transfer of collagen XVII-specific antibodies induces sustained blistering disease in adult mice. AB - BACKGROUND: Bullous pemphigoid is a subepidermal blistering disorder associated with tissue-bound and circulating autoantibodies directed mainly to the hemidesmosomal component collagen XVII. While recapitulating the main immunopathological features of the human disease, frank skin blistering does not develop in the absence of skin rubbing in experimental pemphigoid models that have been established in neonatal mice. Moreover, due to their experimental design they only allow for short-term disease observation. In the present study we aimed to establish a model that reproduces the frank skin blistering seen in patients and allows for longer observation times. METHODS: Rabbit and sheep antibodies specific to several fragments of collagen XVII were generated and the purified antibodies were passively transferred into adult mice. RESULTS: Collagen XVII-specific IgG bound to the basal membrane of the skin and mucous membranes activating murine complement in vivo. Mice injected with collagen XVII-specific antibodies, in contrast to mice receiving control antibodies, developed frank skin blistering disease, reproducing human bullous pemphigoid at the clinical, histological and immunopathological levels. Titres of circulating IgG in the serum of mice correlated with the extent of the clinical disease. Mice receiving sheep antibodies specific to murine collagen XVII showed an early onset and a more active disease when compared to litter mates receiving specific rabbit antibodies. CONCLUSION: This novel animal model for bullous pemphigoid should facilitate further investigations of the pathogenesis of bullous pemphigoid and the development of innovative therapies for this disease. PMID- 23360584 TI - The effects of deprivation and relative deprivation on self-reported morbidity in England: an area-level ecological study. AB - BACKGROUND: Socioeconomic status gradients in health outcomes are well recognised and may operate in part through the psychological effect of observing disparities in affluence. At an area-level, we explored whether the deprivation differential between neighbouring areas influenced self-reported morbidity over and above the known effect of the deprivation of the area itself. METHODS: Deprivation differentials between small areas (population size approximately 1,500) and their immediate neighbours were derived (from the Index of Multiple Deprivation (IMD)) for Lower Super Output Area (LSOA) in the whole of England (n=32482). Outcome variables were self-reported from the 2001 UK Census: the proportion of the population suffering Limiting Long-Term Illness (LLTI) and 'not good health'. Linear regression was used to identify the effect of the deprivation differential on morbidity in different segments of the population, controlling for the absolute deprivation. The population was segmented using IMD tertiles and P2 People and Places geodemographic classification. P2 is a commercial market segmentation tool, which classifies small areas according to the characteristics of the population. The classifications range in deprivation, with the most affluent type being 'Mature Oaks' and the least being 'Urban Challenge'. RESULTS: Areas that were deprived compared to their immediate neighbours suffered higher rates of 'not good health' (beta=0.312, p<0.001) and LLTI (beta=0.278, p<0.001), after controlling for the deprivation of the area itself ('not good health' beta=0.655, p<0.001; LLTI-beta=0.548, p<0.001). The effect of the deprivation differential relative to the effect of deprivation was strongest in least deprived segments (e.g., for 'not good health', P2 segments 'Mature Oaks' beta=0.638; 'Rooted Households'-beta=0.555). CONCLUSIONS: Living in an area that is surrounded by areas of greater affluence has a negative impact on health in England. A possible explanation for this phenomenon is that negative social comparisons between areas cause ill-health. This 'psychosocial effect' is greater still in least deprived segments of the population, supporting the notion that psychosocial effects become more important when material (absolute) deprivation is less relevant. PMID- 23360585 TI - Associations of in utero exposure to perfluorinated alkyl acids with human semen quality and reproductive hormones in adult men. AB - BACKGROUND: Perfluorinated alkyl acids (PFAAs), persistent chemicals with unique water-, dirt-, and oil-repellent properties, are suspected of having endocrine disrupting activity. The PFAA compounds perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are found globally in humans; because they readily cross the placental barrier, in utero exposure may be a cause for concern. OBJECTIVES: We investigated whether in utero exposure to PFOA and PFOS affects semen quality, testicular volume, and reproductive hormone levels. METHODS: We recruited 169 male offspring (19-21 years of age) from a pregnancy cohort established in Aarhus, Denmark, in 1988-1989, corresponding to 37.6% of the eligible sons. Each man provided a semen sample and a blood sample. Semen samples were analyzed for sperm concentration, total sperm count, motility, and morphology, and blood samples were used to measure reproductive hormones. As a proxy for in utero exposure, PFOA and PFOS were measured in maternal blood samples from pregnancy week 30. RESULTS: Multivariable linear regression analysis suggested that in utero exposure to PFOA was associated with lower adjusted sperm concentration (ptrend = 0.01) and total sperm count (ptrend = 0.001) and with higher adjusted levels of luteinizing hormone (ptrend = 0.03) and follicle stimulating hormone (ptrend = 0.01). PFOS did not appear to be associated with any of the outcomes assessed, before or after adjustment. CONCLUSIONS: The results suggest that in utero exposure to PFOA may affect adult human male semen quality and reproductive hormone levels. PMID- 23360587 TI - The short- and long-term fitness consequences of natal dispersal in a wild bird population. AB - Dispersal is a key process in population and evolutionary ecology. Individual decisions are affected by fitness consequences of dispersal, but these are difficult to measure in wild populations. A long-term dataset on a geographically closed bird population, the Mauritius kestrel, offers a rare opportunity to explore fitness consequences. Females dispersed further when the availability of local breeding sites was limited, whereas male dispersal correlated with phenotypic traits. Female but not male fitness was lower when they dispersed longer distances compared to settling close to home. These results suggest a cost of dispersal in females. We found evidence of both short- and long-term fitness consequences of natal dispersal in females, including reduced fecundity in early life and more rapid aging in later life. Taken together, our results indicate that dispersal in early life might shape life history strategies in wild populations. PMID- 23360588 TI - The specificity of metal catalysts in the opening of highly strained polycyclic molecules. PMID- 23360586 TI - Nutrient timing revisited: is there a post-exercise anabolic window? AB - Nutrient timing is a popular nutritional strategy that involves the consumption of combinations of nutrients--primarily protein and carbohydrate--in and around an exercise session. Some have claimed that this approach can produce dramatic improvements in body composition. It has even been postulated that the timing of nutritional consumption may be more important than the absolute daily intake of nutrients. The post-exercise period is widely considered the most critical part of nutrient timing. Theoretically, consuming the proper ratio of nutrients during this time not only initiates the rebuilding of damaged muscle tissue and restoration of energy reserves, but it Does So in a supercompensated fashion that enhances both body composition and exercise performance. Several researchers have made reference to an anabolic "window of opportunity" whereby a limited time exists after training to optimize training-related muscular adaptations. However, the importance - and even the existence - of a post-exercise 'window' can vary according to a number of factors. Not only is nutrient timing research open to question in terms of applicability, but recent evidence has directly challenged the classical view of the relevance of post-exercise nutritional intake with respect to anabolism. Therefore, the purpose of this paper will be twofold: 1) to review the existing literature on the effects of nutrient timing with respect to post-exercise muscular adaptations, and; 2) to draw relevant conclusions that allow practical, evidence-based nutritional recommendations to be made for maximizing the anabolic response to exercise. PMID- 23360589 TI - [Helicobacter pylori: what eradication regimen in a tropical area after the failure of two separate lines of eradication including metronidazole and clarithromycin?]. AB - Helicobacter pylori (H. pylori) resistance against antibiotics is a major challenge, particularly in developing countries. We report a case of H. pylori infection where eradication by two lines of treatment, one including metronidazole and the other clarithromycin, failed, and discuss the management of such a case in a tropical area. This 55-year-old man complained of epigastric pain dating back for three years. A stool antigen test for H. pylori was positive. First-line eradication therapy, which combined a proton pump inhibitor, amoxicillin and metronidazole, was unsuccessful, as was the second-line therapy, which replaced metronidazole by clarithromycin. Third-line treatment, which still included a proton pump inhibitor and amoxicillin but added levofloxacin was successful. A stool antigen test to verify eradication was finally negative. In developing countries, H. pylori eradication must be managed rationally. In particular, fluoroquinolones must be reserved for treatment failure. The stool antigen test appears to be a useful and economical alternative to the urea breath test for verifying eradication. PMID- 23360590 TI - Phase transformation of molecular beam epitaxy-grown nanometer-thick Gd2O3 and Y2O3 on GaN. AB - High quality nanometer-thick Gd2O3 and Y2O3 (rare-earth oxide, R2O3) films have been epitaxially grown on GaN (0001) substrate by molecular beam epitaxy (MBE). The R2O3 epi-layers exhibit remarkable thermal stability at 1100 degrees C, uniformity, and highly structural perfection. Structural investigation was carried out by in situ reflection high energy electron diffraction (RHEED) and ex situ X-ray diffraction (XRD) with synchrotron radiation. In the initial stage of epitaxial growth, the R2O3 layers have a hexagonal phase with the epitaxial relationship of R2O3 (0001)(H)<1120>(H)//GaN(0001)(H)<1120>(H). With the increase in R2O3 film thickness, the structure of the R2O3 films changes from single domain hexagonal phase to monoclinic phase with six different rotational domains, following the R2O3 (201)(M)[020](M)//GaN(0001)(H)<1120>(H) orientational relationship. The structural details and fingerprints of hexagonal and monoclinic phase Gd2O3 films have also been examined by using electron energy loss spectroscopy (EELS). Approximate 3-4 nm is the critical thickness for the structural phase transition depending on the composing rare earth element. PMID- 23360591 TI - Cyclic arginine-glycine-aspartate attenuates acute lung injury in mice after intestinal ischemia/reperfusion. AB - INTRODUCTION: Intestinal ischemia is a critical problem resulting in multiple organ failure and high mortality of 60 to 80%. Acute lung injury (ALI) is a common complication after intestinal ischemia/reperfusion (I/R) injuries and contributes to the high mortality rate. Moreover, activated neutrophil infiltration into the lungs is known to play a significant role in the progression of ALI. Integrin-mediated interaction is involved in neutrophil transmigration. Synthetic peptides containing an arginine-glycine-aspartate sequence compete with adhesive proteins and inhibit integrin-mediated interaction and signaling. Thus, we hypothesized that the administration of a cyclic arginine glycine-aspartate peptide (cRGD) inhibited neutrophil infiltration and provided protection against ALI induced by intestinal I/R. METHODS: Ischemia in adult male C57BL/6 mice was induced by fastening the superior mesenteric artery with 4-0 suture. Forty-five minutes later, the vascular suture was released to allow reperfusion. cRGD (5 mg/kg body weight) or normal saline (vehicle) was administered by intraperitoneal injection 1 hour prior to ischemia. Blood, gut, and lung tissues were collected 4 hours after reperfusion for various measurements. RESULTS: Intestinal I/R caused severe widespread injury to the gut and lungs. Treatment with cRGD improved the integrity of microscopic structures in the gut and lungs, as judged by histological examination. Intestinal I/R induced the expression of beta1, beta2 and beta3 integrins, intercellular adhesion molecule-1, and fibronectin. cRGD significantly inhibited myeloperoxidase activity in the gut and lungs, as well as neutrophils and macrophages infiltrating the lungs. cRGD reduced the levels of TNF-alpha and IL-6 in serum, in addition to IL-6 and macrophage inflammatory protein-2 in the gut and lungs. Furthermore, the number of TUNEL-staining cells and levels of cleaved caspase-3 in the lungs were significantly lowered in the cRGD-treated mice in comparison with the vehicle mice. CONCLUSIONS: Treatment with cRGD effectively protected ALI and gut injury, lowered neutrophil infiltration, suppressed inflammation, and inhibited lung apoptosis after intestinal I/R. Thus, there is potential for developing cRGD as a treatment for patients suffering from ALI caused by intestinal I/R. PMID- 23360592 TI - Impaired emotion regulation in schizophrenia: evidence from event-related potentials. AB - BACKGROUND: Although several aspects of emotion seem to be intact in schizophrenia, there is emerging evidence that patients show an impaired ability to adaptively regulate their emotions. This event-related potential (ERP) study examined whether schizophrenia is associated with impaired neural responses to appraisal frames, that is when negative stimuli are presented in a less negative context. METHOD: Thirty-one schizophrenia out-patients and 27 healthy controls completed a validated picture-viewing task with three conditions: (1) neutral pictures preceded by neutral descriptions ('Neutral'), (2) unpleasant pictures preceded by negative descriptions ('Preappraised negative'), and (3) unpleasant pictures preceded by more neutral descriptions ('Preappraised neutral'). Analyses focused on the late positive potential (LPP), an index of facilitated attention to emotional stimuli that is reduced following cognitive emotion regulation strategies, during four time windows from 300 to 2000 ms post-picture onset. RESULTS: Replicating prior studies, controls showed smaller LPP in Preappraised neutral and Neutral versus Preappraised negative conditions throughout the 300 2000-ms time period. By contrast, patients showed (a) larger LPP in Preappraised neutral and Preappraised negative versus Neutral conditions in the initial period (300-600 ms) and (b) an atypical pattern of larger LPP to Preappraised neutral versus Preappraised negative and Neutral conditions in the 600-1500-ms epochs. CONCLUSIONS: Modulation of neural responses by a cognitive emotion regulation strategy seems to be impaired in schizophrenia during the first 2 s after exposure to unpleasant stimuli. PMID- 23360594 TI - PET a tool for assessing the in vivo tumour cell and its microenvironment? AB - INTRODUCTION AND BACKGROUND: Positron emission tomography (PET) has started to develop beyond its roots in glucose imaging, expanding to study other parameters of the tumour and its microenvironment. SOURCES OF DATA: A review of imaging literature over the past 5 years has shown that functional imaging with PET is starting to exploit our increasing knowledge of genomics and the phenotypic expression of cells and how they interact with their microenvironment. AREAS OF AGREEMENT: For most of those working in this field, there is agreement that therapeutic outcomes for patients can only be obtained by the assessment and continued reassessment not only of the tumour microenvironment, but also how it is changed by treatment. AREAS OF CONTROVERSY: Although PET offers a tool by which the tumour and its microenvironment can be assessed in vivo without the need for multiple interventions, the cost of PET is high and there is a cumulative radiation burden with repeated studies. As the quantity and quality of PET scans increase, we are able to assess tumour cell turn over, metabolism, hypoxia, angiogenesis and a variety of other factors that might affect tumour survival and response to treatment. AREAS TIMELY FOR DEVELOPING RESEARCH: As it is impossible to do everything for every patient, we need to know what are the critical factors in the tumour cell microenvironment in each patient and need to have the tools to assess that factor. PMID- 23360593 TI - Neuro-Behcet's disease in childhood: a focus on the neuro-ophthalmological features. AB - Neuro-Behcet's disease (NBD) involves the central nervous system; peripheral nervous system involvement is not often reported. NBD is quite common in adult patients and occurs rarely during childhood and adolescence. Young patients may share symptoms and signs of NBD with other neuro-ophthalmological disorders (e.g. idiopathic intracranial hypertension); thus, making the differential diagnosis difficult. Neuroimaging is mandatory and necessary for a correct NBD diagnosis but in children radiological examinations are often difficult to perform without sedation. From 1971 to 2011, 130 patients aged <=16 years have been reported with NBD, according to retrospective surveys, case series, and case reports. The origin of the reported cases met the well-known geographical distribution of Behcet's disease (BD); the mean age at presentation of neurological findings was 11.8 years, with male gender prevalence (ratio, 2.9:1). We considered in detail the neuro-ophthalmological features of the 53 cases whose neuroimaging alterations were described with an assigned radiological pattern of the disease (parenchymal: 14 cases, non-parechymal: 35 cases, and mixed: 4 cases). In 19/53 patients (36%), neuro-ophthalmological symptoms anticipated any pathognomonic sign for a BD diagnosis, or only occasional aphtae were recalled by the patients. Family history was positive in 17% of subjects. Headache was reported in 75% of the patients; in those presenting with cerebral vascular involvement, headache was combined to other symptoms of intracranial hypertension. Papilledema was the most frequently reported ophthalmological finding, followed by posterior uveitis. Treatment consisted of systemic steroids in 93% of patients, often combined with other immunosuppressive drugs (especially colchicine and azathioprine). Clinical recovery or improvement was documented in the large majority of patients. Nine subjects had definitive alterations, and one died. Based on our review and personal experience, a delayed diagnosis, and the consequently delayed immunosuppressive treatment, may favour permanent sequelae, in particular, optic atrophy. PMID- 23360596 TI - Effects of post-deposition annealing ambient on band alignment of RF magnetron sputtered Y2O3 film on gallium nitride. AB - The effects of different post-deposition annealing ambients (oxygen, argon, forming gas (95% N2 + 5% H2), and nitrogen) on radio frequency magnetron sputtered yttrium oxide (Y2O3) films on n-type gallium nitride (GaN) substrate were studied in this work. X-ray photoelectron spectroscopy was utilized to extract the bandgap of Y2O3 and interfacial layer as well as establishing the energy band alignment of Y2O3/interfacial layer/GaN structure. Three different structures of energy band alignment were obtained, and the change of band alignment influenced leakage current density-electrical breakdown field characteristics of the samples subjected to different post-deposition annealing ambients. Of these investigated samples, ability of the sample annealed in O2 ambient to withstand the highest electric breakdown field (approximately 6.6 MV/cm) at 10-6 A/cm2 was related to the largest conduction band offset of interfacial layer/GaN (3.77 eV) and barrier height (3.72 eV). PMID- 23360595 TI - Transesophageal echocardiography measurements of aortic annulus diameter using biplane mode in patients undergoing transcatheter aortic valve implantation. AB - BACKGROUND: Aortic stenosis (AS) is a relevant common valve disorder. Severe AS and symptoms and/or left ventricular dysfunction (EF <50%) have the indication for aortic valve replacement (AVR). Majority of the patients with AS are elderly often with co-morbidities and generally have high preoperative risk. Transcatheter aortic valve implantation (TAVI) is offered in this group. Four different sizes of Corevalve prosthesis are available. Correct measurement of aortic size prior to TAVI is of great important to choose the right prosthesis size to avoid among others paravalvular leak or prosthesis patient mismatch.Aim of the study is to assess the aortic annulus diameter in patients undergoing TAVI by biplane (BP) mode using transesophageal echocardiography (TEE) and compare it to two-dimensional (2D) transthoracic echocardiography (TTE) and 2DTEE using three-dimensional (3D) TEE as reference method. METHODS: The study population consisted of 50 patients retrospectively (24 men and 26 women, mean age 85+/-8 years of age) who all had undergone echocardiography examination prior to TAVI. RESULTS: The mean aortic annulus diameter was 20.4+/-2.2 mm with TTE, 22.3+/-2.5 mm with 2DTEE, 22.9+/-1.9 mm with BP-mode and 23.1+/-1.9 mm with 3DTEE. TTE underestimated the mean aortic annulus diameter in comparison to transesophageal imaging modalities (p<0.001). Using 3DTEE, 2% of patients were unsuitable for TAVI due to a too-small AoA (n=1). This figure was similar with BP (4%, n=2; p=1.00) but considerably larger with 2DTTE (36%, n=18; p < 0.001) and 2DTEE (12%, n=6; p=0.06). There was a strong correlation between BP-mode and 3DTEE for assessment of aortic annulus diameter (r-value 0.88) with small mean difference ( 0.2+/-0.9 mm) whereas the other modalities showed larger 95% confidence interval and modest correlation (2DTTE vs. 3DTEE, -6.3 to 0.9 mm, r=0.64 and 2DTEE vs. 3DTEE, -4.8 to 3.2 mm, r=0.61). CONCLUSION: A multi-dimensional method is preferred to assess aortic annulus diameter in TAVI patients since there is risk of underestimation using single plane. Biplane mode is the method of choice in view of speedy post-processing with no need for expensive dedicated software. Lastly, single plane methods lead to misclassification of patients as unsuitable for TAVI. This may be of major clinical importance. PMID- 23360597 TI - The biogeography of marine plankton traits. AB - Changes in marine plankton communities driven by environmental variability impact the marine food web and global biogeochemical cycles of carbon and other elements. To predict and assess these community shifts and their consequences, ecologists are increasingly investigating how the functional traits of plankton determine their relative fitness along environmental and biological gradients. Laboratory, field and modelling studies are adopting this trait-based approach to map the biogeography of plankton traits that underlies variations in plankton communities. Here, we review progress towards understanding the regulatory roles of several key plankton functional traits, including cell size, N2 -fixation and mixotrophy among phytoplankton, and body size, ontogeny and feeding behaviour for zooplankton. The trait biogeographical approach sheds light on what structures plankton communities in the current ocean, as well as under climate change scenarios, and also allows for finer resolution of community function because community trait composition determines the rates of significant processes, including carbon export. Although understanding of trait biogeography is growing, uncertainties remain that stem, in part, from the paucity of observations describing plankton functional traits. Thus, in addition to recommending widespread adoption of the trait-based approach, we advocate for enhanced collection, standardisation and dissemination of plankton functional trait data. PMID- 23360598 TI - [Epidemiology and prognostic value of organ failure during severe malaria in the Principal Military Teaching Hospital of Dakar, Senegal]. AB - We report the results of a retrospective study in the medical intensive care unit of the Principal Military Teaching Hospital of Dakar. The objectives were to determine the epidemiological and clinical aspects of severe malaria and to evaluate the prognostic values of the failure of different organs. Eighty-seven patients were admitted for severe malaria. Their average age was 35 +/- 18.53 with a sex-ratio of 1.71 for men. Mortality was 33.3% and concerned mainly young adults. Neurological failure was the most frequent (79.3%). Hemodynamic failure was the most relevant prognostic factor for mortality, followed by hypoglycemia, respiratory and renal failure. The Simplified Acute Physiology Score II (SAPS II) was reliable in predicting mortality. The mean SAPS II was 44.85, with an expected mortality of 32.6%. PMID- 23360612 TI - A 10-step guide to party conversation for bioinformaticians. PMID- 23360613 TI - Tunable assembly of vanadium dioxide nanoparticles to create porous film for energy-saving applications. AB - Nanoparticle-assembled vanadium dioxide (VO2) films have been easily prepared with the assistance of cetyltrimethylammonium vanadate (CTAV) precursor which exhibits self-assembly properties. The obtained VO2 film has a micro/nano hierarchical porous structure, so its visible-light transmittance is significantly improved (~25% increased compared to continuous film). The VO2 particle density as well as the film porosity can be facilely controlled by adjusting experimental parameters such as dip-coating speed. Accordingly, film optical properties can also be tuned to a large extent, in particular the visible transmittance (Tvis) and near-infrared switching efficiency (DeltaTnir). These VO2 nanoparticle-assembled films prepared by this novel method provide a useful model to research the balance between Tvis and DeltaTnir. PMID- 23360614 TI - Both low birthweight and high birthweight are associated with cognitive impairment in persons with schizophrenia and their first-degree relatives. AB - BACKGROUND: Both low birthweight and high birthweight have been associated with an increased risk for schizophrenia and cognitive impairments in the general population. We assessed the association between birthweight and cognitive performance in persons with schizophrenia and their unaffected first-degree relatives. METHOD: We investigated a population-based family sample comprising persons with schizophrenia (n = 142) and their unaffected first-degree relatives (n = 277). Both patients and relatives were interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version (SCID-CV) and a comprehensive neuropsychological test battery was administered. Information on birthweight was obtained from obstetric records. We used generalized estimating equation (GEE) models to investigate the effect of birthweight, as a continuous variable, on cognitive functioning, adjusting for within-family correlation and relevant covariates. RESULTS: Both low birthweight and high birthweight were associated with lower performance in visuospatial reasoning, processing speed, set-shifting and verbal and visual working memory among persons with schizophrenia and their unaffected first-degree relatives compared to individuals with birthweight in the intermediate range. The group * birthweight interactions were non-significant. CONCLUSIONS: Both low birthweight and high birthweight are associated with deficits in cognition later in life. Schizophrenia does not seem to modify the relationship between birthweight and cognition in families with schizophrenia. PMID- 23360615 TI - Evaluation of the specificity of three enzyme-linked immunosorbent assays for detection of antibodies against Salmonella in bovine bulk milk. AB - BACKGROUND: The Swedish Salmonella control program has been running for decades and has resulted in a low prevalence of Salmonella in Swedish food producing animals. Routine bacteriology is used to detect Salmonella, however, bacteriology is time consuming, costly and has a low sensitivity. Different enzyme-linked immunosorbent assays (ELISAs) have been developed for detection of antibodies against Salmonella Dublin and S. Typhimurium in bovine bulk milk, individual milk samples as well as in sera. Screening bulk milk for antibodies against Salmonella spp. could improve the cost-effectiveness of the surveillance in Swedish dairy cattle, but as characteristics of tests may vary in different populations, tests should always be evaluated in the specific population where they will be used. Hence, the aim of this study was to evaluate the specificities of three bovine ELISAs when used to analyse bulk milk samples from Swedish dairy cattle. A second aim was to compare the performance of the two Dublin ELISAs tested. METHODS: Bulk milk samples for analysis were randomly selected from samples collected within the Swedish bulk milk sampling scheme and analyzed with the three ELISAs; a Danish in-house Dublin ELISA, PrioCHECK((r)) Salmonella Ab bovine Dublin ELISA and PrioCHECK((r)) Salmonella Ab bovine ELISA (hereafter named mixed ELISA). The specificities of the ELISAs were calculated assuming a disease-free status in Sweden i.e. that all test positive samples were assumed to be false positive results. This assumption can be used when a disease is known to be infrequent. RESULTS: The calculated specificities of the two Dublin ELISAs and the mixed ELISA, when using the producer's recommended cut-off value of the corrected optic density percent (ODC%) were 99.4% (95% Confidence Interval (CI): 98.8% -99.8%), 99.4% (95% CI: 98.8% -99.8%) and 97.9% (95% CI: 96.8% -98.7%), respectively. The correlation between the ODC% values of the two Dublin ELISAs was 0.83. CONCLUSIONS: We conclude that the evaluated ELISAs have sufficiently high specificities to be used as supplement to bacteriological examinations in the Swedish Salmonella control program in cattle as well as a primary screening test in routine surveillance for S. Dublin. PMID- 23360617 TI - On protein abundance distributions in complex mixtures. AB - Mass spectrometry, an analytical technique that measures the mass-to-charge ratio of ionized atoms or molecules, dates back more than 100 years, and has both qualitative and quantitative uses for determining chemical and structural information. Quantitative proteomic mass spectrometry on biological samples focuses on identifying the proteins present in the samples, and establishing the relative abundances of those proteins. Such protein inventories create the opportunity to discover novel biomarkers and disease targets. We have previously introduced a normalized, label-free method for quantification of protein abundances under a shotgun proteomics platform (Griffin et al., 2010). The introduction of this method for quantifying and comparing protein levels leads naturally to the issue of modeling protein abundances in individual samples. We here report that protein abundance levels from two recent proteomics experiments conducted by the authors can be adequately represented by Sichel distributions. Mathematically, Sichel distributions are mixtures of Poisson distributions with a rather complex mixing distribution, and have been previously and successfully applied to linguistics and species abundance data. The Sichel model can provide a direct measure of the heterogeneity of protein abundances, and can reveal protein abundance differences that simpler models fail to show. PMID- 23360616 TI - Thermodynamic profiles and nuclear magnetic resonance studies of oligonucleotide duplexes containing single diastereomeric spiroiminodihydantoin lesions. AB - The spiroiminodihydantoins (Sp) are highly mutagenic oxidation products of guanine and 8-oxo-7,8-dihydroguanine in DNA. The Sp lesions have recently been detected in the liver and colon of mice infected with Helicobacter hepaticus that induces inflammation and the development of liver and colon cancers in murine model systems [Mangerich, A., et al. (2012) Proc. Natl. Acad. Sci. U.S.A. 109, E1820-E1829]. The impact of Sp lesions on the thermodynamic characteristics and the effects of the diastereomeric Sp-R and Sp-S lesions on the conformational features of double-stranded 11-mer oligonucleotide duplexes have been studied by a combination of microcalorimetric methods, analysis of DNA melting curves, and two-dimensional nuclear magnetic resonance methods. The nonplanar, propeller-like shapes of the Sp residues strongly diminish the extent of local base stacking interactions that destabilize the DNA duplexes characterized by unfavorable enthalpy contributions. Relative to that of an unmodified duplex, the thermally induced unfolding of the duplexes with centrally positioned Sp-R and Sp-S lesions into single strands is accompanied by a smaller release of cationic counterions (Deltan(Na+) = 0.6 mol of Na+/mol of duplex) and water molecules (Deltan(w) = 17 mol of H2O/mol of duplex). The unfolding parameters are similar for the Sp-R and Sp-S lesions, although their orientations in the duplexes are different. The structural disturbances radiate one base pair beyond the flanking C:G pair, although Watson-Crick hydrogen bonding is maintained at all flanking base pairs. The observed relatively strong destabilization of B-form DNA by the physically small Sp lesions is expected to have a significant impact on the processing of these lesions in biological environments. PMID- 23360618 TI - Energy absorption ability of buckyball C720 at low impact speed: a numerical study based on molecular dynamics. AB - The dynamic impact response of giant buckyball C720 is investigated by using molecular dynamics simulations. The non-recoverable deformation of C720 makes it an ideal candidate for high-performance energy absorption. Firstly, mechanical behaviors under dynamic impact and low-speed crushing are simulated and modeled, which clarifies the buckling-related energy absorption mechanism. One-dimensional C720 arrays (both vertical and horizontal alignments) are studied at various impact speeds, which show that the energy absorption ability is dominated by the impact energy per buckyball and less sensitive to the number and arrangement direction of buckyballs. Three-dimensional stacking of buckyballs in simple cubic, body-centered cubic, hexagonal, and face-centered cubic forms are investigated. Stacking form with higher occupation density yields higher energy absorption. The present study may shed lights on employing C720 assembly as an advanced energy absorption system against low-speed impacts. PMID- 23360619 TI - The relative protein abundance of UGT1A alternative splice variants as a key determinant of glucuronidation activity in vitro. AB - Alternative splicing (AS) is one of the most significant components of the functional complexity of human UDP-glucuronosyltransferase enzymes (UGTs), particularly for the UGT1A gene, which represents one of the best examples of a drug-metabolizing gene regulated by AS. Shorter UGT1A isoforms [isoform 2 (i2)] are deficient in glucuronic acid transferase activity but function as negative regulators of enzyme activity through protein-protein interaction. Their abundance, relative to active UGT1A enzymes, is expected to be a determinant of the global transferase activity of cells and tissues. Here we tested whether i2 mediated inhibition increases with greater abundance of the i2 protein relative to the isoform 1 (i1) enzyme, using the extrahepatic UGT1A7 as a model and a series of 23 human embryonic kidney 293 clonal cell lines expressing variable contents of i1 and i2 proteins. Upon normalization for i1, a significant reduction of 7-ethyl-10-hydroxycamptothecin glucuronide formation was observed for i1+i2 clones (mean of 53%) compared with the reference i1 cell line. In these clones, the i2 protein content varied greatly (38-263% relative to i1) and revealed two groups: 17 clones with i2 < i1 (60% +/- 3%) and 6 clones with i2 >= i1 (153% +/- 24%). The inhibition induced by i2 was more substantial for clones displaying i2 >= i1 (74.5%; P = 0.001) compared with those with i2 < i1 (45.5%). Coimmunoprecipitation supports a more substantial i1-i2 complex formation when i2 exceeds i1. We conclude that the relative abundance of regulatory i2 proteins has the potential to drastically alter the local drug metabolism in the cells, particularly when i2 surpasses the protein content of i1. PMID- 23360620 TI - [Impact of vaccination on admissions for Haemophilus influenzae b meningitis from 2004 to 2008 in Bobo Dioulasso, Burkina Faso]. AB - OBJECTIVE: Vaccination against Haemophilus influenzae type b was introduced in Burkina Faso on 1st January 2006. This study thus sought to determine the impact of the first 30 months of vaccination on admissions for Hib meningitis in the department of pediatrics at the Souro-Sanou University Hospital in Bobo Dioulasso. METHODS AND PATIENTS: Retrospective study of children aged zero to 14 years hospitalized from 1st January 2004 to 30th June 2008 for acute bacterial meningitis (laboratory-confirmed). RESULTS: During the study period, 416 children were admitted for acute bacterial meningitis. The bacterium isolated was identified in 386 cases and unidentified in 30 cases. Hib meningitis accounted for 42.3 % of the cases of identified bacterial meningitis before the introduction of the vaccine (2004 to 2005). This rate declined to 11.8 % for the first 30 months of vaccination (p < 0.001). No cases of Hib meningitis have been reported in the first half of 2008. CONCLUSION: Admissions for Hib meningitis in the Department of Pediatrics have practically disappeared two years after the introduction of the Hib vaccine into Burkina Faso's expanded program on immunization. PMID- 23360622 TI - High-rate and high-energy-density lithium-ion battery anode containing 2D MoS2 nanowall and cellulose binder. AB - Electrochemically stable molybdenum disulfide (MoS2) with a two-dimensional nanowall structure is successfully prepared by a simple two-step synthesis method followed by thermal annealing at 700 degrees C in a reducing atmosphere. MoS2 nanowalls provide a better electrochemical performance and stability when cellulose (CMC) binder is used instead of the usual PVDF. The electrodes exhibit a high specific discharge capacity of 880 mA h g-1 at 100 mA g-1 without any capacity fading for over 50 cycles. The electrode also exhibits outstanding rate capability with a reversible capacity as high as 737 mA h g-1 and 676 mA h g-1 at rates of 500 mA g-1 and 1000 mA g-1 at 20 degrees C, respectively. The excellent electrochemical stability and high specific capacity of the nano structured materials are attributed to the two-dimensional nanowall morphology of MoS2 and the use of cellulose binder. These results are the first of its kind to report a superior stability using bare MoS2 as an active material and CMC as a binder. PMID- 23360621 TI - An arbuscular mycorrhizal fungus significantly modifies the soil bacterial community and nitrogen cycling during litter decomposition. AB - Arbuscular mycorrhizal fungi (AMF) perform an important ecosystem service by improving plant nutrient capture from soil, yet little is known about how AMF influence soil microbial communities during nutrient uptake. We tested whether an AMF modifies the soil microbial community and nitrogen cycling during litter decomposition. A two-chamber microcosm system was employed to create a root-free soil environment to control AMF access to (13) C- and (15) N-labelled root litter. Using a 16S rRNA gene microarray, we documented that approximately 10% of the bacterial community responded to the AMF, Glomus hoi. Taxa from the Firmicutes responded positively to AMF, while taxa from the Actinobacteria and Comamonadaceae responded negatively to AMF. Phylogenetic analyses indicate that AMF may influence bacterial community assembly processes. Using nanometre-scale secondary ion mass spectrometry (NanoSIMS) we visualized the location of AMF transported (13) C and (15) N in plant roots. Bulk isotope ratio mass spectrometry revealed that the AMF exported 4.9% of the litter (15) N to the host plant (Plantago lanceolata L.), and litter-derived (15) N was preferentially exported relative to litter-derived (13) C. Our results suggest that the AMF primarily took up N in the inorganic form, and N export is one mechanism by which AMF could modify the soil microbial community and decomposition processes. PMID- 23360623 TI - First-in-human experience using the Volcano VIBE-RX vascular imaging balloon catheter system (Volcano IVUS-guided Balloon Evaluation - New Zealand: VIBE-NZ Study). AB - AIMS: Intravascular ultrasound (IVUS) is a proven and safe imaging modality used to guide percutaneous coronary intervention (PCI). The Volcano VIBETM RX Vascular Imaging Balloon Catheter is a novel rapid exchange, 0.014" wire-compatible multi lumen conventional balloon catheter modified with the addition of an IVUS transducer proximal to the balloon, delivered via a standard 6 Fr sheath. We sought to evaluate the safety, balloon performance, and image quality of the VIBETM RX in patients scheduled for coronary intervention. METHODS AND RESULTS: Patients aged >21 and <85 years with single or multivessel coronary disease scheduled for PCI due to coronary ischaemic symptoms were included. Those with angiographic features that precluded the safe or informative use of the device were excluded. Twenty-nine patients having angiography because of ischaemic symptoms underwent 44 VIBE RX imaging runs, with balloon dilation in 20. Successful device deployment was achieved in all but one patient. All images were adequate and reproducible. One patient had a non-ST-elevation MI felt to be due to the complexity of the procedure rather than directly related to the VIBETM RX. CONCLUSIONS: The study demonstrated the safety and effectiveness of the VIBETM RX for its intended purpose with minimal failure rate and no directly related complications. PMID- 23360624 TI - Inferring the kinetics of stochastic gene expression from single-cell RNA sequencing data. AB - BACKGROUND: Genetically identical populations of cells grown in the same environmental condition show substantial variability in gene expression profiles. Although single-cell RNA-seq provides an opportunity to explore this phenomenon, statistical methods need to be developed to interpret the variability of gene expression counts. RESULTS: We develop a statistical framework for studying the kinetics of stochastic gene expression from single-cell RNA-seq data. By applying our model to a single-cell RNA-seq dataset generated by profiling mouse embryonic stem cells, we find that the inferred kinetic parameters are consistent with RNA polymerase II binding and chromatin modifications. Our results suggest that histone modifications affect transcriptional bursting by modulating both burst size and frequency. Furthermore, we show that our model can be used to identify genes with slow promoter kinetics, which are important for probabilistic differentiation of embryonic stem cells. CONCLUSIONS: We conclude that the proposed statistical model provides a flexible and efficient way to investigate the kinetics of transcription. PMID- 23360625 TI - Outcomes of liver transplantation for patients with acute liver failure. AB - BACKGROUND: Liver transplantation is a treatment for patients who have acute liver failure (ALF). This study aims to evaluate the outcomes following liver transplantation in patients with ALF and compare them with cirrhotic patients who underwent liver transplantation. METHODS: This retrospective cross-sectional study was conducted at Shiraz Organ Transplant Center between June 2004 and March 2011 to evaluate the clinical presentation and underlying etiology of patients with ALF and their outcomes following liver transplantation. RESULTS: Out of 750 patients who underwent liver transplants, 12 (8 males and 4 females) had a diagnosis of ALF. The cirrhotic group (control) consisted of 20 transplanted patients. ALF patients were younger with a mean age of 18.7 +/- 12.9 years compared to 37.4 +/- 13.6 years in the cirrhotic group (P = 0.001). In the ALF group, 5 (41.66%) underwent partial living related liver transplantation compared to 1 (5%) in the cirrhotic group (P = 0.018). There were significantly more early post-transplant complications observed among patients with ALF compared to the cirrhotic group (P = 0.002). CONCLUSION: Liver transplantation is safe, effective and should be considered in patients diagnosed with ALF. PMID- 23360626 TI - Human leukocyte antigen class I alleles can predict response to pegylated interferon/ribavirin therapy in chronic hepatitis C Egyptian patients. AB - BACKGROUND: Racial differences and broad spectrum response to anti-hepatitis C (anti-HCV) therapy suggest a possible role for host genetic diversity in treatment outcomes. We aim to determine the association and predictive value of certain human leukocyte antigen (HLA) class I alleles with either susceptibility to viral clearance or persistence following pegylated interferon (Peg-IFN) plus ribavirin therapy in chronic hepatitis C (HCV) genotype 4 patients in Egypt. METHODS: This study included 200 unrelated chronic HCV patients who received Peg IFN plus ribavirin therapy [112 patients with sustained virological response (SVR) and 88 non-responders (NR)]. Serological testing of HLA class I antigens (HLA-A and HLA-B alleles) were performed by standard complement-dependent microlymphocytotoxicity assay. RESULTS: The frequency of HLA-A01 was significantly higher in SVR than in NR cases [OR: 0.51; 95% CI: 0.27-0.981; P = 0.042], while the frequency of alleles B38 (P = 0.011), B40 (P < 0.001) and B41 (P < 0.001) was significantly higher in NR cases (OR/95% CI: 7.05/(1.39-18.01), 10.31/3.14-36.1 . On logistic regression analysis, presence of the HLA-A01 allele was associated with SVR (OR: 0.50; 95% CI: 0.28-0.89; P = 0.02) and HLA-B38 can predict non response to therapy (OR: 7.92; 95% CI: 1.67-37.54; P = 0.009) with an overall accuracy of 60%.Severe fibrosis (OR: 3.035; 95% CI: 1.521-6.091; P = 0.002), high viremia (OR: 2.69; 95% CI: 1.11-6.53; P = 0.005) and steatosis (OR: 2.1; 95% CI: 1.002-3.90; P = 0.041) predicted no response with an overall accuracy of 81.8%. CONCLUSION: HLA-A01 and HLA-B38 alleles are associated with and may have a role in the outcome of response to Peg-IFN plus ribavirin therapy in Egyptian patients diagnosed with chronic HCV infection. The use of immunologic markers to predict the outcome of treatment may help pharmacogenetic personalization of treatment for HCV infection. PMID- 23360627 TI - Preliminary study of the level of visfatin and the relationship with insulin resistance in Chinese patients with chronic hepatitis C. AB - BACKGROUND: Many studies have suggested that visfatin expression is closely related to the occurrence of insulin resistance (IR), while the precise role of visfatin in the regulation of IR in chronic hepatitis C (CHC) is not clear. METHODS: We investigated fasting glucose, fasting insulin (FINS), C peptide, visfatin, visfatin mRNA, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, C reactive protein (CRP) and other parameters of 315 patients with CHC and 150 control cases in China. Meanwhile we collected clinical and other laboratory data for further analysis. RESULTS: Compared with the control group, the CHC group had a significant increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), the AST to platelet ratio index (APRI), ratio of AST to ALT (AAR), gammaglutamyl trans-peptidase, IL-6, TNF-alpha, visfatin, visfatin mRNA, FINS, fasting C peptide, and IR index. The visfatin, visfatin mRNA, insulin, IR index, Homabeta cell function index (HBCI), and fasting beta-cell function index (FBCI) of the subjects with high body mass index (BMI) from the CHC sub-group were significantly higher than the normal BMI sub-group of CHC patients. We found a positive correlation between visfatin, visfatin mRNA and BMI, IL-6, TNF-alpha, and IR index. CONCLUSION: Our data suggest that visfatin may be related to IR in Chinese CHC patients. PMID- 23360628 TI - Gastrointestinal and non-gastrointestinal presentation in patients with celiac disease. AB - BACKGROUND: Celiac disease (CD) may have a variety of different presentations. This study has aimed to explore the prevalence of gastrointestinal (GI) and non GI symptoms in patients with CD according to data collected in Italy and Romania (Europe) and Iran (Middle East). METHODS: This is a retrospective cross-sectional study conducted in Iran, Romania and Italy with data collection during the period from May 2009 - May 2011. For each center we included only patients with CD that was confirmed by endoscopy, small bowel biopsies and positive serology. GI symptoms such as abdominal pain, diarrhea, constipation, nausea and vomiting, weight loss and flatulence, as well as additional signs and symptoms of iron deficiency anemia (IDA), osteoporosis, hypertransaminasemia, and other related abnormalities were collected. RESULTS: Overall, 323 women and 127 men, whose mean age at diagnosis was 34.2 +/- 16.47 years were included in this study. Of these, 157 subjects (34.9%) reported at least one GI symptom. The majority of cases had the following primary presenting GI symptoms: diarrhea (13.6%), dyspepsia and constipation (4.0%). Other disease symptoms were reported by 168 (37.3%) patients. The most presenting non-GI symptoms in the majority of cases were anemia (20.7%) and osteopenia (6%). There were statistically significant differences between the majority of symptoms when we compared the reported clinical symptoms from different countries. CONCLUSION: This study indicated that upper abdominal disorders such as abdominal pain and dyspepsia were the most common primary complaints among European patients, whereas Iranian patients had complaints of diarrhea and bloating as the classic presentations of CD. For non GI symptoms, anemia was the most frequent complaint for both Iranian and Italian patients; however it was significantly higher in Iranians. PMID- 23360629 TI - Role of the chemokine fractalkine in a rat model of acute necrotizing pancreatitis and the interventional effect of ulinastatin. AB - BACKGROUND: Severe acute pancreatitis (SAP) is a serious systemic disease with high mortality. This study aims to investigate the role of the chemokine, fractalkine (FKN), in the pathogenesis of SAP and the effects of intervention by ulinastatin on FKN expression in an SAP rat model. METHODS: We randomly divided 72 Sprague Dawley rats into the following groups: SAP, ulinastatin treatment (UT), and control (C). The SAP model was induced by retrograde infusion of 4% sodium taurocholate into the bili-pancreatic ducts of the rats. Rats in the UT group were injected with ulinastatin immediately after establishment of the SAP model. Serum FKN levels were detected by ELISA at various time points. Histopathological analyses of the pancreas and lung were performed. Expressions of FKN mRNA in the tissues of the pancreas and lung were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) at various time points for each group. RESULTS: Serum levels of FKN at 3 h after surgery in the SAP subgroup were significantly higher than those in the C group (P < 0.05). There were no significant differences between the UT and C groups observed at various time points. Expression levels of FKN mRNA in the pancreatic tissues of the SAP group increased gradually. Although we observed no difference between the SAP and C groups (P > 0.05) at 1 hour h after surgery, mRNA levels of FKN in the lung tissues at 3, 6, and 12 h post-surgery in the SAP subgroups were significantly higher than those in the C group for the same time points (P < 0.05). Pathological injury of the pancreatic tissues was more remarkable in the SAP group compared to the UT group. CONCLUSION: FKN may play an important role in the pathogenesis of SAP and SAP-related acute lung injury (ALI). Ulinastatin efficiently interferes with SAP and SAP-related ALI and may be related to inhibition of FKN expression. PMID- 23360630 TI - Changes of bone density in pediatric patients with beta-thalassemia major after allogenic hematopoietic stem cell transplantation. AB - BACKGROUND: Thalassemia major and its treatment by stem cell transplantation can have deleterious effects on bone integrity. This study assesses the adverse effects of transplantation on growing bones of pediatric thalassemic patients. METHODS: Bone mineral density (BMD) of 20 patients from three thalassemia classes whose mean (SD) age was 7.4 (3.8) years were tested with a Norland XR-46 device at baseline (before transplantation), 6 and 12 months after transplantation. RESULTS: At 6 and 12 months after transplantation we observed no significant changes in mean BMD. There were no Z-scores less than -2 among patients. Class 3 thalassemia did not negatively impact BMD. Calcium (Ca), phosphorous (P) and ferritin levels were not significantly related to patients' BMD scores. Transfusion duration and chelation therapy showed positive significant relationships to BMD (g/cm(2)), but no significant relation with the BMD Z-score. The deleterious relation between corticosteroid use and changes in BMD was not significant. In contrast, patients who developed acute graft versus host disease (aGVHD) after transplantation showed significant adverse effects on BMD of their femur (P = 0.020) and spine (P = 0.027). CONCLUSION: Stem cell transplantation in pediatric thalassemic patients who do not develop aGVHD does not appear to have any significant positive or negative effects on BMD. PMID- 23360631 TI - Distribution of myofibroblast cells and microvessels around invasive ductal carcinoma of the breast and comparing with the adjacent range of their normal-to DCIS zones. AB - BACKGROUND: This study seeks to determine the relationships between manifestation of myofibroblasts in the stroma tissue of hyperplastic pre-invasive breast lesions to invasive cancer by investigating clinicopathological data of patients, their effect on steroid receptor expression and HER2, and angiogenesis according to CD34 antigen expression. METHODS: 100 cases of invasive ductal carcinoma were immunohistochemically investigated for the presence of smooth muscle actin (SMA), ER/PR, HER2, anti-CD34 antibody and microvessel count (MVC). Patients were scored in four different zones of invasive areas: invasive cancer, DCIS, fibrocystic disease +/- ductal intraepithelial neoplasia (FCD +/- DIN), and normal tissue. RESULTS: There was a significant difference in stromal myofibroblasts between all areas except for the stroma of DCIS and FCD +/- DIN (P < 0.001). We observed positive significant correlations between stromal myofibroblasts, HER2 expression, and the numbers of involved lymph nodes in invasive cancer, DCIS, and FCD +/- DIN (P < 0.001). More myofibroblasts were present in grade III cases, with the least frequent observed among grade I cases in the stroma of those with invasive disease, DCIS, and FCD +/- DIN (P < 0.001). MVC was inversely related to stromal myofibroblasts in invasive cancer (P < 0.001) and DCIS (P < 0.001), whereas there was a positive correlation in the stroma of FCD +/- DIN (P = 0.002) and normal areas (P = 0.054). There was a significant difference in MVC observed in all areas except for DCIS and FCD +/- DIN (P < 0.001). We noted significant inverse correlations between MVC, HER2 expression, and the numbers of involved lymph nodes in invasive cancer and DCIS (P < 0.001). Most MVC were present in grade I, with the least frequent observed in grade III cases in the stroma of invasive cancer, DCIS and FCD +/- DIN (P < 0.001). CONCLUSION: Angiogenesis can be observed before any significant myofibroblastic changes in the pre-invasive breast lesions. The elevated content of myofibroblasts in stroma of tumor; probably may be a worse prognostic factor and the steps from atypical epithelial hyperplasia to DCIS and then to the invasive carcinoma do not appear to be always part of a linear progression. PMID- 23360632 TI - Sleep quality among health care workers. AB - BACKGROUND: Sleep problems are common complaints in health care workers that can affect quality of life and productivity, both in patients and healthy individuals. This study evaluates the prevalence of low sleep quality in health care workers with no health issues or complaints of sleep problems. METHODS: In this cross-sectional study was conducted on healthy employees of a health care organization in Tehran. The presence of physical and mental health issues and satisfaction from their sleep quality was assessed by means of a self administered questionnaire. Sleep quality was evaluated by the Persian version of the Pittsburgh Sleep Quality Index (PSQI). PSQI scores of 5 or less were considered as good sleep quality. RESULTS: From 925 participants, 56.9% were good sleepers. There was a significant association between poor sleep quality and female sex, divorced, shift-working, and age; it was not associated with education level. Self-rated health (SRH) had a significant positive correlation with sleep quality. CONCLUSION: Poor sleep quality is common in our study population and associated with a lower SRH. The high prevalence of poor sleep quality in a group of healthy non-complaining employees can be an important early sign of underlying physical or mental health issues. Providing screening and monitoring programs to detect the underlying health conditions and their consequent treatment can promote health and productivity of employees and improve society's health, both directly and indirectly. PMID- 23360633 TI - Comparing TCR beta chain variable gene profile skewness between children with tuberculosis and BCG-vaccinated children. AB - BACKGROUND: We compared the T cell antigen receptor (TCR-BV) gene families of peripheral blood mononuclear cells (PMBC) between children with tuberculosis (TB) and those inoculated with the Bacille Calmette Guerin (BCG) vaccine. METHODS: The total RNA was extracted from PMBC of 15 TB children, 15 BCG-vaccinated children and 15 healthy controls. The RNAs were reverse-transcribed and amplified by polymerase chain reaction (PCR). PCR products were separated on 1.5% agarose gel and analyzed with the Genescan technique. RESULTS: Some TCR-BV gene families in TB children and BCG-vaccinated children exhibited a blur band in the predicted position on 1.5% agarose gel, some showed a distinct or fainted band. In general, many shared predominant clonal TCR-BV gene families (Vbeta2, Vbeta16, Vbeta21, Vbeta22) and the restricted-expression families (Vbeta14 and Vbeta17). All the gene families of the control children only exhibited blur bands and polyclonal. CONCLUSIONS: The skewed profile of TCR-BV gene families in TB children and BCG vaccinated children are similar, which may probably explain the protective effects of BCG-vaccine against TB in children. PMID- 23360634 TI - In vivo and in vitro anti-angiogenesis effect of venom-derived peptides (ICD-85). AB - BACKGROUND: Agiogenesis is the development of new blood vessels from pre-existing vasculatures. Although essential in the physiological process, it becomes pathological in various diseases including cancer. Preventing the formation of new blood vessels causes reductions in tumor size and metastasis. This study has been undertaken to elucidate the anti-angiogenesis effects of ICD-85 (derived peptides from venom). METHODS: We evaluated the ICD-85 anti-angiogenesis activity by the in vivo CAM assay and in vitro tube formation assay of human umbilical vein endothelial cells (HUVECs). The anti-proliferative activity of ICD-85 was also determined through MTT assay on HUVECs. RESULTS: Results of this study revealed the anti-proliferative activity of ICD-85 on the HUVEC cell line with an IC50 of 12 MUg/mL. The in vivo CAM assay also clearly showed the prevention of new vascular formation when the chick embryos were exposed to 0.15 ug/disc of ICD 85. In vitro tube formation assay of HUVECs also showed the complete prevention of capillary tube formation on 18 ug/mL. CONCLUSION: Based on the results obtained in this study, ICD-85 has anti-angiogenesis activity as shown by the prevention of capillary tube formation and the CAM assay. PMID- 23360635 TI - A review of psychosocial issues in patients with chronic hepatitis B. AB - Psychosocial issues and health-related quality of life (HRQOL) are important components of care in patients diagnosed with chronic hepatitis B (CHBV). In this review, we searched Medline, ISI Web of Knowledge, Google Scholar and the American Association for the Study of Liver Diseases (AASLD) website (until January 2012) using relevant terms and we categorized the retrieved content into three areas: HRQOL, mental health, and psychosocial issues such as stigma and coping. Increasing severity of CHBV leads to a decline in HRQOL. Cirrhosis worsens HRQOL, whereas treatment and psycho-education improves it. Frequency of mood disorders seems to be increased in patients with CHBV, although not all studies have shown this trend. Some factors such as alcohol consumption and low social support negatively impact patients' mental health. Those with CHBV generally have better HRQOL and mental health than their hepatitis C (HCV) counterparts. Patients with psychiatric disorders, particularly those with prolonged institutionalization, have a generally higher risk of acquiring CHBV infection compared to the general population. Robust studies regarding the stigma in patients with CHBV are lacking, although some studies have suggested a higher degree of perceived stigma in these patients. HRQOL and mental health are significantly affected in CHBV patients, particularly in those with more severe forms of the disease. There are few studies that addressed the effects of intervention in CHBV patients with psychosocial problems. Other subjects necessitating additional research include stigma, coping mechanisms, and other less common, yet important psychosomatic disorders. PMID- 23360636 TI - Neuroendocrine tumor of the gallbladder. AB - Neuroendocrine tumors (NET) arise from neuroendocrine cells and are an exceedingly rare malignancy in the gallbladder. In this case report, a 52-year old woman with complaints of episodic abdominal pain for two months prior was admitted to our hospital. She had no other signs and symptoms and her laboratory tests were within normal limits. Ultrasonography showed a broad-necked mass (26 * 12 mm) in the gallbladder for which she underwent laparoscopic cholecystectomy. The final pathological diagnosis was a high grade neuroendocrine carcinoma of the gallbladder with involvement of the lymph nodes and omentum. The patient received the chemotherapy regimens of gemcitabine plus cisplatin, followed by docetaxel plus sunitinib for her metastatic liver lesions. She also underwent radiofrequency ablation. Serial CT-scans revealed metastatic liver lesions that had decreased in size, with no significant improvement. The patient refused additional treatment and at 46 months, she was doing well with no complaints of any pain, disease recurrence, or metastatic progression. PMID- 23360637 TI - Detection of a novel mutation in the GAA gene in an Iranian child with glycogen storage disease type II. AB - Glycogen storage disease II (GSDII or Pompe disease, OMIM # 232300) is an autosomal recessive hereditary lysosomal disorder. Mutations in the GAA gene usually lead to reduced acid alpha-glucosidase (acid maltase, GAA, OMIM *606800, EC 3.1.26.2) activity, which results in impaired degradation and subsequent accumulation of glycogen within lysosomes. We present an Iranian boy, who was diagnosed with GSDII based upon clinical and biochemical findings. A single adenine insertion (insA) was detected at codon 693 that leads to a predicted premature stop codon at codon 736 in the GAA gene. The parents were heterozygous for the same change. According to the human genome mutation database (www.hgmd.org) and lecture reviews, the detected change is a novel mutation. We suppose that the discovered insertion in the GAA gene might lead to a reduced activity of the gene product. This assumption is in agreement with biochemical and clinical signs in the patient. PMID- 23360638 TI - Photoclinic. Kartagener's syndrome. PMID- 23360639 TI - Brief historical perspectives of malaria in Iran. AB - The history of malaria as a serious human disease dates back to ancient times. For centuries, malaria has been a deadly disease with high morbidity and mortality that profoundly impacted the socioeconomic status of endemic countries. However, its causative agent remained unidentified until the last decades of the nineteenth century. There were no effective synthetic anti-malarial agents until the mid-twentieth century. Currently malaria has been eliminated or pre eliminated in numerous countries; however, this preventable and curable disease remains a significant global health problem. A major concern is drug resistance. Presented here, is a brief look at the history of malaria in Iran and the rest of the world, particularly during the nineteenth and twentieth centuries. PMID- 23360640 TI - Reciprocal influences between maternal language and children's language and cognitive development in low-income families. AB - We examined reciprocal associations between early maternal language use and children's language and cognitive development in seventy ethnically diverse, low income families. Mother-child dyads were videotaped when children were aged 2;0 and 3;0. Video transcripts were analyzed for quantity and lexical diversity of maternal and child language. Child cognitive development was assessed at both ages and child receptive vocabulary was assessed at age 3;0. Maternal language related to children's lexical diversity at each age, and maternal language at age 2;0, was associated with children's receptive vocabulary and cognitive development at age 3;0. Furthermore, children's cognitive development at age 2;0 was associated with maternal language at age 3;0 controlling for maternal language at age 2;0, suggesting bi-directionality in mother-child associations. The quantity and diversity of the language children hear at home has developmental implications for children from low-income households. In addition, children's early cognitive skills further feed into their subsequent language experiences. PMID- 23360642 TI - The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndrome. AB - Fibroblasts derived from the progeroid Werner syndrome (WS) show reduced replicative lifespan and a "stressed" morphology, both phenotypes being alleviated by using the p38 MAP kinase inhibitor SB203580. Because p38 is a major hub for the control of stress-signalling pathways we were interested in examining the possible role for downstream kinases in order to refine our understanding of the role of p38 signalling in regulation of WS cell growth. To this end we treated WS and normal fibroblasts with MK2 inhibitors to determine whether MK2 inhibition would affect either the growth or morphology of WS cells. The first inhibitor, 7,8-dihydroxy-2,4-diamino-3-cyanobenzopyranopyridine (inhibitor 2), resulted in inhibition of WS cell growth and had no effect on morphology, effects that occurred below the level needed to inhibit MK2 and thus suggestive of inhibitor toxicity. The second inhibitor, 2-(2-quinolin-3-ylpyridin-4-yl)-1,5,6,7 tetrahydro-4H-pyrrolo-[3,2-c]pyridin-4-one (CMPD16), resulted in a significant extension of WS fibroblast replicative capacity compared to normal cells. In addition, CMPD16 reverted the WS cellular morphology to that seen in normal dermal fibroblasts. These data suggest that MK2 activity plays a substantial role in proliferation control in WS cells. CMPD16 was not as effective in cellular lifespan extension as SB203580, however, suggesting that, although MK2 is a downstream kinase involved in cell cycle arrest, other p38 targets may play a role. Alternatively, as CMPD16 is toxic to cell growth at levels just above those that extend lifespan, it is possible that the therapeutic window is too small. However, as CMPD16 does show significant effects in WS fibroblasts, this acts as proof-of-principle for the efforts to design and synthesise improved MK2 inhibitors. As MK2 is involved in inflammatory processes and inflammation plays a major role in WS phenotypes, these data suggest MK2 as a potential therapeutic target for the treatment of Werner syndrome. PMID- 23360641 TI - Antiproliferative effect of pHLIP-amanitin. AB - Toxins could be effective anticancer drugs, if their selective delivery into cancer cells could be achieved. We have shown that the energy of membrane associated folding of water-soluble membrane peptides of the pHLIP (pH low insertion peptide) family could be used to move cell-impermeable cargo across the lipid bilayer into the cytoplasm of cancer cells. Here we present the results of a study of pHLIP-mediated cellular delivery of a polar cell-impermeable toxin, alpha-amanitin, an inhibitor of RNA polymerase II. We show that pHLIP can deliver alpha-amanitin into cells in a pH-dependent fashion and induce cell death within 48 h. Translocation capability could be tuned by conjugating amanitin to the C terminus of pHLIP via linkers of different hydrophobicities that could be cleaved in the cytoplasm. pHLIP-SPDP-amanitin, which exhibits 4-5 times higher antiproliferative ability at pH 6 than at pH 7.4, was selected as the best construct. The major mechanism of amanitin delivery is direct translocation (flip) across a membrane by pHLIP and cleavage of the S-S bond in the cytoplasm. The antiproliferative effect was monitored on four different human cancer cell lines. pHLIP-mediated cytoplasmic delivery of amanitin could create great opportunities to use the toxin as a potent pH-selective anticancer agent, which predominantly targets highly proliferative cancer cells at low extracellular pH values. PMID- 23360643 TI - The impact of smoking in the home on the health outcomes of non-smoker occupants in the UK. AB - Smoking in the home remains a key source of exposure to secondhand smoke for non smokers, particularly since the UK public smoking ban in 2007. A systematic literature review was conducted to identify all UK evidence on the impact of secondhand smoke exposure in the home on health and behavioural outcomes in non smoker occupants. MEDLINE, EMBASE and the Cochrane Library were searched to identify all relevant UK empirical studies from 2000 to June 2011. A qualitative overview of the evidence is presented. Exposure to secondhand smoke in UK homes was found to be associated with serious negative health effects in non-smokers, including significantly increased risk of meningococcal carriage (p < 0.001) and disease (p = 0.05) in children and adolescents, cognitive impairment (p < 0.001) in adults, a higher rate of medically attended accidents in children with smoking mothers (p < 0.01), and for non-smoking women, a significant decrease in infant birth weight (p = 0.007). Living in a smoking household significantly increased the risk of future regular smoking in children (p < 0.001). In conclusion, this systematic review has identified strong evidence of an association between secondhand smoke exposure in the home and several serious health conditions. This finding highlights the importance of educating current smokers on the consequences of non-smoker exposure to smoking in the home. PMID- 23360644 TI - [Seasonal variability of intestinal helminths and Schistosoma haematobium in a rural area of the Sahel in Mali]. AB - OBJECTIVE: The objective of this study was to determine the prevalence of intestinal helminths and Schistosoma haematobium before and after the rainy season in Pongonon, Mali. METHODS: Volunteers aged one year and above were included. The Kato-Katz method was used to detect eggs and cysts in stool samples, and Wattman filtration to detect S. haematobium eggs in urine samples. Two cross-sectional surveys were conducted in July and November 2007. RESULTS: In July (beginning of the rainy season), 304 volunteers were included; 278 were seen again in November (at the end of the rainy season). We found more intestinal helminths at the end of the rainy season (8.3%) compared to the beginning of the season (2.9%) (P = 0.01). There was no infection with S. haematobium in July but 7.6% in November (P < 0.001). The prevalence of intestinal helminths in children and adults was similar (P > 0.05), but the prevalence of infection with S. haematobium was higher in children aged 6 to 16 years (17/153) than in adults (2/74) (P = 0.02). CONCLUSION: Infections with helminth and S. Haematobium were both more prevalent at the end of the rainy season. Adults were infected as well as children and may constitute potential reservoirs of parasites. Effective control of these parasitic infections requires mass drug administration programs that take place during the seasons of high parasite egg excretion and that also include adult populations in some areas. PMID- 23360645 TI - Decomposing Indigenous life expectancy gap by risk factors: a life table analysis. AB - BACKGROUND: The estimated gap in life expectancy (LE) between Indigenous and non Indigenous Australians was 12 years for men and 10 years for women, whereas the Northern Territory Indigenous LE gap was at least 50% greater than the national figures. This study aims to explain the Indigenous LE gap by common modifiable risk factors. METHODS: This study covered the period from 1986 to 2005. Unit record death data from the Northern Territory were used to assess the differences in LE at birth between the Indigenous and non-Indigenous populations by socioeconomic disadvantage, smoking, alcohol abuse, obesity, pollution, and intimate partner violence. The population attributable fractions were applied to estimate the numbers of deaths associated with the selected risks. The standard life table and cause decomposition technique was used to examine the individual and joint effects on health inequality. RESULTS: The findings from this study indicate that among the selected risk factors, socioeconomic disadvantage was the leading health risk and accounted for one-third to one-half of the Indigenous LE gap. A combination of all six selected risks explained over 60% of the Indigenous LE gap. CONCLUSIONS: Improving socioeconomic status, smoking cessation, and overweight reduction are critical to closing the Indigenous LE gap. This paper presents a useful way to explain the impact of risk factors of health inequalities, and suggests that reducing poverty should be placed squarely at the centre of the strategies to close the Indigenous LE gap. PMID- 23360646 TI - Simultaneous enhancements of UV resistance and mechanical properties of polypropylene by incorporation of dopamine-modified clay. AB - Inspired by the radical scavenging function of melanin-like materials and versatile adhesive ability of mussel-adhesion proteins, dopamine-modified clay (D clay) was successfully incorporated into polypropylene (PP) using an amine terminated PP oligomer as the compatibilizer. Although the PP/D-clay nanocomposites exhibit intercalated morphology, the incorporation of D-clay greatly improves the thermo-oxidative stability and UV resistance of PP owing to the strong radical scavenging ability of polydopamine (PDA) and large contact area between PP and the PDA coating on clay mineral. Moreover, the reinforcement effect brought by D-clay is fairly significant at very low clay loadings probably owing to the strong interfacial interactions between the layered silicates and the compatibilizer as well as that between the compatibilizer and the PP matrix. The work demonstrates that D-clay is a type of promising nanofiller for thermoplastics used for outdoor applications since it stabilizes and reinforces the polymers simultaneously. PMID- 23360647 TI - Giant left atrium in rheumatic heart disease: the classic signs of left atrial enlargement. PMID- 23360648 TI - Pre-endoscopic Rockall and Blatchford scores to identify which emergency department patients with suspected gastrointestinal bleed do not need endoscopic hemostasis. AB - BACKGROUND: The pre-endoscopic Rockall Score (RS) and the Glasgow-Blatchford Scores (GBS) can help risk stratify patients with upper gastrointestinal bleed who are seen in the Emergency Department (ED). The RS and GBS have yet to be validated in a United States patient population for their ability to discriminate which ED patients with upper gastrointestinal bleed do not need endoscopic hemostasis. OBJECTIVE: We sought to determine whether patients who received a score of zero on either score (the lowest risk) in the ED still required upper endoscopic hemostasis during hospitalization. METHODS: Retrospective electronic medical record chart review was performed during a 3-year period (2007-2009) to identify patients with suspected upper gastrointestinal bleed by ED final diagnosis of gastrointestinal hemorrhage and related terms at a single urban academic ED. The RS and GBS were calculated from ED chart abstraction and the hospital records of admitted patients were queried for subsequent endoscopic hemostasis. RESULTS: Six hundred and ninety patients with gastrointestinal bleed were identified and 86% were admitted to the hospital. One hundred and twenty-two patients had an RS equal to zero; 67 (55%; 95% confidence interval [CI] 46-63%) of these patients were admitted to the hospital and 11 (16%; 95% CI 9-27%) received endoscopic hemostasis. Sixty-three patients had a GBS equal to zero; 15 (24%; 95% CI 15-36%) were admitted to the hospital and 2 (13%; 95% CI 4-38%) received endoscopic hemostasis. CONCLUSIONS: Some patients who were identified as lowest risk by the GBS or RS still received endoscopic hemostasis during hospital admission. These clinical decision rules may be insufficiently sensitive to predict which patients do not require endoscopic hemostasis. PMID- 23360649 TI - Luxatio erecta of the hip. PMID- 23360650 TI - Restraint use in the elderly emergency department patient. AB - BACKGROUND: The elderly frequently suffer from altered mental status and other medical conditions requiring physical or chemical restraint for safety in the Emergency Department (ED). OBJECTIVE: This study examined outcomes of restrained elderly patients in the ED. METHODS: A 2-year retrospective study was conducted in an urban community teaching hospital ED. Included were patients >=65 years of age who were physically restrained in the ED and hospitalized. Data collected included age, gender, restraint indications, restraint type, restraint duration, adverse outcomes, ED discharge diagnosis, ED disposition, hospital length of stay, and disposition. RESULTS: There were 83 patients in the study. Forty-seven (56.6%) were nursing home residents. Twenty-seven (32.5%) were admitted to the intensive care unit. Thirty-five (42.2%) received both chemical and physical restraint. The average number of patient medications on arrival to the ED was eight, and 3 patients were on a medication that could adversely interact with a chemical restraint medication. The mean inpatient length of stay was 7.2 days (SD 5.7 days). Ten patients expired, 14 were discharged home, and 59 were discharged to a nursing facility (8 with new behavioral medications). Of the 36 patients originally presenting to the ED from home, only 11 (30.6%) were discharged back to home. There were no significant differences in outcome between patients who received a combination of both chemical and physical restraints and patients who received physical restraint alone. CONCLUSION: In this 2-year retrospective study, elderly patients placed in physical restraints in the ED had no recorded adverse outcomes. In addition, there were no adverse outcomes when they received both physical and chemical restraint. Elderly patients who were originally admitted from home and subsequently required physical restraint were unlikely to return home. PMID- 23360651 TI - Circulating levels of sTNFR1 as a marker of severe clinical course in schizophrenia. AB - BACKGROUND: Schizophrenia (SZ) has been associated with an imbalance in the inflammatory cytokine TNF-alpha. The objectives of this study were to compare TNF alpha and its soluble receptors' serum levels in individuals with SZ with the levels found in a group of healthy volunteers and to investigate the possible association between these biomarkers and the dimensions and severity of symptoms, clinical outcomes and response to treatment in patients with SZ. METHODS: Fifty four chronically medicated SZ outpatients and 118 healthy controls were included in the study. TNF-alpha levels were measured by Cytometric Bead Assay (CBA), and serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1) and soluble tumor necrosis factor receptor 2 (sTNFR2) were measured by ELISA. RESULTS: sTNFR1 and sTNFR2 were significantly elevated in patients with SZ as compared to the healthy control group. In the group of individuals with SZ, the levels of both types of soluble TNF receptors showed a negative correlation with global functioning. sTNFR1 levels were higher in the treatment-resistant patients as compared to the non-treatment-resistant patients and the controls. sTNFR1 levels were also heightened in patients with SZ and concomitant depression. CONCLUSION: Our findings reinforce that SZ is associated with an inflammatory profile and suggest that sTNFR1 is a marker of a treatment-resistance and severe clinical course in SZ. PMID- 23360652 TI - CGAL: computing genome assembly likelihoods. AB - Assembly algorithms have been extensively benchmarked using simulated data so that results can be compared to ground truth. However, in de novo assembly, only crude metrics such as contig number and size are typically used to evaluate assembly quality. We present CGAL, a novel likelihood-based approach to assembly assessment in the absence of a ground truth. We show that likelihood is more accurate than other metrics currently used for evaluating assemblies, and describe its application to the optimization and comparison of assembly algorithms. Our methods are implemented in software that is freely available at http://bio.math.berkeley.edu/cgal/. PMID- 23360653 TI - Mitral valve repair using multiple MitraClips(r): a dobutamine stress echocardiography evaluation. AB - AIMS: The haemodynamic effect of mitral valve (MV) repair using multiple MitraClips(r) (MC) has not been investigated. The aim of the study was to evaluate the stress performance of MV repair with MC. METHODS AND RESULTS: Twenty consecutive patients (77+/-7 years, 13 men [65%]) after implantation of >2 MitraClips(r) were subsequently evaluated with dobutamine stress echocardiography (DSE). After MC implantation, mean transmitral pressure gradient (TPG) (3.3+/-0.8 mmHg vs. 4.0+/-0.6 mmHg; p<0.001) and mitral valve orifice area (2.9+/-0.3 cm2 vs. 3.9+/-0.4 cm2; p<0.001) were significantly increased during DSE showing a physiological behaviour effect of the MV. LVEF (41+/-18% vs. 46+/-21%; p<0.001) and systolic pulmonary artery pressure (42+/-11 mmHg vs. 44+/-12 mmHg; p=0.014) increased significantly. The degree of MR was stable during stress (p=0.68). At linear regression, only baseline peak TPG was related to stress mean TPG (p<0.001; Beta 0.816; 95% CI: 0.368-0.918). CONCLUSIONS: MV repair using MitraClips(r) should be performed with the aim of maximal reduction of MR degree. MV repair using MC may not lead to pathological degrees of MV stenosis. Although the TPG is significantly increased during stress, it never reaches pathological levels and is always accompanied by a significant increase in MVOA. The degree of residual MR remains unchanged during maximal pharmacological stress. PMID- 23360654 TI - Clampless laparoendoscopic single-site partial nephrectomy for renal cancer with low PADUA score: technique and surgical outcomes. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Laparoendoscopic single-site (LESS) surgery has proved to be immediately applicable in the clinical field, being safe and feasible in the hands of experienced laparoscopic surgeons in well-selected patients. All extirpative and reconstructive urological procedures have been described in the literature, but LESS partial nephrectomy (PN) is one of the most complex procedures and few studies have been published on this subject. The study describes a clampless technique for LESS PN, by reducing the blood pressure and increasing the intra-abdominal pressure of the pneumoperitoneum to 20 mmHg, timed to precisely coincide with excision of the tumour. This technique was found to be safe and feasible in the treatment of low risk T1a RCC. OBJECTIVE: To describe the technique and report the surgical outcomes of clampless laparoendoscopic single-site (LESS) partial nephrectomy (PN) in the treatment of renal cell carcinoma (RCC) with low PADUA score. PATIENTS AND METHODS: Clampless LESS PN was performed in 14 patients with cT1a renal tumours. Indications to perform a clampless LESS PN were low-risk, laterally based renal tumours, located away from the renal hilum, with a PADUA score <=7. Demographic data and peri-operative and postoperative variables were recorded and analysed. Kidney function was evaluated by measuring serum creatinine concentration and estimated glomerular filtration rate (eGFR) pre- and postoperatively and at 6-month follow-up. RESULTS: The median operating time was 120 min and warm ischaemia time was zero in all cases. Only one early complication (Clavien grade 1) was recorded: one patient developed a flank haematoma which it was possible to treat by conservative therapy. Serum creatinine and modification of diet renal disease eGFR were not found to be significantly different pre- and postoperatively and at 6-month follow-up. Definitive pathological results showed 12 pT1a RCCs and two pT1a-chromophobe RCCs. All tumours were removed with negative surgical margins. All patients were satisfied with the cosmetic results. At a median (range) follow-up period of 12 (8-15) months, all patients were alive without evidence of tumour recurrence or port-site metastasis. CONCLUSION: Clampless LESS PN is a safe and feasible surgical procedure in the treatment of low-risk T1a RCC, with excellent cosmetic results. PMID- 23360655 TI - Effect of overexpressing nhaA and nhaR on sodium tolerance and lactate production in Escherichia coli. AB - BACKGROUND: Like other bacteria, Escherichia coli must carefully regulate the intracellular concentration of sodium ion (Na+). During the bacterial production of any organic acid, cations like Na+ invariably accumulate during a process which must maintain a near neutral pH. In this study, the E. coli nhaA gene encoding the Na+/H+ antiporter membrane protein and the nhaR gene encoding the NhaA regulatory protein were overexpressed in wild-type E. coli MG1655 and in MG1655 pflB (ALS1317) which lacks pyruvate formate lyase activity and thus accumulates lactate under anaerobic conditions. RESULTS: Expression of either the nhaA or nhaR gene on the high copy inducible expression vector pTrc99A caused a significant reduction in the growth rate of MG1655. No change in growth rate was observed for MG1655 or ALS1317 for Na+ concentrations of 0.75-0.90 M when the medium copy pBR322 plasmid was used to overexpress the two genes. In a fed-batch process to produce the model acid lactate with NaOH addition for pH control, lactate accumulation ceased in MG1655, MG1655/pBR322, MG1655/pBR322-nhaR and MG1655/pBR322-nhaA when the concentration reached 55-58 g/L. In an identical process lactate accumulation in MG1655/pBR322-nhaAR did not terminate until the concentration reached over 70 g/L. CONCLUSIONS: Although overexpression the genes did not improve growth rate at high Na+ concentrations, the overexpression of nhaA and nhaR together led to a 25% increase in lactate production. Thus, the observed (absence of) impact that these genetic modifications had on growth rate is a poor indicator of their effect on acid accumulation. The overexpression of nhaAR did not cause faster lactate production, but permitted the culture to continue accumulating lactate at 10% greater Na+ concentration. PMID- 23360657 TI - Relaxation breathing improves human glycemic response. AB - OBJECTIVES: This study evaluated a simple relaxation breathing exercise for acute improvement of postprandial glycemic and insulinemic status. DESIGN: Healthy human subjects were randomized to control breathing (CB; n=13) or a relaxation breathing exercise (RB; n=13) that was repeated every 10 minutes for the 30 minutes before and 90 minutes after consuming a glucose challenge (oral glucose tolerance test; OGTT; 75 g/240 mL). Blood samples were collected before, and 30, 60, and 90 minutes post OGTT for glucose and insulin analysis. RESULTS: Blood glucose at 0 minutes (pre-OGTT), and 30, 60, and 90 minutes post-OGTT with continued RB was 93.7+/-1.9, 136.5+/-8.1, 165.7+/-8.1, and 130.2+/-6.9 mg/dL, and 97.1+/-2.4, 173.1+/-8.4, 158.7+/-11.1, and 137.1+/-10.1 with CB, respectively. RB blood glucose was significantly lower at 30 minutes than CB. Glucose area under the curve (AUC) for CB and RB were not significantly different. Plasma insulin for both CB and RB was significantly increased relative to baseline at 30, 60, and 90 minutes. Insulin values for RB tended to be higher than CB at 30 and 60 minutes, although the difference was not statistically significant. Insulin AUC for CB and RB was not significantly different. CONCLUSIONS: Relaxation breathing acutely improves the glycemic response of healthy subjects, and breathing pattern could be important for interpretation of glycemic index measurements. PMID- 23360656 TI - Randomized controlled trial for Salvia sclarea or Lavandula angustifolia: differential effects on blood pressure in female patients with urinary incontinence undergoing urodynamic examination. AB - OBJECTIVES: The aim of this study was to investigate the effect of inhalation of Salvia sclarea (clary sage; clary) or Lavandula angustifolia (lavender) essential oil vapors on autonomic nervous system activity in female patients with urinary incontinence undergoing urodynamic assessment. STUDY DESIGN, LOCATION, AND SUBJECTS: This study was a double-blind, randomized, controlled trial carried out in 34 female patients with urinary incontinence. OUTCOME MEASURE: The subjects were randomized to inhale lavender, clary, or almond (control) oil at concentrations of 5% (vol/vol) each. Systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and salivary cortisol were measured before and after inhalation of these odors for 60 minutes. RESULTS: The clary oil group experienced a significant decrease in systolic blood pressure compared with the control (p=0.048) and lavender oil (p=0.026) groups, a significant decrease in diastolic blood pressure compared with the lavender oil group (p=0.034) and a significant decrease in respiratory rate compared with the control group (p<0.001). In contrast, the lavender oil group tended to increase systolic and diastolic blood pressure compared with the control group. Compared with the control group, inhalation of lavender oil (p=0.045) and clary oil (p<0.001) resulted in statistically significant reductions in respiratory rate. CONCLUSIONS: These results suggest that lavender oil inhalation may be inappropriate in lowering stress during urodynamic examinations, despite its antistress effects, while clary oil inhalation may be useful in inducing relaxation in female urinary incontinence patients undergoing urodynamic assessments. PMID- 23360658 TI - The Khasia tribe of Sylhet District, Bangladesh, and their fast-disappearing knowledge of medicinal plants. PMID- 23360659 TI - Effect of therapeutic horseback riding on balance in community-dwelling older adults with balance deficits. AB - OBJECTIVES: Falls are an important cause of morbidity in older adults. Equine assisted activities including therapeutic riding (TR) benefit balance and neuromuscular control in patients with neurological disabilities but have not been systematically studied in older adults at greater risk for falls due to balance deficits. The effect of an 8-week TR program on measures of balance and quality of life in community-dwelling older adults with established balance deficits was evaluated. DESIGN: This was a pretest-post-test single-group trial of a TR program on measures of balance and quality of life. SETTING: The study was conducted at a Professional Association of Therapeutic Horsemanship (PATH) International Premier riding center. SUBJECTS: The subjects comprised 9 adults (5 female, 4 males) with a mean age 76.4 years (range 71-83 years). INTERVENTIONS: This included an 8-week observation period followed by an 8-week TR program consisting of 1 hour per week of supervised horseback riding and an 8-week follow up period. SUBJECTS received balance testing at weeks 0, 8, 16, and 24 using the Fullerton Advanced Balance Scale (FABS), and quality of life was measured at weeks 8 and 16 using the Rand SF (short form) 36 quality-of-life measure. OUTCOME MEASURES: OUTCOME MEASURES were change in the FABS and Rand SF 36. RESULTS: There was no significant difference in balance scores between the start and end of the observation period. There was a significant improvement in the balance score and perception of general health from the start to the end of the intervention period, and no significant difference between the end of the intervention and the end of study, suggesting that improvements may have been sustained. CONCLUSIONS: TR is a safe activity for older adults with mild to moderate balance deficits and leads to both improvements in balance and quality of life. Longer and larger studies to assess the benefit of equine-assisted activities on improvements in balance and reduction in fall risk are needed. PMID- 23360660 TI - Integration of traditional Chinese medicines and Western medicines for treating diabetes mellitus with coronary heart disease: a systematic review. AB - PURPOSE: Diabetes mellitus with coronary heart disease (DM with CHD) poses a health challenge to people in China and elsewhere in the world. In Traditional Chinese Medicine (TCM), DM with CHD is classified as a type of disease called Xiaoke and Xiongbi. In Asia, TCM has been used to treat Xiaoke and Xiongbi conditions for centuries, especially in China. In this study, it was evaluated whether integrated strategies incorporating both TCM and Western medicines (iTCWM) could improve the curative efficacy of DM with CHD. METHODS: An extensive search for randomized clinical trials (RCTs) published up to November 2011 in either English or Chinese about iTCWM for DM with CHD was conducted. All listings in PubMed, EMBASE, the Cochrane Library, CBM, CNKI, VIP, and the Wanfang database were included in the literature search. The quality of each trial was assessed using the Cochrane Reviewers' Handbook 5.0. Data analysis was performed by the RevMan 5.0 provided by the Cochrane Collaboration. RESULTS: After an initial selection of 207 articles, 21 RCTs and quasi-RCTs were ultimately included in the analysis for this study. All of these trials were conducted in China and published in Chinese journals. The methodological quality of the trials was low in most studies. Selection bias and measurement bias were common in all of the studies. A meta-analysis was not conducted, due to the poor quality of the available studies. CONCLUSIONS: The current state of the literature regarding the utility of iTCWM for the treatment of DM with CHD is inadequate. The poor quality of the available trials makes it difficult to draw any conclusions regarding the efficacy of iTCWM for the treatment of DM with CHD. This study highlights the paucity of reliable clinical evidence for iTCWM and the need for higher quality RCTs to be conducted in the future. PMID- 23360661 TI - RAMESES publication standards: meta-narrative reviews. AB - BACKGROUND: Meta-narrative review is one of an emerging menu of new approaches to qualitative and mixed-method systematic review. A meta-narrative review seeks to illuminate a heterogeneous topic area by highlighting the contrasting and complementary ways in which researchers have studied the same or a similar topic. No previous publication standards exist for the reporting of meta-narrative reviews. This publication standard was developed as part of the RAMESES (Realist And MEta-narrative Evidence Syntheses: Evolving Standards) project. The project's aim is to produce preliminary publication standards for meta-narrative reviews. METHODS: We (a) collated and summarized existing literature on the principles of good practice in meta-narrative reviews; (b) considered the extent to which these principles had been followed by published reviews, thereby identifying how rigor may be lost and how existing methods could be improved; (c) used a three-round online Delphi method with an interdisciplinary panel of national and international experts in evidence synthesis, meta-narrative reviews, policy and/or publishing to produce and iteratively refine a draft set of methodological steps and publication standards; (d) provided real-time support to ongoing meta narrative reviews and the open-access RAMESES online discussion list so as to capture problems and questions as they arose; and (e) synthesized expert input, evidence review and real-time problem analysis into a definitive set of standards. RESULTS: We identified nine published meta-narrative reviews, provided real-time support to four ongoing reviews and captured questions raised in the RAMESES discussion list. Through analysis and discussion within the project team, we summarized the published literature, and common questions and challenges into briefing materials for the Delphi panel, comprising 33 members. Within three rounds this panel had reached consensus on 20 key publication standards, with an overall response rate of 90%. CONCLUSION: This project used multiple sources to draw together evidence and expertise in meta-narrative reviews. For each item we have included an explanation for why it is important and guidance on how it might be reported. Meta-narrative review is a relatively new method for evidence synthesis and as experience and methodological developments occur, we anticipate that these standards will evolve to reflect further theoretical and methodological developments. We hope that these standards will act as a resource that will contribute to improving the reporting of meta-narrative reviews. PMID- 23360663 TI - [Chickenpox: a cause of acute respiratory distress syndrome to bear in mind]. AB - The authors report a case of chickenpox (varicella) in an adult, complicated by acute respiratory distress syndrome and resulting in death. PMID- 23360664 TI - Switching transport through nanopores with pH-responsive polymer brushes for controlled ion permeability. AB - Several nanoporous platforms were functionalized with pH-responsive poly(methacrylic acid) (PMAA) brushes using surface-initiated atom transfer radical polymerization (SI-ATRP). The growth of the PMAA brush and its pH responsive behavior from the nanoporous platforms were confirmed by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and atomic force microscopy (AFM). The swelling behavior of the pH-responsive PMAA brushes grafted only from the nanopore walls was investigated by AFM in aqueous liquid environment with pH values of 4 and 8. AFM images displayed open nanopores at pH 4 and closed ones at pH 8, which rationalizes their use as gating platforms. Ion conductivity across the nanopores was investigated with current voltage measurements at various pH values. Enhanced higher resistance across the nanopores was observed in a neutral polymer brush state (lower pH values) and lower resistance when the brush was charged (higher pH values). By adding a fluorescent dye in an environment of pH 4 or pH 8 at one side of the PMAA-brush functionalized nanopore array chips, diffusion across the nanopores was followed. These experiments displayed faster diffusion rates of the fluorescent molecules at pH 4 (PMAA neutral state, open pores) and slower diffusion at pH 8 (PMAA charged state, closed pores) showing the potential of this technology toward nanoscale valve applications. PMID- 23360662 TI - Response prediction to antidepressants using scalp and source-localized loudness dependence of auditory evoked potential (LDAEP) slopes. AB - The loudness-dependence of the auditory evoked potential (LDAEP) slope may be inversely related to serotonin (5-HT) neurotransmission. Thus, steep LDAEPs tend to predict a positive response to selective serotonin reuptake inhibitor (SSRI) antidepressants, which augment 5-HT. However, LDAEPs also predict outcome to antidepressants indirectly altering 5-HT (e.g. bupropion). Hence, the LDAEP's predicative specificity and sensitivity to antidepressant response/outcome remains elusive. Scalp N1, P2 and N1/P2 LDAEP slopes and standardized low resolution brain electromagnetic tomography (sLORETA)-localized N1 and P2 LDAEP slopes were assessed in depressed individuals (N=51) at baseline, 1 and 12 weeks post-treatment with one of three antidepressant regimens [escitalopram (ESC)+bupropion (BUP), ESC or BUP]. Clinical response was greatest with ESC+BUP at week 1. Treatment responders had steep N1 sLORETA-LDAEP baseline slopes while non-responders had shallow ones. P2 sLORETA-LDAEP slope increases at 1 week existed in responders; decreases were noted in non-responders. Exploratory analyses indicated that more BUP and ESC responders versus non-responders had steep baseline N1 sLORETA-LDAEP slopes. Additionally, slight decreases in scalp P2 LDAEP by week 1 existed for ESC treatment, while slope increases existed with ESC+BUP treatment. Only baseline N1 sLORETA-LDAEP discriminated treatment responders/non-responders. This work confirms that certain LDAEP measures are associated with treatment outcome and appear to be differentially modulated with varying antidepressant drug regimens, though this should be confirmed using larger samples. PMID- 23360666 TI - The longitudinal association of young children's everyday routines to sleep duration. AB - INTRODUCTION: Everyday routines promote children's health. In the present study, we examined whether children's participation in everyday routines at ages 4 and 6 years predicted their sleep duration at age 6 years. METHOD: A secondary analysis of data was performed for 177 families who participated in the Rochester Preschool Children Injuries Study. Mothers were interviewed when their children were ages 4 and 6 years and reported on their children's everyday routines and perceived sleep duration. Relationships were examined by multiple hierarchical regression analysis. RESULTS: It was found that children who participated in more frequent routines at age 4 years were more likely to do so at age 6 years. Children's inadequate sleep duration at age 6 years was predicted by less frequent routines at age 6 years and by inadequate sleep duration at age 4 years after controlling for mothers' ethnicity, mothers' education, and family structure. An indirect relationship of routines at age 4 years to sleep at age 6 years through routines at age 6 years was found. DISCUSSION: Continuous engagement in everyday routines seems to play an important role in children's sleep acquisition. PMID- 23360665 TI - Evolution of ancient functions in the vertebrate insulin-like growth factor system uncovered by study of duplicated salmonid fish genomes. AB - Whole-genome duplication (WGD) was experienced twice by the vertebrate ancestor (2 rounds; 2R), again by the teleost fish ancestor (3R) and most recently in certain teleost lineages (4R). Consequently, vertebrate gene families are often expanded in 3R and 4R genomes. Arguably, many types of "functional divergence" present across 2R gene families will exceed that between 3R/4R paralogs of genes comprising 2R families. Accordingly, 4R offers a form of replication of 2R. Examining whether this concept has implications for molecular evolutionary research, we studied insulin-like growth factor (IGF) binding proteins (IGFBPs), whose six 2R family members carry IGF hormones and regulate interactions between IGFs and IGF1-receptors (IGF1Rs). Using phylogenomic approaches, we resolved the complete IGFBP repertoire of 4R-derived salmonid fishes (19 genes; 13 more than human) and established evolutionary relationships/nomenclature with respect to WGDs. Traits central to IGFBP action were determined for all genes, including atomic interactions in IGFBP-IGF1/IGF2 complexes regulating IGF-IGF1R binding. Using statistical methods, we demonstrate that attributes of these protein interfaces are overwhelming a product of 2R IGFBP family membership, explain 49 68% of variation in IGFBP mRNA concentration in several different tissues, and strongly predict the strength and direction of IGFBP transcriptional regulation under differing nutritional states. The results support a model where vertebrate IGFBP family members evolved divergent structural attributes to provide distinct competition for IGFs with IGF1Rs, predisposing different functions in the regulation of IGF signaling. Evolution of gene expression then acted to ensure the appropriate physiological production of IGFBPs according to their structural specializations, leading to optimal IGF-signaling according to nutritional-status and the endocrine/local mode of action. This study demonstrates that relatively recent gene family expansion can facilitate inference of functional evolution within ancient genetic systems. PMID- 23360667 TI - Clausenawallines G-K, carbazole alkaloids from Clausena wallichii twigs. AB - Five carbazole alkaloids, clausenawallines G-K (1-5), along with 12 known alkaloids (6-17) were isolated from the twigs of Clausena wallichii. Their structures were established using spectroscopic methods and the antibacterial activity of compounds 1-5 was evaluated. PMID- 23360668 TI - An Evaluation of Community Assessment for Public Health Emergency Response (CASPER) in North Carolina, 2003-2010. AB - INTRODUCTION: Community Assessment for Public Health Emergency Response (CASPER) is a group of tools and methods designed by the US Centers for Disease Control and Prevention (CDC) to provide rapid, reliable, and accurate population-based public health information. Since 2003, North Carolina public health professionals have used CASPERs to facilitate public health emergency responses and gather information on other topics including routine community health assessments. PROBLEM: To date, there has been no evaluation of CASPER use by public health agencies at the state or local level in the US. METHODS: Local health departments of North Carolina reported when and how CASPERs were used during the period 2003 to 2010 via an online survey. Data on barriers and future plans for using CASPERs also were collected. RESULTS: Fifty-two of North Carolina's 85 local health departments (61%) completed the survey. Twenty-eight departments reported 46 instances of CASPER use during 2003 to 2010. The majority of CASPERs were performed for community health assessments (n = 20, 43%) or exercises (n = 11, 24%). Fifty-six percent of respondents indicated they were "likely" or "very likely" to use CASPERs in the future; those who had prior experience with CASPERs were significantly more likely (P = .02) to report planned future use of CASPERs compared to those without prior experience with the tool. Lack of training, equipment, and time were the most frequently reported barriers to using CASPERs. CONCLUSIONS: Local public health agencies with clear objectives and goals can effectively use CASPERs in both routine public health practice and disaster settings. PMID- 23360669 TI - Three-dimensional transoesophageal echocardiography for the assessment of clip attachment to the leaflets in percutaneous edge-to-edge repair of the mitral valve. AB - AIMS: Single leaflet clip attachment (SLA) is a prevalent complication in percutaneous edge-to-edge repair of the mitral valve, leading to the recurrence of significant mitral regurgitation. The objective of this retrospective analysis was to evaluate a novel 3-D transoesophageal echocardiographic method for the assessment of clip attachment to the mitral leaflets. METHODS AND RESULTS: We analysed a total of 87 patients treated for symptomatic mitral regurgitation. In 47 patients, clip attachment to the leaflets was assessed by conventional 2-D transoesophageal echocardiography supported by biplane TEE images (biplane TEE group). In 40 patients, clip attachment to the leaflets was assessed by the intraprocedural 3-D volume method in addition to the conventional method (volumetric TEE group). The primary endpoint was defined as clip complications consisting of SLA and clip displacement at any time after clip implantation. Clip complications occurred in nine patients (19.1%) in the biplane TEE group and in two patients (5%) in the volumetric TEE group (p=0.06). Regarding the grade of mitral regurgitation, in the follow-up period we observed a more pronounced deterioration in the biplane TEE group than in the volumetric TEE group. CONCLUSIONS: These findings suggest that the additional use of 3-D volumetric transoesophageal echocardiography for the assessment of clip attachment to the mitral leaflets may contribute to a reduced rate of subsequent clip complications. PMID- 23360670 TI - Accelerated exon evolution within primate segmental duplications. AB - BACKGROUND: The identification of signatures of natural selection has long been used as an approach to understanding the unique features of any given species. Genes within segmental duplications are overlooked in most studies of selection due to the limitations of draft nonhuman genome assemblies and to the methodological reliance on accurate gene trees, which are difficult to obtain for duplicated genes. RESULTS: In this work, we detected exons with an accumulation of high-quality nucleotide differences between the human assembly and shotgun sequencing reads from single human and macaque individuals. Comparing the observed rates of nucleotide differences between coding exons and their flanking intronic sequences with a likelihood-ratio test, we identified 74 exons with evidence for rapid coding sequence evolution during the evolution of humans and Old World monkeys. Fifty-five percent of rapidly evolving exons were either partially or totally duplicated, which is a significant enrichment of the 6% rate observed across all human coding exons. CONCLUSIONS: Our results provide a more comprehensive view of the action of selection upon segmental duplications, which are the most complex regions of our genomes. In light of these findings, we suggest that segmental duplications could be subjected to rapid evolution more frequently than previously thought. PMID- 23360671 TI - Haematuria after prostate brachytherapy. AB - OBJECTIVE: To characterize the incidence and clinical history of gross haematuria after prostate brachytherapy. To identify treatment risk factors for the development of gross haematuria in this setting. PATIENTS AND METHODS: We reviewed haematuria outcomes collected prospectively in 2454 patients treated with transperineal prostate brachytherapy over a 20-year period at a single institution. Patients were followed for a median of 5.9 years. The association of haematuria with age, pretreatment PSA, ethnicity, clinical tumour stage, Gleason score, prostate volume, isotope (iodine 125 or palladium 103), biologically effective dose (BED), external beam radiation, androgen deprivation, development of urinary retention and occurrence of biochemical failure was investigated. RESULTS: A total of 218 men (8.9%) reported gross haematuria at a median time of 772.2 days after implantation. Haematuria was associated with prostate volume >40 cm(3) (P < 0.01), use of external beam radiation (P < 0.01), Gleason score >7 (P = 0.037), Asian ethnicity (P < 0.001), BED >200 Gy (P = 0.01), and freedom from biochemical failure (P = 0.004). On multivariate analysis, prostate volume >40 cm(3) (P = 0.002), external beam radiation, (P = 0.001), and freedom from biochemical failure (P = 0.035) were predictors of haematuria. CONCLUSIONS: Late gross haematuria was observed in a small proportion of men after brachytherapy and may occur with considerable latency. Larger prostate glands, freedom from biochemical failure and external beam radiation are risk factors. PMID- 23360672 TI - Patients' attitudes towards privacy in a Nepalese public hospital: a cross sectional survey. AB - BACKGROUND: Many people in western countries assume that privacy and confidentiality are features of most medical consultations. However, in many developing countries consultations take place in a public setting where privacy is extremely limited. This is often said to be culturally acceptable but there is little research to determine if this is true. This research sought to determine the attitudes of patients in eastern Nepal towards privacy in consultations. A structured survey was administered to a sample of patients attending an outpatients department in eastern Nepal. It asked patients about their attitudes towards physical privacy and confidentiality of information. FINDINGS: The majority of patients (58%) stated that they were not comfortable having other patients in the same room. A similar percentage (53%) did not want other patients to know their medical information but more patients were happy for nurses and other health staff to know (81%). Females and younger patients were more concerned to have privacy. CONCLUSION: The results challenge the conventional beliefs about patients' privacy concerns in Nepal. They suggest that consideration should be given to re-organising existing outpatient facilities and planning future facilities to enable more privacy. The study has implications for other countries where similar conditions prevail. There is a need for more comprehensive research exploring this issue. PMID- 23360674 TI - Genetic variation may modify ovarian reserve in female childhood cancer survivors. AB - STUDY QUESTION: Are genetic polymorphisms, previously identified as being associated with age at menopause in the healthy population, associated with ovarian reserve and predicted age at menopause in adult long-term survivors of childhood cancer? SUMMARY ANSWER: The CT genotype of rs1172822 in the BRSK1 gene is associated with lower serum anti-Mullerian hormone (AMH) levels and a younger predicted age at menopause in adult survivors of childhood cancer. WHAT IS KNOWN ALREADY: Gonadotoxicity is a well-known late side effect of chemotherapy and radiotherapy in adult survivors of childhood cancer. In the healthy population, several genetic polymorphisms are associated with age at natural menopause. Currently, data on the impact of previously identified variants in gene loci associated with ovarian reserve in adult long-term survivors of childhood cancer are lacking. STUDY DESIGN, SIZE, DURATION: We performed a pilot study in a single centre cohort of adult female Caucasian childhood cancer survivors (n = 176). PARTICIPANTS/MATERIALS, SETTING, METHODS: We determined serum AMH levels (a marker of ovarian reserve) in adult survivors of childhood cancer (n = 176) and studied single nucleotide polymorphisms (SNPs) previously reported to be associated with age at natural menopause: BRSK1 (rs1172822), ARHGEF7 (rs7333181), MCM8 (rs236114), PCSK1 (rs271924), IGF2R (rs9457827) and TNF (rs909253). Association analysis was performed using the additive genetic model. Linear regression was conducted to assess the effect of significant polymorphisms in two previously published menopause prediction models. MAIN RESULTS AND THE ROLE OF CHANCE: The CT genotype of rs1172822 in the BRSK1 (BR serine/threonine kinase 1) gene was negatively associated with serum AMH levels in our cohort (odds ratio: 3.15, 95% confidence interval: 1.35-7.32, P = 0.008) and significantly associated with the predicted age at menopause (P = 0.04). The other five SNPs were not associated with serum AMH levels. LIMITATIONS, REASONS FOR CAUTION: This is a pilot study showing preliminary data which must be confirmed. To confirm our findings and enlarge the project, a nationwide genome-wide association (GWA) project on the ovarian reserve in female survivors of childhood cancer should be performed, including a replication cohort. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support the hypothesis that previously identified genetic polymorphisms associated with age at menopause in healthy women may have an effect on the onset of menopause in female survivors of childhood cancer. Our study highlights a new aspect of the influences on the ovarian reserve after childhood cancer, which should be investigated further in a nationwide GWA study. Eventually, this information can help us to improve counselling on fertility preservation prior to cancer treatment based on genetic factors in individual patients. STUDY FUNDING AND CONFLICT OF INTEREST: W.D. is supported by the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Genovum, Merck-Serono, Organon, Schering Plough and Serono. All other authors have nothing to disclose. PMID- 23360675 TI - A genetic association study of NLRP2 and NLRP7 genes in idiopathic recurrent miscarriage. AB - STUDY QUESTION: Do gene polymorphisms of two members of the human innate immune sensor nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing proteins (NLRP) family, NLRP2 and NLRP7, confer susceptibility to idiopathic recurrent miscarriage (RM)? SUMMARY ANSWER: We found a significant association of a tag single-nucleotide polymorphism (SNP) of NLRP7 (rs26949) with idiopathic RM, while a tag SNP of NLRP2 (rs127868) showed a marginally significant association. WHAT IS KNOWN ALREADY: Human NLRP2 and NLRP7 have been suggested to be maternal effect genes, regulating early embryonic development and establishment of maternal imprints. Anecdotal evidence showed women who had experienced at least three consecutive miscarriages without hydatidiform mole carried non-synonymous NLRP7 variants. Whether these two genes are associated with idiopathic RM remains obscure. STUDY DESIGN, SIZE AND DURATION: In this case controlled study, 143 women who had experienced at least two consecutive spontaneous miscarriages (n = 91 women with two miscarriages, n = 52 with three or more) and 149 controls were included between 2004 and 2010. MATERIALS, SETTING, METHODS: A total of five tag SNPs of NLRP2 and eight tag SNPs of NLRP7 were genotyped using the primer extension analysis. The deviation from the Hardy Weinberg equilibrium was checked using chi(2) analysis. The logistic odds ratios (ORs) of RM were estimated with a 95% confidence interval (CI) in multivariate analysis after maternal age adjustment. The false discovery rate (FDR) was used to adjust for multiple testing. Tests for haplotype association with RM were performed. Gene-gene interactions among loci of the two genes were evaluated by using the multifactor dimensionality reduction (MDR) method. MAIN RESULTS AND THE ROLE OF CHANCE: One tag SNP rs269949 of NLRP7 showed significant difference between patients and controls in a recessive model (FDR P = 0.0456, age-adjusted OR (AOR) = 16.49, 95% CI = 2.00-136.11 for the GG genotype). The difference was significant in patients with two consecutive miscarriages and also in those with three or more consecutive miscarriages. Meanwhile, one tag SNP of NLRP2 (rs12768) showed marginal significance between patients and controls in a co-dominant model (FDR P = 0.0505, AOR = 2.15, 95% CI = 1.29-3.58 for the AC genotype). In the haplotype analysis, NLRP2 and NLRP7 did not show any significant difference between the patients and controls. MDR test revealed that there is no significant gene-gene interaction among loci of NLRP2 and NLRP7. LIMITATIONS, REASONS FOR CAUTION: The results may be biased by heterogeneous ethnicities of the Taiwanese Han and a small sample size. The genetic loci responsible for the disease as well as their functional significance also await further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests the role of the NLRP family proteins in RM. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the National Science Council of the Republic of China (NSC-100-2314-B 006-011-MY3). None of the authors have any conflicts of interest. PMID- 23360676 TI - Anti-inflammatory effects of a special carbohydrate-whey protein cake after exhaustive cycling in humans. AB - Intense exercise induces increased levels of pro-inflammatory and anti inflammatory cytokines. Thus, the purpose of this study was to examine the effects of a special cake (consisting of carbohydrate to whey protein 3.5:1) vs. an isocaloric carbohydrate cake on inflammatory markers after exhaustive cycling in humans. Nine subjects received either the experimental or placebo cake in a counterbalanced fashion using a crossover, double-blind, repeated-measures design. They performed one trial involving a 2h exercise on a cycle ergometer at 60-65% VO2max followed by a 4h recovery and then a second trial involving an 1h exercise at 60-65% VO2max which was increased at 95% VO2max. Blood samples were collected pre-exercise, 30 min and 4h post-exercise, post-time Trial and 48 h post-time Trial. Cakes were consumed immediately post-exercise and every 1h for the next 3h. The results showed that consumption of the experimental cake reduced significantly (p<0.05), 4h post-exercise, the pro-inflammatory protein levels IL 6 and CRP compared to the control group by 50% and 46% respectively. Moreover, in the experimental cake group, the level of the anti-inflammatory cytokine IL-10 was higher by 118%, 4h post-exercise, compared to the control group but not statistically significant. PMID- 23360677 TI - RAMESES publication standards: realist syntheses. AB - BACKGROUND: There is growing interest in realist synthesis as an alternative systematic review method. This approach offers the potential to expand the knowledge base in policy-relevant areas - for example, by explaining the success, failure or mixed fortunes of complex interventions. No previous publication standards exist for reporting realist syntheses. This standard was developed as part of the RAMESES (Realist And MEta-narrative Evidence Syntheses: Evolving Standards) project. The project's aim is to produce preliminary publication standards for realist systematic reviews. METHODS: We (a) collated and summarized existing literature on the principles of good practice in realist syntheses; (b) considered the extent to which these principles had been followed by published syntheses, thereby identifying how rigor may be lost and how existing methods could be improved; (c) used a three-round online Delphi method with an interdisciplinary panel of national and international experts in evidence synthesis, realist research, policy and/or publishing to produce and iteratively refine a draft set of methodological steps and publication standards; (d) provided real-time support to ongoing realist syntheses and the open-access RAMESES online discussion list so as to capture problems and questions as they arose; and (e) synthesized expert input, evidence syntheses and real-time problem analysis into a definitive set of standards. RESULTS: We identified 35 published realist syntheses, provided real-time support to 9 on-going syntheses and captured questions raised in the RAMESES discussion list. Through analysis and discussion within the project team, we summarized the published literature and common questions and challenges into briefing materials for the Delphi panel, comprising 37 members. Within three rounds this panel had reached consensus on 19 key publication standards, with an overall response rate of 91%. CONCLUSION: This project used multiple sources to develop and draw together evidence and expertise in realist synthesis. For each item we have included an explanation for why it is important and guidance on how it might be reported. Realist synthesis is a relatively new method for evidence synthesis and as experience and methodological developments occur, we anticipate that these standards will evolve to reflect further methodological developments. We hope that these standards will act as a resource that will contribute to improving the reporting of realist syntheses. PMID- 23360678 TI - New Year's changes. PMID- 23360681 TI - Functionalization of graphene oxide generates a unique interface for selective serum protein interactions. AB - Potential toxicity and risk of inducing allergy and inflammation have always been a great concern of using nanomaterials in biomedicine. In this work, we investigate the serum behaviors of graphene oxide (GO) and how such behaviors are affected by its surface modification such as PEGylation. The results show that, when incubated with human sera, unfunctionalized GO adsorbs a significant amount of serum proteins and strongly induces complement C3 cleavage (part of the complement activation cascade), generating C3a/C3a(des-Arg), an anaphylatoxin involved in local inflammatory responses, whereas PEGylated nano-GO (nGO-PEG) exhibits dramatic reductions in both protein binding in general and complement C3 activation. Moreover, we uncover that PEGylation on GO nanosheets apparently generates an interesting nanointerface, evidenced by the acquired certain selectivity and increased binding capacities of nGO-PEG toward a few serum proteins. Further mass spectrometry analysis identifies six nGO-PEG binding proteins, four of which are immune-related factors, including C3a/C3a(des-Arg). A series of Western blot analysis demonstrate that nGO-PEG binds up to 2-fold amount of C3a/C3a(des-Arg) than unfunctionalized GO, and can efficiently decrease the level of C3a/C3a(des-Arg) in treated sera, preventing the normal interaction of C3a with its receptor. In a proof-of-concept experiment, we demonstrate that nGO-PEG may serve to help eliminate the C3a/C3a(des-Arg) induced by other nanomaterials such as as-made GO, indicating a new strategy to modulate the immune responses evoked by one nanomaterial through the addition of another type of nanomaterial. Our results highlight the great importance of nanobio interface in regulating the biological effects of nanomaterials. PMID- 23360680 TI - Pharmacogenomics of adverse drug reactions. AB - Considerable progress has been made in identifying genetic risk factors for idiosyncratic adverse drug reactions in the past 30 years. These reactions can affect various tissues and organs, including liver, skin, muscle and heart, in a drug-dependent manner. Using both candidate gene and genome-wide association studies, various genes that make contributions of varying extents to each of these forms of reactions have been identified. Many of the associations identified for reactions affecting the liver and skin involve human leukocyte antigen (HLA) genes and for reactions relating to the drugs abacavir and carbamazepine, HLA genotyping is now in routine use prior to drug prescription. Other HLA associations are not sufficiently specific for translation but are still of interest in relation to underlying mechanisms for the reactions. Progress on non-HLA genes affecting adverse drug reactions has been less, but some important associations, such as those of SLCO1B1 and statin myopathy, KCNE1 and drug-induced QT prolongation and NAT2 and isoniazid-induced liver injury, are considered. Future prospects for identification of additional genetic risk factors for the various adverse drug reactions are discussed. PMID- 23360682 TI - At line prediction of PUFA and biohydrogenation intermediates in perirenal and subcutaneous fat from cattle fed sunflower or flaxseed by near infrared spectroscopy. AB - NIRS potential to estimate the proportion of PUFA and their biohydrogenation products in adipose tissues from cattle fed sunflower or flaxseed was tested. Immediately after skinning, perirenal and subcutaneous fat samples from 63 steers were collected, scanned intact at 37 degrees C and 33 degrees C, respectively, over a NIR spectral range from 400 to 2498nm using benchtop equipment and then analyzed for fatty acid composition. NIRS calibrations in perirenal fat showed high predictability for total and major omega-6 and omega-3, conjugated linolenic acids, t,t-conjugated linoleic acids (CLA), non-CLA dienes and trans monounsaturated fatty acids, with R(2) (RMSECV, %) of 0.88-0.89 (0.16-0.20), 0.89 0.91 (0.07-0.08), 0.86-0.89 (0.01-0.09), 0.82 (0.07), 0.89 (0.46) and 0.86-0.88 (0.87-1.29), respectively. NIRS predictions in subcutaneous fat were less reliable, probably due to lower fatty acid variability. The results show NIRS to be a useful technique for the early, fast and relatively inexpensive estimation of proportions of fatty acids with potential human health effects in cattle perirenal fat. PMID- 23360683 TI - A mixed-methods evaluation of a pilot psychosocial intervention group for older people with schizophrenia. AB - BACKGROUND: There is a strong evidence base for psychological treatments in younger adults with schizophrenia, but limited work has been done on adapting these interventions for older people. AIMS: We describe a study of a pilot psychosocial intervention group specifically designed to meet the needs of older people with schizophrenia in NHS settings. METHOD: We used a mixed-methods approach to evaluate the group. We assessed feasibility and acceptability by monitoring uptake and retention in the study. We used a within groups design comparing participants on a range of potentially relevant outcomes at baseline and posttreatment. Treatment acceptability was also assessed by semi-structured interviews conducted at the end of treatment. RESULTS: We recruited 11 participants to the study and 7 of these completed the majority of the group sessions. At a group level participants made improvements in self-esteem and negative symptoms that were statistically significant even in this small sample. Feedback interviews suggested that participants valued the social contact provided by the group and made actual changes in their day-to-day lives as a result of attending. CONCLUSION: The intervention could offer help with some of the secondary disability associated with the diagnosis of schizophrenia and is acceptable to older adults. Further evaluation is, however, warranted. PMID- 23360684 TI - Cyanidin reverses cisplatin-induced apoptosis in HK-2 proximal tubular cells through inhibition of ROS-mediated DNA damage and modulation of the ERK and AKT pathways. AB - Cyanidin is an anthocyanin widely distributed in food diet with novel antioxidant activity. Herein, we investigated the protective effects of cyanidin on HK-2 proximal tubular cells against cisplatin-induced apoptosis and elucidated the underlying mechanisms. The results showed that cisplatin-induced apoptosis in HK 2 cells was significantly attenuated by cyanidin. The cleavage of caspases and PARP, activation of p53 and mitochondrial-mediated apoptosis pathways induced by cisplatin were effectively blocked by cyanidin. Moreover, cyanidin significantly suppressed the overproduction of ROS, and activation of ERK and AKT pathways triggered by cisplatin. Our results indicate that cyanidin exhibits therapeutic potential in prevention of cisplatin-induced nephrotoxicity. PMID- 23360685 TI - Congenital completely buried penis in boys: anatomical basis and surgical technique. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Surgical correction of the congenital completely buried penis (CCBP) is a difficult challenge and there is no unanimous consensus about the surgical 'gold standard' and patient eligibility for surgery. In the present study, dysgenetic fundiform ligaments were found to be attached to the distal or middle shaft of the penis. This abnormality can be successfully corrected by releasing the fundiform ligament and mobilising the scrotal skin to cover the length of the penile shaft. The study shows that the paucity and traction of the penile skin and an abnormal fundiform ligament are important anatomical defects in CCBP. Dorsal curve and severe shortage of penile skin in erectile conditions are the main indications for surgical correction. OBJECTIVE: To present our experience of anatomical findings for congenital completely buried penis (CCBP), which has no unanimous consensus regarding the 'gold standard' for surgical correction and patient eligibility, by providing our surgical technique and illustrations. PATIENTS AND METHODS: Between February 2006 and February 2011, 22 children with a median (range) age of 4.2 (2.5-5.8) years, with CCBP underwent surgical correction by one surgeon. Toilet training and photographs of morning erections by parents were advised before surgery. The abnormal anatomical structure of buried penis during the operation was observed. The technique consisted of the release of the fundiform ligament, fixation of the subcutaneous penile skin at the base of the degloved penis, penoscrotal Z-plasty and mobilisation of the penile and scrotal skin to cover the penile shaft. RESULTS: In reflex erectile conditions, CCBP presents varying degrees of dorsal curve and shortage of penile skin. Dysgenetic fundiform ligaments were found to be attached to the distal or middle shaft of the penis in all patients. All wounds healed well and the cosmetic outcome was good at 6-month follow-up after the repair. CONCLUSION: The appearance of the dorsal curve in CCBP mainly results from the traction of penile dorsal skin and the abnormal attachment of the fundiform ligament to the shaft. This abnormality can be successfully corrected by releasing the abnormal fundiform ligament and mobilising scrotal skin to cover the length of the penile shaft. PMID- 23360686 TI - Automated and visual analysis of commercial urinary dipsticks in dogs, cats and cattle. AB - Two dipsticks developed for human use were evaluated for routine urinalysis and for detection of proteinuria in dogs (n=101), cats (n=50) and cattle (n=100). The aims were to determine their diagnostic usefulness in dogs, cats and cattle and to compare automated versus visual methods of reading. Results obtained with automated reading correlated better with reference methods than visual reading. Correlation with the reference methods was good to excellent for automated estimation of creatinine (dog: r(s)=0.86, cat: r(s)=0.83, cattle: r(s)=0.87) and pH (dog: r(s)=0.96, cat: r(s)=0.91, cattle: rs=0.94). The correlation was good for protein (dog: r(s)=0.88, cat: r(s)=0.91), glucose (cat: r(s)=0.83) and urine protein:creatinine (UPC) ratio (dog: r(s)=0.75, cat: r(s)=0.89). Estimation of proteinuria in cattle and pyuria in cats lacked specificity and detection of isosthenuria lacked sensitivity in all species. Semiquantitative estimation of UPC ratio was specific (100% and 91.2% at a cut-off of 0.2 in cats and 0.4 in dogs, respectively). PMID- 23360687 TI - Evaluation of an autogenous vaccine in cattle against Escherichia coli bearing the CTX-M-14 plasmid. AB - Enteric bacteria with resistance to third and fourth generation cephalosporin antibiotics, especially Escherichia coli bearing the blaCTX-M gene, have been detected in a wide range of food producing animals. However, commercial vaccines for these organisms are not currently available. An autogenous vaccine was prepared from E. coli bearing the blaCTX-M-14 gene and evaluated as a potential control measure to reduce shedding and dissemination of these organisms in cattle. Calves (n=30) received either an autogenous vaccine prepared from E. coli serotype O33 bearing the blaCTX-M-14 gene or a placebo by intramuscular injection on three separate occasions. Two weeks after the final vaccination, all calves were challenged by oral gavage with the O33 CTX-M-14 strain of E. coli (1*10(10) CFU). Faeces, intestinal mucosa and blood samples were taken for enumeration of total and CTX-M-14 E. coli and for assessment of the humoral immune response. The cumulative number of total E. coli excreted at 7 days post-challenge was significantly (p=0.006) lower in the vaccinated group than the placebo group. However, there was no significant difference in the shedding of either CTX-M-14 E. coli or total E. coli between vaccinated and placebo calves throughout the study period. The systemic immune response to E. coli O33 antigen was tested by ELISA and was significantly higher (p<0.001) in vaccinated than placebo calves. However, there was no significant difference in the mucosal immune response. These findings do not support the use of autogenous vaccination for the control of CTX-M-14 E. coli in calves. PMID- 23360688 TI - Accuracy of vertical height measurements on direct digital panoramic radiographs using posterior mandibular implants and metal balls as reference objects. AB - OBJECTIVES: Conventional panoramic radiography, a widely used radiographic examination tool in implant treatment planning, allows evaluation of the available bone height before inserting posterior mandibular implants. Image distortion and vertical magnification due to projection geometry is well described for rotational panoramic radiographs. To assess the accuracy of vertical height measurements on direct digital panoramic radiographs, implants and metal balls positioned in the posterior mandible were used as radio-opaque reference objects. The reproducibility of the measuring method was assessed by the inter- and intraobserver agreements. METHODS: Direct digital panoramic radiographs, performed using a Kodak 8000C (Eastman Kodak Company, Rochester, NY), of 17 partially edentulous patients (10 females, 7 males, mean age 65 years) were selected from an X-ray database gathered during routine clinical evaluation of implant sites. Proprietary software and a mouse-driven calliper were used to measure the radiological length of 25 implants and 18 metal reference balls, positioned in mandibular posterior segments. The distortion ratio (DR) was calculated by dividing the radiological implant length by the implant's real length and the radiological ball height by the ball's real height. RESULTS: Mean vertical DR was 0.99 for implants and 0.97 for balls, and was unrelated to mandibular sites, side, age, gender or observer. Inter- and intraobserver agreements were acceptable for both reference objects. CONCLUSIONS: Vertical measurements had acceptable accuracy and reproducibility when a software-based calibrated measurement tool was used, confirming that digital panoramic radiography can be reliably utilized to determine the pre-operative implant length in premolar and molar mandibular segments. PMID- 23360689 TI - Cardioembolic stroke related to limb-girdle muscular dystrophy 1B. AB - BACKGROUND: Cardioembolic stroke is an under-recognized complication in patients with limb-girdle muscular dystrophy 1B. Here we present a young stroke patient who had a novel lamin A/C gene (LMNA) mutation. CASE PRESENTATION: This is a 39 year-old man who had slowly progressive proximal muscle weakness and cardiac arrhythmia since adolescent and a family history of similar manifestation. He sustained acute ischemic stroke in the left middle cerebral artery territory. Intravenous recombinant tissue plasminogen activator therapy was given with significant neurological improvement. Additionally, genetic sequencing of the LMNA gene of the patient identified a mutation in c.513+1 G>A that resulted in a splicing aberration. CONCLUSION: We suggested that LMNA gene related myopathies should be considered in young stroke patients with long-standing myopathic features. PMID- 23360690 TI - Six-month and one-year clinical outcomes after placement of a dedicated coronary bifurcation stent: a patient-level pooled analysis of eight registry studies. AB - AIMS: Smaller studies have previously shown promising results after Tryton Side Branch StentTM (Tryton Medical, Durham, NC, USA) placement. However, these previous studies were limited by their small sample size and relatively short follow-up. We performed a patient-level pooled analysis to evaluate six-month and one year clinical outcomes of more than 900 patients who were enrolled in eight registries with the Tryton stent. METHODS AND RESULTS: Data from eight Tryton registries, including 905 patients with 929 bifurcation lesions, were pooled on a patient level to form one dataset. The primary outcome was six-month target vessel failure (TVF), defined as the composite of cardiac death, any myocardial infarction, and clinically indicated target vessel revascularisation. Procedural success was defined as successful stent placement and no in-hospital major adverse cardiac events. Multivariable analysis was performed to determine independent predictors for one-year TVF. Follow-up data were available in 97%. Procedural success was 95% and TVF rate was 6.5% at six months and 8.5% at one year. Stent thrombosis occurred in 0.5% of patients. Left main coronary artery bifurcation lesion (HR 6.46) and main branch reference vessel diameter <3.0 mm (HR 2.62) were independent predictors for TVF. CONCLUSIONS: In the real world setting of registries including more than 900 patients, the use of the Tryton stent is associated with procedural and mid-term clinical results that compare very favourably with historical studies. The primary endpoint of TVF was primarily determined by reference vessel diameter of the main branch and left main bifurcation lesion location. PMID- 23360691 TI - Meta-narrative and realist reviews: guidance, rules, publication standards and quality appraisal. AB - Recently, there has been an expansion of different forms of systematic review of research and the development of guidance and standards about particular types of review. These reviews can be best understood within a broad framework of the dimensions on which reviews differ, and how the review methodology relates to the methodology of primary research. Similarly, publication standards can be understood in terms of their relation to other standards such as guidance and rules for undertaking reviews and systems for appraising the quality of reviews. This commentary is written with special reference to the publication standards for meta-narrative and realist reviews being published in BMC Medicine.See related research articles http://www.biomedcentral.com/1741-7015/11/20 and http://www.biomedcentral.com/1741-7015/11/21. PMID- 23360692 TI - Lutein supplementation improves visual performance in Chinese drivers: 1-year randomized, double-blind, placebo-controlled study. AB - OBJECTIVES: Although it is known that the carotenoid lutein can affect visual performance, we still have much to learn about its effect in occupational populations, like drivers. The aim of this study was to examine the effect of lutein supplementation on visual function in healthy drivers with long-term light exposure. METHODS: The study was a randomized, double-blind, placebo-controlled, 1-y intervention study. It included 120 normal participants (drivers). The active (A) group consumed 20 mg of lutein daily. Participants were assessed at baseline, 1, 3, 6, and 12 mo (V0, V1, V2, V3, and V4, respectively). Assessment included visual acuity, serum lutein concentrations, macular pigment optical density (MPOD), and visual performance. At the onset and at the end of the intervention, dietary intakes of lutein and visual-related quality of life were measured. RESULTS: There was a trend (in the active group) toward an increase in best spectacle-corrected visual acuity measured, but there were no significant differences. Serum lutein and central MPOD in the active group increased significantly, whereas no change was observed in the placebo group. We observed significant increases in contrast and glare sensitivity, especially in the mesopic condition. There were significant improvements in the score of the National Eye Institute 25-Item Visual Functioning Questionnaire driving subscale in the active group. CONCLUSIONS: Daily supplementation with 20 mg of lutein increases MPOD levels. Lutein may benefit driving at night and other spatial discrimination tasks carried out under low illumination. PMID- 23360693 TI - MicroCT versus sTSLIM 3D imaging of the mouse cochlea. AB - We made a qualitative and quantitative comparison between a state-of-the-art implementation of micro-Computed Tomography (microCT) and the scanning Thin-Sheet Laser Imaging Microscopy (sTSLIM) method, applied to mouse cochleae. Both imaging methods are non-destructive and perform optical sectioning, respectively, with X rays and laser light. MicroCT can be used on fresh or fixed tissue samples and is primarily designed to image bone rather than soft tissues. It requires complex back-projection algorithms to produce a two-dimensional image, and it is an expensive instrument. sTSLIM requires that a specimen be chemically fixed, decalcified, and cleared; but it produces high-resolution images of soft and bony tissues with minimum image postprocessing and is less expensive than microCT. In this article, we discuss the merits and disadvantages of each method individually and when combined. PMID- 23360695 TI - Effect of nutrition education intervention based on Pender's Health Promotion Model in improving the frequency and nutrient intake of breakfast consumption among female Iranian students. AB - OBJECTIVE: To determine the effectiveness of nutrition education intervention based on Pender's Health Promotion Model in improving the frequency and nutrient intake of breakfast consumption among female Iranian students. DESIGN: The quasi experimental study based on Pender's Health Promotion Model was conducted during April-June 2011. Information (data) was collected by self-administered questionnaire. In addition, a 3 d breakfast record was analysed. P < 0.05 was considered significant. SETTING: Two middle schools in average-income areas of Qom, Iran. SUBJECTS: One hundred female middle-school students. RESULTS: There was a significant reduction in immediate competing demands and preferences, perceived barriers and negative activity-related affect constructs in the experimental group after education compared with the control group. In addition, perceived benefit, perceived self-efficacy, positive activity-related affect, interpersonal influences, situational influences, commitment to a plan of action, frequency and intakes of macronutrients and most micronutrients of breakfast consumption were also significantly higher in the experimental group compared with the control group after the nutrition education intervention. CONCLUSIONS: Constructs of Pender's Health Promotion Model provide a suitable source for designing strategies and content of a nutrition education intervention for improving the frequency and nutrient intake of breakfast consumption among female students. PMID- 23360694 TI - Expression patterns suggest that despite considerable functional redundancy, galectin-4 and -6 play distinct roles in normal and damaged mouse digestive tract. AB - The galectin-4 protein is mostly expressed in the digestive tract and is associated with lipid raft stabilization, protein apical trafficking, wound healing, and inflammation. While most mammalian species, including humans, have a single Lgals4 gene, some mice have two paralogues: Lgals4 and Lgals6. So far, their significant similarities have hindered the analysis of their respective expression and function. We took advantage of two antibodies that discriminate between the galectin-4 and galectin-6 proteins to document their patterns of expression in the normal and the dextran sodium sulfate (DSS)-damaged digestive tract in the mouse. In the normal digestive tract, their pattern of expression from tongue to colon is quite similar, which suggests functional redundancy. However, the presence of galectin-4, but not galectin-6, in the lamina propria of the DSS-damaged colon, its association with luminal colonic bacteria, and differences in subcellular localization of these proteins suggest that they also have distinct roles in the normal and the damaged mouse digestive tract. Our results provide a rare example of ancestral and derived functions evolving after tandem gene duplication. PMID- 23360696 TI - Extracorporeal shockwave lithotripsy to distal ureteric stones: the transgluteal approach significantly increases stone-free rates. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Shockwave lithotripsy (SWL) can be used to treat stones at any position within the ureter, as long as the stone is radio-opaque and there is a path for the shockwave to reach the stone. However the results of SWL to distal ureteric calculi, with the patient in a prone position, were inferior to those of treating stones within the upper ureter. The transguteal approach allows the lithotripsy shockwave to reach the lower ureter via the greater selatle foramen. This study shows that this approach for SWL to distal ureteric calculi is more effective than the prone approach. OBJECTIVE: To compare the outcomes of extracorporeal shockwave lithotripsy (ESWL) for distal ureteric stones treated using the prone and transgluteal (supine) approaches in a tertiary referral stone unit using a fourth generation lithotriptor. PATIENTS AND METHODS: We selected consecutive patients undergoing ESWL to distal ureteric stones over 1 year, during which we changed our treatment protocol from a prone to transgluteal (supine) approach. Patients were treated using the Sonolith Vision Lithotriptor (Technomed Medical Systems, Vaulx-en Velin, France). Outcome was assessed using plain abdominal film of kidney, ureter and bladder (KUB) X-ray taken at 2 weeks then monthly as required. Treatment success was defined as complete clearance of stone fragments and treatment failure was defined as persistence of stone fragments beyond 3 months or the need for ureteroscopy. RESULTS: A total of 38 patients were treated in the prone position and 72 patients using a transgluteal approach. Patient and stone characteristics were identical in both groups. The mean (range) stone size was 7.8 (4-16) mm. The proportions of patients who were stone-free after one treatment session within the prone and transgluteal treatment groups were 40 and 78%, respectively (<0.001). The overall success rates for treatment within the prone and transgluteal groups were 63 and 92%, respectively (<0.001). CONCLUSIONS: Transgluteal ESWL to stones within the distal ureter leads to significantly higher stone-free rates than treatment using the prone approach. The majority of patients are rendered stone-free after one session of treatment and the overall success rates are similar to those of ureteroscopic management. PMID- 23360697 TI - Metastatic breast cancer epidemiology and management with a focus on taxanes. AB - Although considerable treatment advances have been made since the early 2000s, metastatic breast cancer (MBC) continues to provide challenges for patients and healthcare providers. The responsibilities of nurses regarding the management of MBC are extensive. Among other things, nurses must provide patient education, understand treatment administration, and have the ability to perform patient assessments, as well as identify and manage symptoms. The taxanes paclitaxel, docetaxel, and nab-paclitaxel are a class of microtubule-stabilizing agents that are highly active against MBC but have many differences among them (e.g., formulation, administration, efficacy, tolerability profiles). Understanding those differences will aid in improving the overall patient experience. This supplement provides a historical overview of taxanes, examines the differences in their administration, and defines their efficacy and safety profiles and effects on patient quality of life. In addition, methods for assessing taxane-induced neuropathy are discussed from the nursing perspective, and treatment considerations for older adult patients with MBC are provided. PMID- 23360698 TI - Evolution of taxanes in the treatment of metastatic breast cancer. AB - Taxanes have become effective therapies for patients with metastatic breast cancer (MBC); however, understanding the differences among them is important. Each of the taxanes currently approved for treating MBC has a unique formulation, which translates to differences in toxicity profiles and administration considerations. In this article, the rationale for the development of the taxanes paclitaxel, docetaxel, and nab-paclitaxel is reviewed from a historical perspective. The mechanisms of action, formulations, and indications of taxanes also are discussed. The impact of their formulations on clinical practice and patient care, particularly solvent-based versus novel solvent-free formulations, will be reviewed from the nursing perspective. PMID- 23360699 TI - Taxanes as a first-line systemic treatment in metastatic breast cancer. AB - First-line treatment of metastatic breast cancer (MBC) is an important therapeutic setting. Effective treatment of MBC in the initial setting can extend a patient's life and provide significant improvements in quality of life. The taxanes paclitaxel, docetaxel, and nab-paclitaxel have been investigated as first line therapy for MBC requiring chemotherapy in numerous trials. Results from these trials have demonstrated that taxanes are effective treatments in MBC but also have highlighted differences in their toxicity profiles. Those differences must be taken into consideration when deciding the appropriate treatment for each patient. This article explores the differences among the agents in efficacy and safety in the first-line setting for treating MBC. In addition, administration concerns unique to each taxane are discussed. PMID- 23360700 TI - Current methods for the assessment and management of taxane-related neuropathy. AB - Taxane-induced peripheral neuropathy (TIPN) affects a number of patients with breast cancer. To properly manage these patients, nurses must be able to identify and assess TIPN, as well as educate patients on TIPN as a side effect of taxane therapy. This article provides practical suggestions regarding how nurses can incorporate clinically feasible measurement approaches into practice and includes examples of grading TIPN that illustrate the limitations of the current tools and techniques for assessment. For example, a shortened and revised version of the Total Neuropathy Score and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity subscale should be considered for future use. In addition, neuropathy-related results from numerous phase III trials in breast cancer are discussed, and the latest evidence regarding pharmacologic interventions for TIPN is briefly summarized. PMID- 23360701 TI - Quality-of-life considerations with taxane-based therapy in metastatic breast cancer. AB - As with many other types of chemotherapy, taxanes are associated with side effects that can affect patients' quality of life. One of the major side effects of taxane therapy is taxane-induced peripheral neuropathy (TIPN). The development of TIPN is accompanied by troublesome burning, tingling, and numbness; TIPN also can affect patient safety because of the decreased ability to perceive sensations (e.g., pain, heat). Pain and fatigue are common side effects of taxane therapy. These particular symptoms may hinder patients from working or performing daily activities, thus affecting quality of life. This case vignette provides an example of the symptoms that can accompany taxane therapy, including TIPN. The case vignette also demonstrates the long-lasting effects that TIPN can have on patients receiving taxane-based therapy, as well as the hindrance to the ability to work and perform daily activities because of numbness, pain, and fatigue. In addition, identification and management of taxane-related side effects are explored from the nursing perspective, and important aspects of patient education are discussed. PMID- 23360702 TI - Special considerations in the management of older adult patients with metastatic breast cancer. AB - A majority of new cancer cases occur in older adults (aged 65 years and older); however, older adult patients often are underrepresented in clinical trials. Because of this, sufficient evidence is lacking for the creation of treatment guidelines for older adult patients. Evidence has shown that many therapeutic agents are effective in both older and younger adult patients. Although efficacy outcomes may be similar, safety profiles may differ by age because of inherent differences in drug metabolism or other reasons. The underrepresentation of older adult patients in clinical trials is explored in this article, along with the current recommendations for treating older adult patients with metastatic breast cancer (MBC). In addition, current evidence from clinical trials and subanalyses of older adult patients with MBC are discussed. Finally, nursing considerations for the management of older adult patients with MBC are provided. PMID- 23360703 TI - Catalytic and atmospheric effects on microwave pyrolysis of corn stover. AB - Corn stover, which is one of the most abundant agricultural residues around the world, could be converted into valuable biofuels and bio based products by means of microwave pyrolysis. After the reaction at the microwave power level of 500W for the processing time of 30min, the reaction performance under N2 atmosphere was generally better than under CO2 atmosphere. This may be due to the better heat absorbability of CO2 molecules to reduce the heat for stover pyrolysis. Most of the metal-oxide catalysts effectively increased the maximum temperature and mass reduction ratio but lowered the calorific values of solid residues. The gas most produced was CO under N2 atmosphere but CO2 under CO2 atmosphere. Catalyst addition lowered the formation of PAHs and thus made liquid products less toxic. More liquid products and less gas products were generated when using the catalysts possibly due to the existence of the Fischer-Tropsch synthesis. PMID- 23360704 TI - Polymerisation of Kraft lignin from black liquors by laccase from Myceliophthora thermophila: effect of operational conditions and black liquor origin. AB - The capacity of laccase from Myceliophthora thermophila to promote the oxidative polymerisation of Kraft lignin (KL) was evaluated in several conditions of pH, temperature, enzyme dosage and treatment time. Moreover, different black liquors from the Kraft cooking of Eucalyptus globulus and mixture of Pinus pinaster/E. globulus were evaluated in order to determine the effect of the KL source on the polymerisation reaction. Furthermore, one of these black liquors was fractionated by sequential organic solvent fractionation and the polymerisation of the corresponding fractions was tested. Polymerisation products were analysed by size exclusion chromatography and Fourier transform infrared spectroscopy. The results provide evidence of notable lignin modifications after incubation with laccase. Structural oxidation and a notably molecular weight increase were attained, reaching a polymer of 69-fold its initial molecular weight depending on the raw lignin. Moreover, optimum values of reaction conditions were obtained: pH 7.3, 70 degrees C, 2UmL(-1) and 2h. PMID- 23360705 TI - Development of a treatment system for molasses wastewater: the effects of cation inhibition on the anaerobic degradation process. AB - This study evaluated the process performance of a novel treatment system consisting of an acidification reactor, an upflow staged sludge bed (USSB) reactor, an upflow anaerobic sludge blanket reactor, and an aerobic trickling filter for the treatment of a high-strength molasses wastewater with a chemical oxygen demand (COD) of up to 120,000mg/L. The USSB operating at 35 degrees C was capable of achieving an organic loading rate of 11kgCOD/m(3) day with a methane recovery of 62.4% at an influent COD of 120,000mg/L. The final effluent COD was 4520mg/L. The system was effective with regard to nitrification and sulfur removal. Fifty percent inhibition of the bacterial activity of the retained sludge by the cations was determined at 8gK/L for sucrose degradation, 16gK/L for sulfate reduction, and 12gK/L or 9gNa/L for acetoclastic methane production. Cation inhibition of anaerobic degradation reduced the process performance of the USSB. PMID- 23360706 TI - Production of fumaric acid by immobilized Rhizopus arrhizus on net. AB - An immobilization method using net was developed for fumaric acid fermentation by Rhizopus arrhizus RH-07-13. The large surface of the net immobilized enough filamentous mycelia which produced fumaric acid rapidly. Net size and spore concentration were optimized to enhance fermentation performance and 150cm(2) of net size, 0.5*10(6)per ml of spore concentration were selected finally. Compared to free-cell fermentation, fumaric acid production was flat (32.03 vs. 31.23g/L) but fermentation time reduced 83.3% (24 vs. 144h). PMID- 23360707 TI - Furfural formation from the pre-hydrolysis liquor of a hardwood kraft-based dissolving pulp production process. AB - This study aimed to produce furfural from the PHL. Results showed best furfural yield of 32.8% and the furfural selectivity of 37.7% in the monophase system (170 degrees C, 100 min), while they were 60.1% and 69.8%, respectively in the biphase system. The lower furfural selectivity in the monophase system was explained by more side reactions, such as fragmentation, condensation reactions, resinification and others. Model compounds such as: xylose, furfural, syringaldehyde, were used to confirm/identify these side reactions. The addition of dilute sulfuric acid/acetic acid in the system under the same conditions decreased the recovery of furfural. The addition of syringaldehyde into the PHL also led to a decrease in the furfural yield, supporting the conclusion that lignin structures in the PHL may also be involved in the side reactions, thus decreasing the furfural yield. PMID- 23360708 TI - Calcined polyaniline-iron composite as a high efficient cathodic catalyst in microbial fuel cells. AB - A new type of carbon-nitrogen-metal catalyst, PANI-Fe-C, was synthesized by calcination process. According to the results of FT-IR and XPS analysis, polyaniline chain was broken by calcination. Small nitrogen-contained molecular fragments were gasified during calcination process, while the remaining nitrogen atoms were enchased in the new produced multiple carbon rings by C-N and CN bonds and performed as the catalytic active sites and the covalent centers for soluble iron components. Calculated from the polarization curves, a maximum power density of 10.17W/m(3) for the MFC with the synthetic catalyst was obtained, which was slightly higher than the MFC with Pt/C catalyst of 9.56W/m(3). All the results obtained in this paper proved that the newly synthetic nitrogen-carbon-metal catalyst would be a potential alternative to the expensive Pt/C catalyst in the field of MFC. PMID- 23360709 TI - Disruption of the GluR2/GAPDH complex protects against ischemia-induced neuronal damage. AB - BACKGROUND: Excitotoxicity and neuronal death following ischemia involve AMPA (alpha-amino-3hydroxy-5-methylisoxazole-4-propionic acid) glutamate receptors. We have recently reported that the GluR2 subunit of AMPA receptors (AMPARs) forms a protein complex with GAPDH (glyceraldehyde-3-phosphate dehydrogenase). The GluR2/GAPDH complex co-internalizes upon activation of AMPA receptors. Disruption of the GluR2/GAPDH interaction with an interfering peptide protects cells against AMPAR-mediated excitotoxicity and protects against damage induced by oxygen glucose deprivation (OGD), an in vitro model of brain ischemia. OBJECTIVE: We sought to test the hypothesis that disruption of the GluR2/GAPDH interaction with an interfering peptide would protect against ischemia-induced neuronal damage in vivo. METHOD: The rat 4-vessel occlusion (4-VO) model was used to investigate whether the GluR2/GAPDH interaction was enhanced in the hippocampus, and if our newly developed interfering peptide could protect against neuronal death in the ischemic brain area. The transient rat middle cerebral artery occlusion (tMCAo) model was used to determine whether our peptide could reduce infarction volume and improve neurological function. Finally, GAPDH lentiviral shRNA was injected into the brain to reduce GAPDH expression one week prior to tMCAo, to confirm the role of GAPDH in the pathophysiology of brain ischemia. RESULTS: The GluR2/GAPDH interaction is upregulated in the hippocampus of rats subjected to transient global ischemia. Administration of an interfering peptide that is able to disrupt the GluR2/GAPDH interaction in vivo protects against ischemia-induced cell death in rat models of global ischemia and decreases the infarct volume as well as neurological score in a rat model focal ischemia. Consistent with these observations, decreased GAPDH expression also protects against ischemia-induced cell death in an animal model of focal ischemia. CONCLUSION: Disruption of the GluR2/GAPDH interaction protects against ischemia-induced neuronal damage in vivo. The GluR2/GAPDH interaction may be a novel therapeutic target for development of treatment for ischemic stroke. PMID- 23360710 TI - Copper/zinc chelation by clioquinol reduces spinal cord white matter damage and behavioral deficits in a murine MOG-induced multiple sclerosis model. AB - The present study aimed to evaluate the therapeutic potential of clioquinol (CQ), a metal chelator, on multiple sclerosis pathogenesis. Experimental autoimmune encephalomyelitis was induced by immunization with myelin oligodendrocyte glycoprotein (MOG(35-55)) in female mice. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were analyzed. CQ (30mg/kg) was given by gavage once per day for the entire experimental course. CQ profoundly reduced the daily clinical score and incidence rate of EAE mice. The CQ-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and reduced infiltration by encephalitogenic immune cells including CD4, CD8, CD20 and F4/80 positive cells. CQ also remarkably inhibited EAE-associated BBB disruption and MMP-9 activation. Autophagy contributes to clearance of aggregated proteins in astrocytes and neurons. The present study found that EAE increased the induction of autophagy and CQ further increased this expression. Furthermore, the present study found that post-treatment with CQ also reduced the clinical score of EAE and spinal cord demyelination. These results demonstrate that CQ inhibits the clinical features and neuropathological changes associated with EAE. The present study suggests that transition metals may be involved in several steps of multiple sclerosis pathogenesis. PMID- 23360711 TI - Pretest probability assessment combined with point-of-care D-dimer testing allows primary care physicians to rule out pulmonary embolism. PMID- 23360712 TI - Quality assessment metrics for whole genome gene expression profiling of paraffin embedded samples. AB - BACKGROUND: Formalin fixed, paraffin embedded tissues are most commonly used for routine pathology analysis and for long term tissue preservation in the clinical setting. Many institutions have large archives of Formalin fixed, paraffin embedded tissues that provide a unique opportunity for understanding genomic signatures of disease. However, genome-wide expression profiling of Formalin fixed, paraffin embedded samples have been challenging due to RNA degradation. Because of the significant heterogeneity in tissue quality, normalization and analysis of these data presents particular challenges. The distribution of intensity values from archival tissues are inherently noisy and skewed due to differential sample degradation raising two primary concerns; whether a highly skewed array will unduly influence initial normalization of the data and whether outlier arrays can be reliably identified. FINDINGS: Two simple extensions of common regression diagnostic measures are introduced that measure the stress an array undergoes during normalization and how much a given array deviates from the remaining arrays post-normalization. These metrics are applied to a study involving 1618 formalin-fixed, paraffin-embedded HER2-positive breast cancer samples from the N9831 adjuvant trial processed with Illumina's cDNA-mediated Annealing Selection extension and Ligation assay. CONCLUSION: Proper assessment of array quality within a research study is crucial for controlling unwanted variability in the data. The metrics proposed in this paper have direct biological interpretations and can be used to identify arrays that should either be removed from analysis all together or down-weighted to reduce their influence in downstream analyses. PMID- 23360713 TI - Use of antenatal corticosteroids for preterm birth in Latin America: providers knowledge, attitudes and practices. AB - BACKGROUND: Antenatal corticosteroids administered to women at risk of preterm birth is an intervention which has been proved to reduce the risk of respiratory distress syndrome, intraventricular hemorrhage, and neonatal mortality. There is a significant gap in the literature regarding the prevalence of the use of antenatal corticosteroids in Latin American countries and the attitudes and opinions of providers regarding this practice. The aim of this study was to assess the knowledge, attitudes and practices of health care providers regarding the use of antenatal corticosteroids in women at risk of preterm birth in Latin America. METHODS: This was a multicenter, prospective, descriptive study conducted in maternity hospitals in Ecuador, El Salvador, Mexico and Uruguay. Physicians and midwives who provide prenatal care or intrapartum care for women delivering in the selected hospitals were approached using a self-administered questionnaire. Descriptive statistics was used. RESULTS: The percentage of use of ACT in threatened preterm labour (TPL) reported by providers varies from 70% in Mexico to 97% in Ecuador. However, 60% to 20% of the providers mentioned that they would not use this medication in women at risk and would limit its use when there was a threatened preterm labour. In only one country recommended regimens of antenatal corticosteroids are followed by around 90% of providers whereas in the other three countries recommended regimens are followed by only 21%, 61%, 69% of providers. Around 40% of providers mentioned that they would administer a new dose of corticosteroids again, regardless the patient already receiving an entire regimen. Between 11% and 35% of providers, according to the countries, mentioned that they do not have adequate information on the correct use of this medication. CONCLUSIONS: This study shows that the use of this intervention could be improved by increasing the knowledge of Latin American providers on its indications, benefits, and regimens. PMID- 23360714 TI - The impact of transcatheter aortic valve implantation on patients' profiles and outcomes of aortic valve surgery programmes: a multi-institutional appraisal. AB - OBJECTIVES: The aim of this retrospective multicenter study was to assess how the development of transcatheter aortic valve implantation (TAVI) influenced the characteristics and outcomes of patients undergoing aortic valve procedures. METHODS: We reviewed 1395 patients who underwent isolated surgical aortic valve replacement (SAVR) or TAVI in three centres with a high-volume TAVI programme. Patients were divided into two groups: 'Pre-TAVI' (395 patients, 28.3%) and 'Post TAVI' (1000 patients, 71.7%) operated on before and after the introduction of TAVI into clinical practice. We evaluated age, logistic EuroSCORE I (LES) and hospital mortality according to time periods and the procedure performed, whether SAVR or TAVI. RESULTS: 'Post-TAVI' patients were older (78.2 +/- 7.8 vs 76.8 +/- 6.7 years; P = 0.002) and with a significantly higher LES (17.8 +/- 14.7 vs 9.1 +/- 9.2%; P < 0.001) than 'Pre-TAVI' patients. Hospital mortality was not significantly different between groups ('Pre-TAVI' vs 'Post-TAVI': 2 vs 3.4%; P = 0.17). Of the 1000 'Post-TAVI' patients, 605 (60.5%) underwent TAVI and 395 (39.5%), SAVR. Patients undergoing TAVI were older (79.9 +/- 7.1 vs 75.5 +/- 9.2 years; P < 0.001) and with a higher LES (22.9 +/- 15.3 vs 9.7 +/- 9.3%; P < 0.001) than 'Post-TAVI' SAVR patients, but their hospital mortality was similar (3.9 vs 2.5%; P = 0.22). LES was similar between 'Pre-TAVI' and 'Post-TAVI' SAVR patients (9.1 +/- 9.2 vs 9.7 +/- 9.3%; P = 0.26). Furthermore, we did not find significant differences in the overall hospital mortality between SAVR and TAVI patients: 2.3 vs 3.9%, P = 0.08. CONCLUSIONS: This analysis shows that the development of TAVI has caused an increase in the preoperative risk profile of patients scheduled for aortic valve procedures (SAVR or TAVI) without increasing hospital mortality. PMID- 23360715 TI - Two-patch repair of a bicuspid aortic valve with vegetation on its raphe. AB - We report the successful repair of a bicuspid aortic valve with vegetation on its thickened raphe by using two pericardial patches. After excising the vegetation and thickened raphe, the first patch was sewn between the remaining leaflets. Another patch was then sewn at the base of the cusp to create sufficient geometrical height for good coaptation. Our two-patch technique may facilitate intraoperative accommodation of the 3-D shape of the new cusp. PMID- 23360716 TI - Prognostic value of nutritional screening tools for patients scheduled for cardiac surgery. AB - OBJECTIVES: The aim of this study was to assess the prognostic value of different nutritional screening tools in patients undergoing cardiopulmonary bypass, with regard to adverse clinical outcome. METHODS: This prospective cohort study analysed 1193 adult patients who underwent cardiopulmonary bypass. Patients were screened using five nutritional screening tools: Subjective Global Assessment (SGA), Nutritional Risk Screening 2002 (NRS-2002), Malnutrition Universal Screening Tool (MUST), Mini-Nutritional Assessment (MNA) and Short Nutritional Assessment Questionnaire (SNAQ). In-hospital mortality, postoperative complications, length of stay in intensive care unit and length of hospitalization were analysed. Multivariate backward logistic regression analysis was used to assess the independent predictive value of the studied screening tools. RESULTS: In accordance with univariate analysis, malnutrition detected by SNAQ, MUST, NRS-2002 and MNA was associated with postoperative complications (odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.3-2.4; OR 1.9, 95% CI 1.4-2.6; OR 1.8, 95% CI 1.2-2.9 and OR 1.9, 95% CI 1.4-2.6). Malnutrition detected by MUST, NRS-2002, MNA and SGA was associated with intensive care unit stay >2 days (OR 1.5, 95% CI 1.1-2.1; OR 2.3, 95% CI 1.5-3.7; OR 1.7, 95% CI 1.2 2.2 and OR 2.7, 95% CI 1.6-4.6). Prolonged hospitalization (>20 days) was predicted by SNAQ, MUST and MNA (OR 1.4, 95% CI 1-1.9; OR 1.6, 95% CI 1.2-2.2 and OR 1.6, 95% CI 1.2-2.2). In accordance with multivariate analysis, only MUST and MNA independently predicted postoperative complications (OR 1.6, 95% CI 1.1-2.3 and OR 1.6, 95% CI 1.1-2.2). Other independent factors influencing postoperative complications were well-known logistic EuroSCORE (OR 1.06, 95% CI 1-1.1) and the duration of cardiopulmonary bypass in minutes (OR 1.01, 95% CI 1-1.01). CONCLUSIONS: MUST and MNA both have independent predictive values with regard to postoperative complications. Taking into account simplicity, MUST is preferable for the cardiac surgical population. PMID- 23360718 TI - Prostate cancer screening and the management of clinically localized disease. PMID- 23360720 TI - Survival is better after lumpectomy than mastectomy in early breast cancer, US study shows. PMID- 23360719 TI - Comparison of treatment effect sizes associated with surrogate and final patient relevant outcomes in randomised controlled trials: meta-epidemiological study. AB - OBJECTIVE: To quantify and compare the treatment effect and risk of bias of trials reporting biomarkers or intermediate outcomes (surrogate outcomes) versus trials using final patient relevant primary outcomes. DESIGN: Meta epidemiological study. DATA SOURCES: All randomised clinical trials published in 2005 and 2006 in six high impact medical journals: Annals of Internal Medicine, BMJ, Journal of the American Medical Association, Lancet, New England Journal of Medicine, and PLoS Medicine. STUDY SELECTION: Two independent reviewers selected trials. DATA EXTRACTION: Trial characteristics, risk of bias, and outcomes were recorded according to a predefined form. Two reviewers independently checked data extraction. The ratio of odds ratios was used to quantify the degree of difference in treatment effects between the trials using surrogate outcomes and those using patient relevant outcomes, also adjusted for trial characteristics. A ratio of odds ratios >1.0 implies that trials with surrogate outcomes report larger intervention effects than trials with patient relevant outcomes. RESULTS: 84 trials using surrogate outcomes and 101 using patient relevant outcomes were considered for analyses. Study characteristics of trials using surrogate outcomes and those using patient relevant outcomes were well balanced, except for median sample size (371 v 741) and single centre status (23% v 9%). Their risk of bias did not differ. Primary analysis showed trials reporting surrogate endpoints to have larger treatment effects (odds ratio 0.51, 95% confidence interval 0.42 to 0.60) than trials reporting patient relevant outcomes (0.76, 0.70 to 0.82), with an unadjusted ratio of odds ratios of 1.47 (1.07 to 2.01) and adjusted ratio of odds ratios of 1.46 (1.05 to 2.04). This result was consistent across sensitivity and secondary analyses. CONCLUSIONS: Trials reporting surrogate primary outcomes are more likely to report larger treatment effects than trials reporting final patient relevant primary outcomes. This finding was not explained by differences in the risk of bias or characteristics of the two groups of trials. PMID- 23360721 TI - Surgeons set new standards for cosmetic treatments. PMID- 23360722 TI - Peer publishes bill to reinstate legal duty of health secretary to provide NHS. PMID- 23360723 TI - Consultation starts on how to reveal payments from industry to doctors. PMID- 23360717 TI - Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis. AB - OBJECTIVE: To assess for the presence of a sex interaction in the associations of estimated glomerular filtration rate and albuminuria with all-cause mortality, cardiovascular mortality, and end stage renal disease. DESIGN: Random effects meta-analysis using pooled individual participant data. SETTING: 46 cohorts from Europe, North and South America, Asia, and Australasia. PARTICIPANTS: 2,051,158 participants (54% women) from general population cohorts (n=1,861,052), high risk cohorts (n=151,494), and chronic kidney disease cohorts (n=38,612). Eligible cohorts (except chronic kidney disease cohorts) had at least 1000 participants, outcomes of either mortality or end stage renal disease of >= 50 events, and baseline measurements of estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (mL/min/1.73 m(2)) and urinary albumin-creatinine ratio (mg/g). RESULTS: Risks of all-cause mortality and cardiovascular mortality were higher in men at all levels of estimated glomerular filtration rate and albumin-creatinine ratio. While higher risk was associated with lower estimated glomerular filtration rate and higher albumin creatinine ratio in both sexes, the slope of the risk relationship for all-cause mortality and for cardiovascular mortality were steeper in women than in men. Compared with an estimated glomerular filtration rate of 95, the adjusted hazard ratio for all-cause mortality at estimated glomerular filtration rate 45 was 1.32 (95% CI 1.08 to 1.61) in women and 1.22 (1.00 to 1.48) in men (P(interaction)<0.01). Compared with a urinary albumin-creatinine ratio of 5, the adjusted hazard ratio for all-cause mortality at urinary albumin-creatinine ratio 30 was 1.69 (1.54 to 1.84) in women and 1.43 (1.31 to 1.57) in men (P(interaction)<0.01). Conversely, there was no evidence of a sex difference in associations of estimated glomerular filtration rate and urinary albumin creatinine ratio with end stage renal disease risk. CONCLUSIONS: Both sexes face increased risk of all-cause mortality, cardiovascular mortality, and end stage renal disease with lower estimated glomerular filtration rates and higher albuminuria. These findings were robust across a large global consortium. PMID- 23360724 TI - Assessment of the presence of independent flexor digitorum superficialis function in the small fingers of professional string players: is this an example of natural selection? AB - This study estimated the prevalence of independent flexor digitorum superficialis function in the small fingers of 90 violin and viola players. The hypothesis tested was that the independent digital movements required in this population would select out those with absent flexor digitorum superficialis function. Professional string players were tested clinically, using standard and modified tests, for flexor digitorum superficialis function. Two additional physical tests were applied: the gap and stretch tests. These tests assess ring finger movement once the small finger is placed and the instrument is held in the chin-hold position. A statistically significant reduction in the prevalence of absent flexor digitorum superficialis function was confirmed in the musicians compared with a control group and published meta-analysis. This suggests that independent flexor digitorum superficialis function is important for professional musicians playing at an elite level. PMID- 23360726 TI - A protective-compensatory model may reconcile the genetic and the developmental findings in schizophrenia. AB - OBJECTIVE: The neurodevelopmental, the multifactorial-oligogenic and the gene environment diathesis models have provoked advances in schizophrenia research, yet the exact pathophysiology remains indefinable. We broadened our analysis of 20years of findings in adults and children descending from densely affected families in the Quebec population with a founder effect. The goal was to inspect the link between these family-genetic and developmental findings. METHOD: 48 multigenerational families affected by schizophrenia or bipolar disorder represented a quasi-total sample of affected kindreds in the Eastern-Quebec catchment area. Among the 1274 adult family members with lifetime best-estimate diagnoses, 341 had DSM-IV schizophrenia or bipolar disorder. Young offspring of an affected parent were studied with the same clinical, physiological and cognitive measures as the adults. RESULTS: Four new observations emerged: 1. A striking resemblance between the clinical, neuropsychological and genetic findings in these densely affected families and those reported in sporadic samples; 2. A high degree of heterogeneity despite the origin from a founder effect population; 3. Cognitive deficits in some non-affected adult relatives as severe as those in patients; 4. Children descending from kindreds displayed neurodevelopmental endophenotypic anomalies comparable to those of adult patients. CONCLUSION: These four observations could be reconciled under the hypothesis that highly familial and sporadic cases share mechanisms based on defective protective genes, a model to an extent similar to cancer findings. These defective protective genes running in families would longitudinally disturb the compensatory mechanisms in children inheriting them and might be at the core of the schizophrenia process. PMID- 23360725 TI - Association study of neuregulin-1 gene polymorphisms in a North Indian schizophrenia sample. AB - BACKGROUND: Neuregulin-1 (NRG1) gene polymorphisms have been proposed as risk factors for several common disorders. Associations with cognitive variation have also been tested. With regard to schizophrenia (SZ) risk, studies of Caucasian ancestry samples indicate associations more consistently than East Asian samples, suggesting heterogeneity. To exploit the differences in linkage disequilibrium (LD) structure across ethnic groups, we conducted a SZ case-control study (that included cognitive evaluations) in a sample from the north Indian population. METHODS: NRG1 variants (n=35 SNPs, three microsatellite markers) were initially analyzed among cases (DSM IV criteria, n=1007) and controls (n=1019, drawn from two groups) who were drawn from the same geographical region in North India. Nominally significant associations with SZ were next analyzed in relation to neurocognitive measures estimated with a computerized neurocognitive battery in a subset of the sample (n=116 cases, n=170 controls). RESULTS: Three variants and one microsatellite showed allelic association with SZ (rs35753505, rs4733263, rs6994992, and microsatellite 420M9-1395, p<=0.05 uncorrected for multiple comparisons). A six marker haplotype 221121 (rs35753505-rs6994992-rs1354336 rs10093107-rs3924999-rs11780123) showed (p=0.0004) association after Bonferroni corrections. Regression analyses with the neurocognitive measures showed nominal (uncorrected) associations with emotion processing and attention at rs35753505 and rs6994992, respectively. CONCLUSIONS: Suggestive associations with SZ and SZ related neurocognitive measures were detected with two SNPs from the NRG1 promoter region in a north Indian cohort. The functional role of the alleles merits further investigation. PMID- 23360727 TI - Decreased left middle temporal gyrus volume in antipsychotic drug-naive, first episode schizophrenia patients and their healthy unaffected siblings. AB - BACKGROUND: The shared neuropathological characteristics of patients with schizophrenia and their siblings might represent intermediate phenotypes that could be used to investigate genetic susceptibility to the illness. We sought to discover gray matter volume differences in patients with schizophrenia and their unaffected siblings with voxel-based morphometry (VBM). METHODS: We recruited antipsychotic drug-naive, first-episode schizophrenia (FES) patients, their unaffected siblings and age-, sex- and handedness-matched healthy controls. We used VBM to investigate differences in gray matter volume among the 3 groups. RESULTS: There were significant gray matter volumetric differences among the 3 groups in bilateral hippocampal and parahippocampal gyri, bilateral middle temporal gyri, and superior temporal gyri (FDR p<0.05). Patients had significant regional gray matter reduction in all regions listed above compared with healthy volunteers, and their gray matter volume in the right hippocampus and parahippocampus was also lower than the sibling group. The sibling group had significantly lower volumes compared to healthy individuals only in the left middle temporal gyrus, and volume of this region was not different between siblings and patients. CONCLUSIONS: Our findings confirm and extend previous VBM analyses in schizophrenia and it indicate that schizophrenia may be characterized by an abnormal development of cerebral lateralization. Furthermore, these data argue that patients and their unaffected siblings might share decreases in the gray matter volume of the left middle temporal gyrus, and this regional reduction might be a potential endophenotype for schizophrenia. PMID- 23360728 TI - Characterization of polymeric microcapsules containing a low molecular weight peptide for controlled release. AB - A need exists to prolong the release of rapidly metabolized peptides of a low molecular weight, while delivering this peptide without environmental interference. Previous studies have used bovine serum albumin (BSA) as a model peptide to study release characteristics from alginate microcapsules. BSA is 66 kDa in size, while the peptide of interest here, connexin-43 carboxyl-terminus mimetic peptide (alphaCT1), is only 3.4 kDa. Such a change in size results in a much different set of release parameters. Our overall goal is a sustained release over a 24+ h period. Prolonged application of the peptide to a wound site to investigate therapeutic effects is ideal. As a result, a diffusion method using alginate microcapsules, along with the addition of poly-l-lysine and poly-l ornithine, has been explored. We first aimed to establish and characterize our parameters through a set of parametric tests. Variations in polymer coating, change in pH, and changes in loading ratio have previously been shown to effect release using model compounds. Here we test specific changes in these parameters to show effects on the release of alphaCT1. Additionally, the microcapsules were attached to several biomaterials and surgical implants by ultraviolet cross linking to study the effectiveness of attachment and delivery. Analysis and measurements using phase contrast microscopy, scanning electron microscopy, and atomic force microscopy were used to characterize changes in microcapsule morphology. PMID- 23360729 TI - Type 1 diabetes eHealth psychoeducation: youth recruitment, participation, and satisfaction. AB - BACKGROUND: The Internet and other eHealth technologies offer a platform for improving the dissemination and accessibility of psychoeducational programs for youth with chronic illness. However, little is known about the recruitment process and yield of diverse samples in Internet research with youth who have a chronic illness. OBJECTIVE: The purpose of this study was to compare the demographic and clinical characteristics of youth with Type 1 diabetes on recruitment, participation, and satisfaction with 2 eHealth psychoeducational programs. METHODS: Youth with Type 1 diabetes from 4 sites in the United States were invited to participate (N=510) with 320 eligible youth consenting (mean age=12.3, SD 1.1; 55.3% female; 65.2% white; and mean A1C=8.3, SD 1.5). Data for this secondary analysis included demographic information (age, race/ethnicity, and income), depressive symptoms, and recruitment rates, including those who refused at point of contact (22.0%), passive refusers who consented but did not participate (15.3%), and those who enrolled (62.7%). Participation (80% lessons completed) and a satisfaction survey (ie, how helpful, enjoyable) were also analyzed. Chi-square or analysis of variance (ANOVA) analyses were used. RESULTS: There were significant differences in recruitment rates by income and race/ethnicity such that black, Hispanic, or mixed race/ethnicity and low-income youth were more likely to refuse passively compared to white and higher-income youth who were more likely to enroll (P<.001). Participation in program sessions was high, with 78.1% of youth completing at least 4 of 5 sessions. There were no significant differences in participation by program, age, gender, or race/ethnicity. Low-income youth were less likely to participate (P=.002). Satisfaction in both programs was also high (3.9 of 5). There were significant gender, race/ethnicity, and income differences, in that girls (P=.001), black, Hispanic, or mixed race/ethnicity youth (P=.02), and low-income youth (P=.02) reported higher satisfaction. There were no differences in satisfaction by program or age. CONCLUSIONS: Results indicate that black, Hispanic, or mixed race/ethnicity youth and low-income youth with Type 1 diabetes are less likely to enroll in Internet-based research than white and higher-income youth; thus, creative recruitment approaches are needed. Low-income youth were less likely to participate, possibly due to access. However, once enrolled, youth of diverse race/ethnicity and low-income youth with Type 1 diabetes were as highly satisfied with the eHealth programs as white youth and those with higher income. Results suggest that eHealth programs have the potential to reach diverse youth and be appealing to them. PMID- 23360730 TI - Bactericidal mechanisms of Ag2O/TNBs under both dark and light conditions. AB - Ag(2)O/TNBs were fabricated by depositing Ag(2)O nanoparticles on the surface of TiO(2) nanobelts (TNBs). The disinfection activities of Ag(2)O/TNBs on two representative bacterial types: Gram-negative Escherichia coli ATCC15597 and Gram positive Bacillus subtilis, were examined under both dark and visible light conditions. Ag(2)O/TNBs exhibited stronger bactericidal activities than Ag(2)O nanoparticles and TNBs under both dark and light conditions. For both cell types, disinfection effects of Ag(2)O/TNBs were greater under light conditions relative to those under dark conditions. The bactericidal mechanisms of Ag(2)O/TNBs under both dark and light conditions were explored. Ag(+) ions released from Ag(2)O/TNBs did not contribute to the bactericidal activity of Ag(2)O/TNBs under dark conditions, whereas the released Ag(+) ions showed bactericidal activity under visible light irradiation conditions. Active species (H(2)O(2), O(2)(-)., and e(-)) generated by Ag(2)O/TNBs played important roles in the disinfection processes under both dark and visible light irradiation conditions. Without the presence of active species, the direct contact of Ag(2)O/TNBs with bacterial cells had no bactericidal effect. PMID- 23360731 TI - Cortisol-mediated downregulation of the serotonin 1A receptor subtype in the Gulf toadfish, Opsanus beta. AB - In both mammals and teleost fish, serotonin stimulates cortisol secretion via the 5-HT1A receptor. Additionally, a negative feedback loop exists in mammals whereby increased circulating levels of cortisol inhibit 5-HT1A receptor activity. To investigate the possibility of such a feedback mechanism in teleosts, plasma cortisol levels and signaling in Gulf toadfish (Opsanus beta) were manipulated and the role of cortisol in the control of 5-HT1A evaluated. Despite a significant 4-fold increase in plasma [cortisol], crowded toadfish expressed similar amounts of 5-HT1A mRNA transcript as uncrowded toadfish; whereas, cortisol-implanted fish possessed 41.8% less 5-HT1A mRNA transcript compared to vehicle-implanted controls. This cortisol effect appeared to be reversed in RU486 injected fish, which blocks glucocorticoid receptors, as these fish expressed nearly twice as much 5-HT1A receptor transcript as the vehicle-injected fish despite significantly elevated cortisol levels. The binding affinity for the 5 HT1A receptor in the brain did not vary between any groups; however, maximum binding was significantly higher in uncrowded toadfish compared to crowded, and the same significant difference was observed between the maximum binding of vehicle and cortisol-implanted fish. The opposite trend was seen in RU486 injected and vehicle-injected fish, with RU486-injected fish having significantly higher maximal binding compared to vehicle-injected controls. Injection with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin revealed an inhibition of cortisol secretion that was independent of 5-HT1A transcript and protein binding. These results suggest that cortisol plays a role in regulating the 5-HT1A receptor via GR-mediated pathways; however, further study is necessary to elucidate how and where this inhibition is mediated. PMID- 23360732 TI - Targeting NFKB by autophagy to polarize hepatoma-associated macrophage differentiation. AB - Tumor-associated macrophages (TAMs) have been linked to promoting tumor progression by stimulating angiogenesis, cell growth and inflammation. NFKB activity in TAMs may mediate inflammation-associated tumor formation. However, most isolated TAMs from established tumors express a M2 phenotype with less NFKB activation and show a strong immunosuppressive phenomenon. How tumors affect the dynamic of NFKB activity in TAMs, and hence maintain their pro-tumor M2 phenotype is still poorly understood. We recently found that hepatoma-derived toll-like receptor 2 (TLR2)-related ligands are capable of stimulating M2 macrophage differentiation via controlling NFKB RELA/p65 protein homeostasis by selective autophagy. TLR2 signal induces NFKB RELA cytosolic ubiquitination and leads to its degradation by SQSTM1/p62-mediated autophagy. Inhibition of autophagy will rescue NFKB activity and shape the phenotype of hepatoma-polarized M2 macrophages. This suggests that autophagy might play a role in manipulating TAM functions and tumor-associated immune responses. Our study also demonstrates that autophagy can directly control a transcriptional factor in addition to its regulatory molecules. This finding uncovers a new role of autophagy in controlling cellular functions. PMID- 23360733 TI - [Toward the multidisciplinary management of brain metastasis]. PMID- 23360734 TI - A new rapid diagnostic test for detection of anti-Schistosoma mansoni and anti Schistosoma haematobium antibodies. AB - BACKGROUND: Parasitological methods are widely used for the diagnosis of schistosomiasis. However, they are insensitive, particularly in areas of low endemicity, and labour-intensive. Immunoassays based on detection of anti schistosome antibodies have the merit of high sensitivity and recently a rapid diagnostic test (RDT), incorporating Schistosoma mansoni cercarial transformation fluid (SmCTF) for detection of anti-schistosome antibodies in blood has been developed. Here, we assessed the diagnostic performance of the SmCTF-RDT for S. mansoni and S. haematobium infections by comparing it with microscopy for egg detection. METHODS: A cross-sectional survey was carried out in Azaguie, south Cote d'Ivoire. 118 pre-school-aged children submitted two stool and two urine samples, which were subjected to the Kato-Katz and urine filtration methods for the detection of S. mansoni and S. haematobium eggs, respectively. Urine was also subjected to a commercially available cassette test for S. mansoni, which detects circulating cathodic antigen. A finger-prick blood sample was used for the SmCTF RDT for detection of anti-S. mansoni and anti-S. haematobium antibodies. RESULTS: The prevalence of both anti-S. mansoni and anti-S. haematobium antibodies was more than three times higher than the prevalence of infection estimated by egg detection under a microscope. Using quadruplicate Kato-Katz as the reference standard for the diagnosis of S. mansoni infection, the sensitivity, negative predictive value (NPV), and positive predictive value (PPV) of the SmCTF-RDT was 75.0%, 84.2% and 22.5%, respectively. When two urine filtrations were considered as the reference standard for the diagnosis of S. haematobium infection, the sensitivity, NPV and PPV of SmCTF-RDT was 66.7%, 94.9% and 5.1%, respectively. The specificity of SmCTF-RDT, when using egg-detection as the reference standard, was estimated to be 34.4%. This low specificity may be a reflection of the relative insensitivity of the direct diagnostic approaches using microscopy. CONCLUSIONS: The SmCTF-RDT is at least as sensitive as duplicate Kato-Katz and a single urine filtration for detection of S. mansoni and S. haematobium, respectively. Further investigations into the specificity of the test for anti schistosome antibodies are necessary, but our results suggest that it may be a useful tool for mapping the prevalence of anti-schistosome antibodies in a given population pending intervention. PMID- 23360735 TI - Liver dysplasia: US molecular imaging with targeted contrast agent enables early assessment. AB - PURPOSE: To investigate the ability of vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted ultrasonographic (US) microbubbles for the assessment of liver dysplasia in transgenic mice. MATERIALS AND METHODS: Animal experiments were approved by the governmental review committee. Nuclear factor kappaB essential modulator knock-out mice with liver dysplasia and wild-type mice underwent liver imaging by using a clinical US system. Two types of contrast agents were investigated: nontargeted, commercially available, second-generation microbubbles (SonoVue) and clinically translatable PEGylated VEGFR2-targeted microbubbles (BR55). Microbubble kinetics was investigated over the course of 4 minutes. Targeted contrast material-enhanced US signal was quantified 5 minutes after injection. Competitive in vivo binding experiments with BR55 were performed in knock-out mice. Immunohistochemical and hematoxylin-eosin staining of liver sections was performed to validate the in vivo US results. Groups were compared by using the Mann-Whitney test. RESULTS: Peak enhancement after injection of SonoVue and BR55 did not differ in healthy and dysplastic livers (SonoVue, P = .46; BR55, P = .43). Accordingly, immunohistochemical findings revealed comparable vessel densities in both groups. The specificity of BR55 to VEGFR2 was proved by in vivo competition (P = .0262). While the SonoVue signal decreased similarly in healthy and dysplastic livers during the 4 minutes, there was an accumulation of BR55 in dysplastic livers compared with healthy ones. Furthermore, targeted contrast-enhanced US signal indicated a significantly higher site-specific binding of BR55 in dysplastic than healthy livers (P = .005). Quantitative immunohistologic findings confirmed significantly higher VEGFR2 levels in dysplastic livers (P = .02). CONCLUSION: BR55 enables the distinction of early stages of liver dysplasia from normal liver. PMID- 23360736 TI - Integrating MR imaging into the clinical workup of pregnant patients suspected of having appendicitis is associated with a lower negative laparotomy rate: single institution study. AB - PURPOSE: To determine if integrating magnetic resonance (MR) imaging into the workup of right lower quadrant pain in pregnant patients was associated with improved outcomes as measured by the negative laparotomy rate (NLR) and the perforation rate (PR). MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective review of medical records. Two hundred sixty seven pregnant patients who underwent either surgery (n = 82) or an MR imaging examination (n = 217) because of suspicion of appendicitis between January 1, 1996, and August 31, 2011, were identified. Relevant ultrasonographic and MR imaging reports were classified as showing true-positive, false-positive, true negative, false-negative, or equivocal findings. MR imaging utilization was analyzed to define pre- and post-MR imaging cohorts. NLR and PR were calculated for both cohorts and were compared by using a Fisher exact probability test. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for MR imaging were calculated. RESULTS: MR imaging was introduced into the clinical workup in 2004. From 1996 to 2003, the NLR for pregnant patients was 55% (17 of 31), and the PR was 21% (three of 14). From 2004 to 2011, the NLR was 29% (15 of 51), and the PR was 26% (nine of 35). The 47% decline in the NLR ([55%-29%]/55%) was statistically significant (P = .02). The change in PR was not significant (P > .99). The sensitivity, specificity, PPV, and NPV of MR imaging in the diagnosis of appendicitis were 89% (17 of 19), 97% (187 of 193), 74% (17 of 23), and 99% (187 of 189), respectively. CONCLUSION: The routine incorporation of MR imaging into the clinical workup for suspicion of appendicitis in pregnant patients at this institution was associated with a decrease in the NLR of 47% without a significant change in the PR. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12121027/ /DC1. PMID- 23360738 TI - Overinterpretation and misreporting of diagnostic accuracy studies: evidence of "spin". AB - PURPOSE: To estimate the frequency of distorted presentation and overinterpretation of results in diagnostic accuracy studies. MATERIALS AND METHODS: MEDLINE was searched for diagnostic accuracy studies published between January and June 2010 in journals with an impact factor of 4 or higher. Articles included were primary studies of the accuracy of one or more tests in which the results were compared with a clinical reference standard. Two authors scored each article independently by using a pretested data-extraction form to identify actual overinterpretation and practices that facilitate overinterpretation, such as incomplete reporting of study methods or the use of inappropriate methods (potential overinterpretation). The frequency of overinterpretation was estimated in all studies and in a subgroup of imaging studies. RESULTS: Of the 126 articles, 39 (31%; 95% confidence interval [CI]: 23, 39) contained a form of actual overinterpretation, including 29 (23%; 95% CI: 16, 30) with an overly optimistic abstract, 10 (8%; 96% CI: 3%, 13%) with a discrepancy between the study aim and conclusion, and eight with conclusions based on selected subgroups. In our analysis of potential overinterpretation, authors of 89% (95% CI: 83%, 94%) of the studies did not include a sample size calculation, 88% (95% CI: 82%, 94%) did not state a test hypothesis, and 57% (95% CI: 48%, 66%) did not report CIs of accuracy measurements. In 43% (95% CI: 34%, 52%) of studies, authors were unclear about the intended role of the test, and in 3% (95% CI: 0%, 6%) they used inappropriate statistical tests. A subgroup analysis of imaging studies showed 16 (30%; 95% CI: 17%, 43%) and 53 (100%; 95% CI: 92%, 100%) contained forms of actual and potential overinterpretation, respectively. CONCLUSION: Overinterpretation and misreporting of results in diagnostic accuracy studies is frequent in journals with high impact factors. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120527/-/DC1. PMID- 23360737 TI - Contrast material-induced nephrotoxicity and intravenous low-osmolality iodinated contrast material. AB - PURPOSE: To determine whether intravenous low-osmolality iodinated contrast material is associated with post-computed tomography (CT) acute kidney injury (AKI). MATERIALS AND METHODS: Institutional review board approval was obtained and patient consent waived for this HIPAA-compliant retrospective study. CT examinations performed over a 10-year period in adult inpatients with sufficient serum creatinine (SCr) data were identified. A one-to-one propensity-matched matched cohort analysis with multivariate analysis of effects was performed with post-CT AKI as the primary outcome measure (10,121 unenhanced and 10,121 intravenous contrast-enhanced CT examinations in 20,242 patients). Propensity matching was performed with respect to likelihood of patient receiving intravenous contrast material (36 tested covariates). The primary endpoint was post-CT AKI by using Acute Kidney Injury Network SCr criteria; the secondary endpoint was post-CT AKI by using traditional SCr criteria for contrast material induced nephrotoxicity (CIN; SCr increase >=0.5 mg/dL [44.20 MUmol/L] or >=25%). Multivariate subgroup threshold analysis was performed (SCr <1.5 [<132.60 MUmol/L]; >=1.5 to >=2.0 mg/dL [>=132.60 to >=176.80 MUmol/L]) and adjusted for assigned propensity scores. RESULTS: Intravenous low-osmolality iodinated contrast material had a significant effect on the development of post-CT AKI for patients with pre-CT SCr levels of 1.6 mg/dL (141.44 MUmol/L) or greater (odds ratio, 1.45; 95% confidence interval [CI]: 1.11, 1.89;P = .007). This effect strengthened as pre-CT SCr increased. Patients with stable SCr less than 1.5 mg/dL (132.60 MUmol/L) were not at risk for developing CIN (P = .25, power > 95%). Both endpoints demonstrated similar results (eg, SCr >=1.6 mg/dL [141.44 MUmol/L] by using traditional CIN criteria: odds ratio, 1.64; 95% CI: 1.18, 2.28; P = .003). Post-CT AKI was prevalent in both the unenhanced and contrast-enhanced CT subgroups, and it increased with increases in pre-CT SCr. Many risk factors contributed to development of post-CT AKI, regardless of iodinated contrast material. CONCLUSION: Intravenous low-osmolality iodinated contrast material is a nephrotoxic risk factor, but not in patients with a stable SCr level less than 1.5 mg/dL. Many factors other than contrast material can affect post-CT AKI rates. PMID- 23360739 TI - Patterns of illness explaining the associations between posttraumatic stress disorder and the use of CT. AB - PURPOSE: To examine the relationship between posttraumatic stress disorder (PTSD) and computed tomography (CT) utilization and to determine whether there were patterns of comorbid illness that could explain the relationship. MATERIALS AND METHODS: The study was approved by the University of Iowa Institutional Review Board and the Iowa City Veterans Affairs Medical Center Research and Development Committee. By using a retrospective cohort design, a national sample of new veteran enrollees aged 18-35 years was studied. Associations were examined between the presence of PTSD, receipt of at least one and multiple CT scans, comorbid medical conditions (eg, abdominal pain, headaches), and measures of health care utilization (eg, primary care, emergency room, and mental health visits) and the daily probability of the receipt of at least one CT scan before and after a diagnosis of PTSD. Analyses included sequential multivariable generalized linear mixed models to examine the independent relationship between PTSD and CT scan utilization. RESULTS: Among the full cohort, 13.0% (10 018 of 76 812) received at least one CT scan. PTSD was identified in 21.1% (16 182 of 76 812) of the cohort, and 22.9% (3711 of 16 182) of veterans with PTSD received at least one CT scan as compared with 10.4% (6307 of 60 630) of veterans without PTSD (P < .0001). In sequential modeling, comorbid factors explaining the relationship between CT scans and PTSD were traumatic brain injury (odds ratio, 3.54; P < .0001), abdominal pain (odds ratio, 4.01; P < .0001), and headaches (odds ratio, 3.07; P < .0001). Associations were also strong for high levels of emergency room (odds ratio, 2.73; P < .0001) and primary care (odds ratio, 2.38; P < .0001) utilization. The daily chance of receiving a CT scan was seven times higher prior to the recognition of PTSD (daily chance, 0.007 before vs 0.001 after; P < .0001). CONCLUSION: Young veterans with PTSD are receiving more CT scans compared with those without PTSD; the daily probability of receiving CT scans is higher prior to recognition of PTSD. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13121593/-/DC1. PMID- 23360740 TI - Whole-brain analysis of amyotrophic lateral sclerosis by using echo-planar spectroscopic imaging. AB - PURPOSE: To detect regional metabolic differences in amyotrophic lateral sclerosis (ALS) with whole-brain echo-planar spectroscopic imaging. MATERIALS AND METHODS: Sixteen patients with ALS (nine men, seven women; mean age, 56.6 years), five persons suspected of having ALS (four men, one woman; mean age, 62.6 years), and 10 healthy control subjects (five men, five women; mean age, 56.1 years) underwent echo-planar spectroscopic imaging after providing informed consent. The study was approved by the institutional review board and complied with HIPAA. Data were analyzed with the Metabolic Imaging and Data Analysis System software, and processed metabolite maps were coregistered and normalized to a standard brain template. Metabolite maps of creatine (Cr), choline (Cho), and N acetylaspartate (NAA) were segmented into 81 regions with Automated Anatomical Labeling software to measure metabolic changes throughout the brains of patients with ALS. Statistical analysis involved an unpaired, uncorrected, two-sided Student t test. RESULTS: The NAA/Cho ratio across six regions was significantly lower by a mean of 23% (P <= .01) in patients with ALS than in control subjects. These regions included the caudate, lingual gyrus, supramarginal gyrus, and right and left superior and right inferior occipital lobes. The NAA/Cr ratio was significantly lower (P <= .01) in eight regions in the patient group, by a mean of 16%. These included the caudate, cuneus, frontal inferior operculum, Heschl gyrus, precentral gyrus, rolandic operculum, and superior and inferior occipital lobes. The Cho/Cr ratio did not significantly differ in any region between patient and control groups. CONCLUSION: Whole-brain echo-planar spectroscopic imaging permits detection of regional metabolic abnormalities in ALS, including not only the motor cortex but also several other regions implicated in ALS pathophysiologic findings. PMID- 23360741 TI - Effect of intravenous low-osmolality iodinated contrast media on patients with myasthenia gravis. AB - PURPOSE: To determine whether the intravenous administration of low-osmolality contrast material is associated with exacerbation of disease-related symptoms in patients with myasthenia gravis. MATERIALS AND METHODS: This HIPAA-compliant, retrospective cohort study was approved by the institutional review board. The requirement to obtain patient consent was waived. Computed tomography (CT) was performed in 267 patients with clinically confirmed myasthenia gravis between January 1, 1995, and December 31, 2011. CT was performed without intravenous administration of contrast material in 155 patients and with intravenous administration of low-osmolality contrast material in 112. Electronic medical records were searched to identify myasthenia gravis-related symptoms before (<= 14 days) and after (<= 45 days) each CT examination. The Mantel-Cox log-rank test was used to compare the time to symptom progression between the two groups. The Fisher exact test was used to compare rates of disease-related symptoms during three time periods: (a) 0-1 day after CT, (b) 2-7 days after CT, and (c) 8-45 days after CT. RESULTS: The unenhanced and contrast-enhanced CT groups had similar thymectomy rates (P = .97) and disease-related symptom trends before CT (P = .58). The contrast-enhanced CT group was associated with a significant reduction in time to disease-related symptom progression following CT (median time to onset of symptom progression, 2.5 days with contrast-enhanced CT vs 14.0 days with unenhanced CT; P = .05). There were significantly more disease-related symptom exacerbations within 1 day of CT in the contrast-enhanced CT group compared with the unenhanced CT group (6.3% [seven of 112 patients] vs 0.6% [one of 155 patients], respectively; P = .01). Acute exacerbations were primarily respiratory (five patients with new-onset dyspnea [four in contrast-enhanced CT group and one in unenhanced CT group], two patients with progressive dyspnea [both in the contrast-enhanced CT group], and one patient with progressive weakness [in contrast-enhanced CT group]). There was no difference in symptoms between groups at 2-7 days (P = .70) or 8-45 days (P = .99). CONCLUSION: Intravenous administration of low-osmolality contrast material is significantly associated with exacerbation of myasthenia gravis-related symptoms. Exacerbations most commonly manifest as new or progressive acute respiratory compromise. PMID- 23360742 TI - Intravenous contrast material-induced nephropathy: causal or coincident phenomenon? AB - PURPOSE: To determine the causal association and effect of intravenous iodinated contrast material exposure on the incidence of acute kidney injury (AKI), also known as contrast material-induced nephropathy (CIN). MATERIALS AND METHODS: This retrospective study was approved by an institutional review board and was HIPAA compliant. Informed consent was waived. All contrast material-enhanced (contrast group) and unenhanced (noncontrast group) abdominal, pelvic, and thoracic CT scans from 2000 to 2010 were identified at a single facility. Scan recipients were sorted into low- (<1.5 mg/dL), medium- (1.5-2.0 mg/dL), and high-risk (>2.0 mg/dL) subgroups of presumed risk for CIN by using baseline serum creatinine (SCr) level. The incidence of AKI (SCr >= 0.5 mg/dL above baseline) was compared between contrast and noncontrast groups after propensity score adjustment by stratification, 1:1 matching, inverse weighting, and weighting by the odds methods to reduce intergroup selection bias. Counterfactual analysis was used to evaluate the causal relation between contrast material exposure and AKI by evaluating patients who underwent contrast-enhanced and unenhanced CT scans during the study period with the McNemar test. RESULTS: A total of 157,140 scans among 53,439 unique patients associated with 1,510,001 SCr values were identified. AKI risk was not significantly different between contrast and noncontrast groups in any risk subgroup after propensity score adjustment by using reported risk factors of CIN (low risk: odds ratio [OR], 0.93; 95% confidence interval [CI]: 0.76, 1.13; P = .47; medium risk: odds ratio, 0.97; 95% CI: 0.81, 1.16; P = .76; high risk: OR, 0.91; 95% CI: 0.66, 1.24; P = .58). Counterfactual analysis revealed no significant difference in AKI incidence between enhanced and unenhanced CT scans in the same patient (McNemar test: chi(2) = 0.63, P = .43) (OR = 0.92; 95% CI: 0.75, 1.13; P = .46). CONCLUSION: Following adjustment for presumed risk factors, the incidence of CIN was not significantly different from contrast material-independent AKI. These two phenomena were clinically indistinguishable with established SCr-defined criteria, suggesting that intravenous iodinated contrast media may not be the causative agent in diminished renal function after contrast material administration. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12121823/-/DC1. PMID- 23360743 TI - Chain formation and aging process in biocompatible polydisperse ferrofluids: experimental investigation and Monte Carlo simulations. AB - We review the use of Monte Carlo simulations in the description of magnetic nanoparticles dispersed in a liquid carrier. Our main focus is the use of theory and simulation as tools for the description of the properties of ferrofluids. In particular, we report on the influence of polydispersity and short-range interaction on the self-organization of nanoparticles. Such contributions are shown to be extremely important for systems characterized by particles with diameters smaller than 10nm. A new 3D polydisperse Monte Carlo implementation for biocompatible magnetic colloids is proposed. As an example, theoretical and simulation results for an ionic-surfacted ferrofluid dispersed in a NaCl solution are directly compared to experimental data (transmission electron microscopy - TEM, magneto-transmissivity, and electron magnetic resonance - EMR). Our combined theoretical and experimental results suggest that during the aging process two possible mechanisms are likely to be observed: the nanoparticle's grafting decreases due to aggregate formation and the Hamaker constant increases due to oxidation. In addition, we also briefly discuss theoretical agglomerate formation models and compare them to experimental data. PMID- 23360745 TI - Immune responses in liver-directed lentiviral gene therapy. AB - The use of lentiviral vectors (LV)s for in vivo gene therapy is an ideal platform for treating many types of disease. Since LVs can transduce a wide array of cells, support long-term gene expression, and be modified to enhance cell targeting, LVs are a powerful modality to deliver life-long therapeutic proteins. A major limitation facing the use of LVs for in vivo gene therapy is the induction of immune responses, which can reduce the transduction efficiency of LV, eliminate the transduced cells, and inhibit the effect of the therapeutic protein. LV strategies designed to restrict transgene expression to the liver to exploit its naturally tolerogenic properties have proven to significantly reduce the induction of pathogenic immune responses and increase therapeutic efficacy. In this review, we outline the immunological hurdles facing in vivo LV gene therapy and highlight the advantages and limitations of using liver-directed LV gene therapy. PMID- 23360747 TI - Studies on the interaction between triphenyltin and bovine serum albumin by fluorescence and CD spectroscopy. AB - The interaction between triphenyltin (TPT) and bovine serum albumin (BSA) in physiological buffer (pH=7.4) was investigated by the fluorescence quenching technique. The results of fluorescence titration revealed that TPT could strongly quench the intrinsic fluorescence of BSA through a static quenching procedure. The apparent binding constants K and number of binding sites n of TPT with BSA were (7.04+/-0.0057)*10(2) and (0.77+/-0.016) which were obtained by the fluorescence quenching method. The thermodynamic parameters enthalpy change (DeltaH), entropy change (DeltaS) were positive, which indicated that the interaction of TPT with BSA was driven mainly by hydrophobic forces. The process of binding was a spontaneous process in which Gibbs free energy change was negative. The distance r between donor (BSA) and acceptor (TPT) was calculated to be 3.05nm based on Forster's non-radiative energy transfer theory. The results of synchronous fluorescence, three-dimensional fluorescence and Circular Dichroism (CD) spectra showed that the triphenyltin induced conformational changes of BSA. PMID- 23360746 TI - Evolutionary origins of ultrasonic hearing and laryngeal echolocation in bats inferred from morphological analyses of the inner ear. AB - INTRODUCTION: Many mammals have evolved highly adapted hearing associated with ecological specialisation. Of these, bats possess the widest frequency range of vocalisations and associated hearing sensitivities, with frequencies of above 200 kHz in some lineages that use laryngeal echolocation. High frequency hearing in bats appears to have evolved via structural modifications of the inner ear, however, studying these minute features presents considerable challenges and hitherto few such attempts have been made. To understand these adaptations more fully, as well as gain insights into the evolutionary origins of ultrasonic hearing and echolocation in bats, we undertook micro-computed tomography (MUCT) scans of the cochleae of representative bat species from 16 families, encompassing their broad range of ecological diversity. To characterise cochlear gross morphology, we measured the relative basilar membrane length and number of turns, and compared these values between echolocating and non-echolocating bats, as well as other mammals. RESULTS: We found that hearing and echolocation call frequencies in bats correlated with both measures of cochlear morphology. In particular, relative basilar membrane length was typically longer in echolocating species, and also correlated positively with the number of cochlear turns. Ancestral reconstructions of these parameters suggested that the common ancestor of all extant bats was probably capable of ultrasonic hearing; however, we also found evidence of a significant decrease in the rate of morphological evolution of the basilar membrane in multiple ancestral branches within the Yangochiroptera suborder. Within the echolocating Yinpterochiroptera, there was some evidence of an increase in the rate of basilar membrane evolution in some tips of the tree, possibly associated with reported shifts in call frequency associated with recent speciation events. CONCLUSIONS: The two main groups of echolocating bat were found to display highly variable inner ear morphologies. Ancestral reconstructions and rate shift analyses of ear morphology point to a complex evolutionary history, with the former supporting ultrasonic hearing in the common bat ancestor but the latter suggesting that morphological changes associated with echolocation might have occurred later. These findings are consistent with theories that sophisticated laryngeal echolocation, as seen in modern lineages, evolved following the divergence of the two main suborders. PMID- 23360744 TI - Nephrogenic diabetes insipidus: essential insights into the molecular background and potential therapies for treatment. AB - The water channel aquaporin-2 (AQP2), expressed in the kidney collecting ducts, plays a pivotal role in maintaining body water balance. The channel is regulated by the peptide hormone arginine vasopressin (AVP), which exerts its effects through the type 2 vasopressin receptor (AVPR2). Disrupted function or regulation of AQP2 or the AVPR2 results in nephrogenic diabetes insipidus (NDI), a common clinical condition of renal origin characterized by polydipsia and polyuria. Over several years, major research efforts have advanced our understanding of NDI at the genetic, cellular, molecular, and biological levels. NDI is commonly characterized as hereditary (congenital) NDI, arising from genetic mutations in the AVPR2 or AQP2; or acquired NDI, due to for exmple medical treatment or electrolyte disturbances. In this article, we provide a comprehensive overview of the genetic, cell biological, and pathophysiological causes of NDI, with emphasis on the congenital forms and the acquired forms arising from lithium and other drug therapies, acute and chronic renal failure, and disturbed levels of calcium and potassium. Additionally, we provide an overview of the exciting new treatment strategies that have been recently proposed for alleviating the symptoms of some forms of the disease and for bypassing G protein-coupled receptor signaling. PMID- 23360748 TI - Microbially mediated reductive dechlorination of weathered polychlorinated dibenzofurans in Kymijoki sediment mesocosms. AB - Little is known about the potential for indigenous microorganisms to reductively dechlorinate weathered polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) in contaminated sediments. The sediments of River Kymijoki, Finland are heavily contaminated with PCDFs originating from manufacture of the chlorophenol-based fungicide Ky-5. Reductive dechlorination of weathered PCDFs was monitored to examine strategies for stimulating such activities. Amendments with electron donors, a halogenated co-substrate (tetrachlorobenzene, TeCBz), and bioaugmentation with a mixed culture containing Dehalococcoides mccartyi strain 195 were used to stimulate dechlorination activity in 30 L River Kymijoki sediment mesocosms incubated from 18 degrees C to 21 degrees C. An initial onset of dechlorination of octa-, hepta- and hexa-CDFs was observed in all mesocosms in the first 2 years of incubation. During this initial 2-year period, the decrease in the mol% contribution of these PCDFs was coupled with an increase in the mol% contribution of tetra- and penta-CDFs. The ratio of 1,2,3,4,6,7,8- to 1,2,3,4,6,8,9-hepta-CDF increased significantly. Subtle differences were observed between amended and unamended mesocosms. For penta-CDFs, a decreasing mol% ratio of peri vs. total chlorines and increasing mol% ratio of lateral vs. total chlorines was observed in mesocosms amended with TeCBz, suggesting that the amendments may affect pathways of dechlorination. Analysis of congener patterns using principal components analysis supported the observation that dechlorination was most pronounced during the first 2 years. Polymerase chain reaction and denaturing gradient gel electrophoresis (PCR-DGGE) analysis of 16S rRNA genes revealed a diverse Chloroflexi community. This study showed evidence for dechlorination of weathered PCDFs in Kymijoki sediment mesocosms mediated by indigenous microorganisms. PMID- 23360749 TI - Brominated and chlorinated flame retardants in liver of Greenland shark (Somniosus microcephalus). AB - Polybrominated diphenyl ethers (PBDEs) are known brominated flame retardants that have now been banned or phased out in many parts of the world. As a consequence, interest in the environmental occurrence of non-PBDE flame retardants has increased. In the present study several potential PBDE replacement products together with short chained chlorinated paraffins (SCCPs) were assessed in Greenland sharks accidentally caught in waters around Iceland between 2001 and 2003. Non-PBDE flame retardants detected were pentabromoethylbenzene (PBEB), 1,2 bis(2,4,6-tribromophenoxy)ethane (BTBPE) and 2,3,5,6-tetrabromo-p-xylene (TBX). The concentrations were lower than levels of BDE-47 but similar to other PBDE congeners previously reported in Greenland shark. The median concentrations of SCCPs was 430 ng g(-1) fat, similar to individual PCB congeners previously reported. This is the first report of SCCPs, BTBPE, PBEB and TBX in any shark species globally and confirms the usefulness of the Greenland shark as a screening species for environmental contamination in the Arctic and sub-Arctic environment. PMID- 23360750 TI - 82Sr purification procedure using Chelex-100 resin. AB - (82)Rb is a positron-emitting radionuclide widely used in nuclear cardiology. One great advantage is its availability through a generator loaded with (82)Sr. (82)Sr can be produced in a high energy cyclotron by irradiating rubidium chloride target with proton beam. In this paper, we present an extensive study (elution profiles, effect of the elution flow rate) on the use of Chelex-100 resin and ammonia buffer. No significant effect of flow rate was evidenced between 1 and 10mL/min leading us to propose a purification process which can be easily automated. PMID- 23360751 TI - The stability of self-reported adverse experiences in childhood: a longitudinal study on obesity. AB - The literature on the effect of maltreatment has revealed several methodological problems of retrospective studies, such as the validity and stability of retrospective reports, which may be influenced by factors such as one's mental health at the time of the report. This study aims to assess the temporal stability of self-reported adverse childhood experiences at three different time points, separated by 6 months each, and to analyze the relationship between general psychopathology and the number of reported experiences. Thirty obese participants responded to the Portuguese version of the Childhood History Questionnaire, a self-report measure that assesses adverse childhood experiences, and the Brief Symptom Inventory. The results suggest that adverse childhood experiences are common in these participants (time 1: X = 1.87, SD = 1.3; time 2: X = 1.98, SD = 1.6; time 3: X = 1.98, SD = 1.6). The agreement levels, as measured by kappa values, were satisfactory for the dimensions of maltreatment focused on the individual, with kappas ranging between .34 and .44. Our participants did not exhibit psychopathology at any of the time points, and the psychopathological symptoms were not related to total adversity reported. The major contribution of this study is the comparison of self-reports at three time points, separated by significant time intervals, and the inclusion of 10 different dimensions of childhood adversity. The data show an adequate stability in the report of maltreatment toward the individual (abuse and physical neglect) and in specific aspects of adversity in the family. PMID- 23360752 TI - EMEN2: an object oriented database and electronic lab notebook. AB - Transmission electron microscopy and associated methods, such as single particle analysis, two-dimensional crystallography, helical reconstruction, and tomography, are highly data-intensive experimental sciences, which also have substantial variability in experimental technique. Object-oriented databases present an attractive alternative to traditional relational databases for situations where the experiments themselves are continually evolving. We present EMEN2, an easy to use object-oriented database with a highly flexible infrastructure originally targeted for transmission electron microscopy and tomography, which has been extended to be adaptable for use in virtually any experimental science. It is a pure object-oriented database designed for easy adoption in diverse laboratory environments and does not require professional database administration. It includes a full featured, dynamic web interface in addition to APIs for programmatic access. EMEN2 installations currently support roughly 800 scientists worldwide with over 1/2 million experimental records and over 20 TB of experimental data. The software is freely available with complete source. PMID- 23360755 TI - Abnormal hematopoietic phenotypes in Pim kinase triple knockout mice. AB - BACKGROUND: Pim (proviral insertion in murine lymphoma) kinases are a small family of constitutively active, highly conservative serine/threonine oncogenic kinases and have 3 members: Pim1, Pim2, and Pim3. Pim kinases are also implicated in the regulation of B- and T- cell responses to cytokines and hematopoietic growth factors. The roles of Pim kinases in the regulation of primitive hematopoietic stem cells (HSCs) are largely unknown. METHODS: In the current study, Pim1-/-2-/-3-/- triple knockout (TKO) mice were used to determine the role of Pim kinases in hematopoiesis. Peripheral blood hematological parameters were measured in Pim TKO mice and age-matched wild-type (WT) controls. Primary, secondary, and competitive transplantations were performed to assay the long-term repopulating HSCs in Pim TKO mice. In vivo BrdU incorporation assay and ex vivo Ki67 staining and caspase 3 labeling were performed to evaluate the proliferation and apoptosis of HSCs in Pim TKO mice. RESULTS: Compared to age-matched WT controls, Pim TKO mice had lower peripheral blood platelet count and exhibited erythrocyte hypochromic microcytosis. The bone marrow cells from Pim TKO mice demonstrated decreased hematopoietic progenitor colony-forming ability. Importantly, Pim TKO bone marrow cells had significantly impaired capacity in rescuing lethally irradiated mice and reconstituting hematopoiesis in primary, secondary and competitive transplant models. In vivo BrdU incorporation in long term HSCs was reduced in Pim TKO mice. Finally, cultured HSCs from Pim TKO mice showed reduced proliferation evaluated by Ki67 staining and higher rate of apoptosis via caspase 3 activation. CONCLUSIONS: Pim kinases are not only essential in the hematopoietic lineage cell development, but also important in HSC expansion, self-renewal, and long-term repopulation. PMID- 23360753 TI - What's to like about the prion-like hypothesis for the spreading of aggregated alpha-synuclein in Parkinson disease? AB - alpha-Synuclein is a key protein in Parkinson disease. Not only is it the major protein component of Lewy bodies, but it is implicated in several cellular processes that are disrupted in Parkinson disease. Misfolded alpha-synuclein has also been shown to spread from cell-to-cell and, in a prion-like fashion, trigger aggregation of alpha-synuclein in the recipient cell. In this mini-review we explore the evidence that misfolded alpha-synuclein underlies the spread of pathology in Parkinson disease and discuss why it should be considered a prion like protein. PMID- 23360756 TI - Variability in bimanual wheelchair propulsion: consistency of two instrumented wheels during handrim wheelchair propulsion on a motor driven treadmill. AB - BACKGROUND: Handrim wheelchair propulsion is a complex bimanual motor task. The bimanually applied forces on the rims determine the speed and direction of locomotion. Measurements of forces and torques on the handrim are important to study status and change of propulsion technique (and consequently mechanical strain) due to processes of learning, training or the wheelchair configuration. The purpose of this study was to compare the simultaneous outcomes of two different measurement-wheels attached to the different sides of the wheelchair, to determine measurement consistency within and between these wheels given the expected inter- and intra-limb variability as a consequence of motor control. METHODS: Nine able-bodied subjects received a three-week low-intensity handrim wheelchair practice intervention. They then performed three four-minute trials of wheelchair propulsion in an instrumented hand rim wheelchair on a motor-driven treadmill at a fixed belt speed. The two measurement-wheels on each side of the wheelchair measured forces and torques of one of the two upper limbs, which simultaneously perform the push action over time. The resulting data were compared as direct output using cross-correlation on the torque around the wheel axle. Calculated push characteristics such as power production and speed were compared using an intra-class correlation. RESULTS: Measured torque around the wheel axle of the two measurement-wheels had a high average cross-correlation of 0.98 (std=0.01). Unilateral mean power output over a minute was found to have an intra-class correlation of 0.89 between the wheels. Although the difference over the pushes between left and right power output had a high variability, the mean difference between the measurement-wheels was low at 0.03 W (std=1.60). Other push characteristics showed even higher ICC's (>0.9). CONCLUSIONS: A good agreement between both measurement-wheels was found at the level of the power output. This indicates a high comparability of the measurement-wheels for the different propulsion parameters. Data from both wheels seem suitable to be used together or interchangeably in experiments on motor control and wheelchair propulsion performance. A high variability in forces and timing between the left and right side were found during the execution of this bimanual task, reflecting the human motor control process. PMID- 23360757 TI - Clinical phenotypes of chronic obstructive pulmonary disease and asthma: recent advances. AB - Asthma and chronic obstructive pulmonary disease (COPD) are prevalent obstructive lung diseases, both of which are characterized by airflow limitation. Although both represent distinct pathogenic entities, there can be significant clinical and physiologic overlap between the 2 disorders, creating potential management difficulties for clinicians. Although practice guidelines for both conditions outline diagnostic and management strategies, asthma and COPD are highly heterogeneous, and the symptoms of many patients remain poorly controlled despite adherence to current guidelines. Recent advances in phenotyping studies have elucidated heterogeneity in these airway diseases and might represent the best opportunity to enhance diagnosis, predict outcomes, and personalize treatments in patients with asthma and those with COPD. This review will focus on recent advances in describing phenotypic heterogeneity in asthma and COPD, including the evaluation of multiple clinical variables, molecular biomarkers, physiologic and radiologic data, and factors associated with disease progression and frequent exacerbations. PMID- 23360758 TI - The exosome in lung diseases: Message in a bottle. PMID- 23360759 TI - Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. AB - Reduced responsiveness to the anti-inflammatory effects of corticosteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms leading to steroid resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several molecular mechanisms have been identified that might account for reduced steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) alpha after binding corticosteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen activated protein kinase alpha, p38 mitogen-activated protein kinase gamma, and c Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRbeta, which competes with and thus inhibits activated GRalpha; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase delta. Strategies for managing steroid resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase delta inhibitors. Long-acting beta2-agonists can also increase steroid responsiveness by reversing GRalpha phosphorylation. Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments. PMID- 23360760 TI - [Symptomatic management of brain metastasis]. AB - Indications and choice of antiepileptic drugs (AED), treatments for cerebral edema and prophylactic and curative treatments of thromboembolic complications of brain metastasis are discussed. PMID- 23360762 TI - Conservation of globin genes in the "living fossil" Latimeria chalumnae and reconstruction of the evolution of the vertebrate globin family. AB - The (hemo-)globins are among the best-investigated proteins in biomedical sciences. These small heme-proteins play an important role in oxygen supply, but may also have other functions. In addition to well known hemoglobin and myoglobin, six other vertebrate globin types have been identified in recent years: neuroglobin, cytoglobin, globin E, globin X, globin Y, and androglobin. Analyses of the genome of the "living fossil" Latimeria chalumnae show that the coelacanth is the only known vertebrate that includes all eight globin types. Thus, Latimeria can also be considered as a "globin fossil". Analyses of gene synteny and phylogenetic reconstructions allow us to trace the evolution and the functional changes of the vertebrate globin family. Neuroglobin and globin X diverged from the other globin types before the separation of Protostomia and Deuterostomia. The cytoglobins, which are unlikely to be involved in O2 supply, form the earliest globin branch within the jawed vertebrates (Gnathostomata), but do not group with the agnathan hemoglobins, as it has been proposed before. There is strong evidence from phylogenetic reconstructions and gene synteny that the eye-specific globin E and muscle-specific myoglobin constitute a common clade, suggesting a similar role in intracellular O2 supply. Latimeria possesses two alpha- and two beta-hemoglobin chains, of which one alpha-chain emerged prior to the divergence of Actinopterygii and Sarcopterygii, but has been retained only in the coelacanth. Notably, the embryonic hemoglobin alpha-chains of Gnathostomata derive from a common ancestor, while the embryonic beta-chains - with the exception of a more complex pattern in the coelacanth and amphibians - display a clade-specific evolution. Globin Y is associated with the hemoglobin gene cluster, but its phylogenetic position is not resolved. Our data show an early divergence of distinct globin types in the vertebrate evolution before the emergence of tetrapods. The subsequent loss of globins in certain taxa may be associated with changes in the oxygen-dependent metabolism. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. PMID- 23360763 TI - Exploiting the repertoire of CK2 inhibitors to target DYRK and PIM kinases. AB - Advantage has been taken of the relative promiscuity of commonly used inhibitors of protein kinase CK2 to develop compounds that can be exploited for the selective inhibition of druggable kinases other than CK2 itself. Here we summarize data obtained by altering the scaffold of CK2 inhibitors to give rise to novel selective inhibitors of DYRK1A and to a powerful cell permeable dual inhibitor of PIM1 and CK2. In the former case one of the new compounds, C624 (naphto [1,2-b]benzofuran-5,9-diol) displays a potency comparable to that of the first-in-class DYRK1A inhibitor, harmine, lacking however the drawback of drastically inhibiting monoamine oxidase-A (MAO-A) as harmine does. On the other hand the promiscuous CK2 inhibitor 4,5,6,7-tetrabromo-1H-benzimidazole (TBI,TBBz) has been derivatized with a sugar moiety to generate a 1-(beta-D-2' deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole (TDB) compound which inhibits PIM1 and CK2 with comparably high efficacy (IC50 values<100nM) and remarkable selectivity. TDB, unlike other dual PIM1/CK2 inhibitors described in the literature is readily cell permeable and displays a cytotoxic effect on cancer cells consistent with concomitant inhibition of both its onco-kinase targets. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012). PMID- 23360764 TI - Identification of the potential regions of Epap-1 that interacts with V3 loop of HIV-1 gp120. AB - Early pregnancy associated protein-1 (Epap-1), a 90kDa glycoprotein present in first trimester placental tissue, inhibits HIV-1 entry through interaction with HIV-1 gp120 at V3 and C5 regions. In the present study, we have identified the specific 32 mer region of Epap-1 that can interact with V3 loop. This was achieved by docking between Epap-1 molecular model and gp120 and studying the interaction of peptides with gp120 in vitro. Out of four peptides analyzed, two peptides (P-2 and P-3) showed significant interaction with V3 domain (N=8; N=7) of gp120. In the studies conducted using soluble gp120 and virus, peptide P-2 has shown conserved interaction at V3 loop regions recognized by 257D and F425 antibodies and higher anti-viral activity. Also, P-2 inhibited cell fusion mediated dye transfer between gp120 expressing HL2/3 and CD4 expressing Sup T1 cells suggesting its inhibition of viral entry, which is further confirmed by its action on HIV infection mediated by Tat activated beta gal expression in TZM-bl cells. Further optimization of P-2 peptide showed that the anti-viral activity and gp120 interaction residues lie in the N-terminal region of the peptide. These results together suggest that P-2 inhibits viral entry through specific interaction at V3 loop region. PMID- 23360761 TI - Ubiquilin-1 and protein quality control in Alzheimer disease. AB - Single nucleotide polymorphisms in the ubiquilin-1 gene may confer risk for late onset Alzheimer disease (AD). We have shown previously that ubiquilin-1 functions as a molecular chaperone for the amyloid precursor protein (APP) and that protein levels of ubiquilin-1 are decreased in the brains of AD patients. We have recently found that ubiquilin-1 regulates APP trafficking and subsequent secretase processing by stimulating non-degradative ubiquitination of a single lysine residue in the cytosolic domain of APP. Thus, ubiquilin-1 plays a central role in regulating APP biosynthesis, trafficking and ultimately toxicity. As ubiquilin-1 and other ubiquilin family members have now been implicated in the pathogenesis of numerous neurodegenerative diseases, these findings provide mechanistic insights into the central role of ubiquilin proteins in maintaining neuronal proteostasis. PMID- 23360765 TI - Unraveling protein stabilization mechanisms: vitrification and water replacement in a glass transition temperature controlled system. AB - The aim of this study was to elucidate the role of the two main mechanisms used to explain the stabilization of proteins by sugar glasses during drying and subsequent storage: the vitrification and the water replacement theory. Although in literature protein stability is often attributed to either vitrification or water replacement, both mechanisms could play a role and they should be considered simultaneously. A model protein, alkaline phosphatase, was incorporated in either inulin or trehalose by spray drying. To study the storage stability at different glass transition temperatures, a buffer which acts as a plasticizer, ammediol, was incorporated in the sugar glasses. At low glass transition temperatures (<50 degrees C), the enzymatic activity of the protein strongly decreased during storage at 60 degrees C. Protein stability increased when the glass transition temperature was raised considerably above the storage temperature. This increased stability could be attributed to vitrification. A further increase of the glass transition temperature did not further improve stability. In conclusion, vitrification plays a dominant role in stabilization at glass transition temperatures up to 10 to 20 degrees C above storage temperature, depending on whether trehalose or inulin is used. On the other hand, the water replacement mechanism predominantly determines stability at higher glass transition temperatures. PMID- 23360766 TI - Quantitative NMR analysis of Erk activity and inhibition by U0126 in a panel of patient-derived colorectal cancer cell lines. AB - We comparatively analyzed the basal activity of extra-cellular signal-regulated kinase (Erk1/2) in lysates of 10 human colorectal cancer cell lines by semi quantitative Western blotting and time-resolved NMR spectroscopy. Both methods revealed heterogeneous levels of endogenous Erk1/2 activities in a highly consistent manner. Upon treatment with U0126, an inhibitor of mitogen-activated protein kinase kinase (MEK) acting upstream of Erk1/2, Western-blotting and NMR congruently reported specific modulations of cellular phospho-Erk levels that translated into reduced kinase activities. Results obtained in this study highlight the complementary nature of antibody- and NMR-based phospho-detection techniques. They further exemplify the usefulness of time-resolved NMR measurements in providing fast and quantitative readouts of kinase activities and kinase inhibitor efficacies in native cellular environments. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012). PMID- 23360767 TI - Safety of continuous anticoagulation with dabigatran during implantation of cardiac rhythm devices. AB - The perioperative bleeding risk associated with therapeutic anticoagulation at cardiac implantable electronic device implantation has previously been demonstrated to vary by the specific anticoagulant used. Although uninterrupted anticoagulation with warfarin appears to be safe, heparin products have been shown to increase the risk of perioperative bleeding. However, the risk associated with cardiac implantable electronic device implantation with anticoagulation using dabigatran, a novel oral direct thrombin inhibitor, is not known. We performed a prospective observational study of patients receiving dabigatran for anticoagulation who underwent cardiac implantable electronic device implantation from June 2011 through May 2012. The study end points included thromboembolic and bleeding complications within 30 days of surgery. Major bleeding complications were defined as bleeding requiring surgical intervention, prolongation of hospitalization, and discontinuation of the anticoagulant or transfusion of blood products within 30 days of surgery. Minor bleeding complications included the development of a hematoma not requiring additional intervention. The thrombotic end points included stroke, transient ischemic attack, myocardial infarction, pulmonary embolism, and deep vein thrombosis. A total of 25 patients were identified for inclusion. During the index hospitalization, no thromboembolic or bleeding complications developed. No major bleeding complications occurred within 30 days of surgery. One minor bleeding event (4%) occurred within 30 days of surgery in 1 patient who was also receiving dual antiplatelet therapy. In conclusion, although no thromboembolic or major bleeding events were observed, additional studies are required to define the optimal antithrombotic management in the perioperative period. PMID- 23360768 TI - Effect of morbid obesity on in-hospital mortality and coronary revascularization outcomes after acute myocardial infarction in the United States. AB - The aim of this study was to investigate the impact of morbid obesity (body mass index >=40 kg/m(2)) on in-hospital mortality and coronary revascularization outcomes in patients presenting with acute myocardial infarctions (AMI). The Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project was used, and 413,673 patients hospitalized with AMIs in 2009 were reviewed. Morbidly obese patients constituted 3.7% of all patients with AMIs. Analysis of the unadjusted data revealed that morbidly obese patients compared with those not morbidly obese were more likely to undergo any invasive cardiac procedures when presenting with either ST-segment elevation myocardial infarction (97.4% vs 93.8%, p <0.0001) or non-ST-segment elevation myocardial infarction (85.5% vs 80.6%, p <0.0001). The unadjusted mortality rate for morbidly obese patients with AMIs was 3.5%, compared with 5.5% of those not obese (p <0.0001). After adjustment, lower odds of mortality in those morbidly obese compared to those not morbidly remained. In conclusion, patients with morbid obesity had lower odds of in-hospital mortality, compared to those not morbidly obese, consistent with the phenomenon of the "obesity paradox." PMID- 23360769 TI - Relation of statin therapy to psychological functioning in patients with an implantable cardioverter defibrillator. AB - Statin therapy is an important secondary prevention measure in cardiovascular disease. However, the side effects associated with statin use could potentially affect patients' quality of life. Little is known about the influence of statin therapy on the well-being and health status of cardiac patients, in general, and patients with an implantable cardioverter defibrillator (ICD), in particular. We investigated the association between statin therapy and symptoms of anxiety and depression and patients' health status during the 12 months after implantation, reckoning with statin type and dosage. Consecutively implanted ICD patients (n = 409; 78.2% men) completed the Hospital Anxiety and Depression Scale and the Medical Outcomes Study Short Form 36-item Health Survey at baseline and 3, 6, and 12 months after implantation. The data were analyzed using general linear mixed modeling repeated measures multivariate analysis of variance. Of the 409 patients, 60% were prescribed statins. Statin use was independently associated with poorer role limitations-physical (p = 0.001), social functioning (p = 0.007), and role limitations-emotional (p = 0.006) during the 12 months after implantation, independent of statin type, dosage, and other potential confounders. The associations between statin therapy and depression (p = 0.06) and statin therapy and physical functioning (p = 0.05) were borderline significant, and no association was found with anxiety (p >0.05). In conclusion, statin therapy was associated with impaired health status on 3 of the 8 Medical Outcomes Study Short Form 36-item Health Survey health status subdomains. This is the first study of ICD patients to examine the association between statin therapy and patient well-being. Future research is warranted to replicate these findings. PMID- 23360770 TI - The role of membrane fatty acid remodeling in the antitumor mechanism of action of 2-hydroxyoleic acid. AB - The synthetic fatty acid 2-hydroxyoleic acid (2OHOA) is a potent antitumor drug that we rationally designed to regulate the membrane lipid composition and structure. The lipid modifications caused by 2OHOA treatments induce important signaling changes that end up with cell death (Teres et al., 2012 [1]). One of these regulatory effects is restoration of sphingomyelin levels, which are markedly lower in cancer cells compared to normal cells (Barcelo-Coblijn et al., 2011 [2]). In this study, we report another important regulatory effect of 2OHOA on cancer cell membrane composition: a large increase in 2OHOA levels, accounting for ~15% of the fatty acids present in membrane phospholipids, in human glioma (SF767 and U118) and lung cancer (A549) cells. Concomitantly, we observed marked reductions in oleic acid levels and inhibition of stearoyl-CoA desaturase. The impact of these changes on the biophysical properties of the lipid bilayer was evaluated in liposomes reconstituted from cancer cell membrane lipid extracts. Thus, 2OHOA increased the packing of ordered domains and decreased the global order of the membrane. The present results further support and extend the knowledge about the mechanism of action for 2OHOA, based on the regulation of the membrane lipid composition and structure and subsequent modulation of membrane protein-associated signaling. PMID- 23360772 TI - Systems approaches to integrated solid waste management in developing countries. AB - Solid waste management (SWM) has become an issue of increasing global concern as urban populations continue to rise and consumption patterns change. The health and environmental implications associated with SWM are mounting in urgency, particularly in the context of developing countries. While systems analyses largely targeting well-defined, engineered systems have been used to help SWM agencies in industrialized countries since the 1960s, collection and removal dominate the SWM sector in developing countries. This review contrasts the history and current paradigms of SWM practices and policies in industrialized countries with the current challenges and complexities faced in developing country SWM. In industrialized countries, public health, environment, resource scarcity, climate change, and public awareness and participation have acted as SWM drivers towards the current paradigm of integrated SWM. However, urbanization, inequality, and economic growth; cultural and socio-economic aspects; policy, governance, and institutional issues; and international influences have complicated SWM in developing countries. This has limited the applicability of approaches that were successful along the SWM development trajectories of industrialized countries. This review demonstrates the importance of founding new SWM approaches for developing country contexts in post-normal science and complex, adaptive systems thinking. PMID- 23360773 TI - An analysis of the composition and metal contamination of plastics from waste electrical and electronic equipment (WEEE). AB - The compositions of three WEEE plastic batches of different origin were investigated using infrared spectroscopy, and the metal content was determined with inductively coupled plasma. The composition analysis of the plastics was based mainly on 14 samples collected from a real waste stream, and showed that the major constituents were high impact polystyrene (42 wt%), acrylonitrile butadiene-styrene copolymer (38 wt%) and polypropylene (10 wt%). Their respective standard deviations were 21.4%, 16.5% and 60.7%, indicating a considerable variation even within a single batch. The level of metal particle contamination was found to be low in all samples, whereas wood contamination and rubber contamination were found to be about 1 wt% each in most samples. In the metal content analysis, iron was detected at levels up to 700 ppm in the recyclable waste plastics fraction, which is of concern due to its potential to catalyse redox reactions during melt processing and thus accelerate the degradation of plastics during recycling. Toxic metals were found only at very low concentrations, with the exception of lead and cadmium which could be detected at 200 ppm and 70 ppm levels, respectively, but these values are below the current threshold limits of 1000 ppm and 100 ppm set by the Restriction of Hazardous Substances directive. PMID- 23360771 TI - Reduced phosphorylation of GluA1 subunits relates to anxiety-like behaviours in mice. AB - Anxiety and depression are highly prevalent and frequently co-morbid conditions. The ionotropic glutamate receptors N-methyl-D-aspartate and alpha-amino-3-hydroxy 5-methyl-4-isoxazolepropionic acid (AMPA) mediate actions of monoaminergic antidepressants and have been directly targeted by novel fast-acting antidepressants. Less is known about the role of these receptors in anxiety-like states. Here we investigate how two distinct anxiolytic agents, buspirone, a partial 5-HT(1A) agonist, and diazepam, a benzodiazepine, influence phosphorylation of GluA1 subunits of AMPA receptors at the potentiating residue Ser(845) and Ser(831) in corticolimbic regions. To test the functional relevance of these changes, phosphomutant GluA1 mice lacking phosphorylatable Ser(845) and Ser(831) were examined in relevant behavioural paradigms. These mutant mice exhibited a reduced anxiety-like phenotype in the light/dark exploration task and elevated plus maze, but not in the novelty induced hypophagia paradigm. These data indicate that reduced potentiation of the AMPA receptor signalling, via decreased GluA1 phoshorylation, is specifically involved in approach-avoidance based paradigms relevant for anxiety-like behaviours. PMID- 23360774 TI - The effect of long-range order on the elastic properties of Cu3Au. AB - Ab initio calculations, based on the exact muffin-tin orbitals method are used to determine the elastic properties of Cu-Au alloys with Au/Cu ratio 1/3. The compositional disorder is treated within the coherent potential approximation. The lattice parameters and single-crystal elastic constants are calculated for different partially ordered structures ranging from the fully ordered L1(2) to the random face centered cubic lattice. It is shown that the theoretical elastic constants follow a clear trend with the degree of chemical order: namely, C(11) and C(12) decrease, whereas C(44) remains nearly constant with increasing disorder. The present results are in line with the experimental findings that the impact of the chemical ordering on the fundamental elastic parameters is close to the resolution of the available experimental and theoretical tools. PMID- 23360775 TI - Comparison of the therapeutic effects of human and mouse adipose-derived stem cells in a murine model of lipopolysaccharide-induced acute lung injury. AB - INTRODUCTION: Adipose-derived stem cells (ASCs) have emerged as important regulators of inflammatory/immune responses in vitro and in vivo and represent attractive candidates for cell-based therapies for diseases that involve excessive inflammation. Acute lung injury (ALI) is an inflammatory condition for which treatment is mainly supportive due to lack of effective therapies. In this study, the therapeutic effects of ASC-based therapy were assessed in vivo by comparison of the anti-inflammatory properties of both human and murine ASCs in a mouse model of lipopolysaccharide (LPS)-induced ALI. METHODS: Human ASCs (hASCs) or mouse ASCs (mASCs) were delivered to C57Bl/6 mice (7.5 * 105 total cells/mouse) by oropharyngeal aspiration (OA) four hours after the animals were challenged with lipopolysaccharide (15 mg/kg). Mice were sacrificed 24 and 72 hours after LPS exposure, and lung histology examined for evaluation of inflammation and injury. Bronchoalveolar lavage fluid (BALF) was analyzed to determine total and differential cell counts, total protein and albumin concentrations, and myeloperoxidase (MPO) activity. Cytokine expression in the injured lungs was measured at the steady-state mRNA levels and protein levels for assessment of the degree of lung inflammation. RESULTS: Both human and mouse ASC treatments provided protective anti-inflammatory responses. There were decreased levels of leukocyte (for example neutrophil) migration into the alveoli, total protein and albumin concentrations in BALF, and MPO activity after the induction of ALI following both therapies. Additionally, cell therapy with both cell types effectively suppressed the expression of proinflammatory cytokines and increased the anti-inflammatory cytokine interleukin 10 (IL-10). Overall, the syngeneic mASC therapy had a more potent therapeutic effect than the xenogeneic hASC therapy in this model. CONCLUSIONS: Treatment with hASCs or mASCs significantly attenuated LPS-induced acute lung injury in mice. These results suggest a potential benefit for using an ASC-based therapy to treat clinical ALI and may possibly prevent the development of acute respiratory distress syndrome (ARDS). PMID- 23360776 TI - No relation between vitamin D status and physical performance in the oldest old: results from the Belfrail study. AB - BACKGROUND: vitamin D deficiency is a well-known cause of bone loss and fractures but its association, especially among the oldest old, with muscle weakness is less obvious. OBJECTIVE: to investigate the relationship between 25 hydroxyvitamin D (25-OHD) and muscle performance in persons aged 80 years and older. METHODS: baseline results of the Belfrail study, a prospective, population based cohort study were used to study balance, grip strength and gait speed in relation to 25-OHD serum levels in 367 subjects. RESULTS: a sufficient 25-OHD serum level of 30 ng/ml or more was found in 12.8% of the population. The prevalence of vitamin deficiency (20-29 ng/ml), insufficiency (10-19 ng/ml) and severe insufficiency (<10 ng/ml) was 21.5, 33 and 32.7%, respectively. No significant relation between balance, gait speed and grip strength, and serum 25 OHD was detected neither in bivariate analysis nor after adjustment for age, gender, level of education, institutionalisation, smoking status, body mass index, co-morbidity, level of activity, season, CRP, renal function, serum calcium parathyroid hormone levels, vitamin D intake and use of loop or thiazide diuretics. CONCLUSION: in this cohort of octogenarians vitamin D deficiency was highly prevalent. We could not confirm the findings of previous studies showing an association between serum 25-OHD and physical performance in elderly. PMID- 23360777 TI - The role of contractile unit reorganization in force generation in airway smooth muscle. AB - Airway smooth muscle (ASM) cells undergo remodelling and reside in a tissue structure that is subject to heterogenous stress distributions that change dynamically during the breathing cycle. In this paper, we develop a structural model of an ASM cell that consists of contractile units (actin and myosin filaments) in series and parallel, anchored to a nonlinearly elastic cytoskeleton. We mimic a typical experimental protocol that involves isometric force generation through triggering of the contractile machinery, followed by oscillatory length fluctuation of the cell. We use the model to predict the effect of a single instance of rearrangement of the contractile machinery, combined with strain-stiffening of the cytoskeleton, on the force generated by the sarcomeres, and the total force generated by the cell. By linking intra cellular events to whole-cell behaviour, the model reveals mechanistic relationships between structural properties and cell-level force-length loops. We show how contractile force, shortening velocity and sarcomere operating lengths vary as the internal cell architecture is altered. Additionally, we show how interactions between the internal contractile machinery and cytoskeletal structure play a role in the regulation of force generation and hysteresis of the cell. PMID- 23360778 TI - Degradation of Poly(epsilon-caprolactone) by thermophilic Streptomyces thermoviolaceus subsp. thermoviolaceus 76T-2. AB - A thermophilic Streptomyces thermoviolaceus subsp. thermoviolaceus isolate 76T-2 that can degrade poly(epsilon-caprolactone) (PCL) was isolated from soil in Taiwan. Isolate 76T-2 grew well in urea fructose oatmeal medium and exhibited clear zones on agar plates containing PCL, indicating the presence of extracellular PCL depolymerases. The PCL powder present in culture medium was completely degraded within 6 h of culture at 45 degrees C. Two PCL-degrading enzymes were purified to homogeneity from the culture supernatant. The molecular weights of these two enzymes were estimated to be 25 kDa and 55 kDa, respectively. A portion of the N-terminal region of the 25-kDa protein was determined, and the sequence Ala-Asn-Phe-Val-Val-Ser-Glu-Ala thus obtained was identical to that of A64-A71 of the Chi25 chitinase of Streptomyces thermoviolaceus OPC-520. The 25-kDa protein was shown to also degrade chitin, suggesting that isolate 76T-2 has the ability to degrade both PCL and chitin. PMID- 23360779 TI - Benefit of revascularization for stable ischaemic heart disease: the jury is still out. PMID- 23360781 TI - T cell abnormalities in systemic sclerosis with a focus on Th17 cells. AB - Systemic sclerosis (SSc) is a connective tissue disorder characterized by vascular alterations and deregulated fibroblast activation leading to fibrosis of the skin and internal organs. SSc is thought to be an autoimmune disease, owning the presence of auto-antibodies. Genetic studies lend support to the critical role exerted by the immune response in the physiopathology of the disease, since several of the SSc-associated polymorphisms have been found in genes involved in the immune response. Oligoclonal T cells, preferentially producing type 2 cytokines, are present in affected tissues and peripheral blood early in the disease course, and their soluble mediators favor the production of pro-fibrotic and pro-angiogenic factors by fibroblasts, most likely participating in the establishment of fibrosis. More recently, we and others have reported an increased expression of additional T cell subsets, including Th17 cells, and their hallmark cytokines in the peripheral blood, serum and skin of SSc individuals. Here, we will review recent data on the presence of various T helper cells in SSc, and discuss the potential role of Th17 cells in promoting inflammatory responses while keeping fibrosis in check. An understanding of the immune abnormalities characteristic of SSc and their significance, represents a critical step towards the identification of novel therapies that could modify the course of the disease. PMID- 23360780 TI - Lineage shift in Indian strains of Dengue virus serotype-3 (Genotype III), evidenced by detection of lineage IV strains in clinical cases from Kerala. AB - BACKGROUND: Local epidemiology of Dengue is defined by the genetic diversity of the circulating Dengue virus (DENV) strains. This important information is not available for the virus strains from most parts of the Indian subcontinent. The present study focused on the genetic diversity of the serotype 3 DENV strains (DENV-3) from India. RESULTS: A total of 22 DENV-3 strains identified by reverse transcription PCR analysis of serum samples from 709 patients were studied. These samples were collected over a period of 4 years (2008-2011) from dengue fever suspected patients from Kerala, a dengue endemic state in South India. Comparison of a 1740bp nucleotide sequence of the viral Capsid-Pre-membrane-Envelope coding region of our strains and previously reported DENV-3 strains from India, South Asia and South America revealed non-synonymous substitutions that were genotype III-specific as well as sporadic. Evidence of positive selection was detected in the I81 amino acid residue of the envelope protein. Out of the 22 samples, three had I81A and 18 had I81V substitutions. In the phylogenetic analysis by maximum likelihood method the strains from Kerala clustered in two different lineages (lineage III and IV) within genotype III clade of DENV-3 strains. The ten strains that belonged to lineage IV had a signature amino acid substitution T219A in the envelope protein. Interestingly, all these strains were found to be closely related to a Singapore strain GU370053 isolated in 2007. CONCLUSIONS: Our study identifies for the first time the presence of lineage IV strains in the Indian subcontinent. Results indicate the possibility of a recent exotic introduction and also a shift from the existing lineage III strains to lineage IV. Lineage shifts in DENV-3 strains have been attributed to dramatic increase in disease severity in many parts of the world. Hence the present observation could be significant in terms of the clinical severity of future dengue cases in the region. PMID- 23360782 TI - The integration of NSC-derived and host neural networks after rat spinal cord transection. AB - Rebuilding structures that can bridge the injury gap and enable signal connection remains a challenging issue in spinal cord injury. We sought to determine if genetically enhanced expression of TrkC in neural stem cells (NSCs) and neurotrophin-3 in Schwann cells (SCs) co-cultured in a gelatin sponge scaffold could constitute a neural network, and whether it could act as a relay to rebuilt signal connection after spinal cord transection. Indeed, many NSCs in the scaffold assumed neuronal features including formation of synapses. By whole-cell patch clamp, the synapses associated with NSC-derived neurons were excitable. Grafting of the scaffold with differentiating NSCs + SCs into rats with a segment of the spinal cord removed had resulted in a significant functional recovery of the paralyzed hind-limbs. Remarkably, the NSC-derived neurons formed new synaptic contacts suggesting that the scaffold can form a relay for conduction of signals through the injury gap of spinal cord. PMID- 23360783 TI - Enzyme-responsive liposomes modified adenoviral vectors for enhanced tumor cell transduction and reduced immunogenicity. AB - Limitations of adenoviral (Ad) vectors for cancer gene therapy could be overcome by their combination with pharmaceutical technologies. Here we show that an enzyme-responsive liposomal formulation could significantly enhance the tumor cell transduction abilities and reduce the immunogenicity of Ad vectors. In the current research, the enzymatically cleavable PEG-lipids composed of a PEG/matrix metalloproteinase (MMP)-substrate peptide/cholesterol (PPC) were synthesized and characterized by (1)H NMR and TOF MS ES(+). The obtained MMP-cleavable lipids were inserted into the anionic liposomal Ad vectors (AL-Ad) by the post-insertion method. The results of in vitro infection assays indicated that the enzymatically cleavable formulation (PPC-AL-Ad) displayed a much higher gene expression than naked Ad5 and the non-cleavable PEG-lipid modified Ad vectors in tumor cells. More importantly, PPC-AL-Ad induces a lower production of neutralizing antibody and lower innate immune response, as well as significantly reduced liver toxicity in vivo. These findings suggest that PPC-AL-Ad is a promising system for gene delivery in tumor therapy. PMID- 23360785 TI - MicroRNAs in malignant melanoma. AB - Melanoma is the most aggressive form of skin cancer, and the incidence of melanoma has been increasing faster than that of most other cancers. While the survival rate following surgical resection of early-stage primary tumors is nearly 100%, the survival of patients with metastasized tumors is strongly reduced, likely due to resistance to conventional therapies. Therefore, it is important to use new molecular approaches to develop new biomarkers to better prevent and diagnose melanoma. MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally regulate gene expression via repression of translation or direct degradation of their complementary mRNA. In this review, we summarize our current understanding of the involvement of miRNAs and their corresponding targets in melanomagenesis as well as the potential use of miRNAs as biomarkers. PMID- 23360784 TI - The RON receptor tyrosine kinase is a potential therapeutic target in Burkitt lymphoma. AB - BACKGROUND: Aberrant expression of the RON receptor tyrosine kinase is associated with tumor progression and carcinogenesis. The aims of this study were to determine the role and functional mechanisms of RON in Burkitt lymphoma (BL) and to document its potential as a therapeutic target. METHODS: RON expression was determined in BL cell lines by western blot analysis and examined in human lymphoma specimens by both western blotting and immunohistochemistry. The correlation between RON expression and Epstein-Barr virus (EBV) infection was investigated. Raji cells were treated with the Zt/f2 anti-RON mAb and cell viability, colony formation, apoptosis and cell cycle arrest were measured in vitro using cell proliferation assays, colony-forming assays and flow cytometry. Downregulation of RON by Zt/f2 was validated in mice bearing Raji cell xenografts. RESULTS: Immunohistostaining showed a high frequency of RON (+) cells in BL tissues and RON expression strongly correlated with EBV positivity. RON downregulation significantly decreased cell proliferation and colony formation via promotion of apoptosis and cell cycle arrest in Raji cells. The in vivo study showed that RON knockdown inhibits the tumorigenic potential of Raji cells in nude mice. CONCLUSIONS: RON acts as an oncogene in the carcinogenesis and progression of BL and is therefore a potential target for therapeutic intervention. PMID- 23360786 TI - Classical and quantum ordering of protons in cold solid hydrogen under megabar pressures. AB - A combination of state-of-the-art theoretical methods has been used to obtain an atomic-level picture of classical and quantum ordering of protons in cold high pressure solid hydrogen. We focus mostly on phases II and III of hydrogen, exploring the effects of quantum nuclear motion on certain features of these phases (through a number of ab initio path integral molecular dynamics (PIMD) simulations at particular points on the phase diagram). We also examine the importance of van der Waals forces in this system by performing calculations using the optB88-vdW density functional, which accounts for non-local correlations. Our calculations reveal that the transition between phases I and II is strongly quantum in nature, resulting from a competition between anisotropic inter-molecular interactions that restrict molecular rotation and thermal plus quantum fluctuations of the nuclear positions that facilitate it. The transition from phase II to III is more classical because quantum nuclear motion plays only a secondary role and the transition is determined primarily by the underlying potential energy surface. A structure of P2(1)/c symmetry with 24 atoms in the primitive unit cell is found to be stable when anharmonic quantum nuclear vibrational motion is included at finite temperatures using the PIMD method. This structure gives a good account of the infra-red and Raman vibron frequencies of phase II. We find additional support for a C2/c structure as a strong candidate for phase III, since it remains transparent up to 300 GPa, even when quantum nuclear effects are included. Finally, we find that accounting for van der Waals forces improves the agreement between experiment and theory for the parts of the phase diagram considered, when compared to previous work which employed the widely-used Perdew-Burke-Ernzerhof exchange-correlation functional. PMID- 23360787 TI - Evaluation of animal models of obsessive-compulsive disorder: correlation with phasic dopamine neuron activity. AB - Obsessive compulsive disorder (OCD) is a psychiatric condition defined by intrusive thoughts (obsessions) associated with compensatory and repetitive behaviour (compulsions). However, advancement in our understanding of this disorder has been hampered by the absence of effective animal models and correspondingly analysis of the physiological changes that may be present in these models. To address this, we have evaluated two current rodent models of OCD; repeated injection of dopamine D2 agonist quinpirole and repeated adolescent injection of the tricyclic agent clomipramine in combination with a behavioural paradigm designed to produce compulsive lever pressing. These results were then compared with their relative impact on the state of activity of the mesolimbic dopaminergic system using extracellular recoding of spontaneously active dopamine neurons in the ventral tegmental area (VTA). The clomipramine model failed to exacerbate compulsive lever pressing and VTA dopamine neurons in clomipramine treated rats had mildly diminished bursting activity. In contrast, quinpirole treated animals showed significant increases in compulsive lever pressing, which was concurrent with a substantial diminution of bursting activity of VTA dopamine neurons. Therefore, VTA dopamine activity correlated with the behavioural response in these models. Taken together, these data support the view that compulsive behaviours likely reflect, at least in part, a disruption of the dopaminergic system, more specifically by a decrease in baseline phasic dopamine signalling mediated by burst firing of dopamine neurons. PMID- 23360788 TI - High-concentration of BMP2 reduces cell proliferation and increases apoptosis via DKK1 and SOST in human primary periosteal cells. AB - BMP2, a well-known osteoinductive agent approved by FDA, is currently being used for various off-label orthopedic applications. Recently, concerns about its efficacy for off-label use, concentration, and complications have emerged. Interestingly, there is an extremely large discrepancy in BMP2 concentration between clinical use (i.e. 1.5mg/ml) and in vitro studies (50-300 ng/ml). The purpose of this study was to determine the effects of a relatively high concentration of BMP2 on cell proliferation and apoptosis using human primary periosteal cells as BMP2 is generally applied around the periosteum in orthopedic surgeries. We isolated periosteal cells from three independent patients. The cell proliferation assessed by MTT activity was significantly reduced by a high concentration of BMP2 (~2000 ng/ml), while such a reduction was not observed by using a low-concentration of BMP2 (~200 ng/ml). The cell apoptosis assessed by caspase activity was significantly increased by high-concentration BMP2, while such an increase was not observed by low-concentration BMP2. We found that Wnt signaling activity was significantly reduced by high-concentration BMP2 along with a dramatic increase in DKK1 and SOST, key inhibitors of Wnt signaling in bone. The addition of DKK1 or SOST protein to the primary periosteal cells reduced MTT activity and significantly increased caspase activity. Silencing the DKK1 or SOST expression using the siRNA technique normalized cell proliferation and apoptosis in the periosteum-derived cells when exposed to a high concentration BMP2. Taken together, these results suggest that a high concentration BMP2 decreases human periosteal cell proliferation and induces apoptosis via the activation of Wnt inhibitors DKK1 and SOST. This study provides new insights to the effects of high BMP2 concentration on human periosteal cells and brings out the possibility of multiple effects of current BMP2 therapy on various skeletal tissues. PMID- 23360790 TI - Intra-articular delivery of adipose derived stromal cells attenuates osteoarthritis progression in an experimental rabbit model. AB - INTRODUCTION: Cell therapy is a rapidly growing area of research for the treatment of osteoarthritis (OA). This work is aimed to investigate the efficacy of intra-articular adipose-derived stromal cell (ASC) injection in the healing process on cartilage, synovial membrane and menisci in an experimental rabbit model. METHODS: The induction of OA was performed surgically through bilateral anterior cruciate ligament transection (ACLT) to achieve eight weeks from ACLT a mild grade of OA. A total of 2*106 and 6*106 autologous ASCs isolated from inguinal fat, expanded in vitro and suspended in 4% rabbit serum albumin (RSA) were delivered in the hind limbs; 4% RSA was used as the control. Local bio distribution of the cells was verified by injecting chloro-methyl-benzamido-1,1' dioctadecyl-3,3,3'3'-tetra-methyl-indo-carbocyanine per-chlorate (CM-Dil) labeled ASCs in the hind limbs. Cartilage and synovial histological sections were scored by Laverty's scoring system to assess the severity of the pathology. Protein expression of some extracellular matrix molecules (collagen I and II), catabolic (metalloproteinase-1 and -3) and inflammatory (tumor necrosis factor- alpha) markers were detected by immunohistochemistry. Assessments were carried out at 16 and 24 weeks. RESULTS: Labeled-ASCs were detected unexpectedly in the synovial membrane and medial meniscus but not in cartilage tissue at 3 and 20 days from ASC-treatment. Intra-articular ASC administration decreases OA progression and exerts a healing contribution in the treated animals in comparison to OA and 4% RSA groups. CONCLUSIONS: Our data reveal a healing capacity of ASCs in promoting cartilage and menisci repair and attenuating inflammatory events in synovial membrane inhibiting OA progression. On the basis of the local bio-distribution findings, the benefits obtained by ASC treatment could be due to a trophic mechanism of action by the release of growth factors and cytokines. PMID- 23360789 TI - Lysosomal basification and decreased autophagic flux in oxidatively stressed trabecular meshwork cells: implications for glaucoma pathogenesis. AB - Increasing evidence suggests oxidative damage as a key factor contributing to the failure of the conventional outflow pathway tissue to maintain appropriate levels of intraocular pressure, and thus increase the risk for developing glaucoma, a late-onset disease which is the second leading cause of permanent blindness worldwide. Autophagy is emerging as an essential cellular survival mechanism against a variety of stressors, including oxidative stress. Here, we have monitored, by using different methodologies (LC3-I to LC3-II turnover, tfLC3, and Cyto ID), the induction of autophagy and autophagy flux in TM cells subjected to a normobaric hyperoxic model of mild chronic oxidative stress. Our data indicate the MTOR-mediated activation of autophagy and nuclear translocation of TFEB in oxidatively stressed TM cells, as well as the role of autophagy in the occurrence of SA-GLB1/SA-beta-gal. Concomitant with the activation of the autophagic pathway, TM cells grown under oxidative stress conditions displayed, however, reduced cathepsin (CTS) activities, reduced lysosomal acidification and impaired CTSB proteolytic maturation, resulting in decreased autophagic flux. We propose that diminished autophagic flux induced by oxidative stress might represent one of the factors leading to progressive failure of cellular TM function with age and contribute to the pathogenesis of primary open angle glaucoma. PMID- 23360792 TI - Retroperitoneal metastatic germ cell tumor presenting as a psoas abscess: a diagnostic pitfall. AB - Most testicular neoplasms are germ cell tumors, the vast majority of which represent seminomas. Most seminomas present localized to the testis, whereas nonseminomatous germ cell tumors more often present with lymph node metastases. Psoas abscesses generally arise from a contiguous intra-abdominal or pelvic infectious process, an adjacent focus of osteomyelitis or septic emboli from distant infectious foci. In this study, the case of a 24-year-old man who presented with a right psoas mass presumptively diagnosed as an abscess secondary to fever and leukocytosis is presented. The patient had a history of right testicular seminoma, and normal serum levels of alpha-fetoprotein and human chorionic gonadotropin. Surgical exploration and biopsy demonstrated seminoma metastasis. This case represents an extremely unusual clinical presentation of metastatic germ cell tumor presenting as a psoas abscess. This unique case represents an unusual presentation of a recurrent germ cell tumor mimicking a psoas abscess. Awareness of possible metastatic testicular germ cell neoplasm as a psoas abscess could prevent diagnosis delay before retroperitoneal tumor debulking. PMID- 23360791 TI - NPTX2 hypermethylation in pure pancreatic juice predicts pancreatic neoplasms. AB - The neuronal pentraxin II (NPTX2) gene is methylated in over 90% primary pancreatic cancer tissues but rarely in normal pancreatic ductal epithelia. Here, the authors investigated the utility of methylated NPTX2 as a diagnostic marker for pancreatic cancer in pure pancreatic juice samples of patients with benign and malignant pancreatic diseases, including pancreatic cancer, intraductal papillary mucinous neoplasm or chronic pancreatitis using methylation-specific polymerase chain reaction (MSP) and quantitative MSP. MSP assays revealed that the incidence of aberrant NPTX methylation in pure pancreatic juice samples was 64.5% (20 of 31) in patients with pancreatic cancer, 70.0% (7 of 10) in patients with malignant intraductal papillary mucinous neoplasm, 33.3% (2 of 6) in patients with benign intraductal papillary mucinous neoplasm and 21.7% (5 of 23) in patients with chronic pancreatitis. NPTX2 hypermethylation in patients with chronic pancreatitis was significantly lower than that of pancreatic cancer (P < 0.01) or patients with intraductal papillary mucinous neoplasm (P < 0.05). At a cutoff value of 1.39 for quantitative MSP, the incidence of aberrant NPTX2 methylation was 61.3% (19 of 31) in patients with pancreatic cancer, 50.0% (5 of 10) in patients with malignant intraductal papillary mucinous neoplasm, 0% in patients with benign intraductal papillary mucinous neoplasm and 8.7% (2 of 23) in patients with chronic pancreatitis. There was a significant difference in NPTX2 methylation between pancreatic cancer and chronic pancreatitis (P < 0.01). Our findings indicate that detection of aberrant methylation of NPTX2 in pure pancreatic juice samples could be useful as a molecular marker to discriminate between patients with malignant and benign disease of the pancreas. PMID- 23360793 TI - Blastocystis hominis associated acute urticaria. AB - Acute urticaria has many causative factors, which may include infections, medications (nonsteroidal anti-inflammatory drugs, antibiotics, contraceptives and others), insect bites, physical stimuli, allergens or underlying systemic disorders. Blastocystis spp, although ubiquitous in developing countries, is rarely implicated in causing disease in the developed world. The authors present a case of acute urticaria caused by Blastocystis hominis (protozoon parasite) in an elderly farmer in rural United States. This case vignette emphasizes the importance of checking stool for ova and parasites to look for Blastocystis species in patients with urticaria under appropriate clinical settings when other common causative factors of the same have been ruled out. PMID- 23360794 TI - Chorionic plate arterial function is altered in maternal obesity. AB - OBJECTIVES: To characterise Chorionic Plate Artery (CPA) function in maternal obesity, and investigate whether leptin exposure reproduces the obese CPA phenotype in normal-BMI women. STUDY DESIGN: CPA responses to the thromboxane A(2) mimetic U46619 (pre/post leptin incubation), to the nitric oxide donor sodium nitroprusside (SNP) and the occurrence of tone oscillations (pre/post leptin incubation) were assessed in 46 term placentas from women of normal (18.5 24.9) or obese (>30) Body Mass Index (BMI). OUTCOME MEASURES: Area Under the dose response Curve (AUC), maximum response (V(max)), sensitivity (EC(50)) to U46619 (pre/post leptin) and SNP; average vessel tone, oscillation amplitude and frequency (pre/post leptin). RESULTS: U46619 vasoconstriction was similar between BMI categories (p > 0.05), however vasodilatation to SNP was reduced in obesity (AUC p = 0.02, V(max)p = 0.04) compared to normal-BMI women. Leptin incubation altered responses to U46619 in both normal-BMI (EC(50) at 100 ng/ml leptin; p < 0.05) and obese women (AUC at 50 ng/ml; p < 0.05) but vasomotion was unaffected (p > 0.05). CONCLUSIONS: Maternal obesity is associated with altered placental vascular function which may adversely affect placental oxygen and nutrient transport, placing the fetus at risk. Leptin incubation altered CPA vascular function but did not reproduce the obese phenotype. PMID- 23360796 TI - Genomic and epigenomic cross-talks in the regulatory landscape of miRNAs in breast cancer. AB - MicroRNAs (miRNA) are a class of endogenous, small noncoding RNAs found in animals, plants, and viruses that control their target gene expression posttranscriptionally. They are involved in a wide array of biological processes including cell differentiation, development, cell death and homeostasis, and fine tune the regulation of these pathways. Their aberrant expressions have been associated with different diseases. These small RNAs are also known to function as oncogenes, oncosupressor genes, modulators of metastatic spread, and regulators of cancer stem cells. Their deregulation is a hallmark of different cancers types including breast cancer. Despite the growing evidence for their involvement in breast cancer, understanding the interplay between miRNAs and their targets leading to the disease remains largely unknown. Here, we provide a comprehensive story on miRNA signatures of breast cancer, miRNAs in breast cancer stem cells, metastamirs (i.e., metastasis regulatory miRNAs), circulating miRNAs as invasive blood-based biomarkers, and oncomiRs and oncosupressor miRNAs associated with breast cancer. Furthermore, we provide biological insights on their regulation by various mechanisms including genomic alterations and demonstration of a complicated feedback network between miRNAs and epigenetic regulators forming an epigenetics-miRNA regulatory circuit whose disruption may underlie the cause of breast cancer. PMID- 23360795 TI - CPEB1 regulates the expression of MTDH/AEG-1 and glioblastoma cell migration. AB - Cytoplasmic polyadenylation element-binding protein 1 (CPEB1) is an mRNA-binding protein present in both neurons and glia. CPEB1 is capable of both repressing mRNA translation and activating it depending upon its phosphorylation state. CPEB1-bound mRNAs are held in translational dormancy until CPEB1 is phosphorylated, leading to the cytoplasmic polyadenylation of the bound mRNA that triggers translation. Here, we show that CPEB1 can bind to and regulate translation of the mRNA-encoding metadherin (MTDH, also known as AEG-1 and Lyric) in the rat glioblastoma cell line CNS1. MTDH/AEG-1 is being revealed as a critical signaling molecule in tumor progression, playing roles in invasion, metastasis, and chemoresistance. By using a mutant of CPEB1 that cannot be phosphorylated (thereby holding target mRNAs in translational arrest), we show that inhibiting CPEB1-mediated translation blocks MTDH/AEG-1 expression in vitro and inhibits glioblastomas tumor growth in vivo. CPEB1-mediated translation is likely to impact several signaling pathways that may promote tumor progression, but we present evidence suggesting a role in directed cell migration in glioblastoma cells. In addition, reporter mRNA containing CPEB1-binding sites is transported to the leading edge of migrating cells and translated, whereas the same mRNA with point mutations in the binding sites is synthesized perinuclearly. Our findings show that CPEB1 is hyperactive in rat glioblastoma cells and is regulating an important cohort of mRNAs whose increased translation is fueling the progression of tumor proliferation and dispersal in the brain. Thus, targeting CPEB1-mediated mRNA translation might be a sound therapeutic approach. PMID- 23360797 TI - NF-YA underlies EZH2 upregulation and is essential for proliferation of human epithelial ovarian cancer cells. AB - Epithelial ovarian cancer (EOC) accounts for the most gynecologic malignancy associated deaths in the United States. Enhancer of zeste homolog 2 (EZH2), which silences gene expression through generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3), is often overexpressed in EOCs and has been suggested as a therapeutic target. However, the mechanism underlying EZH2 overexpression in EOCs is unknown. Here, we show that EZH2 is upregulated at the transcription level, and two CCAAT boxes in the proximal regions of the human EZH2 gene promoter are critical for its transcription in EOC cells. Indeed, NF-YA, the regulatory subunit of the CCAAT-binding transcription factor NF-Y, is expressed at higher levels in human EOCs than in primary human ovarian surface epithelial (HOSE) cells. In addition, there is a positive correlation between expression of NF-YA and EZH2 in EOCs. Notably, high NF-YA expression predicts shorter overall survival in patients with EOCs. The association of NF-YA with the promoter of the human EZH2 gene is enhanced in human EOC cells compared with primary HOSE cells. Significantly, knockdown of NF-YA downregulates EZH2, decreases H3K27Me3 levels, and suppresses the growth of human EOC cells both in vitro and in a xenograft mouse model. Notably, NF-YA knockdown induces apoptosis of EOC cells and ectopic EZH2 expression partially rescues apoptosis induced by NF-YA knockdown. Together, these data reveal that NF-Y is a key regulator of EZH2 expression and is required for EOC cell proliferation, thus representing a novel target for developing EOC therapeutics. PMID- 23360798 TI - Relationship between a pro- and anti-inflammatory cytokine imbalance and depression in haemodialysis patients. AB - AIM: Depression represents the most frequent psychiatric disorder in patients on maintenance haemodialysis (HD), and it might be associated with secretion of inflammatory cytokines. In this study, we explore the possible correlations between depression and pro-inflammatory (IL-1beta, IL-6, and TNF-alpha), anti inflammatory (IL-10) cytokines, as well as high-sensitivity C-reactive protein (hs-CRP) serum levels. METHODS: Eighty three HD patients were enrolled in this cross-sectional study. Depressive symptoms were measured with the Beck Depression Inventory (BDI), and 'elevated symptoms of depression' were defined as a BDI score of >=16. Biochemical parameters (serum albumin, haemoglobin, ferritin, etc.) and dialysis dosage delivery (kt/v) were assessed. Serum IL-1beta, IL-6, IL 10, TNF-alpha, and hs-CRP levels were measured using an ELISA method. Thirty two, healthy, age- and sex-matched individuals were included as the control group. RESULTS: The prevalence of depression in HD patients was 61.4%. HD Patients with symptoms of depression had lower educational levels compared to non-depressed ones (P = 0.02), but did not differ with respect to age, gender, time on dialysis program, marital status, or smoking habits. Depressed patients also had significantly higher serum levels of IL-6, the IL-6-to-IL-10 ratio, as well as lower haemoglobin levels (P = 0.003, P = 0.002, and P = 0.02 respectively). No differences in mean serum IL-1beta, IL-10, TNF-alpha, or hs-CRP concentrations were noted between the two groups. The BDI scores showed a significant, positive correlation with serum levels of IL-1beta (P = 0.03), IL-6 (P = 0.001), TNF-alpha (P = 0.02), the IL-6-to-IL-10 ratio (P = 0.001), and a negative correlation with haemoglobin levels (P = 0.02). CONCLUSIONS: Maintenance HD patients with symptoms of depression may have higher serum levels of IL-6, a IL-6-to-IL-10 ratio, and lower haemoglobin concentrations. An imbalance between pro- and anti-inflammatory cytokines may play an important role in the pathogenesis of depression in HD patients. PMID- 23360799 TI - Effect of postoperative radiation therapy on mandibular reconstruction using a modular endoprosthesis - a pilot study. AB - The endoprosthetic system has been shown to be a potential option for mandibular reconstruction. The objective of this pilot in vivo animal study was to determine the effects of postoperative radiation using brachytherapy on bone and soft tissue healing in mandibles reconstructed with the endoprosthesis. Six adult Macaca fascicularis mandibles were reconstructed with a cemented endoprosthesis after segmental body resection. The animals were divided into two groups. The test group was subjected to radiation therapy 1 month postoperation while the control group did not receive any radiation. Results showed no major radiation side effects. Mucosal ulcerations and wound dehiscence at the radiated sites healed within 4 weeks. One animal from each group had prosthesis failure and was unable to complete the study. Micro-CT findings indicated no significant differences between the total bone volume percentage (TBV%) of the study and control groups. Histomorphometrical analysis using grading scales also showed no significant differences between the two groups. Under the study conditions, postoperative brachytherapy did not affect the tissue response around the endoprosthesis within the early 6 months postradiation period. The endoprosthesis, therefore, remains a viable reconstructive option when postoperative radiation is prescribed. PMID- 23360801 TI - Stop! Stay tuned for more information. PMID- 23360800 TI - Alternative splicing of AMPA receptor subunits in the 6-OHDA-lesioned rat model of Parkinson's disease and L-DOPA-induced dyskinesia. AB - Abnormal corticostriatal plasticity is a key mechanism of L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). Antagonists at glutamatergic alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, such as IEM 1460, reduce induction and expression of dyskinesia in rat and non-human primate models of PD. AMPA receptor function is regulated by post-transcriptional splicing of subunit mRNA to produce flip and flop isoforms, which may therefore influence corticostriatal plasticity. The aim of this work was to evaluate alterations in alternative splicing of striatal AMPA receptor subunits in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID and PD. Male Sprague-Dawley rats received 12.5 MUg 6-OHDA injections into the right medial forebrain bundle. In experiment 1, to assess acute dyskinesia, rats received L DOPA/benserazide (6/15 mg/kg, i.p.) or vehicle for 21 days. In experiment 2, to assess dyskinesia priming, rats received vehicle, L-DOPA+vehicle or L-DOPA+IEM 1460 (3 mg/kg, i.p.) for 21 days. Animals were humanely killed 1h following final treatment in experiment 1, and 48 h following final treatment in experiment 2. Coronal sections of rostral striatum were processed for in situ hybridisation histochemistry, using oligonucleotide probes specific for the GluR1 and GluR2 subunits and their flip and flop isoforms. L-DOPA treatment increased GluR2-flip mRNA expression in the lesioned striatum of both groups; this was blocked by the Ca(2+)-permeable AMPA receptor antagonist IEM 1460. GluR1-flip expression was increased after 48 h drug washout but not in acute LID. There were no changes in expression of flop isoforms. Alternative splicing of AMPAR subunits contributes to abnormal striatal plasticity in the induction and expression of LID. Increases in GluR2-flip expression depend on activation of Ca(2+)-permeable AMPA receptors, which are a potential target of anti-dyskinetic therapies. PMID- 23360802 TI - Modeling dyskinesia in animal models of Parkinson disease. AB - The treatment of motor symptoms of Parkinson disease (PD) with the dopamine (DA) precursor, l-3,4-dihydroxyphenylalanine (l-DOPA) introduced 50years ago still remains a very effective medication. However, involuntary movements termed l-DOPA induced dyskinesias (LID) appear in the vast majority of PD patients after chronic treatment and may become disabling. Once they appeared, the first dose after a several-weeks drug holiday will trigger them again, showing that l-DOPA has permanently or persistently modified the brain response to DA. LID are very difficult to manage and no drug is yet approved for dyskinesias, aside from a modest benefit with amantadine. New drugs are needed for PD to alleviate parkinsonian symptoms without inducing dyskinesias. Hence, animal models have been developed to seek the mechanisms involved in LID and new drug targets. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was discovered as a contamination of a derivative of heroin taken by drug users and produced similar motor symptoms as idiopathic PD. Since then, MPTP is used extensively to model PD and LID in non-human primates and mice in addition to the classical PD model in rats with a 6-hydroxydopamine (6-OHDA) lesion. This article reviews rodent and non-human primate models of PD that reproduce motor complications induced by DA replacement therapy. Moreover, key biochemical changes in the brain of post-mortem PD patients with LID will be compared to those observed in animal models. Finally, the translational usefulness of drugs found to treat LID in animal models will be compared to their clinical activities. PMID- 23360803 TI - Dermatan 4-O-sulfotransferase1 ablation accelerates peripheral nerve regeneration. AB - Chondroitin sulfate (CS) and dermatan sulfate (DS) proteoglycans are major components of the extracellular matrix implicated in neural development, plasticity and regeneration. While it is accepted that CS are major inhibitors of neural regeneration, the contributions of DS to regeneration have not been assessed. To enable a novel approach in studies on DS versus CS roles during development and regeneration, we generated a mouse deficient in the dermatan 4-O sulfotransferase1 (Chst14(-/-)), a key enzyme in the synthesis of iduronic acid containing modules found in DS but not CS. In wild-type mice, Chst14 is expressed at high levels in the skin and in the nervous system, and is enriched in astrocytes and Schwann cells. Ablation of Chst14, and the assumed failure to produce DS, resulted in smaller body mass, reduced fertility, kinked tail and increased skin fragility compared with wild-type (Chst14(+/+)) littermates, but brain weight and gross anatomy were unaffected. Neurons and Schwann cells from Chst14(-/-) mice formed longer processes in vitro, and Chst14(-/-) Schwann cells proliferated more than Chst14(+/+) Schwann cells. After femoral nerve transection/suture, functional recovery and axonal regrowth in Chst14(-/-) mice were initially accelerated but the final outcome 3months after injury was not better than that in Chst14(+/+) littermates. These results suggest that while Chst14 and its enzymatic products might be of limited importance for neural development, they may contribute to the regeneration-restricting environment in the adult mammalian nervous system. PMID- 23360804 TI - Mindin is a critical mediator of ischemic brain injury in an experimental stroke model. AB - BACKGROUND: Stroke is the second leading cause of death among adults worldwide. Mindin is an ECM protein that plays important roles in regulating inflammation, angiogenesis and neuronal outgrowth. The role of mindin in the context of brain ischemia has not been examined. METHODS AND RESULTS: Transient occlusion of the middle cerebral artery was performed on mindin knockout (KO) mice, mice that carried a neuron-specific constitutively active mindin transgene (TG) and the appropriate controls. The outcome of the ischemia was evaluated by examination of the infarct and edema volumes and by neurological score assessments. The brains were collected 24 h or 3 days following the induced stroke. Compared with the control mice, the mindin KO mice exhibited lower infarct volumes and better outcomes in the neurological tests. Mindin-deficient mice exhibited low expression levels of stroke-induced inflammatory mediators, an attenuated recruitment of inflammatory cells, and inhibited activation of NF-kappaB. The neuronal apoptosis levels were also lower in the brains of the mindin KO mice than in those of the control mice. The mice that expressed a neuron-specific, constitutively active mindin transgene exhibited effects following the cerebral ischemic injury that were the opposite of those that were observed in the mindin KO mice. Moreover, Akt signaling activation was elevated in the ischemic brains of mindin KO mice. CONCLUSIONS: Mindin KO mice exhibited minor infarctions, an attenuated inflammatory response and low levels of neuronal apoptosis following an ischemic insult. These data demonstrate that mindin is a critical mediator of ischemic brain injury in an experimental stroke model. Akt signaling most likely mediates the biological function of mindin in this model of cerebral ischemia. PMID- 23360805 TI - Dopamine-rich grafts alleviate deficits in contralateral response space induced by extensive dopamine depletion in rats. AB - Unilateral infusion of 6-hydroxydopamine into the nigro-striatal pathway in the rat is the most common dopamine lesion model of Parkinson's disease. In the present study, we explore the impact of near complete unilateral loss of dopamine along the nigro-striatal pathway and subsequent cell replacement therapy in a choice reaction time task in rats, with assessment of spatial responding towards either side of the body (ipsilateral or contralateral to the lesion) on alternate days. Results indicated a stable contralateral deficit in response accuracy, reaction times and motor function for 50 consecutive days of testing, with no signs of recovery or compensation. All lesioned rats developed a near-hole bias and displayed prolonged movement and reaction times when responses had to be directed towards a distal response location on the side of the body contralateral to the lesion, as well as a smaller ipsilateral impairment in response accuracy and movement times. Grafts of dopamine-rich tissue into the denervated striatum improved some, but not all, of the deficits induced by the lesion. Specifically, grafted rats performed at a similar level to control animals when assessed on the ipsilateral side, they demonstrated a partial restitution of their ability to respond to far contralateral stimuli, and they exhibited a marked reduction in the time to complete all lateralised responses on both sides. The present characterisation of the task and the effects of cell replacement via primary fetal mesencephalic tissue demonstrate restorative properties in alleviating the marked spatial response bias induced by unilateral loss of dopamine. PMID- 23360807 TI - Delays in medical malpractice litigation in civil law jurisdictions: some evidence from the Italian Court of Cassation. AB - Medical malpractice law and tort reform are contentious issues. In this paper, we focus on Italy as an example of a civil law jurisdiction. Italian medical malpractice law is essentially judge-made law. However, its effectiveness is likely to be curtailed by excessive delays in litigation. Several reforms have been enacted since the late 1980s to correct this situation. By making use of the decisions of the Italian Court of Cassation (which have shaped medical malpractice law) from 1970 to 2009, we show that these reforms had no general statistically significant impact on delays. Recent reduction of delays does not seem to be related to legal reforms but rather explained by other factors. PMID- 23360808 TI - How Cr changes the dislocation core structure of alpha-Fe: the role of magnetism. AB - Cr is a critical alloying element in ferritic steels and its effect on the dislocation core structure of alpha-Fe is examined computationally using a quantum mechanics/molecular mechanics method. We find that Cr can significantly change the dislocation core structure of Fe where magnetism plays a crucial role. The strain-dependent magnetic interaction between Cr and the host Fe atoms is responsible for the dislocation core structure. When Cr is at the tension side of the slip plane, the Cr-Fe magnetic interaction is repulsive, which lowers the dislocation energy and pins the dislocation. When Cr occupies the compression side of the slip plane, the Cr-Fe interaction is attractive which increases the dislocation energy and promotes the dislocation to break away from Cr. PMID- 23360806 TI - Loss of GABAergic neurons in the hippocampus and cerebral cortex of Engrailed-2 null mutant mice: implications for autism spectrum disorders. AB - The homeobox-containing transcription factor Engrailed-2 (En2) is involved in patterning and neuronal differentiation of the midbrain/hindbrain region, where it is prominently expressed. En2 mRNA is also expressed in the adult mouse hippocampus and cerebral cortex, indicating that it might also function in these brain areas. Genome-wide association studies revealed that En2 is a candidate gene for autism spectrum disorders (ASD), and mice devoid of its expression (En2( /-) mice) display anatomical, behavioral and clinical "autistic-like" features. Since reduced GABAergic inhibition has been proposed as a possible pathogenic mechanism of ASD, we hypothesized that the phenotype of En2(-/-) mice might include defective GABAergic innervation in the forebrain. Here we show that the Engrailed proteins are present in postnatal GABAergic neurons of the mouse hippocampus and cerebral cortex, and adult En2(-/-) mice show reduced expression of GABAergic marker mRNAs in these areas. In addition, reduction in parvalbumin (PV), somatostatin (SOM) and neuropeptide Y (NPY) expressing interneurons is detected in the hippocampus and cerebral cortex of adult En2(-/-) mice. Our results raise the possibility of a link between altered function of En2, anatomical deficits of GABAergic forebrain neurons and the pathogenesis of ASD. PMID- 23360809 TI - Continuous innovation: developing and using a clinical database with new technology for patient-centred care--the case of the Swedish quality register for arthritis. AB - OBJECTIVE: We describe and explain the development of a clinical quality database and its use for different clinical, management and patient empowerment purposes. DESIGN: A longitudinal case study covering 1993-2009. SETTING: Rheumatology departments in Swedish hospitals. PARTICIPANTS: Those involved in developing the clinical database and its applications and a limited number of users. INTERVENTION(S): Different methods for inputting and storing clinical and patient data and for analysing and presenting the data to providers and patients. MAIN OUTCOME MEASURE(S): Participants' perceptions of the value of different applications and of influences, which helped and hindered the development of the system. RESULTS: Different innovations were introduced at different times continually to increase the ultility of the clinical data and the clinic- and patient coverage of the clinical data system. Limited interview data show postive patient and provider perceptions of the latest application to collect and present data as time trend visual display in the clinical consultation. CONCLUSIONS: A longitudinal perspective revealed how a clinical quality register was developed and how new technologies not imagined in the early 1990s continue to increase the ultility and value of the clinical database. This historical perspective provided limited evidence of impact, but does provide lessons for current strategies for innovation for quality in health care and of the need to consider innovolution processes, rather than discrete innovations, given the rapid pace of change in new technologies. More evidence is needed of the impact of such registers, and of enhancements, on providers and patients and on costs. PMID- 23360810 TI - The effect of a checklist on the quality of post-anaesthesia patient handover: a randomized controlled trial. AB - OBJECTIVE: Patient handover is an important element of continuity, quality and safety in patient care. Handover without standardized protocols is prone to information loss and might be a possible danger to patient safety. Checklists are established methods that help to structure complex processes in other high-risk fields such as aviation. In the past few years, their implementation has attracted research interest in medicine. We hypothesize that a checklist for handover between anaesthesiologist and post-anaesthesia care unit nurse will increase the amount of information transfer during patient handover after anaesthesia. DESIGN AND SETTING: A total of 120 post-anaesthesia patient handovers were recorded on video and analyzed. Forty handovers before the implementation of the checklist and 80 after the implementation of the checklist, randomized into two groups: with and without the use of the checklist. MAIN OUTCOME MEASURES: An overall number of items handed over, handover of specific items and duration of the handover were analyzed. RESULTS: With the use of the written checklist, the overall items handed over increased significantly from a median of 32.4-48.7%. The duration of handover increased from a median of 86-121 s. Instructions about items that should be included in handovers, but without the use of a written checklist, was not associated with an increase in the number of items handed over or duration of the interview. CONCLUSIONS: This study suggests that the use of a checklist for post-anaesthesia handover might improve the quality of patient handover by increasing the information handed over. PMID- 23360811 TI - Conservative en bloc surgery for aggressive angiomyxoma achieves good local control: analysis of 14 patients from a single institution. AB - BACKGROUND: The purpose of this study was to assess the value of conservative surgery in aggressive angiomyxoma (AA) in our institutional series. METHOD: This was a retrospective review of patients with AA treated at our institution between 1999 and 2010. RESULTS: Fourteen consecutive patients were analyzed: 8 primary tumors and 6 recurrences. Female/male ratio was 13:1; median female age was 36 years. Median size of primary lesions was 12 cm (range, 7-17 cm). Median size of recurrences was 20.5 cm (range, 3-44 cm). Twelve patients were operated on. Two asymptomatic patients whose surgery would have been mutilating were placed under wait and see. Four patients had concomitant visceral resections because of massive infiltration. No tumor rupture was recorded on pathological examination. Margins were R0 (n = 2), R1 (n = 10), and R2 (n = 0). Seven patients (50%) received radiotherapy. Median postoperative follow-up was 69 months, and no patient was lost at follow-up. All patients operated on (primaries and recurrences) had no evidence of recurrence. CONCLUSION: Conservative and planned en bloc surgery achieves good local control with low morbidity. Radiotherapy could enhance local control in advanced disease. Wait and see is an exploratory option for asymptomatic, stable, and nonprogressing AA in which surgery would be mutilating. PMID- 23360812 TI - A detailed study of patients and tumor characteristics of epithelial ovarian cancer in Saudi women. AB - BACKGROUND: The Saudi population is characterized by high parity and intermarriages that may impact ovarian carcinogenesis. Herein, we analyzed the tumor characteristics and outcomes in Saudi patients with epithelial ovarian cancer (EOC). METHODS: Patients with EOC treated at King Faisal Specialist Hospital and Research Center during 1995-2007 were identified retrospectively through a review of their medical records. Patients' and tumor characteristics were collected including age at diagnosis, marital status, parity, histology, stage, treatment rendered, and follow-up data. RESULTS: One hundred-ninety-three patients with EOC were identified in this cohort. The mean age of the patients was 55 +/- 15 years, the mean +/- SD body mass index was 27.0 +/- 5.6 kg/m, and the median parity was approximately 7.0. Whereas 4 patients reported a family history of cancer, 164 women reported negative family history; and it was unknown in 27 cases. Tumor distribution by International Federation of Gynecology and Obstetrics stage was the following: 12 patients (6.2%) had stage I disease at diagnosis, 1 patient (0.5%) stage II disease, 130 patients (67.4%) stage III disease, 39 patients (20.2%) stage IV disease, and that of 11 patients (5.7%) was unknown. Information on residual disease after surgery was available on 98 patients with optimal debulking (<1 cm) achieved in 61 cases. Median progression free survival from end of chemotherapy to recurrence/progression was 11.9 months (95% confidence interval, 9.4-15.2). Tumor histology, size of residual disease, and stage at diagnosis were significant prognostic factors. The patients' age, body mass index, tumor histology, and grade had no impact on survival. CONCLUSIONS: Patients presenting with advanced-stage disease are higher among Saudis than those reported in global literature. Despite high intermarriage rates, reported family history for related cancers was quite low in this cohort. Notably, this is the first study evaluating EOC in Saudi patients. PMID- 23360813 TI - Risk factors for cervical human papillomavirus infection and high-grade intraepithelial lesion in women aged 20 to 31 years in Germany. AB - BACKGROUND: Persistent infection with high-risk human papillomaviruses (HPVs) can lead to cervical intraepithelial lesion and cervical cancer. Sexual behavior and smoking have been identified as risk factors for HPV infection. However, it is unclear which factors account for the persistence of HPV infection and for high grade squamous intraepithelial lesions (HSIL). Therefore, we conducted a study to identify epidemiological risk factors for the following: (1) the presence of HPV among women without a recent diagnosis of HSIL and (2) HSIL. MATERIALS AND METHODS: Participants aged 20 to 31 years were recruited at 2 study sites. All women received a cervical Papanicolaou test, were tested for HPV, and categorized into 1 of 3 different groups: The women of the first group had negative cytological test results and a negative HPV test result (HPV-negative group), and the women of the second group had negative cytological test result but positive HPV test result (HPV-positive group). The third group consisted of women with a diagnosis of HSIL (HSIL group). We first compared the HPV-negative group with the HPV-positive group, and then the HPV-positive group with the HSIL group. RESULTS: One hundred forty-seven women were included: 53 women in the HPV-negative group, 46 women in the HPV-positive group, and 48 women in the HSIL group. Comparing the HPV-negative with the HPV-positive group, we found that more than 5 sexual partners during a lifetime were independently associated with cervical HPV infection, whereas the chance of being infected decreased with older age. Irregular condom use during one-night stands or smoking was associated with HPV infection only in univariable but not multivariable analysis. In contrast, older age and having had genital warts were independently associated with an HSIL diagnosis when comparing the HPV-positive group with the HSIL group. DISCUSSION: Although the study was hampered by its relatively small sample size, our data suggest that main risk factors for the acquisition of HPV infection are a higher number of sexual partners and younger age, whereas older age and genital warts may be epidemiological cofactors in the development of HSIL. PMID- 23360814 TI - Characterization of ovarian tumors and staging ovarian cancer with 3-dimensional power Doppler angiography: correlation with pathologic findings. AB - OBJECTIVE: The aims of this study were to evaluate ovarian tumors with 3 dimensional power Doppler angiography (3-DPDA), to determine its correlation with histology findings, and to explore its role in staging patients with ovarian cancer. METHODS: Three hundred eighteen women with an unknown unilateral pelvic mass were referred for preoperative evaluation by 3-DPDA angiography. Patients' ages ranged from 18 to 72 years (47.4 +/- 13.8 years). Sonographic criteria used for the characterization of ovarian tumors were based on a system that included morphological characteristics, histological evaluation, and Power Doppler imaging. RESULTS: Two hundred twenty-five tumors were histopathologically diagnosed as benign and 93 as malignant. Sensitivity and specificity of the 3 DPDA of ovarian masses reached 93.5% and 92.9%, respectively, whereas positive predictive value was 84.5% and negative predictive value was 97.2%. CONCLUSIONS: Three-dimensional power Doppler sonography is an effective imaging technique for discriminating ovarian neoplasms and classifying them according to histopathology. PMID- 23360815 TI - Five year survival rates can mislead. PMID- 23360816 TI - Case can proceed against doctor who discussed patient's details on train, say judges. PMID- 23360817 TI - Study finds outcomes from spinal surgery are no worse when trainee doctors start work. PMID- 23360818 TI - DePuy knew about hip implant's high failure rate three years before it was recalled. PMID- 23360819 TI - Influence of SNPs in nutrient-sensitive candidate genes and gene-diet interactions on blood lipids: the DiOGenes study. AB - Blood lipid response to a given dietary intervention could be determined by the effect of diet, gene variants or gene-diet interactions. The objective of the present study was to investigate whether variants in presumed nutrient-sensitive genes involved in lipid metabolism modified lipid profile after weight loss and in response to a given diet, among overweight European adults participating in the Diet Obesity and Genes study. By multiple linear regressions, 240 SNPs in twenty-four candidate genes were investigated for SNP main and SNP-diet interaction effects on total cholesterol, LDL-cholesterol, HDL-cholesterol and TAG after an 8-week low-energy diet (only main effect) ,and a 6-month ad libitum weight maintenance diet, with different contents of dietary protein or glycaemic index. After adjusting for multiple testing, a SNP-dietary protein interaction effect on TAG was identified for lipin 1 (LPIN1) rs4315495, with a decrease in TAG of 20.26 mmol/l per A-allele/protein unit (95% CI 20.38, 20.14, P=0.000043). In conclusion, we investigated SNP-diet interactions for blood lipid profiles for 240 SNPs in twenty-four candidate genes, selected for their involvement in lipid metabolism pathways, and identified one significant interaction between LPIN1 rs4315495 and dietary protein for TAG concentration. PMID- 23360820 TI - Soluble alpha-klotho: a novel serum biomarker for the activity of GH-producing pituitary adenomas. AB - OBJECTIVE: Klotho is a lifespan-influencing gene expressed mainly in the kidneys. Soluble alpha-Klotho (alphaKL) is released into the circulation. In this study, we present baseline alphaKL serum levels of patients with acromegaly compared with controls with other pituitary adenomas and assess changes following transsphenoidal surgery. DESIGN: Prospective controlled study. METHODS: We measured soluble alphaKL (sandwich ELISA) and IGF1 (RIA) in sera of 14 patients (eight females and six males) with active acromegaly and in 22 control patients (13 females and nine males) operated for non-GH-producing pituitary adenomas. Immunohistochemical staining for Klotho was performed in resected adenomas and in normal pituitary tissue samples. RESULTS: Soluble alphaKL was high in the acromegaly group preoperatively (median 4217 pg/ml, interquartile range (IQR) 1812-6623 pg/ml) and declined after surgery during early follow-up (2-6 days; median 645 pg/ml, IQR 550-1303 pg/ml) (P<0.001) and during late follow-up (2-3 months post-operatively; median 902 pg/ml, IQR 497-1340 pg/ml; P<0.001). In controls, preoperative soluble alphaKL was significantly lower than in acromegalics, 532 pg/ml (400-677 pg/ml; P<0.001). Following surgery, soluble alphaKL remained low during early and late follow-up - changes over time within the control group were not statistically significant. These results were independent of age, sex and kidney function. Klotho staining was equal or slightly decreased in GH-positive adenomas compared with controls. CONCLUSION: High soluble alphaKL serum levels were specific to GH-producing adenomas and decreased rapidly following adenoma removal. Thus, soluble alphaKL appears to be a new specific and sensitive biomarker reflecting disease activity in acromegaly. Similar Klotho staining patterns in controls and acromegalics suggest that the rise in serum alphaKL is caused by systemic actions of pituitary GH rather than due to increased expression of Klotho by the pituitary (adenoma). PMID- 23360821 TI - Glycosylation of sera thyroglobulin antibody in patients with thyroid diseases. AB - OBJECTIVE: Thyroglobulin antibody (TgAb) is an important autoantibody in thyroid diseases, which is a glycoprotein, predominantly of IgG class. Glycosylation of the IgG-Fc contributes to many effector functions exhibited by antibodies. The aim of our study was to investigate the glycosylation of sera TgAb in patients with different thyroid diseases. DESIGN AND METHODS: Sera from 146 patients were collected and divided into four groups: Hashimoto's thyroiditis (HT, n=90), Graves' disease (GD, n=20), papillary thyroid carcinoma (PTC, n=17), and PTC with histological lymphocytic thyroiditis (PTC-T, n=19). HT patients were further divided into euthyroidism and subclinical and overt hypothyroidism groups. Lectin ELISAs were performed to detect the relative amount of core fucose, terminal galactose, and sialic acid on each TgAb respectively. RESULTS: Among HT, GD, and PTC groups, HT patients had significantly lower core fucose content on TgAb than the other two groups; an increasing trend of sialylation was found in PTC sera (P=0.076) compared with HT groups. PTC-T patients had significantly higher sialylated TgAb than HT and GD patients, and no significant difference was found between PTC and PTC-T. There was no significant difference in the three carbohydrate residue contents on sera TgAb among HT subgroups. In all the patients, negative correlation was found between sialic acid content and TgAb IgG levels (r=-0.736, P<0.001). CONCLUSIONS: Our study showed that glycosylation of sera TgAb varied in different thyroid diseases and it might be involved in pathogenesis of thyroid disorders. PMID- 23360822 TI - Giant left atrium 30 years after surgical mitral valve replacement: an assessment of conservative therapy. PMID- 23360823 TI - TWIST1 regulates the activity of ubiquitin proteasome system via the miR-199/214 cluster in human end-stage dilated cardiomyopathy. AB - BACKGROUND: The transcription factor TWIST1 has been described to regulate the microRNA (miR)-199/214 cluster. Genetic disruption of TWIST1 resulted in a cachectic phenotype and early death of the knock-out mice. This might be connected to the activity of the ubiquitin-proteasome-system (UPS), as miR-199a has been suggested to regulate the ubiquitin E2 ligases Ube2i and Ube2g1. METHODS: Cardiac tissue from explanted hearts of 42 patients with dilated cardiomyopathy and 20 healthy donor hearts were analysed for protein expression of TWIST1 and its inhibitors Id-1, MuRF-1 and MAFbx, the expression of miR-199a, 199b and -214, as well as the activity of the UPS by using specific fluorogenic substrates. RESULTS: TWIST1 was repressed in patients with dilated cardiomyopathy by 43% (p=0.003), while Id1 expression was unchanged. This was paralleled by a reduced expression of miR-199a by 38 +/- 9% (p=0.053), miR-199b by 36 +/- 13% (p=0.019) and miR-214 by 41 +/- 11% (p=0.0158) compared to donor hearts. An increased peptidylglutamyl-peptide-hydrolysing activity (p<0.0001) was observed in the UPS, while the chymotrypsin-like and trypsin-like activities were unchanged. The protein levels of the rate limiting ubiquitin E3-ligases MuRF-1 and MAFbx were up-regulated (p=0.005 and p=0.0156, respectively). Mechanistically silencing of TWIST1 using siRNA in primary rat cardiomyocytes led to a down regulation of the miR-199/214 cluster and to a subsequent up-regulation of Ube2i. CONCLUSION: The TWIST1/miR-199/214 axis is down-regulated in dilated cardiomyopathy, which is likely to play a role in the increased activity of the UPS. This may contribute to the loss of cardiac mass during dilatation of the heart. PMID- 23360824 TI - Effect of butaphosphan and cyanocobalamin on postpartum metabolism and milk production in dairy cows. AB - The aim of this study was to determine the effect of butaphosphan and cyanocobalamin (BTPC) supplementation on plasma metabolites and milk production in postpartum dairy cows. A total of fifty-two Holstein cows were randomly assigned to receive either: (1) 10 ml of saline (NaCl 0.9%, control group); (2) 1000 mg of butaphosphan and 0.5 mg of cyanocobalamin (BTPC1 group); and (3) 2000 mg of butaphosphan and 1.0 mg of cyanocobalamin (BTPC2 group). All cows received injections every 5 days from calving to 20 days in milk (DIM). Blood samples were collected every 15 days from calving until 75 DIM to determine serum concentration of glucose, non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHB), cholesterol, urea, calcium (Ca), phosphorus (P), magnesium (Mg), aminotransferase aspartate (AST) and gamma-glutamyltransferase (GGT). The body condition score (BCS) and milk production were evaluated from calving until 90 DIM. Increasing doses of BTPC caused a linear reduction in plasma concentrations of NEFA and cholesterol. Supplementation of BTPC also reduced concentrations of BHB but it did not differ between the two treatment doses. Milk yield and milk protein had a linear increase with increasing doses of BTPC. A quadratic effect was detected for milk fat and total milk solids according to treatment dose, and BTPC1 had the lowest mean values. Concentrations of glucose, urea, P, Mg, AST, GGT, milk lactose and BCS were not affected by treatment. These results indicate that injections of BTPC during the early postpartum period can reduce NEFA and BHB concentrations and increase milk production in Holstein cows. PMID- 23360825 TI - Overexpression of developmentally regulated GTP-binding protein-2 increases bone loss. AB - The developmentally regulated GTP-binding protein-2 (DRG2) is a novel subclass of GTP-binding proteins. Many functional characteristics of osteoclasts (OC) are associated with small GTPases. We hypothesized that DRG2 affects bone mass via modulating OC activity. Using DRG2 transgenic mice, we investigated the role of DRG2 in bone remodeling. DRG2 overexpression caused a decrease in bone mass and an increase in the number and activity of OC in vivo. DRG2 overexpression increased fusion, spreading, survival, and resorption activity of OC in vitro. Downregulation of DRG2 by siRNA decreased fusion, spreading, and survival of OC, supporting the observations found in DRG2 transgenic OC. Transgenic mature OCs were larger, with actin rings and higher ERK, Akt, Rac1 and Rho activities than wild-type OCs. Inhibition of these proteins abolished the effects of DRG2 on formation of large OCs with actin rings, implying that DRG2 affects cytoskeleton reorganization in a Rac1/Rho/ERK/Akt-dependent manner. In summary, DRG2 is associated with survival and cytoskeleton organization of OC under influence of macrophage colony-stimulating factor, and its overexpression leads to elevated bone resorptive activity of OC, resulting in bone loss. PMID- 23360826 TI - Lymphotoxin-alpha is a novel adiponectin expression suppressor following myocardial ischemia/reperfusion. AB - Recent clinical observations demonstrate adiponectin (APN), an adipocytokine with potent cardioprotective actions, is significantly reduced following myocardial ischemia/reperfusion (MI/R). However, mechanisms responsible for MI/R-induced hypoadiponectinemia remain incompletely understood. Adult male mice were subjected to 30-min MI followed by varying reperfusion periods. Adipocyte APN mRNA and protein expression and plasma APN and TNFalpha concentrations were determined. APN expression/production began to decline 3 h after reperfusion (reaching nadir 12 h after reperfusion), returning to control levels 7 days after reperfusion. Plasma TNFalpha levels began to increase 1 h after reperfusion, peaking at 3 h and returning to control levels 24 h after reperfusion. TNFalpha knockout significantly increased plasma APN levels 12 h after reperfusion but failed to improve APN expression/production 72 h after reperfusion. In contrast, TNF receptor-1 (TNFR1) knockout significantly restored APN expression 12 and 72 h after reperfusion, suggesting that other TNFR1 binding cytokines contribute to MI/R-induced APN suppression. Among many cytokines increased after MI/R, lymphotoxin-alpha (LTalpha) was the only cytokine remaining elevated 24-72 h after reperfusion. LTalpha knockout did not augment APN levels 12 h post reperfusion, but did so by 72 h. Finally, in vitro treatment of adipocytes with TNFalpha and LTalpha at concentrations seen in MI/R plasma additively inhibited APN expression/production in TNFR1-dependent fashion. Our study demonstrates for the first time that LTalpha is a novel suppressor of APN expression and contributes to the sustained hypoadiponectinemia following MI/R. Combining anti TNFalpha with anti-LTalpha strategies may achieve the best effects restoring APN in MI/R patients. PMID- 23360827 TI - CaSR-mediated interactions between calcium and magnesium homeostasis in mice. AB - Calcium (Ca) and magnesium (Mg) homeostasis are interrelated and share common regulatory hormones, including parathyroid hormone (PTH) and vitamin D. However, the role of the calcium-sensing receptor (CaSR) in Mg homeostasis in vivo is not well understood. We sought to investigate the interactions between Mg and Ca homeostasis using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR) (double knockout, DKO). Serum Mg is lower in PTH KO and DKO mice than in WT mice on standard chow, whereas supplemental dietary Ca leads to equivalent Mg levels for all three genotypes. Mg loading increases serum Mg in all genotypes; however, the increase in serum Mg is most pronounced in the DKO mice. Serum Ca is increased with Mg loading in the PTH KO and DKO mice but not in the WT mice. Here, too, the hypercalcemia is much greater in the DKO mice. Serum and especially urinary phosphate are reduced during Mg loading, which is likely due to intestinal chelation of phosphate by Mg. Mg loading decreases serum PTH in WT mice and increases serum calcitonin in both WT and PTH KO mice but not DKO mice. Furthermore, Mg loading elevates serum 1,25-dihydroxyvitamin D in all genotypes, with greater effects in PTH KO and DKO mice, possibly due to reduced levels of serum phosphorus and FGF23. These hormonal responses to Mg loading and the CaSR's role in regulating renal function may help to explain changes in serum Mg and Ca found during Mg loading. PMID- 23360828 TI - Functional characterization of ferret CCL20 and CCR6 and identification of chemotactic inhibitors. AB - CCL20 is currently the only known chemokine ligand for the receptor CCR6, and is a mucosal chemokine involved in normal and pathological immune responses. Although nucleotide sequence data are available for ccl20 and ccr6 sequences from multiple species, the ferret ccl20 and ccr6 sequences have not been determined. To increase our understanding of immune function in ferret models of infection and vaccination, we have used RT-PCR to obtain the ferret ccl20 and ccr6 cDNA sequences and functionally characterize the encoded proteins. The open reading frames of both genes were highly conserved across species and mostly closely related to canine sequences. For functional analyses, single cell clones expressing ferret CCR6 were generated, a ferret CCL20/mouse IgG(2a) fusion protein (fCCL20-mIgG(2a)) was produced, and fCCL20 was chemically synthesized. Cell clones expressing ferret CCR6 responded chemotactically to fCCL20-mIgG2a fusion protein and synthetic ferret CCL20. Chemotaxis inhibition studies identified the polyphenol epigallocatechin-3-gallate and the murine gamma herpesvirus 68 M3 protein as inhibitors of fCCL20. Surface plasmon resonance studies revealed that EGCG bound directly to fCCL20. These results provide molecular characterization of previously unreported ferret immune gene sequences and for the first time identify a broad-spectrum small molecule inhibitor of CCL20 and reveal CCL20 as a target for the herpesviral M3 protein. PMID- 23360830 TI - Residents' corner February 2013. Editorial: 2013, renewal of the Resident Board. PMID- 23360829 TI - Association between polymorphisms in the genes for tumor suppressor protein p53 and its regulator NAD(P)H: quinone oxidoreductase 1 (NQO1) and schizophrenia in a Syrian study cohort. AB - BACKGROUND AND AIMS: The contribution of genetic factors to the susceptibility for developing schizophrenia is well established. Several hypotheses have been developed in an attempt to identify the pathophysiological mechanisms in schizophrenia, with several findings implicating an important role for apoptosis. A limited number of studies investigated the effects of polymorphisms in apoptotic genes on the susceptibility to schizophrenia in different ethnic groups, with none involving an Arab population. The aim of the present study was to investigate the association between multiple polymorphisms in genes for the central apoptotic protein p53 and its regulator NQO1 and the susceptibility for developing schizophrenia in an Arab population from Syria. METHODS: The studied polymorphisms included exon 4 G>C Arg72Pro (rs1042522), IVS3 16 bp Del/Ins (rs17878362), and MspI IVS6+62A>G (rs1625895) of the TP53 gene, and C609T of the NQO1 gene. The study cohort consisted of 90 patients and 144 healthy controls. Association with each of the four polymorphisms was tested under numerous genetic models. The four polymorphisms were genotyped simultaneously using a quadruplex Tetra-Primer ARMS-PCR method described earlier. The combined effects of polymorphisms in NQO1 and TP53 genes were examined. RESULTS: No statistically significant association was found for any of the four polymorphisms. CONCLUSIONS: Our results do not support an association between the studied polymorphisms and schizophrenia in the Syrian population. PMID- 23360831 TI - Prevalence of mycobacteremia among HIV-infected infants and children in northern Tanzania. AB - Mycobacterium tuberculosis is a common cause of bloodstream infections among HIV infected adults in sub-Saharan Africa, and is associated with high morbidity and mortality. We found no cases of mycobacteremia among 93 ill, HIV-infected children in northern Tanzania, despite optimization of laboratory methods and selection of patients thought to be at highest risk for disseminated infection. PMID- 23360832 TI - Insulin resistance and glucose and lipid concentrations in a cohort of perinatally HIV-infected Latin American children. AB - We measured glucose, insulin and lipids in 249 perinatally HIV-infected Latin American children. Only 1 subject had impaired fasting glucose; 6.8% had insulin resistance. Abnormalities in total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were reported for 13%, 13%, 21% and 34%, respectively. Continued follow-up of this population is necessary to characterize the evolution and clinical consequences of these findings. PMID- 23360834 TI - Quasibound states and transport characteristics of Au chains with a substitutional S impurity. AB - Electronic transport properties of short gold atom chains with a single sulfur impurity were studied using density functional theory. It is found that the role of the impurity atom in the transport properties is twofold. First, it acts as a scattering center in the dominating 6s-orbital transmission channel and generally leads to a decrease of the transmission function in a wide energy region around the Fermi level. Second, it gives rise to a quasibound state manifesting as a peak near the Fermi level both in the partial density of states as well as in the transmission function. Because of the hybridization of the sulfur 3p and gold 5d orbitals in its formation, the quasibound state moves locally upward in the gold 5d transmission channel and brings about an enhancement of the transmission function in a narrow energy region near the Fermi level. The height of the peak of the quasibound state in the transmission function depends significantly on the position of the impurity in the chain and its energy varies with the bias voltage. The current-voltage (I-V) characteristics become asymmetric with a departure of the impurity from the central position in the chain and they are nonlinear for small values of the voltage (V < 0.1 V). It is proposed that a careful analysis of the I-V characteristics or the voltage dependence of the differential conductance may be used for unambiguous location of the light impurity in experiments with gold chains. PMID- 23360833 TI - The relationship between vitamin D status and HIV-related complications in HIV infected children and young adults. AB - BACKGROUND: In HIV-infected adults, we and others have shown that vitamin D deficiency is independently associated with increased carotid intima-media thickness (cIMT), a surrogate marker for cardiovascular disease (CVD). This study explored for the first time the relationship between vitamin D and CVD risk in HIV-infected youth. METHODS: This is a cross-sectional assessment of cIMT, inflammation, metabolic markers and vitamin D status in HIV-infected youth and healthy controls. We measured serum 25-hydroxyvitamin D (25(OH)D), fasting lipids, insulin, glucose, inflammatory markers and cIMT. RESULTS: Thirty HIV infected subjects and 31 controls were included. Among HIV-infected subjects, median age was 11 years (37% males; 73% black; similar to controls). HIV-infected subjects' mean (standard deviation) serum 25(OH)D was 24 (35) ng/mL; 70% had 25(OH)D<20 ng/mL (deficient), 23% between 20-30 ng/mL (insufficient) and 7%>30 ng/mL (sufficient); proportions were similar to controls (P=0.17). After adjusting for season, sex and race, there was no difference in serum 25(OH)D between groups (P=0.11). Serum 25(OH)D was not significantly correlated with cIMT, inflammatory markers or lipids. Serum 25(OH)D was negatively correlated with body mass index, insulin resistance, HIV duration, and cumulative use of antiretroviral therapy, non- and nucleoside reverse transcriptase inhibitors. CONCLUSIONS: Most HIV-infected youth have vitamin D deficiency or insufficiency. Despite no direct association between serum 25(OH)D and cIMT, there were notable associations with some CVD risk factors, particularly inverse correlation with insulin resistance. Studies are needed to determine whether CVD risk, including insulin resistance, could be improved with vitamin D supplementation. PMID- 23360835 TI - Effect of dihydrokainate on the capacity of repair of DNA damage and apoptosis induced by doxorubicin. AB - The intention of the current study was to investigate the effect of non-toxic doses of dihydrokainate on the capacity of repair of DNA damage and apoptosis induced by doxorubicin in mouse bone-marrow cells. The scoring of micronuclei and olive tail moment was undertaken in the current study as markers of DNA damage and repair. Apoptosis was analysed by the occurrence of a hypodiploid DNA peak. Oxidative stress markers such as bone-marrow reactive oxygen species, lipid peroxidation, reduced and oxidised glutathione were assessed as a possible mechanism underlying this amelioration. In addition, the influence of dihydrokainate on doxorubicin-induced topoisomerase II inhibition was examined. Dihydrokainate was neither genotoxic nor apoptogenic at doses equivalent to 10 or 20mg/kg/day for 7 days. Pre-treatment of mice with dihydrokainate significantly enhances the repair of doxorubicin-induced DNA damage and reduced doxorubicin induced apoptosis depending on dose. Doxorubicin induced marked biochemical alterations characteristic of oxidative stress, including increased reactive oxygen species, enhanced lipid peroxidation and reduction in the reduced/oxidised glutathione ratio. Prior administration of dihydrokainate ahead of doxorubicin challenge ameliorated these oxidative stress markers. Importantly, dihydrokainate treatment had no antagonising effect on doxorubicin-induced topoisomerase II inhibition. Conclusively, this study provides for the first time that dihydrokainate enhances the repair of doxorubicin-induced DNA damage, which resides, at least in part, in its ability to modulate the cellular antioxidant levels. Based on our data presented, strategies can be developed to enhance the repair of doxorubicin-induced genomic damage in normal cells using dihydrokainate without diminishing doxorubicin's anti-topoisomerase II activity. Thus, improvement of doxorubicin's therapeutic index may be achieved by using dihydrokainate. PMID- 23360837 TI - A progestin (17alpha,20beta-dihydroxy-4-pregnen-3-one) stimulates early stages of spermatogenesis in zebrafish. AB - Recently, evidence has been provided for multiple regulatory functions of progestins during the late mitotic and meiotic phases of spermatogenesis in teleost fish. For example, our previous studies suggested that 17alpha,20beta dihydroxy-4-pregnen-3-one (DHP), potentially via Sertoli cells that express the progesterone receptor (pgr) gene, can contribute to the regulation of zebrafish spermatogenesis. To further our understanding of the function of DHP at early spermatogenetic stages, we investigated in the present study the expression of genes reflecting Sertoli cell function and spermatogenic development in adult zebrafish testis after DHP treatment in tissue culture. Moreover, using an in vivo model of estrogen-mediated down-regulation of androgen production to interrupt adult spermatogenesis, we studied the effects of DHP on estrogen interrupted spermatogenesis. In this model, DHP treatment doubled the testis weight, and all differentiating germ cell types, such as type B spermatogonia and primary spermatocytes, were abundantly present and incorporated the DNA-synthesis marker (BrdU). Accordingly, transcript levels of germ cell marker genes were up regulated. Moreover, transcripts of two Sertoli cell-derived genes anti-mullerian hormone (amh) and gonadal soma-derived growth factor (gsdf) were up-regulated, as were three genes of the insulin-like growth factor signaling system, insulin-like growth factor 2b (igf2b), insulin-like growth factor 3 (igf3) and insulin-like growth factor 1b receptor (igf1rb). We further analyzed the relationship between these genes and DHP treatment using a primary zebrafish testis tissue culture system. In the presence of DHP, only igf1rb mRNA levels showed a significant increase among the somatic genes tested, and germ cell marker transcripts were again up-regulated. Taken together, our results show that DHP treatment induced the proliferation of early spermatogonia, their differentiation into late spermatogonia and spermatocytes as well as expression of marker genes for these germ cell stages. DHP-mediated stimulation of spermatogenesis and hence growth of spermatogenic cysts and the associated increase in Sertoli cell number may in part explain the elevated expression of Sertoli cell genes, but our data also suggest an up-regulation of the activity of the Igf signaling system. PMID- 23360839 TI - Telomere length and cardiorespiratory fitness in marathon runners. AB - BACKGROUND AND AIM: Physical exercise up-regulates telomere-stabilizing proteins in mice, suggesting that physical activity affects telomere length. Several human studies assessing the relationship between physical activity, measured by health or activity surveys, and telomere length have produced conflicting results. The present study sought to explore the association between telomere length and physical fitness measured objectively as maximal oxygen uptake in endurance trained athletes and sedentary controls. METHODS: Seventeen marathon runners and 15 age- and sex-matched healthy, sedentary control subjects participated in the study. Medical history, demographic information, maximal oxygen uptake (VO2 max), and peripheral blood lymphocyte telomere length were measured in all subjects. Statistical analysis was performed to examine the relationship between telomere length and measured variables. RESULTS: Athletes and sedentary controls had similar lymphocyte (0.97 +/- 0.20 vs 1.01 +/- 0.18; P = 0.6) and granulocyte (0.89 +/- 0.11 vs 0.89 +/- 0.12; P = 0.9) telomere lengths. Linear regression analysis showed age as the only variable significantly associated with telomere length (P = 0.007). There was no correlation between VO2 max and telomere length. CONCLUSION: In a cohort of healthy adult athletes and sedentary controls, there was no association between physical activity measured by VO2 max and peripheral blood lymphocyte and granulocyte telomere length. PMID- 23360838 TI - The association between fracture rates and neighborhood characteristics in Washington, DC, children. AB - BACKGROUND: Effects of neighborhood contextual features have been found for many diseases, including bone fractures in adults. Our study objective was to evaluate the association between neighborhood characteristics and pediatric bone fracture rates. We hypothesized that neighborhood indices of deprivation would be associated with higher fracture rates. MATERIALS AND METHODS: Pediatric bone fracture cases treated at a tertiary, academic, urban pediatric emergency department between 2003 and 2006 were mapped to census block groups using geographical information systems software. Fracture rates were calculated as fractures per 1000 children in each census block. Exploratory factor analysis of socioeconomic indicators was performed using 2000 census block data. Factor scores were used to predict odds of bone fracture at the individual level while adjusting for mean age, sex composition, and race/ethnicity composition at census block level using our sample data. RESULTS: We analyzed 3764 fracture visits in 3557 patients representing 349 distinct census blocks groups. Fracture rates among census blocks ranged from 0 to 207 per 1000 children/study period. Logistic regression modeling identified 2 factors (race/education and large families) associated with increased fracture risk. Census variables reflecting African American race, laborer/service industry employment, long-term block group residence, and lower education levels strongly loaded on the race/education factor. The large families factor indicated the children-to-families ratio within the block group. The poverty factor was not independently associated with fracture risk. CONCLUSIONS: Thus, neighborhood characteristics are associated with risk for fractures in children. These results can help inform translational efforts to develop targeted strategies for bone fracture prevention in children. PMID- 23360840 TI - Hypothalamic-pituitary-thyroid axis in patients with Alzheimer disease (AD). AB - OBJECTIVE: We observed the function of hypothalamic-pituitary-thyroid axis in patients with Alzheimer disease (AD) using a case-control study. METHODS: The case was a cohort that included 50 patients with AD. For each case subject, 1 control who was of similar age, sex, daily activities (scale of Lawton), sleep quality (Pittsburgh Sleep Quality Index), and depression (15-item Geriatrics Depression Scale) was recruited. Thyrotropin-releasing hormone (TRH), thyroid stimulating hormone (TSH), total triiodothyronine (TT3), total tetraiodothyronine (TT4), free triiodothyronine (FT3), and free tetraiodothyronine (FT4) were detected using radioimmunity. RESULTS: Compared with the healthy controls, the patients with AD had significantly lower levels of TRH (67.72 +/- 18.44 vs 78.64 +/- 14.31 pmol/L; t = 2.078; P = 0.036), TSH (3.89 +/- 1.22 vs 4.31 +/- 1.07 mIU/L; t = 2.331; P = 0.024), TT3 (1.44 +/- 0.21 vs 1.63 +/- 0.19 nmol/L; t = 3.761; P = 0.018), TT4 (119.71 +/- 18.64 nmol/L vs 129.54 +/- 23.17 nmol/L; t = 1.328; P = 0.044), FT3 (4.01 +/- 1.27 vs 5.41 +/- 0.99 pmol/L; t = 4.976; P = 0.008), and FT4 (9.84 +/- 1.56 vs 12.96 +/- 2.20 pmol/L; t = 5.381; P = 0.006). In the AD cases, none of the correlations between TRH and TSH, TT3, TT4, FT3, and FT4, and between TSH and TT3, TT4, FT3, FT4 was significant. However, in the healthy controls, TRH was significantly correlated with TSH (R = 0.020; P = 0.042) and FT4 (R = 0.015; P = 0.018), and TSH was significantly correlated with TT4 (R = 0.209; P = 0.017) and FT4 (R = 0.215; P = 0.009). CONCLUSION: Alzheimer disease was associated with abnormal function of the hypothalamic-pituitary thyroid axis. PMID- 23360836 TI - Immunopathogenesis of osteoarthritis. AB - Even though osteoarthritis (OA) is mainly considered as a degradative condition of the articular cartilage, there is increasing body of data demonstrating the involvement of all branches of the immune system. Genetic, metabolic or mechanical factors cause an initial injury to the cartilage resulting in release of several cartilage specific auto-antigens, which trigger the activation of immune response. Immune cells including T cells, B cells and macrophages infiltrate the joint tissues, cytokines and chemokines are released from different kinds of cells present in the joint, complement system is activated, and cartilage degrading factors such as matrix metalloproteinases (MMPs) and prostaglandin E2 (PGE2) are released, resulting in further damage to the articular cartilage. There is considerable success in the treatment of rheumatoid arthritis using anti-cytokine therapies. In OA, however, these therapies did not show much effect, highlighting more complex nature of pathogenesis of OA. This needs the development of more novel approaches to treat OA, which may include therapies that act on multiple targets. Plant natural products have this kind of property and may be considered for future drug development efforts. Here we reviewed the studies implicating different components of the immune system in the pathogenesis of OA. PMID- 23360841 TI - Association of MEFV gene mutations with rheumatoid factor levels in patients with rheumatoid arthritis. AB - PURPOSE: Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily affecting the joints. Arthritis disorders are associated with mutations of the Mediterranean fever (MEFV) gene. This gene has already been identified as being responsible for familial Mediterranean fever. The aim of this study was to explore the frequency and clinical significance of MEFV gene mutations in a cohort of Turkish patients with RA. METHODS: The study included 101 patients with RA and 110 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction and restriction fragment length polymorphism for the 5 MEFV gene mutations (M694V, M680I, V726A, E148Q, and P369S). RESULTS: Carrier rates of MEFV gene mutations were 31 (30.7%) of 101 and 26 (23.6%) of 110 in the RA and healthy control groups, respectively (P > 0.05; odds ratio, 1.4; 95% CI, 0.77-2.65). Whereas deformed joint count was relatively higher in the mutation carrier group than those of the noncarrier group, the rheumatoid factor levels were significantly higher in the carrier group of patients with RA (P = 0.001). CONCLUSIONS: The results of this study suggest that MEFV gene mutations are not positively associated with a predisposition to develop RA but might increase the severity of RA. Further research is needed to determine the actual pathogenic role of MEFV mutations in this disease. PMID- 23360842 TI - Usefulness of hemoglobin A(1c) as a criterion to define metabolic syndrome in nondiabetic Chinese adolescents. AB - AIMS: To examine whether hemoglobin A1c (HbA1c) can be used instead of fasting plasma glucose (FPG) to identify nondiabetic Chinese adolescents with metabolic syndrome (MS). METHODS: This was a cross-sectional study involving 910 adolescents (11-16 years; 46.8% girls) with an HbA1c less than or equal to 6.4% and an FPG less than or equal to 6.9 mmol/L. All participants underwent anthropometric and biochemical examinations. Metabolic syndrome was defined using the definition proposed by the International Diabetes Federation (IDF) and the American Heart Association (AHA). Replacement of an FPG greater than or equal to 5.6 mmol/L with an HbA1c greater than or equal to 5.7% yielded 2 HbA1c definitions (IDF-HbA1c and AHA-HbA1c). The use of an HbA1c greater than or equal to 5.7% or an FPG greater than or equal to 5.6 mmol/L in the definition of the glycemic component of the MS was compared. RESULTS: The HbA1c definition resulted in an increase in the population prevalence of MS by 2.4% (IDF-HbA1c) and 2.5% (AHA-HbA1c), respectively (P >= 0.05). The degree of concordance (kappa index) was as high as 0.900 for the concordance between the IDF and IDF-HbA1c definition, and 0.811 between the AHA and AHA-HbA1c definition. Subjects who were diagnosed as normal based on the FPG definition and met the HbA1c definition for MS had more cardiometabolic risk factors (waist circumference, blood pressure, lipid profiles, uric acid, and homeostasis assessment model of insulin resistance; all P < 0.05), indicating that the HbA1c definition identified more subjects with cardiovascular disease-related risk factors. HbA1c greater than or equal to 5.7% was significantly associated with the presence of MS [adjusted odds ratio, 2.61 (1.13-6.01)]. CONCLUSIONS: An HbA1c greater than or equal to 5.7% was associated with the presence of MS and can be considered a surrogate for FPG in the diagnosis of MS in nondiabetic Chinese adolescents. PMID- 23360843 TI - MicroRNA-30b-5p is involved in the regulation of cardiac hypertrophy by targeting CaMKIIdelta. AB - BACKGROUND: MicroRNAs (miRNAs) participate in the regulation of cardiac hypertrophy. However, it remains largely unknown as to how miRNAs are integrated into the hypertrophic program. Ca/calmodulin-dependent protein kinase II (CaMKII) is a hypertrophic signaling marker. It is not yet clear which miRNAs can regulate CaMKIIdelta. PURPOSE: In this study, we identified which miRNAs could regulate CaMKIIdelta and how to regulate CaMKIIdelta. METHODS: Through computational and expression analyses, miR-30b-5p was identified as a candidate regulator of CaMKIIdelta. Quantitative expression analysis of hypertrophic models demonstrated significant down-regulation of miR-30b-5p compared with control groups. Luciferase reporter assay showed that miR-30b-5p could significantly inhibit the expression of CaMKIIdelta. Moreover, through gain-of-function and loss-of function approaches, we found miR-30b-5p could negatively regulate the expression of CaMKIIdelta and miR-30b-5p was a regulator of cardiac hypertrophy. CONCLUSION: Our study demonstrates that the expression of miR-30b-5p is down-regulated in cardiac hypertrophy, and restoration of its function inhibits the expression of CaMKIIdelta, suggesting that miR-30b-5p may act as a hypertrophic suppressor. PMID- 23360844 TI - Mean platelet volume and its relation with arterial stiffness in patients with normotensive polycystic kidney disease. AB - BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) demonstrates cardiovascular manifestations, such as hypertension, myocardial infarction, and increased carotid intimae-media thickness. These complications are the main cause of morbidity and mortality in patients with ADPKD. Platelet activation and arterial stiffness are important manifestations that independently predict cardiovascular events. In the present study, we aimed to investigate the relation between arterial stiffness, mean platelet volume (MPV), and highly sensitive C reactive protein (hs-CRP) in patients with normotensive polycystic kidney disease. METHODS: We included 30 normotensive subjects with ADPKD with an estimated glomerular filtration rate (eGFR) of 60 mL or more per minute per 1.73 m, 30 normotensive subjects with ADPKD with eGFR from 30 to 60 mL/min per 1.73 m, and 30 healthy controls in our study. Pulse wave velocity (PWV), eGFR, spot urine protein-creatinine ratio, MPV, and hs-CRP levels were measured in all participants. In addition, transthoracic echocardiography and ambulatory blood pressure monitoring were performed. RESULTS: Age, sex, biochemical markers, eGFR, hemoglobin level, and platelet count were similar in the ADPKD subjects and the controls. There were significant differences in MPV (9.8 +/- 0.7, 8.7 +/- 0.8, and 8.0 +/- 0.5 femtolitre; P < 0.001) and hs-CRP (6.8 +/- 3.0, 5.3 +/- 2.7, and 2.6 +/- 0.52 mg/L; P < 0.001) in the groups. Additionally, PWV values were increased from healthy subjects to ADPKD patients who have decreased eGFR (5.5 +/ 1.1, 8.8 +/- 1.6, and 10.8 +/- 1.2 m/s; P for trend <0.001). There were significant positive correlations between PWV and MPV (r = 0.401; P = 0.002) and hs-CRP (r = 0.343; P = 0.007) in the patients with ADPKD. Additionally, PWV was independently predicted by MPV (beta = 0.286; P = 0.007), proteinuria (beta = 0.255; P = 0.001), eGFR (beta = -0.479; P < 0.001), and hs-CRP (beta = 0.379; P < 0.001) in the patients with ADPKD. In addition, eGFR, as a sign of severity of disease, was independently predicted by MPV (beta = -0.325; P = 0.003), PWV (beta = -0.471; P < 0.001), and hs-CRP (beta = -0.269; P = 0.008). CONCLUSIONS: Our findings suggest that MPV and hs-CRP levels are associated with increased arterial stiffness in patients with early-stage ADPKD and those with late-stage ADPKD. Also, MPV and hs-CRP were independently associated with the severity of ADPKD. PMID- 23360845 TI - Resistin and leptin levels in acromegaly: lack of correlation with echocardiographic findings. AB - PURPOSE: To find out how resistin and leptin levels were affected in patients with acromegaly and whether there is a relation between resistin levels and cardiac parameters. We also aimed to investigate whether resistin and leptin may be a link between insulin resistance and cardiac functions as well as these affected cardiac functions in the patients with acromegaly. METHODS: We included 30 subjects (15 men and 15 women) who had a diagnosis of acromegaly and 30 healthy (10 men and 20 women) subjects. Serum glucose, insulin, growth hormone, insulinlike growth factor 1 (IGF-1), resistin, and leptin levels were obtained, and insulin resistance of subjects were calculated. Echocardiographic studies of the subjects were performed. RESULTS: Resistin levels of the patients with acromegaly were found lower than controls. This difference was statistically significant (P = 0.001). Leptin levels were lower in the patients with acromegaly than in the controls, but this difference was not statistically significant. Resistin and leptin levels were not correlated with growth hormone, IGF-1, and with insulin-like growth factor binding protein 3 levels. Homeostasis model assessment of insulin resistance was positively correlated with resistin levels. (P = 0.03; r = 0.531) but not correlated with leptin levels. There was a positive correlation between body mass index and leptin levels in the patients with acromegaly (P = 0.007; r = 0.482). Interventricular septum thickness, posterior wall thickness, left ventricle mass index, peak early mitral inflow velocity-peak late mitral inflow velocity ratio, deceleration time, ejection time, isovolumetric relaxation time, velocity propagation, and left ventricular end systolic volume values were significantly greater in the patients with acromegaly. Leptin levels in the acromegalic patients were not correlated with any of them. CONCLUSIONS: We found biventricular hypertrophy and impairment of diastolic and systolic function in the patients with acromegaly. We conclude that changes in resistin and leptin levels are unlikely to account for the insulin resistance of acromegaly. They do not also seem to be contributing factors of cardiovascular changes in patients with acromegaly. PMID- 23360846 TI - Urinary tubular protein-based biomarkers in the rodent model of cisplatin nephrotoxicity: a comparative analysis of serum creatinine, renal histology, and urinary KIM-1, NGAL, and NAG in the initiation, maintenance, and recovery phases of acute kidney injury. AB - BACKGROUND: Several biomarkers are becoming available for the early detection of acute kidney injury (AKI), but few have been directly compared. OBJECTIVE: To compare urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase associated lipocalin (NGAL), and N-acetyl glucosaminidase (NAG) against serum creatinine and renal histological score in the initiation, maintenance, and recovery phases of cisplatin (CP)-induced AKI. METHODS: Sprague-Dawley rats (300 350 g) were injected once through their tail veins with CP (CP group) at 5.5 mg/kg or with same volume of normal saline vehicle (Control group). Rats were euthanized at 2, 4, 6, 12, and 24 hours, and on days 2, 3, 6, and 10 (n = 12 in the CP group and n = 6 in the Control group at each time point), and urine, blood, and kidney samples were analyzed. RESULTS: A significant increase in serum creatinine was noted by day 3 in the CP group versus Control group [1.46 (0.12) vs 0.28 (0.03) mg/dL; mean (SE); P < 0.05]. The renal histology scores for brush border loss and tubular necrosis were significantly higher at 12 and 24 hours, respectively, in the CP group. Urinary kidney injury molecule-1 levels were significantly higher at 24 hours in the CP group than in the Control group [48.26 (13.13) vs 8.21 (3.31) pg/mg creatinine; P < 0.05] and remained elevated through day 10. Both urine NAG and NGAL levels were significantly higher by day 2 in the CP than in the Control group [NAG, 8.19 (0.82) vs 3.48 (0.40) pg/mg creatinine, P G 0.05; NGAL, 2911.80 (368.10) vs 1412.60 (250.20) pg/mg creatinine, P < 0.05]. Urinary NAG remained elevated for 6 days and NGAL for 3 days. CONCLUSIONS: Our study suggests a temporal hierarchy in the ability of certain urinary protein based biomarkers to detect AKI after a well-defined tubular injury. Comparative analyses of urinary biomarkers are warranted in clinical settings such as patients receiving CP to discern the time course and pattern of expression. PMID- 23360847 TI - Inhibition of renin-angiotensin system: implications for diabetes control and prevention. AB - Several large-scale clinical studies have consistently demonstrated that use of inhibitors of renin-angiotensin system such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was associated with significant reduction of new-onset diabetes in patients with insulin resistance such as primary hypertension. Such observations stimulated major investigations into the interaction of angiotensin and insulin signaling systems, which in turn led to the discovery of a cross talk at several steps between the 2 pathways. Evidence from these clinical trials and from the experimental models of insulin resistance including our findings in ZSF rat and other animal models will be discussed in this review. PMID- 23360848 TI - Perifosine and sorafenib combination induces mitochondrial cell death and antitumor effects in NOD/SCID mice with Hodgkin lymphoma cell line xenografts. AB - The effects of the Akt inhibitor perifosine and the RAF/MEK/ERK inhibitor sorafenib were investigated using two CD30(+)Hodgkin lymphoma cell lines (L-540 and HDLM-2) and the CD30(-)HD-MyZ histiocytic cell line. The combined perifosine/sorafenib treatment significantly inhibited mitogen-activated protein kinase and Akt phosphorylation in two of the three cell lines. Profiling of the responsive cell lines revealed that perifosine/sorafenib decreased the amplitude of transcriptional signatures that are associated with the cell cycle, DNA replication and cell death. Tribbles homolog 3 (TRIB3) was identified as the main mediator of the in vitro and in vivo antitumor activity of perifosine/sorafenib. Combined treatment compared with single agents significantly suppressed cell growth (40-80%, P<0.001), induced severe mitochondrial dysfunction and necroptotic cell death (up to 70%, P<0.0001) in a synergistic manner. Furthermore, in vivo xenograft studies demonstrated a significant reduction in tumor burden (P<0.0001), an increased survival time (81 vs 45 days, P<0.0001), an increased apoptosis (2- to 2.5-fold, P<0.0001) and necrosis (2- to 8-fold, P<0.0001) in perifosine/sorafenib-treated animals compared with mice receiving single agents. These data provide a rationale for clinical trials using perifosine/sorafenib combination. PMID- 23360849 TI - The future direction of personalised nutrition: my diet, my phenotype, my genes. AB - Although personalised nutrition is frequently considered in the context of diet gene interactions, increasingly, personalised nutrition is seen to exist at three levels. The first is personalised dietary advice using Internet-delivered services, which ultimately will become automated and which will also draw on mobile phone technology. The second level of personalised dietary advice will include phenotypic information on anthropometry, physical activity, clinical parameters and biochemical markers of nutritional status. It remains possible that in addition to personalised dietary advice based on phenotypic data, advice at that group or metabotype level may be offered where metabotypes are defined by a common metabolic profile. The third level of personalised nutrition will involve the use of genomic data. While the genomic aspect of personalised nutrition is often considered as its main driver, there are significant challenges to translation of data on SNP and diet into personalised advice. The majority of the published data on SNP and diet emanate from observational studies and as such do not offer any cause-effect associations. To achieve this, purpose designed dietary intervention studies will be needed with subjects recruited according to their genotype. Extensive research indicates that consumers would welcome personalised dietary advice including dietary advice based on their genotype. Unlike personalised medicine where genotype data are linked to the risk of developing a disease, in personalised nutrition the genetic data relate to the optimal diet for a given genotype to reduce disease risk factors and thus there are few ethical and legal issues in personalised nutrition. PMID- 23360850 TI - Incivility. PMID- 23360853 TI - The combined use of sucrose and nonnutritive sucking for procedural pain in both term and preterm neonates: an integrative review of the literature. AB - Many agents, both pharmacologic and nonpharmacologic, have been studied to alleviate neonatal pain, and the research is extensive. The 2 most commonly studied nonpharmacologic agents studied have been sucrose and nonnutritive sucking (NNS). There is increasing evidence that the synergistic effect of sucrose and NNS is more effective than the effect of sucrose or NNS alone. The purpose of this integrative review of the literature was to determine whether there is a relationship between the synergistic effect of combining sucrose and NNS administered before and during painful procedures, and reducing procedural pain in both preterm and term neonates. This integrative review indicates that the combination of sucrose and NNS is a safe, effective, and clinically significant means of providing procedural pain relief in neonates, both term and preterm. PMID- 23360855 TI - Antibiotic timing in neonates with suspected hospital-acquired infections. AB - There exists general agreement within neonatology that antibiotics should be administered promptly to neonates with possible bacterial sepsis and meningitis. We initiated a series of quality improvement cycles designed to reduce delays in the initiation of antibiotic therapy to less than 2 hours when hospital-acquired infection (HAI) was suspected. All infants in this study were in neonatal intensive care (level II or III) who were started on antibiotics for a suspected HAI (defined as an infection that occurred 72 hours after admission to the NICU) were audited. Through a series of quality improvement cycles, we analyzed sources of delays in the initiation of antibiotic therapy from the time the order was written through administration. In subsequent cycles, we intervened to reduce delays through education, standardize the evaluation process, and develop an online ordering system that streamlined the workflow patterns in the nurseries and pharmacy. Using a prospective cohort design, we compared antibiotic delivery times after each process improvement cycle. Antibiotic delivery time was reduced from a median of 137.5 minutes to 75 minutes and variation of practice was reduced in terms of standard deviation and range (P < .001). The use of computerized physician order entry significantly improved the writing of STAT orders (P < .0001). A systematic analysis of workflow patterns and efficiencies, coupled with improvement cycles targeting delays and development of a computerized physician order entry system, allowed us to improve antibiotic delivery time in neonates with suspected HAI in an intensive care nursery system. PMID- 23360857 TI - Twin-to-twin transfusion syndrome: a case study. AB - Twin-to-twin transfusion syndrome (TTTS) is a disease that affects roughly 15% of monochorionic twins. Although TTTS is not extremely prevalent, the rate of mortality and morbidly approaches 100% without early detection and treatment. The following case study is a triplet pregnancy that included a set of monochorionic twins affected by TTTS. Typically, it is assumed that monochorionicity can identify the zygosity of twins, which was disproven in this case. Research indicates that there has been an increased rate of monochorionic twins with in vitro fertilization. There is great debate about the most appropriate treatment modality for TTTS. Perinatal treatment followed by neonatal management is the standard of care for TTTS. Implications for the neonatal nurse practitioner and care for the patients are discussed. PMID- 23360858 TI - Horizontal hostility: why you should care. AB - Nurse-to-nurse, or horizontal, hostility creates a multitude of problems. There are a number of specific and direct problems, including impact on the culture of nursing, stress, healthcare economics, and patient outcomes, that are illustrated in the literature. Horizontal hostility is a pervasive and destructive force that must be addressed in every venue in which nursing is involved. This study discusses the problem of horizontal hostility and the impact it has on nursing and healthcare. Nursing theory is applied to practice and provides concepts and frameworks that are utilized to underscore the critical nature of the problem and provide a map for solutions. PMID- 23360859 TI - Preventing necrotizing enterocolitis with standardized feeding protocols: not only possible, but imperative. PMID- 23360860 TI - A national survey of neonatal peripherally inserted central catheter (PICC) practices. AB - PURPOSE: The purpose of this study was to assess and describe the practices involved in the insertion and maintenance of peripherally inserted central catheters (PICCs) in neonates in level III neonatal intensive care units (NICUs) in the United States and to compare the findings with current recommendations and evidence. SUBJECTS: The study included responses from 187 nurses, nurse practitioners, and neonatologists who place PICCs in NICUs representing 43 states. METHODS: A 90-question, multiple-choice survey of a variety of PICC practices was sent to NICU directors and nursing staff responsible for PICC insertion. The explorative survey was sent by electronic and standard mail services. A descriptive analysis of the responses was performed. MAIN OUTCOME MEASURES: Main outcome measures included the response rate to the survey and the summarized responses of multiple categories of PICC practices. PRINCIPAL RESULTS: Of the 460 level III NICUs contacted, 187 returned surveys meeting criteria for analysis, yielding a 42% response rate. Responses showed wide variation of PICC practices in multiple aspects of PICC insertion and maintenance. The greatest level of conformity was seen with the following practices: use of 2 nurses to perform a dressing change, trimming the PICC, using a kit or cart containing insertion supplies, use of maximal sterile barrier precautions during insertion, catheter tip residing in the superior vena cava for upper body insertions, and not heparin locking, infusing blood products, performing catheter repair, or inserting using Modified Seldinger Technique. Some identified practices, such as infusion tubing change and catheter entry techniques, were contrary to current evidence and demonstrated a lack of correct information, and some represented safety concerns for the neonates having PICCs. CONCLUSION: This extensive national survey of NICU PICC practices showed wide variation in multiple aspects of PICC insertion and maintenance. A gap between the evidence and current practice was evident in many facets of training, insertion techniques, and maintenance processes. The data suggest a need for an increase in awareness of clinicians of current practice guidelines and standards and the need for further research to develop an evidence basis for many aspects of PICC care where lacking. PMID- 23360861 TI - Examining the use and outcomes of a new hospital-grade breast pump in exclusively pumping NICU mothers. AB - PURPOSE: To determine whether exclusively pumping mothers of preterm infants could achieve full milk production while using the Ameda Platinum breast pump the first 14 days postpartum. SUBJECTS: Twenty-six mothers who delivered infants between 26 and 32 weeks' gestation at 2 Intermountain Healthcare hospitals completed the study. Mothers could not take milk-enhancing or milk-reducing substances, feed directly at the breast, have had breast surgery, or use any other breast pump during the study. DESIGN: Nonexperimental, descriptive study. METHODS: Mothers were instructed to use the Ameda Platinum breast pump exclusively 8 times daily, for 14 days. They recorded milk volumes, suction pressures, cycle speeds, and time spent pumping. A "Performance Questionnaire" was completed at the end of the study with questions about the ease of use, preferred speed and suction settings, and overall performance of the pump. MAIN OUTCOME MEASURE: Full milk production was defined as 700 mL/d. Speed and suction settings, as well as average pumping session length, were analyzed in relation to categories of maximum milk volumes expressed. RESULTS: The average maximum daily milk volume for all mothers was 817 mL/d. Sixteen mothers produced milk volumes more than 700 mL/d and 9 of these mothers were able to express more than 1000 mL/d. Those with daily milk production more than 700 mL/d used lower suction pressure settings to stimulate the milk ejection reflex and to empty the breast. These higher-producing mothers also chose ending speeds of 50 to 60 cycles per minute, similar to the nutritive sucking pattern of a healthy newborn. Mothers producing less than 500 mL/d used higher suction pressures, faster ending cycle speeds, and longer pumping times. Suction pressures varied widely among all of the mothers and were influenced by the mothers' nipple or breast sensitivity, which varied from mother to mother and day to day. Mothers reported liking separate controls for speed and suction and used them to achieve maximum comfort and milk volume. CONCLUSIONS: The Ameda Platinum breast pump is an effective hospital-grade pump for exclusively pumping mothers to establish full milk production by 14 days postpartum. Separate control of speed and suction allows mothers a wide range of options to achieve greater comfort and multiple milk ejections, both of which contribute to optimal milk expression. PMID- 23360862 TI - Infant mortality among singletons and twins in Japan during 1999-2008 on the basis of risk factors. AB - The infant mortality rate (IMR) among single and twin births from 1999 to 2008 was analyzed using Japanese Vital Statistics. The IMR was 5.3-fold higher in twins than in singletons in 1999 and decreased to 3.9-fold in 2008. The reduced risk of infant mortality in twins relative to singletons may be related, partially, to survival rates, which improved after fetoscopic laser photocoagulation for twin - twin transfusion syndrome. The proportion of neonatal deaths among total infant deaths was 54% for singletons and 74% for twins. Thus, intensive care of single and twin births may be very important during the first month of life to reduce the IMR. The IMR decreased as gestational age (GA) rose in singletons, whereas the IMR in twins decreased as GA rose until 37 weeks and increased thereafter. The IMR was significantly higher in twins than in singletons from the shortest GA (<24 weeks) to 28 weeks as well as >=38 weeks, whereas the IMR was significantly higher in singletons than in twins from 30 to 36 weeks. As for maternal age, the early neonatal and neonatal mortality rates as well as the IMR in singletons were significantly higher in the youngest maternal age group than in the oldest one, whereas the opposite result was obtained in twins. The lowest IMR in singletons was 1.1 per 1,000 live births for >=38 weeks of gestation and heaviest birth weight (>=2,000 g), while the lowest IMR in twins was 1.8 at 37 weeks and >=2,000 g. PMID- 23360863 TI - The capsular polysaccharide and lipopolysaccharide structures of two carbapenem resistant Klebsiella pneumoniae outbreak isolates. AB - Carbapenem resistant Klebsiella pneumoniae (CRKP) are isolated with increasing frequency, especially from immunocompromized patients. The capsular polysaccharide (CPS) types of CPKP were not determined. Investigation of two CRKP isolates from a 2011 outbreak at the Clinical Center, the National Institutes of Health, identified a new capsular type shared by the two isolates, similar to K. pneumonia K19 and K34 but structurally different than any published K. pneumoniae CPS repeating unit: The LPS of the two isolates was found to have no O-specific polysaccharide and the chemical structure of the core oligosaccharides agreed with the published data. If this structure type will be prevalent among CPKP isolates, our findings could facilitate rapid diagnosis and help to develop new therapeutic solutions to this antibiotic resistant pathogen. PMID- 23360864 TI - Medical error in dermatology practice: development of a classification system to drive priority setting in patient safety efforts. AB - BACKGROUND: To date, no study to our knowledge has examined the nature and scope of medical error in dermatology practice. OBJECTIVE: We sought to collect and categorize physician-reported errors in dermatology practice. METHODS: A survey regarding most recent and most serious errors was developed and distributed to dermatologists attending US meetings. A total of 150 responses were received outlining 152 most recent errors and 130 most serious errors. Survey responses, along with classification systems for other specialties, were used to develop a classification system for medical error in dermatology. RESULTS: The respondents' demographics reflected the specialty: 63% were male, 60% were older than 50 years, and 60% were in solo or group private practice. Of the most recent errors reported, 85% happened once a year or less, and 86% did not result in harm to patients. The most common categories of both most recent and most serious errors were related to assessment (41% and 31%, respectively) and interventions (44% and 52%, respectively). Assessment errors were primarily related to investigations, and commonly involved the biopsy pathway. Intervention errors in the most recent and most serious errors were split between those related to medication (54% and 27%) and those related to procedures (46% and 73%). Of note, 5 and 21 wrong-site surgeries were reported in the most recent and most serious errors groups, respectively. LIMITATIONS: Our findings are subject to respondent and recall bias and our classification system, although an important first step, is likely incomplete. CONCLUSION: Our findings highlight several key areas of patient care in need of safety initiatives, namely the biopsy pathway, medication management, and prevention of wrong-site surgery. PMID- 23360865 TI - Dermatologic manifestations of ataxia-telangiectasia syndrome. AB - BACKGROUND: Previous reports on the cutaneous manifestations of ataxia telangiectasia (A-T) have relied on data from small series, in patients not genetically tested for A-T. OBJECTIVE: The aim of our study was to characterize the dermatologic manifestations in patients with A-T followed up at the national A-T clinic in Israel. METHODS: This retrospective cross-sectional study included 32 patients followed up at a multidisciplinary A-T clinic from 2010 to 2012. Complete skin examination was done by a single dermatologist. Information about mutations and neurologic status was extracted from the patients' charts. Relevant demographic, clinical, and laboratory characteristics of all patients were collected and summarized. RESULTS: Of the 32 patients, 97% had ocular telangiectasia, the hallmark of the disease. Telangiectasia on other body parts was less frequent. Pigmentary anomalies included cafe-au-lait macules (84%), hypopigmented macules (44%), and melanocytic nevi (37%). A facial papulosquamous rash was found in 41% of cases. Other manifestations included hypertrichosis and birdlike facies. We did not observe premature hair graying or poliosis. No genotype-phenotype correlation was found in terms of skin manifestations. LIMITATIONS: There was a modest sample size, because of the rarity of the disease. CONCLUSION: Recognition of the ocular and dermatologic manifestations of A-T can facilitate early diagnosis in a child with neurologic deterioration. PMID- 23360866 TI - Cutaneous plasmacytosis: report of 6 cases with or without systemic involvement. AB - BACKGROUND: Cutaneous plasmacytosis and systemic plasmacytosis are rare entities arising primarily in patients of Japanese descent. The origin and exact pathogenesis are poorly understood. OBJECTIVE: We sought to determine clinicopathologic features of cutaneous and systemic plasmacytosis. METHODS: We describe the clinicopathologic features of 6 patients with cutaneous plasmacytosis with or without systemic involvement (male:female = 3:1; mean age: 49.7 years; median age: 50.5 years; age range: 29-64 years). RESULTS: Patients presented clinically with multiple, red-brown infiltrated plaques and flat tumors, mainly located on the trunk. Histology revealed in all cases the presence of clusters of mature plasma cells within the dermis. Lymphoid follicles with reactive germinal centers were seen in 3 cases. Five cases showed the expected polyclonal expression of immunoglobulin light chain by the plasma cells, but monoclonality was observed in 1 case, thus showing overlapping features with cutaneous marginal zone lymphoma. One patient revealed overlapping features with multicentric Castleman disease. LIMITATIONS: This was a retrospective study on a relatively small number of patients. CONCLUSIONS: Despite typical clinical presentation, some of our patients presented with histopathologic and immunohistochemical features that deviated from the conventional appearance. Our observation confirms and expands previous observations of this elusive entity, suggesting that the spectrum of clinicopathologic presentations may be wider than previously recognized. PMID- 23360867 TI - Photoprotective habits of patients with cutaneous lupus erythematosus. AB - BACKGROUND: Previous studies have suggested that patients with cutaneous lupus erythematosus (CLE) are deficient in sunscreen use. Use of other photoprotective methods by patients with CLE has not been assessed to our knowledge. OBJECTIVE: We sought to identify demographic and clinical characteristics of patients with CLE who have the lowest overall sun-protection habits scores, and who are least likely to practice 5 individual photoprotective methods (ie, shade, sunscreen, long sleeves, hat, and sunglasses). METHODS: A total of 105 patients with CLE at the University of Texas Southwestern Medical Center in Dallas completed a survey to evaluate their photoprotective practices. Additional information including demographics and clinical indicators related to CLE was collected from the patients. RESULTS: Patients with medium and dark skin (ie, Fitzpatrick skin types III-VI) and patients aged 31 to 50 years were the least likely CLE subgroups to practice overall photoprotection, as indicated by low sun-protection habits scores (P = .001 and P = .04, respectively). In terms of individual photoprotective methods, male patients with CLE were deficient in sunscreen use, but were more likely to wear hats than female patients with CLE. Sunscreen and sunglasses use was also significantly more infrequent in dark-skinned patients than those with Fitzpatrick skin types I to IV. Patients with CLE between the ages of 41 and 50 years were least likely to wear hats. LIMITATIONS: This study was subject to reporter bias and did not cover barriers to and knowledge of photoprotection. CONCLUSION: Cultural customs and misconceptions shared by those from the general population have a significant influence on the photoprotective habits of this CLE population. These need to be addressed to improve photoprotection rates in these at-risk individuals. PMID- 23360868 TI - Psoriasis and metabolic syndrome: a systematic review and meta-analysis of observational studies. AB - BACKGROUND: Increasing population-based studies have suggested a relationship between psoriasis and metabolic syndrome. OBJECTIVE: The objective of this study was to perform a systematic review and meta-analysis that synthesizes the epidemiologic associations between psoriasis and metabolic syndrome. METHODS: We searched for observational studies from MEDLINE, EMBASE, and Cochrane Central Register from Jan 1, 1980 to Jan 1, 2012. We applied the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines in the conduct of this study. RESULTS: We identified 12 observational studies with a total of 1.4 million study participants fulfilling the inclusion criteria, among whom 41,853 were patients with psoriasis. Based on random-effects modeling of cross-sectional and case-controlled studies, the pooled odds ratio (OR) for metabolic syndrome among patients with psoriasis was 2.26 (95% confidence interval [CI] 1.70-3.01) compared with the general population. Visual inspection of a funnel plot and formal analysis with the Egger test suggested publication bias and absence of small studies in the published literature (P = .03). A dose-response relationship was also observed between psoriasis severity and prevalence of metabolic syndrome. LIMITATIONS: No studies to date have assessed incidence of metabolic syndrome among patients with psoriasis. CONCLUSIONS: Compared with the general population, psoriasis patients have higher prevalence of metabolic syndrome, and patients with more severe psoriasis have greater odds of metabolic syndrome than those with milder psoriasis. PMID- 23360869 TI - L2,3-edge x-ray absorption near-edge spectroscopy analysis of photoisomerism in solid ruthenium-sulfur dioxide complexes. AB - Ru L(2,3) edge x-ray absorption near-edge spectroscopy spectra of four compounds [Ru(SO(2))(NH(3))(4)X]Y (X = water, Y = (+/-)-camphorsulfonate(2); X =water, Y = tosylate(2); X =isonicotinamide, Y = tosylate(2); X =pyridine, Y = triflate(2)) are reported before and after optical excitation, which causes photoinduced linkage isomerism of the SO(2) ligand. Principal component analysis reveals consistent changes in the spectra upon photoisomerization, suggesting a partial oxidation of the Ru ion. These results demonstrate that x-ray absorption near edge spectroscopy is an effective means of probing photoinduced linkage isomerism. PMID- 23360870 TI - Long-term prognosis and outcome in patients with a chest pain syndrome and myocardial bridging: a 64-slice coronary computed tomography angiography study. AB - BACKGROUND: Small case series have associated coronary myocardial bridging (MB) with adverse cardiac events. However, the clinical significance of MB in unselected patients with chest pain remains unclear. The purpose of this study was to explore the relation between the presence of isolated MB and subsequent adverse cardiac events in symptomatic patients referred for coronary computed tomography angiography (CCTA). METHODS AND RESULTS: Three hundred and thirty-four consecutive patients (age 57 +/- 13 years, 43% female) with chest pain and no prior history of coronary artery disease (CAD) who underwent 64-slice CCTA and had no obstructive CAD (>= 50% coronary luminal obstruction) were included. Patients were followed for cardiac events [cardiovascular (CV) death or non-fatal myocardial infarction (MI)] over 6.1 +/- 1 years. Outcomes were compared between patients with MB vs. those without MB using the Cox models. MB was present in 117 out of 334 (35%) patients on CCTA and 80% of MB involved the mid-distal left anterior descending coronary artery. During a mean follow-up duration of 6.1 +/- 1 years, cardiac events occurred in 6 out of 117 (5.1%) patients with, and 7 out of 217 (3.2%) patients without MB (P = 0.40). Univariate predictors of cardiac events were hypertension [hazards ratio (HR) = 10.6, P = 0.002], diabetes mellitus (HR = 4.8, P = 0.01), and older age (HR = 1.1, P = 0.0004). The association of hypertension and age with adverse cardiac events remained statistically significant after adjusting for other variables. Neither the presence nor the extent of MB was associated with an increased risk of cardiac events. CONCLUSION: MB is a common finding on CCTA among patients presenting with chest pain but no obstructive CAD. No association was evident between MB and the risk of CV death or MI. PMID- 23360872 TI - Change and continuity, commonality and diversity. PMID- 23360871 TI - Residents' corner February 2013. sQUIZ your knowledge! An exophytic tumor. Diagnosis: Verrucous carcinoma. PMID- 23360873 TI - Alcohol use during the great recession of 2008-2009. AB - AIMS: The aim of this study was to assess changes in alcohol use in the USA during the Great Recession. METHODS: Drinking participation, drinking frequency, drinking intensity, total alcohol consumption and frequency of binge drinking were assessed in a nationally representative sample of 2,050,431 US women and men aged 18 and older, interviewed between 2006 and 2010. RESULTS: The prevalence of any alcohol use significantly declined during the economic recession, from 52.0% in 2006-2007 to 51.6% in 2008-2009 (P < 0.05), corresponding to 880,000 fewer drinkers (95% confidence interval [CI] 140,000 to 1.6 million). There was an increase, however, in the prevalence of frequent binging, from 4.8% in 2006-2007 to 5.1% in 2008-2009 (P < 0.01), corresponding to 770,000 more frequent bingers (95% CI 390,000 to 1.1 million). Non-Black, unmarried men under 30 years, who recently became unemployed, were at highest risk for frequent binging. CONCLUSION: During the Great Recession there was an increase in abstention from alcohol and a rise in frequent binging. PMID- 23360874 TI - Treated unicameral bone cysts. AB - Unicameral bone cysts (UBCs) are a common benign entity involving the metaphysis of growing bone, occurring within the first two decades of life. Assessment of these lesions, both before and after surgery, is performed routinely utilizing radiographs. We present a review of UBCs at various stages of treatment, including both successful and incomplete healing, and describe the imaging findings throughout their postoperative course. PMID- 23360875 TI - Uncovering strategies to benefit from our gut microbiota: probiotics and prebiotics. PMID- 23360876 TI - Host-microbe interactions: the difficult yet peaceful coexistence of the microbiota and the intestinal mucosa. AB - The immune system has evolved to live in a collaborative relationship with the microbiota, while still serving its seminal function to fight off invasive pathogenic bacteria. The mechanisms that rule the interactions between the intestinal microbiota and the intestinal immune system are the focus of intense research. Here, we describe how the innate immunity is, to a great extent, in charge of the control of the microbiota in the intestine and relies on non specific receptors called pathogen-recognition receptors. While the microbiota has a well-defined effect on the host immune homoeostasis, it has become clear that the opposite is also true, i.e., the mucosal immune system has the capacity to shape the microbial population. The mechanisms that rule the reciprocal regulation between host immunity and commensal bacteria (including specific bacteria) are currently being elucidated and will be described here. A better knowledge of how the host and bacteria interact and how the intestinal microbiota and the immune system are co-regulated will provide the basis for a better understanding of intestinal and systemic immunopathologies and for the development of new therapeutic approaches. PMID- 23360877 TI - Linking the gut microbiota to human health. AB - The human gut is the natural environment for a diverse and dynamic microbial ecosystem, whose structure and functions are presently a major target of research in biomedicine. Experimental studies in germ-free animals performed some decades ago revealed the importance of these microbial communities for normal growth and development and for the maintenance of health in adult life. The host provides habitat and nutrition to the microbial communities and derives many benefits from its symbionts that contribute to metabolic, defensive and trophic functions. Development of novel gene sequencing technologies as well as availability of powerful bioinformatic analysis tools provide new insights into the composition and structure of the human gut microbiota. There is no clear definition of the characteristics of a normal 'healthy' gut microbiota in human subjects, but several disease states have been associated with changes in the composition of faecal and intestinal mucosal communities, including inflammatory bowel diseases, obesity and the metabolic syndrome. Probiotics and prebiotics are used to improve symbiosis between enteric microbiota and the host or restore states of dysbiosis. PMID- 23360878 TI - In vitro cell and tissue models for studying host-microbe interactions: a review. AB - Ideally, cell models should resemble the in vivo conditions; however, in most in vitro experimental models, epithelial cells are cultivated as monolayers, in which the establishment of functional epithelial features is not achieved. To overcome this problem, co-culture experiments with probiotics, dendritic cells and intestinal epithelial cells and three-dimensional models attempt to reconcile the complex and dynamic interactions that exist in vivo between the intestinal epithelium and bacteria on the luminal side and between the epithelium and the underlying immune system on the basolateral side. Additional models include tissue explants, bioreactors and organoids. The present review details the in vitro models used to study host-microbe interactions and explores the new tools that may help in understanding the molecular mechanisms of these interactions. PMID- 23360879 TI - Gut immune system and oral tolerance. AB - Gut mucosal surfaces separate the external environment from the internal sterile environment and so represent a first line of defence system. This barrier faces environments rich in pathogens that have developed effective mechanisms for colonisation of epithelial surfaces and invasion of mucosal tissues, but also harmless antigens such as food, airborne antigens or commensal bacterial flora. The latter represent the vast majority of the encountered antigens and require an appropriate response characterised by either ignorance or active suppression. However, for the former, a robust immune response is needed. Mucosae have developed a complex immune system that is capable of mounting an immune response against pathogenic antigens, while maintaining the required ignorance or active suppression against non-pathogenic antigens. Taking advantage of this knowledge, strategies have been devised to induce oral tolerance to antigens involved in experimental autoimmune disease or human conditions. It is now known that oral tolerance induces the up-regulation and activation of T cells with regulatory properties, a subtype of CD4+ T cells whose function is to regulate functions of other T lymphocytes to avoid excessive immune activation. Amongst them, the Th3 cells (cells that express the latency-associated peptide on the surface and secrete transforming growth factor beta, a cytokine with immunoregulatory properties) are especially relevant in the induction of oral tolerance. Orally fed antigens seek to generate these types of cells in the treatment of autoimmune diseases in experimental animals or human subjects. PMID- 23360880 TI - Sources, isolation, characterisation and evaluation of probiotics. AB - According to the FAO and the WHO, probiotics are 'live microorganisms which, when administered in adequate amounts, confer a health benefit on the host'. The strains most frequently used as probiotics include lactic acid bacteria and bifidobacteria, which are isolated from traditional fermented products and the gut, faeces and breast milk of human subjects. The identification of microorganisms is the first step in the selection of potential probiotics. The present techniques, including genetic fingerprinting, gene sequencing, oligonucleotide probes and specific primer selection, discriminate closely related bacteria with varying degrees of success. Additional molecular methods, such as denaturing gradient gel electrophoresis/temperature gradient gel electrophoresis and fluorescence in situ hybridisation, are employed to identify and characterise probiotics. The ability to examine fully sequenced genomes has accelerated the application of genetic approaches to the elucidation of the functional roles of probiotics. One of the best-demonstrated clinical benefits of probiotics is the prevention and treatment of acute and antibiotic-associated diarrhoea;however, there is mounting evidence for a potential role for probiotics in the treatment of allergies and intestinal, liver and metabolic diseases. There are various mechanisms by which probiotics exert their beneficial effects: regulation of intestinal permeability, normalisation of host intestinal microbiota, improvement of gut immune barrier function, and adjustment between pro- and anti-inflammatory cytokines. The number of studies carried out to test the effects of probiotics in vitro and in animals is enormous. However, the most reliable method of assessing the therapeutic benefits of any probiotic strain is the use of randomised, placebo-controlled trials, which are reviewed in this article [corrected]. PMID- 23360881 TI - Isolation, identification and characterisation of three novel probiotic strains (Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036) from the faeces of exclusively breast-fed infants. AB - The aim of the present study was to isolate, identify and characterise novel strains of lactic acid bacteria and bifidobacteria with probiotic properties from the faeces of exclusively breast-fed infants. Of the 4680 isolated colonies, 758 exhibited resistance to low pH and tolerance to high concentrations of bile salts; of these, only forty-two exhibited a strong ability to adhere to enterocytes in vitro. The identities of the isolates were confirmed by 16S ribosomal RNA (rRNA) sequencing, which permitted the grouping of the forty-two bacteria into three different strains that showed more than 99 % sequence identity with Lactobacillus paracasei, Lactobacillus rhamnosus and Bifidobacterium breve, respectively. The strain identification was confirmed by sequencing the 16S-23S rRNA intergenic spacer regions. Strains were assayed for enzymatic activity and carbohydrate utilisation, and they were deposited in the Collection Nationale de Cultures de Microorganismes (CNCM) of the Institute Pasteur and named L. paracasei CNCM I-4034, B. breve CNCM I-4035 and L. rhamnosus CNCM I-4036. The strains were susceptible to antibiotics and did not produce undesirable metabolites, and their safety was assessed by acute ingestion in immunocompetent and immunosuppressed BALB/c mouse models. The three novel strains inhibited in vitro the meningitis aetiological agent Listeria monocytogenes and human rotavirus infections. B. breve CNCM I-4035 led to a higher IgA concentration in faeces and plasma of mice. Overall, these results suggest that L. paracasei CNCM I-4034, B. breve CNCM I-4035 and L. rhamnosus CNCM I-4036 should be considered as probiotic strains, and their human health benefits should be further evaluated. PMID- 23360882 TI - Competitive inhibition of three novel bacteria isolated from faeces of breast milk-fed infants against selected enteropathogens. AB - Numerous in vitro and in vivo studies conducted using different probiotic micro organisms have demonstrated their ability to interfere with the growth and virulence of a variety of enteropathogens. The reported beneficial effects of the use of probiotics to complement antibiotic therapy or prevent diarrhoea or gastrointestinal infection in infants have increased in recent years. In the present study, we demonstrated the capacity of supernatants obtained from three novel probiotics (Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036) isolated from the faeces of breastfed infants to inhibit the growth of enterotoxigenic and enteropathogenic (EPEC) bacteria, such as Escherichia coli, Salmonella and Shigella. To assess their potential antimicrobial activity, the 17 and 24 h cell-free supernatants broth concentrates (10*) having 1, 2 or 4 % of the three probiotics were incubated with EPEC bacteria strains. After 17 h of co-culture, the supernatants were able to inhibit the growth of E. coli, Salmonella and Shigella up to 40, 55 and 81 %, respectively. However, the inhibitory capacity of some supernatants was maintained or completely lost when the supernatants (pH 3.0) were neutralised (pH 6.5). Overall, these results demonstrated that L. paracasei CNCM I-4034, B. breve CNCM I-4035 and L. rhamnosus CNCM I-4036 produce compounds that exhibited strain specific inhibition of enterobacteria and have the potential to be used as probiotics in functional foods. PMID- 23360883 TI - Host genotype, intestinal microbiota and inflammatory disorders. AB - Intestinal microbiota may influence human physiology and disease risk due to the role it plays in mediating appropriate immune responses to harmful and innocuous antigens. Colonisation of the intestine in early life seems particularly important as it is the main environmental stimulus for immune system maturation. This is a dynamic process, which depends on both environmental and genetic factors. The pathogenesis of inflammatory bowel disease, such as Crohn's disease, involves genetic polymorphisms (e.g. CARD15/nucleotide-binding oligomerisation domain 2) related to an excessive inflammatory response to commensal microbiota and to its unbalanced composition. Atopic diseases have also been linked to imbalances in microbiota and to related genetic factors (e.g. TLR4 and CD14 genes), although these associations are still controversial. Research into the relationship between the genetic risk of developing celiac disease (human leukocyte antigen (HLA)-DQ2/DQ8) and the early colonisation process in infants at family risk of the disease has also reported that the HLA-DQ genotype could influence staphylococcal colonisation. Future observational studies considering both host genetics and microbiota could be critical in defining the complex host microbe interactions and the respective role each plays in inflammatory disorders. PMID- 23360884 TI - Gut microbiota and metabolic disorders: How prebiotic can work? AB - Experimental data in animals, but also observational studies in obese patients, suggest that the composition of the gut microbiota differs in obese v. lean individuals, in diabetic v. non-diabetic patients or in patients presenting other diseases associated with obesity or nutritional dysbalance, such as non-alcoholic steatohepatitis. In the present review, we will describe how changes in the gut microbiota composition and/or activity by dietary fibres with prebiotic properties, can modulate host gene expression and metabolism. We will evaluate their potential relevance in the management of obesity and related metabolic disturbances, in view of the experimental data and intervention studies published up to date. PMID- 23360885 TI - Efficacy of intravenous paracetamol and dexketoprofen on postoperative pain and morphine consumption after a lumbar disk surgery. AB - BACKGROUND: We compared the analgesic effects of intravenous (IV) paracetamol with that of dexketoprofen on postoperative pain and morphine consumption during the first 24 hour after a lumbar disk surgery. METHODS: This prospective, placebo controlled, double blind study investigated the analgesic effects of IV paracetamol and dexketoprofen on postoperative pain, morphine consumption, and morphine-related side effects after a lumbar disk surgery. Sixty American Society of Anesthesiologists 1 or 2 status patients scheduled for elective lumbar disk surgery under general anesthesia were included in the study. Patients were treated using patient-controlled analgesia with morphine for 24 hours after a lumbar disk surgery and randomized to receive IV paracetamol 1 g, dexketoprofen 50 mg, or isotonic saline (placebo). The primary endpoint was pain intensity measured by the visual analogue scale, and secondary endpoints were morphine consumption and related side effects. RESULTS: Pain intensity was lower in the dexketoprofen group (P=0.01) but not in the paracetamol group (P=0.21) when compared with the control group. Cumulative morphine consumption and morphine related side effects did not reveal significant differences between the groups. CONCLUSIONS: The study showed that pain intensity during 24 hours after the lumbar disk surgery was significantly lowered by dexketoprofen, but not with paracetamol, as a supplemental analgesic to morphine patient-controlled analgesia when compared with controls. PMID- 23360886 TI - Carvedilol alleviates adjuvant-induced arthritis and subcutaneous air pouch edema: modulation of oxidative stress and inflammatory mediators. AB - Rheumatoid arthritis (RA) is a systemic inflammatory disease with cardiovascular complications as the leading cause of morbidity. Carvedilol is an adrenergic antagonist which has been safely used in treatment of several cardiovascular disorders. Given that carvedilol has powerful antioxidant/anti-inflammatory properties, we aimed to investigate its protective potential against arthritis that may add further benefits for its clinical usefulness especially in RA patients with concomitant cardiovascular disorders. Two models were studied in the same rat; adjuvant arthritis and subcutaneous air pouch edema. Carvedilol (10mg/kg/day p.o. for 21days) effectively suppressed inflammation in both models with comparable efficacy to the standard anti-inflammatory diclofenac (5mg/kg/day p.o.). Notably, carvedilol inhibited paw edema and abrogated the leukocyte invasion to air pouch exudates. The latter observation was confirmed by the histopathological assessment of the pouch lining that revealed mitigation of immuno-inflammatory cell influx. Carvedilol reduced/normalized oxidative stress markers (lipid peroxides, nitric oxide and protein thiols) and lowered the release of inflammatory cytokines (TNF-alpha & IL-6), and eicosanoids (PGE2 & LTB4) in sera and exudates of arthritic rats. Interestingly, carvedilol, per se, didn't present any effect on assessed biochemical parameters in normal rats. Together, the current study highlights evidences for the promising anti-arthritic effects of carvedilol that could be mediated through attenuation of leukocyte migration, alleviation of oxidative stress and suppression of proinflammatory cytokines and eicosanoids. PMID- 23360887 TI - Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats. AB - Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. PMID- 23360889 TI - Involvement of PKA and HO-1 signaling in anti-inflammatory effects of surfactin in BV-2 microglial cells. AB - Surfactin, one of the most powerful biosurfactants, is a bacterial cyclic lipopeptide. Here, we investigated the anti-neuroinflammatory properties of surfactin in lipoteichoic acid (LTA)-stimulated BV-2 microglial cells. Surfactin significantly inhibited excessive production of the pro-inflammatory mediators TNF-alpha, IL-1beta, IL-6, monocyte chemoattractant protein-1 (MCP-1), prostaglandin E2 (PGE2), nitric oxide (NO) and reactive oxygen species (ROS), and suppressed the expression of matrix metalloproteinase-9 (MMP-9), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Subsequent mechanistic studies revealed that surfactin inhibited LTA-induced nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription-1 (STAT-1) activation. However, surfactin increases the phosphorylation of the STAT-3, a component of the homeostatic mechanism causing anti-inflammatory events. We also demonstrated that surfactin induces heme oxygenase-1 (HO-1) expression and nuclear factor regulated factor-2 (Nrf-2) activation, and that the anti-inflammatory effects of surfactin are abrogated by small interfering RNA-mediated knock-down of HO-1 or Nrf-2. Interestingly, we found that surfactin increased the level of cAMP and induced phosphorylation of cAMP responsive element binding protein (CREB) in microglial cells. Furthermore, treatment with the protein kinase A (PKA) inhibitor, H-89, blocked HO-1 induction by surfactin and abolished surfactin's suppressive effects on ROS and NO production. These results indicate that HO-1 and its upstream effector, PKA, play a pivotal role in the anti-neuroinflammatory response of surfactin in LTA-stimulated microglia. Therefore, surfactin might have therapeutic potential for neuroprotective agents to treat inflammatory and neurodegenerative diseases. PMID- 23360888 TI - Mono-2-ethylhexyl phthalate induces oxidative stress responses in human placental cells in vitro. AB - Di-2-ethylhexyl phthalate (DEHP) is an environmental contaminant commonly used as a plasticizer in polyvinyl chloride products. Exposure to DEHP has been linked to adverse pregnancy outcomes in humans including preterm birth, low birth-weight, and pregnancy loss. Although oxidative stress is linked to the pathology of adverse pregnancy outcomes, effects of DEHP metabolites, including the active metabolite, mono-2-ethylhexyl phthalate (MEHP), on oxidative stress responses in placental cells have not been previously evaluated. The objective of the current study is to identify MEHP-stimulated oxidative stress responses in human placental cells. We treated a human placental cell line, HTR-8/SVneo, with MEHP and then measured reactive oxygen species (ROS) generation using the dichlorofluorescein assay, oxidized thymine with mass-spectrometry, redox sensitive gene expression with qRT-PCR, and apoptosis using a luminescence assay for caspase 3/7 activity. Treatment of HTR-8 cells with 180MUM MEHP increased ROS generation, oxidative DNA damage, and caspase 3/7 activity, and resulted in differential expression of redox-sensitive genes. Notably, 90 and 180MUM MEHP significantly induced mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS2), an enzyme important for synthesis of prostaglandins implicated in initiation of labor. The results from the present study are the first to demonstrate that MEHP stimulates oxidative stress responses in placental cells. Furthermore, the MEHP concentrations used were within an order of magnitude of the highest concentrations measured previously in human umbilical cord or maternal serum. The findings from the current study warrant future mechanistic studies of oxidative stress, apoptosis, and prostaglandins as molecular mediators of DEHP/MEHP-associated adverse pregnancy outcomes. PMID- 23360890 TI - QT interval and antidepressant use: a cross sectional study of electronic health records. AB - OBJECTIVE: To quantify the impact of citalopram and other selective serotonin reuptake inhibitors on corrected QT interval (QTc), a marker of risk for ventricular arrhythmia, in a large and diverse clinical population. DESIGN: A cross sectional study using electrocardiographic, prescribing, and clinical data from electronic health records to explore the relation between antidepressant dose and QTc. Methadone, an opioid known to prolong QT, was included to demonstrate assay sensitivity. SETTING: A large New England healthcare system comprising two academic medical centres and outpatient clinics. PARTICIPANTS: 38,397 adult patients with an electrocardiogram recorded after prescription of antidepressant or methadone between February 1990 and August 2011. MAIN OUTCOME MEASURES: Relation between antidepressant dose and QTc interval in linear regression, adjusting for potential clinical and demographic confounding variables. For a subset of patients, change in QTc after drug dose was also examined. RESULTS: Dose-response association with QTc prolongation was identified for citalopram (adjusted beta 0.10 (SE 0.04), P<0.01), escitalopram (adjusted beta 0.58 (0.15), P<0.001), and amitriptyline (adjusted beta 0.11 (0.03), P<0.001), but not for other antidepressants examined. An association with QTc shortening was identified for bupropion (adjusted beta 0.02 (0.01) P<0.05). Within-subject paired observations supported the QTc prolonging effect of citalopram (10 mg to 20 mg, mean QTc increase 7.8 (SE 3.6) ms, adjusted P<0.05; and 20 mg to 40 mg, mean QTc increase 10.3 (4.0) ms, adjusted P<0.01). CONCLUSIONS: This study confirmed a modest prolongation of QT interval with citalopram, and identified additional antidepressants with similar observed risk. Pharmacovigilance studies using electronic health record data may be a useful method of identifying potential risk associated with treatments. PMID- 23360892 TI - Mass economic migration: the greatest threat to HIV control in India. PMID- 23360891 TI - Effectiveness of PhysioDirect telephone assessment and advice services for patients with musculoskeletal problems: pragmatic randomised controlled trial. AB - OBJECTIVES: To assess the clinical effectiveness, effect on waiting times, and patient acceptability of PhysioDirect services in patients with musculoskeletal problems, compared with usual care. DESIGN: Pragmatic randomised controlled trial to assess equivalence in clinical effectiveness. Patients were individually randomised in a 2:1 ratio to PhysioDirect or usual care. SETTING: Four physiotherapy services in England. PARTICIPANTS: Adults (aged >= 18 years) referred by general practitioners or self referred for musculoskeletal physiotherapy. INTERVENTIONS: PhysioDirect services invited patients to telephone a physiotherapist for initial assessment and advice, followed by face-to-face physiotherapy if necessary. Usual care involved patients joining a waiting list for face-to-face treatment. MAIN OUTCOME MEASURES: Numbers of appointments, waiting time for treatment, and non-attendance rates. Primary outcome was physical health (SF-36v2 physical component score) at six months. Secondary outcomes included four other measures of health outcome, mental component score and scales from the SF-36v2, time lost from work, and patient satisfaction and preference. Participants were not blind to allocation, but outcome data were collected blind to allocation. RESULTS: Of 1506 patients allocated to PhysioDirect and 743 to usual care, 85% provided primary outcome data at six months (1283 and 629 patients, respectively). PhysioDirect patients had fewer face-to-face appointments than usual care patients (mean 1.91 v 3.11; incidence rate ratio 0.59 (95% confidence interval 0.53 to 0.65)), a shorter waiting time (median 7 days v 34 days; arm time ratio 0.32 (0.29 to 0.35)), and lower rates of non-attendance (incidence rate ratio 0.55 (0.41 to 0.73)). After six months' follow-up, the SF-36v2 physical component score was equivalent between groups (adjusted difference in means -0.01 (-0.80 to 0.79)). Health outcome measures suggested a trend towards slightly greater improvement in the PhysioDirect arm at six week follow-up and no difference at six months. There was no difference in time lost from work. PhysioDirect patients were no more satisfied with access to physiotherapy than usual care patients, but had slightly lower satisfaction overall at six months (difference in satisfaction -3.8% (-7.3% to -0.3%); P=0.031). PhysioDirect patients were more likely than usual care patients to prefer PhysioDirect in future. No adverse events were detected. CONCLUSIONS: PhysioDirect is equally clinically effective compared with usual care, provides faster access to physiotherapy, and seems to be safe. However, it could be associated with slightly lower patient satisfaction. TRIAL REGISTRATION: Current Controlled Trials ISRCTN55666618. PMID- 23360893 TI - A theoretical study of luminescent vapochromic compounds including an AuCu2(NHC)2 core. AB - Vapochromic complexes [Au(im(CH(2)py)(2))(2)(Cu(MeCN)(2))(2)](3+) 1, [Au(im(CH(2)py)(2))(2)(Cu(MeOH))(2)](3+) 2 and [Au(im(CH(2)py)(2))(2)(Cu(H(2)O))(2)](3+) 3 were theoretically investigated. The Au-Cu distances of 1 and 2 (4.631 A and 2.767 A, respectively) optimized by the SCS-MP2 method in this work agree with the literature experimental values (4.591 A and 2.792 A). Their structural features are explained by computational results: (i) in 1, two MeCN molecules coordinate with the Cu center, because of the strong coordination ability of MeCN, to afford a four-coordinate tetrahedral-like Cu center. This geometry needs a long Au-Cu distance. (ii) In 2 and 3, only one MeOH or H(2)O molecule coordinates with the Cu center because of their weak coordination abilities, to afford a three-coordinate planar Cu center. Because the three-coordinate Cu center is flexible, the Au-Cu distance becomes short due to the Au-Cu metallophilic interaction, the strength of which is 5.3 kcal mol(-1) at the SCS-MP2 level. The emission energies of 1, 2 and 3 (2.62, 2.40 and 2.38 eV, respectively) calculated here by the B3PW91 agree with their literature experimental values (2.68, 2.47, and 2.39 eV). The lowest energy triplet excited state (T(1)) is assigned as the excitation from the Cu d to the pyridine pi* orbital in 1 and that from the Au-Cu 5d-3d anti-bonding MO to the Au-Cu 6p-4sp bonding MO in 2 and 3. As a result, the emission energy from the T(1) to the ground state is different between these compounds. The difference in Au-Cu distance is one of the important factors for the differences in emission energy and assignment between 1 and others (2 and 3). The vapochromism of these compounds arises from the difference in Au-Cu distance which is determined by the balance between the strengths of the coordination of a gas molecule and the Au-Cu metallophilic interaction; in other words, the Au-Cu heterometallophilic interaction is important for the vapochromic activity of the complex. PMID- 23360894 TI - Towards establishing an occupational threshold for cumulative shear force in the vertebral joint - an in vitro evaluation of a risk factor for spondylolytic fractures using porcine specimens. AB - BACKGROUND: Injury models for spondylolytic fracture of the pars interarticularis have long considered repetitive shear loading as a risk factor without quantifying the relationship between shear force magnitude and fatigue life. This investigation sought to quantify the relationship using a basic in vitro approach. METHODS: Thirty-two (16 C3-C4, 16 C5-C6) porcine cervical specimens were exposed to repetitive shear loading to 20%, 40%, 60%, or 80% of their calculated ultimate anterior shear failure tolerance. Shear force was cyclically applied at 1Hz for 21,600cycles or until bone failure was detected. Cumulative shear force and the number of cycles sustained until failure were calculated. Failure patterns were also documented. FINDINGS: Cumulative shear and the number of cycles sustained prior to failure demonstrated a strong non-linearly decreasing relationship with increased force magnitude. In particular, sustained cumulative shear by the 40% group was 2.52 and 2.63MN*s higher than for the 60% and 80% groups (P<0.0001). Despite undergoing an average of 230 more loading cycles, cumulative shear force sustained by the 60% group was not statistically different from the 80% group. Bilateral fractures of the cranial vertebra's pars interarticularis were most common, but less consistent at higher force magnitudes. INTERPRETATION: Our investigation suggested that pars interarticularis damage may begin non-linearly accumulating with shear forces between 20% and 40% of failure tolerance (approximately 430 to 860N). Models of pars interarticularis injury and estimates of cumulative shear exposure may be enhanced from a tissue-based weighting method for low-back shear. PMID- 23360895 TI - Determination of the influence of walking with orthosis on bone osteoporosis in paraplegic subjects based on the loads transmitted through the body. AB - BACKGROUND: Spinal cord injury is a damage to spinal cord that results in loss of function and mobility below the level of injury. The patients use various orthoses to improve their general health, to decrease bone osteoporosis, and to improve bone mineral density. It was controversial if how much percentage of the loads applied on an orthosis and body complex is transmitted by orthosis. Therefore, it was aimed to determine the magnitude of the loads transmitted by orthosis to find the influence of walking with orthosis on bone mineral density. METHODS: Three spinal cord injured subjects were recruited in this study. They were trained to walk with a reciprocal gait orthosis. The loads applied on the hip joint of the orthosis and body complex, anatomy and orthosis were measured by use of strain gauges and motion analysis system. FINDINGS: The mean values of the force and moments transmitted by the orthosis were significantly less than those of the complex. The mean values of adduction moment transmitted through the orthosis and body complex and by the orthosis structure were 1.06 and 0.49N.m/body weight, respectively. INTERPRETATION: As a higher percentage of loads were transmitted by body than the orthosis, it can be concluded that walking with orthosis could improve bone mineral density, due to the role of bone in transmission of the loads. Therefore, it is recommended that spinal cord injured subjects walk with an orthosis in order to reduce bone osteoporosis, especially for a long period of time. PMID- 23360896 TI - Evaluation of methodologies for assessing the overall diet: dietary quality scores and dietary pattern analysis. AB - This paper aims to describe different approaches for studying the overall diet with advantages and limitations. Studies of the overall diet have emerged because the relationship between dietary intake and health is very complex with all kinds of interactions. These cannot be captured well by studying single dietary components. Three main approaches to study the overall diet can be distinguished. The first method is researcher-defined scores or indices of diet quality. These are usually based on guidelines for a healthy diet or on diets known to be healthy. The second approach, using principal component or cluster analysis, is driven by the underlying dietary data. In principal component analysis, scales are derived based on the underlying relationships between food groups, whereas in cluster analysis, subgroups of the population are created with people that cluster together based on their dietary intake. A third approach includes methods that are driven by a combination of biological pathways and the underlying dietary data. Reduced rank regression defines linear combinations of food intakes that maximally explain nutrient intakes or intermediate markers of disease. Decision tree analysis identifies subgroups of a population whose members share dietary characteristics that influence (intermediate markers of) disease. It is concluded that all approaches have advantages and limitations and essentially answer different questions. The third approach is still more in an exploration phase, but seems to have great potential with complementary value. More insight into the utility of conducting studies on the overall diet can be gained if more attention is given to methodological issues. PMID- 23360897 TI - Homelessness experiences, sexual orientation, and sexual risk taking among high school students in Los Angeles. AB - PURPOSE: Prior studies reported homeless adolescents engage in more sexual risk than their housed peers. However, these comparisons are typically made post hoc by comparing homeless adolescent community-based samples with high school probability samples. This study uses a random sample of high school students to examine homelessness experiences and sexual risk behaviors. METHODS: A supplemental survey to the Youth Risk Behavior Survey containing questions regarding homelessness and sexual health was administered to Los Angeles high school students (N = 1,839). Multivariate logistic regressions assessed the associations between demographics, past year homelessness experiences (i.e., place of nighttime residence), and being sexually active and condom use at last intercourse. RESULTS: Homelessness experiences consisted of staying in a shelter (10.4%), a public place (10.1%), and with a stranger (5.6%). Lesbian, gay, bisexual, transgender, questioning (LGBTQ), younger, and male adolescents were more likely to experience homelessness. LGBTQ adolescents were also more likely to report staying with a stranger and less likely to report staying in a shelter. Compared to adolescents who stayed in shelters, adolescents who stayed with strangers and in public places were more likely to engage in unprotected sex at last intercourse. CONCLUSIONS: Adolescents who report sexual activity and sexual risk taking are more likely to report homelessness experiences. With regard to sexual health, staying with strangers could be a particularly risky form of homelessness; LGBTQ and black adolescents are more likely to experience this form of homelessness. Efforts to reduce homelessness and sexual risk-taking need to recognize the specific vulnerabilities faced by these populations. PMID- 23360898 TI - Physical activity in adolescents: examining influence of the best friend dyad. AB - PURPOSE: The aim of this study was to determine the influence of dyadic friendship relationships on adolescent physical activity (PA) behavior. Unique to this study was examination of the "best friend" dyad. METHODS: Participants were 268 adolescents (13-18 years of age) of both sexes (boys n = 140, girls n = 128), constituting 134 best friendship dyads; 84 were reciprocal best friends and 50 were not. PA was evaluated with the short version of the International Physical Activity Questionnaire. The Actor-Partner Interdependence Model was tested using a hierarchical linear model. First, a null model was run to calculate intraclass correlation coefficient for each type of PA. Next, sex, age, and reciprocity in friendship were included in the model as PA predictors. RESULTS: The null models revealed significant intraclass correlation coefficient values for vigorous PA (VPA) (.32) moderate PA (MPA) (.31), and sitting behavior (.21), but not for walking. Age was the only predictor for VPA, whereas for MPA the predictors were sex and age of the partner. Reciprocity in friendship (best friend) was not a significant predictor for PA. CONCLUSIONS: These results indicate a high degree of similarity between best friend dyad in PA, except for walking. The age and sex of the best friend (partner) were important predictors of MPA. The reciprocity in friendship (being reciprocal best friends) was not a relevant variable. PMID- 23360899 TI - Interaction between nitrous oxide, sevoflurane, and opioids: a response surface approach. AB - BACKGROUND: The interaction of sevoflurane and opioids can be described by response surface modeling using the hierarchical model. We expanded this for combined administration of sevoflurane, opioids, and 66 vol.% nitrous oxide (N2O), using historical data on the motor and hemodynamic responsiveness to incision, the minimal alveolar concentration, and minimal alveolar concentration to block autonomic reflexes to nociceptive stimuli, respectively. METHODS: Four potential actions of 66 vol.% N2O were postulated: (1) N2O is equivalent to A ng/ml of fentanyl (additive); (2) N2O reduces C50 of fentanyl by factor B; (3) N2O is equivalent to X vol.% of sevoflurane (additive); (4) N2O reduces C50 of sevoflurane by factor Y. These four actions, and all combinations, were fitted on the data using NONMEM (version VI, Icon Development Solutions, Ellicott City, MD), assuming identical interaction parameters (A, B, X, Y) for movement and sympathetic responses. RESULTS: Sixty-six volume percentage nitrous oxide evokes an additive effect corresponding to 0.27 ng/ml fentanyl (A) with an additive effect corresponding to 0.54 vol.% sevoflurane (X). Parameters B and Y did not improve the fit. CONCLUSION: The effect of nitrous oxide can be incorporated into the hierarchical interaction model with a simple extension. The model can be used to predict the probability of movement and sympathetic responses during sevoflurane anesthesia taking into account interactions with opioids and 66 vol.% N2O. PMID- 23360900 TI - Targeting purinergic signaling for perioperative organ protection. PMID- 23360901 TI - Little child. PMID- 23360903 TI - A technique for multiple sample intraocular biopsy of choroidal lesions. PMID- 23360902 TI - The functional maturation of M cells is dramatically reduced in the Peyer's patches of aged mice. AB - The transcytosis of antigens across the follicle-associated epithelium (FAE) of Peyer's patches by microfold cells (M cells) is important for the induction of efficient immune responses to mucosal antigens. The mucosal immune response is compromised by ageing, but effects on M cells were unknown. We show that M-cell density in the FAE of aged mice was dramatically reduced. As a consequence, aged Peyer's patches were significantly deficient in their ability to transcytose particulate lumenal antigen across the FAE. Ageing specifically impaired the expression of Spi-B and the downstream functional maturation of M cells. Ageing also dramatically impaired C-C motif chemokine ligand 20 expression by the FAE. As a consequence, fewer B cells were attracted towards the FAE, potentially reducing their ability to promote M-cell maturation. Our study demonstrates that ageing dramatically impedes the functional maturation of M cells, revealing an important ageing-related defect in the mucosal immune system's ability to sample lumenal antigens. PMID- 23360905 TI - AC conductivity of a niobium thin film in a swept magnetic field. AB - We report results of measurements of the ac conductivity of a Nb superconducting thin film in a swept dc magnetic field. In the mixed state the swept dc field creates vortices at the film surface which pass through the film and form the observed ac conductivity. Vortex rate generation does not depend on the value of the dc field and there is a large plateau-like region of dc magnetic fields where the dissipation is approximately constant. A proposed phenomenological model describes quite well the main features of the ac response in these fields, including its dependency on the sweep rate, ac amplitude, frequency, and value of the second and third harmonics. PMID- 23360904 TI - Comparison of resident and mid-level provider productivity in a high-acuity emergency department setting. AB - INTRODUCTION: Mid-level providers (MLPs) are used in many emergency departments (EDs) to provide care in a low-acuity, high-volume setting, and are able to see more patients and generate more relative value units (RVUs) than residents in this setting. It is unknown if MLPs are as productive as emergency medicine residents in a high-acuity setting. OBJECTIVE: To determine if there are productivity differences between residents and MLPs, as defined by patients seen (pt/h) and RVUs generated per hour (RVU/h), in a high-acuity area of the ED. METHODS: This is a retrospective review of emergency medicine residents and MLPs assigned to a high-acuity area of a single 45,000 volume community ED. Number of patients seen and RVUs generated were recorded, and pt/h, RVU/h and RVU/pt were calculated. Two-tailed t test was used to compare resident and MLP performance. RESULTS: 55 MLP and 98 emergency medicine residency shifts were included for comparison. During the study period, MLPs saw 1.56 pt/h (CI +/- 0.14), while residents saw 1.23 pt/h (CI +/- 0.06, p<0.0001). MLPs generated 3.19 RVU/h (CI +/ 0.29), while residents generated 3.33 RVU/h (CI +/- 0.17, p=0.43). Residents generated 2.73 RVU/pt (CI +/- 0.09), while MLPs generated 2.05 RVU/pt (CI +/- 0.09, p<0.0001). In comparing the subgroup of postgraduate year 3 residents (PGY3s) with MLPs, MLPs still saw significantly more patients (1.30 vs 1.56, p=0.003), but PGY3s generated 3.58 RVU/h compared with 3.19 RVU/h for MLPs (p=0.06). PGY3s generated 2.79 RVU/pt compared with 2.05 for MLPs (p<0.0001). CONCLUSIONS: In a high-acuity area of the ED, MLPs see more patients per hour than residents, but generate fewer RVUs per patient. This suggests that residents may document more thoroughly than MLPs. Alternatively, MLPs may elect to see less sick patients even when working in a high-acuity area. PMID- 23360906 TI - Residents' corner February 2013. DeRmpath & Clinic - differential diagnosis in lichenoid reactions. PMID- 23360907 TI - Effect of pH on the photophysical properties of two new carboxylic-substituted iridium(III) complexes. AB - Two cyclometalated iridium(III) complexes have been prepared based on 2-(4 diphenylamino-phenyl)-quinoline and incorporating carboxylic acid ethyl ester ( COOC(2)H(5), (TPAQCE)(2)Irpic and carboxylic acid (-COOH, (TPAQCOOH)(2)Irpic) substituents at the 4-position of the quinoline ligand, respectively. The absorption, emission and (1)H NMR spectra of (TPAQCE)(2)Irpic and (TPAQCOOH)(2)Irpic under alkaline or acidic conditions demonstrate that they respond to the pH of the surrounding solvent environment. The deprotonation of the carboxylic acid group significantly blue-shifts the metal-to-ligand charge transfer absorption band of (TPAQCOOH)(2)Irpic by 48 nm and enhances the emission quantum-yield in DMSO. In addition, (1)H-NMR titration reveals that (TPAQCOOH)(2)Irpic is deprotonated into negatively charged (TPAQCOO(-))(2)Irpic in free DMSO-d(6) solution, and the acid-induced N^O ancillary ligands cleavage or replacement in (TPAQCOOH)(2)Irpic could be ignored. A water-soluble near neutral optical pH probe (TPAQCOOH)(2)Irpic with pK(a) of ~7 is also reported. In aqueous buffer, (TPAQCOOH)(2)Irpic possesses an obvious emission response with an excellent linearity in the pH range of 6.50-8.00, showing a promising application in bioprocessing. PMID- 23360908 TI - The use of blood cell salvage in acetabular fracture internal fixation surgery. AB - OBJECTIVES: To determine if the routine use of intraoperative blood cell salvage in acetabular fracture internal fixation reduces the need for allogenic blood transfusion, is cost effective, and whether it is influenced by the acetabular fracture pattern. DESIGN: A retrospective study. SETTING: Tertiary pelvic and acetabular reconstructive center. PATIENTS/PARTICIPANTS: Patients undergoing internal fixation for acetabular fractures. RESULTS: Eighty consecutive patients were reviewed, comprising 26 elementary fracture (EF) and 54 associated fracture (AF) types. The mean volume of autologous blood transfused was 484 mL. The mean volume of 561 mL of autologous blood transfused in patients with AF types was significantly greater than the mean volume of 325 mL transfused in the EF group (P = 0.007). Additional allogenic blood transfusion was required in 5 (19%) patients with EFs and 15 (28%) patients with AFs (P = 0.418). The mean cost of the blood cell salvage and additional blood products in our study was $223 (L135) for all fracture types ($174/L105 for EF and $246/L149 for AF).When treating AF types, the mean cost of using blood cell salvage was $246 (L149) as compared with the mean predicted cost of not using blood cell salvage and transfusing the equivalent of 1.7 units of allogenic blood instead, which was $463 (L281). These distributions are significantly different (P = 0.01). CONCLUSIONS: The use of blood cell salvage for internal fixation surgery for acetabular fracture is cost effective, particularly when treating AF types, and its routine use is advocated to limit the need for allogenic blood transfusion. PMID- 23360909 TI - The pilon map: fracture lines and comminution zones in OTA/AO type 43C3 pilon fractures. AB - OBJECTIVES: The purpose of this investigation is to define the location and frequency of tibia pilon fracture lines and impaction injury for the most severe variety (OTA/AO type 43C3). PATIENTS/METHODS: Using axial computed tomography scan images, 38 consecutive OTA/AO type 43C3 fractures treated by a single surgeon were analyzed. For each fracture, a map of the fracture lines and zones of comminution was drawn. Each map was digitized and graphically superimposed to create a compilation of fracture lines and zones of comminution. Based on this compilation, major and minor fracture lines were identified and fracture patterns were defined. Specifically, a basic Y pattern, constant across all patients, was identified where the stem of the Y went into the fibula incisura. All other fracture lines were considered secondary and these defined the comminution. RESULTS: One hundred percent of major fracture lines involved the tibiofibular joint and all exited medially in 2 general zones, anterior and posterior to the medial malleolus best described as a Y-shaped pattern. Therefore, 3 main fragments existed in every single case. Comminution was present in 36 of 38 (95%) cases, and it was predominantly located centrally and in the anterolateral quarter. CONCLUSIONS: There is a consistent fracture pattern underlying the majority of OTA/AO type 43C3 pilon fractures that could be defined as 3 main fragments: anterior, medial, and posterior. These result from a major fracture line extending from the fibular incisura and exiting anterior and posterior to the medial malleolus. The comminution commonly distinguishing pilon fractures occurs from secondary fracture lines through the apex of the plafond and in the anterolateral region. Knowledge of this constant pattern should influence surgical approaches and possibly implant design. PMID- 23360910 TI - Intraoperative fluoroscopic evaluation of screw placement during pelvic and acetabular surgery. AB - The surgical treatment of pelvic and acetabular fractures can be technically challenging. Various techniques are available for the reconstruction of pelvic and acetabular fractures. Less invasive percutaneous fracture stabilization techniques, with closed reduction or limited open reduction, have been developed and are gaining popularity in the management of pelvic and acetabular fractures. These techniques require knowledge and interpretation of various fluoroscopic images to ensure appropriate and safe screw placement. Given the anatomic complexity of the intrapelvic structures and the 2-dimensional nature of standard fluoroscopy, multiple images oriented in different planes are needed to assess the accuracy of guide wire and screw placement. This article reviews the fluoroscopic imaging of common screw orientations during pelvic and acetabular surgery. PMID- 23360911 TI - N,N-Chelate-control on the regioselectivity in acetate-assisted C-H activation. AB - Bidentate N,N-pyridylimine or N,N-pyridylamine donors are effective chelating ligands for regiospecific C-H activation at the peri-(C(8))-position of a naphthyl ring on reaction with palladium(ii) acetate; DFT calculations show N,N chelates bias the cyclopalladation towards 6-membered ring products. PMID- 23360912 TI - X-ray absorption spectroscopy and energy storage of Ni-doped cobalt nitride, (Ni(0.33)Co(0.67))N, prepared by a simple synthesis route. AB - Metal nitride (Ni(0.33)Co(0.67))N nanoparticles are prepared by nitridation using NiCo(2)O(4) as a precursor material by heating at 335 degrees C for 2 h in flowing NH(3) + N(2) gas and characterized by X-ray diffraction (XRD), field emission-scanning electron microscopy (FE-SEM), high resolution-transmission electron microscopy (HR-TEM), along with selective area electron diffraction (SAED) and X-ray absorption spectroscopy (XAS) techniques. The X-ray absorption near edge structure (XANES) at the Co K-edge showed that the oxidation state of cobalt is close to 3+. The (Ni(0.33)Co(0.67))N showed a shift in edge energy towards lower values due to Ni-doping to cobalt site. The Li-storage behaviour of (Ni(0.33)Co(0.67))N nanoparticles was evaluated by galvanostatic cycling and cyclic voltammetry in the cells with Li-metal as counter electrode in the voltage range of 0.005-3.0 V at ambient temperature. When cycled at 250 mA g(-1), the first-cycle reversible capacity of 700 (+/-5) mA h g(-1) (~1.9 moles of Li) is obtained. It showed an initial decrease in capacity until the 10(th) cycle and a stable capacity of 400 (+/-5) mA h g(-1) (~1.09 moles of Li) is observed at the end of the 50(th) cycle. Excellent rate capability is also shown when cycling at 500 mA g(-1) (up to 50 cycles). The materials showed excellent Li-ion insertion/extraction, with the coulombic efficiency reaching almost 99% in the range of 10-50 cycles. The average charge and discharge potentials are ~2.03 and ~1.0 V, respectively for the decomposition/formation of Li(3)N as determined by electroanalytical techniques. PMID- 23360913 TI - Anti-inflammatory, analgesic and anti-ulcerogenic effect of total alkaloidal extract from Murraya koenigii leaves in animal models. AB - The fresh leaves of Murraya koenigii are often added to various dishes in Asian countries due to the delicious taste and flavour that they impart. In the present study, the effect of the total alkaloidal extract from Murraya koenigii leaves (MKA) with respect to anti-inflammatory, analgesic and anti-ulcerogenic effects were evaluated using different experimental animal models. Oral supplementation of MKA at 10, 20 and 40 mg kg(-1) body weight successfully and dose-dependently reduced the formation of oedema induced by carrageenan, histamine and serotonin as well as formaldehyde-induced arthritis. In addition, the extract (10, 20 and 40 mg kg(-1), p.o.) attenuated the writhing responses induced by an intraperitoneal injection of acetic acid and late phase of pain response induced by a subplantar injection of formalin in mice. MKA at higher doses (20 and 40 mg kg(-1), p.o) reduced the early phase response induced by formalin as well as reaction time on hot plate models. Interestingly, there was no ulcer score with the ulcerogenic effect of MKA. Moreover, all the doses of MKA (10, 20 and 40 mg kg(-1), p.o) showed promising anti-ulcerogenic activity with protection against acute gastric ulcers induced by ethanol plus hydrochloric acid and aspirin models in a dose dependent manner. PMID- 23360914 TI - Oral azithromycin combined with topical anti-inflammatory agents in the treatment of blepharokeratoconjunctivitis in children. AB - We report 3 children referred for recurrent blepharokeratoconjunctivitis, despite the application of topical antibiotic and anti-inflammatory treatments. Oral azithromycin combined with anti-inflammatory treatment was effective in controlling the disease. PMID- 23360915 TI - Guidelines for automated preschool vision screening: a 10-year, evidence-based update. AB - In 2003 the American Association for Pediatric Ophthalmology and Strabismus Vision Screening Committee proposed criteria for automated preschool vision screening. Recent literature from epidemiologic and natural history studies, randomized controlled trials of amblyopia treatment, and field studies of screening technologies have been reviewed for the purpose of updating these criteria. The prevalence of amblyopia risk factors (ARF) is greater than previously suspected; many young children with low-magnitude ARFs do not develop amblyopia, and those who do often respond to spectacles alone. High-magnitude ARFs increase the likelihood of amblyopia. Although depth increases with age, amblyopia remains treatable until 60 months, with decline in treatment effectiveness after age 5. US Preventive Services Task Force Preventative Services Task Force guidelines allow photoscreening for children older than 36 months of age. Some technologies directly detect amblyopia rather than ARFs. Age based criteria for ARF detection using photoscreening is prudent: referral criteria for such instruments should produce high specificity for ARF detection in young children and high sensitivity to detect amblyopia in older children. Refractive screening for ARFs for children aged 12-30 months should detect astigmatism >2.0 D, hyperopia >4.5 D, and anisometropia >2.5 D; for children aged 31-48 months, astigmatism >2.0 D, hyperopia > 4.0 D, and anisometropia >2.0 D. For children >49 months of age original criteria should be used: astigmatism >1.5 D, anisometropia>1.5 D, and hyperopia >3.5 D. Visually significant media opacities and manifest (not intermittent) strabismus should be detected at all ages. Instruments that detect amblyopia should report results using amblyopia presence as the gold standard. These new American Association for Pediatric Ophthalmology and Strabismus Vision Screening Committee guidelines will improve reporting of results and comparison of technologies. PMID- 23360917 TI - Surrogate decision making: do we have to trade off accuracy and procedural satisfaction? AB - OBJECTIVE: Making surrogate decisions on behalf of incapacitated patients can raise difficult questions for relatives, physicians, and society. Previous research has focused on the accuracy of surrogate decisions (i.e., the proportion of correctly inferred preferences). Less attention has been paid to the procedural satisfaction that patients' surrogates and patients attribute to specific approaches to making surrogate decisions. The objective was to investigate hypothetical patients' and surrogates' procedural satisfaction with specific approaches to making surrogate decisions and whether implementing these preferences would lead to tradeoffs between procedural satisfaction and accuracy. METHODS: Study 1 investigated procedural satisfaction by assigning participants (618 in a mixed-age but relatively young online sample and 50 in an older offline sample) to the roles of hypothetical surrogates or patients. Study 2 (involving 64 real multigenerational families with a total of 253 participants) investigated accuracy using 24 medical scenarios. RESULTS: Hypothetical patients and surrogates had closely aligned preferences: Procedural satisfaction was highest with a patient-designated surrogate, followed by shared surrogate decision-making approaches and legally assigned surrogates. These approaches did not differ substantially in accuracy. Limitations are that participants' preferences regarding existing and novel approaches to making surrogate decisions can only be elicited under hypothetical conditions. CONCLUSIONS: Next to decision making by patient-designated surrogates, shared surrogate decision making is the preferred approach among patients and surrogates alike. This approach appears to impose no tradeoff between procedural satisfaction and accuracy. Therefore, shared decision making should be further studied in representative samples of the general population, and if people's preferences prove to be robust, they deserve to be weighted more strongly in legal frameworks in addition to patient-designated surrogates. PMID- 23360918 TI - Operative drainage following pancreatic resection: analysis of 1122 patients resected over 5 years at a single institution. AB - BACKGROUND: The only prospective randomized trial evaluating the use of intraperitoneal drainage following pancreatic resection was published from our institution approximately 10 years ago. The current study sought to evaluate the evolution of practice over the last 5 years. PATIENTS AND METHODS: Between June 2006 and June 2011, there were 1122 resections performed. Six surgeons were evenly grouped and compared by practice pattern: routine drainers (drains placed > 95%), selective drainers, and routine nondrainers (drains placed ~15%). Prospectively recorded preoperative, operative, and morbidity data were assessed in uni- and multivariate models. RESULTS: Our operative drainage rate was 49% and decreased over time (62% 2006-2008 vs 37% 2009-2011, P < 0.001). Patients without operative drains had significantly lower grade >=3 overall morbidity (26% vs 33%; P = 0.01), shorter hospital stays (7 vs 8 days; P < 0.01), fewer readmissions (20% vs 27%; P = 0.01), and lower rates of grade >=3 pancreatic fistula (16% vs 20%; P = 0.05). Similar reoperation (both <1%), interventional radiology procedures (15% vs 19%; P = 0.1), and mortality rates (2% vs 1%; P = 0.3) were seen in both groups. There were no differences between the routine drainers group (n = 248) and the nondrainers group (n = 478) in grade >=3 fistula or need for interventional radiology-guided procedures. CONCLUSIONS: In this study, operative drains were used nearly half of the time and were associated with longer hospital stay, and higher grade >=3 morbidity, fistula, and readmission rates. They did not decrease the need for reintervention or alter mortality rates. Routine prophylactic drainage after pancreatic resection could be safely abandoned. PMID- 23360920 TI - Liver transplantation for nonresectable liver metastases from colorectal cancer. AB - OBJECTIVE: The objective of this pilot study was to investigate the potential for long-term overall survival (OS) after liver transplantation for colorectal liver metastases (CLMs). BACKGROUND: Patients with nonresectable CLMs have poor prognosis, and few survive beyond 5 years. CLMs are currently considered an absolute contraindication for liver transplantation, although liver transplantation for primary and some secondary liver malignancies shows excellent outcome in selected patients. Before 1995, several liver transplantations for CLMs were performed, but outcome was poor (5-year survival rate: 18%) and liver transplantation for CLMs was abandoned. Since then, the survival rate after liver transplantation in general has improved by almost 30%. On the basis of this, a 5 year survival rate of about 50% after liver transplantation for CLMs could be anticipated. METHODS: In a prospective pilot study, liver transplantation for nonresectable CLMs was performed (n = 21). Main inclusion criteria were liver only CLMs, excised primary tumors, and at least 6 weeks of chemotherapy. RESULTS: Kaplan-Meier estimates of the OS rate at 1, 3, and 5 years were 95%, 68%, and 60%, respectively. Metastatic recurrence of disease was common (mainly pulmonary). However, a significant proportion of the recurrences were accessible for surgery, and at follow-up (after median of 27 months; range, 8-60), 33% had no evidence of disease. Hepatic tumor load before liver transplantation, time from primary surgery to liver transplantation, and progressive disease on chemotherapy were identified as significant prognostic factors. CONCLUSIONS: OS exceeds by far reported outcome for chemotherapy, which is the only treatment option available for this patient group. Furthermore, OS is comparable with liver resection for resectable CLMs and survival after repeat liver transplantation for nonmalignant diseases. Selection strategies based on prognostic factors may further improve the outcome (ClinicalTrials.gov: NCT01311453). PMID- 23360919 TI - Repletion of S-nitrosohemoglobin improves organ function and physiological status in swine after brain death. AB - OBJECTIVE: To determine if reduction in nitric oxide bioactivity contributes to the physiological instability that occurs after brain death and, if so, to also determine in this setting whether administration of a renitrosylating agent could improve systemic physiological status. BACKGROUND: Organ function after brain death is negatively impacted by reduced perfusion and increased inflammation; the magnitude of these responses can impact post-graft function. Perfusion and inflammation are normally regulated by protein S-nitrosylation but systemic assessments of nitric oxide bioactivity after brain death have not been performed. METHODS: Brain death was induced in instrumented swine by inflation of a balloon catheter placed under the cranium. The subjects were then serially assigned to receive either standard supportive care or care augmented by 20 ppm of the nitrosylating agent, ethyl nitrite, blended into the ventilation circuit. RESULTS: Circulating nitric oxide bioactivity (in the form of S nitrosohemoglobin) was markedly diminished 10 hours after induction of brain death-a decline that was obviated by administration of ethyl nitrite. Maintenance of S-nitrosohemoglobin was associated with improvements in tissue blood flow and oxygenation, reductions in markers of immune activation and cellular injury, and preservation of organ function. CONCLUSIONS: In humans, the parameters monitored in this study are predictive of post-graft function. As such, maintenance of endocrine nitric oxide bioactivity after brain death may provide a novel means to improve the quality of organs available for donation. PMID- 23360921 TI - Survival is associated with genetic variation in inflammatory pathway genes among patients with resected and unresected pancreatic cancer. AB - OBJECTIVE: To test whether or not the association between inflammation and pancreatic ductal adenocarcinoma (PC) is facilitated by host susceptibility, specifically by genetic polymorphisms in inflammation-related genes. SUMMARY BACKGROUND DATA: Inflammation has been linked to PC. Reports have cited an increased expression of proinflammatory mediators, such as NF-kappaB and COX, in PC but not in normal adjacent tissue, suggesting a possible role in carcinogenesis. We sought to further understand the role that genetic variants in the NF-kappaB inflammatory pathway play in the development and progression of PC. METHODS: We genotyped 1536 tag single nucleotide polymorphisms (SNPs) in 102 candidate genes of multiple inflammatory pathways in 1308 white patients with PC who were divided into 3 groups on the basis of the extent of disease: resected for cure (n = 400), locally advanced/unresected (n = 443), and metastatic (n = 465). Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression models. Statistical significance was set at less than 0.001 to control for multiple testing. RESULTS: Median age was 67 (28.0 91.0) years, and 57% were men. Median survival for each of the 3 groups (resected, locally advanced, and metastatic) was 23.7, 9.4, and 6.6 months, respectively (P < 0.0001). In the resected group, carriers of a minor allele for either rs3824872 (MAPK8IP1) or rs8064821 (SOCS3) were associated with a 10- and 6 month survival advantage compared with noncarriers in patients with resected disease, with an additional 2-year survival if both minor alleles were present. With locally advanced disease, SNP rs1124736 (IGF1R) was associated with improved survival if they had a copy of the G allele, hazard ratio of 0.57 (95% confidence interval: 0.42-0.77); P = 0.0002. In addition, 4 SNPs in patients with metastatic disease were found to be associated with worse survival and 2 associated with improved overall survival, but the differences in survival were deemed not clinically significant. CONCLUSIONS: SNPs in the inflammatory pathway genes MAPK8IP1 and SOCS3 were associated with increased overall survival in patients undergoing potentially curative resection and may be used in the future as markers to predict survival. Future research is needed to determine the functional relevance of these loci. PMID- 23360922 TI - Failure patterns in resected pancreas adenocarcinoma: lack of predicted benefit to SMAD4 expression. AB - OBJECTIVE: To determine whether SMAD4 expression is associated with recurrence pattern after resection for pancreatic ductal adenocarcinoma (PDA). BACKGROUND: SMAD4 expression status has been reported to be associated with patterns of failure in PDA, but studies have not examined recurrence patterns after resection. METHODS: A tissue microarray was constructed including 127 patients with resected PDA and either short-term (<12 months) or long-term (>30 months) survival. SMAD4 expression was evaluated by immunohistochemistry and categorized as present or lost in tumor cells. Conventional pathologic features (lymph node metastases, positive resection margin, poor grade, and tumor size) were recorded, and disease-specific outcomes (eg, recurrence pattern and early cancer-specific mortality) were determined. RESULTS: Loss of SMAD4 expression in pancreatic adenocarcinoma was identified in 40 of 127 patients (32%). SMAD4 loss occurred in 27% of patients who experienced isolated local recurrence, 33% of patients with a distant recurrence, 33% of patients who experienced local and distant site recurrences, and 25% of patients who were without evidence of recurrence (Fisher exact, P = 0.9). In a multivariate analysis, the presence of regional lymph node metastases was the only factor associated with the development of distant metastases (odds ratio = 4.7, P = 0.02). SMAD4 was neither associated with recurrence pattern (odds ratio = 0.9, P = 0.9) nor associated with early death (odds ratio = 0.5, P = 0.15). CONCLUSIONS: Primary tumor SMAD4 expression status was not a predictor of recurrence pattern in a large cohort of patients with resected PDA. PMID- 23360923 TI - A total laparoscopic approach reduces the infertility rate after ileal pouch-anal anastomosis: a 2-center study. AB - OBJECTIVE: To assess the infertility rate after laparoscopic ileal pouch-anal anastomosis (IPAA). BACKGROUND: Total proctocolectomy with IPAA is known to be associated with postoperative infertility in open surgery, which may be caused by pelvic adhesions affecting the fallopian tubes. However, fertility after laparoscopic IPAA has never been assessed. METHODS: All patients who underwent a total laparoscopic IPAA between 2000 and 2011 and were aged 45 years or less at the time of operation and 18 years or more at the time of data collection were included. The patients answered a fertility questionnaire by telephone. All demographic and perioperative data were prospectively collected. The results were compared with those of controls undergoing laparoscopic appendectomy. RESULTS: Sixty-three patients were included. The mean age at the time of surgery was 31 +/ 9 years (range 14-44). IPAA was performed for ulcerative colitis in 73% of the cases and familial adenomatous polyposis in 17%. The mean follow-up after IPAA was 68 +/- 33 months (range 6-136). Fifty-six patients answered the questionnaire (89%). Half of them already had a child before IPAA. Fifteen patients attempted pregnancy after IPAA, of which 11 (73%) were able to conceive, resulting in 10 ongoing pregnancies and 1 miscarriage. The global infertility rate was 27%. There was no difference in fertility over time compared with the 14 controls who attempted pregnancy during the same period (90% vs 86% at 36 months, P = 0.397). CONCLUSIONS: The infertility rate appears to be lower after laparoscopic IPAA than after open surgery. PMID- 23360924 TI - A comparison between an ultrasound based prediction model (LR2) and the risk of ovarian malignancy algorithm (ROMA) to assess the risk of malignancy in women with an adnexal mass. AB - OBJECTIVE: The identification of novel biomarkers led to the development of the ROMA algorithm incorporating both HE4 and CA125 to predict malignancy in women with a pelvic mass. An ultrasound based prediction model (LR2) developed by the International Ovarian Tumor Analysis (IOTA) study offers better diagnostic performance than CA125 alone. In this study we compared the diagnostic accuracy between LR2 and ROMA. METHODS: This study included women with a pelvic mass scheduled for surgery and enrolled in a previous prospective diagnostic accuracy study. Experienced ultrasound examiners, general gynecologists and trainees supervised by one of the experts performed the preoperative transvaginal ultrasound examinations. Serum biomarkers were taken prior to surgery. Accuracy of LR2 and ROMA was estimated at completion of this study and did not form part of the decision making process. Final outcome was histology of removed tissues and surgical stage if relevant. RESULTS: In total 360 women were evaluated. 216 women had benign disease and 144 a malignancy. Overall test performance of LR2 (AUC 0.952) with 94% sensitivity and 82% specificity was significantly better than ROMA (AUC 0.893) with 84% sensitivity and 80% specificity. Difference in AUC was 0.059 (95% CI: 0.026-0.091; P-value 0.0004). Similar results were obtained when stratified for menopausal status. CONCLUSION: LR2 shows a better diagnostic performance than ROMA for the characterization of a pelvic mass in both pre- and postmenopausal women. These findings suggest that HE4 and CA125 may not play an important role in the diagnosis of ovarian cancer if good quality ultrasonography is available. PMID- 23360925 TI - Highly selective binding of nitric oxide by Co(III) and Fe(III) complexes. AB - In order to construct compounds with highly selective binding activity for NO, two Co(III) and two Fe(III) complexes with square-planar N(2)O(2)-type donor sets, N-[2-(2-hydroxybenzylamino)ethyl]-2-hydroxybenzamide (H(3)L1) and 1,2-bis(2 hydroxybenzoylamino)ethane (H(4)L2), [Co(III)(L1)] (1), Na[Co(III)(L2)] (2), [Fe(III)(L1)] (3), and (PPh(4))[Fe(III)(L2)] (4), were designed and synthesized. These compounds were characterized by electronic absorption, FT-IR, (1)H-NMR spectroscopies, ESI-mass spectrometry, and elemental analyses. The redox potentials of the Co(III) and Fe(III) complexes with L1, 1 and 3, have quasi reversible waves at -0.51 and -0.49 V, respectively, and those with L2, 2 and 4, afforded reversible and irreversible waves at -0.96 and -1.04 V, respectively. Interestingly, all complexes quickly react with NO under an Ar atmosphere to form nitrosyl complexes, as monitored by UV-vis spectroscopy. The formation of nitrosyl complexes was confirmed by the appearance of the N-O stretching vibration at about 1650 cm(-1); 1649 for 1, 1651 for 2, 1648 for 3, and 1650 cm( 1) for 4. The reactivity of each of these complexes with other small molecules such as NO(2)(-), NO(3)(-), CO, and O(2) was also studied. None of the complexes react with CO and O(2). Co(III) complexes 1 and 2 react with NO2(-), while Fe(III) complexes, 3 and 4, do not react with small amounts of NO(2)(-). Complex 3 reacts with NO(2)(-) at concentrations above 100 equiv. of NO(2)(-). We succeeded in preparing complexes with highly selective reactivity for NO. PMID- 23360926 TI - Neutral tricoordinated beryllium(0) compounds--isostructural to BH(3) but isoelectronic to NH(3). AB - The electronic structure and reactivity of neutral tricoordinated Be(0) compounds BeL(3), L = CO (1), NHC (2) and PMe(3) (3) are explored by quantum mechanical calculations. These BeL(3) complexes are found to be planar or nearly planar like electron deficient BH3 but isoelectronic with NH3 and possess three L->Be donor acceptor bonds. The Be atom can be considered as sp(2)-hybridized with a lone pair in the highly diffused 2p(z)-orbital in contrast to the sp(3) hybridization in isoelectronic NH(3). Even though the lone pair on Be is stabilized through pi back donation or hyperconjugative interaction with the ligands, yet it is highly reactive towards Lewis acids such as H(+), BH(3) and W(CO)(5). The calculated gas phase protonation energies reveal that the NHC complex 2 and the trimethylphosphine complex 3 are 'super basic' in nature. Promising ligand property of BeL(3) has also been noted with BH(3) and transition metal fragment W(CO)(5). Besides, the reactivity of 2 and 3 is found to be more as compared to 1. PMID- 23360927 TI - Lattice modes in paraelectric La1/2Na1/2TiO3 by infrared and Raman spectroscopy. AB - The lattice dynamics of La(1/2)Na(1/2)TiO(3) single crystal have been investigated by far-infrared and Raman scattering spectroscopy. Far-IR reflectivity spectra revealed Slater, Last and Axe modes near 140, 190 and 555 cm(-1), respectively. The frequency of the Slater mode decreases by about 10% on cooling, which is enough to account for the observed increase of the low frequency permittivity. The results allowed us to discuss the reasons for the suppressed ferroelectricity of the material. Temperature evolution of the Raman scattering intensity of an oxygen octahedra bending mode near 455 cm(-1) suggests a second-order phase transition towards the perovskite aristotype phase near 870 K. PMID- 23360928 TI - Measuring protein reduction potentials using 15N HSQC NMR spectroscopy. AB - NMR spectroscopy was used to measure reduction potentials of four redox proteins by following multiple (15)N HSQC protein resonances across a titration series using mixtures of oxidised and reduced glutathione. Results for PDI a, PDI ab and DsbA agree with the literature and our result for ERp18 confirms this protein as an oxidoreductase of comparable or greater reducing strength than PDI a. PMID- 23360929 TI - Modes of failure in tubular plant organs. AB - PREMISE OF STUDY: Hollow tubular organs can bend and deform in one of two ways, i.e., either globally in long-wave deformation or locally in short-wave deformation (i.e., Brazier buckling). Either of these two types of behavior can cause death. Understanding the biophysical advantages and disadvantages of possessing hollow plant organs is important therefore to understanding plant ecology and avoiding damage to private or public property. METHODS: We present computer simulations that successfully predict when a hollow organ experiences different modes of failure as a function of organ length and wall thickness as well as material properties. KEY RESULTS AND CONCLUSIONS: When self-supporting, tubular plant organs are amenable to long-wave buckling and Brazier (short-wave) buckling under gravitational or wind-induced forces. For very slender tubes constructed of isotropic tissues, Brazier buckling depends on the outer wall radius and wall thickness (specifically Rt(2)). Particularly for organs constructed of anisotropic tissues, Brazier buckling becomes a complex phenomenon that depends on a number of geometric parameters (including length of the hollow section) as well as the material properties of tissues. This complexity precludes a definitive (canonical) limit to the relationship between wall thickness and outer radius and the safety limits for Brazier buckling. PMID- 23360930 TI - Fruits of Koelreuteria (Sapindaceae) from the Cenozoic throughout the northern hemisphere: their ecological, evolutionary, and biogeographic implications. AB - PREMISE OF THE STUDY: Koelreuteria (Sapindaceae) has four extant deciduous tree species, disjunctly distributed in eastern Asia and the Fiji Islands. While K. paniculata is widely cultivated, the biogeographic origin and evolutionary history of Koelreuteria remain unclear. METHODS: Fruits, pollen, wood, and leaves of closely related extant taxa were examined in comparison with fossil remains to evaluate the fossil record and biogeographic history of Koelreuteria. KEY RESULTS: Overall, characters of capsular fruits are more diagnostic than other organs for this genus. We describe two new species of fruit remains from the Eocene, K. taoana sp. nov. (northeastern China and far eastern Russia) and K. dilcheri sp. nov. (western United States), and give emended descriptions of three species: K. allenii (Lesq.) W. N. Edwards (early-late Eocene of the United States), K. macroptera (Kovats) W. N. Edwards (late Oligocene-early Pliocene of Europe), and K. miointegrifoliola Hu et R. W. Chaney (Miocene of eastern Asia). CONCLUSIONS: Reliable fossil records of capsules and ring-porous wood indicate that Koelreuteria may have originated in North Pacific-Rim area of the northern hemisphere by the early Eocene, representing an early temperate lineage in Sapindaceae adapted for wind dispersal. The fossils herein place a minimum age (ca. 52 Ma) for the divergence of Koelreuteria from tropical genera that appear more basal in the molecular phylogeny of Sapindaceae. Regional extinctions after the Eocene in North America and the Pliocene in Europe, reduced the range of Koelreuteria to eastern Asia, where three species occur today. The present distribution of another species in the Southern Pacific may be explained by long distance dispersal. PMID- 23360931 TI - Journal of Perinatal & Neonatal Nursing. From the editors. PMID- 23360932 TI - Culture counts and cultural competency matters! PMID- 23360933 TI - Nonobstetrical emergencies in the obstetrical unit. PMID- 23360934 TI - What is culturally appropriate care for high-risk infants and families? PMID- 23360935 TI - Are your policies protecting you? PMID- 23360936 TI - Internet resources. PMID- 23360937 TI - The effect of maternal stress and health-related quality of life on birth outcomes among Macao Chinese pregnant women. AB - This study investigated the prevalence of preterm birth and low-birth-weight in Macao. It also evaluated the effects of maternal perceived stress and health related quality of life on these 2 birth outcomes. A quantitative study using a prospective longitudinal design was undertaken in an antenatal clinic in Macao. A community-based sample (N = 581) of pregnant women in their second trimester was recruited; birth outcome data were collected from medical records. Perceived stress was measured using the Perceived Stress Scale, whereas health-related quality of life was measured using the standard SF-12 Health Survey. The prevalence rates of preterm birth and low-birth-weight were found to be 6.4% and 7.1%, respectively. Two multiple logistic regression analyses revealed that participants with past adverse obstetric complications and higher perceived stress levels were more likely to have premature infants. Also, those participants with higher perceived stress levels and poorer health-related quality of life in the physical health domain were more likely to have low-birth weight infants. Preliminary information was provided on risk factors associated with adverse birth outcomes; this could help nurses to design appropriate risk specific interventions for preventing preterm birth and low-birth-weight. PMID- 23360938 TI - Prevalence and predictors of postpartum depression among Arabic Muslim Jordanian women serving in the military. AB - The purpose of this cross-sectional correlational study was to investigate the prevalence of symptoms and psychosocial predictors of postpartum depression (PPD) among Arabic Muslim Jordanian women serving in the military. Jordanian active duty military women who had given birth within the last year (n = 300) and were working in 4 military hospitals participated in the study. Tools used included the Edinburgh Postnatal Depression Scale, the Impact of Event Scale-Revised, and the Multidimensional Perception of Social Support. Sixty-seven percent of study participants had mild to moderate symptoms of PPD, and 16% had high levels of symptoms of PPD. Seventy-five percent reported having adequate social support, and 75% reported perceived stress above the cutoff score. There was a strong positive significant relationship between symptoms of PPD and perceptions of stress. There was a significant moderate negative relationship between symptoms of PPD and perception of social support. Income, intendedness of pregnancy, mode of birth, family social support, and perception of stress were the strongest predictors of PPD. There was a reciprocal relationship between PPD and psychosocial variables, with women having low levels of perceived stress and satisfaction with social support having fewer symptoms of postpartum. These findings demonstrate the need to address the psychosocial needs of Arabic Muslim Jordanian childbearing women serving in the military through comprehensive interventions. Findings highlight the importance of social support in decreasing perceived stress and symptoms of PPD in these women. PMID- 23360940 TI - Promoting cultural humility during labor and birth: putting theory into action during PRONTO obstetric and neonatal emergency training. AB - Maternal and neonatal mortality in Northern Guatemala, a region with a high percentage of indigenous people, is disproportionately high. Initiatives to improve quality of care at local health facilities equipped for births, and increasing the number of births attended at these facilities will help address this problem. PRONTO (Programa de Rescate Obstetrico y Neonatal: Tratamiento Optimo y Oportuno) is a low-tech, high-fidelity, simulation-based, provider-to provider training in the management of obstetric and neonatal emergencies. This program has been successfully tested and implemented in Mexico. PRONTO will now be implemented in Guatemala as part of an initiative to decrease maternal and perinatal mortality. Guatemalan health authorities have requested that the training include training on cultural humility and humanized birth. This article describes the process of curricular adaptation to satisfy this request. The PRONTO team adapted the existing program through 4 steps: (a) analysis of the problem and context through a review of qualitative data and stakeholder interviews, (b) literature review and adoption of a theoretical framework regarding cultural humility and adult learning, (c) adaptation of the curriculum and design of new activities and simulations, and (d) implementation of adapted and expanded curriculum and further refinement in response to participant response. PMID- 23360941 TI - The influence of culture on breast-feeding decisions by African American and white women. AB - The purpose of this study was to examine how culture influenced breast-feeding decisions in African American and white women, using the Theory of Culture Care Diversity and Universality as a framework. One hundred eighty-six participants responded to the following: The word culture means beliefs and traditions passed down by your family and friends. How has culture affected how you plan to feed your baby? Qualitative content analysis was used to analyze the data. Four categories of responses were identified: influences of family, known benefits of breast-feeding, influences of friends, and personal choice. The findings suggest that race alone may not be as influential in infant feeding decisions as other factors. Although some women acknowledged the effect of their cultural background and experiences, most women reported that their culture did not affect their infant feeding decision. In this population, breast-feeding decisions were based on the influences of family, friends, self, and the perceived knowledge of breast feeding benefits. Although breast-feeding statistics are commonly reported by race, cultural influences on infant feeding decisions may transcend race and include the influence of family and friends, learned information from impersonal sources, and information that is shared and observed from other people. PMID- 23360942 TI - A review of postpartum depression, preterm birth, and culture. AB - Postpartum depression (PPD) varies worldwide and is considered a serious issue because of its devastating effects on mothers, families, and infants or children. Preterm birth may be a risk factor for PPD. In 2005, the global incidence of preterm birth was estimated to be 9.6%, and of these births, 85% occurred in Africa and Asia. Among Asian countries, Pakistan has a preterm birth rate of 15.7% and the highest prevalence rate of PPD (63.3%). A literature review was therefore undertaken to better understand the potential contribution of preterm birth to PPD and to identify gaps in the scientific literature. Limited studies compare prevalence rates of PPD in mothers of full-term infants and mothers of preterm infants. Furthermore, meta-analyses examining predictors of PPD have not included preterm birth as a variable. The interrelationship between preterm birth and PPD may be explained by early parental stress and mother-infant interaction among mothers of preterm infants. Culture plays an important role in shaping communication between mothers and their infants and defines social support rituals that may or may not mediate PPD. More research is needed to provide evidence for practice. PMID- 23360944 TI - Neonatal care in the home in northern rural Honduras: a qualitative study of the role of traditional birth attendants. AB - Traditional birth attendants (TBAs) have limited ability to reduce maternal mortality, but may be able to have a significant impact on neonatal survival. This qualitative study explores TBAs' (possessive) experience with neonatal care in a rural Honduran community. In 6 semistructured focus groups, TBAs described services they routinely provide to newborns. Using Atlas.ti, Version 6.0. (ATLAS.ti Scientific Software Development GmbH, University of Berlin), transcripts were coded by bilingual researchers and analyzed by thematic content. TBAs demonstrated limited knowledge of newborn physiology, yet were aware of many internationally recommended practices. Despite attempts to follow recommendations, all TBAs expressed difficulty due to resource constraints. TBAs were strong advocates of immediate breast-feeding and skin-to-skin care, but they did not demonstrate knowledge regarding delayed bathing and thermal care. Most TBAs stated that a sick neonate could be identified immediately at birth; thus, infections or other illnesses developed in later days may be missed. TBAs did not believe they could have averted neonatal complications or deaths that had occurred under their care. For most healthy newborns, TBAs are the primary providers until the 2-month vaccine visit at the healthcare clinic. Improved TBA training focused on infection symptomotology, physiology, and thermoregulation for newborns may increase opportunities for improved health and timely referrals to healthcare facilities. PMID- 23360945 TI - The father at the bedside: patterns of involvement in the NICU. AB - Father's involvement is important to child development, yet little is known about how fathers are involved with their newborns in neonatal intensive care. The purpose of this study was to describe patterns of fathers' involvement with their infants during hospitalization. Eighteen fathers of infants hospitalized were interviewed and asked to describe how they were involved with their infants. Interview, sociodemographic, and infant medical data were analyzed using cross case analysis to describe patterns of involvement. Three patterns were identified. Equal to mother fathers perceived their involvement to be the same as the mothers'. They were intrinsically motivated, not working, and spent many hours daily with their infants. They engaged in skin-to-skin care and bathed their infants. Mother more important fathers viewed the mothers' role as more important. They were working, visited a few hours most days, and perceived their role as supporting the mothers. Reluctant fathers were reticent to become involved, described extrinsic sources of motivation, and were fearful of handling their infants. Not all fathers wish to be involved to the same extent with their infants. Nurses need to assess fathers' preferences and facilitate involvement to the extent that they feel comfortable. PMID- 23360947 TI - You too can help. PMID- 23360946 TI - Stressors, resources, and stress responses in pregnant African American women: a mixed-methods pilot study. AB - This research aimed to develop an initial understanding of the stressors, stress responses, and personal resources that impact African American women during pregnancy, potentially leading to preterm birth. Guided by the ecological model, a prospective, mixed-methods, complementarity design was used with 11 pregnant women and 8 of their significant others. Our integrated analysis of quantitative and qualitative data revealed 2 types of stress responses: high stress responses (7 women) and low stress responses (4 women). Patterns of stress responses were seen in psychological stress and cervical remodeling (attenuation or cervical length). All women in the high stress responses group had high depression and/or low psychological well-being and abnormal cervical remodeling at one or both data collection times. All but 1 woman had at least 3 sources of stress (racial, neighborhood, financial, or network). In contrast, 3 of the 4 women in the low stress responses group had only 2 sources of stress (racial, neighborhood, financial, or network) and 1 had none; these women also reported higher perceived support. The findings demonstrate the importance of periodically assessing stress in African American women during pregnancy, particularly related to their support network as well as the positive supports they receive. PMID- 23360948 TI - Switching p53 states by calcium: dynamics and interaction of stress systems. AB - The integration of calcium and a p53-Mdm2 oscillator model is studied using a deterministic as well as a stochastic approach, to investigate the impact of a calcium wave on single cell dynamics and on the inter-oscillator interaction. The high dose of calcium in the system activates the nitric oxide synthase, synthesizing nitric oxide which then downregulates Mdm2 and influences drastically the p53-Mdm2 network regulation, lifting the system from a normal to a stressed state. The increase in calcium level switches the system to different states, as identified by the different behaviours of the p53 temporal dynamics, i.e. oscillation death to sustain the oscillation state via a mixed state of dampened and oscillation death states. Further increase of the calcium dose in the system switches the system from sustained to oscillation death state again, while an excess of calcium shifts the cell to an apoptotic state. Another important property of the calcium ion is its ability to behave as a synchronizing agent among the interacting systems. The time evolution of the p53 dynamics of the two diffusively coupled systems at stress condition via Ca(2+) shows synchronization between the two systems. The noise contained in the system interestingly helps the system to maintain its stabilized state (normal condition). However, noise has the tendency to destruct the synchronization effect, which means that it tries to restrict the system from external signals to maintain its normal condition. However, at the stress condition, the synchronization rate is found to be faster. PMID- 23360949 TI - Nonpharmacological interventions for ADHD: systematic review and meta-analyses of randomized controlled trials of dietary and psychological treatments. AB - OBJECTIVE: Nonpharmacological treatments are available for attention deficit hyperactivity disorder (ADHD), although their efficacy remains uncertain. The authors undertook meta-analyses of the efficacy of dietary (restricted elimination diets, artificial food color exclusions, and free fatty acid supplementation) and psychological (cognitive training, neurofeedback, and behavioral interventions) ADHD treatments. METHOD: Using a common systematic search and a rigorous coding and data extraction strategy across domains, the authors searched electronic databases to identify published randomized controlled trials that involved individuals who were diagnosed with ADHD (or who met a validated cutoff on a recognized rating scale) and that included an ADHD outcome. RESULTS: Fifty-four of the 2,904 nonduplicate screened records were included in the analyses. Two different analyses were performed. When the outcome measure was based on ADHD assessments by raters closest to the therapeutic setting, all dietary (standardized mean differences=0.21-0.48) and psychological (standardized mean differences=0.40-0.64) treatments produced statistically significant effects. However, when the best probably blinded assessment was employed, effects remained significant for free fatty acid supplementation (standardized mean difference=0.16) and artificial food color exclusion (standardized mean difference=0.42) but were substantially attenuated to nonsignificant levels for other treatments. CONCLUSIONS: Free fatty acid supplementation produced small but significant reductions in ADHD symptoms even with probably blinded assessments, although the clinical significance of these effects remains to be determined. Artificial food color exclusion produced larger effects but often in individuals selected for food sensitivities. Better evidence for efficacy from blinded assessments is required for behavioral interventions, neurofeedback, cognitive training, and restricted elimination diets before they can be supported as treatments for core ADHD symptoms. PMID- 23360950 TI - Cellular uptake and trafficking of polydiacetylene micelles. AB - Polydiacetylene (PDA) micelles coated with either carboxylate-, ammonium-, or methoxy-polyethyleneglycol (PEG) chains were assembled and loaded with a fluorescent dye (DiO). Their interaction with MCF-7 human breast tumor cells was investigated by epi-fluorescence microscopy and fluorescence-activated cell sorting (FACS) to determine their internalization pathway and intracellular fate. It was found that the ionic character of the micelles influenced their internalization kinetics through a caveolae-mediated pathway and that all micelle types behaved somewhat similarly inside cells. PMID- 23360951 TI - Targeted Gene Addition of Microdystrophin in Mice Skeletal Muscle via Human Myoblast Transplantation. AB - Zinc finger nucleases (ZFN) can facilitate targeted gene addition to the genome while minimizing the risks of insertional mutagenesis. Here, we used a previously characterized ZFN pair targeting the chemokine (C-C motif) receptor 5 (CCR5) locus to introduce, as a proof of concept, the enhanced green fluorescent protein (eGFP) or the microdystrophin genes into human myoblasts. Using integrase defective lentiviral vectors (IDLVs) and chimeric adenoviral vectors to transiently deliver template DNA and ZFN respectively, we achieved up to 40% targeted gene addition in human myoblasts. When the O(6)-methylguanine-DNA methyltransferase(P140K) gene was co-introduced with eGFP, the frequency of cells with targeted integration could be increased to over 90% after drug selection. Importantly, gene-targeted myoblasts retained their mitogenic activity and potential to form myotubes both in vitro and in vivo when injected into the tibialis anterior of immune-deficient mice. Altogether, our results could lead to the development of improved cell therapy transplantation protocols for muscular diseases.Molecular Therapy - Nucleic Acids (2013) 2, e68; doi:10.1038/mtna.2012.55; published online 29 January 2013. PMID- 23360953 TI - Interaction of AnxA6 with isolated and artificial lipid microdomains; importance of lipid composition and calcium content. AB - Niemann-Pick type C (NPC) disease is a lipid storage disorder characterized by accumulation of lipids in the late endosome/lysosome (LE/LY) compartment. In our previous report we isolated membranes of the LE/LY compartment from NPC L1 skin fibroblasts with a mutation in the NPC1 gene and found that they were characterized by low fluidity which likely contributed to the impaired function of membrane proteins involved in storage and turnover of cholesterol. In this report we isolated lipid microdomains (DRMs) from membranes of various cellular compartments and observed an increased amount of DRMs in the LE/LY compartment of NPC L1 cells in comparison to control cells, with no change in the DRM content in the plasma membrane. In addition, in the NPC cells, the majority of the cholesterol-interacting protein, AnxA6, which participates in the transport and distribution of cholesterol, translocated to DRMs upon a rise in Ca(2+) concentration. The mechanism of this translocation was further studied in vitro using Langmuir monolayers. We found that Ca(2+) is the main factor which regulates the interaction of AnxA6 with monolayers composed of neutral lipids, such as DPPC and sphingomyelin, and may also determine AnxA6 localization in cholesterol and sphingomyelin enriched microdomains, thus contributing to the etiology of the NPC disease. PMID- 23360952 TI - Intrapulmonary Versus Nasal Transduction of Murine Airways With GP64-pseudotyped Viral Vectors. AB - Persistent viral vector-mediated transgene expression in the airways requires delivery to cells with progenitor capacity and avoidance of immune responses. Previously, we observed that GP64-pseudotyped feline immunodeficiency virus (FIV) mediated gene transfer was more efficient in the nasal airways than the large airways of the murine lung. We hypothesized that in vivo gene transfer was limited by immunological and physiological barriers in the murine intrapulmonary airways. Here, we systematically investigate multiple potential barriers to lentiviral gene transfer in the airways of mice. We show that GP64-FIV vector transduced primary cultures of well-differentiated murine nasal epithelia with greater efficiency than primary cultures of murine tracheal epithelia. We further demonstrate that neutrophils, type I interferon (IFN) responses, as well as T and B lymphocytes are not the major factors limiting the transduction of murine conducting airways. In addition, we observed better transduction of GP64 pseudotyped vesicular stomatitis virus (VSV) in the nasal epithelia compared with the intrapulmonary airways in mice. VSVG glycoprotein pseudotyped VSV transduced intrapulmonary epithelia with similar efficiency as nasal epithelia. Our results suggest that the differential transduction efficiency of nasal versus intrapulmonary airways by FIV vector is not a result of immunological barriers or surface area, but rather differential expression of cellular factors specific for FIV vector transduction.Molecular Therapy - Nucleic Acids (2013) 2, e69; doi:10.1038/mtna.2012.60; published online 29 January 2013. PMID- 23360954 TI - Tremorolytic effects of safinamide in animal models of drug-induced parkinsonian tremor. AB - Safinamide is an alpha-aminoamide derivative that is currently in Phase III clinical trial development as an add-on therapy to levodopa or dopamine agonists for patients with Parkinson's disease. Safinamide is a monoamine oxidase B inhibitor with additional non-dopaminergic actions. The present experiments were performed to evaluate the ability of safinamide to attenuate parkinsonian motor impairments using the tremulous jaw movement model, an animal model of parkinsonian tremor. In rats, tremulous jaw movements can be induced with dopamine (DA) antagonists, DA depletion, and cholinomimetics, and can be reversed by various antiparkinsonian drugs, including L-DOPA, DA agonists, anticholinergics and adenosine A2A antagonists. In these present experiments, tremulous jaw movements were induced with the anticholinesterase galantamine (3.0mg/kg IP), the muscarinic agonist pilocarpine (0.5mg/kg IP), and the dopamine D2 antagonist pimozide (1.0mg/kg IP). Safinamide significantly reduced the number of tremulous jaw movements induced by galantamine, pilocarpine, and pimozide, with consistent effects across all three drugs at a dose range of 5.0-10.0mg/kg. The results of this study support the use of safinamide as a treatment for parkinsonian tremor. PMID- 23360955 TI - Effects of acute ethanol administration and chronic stress exposure on social investigation and 50kHz ultrasonic vocalizations in adolescent and adult male Sprague-Dawley rats. AB - Adolescents drink largely in social situations, likely in an attempt to facilitate social interactions. This study sought to examine alterations in the incentive salience of a social stimulus following repeated stress exposure and acute ethanol administration in adolescent and adult male Sprague-Dawley rats. Subjects were either exposed to 5days of restraint stress, chronic variable stress (CVS), which consisted of a different stressor every day, or non-stressed. On test day, the animals were injected with 0, 0.25, 0.5, or 0.75g/kg ethanol and placed in a social approach test in which they could see, hear, and smell a social conspecific, but could not physically interact with it. All the animals showed an interest in the social stimulus, with adolescents engaging in more social investigation than adults. Restraint stressed adults showed ethanol induced increases in social investigation, while ethanol effects were not seen in any other group. An ethanol-associated increase in 50kHz ultrasonic vocalization (USV) production was only evident in restraint stressed adolescents following 0.75g/kg ethanol. 50kHz USVs were not correlated with time spent investigating the social stimulus in any test condition. These results show that age differences in the facilitatory effects of ethanol on incentive salience of social stimuli are moderated by stress, with the facilitation of social approach by ethanol only evident in restraint stressed adults. PMID- 23360957 TI - Billing practices of local health departments providing 2009 pandemic influenza A (H1N1) vaccine. AB - CONTEXT: In June 2009, the World Health Organization officially declared an influenza pandemic. In the United States, the federal government supplied 2009 H1N1 vaccine at no cost and provided funding for states to implement vaccination programs. Vaccine providers including health departments were permitted to bill insurance plans for administering 2009 H1N1 vaccine. OBJECTIVE: To determine the extent to which local health departments (LHDs) billed for administering 2009 H1N1 vaccine, specific billing practices of LHDs, and factors associated with LHD billing. DESIGN: Cross-sectional study using an Internet-based survey, and semistructured interviews. PARTICIPANTS AND SETTING: Nationally representative stratified random sample of 527 LHDs in the United States. Interviews were conducted among a convenience sample of LHDs. MAIN OUTCOME MEASURE: Proportion of LHDs reporting billing for administering 2009 H1N1 vaccine. RESULTS: A total of 308 health departments (58%) provided responses complete enough for analysis. Most LHDs (82%) had previous experience billing for seasonal influenza vaccination, but only 20% (n = 57) billed for administration of 2009 H1N1 vaccine. Medicare (74%) and Medicaid (80%) were the most commonly billed health care payers; more than half (55%) of LHDs billing for 2009 H1N1 vaccine administration sought reimbursement from one or more private insurance plans. Billing for 2009 H1N1 vaccine administration was more common among LHDs that previously offered seasonal influenza vaccination (P = .003), previously billed for seasonal influenza vaccination (P = .04), and conducted school-located influenza vaccination clinics prior to the 2009-2010 influenza season (P = .002). CONCLUSIONS: Most LHDs elected not to bill for 2009 H1N1 vaccine administration despite prior experience billing for influenza vaccination. It is important to understand barriers to billing and resources needed by LHDs to facilitate billing for vaccination. Developing public health billing capacity will allow LHDs to recoup the costs of providing vaccines to insured persons and may also prepare them to conduct billing activities for other services or during future public health emergencies. PMID- 23360956 TI - Early ontogeny of D-amphetamine-induced one-trial behavioral sensitization. AB - The early ontogeny of D-amphetamine-induced one-trial behavioral sensitization was characterized using male and female preweanling and preadolescent rats. In Experiment 1, rats were injected with saline or D-amphetamine (1, 4, or 8mg/kg) in activity chambers or the home cage on postnatal day (PD) 12, PD 16, PD 20, or PD 24. One day later, rats were challenged with either 0.5 or 2mg/kg D amphetamine and distance traveled was measured in activity chambers for 120min. In Experiment 2, saline or D-amphetamine was administered in activity chambers on PD 24, while a challenge injection of D-amphetamine (0.25-4mg/kg) was given on PD 25. At younger ages (PD 13 and PD 17), a strong sensitized response was evident on the test day regardless of whether rats were pretreated with D-amphetamine (4 or 8mg/kg) before being placed in the activity chamber or 30min after being returned to the home cage. Rats did not display D-amphetamine-induced behavioral sensitization on PD 21, nor was context-dependent sensitization apparent on PD 25 even when a broad dose range of D-amphetamine was used. When low doses of D amphetamine were administered on the pretreatment and test days (1 and 0.5mg/kg, respectively), sensitized responding was not evident at any age. In summary, D amphetamine-induced one-trial behavioral sensitization was only apparent within a narrow developmental window during early ontogeny. This ontogenetic pattern of sensitized responding is similar to the one produced by methamphetamine and distinct from the pattern produced by cocaine. The unique sensitization profiles resulting from repeated D-amphetamine and cocaine treatment may be a consequence of their different mechanisms of action. PMID- 23360958 TI - Planar triazinium cations from vanadyl-mediated ring cyclizations: the thiazole species for efficient nuclear staining and photocytotoxicity. AB - Planar triazinium cationic species from vanadyl-assisted cyclization of 1-(2 thiazolylazo)-2-naphthol (H-TAN, 1), 1-(2-pyridylazo)-2-naphthol (H-PAN, 2), 2 (2'-thiazolylazo)-p-cresol (H-TAC, 3) and 6-(2'-thiazolylazo)-resorcinol (H-TAR, 5) were prepared and characterized. A dioxovanadium(V) species [VO(2)(TAR)] (4) was also isolated. Compounds 1, 2 and 4 were structurally characterized. Both 1 and 2 have planar structures. Complex 4 has V(V)O(3)N(2) coordination geometry. The cyclised triazinium compound forms a radical species within -0.06 to -0.29 V vs. SCE in DMF-0.1 M tetrabutylammonium perchlorate with a second response due to formation of an anionic species. A confocal microscopic study showed higher nuclear uptake for 1 having a fused thiazole moiety than 2 with a fused pyridine ring. The compounds showed a partial intercalative mode of binding to calf thymus DNA. Compound 1 showed plasmid DNA photo-cleavage activity under argon and photocytotoxicity in HeLa and MCF-7 cells with IC(50) values of 15.1 and 3.4 MUM respectively in visible light of 400-700 nm, while being essentially non-toxic in the dark with IC(50) values of 90.4 and 21.9 MUM. A TDDFT study was done to rationalize the experimental data. PMID- 23360959 TI - Self-assembled arginine-coated peptide nanosheets in water. AB - The surfactant-like peptide (Ala)(6)(Arg) is found to self-assemble into 3 nm thick sheets in aqueous solution. Scanning transmission electron microscopy measurements of mass per unit area indicate a layer structure based on antiparallel dimers. At higher concentration the sheets wrap into unprecedented ultrathin helical ribbon and nanotube architectures. PMID- 23360960 TI - The odd association of a C(3h) trisamidinium cation and tosylate anion with a series of linear oxalate-bridged trinuclear heterometallic complexes. AB - A series of six isostructural heterometallic trinuclear oxalate-bridged complexes of the formula (TDbenz)(2)(TsO)(2)[M(II)(H(2)O)(2){(MU ox)M(III)(ox)(2)}(2)].6H(2)O.2CH(3)OH (TDbenz = 1,3,5-tris[2-(1,3 diazolinium)]benzene; TsO = 4-methylbenzenesulfonate; ox = oxalate; M(III) = Fe, M(II) = Mn (1), Fe (2), Co (3); M(III) = Cr, M(II) = Mn (4), Fe (5), Co (6)) have been synthesized from (NH(4))(3)[M(III)(ox)(3)].3H(2)O, the chloride salts of the divalent metal ions and the tosylate salt of 1,3,5-tris[2-(1,3 diazolinium)]benzene (trisamidinium). Whereas the crystal structures of compounds 2, 3, 4 and 5 have been investigated by single-crystal X-ray diffraction, the structures of 1 and 6 have been checked by X-ray powder diffraction. All six compounds are isostructural and crystallise in the P1 space group. The crystals are composed of discrete linear [M(II)(H(2)O)(2){(MU-ox)M(III)(ox)(2)}(2)](4-) trinuclear bimetallic units, trisamidinium and tosylate ions and solvent molecules. The linear trinuclear unit is based on a central trans-diaquametal(II) entity connected to two [M(III)(ox)(3)](3-) (M(III) = Cr(III), Fe(III)) moieties through oxalate bridges. The divalent metal ions, surrounded by six oxygen atoms, adopt a distorted octahedral coordination geometry. The coordination sphere is composed of four oxygen atoms belonging to two oxalate ligands and two trans coordinated water molecules. One of the oxalate ions is coordinated to the central metal centre whereas the other two oxalate ligands are non-bridging. In the crystal, intermolecular hydrogen bonds involving oxalate ligands, solvent molecules and the counter-ions form a complex 3D network. Variable-temperature magnetic susceptibility measurements indicate an antiferromagnetic interaction between the iron(III) and the metal(II) ions (J = -4.23, -6.73, -8.97 cm(-1) for 1, 2 and 3 respectively) whereas this interaction is ferromagnetic when iron(III) is replaced by chromium(III) (J = +1.21, +2.20, +3.63 cm(-1) for 4, 5 and 6 respectively). Moreover, the cobalt(II) derivatives exhibit high D values (D = 29.3 cm(-1) for and D = 27.4 cm(-1) for 6). PMID- 23360962 TI - Cucurbitacin E exhibits anti-inflammatory effect in RAW 264.7 cells via suppression of NF-kappaB nuclear translocation. AB - OBJECTIVE: Cucurbitacin E (CuE), a triterpenoid compound isolated from Cucurbitaceae plants, possesses a wide range of biological activities including anti-inflammatory properties. The present study aimed to investigate the anti inflammatory effect of CuE and the underlying mechanism of action. METHODS: The anti-inflammatory effect of CuE was evaluated in lipopolysaccharide (LPS) stimulated RAW 264.7 cells. Cell proliferation was assessed using a modified MTT assay. Cell cycle distribution was analyzed by propidium iodide staining. The actin cytoskeleton was examined by immunofluorescent staining. The expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta was determined by intracellular cytokine staining. G-actin level and nuclear factor (NF)-kappaB nuclear translocation were detected by immunoblotting. RESULTS: CuE inhibited cell proliferation and induced cell cycle arrest at G2/M phase in RAW 264.7 cells. CuE also suppressed LPS-induced cell spreading and pseudopodia formation. These effects were associated with decreased G-actin level and severe actin aggregation. Moreover, CuE significantly inhibited both TNF-alpha and IL-1beta production in LPS-stimulated RAW 264.7 cells. This was likely mediated by suppressing LPS-induced nuclear translocation of NF-kappaB, a critical transcription factor responsible for pro-inflammatory cytokine expression. CONCLUSION: CuE displayed anti-inflammatory effects through suppression of NF kappaB nuclear translocation leading to a decreased expression of TNF-alpha and IL-1beta in LPS-stimulated RAW 264.7 cells. PMID- 23360963 TI - Degradation of the endoplasmic reticulum by autophagy in plants. AB - Eukaryotic cells have developed sophisticated strategies to contend with environmental stresses faced in their lifetime. Endoplasmic reticulum (ER) stress occurs when the accumulation of unfolded proteins within the ER exceeds the folding capacity of ER chaperones. ER stress responses have been well characterized in animals and yeast, and autophagy has been suggested to play an important role in recovery from ER stress. In plants, the unfolded protein response signaling pathways have been studied, but changes in ER morphology and ER homeostasis during ER stress have not been analyzed previously. Autophagy has been reported to function in tolerance of several stress conditions in plants, including nutrient deprivation, salt and drought stresses, oxidative stress, and pathogen infection. However, whether autophagy also functions during ER stress has not been investigated. The goal of our study was to elucidate the role and regulation of autophagy during ER stress in Arabidopsis thaliana. PMID- 23360964 TI - Efficient genome editing in zebrafish using a CRISPR-Cas system. AB - In bacteria, foreign nucleic acids are silenced by clustered, regularly interspaced, short palindromic repeats (CRISPR)--CRISPR-associated (Cas) systems. Bacterial type II CRISPR systems have been adapted to create guide RNAs that direct site-specific DNA cleavage by the Cas9 endonuclease in cultured cells. Here we show that the CRISPR-Cas system functions in vivo to induce targeted genetic modifications in zebrafish embryos with efficiencies similar to those obtained using zinc finger nucleases and transcription activator-like effector nucleases. PMID- 23360965 TI - RNA-guided editing of bacterial genomes using CRISPR-Cas systems. AB - Here we use the clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated Cas9 endonuclease complexed with dual-RNAs to introduce precise mutations in the genomes of Streptococcus pneumoniae and Escherichia coli. The approach relies on dual-RNA:Cas9-directed cleavage at the targeted genomic site to kill unmutated cells and circumvents the need for selectable markers or counter-selection systems. We reprogram dual-RNA:Cas9 specificity by changing the sequence of short CRISPR RNA (crRNA) to make single- and multinucleotide changes carried on editing templates. Simultaneous use of two crRNAs enables multiplex mutagenesis. In S. pneumoniae, nearly 100% of cells that were recovered using our approach contained the desired mutation, and in E. coli, 65% that were recovered contained the mutation, when the approach was used in combination with recombineering. We exhaustively analyze dual-RNA:Cas9 target requirements to define the range of targetable sequences and show strategies for editing sites that do not meet these requirements, suggesting the versatility of this technique for bacterial genome engineering. PMID- 23360966 TI - Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. AB - We employ the CRISPR-Cas system of Streptococcus pyogenes as programmable RNA guided endonucleases (RGENs) to cleave DNA in a targeted manner for genome editing in human cells. We show that complexes of the Cas9 protein and artificial chimeric RNAs efficiently cleave two genomic sites and induce indels with frequencies of up to 33%. PMID- 23360968 TI - Bibliography-Editors' selection of current world literature. PMID- 23360967 TI - Mendel's law reveals fatal flaws in Bateman's 1948 study of mating and fitness. AB - Bateman's experimental study of Drosophila melanogaster produced conclusions that are now part of the bedrock premises of modern sexual selection. Today it is the most cited experimental study in sexual selection, and famous as the first experimental demonstration of sex differences in the relationship between number of mates and relative reproductive success. We repeated the experimental methodology of the original to evaluate its reliability. The results indicate that Bateman's methodology of visible mutations to assign parentage and reproductive success to subject adults is significantly biased. When combined in offspring, the mutations decrease offspring survival, so that counts of mate number and reproductive success are mismeasured. Bateman's method overestimates the number of subjects with no mates and underestimates the number with one or more mates for both sexes. Here we discuss why Bateman's paper is important and present additional analyses of data from our monogamy trials. Monogamy trials can inform inferences about the force of sexual selection in populations because in monogamy trials male-male competition and female choice are absent. Monogamy trials also would have provided Bateman with an a priori test of the fit of his data to Mendel's laws, an unstated, but vital assumption of his methodology for assigning parentage from which he inferred the number of mates per individual subject and their reproductive success. Even under enforced monogamous mating, offspring frequencies of double mutant, single mutant and no mutant offspring were significantly different from Mendelian expectations proving that Bateman's method was inappropriate for answering the questions he posed. Double mutant offspring (those with a mutation from each parent) suffered significant inviability as did single mutant offspring whenever they inherited their mother's marker but the wild-type allele at their father's marker locus. These inviability effects produced two important inaccuracies in Bateman's results and conclusions. (1) Some matings that actually occurred were invisible and (2) reproductive success of some mothers was under-estimated. Both observations show that Bateman's conclusions about sex differences in number of mates and reproductive success were unwarranted, based on biased observations. We speculate about why Bateman's classic study remained without replication for so long, and we discuss why repetition almost 60 years after the original is still timely, necessary and critical to the scientific enterprise. We highlight overlooked alternative hypotheses to urge that modern tests of Bateman's conclusions go beyond confirmatory studies to test alternative hypotheses to explain the relationship between mate number and reproductive success. PMID- 23360969 TI - Orthogonal synthesis of a heterodimeric ligand for the development of the Gd(III) Ga(III) ditopic complex as a potential pH-sensitive MRI/PET probe. AB - A heterodimeric polyaminocarboxylate ligand based on a DO3A-sulfonamide linked to AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetracarboxylic acid) was synthesised via an orthogonal pathway in order to differentiate the two chelating cages and allow the formation of a Gd(III)-Ga(III) heteroditopic complex. The goal is to create a smart MRI/PET probe with pH dependent relaxivity and with the bimodal imaging approach that enables direct quantification of the stimulus, in this case pH. A (1)H NMR relaxometric study of the Gd-Ga heteroditopic complex addressed the pH modulation of the relaxivity and thus its possible use as an MRI pH sensitive probe. PMID- 23360971 TI - Switching the in-plane easy axis by ion implantation in rare earth based magnetic films. AB - Ar(+) ions have been implanted into Laves phase epitaxial thin films of YFe(2) and DyFe(2). Magneto-optical Kerr effect and vibrating sample magnetometry experiments show that the easy and hard axes of magnetization in both materials rotate through an in-plane angle of 90 degrees , whilst the strength of the magnetic anisotropy remains unaltered. This is supported by OOMMF computational modelling. Atomic force microscopy confirms that the film roughness is not affected by implanted ions. X-ray diffraction data show that the lattice parameter expands upon ion implantation, corresponding to a release of strain throughout the entire film following implantation with a critical fluence of 10(17) Ar(+) ions cm(-2). The anisotropy of the films is linked to the strain and from these data it is concluded that the source of anisotropy alters from one where magnetoelastic and magnetocrystalline effects compete to one which is governed solely by magnetocrystalline effects. The ability to locally tune the source of magnetic anisotropy without affecting the film surface and without inducing or eliminating anisotropy could be important in the fabrication of high density magnetic data storage media, spintronic devices and magneto-optical materials. PMID- 23360970 TI - Cloning and sequencing of the kedarcidin biosynthetic gene cluster from Streptoalloteichus sp. ATCC 53650 revealing new insights into biosynthesis of the enediyne family of antitumor antibiotics. AB - Enediyne natural product biosynthesis is characterized by a convergence of multiple pathways, generating unique peripheral moieties that are appended onto the distinctive enediyne core. Kedarcidin (KED) possesses two unique peripheral moieties, a (R)-2-aza-3-chloro-beta-tyrosine and an iso-propoxy-bearing 2 naphthonate moiety, as well as two deoxysugars. The appendage pattern of these peripheral moieties to the enediyne core in KED differs from the other enediynes studied to date with respect to stereochemical configuration. To investigate the biosynthesis of these moieties and expand our understanding of enediyne core formation, the biosynthetic gene cluster for KED was cloned from Streptoalloteichus sp. ATCC 53650 and sequenced. Bioinformatics analysis of the ked cluster revealed the presence of the conserved genes encoding for enediyne core biosynthesis, type I and type II polyketide synthase loci likely responsible for 2-aza-l-tyrosine and 3,6,8-trihydroxy-2-naphthonate formation, and enzymes known for deoxysugar biosynthesis. Genes homologous to those responsible for the biosynthesis, activation, and coupling of the l-tyrosine-derived moieties from C 1027 and maduropeptin and of the naphthonate moiety from neocarzinostatin are present in the ked cluster, supporting 2-aza-l-tyrosine and 3,6,8-trihydroxy-2 naphthoic acid as precursors, respectively, for the (R)-2-aza-3-chloro-beta tyrosine and the 2-naphthonate moieties in KED biosynthesis. PMID- 23360972 TI - Chlorido-containing ruthenium(II) and iridium(III) complexes as antimicrobial agents. AB - A series of polypyridyl-ruthenium(II) and -iridium(III) complexes that contain labile chlorido ligands, [{M(tpy)Cl}(2){MU-bb(n)}](2/4+) {Cl-Mbb(n); where M = Ru or Ir; tpy = 2,2':6',2''-terpyridine; and bb(n) = bis[4(4'-methyl-2,2' bipyridyl)]-1,n-alkane (n = 7, 12 or 16)} have been synthesised and their potential as antimicrobial agents examined. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of the series of metal complexes against four strains of bacteria - Gram positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA), and Gram negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) - have been determined. All the ruthenium complexes were highly active and bactericidal. In particular, the Cl-Rubb(12) complex showed excellent activity against all bacterial cell lines with MIC values of 1 MUg mL(-1) against the Gram positive bacteria and 2 and 8 MUg mL(-1) against E. coli and P. aeruginosa, respectively. The corresponding iridium(III) complexes also showed significant antimicrobial activity in terms of MIC values; however and surprisingly, the iridium complexes were bacteriostatic rather than bactericidal. The inert iridium(III) complex, [{Ir(phen)(2)}(2){MU-bb(12)}](6+) {where phen = 1,10-phenanthroline) exhibited no antimicrobial activity, suggesting that it could not cross the bacterial membrane. The mononuclear model complex, [Ir(tpy)(Me(2)bpy)Cl]Cl(2) (where Me(2)bpy = 4,4'-dimethyl-2,2'-bipyridine), was found to aquate very rapidly, with the pK(a) of the iridium-bound water in the corresponding aqua complex determined to be 6.0. This suggests the dinuclear complexes [Ir(tpy)Cl}(2){MU-bb(n)}](4+) aquate and deprotonate rapidly and enter the bacterial cells as 4+ charged hydroxo species. PMID- 23360973 TI - Ovularia puerariae Sawada is the hyphomycetous anamorph of a new Marasmius species on living leaves of kudzu (Pueraria montana, Fabaceae). AB - An arthroconidial hyphomycete on living leaves of kudzu (Pueraria montana, Fabaceae), originally described by Sawada in 1959 as Ovularia puerariae, was rediscovered. This anamorph is connected to an unknown Marasmius teleomorph belonging to section Globulares, which develops on the same living leaves. Ultrastructure and LSU rDNA sequence analysis of the anamorph confirm this connection. The fungus does not have only a unique biology among agarics, comparable only to Mycena citricolor, but also has the potential for application as a control agent of kudzu. During comparison with similar anamorph genera, Illosporium graminicola was found to be a synonym for Beniowskia sphaeroidea. PMID- 23360974 TI - Taxonomy and phylogeny of wood-inhabiting hydnoid species in Russulales: two new genera, three new species and two new combinations. AB - Russulales comprises a highly diverse group of species with respect to basidiocarp morphology and hymenophore type. We reconstructed evolutionary histories of Russulales using ITS and nLSU rDNA sequence data with an emphasis on phylogeny of wood-inhabiting hydnoid species in this order. Based on the combination of morphological and molecular evidence, two new genera, three new species and two new combinations are proposed. Dentipellis microspora and D. coniferarum, newly described, were placed outside Hericiaceae but are provisionally treated in Dentipellis due to their morphological similarity to the generic type. Dentipellis leptodon and D. taiwaniana are transferred to the new genus Dentipellicula as D. leptodon and D. taiwaniana, which is designated as the generic type. The new genus Dentipellopsis was erected to accommodate a newly described species D. dacrydicola. Characters are provided in a generic key to distinguish Dentipellicula, Dentipellis and Dentipellopsis that morphologically are highly similar in addition to a key to the current species in Dentipellis. A new species of Gloeodontia was described based on both molecular and morphological data, and a key to this genus also is provided. PMID- 23360975 TI - New and rare Harpellales from Portugal and northwestern Iberian Peninsula: discovering the hidden mycobiota of Galicia-Tras-os-Montes region. AB - The species of Harpellales obtained from a survey of the gut fungi of aquatic arthropods in the Galaico-Portuguese region, also known as the Galicia-Tras-os Montes Zone, are presented. New species include Orphella lusitanica, a close relative of O. helicospora in Plecoptera nymphs and Stachylina pleurospora, in Chironomiidae larvae, both from Galicia and Portugal. Tectimyces gallaecicus, in Ephemeroptera nymphs from Galicia, Spain, morphologically resembles the narrowly distributed T. robustus representing a genus known only from Europe. New geographical records from Portugal include Genistellospora homothallica, Graminella bulbosa, Harpella melusinae, Lancisporomyces vernalis, Legeriomyces ramosus, O. coronata, Simuliomyces microsporus and Smittium simulii. Also three rare taxa are reported from Galicia: Legeriomyces dolabrae and Baetimyces ancorae from Baetidae nymphs and Smittium inexpectans from Chironomidae larvae. PMID- 23360976 TI - A new species and a new record of Diatrypaceae from Panama. AB - Based on opportunistic collections of fungi in Panama, two species of Diatrypaceae (Xylariales) are described and illustrated. One of them, Eutypella semicircularis, found twice on branches probably belonging to Alnus acuminata, is new to science. It differs from known species of Eutypella and Peroneutypa with strongly allantoid or semicircular ascospores, such as E. crustata and P. curvispora, in having larger ascospores that sometimes almost form a circle and broader stromata, among other differences. Molecular data of the ITS rDNA region show that the new species is a sister taxon of Eutypella cerviculata, the type species of the genus Eutypella. Diatrype bermudensis on stems of Guadua angustifolia is reported from Panama for the first time, being known up to now apparently only from Bermuda. PMID- 23360978 TI - The highly conserved, N-terminal (RXXX)8 motif of mouse Shadoo mediates nuclear accumulation. AB - The prion protein (PrP)-known for its central role in transmissible spongiform encephalopathies-has been reported to possess two nuclear localization signals and localize in the nuclei of certain cells in various forms. Although these data are superficially contradictory, it is apparent that nuclear forms of the prion protein can be found in cells in either the healthy or the diseased state. Here we report that Shadoo (Sho)-a member of the prion protein superfamily-is also found in the nucleus of several neural and non-neural cell lines as visualized by using an YFP-Sho construct. This nuclear localization is mediated by the (25-61) fragment of mouse Sho encompassing an (RXXX)8 motif. Bioinformatic analysis shows that the (RXXX)n motif (n=7-8) is a highly conserved and characteristic part of mammalian Shadoo proteins. Experiments to assess if Sho enters the nucleus by facilitated transport gave no decisive results: the inhibition of active processes that require energy in the cell, abolishes nuclear but not nucleolar accumulation. However, the (RXXX)8 motif is not able to mediate the nuclear transport of large fusion constructs exceeding the size limit of the nuclear pore for passive entry. Tracing the journey of various forms of Sho from translation to the nucleus and discerning the potential nuclear function of PrP and Sho requires further studies. PMID- 23360979 TI - Applied techniques for mining natural proteasome inhibitors. AB - In eukaryotic cells, the ubiquitin-proteasome-system (UPS) is responsible for the non-lysosomal degradation of proteins and plays a pivotal role in such vital processes as protein homeostasis, antigen processing or cell proliferation. Therefore, it is an attractive drug target with various applications in cancer and immunosuppressive therapies. Being an evolutionary well conserved pathway, many pathogenic bacteria have developed small molecules, which modulate the activity of their hosts' UPS components. Such natural products are, due to their stepwise optimization over the millennia, highly potent in terms of their binding mechanisms, their bioavailability and selectivity. Generally, this makes bioactive natural products an ideal starting point for the development of novel drugs. Since four out of the ten best seller drugs are natural product derivatives, research in this field is still of unfathomable value for the pharmaceutical industry. The currently most prominent example for the successful exploitation of a natural compound in the UPS field is carfilzomib (Kyprolis(r)), which represents the second FDA approved drug targeting the proteasome after the admission of the blockbuster bortezomib (Velcade(r)) in 2003. On the other hand side of the spectrum, ONX 0914, which is derived from the same natural product as carfilzomib, has been shown to selectively inhibit the immune response related branch of the pathway. To date, there exists a huge potential of UPS inhibitors with regard to many diseases. Both approved drugs against the proteasome show severe side effects, adaptive resistances and limited applicability, thus the development of novel compounds with enhanced properties is a main objective of active research. In this review, we describe the techniques, which can be utilized for the discovery of novel natural inhibitors, which in particular block the 20S proteasomal activity. In addition, we will illustrate the successful implementation of a recently published methodology with the example of a highly potent but so far unexploited group of proteasome inhibitors, the syrbactins, and their biological functions. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf. PMID- 23360977 TI - Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association. AB - Positron emission tomography (PET) of brain amyloid b is a technology that is becoming more available, but its clinical utility in medical practice requires careful definition. To provide guidance to dementia care practitioners, patients, and caregivers, the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened the Amyloid Imaging Taskforce (AIT). The AIT considered a broad range of specific clinical scenarios in which amyloid PET could potentially be used appropriately. Peer-reviewed, published literature was searched to ascertain available evidence relevant to these scenarios, and the AIT developed a consensus of expert opinion. Although empirical evidence of impact on clinical outcomes is not yet available, a set of specific appropriate use criteria (AUC) were agreed on that define the types of patients and clinical circumstances in which amyloid PET could be used. Both appropriate and inappropriate uses were considered and formulated,and are reported and discussed here. Because both dementia care and amyloid PET technology are in active development, these AUC will require periodic reassessment. Future research directions are also outlined, including diagnostic utility and patient-centered outcomes. PMID- 23360981 TI - Non-apoptotic roles of Bcl-2 family: the calcium connection. AB - The existence of the bcl-2 (B-cell lymphoma-2) gene was reported nearly 30 years ago. Yet, Bcl-2 family group of proteins still surprises us with their structural and functional diversity. Since the discovery of the Bcl-2 family of proteins as one of the main apoptosis judges, the precise mechanism of their action remains a hot topic of intensive scientific research and debates. Although extensive work has been performed on the role of mitochondria in apoptosis, more and more studies point out an implication of the endoplasmic reticulum in this process. Interestingly, Bcl-2 family proteins could be localized to both the mitochondria and the endoplasmic reticulum highlighting their crucial role in apoptosis control. In particular, in these organelles Bcl-2 proteins seem to be involved in calcium homeostasis regulation although the mechanisms underlying this function are still misunderstood. We now assume with high degree of certainty that the majority of Bcl-2 family members take part not only in apoptosis regulation but also in other processes important for the cell physiology briefly denominated as "non-apoptotic" functions. Drawing a complete and comprehensive image of Bcl-2 family requires the understanding of their implications in all cellular processes. Here, we review the current knowledge on the control of calcium homeostasis by the Bcl-2 family at the endoplasmic reticulum and at the mitochondria. Then we focus on the non-apoptotic functions of the Bcl-2 proteins in relation with the regulation of this versatile intracellular messenger. This article is part of a Special Issue entitled: 12th European Symposium on Calcium. PMID- 23360980 TI - MEK-1 activates C-Raf through a Ras-independent mechanism. AB - C-Raf is a member of the Ras-Raf-MEK-ERK mitogen-activated protein kinase (MAPK) signaling pathway that plays key roles in diverse physiological processes and is upregulated in many human cancers. C-Raf activation involves binding to Ras, increased phosphorylation and interactions with co-factors. Here, we describe a Ras-independent in vivo pathway for C-Raf activation by its downstream target MEK. Using (32)P-metabolic labeling and 2D-phosphopeptide mapping experiments, we show that MEK increases C-Raf phosphorylation by up-to 10-fold. This increase was associated with C-Raf kinase activation, matching the activity seen with growth factor stimulation. Consequently, coexpression of wildtype C-Raf and MEK was sufficient for full and constitutive activation of ERK. Notably, the ability of MEK to activate C-Raf was completely Ras independent, since mutants impaired in Ras binding that are irresponsive to growth factors or Ras were fully activated by MEK. The ability of MEK to activate C-Raf was only partially dependent on MEK kinase activity but required MEK binding to C-Raf, suggesting that the binding results in a conformational change that increases C-Raf susceptibility to phosphorylation and activation or in the stabilization of the phosphorylated active form. These findings propose a novel Ras-independent mechanism for activating the C-Raf and the MAPK pathway without the need for mutations in the pathway. This mechanism could be of significance in pathological conditions or cancers overexpressing C-Raf and MEK or in conditions where C-Raf-MEK interaction is enhanced due to the down-regulation of RKIP and MST2. PMID- 23360983 TI - Bespoke synthesis of unsymmetrical diaminoboranes by alkaline earth catalysis. AB - Heavier group 2 (Mg, Ca) bis(trimethylsilyl)amides are catalysts for the formation of unsymmetrical diaminoboranes, [(R(2)N)BH(NR'(2))], by dehydrocoupling of amine boranes and protic amines; a process which is proposed to occur by a sequential metal-centred elimination-insertion-elimination mechanism. PMID- 23360982 TI - Calcium responses to synaptically activated bursts of action potentials and their synapse-independent replay in cultured networks of hippocampal neurons. AB - Both synaptic N-methyl-d-aspartate (NMDA) receptors and voltage-operated calcium channels (VOCCs) have been shown to be critical for nuclear calcium signals associated with transcriptional responses to bursts of synaptic input. However the direct contribution to nuclear calcium signals from calcium influx through NMDA receptors and VOCCs has been obscured by their concurrent roles in action potential generation and synaptic transmission. Here we compare calcium responses to synaptically induced bursts of action potentials with identical bursts devoid of any synaptic contribution generated using the pre-recorded burst as the voltage clamp command input to replay the burst in the presence of blockers of action potentials or ionotropic glutamate receptors. Synapse independent replays of bursts produced nuclear calcium responses with amplitudes around 70% of their original synaptically generated signals and were abolished by the L-type VOCC blocker, verapamil. These results identify a major direct source of nuclear calcium from local L-type VOCCs whose activation is boosted by NMDA receptor dependent depolarization. The residual component of synaptically induced nuclear calcium signals which was both VOCC independent and NMDA receptor dependent showed delayed kinetics consistent with a more distal source such as synaptic NMDA receptors or internal stores. The dual requirement of NMDA receptors and L type VOCCs for synaptic activity-induced nuclear calcium dependent transcriptional responses most likely reflects a direct somatic calcium influx from VOCCs whose activation is amplified by synaptic NMDA receptor-mediated depolarization and whose calcium signal is boosted by a delayed input from distal calcium sources mostly likely entry through NMDA receptors and release from internal stores. This article is part of a Special Issue entitled: 12th European Symposium on Calcium. PMID- 23360984 TI - Ruthenium-based complexes containing a benzimidazolium tag covalently connected to N-heterocyclic carbene ligands: environmentally friendly catalysts for olefin metathesis transformations. AB - Two ruthenium-based pre-catalysts containing an ionic tag covalently connected to a N-heterocyclic carbene (NHC) ligand are reported. These novel complexes, bearing a polar benzimidazolium group, are air-stable and can be easily prepared from commercially available reagents. The quaternary benzimidazolium tag allows the efficient separation of ruthenium waste from the metathesis product after reaction. Application in several olefin metathesis transformations leads to desired products of high purity, which exhibit ruthenium contamination levels as low as 1 ppm after simple filtration through a pad of silica gel. PMID- 23360985 TI - [Strokes and hemoglobinopathies in Burkina Faso]. AB - S and C hemoglobinopathies are a group of inherited blood disorders including sickle cell disease, characterized by the presence of abnormal S and C hemoglobins. They are common in tropical Africa. Stroke is a common complication of sickle cell disease. Studies of the relation between these two diseases are virtually nonexistent in sub-saharan Africa. Our work aimed to study the influence of these hemoglobinopathies on the onset of strokes in adults. This cross-sectional study took place from 1st December 2009 to 31st May 2010 at University Hospital Yalgado Ouedraogo. Out of 142 patients admitted to our neurology department during this period, 74 patients had had strokes. Their mean age was 55.9 years and their sex ratio 1.53. Ischemic strokes accounted for 57% of the total, followed by cerebral hemorrhage (39%). Forty-six patients (62%) were AA genotype, 27 (36%) patients had sickle cell trait (16 AC and 11 AS) and three patients were homozygous CC. This study showed a higher prevalence of hemoglobinopathies in patients with stroke than in the general population. Unlike heterozygous SC and homozygous SS forms, the existence of sickle cell trait in this population does not appear to increase the risk of onset of ischemic stroke but may reduce the age at onset of cerebral hemorrhage. PMID- 23360986 TI - Quantitative experimental determination of site-specific magnetic structures by transmitted electrons. AB - Understanding the magnetic structure of materials on a nanometre scale provides fundamental information in the development of novel applications. Here we show a site-specific electron energy-loss magnetic chiral dichroism method, first experimentally demonstrating that the use of transmitted electrons allows us to quantitatively determine atomic site-specific magnetic structure information on a nanometre scale. From one NiFe(2)O(4) nanograin in composite films, we extract its atomic site-specific magnetic circular dichroism spectra and achieve the quantitative magnetic structure information, such as site-specific total magnetic moments and orbital to spin magnetic moment ratios, by constructively selecting the specific dynamical diffraction conditions in electron energy-loss magnetic chiral dichroism experiments. The site-specific electron energy-loss magnetic chiral dichroism method shows its unique ability for solving the site-specific magnetic structure at nanoscale resolution, compared with X-ray magnetic circular dichroism and neutron diffraction. This work opens a door to meet the challenge of exploring the magnetic structures of magnetic materials at the nanoscale using transmitted electrons. PMID- 23360987 TI - The impact of free-ranging domestic cats on wildlife of the United States. AB - Anthropogenic threats, such as collisions with man-made structures, vehicles, poisoning and predation by domestic pets, combine to kill billions of wildlife annually. Free-ranging domestic cats have been introduced globally and have contributed to multiple wildlife extinctions on islands. The magnitude of mortality they cause in mainland areas remains speculative, with large-scale estimates based on non-systematic analyses and little consideration of scientific data. Here we conduct a systematic review and quantitatively estimate mortality caused by cats in the United States. We estimate that free-ranging domestic cats kill 1.4-3.7 billion birds and 6.9-20.7 billion mammals annually. Un-owned cats, as opposed to owned pets, cause the majority of this mortality. Our findings suggest that free-ranging cats cause substantially greater wildlife mortality than previously thought and are likely the single greatest source of anthropogenic mortality for US birds and mammals. Scientifically sound conservation and policy intervention is needed to reduce this impact. PMID- 23360988 TI - Human CLPP reverts the longevity phenotype of a fungal ClpP deletion strain. AB - Mitochondrial maintenance crucially depends on the quality control of proteins by various chaperones, proteases and repair enzymes. While most of the involved components have been studied in some detail, little is known on the biological role of the CLPXP protease complex located in the mitochondrial matrix. Here we show that deletion of PaClpP, encoding the CLP protease proteolytic subunit CLPP, leads to an unexpected healthy phenotype and increased lifespan of the fungal ageing model organism Podospora anserina. This phenotype can be reverted by expression of human ClpP in the fungal deletion background, demonstrating functional conservation of human and fungal CLPP. Our results show that the biological role of eukaryotic CLP proteases can be studied in an experimentally accessible model organism. PMID- 23360989 TI - The phosphatase Dullard negatively regulates BMP signalling and is essential for nephron maintenance after birth. AB - Most kidney nephron components, including glomeruli and renal tubules, derive from the metanephric mesenchyme. The overall differentiation into each component finishes at birth, but the molecular events linking the perinatal and adult kidneys remain elusive. Dullard was cloned from Xenopus kidneys, and encodes a phosphatase that negatively regulates BMP signalling. Here we report that Dullard deletion in the murine metanephric mesenchyme leads to failure of nephron maintenance after birth, resulting in lethality before adulthood. The nephron components are lost by massive apoptosis within 3 weeks after birth, leading to formation of a large hollow with a thin-layered cortex and medulla. Phosphorylated Smad1/5/8 is upregulated in the mutant nephrons, probably through cell-autonomous inhibitory effects of Dullard on BMP signalling. Importantly, administration of the BMP receptor kinase inhibitor LDN-193189 partially rescued the defects caused by Dullard deletion. Thus, Dullard keeps BMP signalling at an appropriate level, which is required for nephron maintenance in the postnatal period. PMID- 23360990 TI - In vitro fabrication of functional three-dimensional tissues with perfusable blood vessels. AB - In vitro fabrication of functional vascularized three-dimensional tissues has been a long-standing objective in the field of tissue engineering. Here we report a technique to engineer cardiac tissues with perfusable blood vessels in vitro. Using resected tissue with a connectable artery and vein as a vascular bed, we overlay triple-layer cardiac cell sheets produced from coculture with endothelial cells, and support the tissue construct with media perfused in a bioreactor. We show that endothelial cells connect to capillaries in the vascular bed and form tubular lumens, creating in vitro perfusable blood vessels in the cardiac cell sheets. Thicker engineered tissues can be produced in vitro by overlaying additional triple-layer cell sheets. The vascularized cardiac tissues beat and can be transplanted with blood vessel anastomoses. This technique may create new opportunities for in vitro tissue engineering and has potential therapeutic applications. PMID- 23360991 TI - Photon-mediated interaction between distant quantum dot circuits. AB - Engineering the interaction between light and matter is an important goal in the emerging field of quantum opto-electronics. Thanks to the use of cavity quantum electrodynamics architectures, one can envision a fully hybrid multiplexing of quantum conductors. Here we use such an architecture to couple two quantum dot circuits. Our quantum dots are separated by 200 times their own size, with no direct tunnel and electrostatic couplings between them. We demonstrate their interaction, mediated by the cavity photons. This could be used to scale up quantum bit architectures based on quantum dot circuits or simulate on-chip phonon-mediated interactions between strongly correlated electrons. PMID- 23360992 TI - Ultrafast universal quantum control of a quantum-dot charge qubit using Landau Zener-Stuckelberg interference. AB - A basic requirement for quantum information processing is the ability to universally control the state of a single qubit on timescales much shorter than the coherence time. Although ultrafast optical control of a single spin has been achieved in quantum dots, scaling up such methods remains a challenge. Here we demonstrate complete control of the quantum-dot charge qubit on the picosecond scale [corrected], orders of magnitude faster than the previously measured electrically controlled charge- or spin-based qubits. We observe tunable qubit dynamics in a charge-stability diagram, in a time domain, and in a pulse amplitude space of the driven pulse. The observations are well described by Landau-Zener-Stuckelberg interference. These results establish the feasibility of a full set of all-electrical single-qubit operations. Although our experiment is carried out in a solid-state architecture, the technique is independent of the physical encoding of the quantum information and has the potential for wider applications. PMID- 23360993 TI - Caribbean-wide decline in carbonate production threatens coral reef growth. AB - Global-scale deteriorations in coral reef health have caused major shifts in species composition. One projected consequence is a lowering of reef carbonate production rates, potentially impairing reef growth, compromising ecosystem functionality and ultimately leading to net reef erosion. Here, using measures of gross and net carbonate production and erosion from 19 Caribbean reefs, we show that contemporary carbonate production rates are now substantially below historical (mid- to late-Holocene) values. On average, current production rates are reduced by at least 50%, and 37% of surveyed sites were net erosional. Calculated accretion rates (mm year(-1)) for shallow fore-reef habitats are also close to an order of magnitude lower than Holocene averages. A live coral cover threshold of ~10% appears critical to maintaining positive production states. Below this ecological threshold carbonate budgets typically become net negative and threaten reef accretion. Collectively, these data suggest that recent ecological declines are now suppressing Caribbean reef growth potential. PMID- 23360995 TI - The Tissint Martian meteorite as evidence for the largest impact excavation. AB - High-pressure minerals in meteorites provide clues for the impact processes that excavated, launched and delivered these samples to Earth. Most Martian meteorites are suggested to have been excavated from 3 to 7 km diameter impact craters. Here we show that the Tissint meteorite, a 2011 meteorite fall, contains virtually all the high-pressure phases (seven minerals and two mineral glasses) that have been reported in isolated occurrences in other Martian meteorites. Particularly, one ringwoodite (75 * 140 MUm(2)) represents the largest grain observed in all Martian samples. Collectively, the ubiquitous high-pressure minerals of unusually large sizes in Tissint indicate that shock metamorphism was widely dispersed in this sample (~25 GPa and ~2,000 degrees C). Using the size and growth kinetics of the ringwoodite grains, we infer an initial impact crater with ~90 km diameter, with a factor of 2 uncertainty. These energetic conditions imply alteration of any possible low-T minerals in Tissint. PMID- 23360994 TI - Src activation by beta-adrenoreceptors is a key switch for tumour metastasis. AB - Noradrenaline can modulate multiple cellular functions important for cancer progression; however, how this single extracellular signal regulates such a broad array of cellular processes is unknown. Here we identify Src as a key regulator of phosphoproteomic signalling networks activated in response to beta-adrenergic signalling in cancer cells. These results also identify a new mechanism of Src phosphorylation that mediates beta-adrenergic/PKA regulation of downstream networks, thereby enhancing tumour cell migration, invasion and growth. In human ovarian cancer samples, high tumoural noradrenaline levels were correlated with high pSrc(Y419) levels. Moreover, among cancer patients, the use of beta blockers was significantly associated with reduced cancer-related mortality. Collectively, these data provide a pivotal molecular target for disrupting neural signalling in the tumour microenvironment. PMID- 23360996 TI - Heat shock factor-1 influences pathological lesion distribution of polyglutamine induced neurodegeneration. AB - A crucial feature of adult-onset neurodegenerative diseases is accumulation of abnormal protein in specific brain regions, although the mechanism underlying this pathological selectivity remains unclear. Heat shock factor-1 is a transcriptional regulator of heat shock proteins, molecular chaperones that abrogate neurodegeneration by refolding and solubilizing pathogenic proteins. Here we show that heat shock factor-1 expression levels are associated with the accumulation of pathogenic androgen receptor in spinal and bulbar muscular atrophy, a polyglutamine-induced neurodegenerative disease. In heterozygous heat shock factor-1-knockout spinal and bulbar muscular atrophy mice, abnormal androgen receptor accumulates in the cerebral visual cortex, liver and pituitary, which are not affected in their genetically unmodified counterparts. The depletion of heat shock factor-1 also expands the distribution of pathogenic androgen receptor accumulation in other neuronal regions. Furthermore, lentiviral mediated delivery of heat shock factor-1 into the brain of spinal and bulbar muscular atrophy mice topically suppresses the pathogenic androgen receptor accumulation and neuronal atrophy. These results suggest that heat shock factor-1 influences the pathological lesion selectivity in spinal and bulbar muscular atrophy. PMID- 23360997 TI - A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration. AB - Semaphorin 4A (Sema4A) has an essential role in photoreceptor survival. In humans, mutations in Sema4A are thought to contribute to retinal degenerative diseases. Here we generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4A(F350C) causes retinal degeneration phenotypes. The F350C mutation results in abnormal localization of the Sema4A protein, leading to impaired endosomal sorting of molecules indispensable for photoreceptor survival. Additionally, protein structural modelling reveals that the side chain of the 350th amino acid is critical to retain the proper protein conformation. Furthermore, Sema4A gene transfer successfully prevents photoreceptor degeneration in Sema4A(F350C/F350C) and Sema4A(-/-) mice. Thus, our findings not only indicate the importance of the Sema4A protein conformation in human and mouse retina homeostasis but also identify a novel therapeutic target for retinal degenerative diseases. PMID- 23360999 TI - Deep proteome profiling of Trichoplax adhaerens reveals remarkable features at the origin of metazoan multicellularity. AB - Genome sequencing of arguably the simplest known animal, Trichoplax adhaerens, uncovered a rich array of transcription factor and signalling pathway genes. Although the existence of such genes allows speculation about the presence of complex regulatory events, it does not reveal the level of actual protein expression and functionalization through posttranslational modifications. Using high-resolution mass spectrometry, we here semi-quantify 6,516 predicted proteins, revealing evidence of horizontal gene transfer and the presence at the protein level of nodes important in animal signalling pathways. Moreover, our data demonstrate a remarkably high activity of tyrosine phosphorylation, in line with the hypothesized burst of tyrosine-regulated signalling at the instance of animal multicellularity. Together, this Trichoplax proteomics data set offers significant new insight into the mechanisms underlying the emergence of metazoan multicellularity and provides a resource for interested researchers. PMID- 23360998 TI - Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53. AB - The tumour suppressor p53 is the most frequently mutated gene in human cancer. Reactivation of mutant p53 by small molecules is an exciting potential cancer therapy. Although several compounds restore wild-type function to mutant p53, their binding sites and mechanisms of action are elusive. Here computational methods identify a transiently open binding pocket between loop L1 and sheet S3 of the p53 core domain. Mutation of residue Cys124, located at the centre of the pocket, abolishes p53 reactivation of mutant R175H by PRIMA-1, a known reactivation compound. Ensemble-based virtual screening against this newly revealed pocket selects stictic acid as a potential p53 reactivation compound. In human osteosarcoma cells, stictic acid exhibits dose-dependent reactivation of p21 expression for mutant R175H more strongly than does PRIMA-1. These results indicate the L1/S3 pocket as a target for pharmaceutical reactivation of p53 mutants. PMID- 23361000 TI - Modular optimization of multi-gene pathways for fatty acids production in E. coli. AB - Microbial fatty acid-derived fuels have emerged as promising alternatives to petroleum-based transportation fuels. Here we report a modular engineering approach that systematically removed metabolic pathway bottlenecks and led to significant titre improvements in a multi-gene fatty acid metabolic pathway. On the basis of central pathway architecture, E. coli fatty acid biosynthesis was re cast into three modules: the upstream acetyl coenzyme A formation module; the intermediary acetyl-CoA activation module; and the downstream fatty acid synthase module. Combinatorial optimization of transcriptional levels of these three modules led to the identification of conditions that balance the supply of acetyl CoA and consumption of malonyl-CoA/ACP. Refining protein translation efficiency by customizing ribosome binding sites for both the upstream acetyl coenzyme A formation and fatty acid synthase modules enabled further production improvement. Fed-batch cultivation of the engineered strain resulted in a final fatty acid production of 8.6 g l(-1). The modular engineering strategies demonstrate a generalized approach to engineering cell factories for valuable metabolites production. PMID- 23361001 TI - Selective escape of proteins from the mitochondria during mitophagy. AB - Mitophagy refers to the degradation of mitochondria by the autophagy system that is regulated by Parkin and PINK1, mutations in the genes for which have been linked to Parkinson's disease. Here we show that certain mitochondrial outer membrane proteins, including FKBP38 and Bcl-2, translocate from the mitochondria to the endoplasmic reticulum (ER) during mitophagy, thereby escaping degradation by autophagosomes. This translocation depends on the ubiquitylation activity of Parkin and on microtubule polymerization. Photoconversion analysis confirmed that FKBP38 detected at the ER during mitophagy indeed represents preexisting protein transported from the mitochondria. The escape of FKBP38 and Bcl-2 from the mitochondria is determined by the number of basic amino acids in their COOH terminal signal sequences. Furthermore, the translocation of FKBP38 is essential for the suppression of apoptosis during mitophagy. Our results thus show that not all mitochondrial proteins are degraded during mitophagy, with some proteins being evacuated to the ER to prevent unwanted apoptosis. PMID- 23361002 TI - Climate change patterns in Amazonia and biodiversity. AB - Precise characterization of hydroclimate variability in Amazonia on various timescales is critical to understanding the link between climate change and biodiversity. Here we present absolute-dated speleothem oxygen isotope records that characterize hydroclimate variation in western and eastern Amazonia over the past 250 and 20 ka, respectively. Although our records demonstrate the coherent millennial-scale precipitation variability across tropical-subtropical South America, the orbital-scale precipitation variability between western and eastern Amazonia exhibits a quasi-dipole pattern. During the last glacial period, our records imply a modest increase in precipitation amount in western Amazonia but a significant drying in eastern Amazonia, suggesting that higher biodiversity in western Amazonia, contrary to 'Refugia Hypothesis', is maintained under relatively stable climatic conditions. In contrast, the glacial-interglacial climatic perturbations might have been instances of loss rather than gain in biodiversity in eastern Amazonia, where forests may have been more susceptible to fragmentation in response to larger swings in hydroclimate. PMID- 23361003 TI - Interplay between myosin IIA-mediated contractility and actin network integrity orchestrates podosome composition and oscillations. AB - Tissue-resident dendritic cells patrol for foreign antigens while undergoing slow mesenchymal migration. Using actomyosin-based structures called podosomes, dendritic cells probe and remodel extracellular matrix topographical cues. Podosomes comprise an actin-rich protrusive core surrounded by an adhesive ring of integrins, cytoskeletal adaptor proteins and actin network filaments. Here we reveal how the integrity and dynamics of protrusive cores and adhesive rings are coordinated by the actomyosin apparatus. Core growth by actin polymerization induces podosome protrusion and provides tension within the actin network filaments. The tension transmitted to the ring recruits vinculin and zyxin and preserves overall podosome integrity. Conversely, myosin IIA contracts the actin network filaments and applies tension to the vinculin molecules bound, counterbalancing core growth and eventually reducing podosome size and protrusion. We demonstrate a previously unrecognized interplay between actin and myosin IIA in podosomes, providing novel mechanistic insights into how actomyosin based structures allow dendritic cells to sense the extracellular environment. PMID- 23361004 TI - Synthetic RNA devices to expedite the evolution of metabolite-producing microbes. AB - An extension of directed evolution strategies to genome-wide variations increases the chance of obtaining metabolite-overproducing microbes. However, a general high-throughput screening platform for selecting improved strains remains out of reach. Here, to expedite the evolution of metabolite-producing microbes, we utilize synthetic RNA devices comprising a riboswitch and a selection module that specifically sense inconspicuous metabolites. Using L-lysine-producing Escherichia coli as a model system, we demonstrated that this RNA device could enrich pathway-optimized strains to up to 75% of the total population after four rounds of enrichment cycles. Furthermore, the potential applicability of this device was examined by successfully extending its application to the case of L tryptophan. When used in conjunction with combinatorial mutagenesis for metabolite overproduction, our synthetic RNA device should facilitate strain improvement. PMID- 23361007 TI - Constraining timescales of focused magmatic accretion and extension in the Afar crust using lava geochronology. AB - As continental rift zones mature the tectonic and volcanic processes associated with crustal extension become confined to narrow magmatic rift zones, reminiscent of oceanic spreading ridges. The formation of these rift zones and the development of ocean-ridge type topography is a significant milestone in rift evolution as it signifies the localization of crustal extension and rift-related volcanism. Here we show that lavas, which erupted since ~200 ka along part of the on-land Red Sea rift system in Afar, Ethiopia, have a consistent age-progression from the rift axis outwards, indicating that axial dyke intrusion has been the primary mechanism of segment growth and that focused magmatic accretion and extension in the crust have remained stable here over this period. Our results suggest that as this rift segment has formed, in thinned and intruded continental crust, the time-averaged surface opening rate has closely approximated the total extension rate between Africa and Arabia. PMID- 23361005 TI - A platform pathway for production of 3-hydroxyacids provides a biosynthetic route to 3-hydroxy-gamma-butyrolactone. AB - The replacement of petroleum feedstocks with biomass to produce platform chemicals requires the development of appropriate conversion technologies. 3 Hydroxy-gamma-butyrolactone has been identified as one such chemical; however, there are no naturally occurring biosynthetic pathways for this molecule or its hydrolyzed form, 3,4-dihydroxybutyric acid. Here we design a novel pathway to produce various chiral 3-hydroxyacids, including 3,4-dihydroxybutyric acid, consisting of enzymes that condense two acyl-CoAs, stereospecifically reduce the resulting beta-ketone and hydrolyze the CoA thioester to release the free acid. Acetyl-CoA serves as one substrate for the condensation reaction, whereas the second is produced intracellularly by a pathway enzyme that converts exogenously supplied organic acids. Feeding of butyrate, isobutyrate and glycolate results in the production of 3-hydroxyhexanoate, 3-hydroxy-4-methylvalerate and 3,4 dihydroxybutyric acid+3-hydroxy-gamma-butyrolactone, respectively, molecules with potential uses in applications from materials to medicines. We also unexpectedly observe the condensation reaction resulting in the production of the 2,3 dihydroxybutyric acid isomer, a potential value-added monomer. PMID- 23361006 TI - Spatial association with PTEX complexes defines regions for effector export into Plasmodium falciparum-infected erythrocytes. AB - Export of proteins into the infected erythrocyte is critical for malaria parasite survival. The majority of effector proteins are thought to export via a proteinaceous translocon, resident in the parasitophorous vacuole membrane surrounding the parasite. Identification of the Plasmodium translocon of exported proteins and its biochemical association with exported proteins suggests it performs this role. Direct evidence for this, however, is lacking. Here using viable purified Plasmodium falciparum merozoites and three-dimensional structured illumination microscopy, we investigate remodelling events immediately following parasite invasion. We show that multiple complexes of the Plasmodium translocon of exported proteins localize together in foci that dynamically change in clustering behaviour. Furthermore, we provide conclusive evidence of spatial association between exported proteins and exported protein 2, a core component of the Plasmodium translocon of exported proteins, during native conditions and upon generation of translocation intermediates. These data provide the most direct cellular evidence to date that protein export occurs at regions of the parasitophorous vacuole membrane housing the Plasmodium translocon of exported proteins complex. PMID- 23361008 TI - Plant tumour biocontrol agent employs a tRNA-dependent mechanism to inhibit leucyl-tRNA synthetase. AB - Leucyl-tRNA synthetases (LeuRSs) have an essential role in translation and are promising targets for antibiotic development. Agrocin 84 is a LeuRS inhibitor produced by the biocontrol agent Agrobacterium radiobacter K84 that targets pathogenic strains of A. tumefaciens, the causative agent of plant tumours. Agrocin 84 acts as a molecular Trojan horse and is processed inside the pathogen into a toxic moiety (TM84). Here we show using crystal structure, thermodynamic and kinetic analyses, that this natural antibiotic employs a unique and previously undescribed mechanism to inhibit LeuRS. TM84 requires tRNA(Leu) for tight binding to the LeuRS synthetic active site, unlike any previously reported inhibitors. TM84 traps the enzyme-tRNA complex in a novel 'aminoacylation-like' conformation, forming novel interactions with the KMSKS loop and the tRNA 3'-end. Our findings reveal an intriguing tRNA-dependent inhibition mechanism that may confer a distinct evolutionary advantage in vivo and inform future rational antibiotic design. PMID- 23361009 TI - Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals. AB - The SNP rs12252-C allele alters the function of interferon-induced transmembrane protein-3 increasing the disease severity of influenza virus infection in Caucasians, but the allele is rare. However, rs12252-C is much more common in Han Chinese. Here we report that the CC genotype is found in 69% of Chinese patients with severe pandemic influenza A H1N1/09 virus infection compared with 25% in those with mild infection. Specifically, the CC genotype was estimated to confer a sixfold greater risk for severe infection than the CT and TT genotypes. More importantly, because the risk genotype occurs with such a high frequency, its effect translates to a large population-attributable risk of 54.3% for severe infection in the Chinese population studied compared with 5.4% in Northern Europeans. Interferon-induced transmembrane protein-3 genetic variants could, therefore, have a strong effect of the epidemiology of influenza in China and in people of Chinese descent. PMID- 23361010 TI - Composite-pulse magnetometry with a solid-state quantum sensor. AB - The sensitivity of quantum magnetometer is challenged by control errors and, especially in the solid state, by their short coherence times. Refocusing techniques can overcome these limitations and improve the sensitivity to periodic fields, but they come at the cost of reduced bandwidth and cannot be applied to sense static or aperiodic fields. Here we experimentally demonstrate that continuous driving of the sensor spin by a composite pulse known as rotary-echo yields a flexible magnetometry scheme, mitigating both driving power imperfections and decoherence. A suitable choice of rotary-echo parameters compensates for different scenarios of noise strength and origin. The method can be applied to nanoscale sensing in variable environments or to realize noise spectroscopy. In a room-temperature implementation, based on a single electronic spin in diamond, composite-pulse magnetometry provides a tunable trade-off between sensitivities in the MUTHz(-1/2) range, comparable with those obtained with Ramsey spectroscopy, and coherence times approaching T(1). PMID- 23361011 TI - Motional averaging in a superconducting qubit. AB - Superconducting circuits with Josephson junctions are promising candidates for developing future quantum technologies. Of particular interest is to use these circuits to study effects that typically occur in complex condensed-matter systems. Here we employ a superconducting quantum bit--a transmon--to perform an analogue simulation of motional averaging, a phenomenon initially observed in nuclear magnetic resonance spectroscopy. By modulating the flux bias of a transmon with controllable pseudo-random telegraph noise we create a stochastic jump of its energy level separation between two discrete values. When the jumping is faster than a dynamical threshold set by the frequency displacement of the levels, the initially separate spectral lines merge into a single, narrow, motional-averaged line. With sinusoidal modulation a complex pattern of additional sidebands is observed. We show that the modulated system remains quantum coherent, with modified transition frequencies, Rabi couplings, and dephasing rates. These results represent the first steps towards more advanced quantum simulations using artificial atoms. PMID- 23361012 TI - The essential role of carefully optimized synthesis for elucidating intrinsic material properties of (Ga,Mn)As. AB - (Ga,Mn)As is at the forefront of spintronics research exploring the synergy of ferromagnetism with the physics and the technology of semiconductors. However, the electronic structure of this model spintronics material has been debated and the systematic and reproducible control of the basic micromagnetic parameters and semiconducting doping trends has not been established. Here we show that seemingly small departures from the individually optimized synthesis protocols yield non-systematic doping trends, extrinsic charge and moment compensation, and inhomogeneities that conceal intrinsic properties of (Ga,Mn)As. On the other hand, we demonstrate reproducible, well controlled and microscopically understood semiconducting doping trends and micromagnetic parameters in our series of carefully optimized epilayers. Hand-in-hand with the optimization of the material synthesis, we have developed experimental capabilities based on the magneto optical pump-and-probe method that allowed us to simultaneously determine the magnetic anisotropy, Gilbert damping and spin stiffness constants from one consistent set of measured data. PMID- 23361013 TI - FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress. AB - The molecular events occurring following the disruption of DNA replication forks are poorly characterized, despite extensive use of replication inhibitors such as hydroxyurea in the treatment of malignancies. Here, we identify a key role for the FBH1 helicase in mediating DNA double-strand break formation following replication inhibition. We show that FBH1-deficient cells are resistant to killing by hydroxyurea, and exhibit impaired activation of the pro-apoptotic factor p53, consistent with decreased DNA double-strand break formation. Similar findings were obtained in murine ES cells carrying disrupted alleles of Fbh1. We also show that FBH1 through its helicase activity co-operates with the MUS81 nuclease in promoting the endonucleolytic DNA cleavage following prolonged replication stress. Accordingly, MUS81 and EME1-depleted cells show increased resistance to the cytotoxic effects of replication stress. Our data suggest that FBH1 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA double-strand breaks. PMID- 23361015 TI - Quality and spaghetti sauce. PMID- 23361016 TI - More about medical students' attendance at lectures. PMID- 23361017 TI - More about medical students' attendance at lectures. PMID- 23361018 TI - Clinical decision making: the need for meaningful research. PMID- 23361019 TI - Clinical decision making: the need for meaningful research. PMID- 23361020 TI - The possible impact of the MMI and GPA on diversity. PMID- 23361021 TI - The possible impact of the MMI and GPA on diversity. PMID- 23361014 TI - The evolution and pathogenic mechanisms of the rice sheath blight pathogen. AB - Rhizoctonia solani is a major fungal pathogen of rice (Oryza sativa L.) that causes great yield losses in all rice-growing regions of the world. Here we report the draft genome sequence of the rice sheath blight disease pathogen, R. solani AG1 IA, assembled using next-generation Illumina Genome Analyser sequencing technologies. The genome encodes a large and diverse set of secreted proteins, enzymes of primary and secondary metabolism, carbohydrate-active enzymes, and transporters, which probably reflect an exclusive necrotrophic lifestyle. We find few repetitive elements, a closer relationship to Agaricomycotina among Basidiomycetes, and expand protein domains and families. Among the 25 candidate pathogen effectors identified according to their functionality and evolution, we validate 3 that trigger crop defence responses; hence we reveal the exclusive expression patterns of the pathogenic determinants during host infection. PMID- 23361022 TI - The possible impact of the MMI and GPA on diversity. PMID- 23361023 TI - Addressing the need for more trainees in psychiatry. PMID- 23361024 TI - Addressing the need for more trainees in psychiatry. PMID- 23361025 TI - Training community-engaged researchers. PMID- 23361026 TI - A makeover for primary care. PMID- 23361027 TI - Commentary: Team science. AB - A revolution in biomedical science is under way, and participation demands the successful integration of new technologies and concepts drawn from many fields, including but not limited to the biologic sciences, the physical sciences, and engineering. This integration, often called team, or interdisciplinary, science, is easy to conceive but surprisingly hard to achieve. The authors reflect on the emerging ways teams assemble, confront institutional and cultural barriers, and integrate trainees. They focus in particular on the article by Ravid and colleagues in this issue of Academic Medicine, which describes three years of their institution's successful experiment to foster interdisciplinary science.The authors acknowledge the impressive outcomes of this experiment but state that the research community should be thinking down the road of ways to evaluate whether the output from team-based science actually has more impact in changing paradigms and opening up new avenues of research; whether more risk-taking science is being performed when science is team based; whether there are fundamental implications for the organization of academic health systems, schools, and departments; what the implications are for training our students; and what the short- and long-term implications are for investigator reward and development. PMID- 23361028 TI - Commentary: What are the benefits of training deaf and hard-of-hearing doctors? AB - Deaf and hard-of-hearing (DHoH) individuals are underrepresented among physicians and physicians-in-training, yet this group is frequently overlooked in the diversity efforts of many medical training programs. The inclusion of DHoH individuals, with their diverse backgrounds, experiences, and struggles, contributes to medical education and health care systems in a variety of ways, including (1) a richer medical education experience for students and faculty resulting in greater disability awareness and knowledge about how to interact with and care for DHoH individuals and their families, (2) the provision of empathetic care desired by many patients and their families, including individuals who have a disability or chronic condition, and (3) the promotion of a more supportive and accessible professional environment for physicians, including older physicians in practice and as educators, who are experiencing age associated decreased hearing acuity or other acquired disabilities.Today, many qualified DHoH individuals face barriers to pursuing medical careers even while physicians who become DHoH can continue to practice medicine. These barriers still exist two decades after the implementation of the Americans with Disabilities Act of 1990 and despite technological advancements and changing attitudes. In light of the findings by Moreland and colleagues, the authors of this commentary discuss reasons to include DHoH individuals in the physician workforce, explain why this group remains underrepresented among physicians, and suggest ways that medical schools and training programs can ensure fair application processes and inclusive educational opportunities for work with DHoH students who are interested in health care careers. PMID- 23361029 TI - Artist's statement: puzzled. PMID- 23361030 TI - Medicine and the arts. The myth of Philoctetes: retold by Sophocles (translated by Hugh Lloyd-Jones). Commentary. PMID- 23361032 TI - Teaching and learning moments: the other hidden curriculum. PMID- 23361033 TI - Evaluation of efficacy of probiotics in prevention of candida colonization in a PICU-a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of probiotics in prevention of Candida colonization in a PICU. DESIGN: Prospective double blinded, randomized controlled trial. SETTING: PICU of a tertiary care teaching hospital in north India. SUBJECTS: One hundred fifty children (106 boys, 44 girls), 3 months to 12 yrs old, on broad spectrum antibiotics for at least 48 hrs were randomized using computer-generated random numbers to receive probiotic mix (EUGI) (n = 75) or placebo (n = 75). INTERVENTION: Patients received one sachet twice a day of either probiotics or placebo for 7 days. Probiotics contained Lactobacillus acidophillus, Lactobacillus rhamnosum, Bifidobacterium longum, Bifidobacterium bifidum, Saccharomyces boulardi, Saccharomyces thermophilus, fructo oligosaccharides; and placebo-contained lactose packed in similar-looking sachets. Rectal swabs for fungal culture were taken at day 0, 7, and 14 of enrollment. Primary outcome measure was prevalence of rectal colonization with Candida on day 14 postenrollment; secondary outcomes were growth of Candida in urine (candiduria) and blood (candidemia). Patients were followed until completion of 14 days study period or death of patient. RESULTS: Demographic and clinical variables were comparable in two groups. Prevalence of Candida colonization on day 0 was similar (15 of 75) in both the groups. On day 7, 27.9% (19 of 68) patients in the probiotic group and 42.6% (29 of 68) patients in the placebo group were colonized (relative risk 0.65; 95% confidence interval 0.41 1.05; p = 0.07), whereas, on day 14, colonization was observed in 31.3% (21 of 67) patients in the probiotic group and 50% (34 of 68) in the placebo group (relative risk 0.63; 95% confidence interval 0.41-0.96; p = 0.02). Thus, the relative reduction in prevalence of Candida colonization on day 7 and 14 in the probiotic group was 34.5% and 37.2%, respectively. The increase in number of colonized patients from day 0 to 7 and day 0 to 14 was significant in the placebo group (p = 0.004 and 0.001, respectively) but not in the probiotic group (p = 0.30 and 0.19, respectively; McNemar test). Candiduria was significantly less common in the probiotic group than in the placebo group (17.3% vs. 37.3%; relative risk 0.46; 95% confidence interval 0.26-0.82; p = 0.006). However, prevalence of candidemia did not differ significantly in two groups (1.6% in the probiotic group vs. 6.35% in placebo group; relative risk 0.46; 95% confidence interval 0.08-2.74; p = 0.39). CONCLUSIONS: Supplementation with probiotics could be a potential strategy to reduce gastrointestinal Candida colonization and candiduria in critically ill children receiving broad spectrum antibiotics. PMID- 23361034 TI - Synthesis of nanostructured copper oxide via oxalate precursors and their sensing properties for hydrogen cyanide gas. AB - In this work, nanostructured copper oxide of varied morphologies and high surface area were prepared by calcination of copper oxalate precursors, and were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, thermogravimetric analysis and differential thermal analysis, and nitrogen adsorption-desorption measurements. The sphere-like CuO (specific surface area: 73 m(2) g(-1)) functionalized QCM resonators were fabricated and explored for HCN sensing. The sensitivity (10 s HCN exposure) of sphere-like CuO functionalized QCM resonators reached as high as 6.53 Hz MUg(-1). The reproducibility and stability of sphere-like CuO functionalized QCM resonators was excellent, and the selectivity was very high with a converse response to examined common chemicals. The high surface area CuO functionalized QCM sensors may be applicable for HCN gas sensing. PMID- 23361035 TI - Cordycepin (3'-deoxyadenosine) pentostatin (deoxycoformycin) combination treatment of mice experimentally infected with Trypanosoma evansi. AB - The aim of this study was to evaluate the anti-trypanosomal effect of treatment with 3'-deoxyadenosine (cordycepin) combined with deoxycoformycin (pentostatin: inhibitor of the enzyme adenosine deaminase) in vitro by using mice experimentally infected with Trypanosoma evansi. In vitro, a dose-dependent trypanocidal effect of cordycepin was observed against the parasite. In the in vivo trials, the two drugs were used individually and in combination of different doses. The drugs when used individually had no curative effect on infected mice. However, the combination of cordycepin (2 mg kg-1) and pentostatin (2 mg kg-1) was 100% effective in the T. evansi-infected groups. There was an increase in levels of some biochemical parameters, especially on liver enzymes, which were accompanied by histological lesions in the liver and kidneys. Based on these results we conclude that treatment using the combination of 3'-deoxyadenosine with deoxycoformycin has a curative effect on mice infected with T. evansi. However, the therapeutic protocol tested led to liver and kidney damage, manifested by hepatotoxicity and nephrotoxicity. PMID- 23361038 TI - Nano- and microsized Eu(3+) and Tb(3+)-doped lanthanide hydroxycarbonates and oxycarbonates. The influence of glucose and fructose as stabilizing ligands. AB - Europium and terbium-doped lanthanum hydroxycarbonate and lanthanum oxycarbonate nanoparticles were fabricated under two different reaction conditions using lanthanide acetate and urea as the starting materials. The photoluminescence properties of these hydroxycarbonate and oxycarbonate particles, and of their colloidal suspensions in water, were studied. The Eu(3+) (5)D(0)->(7)F(J) and Tb(3+) (5)D(4)->(7)F(J) emission spectra and the luminescence lifetimes in the two carbonate matrices were measured. Terbium-doped cerium oxycarbonate particles were synthesized, and the energy transfer process from Ce(3+) to Tb(3+) was investigated. The synthesis of lanthanum and cerium oxycarbonates was also carried out in the presence of stabilizing ligands: glucose and fructose. The influence of these ligands on the structure and luminescence was explored. PMID- 23361036 TI - Protein tyrosine phosphatase receptor type O (Ptpro) regulates cerebellar formation during zebrafish development through modulating Fgf signaling. AB - Protein activities controlled by receptor protein tyrosine phosphatases (RPTPs) play comparably important roles in transducing cell surface signals into the cytoplasm by protein tyrosine kinases. Previous studies showed that several RPTPs are involved in neuronal generation, migration, and axon guidance in Drosophila, and the vertebrate hippocampus, retina, and developing limbs. However, whether the protein tyrosine phosphatase type O (ptpro), one kind of RPTP, participates in regulating vertebrate brain development is largely unknown. We isolated the zebrafish ptpro gene and found that its transcripts are primarily expressed in the embryonic and adult central nervous system. Depletion of zebrafish embryonic Ptpro by antisense morpholino oligonucleotide knockdown resulted in prominent defects in the forebrain and cerebellum, and the injected larvae died on the 4th day post-fertilization (dpf). We further investigated the function of ptpro in cerebellar development and found that the expression of ephrin-A5b (efnA5b), a Fgf signaling induced cerebellum patterning factor, was decreased while the expression of dusp6, a negative-feedback gene of Fgf signaling in the midbrain hindbrain boundary region, was notably induced in ptpro morphants. Further analyses demonstrated that cerebellar defects of ptpro morphants were partially rescued by inhibiting Fgf signaling. Moreover, Ptpro physically interacted with the Fgf receptor 1a (Fgfr1a) and dephosphorylated Fgfr1a in a dose-dependant manner. Therefore, our findings demonstrate that Ptpro activity is required for patterning the zebrafish embryonic brain. Specifically, Ptpro regulates cerebellar formation during zebrafish development through modulating Fgf signaling. PMID- 23361039 TI - Graphenes prepared from multi-walled carbon nanotubes and stacked graphene nanofibers for detection of 2,4,6-trinitrotoluene (TNT) in seawater. AB - The study on explosive materials is paramount due to the potential hazards to national security and health. When disposed of, explosives can cause seawater pollution. The detection of 2,4,6-trinitrotoluene (TNT) in seawater has been examined on two different forms of graphene, mainly graphene prepared from the unzipping of multi-walled carbon nanotubes (MWCNTs) and from the exfoliation of stacked graphene nanofibers (SGNFs). Graphene sheets prepared from MWCNTs exhibited sheet dimensions of 5000 * 300 nm, while graphene prepared from SGNFs exhibited sheet dimensions of 50 * 50 nm. Graphene prepared from MWCNTs was found to exhibit a higher order of sensitivity than the one prepared from nanofibers in both borate buffer solution and seawater. We demonstrate that it is of high importance to study different sources and methods of preparation of graphenes for analytical chemistry applications. PMID- 23361040 TI - Tritium in Japanese precipitation following the March 2011 Fukushima Daiichi Nuclear Plant accident. AB - Tritium concentrations in Japanese precipitation samples collected after the March 2011 accident at the Fukushima Dai-ichi Nuclear Power Plant (FNPP1) were measured. Values exceeding the pre-accident background were detected at three out of seven localities (Tsukuba, Kashiwa and Hongo) southwest of the FNPP1 at distances varying between 170 and 220 km from the source. The highest tritium content was found in the first rainfall in Tsukuba after the accident; however concentrations were 500 times less than the regulatory limit for tritium in drinking water. Tritium concentrations decreased steadily and rapidly with time, becoming indistinguishable from the pre-accident values within five weeks. The atmospheric tritium activities in the vicinity of the FNPP1 during the earliest stage of the accident was estimated to be 1.5*10(3) Bq/m(3), which is potentially capable of producing rainwater exceeding the regulatory limit, but only in the immediate vicinity of the source. PMID- 23361037 TI - Mechanisms of Mediator complex action in transcriptional activation. AB - Mediator is a large multisubunit complex that plays a central role in the regulation of RNA Pol II transcribed genes. Conserved in overall structure and function among eukaryotes, Mediator comprises 25-30 protein subunits that reside in four distinct modules, termed head, middle, tail, and CDK8/kinase. Different subunits of Mediator contact other transcriptional regulators including activators, co-activators, general transcription factors, subunits of RNA Pol II, and specifically modified histones, leading to the regulated expression of target genes. This review is focused on the interactions of specific Mediator subunits with diverse transcription regulators and how those interactions contribute to Mediator function in transcriptional activation. PMID- 23361041 TI - Toxic effects of ZnO nanoparticles towards marine algae Dunaliella tertiolecta. AB - Dose response curve and population growth rate alterations of marine Chlorophyte Dunaliella tertiolecta derived from the exposure to ZnO nanoparticles were evaluated. Bulk ZnO and ionic zinc were also investigated for comparison. At the same time, the aggregation state and particle size distribution were monitored. The evaluated 50% effect concentration (EC50 1.94 [0.78-2.31] mg Zn L(-1)) indicates that nano ZnO is more toxic than its bulk counterpart (EC50 3.57 [2.77 4.80] mg Zn L(-1)). Cross-referencing the toxicity parameters calculated for ZnCl(2) (EC50 0.65 [0.36-0.70] mg Zn L(-1)) and the dissolution properties of the ZnO, it can be gathered that the higher toxicity of nano ZnO is most likely related to the peculiar physicochemical properties of the nanostate with respect to the bulk material. Furthermore growth rate of D. tertiolecta was significantly affected by nano ZnO exposure. Our findings suggest that the primary particle size of the dispersed particles affect the overall toxicity. PMID- 23361042 TI - Contribution of microorganisms to non-extractable residue formation during biodegradation of ibuprofen in soil. AB - Non-extractable residues (NER) formed during biodegradation of organic contaminants in soil are considered to be mainly composed of parent compounds or their primary metabolites with hazardous potential. However, in the case of biodegradable organic compounds, the soil NER may also contain microbial biomass components, for example fatty acids (FA) and amino acids (AA). After cell death, these biomolecules are subsequently incorporated into non-living soil organic matter (SOM) and are stabilised ultimately forming hardly extractable residues of biogenic origin. We investigated biodegradation of (13)C(6)-ibuprofen, in particular the metabolic incorporation of the (13)C-label into FA and AA and their fate in soil over 90 days. (13)C-FA and (13)C-AA amounts in the living microbial biomass fraction initially increased, then decreased over time and were continuously incorporated into the non-living SOM pool. The (13)C-FA in the non living SOM remained stable from day 59 whereas the contents of (13)C-AA slightly increased until the end. After 90 days, nearly all NER were biogenic as they were made up almost completely by natural biomass compounds. The presented data demonstrated that the potential environmental risks related to the ibuprofen derived NER are overestimated. PMID- 23361043 TI - Dual-nanogold-linked bio-barcodes with superstructures for in situ amplified electronic detection of low-abundance proteins. AB - A novel and nonenzyme immunosensing protocol is proposed for ultrahighly sensitive detection of low-abundance-proteins (carcinoembryonic antigen as a model) using dual nanogold-linked complementary bio-barcodes with superstructures for in situ amplified electronic signals. PMID- 23361044 TI - Asymmetric reversal in aged high concentration CuMn alloy. AB - The magnetic hysteresis loops of an aged Cu(81.2)Mn(18.8) alloy sample exhibit significant asymmetric reversal at low temperatures, with high sensitivity to the cooling field. Much of the observed behaviour was explained by considering an ensemble of coherent, ferromagnetically aligned clusters interacting with a randomized spin glass component. A modified Stoner-Wohlfarth model was successfully applied to the data using Monte Carlo simulations, in order to gain insight into the dependence of the cluster shape anisotropy and exchange anisotropy on the cooling field. This model suggested that ferromagnetic clusters grow as the cooling field increases. PMID- 23361045 TI - Highlights in clinical autonomic neuroscience: Autonomic correlates of social cognition. AB - Human beings by nature are relational and in relating to others modulate their autonomic responses. Interpersonal relationships may be stressful or calming depending on social contexts, individual temperaments and personality traits. Not only human relationships, but also interactions with affectionate pets and virtual relationships via social networking technology can elicit autonomic responses. These responses range from sympathetic arousal to vagal modulation of cardiovascular activity, and from changes in energy intake and expenditure to modification of physical exercise habits, all of which have potential implications for health and well-being. PMID- 23361046 TI - Rapid detection of several foodborne pathogens by F0F1-ATPase molecular motor biosensor. AB - F0F1-ATPase within chromatophore was constructed as a molecular motor biosensor through epsilon-subunit antibody-biotin-streptavidin-biotin-AC5-Sulfo-Osu system. Based on probe-DNA specific binding, DNA of several foodborne pathogens Listeria monocytogenes, Salmonella typhimurium, Vibrio parahaemolyticus and Vibrio cholerae was specifically captured by F0F1-ATPase molecular motor biosensors. Loads of DNA decreased the rotation rate of F0F1-ATPase, and led to the decrease of ATP synthesis. The detection of pathogens based on proton flux change driven by ATP-synthesis of F0F1-ATPase, which was indicated by F-DHPE, was monitored by a fluorescence spectrometer. The results demonstrate that the F0F1-ATPase molecular motor biosensor can specifically detect bacterial DNA at low concentration level, and will be a convenient, quick, and promising tool for detecting pathogens. PMID- 23361047 TI - Evaluation of formalin-ether sedimentation and trichrome staining techniques: its effectiveness in detecting Entamoeba histolytica/dispar/moshkovskii in stool samples. AB - This study was conducted to evaluate two routinely microscopic diagnostic methods in comparison with single-round PCR assay as the reference technique to detect Entamoeba histolytica/dispar/moshkovskii. Examination was performed on 500 stool samples obtained from Orang Asli communities in different states of Malaysia using formalin-ether sedimentation, trichrome staining and single-round PCR techniques. Ninety-three stool samples were detected E. histolytica/dispar/moshkovskii positive by routine microscopy, while single-round PCR detected 106 positive samples. Additional positives detected by PCR assay were eventually confirmed to be negative by both microscopic techniques. Detection rate of E. histolytica/dispar/moshkovskii was highest in combination techniques (18.6%), followed by trichrome staining (13.4%) and formalin-ether sedimentation (11.2%) techniques. Single-round PCR detected 21.2% of the stool samples. The sensitivity and specificity of formalin-ether sedimentation and trichrome staining techniques compared to the reference technique were 31.1% (95% CI: 29.0-36.0) and 94.2% (95% CI: 89.8-98.9), and 53.8% (95% CI: 46.0-76.2) and 97.5% (95% CI: 92.8-99.1), respectively. However, the sensitivity [59.4% (95% CI: 48.9-78.5)] of the method increased when both techniques were performed together, but the specificity decreased to 92.4% (95% CI: 81.0-98.0). The agreement between the reference technique, trichrome staining and combination techniques were statistically significant by Kappa statistics (trichrome staining: K = 0.592, p < 0.05; combination techniques: K = 0.543, p < 0.05). Hence, the combination technique is recommended to be used as a screening method in the diagnosis of E. histolytica/dispar/moshkovskii infections either for clinical or epidemiological study. PMID- 23361048 TI - Expert opinion: should stress myocardial perfusion MRI be routinely added to delayed enhancement cardiac MRI studies? PMID- 23361049 TI - Common genetic variants in the 9p21 region and their associations with multiple tumours. AB - BACKGROUND: The chromosome 9p21.3 region has been implicated in the pathogenesis of multiple cancers. METHODS: We systematically examined up to 203 tagging SNPs of 22 genes on 9p21.3 (19.9-32.8 Mb) in eight case-control studies: thyroid cancer, endometrial cancer (EC), renal cell carcinoma, colorectal cancer (CRC), colorectal adenoma (CA), oesophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma and osteosarcoma (OS). We used logistic regression to perform single SNP analyses for each study separately, adjusting for study specific covariates. We combined SNP results across studies by fixed-effect meta analyses and a newly developed subset-based statistical approach (ASSET). Gene based P-values were obtained by the minP method using the Adaptive Rank Truncated Product program. We adjusted for multiple comparisons by Bonferroni correction. RESULTS: Rs3731239 in cyclin-dependent kinase inhibitors 2A (CDKN2A) was significantly associated with ESCC (P=7 * 10(-6)). The CDKN2A-ESCC association was further supported by gene-based analyses (Pgene=0.0001). In the meta-analyses by ASSET, four SNPs (rs3731239 in CDKN2A, rs615552 and rs573687 in CDKN2B and rs564398 in CDKN2BAS) showed significant associations with ESCC and EC (P<2.46 * 10(-4)). One SNP in MTAP (methylthioadenosine phosphorylase) (rs7023329) that was previously associated with melanoma and nevi in multiple genome-wide association studies was associated with CRC, CA and OS by ASSET (P=0.007). CONCLUSION: Our data indicate that genetic variants in CDKN2A, and possibly nearby genes, may be associated with ESCC and several other tumours, further highlighting the importance of 9p21.3 genetic variants in carcinogenesis. PMID- 23361050 TI - Study populations for period analyses of cancer survival. AB - BACKGROUND: Period analysis is increasingly used to compute long-term cancer survival, as it provides better prediction of survival of newly diagnosed patients than traditional cohort analysis. However, the patient population to which period survival estimates best pertain to and which should be described in a study is less obvious. METHODS: Using Finnish Cancer Registry data on 23 common cancer sites, age-standardized period estimates of 5-, 10-, 15-, and 20-year relative survival were computed for each 2-, 5-, and 10-year calendar period in 1954-2003 and compared with survival estimates for two cohorts by means of mean, mean absolute and mean squared differences: a full cohort of all patients potentially contributing some data to the survival analysis and a restricted cohort of patients diagnosed in the period of interest. RESULTS: In most computations, survival estimates for the full cohorts were on average closer to the period estimates for the majority of cancer sites. For 10-year survival, results were less obvious with respect to the mean difference. However, mean squared and mean absolute differences were smaller for the majority of cancers when using the full cohort. CONCLUSION: Our results suggest that the full cohort should be described in reports of period survival analysis. PMID- 23361051 TI - A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma. AB - BACKGROUND: This phase 2 study evaluated trebananib (AMG 386), an investigational peptide-Fc fusion protein that neutralises the interaction between angiopoietins 1/2 and the Tie2 receptor, plus FOLFIRI as second-line treatment for patients with metastatic colorectal cancer. METHODS: Patients had adenocarcinoma of the colon or rectum with progression within 6 months of receiving only one prior fluoropyrimidine/oxaliplatin-based chemotherapy regimen for metastatic disease. All patients received FOLFIRI and were randomised 2:1 to also receive intravenous trebananib 10 mg kg(-1) once weekly (QW) (Arm A) or placebo QW (Arm B). The primary end point was investigator-assessed progression-free survival (PFS). RESULTS: One hundred and forty-four patients were randomised (Arms A/B, n=95/49). Median PFS in Arms A and B was 3.5 and 5.2 months (hazard ratio (HR) 1.23; 95% CI, 0.81-1.86; P=0.33) and median overall survival (OS) was 11.9 and 8.8 months, respectively (HR 0.90; 95% CI; 0.53-1.54; P=0.70). Objective response rate (ORR) was 14% and 0% in Arms A and B, respectively. Incidence of grade >=3 adverse events was similar between treatment arms (Arm A, 61%; Arm B, 65%) and included pulmonary embolism (1%/4%), deep vein thrombosis (5%/2%), and hypertension (1%/0%). CONCLUSION: Administration of trebananib plus FOLFIRI did not prolong PFS compared with placebo plus FOLFIRI. Toxicities were manageable and consistent with those known for FOLFIRI and trebananib. PMID- 23361052 TI - The expression of Axl receptor tyrosine kinase influences the tumour phenotype and clinical outcome of patients with malignant pleural mesothelioma. AB - BACKGROUND: Recent preclinical studies identified Axl, a tyrosine kinase receptor implicated in tumour progression and epithelial-to-mesenchymal transition, as a putative therapeutic target in malignant pleural mesothelioma (MPM), an invariably fatal malignancy with limited treatment options. Here, we studied the expression of Axl and its ligand Gas-6 (growth arrest signal-6) in primary specimens of MPM, correlating their expression levels with tumour phenotype and clinical outcomes. METHODS: Two independent cohorts of consecutive patients diagnosed with MPM were studied: a derivation cohort composed of 63 cases and a validation set of 35 cases. Clinical variables including patients' demographics, tumour stage, histotype, performance status (PS), Axl and Gas-6 staining were tested for predicting overall survival (OS) using univariate and multivariate analyses. RESULTS: In the derivation cohort, Axl (P=0.001) but not Gas-6 overexpression (P=0.35) emerged as a univariate prognostic factor for OS, together with stage (P=0.05), PS (P<0.001) hypoalbuminaemia (P<0.001) and anaemia (P<0.001). Multivariate analyses confirmed Axl overexpression (P=0.01), PS (P=0.01), hypoalbuminaemia (P<0.001) and anaemia (P=0.04) as independent predictors of OS. The prognostic role of Axl overexpression was externally validated in an independent cohort (P=0.03). CONCLUSION: Overexpression of Axl is found in the majority of MPM specimens and influences patient's survival independently from other established prognostic factors. Such information may support patient selection for future trials. PMID- 23361053 TI - Regulation of tamoxifen sensitivity by a PAK1-EBP1 signalling pathway in breast cancer. AB - BACKGROUND: EBP1, an ErbB3-binding protein, sensitises breast cancer cells to tamoxifen in part by decreasing ErbB2 protein levels. The p21-regulated serine/threonine kinase PAK1, implicated in tamoxifen resistance, phosphorylates EBP1 in vitro and in vivo at T261. Phosphorylation of EBP1 at this site induces tamoxifen resistance. We thus postulated that inhibition of PAK1 activity, by restoring EBP1 function, could ameliorate the hormone refractory phenotype of ErbB2-overexpressing breast cancer cells. METHODS: Effects of EBP1 on ErbB2 levels were measured by western blotting. Effects of EBP1 and IPA-3 on tamoxifen sensitivity were measured using a tetrazolium based cell viability assay. RESULTS: Transient transfection studies indicated that an EBP1 T261E mutant, which mimics EPB1 phosphorylated by PAK1, increased ErbB2 protein levels. An EBP1 T261A mutant, unable to be phosphorylated by PAK1, ameliorated PAK1-induced tamoxifen resistance, suggesting that phosphorylation of EBP1 by PAK1 contributes to tamoxifen resistance. We then tested if pharmacological inhibition of PAK1 activity might render hormone resistant cells, which endogenously overexpress PAK1, tamoxifen sensitive. IPA-3, a specific small MW PAK1 inhibitor, sensitised cells to tamoxifen only when EBP1 was ectopically expressed. IPA had no effect on tamoxifen resistance in T47D cells in which EBP1 protein had been ablated by shRNA. The IPA-induced increase in tamoxifen sensitivity was accompanied by a decrease in ErbB2 levels only in EBP1-overexpressing cells. CONCLUSION: These studies suggest that phosphorylation of EBP1 may be one mechanism of PAK1-induced hormone resistance and that PAK1 inhibitors may be useful in cells in which EBP1 is overexpressed. PMID- 23361054 TI - The risk of a subsequent cancer diagnosis after herpes zoster infection: primary care database study. AB - BACKGROUND: Herpes zoster and cancer are associated with immunosuppression. Zoster occurs more often in patients with an established cancer diagnosis. Current evidence suggests some risk of cancer after zoster but is inconclusive. We aimed to assess the risk of cancer following zoster and the impact of prior zoster on cancer survival. METHODS: A primary care database retrospective cohort study was undertaken. Subjects with zoster were matched to patients without zoster. Risk of cancer following zoster was assessed by generating hazard ratios using Cox regression. Time to cancer was generated from the index date of zoster diagnosis. RESULTS: In total, 2054 cancers were identified in 74,029 patients (13,428 zoster, 60,601 matches). The hazard ratio for cancer diagnosis after zoster was 2.42 (95% confidence interval 2.21, 2.66) and the median time to cancer diagnosis was 815 days. Hazard ratios varied between cancers, and were highest in younger patients. There were more cancers in patients with zoster than those without for all age groups and both genders. Prior immunosuppression was not associated with change in risk, and diagnosis of zoster before cancer did not affect survival. CONCLUSION: This study establishes an association between zoster and future diagnosis of cancer having implications for cancer case finding after zoster diagnosis. PMID- 23361055 TI - A comprehensive assessment of the impact of errors in the cancer registration process on 1- and 5-year relative survival estimates. AB - BACKGROUND: When making international comparisons of cancer survival, it is essential reported differences are real effects and not an artefact of potential errors in cancer registration. METHODS: We use simulation methods to assess the impact of various cancer registration errors on commonly reported outcomes of cancer survival (1-, and 5-year relative survival estimates). We draw two samples of patients diagnosed with cancer from one population and introduce potential registration errors in one of the sample populations under various assumptions. We investigate the effect of errors individually as well as the composite effect when combined with other registration errors. RESULTS: The results indicate that high levels of cancer registration errors are necessary to make a noticeable effect on commonly reported metrics of cancer survival. Differences of up to 3 percentage units in the 5-year relative survival proportion are seen under plausible scenarios. CONCLUSION: This study is a comprehensive assessment of cancer registration errors and the consequent impact on commonly reported survival statistics. We show that under plausible scenarios, it is very unlikely that these biases are large enough to explain the variation in international comparisons of cancer survival. Registration errors will also impact on other metrics reported from registry data, such as incidence. PMID- 23361056 TI - Men's preferences for prostate cancer screening: a discrete choice experiment. AB - BACKGROUND: Screening for prostate cancer (PC) may save lives, but overdiagnosis and overtreatment are serious drawbacks. We aimed to determine men's preferences for PC screening, and to elicit the trade-offs they make. METHODS: A discrete choice experiment (DCE) was conducted among a population-based random sample of 1000 elderly men (55-75-years-old). Trade-offs were quantified with a panel latent class model between five PC screening aspects: risk reduction of PC related death, screening interval, risk of unnecessary biopsies, risk of unnecessary treatments, and out-of-pocket costs. RESULTS: The response rate was 46% (459/1000). Men were willing to trade-off 2.0% (CI: 1.6%-2.4%) or 1.8% (CI: 1.3%-2.3%) risk reduction of PC-related death to decrease their risk of unnecessary treatment or biopsy with 10%, respectively. They were willing to pay ?188 per year (CI: ?141-?258) to reduce their relative risk of PC-related death with 10%. Preference heterogeneity was substantial, with men with higher educational levels having a lower probability to opt for PC screening than men with lower educational levels. CONCLUSION: Men were willing to trade-off some risk reduction of PC-related death to be relieved of the burden of biopsies or unnecessary treatments. Increasing knowledge on overdiagnosis and overtreatment, especially for men with lower educational levels, is warranted to prevent unrealistic expectations from PC screening. PMID- 23361057 TI - Cytosine-based nucleoside analogs are selectively lethal to DNA mismatch repair deficient tumour cells by enhancing levels of intracellular oxidative stress. AB - BACKGROUND: DNA mismatch repair deficiency is present in a significant proportion of a number of solid tumours and is associated with distinct clinical behaviour. METHODS: To identify the therapeutic agents that might show selectivity for mismatch repair-deficient tumour cells, we screened a pair of isogenic MLH1 deficient and MLH1-proficient tumour cell lines with a library of clinically used drugs. To test the generality of hits in the screen, selective agents were retested in cells deficient in the MSH2 mismatch repair gene. RESULTS: We identified cytarabine and other related cytosine-based nucleoside analogues as being selectively toxic to MLH1 and MSH2-deficient tumour cells. The selective cytotoxicity we observed was likely caused by increased levels of cellular oxidative stress, as it could be abrogated by antioxidants. CONCLUSION: We propose that cytarabine-based chemotherapy regimens may represent a tumour selective treatment strategy for mismatch repair-deficient cancers. PMID- 23361058 TI - Histone deacetylase inhibitors as radiosensitisers: effects on DNA damage signalling and repair. AB - Many cancers display increased expression of histone deacetylases (HDACs) and therefore transcriptionally inactive chromatin, resulting in the downregulation of genes including tumour suppressor and DNA repair genes. Histone deacetylase inhibitors (HDACi) are a heterogeneous group of epigenetic therapeutics, showing promising anticancer effects in both pre-clinical and clinical settings, in particular the effect of radiosensitisation when administered in combination with radiotherapy. Radiotherapy remains one of the most common forms of cancer treatment, leading to cell death through the induction of DNA double-strand breaks (DSBs). Cells have developed mechanisms to repair such DSB through two major pathways: non-homologous end-joining and homologous recombination. Here, we explore the current evidence for the use of HDACi in combination with irradiation, focusing on the effects of HDACi on DNA damage signalling and repair in vitro. In addition, we summarise the clinical evidence for using HDACi with radiotherapy, a growing area of interest with great potential clinical utility. PMID- 23361060 TI - [Twelve months of colposcopy use at the Brazzaville University Hospital Gynecology Clinic]. AB - OBJECTIVE: To assess the utility of a colposcope after 12 months of use at the Brazzaville University Hospital. PATIENTS AND METHODS: This retrospective study took place in the gynecology unit of the Brazzaville University Hospital and reviewed records dating from January 11, 2010, through January 10, 2011. In all, 150 women (13.5% of all gynecology consultations) underwent colposcopies in the department, for one of two indications: diagnostic colposcopy after an abnormal cervical smear, 91 cases (60.7%), and primary colposcopy in women admitted without a cervical smear, 59 cases (39.3%). High-grade squamous intraepithelial lesions (HGILs) were noted in 36.7% of the cases; the colposcopy was normal in 17.3% of the cases, and squamous cell carcinoma was found in 8.6% of the cases. Colposcopy found HGILs on 14 smears of 24 cervical smears reporting low-grade squamous intraepithelial lesions (LGIL), six of seven initially reported as HGIL, and 10 of 20 initially reported as atypical squamous cells of undetermined significance (ASCUS) on 20. In all, 93 women (62%) had biopsies. Cervical intraepithelial neoplasia 2 (CIN2) lesions were noted on 19 of the 55 biopsies of HGIL colposcopies and CIN3 on four of the 55. DISCUSSION: Colposcopy remains unavailable to too many women, largely because of the difficulty in obtaining a primary cervical smear tests. This also explains the overuse of primary colposcopy or, at least, the uncertainty about its role. PMID- 23361059 TI - Serum microRNA expression profile: miR-1246 as a novel diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma. AB - BACKGROUND: Recent studies have demonstrated that microRNAs (miRNAs) are stably detectable in blood and can serve as useful biomarkers for cancer. METHODS: We performed an miRNA array using serum samples obtained from oesophageal squamous cell carcinoma (ESCC) patients or healthy controls. MiR-1246 was the most markedly elevated in ESCC patients. Therefore, miR-1246 was selected as a candidate for further analysis. The serum miR-1246 level in 46 healthy controls and 101 ESCC patients was evaluated and compared among various clinicopathological characteristics. MiR-1246 expressions in tissue, exosomal, and cellular samples were also examined. RESULTS: Serum miR-1246 alone yielded an receiver-operating characteristic curve area of 0.754, with 71.3% sensitivity and 73.9% specificity for distinguishing ESCC patients from healthy controls. Serum miR-1246 was significantly correlated with the TNM stage and showed to be the strongest independent risk factor for poor survival (HR, 4.032; P=0.017). Unlike the tendency shown in previous reports, miR-1246 was not upregulated in ESCC tissue samples. Furthermore, exosomal miR-1246 did not reflect the abundance in the cell of origin. CONCLUSION: These data support our contention that serum miR 1246 has strong potential as a novel diagnostic and prognostic biomarker in ESCC, and its releasing mechanism is selective and independent of tissue miRNA abundance. PMID- 23361061 TI - Heart rate variability during caregiving and sleep after massage therapy in preterm infants. AB - BACKGROUND: Preterm birth impairs the infant's stress response due to interruption of autonomic nervous system (ANS) development. Preterm infants demonstrate a prolonged and aberrant sympathetic response to stressors. ANS development may be promoted by massage therapy (MT), which has been shown to improve stress response in preterm infants. AIMS: The aim of this study was to compare preterm infant ANS function and stress response during sleep and caregiving epochs, as measured by heart rate variability (HRV), after two weeks of twice-daily MT. STUDY DESIGN: A subset of participants from a larger randomized, masked, controlled trial was used. SUBJECTS: Twenty-one infants (8 males and 13 females) from a larger study of 37 medically stable preterm infants were studied. The infants were receiving full volume enteral feedings with a mean post-menstrual age of 31.4 (MT) and 30.9 (control) weeks. OUTCOME MEASURES: Low to high frequency (LF:HF) ratio of HRV was the outcome of interest. RESULTS: There was a significant group*time*sex interaction effect (p<.05). Male control infants demonstrated a significant decline in LF:HF ratio from baseline to the second caregiving epoch, suggesting decreased mobilization of sympathetic nervous system response when exposed to stressors. Male MT infants demonstrated increased LF:HF ratio during caregiving and decreased LF:HF ratio during sleep epochs, suggesting improved ANS function, although this was not statistically significant. LF:HF ratio was similar in female MT and female control infants during caregiving and sleep. CONCLUSIONS: Control males had decreased HRV compared to MT males. There was no difference in HRV between MT and control females. PMID- 23361062 TI - Understanding photosynthetic light-harvesting: a bottom up theoretical approach. AB - We discuss a bottom up approach for modeling photosynthetic light-harvesting. Methods are reviewed for a full structure-based parameterization of the Hamiltonian of pigment-protein complexes (PPCs). These parameters comprise (i) the local transition energies of the pigments in their binding sites in the protein, the site energies; (ii) the couplings between optical transitions of the pigments, the excitonic couplings; and (iii) the spectral density characterizing the dynamic modulation of pigment transition energies and excitonic couplings by protein vibrations. Starting with quantum mechanics perturbation theory, we provide a microscopic foundation for the standard PPC Hamiltonian and relate the expressions obtained for its matrix elements to quantities that can be calculated with classical molecular mechanics/electrostatics approaches including the whole PPC in atomic detail and using charge and transition densities obtained with quantum chemical calculations on the isolated building blocks of the PPC. In the second part of this perspective, the Hamiltonian is utilized to describe the quantum dynamics of excitons. Situations are discussed that differ in the relative strength of excitonic and exciton-vibrational coupling. The predictive power of the approaches is demonstrated in application to different PPCs, and challenges for future work are outlined. PMID- 23361064 TI - Temporal expectation in focal hand dystonia. AB - Patients with writer's cramp present sensory and representational abnormalities relevant to motor control, such as impairment in the temporal discrimination between tactile stimuli and in pure motor imagery tasks, like the mental rotation of corporeal and inanimate objects. However, only limited information is available on the ability of patients with dystonia to process the time-dependent features (e.g. speed) of movement in real time. The processing of time-dependent features of movement has a crucial role in predicting whether the outcome of a complex motor sequence, such as handwriting or playing a musical passage, will be consistent with its ultimate goal, or results instead in an execution error. In this study, we sought to evaluate the implicit ability to perceive the temporal outcome of different movements in a group of patients with writer's cramp. Fourteen patients affected by writer's cramp in the right hand and 17 age- and gender-matched healthy subjects were recruited for the study. Subjects were asked to perform a temporal expectation task by predicting the end of visually perceived human body motion (handwriting, i.e. the action performed by the human body segment specifically affected by writer's cramp) or inanimate object motion (a moving circle reaching a spatial target). Videos representing movements were shown in full before experimental trials; the actual tasks consisted of watching the same videos, but interrupted after a variable interval ('pre-dark') from its onset by a dark interval of variable duration. During the 'dark' interval, subjects were asked to indicate when the movement represented in the video reached its end by clicking on the space bar of the keyboard. We also included a visual working memory task. Performance on the timing task was analysed measuring the absolute value of timing error, the coefficient of variability and the percentage of anticipation responses. Patients with writer's cramp exhibited greater absolute timing error compared with control subjects in the human body motion task (whereas no difference was observed in the inanimate object motion task). No effect of group was documented on the visual working memory tasks. Absolute timing error on the human body motion task did not significantly correlate with symptom severity, disease duration or writing speed. Our findings suggest an alteration of the writing movement representation at a central level and are consistent with the view that dystonia is not a purely motor disorder, but it also involves non-motor (sensory, cognitive) aspects related to movement processing and planning. PMID- 23361063 TI - Words and objects at the tip of the left temporal lobe in primary progressive aphasia. AB - Eleven of 69 prospectively enrolled primary progressive aphasics were selected for this study because of peak atrophy sites located predominantly or exclusively within the anterior left temporal lobe. Cortical volumes in these areas were reduced to less than half of control values, whereas average volume elsewhere in the left hemisphere deviated from control values by only 8%. Failure to name objects emerged as the most consistent and severe deficit. Naming errors were attributed to pure retrieval failure if the object could not be named even when the denoting word was understood, the object recognized and the two accurately matched. Surprisingly many of the naming errors reflected pure retrieval failures, without discernible semantic or associative component. The remaining set of errors had associative components. These errors reflected the inability to define the word denoting the object more often than the inability to define the nature of the pictured object. In a separate task where the same object had to be linked to verbal or non-verbal associations, performance was abnormal only in the verbal format. Excessive taxonomic interference was observed for picture-word, but not picture-picture, matching tasks. This excessive interference reflected a blurring of intra- rather than inter-category distinctions as if the acuity of word-object associations had been diminished so that correspondences were easier to recognize at generic than specific levels. These dissociations between verbal and non-verbal markers of object knowledge indicate that the reduced neural mass at peak atrophy sites of the left temporal tip, accounting for half or more of the presumed premorbid volume, was unlikely to have contained domain-independent semantic representations of the type that would be expected in a strictly amodal hub. A more likely arrangement entails two highly interactive routes--a strongly left lateralized temporosylvian language network for verbal concepts, and a presumably more bilateral or right-sided inferotemporal/fusiform object recognition network, which remained relatively spared because peak atrophy sites were concentrated on the left. The current results also suggest that the left anterior temporal neocortex should be inserted into the language network where it is likely to play a major role in selecting verbal labels for objects and mediating the progression of word comprehension from generic to specific levels of precision. PMID- 23361065 TI - Overlapping cortical malformations and mutations in TUBB2B and TUBA1A. AB - Polymicrogyria and lissencephaly are causally heterogeneous disorders of cortical brain development, with distinct neuropathological and neuroimaging patterns. They can be associated with additional structural cerebral anomalies, and recurrent phenotypic patterns have led to identification of recognizable syndromes. The lissencephalies are usually single-gene disorders affecting neuronal migration during cerebral cortical development. Polymicrogyria has been associated with genetic and environmental causes and is considered a malformation secondary to abnormal post-migrational development. However, the aetiology in many individuals with these cortical malformations is still unknown. During the past few years, mutations in a number of neuron-specific alpha- and beta-tubulin genes have been identified in both lissencephaly and polymicrogyria, usually associated with additional cerebral anomalies including callosal hypoplasia or agenesis, abnormal basal ganglia and cerebellar hypoplasia. The tubulin proteins form heterodimers that incorporate into microtubules, cytoskeletal structures essential for cell motility and function. In this study, we sequenced the TUBB2B and TUBA1A coding regions in 47 patients with a diagnosis of polymicrogyria and five with an atypical lissencephaly on neuroimaging. We identified four beta tubulin and two alpha-tubulin mutations in patients with a spectrum of cortical and extra-cortical anomalies. Dysmorphic basal ganglia with an abnormal internal capsule were the most consistent feature. One of the patients with a TUBB2B mutation had a lissencephalic phenotype, similar to that previously associated with a TUBA1A mutation. The remainder had a polymicrogyria-like cortical dysplasia, but the grey matter malformation was not typical of that seen in 'classical' polymicrogyria. We propose that the cortical malformations associated with these genes represent a recognizable tubulinopathy-associated spectrum that ranges from lissencephalic to polymicrogyric cortical dysplasias, suggesting shared pathogenic mechanisms in terms of microtubular function and interaction with microtubule-associated proteins. PMID- 23361066 TI - CHOP regulates the p53-MDM2 axis and is required for neuronal survival after seizures. AB - Hippocampal sclerosis is a frequent pathological finding in patients with temporal lobe epilepsy and can be caused by prolonged single or repeated brief seizures. Both DNA damage and endoplasmic reticulum stress have been implicated as underlying molecular mechanisms in seizure-induced brain injury. The CCAAT/enhancer-binding protein homologous protein (CHOP) is a transcriptional regulator induced downstream of DNA damage and endoplasmic reticulum stress, which can promote or inhibit apoptosis according to context. Recent work has proposed inhibition of CHOP as a suitable neuroprotective strategy. Here, we show that transcript and protein levels of CHOP increase in surviving subfields of the hippocampus after prolonged seizures (status epilepticus) in mouse models. CHOP was also elevated in the hippocampus from epileptic mice and patients with pharmacoresistant epilepsy. The hippocampus of CHOP-deficient mice was much more vulnerable to damage in mouse models of status epilepticus. Moreover, compared with wild-type animals, CHOP-deficient mice subject to status epilepticus developed more spontaneous seizures, displayed protracted hippocampal neurodegeneration and a deficit in a hippocampus-dependent object-place recognition task. The absence of CHOP was associated with a supra-maximal induction of p53 after status epilepticus, and inhibition of p53 abolished the cell death-promoting consequences of CHOP deficiency. The protective effect of CHOP could be partly explained by activating transcription of murine double minute 2 that targets p53 for degradation. These data demonstrate that CHOP is required for neuronal survival after seizures and caution against inhibition of CHOP as a neuroprotective strategy where excitotoxicity is an underlying pathomechanism. PMID- 23361067 TI - Bilateral acute necrosis of the globi pallidi and rhabdomyolysis due to combined methadone and benzodiazepine toxicity. AB - Methadone continues to be a widely used maintenance therapy for opiate dependence. However, methadone-related deaths have been reported frequently for over 4 decades now. Anoxic brain injury with pulmonary edema secondary to respiratory depression is the recognized mechanism of methadone death, although pathological intracranial findings are rarely described in methadone deaths. A selective area of brain injury has never been reported with methadone use. We present a case of a 23-year-old man who had acute necrosis of the bilateral globi pallidi in the brain and systemic rhabdomyolysis after ingesting methadone and nasally insufflating alprazolam. We also present a review of the literature on deaths following opioid use and associated brain injury. PMID- 23361068 TI - Homicide by poisoning. AB - By studying the number and method of homicidal poisoning in Miami-Dade County, Florida; New York City, NY; Oakland County, Michigan; and Sweden, we have confirmed that this is an infrequently established crime.Several difficulties come with the detection of homicidal poisonings. Presenting symptoms and signs are often misdiagnosed as natural disease, especially if the crime is committed in a hospital environment, suggesting that an unknown number of homicides go undetected.In the reported cases analyzed, the lethal agent of choice has changed over the years. In earlier years, traditional poisons such as arsenic, cyanide, and parathion were frequently used. Such poisonings are nowadays rare, and instead, narcotics are more commonly detected in victims of this crime. PMID- 23361069 TI - Skull base injury leading to death after conventional septoplasty. AB - Treatment of nasal obstruction with conventional septoplasty is a very common operation in otorhinolaryngology. There are considerable complications that may become even life threatening. We report a rare complication of septoplasty, namely, skull base injury. The possible mechanisms and treatment modality are discussed. Like other similar procedures, prevention of the skull base injury is more important than its treatment. Correct knowledge about anatomy of the region and meticulous manipulation and instrumentation are the most considerable topics. PMID- 23361070 TI - Identification of skeletal fractures before and after removal of soft tissue: a case report. AB - Evaluation of decomposed individuals by forensic pathologists is a common occurrence; however, complete removal of soft tissue to closely examine the skeletal elements of these individuals is not common. The decomposition process can mask injuries and impair examination of the skeleton. The case presented by the authors illustrates how complete removal of soft tissue from individuals who have undergone advanced decomposition is necessary to identify all fractures of the skeletal elements. Although removal of the soft tissue from all decomposed remains is not possible, this case shows how carefully the choice of whether to deflesh these remains should be made. PMID- 23361071 TI - Burial of piglet carcasses in cement: a study of macroscopic and microscopic alterations on an animal model. AB - Scarce experimental data exist describing postmortem effects of burial in cement. The scanty literature presents several case reports, but no experimental study. To perform a pilot study, the following experimental system was designed: 4 piglet corpses, who died of natural causes, were encased in concrete. After 1, 2, 3, and 6 months, a block was opened, and autopsy and microscopic analyses were performed. At the first month, initial putrefaction had started, and hindlegs were partly skeletonized. At the second month, both forelegs and hindlegs were partly skeletonized, and the abdomen and back showed advanced putrefaction. At the third month, the samples showed areas of mummification at the abdomen within a general context of initial putrefaction. At the sixth month, the sample showed wide adipocere formation. Histological findings revealed in some analyzed tissues (epithelium, dermis, adipose, and subcutaneous muscular tissues) a well-defined histological pattern even at 3 months after encasement in concrete: this means that microscopic changes may be delayed in concrete and that it may be worth performing histological analyses even in such kind of decomposed material. PMID- 23361072 TI - The forensic aspects of contemporary disintegrating rifle bullets. AB - A relatively new type of rifle bullet has appeared in the last few years that contains no lead and rapidly disintegrates into very small particles and jacket fragments immediately upon entry into soft tissue. These bullets are intended for use by 'varmint' hunters in high-velocity centerfire rifles where the effect on such animals as prairie dogs, gophers, ground hogs, and other similarly sized animals is nothing short of explosive. The shooting of much larger animals to include human beings will typically result in nonperforating wounds with short wound paths. X-ray views of a decedent or gunshot victim will lack any recognizable bullet or projectile. Only 1 jacket fragment among the many present in the wound tract is suitable for subsequent firearms identification purposes, namely, the small copper disc that represents the base or heel of the bullet jacket. This small circular fragment bears vestiges of the rifling marks of the responsible firearm.This article will aid the forensic pathologist in recognizing gunshot wounds produced by these atypical bullets and the importance of recovering the base portion of the disintegrated bullet jacket. PMID- 23361073 TI - Range of fire determination from the pseudostippling of skin by shotshell buffer material. AB - The plastic buffer material in certain American shotgun shells emerges from the muzzle with the same velocity as the pellets that it was intended to protect from deformation during the very high accelerative forces associated with the discharge process. These small plastic particles spread out quickly over distance in a predictable, reproducible, and uniform manner as they lose velocity because of air resistance. If these plastic particles strike skin with sufficient velocity and energy, they will produce stipple marks whose distribution and density can be used to establish range of fire. This can be of critical importance in the reconstruction of a shooting involving this type of ammunition. PMID- 23361074 TI - Rifle wounds: a review of range and location as pertaining to manner of death. PMID- 23361075 TI - Suicide by hydrogen sulfide inhalation. AB - The authors report a case of suicide by hydrogen sulfide in Australia. A young woman was located in a car wearing protective eyewear. A tub of foamy yellow substance and a quantity of hydrochloric acid and lime sulfur were also located in the rear of the vehicle. Morphological findings at autopsy were nonspecific. Toxicologic analysis of a specimen of leg blood detected elevated levels of methemoglobin. If Australia follows a similar trend to Japan and the United States, it is possible that incidences of such cases will rise, probably because of Internet dissemination. From a public health perspective, emergency service providers and forensic case workers should be aware of the potential hazards to themselves and others when dealing with such cases. PMID- 23361076 TI - Implementation and user satisfaction with forensic laboratory information systems in death investigation offices. AB - The use of laboratory information management systems (LIMSs) in forensic pathology and death investigation systems has lagged behind the greater pathology community. Yet the logistical needs of a modern medical examiner or coroner office could be well served by a robust forensic LIMS, and the data stored in a forensic LIMS could be effectively mined for the protection of the public's health and safety.In spring 2007, the National Association of Medical Examiners conducted a survey of its members to determine the use of and satisfaction with forensic LIMS. This survey was repeated in the fall of 2011. The responses to the 2 surveys were compared to note any trends or changes to LIMS use by medical examiners and coroners.Although the use of LIMS has increased in the 4 1/2 years between surveys, 18% of death investigation systems still do not have a forensic LIMS. The percentage of offices with home-developed systems has increased, whereas the user's satisfaction with these systems has decreased. This may be due to limited budgets to either purchase or develop systems. The integration of images into these systems has increased, but not nearly to the level that should be present in an image-dependent field. Users of these systems are cognizant of the features that a forensic LIMS should have to ensure the smooth operation of a death investigation office. PMID- 23361077 TI - Complicated suicide versus autoeroticism?: a case involving multiple drugs and a porta-potty. AB - In this report, a unique and bizarre case of complicated suicide is presented. The decedent was found dead in the basin of a porta-potty, wearing women's pantyhose, jewelry, and makeup. The initial investigation was suspect for homicide. Although an autoerotic accidental death cannot be excluded, the patient's medical history and autopsy results provided evidence for suicide, including several substances positive in his serum. Tramadol was quantified to be 140 mg/L, approximately 470 times the therapeutic range. Moreover, formaldehyde was also present, presumably absorbed from the contents of the chemical toilet. An exhaustive search could not reveal similar circumstances of suicide in a porta potty or with the levels of tramadol found in the decedent. PMID- 23361078 TI - Connexin43 and angiotensin II alterations in hearts of rats having undergone an acute exposure to alcohol. AB - INTRODUCTION: Alcohol-induced heart damage is associated with enzyme and protein alterations. The purpose of this study was to investigate alcohol-induced alterations in cardiac connexin 43 (Cx43) and angiotensin II (Ang II) after acute alcohol administration. METHOD: Male Wistar rats were randomly divided into 2 groups: a control group and an ethanol group. The ethanol group intraperitoneally received 3.8 g/kg ethanol; the controls were given the same amount of saline via the same route. After the righting reflex disappeared, midsternotomy was performed in all animals. Immunohistochemical analysis was performed to evaluate protein expression of Cx43 and Ang II. Sections were analyzed by digital image analysis. RESULT: The expression of Cx43 was significantly reduced after acute ethanol treatment, with the integrated optical density lower when compared with control (P < 0.05). The expression of Ang II was significantly increased after acute ethanol treatment, supported by integrated optical density when compared with control (P < 0.05). CONCLUSIONS: In summary, cardiac protein expression of Cx43 and Ang II were found to be significantly altered after acute ethanol treatment, suggesting that these 2 proteins may be important underlying mechanisms of vulnerability to oxidative injury in the heart during acute ethanol. The present study indicated that acute ethanol toxicity caused different alterations in heart proteins that would be related to oxidative stress. PMID- 23361079 TI - An experimental study on the macroscopic findings of ligature marks using a murine model. AB - Macroscopic findings of ligature marks are mainly affected by the characteristics of the ligature, the severity of external forces acting on the ligature, and the period that the neck has been pressed by the ligature. Therefore, the appearances of ligature marks formed by ligatures with the same characteristics differ depending on 2 factors: force and time. To examine which of these factors contributes more significantly to the macroscopic findings of ligature marks, a semiquantitative and experimental study using a murine model was performed. We experimentally made artificial ligature marks by hanging different sized weights using a vinyl band on dehaired legs of rats for different periods, both intravitally and postmortemly.After weights of 1, 3, and 6 kg with vinyl bands were hung on the legs of rats for 0 to 24 hours, the depths of ligature marks were semiquantitatively evaluated in 4 grades. Macroscopic examination and statistical analysis revealed that the appearance of ligature marks is not affected by whether they are formed intravitally or postmortemly but that it is equally affected by the severity of force and the duration of force application. We believe that the results of this study will be helpful to determine the characteristics of ligature and the period of hanging or strangulation time in the practice of forensic medicine. PMID- 23361080 TI - Examination of histological samples from submerged carrion to aid in the determination of postmortem submersion interval. AB - The use of histology in the as a tool for estimating postmortem intervals has rarely been explored but it has the potential for offering medical examiners an additional means for estimating the postmortem submersion interval (PMSI) during a death investigation. This study used perinatal piglets as human analogs which were submerged in freshwater for various time intervals. Each piglet was extracted from the water and underwent a necropsy examination during which histological samples were collected. The samples revealed that the necrotic tissue decomposed relatively predictably over time and that this decompositional progression may have the potential to be used via a scoring system to determine or aid in determining the PMSI. This method for calculating PMSI allows for normalization between piglets of various mass and body types. It also prevents any contamination of the remains via algae growth and animal activity that may exacerbate and possibly exaggerate PMSI calculation. PMID- 23361081 TI - High-voltage suicidal electrocution with multiple exit wounds. AB - Poisoning, hanging, and burning are the usual methods adopted by people to commit suicide. Suicide by electrocution and that too high voltage is one of the rarest methods adopted for the purpose. We report the case of a young man who committed suicide by climbing up a 25-ft-high electric pole. The deceased was a regular alcoholic and was under severe depression for a long time because of his personal problems. He survived for more than 2 days after the incident. His serum urea and creatinine levels were elevated, so were the creatine kinase total and creatine kinase-MB level. The method adopted and the findings make this case a rare scientific report. Moreover, to the best of our knowledge, this is the first reported case in an English scientific literature of a high-voltage suicidal electrocution with multiple exit wounds. The circumstances surrounding the manner of electrocution and the features of electric injuries are presented and discussed. PMID- 23361082 TI - Subdural hematoma occurrence: comparison between ethanol and cocaine use at death. AB - OBJECTIVE: The objective of this study was to show that, in a medical examiner population, ethanol intoxication is associated with an increase in the occurrence of subdural hematoma (SDH), whereas the presence of cocaine is not associated with an increase in the occurrence of SDH. DESIGN: This was a retrospective evaluation of 967 SDH including the investigative information, autopsy, and toxicological findings derived from 18,314 medical examiner cases over 8 years. RESULTS: Subdural hematoma is found in 7% to 9% of cases with either no ethanol or less than 100 mg/dL of ethanol. Subdural hematoma is found in 18% of cases with ethanol levels of greater than 100 mg/dL. Subdural hematoma is found in 11% of cases negative for cocaine, whereas SDH is found in 9% of cases with any form of cocaine present at death. PMID- 23361083 TI - Development and resolution of secondary autoimmunity after autologous haematopoietic stem cell transplantation for systemic lupus erythematosus: competition of plasma cells for survival niches? PMID- 23361084 TI - Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. AB - OBJECTIVE: To evaluate the efficacy and safety of secukinumab, a fully human, anti-interleukin (IL)-17A monoclonal antibody, in patients with psoriatic arthritis (PsA). METHODS: 42 patients with active PsA fulfilling ClASsification for Psoriatic ARthritis (CASPAR) criteria were randomly assigned (2:1) to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one sided p<0.1). RESULTS: Primary endpoint: ACR20 responses at week 6 were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, 'good' European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient. CONCLUSIONS: Although the primary endpoint was not met, clinical responses, acute phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. Secukinumab exhibited satisfactory safety. Larger clinical trials of secukinumab in PsA are warranted. PMID- 23361085 TI - Predictors of preterm birth in patients with mild systemic lupus erythematosus. AB - OBJECTIVE: While increased disease activity is the best predictor of preterm birth in women with systemic lupus erythematosus (SLE), even women with low disease activity are at increased risk of this complication. Biomarkers that would identify at-risk pregnancies could allow interventions to prevent preterm birth. METHOD: Measures of SLE activity, inflammation, placental health and renal function between 20 and 28 weeks gestation (mid-gestation) were correlated to preterm birth and gestational age at delivery in a prospective cohort of pregnant women with SLE. RESULT: Of the 40 pregnancies in 39 women, all with mild-moderate SLE disease, 9 (23.7%) of the 38 live births were delivered preterm. Low C4 was the only marker of SLE activity associated with younger gestational age at delivery. Elevated ferritin and lower oestradiol correlated with younger gestational age at delivery. Renal function remained normal during all pregnancies at mid-gestation and did not correlate with preterm birth. Higher serum uric acid, however, correlated with younger gestational age at delivery. CONCLUSIONS: In women with SLE with mild-moderate disease activity, ferritin, oestradiol and uric acid levels at mid-gestation may predict preterm birth. These markers may prove to be clinically useful in identifying pregnancies at particularly high risk for adverse outcomes. PMID- 23361086 TI - PRIDE Cluster: building a consensus of proteomics data. PMID- 23361087 TI - Accelerating 3B single-molecule super-resolution microscopy with cloud computing. PMID- 23361088 TI - ImageJ plug-in for Bayesian analysis of blinking and bleaching. PMID- 23361089 TI - Where stem cells call home. PMID- 23361090 TI - A ligand's-eye view of protein similarity. PMID- 23361091 TI - A third-generation method reveals cell lineage ancestry. PMID- 23361092 TI - High prevalence of Leucocytozoon spp. in the endangered yellow-eyed penguin (Megadyptes antipodes) in the sub-Antarctic regions of New Zealand. AB - Yellow-eyed penguins (YEPs) have suffered major population declines over the past 30 years, with no single cause established. Leucocytozoon was first identified in yellow-eyed penguins in 2005. During the 2008/09 breeding season, a high mortality was seen in both mainland yellow-eyed penguins as well as those on Enderby Island of the Auckland Islands archipelago. A high overall prevalence of Leucocytozoon spp. in association with a high incidence of chick mortality was observed during this period on Enderby Island. One chick had histological evidence of leucocytozoonosis with megaloschizonts in multiple organs throughout its body. In addition, a high prevalence (73.7%) of Leucocytozoon was observed by PCR in the blood of adult Enderby yellow-eyed penguins taken during the 2006/07 season. These findings were different from the low prevalence detected by PCR on the coast of the South Island (11%) during the 2008/2009 breeding session and earlier on Campbell Island (21%) during the 2006/2007 breeding session. The Leucocytozoon spp. sequences detected lead us to conclude that the Leucocytozoon parasite is common in yellow-eyed penguins and has a higher prevalence in penguins from Enderby Island than those from Campbell Island and the mainland of New Zealand. The Enderby Island yellow-eyed penguins are infected with a Leucocytozoon spp. that is genetically distinct from that found in other yellow eyed penguin populations. The role of Leucocytozoon in the high levels of chick mortality in the yellow-eyed penguins remains unclear. PMID- 23361093 TI - Near-infrared photochromic behavior in a donor-acceptor type diarylethene modulated by the cyanide anion. AB - Two new near-infrared (NIR) photochromic compounds, containing both electron donating (D) and accepting groups (A), have been developed and their NIR photochromic and fluorescence performances can be modulated by the cyanide anion. Such a colorimetric cyanide sensor has been achieved based on this donor photochromic bridge-acceptor system. PMID- 23361095 TI - Filling a nanoporous substrate by dewetting of thin films. AB - Following a simple thermodynamic model, which predicts that an array of non wettable pores can be filled by dewetting of sufficiently thin films, we use molecular dynamics to simulate the rupture of nanometre-thick liquid Au films on nanoporous substrates. Our simulations clearly exhibit spinodal dewetting and hole nucleation, and some of the metal is indeed absorbed by non-wettable pores solely as a virtue of the Laplace pressure acting on dewetted droplets and rivulet-like structures. Finally, we show that the fraction of absorbed Au can be increased through patterning of the initial film. PMID- 23361094 TI - Effects of methylnaltrexone on guinea pig gastrointestinal motility. AB - The purpose of the present study was to compare the effects of methylnaltrexone (MNTX), a peripherally acting MU opioid receptor (MUOR) antagonist, on gastrointestinal (GI) motility in naive vs. opiate chronically treated guinea pigs in vitro and in vivo. We have used the electrically stimulated muscle twitch contractions of longitudinal muscle-myenteric plexus (LMMP) preparations and total GI transit as measure of GI motility. In LMMP preparations of naive guinea pigs, MNTX (1-30 MUM) induced a significant, dose-response reduction of morphine induced inhibition of electrically stimulated muscle twitch contractions, with an IC50 of 9.4 10(-8)M. By contrast, MNTX abolished the inhibitory effect of acute morphine at any concentrations tested (1-30 MUM) in the guinea pigs chronically treated with opiates. In vivo, MNTX (10-50 mg s.c.) did not affect GI transit in naive guinea pigs when administered acutely or for five consecutive days, but reversed the GI transit delay induced by chronic morphine treatment. These findings show that MNTX is effective in reversing opiate-induced inhibition of GI motility acting at peripheral MU opioid receptors, but does not exert a pharmacologic effect on GI transit in the absence of opiate stimulation. PMID- 23361096 TI - Preoperative risk factors influencing the incidence of postoperative sepsis in human immunodeficiency virus-infected patients: a retrospective cohort study. AB - BACKGROUND: Compared to noninfected patients, human immunodeficiency virus (HIV) infected patients undergoing surgery have an increased postoperative risk of developing sepsis. We aimed to investigate the preoperative risk factors that affect the incidence of sepsis after surgery in HIV-infected patients. METHODS: Clinical parameters of 215 patients with HIV/acquired immunodeficiency syndrome (AIDS) who had undergone surgery between January 2011 and February 2012 were examined retrospectively for the effect of HIV/AIDS on the incidence of postoperative sepsis. RESULTS: Logistic regression analysis identified four independent risk factors of postoperative sepsis in HIV-infected patients: CD4 counts [B = -0.007, odds ratio (OR) 0.993]; blood albumin levels (B = -0.077, OR 0.926); surgical infection (B = 1.887, OR 6.598); major surgery (B = 1.013, OR 2.754). The incidence of postoperative sepsis was high with CD4 counts <= 100 cells/MUl, albumin levels <35 g/L, the presence of surgical infection, the patient had undergone major surgery--81.25%, 39/48; 76.47%, 26/34; 70.73%, 29/41; and 54.76%, 46/84, respectively, compared to that of the total cohort (40.93%, 88/215). When CD4 counts were >350 cells/MUl, the incidence of postoperative sepsis was significantly lower (16.36%, 9/55). CONCLUSIONS: Low CD4 cell counts, hypoalbuminemia, surgical infection, and major surgery are independent risk factors for the development of postoperative sepsis among HIV-infected patients. CD4 cell numbers and albumin levels negatively correlated with the incidence of postoperative sepsis, whereas surgical infections and major surgical procedures positively correlated with the incidence of postoperative sepsis. PMID- 23361098 TI - Catalytic "triangles": binding of iron in task-specific ionic liquids. AB - A new class of task-specific ionic liquids (ILs) which contain septuply positively charged {Fe(3)(III)O(RCOO)(6)L(3)}(7+) triangles has been synthesized and structurally characterized. Such metal-containing ILs can be repeatedly used as alternative catalysts in the synthesis of 2-pyrrolo-3'-yloxindole or the condensation of indoles with various aldehydes. PMID- 23361097 TI - Laparoscopic surgery for rectal cancer: outcomes in 513 patients. AB - BACKGROUND: Few reports have demonstrated the feasibility and efficacy of laparoscopic resection in patients with rectal cancer (RC). The objective of the present study was to assess the effectiveness of laparoscopic resection for RC, with an emphasis on perioperative variables and long-term oncological outcomes. METHODS: This prospective study was carried out between January 2005 and September 2010 and included 513 patients diagnosed with RC who underwent laparoscopic surgery. Patients with locally advanced RC (cT3/cT4 or N+) received neoadjuvant treatment. Adjuvant treatment was applied to patients with stage II/III disease or according to the neoadjuvant protocol. All patients were followed-up prospectively for the evaluation of complications and oncological outcome. Survival rate analysis was performed using the Kaplan-Meier method. RESULTS: Sphincter-preserving surgery was performed on 389 patients, and the remaining 124 patients underwent abdominoperineal resection. Perioperative mortality occurred in only one patient (0.2 %), and 27 (5.3 %) intraoperative complications were recorded. The most common postoperative complication was anastomotic leakage (5.5 %). The conversion rate was 6.4 %. The mean number of harvested lymph nodes was 23.6 +/- 13. The mean distance to the distal margin was 2.6 +/- 1.9 (0-7) cm. Distal margin positivity was detected in 9 (1.7 %) patients. The circumferential margin was positive in 39 (7.6 %) cases. After a median follow-up period of 30 (1-78) months, recurrence occurred in a total of 59 patients (11.5 %). Local recurrence was detected in 16 patients (3.1 %), and both local and distant recurrence was found in 7 patients (1.4 %). Distant recurrence only was detected in 43 patients (8.4 %). The overall 5-year survival rate was 84 %, and the 5-year disease-free survival rate was 77.4 %. The local recurrence free survival rate was 98.4 % at 2 years, 95.7 % at 3 years, and 94.3 % at 5 years. CONCLUSIONS: Our results, together with the review of the literature, clearly demonstrate that laparoscopic resection for RC is a feasible method at specialized high-volume centers. The long-term outcomes are at least as good as those from open surgery as long as the principles of oncologic surgery are respected and faithfully performed. PMID- 23361099 TI - PCR-SSCP-based reconstruction of the original fungal flora of heat-processed meat products. AB - Food processing of spoiled meat is prohibited by law, since it is a deception and does not comply with food safety aspects. In general, spoilage of meat is mostly caused by bacteria. However, a high contamination level of fungi could be also found in some meat or meat products with certain preserving conditions. In case that unhygienic meat is used to produce heat processed products, the microorganisms will be deactivated by heat, so that they cannot be detected by a standard cultivation method. Therefore, this study aimed to develop and apply a molecular biological method--polymerase chain reaction and single strand conformation polymorphism (PCR-SSCP)--to reconstruct the original fungal flora of heat processed meat. Twenty primer pairs were tested for their specificity for fungal DNA. Since none of them fully complied with all study criteria (such as high specificity and sensitivity for fungal DNA; suitability of the products for PCR-SSCP) in the matrix "meat", we designed a new reverse primer, ITS5.8R. The primer pair ITS1/ITS5.8R amplified DNA from all tested fungal species, but not DNA from meat-producing animals or from ingredients of plant origin (spices). For the final test, 32 DNA bands in acrylamide gel from 15 meat products and 1 soy sauce were sequenced-all originating from fungal species, which were, in other studies, reported to contaminate meat e.g. Alternaria alternata, Aureobasidium pullulans, Candida rugosa, C. tropicalis, C. zeylanoides, Eurotium amstelodami and Pichia membranifaciens, and/or spices such as Botrytis aclada, Guignardia mangiferae, Itersonilia perplexans, Lasiodiplodia theobromae, Lewia infectoria, Neofusicoccum parvum and Pleospora herbarum. This confirms the suitability of PCR SSCP to specifically detect fungal DNA in heat processed meat products, and thus provides an overview of fungal species contaminating raw material such as meat and spices. PMID- 23361100 TI - Facile synthesis of a surface plasmon resonance-enhanced Ag/AgBr heterostructure and its photocatalytic performance with 450 nm LED illumination. AB - In this paper, a plasmonic Ag/AgBr heterostructure was reduced by AgBr, which was successfully synthesized by a facile hydrothermal process at a temperature as low as 90 degrees C. The morphological and structural observation, crystallinity and optical performance of the products grown were carried out by using scanning electron microscopy, X-ray diffraction, energy dispersive spectrometry and UV-vis diffuse reflectance spectroscopy. The photocatalytic activities of Ag/AgBr heterostructures were evaluated by the degradation of methylene blue under 450 nm LED arrays. The results revealed that the plasmonic Ag/AgBr heterostructures exhibited much higher photocatalytic activities than pure AgBr and commercial Degussa P25. The visible-light photocatalytic activity enhancement of Ag/AgBr heterostructures could be attributed to the surface plasmon resonance and its synergistic effect on the photosensitive AgBr. Furthermore, a mechanism of the plasmon synergistically enhanced photocatalytic process was proposed. PMID- 23361101 TI - Multiple dosing of ephedra-free dietary supplements: hemodynamic, electrocardiographic, and bacterial contamination effects. AB - Four popular ephedra-free dietary supplements were evaluated for their effects on heart rate (HR), blood pressure (BP), and electrocardiographic (ECG) parameters. Twelve healthy men participated in a study randomized for product sequence, with a 21-day washout period between supplement-administration phases. Throughout the study, Holter monitors were used to assess ECG and HR activity. BP was assessed automatically on multiple occasions. The supplements were ingested three times daily for 3 days. Caffeine content, microbial load, and serum caffeine concentrations were determined. Mean systolic (SBP) and diastolic BP (DBP) readings showed significant increases relative to baseline (10.8 +/- 2.5 and 5.3 +/- 3.1 mm Hg, respectively; P < 0.05). All supplements significantly increased HR and decreased bradycardia runs; abnormal atrial/ventricular events were frequently noted. Gastrointestinal and sympathomimetic symptoms were also common. Two supplements were heavily contaminated with Bacillus species. In light of these findings, the use of ephedra-free dietary supplements should be discouraged in individuals with hypertension, diabetes, or other cardiovascular diseases. PMID- 23361102 TI - Impact of OATP1B1, MDR1, and CYP3A4 expression in liver and intestine on interpatient pharmacokinetic variability of atorvastatin in obese subjects. AB - Individual variability in expression and function of organic anion-transporting polypeptide 1B1 (OATP1B1), multidrug resistance protein 1 (MDR1), and/or cytochrome P450 3A4 (CYP3A4) may impact the clinical response of many drugs. We investigated the correlation between expression of these proteins and pharmacokinetics of atorvastatin, a substrate of all three, in 21 obese patients with paired biopsies from liver and intestinal segments. The patients were also screened for the SLCO1B1 c.521T->C variant alleles. Approximately 30% (r(2) = 0.28) of the variation in oral clearance (CL/F) of atorvastatin was explained by hepatic OATP1B1 protein expression (P = 0.041). Patients carrying the SLCO1B1 c.521C variant allele (homozygous, n = 4; heterozygous, n = 2) exhibited 45% lower CL/F of atorvastatin than the c.521TT carriers (P = 0.067). No association between hepatic and intestinal expression of MDR1 or CYP3A4 and atorvastatin pharmacokinetics was found (P > 0.149). In conclusion, this study suggests that OATP1B1 phenotype is more important than CYP3A4 and MDR1 phenotypes for the individual pharmacokinetic variability of atorvastatin. PMID- 23361104 TI - Intracellular drug concentrations. AB - Many drug targets are intracellular. To access them, a drug molecule must pass through the cell membrane, a process often facilitated or impeded by transporters. Once in the cytoplasm, basic molecules may become concentrated in organelles. To predict the pharmacologic effect accurately, there must be data concerning the concentration at the target, which is difficult to measure. Techniques that combine mass spectrometry and imaging techniques (matrix-assisted laser desorption/ionization, secondary ion mass spectrometry (SIMS), and nanoSIMS) have promise in addressing this problem. PMID- 23361103 TI - Personalized cancer medicine: molecular diagnostics, predictive biomarkers, and drug resistance. AB - The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution. PMID- 23361106 TI - [Rhinoscleroma: two cases in Bobo-Dioulasso in Burkina Faso]. AB - INTRODUCTION: Rhinoscleroma is a chronic granulomatous infection of the respiratory tract due to Klebsiella rhinoscleromatis (K. rhinoscleromatis). PATIENTS AND METHOD: We observed two cases of rhinoscleroma in the Souro-Sanou university hospital of Bobo-Dioulasso, Burkina Faso, over a 9-year period (2009 to 2010). RESULTS: A 19-year-old man and a 38-year-old woman both consulted with obstructive granuloma of the nasal fossae; one also had a velar localization. The treatment consisted of surgical debridement and antibiotic therapy (ciprofloxacin). Good results followed the surgery. On follow-up after two and one and a half years, we observed no relapse. CONCLUSION: The diagnosis of rhinoscleroma should be considered for any obstructive tumor of the nasal fossae. Histopathological examination contributes to the diagnosis. PMID- 23361105 TI - Contribution of endogenous bradykinin to fibrinolysis, inflammation, and blood product transfusion following cardiac surgery: a randomized clinical trial. AB - Bradykinin increases during cardiopulmonary bypass (CPB) and stimulates the release of nitric oxide, inflammatory cytokines, and tissue-type plasminogen activator (t-PA), acting through its B2 receptor. This study tested the hypothesis that endogenous bradykinin contributes to the fibrinolytic and inflammatory response to CPB and that bradykinin B2 receptor antagonism reduces fibrinolysis, inflammation, and subsequent transfusion requirements. Patients (N = 115) were prospectively randomized to placebo, epsilon-aminocaproic acid (EACA), or HOE 140, a bradykinin B2 receptor antagonist. Bradykinin B2 receptor antagonism decreased intraoperative fibrinolytic capacity as much as EACA, but only EACA decreased D-dimer formation and tended to decrease postoperative bleeding. Although EACA and HOE 140 decreased fibrinolysis and EACA attenuated blood loss, these treatments did not reduce the proportion of patients transfused. These data suggest that endogenous bradykinin contributes to t-PA generation in patients undergoing CPB, but that additional effects on plasmin generation contribute to decreased D-dimer concentrations during EACA treatment. PMID- 23361107 TI - [Prevention of nosocomial infections by bundles. Evidence and practical implementation]. AB - There are numerous guidelines for the prevention of hospital-acquired infections; however, adherence to these guidelines is only limited. The bundle concept was developed to facilitate the implementation by prioritizing certain measures. A bundle contains 3-5 evidence-based key interventions. The bundle concept has been successfully applied to reduce central catheter-related bloodstream infections and ventilation-associated pneumonia whereby only strict compliance can help to reduce infections; therefore, the right implementation strategy is essential. This means accurate planning, delegation of responsibilities, education, control of compliance and infection surveillance. PMID- 23361108 TI - Non-invasive measurement of liver and pancreas fibrosis in patients with cystic fibrosis. AB - BACKGROUND: Patients with cystic fibrosis (CF) have a relevant morbidity and mortality caused by CF-related liver-disease. While transient elastography (TE) is an established elastography method in hepatology centers, Acoustic-Radiation Force-Impulse (ARFI)-Imaging is a novel ultrasound-based elastography method which is integrated in a conventional ultrasound-system. The aim of the present study was to evaluate the prevalence of liver-fibrosis in patients with CF using TE, ARFI-imaging and fibrosis blood tests. METHODS: 106 patients with CF were prospectively included in the present study and received ARFI-imaging of the left and right liver-lobe, ARFI of the pancreas TE of the liver and laboratory evaluation. RESULTS: The prevalence of liver-fibrosis according to recently published best practice guidelines for CFLD was 22.6%. Prevalence of significant liver-fibrosis assessed by TE, ARFI-right-liver-lobe, ARFI-left-liver-lobe, Fibrotest, Fibrotest-corrected-by-haptoglobin was 17%, 24%, 40%, 7%, and 16%, respectively. The best agreement was found for TE, ARFI-right-liver-lobe and Fibrotest-corrected-by-haptoglobin. Patients with pancreatic-insufficiency had significantly lower pancreas-ARFI-values as compared to patients without. CONCLUSIONS: ARFI-imaging and TE seem to be promising non-invasive methods for detection of liver-fibrosis in patients with CF. PMID- 23361109 TI - Impaired CFTR function in mild cystic fibrosis associated with the S977F/T5TG12complex allele in trans with F508del mutation. AB - BACKGROUND: The S977F mutation (c.2930C>T) in the CFTR gene (CFTR/ABCC7) is extremely rare. We describe the case of an adult patient carrying the complex allele S977F/T5TG12 in trans with the F508del mutation. Mild respiratory manifestations arose in adulthood associated with azoospermia, acute pancreatitis, minor hemoptysis and Cl(-) levels ranging from 40 to 42 mEq/L. METHOD: Diagnosis was confirmed by repeated NPD measurements, genetic DHPLC analysis and a recently described functional assay measuring cAMP-dependent cell depolarization in peripheral blood monocytes. RESULTS: NPD measurements, DHPLC and monocyte functional assay (CF index=-18). Results were consistent with a CF phenotype. CONCLUSIONS: The combined application of DHPLC and NPD analysis in the algorithm for CF diagnosis appears useful for the management of similar cases. In addition, the novel monocyte functional assay might contribute to improve our diagnostic capability, counseling and better treatment of these challenging clinical cases. PMID- 23361110 TI - Exhaled molecular profiles in the assessment of cystic fibrosis and primary ciliary dyskinesia. AB - BACKGROUND: Early diagnosis and monitoring of disease activity are essential in cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). We aimed to establish exhaled molecular profiles as the first step in assessing the potential of breath analysis. METHODS: Exhaled breath was analyzed by electronic nose in 25 children with CF, 25 with PCD and 23 controls. Principle component reduction and canonical discriminant analysis were used to construct internally cross-validated ROC curves. RESULTS: CF and PCD patients had significantly different breath profiles when compared to healthy controls (CF: sensitivity 84%, specificity 65%; PCD: sensitivity 88%, specificity 52%) and from each other (sensitivity 84%, specificity 60%). Patients with and without exacerbations had significantly different breath profiles (CF: sensitivity 89%, specificity 56%; PCD: sensitivity 100%, specificity 90%). CONCLUSION: Exhaled molecular profiles significantly differ between patients with CF, PCD and controls. The eNose may have potential in disease monitoring based on the influence of exacerbations on the VOC-profile. PMID- 23361111 TI - Granzyme B-dependent and perforin-independent DNA fragmentation in intestinal epithelial cells induced by anti-CD3 mAb-activated intra-epithelial lymphocytes. AB - We previously found that an i.p. injection of anti-CD3 monoclonal antibody (mAb) into mice caused DNA fragmentation in the intestinal villous epithelial cells (IVECs) of the duodenum and the jejunum. In this study, in order to elucidate the mechanism of DNA fragmentation in IVECs, we searched for the inducer(s) of DNA fragmentation by using immunohistochemistry. The release of cytoplasmic granules from intraepithelial lymphocytes (IELs) and the formation of large gaps between IELs and IVECs were observed electron microscopically after antibody administration. The presence and distribution pattern of Granzyme B (GrB), a serine protease in cytolytic granules present in cytotoxic T lymphocytes and natural killer cells and considered to be the responsible molecule for DNA fragmentation in target cells, was examined in detail in intestinal villi by immunohistology. GrB was detected in cytoplasmic granules in nearly all IELs. The time-kinetics of granule release from IELs after mAb injection coincided not only with that of the extracellular diffusion of GrB, but also with that of DNA fragmentation in IVECs. On the other hand, perforin (Pfn), assumed to cooperate with GrB in DNA fragmentation, could not be detected in IELs, and its release was not confirmed after the anti-CD3 mAb injection. Anti-CD3 mAb injection also induced DNA fragmentation in IVECs in Pfn-knockout mice. These results support the notion that DNA fragmentation in IVECs by the stimulated IELs in the present study is induced by a mechanism involving GrB, but independent of Pfn. PMID- 23361112 TI - Type D personality is associated with low cardiovascular reactivity to acute mental stress in heart failure patients. AB - BACKGROUND: The distressed (Type D) personality is associated with adverse coronary heart disease outcomes, but the mechanisms accounting for this association remain to be elucidated. We examined whether myocardial and hemodynamic responses to mental stress are disrupted in Type D patients with chronic heart failure (HF). METHODS: Ninety-nine HF patients (mean age 65+/ 12years; 75% men) underwent a public speech task, during which heart rate (HR) and blood pressure (BP) were recorded. Type D personality and its components negative affectivity (NA) and social inhibition (SI) were assessed with the DS14. General linear models with repeated measures and logistic regression were used to assess differences in stress response and recovery. RESULTS: Type D personality was associated with a reduced HR response (F1,93=4.31, p<.05) independent of the use of beta adrenergic blocking agents and the presence of atrial fibrillation. There were no differences between HF patients with and without a Type D personality with respect to the BP response. Examining continuous NA and SI scores and their interaction (NA*SI), revealed a significant association of NA*SI with the SBP response (F1,93=4.11, p<.05), independent of BP covariates. Results with respect to HR and DBP responses were comparable to the findings using the dichotomous Type D measure. No significant associations between Type D and recovery patterns were found. CONCLUSION: HF patients with Type D personality may show an inadequate response to acute social stress, characterized by a blunted HR response. PMID- 23361113 TI - Clarifying the nature of startle habituation using latent curve modeling. AB - Startle habituation is present in all startle studies, whether as a dependent variable, discarded habituation block, or ignored nuisance. However, there is still much that remains unknown about startle habituation, including the following: (1) what is the nature of the startle habituation curve?; (2) at what point does startle habituation approach an asymptote?; and (3) are there gender differences in startle habituation? The present study investigated these three questions in a sample of 94 undergraduates using both traditional means-based statistical methods and latent curve modeling. Results provided new information about the nature of the startle habituation curve, indicated that the optimal number of habituation trials with a 100dB startle stimulus is 13, and showed that females display greater startle reactivity but habituate toward the same level as males. PMID- 23361114 TI - Machine learning approach for classification of ADHD adults. AB - Machine learning techniques that combine multiple classifiers are introduced for classifying adult attention deficit hyperactivity disorder (ADHD) subtypes based on power spectra of EEG measurements. The analyzed sample includes 117 adults (67 ADHD, 50 controls). The measurements are taken for four different conditions: two resting conditions (eyes open and eyes closed) and two neuropsychological tasks (visual continuous performance test and emotional continuous performance test). We divide the sample into four data sets, one for each condition. Each data set is used for training of four different support vector machine classifiers, while the output of classifiers is combined using logical expression derived from the Karnaugh map. The results show that this approach improves the discrimination between ADHD and control groups, as well as between ADHD subtypes. PMID- 23361115 TI - Solid-phase based on-chip DNA purification through a valve-free stepwise injection of multiple reagents employing centrifugal force combined with a hydrophobic capillary barrier pressure. AB - In this paper, we demonstrate a simple technique for sequentially introducing multiple sample liquids into microchannels driven by centrifugal force combined with a hydrophobic barrier pressure and apply the technique for performing solid phase based on-chip DNA purification. Three microchannels with varying widths, all equipped with independent sample reservoirs at the inlets, were fabricated on a hydrophobic elastomer, poly(dimethylsiloxane) (PDMS). First, glass beads were packed inside the reaction chamber, and a whole cell containing the DNA extract was introduced into the widest channel by applying centrifugal force for physical adsorption of the DNA onto the glass beads. Next, washing and elution solutions were sequentially introduced into the intermediate and narrowest microchannels, respectively, by gradually increasing the amount of centrifugal force. Through a precise manipulation of the centrifugal force, the DNA adsorbed onto the glass beads was successfully washed and eluted in a continuous manner without the need to introduce each solution manually. A stepwise injection of liquids was successfully demonstrated using multiple ink solutions, the results of which corresponded well with the theoretical analyses. As a practical application, the D1S80 locus of human genomic DNA, which is widely used for forensic purposes, was successfully purified using the microdevice introduced in this study, as demonstrated through successful target amplification. This will pave the way for the construction of a control-free valve system for realizing on-chip DNA purification, which is one of the most labor-intensive and hard-to-miniaturize components, on a greatly simplified and miniaturized platform employing hydrophobic PDMS. PMID- 23361116 TI - Renal function outcomes for multifocal renal neoplasms managed by radiofrequency ablation. AB - PURPOSE: To evaluate renal function changes related to radiofrequency ablation (RFA) for the treatment of multifocal renal neoplasms. METHODS: This is an institutional review board-approved, Health Insurance Portability and Accountability Act compliant retrospective study of all patients treated with computed tomography guided RFA for multifocal renal neoplasms at one institution. Fifty-seven subjects, mean age 70 (range 37-88) years, underwent RFA of 169 renal neoplasms (average size 2.0 cm). Subjects had between 2 and 8 (mean 2.96) neoplasms ablated. Estimated glomerular filtration rate (eGFR) was measured before and after RFA. Complications related to RFA were recorded. RESULTS: eGFR decreased on average of 4.4 % per tumor treated and 6.7 % per ablation session (average 1.76 tumors treated per session). For subjects with the largest neoplasm measuring >3 cm, eGFR decreased an average of 14.5 % during the course of their treatment. If the largest neoplasm measured 2-3 cm, eGFR decreased an average of 7.7 %, and if the largest neoplasm measured <2 cm, eGFR decreased an average of 3.8 %. Subjects with reduced baseline renal function were more likely to have a greater decline in eGFR after RFA. There was a minor complication rate of 6.3 % (6 of 96 sessions), none of which required treatment, and a major complication rate of 4.2 % (4 of 96 sessions). CONCLUSION: RFA for the treatment of multifocal renal neoplasms results in mild decline of renal function. PMID- 23361117 TI - Portal vein embolization before right hepatectomy: improved results using n-butyl cyanoacrylate compared to microparticles plus coils. AB - BACKGROUND: There is currently no consensus in the literature on which embolic agent induces the greatest degree of liver hypertrophy after portal vein embolization (PVE). Only experimental results in a pig model have demonstrated an advantage of n-butyl-cyanoacrylate (NBCA) over 3 other embolic materials (hydrophilic gel, small and large polyvinyl alcohol particles) for PVE. Therefore, the aim of this human study was to retrospectively compare the results of PVE using NBCA with those using spherical microparticles plus coils. METHODS: A total of 34 patients underwent PVE using either NBCA (n = 20), or spherical microparticles plus coils (n = 14). PVE was decided according to preoperative volumetry on the basis of contrast-enhanced CT. Groups were compared for age, sex, volume of the left lobe before PVE and future remnant liver ratio (FRL) (volume of the left lobe/total liver volume - tumor volume). The primary end point was the increase in left lobe volume 1 month after PVE. Secondary end points were procedure complications and biological tolerance. RESULTS: Both groups were similar in terms of age, sex ratio, left lobe volume, and FRL before PVE. NBCA induced a greater increase in volume after PVE than did microparticles plus coils (respectively, +74 +/- 69 % and +23 +/- 14 %, p < 0.05). The amount of contrast medium used for the procedure was significantly larger when microparticles and coils rather than NBCA were used (respectively, 264 +/- 43 ml and 162 +/- 34 ml, p < 0.01). The rate of PVE complications as well as the biological tolerance was similar in both groups. CONCLUSION: NBCA seems more effective than spherical microparticles plus coils to induce left-lobe hypertrophy. PMID- 23361118 TI - Combined pharmacomechanical thrombolysis of complete portomesenteric thrombosis in a liver transplant recipient. AB - Treatment options for portomesenteric venous thrombosis range from anticoagulation to surgery, depending on chronicity, severity of symptoms, extent of thrombosis, and the availability of local expertise. For acute and subacute cases, a variety of endovascular options have been described in limited published series and case reports, including thrombolysis and mechanical thrombectomy. We report what is to our knowledge the first case in which the Trellis pharmacomechanical thrombolysis device was used successfully to treat complete acute thrombosis of the entire superior mesenteric vein and the entire portal vein with extension into all segmental intrahepatic portal branches in a young adult after liver transplantation. This device, coupled with adjunctive techniques using balloon catheters, facilitated complete restoration of flow, resulting in graft salvage and long-term patency. PMID- 23361119 TI - MR-guided periarterial ethanol injection for renal sympathetic denervation: a feasibility study in pigs. AB - PURPOSE: To evaluate the feasibility and efficacy of image-guided periarterial ethanol injection as an alternative to transluminal radiofrequency ablation. METHODS: Unilateral renal periarterial ethanol injection was performed under general anesthesia in 6 pigs with the contralateral kidney serving as control. All interventions were performed in an open 1.0 T MRI system under real-time multiplanar guidance. The injected volume was 5 ml (95 % ethanol labelled marked MR contrast medium) in 2 pigs and 10 ml in 4 pigs. Four weeks after treatment, the pigs underwent MRI including MRA and were killed. Norepinephrine (NE) concentration in the renal parenchyma served as a surrogate parameter to analyze the efficacy of sympathetic denervation. In addition, the renal artery and sympathetic nerves were examined histologically to identify evidence of vascular and neural injury. RESULTS: In pigs treated with 10 ml ethanol, treatment resulted in neural degeneration. We found a significant reduction of NE concentration in the kidney parenchyma of 53 % (p < 0.02) compared with the untreated contralateral kidney. In pigs treated with 5 ml ethanol, no significant changes in histology or NE were observed. There was no evidence of renal arterial stenosis in MRI, macroscopy or histology in any pig. CONCLUSION: MR-guided periarterial ethanol injection was feasible and efficient for renal sympathetic denervation in a swine model. This technique may be a promising alternative to the catheter-based approach in the treatment of resistant arterial hypertension. PMID- 23361120 TI - Elevating endogenous GABA levels with GAT-1 blockade modulates evoked but not induced responses in human visual cortex. AB - The electroencephalographic/magnetoencephalographic (EEG/MEG) signal is generated primarily by the summation of the postsynaptic currents of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally connected to GABAergic interneurons. Here we investigated the relative sensitivity of visual evoked and induced responses to altered levels of endogenous GABAergic inhibition. To do this, we pharmacologically manipulated the GABA system using tiagabine, which blocks the synaptic GABA transporter 1, and so increases endogenous GABA levels. In a single-blinded and placebo-controlled crossover study of 15 healthy participants, we administered either 15 mg of tiagabine or a placebo. We recorded whole-head MEG, while participants viewed a visual grating stimulus, before, 1, 3 and 5 h post tiagabine ingestion. Using beamformer source localization, we reconstructed responses from early visual cortices. Our results showed no change in either stimulus-induced gamma-band amplitude increases or stimulus-induced alpha amplitude decreases. However, the same data showed a 45% reduction in the evoked response component at ~80 ms. These data demonstrate that, in early visual cortex the evoked response shows a greater sensitivity compared with induced oscillations to pharmacologically increased endogenous GABA levels. We suggest that previous studies correlating GABA concentrations as measured by magnetic resonance spectroscopy to gamma oscillation frequency may reflect underlying variations such as interneuron/inhibitory synapse density rather than functional synaptic GABA concentrations. PMID- 23361121 TI - Self-assembly of mesoporous CuO nanosheets-CNT 3D-network composites for lithium ion batteries. AB - A facile, flexible and large-scale technique was proposed to prepare a CuO-CNT 3D network composite with the aid of electrostatic interactions in aqueous solution. The composite greatly improves the electrochemical performance. At a rate of 0.1 C, the cycling discharge capacity of the optimal composite is more than 2.3 times of that of unmodified mesoporous CuO nanosheets as the active material in an anode after 40 cycles. PMID- 23361122 TI - Gaining insight into the chemistry of lipoxygenases: a computational investigation into the catalytic mechanism of (8R)-lipoxygenase. AB - Lipoxygenases (LOXs) are ubiquitous in nature and catalyze a range of life essential reactions within organisms. In particular they are critical to the formation of eicosanoids, which are critical for normal cell function. However, a number of important questions about the reactivity and mechanism of these enzymes still remain. Specifically, although the initial step in the mechanism of LOXs has been well studied, little is known of subsequent steps. Thus, with use of a quantum mechanical/molecular mechanical approach, the complete catalytic mechanism of (8R)-LOX was investigated. The results have provided a better understanding of the general chemistry of LOXs as a whole. In particular, from comparisons with soybean LOX-1, it appears that the initial proton-coupled electron transfer may be very similar among all LOXs. Furthermore, LOXs appear to undergo multistate reactivity where potential spin inversion of an electron may occur either in the attack of O(2) or in the regeneration of the active site. Lastly, it is shown that with the explicit modeling of the environment, the regeneration of the active center likely occurs via the rotation of the intermediate followed by an outer-sphere [Formula: see text] transfer as opposed to the formation of a "purple intermediate" complex. PMID- 23361123 TI - Photoconductive properties of a pi-conjugated alpha-cyclodextrin containing [2]rotaxane and its corresponding molecular dumbbell. AB - The photoconductive properties of an azo-containing [2]rotaxane, bearing a pi conjugated axial part and its corresponding dumbbell compound are investigated. Structural effects on the observed photoconductive behavior in both cases are discussed. The photoresponsive behavior of the title [2]rotaxane was proved to be more intense than that of its analogue lacking the alpha-cyclodextrin (alpha-CyD) macrocycle. A mechanism of the photoinduced charge transport in both cases is proposed. PMID- 23361124 TI - Evidence-based consensus on the insertion of central venous access devices: definition of minimal requirements for training. AB - There is a lack of standard minimal requirements for the training of insertion techniques and maintenance of central venous access devices (CVADs). An international evidence-based consensus task force was established through the World Congress of Vascular Access (WoCoVA) to provide definitions and recommendations for training and insertion of CVADs. Medical literature published from February 1971 to April 2012 regarding 'central vascular access', 'training', 'competency', 'simulation', and 'ultrasound' was reviewed on Pubmed, BioMed Central, ScienceDirect, and Scopus databases. The GRADE and the GRADE-RAND methods were utilized to develop recommendations. Out of 156 papers initially identified, 83 papers described training for central vascular access placement. Sixteen recommendations are proposed by this task force, each with an evidence level, degree of consensus, and recommendation grade. These recommendations suggest central venous access education include didactic or web-based teaching with insertion procedure, infection prevention, complications, care, and maintenance of devices, along with laboratory models and tools for simulation practice incorporating ultrasound. Clinical competence should be determined by observation during clinical practice using a global rating scale rather than by the number of procedures performed. Ensuring safe insertion and management of central venous devices requires standardized education, simulation practice, and supervised insertions. PMID- 23361125 TI - Biodegradation and proton exchange using natural rubber in microbial fuel cells. AB - Microbial fuel cells (MFCs) generate electricity from waste but to date the technology's development and scale-up has been held-up by the need to incorporate expensive materials. A costly but vital component is the ion exchange membrane (IEM) which conducts protons between the anode and cathode electrodes. The current study compares natural rubber as an alternative material to two commercially available IEMs. Initially, the material proved impermeable to protons, but gradually a working voltage was generated that improved with time. After 6 months, MFCs with natural rubber membrane outperformed those with anion exchange membrane (AEM) but cation exchange membrane (CEM) produced 109 % higher power and 16 % higher current. After 11 months, polarisation experiments showed a decline in performance for both commercially available membranes while natural rubber continued to improve and generated 12 % higher power and 54 % higher current than CEM MFC. Scanning electron microscope images revealed distinct structural changes and the formation of micropores in natural latex samples that had been employed as IEM for 9 months. It is proposed that the channels and micropores formed as a result of biodegradation were providing pathways for proton transfer, reflected by the steady increase in power generation over time. These improvements may also be aided by the establishment of biofilms that, in contrast, caused declining performance in the CEM. The research demonstrates for the first time that the biodegradation of a ubiquitous waste material operating as IEM can benefit MFC performance while also improving the reactor's lifetime compared to commercially available membranes. PMID- 23361126 TI - A global proteome study of Mycobacterium gilvum PYR-GCK grown on pyrene and glucose reveals the activation of glyoxylate, shikimate and gluconeogenetic pathways through the central carbon metabolism highway. AB - Various hydrocarbons have been released into the environment as a result of industrialization. An effective way of removing these materials without further environmental contamination is microbial bioremediation. Mycobacterium gilvum PYR GCK, a bacteria isolated from a PAH polluted estuary, was studied using comparative shotgun proteomics to gain insight on its molecular activity while using pyrene and glucose as sole carbon and energy sources. Based on annotated genomic information, a confirmation analysis was first performed to confirm its pyrene degradation activity, using gas chromatography-mass spectrometry technology. One dimensional gel electrophoresis and liquid chromatography-mass spectrometry technologies employed in the proteomics analysis revealed the expression of pyrene degrading gene products along with upregulated expression of proteins functioning in the glyoxylate and shikimate pathways, in the pyrene induced cells. The study also revealed the pathway of pyrene degraded intermediates, via partial gluconeogenesis, into the pentose phosphate pathway to produce precursors for nucleotides and amino acids biosynthesis. PMID- 23361127 TI - Strains of the soil fungus Mortierella show different degradation potentials for the phenylurea herbicide diuron. AB - Microbial pesticide degradation studies have until now mainly focused on bacteria, although fungi have also been shown to degrade pesticides. In this study we clarify the background for the ability of the common soil fungus Mortierella to degrade the phenylurea herbicide diuron. Diuron degradation potentials of five Mortierella strains were compared, and the role of carbon and nitrogen for the degradation process was investigated. Results showed that the ability to degrade diuron varied greatly among the Mortierella strains tested, and the strains able to degrade diuron were closely related. Degradation of diuron was fastest in carbon and nitrogen rich media while suboptimal nutrient levels restricted degradation, making it unlikely that Mortierella utilize diuron as carbon or nitrogen sources. Degradation kinetics showed that diuron degradation was followed by formation of the metabolites 1-(3,4-dichlorophenyl)-3 methylurea, 1-(3,4-dichlorophenyl)urea and an hitherto unknown metabolite suggested to be 1-(3,4-dichlorophenyl)-3-methylideneurea. PMID- 23361129 TI - Trauma. PMID- 23361128 TI - Cardiac output monitoring in septic shock: evaluation of the third-generation Flotrac-Vigileo. AB - Continuous cardiac index (CI) monitoring is frequently used in critically ill patients. Few studies have compared the pulse contour-based device FloTrac/Vigileo to pulmonary artery thermodilution (PAC) in terms of accuracy for CI monitoring in septic shock. The aim of our study was to compare the third generation FloTrac/Vigileo to PAC in septic shock. Eighteen patients with septic shock requiring monitoring by PAC were included in this study. We monitored CI using both FloTrac/Vigileo and continuous thermodilution (PAC-CI). Hemodynamic data were recorded every hour or every 2 min during fluid challenges. The primary endpoint was the global agreement of all CI-paired measurements determined using the Bland-Altman method adapted to replicated data. We tested the linearity of the bias by regression analysis, and compared the reactivity of the 2 techniques during fluid challenges. A receiver operating characteristic (ROC) curve analysis tested the ability of FloTrac/Vigileo to detect concordant and significative CI changes, using PAC-CI as the reference method. Overall, 1,201 paired CI measurements were recorded. The Bland-Altman analysis for global agreement of the 2 techniques showed a bias of -0.1 +/- 2.1 L min(-1) m(-2) and a percentage error of 64 %. The overall correlation coefficient between PAC-CI and FloTrac/Vigileo CI was 0.47 (p < 0.01), with r(2) = 0.22. The area under the curve of the ROC curve for detecting concordant and significant changes in CI was 0.72 (0.53; 0.87). In our study, third-generation Flowtrac-Vigileo appears to be too inaccurate to be recommended for CI monitoring in septic shock. PMID- 23361130 TI - Resuscitation beyond the abdominal compartment syndrome. AB - PURPOSE OF REVIEW: In the 1980s, we witnessed tremendous advances in trauma care including trauma system development, advanced trauma life support, damage control surgery and ICU resuscitation. As a result, patients who used to bleed to death in the operating room survived. However, many went on to develop multiple organ failure (MOF) and in the mid-1990s, an epidemic of abdominal compartment syndrome (ACS) that emerged in these MOF survivors stimulated fundamental changes in early management of patients arriving in shock with severe bleeding. RECENT FINDINGS: In the early 2000s, a massive transfusion protocol (emphasizing aggressive use of fresh frozen plasma) coupled with hypotensive resuscitation and rapid hemorrhage control were implemented and refined at a busy level I trauma center in Houston, Texas, USA. These changes were associated with a 50% reduction in mortality in massive transfusion patients, and ACS virtually disappeared. SUMMARY: ACS is a modifiable link in the MOF cascade to death after severe shock. However, as ACS disappears, MOF is still occurring. Although fewer patients are dying of MOF, it remains the leading cause of prolonged ICU stays and long-term disability. This experience underscores the importance of ongoing epidemiologic characterization of postinjury MOF. PMID- 23361131 TI - Bibliography. Current world literature. Renal system. PMID- 23361133 TI - Highly fluorescent complexes with gold, palladium or platinum linked to perylene through a tetrafluorophenyl group. AB - Treatment of 3-(1-hexynyl)perylene with Co2(CO)8 resulted in the formation of the dinuclear cobalt complex [Co2(CO)6(MU-eta(2)-C4H9C=C-Per)] (Per = 3-perylenyl) (1). The perylene derivatives 3-(2,3,5,6-tetrafluorophenyl)perylene (PerC6F4H) and 3-(2,3,5,6-tetrafluorophenyl)-9(10)hexylperylene (C6-PerC6F4H) were prepared and used to synthesize [AuR(CN(t)Bu)] (R = PerC6F4 2a), [AuR(CN(C6H2)-3,4,5 (OC12H25)3)] (R = PerC6F4 (3a), R = C6-PerC6F4 (3b)), trans-[PdR(PR'3)2X] (R = PerC6F4, R' = Ph, X = I (4a)); (R = C6-PerC6F4, R' = Ph, X = I (4b)); (R = PerC6F4, R' = Et, X = I (5a)); (R = C6-PerC6F4, R' = Et, X = I (5b)); (R = PerC6F4, R' = Ph, X = NCS (6a)), and trans-[Pd(PerC6F4)(PEt3)2X] (X = Br (7a); X = I (8a)). The molecular structure of complexes 1, 2a and 6a has been determined by X-ray diffraction analysis. The perylenyl fragments of complexes 2a or 6a are essentially planar and make dihedral angles to the tetrafluorophenyl plane of 57.49 degrees (2a) and 77.75 degrees (6a). No pi-pi stacking of perylenyl rings is observed in any of the three molecules, but 2a shows association of two monomers (arranged almost antiparallel), with an Au...Au distance of 3.114 A. DFT calculations were performed on the absorption spectra of representative PerC6F4Y (Y = H, F, Au(CNMe), PtBr(PMe3)2 and PdBr(PMe3)2). All complexes exhibit fluorescence associated with the perylene fragment with emission quantum yields, in solution at room temperature, in the range 0.20-0.90 and emission lifetimes ~4 ns, and no significant differences in the emission maxima, due to an efficient electronic decoupling of the metal fragment from the HOMO and LUMO of the perylene chromophore. The latter is confirmed by DFT calculations. PMID- 23361134 TI - Enantioselective formal synthesis of ent-rhynchophylline and ent isorhynchophylline. AB - Starting from (S)-tryptophanol, a formal synthesis of ent-rhynchophylline and ent isorhynchophylline, involving stereoselective cyclocondensation, spirocyclization, and alkylation reactions, and the final adjustment of the oxidation level at the oxindole and piperidine moieties, is reported. PMID- 23361135 TI - Prediction of heart rate response to conclusion of the spontaneous breathing trial by fluctuation dissipation theory. AB - The non-equilibrium fluctuation dissipation theorem is applied to predict how critically ill patients respond to treatment, based upon data currently collected by standard hospital monitoring devices. This framework is demonstrated on a common procedure in critical care: the spontaneous breathing trial. It is shown that the responses of groups of similar patients to the spontaneous breathing trial can be predicted by the non-equilibrium fluctuation dissipation approach. This mathematical framework, when fully formed and applied to other clinical interventions, may serve as part of the basis for personalized critical care. PMID- 23361136 TI - Mortality in middle-aged men with obstructive sleep apnea in Finland. AB - INTRODUCTION: Obstructive sleep apnea (OSA) has been associated with an elevated rate of cardiovascular mortality. However, this issue has not been investigated in patients with elevated proneness to cardiovascular diseases. Our hypothesis was that OSA would have an especially adverse effect on the risk of cardiovascular mortality in Finnish individuals exhibiting elevated proneness for coronary heart diseases. METHODS: Ambulatory polygraphic recordings from 405 men having suspected OSA were retrospectively analyzed. The patients were categorized regarding sleep disordered breathing into a normal group (apnea hypopnea index (AHI) < 5, n = 104), mild OSA group (5 <= AHI < 15, n = 100), and moderate to severe OSA group (AHI >= 15, n = 201). In addition, basic anthropometric and health data were collected. In patients who died during the follow-up period (at least 12 years and 10 months), the primary and secondary causes of death were recorded. RESULTS: After adjustment for age, BMI, and smoking, the patients with moderate to severe OSA suffered significantly (p < 0.05) higher mortality (hazard ratio 3.13) than their counterparts with normal recordings. The overall mortality in the moderate to severe OSA group was 26.4 %, while in the normal group it was 9.7 %. Hazard ratio for cardiovascular mortality was 4.04 in the moderate to severe OSA and 1.87 in the mild OSA group. CONCLUSIONS: OSA seems to have an especially adverse effect on the cardiovascular mortality of patients with an elevated genetic susceptibility to coronary heart diseases. When considering that all our patients had possibility of continuous positive airway pressure treatment and our reference group consisted of patients suffering from daytime somnolence, the hazard ratio of 4.04 for cardiovascular mortality in patients with moderate to severe disease is disturbingly high. PMID- 23361137 TI - The impact of diet and lifestyle management strategies for obstructive sleep apnoea in adults: a systematic review and meta-analysis of randomised controlled trials. AB - PURPOSE: To systematically evaluate the impact of diet, exercise and lifestyle modification programmes on indices of obesity, Obstructive Sleep Apnoea (OSA) parameters and quality of life (QoL) in adults with OSA. METHODS: Electronic databases were searched to identify randomised controlled trials published in English with an intervention based on dietary weight loss, exercise and/or lifestyle programme in adults with OSA. Meta-analyses were conducted using random effects models. RESULTS: Twelve studies met the inclusion criteria with nine comparing similar interventions. Diet and diet plus continuous positive airway pressure (CPAP) therapy were compared in three studies (n = 261), and intensive lifestyle programmes and routine care were compared in six studies (n = 483). Diet with CPAP therapy reduced weight by -2.64 kg (95 % Confidence Interval (CI) 3.98, -1.30, I (2) = 0 %) compared with diet alone. No differences were observed for QoL or Epworth Sleepiness Scale. A significant reduction in weight was seen in participants receiving an intensive lifestyle intervention of -5.65 kg (95 % CI -10.91, -0.40, I(2) = 95.7 %) compared with controls. Reductions were also observed for waist circumference (-5.80 cm, 95 % CI -8.64, -2.96, I(2) = 77.7 %), body mass index (BMI) (-2.33 kg/m(2), 95 % CI -3.41, -1.24, I(2) = 78.8 %) and the Apnoea Hypopnoea Index (AHI) (-4.55 events/h, 95 % CI -7.12, -1.98, I(2) = 54.4 %) but with high levels of heterogeneity. CONCLUSIONS: Intensive lifestyle management can significantly reduce obesity indices and improve AHI. Future research is required to investigate this effect due to a limited number of studies identified. PMID- 23361138 TI - Levels of TBARS are inversely associated with lowest oxygen saturation in obese patients with OSAS. AB - PURPOSE: The aim of this study was to investigate the most important factors that determine lipid peroxidation in obese patients with obstructive sleep apnoea syndrome (OSAS). METHODS: Twenty-one obese patients with OSAS based on overnight attended polysomnography were included. Thiobarbituric acid reactive substances (TBARS) were measured in serum. Anthropometric measurements were carried out. Dietary habits were assessed by a standardised food frequency questionnaire. RESULTS: Spearman's correlation analysis showed significant positive correlations between TBARS and apnoea-hypopnoea index and desaturations/hour while negative between TBARS and mean/lowest oxygen saturation. The most significant predicting factor in the multiple linear regression model was lowest oxygen saturation. CONCLUSIONS: This study has revealed an independent association between lowest oxygen saturation and TBARS levels after controlling for age, gender, diet and obesity in predominantly male patients with moderate to severe OSAS. PMID- 23361140 TI - Supernumerary intrathoracic rib. PMID- 23361139 TI - In vitro hypoxic cytotoxicity and hypoxic radiosensitization. Efficacy of the novel 2-nitroimidazole N,N,N-tris[2-(2-nitro-1H-imidazol-1-yl)ethyl]amine. AB - BACKGROUND AND PURPOSE: Tumor hypoxia is a major problem in radiation therapy of solid tumors because of the radiosensitizing effect of oxygen. Nitroimidazole containing compounds are oxygen mimetics accumulating in hypoxic tumor areas. However, the broad use of 2-nitroimidazoles as a hypoxic radiosensitizer is limited by their partially low efficacy and/or high neurotoxicity. MATERIALS AND METHODS: Here, we characterized the in vitro hypoxic cytotoxicity and hypoxic radiosensitizing efficacy of N,N,N-tris [2-(2-nitro-1H-imidazol-1-yl)ethyl]amine (PRC) in a hypoxia-sensitive lymphoma and a hypoxia-resistant glioblastoma cell line by colony formation assay and flow cytometry. RESULTS: PRC exerted high hypoxic cytotoxic and radiosensitizing action on both cell lines at almost absent toxicity under normoxic conditions. In particular, under hypoxia, but not normoxia, PRC targeted the mitochondria resulting in oxidative stress, G(2)/M cell cycle arrest, and triggering of the intrinsic apoptosis pathway. CONCLUSION: Our in vitro findings suggest that PRC might be a promising new 2-nitroimidazole for improving radiation therapy of hypoxic tumors in vivo. PMID- 23361141 TI - Male circumcision: risk versus benefit. PMID- 23361142 TI - Surgical patients' and nurses' opinions and expectations about privacy in care. AB - The purpose of this study was to determine the opinions and expectations of patients and nurses about privacy during a hospital admission for surgery. The study explored what enables and maintains privacy from the perspective of Turkish surgical patients and nurses. The study included 102 adult patients having surgery and 47 nurses caring for them. Data were collected via semistructured questionnaire by face-to-face interviews. The results showed that patients were mostly satisfied by the respect shown to their privacy by the nurses but were less confident of the confidentiality of their personal data. It was found that patients have expectations regarding nursing approaches and attitudes about acknowledging and respecting patient autonomy and confidentiality. It is remarkable that while nurses focused on the physical dimension of privacy, patients focused on informational and psychosocial dimensions of privacy, as well as its physical dimension. PMID- 23361143 TI - Older people in long-term care settings as research informants: ethical challenges. AB - Conducting nursing research in long-term care facilities and with samples of older people requires careful attention to research ethics and the ethical conduct of the study. This review analysed the research ethics of the empirical studies that focus on older people in long-term care settings as research participants. Articles (n = 66) focussing on older people in long-term care settings as research informants were retrieved from an electronic search of MEDLINE (1990 to February 2012) using the MESH terms 'Nursing' AND 'Long-term care' (578 citations) and 'Institutionalization' and 'Nursing' (89 citations). Ethical approval procedure was reported in more than half of the studies (58%) and informed consent in two-thirds of the studies (70%). Ethical issues in data collection were described in most of the articles, but only a few reported ethics in problem statement, reporting or presenting implications. There is a need to focus on reporting research ethics and procedures in empirical research on vulnerable people. PMID- 23361144 TI - Nurses' dilemmas concerning support of relatives in mental health care. AB - Relatives of persons with severe mental illness face a straining life situation and need support. Exclusion of relatives in mental health care has long been reported. The aim of this study was to describe conceptions of nurses in mental health care about supporting relatives of persons with severe mental illness. Focus group interviews with nurses from all levels of mental health care in Norway were performed. A phenomenographic approach was used. The nurses found that their responsibility first and foremost was the patient, especially to develop an alliance with him or her. Additional premises for supporting relatives were the context framing the nursing care, aspects of the actors, and relational concerns between them. Competing or contradictory demands were found within these premises. Two paths were identified concerning the nurses' support of relatives: seeing the relative in the shadow of the patient or as an individual person. PMID- 23361145 TI - Mind the gaps in ethical regulations of nursing research. AB - The introduction of and the commitment to evidence-based nursing in all care settings have led to a rapid increase of intervention and outcome-based research programs. Yet, the topics of nursing research are not only affected by interventions and outcomes but also affected by the concept of caring derived from humanistic philosophy. Considering this twofold orientation of nursing science, nuanced ethical regulations for nursing research programs are called for. In addition to the different research approaches, further arguments for ethical regulations are as follows: first, the different degrees of contextualization and the variety of participation models regarding the target groups; second, the capacities and opportunities of participants; and third, the caring relationship between nurses and research subjects. To capture these special features of nursing science, four approaches to fill the gaps in existing ethical regulations for nursing research are proposed: (a) process orientation, (b) community orientation, (c) context orientation, and (d) relation orientation. PMID- 23361146 TI - Recognizing bioethical issues and ethical qualification in nursing students and faculty in South Korea. AB - The role of nursing faculty members in charge of ethics education is important. Although all nursing students receive the same bioethics education, their experiences differ, related to ethical qualification, which depends on the personal socialization process. This Korean study aimed to provide nursing faculty members with the basic data to help them develop as bioethics experts and provide nursing students with knowledge to improve their ethical decision-making abilities. We used a survey design to assess recognition of bioethical issues and ethical qualification in nursing students and faculty members. A total of 1225 undergraduate students and 140 faculty members participated in this study. The results revealed that nursing students and nursing faculty members generally understood the seriousness of various bioethical issues and both considered the most serious issue to concern abortion. Ethical behavior can be improved by education, and accordingly, nursing ethics should be a mandatory subject, rather than an elective one. PMID- 23361147 TI - Dealing with troubled conscience in municipal care of older people. AB - Troubled conscience may jeopardize the health of healthcare personnel and, hence, the quality of care provided. Learning more about how personnel deal with their troubled conscience therefore seems important. The aim of this study was to describe personnel's experiences of how they deal with troubled conscience generated in their daily work in municipal care of older people. Interviews were conducted with 20 care providers and analysed with a thematic content analysis. The findings show that in order to deal with troubled conscience, personnel dialogued with themselves and with others. They took measures in a direction they perceived to be correct, and they expressed a need for distancing and re energizing. It is of importance to share situations that generate troubled conscience in order to find ways to deal with them. Reconsidering one's ways of dealing with troubled conscience may give care providers an opportunity to reach consensus within themselves. PMID- 23361148 TI - Spirituality and post-graduate students' attitudes towards blood donation. AB - College students have become more representative as blood donors, mainly to help other people. This study ascertained the association between spirituality and adherence or intention to donate blood in post-graduate students. In this quantitative and cross-sectional study, participants were 281 students from a post-graduate programme at a Brazilian public university. After complying with ethical requirements, data were collected through a questionnaire for sociodemographic characterization and identification of blood donation practices, followed by the Spiritual Well-Being Scale. Descriptive statistics and parametric tests were used for data analysis. A total of 74% of the participants were female and 26% were male. Previous experience and/or intention to donate blood were found in 75.3%; 14.3% donated blood periodically. In addition, 12.2% were not adept to donation and 12.5% were inapt. Spiritual Well-Being scores were similar between individuals who are not adept and those who donate periodically. In conclusion, in the sample, spirituality and blood donation are not associated, but spiritual well-being and gender are. To enhance blood donation, further research is needed. PMID- 23361149 TI - A few thoughts on "Interventional radiology in the management of benign biliary stenoses, biliary leaks and fistulas: a pictorial review". PMID- 23361150 TI - Reply to: A few thoughts on "Interventional radiology in the management of benign biliary stenoses, biliary leaks and fistulas: a pictorial review". PMID- 23361151 TI - Erratum to: MRI and CT of anal carcinoma: a pictorial review. PMID- 23361152 TI - Fluctuating selection and immigration as determinants of the phenotypic composition of a population. AB - It is important to identify the factors that affect the evolutionary potential of populations to respond to environmental changes. Such processes are for example the ones affecting the amount of heritable phenotypic variation in a population. We examined factors explaining the wide phenotypic variation in the genetically determined black-brown dorsal colouration of male pied flycatchers (Ficedula hypoleuca) during a period of >50 years in a northern European breeding population. We demonstrate that the temperature-dependent relative breeding success of brown males predicts the inter-annual change in the proportion of the brown male phenotype. The proportion of brown males also appears to reflect immigration from Central Europe, where the brown type prevails due to local selection pressure. Warm springs in northern Central Europe had a positive effect on the proportion of the brown phenotype in the north in the early part of the study period, which suggests prolonged migration in favourable conditions. However, the association between warm springs and a high proportion of brown males has weakened from the 1950s to the present, which may explain why the proportion of the brown males in our study area decreased by a third during the period 1954 to 2008. This is likely a result of decreasing population size in Central Europe. These results demonstrate that temporal variation in environmental conditions is maintaining variation in the pied flycatcher male phenotype. They also indicate that climate warming has the potential to change the population composition both through temperature-dependent selection and environmental factors affecting long-distance immigration. PMID- 23361153 TI - Ant exclusion in citrus over an 8-year period reveals a pervasive yet changing effect of ants on a Mediterranean spider assemblage. AB - Ants and spiders are ubiquitous generalist predators that exert top-down control on herbivore populations. Research shows that intraguild interactions between ants and spiders can negatively affect spider populations, but there is a lack of long-term research documenting the strength of such interactions and the potentially different effects of ants on the diverse array of species in a spider assemblage. Similarly, the suitability of family-level surrogates for finding patterns revealed by species-level data (taxonomic sufficiency) has almost never been tested in spider assemblages. We present a long-term study in which we tested the impact of ants on the spider assemblage of a Mediterranean citrus grove by performing sequential 1-year experimental exclusions on tree canopies for 8 years. We found that ants had a widespread influence on the spider assemblage, although the effect was only evident in the last 5 years of the study. During those years, ants negatively affected many spiders, and effects were especially strong for sedentary spiders. Analyses at the family level also detected assemblage differences between treatments, but they concealed the different responses to ant exclusion shown by some related spider species. Our findings show that the effects of experimental manipulations in ecology can vary greatly over time and highlight the need for long-term studies to document species interactions. PMID- 23361154 TI - Desorption of single-stranded nucleic acids from graphene oxide by disruption of hydrogen bonding. AB - Graphene oxide (GO) is known to interact with single-stranded nucleic acids through pi-stacking interactions and hydrogen bonds between the nucleobases and the hexagonal cells of GO. It also quenches the fluorescence when the fluorophore comes near to the GO mesh. When single-stranded (ss) regions of either DNA or RNA are present, those regions were adsorbed onto the surface of GO with a quenching of fluorescence located proximally to the GO surface. We demonstrated that bound single-stranded nucleic acids can be readily dissociated from GO by disrupting hydrogen bonding with urea, which was confirmed with fluorescence measurement and gel electrophoresis. Hydrogen bonding mainly contributes to the interaction between GO and single-stranded nucleic acids such as ssDNA and RNA. The GO-coated mesoporous silica nanoparticles (GO-MSNs) were synthesized for better separation of RNAs from cells. Cellular RNAs were readily adsorbed and eluted with ease by using GO-MSN and urea, respectively, demonstrating that GO-MSN and urea elution is a facile RNA extraction method. PMID- 23361155 TI - Could zinc supplementation improve bone status in growth hormone (GH) deficient children? PMID- 23361156 TI - Factors determining the risk of the metabolic syndrome: is there a central role for adiponectin? AB - BACKGROUND AND OBJECTIVES: The pathogenesis of the metabolic syndrome (MetS) is not well understood. This review is based on the hypothesis that both traditional and emerging risk factors act through adiponectin. SUBJECTS AND METHODS: We conducted a search of the literature using prominent electronic databases and search terms that included in combination: adiponectin, diet, dietary patterns, exercise, metabolic rate, MetS and testosterone. Articles were restricted to studies conducted on adult humans, reported in English and within the time period 2000-2012. RESULTS AND CONCLUSIONS: Both traditional and emerging risk factors associated with the MetS show some evidence of exerting their influence through adiponectin. High-quality randomized controlled trials that alter adiponectin levels are required to further corroborate this hypothesis. PMID- 23361157 TI - Relationship between BMI and body fatness in three European countries. AB - BACKGROUND/OBJECTIVES: Body fatness and heart disease risk factors can differ considerably between ethnities for a given body mass index (BMI). Information is lacking on differences between various Caucasian populations within Europe. The aim was to investigate the differences in anthropometrics and risk factors between adults from Iceland, Spain and Ireland. SUBJECT/METHODS: This was a secondary analysis of the baseline data from the SEAFOODplus YOUNG intervention study, in which 324 subjects (20-40 years, BMI 27.5-32.5 kg/m(2), from Iceland, Spain and Ireland) participated. Fasting glucose, insulin, blood lipids and body compossition were measured, insulin resistance was calculated using the homeostasis model assessment of insulin resistance. RESULTS: Although age and BMI did not differ between Spanish, Irish and Icelandic subjects, Irish subjects had significantly higher waist circumference (3.2 and 6.7 cm) and body fat percentage (4.4 and 2.0%) compared with Icelandic and Spanish participants, respectively. Irish participants had also more unfavorable cardio-metabolic risk factors compared with Spanish and Icelandic subjects. However, correction for waist attenuated the observed differences considerably, in particular for total cholesterol, low-density lipoprotein and triglycerides. CONCLUSIONS: Despite having near identical BMI and age, our results show that study participants from different populations within Europe differ considerably in cardio-metabolic risk factors, partly due to differences in body fat distribution. PMID- 23361159 TI - Addressing malnutrition while avoiding obesity: minding the balance. AB - Latin America has experienced rapid demographic, epidemiological and nutrition changes that have successfully contributed to decreasing undernutrition, but concomitantly have resulted in an increase of obesity and associated conditions; in this paper we propose that policies to address undernutrition have not adapted at a sufficiently rapid pace to address the emerging challenges. Taking Chile as an example we show that health promotion policies, implemented only when the obesity epidemic was well advanced, have succeeded in establishing effective regulatory frameworks and in implementing national large-scale programs for treatment; however, they have been insufficient in preventing obesity. The main lessons learned are: (1) Failure to monitor existing malnutrition programs for changing needs and true effectiveness can have unintended consequences. (2) Institutions and professionals working in nutrition and health need to assess changing scenarios and redefine their priorities for action accordingly. (3) There is a need to provide updated information to decision makers, program planners and to the population at large on how to promote and achieve healthy food consumption and active living considering local context. Timely policies and interventions to address these issues may contribute to the prevention of the obesity epidemic in transitional countries, particularly among low socioeconomic groups. PMID- 23361158 TI - Effects of high-dose cholecalciferol on serum markers of inflammation and immunity in patients with early chronic kidney disease. AB - BACKGROUND/OBJECTIVES: Vitamin D has anti-inflammatory and immune-regulating properties. We aimed to determine if high-dose cholecalciferol supplementation for 1 year in subjects with early chronic kidney disease (CKD) improved circulating markers of inflammation and immunity. SUBJECTS/METHODS: In this double-blind, randomized, placebo-controlled trial, 46 subjects with early CKD (stages 2 and 3) were supplemented with oral cholecalciferol (50 000 IU weekly for 12 weeks followed by 50 000 IU every other week for 40 weeks) or a matching placebo for 1 year. Serum tumor necrosis factor-alpha, interleukin-6, monocyte chemoattractant protein-1 (MCP-1), interferon gamma-induced protein-10 and neutrophil gelatinase-associated lipocalin were measured at baseline, 12 weeks and 1 year. Serum cathelicidin (LL-37) was measured at baseline and 12 weeks. An in vitro experiment was performed to investigate the effect of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) treatment on MCP-1 secretion in THP-1 monocytes activated with lipopolysaccharide (LPS) and Pseudomonas aeruginosa. RESULTS: By 12 weeks, serum MCP-1 decreased in the cholecalciferol group (66.2+/-2.5 to 60.8+/-2.6 pg/ml, group-by-time interaction P=0.02) but was not different from baseline at 1 year. Other markers of inflammation and immunity did not change. In vitro, LPS- and Pseudomonas-activated monocytes treated with 1,25(OH)2D3 had significantly less MCP-1 secretion compared with untreated cells. CONCLUSIONS: High-dose cholecalciferol decreased serum MCP-1 concentrations by 12 weeks in patients with early CKD, although the decrease was not maintained for the remainder of the year. In vitro results confirm an MCP-1-lowering effect of vitamin D. Future studies should determine if vitamin D-mediated reductions in MCP-1 concentrations reflect improved clinical outcomes. PMID- 23361160 TI - Water: neglected, unappreciated and under researched. AB - Water, an essential nutrient, is often ignored in reports of dietary surveys and nutrition. Although it is ubiquitous in foods and beverages, the attention is often focused on the minerals or calorific values of the fluids imbibed rather than the water per se. Water is often taken for granted by many in Western countries due to its abundant availability through water systems. In developing countries, however, water and sanitation raise significant problems. This review overviews (i) the global perspective of the potable water supply, (ii) human rights and water, (iii) dietary guidelines and sources of water and (iv) the physiology of water balance. Gaps in knowledge and understanding around hydration and water requirements are also discussed. Nutritionists are urged to look at the bigger picture of the global water supply and to use good judgement and common sense when advising on water requirements. PMID- 23361161 TI - Dietary advanced glycation end-product restriction for the attenuation of insulin resistance, oxidative stress and endothelial dysfunction: a systematic review. AB - The benefits of advanced glycation end-product (AGE)-restricted diets in humans are unclear. This review aimed to determine the effect of dietary AGE restriction on the inflammatory profiles of healthy adults and adults with diabetes or renal failure. Eight computer databases were searched for controlled feeding trials published in English between January 1997 and December 2012. Human trials were included if at least one group received an AGE-restricted dietary intervention. A total of 12 trials reporting on 289 participants were included in the review. Five trials (42%) were of high methodological quality. Meta-analysis of two long term (16 week) trials provided evidence favoring an AGE-restricted diet for the reduction of 8-isoprostanes (standardized mean difference 0.9; 95% confidence interval (CI): 0.3-1.5) and tumor necrosis factor-alpha (1.3; 95% CI: 0.6-1.9) in healthy adults. Intermediate-term dietary AGE restriction in adults with chronic renal failure reduced serum VCAM-1 (0.9; 95% CI: 0.1-1.7). Individual trials provided some evidence that long-term dietary AGE restriction reduces HOMA-IR (1.4; 95% CI: 0.3-2.6) and AGE-modified low-density lipoprotein (2.7; 95% CI: 1.6 3.9) in adults with type 2 diabetes. Generalisability is limited, as 75% of studies were of less than 6 weeks duration and more than half were of low methodological quality. Evidence quality ranged from low to very low, limiting the conclusions that can be drawn from this review. There is currently insufficient evidence to recommend dietary AGE restriction for the alleviation of the proinflammatory milieu in healthy individuals and patients with diabetes or renal failure. Additional long-term high-quality RCTs with larger sample sizes measuring patient-important outcomes are required to strengthen the evidence supporting the effects of AGE-restricted diets. PMID- 23361162 TI - Acute alcohol effects on attentional bias are mediated by subcortical areas associated with arousal and salience attribution. AB - Acute alcohol ingestion increases attentional bias to alcohol-related stimuli; however, the underlying cognitive and brain mechanisms remain unknown. We combined functional magnetic resonance imaging (fMRI) with performance of a dual task that probed attentional distraction by alcohol-related stimuli during 'conflict' processing: the Concurrent Flanker/Alcohol-Attentional bias task (CFAAT). In this task, an Eriksen Flanker task is superimposed on task-unrelated background pictures with alcohol-associated or neutral content. Participants respond to the direction of a central 'target' arrow and ignore adjacent congruent (low cognitive load) or incongruent (high cognitive load) 'flanking' arrows. Using a between-subject design, 40 healthy moderate-to-heavy social drinkers received either no alcohol (placebo), 0.4 g/kg (low dose), or 0.8 g/kg (high dose) of alcohol, and underwent fMRI while performing the CFAAT. The low alcohol dose, relative to placebo, increased response latencies on trials with alcohol-associated backgrounds and, under low cognitive load, increased the activity evoked by these pictures within a medial hypothalamic region. Under high cognitive load, the low alcohol dose, relative to placebo, elicited greater activity within a more lateral hypothalamic region, and reduced activity within frontal motor areas. The high alcohol dose, relative to placebo, did not reliably affect response latencies or neural responses to background images, but reduced overall accuracy under high cognitive load. This effect correlated with changes in reactivity within medial and dorsal prefrontal cortices. These data suggest that alcohol at a low dose primes attentional bias to alcohol-associated stimuli, an effect mediated by activation of subcortical hypothalamic areas implicated in arousal and salience attribution. PMID- 23361163 TI - Isolation and structural identification of the trihydroxamate siderophore vicibactin and its degradative products from Rhizobium leguminosarum ATCC 14479 bv. trifolii. AB - The Rhizobia are a group of free-living soil bacteria known for their ability to symbiotically infect the roots of specific host plants as well as to produce siderophores in order to compete with other microorganisms for the limited availability of iron in the rhizosphere. In this study, Rhizobium leguminosarum ATCC 14479, which preferentially infects the red clover Trifolium pratense, was found to produce the trihydroxamate siderophore vicibactin (C33H55N6O15) under iron restricted conditions. In addition, two other iron-binding, siderophore-like compounds: C20H36N4O10, C31H55N6O15, were isolated and purified from the culture media. Due to the structural similarity of the latter compounds to vicibactin based on electrospray-mass spectrometry and nuclear magnetic resonance data, these heretofore unreported molecules are thought to be either modified or degraded products of vicibactin. Although vicibactin has previously been found to be commonly produced by other rhizobial strains, this is the first time it has been chemically characterized from a clover infecting strain of R. leguminosarum. PMID- 23361164 TI - Understanding CeO2 as a Deacon catalyst by probe molecule adsorption and in situ infrared characterisations. AB - CeO(2) has been identified as an efficient catalyst for HCl oxidation in the temperature range of 623-723 K provided that the oxygen content in the feed mixture was sufficiently high to avoid bulk chlorination and thus deactivation. Here we characterise ceria in its fresh and post-reaction states by adsorption of CO(2), NH(3) and CO. Micro-calorimetry, FTIR and TPD experiments are complemented by DFT calculations, which assess adsorption energies and vibrational frequencies. The calculations were performed on the lowest energy surface, CeO(2)(111), with perfect termination and with various degrees of hydroxylation and/or chlorination. Both experiments and calculations suggest that the basic character of the ceria surface has been eliminated upon reaction in HCl oxidation, indicating that most of the basic lattice O sites are exchanged by chlorine and that the OH groups formed are rather acidic. The density and the strength of surface acidic functions increased significantly upon reaction. An in situ FTIR reaction cell has been designed and constructed to study the evolution of OH group density of the ceria surface during HCl oxidation. The effect of experimental variables, such as pO(2), pHCl and temperature, has been investigated. We found that the OH group density positively correlated with the reactivity in the pO(2) and temperature series, whereas negative correlation was observed when pHCl was varied. Implications of the above observations to the reaction mechanism are discussed. PMID- 23361165 TI - Molecular typing of Paenibacillus larvae strains isolated from Bulgarian apiaries based on repetitive element polymerase chain reaction (Rep-PCR). AB - The aim of the present study was to perform molecular typing of Paenibacillus larvae (P. larvae) isolates from Bulgarian apiaries with repetitive element polymerase chain reaction (rep-PCR) using BOX A1R, MBO REP1, and ERIC primers. A total of 96 isolates collected from brood combs with clinical symptoms of American foulbrood originating from apiaries located in different geographical regions of Bulgaria, a reference strain P. larvae NBIMCC 8478 and 30 commercial honey samples with Bulgarian origin were included in the study. Rep-PCR fingerprinting analysis revealed two genotypes ab and AB of P. larvae isolates from brood combs and honey samples. A combination of genotypes ab/AB was detected in one apiary and honey sample. The prevailing genotype ab was found in 78.1 % of brood combs isolates as well as in the reference strain whereas genotype AB was determined in 21.9 % of isolates. The examination of honey samples confirmed the preponderance of ab genotype which was demonstrated in 20 of 30 samples analyzed. In conclusion, the genetic epidemiology of P. larvae revealed two genotypes--ab and AB for Bulgarian strains. Developed protocols for molecular typing of P. larvae are reliable and may be used to trace the source of infection. PMID- 23361166 TI - Phage type 187 as a separate subunit MboI restriction site within the Staphylococcus aureus species. AB - The aim of this study was to use MboI restriction of pta gene fragment to compare the strains of Staphylococcus aureus phage type 187 and other phage types of S. aureus isolated from humans and dogs, as well as canine S. intermedius group strains. The study included 395 human and canine staphylococcal strains representing S. aureus, S. intermedius, and S. pseudintermedius species. The strains were identified with classic phenotypic methods and by the presence of species-specific thermostable nuclease (nuc SA) gene. All the strains were subjected to the analysis of MboI restriction site of pta gene fragment with PCR RFLP method. Nearly, all human and animal strains of S. aureus possessed 156- and 164-bp restriction fragments. One of the human strains lacked the 320-bp amplification product. In the case of all S. aureus phage type 187, the amplification product of pta gene was insusceptible to cutting with MboI restrictase. None of S. intermedius strains possessed restriction sites present in the product of amplification of pta gene, while all the strains of S. pseudintermedius had 213- and 107-bp restriction fragments. In conclusion, our findings regarding S. aureus phage type 187 reveal that within the population of strains of S. aureus species, these bacteria represent a group with distinct properties. PMID- 23361168 TI - Reactivity of C,N-chelated organoboron compounds with lithium anilides--formation of unexpected 1,2,3-trisubstituted 1H-2,1-benzazaboroles. AB - A set of C,N-intramolecularly coordinated boranes containing various C,N chelating ligands L(1-3) (where L(1) = [o-(CH=NtBu)C6H4], L(2) = [o-(CH=N-2,6 iPr2C6H3)C6H4], L(3) = [o-(CH2NMe2)C6H4]); L(1-3)BCl2 (for 1 L = L(1), for 2 L = L(2), for 5 L = L(3)), L(1)BPhCl (3) and L(1)BCy2 (4) (where Cy = cyclohexyl) were synthesized and fully characterized by multinuclear NMR spectroscopy and in cases of 1 and 3-5 by the single crystal X-ray diffraction analysis. The reaction of with the anilides ArNHLi (Ar = 2,6-Me2C6H3 or 2,6-iPr2C6H3) proceeded via unexpected addition of anilide across the C=N bond yielding 1,2,3-trisubstituted 1H-2,1-benzazaboroles 6-11, whose structures were unambiguously established by single crystal X-ray diffraction analysis (except for 11) and multinuclear NMR spectroscopy. In contrast, compounds 4 and 5 were inert towards ArNHLi. The investigation dealing with the reaction mechanism between the parent boranes 1-3 and ArNHLi revealed that amidolithiation of the C=N double bond involved in the ligand backbones is the crucial step of the whole reaction. The C=N double bond in 1-3 is activated by its coordination to the ortho bonded Lewis acidic boron center, which was also proven by the fact that the non-substituted ligand L(1)H did not react with ArNHLi under the same reaction conditions in an analogous reaction. PMID- 23361172 TI - Asymmetric rearrangement of racemic epoxides catalyzed by chiral Bronsted acids. AB - This paper describes a chiral Bronsted acid catalyzed asymmetric 1,2 rearrangement of racemic epoxides via a hydrogen-shift process for the synthesis of chiral aldehydes, and, followed by a reduction, a variety of optically active alcohols can be furnished in moderate yields with up to 50% ee. Especially, a facile one-pot synthesis of chiral alcohols directly from simple alkenes by a sequential epoxidation, rearrangement, and reduction has also been realized. PMID- 23361170 TI - Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. AB - OBJECTIVE: The aim of this work was to study the role of ospemifene, a novel selective estrogen receptor modulator, in the treatment of vulvar and vaginal atrophy in postmenopausal women with moderate to severe dyspareunia and physiological vaginal changes. METHODS: This multicenter phase 3 study used a randomized, double-blind, parallel-group design to compare the efficacy, safety, and tolerability of oral ospemifene 60 mg/day versus placebo. A total of 605 women aged 40 to 80 years who self-reported a most bothersome symptom of dyspareunia and had a diagnosis of vulvar and vaginal atrophy were randomized to take a once-daily dose of ospemifene (n = 303) or placebo (n = 302) for 12 weeks. RESULTS: Analysis of the intent-to-treat (n = 605) population found the efficacy of ospemifene to be significantly greater than that of placebo for each of the following coprimary endpoints: percentages of parabasal and superficial cells, vaginal pH, and severity of dyspareunia. With ospemifene, the percentage of parabasal cells and vaginal pH significantly decreased; the percentage of superficial cells significantly increased; and dyspareunia was significantly reduced versus placebo (all P < 0.0001, except for dyspareunia: P = 0.0001). Among the randomized women, 186 (61.4%) in the ospemifene group and 154 (51.0%) in the placebo group reported at least one treatment-emergent adverse event. Hot flushes were the most frequently reported treatment-related adverse event (ospemifene 6.6% vs placebo 3.6%); only one participant discontinued in each group. As determined by the investigators, no serious adverse events related to the study drug were reported. CONCLUSIONS: In this study, once-daily oral ospemifene 60 mg was effective for the treatment of vulvar and vaginal atrophy in postmenopausal women with dyspareunia. PMID- 23361173 TI - Molecular probes for the detection and identification of ichthyotoxic marine microalgae of the genus Pseudochattonella (Dictyochophyceae, Ochrophyta). AB - Phytoflagellates of the genus Pseudochattonella (Dictyochophyceae, Ochrophyta) form blooms in marine coastal waters in northern Europe, Japan, and New Zealand that at times cause fish kills with severe losses for the aquaculture industry. The aim of this study was to develop molecular probes for the detection and identification of Pseudochattonella at the genus and species level. A variety of probes were developed and applied to either dot blot hybridization, (q)PCR, or microarray format. In the dot blot hybridization assay, five different oligonucleotide probes targeting the small subunit (SSU) rDNA were tested against DNA from 18 microalgal strains and shown to be specific to the genus Pseudochattonella. A genus-specific PCR assay was developed by identifying an appropriate primer pair in the SSU-internal transcribed spacer 1 (ITS1) rDNA region. Its specificity was tested by screening against both target and non target strains, and the assay was used to confirm the presence or absence of Pseudochattonella species in environmental samples. In order to distinguish between the two species of the genus, two PCR primer pairs each biased towards one of the species were designed in the large subunit (LSU) rDNA D1 domain and used for quantitative real-time PCR. Five selected probes (three SSU and two LSU rDNA) were adapted for the use on microarrays and included on a prototype multi species microarray for the detection of harmful algae ( http://www.midtal.com ). Finally, microarrays and qPCR were used for the monthly monitoring of a sampling site in outer Oslofjorden during a 1-year period. Members of Pseudochattonella are difficult to identify by light microscopy in Lugol's preserved samples, and the two species Pseudochattonella verruculosa and Pseudochattonella farcimen can be morphologically distinguished only by transmission electron microscopy. The molecular probes designed in this study will be a valuable asset to microscopical detection methods in the monitoring of harmful algae and for biogeographical and ecological studies of this genus. PMID- 23361174 TI - Fractionation and mobility of metals in bauxite red mud. AB - Red mud (RM) is a strongly alkaline residue generated in enormous amounts worldwide from bauxite refining using the Bayer chemical process. RM is composed mainly of Fe, Ti and Al oxides and hydroxides, but it also contains an array of trace metals and metalloids at different concentrations. The purpose of this paper is to assess the potential mobility of metals in RM, with special emphasis on pH effect. The 'operational' distribution and leachability of metals within/from RM was studied by applying a sequential extraction procedure (SEP) and several leaching tests (rapid titration, equilibration acidification, batch leaching with acetic acid and also the toxicity characteristics leaching procedure (TCLP) and the DIN 38414-S4 procedures, used as reference methods) carried out at different pH, solid/liquid ratio, extraction period and type of acid (HCl or acetic acid). Chemical analysis showed that, in addition to the major metals Fe, Al and Ti, RM contains several trace metals, some of them (Cr, Cu and Ni) in concentrations exceeding the regulatory limits. SEP showed that a majority of the metals in the RM (between the 32.2+/-8.5 for Cd and 95.3+/-0.4% for Ni) were found in the residual fraction, suggesting that they are not readily mobile under normal environmental conditions. Leaching tests performed at different pH showed that a significant fraction of the metals is mobilised from RM only under very strong acid conditions (pH<2), whereas Al is released in considerable amounts at pH<5.3. Among the trace metals, Cr requires special attention because of its relative high concentration in RM and the higher concentrations of this metal mobilised at low pH. The leaching tests using acetic acid showed that the standard TCLP largely underestimates the release of trace metals from RM, and therefore it is not advisable to evaluate the actual potential leaching of trace metals from this residue. PMID- 23361175 TI - New insights into pesticide photoprotection. AB - Photolysis may be a significant route of pesticide dissipation on crops, leading to an increase of pesticide use. Spraying strong absorbing compounds (photoprotector) along with pesticide is an attractive strategy to prevent the photodegradation phenomenon. The aim of this study is to get a better understanding of the parameters governing the photoprotection efficiency. Experiments were conducted using formulated sulcotrione as a pesticide and a grape wine extract as a photoprotector. These compounds were irradiated using simulated solar light as dried deposits on carnauba wax films or on disks of tobacco leaves and analyzed by ultra performance liquid chromatography ultraviolet (UV), spectroscopy, and microscopy. It is shown that photolysis is faster on leaves than on carnauba wax and that the photoprotection effect of grape wine extract is more efficient on leaves than on wax. Images recorded by microscopy bring evidence that deposits are very different on the two supports both in the absence and in the presence of the photoprotector. The grape wine extract plays a double role; it is antioxidant and UV screen. Photoprotection by the grape wine extract is a complex mixing of UV screen and antioxidant effects. The UV screen effect can be rationalized by considering the rate of light absorption by sulcotrione. Our results demonstrate that the rates of sulcotrione phototransformation are mainly governed by the repartition of the deposit on the solid support. PMID- 23361176 TI - Decolorization and detoxification of two textile industry effluents by the laccase/1-hydroxybenzotriazole system. AB - The aim of this work was to determine the optimal conditions for the decolorization and the detoxification of two effluents from a textile industry effluent A (the reactive dye bath Bezactive) and effluent B (the direct dye bath Tubantin)-using a laccase mediator system. Response surface methodology (RSM) was applied to optimize textile effluents decolorization. A Box-Behnken design using RSM with the four variables pH, effluent concentration, 1-hydroxybenzotriazole (HBT) concentration, and enzyme (laccase) concentration was used to determine correlations between the effects of these variables on the decolorization of the two effluents. The optimum conditions for pH and concentrations of HBT, effluent and laccase were 5, 1 mM, 50 % and 0.6 U/ml, respectively, for maximum decolorization of effluent A (68 %). For effluent B, optima were 4, 1 mM, 75 %, and 0.6 U/ml, respectively, for maximum decolorization of approximately 88 %. Both effluents were treated at 30 degrees C for 20 h. A quadratic model was obtained for each decolorization through this design. The experimental and predicted values were in good agreement and both models were highly significant. In addition, the toxicity of the two effluents was determined before and after laccase treatment using Saccharomyces cerevisiae, Bacillus cereus, and germination of tomato seeds. PMID- 23361177 TI - Cr(VI) sorption by free and immobilised chromate-reducing bacterial cells in PVA alginate matrix: equilibrium isotherms and kinetic studies. AB - Chromate-resistant bacterial strain isolated from the soil of tannery was studied for Cr(VI) bioaccumulation in free and immobilised cells to evaluate its applicability in chromium removal from aqueous solution. Based on the comparative analysis of the 16S rRNA gene, and phenotypic and biochemical characterization, this strain was identified as Paenibacillus xylanilyticus MR12. Mechanism of Cr adsorption was also ascertained by chemical modifications of the bacterial biomass followed by Fourier transform infrared spectroscopy analysis of the cell wall constituents. The equilibrium biosorption analysed using isotherms (Langmuir, Freundlich and Dubinin-Redushkevich) and kinetics models (pseudo-first order, second-order and Weber-Morris) revealed that the Langmuir model best correlated to experimental data, and Weber-Morris equation well described Cr(VI) biosorption kinetics. Polyvinyl alcohol alginate immobilised cells had the highest Cr(VI) removal efficiency than that of free cells and could also be reused four times for Cr(VI) removal. Complete reduction of chromate in simulated effluent containing Cu(2+), Mg(2+), Mn(2+) and Zn(2+) by immobilised cells, demonstrated potential applications of a novel immobilised bacterial strain MR12, as a vital bioresource in Cr(VI) bioremediation technology. PMID- 23361178 TI - Treatment of 2,4-D, mecoprop, and dicamba using membrane bioreactor technology. AB - Phenoxyacetic and benzoic acid herbicides are widely used agricultural, commercial, and domestic pesticides. As a result of high water solubility, mobility, and persistence, 2,4-dichlorophenoxyacetic acid (2,4-D), methylchlorophenoxypropionic acid (mecoprop), and 3,6-dichloro-2-methoxybenzoic acid (dicamba) have been detected in surface and waste waters across Canada. As current municipal wastewater treatment plants do not specifically address chronic, trace levels of contaminants like pesticides, an urgent need exists for an efficient, environmentally friendly means of breaking down these toxic herbicides. A commercially available herbicide mix, WeedEx, containing 2,4-D, mecoprop, and dicamba, was subjected to treatment using membrane bioreactor (MBR) technology. The three herbicides, in simulated wastewater with a chemical oxygen demand of 745 mg/L, were introduced to the MBR at concentrations ranging from 300 MUg/L to 3.5 mg/L. Herbicides and biodegradation products were extracted from MBR effluent using solid-phase extraction followed by detection using high performance liquid chromatography coupled with mass spectrometry. 2,4-D was reduced by more than 99.0 % within 12 days. Mecoprop and dicamba were more persistent and reduced by 69.0 and 75.4 %, respectively, after 112 days of treatment. Half-lives of 2,4-D, mecoprop and dicamba during the treatment were determined to be 1.9, 10.5, and 28.3 days, respectively. Important water quality parameters of the effluent such as dissolved oxygen, pH, ammonia, chemical oxygen demand, etc. were measured daily. MBR was demonstrated to be an environmentally friendly, compact, and efficient method for the treatment of toxic phenoxyacetic and benzoic acid herbicides. PMID- 23361179 TI - Health care industries: potential generators of genotoxic waste. AB - Health care waste includes all the waste generated by health care establishments, research facilities, and laboratories. This constitutes a variety of chemical substances, such as pharmaceuticals, radionuclides, solvents, and disinfectants. Recently, scientists and environmentalists have discovered that wastewater produced by hospitals possesses toxic properties due to various toxic chemicals and pharmaceuticals capable of causing environmental impacts and even lethal effects to organisms in aquatic ecosystems. Many of these compounds resist normal wastewater treatment and end up in surface waters. Besides aquatic organisms, humans can be exposed through drinking water produced from contaminated surface water. Indeed, some of the substances found in wastewaters are genotoxic and are suspected to be potential contributors to certain cancers. The aim of this study was to evaluate the genotoxic and cytotoxic potential of wastewaters from two hospitals and three clinical diagnostic centers located in Jaipur (Rajasthan State), India using the prokaryotic Salmonella mutagenicity assay (Ames assay) and the eukaryotic Saccharomyces cerevisiae respiration inhibition assay. In the Ames assay, untreated wastewaters from both of the health care sectors resulted in significantly increased numbers of revertant colonies up to 1,000-4,050 as measured by the Salmonella typhimurium TA98 and TA100 strains (with and without metabolic activation) after exposure to undiluted samples, which indicated the highly genotoxic nature of these wastewaters. Furthermore, both hospital and diagnostic samples were found to be highly cytotoxic. Effective concentrations at which 20 % (EC20) and 50 % (EC50) inhibition of the respiration rate of the cells occurred ranged between ~0.00 and 0.52 % and between 0.005 and 41.30 % (calculated with the help of the MS excel software XLSTAT 2012.1.01; Addinsoft), respectively, as determined by the S. cerevisiae assay. The results indicated that hospital wastewaters contain genotoxic and cytotoxic components. In addition, diagnostic centers also represent small but significant sources of genotoxic and cytotoxic wastes. PMID- 23361180 TI - Occurrence of polybrominated diphenyl ethers (PBDEs) and 2,2',4,4',5,5' hexabromobiphenyl (BB-153) in water samples from the Diep River, Cape Town, South Africa. AB - Until recently, studies reporting the concentrations of polybrominated diphenyl ethers (PBDEs) as well as polybrominated biphenyls (PBBs) are generally scarce in the literature. Consequently, this study was aimed to investigate the occurrence and concentrations of certain PBDE congeners (BDE 28, 47, 100, 99, 154, 153, 183 and 209) and BB 153 in river water samples collected bi-monthly from the Diep River. The routine analyses of the target compounds were performed using a high capillary GC-microelectron capture detection, while their structural elucidation was assessed using GC-TOF-MS technique. The overall mean concentrations of the sum of the eight PBDE congeners were 2.60, 4.83 and 4.29 ng/L for the upstream, point of discharge and downstream sampling points, respectively. Similarly, the overall mean concentrations of BB 153 were 0.25, 4.85 and 1.56 ng/L for the upstream, point of discharge and downstream sampling points, respectively. BDE 47 was the dominant congener found in these samples contributing between 19 and 26 % to the total PBDEs across the sampling points. The statistical analyses performed on the results obtained showed that all the congeners, except BDE 209 in certain instances, had strong positive correlations with one another, thus suggesting that these contaminants could be emanating from the same source. In this study, potential sources of these pollutants other than WWTP discharges into the investigated river were also identified. However, the relatively high concentrations of the target compounds found at the point of discharge sampling point coupled with the large volume of treated effluent being discharged suggested that the contributions from this source could be very significant over time. PMID- 23361181 TI - Performance of a field-scale permeable reactive barrier based on organic substrate and zero-valent iron for in situ remediation of acid mine drainage. AB - A permeable reactive barrier (PRB) was installed in Aznalcollar (Spain) in order to rehabilitate the Agrio aquifer groundwater severely contaminated with acid mine drainage after a serious mining accident. The filling material of the PRB consisted of a mixture of calcite, vegetal compost and, locally, Fe(0) and sewage sludge. Among the successes of the PRB are the continuous neutralisation of pH and the removal of metals from groundwater within the PRB (removals of >95%). Among the shortcomings are the improper PRB design due to the complexity of the internal structure of the Agrio alluvial deposits (which resulted in an inefficient capture of the contaminated plume), the poor degradability of the compost used and the short residence time within the PRB (which hindered a complete sulphate reduction), the clogging of a section of the PRB and the heterogeneities of the filling material (which resulted in preferential flows within the PRB). Undoubtedly, it is only through accumulated experience at field scale systems that the potentials and limits of the PRB technology can be determined. PMID- 23361182 TI - Controlling the feed rate of glucose and propanol for the enhancement of erythromycin production and exploration of propanol metabolism fate by quantitative metabolic flux analysis. AB - In this paper, several different fermentation experiments were designed to address whether modulating glucose and propanol feeds could benefit the production level of erythromycin during pilot plant (30 L) fermentation. Results showed that glucose feed rate (determined by a set high or low culture pH) had no effect on erythromycin production, indicating that glucose was not the limiting factor for erythromycin biosynthesis under these conditions. It was found that decreasing glucose feed could stimulate the consumption of propanol, and the high erythromycin production (12.49 +/- 0.50 mg ml-1) was achieved by controlling the feed rates of glucose and propanol. The quantitative metabolic flux analysis disclosed that high propanol consumption increased the pool size of propionyl-CoA (~2.147 mmol g-1 day-1) and methylmalonyl-CoA (~1.708 mmol g-1 day-1). It was also found that 45-77 % of the propanol went into the TCA cycle which strengthened the conclusion that blocking the propionate pathway to TCA cycle could lead to a significant increase in erythromycin production in carbohydrate based media (Reeves et al. Ind Microbiol Biotechnol 7:600-609, 2006). In addition, the results also suggested that a relative low intracellular ATP level resulting from low glucose feed did not limit the erythromycin biosynthesis, and a relatively high NADPH should be beneficial for erythromycin biosynthesis. PMID- 23361183 TI - Cloning and characterization of a thermostable endo-arabinanase from Phanerochaete chrysosporium and its synergistic action with endo-xylanase. AB - Putative arabinanase (PcARA) was cloned from cDNA of Phanerochaete chrysosporium. The gene sequencing indicated that PcARA consisted of 939 nucleotides that encodes for 312 amino acid arabinanase-polypeptide chain, including a signal peptide of 19 amino acids. Three-dimensional homology indicated that this enzyme is a five-bladed beta-propeller, belonging to glycosidase family 43 and its secondary structure is consisted of 24 beta-sheets. The PcARA-cDNA was expressed in Pichia pastoris using pPICZalphaC. SDS-PAGE of purified arabinanase showed a single band of 33 kDa that is very close to theoretical molecular mass of 33.9 kDa calculated by its amino acid content. Recombinant arabinanase (rPcARA) exhibited maximum activity at pH and temperature of 5.0 and 60 degrees C, respectively. End-product analysis of debranched arabinan hydrolysis by thin layer chromatography indicated that rPcARA acted as endo-type. The synergistic action of rPcARA with recombinant xylanase resulted in 72 and 9.3 % release of total soluble sugar of arabinoxylan and NaOH-pretreated barley straw, respectively. PMID- 23361184 TI - Bioethanol production from brown seaweed, Undaria pinnatifida, using NaCl acclimated yeast. AB - Strain improvement of Pichia angophorae KCTC 17574 was successfully carried out for bioethanol fermentation of seaweed slurry with high salt concentration. P. angophorae KCTC 17574 was cultured under increasing salinity from five practical salinity unit (psu, 0/00) to as high as 100 psu for 723 h. The seaweed, Undaria pinnatifida (sea mustard, Miyuk), was fermented to produce bioethanol using high salt acclimated yeast. The pretreatment of U. pinnatifida was optimized using thermal acid hydrolysis to obtain a high monosaccharide yield. Optimal pretreatment conditions of 75 mM H(2)SO(4) and 13 % (w/v) slurry at 121 degrees C for 60 min were determined using response surface methodology. A maximum monosaccharide content of 28.65 g/L and the viscosity of 33.19 cP were obtained. The yeasts cultured under various salinity concentrations were collected and inoculated to the pretreated seaweed slurry after the neutralization using 5 N NaOH. The pretreated slurry was fermented with the inoculation of 0.1 g dcw/L of P. angophorae KCTC 17574 strain obtained at 90 psu. The maximum ethanol concentration of 9.42 g/L with 27 % yield of theoretical case of ethanol production from total carbohydrate of U. pinnatifida was obtained. PMID- 23361185 TI - Development of thin-film photo-bioreactor and its application to outdoor culture of microalgae. AB - Photosynthetic microalgae have received much attention as a microbial source of diverse useful biomaterials through CO(2) fixation and various types of photo bioreactors have been developed for efficient microalgal cultivation. Herein, we developed a novel thin-film photo-bioreactor, which was made of cast polypropylene film, considering outdoor mass cultivation. To develop optimal design of photo-bioreactor, we tested performance of three shapes of thin-film photo-bioreactors (flat, horizontal and vertical tubular shapes) and various parts in the bioreactor. Collectively, vertical tubular bioreactor with H/D ratio 6:1 and cylindrical stainless steel spargers showed the most outstanding performance. Furthermore, the photo-bioreactor was successfully applied to the cultivation of other microalgae such as Chlamydomonas reinhardtii and Chlorella vulgaris. The scalability of photo-bioreactor was confirmed by gradually increasing culture volume from 4 to 25 L and the biomass productivity of each reactor was quite consistent (0.05-0.07 g/L/day) during the cultivation of H. pluvialis under indoor and outdoor conditions. Especially, we also achieved dry cell weight of 4.64 g/L and astaxanthin yield of 218.16 mg/L through long-term cultivation (100 days) under outdoor condition in 15 L photo-bioreactor using Haematococcus pluvialis, which means that the astaxanthin yield from outdoor cultivation is equal or superior to that obtained from controlled indoor condition. Therefore, these results indicate that we can apply this approach to development of optimal photo-bioreactor for the large-scale culture of microalgae and production of useful biomaterials under outdoor condition. PMID- 23361186 TI - Efficient production of 1,3-propanediol from glycerol upon constitutive expression of the 1,3-propanediol oxidoreductase gene in engineered Klebsiella pneumoniae with elimination of by-product formation. AB - In the present study, we developed an efficient method of 1,3-propanediol (1,3 PD) production from glycerol by genetic engineering of Klebsiella pneumoniae AK mutant strains. The proposed approach eliminated by-product formation and IPTG induction resulted in maximal production of 1,3-PD. A series of recombinant strains was designed to constitutively express the dhaB and/or dhaT genes, using the bacteriophage T5 P(DE20) promoter and the rho-independent transcription termination signal of the Rahnella aquatilis levansucrase gene. Among these strains, AK/pConT expressing dhaT alone gave the highest yield of 1,3-PD. Fed batch fermentation resulted in efficient production of 1,3-PD from either pure or crude glycerol, without by-product formation. PMID- 23361188 TI - 17beta-estradiol impedes Bax-involved mitochondrial apoptosis of retinal nerve cells induced by oxidative damage via the phosphatidylinositol 3-kinase/Akt signal pathway. AB - Oxidative stress leading to retinal nerve cells (RNCs) apoptosis is a major cause of neurodegenerative disorders of the retina. 17beta-Estradiol (E2) has been suggested to be a neuroprotective agent in the central nervous system; however, at present, the underlying mechanisms are not well understood, and the related research on the RNCs is less reported. Here, in order to investigate the protective role and mechanism of E2 against oxidative stress-induced damage on RNCs, the transmission electron microscopy and annexin V-FITC/propidium iodide assay were applied to detect the RNCs apoptosis. Western blot and real-time PCR were used to determine the expression of the critical molecules in Bcl-2 and caspase family associated with apoptosis. The transmission electron microscopy results showed that H(2)O(2) could induce typical features of apoptosis in RNCs, including formation of the apoptosome. E2 could, however, suppress the H(2)O(2) induced morphological changes of apoptosis. Intriguingly, we observed E2-mediated phagocytic scavenging of apoptosome. In response to H(2)O(2)-induced apoptosis, Bax, acting as one of the pivotal pro-apoptotic members of Bcl-2 family, increased significantly, which directly resulted in an increased ratio of Bax to anti-apoptotic protein Bcl-2 (Bax/Bcl-2). Additionally, caspases 9 and 3, which are the critical molecules of the mitochondrial apoptosis pathway, were activated by H(2)O(2). In contrast, E2 exerted anti-apoptotic effects by reducing the expression of Bax to decrease the ratio of Bax/Bcl-2 and impeded the caspases 9/3 activation. Moreover, LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, could sharply block the effect of E2 in reducing the percentage of apoptotic cells resistance to H(2)O(2). And the attenuation of Bax, the reduced activities of caspases 9/3 and the impeded release of mitochondrial cytochrome c mediated by E2 resistance to H(2)O(2) damage were significantly retrieved by LY294002 administration. Taken together, E2 protects the RNCs against H(2)O(2)-induced apoptosis by significantly inhibiting the Bax-involved mitochondrial apoptosis via the activation of PI3K/Akt signal pathway. PMID- 23361189 TI - Spiral ganglion cell morphology in guinea pigs after deafening and neurotrophic treatment. AB - It is well known that spiral ganglion cells (SGCs) degenerate in hair-cell depleted cochleas and that treatment with exogenous neurotrophins can prevent this degeneration. Several studies reported that, in addition, SGC size decreases after deafening and increases after neurotrophic treatment. The dynamics of these cell size changes are not well known. In a first experiment we measured size, shape (circularity) and intracellular density of SGCs in guinea pigs at various moments after deafening (1, 2, 4, 6, and 8 weeks) and at various cochlear locations. In a second experiment, the effect of treatment with brain-derived neurotrophic factor (BDNF) on SGC morphology was investigated at various cochlear locations in deafened guinea pigs. We found that SGC size gradually decreased after deafening in the basal and middle cochlear turns. Already after one week a decrease in size was observed, which was well before the number of SGCs started to decrease. After BDNF treatment SGCs became noticeably larger than normal throughout the cochlea, including the middle and apical turns, whereas an effect on survival of SGCs was primarily observed in the basal turn. Thus, both after deafening and after neurotrophic treatment a change in size occurs before survival is affected. Morphological changes were not restricted to a subpopulation of SGCs. We argue that although changes in cell size and changes in survival might be manifestations of two separate mechanisms, morphological measures such as size, circularity and intracellular density are indicative for survival and degeneration. PMID- 23361191 TI - Localized surface plasmon resonance light-scattering detection of Hg(II) with 3 aminopropyltriethoxysilane-assisted synthesis of highly stabilized Ag nanoclusters. AB - We employed 3-aminopropyltriethoxysilane to assist the synthesis of Ag NCs using polyethyleneimine as the template for detecting Hg(2+) by localized surface plasmon resonance light-scattering technology. The developed selective and sensitive method presaged more opportunities for application in environmental systems. PMID- 23361190 TI - The mitochondrion: a perpetrator of acquired hearing loss. AB - Age, drugs, and noise are major causes of acquired hearing loss. The involvement of reactive oxygen species (ROS) in hair cell death has long been discussed, but there is considerably less information available as to the mechanisms underlying ROS formation. Most cellular ROS arise in mitochondria and this review will evaluate evidence for mitochondrial pathology in general and dysfunction of the mitochondrial respiratory chain in particular in acquired hearing loss. We will discuss evidence that different pathways can lead to the generation of ROS and that oxidative stress might not necessarily be causal to all three pathologies. Finally, we will detail recent advances in exploiting knowledge of aminoglycoside mitochondria interactions for the development of non-ototoxic antibacterials. This article is part of a Special Issue entitled "Annual Reviews 2013". PMID- 23361193 TI - Search for biomarkers in chronic obstructive pulmonary disease: current status. AB - PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a condition principally defined by airflow limitation that is not fully reversible. The main trigger, inhalation of noxious gases or particles (usually smoke) leads to complex pathology, including inflammation of the large and small airways, and destruction of the lung parenchyma. Overlap in pathophysiology with other chronic airways diseases leads to challenges in differential diagnosis, and furthermore, periodic exacerbations of disease symptoms also increase the complexity of the disease diagnosis and prediction of outcome. There is recognized need for biomarkers to aid in the determination of disease diagnosis, progression and response to intervention. This review describes the current status of biomarker identification in COPD. RECENT FINDINGS: Biomarkers of disease can take many forms other than the classical protein in serum, and their utility is dependent upon the clinical question to be addressed. No single protein marker has been adopted for routine clinical use to date. This review addresses the key issues around biomarker identification and utility in both stable and exacerbating COPD. SUMMARY: Biomarker identification in COPD is still a developing field, with increasing interest in patient phenotyping probably reflecting the challenges of biomarker development in a complex disease. PMID- 23361192 TI - Involvement in bullying as predictor of suicidal ideation among 12- to 15-year old Norwegian adolescents. AB - The aim of this study was to examine relationships between bullying and suicidal ideation. A total of 2,464 adolescents in Norway were assessed at two time points, 1 year apart [i.e., at ages 14 (T1) and 15 (T2)], with identical questionnaires. Suicidal ideation was measured by four items including both active and passive suicidal thoughts. ANOVA and standard linear regression methods were applied. Both bullied adolescents and adolescents who were aggressive toward others had significantly higher levels of suicidal ideation (p < 0.001) at age 14 (T1) than noninvolved adolescents. In the group being bullied, girls had higher levels of suicidal ideation than boys did. This was not the case for the group of adolescents who were the aggressors. In cross-sectional multivariate analyses, both being bullied and being aggressive toward others were significant (p < 0.001) predictors of suicidal ideation at age 14 (T1), when gender, age and socioeconomic status, and depressing symptom levels were controlled for. In the controlled longitudinal multivariate analyses, being bullied (p < 0.001) at age 14 (T1) predicted suicidal ideation at age 15 (T2), while aggressiveness toward others did not. Bullied adolescents (both genders) were at risk for suicidal ideation, and having an additional risk if they were depressed. PMID- 23361194 TI - Susceptibility to viral infections in chronic obstructive pulmonary disease: role of epithelial cells. AB - PURPOSE OF REVIEW: The aim is to understand how airway epithelial cells with compromised innate defense mechanisms enhance susceptibility to respiratory virus infections in chronic obstructive pulmonary disease (COPD). RECENT FINDINGS: Exacerbations associated with respiratory viruses are more severe and increase disease severity in COPD. Airway epithelial cells cultured from COPD patients show excessive innate immune response to viral infection and higher viral load compared with normal cells. SUMMARY: Airway epithelial cells are the first line of defense in the lung and are equipped with several lines of innate defense mechanisms to fight against invading pathogens including viruses. Under normal conditions, mucociliary and barrier functions of airway epithelial cells prevent virus binding and entry into the cells. Virus-infected airway epithelial cells also express various cytokines, which recruit and activate innate and adaptive immune cells ultimately controlling the infection and tissue damage. In COPD however, compromised mucociliary and barrier functions may increase virus binding and allow virus entry into airway epithelial cells. Virus-infected COPD airway epithelial cells also show disproportionate cytokine expression leading to inappropriate recruitment and activation of innate and adaptive immune cells. COPD airway epithelial cells also show defective antiviral responses. Such defects in innate defense mechanisms may increase susceptibility to viral infections and disease severity in COPD. PMID- 23361195 TI - Sex and race factors in early-onset COPD. AB - PURPOSE OF REVIEW: Unlike other major diseases, mortality for chronic obstructive pulmonary disease (COPD) continues to increase. In recent years, COPD has evolved to increasingly affect women, minorities, and individuals from low socioeconomic groups. In women and African-Americans, evidence exists supporting the earlier development of COPD after less lifetime smoking. This review highlights new information on racial and sex differences in COPD. RECENT FINDINGS: Sex and related hormonal changes affect T-cell phenotypes, immunity, and smoking-related metabolism of toxic intermediate metabolites. Alterations in the bronchoalveolar lavage proteome of women, but not of men, have allowed the differentiation of healthy female smokers from smokers with COPD. Sex significantly influences levels of inflammatory cytokines and correlates with different clinical and physiological parameters in female COPD patients. African-Americans with COPD are younger, smoke less, are more likely to currently smoke, and have worse health related quality of life (QOL). African-Americans are more likely to report hospitalized exacerbations that impact QOL. African-Americans with COPD and asthma are nearly four times more likely to experience exacerbations. SUMMARY: There are sex-specific and race-related differences in the manifestation of COPD. These differences warrant further physiologic, biologic, and genetic investigations. PMID- 23361196 TI - Long-term respiratory health effects in textile workers. AB - PURPOSE OF REVIEW: Over 60 million people worldwide work in the textile or clothing industry. Recent studies have recognized the contribution of workplace exposures to chronic lung diseases, in particular chronic obstructive pulmonary disease (COPD). Early studies in textile workers have focused on the relationship between hemp or cotton dust exposure and the development of a syndrome termed byssinosis. The purpose of this review is to evaluate the effect of long-term exposure to organic dust in textile workers on chronic respiratory disease in the broader context of disease classifications, such as reversible or irreversible obstructive lung disease (i.e. asthma or COPD), and restrictive lung disease. RECENT FINDINGS: Cessation of exposure to cotton dust leads to improvement in lung function. Recent animal models have suggested a shift in the lung macrophage:dendritic cell population ratio as a potential mechanistic explanation for persistent inflammation in the lung due to repeated cotton dust-related endotoxin exposure. Other types of textile dust, such as silk, may contribute to COPD in textile workers. SUMMARY: Textile dust-related obstructive lung disease has characteristics of both asthma and COPD. Significant progress has been made in the understanding of chronic lung disease due to organic dust exposure in textile workers. PMID- 23361198 TI - Current world literature. PMID- 23361197 TI - Mortality in chrysotile asbestos workers in China. AB - PURPOSE OF REVIEW: China has been the world's top chrysotile asbestos consumer and producer. However, the national mortality rate for asbestos-related diseases, particularly from malignancies, is unknown. This review elaborates recent studies on cancer mortality and nonmalignant respiratory diseases in Chinese chrysotile asbestos workers. RECENT FINDINGS: Studies conducted in asbestos products factory workers and miners have demonstrated strong associations between exposure to chrysotile and mortality rates for lung cancer and nonmalignant respiratory diseases. Mortality rates for lung cancer and nonmalignant respiratory diseases in both asbestos workers and miners are four and three times higher, respectively, than expected, which are greater than those seen in studies from western countries, likely a reflection of heavier exposures and less effective protection for workers. An increased risk of gastrointestinal cancer was also detected in chrysotile miners. There have been surprisingly few reported cases of mesothelioma, however, which could, at least partially, indicate a problem in diagnosis. SUMMARY: Given the substantially increased death risks for lung cancer and nonmalignant respiratory diseases, urgent efforts must be made to implement occupational health and safety regulations and decrease workers' exposures to prevent a future heavier disease burden. Meanwhile, improvements in diagnostics and systematic recording of the incidence and mortality of asbestos-related diseases are needed. PMID- 23361201 TI - [Sexual and reproductive health: sociological perspectives]. PMID- 23361202 TI - [Sexual and contraceptive behavior of teenagers and young adults. Selected results of the BZgA study "Youth Sexuality 2010"]. AB - The BZgA study "Youth Sexuality 2010" clarifies the changes that have occurred in the sexual and contraceptive behavior of teenagers and young adults over the last 30 years. Among young Germans, there is now more gender similarity regarding both the age at which intercourse first takes place and contraceptive behavior. The proportion of German teenagers who take no contraceptive precautions when they have intercourse for the first time is now 8%, a lower figure than ever previously recorded. Communication about contraception, both at home and between the partners, is making a substantial contribution to responsible contraceptive behavior on the part of teenagers and young adults. Alongside education about sexuality in the family and at school, there are also structural influences on the positive developments witnessed in Germany. And yet there are still target groups that are inadequately reached. Many migrants are less well informed about bodily processes, their contraceptive practice is not as good, and their religious background tends to exclude them from access to information. Disabled teenagers and young adults constitute a target group about which to date we have insufficient knowledge. Education and social deprivation continue to be important factors in the differences seen in sexual and contraceptive behavior. In this area, proactive efforts are necessary. PMID- 23361203 TI - [Reproductive health of women. Family planning and "reproductive rights" in Germany]. AB - The WHO (World Health Organization) definition of reproductive health establishes reproductive rights for women and men. This includes the capability to reproduce and the freedom to decide, if, when, and how often to do so. In this article the implementation of these rights in Germany is evaluated, focusing on selected aspects of family planning. Findings from empirical studies, surveys, and official registers on fertility intentions, on births, on contraception, and on abortion are compiled. Moreover, the influence of social aspects on reproductive health (education, migration background) is discussed. Records show high standards regarding information and access to contraceptives; however, more action and research are needed in three regards. First, men and women have fewer children than they would like to have, and the desire to have (more) children is deferred systematically. Second, the number and rate of abortions should be reduced. And third, more attention should be paid to social determinants that influence the access to reproductive health. Furthermore, the special needs of migrants should be taken into account. PMID- 23361200 TI - Microsecond folding experiments and simulations: a match is made. AB - For the past two decades, protein folding experiments have been speeding up from the second or millisecond time scale to the microsecond time scale, and full-atom simulations have been extended from the nanosecond to the microsecond and even millisecond time scale. Where the two meet, it is now possible to compare results directly, allowing force fields to be validated and refined, and allowing experimental data to be interpreted in atomistic detail. In this perspective we compare recent experiments and simulations on the microsecond time scale, pointing out the progress that has been made in determining native structures from physics-based simulations, refining experiments and simulations to provide more quantitative underlying mechanisms, and tackling the problems of multiple reaction coordinates, downhill folding, and complex underlying structure of unfolded or misfolded states. PMID- 23361204 TI - [Child sexual abuse. Epidemiology, clinical diagnostics, therapy, and prevention]. AB - The article provides an overview of the research on sexual abuse and the current political developments in Germany. First, the terminology of sexual child abuse is discussed, followed by the presentation of epidemiological data. The section on diagnostics and therapy shows that--because of mostly nonspecific indicators- the diagnosis of child sexual abuse is very difficult to define. Child sexual abuse is discussed as a traumatic experience for children and adolescents with different psychiatric and physical diseases. Current studies have shown that especially cognitive behavioral therapeutic-oriented approaches are effective in curing posttraumatic stress disorders. Based on the new German Child Protection Act, the focus lies on the clarification of confidentiality for medical professionals and their right to consulting services for child protection. In conclusion, guidelines and minimum standards for a child prevention and protection model are presented as well as institutional recommendations addressed to all institutions (also clinical) that take care of or treat children and adolescents. PMID- 23361205 TI - Positive sexuality and its impact on overall well-being. AB - Historically, the issue of sexual health has been largely considered with respect to the associated negative health outcomes. The dangers of sexual activity such as sexually transmitted infections (STIs), HIV/AIDS, unintended pregnancy, sexual coercion, and sexual violence have dominated the attention of those working in the field. Over the last 20 years, and particularly in the last decade, an increasing number of people from a variety disciplines that address issues of sexual health have developed a new discourse concerning the positive aspects of sexuality. This review of the literature explores this emerging discourse. The results indicate that sexual health, physical health, mental health, and overall well-being are all positively associated with sexual satisfaction, sexual self esteem, and sexual pleasure. The beneficial effects of sexual satisfaction should be integrated into programs that seek to improve these diverse health outcomes through service delivery, prevention, and sexuality education. PMID- 23361206 TI - [The sexual health of men from a sexual-medical perspective]. AB - Men's sexual health can be impaired by a variety of sexual disorders, including numerous sexual dysfunctions (primary or due to general medical conditions or their treatment), but also paraphilias and gender identity disorders. These different disorders are often interwoven. This paper offers an overview of the prevalence, symptoms, and etiological factors of major sexual-medical disorders and of the basics of diagnostics and therapy. Special emphasis is given to the couple dimension and the biopsychosocial foundation of human sexuality, which requires an interdisciplinary approach. The paper argues for an improvement of continuing education in sexual medicine for healthcare providers in an effort to satisfy patients' needs for preservation or restoration of sexual health as a major component of quality of life. PMID- 23361207 TI - Sexuality and old age. AB - Sexuality in older people is a multifaceted field of study. Ageing may offer opportunities for and restrictions on sexuality. Ageing individuals may have increased time for and may wish to explore their sexuality, for example, by considering a same-sex relationship, after a long-term partner dies. However, they may also lack a partner or autonomy. They may develop or have increased symptoms from chronic diseases. Consequent medication may affect their sexual functioning. Their attitudes to sex often change and their capacity for sexual activity may diminish unless they seek help. However, they may lack the confidence to do so and the health professionals consulted may be disinclined or ill-equipped to assist them. They may have concerns regarding how their sexuality or their sexual orientation would be perceived should they require residential care or start to lose their memory. We consider the recent work relating to this broad range of influences on sexuality in old age and conclude that, whilst the challenge for researchers is to accurately clarify the impact of individual factors on sexuality and identify helpful potential interventions, increased academic and educational focus on this area is enhancing the prospects for a sexually enjoyable old age. PMID- 23361208 TI - [Sexual orientations]. AB - In this paper we study the concept of sexual orientation and its components by comparing the common orientations of hetero-, homo-, and bisexuality with alternative concepts suitable for describing persons with psychosexual and somatosexual divergencies (e.g., transgender or intersex developments). An assessment of these divergencies as well as their prevalence and societal influences are presented. Empirical findings on the relationship between sexual orientation and mental health are examined against the background of the sexual minority stress model, looking especially at the risks and the opportunities associated with belonging to a sexual minority. The paper also focuses on the normative power of a monosexual model. Finally, sexual orientation is conceptualized as an umbrella term encompassing both conscious and unconscious elements, including the aspects of sexual behavior, sexual identity, fantasies, and attraction. PMID- 23361209 TI - [Intersexuality not transsexuality. Delineation, new results, and proposals]. AB - Physical and psychosocial aspects of intersexuality (disorders of sex development, DSD) are described here. Differences between intersexuality and transsexuality are elaborated upon, especially in terms of coping with the diagnosis and treatment recommendations when dealing with an "ambiguous" or "false" body and with the disclosure of the physical conditions. The results of the Hamburg evaluation study, which was carried out between 2002 and 2008 on intersex adults, are summarized. These results have formed the basis of the comprehensive interdisciplinary book Intersexualitat kontrovers (Controversial Intersexuality ) published in 2012. An outline of the recommendations published in February 2012 by the German National Ethics Committee (Deutscher Ethikrat) on Intersexuality is also provided. Finally, the "dangers" of sex reassignment and gender change are questioned and an opening up of the binary view of sex and gender is proposed. PMID- 23361210 TI - New approaches to sexuality education and underlying paradigms. AB - The issue of sexuality education has been--and still is--contested to varying degrees. While sexuality education in many western European countries has a long tradition going back to the 1950s, in other parts of the world it became more prominent after the onset of the HIV epidemic in the 1980s. At present, the field is characterized by different underlying paradigms often rooted in moral convictions. The dominant approach in the US to sexuality education is mainly influenced by public health concerns--including prevention of HIV and other sexually transmitted infections (STIs), unintended pregnancies, and possibly sexual abuse. This approach may include"abstinence-only" messages, but could also be more open and offer comprehensive information as a means to harm reduction. Another approach, rooted in a European understanding of sexuality education and published in the"Standards for Sexuality Education in Europe" (2010), is based on the human rights of children and adolescents to access information and education and at its core has a positive understanding of sexuality. This article highlights international developments around sexuality education, with a focus on Europe. It also compares differences in approaches and their often implicit underlying paradigms, with the aim of generating more international discussion on the advantages and disadvantages of these different approaches. International organizations need to be aware of the different approaches and need to reflect them in their work. PMID- 23361211 TI - The World Health Organization's work on adolescent sexual and reproductive health. AB - This paper examines the contribution of the World Health Organization to the field of adolescent sexual and reproductive health (ASRH) from the early 1980s to the present. It is based on published documents and on the experiences of WHO staff members who have been part of much of this journey. It recalls the responses of the organization to the (then) new HIV/AIDS pandemic and to the first calls for a global public health response to early pregnancy. It also highlights selected milestones in the organization's work in the ASRH field over the last 25 years. It concludes with an analysis of where the ASRH field stands today and what the organization is doing to strengthen the epidemiologic and evidence base for action, to build consensus and coordination, and most importantly to support country level action, in cooperation with organizations within and outside the United Nations system. In defining its niche in a rapidly evolving and increasingly crowded field, the WHO's mission on ASRH is to contribute to a world in which the importance of ensuring the sexual and reproductive health of adolescents is understood, accepted, and acted upon by adolescents themselves, by their families and communities, by the workforces of different sectors, by civil society bodies, and by leaders and decision makers. PMID- 23361212 TI - [Prevention of sexually transmitted infections (STI) in Germany. From HIV to STI prevention]. AB - The strategy of "social learning" has been established as the decisive basis for the development of prevention measures in the field of HIV/AIDS in Germany. In recent years, HIV/AIDS prevention has been expanded to include sexually transmitted infections (STI), and the"Don't Give AIDS a Chance" umbrella campaign of the Federal Centre for Health Education (Bundeszentrale fur gesundheitliche Aufklarung, BZgA) has gradually developed into an integrated HIV/STI campaign. The population currently has a comparatively low level of knowledge regarding STI. The integrated HIV/STI campaign faces the challenge of firstly sensitizing the entire population to the subject of STI. The declared aims of this expanded campaign are to successively increase the level of knowledge, to motivate and enable the public to protect themselves, and to promote communication skills regarding STI. At the same time, it is essential to increase cooperation with the medical community and medical scientific societies for the purpose of prevention work. PMID- 23361213 TI - [Preimplantation and prenatal counseling. Interdisciplinary and multiprofessional approach]. AB - Several new legal regulations and guidelines introduced in 2010 have changed the duties involved in medical information and counseling on preimplantation genetics (PGD) and prenatal diagnosis (PND).These regulations share the goal of a high quality health service offering patients interdisciplinary and multidisciplinary expertise, especially taking into account psychological and social aspects. This contribution presents crucial elements for cooperating counseling in the PGD and PND fields. It considers results from a nationwide survey of all professional groups involved in counseling after a pathological prenatal diagnosis according to the law. Crucial to interdisciplinary counseling are choosing the appropriate medical specialty for referral, a positive basis for cooperation, and the right time for consulting another doctor. Several central issues have been identified for successful multidisciplinary counseling: identifying the suitable moment and method to establish contact between the patient and psychosocial counselor, focusing on PGD and PND centers as well as on the transparent qualifications of psychosocial counselors, and appreciating the importance of cooperation. PMID- 23361214 TI - [The Genetic Engineering Commission (GEKO) Guide to the Requirements for the implementation of genetic screening in accordance with Section 23 2 No. 6 GenDG. In the version of 16.11.2012, published and entered into force on 03.12.2012]. PMID- 23361215 TI - [Notice of Commission Decision of genetic diagnostics (GEKO) from 16.11.2012 in accordance with a change in the policy for the requirements on the content of education in genetic testing for medical purposes 23 para 2 No. 3 GenDG published on 27.04.2012, and in force on 25.05.2012. (Bundesgesundheitsbl, health researchers, health 55 (8) :1071-1075th http://link.springer.com/article/10.1007/s00103-012-1521-4)]. PMID- 23361216 TI - [The Genetic Engineering Commission (GEKO) for the requirements for the contents of the Enlightenment in genetic testing for medical purposes in accordance with S 23 para 2 No. 3 GenDG Policy. In the version of 27.04.2012 (published and entered into force on 25.05.2012, published in the Federal Health Gazette Health Research Health 2012; 55 (8) :1071-1075). Amended on 16.11.2012 published and entered into force on 3:12. , 2012]. PMID- 23361217 TI - Does the type of tibial component affect mechanical alignment in unicompartmental knee replacement? AB - PURPOSE: There are a number of factors responsible for the longevity of unicompartmental knee replacements (UKR). These include the magnitude of postoperative alignment and the type of material used. The effect of component design and material on postoperative alignment, however, has not been explored. MATERIALS AND METHODS: We retrospectively reviewed 89 patients who underwent UKR with robotic guidance. Patients were divided into two groups, according to whether they had received an all-polyethylene inlay component (Inlay group) or a metal-backed onlay component (Onlay group). We explored the magnitude of mechanical alignment correction obtained in both groups. RESULTS: Mean postoperative mechanical alignment was significantly closer to neutral in the Onlay group (mean=2.8 degrees ; 95% CI=2.4 degrees , 3.2 degrees ) compared to the Inlay group (mean=3.9 degrees ; 95% CI=3.4 degrees , 4.4 degrees ) (R2=0.65; P=0.003), adjusting for gender, BMI, age, side and preoperative mechanical alignment (Fig. 2). Further exploration revealed that the thickness of the tibial polyethyelene insert had a significant effect on postoperative alignment when added to the model (R2=0.68; P=0.01). CONCLUSION: Patients who received a metal backed Onlay tibial component obtained better postoperative mechanical alignment compared to those who received all-polyethylene Inlay prostheses. The thicker overall construct of Onlay prostheses appears to be an important determinant of postoperative alignment. Considering their higher survivorship rates and improved postoperative mechanical alignment, Onlay prostheses should be the first option when performing medial UKR. PMID- 23361218 TI - Management of uterine leiomyomas in pregnancy: review of literature. AB - The incidence of uterine myomas in pregnancy is estimated from 0.1 to 3.9 %. Although a lot of women with uterine fibroids bring the pregnancy without adverse events, data provided in the literature suggest that uterine fibromyomas are associated with several complications. The most important clinic question concerns the impact of myoma on pregnancy and, in some cases, the possibility of a surgical treatment that guarantees a good security for the pregnancy course and the conservation of reproductive capacity. Electronic search of Pubmed between 1993 and 2011, using specific keywords. Management of leiomyomas in pregnancy is conservative and limited, when it is necessary, to medical therapy. The main conditions that induce inevitably the surgical procedure are the torsion of pedunculated fibroid or rare cases of necrosis and resultant inflammatory peritoneal reaction. Laparoscopy technique has several advantages in comparison to previous techniques such as best postoperative course with reduction of pain, fast recovery, less hospitalization and, absence of large and unaesthetic scars. The importance of maternal and fetal welfare thus requires a careful evaluation of several factors that, varying from case to case, lead the authors to choose the most appropriate management. PMID- 23361219 TI - Inference of identity by descent in population isolates and optimal sequencing studies. AB - In an isolated population, individuals are likely to share large genetic regions inherited from common ancestors. Identity by descent (IBD) can be inferred from SNP genotypes, which is useful in a number of applications, including identifying genetic variants influencing complex disease risk, and planning efficient cohort sequencing strategies. We present ANCHAP--a method for detecting IBD in isolated populations. We compare accuracy of the method against other long-range and local phasing methods, using parent-offspring trios. In our experiments, we show that ANCHAP performs similarly as the other long-range method, but requires an order of-magnitude less computational resources. A local phasing model is able to achieve similar sensitivity, but only at the cost of higher false discovery rates. In some regions of the genome, the studied individuals share haplotypes particularly often, which hints at the history of the populations studied. We demonstrate the method using SNP genotypes from three isolated island populations, as well as in a cohort of unrelated individuals. In samples from three isolated populations of around 1000 individual each, an average individual shares a haplotype at a genetic locus with 9-12 other individuals, compared with only 1 individual within the non-isolated population. We describe an application of ANCHAP to optimally choose samples in resequencing studies. We find that with sample sizes of 1000 individuals from an isolated population genotyped using a dense SNP array, and with 20% of these individuals sequenced, 65% of sequences of the unsequenced subjects can be partially inferred. PMID- 23361220 TI - MUTYH-associated polyposis (MAP): evidence for the origin of the common European mutations p.Tyr179Cys and p.Gly396Asp by founder events. AB - MUTYH-associated polyposis (MAP) is an autosomal recessive adenomatous polyposis caused by biallelic germline mutations of the base-excision-repair gene MUTYH. In MAP patients of European origin, the combined allele frequency of the mutations p.Tyr179Cys and p.Gly396Asp ranges between 50 and 82%, while these mutations have not been identified in Far Eastern Asian populations, supporting the hypothesis that a founder effect has occurred at some point in European history. To investigate the natural history of the two common European MUTYH alleles, we genotyped six gene-flanking microsatellite markers in 80 unrelated Italian and German MAP patients segregating one or both mutations and calculated their age in generations (g) by using DMLE+2.2 software. Three distinct common haplotypes, one for p.Tyr179Cys and two for p.Gly396Asp, were identified. Estimated mutation ages were 305 g (95% CS: 271-418) for p.Tyr179Cys and 350 g (95% CS: 313-435) for p.Gly396Asp. These results provide evidence for strong founder effects and suggest that the p.Tyr179Cys and p.Gly396Asp mutations derive from ancestors who lived between 5-8 thousand years and 6-9 thousand years B.C., respectively. PMID- 23361221 TI - Clinical utility gene card for: Gorlin syndrome--update 2013. PMID- 23361222 TI - Molecular and clinical delineation of the 17q22 microdeletion phenotype. AB - Deletions involving 17q21-q24 have been identified previously to result in two clinically recognizable contiguous gene deletion syndromes: 17q21.31 and 17q23.1 q23.2 microdeletion syndromes. Although deletions involving 17q22 have been reported in the literature, only four of the eight patients reported were identified by array-comparative genomic hybridization (array-CGH) or flourescent in situ hybridization. Here, we describe five new patients with 1.8-2.5-Mb microdeletions involving 17q22 identified by array-CGH. We also present one patient with a large karyotypically visible deletion involving 17q22, fine-mapped to ~8.2 Mb using array-CGH. We show that the commonly deleted region in our patients spans 0.24 Mb and two genes; NOG and C17ORF67. The function of C17ORF67 is not known, whereas Noggin, the product of NOG, is essential for correct joint development. In common with the 17q22 patients reported previously, the disease phenotype of our patients includes intellectual disability, attention deficit hyperactivity disorder, conductive hearing loss, visual impairment, low set ears, facial dysmorphology and limb anomalies. All patients displayed NOG-related bone and joint features, including symphalangism and facial dysmorphology. We conclude that these common clinical features indicate a novel clinically recognizable, 17q22 contiguous microdeletion syndrome. PMID- 23361223 TI - Genome-wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome. AB - We identified a novel homozygous 15q13.3 microdeletion in a young boy, with a complex neurodevelopmental disorder characterized by severe cerebral visual impairment with additional signs of congenital stationary night blindness, congenital hypotonia with areflexia, profound intellectual disability, and refractory epilepsy. The mechanisms by which the genes in the deleted region exert their effect are unclear. In this paper, we probed the role of downstream effects of the deletions as a contributing mechanism to the molecular basis of the observed phenotype. We analyzed gene expression of lymphoblastoid cells derived from peripheral blood of the proband and his relatives to ascertain the relative effects of the homozygous and heterozygous deletions. We identified 267 genes with apparent differential expression between the proband with the homozygous deletion and 3 age- and sex-matched typically developing controls. Several of the differentially expressed genes are known to influence neurodevelopment and muscular function, and thus may contribute to the observed cognitive impairment and hypotonia. We further investigated the role of CHRNA7 by measuring TNFalpha modulation (a potentially important pathway in regulating synaptic plasticity). We found that the cell line with the homozygous deletion lost the ability to inhibit the activation of tumor necrosis factor-alpha secretion. Our findings suggest downstream genes that may have been altered by the 15q13.3 homozygous deletion, and thus contributed to the severe developmental encephalopathy of the proband. Furthermore, we show that a potentially important pathway in learning and development is affected by the deletion of CHRNA7. PMID- 23361224 TI - Trends in maternal age distribution and the live birth prevalence of Down's syndrome in England and Wales: 1938-2010. AB - There have been concerns about the effects of increases in maternal age since the 1980s on the prevalence of Down's syndrome. This study examined changes in the distribution of maternal age in England and Wales from 1938 to 2010. The live birth prevalence of Down's syndrome in the absence of screening and subsequent termination was estimated using the numbers of babies born in England and Wales according to maternal age and the maternal age-related risk of a birth with Down's syndrome. The proportion of women age 35 years or older at the time of giving birth reached a peak of 20% in 1945, declined to 5.5% in 1977 and rose to 20% in 2007. In the absence of screening and subsequent termination, the estimated live birth prevalence of Down's syndrome would have mirrored these changes (2.3 per 1000 births in 1945, 1.2 per 1000 in 1976 and 2.2 per 1000 in 2007). The observed live birth prevalence (recorded by the National Down Syndrome Cytogenetic Register) was1.0 per 1000 from 1989 to 2010, due to screening and subsequent termination. In conclusion since the 1980s there has been an increase in the mean maternal age and in the expected prevalence of Down's syndrome. When put in a longer historical context the current expected live birth prevalence is similar to that in the 1940s and the observed live birth prevalence is about 54% less than expected, due to screening and subsequent termination, and has remained reasonably constant since 1989 at 1.0 per 1000 births. PMID- 23361225 TI - The role of good manufacturing practices for preventing dietary supplement adulteration. PMID- 23361226 TI - Profiling and quantifying polar lipids in milk by hydrophilic interaction liquid chromatography coupled with evaporative light-scattering and mass spectrometry detection. AB - In this work, a high-performance liquid chromatography with evaporative light scattering detection method has been developed and applied for quantification of the polar content of the lipid fraction in milk samples of different origin. From a chromatographic stand-point, a 4.6-mm I.D. hydrophilic interaction liquid chromatography column was employed to attain a baseline separation of major phospholipid classes contained in the various milk samples tested. Quantitative analysis was performed by the external calibration method using reference material solutions in the 5-100 mg/L concentration range. Analytical recoveries ranging from 57 to 100%, and repeatability data lower than 8.04% were obtained on a skimmed cow's milk sample. The crude cow milk was the most abundant (0.04%) in phospholipids and donkey milk was the poorest (0.004%). Quantitative differences were determined in the phospholipid content of the milk samples tested. Finally, characterization of phospholipid profile and fatty acid composition of the different samples was carried out by an ion trap-time of flight mass spectrometer and gas chromatography coupled to flame ionization and mass spectrometry detection. A thorough screening of the polar lipid composition of milk samples of different origin is here outlined, for the first time. PMID- 23361228 TI - A 3-D open-framework material with intrinsic chiral topology used as a stationary phase in gas chromatography. AB - Compared with liquid chromatography and capillary electrophoresis, the diversity of gas chromatography chiral stationary phases is rather limited. Here, we report the fabrication of Co(D-Cam)1/2(bdc)1/2(tmdpy) (D-Cam = D-camphoric acid; bdc = 1,4-benzenedicarboxylate; tmdpy = 4,4'-trimethylenedipyridine)-coated open tubular columns for high-resolution gas chromatographic separation of compounds. The Co(D-Cam)1/2(bdc)1/2(tmdpy) compound possesses a 3-D framework containing enantiopure building blocks embedded in intrinsically chiral topological nets. In this study, two fused-silica open tubular columns with different inner diameters and lengths, including column A (30 m * 530 MUm i.d.) and column B (2 m * 75 MUm i.d.), were prepared by a dynamic coating method using Co-(D Cam)1/2(bdc)1/2(tmdpy) as the stationary phase. The chromatographic properties of the two columns were investigated using n-dodecane as the test compound at 120 degrees C. The number of theoretical plates (plates/m) of the two metal-organic framework columns was 1,450 and 3,100, respectively. The separation properties were evaluated using racemates, isomers, alkanes, alcohols, and Grob's test mixture. The limit of detection and limit of quantification were found to be 0.125 and 0.417 ng for citronellal enantiomers, respectively. Repeatability (n = 6) showed lower than 0.25 % relative standard deviation (RSD) for retention times and lower than 2.2 % RSD for corrected peak areas. The experimental results showed that the stationary phase has excellent selectivity and also possesses good recognition ability toward these organic compounds, especially chiral compounds. PMID- 23361229 TI - Screening interaction between ochratoxin A and aptamers by fluorescence anisotropy approach. AB - By taking advantage of the intrinsic fluorescence of ochratoxin A (OTA), we present a fluorescence anisotropy approach for rapid analysis of the interactions between OTA and aptamers. The specific binding of OTA with a 36-mer aptamer can induce increased fluorescence anisotropy (FA) of OTA as the result of the freedom restriction of OTA and the increase of molecular volume, and the maximum FA change is about 0.160. This FA approach enables an easy way to investigate the effects of buffer compositions like metal ions on the affinity binding. FA analysis shows the interaction between OTA and aptamer is greatly enhanced by the simultaneous presence of Ca(2+) and Na(+), while the binding affinity of aptamer decreases more than 18-fold when only Ca(2+) exists, and the binding is completely lost when Ca(2+) is absent. Crucial region of the aptamer for binding can be mapped through FA analysis and aptamer mutation. The demonstrated FA approach maintains the advantages of FA in simplicity, rapidity, and robustness. This investigation will help the development of aptamer-based assays for OTA detection in optimizing the binding conditions, modification of aptamers, and rational design. PMID- 23361227 TI - Quantitative, solution-phase profiling of multiple transcription factors in parallel. AB - Transcription factors are regulatory proteins that bind to specific sites of chromosomal DNA to enact responses to intracellular and extracellular stimuli. Transcription factor signalling networks are branched and interconnected so that any single transcription factor can activate many different genes and one gene can be activated by a combination of different transcription factors. Thus, trying to characterize a cellular response to a stimulus by measuring the level of only one transcription factor potentially ignores important simultaneous events that contribute to the response. Hence, parallel measurements of transcription factors are necessary to capture the breadth of valuable information about cellular responses that would not be obtained by measuring only a single transcription factor. We have sought to develop a new, scalable, flexible, and sensitive approach to analysis of transcription factor levels that complements existing parallel approaches. Here, we describe proof-of-principle analyses of purified human transcription factors and breast cancer nuclear extracts. Our assay can successfully quantify transcription factors in parallel with ~10-fold better sensitivity than current techniques. Sensitivity of the assay can be further increased by 200-fold through the use of PCR for signal amplification. PMID- 23361230 TI - 2-methiopropamine, a thiophene analogue of methamphetamine: studies on its metabolism and detectability in the rat and human using GC-MS and LC-(HR)-MS techniques. AB - 2-Methiopropamine [1-(thiophen-2-yl)-2-methylaminopropane, 2-MPA], a thiophene analogue of methamphetamine, is available from online vendors selling "research chemicals." The first samples were seized by the German police in 2011. As it is a recreational stimulant, its inclusion in routine drug screening protocols should be required. The aims of this study were to identify the phase I and II metabolites of 2-MPA in rat and human urine and to identify the human cytochrome P450 (CYP) isoenzymes involved in its phase I metabolism. In addition, the detectability of 2-MPA in urine samples using the authors' well-established gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-linear ion trap-mass spectrometry (LC-MS(n)) screening protocols was also evaluated. The metabolites were isolated from rat and human urine samples by solid-phase extraction without or following enzymatic cleavage of conjugates. The phase I metabolites, following acetylation, were separated and identified by GC-MS and/or liquid chromatography-high-resolution linear ion trap mass spectrometry (LC-HR MS(n)) and the phase II metabolites by LC-HR-MS(n). The following major metabolic pathways were proposed: N-demethylation, hydroxylation at the side chain and at the thiophene ring, and combination of these transformations followed by glucuronidation and/or sulfation. CYP1A2, CYP2C19, CYP2D6, and CYP3A4 were identified as the major phase I metabolizing enzymes. They were also involved in the N-demethylation of the analogue methamphetamine and CYP2C19, CYP2D6, and CYP3A4 in its ring hydroxylation. Following the administration of a typical user's dose, 2-MPA and its metabolites were identified in rat urine using the authors' GC-MS and the LC-MS(n) screening approaches. Ingestion of 2-MPA could also be detected by both protocols in an authentic human urine sample. PMID- 23361231 TI - Nanoporous platinum thin films synthesized by electrochemical dealloying for nonenzymatic glucose detection. AB - Nanoporous Pt thin films were prepared by simultaneous deposition of Pt and Si and subsequent dealloying of Si out of the Pt(x)Si(1-x) films. The x values were easily controlled in the range of 0.10 to 0.90 by the distances between the sample position and the target positions and by the plasma power for the targets. With a roughness factor of around 40, the nanoporous Pt films showed enough sensitivity, selectivity, and detection limit for glucose and interfering species. Multiple nanoporous Pt films with similar roughness factors were easily fabricated using this method, which showed good enough and similar performance to other reported glucose sensors, suggesting a simple and quality controlled manufacturing method for nanoporous Pt films as nonenzymatic glucose sensors. PMID- 23361232 TI - Poverty, problem behavior, and promise: differential susceptibility among infants reared in poverty. AB - Do infants reared in poverty exhibit certain physiological traits that make them susceptible to the positive and negative features of their caregiving environment? Guided by theories of differential susceptibility and biological sensitivity to context, we evaluated whether high baseline respiratory sinus arrhythmia (RSA) operates as a susceptibility factor among infants reared in poverty (N = 73). Baseline RSA at 5 months, the quality of the attachment relationship at 17 months, and the interaction of these two factors were included in our models as predictors of problem behavior at 17 months. Consistent with theory, results showed no significant differences in problem behavior among infants with low baseline RSA; however, infants with high baseline RSA exhibited the lowest levels of problem behavior if reared in an environment that fostered security, and they exhibited the highest levels of problem behavior if reared in an environment that fostered disorganization. These results have important implications for the psychological health of infants living in poverty. PMID- 23361233 TI - Making sense of nonsense: the visual salience of units determines sensitivity to magnitude. AB - When are people sensitive to the magnitude of numerical information presented in unfamiliar units, such as a price in a foreign currency or a measurement of an unfamiliar product attribute? We propose that people exhibit deliberational blindness, a failure to consider the meaning of even unfamiliar units. When an unfamiliar unit is not salient, people fail to take their lack of knowledge into account, and their judgments reflect sensitivity to the magnitude of the number. However, subtly manipulating the visual salience of the unit (e.g., enlarging its font size relative to the font size of the number) prompts recognition of the unit's unfamiliarity and reduces magnitude sensitivity. In five experiments, we demonstrated this unit-salience effect, provided evidence for deliberational blindness, and ruled out alternative explanations, such as nonperception and fluency. These findings have implications for decision making involving numerical information expressed in both unfamiliar units and familiar but poorly calibrated units. PMID- 23361234 TI - Abstracts of the XXXII National Meeting of the Italian Society for the Study of Connective Tissues (SISC) Meeting. Bologna, Italy. October 20-21, 2012. PMID- 23361235 TI - Expression of parafibromin in major renal cell tumors. AB - Parafibromin, encoded by HRPT2 gene, is a recently identified tumor suppressor. Complete and partial loss of its expression have been observed in hyperparathyroidism-jaw tumor (HPT-JT), parathyroid carcinoma, breast carcinoma, lung carcinoma, gastric and colorectal carcinoma. However, little has been known about its expression in renal tumors. In order to study the expression of parafibromin in a series of the 4 major renal cell tumors - clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), chromophobe renal cell carcinoma (chRCC) and oncocytoma. One hundred thirty nine renal tumors including 61 ccRCCs, 37 pRCCs, 22 chRCCs and 19 oncocytomas were retrieved and used for the construction of renal tissue microarrays (TMAs). The expression of parafibromin was detected by immunohistochemical method on the constructed TMAs. Positive parafibromin stains are seen in 4 out of 61 ccRCCs (7%), 7 out of 37 pRCCs (19%), 12 out of 23 chRCCs (52%) and all 19 oncocytomas (100%). Parafibromin expression varies significantly (P< 8.8 x10-16) among the four major renal cell tumors and were correlated closely with tumor types. No correlation of parafibromin expression with tumor staging in ccRCCs, pRCCs and chRCCs, and Fuhrman nuclear grading in ccRCCs and pRCCs. In summary, parafibromin expression was strongly correlated with tumor types, which may suggest that it plays a role in the tumorigenesis in renal cell tumors. PMID- 23361236 TI - MUC1 marks collecting tubules, renal vesicles, comma- and S-shaped bodies in human developing kidney tubules, renal vesicles, comma- and s-shaped bodies in human kidney. AB - MUC1 is a transmembrane glycoprotein, apically expressed in most epithelial cells, used in the differential diagnosis of carcinomas and for discrimination of tumors of non-epithelial origin showing epithelioid features. Little attention has been paid so far though, on its possible significance in embryonic tissues. A preliminary study from our group revealed MUC1 expression in the cap mesenchymal cells during human nephrogenesis, suggesting a role for MUC1 in the process of mesenchymal-to-epithelial transition. This study aimed at investigating the expression pattern of MUC1 in various developing structures of human fetal kidney. Expression of MUC1 was examined in kidneys of 5 human fetuses. MUC1 immunoreactivity was detected in ureteric bud tips, in collecting tubules, in cap mesenchymal cells undergoing the initial phases of mesenchymal-to-epithelial transition, in renal vesicles, comma-bodies, and S-shaped bodies. Our previous preliminary report suggested a role for MUC1 in the initial phases of the process of mesenchymal-to-epithelial transition. The present data suggest that MUC1 expression characterizes multiple structures during human nephrogenesis, from the ureteric bud, to the initial phases of mesenchymal-to-epithelial transition and that MUC1 should be added to the genes activated during the process of mesenchymal-to-epithelial transition in the cap mesenchyme of human kidney. PMID- 23361238 TI - Degenerative effects in rat eyes after experimental ocular hypertension. AB - This study was used to evaluate the degenerative effects on the retina and eye cup sections after experimental induction of acute ocular hypertension on animal models. In particular, vascular events were directly focused in this research in order to assess the vascular remodeling after transient ocular hypertension on rat models. After local anaesthesia by administration of eye drops of 0.4% oxibuprocaine, 16 male adult Wistar rats were injected in the anterior chamber of the right eye with 15 uL of methylcellulose (MTC) 2% in physiological solution. The morphology and the vessels of the retina and eye-cup sections were examined in animals sacrificed 72 h after induction of ocular hypertension. In retinal fluorescein angiographies (FAGs), by means of fluorescein isothiocyanate coniugated dextran (FITC), the radial venules showed enlargements and increased branching, while the arterioles appeared focally thickened. The length and size of actually perfused vessels appeared increased in the whole superficial plexus. In eye-cup sections of MTC-injected animals, in deep plexus and connecting layer there was a bigger increase of vessels than in controls. Moreover, the immunolocalization of astrocytic marker glial fibrillary acidic protein (GFAP) revealed its increased expression in internal limiting membrane and ganglion cell layer, as well as its presence in Muller cells. Finally, the pro-angiogenic factor vascular endothelial growth factor (VEGF) was found to be especially expressed by neurones of ganglion cell layer, both in control and in MTC-injected eyes. The data obtained in this experimental model on the interactions among glia, vessels and neurons should be useful to evaluate if also in glaucomatous patients the activation of vessel-adjacent glial cells might play key roles in following neuronal dysfunction. PMID- 23361237 TI - Dipeptidylpeptidase--IV, a key enzyme for the degradation of incretins and neuropeptides: activity and expression in the liver of lean and obese rats. AB - Given the scarcity of donors, moderately fatty livers (FLs) are currently being considered as possible grafts for orthotopic liver transplantation (OLT), notwithstanding their poor tolerance to conventional cold preservation. The behaviour of parenchymal and sinusoidal liver cells during transplantation is being studied worldwide. Much less attention has been paid to the biliary tree, although this is considered the Achille's heel even of normal liver transplantation. To evaluate the response of the biliary compartment of FLs to the various phases of OLT reliable markers are necessary. Previously we demonstrated that Alkaline Phosphatase was scarcely active in bile canaliculi of FLs and thus ruled it out as a marker. As an alternative, dipeptidylpeptidase-IV (DPP-IV), was investigated. This ecto-peptidase plays an important role in glucose metabolism, rapidly inactivating insulin secreting hormones (incretins) that are important regulators of glucose metabolism. DPP-IV inhibitors are indeed used to treat Type II diabetes. Neuropeptides regulating bile transport and composition are further important substrates of DPP-IV in the enterohepatic axis. DPP-IV activity was investigated with an azo-coupling method in the liver of fatty Zucker rats (fa/fa), using as controls lean Zucker (fa/+) and normal Wistar rats. Protein expression was studied by immunofluorescence with the monoclonal antibody (clone 5E8). In Wistar rat liver, DPP-IV activity and expression were high in the whole biliary tree, and moderate in sinusoid endothelial cells, in agreement with the literature. Main substrates of DPP-IV in hepatocytes and cholangiocytes could be incretins GLP-1 and GIP, and neuropeptides such as vasoactive intestinal peptide (VIP) and substance P, suggesting that these substances are inactivated or modified through the biliary route. In lean Zucker rat liver the enzyme reaction and protein expression patterns were similar to those of Wistar rat. In obese rat liver the patterns of DPP-IV activity and expression in hepatocytes reflected the morphological alterations induced by steatosis as lipid-rich hepatocytes had scarce activity, located either in deformed bile canaliculi or in the sinusoidal and lateral domains of the plasma membrane. These findings suggest that bile canaliculi in steatotic cells have an impaired capacity to inactivate incretins and neuropeptides. Incretin and/or neuropeptide deregulation is indeed thought to play important roles in obesity and insulin-resistance. No alteration in enzyme activity and expression was found in the upper segments of the biliary tree of obese respect to lean Zucker and Wistar rats. In conclusion, this research demonstrates that DPP-IV is a promising in situ marker of biliary functionality not only of normal but also of fatty rats. The approach, initially devised to investigate the behaviour of the liver during the various phases of transplantation, appears to have a much higher potentiality as it could be further exploited to investigate any pathological or stressful conditions involving the biliary tract (i.e., metabolic syndrome and cholestasis) and the response of the biliary tract to therapy and/or to surgery. PMID- 23361239 TI - Celecoxib treatment does not alter recruitment and activation of osteoclasts in the initial phase of experimental tooth movement. AB - In a previous study, we reported that the short-term treatment with celecoxib, a non-steroidal anti-inflammatory drug (NSAID) attenuates the activation of brain structures related to nociception and does not interfere with orthodontic incisor separation in rats. The conclusion was that celecoxib could possibly be prescribed for pain in orthodontic patients. However, we did not analyze the effects of this drug in periodontium. The aim of this follow-up study was to analyze effects of celecoxib treatment on recruitment and activation of osteoclasts and alveolar bone resorption after inserting an activated orthodontic appliance between the incisors in our rat model. Twenty rats (400-420 g) were pretreated through oral gavage with celecoxib (50 mg/kg) or vehicle (carboxymethylcellulose 0.4%). After 30 min, they received an activated (30 g) orthodontic appliance, set not to cause any palate disjunction. In sham animals, the appliance was immediately removed after introduction. All animals received ground food and, every 12 h, celecoxib or vehicle. After 48 h, they were anesthetized and transcardiacally perfused through the aorta with 4% formaldehyde. Subsequently, maxillae were removed, post-fixed and processed for histomorphometry or immunohistochemical analyses. As expected, incisor distalization induced an inflammatory response with certain histological changes, including an increase in the number of active osteoclasts at the compression side in group treated with vehicle (appliance: 32.2 +/- 2.49 vs sham: 4.8 +/- 1.79, P<0.05) and celecoxib (appliance: 31.0 +/- 1.45 vs sham: 4.6 +/- 1.82, P<0.05). The treatment with celecoxib did not modify substantially the histological alterations and the number of active osteoclasts after activation of orthodontic appliance. Moreover, we did not see any difference between the groups with respect to percentage of bone resorption area. Taken together with our previous results we conclude that short-term treatment with celecoxib can indeed be a therapeutic alternative for pain relieve during orthodontic procedures. PMID- 23361240 TI - AUTOCOUNTER, an ImageJ JavaScript to analyze LC3B-GFP expression dynamics in autophagy-induced astrocytoma cells. AB - An ImageJ JavaScript, AUTOCOUNTER, was specifically developed to monitor and measure LC3B-GFP expression in living human astrocytoma cells, namely T98G and U373-MG. Discrete intracellular GFP fluorescent spots derived from transduction of a Baculovirus replication-defective vector (BacMam LC3B-GFP), followed by microscope examinations at different times. After viral transgene expression, autophagy was induced by Rapamycin administration and assayed in ph-p70S6K/p70S6K and LC3B immunoblotting expression as well as by electron microscopy examinations. A mutated transgene, defective in LC3B lipidation, was employed as a negative control to further exclude fluorescent dots derived from protein intracellular aggregation. The ImageJ JavaScript was then employed to evaluate and score the dynamics changes of the number and area of LC3B-GFP puncta per cell in time course assays and in complex microscope examinations. In conclusion, AUTOCOUNTER enabled to quantify LC3B-GFP expression and to monitor dynamics changes in number and shapes of autophagosomal-like vesicles: it might therefore represent a suitable algorithmic tool for in vitro autophagy modulation studies. PMID- 23361242 TI - Overexpression of ubiquitin-specific protease 22 predicts poor survival in patients with early-stage non-small cell lung cancer. AB - Ubiquitin-specific protease 22 (USP22), a novel ubiquitin hydrolase, has been implicated in oncogenesis and cancer progression in various types of human cancer. However, the clinical significance of USP22 expression in non-small cell lung cancer (NSCLC) has not been determined. In the present study, USP22 messenger RNA (mRNA) and protein levels were analyzed by quantitative real-time polymerase chain reaction (PCR) and western blot analysis in 30 cases of NSCLC and in corresponding non-tumor tissue samples. Furthermore, immunohistochemistry was performed to detect USP22 protein expression in 86 primary tumor tissues derived from clinically annotated NSCLC cases at stage I-II. In our analysis we found that both USP22 mRNA and protein levels in NSCLC tissues were significantly higher than those in corresponding non-tumor tissues and that there was a significant correlation between the expression of USP22 mRNA and protein (P=0.000, kappa=0.732). In addition, a high-level of USP22 expression was observed in 53.3% (39 out of 86) cases and it was correlated with large tumor size (P=0.029) and lymph node metastasis (P=0.026). Patients with tumors displaying a high-level of USP22 expression showed significantly shorter survival (P=0.006, log-rank test). Importantly, multivariate analysis showed that high USP22 protein expression was an independent prognostic factor for NSCLC patients (P=0.003). In sum, our data suggest that USP22 plays an important role in NSCLC progression at the early stage, and that overexpression of USP22 in tumor tissues could be used as a potential prognostic marker for patients with early clinical stage of NSCLC. PMID- 23361241 TI - Nuclear damages and oxidative stress: new perspectives for laminopathies. AB - Mutations in genes encoding nuclear envelope proteins, particularly LMNA encoding the A-type lamins, cause a broad range of diverse diseases, referred to as laminopathies. The astonishing variety of diseased phenotypes suggests that different mechanisms could be involved in the pathogenesis of laminopathies. In this review we will focus mainly on two of these pathogenic mechanisms: the nuclear damages affecting the chromatin organization, and the oxidative stress causing un-repairable DNA damages. Alteration in the nuclear profile and in chromatin organization, which are particularly impressive in systemic laminopathies whose cells undergo premature senescence, are mainly due to accumulation of unprocessed prelamin A. The toxic effect of these molecular species, which interfere with chromatin-associated proteins, transcription factors, and signaling pathways, could be reduced by drugs which reduce their farnesylation and/or stability. In particular, inhibitors of farnesyl transferase (FTIs), have been proved to be active in rescuing the altered cellular phenotype, and statins, also in association with other drugs, have been included into pilot clinical trials. The identification of a mechanism that accounts for accumulation of un-repairable DNA damage due to reactive oxygen species (ROS) generation in laminopathic cells, similar to that found in other muscular dystrophies (MDs) caused by altered expression of extracellular matrix (ECM) components, suggests that anti-oxidant therapeutic strategies might prove beneficial to laminopathic patients. PMID- 23361243 TI - Detection and characterisation of NAD(P)H-diaphorase activity in Dictyostelium discoideum cells (Protozoa). AB - In Dictyostelium discoideum (D. discoideum), compounds generating nitric oxide (NO) inhibit its aggregation and differentiation without altering cyclic guanosine monophosphate (cGMP) production. They do it by preventing initiation of cyclic adenosine monophosphate (cAMP) pulses. Furthermore, these compounds stimulate adenosine diphosphate (ADP)-ribosylation of a 41 kDa cytosolic protein and regulate the glyceraldehyde-3-phospate dehydrogenase activity. Yet, although D. discoideum cells produce NO at a relatively constant rate at the onset of their developmental cycle, there is still no evidence of the presence of nitric oxide synthase (NOS) enzymes. In this work, we detect the nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) activity in D. discoideum and we characterise it by specific inhibitors and physical-chemical conditions that allegedly distinguish between NOS-related and -unrelated NADPH-d activity. PMID- 23361245 TI - DNA breakage detection-fluorescence in situ hybridization (DBD-FISH) in buccal cells. AB - DNA breakage detection-fluorescence in situ hybridization (DBD-FISH) is a recently developed technique that allows cell-by-cell detection and quantification of DNA breakage in the whole genome or within specific DNA sequences. The present investigation was conducted to adapt the methodology of DBD-FISH to the visualization and evaluation of DNA damage in buccal epithelial cells. DBD-FISH revealed that DNA damage increased significantly according to H2O2 concentration (r2=0.91). In conclusion, the DBD-FISH technique is easy to apply in buccal cells and provides prompt results that are easy to interpret. Future studies are needed to investigate the potential applicability of a buccal cell DBD-FISH model to human biomonitoring and nutritional work. PMID- 23361244 TI - Radioprotective potential of histamine on rat small intestine and uterus. AB - The aim of this study was to improve knowledge about histamine radioprotective potential investigating its effect on reducing ionising radiation-induced injury and genotoxic damage on the rat small intestine and uterus. Forty 10-week-old male and 40 female Sprague-Dawley rats were divided into 4 groups. Histamine and histamine-5Gy groups received a daily subcutaneous histamine injection (0.1 mg/kg) starting 24 h before irradiation. Histamine-5Gy and untreated-5Gy groups were irradiated with a dose of whole-body Cesium-137 irradiation. Three days after irradiation animals were sacrificed and tissues were removed, fixed, and stained with haematoxylin and eosin, and histological characteristics were evaluated. Proliferation, apoptosis and oxidative DNA markers were studied by immunohistochemistry, while micronucleus assay was performed to evaluate chromosomal damage. Histamine treatment reduced radiation-induced mucosal atrophy, oedema and vascular damage produced by ionising radiation, increasing the number of crypts per circumference (239 +/- 12 vs 160 +/- 10; P<0.01). This effect was associated with a reduction of radiation-induced intestinal crypts apoptosis. Additionally, histamine decreased the frequency of micronuclei formation and also significantly attenuated 8-OHdG immunoreactivity, a marker of DNA oxidative damage. Furthermore, radiation induced flattening of the endometrial surface, depletion of deep glands and reduced mitosis, effects that were completely blocked by histamine treatment. The expression of a proliferation marker in uterine luminal and glandular cells was markedly stimulated in histamine treated and irradiated rats. The obtained evidences indicate that histamine is a potential candidate as a safe radioprotective agent that might increase the therapeutic index of radiotherapy for intra-abdominal and pelvic cancers. However, its efficacy needs to be carefully investigated in prospective clinical trials. PMID- 23361246 TI - Effect of retinoic acid on the nitrergic innervation of meibomian glands in rats. AB - The purpose of this study was to investigate the effect of prenatal administration of retinoic acid (RA) on the development of nicotinamide adenine dinucleotide diaphorase (NADPH-d) positive structures in the rat Meibomian glands. One mg/kg of RA was applied to pregnant Wistar rats intraperitonaelly during the gestational period in each of the 12th-14th embryonic days (totally 3 mg/kg). Sections of the central upper eyelids were investigated in rat pups on the 14th postnatal day. They were processed histochemically for NADPH-d, to study the presence and distribution of nitric oxide synthase (NOS) positive nerve structures. NADPH-d staining of Meibomian glands was compared in two groups of rat pups. In the control group, eyelids of 14 day-old rats were studied with no experimental intervention. The second group consisted of rat pups which were prenatally administered the excess of RA. Histochemical analysis of control eyelids revealed numerous NADPH-d well-stained acini of Meibomian glands arranged tightly into groups. Intensively stained vessels and NADPH-d/NOS-positive nerve fibers bordered acini of Meibomian glands. These structures were present in the submucosal layer as well. The analysis of RA group showed less numerous, shrunken acini of Meibomian glands that were seen not only smaller in size, but also in density of their staining and the amount of nitrergic nerve fibers around acini were considerably lowered. In the submucosa differences were noticed compared to the control group, there were numerous NADPH-d stained vessels accompanied by NADPH-d/NOS-positive nerve fibers. The excess of RA during the prenatal period may influence on the development and morphology of NADPH-d positive structures of rat's Meibomian glands. PMID- 23361253 TI - [Tumor in the small intestine in Peutz-Jeghers syndrome]. AB - Epithelial misplacement can be present in small bowel polyps of patients with Peutz-Jeghers syndrome and can mimic invasive malignancy. For recognizing epithelial misplacement, which can also have dysplastic changes, it is helpful to demonstrate the associated lamina propria and the lack of desmoplastic response. Intramural mucinous cysts are frequently seen in the setting of epithelial misplacement. PMID- 23361254 TI - The realities of the Liverpool care pathway. PMID- 23361247 TI - On the future contents of a small journal of histochemistry. AB - In the last three years, more than 70,000 scientific articles have been published in peer reviewed journals on the application of histochemistry in the biomedical field: most of them did not appear in strictly histochemical journals, but in others dealing with cell and molecular biology, medicine or biotechnology. This proves that histochemistry is still an active and innovative discipline with relevance in basic and applied biological research, but also demonstrates that especially the small histochemical Journals should likely reconsider their scopes and strategies to preserve their authorship. A review of the last three years volumes of the European Journal of Histochemistry, taken as an example of a long time established small Journal, confirmed that the published articles were widely heterogeneous in their topics and experimental models, as in this Journal's tradition. This strongly suggests that a Journal of histochemistry should keep its role as a forum open to an audience as broad as possible, publishing papers on cell and tissue biology in a wide variety of models. This will improve knowledge of the basic mechanisms of development and differentiation, while helping to increase the number of potential authors since scientists who generally do not use histochemistry in their research will find hints for the applications of histochemical techniques to novel still unexplored subjects. PMID- 23361257 TI - Adsorbed and near surface structure of ionic liquids at a solid interface. AB - The structure of solid-ionic liquid (IL) interfaces has been characterised with unprecedented clarity by employing a range of atomic force microscopy (AFM) imaging techniques and tip pressures appropriate for the system under study. Soft contact and amplitude-modulation (AM) AFM imaging have been used to elucidate the lateral structure of ILs adsorbed onto mica, and in the near surface ion layers. Data is presented for ethylammonium nitrate (EAN) and 1-ethyl-3-methylimidazolium bis(trifluoro-methylsulfonyl)imide (EMIm TFSI). Whereas EAN is a protic IL that forms a nanostructured sponge phase in the bulk, EMIm TFSI is aprotic and has weak (or absent) bulk association structure. Comparison of results obtained for the two liquids elucidates how the strength of bulk liquid morphology effects lateral organisation at the surface, and any effect of IL class, i.e. protic versus aprotic. Imaging reveals EAN self assembles at the solid surface in a worm like morphology, whereas EMIm cations adsorb in a more isolated fashion, but still in rows templated by the mica surface. To the authors' knowledge, the wormlike structures present at the EAN-mica interface are the smallest self assembled aggregates ever imaged on a solid surface. PMID- 23361256 TI - DNA repair mechanisms in Huntington's disease. AB - The human genome is under continuous attack by a plethora of harmful agents. Without the development of several dedicated DNA repair pathways, the genome would have been destroyed and cell death, inevitable. However, while DNA repair enzymes generally maintain the integrity of the whole genome by properly repairing mutagenic and cytotoxic intermediates, there are cases in which the DNA repair machinery is implicated in causing disease rather than protecting against it. One case is the instability of gene-specific trinucleotides, the causative mutations of numerous disorders including Huntington's disease. The DNA repair proteins induce mutations that are different from the genome-wide mutations that arise in the absence of repair enzymes; they occur at definite loci, they occur in specific tissues during development, and they are age-dependent. These latter characteristics make pluripotent stem cells a suitable model system for triplet repeat expansion disorders. Pluripotent stem cells can be kept in culture for a prolonged period of time and can easily be differentiated into any tissue, e.g., cells along the neural lineage. Here, we review the role of DNA repair proteins in the process of triplet repeat instability in Huntington's disease and also the potential use of pluripotent stem cells to investigate neurodegenerative disorders. PMID- 23361255 TI - alpha-Synuclein and mitochondrial dysfunction in Parkinson's disease. AB - alpha-Synuclein (SNCA) is a substantive component of Lewy bodies, the pathological hallmark of Parkinson's disease (PD). The discovery and subsequent derivation of its role in PD has led to a suprising but fruitful convergence of the fields of biochemistry and molecular genetics. In particular, the manipulation of the cell lines of a number of forms of familial PD has implicated SNCA in distinct and diverse biochemical pathways related to its pathogenesis. This current and rapidly evolving concept indicates PD is a disease in which interacting pathways of oxidative stress, mitochondrial dysfunction and impaired regulation of protein turnover interact to cause dopaminergic cell dysfunction and death. SNCA has a central role in these processes and manipulation of its expression, degradation and aggregation appear to be promising neuroprotective therapeutic targets. PMID- 23361258 TI - Management of peripancreatic fluid collections following partial pancreatectomy: a comparison of percutaneous versus EUS-guided drainage. AB - BACKGROUND: Peripancreatic fluid collections (PFCs) occur in up to 30 % of patients following partial pancreatic resections. Traditionally, postoperative PFCs are managed via percutaneous drainage (PD). EUS-guided transgastric drainage has been shown to be effective for the management of PFCs secondary to acute pancreatitis. However, there are limited data on the use of EUS-guided drainage (EUSD) for the management of postoperative PFCs. OBJECTIVE: To compare the safety and efficacy of PD versus EUSD of PFCs in patients who have undergone partial pancreatic resections. DESIGN: Retrospective analysis of patients with symptomatic PFCs following pancreatic enucleation or distal pancreatectomy at MSKCC between January 2008 and December 2010. Patients were identified using an electronic medical records query in addition to a prospectively maintained pancreatic surgery complications database. SETTING: Single, academic, tertiary referral center. PATIENTS: Twenty-three patients with symptomatic PFCs following pancreatic enucleation or distal pancreatectomy were retrospectively identified. INTERVENTIONS: CT-guided PD versus endoscopic ultrasound-guided drainage (EUSD) MAIN OUTCOME MEASURES: Outcomes included technical success, clinical success, number of interventions, and complications. Technical success was defined as successful localization of the PFC by fine-needle aspiration and placement of a drainage catheter or stent. Clinical success was defined as radiographic resolution of the PFC and removal of the drain or stent, without the need for an alternative drainage procedure or surgery. RESULTS: PD was initially performed in 14 patients and EUSD initially in 9 patients. Three patients with initial PD had recurrence of PFC after removal of the external drain and underwent subsequent EUSD. The mean size of the fluid collections was 10.0 cm in the PD group and 8.9 cm in the EUSD group. Technical success was achieved in all patients in both groups. Clinical success was achieved in 11 of 14 (79 %) patients in the PD group compared with 11 of 11 (100 %) in the EUSD group, with one patient in the EUSD group lost to follow-up. One patient with initial PD required two additional percutaneous procedures before complete PFC resolution. Five EUSD patients required repeat endoscopy for stent revision or necrosectomy. The median number of interventions was two [range 1-5] in the PD group and two [range 1-5] in the EUSD group. The median number of days the drainage catheters were in place was 44.5 [range 2-87] in the PD group versus 57 [range 32-217] in the EUSD group. There were no procedure-related complications in either group. Adverse events in the PD group included splenic artery stump bleeding, pleural effusion, cysto colonic and cysto-cutaneous fistulae, and persistent catheter site pain. One patient in the EUSD group developed a small-bowel obstruction and bleeding gastric ulcer. LIMITATIONS: Retrospective, nonrandomized study and small numbers. CONCLUSIONS: EUSD of postoperative PFCs appears to be safe and technically feasible. This technique appears to be as successful as PD for the management of PFCs with the advantage of not requiring an external drainage apparatus and should be considered as a therapeutic option in this group of patients. Further evaluation, with analysis of cost and quality of life, should be considered in a prospective, randomized trial. PMID- 23361261 TI - Si-C bond cleavage by hydride complexes of rhodium and iridium: comparison of Si C(sp(2)) and Si-C(sp(3)) activation. AB - Single Si-C(R) (R = Ph, Me, Et) bond activation in {o (Ph(2)P)C(6)H(4)}(2)Si(Me)(R) induced by Rh(H)(CO)(PPh(3))(3) was developed. The efficiency of Si-C(R) bond breaking reactions increased at 60 degrees C in the order Si-C(Et) < Si-C(Me) < Si-C(Ph) and strongly depended on the reaction temperature. Elevating the reaction temperature promoted Si-C(Me) over Si-C(Ph) bond activation, demonstrating that Si-C(Me) cleavage is entropically favored but enthalpically unfavored in comparison with Si-C(Ph) bond cleavage. PMID- 23361260 TI - Comparison of results from a randomized trial 1 year after laparoscopic Nissen and Toupet fundoplications. AB - BACKGROUND: The fundoplication of choice for the surgical treatment of gastroesophageal reflux disease (GERD) still is debated. Multichannel intraluminal impedance monitoring (MII) has not been used to compare objective data, and comparative subjective data on laparoscopic Nissen and Toupet fundoplications are scarce. METHODS: This study randomly allocated 125 patients with documented chronic GERD to either laparoscopic floppy Nissen fundoplication (LNF; n = 62) or laparoscopic Toupet fundoplication (LTF; n = 63). The Gastrointestinal Quality of Life Index (GIQLI), symptom grading, esophageal manometry, and MII data were documented preoperatively and 1 year after surgery. The pre- and postprocedure data were compared. Statistical significance was set at a p value lower than 0.01 (NCT01321294). RESULTS: Both procedures resulted in significantly improved GIQLI and GERD symptoms. Preoperative dysphagia improved in both groups, but the improvement reached significance only in the LTF group. The ability to belch was shown to be significantly more decreased after LNF than after LTF. Gas-bloat and "atypical" extraesophageal symptoms also were decreased after surgery (p < 0.01). However, bowel symptoms were virtually unchanged in both groups. Both procedures resulted in significantly improved lower esophageal sphincter pressures. The improvement was greater in the LNF group than in the LTF group (p < 0.01). The DeMeester score and the numbers of total, acid, proximal, upright, and recumbent reflux episodes decreased in both groups after surgery (p < 0.01). No significant difference between the procedures in terms of MII data was found. Six patients (4.8 %) had to undergo reoperation because of intrathoracic slipping of the wrap. All the patients had undergone LNF. CONCLUSIONS: Both procedures proved to be equally effective in improving quality of life and GERD symptoms. However, the reoperation and dysphagia rates were lower and the ability to belch was higher after LTF than after LNF. PMID- 23361259 TI - Laparoscopy-assisted gastrectomy versus open gastrectomy for resectable gastric cancer: an update meta-analysis based on randomized controlled trials. AB - BACKGROUND: We carry out a meta-analysis to evaluate the effectiveness and safety of laparoscopy-assisted gastrectomy (LAG) versus open gastrectomy for resectable gastric cancer. METHODS: We searched EMBASE, the Cochrane Library, PubMed, Science Citation Index (SCI), Chinese biomedicine literature database to identify randomized controlled trials (RCTs) from their inception to April 2012. Meta analyses were performed using RevMan 5.0 software. It was in line with the preferred reporting items for systematic reviews and meta-analyses statement. The quality of evidence was assessed by GRADEpro 3.6. RESULTS: Eight RCTs totaling 784 patients were analyzed. Compared with open gastrectomy group, no significant differences were found in postoperative mortality (OR = 1.49; 95 % CI 0.29-7.79), anastomotic leakage (OR = 1.02; 95 % CI 0.24-4.27) , overall mean number of harvested lymph nodes [weighed mean difference (MD) = -3.17; 95 % CI -6.39 to 0.05]; the overall postoperative complication morbidity (OR = 0.54; 95 % CI 0.36 0.82), estimated blood loss (MD = -107.23; 95 % CI -148.56 to -65.89,) frequency of analgesic administration (MD = -1.69; 95 % CI -2.18 to -1.21, P < 0.00001), incidence of pulmonary complications (OR = 0.43, 95 % CI 0.20-0.93, P = 0.03) were significantly less in LAG group; LAG had shorter time to start first flatus (MD = -0.23; 95 % CI -0.41 to -0.05) and decreased hospital stay (MD = -1.72; 95 % CI -3.40 to 0.04), but, LAG still had longer operation time (MD = 76.70; 95 % CI 51.54-101.87). CONCLUSIONS: On the basis of this meta-analysis we conclude that although LAG was still a time-consuming and technically dependent procedure, it has the advantage of better short-term outcome. Long term survival data from other studies are urgently needed to estimate the survival benefit of this technique. PMID- 23361262 TI - Theoretical study on the functionalization of BC2N nanotube with amino groups. AB - Using density functional theory calculations, we investigated properties of a functionalized BC2N nanotube with NH3 and five other NH2-X molecules in which one of the hydrogen atoms of NH3 is substituted by X = -CH3, -CH2CH3, -COOH, -CH2COOH and -CH2CN functional groups. It was found that NH3 can be preferentially adsorbed on top of the boron atom, with adsorption energy of -12.0 kcal mol(-1). The trend of adsorption-energy change can be correlated with the trend of relative electron-withdrawing or -donating capability of the functional groups. The adsorption energies are calculated to be in the range of -1.8 to -14.2 kcal mol(-1), and their relative magnitude order is found as follows: H2N(CH2CH3) > H2N(CH3) > NH3 > H2N(CH2COOH) > H2N(CH2CN) > H2N(COOH). Overall, the functionalization of BC2N nanotube with the amino groups results in little change in its electronic properties. The preservation of electronic properties of BC2N coupled with the enhancement of solubility renders their chemical modification with either NH3 or amino functional groups to be a way for the purification of BC2N nanotubes. PMID- 23361263 TI - Protein lysine acetylation analysis: current MS-based proteomic technologies. AB - Protein lysine acetylation (Kac), including histone acetylation and non-nuclear protein acetylation, is a dynamic and reversible post-translational modification for cellular regulation. The modified proteins play a key role in regulating chromatin structure, transcriptional activity and metabolic pathways, thus contributing to diverse cellular processes like transcription, cell cycle regulation, apoptosis and senescence. Therefore, targeting protein acetylation represents a potentially promising strategy for certain diseases, such as cancer. However, global identification of protein acetylation is a major bottleneck due to its dynamic property and rather low abundance. Tremendous efforts have been made to develop mass spectrometry (MS)-based proteomic technologies for this purpose from diverse cellular sources. The present review has tried to provide an overview of current strategies employed for Kac identification from histone to system-wide Kac analysis, including enrichment techniques, chromatographic separation strategies, and mass spectrometry methods. PMID- 23361264 TI - Review of clinical trials for mitochondrial disorders: 1997-2012. AB - Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, alpha lipoate, and CoQ10), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, open-label/controlled, or double-blind/placebo controlled/crossover. Primary outcomes have ranged from single, clinically relevant scores to multiple measures. Eight of these trials have been well controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes. PMID- 23361265 TI - Self-organizing surface-initiated polymerization, templated self-sorting and templated stack exchange: synthetic methods to build complex systems. AB - In nature, spectacular function is achieved by highly sophisticated supramolecular architectures. Little is known what we would obtain if we could create complexity with similar precision, because the synthetic methods to do so are not available. This account summarizes recent approaches conceived to improve on this situation. With self-organizing surface-initiated polymerization (SOSIP), charge-transporting stacks can be grown directly on solid substrates with molecular-level precision. The extension to templated self-sorting (SOSIP-TSS) offers a supramolecular approach to multicomponent architectures. A solid theoretical framework for the transcription of information by templated self sorting has been introduced, intrinsic templation efficiencies up to 97% have been achieved, and the existence of self-repair has been shown. The extension to templated stack exchange (SOSIP-TSE) offers the complementary covalent approach. Compatibility of this robust method with the creation of double-channel architectures with antiparallel two-component gradients has been demonstrated. PMID- 23361266 TI - Nexus: plexus redeeming doctors. PMID- 23361267 TI - Antimetabolites: established cancer therapy. AB - Cell death has been divided into two main types: programmed cell death, in which the cell plays an active role, and passive (necrotic) cell death. Senescence arrest, accelerated senescence and differentiation are also responses that can be induced in response to DNA-damaging agents. Apoptosis may occur as a primary event following chemotherapy, in which genes that regulate apoptosis will influence the outcome of therapy or, alternatively, as an event secondary to the induction of lethal damage that involves the subsequent processing of cellular damage. The particular type of response induced is highly dependent on the agent and dose employed, the type of DNA damage induced as well as the genetic and cellular phenotypes. It has been proposed that apoptosis may play a lesser role in tumor response to radiation in comparison with the induction of cell death through mitotic catastrophe or a senescence-like irreversible growth arrest. However, in comparison with the induction of apoptosis, there is a lack of as much definitive information on other cell death processes that occur in cancer cells in response to chemotherapeutic agents, including antimetabolites. This article reviews what is known about these processes at the present time in response to experimental or clinically used agents that are analogs of 5 fluorouracil, cytidine or purines, hydroxyurea, or that belong to the family of folate antagonists. PMID- 23361268 TI - Autoimmunity in the elderly: Implications for cancer. AB - Immunosenescence is the aging process involving the immune system competencies. These changes imply a reduced level of immunosurveillance against cancer onset and the occurrence of autoimmune phenomena. The clinical presentation of autoimmune diseases in the elderly is characterized in most cases by atypical features, insidious presentation and poor specificity of laboratory parameters. The role of autoimmune reactivity in the elderly either as a consequence of or as a risk factor for cancer development has aroused great interest among clinicians and researchers, as well as the influence of a chronic inflammatory state as a predisposing factor for autoimmunity and cancer occurrence. Particularly, we have investigated the pathogenetic effect of two cell subsets, Treg cells and Th17 lymphocytes, involved in the control mechanisms both of autoimmune reactions and cancer onset, as the possible future approach to treat cancer in older adults. PMID- 23361269 TI - Dose verification to cochlea during gamma knife radiosurgery of acoustic schwannoma using MOSFET dosimeter. AB - AIM: Dose verification to cochlea using metal oxide semiconductor field effect transistor (MOSFET) dosimeter using a specially designed multi slice head and neck phantom during the treatment of acoustic schwannoma by Gamma Knife radiosurgery unit. MATERIALS AND METHODS: A multi slice polystyrene head phantom was designed and fabricated for measurement of dose to cochlea during the treatment of the acoustic schwannoma. The phantom has provision to position the MOSFET dosimeters at the desired location precisely. MOSFET dosimeters of 0.2 mm x 0.2 mm x 0.5 MUm were used to measure the dose to the cochlea. CT scans of the phantom with MOSFETs in situ were taken along with Leksell frame. The treatment plans of five patients treated earlier for acoustic schwannoma were transferred to the phantom. Dose and coordinates of maximum dose point inside the cochlea were derived. The phantom along with the MOSFET dosimeters was irradiated to deliver the planned treatment and dose received by cochlea were measured. RESULTS: The treatment planning system (TPS) estimated and measured dose to the cochlea were in the range of 7.4 - 8.4 Gy and 7.1 - 8 Gy, respectively. The maximum variation between TPS calculated and measured dose to cochlea was 5%. CONCLUSION: The measured dose values were found in good agreement with the dose values calculated using the TPS. The MOSFET dosimeter can be a suitable choice for routine dose verification in the Gamma Knife radiosurgery. PMID- 23361270 TI - The in vivo antitumor effects on human COLO 205 cancer cells of the 4,7-dimethoxy 5-(2-propen-1-yl)-1,3-benzodioxole (apiole) derivative of 5-substituted 4,7 dimethoxy-5-methyl-l,3-benzodioxole (SY-1) isolated from the fruiting body of Antrodia camphorate. AB - CONTEXT: The compound 4,7-dimethoxy-5-(2-propen-1-yl)-1,3-benzodioxole (apiole) has been isolated from several different plant species, including Petroselinum sativum. Our recent study found that apiole is a chemical derivative of 4,7 dimethoxy-5-methyl-l,3-benzodioxole (SY-1), which has been isolated from dried Antrodia camphorata (AC ) fruiting bodies, a traditional Chinese medicine with antitumor properties. AIMS: Our previous in vitro study demonstrated that apiole inhibits the growth of human colon (COLO 205) cancer cells through the arrest of the cell cycle in G0/G1 phase. The in vivo antitumor effects of apiole were evaluated in this study. SETTING AND DESIGN: Apiole was administered to mice at 1 30 mg/kg body weight through intraperitoneal (I.P.) injection three times per week (defined as a dosage of 1*-30*). MATERIALS AND METHODS: The in vivo antitumor effects of apiole were evaluated in mice with xenografts of COLO 205 cells. STATISTICAL ANALYSIS: All of the data are reported as the means +/- S.E. Comparisons were performed with a one-way analysis of variance (ANOVA) followed by a Fisher's least significant difference test. Significance was defined as P < 0.05. RESULTS: Apiole (> 1*) markedly decreased the growth of COLO 205 human colon cancer cell tumor xenografts in an athymic nude mouse model system through the up-regulation of cell cycle regulators, such as p53, p21/Cip1, and p27/Kip1. The apiole-induced increase in G0/G1 phase cell cycle regulators was also associated with a significant decrease in the expression of cyclins D1 and D3. Surprisingly, statistically significantly higher tumor volumes were observed in mice that received 5* apiole compared with 30* apiole-treated mice (P < 0.05). No gross signs of toxicity were observed (e.g., body weight changes, general appearance, or individual organ effects) in any group. CONCLUSIONS: Our results show, for the first time, the promising antitumor effects of apiole against colon tumors in an in vivo xenograft model. PMID- 23361271 TI - Angiogenesis and mast cell density in invasive pulmonary adenocarcinoma. AB - INTRODUCTION: Angiogenesis and mast cells affect the behavior of pulmonary adenocarcinoma. Measuring the angiogenesis and mast cell density (MCD) and their effect on survival of the patients may be helpful to guide the use of cancer chemotherapeutic agents which target tumor angiogenesis and mast cells. MATERIALS AND METHODS: It was a descriptive study, conducted at Gulab Devi Chest Hospital and University of Health Sciences Lahore. It included 23 newly diagnosed, adult patients of invasive pulmonary adenocarcinoma. Clinical history was obtained and biopsy specimen was processed. Angiogenesis was determined by immunohistochemical staining with CD34. Mast cells were counted in toluidine blue stained sections. Patients were followed-up till death. RESULTS: Mean age of the patients was 54.83 +/- 2.799 years. Majority (60.9%) were males. Only 39.1% patients were smokers. Morphologically, large proportions of tumors (73.9%) were nonmucinous and moderately or poorly differentiated. Majority (69.6%) of patients presented at advanced stage (Tumor-Node-Metastasis staging (TNM )III and IV). Mean microvascular density (MVD) was 13.04 +/- 1.12 and mean MCD was 3.26 +/- 0.36 per high power field (HPF). High MVD was associated with poor differentiation and advanced stage and correlated with poor survival (P = 0.0001). High MCD was associated with high grade but not with the advance stage of disease. However, high MCD correlated with poor survival (P = 0.047). Moreover, MCD was positively correlated with angiogenesis (r = 0.727, P = 0.0001). Treatment did not affect the survival significantly (P = 0.069). CONCLUSION: High angiogenesis and MCD predict poor survival and are positively correlated with each other and with the histological grades in pulmonary adenocarcinoma. High angiogenesis is also associated with advance TNM stage of disease. PMID- 23361272 TI - The factors that have an impact on the development of brain metastasis in the patients with breast cancer. AB - BACKGROUND: To evaluate the factors that have an impact on the development of brain metastasis in patients with breast cancer. MATERIALS AND METHODS: Among the patients who were followed-up and treated for breast cancer between January 2000 and January 2010, the ones with brain metastasis were included to the analysis. Metastatic breast cancer patients without brain metastasis, which had similar duration of follow-up and median age were included as the control group. Both group were compared for prognostic and predictive factors in terms of relationship between with or without brain metastasis and survival. RESULTS: There were a total of 63 female patients with metastatic breast cancer who had brain metastasis and the researchers enrolled the same number of female patients as the control group. In the univariate analysis, as a significant finding, it was found that, the patients with breast cancer who had brain metastasis had vascular invasion positivity, human epidermal growth factor receptor-2 (HER-2) positivity, a rare detection of invasive lobular carcinoma component in the tumor, estrogen receptor negativity, and no bone and liver metastasis and they did not receive chemotherapy due to several reasons after the detection of metastasis in any organ. In the multivariate analysis, HER-2 positivity, no bone and liver metastasis and not receiving chemotherapy due to several reasons after the detection of metastasis in any organ were detected as significant findings. CONCLUSIONS: As the prognostic and predictive factors showing the development of brain metastasis in breast cancer patients may be identified, follow-up also including the brain is important in order to take preventive measures. PMID- 23361273 TI - Cannabinoid receptor 2 is upregulated in melanoma. AB - AIMS: To investigate the expression of CB 2 in normal skin, pigmented nevus, and malignant melanoma; analyze its relation with genesis; and development of malignant melanoma. MATERIALS AND METHODS: In our study, we detected the expression of CB 2 in 20 cases of melanoma, nevus tissue, and normal skin tissues, respectively, by using immunohistochemistry, in situ hybridization, and RT-PCR. Moreover, we investigated the localization and expression of CB 2 in human melanoma cell line A375 and human immortalized keratinocyte cell line HaCaT by using immunofluorescence and western blotting. RESULTS: Our data revealed that CB 2 is unregulated in melanoma. CONCLUSIONS: CB 2 plays a role in the development of melanoma. PMID- 23361274 TI - Experimental and Monte Carlo study of the effect of the presence of dry air, cortical bone inhomogeneities and source position on dose distribution of the mHDR-v2 source. AB - BACKGROUND: Recently it was data wise established that there is a considerable dose difference due to source position from the surface of the patient, and due to the presence of inhomogeneities. AIM: It aims at to find out the dose difference due to source position, and inhomogenieties in water phantom of high dose rate (HDR)(192) Ir mHDR-v2 source by experiment and by Monte Carlo (MC) simulation GEANT4 code. MATERIALS AND METHODS: The measured study of the source was done using an in-air ionization chamber, water phantom while the calculated study was done by modeling the water phantom and its water, inhomogeneities, position of source, and points of calculation. RESULTS: The measured and calculated dose differences are 5.48 to 6.46% and 5.43 to 6.44% respectively higher in the presence of dry air and 4.40 to 4.90% and 4.38 to 4.88% respectively lower in the presence of cortical bone. However, for the study of the effect of source position on dose distribution, when the source was positioned at a 1 cm distance from the surface of water phantom, the near points between 1 cm and 2 cm are 2 to 3.5% and 2.1-3.7% underdose and for distant points from 3 cm to 8 cm from the source are 4 to 15% and 4.1 to 15.8% underdose for measured and calculated studies, respectively, to the dose when the source was positioned at midpoint of water phantom. CONCLUSION: These results can be used in the treatment planning system. PMID- 23361275 TI - Norathyriol suppresses transformation in JB6 P+ cells by the inhibition of Akt. AB - CONTEXT: Chemoprevention has been acknowledged as an important and practical strategy for the management of skin cancer. Norathyriol, a naturally occurring compound present in various plants, has a potent anticancer-promoting activity. AIMS: The aim was to investigate the chemopreventive activity of norathyriol on JB6 P+ cells. MATERIALS AND METHODS: A soft agar assay was used to detect the effect of norathyriol on cell transformation. The activator protein-1 (AP-1) transactivation activity was examined by the luciferase assay. RESULTS: Norathyriol inhibited epidermal growth factor (EGF)- and 12-O tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic cell transformation in a dose-dependent manner. The activation of activator protein-1 was dose dependently suppressed by norathyriol treatment. Western blot data revealed that norathyriol attenuated the phosphorylation of Akt. CONCLUSIONS: Norathyriol exerts a potent chemopreventive activity by inhibiting Akt activation in neoplastic cell transformation. PMID- 23361276 TI - Establishing a framework to implement 4D XCAT phantom for 4D radiotherapy research. AB - AIMS: To establish a framework to implement the 4D integrated extended cardiac torso (XCAT) digital phantom for 4D radiotherapy (RT) research. MATERIALS AND METHODS: A computer program was developed to facilitate the characterization and implementation of the 4D XCAT phantom. The program can (1) generate 4D XCAT images with customized parameter files; (2) review 4D XCAT images; (3) generate composite images from 4D XCAT images; (4) track motion of selected region-of interested (ROI); (5) convert XCAT raw binary images into DICOM format; (6) analyse clinically acquired 4DCT images and real-time position management (RPM) respiratory signal. Motion tracking algorithm was validated by comparing with manual method. Major characteristics of the 4D XCAT phantom were studied. RESULTS: The comparison between motion tracking and manual measurements of lesion motion trajectory showed a small difference between them (mean difference in motion amplitude: 1.2 mm). The maximum lesion motion decreased nearly linearly (R 2 = 0.97) as its distance to the diaphragm (DD) increased. At any given DD, lesion motion amplitude increased nearly linearly (R 2 range: 0.89 to 0.95) as the inputted diaphragm motion increased. For a given diaphragm motion, the lesion motion is independent of the lesion size at any given DD. The 4D XCAT phantom can closely reproduce irregular breathing profile. The end-to-end test showed that clinically comparable treatment plans can be generated successfully based on 4D XCAT images. CONCLUSIONS: An integrated computer program has been developed to generate, review, analyse, process, and export the 4D XCAT images. A framework has been established to implement the 4D XCAT phantom for 4D RT research. PMID- 23361277 TI - Correlation of expression pattern of aquaporin-1 in primary central nervous system tumors with tumor type, grade, proliferation, microvessel density, contrast-enhancement and perilesional edema. AB - OBJECTIVES: Brain edema, a hallmark of malignant brain tumors, continues to be a major cause of mortality. The underlying molecular mechanisms are poorly understood and thought to be mediated through membrane water-channels: aquaporins (AQP1,4,9). The abnormal upregulation of AQP1 in certain glial neoplasms has suggested a potential role in tumor pathogenesis, apart from being a novel target for newer therapeutic regimen. This study was undertaken to evaluate the expression of AQP1 in primary CNS tumors of various histologic types and grades, and its correlation with contrast-enhancement, perilesional edema, histomorphology, proliferation index and microvessel density. MATERIALS AND METHODS: Biopsy tissues from 30 patients (10 each from gliomas, meningiomas and other primary CNS tumors) were studied. Autopsy brain sections served as control. AQP1-immunoreactivity was correlated with histomorphology, radiology, proliferation index and microvessel density (MVD). RESULTS: AQP1 expression was increased in gliomas and ependymal tumors as compared to meningiomas. Intratumoral expression was homogenous in high-grade and membranous in low-grade neoplasms, while peritumoral areas showed expression around vessels and reactive astrocytes. High-grade tumors showed peritumoral upregulation, while low-grade had intense intratumoral expression. A trend of positive correlation was observed between AQP1-immunopositivity and increasing grade, higher MIB-1LI, increasing contrast-enhancement and more perilesional edema, and elevated MVD with raised AQP1:MVD ratio. CONCLUSIONS: AQP1-immunoexpression had a good correlation with high-grade tumors. AQP-upregulation in perilesional areas of high-grade tumors suggests its role in vasogenic edema. Further studies involving other AQP molecules, vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1 alpha (HIF-1alpha) should be undertaken to evaluate its possible role as a potential surrogate marker of high-grade tumors heralding poor outcome, inhibition of which may serve as the basis for future targeted therapy. PMID- 23361278 TI - Pre-cancerous (DNA and chromosomal) lesions in professional sports. AB - CONTEXT: Exhaustive exercises may become detrimental, causing disturbance of intracellular oxidant-antioxidant balance and damage to macromolecules, leading to genomic instability when DNA/chromosomes get damaged. As these are precancerous lesions, cancer occurrence is probable. Because professional sports requires high-intensity training and increasing physical demand, there may occur cellular genomic instability. AIM: To evaluate genetic damage at DNA and chromosomal levels in hockey and baseball-soft ball players and compare with levels in age- and sex-matched sedentary controls. SETTING AND DESIGN: Players professionally active in their sport from 3 to 11 years on a daily training session of 4h/day were contacted during their camps, and the study was approved by the Institutional Ethics Committee. All participants were healthy individuals, not on any medication and were not taking any supplements. MATERIALS AND METHODS: Genetic damage using the single cell gel electrophoresis assay and buccal micronucleus cytome assay of 56 individuals (36 players and 20 controls) was evaluated. STATISTICAL ANALYSIS USED: Student's t -test, ANOVA, Pearson correlation and linear regression and Chi-square analysis were performed. RESULTS: Players had significantly elevated levels of genetic damage. There were no gender differences and also no significant difference in the genetic damage incurred in both sports types. However, the extent of DNA migration in hockey players was higher. CONCLUSION: Significantly increased genomic instability in players of both sports was observed. Both repaired and repairable genetic damage cells were observed in different tissues of the same subject. The presence of such genetic damage implies that these players are at an individual risk from cancer- and age-related diseases. PMID- 23361279 TI - Immunohistochemical correlation of epidermal growth factor receptor and c-erbB-2 with histopathologic grading of mucoepidermoid carcinoma. AB - OBJECTIVE: Mucoepidermoid carcinoma is the most common salivary gland malignancy with highly variable biologic potential that correlates with the histopathologic grade of the tumor. Therefore, identification of the histopathologic grade of the mucoepidermoid carcinoma is very important in the treatment and determination of the final prognosis. The present study was performed to survey immunohistochemically Epidermal Growth Factor ReceptorEGFR and c-erbB-2 expression in different grades of mucoepidermoid carcinoma. MATERIALS AND METHODS: This retrospective study included 46 formalin-fixed, paraffin-embedded blocks of mucoepidermoid carcinoma. Based on histopathologic parameters, samples were classified into three grades. Then new sections were made and stained by immunohistochemistry (IHC) method for EGFR and c-erbB-2. Finally, EGFR and c-erbB 2 expression and their correlation with histopathologic grading were statistically analyzed by ANOVA. Nineteen samples of normal salivary gland tissue were also chosen as control group. RESULTS: The means of EGFR and c-erbB-2 were 71%, 71%, respectively. Statistically significant correlation was found between EGFR expression and histopathologic grading of mucoepidermoid carcinoma of salivary glands (P < 0.001). There was no statistically significant correlation between histopathologic grading of salivary gland mucoepidermoid carcinoma and c erbB-2 expression (P = 0.60). CONCLUSION: There is a parallelism between an increase in EGFR expression and increase in the histopathologic grading of salivary gland mucoepidermoid carcinoma. Therefore, the biologic behavior of salivary gland mucoepidermoid carcinoma can be determined by EGFR expression and it is a useful technique for determination of tumor grades and probably their prognosis. PMID- 23361280 TI - A comparative analysis of langerhans cell in oral epithelial dysplasia and oral squamous cell carcinoma using antibody CD-1a. AB - BACKGROUND: The integrity of the immune system is necessary to control tumor progression and a compromised state contributes to tumor escape. AIMS: The study intends to evaluate the presence and distribution pattern of Langerhans cells (LC) in Oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) oral epithelial dysplasia and oral squamous cell carcinoma and elucidate their role. The study analyses LC in histological zones of the epithelium and connective tissue, which has seldom been attempted previously. MATERIALS AND METHODS: Forty-five microscopic sections (i.e. 5 normal, 15 OED and 25 OSCC) were examined for expression of LC marker CD1a using immunohistochemistry. LCs were counted in zones of epithelium and connective tissue. STATISTICAL ANALYSIS USED: Results were analyzed using SPSS Version 16.0 and subjected to one-way ANOVA comparison and Student's t-test and Wilcoxon Z test. RESULTS: Significant decline in LC count was observed with progressing grade of OED and OSCC. The basal and suprabasal zones in OED and superficial zone in OSCC exhibited the highest density of LCs. The low LC count in severe dysplasia was attributed to paucity in the basal zone. There was a significant paucity of LCs in the sub-epithelial zone of all the grades of OSCC, with high influx of LCs within the tumor stroma. Also, poorly differentiated OSCC exhibited a significant decrease in the LC count within the overlying epithelium as well as the tumor stroma. CONCLUSION: The present study suggests that there is a recruitment of LCs in the neoplastic process. Changes observed in LC distribution within the zones of dysplastic epithelium and tumor stroma can be interpreted as their pathophysiologic function. PMID- 23361281 TI - Immunohistochemical expression of IDH1 in gliomas: a tissue microarray-based approach. AB - BACKGROUND: Mutations in the gene encoding isocitrate dehydrogenase (IDH1) have been reported in gliomas. This study analyses a series of 184 glioma cases in a tissue microarray (TMA)-based approach to assess the frequency of R132H point mutations in formalin-fixed, paraffin-embedded tissue samples. MATERIALS AND METHODS: A total of 195 gliomas (30 pilocytic astrocytoma (PA), 45 diffuse astrocytoma [DA], 75 glioblastoma multiforme [GBM], 25 oligodendroglioma [OLIG] and 20 ependymoma [EPEN]). A TMA of core size 1.0 mm was constructed using a semi automatic tissue arrayer. Immunohistochemical staining for IDH1, p53 and EGFR proteins was performed by the labeled sterptavidin avidin biotin LSAB method. RESULTS: The frequency of mutant IDH1 detection by immunohistochemistry on formalin-fixed, paraffin-embedded tissue was 15.8% in 29/184 tumors found suitable for evaluation. DA, OLIG and GBM showed IDH1 expression in 17/40 (42.5%), 5/22 (22.7%) and 7/72 (9.7%) cases, respectively. Of all the GBMs, prim GBM showed immunoexpression in 1/7 (1.5%) while sec-GBM showed IDH1 expression in 6/7 (85.7%). PA and EPEN did not react with anti-IDH1 antibody. DA and GBM showed positive correlation with p53, but IDH1 and EGFR coexpression was rare. CONCLUSION: Monoclonal antibody to IDH1 (R132) is a useful and less-labor intensive method to detect mutations in gliomas. IDH1 is a useful immunohistochemical marker to differentiate reactive gliosis from low-grade astrocytoma, has potential as an independent prognostic marker and also helps in distinguishing primary from secondary GBM. Its sensitivity and specificity need to be assessed by simultaneous sequencing and its validation on clinically annotated samples. PMID- 23361282 TI - Cytomorphological profile of neoplastic effusions: an audit of 10 years with emphasis on uncommonly encountered malignancies. AB - CONTEXT: The diagnosis of metastatic cancer in fluids is of capital importance as, in most such instances, a rapid fatal outcome of the disease is anticipated. AIM: To determine the spectrum and cytomorphological features of the common and unusual malignancies presenting with effusions. METHODS AND MATERIALS: A total of 11,562 effusion samples received for cytopathological examination over a 10-year period were analyzed retrospectively. Cytomorphological features of neoplastic effusions were studied. Special stains and immunocytochemistry (ICC) were performed to aid the diagnosis in difficult cases. OBSERVATIONS: The effusion samples comprised of pleural (5018), peritoneal (6340) and pericardial (204) fluids. A definitive diagnosis of classifiable malignancy could be given in 836 (7.3%) of these cases (5.7% adenocarcinomas and 1.6% uncommon malignancies). Adenocarcinoma was the most frequent cause of malignant pleural (70%) and peritoneal effusions (86.9%). The most common primary site for pleural metastasis was lung (35.7%), while for peritoneal metastasis, it was the ovary (54.3%). Among the uncommon neoplastic effusions, hematopoeitic malignancies were the most frequent, followed by squamous cell carcinomas. Primary malignant mesotheliomas were the most challenging to diagnose on effusion cytology. ICC was useful to arrive at a definitive diagnosis in difficult cases. CONCLUSIONS: Cytology is a useful tool to detect malignant effusions. However, in uncommon malignancies presenting as effusions, a detailed clinical history and ancillary investigations are often required to make a correct diagnosis. PMID- 23361283 TI - Dosimetry parameters calculation of two commercial iodine brachytherapy sources using SMARTEPANTS with EPDL97 library. AB - AIM: Simulating Many Accumulative Rutherford Trajectories Electron Photon and Neutral Transport Solver (SMARTEPANTS) is a discrete ordinates S N Boltzmann/Spencer-Lewis solver that was developed during 1988-1993 by William Filippone and his students. The code calculates particle fluxes, leakage currents as well as energy and charge deposition for coupled electron/photon in x-y-z geometries both in forward and in adjoin modes. Originally, SMARTEPANTS was designed to utilize CEPXS cross-section library for shielding calculation in satellite electronics. The aim of this study was to adapt SMARTEPANTS to use a new photon cross-section library from Evaluated Photon Data Library, 1997 version (EPDL97) for intravascular brachytherapy (125)Isimulations. MATERIALS AND METHODS: A MATLAB (MathworkNatick, Massachusetts) program was written to generate an updated multigroup-Legendre cross-section from EPDL97. The new library was confirmed by simulating intravascular brachytherapy Best(r) Model 2301 and Intersource (125)I dosimetry parameters using SMARTEPANTS with different energy groups (g), Legendre moments (L) and discrete ordinate orders (S). RESULTS: The dosimetry parameters for these sources were tabulated and compared with the data given by AAPM TG-43 and other reports. The computation time for producing TG-43 parameters was about 29.4 min in case of g = 20, L = 7 and S = 16. CONCLUSION: The good agreement between the results of this study and previous reports and high computational speed suggest that SMARTEPANTS could be extended to a real time treatment planning system for (125)I brachytherapy treatments. PMID- 23361285 TI - Fine needle aspiration cytology of oral and oropharyngeal lesions with an emphasis on the diagnostic utility and pitfalls. AB - AIM: This study was undertaken to evaluate the diagnostic utility and pitfalls of fine needle aspiration cytology (FNAC) in oral and oropharyngeal lesions. MATERIALS AND METHODS: This was a retrospective audit of oral and oropharyngeal lesions diagnosed with FNAC over a period of six years (2005-2010). RESULTS: Oral/oropharyngeal lesions [n=157] comprised 0.35% of the total FNAC load. The age ranged 1-80 years with the male: female ratio being 1.4:1. Aspirates were inadequate in 7% cases. Histopathology was available in 73/157 (46.5%) cases. Palate was the most common site of involvement [n=66] followed by tongue [n=35], buccal mucosa [n=18], floor of the mouth [n=17], tonsil [n=10], alveolus [n=5], retromolar trigone [n=3], and posterior pharyngeal wall [n=3]. Cytodiagnoses were categorized into infective/inflammatory lesions and benign cysts, and benign and malignant tumours. Uncommon lesions included ectopic lingual thyroid and adult rhabdomyoma of tongue, and solitary fibrous tumor (SFT), and leiomyosarcoma in buccal mucosa. A single false-positive case was dense inflammation with squamous cells misinterpreted as squamous cell carcinoma (SCC) on cytology. There were eight false-negative cases mainly due to sampling error. One false-negative case due to interpretation error was in a salivary gland tumor. The sensitivity of FNAC in diagnosing oral/oropharyngeal lesions was 71.4%; specificity was 97.8% with diagnostic accuracy of 87.7%. CONCLUSIONS: Salivary gland tumors and squamous cell carcinoma (SCC) are the most common lesions seen in the oral cavity. FNAC proves to be highly effective in diagnosing the spectrum of different lesions in this region. Sampling error is the main cause of false negative cases in this region. PMID- 23361284 TI - Positron emission tomography/computed tomography and esophageal cancer in the clinical practice: How does it affect the prognosis? AB - AIMS: The aim of this study was to assess the diagnostic value of positron emission tomography/computed tomography (PET/CT) in staging of esophageal cancer and to evaluate the prognostic role of metabolic parameters before and after neo adjuvant treatment. SETTINGS AND DESIGN: Mono-institutional retrospective study. MATERIALS AND METHODS: We retrospectively evaluated 29 patients who underwent PET/CT at initial staging and after neo-adjuvant therapy. Metabolic parameters were calculated: mean, average, maximum standardized uptake value (SUVmax), and total lesion glycolysis (TLG). Diagnostic advantages of PET/CT over conventional imaging (CI) were determined. The relationships between baseline and after therapy SUVmax and TLG, change in SUV and TLG (reported as ?) for the primary tumor and prognosis were assessed. STATISTICAL ANALYSIS USED: Non-parametric statistic (e.g. Wilcoxon test and chi-square test). RESULTS: Twenty-nine patients were eligible for the initial staging. Thirteen patients were incorrectly staged based on CI; PET/CT was able to identify distant lymph nodes in seven patients (59%) and distant metastases in four (31%). The median SUVmax before and after neoadjuvant therapy was 10.38 and 3.53 (P = 0.0005), respectively. Only few semi quantitative parameters obtained by PET/CT after neoadjuvant therapy seemed to have a prognostic value. TLG and ?TLG were significantly different between disease-free and died patients (0.49 versus 15.51 and 100% versus 94%, respectively; all P = <0.05). CONCLUSIONS: PET/CT is confirmed as being able to detect distant metastases and to avoid unnecessary surgery. Although not routinely reported, post-neoadjuvant TLG and ?TLG might be considered as useful prognostic parameters and should be further evaluated prospectively. PMID- 23361286 TI - Squamous cell carcinoma of lung metastasizinig in breast. AB - Metastasis in breast from extra-mammary malignancy is rare and lung is the third most common primary site when such a metastasis occurs. Small cell carcinoma and adenocarcinoma are two histological varieties of lung carcinoma that may metastasize to breast and squamous cell type is very rare. Here we report a case of squamous cell carcinoma of lung that metastasized in the breast and mimicked primary breast carcinoma. PMID- 23361287 TI - Primary cutaneous adenoid cystic carcinoma of the chest wall: a rare entity. AB - Primary Cutaneous Adenoid Cystic Carcinoma (PCACC) is a rare form of cutaneous carcinoma. It closely resembles adenoid cystic carcinoma of salivary glands. The lesion tends to infiltrate and recur locally but rarely metastasizes to distant organs and lymph nodes. We present here a case of a31-year-old male with complaints of swellings in the chest wall and scalp, progressively increasing in size over a period of 10 years. Clinical diagnosis of sebaceous cysts of scalp and chest wall was made. Histopathology revealed PCACC of the chest wall and dermoid cyst of the scalp. PMID- 23361288 TI - Skull-base Ewing sarcoma with multifocal extracranial metastases. AB - Intracranial occurrence of Ewing sarcoma (ES) is unusual, with a skull-base location being anecdotal. We report a 29-year-old man who presented with rapidly progressive ophthalmoplegia, and was found to be harboring an infiltrative lesion involving the sphenoid sinus, sella, and clivus. He underwent trans-sphenoidal decompression of the lesion which was histologically suggestive of ES. He developed paraparesis 2 weeks after commencing adjuvant therapy. Imaging revealed two thoracic extradural lesions and florid vertebral and pulmonary metastases. This is the first report in indexed literature of a primary intracranial ES on the skull-base with disseminated extracranial disease. PMID- 23361289 TI - Choroid as the first recurrence site: 13 years after breast carcinoma. AB - Breast carcinoma is one of the most common primary tumors of metastatic choroidal tumors. The average time from the breast cancer diagnosis to metastasis to the eye and orbit has been reported to be approximately 4 years. We report an unusual case of the choroid as the first recurrence site in a 48-year-old woman with a history of breast cancer. In our reported case, the patient had a 13-year interval between the breast cancer surgery and the identification of the first and sole metastasis to the choroid. We present this unusual case, and to analyze the clinical, histopathological and immunohistochemical findings, so as to differential diagnosis from other choroidal tumors. PMID- 23361290 TI - Primary malignant lymphoma of the parotid gland. AB - Lymphoma of the salivary gland accounts for 5% of cases of extranodal lymphoma and 10% of malignant salivary gland tumors. Most primary salivary gland lymphomas are B marginal zone lymphomas arising on a background of sialadenitis associated with an autoimmune disorder such as Sjorgen's syndrome. This report describes a case of primary B-cell lymphoma arising in the parotid gland in a middle-aged female, which was not associated with an autoimmune disorder. Immunohistochemistry studies confirmed the clonal B-cell nature of the tumor. This case highlights the fact that B-cell lymphoma in the salivary gland can go unrecognized due to its non-specific symptoms and requires immunohistochemistry studies for confirmation. We present this case for its rarity. PMID- 23361291 TI - A rare posterior cranial fossa tumor. AB - Among tumors of the central nervous system, tumors of the mixed glioneuronal type form an important recognized subset. Some of the examples for mixed glioneuronal tumors include gangliocytoma, dysembryoplastic neuroepithelial tumor (DNT), ganglioglioma, anaplastic ganglioglioma, and central neurocytoma. The rosette forming glioneuronal tumor (RGNT) of the fourth ventricle is a new entity that has only slowly emerged in the literature due to its prior classification with other low-grade mixed glial and neuronal tumors. These tumors are relatively infrequent lesions, and therefore, they can be challenging to diagnose for the practicing pathologist. This is a rare biphasic tumor with clearly defined neurocytic and glial components. The tumor is found exclusively in the posterior fossa, where it arises in the midline, usually occupying a substantial fraction of the fourth ventricle, and it is observed by magnetic resonance imaging (MRI) as a circumscribed, solid mass with heterogeneous contrast enhancement. We describe here a case of RGNT occurring in a 22-year-old male. PMID- 23361292 TI - Extranodal Rosai-Dorfman Disease presenting as spinal extradural lesion: a case report with a review of the literature. AB - Sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease (RDD) is a rare, but well-documented entity. We report a male patient who presented with progressive paraparesis, with thoracolumbar extradural lesion (from D11 to L2 level) on magnetic resonance imaging (MRI). He underwent D12-L2 laminectomy followed by total removal of extradural spinal space-occupying lesion (SOL). Histopathological diagnosis of the lesion was RDD. Four weeks after surgery, he was treated with external beam radiotherapy, total dose: 50.4GY in 28 fractions. On three-month follow-up, he did not have any neurological deficits. There was no evidence of other extranodal or lymph node involvement. This case has been reported on account of rare presentation of this disease as spinal extradural lesion. Pertinent literature has been reviewed. PMID- 23361293 TI - Oral tuberculosis following successful treatment of oral malignancy. AB - Coexistence of tuberculosis and neoplastic lesion in the oral cavity is a rare phenomenon. Till date, only three such cases have been reported in the English literature. A case of oral tuberculosis manifesting 3 months following the successful treatment of cancer of the oral tongue with chemoradiotherapy is presented. The diagnostic dilemma it posed, and its eventual successful control by anti-tubercular treatment, is discussed. PMID- 23361294 TI - Requesting clarifications concerning the case report on 'extraskeletal Ewing sarcoma of the sinonasal tract. PMID- 23361295 TI - Immunoglobulin a multiple myeloma associated with sweet syndrome. PMID- 23361296 TI - Gall bladder cancer in a child: a rare occurrence. PMID- 23361297 TI - Extensive 99mTc-MDP uptake in metastasis to contralateral pleura from osteosarcoma of femur: an indirect measure of extent of disease involvement at diagnosis. PMID- 23361298 TI - Advantages of surgical extirpation in addition to radioiodine therapy in differentiated thyroid carcinoma patients with a solitary large-volume skeletal metastasis with small-volume oligometastatic disease in the rest of the whole body. PMID- 23361299 TI - Inhibition of rapamycin-induced AKT activation elicits differential antitumor response in head and neck cancers. AB - The PI3K/AKT/mTOR pathway is an important signaling axis that is perturbed in majority of cancers. Biomarkers such as pS6RP, GLUT1, and tumor FDG uptake are being evaluated in patient stratification for mTOR pathway inhibitors. In the absence of a clear understanding of the underlying mechanisms in tumor signaling, the biomarker strategy for patient stratification is of limited use. Here, we show that no discernible correlation exists between FDG uptake and the corresponding Ki67, GLUT1, pS6RP expression in tumor biopsies from patients with head and neck cancer. Correlation between GLUT1 and pS6RP levels in tumors was observed but elevated pS6RP was noticed even in the absence of concomitant AKT activation, suggesting that other downstream molecules of PI3K/AKT and/or other pathways upstream of mTOR are active in these tumors. Using an ex vivo platform, we identified putative responders to rapamycin, an mTOR inhibitor in these tumors. However, rapamycin did not induce antitumor effect in the majority of tumors with activated mTOR, potentially attributable to the observation that rapamycin induces feedback activation of AKT. Accordingly, treatment of these tumors with an AKT inhibitor and rapamycin uniformly resulted in abrogation of mTOR inhibition-induced AKT activation in all tumors but failed to induce antitumor response in a subset. Phosphoproteomic profiling of tumors resistant to dual AKT/mTOR inhibitors revealed differential activation of multiple pathways involved in proliferation and survival. Collectively, our results suggest that, in addition to biomarker-based segregation, functional assessment of a patient's tumor before treatment with mTOR/AKT inhibitors may be useful for patient stratification. PMID- 23361300 TI - Phosphorylation of ribosomal protein S6 attenuates DNA damage and tumor suppression during development of pancreatic cancer. AB - The signaling pathways that mediate the development of pancreatic ductal adenocarcinoma (PDAC) downstream of mutant Kras remain incompletely understood. Here, we focus on ribosomal protein S6 (rpS6), an mTOR effector not implicated previously in cancer. Phosphorylation of rpS6 was increased in pancreatic acinar cells upon implantation of the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) or transgenic expression of mutant Kras. To examine the functional significance of rpS6 phosphorylation, we used knockin mice lacking all five phosphorylatable sites in rpS6 (termed rpS6(P-/-) mice). Strikingly, the development of pancreatic cancer precursor lesions induced by either DMBA or mutant Kras was greatly reduced in rpS6(P-/-) mice. The rpS6 mutants expressing oncogenic Kras showed increased p53 along with increased staining of gamma-H2AX and 53bp1 (Trp53bp1) in areas of acinar ductal metaplasia, suggesting that rpS6 phosphorylation attenuates Kras-induced DNA damage and p53-mediated tumor suppression. These results reveal that rpS6 phosphorylation is important for the initiation of pancreatic cancer. PMID- 23361303 TI - [Prophylactic central lymph node dissection improves prognosis for papillary thyroid cancer]. PMID- 23361301 TI - Deficiency of phospholipase A2 group 7 decreases intestinal polyposis and colon tumorigenesis in Apc(Min/+) mice. AB - Platelet-activating factor (PAF) is a naturally occurring phospholipid that mediates diverse effects such as physiological and pathological inflammation, immunosuppression, and cancer. Several lines of evidence support both positive and negative roles for PAF in carcinogenesis. PAF stimulates cell growth, oncogenic transformation, and metastasis, but can also limit proliferation and induce apoptosis. The biological context and microenvironment seem to define whether PAF has pro- or anticarcinogenic effects. To investigate the role of exacerbated PAF signaling in colon cancer, we conducted cell-based and in vivo studies using genetically engineered mice lacking expression of phospholipase A2 group 7 (PLA2G7), an enzyme that specifically metabolizes PAF and structurally related glycerophospholipids. Absence of Pla2g7 robustly decreased intestinal polyposis and colon tumor formation in Apc(Min)(/+) mice, suggesting an antitumorigenic role for PAF in settings characterized by aberrant function of the tumor suppressor Adenomatous polyposis coli (Apc). In colonic epithelial cells, exposure to a PAF analog led to dephosphorylation of Akt at serine-473 and induction of apoptosis. The mechanism of this response involved formation of a complex between beta-arrestin 1 and the Akt phosphatase PHLPP2, and activation of the intrinsic pathway of apoptosis. Our results suggest that strategies based on inhibiting PLA2G7 activity or increasing PAF-mediated signaling hold promise for the treatment of intestinal malignancies that harbor mutations in APC. PMID- 23361302 TI - Higher-order action planning for individual and joint object manipulations. AB - Many actions involve multiple action steps, which raises the question how far ahead people plan when they perform such actions. Here, we examined higher-order planning for action sequences and whether people planned similarly or differently when acting individually or together with an action partner. For individual performances, participants picked up an object with one hand and passed it to their other hand before placing it onto a target location. For joint performances, they picked up the object and handed it to their action partner, who placed it onto the target location. Each object could be grasped at only two possible grasping positions, implying that the first selected grasp on the object determined the postures for the rest of the action sequence. By varying the height of the target shelf, we tested whether people planned ahead and modulated their grasp choices to avoid uncomfortable end postures. Our results indicated that participants engaged in higher-order planning, but needed task experience before demonstrating such planning during both individual and joint performances. The rate of learning was similar in the two conditions, and participants transferred experience from individual to joint performance. Our results indicate similarity in mechanisms underlying individual and joint action sequence planning. PMID- 23361304 TI - Antenatal manifestations of mitochondrial disorders. AB - Mitochondrial respiratory chain diseases are a heterogeneous group of pathologies caused by genetic alterations affecting mitochondrial energy production. Theoretically, this deficiency may lead to any symptoms, in any organ or tissue, at any age even before birth. The aim of our study was to identify the frequency and characterize antenatal manifestations identifying possible associations between mitochondrial disease and more specific and earlier manifestation. We retrospectively review the files of 44 paediatric subjects with genetic and biochemical alterations of respiratory chain identified in the first decade of life and compare data with a control group (n = 88). Our results show that maternal age was similar in both groups. The female gender was predominant in patients group. Gestational age at delivery was similar in both groups. Concerning birth weight, it was significantly lower (p = 0.001) in patients (2899.9 +/- 538.3 vs. 3246.6 +/- 460.2 g). Fifteen pregnancies of the patients group were considered abnormal. Our findings show that intrauterine growth restriction was the most frequent antenatal feature observed. Neonatal morbidity was significantly higher (fivefold) in patients (p < 0.001). The clinical findings are independent of the molecular defect type. Our results are preliminary and more studies are needed, in order to learn more about mitochondrial physiology and activity in embryological development for the assessment of mitochondrial disease progress in fetal life. However, the present work is a significant contribution, given the scarcity of information in this field. PMID- 23361306 TI - New inhibitors of alpha-glucosidase in Salacia hainanensis Chun et How. AB - The methanol extract from roots of Salacia hainanensis Chun et How afforded three new compounds, 24,26-dihydroxy-25-methoxy-tirucall-9-en-3-one (1), 2beta,3beta,22alpha-trihydroxy-lup-20(29)-ene (2) and 3beta-hydroxy-2-carbonyl lupan-29-oic acid (3), along with six known triterpenoids (4-9). Their structures were established on the basis of spectral analysis, in particular according to the data obtained by two-dimensional-NMR and high-resolution mass spectra experiments. Some of them showed much stronger inhibitory activity towards alpha glucosidase than the positive control (acarbose, IC50 10.2 MUM). PMID- 23361305 TI - Left ventricular noncompaction (LVNC) and low mitochondrial membrane potential are specific for Barth syndrome. AB - Barth syndrome (BTHS) is an X-linked mitochondrial defect characterised by dilated cardiomyopathy, neutropaenia and 3-methylglutaconic aciduria (3-MGCA). We report on two affected brothers with c.646G > A (p.G216R) TAZ gene mutations. The pathogenicity of the mutation, as indicated by the structure-based functional analyses, was further confirmed by abnormal monolysocardiolipin/cardiolipin ratio in dry blood spots of the patients as well as the occurrence of this mutation in another reported BTHS proband. In both brothers, 2D-echocardiography revealed some features of left ventricular noncompaction (LVNC) despite marked differences in the course of the disease; the eldest child presented with isolated cardiomyopathy from late infancy, whereas the youngest showed severe lactic acidosis without 3-MGCA during the neonatal period. An examination of the patients' fibroblast cultures revealed that extremely low mitochondrial membrane potentials (mtDeltaPsi about 50 % of the control value) dominated other unspecific mitochondrial changes detected (respiratory chain dysfunction, abnormal ROS production and depressed antioxidant defense). 1) Our studies confirm generalised mitochondrial dysfunction in the skeletal muscle and the fibroblasts of BTHS patients, especially a severe impairment in the mtDeltaPsi and the inhibition of complex V activity. It can be hypothesised that impaired mtDeltaPsi and mitochondrial ATP synthase activity may contribute to episodes of cardiac arrhythmia that occurred unexpectedly in BTHS patients. 2) Severe lactic acidosis without 3-methylglutaconic aciduria in male neonates as well as an asymptomatic mild left ventricular noncompaction may characterise the ranges of natural history of Barth syndrome. PMID- 23361307 TI - Clinical and prognostic usefulness of serum proteomic profile in hepatic colorectal metastases: a pilot prospective study. AB - PURPOSE: To analyze the use of proteomic profiles to discriminate healthy from patients with colorectal liver metastases (CLM) and to predict neoplastic recurrence after CLM resection. METHODS: From April 2005 to October 2008, 70 patients operated for first curative resection of CLM and 60 healthy controls underwent determination of preoperative serum proteomic profile. We performed a preliminary training with patients and controls and obtained a classification system based on these patients' proteomic profiles training. The system was then tested about the ability to predict the colon versus rectum origin, metachronous or synchronous appearance, risk of recurrence after CLM resection and whether a sample was from a control or a CLM patient. RESULTS: Sensitivity, specificity, positive and negative predictive values for detecting CLM patients were 75, 100, 100 and 54.6 %, respectively. Best CLM appearance time identification was 50 % and primary tumor origin identification was 62.5 %. Best classifications of neoplastic recurrence within the first year after CLM resection and during the follow-up period were 47.5 and 45 %, respectively. Larger training sets and prevalence-based training sets led to better classification of patients and characteristics. CONCLUSION: Proteomic profiles are a promising tool for discriminating CLM patients from healthy patients and for predicting neoplastic recurrence. PMID- 23361308 TI - The case for intrinsically disordered proteins playing contributory roles in molecular recognition without a stable 3D structure. AB - The classical 'lock-and-key' and 'induced-fit' mechanisms for binding both originated in attempts to explain features of enzyme catalysis. For both of these mechanisms and for their recent refinements, enzyme catalysis requires exquisite spatial and electronic complementarity between the substrate and the catalyst. Thus, binding models derived from models originally based on catalysis will be highly biased towards mechanisms that utilize structural complementarity. If mere binding without catalysis is the endpoint, then the structural requirements for the interaction become much more relaxed. Recent observations on specific examples suggest that this relaxation can reach an extreme lack of specific 3D structure, leading to molecular recognition with biological consequences that depend not only upon structural and electrostatic complementarity between the binding partners but also upon kinetic, entropic, and generalized electrostatic effects. In addition to this discussion of binding without fixed structure, examples in which unstructured regions carry out important biological functions not involving molecular recognition will also be discussed. Finally, we discuss whether 'intrinsically disordered protein' (IDP) represents a useful new concept. PMID- 23361309 TI - Protein flexibility, not disorder, is intrinsic to molecular recognition. AB - An 'intrinsically disordered protein' (IDP) is assumed to be unfolded in the cell and perform its biological function in that state. We contend that most intrinsically disordered proteins are in fact proteins waiting for a partner (PWPs), parts of a multi-component complex that do not fold correctly in the absence of other components. Flexibility, not disorder, is an intrinsic property of proteins, exemplified by X-ray structures of many enzymes and protein-protein complexes. Disorder is often observed with purified proteins in vitro and sometimes also in crystals, where it is difficult to distinguish from flexibility. In the crowded environment of the cell, disorder is not compatible with the known mechanisms of protein-protein recognition, and, foremost, with its specificity. The self-assembly of multi-component complexes may, nevertheless, involve the specific recognition of nascent polypeptide chains that are incompletely folded, but then disorder is transient, and it must remain under the control of molecular chaperones and of the quality control apparatus that obviates the toxic effects it can have on the cell. PMID- 23361310 TI - Acute kidney injury: an intensivist's perspective. AB - The changing epidemiology of acute kidney injury (AKI) in adults and children has resulted in more patients being treated for kidney injury occurring in the context of multi-organ failure requiring treatment in the intensive care unit (ICU). AKI complicating critical illness has complex, multi-factorial etiology, and supportive care, including organ support, remains the mainstay of therapy. In the day-to-day management of AKI in the ICU two of the major challenges are the inadequacy of current diagnostics for the early identification of AKI and the relationship between hemodynamic resuscitation strategies and the development of AKI. This review focuses on these areas from the intensivist's perspective. Given that the diagnosis of AKI is often delayed, the prevention of complications and limitation of secondary renal injury are of particular importance. Fluid overload is increasingly being associated with adverse patient outcomes in critical illness and may contribute to persistent renal dysfunction. Thus, hemodynamic management strategies in AKI should be tailored to limit fluid overload as much as possible. PMID- 23361313 TI - Facile solution synthesis of Ag@Pt core-shell nanoparticles with dendritic Pt shells. AB - Ag@Pt nanoparticles with various dendritic Pt shells were successfully synthesized by using nonionic surfactants at room temperature. Our recent study demonstrated that the addition of nonionic surfactant plays an important key role in the synthesis of dendritic Pt nanostructures (J. Am. Chem. Soc., 2010, 132, 13636). Here we extend this synthetic concept to prepare various Ag@Pt nanoarchitectures. The different nanostructured Pt shells on the Ag core were confirmed by ultraviolet-visible absorption spectroscopy and transmission electron microscopy. As a preliminary electrochemical application, the obtained Ag@Pt nanostructures were applied in the methanol oxidation reaction (MOR) in 0.5 M H(2)SO(4) solution containing 0.5 M methanol. The Ag@Pt nanoparticles with thin dendritic Pt shells show superior CO-tolerance performance with a I(f)/I(b) value reaching 3.71. Our Ag@Pt nanostructures with good CO tolerant activity will be prominent catalysts for MOR. PMID- 23361312 TI - Perioperative management of a patient with failed fontan physiology. PMID- 23361311 TI - Fluid management in the critically ill child. AB - Fluid management has a major impact on the duration, severity and outcome of critical illness. The overall strategy for the acutely ill child should be biphasic. Aggressive volume expansion to support tissue oxygen delivery as part of early goal-directed resuscitation algorithms for shock--especially septic shock--has been associated with dramatic improvements in outcome. Recent data suggest that the cost-benefit of aggressive fluid resuscitation may be more complex than previously thought, and may depend on case-mix and the availability of intensive care. After the resuscitation phase, critically ill children tend to retain free water while having reduced insensible losses. Fluid regimens that limit or avoid positive fluid balance are associated with a reduced length of hospital stay and fewer complications. Identifying the point at which patients change from the 'early shock' pattern to the later 'chronic critical illness' pattern remains a major challenge. Very little data are available on the choice of fluids, and most of the information that is available arises from studies of critically ill adults. There is therefore an urgent need for high-quality trials of both resuscitation and maintenance fluid regimens in critically ill children. PMID- 23361314 TI - From kinetic-structure analysis to engineering crystalline fiber networks in soft materials. AB - Understanding the role of kinetics in fiber network microstructure formation is of considerable importance in engineering gel materials to achieve their optimized performances/functionalities. In this work, we present a new approach for kinetic-structure analysis for fibrous gel materials. In this method, kinetic data is acquired using a rheology technique and is analyzed in terms of an extended Dickinson model in which the scaling behaviors of dynamic rheological properties in the gelation process are taken into account. It enables us to extract the structural parameter, i.e. the fractal dimension, of a fibrous gel from the dynamic rheological measurement of the gelation process, and to establish the kinetic-structure relationship suitable for both dilute and concentrated gelling systems. In comparison to the fractal analysis method reported in a previous study, our method is advantageous due to its general validity for a wide range of fractal structures of fibrous gels, from a highly compact network of the spherulitic domains to an open fibrous network structure. With such a kinetic-structure analysis, we can gain a quantitative understanding of the role of kinetic control in engineering the microstructure of the fiber network in gel materials. PMID- 23361315 TI - Structure-based in silico identification of ubiquitin-binding domains provides insights into the ALIX-V:ubiquitin complex and retrovirus budding. AB - The ubiquitylation signal promotes trafficking of endogenous and retroviral transmembrane proteins. The signal is decoded by a large set of ubiquitin (Ub) receptors that tether Ub-binding domains (UBDs) to the trafficking machinery. We developed a structure-based procedure to scan the protein data bank for hidden UBDs. The screen retrieved many of the known UBDs. Intriguingly, new potential UBDs were identified, including the ALIX-V domain. Pull-down, cross-linking and E3-independent ubiquitylation assays biochemically corroborated the in silico findings. Guided by the output model, we designed mutations at the postulated ALIX-V:Ub interface. Biophysical affinity measurements using microscale thermophoresis of wild-type and mutant proteins revealed some of the interacting residues of the complex. ALIX-V binds mono-Ub with a K(d) of 119 MUM. We show that ALIX-V oligomerizes with a Hill coefficient of 5.4 and IC(50) of 27.6 MUM and that mono-Ub induces ALIX-V oligomerization. Moreover, we show that ALIX-V preferentially binds K63 di-Ub compared with mono-Ub and K48 di-Ub. Finally, an in vivo functionality assay demonstrates the significance of ALIX-V:Ub interaction in equine infectious anaemia virus budding. These results not only validate the new procedure, but also demonstrate that ALIX-V directly interacts with Ub in vivo and that this interaction can influence retroviral budding. PMID- 23361316 TI - Emerging lymphae for the fountain of life. AB - The lymphatic system is indispensable for the collection and cycling of tissue extravasated fluids, macromolecules and immune cells into the bloodstream. Different mechanisms, including sprouting, ballooning and budding of lymphatic endothelial cells from the cardinal vein, have been proposed for lymphatic vessel formation during mammalial embryogenesis. Hagerling et al (2013) now provide a cell-scale model of lymphoangiogenesis by applying selective plane illumination based ultramicroscopy (Becker et al, 2008) to wholemount-immunostained mouse embryos. They describe VEGFR-3, VEGF-C and CCBE1 as key regulators of lymphatic endothelial cell budding and migration at the early emergence of lymphatics from venous endothelium. PMID- 23361317 TI - Lateral thinking: CaMKII uncouples kainate receptors from mossy fibre synapses. PMID- 23361318 TI - Prophase pathway-dependent removal of cohesin from human chromosomes requires opening of the Smc3-Scc1 gate. AB - Faithful transmission of chromosomes during eukaryotic cell division requires sister chromatids to be paired from their generation in S phase until their separation in M phase. Cohesion is mediated by the cohesin complex, whose Smc1, Smc3 and Scc1 subunits form a tripartite ring that entraps both DNA double strands. Whereas centromeric cohesin is removed in late metaphase by Scc1 cleavage, metazoan cohesin at chromosome arms is displaced already in prophase by proteolysis-independent signalling. Which of the three gates is triggered by the prophase pathway to open has remained enigmatic. Here, we show that displacement of human cohesin from early mitotic chromosomes requires dissociation of Smc3 from Scc1 but no opening of the other two gates. In contrast, loading of human cohesin onto chromatin in telophase occurs through the Smc1-Smc3 hinge. We propose that the use of differently regulated gates for loading and release facilitates unidirectionality of DNA's entry into and exit from the cohesin ring. PMID- 23361319 TI - The impact of collective efficacy on risks for adolescents' perpetration of dating violence. AB - Given prevalence rates and negative consequences that adolescents' perpetration of dating violence may have on an individual's well-being and future relationships, it is imperative to explore factors that may increase or reduce its occurrence. Thus, we aimed to identify how multiple contextual risk factors (individual, family, schools, and neighborhoods) were related to adolescents' perpetration of dating violence over a 6 year period. Then, we assessed how neighborhood collective efficacy, an important predictor of urban youths' well being, buffered the relationship between each of the risk factors and adolescents' perpetration of dating violence. Three waves of data from the Welfare, Children, and Families: A Three-City Study were used (N = 765; Ages 16 20 at Wave 3). The sample is 53 % female, 42 % African-American, and 53 % Hispanic. For the total sample, drug and alcohol use, low parental monitoring, academic difficulties, and involvement with antisocial peers were significant early risk factors for perpetration of dating violence in late adolescence. Risk factors also varied by adolescents' race and sex. Finally, perceived neighborhood collective efficacy buffered the relationship between early academic difficulties and later perpetration of dating violence for Hispanic males. These results imply that multiple systems should be addressed in dating violence prevention programs. PMID- 23361320 TI - Mouse models of atherosclerosis: explaining critical roles of lipid metabolism and inflammation. AB - Atherosclerosis is the most common cause of death globally. It is a complex disease involving morphological and cellular changes in vascular walls. Studying molecular mechanism of the disease is hindered by disease complexity and lack of robust noninvasive diagnostics in human. Mouse models are the most popular animal models that allow researchers to study the mechanism of disease progression. In this review we discuss the advantage and development of mouse as a model for atherosclerotic research. Along with commonly used models, this review discusses strains that are used to study the role of two critical processes associated with the disease-lipid metabolism and inflammation. PMID- 23361321 TI - Retrosigmoid intradural inframeatal approach: indications and technique. AB - BACKGROUND: Surgery of lesions of the petrous apex involving the inframeatal/infralabyrinthine area is challenging and related to a high risk of complications. Various extensive skull-base approaches have been used. OBJECTIVE: To present and evaluate our experience with a new hearing-preserving extension of the retrosigmoid approach to the inframeatal/infralabyrinthine area. METHODS: The approach was used in 3 patients harboring lesions in the petrous apex with variable extension in the inframeatal/infralabyrinthine region. The surgical accessibility of the lesions offered by the approach, the completeness of tumor removal, and the outcome, in particular, the functional outcome and complication rate, were assessed. RESULTS: The tumor could be resected from the target area in all cases. No approach-related complications occurred. Serviceable hearing and normal facial nerve functions were preserved in all cases. CONCLUSION: Our initial experience with the retrosigmoid inframeatal approach showed that it provides sufficient access to the area and offers the possibility of complete tumor removal. It allows for hearing and facial nerve functional preservation. The approach is safe and related to a very low complication rate. PMID- 23361322 TI - Is there an identifiable intact medial wall of the cavernous sinus? Macro- and microscopic anatomical study using sheet plastination. AB - BACKGROUND: The medial wall of the cavernous sinus is believed to play a significant role in determining the direction of growth of pituitary adenomas and in planning pituitary surgery. However, it remains unclear whether there is a dural wall between the pituitary gland and the cavernous sinus. OBJECTIVE: To identify and trace the membranelike structures medial to the cavernous sinus and around the pituitary gland and their relationships with surrounding structures. METHODS: Sixteen cadavers (7 females and 9 males; age range, 54-89 years; mean age, 77 years) were used in this study and prepared as 16 sets of transverse (5 sets), coronal (2 sets), and sagittal (9 sets) plastinated sections that were examined at both macro- and microscopic levels. RESULTS: The pituitary gland was fully enclosed in a fibrous capsule, but the components and thickness of the capsule varied on different aspects of the gland. The meningeal dural layer was sandwiched between the anterosuperior aspect of the gland capsule and the cavernous sinus. Posteroinferiorly, however, this dural layer disappeared as it fused with the capsule. A weblike loose fibrous network connected the capsule, carotid artery, venous plexus, and the dura of the middle cranial fossa. CONCLUSION: The medial wall of the cavernous sinus consists of both the meningeal dura and weblike loose fibrous network, which are located at the anterosuperior and posteroinferior aspects, respectively. PMID- 23361323 TI - Mobilization of the sphenoparietal sinus: a simple technique to preserve prominent frontobasal bridging veins during surgical clipping of anterior communicating artery aneurysms: technical case report. AB - BACKGROUND AND IMPORTANCE: Bridging veins arising from the frontal base (frontobasal bridging veins, FBBVs) can pose obstacles when performing clipping of anterior communicating artery (ACoA) aneurysms via the pterional approach. Although FBBVs can in general be sacrificed without critical complications to achieve an adequate retraction of the frontal lobe, neurosurgeons sometimes encounter postoperative venous infarction or contusion of the retracted frontal lobe, which may be accounted for by the damage to the venous drainage system. Thus, preservation of intracranial veins is desirable to prevent postoperative venous complications, especially when they are prominent. CLINICAL PRESENTATION: A 66-year-old female patient was revealed to have multiple unruptured aneurysms at the ACoA, bilateral middle cerebral arteries, and the left internal carotid artery. In the first stage of the operation, clipping of the right middle cerebral artery and ACoA aneurysms was performed via a right pterional approach. Because the ACoA aneurysm was located at a high position and projecting posteriorly, a transsylvian "lateral" trajectory was preferred to a subfrontal "anterior" trajectory. Intraoperatively, her FBBV was revealed to be so prominent that the sacrifice would be harmful. Thus, we performed posteriorward displacement of the sphenoparietal sinus extradurally, thereby achieving adequate retraction of the frontal lobe intradurally without sacrificing the FBBV. With this simple technique, the ACoA aneurysm was successfully treated. CONCLUSION: This technique is useful for retracting the frontal lobe sufficiently to enable establishment of an appropriate surgical field for a pterional approach to ACoA aneurysms with prominent FBBVs. PMID- 23361324 TI - Supra-psoas shallow docking in lateral interbody fusion. AB - BACKGROUND: Lateral interbody fusion techniques have been linked with considerable postoperative morbidity, often the outcome of direct psoas trauma. The most common neurological postoperative complications are transient motor weakness/palsy and sensory dysesthesia, which can be permanent. It appears that these neural complications are a result of passing through the psoas muscle where the potential for nerve injury is significant. The supra-psoas shallow docking method may be a safer alternative and may help minimize morbidities by eliminating or reducing direct psoas injury. OBJECTIVE: To describe the operative technique of performing lateral interbody fusion using supra-psoas retractor docking. METHODS: The authors describe the surgical technique including side selection, positioning, and patient outcomes. RESULTS: Fifteen patients were treated with the supra-psoas shallow docking method. Specifically, no patient reported weakness, numbness, and/or pain on the side that underwent the surgery. In these cases, performing lateral transpsoas interbody fusion using supra-psoas shallow docking appeared to minimize the most common neurological postoperative complications of the surgery, motor weakness/palsy and sensory dysesthesia, which may be a result of dilation of the psoas muscle. CONCLUSION: The shallow docking technique may decrease postoperative morbidities by docking on top of psoas muscle instead of passing through it. An important potential benefit of this approach is direct visualization of the lumbosacral plexus, which may potentially minimize the postoperative neurological morbidity often encountered in patients after this surgery. PMID- 23361325 TI - Microsurgical resection of large medial sphenoid wing meningiomas: technique. PMID- 23361326 TI - ScalaBLAST 2.0: rapid and robust BLAST calculations on multiprocessor systems. AB - MOTIVATION: BLAST remains one of the most widely used tools in computational biology. The rate at which new sequence data is available continues to grow exponentially, driving the emergence of new fields of biological research. At the same time, multicore systems and conventional clusters are more accessible. ScalaBLAST has been designed to run on conventional multiprocessor systems with an eye to extreme parallelism, enabling parallel BLAST calculations using >16 000 processing cores with a portable, robust, fault-resilient design that introduces little to no overhead with respect to serial BLAST. PMID- 23361327 TI - The majority of endogenous microRNA targets within Alu elements avoid the microRNA machinery. AB - MOTIVATION: The massive spread of repetitive elements in the human genome presents a substantial challenge to the organism, as such elements may accidentally contain seemingly functional motifs. A striking example is offered by the roughly one million copies of Alu repeats in the genome, of which ~0.5% reside within genes' untranslated regions (UTRs), presenting ~30 000 novel potential targets for highly conserved microRNAs (miRNAs). Here, we examine the functionality of miRNA targets within Alu elements in 3'UTRs in the human genome. RESULTS: Using a comprehensive dataset of miRNA overexpression assays, we show that mRNAs with miRNA targets within Alus are significantly less responsive to the miRNA effects compared with mRNAs that have the same targets outside Alus. Using Ago2-binding mRNA profiling, we confirm that the miRNA machinery avoids miRNA targets within Alus, as opposed to the highly efficient binding of targets outside Alus. We propose three features that prevent potential miRNA sites within Alus from being recognized by the miRNA machinery: (i) Alu repeats that contain miRNA targets and genuine functional miRNA targets appear to reside in distinct mutually exclusive territories within 3'UTRs; (ii) Alus have tight secondary structure that may limit access to the miRNA machinery; and (iii) A-to-I editing of Alu-derived mRNA sequences may divert miRNA targets. The combination of these features is proposed to allow toleration of Alu insertions into mRNAs. Nonetheless, a subset of miRNA targets within Alus appears not to possess any of the aforementioned features, and thus may represent cases where Alu insertion in the genome has introduced novel functional miRNA targets. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23361328 TI - Bayesian analysis of gene essentiality based on sequencing of transposon insertion libraries. AB - MOTIVATION: Next-generation sequencing affords an efficient analysis of transposon insertion libraries, which can be used to identify essential genes in bacteria. To analyse this high-resolution data, we present a formal Bayesian framework for estimating the posterior probability of essentiality for each gene, using the extreme-value distribution to characterize the statistical significance of the longest region lacking insertions within a gene. We describe a sampling procedure based on the Metropolis-Hastings algorithm to calculate posterior probabilities of essentiality while simultaneously integrating over unknown internal parameters. RESULTS: Using a sequence dataset from a transposon library for Mycobacterium tuberculosis, we show that this Bayesian approach predicts essential genes that correspond well with genes shown to be essential in previous studies. Furthermore, we show that by using the extreme-value distribution to characterize genomic regions lacking transposon insertions, this method is capable of identifying essential domains within genes. This approach can be used for analysing transposon libraries in other organisms and augmenting essentiality predictions with statistical confidence scores. PMID- 23361329 TI - BioGranat-IG: a network analysis tool to suggest mechanisms of genetic heterogeneity from exome-sequencing data. AB - MOTIVATION: Recent exome-sequencing studies have successfully identified disease causing sequence variants for several rare monogenic diseases by examining variants common to a group of patients. However, the current data analysis strategies are only insufficiently able to deal with confounding factors such as genetic heterogeneity, incomplete penetrance, individuals lacking data and involvement of several genes. RESULTS: We introduce BioGranat-IG, an analysis strategy that incorporates the information contained in biological networks to the analysis of exome-sequencing data. To identify genes that may have a disease causing role, we label all nodes of the network according to the individuals that are carrying a sequence variant and subsequently identify small subnetworks linked to all or most individuals. Using simulated exome-sequencing data, we demonstrate that BioGranat-IG is able to recover the genes responsible for two diseases known to be caused by variants in an underlying complex. We also examine the performance of BioGranat-IG under various conditions likely to be faced by the user, and show that its network-based approach is more powerful than a set cover-based approach. PMID- 23361330 TI - Transfer of a protein pattern from self-assembled DNA origami to a functionalized substrate. AB - Patterns of the protein streptavidin on DNA origami are printed onto a functionalized surface. The streptavidins are linked to DNA via a disulfide spacer and these conjugates self-organise into a predetermined pattern on DNA origami. The structure immobilises on a biotin-SAM-functionalized Au surface. By disulfide cleavage the origami is separated from the streptavidins, leaving the protein pattern at the surface. PMID- 23361331 TI - Barton esters for initiator-free radical cyclisation with heteroaromatic substitution. AB - S-(1-Oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium hexafluorophosphate (HOTT) facilitates the first examples of efficient radical cyclisation with (hetero)aromatic substitution via Barton ester intermediates. Cyclopropyl and alkyl radicals allow access to five, six and seven-membered alicyclic-ring fused heterocycles with and without an additional fused cyclopropane, including the skeleton of the anti-cancer agent, cyclopropamitosene, expanded, and diazole analogues. Radical initiators are not required for cyclisation from carboxylic acid precursors. PMID- 23361332 TI - Anionic and zwitterionic copper(I) complexes incorporating an anionic N heterocyclic carbene decorated with a malonate backbone: synthesis, structure and catalytic applications. AB - The anionic malonate-derived N-heterocyclic carbenes (maloNHCs) react cleanly and rapidly with copper chloride to generate the anionic complexes of type [(maloNHC)CuCl].Li, which crystallize in the solid state either in an oligomeric trimer arrangement or in polymeric helixes depending on the substitution pattern and the solvent. Ten zwitterionic heteroleptic Cu(I) complexes combining the anionic maloNHC and a neutral imidazol-2-ylidene are also obtained in a very selective manner and fully characterized. Whereas the anionic complexes are relatively active catalysts for the hydrosilylation of carbonyl compounds, the zwitterionic complexes reveal to be efficient and extremely robust pre-catalysts for the intramolecular cyclopropanation reaction of a diazo ester and outperform the corresponding cationic Cu(i) complexes with classical imidazol-2-ylidenes. PMID- 23361333 TI - Bone geometry according to menstrual function in female endurance athletes. AB - Athletes have higher bone mineral density (BMD) relative to nonathletes. In amenorrheic athletes BMD may be compromised by estrogen deficiency, but it is unknown whether this is accompanied by structural differences. We compared femoral neck bone geometry and density of a-/oligomenorrheic athletes (AAs), eumenorrheic athletes (EAs), and eumenorrheic controls (ECs). We recruited 156 women: (68 endurance athletes and 88 controls). Femoral neck BMD, section modulus (Z), and width were measured using dual-energy X-ray absorptiometry. Menstrual function was assessed by questionnaire and classified as EA (>=10 periods/year) or AA (<=9 periods/year): 24 athletes were AA and 44 EA. Femoral neck BMD was significantly higher in EA than AA (8 %, difference) and EC (11 % difference): mean [SE] 1.118 [0.015], 1.023 [0.020] and 0.999 [0.014] g cm(-2), respectively; p < 0.001. Z was significantly higher in EA than EC (11 % difference): EA 667 [19], AA 625 [21], and EC 592 [10] cm(3); p < 0.001. Femoral neck width did not differ between groups. All differences persisted after adjustment for height, age, and body mass. The higher femoral neck Z and BMD in athletes, despite similar width, may indicate that exercise-related bone gains are endosteal rather than periosteal. Athletes with amenorrhea had smaller increments in bone mass rather than structural adaptation. The maintained femoral neck width in controls may be an adaptive mechanism to conserve bone strength in bending despite inactivity-related bone decrement. PMID- 23361335 TI - Organelle dynamics: deubiquitylating mitofusin. PMID- 23361334 TI - Amino acid signalling upstream of mTOR. AB - Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that is part of mTOR complex 1 (mTORC1), a master regulator that couples amino acid availability to cell growth and autophagy. Multiple cues modulate mTORC1 activity, such as growth factors, stress, energy status and amino acids. Although amino acids are key environmental stimuli, exactly how they are sensed and how they activate mTORC1 is not fully understood. Recently, a model has emerged whereby mTORC1 activation occurs at the lysosome and is mediated through an amino acid sensing cascade involving RAG GTPases, Ragulator and vacuolar H(+)-ATPase (v ATPase). PMID- 23361336 TI - How to educate prescribers in antimicrobial stewardship practices. AB - Widespread antimicrobial use has compromised its value, leading to a crisis of antimicrobial resistance. A major cause of misuse is insufficient knowledge of prescribing of antimicrobials in many categories of professionals. An important principle of antimicrobial stewardship is avoiding selection pressure in the patient, both on pathogen and commensal by avoiding unnecessary use, choosing the least broad-spectrum antibiotic, adequate doses, a good timing and the shortest possible duration. Up to now, most educational efforts have been targeted at professionals (mostly medical doctors) after their training and at the adult public. In the past few years, progress has been made in educating children. It is now crucial that academia and ministries of Health and Education jointly focus on an adapted undergraduate medical/professional curriculum that teaches all necessary principles of microbiology, infectious diseases and clinical pharmacology, with emphasis on the principles of prudent prescribing. PMID- 23361337 TI - The tympanic membrane displacement analyser for monitoring intracranial pressure in children. AB - PURPOSE: Raised intracranial pressure (ICP) is a potentially treatable cause of morbidity and mortality but tools for monitoring are invasive. We sought to investigate the utility of the tympanic membrane displacement (TMD) analyser for non-invasive measurement of ICP in children. METHODS: We made TMD observations on normal and acutely comatose children presenting to Kilifi District Hospital (KDH) at the rural coast of Kenya and on children on follow-up for idiopathic intracranial hypertension at Evelina Children's Hospital (ECH), in London, UK. RESULTS: We recruited 63 patients (median age 3.3 (inter-quartile range (IQR) 2.0 4.3) years) at KDH and 14 children (median age 10 (IQR 5-11) years) at ECH. We observed significantly higher (more negative) TMD measurements in KDH children presenting with coma compared to normal children seen at the hospital's outpatient department, in both semi-recumbent [mean -61.3 (95 % confidence interval (95 % CI) -93.5 to 29.1) nl versus mean -7.1 (95 % CI -54.0 to 68.3) nl, respectively; P = 0.03] and recumbent postures [mean -61.4 (95 % CI -93.4 to 29.3) nl, n = 59) versus mean -25.9 (95 % CI -71.4 to 123.2) nl, respectively; P = 0.03]. We also observed higher TMD measurements in ECH children with raised ICP measurements, as indicated by lumbar puncture manometry, compared to those with normal ICP, in both semi-recumbent [mean -259.3 (95 % CI -363.8 to -154.8) nl versus mean 26.7 (95 % CI -52.3 to 105.7) nl, respectively; P < 0.01] and recumbent postures [mean -137.5 (95 % CI -260.6 to -14.4) nl versus mean 96.6 (95 % CI 6.5 to 186.6) nl, respectively; P < 0.01]. CONCLUSION: The TMD analyser has a potential utility in monitoring ICP in a variety of clinical circumstances. PMID- 23361339 TI - Statin use and risk of bladder cancer: a meta-analysis. AB - PURPOSE: Emerging evidence suggests that statins may decrease the risk of cancers. However, available evidence on bladder cancer is conflicting. To quantify the association between statin use and risk of bladder cancer, we performed a detailed meta-analysis of published studies regarding this subject. METHODS: A literature search was carried out using MEDLINE, EMBASE, and OVID databases between January 1966 and October 2012. Before meta-analysis, between study heterogeneity and publication bias were assessed using adequate statistical tests. Fixed- and random-effect models were used to estimate summary relative risks (RR) and the corresponding 95 % confidence intervals (CIs). Potential sources of heterogeneity were detected by meta-regression. Subgroup analyses, sensitivity analysis, and cumulative meta-analysis were also performed. RESULTS: A total of 13 (three RCTs, five cohort, and five case-control) studies contributed to the analysis. There was heterogeneity among the studies, but no publication bias. Pooled results indicated a nonsignificant increase in total bladder cancer risk among all statin users [RR = 1.07, 95 % CI (0.95, 1.21)]. Long-term statin use did not significantly affect the risk of total bladder cancer [RR = 1.21, 95 % CI (0.92, 1.59)]. In our subgroup analyses, the results were not substantially affected by study design, region, and confounder adjustment. Furthermore, sensitivity analysis confirmed the stability of the results. CONCLUSIONS: The findings of this meta-analysis suggested that there was no association between statin use and risk of bladder cancer. More studies, especially RCTs, are needed to confirm this association. PMID- 23361340 TI - Statins and colorectal cancer risk: a longitudinal study. AB - PURPOSE: Studies evaluating the association between statins and colorectal cancer (CRC) have used various methods to address bias and have reported mixed findings. We sought to assess the association in a large cohort of residents in Emilia Romagna, Italy, using multiple methods to address different sources of confounding. We also sought to explore potential effect measure modification by sex. METHODS: We conducted a retrospective cohort study using the 2003-2010 healthcare database of Emilia-Romagna, Italy. We identified all initiators of statins; initiators of glaucoma medications served as the comparison group to account for confounding by healthy user bias. We followed patients longitudinally to identify CRC cases in hospital discharge data. We used multivariable Cox regression analyses to adjust for confounding by CRC risk factors and we conducted a sensitivity analysis using propensity score matching. RESULTS: After multivariable adjustment, initiators of statins had a lower incidence rate of CRC as compared to initiators of glaucoma drugs [hazard ratio (HR) 0.79; 95 % CI 0.69 0.90]. In sex-stratified analyses we observed a protective effect in men (HR 0.77; 95 % CI 0.67-0.88) but not in women (HR 0.96; 95 % CI 0.82-1.1). Results were similar in propensity score analyses. CONCLUSIONS: After adjusting for observed risk factors, statin initiation versus glaucoma drug initiation was associated with a reduced risk of CRC in men but not in women. While this study is subject to many limitations, it corroborates a previous study that found sex differences in the association between statins and CRC. PMID- 23361338 TI - Associations of serum 25-hydroxyvitamin D with overall and breast cancer-specific mortality in a multiethnic cohort of breast cancer survivors. AB - PURPOSE: Despite limited evidence on the association of vitamin D with outcomes in breast cancer survivors, some clinicians advise breast cancer patients to use vitamin D supplements. More evidence is needed to inform these recommendations. METHODS: In the Health, Eating, Activity, and Lifestyle study, we examined associations of post-treatment serum concentrations of 25-hydroxyvitamin D (25(OH)D) on overall and breast cancer-specific mortality in 585 breast cancer survivors from western Washington State, New Mexico, and Los Angeles County. 25(OH)D was measured in stored blood collected 2 years post-enrollment. Outcomes were ascertained from the Surveillance, Epidemiology, and End Results registries and medical records. Cox proportional hazards models were fit to assess associations of serum 25(OH)D with overall and breast cancer-specific mortality. RESULTS: After a median follow-up of 9.2 years; 110 women died, including 48 from breast cancer. Standard cut points classified 211 (31.6 %) women as serum 25(OH)D deficient (<20 ng/mL), 189 (32.2 %) as insufficient (20-30 ng/mL), and 185 (36.2 %) as sufficient (>30 ng/mL). Compared to women with deficient 25(OH)D, those in the sufficient ranges had a decreased risk of overall mortality (age-adjusted HR = 0.58; 95 % CI 0.36-0.96); however, multivariate adjustments attenuated the association (HR = 0.90; 95 % CI 0.50-1.61). No association was found between serum 25(OH)D and breast cancer-specific mortality (sufficient: HR = 1.21; 95 % CI 0.52-2.80) in multivariate models. CONCLUSION: In this breast cancer cohort, higher serum 25(OH)D may be associated with improved survival, but results were not statistically significant and must be interpreted with caution. The potential prognostic effect of vitamin D from diet, supplements, or both should be evaluated in future larger studies with additional endpoints from breast cancer patients. PMID- 23361341 TI - Peculiarities of extracellular potentials produced by deep muscles. Part 1: single fibre potential fields. AB - The similarity among surface electromyography (EMG) signals recorded by the poles of electrode arrays above deep muscles like erector spinae is a substantial obstacle in determining major muscle characteristics. What makes EMG signals so different when detected at various distances from the fibres? To answer this question, we simulated and analyzed extracellular potential fields produced by a single muscle fibre. We considered the fields at a few specific time instants. They corresponded to the origination of two depolarized zones at the end-plate, their propagation along both semi-fibres, and extinction at the fibre-ends. We used intracellular action potentials and muscle fibre propagation velocities typical for non-fatigued or fatigued muscle fibres. We have shown that at relatively small distances from the fibre, the strong potential fields are concentrated mainly near the sources. The interaction between potential fields is weak and the propagation of the fields and EMG signals in relatively long fibres is clearly apparent. At large distances, the potential fields are wide and the interaction between the fields produced by the two depolarized zones is strong. The total potential field could remain non-propagating during the entire main phase. As a result, the propagation will be obscured also in EMG signals. PMID- 23361342 TI - Modeling and analysis of coagulated liver tissue and its interaction with a scalpel blade. AB - Radiofrequency-assisted methods have been used in hepatectomy--the resection process of removing liver tissue which encapsulates the tumor from the liver organ. A prototype was built to enable smooth surgical transition between radiofrequency ablation and liver resection. There is a lack of literature on mechanical properties of radiofrequency-ablated liver tissue and the tool-tissue interaction during cutting. This led to our study on coagulated tissue mechanical properties and modeling of its dynamic interaction with a scalpel blade. A novel mechanical model was proposed to mimic the mechanical behavior of radiofrequency ablated liver tissue. The model is able to account for the viscoelastic behavior of the ablated tissue in both compression and relaxation tests. Experiments were performed to validate the proposed model. In addition, a knife blade-tissue interaction model is proposed to demonstrate the potential of integrating the proposed model for application in device design. PMID- 23361343 TI - Retraction note to: Low dose lidocaine for refractory seizures in preterm neonates. Indian J Pediatr (May 2011) 78(5):625-6. PMID- 23361344 TI - [Chronic kidney diseases: positive effect of exercise training]. PMID- 23361345 TI - [Are antiplatelet agents effective in intermittent claudication?]. PMID- 23361346 TI - [Do fish and long chain omega 3 fatty acids prevent stroke? - Fish prevents stroke - the reason remains unexplained]. PMID- 23361347 TI - [Obesity in the population of North Rhine-Westphalia and its communities in the 2009 German Microcensus: prevalence, illness and prevention potential]. AB - BACKGROUND AND OBJECTIVE: There are only few data about regional and social disparities in obesity, the related diseases, and related morbidity in Germany. METHODS: The 2009 Microcensus regional file North Rhine-Westphalia was used for this analysis. The Microcensus represents a decentralised household survey. The selection rate of the random sample survey was 1 % of the population. RESULTS can be extrapolated at state and community levels in North Rhine-Westphalia. The body weight and the height were reported by 72 % of the interviewees above 18 years in the voluntary health supplementary programme (N = 10 705 000). RESULTS: About 11 % of the adults above 18 years in North Rhine-Westphalia are obese class I, further 3 % of the adults are obese class II and 1 % are obese class III according to Body-Mass-Index classification. After adjustment for age, male and female adults with obesity have a highly significantly elevated odds ratio of 1.4 and 1.7 for illness or accident injury at the survey date. Obesity prevalence is associated with officially confirmed disability.There is a social gradient in the prevalence of obesity in the population of employable age (18-64 years). The probability of obesity decreases with the rise of the level of education. Male and female blue-collar workers and female jobseekers were more often obese. The Microcensus shows distinct disparities in obesity prevalence between the communities in the population of employable age. CONCLUSION: The Microcensus may have potential for a harmonized monitoring concerning obesity. But there is a need for further research in regard to the methods. The regional and social disparities in obesity prevalence reveal needs for interventions to combat obesity. PMID- 23361348 TI - [Organ-invasive carcinoma of the pararenal gland involving the inferior vena cava: successful curative and interdisciplinary surgical management]. AB - HISTORY AND ADMISSION FINDINGS: A 61-year-old woman presented with a 2-month history of progressive deterioration, increasing exertional dyspnoea and pain in the right upper abdomen (past medical history: bronchial asthma and hypertension). The physical examination showed mild generalized weakness, tenderness in the right upper abdomen, and ascites. INVESTIGATIONS: Laboratory studies did not reveal any hormonal abnormalities. A CT angiogram revealed a mass of the right adrenal gland with distinct invasion into the inferior vena cava, and tumour thrombosis that extended proximally into the right atrium. Distally, the tumour ended at the caudate lobe of the liver with an extensive peripherally engulfed thrombus from the inferior vena cava down to the common iliac veins. TREATMENT AND COURSE: An open right adrenalectomy with resection of the periadrenal tissue and extirpation of the intracaval tumour thrombus (by cavotomy under digital occlusion of the blood flow from the vena cava into the right atrium) was carried out with no significant postoperative complications. Subsequently, the patient underwent adjuvant mitotane therapy for three years. So far, no recurrence has occurred during a course of 7 years. CONCLUSION: Tumour induced thrombotic occlusion of the inferior vena cava and other veins is rare, especially with right atrium involvement. In the absence of other effective treatment options, the combination of radical resection and adjuvant mitotane therapy remains the only successful curative treatment for primary invasive adrenal gland carcinoma. PMID- 23361349 TI - [Painful swollen joints with weakness: what's behind all this? Case 1/2013]. AB - HISTORY AND ADMISSION FINDINGS: We report on a 58-year-old patient with weight loss, weakness and polyarthralgia. She reported of recurrent drops, painful joints and muscle weakness. INVESTIGATIONS: The patient had swollen joints, clubbing and cachexia. The radiogram of the hands and feet showed a hypertrophic oseoarthropathy. In further investigations we found a tumor in the upper left lung. The histology findings showed a adenocarcinoma of the lung. DIAGNOSIS, TREATMENT AND COURSE: The diagnosis of a secondary hypertrophic osteoarthropathy (Pierre Marie-Bamberger syndrome) due to a adenocarcinoma of the lung was made. The patient refused a radiochemotherapy and decided to go on vacation. Further course is unknown. CONCLUSIONS: Arthralgia is a common symptom for medical consultation. Pierre Marie-Bamberger syndrome is a rare cause of paraneoplastic arthritis. Notice that unspecific symptoms like weakness, weight loss and arthritis may result from paraneoplastic tumor disease. PMID- 23361350 TI - [45-year-old patient with facial swelling]. PMID- 23361351 TI - [Chronic dizziness and vertigo from a neurologists' perspective]. AB - Dizziness and vertigo are among the most common symptoms in neurology and medicine in general. The differential diagnosis may be simplified by systematic and careful assessment of presenting symptoms. The most common conditions associated with vertigo and dizziness can be diagnosed by patient history and physical examination alone. Extensive apparative diagnostic work-up is seldomly required and often not helpful. The majority of these disorders can be well treated and have an excellent prognosis, when diagnosed adequately and within a reasonable time frame to prevent the development of chronic disease. PMID- 23361352 TI - [Positional paper of the German working group "cardiopulmonary exercise testing" to ventilatory and metabolic (lactate) thresholds]. AB - Thresholds in cardiopulmonary exercise testing are necessary for the evaluation of motivation and cooperation in exercise, for training programs, in transplant medicine, preoperative evaluation and medical assessments. There is a hardly comprehensible number of terminologies concerning these thresholds and their definitions. This hampers the comparison of protocols and studies and leads to incertainties in terminologies and interpretations of cardiopulmonary exercise tests. Based on literature a definition of thresholds was undertaken. Thresholds should be regarded from a conceptional and an operational (methodological) point of view. The conceptional model means, that there are two ventilatory thresholds (VT1 and VT2) and two metabolic thresholds (lactate threshold [LT] 1 and 2 ). These thresholds are pathophysiologically based. Both threshold concepts determinate the beginning and the end of the aerobic-anaerobic transition. The lactate thresholds determine the metabolic changes, whereas the ventilator thresholds 1 and 2 represent the ventilatory response to the metabolic changes. VT1 represents the subsequent increase of ventilation and CO2-output relative to oxygen uptake as a consequence of an increase of lactate and a necessary lactate buffering. VT2 is characterized by an exceeding of lactate-steady-state, resulting in excess lactate, metabolic acidosis and overproportional rise of ventilation. The operational concept describes the method, which is used for determination of the different lactate and ventilatory thresholds. In a further step this can be completed by indicating the exercise protocol which was applied. PMID- 23361353 TI - [Pharmacovigilance and herbal hepatotoxicity: critical aspects and solutions]. AB - Under clinical aspects and in private practice liver diseases are rarely considered in causal connection with the use of herbal drugs and herbal dietary supplements, but in suspected cases a thorough clinical and regulatory causality assessment is mandatory. In initially assumed herbal hepatotoxicity and associated regulatory evaluations by the German regulatory agency, definitions for hepatotoxicity were consistently lacking, upon which causality assssment may have been based. For the description of a risk, even patients were included with lack of established temporal association between herbal use and the appearance the adverse drug reaction (ADR) or with unknown actual liver values, only slightly increased liver values, isolated increased gamma-glutamyltransferase, or overt alternative causes including comedication. This continuously led to regulatory high initial case numbers, which were not fundamentally based on clinical and scientific criteria. Heavily debated is also the regulatory use of the WHO method for causality assessment purposes, because this liver unspecific algorithm is neither validated for liver injury nor for any common ADR; this approach therefore is obsolete for a reproducible causality evaluation. Instead, we urgently recommend to use the scale of CIOMS (Council for International Organizations of Medical Sciences), which is liver specific and validated for hepatotoxicity. This is the only way to circumvent future absolute unnecessary and redundant scientific discussions in the regulatory field. PMID- 23361354 TI - Quantification of photocatalytic hydrogen evolution. AB - A new photoreactor with defined irradiation geometry was developed and tested for the water reduction reaction using carbon nitride ("C(3)N(4)") as a photocatalyst. The hydrogen evolution rate was investigated with a sun simulator (I = 1000 W m(-2)) in two different operation modes: circulation and stirring of the catalyst dispersion. Only in the stirred mode, where shear stress is lower, a stable hydrogen evolution rate of about 0.41 L m(-2) h(-1) is obtained. It is confirmed by experiments with D(2)O that hydrogen is obtained from the water splitting process and not by dehydrogenation of the sacrificial agent. The obtained rate results in an efficiency of <0.1% based on a reference experiment with a photovoltaic-powered electrolysis setup. The change from distilled water to tap or simulated sea water results in a lower hydrogen evolution rate of about 50%. PMID- 23361355 TI - Microfluidic fabrication of photo-responsive hydrogel capsules. AB - We report thermo- and photo-responsive hydrogel capsules, providing controlled encapsulation and triggered release of water-soluble encapsulants. Monodisperse O/W/O (oil-in-water-in-oil) double-emulsion drops are produced in a capillary microfluidic device as templates, which transform into hydrogel capsules upon polymerization of thermo-sensitive monomers in the water phase containing gold nanorods. PMID- 23361356 TI - Identification of pyrroloindoline-containing cyclic hexapeptides in the metabolites of Streptomyces alboflavus 313 by HPLC-DAD-ESI-MS/MS. AB - To investigate the chemical biodiversity of biologically active cyclic hexapeptides in the metabolites from microorganisms, the fermentation broth of Streptomyces alboflavus 313 was analyzed using HPLC, equipped with a diode array detector (DAD), coupled with ESI tandem MS (HPLC-DAD-ESI-MS/MS). In the mass spectra of cyclic hexapeptides, predominant ions [M+H](+), as well as [M 18+H](+), [M-28+H](+) and [M+Na](+), were observed and used to determine the molecular masses, while fragmentation reactions of [M+H](+) were recorded to provide information on the contents of amino acids and their linkage sequence. Based on the fragmentation patterns and comparison with standards, 15 pyrroloindoline-containing natural cyclic hexapeptides, cp01-15, were identified from the microorganism and six of these are reported for the first time. PMID- 23361357 TI - Isolation and structural elucidation of glucoside congeners of platencin from Streptomyces platensis SB12600. PMID- 23361358 TI - Novel derivatives of aclacinomycin A block cancer cell migration through inhibition of farnesyl transferase. AB - In the course of screening for an inhibitor of farnesyl transferase (FTase), we identified two compounds, N-benzyl-aclacinomycin A (ACM) and N-allyl-ACM, which are new derivatives of ACM. N-benzyl-ACM and N-allyl-ACM inhibited FTase activity with IC50 values of 0.86 and 2.93 MUM, respectively. Not only ACM but also C-10 epimers of each ACM derivative failed to inhibit FTase. The inhibition of FTase by N-benzyl-ACM and N-allyl-ACM seems to be specific, because these two compounds did not inhibit geranylgeranyltransferase or geranylgeranyl pyrophosphate (GGPP) synthase up to 100 MUM. In cultured A431 cells, N-benzyl-ACM and N-allyl-ACM also blocked both the membrane localization of H-Ras and activation of the H-Ras dependent PI3K/Akt pathway. In addition, they inhibited epidermal growth factor (EGF)-induced migration of A431 cells. Thus, N-benzyl-ACM and N-allyl-ACM inhibited EGF-induced migration of A431 cells by inhibiting the farnesylation of H-Ras and subsequent H-Ras-dependent activation of the PI3K/Akt pathway. PMID- 23361359 TI - Synthetic studies of the spirocyclic cyclohexene part of versipelostatin, a novel GRP78/Bip molecular chaperone downregulator. AB - The spirocyclic part consisting of an alpha-acylated tetronic acid and a multisubstituted cyclohexene embedded in versipelostatin, a novel GRP78/Bip molecular chaperone downregulator, has been synthesized in enantiomerically pure form. The asymmetric synthesis of the targeted spiro[4.5]-1-oxa-7-decen-2,4-dione derivative was characterized by (1) stereoselective allylation at the alpha carbon of methylmalonate diester, in which one carboxylic acid was esterified with a D-glucose-derived chiral template, (2) construction of the tetrasubstituted cyclohexenone substructure by high-yielding ring-closing metathesis and (3) stereoselective construction of the spirocyclic tetronic acid part starting from the cyclohexenone obtained as the ring-closing metathesis product. PMID- 23361360 TI - The effects of amplitude normalization and EMG targets on cVEMP interaural amplitude asymmetry. AB - OBJECTIVES: The purpose of this investigation was to determine whether the use of visual feedback of tonic electromyographic (EMG) activity, or the use of amplitude normalization techniques would reduce significantly the variability in cervical vestibular evoked myogenic potential (cVEMP) P13-N23 interaural amplitude asymmetry data in otologically and neurologically intact children and adults. DESIGN: There were 97 subjects, both pediatric and adult, from whom the authors recorded cVEMPs with and without the use of an EMG target and amplitude normalization techniques. The four conditions were: (1) conventional recording (condition 1), (2) conventional recording with an EMG target (condition 2), (3) same as condition 1, with the addition of postacquisition amplitude normalization techniques, and (4) same as condition 2, with the addition of postacquisition amplitude normalization techniques. The absolute peak to peak amplitude of positive-negative response (P13-N23), absolute latency of P13, and the left or right amplitude asymmetry of P13-N23 were measured. RESULTS: Neither P13-N23 amplitudes nor latencies, neither mean root mean square (RMS) of the full wave rectified EMG activity, nor the standard deviation of the RMS EMG activity differed significantly when subjects were, and were not, asked to ensure their tonic EMG activity exceeded a visual target (i.e., representing >50 uV RMS EMG). Amplitude normalization of the cVEMP waveforms failed to reduce significantly the variability in the amplitude asymmetry data. CONCLUSIONS: Activating the sternocleidomastoid muscle with the patient in a semirecumbent position, with head turned away from the stimulated ear and head elevated (i.e., an optimal activation technique) was sufficient to produce the highest amplitude cVEMPs with an acceptable amount of variability in subjects of all ages. Group data suggested that the use of visual targets and amplitude normalization routines did not reduce significantly the variability in cVEMP interaural amplitude asymmetry measures. However, in isolated cases amplitude normalization converted an "abnormal" cVEMP into a "normal" cVEMP although the reverse occurred as well, suggesting that these techniques may be beneficial for a subset of patients receiving a less than perfectly administered test procedure. PMID- 23361361 TI - Comparative SRY incorporation on the regulatory regions of pluripotency/differentiation genes in human embryonic carcinoma cells after retinoic acid induction. AB - Members of the SOX (SRY box) family proteins play critical roles in multiple aspects of development. SRY, as a founder member of SOX family, has been long believed to be involved in the development of sexual gonads by triggering signaling cascades which lead to the formation of testis or ovary from bipotential gonads. However, less is known about other potential regulatory roles of SRY in the development and differentiation. In order to gain further insight into the possible roles of SRY during development, we looked into possible SRY regulated genes and their levels of expression in a human embryonic carcinoma cell line, named NTera2, before and after induction of differentiation. For this respect, SRY incorporation on the regulatory regions of two groups of genes including OCT4, NANOG, and SOX2 as pluripotency marker genes, and NESTIN and PAX6 as differentiation marker genes were evaluated quantitatively. Chromatin immunoprecipitation using SRY antibody was performed on chromatin extract of a human embryonic carcinoma cell line, NT2/NTERA-2, before and after onset of differentiation. The results showed that incorporation of SRY in both groups of genes was increased after induction of differentiation. Besides, lower expression of OCT4, SOX2, and NANOG and higher expression of PAX6 and NESTIN genes in differentiated cells suggest that SRY may act as a transcription repressor for pluripotency-associated genes and as a transcription activator for differentiation-related genes. PMID- 23361362 TI - The apical sorting signal for human GLUT9b resides in the N-terminus. AB - The two splice variants of human glucose transporter 9 (hGLUT9) are targeted to different polarized membranes. hGLUT9a traffics to the basolateral membrane, whereas hGLUT9b traffics to the apical region. This study examines the sorting mechanism of these variants, which differ only in their N-terminal domain. Mutating a di-leucine motif unique to GLUT9a did not affect targeting. Chimeric proteins were made using GLUT1, a basolaterally targeted transporter, and GLUT3, an apically targeted protein whose signal lies in the C-terminus. Overexpression of the chimeric proteins in polarized cells demonstrates that the N-terminus of hGLUT9b contains a signal capable of redirecting GLUT1 to the apical membrane. The N-terminus of hGLUT9a, however, does not contain a basolateral signal sufficient enough to redirect GLUT3. Portions of the GLUT9a N-terminus were substituted with corresponding portions of the GLUT9b N-terminus to determine the motif responsible for apical targeting. The first 16 amino acids were not found to be a sufficient apical signal. The last ten amino acids of the N-termini differ only in amino-acid class at one location. In the B-form, leucine, a hydrophobic residue, is substituted for lysine, a basic residue, found in the A form. However, mutation of the leucine in hGLUT9b to a lysine resulted in retention of the apical signal. We therefore believe the apical signal exists as an interplay between the final ten amino acids of the N-terminus and another motif within the protein such as the intracellular loop or other motifs within the N-terminus. PMID- 23361363 TI - Attenuation of increased secretory leukocyte protease inhibitor, matricellular proteins and angiotensin II and left ventricular remodeling by candesartan and omapatrilat during healing after reperfused myocardial infarction. AB - While secretory-leukocyte-protease-inhibitor (SLPI) may promote skin wound healing, its role in infarct healing after reperfused myocardial infarction (RMI) remains unclear. Short-term intravenous angiotensin II (AngII) receptor blocker therapy with candesartan (CN) attenuates increased SLPI and markers of early matrix/left ventricular (LV) in acute RMI. To determine whether reducing effects of AngII with CN or the vasopeptidase inhibitor omapatrilat (OMA) during the healing phase after RMI attenuates SLPI and other mediators of healing and matrix/LV remodeling, we measured these in Sprague-Dawley rats randomized to oral placebo, CN (30 mg/kg/day) or OMA (10 mg/kg/day) therapy during healing between days 2 and 23 after RMI and sham. On day-25, RMI-placebo showed significant LV remodeling, systolic/diastolic dysfunction and impaired passive compliance, and ischemic zone increases in SLPI, secreted-protein-acidic-and-rich-in-cysteine (SPARC) and osteopontin (OPN) mRNA and protein. In addition, metalloproteinase (MMP)-9 and -2, a-disintegrin-and-metalloproteinase (ADAM)-10 and -17, inducible nitric-oxide-synthase (iNOS), pro-inflammatory cytokines interleukin (IL)-6, and tumor necrosis factor-alpha, transforming growth factor (TGF)-beta(1) and its signaling molecule p-Smad-2, myeloperoxidase (MPO), AngII, MPO-positive granulocytes, MAC387-positive macrophages and monocytes, scar collagens, cardiomyocyte and fibroblast apoptosis, and microvascular no-reflow also increased whereas anti-inflammatory cytokine IL-10 decreased. Both CN and OMA attenuated all the changes except IL-10, which normalized. Thus, CN or OMA treatment during healing after RMI results in attenuation of SLPI as well as tissue AngII and mediators of inflammation and matrix/LV remodeling including SPARC, OPN, and ADAMs. Whether increasing SLPI on top of background AngII inhibition or therapy such as CN or OMA might produce added remodeling benefit needs study. PMID- 23361364 TI - Protective effects of azelaic acid against high-fat diet-induced oxidative stress in liver, kidney and heart of C57BL/6J mice. AB - Excess fat intake induces hyperinsulinaemia, increases nutrient uptake and lipid accumulation, amplifies ROS generation, establishes oxidative stress and morphological changes leading to tissue injury in the liver, kidney and heart of high-fat diet (HFD)-fed mice. The effect of azelaic acid (AzA), a C9 alpha,omega dicarboxylic acid, against HFD-induced oxidative stress was investigated by assaying the activities and levels of antioxidants and oxidative stress markers in the liver, kidney and heart of C57BL/6J mice. Mice were segregated into two groups, one fed standard diet (NC) and the other fed high-fat diet (HFD) for 15 weeks. HFD-fed mice were subjected to intragastric administration of AzA (80 mg/kg BW)/RSG (10 mg/kg BW) during 11-15 weeks. Glucose, insulin, triglycerides, hepatic and nephritic markers were analysed in the plasma and the activity of enzymatic, non-enzymatic antioxidants and lipid peroxidation markers were examined in the plasma/erythrocytes, liver, kidney and heart of normal and experimental mice. We inferred significant decrease in enzymatic and non enzymatic antioxidants along with significant increase in glucose, insulin, hepatic and nephritic markers, triglycerides and lipid peroxidation markers in HFD-fed mice. Administration of AzA could positively restore the levels of plasma glucose, insulin, triglycerides, hepatic and nephritic markers to near normal. AzA increased the levels of enzymatic and nonenzymatic antioxidants with significant reduction in the levels of lipid peroxidation markers. Histopathological examination of liver, kidney and heart substantiated these results. Hence, we put forward that AzA could counteract the potential injurious effects of HFD-induced oxidative stress in C57BL/6J mice. PMID- 23361365 TI - Docosahexaenoic acid and eicosapentaenoic acid reduce C-reactive protein expression and STAT3 activation in IL-6-treated HepG2 cells. AB - C-reactive protein (CRP), an acute phase protein in humans, is predominantly produced by hepatocytes in response to interleukin-6 (IL-6). Several epidemiological studies have reported that dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs) is inversely associated with serum CRP concentration. However, the molecular mechanism by which n-3 PUFAs reduce the serum CRP level in HepG2 cells remains unclear. The aims of this study were to examine the effect of the n-3 PUFAs, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), on the modulation of IL-6-induced CRP expression and to explore its possible mechanisms. We demonstrated that DHA and EPA inhibited IL-6-induced CRP protein and mRNA expression, as well as reduced CRP promoter activity in HepG2 cells. Knockdown of Signal Transducer and Activator of Transcription 3 (STAT3) and CCAAT box/Enhancer-Binding Protein beta (C/EBPbeta) by small interfering RNAs (siRNAs) significantly decreased IL-6-induced CRP promoter activity. Gel electrophoresis mobility shift assays (EMSA) showed that pretreatment with DHA and EPA decreased IL-6-induced STAT3 DNA binding activity but not C/EBPbeta. By western blot analysis, DHA and EPA inhibited IL-6-induced STAT3 phosphorylation but not ERK1/2 or C/EBPbeta. The suppression of the phosphorylation of STAT3 by DHA and EPA was further verified by immunofluorescence staining. Taken together, our results demonstrate that DHA and EPA are able to reduce IL-6-induced CRP expression in HepG2 cells via an inhibition of STAT3 activation. This mechanism, which explains the inhibitory effect of n-3 PUFAs on the CRP expression, provides new insights into the beneficial anti-inflammatory effect of n-3 PUFAs. PMID- 23361366 TI - Non-reentrant atrioventricular nodal tachycardia. PMID- 23361367 TI - Occlusion of the left main stem: a rare, but life-threatening complication of transcatheter aortic valve implantation with the Medtronic CoreValveTM prosthesis. PMID- 23361368 TI - Dichloroacetate reverses the hypoxic adaptation to bevacizumab and enhances its antitumor effects in mouse xenografts. AB - Inhibition of vascular endothelial growth factor increases response rates to chemotherapy and progression-free survival in glioblastoma. However, resistance invariably occurs, prompting the urgent need for identification of synergizing agents. One possible strategy is to understand tumor adaptation to microenvironmental changes induced by antiangiogenic drugs and test agents that exploit this process. We used an in vivo glioblastoma-derived xenograft model of tumor escape in presence of continuous treatment with bevacizumab. U87-MG or U118 MG cells were subcutaneously implanted into either BALB/c SCID or athymic nude mice. Bevacizumab was given by intraperitoneal injection every 3 days (2.5 mg/kg/dose) and/or dichloroacetate (DCA) was administered by oral gavage twice daily (50 mg/kg/dose) when tumor volumes reached 0.3 cm(3) and continued until tumors reached approximately 1.5-2.0 cm(3). Microarray analysis of resistant U87 tumors revealed coordinated changes at the level of metabolic genes, in particular, a widening gap between glycolysis and mitochondrial respiration. There was a highly significant difference between U87-MG-implanted athymic nude mice 1 week after drug treatment. By 2 weeks of treatment, bevacizumab and DCA together dramatically blocked tumor growth compared to either drug alone. Similar results were seen in athymic nude mice implanted with U118-MG cells. We demonstrate for the first time that reversal of the bevacizumab-induced shift in metabolism using DCA is detrimental to neoplastic growth in vivo. As DCA is viewed as a promising agent targeting tumor metabolism, our data establish the timely proof of concept that combining it with antiangiogenic therapy represents a potent antineoplastic strategy. PMID- 23361369 TI - Enhanced detection of ubiquitin isopeptides using reductive methylation. AB - Identification of ubiquitination (Ub) sites is of great interest due to the critical roles that the modification plays in cellular regulation. Current methods using mass spectrometry rely upon tryptic isopeptide diglycine tag generation followed by database searching. We present a novel approach to ubiquitin detection based upon the dimethyl labeling of isopeptide N-termini glycines. Ubiquitinated proteins were digested with trypsin and the resulting peptide mixture was derivatized using formaldehyde-D2 solution and sodium cyanoborohydride. The dimethylated peptide mixtures were next separated by liquid chromatography and analyzed on a quadrupole-TOF based mass spectrometer. Diagnostic b2' and a1' ions released from the isopeptide N-terminus upon collision-induced dissociation (CID) were used to spectrally improve the identification of ubiquitinated isopeptides. Proof of principle was established by application to a ubiquitinated protein tryptic digest spiked into a six protein mix digest background. Extracted ion chromatograms of the a1' and b2' diagnostic product ions from the diglycine tag resulted in a significant reduction in signal complexity and demonstrated a selectivity towards the identification of diglycine branched isopeptides. The method was further shown to be capable of identifying diglycine isopeptides resulting from in-gel tryptic digests of ubiquitin enriched material from a His-Ub transfected cell line. We envisage that these ions may be utilized in global ubiquitination studies with post-acquisition MS/MS (or MSe) data interrogation on high resolution hybrid mass spectrometers. ? PMID- 23361370 TI - Exploring radical migration pathways in peptides with positional isomers, deuterium labeling, and molecular dynamics simulations. AB - One of the keys for understanding radical directed dissociation in peptides is a detailed knowledge of the factors that mediate radical migration. Peptide radicals can be created by a variety of means; however, in most circumstances, the originally created radicals must migrate to alternate locations in order to facilitate fragmentation such as backbone cleavage or side chain loss. The kinetics of radical migration are examined herein by comparing results from ortho , meta-, and para-benzoyl radical positional isomers for several peptides. Isomers of a constrained cyclic peptide generated by several orthogonal radical initiators are also probed as a function of charge state. Cumulatively, the results suggest that small changes in radical position can significantly impact radical migration, and overall structural flexibility of the peptide is also an important controlling factor. A particularly interesting pathway for the peptide RGYALG that is sensitive to ortho versus meta or para substitution was fully mapped out by a suite of deuterium labeled peptides. This data was then used to optimize parameters in molecular dynamics-based simulations, which were subsequently used to obtain further insight into the structural underpinnings that most strongly influence the kinetics of radical migration. PMID- 23361371 TI - Elimination of benzene from protonated N-benzylindoline: benzyl cation/proton transfer or direct proton transfer? AB - Collision-induced dissociation (CID) of protonated N-benzylindoline and its derivatives was investigated by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Elimination of benzene was observed besides hydride transfer and electron transfer reactions. D-labeling experiments and accurate mass determinations of the product ions confirm that the external proton is retained in the fragment ion, and the elimination reaction was proposed to be initiated by benzyl cation transfer rather than proton transfer. Benzyl cation transfer from the nitrogen atom to one of the sp(2)-hybridized carbon atoms in the indoline core is the key step, and subsequent proton transfer reaction leads to the elimination of benzene. Density functional theory (DFT)-based calculations were performed and the computational results also support the benzyl cation/proton transfer mechanism. Figure ? PMID- 23361372 TI - Nanoscale heat transfer--from computation to experiment. AB - Heat transfer can differ distinctly at the nanoscale from that at the macroscale. Recent advancement in computational and experimental techniques has enabled a large number of interesting observations and understanding of heat transfer processes at the nanoscale. In this review, we will first discuss recent advances in computational and experimental methods used in nanoscale thermal transport studies, followed by reviews of novel thermal transport phenomena at the nanoscale observed in both computational and experimental studies, and discussion on current understanding of these novel phenomena. Our perspectives on challenges and opportunities on computational and experimental methods are also presented. PMID- 23361374 TI - Poor sleep, hazardous breathing: an overview of obstructive sleep apnea. AB - Obstructive sleep apnea is a chronic disorder resulting from upper airway collapse during sleep. It is linked to a variety of health and safety risks but can often be effectively treated. This article provides an overview of the disorder, including an evidence-based approach to diagnosis and management. PMID- 23361373 TI - Epidermal growth factor receptor (EGFR) mutation and personalized therapy in advanced nonsmall cell lung cancer (NSCLC). AB - Before 2009, nonsmall cell lung cancer (NSCLC) was one disease entity treated by cytotoxic chemotherapy that provided a response rate of 20-35 % and a median survival time (MST) of 10-12 months. In 2004, it was found that activated mutations of the epidermal growth factor receptor (EGFR) gene were present in a subset of NSCLC and that tumors with EGFR mutations were highly sensitive to EGFR tyrosine kinase inhibitors (TKI). Four phase III studies (North East Japan (NEJ) 002, West Japan Thoracic Oncology Group (WJTOG) 3405, OPTIMAL, and EUROTAC) prospectively compared TKI (gefitinib or erlotinib) with cytotoxic chemotherapy as first-line therapy in EGFR-mutated NSCLC. These studies confirmed that progression-free survival (PFS) with TKIs (as the primary endpoint) was significantly longer than that with standard chemotherapy (hazard ratio [HR] = 0.16-0.49) from 2009 to 2011. Although the NEJ 002 study showed identical overall survival (OS) between the arms (HR = 0.89), quality of life (QoL) was maintained much longer in patients treated with gefitinib. In conclusion, TKI should be considered as the standard first-line therapy in advanced EGFR-mutated NSCLC. Since 2009, a new step has been introduced in the treatment algorithm for advanced NSCLC. PMID- 23361375 TI - Uncovering common bacterial skin infections. AB - The four most common bacterial skin infections are impetigo, erysipelas, cellulitis, and folliculitis. This article summarizes current information about the etiology, clinical presentation, diagnosis, prevention, treatment, and implications for primary care practice needed to effectively diagnose and treat common bacterial skin infections. PMID- 23361377 TI - Ligations of N-acyl tryptophan units to give native peptides via 7-, 10-, 11- and 12-membered cyclic transition states. AB - N-Acyl tryptophan isopeptides undergo acyl transfer in chemical ligations via 7-, 10-, 11- and 12-membered cyclic transition states to yield natural peptides, representing the first examples of successful isopeptide ligations from N-acyl tryptophan units. PMID- 23361376 TI - Engineering of bacterial phytochromes for near-infrared imaging, sensing, and light-control in mammals. AB - Near-infrared light is favourable for imaging in mammalian tissues due to low absorbance of hemoglobin, melanin, and water. Therefore, fluorescent proteins, biosensors and optogenetic constructs for optimal imaging, optical readout and light manipulation in mammals should have fluorescence and action spectra within the near-infrared window. Interestingly, natural Bacterial Phytochrome Photoreceptors (BphPs) utilize the low molecular weight biliverdin, found in most mammalian tissues, as a photoreactive chromophore. Due to their near-infrared absorbance BphPs are preferred templates for designing optical molecular tools for applications in mammals. Moreover, BphPs spectrally complement existing genetically-encoded probes. Several BphPs were already developed into the near infrared fluorescent variants. Based on the analysis of the photochemistry and structure of BphPs we suggest a variety of possible BphP-based fluorescent proteins, biosensors, and optogenetic tools. Putative design strategies and experimental considerations for such probes are discussed. PMID- 23361378 TI - 1H, 13C, and 15N resonance assignments of mouse lipocalin-type prostaglandin D synthase/substrate analog complex. AB - Lipocalin-type Prostaglandin D synthase (L-PGDS) acts as the PGD2-synthesizing enzyme in the brain of various mammalian species. It belongs to the lipocalin superfamily and is the first member of this family to be recognized as an enzyme. Although the solution and crystal structure of L-PGDS has been determined to understand the molecular mechanism of catalytic reaction, the structural analysis of L-PGDS in complex with its substrate remains to be performed. Here, we present the nearly complete assignment of the backbone and side chain resonances of L PGDS/substrate analog (U-46619) complex. This study lays the essential basis for further understanding the substrate recognition mechanism of L-PGDS. PMID- 23361379 TI - 1H, 15N and 13C assignments of a putative peptidyl prolyl cis-trans isomerase FKBP12 from Trypanosoma brucei. AB - TbFKBP12 is a putative peptidyl prolyl cis-trans isomerase from Trypanosoma brucei, causative agent of the African trypanosomiasis or sleeping sickness. It interacts with the immunosuppressive drug rapamycin inhibiting the formation of TORC2 complex leading to parasite death by inhibiting cell proliferation through cytokinesis blockade. Moreover, RNAi silencing of TbFKBP12 revealed essential function in both procyclic and bloodstream forms. Both facts make TbFKBP12 an attractive target for ligand development and thus structural data is desirable. In this work we report the NMR resonance assignments for (1)H, (15)N and (13)C nuclei in the backbone and side chains of the TbFKBP12 as basis for further studies of structure, backbone dynamics, interaction mapping and drug screening. PMID- 23361380 TI - Breast cancer trends in Israeli Jewish and Arab women, 1996-2007. AB - Breast cancer is the most common malignancy in Israeli Jewish and Arab women. The main objective of this study was to reexamine the trends in breast cancer incidence, mortality, and survival in Israel in 1996 through 2007, as well as the use of mammography. Data were obtained from the Israel National Cancer Registry, the Central Bureau of Statistics, and National Health Surveys. Incidence and mortality rates per 100 000 are age adjusted to the world standard population. Time trends are presented using the joinpoint regression analysis. The relative survival was calculated for the diagnosis years 1996-2003. Data on mammography performance were obtained from the Knowledge, Attitudes and Practices surveys carried out in 2002-2008. From 1996 through 2007, the incidence of in-situ breast cancer increased in both subpopulations whereas the incidence of invasive breast cancer decreased by 3% for Jewish women and increased by 98% for Arab women (P value for 'between-populations' differences <0.001). Reports on having had a mammogram in the last 2 years increased by 16% in Jewish women and by 17% in Arab women in 2002 through 2008 (P=0.880). Breast cancer mortality rates decreased significantly from 24.7 in 1996 to 19.0 in 2007 in Jewish women, but remained stable in Arab women (P=0.041). The 5-year relative survival increased in both subpopulations (P=0.420). The incidence of breast cancer has been stable in Jewish women, but had been increasing rapidly in Arab women throughout 1996-2007. The differences indicate an epidemiologic transition in the Arab minority in Israel. Efforts should focus not only on secondary but also on primary prevention strategies. PMID- 23361381 TI - Kinetic trapping of the host-guest association intermediate and its transformation into a thermodynamic inclusion complex. AB - The molecular recognition and self-assembly between host cucurbit[6]uril and guest adrenaline led to kinetic trapping and crystallization of the intermediate exclusion complex, which was characterized by X-ray diffraction. The crystalline kinetic complex undergoes slow spontaneous dissolution and subsequently recrystallizes as a thermodynamic inclusion complex. PMID- 23361382 TI - The role of sinus surgery in children. AB - OBJECTIVES/HYPOTHESIS: To critically review the current literature discussing the outcome of endoscopic sinus surgery (ESS) in children with chronic rhinosinusitis (CRS). STUDY DESIGN: Literature review. METHODS: PubMed database and the Cochrane Library were searched. The PubMed search included all English-language literature published between January 1990 and July 2012 discussing the role of ESS in children with CRS. Studies that included patients with cystic fibrosis, primary immunodeficiency disorders, or ciliary dysmotility disorders were excluded. RESULTS: Of the 507 articles retrieved from the primary research strategy, 11 studies were included for further discussion. There were no randomized controlled studies. The rate of success of pediatric ESS ranged from 82% to 100% in selected patients. Children undergoing ESS for CRS usually have more severe disease compared to those who get medical treatment or adenoidectomy. The extracted rate of complication was 1.4%, with no cases of cerebrospinal fluid leak or major orbital injury such as hematoma or blindness reported. CONCLUSIONS: ESS offers a surgical alternative in the treatment of CRS in children with an excellent safety profile. There remains a need for higher level studies addressing the indications of ESS in children. PMID- 23361384 TI - Glia: an astrocytic generation gap. PMID- 23361385 TI - Auditory system: turn it up a notch. PMID- 23361383 TI - Role of diuretics and lipid formulations in the prevention of amphotericin B induced nephrotoxicity. AB - PURPOSE: To collect available clinical data to define the role of diuretics and lipid formulations in the prevention of amphotericin B (AmB)-induced nephrotoxicity (AIN) in human populations. METHOD: A literature search was performed in the following databases: Scopus, Medline, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. RESULTS AND CONCLUSION: Co-administration of mannitol failed to show any clinically significant benefit in preventing AIN. Potassium-sparing diuretics, such as amiloride and spironolactone, have been shown to have beneficial effects as an alternative or adjunct to oral/parenteral potassium supplements in preventing hypokalemia due to AmB. Lipid-based formulations of AmB are clinically effective and safe in preventing AIN. However, due to their high cost and limited accessibility, these formulations are generally used as second-line antifungal therapy in cases of conventional AmB refractoriness and/or intolerance or pre existing renal dysfunction. The potential effects of other nephroprotective agents, such as N-acetylcysteine, AIN merit further considerations and investigations. PMID- 23361387 TI - Electronic bond tuning with heterocyclic carbenes. AB - We discuss the impact of the nature of the heterocyclic carbene ring, when used as a complex forming ligand, on the relative stability of key intermediates in three typical Ru, Pd and Au promoted reactions. Results show that P-heterocyclic carbenes have a propensity to increase the bonding of the labile ligand and of the substrate in Ru-promoted olefin metathesis, whereas negligible impact is expected on the stability of the ruthenacycle intermediate. In the case of Pd cross-coupling reactions, dissociation of a P-heterocyclic carbene is easier than dissociation of the N-heterocyclic analogue. In the case of the Au-OH synthon, the Au-OH bond is weakened with the P-heterocyclic carbene ligands. A detailed energy decomposition analysis is performed to rationalize these results. PMID- 23361388 TI - Biopsychosocial function analyses changes the assessment of the ability to work in patients on long-term sick-leave due to chronic musculoskeletal pain: the role of undiagnosed mental health comorbidity. AB - AIMS: To study the prevalence of somatic and mental health comorbidity and the use of opioid medication among patients on long-term sick-leave due to chronic musculoskeletal pain (CMP); to compare an orthopaedic-based assessment of ability to work with a team assessment; to investigate the relationship between intensity of pain and psychosocial characteristics in this group. METHODS: A cross sectional study was carried out with 174 consecutive patients on sick-leave for a mean of 21 months. All were referred from the Social Insurance Office for orthopaedic evaluation and assessment of the ability to work. Of them, only 83/174 patients were referred by the Office for psychiatric evaluation. RESULTS: Neck pain was the main cause of disability. Patients with neck pain often suffered pain in more than two sites, and greater intensity of pain. Thirty-four percent of all participants had been prescribed opioid medication before consultation. Degrees of disability, unemployment, low degree of education and to be an immigrant were related to intensity of pain. Unrecognized psychiatric disorders changed the main cause of inability to work in 69% of patients who underwent both orthopaedic and psychiatric evaluation. CONCLUSIONS: An evaluation based on biopsychosocial function is valuable in reaching an accurate assessment of the patient's diagnosis, and ability to work in CMP. Ability to work and degree of sick-leave in patients on long-term sick-leave is determined to a large extent by undiagnosed mental health comorbidities, and not solely somatic complaints. PMID- 23361386 TI - Axonal transport deficits and neurodegenerative diseases. AB - The intracellular transport of organelles along an axon is crucial for the maintenance and function of a neuron. Anterograde axonal transport has a role in supplying proteins and lipids to the distal synapse and mitochondria for local energy requirements, whereas retrograde transport is involved in the clearance of misfolded and aggregated proteins from the axon and the intracellular transport of distal trophic signals to the soma. Axonal transport can be affected by alterations to various components of the transport machinery. Here, we review the current state of knowledge about axonal transport defects that might contribute to the pathogenesis of particular neurodegenerative diseases. PMID- 23361390 TI - On the nature of the delayed "inhibitory" cueing effects generated by uninformative arrows at fixation. AB - When the interval between a spatially uninformative arrow and a visual target is short (<500 ms), response times (RTs) are fastest when the arrow points to the target. When this interval exceeds 500 ms, there is a near-universal absence of an effect of the arrow on RTs. Contrary to this expected pattern of results, Taylor and Klein (J Exp Psychol Hum Percept Perform 26:1639-1656, 2000) observed that RTs were slowest when a to-be-localized visual target occurred in the direction of a fixated arrow presented 1 s earlier (i.e., an "inhibitory" Cueing effect; ICE). Here we examined which factor(s) may have allowed the arrow to generate an ICE. Our experiments indicated that the ICE was a side effect of subthreshold response activation attributable to a task-induced association between the arrow and a keypress response. Because the cause of this ICE was more closely related to subthreshold keypress activation than to oculomotor activation, we considered that the effect might be more similar to the negative compatibility effect (NCE) than to inhibition of return (IOR). This similarity raises the possibility that classical IOR, when caused by a spatially uninformative peripheral onset event and measured by a keypress response to a subsequent onset, might represent, in part, another instance of an NCE. Serendipitously, we discovered that context (i.e., whether an uninformative peripheral onset could occur at the time of an uninformative central arrow) ultimately determined whether the "inhibitory" aftermath of automatic response activation would affect output or input pathways. PMID- 23361389 TI - Effects of a dietetic treatment in older, undernourished, community-dwelling individuals in primary care: a randomized controlled trial. AB - PURPOSE: Undernutrition is a prevalent problem in older, community-dwelling individuals. Aim of this study was to determine the effects of a dietetic treatment in older, undernourished, community-dwelling individuals. METHODS: A parallel randomized controlled trial was performed in 146 non-institutionalized, undernourished individuals aged >=65 years in primary care. Participants were randomly assigned to the intervention (referral to and treatment by a trained dietitian) or control group (no referral). Body weight, physical performance, handgrip strength, energy intake, protein intake and fat-free mass were assessed at baseline, after 3 months and after 6 months. RESULTS: All randomized participants (n = 146) were included in the intention-to-treat generalized estimating equations analysis (72 in intervention and 74 in control group). No treatment effect was found on the primary outcomes body weight (beta = 0.49 kg, 95% CI: -0.15-1.12), physical performance (beta = 0.15 points, 95% CI: -0.33 0.64) and handgrip strength (beta = 0.49 kg, 95% CI: -0.62-1.60). Furthermore, no treatment effect was found for the secondary outcomes. Predefined subgroup analyses showed a treatment effect on body weight in physically active participants (beta = 1.25 kg, 95% CI: 0.70-2.11) and not in inactive participants (beta = -0.20 kg, 95% CI: -1.16-0.75). CONCLUSIONS: After 6 months, a dietetic treatment by trained dietitians does not lead to increases in body weight and physical functioning in older, undernourished, community-dwelling individuals. PMID- 23361391 TI - Ultrasonographic markers of vascular risk in patients with asymptomatic carotid stenosis. AB - Six-hundred twenty-one subjects with unilateral asymptomatic severe internal carotid artery (ICA) stenosis were prospectively evaluated with a median follow up of 27 months (min=6, max=68). Vascular risk profile, plaque characteristic, stenosis progression, and common carotid artery intima-media thickness (IMT) were investigated in all patients. Outcome measures were occurrence of ischemic stroke ipsilateral to ICA stenosis and vascular death, while myocardial infarction, contralateral strokes, and transient ischemic attack were considered as competing events. A total of 99 subjects (15.9%) suffered from a vascular event. Among them, 39 were strokes ipsilateral to the stenosis (6.3%). Degree of stenosis, stenosis progression, and common carotid artery IMT resulted as independent predictive factors of ipsilateral stroke. Considering a stenosis of 60% to 70% as reference, a degree between 71% and 90% increased the risk by 2.45, while a degree between 91% and 99% increased the risk by 3.26. The progression of stenosis was a strong risk factor (hazard ratio=4.32). Finally, the role of carotid IMT was confirmed as crucial additional measure, with an increased risk by 25% for each 0.1 mm IMT increase. Our data suggest that IMT, stenosis progression and severity should be considered as risk factors for cerebrovascular events in asymptomatic subjects with severe ICA stenosis. PMID- 23361392 TI - Age-related changes in spontaneous oscillations assessed by wavelet transform of cerebral oxygenation and arterial blood pressure signals. AB - The study aims to assess the spontaneous oscillations in elderly subjects based on the wavelet transform of cerebral oxygenation (CO) and arterial blood pressure (ABP) signals. Continuous recordings of near-infrared spectroscopy (NIRS) and ABP signals were obtained from simultaneous measurements in 20 young subjects (age: 27.3 +/- 7.1 years) and 15 elderly subjects (age: 70.8 +/- 5.1 years) at rest. Using spectral analysis based on wavelet transform, five frequency intervals were identified (I, 0.005 to 0.02 Hz; II, 0.02 to 0.06 Hz; III, 0.06 to 0.15 Hz; IV, 0.15 to 0.40 Hz; and V, 0.40 to 2.0 Hz). The average amplitudes of the Delta[HbO2] and tissue oxygenation index in intervals I to V and the relative amplitudes in intervals IV and V were significantly lower in elderly subjects than in young subjects (P<0.05). In addition, the relative amplitudes of the ABP in interval I were significantly lower in elderly subjects than in young subjects (P=0.016). The present findings suggest the presence of a cerebrovascular degenerative process caused by aging. Spontaneous oscillations in the CO could be used as an indicator of cerebrovascular changes and could be used to identify the risk for cerebrovascular degenerative processes. PMID- 23361393 TI - Superiority of preventive antibiotic treatment compared with standard treatment of poststroke pneumonia in experimental stroke: a bed to bench approach. AB - Stroke patients are prone to life-threatening bacterial pneumonia. Previous experimental stroke studies have demonstrated that preventive antibiotic treatment (PAT) improves outcome compared with placebo treatment, which however does not model the clinical setting properly. Here we investigate whether PAT is superior to the current clinical 'gold standard' for treating poststroke infections. Therefore, we modeled stroke care according to the current stroke guidelines recommending early antibiotic treatment after diagnosing infections. To reliably diagnose pneumonia in living mice, we established a general health score and a magnetic resonance imaging protocol for radiologic confirmation. Compared with standard treatment after diagnosis by these methods, PAT not only abolished pneumonia successfully but also improved general medical outcome. Both, preventive and standard antibiotic treatment using enrofloxacin improved survival in a similar way compared with placebo treatment. However, in contrast to standard treatment, only PAT improved functional outcome assessed by gait analysis. In conclusion, standard and preventive treatment approach reduced poststroke mortality, however at the cost of a worse neurologic outcome compared with preventive approach. These data support the concept of PAT for treating patients at risk for poststroke infections and warrant phase III trials to prove this concept in clinical setting. PMID- 23361394 TI - Induction of hyperhomocysteinemia models vascular dementia by induction of cerebral microhemorrhages and neuroinflammation. AB - Vascular dementia (VaD) is the second leading cause of dementia behind Alzheimer's disease (AD) and is a frequent comorbidity with AD, estimated to occur in as many as 40% of AD patients. The causes of VaD are varied and include chronic cerebral hypoperfusion, microhemorrhages, hemorrhagic infarcts, or ischemic infarcts. We have developed a model of VaD by inducing hyperhomocysteinemia (HHcy) in wild-type mice. By placing wild-type mice on a diet deficient in folate, B6, and B12 and supplemented with excess methionine, we induced a moderate HHcy (plasma level homocysteine 82.93 +/- 3.561 MUmol). After 11 weeks on the diet, the hyperhomocysteinemic mice showed a spatial memory deficit as assessed by the 2-day radial-arm water maze. Also, magnetic resonance imaging and subsequent histology revealed significant microhemorrhage occurrence. We found neuroinflammation induced in the hyperhomocysteinemic mice as determined by elevated interleukin (IL)-1beta, tumor necrosis factor (TNF)alpha, and IL-6 in brain tissue. Finally, we found increased expression and increased activity of the matrix metalloproteinase 2 (MMP2) and MMP9 systems that are heavily implicated in the pathogenesis of cerebral hemorrhage. Overall, we have developed a dietary model of VaD that will be valuable for studying the pathophysiology of VaD and also for studying the comorbidity of VaD with other dementias and other neurodegenerative disorders. PMID- 23361395 TI - Multivariate spatial covariance analysis of 99mTc-exametazime SPECT images in dementia with Lewy bodies and Alzheimer's disease: utility in differential diagnosis. AB - We examined (99m)Tc-exametazime brain blood flow single-photon emission computed tomography (SPECT) images using a spatial covariance analysis (SCA) approach to assess its diagnostic value in distinguishing dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). Voxel SCA was simultaneously applied to a set of preprocessed images (AD, n=40; DLB, n=26), generating a series of eigenimages representing common intercorrelated voxels in AD and DLB. Linear regression derived a spatial covariance pattern (SCP) that discriminated DLB from AD. To investigate the diagnostic value of the model SCP, the SCP was validated by applying it to a second, independent, AD and DLB cohort (AD, n=34; DLB, n=29). Mean SCP expressions differed between AD and DLB (F(1,64)=36.2, P<0.001) with good diagnostic accuracy (receiver operating characteristic (ROC) curve area 0.87, sensitivity 81%, specificity 88%). Forward application of the model SCP to the independent cohort revealed similar differences between groups (F(1,61)=38.4, P<0.001), also with good diagnostic accuracy (ROC 0.86, sensitivity 80%, specificity 80%). Multivariate analysis of blood flow SPECT data appears to be robust and shows good diagnostic accuracy in two independent cohorts for distinguishing DLB from AD. PMID- 23361396 TI - Cannabis and psychosis: what causes what? AB - Converging lines of evidence suggest that cannabinoids can produce a full range of transient schizophrenia-like positive, negative and cognitive symptoms. Cannabinoids also produce some psychophysiological deficits also known to be present in schizophrenia. It is also clear that, in individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Increasing evidence suggests that early and heavy cannabis exposure may increase the risk of developing a psychotic disorder such as schizophrenia. The relationship between cannabis exposure and schizophrenia fulfills some, but not all, of the usual criteria for causality. However, most people who use cannabis do not develop schizophrenia, and many people diagnosed with schizophrenia have never used cannabis. Therefore, it is likely that cannabis exposure is a "component cause" that interacts with other factors to "cause" schizophrenia or other psychotic disorders, but is neither necessary nor sufficient to do so alone. Further work is necessary to identify the factors that underlie individual vulnerability to cannabinoid-related psychosis and to elucidate the biological mechanisms underlying this risk. PMID- 23361397 TI - Stronger evidence is needed before accepting that cannabis plays an important role in the aetiology of schizophrenia in the population. AB - Schizophrenia is a debilitating but poorly understood condition with very few known modifiable risk factors. Cannabis use can acutely induce psychotic experiences, but its causal relationship to schizophrenia is less well understood. Longitudinal cohort studies suggest that the association between cannabis and psychotic outcomes is not due to chance or reverse causation. However, the association could be due to bias or residual confounding. Methods that can test alternative explanations in greater depth are required. This is especially important as ecological studies have found little association between the increase in cannabis use over recent decades and incidence of psychotic disorders; public health models suggest that cannabis use may need to be treated and prevented in many thousands of users in order to prevent one case of schizophrenia. We believe that, while such uncertainty exists, there is a scientific duty to continue to investigate the role of cannabis in the aetiology of schizophrenia and that the policy case for considering cannabis exposure as a critical target for preventing schizophrenia is yet to be made. However, due to other evidence of the harms of cannabis use, this should not affect the public health message that cannabis can be harmful and that cannabis dependence should be prevented. PMID- 23361398 TI - A mechanistic study of the electrochemical oxygen reduction on the model semiconductor n-Ge(100) by ATR-IR and DFT. AB - The electrochemical oxygen reduction reaction (ORR) on a n-Ge(100) surface in 0.1 M HClO4 was investigated in situ and operando using a combination of attenuated total reflection infrared (ATR-IR) spectroscopy and density functional (DFT) calculations. The vibrational modes of the detected intermediates were assigned based on DFT calculations of solvated model clusters such as Ge-bound superoxides and peroxides. ATR-IR shows the Ge-bound superoxide with a transition dipole moment oriented at (28 +/- 10) degrees with respect to the surface normal. At slightly negative potentials, the surface-bound peroxide is identified by an OOH bending mode as a further intermediate, oriented at a similar angle. At strongly negative potentials, a surface-bound perchlorate is found. The findings indicate a multistep mechanism of the ORR. The reaction is furthermore coupled with the hydrogen evolution reaction (HER). PMID- 23361399 TI - A virtual culture of CD4+ T lymphocytes. AB - The CD4+ T cell lineages Th1, Th2, Th17, and Treg, are mammalian cell types that differentiate from the common precursor naive CD4+ T cell. While there is a wealth of experimental data regarding the molecular and cellular signals involved in the differentiation of CD4+ T cells in vitro, there is still no consensus regarding the structure of the network of interactions at the molecular and cellular levels controlling this differentiation process. In this work, a virtual culture of cells is constructed by interconnecting several instances of an updated version of the regulatory network controlling the differentiation process of CD4+ T cells in mice. The virtual culture is a multi-compartment model with an instance of a regulatory network inside each compartment, thus simulating a simplified version of a cell culture in a well-stirred reactor. The virtual culture is able to describe the stable molecular expression patterns described for fully differentiated CD4+ T cells in mice, as well as the differentiation process from a precursor to a given effector cell in response to specific molecular stimuli. PMID- 23361400 TI - Indicators show differences in antibiotic use between general practitioners and paediatricians. AB - The purpose of this investigation was to adapt to an individual physician level and to the paediatric context a set of drug-specific indicators of outpatient antibiotic use developed by the European Surveillance of Antimicrobial Consumption (ESAC) project, and to describe the differences in antibiotic prescriptions between general practitioners (GPs) and paediatricians. We conducted a retrospective cross-sectional study analysing antibiotic prescriptions in 2009 for children below 16 years of age in south-eastern France, using the National Health Insurance (NHI) outpatient reimbursement database. A generalised linear model adjusted on physicians' characteristics and patient population characteristics was used to compare indicators between GPs and paediatricians. We included 4,921 self-employed GPs and 301 paediatricians. Penicillins accounted for 47% and 45% of all antibiotics prescribed by GPs and paediatricians, respectively, followed by cephalosporins (33% and 39%) and macrolides (14% and 9%). In both specialties, there were around 70% more antibiotic prescriptions during the winter quarters compared to the summer quarters. The 13 indicators we calculated showed wide variations in antibiotic prescriptions among GPs, among paediatricians, and between GPs and paediatricians. In an adjusted econometric model, GPs were found to issue 54% more antibiotic prescriptions than paediatricians, whereas paediatricians used a significantly higher proportion of co-amoxiclav (18% vs. 12%) and cephalosporins (39% vs. 33%) and a significantly lower proportion of macrolides (9% vs. 14%) compared to GPs. A set of 13 indicators may be calculated using reimbursement data to describe outpatient antibiotic use at the physician level. We observed very different prescribing profiles between GPs and paediatricians. PMID- 23361401 TI - Impact of a computerized alert system for bacteremia notification on the appropriate antibiotic treatment of Staphylococcus aureus bloodstream infections. AB - A computerized alert system (CAS) has been introduced to notify bacteremia in real time. We evaluated the impact of the CAS on the administration of appropriate antibiotics in patients with Staphylococcus aureus bloodstream infections (BSIs). We retrospectively reviewed the medical records of patients with S. aureus BSI for each 1-year control and intervention periods, before and after the implementation of the CAS. The proportions of appropriate antibiotic treatment were compared between the control and intervention periods. The 30-day mortality of S. aureus bacteremia was also assessed in the study population. A total of 313 patients were included in the study. Appropriate antibiotics were initiated 7 h earlier in the intervention period (mean time, 13.5 h vs. 20.0 h; p = 0.136). The administration of appropriate antibiotics within the 24 h after blood acquisition was similar between the two periods, but this significantly increased from 3.3% in the control period to 10.6% in the intervention during the 24-36 h interval (p = 0.012). In the subgroup analysis, similar trends were observed in patients with methicillin-resistant isolates (6.7% vs. 18.2%; p = 0.032) and hospital-onset infection (3.5% vs. 17.1 %; p = 0.004). The independent risk factors for 30-day mortality of S. aureus bacteremia were age, a high Pitt bacteremia score, an increased Charlson's weighted index of comorbidity, and hospital-onset infection, although the appropriateness of antibiotic therapy within 36 h and the CAS were not identified as predictors. The CAS increased the proportion of appropriate antimicrobial therapy during the 24-36 h interval after bacteremia onset in patients with S. aureus BSIs. PMID- 23361403 TI - Combinatorial tuning of peptidic drug candidates: high-affinity matriptase inhibitors through incremental structure-guided optimization. AB - Herein we report a convenient strategy for the development of novel, highly potent peptidic inhibitors of the trypsin-like serine protease matriptase based on the monocyclic variant of the sunflower trypsin inihibitor-1 (SFTI-1[1,14]). We screened SFTI-1[1,14] variants possessing incremental modifications of the parent peptide for beneficial binding properties. This compound library comprising 6 peptides and 16 triazole-containing peptidomimetics was established via structure-guided rational design and synthesized using a divergent strategy employing "copper-click" chemistry. The most favorable amino acid substitutions were combined in one framework yielding potent SFTI-1-derived matriptase inhibitor-1 (SDMI-1) and the truncated dodecapeptide variant (SDMI-2) with single digit nanomolar inhibition constants. In silico studies indicated that the improved matriptase affinity compared to the parent peptide is caused by the successful establishment of additional favorable proton donor-acceptor interactions between basic inhibitor side chains and acidic residues on the surface of the target enzyme. SDMI-1 and 2 are potent inhibitors of the pharmaceutically relevant protease matriptase at a near physiological pH and, thus, may find applications in therapy or diagnostics. PMID- 23361404 TI - Microfluidic platforms for RNA interference screening of virus-host interactions. AB - RNA interference (RNAi) is a powerful tool for functional genomics with the capacity to comprehensively analyze host-pathogen interactions. High-throughput RNAi screening is used to systematically perturb cellular pathways and discover therapeutic targets, but the method can be tedious and requires extensive capital equipment and expensive reagents. To aid in the development of an inexpensive miniaturized RNAi screening platform, we have developed a two part microfluidic system for patterning and screening gene targets on-chip to examine cellular pathways involved in virus entry and infection. First, a multilayer polydimethylsiloxane (PDMS)-based spotting device was used to array siRNA molecules into 96 microwells targeting markers of endocytosis, along with siRNA controls. By using a PDMS-based spotting device, we remove the need for a microarray printer necessary to perform previously described small scale (e.g. cellular microarrays) and microchip-based RNAi screening, while still minimizing reagent usage tenfold compared to conventional screening. Second, the siRNA spotted array was transferred to a reversibly sealed PDMS-based screening platform containing microchannels designed to enable efficient cell loading and transfection of mammalian cells while preventing cross-contamination between experimental conditions. Validation of the screening platform was examined using Vesicular stomatitis virus and emerging pathogen Rift Valley fever virus, which demonstrated virus entry pathways of clathrin-mediated endocytosis and caveolae mediated endocytosis, respectively. The techniques here are adaptable to other well-characterized infection pathways with a potential for large scale screening in high containment biosafety laboratories. PMID- 23361405 TI - [Status quo of children's preventative medicine programmes--results of the first German nationwide workshop 2011 in Frankfurt am Main]. AB - 10 of the 13 federal states presented their structures, implementation methods and results as part of the nationwide workshop for children's preventative medicine and early recognition projects for Germany on 9th September 2011 in Frankfurt am Main. This was the first time a full overview of all programmes of this kind in Germany has been possible. The programmes and data from these 10 presentations were analysed and compared. Despite the many differences between the legal frameworks and structural implementation, the programmes also displayed similarities in the implementation and in the problems which arise. Significantly improved participation rates for early recognition check-ups have been achieved in the context of the programmes. Previously, only a few detailed evaluations for the detection of risks to children's welfare and other effects such as vaccination rates and improvements in children's health through more advice and care were available. PMID- 23361406 TI - [The quality of the German health-care system in an international comparison - a systematic review]. AB - OBJECTIVES: Studies assessing the quality of the German health-care system in an international comparison come to different results. Therefore, this review aims to investigate how the German health-care system is evaluated in comparison to other health-care systems by reviewing international publications. Results show starting points for ways to improve the German health-care system, to maintain and expand its strengths as well as to derive strategies for solving identified problems. METHODS: A systematic review searching different databases [library catalogues, WorldCat (including MEDLINE and OAIster-search), German National Library, Google Scholar and others]. Search requests were addressed to English or German language publications for the time period 2000-2010 (an informal search was conducted in October 2011 for an update). Results of the identified studies were aggregated and main statements derived. RESULTS: In total, 13 publications assessing the German health-care system in an international comparison were identified. These comparisons are based on 377 measures. After aggregation, 244 substantially different indicators remained, which were dedicated to 14 categories. It became apparent that the German health-care system can be characterised by a high level of expenses, a well-developed health-care infrastructure as well as a high availability of personal and material resources. Outcome measures demonstrate heterogeneous results. It can be stated that, particularly in this field, there is potential for further improvement. The utilisation of health-care services is high, the access is mostly not regulated and out of pocket payments can pose a barrier for patients. Waiting times are not regarded as a major weakness. Although civic satisfaction seems to be acceptable, a large portion of the citizens calls for elementary modifications. Especially, more patient-centred health-care delivery should be addressed as well as management of information and the adoption of meaningful electronic assistance systems. CONCLUSION: The presented results show starting points on the way to further improve the German health-care system. It is necessary to maintain and expand its strengths as well as to derive strategies for solving identified weaknesses. This can be done with confidence since, according to Donabedian, a high structural quality represents an important fundament to improve outcome and process measures. PMID- 23361407 TI - Evidence-based information on mammography screening in Austria--reality or more pie in the sky? AB - INTRODUCTION: Health literacy is gaining increasing importance in prevention and health care. This is the case for patients and for health-care professionals. Information and risk communication should comply with defined criteria and strengthen health literacy as they are a prerequisite for informed decision making. METHODS: In this study, we analyse the content of the printed information material (brochures and pamphlets) on mammography screening for consumers that were distributed in Austria in 2011. RESULTS: The evaluation of the 11 brochures shows that the content does not comply with the prerequisites for informed decision making. CONCLUSIONS: Since the last study - published in 2004 - the situation has only slightly improved. The authors reemphasise the need for a targeted multimodal information campaign. This is particularly important as a systematic national mammography screening program in compliance with the guidelines of the European Commission will be introduced in Austria in 2013. PMID- 23361409 TI - Non-compliance and instrumental variables in behavioural medicine: a commentary on van Dongen et al. PMID- 23361408 TI - The dentin matrix acidic phosphoprotein 1 (DMP1) in the light of mammalian evolution. AB - Dentin matrix acidic phosphoprotein 1 (DMP1) is an acidic, highly phosphorylated, noncollagenous protein secreted during dentin and bone formation. Previous functional studies of DMP1 have revealed various motifs playing a role in either mineralization or cell differentiation. We performed an evolutionary analysis of DMP1 to identify residues and motifs that were conserved during 220 millions years (Ma) of mammalian evolution, and hence have an important function. In silico search provided us with 41 sequences that were aligned and analyzed using the Hyphy program. We showed that DMP1 contains 55 positions that were kept unchanged for 220 Ma. We also defined in a more precise manner some motifs that were already known (i.e., cleavage sites, RGD motif, ASARM peptide, glycosaminoglycan chain attachment site, nuclear localization signal sites, and dentin sialophosphoprotein-binding site), and we found five, highly conserved, new functional motifs. In the near future, functional studies could be performed to understand the role played by them. PMID- 23361411 TI - Conscientiousness versus executive function as predictors of health behaviors and health trajectories. PMID- 23361410 TI - Chronic fatigue and personality: a twin study of causal pathways and shared liabilities. AB - BACKGROUND: The etiology of chronic fatigue syndrome (CFS) remains unknown. Personality traits influence well-being and may play a role in CFS and unexplained chronic fatigue. PURPOSE: This study aimed to examine the association of emotional instability and extraversion with chronic fatigue and CFS in a genetically informative sample. METHODS: We evaluated 245 twin pairs for two definitions of chronic fatigue. They completed the Neuroticism and Extraversion subscales of the NEO Five Factor Inventory. Using a co-twin control design, we examined the association between personality and chronic fatigue. RESULTS: Higher emotional instability was associated with both definitions of chronic fatigue and was confounded by shared genetics. Lower extraversion was also associated with both definitions of fatigue, but was not confounded by familial factors. CONCLUSIONS: Both emotional instability and extraversion are related to chronic fatigue and CFS. Whereas emotional instability and chronic fatigue are linked by shared genetic mechanisms, the relationship with extraversion may be causal and bidirectional. PMID- 23361412 TI - A different route to functional polyolefins: olefin-carbene copolymerisation. AB - Copolymerisation of carbenes and olefins (ethene), mediated by Rh-based catalyst precursors, is presented as a new, proof-of-concept methodology for the controlled synthesis of functional polymers. The reactions studied show that olefin-carbene polymerisation reactions provide a viable alternative to more traditional olefin polymerization techniques. Rh(III)-catalyst precursors, while active in the homopolymerisation of either olefins or carbenes, proved to be virtually inactive in olefin-carbene copolymerization. Conversely, the use of Rh(I)(cod) catalyst precursors allows the synthesis of high molecular-weight, highly functionalized copolymers. The reactions yield a mixture of copolymers and some carbene homopolymers, which proved to be difficult to separate. Polyethylene was not formed under the applied reaction conditions. The average ethene content in this mixture could be increased up to 11%, although analysis of the mixture revealed that the ethene content in fractions of the copolymer mixture can be as high as 70%. Attempts to increase the ethene content by increasing the ethene pressure unexpectedly led to lower average ethene contents, which is most likely due to changes in the ratio of copolymers vs. carbene homopolymer. This behaviour is most likely a result of the reactivity difference of different active Rh species formed under the applied reaction conditions. Apparently, higher ethene concentrations slow down the copolymerisation process (mediated by yet unidentified Rh-species) compared to the formation of homopolymers (mediated by different Rh-catalysts; most likely (allyl)Rh(III)-alkyl species), thereby changing the product ratio in favour of the homopolymer. The average ethene content in the copolymer mixture therefore decreases, while the ethene content within the copolymer fraction has likely increased at higher ethene concentrations (but simply less copolymer is formed). The obtained copolymers exhibit a blocky microstructure, with the functional blocks being highly stereoregular. Branching does occur and the functional groups are present in the polymer backbone as well as at the branches. Formation of copolymers was confirmed by Maldi-ToF analysis, which revealed incorporation of several ethene units into the copolymers. PMID- 23361413 TI - Achiral CdSe quantum dots exhibit optical activity in the visible region upon post-synthetic ligand exchange with D- or L-cysteine. AB - Semiconductor cadmium selenide (CdSe) quantum dots (QDs) exhibited mirror-image circular dichroism (CD) spectra in the visible region (350-570 nm) after replacing the trioctylphosphine oxide/oleic acid ligands on achiral nanocrystals with D- and L-cysteines. Chiroptical properties of cysteine-capped CdSe QDs depend on their size and can be fine-tuned by changing the radius of QDs. PMID- 23361414 TI - What justifies the United States ban on federal funding for nonreproductive cloning? AB - This paper explores how current United States policies for funding nonreproductive cloning are justified and argues against that justification. I show that a common conceptual framework underlies the national prohibition on the use of public funds for cloning research, which I call the simple argument. This argument rests on two premises: that research harming human embryos is unethical and that embryos produced via fertilization are identical to those produced via cloning. In response to the simple argument, I challenge the latter premise. I demonstrate there are important ontological differences between human embryos (produced via fertilization) and clone embryos (produced via cloning). After considering the implications my argument has for the morality of publicly funding cloning for potential therapeutic purposes and potential responses to my position, I conclude that such funding is not only ethically permissible, but also humane national policy. PMID- 23361415 TI - The 'I see you' prey-predator signal of Apis cerana is innate. AB - An 'I see you' (ISY) prey-predator signal can co-evolve when such a signal benefits both prey and predator. The prey benefits if, by producing the signal, the predator is likely to break off an attack. The predator benefits if it is informed by the signal that the prey is aware of its presence and can break off what is likely to be an unsuccessful and potentially costly hunt. Because the signal and response co-evolve in two species, the behaviour underlying an ISY signal is expected to have a strong genetic component and cannot be entirely learned. An example of an ISY signal is the 'shimmering' behaviour performed by Asian hive bee workers in the presence of their predator Vespa velutina. To test the prediction that bee-hornet signalling is heritable, we let honey bee workers of two species emerge in an incubator so that they had never been exposed to V. velutina. In Apis cerana, the shimmering response developed 48 h post-emergence, was strong after 72 h and increased further over 2 weeks. In contrast, A. mellifera, which has evolved in the absence of Asian hornets, did not produce the shimmering signal. In control tests, A. cerana workers exposed to a non threatening butterfly did not respond with the shimmering signal. PMID- 23361416 TI - SCA with rotation to distinguish common and distinctive information in linked data. AB - Often data are collected that consist of different blocks that all contain information about the same entities (e.g., items, persons, or situations). In order to unveil both information that is common to all data blocks and information that is distinctive for one or a few of them, an integrated analysis of the whole of all data blocks may be most useful. Interesting classes of methods for such an approach are simultaneous-component and multigroup factor analysis methods. These methods yield dimensions underlying the data at hand. Unfortunately, however, in the results from such analyses, common and distinctive types of information are mixed up. This article proposes a novel method to disentangle the two kinds of information, by making use of the rotational freedom of component and factor models. We illustrate this method with data from a cross cultural study of emotions. PMID- 23361417 TI - Immobilisation of hydroxynitrile lyases. AB - Hydroxynitrile lyases are a versatile group of enzymes that are applied both in the laboratory and on an industrial scale. What makes them particularly interesting is that to date five structurally unrelated categories of hydroxynitrile lyases have been discovered. Given their great importance they have often been immobilised utilising many different methodologies. Therefore the hydroxynitrile lyases are ideally suited to compare different immobilisation methods and their dependence on the structural features of the enzyme in question, since the activity is the same in all cases. This review examines all the different immobilisation methods applied to hydroxynitrile lyases and draws conclusions on the effect of the approach. PMID- 23361418 TI - Decontamination of outdoor school swimming pools in Fukushima after the nuclear accident in March 2011. AB - Because of radioactive fallout resulting from the Fukushima Daiichi Nuclear Power Plant (NPP) accident, water discharge from many outdoor swimming pools in Fukushima was suspended out of concern that radiocesium in the pool water would flow into farmlands. The Japan Atomic Energy Agency has reviewed the existing flocculation method for decontaminating pool water and established a practical decontamination method by demonstrating the process at eight pools in Fukushima. In this method, zeolite powder and a flocculant are used for capturing radiocesium present in pool water. The supernatant is discharged if the radiocesium concentration is less than the targeted level. The radioactive residue is collected and stored in a temporary storage space. Radioactivity concentration in water is measured with a NaI(Tl) or Ge detector installed near the pool. The demonstration results showed that the pool water in which the radiocesium concentration was more than a few hundred Bq L was readily purified by the method, and the radiocesium concentration was reduced to less than 100 Bq L. The ambient dose rates around the temporary storage space were slightly elevated; however, the total increase was up to 30% of the background dose rates when the residue was shielded with sandbags. PMID- 23361419 TI - Analysis of uranium concentration in drinking water samples using ICPMS. AB - Uranium concentration in drinking water samples collected from some areas of Northern Rajasthan has been measured using inductively coupled plasma mass spectrometry. The water samples were taken from hand pumps. The uranium concentration in water samples varies from 2.54-133.0 MUg L with a mean value of 38.48 MUg L. The uranium concentration in most of the drinking water samples exceeds the safe limit (30 MUg L) recommended by the World Health Organization. The annual effective dose associated with drinking water due to uranium concentration is estimated from its annual intake using dosimetric information based on ICRP 72. The resulting value of the annual effective dose from drinking water sources is in the range of 2.11-110.45 MUSv. The annual effective dose in one of the samples was found to be greater than WHO-recommended level of 100 MUSv y. PMID- 23361420 TI - Statistical considerations for improved signal identification from repeated measurements at low signal-to-background ratios. AB - Continuously repeated or frequent periodic measurements of the radiation environment in the absence of an identified source of ionizing radiation provide large data sets on the ambient background. Statistical evaluation of these data allows for the identification and quantification of the relevant background distribution parameters paramount to establishing a well characterized background distribution. Given this distribution, the determination of characteristic limits, such as the decision threshold, follows standard procedures. However, the data used to establish these characteristic limits contain additional information on the probabilities for future individual measurement results, which can be employed to improve the detection system capabilities for signal identification at low signal-to-background ratios. In particular, a statistical evaluation of the time history of individual, independent measurements allows for the establishment of new decision thresholds with the same prescribed probability of error of the first kind but with a lower value than the decision threshold obtained from standardized procedures. A rigorous mathematical and statistical treatment of multiple data from a well characterized background distribution is presented, together with an analysis of the relevant operational restrictions and statistical conditions for which an improved lower decision threshold can be obtained. A set of initial projections toward the application of appropriate statistical algorithms is intended to provide a basis for further investigation of these statistical considerations for their implementation in continuous scanning or screening operations or in individual or environmental monitoring programs. PMID- 23361421 TI - Analysis of naturally-occurring radionuclides in coal combustion fly ash, gypsum, and scrubber residue samples. AB - Coal combustion residues from coal-fired power plants can be advantageous for use in building and construction materials. These by-products contain trace quantities of naturally occurring radionuclides from the uranium and thorium series, as well as other naturally occurring radionuclides such as K. Analysis was performed on samples of coal fly ash, flue gas desulfurization, gypsum and scrubber sludges, fixated scrubber sludges, and waste water filter cakes sampled from multiple coal-fired power plants in the United States. The radioactive content of U and Th decay series nuclides was determined using gamma photopeaks from progeny Pb at 352 keV and Tl at 583 keV, respectively; K specific activities were determined using the 1,461 keV photopeak. The samples were hermetically sealed to allow for secular equilibrium between the radium parents and the radon and subsequent progeny. Samples were analyzed in a common geometry using two high purity germanium photon detectors with low energy detection capabilities. The specific activities (Bq kg) were compared to results from literature studies including different building materials and fly ash specific activities. Fly ash from bituminous and subbituminous coals had U specific activities varying from 30 217 Bq kg (mean + 1 s.d. 119 +/- 45 Bq kg) and 72-209 Bq kg (115 +/- 40 Bq kg), respectively; Th specific activities from 10-120 Bq kg (73 +/- 26 Bq kg) and 53 110 Bq kg (81 +/- 18 Bq kg), respectively; and K specific activities from 177 to 928 Bq kg (569 +/- 184 Bq kg) and 87-303 Bq kg (171 +/- 69 Bq kg), respectively. Gypsum samples had U, Th, and K specific activities approximately one order of magnitude less than measured for fly ash samples. PMID- 23361422 TI - Retention and excretion of 3H in rats following the intratracheal intubation of tritiated pump oil. AB - Saturated hydrocarbon mineral oils in vacuum pumps used in 3H handling facilities often contain significant amounts of 3H (as much as several hundred GBq L-1), and during maintenance the air around an open pump may contain MBq L of volatile and aerosol species. It follows that H-contaminated pump oils pose a workplace hazard especially if inhaled deposits are retained in the lung. A long-term study (1-y duration) was undertaken to establish the retention time of 3H-pump oil in the lungs of rats. Excretion data was collected to establish the mechanism of oil clearance from the lung. Finally, liver data was collected both to indicate the levels of H in the rat body and to indicate either the presence or absence of the transfer of unmetabolized pump oil within cells from the lungs to liver. Within 1 d following intubation into the trachea, ~16.5% of the emulsified pump oil had been rapidly mechanically cleared to feces, and 1.1%, present as HTO, or exchangeable H, was excreted in urine. 69.4% of the instilled dose remained in the lungs as the initial alveolar burden. Subsequently, H cleared from the lungs with a retention half-time of of 223 d. The lung burden was mostly cleared to feces-indicating that the pump oil droplets remaining in the lungs were behaving like insoluble particles, but the kinetics of clearance of particles and oil droplets may be different. Overall, it is concluded that inhaled H-pump oil should most likely be regarded as an insoluble particulate (ICRP Inhalation Type S) for the purposes of radiological protection dosimetry, but the possibility of Type M behavior cannot be excluded. PMID- 23361423 TI - A novel shielding scheme studied by the Monte Carlo method for electron beam radiotherapy. AB - Lead that has been employed widely for shielding in electron beam radiotherapy can produce bremsstrahlung photons during the shielding process. A novel shielding scheme with a two-layer structure has been studied using a Monte Carlo method in order to reduce this bremsstrahlung effect. Compared with the conventional lead, the novel shielding scheme, comprised of a Styrene-Ethylene Butylene-Styrene Block Co-polymer (SEBS) above and lead below, can efficiently reduce the generation of bremsstrahlung while providing better shielding for incident electrons. Therefore, this novel shielding scheme may play an important role in future applications. PMID- 23361424 TI - Joint analysis of three European nested case-control studies of lung cancer among radon exposed miners: exposure restricted to below 300 WLM. AB - Analyses of lung cancer risk were carried out using restrictions to nested case control data on uranium miners in the Czech Republic, France, and Germany. With the data restricted to cumulative exposures below 300 working-level-months (WLM) and adjustment for smoking status, the excess relative risk (ERR) per WLM was 0.0174 (95% CI: 0.009-0.035), compared to the estimate of 0.008 (95% CI: 0.004 0.014) using the unrestricted data. Analysis of both the restricted and unrestricted data showed that time since exposure windows had a major effect; the ERR/WLM was six times higher for more recent exposures (5-24 y) than for more distant exposures (25 y or more). Based on a linear model fitted to data on exposures <300 WLM, the ERR WLM of lung cancer at 30 y after exposure was estimated to be 0.021 (95% CI: 0.011-0.040), and the risks decreased by 47% per decade increase in time since exposure. The results from analyzing the joint effects of radon and smoking were consistent with a sub-multiplicative interaction; the ERR WLM was greater for non-smokers compared with current or ex smokers, although there was no statistically significant variation in the ERR WLM by smoking status. The patterns of risk with radon exposure from the combined European nested case-control miner analysis were generally consistent with those based on the BEIR VI Exposure-Age-Concentration model. Based on conversions from WLM to time weighted averaged radon concentration (expressed per 100 Bq m), the results from this analysis of miner data were in agreement with those from the joint analysis of the European residential radon studies. PMID- 23361425 TI - Radiofrequency exposure in Greek indoor environments. AB - This is the first measurement campaign that takes place in Greece in order to assess the exposure levels in different microenvironments (offices, bedrooms, living rooms, schools). Due to the exponential growth in the use of wireless network devices, the aim of this work was to perform indoor measurements with the use of personal dosimeters. The measurement period was 3 d in each of the 40 different locations that were selected, both in the urban and suburban area of Thessaloniki, the second largest city of Greece. The measurements took place from 23 July 2010 to 19 January 2012. After processing the obtained data with the robust regression on order statistics (ROS) method, various statistical exposure quantities were calculated. Compared to similar measurement campaigns across Europe, a larger proportion of measurement data above the detection limit for specific frequency bands (at most 56% for the DCS Rx frequency band) was found. Furthermore, mean exposure levels in the mobile downlink frequency bands were higher than those in other studies (GSM Rx: 0.259 V m, DCS Rx: 0.131 V m, UMTS Rx: 0.12 V m), yet many times below the ICNIRP guidelines. On the other hand, maximum exposures were found to be of the same magnitude (GSM Rx: 0.38 V m, DCS Rx: 0.3 V m, UMTS Rx: 0.28 V m). These measurement results indicate that signals from mobile base stations are dominant in workplaces and schools, whereas wireless phones and computer networks play the leading role in home environments. While the former reach their maximum values during daytime, the latter have an observable increase in the evening after work hours. PMID- 23361426 TI - Rapid measurement of 89,90Sr radioactivity in rinse water. AB - Rapid measurement of radioactivity from Sr in aqueous solutions is performed using a technique combining a strontium rad disk and a picobeta spectrometer. Identification of Sr radionuclides is accomplished in as little as 90 min in a radiation-tainted solution that contains more highly radioactive cesium. It is possible to perform triage by assessing skin exposure doses in this short time. This simple technique could be used in mobile laboratories. Sr having 1 Bq radioactivities are measured in 10 kBq Cs in aqueous solution. The radioactivity contained in rinse water used to decontaminate the feet of workers who stepped into highly contaminated water in the basement of the turbine building of Unit 3 at the Fukushima Daiichi nuclear power station was measured. The amount of Sr radioactivity in rinse water using the authors' rapid measurement technique (0.29 Bq mL) and a traditional method agree well, with 3.6% difference. Based on this agreement, this technique is confirmed to be useful for rapid measurement of Sr radioactivities. PMID- 23361427 TI - Accumulation, organ distribution, and excretion kinetics of 241Am in Mayak Production Association workers. AB - Americium-241 (241Am) is the second most significant radiation hazard after 239Pu at some of the Mayak Production Association facilities. This study summarizes current data on the accumulation, distribution, and excretion of americium compared with plutonium in different organs from former Mayak PA workers. Americium and plutonium were measured in autopsy and bioassay samples and correlated with the presence or absence of chronic disease and with biological transportability of the aerosols encountered at different workplaces. The relative accumulation of 241Am was found to be increasing in the workers over time. This is likely from 241Pu that increases with time in reprocessed fuel and from the increased concentrations of 241Am and 241Pu in inhaled alpha-active aerosols. While differences were observed in lung retention with exposures to different industrial compounds with different transportabilities (i.e., dioxide and nitrates), there were no significant differences in lung retention between americium and plutonium within each transportability group. In the non-pulmonary organs, the highest ratios of 241Am/241Am + SPu were observed in the skeleton. The relative ratios of americium in the skeleton versus liver were significantly greater than for plutonium. The relative amounts of americium and plutonium found in the skeleton compared with the liver were even greater in workers with documented chronic liver diseases. Excretion rates of 241Am in ''healthy'' workers were estimated using bioassay and autopsy data. The data suggest that impaired liver function leads to reduced hepatic 241Am retention, leading to increased 241Am excretion. PMID- 23361428 TI - Assessment of natural radioactivity and radiological hazards in building materials used in Yan'an, China. AB - The concentration of natural radionuclides in commonly used building materials collected from Yan'an, China, was determined using gamma ray spectroscopy with a NaI(Tl) detector. The activity concentration of 226Ra, 232Th, and 40K in the studied building materials ranges from 9.4-73.1, 11.5-86.9, and 258.9-1,055.1 Bq kg-1, respectively. The concentrations for these natural radionuclides were compared with the reported data of other countries and the world mean values for soil. The radium equivalent activity (Raeq), external hazard index (Hex), internal hazard index (Hin), indoor air absorbed dose rate, and annual effective dose rate due to natural radionuclides in samples were estimated to assess radiological hazards for people living in dwellings made of the studied building materials. The calculated Raeq values of all building materials (75.7-222.1 Bq kg 1) are lower than the limit of 370 Bq kg-1. The values of Hex and Hin are less than unity. The mean values of indoor air absorbed dose rates of all building materials (101.0 +/- 14.1-177.0 +/- 6.8 nGy h-1) are higher than the world population-weighted average of 84 nGy h-1, while the mean values of annual effective dose range from 0.50 +/- 0.07-0.87 +/- 0.03 mSv y-1, which are lower than the recommended limit of 1 mSv y-1. It is found that these materials may be used safely as construction materials and do not pose significant radiation hazards to inhabitants. PMID- 23361430 TI - Health Physics Society prospectus. PMID- 23361432 TI - Large balloon dilation for the treatment of recurrent bile duct stones prevents short-term recurrence in patients with previous endoscopic sphincterotomy. AB - BACKGROUND/PURPOSE: Our previous study revealed the efficacy and safety of the large balloon dilation (LBD) technique. However, there is insufficient objective data about the recurrence rate. The aim of this study was to compare the recurrence rate of common bile duct (CBD) stones between patients treated with and without LBD. METHODS: Patients with recurrent CBD stones treated between April 2006 and August 2010, and who had a history of endoscopic sphincterotomy (ES), were enrolled. Patients were excluded if they had a CBD diameter of less than 10 mm or if the diameter of their largest CBD stone was <10 mm. RESULTS: A total of 62 consecutive patients were investigated. From April 2006 to November 2007, 32 patients were treated without LBD (non-LBD group; historical control). From December 2007 to August 2010, 30 patients underwent LBD (LBD group). The median follow-up times in the LBD and non-LBD groups were 517 and 1034 days (p < 0.001), respectively. Kaplan-Meier analysis revealed a significantly lower incidence of recurrent CBD stones in the LBD group than in the non-LBD group (p = 0.048). CONCLUSIONS: LBD reduces the short-term recurrence of CBD stones in patients with previous ES. PMID- 23361433 TI - Matrix metalloproteinase inhibition protects CyPD knockout mice independently of RISK/mPTP signalling: a parallel pathway to protection. AB - The mitochondrial permeability transition pore (mPTP) is widely accepted as an end-effector mechanism of conditioning protection against injurious ischaemia/reperfusion. However, death can be initiated in cells without pre requisite mPTP opening, implicating alternate targets for ischaemia/reperfusion injury amelioration. Matrix metalloproteinases (MMP) are known to activate extrinsic apoptotic cascades and therefore we hypothesised that MMP activity represents an mPTP-independent target for augmented attenuation of ischaemia/reperfusion injury. In ex vivo and in vivo mouse hearts, we investigated whether the MMP inhibitor, ilomastat (0.25 MUmol/l), administered upon reperfusion could engender protection in the absence of cyclophilin-D (CyPD), a modulator of mPTP opening, against injurious ischaemia/reperfusion. Ilomastat attenuated infarct size in wild-type (WT) animals [37 +/- 2.8 to 22 +/- 4.3 %, equivalent to ischaemic postconditioning (iPostC), used as positive control, 27 +/- 2.1 %, p < 0.05]. Control CyPD knockout (KO) hearts had smaller infarcts than control WT (28 +/- 4.2 %) and iPostC failed to confer additional protection, yet ilomastat significantly attenuated infarct size in KO hearts (11 +/- 3.0 %, p < 0.001), and similar protection was also seen in isolated cardiomyocytes. Moreover, ilomastat, unlike the cyclophilin inhibitor cyclosporine-A, had no impact upon reactive oxygen species-mediated mPTP opening. While MMP inhibition was associated with increased Akt and ERK phosphorylation, neither Wortmannin nor PD98059 abrogated ilomastat-mediated protection. We demonstrate that MMP inhibition is cardioprotective, independent of Akt/ERK/CyPD/mPTP activity and is additive to the protection observed following inhibition of mPTP opening, indicative of a parallel pathway to protection in ischaemic/reperfused heart that may have clinical applicability in attenuating injury in acute coronary syndromes and deserve further investigation. PMID- 23361434 TI - Efficacy of herpes virus helicase-primase inhibitor, ASP2151, for treating herpes simplex keratitis in mouse model. AB - AIMS: To determine the efficacy of a new helicase-primase inhibitor, ASP2151, for treating herpetic keratitis. METHODS: Murine corneas were infected with herpes simplex virus type 1 (HSV-1). ASP2151 was administered orally or topically, and the severity of epithelial dendritic keratitis was determined. The effectiveness of ASP2151 was compared with that of acyclovir and valacyclovir. The reduction of the amount of HSV in tears, enucleated eyes and trigeminal ganglia was determined by real-time PCR or plaque assay. RESULTS: Orally administered ASP2151 reduced the epithelial keratitis score significantly more than that of the vehicle treated group (p<0.01). It also lowered the HSV-DNA levels in the tears significantly more than that by valacyclovir (p<0.01). ASP2151 ointment resulted in the same reduction of the keratitis score as acyclovir ointment, and lowered the HSV DNA in tears more than acyclovir ointment. Topical instillation of ASP2151 improved the herpetic dendritic keratitis score significantly and reduced the titre of HSV DNA in the tears in a dose-responsive way. CONCLUSIONS: ASP2151 had significantly better anti-HSV activity against herpes simplex keratitis than valacyclovir and acyclovir after systemic or topical use. These findings indicate that ASP2151 should be considered as an alternative treatment for herpes simplex keratitis. PMID- 23361435 TI - Investigation of the peptidoglycan sensing molecule, PGLYRP-2, in murine inflammatory uveitis. AB - BACKGROUND/AIM: Peptidoglycan (PGN) recognition proteins (PGLYRPs) are innate immune molecules that recognise bacterial cell wall PGN, and participate in several inflammatory diseases such as arthritis. We sought to elucidate the contribution of PGLYRPs in murine uveitis (intraocular inflammatory disease) elicited by PGN, and the extent to which systemically administered PGN alters uveitis compared with arthritis versus locally triggered ocular responses. METHODS: Mice deficient for PGLYRP-2, PGLYRP-3 or PGLYRP-4 were administered PGN by an intraperitoneal or intraocular injection. Arthritis was assessed by near infrared imaging and histopathology, while uveitis was measured by intravital videomicroscopy and histopathology. RESULTS: Systemic PGN exposure predisposed to arthritis through a PGLYRP-2 dependent mechanism. By contrast, systemic PGN exposure did not predispose to uveitis, and PGLYRP-2 deficiency had no impact on the development the uveitis. When PGN was administered locally, a robust uveitis ensued, which occurred independently of PGLYRP-2. Regardless of whether PGN was administered systemically or locally, neither PGLYRP-3 nor PGLYRP-4 deficiency significantly altered ocular inflammation compared with wild-type control animals. CONCLUSIONS: Our findings highlight the complexity of PGLYRPs and how PGLYRP-2 may use different molecular pathways in the joints versus eyes. Collectively, our results support a non-essential or redundant role for PGLYRPs 2, -3, -4 in uveitis. PMID- 23361436 TI - Osteoporosis among older Saudis: risk of fractures and unmet needs. AB - Using FRAX(r), this study aimed at estimating 10-years probability of osteoporosis (OP)-related fractures and identifies those in need of OP treatment among primary care attendees in Saudi Arabia. Of those aged >= 60 years, 14.4 and 18.4 % scored probabilities for major and hip fractures respectively suggesting OP treatment. Predictors for receiving OP screening included the presence of multiple clinical risk factors, occurrence of fragility fractures and physicians recommendation. PURPOSE: This study aimed at estimating the 10-years probability of osteoporosis (OP)-related fractures and identifying those in need of OP treatment among Saudi adults attending primary care centers (PHCs) in Al Hassa, Saudi Arabia, using FRAX(r) calculator and to determine factors possibly influence receiving of OP screening among them. SUBJECTS AND METHODS: A total of 1,251 Saudi aged >= 40 years, of both genders, were recruited from four urban and three rural randomly selected PHCs. All were subjected to anthropometric measurements followed by a personal interview with structured questionnaire to asses OP clinical risk factors (CRFs) and possible correlates for receiving OP screening. Ten-year probabilities for major osteoporotic and hip fractures were calculated using the Lebanese version of FRAX(r) calculator. RESULTS: Of participants aged >= 60 years, 14.4 and 18.4 % were identified with probability scores for major osteoporotic and hip fractures respectively, suggesting OP treatment. Out of sampled population, 16.1 % received OP screening. The presence of >=two OP CRFs (odds ratio OR = 4.45), being aware of OP (OR = 2.89), physician recommendation of OP screening (OR = 2.01), and history of fragility fracture (OR = 1.92) were all possible positive predictors for receiving OP screening. CONCLUSION: A sizable portion of the sampled older Saudis especially those aged >= 60 years are at high risk for OP-related fractures indicative to receive OP treatment. Occurrence of fragility fractures, multiplicity of CRFs and physician's recommendations are significant positive predictors to receive OP screening among them. PMID- 23361437 TI - Does insufficient access to dual-energy X-ray absorptiometry (DXA) stifle the provision of quality osteoporosis care in New Zealand? AB - Access to dual-energy X-ray absorptiometry (DXA) scanning varies significantly throughout New Zealand with the majority of scans funded privately or through the health industry. Barriers to access need to be addressed if osteoporosis guidelines are to be implemented across the country equitably, to reduce the incidence and cost of fragility fractures in New Zealand. PURPOSE: This study aims (1) to estimate the number of dual-energy X-ray absorptiometry scans performed in New Zealand, (2) to determine funding sources of DXA scans and (3) to determine the level of regional variation in access. METHODS: DXA scan providers in New Zealand were accessed through a nationwide database and asked to provide data on DXA scans performed in 2007. The numbers of DXA scans performed in each District Health Board (DHB) region were calculated by using a funding source and compared with DHB population estimates provided by Statistics New Zealand for 2007. RESULTS: In New Zealand in 2007, 33,104 DXA scans were performed, with a population rate of 78.1 DXA scans per annum per 10,000 general population, significantly less than international guidelines. There were important regional differences in access to DXA scanning. Funding for scans was predominately by private and pharmaceutical industry funders. DHBs funded only 31 % of DXA scans during this time period. CONCLUSIONS: Access to DXA scan technology varies significantly throughout New Zealand, with the majority of DXA scans funded by the private sector or health industry. Barriers to access need to be addressed if osteoporosis guidelines are to be implemented across the country in an equitable fashion and so reduce the incidence and cost of fragility fractures to New Zealand. PMID- 23361438 TI - Interval estimation of random effects in proportional hazards models with frailties. AB - Semi-parametric frailty models are widely used to analyze clustered survival data. In this article, we propose the use of the hierarchical likelihood interval for individual frailties. We study the relationship between hierarchical likelihood, empirical Bayesian, and fully Bayesian intervals for frailties. We show that our proposed interval can be interpreted as a frequentist confidence interval and Bayesian credible interval under a uniform prior. We also propose an adjustment of the proposed interval to avoid null intervals. Simulation studies show that the proposed interval preserves the nominal confidence level. The procedure is illustrated using data from a multicenter lung cancer clinical trial. PMID- 23361439 TI - Can we control the electronic energy transfer in molecular dyads through metal nanoparticles? A QM/continuum investigation. AB - Metal nanoparticles (MNPs) can have a dramatic effect on the electronic energy transfer (EET) between donor and acceptor molecular dyes. In addition, such an effect can be modulated by the presence of a solvent. Here we present a novel multiscale QM/continuum approach which can both treat MNP-solvent-mediated EET and take into account the effects of the MNPs in all the photophysical processes into play (absorption and emission), including the competitive energy transfer from the molecular systems to the metal. By applying such a unified theoretical framework, we show that the excitonic interactions in stacked dimers are generally reduced by the presence of MNPs. In contrast, for setups in which the two transferring moieties are separated by the MNPs, the presence of the metal results in a direct enhancement of the coupling but, when the competing process of quenching by the MNP is also considered, the final effect is almost invariably a reduction of the efficiency of the EET process. Only for particular donor-MNP acceptor setups, the model shows that waveguide-like behavior can be obtained, in these cases the excitation energy of the donor can be transferred to the acceptor over distances much longer than those allowed by the conventional Forster mechanism. PMID- 23361440 TI - European solvent industry group generic exposure scenario risk and exposure tool. AB - The European Solvents Industry Group (ESIG) Generic Exposure Scenario (GES) Risk and Exposure Tool (EGRET) was developed to facilitate the safety evaluation of consumer uses of solvents, as required by the European Union Registration, Evaluation and Authorization of Chemicals (REACH) Regulation. This exposure-based risk assessment tool provides estimates of both exposure and risk characterization ratios for consumer uses. It builds upon the consumer portion of the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) tool by implementing refinements described in ECETOC TR107. Technical enhancements included the use of additional data to refine scenario defaults and the ability to include additional parameters in exposure calculations. Scenarios were also added to cover all frequently encountered consumer uses of solvents. The TRA tool structure was modified to automatically determine conditions necessary for safe use. EGRET reports results using specific standard phrases in a format consistent with REACH exposure scenario guidance, in order that the outputs can be readily assimilated within safety data sheets and similar information technology systems. Evaluation of tool predictions for a range of commonly encountered consumer uses of solvents found it provides reasonable yet still conservative exposure estimates. PMID- 23361443 TI - Association of ozone and particulate air pollution with out-of-hospital cardiac arrest in Helsinki, Finland: evidence for two different etiologies. AB - Out-of-hospital cardiac arrest (OHCA) has been previously associated with exposure to particulate air pollution. However, there is uncertainty about the agents and mechanisms that are involved. We aimed to determine the association of gases and particulates with OHCA, and differences in pollutant effects on OHCAs due to acute myocardial infarction (AMI) vs those due to other causes. Helsinki Emergency Medical Services provided data on OHCAs of cardiac origin (OHCA_Cardiac). Hospital and autopsy reports determined whether OHCAs were due to AMI (OHCA_MI) or other cardiac causes (OHCA_Other). Pollutant data was obtained from central ambient monitors. A case-crossover analysis determined odds ratios (ORs) for hourly lagged exposures (Lag 0-3) and daily lagged exposures (Lag 0d 3d), expressed per interquartile range of pollutant level. For OHCA_Cardiac, elevated ORs were found for PM(2.5) (Lag 0, 1.07; 95% confidence interval (CI): 1.01-1.13) and ozone (O(3)) (Lag 2d, 1.18; CI: 1.03-1.35). For OHCA_MI, elevated ORs were found for PM(2.5) (Lag 0, 1.14; CI: 1.03-1.27; Lag 0d, 1.17; CI: 1.03 1.33), accumulation mode particulate (Acc) (Lag 0d, 1.19; CI: 1.04-1.35), NO (Lag 0d, 1.07; CI: 1.01-1.13), and ultrafine particulate (Lag 0d, 1.27; CI: 1.05 1.54). For OHCA_Other, elevated ORs were found only for O(3) (Lag 1d, 1.26; CI: 1.07-1.48; Lag 2d, 1.30; CI: 1.11-1.53). Results from two-pollutant models, with one of the pollutants either PM(2.5) or O(3), suggested that associations were primarily due to effects of PM(2.5) and O(3), rather than other pollutants. The results suggest that air pollution triggers OHCA via two distinct modes: one associated with particulates leading to AMI and one associated with O(3) involving etiologies other than AMI, for example, arrhythmias or respiratory insufficiency. PMID- 23361442 TI - Intra-urban spatial variability in wintertime street-level concentrations of multiple combustion-related air pollutants: the New York City Community Air Survey (NYCCAS). AB - Although intra-urban air pollution differs by season, few monitoring networks provide adequate geographic density and year-round coverage to fully characterize seasonal patterns. Here, we report winter intra-urban monitoring and land-use regression (LUR) results from the New York City Community Air Survey (NYCCAS). Two-week integrated samples of fine particles (PM(2.5)), black carbon (BC), nitrogen oxides (NO(x)) and sulfur dioxide (SO(2)) were collected at 155 city wide street-level locations during winter 2008-2009. Sites were selected using stratified random sampling, randomized across sampling sessions to minimize spatio-temporal confounding. LUR was used to identify GIS-based source indicators associated with higher concentrations. Prediction surfaces were produced using kriging with external drift. Each pollutant varied twofold or more across sites, with higher concentrations near midtown Manhattan. All pollutants were positively correlated, particularly PM(2.5) and BC (Spearman's r=0.84). Density of oil burning boilers, total and truck traffic density, and temporality explained 84% of PM(2.5) variation. Densities of total traffic, truck traffic, oil-burning boilers and industrial space, with temporality, explained 65% of BC variation. Temporality, built space, bus route location, and traffic density described 67% of nitrogen dioxide variation. Residual oil-burning units, nighttime population and temporality explained 77% of SO(2) variation. Spatial variation in combustion related pollutants in New York City was strongly associated with oil-burning and traffic density. Chronic exposure disparities and unique local sources can be identified through year-round saturation monitoring. PMID- 23361441 TI - The impact of drinking water, indoor dust and paint on blood lead levels of children aged 1-5 years in Montreal (Quebec, Canada). AB - Lead is neurotoxic at very low dose and there is a need to better characterize the impact of domestic sources of lead on the biological exposure of young children. A cross-sectional survey evaluated the contribution of drinking water, house dust and paint to blood lead levels (BLLs) of young children living in old boroughs of Montreal (Canada). Three hundred and six children aged 1 to 5 years and currently drinking tap water participated in the study. For each participant, residential lead was measured in kitchen tap water, floor dust, windowsill dust and house paint and a venous blood sample was analyzed. Multivariate logistic regression was used to evaluate the association between elevated BLL in the children (>= 75th percentile) and indoor lead contamination by means of odds ratios (OR) using 95% confidence intervals (CI). There was an association between BLL >=75th percentile (1.78 MUg/dL) and water lead when the mean water concentration was >3.3 MUg/L: adjusted OR=4.7 (95% CI: 2.1-10.2). Windowsill dust loading >14.1 MUg/ft(2) was also associated with BLL >=1.78 MUg/dL: adjusted OR=3.2 (95% CI: 1.3-7.8). Despite relatively low BLLs, tap water and house dust lead contribute to an increase of BLLs in exposed young children. PMID- 23361444 TI - Synthesis of 2,4-unsubstituted quinoline-3-carboxylic acid ethyl esters from arylmethyl azides via a domino process. AB - A convenient synthesis of 2,4-unsubstituted quinoline-3-carboxylic acid ethyl esters via a domino process is described. The synthesis employs arylmethyl azides as the precursor which undergoes an acid-promoted rearrangement to give an N-aryl iminium ion. Following the addition with ethyl 3-ethoxyacrylate, intramolecular electrophilic aromatic substitution, elimination and subsequent oxidation, the quinoline products were obtained in moderate to excellent yields. PMID- 23361446 TI - The Tolman electronic parameter (TEP) and the metal-metal electronic communication in ditopic NHC complexes. AB - Whereas the electronic communication between metals in dimetallic organometallic compounds is often assessed through cyclic voltammetric measurements, we have found that the variations in the Tolman electronic parameter (TEP) can also be an alternative and effective way of determining this type of interaction. The TEP values of several (CO)3Ni-NHC-X systems with five different ditopic NHC ligand systems [triazolyldiylidene (A), bis(imidazolylidene) (B), benzobis(imidazolylidene) (C), cyclopenta[f,g]acenaphthylenebis(imidazolylidene) (D) and bis(imidazolidinylidene) (F)] were determined by means of DFT calculations. Based on these values, the electron-withdrawing character of the X metal fragments employed in this study was found to increase in the order IrCp(CO) -> RhCl(COD) -> Ni(CO)3 -> Cr(CO)5 -> RhCl(CO)2. We found that the degree of electronic interaction through the ditopic NHC ligands is the strongest in A, followed by B and F, while being weak in B and C. The TEP values and the quantitative analysis of the upper molecular orbitals of A and F and their (CO)3Ni-NHC-Ni(CO)3 complexes strongly suggest that the principal electronic interaction between the metal centres of the M-NHC-M' complexes is of sigma-type, via the delocalized HOMO and HOMO - 1 orbitals of the NHC ligands. PMID- 23361445 TI - The use of a fully integrated electronic medical record to minimize cumulative lifetime radiation exposure from CT scanning to detect urinary tract calculi. AB - In order to determine the effects of implementation of an electronic medical record on rates of repeat computed tomography (CT) scanning in the emergency department (ED) setting, we analyzed the utilization of CT of the kidneys, ureters, and bladder (CT KUB) for the detection of urinary tract calculi for periods before and after the implementation of a hospital-wide electronic medical record system. Rates of repeat CT scanning within a 6-month period of previous scan were determined pre- and post-implementation and compared. Prior to implementation, there was a 6-month repeat rate of 6.2 % compared with the post implementation period, which was associated with a 6-month repeat rate of 4.1 %. Statistical analysis using a two-sample, one-tailed t test for difference of means was associated with a p value of 0.00007. This indicates that the implementation of the electronic medical record system was associated with a 34 % decrease in 6-month repeat CT KUB scans. We conclude that the use of an electronic medical record can be associated with a decrease in utilization of unnecessary repeat CT imaging, leading to decreased cumulative lifetime risk for cancer in these patients and more efficient utilization of ED and radiologic resources. PMID- 23361447 TI - The progression risk factors of children with transfusion-independent non-severe aplastic anemia. AB - Non-severe aplastic anemia (NSAA) in children is a rare, idiopathic condition of bone marrow insufficiency that can resolve spontaneously, persist for months or years, or progress to severe aplastic anemia (SAA). We reviewed clinical and laboratory data of patients diagnosed with transfusion-independent non-severe aplastic anemia (NSAA) from 1996 to 2009 at the Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College, and analyzed the clinical course and outcomes in these patients. NSAA was defined as bone marrow cellularity <50 % and two or three cytopenias that persisted for 6 weeks or more: absolute neutrophil count (ANC) <1.5 * 10(9)/L, absolute reticulocyte count (ARC) <40 * 10(9)/L, platelet count <100 * 10(9)/L, without meeting criteria for SAA (bone marrow cellularity <30 % and two or three cytopenias: ANC <0.5 * 10(9)/L, ARC <20 * 10(9)/L, platelet count <20 * 10(9)/L). All patients were treated with reasonable supportive care, cyclosporine A, and stanozolol (0.1 mg/kg/day). Of a total of 284 patients, 117 (41.2 %) were female, and 167 (58.8 %) were male. With a median follow-up of 43 months (range 2-196 months), 38 patients (13.4 %) progressed to transfusion-dependent NSAA and among them 26 patients (9.2 %) progressed to SAA. One hundred and ninety-eight patients (69.7 %) had persistent NSAA. Forty-eight patients (16.9 %) showed the complete resolution of NSAA. The Kaplan-Meier estimates of all patients for progression-free survival were 86 +/- 2.7 % and 66 +/- 7.3 % at 60 and 120 months after diagnosis, respectively. Patients with ANC <1.0 * 10(9)/L or female had a higher probability of progression to transfusion-dependent NSAA (18.5 vs. 5.4 %, respectively; p = 0.002, and 17.1 vs. 10.8 %, respectively; p = 0.022). The patients with ARC <60 * 10(9)/L or with ANC <1.0 * 10(9)/L had a higher probability of progression to SAA (11.5 vs. 3.6 %, respectively; p = 0.035, and 12.7 vs. 3.6 %, respectively; p = 0.011). A categorical risk factor analysis showed that patients with ANC <1 * 10(9)/L had a higher probability of progression to SAA (p = 0.03) and had a higher probability of progression to transfusion-dependent AA (p = 0.007). NSAA patients may be benefited from early intervention with cyclosporine A and stanozolol. PMID- 23361448 TI - [Epithelial dystrophies and degenerations of the cornea]. PMID- 23361449 TI - [Sterile keratitis]. PMID- 23361450 TI - [Intravitreal application of drugs 2013]. PMID- 23361451 TI - Availability of heavy metals (Cd, Pb, And Cr) in agriculture from commercial fertilizers. AB - The purpose of this study was to investigate the availability of the heavy metals cadmium (Cd), lead (Pb), and chromium (Cr) to soil and maize plants fertilized with different sources and doses of zinc (Zn) in a Rhodic Eutrudox soil. For that purpose, concentrations of Cd, Pb, and Cr were evaluated in leaf tissue and grains of maize plants and in 0-20 and 20-40 cm soil layers after fertilization with four doses of Zn from eight different sources of fertilizer. There was no accumulation of Cd, Pb, and Cr in maize grain and Cd and Cr in leaf tissue of the plants; nevertheless, there was accumulation of Pb in leaf tissue, showing its availability throughout different sources of Zn and consequent uptake by plants. Regarding the soil, it was observed that fertilizer from the different sources made Cd, Pb, and Cr available at increasing amounts proportional to increased Zn doses. Under experimental conditions, fertilization with Zn increased concentrations of heavy metals Cd, Pb and Cr in soil, further highlighting the importance of conducting more studies related to the application of mineral fertilizers for micronutrient supply and the availability of heavy metals. PMID- 23361452 TI - Phenothiazine as an aromatic capping group to construct a short peptide-based 'super gelator'. AB - We report a 'super-gelator' of a short peptide capped with phenothiazine acetic acid. PMID- 23361453 TI - [Male circumcision is not associated with an increased prevalence of erectile dysfunction: results of the Cottbus 10,000-men survey]. AB - BACKGROUND: There are conflicting data regarding the significance of the presence of the male prepuce or circumcision on erectile function and sexual satisfaction in men. MATERIALS AND METHODS: A total of 10,000 men selected according to the age distribution of the city of Cottbus (Brandenburg, Germany) were provided with a questionnaire comprised of 35 items integrating the International Index of Erectile Function (IIEF-6) and further questions on sexual quality of life, comorbidities and previous surgical treatment. Of the men who completed the questionnaire 2,499 were living in a partnership and formed the study group for this survey. Based on the IIEF-6, two study endpoints (SEP) were defined (point values <= 25/SEP1 and <= 21/SEP2). By multivariable logistic regression analysis the independent influence of previous circumcision on both endpoints was assessed. Furthermore, a correlation between sexual satisfaction of men and circumcision was also analyzed. RESULTS: Of the study group167 men had undergone circumcision (6.7 %). Erectile dysfunction (ED) was present in 40.1 % of men based on SEP1 (minor to severe ED) and in 27.8 % based on SEP2 (moderate to severe ED). Based on SEP1 as well as SEP2 age, history of smoking, hypertension, diabetes, chronic ischemic heart disease, peripheral arterial obstructive disease, cirrhosis of the liver and history of pelvic surgery were found to have an independent influence on the presence of ED. A status after circumcision did not show an independent influence on either study endpoints (SEP1: OR 1.36, p=0.174; SEP2: OR 1.42, p=0.175). Furthermore, there was no significant correlation between sexual satisfaction of men and a history of circumcision. CONCLUSIONS: Based on the present study which represents the largest survey worldwide on male ED using the IIEF as a validated instrument, it could not be confirmed that the prevalence of ED is increased in men following circumcision. Sexual satisfaction of men in this study was independent of the presence of the prepuce. PMID- 23361454 TI - Enhanced selectivity of CO(2) over CH(4) in sulphonate-, carboxylate- and iodo functionalized UiO-66 frameworks. AB - Three new functionalized UiO-66-X (X = -SO(3)H, 1; -CO(2)H, 2; -I; 3) frameworks incorporating BDC-X (BDC: 1,4-benzenedicarboxylate) linkers have been synthesized by a solvothermal method using conventional electric heating. The as-synthesized (AS) as well as the thermally activated compounds were characterized by X-ray powder diffraction (XRPD), diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, thermogravimetric (TG), and elemental analysis. The occluded H(2)BDC-X molecules can be removed by exchange with polar solvent molecules followed by thermal treatment under vacuum leading to the empty-pore forms of the title compounds. Thermogravimetric analysis (TGA) and temperature-dependent XRPD (TDXRPD) experiments indicate that 1, 2 and 3 are stable up to 260, 340 and 360 degrees C, respectively. The compounds maintain their structural integrity in water, acetic acid and 1 M HCl, as verified by XRPD analysis of the samples recovered after suspending them in the respective liquids. As confirmed by N(2), CO(2) and CH(4) sorption analyses, all of the thermally activated compounds exhibit significant microporosity (S(Langmuir): 769-842 m(2) g(-1)), which are comparable to that of the parent UiO-66 compound. Compared to the unfunctionalized UiO-66 compound, all the three functionalized solids possess higher ideal selectivity in adsorption of CO(2) over CH(4) at 33 degrees C. PMID- 23361455 TI - A novel enzyme-catalyzed synthesis of N-substituted pyrrole derivatives. AB - A novel method for the synthesis of substituted pyrroles catalyzed by alpha amylase from hog pancreas via Paal-Knorr reaction was developed. A series of pyrrole derivatives were synthesized under mild conditions and the products were obtained with good to excellent yields (60-99 %). The impact of factors, such as solvents, enzyme amount, and temperature, on the reaction were investigated. This study reports an efficient route for the synthesis of N-substituted pyrrole derivatives. PMID- 23361456 TI - Efficacy of combined metformin-letrozole in comparison with bilateral ovarian drilling in clomiphene-resistant infertile women with polycystic ovarian syndrome. AB - OBJECTIVES: To compare the hormonal-metabolic profiles and reproductive outcomes between women receiving metformin plus letrozole and women undergoing bilateral ovarian drilling in clomiphene citrate (CC)-resistant women with polycystic ovary syndrome (PCOS). METHODS: In this randomized study, 146 patients were randomly allocated into group 1 (n = 73) who received metformin plus letrozole, and group 2 (n = 73) who underwent bilateral ovarian drilling. Comparison was done between the basal and after treatment biochemical values for each group, in addition reproductive outcomes after treatment were compared between both groups. RESULTS: There was significant reduction in testosterone (p <= 0.001), fasting insulin (p <= 0.001), and fasting glucose/fasting insulin ratio (p = 0.029) in metformin plus letrozole group, while there was significant reduction in FSH, LH and LH/FSH ratio in bilateral drilling group (p <= 0.001, 0.001 and 0.001). No significant difference in cycle regularity (p = 0.82), ovulation (p = 0.24), pregnancy rate (p = 0.32) and abortion rate (p = 0.51) between both groups. CONCLUSION: Both metformin plus letrozole and bilateral ovarian drilling are similarly effective as second-line strategies for the treatment of women with PCOS who do not conceive with CC. PMID- 23361457 TI - Evaluation of HE4 as an extrabiomarker to CA125 to improve detection of ovarian carcinoma: is it time for a step forward? AB - PURPOSE: To evaluate human epididymis protein 4 (HE4) as an extrabiomarker to cancer antigen 125 (CA125) to improve the detection of ovarian carcinoma. METHODS: Sixty patients with ovarian carcinoma, 50 patients with benign ovarian tumors and 30 healthy women were included in the present study. Serum concentration of HE4 was assayed using ELISA technique, while CA125 was assayed using chemiluminescent enzyme immunoassay. RESULTS: The median CA125 and HE4 serum values were significantly higher among ovarian cancer patients when compared with healthy control However, the median serum levels of CA125 but not HE4 were significantly higher among patients with benign ovarian tumors as compared to healthy women. Based on the receiver operator characteristics curve analysis, HE4 had higher sensitivities than CA125 for the detection of ovarian cancer at 90, 95 and 98 % specificities and the combination of both markers yielded a higher sensitivity than either alone. However, CA125 but not HE4 had higher sensitivities for the detection of benign ovarian tumors at the same specificities. In addition, a positive correlation was observed between HE4 and CA125 among patients with ovarian carcinoma. CONCLUSION: HE4 is a valuable marker for ovarian cancer diagnosis and when combined with CA125, they had a higher sensitivity at a set specificity, thus providing a more accurate predictor of ovarian cancer than either alone. PMID- 23361458 TI - Fetal growth restriction and maternal smoking in the Macedonian Roma population: a causality dilemma. AB - PURPOSE: Macedonia is one of the top five countries globally in reported smoking rates. Over 10 % of the population consists of the underprivileged Roma minority. We aimed to determine whether Roma ethnicity is an independent risk factor for adverse pregnancy outcome or merely mediating maternal smoking. METHODS: Maternal data were retrieved from the perinatal computerized database for all deliveries during 2007-2011 at the only Clinical Hospital in Bitola, Macedonia. Multivariable regression models were constructed to control for confounders. RESULTS: Of nearly 7,000 deliveries, 8.65 % were of maternal Roma ethnicity and 40 % of the Romani women admitted to regularly smoke during pregnancy. Both Roma ethnicity and maternal smoking were significantly associated with the absence of maternal education, history of abortions and intra uterine growth restriction (IUGR) in the univariate analysis. Both maternal Roma ethnicity (OR 2.46, 95 % CI 1.79-3.38) and smoking status (OR 1.37, 95 % CI 1.02-1.85) were found to be independent predictors of IUGR using the multivariate analysis. Lower birthweight and smaller head circumference were both independently associated with Roma ethnicity and smoking. CONCLUSIONS: Underprivileged ethnic background is a significant risk factor for IUGR, independent of maternal smoking status. To the best of our knowledge, this is the first publication focusing on pregnancy outcome in Romani Macedonian parturients. PMID- 23361459 TI - HRTEM and STEM-HAADF characterisation of Au-TiO2 and Au-Al2O3 catalysts for a better understanding of the parameters influencing their properties in CO oxidation. AB - Gold catalysts supported on titania (Au-TiO(2)) and alumina (Au-Al(2)O(3)) were prepared by deposition-precipitation with urea and then activated before characterisation and reaction in CO oxidation, either by calcination in air at 500 degrees C or reduction under H(2) at 300 degrees C. Gold nanoparticles with average size in the range 2-4 nm were obtained, with calcination leading to larger gold nanoparticles than reduction. For Au-TiO(2), high activity was observed in CO oxidation at room temperature, independent of the activation treatment. This high activity could not be correlated to the presence of sub nanometer gold clusters as reported in the literature, since they could not be detected by atomic-resolution high-angle annular dark-field scanning-transmission electron microscopy (HAADF-STEM). In the case of Au-Al(2)O(3), the performance in CO oxidation was found to strongly depend on the water content in the reaction gas feed and on the activation conditions, with calcination resulting in a poorly active catalyst whereas reduction gave activity of the same order as Au-TiO(2). A comparative study of Au-TiO(2) and Au-Al(2)O(3) by electron microscopy did not reveal distinct differences in the shapes of the Au nanoparticles, which are mostly flattened through interaction with the substrate in both samples, with side profile shapes varying from rounded hemispherical to well faceted truncated cubo-octahedra. More faceting is found for the samples calcined at 500 degrees C than reduced at 300 degrees C. Various possible parameters affecting the catalytic properties of gold in CO oxidation are discussed in the context of the relevant literature. PMID- 23361460 TI - Mini-chromosome maintenance complexes form a filament to remodel DNA structure and topology. AB - Deregulation of mini-chromosome maintenance (MCM) proteins is associated with genomic instability and cancer. MCM complexes are recruited to replication origins for genome duplication. Paradoxically, MCM proteins are in excess than the number of origins and are associated with chromatin regions away from the origins during G1 and S phases. Here, we report an unusually wide left-handed filament structure for an archaeal MCM, as determined by X-ray and electron microscopy. The crystal structure reveals that an alpha-helix bundle formed between two neighboring subunits plays a critical role in filament formation. The filament has a remarkably strong electro-positive surface spiraling along the inner filament channel for DNA binding. We show that this MCM filament binding to DNA causes dramatic DNA topology change. This newly identified function of MCM to change DNA topology may imply a wider functional role for MCM in DNA metabolisms beyond helicase function. Finally, using yeast genetics, we show that the inter subunit interactions, important for MCM filament formation, play a role for cell growth and survival. PMID- 23361461 TI - TDP1 is an HMG chromatin protein facilitating RNA polymerase I transcription in African trypanosomes. AB - Unusually for a eukaryote, Trypanosoma brucei transcribes its variant surface glycoprotein (VSG) gene expression sites (ESs) in a monoallelic fashion using RNA polymerase I (Pol I). It is still unclear how ES transcription is controlled in T. brucei. Here, we show that the TDP1 architectural chromatin protein is an essential high mobility group box (HMGB) protein facilitating Pol I transcription in T. brucei. TDP1 is specifically enriched at the active compared with silent VSG ES and immediately downstream of ribosomal DNA promoters and is abundant in the nucleolus and the expression site body subnuclear compartments. Distribution of TDP1 at Pol I-transcribed loci is inversely correlated with histones. Depletion of TDP1 results in up to 40-90% reduction in VSG and rRNA transcripts and a concomitant increase in histones H3, H2A and H1 at these Pol I transcription units. TDP1 shares features with the Saccharomyces cerevisiae HMGB protein Hmo1, but it is the first architectural chromatin protein facilitating Pol I-mediated transcription of both protein coding genes as well as rRNA. These results show that TDP1 has a mutually exclusive relationship with histones on actively transcribed Pol I transcription units, providing insight into how Pol I transcription is controlled. PMID- 23361462 TI - Structural insights into RISC assembly facilitated by dsRNA-binding domains of human RNA helicase A (DHX9). AB - Intensive research interest has focused on small RNA-processing machinery and the RNA-induced silencing complex (RISC), key cellular machines in RNAi pathways. However, the structural mechanism regarding RISC assembly, the primary step linking small RNA processing and RNA-mediated gene silencing, is largely unknown. Human RNA helicase A (DHX9) was reported to function as an RISC-loading factor, and such function is mediated mainly by its dsRNA-binding domains (dsRBDs). Here, we report the crystal structures of human RNA helicase A (RHA) dsRBD1 and dsRBD2 domains in complex with dsRNAs, respectively. Structural analysis not only reveals higher siRNA duplex-binding affinity displayed by dsRBD1, but also identifies a crystallographic dsRBD1 pair of physiological significance in cooperatively recognizing dsRNAs. Structural observations are further validated by isothermal titration calorimetric (ITC) assay. Moreover, co immunoprecipitation (co-IP) assay coupled with mutagenesis demonstrated that both dsRBDs are required for RISC association, and such association is mediated by dsRNA. Hence, our structural and functional efforts have revealed a potential working model for siRNA recognition by RHA tandem dsRBDs, and together they provide direct structural insights into RISC assembly facilitated by RHA. PMID- 23361463 TI - Cation-dependent folding of 3' cap-independent translation elements facilitates interaction of a 17-nucleotide conserved sequence with eIF4G. AB - The 3'-untranslated regions of many plant viral RNAs contain cap-independent translation elements (CITEs) that drive translation initiation at the 5'-end of the mRNA. The barley yellow dwarf virus-like CITE (BTE) stimulates translation by binding the eIF4G subunit of translation initiation factor eIF4F with high affinity. To understand this interaction, we characterized the dynamic structural properties of the BTE, mapped the eIF4G-binding sites on the BTE and identified a region of eIF4G that is crucial for BTE binding. BTE folding involves cooperative uptake of magnesium ions and is driven primarily by charge neutralization. Footprinting experiments revealed that functional eIF4G fragments protect the highly conserved stem-loop I and a downstream bulge. The BTE forms a functional structure in the absence of protein, and the loop that base pairs the 5' untranslated region (5'-UTR) remains solvent-accessible at high eIF4G concentrations. The region in eIF4G between the eIF4E-binding site and the MIF4G region is required for BTE binding and translation. The data support the model in which the eIF4F complex binds directly to the BTE which base pairs simultaneously to the 5'-UTR, allowing eIF4F to recruit the 40S ribosomal subunit to the 5'-end. PMID- 23361464 TI - Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences. AB - The heterogeneous collection of nucleosome remodelling and deacetylation (NuRD) complexes can be grouped into the MBD2- or MBD3-containing complexes MBD2-NuRD and MBD3-NuRD. MBD2 is known to bind to methylated CpG sequences in vitro in contrast to MBD3. Although functional differences have been described, a direct comparison of MBD2 and MBD3 in respect to genome-wide binding and function has been lacking. Here, we show that MBD2-NuRD, in contrast to MBD3-NuRD, converts open chromatin with euchromatic histone modifications into tightly compacted chromatin with repressive histone marks. Genome-wide, a strong enrichment for MBD2 at methylated CpG sequences is found, whereas CpGs bound by MBD3 are devoid of methylation. MBD2-bound genes are generally lower expressed as compared with MBD3-bound genes. When depleting cells for MBD2, the MBD2-bound genes increase their activity, whereas MBD2 plus MBD3-bound genes reduce their activity. Most strikingly, MBD3 is enriched at active promoters, whereas MBD2 is bound at methylated promoters and enriched at exon sequences of active genes. PMID- 23361465 TI - Epigenetic diversity of Kaposi's sarcoma-associated herpesvirus. AB - Spontaneous lytic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) occurs at a low rate in latently infected cells in disease and culture. This suggests imperfect epigenetic maintenance of viral transcription programs, perhaps due to variability in chromatin structure at specific loci across the population of KSHV episomal genomes. To characterize this locus-specific chromatin structural diversity, we used MAPit single-molecule footprinting, which simultaneously maps endogenous CG methylation and accessibility to M.CviPI at GC sites. Diverse chromatin structures were detected at the LANA, RTA and vIL6 promoters. At each locus, chromatin ranged from fully closed to fully open across the population. This diversity has not previously been reported in a virus. Phorbol ester and RTA transgene induction were used to identify chromatin conformations associated with reactivation of lytic transcription, which only a fraction of episomes had. Moreover, certain chromatin conformations correlated with CG methylation patterns at the RTA and vIL6 promoters. This indicated that some of the diverse chromatin conformations at these loci were epigenetically distinct. Finally, by comparing chromatin structures from a cell line infected with constitutively latent virus, we identified products of lytic replication. Our findings show that epigenetic drift can restrict viral propagation by chromatin compaction at latent and lytic promoters. PMID- 23361467 TI - Efficient self-assembly of DNA-functionalized fluorophores and gold nanoparticles with DNA functionalized silicon surfaces: the effect of oligomer spacers. AB - Although strategies for the immobilization of DNA oligonucleotides onto surfaces for bioanalytical and top-down bio-inspired nanobiofabrication approaches are well developed, the effect of introducing spacer molecules between the surface and the DNA oligonucleotide for the hybridization of nanoparticle-DNA conjugates has not been previously assessed in a quantitative manner. The hybridization efficiency of DNA oligonucleotides end-labelled with gold nanoparticles (1.4 or 10 nm diameter) with DNA sequences conjugated to silicon surfaces via hexaethylene glycol phosphate diester oligomer spacers (0, 1, 2, 6 oligomers) was found to be independent of spacer length. To quantify both the density of DNA strands attached to the surfaces and hybridization with the surface-attached DNA, new methodologies have been developed. Firstly, a simple approach based on fluorescence has been developed for determination of the immobilization density of DNA oligonucleotides. Secondly, an approach using mass spectrometry has been created to establish (i) the mean number of DNA oligonucleotides attached to the gold nanoparticles and (ii) the hybridization density of nanoparticle oligonucleotide conjugates with the silicon surface-attached complementary sequence. These methods and results will be useful for application with nanosensors, the self-assembly of nanoelectronic devices and the attachment of nanoparticles to biomolecules for single-molecule biophysical studies. PMID- 23361466 TI - Characterization of MicA interactions suggests a potential novel means of gene regulation by small non-coding RNAs. AB - MicA is a small non-coding RNA that regulates ompA mRNA translation in Escherichia coli. MicA has an inhibitory function, base pairing to the translation initiation region of target mRNAs through short sequences of complementarity, blocking their ribosome-binding sites. The MicA structure contains two stem loops, which impede its interaction with target mRNAs, and it is thought that the RNA chaperone protein Hfq, known to be involved in MicA regulation of ompA, may structurally remodel MicA to reveal the ompA-binding site for cognate pairing. To further characterize these interactions, we undertook biochemical and biophysical studies using native MicA and a 'stabilized' version, modified to mimic the conformational state of MicA where the ompA-binding site is exposed. Our data corroborate two proposed roles for Hfq: first, to bring both MicA and ompA into close proximity, and second, to restructure MicA to allow exposure of the ompA-binding site for pairing, thereby demonstrating the RNA chaperone function of Hfq. Additionally, at accumulated MicA levels, we identified a Mg(2+)-dependent self-association that occludes the ompA-recognition region. We discuss the potential contribution of an Mg(2+)-mediated conformational switch of MicA for the regulation of MicA function. PMID- 23361468 TI - Efficacy of ultrasound-guided transversus abdominis plane block after laparoscopic bariatric surgery: a double blind, randomized, controlled study. AB - BACKGROUND: The efficacy of ultrasound-guided transversus abdominis plane (USG TAP) block as a part of multimodal analgesia was evaluated in morbidly obese patients undergoing laparoscopic bariatric surgery. METHODS: We studied 100 patients with body mass index > 35 kg/m2. They were randomly allocated to study (USG-TAP) and control groups. Pain scores at rest and on movement at various time points up to 24 postoperative hours were compared. Other parameters evaluated were patients requiring Tramazac hydrochloride (TMZ) as rescue analgesic, sedation score, time to ambulate, any adverse events, and patient satisfaction. RESULTS: The median visual analogue scale pain score of the study (USG-TAP) group was consistently lower at 1, 3, 6, 12, and 24 h at rest and on movement, in the postoperative period. Number of patients requiring TMZ required in the first, third, and sixth hour was significantly lower in the USG-TAP group. The prolonged sedative effect of the TMZ affected the time to ambulate. Patients in the control group remained more sedated. Four patients in the control group required BIPAP support postoperatively; no adverse event was observed. Time to ambulate was 6.3 +/- 1.8 h in USG-TAP and 8 +/- 1.8 h in control groups; P < 0.001. Patient satisfaction scores were significantly higher in the USG-TAP group; P < 0.001. CONCLUSIONS: Our study demonstrates that the USG-TAP as part of multimodal analgesic technique in morbidly obese patients undergoing laparoscopic gastric bypass reduces opioid requirement, improves pain score, decreases sedation, promotes early ambulation, and has greater patient satisfaction. PMID- 23361469 TI - ProSealTM LMA increases safe apnea period in morbidly obese patients undergoing surgery under general anesthesia. AB - BACKGROUND: Morbidly obese patients are at risk of hypoxemia at the time of induction of anesthesia. The aim of this study was to assess the possible increase in the safe apnea time with the use of ProSeal laryngeal mask airway (PLMA) as a conduit prior to laryngoscope-guided intubation in morbidly obese patients undergoing surgery under general anesthesia. METHODS: Hundred patients with BMI greater than 35 kg/m2, undergoing surgery under general anesthesia, were randomly divided to receive either PLMA or facemask with oropharyngeal airway (FM) as the airway device. Following preoxygenation with 100% oxygen with continuous positive airway pressure of 10 cm H2O, in ramp position for 5 min the patients were made apneic. From start of apnea to the time to reach SpO2 to 92% was recorded as safe apnea time. Ventilation was initiated and time to reach SpO2 of 100% was recorded as recovery time. RESULTS: The mean safe apnea time was 205 (96-320)s in FM vs. 337 (176-456) s in PLMA (P = 0.0000). The mean recovery period was 49 (36-68)s in FM vs. 42(30-56)s in PLMA groups (P = 0.0000). Arterial blood gas analysis showed significant difference in pO2 between the two groups. CONCLUSION: The use of ProSeal laryngeal mask airway prior to laryngoscope-guided intubation is beneficial in increasing safe apnea period and achieving faster recovery from hypoxemia in morbidly obese patients. PMID- 23361470 TI - Landlords' experiences of housing tenants suffering from severe mental illness: a Swedish empirical study. AB - The aim of this Swedish study was to describe landlords' experiences of having tenants suffering from severe mental illness. Sixteen landlords working in private and public housing agencies participated in open in-depth interviews. Data were subjected to a thematic latent content analysis. The results showed that having tenants with severe mental illness entails being confronted with various difficult circumstances, ranging from mismanagement of apartments to sensitivity among neighbours as well as issues regarding provocative behaviour. It involved providing assistance that was far beyond their professional obligations and to be neglected by the community-based psychiatric service system when in need of help. In order to support landlords and to prevent evictions of individuals with severe mental illness, community-based psychiatric services need to be more pro-active in their attempts to achieve collaboration with the parties at hand. PMID- 23361471 TI - Biological safety studies of gemifloxacin mesylate and related substances. AB - PURPOSE: The aim of this study was to evaluate the cytotoxic, phototoxic, genotoxic and photogenotoxic potential of gemifloxacin mesylate (GFM), its main synthetic impurity (SI) and one isolated and structurally elucidated degradation product (DP). METHODS: The neutral red uptake (NRU) and reduction of 2,5-diphenyl 3,-(4,5-dimethyl-2-thiazolyl)tetrazolium bromide (MTT) assays were performed as in vitro endpoints to evaluate cytotoxicity and phototoxicity in a 3T3 cell line, and predict toxicity and/or phototoxicity after systemic administration of the drug. The in vitro alkaline single-cell electrophoresis (comet) assay was used to evaluate the genotoxic and photogenotoxic potential of the substances using the same cell line. RESULTS: The results showed that the SI and the DP are more cytotoxic and phototoxic than the drug GFM using the 3T3 cell line. In the comet assay, the drug GFM was found to be more genotoxic and photogenotoxic than its related substances. CONCLUSIONS: Our findings highlight the relevance of the biological safety studies to increase the knowledge regarding the toxic potential of the related substances, which can be associated with the drug side effects and toxicity. PMID- 23361472 TI - Prevention of needle-tract seeding by two-step freezing after lung cancer biopsy. AB - Fine-needle aspiration biopsy is a method to detect malignancy for undetermined pulmonary nodules, but has the potential to spread malignant cells from the tumor to the pleural cavity or chest wall. We developed a two-step freezing method to avoid needle-tract seeding, by use of percutaneous cryoablation after biopsy but before the biopsy needle was removed. A man aged 72 years was admitted because of a large mass in right upper lobe. After biopsy, the patient underwent surgery. Pathological assessment of the resected tumor showed that tissue around the biopsy probe and cryoprobe had been killed before needle withdrawal. PMID- 23361473 TI - Reply to the letter by Lai et al. regarding "body mass index is the most useful predictive factor for the onset of nonalcoholic fatty liver disease: a community based retrospective longitudinal study". PMID- 23361475 TI - Sequential selective enrichment of phosphopeptides and glycopeptides using amine functionalized magnetic nanoparticles. AB - As two of the most common and important post-translational modifications (PTMs) of proteins, glycosylation and phosphorylation play critical roles in biological processes. Because of the low abundance of phosphopeptides/glycopeptides, specific and sensitive strategies are especially indispensable for the identification of protein phosphorylation and glycosylation by mass spectrometry (MS). However, most of those previously reported methods only focused on enriching either phosphopeptides or glycopeptides rather than enriching both of them. In the present study, amine-functionalized magnetic nanoparticles were synthesized in a one-pot procedure and successfully used for selective enrichment of both phosphopeptides and glycopeptides. The selectivity of this method was demonstrated by analyzing the mixture of peptides/phosphopeptides/glycopeptides at molar ratio of 10:1:1; the post-enrichment recovery was 88% and 76% for phosphopeptides and glycopeptides respectively. The sensitivity was at the fmol level for both of the phosphopeptides and glycopeptides. In addition, sequence coverage was increased from 25.6% to 51.8% corresponding to a 102% increase for a model protein asialofetuin. These newly identified phosphopeptides or glycopeptides provided additional sequence information, which was beneficial to the protein identification. PMID- 23361476 TI - Joshua P. Klein, MD, PhD. PMID- 23361474 TI - Ets1 and heat shock factor 1 regulate transcription of the Transformer 2beta gene in human colon cancer cells. AB - BACKGROUND: Transformer (Tra) 2beta is a member of the serine/arginine-rich (SR) like protein family that regulates alternative splicing of numerous genes in a concentration-dependent manner. Several types of cancer cells up-regulate Tra2beta expression, while the regulatory mechanism of Tra2beta expression remains to be elucidated. In this study, we examined the transcriptional regulation and possible functions of Tra2beta in human colon cancer cells. METHODS: We cloned 959 bp-upstream of the human TRA2beta 5'-flank into luciferase constructs. Chromatin immunoprecipitation (ChIP) was employed to identify crucial cis element(s) and trans activator(s) of the TRA2beta promoter. Tra2beta expression in the human colon and colon cancer tissues was examined by immunohistochemistry. RESULTS: In response to sodium arsenite, colon cancer cells (HCT116) increased levels of TRA2beta1 mRNA encoding a functional, full-length Tra2beta with a peak around 6 h without changing its mRNA stability. Transient expression assays using a reporter gene driven by serially truncated TRA2beta promoters and Chip assay demonstrated that an Ets1-binding site present at -64 to -55 bp was crucial for basal transcription, while three heat shock elements (HSEs) located at -145 to -99 bp mediated the oxidant-induced transactivation of TRA2beta. Tra2beta knockdown caused apoptosis of HCT116 cells. Tra2beta were preferentially expressed in proliferative compartment of normal human colonic glands and adenocarcinomas, where Ets1 and heat shock factor 1 were also highly expressed. CONCLUSIONS: Our results suggest that oxidative stress-responsive Tra2beta may play an important role in colon cancer growth. PMID- 23361477 TI - Diagnostic neuroimaging. PMID- 23361478 TI - Neuroimaging of the afferent visual system. AB - Neuroimaging studies provide a useful tool for the clinician evaluating a patient with visual loss. In this review, we discuss the use of magnetic resonance imaging (MRI), computed tomography (CT), orbital ultrasound, and optical coherence tomography (OCT) for evaluating causes of visual loss affecting the afferent visual system. The imaging characteristics of diseases affecting the optic nerve, orbit, sellar and parasellar region, optic tracts, and retrogeniculate visual pathways will be discussed. PMID- 23361479 TI - Imaging of the pituitary and parasellar region. AB - The sellar and parasellar region is anatomically complex and encompasses many important vascular, endocrine, and neural structures. Pathology that arises within this region is often similarly complex, and requires a combination of endocrinologic, ophthalmologic, and neurologic examinations combined with advanced neuroimaging modalities. Magnetic resonance imaging (MRI) has become the gold standard for characterization of sellar and parasellar pathology due to the high contrast and detail it provides. Computed tomography (CT) allows for identification of bony involvement of lesions and also the general bony anatomy of the sellar region. Both modalities combined allow for complete characterization of sellar and parasellar pathology. PMID- 23361480 TI - Clinical anatomy and imaging of the cranial nerves and skull base. AB - Evaluation of patients with cranial neuropathies requires an understanding of brainstem anatomy and nerve pathways. Advances in neuroimaging, particularly high spatial resolution magnetic resonance imaging (MRI), have enabled visualization of these tiny structures and their related pathology. This review provides an approach toward using imaging in the evaluation of cranial nerve (CN) and skull base anatomy and pathology. Because brainstem nuclei are inextricably linked to the information contained within CNs, they are briefly mentioned whenever relevant; however, a comprehensive discussion of brainstem syndromes is beyond the scope of this review. PMID- 23361481 TI - Neuroimaging in neurodegenerative dementias. AB - Neurodegenerative dementias are characterized by insidious onset and gradual progression of cognitive dysfunction, initially relatively focal with respect to cognitive domains and brain regions involved. Neuroimaging techniques have contributed enormously to both our understanding of large-scale network specificity in neurodegenerative syndromes and our ability to make clinical diagnoses of syndromes such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), posterior cortical atrophy (PCA), logopenic primary progressive aphasia (PPA), agrammatic PPA, semantic dementia (SD), behavioral variant frontotemporal dementia (bvFTD), corticobasal syndrome (CBS), and progressive supranuclear palsy syndrome (PSPS). More importantly, rapid advances in imaging and computational techniques promise to improve our ability to make pathologic diagnoses of AD, DLB, and frontotemporal lobar degeneration (FTLD) pathologies in vivo at an early stage of illness. Neuroimaging is thus integral to the development and application of disease modifying therapies for neurodegenerative illnesses. PMID- 23361482 TI - Neuroimaging in the evaluation of epilepsy. AB - Neuroimaging has provided extraordinary insight into the pathologic substrate of epilepsy. The excellent spatial resolution and soft tissue contrast of magnetic resonance imaging (MRI) allows identification of a substantial number of pathologies including hippocampal sclerosis, malformations of cortical development, low grade tumors, and vascular abnormalities, among others. Complementary imaging modalities such as positron emission tomography, single photon emission computed tomography, and magnetoencephalography can be diagnostically helpful as well. Identification of a pathologic substrate is particularly important in patients with medically refractory epilepsy who are undergoing evaluation for surgery, and essential in determining the likelihood of seizure freedom after surgical intervention. This article reviews current and emerging neuroimaging techniques in the field of epilepsy. PMID- 23361484 TI - Vascular imaging of the head and neck. AB - Pathologies of the cranial and cervical vasculature are often devastating and require rapid and accurate anatomic delineation. The clinical scenario will often dictate the most appropriate imaging modality warranted. In this review, we will discuss the application of magnetic resonance angiography (MRA), computed tomographic angiography (CTA), and digital subtraction angiography (DSA) in the evaluation of cerebrovascular diseases with an emphasis on ischemic and hemorrhagic stroke. Noninvasive modalities such as MRA and CTA are becoming widely available and increasingly sensitive for most pathologies, but DSA continues to be the gold standard in cases of diagnostic ambiguity and is increasingly utilized with advances in endovascular treatments. PMID- 23361486 TI - Positron emission tomography applications in clinical neurology. AB - Positron emission tomography (PET) is a molecular imaging technique for developing maps of functional and biochemical activity in target tissues in vivo. PET has led to significant insights into nervous system biology, physiology, and pathophysiology in health and disease. Several of these insights and applications have a direct usefulness for the clinical neurologist. Although [F 18]fluorodeoxyglucose (FDG-) PET has remained a workhorse of PET imaging, many other radiolabeled biomolecules have been studied using PET. This article aims to provide an overview of current clinical usefulness of PET across the neurologic subspecialties including dementias, movement disorders, epilepsy, brain tumors, and neurologic infectious and inflammatory diseases. PMID- 23361485 TI - Transcranial Doppler ultrasound: technique and application. AB - Transcranial Doppler (TCD) ultrasound provides rapid, noninvasive, real-time measures of cerebrovascular function. TCD can be used to measure flow velocity in the basal arteries of the brain to assess relative changes in flow, diagnose focal vascular stenosis, or to detect embolic signals within these arteries. TCD can also be used to assess the physiologic health of a particular vascular territory by measuring blood flow responses to changes in blood pressure (cerebral autoregulation), changes in end-tidal CO2 (cerebral vasoreactivity), or cognitive and motor activation (neurovascular coupling or functional hyperemia). TCD has established utility in the clinical diagnosis of a number of cerebrovascular disorders such as acute ischemic stroke, vasospasm, subarachnoid hemorrhage, sickle cell disease, as well as other conditions such as brain death. Clinical indication and research applications for this mode of imaging continue to expand. In this review, the authors summarize the basic principles and clinical utility of TCD and provide an overview of a few TCD research applications. PMID- 23361487 TI - Guidelines for acquiring and reporting clinical neurospectroscopy. AB - Since the advent of CPT 76390 in 1998, magnetic resonance spectroscopy (MRS) of the brain, or neurospectroscopy, has moved from the realm of academic research into that of the clinical world. All major MR manufacturers have aided in the endeavor by automating neurospectroscopy so that it no longer requires an MR physicist and is a push-button technique that can be run by technologists just as a typical MR sequence. Thousands of studies have demonstrated the clinical efficacy of neurospectroscopy, and there are many medical reviews of how this technique can be applied across a wide range of neurologic disorders. However, few studies address the practical issue of acquiring and reporting neurospectroscopy in a clinical practice. Based on clinical experience at three different sites across the country and nearly two decades of applications training for technologists and radiologists at international clinical neurospectroscopy courses, the guidelines described in this article demonstrate proven protocols for clinical diagnosis and outline the strategies involved in acquiring, interpreting, and reporting clinical neurospectroscopy successfully. A standard operating procedure used across the three sites is described and high reproducibility across different platforms is shown. PMID- 23361483 TI - Advanced neuroimaging in traumatic brain injury. AB - Advances in structural and functional neuroimaging have occurred at a rapid pace over the past two decades. Novel techniques for measuring cerebral blood flow, metabolism, white matter connectivity, and neural network activation have great potential to improve the accuracy of diagnosis and prognosis for patients with traumatic brain injury (TBI), while also providing biomarkers to guide the development of new therapies. Several of these advanced imaging modalities are currently being implemented into clinical practice, whereas others require further development and validation. Ultimately, for advanced neuroimaging techniques to reach their full potential and improve clinical care for the many civilians and military personnel affected by TBI, it is critical for clinicians to understand the applications and methodological limitations of each technique. In this review, we examine recent advances in structural and functional neuroimaging and the potential applications of these techniques to the clinical care of patients with TBI. We also discuss pitfalls and confounders that should be considered when interpreting data from each technique. Finally, given the vast amounts of advanced imaging data that will soon be available to clinicians, we discuss strategies for optimizing data integration, visualization, and interpretation. PMID- 23361488 TI - Cerebral perfusion imaging. AB - Recent advances are allowing computed tomography (CT) and magnetic resonance imaging (MRI) to add diagnostic information derived from microscopic-scale brain structure, pathology, and physiology to the gross pathologic information that has been the core of brain imaging diagnosis since the 1980s. Physiologic imaging with MR perfusion weighted imaging has joined MR diffusion imaging as an essential components of stroke and brain tumor MRI. At the same time, the volume scanning revolution in CT technology has dramatically decreased the radiation doses required for CT perfusion imaging by allowing routine simultaneous CT perfusion and noninvasive dynamic bone subtracted CT angiography (CTA) without a significant increase in radiation dose over conventional head CT-CTA alone. Although ongoing research and clinical trials is needed to define more precisely how these techniques can best be exploited to improve clinical care and patient outcomes, in the acute stroke and subarachnoid hemorrhage populations the radiation risk associated with CT perfusion imaging is negligible and the physiologic information promises significant patient safety benefits. PMID- 23361490 TI - Imaging findings in cancer therapy-associated neurotoxicity. AB - Cancer therapy can cause several neurotoxic syndromes that are associated with distinct findings on cranial imaging. With the use of more aggressive and combined treatment modalities in oncology and prolonged overall patient survival, neurotoxicity has been reported with increasing frequency in patients with brain cancer and malignancies outside the nervous system. Both cranial irradiation and chemotherapy can be harmful to the nervous system, and be associated with acute and chronic nervous system toxicity. Here we discuss features and imaging characteristics of common neurotoxic syndromes, such as cerebrovascular complications, reversible leukoencephalopathy syndrome, progressive white matter injury, and diffuse brain atrophy. Neurologist and oncologists need to be familiar with the pattern, time course, and evolution of both acute and long-term neurologic complications of cancer therapy. Identification of causative agents and appropriate distinction between treatment-related toxicity and tumor associated complications are critical steps to improve treatment monitoring and overall patient care. PMID- 23361491 TI - Laparoscopy decreases the laparotomy rate in hemodynamically stable patients with blunt abdominal trauma. AB - BACKGROUND: This study evaluated the use of laparoscopy in hemodynamically stable patients with blunt abdominal trauma. METHODS: We retrospectively reviewed the medical records of hemodynamically stable blunt abdominal trauma patients. Patients admitted from July 1, 2003, to June 30, 2006 (prior to the adoption of laparoscopy for patients with blunt abdominal trauma) were categorized as group A. Patients admitted from July 1, 2007, to June 30, 2010, when laparoscopy was included in the algorithm for the management of blunt abdominal trauma, were categorized as group B. RESULTS: There were 47 patients in group A and 57 patients in group B. There were no significant differences in demographic characteristics, injury severity score, and injuries requiring surgical intervention between the groups (all, P > .05). Patients in group B had a shorter hospital stay (11 days vs 21 days, P < .001) and shorter ICU stay (0 [0, 1] days vs. 0 [0, 9] days, P = .029). In group A, 6 of 47 patients (12.8%) underwent a nontherapeutic laparotomy. In contrast, 9 of 57 patients (15.8%) in group B avoided a nontherapeutic laparotomy because no significant intra-abdominal findings warranting an intervention were disclosed by laparoscopy. The incidence of laparotomy for patients with significant injuries in group B was lower than in group A (4.2% vs. 100.0%; P < .001). There was no difference in the complication rate between the groups. CONCLUSIONS: Laparoscopy is feasible and safe for the diagnosis and treatment of hemodynamically stable patients with blunt abdominal trauma and can reduce the laparotomy rate. PMID- 23361489 TI - Clinical applications and future directions of functional MRI. AB - First described for use in mapping the human visual cortex in 1991, functional magnetic resonance imaging (fMRI) is based on blood-oxygen level dependent (BOLD) changes in cortical regions that occur during specific tasks. Typically, an overabundance of oxygenated (arterial) blood is supplied during activation of brain areas. Consequently, the venous outflow from the activated areas contains a higher concentration of oxyhemoglobin, which changes the paramagnetic properties of the tissue that can be detected during a T2-star acquisition. fMRI data can be acquired in response to specific tasks or in the resting state. fMRI has been widely applied to studying physiologic and pathophysiologic diseases of the brain. This review will discuss the most common current clinical applications of fMRI as well as emerging directions. PMID- 23361492 TI - Comparison between US and MRI in the prenatal assessment of lung malformations. AB - BACKGROUND: The contribution of MRI in the prenatal evaluation of congenital lung abnormalities (CLA) has not been extensively investigated. OBJECTIVE: (1) To compare diagnostic accuracy and assessment of prognostic factors between US and MRI in CLA and (2) to assess the diagnosis agreement between prenatal imaging and postnatal diagnosis. MATERIALS AND METHODS: We included 23 consecutive fetuses who underwent concomitant US and MRI during gestation as well as postnatal CT and surgery (n = 22). RESULTS: US-MRI sets were performed at median gestational age of 26 (n = 16) and 34 (n = 22) weeks. Postnatal diagnoses were 11 congenital pulmonary airway malformations (CPAM), 4 bronchopulmonary sequestrations (BPS), 6 hybrid lesions and 2 cysts. US and MRI agreement was significantly better during the second trimester than during the third one (P = 0.02). Disagreements were related to missed cysts (n = 5), mediastinal shift (n = 6) and vessels (n = 5). US and MRI diagnosis agreement was present in 20 cases, including 5 cases of misdiagnosis. US and MRI were concordant with postnatal diagnosis in 17 and 16 cases, respectively. CONCLUSION: In our series, no clear superiority of MRI over US in the prenatal evaluation of CLA was demonstrated, but US better demonstrated systemic feeding vessels and MRI cysts and normal lung adjacent to the lesion. PMID- 23361493 TI - CT imaging features of eosinophilic colitis in children. AB - BACKGROUND: Eosinophilic colitis (EC) is a gastrointestinal disease of undetermined etiology whose clinical features overlap with those of the inflammatory bowel diseases. To the best of our knowledge, the CT imaging features of EC have not been described in children. OBJECTIVE: To report and analyze the clinical, imaging and histological findings in seven children with EC. MATERIALS AND METHODS: Children with EC were identified in a pediatric pathology database, and those with CT imaging within 2 months of diagnosis were included, totaling seven children. Clinical, imaging and pathological features were reviewed and analyzed. RESULTS: The most common presenting symptoms were abdominal pain, bloody diarrhea and rectal bleeding. EC was characterized as a dense and predominantly eosinophilic inflammatory infiltrate in the lamina propria or epithelium without granulomas. CT scans were abnormal in six children (86%), demonstrating colonic wall thickening, predominantly cecal, in five (71%), mild to moderate terminal ileal thickening in two (29%), and pneumatosis in one (14%). Right colonic involvement was greater than terminal ileal involvement. CONCLUSION: CT imaging findings in children with EC include right colonic wall thickening of variable extent downstream and absent or mild involvement of the terminal ileum. EC should be considered in the differential diagnosis in children presenting with abdominal pain and bloody diarrhea. PMID- 23361495 TI - Ultrastructural analysis of different-made staplers' staples. PMID- 23361494 TI - Clinical manifestations and MRI features of vaginal endodermal sinus tumors in four children. AB - BACKGROUND: Vaginal endodermal sinus tumor is a rare entity. OBJECTIVE: The purpose of this study was to report the clinical manifestations and MRI features in a case series. MATERIALS AND METHODS: Children with vaginal endodermal sinus tumor admitted to our hospitals between January 2008 and August 2012 were included. MRI was performed in all four children and diffusion-weighted imaging was performed in two children. RESULTS: Four children, mean age 14 months, were included. All had a history of vaginal bleeding. Serum alpha-fetoprotein was significantly elevated on admission. Relative to muscle, the vaginal masses were uniformly isointense on T1-weighted images, heterogeneously hyperintense on T2 weighted images and heterogeneously enhancing on contrast-enhanced images. The vaginal masses were obviously hyperintense on diffusion-weighted images (b value, 800 s/mm(2)). Extravaginal invasion was observed in three children. Pelvic lymphadenopathy was noted in two children and pulmonary metastasis was found in one child. CONCLUSION: MRI may contribute in the evaluation of vaginal endodermal sinus tumors. PMID- 23361496 TI - Endoanal ultrasound in anal fistulas. Is there any influence on postoperative outcome? PMID- 23361498 TI - A dual-emission and large Stokes shift fluorescence probe for real-time discrimination of ROS/RNS and imaging in live cells. AB - A novel dual-emission fluorescence probe has been developed for specific and sensitive detection of hypochlorite (ClO(-)). Upon addition of ClO(-), significant changes in fluorescence emission intensity at two discrete wavelengths were observed. Meanwhile OONO(-) led to only a single-channel fluorescence enhancement. This feature makes it a clear advantage in distinguishing ClO(-), RNS from other ROS. PMID- 23361497 TI - Local excision with adjuvant imatinib therapy for anorectal gastrointestinal stromal tumors. AB - Rectal gastrointestinal stromal tumors (GISTs) are uncommon, and the role of local excision versus a more extensive resection after the advent of effective targeted chemotherapy with imatinib is not known. Our aim is to present two cases of large anorectal GIST treated with local excision through a new anterolateral trans-sphincteric approach followed by adjuvant therapy with imatinib. Two patients (both males, 68 and 63 years old) presented at our institution with anorectal GIST in the period October-November 2010. Their medical records, pathology results, and imaging studies were retrospectively reviewed. Both patients presented with an anterior perianal mass. Imaging studies were characteristic of GIST originating in the lower rectum, circumscribed by a pseudocapsule, and protruding into the ischiorectal fossa. Both patients underwent local excision via an anterolateral trans-sphincteric approach. Both tumors were removed intact, with microscopically negative margins. The maximum tumor diameter was 8 and 9 cm, and the diagnosis of GIST was confirmed by positive CD117 and CD34 staining in both cases. Both tumors had a high (>5/50HPF) mitotic index. The patients had an uneventful postoperative course and were discharged on days 5 and 6. Both patients were started on imatinib 400 mg bid postoperatively. Postoperative magnetic resonance imaging and positron emission tomography computed tomography were carried out at 12 months and did not reveal any signs of recurrence. The patients are currently disease-free at 24 and 23 months of follow-up. In selected cases, complete excision of rectal GIST with negative margins is feasible via a trans-sphincteric approach. With the use of adjuvant therapy, which is currently advocated in all high-risk cases, it is possible that local excision with its reduced morbidity may become a viable alternative, especially in patients who would otherwise require abdominoperineal excision such as the two presented here. Prospective studies with longer follow up are needed to confirm adequate oncologic results. PMID- 23361499 TI - Congenital chloride diarrhea presenting in newborn as a rare cause of meconium ileus. AB - Postpartum abdominal distention and meconium ileus may occur due to intestinal obstruction, Hirschprung disease or cystic fibrosis. However, other rare and challenging etiologies such as congenital chloride diarrhea (CCD) should be included in differential diagnosis of such presentation. We present a premature baby girl who had distended abdomen and lack of meconium immediately after birth. Surgical etiology was excluded and she was mistakenly suspected of having cystic fibrosis due to meconium ileus. CCD was diagnosed by recognition of watery diarrhea in association with hyponatremic, hypochloremic metabolic acidosis. Mutation analysis confirmed the diagnosis. PMID- 23361500 TI - Novel NKX2.1 mutation associated with hypothyroidism and lethal respiratory failure in a full-term neonate. AB - We report a case of lethal neonatal hypoxic respiratory failure and hypothyroidism in an infant with a novel missense mutation in NKX2.1. PMID- 23361501 TI - In response to mortality in preterm infants with respiratory distress syndrome treated with poractant alfa, calfactant or beractant: a retrospective study. PMID- 23361502 TI - Response to Dr Egan's letter. PMID- 23361503 TI - Solvent and metal dependent (1)H NMR hyperfine shifts in paramagnetic pentaamminemetal cyanide-bridged mixed-valence complexes. AB - (1)H NMR resonances, in several aprotic solvents, are reported for axial and equatorial ammonias coordinated to a single spin paramagnetic centre in the Robin Day Class II cyanide-bridged mixed-valence cations [(OC)(5)Cr(MU CN)M(NH(3))(5)](2+) (M = Ru, Os) as well as in the complex [(OC)(5)Re(MU CN)Ru(NH(3))(5)](3+), whose synthesis and properties are reported herein. Using the appropriate isotropic hexaammine complex as a reference, the chemical shift difference between the ammonia protons, delta(ax) - delta(eq), is found to be very sensitive to the paramagnetic metal (M), the remote diamagnetic metal (Cr or Re) and also to the donor properties of the solvent (as well as the counter-ion) as a result of hydrogen bonding interactions. The difference varies linearly with the MMCT energy, and in [(OC)(5)Re(MU-CN)Ru(NH(3))(5)](3+) can be tuned from positive (delta(ax) > delta(eq)) to negative (delta(ax) < delta(eq)) through zero (delta(ax) = delta(eq)) by the choice of solvent. This reflects the sign and magnitude of the axial ligand field parameter which is in turn a result of changes in the pi-donor-acceptor interactions between the donor-cyanide bridging group and the pentaammine metal unit. PMID- 23361504 TI - Validity of axial length measurements for monitoring myopic progression in orthokeratology. AB - PURPOSE: To investigate the short-term effect of orthokeratology (ortho-k) lens wear on the anterior segment length for validating the use of axial length for monitoring myopic progression after ortho-k treatment. METHODS: THIRTY-SEVEN AND 39 SUBJECTS (AGES: 7-10 years) were randomly assigned to wear ortho-k and single vision spectacles, respectively. Central corneal thickness (CCT), anterior chamber depth (ACD), crystalline lens thickness (LT), and anterior segment length (ASL: summation of CCT, ACD, and LT) were measured before and 6 months after the treatment under cycloplegia. Changes in these parameters were evaluated and compared between the two groups of subjects. RESULTS: There were no significant between-group differences in the baseline data (P > 0.37). After 6 months of lens wear, in the ortho-k group, CCT was significantly reduced by 0.009 +/- 0.009 mm (P < 0.001), whereas ACD and LT remained unchanged (P > 0.15). In the spectacle group, ACD was significantly increased by 0.01 +/- 0.03 mm (P = 0.008), whereas CCT and LT remained unchanged (P > 0.06). In both groups of subjects, ASL did not appreciably change but axial length was significantly increased by 0.10 +/- 0.10 mm and 0.20 +/- 0.11 mm in the ortho-k and the spectacle groups, respectively (P < 0.001). CONCLUSIONS: Eyeball elongation occurred in children wearing both ortho k and single-vision spectacles. Since ASL was not affected by ortho-k treatment, axial length measured reflects the true growth of the eyeball and is a valid parameter for monitoring myopic progression in ortho-k treated eyes. PMID- 23361505 TI - Macular Bruch's membrane defects and axial length: association with gamma zone and delta zone in peripapillary region. AB - PURPOSE: To examine histomorphometrically the macular region of highly myopic eyes. METHODS: On horizontal anterior-posterior histological sections, we examined the posterior pole of 138 human globes (axial length: 20-35 mm). In the parapapillary region, we differentiated between the beta zone (Bruch's membrane without RPE), gamma zone (parapapillary region without Bruch's membrane), and delta zone (elongated and thinned gamma zone). RESULTS: In 12 (8.7%) eyes, a macular Bruch's membrane defect (MBMD) was detected. The MBMD showed a complete lack of RPE and choriocapillaris, and an almost complete lack of photoreceptors. Presence of MBMD was associated with longer axial length (P < 0.001), longer gamma zone (P = 0.04) and delta zone (P < 0.001), thinner peripapillary scleral flange, and thinner sclera just outside of the optic nerve meninges (P < 0.001) and at the posterior pole (P < 0.001). An MBMD was found only in eyes with an axial length of 27 mm or longer. MBMD prevalence in highly myopic eyes was 12/39 or 30.8%. MBMD presence was not significantly related to length of beta zone (P = 0.09). In multivariate binary regression analysis, MBMD presence was significantly (P < 0.001) associated only with axial length. CONCLUSIONS: Highly myopic eyes (axial length >=27mm) can show an MBMD associated with complete loss of RPE and choriocapillaris, and marked reduction of photoreceptors and large choroidal vessels. MBMD presence was strongly associated with axial length and indirectly with parapapillary gamma zone and delta zone. The myopia-associated secondary MBMDs may occur parallel to the myopia-associated widening of Bruch's membrane opening around the optic nerve head. PMID- 23361506 TI - Abnormal thickening as well as thinning of the photoreceptor layer in intermediate age-related macular degeneration. AB - PURPOSE: To investigate the relationship between photoreceptor layers overlying and adjacent to large drusen in intermediate nonneovascular AMD. METHODS: Patients with AMD (n = 41; aged 53-83 years) and elderly control subjects without eye disease (n = 10; aged 51-79 years) were studied with spectral-domain optical coherence tomography. Characteristics of large drusen (>=125 MUm) were measured and the thickness of photoreceptor laminae overlying drusen and in retinal regions neighboring the drusen were quantified. RESULTS: There were 750 large drusen in 63 intermediate AMD eyes studied. The width of the drusen sampled averaged 352 MUm (SD = 153) and the height averaged 78 MUm (SD = 31). There was significant reduction of the photoreceptor outer nuclear layer (ONL) thickness overlying 92% of the drusen. The thickness of the layer corresponding to photoreceptor inner and outer segments above drusen was also reduced, and the reduction was proportional to ONL thickness. In a substantial fraction (~20%) of normally laminated paradrusen locations sampled within ~300 MUm of peak drusen height, ONL thickness was significantly increased compared with age and retinal location-matched normal values. Topographical analyses of the macula showed ONL thickening occurring in paradrusen regions as well as retinal locations distant from drusen. CONCLUSIONS: Reductions in the photoreceptor laminae overlying drusen were detectable and this is consistent with histological studies revealing neuronal degeneration in AMD. ONL thickening in some macular areas of AMD eyes has not been previously reported and may be an early phenotypic marker for photoreceptor stress, as it has been speculated to be in hereditary retinal degenerations. PMID- 23361508 TI - Pharmacokinetics of ranibizumab in patients with neovascular age-related macular degeneration: a population approach. AB - PURPOSE: To characterize ranibizumab pharmacokinetics in patients with AMD. METHODS: A population approach of nonlinear mixed-effect pharmacokinetic modeling based on concentration-time data from 2993 serum samples from 674 AMD patients enrolled in 5 phase 1 to 3 clinical trials of single or multiple intravitreal (ITV) doses of ranibizumab (0.3-2.0 mg/eye) administered biweekly or monthly for up to 24 months. RESULTS: A TOTAL OF 696 CONCENTRATION-TIME RECORDS FROM 229 SUBJECTS WITH ONE OR MORE MEASURABLE TOTAL SERUM RANIBIZUMAB CONCENTRATIONS WERE ANALYZED. THE SYSTEMIC CONCENTRATION-TIME DATA FOR RANIBIZUMAB WERE BEST DESCRIBED BY A ONE-COMPARTMENT MODEL WITH FIRST-ORDER ABSORPTION INTO AND FIRST ORDER ELIMINATION FROM THE SYSTEMIC CIRCULATION. VITREOUS ELIMINATION HALF-LIFE (T1/2) WAS CALCULATED TO BE 9 DAYS AND THE INTRINSIC SYSTEMIC ELIMINATION T1/2 WAS CALCULATED TO BE APPROXIMATELY 2 HOURS. FOLLOWING ITV ADMINISTRATION, RANIBIZUMAB EGRESSES SLOWLY INTO THE SYSTEMIC CIRCULATION, RESULTING IN AN APPARENT SERUM T1/2 OF 9 DAYS. SYSTEMIC-TO-VITREOUS EXPOSURE RATIO WAS ESTIMATED TO BE 1: 90,000. With monthly and quarterly ITV regimens, the serum concentrations of ranibizumab at steady-state for both the 0.3 and 0.5 mg/eye dose levels were estimated to be below the range needed to inhibit VEGF-A-induced endothelial cell proliferation in vitro by 50% at all times. CONCLUSIONS: Systemic exposure to ranibizumab after ITV injection was very low due to elimination on reaching systemic circulation from the vitreous. Population pharmacokinetic analysis of data from a representative sample of AMD patients did not identify clinically significant sources or correlates of variability in ranibizumab exposure. (ClinicalTrials.gov numbers, NCT00056836, NCT00056823.). PMID- 23361507 TI - A novel fluorescent lipid probe for dry eye: retrieval by tear lipocalin in humans. AB - PURPOSE: A fluorescent probe was used to identify mucin-depleted areas on the ocular surface and to test the hypothesis that tear lipocalin retrieves lipids from the eyes of normal and dry eye subjects. METHODS: Fluorescein-labeled octadecyl ester, FODE, was characterized by mass spectrometry and absorbance spectrophotometry. The use of FODE to define mucin defects was studied with impression membranes under conditions that selectively deplete mucin. The kinetics of FODE removal from the ocular surface were analyzed by sampling tears from control and dry eye patients at various times. The tear protein-FODE complexes were isolated by gel filtration and ion exchange chromatographies, monitored with absorption and fluorescent spectroscopies, and analyzed by gel electrophoresis. Immunoprecipitation verified FODE complexed to tear lipocalin in tears. RESULTS: FODE exhibits an isosbestic point at 473 nm, pKa of 7.5, and red shift relative to fluorescein. The low solubility of FODE in buffer is enhanced with 1% Tween 80 and ethanol. FODE adheres to the ocular surface of dry eye patients. FODE produces visible staining at the contact sites of membranes, which correlates with removal of mucin. Despite the fact that tear lipocalin is reduced in dry eye patients, FODE removal follows similar rapid exponential decay functions for all subjects. FODE is bound to tear lipocalin in tears. CONCLUSIONS: Tear lipocalin retrieves lipid rapidly from the human ocular surface in mild to moderate dry eye disease and controls. With improvements in solubility, FODE may have potential as a fluorescent probe to identify mucin depleted areas. PMID- 23361509 TI - Na+-independent nucleoside transporters regulate adenosine and hypoxanthine levels in Muller cells and the inner blood-retinal barrier. AB - PURPOSE: To elucidate the mechanism(s) of hypoxanthine production in Muller cells and the elimination of hypoxanthine across the inner blood-retinal barrier (BRB). METHODS: The hypoxanthine biosynthesis and adenosine transport in Muller cells were investigated using a conditionally immortalized rat Muller cell line, TR MUL5 cells. The elimination of hypoxanthine across the inner BRB was assessed by an in vivo microdialysis method and an in vitro transport study using a conditionally immortalized rat retinal capillary endothelial cell line, TR-iBRB2 cells. RESULTS: [(3)H]Hypoxanthine was detected in TR-MUL5 cells and TR-MUL5 cell cultured medium 3 hours after [(3)H]adenosine incubation, indicating that the hypoxanthine is produced in TR-MUL5 cells. [(3)H]Adenosine was taken up into TR MUL5 cells, which express mRNAs of nucleoside transporters (ENT1-2 and CNT1-2), in an Na(+)-independent and concentration-dependent manner (Km = 20 MUM). Moreover, 100 MUM nitrobenzylmercaptopurine riboside (NBMPR) and azidothymidine, which are inhibitors of ENT2, inhibited [(3)H]adenosine uptake, suggesting that ENT2 is a major contributor to adenosine transport in Muller cells. [(3)H]Hypoxanthine was eliminated from the rat vitreous humor and this process was inhibited in the presence of NBMPR. [(3)H]Hypoxanthine uptake by TR-iBRB2 cells took place in an Na(+)-independent and concentration-dependent manner with Km values of 4.3 MUM and 2.9 mM, and was inhibited by 100 MUM NBMPR. CONCLUSIONS: Our findings suggest that hypoxanthine is produced from adenosine in Muller cells and ENT2 plays a major role in adenosine uptake in Muller cells. Hypoxanthine in the retina is eliminated via Na(+)-independent equilibrative nucleoside transporters. PMID- 23361510 TI - The decline in attentional visual fields over time among older participants in the Salisbury Eye Evaluation Driving Study. AB - PURPOSE: The loss of attentional visual field (AVF) has been linked to poor mobility and car crashes. We investigated the risk factors associated with a decrease in AVF over time among participants in the Salisbury Eye Evaluation Driving Study (SEEDS). METHODS: In a longitudinal cohort of 968 individuals ages 67 to 87, demographic, medical, visual, and cognitive factors were obtained at baseline (2005-2006) and follow-up (2007-2008) using structured medical questionnaires and onsite examinations. Using the standard deviation for the difference in AVF over 2 years of 4.3 degrees , two subgroups were created: Those who lost 5 degrees or more in two years and those who had no loss (i.e., loss of 5 degrees or less, or no loss). Age-adjusted and multivariate odds ratios (OR) with 95% confidence intervals (95% CI) for each explanatory factor were determined using logistic regression. RESULTS: The overall change in AVF was 0.34 degrees (SD = 4.32), which was a significant decline from baseline. of the population, 14% lost 5 degrees or more of AVF. The following determinants were associated with a minimum loss of 5 degrees over 2 years: female sex (OR = 1.59, P = 0.03), history of stroke (OR = 1.90, P = 0.03), depression (OR = 1.07, P = 0.02), a lower baseline Trails A and B scores (OR = 1.09, P = 0.003 and OR = 1.02, P = 0.02, respectively), and lower baseline visual acuity (OR = 1.21, P = 0.03). In addition, decline was related to a lower baseline measure of auditory attention (OR = 1.14, P = 0.007) and lower baseline visual fields in the central 20 degrees (OR = 1.24, P = 0.01). CONCLUSIONS: Loss in AVF over time is related independently to decrements in cognition and vision. The higher odds of loss in female subjects, independent of these factors, deserves further research. PMID- 23361511 TI - Higher order aberrations in children with Down syndrome. AB - PURPOSE: Down syndrome (DS) is associated with ocular abnormalities and reduced visual function. Studies report atypical optical structures in the DS eye such as thinner, steeper corneae and thinner crystalline lenses and, functionally, a degrading influence of the optics on acuity. This study further investigates optical quality in DS by comparing higher order ocular aberrations (HOAs) in DS and control eyes. METHODS: Participants were 44 children with DS (6-16 years) and 209 age-matched controls. All participants were free from corneal or lenticular pathology. HOAs were measured following cycloplegia using Shack-Hartmann aberrometry. HOAs were analyzed over a 3-mm and 5-mm pupil using Zernike polynomials from third-sixth order. Optical quality was explored using Visual Strehl ratios (VSX) and equivalent defocus values. RESULTS: HOAs were measured successfully from 68% of the DS group and 95% of controls. Root mean square of total combined HOAs, third, and sixth orders and coma were significantly greater in the DS group (P < 0.005). Significant differences were found between groups for Zernike coefficients Z3(-3), Z3(3), Z0(4), (P < 0.013). VSX and equivalent defocus values indicated significantly poorer optical quality in DS eyes (P < 0.02). CONCLUSIONS: Children with DS have greater HOAs and reduced central optical quality compared with typically developing children. Whilst the differences in HOAs between the groups reached statistical significance, they were not of pathological proportions and the DS eye maintains relatively good optical quality considering the degree of ametropia and atypical optical structures often found amongst these children. The subtle reduction in optical quality may, however, compound the visuocortical deficits previously reported in DS. PMID- 23361512 TI - Automated classification of severity of age-related macular degeneration from fundus photographs. AB - PURPOSE: To evaluate an automated analysis of retinal fundus photographs to detect and classify severity of age-related macular degeneration compared with grading by the Age-Related Eye Disease Study (AREDS) protocol. METHODS: Following approval by the Johns Hopkins University School of Medicine's Institution Review Board, digitized images (downloaded AT http://www.ncbi.nlm.nih.gov/gap/) of field 2 (macular) fundus photographs from AREDS obtained over a 12-year longitudinal study were classified automatically using a visual words method to compare with severity by expert graders. RESULTS: Sensitivities and specificities, respectively, of automated imaging, when compared with expert fundus grading of 468 patients and 2145 fundus images are: 98.6% and 96.3% when classifying categories 1 and 2 versus categories 3 and 4; 96.1% and 96.1% when classifying categories 1 and 2 versus category 3; 98.6% and 95.7% when classifying category 1 versus category 3; and 96.0% and 94.7% when classifying category 1 versus categories 3 and 4; CONCLUSIONS: Development of an automated analysis for classification of age-related macular degeneration from digitized fundus photographs has high sensitivity and specificity when compared with expert graders and may have a role in screening or monitoring. PMID- 23361514 TI - Estimation of spontaneous blinking main sequence in normal subjects and patients with Graves' upper eyelid retraction. AB - PURPOSE: We quantified the main sequence of spontaneous blinks in normal subjects and Graves' disease patients with upper eyelid retraction using a nonlinear and two linear models, and examined the variability of the main sequence estimated with standard linear regression for 10-minute periods of time. METHODS: A total of 20 normal subjects and 12 patients had their spontaneous blinking measured with the magnetic search coil technique when watching a video during one hour. The main sequence was estimated with a power-law function, and with standard and trough the origin linear regressions. Repeated measurements ANOVA was used to test the mean sequence stability of 10-minute bins measured with standard linear regression. RESULTS: In 95% of the sample the correlation coefficients of the main sequence ranged from 0.60 to 0.94. Homoscedasticity of the peak velocity was not verified in 20% of the subjects and 25% of the patients. The power-law function provided the best main sequence fitting for subjects and patients. The mean sequence of 10-minute bins measured with standard linear regression did not differ from the one-hour period value. For the entire period of observation and the slope obtained by standard linear regression, the main sequence of the patients was reduced significantly compared to the normal subjects. CONCLUSIONS: Standard linear regression is a valid and stable approximation for estimating the main sequence of spontaneous blinking. However, the basic assumptions of the linear regression model should be examined on an individual basis. The maximum velocity of large blinks is slower in Graves' disease patients than in normal subjects. PMID- 23361513 TI - Brillouin microscopy of collagen crosslinking: noncontact depth-dependent analysis of corneal elastic modulus. AB - PURPOSE: Corneal collagen crosslinking (CXL) is designed to halt the progression of keratoconus and corneal ectasia by inducing corneal stiffening. However, it currently is difficult to monitor and evaluate CXL outcome objectively due to the lack of suitable methods to characterize corneal mechanical properties. We validated noncontact Brillouin microscopy to quantify corneal mechanical properties before and after CXL. METHODS: CXL was performed on fresh porcine eyes using various presoaking times and light doses, with or without epithelial debridement. From Brillouin maps of corneal elastic modulus, stiffness and average modulus of anterior, middle, and posterior stroma were analyzed. Corneal stiffening index (CSI) was introduced as a metric to compare the mechanical efficacy of a given CXL protocol with respect to the standard protocol (30-minute riboflavin presoak, 3 mW/cm2 ultraviolet illumination for 30 minutes). RESULTS: Brillouin corneal stiffness increased significantly (P < 0.001) by epi-off and epi-on CXL. The increase of Brillouin modulus was depth-dependent, indicating that anterior stromal stiffening contributes the most to mechanical outcome. The increase of anterior Brillouin modulus was linearly proportional to the light dose (R2 > 0.98). Compared to the standard epi-off procedure, a typical epi-on procedure resulted in a third of stiffness increase in porcine corneas (CSI = 33). CONCLUSIONS: Brillouin microscopy allowed imaging and quantifying CXL induced mechanical changes without contact in a depth-dependent manner at high spatial resolution. This technique may be useful to evaluate the mechanical outcomes of CXL procedures, to compare different crosslinking agents, and for real-time monitoring of CXL in clinical and experimental settings. PMID- 23361515 TI - Heterolytic activation of dihydrogen by platinum and palladium complexes. AB - Wide bite angle diphosphine ligands were used to prepare [(diphosphine)M(2 (diphenylphosphino)pyridine)](2+) complexes (M = Pd, Pt). Except for the ligand with the largest bite angle, 2-(diphenylphosphino)pyridine coordinates in a bidentate mode leading to bis-chelate complexes. In the case of Xantphos (9,9 dimethyl-4,5-bis(diphenylphosphino)-xanthene, betan = 111 degrees ) two types of complexes are formed, in which 2-(diphenylphosphino)pyridine coordinates in a mono- or bidentate fashion, respectively. The crystal structures of three of the Pt complexes were determined. The X-ray crystal structure of [(Xantphos)-Pt(2 (diphenylphosphino)pyridine)](2+) shows that Xantphos coordinates in a tridentate P,O,P fashion. Under dihydrogen pressure, the pyridyl moiety in the platinum complexes can de-coordinate to provide a vacant coordination site at the metal center. Furthermore it can act as an internal base to assist the heterolytic cleavage of dihydrogen. The reaction yields a platinum hydride with a protonated pyridine moiety in close proximity to one another. The structure as well as the reactivity of the complexes towards dihydrogen is governed by the steric requirements of the diphosphines. The crystal structure of [(dppf)PtH(2 (diphenylphosphino)pyridinium)](OTf)2 has been determined. Palladium complexes containing DPEphos or Xantphos decompose under dihydrogen pressure. In the case of dppf slow heterolytic splitting of dihydrogen occurs to form the hydride complex [(dppf)PdH(2-(diphenylphosphino)pyridinium)](OTf)2 which contains a protonated 2-(diphenylphosphino)pyridine ligand. In solution, this compound slowly undergoes P-C bond cleavage of the 2-(diphenylphosphino)pyridine ligand to form [(dppf)Pd(PHPh2)(eta(1)-C5H4NH)](OTf)2. When the 6-methyl-2 pyridyldiphenylphosphine ligand is used, the reaction of the palladium complex with dihydrogen is very fast and the hydride complex immediately rearranges to the diphenylphosphino compound resulting from P-C bond cleavage. PMID- 23361516 TI - Compliance boundaries for multiple-frequency base station antennas in three directions. AB - In this article, compliance boundaries and allowed output powers are determined for the front, back, and side of multiple-frequency base station antennas, based on the root-mean-squared electric field, the whole-body averaged specific absorption rate (SAR), and the 10 g averaged SAR in both the limbs and the head and trunk. For this purpose, the basic restrictions and reference levels defined by the International Commission on Non-Ionizing Radiation Protection (ICNIRP) for both the general public and occupational exposure are used. The antennas are designed for Global System for Mobile Communications around 900 MHz (GSM900), GSM1800, High Speed Packet Access (HSPA), and Long Term Evolution (LTE), and are operated with output powers at the individual frequencies up to 300 W. The compliance boundaries are estimated using finite-difference time-domain simulations with the Virtual Family Male and have been determined for three directions with respect to the antennas for 800, 900, 1800, and 2600 MHz. The reference levels are not always conservative when the radiating part of the antenna is small compared to the length of the body. Combined compliance distances, which ensure compliance with all reference levels and basic restrictions, have also been determined for each frequency. A method to determine a conservative estimation of compliance boundaries for multiple-frequency (cumulative) exposure is introduced. Using the errors on the estimated allowed powers, an uncertainty analysis is carried out for the compliance distances. Uncertainties on the compliance distances are found to be smaller than 122%. PMID- 23361517 TI - Structural and up-conversion properties of Er3+ and Yb3+ co-doped Y2Ti2O7 phosphors. AB - Y(2)Ti(2)O(7) (YTO) and Er(3+)/Yb(3+) co-doped Y(2)Ti(2)O(7) (EYYTO) phosphors have been prepared by solid-state reaction method. Structures of YTO and EYYTO phosphors are identified as face centered cubic pyrochlores. Up-conversion emission spectra of EYYTO under 976 nm excitation is studied, which revealed three prominent emission lines at ~524, 548 and 661 nm originating from (2)H(11/2)->(4)I(15/2), (4)S(3/2)->(4)I(15/2) and (4)F(9/2)->(4)I(15/2) electronic transitions of Er(3+) ion, respectively in green and red regions. The power dependence study suggests that these bands arise due to two photon absorption. The monodispersed laser ablated colloidal solution of EYYTO shows strong red and green emissions on excitation with 976 nm laser. The variation of luminescence intensity at different laser excitation powers is observed and thus a color can be tuned. The photoluminescence lifetime of green band at 548 nm ((4)S(3/2) level) has been found to be ~446 MUs. PMID- 23361518 TI - In response to extracapsular dissection for benign parotid tumors: a meta analysis. PMID- 23361519 TI - Effects of methylphenidate on resting-state brain activity in normal adults: an fMRI study. AB - Methylphenidate (MPH) is one of the most commonly used stimulants for the treatment of attention deficit hyperactivity disorder (ADHD). Although several studies have evaluated the effects of MPH on human brain activation during specific cognitive tasks using functional magnetic resonance imaging (fMRI), few studies have focused on spontaneous brain activity. In the current study, we investigated the effect of MPH on the intra-regional synchronization of spontaneous brain activity during the resting state in 18 normal adult males. A handedness questionnaire and the Wechsler Adult Intelligence Scale were applied before medication, and a resting-state fMRI scan was obtained 1 h after medication (20 mg MPH or placebo, order counterbalanced between participants). We demonstrated that: (1) there were no significant differences in the performance of behavioral tasks between the MPH and placebo groups; (2) the left middle and superior temporal gyri had stronger MPHrelated regional homogeneity (ReHo); and (3) the left lingual gyrus had weaker MPH-related ReHo. Our findings showed that the ReHo in some brain areas changes with MPH compared to placebo in normal adults, even though there are no behavioral differences. This method can be applied to patients with mental illness who may be treated with MPH, and be used to compare the difference between patients taking MPH and normal participants, to help reveal the mechanism of how MPH works. PMID- 23361520 TI - Spatiotemporal dynamics of high-K+-induced epileptiform discharges in hippocampal slice and the effects of valproate. AB - The epileptic seizure is a dynamic process involving a rapid transition from normal activity to a state of hypersynchronous neuronal discharges. Here we investigated the network properties of epileptiform discharges in hippocampal slices in the presence of high K(+) concentration (8.5 mmol/L) in the bath, and the effects of the anti-epileptic drug valproate (VPA) on epileptiform discharges, using a microelectrode array. We demonstrated that epileptiform discharges were predominantly initiated from the stratum pyramidale layer of CA3a b and propagated bi-directionally to CA1 and CA3c. Disconnection of CA3 from CA1 abolished the discharges in CA1 without disrupting the initiation of discharges in CA3. Further pharmacological experiments showed that VPA at a clinically relevant concentration (100 MUmol/L) suppressed the propagation speed but not the rate or duration of high-K(+)-induced discharges. Our findings suggest that pacemakers exist in the CA3a-b region for the generation of epileptiform discharges in the hippocampus. VPA reduces the conduction of such discharges in the network by reducing the propagation speed. PMID- 23361521 TI - Interactive effects of morphine and dopaminergic compounds on spatial working memory in rhesus monkeys. AB - Opiates and dopamine (DA) play key roles in learning and memory in humans and animals. Although interactions between these neurotransmitters have been found, their functional roles remain to be fully elucidated, and their dysfunction may contribute to human diseases and addiction. Here we investigated the interactions of morphine and dopaminergic neurotransmitter systems with respect to learning and memory in rhesus monkeys by using the Wisconsin General Test Apparatus (WGTA) delayed-response task. Morphine and DA agonists (SKF-38393, apomorphine and bromocriptine) or DA antagonists (SKF-83566, haloperidol and sulpiride) were co administered to the monkeys 30 min prior to the task. We found that dose patterned co-administration of morphine with D1 or D2 antagonists or agonists reversed the impaired spatial working memory induced by morphine or the compounds alone. For example, morphine at 0.01 mg/kg impaired spatial working memory, while morphine (0.01 mg/kg) and apomorphine (0.01 or 0.06 mg/kg) co-treatment ameliorated this effect. Our findings suggest that the interactions between morphine and dopaminergic compounds influence spatial working memory in rhesus monkeys. A better understanding of these interactive relationships may provide insights into human addiction. PMID- 23361522 TI - Grand Research Plan for Neural Circuits of Emotion and Memory--current status of neural circuit studies in China. AB - During recent years, major advances have been made in neuroscience, i.e., asynchronous release, three-dimensional structural data sets, saliency maps, magnesium in brain research, and new functional roles of long non-coding RNAs. Especially, the development of optogenetic technology provides access to important information about relevant neural circuits by allowing the activation of specific neurons in awake mammals and directly observing the resulting behavior. The Grand Research Plan for Neural Circuits of Emotion and Memory was launched by the National Natural Science Foundation of China. It takes emotion and memory as its main objects, making the best use of cutting-edge technologies from medical science, life science and information science. In this paper, we outline the current status of neural circuit studies in China and the technologies and methodologies being applied, as well as studies related to the impairments of emotion and memory. In this phase, we are making efforts to repair the current deficiencies by making adjustments, mainly involving four aspects of core scientific issues to investigate these circuits at multiple levels. Five research directions have been taken to solve important scientific problems while the Grand Research Plan is implemented. Future research into this area will be multimodal, incorporating a range of methods and sciences into each project. Addressing these issues will ensure a bright future, major discoveries, and a higher level of treatment for all affected by debilitating brain illnesses. PMID- 23361523 TI - Pathotype-specific QTL for stem rust resistance in Lolium perenne. AB - A genetic map populated with RAD and SSR markers was created from F1 progeny of a stem rust-susceptible and stem rust-resistant parent of perennial ryegrass (Lolium perenne). The map supplements a previous map of this population by having markers in common with several other Lolium spp. maps including EST-SSR anchor markers from a consensus map published by other researchers. A QTL analysis was conducted with disease severity and infection type data obtained by controlled inoculation of the population with each of two previously characterized pathotypes of Puccinia graminis subsp. graminicola that differ in virulence to different host plant genotypes in the F1 population. Each pathotype activated a specific QTL on one linkage group (LG): qLpPg1 on LG7 for pathotype 101, or qLpPg2 on LG1 for pathotype 106. Both pathotypes also activated a third QTL in common, qLpPg3 on LG6. Anchor markers, present on a consensus map, were located in proximity to each of the three QTL. These QTL had been detected also in previous experiments in which a genetically heterogeneous inoculum of the stem rust pathogen activated all three QTL together. The results of this and a previous study are consistent with the involvement of the pathotype-specific QTL in pathogen recognition and the pathotype-nonspecific QTL in a generalized resistance response. By aligning the markers common to other published reports, it appears that two and possibly all three of the stem rust QTL reported here are in the same general genomic regions containing some of the L. perenne QTL reported to be activated in response to the crown rust pathogen (P. coronata). PMID- 23361524 TI - A plasmonic blood glucose monitor based on enzymatic etching of gold nanorods. AB - A simple colorimetric assay for blood glucose has been developed based on enzymatic engineering of gold nanorods by glucose oxidase (GOx)-mediated oxidative etching of gold nanorods. PMID- 23361525 TI - Immunomodulatory activity of Bengkoang (Pachyrhizus erosus) fiber extract in vitro and in vivo. AB - Bengkoang (Pachyrhizus erosus (L.) Urban) is one of the most popular edible root vegetables in Indonesia. Bengkoang contains fairly large amounts of carbohydrates and crude fiber. The purpose of this research is to evaluate the immunomodulatory effect of the bengkoang fiber extract (BFE) in vitro and in vivo. BFE was prepared by heating the powder of bengkoang fiber suspended in distilled water at 121 degrees C for 20 min. BFE facilitated IgM production by the human hybridoma cell line HB4C5 cells. In addition, production of IgM, IgG, and IgA by mouse primary splenocytes was facilitated by BFE in a dose-dependent manner. BFE also significantly facilitated production of both interleukin-5 and interleukin-10 by splenocytes. Immunoglobulin production by lymphocytes from the spleen, Peyer's patch, and mesenteric lymph node were significantly activated by oral administration of BFE to mice for 14 days. The serum immunoglobulin levels of IgG, IgM, and IgA were also significantly enhanced. Furthermore, cytokine production by lymphocytes from the spleen, Peyer's patch, and mesenteric lymph node were also facilitated by oral administration of BFE. These results suggest that BFE has positive effects on the immune system in vitro and in vivo. PMID- 23361526 TI - Improved survival in limited scleroderma-related pulmonary artery hypertension. AB - Reportedly, patients with scleroderma-related pulmonary hypertension (SSc-PAH) respond poorly to new vasoactive drugs (NVD). Forty-nine SSc-PAH patients underwent right heart catheterization (RHC) and, according to NVD availability, divided as follows: Group 1 (n = 23, from 1999 to 2004, poor availability), and Group 2 (n = 26, from 2005 to 2010, good availability). Before diagnostic RHC, NVD had been given to 30 % of the patients in Group 1, and 58 % of those in Group 2 (p = 0.049). At diagnosis, patients in Group 1 had greater heart dilatation (p < 0.01), higher mean pulmonary artery pressure (p < 0.05), lower pulmonary artery capacitance (p < 0.05), and lower carbon monoxide lung diffusing capacity (DLco, p < 0.05) than those in Group 2. At a median follow-up time of 15.5 months, DLco further decreased in Group 1 (p < 0.05), whereas cardiac index increased in Group 2 (p < 0.05). At 36 months of follow-up, 72.4 % of the patients in Group 2 were still alive as opposed to 30.4 % in Group 1 (p = 0.02). In multivariate analysis, DLco and mixed venous oxygen saturation (SvO2) were independent predictors of survival. A value of DLco <7.2 mL/mmHg/min was associated with a hazard ratio (HR) of 5.3 (p < 0.001); for SvO2 <63.8 %, the HR was 3.7 (p < 0.01).NVD have beneficial effects in patients with SSc-PAH. Both DLco and SvO2 are predictors of survival and may assist in planning treatment. PMID- 23361527 TI - Detailed cognitive function and use of drugs with anticholinergic properties in older people: a community-based cross-sectional study. AB - BACKGROUND: Many potentially inappropriate drugs prescribed to older people have anticholinergic properties and may therefore be harmful. Drugs with anticholinergic properties (DAPs) are associated with cognitive decline. OBJECTIVE: Our aim was to study the profile of various cognitive functions related to current use of DAPs. METHODS: A cross-sectional study was conducted in Helsinki, Finland, and included 400 home-dwelling individuals aged 75-90 years without major clinical dementia but with a history of stable atherosclerotic disease who were participants of the DEBATE (Drugs and Evidence-Based Medicine in the Elderly) study. The cognition of the users (n = 295) and non-users (n = 105) of DAPs was measured with the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery. RESULTS: Use of DAPs was statistically significantly associated with a low score in verbal fluency, in naming, and on the Mini-Mental State Examination (MMSE). In the logistic regression analysis, the difference remained for low verbal fluency (odds ratio [OR] 1.84, 95 % CI 1.02-3.32; p = 0.044) and naming (OR 1.81, 95 % CI 1.09-3.00; p = 0.021) but not for MMSE score after adjusting for age, sex and education. CONCLUSIONS: Performances for verbal fluency and naming were poorer in DAP users than in non users, suggesting a possible impairment of executive functioning and semantic memory. The dimensions of the CERAD test assessing episodic memory-the subtests that are the most sensitive in terms of detecting early Alzheimer's disease-did not show differences between users and non-users of DAPs. PMID- 23361528 TI - Pandemic serotypes of Vibrio cholerae isolated from ships' ballast tanks and coastal waters: assessment of antibiotic resistance and virulence genes (tcpA and ctxA). AB - There is concern that ships' ballasting operations may disseminate Vibrio cholerae to ports throughout the world. Given evidence that the bacterium is indeed transported by ships, we isolated pandemic serotypes O1 and O139 from ballast tanks and characterized them with respect to antibiotic resistance and virulence genes ctxA and tcpA. We carried out concurrent studies with V. cholerae isolated from coastal waters. Of 284 isolates, 30 were serotype O1 and 59 were serotype O139. These serotypes were overrepresented in ballast tanks relative to the coastal waters sampled. All locations, whether coastal waters or ballast tanks, yielded samples from which serotype O1, O139, or both were isolated. There were three groups among the 62 isolates for which antibiotic characterization was conclusive: those exhibiting beta-lactamase activity and resistance to at least one of the 12 antibiotics tested; those negative for beta-lactamase but having antibiotic resistance; those negative for beta-lactamase and registering no antibiotic resistance. When present, antibiotic resistance in nearly all cases was to ampicillin; resistance to multiple antibiotics was uncommon. PCR assays revealed that none of the isolates contained the ctxA gene and only two isolates, one O139 and one O1, contained the tcpA gene; both isolates originated from ballast water. These results support the bacteriological regulations proposed by the International Maritime Association for discharged ballast water. PMID- 23361529 TI - Bone union rate with autologous iliac bone versus local bone graft in posterior lumbar interbody fusion (PLIF): a multicenter study. AB - PURPOSE: The purpose of this study is to compare bone union rate between autologous iliac bone and local bone graft in patients treated by posterior lumbar interbody fusion (PLIF) using carbon cage for single level interbody fusion. METHODS: The subjects were 106 patients whose course could be observed for at least 2 years. The diagnosis was lumbar spinal canal stenosis in 46 patients, herniated lumbar disk in 12 patients and degenerative spondylolisthesis in 51 patients. Single interbody PLIF was done using iliac bone graft in 53 patients and local bone graft in 56 patients. Existence of pseudo-arthrosis on X P (AP and lateral view) was investigated during the same follow up period. RESULTS: No significant differences were found in operation time and blood loss. Significant differences were also not observed in fusion grade at any follow up period or in fusion progression between the two groups. Donor site pain continued for more than 3 months in five cases (9%). The final fusion rate was 96.3 versus 98.3%. CONCLUSIONS: Almost the same results in fusion were obtained from both the local bone group and the autologous iliac bone group. Fusion progression was almost the same. Complications at donor sites were seen in 19% of the cases. From the above results, it was concluded that local bone graft is as beneficial as autologous iliac bone graft for PLIF at a single level. PMID- 23361530 TI - Minimal access bilateral transforaminal lumbar interbody fusion for high-grade isthmic spondylolisthesis. AB - PURPOSE: Minimally invasive or "minimal access surgery" (MAS) is being utilized with increasing frequency to reduce approach-related morbidity in the lumbar spine. This paper describes our minimal access technique for posterior bilateral transforaminal lumbar interbody fusion (TLIF) and spinal instrumentation in a patient with high-grade spondylolisthesis grade (Myerding Grade III) with 5-year follow-up. METHODS: A 24-year-old lady presented with mechanical back pain and left leg L5 radiculopathy. On examination, she was a thin lady with an obvious step deformity in the lower lumbar spine and otherwise, a normal neurological examination. Imaging showed a grade III isthmic L5-S1 spondylolisthesis with foraminal stenosis and focal kyphotic alignment of 20 degrees [slip angle (SA) = 70 degrees ]. Conservative measures had failed, and a decision was made to proceed with a MAS-TLIF approach. RESULTS: The estimated blood loss was less than 100 ml, operating time 150 min, and post-operative hospital stay was 4 days. Post operatively the patient had significant improvement of back and radicular pain. Improvement in ODI was substantial and sustained at 5 years. A solid fusion was achieved at 8 months. The slip percentage improved from 68 % (pre-op) to 28 % (post-op) and the focal alignment to 20 degrees lordosis (SA = 110 degrees ). CONCLUSIONS: A MAS approach for selected patients with a mobile high-grade spondylolisthesis is feasible, safe and clinically effective, with the added benefit of reduced soft-tissue disruption. Our result of this technique suggests that the ability to correct focal deformity, and achieve excellent radiographic and clinical outcome is similar to the open procedure. PMID- 23361561 TI - Quantification of protein expression in cells and cellular subcompartments on immunohistochemical sections using a computer supported image analysis system. AB - Quantification of protein expression based on immunohistochemistry (IHC) is an important step for translational research and clinical routine. Several manual ('eyeballing') scoring systems are used in order to semi-quantify protein expression based on chromogenic intensities and distribution patterns. However, manual scoring systems are time-consuming and subject to significant intra- and interobserver variability. The aim of our study was to explore, whether new image analysis software proves to be sufficient as an alternative tool to quantify protein expression. For IHC experiments, one nucleus specific marker (i.e., ERG antibody), one cytoplasmic specific marker (i.e., SLC45A3 antibody), and one marker expressed in both compartments (i.e., TMPRSS2 antibody) were chosen. Stainings were applied on TMAs, containing tumor material of 630 prostate cancer patients. A pathologist visually quantified all IHC stainings in a blinded manner, applying a four-step scoring system. For digital quantification, image analysis software (Tissue Studio v.2.1, Definiens AG, Munich, Germany) was applied to obtain a continuous spectrum of average staining intensity. For each of the three antibodies we found a strong correlation of the manual protein expression score and the score of the image analysis software. Spearman's rank correlation coefficient was 0.94, 0.92, and 0.90 for ERG, SLC45A3, and TMPRSS2, respectively (p?0.01). Our data suggest that the image analysis software Tissue Studio is a powerful tool for quantification of protein expression in IHC stainings. Further, since the digital analysis is precise and reproducible, computer supported protein quantification might help to overcome intra- and interobserver variability and increase objectivity of IHC based protein assessment. PMID- 23361562 TI - SSRI use during pregnancy and risk of stillbirth and neonatal mortality. AB - OBJECTIVE: The authors investigated whether in utero exposure to selective serotonin reuptake inhibitors (SSRIs) increases the risk of stillbirth or neonatal mortality. METHOD: The authors conducted a population-based cohort study using the Danish Fertility Database to identify every birth in Denmark between 1995 and 2008. Time of exposure to SSRIs was calculated on the basis of standard treatment dosages and dispensed pack sizes according to the prescription register. Exposure was divided into first-, second-, and third-trimester exposure. Multivariate logistic regression models were used. RESULTS: The authors identified 920,620 births; the incidence of stillbirths was 0.45%, and the incidence of neonatal mortality was 0.34%. A total of 12,425 offspring were exposed to an SSRI during pregnancy. Stillbirth was not associated with first trimester SSRI use (adjusted odds ratio=0.77, 95% CI=0.43-1.36), first- and second-trimester use (odds ratio=0.84, 95% CI=0.40-1.77), or first-, second-, and third-trimester use (odds ratio=1.06, 95% CI=0.71-1.58). Neonatal mortality was not associated with SSRI first-trimester use (odds ratio=0.56, 95% CI=0.25-1.24), first- and second-trimester use (odds ratio=0.90, 95% CI=0.37-2.17), or first-, second-, and third-trimester use (odds ratio=1.27, 95% CI=0.82-1.99). CONCLUSIONS: This study found no association between exposure to SSRIs during pregnancy and stillbirth or neonatal mortality. PMID- 23361532 TI - Degenerative lumbar scoliosis in Chinese Han population: prevalence and relationship to age, gender, bone mineral density, and body mass index. AB - PURPOSE: To investigate the prevalence of degenerative lumbar scoliosis (DLS) in Chinese Han population, as well as its correlation with age, gender, bone mineral density (BMD), and body mass index (BMI); and to determine factors that might affect the curve severity. METHODS: A prospective study was performed on adults visiting the dual-energy X-ray absorption clinics for physical examination from January 2011 to March 2012. 2,395 subjects aged older than 40 years and having no history of previous spinal trauma, surgeries or scoliosis, were enrolled in this study. A logistic regression analysis was performed to determine the independent variables related to the presence of scoliosis. Besides, the relationship between curve severity and these variables was also analyzed with partial linear correlation analysis. RESULTS: The prevalence of DLS was approximately 13.3 %. The logistic regression analysis showed that age, T score, and gender all had remarkable correlation with the occurrence of DLS, with the odd ratios being 4.2, 1.5, and 1.6, respectively. According to the receiver operating characteristics curve, the best dividing point for age and T score of female subjects was 65 and 2.0, respectively. Partial linear correlation analysis indicated that there existed no obvious correlation between the above variables and the severity of scoliosis. CONCLUSION: The prevalence of DLS in Chinese Han population aged older than 40 years was approximately 13.3 %, which had a significant correlation with age, gender, and BMD. Osteopenia, gender of female, and aged older than 65 years could contribute to the presence of DLS. The curve severity was not associated with age, gender, BMI, or BMD. PMID- 23361531 TI - The challenge and advancement of annulus fibrosus tissue engineering. AB - BACKGROUND: Intervertebral disc degeneration, a main cause of back pain, is an endemic problem and a big economic burden for the health care system. Current treatments are symptom relieving but do not address underlying problems biological and structural deterioration of the disc. Tissue engineering is an emerging approach for the treatment of intervertebral disc degeneration since it restores the functionality of native tissues. Although numerous studies have focused on the nucleus pulposus tissue engineering and achieved successes in laboratory settings, disc tissue engineering without annulus fibrosus for the end stage of disc degeneration is deemed to fail. The purpose of this article is to review the advancement of annulus fibrosus tissue engineering. MATERIAL AND METHODS: Relevant articles regarding annulus fibrosus tissue engineering were identified in PubMed and Medline databases. RESULTS: The ideal strategy for disc regeneration is to restore the function and integrity of the disc by using biomaterials, native matrices, growth factors, and cells that producing matrices. In the past decades there are tremendous advancement in annulus fibrosus tissue engineering including cell biology, biomaterials, and whole disc replacement. The recent promising results on whole disc tissue engineering-a composite of annulus fibrosus and nucleus pulposus-make the tissue engineering approach more appealing. CONCLUSION: Despite the promising results in disc tissue engineering, there is still much work to be done regarding the clinical application. PMID- 23361563 TI - Large-to-small end-to-side anastomosis to the internal mammary vein: a solution to vessel size discrepancy. PMID- 23361565 TI - Lead(II) tetrafluoroborate and hexafluorophosphate complexes with crown ethers, mixed O/S- and O/Se-donor macrocycles and unusual [BF(4)](-) and [PF(6)](-) coordination. AB - The reaction of Pb[BF(4)](2) in H(2)O/MeCN solution with the macrocycle 18-crown 6 gave the dinuclear complex [{Pb(18-crown-6)(H(2)O)(MU(2)-BF(4))}(2)][BF(4)](2), containing two nine-coordinate lead centres, each bound to all six oxygens of a crown ligand, one water molecule and bridged by two MU(2)-BF(4) groups. In contrast, the oxa-thia crown [18]aneO(4)S(2) gave the mononuclear [Pb([18]aneO(4)S(2))(H(2)O)(2)(BF(4))][BF(4)] in which the lead is coordinated O(4)S(2) within the puckered ring of the macrocycle, and with two water molecules on one side of the plane and a chelating (kappa(2)) BF(4)(-) on the other. The [Pb([18]aneO(4)Se(2))(BF(4))2] has the two BF(4)(-) groups arranged mutually cis and with the macrocycle folded; within each BF(4)(-) group the Pb-F distances differ by ~0.5 A, producing a very unsymmetrical chelate. The 15-membered ring macrocycles 15-crown-5 and [15]aneO(3)S(2) produce sandwich complexes [Pb(macrocycle)(2)][BF(4)](2) which contain 10-coordinate lead centres. Pb[PF(6)](2) in H(2)O/MeCN solution formed [Pb(18-crown 6)(H(2)O)(2)(PF(6))][PF(6)] and [Pb([18]aneO(4)S(2))(H(2)O)(2)(PF(6))][PF(6)] which contain weak kappa(2)-coordination of the PF(6)(-) group on the opposite side of the macrocyclic ring to two coordinated water molecules, giving 10 coordinate lead. In contrast, [Pb([18]aneO(4)Se(2))(PF(6))(2)] has two kappa(2) coordinated PF(6)(-) groups disposed cis, with a very folded macrocycle conformation. In [Pb(18-crown-6)(NO(3))(PF(6))] a chelating nitrate group occupies the coordination sites at Pb(II) instead of the two water molecules, and the weakly coordinating PF(6)(-) group is tridentate. The crystal structures of the lead nitrate complexes, [Pb(15-crown-5)(NO(3))(2)] and [Pb([18]aneO(4)Se(2))(NO(3))(2)], containing nine- and 10-coordinate lead respectively, are also reported. In solution the complexes are labile, and both conductivity and (19)F NMR spectroscopic studies show the BF(4)(-) and PF(6)(-) groups are dissociated, whereas in the nitrate complexes the anion coordination is retained in solution. The identification of the coordination modes of the NO(3)(-) and BF(4)(-) groups in the solid complexes by IR spectroscopy is discussed. PMID- 23361564 TI - Inherited variant on chromosome 11q23 increases susceptibility to IDH-mutated but not IDH-normal gliomas regardless of grade or histology. AB - INTRODUCTION: Recent discoveries of inherited glioma risk loci and acquired IDH mutations are providing new insights into glioma etiology. IDH mutations are common in lower grade gliomas and secondary glioblastomas and uncommon in primary glioblastomas. Because the inherited variant in 11q23 has been associated with risk of lower grade glioma and not with glioblastomas, we hypothesized that this variant increases susceptibility to IDH-mutated gliomas, but not to IDH-wild-type gliomas. METHODS: We tested this hypothesis in patients with glioma and controls from the San Francisco Adult Glioma Study, the Mayo Clinic, and Illumina controls (1102 total patients, 5299 total controls). Case-control additive associations of 11q23 risk alleles (rs498872, T allele) were calculated using logistic regression, stratified by tumor IDH status (mutated or wild-type) and by histology and grade. We also adjusted for the recently discovered 8q24 glioma risk locus rs55705857 G allele. RESULTS: The 11q23 glioma risk locus was associated with increased risk of IDH-mutated gliomas of all histologies and grades (odds ratio [OR] = 1.50; 95% confidence interval [CI] = 1.29-1.74; P = 1.3X10(-7)) but not with IDH-wild-type gliomas of any histology or grade (OR = 0.91; 95% CI = 0.81-1.03; P = 0.14). The associations were independent of the rs55705857 G allele. CONCLUSION: A variant at the 11q23 locus increases risk for IDH-mutated but not IDH-wild-type gliomas, regardless of grade or histology. PMID- 23361566 TI - Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary? AB - Pharmacokinetic studies of daptomycin in septic patients indicate that pharmacokinetic parameters may be altered. The purpose of this clinical investigation is to determine the pharmacokinetics of daptomycin in a population of hospitalized patients with clinically significant gram-positive infections and receiving daptomycin. Daptomycin was measured using an isocratic HPLC technique. Thirty-five patients suffering from gram-positive severe infections and receiving daptomycin were included in the study. Patients were divided into two groups, depending on the dose of daptomycin received: group A, including 24 patients receiving 6 mg/kg/day daptomycin and group B, 11 patients receiving 8 mg/kg/day. Patients receiving a daptomycin dosage of 8 mg/kg/day had significantly higher values of mean C max and AUC0-24. Each group was further divided into three subgroups, according to the creatinine clearance (CrCl) values: (1) patients with a CrCl >80 ml/min, (2) patients with CrCl ranging between 80 and 40 ml/min, and (3) patients with CrCl <40 ml/min. Compared to patients with normal renal function, those with CrCl <40 ml/min had higher mean values of minimum concentration (C min) (p < 0.001), AUC0-24 (p = 0.03), and prolonged plasma half time (p < 0.001). These differences were present both in patients receiving 6 and those with 8 mg/kg/day. However, in each of the three subgroups with different degrees of renal function a marked variability of pharmacokinetics parameters was observed. The factors associated with increased mortality were an infection acquired in the ICU, hypoalbuminemia, and AUC/MIC <666. The marked variability that characterizes daptomycin pharmacokinetics in these patients suggest the monitoring of the main pharmacokinetic parameters in this clinical setting. PMID- 23361567 TI - Accuracy of density functional theory in the prediction of carbon dioxide adsorbent materials. AB - Density functional theory (DFT) has become the computational method of choice for modeling and characterization of carbon dioxide adsorbents, a broad family of materials which at present are urgently sought after for environmental applications. The description of polar carbon dioxide (CO(2)) molecules in low coordinated environments like surfaces and porous materials, however, may be challenging for local and semi-local DFT approximations. Here, we present a thorough computational study in which the accuracy of DFT methods in describing the interactions of CO(2) with model alkali-earth-metal (AEM, Ca and Li) decorated carbon structures, namely anthracene (C(14)H(10)) molecules, is assessed. We find that gas-adsorption energies and equilibrium structures obtained with standard (i.e. LDA and GGA), hybrid (i.e. PBE0 and B3LYP) and van der Waals exchange-correlation functionals of DFT dramatically differ from the results obtained with second-order Moller-Plesset perturbation theory (MP2), an accurate computational quantum chemistry method. The major disagreements found can be mostly rationalized in terms of electron correlation errors that lead to wrong charge-transfer and electrostatic Coulomb interactions between CO(2) and AEM-decorated anthracene molecules. Nevertheless, we show that when the concentration of AEM atoms in anthracene is tuned to resemble as closely as possible the electronic structure of AEM-decorated graphene (i.e. an extended two dimensional material), hybrid exchange-correlation DFT and MP2 methods quantitatively provide similar results. PMID- 23361568 TI - Pseudobowel perforation following endoscopic retrograde cholangiopancreatography. AB - We report two cases of pneumoperitoneum following endoscopic retrograde cholangiopancreatography for retained common bile duct (CBD) stones. These post cholecystectomy patients underwent sphincterotomy, CBD clearance, and "T" tube removal at the same time. Post-procedure, both of the patients developed pneumoperitoneum. Pneumoperitoneum developed as a result of air traversing from the duodenum to the peritoneum through the ruptured "T" tube tract. "T" tube removal in the same sitting as sphincterotomy and CBD clearance may lead to pneumoperitoneum, which can be managed conservatively. PMID- 23361569 TI - Maintaining muscle strength in Crohn's disease: can a vitamin D daily keep muscle loss away? PMID- 23361570 TI - Transcatheter embolotherapy for gastrointestinal bleeding: a single center review of safety, efficacy, and clinical outcomes. AB - PURPOSE: The purpose of this study was to assess safety, efficacy, and clinical outcomes following transcatheter arterial embolization (TAE) of acute gastrointestinal (GI) bleeding. MATERIALS AND METHODS: Ninety-five patients (male:female ratio = 53:42, mean age 62 years) that underwent 95 TAEs for GI hemorrhage between 2002 and 2010 were retrospectively studied. Seventy-six of 95 (80 %) patients had upper GI bleeds and 19/95 (20 %) patients had lower GI bleeds. A mean of 7 (range 0-27) packed red blood cell units were transfused pre procedure, and 90/95 (95 %) procedures were urgent or emergent. Twenty-seven of 95 (28 %) patients were hemodynamically unstable. Measured outcomes included procedure technical success, adverse events, and 30-day rebleeding and mortality rates. RESULTS: Bleeding etiology included peptic ulcer disease (45/95, 47 %), cancer (14/95, 15 %), diverticulosis (13/95, 14 %), and other (23/95, 24 %). Vessels embolized (n = 109) included gastroduodenal (42/109, 39 %), pancreaticoduodenal (22/109, 20 %), gastric (21/109, 19 %), superior mesenteric (12/109, 11 %), inferior mesenteric (8/109, 7 %), and splenic (4/109, 4 %) artery branches. Technical success with immediate hemostasis was achieved in 93/95 (98 %) cases. Most common embolic agents included coils (66/109, 61 %) and/or gelatin sponge (19/109, 17 %). Targeted versus empiric embolization were performed in 57/95 (60 %) and 38/95 (40 %) cases, respectively. Complications included bowel ischemia (4/95, 4 %) and coil migration in 3/95 (3 %). 30-day rebleeding rate was 23 % (22/95). Overall 30-day mortality rate was 18 % (16/89). Empiric embolization resulted in similar rebleeding (23 vs 24 %) but higher mortality (31 vs 9 %) rates compared to embolization for active extravasation. CONCLUSIONS: TAE controlled GI bleeding with high technical success, safety, and efficacy, and should be considered when endoscopic therapy is not feasible or unsuccessful. PMID- 23361571 TI - TGF-beta1 secreted by hepatocellular carcinoma induces the expression of the Foxp3 gene and suppresses antitumor immunity in the tumor microenvironment. AB - AIM: The purpose of this study was to explore the mechanisms of TGF-beta1 mediated immunosuppression in tumor stroma. METHODS: The expression of TGF-beta1 was investigated in Huh7, Hep 3B, SGC-7901, Eca-109 and Hepa1-6 cell lines using immunofluorescence. Knocked-down TGF-beta1 of the Hepa1-6 cell line was established through lentivirus-based RNA interference. The interference efficiency of the TGF-beta1 gene was tested by real-time PCR and ELISA; the expression of Foxp3, IFN-gamma and CD83 in CD4(+), CD8(+) or dendritic cells was examined via flow cytometry; and the tumorigenic ability of the cancer cells was investigated in the animal experiments. RESULTS: The diverse digestive cancer cells were found to secrete TGF-beta1, mRNA of which was knocked down by 78 % thanks to lentivirus-based interference in Hepa1-6 cells. Flow cytometry showed that CD4(+)CD25(+)Foxp3(+) regulatory T cells significantly increased in hepatocellular carcinoma patients when compared with those in the healthy controls. The supernatant from Hepa1-6 cells and recombinant TGF-beta1 significantly induced the expression of Foxp3 gene in vitro, while that from sh TGF-beta1 Hepa1-6 cells restored it. Hepa1-6 cells inhibited IFN-gamma and CD83 expression in CD8(+) or dendritic cells by secreting TGF-beta1. The animal experiments indicated that the knockdown TGF-beta1 gene impaired the tumorigenic ability of Hepa1-6 cells. CONCLUSION: TGF-beta1, expressed in cancer cells, might be a potential therapeutic target for cancer treatment. PMID- 23361572 TI - Prior endoscopy in patients with newly diagnosed celiac disease: a missed opportunity? AB - BACKGROUND: Celiac disease (CD) is under-diagnosed in the United States, and factors related to the performance of endoscopy may be contributory. AIM: To identify newly diagnosed patients with CD who had undergone a prior esophagogastroduodenoscopy (EGD) and examine factors contributing to the missed diagnosis. METHODS: We identified all patients age >= 18 years whose diagnosis of CD was made by endoscopy with biopsy at our institution (n = 316), and searched the medical record for a prior EGD. We compared those patients with a prior EGD to those with without a prior EGD with regard to age at diagnosis and gender, and enumerated the indications for EGD. RESULTS: Of the 316 patients diagnosed by EGD with biopsy at our center, 17 (5 %) had previously undergone EGD. During the prior non-diagnostic EGD, a duodenal biopsy was not performed in 59 % of the patients, and >= 4 specimens (the recommended number) were submitted in only 29 % of the patients. On the diagnostic EGD, >= 4 specimens were submitted in 94 %. The mean age of diagnosis of those with missed/incident CD was 53.1 years, slightly older than those diagnosed with CD on their first EGD (46.8 years, p = 0.11). Both groups were predominantly female (missed/incident CD: 65 vs. 66 %, p = 0.94). CONCLUSIONS: Among 17 CD patients who had previously undergone a non diagnostic EGD, non-performance of duodenal biopsy during the prior EGD was the dominant feature. Routine performance of duodenal biopsy during EGD for the indications of dyspepsia and reflux may improve CD diagnosis rates. PMID- 23361573 TI - Osteopontin: participation in inflammation or mucosal protection in inflammatory bowel diseases? AB - BACKGROUND: Osteopontin (OPN) is associated with the Th1 immune response in inflammatory bowel diseases (IBD). While OPN has been shown to play an important role in maintaining the epithelial barrier, its role in IBD remains unclear. AIM: The aim of this study was to assess OPN function in patients with IBD and in the mouse colitis model. METHODS: Osteopontin expression in colonic samples from IBD patients was determined by a semi-quantitative immunohistochemical staining method. Colitis in BALB/c mice was induced by 5 % dextran sodium sulfate (DSS), followed by treatment with salazosulfapyridine (SASP) and infliximab, respectively. The plasma OPN concentration was measured by an enzyme-linked immunosorbent assay. The expression of OPN in colonic tissues was detected by reverse transcriptase PCR, real-time PCR and Western blot, and the localization of OPN was determined by a semi-quantitative immunohistochemical staining method. The immune function of OPN was investigated by measuring the production of cytokines, and the amount of cytokines produced was then used to determine OPN immune functions. RESULTS: Osteopontin expression in intestinal epithelial cells was significantly lower in IBD patients than in controls, while its expression in lamina propria exudative cells was significantly higher in IBD patients than in controls. In DSS-induced mice, OPN expression in plasma and colonic tissues increased significantly, and this increase was significantly reduced after the mice were treated with SASP and infliximab. OPN promoted the Th1 immune response and strengthened inflammation in the mouse colitis model. CONCLUSIONS: Our results indicate that OPN plays an important role in the immune response and is also involved in the mucosal protective mechanism in IBD. PMID- 23361574 TI - Predisposing factors of hepatocellular carcinoma recurrence following complete remission in response to transarterial chemoembolization. AB - BACKGROUND AND AIM: The aim of our study was to determine the predictors of recurrences in hepatocellular carcinoma (HCC) patients who had achieved complete remission (CR) by transarterial chemoembolization (TACE). METHODS: A total of 220 consecutive HCC patients who had achieved CR by TACE were followed for a median 72 months. CR was defined as complete lipiodol uptake based on the results of lipiodol-computed tomography 4 weeks after TACE and no additional tumor staining on the follow-up angiography. Recurrence patterns were classified as local recurrence and secondary tumor, respectively, in relation to the location of recurrence; early and late recurrence were classified in relation to recurrence time. RESULTS: Recurrence of HCC was observed in 169 patients (77 %), of whom 91 (54 %) had local recurrences, 61 (36 %) had secondary tumor, and 17 (10 %) had both. There were 45 (27 %) early and 124 (73 %) late recurrences. Local recurrence developed more frequently in patients with early recurrence than in those with late recurrence (62 vs. 51 %, respectively), while secondary tumor was detected more commonly in patients with late recurrence than in those with early recurrence (39 vs. 29 %, respectively; P < 0.001). In multivariate analyses, multinodularity [hazard ratio (HR) 2.351, P = 0.023] and a persistently high serum alpha-fetoprotein level following CR (HR 3.173, P < 0.001) were significant predictors of early recurrence. Older age (>= 60 years; HR 1.531, P = 0.043), advanced Child-Pugh class (HR 1.983, P = 0.002), and the association with cirrhosis (HR 1.756, P = 0.028) were predictors of late recurrence following CR. CONCLUSIONS: Early recurrences following CR by TACE may be due mainly to undetectable remaining tumors, whereas late recurrences may be caused by newly appearing tumors in patients with a background of advanced cirrhotic liver. PMID- 23361575 TI - 5-ASA induced recurrent myopericarditis and cardiac tamponade in a patient with ulcerative colitis. PMID- 23361576 TI - Combination of radiofrequency ablation with transarterial chemoembolization for hepatocellular carcinoma: a meta-analysis. AB - BACKGROUND: Recent studies suggest that the combination of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) may have a synergistic effect for hepatocellular carcinoma (HCC). AIMS: The aim of this meta-analysis was to compare the effectiveness of combination of RFA and TACE with that of RFA alone in patients with HCC. METHODS: Randomized controlled trials and retrospective cohort studies comparing RFA plus TACE with RFA alone for HCC were included into this meta-analysis. Study quality was rated with a standardized scale and the strength of evidence was also rated by using the Grading of Recommendations Assessment, Development, and Evaluation system (GRADE system). RESULTS: Meta-analyses showed that the combination of RFA and TACE was obviously associated with higher survival rates (OR1-year = 2.06, 95 % CI 1.46-2.91, P < 0.001; OR3-year = 1.93, 95 % CI 1.18-3.15, P = 0.009; OR5-year = 1.87, 95 % CI 1.23-2.83, P = 0.003). The overall quality of the evidence was judged to be low by using the GRADE system. CONCLUSIONS: The combination of TACE with RFA can improve the overall survival rate and provides better prognosis for patients with HCC, but more randomized controlled trials using large sample sizes are needed to provide sufficient evidence. PMID- 23361577 TI - Swimming through the gut: implications of fluid transport on the microbiome. PMID- 23361578 TI - Differential diagnosis of major depression and bipolar disorder. PMID- 23361579 TI - A multi-study analysis of conceptual and measurement issues related to health research on acculturation in Latinos. AB - PURPOSE: The aims of the study were to evaluate the orthogonality of acculturation for Latinos. DESIGN: Regression analyses were used to examine acculturation in two Latino samples (N = 77; N = 40). In a third study (N = 673), confirmatory factor analyses compared unidimensional and bidimensional models. METHOD: Acculturation was assessed with the ARSMA-II (Studies 1 and 2), and language proficiency items from the Children of Immigrants Longitudinal Study (Study 3). RESULTS: In Studies 1 and 2, the bidimensional model accounted for slightly more variance (R (2)Study 1 = .11; R (2)Study 2 = .21) than the unidimensional model (R (2)Study 1 = .10; R (2)Study 2 = .19). In Study 3, the bidimensional model evidenced better fit (Akaike information criterion = 167.36) than the unidimensional model (Akaike information criterion = 1204.92). DISCUSSION: Acculturation is multidimensional. IMPLICATIONS: Care providers should examine acculturation as a bidimensional construct. PMID- 23361580 TI - Evaluation of the effects of weak and moderate static magnetic fields on the characteristics of human low density lipoprotein in vitro. AB - It has been suggested that exposure to electromagnetic fields may be a risk factor for cardiovascular disease in humans. Low density lipoprotein (LDL) modifications such as peroxidation and aggregation have been implicated in the pathogenesis of atherosclerosis. The present study investigated the effects of weak (0.125-0.5 mT) and moderate (1-4 mT) static magnetic fields (SMFs) on LDL oxidation, aggregation and zeta potential in vitro. Our results demonstrated that magnetic flux densities of 0.25 and 0.5 mT decreased, and magnetic flux densities of 3 and 4 mT increased the zeta potential and LDL oxidation in comparison with the control samples. All doses of SMFs increased the LDL aggregation in a time- and dose-dependent manner. It is concluded that SMFs can alter the susceptibility of LDL to oxidation and this alteration is dependent on the applied magnetic flux density. The SMF, in addition to its role in the production and stabilization of free radicals and promotion of lipid peroxidation, may influence the metabolism of lipoproteins and their interaction with other molecules such as apolipoproteins, enzymes and receptors through the alteration of the LDL zeta potential and its particles tendency to aggregation. PMID- 23361581 TI - In reference to Accuracy of fine-needle aspiration and imaging in the preoperative workup of salivary gland mass lesions treated surgically. PMID- 23361582 TI - Virus-like particles with removable cyclodextrins enable glutathione-triggered drug release in cells. AB - The efficient delivery of hydrophobic drugs into target cells without the use of organic solvents or chemical linkage to delivery carriers is an important theme in the biomedical and pharmaceutical field. In this study, we synthesized virus like particles (VLPs) coupled with cyclodextrins (CDs) as hydrophobic pockets through disulfide bonds inside the VLPs, where hydrophobic drugs can be incorporated. We report here the intracellular delivery of hydrophobic dyes or drugs encapsulated in VLPs through CDs with high efficiency and their subsequent release in cells in response to glutathione. As a model anticancer drug, paclitaxel (PTX)-CD complexes were encapsulated inside VLPs and the cytotoxic drug activity of PTX loaded VLPs against NIH3T3 cells was evaluated by CCK-8 assay. PTX-loaded VLPs exhibited a dose-dependent cytotoxic effect with a 20-fold smaller IC(50) than that of free PTX dissolved in DMSO. These results indicate that VLPs with removable CDs afford highly promising carriers of hydrophobic drugs without chemical modification of drugs. PMID- 23361584 TI - An advanced cathode for Na-ion batteries with high rate and excellent structural stability. AB - Layered P2-Na(x)[Ni(1/3)Mn(2/3)]O(2) (0 < x < 2/3) is investigated as a cathode material for Na-ion batteries. A combination of first principles computation, electrochemical and synchrotron characterizations is conducted to elucidate the working mechanism for the improved electrochemical properties. The reversible phase transformation from P2 to O2 is observed. New configurations of Na-ions and vacancy are found at x = 1/3 and 1/2, which correspond to the intermediate phases upon the electrochemical cycling process. The mobility of Na-ions is investigated using the galvanostatic intermittent titration technique (GITT) and the Na diffusion barriers are calculated by the Nudged Elastic Band (NEB) method. Both techniques prove that the mobility of Na-ions is faster than Li-ions in the O3 structure within the 1/3 < x < 2/3 concentration region. Excellent cycling properties and high rate capability can be obtained by limiting the oxygen framework shift during P2-O2 phase transformation, suggesting that this material can be a strong candidate as a sustainable low-cost Na-ion battery cathode. PMID- 23361583 TI - Hepatic isoprenoid metabolism in a rat model of Smith-Lemli-Opitz Syndrome. AB - Elevated (4 to 7-fold) levels of urinary dolichol and coenzyme Q and substantially longer chain lengths for urinary dolichols have been reported in Smith-Lemli-Opitz Syndrome (SLOS) patients, compared to normal subjects. We investigated the possibility of similar alterations in hepatic, nonsterol isoprenoids in a well-established rat model of SLOS. In this model, the ratio of 7-dehydrocholesterol (7DHC) to cholesterol (Chol) in serum approached 15:1; however, total sterol mass in serum decreased by >80 %. Livers from treated rats had 7DHC/Chol ratios of ~32:1, but the steady-state levels of total sterols were >40 % those of livers from age-matched (3-month-old) control animals. No significant differences in the levels of LDL receptor or HMG-CoA reductase were observed. The levels of dolichol and coenzyme Q were elevated only modestly (by 64 and 31 %, respectively; p < 0.05, N = 6) in the livers of the SLOS rat model compared to controls; moreover, the chain lengths of these isoprenoids were not different in the two groups. We conclude that hepatic isoprenoid synthesis is marginally elevated in this animal model of SLOS, but without preferential shunting to the nonsterol branches (dolichol and coenzyme Q) of the pathway and without alteration of normal dolichol chain lengths. PMID- 23361585 TI - Implications of microRNAs in the pathogenesis of diabetes. AB - Diabetes is a complex metabolic disease with an etiology that includes genetic, epigenetic and environmental factors that lead to several different defects of glucose homeostasis, primarily in the pancreatic beta-cells, liver, muscle, and adipose tissues. MicroRNAs (miRNAs) have recently emerged as important regulators in post-transcriptional gene expression. Although the target genes and biological functions of individual miRNAs remain largely unknown, previous studies have shown them to be important regulators of diverse biological processes, in both normal and pathological states. In the past decade, an increasing number of studies have focused on the regulatory roles of miRNAs in metabolism; thus, miRNAs play an important role in the pathogenesis of diabetes. This review summarizes recent findings related to the roles of miRNAs in diabetes. The information presented herein might be useful for the future development of miRNAs as diagnostic and therapeutic targets in diabetes. PMID- 23361586 TI - Transcriptional regulators of hepatic gluconeogenesis. AB - Glucose is a primary fuel for generating energy in basic daily activities. Thus, glucose homeostasis is tightly regulated by counter-regulatory hormones such as glucagon, cortisol, and insulin, which affect key organs including liver, skeletal muscle, pancreas, and adipocytes. Among metabolic tissues, liver plays a critical role in controlling glucose production under various hormonal and metabolic cues. Under fasting, acute activation of both glycogenolysis and gluconeogenesis is achieved by post-translational modification or allosteric activation of key rate-limiting enzymes, thereby enabling enhanced glucose production from the liver to maintain glucose homeostasis. More prolonged fasting or starvation leads to the chronic activation of gluconeogenesis that requires increased expression of key enzymes in the pathway, which is turned off under feeding conditions by the molecular events that are initiated by insulin. This process is normally achieved by the regulation of gene expression at the level of transcription. Recently, the transcriptional regulators of hepatic gluconeogenesis are considered as potential therapeutic targets for the treatment of type 2 diabetes. In this review, we would like to discuss the current knowledge regarding the key transcriptional activators and inhibitors of hepatic gluconeogenic program to provide the better insight into the control of glycemia in the disease status. PMID- 23361587 TI - Anti-aging molecule, Sirt1: a novel therapeutic target for diabetic nephropathy. AB - Caloric restriction prolongs the lifespan of many species. Therefore, investigators have researched the usefulness of caloric restriction for healthy lifespan extension. Sirt1, an NAD(+)-dependent deacetylase, was identified as a molecule necessary for caloric restriction-related anti-aging strategies. Sirt1 functions as an intracellular energy sensor to detect the concentration of NAD(+), and controls in vivo metabolic changes under caloric restriction and starvation through its deacetylase activity to many targets including histones, nuclear transcriptional factors, and enzymes. During the past decade, investigators have reported the relationship between disturbance of Sirt1 activation and the onset of aging- and obesity-associated diseases such as diabetes, cardiovascular disease and neurodegenerative disorders. Consequently, a calorie restriction-mimetic action of Sirt1 is now expected as a new therapy for these diseases. In addition, recent studies have gradually clarified the role of Sirt1 in the onset of kidney disease. Its activation may also become a new target of treatment in the patients with chronic kidney disease including diabetic nephropathy. In this article, we would like to review the role of Sirt1 in the onset of kidney disease based on previous studies, and discuss its possibility as the target of treatment in diabetic nephropathy. PMID- 23361588 TI - Molecular selective binding of basic amino acids by a water-soluble pillar[5]arene. AB - Highly selective binding of basic amino acids, i.e. lysine, arginine, and histidine, by a negatively charged carboxylatopillar[5]arene (CP5A) is reported. And the complexation behavior of the CP5A host towards lysine metabolites including cadaverine (Cad), acetyl-l-lysine (AcLys) and trimethyl-l-lysine (TMLys) is also described. PMID- 23361589 TI - Efficacy of aerosolized celecoxib encapsulated nanostructured lipid carrier in non-small cell lung cancer in combination with docetaxel. AB - PURPOSE: Evaluation of in-vivo anticancer activity of aerosolized Celecoxib encapsulated Nanolipidcarriers (Cxb-NLC) as a single therapeutic agent and combined with intravenously administered Docetaxel (Doc) against non-small cell lung cancer. METHODS: Cxb-NLC were prepared by high-pressure homogenization and were characterized for its physicochemical characteristics. Metastatic A549 tumor model in Nu/Nu mice was used to evaluate response of aerosolized Cxb-NLC & Doc. Isolated lung tumor samples were analyzed for: a) DNA fragmentation and cleaved caspase-3 by immunohistochemistry, b) apoptotic and angiogenic protein markers by western blot, c) global proteomic alterations by an isobaric labeling quantitative proteomic method and d) toxicity studies of NLC. RESULTS: The particle size of Cxb-NLC was 217 +/- 20 nm, while entrapment efficiency was more than 90%. Cxb-NLC and Doc alone and in combination showed 25 +/- 4%, 37 +/- 5%, and 67 +/- 4% reduction in tumor size respectively compared to control. Proteomic analysis with combination treatment further revealed significantly decreased expression of multiple pro-survival and pro-metastasis proteins as well as tumor invasion markers and the expression of S100 family proteins, such as S100A6 and S100P were decreased by 2.5 and 1.6 fold. CONCLUSIONS: Combination therapy with Cxb-NLC and Doc showed significant reduction in tumor growth which was further confirmed by proteomic analysis. PMID- 23361590 TI - Effect of treatment regimen on the immunogenicity of human interferon Beta in immune tolerant mice. AB - PURPOSE: Interferon beta is commonly used as therapeutic in the first line of therapy for multiple sclerosis. However, depending on the product, it induces an antibody response in up to 60% of patients. This study evaluated the impact of therapy related factors like dose, route of administration and administration frequency on the immunogenicity of one of the originator interferon beta drugs (Betaferon(r)) in an immune tolerant transgenic mouse model. METHODS: Immune tolerant transgenic mice received injections with Betaferon(r) via different routes, doses and injection frequencies. Anti-drug antibody (ADA) production was measured by ELISA to assess immunogenicity. RESULTS: A single injection of Betaferon(r) was found to be sufficient for the induction of ADAs. The antibody titer was enhanced with increasing dose and treatment frequency. Among the tested administration routes, the intravenous route was the most immunogenic one, which is in contradiction with one of the dogma in immunogenicity research according to which subcutaneous administration is the most immunogenic route. Intramuscular, intraperitoneal and subcutaneous injections resulted in comparable immunogenicity. CONCLUSION: This study shows that treatment related factors affect significantly immunogenicity of Betaseron(r) and therefore substantiate the need for further studies on these factors in patients. PMID- 23361591 TI - Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial. AB - AIMS/HYPOTHESIS: Increased inflammation and oxidative stress are associated with insulin resistance (IR) and metabolic disorders. Serum histidine levels are lower and are negatively associated with inflammation and oxidative stress in obese women. The objective of this study was to evaluate the efficacy of histidine supplementation on IR, inflammation, oxidative stress and metabolic disorders in obese women with the metabolic syndrome (MetS). METHODS: A total of 100 obese women aged 33-51 years with BMI >= 28 kg/m2 and diagnosed with MetS were included following a health examination in the community hospital in this randomised, double-blinded, placebo-controlled trial. Participants were allocated to interventions by an investigator using sequentially numbered sealed envelopes and received 4 g/day histidine (n = 50) or identical placebo (n = 50) for 12 weeks. Participants then attended the same clinic every 2 weeks for scheduled interviews and to count tablets returned. Serum histidine, HOMA-IR, BMI, waist circumference, fat mass, serum NEFA, and variables connected to inflammation and oxidative stress were measured at baseline and 12 weeks. Participants, examining physicians and investigators assessing the outcomes were blinded to group assignment. In addition, the inflammatory mechanisms of histidine were also explored in adipocytes. RESULTS: At 12 weeks, a total of 92 participants completed this trail. Compared with the placebo group (n = 47), histidine supplementation significantly decreased HOMA-IR (-1.09 [95% CI -1.49, -0.68]), BMI (-0.86 kg/m2 [95% CI -1.55, -0.17]), waist circumference (-2.86 cm [95% CI 3.86, -1.86]), fat mass (-2.71 kg [95% CI -3.69, -1.73]), serum NEFA (-173.26 MUmol/l [95% CI -208.57, -137.94]), serum inflammatory cytokines (TNF-alpha, 3.96 pg/ml [95% CI -5.29, -2.62]; IL-6, -2.15 pg/ml [95% CI -2.52, -1.78]), oxidative stress (superoxide dismutase, 17.84 U/ml [95% CI 15.03, 20.65]; glutathione peroxidase, 13.71 nmol/ml [95% CI 9.65, 17.78]) and increased serum histidine and adiponectin by 18.23 MUmol/l [95% CI 11.74, 24.71] and 2.02 ng/ml [95% CI 0.60, 3.44] in histidine supplementation group (n = 45), respectively. There were significant correlations between changes in serum histidine and changes of IR and its risk factors. No side effects were observed during the intervention. In vitro study indicated that histidine suppresses IL6 and TNF mRNA expression and nuclear factor kappa-B (NF-kappaB) protein production in palmitic acid-induced adipocytes in a dose-dependent manner, and these changes were diminished by an inhibitor of NF-kappaB. CONCLUSIONS/INTERPRETATION: Histidine supplementation could improve IR, reduce BMI, fat mass and NEFA and suppress inflammation and oxidative stress in obese women with MetS; histidine could improve IR through suppressed pro-inflammatory cytokine expression, possibly by the NF-kappaB pathway, in adipocytes. PMID- 23361592 TI - Correlation between atmospheric pressure changes and abdominal aortic aneurysm rupture: results of a single-center study. AB - PURPOSE: There is much interest in all factors that influence the etiopathogenesis of abdominal aortic aneurysm (AAA) rupture. Apart from the well established factors such as arterial hypertension, smoking, age, and genetic predisposition, less common factors that may play a role in the mechanism of the rupture are the subject of much discussion. These include atmospheric conditions, temperature, and atmospheric pressure. We conducted this study to investigate the effects of the absolute value of atmospheric pressure and its changes on the frequency of AAA rupture. METHODS: We retrospectively examined 54 patients who underwent treatment for a ruptured AAA at the Clinic of Surgery in the University Hospital in Pilsen between 1 January 2005 and 31 December 2009. We collected data on the atmospheric pressure in this period from the Czech Hydrometeorological Institute in Pilsen. RESULTS: We did not find a significant difference in atmospheric pressure values between the days when the rupture occurred versus the other days (p < 0.5888). Moreover, we did not find significant changes in the atmospheric pressure during the 48 h preceding the rupture (Student's test p < 0.4434) versus the day of rupture or in the mean atmospheric pressure in that month. CONCLUSION: These findings suggest that atmospheric pressure and its changes do not affect the pathogenesis of AAA rupture. PMID- 23361593 TI - Long-term outcomes of emergency Lichtenstein hernioplasty for incarcerated inguinal hernia. AB - PURPOSE: To evaluate the long-term outcomes of emergency Lichtenstein hernioplasty for incarcerated inguinal hernia. METHODS: The subjects of this prospective, observational study were 24 patients who underwent emergency Lichtenstein hernioplasty for an incarcerated inguinal hernia between September 2002 and January 2006 at the Faculty of Medicine Siriraj Hospital, Thailand. Patients with bowel strangulation and recurrent hernia were excluded. We evaluated the long-term outcomes over at least a 2-year follow-up. RESULTS: Long term follow-up was completed for 20 patients (83.3 %). All of the patients were men, with a median age of 60 years (range 19-78 years) at the time of surgery. The median time to resumption of normal daily activities was 3 weeks (range 1-8 weeks). None of the patients had inguinal paresthesia persisting beyond 1 month after the operation. One patient (5 %) experienced chronic groin pain, which subsided within 4 months after surgery. Clinical recurrence was detected in two patients (10 %) during a median follow-up period of 6 years (range 2.3-7.6 years). Contralateral inguinal hernia was found in two patients (10 %) during follow-up. CONCLUSIONS: Lichtenstein hernioplasty is a safe and effective operation for non-strangulated incarcerated inguinal hernia, with a recurrence rate of 10 % at the median follow-up time of 6 years. Chronic groin pain and inguinal paresthesia were rare in this series. PMID- 23361594 TI - Relative contraindications for percutaneous tracheostomy: from the surgeons' perspective. AB - PURPOSE: Percutaneous tracheostomy (PT) has gained worldwide acceptance as a bedside procedure by intensivists, but its popularity has declined based on reports of some relative contraindications. The aim of this study was to ascertain the perioperative comorbidities of PT when it is performed by surgeons with experience performing standard tracheostomy. METHODS: Prospective data were collected and analyzed for consecutive PTs performed in intensive care units. RESULTS: No procedure-related mortality occurred in the present study. No significant differences in perioperative comorbidities, such as transient hemodynamic instability and postoperative wound infection, were noted between the relative contraindication (RC) and normal condition (NC) groups. Otherwise, instrument failure (5 cases, p = 0.052) and procedure failure (2 cases, p = 0.222) occurred in the RC group, but not in the NC group. Two patients in the NC group and one patient in the RC group needed to undergo a reoperation to check for bleeding. In a subgroup analysis, more bleeding events were noted for the patients with coagulopathy (p = 0.057), and premature extubation of the endotracheal tube/instrument failure (p = 0.073) was more common in the patients with neck anatomical difficulty in the RC group. CONCLUSIONS: For patients with relative contraindications, the potential of using PT should be determined on an individual basis. Special attention should be paid to the possibility of instrument failure and bleeding events for the patients with relative contraindications for PT. PMID- 23361595 TI - Role of the intraluminal contents and the continuity of intrinsic neurons in intracolonic capsaicin-induced contraction and defecation in dogs. AB - PURPOSE: We, herein, examined the role of the intraluminal contents and continuity of colonic intrinsic neurons in intracolonic capsaicin-induced enhancement of colonic motility and defecation. METHODS: Five beagle dogs were equipped with three strain gauge force transducers throughout the colon. The colonic contractile activity in response to intracolonic capsaicin was studied in intact dogs, dogs after colonic cleansing and dogs with transection/re anastomosis (T/R) between the proximal and middle colon. The effects of intravenous yohimbine, a alpha2 adrenergic antagonist, on the colonic motility and defecation were also studied in the same models. RESULTS: In intact dogs, capsaicin (10 mg) and yohimbine (2 mg/kg) immediately induced contractions throughout the colon, with defecation occurring in all experiments. In dogs after colonic cleansing and T/R, the capsaicin (10 mg)-induced enhancement of colonic motility was decreased in the middle and distal colon, and capsaicin-induced defecation was observed in 0-20 % of experiments (p < 0.05 compared to intact dogs). The effect of yohimbine (2 mg/kg) in inducing colonic contractions was unaltered after colonic cleansing and T/R; in contrast, yohimbine-induced defecation was not observed after colonic cleansing, but was unchanged after T/R. CONCLUSIONS: The continuity of the colonic intrinsic nerves as well as the intraluminal contents appear to play an important role in the colonic motor response to intracolonic capsaicin. PMID- 23361596 TI - Modified gastrointestinal failure score for patients with severe acute pancreatitis. AB - PURPOSE: No consensus has been reached to define gastrointestinal failure (GIF) associated with severe acute pancreatitis (SAP). Reintam and colleagues proposed a scoring system of GIF for critically ill patients, but its suitability for patients with SAP is questionable. The present study evaluates a modified GIF score we developed to assess the GIF of patients with SAP. METHODS: The subjects of this study were 52 patients with SAP treated between September 2010 and July 2011. We recorded the Reintam's GIF score, our modified GIF score, the acute physiology and chronic health evaluation (APACHE) II score, the sequential organ failure assessment (SOFA) score, and other clinical values during the first 3 days after admission. The prognostic value of the modified GIF score, for evaluating the severity and outcomes of SAP, was also assessed. RESULTS: Compared with the Reintam's GIF score, the modified GIF score seemed to be more valuable for predicting hospital mortality (the area under curve, AUC 0.915 vs. 0.850), multiple organ dysfunction syndrome (MODS) (AUC 0.829 vs. 0.766), and pancreatic infection (AUC 0.796 vs. 0.776). Moreover, combining the modified GIF score and the SOFA or APACHEII scores resulted in more accurate prediction of the prognosis of SAP than either score alone. CONCLUSION: The modified GIF score is useful for assessing gastrointestinal system function, which may serve as an early prognostic tool to evaluate the severity and predict the outcomes of SAP. PMID- 23361597 TI - Intraoperative mechanical and chemical pleurodesis with 50 % glucose solution for secondary spontaneous pneumothorax in patients with pulmonary emphysema. AB - PURPOSE: Secondary spontaneous pneumothorax is life-threatening for patients with pulmonary emphysema. To prevent recurrence, intraoperative pleurodesis is performed in addition to bullectomy. We report the therapeutic process and effectiveness of adding mechanical plus chemical pleurodesis, with a 50 % glucose solution, to bullectomy, for patients with pulmonary emphysema-related pneumothorax. METHODS: The subjects were 20 patients (19 men and 1 woman; mean age 68 years) with pulmonary emphysema-related pneumothorax. After bullectomy was completed, 500 mL of a 50 % glucose solution was injected into the pleural cavity, followed by mechanical pleurodesis performed via ablation of the parietal pleura. RESULTS: The volume of pleural effusion decreased on postoperative day (POD) 1, and the temperature decreased on POD 2. The blood sugar levels increased on the day of surgery but decreased on POD 1. The mean postoperative follow-up period was 521 days. One patient died of pneumonia on POD 24. All other patients survived without pneumothorax recurrence. CONCLUSIONS: These results demonstrated the effectiveness of our treatment process for pulmonary emphysema-related pneumothorax. The fact that no patient experienced pneumothorax recurrence suggests that mechanical and chemical pleurodesis with 50 % glucose solution might be effective prophylaxis. PMID- 23361599 TI - Real estate of monolayer permeability: location location location. PMID- 23361601 TI - 'Week against hypertension' : an italian experience for promoting knowledge and improving control of hypertension. PMID- 23361602 TI - Antihypertensive drugs and coronary artery disease : evidence from controlled trials. AB - A reduction in blood pressure (BP) levels is the most important mechanism accounting for the reduction in cardiovascular complications induced by treatment. However, results of recent clinical trials and meta-analyses have shown that antihypertensive drugs possess important ancillary properties that might play an additional role in the prevention of cardiovascular disease.Reviewing the literature, ACE inhibitors seem to have ancillary properties that can contribute to influence the risk of coronary artery disease with mechanisms partially independent of BP reduction.On the other hand, dihydropyridine calcium channel blockers, such as amlodipine, have been proven to lower the incidence of stroke but their use seems to be effective in relieving symptoms of coronary artery disease and reducing the rate of revascularisation procedures. PMID- 23361603 TI - Global cardiovascular risk : the role of plasma lipids. AB - Atherosclerosis is a multifactorial disease. This is supported by a large body of clinical and experimental data collected during the last 30 years, either in observational or in interventional clinical trials. During these years, a large number of risk factors and clinical conditions, closely related to the development of atherosclerosis, have been identified. The most relevant risk factors for cardiovascular disease are hyperlipidaemia, arterial hypertension, diabetes mellitus, cigarette smoking and family history.Cardiovascular risk factors interact with each other in a complex, and not fully elucidated fashion, contributing to the definition of a 'global cardiovascular risk profile'. Thus, the cardiovascular risk profile must be evaluated (through algorithms or risk charts) for each individual. Patients presenting with multiple cardiovascular risk factors have a higher risk of developing a major cardiovascular event, and in these patients a strict control of risk factors leads to an effective prevention of cardiovascular disease.In this latter regard, hypercholesterolemia deserves a 'dynamic' role. The most recent guidelines for the management of patients with hyperlipidaemia underscore the need for a more strict metabolic control in patients with prior cardiovascular events (secondary prevention), and also in patients with no evidence of cardiovascular disease (primary prevention), in which the concomitant presence of multiple risk factors or diabetes confers a high risk (e.g. patients with previous myocardial infarction or stroke). PMID- 23361604 TI - Importance of Rapid and Effective Reduction of Blood Pressure in Treating Hypertension for the Prevention of Cardiovascular Diseases : A Lesson from the VALUE Study. AB - The efficacy of antihypertensive medications in reducing the high blood pressure (BP) levels in patients with hypertension has been demonstrated, but the incidence of cardiovascular diseases in treated hypertensive subjects is still higher compared with subjects with normal BP values. This discrepancy could chiefly stem from: (a) the inability of the pharmacological treatment to normalise BP levels in all treated patients; (b) poor pre-evaluation of cerebral, cardiac and renal damage involvement in treated patients; and (c) the inappropriate choice of antihypertensive drug. If we consider that the recent guidelines on the treatment of hypertension have further reduced the thresholds of normal BP values (e.g. 120-129mm Hg for systolic and 80-84mm Hg for diastolic BP), we can hypothesise that in Italy today optimal control of BP in patients with hypertension could be further reduced, when compared with the past, and could be estimated to be obtained at present in only 25% of treated patients. This situation is of course unacceptable and efforts should be made by educational institutions to recommend that physicians apply current recommendations from the guidelines, aiming at properly normalising BP in treated hypertensive patients.The BP Treatment Trialists' collaboration study demonstrated that in treated hypertensive patients the extent of BP reduction by different drugs between randomised groups is closely associated with a reduction in cardiovascular risk. Recently the results from the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) study showed that in treated hypertensive patients who are 'at high risk to develop cardiovascular events' even a small reduction of 3-4mm Hg in systolic BP, obtained immediately after starting therapy, could have a great impact on reducing the risk of developing cardiovascular diseases, such as myocardial infarction and stroke. In this trial, in the group of patients treated with a therapeutic regimen based on a calcium antagonist (amlodipine), there was significantly better control of BP values, resulting in a significant decrease in cardiovascular total events, compared with the group treated with a regimen based on an angiotensin II receptor blocking agent (valsartan).The key message of the VALUE study is that the reduction in BP, especially in high-risk patients, is more important than the mechanisms of action of the antihypertensive drugs, and that normalisation of BP may reduce the incidence of cardiovascular events. With regard to this latter point, it is evident how in future we cannot be satisfied with treatment of hypertensive patients until normalisation of BP is obtained, and normal BP levels should be reached as quickly as possible in the general population. PMID- 23361605 TI - Adverse effects of statins : how should cardiologists and general physicians manage them in clinical practice? AB - A key role in the pathogenesis of atherosclerotic lesions is represented by cholesterol deposition in the arterial vessel wall, and a large body of international, randomised, controlled clinical trials have shown that the clinical use of drugs that are active in lowering serum cholesterol concentrations, such as competitive inhibitors of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase (collectively defined as 'statins'), produces significant reductions of cardiovascular mortality and morbidity through different and sometimes not fully elucidated mechanisms. However, it is important to consider that the patients who get the largest benefit from taking statins (frequently at high doses) are at the same time those with the highest risk of presenting adverse effects related to the use of these drugs. These patients are usually elderly, hypertensive and diabetic, often have renal function impairment or other associated clinical conditions and are usually receiving multiple therapies. Consequently, these patients may be exposed to adverse effects caused by pharmacological interactions of other drug classes with statins. Because of this, cardiologists need to be properly aware of the beneficial potential of these compounds but also of the potential limits and risks associated with the use of statins in the population at large.This article is aimed at examining the safety profile linked to the clinical use of statins and suggesting an adequate management to prevent the potential adverse effects while taking advantage of the outstanding cardiovascular benefits of statins. PMID- 23361607 TI - Application of hypertension guidelines in clinical practice. PMID- 23361606 TI - Selected Abstracts from the XXII National Congress of the Italian Society of Hypertension: 2005 September 27-30, Turin, Italy. PMID- 23361608 TI - Industry pulse : editorial development by adis international limited, Italy. PMID- 23361609 TI - Osteogenic medium is superior to growth factors in differentiation of human adipose stem cells towards bone-forming cells in 3D culture. AB - Human adipose stem cells (hASCs) have been recently used to treat bone defects in clinical practice. Yet there is a need for more optimal scaffolds and cost effective approaches to induce osteogenic differentiation of hASCs. Therefore, we compared the efficiency of bone morphogenetic proteins (BMP-2 and BMP-7), vascular endothelial growth factor (VEGF), and osteogenic medium (OM) for the osteo-induction of hASCs in 3D culture. In addition, growth factors were tested in combination with OM. Commercially available bioactive glass scaffolds (BioRestore) and biphasic calcium phosphate granules (BoneCeramic) were evaluated as prospective carriers for hASCs. Both biomaterials supported hASC-viability, but BioRestore resulted in higher cell number than BoneCeramic, whereas BoneCeramic supported more significant collagen production. The most efficient osteo-induction was achieved with plain OM, promoting higher alkaline phosphatase activity and collagen production than growth factors. In fact, treatment with BMP 2 or VEGF did not increase osteogenic differentiation or cell number significantly more than maintenance medium with either biomaterial. Moreover, BMP 7 treatment consistently inhibited proliferation and osteogenic differentiation of hASCs. Interestingly, there was no benefit from growth factors added to OM. This is the first study to demonstrate that OM enhances hASC-differentiation towards bone-forming cells significantly more than growth factors in 3D culture. PMID- 23361610 TI - Biofilm formation by staphylococci on fresh, fresh-frozen and processed human and bovine bone grafts. AB - Biofilm formation is a multi-step process influenced by surface properties. We investigated early and mature biofilm of Staphylococcus aureus on 4 different biological calcium phosphate (CaP) bone grafts used for filling bone defects. We investigated standardised cylinders of fresh and fresh-frozen human bone grafts were harvested from femoral heads; processed humanand bovine bone grafts were obtained preformed. Biofilm formation was done in tryptic soy broth (TSB) using S. aureus (ATCC 29213) with static conditions. Biofilm density after 3 h (early biofilm) and 24 h (mature biofilm) was investigated by sonication and microcalorimetry. After 3 h, bacterial density was highest on fresh frozenandfresh bone grafts. After 24 h, biofilm density was lowest on freshbone grafts (p < 0.001) compared to the other 3 materials, which did not differ quantitatively (p > 0.05). The lowest increase in bacterial density was detected on fresh bone grafts (p < 0.001). Despite normal shaped colonies, we found additional small colonies on the surface of the fresh and fresh-frozen samples by sonication. This was also apparent in microcalorimetric heat-flow curves. The four investigated CaP bone grafts showed minor structural differences in architecture but marked differences concerning serum coverage and the content of bone marrow, fibrous tissue and bone cells. These variations resulted in a decreased biofilm density on freshand fresh-frozenbone grafts after 24 h, despite an increased early biofilm formation and might also be responsible for the variations in colony morphology (small colonies). Detection of small colony variants by microcalorimetry might be a new approach to improve the understanding of biofilm formation. PMID- 23361611 TI - Selective oxidation of thiourea with H(2)O(2) catalyzed by [Ru(III)(edta)(H(2)O)](-): kinetic and mechanistic studies. AB - Reported here is the first example of a ruthenium complex, [Ru(III)(edta)(H(2)O)](-) (edta(4-) = ethylenediaminetetraacetate), that catalyzes the oxidation of thiourea (TU) in the presence of H(2)O(2). The kinetics and mechanism of this reaction were investigated in detail by using rapid-scan spectrophotometry as a function of both the hydrogen peroxide and thiourea concentrations at pH 4.9 and 25 degrees C. Spectral analyses and kinetic data clearly support a catalytic process in which hydrogen peroxide reacts directly with thiourea coordinated to the Ru(III)(edta) complex. HPLC product analyses revealed the formation of formamidine disulfide (TU(2)) as a major product at the end of the catalytic process, however, formation of other products like thiourea dioxide (TUO(2)), thiourea dioxide (TUO(3)) and sulfate was also observed after longer reaction times. Catalytic intermediates such as [Ru(III)(edta)(OOH)](2-) and [Ru(V)(edta)(O)](-) were evidently found to be non reactive in catalyzing the oxidation of thiourea by H(2)O(2) under the specified conditions. PMID- 23361612 TI - Abnormalities of dorsolateral prefrontal function in women with premenstrual dysphoric disorder: a multimodal neuroimaging study. AB - OBJECTIVE: To investigate the neural substrate of premenstrual dysphoric disorder (PMDD), the authors used [15O]H2O positron emission tomography (PET) regional cerebral blood flow (rCBF) and blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signal measurements during working memory in conjunction with a 6-month hormone manipulation protocol. METHOD: PET and fMRI scans were obtained from women with prospectively confirmed PMDD and asymptomatic comparison subjects while they completed the n-back task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate, leuprolide plus estradiol, and leuprolide plus progesterone. Fifteen patients and 15 matched comparison subjects underwent PET imaging. Fourteen patients and 14 comparison subjects underwent fMRI. For each hormone condition, rCBF was measured with [15O]H2O PET, and BOLD signal was measured with fMRI, both during an n-back working memory paradigm. Global Assessment of Functioning Scale (GAF) scores and clinical characteristics were obtained for each patient before hormone manipulation, and symptoms were measured before and during the protocol. RESULTS: In both the PET and fMRI studies, a main effect of diagnosis was observed, with PMDD patients showing greater prefrontal activation than comparison subjects. In the patient group, the degree to which dorsolateral prefrontal cortex activation was abnormally increased correlated with several dimensions of disease: disability as indicated by GAF scores, age at symptom onset, duration of PMDD, and differences in pre- and postmenses PMDD symptoms. CONCLUSIONS: Abnormal working memory activation in PMDD, specifically in the dorsolateral prefrontal cortex, is related to PMDD severity, symptoms, age at onset, and disease burden. These results support the clinical relevance of the findings and the proposal that dorsolateral prefrontal cortex dysfunction represents a substrate of risk for PMDD. The concordance of the fMRI and PET data attests to the neurobiological validity of the results. PMID- 23361613 TI - Rhodnius prolixus lipophorin: lipid composition and effect of high temperature on physiological role. AB - Lipophorin is a major lipoprotein that transports lipids in insects. In Rhodnius prolixus, it transports lipids from midgut and fat body to the oocytes. Analysis by thin-layer chromatography and densitometry identified the major lipid classes present in the lipoprotein as diacylglycerol, hydrocarbons, cholesterol, and phospholipids (PLs), mainly phosphatidylethanolamine and phosphatidylcholine. The effect of preincubation at elevated temperatures on lipophorin capacity to deliver or receive lipids was studied. Transfer of PLs to the ovaries was only inhibited after preincubation of lipophorin at temperatures higher than 55 degrees C. When it was pretreated at 75 degrees C, maximal inhibition of phospholipid transfer was observed after 3-min heating and no difference was observed after longer times, up to 60 min. The same activity was also obtained when lipophorin was heated for 20 min at 75 degrees C at protein concentrations from 0.2 to 10 mg/ml. After preincubation at 55 degrees C, the same rate of lipophorin loading with PLs at the fat body was still present, and 30% of the activity was observed at 75 degrees C. The effect of temperature on lipophorin was also analyzed by turbidity and intrinsic fluorescence determinations. Turbidity of a lipophorin solution started to increase after preincubations at temperatures higher than 65 degrees C. Emission fluorescence spectra were obtained for lipophorin, and the spectral area decreased after preincubations at 85 degrees C or above. These data indicated no difference in the spectral center of mass at any tested temperature. Altogether, these results demonstrate that lipophorin from R. prolixus is very resistant to high temperatures. PMID- 23361614 TI - Effect of axial length on myopic choroidal neovascularization. PMID- 23361615 TI - Tuning a menage a trois: co-evolution and co-adaptation of nuclear and organellar genomes in plants. AB - Plastids and mitochondria arose through endosymbiotic acquisition of formerly free-living bacteria. During more than a billion years of subsequent concerted evolution, the three genomes of plant cells have undergone dramatic structural changes to optimize the expression of the compartmentalized genetic material and to fine-tune the communication between the nucleus and the organelles. The chimeric composition of many multiprotein complexes in plastids and mitochondria (one part of the subunits being nuclear encoded and another one being encoded in the organellar genome) provides a paradigm for co-evolution at the cellular level. In this paper, we discuss the co-evolution of nuclear and organellar genomes in the context of environmental adaptation in species and populations. We highlight emerging genetic model systems and new experimental approaches that are particularly suitable to elucidate the molecular basis of co-adaptation processes and describe how nuclear-cytoplasmic co-evolution can cause genetic incompatibilities that contribute to the establishment of hybridization barriers, ultimately leading to the formation of new species. PMID- 23361616 TI - Management of vasospasm in ruptured unsecured intracranial vascular lesions: review of 10 cases. AB - INTRODUCTION: Risks associated with endovascular management remain unaddressed for post-hemorrhagic cerebral vasospasm (PHCV) caused by pathologies that cannot be secured or identified before vasospasm treatment. This retrospective study reviews our 10 year experience in the difficult scenario of subarachnoid hemorrhage (SAH) with vasospasm, including intra-arterial vasodilators or percutaneous transluminal angioplasty (PTA) to vessels feeding a ruptured unsecured lesion. METHODS: 10 SAH patients with ruptured unsecured vascular lesions underwent 44 endovascular treatments for PHCV (2002-2011). We defined unsecured as an untreated aneurysm/dissection, incompletely coiled aneurysm, dissection covered with self-expanding nitinol stents, or angiographically negative SAH. Treatments were categorized by location of the ruptured unsecured (partial or complete) lesion relative to the vessel treated for vasospasm. RESULTS: Our 10 patients with four aneurysms, four dissections, and two angiographically negative SAH accounted for 10.3% of SAH patients who underwent angiography for vasospasm. No procedure related complications occurred when treating vessels not supplying the index lesion or with angiographically negative SAH. Of the endovascular treated vessels supplying partially secured lesions, one (6.3%) fatal complication occurred; none of these patients receiving only vasodilators had complications. With endovascular treatment of PHCV with completely unsecured lesions, one (33%) complication was fatal. CONCLUSIONS: Endovascular treatment appeared safe for PHCV for vessels not supplying the index arterial lesion and for angiographically negative SAH. Vasodilators were safe for vessels harboring partially secured, ruptured lesions (eg, incompletely coiled aneurysms, stented dissections). Following two major complications, the safety of administering vasodilators or performing PTA to vessels supplying completely unsecured vascular lesions remains inconclusive and should be used cautiously. PMID- 23361617 TI - Strongly coupled inorganic-nano-carbon hybrid materials for energy storage. AB - The global shift of energy production from fossil fuels to renewable energy sources requires more efficient and reliable electrochemical energy storage devices. In particular, the development of electric or hydrogen powered vehicles calls for much-higher-performance batteries, supercapacitors and fuel cells than are currently available. In this review, we present an approach to synthesize electrochemical energy storage materials to form strongly coupled hybrids (SC hybrids) of inorganic nanomaterials and novel graphitic nano-carbon materials such as carbon nanotubes and graphene, through nucleation and growth of nanoparticles at the functional groups of oxidized graphitic nano-carbon. We show that the inorganic-nano-carbon hybrid materials represent a new approach to synthesize electrode materials with higher electrochemical performance than traditional counterparts made by simple physical mixtures of electrochemically active inorganic particles and conducting carbon materials. The inorganic-nano carbon hybrid materials are novel due to possible chemical bonding between inorganic nanoparticles and oxidized carbon, affording enhanced charge transport and increased rate capability of electrochemical materials without sacrificing specific capacity. Nano-carbon with various degrees of oxidation provides a novel substrate for nanoparticle nucleation and growth. The interactions between inorganic precursors and oxidized-carbon substrates provide a degree of control over the morphology, size and structure of the resulting inorganic nanoparticles. This paper reviews the recent development of inorganic-nano-carbon hybrid materials for electrochemical energy storage and conversion, including the preparation and functionalization of graphene sheets and carbon nanotubes to impart oxygen containing groups and defects, and methods of synthesis of nanoparticles of various morphologies on oxidized graphene and carbon nanotubes. We then review the applications of the SC-hybrid materials for high performance lithium ion batteries, rechargeable Li-S and Li-O2 batteries, supercapacitors and ultrafast Ni-Fe batteries, and new electrocatalysts for oxygen reduction, oxygen evolution and hydrogen evolution reactions. PMID- 23361618 TI - Recent advances in Many Body Dissipative Particles Dynamics simulations of liquid vapor interfaces. AB - Many Body Dissipative Particles Dynamics (MDPD) simulation is a novel promising mesoscopic method to model the liquid-vapor interfaces. Based upon works of Paganobarraga and Frenkel (J. Chem. Phys. 15, 5015 (2001)) and Trofimov (J. Chem. Phys. 117, 9383 (2002)) and of Warren (Phys. Rev. E 68, 066702 (2003)) this method has been critically reviewed during this last decade. We propose here to give an overview of the Many Body Dissipative Particles Dynamic simulation within the framework of the liquid-vapor interfaces. We recall the theoretical background of MDPD and we present some recent results of systems of interest such as water liquid-vapor interfaces and salt effect on water surface tension. Additionally we discuss the ability of MDPD to capture the mechanisms at the mesoscopic scale through the formation of micelles and the coalescence of a nanodroplet water on water surface. PMID- 23361619 TI - Purkinje cell simple spike discharge encodes error signals consistent with a forward internal model. AB - Processing motor errors is essential for online control of goal-directed movements and motor learning. Evidence from psychophysical and imaging studies supports the long-standing view that error processing is central to cerebellar function. The dominant view is that error-related signals are encoded in the complex spike discharge of Purkinje cells. However, the findings are inconsistent on whether complex spike activity correlates with motor errors. Recently, we examined if simple spike firing carries error signals in monkeys trained to manually track a randomly moving target. The task requires continuous processing of motor errors characterized by the relative movements between the hand-driven cursor and the target center. Linear regression models show that error parameters are robustly represented in the simple spike activity of most Purkinje cells. At the single cell level, the error signals are encoded independently and integrated with kinematic signals. In a large majority of Purkinje cells, correlation strengths between the simple spike discharge and an error parameter have bimodal profiles with respect to time, exhibiting a local maxima corresponding to firing leading the behavior and another one corresponding to firing lagging behavior. The bimodal temporal profiles suggest that individual error parameters are dually encoded as both an internal prediction used for feedback-independent, compensatory movements and the actual sensory feedback used to monitor performance. Approximately 75 % of the dual representations have opposing modulations of the simple spike activity, one increasing firing and the other depressing firing, as reflected by the reversed signs of the regression coefficients corresponding to the local maxima of the R (2) profile. These dual representations of individual parameters with opposing modulation of the simple spike firing are consistent with the signals needed to generate sensory prediction errors used to update an internal model. PMID- 23361620 TI - Suitability of the ovine model for simulation training in rhinology. PMID- 23361621 TI - A phase I trial of KX2-391, a novel non-ATP competitive substrate-pocket- directed SRC inhibitor, in patients with advanced malignancies. AB - BACKGROUND: Src kinase is central to tumor cell proliferation, apoptosis, and metastasis. KX2-391 is a synthetic, orally bioavailable small molecule inhibitor of Src tyrosine kinase (TK) signaling and tubulin polymerization. This compound is distinct from other Src kinase inhibitors by targeting the peptide substrate rather than the ATP binding site; the binding site on hetero-dimeric tubulin is novel and distinct from the taxanes and other known tubulin inhibitors. METHODS: This multicenter Phase I trial utilized a 4 + 2 study design to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics (PK) of KX2-391 in patients with refractory solid tumors. RESULTS: Forty-four (44) patients (18 M, 26 F; median age, 59) were enrolled in 9 dose cohorts. Dose-limiting toxicities, all reversible within 7 days, occurred in 7 patients and consisted of elevated AST (n = 4), ALT (n = 2), neutropenia (n = 1), thrombocytopenia (n = 1), failure to thrive (n = 1) and anorexia (n = 1). The MTD is 40 mg BID continuously. Eleven patients had stable disease for >= 4 months, including patients with ovarian, carcinoid, papillary thyroid, prostate, pancreas and head and neck cancer. Patients with prostate and pancreatic cancer also had significant biomarker decreases (PSA, 205 ng/mL to 39 ng/mL; CA19-9, 38,838 U/mL to 267 U/mL). The ovarian cancer patient has had stable disease > 12 months. KX2-391 was orally available, rapidly absorbed, and exposure was proportional to dose across the range investigated. CONCLUSIONS: KX2-391 has a favorable pharmacokinetic profile, is well tolerated, demonstrates preliminary evidence of biologic activity, and warrants further evaluation in Phase II trials. PMID- 23361622 TI - Transcription of atp1 is influenced by both genomic configuration and nuclear background in the highly rearranged mitochondrial genomes of Silene vulgaris. AB - An extraordinary variation in mitochondrial DNA sequence exists in angiosperm Silene vulgaris. The atp1 gene is flanked by very variable regions, as deduced from four completely sequenced mitochondrial genomes of this species. This diversity contributed to a highly variable transcript profile of this gene observed across S. vulgaris populations. We examined the atp1 transcript in the KOV mitochondrial genome and found three 5' ends, created most likely by the combination of transcription initiation and RNA processing. Most atp1 transcripts terminated about 70 bp upstream of the translation stop codon, which was present in only 10 % of them. Controlled crosses between a KOV mother and a geographically distant pollen donor (Krasnoyarsk, Russia) showed that nuclear background also affected atp1 transcription. The distant pollen donor introduced the factor(s) preventing the formation of a long 2,100 nt-transcript, because this long atp1 transcript reappeared in the progeny from self-crosses. The highly rearranged mitochondrial genomes with a variation in gene flanking regions make S. vulgaris an excellent model for the study of mitochondrial gene expression in plants. PMID- 23361623 TI - The BTBD9 gene may be associated with antipsychotic-induced restless legs syndrome in schizophrenia. AB - OBJECTIVE: A genome-wide association study and several replication studies have shown significant association between BTBD9 gene single nucleotide polymorphisms and restless legs syndrome (RLS). The aim of this study is to investigate the association between the BTBD9 gene polymorphisms and antipsychotic-induced RLS in schizophrenic patients. METHODS: Restless legs syndrome symptoms were evaluated using the diagnostic criteria of the International Restless Legs Syndrome Study Group in 190 Korean schizophrenic patients. We genotyped the rs9357271 and rs3923809 polymorphisms of the BTBD9 gene in schizophrenic patients with (n = 96) and without (n = 94) RLS symptoms. RESULTS: There was a significant difference in the allele frequency (chi(2) = 8.14, p = 0.004) of the rs9357271 polymorphism between schizophrenic patients with and without RLS symptoms. Significant genotypic association of this single nucleotide polymorphisms with RLS symptoms was also observed for the dominant model (chi(2) = 10.32, p = 0.001) and heterozygous model (chi(2) = 10.9, p = 0.001). When we compared the frequencies of the rs3923809-rs9357271 haplotypes between the two groups, the overall haplotype frequencies were significantly different (permuted p = 0.037), and the A-T haplotype was significantly more frequent in the RLS symptom group than in the no RLS symptom group (0.112 vs. 0.041, permuted p = 0.007). CONCLUSIONS: These data suggest that the BTBD9 gene is associated with antipsychotic-induced RLS symptoms in schizophrenic patients. PMID- 23361624 TI - The strain and thermal induced tunable charging phenomenon in low power flexible memory arrays with a gold nanoparticle monolayer. AB - The strain and temperature dependent memory effect of organic memory transistors on plastic substrates has been investigated under ambient conditions. The gold (Au) nanoparticle monolayer was prepared and embedded in an atomic layer deposited aluminum oxide (Al(2)O(3)) as the charge trapping layer. The devices exhibited low operation voltage, reliable memory characteristics and long data retention time. Experimental analysis of the programming and erasing behavior at various bending states showed the relationship between strain and charging capacity. Thermal-induced effects on these memory devices have also been analyzed. The mobility shows ~200% rise and the memory window increases from 1.48 V to 1.8 V when the temperature rises from 20 degrees C to 80 degrees C due to thermally activated transport. The retention capability of the devices decreases with the increased working temperature. Our findings provide a better understanding of flexible organic memory transistors under various operating temperatures and validate their applications in various areas such as temperature sensors, temperature memory or advanced electronic circuits. Furthermore, the low temperature processing procedures of the key elements (Au nanoparticle monolayer and Al(2)O(3) dielectric layer) could be potentially integrated with large area flexible electronics. PMID- 23361626 TI - How to explain and exploit the beneficial effects of high-volume hemofiltration on hemodynamics and strong ion gap. PMID- 23361628 TI - Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. AB - PURPOSE: Evidence of efficacy and safety of, and especially mortality related to, recombinant human thrombomodulin (rhTM) treatment for sepsis-induced disseminated intravascular coagulation (DIC) is limited. We hypothesized that patients with sepsis-induced DIC receiving treatment with rhTM would have improved mortality compared with those with similar acuity who did not. METHODS: This retrospective cohort study conducted in three tertiary referral hospitals in Japan between January 2006 and June 2011 included all patients with sepsis-induced DIC who required ventilator management. Primary endpoint was in-hospital mortality, with duration of intensive care unit treatment, changes in DIC scores and rate of bleeding complications as secondary endpoints. Regression technique was used to develop a propensity model adjusted for baseline imbalances between groups. RESULTS: Eligible were 162 patients with sepsis-induced DIC; 68 patients received rhTM and 94 did not. Patients receiving rhTM had higher severity of illness according to baseline characteristics. After adjusting for these imbalances by stratified propensity score analysis, treatment with rhTM was significantly associated with reduced in-hospital mortality (adjusted hazard ratio, 0.45; 95 % confidential interval, 0.26-0.77; p = 0.013). An association between rhTM treatment and higher numbers of intensive care unit-free days, ventilator-free days, and vasopressor-free days were observed. DIC scores were significantly decreased in the rhTM group compared with the control group in the early period after rhTM treatment, whereas the incidence of bleeding-related adverse events did not differ between the two groups. CONCLUSIONS: Therapy with rhTM may be associated with reduced in-hospital mortality in adult mechanically ventilated patients with sepsis-induced DIC. PMID- 23361631 TI - Weaning children from mechanical ventilation with a computer-driven protocol: a pilot trial. AB - PURPOSE: Duration of weaning from mechanical ventilation is decreased with the use of written protocols in adults. In children, the use of written protocols has not had such an impact. METHODS AND MEASUREMENTS: We conducted a single-center trial to assess the feasibility of conducting a multicenter randomized clinical trial comparing the duration of weaning from mechanical ventilation in those managed by a computer-driven explicit protocol versus usual care. Mechanically ventilated children aged between 2 and 17 years on pressure support and not receiving inotropes were included. After randomization, children were weaned either by usual care (n = 15) that was characterized by no protocolized decisions by attending physicians, or by a computer-driven protocol (Smartcare/PSTM, Drager Medical) (n = 15). Weaning duration until first extubation was the primary outcome. For comparison, a Mann-Whitney U test was employed (p < 0.05). RESULTS: Patients characteristics at inclusion were similar. The median duration of weaning was 21 h (range 3-142 h) in the SmartCare/PSTM group and 90 h (range 4 552 h) in the usual care group, p = 0.007. The rate of reintubation within 48 h after extubation and the rate of noninvasive ventilation after extubation in the SmartCare/PSTM and usual care groups were 2/15 versus 1/15 and 2/15 versus 2/15, respectively. CONCLUSIONS: A pediatric randomized trial on mechanical ventilation with a computerized protocol in North America is feasible. A computer-driven protocol that also manages children younger than 2 years old would help to decrease the number of PICU admissions screened in a multicentre trial on this topic. PMID- 23361630 TI - Accuracy of plasma neutrophil gelatinase-associated lipocalin in the early diagnosis of contrast-induced acute kidney injury in critical illness. AB - PURPOSE: Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker for acute kidney injury (AKI). We evaluated the diagnostic and prognostic accuracies of plasma NGAL (pNGAL) for contrast-induced AKI (CI-AKI) in critically ill patients. METHODS: In a prospective observational study in two adult intensive care units in a university hospital, 100 consecutive critically ill patients with stable serum creatinine concentrations up to 48 h before contrast medium (CM) injection were enrolled. Serial blood sampling for pNGAL analysis was performed at enrolment, 2, 6, and 24 h after CM injection. The primary outcome was CI-AKI, defined by AKIN criteria, within the first 72 h following CM injection. Secondary outcomes were the need for renal replacement therapy (RRT) and mortality. RESULTS: Of the 98 patients analyzed, 30 developed CI-AKI. The pNGAL levels did not differ in patients with or without CI-AKI, and were higher in septic patients compared to nonseptic patients, and in patients with AKI preceding CM injection. The discriminative value of pNGAL to predict CI AKI and mortality was poor; although, it did predict the need for RRT requirement after CM injection (area under receiver-operating characteristic curve, 0.85, 0.80, 0.83 and 0.86 at H0, H2, H6 and H24, respectively). CONCLUSION: CI-AKI was common in critically ill patients. pNGAL levels were higher in patients with sepsis or previous AKI, but did not help to diagnose CI-AKI any earlier than serum creatinine after CM injection. However, pNGAL could be of interest to detect patients at risk of subsequent RRT requirement. PMID- 23361632 TI - Targeting tumour necrosis factor-alpha in hypoxia and synaptic signalling. AB - Tumour necrosis factor (TNF)-alpha is a pro-inflammatory cytokine, which is synthesised and released in the brain by astrocytes, microglia and neurons in response to numerous internal and external stimuli. It is involved in many physiological and pathophysiological processes such as gene transcription, cell proliferation, apoptosis, synaptic signalling and neuroprotection. The complex actions of TNF-alpha in the brain are under intense investigation. TNF-alpha has the ability to induce selective necrosis of some cells whilst sparing others and this has led researchers to discover multiple activated signalling cascades. In many human diseases including acute stroke and inflammation and those involving hypoxia, levels of TNF-alpha are increased throughout different brain regions. TNF-alpha signalling may also have several positive and negative effects on neuronal function including glutamatergic synaptic transmission and plasticity. Exogenous TNF-alpha may also exacerbate the neuronal response to hypoxia. This review will summarise the actions of TNF-alpha in the central nervous system on synaptic signalling and its effects during hypoxia. PMID- 23361633 TI - A novel case of laparoscopic ureterolithotomy in a partial duplex ureteric collecting system: can open procedures still be justified in the minimally invasive era? AB - BACKGROUND: Impacted ureteric stones can pose a treatment challenge due to the high level of failure of ESWL and endourological approaches. Laparoscopic ureterolithotomy can provide a safe and successful alternative to these and open, invasive procedures. METHODS: Interval laparoscopic ureterolithtomy was carried out following placement of a percutaneous nephrostomy. This was performed through an trans-peritoneal approach with the ureterotomy closed by intracorporeal suturing and placement of a JJ stent without the need for an abdominal wound drain. CONCLUSION: Laparoscopic ureterolithotomy is a safe, minimally invasive method of managing large, impacted ureteric stones with minimal associated patient morbidity. PMID- 23361634 TI - An evidence-based assessment of primary care needs in an economically deprived urban community. AB - BACKGROUND: As healthcare and longevity improve and fertility rates decline, we see a demographic shift towards a predominantly elderly population. Because ageing brings its own physiological changes and complications, the need arises for practical and feasible approaches in providing the healthcare required by this population. With government strategy promoting enhanced community-based healthcare, the development of primary care infrastructure should reflect population needs. AIMS: To describe the profile of older patients attending a general practice in an underprivileged urban setting, specifically initial medical presentation, referrals for secondary care, and the medicines prescribed to them. To thereby enhance our understanding of the primary care requirements of elderly people in this setting. METHODS: The anonymised records of an older patient cohort (n=427, age>55 years) that presented to a General Practice over a 12-month period were retrospectively analysed to determine the nature of the clinical encounters, subsequent referral patterns and drugs prescribed. RESULTS: There were 3,448 discrete clinical encounters (mean=8.0 per patient), predominantly for respiratory conditions, leading to 401 issued scripts and to 216 patients being referred for secondary care. Women were referred more often than men. There was a notable need for specialised dietary advice and drug prescribing was often complex. CONCLUSION: This study provides evidence of primary care needs in an economically deprived area of an Irish city highlighting the complexity of associated prescribing and secondary care referrals in this setting. PMID- 23361635 TI - Microsurgical endoscopy-assisted presigmoid retrolabyrinthine approach as a minimally invasive surgical option for the treatment of medium to large vestibular schwannomas. AB - BACKGROUND: Treatment of vestibular schwannomas presents many controversial aspects, from the indication to the selection of the best treatment option. In the era of stereotactic radiotherapy, microsurgery has to be competitive in terms of providing the best chances of functional preservation and complete tumor removal. The two most commonly used surgical approaches are the retrosigmoid suboccipital and the presigmoid translabyrinthine. We describe the endoscopy assisted presigmoid retrolabyrinthine approach (EAPRA) aiming at combining the advantages of the retrosigmoid and translabyrinthine techniques. METHODS: For 2 years (from May 2009 to June 2011), the EAPRA was used to remove medium to large sporadic vestibular schwannomas in ten patients. RESULTS: Complete tumor removal was obtained in eight patients, postoperative transient facial nerve function impairment or worsening was observed in two, and one had hearing deterioration postoperatively. No threatening complications occurred after surgery, and the length of hospitalization was usually less than 10 days. CONCLUSIONS: The EAPRA can provide direct access to the CPA along with labyrinthine complex conservation, allowing hearing function preservation and minimal cerebellar retraction. Endoscopic assistance is a crucial adjunct in the presigmoid retrolabyrinthine approach in order to address the limits imposed by labyrinthine complex preservation. It ensures complete visualization of the intracanalicular portion of the schwannoma, thus improving the rate of a radical tumor resection. The EAPRA could represent a valid surgical option in vestibular schwannoma surgery. PMID- 23361636 TI - Rare serious complications of erlotinib therapy. PMID- 23361637 TI - Effect of carotid endarterectomy on cognitive function in patients with asymptomatic carotid artery stenosis. AB - BACKGROUND: This study was conducted to determine if patients with asymptomatic carotid artery stenosis show cognitive function decline, and if they experience any changes in cognitive function after carotid endarterectomy (CEA). METHOD: Cognitive function was examined in 15 patients (12 males and three females, 70.0 +/- 6.5 years) with asymptomatic carotid artery stenosis before and 3 months after CEA. Cognitive function was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), two subtests of the Wechsler Adult Intelligence Scale-Revised (WAIS-R 2 subtests), and the Japanese version of National Adult Reading Test (JART). The patients' average scores were compared with the normal average by one-sample t-tests, and the before and after scores were compared with paired t-tests. Changes in each patient were calculated from difference before and after CEA using 95 % confidence intervals. RESULTS: Before surgery, patients showed significant cognitive decline in RBANS total scale and immediate memory, language, and attention. At 3 months after CEA, the total scale and the immediate memory were not significantly different from the normal average. The average total scale score, the immediate memory and attention, and the WAIS-R 2 subtests scores were increased after treatment. Changes in each patient were calculated from the scores before and after CEA. At 3 months after CEA, the rate of increase in RBANS scores were 60.0 % of the patients for immediate memory, 26.7 % for visuospatial/constructional, 33.3 % for language and attention, 26.7 % for delayed memory, 47.7 % for total scale and 26.7 % for WAIS R 2 subtests. Thus, so-called asymptomatic patients exhibit mild cognitive impairment before surgery, but after CEA, patients recover normal memory abilities. CONCLUSIONS: Our findings of mild cognitive dysfunction in asymptomatic patients suggest that they might be symptomatic after all. PMID- 23361638 TI - Solvatochromic behavior of chiral mesoporous metal-organic frameworks and their applications for sensing small molecules and separating cationic dyes. AB - Two anionic metal-organic frameworks (MOFs) with 1D mesoporous tubes (1) and chiral mesoporous cages (2) have been rationally constructed by means of a predesigned size-extended hexatopic ligand, namely, 5,5',5''-(1,3,5-triazine 2,4,6-triyl)tris- (azanediyl)triisophthalate (TATAT). Charge neutrality is achieved by protonated dimethylamine cations. Notably, the two MOFs can be used to separate large molecules based on ionic selectivity rather than the size exclusion effect so far reported in the literature. Owing to the imino triazine backbone and carboxyl groups of the hexatopic ligand, which provide important host-guest interactions, rare solvatochromic phenomena of 1 and 2 are observed on incorporating acetone and ethanol guests. Furthermore, guest-dependent luminescence properties of compound 2 were investigated, and the results show that luminescence intensity is significantly enhanced in toluene and benzene, while quenching effects are observed in acetone and ethanol. Thus, compound 2 may be a potential material for luminescent probes. PMID- 23361641 TI - Comparative antibacterial effects of moxifloxacin and levofloxacin on Streptococcus pneumoniae strains with defined mechanisms of resistance: impact of bacterial inoculum. AB - OBJECTIVES: We aim to further define the impact of the mechanism of fluoroquinolone resistance and inoculum load on the pharmacodynamic effects of levofloxacin and moxifloxacin on Streptococcus pneumoniae. METHODS: The antibacterial effects of and emergence of resistance (EoR) to moxifloxacin (400 mg once daily) or levofloxacin (750 mg once daily or 500 mg twice daily) were compared using five S. pneumoniae strains containing no known resistance mechanisms, efflux resistance mechanisms, a parC mutation or parC and gyrA mutations, at high (10(8) cfu/mL) and low (10(6) cfu/mL) inocula. An in vitro pharmacokinetic model was used and simulations were performed over 96 h. After drug exposure, isolates were tested for the presence of efflux pumps and mutations in the quinolone resistance-determining regions. RESULTS: A high inoculum diminished the antibacterial effect of moxifloxacin and levofloxacin. Levofloxacin at both dosages produced EoR with all strains. Levofloxacin regimens with AUC/MIC ratios <100 produced EoR. Moxifloxacin produced EoR with the parC strain only. CONCLUSIONS: Levofloxacin dosing regimens with low AUC/MIC ratios select for efflux pump overexpression, leading to fluoroquinolone resistance. Levofloxacin dosing may select for gyrA mutations, inducing moxifloxacin resistance. These data confirm that a fluoroquinolone AUC/MIC ratio of >100 is required for prevention of EoR. PMID- 23361642 TI - Prevalence of pre-existing resistance-associated mutations to rilpivirine, emtricitabine and tenofovir in antiretroviral-naive patients infected with B and non-B subtype HIV-1 viruses. AB - OBJECTIVES: The prevalence of rilpivirine, emtricitabine and tenofovir resistance associated mutations (RAMs), described in vitro and in vivo, was determined in antiretroviral-naive patients. PATIENTS AND METHODS: From 2008 to 2011, 1729 treatment-naive patients were tested for resistance by bulk sequencing. We studied the primary rilpivirine RAMs (K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C and M230I/L) and other potential rilpivirine-associated mutations (V90I, L100I, K101T, E138S, V179D/I, Y188L, V189I, G190A/E/S and M230V). We also studied the M184V/I and K65R mutations for emtricitabine and tenofovir, respectively. RESULTS: Among 1729 sequences, half of patients had B-subtype viruses and the other half non-B (with 26.7% CRF02, n=461). Primary rilpivirine RAMs were infrequent (4.6%, n=79) and the most prevalent were E138A (3%, n=52), E138K, (0.3%, n=5), H221Y (0.3%, n=5), E138G (0.2%, n=4) and Y181C (0.2%, n=4). The frequency of the primary rilpivirine RAMs was similar between B and non-B subtypes. The other potential rilpivirine-associated mutations that were most prevalent were V179I (8.4%, n=145), V90I (3.8%, n=65) and V189I (2.3%, n=40). The common V179I, V189I and V90I polymorphisms have not been associated with virological failure in Phase 3 clinical studies. By the ANRS algorithm, 4.9% (n=84) of samples were resistant to rilpivirine, 3.7% (n=32) of B-subtype viruses versus 6% (n=52) of non-B-subtype viruses (P=0.02, chi(2) test). The prevalence of K65R and M184I/V was 0.06% (1/1729) and 1% (18/1729), respectively. The prevalence of K103N was 2% (35/1729). CONCLUSIONS: The prevalence of rilpivirine, emtricitabine and tenofovir resistance mutations was very low in antiretroviral naive patients. The prevalence of resistance to rilpivirine (4.9%, n=84) was not statistically different from the prevalence of efavirenz and nevirapine resistance in our population. PMID- 23361643 TI - pMdT1, a small ColE1-like plasmid mobilizing a new variant of the aac(6')-Ib-cr gene in Salmonella enterica serovar Typhimurium. AB - OBJECTIVES: To characterize a 5.9 kb aac(6')-Ib-cr-harbouring plasmid that was detected in a clinical Salmonella Typhimurium DT104B strain. METHODS: Extraction and purification of plasmid DNA and electrotransformation assays were carried out in order to obtain kanamycin-resistant transformants. MICs of several fluoroquinolones and aminoglycosides were determined. DNA sequencing was performed by primer walking on purified plasmid preparations. The new plasmid nucleotide sequence was analysed and compared with available sequences using bioinformatic tools. RESULTS: pMdT1 is a 5.9 kb mobilizable ColE1-like plasmid that harbours aac(6')-Ib-cr4, a gene encoding a new variant of the AAC(6')-Ib-cr protein (225 amino acids). This active protein conferred resistance to tobramycin and kanamycin, and also decreased susceptibility to ciprofloxacin and norfloxacin in the transformant strain, as MICs demonstrated. The mobilization region, necessary for horizontal transfer and composed of the mobA, mobB, mobC and mobD genes, displayed a high degree of identity with those from representative ColE1 like plasmids. The basis of mobility (bom), oriT and origin of replication regions were also detected. Apart from the acetylase-encoding gene, three other open reading frames (ORFs) were determined. No similarities were found when the ORF1 sequence was compared with the sequences included in GenBank. The deduced ORF2 protein predicted a CopG-like structure characteristic of transcriptional regulators, and the deduced ORF3 protein was identical to macrophage stimulating factors. CONCLUSIONS: The pMdT1 is the smallest mobilizable ColE1-like plasmid containing an aac(6')-Ib-cr gene that has been described so far. PMID- 23361644 TI - cDNA cloning and sequence determination of the pheromone biosynthesis activating neuropeptide from the seabuckthorn carpenterworm, Holcocerus hippophaecolus (Lepidoptera: Cossidae). AB - The PBAN (pheromone biosynthesis activating neuropeptide)/pyrokinin peptides comprise a major neuropeptide family characterized by a common FXPRL amide at the C-terminus. These peptides are actively involved in many essential endocrine functions. For the first time, we reported the cDNA cloning and sequence determination of the PBAN from the seabuckthorn carpenterworm, Holcocerus hippophaecolus, by using rapid amplification of cDNA ends. The full-length cDNA of Hh-DH-PBAN contained five peptides: diapause hormone (DH) homolog, alpha neuropeptide (NP), beta-NP, PBAN, and gamma-NP. All of the peptides were amidated at their C-terminus and shared a conserved motif, FXPR (or K) L. Moreover, Hh-DH PBAN had high homology to the other members of the PBAN peptide family: 56% with Manduca sexta, 66% with Bombyx mori, 77% with Helicoverpa zea, and 47% with Plutella xylostella. Phylogenetic analysis revealed that Hh-DH-PBAN was closely related to PBANs from Noctuidae, demonstrated by the relatively higher similarity compared with H. zea. In addition, real-time quantitative PCR (qRT-PCR) analysis showed that Hh-DH-PBAN mRNA expression peaked in the brain-subesophageal ganglion (Br-SOG) complex, and was also detected at high levels during larval and adult stages. The expression decreased significantly after pupation. These results provided information concerning molecular structure characteristics of Hh-DH PBAN, whose expression profile suggested that the Hh-DH-PBAN gene might be correlated with larval development and sex pheromone biosynthesis in females of the H. hippophaecolus. PMID- 23361645 TI - Convincing evidence from controlled and uncontrolled studies on the lipid lowering effect of a statin. PMID- 23361625 TI - Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. AB - OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first choice vasopressor to maintain mean arterial pressure >=65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of <=100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) <150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are >180 mg/dL, targeting an upper blood glucose <=180 mg/dL (1A); equivalency of continuous veno venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients. PMID- 23361646 TI - Monitoring of growth and physiological activities of biofilm during succession on polystyrene from activated sludge under aerobic and anaerobic conditions. AB - The present research work monitored the successive biofilm development and its catabolic role in the degradation of polystyrene (PS). PS material was artificially colonized with biofilm by incubating it with activated sludge under aerobic and anaerobic conditions. Biofilm formation was monitored by gravimetric weight analysis, spectrophotometric absorbance technique, heterotrophic plate count, and scanning electron microscopy under aerobic and anaerobic conditions. The wet weight (1.59 and 1.17 g) and dry weight (0.41 and 0.08 g) of a biofilm showed a significant constant increase under aerobic and anaerobic conditions, respectively, from first till 9 weeks of incubation. Plate count of the selected bacteria (Escherichia coli, Salmonella typhimurium, Shigella dysenteriae, Pseudomonas aeruginosa) considerably declined (90-99 %) in the biofilm after seventh and fifth weeks of incubation under aerobic and anaerobic conditions, respectively, indicating a positive shift from pathogenic to beneficial microbial community. While most probable number index of fecal coliforms and E. coli in the sludge showed more reduction (98 and 99 %) under aerobic as compare to anaerobic conditions (86 and 91 %) after 9 weeks of biofilm formation on PS cubes. Correspondingly, the decreasing levels of chemical oxygen demand and biochemical oxygen demand (up to 73 %) showed signs of sludge digestion. Scanning electron microscope coupled with energy dispersive X-ray spectroscope revealed nature of PS media containing high carbon content. However, biofilm development proved to be involved in the biochemical transformation of the PS medium as indicated by Fourier transform infrared spectroscopy. PMID- 23361647 TI - Critical Role for hierarchical geospatial analyses in the design of fluvial research, assessment, and management. AB - River science and management can be conducted at a range of spatiotemporal scales from reach to basin levels as long as the project goals and questions are matched correctly with the study design's spatiotemporal scales and dependent variables. These project goals should also incorporate information on the hydrogeomorphically patchy nature of riverine macrosystems which is only partially predictable in type and location from a river's headwaters to its terminus. This patchiness significantly affects a river's habitat template, and thus community structure, ecosystem function, and responses to perturbations. Our manuscript is designed for use by senior administrators at government agencies through entry-level river scientists. It analyzes common challenges in project design and recommends solutions based partially on hierarchical analyses that combine geographic information systems and multivariate statistical analysis to enable self-emergence of a stream's patchy structure. These approaches are useful at all spatial levels and can vary from primary reliance on geospatial techniques at the valley level to a greater dependence on field-based measurements and expert opinion at the reach level. Comparative uses of functional process zones (FPZs = valley-scale hydrogeomorphic patches), ecoregions, hydrologic unit codes, and reaches in project designs are discussed along with other comparative approaches for stream classification and analysis of species distributions (e.g., GAP analysis). Use of hierarchical classification of patch structure for sample stratification, reference site selection, ecosystem services, rehabilitation, and mitigation are briefly explored. PMID- 23361648 TI - Quantification of PAHs and chlorinated compounds by novel solid-phase microextraction based on the arrays of tin oxide nanorods. AB - The results of an innovative study on a new and highly efficient stationary phase based on the SnO2 nanorods coating on fused silica have been reported in this paper. SnO2 nanorods have been grown on fused silica fibers using a hydrothermal process. The extraction properties of the fiber were investigated using headspace solid-phase microextraction (HS-SPME) mode coupled with gas chromatography-mass spectrometry detection for 1,4-dichloro-2-nitrobenzene, biphenyl, and acenaphthene. The effect of different variables on extraction efficiency was studied simultaneously using Box-Behnken method as experimental design. The variables of interest in the HS-SPME were salt effect, adsorption temperature, extraction, and desorption time. Under optimal conditions, the calibration curves were linear up to 10(2)-10(5) ng L(-1) (R(2) > 0.998) with detection limits of 10(-3), 10(-1), and 10 ng L(-1) for acenaphthene, biphenyl, and 1,4-dichloro-2 nitrobenzene, respectively. The relative standard deviations for single fiber and fiber to fiber were less than 9.8 and 12.5 %, respectively. The high stability of the SnO2 nanostructure coating is proved at relatively high temperatures (up to 300 degrees C) with a high extraction capacity and long lifespan (more than 100 times). By applying the proposed technique, promising recoveries (93-98 %) were obtained in the analysis of environmental water samples. PMID- 23361649 TI - The synthesis and antiparasitic activity of aryl- and ferrocenyl-derived thiosemicarbazone ruthenium(II)-arene complexes. AB - A series of aryl-functionalized and ferrocenyl monothiosemicarbazone compounds (L1-L4) were synthesized in moderate yields via a general Schiff-base condensation reaction. The thiosemicarbazone (TSC) ligands were reacted with the ruthenium dimer [Ru(Ar)(MU-Cl)Cl](2) (Ar = benzene; p-cymene) to yield a series of cationic mononuclear ruthenium(II)-arene thiosemicarbazone complexes of the general type [Ru(Cl)(TSC)(Ar)]Cl (1-8). The thiosemicarbazone ligands act as bidentate chelating ligands that coordinate to the ruthenium(ii) ion via the imine nitrogen and the thione sulfur atoms. The thiosemicarbazone ligands, as well as their metal complexes, were characterized by NMR, IR spectroscopy and ESI(+)-mass spectrometry. The molecular structure of the mononuclear ruthenium(II)-arene thiosemicarbazone complex (6) was determined by single crystal X-ray diffraction analysis. The ruthenium(II)-arene thiosemicarbazone complexes were further evaluated for their in vitro antiparasitic activities against the Plasmodium falciparum chloroquine-sensitive (NF54) and chloroquine resistant (Dd2) strains, as well as the G3 strain of Trichomonas vaginalis. PMID- 23361650 TI - Tibial inlay reconstruction of the medial collateral ligament using Achilles tendon allograft for the treatment of medial instability of the knee. AB - Although various surgical procedures have been described for the medical collateral ligament (MCL) reconstruction, none can accurately reestablish its original anatomy and orientation. The purpose of this study was to present a technique restoring the anatomy and stability of the medial knee with an Achilles tendon allograft using a tibial inlay technique. The bone block was fixed into a cancellous trough created on the medial surface of the tibia with a cancellous screw and washer, while the tendinous portion was fixed into the femoral insertion site of the superficial MCL with a bioabsorbable interference screw. This technique can successfully reproduce the native anatomy and orientation of the MCL. PMID- 23361651 TI - The Videoinsight(r) method: improving rehabilitation following anterior cruciate ligament reconstruction--a preliminary study. AB - PURPOSE: The purpose of this randomized double blind controlled study was to investigate if the vision of contemporary art video according to the Videoinsight((r)) method could produce better short-term clinical and subjective outcomes after anterior cruciate ligament (ACL) reconstruction. METHODS: One hundred and six patients treated with single-bundle ACL reconstruction plus extra articular tenodesis were enrolled in this study and randomly assigned to Group A (53 patients) and Group B (53 patients). Group A received one art video that was established to produce positive and therapeutic "insight", while Group B received one art video with an "insight" unfavourable to the psychological recovery. All patients were instructed to watch the video 3 times a week for the first 2 months during the execution of the same rehabilitative protocol. Patients were evaluated pre-operatively and 3 months after surgery with Tegner, subjective International Knee Documentation Committee (IKDC), physical and mental SF-36 scores and Tampa Scale of Kinesiophobia (TSK). Time to crutches discharge was collected at final follow-up as well. RESULTS: Five patients were lost to follow-up and 101 patients (Group A: 51 patients; Group B: 50 patients) were available at mean 3.0 +/- 0.2 months follow-up. Age at surgery was 33.0 +/- 17.0 years. The two groups were homogeneous regarding pre-operative demographic data, meniscal lesions and clinical outcomes. Significant improvements were observed in Group A compared to Group B at final follow-up for subjective IKDC (82.0 +/- 13.8 vs. 71.0 +/- 19.7, p = 0.0470), TKS (28.1 +/- 6.0 vs. 32.0 +/- 5.8, p = 0.0141) and time to crutches discharge (20.9 +/- 5.0 vs. 26.5 +/- 8.2 days, p = 0.0012). A positive significant correlation between TSK and time to crutches discharge (r = 0.35, p = 0.0121) was observed. CONCLUSIONS: The Videoinsight((r)) method combined to adequate rehabilitation could be an effective tool in order to improve short-term clinical and functional outcomes in patients who underwent ACL reconstruction. PMID- 23361653 TI - Narrow bandgap colloidal metal chalcogenide quantum dots: synthetic methods, heterostructures, assemblies, electronic and infrared optical properties. AB - The chemistry, material processing and fundamental understanding of colloidal semiconductor nanocrystals (quantum dots) are advancing at an astounding rate, bringing the prospects of widespread commercialization of these novel and exciting materials ever closer. Interest in narrow bandgap nanocrystals in particular has intensified in recent years, and the results of research worldwide point to the realistic prospects of applications for these materials in solar cells, infrared optoelectronics (e.g. lasers, optical modulators, photodetectors and photoimaging devices), low cost/large format microelectronics, and in biological imaging and biosensor systems to name only some technologies. Improvements in fundamental understanding and material quality are built on a vast body of experience spread over many different methods of colloidal synthetic growth, each with their own strengths and weaknesses for different materials and sometimes with regard to particular applications. The nanocrystal growth expertise is matched by a rapidly expanding, and highly interdisciplinary, understanding of how best to assemble these materials into films or hybrid composites and thereby into useful devices, and again there are many different strategies that can be adopted. In this review we have attempted to survey and compare the recent work on colloidal synthesis, film and nanocrystal composite material fabrication, concentrating on narrow bandgap chalcogenide materials and some of their topical applications in the solar energy and biological fields. Since these applications are attracting rising interest across a wide range of disciplines, from the biological sciences, device engineering, and materials processing fields as well as the physics and synthetic chemistry communities, we have endeavoured to make the review of these narrow bandgap nanomaterials both comprehensive and accessible to newcomers to the area. PMID- 23361652 TI - Is there a relationship between tracking ability, joint position sense, and functional level in patellofemoral pain syndrome? AB - PURPOSE: This prospective cohort study investigated proprioception and motor control changes in patients with patellofemoral pain syndrome (PFPS), and how these changes related to knee function, pain, muscle strength and muscle endurance. METHODS: The study included 43 women diagnosed with unilateral patellofemoral pain syndrome. Thirty-one healthy women were recruited as control group. Peak quadriceps femoris and hamstring muscle isokinetic torques were recorded at 60 and 180 degrees /s. Joint position sense was tested by active reproduction of joint position during horizontal squat performance. Muscle coordination and motor control ability were tested by a multi-joint lower limb tracking-trajectory test. Muscle endurance was tested using a computerized functional squat system. Severity of pain in during stair ascent/descent, squatting, and prolonged sitting with knees 90 degrees flexed were measured using a 10 category modified visual analogue scale. Functional levels of patients were determined using Kujala patellofemoral scores. RESULTS: Active reproduction of joint position did not differ between PFPS and control groups. However, tracking-trajectory error was significantly higher in PFPS group than control subjects. Hamstring and quadriceps peak isokinetic torque and muscle endurance scores were significantly lower in the PFPS group. Kujala patellofemoral score displayed significant relationships with peak isokinetic quadriceps torque, knee pain, and joint position sense scores. Pain during stair descent, sitting, and quadriceps torque at 180 degrees /s explained 57.7 % of the variation in Kujala patellofemoral score. CONCLUSION: Although lower extremity joint position sense did not differ between groups, the PFPS group displayed a target-trajectory muscular coordination deficit, decreased muscular endurance, and decreased muscular strength compared to control group subjects. Pain level directly related to motor control performance while joint position sense scores did not. Knee pain and impaired strength related more to functional performance impairment than joint position sense scores in patients with PFPS. PMID- 23361654 TI - Silicone ring tourniquet versus pneumatic cuff tourniquet in carpal tunnel release: a randomized comparative study. AB - BACKGROUND: The aim of the present study was to compare the pain levels resulting from the use of a silicone ring tourniquet (SRT) to those resulting from the use of a classic pneumatic cuff tourniquet (PT) in patients undergoing carpal tunnel release under local anesthesia. MATERIALS AND METHODS: Fifty patients that underwent carpal tunnel release under local anesthesia were randomized using the technique of stratified randomization by minimization. A forearm tourniquet was applied: a standard PT was used in 25 patients, and an SRT was used in the other 25 patients (the model of SRT used was selected according to the standard systolic blood pressure). Patient demographics and complications were recorded. Pain levels were assessed with the visual analogue scale and were recorded (a) just after tourniquet application, (b) 5 min after tourniquet application, and (c) just before tourniquet removal. RESULTS: There was no statistical significant difference in patient demographics between the two groups. The mean tourniquet time was similar for both groups (p = 1.000). The difference between the mean final pain level and the mean initial pain level was statistically significant for the SRT group (p = 0.010) and highly statistically significant for the PT group (p < 0.001). The mean final pain level for the PT group was higher than that for the SRT group (p = 0.043). CONCLUSIONS: According to the findings of this study, in patients who underwent carpal tunnel release under local anesthesia, the pain levels at the end of the operation and those just before the removal of the tourniquet were higher in the PT group than in the SRT group of patients. PMID- 23361655 TI - The pharmacology of Tourette syndrome. AB - Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterised by multiple motor and vocal tics, plus associated behavioural symptoms. Tics are defined as sudden, rapid, repetitive non-rhythmic movements (motor tics) or vocalisations (vocal tics). Tics are distressing symptoms and can lead to considerable disruption to social functioning and quality of life. Converging evidence from different lines of research suggests that the pathophysiology of TS involves altered dopaminergic transmission in the cortico-striatal-thalamo cortical circuits, along with other neurotransmitter systems. Pharmacotherapy is currently the treatment of choice in patients with moderate-to-severe tics, particularly when associated with deterioration in social, occupational or academic performance. This review will focus on the recent evidence base supporting the use of different medication classes for the treatment of tics in TS. The recent publication of the European and Canadian guidelines on the management of TS are based on experts' consensus and highlight the need for randomised controlled trials, especially with regards to newly developed pharmacological agents. PMID- 23361656 TI - Evaluation of selective human MAO inhibitory activities of some novel pyrazoline derivatives. AB - A series of 1-[2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetyl]-3,5-diaryl-4,5 dihydro-1H-pyrazole derivatives were prepared by reacting 2-((5-methyl/chloro)-2 benzoxazolinone-3-yl)acetylhydrazine with appropriate chalcones. The chemical structures of all compounds were confirmed by elemental analyses, IR, (1)H NMR and ESI-MS. All the compounds were investigated for their ability to selectively inhibit monoamine oxidase (MAO) by in vitro tests. MAO activities of the compounds were compared with moclobemide and selegiline and all the compounds were found to inhibit human MAO-A selectively. The inhibition profile was found to be competitive and reversible for all compounds by in vitro tests. Among the compounds examined, compounds 5ae, 5af and 5ag were more selective than moclobemide, with respect to the K i values experimentally found. In addition, the compound 5bg showed MAO-A inhibitor activity as well as moclobemide. A series of experimentally tested compounds (5ae-5ch) were docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The AUTODOCK 4.01 program was employed to perform automated molecular docking. PMID- 23361657 TI - Characterizing liability for cranial nerve injuries: a detailed analysis of 209 malpractice trials. AB - OBJECTIVES/HYPOTHESIS: The potential for adverse events with lasting functional effects makes cranial nerve (CN) injury a target for litigation. Our objective was to comprehensively examine records of malpractice trials and detail issues influencing outcomes. STUDY DESIGN: Retrospective analysis. METHODS: The Westlaw database (Thomson Reuters, New York, NY) was searched for jury verdict reports related to medical malpractice and CN injury. After excluding nonrelevant cases, we examined 209 trials for characteristics including nerve(s) injured, alleged causes of malpractice, demographic information, specialty, and outcome. RESULTS: The most commonly litigated CNs were VII (24.4%) and II (19.6%). Sixty-nine (33.0%) trials resulted in damages awarded. Outcomes varied, ranging from a 29.2% plaintiff success rate for CN XI injury to 48.4% for CN II injury. Plaintiffs had less success with increasing age. Average damages awarded were $1.7 million. The most commonly named defendants were otolaryngologists and general surgeons. Individual considerations varied but commonly included alleged deficits in informed consent (25.4%), unnecessary procedures (14.8%), undergoing additional surgery (25.8%), and untimely recognition of complications (23.9%). CONCLUSIONS: Malpractice trials were resolved in the defendant's favor the majority of the time. In cases where plaintiffs were successful, however, awards were considerable, averaging nearly $2 million. Factors influencing case outcome included age, location, perceived deficits in informed consent, allegedly unnecessary surgery, requiring additional surgery to repair a complication, and untimely recognition of complications. Although specific factors should be taken into consideration with each procedure, providing detailed informed consent and communicating with patients regarding expectations may minimize liability. PMID- 23361658 TI - Spectroscopic properties of the Chlorophyll a-Chlorophyll c 2-Peridinin-Protein Complex (acpPC) from the coral symbiotic dinoflagellate Symbiodinium. AB - Femtosecond time-resolved transient absorption spectroscopy was performed on the chlorophyll a-chlorophyll c 2-peridinin-protein-complex (acpPC), a major light harvesting complex of the coral symbiotic dinoflagellate Symbiodinium. The measurements were carried out on the protein as well on the isolated pigments in the visible and the near-infrared region at 77 K. The data were globally fit to establish inter-pigment energy transfer paths within the scaffold of the complex. In addition, microsecond flash photolysis analysis was applied to reveal photoprotective capabilities of carotenoids (peridinin and diadinoxanthin) in the complex, especially the ability to quench chlorophyll a triplet states. The results demonstrate that the majority of carotenoids and other accessory light absorbers such as chlorophyll c 2 are very well suited to support chlorophyll a in light harvesting. However, their performance in photoprotection in the acpPC is questionable. This is unusual among carotenoid-containing light-harvesting proteins and may explain the low resistance of the acpPC complex against photoinduced damage under even moderate light conditions. PMID- 23361832 TI - Cariprazine in bipolar disorder: clinical efficacy, tolerability, and place in therapy. AB - Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist in late stage clinical development for the treatment of bipolar disorder (manic/mixed and depressive episodes), as well as for schizophrenia, and as an adjunctive agent for the treatment of major depressive disorder. Three phase 2 or 3, 3-week, randomized controlled trials in bipolar mania or mixed episodes have been completed and reported as poster presentations or in press releases by the manufacturer. Superiority over placebo on the Young Mania Rating Scale total score was evidenced for daily doses of cariprazine 3-12 mg/day. In short-term randomized controlled trials, cariprazine does not appear to adversely impact metabolic variables, prolactin, or the electrocardiogram (ECG) QT interval. The most commonly encountered adverse events in the mania trials were extrapyramidal disorder, akathisia, insomnia, vomiting, restlessness, sedation, vision blurred, and pain in extremity in the phase 2 trial where this was presented in a poster, and akathisia, extrapyramidal disorder, tremor, dyspepsia, vomiting, dizziness, diarrhea, somnolence, restlessness, and pyrexia for the phase 3 trial where this was presented in a poster. With the exception of akathisia and extrapyramidal disorder, the differences in incidence versus placebo for these events were generally small. If approved by regulatory authorities, cariprazine would join aripiprazole as the second dopamine receptor partial agonist antipsychotic available for clinical use in persons with bipolar mania or mixed episodes. Cariprazine differs from aripiprazole in terms of dopamine D3 receptor selectivity. Further studies would be helpful to discern the distinguishing features of cariprazine from other antimanic agents. PMID- 23361833 TI - Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy. AB - Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist in late stage clinical development for the treatment of schizophrenia, as well as for bipolar disorder (manic/mixed and depressive episodes), and as an adjunctive agent for the treatment of major depressive disorder. Four phase 2 or 3, 6-week, randomized controlled trials in acute schizophrenia have been completed and reported as poster presentations or in press releases by the manufacturer. Superiority over placebo on the Positive and Negative Syndrome Scale total score was evidenced for cariprazine in daily doses of 1.5, 3.0, 4.5, 6.0, 1.5-4.5, 3.0 6.0, and 6.0-9.0 mg. A randomized controlled trial for the prevention of relapse of schizophrenia is ongoing. In short-term, randomized controlled trials, cariprazine does not appear to adversely impact metabolic variables, prolactin, or the electrocardiogram (ECG) QT interval. In the fixed-dose study of cariprazine that tested 1.5, 3.0, and 4.5 mg/day, the most commonly encountered adverse events were insomnia, extrapyramidal disorder, sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation. However, the differences in incidence versus placebo for these events were generally small. If approved by regulatory authorities, cariprazine would join aripiprazole as the second dopamine receptor partial agonist antipsychotic available for clinical use. Cariprazine differs from aripiprazole in terms of dopamine D3 receptor selectivity. Further studies would be helpful to discern the distinguishing features of cariprazine from other second-generation antipsychotics. PMID- 23361834 TI - A comparison of the anticancer properties of isoxanthohumol and 8 prenylnaringenin using in vitro models of colon cancer. AB - The hops plant (Humulus lupulus L.) is an essential ingredient in beer and contains a number of potentially bioactive prenylflavonoids, the predominant being the weakly estrogenic isoxanthohumol (Ix), which can be converted to the more strongly estrogenic 8-PN by the colonic microbiota. The aim of this study was to investigate the biological activity of 8-PN and Ix using in vitro models representing key stages of colorectal carcinogenesis, namely cell growth and viability (MTT assay), cell-cycle progression (DNA content assay), DNA damage (Comet assay), and invasion (Matrigel assay). A significant decrease in Caco-2 cell viability was noted after both 8-PN and Ix treatments at the higher doses (40 and 50 MUM, respectively) although the impact on cell cycle differed between the two compounds. The decreased cell viability observed after Ix treatment was associated with a concentration-dependent increase in G2/M and an increased sub G1 cell-cycle fraction, whereas treatment with 8-PN was associated with an elevated G0/G1 and an increased sub-G1 cell-cycle fraction. Significant antigenotoxic activity was noted at all 8-PN concentrations tested (5-40 MUM). Although significant antigenotoxic activity was also noted with Ix treatment at <=25 MUM, at a higher dose, Ix itself exerted genotoxic activity. In a dose dependent manner, both compounds inhibited HT115 cell invasion with reductions up to 52 and 46% for Ix and 8-PN, respectively, in comparison to untreated cells. This study demonstrated that both Ix and its gut microbial metabolite 8-PN exert anticancer effects on models of key stages of colon tumourigenesis. PMID- 23361835 TI - Substance P- and choline acetyltransferase immunoreactivities in somatostatin containing, human submucosal neurons. AB - The submucous layers of human small and large intestines contain at least two separate neuron populations. Besides morphological features, they differ in their immunoreactivities for calretinin (CALR) and somatostatin (SOM), respectively. In this study, submucosal wholemounts of 23 patients or body donors (including all segments of small intestine and colon) were immunohistochemically quadruple stained for CALR and SOM as well as for substance P (SP) and choline acetyltransferase (ChAT). We found that all SOM-positive neurons co-stained for ChAT and the majority for SP [between 50% in the small intestinal external submucosal plexus (ESP) and 75% in the colonic ESP]. In contrast, a majority of CALR-neurons contained ChAT (between 77% in the small intestinal ESP and 92% in the large intestinal ESP) whereas less than 4% of CALR-neurons were co immunoreactive for SP. Another set of wholemounts was co-stained for peripherin, a marker enabling morphological analysis. Where identifiable, both SOM alone- and SOM/SP-neurons displayed a uniaxonal (supposed pseudouniaxonal) morphology. We suggest that the chemical code of SOM-immunoreactive, human submucosal neurons may be "ChAT+/SOM+/SP+/-". In additional sections double stained for SOM and SP, we regularly found double-labelled nerve fibres only in the mucosa. In contrast, around submucosal arteries mostly SOM alone- fibres were found and the muscularis propria contained numerous SP-alone fibres. We conclude that the main target of submucosal SOM(/SP)-neurons may be the mucosa. Due to their morpho-chemical similarity to human myenteric type II neurons, we further suggest that one function of human submucosal SOM-neurons may be a primary afferent one. PMID- 23361836 TI - Biotransformations of anticancer ruthenium(III) complexes: an X-ray absorption spectroscopic study. AB - An anti-metastatic drug, NAMI-A ((ImH)[Ru(III) Cl4 (Im)(dmso)]; Im=imidazole, dmso=S-bound dimethylsulfoxide), and a cytotoxic drug, KP1019 ((IndH)[Ru(III) Cl4 (Ind)2 ]; Ind=indazole), are two Ru-based anticancer drugs in human clinical trials. Their reactivities under biologically relevant conditions, including aqueous buffers, protein solutions or gels (e.g, albumin, transferrin and collagen), undiluted blood serum, cell-culture medium and human liver (HepG2) cancer cells, were studied by Ru K-edge X-ray absorption spectroscopy (XAS). These XAS data were fitted from linear combinations of spectra of well characterised Ru compounds. The absence of XAS data from the parent drugs in these fits points to profound changes in the coordination environments of Ru(III) . The fits point to the presence of Ru(IV/III) clusters and binding of Ru(III) to S-donor groups, amine/imine and carboxylato groups of proteins. Cellular uptake of KP1019 is approximately 20-fold higher than that of NAMI-A under the same conditions, but it diminishes drastically after the decomposition of KP1019 in cell-culture media, which indicate that the parent complex is taken in by cells through passive diffusion. PMID- 23361837 TI - Metabolic syndrome and metabolic abnormalities in bipolar disorder: a meta analysis of prevalence rates and moderators. AB - OBJECTIVE: Patients with bipolar disorder have high levels of cardiovascular disease risk factors. The presence of metabolic syndrome significantly influences future cardiovascular disease morbidity and mortality. The authors sought to clarify the prevalence and moderators of metabolic syndrome in bipolar patients, accounting for subgroup differences. METHOD: The authors searched MEDLINE, PsycINFO, EMBASE, and CINAHL through April 2012 for research reporting metabolic syndrome prevalence rates in bipolar patients. Medical subject headings "metabolic syndrome" and "bipolar" were used in the title, abstract, or index term fields. Manual searches were conducted using the reference lists from identified articles. RESULTS: The search yielded 81 articles in 37 publications (N=6,983). The overall metabolic syndrome rate was 37.3% (95% confidence interval [CI]=36.1-39.0) using any standardized metabolic syndrome criteria. Compared with general population groups, bipolar patients had higher metabolic syndrome rates (odds ratio=1.98; 95% CI=1.74-2.25). In bipolar patients, older age had a modest effect on the metabolic syndrome rate. The strongest moderator was the region in which the study took place, with the highest rates observed in New Zealand and Australia (64.2% [95% CI=38.3-83.9]) and North America (49.3% [95% CI=29.7 69.3]). Metabolic syndrome was significantly more prevalent in patients currently treated with antipsychotics (45.3% [95% CI=39.6-50.9] than in patients who were antipsychotic free (32.4% [95% CI=27.5-37.4]; odds ratio=1.72 [95% CI=1.24 2.38]). CONCLUSIONS: These findings strongly support the claim that patients with bipolar disorder are at high risk for metabolic syndrome and related cardiovascular morbidity and mortality and require regular monitoring and adequate preventive efforts and treatment for cardio-metabolic risk factors. These findings further suggest that the risk of metabolic syndrome is greater in bipolar patients taking prescribed antipsychotic medication. PMID- 23361838 TI - Does an upper respiratory tract infection during pregnancy affect perinatal outcomes? A literature review. AB - Upper respiratory tract infection (URTI) is a ubiquitous but often benign pathology most commonly of viral etiology. This review focuses on perinatal outcomes following URTI during pregnancy. Few data exist on the explicit topic of URTI and adverse perinatal outcomes. The entire URTI burden among pregnant women is not properly represented by the studies included in this review, because only those infections severe enough to warrant hospitalization have been studied. Most probably, the number of URTIs in pregnant women not requiring hospitalization is far larger, but this has yet to be quantified. Clearly, there are logistical barriers to obtaining such statistics. Severe URTI requiring hospitalization during pregnancy was noted to be associated with adverse perinatal complications. URTI was found to be positively correlated with preterm delivery (PTD; less than 37 weeks gestation), lower birth weight, and cesarean deliveries, without a significant effect on the rates of perinatal mortality or low Apgar scores. There appears to be a possible link between various infectious processes that occur during pregnancy and the outcome of a PTD. The inflammatory environment present during infection includes high levels of cytokines that are known to increase prostaglandins, which, in turn, can induce preterm birth. Further studies should evaluate whether URTI not requiring hospitalization has any effect on perinatal outcomes. PMID- 23361839 TI - An integrated high-throughput strategy for rapid screening of poly(gamma-glutamic acid)-producing bacteria. AB - Poly(gamma-glutamic acid) (gamma-PGA) is a promising biomaterial with a wide range of unique applications. To extensively screen gamma-PGA-producing bacteria with high yield and different molecular weight, we developed an integrated high throughput strategy. Firstly, gamma-PGA-producing bacteria were selected in a primary screen plate containing a basic dye (neutral red) based on the concentric zone formed through the electrostatic interaction between the dye and the secreted acidic polymer gamma-PGA. Then, the isolates were cultured in 50 ml tubes instead of 250 ml flasks. A good correlation of fermentation results in 50 ml tubes and 250 ml flasks was observed. Thirdly, the gamma-PGA yield and weight average molecular weight (M (w)) were simultaneously determined by spectrophotomic assay (UV assay) and neutral red plate assay. The results showed that the diameter of the concentric zone varied among isolates and was negatively correlated with the weight-average molecular weight of gamma-PGA. The accuracy of the methods was comparable to that of high-performance liquid chromatography and gel permeation chromatography assay. Lastly, gamma-PGA obtained from the target isolates was rapidly identified using thin layer chromatography assay. With this strategy, 13 bacteria with high yield and various molecular weights of gamma-PGA from 500 obvious single colonies on the primary screen plate were obtained. PMID- 23361840 TI - Reduction of volatile acidity of acidic wines by immobilized Saccharomyces cerevisiae cells. AB - Excessive volatile acidity in wines is a major problem and is still prevalent because available solutions are nevertheless unsatisfactory, namely, blending the filter-sterilized acidic wine with other wines of lower volatile acidity or using reverse osmosis. We have previously explored the use of an empirical biological deacidification procedure to lower the acetic acid content of wines. This winemaker's enological practice, which consists in refermentation associated with acetic acid consumption by yeasts, is performed by mixing the acidic wine with freshly crushed grapes, musts, or marc from a finished wine fermentation. We have shown that the commercial strain Saccharomyces cerevisiae S26 is able to decrease the volatile acidity of acidic wines with a volatile acidity higher than 1.44 g L(-1) acetic acid, with no detrimental impact on wine aroma. In this study, we aimed to optimize the immobilization of S26 cells in alginate beads for the bioreduction of volatile acidity of acidic wines. We found that S26 cells immobilized in double-layer alginate-chitosan beads could reduce the volatile acidity of an acidic wine (1.1 g L(-1) acetic acid, 12.5 % (v/v) ethanol, pH 3.12) by 28 and 62 % within 72 and 168 h, respectively, associated with a slight decrease in ethanol concentration (0.7 %). Similar volatile acidity removal efficiencies were obtained in medium with high glucose concentration (20 % w/v), indicating that this process may also be useful in the deacidification of grape musts. We, therefore, show that immobilized S. cerevisiae S26 cells in double layer beads are an efficient alternative to improve the quality of wines with excessive volatile acidity. PMID- 23361841 TI - Role of the cmcH-ccaR intergenic region and ccaR overexpression in cephamycin C biosynthesis in Streptomyces clavuligerus. AB - The effect of the CcaR regulatory protein on expression of the cephamycin C gene cluster is studied. Quantitative reverse transcription PCR (qRT-PCR) expression analysis of the cephamycin biosynthesis genes in the ccaR-disrupted strain, S. clavuligerus ccaR::aph, revealed that in the absence of CcaR, the lat and cmcI genes expression was reduced 2,200- and 1,087-fold compared with the wild type. Expression of pcbAB-pcbC-cefD-cefE-cmcJ-cmcH and blp was 225- to 359-fold lower, while expression of pcbR-pbpA-bla and orf10 was only slightly affected if at all, indicating that resistance and regulatory genes are not under CcaR control as opposed to pathway biosynthetic genes. In the intergenic cmcH-ccaR region, a small messenger RNA (mRNA) overlaps with the cmcH transcription terminator. Deletion of 688 bp of the intergenic region results in a strain, S. clavuligerus DeltaRI, still able to produce cephamycin C and clavulanic acid but at levels 30 40% lower than the parental strain. Therefore, specific sequences in the intergenic region upstream of ccaR enhance the expression of ccaR but are not essential for its expression. Strains containing an additional ccaR gene integrated in the chromosome, S. clavuligerus pSET-PC, or multiple copies of ccaR expressed from the PglpF promoter, S. clavuligerus pAK23, were constructed. Fermentations of the pAK23 strain resulted in a 6.1-fold increase in specific cephamycin C production relative to the wild type. In the same experiments, qRT PCR analysis of the cephamycin biosynthesis genes showed a 5.1-fold increase in ccaR expression and similar increases in expression of lat and cmcI, while expression of other cluster genes were increased in the order of 2- to 3-fold. PMID- 23361842 TI - Large scale synthesis of photoluminescent carbon nanodots and their application for bioimaging. AB - Carbon nanodots (CDs) have been synthesized at gram scale with a high yield (41.8%) by carbonization of sucrose with oil acid in one simple step. The synthesized CDs are monodisperse with a narrow size distribution (average 1.84 nm in size), and show a high fluorescence quantum yield (21.6%) without passivation. The PL intensity of the obtained CDs is pH independent over a range of 2-8. Besides, their PL intensity remains unchanged even after six hours of UV excitation and six months of storage, exhibiting excellent stability. The obtained CDs have been used for cell imaging. The results demonstrate that the prepared CDs have great potential for real applications. PMID- 23361843 TI - Concise Review: early embryonic erythropoiesis: not so primitive after all. AB - In the developing embryo, hematopoiesis begins with the formation of primitive erythroid cells (EryP), a distinct and transient red blood cell lineage. EryP play a vital role in oxygen delivery and in generating shear forces necessary for normal vascular development. Progenitors for EryP arise as a cohort within the blood islands of the mammalian yolk sac at the end of gastrulation. As a strong heartbeat is established, nucleated erythroblasts begin to circulate and to mature in a stepwise, nearly synchronous manner. Until relatively recently, these cells were thought to be "primitive" in that they seemed to more closely resemble the nucleated erythroid cells of lower vertebrates than the enucleated erythrocytes of mammals. It is now known that mammalian EryP do enucleate, but not until several days after entering the bloodstream. I will summarize the common and distinguishing characteristics of primitive versus definitive (adult type) erythroid cells, review the development of EryP from the emergence of their progenitors through maturation and enucleation, and discuss pluripotent stem cells as models for erythropoiesis. Erythroid differentiation of both mouse and human pluripotent stem cells in vitro has thus far reproduced early but not late red blood cell ontogeny. Therefore, a deeper understanding of cellular and molecular mechanisms underlying the differences and similarities between the embryonic and adult erythroid lineages will be critical to improving methods for production of red blood cells for use in the clinic. PMID- 23361845 TI - Acute exercise increases circulating inflammatory markers in overweight and obese compared with lean subjects. AB - The primary aim of the present study was to investigate if overweight and obese compared to lean individuals displayed differences in levels of inflammatory markers in circulation, skeletal muscle (SM) and adipose tissue (AT) after acute exercise. Fifteen lean (BMI: 22.4 +/- 2 kg/m(2)) and 16 overweight or obese (BMI 31.8 +/- 3 kg/m(2)) individuals were included in the study. They completed 120 min of ergometer bicycling at 55-60 % of maximal heart rate. Blood samples were obtained at baseline (T = 0), after 60 (T = 60) and 120 min of exercise (T = 120), and analyzed using an ELISA method. SM and AT biopsies were obtained at T0 and T120, and mRNA expression was investigated using a Real-time RT-PCR method. Circulating IL-6, TNF-alpha, IL-8, and IL-15 all increased at T = 120 min (p < 0.01). Circulating IL-6 and IL-15 increased in all subjects at T = 120 min (p < 0.01), but only the increase of IL-6 was significantly higher in overweight and obese subjects (p < 0.05), and was positively correlated with body fat percentage (p < 0.01). Circulating IL-8 and TNF-alpha were increased in overweight and obese (p < 0.05) but not in lean subjects. Acute exercise induced an increase in IL-6 mRNA expression in SM biopsies (p < 0.05). IL-6 as well as adiponectin mRNA expression was increased in AT biopsies (p < 0.05); however, no effect of body weight was found. The findings suggest that the systemic inflammatory response to acute exercise is different in lean compared to overweight and obese subjects, with a more pronounced increase in inflammatory markers (e.g., IL-6, IL-8, and TNF-alpha) in overweight and obese individuals. PMID- 23361844 TI - Pitx2-mediated cardiac outflow tract remodeling. AB - BACKGROUND: Heart morphogenesis involves sequential anatomical changes from a linear tube of a single channel peristaltic pump to a four-chamber structure with two channels controlled by one-way valves. The developing heart undergoes continuous remodeling, including septation. RESULTS: Pitx2-null mice are characterized by cardiac septational defects of the atria, ventricles, and outflow tract. Pitx2-null mice also exhibited a short outflow tract, including unseptated conus and deformed endocardial cushions. Cushions were characterized with a jelly-like structure, rather than the distinct membrane-looking leaflets, indicating that endothelial mesenchymal transition was impaired in Pitx2(-/-) embryos. Mesoderm cells from the branchial arches and neural crest cells from the otic region contribute to the development of the endocardial cushions, and both were reduced in number. Members of the Fgf and Bmp families exhibited altered expression levels in the mutants. CONCLUSIONS: We suggest that Pitx2 is involved in the cardiac outflow tract septation by promoting and/or maintaining the number and the remodeling process of the mesoderm progenitor cells. Pitx2 influences the expression of transcription factors and signaling molecules involved in the differentiation of the cushion mesenchyme during heart development. PMID- 23361847 TI - Multivalent glycocalixarenes for recognition of biological macromolecules: glycocalyx mimics capable of multitasking. AB - The glycoside cluster effect, a special case of multivalency involving carbohydrates, is a powerful tool exploited by Nature to make relatively weak interactions stronger and more specific. Organic and supramolecular chemists have been applying this concept and are devising a plethora of neo-glycoconjugates which can interfere with a series of pathological events such as infections due to viruses and bacteria, tumour progression and migration, and inflammation processes. In the present Tutorial Review, we will illustrate the factors that make calixarenes, the cyclic oligomers obtained by the condensation of phenols/resorcinols and aldehydes, unique scaffolds for the construction of multivalent glycosylated ligands, individually analysing how structural parameters such as the size, valency, conformation, self-assembling behaviour of the macrocycle and especially the topology of the saccharide presentation in space influence the biological properties. We will not only survey the most significant results obtained to date in the inhibition of carbohydrate binding proteins (lectins), but we will also try to paint a picture of the potential that multivalent glycocalixarenes might have in bionanotechnology and nanomedicine, that are especially related to their combined ability to load cargo and to specifically deliver that cargo to target cells. PMID- 23361846 TI - Role of cytochrome P4502B6 in methadone metabolism and clearance. AB - Methadone N-demethylation in vitro is catalyzed by hepatic cytochrome P4502B6 (CYP2B6) and CYP3A4, but clinical disposition is often attributed to CYP3A4. This investigation tested the hypothesis that CYP2B6 is a prominent CYP isoform responsible for clinical methadone N-demethylation and clearance, using the in vivo mechanism-based CYP2B6 inhibitor ticlopidine, given orally for 4 days. A preliminary clinical investigation with the CYP3A4/5 substrate probe alfentanil established that ticlopidine did not inhibit intestinal or hepatic CYP3A4/5. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone before and after ticlopidine. Ticlopidine significantly and stereoselectively (S > R) inhibited methadone N-demethylation, decreasing plasma metabolite/methadone area under the curve ratios and metabolite formation clearances. Ticlopidine also significantly increased the dose-adjusted plasma area under the curve for R- and S-methadone by 20% and 60%, respectively, after both intravenous and oral dosing. CYP2B6 inhibition reduces methadone N-demethylation and clearance, and alters methadone concentrations, demonstrating an important role for CYP2B6 in clinical methadone disposition. PMID- 23361848 TI - Characterization of anxiolytic and neuropharmacological activities of Silexan. AB - Silexan is an essential oil produced from Lavandula angustifolia flowers with proven clinical efficacy for the treatment of anxiety disorders. The present study was conducted to assess its anxiolytic activity and to screen for neuropharmacological properties in rats and mice of either sex. Silexan (3, 10, and 30 mg/kg, intraperitoneally), lorazepam (5 mg/kg, p.o.), or diazepam (3 mg/kg, p.o.) were administered once daily for 7 consecutive days. Experiments were conducted 1 h after the last drug or vehicle administration. All the three doses of Silexan showed significant and dose-dependent anxiolytic activity in the used pharmacological models (open-field test, elevated plus-maze test, elevated zero-maze test, social interaction test, and novelty-induced suppressed feeding latency test), which was comparable to that of the standard anxiolytic agent lorazepam. In addition, Silexan amplified pentobarbital-induced sleeping time, but in contrast to diazepam was found to be devoid of any significant effect on locomotor activity and muscle-grip performance. PMID- 23361849 TI - Candelabra aloe (Aloe arborescens) in the therapy and prophylaxis of upper respiratory tract infections: traditional use and recent research results. AB - Aloe arborescens (Candelabra Aloe) has been used in the treatment of upper respiratory tract infections in Central and Eastern European countries for many decades. Originally introduced to support the healing and recovery in cornea transplant patients, aqueous A. arborescens extracts soon became popular in the treatment of upper respiratory tract infections with a focus on toddlers and children. Recent preclinical and clinical data show that immunomodulatory, antiinflammatory, and antiviral effects contribute to its therapeutic efficacy. Based on its well documented, longstanding traditional use and its excellent safety and tolerability, A. arborescens may be considered a valuable addition to the spectrum of herbal medicinal products for the treatment and prophylaxis of upper respiratory tract infections, in particular common cold, in adults and children. PMID- 23361850 TI - [Overview: liver tumors]. AB - Since the introduction of abdominal ultrasound liver lesions have been increasingly detected. Being usually diagnosed by chance these lesions create psychological stress among patients because a potential malignant disease has to be taken into consideration. The increasing use of oral contraceptives with high estrogen doses starting in the 1980s led to a rising incidence of adenomas, whose natural history differed from those described in surgical and autoptic studies. This fact brought about a change towards a modern pathophysiologic and prognostic differentiation. Current histologic and molecular biological techniques are able to distinguish benign adenomas from those with malignant potential. PMID- 23361851 TI - Activation of RhoA in alcohol-induced intestinal barrier dysfunction. AB - Ras homolog gene family, member A (RhoA) is a small GTPase protein known to regulate multiple cellular processes. In the present study, we used both an alcohol-fed mouse model and an alcohol-treated Caco-2 intestinal epithelial cell monolayer in vitro model to investigate whether RhoA is involved in alcohol induced intestinal barrier dysfunction as well as the underlying mechanisms. We found that chronic alcohol exposure significantly increased both intestinal RhoA mRNA and protein levels in mice and alcohol treatment also increased RhoA activity in Caco-2 cells. The alcohol-induced elevation in RhoA activity was accompanied by an increase in inducible nitric oxide synthase (iNOS) expression and prevented by N6-(1-iminoethyl)-L-lysine dihydrochloride (L-NIL) or small interfering RNA (siRNA) specific for iNOS. Furthermore, alcohol treatment with Caco-2 cells resulted in a significant decrease in the epithelial transepithelial electrical resistance (TEER) value, which was attenuated by knockdown of RhoA. Taken together, our findings suggest that iNOS-mediated activation of RhoA appears to be one of the important mechanisms contributing to the deleterious effects of alcohol on intestinal barrier function. PMID- 23361852 TI - DMT1 as a candidate for non-transferrin-bound iron uptake in the peripheral nervous system. AB - Iron, either in its chelated form or as holotransferrin (hTf), prevents the dedifferentiation of Schwann cells (SC), cells responsible for the myelination of the peripheral nervous system (PNS). This dedifferentiation is promoted by serum deprivation through cAMP release, PKA activation, and CREB phosphorylation. Since iron elicits its effect in a transferrin (Tf)-free environment, in this work we postulate that non-transferrin-bound iron (NTBI) uptake must be involved. Divalent metal transporter 1(DMT1) has been widely described in literature as a key player in iron metabolism, but never before in the PNS context. The presence of DMT1 was demonstrated in nerve homogenate, isolated adult-rat myelin, and cultured SC by Western Blot (WB) analysis and confirmed through its colocalization with S-100beta (SC marker) by immunocytochemical and immunohistochemical analyses. Furthermore, the existence of its mRNA was verified in sciatic nerve homogenate by RT-PCR and throughout SC maturational stages. Finally, we describe DMT1's subcellular location in the plasma membrane by confocal microscopy of SC and WB of different subcellular fractions. These data allow us to suggest the participation of DMT1 as part of a Tf independent iron uptake mechanism in SC and lead us to postulate a crucial role for iron in SC maturation and, as a consequence, in PNS myelination. PMID- 23361853 TI - Catalyst-free intramolecular formal carbon insertion into sigma-C-C bonds: a new approach toward phenanthrols and naphthols. AB - The different reactivity of two kinds of carbonyl groups in keto aldehyde substrates has been exploited for the synthesis of phenanthrols, naphthols, and their heteroatom-containing analogues. Key to this highly efficient and robust methodology is the catalyst-free intramolecular formal diazo carbon insertion of N-tosylhydrazones into keto C-C bonds. PMID- 23361854 TI - Intra-session test-retest reliability of pelvic floor muscle electromyography during running. AB - INTRODUCTION AND HYPOTHESIS: The prevalence of female stress urinary incontinence is high, and young adults are also affected, including athletes, especially those involved in "high-impact" sports. To date there have been almost no studies testing pelvic floor muscle (PFM) activity during dynamic functional whole body movements. The aim of this study was the description and reliability test of PFM activity and time variables during running. METHODS: A prospective cross sectional study including ten healthy female subjects was designed with the focus on the intra-session test-retest reliability of PFM activity and time variables during running derived from electromyography (EMG) and accelerometry. RESULTS: Thirteen variables were identified based on ten steps of each subject: Six EMG variables showed good reliability (ICC 0.906-0.942) and seven time variables did not show good reliability (ICC 0.113-0.731). Time variables (e.g. time difference between heel strike and maximal acceleration of vaginal accelerator) showed low reliability. However, relevant PFM EMG variables during running (e.g., pre activation, minimal and maximal activity) could be identified and showed good reliability. CONCLUSION: Further adaptations regarding measurement methods should be tested to gain better control of the kinetics and kinematics of the EMG probe and accelerometers. To our knowledge this is the first study to test the reliability of PFM activity and time variables during dynamic functional whole body movements. More knowledge of PFM activity and time variables may help to provide a deeper insight into physical strain with high force impacts and important functional reflexive contraction patterns of PFM to maintain or to restore continence. PMID- 23361855 TI - Changes in female sexual function after pelvic organ prolapse repair: role of hysterectomy. AB - INTRODUCTION AND HYPOTHESIS: Incontinence and pelvic organ prolapse (POP) have an impact on sexuality. Few studies evaluate the impact of hysterectomy on sexual function. We designed the present observational prospective longitudinal cohort study in order to evaluate the impact of uterus preservation after POP repair on sexual function. METHODS: Between January 2006 and January 2011, 107 patients with POP, mean age 58 +/- 8.9 years, underwent colposacropexy with or without hysterectomy. All the women without uterine disease were offered the chance to preserve the uterus. All patients gave written informed consent and completed the Female Sexual Function Index (FSFI) questionnaire, before and after surgery, provided detailed case history, underwent urogynaecological examination and urodynamic assessment and completed the Urogenital Distress Inventory short form (UDI-6) and Incontinence Impact on Quality of Life short form (IIQ-7) questionnaires, and the satisfaction Visual Analogue Scale (VAS). One year after surgery patients repeated the FSFI questionnaire and underwent a clinical check up. The primary end-point was post-operative sexual function as evaluated by the FSFI, the secondary end-points were objective anatomical and subjective success, defined respectively as no prolapse and no incontinence-related symptoms. RESULTS: Sixty-eight patients were included: 32 underwent uterus-sparing surgery and 36 hysterectomy plus colposacropexy. After surgery both groups had significant improvements in the total FSFI score and in the domains of desire, arousal and orgasm. The median post-operative scores of desire, arousal, and orgasm domains showed significant improvements in the uterus-sparing group compared with the hysterectomy group. None of the women had a uterine or vault prolapse recurrence. CONCLUSIONS: Our data demonstrate that POP plays a role in female sexual dysfunction and uterus sparing surgery is associated with a greater improvement in sexual function. PMID- 23361856 TI - IUGA-ICS terminology and standardization documents: maximal use offers maximum patient and academic benefit. PMID- 23361857 TI - Diagnosis and treatment of idiopathic intracranial hypertension (IIH) in children and adolescents. AB - Idiopathic intracranial hypertension (IIH) is characterized by symptoms and signs of elevated intracranial pressure, elevated cerebrospinal fluid (CSF) pressure, normal CSF content, and normal brain with normal or small ventricles on neuroimaging studies. IIH in children has a wide spectrum of clinical presentation. Diagnostic criteria with modifications to adapt to the variations in children are discussed. Diagnostic and therapeutic options are reviewed. PMID- 23361858 TI - Utility of 99mTc-labelled antimicrobial peptide ubiquicidin (29-41) in the diagnosis of diabetic foot infection. AB - PURPOSE: Detection of osteomyelitis beneath a diabetic foot ulcer is imperative for proper management; however, accurate and noninvasive diagnosis of osteomyelitis remains a challenge. Ubiquicidin 29-41 (UBI 29-41) is a synthetic antimicrobial peptide fragment reported to be highly infection-specific. (99m)Tc UBI 29-41 has recently been reported to be a promising radiotracer for infection imaging. The aim of this prospective study was to evaluate the utility of (99m)Tc UBI 29-41 scintigraphy in diabetic patients with suspected osteomyelitis of the foot. METHODS: Included in the study were 65 patients with type 2 diabetes mellitus and foot ulcer and with clinical suspicion of osteomyelitis . Each patient had a three-phase bone scan and a (99m)Tc-UBI scan at 30 and 60 min after injection. The scan was considered to be consistent with osteomyelitis when the (99m)Tc-UBI 29-41 uptake was concordant with the (99m)Tc-MDP uptake. It was considered negative for osteomyelitis if there was no uptake of (99m)Tc-UBI 29-41 or if (99m)Tc-UBI 29-41 accumulated in an area not concordant with the abnormal uptake of (99m)Tc-MDP on the bone scan. In the latter case a diagnosis of soft tissue infection was made. Bone infection was confirmed by bone biopsy/culture and by clinical and radiological follow-up. RESULTS: Final analysis was done in 55 patients. Osteomyelitis was confirmed in 37 patients, and 18 patients were free of bone infection. (99m)Tc-UBI 29-41 was positive in all 37 patients and with the bone scan as the reference for the bone identified all osteomyelitic foci (68 in total). (99m)Tc-UBI 29-41 was negative for osteomyelitis in all 18 patients, and 17 of these patients were diagnosed with soft-tissue infection ((99m)Tc-UBI 29-41 accumulation without concordant abnormal uptake on bone scintigraphy). The sensitivity, specificity and accuracy of (99m)Tc-UBI 29-41 scan in combination with three-phase bone scan for the diagnosis of osteomyelitis in diabetic foot was 100 %. Accuracy for soft-tissue infection was also 100 %. Maximum accumulation of the (99m)Tc-UBI 29-41 with maximum target to background activity was observed in the infectious foci at 30 min after injection. CONCLUSION: Tc-UBI 29-41 may be a useful agent for the accurate diagnosis of bone infection in diabetic foot because of the high accuracy demonstrated in this pilot study. It was able to differentiate between bone and soft-tissue involvement effectively in combination with a bone scan. PMID- 23361859 TI - When should we recommend use of dual time-point and delayed time-point imaging techniques in FDG PET? AB - FDG PET and PET/CT are now widely used in oncological imaging for tumor characterization, staging, restaging, and response evaluation. However, numerous benign etiologies may cause increased FDG uptake indistinguishable from that of malignancy. Multiple studies have shown that dual time-point imaging (DTPI) of FDG PET may be helpful in differentiating malignancy from benign processes. However, exceptions exist, and some studies have demonstrated significant overlap of FDG uptake patterns between benign and malignant lesions on delayed time-point images. In this review, we summarize our experience and opinions on the value of DTPI and delayed time-point imaging in oncology, with a review of the relevant literature. We believe that the major value of DTPI and delayed time-point imaging is the increased sensitivity due to continued clearance of background activity and continued FDG accumulation in malignant lesions, if the same diagnostic criteria (as in the initial standard single time-point imaging) are used. The specificity of DTPI and delayed time-point imaging depends on multiple factors, including the prevalence of malignancies, the patient population, and the cut-off values (either SUV or retention index) used to define a malignancy. Thus, DTPI and delayed time-point imaging would be more useful if performed for evaluation of lesions in regions with significant background activity clearance over time (such as the liver, the spleen, the mediastinum), and if used in the evaluation of the extent of tumor involvement rather than in the characterization of the nature of any specific lesion. Acute infectious and non-infectious inflammatory lesions remain as the major culprit for diminished diagnostic performance of these approaches (especially in tuberculosis-endemic regions). Tumor heterogeneity may also contribute to inconsistent performance of DTPI. The authors believe that selective use of DTPI and delayed time-point imaging will improve diagnostic accuracy and interpretation confidence in FDG PET imaging. PMID- 23361861 TI - Use of multimodality imaging to diagnose cardiac sarcoidosis as well as identify recurrence following heart transplantation. PMID- 23361860 TI - 18F-FDG PET SUVmax as an indicator of histopathologic response after neoadjuvant chemotherapy in extremity osteosarcoma. AB - PURPOSE: This study evaluated the usefulness of the maximum standardized uptake value (SUVmax) as a measure of histologic response to neoadjuvant chemotherapy in patients with extremity osteosarcoma. The correlation between [(18) F]FDG PET SUVmax values and histologic response to preoperative chemotherapy was also assessed prospectively using PET/MRI. METHODS: A total of 26 consecutive patients with high-grade osteosarcoma were prospectively enrolled. All patients underwent parallel PET and MRI scans before and after neoadjuvant chemotherapy. Using the PET and MRI images and pathologic mapping, we assessed the percentage necrosis by histology at the highest metabolic activity point in the tumors. This was defined as the minimum histologic response. The predictive values of SUVmax before (SUV1) and after (SUV2) chemotherapy and the SUV change ratio were determined. Correlations were also investigated among SUV2, minimum histologic response and histologic response. RESULTS: Histologically, 13 patients were classified as good responders and 13 as poor responders. Patients with an SUV2 of >5 showed a poor histologic response. A significant correlation was found between SUV2 and histologic response (Spearman's rho -0.642; P < 0.001), and SUV2 and histologic response were both found to be significantly correlated with minimum histologic response (Spearman's rho -0.515 and 0.911; P = 0.007 and P < 0.001, respectively). CONCLUSION: A SUVmax of more than 5 after neoadjuvant chemotherapy identified the majority of histologic nonresponders (sensitivity 61.3 %, PPV 88.9 %). Tumor necrosis at the point of maximum metabolic activity was found to be significantly correlated with the histologic response of entire resected specimen. PMID- 23361862 TI - Reaction of N-heterocyclic silylenes with thioketone: formation of silicon-sulfur three (Si-C-S)- and five (Si-C-C-C-S)-membered ring systems. AB - Three- and five-membered rings that bear the (Si-C-S) and (Si-C-C-C-S) unit have been synthesized by the reactions of LSiCl (1; L=PhC(NtBu)2 ) and L'Si (2; L'=CH{(C?CH2 )(CMe)(2,6-iPr2 C6 H3 N)2 }) with the thioketone 4,4' bis(dimethylamino)thiobenzophenone. Treatment of 4,4' bis(dimethylamino)thiobenzophenone with LSiCl at room temperature furnished the [1+2]-cycloaddition product silathiacyclopropane 3. However, reaction of 4,4' bis(dimethylamino)thiobenzophenone with L'Si at low temperature afforded a [1+4] cycloaddition to yield the five-membered ring product 4. Compounds 3 and 4 were characterized by NMR spectroscopy, EIMS, and elemental analysis. The molecular structures of 3 and 4 were unambiguously established by single-crystal X-ray structural analysis. The room-temperature reaction of 4,4' bis(dimethylamino)thiobenzophenone with L'Si resulted in products 4 and 5, in which 4 is the dearomatized product and 5 is formed under the 1,3-migration of a hydrogen atom from the aromatic phenyl ring to the carbon atom of the C?S unit. Furthermore, the optimized structures of probable products were investigated by using DFT calculations. PMID- 23361863 TI - A new betasatellite associated with cotton leaf curl Burewala virus infecting tomato in India: influence on symptoms and viral accumulation. AB - A begomovirus and its associated alpha- and betasatellite were detected in tomato plants affected with leaf curl disease. Based on a nucleotide sequence identity of 99 %, this begomovirus was designated an isolate of cotton leaf curl Burewala virus (CLCuBuV). The alphasatellite exhibited 93 % sequence identity to cotton leaf curl Burewala alphasatellite (CLCuBuA) and is hence referred to here as a variant of CLCuBuA. The detected betasatellite was recombinant in nature and showed 70 % sequence identity to the known betasatellites. Inoculation of healthy tomato with CLCuBuV plus betasatellite, either in the presence or the absence of alphasatellite, led to typical leaf curling, while inoculation with CLCuBuV in the absence of betasatellite resulted in mild symptoms. This confirmed the role of the betasatellite in expression of disease symptoms. We propose to name the newly detected betasatellite tomato leaf curl Hajipur betasatellite (ToLCHJB). PMID- 23361864 TI - PTCA with drug-coated balloons is associated with immediate decrease of coronary flow reserve. AB - INTRODUCTION: Drug-coated balloons (DCB) are being increasingly used in interventional cardiology. The effect of DCB on acute changes of coronary flow reserve (CFR) has never been reported. METHODS: Patients with in-stent restenosis or with contraindication for use of clopidogrel were included in this study. The FloWire was used to assess CFR before and immediately after conventional balloon angioplasty and after the use of In.Pact, a paclitaxel-coated balloon. In a sub selection of patients, CFR was measured immediately and then 2, 5, and 10 min post-DCB. RESULTS: Thirty patients (18 males, 60%) with a total of 32 lesions were studied. Comparison of CFR pre- and post-conventional balloon angioplasty was not statistically significant (P = 0.95). CFR dropped significantly after the use of In.Pact (n = 32, 1.59 +/- 0.49 vs. 1.22 +/- 0.28, P < 0.0001) and showed a statistically significant improvement over 10 min in a subset of patients (n = 6, P = 0.01). Implantation of a coronary stent after the use of In.Pact rapidly improved CFR (n = 10, P = 0.0004). CONCLUSIONS: We describe a novel phenomenon of acute decrease in CFR after the use of DCB. This phenomenon is temporary and spontaneously improves after approximately 10 min. The exact pathophysiological mechanism remains unclear and further studies are warranted to study the long term effects of acute CFR drop after use of DCB. PMID- 23361865 TI - High hydrostatic pressure induces synthesis of heat-shock proteins and trehalose 6-phosphate synthase in Anastrepha ludens larvae. AB - The Mexican fruit fly (Anastrepha ludens) is responsible for losses of up to 25% of crops such as mango and citrus fruits in Central America and Mexico. The larval life cycle of A. ludens comprises three stages with a duration ranging from 3 to 8 days. Because of the damage caused by A. ludens, several methods of control have been studied and implemented. High hydrostatic pressures (HHP) are currently applied to foods and it is now proposed to be employed to inactivate eggs and larvae of A. ludens. Originally HHP was designed to inactivate microorganisms, since it exerts marked effects on cell morphology, and can affect enzymatic reactions and genetic mechanisms of microbial cells, with no major changes altering the sensory or nutritional quality of the foodstuff. In this study, A. ludens in two larval stages (5- and 8-day-old) were subjected to HHP treatments. The biochemical response of the larvae of A. ludens was dependent on their stage of development. The third larval stage (L3) developed a better protection mechanism based on the synthesis of stress proteins or heat-shock proteins (HSPs) and the enzyme trehalose-6-phosphate synthase, which are linked and possibly act together to achieve greater survivability to stress caused by hydrostatic pressure. PMID- 23361867 TI - Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: method development, drug distribution and interpretation of results. AB - To date, the Toxicology Section of the Montgomery County Coroner's Office/Miami Valley Regional Crime Laboratory has identified six synthetic cathinones, commonly found in bath salt products, in 43 cases. Thirty-two cases will be reviewed here, including all of the postmortem cases, all of the human performance cases that had blood specimens submitted, and one urine-only human performance case. The following compounds have been confirmed: 3,4 methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), pyrovalerone, pentylone, alpha-pyrrolidinopentiophenone (alpha-PVP) and methedrone. The method also screens for mephedrone, butylone and 3 fluoromethcathinone. Case demographics show 42 white males and females ranging in age from 19 to 53 years. The remaining case was that of a 34-year-old Hispanic male. The 43 cases represent 17 driving under the influence, two domestic violence, four suicides, 12 overdoses, six accidents, one drug-facilitated assault and one homicide. Data will be presented on the distribution of some of these cathinones in various matrices. After review, blood concentration does not appear to predict outcome regarding fatalities or impairment. The highest MDPV concentration occurred in a suicide by hanging and the highest methylone concentration was in a driver. The confirmation method is a liquid-liquid extraction with detection by liquid chromatography triple quadrupole mass spectrometry using electrospray ionization in multiple reaction monitoring mode. PMID- 23361866 TI - Stigmatizing attitudes toward mental illness among racial/ethnic older adults in primary care. AB - OBJECTIVE: The current study applies the perceived stigma framework to identify differences in attitudes toward mental health and mental health treatment among various racial/ethnic minority older adults with common mental health problems including depression, anxiety disorders, or at-risk alcohol use. Specifically, this study examines to what extent race/ethnicity is associated with differences in (1) perceived stigma of mental illness and (2) perceived stigma for different mental health treatment options. METHODS: Analyses were conducted using baseline data collected from participants who completed the SAMHSA Mental Health and Alcohol Abuse Stigma Assessment, developed for the PRISM-E (Primary Care Research in Substance Abuse and Mental Health for the Elderly) study, a multisite randomized trial for older adults (65+ years) with depression, anxiety, or at risk alcohol consumption. The final sample consisted of 1247 non-Latino Whites, 536 African-Americans, 112 Asian-Americans, and 303 Latinos. RESULTS: African Americans and Latinos expressed greater comfort in speaking to primary care physicians or mental health professionals concerning mental illness compared with non-Latino Whites. Asian-Americans and Latinos expressed greater shame and embarrassment about having a mental illness than non-Latino Whites. Asian Americans expressed greater difficulty in seeking or engaging in mental health treatment. CONCLUSIONS: Racial/ethnic differences exist among older adults with mental illness with respect to stigmatizing attitudes toward mental illness and mental health treatment. Results of this study could help researchers and clinicians educate racial/ethnic minority older adults about mental illness and engage them in much needed mental health services. PMID- 23361868 TI - Glutamate transporter type 3 knockout leads to decreased heart rate possibly via parasympathetic mechanism. AB - Parasympathetic tone is a dominant neural regulator for basal heart rate. Glutamate transporters (EAAT) via their glutamate uptake functions regulate glutamate neurotransmission in the central nervous system. We showed that EAAT type 3 (EAAT3) knockout mice had a slower heart rate than wild-type mice when they were anesthetized. We design this study to determine whether non anesthetized EAAT3 knockout mice have a slower heart rate and, if so, what may be the mechanism for this effect. Young adult EAAT3 knockout mice had slower heart rates than those of their littermate wild-type mice no matter whether they were awake or anesthetized. This difference was abolished by atropine, a parasympatholytic drug. Carbamylcholine chloride, a parasympathomimetic drug, equally effectively reduced the heart rates of wild-type and EAAT3 knockout mice. Positive immunostaining for EAAT3 was found in the area of nuclei deriving fibers for vagus nerve. There was no positive staining for the EAATs in the sinoatrial node. These results suggest that EAAT3 knockout mice have a slower heart rate at rest. This effect may be caused by an increased parasympathetic tone possibly due to increased glutamate neurotransmission in the central nervous system. These findings indicate that regulation of heart rate, a vital sign, is one of the EAAT biological functions. PMID- 23361869 TI - Molecular characterization of DNA repair protein Ku70 from Vitis vinifera and its purification from transgenic tobacco. AB - The DNA double strand break repair in plants is preferentially by non homologous end joining (NHEJ) pathway. A key protein of NHEJ pathway is Ku70. We have identified Ku70 homolog (VvKu70) from grapevine genome database. In this report we characterize a Ku70 homologue from Vitis vinifera cv. Mango. The VvKu70 expression was found to increase strongly in response to gamma radiation. The transcript level of VvKu70 was found to increase up to 36 h in gamma irradiated shoots of grapevine. The expression of VvKu70 was found in many organs like stem, leaves and roots. A GFP fused VvKu70 protein was found to be nuclear localized which indicates that the VvKu70 is a nuclear localized protein. The VvKu70 identified by in silico approaches is present as a single copy number in V. vinifera cv. Mango genome. The VvKu70-GFP fused protein possesses ATPase activity and fails to bind dsDNA but binds ssDNA. PMID- 23361870 TI - Distinct roles for N-Cadherin linked c-Src and fyn kinases in lens development. AB - BACKGROUND: Src family tyrosine kinases (SFKs) are often coincidently expressed but few studies have dissected their individual functions in the same cell during development. Using the classical embryonic lens as our model, we investigated SFK signaling in the regulation of both differentiation initiation and morphogenesis, and the distinct functions of c-Src and Fyn in these processes. RESULTS: Blocking SFK activity with the highly specific inhibitor PP1 induced initiation of the lens differentiation program but blocked lens fiber cell elongation and organization into mini lens-like structures called lentoids. These dichotomous roles for SFK signaling were discovered to reflect distinct functions of c-Src and Fyn and their differentiation-state-specific recruitment to and action at N cadherin junctions. c-Src was highly associated with the nascent N-cadherin junctions of undifferentiated lens epithelial cells. Its siRNA knockdown promoted N-cadherin junctional maturation, blocked proliferation, and induced lens cell differentiation. In contrast, Fyn was recruited to mature N-cadherin junctions of differentiating lens cells and siRNA knockdown suppressed differentiation specific gene expression and blocked morphogenesis. CONCLUSIONS: Through inhibition of N-cadherin junction maturation, c-Src promotes lens epithelial cell proliferation and the maintenance of the lens epithelial cell undifferentiated state, while Fyn, signaling downstream of mature N-cadherin junctions, promotes lens fiber cell morphogenesis. PMID- 23361871 TI - Impact of bosentan on exercise capacity in adults after the Fontan procedure: a randomized controlled trial. AB - AIMS: An endothelin-1 receptor blocker, shown to be effective in patients with pulmonary arterial hypertension, might decrease pulmonary vascular resistance to increase cardiac filling and consequently improve exercise capacity in Fontan patients. METHODS AND RESULTS: This was a prospective, multicentre randomized open label trial in Fontan patients. One group received bosentan for 6 months. The other group did not receive study medication for the first 3 months, followed by bosentan for 6 months. The primary endpoint was exercise capacity, and secondary endpoints were NT-proBNP level, cardiac output, SF-36 (Short Form-36) quality of life (QoL), and NYHA class. Forty-two adults (median age 29 (range 18 56) years, 52% male, 88% NYHA class I-II) from five tertiary referral centres participated in the study. Ten patients were on diuretics. Ten patients were not motivated to finish the study. Analysis of all 32 patients who finished the study at 6 months of treatment showed that mean peak V'O2 (24 vs. 25 mL/kg/min), median SQUASH score (6614 vs. 6390), median NT-proBNP (314 vs. 274 ng/L), and mental QoL (50 vs. 51) remained unchanged as compared with baseline (P = NS, for all). After treatment, NYHA class had improved in 6 (19%), was unchanged in 24 (75%), and declined in 2 (6%) patients. Subgroup analysis on age, ventricular morphology, type of Fontan circulation, or baseline NT-proBNP level did not reveal efficacy of bosentan. Six transient adverse effects were reported. CONCLUSION: An increased NT-proBNP level was present in the majority of Fontan patients. Six months of bosentan treatment was not beneficial. Trial registration NTR1557. PMID- 23361873 TI - Localized conjunctival extra-nodal marginal zone B cell lymphoma with presumed Paraproteinic Crystalline Keratopathy. AB - Crystalline corneal deposits have been well reported in individual cases of lymphoproliferative disorders associated with hyper-gammaglobulinemia, hence called 'Crystalline Paraproteinemic Keratopathy'. This is the first report of corneal deposits in a case of localised conjunctival B-cell Lymphoma without paraproteinaemia/hyper-gammaglobulinemia, hence called 'Presumed Paraproteinic Crystalline Keratopathy'. PMID- 23361872 TI - EZH2 and CD79B mutational status over time in B-cell non-Hodgkin lymphomas detected by high-throughput sequencing using minimal samples. AB - BACKGROUND: Numerous genomic abnormalities in B-cell non-Hodgkin lymphomas (NHLs) have been revealed by novel high-throughput technologies, including recurrent mutations in EZH2 (enhancer of zeste homolog 2) and CD79B (B cell antigen receptor complex-associated protein beta chain) genes. This study sought to determine the evolution of the mutational status of EZH2 and CD79B over time in different samples from the same patient in a cohort of B-cell NHLs, through use of a customized multiplex mutation assay. METHODS: DNA that was extracted from cytological material stored on FTA cards as well as from additional specimens, including archived frozen and formalin-fixed histological specimens, archived stained smears, and cytospin preparations, were submitted to a multiplex mutation assay specifically designed for the detection of point mutations involving EZH2 and CD79B, using MassARRAY spectrometry followed by Sanger sequencing. RESULTS: All 121 samples from 80 B-cell NHL cases were successfully analyzed. Mutations in EZH2 (Y646) and CD79B (Y196) were detected in 13.2% and 8% of the samples, respectively, almost exclusively in follicular lymphomas and diffuse large B-cell lymphomas. In one-third of the positive cases, a wild type was detected in a different sample from the same patient during follow-up. CONCLUSIONS: Testing multiple minimal tissue samples using a high-throughput multiplex platform exponentially increases tissue availability for molecular analysis and might facilitate future studies of tumor progression and the related molecular events. Mutational status of EZH2 and CD79B may vary in B-cell NHL samples over time and support the concept that individualized therapy should be based on molecular findings at the time of treatment, rather than on results obtained from previous specimens. Cancer (Cancer Cytopathol) 2013;121:377-386. (c) 2013 American Cancer Society. PMID- 23361874 TI - Diagnostic evaluation of bone densitometric size adjustment techniques in children with and without low trauma fractures. AB - Several established methods are used to size adjust dual-energy X-ray absorptiometry (DXA) measurements in children. However, there is no consensus as to which method is most diagnostically accurate. All size-adjusted bone mineral density (BMD) values were more diagnostically accurate than non-size-adjusted values. The greatest odds ratio was estimated volumetric BMD for vertebral fracture. INTRODUCTION: The size dependence of areal bone density (BMDa) complicates the use of DXA in children with abnormal stature. Despite several size adjustment techniques being proposed, there is no consensus as to the most appropriate size adjustment technique for estimating fracture risk in children. The aim of this study was to establish whether size adjustment techniques improve the diagnostic ability of DXA in a cohort of children with chronic diseases. METHODS: DXA measurements were performed on 450 children, 181 of whom had sustained at least one low trauma fracture. Lumbar spine (L2-L4) and total body less head (TBLH) Z-scores were calculated using different size adjustment techniques, namely BMDa and volumetric BMD for age (bone mineral apparent density (BMAD)); bone mineral content (BMC) and bone area for height; BMC for bone area; BMC for lean mass (adjusted for height); and BMC for bone and body size. RESULTS: Unadjusted L2-L4 and TBLH BMDa were most sensitive but least specific at distinguishing children with fracture. All size adjustments reduced sensitivity but increased post-test probabilities, from a pre-test probability of 40 % to between 58 and 77 %. The greatest odds ratio for fracture was L2-L4 BMAD for a vertebral fracture and TBLH for lean body mass (LBM) (adjusted for height) for a long bone fracture with diagnostic odds ratios of 9.3 (5.8-14.9) and 6.5 (4.1 10.2), respectively. CONCLUSION: All size adjustment techniques improved the predictive ability of DXA. The most accurate method for assessing vertebral fracture was BMAD for age. The most accurate method for assessing long bone fracture was TBLH for LBM adjusted for height. PMID- 23361875 TI - Drug rash with eosinophilia and systemic symptoms (DRESS) in patients receiving strontium ranelate. AB - We have reviewed 47 drug rash with eosinophilia and systemic symptoms (DRESS) cases associated to strontium ranelate reported up to March 2011 to the Marketing Holder. The main signs were skin rash, fever, face oedema hypereosinophilia and liver involvement. For ten patients, persistence of DRESS symptoms was reported at the latest news obtained, and DRESS was identified as the direct cause of death in one case. The maximum incidence of DRESS associated with strontium ranelate was 1/24,112 [95 % CI (1/14,859; 1/42,194)] newly treated patients in France. Because DRESS is a severe drug reaction, the occurrence of a rash in a patient treated with strontium ranelate should lead to prompt and permanent treatment discontinuation. INTRODUCTION: This study aims to describe cases of DRESS reported to the Marketing Authorisation Holder worldwide for patients receiving strontium ranelate by practitioner or by regulatory authorities. METHODS: Spontaneously reported hypersensitivity events from the strontium ranelate pharmacovigilance database since marketing authorisation (2004) to March 2011 were reviewed by an expert committee. Cases of DRESS were classified as established, probable, possible or no DRESS according to expert judgement. National incidences of DRESS were estimated in relation to the number of newly treated patients. RESULTS: Up to March 2011, 325 cases of strontium ranelate induced hypersensitivity events were assessed from which 47 DRESS cases were confirmed. Mean age was 68.7 years and besides skin rash, the main signs and symptoms were hypereosinophilia, liver involvement, fever and face oedema. Median time to skin reaction was 33.5 days after treatment start. Most patients (62 %) recovered at the time of reporting or were recovering. For ten patients, persistence of DRESS symptoms was reported at the latest news obtained. Relapses were observed in a single case. The mortality rate was 8.5 %. The maximum incidence of DRESS associated with strontium ranelate was 1/24,112 [95 % CI (1/14,859; 1/42,194)] newly treated patients in France. CONCLUSION: DRESS is a well-identified and characterised adverse reaction to strontium ranelate. This risk should be integrated in the risk-benefit balance evaluation of patient treatment, and the occurrence of a rash should lead to prompt and permanent treatment discontinuation with careful follow-up. PMID- 23361876 TI - CX3CL1/CX3CR1 regulates nerve injury-induced pain hypersensitivity through the ERK5 signaling pathway. AB - Peripheral nerve injury induces the cleavage of CX3CL1 from the membrane of neurons, where the soluble CX3CL1 subsequently plays an important role in the transmission of nociceptive signals between neurons and microglia. Here we investigated whether CX3CL1 regulates microglia activation through the phosphorylation of extracellular signal-regulated protein kinase 5 (ERK5) in the spinal cord of rats with spinal nerve ligation (SNL). ERK5 and microglia were activated in the spinal cord after SNL. The knockdown of ERK5 by intrathecal injection of antisense oligonucleotides suppressed the hyperalgesia and nuclear impact of nuclear factor-kappaB induced by SNL. The blockage of CX3CR1, the receptor of CX3CL1, significantly reduced the level of ERK5 activation following SNL. In addition, the antisense knockdown of ERK5 reversed the CX3CL1-induced hyperalgesia and spinal microglia activation. Our study suggests that CX3CL1/CX3CR1 regulates nerve injury-induced pain hypersensitivity through the ERK5 signaling pathway. PMID- 23361877 TI - Detecting active inflammation and fibrosis in pediatric Crohn's disease: prospective evaluation of MR-E and CT-E. AB - Symptoms of Crohn's disease (CD) can be due to active inflammation or fibrosis. Differentiating these based on clinical presentation, endoscopy, laboratory parameters, and clinical scoring methods can be inaccurate and/or invasive. As therapy decisions are often directed based on whether active disease or fibrosis is present, a reliable and non-invasive test to distinguish these two etiologies would be a powerful clinical tool. CT enterography (CT-E) and MR enterography (MR E) are two non-invasive imaging modalities tailored to evaluate the small bowel. The purpose of our study was to compare the ability of MR-E and CT-E to assess for active inflammation and mural fibrosis in patients with known CD as compared to a histologic reference standard. After obtaining MR-E and CT-E on the same day, a total of 61 histologic samples were obtained from twelve subjects aged 12 20 years via full-thickness bowel resection or endoscopy. These were evaluated by the pathologist for active inflammation and fibrosis. We found that while CT-E and MR-E were similar in their accuracies of depicting active inflammation, MR-E was significantly more sensitive in detecting fibrosis. Because of this and the lack of ionizing radiation from MR-E, we believe that MR-E rather than CT-E should serve as the primary imaging modality for the assessment of CD pediatric patients with non-acute clinical exacerbations. PMID- 23361878 TI - Reflections from MAQ editors 2006-2012, and introduction to a special focus section. PMID- 23361879 TI - What is life worth? Exploring biomedical interventions, survival, and the politics of life. PMID- 23361880 TI - (Bio)sociality and HIV in Tanzania: finding a living to support a life. AB - This article addresses life on antiretroviral therapy in rural Tanzania. It argues that a nuanced understanding of theories of biosociality requires us to take sociality and locality as seriously as we do "bio." People living with HIV associate on the basis of preexisting social relations, not just on the basis of their biological status. Their CD4 counts do not only measure immunological processes but also index social conditions of hunger. The pharmaceutical that gives them life insists that they eat and rest more than austere financial circumstances allow. Many join HIV groups, but these do not enable the kinds of "citizenship" that have been described elsewhere. Patient activism is stifled by bureaucratic antipolitics mechanisms inherited from postcolonial restrictions on political association. Instead, they enter an NGO economy that values their biological status because they attract income from donors, but does little to enable the living that they need. PMID- 23361881 TI - Struggling with AIDS in South Africa: the space of the everyday as a field of recognition. AB - The space of volunteering is often seen as a place for rebuilding a world for individuals for whom life has been destroyed by the discovery of AIDS infection. People living with AIDS get involved in HIV support groups, become volunteers, and take care for each other. Without denying the reality of these processes leading to a "positive life" this article questions narratives of the transformation of the self-implied in the "caring for other" logic and argues that other spheres of life, less discernable because inscribed in the ordinary and in the intimacy of domestic life are at least as important as the involvement in biomedical care. The limits of voluntary work is highlighted and contrasted with a presentation of how life, love and affection is reconfigured within everyday life, leading to a consideration of people's struggles to build spaces of recognition. The argument of this article is built on a three year ethnography (2001-04) carried out in Soweto and Alexandra townships (South Africa). PMID- 23361882 TI - What is life worth? A rough guide to valuation. AB - In this speculative article, the aim is to elaborate a definition of life that is not biological, and a valuation of it that is not commodified. This is undertaken by the development of an understanding of death as a process which is embedded in the life of a community. The idea is that we can best understand what life is worth by first understanding what death means. PMID- 23361883 TI - Self-care at the margins: meals and meters in migrants' diabetes tactics. AB - Drawing on ethnographic fieldwork in 2006 and 2007, this article examines Turkish migrants' everyday practices of diabetes self-management in Berlin, Germany. To avoid diabetes complications, Turkish Berliners became self-carers who altered food choices, cooking and eating practices, and made their self-care practices visible with the help of blood sugar self-testing. Rather than representing the common image of the disadvantaged migrant patient they assumed the role of "expert patients" and their self-care was a deliberate practice to make their chronic illness experience manageable and tangible where formal support by the German healthcare system was inadequate. This article thus aims to interrogate both "self" and "care" in the context of "self-care at the margins" and draw on de Certeau's tactics of the ordinary person that make everyday life habitable. PMID- 23361884 TI - HIV and the moral economy of survival in an East African City. AB - Based on fieldwork in the city of Kisumu, Kenya, the article examines the survival of HIV-positive people on antiretroviral (ARV) medicines and situates this within broader moral economies of their lives-in matters of food, hunger, social relationships, and networks of care, including NGOs. Through locating survival at the level of individual adherence to medication, ARV programs medicalize it. Yet their focus on the intimate relation between medicine and food also opens up spaces in which the material conditions of life can be articulated. The article follows these spaces, from the clinic to the economy of NGO interventions and community-based groups, paying attention to how hunger and material needs are visible in some spaces and invisible in others, and to how people have learned to articulate their "needs." In this economy, HIV identities accrue moral and economic value, as through them people become visible to the flow of funds and the distribution of goods organized by NGOs. PMID- 23361885 TI - Culture and carelessness: constituting disability in South India. AB - Professional and lay explanations of disability, collected via interviews and participant-observation during fieldwork in Hyderabad, South India, identify "carelessness" and "superstition" as major impediments to good health among the general population, and education as the key solution. In that such findings suggest a valorization of personal responsibility for self-care, the Foucauldian concept of biopower appeared a salient framework for analysis. Although illuminating, however, biopower was ultimately inadequate for explaining what emerged, on closer analysis, as significant discrepancies between assumptions about how disabled people engaged with healthcare services and their actual beliefs and practices; and between the moral interpretations different stakeholders made of "carelessness" in describing perceived causes of disability. My data also suggested that education was not in itself a key determinant in people's healthcare decisions. This article explores these differences between official and demotic discourses concerning the causes of disability and attempts to account for them ethnographically. PMID- 23361886 TI - Viability: a cultural calculus of personhood at the beginnings of life. AB - This article addresses birth and the recognition of personhood. It is about the calculated acts of recognition that take place at the beginnings of life when the obligation to protect and extend physical care is uncertain. It examines these dilemmas from the perspective of clinicians and scientists who assist in birth through their work with embryos, fetuses, and extremely premature infants in the United States. Through multisited ethnography and in-depth interviews at a leading U.S. teaching hospital, this article argues that the concept of viability operates as a placeholder for the recognition of personhood at the beginnings of life. Articulated in a language of survival and stratified by gestational age, this article explores how viability is a central organizing principle in the management of birth. It aims to situate questions about the value of life to the maternity unit where patients and clinicians face choices about the kinds of viability-and as a result persons-that are possible and desired within the contemporary culture of hospital births. PMID- 23361887 TI - Native American embodiment of the chronicities of modernity: reservation food, diabetes, and the metabolic syndrome among the Kiowa, Comanche, and Apache. AB - As a physical embodiment of modernity, the prevalence of obesity, diabetes, and the metabolic syndrome (MetS) among Native Americans reflects their body's biological response to social and cultural structures that routinize daily behaviors and contain their physical body. This article explains why Native Americans were one of the earliest populations manifesting this epidemic. Ethnohistorical methods identify the conjuncture of chronic behaviors among Kiowa, Comanche, and Apache of Oklahoma that promote inactivity, overnutrition, and psychosocial stresses. Correspondence and primary documents of Federal Indian Agents who managed the reservation food rations and annuity systems beginning in the 1860s, details a culture history of nutrition and food technologies that standardized and established the unhealthy modern diet that continues among Native Americans today. By identifying structural chronicities affecting specific populations and life situations, policies and interventions can be more effective in promoting positive changes for reducing the global pandemic of diabetes and MetS. PMID- 23361888 TI - Dead bodies matter: gift giving and the unveiling of body donor monuments in the Netherlands. AB - Body donors are people who voluntarily donate their entire body, after death, to anatomical science. Based on anthropological fieldwork in the Netherlands this article explores the construction of body donor monuments since 2007. These developments are analyzed by means of gift-giving theories. Body donation is a practice in which the medical and scientific value of the donor bodies has always been praised. Increasingly the fact that the bodies represent real human beings who have mourning relatives has also been acknowledged. This change in attitude has resulted in a desire on the part of anatomical professionals to give back a monument, not only for the donors themselves but also, in particular, for the donors' relatives. The great public interest in the monuments has revealed that many of the bereaved, in the absence of having the physical body of the donor, need a symbolic final resting place for their loved ones. PMID- 23361889 TI - The expression of GintPT, the phosphate transporter of Rhizophagus irregularis, depends on the symbiotic status and phosphate availability. AB - The development of mutualistic interactions with arbuscular mycorrhizal (AM) fungi is one of the most important adaptation of terrestrial plants to face mineral nutrition requirements. As an essential plant nutrient, phosphorus uptake is acknowledged as a major benefit of the AM symbiosis, but the molecular mechanisms of its transport as inorganic phosphate (Pi) from the soil to root cells via AM fungi remain poorly known. Here we monitored the expression profile of the high-affinity phosphate transporter (PT) gene (GintPT) of Rhizophagus irregularis (DAOM 197198) in fungal structures (spores, extraradical mycelium and arbuscules), under different Pi availability, and in respect to plant connection. GintPT resulted constitutively expressed along the major steps of the fungal life cycle and the connection with the host plant was crucial to warrant GintPT high expression levels in the extraradical mycelium. The influence of Pi availability on gene expression of the fungal GintPT and the Medicago truncatula symbiosis specific Pi transporter (MtPT4) was examined by qRT-PCR assay on microdissected arbusculated cells. The expression profiles of both genes revealed that these transporters are sensitive to changing Pi conditions: we observed that MtPT4 mRNA abundance is higher at 320 than at 32 MUM suggesting that the flow towards the plant requires high concentrations. Taken on the whole, the findings highlight novel traits for the functioning of the GintPT gene and offer a molecular scenario to the models describing nutrient transfers as a cooperation between the mycorrhizal partners. PMID- 23361890 TI - Multiple ketolases involved in light regulation of canthaxanthin biosynthesis in Nostoc punctiforme PCC 73102. AB - In the genome of Nostoc punctiforme PCC 73102, three functional beta-carotene ketolase genes exist, one of the crtO and two of the crtW type. They were all expressed and their corresponding enzymes were functional inserting 4-keto groups into beta-carotene as shown by functional pathway complementation in Escherichia coli. They all synthesized canthaxanthin but with different efficiencies. Canthaxanthin is the photoprotective carotenoid of N. punctiforme PCC 73102. Under high-light stress, its synthesis was enhanced. This was caused by up regulation of the transcripts of two genes in combination. The first crtB encoding phytoene synthase is the gate way enzyme of carotenogenesis resulting in an increased inflow into the pathway. The second was the ketolase gene crtW148 which in high light takes over beta-carotene conversion into canthaxanthin from the other ketolases. The other ketolases were down-regulated under high-light conditions. CrtW148 was also exclusively responsible for the last step in 4-keto myxoxanthophyll synthesis. PMID- 23361891 TI - Bis(tetrasulfato)palladate, [Pd(S(4)O(13))(2)](2-). AB - SOS: The first coordination compound containing polysulfate ligands was obtained under harsh conditions from the reaction of K(2)[PdCl(4)] and SO(3). The compound contains a Pd(2+) ion coordinated by two chelating tetrasulfate anions (see structure, Pd red, S yellow, O blue), which leads to a significant stabilization of the polysulfate anions compared to their uncoordinated analogues. PMID- 23361892 TI - Phase 2 study of pre-excision single-dose intraoperative radiation therapy for early-stage breast cancers: six-year update with application of the ASTRO accelerated partial breast irradiation consensus statement criteria. AB - BACKGROUND: Intraoperative radiation therapy (IORT) allows delivery of high-dose radiation at the time of lumpectomy, potentially sparing adjuvant daily radiation. A phase 2 study of pre-excision IORT was performed for early-stage breast cancer. METHODS: Patients >= 48 years of age with invasive ductal carcinoma, <= 3 cm, and clinically node-negative were eligible for this study, which was approved by institutional review board. Ultrasound was used to select electron energy and cone size to cover the tumor plus 1.5- to 2.0-cm lateral margins and 1-cm-deep margins (90% isodose). Fifteen Gy was delivered with a Mobetron irradiator, and immediate needle-localized partial mastectomy followed. Local event results were updated using the Kaplan-Meier method. RESULTS: A total of 53 patients received IORT alone. Median age was 63 years, and median tumor size was 1.2 cm. Of these, 81% were positive for estrogen receptor or progesterone receptor, 11% were positive for human epidermal growth factor receptor 2, and 15% were triple-negative. Also, 42%, 49%, and 9% would have fallen into the Suitable, Cautionary, and Unsuitable groups, respectively, of the American Society of Therapeutic Radiation Oncology consensus statement for accelerated partial breast irradiation. Median follow-up was 69 months. Ipsilateral events occurred in 8 of 53 patients. The 6-year actuarial rate of ipsilateral events was 15% (95% confidence interval = 7%-29%). The crude event rate for Suitable and Cautionary groups was 1 of 22 (5%) and 7 of 26 (27%), respectively. Overall survival was 94.4%, and breast cancer-specific survival was 100%. CONCLUSIONS: The rate of local events in this study is a matter of concern, especially in the Cautionary group. On the basis of these findings, pre-excision IORT, as delivered in this study, may not provide adequate local control for less favorable early-stage breast cancers. PMID- 23361893 TI - Revealing unexpected mechanisms for nucleophilic attack on S-S and Se-Se bridges. AB - The reactivity of disulfide and diselenide derivatives towards F(-) and CN(-) nucleophiles has been investigated by means of B3PW91/6-311+G(2df,p) calculations. This theoretical survey shows that these processes, in contrast with the generally accepted view of disulfide and diselenide linkages, do not always lead to S?S or Se?Se bond cleavage. In fact, S?S or Se?Se bond fission is the most favorable process only when the substituents attached to the S or the Se atoms are not very electronegative. Highly electronegative substituents (X) strongly favor S?X bond fission. This significant difference in the observed reactivity patterns is directly related to the change in the nature of the LUMO orbital of the disulfide or diselenide derivative as the electronegativity of the substituents increases. For weakly electronegative substituents, the LUMO is a sigma-type S?S (or Se?Se) antibonding orbital, but as the electronegativity of the substituents increases the pi-type S?X antibonding orbital stabilizes and becomes the LUMO. The observed reactivity also changes with the nature of the nucleophile and with the S or Se atom that undergoes the nucleophilic attack in asymmetric disulfides and diselenides. The activation strain model provides interesting insights into these processes. There are significant similarities between the reactivity of disulfides and diselenides, although some dissimilarities are also observed, usually related to the different interaction energies between the fragments produced in the fragmentation process. PMID- 23361894 TI - Mitochondrial-dependent anticancer activity of delta-tocotrienol and its synthetic derivatives in HER-2/neu overexpressing breast adenocarcinoma cells. AB - Anticancer activity and mitochondrial mechanism of the vitamin E form delta tocotrienol (delta-T3) was investigated in HER-2/neu-overexpressing human SKBR3 and murine TUBO breast cancer cells. delta-T3 was confirmed to possess high cytotoxic and apoptotic activity in SKBR3 cells as compared with all natural forms of vitamin E and several synthetic forms that included novel derivatives with the same backbone of delta-T3 such as delta-tocotrienyl-succinyl amide (delta-T3AS) and the redox-active analogue delta-tocotrienyl amine (delta-T3NH2). As observed in the case of alpha-TOS, a prototypical anticancer drug derived from alpha-tocopherol, succinylation of delta-T3 enhanced citotoxicity and apoptotic activity of the vitamer. delta-T3 induced apoptosis of SKBR3 cells was associated with mitochondrial destabilization, energy failure, and unbalanced activity of stress/survival MAPKs, namely p38 and ERK1/2 pathways. An increased generation of ROS followed to such a series of early events. Enhanced activity of delta-T3 in this human carcinoma cell line was characterized by the sustained uptake and oxidative transformation to the quinone derivative delta-T3Q, thereby suggesting redox effects in SKBR3 mitochondria by this vitamer. Viability and uptake data show a different pattern of responses in TUBO cells with higher response to synthetic derivatives of delta-T3 than in SKBR3 cells. In conclusion, synthetic derivatives of delta-T3 with enhanced apoptotic activity in breast carcinoma cells are investigated for the first time in this study also describing mechanistic aspects of mitochondrial effects of delta-T3. Further investigation in preclinical models of HER2/neu-high breast adenocarcinoma is underway to identify other and more effective forms of VE in this type of cancer. PMID- 23361895 TI - Role of preoperative colonoscopy in patients with gastric cancer: a case control study of the prevalence of coexisting colorectal neoplasms. AB - BACKGROUND: We evaluated the prevalence of coexisting asymptomatic colorectal neoplasm (CRN) in patients with gastric cancer (GC). METHODS: Preoperative colonoscopic examinations were performed in 495 patients with GC who underwent gastrectomy between January 2009 and December 2010. To compare the prevalence of CRN in these patients with that in a normal population, we selected 495 sex- and age-matched persons who underwent colonoscopies for health screening. Risk factors for CRN were evaluated by univariate and multivariate analyses. RESULTS: The overall incidence of CRN was 41.8 % (414/990). The prevalence of overall CRN, high-risk CRN, and colorectal carcinoma (CRC) were significantly higher in the GC group than in the control group (overall CRN: 48.9 % vs. 34.7 %; high-risk CRN: 28.3 % vs. 13.5 %; CRC: 2.6 % vs. 0.2 %; all P < 0.001). The presence of GC [odds ratio (OR), 1.82; 95 % confidence interval (CI), 1.4-2.38; P < 0.001], age >=50 years (OR, 2.58; 95 % CI, 1.75-3.81; P < 0.001), and male sex (OR, 2.28; 95 % CI, 1.72-3.02; P < 0.001) were risk factors for overall CRN. In patients with GC, age >=40 years (OR, 3.22; 95 % CI, 1.24-8.37; P = 0.016) and male sex (OR, 3.21; 95 % CI, 2.17-4.76; P < 0.001) were risk factors for overall CRN. CONCLUSIONS: The prevalence of coexisting CRN, including CRC, was higher in patients with GC than in the normal population. Preoperative colonoscopy is strongly indicated in patients with GC who are male and/or >=40 years of age. PMID- 23361896 TI - Level VII is an important component of central neck dissection for papillary thyroid cancer. AB - BACKGROUND: Therapeutic central neck dissection (CND) is an accepted part of the management of papillary thyroid carcinoma (PTC), while prophylactic CND remains controversial. Regardless of the indication for CND, the lower anatomic border of the central compartment, specifically the inclusion or otherwise of level VII, is not always clearly defined in the literature. This study aimed to determine if the routine inclusion of level VII lymph node dissection as part of CND confers increased utility in the detection of macrometastatic lymph nodes compared with level VI dissection alone. METHOD: This was a prospective cohort study of patients undergoing CND for PTC at a tertiary referral center. All patients received either a prophylactic or therapeutic CND. The CND specimens were divided by the surgeon into level VI and level VII at the level of the suprasternal notch and submitted separately for histopathology. Criteria for macroscopic lymph node disease were taken from the American Joint Committee on Cancer (AJCC) recommendations for breast cancer. RESULTS: A total of 45 patients with PTC underwent total thyroidectomy and routine CND, at a tertiary referral center; 77 % of the therapeutic CND group had positive level VI lymph nodes, and 38 % had positive level VII lymph nodes. Of the prophylactic CND group, 50 % of patients had positive level VI nodes and 16 % has positive level VII nodes detected. All patients with positive level VII lymph nodes in the prophylactic CND group had macrometastatic disease. Temporary hypocalcemia rate was 31 % in the therapeutic group and 6 % in the prophylactic CND group. One patient experienced permanent hypoparathyroidism. There was no vascular injury or recurrent laryngeal nerve palsy in either group. CONCLUSIONS: CND incorporating both level VI and level VII can be undertaken safely through a cervical incision with no increased risk of permanent complications of hypoparathyroidism or recurrent laryngeal nerve injury. Failure to include level VII as part of CND will leave significant macrometastatic nodal disease behind in both therapeutic and prophylactic dissections. As level VII is in direct anatomic continuity with the pretracheal level VI nodes, it should be routinely included as part of every CND. PMID- 23361897 TI - The impact of perineural invasion and/or lymphovascular invasion on the survival of early-stage oral squamous cell carcinoma patients. AB - BACKGROUND: For early-stage oral squamous cell carcinoma (OSCC) patients, the impact of perineural invasion (PNI) and lymphovascular invasion (LVI) on disease control and survival has not been clarified. METHODS: The medical records of all early-stage OSCC patients who underwent curative surgery between 2004 and 2009 were reviewed. RESULTS: A total of 442 early stage patients were included in this study. There were 360 patients in group A (without PNI or LVI) and 82 patients in group B (with PNI and/or LVI). Between groups A and B patients, there were no significant differences in the 5-year disease-free survival (73.8 vs 68.7 %, p = 0.48) and overall survival (90.9 vs 86.1 %, p = 0.25). Between groups A and B patients without postoperative radiotherapy (PORT), there were no significant differences in the 5-year disease-free survival (73.8 vs 70.2 %, p = 0.51) and overall survival (90.9 vs 85.2 %, p = 0.18). Between group B patients with and without PORT, there was no significant difference in either the disease-free survival (61.1 vs 70.2 %, p = 0.98) and overall survival (88.9 vs 85.2 %, p = 0.64). Multivariate analyses revealed that PNI, LVI, and PORT could not provide significant effect on treatment outcome. CONCLUSIONS: PNI and LVI were not significant risk factors for the disease control and overall survival for early stage OSCC patients. Furthermore, PORT could not provide an additional benefit for the disease control and overall survival for stages I and II OSCC patients with PNI and/or LVI. PMID- 23361898 TI - Evidence that proliferation of golgi apparatus depends on both de novo generation from the endoplasmic reticulum and formation from pre-existing stacks during the growth of tobacco BY-2 cells. AB - In higher plants, the numbers of cytoplasmic-distributed Golgi stacks differ based on function, age and cell type. It has not been clarified how the numbers are controlled, whether all the Golgi apparatus in a cell function equally and whether the increase in Golgi number is a result of the de novo formation from the endoplasmic reticulum (ER) or fission of pre-existing stacks. A tobacco prolyl 4-hydroxylase (NtP4H1.1), which is a cis-Golgi-localizing type II membrane protein, was tagged with a photoconvertible fluorescent protein, mKikGR (monomeric Kikume green red), and expressed in tobacco bright yellow 2 (BY-2) cells. Transformed cells were exposed to purple light to convert the fluorescence from green to red. A time-course analysis after the conversion revealed a progressive increase in green puncta and a decrease in the red puncta. From 3 to 6 h, we observed red, yellow and green fluorescent puncta corresponding to pre existing Golgi; Golgi containing both pre-existing and newly synthesized protein; and newly synthesized Golgi. Analysis of the number and fluorescence of Golgi at different phases of the cell cycle suggested that an increase in Golgi number with both division and de novo synthesis occurred concomitantly with DNA replication. Investigation with different inhibitors suggested that the formation of new Golgi and the generation of Golgi containing both pre-existing and newly synthesized protein are mediated by different machineries. These results and modeling based on quantified results indicate that the Golgi apparatuses in tobacco BY-2 cells are not uniform and suggest that both de novo synthesis from the ER and Golgi division contribute almost equally to the increase in proliferating cells. PMID- 23361899 TI - Awake craniotomy in a developmentally delayed blind man with cognitive deficits. AB - PURPOSE: To describe the complex perioperative considerations and anesthetic management of a cognitively delayed blind adult male who underwent awake craniotomy to remove a left anterior temporal lobe epileptic focus. CLINICAL FEATURES: A 28-yr-old left-handed blind cognitively delayed man was scheduled for awake craniotomy to resect a left anterior temporal lobe epileptic focus due to intractable epilepsy despite multiple medications. His medical history was also significant for retinopathy of prematurity that rendered him legally blind in both eyes and an intracerebral hemorrhage shortly after birth that resulted in a chronic brain injury and developmental delay. His cognitive capacity was comparable with that of an eight year old. Since patient cooperation was the primary concern during the awake electrocorticography phase of surgery, careful assessment of the patient's ability to tolerate the procedure was undertaken. There was extensive planning between surgeons and anesthesiologists, and a patient-specific pharmacological strategy was devised to facilitate surgery. The operation proceeded without complication, the patient has remained seizure-free since the procedure, and his quality of life has improved dramatically. CONCLUSION: This case shows that careful patient assessment, effective interdisciplinary communication, and a carefully tailored anesthetic strategy can facilitate an awake craniotomy in a potentially uncooperative adult patient with diminished mental capacity and sensory deficits. PMID- 23361900 TI - Prolonged use of the LMA SupremeTM. PMID- 23361902 TI - Public reporting of cardiovascular care: an opportunity to shape the future. PMID- 23361901 TI - Modulation of antioxidant machinery in alpha-tocopherol-enriched transgenic Brassica juncea plants tolerant to abiotic stress conditions. AB - The antioxidant machinery in plants consists of several components with unique or overlapping functions that combat the deleterious production of reactive oxygen species (ROS) induced by stress conditions. Tocopherols are a group of powerful antioxidants having additional roles in signaling and gene expression, with alpha tocopherol being the most potent form. In the present study, we used wild-type (WT) and alpha-tocopherol-enriched transgenic (TR) Brassica juncea plants grown under salt, heavy metal, and osmotic stress to compare their relative tolerance to these stresses and to assess the effects of increased alpha-tocopherol content on the other antioxidative enzymes and molecules. The oxidative damage caused by induced stress was lower in TR plants compared to WT plants as assessed by their higher relative water content and lower electrolyte leakage, malondialdehyde content as well as H(2)O(2) accumulation. Lesser superoxide and H(2)O(2) accumulation was also observed by histochemical staining in TR seedlings exposed to stress. Though no significant differences were evident under normal growth conditions, TR plants showed higher activities and transcript levels of antioxidant enzymes superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase than WT plants under similar stress conditions. A decrease in ascorbate and glutathione content with marginally higher reductive ratios of these compounds was also observed in TR plants under the stress conditions. Our findings implicate the role of higher alpha-tocopherol levels in conferring better tolerance against salt, heavy metal, and osmotic stresses and also establish the existence of interplay between this lipid-soluble antioxidant and other water-soluble components of plant antioxidant defense. PMID- 23361903 TI - A simple HPV 18 detection method based on ultra specific primer immobilized on glass slides. AB - This study was carried out to develop a simple and inexpensive method for detection of Human papillomavirus (HPV 18) based on irreversible immobilization of ultra specific primer on silanized glass slides. This method is revealed by Blue Green Loading Dye I (LGC) and compared with conventional polymerase chain reaction (PCR) for endocervical samples. The new method was tested in 40 DNA samples with precancer uterine lesions of women treated in Hospital of Recife PE, Brazil. DNA samples were extracted using Wizard Genomic DNA Purification Kit according to manufacturer's instructions. The samples were tested for HPV 18 by conventional PCR (PCRc) and the products visualized on 1.2% agarose gel, with LGC under UV 260 nm. After that the positive and negative samples to HPV 18 were tested by immobilization method and the results visualized with LGC under UV 260 nm. Both PCRc and immobilization method showed high degree of correlation (95%), whereas comparison between PCRc and immobilization method showed good correlation (100%). PCRc is widely known for detection of HPV because of its high sensitivity and efficiency, but due to high cost it is not yet standardized for use in public health laboratories. In our study, the single-stranded DNA immobilized method on a glass slide was effective in screening for HPV revealed by Blue Green and may be an alternative method for diagnosis of HPV once it offers a fast, and easy handling. PMID- 23361904 TI - Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group. AB - In a previous publication on new terminology, definitions, and outcome criteria for immune thrombocytopenia (ITP), the International Working Group (IWG) on ITP acknowledged that response to treatment should consist of clinically meaningful end points such as bleeding manifestations and that platelet count may not be the ideal parameter for capturing the benefits of therapy. The IWG now proposes a consensus-based ITP-specific bleeding assessment tool (ITP-BAT) with definitions and terminology consistent with those adopted for other bleeding disorders. Bleeding manifestations were grouped into three major domains: skin (S), visible mucosae (M), and organs (O), with gradation of severity (SMOG). Each bleeding manifestation is assessed at the time of examination. Severity is graded from 0 to 3 or 4, with grade 5 for any fatal bleeding. Bleeding reported by the patient without medical documentation is graded 1. Within each domain, the same grade is assigned to bleeding manifestations of similar clinical impact. The "worst bleeding manifestation since the last visit" (observation period) is graded (a suitable database collection form is provided), and the highest grade within each domain is recorded. The SMOG system provides a consistent description of the bleeding phenotype in ITP, and the IWG unanimously supports its adoption and validation in future clinical studies. PMID- 23361905 TI - Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms. AB - Leukemic transformation (LT) is a rare but fatal complication of Philadelphia negative myeloproliferative neoplasms (MPNs) for which optimal treatment strategies are not known. At our center, we have adopted a treatment approach for LT where patients within the transplant age group who have a reasonable fitness level are treated with curative intent and offered induction chemotherapy. Subsequently, those who respond and have a suitable donor are considered for allogeneic hematopoietic cell transplantation (HCT). In this study, we evaluated the clinical outcomes of this treatment approach in 75 patients with LT. The 2 year overall survival (OS) from the time of LT was 15%. A total of 39 patients (52%) were treated with curative intent (induction +/- HCT) and had a 2-y OS of 26% compared with 3% in those noncuratively treated (P < .0001). In the curative intent group, 18 individuals (46%) achieved complete remission (CR) or CR with incomplete recovery and 12 (31%) reverted to a chronic MPN phase, with 17 patients undergoing HCT. Survival of patients posttransplant was significantly improved compared with those who responded to induction but were not transplanted (2-y OS of 47% vs 15%; P = .03). Thus, induction chemotherapy followed by HCT has the potential for long-term disease control in select patients with LT preceded by a MPN. PMID- 23361906 TI - Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas. AB - Hypoxia-inducible factors (HIFs) control the cellular response to hypoxia and, when dysregulated, contribute to tumorigenesis. Previously, we identified 2 gain of-function somatic mutations in patients presenting with multiple paragangliomas or somatostatinomas, and polycythemia. Here, we report 2 additional unique HIF2A mutations, which disrupt the hydroxylation domain recognized by prolyl hydroxylase domain-2 containing protein, leading to stabilization of HIF-2alpha and increased expression of hypoxia-related genes. PMID- 23361908 TI - Who is the better donor for older hematopoietic transplant recipients: an older aged sibling or a young, matched unrelated volunteer? AB - Older patients are increasingly undergoing allogeneic hematopoietic transplantation. A relevant question is whether outcomes can be improved with a younger allele-level 8/8 HLA-matched unrelated donor (MUD) rather than an older HLA-matched sibling (MSD). Accordingly, transplants in leukemia/lymphoma patients age >=50 years were analyzed comparing outcomes for recipients of MSD >=50 (n = 1415) versus MUD <50 years (n = 757). Risks of acute graft-versus-host disease (GVHD) grade 2 to 4 (hazard ratio [HR], 1.63; P < .001), 3 to 4 (HR, 1.85; P < .001), and chronic GVHD (HR, 1.48; P < .0001) were higher after MUD compared with MSD transplants. The effect of donor type on nonrelapse mortality (NRM), relapse, and overall mortality was associated with performance score. For patients with scores of 90 or 100, NRM (HR, 1.42; P = .001), relapse (HR, 1.45; P < .001), and overall mortality (HR, 1.28; P = .001) risks were higher after MUD transplants. For patients with scores below 90, NRM (HR, 0.96; P = .76), relapse (HR, 0.86; P = .25), and overall mortality (HR, 0.90; P = .29) were not significantly different after MUD and MSD transplants. These data favor an MSD over a MUD in patients age >=50 years. PMID- 23361907 TI - Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l. AB - The t(6;11)(q27;q23) is a recurrent chromosomal rearrangement that encodes the MLLAF6 fusion oncoprotein and is observed in patients with diverse hematologic malignancies. The presence of the t(6;11)(q27;q23) has been linked to poor overall survival in patients with AML. In this study, we demonstrate that MLL-AF6 requires continued activity of the histone-methyltransferase DOT1L to maintain expression of the MLL-AF6-driven oncogenic gene-expression program. Using gene expression analysis and genome-wide chromatin immunoprecipitation studies followed by next generation sequencing, we found that MLL-fusion target genes display markedly high levels of histone 3 at lysine 79 (H3K79) dimethylation in murine MLL-AF6 leukemias as well as in ML2, a human myelomonocytic leukemia cell line bearing the t(6;11)(q27;q23) translocation. Targeted disruption of Dot1l using a conditional knockout mouse model inhibited leukemogenesis mediated by the MLL-AF6 fusion oncogene. Moreover, both murine MLL-AF6-transformed cells as well as the human MLL-AF6-positive ML2 leukemia cell line displayed specific sensitivity to EPZ0004777, a recently described, selective, small-molecule inhibitor of Dot1l. Dot1l inhibition resulted in significantly decreased proliferation, decreased expression of MLL-AF6 target genes, and cell cycle arrest of MLL-AF6-transformed cells. These results indicate that patients bearing the t(6;11)(q27;q23) translocation may benefit from therapeutic agents targeting aberrant H3K79 methylation. PMID- 23361909 TI - Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice. AB - B-cell lymphoma 11A (BCL11A) downregulation in human primary adult erythroid progenitors results in elevated expression of fetal gamma-globin. Recent reports showed that BCL11A expression is activated by KLF1, leading to gamma-globin repression. To study regulation of erythropoiesis and globin expression by KLF1 and BCL11A in an in vivo model, we used mice carrying a human beta-globin locus transgene with combinations of Klf1 knockout, Bcl11a floxed, and EpoR(Cre) knockin alleles. We found a higher percentage of reticulocytes in adult Klf1(wt/ko) mice and a mild compensated anemia in Bcl11a(cko/cko) mice. These phenotypes were more pronounced in compound Klf1(wt/ko)::Bcl11a(cko/cko) mice. Analysis of Klf1(wt/ko), Bcl11a(cko/cko), and Klf1(wt/ko)::Bcl11a(cko/cko) mutant embryos demonstrated increased expression of mouse embryonic globins during fetal development. Expression of human gamma-globin remained high in Bcl11a(cko/cko) embryos during fetal development, and this was further augmented in Klf1(wt/ko)::Bcl11a(cko/cko) embryos. After birth, expression of human gamma globin and mouse embryonic globins decreased in Bcl11a(cko/cko) and Klf1(wt/ko)::Bcl11a(cko/cko) mice, but the levels remained much higher than those observed in control animals. Collectively, our data support an important role for the KLF1-BCL11A axis in erythroid maturation and developmental regulation of globin expression. PMID- 23361910 TI - Autologous stem cell transplantation for enteropathy-associated T-cell lymphoma: a retrospective study by the EBMT. AB - Enteropathy-associated T-cell lymphoma (EATL) is a rare subtype of peripheral T cell lymphomas with a poor prognosis. Autologous stem cell transplantation (ASCT) was retrospectively evaluated as a consolidation or salvage strategy for EATL. The analysis included 44 patients who received ASCT for EATL between 2000 and 2010. Thirty-one patients (70%) were in first complete or partial remission at the time of the ASCT. With a median follow-up of 46 months, relapse incidence, progression-free survival, and overall survival were 39%, 54%, and 59% at 4 years, respectively, with only one relapse occurring beyond 18 months posttransplant. There was a trend for better survival in patients transplanted in first complete or partial remission at 4 years (66% vs 36%; P = .062). ASCT is feasible in selected patients with EATL and can yield durable disease control in a significant proportion of the patients. PMID- 23361911 TI - Dialysis adequacy in Chinese anuric peritoneal dialysis patients. AB - PURPOSE: We aimed in this study to explore how lower-protein diet would affect dialysis adequacy in anuric peritoneal dialysis (PD) patients. METHODS: Patients' demographic features were collected, namely age, gender, weight, height, underlying renal disease, and time on PD. Urea kinetic model was used to assess solute clearance. A consecutive 3-day dietary record was collected to evaluate dietary protein intake (DPI), and normalized protein nitrogen appearance (nPNA) was also calculated to reflect protein intake. Blood samples were collected to measure hemoglobin and biochemistry. Patient's nutritional status was assessed by biochemistry, handgrip strength, and subjective global assessment (SGA). Body fluid distribution was measured by body composition monitor. RESULTS: Patients were 60.8 +/- 14.92 years old, and the time on PD was 40.15 +/- 22.90 months. Daily prescribed dialysis dose was 7,178 +/- 1,326 mL. Kt/V was 1.6 +/- 0.32. DPI was 0.8 +/- 0.25 g/kg/day. nPNA was 0.9 +/- 0.21 g/kg/day. Serum albumin was 39.42 +/- 4.83 g/L. Prevalence of malnutrition (assessed by SGA) was 20.2 %. Serum phosphate and serum bicarbonate were 1.68 +/- 0.47 and 27.16 +/- 3.49 mmol/L, respectively. Systolic blood pressure and diastolic blood pressure were 123.4 +/- 20.0 and 74.2 +/- 12.6 mmHg, respectively. Patients with nPNA less than 0.6 had significantly lower serum albumin concentrations than the average, and patients with nPNA more than 1.2 g/kg/day had significantly higher levels of serum phosphate and serum urea than the average. CONCLUSIONS: Our study suggested that anuric PD patients could achieve adequate dialysis even under lower solute clearance. And lower-protein diet contributed largely to adequate dialysis in these patients. PMID- 23361912 TI - Surveillance for small renal masses: retrospective analysis of a cohort of 42 patients with long-term follow-up. AB - PURPOSE: To provide our experience with active surveillance in patients incidentally diagnosed with small renal masses and show the results of long-term follow-up. PATIENTS AND METHODS: We retrospectively evaluated a cohort of 42 patients diagnosed with small renal mass (<= 4 cm in diameter). All patients had clinical and radiological follow-up every 6 months. We evaluated the differences between patients who remained on surveillance and those who underwent surgical delayed intervention and the correlations between clinical variables and size growth rate. RESULTS: The mean patients' age was 75 years (66-90); the mean follow-up was 69.4 months (range 35-168). The median initial tumor size at presentation was 2.5 cm (range 1-4.3), and the median estimated tumor volume was 8.6 cm(3) (range 1.7-42.3). The median growth rate of the cohort was 0.8 cm/year (range 0.2-2.9), and the median volumetric growth rate was 9.1 cm(3)/year (range 0-19.6). Death for metastatic disease occurred in 2 patients died due to metastatic disease (4.7 %). No correlation was found between initial tumor size and size growth rate. The mean growth rate of the group of patients who underwent surgery was higher than in those who remained on surveillance (1.8 vs. 0.4 cm/year; P < 0.001). CONCLUSIONS: The most of small renal masses initially managed by surveillance will grow slowly and will have a low metastatic potential. Tumor size at diagnosis is not able to predict the natural history of renal masses, even if malignant disease may have a higher growth rate. In elderly patients with relevant co-morbidities, surveillance can be a reasonable option alternative to surgery. PMID- 23361914 TI - [(3)H]UR-PLN196: a selective nonpeptide radioligand and insurmountable antagonist for the neuropeptide Y Y(2) receptor. AB - Radioing in on NPY: Attachment of a [2,3-(3)H]propionyl group through an appropriate linker to the guanidine group of an (S)-argininamide-type neuropeptide Y (NPY) Y(2) receptor antagonist resulted in a subtype-selective radioligand. PMID- 23361913 TI - Cell-autonomous sex determination outside of the gonad. AB - BACKGROUND: The classic model of sex determination in mammals states that the sex of the individual is determined by the type of gonad that develops, which in turn determines the gonadal hormonal milieu that creates sex differences outside of the gonads. However, XX and XY cells are intrinsically different because of the cell-autonomous sex-biasing action of X and Y genes. RESULTS: Recent studies of mice, in which sex chromosome complement is independent of gonadal sex, reveal that sex chromosome complement has strong effects contributing to sex differences in phenotypes such as metabolism. Adult mice with two X chromosomes (relative to mice with one X chromosome) show dramatically greater increases in body weight and adiposity after gonadectomy, irrespective of their gonadal sex. When fed a high-fat diet, XX mice develop striking hyperinsulinemia and fatty liver, relative to XY mice. The sex chromosome effects are modulated by the presence of gonadal hormones, indicating an interaction of the sex-biasing effects of gonadal hormones and sex chromosome genes. CONCLUSIONS: Other cell-autonomous sex chromosome effects are detected in mice in many phenotypes. Birds (relative to eutherian mammals) are expected to show more widespread cell-autonomous sex determination in non-gonadal tissues, because of ineffective sex chromosome dosage compensation mechanisms. PMID- 23361915 TI - A validation study of the FocalPoint GS imaging system for gynecologic cytology screening. AB - BACKGROUND: Studies of the performance of the automated FocalPoint Guided Screening (FPGS) imaging system in gynecologic cytology screening relative to manual screening have yielded conflicting results. In view of this uncertainty, a validation study of the FPGS was conducted before its potential adoption in 2 large laboratories in Ontario. METHODS: After an intense period of laboratory training, a cohort of 10,233 current and seeded abnormal slides were classified initially by FPGS. Manual screening and reclassification blinded to the FPGS results were then performed. Any adequacy and/or cytodiagnostic discrepancy between the 2 screening methods subsequently was resolved through a consensus process (truth). The performance of each method's adequacy and cytodiagnosis vis a-vis the truth was established. The sensitivity and specificity of each method at 4 cytodiagnostic thresholds (atypical squamous cells of undetermined significance or worse [ASC-US+], low-grade squamous intraepithelial lesion or worse [LSIL+], high-grade squamous intraepithelial lesion or worse [HSIL+], and carcinoma) were compared. The false-negative rate for each cytodiagnosis was determined. RESULTS: The performance of FPGS in detecting carcinoma, HSIL+, and LSIL+ was no different from the performance of manual screening, but the false negative rates for LSIL and ASC-US were higher with FPGS than with manual screening. CONCLUSIONS: The results from this validation study in the authors' laboratory environment provided no evidence that FPGS has diagnostic performance that differs from manual screening in detecting LSIL+, HSIL+, or carcinoma. PMID- 23361916 TI - The mechanism of caseinolytic protease (ClpP) inhibition. PMID- 23361917 TI - Brief report: parent verbal responsiveness and language development in toddlers on the autism spectrum. AB - This study examined the longitudinal associations between parent verbal responsiveness and language 3 years later in 34 toddlers with a diagnosis of an autism spectrum disorder. Parent-child play samples were coded for child engagement and communication acts and for parent verbal responsiveness. Measures of responsive verbal behaviors were used to predict language gain scores 3 years later. Parent directives for language that followed into the child's focus of attention were predictive of child receptive language gains. Parent comments that followed into the child's focus of attention yielded differential effects depending on initial levels of child language. Children who were minimally verbal at age 21/2 benefited from parent comments that followed into the their focus of attention, whereas children who were verbally fluent did not demonstrate such a benefit. PMID- 23361918 TI - Improving socialization for high school students with ASD by using their preferred interests. AB - There has been a paucity of research on effective social interventions for adolescents with autism spectrum disorders (ASD) in inclusive high school settings. The literature, however, suggests that incorporating the student with ASD's special interests into activities may help improve their socialization with typical peers. Within the context of a multiple baseline across participants design, we implemented lunchtime activities incorporating the adolescent with ASD's preferred interests that were similar to ongoing activities already available at the schools. Results showed this increased both level of engagement and their rate of initiations made to typical peers. Social validation measures suggest that both adolescents with ASD and typical peers enjoyed participating in these activities and that the results generalized to other similar activities. PMID- 23361919 TI - Dielectrophoresis 2011--part I. PMID- 23361920 TI - Electrodeless dielectrophoresis for bioanalysis: theory, devices and applications. AB - Dielectrophoresis is a non-destructive, label-free method to manipulate and separate (bio-) particles and macromolecules. The mechanism is based on the movement of polarizable objects in an inhomogeneous electric field. Here, microfluidic devices are reviewed that generate those inhomogeneous electric fields with insulating posts or constrictions, an approach called electrodeless or insulator-based dielectrophoresis. Possible advantages compared to electrode based designs are a less complex, monolithic fabrication process with low-cost polymeric substrates and no metal surface deterioration within the area of sample analysis. The electrodeless design has led to novel devices, implementing the functionality directly into the channel geometry and covering many areas of bioanalysis, like manipulation and separation of particles, cells, DNA, and proteins. PMID- 23361921 TI - Electrokinetic motion of a deformable particle: dielectrophoretic effect. AB - Electrokinetics-induced motion and deformation of a hyperelastic particle confined in a slit microchannel has been numerically investigated for the first time with a full consideration of the fluid-particle-electric field interactions and the dielectrophoretic (DEP) effect. When the initial orientation of a cylindrical particle with respect to the applied electric field, theta(p0), is 90 degrees , the particle tends to curl up as a "C" shape when moving from left to right. The electrokinetics-induced particle deformation is due to the joint effects of the shear force arising from the non-uniform Smoluchowski slip velocity on the particle surface and the asymmetric DEP force with respect to the center of the deformed particle arising from the spatially non-uniform electric field surrounding the particle. The electrokinetics-induced particle deformation is opposite to that of a particle moving in the same direction subjected to a pressure-driven flow. When the initial particle orientation is 03 standard deviation [SD], 99.7th percentile) have been correlated to mutations in the gene phosphatase and tensin homolog (PTEN). However, the phenotypic and genetic characterization of the remaining cases remains unclear. We report the phenotypic classification and genetic testing evaluation of a cohort of 33 patients with autism and macrocephaly. Within our cohort, we confirm the association of PTEN mutations and extreme macrocephaly (>3 SD, 99.7th percentile) and identify mutations in 22% of cases, including three novel PTEN mutations. In addition, we define three phenotypic subgroups: (a) those cases associated with somatic overgrowth, (b) those with disproportionate macrocephaly, and (c) those with relative macrocephaly. We have devised a novel way to segregate patients into these subgroups that will aide in the stratification of autism macrocephaly cases. Within these subgroups, we further expand the genetic etiologies for autism cases with macrocephaly by describing two novel suspected pathogenic copy number variants located at 6q23.2 and 10q24.32. These findings demonstrate the phenotypic heterogeneity of autism cases associated with macrocephaly and their genetic etiologies. The clinical yield from PTEN mutation analysis is 22% and 9% from chromosomal microarray (CMA) testing within this cohort. The identification of three distinct phenotypic subgroups within macrocephaly autism patients may allow for the identification of their respective distinct genetic etiologies that to date have remained elusive. PMID- 23361947 TI - Identification of a small-molecule inhibitor of HIV-1 assembly that targets the phosphatidylinositol (4,5)-bisphosphate binding site of the HIV-1 matrix protein. AB - The development of drug resistance remains a critical problem for current HIV-1 antiviral therapies, creating a need for new inhibitors of HIV-1 replication. We previously reported on a novel anti-HIV-1 compound, N(2)-(phenoxyacetyl)-N-[4-(1 piperidinylcarbonyl)benzyl]glycinamide (14), that binds to the highly conserved phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P(2)) binding pocket of the HIV-1 matrix (MA) protein. In this study, we re-evaluate the hits from the virtual screen used to identify compound 14 and test them directly in an HIV-1 replication assay using primary human peripheral blood mononuclear cells. This study resulted in the identification of three new compounds with antiviral activity; 2-(4-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl})-1-piperazinyl) N-(4-methylphenyl)acetamide (7), 3-(2-ethoxyphenyl)-5-[[4-(4 nitrophenyl)piperazin-1-yl]methyl]-1,2,4-oxadiazole (17), and N-[4-ethoxy-3-(1 piperidinylsulfonyl)phenyl]-2-(imidazo[2,1-b][1,3]thiazol-6-yl)acetamide (18), with compound 7 being the most potent of these hits. Mechanistic studies on 7 demonstrated that it directly interacts with and functions through HIV-1 MA. In accordance with our drug target, compound 7 competes with PI(4,5)P(2) for MA binding and, as a result, diminishes the production of new virus. Mutation of residues within the PI(4,5)P(2) binding site of MA decreased the antiviral effect of compound 7. Additionally, compound 7 displays a broadly neutralizing anti-HIV activity, with IC(50) values of 7.5-15.6 MUM for the group M isolates tested. Taken together, these results point towards a novel chemical probe that can be used to more closely study the biological role of MA and could, through further optimization, lead to a new class of anti-HIV-1 therapeutics. PMID- 23361948 TI - Color-coded audio computer-assisted self-interviews (C-ACASI) for poorly educated men and women in a semi-rural area of South India: "good, scary and thrilling". AB - It is challenging to collect accurate and complete data on sensitive issues such as sexual behaviors. Our objective was to explore experience and perceptions regarding the use of a locally programmed color-coded audio computer-assisted self interview (C-ACASI) system among men and women in a semi-rural setting in south India. We conducted a mixed-methods cross-sectional survey using semi structured interviews among 89 truck drivers and 101 truck driver wives who had participated earlier in the C-ACASI survey across a predominantly rural district in Tamil Nadu. To assess the color-coded format used, descriptive quantitative analysis was coupled with thematic content analysis of qualitative data. Only 10% of participants had ever used a computer before. Nearly 75% did not report any problem in using C-ACASI. The length of the C-ACASI survey was acceptable to 98% of participants. Overall, 87% of wives and 73% of truck drivers stated that C ACASI was user-friendly and felt comfortable in responding to the sensitive questions. Nearly all (97%) participants reported that using C-ACASI encouraged them to respond honestly compared to face-to-face personal interviews. Both the drivers and wives expressed that C-ACASI provided confidentiality, privacy, anonymity, and an easy mechanism for responding truthfully to potentially embarrassing questions about their personal sexual relationships. It is feasible and acceptable to use C-ACASI for collecting sensitive data from poorly computer literate, non-English-speaking, predominantly rural populations of women and men. Our findings support the implementation of effective and culturally sensitive C ACASI for data collection, albeit with additional validation. PMID- 23361949 TI - D-Lactate production as a function of glucose metabolism in Saccharomyces cerevisiae. AB - Methylglyoxal, a reactive, toxic dicarbonyl, is generated by the spontaneous degradation of glycolytic intermediates. Methylglyoxal can form covalent adducts with cellular macromolecules, potentially disrupting cellular function. We performed experiments using the model organism Saccharomyces cerevisiae, grown in media containing low, moderate and high glucose concentrations, to determine the relationship between glucose consumption and methylglyoxal metabolism. Normal growth experiments and glutathione depletion experiments showed that metabolism of methylglyoxal by log-phase yeast cultured aerobically occurred primarily through the glyoxalase pathway. Growth in high-glucose media resulted in increased generation of the methylglyoxal metabolite D-lactate and overall lower efficiency of glucose utilization as measured by growth rates. Cells grown in high-glucose media maintained higher glucose uptake flux than cells grown in moderate-glucose or low-glucose media. Computational modelling showed that increased glucose consumption may impair catabolism of triose phosphates as a result of an altered NAD+:NADH ratio. PMID- 23361950 TI - Use of thrombolysis in myocardial infarction risk score to predict bleeding complications in patients with unstable angina and non-ST elevation myocardial infarction undergoing percutaneous coronary intervention. AB - Thrombolysis in myocardial infarction (TIMI) is a prognostic score developed for managing the high risk of cardiac events immediately after unstable angina and non-ST elevation myocardial infarction (UA/NSTEMI). In Asian populations that have a higher rate of bleeding complications, data about TIMI score are lacking. Using a Japanese multicenter registry, we investigated the impact of utilizing TIMI score in UA/NSTEMI patients, focusing on bleeding complications. The TIMI score was calculated for 587 patients who underwent percutaneous coronary intervention (PCI) for UA/NSTEMI (2008-2010). They were classified into low-risk (TIMI score 0-2, N = 268, 45.6 %), intermediate-risk (TIMI score 3-4, N = 264, 45.0 %) and high-risk (TIMI score 5-7, N = 55, 9.4 %) groups; patient characteristics for each group were statistically analyzed. The patients in the higher TIMI score group were older (p < 0.001), had lower GFR (p = 0.021) and hemoglobin level after PCI (p < 0.001), and severe coronary disease pattern (p = 0.014 and p = 0.023, respectively, for left main and three-vessel disease). The TIMI score was significantly associated with requirement of blood transfusion (low-risk, moderate-risk, and high-risk groups: 1.1, 4.2, and 7.3 %, respectively; p = 0.021), and the incidence of access site bleeding (1.1, 2.7, and 5.5 %, p = 0.112). The TIMI score might aid in subjectively quantifying the risk of in-hospital complication rates such as access site bleeding. PMID- 23361951 TI - Clinical outcome after endovascular treatment for isolated common femoral and popliteal artery disease. AB - The safety and patency of endovascular treatment (EVT) in isolated common femoral artery (CFA) and popliteal artery (PA) remain poorly understood. We investigated the efficacy after EVT for isolated CFA and PA disease. This study was performed as a multicenter retrospective registry of a prospectively maintained database. Between January 2001 and December 2010, consecutive 183 patients (214 lesions; CFA 111, PA 103) who received endovascular procedure for de novo isolated CFA and PA disease were enrolled. The main endpoints of this study were primary and secondary patency after EVT. Procedure success was 95.8 %. The 1- and 5-year primary patencies for CFA (PA) lesions after EVT were 73.5 % (75.5 %) and 46.9 % (56.2 %), respectively. There was no significant difference of primary patency rate between CFA and PA (46.9 vs. 56.2 % at 5-year, p = 0.83). However, secondary patency significantly differed between CFA and PA (97.6 vs. 86.2 % at 5-year, p = 0.009). Stent placement was not effective for the reduction of restenosis in both CFA and PA lesion. On multivariate analysis to define the predictors of primary patency for the CFA, renal failure, coronary artery disease, calcified lesion and residual stenosis after EVT were independent predictors. Also, the predictors of primary patency for the PA were BMI, reference vessel diameter, anemia and residual stenosis after EVT. Short-term patency after EVT for isolated CFA and PA lesion seems to be feasible. However, long-term patency was not promising. Furthermore, stent placement does not improve the primary patency. PMID- 23361952 TI - Age trends of bone mineral density and percentile curves in healthy Chinese children and adolescents. AB - The clinical utility of dual-energy X-ray absorptiometry (DXA) measurement requires appropriate normative values, designed to be diverse with respect to age, gender and ethnic background. The purpose of this study was to generate age related trends for bone density in Chinese children and adolescents, and to establish a gender-specific reference database. A total of 1,541 Chinese children and adolescents aged from 5 to 19-years were recruited from southern China. Bone mineral density (BMD), bone mineral content (BMC), and bone area (BA) were measured for the total body (TB) and total body less head (TBLH). The height-for age, height-for-BA, and BMC-for-BA percentile curves were developed using the least mean square method. TB BMD and TBLH BMD were highly correlated. After 18 years, TB BMD was significantly higher in boys than girls. For TB BMC and TBLH BMC, gender differences were found in age groups 12 years and 16-19 years; however, the TBLH BMD was significantly different between genders >16 years. The head region accounted for 13-52 and 16-49 % of the TB BMC in boys and girls, respectively. Furthermore, the percentages were negatively correlated with age and height. This study describes a gender-specific reference database for Chinese children and adolescents aged 5-19 years. These normative values could be used for clinical assessment in this population. PMID- 23361953 TI - Novel cell-based assay reveals associations of circulating serum AhR-ligands with metabolic syndrome and mitochondrial dysfunction. AB - Serum concentrations of environmental pollutants have been positively correlated with diabetes and metabolic syndrome in epidemiologic studies. In turn, abnormal mitochondrial function has been associated with the diseases. The relationships between these variables, however, have not been studied. We developed novel cell based aryl hydrocarbon receptor (AhR) agonist bioassay system without solvent extraction process and analyzed whether low-dose circulating AhR ligands in human serum are associated with parameters of metabolic syndrome and mitochondrial function. Serum AhR ligand activities were measured as serum 2,3,7,8 tetrachlorodibenzo-p-dioxin equivalent (sTCDDeq) in pM using 10 MUL human sera from 97 Korean participants (47 with glucose intolerance and 50 matched controls, average age of 46.6 +/- 9.9 years, 53 male and 45 female). sTCDDeq were higher in participants with glucose intolerance than normal controls and were positively associated (P < 0.01) with obesity, blood pressure, serum triglyceride, and fasting glucose, but not with HDL-cholesterol. Body mass index was in a positive linear relationship with serum AhR ligands in healthy participants. When myoblast cells were incubated with human sera, ATP generating power of mitochondria became impaired in an AhR ligand concentration-dependent manner. Our results support that circulating AhR ligands may directly reduce mitochondrial function in tissues, leading to weight gain, glucose intolerance, and metabolic syndrome. Our rapid cell-based assay using minute volume of human serum may provide one of the best monitoring systems for circulating AhR ligands, good clinical biomarkers for the progress of disease and therapeutic efficacy. PMID- 23361955 TI - Spontaneous cutaneous endometriosis: a diagnostic challenge in plastic surgery. PMID- 23361954 TI - Cosmetic shell fitting over a sensitive cornea in mild phthisis bulbi using total conjunctival flap. AB - BACKGROUND: Cosmetic scleral shells provide a superior alternative to enucleation or evisceration in the setting of phthisis bulbi. However, corneal irritation often minimizes the wearing time of a scleral shell. This study aimed to evaluate the clinical effectiveness of a total conjunctival flap covering in the management of mild phthisis bulbi with a sensitive cornea. METHODS: The surgical technique involved a total conjunctival flap covering combined with superficial lamellar keratectomy to allow the fitting of a cosmetic scleral shell over a sensitive cornea. The records of patients with mild phthisis bulbi who underwent this technique from September 2003 through July 2011 were reviewed. Postoperative and long-term complications were noted. Outcome measures included cosmetic appearance, complications, and patient satisfaction. RESULTS: A total of 58 patients (58 eyes) were identified. The mean age at surgery was 28.5 years (range=2-65 years) and the mean follow-up period (follow-up rate=66%) was 42.6 months (range=6-98 months). Postoperative complications like epithelial inclusion cyst (one eye), intolerance of scleral shell wear (2 eyes), and deterioration of phthisis bulbi (3 eyes) were observed during the follow-up interval. Surgical success was achieved in 52 subjects (90%) with the desired prosthetic appearance and motility and no further intervention was required. CONCLUSION: The total conjunctival flap is an easy and effective globe-conserving alternative to enucleation or evisceration in the cosmetic rehabilitation of patients with mild phthisis bulbi. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23361956 TI - The ocular stick as wound dressing in lower-eyelid reconstruction. PMID- 23361957 TI - Eyelid thickening and ptosis associated with pachydermoperiostosis: a case report and review of literature. AB - The case of a 27-year-old Chinese patient with bilateral eyelid thickening and ptosis secondary to the rare condition of pachydermoperiostosis is presented. Surgical treatment was performed by horizontal tightening via a full-thickness wedge resection combined with levator shortening and advancement. Satisfactory aesthetic and functional results were achieved. The histopathology of eyelid tissue showed sebaceous gland hyperplasia and chronic inflammatory response. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23361958 TI - Correction of true hanging columella using medial crural tuck-up technique. AB - BACKGROUND: The nasal tip and columella are the two main key components that affect the results of a successful and aesthetically satisfactory rhinoplasty. A true hanging columella is a deformity in which the caudal border of the columella has a downward bowing appearance due to disproportion between the ala nasi and the columella, which is usually congenital. In the management of this challenging deformity, a thorough understanding and consideration of tip dynamics and the anatomical causes address the proper technique to be used. In this study we present our clinical experience with the medial crural tuck-up technique used on 53 consecutive patients with a true hanging columella. METHODS: A total of 1,421 patients underwent rhinoplasty between January 2005 and September 2011; 53 of those patients (age range=20-37 years; mean=27.3 years), who underwent this technique, were involved in the study. Thirty-eight patients were followed up for more than 1 year. RESULTS: The results were evaluated by comparing postoperative photos with preoperative photographic documentation. The appearance of the nasal tip and columella remained fine and stable over the 1 year of follow-up. CONCLUSION: Despite its limitation of applicability in secondary cases, the advantages of this technique are that it does not require conchal or costal cartilage and the desired tip rotation and projection can be done with ease. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23361959 TI - Anatomical evidence of microbial biofilms in an alloplastic nasal implant. AB - Recently, bacterial biofilms have been proposed as a potential cause of the extreme resistance to antibiotics and impaired host responses in potentially infected facial implants. As opposed to the bacteria in a free-floating or planktonic state, biofilms exist in a sessile form, adherent to a solid or liquid interface and become embedded in a complex matrix that is oftentimes impenetrable to modern day antibiotics. This can lead to chronic infection of implants which ultimately necessitates their removal in a majority of cases. In this novel case report, we show the histomorphological appearance of biofilm formation in a patient with an alloplastic nasal implant that was persistently infected and had to be removed. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23361960 TI - Patchy areolar hyperpigmentation 6 years after augmentation mastopexy: a case report. AB - A 42-year-old primigravida woman of 20 weeks gestation was referred to the authors for the treatment of a suspected malignant melanoma of her left areola. She had undergone bilateral augmentation mammoplasty with periareolar mastopexy elsewhere 6 years previously. Her history included partial necrosis of her left areola in the immediate postoperative period that required a long time to heal and had resulted in partial areolar depigmentation. Her left areola had a few patches of hyperpigmentation at her presentation to the authors. Specimens removed from eight involved areas showed a tissue diagnosis of benign areolar melanosis. The hyperpigmentation completely disappeared after delivery. This case is reported because of its rarity as well as its nonmalignant and self-resolving nature. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23361961 TI - Hyposmolality differentially and spatiotemporally modulates levels of glutamine synthetase and serine racemase in rat supraoptic nucleus. AB - Prolonged hyposmotic challenge (HOC) has a dual effect on vasopressin (VP) secretion [Yagil and Sladek (1990) Am J Physiol 258(2 Pt 2):R492-R500]. We describe an electrophysiological correlate of this phenomenon, whereby in vitro HOC transiently reduced the firing activity of VP neurons within the supraoptic nucleus of brain slices, which was followed by a rebound increase of their activity; this was paralleled by changes in the level of proteins relevant to astroglia-neuronal interactions. Hence, in vitro HOC transiently (at 5 min) increased the level of astrocyte-specific glial fibrillary acidic protein (GFAP), which then declined to control or base level (at 20 min); this was blocked by the gliotoxin L-aminoadipic acid, but not by tetanus toxin, which was used to inhibit neurotransmission. Similarly, in vivo HOC led to changes in GFAP level, which after an early increase (10 min) returned to normal (30 min). Immunoassays revealed that neuronal, but not astrocytic, expression of serine racemase (SR) was increased at the late stage of HOC in vivo, whereas at an early stage there was a transient increase in level of the astrocyte-specific glutamine synthetase (GS). Furthermore, there was an increased molecular association between GFAP and GS at 10 min, whereas SR increased its association with the neuronal nuclear antigen NeuN at 30 min. These results suggest that the dual effect of HOC on VP neuronal secretion/activity could be related to metabolic/signaling changes in astrocytes (glutamate-glutamine conversion) and neurons (D-serine synthesis/ammonia production), which may account for the rebound in VP neuronal activity, presumably by promoting the activation of neuronal glutamate receptors. PMID- 23361962 TI - Educational paper: decreasing the burden of cardiovascular disease in childhood cancer survivors: an update for the pediatrician. AB - The cardiovascular impact of cancer therapies on the heart is one of the major concerns in the long-term follow-up of childhood cancer survivors (CCSs). Long term cardiovascular effects include the development of left ventricular dysfunction resulting in congestive heart failure and ischemic heart disease, as well as valvular and pericardial disease. This is mainly ascribed to the cardiotoxic side effects of chemotherapeutic agents (especially anthracyclines) and radiotherapy, but other factors such as radiation and inflammation play a role in the effect of childhood cancer on the cardiovascular health. The most concerning effect is the high incidence of symptomatic heart failure in CCS patients treated with anthracyclines. More than 50 % of CCSs treated with anthracyclines develop asymptomatic left ventricular dysfunction after cancer therapy, with approximately 5 % developing clinical signs of heart failure during long-term follow-up. Once CCS patients develop congestive heart failure, prognosis is poor and is not influenced by current medical treatment strategies. To reduce the long-term burden of cardiovascular disease in pediatric cancer patients, a diversified approach will be necessary. In the acute phase, prevention of cardiac damage through the use of cardioprotective agents (e.g., dexrazoxane) or by administering less cardiotoxic chemotherapeutic agents is to be considered. A recent randomized trial suggested that the use of dexrazoxane reduced cardiac toxicity without affecting cancer outcomes. Especially patients requiring high doses of chemotherapeutic agents could benefit from this approach. Recent data suggest that genetic testing might identify patients at higher risk for cardiotoxicity. This seems mainly related to genes involved in drug metabolism. This would allow personalized approach adjusting chemotherapy based on cardiovascular risk profiling. This could be combined with newer monitoring strategies in the acute phase using newer echocardiographic techniques and biomarker screening to identify patients with early damage to the myocardium. For the long-term CCS cohort, early detection and treatment of early dysfunction prior to the development of congestive heart failure could potentially improve long-term outcomes. Promoting healthy lifestyles and controlling additional cardiovascular risk factors (e.g., obesity, diabetes, arterial hypertension) is an important task for every physician involved in the care of this growing cohort. PMID- 23361963 TI - Body weight and the medial longitudinal foot arch: high-arched foot, a hidden problem? AB - This study had two objectives. First, to determine the prevalence of hollow (high arched) and flat foot among primary school children in Cracow (Poland). Second, to evaluate the relationship between the type of medial longitudinal arch (MLA; determined by the Clarke's angle) and degree of fatness. The prevalence of underweight, overweight, and obesity was determined by means of IOTF cut-offs with respect to age and gender. A sample of 1,115 children (564 boys and 551 girls) aged between 3 and 13 years was analyzed. In all age groups, regardless of gender, high-arched foot was diagnosed in the majority of children. A distinct increase in the number of children with high-arched foot was observed between 7- and 8-year olds. Regardless of the gender, high-arched foot was more common among underweight children. In the group of obese children, the biggest differences were attributed to gender. High-arched foot was the most frequently observed among boys. In all gender and obesity level groups, the flat foot was more common among boys than among girls. CONCLUSIONS: High-arched foot is the most common foot defect among children 3-13 years old regardless of gender. Flat foot is least frequently observed in children 3-13 years old. A statistic correlation between MLA and adiposity is observed. Stronger correlation is observed among girls. PMID- 23361965 TI - A structured monodisperse PEG for the effective suppression of protein aggregation. AB - Part of the solution: A PEG with a discrete triangular structure exhibits hydrophilicity/hydrophobicity switching upon increasing temperatures, and suppresses the thermal aggregation of lysozyme to retain nearly 80 % of the enzymatic activity. CD and NMR spectroscopic studies revealed that, with the structured PEG, the higher-order structures of lysozyme persist at high temperature, and the native conformation is recovered after cooling. PMID- 23361964 TI - Major reduction of rotavirus, but not norovirus, gastroenteritis in children seen in hospital after the introduction of RotaTeq vaccine into the National Immunization Programme in Finland. AB - Universal rotavirus (RV) vaccination is expected to reduce hospitalizations for acute gastroenteritis (GE) of children by eliminating most of severe RVGE, but it does not have any effect on norovirus (NV), the second most common causative agent of GE in children. After the introduction of the RV vaccine into the National Immunization Programme (NIP) of Finland in 2009, we conducted a prospective 2-year survey of GE in children seen in Tampere University Hospital either as outpatients or inpatients and compared the results with a similar 2 year survey conducted prior to NIP in the years 2006-2008. Compared with the pre NIP 2-year period, in 2009-2011, hospitalizations for RVGE were reduced by 76 % and outpatient clinic visits were reduced by 81 %. NVGE showed a slight decreasing trend and accounted for 34 % of all cases of GE seen in hospital in pursuance of RVGE having decreased to 26 % (down from 52 %). In cases admitted to the hospital ward, RV accounted for 28 % and NV accounted for 37 %.The impact of RV vaccination was reflected as a 57 % decrease in all hospital admissions and 62 % decrease in all outpatient clinic visits for GE of any cause. CONCLUSION: RV vaccination in NIP has led to a major reduction of hospital admissions and clinic visits due to RVGE, but has had no effect on NVGE. After 2 years of NIP, NV has become the leading cause of acute GE in children seen in hospital. PMID- 23361966 TI - In vitro degradation of four magnesium-zinc-strontium alloys and their cytocompatibility with human embryonic stem cells. AB - Magnesium alloys have attracted great interest for medical applications due to their unique biodegradable capability and desirable mechanical properties. When designed for medical applications, these alloys must have suitable degradation properties, i.e., their degradation rate should not exceed the rate at which the degradation products can be excreted from the body. Cellular responses and tissue integration around the Mg-based implants are critical for clinical success. Four magnesium-zinc-strontium (ZSr41) alloys were developed in this study. The degradation properties of the ZSr41 alloys and their cytocompatibility were studied using an in vitro human embryonic stem cell (hESC) model due to the greater sensitivity of hESCs to known toxicants which allows to potentially detect toxicological effects of new biomaterials at an early stage. Four distinct ZSr41 alloys with 4 wt% zinc and a series of strontium compositions (0.15, 0.5, 1, and 1.5 wt% Sr) were produced through metallurgical processing. Their degradation was characterized by measuring total mass loss of samples and pH change in the cell culture media. The concentration of Mg ions released from ZSr41 alloy into the cell culture media was analyzed using inductively coupled plasma atomic emission spectroscopy. Surface microstructure and composition before and after culturing with hESCs were characterized using field emission scanning electron microscopy and energy dispersive X-ray spectroscopy. Pure Mg was used as a control during cell culture studies. Results indicated that the Mg Zn-Sr alloy with 0.15 wt% Sr provided slower degradation and improved cytocompatibility as compared with pure Mg control. PMID- 23361967 TI - Thermosensitive behavior in cell culture media and cytocompatibility of a novel copolymer: poly(N-isopropylacrylamide-co-butylacrylate). AB - Cell sheet technology is a promising step forward in tissue engineering. Cell sheets are usually generated using Poly(N-isopropylacrylamide) hydrogels due to their swelling change around the lower critical solution temperature (LCST). Nevertheless, LCST can be affected by cell culture medium components and therefore it is necessary to ensure that the polymer preserves its thermosensitivity under these conditions. We propose a novel thermosensitive crosslinked-copolymer: Poly(N-isopropylacrylamide-co-butylacrylate). This copolymer is shown to be cytocompatible and thermosensitive under cell culture medium conditions, and besides, it can be synthesized inexpensively. Thermosensitivity was investigated by determining the LCST with differential scanning calorimetry and swelling/ratio measurements. Cytocompatibility and capacity to deliver cell sheets were studied employing 3T3 and human oral epithelial cells. In conclusion, we obtained a thermosensitive copolymer that allows cell sheet formation/detachment by using a simple and low-cost polymerization method. Furthermore, crosslinking allows easy manipulation of cell sheets growing on the copolymer for potential in situ applications. PMID- 23361968 TI - Increased survival associated with surgery and radiation therapy in metastatic gastric cancer: a Surveillance, Epidemiology, and End Results database analysis. AB - BACKGROUND: Patients with metastatic gastric cancer have poor survival. The purpose of this study was to compare outcomes of metastatic gastric cancer patients stratified by surgery and radiation therapy. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was accessed to identify patients with AJCC M1 stage IV gastric cancer (based on the American Joint Committee on Cancer Cancer Staging Manual, 6th edition) between 2004 thru 2008. Patients were divided into 4 groups: group 1, no surgery or radiation; group 2, radiation alone; group 3, surgery alone; group 4, surgery and radiation. Survival analysis was determined by Kaplan-Meier and log-rank analysis. Multivariate analysis (MVA) was analyzed by the Cox proportional hazard ratio model. RESULTS: A total of 5072 patients were identified. Surgery and/or radiation were associated with a survival benefit. Median and 2-year survival for groups 1, 2, 3, and 4 was 7 months and 8.2%, 8 months and 8.9%, 10 months and 18.2%, and 16 months and 31.7%, respectively (P < .00001). MVA for all patients revealed that surgery and radiation were associated with decreased mortality whereas T-stage, N-stage, age, signet ring histology, and peritoneal metastases were associated with increased mortality. In patients treated with surgery, MVA showed that radiation was associated with decreased mortality, whereas T-stage, N-stage, age, removal of < 15 lymph nodes, signet ring histology, and peritoneal metastases was associated with increased mortality. Age was the only prognostic factor in patients who did not undergo surgery. CONCLUSIONS: Surgery and radiation are associated with increased survival in a subset of patients with metastatic gastric cancer. Prospective trials will be needed to address the role and sequence of surgery and radiation in metastatic gastric cancer. PMID- 23361969 TI - Improved cell disruption of Pichia pastoris utilizing aminopropyl magnesium phyllosilicate (AMP) clay. AB - An efficient method for Pichia cell disruption that employs an aminopropyl magnesium phyllosilicate (AMP) clay-assisted glass beads mill is presented. AMP clay is functionalized nanocomposite resembling the talc parent structure Si8Mg6O20(OH)4 that has been proven to permeate the bacterial membrane and cause cell lysis. The recombinant capsid protein of cowpea chlorotic mottle virus (CCMV) expressed in Pichia pastoris GS115 was used as demonstration system for their ability of self-assembly into icosahedral virus-like particles (VLPs). The total protein concentration reached 4.24 mg/ml after 4 min treatment by glass beads mill combined with 0.2 % AMP clay, which was 11.2 % higher compared to glass beads mill only and the time was half shortened. The stability of purified CCMV VLPs illustrated AMP clay had no influence on virus assembly process. Considering the tiny amount added and simple approach of AMP clay, it could be a reliable method for yeast cell disruption. PMID- 23361970 TI - Management of soybean oil refinery wastes through recycling them for producing biosurfactant using Pseudomonas aeruginosa MR01. AB - Biosurfactant production through a fermentation process involving the biodegradation of soybean oil refining wastes was studied. Pseudomonas aeruginosa MR01 was able to produce extracellular biosurfactant when it was cultured in three soybean oil refinement wastes; acid oil, deodorizer distillate and soapstock, at different carbon to nitrogen ratios. Subsequent fermentation kinetics in the three types of waste culture were also investigated and compared with kinetic behavior in soybean oil medium. Biodegradation of wastes, biosurfactant production, biomass growth, nitrate consumption and the number of colony forming units were detected in four proposed media, at specified time intervals. Unexpectedly, wastes could stimulate the biodegradation activity of MR01 bacterial cells and thus biosurfactant synthesis beyond that of the refined soybean oil. This is evident from higher yields of biodegradation and production, as revealed in the waste cultures (Ydeg|(Soybean oil) = 53.9 % < Ydeg|(wastes) and YP/S|(wastes) > YP/S|(Soybean oil) = 0.31 g g(-1), respectively). Although production yields were approximately the same in the three waste cultures (YP/S|(wastes) =/~ 0.5 g g(-1)), microbial activity resulted in higher yields of biodegradation (96.5 +/- 1.13 %), maximum specific growth rate (MU max = 0.26 +/- 0.02 h(-1)), and biosurfactant purity (89.6 %) with a productivity of 14.55 +/- 1.10 g l(-1), during the bioconversion of soapstock into biosurfactant. Consequently, applying soybean oil soapstock as a substrate for the production of biosurfactant with commercial value has the potential to provide a combination of economical production with environmental protection through the biosynthesis of an environmentally friendly (green) compound and reduction of waste load entering the environment. Moreover, this work inferred spectrophotometry as an easy method to detect rhamnolipids in the biosurfactant products. PMID- 23361971 TI - Lactobacillus rhamnosus GG antagonizes Giardia intestinalis induced oxidative stress and intestinal disaccharidases: an experimental study. AB - The present study describes the in vivo modulatory potential of Lactobacillus rhamnosus GG (LGG), an effective probiotic, in Giardia intestinalis-infected BALB/c mice. Experimentally, it was observed that oral administration of lactobacilli prior or simultaneous with Giardia trophozoites to mice, efficiently (p < 0.05) reduced both the severity and duration of giardiasis. More specifically, probiotics fed, Giardia-infected mice, showed a significant increase in the levels of antioxidants [reduced glutathione (GSH) and superoxide dismutase (SOD)] and intestinal disaccharidases [sucrase and lactase] and decreased levels of oxidants in the small intestine, in comparison with Giardia infected mice. Histopathological findings also revealed almost normal cellular morphology of the small intestine in probiotic-fed Giardia-infected mice compared with fused enterocytes, villous atrophy and increased infiltration of lymphocytes in Giardia-infected mice. The results of the present study has shed new light on the anti-oxidative properties of LGG in Giardia mediated tissue injury, thereby suggesting that the effects of probiotic LGG are biologically plausible and could be used as an alternative microbial interference therapy. PMID- 23361973 TI - Interaction mechanism of CO2 ambient adsorption on transition-metal-coated boron sheets. PMID- 23361972 TI - Isolation, characterization and evaluation of hyper 2-propanol producing bacteria from Singapore environment. AB - Three hyper 2-propanol producing strains were isolated from Singapore environment using an enrichment step and a high through-put screening step. The analysis of the amplified 16S rDNA revealed that the isolates belonged to Clostridium species and they were named as Clostridium sp. BT10-1, Clostridium sp. M10-1 and Clostridium sp. PU31-4. At 1 L scale, the 2-propanol titer of these positive strains was 1.6-2.1 times of that of Clostridium beijerinckii NRRL B593, which is so far the most efficient natural 2-propanol producer. The highest 2-propanol titer was achieved by isolate BT10-6 and it was 5.26 g/L (87.5 mM). These three positive strains BT10-6, M10-1 and PU31-4 consumed glucose almost completely in 40-48 h and gave 2-propanol productivity at 0.132, 0.118 and 0.087 g/L/h, respectively, which is 3.0-4.6 times of 0.029 g/L/h given by C. beijerinckii NRRL B593. Butanol was also produced by these positive strains with a slightly lower butanol titer and higher butanol productivity, compared to butanol control strain C. beijerinckii NCIMB 8052. PMID- 23361974 TI - Flocculation optimization of microalga Nannochloropsis oculata. AB - The objective of this work was to understand and optimize the flocculation of a marine alga Nannochloropsis oculata with two cationic salts, aluminum sulfate (AS), and ferric chloride (FC). Based on single-factor and response-surface methodology experiments, second-order polynomial models were developed to examine the effect of initial algal biomass concentration (IABC), pH, and flocculant dose (FD) on final solid concentration of algae (SCA). The experimental and modeling results showed that SCA favored low pH, which however was undesirable to biomass recovery rate. There existed a positive stoichiometric relationship between FD and IABC; higher IABC required higher FD, and vice versa, for higher SCA. Optimum flocculation conditions were predicted at IABC of 1.7 g/l, pH8.3, and FD of 383.5 MUM for AS, and IABC of 2.2 g/l, pH7.9, and FD of 438.1 MUM for FC, under which the predicted maximum SCA were 32.98 and 30.10 g/l using AS and FC, respectively. The predictions were close to validation experimental results, indicating that the models can be used to guide and optimize the flocculation of N. oculata using AS and FC as the flocculants. PMID- 23361975 TI - Drospirenone-containing oral contraceptives and risk of adverse outcomes after myocardial infarction. AB - BACKGROUND: The association between oral contraceptives (OC) and myocardial infarction remains controversial. The new generation contraceptive Yasmin (30 ug ethinyl estradiol and 3 mg drospirenone) has a lower estrogen and newer progestin component. To date, there are no data available for the myocardial infarction risk and outcome for drospirenone. We aimed to investigate the effect of Yasmin use on cardiovascular outcomes in patients with acute ST segment elevation myocardial infarction (STEMI) undergoing primary angioplasty. METHODS: We retrospectively evaluated 1851 patients who underwent primary angioplasty for acute STEMI. Of them, 440 female patients (23.8%) composed the study population and 12 female (2.7%) were taking the oral contraceptive-Yasmin at the time of infarction. Patients were divided into two groups based on their age (>=50 (n = 339) and <50 years old). Patients under 50 years-old (n = 101) were separated into two groups according to use of OC therapy (OC (+) group n = 12; OC (-) group n = 89). RESULTS: Patients who were older than 50-year-old were more likely to have comorbid conditions like diabetes mellitus and hypertension than other groups. Current smoking status was significantly higher in OC (+) group than OC ( ) group (P = 0.007). There was a significant difference in favour of OC (+) group when compared with OC (-) group for the increased angiographic thrombus burden according to both TIMI and Yip classification (P = 0.045 and P = 0.029, respectively). The incidence of final TIMI 3 flow and post-procedural complete ST resolution were significantly lower in OC (+) group (P = 0.019, P = 0.002, respectively). In multivariate logistic regression analysis, use of OC was found to be an independent predictor of high grade thrombus burden (OR 5.13, 95% CI 1.07-24.60, P = 0.04). CONCLUSION: This is the first study to evaluate the myocardial infarction risk and its subsequent clinical sequelae in women having a STEMI while taking the OC-Yasmin. Women on the oral contraception Yasmin, who underwent coronary revascularization had a lower post-procedural complete ST resolution and worse left ventricular function. Furthermore, OC use with Yasmin is an independent predictor of a high-grade thrombus burden. PMID- 23361976 TI - A novel neurofibromin (NF1) interaction with the leucine-rich pentatricopeptide repeat motif-containing protein links neurofibromatosis type 1 and the French Canadian variant of Leigh's syndrome in a common molecular complex. AB - Loss-of-function mutations and deletions in the neurofibromin tumor suppressor gene (NF1) cause neurofibromatosis type 1 (NF-1), the most common inherited syndrome of the nervous system in humans, with a birth incidence of 1:3,000. The most visible features of NF-1 are the neoplastic manifestations caused by the loss of Ras-GTPase-activating protein (Ras-GAP) activity mediated through the GAP related domain (GRD) of neurofibromin (NF1), the protein encoded by NF1. However, the syndrome is also characterized by cognitive dysfunction and a number of developmental abnormalities. The molecular etiology of many of these nonneoplastic phenotypes remains unknown. Here we show that the tubulin-binding domain (TBD) of NF1 is a binding partner of the leucine-rich pentatricopeptide repeat motif-containing (LRPPRC) protein. These two proteins complex with Kinesin 5B, hnRNP A2, Staufen1, and Myelin Basic Protein (MBP) mRNA, likely in RNA granules. This interaction is of interest in that it links NF-1 with Leigh's syndrome, French Canadian variant (LSFC), an autosomal recessive neurodegenerative disorder that arises from mutations in the LRPPRC gene. Our findings provide clues to how loss or mutation of NF1 and LRPPRC may contribute to the manifestations of NF-1 and LSFC. PMID- 23361978 TI - Predictive models for cellular signaling networks. AB - This chapter provides an introduction to the formulation and analysis of differential-equation-based models for biological regulatory networks. In the first part, we discuss basic reaction types and the use of mass action kinetics and of simplifying approximations in the development of models for biological signaling. In the second part we introduce phase plane and linear stability analysis to evaluate the time evolution and identify the long-term attractors of dynamic systems. We then discuss the use of bifurcation diagrams to evaluate the parameter dependency of qualitative network behaviors (i.e., the emergence of oscillations or switches), and we give measures for the sensitivity and robustness of the signaling output. PMID- 23361977 TI - Carboxylic acid (bio)isosteres in drug design. AB - The carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant drawbacks, including metabolic instability, toxicity, as well as limited passive diffusion across biological membranes. To avoid some of these shortcomings while retaining the desired attributes of the carboxylic acid moiety, medicinal chemists often investigate the use of carboxylic acid (bio)isosteres. The same type of strategy can also be effective for a variety other purposes, for example, to increase the selectivity of a biologically active compound or to create new intellectual property. Several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this strategy is generally found to be dependent upon the particular context (i.e., the characteristic properties of the drug and the drug-target). As a result, screening of a panel of isosteres is typically required. In this context, the discovery and development of novel carboxylic acid surrogates that could complement the existing palette of isosteres remains an important area of research. The goal of this Minireview is to provide an overview of the most commonly employed carboxylic acid (bio)isosteres and to present representative examples demonstrating the use and utility of each isostere in drug design. PMID- 23361979 TI - Analyzing and constraining signaling networks: parameter estimation for the user. AB - The behavior of most dynamical models not only depends on the wiring but also on the kind and strength of interactions which are reflected in the parameter values of the model. The predictive value of mathematical models therefore critically hinges on the quality of the parameter estimates. Constraining a dynamical model by an appropriate parameterization follows a 3-step process. In an initial step, it is important to evaluate the sensitivity of the parameters of the model with respect to the model output of interest. This analysis points at the identifiability of model parameters and can guide the design of experiments. In the second step, the actual fitting needs to be carried out. This step requires special care as, on the one hand, noisy as well as partial observations can corrupt the identification of system parameters. On the other hand, the solution of the dynamical system usually depends in a highly nonlinear fashion on its parameters and, as a consequence, parameter estimation procedures get easily trapped in local optima. Therefore any useful parameter estimation procedure has to be robust and efficient with respect to both challenges. In the final step, it is important to access the validity of the optimized model. A number of reviews have been published on the subject. A good, nontechnical overview is provided by Jaqaman and Danuser (Nat Rev Mol Cell Biol 7(11):813-819, 2006) and a classical introduction, focussing on the algorithmic side, is given in Press (Numerical recipes: The art of scientific computing, Cambridge University Press, 3rd edn., 2007, Chapters 10 and 15). We will focus on the practical issues related to parameter estimation and use a model of the TGFbeta-signaling pathway as an educative example. Corresponding parameter estimation software and models based on MATLAB code can be downloaded from the authors's web page ( http://www.bsse.ethz.ch/cobi ). PMID- 23361980 TI - A tutorial on mathematical modeling of biological signaling pathways. AB - Mathematical models have been widely used in the studies of biological signaling pathways. Among these studies, two systems biology approaches have been applied: top-down and bottom-up systems biology. The former approach focuses on X-omics researches involving the measurement of experimental data in a large scale, for example proteomics, metabolomics, or fluxomics and transcriptomics. In contrast, the bottom-up approach studies the interaction of the network components and employs mathematical models to gain some insights about the mechanisms and dynamics of biological systems. This chapter introduces how to use the bottom-up approach to establish mathematical models for cell signaling studies. PMID- 23361981 TI - Bistability in one equation or fewer. AB - When several genes or proteins modulate one another's activity as part of a network, they sometimes produce behaviors that no protein could accomplish on its own. Intuition for these emergent behaviors often cannot be obtained simply by tracing causality through the network in discreet steps. Specifically, when a network contains a feedback loop, biologists need specialized tools to understand the network's behaviors and their necessary conditions. This analysis is grounded in the mathematics of ordinary differential equations. We, however, will demonstrate the use of purely graphical methods to determine, for experimental data, the plausibility of two network behaviors, bistability and irreversibility. We use the Xenopus laevis oocyte maturation network as our example, and we make special use of iterative stability analysis, a graphical tool for determining stability in two dimensions. PMID- 23361982 TI - Mathematical investigation of how oncogenic ras mutants promote ras signaling. AB - We have used a mathematical model of the Ras signaling network to link observable biochemical properties with cellular levels of RasGTP. Although there is abundant data characterizing Ras biochemistry, attributing specific changes in biochemical properties to observed phenotypes has been hindered by the scope and complexity of Ras regulation. A mathematical model of the Ras signaling module, therefore, appeared to be of value for this problem. The model described the core architecture shared by pathways that signal through Ras. Mass-action kinetics and ordinary differential equations were used to describe network reactions. Needed parameters were largely available in the published literature and resulted in a model with good agreement to experimental data. Computational analysis of the model resulted in several unanticipated predictions and suggested experiments that subsequently validated some of these predictions. PMID- 23361983 TI - Modeling miRNA regulation in cancer signaling systems: miR-34a regulation of the p53/Sirt1 signaling module. AB - MicroRNAs (miRNAs) are a family of small regulatory RNAs whose function is to regulate the activity and stability of specific messenger RNA targets through posttranscriptional regulatory mechanisms. Most of the times signaling systems involving miRNA modulation are not linear pathways in which a certain transcription factor activate the expression of miRNAs that posttranscriptionally represses targeting proteins, but complex regulatory structures involving a variety of feedback-loop architectures.In this book chapter, we define, discuss, and apply a Systems Biology approach to investigate dynamical features of miRNA regulation, based on the integration of experimental evidences, hypotheses, and quantitative data through mathematical modeling. We further illustrate the approach using as case study the signaling module composed by the proteins p53, Sirt1, and the regulatory miRNA miR-34a. The model was used not only to investigate different possible designs of the silencing mechanism exerted by miR 34a on Sirt1 but also to simulate the dynamics of the system under conditions of (pathological) deregulation of its compounds. PMID- 23361984 TI - Design of experiments to investigate dynamic cell signaling models. AB - This chapter describes approaches to make use of dynamic models of cell signaling systems in order to optimize experiments in cell biology. We are particularly focusing on the question of how small molecule inhibitors or activators can best be used to get the most information out of a limited number of experiments when only a handful of molecular species can be measured. One goal addressed by this chapter is to find time course experiments to discriminate between rivaling molecular mechanisms. The other goal is to find experiments that are useful for inferring rate constants, binding affinities, concentrations, and other model parameters from time course data. Both are treated as optimal control problems in which rapid pharmacological perturbation schemes are identified in silico in order to close an experimental cycle from modeling back to the laboratory bench. PMID- 23361985 TI - Mathematical modeling of biochemical systems with PottersWheel. AB - The program PottersWheel has been developed to provide an intuitive and yet powerful framework for data-based modeling of dynamical systems like biochemical reaction networks. Its key functionality is multi-experiment fitting, where several experimental data sets from different laboratory conditions are fitted simultaneously in order to improve the estimation of unknown model parameters, to check the validity of a given model, and to discriminate competing model hypotheses. New experiments can be designed interactively. Models are either created text-based or using a visual model designer. Dynamically generated and compiled C files provide fast simulation and fitting procedures. Each function can either be accessed using a graphical user interface or via command line, allowing for batch processing within custom Matlab scripts. PottersWheel is designed as a Matlab toolbox, comprises 250,000 lines of Matlab and C code, and is freely available for academic usage at www.potterswheel.de . PMID- 23361986 TI - Rule-based modeling of signal transduction: a primer. AB - Biological cells accomplish their physiological functions using interconnected networks of genes, proteins, and other biomolecules. Most interactions in biological signaling networks, such as bimolecular association or covalent modification, can be modeled in a physically realistic manner using elementary reaction kinetics. However, the size and combinatorial complexity of such reaction networks have hindered such a mechanistic approach, leading many to conclude that it is premature and to adopt alternative statistical or phenomenological approaches. The recent development of rule-based modeling languages, such as BioNetGen (BNG) and Kappa, enables the precise and succinct encoding of large reaction networks. Coupled with complementary advances in simulation methods, these languages circumvent the combinatorial barrier and allow mechanistic modeling on a much larger scale than previously possible. These languages are also intuitive to the biologist and accessible to the novice modeler. In this chapter, we provide a self-contained tutorial on modeling signal transduction networks using the BNG Language and related software tools. We review the basic syntax of the language and show how biochemical knowledge can be articulated using reaction rules, which can be used to capture a broad range of biochemical and biophysical phenomena in a concise and modular way. A model of ligand-activated receptor dimerization is examined, with a detailed treatment of each step of the modeling process. Sections discussing modeling theory, implicit and explicit model assumptions, and model parameterization are included, with special focus on retaining biophysical realism and avoiding common pitfalls. We also discuss the more advanced case of compartmental modeling using the compartmental extension to BioNetGen. In addition, we provide a comprehensive set of example reaction rules that cover the various aspects of signal transduction, from signaling at the membrane to gene regulation. The reader can modify these reaction rules to model their own systems of interest. PMID- 23361987 TI - Computational modeling of signal transduction networks: a pedagogical exposition. AB - We give a pedagogical introduction to computational modeling of signal transduction networks, starting from explaining the representations of chemical reactions by differential equations via the law of mass action. We discuss elementary biochemical reactions such as Michaelis-Menten enzyme kinetics and cooperative binding, and show how these allow the representation of large networks as systems of differential equations. We discuss the importance of looking for simpler or reduced models, such as network motifs or dynamical motifs within the larger network, and describe methods to obtain qualitative behavior by bifurcation analysis, using freely available continuation software. We then discuss stochastic kinetics and show how to implement easy-to-use methods of rule based modeling for stochastic simulations. We finally suggest some methods for comprehensive parameter sensitivity analysis, and discuss the insights that it could yield. Examples, including code to try out, are provided based on a paper that modeled Ras kinetics in thymocytes. PMID- 23361988 TI - Modeling spatiotemporal dynamics of bacterial populations. AB - Quantitative modeling of spatiotemporal dynamics of cells facilitates understanding and engineering of biological systems. Using a synthetic bacterial ecosystem as a workbench, we present the approach to mathematically simulate the spatiotemporal population dynamics of the ecosystem. A description of ecosystem's genetic construction and model development is firstly given. Parameter estimation and computational approach for the derived partial differential equations (PDEs) are then given. Spatiotemporal pattern formation is computed by numerically solving the PDE model. Biodiversity of the ecosystem and its impacts by cellular seeding distance and motility are computed according to the cell distribution patterns. PMID- 23361989 TI - Discrete dynamic modeling of signal transduction networks. AB - Newly available experimental data characterizing different processes involved in signaling pathways have provided the opportunity for network analysis and modeling of these interacting pathways. Current approaches in studying the dynamics of signaling networks fall into two major groups, namely, continuous and discrete models. The lack of kinetic information for biochemical interactions has limited the wide applicability of continuous models. To address this issue, discrete dynamic models, based on a qualitative description of a system's variables, have been applied for the analysis of biological systems with many unknown parameters. The purpose of this chapter is to give a detailed description of Boolean modeling, the simplest type of discrete dynamic modeling, and the ways in which it can be applied to analyze the dynamics of signaling networks. This is followed by practical examples of a Boolean dynamic framework applied to the modeling of the abscisic acid signal transduction network in plants as well as the T-cell survival signaling network in humans. PMID- 23361990 TI - Analytic methods for modeling stochastic regulatory networks. AB - Recent single-cell experiments have revived interest in the unavoidable or intrinsic noise in biochemical and genetic networks arising from the small number of molecules of the participating species. That is, rather than modeling regulatory networks in terms of the deterministic dynamics of concentrations, we model the dynamics of the probability of a given copy number of the reactants in single cells. Most of the modeling activity of the last decade has centered on stochastic simulation, i.e., Monte Carlo methods for generating stochastic time series. Here we review the mathematical description in terms of probability distributions, introducing the relevant derivations and illustrating several cases for which analytic progress can be made either instead of or before turning to numerical computation. Analytic progress can be useful both for suggesting more efficient numerical methods and for obviating the computational expense of, for example, exploring parametric dependence. PMID- 23361991 TI - Use of birth certificates to examine maternal occupational exposures and autism spectrum disorders in offspring. AB - The continuing rise in the prevalence of autism spectrum disorders has led to heightened interest in the role of nongenetic factors, including exogenous exposures, but little research has been conducted. To explore a possible role in autism etiology, we used data available from our prior studies to examine potential occupational exposures, as these may occur at higher levels than environmental exposures. Parental occupation was obtained from birth certificates for 284 children with autism and 659 controls, born in 1994 in the San Francisco Bay Area. Self-reported occupation and industry were coded into eight exposure/chemical groups based on potential neurotoxicity or reprotoxicity by a board-certified physician in occupational medicine and an industrial hygienist blinded to case-control status. Mothers of autistic children were twice as likely to work in occupations considered exposed (14.4%) as mothers of controls (7.2%) (adjusted odds ratio [AOR] 2.3 [95% confidence interval {CI} 1.3-4.2]). The exposure categories of the greatest frequency among case mothers were exhaust and combustion products (AOR = 12.0 [95% CI 1.4-104.6]) and disinfectants (AOR = 4.0 [95% CI 1.4-12.0]). Paternal occupational exposure was not associated with autism, potentially consistent with a direct in-utero exposure effect. There are several limitations of this hypothesis-generating study, including lack of detail on workplace and job duties, leading to possible misclassification and low proportion exposed. However, this misclassification would not be biased by case control status and is unlikely to explain the associations we did find, suggesting that further research on exogenous exposures may yield useful etiologic clues. PMID- 23361992 TI - CT-measured bone attenuation in patients with chronic obstructive pulmonary disease: relation to clinical features and outcomes. AB - Osteoporosis is highly prevalent in chronic obstructive pulmonary disease (COPD) patients and has been related to several clinical features. However, most studies have been in relatively small COPD cohorts. Therefore, the objectives of this study were to compare bone attenuation measured on low-dose chest computed tomography (CT) between COPD subjects and smoker and nonsmoker controls, and to relate bone attenuation to clinical parameters, inflammatory biomarkers, and outcomes in a large, well-characterized COPD cohort. We studied 1634 COPD subjects, 259 smoker controls, and 186 nonsmoker controls who participated in a large longitudinal study (ECLIPSE). We measured bone attenuation, extent of emphysema, and coronary artery calcification (Agatston score) on baseline CT scans, and clinical parameters, inflammatory biomarkers, and outcomes. Bone attenuation was lower in COPD subjects compared with smoker and nonsmoker controls (164.9 +/- 49.5 Hounsfield units [HU] versus 183.8 +/- 46.1 HU versus 212.1 +/- 54.4 HU, p < 0.001). Bone attenuation was not significantly different between COPD subjects and smoker controls after adjustment for age, sex, and pack years of smoking. In the COPD subjects, bone attenuation correlated positively with forced expiratory volume in 1 second (FEV1, r = 0.062, p = 0.014), FEV1/forced vital capacity (FVC) ratio (r = 0.102, p < 0.001), body mass index (r = 0.243, p < 0.001), fat-free mass index (FFMI, r = 0.265, p < 0.001), and C reactive protein (r = 0.104, p < 0.001), and correlated negatively with extent of emphysema (r = -0.090, p < 0.001), Agatston score (r = -0.177, p < 0.001), and interleukin-8 (r = -0.054, p = 0.035). In a multiple regression model, older age, lower FFMI and higher Agatston score were associated with lower bone attenuation. Lower bone attenuation was associated with higher exacerbation (r = -0.057, p = 0.022) and hospitalization (r = -0.078, p = 0.002) rates but was not associated with all-cause mortality. In conclusion, CT-measured bone attenuation was lower in COPD subjects compared with nonsmoker controls but not compared with smoker controls, after adjustment for age, sex, and pack-years of smoking. In the COPD subjects, bone attenuation was associated with age, body composition, and coronary artery calcification but was not associated with all-cause mortality. PMID- 23361993 TI - Microbial diversity in the coralline sponge Vaceletia crypta. AB - Coralline sponges of the genus Vaceletia are regarded as 'living fossils', the only recent members of the so-called 'sphinctozoan-type' sponges that contributed to reef-building during the Palaeozoic and Mesozoic eras. Vaceletia species were thought to be extinct until the discovery of Vaceletia crypta in the 1970s. Here, we used molecular methods to provide first insights into the microbial diversity of these coralline sponges. Both denaturing gradient gel electrophoresis (DGGE) analyses of 19 Vaceletia specimens and the analysis of 427 clones from a bacterial 16S rRNA gene clone library of a specimen of V. crypta from the Great Barrier Reef (Australia) revealed high diversity and a complex composition with a relatively uniform phylogenetic distribution. Only a single archaeal 16S rRNA phylotype was recovered. The most abundant bacteria were the Chloroflexi (35 %). Of the microbial community, 58 % consisted of the Gammaproteobacteria, Gemmatimonadetes, Actinobacteria, Nitrospira, Deltaproteobacteria, Deferribacteres and Acidobacteria, with nearly equal representation. Less abundant members of the microbial community belonged to the Alphaproteobacteria (3 %), as well as to the Poribacteria, Betaproteobacteria, Cyanobacteria, Spirochaetes, Bacteroidetes, Deinococcus-Thermus and Archaea (all together 4 %). Of the established 96 OTUs, 88 % were closely related to other sponge-derived sequences and thereof 71 OTUs fell into sponge- or sponge-coral specific clusters, which underscores that the "living fossil" coralline sponge Vaceletia shares features of its microbial community with other sponges. The DGGE cluster analysis indicated distinct microbial communities in the different growth forms (solitary and colonial) of Vaceletia species. PMID- 23361994 TI - Salinispora pacifica sp. nov., an actinomycete from marine sediments. AB - A polyphasic analysis was carried out to clarify the taxonomic status of four marine actinomycete strains that share a phylogenetic relationship and phenotypic characteristics with the genus Salinispora. These strains formed a distinct lineage within the Salinispora 16S rRNA and gyrB trees and were found to possess a range of phenotypic properties and DNA:DNA hybridization values that distinguished them from the type strains of the two validly named species in this genus, Salinispora tropica (CNB-440(T), ATCC BAA-916(T)) and Salinispora arenicola (CNH-643(T), ATCC BAA-917(T)). The combined genotypic and phenotypic data support this conclusion. It is proposed that the strains be designated as Salinispora pacifica sp. nov., the type strain of which is CNR-114(T) (DSMZ YYYYT = KACC 17160(T)). PMID- 23361995 TI - Repulsive migration of Schwann cells induced by Slit-2 through Ca2+-dependent RhoA-myosin signaling. AB - Schwann cells migrate along axons before initiating myelination during development and their migration facilitates peripheral nerve regeneration after injury. Axon guidance molecule Slit-2 is highly expressed during peripheral development and nerve regeneration; however, whether Slit-2 regulates the migration of Schwann cells remains a mystery. Here we show that Slit-2 receptor Robo-1 and Robo-2 were highly expressed in Schwann cells in vitro and in vivo. Using three distinct migration assays, we found that Slit-2 repelled the migration of cultured Schwann cells. Furthermore, frontal application of a Slit-2 gradient to migrating Schwann cells first caused the collapse of leading front, and then reversed soma translocation of Schwann cells. The repulsive effects of Slit-2 on Schwann cell migration depended on a Ca(2+) signaling release from internal stores. Interestingly, in response to Slit-2 stimulation, the collapse of leading front required the loss of F-actin and focal adhesion, whereas the subsequent reversal of soma translocation depended on RhoA-Rock-Myosin signaling pathways. Taken together, we demonstrate that Slit-2 repels the migration of cultured Schwann cells through RhoA-Myosin signaling pathways in a Ca(2+) dependent manner. PMID- 23361996 TI - Twin anemia-polycythemia sequence in a case of monoamniotic twins. AB - Twin anemia-polycythemia sequence (TAPS) complicates up to 6% of monochorionic diamniotic twin pregnancies, typically in the late second or third trimester. The presence of only a few and very small arteriovenous vascular anastomoses characterizes the underlying angioarchitecture at the chorionic plate in cases of TAPS. In monoamniotic twins, large vascular anastomoses can usually be seen at the placental vascular equator, and therefore one would not expect the development of TAPS in monoamniotic twins. We report a case of TAPS in a monoamniotic pregnancy at 26 + 5 weeks' gestation which responded favorably to fetoscopic laser coagulation of the small placental anastomoses, resolving severe anemia in one twin and polycythemia in the other. The pregnancy continued until 32 + 5 weeks, when worsening cord entanglement with increased resistance and the development of postsystolic notches in the umbilical artery of one twin prompted delivery by Cesarean section. There was only a moderate difference in neonatal hemoglobin concentrations, with the former polycythemic twin needing a single partial volume exchange transfusion. The postnatal course of the neonates was uneventful, according to their gestational age at birth. To our knowledge this is the first case report describing successful laser therapy for TAPS in monoamniotic twins. PMID- 23361997 TI - Determination of labile chiral supramolecular ion pairs by chromatographic NMR spectroscopy. PMID- 23361998 TI - Microhydration effects on the intermediates of the S(N)2 reaction of iodide anion with methyl iodide. PMID- 23361999 TI - Late-onset inflammatory adverse reactions related to soft tissue filler injections. AB - An ever-increasing number of persons seek medical solutions to improve the appearance of their aging skin or for aesthetic and cosmetic indications in diverse pathological conditions, such as malformations, trauma, cancer, and orthopedic, urological, or ophthalmological conditions. Currently, physicians have many different types of dermal and subdermal fillers, such as non-permanent, permanent, reversible, or non-reversible materials. Despite the claims of manufacturers and different authors that fillers are non-toxic and non immunogenic or that complications are very uncommon, unwanted side effects do occur with all compounds used. Implanted, injected, and blood-contact biomaterials trigger a wide variety of adverse reactions, including inflammation, thrombosis, and excessive fibrosis. Usually, these adverse reactions are associated with the accumulation of large numbers of mononuclear cells. The adverse reactions related to fillers comprise a broad range of manifestations, which may appear early or late and range from local to systemic. Clinicians should be aware of them since the patient often denies the antecedent of injection or is unaware of the material employed. Most of these adverse effects seem to have an immunological basis, the fillers acting more as adjuvants than as direct T-cell activators, on a background of genetic predisposition. Their treatment has not been the subject of well-designed studies; management of both acute and systemic reactions is often difficult, and requires anti-inflammatory and occasionally immunosuppressive therapy. The clinical, pathological, and therapeutic aspects of inflammatory and immune-mediated late-onset adverse reactions related to soft tissue filler injections are thoroughly reviewed herein. PMID- 23362001 TI - Usefulness of 11C-choline positron emission tomography for genital chlamydial infection assessment in a BALB/c murine model. AB - PURPOSE: The aim of this study is to explore the feasibility of 11C-Choline PET in the assessment of the degree of inflammation in the Chlamydia muridarum genital infection model. PROCEDURES: Forty female Balb/c mice received 2.5 mg of medroxyprogesterone acetate i.m. 9 and 2 days prior to the infection: 21 mice were infected by C. muridarum into the vaginal vault, 12 mice were treated with inactivated chlamydiae, and 7 mice were SPG buffer-treated as negative controls. Three healthy control mice were not treated with progesterone. Mice in each category were randomly subdivided in two groups: (1) sacrificed at 5, 10, 15, and 20 days for histological analysis and (2) undergoing 11C-Choline PET at days 5, 10, and 20 post-infection (20 MBq of 11C-Choline, uptake time of 10 min, acquisition through a small-animal PET tomograph for 15 min). RESULTS: Infected animals showed a significantly higher standardized uptake value than both controls and animals inoculated with heat-inactivated chlamydiae in each PET scan (P<0.05). All organs of the infected animals had scores of inflammation ranging between 2 and 3 at day 5, decreasing to 1-2 at day 20. CONCLUSIONS: This preliminary result demonstrated that 11C-Choline PET can highlight a specific proliferation mechanism of inflammatory cells induced by C. muridarum, thanks to a very high sensitivity in detecting very small amounts of tracer in inflammatory cells. PMID- 23362000 TI - A 18F-labeled BF-227 derivative as a potential radioligand for imaging dense amyloid plaques by positron emission tomography. AB - PURPOSE: The aims of this study were to evaluate the binding and pharmacokinetics of novel 18F-labeled ethenyl-benzoxazole derivatives (i.e., [18F] fluorinated amyloid imaging compound of Tohoku university ([18F]FACT)) as amyloid positron emission tomography (PET) tracers and to assess [18F]FACT efficacy in imaging of Alzheimer's disease (AD). PROCEDURES: Binding assay was conducted using synthetic amyloid-beta (Abeta) fibrils, fluorescence microscopy, and autoradiogram in three postmortem AD brains. Pharmacokinetics of [18F]FACT was assessed using 12 Crj:CD 1 (ICR) mice. In vivo binding ability with brain amyloid was investigated using amyloid precursor protein (APP) transgenic mouse. Clinical PET scanning using [18F]FACT was performed in ten healthy controls and ten mild cognitive impairment and ten AD patients. RESULTS: [18F]FACT showed high binding affinity for synthetic Abeta fibrils, preferential binding to dense cored plaques in brain sections, and excellent brain uptake and rapid clearance in mice. Injection in APP mice resulted in specific in vivo labeling of amyloid deposits in the brain. PET scans of AD patients showed significantly higher [18F]FACT uptake in the neocortex compared to controls (P<0.05, Kruskal-Wallis test). CONCLUSION: [18F]FACT is a promising agent for imaging dense Abeta plaques in AD. PMID- 23362002 TI - Acute myocardial infarction: an uncommon complication of takotsubo cardiomyopathy. AB - Transient left ventricular apical ballooning or Takotsubo syndrome (TS) is characterized by transient left ventricular dysfunction, electrocardiographic changes that mimic acute myocardial infarction (AMI), and minimal release of myocardial enzymes, with no evidence of obstructive coronary artery disease. Although prognosis and outcome are relatively good, reported complications include intraventricular thrombi and embolic events. We report an extremely rare case of AMI complicating the early in-hospital course of a patient with TS. PMID- 23362004 TI - On collegiality and role models. PMID- 23362003 TI - Common trace elements alleviate pain in an experimental mouse model. AB - Trace elements represent a group of essential metals or metaloids necessary for life, present in minute amounts. Analgesic adjuvants can enhance the effect of other pain drugs or be used for pain control themselves. Previous studies on the effects of trace elements on nociception and their potential use as analgesic adjuvants have yielded conflicting results. In this study, we tested the hypothesis that three vital trace elements (Zn2+, Mg2+, Cu2+) have direct antinociceptive effects. Groups of eight Swiss mice were intraperitoneally (i.p) injected with incremental concentrations of Zn2+ sulfate (0.5, 2.0 mg/kg), Zn2+ citrate (0.125, 0.5 mg/kg), Mg2+ chloride (37.5, 75, 150 mg/kg), Cu2+ chloride (0.5, 1.0, 2.0 mg/kg), and Cu2+ sulfate (0.5, 1.0 mg/kg) or saline (control). Evaluations were made by hot plate (HP) and tail flick (TF) tests for central antinociceptive effect, writhing test (WT) for visceral antinociceptive effect, and activity cage (AC) test for spontaneous behavior. Zn2+ induced pain inhibition in HP/TF tests (up to 17%) and WT (up to 25%), with no significant differences among the salts used. Mg2+ salts induced pain inhibition for all performed tests (up to 85% in WT). Cu2+ salts showed antinociceptive effects for HP/TF (up to 28.6%) and WT (57.28%). Only Mg2+ and Cu2+ salts have displayed significant effects in AC (Mg2+ anxiolytic/depressant effect; Cu2+ anxiolytic effect). We interpret these data to mean that all tested trace elements induced antinociceptive effects in central and visceral pain tests. Our data indicate the potential use of these cheap adjuvants in pain therapy. PMID- 23362005 TI - Enantiospecific photochemical transformations under elevated pressure. AB - Enantiospecific axial-to-point chiral transfer in light-induced transformations was efficient under elevated pressure at high temperatures. Model photoreactions with atropisomeric compounds showed higher enantioselectivity in the photoproducts under elevated pressure. The ee values in the photoproducts were rationalized based on the increased stability of optically pure atropisomeric compounds at elevated pressure, even at high temperatures. PMID- 23362006 TI - Preparation of helical mesoporous tantalum oxide nanotubes through a sol-gel transcription approach. PMID- 23362007 TI - Fibroblast growth factor, estrogen, and prolactin receptor features in different grades of prostatic adenocarcinoma in elderly men. AB - The objective was to characterize and associate the receptor reactivities of fibroblastic growth factor (FGF)-2, FGF-7, FGF-8, epidermal growth factor (EGF), alpha-actin and vimentin in relation to the androgen receptor (AR), alpha and beta estrogen receptors (ERalpha and ERbeta), and prolactin receptor in the prostate of elderly men showing low- and high-grade adenocarcinoma. Thirty prostatic samples were taken from 60- to 90-year-old patients without prostatic lesions and with low-grade cancer and high-grade cancer, from the University Hospital, School of Medicine, the State University of Campinas. The results showed that increased FGF-2, FGF-7, and FGF-8 receptor reactivities and decreased AR reactivity were verified in both high- and low-grade cancer. However, the FGF 8 receptor showed greater involvement at the beginning of the malignancy alterations. Increased EGF receptor (EGFR) reactivity and diminished alpha-actin immunohistochemistry were identified in both cancer groups. Also, increased ERalpha, PR, and vimentin receptors were verified in both cancer groups. To conclude, the ERalpha involvement in the reactive stroma activation led to a microenvironment, which was favorable to cancer progression, due to maximizing stromal imbalance. The prolactin could be related to cancer progression due to its interaction with ERalpha action, indicating that this hormone could be a relevant target to prevent the estrogenic effects in the prostatic lesions. Both FGF receptor (FGFR)-2 and FGFR-8 play a fundamental role in the early stages of prostate cancer, suggesting that these molecules could be a promising therapeutic target. The differential localization of the fibroblastic factors between the prostatic epithelium and stroma of elderly men, who presented prostate cancer, could indicate a favorable distinction for tumoral progression. PMID- 23362008 TI - Functional protein-organic/inorganic hybrid nanomaterials. AB - Nanotechnology offers immense opportunities for regulating and improving biological functions of proteins in vitro. Recent years have witnessed growing efforts to develop protein-incorporated hybrid nanostructured materials with potential applications in functional materials, enzymatic catalysis, drug delivery, and analytical sciences. In this review, recent advances in functional protein-organic/inorganic hybrid nanomaterials are discussed with an emphasis on the novel preparation methods, resulting nanostructures, and their potential applications in drug delivery and enzymatic catalysis. Future directions toward the rational design of these bionanomaterials are suggested. PMID- 23362009 TI - Three mutually informative ways to understand the genetic relationships among behavioral disinhibition, alcohol use, drug use, nicotine use/dependence, and their co-occurrence: twin biometry, GCTA, and genome-wide scoring. AB - Behavioral disinhibition is a trait hypothesized to represent a general vulnerability to the development of substance use disorders. We used a large community-representative sample (N = 7,188) to investigate the genetic and environmental relationships among measures of behavioral disinhibition, Nicotine Use/Dependence, Alcohol Consumption, Alcohol Dependence, and Drug Use. First, using a subsample of twins (N = 2,877), we used standard twin models to estimate the additive genetic, shared environmental, and non-shared environmental contributions to these five traits. Heritabilities ranged from .42 to .58 and shared environmental effects ranged from .12 to .24. Phenotypic correlations among the five traits were largely attributable to shared genetic effects. Second, we used Genome-wide Complex Trait Analysis (GCTA) to estimate as a random effect the aggregate genetic effect attributable to 515,384 common SNPs. The aggregated SNPs explained 10-30 % of the variance in the traits. Third, a genome wide scoring approach summed the actual SNPs, creating a SNP-based genetic risk score for each individual. After tenfold internal cross-validation, the SNP sumscore correlated with the traits at .03 to .07 (p < .05), indicating small but detectable effects. SNP sumscores generated on one trait correlated at approximately the same magnitude with other traits, indicating detectable pleiotropic effects among these traits. Behavioral disinhibition thus shares genetic etiology with measures of substance use, and this relationship is detectable at the level of measured genomic variation. PMID- 23362010 TI - Functionalization of the 3'-ends of DNA and RNA strands with N-ethyl-N-coupled nucleosides: a promising approach to avoid 3'-exonuclease-catalyzed hydrolysis of therapeutic oligonucleotides. AB - The development of nucleic acid derivatives to generate novel medical treatments has become increasingly popular, but the high vulnerability of oligonucleotides to nucleases limits their practical use. We explored the possibility of increasing the stability against 3'-exonucleases by replacing the two 3'-terminal nucleotides by N-ethyl-N-coupled nucleosides. Molecular dynamics simulations of 3'-N-ethyl-N-modified DNA:Klenow fragment complexes suggested that this kind of alteration has negative effects on the correct positioning of the adjacent scissile phosphodiester bond at the active site of the enzyme, and accordingly was expected to protect the oligonucleotide from degradation. We verified that these modifications conferred complete resistance to 3'-exonucleases. Furthermore, cellular RNAi experiments with 3'-N-ethyl-N-modified siRNAs showed that these modifications were compatible with the RNAi machinery. Overall, our experimental and theoretical studies strongly suggest that these modified oligonucleotides could be valuable for therapeutic applications. PMID- 23362011 TI - HIV infection is strongly associated with hip fracture risk, independently of age, gender, and comorbidities: a population-based cohort study. AB - HIV infection and antiretroviral therapies have detrimental effects on bone metabolism, but data on their impact on fracture risk are controversial. We conducted a population-based cohort study to explore the association between clinical diagnosis of HIV infection and hip and major osteoporotic fracture risk. Data were obtained from the SIDIAP(Q) database, which contains clinical information for >2 million patients in Catalonia, Spain (30% of the population). We screened the database to identify participants with a clinical diagnosis of HIV infection, and ascertained incident hip and osteoporotic major fractures in the population aged 40 years or older in 2007 to 2009. In addition, data on incident fractures involving hospital admission were obtained from the Hospital Admissions database. Cox regression models were used to estimate hazard ratios (HRs) for the HIV-infected versus uninfected participants. Models were adjusted for age, sex, body mass index, smoking status, alcohol drinking, oral glucocorticoid use, and comorbid conditions (Charlson index). Among 1,118,156 eligible participants, we identified 2489 (0.22%) subjects with a diagnosis of HIV/AIDS. Age- and sex-adjusted HR for HIV/AIDS were 6.2 (95% confidence interval [CI] 3.5-10.9; p < 0.001) and 2.7 (2.01-3.5; p < 0.001) for hip and major fractures, respectively; this remained significant after adjustment for all mentioned potential confounders: HR 4.7 (2.4-9.5; p < 0.001) and 1.8 (1.2-2.5; p = 0.002). After stratifying by age, the association between HIV infection and major fractures was attenuated for those aged <59 years (adjusted HR 1.35 [0.88 2.07], p = 0.17) but appeared stronger in older patients (adjusted HR 2.11 [1.05 4.22], p = 0.035). We report a strong association between HIV infection and hip fracture incidence, with an almost fivefold increased risk in the HIV infected, independent of sex, age, smoking, alcohol drinking, and comorbidities. Similarly, we demonstrate a 75% higher risk of all clinical fractures and a 60% increase in risk of non-hip clinical fractures among patients with a diagnosis of HIV infection. PMID- 23362012 TI - Glycogen synthase kinase-3 inhibition prevents learning deficits in diabetic mice. AB - There is an increasing awareness that diabetes has an impact on the central nervous system, with reports of impaired learning, memory, and mental flexibility being more common in diabetic subjects than in the general population. Insulin deficient diabetic mice also display learning deficits associated with defective insulin-signaling in the brain and increased activity of GSK3. In the present study, AR-A014418, a GSK3beta inhibitor, and TX14(A), a neurotrophic factor with GSK3 inhibitory properties, were tested against the development of learning deficits in mice with insulin-deficient diabetes. Treatments were started at onset of diabetes and continued for 10 weeks. Treatment with AR-A014418 or TX14(A) prevented the development of learning deficits, assessed by the Barnes maze, but only AR-A014418 prevented memory deficits, as assessed by the object recognition test. Diabetes-induced increased levels of amyloid beta protein and phosphorylated tau were not significantly affected by the treatments. However, the diabetes-induced decrease in synaptophysin, a presynaptic protein marker of hippocampal plasticity, was partially prevented by both treatments. These results suggest a role for GSK3 and/or reduced neurotrophic support in the development of cognitive deficits in diabetic mice that are associated with synaptic damage. PMID- 23362013 TI - Dosing of iodinated contrast volume: a new simple algorithm to stratify the risk of contrast-induced nephropathy in patients with acute coronary syndrome. AB - OBJECTIVES AND BACKGROUND: Previous studies on contrast-induced nephropathy (CIN) have identified contrast volume (CV) as a risk factor. The aim of our research was to define the safe dose of contrast media based on absolute CV, maximum allowable contrast dose (MACD) and estimated glomerular filtrate rate (eGFR). METHODS AND RESULTS: A total of 940 consecutive patients with acute coronary syndrome (ACS) were enrolled. Fifty-four patients developed CIN. MACD was defined as 5*body weight/serum creatinine. When using a CV higher than MACD, CIN-risk was increased 19-fold (OR 9.810-39.307, P < 0.001). For the CV/eGFR ratio, we found that for every increase of one-tenth, CIN-risk increased by 4.9% (OR 1.037-1.061, P < 0.001). The discriminative ability of CV (C statistic = 0.626 +/- 0.038) was significantly lower than for the CV/MACD (C statistic = 0.782 +/- 0.036, P = 0.003) and CV/eGFR (C statistics: 0.796 +/- 0.033 for MDRD-4, 0.796 +/- 0.034 for Cockcroft-Gault, and 0.803 +/- 0.033 for CKD-EPI; P < 0.001). There were no differences in the discriminative ability to predict CIN between the three eGFR equations. The combination of CV/MACD and CV/eGFR in a single protocol increases the positive predictive value of the Mehran risk score (40.7% vs. 8.8%) with the same sensitivity (90.7% vs. 83.3%). High doses of relative CV (CV/MACD and CV/eGFR) were also significantly associated with higher in-hospital mortality, reinfarction, and heart failure. CONCLUSIONS: A sequential protocol based on CV/MACD and CV/eGFR appropriately identified those ACS patients who developed CIN, with predictive values similar to a Mehran score, reducing the false positive rate. It is also useful to predict risk of in-hospital cardiac events regardless of GRACE score. PMID- 23362015 TI - Single, double, triple bonds and chains: the formation of electron-precise B-B bonds. AB - The construction of boron-boron bonds, despite the intense synthetic interest in diboranes and the high B-B bond enthalpy, is still difficult, uncontrollable, and unpredictable. Methods for the construction of B-B multiple bonds are rarer still. These problems have witnessed some progress in recent years; this Minireview attempts to provide a background to the history of B-B bond synthesis and summarize the recent results in the area. PMID- 23362016 TI - Highly emissive boron ketoiminate derivatives as a new class of aggregation induced emission fluorophores. AB - A series of boron ketoiminate derivatives that exhibited clear aggregation induced emission (AIE) characteristics (in THF: Phi(PL)<=0.01; in the solid state: Phi(PL)=0.30-0.76) were prepared by the reactions of 1,3-enaminoketone derivatives with boron trifluoride-diethyl etherate. The structures and optical properties were investigated by UV-visible spectroscopy, photoluminescent (PL) spectroscopy, and X-ray single-crystal measurements. These results indicate that the AIE characteristics were derived from molecular motions of the boron chelating rings with a boron-nitrogen (B-N) bond. Furthermore, the optical properties were controllable by steric hindrance of the substituted groups on the nitrogen atom. PMID- 23362014 TI - Comparison of age at natural menopause in BRCA1/2 mutation carriers with a non clinic-based sample of women in northern California. AB - BACKGROUND: Germline mutations in BRCA1 and BRCA2 (BRCA1/2) are related to an increased lifetime risk of developing breast and ovarian cancer. Although risk reducing salpingo-oophorectomy reduces the risk of both cancers, loss of fertility is a major concern. A recent study suggested an association between BRCA1 mutation and occult primary ovarian insufficiency. The objective of the current study was to determine whether BRCA1/2 mutation carriers have an earlier onset of natural menopause compared with unaffected women. METHODS: White carriers of the BRCA1/2 gene (n = 382) were identified within the Breast Cancer Risk Program Registry at the University of California at San Francisco and compared with non-clinic-based white women in northern California (n = 765). The 2 groups were compared with regard to median age at the time of natural menopause before and after adjustment for known risk factors, and the role of smoking within each group was examined using the Kaplan-Meier approach for unadjusted analyses and Cox proportional hazards regression analyses for adjusted analyses. RESULTS: The median age at the time of natural menopause in the BRCA1/2 carriers was significantly younger than among the unaffected sample (50 years vs 53 years; P < .001). The unadjusted hazard ratio for natural menopause when comparing BRCA1/2 carriers with unaffected women was 4.06 (95% confidence interval, 3.03 5.45) and was 3.98 (95% confidence interval, 2.87-5.53) after adjusting for smoking, parity, and oral contraceptive use. For BRCA1/2 carriers who were current heavy smokers (smoking >= 20 cigarettes/day), the median age at natural menopause was 46 years versus 49 years for nonsmokers (P = .027). CONCLUSIONS: The BRCA1/2 mutation was associated with a significantly earlier age at natural menopause, and heavy smoking compounded this risk. Because the relationship between menopause and the end of natural fertility is considered to be fixed, these findings suggest the risk of earlier infertility among BRCA1/2 carriers. PMID- 23362017 TI - Laser extraction of a defibrillator lead from a persistent left superior vena cava. PMID- 23362018 TI - Uncontrolled forward motion of an ablation catheter through a recently available deflectable sheath. PMID- 23362020 TI - Late pulmonary vein reconnection: insights into mechanisms of atrial fibrillation recurrence after pulmonary vein isolation. PMID- 23362019 TI - Comparison of effects on coagulation and inflammatory markers using a duty-cycled bipolar and unipolar radiofrequency pulmonary vein ablation catheter vs. a cryoballoon catheter for pulmonary vein isolation. AB - AIMS: Thrombo-embolic events are one of the most feared complications related to atrial fibrillation (AF) ablation. Since radiofrequency (RF) energy is thought to be associated with a higher risk of thrombus formation than cryoenergy, the purpose of this study was to assess if the degree of activation of coagulation and inflammatory markers differed between ablation procedures performed with a cryoballoon catheter vs. a RF energy-based pulmonary vein ablation catheter (PVAC), respectively. METHODS AND RESULTS: Thirty patients referred for AF ablation were randomized to pulmonary vein isolation with either the cryoballoon or the PVAC. Biomarkers were studied for endothelial damage (von Willebrand factor antigen), platelet activation (soluble P-selectin), and coagulation activity [prothrombin fragment 1 + 2 (F1 + 2) and D-dimer] at five different time points during the procedure. Troponin I (Trop I) and C-reactive protein were analysed to reflect myocardial destruction and inflammatory activity. Markers of endothelial damage and platelet activation increased after ablation in both the cryo and the RF group. Similarly, the D-dimer levels increased significantly (P = 0.001) in both groups, whereas the F1 + 2 levels increased after the transseptal puncture only (P = 0.001). The overall activation of the coagulation system was, however, comparable between the groups. The cryoballoon was associated with higher Trop I compared with the PVAC (P < 0.001), but the ratios between biomarkers and Trop I were higher with the PVAC than with the cryoballoon. CONCLUSION: Even though the cryoballoon causes a higher degree of myocardial destruction than the PVAC, markers of coagulation, endothelial damage, and inflammation were comparable between the two techniques. PMID- 23362021 TI - Effectiveness of remote monitoring of CIEDs in detection and treatment of clinical and device-related cardiovascular events in daily practice: the HomeGuide Registry. AB - AIMS: The HomeGuide Registry was a prospective study (NCT01459874), implementing a model for remote monitoring of cardiac implantable electronic devices (CIEDs) in daily clinical practice, to estimate effectiveness in major cardiovascular event detection and management. METHODS AND RESULTS: The workflow for remote monitoring [Biotronik Home Monitoring (HM)] was based on primary nursing: each patient was assigned to an expert nurse for management and to a responsible physician for medical decisions. In-person visits were scheduled once a year. Seventy-five Italian sites enrolled 1650 patients [27% pacemakers, 27% single chamber implantable cardioverter defibrillators (ICDs), 22% dual-chamber ICDs, 24% ICDs with cardiac resynchronization therapy]. Population resembled the expected characteristics of CIED patients. During a 20 +/- 13 month follow-up, 2471 independently adjudicated events were collected in 838 patients (51%): 2033 (82%) were detected during HM sessions; 438 (18%) during in-person visits. Sixty were classified as false-positive, with generalized estimating equation-adjusted sensitivity and positive predictive value of 84.3% [confidence interval (CI), 82.5-86.0%] and 97.4% (CI, 96.5-98.2%), respectively. Overall, 95% of asymptomatic and 73% of actionable events were detected during HM sessions. Median reaction time was 3 days [interquartile range (IQR), 1-14 days]. Generalized estimating equation-adjusted incremental utility, calculated according to four properties of major clinical interest, was in favour of the HM sessions: +0.56 (CI, 0.53-0.58%), P < 0.0001. Resource consumption: 3364 HM sessions performed (76% by nurses), median committed monthly manpower of 55.5 (IQR, 22.0-107.0) min * health personnel/100 patients. CONCLUSION: Home Monitoring was highly effective in detecting and managing clinical events in CIED patients in daily practice with remarkably low manpower and resource consumption. PMID- 23362022 TI - Assessing repeatability of 3D Doppler indices obtained by static 3D and STIC power Doppler: a combined in-vivo/in-vitro flow phantom study. AB - OBJECTIVES: To compare the variability in vascularization flow index (VFI) seen in serial acquisitions obtained using spatiotemporal image correlation (STIC) and using conventional static three-dimensional (3D) power Doppler (PD), for both in vitro and in-vivo models, and to evaluate whether the curves formed by VFI values obtained from successive 'frames' in a STIC dataset are consistent and resemble the waveforms obtained by spectral Doppler analysis. METHODS: The study was divided into two parts: in the first part (the in-vitro model) we scanned a flow phantom, while in the second part (the in-vivo model) we scanned a common carotid artery. Conventional static 3D and STIC-PD datasets were alternately acquired from these two models. VFI values were assessed from 0.38-cm(3) spherical samples of the main flow region in the static 3D datasets and in every frame of the STIC datasets. The variance of the minimum, mean and maximum VFI values from each STIC dataset was compared with the variance of VFI values from the static 3D datasets. RESULTS: Ten static 3D and 10 STIC datasets were acquired from each model. Analysis of the in-vitro and in-vivo models showed a significant reduction in the variance of VFI values obtained using STIC as compared to static datasets. Additionally, we observed that the curves formed by VFI values obtained from successive frames in each STIC dataset were consistent across different datasets and that they resembled the waveforms obtained by spectral Doppler in both models. CONCLUSIONS: 3D-PD indices derived from STIC are more stable than those obtained from conventional static 3D-PD datasets. The curves of VFI throughout a reconstructed cardiac cycle using STIC are repeatable and resemble those obtained by spectral Doppler analysis of the vessel. PMID- 23362024 TI - Ligand functionalization and its effect on CO2 adsorption in microporous metal organic frameworks. AB - We report two new 3D structures, [Zn3(bpdc)3(2,2'-dmbpy)] (DMF)x(H2O)y (1) and [Zn3(bpdc)3(3,3'-dmbpy)].(DMF)4(H2O)0.5 (2), by methyl functionalization of the pillar ligand in [Zn3(bpdc)3(bpy)] (DMF)4.(H2O) (3) (bpdc=biphenyl-4,4' dicarboxylic acid; z,z'-dmbpy=z,z'-dimethyl-4,4'-bipyridine; bpy=4,4' bipyridine). Single-crystal X-ray diffraction analysis indicates that 2 is isostructural to 3, and the power X-ray diffraction (PXRD) study shows a very similar framework of 1 to 2 and 3. Both 1 and 2 are 3D porous structures made of Zn3(COO)6 secondary building units (SBUs) and 2,2'- or 3,3'-dmbpy as pillar ligand. Thermogravimetric analysis (TGA) and PXRD studies reveal high thermal and water stability for both compounds. Gas-adsorption studies show that the reduction of surface area and pore volume by introducing a methyl group to the bpy ligand leads to a decrease in H2 uptake for both compounds. However, CO2 adsorption experiments with 1' (guest-free 1) indicate significant enhancement in CO2 uptake, whereas for 2' (guest-free 2) the adsorbed amount is decreased. These results suggest that there are two opposing and competitive effects brought on by methyl functionalization: the enhancement due to increased isosteric heats of CO2 adsorption (Q(st)), and the detraction due to the reduction of surface area and pore volume. For 1', the enhancement effect dominates, which leads to a significantly higher uptake of CO2 than its parent compound 3' (guest-free 3). For 2', the detraction effect predominates, thereby resulting in reduced CO2 uptake relative to its parent structure 3'. IR and Raman spectroscopic studies also present evidence for strong interaction between CO2 and methyl functionalized pi moieties. Furthermore, all compounds exhibit high separation capability for CO2 over other small gases including CH4, CO, N2, and O2. PMID- 23362023 TI - EGF stimulates Muller glial proliferation via a BMP-dependent mechanism. AB - Muller glia, the major type of glia in the retina, are mitotically quiescent under normal conditions, though they can be stimulated to proliferate in some pathological states. Among these stimuli, EGF is known to be a potent mitogen for Muller glia. However, the signaling pathways required for EGF-mediated proliferation of Muller glia are not clearly understood. In this study, postnatal day 12 (P12) or adult trp53(-/-) mouse retinas were explanted and cultured in the presence of EGF to stimulate Muller glial proliferation. Treatment with signaling inhibitors showed that activation of both MEK/ERK1/2 and PI3K/AKT pathways is required for EGF-induced proliferation of Muller glia. Interestingly, BMP/Smad1/5/8 activation downstream of PI3K/AKT signaling was also necessary for robust Muller glial proliferation, though activation of BMP/Smad1/5/8 signaling alone failed to stimulate their proliferation. In dissociated Muller glial culture, treatment with EGF induced the upregulation of Bmp7, and this upregulation was blocked significantly by co-treatment with the BMP inhibitor dorsomorphin, suggesting that BMP/Smad1/5/8 activation is mediated at least in part by an autocrine mechanism in Muller glia. A better understanding of how BMP/Smad1/5/8 signaling is involved in glial proliferation may have important implications for proliferative disorders, as well as for retinal regeneration in mammalian retinas. PMID- 23362025 TI - Special issue on developmental delay. AB - A significant percentage of children, ages 0-5 years, present with developmental delays. Delays can be global (GDD), when two or more developmental areas manifest at least 6 months delays, or specific (SDD)when it relates to a single functional area. This special issue reviews etiologies as well as clinical and research uses of the term, focusing on the potential for arriving at earlier specific diagnoses in cases of CP, ADHD, ASD and language impairments (LI). PMID- 23362026 TI - Perinatal and early postnatal factors underlying developmental delay and disabilities. AB - A delay in meeting developmental milestones may be secondary to perinatal events, involving complicated interactions between mother and fetus during delivery. Maternal factors including weight, diet, and morbidities can affect neonatal adaptation and later development. Prematurity, low birth weight, and previous intrauterine insults as well as complications during delivery of a previously normal fetus increase the risk for perinatal stress. In this article, the literature on perinatal and early postnatal factors that underlie risks for developmental delay and disabilities is reviewed. Studies that concern neuroprotective therapies and prediction of long-term neurologic outcome by clinical examination, neuroimaging techniques, and electroencephalographic studies are reviewed as well. PMID- 23362027 TI - Prenatal exposures associated with neurodevelopmental delay and disabilities. AB - Neurobehavioral teratology refers to the study of the abnormal development of the structure and the behavioral functions of the central nervous system, which result from exposure to exogenous agents during prenatal development. The focus of this review is the effects of various prenatal exposures on human neurodevelopment. Studies that deal with the adverse effects of infectious agents (rubella, cytomegalovirus, and toxoplasma), teratogenic drugs (e.g., antiepileptic drugs such as phenytoin, valproate, and carbamazepine, coumarin derivatives, and retinoids), alcohol, and other substances of abuse will be reviewed. Additionally, prenatal exposure to industrial or environmental chemicals (e.g., lead, methylmercury, and polycarbonated biphenyls) as well as exposure of the embryo or fetus to high amounts of ionizing radiation will be addressed. Possible mechanisms of selected neurobehavioral teratogens will also be discussed. PMID- 23362028 TI - Global developmental delay and mental retardation--a pediatric perspective. AB - Pediatricians play a leading role in the detection, diagnosis, and management of children with global developmental delay (GDD) and mental retardation (MR). Assessment, investigation, and consultation with the family are the prime responsibility of the developmental pediatrician, in collaboration with a multidisciplinary team. The model used by the developmental pediatrician depends on the community health framework. Significant progress has been recently achieved in identifying underlying etiologies, using a variety of laboratory tests including neuroimaging and genetic and metabolic investigations. Although being used to achieve an acceptable yield, this progress in diagnostic investigations should be associated with proper weighing of the value of each test to the diagnostic process. Optimal utilization of this rapidly expanding knowledge can only be accomplished in the setting of in-depth clinical evaluation, including a thoughtful assessment of the child and family needs. In this article, the literature on the process of clinical evaluation and laboratory work-up of the child with GDD/MR is reviewed, with an emphasis on a multidisciplinary team approach to the child and family needs. An integrated model used by the developmental pediatrician that relates to the process of evaluation and management as well as the consequences of the diagnosis on the child, his/her family, and the community is suggested. PMID- 23362029 TI - Fetal and infant spontaneous general movements as predictors of developmental disabilities. AB - The challenge of identifying infants who are at risk for developmental delay and possible adverse neurodevelopmental outcome demands methods of evaluation that will lead to early intervention to minimize developmental disability and to maximize the infant's potential. A qualitative assessment of spontaneous general movements (GMs) in the preterm, term, and young infant at risk is a valid and reliable tool for evaluation (Prechtl [1990] Early Hum. Dev. 23:151-158). The aim of this review is to describe the theoretical and clinical bases for the assessment of GMs and its relationship to developmental delay and brain dysfunction. Thirty-seven studies related to the predictive validity of GMs were included in this review. Results suggested that consistent cramped synchronized GMs are highly predictive of later development of cerebral palsy. The fidgety movement quality that appears at the age of 2 to 3 months was found to be a most sensitive predictor of neurodevelopmental outcome in different populations of infants. PMID- 23362030 TI - Preterm birth: neuropsychological profiles and atypical developmental pathways. AB - Preterm birth is characterized by multiple interacting atypical constraints affecting different aspects of neuropsychological development. In the first years of life, perceptual, motor, and communicative-linguistic abilities, as well as attention, processing speed, and memory are affected by preterm birth resulting in cascading effects on later development. From school age to adolescence, a catch-up of simpler competencies (i.e., receptive lexicon) along with a more selective effect on more complex competencies (i.e., complex linguistic functions, math, motor, and executive functions) are observed, as well as a relevant incidence of behavioral outcomes. A wide heterogeneity in preterm children's neuropsychological profiles is described depending on the interaction among the degree of neonatal immaturity, medical complications, neurological damages/alterations, environmental and social factors. Severe neuromotor and sensory damages are not frequent, while low severity impairments are common among preterm children. It is argued that developmental pathways of preterm children are atypical, and not merely delayed, and are characterized by different developmental patterns and relationships among competencies. PMID- 23362031 TI - Cerebral palsy--don't delay. AB - Cerebral palsy (CP) is the most severe physical disability within the spectrum of developmental delay. CP is an umbrella term describing a group of motor disorders, accompanied by many associated impairments. The disability is a result of injuries to the developing brain occurring any time from the first trimester of pregnancy through to early childhood. However, for the great majority, their full etiological causal pathway remains unclear. It is important to discriminate as early as possible between: (a) mild or nonspecific motor delay, (b) developmental coordination disorder, (c) syndromes, (d) metabolic and progressive conditions, and (e) CP with its various motor types and distributions. The most promising predictive tool for CP is the general movements assessment, which assesses the quality of spontaneous movements of infants in the first 4 months of life. We propose a change in diagnostic practice. We recommend a shift away from referral for intervention following a formal (most often late) description of CP, to one of referral for intervention which occurs immediately once an infant is considered "at risk" of CP. PMID- 23362032 TI - Differentiating autism spectrum disorder from other developmental delays in the first two years of life. AB - Advances in the identification of the early signs of autism spectrum disorder (ASD) have occurred despite the heterogeneity of the disorder and its variable onset and presentation. Using various methodologies including retrospective studies, community samples, and sibling cohorts, researchers have identified behavioral markers of the disorder that emerge over the first 2 years of life. However, there are characteristics of ASD that overlap with other types of developmental delay (DD), which may complicate differential diagnosis in young children. A review of the literature was conducted to identify the most promising behavioral markers that distinguish ASD from other types of DD in the first 2 years of life. The review identified profiles of behavioral markers in the social realm by 12 months and in the communication realm by 18 months, which along with additional atypical motor behaviors could distinguish ASD from DD. This constellation of features coupled with a flat or declining trajectory in specific aspects of social and communication development, may assist clinicians in targeting early interventions to at-risk infants. PMID- 23362033 TI - Late talkers: do good predictors of outcome exist? AB - Both small-scale and epidemiological longitudinal studies of early language delay indicate that most late talkers attain language scores in the average range by age 5, 6, or 7. However, late talker groups typically obtain significantly lower scores than groups with typical language histories on most language measures into adolescence. These findings support a dimensional account of language delay, whereby late talkers and typically developing peers differ quantitatively on a hypothetical language ability spectrum. Variation in language ability is presumed to derive from variation in skills subserving language, such as auditory perception/processing, word retrieval, verbal working memory, motor planning, phonological discrimination, and grammatical rule learning. Expressive language screening at 18-35 months can serve an important public health function by identifying children whose expressive delay is secondary to autism spectrum disorder, intellectual disability, hearing impairment, receptive language delay, or demographic risk. Finally, the review suggests that demographic risk associated with low SES may become more important as a causal factor in language delay as children get older. PMID- 23362034 TI - Identifying early-risk markers and developmental trajectories for language impairment in neurodevelopmental disorders. AB - The effective identification of neurodevelopmental disorders is essential for early diagnosis and provision of intervention services. For many of these conditions, one of the primary domains of abnormality is language development. This review addresses what is known about the earliest indicators of language impairment across a range of neurodevelopmental disorders; consideration is given to both behavioral and neural markers, as well as patterns of change over time. A summary of the current state of the field, including challenges in research, is presented. The earliest features of the language phenotype in Down syndrome, Williams syndrome, Fragile X, specific language impairment (SLI), and autism spectrum disorder (ASD) are described, along with recent findings in the early neural markers of language impairment in SLI and ASD. PMID- 23362035 TI - Early language delay and specific language impairment. AB - Early language delay (ELD) is a warning sign that may presage the presence of a later language impairment (LI). In order to allow more targeted identification and earlier intervention for LI, better diagnostic measures for toddlers are needed. Development of accurate predictive/diagnostic models requires consideration of a set of complex interrelated questions around definition, causality, and theories of LIs. A multifactorial model of language development and LI is essential to increase the accuracy of prediction. This article examines what is known about LI in the preschool years and language delay in toddlers, and examines these in relation to the Procedural Deficit Hypothesis (Ullman and Pierpont, [2005] Cortex 41:399-433] and the Statistical Learning Account (Stokes et al., [2012a] J Speech Lang Hear Res; Stokes et al., [2012b] J Child Lang 39:105-129) to suggest a new framework for characterizing ELD to better assist prediction of later LI. PMID- 23362036 TI - Early developmental cues for diagnosis of attention deficit/hyperactivity disorder in young children. AB - Attention deficit hyperactivity disorder (ADHD) is a childhood-onset disorder that is considered one of the most common neurobehavioral disorders. The symptoms of ADHD should be cast, not as static or fixed neurobehavioral deficits, but rather in terms of underlying developmental processes. Targeting attentional disorders early in life can bring about fundamental alterations in the pathogenesis of ADHD, and thus prevent or moderate the course of the disorder. The developmental approach can enable predictions concerning characteristics of ADHD that develop over time and inform us about multiple risk and protective factors that transact to impact its development, as well as the development of a broad range of associated co-morbid features. In this review, we describe the complex factors that predict and mediate the developmental course of ADHD, providing early cues for ADHD diagnosis and intervention in young children that will optimize outcome. PMID- 23362037 TI - Developmental delay revisited. AB - This article presents current neurobiological concepts that highlight the critical role of chronological age in determining optimal development. The role of sensitive periods, experience expectancy, gene expression, and gene-age interactions is discussed. The debate between "splitters" and "lumpers" is presented in light of the review articles in this special issue. The conclusion from this study is that in a significant proportion of cases, earlier diagnoses are possible, avoiding the all-encompassing developmental delay/global developmental delay, and opening up possibilities of early interventions. It is further argued that research methodology might benefit from early diagnoses as well. PMID- 23362038 TI - Torsades de pointes after administration of low-dose aripiprazole. AB - OBJECTIVE: To describe a case of torsades de pointes (TdP) in a patient treated with aripiprazole. CASE SUMMARY: A 42-year-old white male with schizophrenia, diabetes, hypertension, and a history of stroke was admitted to the intensive care unit following 2 days of fever, diarrhea, and altered mental status. Following the resolution of his acute illness, previous therapy with quetiapine 400 mg orally at bedtime was resumed for schizophrenia and presumed delirium. Quetiapine was discontinued after 1 dose because of QTc interval prolongation. Twenty-three days later, with a baseline QTc interval of 414 milliseconds, aripiprazole 2.5 mg orally once daily was initiated. Following 5 days of aripiprazole therapy, the patient had a cardiac arrest due to TdP. Normal sinus rhythm was restored after 30 seconds of cardiopulmonary resuscitation, 1 shock of 200 Joules, and 4 g of intravenous magnesium sulfate. Serial electrocardiographs obtained after aripiprazole discontinuation revealed resolution of QTc interval prolongation. DISCUSSION: Aripiprazole is a second-generation antipsychotic that may be selected for patients with prolonged QTc intervals and at risk for TdP. Data from trials indicate that aripiprazole has minimal effects on the QTc interval. However, in this case, aripiprazole was associated with TdP in a patient with minimal risk factors. The Naranjo probability scale was used to determine a probable association between aripiprazole and the development of TdP. To our knowledge, this is the first reported case of TdP associated with the use of aripiprazole. CONCLUSIONS: Five days of low-dose aripiprazole therapy was associated with the development of TdP in a man with minimal risk factors. Clinicians should be aware of this potential adverse drug event with aripiprazole. PMID- 23362039 TI - Prevalence of concomitant use of alcohol and sedative-hypnotic drugs in middle and older aged persons: a systematic review. AB - OBJECTIVE: To systematically review the prevalence of concomitant alcohol and sedative-hypnotic use among middle-aged and older persons. DATA SOURCES: A bibliographic search of English-language literature was performed using MEDLINE, EMBASE, and PsycINFO (January 1990-August 2012). The reference lists of all included articles were screened for additional relevant articles not identified by any of the bibliographic searches. STUDY SELECTION AND DATA EXTRACTION: Population-based studies in which the mean age of participants was 40 years or older were included. For a study to be included in the review, alcohol use had to be reported in terms of the quantity or frequency consumed. Data from included articles were extracted using a standardized data extraction tool. DATA SYNTHESIS: Five population-based studies conducted in North America, 10 in Europe, and 1 in Australia were included in the review. Up to 88% of men and 79% of women who used sedative-hypnotics also consumed alcohol. Up to 28% of those who consumed alcohol were concomitant users of sedative-hypnotics. Alcohol was consumed at higher levels among middle-aged than older persons. Risky drinking (eg, binge drinking, heavy drinking) was more prevalent among middle-aged than older persons. In contrast, sedative-hypnotic use was more prevalent among older persons. CONCLUSIONS: Our review identified a higher prevalence of alcohol consumption among middle-aged than older persons. However, middle-aged persons may experience harm from alcohol/sedative-hypnotic drug interactions due to risky drinking behavior. Despite lower levels of alcohol consumption, older persons may be more susceptible to addictive central nervous system effects than younger persons because of physiologic changes in psychotropic drug and alcohol metabolism. Clinicians should consider patients' alcohol consumption patterns before prescribing sedative-hypnotic drugs. PMID- 23362040 TI - Survival after amphotericin B overdose treated with plasmapheresis. AB - OBJECTIVE: To report a case of accidental amphotericin B overdose that was treated with plasmapheresis. CASE SUMMARY: A 60-year-old woman with a history of kidney transplant 4 years prior to presentation for a congenital abnormality was admitted for a suspected systemic fungal infection. The patient inadvertently received intravenous amphotericin B deoxycholate 250 mg (4.3 mg/kg) over 2 hours instead of prescribed liposomal amphotericin B. The medication error was discovered 16 hours after administration. She had normal vital signs at that time and reported abdominal pain and general malaise. Results of a metabolic panel were significant for a creatinine level of 2.1 mg/dL and CO2 of 17 mg/dL. Her serum amphotericin B concentration 33 hours after the initial dose was 4.9 MUg/mL. She subsequently received 5 courses of plasmapheresis and 3 courses of hemodialysis and ultimately did not develop any further renal injury, as well as hemolysis, cardiovascular collapse, dysrhythmias, or severe electrolyte abnormalities. DISCUSSION: The dosing differences between nonliposomal and liposomal preparations of amphotericin B can be as high as 50-fold. Reported adverse events from overdose in both animal models and human case reports include renal insufficiency, hemolysis, thrombocytopenia, electrolyte abnormality, and cardiac dysrhythmias. There have been previous reports of similar errors that have led to death. Furthermore, amphotericin B has been shown to be poorly dialyzable. Our patient's serum amphotericin B concentration decreased after she received plasmapheresis, and she did not develop severe complications. CONCLUSIONS: We describe a patient who survived a 4-fold overdose of amphotericin B because of a medication error. The use of plasmapheresis may have enhanced the elimination of amphotericin B and may have contributed to the positive outcome. However, the role of plasmapheresis in amphotericin overdose is not fully understood. PMID- 23362041 TI - Foodborne botulism treated with heptavalent botulism antitoxin. AB - OBJECTIVE: To report a case of foodborne botulism and subsequent use of the investigational heptavalent botulism antitoxin (H-BAT). CASE SUMMARY: A 60-year old man was hospitalized with blurred vision, diplopia, and dysarthria. On hospital day 2, the patient was transferred to the intensive care unit for progressive fatigable weakness with ptosis, dysphagia, dysarthria, and nausea. Secondary to worsening respiratory distress, the patient was intubated and placed on a ventilator. The patient could open his eyes only with assistance but still had normal strength in all extremities. H-BAT was administered 48 hours after presentation for possible botulism. The patient then revealed that he consumed home-canned corn several days prior to admission. On hospital day 8, botulinum neurotoxin was confirmed in the patient's serum and the home-canned corn. The patient slowly regained muscle strength and was discharged to a long-term acute care facility on hospital day 22. DISCUSSION: Foodborne botulism is caused by a neurotoxin from Clostridium botulinum and usually occurs after the consumption of improperly prepared home-canned food. Botulism is characterized by symmetrical descending paralysis that may progress to respiratory arrest. The standard confirmatory test for botulism is a mouse bioassay to prove the presence of botulinum neurotoxin. Outside of supportive care, the treatment options for botulism are limited. Individuals with botulism often require intensive care unit monitoring and potentially ventilatory support. H-BAT, the only treatment available for botulism in patients older than 1 year, is a purified and despeciated equine-derived immunoglobulin active against all known botulinum neurotoxins. H-BAT's despeciation significantly reduces the risk of hypersensitivity reactions, anaphylaxis, and serum sickness. CONCLUSIONS: In a confirmed case of foodborne botulism treated with H-BAT, the patient tolerated H BAT and did not develop any hypersensitivity reactions or serum sickness. PMID- 23362043 TI - Delineating breast cancer cell interactions with engineered bone microenvironments. AB - The mechanisms leading to colonization of metastatic breast cancer cells (BCa) in the skeleton are still not fully understood. Here, we demonstrate that mineralized extracellular matrices secreted by primary human osteoblasts (hOBM) modulate cellular processes associated with BCa colonization of bone. A panel of four BCa cell lines of different bone-metastatic potential (T47D, SUM1315, MDA-MB 231, and the bone-seeking subline MDA-MB-231BO) was cultured on hOBM. After 3 days, the metastatic BCa cells had undergone morphological changes on hOBM and were aligned along the hOBM's collagen type I fibrils that were decorated with bone-specific proteins. In contrast, nonmetastatic BCa cells showed a random orientation on hOBM. Atomic force microscopy-based single-cell force spectroscopy revealed that the metastatic cell lines adhered more strongly to hOBM compared with nonmetastatic cells. Function-blocking experiments indicated that beta1 integrins mediated cell adhesion to hOBM. In addition, metastatic BCa cells migrated directionally and invaded hOBM, which was accompanied by enhanced MMP-2 and -9 secretion. Furthermore, we observed gene expression changes associated with osteomimickry in BCa cultured on hOBM. As such, osteopontin mRNA levels were significantly increased in SUM1315 and MDA-MB-231BO cells in a beta1 -integrin dependent manner after growing for 3 days on hOBM compared with tissue culture plastic. In conclusion, our results show that extracellular matrices derived from human osteoblasts represent a powerful experimental platform to dissect mechanisms underlying critical steps in the development of bone metastases. PMID- 23362044 TI - Ultrastructural characterization of surface-induced platelet activation on artificial materials by transmission electron microscopy. AB - Platelet adhesion is one of the most pivotal events of blood clotting for artificial surfaces. However, the mechanisms of surface-induced platelet activation have not been fully been elucidated or visualized so far. In this study, we attempted to observe the internal structures and adhesion interfaces of human platelets attached to artificial surfaces by transmission electron microscopy (TEM) during the platelet activation process. We prepared observation samples by a conventional embedding method using EPON 812 resin. The sectioning was sliced perpendicular to the a-platelet/material interface. Observation by TEM indicates that internal granules coalesce in the center of the platelet accompanied by pseudopodial growth in the early stage of platelet activation. Pseudopodia from a platelet attach to the material interface not along a plane but at a point. In addition, along with the process of platelet activation, the gap between the platelet membrane and the material surface at the interface disappeared and a-platelet/material adhesion became much tighter. In the fully activated platelet stage, the platelet becomes thinner and tightly adheres to the substrate. As a result of comparative observation of an adherent platelet on polycarbonate (PC) and on amorphous carbon (a-C:H), it was found that internal granules release was inhibited more remarkably on a-C:H coating rather than on PC. Despite numerous technical difficulties in preparing sectional samples, such a study might prove the essential mechanism of biomaterial-related thrombosis, and it might become possible to modify the surfaces of materials to minimize material-related thrombosis. PMID- 23362046 TI - Flexibility and reactivity in promiscuous enzymes. AB - Best of both worlds: The interplay of active site reactivity and the dynamic character of proteins allows enzymes to be promiscuous and--sometimes--remarkably efficient at the same time. This review analyses the roles structural flexibility and chemical reactivity play in the catalytic mechanism of selected enzymes. PMID- 23362045 TI - Intakes of vitamin C and carotenoids and risk of amyotrophic lateral sclerosis: pooled results from 5 cohort studies. AB - OBJECTIVE: Prior research has suggested the possible role of oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS). Prospective data examining dietary antioxidants such carotenoids and vitamin C are limited. METHODS: Risk of ALS associated with carotenoid and vitamin C intake was investigated in 5 prospective cohorts: the National Institutes of Health Association of American Retired Persons Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort, the Health Professionals Follow-up Study (HPFS), and the Nurses Health Study (NHS). ALS deaths were documented using the National Death Index, and confirmed nonfatal ALS cases were included from HPFS and NHS. A total of 1,153 ALS deaths occurred among 1,100,910 participants (562,942 men; 537,968 women). Participants were categorized into cohort-specific quintiles of intake for dietary variables. We applied Cox proportional hazards regression to calculate cohort-specific risk ratios (RRs), and pooled results using random-effects methods. RESULTS: A greater total major carotenoids intake was associated with a reduced risk of ALS (pooled, multivariate-adjusted RR for the highest to the lowest quintile = 0.75, 95% confidence interval [CI] = 0.61-0.91, p for trend = 0.004). Individually, higher dietary intakes of beta-carotene and lutein were inversely associated with ALS risk. The pooled multivariate RRs comparing the highest to the lowest quintile for beta-carotene and lutein were 0.85 (95% CI = 0.64-1.13, p for trend = 0.03) and 0.79 (95% CI = 0.64-0.96, p for trend = 0.01), respectively. Lycopene, beta cryptoxanthin, and vitamin C were not associated with reduced risk of ALS. INTERPRETATION: Consumption of foods high in carotenoids may help prevent or delay onset of ALS. PMID- 23362047 TI - Comparative analysis of two members of the metal ion-containing group III-alcohol dehydrogenases from Dickeya zeae. AB - PURPOSE OF WORK: A pair of NAD(+)- and NADP(+)-dependent group III-alcohol dehydrogenases was characterized from the enterobacterium, Dickeya zeae, to expand our understanding of the distribution and biochemical properties of this interesting group of enzymes. Two putative group III-alcohol dehydrogenases (ADHs) were identified in the genome of Dickeya zeae. Amino acid alignments and phylogenetic analysis revealed that Adh3.1 and Adh3.2 are only distantly related (~25 % identity at the protein level). Both proteins were purified to homogeneity after heterologous expression in E. coli. A specific activity of 1.8 U/mg was measured for the NAD(+)-dependent enzyme Adh3.1 with ethanol used as substrate, while NADPH-dependent Adh3.2 preferred butanal (29.1 U/mg) as substrate. Maximum activity for Adh3.1 was at 50 degrees C and pH 10 and for Adh3.2 at 70 degrees C and pH 6. Cell viability assays were used to confirm activity towards butanal and glyoxals. Biochemical characterization and phylogenetic analyses led to the hypothesis that Adh3.1 and Adh3.2 are probably the result of an ancient gene duplication event followed by functional diversification. PMID- 23362048 TI - Synthetic methods for preparing ionic liquids containing hypophosphite and carbon extended dicyanamide anions. PMID- 23362049 TI - Loss of cell-extracellular matrix interaction triggers retinal regeneration accompanied by Rax and Pax6 activation. AB - The whole retina regenerates from retinal pigmented epithelial (RPE) cells by transdifferentiation in the adult newt and Xenopus laevis when it is surgically removed. We produced a transgenic animal line, in which EGFP expression is under the control of Rax pomotor. Using F1 and F2 generations, we analyzed Rax-EGFP expression during retinal regeneration in a tissue culture model. In the culture, 4 zones were distinguished as RPE cells migrating outwards from the periphery of the explant: the explant zone, epithelial zone, transition zone and differentiation zone. Expression of transcription factors such as Pax6 and Rax EGFP was observed in different zones. Rax-EGFP expression preceded Pax6 expression, and the expression of both genes occurred in RPE cells that had lost contact with the basement membrane facing the choroid. We have developed a new culture method in which RPE tissues are embedded in Matrigel. This method has many advantages over the previous gel-overlay method to reproduce construction of 3D-retinal structures and clearly showed that RPE cells need to be detached from the choroid before entering the regeneration pathway. The present results indicate that the temporal changes in cell-cell and cell-extracellular matrix interactions regulate transdifferentiation. PMID- 23362050 TI - Seed-mediated synthesis of single-crystal gold nanospheres with controlled diameters in the range 5-30 nm and their self-assembly upon dilution. AB - Single-crystal gold nanospheres with controlled diameters in the range 5-30 nm were synthesized by using a facile approach that was based on successive seed mediated growth. The key to the success of this synthesis was the use of hexadecyltrimethylammonium chloride (CTAC) as a capping agent and a large excess of ascorbic acid as a reductant to ensure fast reduction and, thus, single crystallinity and a spherical shape of the resultant nanoparticles. The diameters of the gold nanospheres could be readily controlled by varying the amount of seeds that were introduced into the reaction system. The gold nanospheres could be produced with uniform diameters of up to 30 nm; thus, their localized surface plasmon resonance properties could be directly compared with the results that were obtained from theoretical calculations. Interestingly, we also found that these gold nanospheres self-assembled into dimers, larger aggregates, and wavy nanowires when they were collected by centrifugation, dispersed in deionized water, and then diluted to different volumes with deionized water. PMID- 23362051 TI - Biparietal diameter at 11-13 weeks' gestation in fetuses with open spina bifida. AB - OBJECTIVE: To ascertain the reported association between reduced biparietal diameter (BPD) at 11-13 weeks' gestation and open spina bifida and to investigate its predictive value in a single-center study. METHODS: This was a retrospective study of fetuses in which BPD was measured at 11-13 weeks' gestation, including 27 fetuses with isolated open spina bifida subsequently diagnosed at 16-24 weeks and 7775 unaffected controls. BPD values were converted into multiples of the expected median (MoM) after adjustment for crown-rump length and maternal characteristics. Multivariable logistic regression analysis was used to determine the maternal characteristics significantly associated with spina bifida. The performance of screening was determined by receiver-operating characteristics curve analysis. BPD values at 11-13 weeks' gestation were compared with those measured in the second trimester using Z-scores. RESULTS: BPD values at 11-13 weeks' gestation were below the 5(th) centile in 44.4% of cases of open spina bifida. In these fetuses, the median BPD MoM value was significantly smaller than that in the control group (0.930 vs 0.998 MoM; P < 0.0001). Multivariable logistic regression analysis showed a significant contribution from maternal age (P = 0.008) and BMI (P = 0.028) to the association between BPD MoM and spina bifida. The detection rate using BPD measurements in the first trimester was 55.6% with a false-positive rate of 11.6%. In fetuses with open spina bifida, the BPD Z-scores were significantly lower at 16-24 weeks compared to those recorded at 11-13 weeks (median, -1.71 (range, -3.98 to -0.20) vs -1.30 (-3.75 to 2.61); P = 0.006). CONCLUSION: Fetuses with open spina bifida have a smaller BPD in the first trimester. This observation may be useful in early screening. It is likely that a combination of maternal characteristics such as age and BMI, fetal BPD and maternal serum alpha-fetoprotein measured in the first trimester would provide a clinically useful screening test for open spina bifida. PMID- 23362052 TI - One molecule, two atoms, three views, four bonds? PMID- 23362053 TI - Transverse cervical nerve: implications for dental anesthesia. AB - The inferior alveolar nerve block (IANB) has the highest failure incidence of any dental anesthetic technique. Many authors have outlined potential reasons for these failures in permanent lower molars, including accessory innervations from the mylohyoid and mental foramen. However, the potential accessory innervation of posterior mandibular teeth from the transverse cervical nerve (TCN), a branch of ventral rami from the C2-C3 spinal nerves from the cervical plexus (CP), has been difficult to assess as a result of the small size and thickness of the mandibular accessory foramina and nerve branches, as well as due to the dissection technique performed. The goal of this study was to identify and trace the CP branches from fresh human cadaver tissue samples using the Sihler's technique. Two fresh human cadaver samples were used. Samples were fixed in neutralized formalin, macerated in potassium hydroxide, decalcified in acetic acid, stained in Ehrlich's hematoxylin, destained in acetic acid, and cleared in glycerin. Both specimens skin was dissected. The Sihler's technique delineated all nerves three dimensionally and helped to disclose structures of small size and thickness. The TCN from the CP, stained in blue, innervated the posterior mandible in one of the two samples. These results confirmed that the CP may supply accessory innervation to the inferior border of the posterior mandible through the TCN. These findings illustrate variations of anatomy that may account for IANB failures in posterior mandibular teeth and allows for clinical decisions for implementing supplemental anesthetic techniques. PMID- 23362054 TI - Maternal smoking during pregnancy and childhood overweight and fat distribution: the KOALA Birth Cohort Study. AB - What is already known about this subject There is an association between maternal smoking during pregnancy and higher body mass index (BMI) and overweight in childhood. What this study adds The association between maternal smoking during pregnancy and childhood overweight develops with age, starting with a lower birth weight, followed by weight catch-up in the first year after birth, finally leading to overweight at school age. Children of mothers who had smoked during pregnancy had a higher risk of exceeding the 85th percentile of BMI, waist circumference and total skinfold thickness at school age. BACKGROUND: Maternal smoking during pregnancy is associated with childhood overweight, but the association with fat distribution is not clear. OBJECTIVE: To explore the longitudinal association between smoking during pregnancy and childhood overweight and fat distribution. METHODS: In the KOALA Birth Cohort Study, repeated questionnaires were administered to 2698 mother-child pairs, including questions on smoking at 14 and 34 weeks of pregnancy. Main outcomes were birth weight, weight gain in the first year, body mass index (BMI) z-scores and overweight (BMI >=85th percentile) at 1, 2, 4-5 and 6-7 years (n = 1730) and waist circumference and four skinfold thicknesses measured at home visits at age 6-7 years in a subgroup (n = 418). We used multivariable linear and logistic regression, with generalized estimating equations (GEE) for repeated measurements. RESULTS: Maternal smoking was associated with lower birth weight, higher weight gain in the first year and increasing overweight after infancy (change with age P = 0.02 in the GEE). Maternal smoking vs. non-smoking during pregnancy was associated with a higher risk of the child exceeding the 85th percentile of BMI (adjusted odds ratio [aOR] 3.72; 95% CI 1.33-10.4), waist circumference (aOR 2.65; 95% CI 1.06-6.59) and sum of skinfold thicknesses (aOR 4.45; 95% CI 1.63-12.2) at the age of 6-7 years. CONCLUSIONS: Maternal smoking during pregnancy is associated with lower birth weight, weight catch-up and development of overweight into childhood. PMID- 23362056 TI - Symptomatic cholecystolithiasis after cholecystectomy. AB - A 43-year-old woman was admitted to the gastroenterology department with colicky pain in the upper abdomen. Four years earlier, she had undergone a laparoscopic cholecystectomy because of cholecystitis. She recognised her current complaints from that previous episode. An endoscopic retrograde cholangiopancreatography showed a cavity with a diameter of 2 cm which contained multiple concrements near the liver hilus. An elective surgical exploration was performed. Near the clip of the previous cholecystectomy a bulging of the biliary tract with its own duct was visualised and resected. Histological examination of this "neo" gallbladder showed that the bulging was consistent with the formation of a reservoir secondary to bile leakage, probably caused by a small peroperative lesion of the common bile duct during the previous cholecystectomy. In conclusion, our patient presented with colicky pain caused by concrements inside a 'neo' gallbladder. PMID- 23362057 TI - Rare vascular perforation complicating radial approach to percutaneous coronary angioplasty. AB - A transradial arterial approach to coronary angiography and percutaneous coronary intervention has become increasingly embraced by cardiologists as it is associated with decreased vascular complications and allows early mobilisation of patients when compared with transfemoral arterial access. Major vascular complication post-transradial access is uncommon. We describe a very rare case of perforation of the costocervical trunk (a branch of the right subclavian artery at the site of the thoracic inlet) presenting shortly after percutaneous transradial coronary intervention. The resulting rapidly expanding cervical haematoma caused airway compromise necessitating emergent intubation in the catheter laboratory recovery area. Transfemoral catheter coil embolisation of the feeder artery was successful in obliterating blood flow to the perforated vessel with eventual resolution of the neck haematoma. PMID- 23362058 TI - Berardinelli-Seip syndrome: highlight of treatment challenge. AB - Berardinelli-Seip congenital lipodystrophy (BSCL) syndrome is a rare autosomal recessive disease characterised by lipoatrophy and associated with deregulations of glycidic and lipid metabolism. We report three BSCL cases with its typical clinical picture and complications. Clinically, they all show marked atrophy of adipose tissue, acromegaly, acanthosis nigricans and tall stature. Two cases present attention deficit hyperactivity and developmental learning disorders; another patient has hypertrophic myocardiopathy and polycystic ovary syndrome. In all the cases AGPAT2 was the identified mutation. All the cases present hypertriglyceridemia. One case has developed hyperinsulinism controlled with metformin and another case already has type 2 diabetes with a difficult clinical control. There is no curative treatment and the current treatment options are based only on symptomatic control of the complications. Recently, published studies showed that leptin-replacement therapy appears a promising tool in the metabolic correction of BSCL complications, highlighting the importance of further investigations in BSCL treatment. PMID- 23362059 TI - Metastatic adenocarcinoma of the colon in a 21-year-old African-American woman. PMID- 23362060 TI - Platypnea orthodeoxia: a 'laid-back' case of dyspnoea. AB - A man with end-stage liver disease who presented with shortness of breath. He exhibited clinical platypnea (worsening shortness of breath on sitting up) and orthodeoxia (oxygen desaturation on sitting up). Follow-up investigations led to the diagnosis of hepatopulmonary syndrome. PMID- 23362061 TI - Sequelae of dental trauma: the malformed tooth. AB - Here, we report a case of 10-year-old boy who came with a complaint of missing upper front teeth and was also concerned about his aesthetics. Significant history of trauma was present in his toddler period. Diagnosis of malformed upper right central incisor (11) by radiological investigations was carried out. Surgery was performed and there was removal of the impacted malformed upper right central incisor (11). Healing was uneventful. The patient is under follow-up for aesthetic rehabilitation to be carried out. PMID- 23362062 TI - Is endovascular therapy the right choice for treatment of functional compression of anomalous right coronary artery arising from left coronary sinus with interarterial course? AB - We report a case of successful percutaneous coronary intervention (PCI) for reversible ischaemia owing to an anomalous right coronary artery arising from the left coronary sinus with malignant interarterial course and not associated with obstructive coronary artery disease (CAD). PCI for treatment of functional compression of the ostioproximal intramural segment of the anomalous vessel, though described in the literature, is technically challenging, requiring appropriate hardware selection; the peculiar anatomical milieu, in the absence of atherosclerotic CAD, lends itself to an uncertain long-term outcome following endovascular therapy with stenting. PMID- 23362063 TI - A previously unreported serious adverse event during balloon sinuplasty. AB - Balloon sinuplasty is considered as a minimally invasive procedure for the treatment of chronic rhinosinusitis. In this case report we describe how a patient undergoing balloon sinuplasty sustained an intraoperative cardiac arrest with no cardiac history. Postoperative investigations were all normal. The patient was discharged on the first postoperative day and further outpatient tests were normal. We postulate that this event occurred due to profound vagal stimulation either on instrumentation of the maxillary mucosa or when the orbit was accidently breached during instrumentation of the right frontal recess. The authors conclude that balloon sinuplasty, despite being minimally invasive surgery, should be performed under the supervision of an anaesthesiologist with the ability of cardiac monitoring and immediate treatment because of possible arrhythmias. PMID- 23362064 TI - Intraoral lipoma: a rare clinical entity. AB - Lipoma is a painless soft tissue tumour of the mesenchymal origin, which is slow growing and well circumscribed. The occurrence of lipoma is rare in the oral cavity (1-4%); however, the frequency is much higher in the head and neck region. The tumour is mostly present in the buccal mucosa, lips, tongue, palate, buccal sulcus and floor of the mouth. Sometimes the tumour becomes large enough to cause difficulty in speech and mastication. Histologically, lipoma is composed of mature fat cells, surrounded by normal fat. We present two cases of intraoral lipoma in two female patients. PMID- 23362065 TI - Therapeutic dilemma in a case of acute coronary syndrome (ACS). AB - An adult male labourer, a smoker and alcoholic was admitted to our hospital with a short history of fever, myalgia, breathlessness and oliguria. On examination he was icteric and hypotensive. Calf muscle tenderness was present. A provisional diagnosis of leptospirosis was made and he was started on treatment with crystalline penicillin. Blood pressure (BP) did not improve with fluids. Inotropes were started. The patient was taken for Slow Low Efficiency Daily Dialysis (SLEDD) during which he developed chest pain. ECG showed an anterolateral myocardial infarction (MI). He also complained of breathlessness and haemoptysis. Antiplatelets were withheld in view of thrombocytopaenia and haemoptysis; heparin could not be given because of the deranged coagulation parameters. The patient was managed symptomatically with nitrates. After the BP improved SLEDD was restarted. On day 3 of admission the patient became tachypnoeic and hypoxic, bilateral coarse crackles were present on auscultation. He was intubated and mechanically ventilated. Suctioning of endotracheal tube revealed fresh blood, and chest CT revealed alveolar haemorrhage. In spite of aggressive resuscitative measures, mechanical ventilation and antibiotics, the patient expired on the 12th day following admission. PMID- 23362066 TI - Infective endocarditis developing serious multiple complications. AB - A 20-year-old female patient with no history of heart disease presented to the hospital with high fever, cough and sputum. On the third day of hospitalisation, left facial paralysis developed and cranial revealed an infarct in the right frontoparietotemporal lobe. Transthoracic echocardiography revealed 1.5 * 2 cm sized vegetation on the mitral valve and severe mitral regurgitation. On the 11th day of hospitalisation, multiple emboli were shown to be present in the left iliac artery. Since the patient had recurrent septic emboli despite 3 weeks of treatment, a surgical intervention was planned. The vegetation was removed and the mitral valve was replaced by mechanical prostheses. During the postoperative period, acute renal failure developed in the patient. The treatment was completed in 6 weeks with full recovery. This case confirms that infective endocarditis may present with various clinical situations, and that a high index of suspicion and surgical intervention, in addition to aggressive antibiotic therapy, is lifesaving. PMID- 23362067 TI - Cardiac tumour masquerades as mid-life (menopause) event. AB - Atrial myxomas are the most common primary cardiac tumours encountered. Their detection may be incidental, owing to embolic events, intracardiac obstructive features or in some cases, non-specific constitutional symptoms. We describe a middle-aged woman attributing constitutional symptoms to menopause, but later determined to be due to an atrial myxoma. PMID- 23362068 TI - Stroke due to typical thrombotic thrombocytopenic purpura treated successfully with intravenous thrombolysis and therapeutic plasma exchange. AB - We report a case of a 39-year-old man with expressive aphasia due to occlusion of the temporal stem of the left middle cerebral artery. Laboratory tests showed microangiopathic haemolytic anaemia and thrombocytopenia. A thrombotic thrombocytopenic purpura (TTP) was diagnosed, and thrombolytic therapy (TT) with alteplase followed by therapeutic plasma exchange (TPE) were performed with complete resolution of symptoms. The gold standard TTP treatment is TPE, and its delay can be lethal. The use of TT in TTP is controversial and has potential risks. This case shows a successful TT in a patient with typical TTP presenting as a stroke due to a large cerebral artery occlusion. PMID- 23362070 TI - SIADH and partial hypopituitarism in a patient with intravascular large B-cell lymphoma: a rare cause of a common presentation. AB - Hyponatraemia is a very common electrolyte abnormality with varied presenting features depending on the underlying cause. The authors report the case of a 75 year-old, previously fit, gentleman who presented with weight loss, lethargy and blackouts. He required four admissions to the hospital over an 8-month period. Investigations revealed persistent hyponatraemia consistent with a diagnosis of syndrome of inappropriate antidiuretic hormone secretion, macrocytic anaemia and partial hypopituitarism. Unfortunately, all other investigations that were performed failed to identify the underlying cause and a diagnosis of intravascular large B-cell lymphoma was only confirmed following postmortem studies. The authors recommend that endocrinologists should be involved at the outset in the management of patients with persistent hyponatraemia and that intravascular large B-cell lymphoma should be considered in the differential diagnosis of hyponatraemia. PMID- 23362071 TI - Complications of facial fillers: resource implications for NHS hospitals. AB - Facial rejuvenation seeks to reverse the negative sequelae of multiple factors but most importantly of genetic predisposition, sun damage and smoking. With the advent of the so-called 'non-surgical' techniques, and perhaps fuelled by these austere times, volumetric facial augmentation using dermal fillers has soared in popularity among both patients and practitioners. However, legislation has yet to keep pace with the change in clinical practices leaving patients poorly informed and with no protection against unscrupulous suppliers and unregulated practitioners. When things go wrong, patients often turn to the National Health Service (NHS) to rectify both the acute and chronic sequelae resulting in potentially difficult ethical and resource implications. Here, we report one of an increasing number of cases presenting to our NHS craniofacial service with acute filler-related complications. PMID- 23362072 TI - Running biomechanics in a long-term monitored recreational athlete with a history of Achilles tendon rupture. AB - This study represented a unique opportunity to understand changes in the human motion biomechanics during basic locomotion within a time interval of 4 years, when the monitored individual regained his original aerobic fitness, running performance and body mass index as prior to the injury. The participant visited the laboratory a month prior to the injury and during 4 years after the surgery. The surgery, subsequent rehabilitation and a 4-year running training programme in the studied recreational athlete did not completely eliminate the consequences of the Achilles tendon rupture. The function muscle deficit is namely manifested by a lower net plantar flexion moment and a lower net-generated ankle joint power during the take-off in the stance phase. The greater dorsal flexion in the affected ankle joint at the first contact with the ground and consequently higher peaks of ground reaction forces during running are consequences of the longer Achilles tendon in the affected lower extremity and weakened calf muscles. PMID- 23362073 TI - Warfarin-induced skin necrosis diagnosed on clinical grounds and treated with maggot debridement therapy. AB - A patient with a history of deep vein thrombosis presented with painful bruising and blistering on his left leg 7-10 days after warfarin treatment. A complicated 2-month treatment followed, where vasculitis was originally diagnosed from histological findings before the final diagnosis of warfarin-induced skin necrosis (WISN) was made on clinical grounds. Warfarin was stopped, reversed and low molecular weight heparin started but, the lesions had progressed to full thickness necrosis. This was originally treated with conventional surgical debridement before introducing maggot debridement therapy (MDT) in an effort to try to salvage the limb. PMID- 23362074 TI - Penicillium marneffei presenting as an immune reconstitution inflammatory syndrome (IRIS) in a patient with advanced HIV. AB - A 62-year-old British man with advanced HIV was established on antiretroviral therapy and treatment for disseminated Mycobacterium avium complex and Cytomegalovirus infections. One month later he re-presented with epigastric pain, an epigastric mass and skin lesions. Abdominal imaging revealed large volume lymphadenopathy, which was not present on previous imaging. Blood cultures yielded Penicillium marneffei, a dimorphic fungus endemic to South-east Asia. The patient had spent several years travelling in Thailand prior to the diagnosis of HIV. Penicilliosis is a common AIDS-defining illness in endemic areas, but remains rare in Europe. In this case, it presented in the context of a rapidly decreasing viral load as an immune reconstitution inflammatory syndrome. The challenges of management in the context of multiple comorbidities and polypharmacy are discussed. PMID- 23362075 TI - Peanut aspiration leading to pneumorrhachis in a pre-schooler. PMID- 23362076 TI - Poststroke apathy. PMID- 23362077 TI - Histological features of carotid plaque in patients with ocular ischemia versus cerebral events. AB - BACKGROUND AND PURPOSE: Patients with carotid artery stenosis and ocular ischemic events have a much lower risk of future ipsilateral ischemic stroke on medical treatment and lower procedural risks for endarterectomy and stenting than patients with cerebral ischemic events, and are closer in risk to patients with asymptomatic stenosis. The reasons for this difference in prognosis are not fully understood, but may reflect differences in carotid plaque pathology. METHODS: In consecutive patients undergoing carotid endarterectomy for recently symptomatic stenosis (Oxford Plaque Study, Athero-Express Study), we compared carotid plaque histology (using validated semiquantitative scales) in those who had cerebral events within the last 6 months (n=1317) versus those with ocular events only (n=323). RESULTS: Compared with plaques from patients with ocular events only, those from patients with cerebral events had significantly more large lipid core (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.05-1.82; P=0.02), inflammation (OR, 1.32; 95% CI, 1.02-1.72; P=0.04) and overall plaque instability (OR, 1.37; 95% CI, 1.05-1.80; P=0.02), and less fibrous content (OR, 0.71; 95% CI, 0.54-0.92; P=0.01), and calcification (OR, 0.70; 95% CI, 0.54-0.91; P=0.008). The overall number of histological features known to be associated with vulnerable plaque was greater in patients with cerebral events than in those with ocular events (P=0.002). CONCLUSIONS: Carotid plaques from patients undergoing endarterectomy for previous ocular ischemic events have fewer vulnerable plaque features than those from patients with recent cerebral ischemic events, possibly explaining some of the differences in risk of stroke between these groups. PMID- 23362078 TI - Short-term dose-response characteristics of 2-iminobiotin immediately postinsult in the neonatal piglet after hypoxia-ischemia. AB - BACKGROUND AND PURPOSE: To determine the optimal dose of 2-iminobiotin (2-IB) for the treatment of moderate to severe asphyxia in a neonatal piglet model of hypoxia-ischemia. METHODS: Newborn piglets were subjected to a 30-minute hypoxia ischemia insult and randomly treated with vehicle or 2-IB (0.1 mg/kg, 0.2 mg/kg, or 1.0 mg/kg). aEEG background and seizure activity were scored after hypoxia ischemia every 4 h until 24 h and at 48 h and neurobehavioral scores were obtained. Brain tissue was collected and processed for analysis of caspase-3 activity, histology, and tyrosine nitration. RESULTS: A dose range of 0.1 to 1.0 mg/kg/dose of 2-IB improved short-term outcome as demonstrated by an increased survival with a normal aEEG and decreased nitrotyrosine staining in the 2-IB treated animals, indicating decreased cellular damage. Neurobehavior, caspase-3 activity in thalamus, and histology scores were not significantly different. CONCLUSIONS: Based on survival with a normal aEEG, 0.2 mg/kg 2-IB is likely to be the most appropriate dose for use in future clinical trials in neonates with perinatal hypoxia-ischemia. PMID- 23362079 TI - G protein-coupled estrogen receptor agonist improves cerebral microvascular function after hypoxia/reoxygenation injury in male and female rats. AB - BACKGROUND AND PURPOSE: Reduced risk and severity of stroke in adult females are thought to depend on normal levels of endogenous estrogen, which is a known neuro and vasoprotective agent in experimental cerebral ischemia. Recently, a novel G protein-coupled estrogen receptor (GPER, formerly GPR30) has been identified and may mediate the vasomotor and -protective effects of estrogen. However, the signaling mechanisms associated with GPER in the cerebral microcirculation remain unclear. We investigated the mechanism of GPER-mediated vasoreactivity and also its vasoprotective effect after hypoxia/reoxygenation (H/RO) injury. METHODS: Rat cerebral penetrating arterioles from both sexes were isolated, cannulated, and pressurized. Vessel diameters were recorded by computer-aided videomicroscopy. To investigate vasomotor mechanism of the GPER agonist (G-1), several inhibitors with or without endothelial impairment were tested. Ischemia/reperfusion injury was simulated using H/RO. Vasomotor responses to adenosine triphophate after H/RO were measured with or without G-1 and compared with controls. RESULTS: G-1 produced a vasodilatory response, which was partially dependent on endothelium derived nitric oxide (NO) but not arachidonic acid cascades and endothelial hyperpolarization factor. Attenuation of G-1-vasodilation by the NO synthase inhibitor and endothelium-impairment were greater in vessels from female than male animals. G-1 treatment after H/RO injury fully restored arteriolar dilation to adenosine triphophate compared with controls. CONCLUSIONS: GPER agonist elicited dilation, which was partially caused by endothelial NO pathway and induced by direct relaxation of smooth muscle cells. Further, GPER agonist restored vessel function of arterioles after H/RO injury and may play an important role in the ability of estrogen to protect the cerebrovasculature against ischemia/reperfusion injury. PMID- 23362080 TI - Association of parental stroke with brain injury and cognitive measures in offspring: the Framingham Heart Study. AB - BACKGROUND AND PURPOSE: Parental stroke has been related to an increased risk of stroke in the offspring. This study examines whether parental stroke is also associated with increased vascular brain injury and poorer cognitive performance among offspring free of clinical stroke. METHODS: Multivariable regression analyses were used to relate parental stroke to cross-sectional and change in brain magnetic resonance imaging measures and cognitive function among the offspring, with and without adjustment for vascular risk factors. RESULTS: Stroke and dementia-free Framingham Offspring (n=1297, age, 61+/-9 years, 54% women) were studied. Parental stroke by age 65 years was associated with a higher baseline white matter hyperintensity volume (beta=0.17+/-0.08; P=0.027) and with lower visual memory performance (beta= -0.80+/-0.34; P=0.017). During a 6-year follow-up, parental stroke was also associated with increase in white matter hyperintensity volume (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.03 3.38) and decline in executive function (Trails B-A; OR, 1.81; 95% CI, 1.06 3.09). The associations with white matter hyperintensity volume and visual memory attenuated after additional adjustment for concomitant vascular risk factors. CONCLUSIONS: Parental stroke by age 65 years is associated with increased vascular brain injury and lower memory in offspring equivalent to 3 and 7 years of brain aging, respectively. This may be partly attributed to inheritance of vascular risk factors. PMID- 23362081 TI - Intra-arterial cell transplantation provides timing-dependent cell distribution and functional recovery after stroke. AB - BACKGROUND AND PURPOSE: Intra-arterial cell transplantation offers a novel therapeutic strategy for stroke; however, it remains unclear how the timing of cell administration affects cell distribution, brain repair processes, and functional recovery. Here, we investigate the hypothesis that the timing of cell transplantation changes the behavior of the cell graft and the host environment in a way that affects functional recovery. METHODS: Rats received human mesenchymal stem cells via the internal carotid artery at 1, 4, or 7 days (D1, D4, or D7) after middle cerebral artery occlusion and reperfusion. Animals were euthanized at various time points to assess cell distribution, infiltration of activated microglia, expression of brain-derived neurotrophic factor, reactive astrocytes, angiogenesis, and functional recovery. RESULTS: Human mesenchymal stem cells were widely distributed both in the peri-infarct and core in D1, and dominantly in the peri-infarct in D4. Very few cells were observed on D7. At day 7 poststroke, microglia activation was significantly suppressed in both the peri infarct and core in D1, and predominantly in the peri-infarct in D4. At day 21 poststroke, brain-derived neurotrophic factor was widely distributed throughout the peri-infarct in D1 and D4, along with many reactive astrocytes and considerable angiogenesis. Motor function improved earlier in D1 and later in D4, but no recovery was obtained in D7. CONCLUSIONS: Our results indicate that intra arterial cell transplantation provides timing-dependent cell distribution and poststroke functional recovery via a combination of neuroprotection, reactive astrocyte enhancement, and angiogenesis. PMID- 23362082 TI - Chronic apraxia of speech and Broca's area. AB - BACKGROUND AND PURPOSE: Apraxia of speech (AOS) is an impairment of motor planning and programming of speech articulation and is often considered an important stroke syndrome, localizable to Broca's area. However, an influential study raised doubts on this localization and reported that AOS is attributable to lesions of the anterior insula, based on an association between chronic AOS and anterior insula lesions. We hypothesized that chronic AOS is associated with large lesions (which include the insula) or lesions to Broca's area. Method- We tested 34 participants with chronic left supratentorial stroke on an AOS battery and obtained concurrent magnetic resonance imaging. We evaluated associations between AOS and locations and volume of infarct. RESULTS: The presence of chronic AOS (n=17) was associated with volume of infarct, but was also associated with infarct in Broca's area (and several other regions, but not anterior insula) in both volume- and age-adjusted linear regression and the dichotomous analysis. Carotid dissection was more common, and cardioembolism less common, as a cause of stroke in patients with AOS compared with those without. Severity of AOS was also strongly associated with lesion volume. CONCLUSIONS: Persistence of AOS after 12 months is associated with large left hemispheric stroke and strokes that involve Broca's area or other relatively anterior areas to which it is structurally or functionally connected. Patients with such lesions may benefit from early training in the use of technologies to support speech production and communication. PMID- 23362083 TI - Selective serotonin reuptake inhibitors for stroke recovery: a systematic review and meta-analysis. PMID- 23362084 TI - European Stroke Organisation recommendations to establish a stroke unit and stroke center. PMID- 23362086 TI - Effects of institutional caseload of subarachnoid hemorrhage on mortality: a secondary analysis of administrative data. AB - BACKGROUND AND PURPOSE: Procedures requiring specific skill sets often have been shown to depend on institutional volume, that is, centers receiving a higher volume observe better outcomes in those patients. This relationship recently has been shown to exist for subarachnoid hemorrhage(SAH) patients in a large study in the United States. We aim to examine this relationship for SAH patients in England, restricting analysis to specialist neurosurgical units. METHODS: Aggregate counts of patients with SAH in 25 specialist neuroscience centers in England, from 2005 to 2011, were obtained from the Hospital Episode Statistics database maintained by the National Health Service Information Center. These data were linked with national mortality statistics to obtain counts of deaths. Poisson regression was used to investigate the relationship between institutional caseload of SAH and 6-month mortality from any cause. Six-month mortality rates and mortality ratios were computed. RESULTS: Annual institutional caseload of admissions with SAH was inversely related to 6-month mortality (P=0.009; r(2)=0.26). Each 100-patient increase in annual patient volume was associated with a 24% reduction in mortality (adjusted mortality ratio, 0.76; confidence interval, 0.67-0.87). This relationship was consistent across the entire range of annual institutional caseloads examined (29-367 cases for the lowest and highest volumes seen in a single center in 1 year). CONCLUSIONS: Our results provide support for management of SAH at high-volume centers and suggest that health care policy in this setting should pursue regionalization while ensuring an adequate geographic spread of access to care. PMID- 23362085 TI - Common variants within oxidative phosphorylation genes influence risk of ischemic stroke and intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH). METHODS: This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts. RESULTS: IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio [OR], 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008). CONCLUSIONS: This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences. PMID- 23362088 TI - Postnatal development of echolocation abilities in a bottlenose dolphin (Tursiops truncatus): temporal organization. AB - In spite of all the information available on adult bottlenose dolphin (Tursiops truncatus) biosonar, the ontogeny of its echolocation abilities has been investigated very little. Earlier studies have reported that neonatal dolphins can produce both whistles and burst-pulsed sounds just after birth and that early pulsed sounds are probably a precursor of echolocation click trains. The aim of this research is to investigate the development of echolocation signals in a captive calf, born in the facilities of the Acquario di Genova. A set of 81 impulsive sounds were collected from birth to the seventh postnatal week and six additional echolocation click trains were recorded when the dolphin was 1 year old. Moreover, behavioral observations, concurring with sound production, were carried out by means of a video camera. For each sound we measured five acoustic parameters: click train duration (CTD), number of clicks per train, minimum, maximum, and mean click repetition rate (CRR). CTD and number of clicks per train were found to increase with age. Maximum and mean CRR followed a decreasing trend with dolphin growth starting from the second postnatal week. The calf's first head scanning movement was recorded 21 days after birth. Our data suggest that in the bottlenose dolphin the early postnatal weeks are essential for the development of echolocation abilities and that the temporal features of the echolocation click trains remain relatively stable from the seventh postnatal week up to the first year of life. PMID- 23362087 TI - Pyk2 regulates megakaryocyte-induced increases in osteoblast number and bone formation. AB - Preclinical and clinical evidence from megakaryocyte (MK)-related diseases suggests that MKs play a significant role in maintaining bone homeostasis. Findings from our laboratories reveal that MKs significantly increase osteoblast (OB) number through direct MK-OB contact and the activation of integrins. We, therefore, examined the role of Pyk2, a tyrosine kinase known to be regulated downstream of integrins, in the MK-mediated enhancement of OBs. When OBs were co cultured with MKs, total Pyk2 levels in OBs were significantly enhanced primarily because of increased Pyk2 gene transcription. Additionally, p53 and Mdm2 were both decreased in OBs upon MK stimulation, which would be permissive of cell cycle entry. We then demonstrated that OB number was markedly reduced when Pyk2-/ OBs, as opposed to wild-type (WT) OBs, were co-cultured with MKs. We also determined that MKs inhibit OB differentiation in the presence and absence of Pyk2 expression. Finally, given that MK-replete spleen cells from GATA-1 deficient mice can robustly stimulate OB proliferation and bone formation in WT mice, we adoptively transferred spleen cells from these mice into Pyk2-/- recipient mice. Importantly, GATA-1-deficient spleen cells failed to stimulate an increase in bone formation in Pyk2-/- mice, suggesting in vivo the important role of Pyk2 in the MK-induced increase in bone volume. Further understanding of the signaling pathways involved in the MK-mediated enhancement of OB number and bone formation will facilitate the development of novel anabolic therapies to treat bone loss diseases. PMID- 23362089 TI - Gold-catalyzed annulations of 2-alkynyl benzaldehydes with vinyl ethers: synthesis of dihydronaphthalene, isochromene, and bicyclo[2.2.2]octane derivatives. AB - With the suitable selection of a gold catalyst as well as the appropriate control of the reaction conditions, various new gold-catalyzed cyclizations of 2-alkynyl benzaldehyde with acyclic or cyclic vinyl ethers have been developed. Acetal tethered dihydronaphthalene and isochromenes were obtained from the reactions of 2-alkynyl benzaldehydes with acyclic vinyl ethers under mild conditions. And, more interestingly, the gold-catalyzed reactions of 2-alkynyl benzaldehyde with a cyclic vinyl ether afforded the bicyclo[2.2.2]octane derivative involving two molecules of cyclic vinyl ethers. These products contain interesting substructures that have been found in many biologically active molecules and natural products. In addition, a gold-catalyzed homo-dimerization of 2 phenylethynyl benzaldehyde 1a was observed when the reaction was carried out in the absence of vinyl ether, affording a set of separable diastereomeric products. Plausible mechanisms for these transformations are discussed; a gold-containing benzopyrylium was regarded as the crucial intermediate by which a number of these new transformations took place. PMID- 23362090 TI - Role of HSP70 in the regulation of the testicular apoptosis in a seasonal breeding teleost Prochilodus argenteus from the Sao Francisco River, Brazil. AB - This study investigated the relationship among heat shock protein 70 (HSP70), proliferating cell nuclear antigen (PCNA), and testicular apoptosis during a breeding cycle of Prochilodus argenteus, a neotropical migratory characiform fish of importance in commercial fishery from the Sao Francisco River basin. A total of 48 (12 fish/sampling) adult males were caught using casting and drifting nets in four samplings from June 2008 to March 2009. Immunohistochemistry, Western blotting, terminal transferase-mediated dUTP nick-end labeling (TUNEL), enzyme linked immunosorbent assay (ELISA), and caspase-3 colorimetric assay were assessed in different phases of spermatogenesis. Labeling for HSP70 occurred in spermatogonia (SPG(A) 18.0+/-1.5 and SPGB 27.9+/-1.0 in 100 mm(2), respectively) and Sertoli cells in all sampling periods, with higher values in June (resting period) while spermatocytes were labeled in September (maturation period) and December (ripe period). For PCNA, immunoreaction was predominant in spermatogonia in June and September, while primary spermatocytes were labeled mainly in December (18.7+/-2.0). TUNEL-positive reaction occurred throughout the sampling periods, and labeling was detected in the nucleus of germ cells in all developmental phases, except spermatozoa. By ELISA, total HSP70 in testis increased significantly from June to December, and decreased in March (regression period), P<0.05. Caspase-3 activity decreased from June to December and increased in March. Taken together, our results suggest that HSP70 may protect the germ cells from caspase-3-dependent apoptosis during testicular activity and, reduction of HSP70 and increase of apoptosis contribute for testicular remodeling after the breeding season in wild populations of P. argenteus in the Sao Francisco River. PMID- 23362091 TI - Science to practice: can transarterial embolotherapy be used as a viable alternative to treat obesity? AB - Embolization of branches of the left gastric artery that supply the fundus of the stomach may reduce systemic levels of the appetite hormone ghrelin and may result in weight control. PMID- 23362092 TI - New OPTN/UNOS policy for liver transplant allocation: standardization of liver imaging, diagnosis, classification, and reporting of hepatocellular carcinoma. PMID- 23362093 TI - TAC: AOITROMJA? (the acronym conundrum: advancing or impeding the readability of medical journal articles?). PMID- 23362094 TI - Interventional oncologic approaches to liver metastases. AB - Metastatic liver disease is the most common cause of death in cancer patients. Complete surgical resection is currently considered the only curative treatment, with only about 25% of patients being amenable to surgery. Therefore, a variety of interventional oncologic techniques have been developed for treating secondary liver malignancies. The aim of these therapies is either to allow patients with unresectable tumors to become surgical candidates, provide curative treatment options in nonsurgical candidates, or improve survival in a palliative or even curative approach. Among these interventional therapies are transcatheter therapies such as portal vein embolization, hepatic artery infusion chemotherapy, transarterial chemoembolization, and radioembolization, as well as interstitial techniques, particularly radiofrequency ablation as the most commonly applied technique. The rationale, application and clinical results of each of these techniques are reviewed on the basis of the current literature. Future prospects such as gene therapy and immunotherapy are introduced. PMID- 23362095 TI - Hypovascular nodules in patients with chronic liver disease: risk factors for development of hypervascular hepatocellular carcinoma. AB - PURPOSE: To identify patient characteristics and magnetic resonance (MR) imaging findings associated with subsequent hypervascularization in hypovascular nodules that show hypointensity on hepatobiliary phase gadoxetic acid-enhanced MR images in patients with chronic liver diseases. MATERIALS AND METHODS: Institutional review board approval was obtained, and informed consent was waived. At multiple follow-up gadoxetic acid-enhanced MR imaging examinations of 68 patients, 160 hypovascular nodules were retrospectively reviewed. A Cox regression model for hypervascularization was developed to explore the association of baseline characteristics, including patient factors (Child-Pugh classification, etiology of liver disease, history of local therapy for hepatocellular carcinoma [HCC], and coexistence of hypervascular HCC) and MR imaging findings (fat content, signal intensity on T2-weighted images, and nodule size). In addition, the growth rate was calculated as the reciprocal of tumor volume doubling time to investigate its relationship with subsequent hypervascularization by using receiver operating characteristic and Kaplan-Meier analyses. RESULTS: The prevalence of subsequent hypervascularization was 31% (50 of 160 nodules). Independent Cox multivariable predictors of increased risk of hypervascularization were hyperintensity on T2-weighted images (hazard ratio [HR] = 8.7; 95% confidence interval [CI]: 3.6, 20.8), previous local therapy for hypervascular HCC (HR = 5.0; 95% CI: 1.8, 13.6), Child-Pugh B cirrhosis (HR = 3.6; 95% CI: 1.4, 9.5) and coexistence of hypervascular HCC (HR = 2.0; 95% CI: 1.0, 3.8). The mean growth rate was significantly higher in nodules that showed subsequent hypervascularization than in those without hypervascularization. Kaplan-Meier analysis based on the receiver operating characteristic cutoff level (1.8 * 10(-3)/day [tumor volume doubling time, 542 days]) showed that nodules with a higher growth rate had a significantly higher incidence of hypervascularization (P = 5.2 * 10(-8), log-rank test). CONCLUSION: Hyperintensity on T2-weighted images is an independent and strong risk factor at baseline for subsequent hypervascularization in hypovascular nodules in patients with chronic liver disease. Tumor volume doubling time of less than 542 days was associated with a high rate of subsequent hypervascularization. PMID- 23362097 TI - Case 190: papillary fibroelastoma of the pulmonary valve. PMID- 23362098 TI - Mammographic surveillance after breast conservation therapy. PMID- 23362099 TI - Acceleration of 1H MR metabolic imaging with compressed sensing. PMID- 23362100 TI - Metal artifact reduction software must be used with caution. PMID- 23362101 TI - MR enterography versus MR enteroclysis. PMID- 23362102 TI - MR imaging of the small bowel: is MR enteroclysis the only valid first-line investigation? PMID- 23362103 TI - Synthesis of multifunctional bioresponsive polymers for the management of chronic wounds. AB - Novel multifunctional bioresponsive gelatin and alginate based hydrogels with in built antioxidant regenerating system and antimicrobial properties were successfully synthesized. These hydrogels are based on the versatile reactions catalyzed by cellobiose dehydrogenase (CDH). CDH uses cellobiose and cello oligosacharides as electron donors to reduce oxidized phenolic antioxidants, quinones, or molecular oxygen to H2O2 (a well-known antimicrobial agent). The antioxidant regenerating system consisting of CDH and cellobiose increased the ability of catechol to quench nitric oxide (NO), superoxide (O2-) and hydroxyl radicals (OH*) in solution and when incorporated into hydrogels. The CDH loaded into the hydrogels free of oxidized phenolic antioxidants and quinones reduced molecular to H2O2 resulting in the complete inhibition of the growth of Stapylococcus aeureus, Bacillus subtilis, Pseudomonas putida, Escherichia coli and Cellulomonasmicrobium cellulans. This study therefore presents a new concept for synthesizing multifunctional bioresponsive chronic wound dressing polymers with in-built continuous antioxidant system able to continuously quench [reactive oxygen species (ROS) and reactive nitrogen species (RNOS)], and antimicrobial properties able to prevent microbial colonization of wound. PMID- 23362104 TI - Hydrodynamically driven self-assembly of giant vesicles of metal nanoparticles for remote-controlled release. AB - The hydrodynamics of laminar flow in a microfluidic device has been used to control the continuous self-assembly of gold nanoparticles (NPs) tethered with amphiphilic block copolymers. Spherical micelles, giant vesicles (500 nm-2.0 MUm), or disk-like micelles could be formed by varying the flow rates of fluids. Such vesicles can release encapsulated hydrophilic species by using near-IR light. PMID- 23362105 TI - Glycan sequence-dependent Nod2 activation investigated by using a chemically synthesized bacterial peptidoglycan fragment library. AB - Nucleotide oligomerization domain-containing protein 2 (Nod2), an innate immune receptor, recognizes bacterial cell-wall peptidoglycan (PGN), the minimum ligand of which is muramyl dipeptide (MDP). Enzymatic digestion of PGN appears to be important for Nod2 recognition. PGN is degraded by muramidase or glucosamidase through a process that produces two types of glycan sequence; glycans containing GlcNAcbeta(1->4)MurNAc or MurNAcbeta(1->4)GlcNAc. In this report, a range of disaccharide or tetrasaccharide fragments of each sequence were chemically synthesized, and their activities in stimulating human Nod2 (hNod2) were investigated. The results reveal that hNod2 recognitions is dependent on the glycan sequence, as demonstrated by comparing the activities of glycans with the same peptide moieties. (MurNAcbeta(1->4)GlcNAc)(2) -containing structures exhibited stronger activity than those containing (GlcNAcbeta(1->4)MurNAc)(2) . The results suggest that differences in the enzymatic degradation process affect the host's immunomodulation process. PMID- 23362106 TI - Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis. AB - OBJECTIVE: To compare early vs late administration of low-dose aspirin on the risk of perinatal death and adverse perinatal outcome. METHODS: Databases were searched for keywords related to aspirin and pregnancy. Only randomized controlled trials that evaluated the prophylactic use of low-dose aspirin (50-150 mg/day) during pregnancy were included. The primary outcome combined fetal and neonatal death. Pooled relative risks (RR) with their 95% CIs were compared according to gestational age at initiation of low-dose aspirin (<= 16 vs > 16 weeks of gestation). RESULTS: Out of 8377 citations, 42 studies (27 222 women) were included. Inclusion criteria were risk factors for pre-eclampsia, including: nulliparity, multiple pregnancy, chronic hypertension, cardiovascular or endocrine disease, prior gestational hypertension or fetal growth restriction, and/or abnormal uterine artery Doppler. When compared with controls, low-dose aspirin started at <= 16 weeks' gestation compared with low-dose aspirin started at >16 weeks' gestation was associated with a greater reduction of perinatal death (RR = 0.41 (95% CI, 0.19-0.92) vs 0.93 (95% CI, 0.73-1.19), P = 0.02), pre eclampsia (RR = 0.47 (95% CI, 0.36-0.62) vs 0.78 (95% CI, 0.61-0.99), P < 0.01), severe pre-eclampsia (RR = 0.18 (95% CI, 0.08-0.41) vs 0.65 (95% CI, 0.40-1.07), P < 0.01), fetal growth restriction (RR = 0.46 (95% CI, 0.33-0.64) vs 0.98 (95% CI, 0.88-1.08), P < 0.001) and preterm birth (RR = 0.35 (95% CI, 0.22-0.57) vs 0.90 (95% CI, 0.83-0.97), P < 0.001). CONCLUSION: Low-dose aspirin initiated at <= 16 weeks of gestation is associated with a greater reduction of perinatal death and other adverse perinatal outcomes than when initiated at >16 weeks. PMID- 23362107 TI - Synthesis, physical properties, and self-assembly of a novel asymmetric aroyleneimidazophenazine. AB - The synthesis, physical properties, and self-assembly of a novel asymmetric aroyleneimidazophenazine (IZ1) is reported. The as-prepared IZ1 nanowires display an obvious red fluorescence. A heterojunction light-emitting diode (LED) device with the structure ITO/IZ1 nanowires/p-SiC/Al (10 nm)/Ti (80 nm)/Al (380 nm)/ITO was fabricated, and electroluminescence emission with two peaks at about 412 nm and 613 nm was detected with a forward bias ranging from 5 to 10 V. PMID- 23362108 TI - Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma. AB - The strong associations between oral squamous cell carcinoma (OSCC) and dietary habits such as alcohol consumption (A), betel quid chewing (B) and cigarette smoking (C) and its predominance in men have been well documented; however, systemic analysis of OSCC is limited. Our study applied high-throughput screening methods to identify causative epigenetic targets in a cohort of men with ABC associated OSCC. We identified BEX1 and LDOC1 as two epigenetically silenced X linked tumour suppressors and demonstrated a functional link between the transcription of BEX1 and LDOC1 and promoter hypermethylation. Methylation of the BEX1 and LDOC1 promoters was associated significantly (p < 0.0001) with OSCC and were detected in 75% (42/56) and 89% (50/56) of the samples, respectively. We observed concordant increases in the methylation of both genes in 71% (40/56) of the tumours, and potent in vitro and in vivo growth inhibitory effects in OSCC cells ectopically expressing BEX1 and/or LDOC1. Restored expression of BEX1 and LDOC1 suppressed the nuclear factor-kappaB (NF-kappaB) signalling pathway, which is the most frequently hyperactivated signalling pathway in OSCC. This suppression might result from decreased p50 and p65 expression. These findings suggest that silencing of BEX1 and LDOC1 by promoter hypermethylation might represent a critical event in the molecular pathogenesis of OSCC and account for the oncogenic effects of ABC exposure and the male predominance of OSCC occurrence. Microarray data are available in the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/) PMID- 23362109 TI - The P2Y13 receptor regulates extracellular ATP metabolism and the osteogenic response to mechanical loading. AB - ATP release and subsequent activation of purinergic receptors has been suggested to be one of the key transduction pathways activated by mechanical stimulation of bone. The P2Y(13) receptor, recently found to be expressed by osteoblasts, has been suggested to provide a negative feedback pathway for ATP release in different cell types. Therefore, we hypothesized that the P2Y(13) receptor may contribute to the mediation of osteogenic responses to mechanical stimulation by regulating ATP metabolism by osteoblasts. To test this hypothesis, wild-type (WT) and P2Y(13) receptor knockout (P2Y(13)R-/-) mice were subject to non-invasive axial mechanical loading of the left tibiae to induce an osteogenic response. Micro-computed tomography analysis showed mechanical loading induced an osteogenic response in both strains of mice in terms of increased total bone volume and cortical bone volume, with the P2Y(13)R-/- mice having a significantly greater response. The extent of the increased osteogenic response was defined by dynamic histomorphometry data showing dramatically increased bone formation and mineral apposition rates in P2Y(13)R-/- mice compared with controls. In vitro, primary P2Y(13)R-/- osteoblasts had an accumulation of mechanically induced extracellular ATP and reduced levels of hydrolysis. In addition, P2Y(13)R-/- osteoblasts also had a reduction in their maximal alkaline phosphatase (ALP) activity, one of the main ecto-enzymes expressed by osteoblasts, which hydrolyzes extracellular ATP. In conclusion, deletion of the P2Y(13) receptor leads to an enhanced osteogenic response to mechanical loading in vivo, possibly because of the reduced extracellular ATP degradation by ALP. The augmented osteogenic response to mechanical stimulation, combined with suppressed bone remodeling activities and protection from OVX-induced bone loss after P2Y(13) receptor depletion as previously described, suggests a potential role for P2Y(13) receptor antagonist-based therapy, possibly in combination with mechanical loading, for the treatment of osteoporosis. PMID- 23362110 TI - Measuring distortion of skeletal elements in Lodox Statscan-generated images. AB - Due to a scarcity of available skeletal material, anthropologists and other practitioners face difficulties with either the creation or validation of techniques used to estimate a biological profile in subadults. To address this problem, radiographic images of living individuals are often used in lieu of dry skeletal elements. However, radiographic images suffer from distortion. Some problems with metric analyses when using radiographic images may be addressed with the Lodox Statscan, an X-ray machine that claims to produce minimal distortion along the scan-axis due to a linear slot-scanning design. The purpose of this research was to measure the distortion of skeletal elements in radiographic images generated from a Lodox Statscan. Skeletal elements subject to multiple imaging variables that affect distortion were radiographed, measured, and then compared to the dry bone measurements through multiple approaches. An 85% percent agreement within a +/-1 mm range and a 97% agreement within a +/-2 mm range was obtained. Percent difference results demonstrate that slot-axis measurements incurred more distortion than scan-axis measurements (11.8% and 2.7%, respectively). Inclusion of foam results in 4.5% more error than when foam is not included in the image. Angled scan-axis measurements also incurred more distortion than either nonangled slot- and scan-axis measurements. A Bland Altmanplot reveals an overall agreement between the radiographic and dry bonemeasurements, with most measurements falling within the upper and lower limits. Similar measurement error is found in Statscan radiographic and dry bone measurements; therefore, the Statscan offers a radiographic venue to collect metric data. PMID- 23362111 TI - Functional magnetic resonance imaging adaptation reveals the cortical networks for processing grasp-relevant object properties. AB - Grasping behaviors require the selection of grasp-relevant object dimensions, independent of overall object size. Previous neuroimaging studies found that the intraparietal cortex processes object size, but it is unknown whether the graspable dimension (i.e., grasp axis between selected points on the object) or the overall size of objects triggers activation in that region. We used functional magnetic resonance imaging adaptation to investigate human brain areas involved in processing the grasp-relevant dimension of real 3-dimensional objects in grasping and viewing tasks. Trials consisted of 2 sequential stimuli in which the object's grasp-relevant dimension, its global size, or both were novel or repeated. We found that calcarine and extrastriate visual areas adapted to object size regardless of the grasp-relevant dimension during viewing tasks. In contrast, the superior parietal occipital cortex (SPOC) and lateral occipital complex of the left hemisphere adapted to the grasp-relevant dimension regardless of object size and task. Finally, the dorsal premotor cortex adapted to the grasp relevant dimension in grasping, but not in viewing, tasks, suggesting that motor processing was complete at this stage. Taken together, our results provide a complete cortical circuit for progressive transformation of general object properties into grasp-related responses. PMID- 23362112 TI - Are there really twice as many bovid species as we thought? PMID- 23362113 TI - Stepwise metal-ligand cooperation by a reversible aromatization/deconjugation sequence in ruthenium complexes with a tetradentate phenanthroline-based ligand. AB - The synthesis and reactivity of ruthenium complexes containing the tetradentate phenanthroline-based phosphine ligand 2,9-bis((di-tert-butylphosphino)methyl) 1,10-phenanthroline (PPhenP) is described. The hydrido chloro complex [RuHCl(PPhenP)] (2) undergoes facile dearomatization upon deprotonation of the benzylic position, to give [RuH(PPhenP-H)] (4). Addition of dihydrogen to 4 causes rearomatization of the phenanthroline moiety to trans-[Ru(H)(2)(PPhenP)] (5), followed by hydrogenation of an aromatic heterocycle in the ligand backbone, to give a new dearomatized and deconjugated complex [RuH(PPhenP*-H)] (6). These aromatization/deconjugation steps of the coordinated ligand were demonstrated to be reversible and operative in the dehydrogenation of primary alcohols without the need for a hydrogen acceptor. This aromatization/deconjugation sequence constitutes an unprecedented mode of a stepwise cooperation between the metal center and the coordinated ligand. PMID- 23362114 TI - Letter to the editor Re: Wei, Li-Cheng et al. J Orthop Res 30:1572-1576 2012. PMID- 23362115 TI - Efficacy of different final irrigant activation protocols on smear layer removal by EDTA and citric acid. AB - The aim of this study was to evaluate the influence of different activation protocols for chelating agents used after chemo-mechanical preparation (CMP), for smear layer (SL) removal. Forty-five single-rooted human premolars with straight canals and fully formed apex were selected. The specimens were randomly divided into three groups depending on the chelating agent used for smear layer removal: distilled water (DW, control group); 17% ethylenediaminetetraacetic acid (EDTA); and 10% citric acid (CA). Each group was further divided into three subgroups according to the activation protocol used: no-activation (NA), manual dynamic activation (MDA), or sonic activation (SA). After CMP, all specimens were sectioned and processed for observation of the apical thirds by using scanning electron microscopy (SEM). Two calibrated evaluators attributed scores to each specimen. The differences between activation protocols were analyzed with Kruskal Wallis and Mann-Whitney U tests. Friedman and Wilcoxon signed rank tests were used for comparison between each root canal third. When chelating agents were activated, either by MDA or SA, it was obtained the best cleaning results with no significant difference between EDTA and CA (P > 0.05). Sonic activation showed the best results when root canal thirds were analyzed, in comparison to MDA and NA groups (P < 0.05). The activation of chelating agents, independent of the protocol used, benefits smear layer removal from root canals. PMID- 23362116 TI - CrbpI regulates mammary retinoic acid homeostasis and the mammary microenvironment. AB - Cellular retinol-binding protein, type I (CrbpI), encoded by retinol-binding protein, type 1 (Rbp1), is a chaperone of vitamin A (retinol) that is epigenetically silenced in ~25% of human breast cancers. CrbpI delivers vitamin A to enzymes for metabolism into an active metabolite, all-trans retinoic acid (atRA), where atRA is essential to cell proliferation, apoptosis, differentiation, and migration. Here, we show the effect of CrbpI loss on mammary atRA homeostasis using the Rbp1(-/-) mouse model. Rbp1(-/-) mouse mammary tissue has disrupted retinoid homeostasis that results in 40% depleted endogenous atRA. CrbpI loss and atRA depletion precede defects in atRA biosynthesis enzyme expression. Compensation by CrbpIII as a retinoid chaperone does not functionally replace CrbpI. Mammary subcellular fractions isolated from Rbp1(-/-) mice have altered retinol dehydrogenase/reductase (Rdh) enzyme activity that results in 24 42% less atRA production. Rbp1(-/-) mammary tissue has epithelial hyperplasia, stromal hypercellularity, increased collagen, and increased oxidative stress characteristic of atRA deficiency and early tissue dysfunction that precedes tumor formation. Consistent with the findings from the Rbp1(-/-) mouse, tumorigenic epithelial cells lacking CrbpI expression produce 51% less atRA. Together, these data show that CrbpI loss disrupts atRA homeostasis in mammary tissue, resulting in microenvironmental defects similar to those observed at the early stages of tumorigenesis. PMID- 23362117 TI - Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1alpha-Fndc5 pathway in muscle. AB - Myostatin (Mstn) is predominantly expressed in skeletal muscles and plays important roles in regulating muscle growth and development, as well as fat deposition. Mstn-knockout (Mstn(-/-)) mice exhibit increased muscle mass due to both hypertrophy and hyperplasia, and leaner body composition due to reduced fat mass. Here, we show that white adipose tissue (WAT) of Mstn(-/-) develops characteristics of brown adipose tissue (BAT) with dramatically increased expression of BAT signature genes, including Ucp1 and Pgc1alpha, and beige adipocyte markers Tmem26 and CD137. Strikingly, the observed browning phenotype is non-cell autonomous and is instead driven by the newly defined myokine irisin (Fndc5) secreted from Mstn(-/-) skeletal muscle. Within the muscle, Mstn(-/-) leads to increased expression of AMPK and its phosphorylation, which subsequently activates PGC1alpha and Fndc5. Together, our study defines a paradigm of muscle fat crosstalk mediated by Fndc5, which is up-regulated and secreted from muscle to induce beige cell markers and the browning of WAT in Mstn(-/-) mice. These results suggest that targeting muscle Mstn and its downstream signaling represents a therapeutic approach to treat obesity and type 2 diabetes. PMID- 23362119 TI - Dynamic perfusion bioreactor system for 3D culture of rat bone marrow mesenchymal stem cells on nanohydroxyapatite/polyamide 66 scaffold in vitro. AB - The aim of the study was to investigate the biocompatibility and osteogenic effectiveness of the porous nanohydroxyapatite/polyamide 66 (n-HA/PA66) scaffold material that was cultured with the rat bone marrow mesenchymal stem cells (rBMSCs), under the static culture condition and the dynamic perfusion culture condition in vitro, and to investigate whether the 3D perfusion culture condition was better in provoking proliferation of rBMSCs than the 3D static culture condition. The Methyl thiazolyl tetrazolium (MTT) assay, alkaline phosphatase (ALP) activity assay, Osteocalcin (OCN) assay and scanning electron microscope (SEM) were used to observe the proliferation and differentiation of rBMSCs. The samples were respectively harvested at 1st, 3rd, 7th, 14th, and 21st days and effect comparisons were made between the two of the culture conditions. The results showed that values of MTT, ALP, and OCN were increased continuously and revealed a significant difference between the two culture conditions (p < 0.05). On the 14th day, SEM revealed calcified nodules 2-8 MUm in diameter in the lamellar structure. Under the static culture condition, the pores were covered with the cells looking like a piece of blanket, but under the perfusion culture condition the cells were observed to have a 3D lamellar structure. In conclusion, the porous n-HA/PA66 scaffold material can be used as a good candidate material for the bone scaffold construction in the tissue engineering because of its excellent 3D structure, which can greatly improve the proliferation and differentiation of rBMSCs and make them proliferate and osteogenesis even better under the perfusion culture condition. PMID- 23362120 TI - Regio- and enantioselective aminofluorination of alkenes. AB - Enantio- and regioselective: The intramolecular enantioselective aminofluorination of unactivated olefins was achieved by using a chiral iodo(III) difluoride salt. A highly regioselective aminofluorination of styrenes to access 2-fluoro-2-phenylethanamines was also developed. PMID- 23362118 TI - Extracellular UDP enhances P2X-mediated bladder smooth muscle contractility via P2Y(6) activation of the phospholipase C/inositol trisphosphate pathway. AB - Bladder dysfunction characterized by abnormal bladder smooth muscle (BSM) contractions is pivotal to the disease process in overactive bladder, urge incontinence, and spinal cord injury. Purinergic signaling comprises one key pathway in modulating BSM contractility, but molecular mechanisms remain unclear. Here we demonstrate, using myography, that activation of P2Y6 by either UDP or a specific agonist (MRS 2693) induced a sustained increase in BSM tone (up to 2 mN) in a concentration-dependent manner. Notably, activation of P2Y6 enhanced ATP mediated BSM contractile force by up to 45%, indicating synergistic interactions between P2X and P2Y signaling. P2Y6-activated responses were abolished by phospholipase C (PLC) and inositol trisphosphate (IP3) receptor antagonists U73122 and xestospongin C, demonstrating involvement of the PLC/IP3 signal pathway. Mice null for Entpd1, an ectonucleotidase on BSM, demonstrated increased force generation on P2Y6 activation (150%). Thus, in vivo perturbations to purinergic signaling resulted in altered P2Y6 activity and bladder contractility. We conclude that UDP, acting on P2Y6, regulates BSM tone and in doing so selectively maximizes P2X1-mediated contraction forces. This novel neurotransmitter pathway may play an important role in urinary voiding disorders characterized by abnormal bladder motility. PMID- 23362121 TI - Small-molecule-mediated axonal branching in Caenorhabditis elegans. AB - An in vivo system for monitoring small-molecule-mediated neuronal branching has been developed by using C. elegans. Growth-promoting compounds can be detected by visual inspection of GFPlabeled cholinergic neurons, as axonal branching occurs following treatment with neurotrophic agents. Investigation of the structure activity relationship of the neurotrophic natural product clovanemagnolol (1) led us to a comparable chemically edited derivative. PMID- 23362122 TI - Toward photopatternable thin film optical sensors utilizing reactive polyphenylacetylenes. AB - Substituted polyphenylacetylenes featuring reactive pentafluorophenyl (PFP) ester moieties are synthesized. Parts of the reactive PFP groups are then converted with a mono ortho-nitrobenzyl-protected diamine in variable ratios. Thin films are prepared from these copolymers and irradiated with UV light (lambda = 365 nm), resulting in crosslinking of the irradiated areas and hence enabling a photopatterning. We found that during the photocrosslinking process, the excess of PFP ester moieties is stable and remained intact, enabling a subsequent post polymerization modification step with amines. Noteworthy, this subsequent modification with amines results in a dramatically shift in the UV-vis absorption spectra, rendering these patterned conjugated polymer films ideal candidates for optical sensors. PMID- 23362123 TI - Kinetic analysis of the toxicity of pharmaceutical excipients Cremophor EL and RH40 on endothelial and epithelial cells. AB - Cremophor EL and RH40 are widely used excipients in oral and intravenous drug formulations such as Taxol infusion to improve drug dissolution and absorption. Studies indicate that Cremophors, especially EL, have toxic side effects, but few data are available on endothelial and epithelial cells, which form biological barriers and are directly exposed to these molecules. Human hCMEC/D3 brain endothelial and Caco-2 epithelial cells were treated with Cremophor EL and RH40 in the 0.1-50 mg/mL concentration range. Cell toxicity was monitored by real-time cell microelectronic sensing and verified by lactate dehydrogenase release and 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and morphological methods. Cremophors caused dose- and time-dependent damage in both cell types. In endothelial cells, 0.1 mg/mL and higher concentrations, in epithelial cells, concentrations of 5 mg/mL and above were toxic, especially at longer incubations. Cell death was also proven by double fluorescent staining of cell nuclei. Immunostaining for tight junction proteins claudin-4 and -5 showed barrier disruption in cells treated by surfactants at 24 h. In conclusion, Cremophor EL and RH40 in concentrations corresponding to clinical doses caused endothelial and epithelial toxicity. Endothelial cells were more sensitive to surfactant treatment than epithelial cells, and Cremophor EL was more toxic than RH40 in both cell types. PMID- 23362124 TI - Two-photon excited fluorescence imaging of endogenous contrast in a mouse model of ovarian cancer. AB - BACKGROUND AND OBJECTIVE: Ovarian cancer has an extremely high mortality rate resulting from poor understanding of the disease. In order to aid understanding of disease etiology and progression, we identify the endogenous fluorophores present in a mouse model of ovarian cancer and describe changes in fluorophore abundance and distribution with age and disease. STUDY DESIGN/MATERIALS AND METHODS: A mouse model of ovarian cancer was created by dosing with 4 vinylcyclohexene diepoxide, which induces follicular apoptosis (simulating menopause), and 7,12-dimethylbenz[a]anthracene, a known carcinogen. Imaging of ovarian tissue was completed ex vivo with a multiphoton microscope using excitation wavelength of 780 nm and emission collection from 405 to 505 nm. Two photon excited fluorescence images and corresponding histologic sections with selective stains were used to identify endogenous fluorophores. RESULTS: The majority of collected fluorescence emission was attributed to NADH and lipofuscin, with additional contributions from collagen and elastin. Dim cellular fluorescence from NADH did not show observable changes with age. Changes in ovarian morphology with disease development frequently caused increased fluorescence contributions from collagen and adipose tissue-associated NADH. Lipofuscin fluorescence was much brighter than NADH fluorescence and increased as a function of both age and disease. CONCLUSIONS: Our finding of NADH fluorescence patterns similar to that seen previously in human ovary, combined with the observation of lipofuscin accumulation with age and disease also seen in human organs, suggests that the findings from this model may be relevant to human ovarian disease. Increased lipofuscin fluorescence might be used as an indicator of disease in the ovary and this finding warrants further study. PMID- 23362126 TI - Enantioselective total syntheses of (+)-gallocatechin, (-)-epigallocatechin, and 8-C-ascorbyl-(-)-epigallocatechin. PMID- 23362125 TI - Variation in tibial functionality and fracture susceptibility among healthy, young adults arises from the acquisition of biologically distinct sets of traits. AB - Physiological systems like bone respond to many genetic and environmental factors by adjusting traits in a highly coordinated, compensatory manner to establish organ-level function. To be mechanically functional, a bone should be sufficiently stiff and strong to support physiological loads. Factors impairing this process are expected to compromise strength and increase fracture risk. We tested the hypotheses that individuals with reduced stiffness relative to body size will show an increased risk of fracturing and that reduced strength arises from the acquisition of biologically distinct sets of traits (ie, different combinations of morphological and tissue-level mechanical properties). We assessed tibial functionality retrospectively for 336 young adult women and men engaged in military training, and calculated robustness (total area/bone length), cortical area (Ct.Ar), and tissue-mineral density (TMD). These three traits explained 69% to 72% of the variation in tibial stiffness (p < 0.0001). Having reduced stiffness relative to body size (body weight * bone length) was associated with odds ratios of 1.5 (95% confidence interval [CI], 0.5-4.3) and 7.0 (95% CI, 2.0-25.1) for women and men, respectively, for developing a stress fracture based on radiography and scintigraphy. K-means cluster analysis was used to segregate men and women into subgroups based on robustness, Ct.Ar, and TMD adjusted for body size. Stiffness varied 37% to 42% among the clusters (p < 0.0001, ANOVA). For men, 78% of stress fracture cases segregated to three clusters (p < 0.03, chi-square). Clusters showing reduced function exhibited either slender tibias with the expected Ct.Ar and TMD relative to body size and robustness (ie, well-adapted bones) or robust tibias with reduced residuals for Ct.Ar or TMD relative to body size and robustness (ie, poorly adapted bones). Thus, we show there are multiple biomechanical and thus biological pathways leading to reduced function and increased fracture risk. Our results have important implications for developing personalized preventative diagnostics and treatments. PMID- 23362127 TI - Marsupial morphology of reproduction: South America opossum male model. AB - This study aims to describe the morphology of Didelphis sp. male genital organs (penis, testes, epididymis, ductus deferens, prostate, and bulbourethral gland). Ten male animals were used, eight for macroscopic and light microscopy analysis, and two for scanning electron microscopy. The testes and epididymis showed similarity to other eutherian mammals. The bifid penis showed the urethra ending in the medial region where the bifurcation begins, occurring in each segment extension of the urethral groove until the beginning of the glans. Histologically, the penis consists of a cavernous and spongy body, covered by stratified squamous epithelium with loose connective tissue. The urethra was lined by transitional stratified epithelium. In the prostate, prostatic segments were found consisting of tubular glands in a radial arrangement around the urethra, coated externally by a dense connective tissue associated with a relatively thick layer of smooth muscle arranged in two layers that surround the glandular tissue. The animals had three pairs of bulbourethral glands placed at the membranous and cavernous urethra junction with descending and parallel excretory ducts ending caudally in the urethral lumen. PMID- 23362128 TI - Degenerative trends of the palmaris longus muscle in a South African population. AB - The literature reports that the palmaris longus muscle (PL) is only found in mammals in which the forelimbs are weight-bearing extremities. It is suggested that the function of this muscle has been taken over by the other flexors in the forearm. Terms used in the literature to describe the diminishing of this muscle include retrogressive or phylogenetic degenerative trends. The aims of this study were to determine the prevalence of PL in a South African population and whether a phylogenetic degenerative trend for the PL exists. To determine the prevalence of the PL, five groups, representing different age intervals (Years 0-20, 21-40, 41-60, 61-80, and 81-99) were used. A sample of 706 participants of various ages was randomly selected. Statistical analysis included comparisons of the prevalence of the muscle between males and females and left and right sides, using a student t-test. A Chi-squared test was used to determine a possible phylogenetic degenerative trend of PL within the five groups. The sample yielded a bilateral absence of the PL in 11.9% of the cases. The muscle was unilaterally absent on the left side in 7.65% and 6.94% on the right side. The Chi-squared tests revealed a P-value of 0.27 for the left arm and 0.39 for the right arm. No obvious trend could be established for the phylogenetic degeneration of the PL in this study. It would appear that the PL muscle should not be considered as a phylogenetically degenerating muscle in a South African population. PMID- 23362129 TI - Large-scale production of hierarchical TiO2 nanorod spheres for photocatalytic elimination of contaminants and killing bacteria. AB - We report a facile non-hydrothermal method for the large-scale production of hierarchical TiO(2) nanorod spheres for the photocatalytic elimination of contaminants and killing bacteria. Crescent Ti/RF spheres were prepared by deliberately adding titanium trichloride (TiCl(3)) to the reaction of resorcinol (R) and formaldehyde (F) in an open reactor under heating and stirring. The hierarchical TiO(2) nanorod spheres were obtained by calcining the crescent Ti/RF spheres in a furnace in air to burn off the RF spheres. This method has many merits, such as large-scale production, good crystallisation of TiO(2), and good reproducibility, all of which are difficult to realise by conventional hydrothermal methods. The calcination temperature plays a significant role in influencing the morphology, crystallisation, porosity, Brunauer-Emmett-Teller (BET) specific surface area, and hierarchy of the TiO(2) nanorod spheres, thus resulting in different photocatalytic performances under UV light and solar light irradiation. The experimental results have demonstrated that the hierarchical TiO(2) nanorod spheres obtained after calcination of the crescent Ti/RF spheres at different temperatures displayed similar photocatalytic activities under irradiation with UV light. We attribute this to a balance of opposing effects of the investigated factors. A higher calcination temperature leads to greater light absorption capability of the TiO(2) nanorod spheres, thus resulting in higher photocatalytic antibacterial activity under solar light irradiation. It is also interesting to note that the hierarchical TiO(2) nanorod spheres displayed intrinsic antibacterial activity in the absence of light irradiation, apparently because their sharp outward spikes can easily pierce and penetrate the walls of bacteria. In this study, the sharpest hierarchical TiO(2) nanorod spheres were obtained after calcination at 500 degrees C, and these exhibited the highest antibacterial activity without light irradiation. A higher calcination temperature proved detrimental to the sharpness of the TiO(2) nanorods, thus reducing their intrinsic antibacterial activity. PMID- 23362130 TI - Amino acid-selective segmental isotope labeling of multidomain proteins for structural biology. AB - Current solution NMR techniques enable structural investigations of proteins in molecular particles with sizes up to several hundred kDa. However, the large molecular weight of proteins in such systems results in increased numbers of NMR signals, and the resulting spectral overlap typically imposes limitations. For multidomain proteins, segmental isotope labeling of individual domains facilitates the spectral interpretation by reducing the number of signals, but for large domains with small signal dispersion, signal overlap can persist. To overcome limitations arising from spectral overlap, we present a strategy that combines cell-free expression and ligation of the expressed proteins to produce multidomain proteins with selective amino acid-type labeling in individual domains. The bottleneck of intrinsically low cell-free expression yields of precursor molecules was overcome by introducing new fusion constructs that allowed milligram production of ligation-competent domains labeled in one or multiple amino acid types. Ligation-competent unlabeled partner domains were produced in vivo, and subsequent domain ligation was achieved by using an on column strategy. This approach is illustrated with two multidomain RNA-binding proteins, that is, the two C-terminal RNA-recognition motifs of the human polypyrimidine tract-binding protein, and two highly homologous helix-turn-helix domains of the human glutamyl-prolyl-tRNA synthetase. PMID- 23362131 TI - The effect of particle size on the osteointegration of injectable silicate substituted calcium phosphate bone substitute materials. AB - Calcium phosphate (CaP) particles as a carrier in an injectable bone filler allows less invasive treatment of bony defects. The effect of changing granule size within a poloxamer filler on the osteointegration of silicate-substituted calcium phosphate (SiCaP) bone substitute materials was investigated in an ovine critical-sized femoral condyle defect model. Treatment group (TG) 1 consisted of SiCaP granules sized 1000-2000 MUm in diameter (100 vol %). TG2 investigated a granule size of 250-500 MUm (75 vol %), TG3 a granule size of 90-125 MUm (75 vol %) and TG4 a granule size of 90-125 MUm (50 vol %). Following a 4 and 8 week in vivo period, bone area, bone-implant contact, and remaining implant area were quantified within each defect. At 4 weeks, significantly increased bone formation was measured in TG2 (13.32% +/- 1.38%) when compared with all other groups (p = 0.021 in all cases). Bone in contact with the bone substitute surface was also significantly higher in TG2. At 8 weeks most new bone was associated within defects containing the smallest granule size investigated (at the lower volume) (TG4) (42.78 +/- 3.36%) however this group was also associated with higher amounts of fragmented SiCaP. These smaller particles were phagocytosed by macrophages and did not appear to have a negative influence on healing. In conclusion, SiCaP granules of 250-500 MUm in size may be a more suitable scaffold when used as an injectable bone filler and may be a convenient method for treating bony defects. PMID- 23362132 TI - Premaxillary protrusion assessment by the maxilla-nasion-mandible angle in fetuses with facial clefts. AB - OBJECTIVE: The aim of the study was to measure the degree of premaxillary protrusion in fetuses with orofacial clefts of various severities. METHODS: The maxilla-nasion-mandible (MNM) angle was measured retrospectively on by multiplanar corrected volumes. Sixty-two fetuses with orofacial clefts and known outcome volumes of the fetal head were available. RESULTS: In 48 of the 62 cases, the MNM angle could be measured [mean gestational age 23 (range, 18-30) weeks]. The mean MNM angle was normal in all nine cases with cleft lip and intact alveolar ridge (15.2 degrees ; range, 12.5 degrees - 16.9 degrees ). In 24 cases with unilateral cleft lip with or without cleft palate (UCL/P), the mean MNM angle was 20.0 degrees (range, 13.3-26.2 degrees ), being above the 95th percentile in 79% (n = 19) and normal in 21% (n = 5). In 14 bilateral cleft lip and palate (BCL/P) cases, the mean MNM angle was 26.5 degrees (range, 19.2 degrees -33.7 degrees ) and above the 95th percentile in all cases. There was no difference in MNM angle between isolated clefts and clefts associated with other anomalies. In one case with a Tessier 4 cleft, the MNM angle was above the 95th percentile (25.2 degrees ). CONCLUSION: The premaxilla tends to protrude in both BCL/P as UCL/P cases. The degree of protrusion varies greatly, especially in the BCL/P group. PMID- 23362133 TI - An organosilicon cluster with an octasilacuneane core: a missing silicon cage motif. AB - Cagey silicon: A silicon cluster, consisting of sixteen silicon atoms and composed of an octasilacuneane core (red, see picture) fused with cyclotetrasilanes (orange), was synthesized by reductive tetramerization of tetrachlorocyclotetrasilane. Analytical and theoretical studies reveal the unique structural and electronic features of this organosilicon cluster. PMID- 23362134 TI - Recent development of hypercrosslinked microporous organic polymers. AB - Hypercrosslinked polymers (HCPs) are currently receiving great interest due to their easy preparation, high chemical and thermal stability, and low cost. Combined with the lightweight properties and high surface areas HCPs can be considered as promising materials for gas storage and separation, catalysis, and heavy metal ions removal in wastewater treatment. This Feature Article summarizes strategies for the preparation of HCPs, comprising the post-crosslinking of "Davankov-type" resins, direct polycondensation of aromatic chloromethyl (or hydroxymethyl) monomers, and knitting aromatic compound polymers (KAPs). The HCPs applications, such as H2 storage, CO2 capture, and heterogeneous catalysis, are also discussed throughout in the article. Finally, the outlook of this research area is given. PMID- 23362137 TI - Osteoarthritic versus osteoporotic bone and intra-skeletal variations in normal bone: evaluation with uCT and bone histomorphometry. AB - Several studies have shown that in contrast to osteoporosis (OP), osteoarthritis (OA) is characterized by high bone mineral density (BMD). Bone strength not only depends on mineral content as determined by dual X-ray absorptiometry (DXA), but also on bone microarchitecture. We studied intertrochanteric bone from normal controls and OA and OP patients by bone histomorphometry (BHM) and microcomputed tomography (uCT) as well as DXA in order to first, test the differences between OA and OP comparing both groups to healthy controls, second, to assess variations between three different skeletal sites in controls and third, to determine the level of agreement between uCT, BHM, and DXA. Analysis was performed on 115 samples from OA and OP patients, and controls. We found significant differences between OA and OP samples in structural parameters and in the osteoid fraction (p < 0.05). The majority of the intra-skeletal differences were shown between lumbar spine and femoral head samples (p < 0.05). Significant agreements were found between uCT and BHM and DXA (r = 0.32-0.45, p < 0.05). Our findings suggest differences in intertrochanteric bone between OA and OP, the age-related intra skeletal variations and a correlation between microscopic and macroscopic bone evaluation methods. PMID- 23362135 TI - Tumor localization and biochemical response to cure in tumor-induced osteomalacia. AB - Tumor-induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor-23 (FGF23)-secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and postoperative biochemical changes in 31 subjects with TIO. All had failed either initial localization, or relocalization (in case of recurrence or metastases) at outside institutions. Functional imaging with 111Indium-octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and 18fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT, MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20 of 31 subjects (64.5%). Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16 of 20 FDG-PET/CT imaging. Eighteen of 19 (95%) were positive on octreo-SPECT, and 14 of 16 (88%) on FDG-PET/CT. Twelve of 20 subjects underwent VS; 10 of 12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were as follows: sensitivity = 0.95, specificity = 0.64, PPV = 0.82, and NPV = 0.88 for octreo SPECT; sensitivity = 0.88, specificity = 0.36, PPV = 0.62, and NPV = 0.50 for FDG PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up. Serum phosphorus returned to normal in all subjects within 1 to 5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25-dihydroxyvitamin D3 (1,25D) rose and exceeded the normal range. In this systematic approach to tumor localization in TIO, octreo SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation. PMID- 23362136 TI - Clinical and molecular characterisation of hyperinsulinaemic hypoglycaemia in infants born small-for-gestational age. AB - OBJECTIVE: To characterise the phenotype and genotype of neonates born small-for gestational age (SGA; birth weight <10th centile) who developed hyperinsulinaemic hypoglycaemia (HH). METHODS: Clinical information was prospectively collected on 27 SGA neonates with HH, followed by sequencing of KCNJ11 and ABCC8. RESULTS: There was no correlation between the maximum glucose requirement and serum insulin levels. Serum insulin level was undetectable in five infants (19%) during hypoglycaemia. Six infants (22%) required diazoxide treatment >6 months. Normoglycaemia on diazoxide <5 mg/kg/day was a safe predictor of resolved HH. Sequencing of KCNJ11/ABCC8 did not identify any mutations. CONCLUSIONS: Serum insulin levels during hypoglycaemia taken in isolation can miss the diagnosis of HH. SGA infants may continue to have hypofattyacidaemic hypoketotic HH beyond the first few weeks of life. Recognition and treatment of this group of patients are important and may have important implications for neurodevelopmental outcome of these patients. PMID- 23362138 TI - Improvement on the catalytic performance of Mg-Zr mixed oxides for furfural acetone aldol condensation by supporting on mesoporous carbons. AB - A new procedure for improving the performance of the most common catalysts used in aqueous-phase aldol condensation (Mg-Zr mixed oxides) reactions is presented. This reaction is of interest for upgrading carbohydrate feedstocks. The procedure involves supporting Mg-Zr oxides on non-microporous carbonaceous materials, such as carbon nanofibers (CNFs) or high-surface-area graphites (HSAGs), using either incipient wetness or coprecipitation procedures. The use of HSAGs together with the coprecipitation method provides the best performance. Results obtained for the cross-condensation of acetone and furfural at 323 K reveal that the catalyst performance is greatly improved compared to the bulk oxides (96.5 % conversion vs. 81.4 % with the bulk oxide; 87.8 % selectivity for C13 and C8 adducts vs. 76.2 % with the bulk oxide). This difference is even more prominent in terms of rates per catalytically active basic site (four and seven times greater for C8 and C13 adducts, respectively). The improved performance is explained in terms of a more appropriate basic site distribution and by greater interaction of the reactants with the carbon surface. In addition, deactivation behavior of the catalyst is improved by tuning the morphology of the carbonaceous support. An important enhancement of the catalytic stability can be obtained selecting a HSAG with an appropriate pore diameter. With HSAG100 the activity decreased by less than 20 % between successive reaction cycles and the selectivity for the condensation products remained almost unaltered. The decrease is greater than 80 % for the bulk oxides tested at these conditions, with important increases in the selectivity for by-product formation. PMID- 23362140 TI - Humphrey Ridley (1653-1708): forgotten neuroanatomist and neurophysiologist. AB - Humphrey Ridley is a little known character in the history of anatomy and physiology. Born in 1653, Ridley was a physician and anatomist who followed the research done by Willis, Vieussens, and Galen. Outside of a cursory knowledge of his birth and death, readers have only two remnants of his contributions to science: The Anatomy of the Brain, containing its Mechanism and Physiology and Observationes Quaedam Medico-Practicae et Physiologicae de Asthmate et Hydrophobia. The former text was the first book in the English language written on the human brain. Ridley's studies using cadavers executed by hanging provided him with a novel view of the venous drainage and lymphatic system not seen as accurately by those before him. Since the study of the brain was still largely in its infancy, he was not without his errors of deduction as to the purpose of parts of the brain and its pathologies. With his dissections, however, Ridley was able to build on the collective knowledge of neuroanatomy and provided new insight into brain structure and function. The current paper reviews what is known of Ridley's life and contributions to neuroanatomy and neurophysiology. PMID- 23362139 TI - Mapping white matter integrity in elderly people with HIV. AB - People with HIV are living longer as combination antiretroviral therapy (cART) becomes more widely available. However, even when plasma viral load is reduced to untraceable levels, chronic HIV infection is associated with neurological deficits and brain atrophy beyond that of normal aging. HIV is often marked by cortical and subcortical atrophy, but the integrity of the brain's white matter (WM) pathways also progressively declines. Few studies focus on older cohorts where normal aging may be compounded with HIV infection to influence deficit patterns. In this relatively large diffusion tensor imaging (DTI) study, we investigated abnormalities in WM fiber integrity in 56 HIV+ adults with access to cART (mean age: 63.9 +/- 3.7 years), compared to 31 matched healthy controls (65.4 +/- 2.2 years). Statistical 3D maps revealed the independent effects of HIV diagnosis and age on fractional anisotropy (FA) and diffusivity, but we did not find any evidence for an age by diagnosis interaction in our current sample. Compared to healthy controls, HIV patients showed pervasive FA decreases and diffusivity increases throughout WM. We also assessed neuropsychological (NP) summary z-score associations. In both patients and controls, fiber integrity measures were associated with NP summary scores. The greatest differences were detected in the corpus callosum and in the projection fibers of the corona radiata. These deficits are consistent with published NP deficits and cortical atrophy patterns in elderly people with HIV. PMID- 23362141 TI - Gene expression profiling of gastrocnemius of "minimuscle" mice. AB - Few studies have investigated heterogeneity of selection response in replicate lines subjected to equivalent selection. We developed four replicate lines of mice based on high levels of voluntary wheel running (high runner or HR lines) while also maintaining four nonselected control lines. This led to the unexpected discovery of the HR minimuscle (HRmini) phenotype, recognized by a 50% reduction in hindlimb muscle mass, which became fixed in 1 of the four HR selected lines. Here, we report genome-wide expression profiling describing transcriptome differences between HRnormal and HRmini medial gastrocnemius. Consistent with the known reduction of type IIB fibers in HRmini, Myh4 gene expression was -8.82-fold less (P = 0.0001) in HRmini, which was closely associated with differences in the "calcium signaling" canonical pathway, including structural genes (e.g., Mef2c, twofold greater in HRmini, P = 0.0003) and myogenic factors (e.g., Myog, 3.8-fold greater in HRmini, P = 0.0026) associated with slow-type myofibers. The gene that determines the HRmini phenotype is known to reside in a 2.6335-Mb interval on mouse chromosome 11 and 7 genes (Myh10, Chrnb1, Acadvl, Senp3, Gabarap, Eif5a, and Clec10a) from this region were differentially expressed. Verification by real time PCR confirmed 1.5-fold greater (P < 0.05) expression of very long chain acyl CoA dehydrogenase (Acadvl) in HRmini. Ten other genes associated with fatty acid metabolism were also upregulated in HRmini, suggesting differences in the ability to metabolize fatty acids in HRnormal and HRmini muscles. This work provides a resource for understanding differences in muscle phenotypes in populations exhibiting high running capacity. PMID- 23362142 TI - Higher cardiorespiratory fitness attenuates arterial stiffening associated with the Ala54Thr polymorphism in FABP2. AB - Fatty acid binding protein 2 (FABP2) Ala54Thr polymorphism is a candidate gene associated with the risk of cardiovascular disease. Habitual exercise brings higher cardiorespiratory fitness and results in the improvement of cardiovascular disease risk. However, the effect of cardiorespiratory fitness level and FABP2 Ala54Thr polymorphism on the risk of cardiovascular diseases remains unclear. In the present study, a cross-sectional investigation of 837 Japanese men and women was performed to clarify the effects of cardiorespiratory fitness on the relationship between risk of cardiovascular disease and FABP2 Ala54Thr gene polymorphism. The study subjects were divided into high-cardiorespiratory fitness (High-Fit) and low-cardiorespiratory fitness (Low-Fit) groups based on the median value of peak oxygen uptake in each sex and decade. The FABP2 Ala54Thr polymorphism did not significantly affect carotid beta-stiffness or blood pressure. In the Low-Fit group, carotid beta-stiffness, systolic blood pressure, and diastolic blood pressure were higher for individuals with the Ala/Ala genotype compared with those with the Ala/Thr or Thr/Thr genotype, whereas no differences were observed in the High-Fit group. Additionally, serum triglyceride and plasma glucose levels were lower and serum high-density lipoprotein cholesterol levels were higher in the High-Fit group compared with the Low-Fit group; the FABP2 Ala54Thr polymorphism did not significantly affect these parameters. These results suggest that the higher cardiorespiratory fitness may attenuate the changes in central arterial stiffness and blood pressure that are associated with the FABP2 genotype. PMID- 23362143 TI - MicroRNA 299-3p modulates replicative senescence in endothelial cells. AB - MicroRNAs (miRNAs) regulate various cellular processes. While several genes associated with replicative senescence have been described in endothelial cells, miRNAs that regulate these genes remain largely unknown. The present study was designed to identify miRNAs associated with replicative senescence and their target genes in human umbilical vein endothelial cells (HUVECs). An integrated miRNA and gene profiling approach revealed that hsa-miR-299-3p is upregulated in senescent HUVECs compared with the young cells, and one of its target genes could be IGF1. IGF1 was upregulated in senescent compared with young HUVECs, and knockdown of hsa-miR-299-3p dose-dependently increased the mRNA expression of IGF1, more significantly observed in the presenescent cells (passage 19) compared with the senescent cells (passage 25). Knockdown of hsa-miR-299-3p also resulted in significant reduction in the percentage of cells positively stained for senescence-associated beta-galactosidase and increases in cell viability measured by MTT assay but marginal increases in cell proliferation and cell migration capacity measured by real-time growth kinetics analysis. Moreover, knockdown of hsa-miR-299-3p also increased proliferation of cells treated with H2O2 to induce senescence. These findings suggest that hsa-miR-299-3p may delay or protect against replicative senescence by improving the metabolic activity of the senesced cells but does not stimulate growth of the remaining cells in senescent cultures. Hence, these findings provide an early insight into the role of hsa-miR 299-3p in the modulation of replicative senescence in HUVECs. PMID- 23362144 TI - Functional polymorphisms affecting the clinically important arginine-137 residue of AVPR2 do not influence serum sodium concentration at the population level. AB - The protein product of the AVPR2 gene, coding for the arginine vasopressin receptor type 2, is essential for vasopressin-dependent concentration of the urine. The arginine residue at position 137 in the protein product of this gene is uniquely pivotal for function. The R137H mutant inactivates the receptor conferring congenital nephrogenic diabetes insipidus, whereas activating mutations at this same residue (i.e., R137C and R137L) confer pathological water retention in the nephrogenic syndrome of inappropriate antidiuresis. These mutations were discovered in human subjects with conspicuous phenotypes in clinical water balance. Prevalence of these polymorphisms among asymptomatic individuals has not been assessed, nor has their contribution to broad interindividual variation in serum sodium concentration; no data addressing minor allele frequency are available. We genotyped two large cohorts using a validated high-throughput Pyrosequencing-based assay that we designed to capture the totality of pathological variation at this important residue. In the Osteoporotic Fractures in Men (MrOS) Study, all participants were male (i.e., hemizygous for AVPR2 gene on the X-chromosome), and participants were oversampled at the extremes of the population distribution for serum sodium concentration. In the Offspring Cohort of the Framingham Heart Study, male and female participants were genotyped. No pathological variants affecting R137 were detected among the 5,142 AVPR2 alleles successfully genotyped. Even at the population extremes of serum sodium distribution, we estimate minor allele frequency < 0.06%. We conclude that these disease-associated variants are exceedingly uncommon and do not contribute broadly to interindividual variability in serum sodium concentration or to its heritability. PMID- 23362145 TI - Nuclear receptor atlas of female mouse liver parenchymal, endothelial, and Kupffer cells. AB - The liver consists of different cell types that together synchronize crucial roles in liver homeostasis. Since nuclear receptors constitute an important class of drug targets that are involved in a wide variety of physiological processes, we have composed the hepatic cell type-specific expression profile of nuclear receptors to uncover the pharmacological potential of liver-enriched nuclear receptors. Parenchymal liver cells (hepatocytes) and liver endothelial and Kupffer cells were isolated from virgin female C57BL/6 wild-type mice using collagenase perfusion and counterflow centrifugal elutriation. The hepatic expression pattern of 49 nuclear receptors was generated by real-time quantitative PCR using the NUclear Receptor Signaling Atlas (NURSA) program resources. Thirty-six nuclear receptors were expressed in total liver. FXR-alpha, EAR2, LXR-alpha, HNF4-alpha, and CAR were the most abundantly expressed nuclear receptors in liver parenchymal cells. In contrast, NUR77, COUP-TFII, LXR alpha/beta, FXR-alpha, and EAR2 were the most highly expressed nuclear receptors in endothelial and Kupffer cells. Interestingly, members of orphan receptor COUP TF family showed a distinct expression pattern. EAR2 was highly and exclusively expressed in parenchymal cells, while COUP-TFII was moderately and exclusively expressed in endothelial and Kupffer cells. Of interest, the orphan receptor TR4 showed a similar expression pattern as the established lipid sensor PPAR-gamma. In conclusion, our study provides the most complete quantitative assessment of the nuclear receptor distribution in liver reported to date. Our gene expression catalog suggests that orphan nuclear receptors such as COUP-TFII, EAR2, and TR4 may be of significant importance as novel targets for pharmaceutical interventions in liver. PMID- 23362146 TI - Fixed-component lanthanide-hybrid-fabricated full-color photoluminescent films as vapoluminescent sensors. AB - Full-color lanthanide (Ln) photoluminescent materials have attracted considerable interest owing to their potential applications in display systems and lighting technologies. Herein, full-color photoluminescent films have been designed and fabricated facilely with a fixed-component Ln-based (Ln=Tb and Eu) polymer hybrid doped with a proton-sensitive amide-type beta-diketonated photosensitizer, N-(2 pyridinyl)benzoylacetamide (HPBA). The tunable photoluminescence emissions of the films are achieved by changing the amounts of OH(-) in the hybrid rather than varying the relative concentrations of the lanthanide ions and photosensitizers, thus representing a new paradigm for full-color displays. The emission color can also be finely tuned through the variation of the excitation wavelength, and white-light emission can be achieved when the given film is excited at the visible region (405 nm). The photophysical properties and the mechanisms of the intra- and intermolecular energy transfer before and after deprotonation have been investigated in detail. Meanwhile, the films might find application as vapoluminescent sensors due to their good stability, sensitivity, reversibility, and quick response when triggered by a base-acid vapor. PMID- 23362147 TI - Characterization of the bafilomycin biosynthetic gene cluster from Streptomyces lohii. AB - New hope for old bones: The plecomacrolide bafilomycin has been explored for decades as an anti-osteoporotic. However, its structural complexity has limited the synthesis of analogues. The cloning of the bafilomycin biosynthetic gene cluster from the environmental isolate Streptomyces lohii opens the door to the production of new analogues through bioengineering. PMID- 23362148 TI - Pulsed electromagnetic fields on postmenopausal osteoporosis in Southwest China: a randomized, active-controlled clinical trial. AB - A randomized, active-controlled clinical trial was conducted to examine the effect of pulsed electromagnetic fields (PEMFs) on women with postmenopausal osteoporosis (PMO) in southwest China. Forty-four participants were randomly assigned to receive alendronate or one course of PEMFs treatment. The primary endpoint was the mean percentage change in bone mineral density of the lumbar spine (BMDL), and secondary endpoints were the mean percentage changes in left proximal femur bone mineral density (BMDF), serum 25OH vitamin D3 (25(OH)D) concentrations, total lower-extremity manual muscle test (LE MMT) score, and Berg Balance Scale (BBS) score. The BMDL, BMDF, total LE MMT score and BBS score were recorded at baseline, 5, 12, and 24 weeks. Serum concentrations of 25(OH)D were measured at baseline and 5 weeks. Using a mixed linear model, there was no significant treatment difference between the two groups in the BMDL, BMDF, total LE MMT score, and BBS score (P >= 0.05). For 25(OH)D concentrations, the effects were also comparable between the two groups (P >= 0.05) with the Mann-Whitney's U test. These results suggested that a course of PEMFs treatment with specific parameters was as effective as alendronate in treating PMO within 24 weeks. PMID- 23362151 TI - Mechanistic switch in dual gold catalysis of diynes: C(sp(3))-H activation through bifurcation--vinylidene versus carbene pathways. AB - The other side of the mountain: Changing the framework of diyne systems opens up new cyclization modes for dual gold catalysis. Instead of a 5-endo cyclization and gold vinylidenes a 6-endo cyclization gives rise to gold-stabilized carbenes as key intermediates for selective C-H insertions. PMID- 23362149 TI - Vitamin D activation of functionally distinct regulatory miRNAs in primary human osteoblasts. AB - When bound to the vitamin D receptor (VDR), the active form of vitamin D, 1,25 dihydroxyvitamin D (1,25D) is a potent regulator of osteoblast transcription. Less clear is the impact of 1,25D on posttranscriptional events in osteoblasts, such as the generation and action of microRNAs (miRNAs). Microarray analysis using replicate (n = 3) primary cultures of human osteoblasts (HOBs) identified human miRNAs that were differentially regulated by >1.5-fold following treatment with 1,25D (10 nM, 6 hours), which included miRNAs 637 and 1228. Quantitative reverse transcription PCR analyses showed that the host gene for miR-1228, low density lipoprotein receptor-related protein 1 (LRP1), was coinduced with miR 1228 in a dose-dependent fashion following treatment with 1,25D (0.1-10 nM, 6 hours). By contrast, the endogenous host gene for miR-637, death-associated protein kinase 3 (DAPK3), was transcriptionally repressed by following treatment with 1,25D. Analysis of two potential targets for miR-637 and miR-1228 in HOB, type IV collagen (COL4A1) and bone morphogenic protein 2 kinase (BMP2K), respectively, showed that 1,25D-mediates suppression of these targets via distinct mechanisms. In the case of miR-637, suppression of COL4A1 appears to occur via decreased levels of COL4A1 mRNA. By contrast, suppression of BMP2K by miR-1228 appears to occur by inhibition of protein translation. In mature HOBs, small interfering RNA (siRNA) inactivation of miR-1228 alone was sufficient to abrogate 1,25D-mediated downregulation of BMP2K protein expression. This was associated with suppression of prodifferentiation responses to 1,25D in HOB, as represented by parallel decrease in osteocalcin and alkaline phosphatase expression. These data show for the first time that the effects of 1,25D on human bone cells are not restricted to classical VDR-mediated transcriptional responses but also involve miRNA-directed posttranscriptional mechanisms. PMID- 23362152 TI - In vivo efficacy of fresh versus frozen osteochondral allografts in the goat at 6 months is associated with PRG4 secretion. AB - The long-term efficacy of osteochondral allografts is due to the presence of viable chondrocytes within graft cartilage. Chondrocytes in osteochondral allografts, especially those at the articular surface that normally produce the lubricant proteoglycan-4 (PRG4), are susceptible to storage-associated death. The hypothesis of this study was that the loss of chondrocytes within osteochondral grafts leads to decreased PRG4 secretion, after graft storage and subsequent implant. The objectives were to determine the effect of osteochondral allograft treatment (FROZEN vs. FRESH) on secretion of functional PRG4 after (i) storage, and (ii) 6 months in vivo in adult goats. FROZEN allograft storage reduced PRG4 secretion from cartilage by ~85% compared to FRESH allograft storage. After 6 months in vivo, the PRG4-secreting function of osteochondral allografts was diminished with prior FROZEN storage by ~81% versus FRESH allografts and by ~84% versus non-operated control cartilage. Concomitantly, cellularity at the articular surface in FROZEN allografts was ~96% lower than FRESH allografts and non-operated cartilage. Thus, the PRG4-secreting function of allografts appears to be maintained in vivo based on its state after storage. PRG4 secretion may be not only a useful marker of allograft performance, but also a biological process protecting the articular surface of grafts following cartilage repair. PMID- 23362154 TI - Pt-like behavior of high-performance counter electrodes prepared from binary tantalum compounds showing high electrocatalytic activity for dye-sensitized solar cells. AB - Ta-based compounds show Pt-like behavior: Binary tantalum compounds as counter electrodes (CEs) in dye-sensitized solar cells (DSCs) demonstrate Pt-like electrocatalytic activity and competitive photovoltaic performance, matching the performance of DSCs with Pt CEs. The first-principle density functional theory (DFT) calculations provide a strategy for understanding the relationship between the electronic structure and the catalytic activity of CE catalysts in DSCs. PMID- 23362155 TI - Influence of gasoline inhalation on the enantioselective pharmacokinetics of fluoxetine in rats. AB - Fluoxetine is used clinically as a racemic mixture of (+)-(S) and (-)-(R) enantiomers for the treatment of depression. CYP2D6 catalyzes the metabolism of both fluoxetine enantiomers. We aimed to evaluate whether exposure to gasoline results in CYP2D inhibition. Male Wistar rats exposed to filtered air (n = 36; control group) or to 600 ppm of gasoline (n = 36) in a nose-only inhalation exposure chamber for 6 weeks (6 h/day, 5 days/week) received a single oral 10 mg/kg dose of racemic fluoxetine. Fluoxetine enantiomers in plasma samples were analyzed by a validated analytical method using LC-MS/MS. The separation of fluoxetine enantiomers was performed in a Chirobiotic V column using as the mobile phase a mixture of ethanol:ammonium acetate 15 mM. Higher plasma concentrations of the (+)-(S)-fluoxetine enantiomer were found in the control group (enantiomeric ratio AUC((+)-(S)/(-)-(R)) = 1.68). In animals exposed to gasoline, we observed an increase in AUC(0-infinity) for both enantiomers, with a sharper increase seen for the (-)-(R)-fluoxetine enantiomer (enantiomeric ratio AUC((+)-(S)/(-)-(R)) = 1.07), resulting in a loss of enantioselectivity. Exposure to gasoline was found to result in the loss of enantioselectivity of fluoxetine, with the predominant reduction occurring in the clearance of the (-)-(R) fluoxetine enantiomer (55% vs. 30%). PMID- 23362153 TI - Associations between T1 white matter lesion volume and regional white matter microstructure in aging. AB - White matter lesions, typically manifesting as regions of signal intensity abnormality (WMSA) on MRI, increase in frequency with age. However, the role of this damage in cognitive decline and disease is still not clear, as lesion volume has only loosely been associated with clinical status. Diffusion tensor imaging (DTI) has been used to examine the quantitative microstructural integrity of white matter, and has applications in the examination of subtle changes to tissue that appear visually normal on conventional imaging. The primary goal of this study was to determine whether major macrostructural white matter damage, (total WMSA volume), is associated with microstructural integrity of normal appearing white matter, and if these macrostructural changes fully account for microstructural changes. Imaging was performed in 126 nondemented individuals, ages 43-85 years, with no history of cerebrovascular disease. Controlling for age, greater WMSA volume was associated with decreased fractional anisotropy (FA) in widespread brain regions. Patterns were similar for FA and radial diffusivity but in contrast, WMSA was associated with axial diffusivity in fewer areas. Age was associated with FA in several regions, and many of these effects remained even when controlling for WMSA volume, suggesting the etiology of WMSAs does not fully account for all age-associated white matter deterioration. These results provide evidence that WMSA volume is associated with the integrity of normal appearing white matter. In addition, our results suggest that overt lesions may not account for the association of increasing age with decreased white matter tissue integrity. PMID- 23362156 TI - Enhanced performance of benzothieno[3,2-b]thiophene (BTT)-based bottom-contact thin-film transistors. AB - Three new benzothieno[3,2-b]thiophene (BTT; 1) derivatives, which were end functionalized with phenyl (BTT-P; 2), benzothiophenyl (BTT-BT; 3), and benzothieno[3,2-b]thiophenyl groups (BBTT; 4; dimer of 1), were synthesized and characterized in organic thin-film transistors (OTFTs). A new and improved synthetic method for BTTs was developed, which enabled the efficient realization of new BTT-based semiconductors. The crystal structure of BBTT was determined by single-crystal X-ray diffraction. Within this family, BBTT, which had the largest conjugation of the BTT derivatives in this study, exhibited the highest p-channel characteristic, with a carrier mobility as high as 0.22 cm(2) V(-1) s(-1) and a current on/off ratio of 1*10(7) , as well as good ambient stability for bottom contact/bottom-gate OTFT devices. The device characteristics were correlated with the film morphologies and microstructures of the corresponding compounds. PMID- 23362157 TI - Locally duplicated ohnologs evolve faster than nonlocally duplicated ohnologs in Arabidopsis and rice. AB - Whole-genome duplications (WGDs) have recurred in the evolution of angiosperms, resulting in many duplicated chromosomal segments. Local gene duplications are also widespread in angiosperms. WGD-derived duplicates, that is, ohnologs, and local duplicates often show contrasting patterns of gene retention and evolution. However, many genes in angiosperms underwent multiple gene duplication events, possibly by different modes, indicating that different modes of gene duplication are not mutually exclusive. In two representative angiosperm genomes, Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), we found that 9.6% and 11.3% of unique ohnologs, corresponding to 15.5% and 17.1% of ohnolog pairs, were also involved in local duplications, respectively. Locally duplicated ohnologs are widely distributed in different duplicated chromosomal segments and functionally biased. Coding sequence divergence between duplicated genes is denoted by nonsynonymous (Ka) and synonymous (Ks) substitution rates. Locally duplicated ohnolog pairs tend to have higher Ka, Ka/Ks, and gene expression divergence than nonlocally duplicated ohnolog pairs. Locally duplicated ohnologs also tend to have higher interspecies sequence divergence. These observations indicate that locally duplicated ohnologs evolve faster than nonlocally duplicated ohnologs. This study highlights the necessity to take local duplications into account when analyzing the evolutionary dynamics of ohnologs. PMID- 23362158 TI - Raman spectroscopic imaging for the real-time detection of chemical changes associated with docetaxel exposure. AB - There is an urgent need for methods allowing for a fast, non-invasive, sensitive and selective monitoring of the effectiveness of anticancer drugs during the course of a chemotherapeutic treatment of cancer patients. The possibility of predicting and controlling the efficiency of chemotherapeutic agents for every patient individually enables a personalized therapy with largely improved success rates. The results presented herein demonstrate that Raman microspectroscopy is perfectly suited to monitor the impact of chemotherapeutic agents on living cells. The influence of the clinically well-established chemotherapeutic docetaxel on both the morphology and also biochemistry of living colon cancer cells (HT-29) has been studied by means of Raman spectroscopy in combination with modern chemometric approaches. The work presented paves the way for establishing Raman spectroscopy as a monitoring tool of the effectiveness of a chemotherapy treatment and can therefore be seen as a step towards personalized therapy. PMID- 23362159 TI - Shape- and nitric oxide flux-dependent bactericidal activity of nitric oxide releasing silica nanorods. AB - Silica nanorods (SNRs) are synthesized and then functionalized with aminoalkoxysilanes to prepare a new class of nitric oxide (NO)-releasing materials. The aspect ratio and size of the SNRs are tuned by varying the temperature, pH, and silane concentration used during the surfactant-templated synthesis. N-Diazeniumdiolate nitric oxide (NO) donors are formed on the secondary amine-functionalized SNRs by reaction with NO gas under basic conditions. Particle surface modifications are employed to manipulate the NO release kinetics. The diverse morphology (i.e., aspect ratio ~1-8), NO-release kinetics (2000-14,000 ppb NO/mg particle) and similar sizes (i.e., particle volume ~0.02 MUm3) of the resulting NO-releasing SNRs facilitates further studies of how particle shape and NO flux impacts bactericidal activity against Gram positive Staphylococcus aureus (S. aureus) and Gram-negative Pseudomonas aeruginosa (P. aeruginosa) bacteria. The bactericidal efficacies of these materials improves with increasing particle aspect ratio and initial NO flux. Both chemical (i.e., NO-release kinetics) and physical (i.e., morphology) properties greatly influenced the bactericidal activity of these materials. PMID- 23362160 TI - Fulvenes as effective dipolarophiles in copper(I)-catalyzed [6+3] cycloaddition of azomethine ylides: asymmetric construction of piperidine derivatives. PMID- 23362161 TI - Letter to the editor Re: Wei, Li-Cheng et al. J Orthop Res 30:1572-1576 2012. PMID- 23362162 TI - Comparison of targeted next-generation sequencing (NGS) and real-time PCR in the detection of EGFR, KRAS, and BRAF mutations on formalin-fixed, paraffin-embedded tumor material of non-small cell lung carcinoma-superiority of NGS. AB - The development of tyrosine kinase inhibitor treatments has made it important to test cancer patients for clinically significant gene mutations that influence the benefit of treatment. Targeted next-generation sequencing (NGS) provides a promising method for diagnostic purposes by enabling the simultaneous detection of multiple mutations in various genes in a single test. The aim of our study was to screen EGFR, KRAS, and BRAF mutations by targeted NGS and commonly used real time polymerase chain reaction (PCR) methods to evaluate the feasibility of targeted NGS for the detection of the mutations. Furthermore, we aimed to identify potential novel mutations by targeted NGS. We analyzed formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens from 81 non-small cell lung carcinoma patients. We observed a significant concordance (from 96.3 to 100%) of the EGFR, KRAS, and BRAF mutation detection results between targeted NGS and real time PCR. Moreover, targeted NGS revealed seven nonsynonymous single-nucleotide variations and one insertion-deletion variation in EGFR not detectable by the real-time PCR methods. The potential clinical significance of these variants requires elucidation in future studies. Our results support the use of targeted NGS in the screening of EGFR, KRAS, and BRAF mutations in FFPE tissue material. PMID- 23362163 TI - Validation of the automated method VIENA: an accurate, precise, and robust measure of ventricular enlargement. AB - BACKGROUND: In many retrospective studies and large clinical trials, high resolution, good-contrast 3DT1 images are unavailable, hampering detailed analysis of brain atrophy. Ventricular enlargement then provides a sensitive indirect measure of ongoing central brain atrophy. Validated automated methods are required that can reliably measure ventricular enlargement and are robust across magnetic resonance (MR) image types. AIM: To validate the automated method VIENA for measuring the percentage ventricular volume change (PVVC) between two scans. MATERIALS AND METHODS: Accuracy was assessed using four image types, acquired in 15 elderly patients (five with Alzheimer's disease, five with mild cognitive impairment, and five cognitively normal elderly) and 58 patients with multiple sclerosis (MS), by comparing PVVC values from VIENA to manual outlining. Precision was assessed from data with three imaging time points per MS patient, by measuring the difference between the direct (one-step) and indirect (two-step) measurement of ventricular volume change between the first and last time points. The stringent concordance correlation coefficient (CCC) was used to quantify absolute agreement. RESULTS: CCC of VIENA with manual measurement was 0.84, indicating good absolute agreement. The median absolute difference between two step and one-step measurement with VIENA was 1.01%, while CCC was 0.98. Neither initial ventricular volume nor ventricular volume change affected performance of the method. DISCUSSION: VIENA has good accuracy and good precision across four image types. VIENA therefore provides a useful fully automated method for measuring ventricular volume change in large datasets. CONCLUSION: VIENA is a robust, accurate, and precise method for measuring ventricular volume change. PMID- 23362164 TI - beta-endorphin-induced inhibition of vitellogenic follicular growth in the fish Oreochromis mossambicus: evidence for opioidergic mediation of ovarian stress response. AB - The opioid peptide beta-endorphin (beta-EP) is known to play modulatory role in vertebrate reproduction. The objective of the present study was to determine the influence of beta-EP and the opioid receptor antagonist naltrexone (NALT) on follicular development in normal, and stressed female tilapia Oreochromis mossambicus. Administration of 4 ug beta-EP, but not 0.5 or 1.5 ug beta-EP daily for 22 days caused a significant reduction in the mean GSI, HSI, and number of Stage IV (vitellogenic) follicles compared to experimental controls during the prespawning phase of the ovarian cycle. Furthermore, the Stage V (vitellogenic) follicles were completely absent during the prespawning phase concomitant with the significantly lower serum levels of estradiol and cortisol in 4 ug beta-EP treated fish compared to experimental controls. On the other hand, exposure of the fish to mild acute stressors for 22 days caused changes in the ovary similar to that of high dose of beta-EP, whereas administration of NALT attenuated these effects. The results reveal that beta-EP exerts inhibitory effect on the vitellogenic follicular growth through the suppression of ovarian steroidogenesis. The study provides evidence for the opioidergic mediation of the ovarian stress response for the first time in fish. PMID- 23362165 TI - Primary ciliary dyskinesia. PMID- 23362166 TI - Spontaneous pulmonary hernia: a case report. AB - Hernia is defined as the protrusion of a totally or partially displaced organ from its normal visceral cavity. Most hernias occur at the level of the abdominal wall, because of a muscular defect. Pulmonary hernias are extremely rare and can be congenital or acquired. We present a 64-year-old patient who developed a spontaneous pulmonary hernia after a severe coughing episode. We describe the clinical features, diagnosis, and successful treatment. PMID- 23362167 TI - Individualized PEEP setting in subjects with ARDS: a randomized controlled pilot study. AB - BACKGROUND: Low-tidal-volume ventilation may be associated with repetitive opening and closing of terminal airways. The use of PEEP is intended to keep the alveoli open. No method of adjusting the optimal PEEP has shown to be superior or to improve clinical outcomes. We conducted a pilot study to evaluate the effect of setting an individualized level of PEEP at the highest compliance on oxygenation, multiple-organ-dysfunction, and survival in subjects with ARDS. METHODS: Subjects with ARDS ventilated with low tidal volumes and limitation of airway pressure to 30 cm H2O were randomized to either a compliance-guided PEEP group or an FIO2-guided group. RESULTS: Of the 159 patients with ARDS admitted during the study period, 70 met the inclusion criteria. Subjects in the compliance-guided group showed nonsignificant improvements in PaO2/FIO2 during the first 14 days, and in 28-day mortality (20.6% vs. 38.9%, P = .12). Multiple organ-dysfunction-free days (median 6 vs 20.5 d, P = .02), respiratory-failure free days (median 7.5 vs 14.5 d, P = .03), and hemodynamic-failure-free days (median 16 vs 22 d, P = .04) at 28 days were significantly lower in subjects with compliance-guided setting of PEEP. CONCLUSIONS: In ARDS subjects, protective mechanical ventilation with PEEP application according to the highest compliance was associated with less organ dysfunction and a strong nonsignificant trend toward lower mortality. ClinicalTrials.gov Number NCT01119872. PMID- 23362168 TI - Predicting walking-induced oxygen desaturations in COPD patients: a statistical model. AB - BACKGROUND: Oxygen desaturation during walking can have important consequence on prognosis of COPD patients. However, a standard 6-min walk test (6MWT), useful in detecting desaturation in COPD patients, can be difficult to execute in some settings of COPD management, as in the community healthcare service. We evaluated a new scoring system for the risk of oxygen desaturation during walking in COPD patients: the walking desaturation score. METHODS: We collected data from symptomatic COPD in-patients admitted for rehabilitation (derivation cohort) and out-patients referred to the local community health service (validation cohort). S(pO2) was monitored during 6MWT, and the subjects were classified as walking desaturators or non-desaturators. By a regression analysis model we assigned a weighted score proportional to the measured percentage of explained variance for each variable. Risk estimates were computed as odds ratios. A receiver operating characteristic curve analysis and a Hosmer-Lemeshow goodness-of-fit test were then performed to measure discrimination and calibration of walking desaturation score. RESULTS: Baseline characteristics in the derivation cohort (n = 435, 74% of whom were walking desaturators) and the validation cohort (n = 238, 37% of whom were walking desaturators) were different. Resting arterial oxygen saturation measured from an arterial blood sample, P(aO2), and percent-of predicted FEV1 were the variables that predicted walking desaturation. The proportion of walking desaturators (and odds ratio estimate) gradually increased according to walking desaturation score (range 0-6) and associated categories of desaturation risk (total walking desaturation score: low 0 or 1, high 2-3, very high 4-6) (chi-square P < .001). There was considerable predictive discrimination (area under the curve 0.90, 95% CI 0.86-0.93, P < .001), and calibration (Hosmer Lemeshow chi-square 1.31, P = .86) values have been shown. CONCLUSIONS: Walking desaturation score accurately predicts and classifies the risk of walking desaturation in COPD patients. ClinicalTrials.gov Number NCT01303913. PMID- 23362169 TI - Diabetic myonecrosis in a cystic fibrosis patient. AB - Cystic fibrosis (CF) related diabetes is an increasingly common comorbidity in CF patients, with scarce data on end-stage complications in the CF population. We report the case of a 32-year-old with poorly controlled diabetes presenting with sub-acute leg pain and focal quadriceps tenderness. Neuromuscular testing and extensive workup revealed diabetic myonecrosis. To our knowledge, this is the first reported case of diabetic myonecrosis in a patient with CF, and highlights the need for pulmonary physicians to recognize this diabetic complication in CF patients, which is associated with a poor long-term prognosis and existing microvascular complications. PMID- 23362170 TI - Synthesis and characterization of carbazole-based expanded thiaporphyrins. PMID- 23362171 TI - Synthesis and characterization of the first 2D neptunyl structure stabilized by side-on cation-cation interactions. PMID- 23362172 TI - Near-field plasmonic functionalization of light harvesting oxide-oxide heterojunctions for efficient solar photoelectrochemical water splitting: the AuNP/ZnFe2O4/ZnO system. PMID- 23362173 TI - In search of lost platinum. PMID- 23362174 TI - Power spectral analysis of the effects of epinephrine, norepinephrine, dobutamine and dopexamine on microcirculation following free tissue transfer. AB - BACKGROUND: The use of pressor drugs after microsurgical free tissue transfer remains controversial because of potential vasoconstrictor effects on the free flap. Noninvasive monitoring of free flaps with laser Doppler flowmetry may provide further information regarding the local regulation of blood flow in the flap tissues during pressor infusions. This study evaluated the effects of four commonly used pressor agents. METHODS: Twenty four patients (25 data sets) undergoing head and neck cancer resection and free flap reconstruction were recruited. Epinephrine, norepinephrine, dopexamine, and dobutamine were infused in a random order at four infusion rates, after surgery, with free flap and control area (deltoid region) laser Doppler skin blood flow monitoring. Frequency analysis of the Doppler waveform was performed utilizing the time period immediately before the first drug infusion for each patient as baseline. RESULTS: At baseline there was less power at the 0.002-0.6 Hz frequency in the flap compared with control tissue consistent with surgical denervation. At maximum epinephrine infusion rates, the control of blood flow moved toward (i.e., proportion of power increased in) the lower frequencies, as smooth muscle mediated (myogenic) control began to dominate blood flow, an effect most marked with norepinephrine. Dobutamine and dopexamine had little effect on control of blood flow. CONCLUSIONS: Denervation of free flap tissue is demonstrable using spectral analysis of laser Doppler blood flow signals. With norepinephrine the control of blood flow shifts toward low frequency vasomotion where blood flow depends mostly on average blood pressure, making it potentially the most suitable agent following free tissue transfer. PMID- 23362175 TI - Breakpoint characterization of the der(19)t(11;19)(q13;p13) in the ovarian cancer cell line SKOV-3. AB - About 20% of ovarian carcinomas show alterations of 19p13 and/or 19q13 in the form of added extra material whose origin often is from chromosome 11. Based on earlier spectral karyotype analysis of the ovarian cancer cell line SKOV-3, which shows an unbalanced translocation der(19)t(11;19), the aim of this study was to determine the precise breakpoints of that derivative chromosome. After rough delimitation of the breakpoints of microdissected derivative chromosomes by array analysis, we designed a matrix of primers spanning 11q13.2 and 19p13.2 detecting multiple amplicons on genomic and cDNA. Sequencing the amplicons, accurate localization of both breakpoints on both chromosomes was possible and we found that exon 14 of HOOK2 from chromosome 19 and exon 2 of ACTN3 from chromosome 11 were fused in the derivative chromosome. The breakpoint in the HOOK2 gene was in an intrinsic triplet of nucleic acids leading to a shift in the ACTN3 reading frame in the derivative chromosome. This frameshift alteration should give rise to an early stop codon causing a loss of function of ACTN3. Signals in two dimensional Western blotting exactly match to calculated molecular mass and the isoelectric point of the fusion protein. PMID- 23362176 TI - Enteric alpha-synuclein expression is increased in Parkinson's disease but not Alzheimer's disease. AB - BACKGROUND AND OBJECTIVE: Alpha-synuclein (alpha-Syn) is immunohistochemically detectable in enteric neurons in some subjects. We determined its age distribution in the general autopsy population and in an age-matched subset investigated differences with Parkinson's (PD) and Alzheimer's diseases (AD). METHODS: Archival autopsy samples of colon from 95 cases (77 general population, 10 PD, and 8 AD) were immunostained with monoclonal antibody KM51. alpha-Syn detectability was semiquantitatively graded 1 to 3. RESULTS: alpha-Syn was detectable in 52% of the general population, and its level of expression did not change between ages 40 and 91. All PD subjects were alpha-Syn positive, with higher prevalence (P = 0.001) and grade (P = 0.003) than age-matched controls. AD subjects were no more likely to be alpha-Syn positive or have a higher grade than controls. CONCLUSIONS: Either PD develops selectively in the enterically alpha Syn-positive population subset or PD induces this expression. Absence of increased alpha-Syn expression in AD points to differences in pathogenesis. PMID- 23362177 TI - Palladium-based nanostructures with highly porous features and perpendicular pore channels as enhanced organic catalysts. AB - Channeling a good catalyst: Highly porous palladium nanostructures (pPdNs) with perpendicular pore channels were prepared under mild conditions. The combination of high surface area and rich edge/corner atoms gives pPdNs better catalytic performance than known Pd catalysts for the hydrogenation of nitrobenzene and styrene and the Suzuki coupling reaction. PMID- 23362178 TI - Intestinal clostridial counts have no diagnostic value in the diagnosis of enterotoxaemia in veal calves. AB - Enterotoxaemia is an important cause of sudden death in veal calves. This study aimed to evaluate intestinal Clostridium perfringens counts as a diagnostic tool for enterotoxaemia. Field necropsies were conducted on 48 sudden death cases in Belgian Blue veal farms. In 31/48 suddenly deceased calves, the diagnosis of enterotoxaemia was made based on haemorrhagic lesions in the small intestines, while in seven of these cases, no clear-cut diagnosis could be made based on macroscopic appearance of the gut. In the 10 remaining calves, a definitive cause of death other than enterotoxaemia could be identified. Samples of the intestinal content were taken for quantification of C perfringens. After matching cases and controls for diet, and the interval between death and sampling, no significant differences could be detected between the mean C perfringens counts of the small intestines in enterotoxaemia cases and counts in the matching segments in the control group. These results indicate that intestinal C perfringens counts cannot be advised as a discriminative postmortem diagnostic tool for enterotoxaemia in veal calves, not even when sampled within three hours after death. PMID- 23362179 TI - Equine hoof canker: a clinical trial of topical cisplatin chemotherapy. PMID- 23362180 TI - Seroprevalence study of leptospirosis in horses in northern Poland. PMID- 23362181 TI - Effects of different fentanyl anaesthetic mixtures on cortico-adrenal function in rabbits. PMID- 23362182 TI - Breeding success of barn owls reflects risk of hantavirus infection. PMID- 23362183 TI - Unsymmetrical binding modes of the HOPNO inhibitor of tyrosinase: from model complexes to the enzyme. AB - The deciphering of the binding mode of tyrosinase (Ty) inhibitors is essential to understand how to regulate the tyrosinase activity. In this paper, by combining experimental and theoretical methods, we studied an unsymmetrical tyrosinase functional model and its interaction with 2-hydroxypyridine-N-oxide (HOPNO), a new and efficient competitive inhibitor for bacterial Ty. The tyrosinase model was a dinuclear copper complex bridged by a chelated ring with two different complexing arms (namely (bis(2-ethylpyridyl)amino)methyl and (bis(2 methylpyridyl)amino)methyl). The geometrical asymmetry of the complex induces an unsymmetrical binding of HOPNO. Comparisons have been made with the binding modes obtained on similar symmetrical complexes. Finally, by using quantum mechanics/molecular mechanics (QM/MM) calculations, we studied the binding mode in tyrosinase from a bacterial source. A new unsymmetrical binding mode was obtained, which was linked to the second coordination sphere of the enzyme. PMID- 23362184 TI - Segregating cognitive functions within hippocampal formation: a quantitative meta analysis on spatial navigation and episodic memory. AB - The most important cognitive domains where hippocampal formation is crucially involved are navigation and memory. Some evidence suggests that different hippocampal subregions mediate these domains. However, a quantitative meta analysis on neuroimaging studies of spatial navigation versus memory is lacking. By means of activation likelihood estimation (ALE), we investigate concurrence of brain regions activated during spatial navigation encoding and retrieval as well as during episodic memory encoding and retrieval tasks in humans. During encoding in spatial navigation, activity was located in more posterior regions of the hippocampal formation, whereas episodic memory encoding was located in more anterior regions. Retrieval in spatial navigation was more strongly lateralized to the right compared to episodic memory retrieval. Within studies on spatial navigation retrieval, immediate recall was located more posterior and delayed recall more anterior. Overlap between concurrence of activation in spatial navigation and episodic memory was rather limited in comparison to uniquely involved regions. This argues in favor of two distinct networks, one for spatial navigation the other for episodic memory within the hippocampal formation. PMID- 23362185 TI - INS-1 cell glucose-stimulated insulin secretion is reduced by the downregulation of the 67 kDa laminin receptor. AB - Understanding beta cell-extracellular matrix (ECM) interactions can advance our knowledge of the mechanisms that control glucose homeostasis and improve culture methods used in islet transplantation for the treatment of diabetes. Laminin is the main constituent of the basement membrane and is involved in pancreatic beta cell survival and function, even enhancing glucose-stimulated insulin secretion. Most of the studies on cell responses towards laminin have focused on integrin mediated interactions, while much less attention has been paid on non-integrin receptors, such as the 67 kDa laminin receptor (67LR). The specificity of the receptor-ligand interaction through the adhesion of INS-1 cells (a rat insulinoma cell line) to CDPGYIGSR-, GRGDSPC- or CDPGYIGSR + GRGDSPC-covered surfaces was evaluated. Also, the effects of the 67LR knocking down over glucose-stimulated insulin secretion were investigated. Culture of the INS-1 cells on the bioactive surfaces was improved compared to the low-fouling carboxymethyl dextran (CMD) surfaces, while downregulation of the 67LR resulted in reduced cell adhesion to surfaces bearing the CDPGYIGSR peptide. Glucose-stimulated insulin secretion was hindered by downregulation of the 67LR, regardless of the biological motif available on the biomimetic surfaces on which the cells were cultured. This finding illustrates the importance of the 67LR in glucose-stimulated insulin secretion and points to a possible role of the 67LR in the mechanisms of insulin secretion. PMID- 23362186 TI - Nanoscale control of polyoxometalate assembly: a {Mn8W4} cluster within a {W36Si4Mn10} cluster showing a new type of isomerism. AB - Two near isomeric clusters containing a novel {Mn(8)W(4)} Keggin cluster within a [W(36)Mn(10)Si(4)O(136)(OH)(4)(H(2)O)8](24-) cluster are reported: K(10)Li(14)[W(36)Si(4)O(136)Mn(II)(10)(OH)(4)(H(2)O)(8)] (1) and K(10)Li1(3.5)Mn(0.25)[W(36)Si(4)O(136)Mn(II)(10)(OH)(4)(H(2)O)(8) ] (1'). Bulk characterization of the clusters has been carried out by single crystal X-ray structure analysis, ICP-MS, TGA, ESI-MS, CV and SQUID-magnetometer analysis. X ray analysis revealed that 1' has eight positions within the central Keggin core that were disordered W/Mn whereas 1 contained no such disorder. This subtle difference is due to a differences is how the two clusters assemble and recrystallize from the same mother liquor and represents a new type of isomerism. The rapid recrystallization process was captured via digital microscopy and this uncovered two "intermediate" types of crystal which formed temporarily and provided nucleation sites for the final clusters to assemble. The intermediates were investigated by single crystal X-ray analysis and revealed to be novel clusters K(4)Li(22)[W(36)Si(4)Mn(7)O(136)(H(2)O)(8)].56H(2)O (2) and Mn(2)K(8)Li(14)[W(36)Si(4)Mn(7)O(136)(H(2)O)(8)].45H(2)O (3). The intermediate clusters contained different yet related building blocks to the final clusters which allowed for the postulation of a mechanism of assembly. This demonstrates a rare example where the use X-ray crystallography directly facilitated understanding the means by which a POM assembled. PMID- 23362187 TI - Nanotopographical cues augment mesenchymal differentiation of human embryonic stem cells. AB - The production of bone-forming osteogenic cells for research purposes or transplantation therapies remains a significant challenge. Using planar polycarbonate substrates lacking in topographical cues and substrates displaying a nanotopographical pattern, mesenchymal differentiation of human embryonic stem cells is directed in the absence of chemical factors and without induction of differentiation by embryoid body formation. Cells incubated on nanotopographical substrates show enhanced expression of mesenchymal or stromal markers and expression of early osteogenic progenitors at levels above those detected in cells on planar substrates in the same basal media. Evidence of epithelial-to mesenchymal transition during substrate differentiation and DNA methylation changes akin to chemical induction are also observed. These studies provide a suitable approach to overcome regenerative medical challenges and describe a defined, reproducible platform for human embryonic stem cell differentiation. PMID- 23362188 TI - Similar problem in the activities of daily living but different experience: a qualitative analysis in six rheumatic conditions and eight European countries. AB - OBJECTIVE: The aim of the present study was to compare and contrast the concepts of functioning in daily life which were important to patients with different rheumatological conditions. METHOD: The study comprised a qualitative analysis of 44 focus groups in eight European countries, in 229 patients with fibromyalgia, hand osteoarthritis, psoriatic arthritis, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis, using the World Health Organization, 2001 International Classification of Functioning, Disability and Health as a framework. Concepts and - where necessary - also sub-concepts and transcripts were combined and compared independently by two researchers who, in case of disagreement, achieved consensus through discussion. RESULTS: Twenty concepts out of 109 (e.g. body image, fatigue, emotional issues, mobility and hand function) were similarly described in all six diseases. However, even if the same concept was mentioned, patients' experiences were different, such as mental AND physical aspects limiting the ability to drive in patients with fibromyalgia compared with ONLY physical problems in all other diseases. Within body functions and structures, several concepts were relevant for certain conditions only. CONCLUSION: A large number of similar problems are mentioned as 'typical' by patients with different rheumatic conditions. These could probably be targeted, using a disease-specific approach, in interventions by non-physician health professionals. PMID- 23362189 TI - Electrochemical resolution of multiple redox events for graphene quantum dots. AB - Quantum dots: A sequential, single-electron charging process of monodisperse graphene quantum dots (GQDs) encapsulated in a dodecylamine envelope, facilitating a capacitance of a few attofarads is reported. The average GQDs dimensions, as ascertained from high-resolution transmission electron microscopy and atomic force microscopy, of about 3+/-0.3, 2.6+/-0.2, and 2.2+/-0.3 nm control this unprecedented behavior. PMID- 23362190 TI - A new family of trinuclear nickel(II) complexes as single-molecule magnets. AB - Three new trinuclear nickel (II) complexes with the general composition [Ni3 L3 (OH)(X)](ClO4 ) have been prepared in which X=Cl(-) (1), OCN(-) (2), or N3(-) (3) and HL is the tridentate N,N,O donor Schiff base ligand 2-[(3 dimethylaminopropylimino)methyl]phenol. Single-crystal structural analyses revealed that all three complexes have a similar Ni3 core motif with three different types of bridging, namely phenoxido (MU2 and MU3 ), hydroxido (MU3 ), and MU2 -Cl (1), MU1,1 -NCO (2), or MU1,1 -N3 (3). The nickel(II) ions adopt a compressed octahedron geometry. Single-crystal magnetization measurements on complex 1 revealed that the pseudo-three-fold axis of Ni3 corresponds to a magnetic easy axis, being consistent with the magnetic anisotropy expected from the coordination structure of each nickel ion. Temperature-dependent magnetic measurements indicated ferromagnetic coupling leading to an S=3 ground state with 2J/k=17, 17, and 28 K for 1, 2, and 3, respectively, with the nickel atoms in an approximate equilateral triangle. The high-frequency EPR spectra in combination with spin Hamiltonian simulations that include zero-field splitting parameters DNi /k=-5, -4, and -4 K for 1, 2, and 3, respectively, reproduced the EPR spectra well after a anisotropic exchange term was introduced. Anisotropic exchange was identified as Di,j /k=-0.9, -0.8, and -0.8 K for 1, 2, and 3, respectively, whereas no evidence of single-ion rhombic anisotropy was observed spectroscopically. Slow relaxation of the magnetization at low temperatures is evident from the frequency-dependence of the out-of-phase ac susceptibilities. Pulsed-field magnetization recorded at 0.5 K shows clear steps in the hysteresis loop at 0.5-1 T, which has been assigned to quantum tunneling, and is characteristic of single-molecule magnets. PMID- 23362191 TI - Further pharmacological evaluation of a novel synthetic peptide bradykinin B2 receptor agonist. AB - We recently identified a novel human B2 receptor (B2R) agonist [Hyp(3),Thi(5),(N)Chg(7),Thi(8)]-bradykinin (NG291) with greater in vitro and in vivo potency and duration of action than natural bradykinin (BK). Here, we further examined its stability and selectivity toward B2R. The hypotensive, antithrombotic, and profibrinolytic functions of NG291 relative to BK and its analogue ([Hyp(3),Thi(5),(4-Me)Tyr(8)(PsiCH(2)NH)Arg(9)]-BK) (RMP-7) were also tested. Contraction assays using isolated mouse stomachs (containing kinin B1R, B2R, and kininase I- and II-like activities) showed that NG291 is a more potent contractant than BK and is inhibited by HOE-140 (B2R antagonist) but unaffected by R954 (B1R antagonist), whereas both decreased the potency of BK. In stomach tissues from B2R knockout mice, BK maintained its activity via B1R, whereas NG291 had no contractile effect, indicating that it was selective for B2R. Unlike BK, NG291 was not degraded by rabbit lung ACE. Comparing intravenously administered BK and NG291 revealed that NG291 exhibited more potent and prolonged hypotensive action and greater antithrombotic and profibrinolytic activities. These effects were of comparable magnitude to RMP-7 and were absent in B2R knockout mice. We concluded that NG291 is a novel biostable B2R-selective agonist that may prove suitable for investigating the (pre)clinical cardioprotective efficacy of B2R activation. PMID- 23362192 TI - Expression and translation of the COX-1b gene in human cells--no evidence of generation of COX-1b protein. AB - Cyclooxygenase 1b (COX-1b) is a splice variant of COX-1, containing a retained intron 1 within the signal peptide sequence. COX-1b mRNA is found in many species, but the existence of a functionally active protein, which is possibly related to different species-dependent lengths of intron 1, is controversially discussed. The human intron 1 comprises 94 bp, and the resulting frameshift at the intron 1-exon 2 junction creates a premature stop codon. Nevertheless, full length human COX-1b protein expression, including translated intron 1 and the signal peptide, has been reported and was explained by a frameshift repair. In this study, the fate of COX-1b mRNA in a human overexpression system is analyzed. Independent of the hypothetical frameshift repair mechanism, the splicing of the COX-1b intron 1, resulting in COX-1 mRNA and removal of the signal peptide during protein maturation, with subsequent generation of a COX-1 protein is demonstrated. PMID- 23362194 TI - Deciphering the emerging role of SUMO conjugation in the hypoxia-signaling cascade. AB - By driving the primary transcriptional response, the hypoxia inducible factor (HIF) is a master player of the hypoxia-signaling cascade, activation of which is essential to maintain oxygen homeostasis. HIF is formed by the interaction of a constitutive HIF-1beta subunit with a HIF-alpha subunit tightly regulated through the concerted action of the prolyl hydroxylase domain containing proteins (PHDs) and factor inhibiting HIF. In well-oxygenated cells, HIF-alpha prolyl hydroxylation by PHDs is the recognition signal for the binding of the ubiquitin E3 ligase pVHL, allowing protein poly-ubiquitination and degradation by the proteasome. Factor inhibiting HIF-mediated asparaginyl hydroxylation prevents interaction with the CBP/p300 coactivator and hence reduces HIF-dependent transcriptional activity. Upon low oxygen availability, HIF-alpha hydroxylation is blocked, resulting in protein stabilization and HIF complex activation. Post translational modifications other than hydroxylation appear to be important in the cellular response to hypoxia. Small ubiquitin-like modifier (SUMO) is a 10 kDa protein readily conjugated to the lysine (K) residues of numerous cellular substrates in a sequential process termed SUMOylation. Recent data support the idea that a fine balance in SUMOylation/deSUMOylation is required for the adequate activation of the hypoxia-signaling cascade. In the present review, we will concentrate on the mechanisms of SUMOylation and its consequences in the cellular response to hypoxia. PMID- 23362193 TI - Plasma kallikrein-kinin system and diabetic retinopathy. AB - Diabetic retinopathy (DR) occurs, to some extent, in most people with at least 20 years' duration of diabetes mellitus. The progression of DR to its sight threatening stages is usually associated with the worsening of underlying retinal vascular dysfunction and disease. The plasma kallikrein-kinin system (KKS) is activated during vascular injury, where it mediates important functions in innate inflammation, blood flow, and coagulation. Recent findings from human vitreous proteomics and experimental studies on diabetic animal models have implicated the KKS in contributing to DR. Vitreous fluid from people with advanced stages of DR contains increased levels of plasma KKS components, including plasma kallikrein (PK), coagulation factor XII, and high-molecular-weight kininogen. Both bradykinin B1 and B2 receptor isoforms (B1R and B2R, respectively) are expressed in human retina, and retinal B1R levels are increased in diabetic rodents. The activation of the intraocular KKS induces retinal vascular permeability, vasodilation, and retinal thickening, and these responses are exacerbated in diabetic rats. Preclinical studies have shown that the administration of PK inhibitors and B1R antagonists to diabetic rats ameliorates retinal vascular hyperpermeability and inflammation. These findings suggest that components of plasma KKS are potential therapeutic targets for diabetic macular edema. PMID- 23362195 TI - Hydroxylase-dependent regulation of the NF-kappaB pathway. AB - Hypoxia is associated with a diverse range of physiological and pathophysiological processes, including development, wound healing, inflammation, vascular disease and cancer. The requirement that eukaryotic cells have for molecular oxygen as the terminal electron acceptor for the electron transport chain means that the maintenance of oxygen delivery is key for bioenergetic homeostasis. Metazoans have evolved an effective way to adapt to hypoxic stress at the molecular level through a transcription factor termed the hypoxia inducible factor. A family of oxygen-sensing hydroxylases utilizes molecular oxygen as a co-substrate for the hydroxylation of hypoxia inducible factor alpha subunits, thereby reducing its expression and transcriptional activity when oxygen is available. Recent studies have indicated that other hypoxia-responsive transcriptional pathways may also be hydroxylase-dependent. In this review, we will discuss the role of hydroxylases in the regulation of NF-kappaB, a key regulator of immunity and inflammation. Developing our understanding of the role of hydroxylases in hypoxic inflammation may identify novel therapeutic approaches in chronic inflammatory disease. PMID- 23362196 TI - Recent advances in the electrochemistry and spectroelectrochemistry of membrane proteins. AB - Integral membrane proteins are encountered in fundamental natural processes, such as photosynthesis and respiration. The relation between the structure of the proteins and their function and dynamics are still not clear in most cases. Once fully understood, these processes could ultimately help researchers to develop alternative methods for producing energy, either from light or biomass. They could also lead to more efficient antibiotics, which would selectively inhibit a specific membrane protein of pathogenic bacteria. Since the chemical reactions involved in both photosynthesis and respiration are redox reactions, electrochemical methods can play a considerable role in uncovering their mechanisms. The electrochemical characterization of membrane proteins is, however, quite challenging. An overview on the techniques used for the characterization of membrane proteins, including classical approaches such as voltammetry and spectroelectrochemistry, and recent developments, such as their combination with surface-enhanced techniques is given. PMID- 23362197 TI - Hydrolysis of dipeptide derivatives reveals the diversity in the M49 family. AB - Dipeptidyl peptidase III, a metallopeptidase of the M49 family, was first identified (in the pituitary) by its specific cleavage of diarginyl arylamides, which have been used as preferred assay substrates until now. Here we examined the activity of the yeast and human dipeptidyl peptidase III in parallel. The human enzyme preferred Arg(2)-beta-naphthylamide and showed 620-fold higher k(cat)/K(m) for this substrate. In contrast, the yeast enzyme did not display a preference for any of the X-Arg-beta-naphthylamide analyzed. The replacement of Gly(505) with Asp, resulted in a less active, but more selective, yeast enzyme form. These results indicate diversity in cleavage specificity in the M49 family. PMID- 23362198 TI - Influence of partial unfolding and aggregation of human stefin B (cystatin B) EPM1 mutants G50E and Q71P on selective cleavages by cathepsins B and S. AB - Human stefins and cystatins are physiologically important cysteine proteinase inhibitors, acting as a first line of defense against undesirable proteolysis. Mutations in the cystatin B gene cause a rare form of epilepsy EPM1. Its two missense mutants, G50E and Q71P, lack the inhibitory activity and are partially unfolded, which leads to changes in their aggregation behavior, both in vitro and in the cell. SDS-PAGE and MALDI-TOF mass spectrometry were used to follow the hydrolysis of human stefin B wild type, G50E and Q71P, by cathepsins B and S in vitro. Cathepsin S was found to degrade both mutants, with Q71P being degraded faster. This correlates with the openness of the protein structure, Q71P having more exposed hydrophobic surfaces. Cathepsin B acted more selectively, degrading G50E into smaller fragments, while still leaving a portion of the full-length protein intact. Q71P was cleaved only at the exposed N-terminal end. The co localization of stefin B wild type and EPM1 mutants with cathepsins showed that cathepsins accumulate around the aggregates formed by the EPM1 mutants. We hypothesize that the aggregation of both full-length mutants prevents the cathepsin molecule from accessing the substrate protein's core, whereas the cleaved fragments would be expected to aggregate stronger. PMID- 23362199 TI - Clinical impact of an angiotensin I-converting enzyme insertion/deletion and kinin B2 receptor +9/-9 polymorphisms in the prognosis of renal transplantation. AB - There is a consensus in the scientific literature that supports the importance of the kallikrein kinin and renin angiotensin systems in renal physiology, but few studies have investigated their importance after renal transplantation. The aim of this study was to investigate the clinical effects of the insertion/deletion polymorphism in the angiotensin I-converting enzyme (ACE) gene and the +9/-9 polymorphism in the kinin B2 receptor (B2R) gene in kidney-transplanted patients (n=215 ACE, n=203 B2R) compared with 443 healthy individuals. Demographic results showed that there is a higher frequency of the D allele (high plasma ACE activity) and +9 allele (lower B2R expression) in transplant patients compared with control individuals. We also observed a higher frequency of these alleles in patients who had an elevated level of plasma creatinine. At day 7 post transplantation, we found a higher prevalence of individuals with the DD genotype with elevated plasma creatinine level. Furthermore, individuals with the DD genotype had a higher chronic allograft dysfunction and graft loss compared with the II patient genotype, which showed no loss of graft. Taken together, our data suggest that the DD genotype is an indicator of an unfavorable prognosis following renal transplantation and could be related to kinin modulation. PMID- 23362200 TI - Role of hypoxia inducible factor-1alpha for interferon synthesis in mouse dendritic cells. AB - Dendritic cells (DCs) are an important link between innate and adaptive immunity. DCs get activated in inflamed tissues where oxygen tension is usually low, which requires the transcription factor hypoxia inducible factor (HIF)-1 for cellular adaptation. To investigate whether the HIF-1 transcriptional complex plays a pivotal role in the function of DCs, we compared the effects of exogenous inflammatory stimuli and hypoxia on HIF-1alpha in bone marrow-derived DCs from wild type and myeloid-specific HIF-1alpha knock-out mice. We showed that the Toll like receptor ligands lipopolysaccharides and cytosine-phosphatidyl-guanines significantly induce HIF-1alpha mRNA and protein, leading to elevated HIF-1 target gene expression of vascular endothelial growth factor. In contrast, polyinosinic:polycytidylic acid did not show comparable effects. Furthermore the potential to up-regulate inflammatory cytokines critically influences DC function. Our data demonstrate that HIF-1alpha protein is needed for adequate production of interferon-alpha and -beta. In co-cultures of DCs and cytotoxic T cells, we observed that DCs lacking active HIF-1alpha protein induce significantly less CD278 and granzyme B mRNA in T cells. We conclude that HIF 1alpha plays a crucial role in DC interferon production and T cell activation, linking the innate and adaptive immune system. PMID- 23362201 TI - Hydroxynonenal-stimulated activity of the uncoupling protein in Acanthamoeba castellanii mitochondria under phosphorylating conditions. AB - The influence of 4-hydroxy-2-nonenal (HNE), a lipid peroxidation end product, on the activity of the amoeba Acanthamoeba castellanii uncoupling protein (AcUCP) in isolated phosphorylating mitochondria was studied. Under phosphorylating conditions, exogenously added HNE induced GTP-sensitive AcUCP-mediated mitochondrial uncoupling. The HNE-induced proton leak decreased the yield of oxidative phosphorylation in an HNE concentration-dependent manner. The present study describes how the contributions of ATP synthase and HNE-induced AcUCP in phosphorylating respiration vary when the rate of succinate oxidation is decreased by limiting succinate uptake or inhibiting complex III activity within the range of a constant membrane potential. In phosphorylating mitochondria, at a given HNE concentration (100 MUM), the efficiency of AcUCP in mitochondrial uncoupling increased as the respiratory rate decreased because the AcUCP contribution remained constant while the ATP synthase contribution decreased with the respiratory rate. HNE-induced uncoupling can be inhibited by GTP only when ubiquinone is sufficiently oxidized, indicating that in phosphorylating A. castellanii mitochondria, the sensitivity of AcUCP activity to GTP depends on the redox state of the membranous ubiquinone. PMID- 23362202 TI - pK(a) values and redox potentials of proteins. What do they mean? AB - In this article, we review a microstate model that uses protonation and redox microstates in order to understand the complex pH and redox titration of proteins and other polyelectrolytes. From this model, it becomes obvious that it is impossible to assign pK(a) values or redox potentials to individual protonatable or redox-active sites in a protein in which many of such sites interact. Instead each site is associated with many microscopic equilibrium constants that may lead to irregular or even non-monotonic titration curves of some groups. The microstate model provides a closed theoretical framework to discuss such phenomena. PMID- 23362203 TI - Mechanistic aspects of sodium-binding sites in LeuT-like fold symporters. AB - Secondary active transporters are of paramount biological impact in all living cells, facilitating the movement of many different substrates across the membrane against a concentration gradient. The uphill transport of one substrate is coupled to the downhill transport of another and driven by the electrochemical gradient. In the last decade, an increasing number of atomic structures of secondary transporters have been reported, confirming a very fundamental mechanistic concept known as the alternating-access cycle. The wealth of structures of transporters sharing the so-called LeuT-like fold that is characterized by two five-transmembrane-helix repeats sharing a 2-fold inverted pseudo symmetry has raised big hopes to finally describe alternating access on a molecular level. Although comparing the individual transporter states of different LeuT-like fold transporters revealed striking similarities, the coupling process, which represents the heart of secondary transport, is far from being understood. Here, we review the structural, functional, and biophysical validation of sodium-binding sites in four different LeuT-like fold transporters. The conservation of sodium sites is discussed in light of their role as key elements connecting symmetry-related structural domains, which are involved in substrate translocation. Moreover, we highlight their crucial roles in conformational changes of LeuT-like fold transporters and their implication on a unifying mechanism in secondary transport. PMID- 23362204 TI - Hypoxia increases the yield of photoreceptors differentiating from mouse embryonic stem cells and improves the modeling of retinogenesis in vitro. AB - Retinitis pigmentosa (RP), a genetically heterogeneous group of diseases together with age-related macular degeneration (AMD), are the leading causes of permanent blindness and are characterized by the progressive dysfunction and death of the light sensing photoreceptors of the retina. Due to the limited regeneration capacity of the mammalian retina, the scientific community has invested significantly in trying to obtain retinal progenitor cells from embryonic stem cells (ESC). These represent an unlimited source of retinal cells, but it has not yet been possible to achieve specific populations, such as photoreceptors, efficiently enough to allow them to be used safely in the future as cell therapy of RP or AMD. In this study, we generated a high yield of photoreceptors from directed differentiation of mouse ESC (mESC) by recapitulating crucial phases of retinal development. We present a new protocol of differentiation, involving hypoxia and taking into account extrinsic and intrinsic cues. These include niche specific conditions as well as the manipulation of the signaling pathways involved in retinal development. Our results show that hypoxia promotes and improves the differentiation of mESC toward photoreceptors. Different populations of retinal cells are increased in number under the hypoxic conditions applied, such as Crx-positive cells, S-Opsin-positive cells, and double positive cells for Rhodopsin and Recoverin, as shown by immunofluorescence analysis. For the first time, this manuscript reports the high efficiency of differentiation in vivo and the expression of mature rod photoreceptor markers in a large number of differentiated cells, transplanted in the subretinal space of wild-type mice. PMID- 23362205 TI - Recombinant human collagen III gel for transplantation of autologous skin cells in porcine full-thickness wounds. AB - Complex skin wounds, such as chronic ulcers and deep burns, require lengthy treatments and cause extensive burdens on healthcare and the economy. Use of biomaterials and cell transplantation may improve traditional treatments and promote the healing of difficult-to-treat wounds. In this study, we investigated the use of recombinant human collagen III (rhCol-III) gel as a delivery vehicle for cultured autologous skin cells (keratinocytes only or keratinocyte-fibroblast mixtures). We examined its effect on the healing of full-thickness wounds in a porcine wound-healing model. Two Landrace pigs were used for the study. Fourteen deep dermal wounds were created on the back of each pig with an 8 mm biopsy punch. Syringes containing acellular rhCol-III gel (n = 8) or rhCol-III gel with autologous keratinocytes (n = 8) or rhCol-III gel with autologous keratinocytes and fibroblasts (n = 8) were applied into wounds. Untreated wounds were used as controls for the treatment groups (n = 4). We used rhCol-III gel to manufacture a cell-delivery syringe containing autologous skin cells. In a full-thickness wound healing model, we observed that rhCol-III gel enhances early granulation tissue formation. Interestingly, we found cell type-dependent differences in the stability of rhCol-III in vivo. Fibroblast-containing gel was effectively removed from the wound, whereas gels without cells or with keratinocytes only remained intact. Our results demonstrate that the properties of rhCol-III gel for skin cell transplantation can be significantly altered in a cell type-dependent manner. PMID- 23362206 TI - Multifarious roles of intrinsic disorder in proteins illustrate its broad impact on plant biology. AB - Intrinsically disordered proteins (IDPs) are highly abundant in eukaryotic proteomes. Plant IDPs play critical roles in plant biology and often act as integrators of signals from multiple plant regulatory and environmental inputs. Binding promiscuity and plasticity allow IDPs to interact with multiple partners in protein interaction networks and provide important functional advantages in molecular recognition through transient protein-protein interactions. Short interaction-prone segments within IDPs, termed molecular recognition features, represent potential binding sites that can undergo disorder-to-order transition upon binding to their partners. In this review, we summarize the evidence for the importance of IDPs in plant biology and evaluate the functions associated with intrinsic disorder in five different types of plant protein families experimentally confirmed as IDPs. Functional studies of these proteins illustrate the broad impact of disorder on many areas of plant biology, including abiotic stress, transcriptional regulation, light perception, and development. Based on the roles of disorder in the protein-protein interactions, we propose various modes of action for plant IDPs that may provide insight for future experimental approaches aimed at understanding the molecular basis of protein function within important plant pathways. PMID- 23362207 TI - HISTONE DEACETYLASE19 interacts with HSL1 and participates in the repression of seed maturation genes in Arabidopsis seedlings. AB - The seed maturation genes are specifically and highly expressed during late embryogenesis. In this work, yeast two-hybrid, bimolecular fluorescence complementation, and coimmunoprecipitation assays revealed that HISTONE DEACETYLASE19 (HDA19) interacted with the HIGH-LEVEL EXPRESSION OF SUGAR INDUCIBLE GENE2-LIKE1 (HSL1), and the zinc-finger CW [conserved Cys (C) and Trp (W) residues] domain of HSL1 was responsible for the interaction. Furthermore, we found that mutations in HDA19 resulted in the ectopic expression of seed maturation genes in seedlings, which was associated with increased levels of gene activation marks, such as Histone H3 acetylation (H3ac), Histone H4 acetylation (H4ac), and Histone H3 Lys 4 tri-methylation (H3K4me3), but decreased levels of the gene repression mark Histone H3 Lys 27 tri-methylation (H3K27me3) in the promoter and/or coding regions. In addition, elevated transcription of certain seed maturation genes was also found in the hsl1 mutant seedlings, which was also accompanied by the enrichment of gene activation marks but decreased levels of the gene repression mark. Chromatin immunoprecipitation assays showed that HDA19 could directly bind to the chromatin of the seed maturation genes. These results suggest that HDA19 and HSL1 may act together to repress seed maturation gene expression during germination. Further genetic analyses revealed that the homozygous hsl1 hda19 double mutants are embryonic lethal, suggesting that HDA19 and HSL1 may play a vital role during embryogenesis. PMID- 23362208 TI - HDA18 affects cell fate in Arabidopsis root epidermis via histone acetylation at four kinase genes. AB - The differentiation of hair (H) and non-hair (N) cells in the Arabidopsis thaliana root epidermis is dependent on positional relationships with underlying cortical cells. We previously found that histone acetylation relays positional information and that a mutant altered in the histone deacetylase gene family member HISTONE DEACETYLASE 18 (HDA18) exhibits altered H and N epidermal cell patterning. Here, we report that HDA18 has in vitro histone deacetylase activity and that both mutation and overexpression of HDA18 led to cells at the N position having H fate. The HDA18 protein physically interacted with histones related to a specific group of kinase genes, which are demonstrated in this study to be components of a positional information relay system. Both down- and upregulation of HDA18 increased transcription of the targeted kinase genes. Interestingly, the acetylation levels of histone 3 lysine 9 (H3K9), histone 3 lysine 14 (H3K14) and histone 3 lysine 18 (H3K18) at the kinase genes were differentially affected by down- or upregulation of HDA18, which explains why the transcription levels of the four HDA18-target kinase genes increased in all lines with altered HDA18 expression. Our results reveal the surprisingly complex mechanism by which HDA18 affects cellular patterning in Arabidopsis root epidermis. PMID- 23362209 TI - PECTIN METHYLESTERASE INHIBITOR6 promotes Arabidopsis mucilage release by limiting methylesterification of homogalacturonan in seed coat epidermal cells. AB - Imbibed seeds of the Arabidopsis thaliana accession Djarly are affected in mucilage release from seed coat epidermal cells. The impaired locus was identified as a pectin methylesterase inhibitor gene, PECTIN METHYLESTERASE INHIBITOR6 (PMEI6), specifically expressed in seed coat epidermal cells at the time when mucilage polysaccharides are accumulated. This spatio-temporal regulation appears to be modulated by GLABRA2 and LEUNIG HOMOLOG/MUCILAGE MODIFIED1, as expression of PMEI6 is reduced in mutants of these transcription regulators. In pmei6, mucilage release was delayed and outer cell walls of epidermal cells did not fragment. Pectin methylesterases (PMEs) demethylate homogalacturonan (HG), and the majority of HG found in wild-type mucilage was in fact derived from outer cell wall fragments. This correlated with the absence of methylesterified HG labeling in pmei6, whereas transgenic plants expressing the PMEI6 coding sequence under the control of the 35S promoter had increased labeling of cell wall fragments. Activity tests on seeds from pmei6 and 35S:PMEI6 transgenic plants showed that PMEI6 inhibits endogenous PME activities, in agreement with reduced overall methylesterification of mucilage fractions and demucilaged seeds. Another regulator of PME activity in seed coat epidermal cells, the subtilisin-like Ser protease SBT1.7, acts on different PMEs, as a pmei6 sbt1.7 mutant showed an additive phenotype. PMID- 23362210 TI - Belief in AIDS-related conspiracy theories and mistrust in the government: relationship with HIV testing among at-risk older adults. AB - PURPOSE: One in 4 persons living with HIV/AIDS is an older adult (age 50 or older); unfortunately, older adults are disproportionately diagnosed in late stages of HIV disease. Psychological barriers, including belief in AIDS-related conspiracy theories (e.g., HIV was created to eliminate certain groups) and mistrust in the government, may influence whether adults undergo HIV testing. We examined relationships between these factors and recent HIV testing among at risk, older adults. DESIGN AND METHODS: This was a cross-sectional study among older adults enrolled in a large venue-based study. None had a previous diagnosis of HIV/AIDS; all were seeking care at venues with high HIV prevalence. We used multiple logistic regression to estimate the associations between self-reported belief in AIDS-related conspiracy theories, mistrust in the government, and HIV testing performed within the past 12 months. RESULTS: Among the 226 participants, 30% reported belief in AIDS conspiracy theories, 72% reported government mistrust, and 45% reported not undergoing HIV testing within the past 12 months. Belief in conspiracy theories was positively associated with recent HIV testing (adjusted odds ratio [OR] = 1.94, 95% confidence interval [CI] = 1.05-3.60), whereas mistrust in the government was negatively associated with testing (OR = 0.43, 95% CI = 0.26-0.73). IMPLICATIONS: Psychological barriers are prevalent among at-risk older adults seeking services at venues with high HIV prevalences and may influence HIV testing. Identifying particular sources of misinformation and mistrust would appear useful for appropriate targeting of HIV testing strategies. PMID- 23362211 TI - Neuroprotective effects of formononetin against NMDA-induced apoptosis in cortical neurons. AB - Formononetin (FMNT) is an isoflavone found in many herbs including Trifolium pratense L., Spatholobus suberectus Dunn., and Astragalus mongholicus Bunge. The purpose of this study is to investigate pharmacological properties of FMNT on neurotoxicity induced by N-methyl-D-asparate (NMDA) in primary-cultured cortical neurons. The cell viability was significantly decreased after exposure to NMDA (200 MUM) for 40 min. Pretreatment of FMNT (10 MUM) for 12 h significantly attenuated the cell loss induced by NMDA exposure. Flow cytometry analysis revealed that treatment of FMNT attenuated the number of apoptotic cells, especially the early phase apoptotic cells, induced by NMDA exposure. Western blot analysis showed that FMNT regulated the expression of apoptosis-related proteins by increasing the levels of Bcl-2 and pro-caspase-3 and decreasing the levels of Bax and caspase-3. These findings demonstrate that FMNT is capable of protecting neurons from NMDA-evoked excitotoxic injury and has a potential perspective to the clinical treatment for neurodegenerative disorders in central nervous system. PMID- 23362212 TI - Gold nanotip array for ultrasensitive electrochemical sensing and spectroscopic monitoring. AB - A gold nanotip array platform with a combination of ultrasensitive electrochemical sensing and spectroscopic monitoring capability is reported. Adenosine triphosphate is detected down to 1 pM according to the impedance changes in response to aptamer-specific binding. Furthermore, the local molecular information can be monitored at the individual plasmonic nanotips, and hence provide the capability for a better understanding of complex biological processes. PMID- 23362213 TI - Does hydrogen-bonding donation to manganese(IV)-oxo and iron(IV)-oxo oxidants affect the oxygen-atom transfer ability? A computational study. AB - Iron(IV)-oxo intermediates are involved in oxidations catalyzed by heme and nonheme iron enzymes, including the cytochromes P450. At the distal site of the heme in P450 Compound I (Fe(IV) -oxo bound to porphyrin radical), the oxo group is involved in several hydrogen-bonding interactions with the protein, but their role in catalysis is currently unknown. In this work, we investigate the effects of hydrogen bonding on the reactivity of high-valent metal-oxo moiety in a nonheme iron biomimetic model complex with trigonal bipyramidal symmetry that has three hydrogen-bond donors directed toward a metal(IV)-oxo group. We show these interactions lower the oxidative power of the oxidant in reactions with dehydroanthracene and cyclohexadiene dramatically as they decrease the strength of the O?H bond (BDEOH ) in the resulting metal(III)-hydroxo complex. Furthermore, the distal hydrogen-bonding effects cause stereochemical repulsions with the approaching substrate and force a sideways attack rather than a more favorable attack from the top. The calculations, therefore, give important new insights into distal hydrogen bonding, and show that in biomimetic, and, by extension, enzymatic systems, the hydrogen bond may be important for proton-relay mechanisms involved in the formation of the metal-oxo intermediates, but the enzyme pays the price for this by reduced hydrogen atom abstraction ability of the intermediate. Indeed, in nonheme iron enzymes, where no proton relay takes place, there generally is no donating hydrogen bond to the iron(IV)-oxo moiety. PMID- 23362215 TI - Wogonin attenuates endotoxin-induced prostaglandin E2 and nitric oxide production via Src-ERK1/2-NFkappaB pathway in BV-2 microglial cells. AB - Microglia are the major component of intrinsic brain immune system in neuroinflammation. Although wogonin expresses anti-inflammatory function in microglia, little is known about the molecular mechanisms of the protective effect of wogonin against microglia activation. The aim of this study was to evaluate how wogonin exerts its anti-inflammatory function in BV2 microglial cells after LPS/INFgamma administration. Wogonin not only inhibited LPS/ INFgamma induced PGE2 and NO production without affecting cell viability but also exhibited parallel inhibition on LPS/INFgamma-induced expression of iNOS and COX 2 in the same concentration range. While LPS/INFgamma-induced expression of P-p65 and P-IkappaB was inhibited by wogonin-only weak inhibition on P-p38 and P-JNK were observed, whereas it significantly attenuated the P-ERK1/2 and its upstream activators P-MEK1/2 and P-Src in a parallel concentration-dependent manner. These results indicated that the blockade of PGE2 and NO production by wogonin in LPS/INFgamma-stimulated BV2 cells is attributed mainly to interference in the Src MEK1/2-ERK1/2-NFkappaB-signaling pathway. PMID- 23362214 TI - Fibronectin mediates correct positioning of the interrenal organ in zebrafish. AB - BACKGROUND: Fibronectin (Fn) forms a centripetal gradient during the fetal adrenal gland organogenesis, and modulates hormone responsiveness of adrenocortical cells in the primary culture. However, how Fn is involved in organ formation of the adrenal gland remains unclear. RESULTS: In this study, we found that Fn accumulates around migrating ff1b-expressing interrenal cells, which were marked by the ff1b promoter-driven transgenic fluorescence, during the course of interrenal organ assembly. The interrenal cells displaying the migratory phenotype were absent in the fn1 mutant, while specification and kidney association of the interrenal tissue remained normal. The Fn deposition in the interrenal microenvironment was severely reduced in the vessel-deficient ets1b morphant, implying its origin of synthesis from the peri-interrenal vasculature. In the fn1 mutant, early-migrating chromaffin cells were capable of interacting with steroidogenic interrenal cells, yet continuous migration and midline convergence of chromaffin cells were disrupted. Migration defects of both interrenal and chromaffin lineages, in the absence of Fn, thus led to incomplete interrenal organ assembly in aberrant positions. CONCLUSIONS: Our results indicate that Fn is essential for patterning interrenal organ formation, by modulating the migratory behavior of both steroidogenic interrenal and chromaffin cells. PMID- 23362216 TI - Interplay of cascade oxidative cyclization and hydride shifts in the synthesis of the ABC spiroketal ring system of pectenotoxin-4. AB - Concepts: The formation of stereochemically defined bis-THF units through a double cyclization and a hydride-shift-initiated route to spiroketals is described (see scheme; Xc=chiral auxiliary). The resulting sequence has been used in a synthesis of the C1-16 fragment of the naturally occurring antitumor agent pectenotoxin-4. PMID- 23362218 TI - Concise review: the dynamics of induced pluripotency and its behavior captured in gene network motifs. AB - The flexibility of cellular identity is clearly demonstrated by the possibility to reprogram fully differentiated somatic cells to induced pluripotent stem (iPS) cells through forced expression of a set of transcription factors. The generation of iPS cells is of great interest as they provide a tremendous potential for regenerative medicine and an attractive platform to investigate pluripotency. Despite having gathered much attention, the molecular details and responsible gene regulatory networks during the reprogramming process are largely unresolved. In this review, we analyze the sequence and dynamics of reprogramming to construct a timeline of the molecular events taking place during induced pluripotency. We use this timeline as a road map to explore the distinct phases of the reprogramming process and to suggest gene network motifs that are able to describe its systems behavior. We conclude that the gene networks involved in reprogramming comprise several feedforward loops combined with autoregulatory behavior and one or more AND gate motifs that can explain the observed dynamics of induced pluripotency. Our proposed timeline and derived gene network motif behavior could serve as a tool to understand the systems behavior of reprogramming and identify key transitions and/or transcription factors that influence somatic cell reprogramming. Such a systems biology strategy could provide ways to define and explore the use of additional regulatory factors acting at defined gene network motifs to potentially overcome the current challenges of inefficient, slow, and partial somatic cell reprogramming and hence set ground of using iPS cells for clinical and therapeutic use. PMID- 23362217 TI - Quantification of Mesenchymal Stem Cells (MSCs) at sites of human prostate cancer. AB - Circulating bone marrow-derived Mesenchymal Stem Cells (BM-MSCs) have an innate tropism for tumor tissue in response to the inflammatory microenvironment present in malignant lesions. The prostate is bombarded by numerous infectious and inflammatory insults over a lifetime. Chronic inflammation is associated with CXCL12, CCL5, and CCL2, which are highly overexpressed in prostate cancer. Among other cell types, these chemoattractant stimuli recruit BM-MSCs to the tumor. MSCs are minimally defined as plastic-adhering cells characterized by the expression of CD90, CD73, and CD105 in the absence of hematopoietic markers, which can differentiate into osteoblasts, chondrocytes, and adipocytes. MSCs are immunoprivileged and have been implicated in tumorigenesis through multiple mechanisms, including promoting proliferation, angiogenesis, and metastasis, in addition to the generation of an immunosuppressive microenvironment. We have demonstrated that MSCs represent 0.01-1.1% of the total cells present in core biopsies from primary human prostatectomies. Importantly, these analyses were performed on samples prior to expansion in tissue culture. MSCs in these prostatectomy samples are FAP-, CD90-, CD73-, and CD105-positive, and CD14-, CD20 , CD34-, CD45-, and HLA-DR-negative. Additionally, like BM-MSCs, these prostate cancer-derived stromal cells (PrCSCs) were shown to differentiate into osteoblasts, adipocytes and chondrocytes. In contrast to primary prostate cancer derived epithelial cells, fluorescently-labeled PrCSCs and BM-MSCs were both shown to home to CWR22RH prostate cancer xenografts following IV injection. These studies demonstrate that not only are MSCs present in sites of prostate cancer where they may contribute to carcinogenesis, but these cells may also potentially be used to deliver cytotoxic or imaging agents for therapeutic and/or diagnostic purposes. PMID- 23362219 TI - Testosterone alters genomic responses to song and monoaminergic innervation of auditory areas in a seasonally breeding songbird. AB - Behavioral responses to social stimuli often vary according to endocrine state. Our previous work has suggested that such changes in behavior may be due in part to hormone-dependent sensory processing. In the auditory forebrain of female white-throated sparrows, expression of the immediate early gene ZENK (egr-1) is higher in response to conspecific song than to a control sound only when plasma estradiol reaches breeding-typical levels. Estradiol also increases the number of detectable noradrenergic neurons in the locus coeruleus and the density of noradrenergic and serotonergic fibers innervating auditory areas. We hypothesize, therefore, that reproductive hormones alter auditory responses by acting on monoaminergic systems. This possibility has not been examined in males. Here, we treated non-breeding male white-throated sparrows with testosterone to mimic breeding-typical levels and then exposed them to conspecific male song or frequency-matched tones. We observed selective ZENK responses in the caudomedial nidopallium only in the testosterone-treated males. Responses in another auditory area, the caudomedial mesopallium, were selective regardless of hormone treatment. Testosterone treatment reduced serotonergic fiber density in the auditory forebrain, thalamus, and midbrain, and although it increased the number of noradrenergic neurons detected in the locus coeruleus, it reduced noradrenergic fiber density in the auditory midbrain. Thus, whereas we previously reported that estradiol enhances monoaminergic innervation of the auditory pathway in females, we show here that testosterone decreases it in males. Mechanisms underlying testosterone-dependent selectivity of the ZENK response may differ from estradiol-dependent ones PMID- 23362221 TI - Is having rheumatoid arthritis a fate worse than death? PMID- 23362220 TI - High bone mass is associated with an increased prevalence of joint replacement: a case-control study. AB - OBJECTIVE: Epidemiological studies have shown an association between OA and increased BMD. To explore the nature of this relationship, we examined whether the risk of OA is increased in individuals with high bone mass (HBM), in whom BMD is assumed to be elevated due to a primary genetic cause. METHODS: A total of 335,115 DXA scans were screened to identify HBM index cases (defined by DXA scan as an L1 Z-score of >=+3.2 and total hip Z-score >=+1.2, or total hip Z-score >=+3.2 and L1 Z-score >=+1.2). In relatives, the definition of HBM was L1 Z-score plus total hip Z-score >=+3.2. Controls comprised unaffected relatives and spouses. Clinical indicators of OA were determined by structured assessment. Analyses used logistic regression adjusting for age, gender, BMI and social deprivation. RESULTS: A total of 353 HBM cases (mean age 61.7 years, 77% female) and 197 controls (mean age 54.1 years, 47% female) were included. Adjusted NSAID use was more prevalent in HBM cases versus controls [odds ratio (OR) 2.17 (95% CI 1.10, 4.28); P = 0.03]. The prevalence of joint replacement was higher in HBM cases (13.0%) than controls (4.1%), with an adjusted OR of 2.42 (95% CI 1.06, 5.56); P = 0.04. Adjusted prevalence of joint pain and knee crepitus did not differ between cases and controls. CONCLUSION: HBM is associated with increased prevalence of joint replacement surgery and NSAID use compared with unaffected controls. PMID- 23362222 TI - Body weight at early and middle adulthood, weight gain and persistent overweight from early adulthood are predictors of the risk of total knee and hip replacement for osteoarthritis. AB - OBJECTIVES: To examine the relationships between weight at early and middle adulthood and adult weight gain and the risk of total knee and hip replacement for OA. METHODS: At baseline interview during 1990-94, 38,149 participants [mean age 54.9 (S.D. 8.6) years] of the Melbourne Collaborative Cohort Study were asked to recall their weight at age 18-21 years and had their middle age height and weight measured. Total knee and hip replacement for OA between 2001 and 2009 was determined by linking the cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. RESULTS: Greater weight and BMI at age 18-21 years and middle age, weight gain and persistent overweight during this time were associated with an increased risk of total knee and hip replacement. Middle age weight [hazard ratio (HR) per 5 kg 1.25 (95% CI 1.23, 1.27) for knee vs 1.11 (1.09, 1.14) for hip] and BMI [HR per 5 kg/m(2) 1.80 (1.72, 1.89) vs 1.29 (1.21, 1.37)] and adult weight gain [HR per 5 kg 1.25 (1.23, 1.28) vs 1.10 (1.07, 1.13)] were more strongly associated with the risk of total knee replacement than total hip replacement (P for heterogeneity of HRs <0.0001). CONCLUSION: Greater body weight and BMI at early and middle adulthood, weight gain and persistent overweight from early to middle adulthood are risk factors for knee and hip OA. Adult weight gain confers stronger risk on knee OA than hip OA. Weight control from early adulthood and avoiding weight gain are important for the prevention of OA. PMID- 23362223 TI - Alarmins in tendinopathy: unravelling new mechanisms in a common disease. AB - Tendon disorders-tendinopathies-are the primary reason for musculoskeletal consultation in primary care in the UK and account for up to 30% of rheumatological consultations. While the molecular pathophysiology of tendinopathy remains incompletely understood, recent observations concerning repetitive stress and cellular load provide important mechanistic insight implicating a role for tissue alarmins. These in turn have an emerging effector role in many disease processes across the rheumatological diseases. Intracellular alarmins, also called damage-associated molecular patterns, are rapidly released following non-programmed cell death, are key effectors of the innate immune system and critically restore homeostasis by promoting the reconstruction of the affected tissue. Recent investigations have highlighted a key role for several alarmins including hypoxia-induced elements, cytokines and heat shock proteins affecting tissue rescue mechanisms in tendon pathology. This review aims to provide an overview of the biology of alarmins in the context of inflammatory mediators and matrix regulation in tendinopathy. PMID- 23362224 TI - Graphene oxide-based fluorescent biosensor for protein detection via terminal protection of small-molecule-linked DNA. AB - A fluorescence method for protein detection is developed based on terminal protection of small-molecule-linked DNA by target protein and a graphene oxide assisted DNA assay strategy. This design results in fluorescence-enhanced detection that is sensitive and selective for the target protein. PMID- 23362225 TI - Conditional expression of the dominant-negative TGF-beta receptor type II elicits lingual epithelial hyperplasia in transgenic mice. AB - BACKGROUND: The transforming growth factor-beta (TGF-beta) signaling pathway is generally believed to be a potent inhibitor of proliferation. However, many epithelia lacking the essential Tgfbr2 gene still maintain normal tissue homeostasis. Here, transgenic mice expressing rtTA from the human keratin 14 (K14) promoter were used to generate an inducible dominant-negative TGF-beta receptor type II (Tgfbr2) mutant model, which allowed us to distinguish between the primary and secondary effects of TGF-beta signaling disruption by Doxycycline treatment in K14+ epithelial stem cells. RESULTS: We showed that in mice lacking TGF-beta signaling in K14+ cells, invasive carcinomas developed on the ventral surface of the tip of the tongue, while filiform papillae on the dorsal surface showed different pathological changes from the tip to the posterior of the tongue. In addition, acetylation levels of histone H4 and histone H3 rapidly increased, while pMAPK activity was enhanced and Jagged2 inactivated in lingual epithelia after disruption of TGF-beta signaling. CONCLUSIONS: Our results contribute to the understanding of TGF-beta signaling in regulating homeostasis and carcinogenesis in lingual epithelia. PMID- 23362226 TI - Ultrastructural changes during spermatogenesis, biochemical and hormonal evidences of testicular toxicity caused by TBT in freshwater prawn Macrobrachium rosenbergii (De Man, 1879). AB - The present investigation documents the impact of tributyltin (TBT) on the ultrastructural variation of spermatogenesis in freshwater prawn Macrobrachium rosenbergii. The environmentally realistic concentration of TBT can cause damages to the endocrine and reproductive physiology of crustaceans. In this context, three concentrations viz. 10, 100, and 1000 ng/L were selected and exposed to prawns for 90 days. The TBT exposed prawn exhibited decrease the reproductive activity as evidenced by sperm count and sperm length compared to control. Histopathological results revealed the retarded testicular development, abnormal structure of seminiferous tubule, decrease in the concentration of spermatozoa, diminution of seminiferous tubule membrane, abundance of spermatocytes and vacuolation in testis of treated prawns. Ultrastructural study also confirmed the impairment of spermatogenesis in treated prawns. Furthermore, radioimmunoassay (RIA) clearly documented the reduction of testosterone level in TBT exposed groups. Thus, TBT substantially reduced the level of male sex hormone as well as biochemical constituents which ultimately led to impairment of spermatogenesis in the freshwater male prawn M. rosenbergii. PMID- 23362227 TI - Enantioselective palladium-catalyzed decarboxylative allylation of carbazolones and indolones: formal synthesis of (+)-kopsihainanine A. PMID- 23362228 TI - Histone acetyltransferase cofactor Trrap maintains self-renewal and restricts differentiation of embryonic stem cells. AB - Chromatin states are believed to play a key role in distinct patterns of gene expression essential for self-renewal and pluripotency of embryonic stem cells (ESCs); however, the genes governing the establishment and propagation of the chromatin signature characteristic of pluripotent cells are poorly understood. Here, we show that conditional deletion of the histone acetyltransferase cofactor Trrap in mouse ESCs triggers unscheduled differentiation associated with loss of histone acetylation, condensation of chromatin into distinct foci (heterochromatization), and uncoupling of H3K4 dimethylation and H3K27 trimethylation. Trrap loss results in downregulation of stemness master genes Nanog, Oct4, and Sox2 and marked upregulation of specific differentiation markers from the three germ layers. Chromatin immunoprecipitation-sequencing analysis of genome-wide binding revealed a significant overlap between Oct4 and Trrap binding in ESCs but not in differentiated mouse embryonic fibroblasts, further supporting a functional interaction between Trrap and Oct4 in the maintenance of stemness. Remarkably, failure to downregulate Trrap prevents differentiation of ESCs, suggesting that downregulation of Trrap may be a critical step guiding transcriptional reprogramming and differentiation of ESCs. These findings establish Trrap as a critical part of the mechanism that restricts differentiation and promotes the maintenance of key features of ESCs. PMID- 23362229 TI - The process of apoptosis in a holocrine gland as shown by the avian uropygial gland. AB - This study was designed to elucidate the presence of apoptosis and the localization of apoptosis-related Bax and survivin proteins and proliferating cell nuclear antigen (PCNA) within the chicken uropygial gland, a specialized holocrine secretory gland. In day-old chicks, survivin and Bax immunoreactivities were observed in the cell cytoplasm of the germinative and secretory layers of the luminal epithelium and tubules. During this period, the TUNEL reaction, an indication of apoptosis, was only sporadically positive in the tubules. From the 7th day to the 150th day of posthatching, survivin was detected in the cytoplasm of cells in the germinative layer and in the nuclei of some cells in the secretory layers of the gland. The germinative layer cells showed weak homogeneous cytoplasmic staining for Bax, whereas the cells of the secretory and intermediate layers of luminal epithelium and tubules exhibited granular cytoplasmic staining. After day 7, TUNEL-positive cells were observed in the secretory and degenerative layers of the luminal epithelium and central tubules. After day 12, some TUNEL-positive cells were also seen in the peripheral tubules. At all posthatch ages, the cytoplasm and nucleus of the germinative layers of luminal epithelium and tubules reacted with PCNA, whereas only a small number of cell nuclei in the secretory layers were immunopositive. These results support the theory that specific PCNA/Bax/survivin expression patterns could reflect particular cell differentiation states in the uropygial gland and that holocrine secretion in the gland is realized mainly by way of apoptosis. PMID- 23362230 TI - Preliminary extraction of tannins by 1-butyl-3-methylimidazole bromide and its subsequent removal from Galla chinensis extract using macroporous resins. AB - In recent years, ionic liquids have become increasingly attractive as 'green solvents' used in the extraction of bioactive compounds from natural plant. However, the separation of ionic liquid from the target compounds was difficult, due to their low vapour pressure and high stabilities. In our study, ionic liquid based ultrasonic and microwave-assisted extraction was used to obtain the crude tannins, then the macroporous resin adsorption technology was further employed to purify the tannins and remove the ionic liquid from crude extract. The results showed that XDA-6 had higher separation efficiency than other tested resins, and the equilibrium experimental data were well fitted to Langmuir isotherms. Dynamic adsorption and desorption were performed on XDA-6 packed in glass columns to optimise the separation process. The optimum conditions as follows: the ratio of column height to diameter bed was 1:8, flow rate 1 BV/h (bed volume per hour), 85% ethanol was used as eluant while the elution volume was 2 BV. Under the optimised conditions, the adsorption and desoption rate of tannins in XDA-6 were 94.81 and 91.63%, respectively. The content of tannins was increased from 70.24% in Galla chinensis extract to 85.12% with a recovery of 99.06%. The result of ultra-performance liquid chromatography (UPLC)-MS/MS analysis showed that [bmim]Br could be removed from extract. PMID- 23362231 TI - Heavy metal influence on BDE-47 uptake in the human KERTr keratinocyte cell line. AB - Significant correlations between concentrations of PBDEs and heavy metals were observed in the human body. However, there is a lack of evidence on the linkage between the uptake of heavy metals and PBDEs. This study is the first report on the BDE-47 uptake profile in a human cell line. Hg and As exposures to KERTr (human skin derived keratinocyte) did not significantly (p > 0.05) affect the uptake of BDE47, whereas Pb and Cd significantly (p < 0.05) affected the uptake of BDE-47 in KERTr. The change in Km was minor after exposure to all heavy metals. The maximum transport rate (Vmax) after exposure to Pb (Vmax: 5.23 +/- 0.49) and As (Vmax: 4.95 +/- 0.60) was significantly increased when compared with the background of the KERTr cell line (Vmax: 4.07 +/- 0.35). Real-time RT-PCR indicated that OATP-B, OATP-D, and OATP-E were expressed in the KERTr cell line. The upregulation or downregulation of OATP B and D genes were minor after exposure to heavy metals, but the OATP E gene was upregulated by three to fourfold in KERTr cell line after exposure to Pb an Cd, which may explain the significant increase of uptake of BDE-47 in KERTr after exposures to Pb and Cd. This study indicated that the uptake effects should be considered when performing risk assessment of human exposure to PBDEs and heavy metal. PMID- 23362232 TI - Multistep enzymatic synthesis of long-chain alpha,omega-dicarboxylic and omega hydroxycarboxylic acids from renewable fatty acids and plant oils. AB - A multistep enzyme catalysis was successfully implemented to produce long-chain alpha,omega-dicarboxylic and omega-hydroxycarboxylic acids from renewable fatty acids and plant oils. Sebacic acid as well as omega-hydroxynonanoic acid and omega-hydroxytridec-11-enoic acid were produced from oleic and ricinoleic acid. PMID- 23362233 TI - Pericardial fluid cytology: an analysis of 128 specimens over a 6-year period. AB - BACKGROUND: Pericardial fluid (PF) accumulates through various mechanisms and cytology is part of the workup to determine the specific etiology, primarily to rule in or rule out malignancy. To the best of the authors' knowledge, the current study is the largest systematic evaluation of PF cytology performed to date. METHODS: PF specimens collected over 6 years were retrieved. Clinical history, laboratory, cytologic, and pericardial biopsy results were recorded. RESULTS: A total of 128 PF specimens were obtained from 113 patients (56 males and 57 females), representing 4.5% of all fluids. Of these, 95 cases (74.2%) were benign, 2 (1.6%) had "severely atypical cells, " and 31 cases (24.2%) were malignant. The most common etiologies for benign PF specimens were neoplasm (23.1%), idiopathic (19%), infection (14.7%), and connective tissue disease (12.6%). The most common neoplasm producing malignant PF was lung carcinoma, both in males (75%) and females (52.2%), with adenocarcinoma being the most common type (72.2%). In females, breast carcinoma was the second most common neoplasm (39.1%). Approximately 87.1% of patients with malignant PF specimens had a prior history of malignancy and approximately 32.7% underwent a concomitant pericardial biopsy. The false-negative rate for cytology was 14.7% (hematologic malignancies [2 cases], metastatic sarcoma [1 case], and sarcoidosis [1 case] not detected) and that for pericardial biopsy was 40% (metastatic carcinoma [4 cases] not detected). CONCLUSIONS: PF specimens are uncommon. A specific interpretation is rendered in approximately 98.4% of cases. Lung carcinoma is the most common tumor to produce malignant PF in both males and females. Approximately 87.1% of patients with malignant PF have a known history of malignancy. Although cytology is superior to pericardial biopsy in diagnosing metastatic carcinoma, other tumors may go undetected in the PF. PMID- 23362234 TI - Role of WT1-ZNF224 interaction in the expression of apoptosis-regulating genes. AB - The transcription factor Wilms' tumor gene 1, WT1, is implicated both in normal developmental processes and in the generation of a variety of solid tumors and hematological malignancies. Physical interactions of other cellular proteins with WT1 are known to modulate its function. We previously identified the Kruppel-like zinc-finger protein, ZNF224, as a novel human WT1-associating protein that enhances the transcriptional activation of the human vitamin D receptor promoter by WT1. Here, we have analyzed the effects of WT1-ZNF224 interaction on the expression of apoptosis-regulating genes in the chronic myelogenous leukemia (CML) K562 cell line. The results demonstrated that ZNF224 acts in fine tuning of WT1-dependent control of gene expression, acting as a co-activator of WT1 in the regulation of proapoptotic genes and suppressing WT1 mediated transactivation of antiapoptotitc genes. Moreover, the DNA damaging drug cytosine arabinoside (ara C) induces expression of ZNF224 in K562 cells and this induction enhances cell apoptotic response to ara-C. These findings suggest that ZNF224 can be a mediator of DNA damage-induced apoptosis in leukemia cells. PMID- 23362235 TI - A review of violent incidents in a multilevel secure forensic psychiatric hospital: is there a seasonal variation? AB - There have been several attempts made to reduce the occurrence of violence in hospital settings, with most professional organizations taking a stance. The impact of violent incidence on the therapeutic environment and the cost in human terms led to the declaration by the World Health Organization that violence is a public health problem. There are strategies for reducing violence that flow out of known trends. We sought to examine the trends in institutional violence in a contextual sense. We reviewed the records of all incidents of violence, categorized by severity, victims and trends over five years in a multilevel secure forensic hospital in Canada. The rate of violence perpetrated by female patients was significantly higher than for male patients. Higher occurrence of violence was recorded in the winter months compared with any other season and was related to unstructured activities. There is a window of opportunity to develop some engaging programmes during the long winter months and improve supervision at all times of unstructured activity. The reasons for increased women perpetration and the winter peak of violence require further investigation. PMID- 23362236 TI - Sudden death in advanced abdominal pregnancy: a case report and discussion of the related medicolegal issues. AB - We report sudden unexpected death in a 35-year-old woman with pregnancy of seven months duration. There was an allegation by the parents of the woman that she was subjected to an assault prior to death. Autopsy examination showed an abdominal pregnancy with a dead fetus, ruptured gestational sac, massive haemorrhage and secondary placental attachment. During her antenatal check-ups, she had persistently complained of abdominal pain and loose stools, but the diagnosis of abdominal pregnancy was missed clinically and on ultrasound scan. In this paper we discuss the diagnostic difficulties and medicolegal issues in such cases. PMID- 23362238 TI - Human mesenchymal stromal cells: identifying assays to predict potency for therapeutic selection. AB - Multipotent mesenchymal stromal cells (MSCs) have the potential to repair and regenerate damaged tissues, making them attractive candidates for cell-based therapies. To maximize efficacy of MSCs, prediction of their therapeutic abilities must be made so that only the best cells will be used. Our goal was to identify feasible and reproducible in vitro assays to predict MSC potency. We generated cell lines from 10 normal human bone marrow samples and used the International Society for Cellular Therapy's minimal criteria to define them as MSCs: plastic adherence, appropriate surface marker expression, and trilineage differentiation. Each MSC line was further characterized by its growth, proliferation, and viability as determined by cell count, bromodeoxyuridine incorporation, and cellular ATP levels, respectively. To determine whether these tests reliably predict the therapeutic aptitude of the MSCs, several lines were implanted in vivo to examine their capacity to engraft and form granulation tissue in a well-established murine wound model using polyvinyl alcohol sponges. Long-term engraftment of MSCs in the sponges was quantified through the presence of the human-specific Alu gene in sponge sections. Sections were also stained for proliferating cells, vascularity, and granulation tissue formation to determine successful engraftment and repair. We found that high performance in a combination of the in vitro tests accurately predicted which lines functioned well in vivo. These findings suggest that reliable and reproducible in vitro assays may be used to measure the functional potential of MSCs for therapeutic use. PMID- 23362239 TI - Ca2+-dependent phosphorylation of Ca2+ cycling proteins generates robust rhythmic local Ca2+ releases in cardiac pacemaker cells. AB - The spontaneous beating of the heart is governed by spontaneous firing of sinoatrial node cells, which generate action potentials due to spontaneous depolarization of the membrane potential, or diastolic depolarization. The spontaneous diastolic depolarization rate is determined by spontaneous local submembrane Ca2+ releases through ryanodine receptors (RyRs). We sought to identify specific mechanisms of intrinsic Ca2+ cycling by which sinoatrial node cells, but not ventricular myocytes, generate robust, rhythmic local Ca2+ releases. At similar physiological intracellular Ca2+ concentrations, local Ca2+ releases were large and rhythmic in permeabilized sinoatrial node cells but small and random in permeabilized ventricular myocytes. Furthermore, sinoatrial node cells spontaneously released more Ca2+ from the sarcoplasmic reticulum than did ventricular myocytes, despite comparable sarcoplasmic reticulum Ca2+ content in both cell types. This ability of sinoatrial node cells to generate larger and rhythmic local Ca2+ releases was associated with increased abundance of sarcoplasmic reticulum Ca2+-ATPase (SERCA), reduced abundance of the SERCA inhibitor phospholamban, and increased Ca2+-dependent phosphorylation of phospholamban and RyR. The increased phosphorylation of RyR in sinoatrial node cells may facilitate Ca2+ release from the sarcoplasmic reticulum, whereas Ca2+ dependent increase in phosphorylation of phospholamban relieves its inhibition of SERCA, augmenting the pumping rate of Ca2+ required to support robust, rhythmic local Ca2+ releases. The differences in Ca2+ cycling between sinoatrial node cells and ventricular myocytes provide insights into the regulation of intracellular Ca2+ cycling that drives the automaticity of sinoatrial node cells. PMID- 23362241 TI - Embed dynamic content in your poster. AB - A new technology has emerged that will facilitate the presentation of dynamic or otherwise inaccessible data on posters at scientific meetings. Video, audio, or other digital files hosted on mobile-friendly sites can be linked to through a quick response (QR) code, a two-dimensional barcode that can be scanned by smartphones, which then display the content. This approach is more affordable than acquiring tablet computers for playing dynamic content and can reach many users at large conferences. This resource details how to host videos, generate QR codes, and view the associated files on mobile devices. PMID- 23362240 TI - Vemurafenib potently induces endoplasmic reticulum stress-mediated apoptosis in BRAFV600E melanoma cells. AB - The V600E mutation in the kinase BRAF is frequently detected in melanomas and results in constitutive activation of BRAF, which then promotes cell proliferation by the mitogen-activated protein kinase signaling pathway. Although the BRAFV600E kinase inhibitor vemurafenib has remarkable antitumor activity in patients with BRAFV600E-mutated melanoma, its effects are limited by the onset of drug resistance. We found that exposure of melanoma cell lines with the BRAFV600E mutation to vemurafenib decreased the abundance of antiapoptotic proteins and induced intrinsic mitochondrial apoptosis. Vemurafenib-treated melanoma cells showed increased cytosolic concentration of calcium, a potential trigger for endoplasmic reticulum (ER) stress, which can lead to apoptosis. Consistent with an ER stress-induced response, vemurafenib decreased the abundance of the ER chaperone protein glucose-regulated protein 78, increased the abundance of the spliced isoform of the transcription factor X-box binding protein 1 (XBP1) (which transcriptionally activates genes involved in ER stress responses), increased the phosphorylation of the translation initiation factor eIF2alpha (which would be expected to inhibit protein synthesis), and induced the expression of ER stress related genes. Knockdown of the ER stress response protein activating transcription factor 4 (ATF4) significantly reduced vemurafenib-induced apoptosis. Moreover, the ER stress inducer thapsigargin prevented invasive growth of tumors formed from vemurafenib-sensitive melanoma cells in vivo. In melanoma cells with low sensitivity or resistance to vemurafenib, combination treatment with thapsigargin augmented or induced apoptosis. Thus, thapsigargin or other inducers of ER stress may be useful in combination therapies to overcome vemurafenib resistance. PMID- 23362242 TI - Single-site colectomy with miniature in vivo robotic platform. AB - There has been a continuing push to reduce the invasiveness of surgery by accessing the abdominal cavity through a single incision, such as with laparoendoscopic single-site (LESS) surgery. Although LESS procedures offer significant benefits, added complexities still inhibit the procedures. Robotic surgery is proving to be an excellent option to overcome these limitations. This paper presents the experimental results of the single-incision in vivo surgical robot (SISR), a multifunctional, dexterous, two-armed robot capable of performing surgical tasks while overcoming the issues associated with manual LESS operations. In vivo surgical procedures have been used to demonstrate the efficacy of using a robotic platform over traditional laparoscopic tools. The most recent experimental test resulted in the first successful in vivo robotic LESS colectomy utilizing a robot completely contained within the abdominal cavity. In this test, SISR showed significant benefits including access to all quadrants in the peritoneal cavity and improved dexterity. PMID- 23362243 TI - A comprehensive 3-D framework for automatic quantification of late gadolinium enhanced cardiac magnetic resonance images. AB - Late gadolinium enhanced (LGE) cardiac magnetic resonance (CMR) can directly visualize nonviable myocardium with hyperenhanced intensities with respect to normal myocardium. For heart attack patients, it is crucial to facilitate the decision of appropriate therapy by analyzing and quantifying their LGE CMR images. To achieve accurate quantification, LGE CMR images need to be processed in two steps: segmentation of the myocardium followed by classification of infarcts within the segmented myocardium. However, automatic segmentation is difficult usually due to the intensity heterogeneity of the myocardium and intensity similarity between the infarcts and blood pool. Besides, the slices of an LGE CMR dataset often suffer from spatial and intensity distortions, causing further difficulties in segmentation and classification. In this paper, we present a comprehensive 3-D framework for automatic quantification of LGE CMR images. In this framework, myocardium is segmented with a novel method that deforms coupled endocardial and epicardial meshes and combines information in both short- and long-axis slices, while infarcts are classified with a graph-cut algorithm incorporating intensity and spatial information. Moreover, both spatial and intensity distortions are effectively corrected with specially designed countermeasures. Experiments with 20 sets of real patient data show visually good segmentation and classification results that are quantitatively in strong agreement with those manually obtained by experts. PMID- 23362244 TI - Development of a wireless sensor for the measurement of chicken blood flow using the laser Doppler blood flow meter technique. AB - Here, we report the development of an integrated laser Doppler blood flow micrometer for chickens. This sensor weighs only 18 g and is one of the smallest sized blood flow meters, with no wired line, these are features necessary for attaching the sensor to the chicken. The structure of the sensor chip consists of two silicon cavities with a photo diode and a laser diode, which was achieved using the microelectromechanical systems technique, resulting in its small size and significantly low power consumption. In addition, we introduced an intermittent measuring arrangement in the measuring system to reduce power consumption and to enable the sensor to work longer. We were successfully able to measure chicken blood flow for five consecutive days, and discovered that chicken blood flow shows daily fluctuations. PMID- 23362246 TI - Increasing the automation of a 2D-3D registration system. AB - Routine clinical use of 2D-3D registration algorithms for Image Guided Surgery remains limited. A key aspect for routine clinical use of this technology is its degree of automation, i.e., the amount of necessary knowledgeable interaction between the clinicians and the registration system. Current image-based registration approaches usually require knowledgeable manual interaction during two stages: for initial pose estimation and for verification of produced results. We propose four novel techniques, particularly suited to vertebra-based registration systems, which can significantly automate both of the above stages. Two of these techniques are based upon the intraoperative "insertion" of a virtual fiducial marker into the preoperative data. The remaining two techniques use the final registration similarity value between multiple CT vertebrae and a single fluoroscopy vertebra. The proposed methods were evaluated with data from 31 operations (31 CT scans, 419 fluoroscopy images). Results show these methods can remove the need for manual vertebra identification during initial pose estimation, and were also very effective for result verification, producing a combined true positive rate of 100% and false positive rate equal to zero. This large decrease in required knowledgeable interaction is an important contribution aiming to enable more widespread use of 2D-3D registration technology. PMID- 23362245 TI - Image-based modeling and precision medicine: patient-specific carotid and coronary plaque assessment and predictions. AB - Atherosclerotic plaques may rupture without warning and cause acute cardiovascular events such as heart attack and stroke. Current clinical screening tools are insufficient to identify those patients with risks early and prevent the adverse events from happening. Medical imaging and image-based modeling have made considerable progress in recent years in identifying plaque morphological and mechanical risk factors which may be used in developing improved patient screening strategies. The key steps and factors in image-based models for human carotid and coronary plaques were illustrated, as well as grand challenges facing the researchers in the field to develop more accurate screening tools. PMID- 23362247 TI - RubiX: combining spatial resolutions for Bayesian inference of crossing fibers in diffusion MRI. AB - The trade-off between signal-to-noise ratio (SNR) and spatial specificity governs the choice of spatial resolution in magnetic resonance imaging (MRI); diffusion weighted (DW) MRI is no exception. Images of lower resolution have higher signal to noise ratio, but also more partial volume artifacts. We present a data-fusion approach for tackling this trade-off by combining DW MRI data acquired both at high and low spatial resolution. We combine all data into a single Bayesian model to estimate the underlying fiber patterns and diffusion parameters. The proposed model, therefore, combines the benefits of each acquisition. We show that fiber crossings at the highest spatial resolution can be inferred more robustly and accurately using such a model compared to a simpler model that operates only on high-resolution data, when both approaches are matched for acquisition time. PMID- 23362248 TI - A piecewise monotone subgradient algorithm for accurate L1-TV based registration of physical slices with discontinuities in microscopy. AB - Image registration tasks are often formulated in terms of minimization of a functional consisting of a data fidelity term penalizing the mismatch between the reference and the target image, and a term enforcing smoothness of shift between neighboring pairs of pixels (a min-sum problem). Most methods for deformable image registration use some form of interpolation between matching control points. The interpolation makes it impossible to account for isolated discontinuities in the deformation field that may appear, e.g., when a physical slice of a microscopy specimen is ruptured by the cutting tool. For registration of neighboring physical slices of microscopy specimens with discontinuities, Janacek proposed an L1-distance data fidelity term and a total variation (TV) smoothness term, and used a graph-cut (GC) based iterative steepest descent algorithm for minimization. The L1-TV functional is nonconvex; hence a steepest descent algorithm is not guaranteed to converge to the global minimum. Schlesinger presented transformation of max-sum problems to minimization of a dual quantity called problem power, which is--contrary to the original max-sum functional--convex. Based on Schlesinger's solution to max-sum problems we developed an algorithm for L1-TV minimization by iterative multi-label steepest descent minimization of the convex dual problem. For Schlesinger's subgradient algorithm we proposed a novel step control heuristics that considerably enhances both speed and accuracy compared with standard step size strategies for subgradient methods. It is shown experimentally that our subgradient scheme achieves consistently better image registration than GC in terms of lower values both of the composite L1-TV functional, and of its components, i.e., the L1 distance of the images and the transformation smoothness TV, and yields visually acceptable results even in cases where the GC based algorithm fails. The new algorithm allows easy parallelization and can thus be sped up by running on multi core graphic processing units. PMID- 23362249 TI - Application of radial ray based segmentation to cervical lymph nodes in CT images. AB - The 3D-segmentation of lymph nodes in computed tomography images is required for staging and disease progression monitoring. Major challenges are shape and size variance, as well as low contrast, image noise, and pathologies. In this paper, radial ray based segmentation is applied to lymph nodes. From a seed point, rays are cast into all directions and an optimization technique determines a radius for each ray based on image appearance and shape knowledge. Lymph node specific appearance cost functions are introduced and their optimal parameters are determined. For the first time, the resulting segmentation accuracy of different appearance cost functions and optimization strategies is compared. Further contributions are extensions to reduce the dependency on the seed point, to support a larger variety of shapes, and to enable interaction. The best results are obtained using graph-cut on a combination of the direction weighted image gradient and accumulated intensities outside a predefined intensity range. Evaluation on 100 lymph nodes shows that with an average symmetric surface distance of 0.41 mm the segmentation accuracy is close to manual segmentation and outperforms existing radial ray and model based methods. The method's inter observer-variability of 5.9% for volume assessment is lower than the 15.9% obtained using manual segmentation. PMID- 23362250 TI - A low-complexity ECG feature extraction algorithm for mobile healthcare applications. AB - This paper introduces a low-complexity algorithm for the extraction of the fiducial points from the Electrocardiogram (ECG). The application area we consider is that of remote cardiovascular monitoring, where continuous sensing and processing takes place in low-power, computationally constrained devices, thus the power consumption and complexity of the processing algorithms should remain at a minimum level. Under this context, we choose to employ the Discrete Wavelet Transform (DWT) with the Haar function being the mother wavelet, as our principal analysis method. From the modulus-maxima analysis on the DWT coefficients, an approximation of the ECG fiducial points is extracted. These initial findings are complimented with a refinement stage, based on the time domain morphological properties of the ECG, which alleviates the decreased temporal resolution of the DWT. The resulting algorithm is a hybrid scheme of time and frequency domain signal processing. Feature extraction results from 27 ECG signals from QTDB, were tested against manual annotations and used to compare our approach against the state-of-the art ECG delineators. In addition, 450 signals from the 15-lead PTBDB are used to evaluate the obtained performance against the CSE tolerance limits. Our findings indicate that all but one CSE limits are satisfied. This level of performance combined with a complexity analysis, where the upper bound of the proposed algorithm, in terms of arithmetic operations, is calculated as 2:423N + 214 additions and 1:093N + 12 multiplications for N 861 or 2:553N + 102 additions and 1:093N +10 multiplications for N > 861 (N being the number of input samples), reveals that the proposed method achieves an ideal trade-off between computational complexity and performance, a key requirement in remote CVD monitoring systems. PMID- 23362251 TI - Design and development of a Virtual Dolphinarium for children with autism. AB - The recent proliferation of virtual reality (VR) technology applications in the autism therapy to promote learning and positive behavior among such children has produced optimistic results in developing a variety of skills and abilities in them. Dolphin-assisted therapy has also become a topic of public and research interest for autism intervention and treatment. This paper will present an innovative design and development of a Virtual Dolphinarium for potential autism intervention. Instead of emulating the swimming with dolphins, our virtual dolphin interaction program will allow children with autism to act as dolphin trainers at the poolside and to learn (nonverbal) communication through hand gestures with the virtual dolphins. Immersive visualization and gesture-based interaction are implemented to engage children with autism within an immersive room equipped with a curved screen spanning a 320( degrees ) and a high-end five panel projection system. This paper will also report a pilot study to establish trial protocol of autism screening to explore the participants' readiness for the virtual dolphin interaction. This research will have two potential benefits in the sense of helping children with autism and protecting the endangered species. PMID- 23362252 TI - Mechanisms governing the endosomal membrane recruitment of the core retromer in Arabidopsis. AB - The retromer complex localizes to endosomal membranes and is involved in protein trafficking. In mammals, it is composed of a dimer of sorting nexins and of the core retromer consisting of vacuolar protein sorting (VPS)26, VPS29, and VPS35. Although homologs of these proteins have been identified in plants, how the plant retromer functions remains elusive. To better understand the role of VPS components in the assembly and function of the core retromer, we characterize here Arabidopsis vps26-null mutants. We show that impaired VPS26 function has a dramatic effect on VPS35 levels and causes severe phenotypic defects similar to those observed in vps29-null mutants. This implies that functions of plant VPS26, VPS29, and VPS35 are tightly linked. Then, by combining live-cell imaging with immunochemical and genetic approaches, we report that VPS35 alone is able to bind to endosomal membranes and plays an essential role in VPS26 and VPS29 membrane recruitment. We also show that the Arabidopsis Rab7 homolog RABG3f participates in the recruitment of the core retromer to the endosomal membrane by interacting with VPS35. Altogether our data provide original information on the molecular interactions that mediate assembly of the core retromer in plants. PMID- 23362253 TI - Physical interaction between MYCN oncogene and polycomb repressive complex 2 (PRC2) in neuroblastoma: functional and therapeutic implications. AB - CLU (clusterin) is a tumor suppressor gene that we have previously shown to be negatively modulated by the MYCN proto-oncogene, but the mechanism of repression was unclear. Here, we show that MYCN inhibits the expression of CLU by direct interaction with the non-canonical E box sequence CACGCG in the 5'-flanking region. Binding of MYCN to the CLU gene induces bivalent epigenetic marks and recruitment of repressive proteins such as histone deacetylases and Polycomb members. MYCN physically binds in vitro and in vivo to EZH2, a component of the Polycomb repressive complex 2, required to repress CLU. Notably, EZH2 interacts with the Myc box domain 3, a segment of MYC known to be essential for its transforming effects. The expression of CLU can be restored in MYCN-amplified cells by epigenetic drugs with therapeutic results. Importantly, the anticancer effects of the drugs are ablated if CLU expression is blunted by RNA interference. Our study implies that MYC tumorigenesis can be effectively antagonized by epigenetic drugs that interfere with the recruitment of chromatin modifiers at repressive E boxes of tumor suppressor genes such as CLU. PMID- 23362254 TI - Alternative substrate kinetics of Escherichia coli ribonuclease P: determination of relative rate constants by internal competition. AB - A single enzyme, ribonuclease P (RNase P), processes the 5' ends of tRNA precursors (ptRNA) in cells and organelles that carry out tRNA biosynthesis. This substrate population includes over 80 different competing ptRNAs in Escherichia coli. Although the reaction kinetics and molecular recognition of a few individual model substrates of bacterial RNase P have been well described, the competitive substrate kinetics of the enzyme are comparatively unexplored. To understand the factors that determine how different ptRNA substrates compete for processing by E. coli RNase P, we compared the steady state reaction kinetics of two ptRNAs that differ at sequences that are contacted by the enzyme. For both ptRNAs, substrate cleavage is fast relative to dissociation. As a consequence, V/K, the rate constant for the reaction at limiting substrate concentrations, reflects the substrate association step for both ptRNAs. Reactions containing two or more ptRNAs follow simple competitive alternative substrate kinetics in which the relative rates of processing are determined by ptRNA concentration and their V/K. The relative V/K values for eight different ptRNAs, which were selected to represent the range of structure variation at sites contacted by RNase P, were determined by internal competition in reactions in which all eight substrates were present simultaneously. The results reveal a relatively narrow range of V/K values, suggesting that rates of ptRNA processing by RNase P are tuned for uniform specificity and consequently optimal coupling to precursor biosynthesis. PMID- 23362255 TI - Isomerase Pin1 stimulates dephosphorylation of tau protein at cyclin-dependent kinase (Cdk5)-dependent Alzheimer phosphorylation sites. AB - Neurodegenerative diseases associated with the pathological aggregation of microtubule-associated protein Tau are classified as tauopathies. Alzheimer disease, the most common tauopathy, is characterized by neurofibrillary tangles that are mainly composed of abnormally phosphorylated Tau. Similar hyperphosphorylated Tau lesions are found in patients with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) that is induced by mutations within the tau gene. To further understand the etiology of tauopathies, it will be important to elucidate the mechanism underlying Tau hyperphosphorylation. Tau phosphorylation occurs mainly at proline-directed Ser/Thr sites, which are targeted by protein kinases such as GSK3beta and Cdk5. We reported previously that dephosphorylation of Tau at Cdk5-mediated sites was enhanced by Pin1, a peptidyl-prolyl isomerase that stimulates dephosphorylation at proline-directed sites by protein phosphatase 2A. Pin1 deficiency is suggested to cause Tau hyperphosphorylation in Alzheimer disease. Up to the present, Pin1 binding was only shown for two Tau phosphorylation sites (Thr-212 and Thr-231) despite the presence of many more hyperphosphorylated sites. Here, we analyzed the interaction of Pin1 with Tau phosphorylated by Cdk5-p25 using a GST pulldown assay and Biacore approach. We found that Pin1 binds and stimulates dephosphorylation of Tau at all Cdk5-mediated sites (Ser-202, Thr-205, Ser-235, and Ser-404). Furthermore, FTDP-17 mutant Tau (P301L or R406W) showed slightly weaker Pin1 binding than non-mutated Tau, suggesting that FTDP-17 mutations induce hyperphosphorylation by reducing the interaction between Pin1 and Tau. Together, these results indicate that Pin1 is generally involved in the regulation of Tau hyperphosphorylation and hence the etiology of tauopathies. PMID- 23362256 TI - Conserved cysteine residues provide a protein-protein interaction surface in dual oxidase (DUOX) proteins. AB - Intramolecular disulfide bond formation is promoted in oxidizing extracellular and endoplasmic reticulum compartments and often contributes to protein stability and function. DUOX1 and DUOX2 are distinguished from other members of the NOX protein family by the presence of a unique extracellular N-terminal region. These peroxidase-like domains lack the conserved cysteines that confer structural stability to mammalian peroxidases. Sequence-based structure predictions suggest that the thiol groups present are solvent-exposed on a single protein surface and are too distant to support intramolecular disulfide bond formation. To investigate the role of these thiol residues, we introduced four individual cysteine to glycine mutations in the peroxidase-like domains of both human DUOXs and purified the recombinant proteins. The mutations caused little change in the stabilities of the monomeric proteins, supporting the hypothesis that the thiol residues are solvent-exposed and not involved in disulfide bonds that are critical for structural integrity. However, the ability of the isolated hDUOX1 peroxidase-like domain to dimerize was altered, suggesting a role for these cysteines in protein-protein interactions that could facilitate homodimerization of the peroxidase-like domain or, in the full-length protein, heterodimeric interactions with a maturation protein. When full-length hDUOX1 was expressed in HEK293 cells, the mutations resulted in decreased H2O2 production that correlated with a decreased amount of the enzyme localized to the membrane surface rather than with a loss of activity or with a failure to synthesize the mutant proteins. These results support a role for the cysteine residues in intermolecular disulfide bond formation with the DUOX maturation factor DUOXA1. PMID- 23362257 TI - Crosstalk between caveolin-1/extracellular signal-regulated kinase (ERK) and beta catenin survival pathways in osteocyte mechanotransduction. AB - Osteocyte viability is a critical determinant of bone strength and is promoted by both mechanical stimulation and activation of the Wnt signaling pathway. Earlier studies demonstrated that both stimuli promote survival of osteocytes by activating the ERKs. Here, we show that there is interaction between the caveolin 1/ERK and Wnt/beta-catenin signaling pathways in the transduction of mechanical cues into osteocyte survival. Thus, ERK nuclear translocation and anti-apoptosis induced by mechanical stimulation are abolished by the Wnt antagonist Dkk1 and the beta-catenin degradation stimulator Axin2. Conversely, GSK3beta phosphorylation and beta-catenin accumulation induced by mechanical stimulation are abolished by either pharmacologic inhibition of ERKs or silencing caveolin-1. In contrast, the canonical Wnt signaling inhibitor dominant-negative T cell factor does not alter ERK nuclear translocation or survival induced by mechanical stimulation. These findings demonstrate that beta-catenin accumulation is an essential component of the mechanotransduction machinery in osteocytes, albeit beta-catenin/T cell factor-mediated transcription is not required. The simultaneous requirement of beta-catenin for ERK activation and of ERK activation for beta-catenin accumulation suggests a bidirectional crosstalk between the caveolin-1/ERK and Wnt/beta-catenin pathways in mechanotransduction leading to osteocyte survival. PMID- 23362258 TI - C-terminal amidation of an osteocalcin-derived peptide promotes hydroxyapatite crystallization. AB - Genesis of natural biocomposite-based materials, such as bone, cartilage, and teeth, involves interactions between organic and inorganic systems. Natural biopolymers, such as peptide motif sequences, can be used as a template to direct the nucleation and crystallization of hydroxyapatite (HA). In this study, a natural motif sequence consisting of 13 amino acids present in the first helix of osteocalcin was selected based on its calcium binding ability and used as substrate for nucleation of HA crystals. The acidic (acidic osteocalcin-derived peptide (OSC)) and amidic (amidic osteocalcin-derived peptide (OSN)) forms of this sequence were synthesized to investigate the effects of different C termini on the process of biomineralization. Electron microscopy analyses show the formation of plate-like HA crystals with random size and shape in the presence of OSN. In contrast, spherical amorphous calcium phosphate is formed in the presence of OSC. Circular dichroism experiments indicate conformational changes of amidic peptide to an open and regular structure as a consequence of interaction with calcium and phosphate. There is no conformational change detectable in OSC. It is concluded that HA crystal formation, which only occurred in OSN, is attributable to C-terminal amidation of a natural peptide derived from osteocalcin. It is also proposed that natural peptides with the ability to promote biomineralization have the potential to be utilized in hard tissue regeneration. PMID- 23362259 TI - Inhibition of G-protein-coupled receptor kinase 2 (GRK2) triggers the growth promoting mitogen-activated protein kinase (MAPK) pathway. AB - Inhibition of G-protein-coupled receptor kinase 2 (GRK2) is an emerging treatment option for heart failure. Because GRK2 is also indispensable for growth and development, we analyzed the impact of GRK2 inhibition on cell growth and proliferation. Inhibition of GRK2 by the dominant-negative GRK2-K220R did not affect the proliferation of cultured cells. In contrast, upon xenograft transplantation of cells into immunodeficient mice, the dominant-negative GRK2 K220R or a GRK2-specific peptide inhibitor increased tumor mass. The enhanced tumor growth upon GRK2 inhibition was attributed to the growth-promoting MAPK pathway because dual inhibition of the GRK2 and RAF-MAPK axis by the Raf kinase inhibitor protein (RKIP) did not increase tumor mass. The MAPK cascade contributed to the cardioprotective profile of GRK2 inhibition by preventing cardiomyocyte death, whereas dual inhibition of RAF/MAPK and GRK2 by RKIP induced cardiomyocyte apoptosis, cardiac dysfunction, and signs of heart failure. Thus, cardioprotective signaling induced by GRK2 inhibition is overlapping with tumor growth promotion. PMID- 23362260 TI - Signaling through myosin light chain kinase in smooth muscles. AB - Ca(2+)/calmodulin-dependent myosin light chain kinase (MLCK) phosphorylates smooth muscle myosin regulatory light chain (RLC) to initiate contraction. We used a tamoxifen-activated, smooth muscle-specific inactivation of MLCK expression in adult mice to determine whether MLCK was differentially limiting in distinct smooth muscles. A 50% decrease in MLCK in urinary bladder smooth muscle had no effect on RLC phosphorylation or on contractile responses, whereas an 80% decrease resulted in only a 20% decrease in RLC phosphorylation and contractile responses to the muscarinic agonist carbachol. Phosphorylation of the myosin light chain phosphatase regulatory subunit MYPT1 at Thr-696 and Thr-853 and the inhibitor protein CPI-17 were also stimulated with carbachol. These results are consistent with the previous findings that activation of a small fraction of MLCK by limiting amounts of free Ca(2+)/calmodulin combined with myosin light chain phosphatase inhibition is sufficient for robust RLC phosphorylation and contractile responses in bladder smooth muscle. In contrast, a 50% decrease in MLCK in aortic smooth muscle resulted in 40% inhibition of RLC phosphorylation and aorta contractile responses, whereas a 90% decrease profoundly inhibited both responses. Thus, MLCK content is limiting for contraction in aortic smooth muscle. Phosphorylation of CPI-17 and MYPT1 at Thr-696 and Thr-853 were also stimulated with phenylephrine but significantly less than in bladder tissue. These results indicate differential contributions of MLCK to signaling. Limiting MLCK activity combined with modest Ca(2+) sensitization responses provide insights into how haploinsufficiency of MLCK may result in contractile dysfunction in vivo, leading to dissections of human thoracic aorta. PMID- 23362261 TI - Decoding mechanism of non-universal genetic codes in Loligo bleekeri mitochondria. AB - Non-universal genetic codes are frequently found in animal mitochondrial decoding systems. In squid mitochondria, four codons deviate from the universal genetic code, namely AUA, UGA, and AGA/AGG (AGR) for Met, Trp, and Ser, respectively. To understand the molecular basis for establishing the non-universal genetic code, we isolated and analyzed five mitochondrial tRNAs from a squid, Loligo bleekeri. Primary structures of the isolated tRNAs, including their post-transcriptional modifications, were analyzed by mass spectrometry. tRNA(Met)(AUR) possessed an unmodified cytidine at the first position of the anticodon, suggesting that the AUA codon is deciphered by CAU anticodon via non-canonical A-C pairing. We identified 5-taurinomethyluridine (taum(5)U) at the first position of the anticodon in tRNA(Trp)(UGR). taum(5)U enables tRNA(Trp) to decipher UGR codons as Trp. In addition, 5-taurinomethyl-2-thiouridine (taum(5)s(2)U) was found in mitochondrial tRNAs for Leu(UUR) and Lys in L. bleekeri. This is the first discovery of taum(5)U and taum(5)s(2)U in molluscan mitochondrial tRNAs. PMID- 23362262 TI - Transforming growth factor beta integrates Smad 3 to mechanistic target of rapamycin complexes to arrest deptor abundance for glomerular mesangial cell hypertrophy. AB - In many renal diseases, transforming growth factor beta (TGFbeta)-stimulated canonical Smad 3 and noncanonical mechanistic target of rapamycin (mTOR) promote increased protein synthesis and mesangial cell hypertrophy. The cellular underpinnings involving these signaling molecules to regulate mesangial cell hypertrophy are not fully understood. Deptor has recently been identified as an mTOR interacting protein and functions as an endogenous inhibitor of the kinase activity for both TORC1 and TORC2. Prolonged incubation of mesangial cells with TGFbeta reduced the levels of deptor concomitant with an increase in TORC1 and TORC2 activity. Sustained TGFbeta activation was required to inhibit association of deptor with mTOR, whereas rapid activation had no effect. Using the mTOR inhibitor PP242, we found that TGFbeta-induced both early and sustained activation of TORC1 and TORC2 was necessary for deptor suppression. PP242-induced reversal of deptor suppression by TGFbeta was associated with a significant inhibition of TGFbeta-stimulated protein synthesis and hypertrophy. Interestingly, expression of siRNA against Smad 3 or Smad 7, which blocks TGFbeta receptor-specific Smad 3 signaling, prevented TGFbeta-induced suppression of deptor abundance and TORC1/2 activities. Furthermore, overexpression of Smad 3 decreased deptor expression similar to TGFbeta stimulation concomitant with increased TORC1 and TORC2 activities. Finally, knockdown of deptor reversed Smad 7-mediated inhibition of protein synthesis and mesangial cell hypertrophy induced by TGFbeta. These data reveal the requirement of both early and late activation of mTOR for TGFbeta-induced protein synthesis. Our results support that TGFbeta stimulated Smad 3 acts as a key node to instill a feedback loop between deptor down-regulation and TORC1/2 activation in driving mesangial cell hypertrophy. PMID- 23362263 TI - TAp73 protein stability is controlled by histone deacetylase 1 via regulation of Hsp90 chaperone function. AB - Histone deacetylases (HDACs) play important roles in fundamental cellular processes, and HDAC inhibitors are emerging as promising cancer therapeutics. p73, a member of the p53 family, plays a critical role in tumor suppression and neural development. Interestingly, p73 produces two classes of proteins with opposing functions: the full-length TAp73 and the N-terminally truncated DeltaNp73. In the current study, we sought to characterize the potential regulation of p73 by HDACs and found that histone deacetylase 1 (HDAC1) is a key regulator of TAp73 protein stability. Specifically, we showed that HDAC1 inhibition by HDAC inhibitors or by siRNA shortened the half-life of TAp73 protein and subsequently decreased TAp73 expression under normal and DNA damage induced conditions. Mechanistically, we found that HDAC1 knockdown resulted in hyperacetylation and inactivation of heat shock protein 90, which disrupted the interaction between heat shock protein 90 and TAp73 and thus promoted the proteasomal degradation of TAp73. Functionally, we found that down-regulation of TAp73 was required for the enhanced cell migration mediated by HDAC1 knockdown. Together, we uncover a novel regulation of TAp73 protein stability by HDAC1-heat shock protein 90 chaperone complex, and our data suggest that TAp73 is a critical downstream mediator of HDAC1-regulated cell migration. PMID- 23362264 TI - Mechanisms of action of hormone-sensitive lipase in mouse Leydig cells: its role in the regulation of the steroidogenic acute regulatory protein. AB - Hormone-sensitive lipase (HSL) catalyzes the hydrolysis of cholesteryl esters in steroidogenic tissues and, thus, facilitates cholesterol availability for steroidogenesis. The steroidogenic acute regulatory protein (StAR) controls the rate-limiting step in steroid biosynthesis. However, the modes of action of HSL in the regulation of StAR expression remain obscure. We demonstrate in MA-10 mouse Leydig cells that activation of the protein kinase A (PKA) pathway, by a cAMP analog Bt2cAMP, enhanced expression of HSL and its phosphorylation (P) at Ser-660 and Ser-563, but not at Ser-565, concomitant with increased HSL activity. Phosphorylation and activation of HSL coincided with increases in StAR, P-StAR (Ser-194), and progesterone levels. Inhibition of HSL activity by CAY10499 effectively suppressed Bt2cAMP-induced StAR expression and progesterone synthesis. Targeted silencing of endogenous HSL, with siRNAs, resulted in increased cholesteryl ester levels and decreased cholesterol content in MA-10 cells. Depletion of HSL affected lipoprotein-derived cellular cholesterol influx, diminished the supply of cholesterol to the mitochondria, and resulted in the repression of StAR and P-StAR levels. Cells overexpressing HSL increased the efficacy of liver X receptor (LXR) ligands on StAR expression and steroid synthesis, suggesting HSL-mediated steroidogenesis entails enhanced oxysterol production. Conversely, cells deficient in LXRs exhibited decreased HSL responsiveness. Furthermore, an increase in HSL was correlated with the LXR target genes, steroid receptor element-binding protein 1c and ATP binding cassette transporter A1, demonstrating HSL-dependent regulation of steroidogenesis predominantly involves LXR signaling. LXRs interact/cooperate with RXRs and result in the activation of StAR gene transcription. These findings provide novel insight and demonstrate the molecular events by which HSL acts to drive cAMP/PKA-mediated regulation of StAR expression and steroidogenesis in mouse Leydig cells. PMID- 23362265 TI - Sarco(endo)plasmic reticulum calcium ATPase (SERCA) inhibition by sarcolipin is encoded in its luminal tail. AB - The sarco(endo)plasmic reticulum calcium ATPase (SERCA) is regulated in a tissue dependent manner via interaction with the short integral membrane proteins phospholamban (PLN) and sarcolipin (SLN). Although defects in SERCA activity are known to cause heart failure, the regulatory mechanisms imposed by PLN and SLN could have clinical implications for both heart and skeletal muscle diseases. PLN and SLN have significant sequence homology in their transmembrane regions, suggesting a similar mode of binding to SERCA. However, unlike PLN, SLN has a conserved C-terminal luminal tail composed of five amino acids ((27)RSYQY), which may contribute to a distinct SERCA regulatory mechanism. We have functionally characterized alanine mutants of the C-terminal tail of SLN using co reconstituted proteoliposomes of SERCA and SLN. We found that Arg(27) and Tyr(31) are essential for SLN function. We also tested the effect of a truncated variant of SLN (Arg(27)stop) and extended chimeras of PLN with the five luminal residues of SLN added to its C terminus. The Arg(27)stop form of SLN resulted in loss of function, whereas the PLN chimeras resulted in superinhibition with characteristics of both PLN and SLN. Based on our results, we propose that the C terminal tail of SLN is a distinct, essential domain in the regulation of SERCA and that the functional properties of the SLN tail can be transferred to PLN. PMID- 23362266 TI - Estrogen receptor alpha mediates proliferation of osteoblastic cells stimulated by estrogen and mechanical strain, but their acute down-regulation of the Wnt antagonist Sost is mediated by estrogen receptor beta. AB - Mechanical strain and estrogens both stimulate osteoblast proliferation through estrogen receptor (ER)-mediated effects, and both down-regulate the Wnt antagonist Sost/sclerostin. Here, we investigate the differential effects of ERalpha and -beta in these processes in mouse long bone-derived osteoblastic cells and human Saos-2 cells. Recruitment to the cell cycle following strain or 17beta-estradiol occurs within 30 min, as determined by Ki-67 staining, and is prevented by the ERalpha antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2 piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride. ERbeta inhibition with 4 [2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-beta]pyrimidin-3-yl] phenol (PTHPP) increases basal proliferation similarly to strain or estradiol. Both strain and estradiol down-regulate Sost expression, as does in vitro inhibition or in vivo deletion of ERalpha. The ERbeta agonists 2,3-bis(4-hydroxyphenyl) propionitrile and ERB041 also down-regulated Sost expression in vitro, whereas the ERalpha agonist 4,4',4"-[4-propyl-(1H)-pyrazol-1,3,5-triyl]tris-phenol or the ERbeta antagonist PTHPP has no effect. Tamoxifen, a nongenomic ERbeta agonist, down-regulates Sost expression in vitro and in bones in vivo. Inhibition of both ERs with fulvestrant or selective antagonism of ERbeta, but not ERalpha, prevents Sost down-regulation by strain or estradiol. Sost down-regulation by strain or ERbeta activation is prevented by MEK/ERK blockade. Exogenous sclerostin has no effect on estradiol-induced proliferation but prevents that following strain. Thus, in osteoblastic cells the acute proliferative effects of both estradiol and strain are ERalpha-mediated. Basal Sost down-regulation follows decreased activity of ERalpha and increased activity of ERbeta. Sost down-regulation by strain or increased estrogens is mediated by ERbeta, not ERalpha. ER-targeting therapy may facilitate structurally appropriate bone formation by enhancing the distinct ligand-independent, strain-related contributions to proliferation of both ERalpha and ERbeta. PMID- 23362267 TI - Bacterial small RNA-based negative regulation: Hfq and its accomplices. AB - A large group of bacterial small regulatory RNAs (sRNAs) use the Hfq chaperone to mediate pairing with and regulation of mRNAs. Recent findings help to clarify how Hfq acts and highlight the role of the endonuclease RNase E and its associated proteins (the degradosome) in negative regulation by these sRNAs. sRNAs frequently uncouple transcription and translation by blocking ribosome access to the mRNA, allowing other proteins access to the mRNA. As more examples of sRNA mediated regulation are studied, more variations on how Hfq, RNase E, and other proteins collaborate to bring about sRNA-based regulation are being found. PMID- 23362269 TI - Phosphatidic acid-dependent recruitment and function of the Rac activator DOCK1 during dorsal ruffle formation. AB - Activation of receptor tyrosine kinases leads to the formation of two different types of plasma membrane structures: peripheral ruffles and dorsal ruffles. Although the formation of both ruffle types requires activation of the small GTPase Rac, the difference in kinetics suggests that a distinct regulatory mechanism operates for their ruffle formation. DOCK1 and DOCK5 are atypical Rac activators and are both expressed in mouse embryonic fibroblasts (MEFs). We found that although PDGF-induced Rac activation and peripheral ruffle formation were coordinately regulated by DOCK1 and DOCK5 in MEFs, DOCK1 deficiency alone impaired dorsal ruffle formation in MEFs. Unlike DOCK5, DOCK1 bound to phosphatidic acid (PA) through the C-terminal polybasic amino acid cluster and was localized to dorsal ruffles. When this interaction was blocked, PDGF-induced dorsal ruffle formation was severely impaired. In addition, we show that phospholipase D, an enzyme that catalyzes PA synthesis, is required for PDGF induced dorsal, but not peripheral, ruffle formation. These results indicate that the phospholipase D-PA axis selectively controls dorsal ruffle formation by regulating DOCK1 localization. PMID- 23362268 TI - hCOA3 stabilizes cytochrome c oxidase 1 (COX1) and promotes cytochrome c oxidase assembly in human mitochondria. AB - Cytochrome c oxidase (COX) or complex IV of the mitochondrial respiratory chain plays a fundamental role in energy production of aerobic cells. In humans, COX deficiency is the most frequent cause of mitochondrial encephalomyopathies. Human COX is composed of 13 subunits of dual genetic origin, whose assembly requires an increasing number of nuclear-encoded accessory proteins known as assembly factors. Here, we have identified and characterized human CCDC56, an 11.7-kDa mitochondrial transmembrane protein, as a new factor essential for COX biogenesis. CCDC56 shares sequence similarity with the yeast COX assembly factor Coa3 and was termed hCOA3. hCOA3-silenced cells display a severe COX functional alteration owing to a decreased stability of newly synthesized COX1 and an impairment in the holoenzyme assembly process. We show that hCOA3 physically interacts with both the mitochondrial translation machinery and COX structural subunits. We conclude that hCOA3 stabilizes COX1 co-translationally and promotes its assembly with COX partner subunits. Finally, our results identify hCOA3 as a new candidate when screening for genes responsible for mitochondrial diseases associated with COX deficiency. PMID- 23362270 TI - Mechanical stretch inhibits lipopolysaccharide-induced keratinocyte-derived chemokine and tissue factor expression while increasing procoagulant activity in murine lung epithelial cells. AB - Previous studies have shown that the innate immune stimulant LPS augments mechanical ventilation-induced pulmonary coagulation and inflammation. Whether these effects are mediated by alveolar epithelial cells is unclear. The alveolar epithelium is a key regulator of the innate immune reaction to pathogens and can modulate both intra-alveolar inflammation and coagulation through up-regulation of proinflammatory cytokines and tissue factor (TF), the principal initiator of the extrinsic coagulation pathway. We hypothesized that cyclic mechanical stretch (MS) potentiates LPS-mediated alveolar epithelial cell (MLE-12) expression of the chemokine keratinocyte-derived cytokine (KC) and TF. Contrary to our hypothesis, MS significantly decreased LPS-induced KC and TF mRNA and protein expression. Investigation into potential mechanisms showed that stretch significantly reduced LPS-induced surface expression of TLR4 that was not a result of increased degradation. Decreased cell surface TLR4 expression was concomitant with reduced LPS-mediated NF-kappaB activation. Immunofluorescence staining showed that cyclic MS markedly altered LPS-induced organization of actin filaments. In contrast to expression, MS significantly increased LPS-induced cell surface TF activity independent of calcium signaling. These findings suggest that cyclic MS of lung epithelial cells down-regulates LPS-mediated inflammatory and procoagulant expression by modulating actin organization and reducing cell surface TLR4 expression and signaling. However, because LPS-induced surface TF activity was enhanced by stretch, these data demonstrate differential pathways regulating TF expression and activity. Ultimately, loss of LPS responsiveness in the epithelium induced by MS could result in increased susceptibility of the lung to bacterial infections in the setting of mechanical ventilation. PMID- 23362271 TI - Mutations in the putative dimer-dimer interfaces of the measles virus hemagglutinin head domain affect membrane fusion triggering. AB - Measles virus (MV), an enveloped RNA virus belonging to the Paramyxoviridae family, enters the cell through membrane fusion mediated by two viral envelope proteins, an attachment protein hemagglutinin (H) and a fusion (F) protein. The crystal structure of the receptor-binding head domain of MV-H bound to its cellular receptor revealed that the MV-H head domain forms a tetrameric assembly (dimer of dimers), which occurs in two forms (forms I and II). In this study, we show that mutations in the putative dimer-dimer interface of the head domain in either form inhibit the ability of MV-H to support membrane fusion, without greatly affecting its cell surface expression, receptor binding, and interaction with the F protein. Notably, some anti-MV-H neutralizing monoclonal antibodies are directed to the region around the dimer-dimer interface in form I rather than receptor-binding sites. These observations suggest that the dimer-dimer interactions of the MV-H head domain, especially that in form I, contribute to triggering membrane fusion, and that conformational shift of head domain tetramers plays a role in the process. Furthermore, our results indicate that although the stalk and transmembrane regions may be mainly responsible for the tetramer formation of MV-H, the head domain alone can form tetramers, albeit at a low efficiency. PMID- 23362272 TI - Soluble epoxide hydrolase dimerization is required for hydrolase activity. AB - Soluble epoxide hydrolase (sEH) plays a key role in the metabolic conversion of the protective eicosanoid 14,15-epoxyeicosatrienoic acid to 14,15 dihydroxyeicosatrienoic acid. Accordingly, inhibition of sEH hydrolase activity has been shown to be beneficial in multiple models of cardiovascular diseases, thus identifying sEH as a valuable therapeutic target. Recently, a common human polymorphism (R287Q) was identified that reduces sEH hydrolase activity and is localized to the dimerization interface of the protein, suggesting a relationship between sEH dimerization and activity. To directly test the hypothesis that dimerization is essential for the proper function of sEH, we generated mutations within the sEH protein that would either disrupt or stabilize dimerization. We quantified the dimerization state of each mutant using a split firefly luciferase protein fragment-assisted complementation system. The hydrolase activity of each mutant was determined using a fluorescence-based substrate conversion assay. We found that mutations that disrupted dimerization also eliminated hydrolase enzymatic activity. In contrast, a mutation that stabilized dimerization restored hydrolase activity. Finally, we investigated the kinetics of sEH dimerization and found that the human R287Q polymorphism was metastable and capable of swapping dimer partners faster than the WT enzyme. These results indicate that dimerization is required for sEH hydrolase activity. Disrupting sEH dimerization may therefore serve as a novel therapeutic strategy for reducing sEH hydrolase activity. PMID- 23362273 TI - Topology of NBCe1 protein transmembrane segment 1 and structural effect of proximal renal tubular acidosis (pRTA) S427L mutation. AB - In the kidney proximal tubule, NBCe1-A plays a critical role in absorbing HCO3(-) from cell to blood. NBCe1-A transmembrane segment 1 (TM1) is involved in forming part of the ion permeation pathway, and a missense mutation S427L in TM1 impairs ion transport, causing proximal renal tubular acidosis. In the present study, we examined the topology of NBCe1-A-TM1 in detail and its structural perturbation induced by S427L. We analyzed the N-terminal cytoplasmic region (Cys-389-Gln-424) of NBCe1-A-TM1 using the substituted cysteine scanning accessibility method combined with extensive chemical stripping, in situ chemical probing, and functional transport assays. NBCe1-A-TM1 was previously modeled on the anion exchanger 1 TM1 (AE1-TM1); however, our data demonstrated that the topology of AE1-TM1 differs significantly from NBCe1-A-TM1. Our findings revealed that NBCe1 A-TM1 is unusually long, consisting of 31 membrane-embedded amino acids (Phe-412 to Thr-442). The linker region (Arg-394-Pro-411) between the N terminus of TM1 and the cytoplasmic domain is minimally exposed to aqueous and is potentially folded in a helical structure that intimately interacts with the NBCe1-A cytoplasmic domain. In contrast, AE1-TM1 contains 25 amino acids connected to an aqueous-exposed cytoplasmic region. Based on our new NBCe1-A-TM1 model, Ser-427 resides in the middle of TM1. Leucine substitution at Ser-427 blocks the normal aqueous access to Thr-442, Ala-435, and Lys-404, implying a significant alteration of NBCe1-TM1 orientation. Our study provides novel structural insights into the pathogenic mechanism of S427L in mediating proximal renal tubular acidosis. PMID- 23362274 TI - Sialylneolacto-N-tetraose c (LSTc)-bearing liposomal decoys capture influenza A virus. AB - Influenza is a severe disease in humans and animals with few effective therapies available. All strains of influenza virus are prone to developing drug resistance due to the high mutation rate in the viral genome. A therapeutic agent that targets a highly conserved region of the virus could bypass resistance and also be effective against multiple strains of influenza. Influenza uses many individually weak ligand binding interactions for a high avidity multivalent attachment to sialic acid-bearing cells. Polymerized sialic acid analogs can form multivalent interactions with influenza but are not ideal therapeutics due to solubility and toxicity issues. We used liposomes as a novel means for delivery of the glycan sialylneolacto-N-tetraose c (LSTc). LSTc-bearing decoy liposomes form multivalent, polymer-like interactions with influenza virus. Decoy liposomes competitively bind influenza virus in hemagglutination inhibition assays and inhibit infection of target cells in a dose-dependent manner. Inhibition is specific for influenza virus, as inhibition of Sendai virus and respiratory syncytial virus is not observed. In contrast, monovalent LSTc does not bind influenza virus or inhibit infectivity. LSTc decoy liposomes prevent the spread of influenza virus during multiple rounds of replication in vitro and extend survival of mice challenged with a lethal dose of virus. LSTc decoy liposomes co localize with fluorescently tagged influenza virus, whereas control liposomes do not. Considering the conservation of the hemagglutinin binding pocket and the ability of decoy liposomes to form high avidity interactions with influenza hemagglutinin, our decoy liposomes have potential as a new therapeutic agent against emerging influenza strains. PMID- 23362275 TI - Thioredoxin-related protein 32 (TRP32) specifically reduces oxidized phosphatase of regenerating liver (PRL). AB - PRL family constitutes a unique class of phosphatases associated with metastasis. The phosphatase activity of PRL has been reported to be important for promoting metastasis, and it is inactivated by reversible oxidation of its catalytic cysteine. Here, we show that TRP32 specifically reduces PRL. Reduction of oxidized PRL in cells is inhibited by 2,4-dinitro-1-chlorobenzene, an inhibitor of TRX reductase. In vitro assays for the reduction of PRL show that only TRP32 can potently reduce oxidized PRL, whereas other TRX-related proteins linked to TRX reductase show little or no reducing activity. Indeed, TRP32 knockdown significantly prolongs the H2O2-induced oxidation of PRL. Binding analyses reveal that the unique C-terminal domain of TRP32 is required and sufficient for its direct interaction with PRL. These results suggest that TRP32 maintains the reduced state of PRL and thus regulates the biological function of PRL. PMID- 23362276 TI - H2O2 regulates lung epithelial sodium channel (ENaC) via ubiquitin-like protein Nedd8. AB - Redundancies in both the ubiquitin and epithelial sodium transport pathways allude to their importance of proteolytic degradation and ion transport in maintaining normal cell function. The classical pathway implicated in ubiquitination of the epithelial sodium channel (ENaC) involves Nedd4-2 regulation of sodium channel subunit expression and has been studied extensively studied. However, less attention has been given to the role of the ubiquitin-like protein Nedd8. Here we show that Nedd8 plays an important role in the ubiquitination of ENaC in alveolar epithelial cells. We report that the Nedd8 pathway is redox-sensitive and that under oxidizing conditions Nedd8 conjugation to Cullin-1 is attenuated, resulting in greater surface expression of alpha-ENaC. This observation was confirmed in our electrophysiology studies in which we inhibited Nedd8-activating enzyme using MLN4924 (a specific Nedd8-activating enzyme inhibitor) and observed a marked increase in ENaC activity (measured as the product of the number of channels (N) and the open probability (Po) of a channel). These results suggest that ubiquitination of lung ENaC is redox sensitive and may have significant implications for our understanding of the role of ENaC in pulmonary conditions where oxidative stress occurs, such as pulmonary edema and acute lung injury. PMID- 23362278 TI - Testing the sulfotransferase molecular pore hypothesis. AB - Human cytosolic sulfotransferases (SULTs) regulate the activities of hundreds of signaling metabolites via transfer of the sulfuryl moiety (-SO3) from activated sulfate (3'-phosphoadenosine 5'-phosphosulfate) to the hydroxyls and primary amines of xeno- and endobiotics. How SULTs select substrates from the scores of competing ligands present in a cytosolic milieu is an important issue in the field. Selectivity appears to be sterically controlled by a molecular pore that opens and closes in response to nucleotide binding. This point of view is fostered by structures showing nucleotide-dependent pore closure and the fact that nucleotide binding induces an isomerization that restricts access to the acceptor-binding pocket. Molecular dynamics models underscore the importance of pore isomerization in selectivity and predict that specific molecular linkages stabilize the closed pore in response to nucleotide binding. To test the pore model, these linkages were disrupted in SULT2A1 via mutagenesis, and the effects on selectivity were determined. The mutations uncoupled nucleotide binding from selectivity and produced enzymes that no longer discriminated between large and small substrates. The mutations did not affect the affinity or turnover of small substrates but resulted in a 183-fold gain in catalytic efficiently toward large substrates. Models predict that an 11-residue "flap" covering the acceptor binding pocket can open and admit large substrates when nucleotide is bound; a mutant structure demonstrated that this is so. In summary, the model was shown to be a robust, accurate predictor of SULT structure and selectivity whose general features will likely apply to other members of the SULT family. PMID- 23362277 TI - NrdH-redoxin of Mycobacterium tuberculosis and Corynebacterium glutamicum dimerizes at high protein concentration and exclusively receives electrons from thioredoxin reductase. AB - NrdH-redoxins are small reductases with a high amino acid sequence similarity with glutaredoxins and mycoredoxins but with a thioredoxin-like activity. They function as the electron donor for class Ib ribonucleotide reductases, which convert ribonucleotides into deoxyribonucleotides. We solved the x-ray structure of oxidized NrdH-redoxin from Corynebacterium glutamicum (Cg) at 1.5 A resolution. Based on this monomeric structure, we built a homology model of NrdH redoxin from Mycobacterium tuberculosis (Mt). Both NrdH-redoxins have a typical thioredoxin fold with the active site CXXC motif located at the N terminus of the first alpha-helix. With size exclusion chromatography and small angle x-ray scattering, we show that Mt_NrdH-redoxin is a monomer in solution that has the tendency to form a non-swapped dimer at high protein concentration. Further, Cg_NrdH-redoxin and Mt_NrdH-redoxin catalytically reduce a disulfide with a specificity constant 1.9 * 10(6) and 5.6 * 10(6) M(-1) min(-1), respectively. They use a thiol-disulfide exchange mechanism with an N-terminal cysteine pKa lower than 6.5 for nucleophilic attack, whereas the pKa of the C-terminal cysteine is ~10. They exclusively receive electrons from thioredoxin reductase (TrxR) and not from mycothiol, the low molecular weight thiol of actinomycetes. This specificity is shown in the structural model of the complex between NrdH redoxin and TrxR, where the two surface-exposed phenylalanines of TrxR perfectly fit into the conserved hydrophobic pocket of the NrdH-redoxin. Moreover, nrdh gene deletion and disruption experiments seem to indicate that NrdH-redoxin is essential in C. glutamicum. PMID- 23362279 TI - Cyr61, a matricellular protein, is needed for dendritic arborization of hippocampal neurons. AB - The shape of the dendritic arbor is one of the criteria of neuron classification and reflects functional specialization of particular classes of neurons. The development of a proper dendritic branching pattern strongly relies on interactions between the extracellular environment and intracellular processes responsible for dendrite growth and stability. We previously showed that mammalian target of rapamycin (mTOR) kinase is crucial for this process. In this work, we performed a screen for modifiers of dendritic growth in hippocampal neurons, the expression of which is potentially regulated by mTOR. As a result, we identified Cyr61, an angiogenic factor with unknown neuronal function, as a novel regulator of dendritic growth, which controls dendritic growth in a beta1 integrin-dependent manner. PMID- 23362280 TI - Dyrk2-associated EDD-DDB1-VprBP E3 ligase inhibits telomerase by TERT degradation. AB - Telomerase maintains the telomere, a specialized chromosomal end structure that is essential for genomic stability and cell immortalization. Telomerase is not active in most somatic cells, but its reactivation is one of the hallmarks of cancer. In this study, we found that dual-specificity tyrosine-(Y) phosphorylation-regulated kinase 2 (Dyrk2) negatively regulates telomerase activity. Dyrk2 phosphorylates TERT protein, a catalytic subunit of telomerase. Phosphorylated TERT is then associated with the EDD-DDB1-VprBP E3 ligase complex for subsequent ubiquitin-mediated TERT protein degradation. During the cell cycle, Dyrk2 interacts with TERT at the G2/M phase and induces degradation. In contrast, depletion of endogenous Dyrk2 disrupts the cell cycle-dependent regulation of TERT and elicits the constitutive activation of telomerase. Similarly, a Dyrk2 nonsense mutation identified in breast cancer compromises ubiquitination-mediated TERT protein degradation. Our findings suggest the novel molecular mechanism of kinase-associated telomerase regulation. PMID- 23362281 TI - Protein kinase A modulates transforming growth factor-beta signaling through a direct interaction with Smad4 protein. AB - Transforming growth factor beta (TGFbeta) signaling normally functions to regulate embryonic development and cellular homeostasis. It is increasingly recognized that TGFbeta signaling is regulated by cross-talk with other signaling pathways. We previously reported that TGFbeta activates protein kinase A (PKA) independent of cAMP through an interaction of an activated Smad3-Smad4 complex and the regulatory subunit of the PKA holoenzyme (PKA-R). Here we define the interaction domains of Smad4 and PKA-R and the functional consequences of this interaction. Using a series of Smad4 and PKA-R truncation mutants, we identified amino acids 290-300 of the Smad4 linker region as critical for the specific interaction of Smad4 and PKA-R. Co-immunoprecipitation assays showed that the B cAMP binding domain of PKA-R was sufficient for interaction with Smad4. Targeting of B domain regions conserved among all PKA-R isoforms and exposed on the molecular surface demonstrated that amino acids 281-285 and 320-329 were required for complex formation with Smad4. Interactions of these specific regions of Smad4 and PKA-R were necessary for TGFbeta-mediated increases in PKA activity, CREB (cAMP-response element-binding protein) phosphorylation, induction of p21, and growth inhibition. Moreover, this Smad4-PKA interaction was required for TGFbeta induced epithelial mesenchymal transition, invasion of pancreatic tumor cells, and regulation of tumor growth in vivo. PMID- 23362282 TI - An N-terminal fragment of the prion protein binds to amyloid-beta oligomers and inhibits their neurotoxicity in vivo. AB - A hallmark of Alzheimer disease (AD) is the accumulation of the amyloid-beta (Abeta) peptide in the brain. Considerable evidence suggests that soluble Abeta oligomers are responsible for the synaptic dysfunction and cognitive deficit observed in AD. However, the mechanism by which these oligomers exert their neurotoxic effect remains unknown. Recently, it was reported that Abeta oligomers bind to the cellular prion protein with high affinity. Here, we show that N1, the main physiological cleavage fragment of the cellular prion protein, is necessary and sufficient for binding early oligomeric intermediates during Abeta polymerization into amyloid fibrils. The ability of N1 to bind Abeta oligomers is influenced by positively charged residues in two sites (positions 23-31 and 95 105) and is dependent on the length of the sequence between them. Importantly, we also show that N1 strongly suppresses Abeta oligomer toxicity in cultured murine hippocampal neurons, in a Caenorhabditis elegans-based assay, and in vivo in a mouse model of Abeta-induced memory dysfunction. These data suggest that N1, or small peptides derived from it, could be potent inhibitors of Abeta oligomer toxicity and represent an entirely new class of therapeutic agents for AD. PMID- 23362283 TI - Dentin phosphophoryn activates Smad protein signaling through Ca2+-calmodulin dependent protein kinase II in undifferentiated mesenchymal cells. AB - Dentin phosphophoryn (DPP) is a major noncollagenous protein in the dentin matrix. In this study, we demonstrate that pluripotent stem cells such as C3H10T1/2 and human bone marrow cells can be committed to the osteogenic lineage by DPP. Treatment with DPP can stimulate the release of intracellular Ca(2+). This calcium flux triggered the activation of Ca(2+)-calmodulin-dependent protein kinase II (CaMKII). Activated CaMKII induced the phosphorylation of Smad1 and promoted nuclear translocation of p-Smad1. Inhibition of store Ca(2+) depletion by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) or down-regulation of CaMKII by KN-62, a selective cell-permeable pharmacological inhibitor or a dominant negative plasmid of CaMKII, blocked DPP-mediated Smad1 phosphorylation. Activation of Smad1 resulted in the expression of osteogenic markers such as Runx2, Osterix, DMP1, Bone sialoprotein, Osteocalcin, NFATc1, and Schnurri-2, which have been implicated in osteoblast differentiation. These findings suggest that DPP is capable of triggering commitment of pluripotent stem cells to the osteogenic lineage. PMID- 23362284 TI - Association of human leukocyte antigen alleles and nevirapine hypersensitivity in a Malawian HIV-infected population. AB - BACKGROUND: The nonnucleoside reverse transcriptase inhibitor nevirapine is the cornerstone of treatment for human immunodeficiency virus (HIV) in many sub Saharan African countries. However, nevirapine is associated with a 6%-10% risk of developing a hypersensitivity reaction, with different phenotypes, including the blistering conditions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Our aim was to identify predictive human leukocyte antigen (HLA) markers that are associated with nevirapine hypersensitivity. METHODS: We identified 117 HIV-infected Malawian adults with nevirapine hypersensitivity (15 drug-induced liver injury [DILI], 33 SJS/TEN, 20 hypersensitivity syndrome, and 46 nevirapine-induced rash plus 3 with both DILI and SJS phenotype) and 155 age-, sex- and ethnicity-matched nevirapine-exposed controls. HLA typing for 5 loci (A, B, C, DRB1, and DQB1) was undertaken using a sequence-based high-resolution protocol. Logistic regression analysis included CD4(+) cell count as a covariate. RESULTS: HLA-C*04:01 was found to markedly increase the risk for SJS (odds ratio [OR] = 17.52; 95% confidence interval, 3.31-92.80) and all hypersensitivity phenotypes (OR = 2.64; 95% CI, 1.13-6.18) when compared to the baseline rare allele group in a binary logistic regression model. The OR for absolute risk of SJS/TEN associated with carriage of HLA-C*04:01 was 5.17 (95% CI, 2.39-11.18). Positive predictive value was 2.6% and negative predictive value was 99.2%. In addition, a number of alleles within the HLA-DQB1 loci protected against nevirapine-induced hypersensitivity phenotypes. CONCLUSIONS: Our study has identified HLA-C*04:01 carriage as a risk factor for nevirapine-induced SJS/TEN in a Malawian HIV cohort. Validation of these findings in a larger cohort of patients and mechanistic investigation of the pathogenesis are required. PMID- 23362285 TI - Early versus delayed antiretroviral therapy and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitis. AB - BACKGROUND: The burden of Cryptococcus neoformans in cerebrospinal fluid (CSF) predicts clinical outcomes in human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) and is lower in patients on antiretroviral therapy (ART). This study tested the hypothesis that initiation of ART during initial treatment of HIV/CM would improve CSF clearance of C. neoformans. METHODS: A randomized treatment-strategy trial was conducted in Botswana. HIV-infected, ART naive adults aged>=21 years initiating amphotericin B treatment for CM were randomized to ART initiation within 7 (intervention) vs after 28 days (control) of randomization, and the primary outcome of the rate of CSF clearance of C. neoformans over the subsequent 4 weeks was compared. Adverse events, including CM immune reconstitution inflammatory syndrome (CM-IRIS), and immunologic and virologic responses were compared over 24 weeks. RESULTS: Among 27 subjects enrolled (13 intervention and 14 control), [corrected] the median times to ART initiation were 7 (interquartile range [IQR], 5-10) and 32days (IQR, 28-36), respectively. The estimated rate of CSF clearance did not differ significantly by treatment strategy (-0.32 log10 colony-forming units [CFU]/mL/day+/-0.20 intervention and -0.52 log10 CFUs/mL/day (+/-0.48) control, P=.4). Two of 13 (15%) and 5 of 14 (36%) subjects died in the intervention and control arms, respectively (P=0.39). Seven of 13 subjects (54%) in the intervention arm vs 0 of 14 in the control arm experienced CM-IRIS (P=.002). CONCLUSIONS: Early ART was not associated with improved CSF fungal clearance, but resulted in a high risk of CM-IRIS. Further research on optimal incorporation of ART into CM care is needed. CLINICAL TRIALS REGISTRATION: NCT00976040. PMID- 23362286 TI - Prevention of tuberculosis in older adults in the United States: obstacles and opportunities. AB - BACKGROUND: Persons >=65 are a growing proportion of the US population and are at increased risk for tuberculosis disease. The objective of the study was to examine rates and identify risk factors for tuberculosis among older adults in the United States. METHODS: Average rates and rate ratios for tuberculosis by age group, race/ethnicity, country of birth, calendar year, and long-term care facility residence were calculated using Centers for Disease Control and Prevention tuberculosis case reports and Census Bureau data. RESULTS: Older adults accounted for 21.9% of tuberculosis cases in the United States between 1993 and 2008. Average yearly tuberculosis rates over sixteen years were 10.9 per 100 000 (95% confidence interval [CI], 10.8-11.0) in older adults compared with 7.3 per 100 000 (95% CI, 7.3-7.4) in persons aged 21-64 (rate ratio [RR], 1.5; 95% CI, 1.5-1.5). Among older adults, tuberculosis rates increased with age from 9.6 per 100 000 in persons aged 65-74 to 14.2 per 100 000 in persons aged >=85 years. Older persons at higher risk for tuberculosis include men (RR, 2.1; 95% CI, 2.1-2.2), American Indians/Alaska Natives (RR 3.6; 95% CI, 3.4-3.9), those in long-term care facilities (RR 2.3; 95% CI, 2.2-2.3), and the foreign-born (RR 5.1; 95% CI, 5.0-5.2). CONCLUSIONS: Elimination of tuberculosis in the United States will require addressing the substantial burden of disease among older persons, especially men, non-whites, long-term care facility residents, and foreign-born persons. Use of interferon-gamma release assay testing may help prioritize persons with greatest need for treatment of latent tuberculosis infection, as new shorter and less toxic regimens make latent tuberculosis treatment in older adults more attractive. PMID- 23362287 TI - Closing in on the target: sustained virologic response in hepatitis C virus genotype 1 infection response-guided therapy. AB - Retrospective analyses of the boceprevir and telaprevir phase 3 trial data demonstrate the clinical relevance of detected but not quantifiable hepatitis C virus (HCV) genotype 1 RNA during treatment. These analyses illustrate the importance of using precise and standard terminology in reporting low-level HCV RNA results for consistent data collection across clinical trials, and to ensure optimal virologic response-guided treatment decision making in clinical practice. In the context of currently available quantitative HCV RNA assays, we clarify that unquantifiable HCV RNA should be classified as target detected or target not detected, as both have been shown to reflect clinically different qualitative HCV RNA levels during treatment. Additionally, use of terms such as "undetectable" or "below limit of detection" should be avoided as such terms are imprecise, not consistently defined, and often misinterpreted. PMID- 23362288 TI - Safety and effectiveness of a nurse-led outreach program for assessment and treatment of chronic hepatitis C in the custodial setting. AB - BACKGROUND: The global burden of disease attributable to chronic hepatitis C virus (HCV) is very large, yet the uptake of curative antiviral therapies remains very low, reflecting the marginalized patient population and the arduous nature of current treatments. METHODS: The safety and effectiveness of a nurse-led model of care of inmates with chronic HCV was evaluated in 3 Australian correctional centers. The model featured protocol-driven assessment, triage, and management of antiviral therapy by specifically trained nurses, with specialist physician support utilizing telemedicine. Outcomes were evaluated qualitatively with key informant interviews, and quantitatively with patient numbers completing key clinical milestones and adverse events. RESULTS: A total of 391 patients with chronic HCV infection were enrolled, of whom 141 (36%) completed the clinical and laboratory evaluations for eligibility for antiviral therapy over 24 months. Treatment was initiated in 108 patients (28%), including 85 (79%) triaged for specialist review conducted by telemedicine only. The demographic and clinical characteristics of the patients who entered the model and completed workup and those who initiated treatment featured a high prevalence of individuals of indigenous background, injection drug users, and those with psychiatric disorder. Serious adverse events occurred in 13 of 108 treated patients (12%) with discontinuation in 8 (7%). The sustained virologic response rate among those with complete follow-up data (n=68) was 69%, and by intention-to treat analysis was 44%. CONCLUSIONS: This nurse-led and specialist-supported assessment and treatment model for inmates with chronic HCV offers potential to substantively increase treatment uptake and reduce the burden of disease. PMID- 23362289 TI - Traditional chinese medicine: an alternative treatment option for refractory recurrent urinary tract infections. PMID- 23362290 TI - Endemic mycoses: overlooked diseases in China. PMID- 23362291 TI - Congenital toxoplasma infection: monthly prenatal screening decreases transmission rate and improves clinical outcome at age 3 years. AB - BACKGROUND: Toxoplasma infection during pregnancy exposes the fetus to risks of congenital infection and sequelae that depend heavily on gestational age (GA) at time of infection. Accurate risk estimates by GA are necessary to counsel parents and improve clinical decisions. METHODS: We analyzed data from pregnant women diagnosed with acute Toxoplasma infection in Lyon (France) from 1987 to 2008 and assessed how the risks of congenital toxoplasmosis and of clinical signs at age 3 years vary depending on GA at the time of maternal infection. RESULTS: Among 2048 mother-infant pairs, 93.2% of mothers received prenatal treatment and 513 (24.7%) fetuses were infected. Because of a significant reduction in risk since 1992 when monthly screening was introduced (59.4% vs 46.6% at 26 GA weeks; P = .038), probabilities of infection were estimated on the basis of maternal infections diagnosed after mid-1992 (n = 1624). Probabilities of congenital infection were <10% for maternal infections before 12 weeks of gestation, rose to 20.0% at 19 weeks, and then continued increasing to 52.3% and almost 70% at 28 and 39 GA weeks, respectively. Because of a significant reduction in risk of clinical signs of congenital toxoplasmosis in infected children born from mothers diagnosed after 1995 when polymerase chain reaction testing on amniotic fluid was initiated (87/794 vs 46/1150; P = .012), probabilities of clinical signs at 3 years were estimated based on 1015 maternal infections diagnosed after 1995 including 207 infected children, with symptoms in 46 (22.2%). CONCLUSIONS: These analyses demonstrated that introduction of monthly prenatal screening and improvement in antenatal diagnosis were associated with a significant reduction in the rate of congenital infection and a better outcome at 3 years of age in infected children. Our updated estimates will improve individual management and counseling in areas where genotype II Toxoplasma is predominant. PMID- 23362292 TI - Reply to Baugh. PMID- 23362293 TI - Herd protection by a bivalent killed whole-cell oral cholera vaccine in the slums of Kolkata, India. AB - BACKGROUND: We evaluated the herd protection conferred by an oral cholera vaccine using 2 approaches: cluster design and geographic information system (GIS) design. METHODS: Residents living in 3933 dwellings (clusters) in Kolkata, India, were cluster-randomized to receive either cholera vaccine or oral placebo. Nonpregnant residents aged>=1 year were invited to participate in the trial. Only the first episode of cholera detected for a subject between 14 and 1095 days after a second dose was considered. In the cluster design, indirect protection was assessed by comparing the incidence of cholera among nonparticipants in vaccine clusters vs those in placebo clusters. In the GIS analysis, herd protection was assessed by evaluating association between vaccine coverage among the population residing within 250 m of the household and the occurrence of cholera in that population. RESULTS: Among 107 347 eligible residents, 66 990 received 2 doses of either cholera vaccine or placebo. In the cluster design, the 3-year data showed significant total protection (66% protection, 95% confidence interval [CI], 50%-78%, P<.01) but no evidence of indirect protection. With the GIS approach, the risk of cholera among placebo recipients was inversely related to neighborhood-level vaccine coverage, and the trend was highly significant (P<.01). This relationship held in multivariable models that also controlled for potentially confounding demographic variables (hazard ratio, 0.94 [95% CI, .90 .98]; P<.01). CONCLUSIONS: Indirect protection was evident in analyses using the GIS approach but not the cluster design approach, likely owing to considerable transmission of cholera between clusters, which would vitiate herd protection in the cluster analyses. CLINICAL TRIALS REGISTRATION: NCT00289224. PMID- 23362294 TI - IDSA guidelines on group A streptococcal pharyngitis vis-a-vis tonsillectomy recommendations. PMID- 23362297 TI - Reply to Trezza et Al. PMID- 23362298 TI - Rapid detection of antibiotic-resistant organism carriage for infection prevention. AB - Rapid detection of multidrug-resistant organism (MDRO) carriers could help reduce MDRO infections by allowing for faster institution of prevention measures. However, improving the turnaround time (TAT) of a test requires attention to more than the analytic TAT, and will only occur if postanalytic processes (test reporting and care interventions) are also rapid and efficient. Obstacles to rapid MDRO test development include complex evolving resistance mechanisms, performance directly on mixed samples (eg, nares, stool), and adaptation of new methods for routine clinical diagnostic use. Existing data to support the clinical utility of rapid detection (vs standard culture methods) are scant. For these reasons, rapid detection of MDRO carriers remains a work in progress. Future efforts should be on developing rapid tests to detect multidrug-resistant gram-negative rods, particularly those harboring beta-lactamases, and on performing clinical trials to determine how best to incorporate rapid detection of MDRO carriage into healthcare-associated infection prevention efforts. PMID- 23362296 TI - SWIFT: prospective 48-week study to evaluate efficacy and safety of switching to emtricitabine/tenofovir from lamivudine/abacavir in virologically suppressed HIV 1 infected patients on a boosted protease inhibitor containing antiretroviral regimen. AB - BACKGROUND: In the United States, emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) is a preferred nucleoside reverse transcriptase inhibitor (NRTI) backbone with lamivudine/abacavir (3TC/ABC) as a commonly used alternative. For patients infected with human immunodeficiency virus (HIV-1) virologically suppressed on a boosted protease inhibitor (PI) + 3TC/ABC regimen, the merits of switching to FTC/TDF as the NRTI backbone are unknown. METHODS: SWIFT was a prospective, randomized, open-label 48-week study to evaluate efficacy and safety of switching to FTC/TDF. Subjects receiving 3TC/ABC + PI + ritonavir (RTV) with HIV-1 RNA < 200 c/mL >=3 months were randomized to continue 3TC/ABC or switch to FTC/TDF. The primary endpoint was time to loss of virologic response (TLOVR) with noninferiority measured by delta of 12%. Virologic failure (VF) was defined as confirmed rebound or the last HIV-1 RNA measurement on study drug >=200 c/mL. RESULTS: In total, 311 subjects were treated in this study (155 to PI + RTV + FTC/TDF, 156 to PI + RTV + 3TC/ABC). Baseline characteristics were similar between the arms: 85% male, 28% black, median age, 46 years; and median CD4 532 cells/mm(3). By TLOVR through week 48, switching to FTC/TDF was noninferior compared to continued 3TC/ABC (86.4% vs 83.3%, treatment difference 3.0% (95% confidence interval, -5.1% to 11.2%). Fewer subjects on FTC/TDF experienced VF (3 vs 11; P = .034). FTC/TDF showed greater declines in fasting low-density lipoproteins (LDL), total cholesterol (TC), and triglycerides (TG) with significant declines in LDL and TC beginning at week 12 with no TC/HDL ratio change. Switching to FTC/TDF showed improved NCEP thresholds for TC and TG and improved 10-year Framingham TC calculated scores. Decreased estimated glomerular filtration rate [corrected] (eGFR) was observed in both arms with a larger decrease in the FTC/TDF arm. CONCLUSIONS: Switching to FTC/TDF from 3TC/ABC maintained virologic suppression, had fewer VFs, improved lipid parameters and Framingham scores but decreased eGFR. CLINICALTRIALS.GOV IDENTIFIER: NCT00724711. PMID- 23362299 TI - Fluoroquinolones and the risk of serious arrhythmia. PMID- 23362301 TI - Biophysical and size-dependent perspectives on plant evolution. AB - Physical laws and processes have profoundly influenced plant evolution. Their effects are invariably size dependent and thus subject to scaling as well as biophysical analyses even though these effects differ depending upon the fluid (water or air) in which plants evolve. Although organisms cannot obviate the effects of physical laws and processes, the consequences of these effects can be altered by ontogenetic or phylogenetic alterations in geometry, shape, or orientation as well as in body size. These assertions are examined using theoretical insights and empirical data drawn from extant and fossil plants pertinent to four evolutionary transitions: (1) the evolution of multicellularity, (2) the transition from an aquatic to an aerial habitat, (3) the evolution of vascular tissues, and (4) the evolution of secondary growth by the independent acquisition of cambia. This examination shows how physical laws limit phenotypic expression, but how they also simultaneously provide alternative, potentially adaptive possibilities. PMID- 23362300 TI - Protein tyrosine nitration in pea roots during development and senescence. AB - Protein tyrosine nitration is a post-translational modification mediated by reactive nitrogen species (RNS) that is associated with nitro-oxidative damage. No information about this process is available in relation to higher plants during development and senescence. Using pea plants at different developmental stages (ranging from 8 to 71 days), tyrosine nitration in the main organs (roots, stems, leaves, flowers, and fruits) was analysed using immunological and proteomic approaches. In the roots of 71-day-old senescent plants, nitroproteome analysis enabled the identification a total of 16 nitrotyrosine-immunopositive proteins. Among the proteins identified, NADP-isocitrate dehydrogenase (ICDH), an enzyme involved in the carbon and nitrogen metabolism, redox regulation, and responses to oxidative stress, was selected to evaluate the effect of nitration. NADP-ICDH activity fell by 75% during senescence. Analysis showed that peroxynitrite inhibits recombinant cytosolic NADP-ICDH activity through a process of nitration. Of the 12 tyrosines present in this enzyme, mass spectrometric analysis of nitrated recombinant cytosolic NADP-ICDH enabled this study to identify the Tyr392 as exclusively nitrated by peroxynitrite. The data as a whole reveal that protein tyrosine nitration is a nitric oxide-derived PTM prevalent throughout root development and intensifies during senescence. PMID- 23362302 TI - Prophylactic radiofrequency ablation in asymptomatic patients with Wolff Parkinson-White is not yet a good strategy: a decision analysis. AB - BACKGROUND: Therapeutic management of asymptomatic patients with a Wolff Parkinson-White (WPW) pattern is controversial. We compared the risk:benefit ratios between prophylactic radiofrequency ablation and no treatment in asymptomatic patients with WPW. METHODS AND RESULTS: Decision analysis software was used to construct a risk-benefit decision tree. The target population consisted of 20- to 40-year-old asymptomatic patients with WPW without structural fatal heart disease or a family history of sudden cardiac death. Baseline estimates of sudden death and radiofrequency ablation complication rates were obtained from the literature, an empirical data survey, and expert opinion. The outcome measure was death within 10 years. Sensitivity analyses determined the variables that significantly impacted the decision to ablate or not. Threshold analyses evaluated the effects of key variables and the optimum policy. At baseline, the decision to ablate resulted in a reduction of mortality risk of 8.8 patients for 1000 patients compared with abstention. It is necessary to treat 112 asymptomatic patients with WPW to save one life over 10 years. Sensitivity analysis showed that 3 variables significantly impacted the decision to ablate: (1) complication of radiofrequency ablation, (2) success of radiofrequency ablation, and (3) sudden death in asymptomatic patients with WPW. CONCLUSIONS: This study provides a decision aid for treating asymptomatic patients with the WPW ECG pattern. Using the model and the population we tested, prophylactic catheter ablation is not yet ready for widespread clinical use. PMID- 23362304 TI - No-reflow phenomenon: pathophysiology, diagnosis, prevention, and treatment. A review of the current literature and future perspectives. AB - No-reflow is responsible for 40% of the primary percutaneous coronary intervention without complete myocardial reperfusion despite successful reopening of the infarct-related artery. This review describes the main pathophysiological mechanisms of no-reflow, its clinical manifestation, including the strong association with increased in-hospital mortality, malignant arrhythmias, and cardiac failure as well as the diagnostic methods. The latter ranges from simple angiographic thrombolysis in myocardial infarction grade score to more complex angiographic indexes, imaging techniques such as myocardial contrast echo or cardiac magnetic resonance, and surrogate clinical end points such as ST-segment resolution. This review also summarizes the strategies of prevention and treatment of no-reflow, considering the most recent studies results regarding medical therapy and devices. PMID- 23362305 TI - B cell receptor-induced Ca2+ mobilization mediates F-actin rearrangements and is indispensable for adhesion and spreading of B lymphocytes. AB - B cells acquire membrane-bound cognate antigens from the surface of the APCs by forming an IS, similar to that seen in T cells. Recognition of membrane-bound antigens on the APCs initiates adhesion of B lymphocytes to the antigen-tethered surface, which is followed by the formation of radial lamellipodia-like structures, a process known as B cell spreading. The spreading response requires the rearrangement of the submembrane actin cytoskeleton and is regulated mainly via signals transmitted by the BCR. Here, we show that cytoplasmic calcium is a regulator of actin cytoskeleton dynamics in B lymphocytes. We find that BCR induced calcium mobilization is indispensible for adhesion and spreading of B cells and that PLCgamma and CRAC-mediated calcium mobilization are critical regulators of these processes. Measuring calcium and actin dynamics in live cells, we found that a generation of actin-based membrane protrusion is strongly linked to the dynamics of a cytoplasmic-free calcium level. Finally, we demonstrate that PLCgamma and CRAC channels regulate the activity of actin severing protein cofilin, linking BCR-induced calcium signaling to the actin dynamics. PMID- 23362303 TI - Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. AB - BACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n 7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of >=1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7*10(-11)) and lower 18:0 (P=2.2*10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6*10(-13)) and 18:1n-9 (P=2.2*10(-32)) and lower 18:0 (P=1.3*10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8*10(-9)). GCKR (glucokinase regulator; P=9.8*10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7*10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2 like 1; P=5.7*10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1*10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology. PMID- 23362306 TI - Reduction of indoxyl sulfate by AST-120 attenuates monocyte inflammation related to chronic kidney disease. AB - Accelerated cardiovascular disease is a frequent complication of CKD. Monocyte mediated inflammation and adhesion of monocytes to vascular endothelium are key events in atherogenesis. An oral adsorbent, AST-120, retards renal function deterioration by lowering IS, which is known to accumulate in CKD patients. However, the effect of AST-120 on CKD-related monocyte activation is unknown. We aimed to determine whether AST-120 improves monocyte-mediated inflammation through IS reduction. Flow cytometric analysis showed that Mac-1 expression and ROS production were significantly higher in peripheral blood monocytes of subtotal Nx CKD mice than in sham-operated mice. AST-120 treatment significantly decreased Mac-1 expression and ROS production in CKD model mice. Furthermore, administration of IS induced monocyte-mediated inflammation and ROS generation. In vitro studies indicated that IS dose-dependently increased THP-1 monocytic cell adhesion to IL-1beta-activated HUVECs under physiological flow conditions. IS also induced monocyte-mediated inflammation and ROS production in THP-1 cells. Phosphorylation of p38 MAPK and membrane translocation of NAD(P)H oxidase subunit p47phox in THP-1 cells were induced by IS. Both SB203580 (p38 MAPK inhibitor) and apocynin [NAD(P)H oxidase inhibitor] reduced THP-1 cell adhesion to HUVECs. Apocynin also inhibited IS-induced ROS production in THP-1 cells. IS induced monocyte-driven inflammation through NAD(P)H oxidase- and p38 MAPK-dependent pathways in monocytes. The main finding of this study was that AST-120 inhibited monocyte activation by reducing IS in vivo. This provides new insights on how AST 120 attenuates the progression of atherosclerosis in CKD. PMID- 23362307 TI - Endovascular treatment for infrainguinal vessels in patients with critical limb ischemia: OLIVE registry, a prospective, multicenter study in Japan with 12-month follow-up. AB - BACKGROUND: Recent technical advances have made endovascular treatment (EVT) an alternative first-line treatment for critical limb ischemia. METHODS AND RESULTS: A prospective multicenter study was conducted to evaluate the clinical outcomes of 314 Japanese critical limb ischemia patients (mean age, 73+/-10 years) with infrainguinal arterial lesions who underwent EVT. Patients were enrolled from December 2009 to July 2011 and were followed-up for 12 months. The primary end point was amputation-free survival (AFS) at 12 months. Secondary end points were anatomic, clinical, and hemodynamic measures, including 12-month freedom from major adverse limb events. The 12-month AFS rate was 74%, with body mass index <18.5 (hazard ratio [HR], 2.22; P=0.008), heart failure (HR, 1.73; P=0.04), and wound infection (HR, 1.89; P=0.03) associated with a poor prognosis for AFS. The 12-month major adverse limb event-free rate was 88%, with hemodialysis (HR, 1.98; P=0.005), heart failure (HR, 1.69; P=0.02), and Rutherford classification 6 (HR, 2.25; P=0.002) associated with a poor prognosis for major adverse limb events. The median time for wound healing was 97 days, with body mass index <18.5 (HR, 0.54; P=0.03) and wound infection (HR, 0.60; P=0.04) being significant risk factors for unhealed wounds after EVT. At 12 months, 34% had undergone reintervention (bypass surgery, 2.6%; repeat EVT, 31.7%), and 73% were major adverse event-free. CONCLUSIONS: The high reintervention rate notwithstanding, EVT was an effective treatment for Japanese critical limb ischemia patients with infrainguinal disease, with satisfactory AFS and major adverse limb event-free rates. The results of this study will be helpful for the future evaluation of critical limb ischemia therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr. Unique identifier: UMIN000002830. PMID- 23362308 TI - Procedural safety and predictors of acute outcome of intracoronary administration of progenitor cells in 775 consecutive procedures performed for acute myocardial infarction or chronic heart failure. AB - BACKGROUND: Cell-based therapies are a promising option in patients with acute myocardial infarction or chronic heart failure (CHF). However, administration of cells requires intracoronary or intracardiac instrumentation, which is potentially associated with periprocedural risks. Therefore, we analyzed periprocedural complications and 30-day outcome in 775 consecutive procedures of intracoronary administration of progenitor cells using the stop-flow technique. METHODS AND RESULTS: Indications for cell administration were acute myocardial infarction (n=126) and CHF of ischemic (n=562) or nonischemic (n=87) etiology. Vessel injury was observed in a total of 9 procedures (1.2%) and could be promptly managed by additional progenitor cell injection (PCI) in all but 1 case. No procedural deaths were observed. A periprocedural increase in troponin T was observed in 3.2% of the CHF procedures, in which no concomitant PCI was performed and troponin levels were not elevated before the procedure. Independent significant predictors of troponin T increase were higher New York Heart Association (NYHA) class (NYHA I versus NYHA IV; P=0.01; NYHA I versus III; P=0.19; NYHA I versus II; P=0.55), concomitant revascularization (P<0.01), presence of elevated troponin T before the procedure (P<0.01), and peripheral occlusive disease (P=0.04). At 30 days, there were 4 deaths (0.5%), 1 stroke (0.13%), 8 acute myocardial infarctions (1%), and 5 hospitalizations for exacerbation of heart failure (0.64%). CONCLUSIONS: Intracoronary infusion of progenitor cells can be performed with adequate safety in patients with acute myocardial infarction or CHF, because the safety profile was similar to what is usually expected from a coronary angiogram in the present cohort. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00962364, NCT00284713, and NCT00289822. PMID- 23362309 TI - A description of mixed group validation. AB - Mixed group validation (MGV) is a statistical model for estimating the diagnostic accuracy of tests. Unlike the more common approach to estimating criterion related validity, known group validation (KGV), MGV does not require a perfect external validity criterion. The present article describes MGV by (a) specifying both the standard error associated with MGV validity estimates and the effect of assumption violation, (b) recommending required sample sizes under various study conditions, (c) evaluating whether assumption violation can be identified, and (d) providing a simulated example of an MGV with imperfect base rate estimates. It is concluded that MGV will always have a wider margin of error than KGV, MGV performs best when the research design approximates a KGV design, the effect of assumption violation depends on the severity of the assumption violation and also the value of the base rates, and that assumption violation may only be detected in severe cases. PMID- 23362310 TI - RORgammat+IL-17+ neutrophils play a critical role in hepatic ischemia-reperfusion injury. PMID- 23362311 TI - Context-specific microRNA function in developmental complexity. AB - Since their discovery, microRNAs (miRNA) have been implicated in a vast array of biological processes in animals, from fundamental developmental functions including cellular proliferation and differentiation, to more complex and specialized roles such as long-term potentiation and synapse-specific modifications in neurons. This review recounts the history behind this paradigm shift, which has seen small non-coding RNA molecules coming to the forefront of molecular biology, and introduces their role in establishing developmental complexity in animals. The fundamental mechanisms of miRNA biogenesis and function are then considered, leading into a discussion of recent discoveries transforming our understanding of how these molecules regulate gene network behaviour throughout developmental and pathophysiological processes. The emerging complexity of this mechanism is also examined with respect to the influence of cellular context on miRNA function. This discussion highlights the absolute imperative for experimental designs to appreciate the significance of context specific factors when determining what genes are regulated by a particular miRNA. Moreover, by establishing the timing, location, and mechanism of these regulatory events, we may ultimately understand the true biological function of a specific miRNA in a given cellular environment. PMID- 23362312 TI - The polarity protein Scrib is essential for directed endothelial cell migration. AB - RATIONALE: Polarity proteins are involved in the apico-basal orientation of epithelial cells, but relatively little is known regarding their function in mesenchymal cells. OBJECTIVE: We hypothesized that polarity proteins also contribute to endothelial processes like angiogenesis. METHODS AND RESULTS: Screening of endothelial cells revealed high expression of the polarity protein Scribble (Scrib). On fibronectin-coated carriers Scrib siRNA (siScrib) blocked directed but not random migration of human umbilical vein endothelial cells and led to an increased number and disturbed orientation of cellular lamellipodia. Coimmunoprecipitation/mass spectrometry and glutathione S-transferase (GST) pulldown assays identified integrin alpha5 as a novel Scrib interacting protein. By total internal reflection fluorescence (TIRF) microscopy, Scrib and integrin alpha5 colocalize at the basal plasma membrane of endothelial cells. Western blot and fluorescence activated cell sorting (FACS) analysis revealed that silencing of Scrib reduced the protein amount and surface expression of integrin alpha5 whereas surface expression of integrin alphaV was unaffected. Moreover, in contrast to fibronectin, the ligand of integrin alpha5, directional migration on collagen mediated by collagen-binding integrins was unaffected by siScrib. Mechanistically, Scrib supported integrin alpha5 recycling and protein stability by blocking its interaction with Rab7a, its translocation into lysosomes, and its subsequent degradation by pepstatin-sensitive proteases. In siScrib-treated cells, reinduction of the wild-type protein but not of PSD95, Dlg, ZO-1 (PDZ), or leucine rich repeat domain mutants restored integrin alpha5 abundance and directional cell migration. The downregulation of Scrib function in Tg(kdrl:EGFP)(s843) transgenic zebrafish embryos delayed the angiogenesis of intersegmental vessels. CONCLUSIONS: Scrib is a novel regulator of integrin alpha5 turnover and sorting, which is required for oriented cell migration and sprouting angiogenesis. PMID- 23362313 TI - Health risk behaviors in adolescents and emerging adults with congenital heart disease: psychometric properties of the Health Behavior Scale-Congenital Heart Disease. AB - BACKGROUND: To optimize long-term outcomes, patients with congenital heart disease (CHD) should adopt health-promoting behaviors. Studies on health behavior in afflicted patients are scarce and comparability of study results is limited. To enlarge the body of evidence, we have developed the Health Behavior Scale Congenital Heart Disease (HBS-CHD). AIMS: We examined the psychometric properties of the HBS-CHD by providing evidence for (a) the content validity; (b) validity based on the relationships with other variables; (c) reliability in terms of stability; and (d) responsiveness. METHODS: Ten experts rated the relevance of the HBS-CHD items. The item content validity index (I-CVI) and the averaged scale content validity index (S-CVI/Ave); the modified multi-rater Kappa and proportion of missing values for each question were calculated. Relationships with other variables were evaluated using six hypotheses that were tested in 429 adolescents with CHD. Stability of the instrument was assessed using Heise's method; and responsiveness was tested by calculating the Guyatt's Responsiveness Index (GRI). RESULTS: Overall, 86.3% of the items had a good to excellent content validity; the S-CVI/Ave (0.81) and multi-rater Kappa (0.78) were adequate. The average proportion of missing values was low (1.2%). Because five out of six hypotheses were confirmed, evidence for the validity of the HBS-CHD based on relationships with other variables was provided. The stability of the instrument could not be confirmed based on our data. The GRI showed good to excellent capacity of the HBS CHD to detect clinical changes in the health behavior over time. CONCLUSION: We found that the HBS-CHD is a valid and responsive questionnaire to assess health behaviors in patients with CHD. PMID- 23362314 TI - Kidney disease and increased mortality risk in type 2 diabetes. AB - Type 2 diabetes associates with increased risk of mortality, but how kidney disease contributes to this mortality risk among individuals with type 2 diabetes is not completely understood. Here, we examined 10-year cumulative mortality by diabetes and kidney disease status for 15,046 participants in the Third National Health and Nutrition Examination Survey (NHANES III) by linking baseline data from NHANES III with the National Death Index. Kidney disease, defined as urinary albumin/creatinine ratio >=30 mg/g and/or estimated GFR <=60 ml/min per 1.73 m(2), was present in 9.4% and 42.3% of individuals without and with type 2 diabetes, respectively. Among people without diabetes or kidney disease (reference group), 10-year cumulative all-cause mortality was 7.7% (95% confidence interval [95% CI], 7.0%-8.3%), standardized to population age, sex, and race. Among individuals with diabetes but without kidney disease, standardized mortality was 11.5% (95% CI, 7.9%-15.2%), representing an absolute risk difference with the reference group of 3.9% (95% CI, 0.1%-7.7%), adjusted for demographics, and 3.4% (95% CI, -0.3% to 7.0%) when further adjusted for smoking, BP, and cholesterol. Among individuals with both diabetes and kidney disease, standardized mortality was 31.1% (95% CI, 24.7%-37.5%), representing an absolute risk difference with the reference group of 23.4% (95% CI, 17.0%-29.9%), adjusted for demographics, and 23.4% (95% CI, 17.2%-29.6%) when further adjusted. We observed similar patterns for cardiovascular and noncardiovascular mortality. In conclusion, those with kidney disease predominantly account for the increased mortality observed in type 2 diabetes. PMID- 23362315 TI - Prognostic significance of silent myocardial infarction in newly diagnosed type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 79. AB - BACKGROUND: We aimed to determine the prevalence of silent myocardial infarction (SMI) in people with newly diagnosed type 2 diabetes mellitus and its relationships to future myocardial infarction (MI) and all-cause mortality. METHODS AND RESULTS: We examined data from the 5102 patients in the 30-year UK Prospective Diabetes Study (UKPDS) and used Cox proportional hazards regression to examine outcomes by SMI status. Of 1967 patients with complete baseline data, 326 (16.6%) had ECG evidence of SMI (Minnesota codes 1.1 or 1.2) at enrollment. Those with SMI were more likely to be older, female, sedentary, and nonsmokers compared with those without SMI. Their mean blood pressure was greater despite more intensive antihypertensive treatment; they were more likely to be taking aspirin and lipid-lowering therapy; and they had a greater prevalence of microangiopathy. Fully adjusted hazard ratios for those with versus those without SMI in multivariate models that included UKPDS Risk Engine variables were 1.58 (95% confidence interval, 1.22-2.05) for fatal MI and 1.31 (95% confidence interval, 1.10-1.56) for all-cause mortality. Hazard ratios for first fatal or nonfatal MI and for first nonfatal MI were nonsignificant. The net reclassification index showed no improvement when SMI was added to these models, and the integrated discrimination index showed that SMI marginally improved the prediction of fatal MI and all-cause mortality. CONCLUSIONS: About 1 in 6 UKPDS patients with newly diagnosed type 2 diabetes mellitus had evidence of SMI, which was independently associated with an increased risk of fatal MI and all-cause mortality. However, identification of SMI does not add substantively to current UKPDS Risk Engine predictive variables. CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com. Identifier: ISRCTN number 75451837. PMID- 23362316 TI - Attitudes toward HPV vaccination among low-income and minority parents of sons: a qualitative analysis. AB - OBJECTIVE: To characterize the attitudes of low-income and minority parents/guardians toward vaccinating sons against human papillomavirus (HPV). METHODS: In 2010-2011, we conducted qualitative interviews with 68 black, 24 white, and 28 Latino parents/guardians of sons. We identified attitudes related to HPV vaccination, vaccine mandates for males and females, and adolescent male sexuality using constructs from the Health Belief Model and methods based in grounded theory. RESULTS: Most participants were concerned that their sons could be exposed to HPV through sexual experimentation and believed that the consequences of HPV infection could be severe; thus, 75% would accept HPV vaccine for their sons. Yet the lack of efficacy and safety information specifically pertaining to males posed barriers. More black (73%) and Latino (86%) than white (44%) participants supported school-entry requirements for HPV vaccination. CONCLUSIONS: Low-income and minority parents/guardians were generally receptive toward vaccinating their sons against HPV; racial/ethnic differences emerged regarding school-entry mandates. PMID- 23362317 TI - 15O PET measurement of blood flow and oxygen consumption in cold-activated human brown fat. AB - Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, PET imaging using the glucose analog (18)F-FDG has shown unequivocally the existence of functional BAT in adult humans, suggesting that many humans retain some functional BAT past infancy. The objective of this study was to determine to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and (18)F-FDG tracer uptake. METHODS: Twenty-five healthy adults (15 women and 10 men; mean age +/- SD, 30 +/- 7 y) underwent triple-oxygen scans (H2(15)O, C(15)O, and (15)O2) as well as measurements of daily energy expenditure (DEE; kcal/d) both at rest and after exposure to mild cold (15.5 degrees C [60 degrees F]) using indirect calorimetry. The subjects were divided into 2 groups (high BAT and low BAT) based on the presence or absence of (18)F-FDG tracer uptake (standardized uptake value [SUV] > 2) in cervical-supraclavicular BAT. Blood flow and oxygen extraction fraction (OEF) were calculated from dynamic PET scans at the location of BAT, muscle, and white adipose tissue. Regional blood oxygen saturation was determined by near-infrared spectroscopy. The total energy expenditure during rest and mild cold stress was measured by indirect calorimetry. Tissue-level metabolic rate of oxygen (MRO2) in BAT was determined and used to calculate the contribution of activated BAT to DEE. RESULTS: The mass of activated BAT was 59.1 +/- 17.5 g (range, 32-85 g) in the high-BAT group (8 women and 1 man; mean age, 29.6 +/- 5.5 y) and 2.2 +/- 3.6 g (range, 0-9.3 g) in the low-BAT group (9 men and 7 women; mean age, 31.4 +/- 10 y). Corresponding maximal SUVs were significantly higher in the high-BAT group than in the low-BAT group (10.7 +/- 3.9 vs. 2.1 +/- 0.7, P = 0.01). Blood flow values were significantly higher in the high-BAT group than in the low-BAT group for BAT (12.9 +/- 4.1 vs. 5.9 +/- 2.2 mL/100 g/min, P = 0.03) and white adipose tissue (7.2 +/- 3.4 vs. 5.7 +/- 2.3 mL/100 g/min, P = 0.03) but were similar for muscle (4.4 +/- 1.9 vs. 3.9 +/- 1.7 mL/100 g/min). Moreover, OEF in BAT was similar in the 2 groups (0.51 +/- 0.17 in high-BAT group vs. 0.47 +/- 0.18 in low BAT group, P = 0.39). During mild cold stress, calculated MRO2 values in BAT increased from 0.97 +/- 0.53 to 1.42 +/- 0.68 mL/100 g/min (P = 0.04) in the high BAT group and were significantly higher than those determined in the low-BAT group (0.40 +/- 0.28 vs. 0.51 +/- 0.23, P = 0.67). The increase in DEE associated with BAT oxidative metabolism was highly variable in the high-BAT group, with an average of 3.2 +/- 2.4 kcal/d (range, 1.9-4.6 kcal/d) at rest, and increased to 6.3 +/- 3.5 kcal/d (range, 4.0-9.9 kcal/d) during exposure to mild cold. Although BAT accounted for only a small fraction of the cold-induced increase in DEE, such increases were not observed in subjects lacking BAT. CONCLUSION: Mild cold induced thermogenesis in BAT accounts for 15-25 kcal/d in subjects with relatively large BAT depots. Thus, although the presence of active BAT is correlated with cold-induced energy expenditure, direct measurement of MRO2 indicates that BAT is a minor source of thermogenesis in humans. PMID- 23362318 TI - Cultivation of an obligate Fe(II)-oxidizing lithoautotrophic bacterium using electrodes. AB - Fe(II)-oxidizing aerobic bacteria are poorly understood, due in part to the difficulties involved in laboratory cultivation. Specific challenges include (i) providing a steady supply of electrons as Fe(II) while (ii) managing rapid formation of insoluble Fe(III) oxide precipitates and (iii) maintaining oxygen concentrations in the micromolar range to minimize abiotic Fe(II) oxidation. Electrochemical approaches offer an opportunity to study bacteria that require problematic electron donors or acceptors in their respiration. In the case of Fe(II)-oxidizing bacteria, if the electron transport machinery is able to oxidize metals at the outer cell surface, electrodes poised at potentials near those of natural substrates could serve as electron donors, eliminating concentration issues, side reactions, and mineral end products associated with metal oxidation. To test this hypothesis, the marine isolate Mariprofundus ferrooxydans PV-1, a neutrophilic obligate Fe(II)-oxidizing autotroph, was cultured using a poised electrode as the sole energy source. When cells grown in Fe(II)-containing medium were transferred into a three-electrode electrochemical cell, a cathodic (negative) current representing electron uptake by bacteria was detected, and it increased over a period of weeks. Cultures scraped from a portion of the electrode and transferred into sterile reactors consumed electrons at a similar rate. After three transfers in the absence of Fe(II), electrode-grown biofilms were studied to determine the relationship between donor redox potential and respiration rate. Electron microscopy revealed that under these conditions, M. ferrooxydans PV-1 attaches to electrodes and does not produce characteristic iron oxide stalks but still appears to exhibit bifurcate cell division. IMPORTANCE Electrochemical cultivation, supporting growth of bacteria with a constant supply of electron donors or acceptors, is a promising tool for studying lithotrophic species in the laboratory. Major pitfalls present in standard cultivation methods used for metal-oxidizing microbes can be avoided by the use of an electrode as the sole electron donor. Electrochemical cultivation also offers a window into the poorly understood metabolism of microbes such as obligate Fe(II), Mn(II), or S(0) oxidizers by replacing the electron source with the controlled surface of an electrode. The elucidation of redox-dependent behavior of these microbes could enhance industrial applications tuned to oxidation of specific metals, provide insight into how bacteria evolved to compete with oxygen for reactive metal species, and model geochemical impacts of their metabolism in the environment. PMID- 23362319 TI - Quantifying pathogen surveillance using temporal genomic data. AB - With the advent of deep sequencing, genomic surveillance has become a popular method for detection of infectious disease, supplementing information gathered by classic clinical or serological techniques to identify host-determinant markers and trace the origin of transmission. However, two main factors complicate genomic surveillance. First, pathogens exhibiting high genetic diversity demand higher levels of scrutiny to obtain an accurate representation of the entire population. Second, current systems of detection are nonuniform, with significant gaps in certain geographic locations and animal reservoirs. Despite past unforeseen pandemics like the 2009 swine-origin H1N1 influenza virus, there is no standardized way of evaluating surveillance. A more complete surveillance system should capture a greater proportion of pathogen diversity. Here we present a novel quantitative method of assessing the completeness of genomic surveillance that incorporates the time of sequence collection, as well as the pathogen's evolutionary rate. We propose the q2 coefficient, which measures the proportion of sequenced isolates whose closest neighbor in the past is within a genetic distance equivalent to 2 years of evolution, roughly the median time of changing strain selection for influenza A vaccines. Easily interpretable and significantly faster than other methods, the q2 coefficient requires no full phylogenetic characterization or use of arbitrary clade definitions. Application of the q2 coefficient to influenza A virus confirmed poor sampling of swine and avian populations and identified regions with deficient surveillance. We demonstrate that the q2 coefficient can not only be applied to other pathogens, including dengue and West Nile viruses, but also used to describe surveillance dynamics, particularly the effects of different public health policies. IMPORTANCE: Surveillance programs have become key assets in determining the emergence or prevalence of pathogens circulating in human and animal populations. Genomic surveillance, in particular, provides comprehensive information on the history of isolates and potential molecular markers for infectivity and pathogenicity. Current techniques for evaluating genomic surveillance are inaccurate, ignoring the pathogen's evolutionary rate and biodiversity, as well as the timing of sequence collection. Using sequence data, we propose the q2 coefficient as a quantitative measure of surveillance completeness that combines elements of time and evolution without defining arbitrary criteria for clades or species. Through several case studies of influenza A, dengue, and West Nile viruses, we employed the q2 coefficient to identify sampling deficiencies in different host species and locations, as well as examine the effects of different public health policies through historical records of the q2 coefficient. These results can guide public health agencies to focus resource allocation and virus collection to bolster specific problems in surveillance. PMID- 23362320 TI - Control of Candida albicans metabolism and biofilm formation by Pseudomonas aeruginosa phenazines. AB - Candida albicans has developmental programs that govern transitions between yeast and filamentous morphologies and between unattached and biofilm lifestyles. Here, we report that filamentation, intercellular adherence, and biofilm development were inhibited during interactions between Candida albicans and Pseudomonas aeruginosa through the action of P. aeruginosa-produced phenazines. While phenazines are toxic to C. albicans at millimolar concentrations, we found that lower concentrations of any of three different phenazines (pyocyanin, phenazine methosulfate, and phenazine-1-carboxylate) allowed growth but affected the development of C. albicans wrinkled colony biofilms and inhibited the fungal yeast-to-filament transition. Phenazines impaired C. albicans growth on nonfermentable carbon sources and led to increased production of fermentation products (ethanol, glycerol, and acetate) in glucose-containing medium, leading us to propose that phenazines specifically inhibited respiration. Methylene blue, another inhibitor of respiration, also prevented the formation of structured colony biofilms. The inhibition of filamentation and colony wrinkling was not solely due to lowered extracellular pH induced by fermentation. Compared to smooth, unstructured colonies, wrinkled colony biofilms had higher oxygen concentrations within the colony, and wrinkled regions of these colonies had higher levels of respiration. Together, our data suggest that the structure of the fungal biofilm promotes access to oxygen and enhances respiratory metabolism and that the perturbation of respiration by bacterial molecules such as phenazines or compounds with similar activities disrupts these pathways. These findings may suggest new ways to limit fungal biofilms in the context of disease. IMPORTANCE Many of the infections caused by Candida albicans, a major human opportunistic fungal pathogen, involve both morphological transitions and the formation of surface-associated biofilms. Through the study of C. albicans interactions with the bacterium Pseudomonas aeruginosa, which often coinfects with C. albicans, we have found that P. aeruginosa-produced phenazines modulate C. albicans metabolism and, through these metabolic effects, impact cellular morphology, cell-cell interactions, and biofilm formation. We suggest that the structure of C. albicans biofilms promotes access to oxygen and enhances respiratory metabolism and that the perturbation of respiration by phenazines inhibits biofilm development. Our findings not only provide insight into interactions between these species but also provide valuable insights into novel pathways that could lead to the development of new therapies to treat C. albicans infections. PMID- 23362321 TI - NEAT1 long noncoding RNA and paraspeckle bodies modulate HIV-1 posttranscriptional expression. AB - Most of the human genome is transcribed into protein-noncoding RNAs (ncRNAs), including small ncRNAs and long ncRNAs (lncRNAs). Over the past decade, rapidly emerging evidence has increasingly supported the view that lncRNAs serve key regulatory and functional roles in mammal cells. HIV-1 replication relies on various cell functions. To date, while the involvement of host protein factors and microRNAs (miRNAs) in the HIV-1 life cycle has been extensively studied, the relationship between lncRNAs and HIV-1 remains uncharacterized. Here, we have profiled 83 disease-related lncRNAs in HIV-1-infected T cells. We found NEAT1 to be one of several lncRNAs whose expression is changed by HIV-1 infection, and we have characterized its role in HIV-1 replication. We In the abstract, added definition of INS OK, or should "cis-acting" be added?report here that the knockdown of NEAT1 enhances virus production through increased nucleus-to cytoplasm export of Rev-dependent instability element (INS)-containing HIV-1 mRNAs. IMPORTANCE Long protein-noncoding RNAs (lncRNAs) play roles in regulating gene expression and modulating protein activities. There is emerging evidence that lncRNAs are involved in the replication of viruses. To our knowledge, this report is the first to characterize a role contributed by an lncRNA, NEAT1, to HIV-1 replication. NEAT1 is essential for the integrity of the nuclear paraspeckle substructure. Based on our findings from NEAT1 knockdown, we have identified the nuclear paraspeckle body as another important subcellular organelle for HIV-1 replication. PMID- 23362322 TI - Host pathways important for Coxiella burnetii infection revealed by genome-wide RNA interference screening. AB - Coxiella burnetii is an intracellular pathogen that replicates within a lysosome like vacuole. A Dot/Icm type IVB secretion system is used by C. burnetii to translocate effector proteins into the host cytosol that likely modulate host factor function. To identify host determinants required for C. burnetii intracellular growth, a genome-wide screen was performed using gene silencing by small interfering RNA (siRNA). Replication of C. burnetii was measured by immunofluorescence microscopy in siRNA-transfected HeLa cells. Newly identified host factors included components of the retromer complex, which mediates cargo cycling between the endocytic pathway and the Golgi apparatus. Reducing the levels of the retromer cargo-adapter VPS26-VPS29-VPS35 complex or retromer associated sorting nexins abrogated C. burnetii replication. Several genes, when silenced, resulted in enlarged vacuoles or an increased number of vacuoles within C. burnetii-infected cells. Silencing of the STX17 gene encoding syntaxin-17 resulted in a striking defect in homotypic fusion of vacuoles containing C. burnetii, suggesting a role for syntaxin-17 in regulating this process. Lastly, silencing host genes needed for C. burnetii replication correlated with defects in the translocation of Dot/Icm effectors, whereas, silencing of genes that affected vacuole morphology, but did not impact replication, did not affect Dot/Icm translocation. These data demonstrate that C. burnetii vacuole maturation is important for creating a niche that permits Dot/Icm function. Thus, genome wide screening has revealed host determinants involved in sequential events that occur during C. burnetii infection as defined by bacterial uptake, vacuole transport and acidification, activation of the Dot/Icm system, homotypic fusion of vacuoles, and intracellular replication. IMPORTANCE: Q fever in humans is caused by the bacterium Coxiella burnetii. Infection with C. burnetii is marked by its unique ability to replicate within a large vacuolar compartment inside cells that resembles the harsh, acidic environment of a lysosome. Central to its pathogenesis is the delivery of bacterial effector proteins into the host cell cytosol by a Dot/Icm type IVB secretion system. These proteins can interact with and manipulate host factors, thereby leading to creation and maintenance of the vacuole that the bacteria grow within. Using high-throughput genome-wide screening in human cells, we identified host factors important for several facets of C. burnetii infection, including vacuole transport and membrane fusion events that promote vacuole expansion. In addition, we show that maturation of the C. burnetii vacuole is necessary for creating an environment permissive for the Dot/Icm delivery of bacterial effector proteins into the host cytosol. PMID- 23362323 TI - Functional analysis of genes in regions commonly amplified in high-grade serous and endometrioid ovarian cancer. AB - PURPOSE: Ovarian cancer has the highest mortality rate of all the gynecologic malignancies and is responsible for approximately 140,000 deaths annually worldwide. Copy number amplification is frequently associated with the activation of oncogenic drivers in this tumor type, but their cytogenetic complexity and heterogeneity has made it difficult to determine which gene(s) within an amplicon represent(s) the genuine oncogenic driver. We sought to identify amplicon targets by conducting a comprehensive functional analysis of genes located in the regions of amplification in high-grade serous and endometrioid ovarian tumors. EXPERIMENTAL DESIGN: High-throughput siRNA screening technology was used to systematically assess all genes within regions commonly amplified in high-grade serous and endometrioid cancer. We describe the results from a boutique siRNA screen of 272 genes in a panel of 18 ovarian cell lines. Hits identified by the functional viability screen were further interrogated in primary tumor cohorts to determine the clinical outcomes associated with amplification and gene overexpression. RESULTS: We identified a number of genes as critical for cellular viability when amplified, including URI1, PAK4, GAB2, and DYRK1B. Integration of primary tumor gene expression and outcome data provided further evidence for the therapeutic use of such genes, particularly URI1 and GAB2, which were significantly associated with survival in 2 independent tumor cohorts. CONCLUSION: By taking this integrative approach to target discovery, we have streamlined the translation of high-resolution genomic data into preclinical in vitro studies, resulting in the identification of a number of genes that may be specifically targeted for the treatment of advanced ovarian tumors. PMID- 23362324 TI - Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: a phase II study. AB - PURPOSE: We conducted a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Patients with histologically confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months. Other endpoints included response rates, overall survival (OS), pharmacokinetics (PK), and biomarkers for cediranib. RESULTS: Cediranib treatment resulted in an estimated 3-month PFS rate of 77% (60%, 99%). Median PFS was 5.3 (3.5,9.7) months, stable disease was seen in 5/17 patients (29%), and median OS was 11.7 (7.5-13.6) months. Grade 3 toxicities included hypertension (29%), hyponatremia (29%), and hyperbilirubinemia (18%). Cediranib PK were comparable to those seen in cancer patients with normal hepatic function. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2, and Ang-2 decreased after cediranib treatment. PFS was inversely correlated with baseline levels of VEGF, sVEGFR2, and bFGF and with on treatment levels of bFGF and IGF-1, and directly associated with on-treatment levels of IFN-gamma. OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-alpha, CAIX, and CD34(+)CD133(+)CD45(dim) circulating progenitor cells and on-treatment levels of sVEGFR2. CONCLUSIONS: Despite the limitations of primary endpoint selection, cediranib at 30-mg daily showed a high incidence of toxicity and preliminary evidence of antitumor activity in advanced HCC. Hepatic dysfunction did not seem to affect the steady-state PK of cediranib. Exploratory studies suggested proangiogenic and inflammatory factors as potential biomarkers of anti-VEGF therapy in HCC. PMID- 23362325 TI - First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma. AB - PURPOSE: GC33 is a novel recombinant fully humanized monoclonal antibody that binds to human glypican-3 (GPC3). The antitumor activity of GC33 was shown in preclinical models of hepatocellular carcinoma (HCC). This first-in-man clinical trial was conducted to evaluate the safety, pharmacokinetic characteristics, and preliminary efficacy of GC33 in patients with advanced HCC. EXPERIMENTAL DESIGN: Patients with measurable, histologically proven, advanced HCC were enrolled to a dose-escalation study of GC33 (2.5-20 mg/kg) given intravenously weekly. The primary endpoint was to determine the maximum tolerated dose of GC33 for further development. Pharmacokinetic characteristics were measured in serum samples. Immunohistochemistry was conducted on tumor biopsies to evaluate GPC3 expression. Tumor response was assessed every 8 weeks using Response Evaluation Criteria in Solid Tumors criteria. RESULTS: Twenty patients were enrolled and treated with GC33. A maximum tolerated dose was not reached as there were no dose-limiting toxicities (DLT) up to the highest planned dose level. Common adverse events with all grades included fatigue (50%), constipation (35%), headache (35%), and hyponatremia (35%). The incidence of adverse events seemed not to be dose dependent. Trough serum concentrations at steady state were in excess of target concentration at doses of 5 mg/kg or greater. Median time to progression (TTP) was 26.0 weeks in the GPC3 high expression group and 7.1 weeks in the low expression group (P = 0.033). CONCLUSION: This study shows that GC33 was well tolerated in advanced HCC and provides preliminary evidence that GPC3 expression in HCC may be associated with the clinical benefit to GC33 that warrants prospective evaluation. PMID- 23362326 TI - Plasma microRNAs as novel biomarkers for endometriosis and endometriosis associated ovarian cancer. AB - PURPOSE: Endometriosis, a largely benign, chronic inflammatory disease, is an independent risk factor for endometrioid and clear cell epithelial ovarian tumors. We aimed to identify plasma miRNAs that can be used to differentiate patients with endometriosis and ovarian cancer from healthy individuals. EXPERIMENTAL DESIGN: We conducted a two-stage exploratory study to investigate the use of plasma miRNA profiling to differentiate between patients with endometriosis, patients with endometriosis-associated ovarian cancer (EAOC), and healthy individuals. In the first stage, using global profiling of more than 1,000 miRNAs via reverse transcriptase quantitative PCR (RT-qPCR) in a 20-patient initial screening cohort, we identified 23 candidate miRNAs, which are differentially expressed between healthy controls (n = 6), patients with endometriosis (n = 7), and patients with EAOC (n = 7) based on the fold changes. In the second stage, the 23 miRNAs were further tested in an expanded cohort (n = 88) of healthy individuals (n = 20), endometriosis (n = 33), EAOC (n = 14), and serous ovarian cancer cases (SOC; n = 21, included as controls). RESULTS: We identified three distinct miRNA signatures with reliable differential expression between healthy individuals, patients with endometriosis, and patients with EAOC. When profiled against the control SOC category, our results revealed different miRNAs, suggesting that the identified signatures are reflective of disease specific pathogenic mechanisms. This was further supported by the fact that the majority of miRNAs differentially expressed in human EAOCs were mirrored in a double transgenic mouse EAOC model. CONCLUSION: Our study reports for the first time that distinct plasma miRNA expression patterns may serve as highly specific and sensitive diagnostic biomarkers to discriminate between healthy, endometriosis, and EAOC cases. PMID- 23362327 TI - Serum antibodies to blood group A predict survival on PROSTVAC-VF. AB - PURPOSE: There is evidence that therapeutic cancer vaccines can lengthen survival for some patients with cancer, but responses vary widely from one person to another. Methods to predict clinical outcomes will advance the field and provide new insights into critical determinants of in vivo efficacy. EXPERIMENTAL DESIGN: This retrospective study included 141 subjects from phase II trials of PROSTVAC VF, a poxvirus-based cancer vaccine currently in phase III clinical trials for advanced prostate cancer. A glycan microarray was used to profile prevaccination antiglycan antibody populations in sera as potential biomarkers for PROSTVAC-VF. The screen for predictive biomarkers identified antiglycan antibodies that consistently stratified subjects into groups with different Kaplan-Meier survival estimates. Because of the potential for overfitting, a permutation test was used to estimate the false discovery rate. RESULTS: Prevaccination antibody levels to blood group A trisaccharide (BG-Atri) were found to have a statistically significant correlation with survival. Long-term survival was approximately doubled in subjects with abundant anti-BG-Atri immunoglobulin M (IgM) relative to subjects with little or no preexisting IgM for BG-Atri. This survival correlation was specific to vaccine treatment, as no correlation was observed in control patients immunized with wild-type poxviruses lacking the key tumor antigen, prostate-specific antigen (PSA). Moreover, anti-BG-Atri IgM levels were not correlated with general measures of disease severity, such as PSA levels, Gleason score, or Halabi predicted survival. CONCLUSION: In addition to reporting a new potentially predictive biomarker for PROSTVAC-VF, this study highlights the use of glycan microarray technology for improving our understanding of vaccine immunology. Clin Cancer Res; 19(5); 1290-9. (c)2012 AACR. PMID- 23362330 TI - Family planning in Brazil: why not tubal sterilisation during childbirth? AB - Sterilisation is the most desired method of contraception worldwide. In 1996, the Brazilian Congress approved a family planning law that legitimised female and male sterilisation, but forbade sterilisation during childbirth. As a result of this law, procedures currently occur in a clandestine nature upon payment. Despite the law, sterilisations continue to be performed during caesarean sections. The permanence of the method is an important consideration; therefore, information about other methods must be made available. Tubal sterilisation must not be the only choice. We argue that review of this restriction will not contribute to the increase in caesarean sections but will allow for greater sterilisation choice for men and women. PMID- 23362328 TI - Quantitative fragmentome mapping reveals novel, domain-specific partners for the modular protein RepoMan (recruits PP1 onto mitotic chromatin at anaphase). AB - RepoMan is a protein phosphatase 1 (PP1) regulatory subunit that targets the phosphatase to key substrates throughout the cell cycle. Most work to date has focused on the mitotic roles of RepoMan/PP1, although equally important interphase role(s) have been demonstrated. Initial mapping of the interactome of nuclear RepoMan, both endogenous and tagged, was complicated by various factors, including antibody cross-reactivity and low sensitivity of the detection of chromatin-associated partners above the high background of proteins that bind nonspecifically to affinity matrices. We therefore adapted the powerful combination of fluorescence imaging with labeling-based quantitative proteomics to map the "fragmentomes" of specific regions of RepoMan. These regions demonstrate distinct localization patterns and turnover dynamics that reflect underlying binding events. The increased sensitivity and signal-to-noise ratio provided by this unique approach facilitated identification of a large number of novel RepoMan interactors, several of which were rigorously validated in follow up experiments, including the association of RepoMan/PP1 with a specific PP2A B56gamma complex, interaction with ribosomal proteins and import factors involved in their nucleocytoplasmic transport and interaction with proteins involved in the response to DNA damage. This same strategy can be used to investigate the cellular roles of other modular proteins. PMID- 23362329 TI - Metabolomics coupled with proteomics advancing drug discovery toward more agile development of targeted combination therapies. AB - To enhance the therapeutic efficacy and reduce the adverse effects of traditional Chinese medicine, practitioners often prescribe combinations of plant species and/or minerals, called formulae. Unfortunately, the working mechanisms of most of these compounds are difficult to determine and thus remain unknown. In an attempt to address the benefits of formulae based on current biomedical approaches, we analyzed the components of Yinchenhao Tang, a classical formula that has been shown to be clinically effective for treating hepatic injury syndrome. The three principal components of Yinchenhao Tang are Artemisia annua L., Gardenia jasminoids Ellis, and Rheum Palmatum L., whose major active ingredients are 6,7-dimethylesculetin (D), geniposide (G), and rhein (R), respectively. To determine the mechanisms underlying the efficacy of this formula, we conducted a systematic analysis of the therapeutic effects of the DGR compound using immunohistochemistry, biochemistry, metabolomics, and proteomics. Here, we report that the DGR combination exerts a more robust therapeutic effect than any one or two of the three individual compounds by hitting multiple targets in a rat model of hepatic injury. Thus, DGR synergistically causes intensified dynamic changes in metabolic biomarkers, regulates molecular networks through target proteins, has a synergistic/additive effect, and activates both intrinsic and extrinsic pathways. PMID- 23362332 TI - Research to reality (R2R) mentorship program: building partnership, capacity, and evidence. AB - Despite a wealth of intervention research in cancer control, full integration of evidence-based interventions into practice often fails, at least in part because of inadequate collaboration between practitioners and researchers. The National Cancer Institute piloted a mentorship program designed for practitioners to improve their ability to navigate evidence-based decision making within a context of inadequate resources, political barriers, and organizational constraints. The National Cancer Institute simultaneously sought to provide opportunities for practitioners and researchers to share and learn from each other. We identified four key successes and challenges related to translation as experienced by mentees: (a) establishing and maintaining partnerships, (b) data collection and analysis, (c) navigating context, and (d) program adaptation and evaluation. Mentorship programs have the potential to facilitate increased and more successful integration of evidence-based interventions into practice by promoting and building the capacity for collaborative decision making and generating in depth understanding of the translation barriers and successes as well as strategies to address the complex contextual issues relative to implementation. PMID- 23362333 TI - Advocating for environmental changes to increase access to parks: engaging promotoras and youth leaders. AB - Access to physical activity opportunities are limited in underserved communities. Community-based programs can increase promotoras and youth leaders' capacity to advocate for built environmental changes. Promotoras and youth leaders were trained on walkability assessment, park audits, and advocacy. The youth and promotoras from one church located adjacent to a park implemented a community survey, conducted walk audits, and engaged in consciousness-raising activities about environmental factors that affect communities. They also mobilized community members to advocate for a nearby park. Advocacy tactics included attending and making presentations at the City Council, planning meetings, organizing health fairs, and speaking to community members. The following changes were made at the park: removed overgrown plants, relocated storage container, increased park security (i.e., lighting, fencing), improved safety (i.e., covered sewer drain, sand lot removed), enhanced amenities (i.e., drinking fountain, bathroom, benches, tables), improved pedestrian safety in park (i.e., leveled the old and added new walking paths), and improved children's play area (i.e., new play equipment, fencing). The current program highlights factors that contributed to park changes and challenges in increasing access to parks. Furthermore, the current study notes steps that other programs can take to make environmental changes. PMID- 23362334 TI - An application of a diabetes knowledge scale for low-literate Hispanic/Latinos. AB - PURPOSE: The threefold purpose of this study is to assess diabetes knowledge among Hispanic/Latinos attending a culturally sensitive, empowerment-based, diabetes self-management education program; second, to examine the utility of the Spoken Knowledge in Low Literacy in Diabetes (SKILLD) scale as an assessment tool for this population; and third, to assess the relationship between hemoglobin A1C and knowledge improvement in the intervention group. METHOD: A prospective, quasi experimental, repeated-measure design tested pre- and post-A1C and diabetes knowledge using the SKILLD scale. The sample consisted of 71 in the intervention group and 64 controls. RESULTS: Most participants were female, marginally acculturated, and, on average, 60 years of age. Both groups were similar in baseline diabetes knowledge score (median 6 out of 10), and higher literacy was significantly related to increased baseline knowledge. The intervention group significantly improved at follow-up compared with the controls: Participants in the intervention with low baseline knowledge scores had a mean follow-up score of 5.6; those with a high baseline score had a mean score of 7.6. The intervention cohort scored significantly better in knowing why to see an eye doctor, what are normal fasting blood glucose and A1C, and understanding long-term diabetes complications. Increased knowledge of a normal fasting blood glucose level had a significant effect on follow-up A1C in the intervention group. CONCLUSION: The intervention favorably affects diabetes knowledge, and the SKILLD scale has utility with low-literate Hispanic/Latinos. The significant impact on A1C by diabetes knowledge gain shows that the empowerment-based diabetes self-management education was successful for this ethnic population. PMID- 23362335 TI - Clown intervention to reduce preoperative anxiety in children and parents: a randomized controlled trial. AB - This study investigated whether a clown doctor intervention could reduce preoperative anxiety in children hospitalized for minor surgery and in their parents. A randomized controlled trial was conducted with 77 children and 119 parents: the clown group consisted of 52 children accompanied in the preoperating room by their parents (n = 89) and two clowns while the comparison group consisted of children accompanied by the parents only. The clown intervention significantly reduced the children's preoperative anxiety: children benefited from the clown's presence and showed better adjustment than children in the comparison group. Mothers in Comparison Group showed higher anxiety. PMID- 23362336 TI - Massage on experimental pain in healthy females: a randomized controlled trial. AB - This randomized controlled study evaluated the effect of massage on affect, relaxation, and experimental pain induced by electrical stimulation. Participants were 96 healthy women (M age = 20.13 +/- 5.93 years; 84.4% White) randomly assigned to a 15-minute no-treatment control, guided imagery, massage or massage plus guided imagery condition. Multilevel piecewise modeling revealed no group differences in pain intensity, threshold, or tolerance. The two massage conditions generally reported decreased pain unpleasantness, lower unpleasant affect, maintenance of pleasant affect, and increased relaxation compared to the no-treatment condition. The results suggest that massage may alter immediate affective qualities in the context of pain. PMID- 23362337 TI - Sexual behaviors in male sex workers in Spain: modulating factors. AB - This study analyzed how the culture of origin, educational level, sexual orientation, and experience of male sex workers may mediate their commercial sexual behaviors. A total of 100 Spanish agency male sex workers were interviewed. Most of them were young men, Latin American, homosexual, and had middle-level education. Our results showed that cultural differences and sexual orientation could influence male sex workers when engaging in sexual behaviors with their clients. Social and health projects with male sex workers may have to take into account sexual myths and taboos related to sexual orientation and cultural differences. PMID- 23362339 TI - A consumer satisfaction survey of civilly committed sex offenders in Illinois. AB - The purpose of this study was to obtain feedback from civilly committed sex offenders (N = 113) about the components of treatment that they believed to be most important and helpful in preventing reoffense. Participants were also asked to rate their satisfaction with the treatment process and therapists. Victim empathy and accountability were rated as the most important elements of treatment, along with skills for preventing relapse and methods for controlling sexual arousal. There was a fairly robust correlation between client perceptions of importance and satisfaction on most treatment components. Some clients expressed concerns about respect, confidentiality, and judgmental attitudes of some therapists. Because civilly committed sex offenders are considered to be among the most likely to reoffend, strategies are discussed for engagement of this population in a meaningful process of change. PMID- 23362338 TI - A randomized controlled trial of mindfulness-based stress reduction for women with early-stage breast cancer receiving radiotherapy. AB - PURPOSE: To testthe relative effectiveness of a mindfulness-based stress reduction program (MBSR) compared with a nutrition education intervention (NEP) and usual care (UC) in women with newly diagnosed early-stage breast cancer (BrCA)undergoing radiotherapy. METHODS: Datawere available from a randomized controlled trialof 172 women, 20 to 65 years old, with stage I or II BrCA. Data from women completing the 8-week MBSR program plus 3 additional sessions focuses on special needs associated with BrCA were compared to women receiving attention control NEP and UC. Follow-up was performed at 3 post-intervention points: 4 months, and 1 and 2 years. Standardized, validated self-administered questionnaires were used to assess psychosocial variables. Descriptive analyses compared women by randomization assignment. Regression analyses, incorporating both intention-to-treat and post hoc multivariable approaches, were used to control for potential confounding variables. RESULTS: A subset of 120 women underwent radiotherapy; 77 completed treatment prior to the study, and 40 had radiotherapy during the MBSR intervention. Women who actively received radiotherapy (art) while participating in the MBSR intervention (MBSR-art) experienced a significant (P < .05) improvement in 16 psychosocial variables compared with the NEP-art, UC-art, or both at 4 months. These included health related, BrCA-specific quality of life and psychosocial coping, which were the primary outcomes, and secondary measures, including meaningfulness, helplessness, cognitive avoidance, depression, paranoid ideation, hostility, anxiety, global severity, anxious preoccupation, and emotional control. CONCLUSIONS: MBSR appears to facilitate psychosocial adjustment in BrCA patients receiving radiotherapy, suggesting applicability for MBSR as adjunctive therapy in oncological practice. PMID- 23362340 TI - Isolation of Tritrichomonas foetus from cats sampled at a cat clinic, cat shows and a humane society in southern Ontario. AB - Tritrichomonas foetus is a protozoan parasite that has been associated with chronic diarrhea in cats. This study aimed to determine (i) the prevalence of T foetus shedding in cats from three different populations in southern Ontario, and (ii) associations between the presence of T foetus and potential cat management, health and demographic risk factors. A cross-sectional study was conducted involving 140 cats from a cat clinic in Guelph, 46 cats from a humane society in Guelph and 55 cats from two cat shows. Risk factor information was assessed through a questionnaire. The InPouch TF (feline) culture method was used to determine the presence of T foetus in all samples. Polymerase chain reaction was conducted on all samples positive by the InPouch TF, as well as 132 negative samples. The assays were interpreted in series and the prevalence of T foetus shedding and 95% confidence intervals (CI) were estimated at 0.7% (95% CI: 0.0 3.9%; n = 140) from the cat clinic, 0% (95% CI: 0.0-7.7%; n = 46) from the humane society and 23.6% (95% CI: 13.2-37.0%; n = 55) from the cat shows. 'Attendance at cat shows' was the only variable significant in both the univariable and multivariable analyses (P <0.05). No significant association was found between the presence of T foetus and diarrhea at the time of sampling or having a history of diarrhea in the past 6 months. The prevalence of T foetus was highly variable among populations of cats in southern Ontario, with shedding being most common in show cats. PMID- 23362341 TI - Preliminary evaluation of a quantitative polymerase chain reaction assay for diagnosis of feline immunodeficiency virus infection. AB - Enzyme-linked immunosorbent assay (ELISA) has high sensitivity and specificity for detection of feline immunodeficiency virus (FIV) antibodies, but does not distinguish between infection and vaccination. Real-time quantitative PCR (qPCR) assays may distinguish infected from vaccinated cats. Performance of a commercial qPCR assay was assessed with blood samples from 29 FIV-infected non-vaccinated, 26 FIV-uninfected vaccinated and 35 FIV-uninfected non-vaccinated cats. FIV infection status of cats was assigned based on a combination of vaccination and medical history, prevention of contact with potentially infected cats and two FIV antibody ELISA results. Test sensitivity and specificity were determined against this gold standard. The qPCR test yielded positive results in samples from 23/29 FIV-infected non-vaccinated, 2/26 FIV-uninfected vaccinated and 0/35 FIV uninfected non-vaccinated cats. It was concluded that the qPCR test was moderately sensitive and highly specific for the diagnosis of FIV infection, and that it may be suitable for ruling out FIV infection in cats with a positive antibody ELISA result and unknown vaccination history. PMID- 23362342 TI - Discrepancy between use of lean body mass or nitrogen balance to determine protein requirements for adult cats. AB - This study was undertaken to contrast the minimum protein intake needed to maintain nitrogen balance or lean body mass (LBM) in adult cats using a prospective evaluation of 24 adult, neutered male cats fed one to three different diets. Following a 1-month baseline period during which all cats consumed a 34% protein diet, cats were fed a 20% (LO), 26% (MOD) or 34% (HI) protein diet for 2 months. During the baseline period and following the 2-month feeding period, nitrogen balance was assessed using a 96-h complete collection of urine and feces, and LBM was assessed using dual energy X-ray absorptiometry. Weight loss increased in a linear manner with decreasing protein intake (P <0.01), despite no significant difference in calorie intake. Linear regression of the data indicated that approximately 1.5 g protein/kg (2.1 g/kg(0.75)) body weight is needed to maintain nitrogen balance, while 5.2 g protein/kg (7.8 g/kg(0.75)) body weight is needed to maintain LBM. This study provides evidence that nitrogen balance studies are inadequate for determining optimum protein requirements. Animals, including cats, can adapt to low protein intake and maintain nitrogen balance while depleting LBM. Loss of LBM and an associated reduction in protein turnover can result in compromised immune function and increased morbidity. Current Association of American Feed Control Officials (AAFCO) and National Research Council (NRC) standards for protein adequacy may not provide adequate protein to support LBM. The minimum daily protein requirement for adult cats appears to be at least 5.2 g/kg (7.8 g/kg(0.75)) body weight, well in excess of current AAFCO and NRC recommendations. Further research is needed to determine the effect, if any, of body condition, age and gender on protein requirements. PMID- 23362343 TI - Stem cells living with a Notch. AB - Notch signaling has been shown over the past few decades to play fundamental roles in a plethora of developmental processes in an evolutionarily conserved fashion. Notch-mediated cell-to-cell signaling is involved in many aspects of embryonic development and control of tissue homeostasis in a variety of adult tissues, and regulates stem cell maintenance, cell differentiation and cellular homeostasis. The focus of this Review is the role of Notch signaling in stem cells, comparing insights from flies, fish and mice to highlight similarities, as well as differences, between species, tissues and stem cell compartments. PMID- 23362345 TI - Auxin-associated initiation of vascular cell differentiation by LONESOME HIGHWAY. AB - Plant vascular tissues are essential for the existence of land plants. Many studies of transcriptional regulation and cell-cell communication have revealed the process underlying the development of vascular tissues from vascular initial cells. However, the initiation of vascular cell differentiation is still a mystery. Here, we report that LONESOME HIGHWAY (LHW), which encodes a bHLH transcription factor, is expressed in pericycle-vascular mother cells at the globular embryo stage and is required for proper asymmetric cell division to generate vascular initial cells. In addition, ectopic expression of LHW elicits an ectopic auxin response. Moreover, LHW is required for the correct expression patterns of components related to auxin flow, such as PIN-FORMED 1 (PIN1), MONOPTEROS (MP) and ATHB-8, and ATHB-8 partially rescues the vascular defects of lhw. These results suggest that LHW functions as a key regulator to initiate vascular cell differentiation in association with auxin regulation. PMID- 23362344 TI - Human pluripotent stem cells: an emerging model in developmental biology. AB - Developmental biology has long benefited from studies of classic model organisms. Recently, human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, have emerged as a new model system that offers unique advantages for developmental studies. Here, we discuss how studies of hPSCs can complement classic approaches using model organisms, and how hPSCs can be used to recapitulate aspects of human embryonic development 'in a dish'. We also summarize some of the recently developed genetic tools that greatly facilitate the interrogation of gene function during hPSC differentiation. With the development of high-throughput screening technologies, hPSCs have the potential to revolutionize gene discovery in mammalian development. PMID- 23362346 TI - Cbx4 regulates the proliferation of thymic epithelial cells and thymus function. AB - Thymic epithelial cells (TECs) are the main component of the thymic stroma, which supports T-cell proliferation and repertoire selection. Here, we demonstrate that Cbx4, a Polycomb protein that is highly expressed in the thymic epithelium, has an essential and non-redundant role in thymic organogenesis. Targeted disruption of Cbx4 causes severe hypoplasia of the fetal thymus as a result of reduced thymocyte proliferation. Cell-specific deletion of Cbx4 shows that the compromised thymopoiesis is rooted in a defective epithelial compartment. Cbx4 deficient TECs exhibit impaired proliferative capacity, and the limited thymic epithelial architecture quickly deteriorates in postnatal mutant mice, leading to an almost complete blockade of T-cell development shortly after birth and markedly reduced peripheral T-cell populations in adult mice. Furthermore, we show that Cbx4 physically interacts and functionally correlates with p63, which is a transcriptional regulator that is proposed to be important for the maintenance of the stemness of epithelial progenitors. Together, these data establish Cbx4 as a crucial regulator for the generation and maintenance of the thymic epithelium and, hence, for thymocyte development. PMID- 23362347 TI - Unusual chromatin status and organization of the inactive X chromosome in murine trophoblast giant cells. AB - Mammalian X-chromosome inactivation (XCI) enables dosage compensation between XX females and XY males. It is an essential process and its absence in XX individuals results in early lethality due primarily to extra-embryonic defects. This sensitivity to X-linked gene dosage in extra-embryonic tissues is difficult to reconcile with the reported tendency of escape from XCI in these tissues. The precise transcriptional status of the inactive X chromosome in different lineages has mainly been examined using transgenes or in in vitro differentiated stem cells and the degree to which endogenous X-linked genes are silenced in embryonic and extra-embryonic lineages during early postimplantation stages is unclear. Here we investigate the precise temporal and lineage-specific X-inactivation status of several genes in postimplantation mouse embryos. We find stable gene silencing in most lineages, with significant levels of escape from XCI mainly in one extra-embryonic cell type: trophoblast giant cells (TGCs). To investigate the basis of this epigenetic instability, we examined the chromatin structure and organization of the inactive X chromosome in TGCs obtained from ectoplacental cone explants. We find that the Xist RNA-coated X chromosome has a highly unusual chromatin content in TGCs, presenting both heterochromatic marks such as H3K27me3 and euchromatic marks such as histone H4 acetylation and H3K4 methylation. Strikingly, Xist RNA does not form an overt silent nuclear compartment or Cot1 hole in these cells. This unusual combination of silent and active features is likely to reflect, and might underlie, the partial activity of the X chromosome in TGCs. PMID- 23362348 TI - HNF1B controls proximal-intermediate nephron segment identity in vertebrates by regulating Notch signalling components and Irx1/2. AB - The nephron is a highly specialised segmented structure that provides essential filtration and resorption renal functions. It arises by formation of a polarised renal vesicle that differentiates into a comma-shaped body and then a regionalised S-shaped body (SSB), with the main prospective segments mapped to discrete domains. The regulatory circuits involved in initial nephron patterning are poorly understood. We report here that HNF1B, a transcription factor known to be involved in ureteric bud branching and initiation of nephrogenesis, has an additional role in segment fate acquisition. Hnf1b conditional inactivation in murine nephron progenitors results in rudimentary nephrons comprising a glomerulus connected to the collecting system by a short tubule displaying distal fates. Renal vesicles develop and polarise normally but fail to progress to correctly patterned SSBs. Major defects are evident at late SSBs, with altered morphology, reduction of a proximo-medial subdomain and increased apoptosis. This is preceded by strong downregulation of the Notch pathway components Lfng, Dll1 and Jag1 and the Irx1/2 factors, which are potential regulators of proximal and Henle's loop segment fates. Moreover, HNF1B is recruited to the regulatory sequences of most of these genes. Overexpression of a HNF1B dominant-negative construct in Xenopus embryos causes downregulation specifically of proximal and intermediate pronephric segment markers. These results show that HNF1B is required for the acquisition of a proximo-intermediate segment fate in vertebrates, thus uncovering a previously unappreciated function of a novel SSB subcompartment in global nephron segmentation and further differentiation. PMID- 23362349 TI - Hepatocyte nuclear factor 1beta controls nephron tubular development. AB - Nephron morphogenesis is a complex process that generates blood-filtration units (glomeruli) connected to extremely long and patterned tubular structures. Hepatocyte nuclear factor 1beta (HNF1beta) is a divergent homeobox transcription factor that is expressed in kidney from the first steps of nephrogenesis. Mutations in HNF1B (OMIM #137920) are frequently found in patients with developmental renal pathologies, the mechanisms of which have not been completely elucidated. Here we show that inactivation of Hnf1b in the murine metanephric mesenchyme leads to a drastic tubular defect characterized by the absence of proximal, distal and Henle's loop segments. Nephrons were eventually characterized by glomeruli, with a dilated urinary space, directly connected to collecting ducts via a primitive and short tubule. In the absence of HNF1beta early nephron precursors gave rise to deformed S-shaped bodies characterized by the absence of the typical bulge of epithelial cells at the bend between the mid and lower segments. The lack of this bulge eventually led to the absence of proximal tubules and Henle's loops. The expression of several genes, including Irx1, Osr2 and Pou3f3, was downregulated in the S-shaped bodies. We also observed decreased expression of Dll1 and the consequent defective activation of Notch in the prospective tubular compartment of comma- and S-shaped bodies. Our results reveal a novel hierarchical relationship between HNF1beta and key genes involved in renal development. In addition, these studies define a novel structural and functional component of S-shaped bodies at the origin of tubule formation. PMID- 23362350 TI - Genetic lineage labeling in zebrafish uncovers novel neural crest contributions to the head, including gill pillar cells. AB - At the protochordate-vertebrate transition, a new predatory lifestyle and increased body size coincided with the appearance of a true head. Characteristic innovations of this head are a skull protecting and accommodating a centralized nervous system, a jaw for prey capture and gills as respiratory organs. The neural crest (NC) is a major ontogenetic source for the 'new head' of vertebrates and its contribution to the cranial skeleton has been intensively studied in different model organisms. However, the role of NC in the expansion of the respiratory surface of the gills has been neglected. Here, we use genetic lineage labeling to address the contribution of NC to specific head structures, in particular to the gills of adult zebrafish. We generated a sox10:ER(T2)-Cre line and labeled NC cells by inducing Cre/loxP recombination with tamoxifen at embryonic stages. In juvenile and adult fish, we identified numerous established NC derivatives and, in the cranium, we precisely defined the crest/mesoderm interface of the skull roof. We show the NC origin of the opercular bones and of multiple cell types contributing to the barbels, chemosensory organs located in the mouth region. In the gills, we observed labeled primary and secondary lamellae. Clonal analysis reveals that pillar cells, a craniate innovation that mechanically supports the filaments and forms gill-specific capillaries, have a NC origin. Our data point to a crucial role for the NC in enabling more efficient gas exchange, thus uncovering a novel, direct involvement of this embryonic tissue in the evolution of respiratory systems at the protochordate-vertebrate transition. PMID- 23362359 TI - Editorial. PMID- 23362351 TI - Year of the author. More evidence and prospective studies needed in the field of feline medicine. PMID- 23362360 TI - Correlation between student performances on course level integrated clinical skills examinations and objective structured clinical examinations in a chiropractic college program. AB - PURPOSE: This retrospective study measured correlation of student performance between 2 objective structured clinical examinations (OSCEs) and an introductory integrated clinical skills course that preceded the OSCEs. The hypothesis was that there would be a strong, positive correlation between the earlier level examinations and the upper level OSCE, high enough that earlier examinations could be viewed as predictors of upper level OSCE performance. METHODS: Using student scores for 5 academic terms of upper level OSCEs for 2008-2009 (n = 208) and respective earlier scores, correlation coefficients were calculated for the upper level OSCE and Clinical Skills course, and upper and lower level OSCEs. Multiple linear regression analysis was used to evaluate how well the lower level OSCE and clinical skills scores, both as lone and combined independent variables, predicted the upper level OSCE scores. RESULTS: There was at least a moderate correlation between both sets of scores: r = .51 (p < .001) between upper level OSCE and clinical skills course, r = .54 (p < .001) between the upper and lower level OSCEs. A combination of clinical skills and lower level OSCE scores suggested a moderate prediction of upper level OSCE scores (R(2) = .38.) CONCLUSIONS: Correlations were found to be of at least a moderate level. According to linear regression analysis, a combination of the earlier scores was moderately predictive for the upper level OSCE. More research could be done to determine additional components of student performance. PMID- 23362362 TI - Background, expectations and beliefs of a chiropractic student population: a cross-sectional survey. AB - PURPOSE: Research encompassing the characteristics of chiropractic students is limited. The purpose of our study was to evaluate a current chiropractic student population enrolled at a chiropractic college concerning demographics, expectations, and beliefs. METHODS: A 44-item survey was administered to volunteer participants. Direct verbal interaction in a classroom setting to potential participants was the recruitment strategy used. Data were collected and stored on a safe network. Percentages for all responses were calculated and means were recorded where appropriate. RESULTS: A total of 664 students participated of 877 potential eligible candidates (75%). The respondents tended to be 21-25 years of age, Caucasian, and male. Most respondents expected to work in a private practice immediately following graduation and anticipated an annual income of at least $100,000 eventually. Respondents preferred the retaining of the term, "subluxation," and identified the importance of new and emerging scientific data. Additionally, respondents held the viewpoint that some non-musculoskeletal diseases can be treated effectively with spinal manipulation as a primary treatment. CONCLUSIONS: The majority of chiropractic students in our study were represented by specific demographic characteristics, and a strong favoritism toward the expectations of working in a private practice setting and earning at least $100,000 per year at some point in their career. Distinct beliefs are shared between chiropractic students and practicing chiropractors in North America, and certain aspects of students in our study are comparable to chiropractic students in similar studies. PMID- 23362363 TI - Demographic and clinical characteristics of new patients presenting to a community teaching clinic. AB - PURPOSE: We compare patient populations attending chiropractors in the field to those in teaching clinics to allow educational institutions to determine if students are exposed to a similar case mix. The purpose of our study was to describe and compare descriptively the clinical case mix of a recently opened community-based teaching clinic to previously published practice data. METHODS: A retrospective descriptive cross-sectional study was conducted using new patient records completed at a clinic. Data were extracted using a specifically designed abstraction form. RESULTS: We manually abstracted 649 files. A total of 580 new patient files was included in the analysis, among which 57.7% included female patients with a mean age of 43 years (SD 18), and 42.1% presented with a chief complaint of more than one year in duration. The vast majority of patients complained of spinal pain (81.4%), most commonly low back pain. Almost 92% of the diagnoses were classified as simple (sprain/strain). The average number of visits per patient was 7.4 (SD 11.3); 54.7% received spinal manipulation on their first visit. The majority of patients were referred by the treating intern (64.8%) and about 24% of patients were local residents. CONCLUSIONS: Our study contributed to the few studies detailing patients attending chiropractic academic teaching clinics. It provided benchmark demographic and clinical data that may be used for operational planning. Our study suggested that the case mix of this teaching clinic provides interns with appropriate learning opportunities to achieve entry to practice competencies. PMID- 23362364 TI - A retrospective analysis of the cultural competence of chiropractic students in a public health course. AB - PURPOSE: Diverse communities require chiropractors to be culturally competent to serve diverse populations. The purpose of this analysis is to describe the effect on knowledge and confidence to serve diverse populations following 6 hours of cultural competency training. METHODS: Using a quasi-experimental one-group design, a paired t-test using a 40-item questionnaire to assess knowledge and a 15-item questionnaire to rate confidence was used for the stated purpose. RESULTS: A total of 45 students completed the 40-item questionnaire and 48 students completed the 15-item questionnaire. Analyses showed significant increases from pre-to post-training (Delta score = 21.34%; p < 0.001) in knowledge to serve diverse populations; but in confidence no significant change was found (Delta score = 0.24; p = 0.26). However, when accounting for sex differences, female students showed a significant increase in confidence with 7 of the 15 items at p < 0.05, while male students did not achieve signifi-cant changes in any of these items. CONCLUSIONS: The knowledge of chiropractic students increased significantly following a course in cultural competence. Their confidence to serve diverse populations, however, did not change significantly. Further examination of the data revealed that baseline measures on confidence may be relatively high. Further study is required to determine the covariates of successful training in cultural competency. PMID- 23362365 TI - An international survey of gross anatomy courses in chiropractic colleges. AB - PURPOSE: The purpose of this study is to provide the first comprehensive description of gross anatomy course design in chiropractic colleges internationally and to provide baseline data for future investigation, future comparison with other health care professions, and identification of trends. METHODS: A 72-question cross-sectional electronic survey was sent to the anatomy department chair at 36 chiropractic colleges internationally using Zoomerang, a web-based survey instrument. To augment the survey response data, public sources of data also were collected. RESULTS: Forty-four percent of the electronic surveys were returned and information was gathered for 31 institutions from public sources. These results indicate (1) the most common degrees held by anatomy faculty were MS and PhD in anatomy, and DC degrees; (2) 75% of institutions utilized human cadavers and 75% presented laboratory anatomical demonstrations; (3) 62% used PowerPoint and 100% provided students with copies of lecture presentations; (4) 88% required attendance in laboratory and 50% in lecture; (5) 69% issued one grade for lecture and laboratory; (6) 100% of laboratory examinations were anatomical identification; and (7) 80% of written examinations were multiple-choice format. CONCLUSIONS: While individual variations existed, chiropractic institutions internationally have similar gross anatomy faculty, course design, delivery methods, and assessment methods. PMID- 23362367 TI - Association of chiropractic colleges educational conference and research agenda conference 2012. PMID- 23362366 TI - Evidence-based chiropractic education: are we equipping graduates for clinical practice with improved patient outcomes? AB - Evidence-based practice has emerged as a driving factor in current curriculum development in chiropractic education. This commentary discusses educational strategies incorporating evidence-based practices in the doctor of chiropractic curriculum and explores whether all five steps of the evidence-based process and patient outcomes from evidence-based practice are being assessed. PMID- 23362368 TI - The Molecular Evolutionary Patterns of the Insulin/FOXO Signaling Pathway. AB - The insulin/insulin growth factor-1(IGF1)/FOXO (IIF) signal transduction pathway plays a core role in the endocrine system. Although the components of this pathway have been well characterized, the evolutionary pattern remains poorly understood. Here, we perform a comprehensive analysis to study whether the differences of signaling transduction elements exist as well as to determine whether the genes are subject to equivalent evolutionary forces and how natural selection shapes the evolution pattern of proteins in an interacting system. Our results demonstrate that most IIF pathway components are present throughout all animal phyla investigated here, and they are under strong selective constraint. Remarkably, we detect that the components in the middle of the pathway undergo stronger purifying selection, which is different from previous similar reports. We also find that the d(N)/d(S) may be influenced by quite complicated factors including codon bias, protein length among others. PMID- 23362370 TI - Balloon dilation in sporadic inclusion body myositis patients with Dysphagia. AB - Here, we describe balloon catheter dilation at the upper esophageal sphincter (UES) in three sporadic inclusion body myositis (s-IBM) patients with dysphagia. Initially, we performed IVIg therapy, and, three months later, switched to balloon dilation therapy. A 12-Fr balloon catheter was inserted from the mouth under fluoroscopy and the balloon inflated at the UES. The catheter was pulled back and re-inserted several times. We examined videofluoroscopy (VF) and pressure at the oropharynx, hypopharynx and UES using computed pharyngoesophageal manometry (CPM). Before both therapies, the VF study revealed a very small amount of barium paste passing through the UES. After balloon dilation therapy, as well as IVIg, subjective complaints of dysphagia disappeared and the VF study revealed an increased amount of barium paste passing through the UES. We conclude that balloon dilation therapy is a complementary method for conventional dysphagia therapies in s-IBM patients with dysphagia. PMID- 23362369 TI - PREPACT 2.0: Predicting C-to-U and U-to-C RNA Editing in Organelle Genome Sequences with Multiple References and Curated RNA Editing Annotation. AB - RNA editing is vast in some genetic systems, with up to thousands of targeted C to-U and U-to-C substitutions in mitochondria and chloroplasts of certain plants. Efficient prognoses of RNA editing in organelle genomes will help to reveal overlooked cases of editing. We present PREPACT 2.0 (http://www.prepact.de) with numerous enhancements of our previously developed Plant RNA Editing Prediction & Analysis Computer Tool. Reference organelle transcriptomes for editing prediction have been extended and reorganized to include 19 curated mitochondrial and 13 chloroplast genomes, now allowing to distinguish RNA editing sites from "pre edited" sites. Queries may be run against multiple references and a new "commons" function identifies and highlights orthologous candidate editing sites congruently predicted by multiple references. Enhancements to the BLASTX mode in PREPACT 2.0 allow querying of complete novel organelle genomes within a few minutes, identifying protein genes and candidate RNA editing sites simultaneously without prior user analyses. PMID- 23362371 TI - Combination of left ventricular noncompaction and partial atrioventricular canal defect in a 21-year-old male: a case report. AB - INTRODUCTION: Left ventricular noncompaction (LVNC) is classified as a genetic cardiomyopathy characterized by a progressive systolic dysfunction. It may occur alone or in association with congenital cardiac anomalies. The combination of left ventricular noncompaction with partial atrioventricular canal defect is rare and has not, to our knowledge, been described previously. CASE PRESENTATION: A 21 year-old male who traveled to our center from a neighboring country presented with signs of heart failure. Transthorarcic echocardiography showed prominent trabeculations in the left ventricle predominantly in the left ventricle involving the apical lateral and mid anterolateral segments associated with a partial atrioventricular canal defect. There was a biventricular systolic dysfunction. There was good response to medical treatment. CONCLUSION: This case stresses the importance of maintaining a high degree of suspicion for this rare cardiomyopathy and the need to systematically look for other associated anomalies in order to institute proper short- and long-term managements. PMID- 23362373 TI - A 37-year-old man with a black spot in his vision. PMID- 23362372 TI - Safety and efficacy of cabazitaxel in the docetaxel-treated patients with hormone refractory prostate cancer. AB - Prostate cancer (PC) is one of the most common cancers and is a leading cause of death. Its initial growth is dependent on androgens; most patients show an initial response to hormonal therapy but will experience disease progression when PC becomes resistant to castration. In 2004, two key randomized controlled trials demonstrated a benefit for docetaxel-based regimens in the treatment of men with castration-resistant prostate cancer (CRPC). Cabazitaxel (XRP6258, TXD258, and RPR116258A), a tubulin-binding taxane drug as potent as docetaxel in cell lines, was the first treatment able to prolong survival for metastatic CRPC in the post docetaxel setting. This review describes pharmacologic parameters of this agent followed by a review of clinical trials involving cabazitaxel. Other available treatments and the place of cabazitaxel in metastatic CRPC setting are discussed. PMID- 23362374 TI - A 54-year-old woman with bluish discoloration of her sclera. PMID- 23362375 TI - Systemic non-Hodgkin's lymphoma involving the orbit and leptomeninges. AB - We report a case of diffuse large B-cell lymphoma in a 46-year-old female presenting in an unusual manner with stage IVB disease including concurrent orbital and leptomeningeal involvement. The cytologic features and cytogenetics of the malignancy are noted, and the management and progression of the disease, with attention to orbital involvement, is recorded for a period of over 2.5 years, until the patient's death. PMID- 23362376 TI - A 7-year-old boy with a right anterior orbital mass. PMID- 23362377 TI - Nonspecific uptake and homeostasis drive the oceanic cadmium cycle. AB - The global marine distributions of Cd and phosphate are closely correlated, which has led to Cd being considered as a marine micronutrient, despite its toxicity to life. The explanation for this nutrient-like behavior is unknown because there is only one identified biochemical function for Cd, an unusual Cd/Zn carbonic anhydrase. Recent developments in Cd isotope mass spectrometry have revealed that Cd uptake by phytoplankton causes isotopic fractionation in the open ocean and in culture. Here we investigate the physiochemical pathways that fractionate Cd isotopes by performing subcellular Cd isotope analysis on genetically modified microorganisms. We find that expression of the Cd/Zn carbonic anhydrase makes no difference to the Cd isotope composition of whole cells. Instead, a large proportion of the Cd is partitioned into cell membranes with a similar direction and magnitude of Cd isotopic fractionation to that seen in surface seawater. This observation is well explained if Cd is mistakenly imported with other divalent metals and subsequently managed by binding within the cell to avoid toxicity. This process may apply to other divalent metals, whereby nonspecific uptake and subsequent homeostasis may contribute to elemental and isotopic distributions in seawater, even for elements commonly considered as micronutrients. PMID- 23362379 TI - Genotypic recognition and spatial responses by rice roots. AB - Root system growth and development is highly plastic and is influenced by the surrounding environment. Roots frequently grow in heterogeneous environments that include interactions from neighboring plants and physical impediments in the rhizosphere. To investigate how planting density and physical objects affect root system growth, we grew rice in a transparent gel system in close proximity with another plant or a physical object. Root systems were imaged and reconstructed in three dimensions. Root-root interaction strength was calculated using quantitative metrics that characterize the extent to which the reconstructed root systems overlap each other. Surprisingly, we found the overlap of root systems of the same genotype was significantly higher than that of root systems of different genotypes. Root systems of the same genotype tended to grow toward each other but those of different genotypes appeared to avoid each other. Shoot separation experiments excluded the possibility of aerial interactions, suggesting root communication. Staggered plantings indicated that interactions likely occur at root tips in close proximity. Recognition of obstacles also occurred through root tips, but through physical contact in a size-dependent manner. These results indicate that root systems use two different forms of communication to recognize objects and alter root architecture: root-root recognition, possibly mediated through root exudates, and root-object recognition mediated by physical contact at the root tips. This finding suggests that root tips act as local sensors that integrate rhizosphere information into global root architectural changes. PMID- 23362382 TI - Floating anterior lens capsule: an unusual case of true exfoliation. AB - A rare case of delamination and replication of the anterior lens capsule into prominent floating folds in the anterior chamber approximately 55 years after a penetrating injury to the eye and anterior lens capsule is reported. Classically, true exfoliation of the anterior lens capsule has been reported in individuals who have been exposed to intense heat over a prolonged period. However, more recently cases of true exfoliation of the anterior lens capsule have been reported in patients who have not been occupationally exposed to high temperatures and associated infrared radiation. A brief review of the literature concerning true exfoliation of the lens capsule in the absence of intense heat exposure is included. Associations with trauma, inflammation, advanced age, hyperopia, glaucoma, and capsular protein abnormality have been reported, but the pathogenesis of this rare clinical finding remains conjectural. PMID- 23362380 TI - Identification of T6SS-dependent effector and immunity proteins by Tn-seq in Vibrio cholerae. AB - Type VI protein secretion system (T6SS) is important for bacterial competition through contact-dependent killing of competitors. T6SS delivers effectors to neighboring cells and corresponding antagonistic proteins confer immunity against effectors that are delivered by sister cells. Although T6SS has been found in more than 100 gram-negative bacteria including many important human pathogens, few T6SS-dependent effector and immunity proteins have been experimentally determined. Here we report a high-throughput approach using transposon mutagenesis and deep sequencing (Tn-seq) to identify T6SS immunity proteins in Vibrio cholerae. Saturating transposon mutagenesis was performed in wild type and a T6SS null mutant. Genes encoding immunity proteins were predicted to be essential in the wild type but dispensable in the T6SS mutant. By comparing the relative abundance of each transposon mutant in the mutant library using deep sequencing, we identified three immunity proteins that render protection against killing by T6SS predatory cells. We also identified their three cognate T6SS secreted effectors and show these are important for not only antibacterial and antieukaryotic activities but also assembly of T6SS apparatus. The lipase and muramidase T6SS effectors identified in this study underscore the diversity of T6SS-secreted substrates and the distinctly different mechanisms that target these for secretion by the dynamic T6SS organelle. PMID- 23362383 TI - A 7-week-old infant with right upper eyelid mass. PMID- 23362384 TI - Anomalous vessels over a trabeculectomy bleb in Sturge-Weber syndrome. AB - Trabeculectomy for treatment of glaucoma associated with Sturge-Weber syndrome has a poor success rate. We report the presence of anomalous vessels over the trabeculectomy bleb in a patient with Sturge-Weber syndrome after trabeculectomy combined with mitomycin. PMID- 23362385 TI - A case of bilateral, spontaneous absorption of lenses. AB - Spontaneous absorption of lenses or cataracts is rare. We report a case of bilateral spontaneous lens absorption in a 36-year-old woman for which no cause could be determined despite extensive laboratory testing. PMID- 23362386 TI - Prolene monofilament suture in Boston Keratoprosthesis surgery. AB - Toxic reaction to nylon following uncomplicated cataract surgery and vitrectomy has been documented in the literature. We report the case of an aniridic patient with a known adverse reaction to nylon in whom Prolene suture was used in Boston Keratoprosthesis type 1 (KPro) surgery. During follow-up the cornea was checked for signs of inflammation and toxic reaction; at last follow-up (18 months) the patient showed no signs of complications due to Prolene. Our study suggests that Prolene suture may be used as an alternative to nylon in Boston KPro surgery in patients with a history of nylon toxicity. PMID- 23362387 TI - Perioperative spontaneous bilateral suprachoroidal hemorrhage. AB - Suprachoroidal hemorrhage is a rare condition, occurring most commonly in the perioperative period, although cases of unilateral spontaneous hemorrhages have been reported. We report a case of bilateral spontaneous suprachoroidal hemorrhage and discuss the potential causative factors. PMID- 23362388 TI - A 16-year-old girl with bilateral optic disc swelling. PMID- 23362389 TI - The effect of a visual aid on the comprehension of cataract surgery in a rural, indigent South Indian population. AB - PURPOSE: To determine whether a visual aid improves the understanding and retention of information presented during informed consent for rural, indigent patients presenting for cataract surgery. MATERIALS AND METHODS: This was a randomized, unmasked, interventional study. We recruited patients who presented to the Hande Surgical Hospital in Chennai, India, for cataract surgery. Patients were randomized into two groups: verbal consent alone (group A) and verbal consent plus a poster (group B). Both groups completed an 11-question true/false quiz immediately before and after informed consent and one day after surgery. RESULTS: A total of 60 patients were recruited for the study, with 30 randomly assigned to each group; 23 patients from group A and 17 from group B completed the study. Informed consent improved patient scores in both groups; however, group B had significantly higher mean scores on postoperative day 1 (7.4 vs 8.7, P = 0.005) and significantly greater improvement in mean scores from pre-informed consent to postoperative day 1 (1.3 vs 3.6, P = 0.002). CONCLUSIONS: Informed consent improves patient understanding of cataract surgery. Using a visual aid during informed consent for cataract surgery improves understanding and retention of information more than verbal consent alone in a rural South Indian population. PMID- 23362390 TI - Combined intravitreal ranibizumab and verteporfin photodynamic therapy versus ranibizumab alone for the treatment of age-related macular degeneration. AB - PURPOSE: To compare same-day combined therapy of photodynamic therapy with verteporfin (PDT-V) and intravitreal ranibizumab versus monotherapy with ranibizumab for the treatment of choroidal neovascularization. METHODS: IN THIS PROSPECTIVE STUDY, THE TOTAL NUMBER OF EYES WAS RANDOMIZED INTO TWO GROUPS: in the first, treatment consisted of a combined therapy of PDT-V and ranibizumab 0.5 mg on the same day; in the second, ranibizumab 0.5 mg in 3 monthly injections. Best-corrected visual acuity (BCVA) and central macular thickness (CMT) on optical coherence tomography (OCT) were recorded before and 6 months after treatment. RESULTS: A total of 47 eyes of 47 subjects were enrolled in the study. In the combined-therapy group (group 1), the mean baseline BCVA +/- standard deviation (SD) was 32.65 +/- 11.09 letters (Snellen equivalent, 20/59); in the ranibizumab-alone group (group 2), 29.13 +/- 9.03 letters (20/70). At 6 months' follow-up, in group 1 the mean baseline BCVA was 39.06 +/- 10.12 letters (20/42); in group 2, 33.87 +/- 12.06 letters (20/57). Improvement was significant in both group 1 (P = 0.03) and group 2 (P = 0.002). In group 1, the mean CMT at baseline +/- SD was 315 +/- 95.49 MUm; in group 2, 306.33 +/- 71.61 MUm. At 6 months' follow-up, in group 1 it was 202 +/- 52.02 MUm; in group 2, 226 +/- 65.58 MUm. Reduction was significant in both group 1 (P = 0.0007) and group 2 (P = 0.00001). After 6-months, the rate of retreated eyes was 29.4% in group 1 and 43.3% in group 2. The need for retreatment did not depend on the treatment protocol (P = 0.34). CONCLUSIONS: From a functional and anatomic point of view, the two treatments showed equivalent efficacy, with fewer retreatments in group 1. No serious adverse events, such as retinal detachment, endophthalmitis, or ocular hypertension occurred in either group. PMID- 23362391 TI - Acute systemic histoplasmosis associated with chorioretinitis in an immunocompetent adolescent. AB - Histoplasmosis is an endemic, systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum. A minority of patients develop asymptomatic chorioretinitis known as presumed ocular histoplasmosis syndrome (POHS), which is typically associated with chorioretinal scarring and peripapillary atrophy and occasionally with choroidal neovascularization secondary to maculopathy. We report a case of acute severe bilateral chorioretinitis associated with disseminated H. capsulatum in an immunocompetent adolescent boy living in an endemic area. The chorioretinitis did not respond to systemic antifungal therapy, but both his systemic illness and ocular lesions resolved with the addition of systemic steroids. PMID- 23362392 TI - Idiopathic pupillary capture 7 years after extracapsular cataract extraction and intraocular lens implantation. AB - Pupillary capture is a pathology commonly associated with traumatic or inflammatory processes of the eye. We present a case of idiopathic pupillary capture, 7 years after extracapsular cataract extraction and intraocular lens implantation. This case highlights the need for ongoing patient surveillance, especially in elderly patients who are less able to detect subtle changes in their vision. PMID- 23362393 TI - Immediate loss of vision due to retinal pigment epithelial tear after anti angiogenesis treatment of pigment epithelial detachment. AB - Intravitreal injection of ranibizumab, an antivascular endothelial growth factor (VEGF) drug, is currently the primary treatment for wet age-related macular degeneration (AMD) in the UK. Use of ranibizumab for the treatment of isolated pigment epithelial detachments (PEDs) without the presence of an occult choroidal neovascular membrane has not been studied in a randomized controlled fashion and is strictly off-label. One possible complication of intravitreal injection of the drug is retinal pigment epithelial (RPE) tear. To date, the etiology of RPE tear associated with intravitreal injection is unknown; it could be attributed to rapid contraction of the neovascular membrane by fibrosis, perhaps triggered by the drug. We report a case of an RPE tear occurring less than a minute after intravitreal injection of ranibizumab for a fibrovascular PED. To our knowledge, this is the first report of such a case. PMID- 23362394 TI - Chorioretinal atrophy after electrical injury. AB - A 26-year-old-man who had suffered a severe electrical injury 3 years previously presented with blurred vision in his left eye caused by a posterior subcapsular cataract with nuclear sclerotic changes and peripapillary chorioretinal scarring. The pattern of retinal atrophy surrounding the optic nerve suggests a possible path of electrical current to the eye and demonstrates the selective tissuedamage that may occur in electrical injuries. PMID- 23362395 TI - Keratoprosthesis in congenital hereditary endothelial dystrophy after multiple failed grafts. AB - Congenital hereditary endothelial dystrophy (CHED) has historically been managed with penetrating keratoplasty (PK), with moderate success, and, more recently, with Descemet's stripping endothelial keratoplasty (DSEK). The possibility of repeated graft failures with CHED, however, makes alternative surgical procedures desirable. To our knowledge, this is the first reported use of a keratoprosthesis for management of CHED in a patient with multiple graft failures. The patient has been successfully followed for 5 years, has 20/30 vision, and no glaucoma. PMID- 23362396 TI - A 6-week-old baby boy with discharge. PMID- 23362397 TI - A 53-year-old woman with a severe headache, bilateral eye pain, blurred vision, and photophobia. PMID- 23362398 TI - Boston Keratoprosthesis: expanding the boundaries. PMID- 23362399 TI - Concurrence of retinitis pigmentosa and central serous retinopathy. AB - We describe a patient with concurrent retinitis pigmentosa and central serous chorioretinopathy. Both conditions involve dysfunction of the retinal pigment epithelium and evince distinct clinical, angiographic, and electrophysiologic features. Potential pathophysiologic connections are explored. PMID- 23362400 TI - Concurrent endophthalmitis and orbital cellulitis in a child with congenital glaucoma and a glaucoma drainage device. AB - A 3-year-old monocular boy with a history of congenital glaucoma and aqueous shunt implantation presented with periorbital swelling, erythema, and purulent discharge in his seeing right eye. Examination revealed an extensive hypopyon. Computed tomography (CT) showed right-sided proptosis, and a displaced aqueous shunt device deep in the orbit. Significant purulent fluid was encountered when the device was removed; vitreous and orbital cultures revealed Streptococcus pneumoniae. The patient received intravitreal, topical, intravenous, and oral antibiotics as well as intraocular tissue plasminogen activator and topical steroid. Orbital and intraocular inflammation decreased significantly but he developed a cataract, further complicated by a retinal detachment. PMID- 23362401 TI - Bilateral persistent pupillary membranes associated with cataract. AB - Exuberant persistent pupillary membranes (PPM) are rare in adult eyes. We report the case of a 53-year-old man diagnosed with bilateral, profuse, persistent pupillary membranes and unilateral cataract. PMID- 23362402 TI - Anterior capsular rupture following blunt ocular injury. AB - A 10-year-old boy suffered a large, oblique anterior capsular tear following blunt injury to his right eye. The boy was followed daily for hyphema resolution and progressive traumatic cataract formation. After the hyphema had resolved, the lens was removed using an anterior approach and an intraocular lens was placed with excellent visual outcome. PMID- 23362403 TI - Pigment deposition on the central aspect of the posterior lens capsule in pigmentary dispersion. AB - We describe a case of an increasing pigmentary plaque on the posterior surface of the lens during follow-up of a case of pigment dispersion syndrome and suggest that this is a new sign of pigment dispersion. PMID- 23362404 TI - A failed corneal graft as a support for the Boston Keratoprosthesis type 1. AB - The implantation of the Boston Keratoprosthesis (KPro) requires a corneal button, which is usually taken from a donor. Scarcity of donor tissue has been a major limiting factor in transplant surgery. Recently, autologous recipient cornea has been reported as support for the KPro. We report the successful use of an ipsilateral failed corneal graft as the carrier tissue for a patient requiring combined pars plana vitrectomy and KPro implantation. PMID- 23362405 TI - A 39-year-old woman with unilateral metamorphosias. PMID- 23362406 TI - Optical coherence tomography changes in macular CMV retinitis. AB - Cytomegalovirus (CMV) retinitis characteristically causes peripheral retinitis with associated vasculitis. It rarely begins in the macula or causes macular necrosis exclusively. We report a case of unilateral macular CMV retinitis in a 65-year-old immunosuppressed patient and document changes in the macula during treatment through optical coherence tomography (OCT). PMID- 23362407 TI - A 31-year-old man with vitritis, chorioretinitis, and hydrocephalus. PMID- 23362408 TI - The first Iranian recommendations on prevention, evaluation and management of high blood pressure. AB - This paper presents the complete report of the first Iranian Recommendations on Prevention, Evaluation and Management of High Blood Pressure. The purpose is to provide an evidence-based approach to the prevention, management and control of hypertension (HTN) by adapting the most internationally known and used guidelines to the local health care status with consideration of the currently available data and based on the locally conducted researches on HTN as well as social and health care requirements. A working group of national and international experts participated in discussions and collaborated in decision-making, writing and reviewing the whole report. Multiple subcommittees worked together to review the recent national and international literature on HTN in different areas. We used the evaluation tool that is called "AGREE" and considered a score of > 60% as a high score. We adapted the Canadian Hypertension Education Program (CHEP), the United Kingdom's National Institute for Health and Clinical Excellence (NICE) and the US-based joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC7). The key topics that are highlighted in this report include: The importance of ambulatory and self-measurement of blood pressure, evaluation of cardiovascular risk in HTN patients, the role of lifestyle modification in the prevention of HTN and its control with more emphasis on salt intake reduction and weight control, introducing pharmacotherapy suitable for uncomplicated HTN or specific situations and the available drugs in Iran, highlighting the importance of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers and calcium channel blockers as the first line therapy in many situations, the non-use of beta blockers as the first time treatment except in specific conditions, treating HTN in women, children, obese and elderly patients, the patient compliance to improve HTN control, practical guidelines to improve the patient's information on knowing their risk and self care as well as a quick reference guide that can serve as simplified guidelines for physicians. The working team decided to update these recommendations every two years. PMID- 23362409 TI - Regional initiatives in support of surveillance in East Africa: The East Africa Integrated Disease Surveillance Network (EAIDSNet) Experience. AB - The East African Integrated Disease Surveillance Network (EAIDSNet) was formed in response to a growing frequency of cross-border malaria outbreaks in the 1990s and a growing recognition that fragmented disease interventions, coupled with weak laboratory capacity, were making it difficult to respond in a timely manner to the outbreaks of malaria and other infectious diseases. The East Africa Community (EAC) partner states, with financial support from the Rockefeller Foundation, established EAIDSNet in 2000 to develop and strengthen the communication channels necessary for integrated cross-border disease surveillance and control efforts. The objective of this paper is to review the regional EAIDSNet initiative and highlight achievements and challenges in its implementation. Major accomplishments of EAIDSNet include influencing the establishment of a Department of Health within the EAC Secretariat to support a regional health agenda; successfully completing a regional field simulation exercise in pandemic influenza preparedness; and piloting a web-based portal for linking animal and human health disease surveillance. The strategic direction of EAIDSNet was shaped, in part, by lessons learned following a visit to the more established Mekong Basin Disease Surveillance (MBDS) regional network. Looking to the future, EAIDSNet is collaborating with the East, Central and Southern Africa Health Community (ECSA-HC), EAC partner states, and the World Health Organization to implement the World Bank-funded East Africa Public Health Laboratory Networking Project (EAPHLNP). The network has also begun lobbying East African countries for funding to support EAIDSNet activities. PMID- 23362410 TI - Southeastern European Health Network (SEEHN) Communicable Diseases Surveillance: a decade of bridging trust and collaboration. AB - The communicable disease threats and changes that began emerging in south-east Europe in the early 1990s - after a decade of war and while political and health systems region-wide were undergoing dramatic changes - demanded a novel approach to infectious disease surveillance. Specifically, they called for an approach that was focused on cross-border collaboration and aligned with European Union standards and requirements. Thus, the Southeastern European Health network (SEEHN) was established in 2001 as a cooperative effort among the governments of Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Moldova, Montenegro, Romania, Serbia, and the former Yugoslav Republic of Macedonia. In 2002, SEEHN initiated a communicable diseases project aimed at strengthening both national and regional surveillance systems with a focus on cross-border collaboration. Over time, SEEHN has nurtured growth of a regional fabric of SEE experts in communicable diseases surveillance and response who are able to discuss emerging issues and best practices at any time and without being constrained by the rigidity of traditional or existing systems. Main achievements to date include joint preparation of influenza pandemic preparedness plans at both national and regional levels and the introduction of molecular techniques into influenza surveillance laboratories region-wide. Here, we describe the history of the SEEHN communicable disease project; major activities and accomplishments; and future sustainability of the regional infectious disease surveillance network that has emerged and grown over the past decade. PMID- 23362411 TI - Mekong Basin Disease Surveillance (MBDS): a trust-based network. AB - The Mekong Basin Disease Surveillance (MBDS) network was formally established in 2001 through a Memorandum of Understanding signed by six Ministers of Health of the countries in the Greater Mekong sub-region: Cambodia, China (Yunnan and Guangxi), Lao PDR, Myanmar, Thailand and Vietnam. The main areas of focus of the network are to: i) improve cross-border infectious disease outbreak investigation and response by sharing surveillance data and best practices in disease recognition and reporting, and by jointly responding to outbreaks; ii) develop expertise in epidemiological surveillance across the countries; and iii) enhance communication between the countries. Comprised of senior health officials, epidemiologists, health practitioners, and other professionals, the MBDS has grown and matured over the years into an entity based on mutual trust that can be sustained into the future. Other regions have started emulating the network's pioneering work. In this paper, we describe the development of MBDS, the way in which it operates today, and some of its achievements. We present key challenges the network has faced and lessons its members have learned about how to develop sufficient trust for health and other professionals to alert each other to disease threats across national borders and thereby more effectively combat these threats. PMID- 23362412 TI - Creating a global dialogue on infectious disease surveillance: connecting organizations for regional disease surveillance (CORDS). AB - Connecting Organizations for Regional Disease Surveillance (CORDS) is an international non-governmental organization focused on information exchange between disease surveillance networks in different areas of the world. By linking regional disease surveillance networks, CORDS builds a trust-based social fabric of experts who share best practices, surveillance tools and strategies, training courses, and innovations. CORDS exemplifies the shifting patterns of international collaboration needed to prevent, detect, and counter all types of biological dangers - not just naturally occurring infectious diseases, but also terrorist threats. Representing a network-of-networks approach, the mission of CORDS is to link regional disease surveillance networks to improve global capacity to respond to infectious diseases. CORDS is an informal governance cooperative with six founding regional disease surveillance networks, with plans to expand; it works in complement and cooperatively with the World Health Organization (WHO), the World Organization for Animal Health (OIE), and the Food and Animal Organization of the United Nations (FAO). As described in detail elsewhere in this special issue of Emerging Health Threats, each regional network is an alliance of a small number of neighboring countries working across national borders to tackle emerging infectious diseases that require unified regional efforts. Here we describe the history, culture and commitment of CORDS; and the novel and necessary role that CORDS serves in the existing international infectious disease surveillance framework. PMID- 23362413 TI - Enhanced surveillance for detection and management of infectious diseases: regional collaboration in the middle East. AB - Formed before international negotiations of the revised International Health Regulations (IHR), the Middle East Consortium for Infectious Disease Surveillance (MECIDS) is a regional collaboration aimed at facilitating implementation of the revised IHR and, more broadly, improving the detection and control of infectious disease outbreaks among neighboring countries in an area of continuous dispute. Initially focused on enhancing foodborne disease surveillance, MECIDS has expanded the scope of its work to also include avian and pandemic influenza and other emerging and re-emerging infectious diseases. Here, we describe the history and governance of MECIDS, highlighting key achievements over the consortium's seven-year history, and discuss the future of MECIDS. PMID- 23362414 TI - The evolution and expansion of regional disease surveillance networks and their role in mitigating the threat of infectious disease outbreaks. AB - We examine the emergence, development, and value of regional infectious disease surveillance networks that neighboring countries worldwide are organizing to control cross-border outbreaks at their source. The regional perspective represented in the paper is intended to serve as an instructive framework for others who decide to launch such networks as new technologies and emerging threats bring countries even closer together. Distinct from more formal networks in geographic regions designated by the World Health Organization (WHO), these networks usually involve groupings of fewer countries chosen by national governments to optimize surveillance efforts. Sometimes referred to as sub regional, these "self-organizing" networks complement national and local government recognition with informal relationships across borders among epidemiologists, scientists, ministry officials, health workers, border officers, and community members. Their development over time reflects both incremental learning and growing connections among network actors; and changing disease patterns, with infectious disease threats shifting over time from local to regional to global levels. Not only has this regional disease surveillance network model expanded across the globe, it has also expanded from a mostly practitioner-based network model to one that covers training, capacity-building, and multidisciplinary research. Today, several of these networks are linked through Connecting Organizations for Regional Disease Surveillance (CORDS). We explore how regional disease surveillance networks add value to global disease detection and response by complementing other systems and efforts, by harnessing their power to achieve other goals such as health and human security, and by helping countries adapt to complex challenges via multi-sectoral solutions. We note that governmental commitment and trust among participating individuals are critical to the success of regional infectious disease surveillance networks. PMID- 23362415 TI - Clinical laboratory networks contribute to strengthening disease surveillance: The RESAOLAB Project in West Africa. PMID- 23362416 TI - Promising pathways for regional disease surveillance networks. PMID- 23362417 TI - The Southern African Centre for infectious disease surveillance: a one health consortium. AB - Formed in 2008, the Southern African Centre for Infectious Disease Surveillance (SACIDS) is a One Health consortium of academic and research institutions involved with infectious diseases of humans and animals. Operating in partnership with world-renowned centres of research in industrialised countries, its mission is to harness innovations in science and technology for improving southern Africa's capacity to detect, identify, monitor (DIM) and manage the risk posed by infectious diseases of humans, animals, and ecosystems. The consortium's major capacity development activities include a series of One Health-based Master of Science (MSc) courses and a five-year DIM-driven research program. Additionally, SACIDS organized Africa's first One Health conference, in July 2011. This paper describes these and other major activities that SACIDS has undertaken to improve infectious disease surveillance across southern Africa. The paper also describes the role and collaboration of SACIDS with other national, regional and international consortia/networks that share a vision and interest in promoting novel approaches to infectious disease surveillance and outbreak response. PMID- 23362418 TI - Key findings and lessons from an evaluation of the Rockefeller Foundation's Disease Surveillance Networks Initiative. PMID- 23362419 TI - Sustaining a regional emerging infectious disease research network: a trust-based approach. AB - The Asia Partnership on Emerging Infectious Diseases Research (APEIR) was initiated in 2006 to promote regional collaboration in avian influenza research. In 2009, the partnership expanded its scope to include all emerging infectious diseases. APEIR partners include public health and animal researchers, officials and practitioners from Cambodia, China, Lao PDR, Indonesia, Thailand and Vietnam. APEIR has accomplished several major achievements in three key areas of activity: (i) knowledge generation (i.e., through research); (ii) research capacity building (e.g., by developing high-quality research proposals, by planning and conducting joint research projects, by adopting a broader Ecohealth/OneHealth approach); and (iii) policy advocacy (e.g., by disseminating research results to policy makers). This paper describes these achievements, with a focus on the partnership's five major areas of emerging infectious disease research: wild migratory birds, backyard poultry systems, socio-economic impact, policy analysis, and control measures. We highlight two case studies illustrating how the partnership's research results are being used to inform policy. We also highlight lessons learned after five years of working hard to build our partnership and the value added by a multi-country, multi-sectoral, multi disciplinary research partnership like APEIR. PMID- 23362420 TI - Prospective randomized clinical trial of laparoscopic sleeve gastrectomy versus open Roux-en-Y gastric bypass for the management of patients with morbid obesity. AB - INTRODUCTION: Roux-en-Y gastric bypass (RYGB) is considered the gold standard bariatric procedure with documented safety and effectiveness. Laparoscopic sleeve gastrectomy (LSG) is a newer procedure being done with increasing frequency. Randomized comparisons of LSG and other bariatric procedures are limited. We present the results of the first prospective randomized trial comparing LSG and RYGB in the Polish population. AIM: To assess the efficacy and safety of LSG versus RYGB in the treatment of morbid obesity and obesity-related comorbidities. MATERIAL AND METHODS: Seventy-two morbidly obese patients were randomized to RYGB (36 patients) or LSG (36 patients). Both groups were comparable regarding age, gender, body mass index (BMI) and comorbidities. The follow-up period was at least 12 months. Baseline and 6 and 12 month outcomes were analyzed including assessment of percent excess weight lost (%EWL), reduction in BMI, morbidity (minor, major, early and late complications), mortality, reoperations, comorbidities and nutritional deficiencies. RESULTS: There was no 30-day mortality and no significant difference in major complication rate (0% after RYGB and 8.3% after LSG, p > 0.05) or minor complication rate (16.6% after RYGB and 10.1% after LSG, p > 0.05). There were no early reoperations after RYGB and 2 after LSG (5.5%) (p > 0.05). Weight loss was significant after RYGB and LSG but there was no difference between both groups at 6 and 12 months of follow-up. At 12 months %EWL in RYGB and LSG groups reached 64.2% and 67.6% respectively (p > 0.05). There was no significant difference in the overall prevalence of comorbidities and nutritional deficiencies. CONCLUSIONS: Both LSG and RYGB produce significant weight loss at 6 and 12 months after surgery. The procedures are equally effective with regard to %EWL, reduction in BMI and amelioration of comorbidities at 6 and 12 months of follow-up. Laparoscopic sleeve gastrectomy and RYGB are comparably safe techniques with no significant differences in minor and major complication rates at 6 and 12 months. PMID- 23362421 TI - Single loop-and-clips technique (KING closure) for gastrotomy closure after transgastric ovariectomy: a survival experiment. AB - INTRODUCTION: A safe closure technique of transluminal access is essential for the widespread application of natural orifice transluminal endoscopic surgery (NOTES). AIM: To evaluate the feasibility and effectiveness of a novel single loop-and-clips closure technique (KING closure). MATERIAL AND METHODS: An experimental survival study using female laboratory pigs was performed. A gastrotomy was performed using a standard percutaneous endoscopic gastrostomy technique. A peritoneoscopy with an ovariectomy was then performed with a double channel endoscope, on a total of 14 pigs. Two different techniques of gastrotomy closure were analysed: a loop-and-clips closure technique (n = 7) and a standard closure using endoclips (n = 7). After a follow-up period of 30 days, the animals were euthanized for post-mortem examination. RESULTS: In the "loop-and-clip" closure group, the correct placement of an endoloop and clips was achieved in all animals. At necropsy, no animal showed signs of an abscess or peritonitis. Histological examination demonstrated a patent full-thickness gastric wall closure without evidence of local complications in all instances. In the "clips" group, the gastrotomy closure was assessed as probably unsafe in three animals. At necropsy 3 (42.9%) abscesses and 1 (14.3%) case of peritonitis were found. CONCLUSIONS: A single loop-and-clips closure technique (KING closure) represents a feasible, simple and effective method of gastric incision closure. It appears to be superior to the standard endoscopic closure technique using clips. PMID- 23362422 TI - Conversion risk factors in laparoscopic colorectal surgery. AB - INTRODUCTION: This study is aimed at identifying important risk factors associated with conversion of laparoscopic colorectal surgery. Laparoscopic surgery is usually associated with less operative trauma, more favourable post operative course and lower morbidity than open surgery. However, conversion is connected with some risks according to some authors. AIM: To identify the risk factors associated with conversion and to create a model to predict possible conversion for a patient before surgery. MATERIAL AND METHODS: The source data file contained information about 649 patients who underwent laparoscopic colorectal surgery between 2001 and 2009 at the University Hospital Ostrava, Czech Republic. Conversion to open surgery was necessary in 54 cases. The variables gender, body mass index (BMI), American Society of Anesthesiologists (ASA) classification, stage of disease, number of previous operations and operation severity were included in the analysis as the potential risk factors of conversion. Discriminant analysis was used for the data evaluation; statistical software SPSS 17 and NCSS 2004 were used for the calculations. RESULTS: The created model had only low discriminating ability. The variable ASA classification was identified as the most important risk factor of conversion, followed by the variables operation severity, gender and BMI. CONCLUSIONS: Discriminant analysis did not find the chosen input variables satisfactory enough to make a reasonable model for the prediction of conversion. The expected fact was confirmed that large bowel surgery and greater BMI mean greater risk of conversion, whereas there is no reason to refuse laparoscopy for a patient with higher ASA classification. PMID- 23362423 TI - Urgent endoscopy in elderly patients with non-variceal upper gastrointestinal bleeding. AB - INTRODUCTION: Age of the patient is an important prognostic factor in patients with non-variceal upper gastrointestinal bleeding (UGIB). Despite that fact, current treatment algorithms do not differentiate UGIB management according to the patient's age. AIM: To compare treatment outcomes in patients below and above 75 years of age, treated for UGIB with urgent endoscopy. MATERIAL AND METHODS: Prospective analysis of treatment outcomes in 295 patients with non-variceal UGIB divided into two age groups (group A < 75 years of age, group B > 75 years of age). Urgent endoscopy (up to 3 h since admission) was performed in 292 patients. The groups were compared in regards to the duration of symptoms, previous UGIB, presence of factors predisposing to UGIB (NSAIDs, peptic ulcer disease, liver cirrhosis, and previous gastrointestinal surgery), haemodynamic state and haemoglobin (Hb) levels on admission. We analysed the causes of UGIB, severity of UGIB on the Forrest scale, type of endoscopic bleeding control method, and co morbidities with use of the Charlson Co-morbidity Index (CCI). Treatment outcomes were assessed in regard of mortality rate, UGIB-recurrence rate, duration of hospital stay, amount of transfused blood products and the requirement of intensive therapy unit (ITU) or other departments' admissions. Patients were followed until their discharge home. RESULTS: Mortality rate was 6.8% (group A vs. B: 3.5% vs. 18.7%; p = 0.001). Upper gastrointestinal bleeding recurrence was noted in 12.2% of patients (group A vs. B: 12.5% vs. 10.9%; p = 0.73). 2.4% of patients required surgery for UGIB (group A vs. B: 1.7% vs. 4.7%; p = 0.16). Patients in group B required ITU admission more frequently (group A vs. B: 1% vs. 4.7%; p < 0.01). The mean hospital stay (4.3 days) and the mean number of transfused packed red blood cells (PRBCs) (2.35 Units) did not differ between the groups. Patients in group B used NSAIDS much more frequently, more often had hypovolaemic shock and had a higher CCI score. CONCLUSIONS: Urgent endoscopy is an important and broadly accepted method of treatment of UGIB. Despite strict adherence to the modern UGIB-treatment algorithms, mortality remains high in the elderly. Thus, these patients need particular attention. The presented study indicates that the standard management might not be sufficient in elderly patients. PMID- 23362424 TI - Impact of laparoscopic sleeve gastrectomy on body mass index, ghrelin, insulin and lipid levels in 100 obese patients. AB - INTRODUCTION: A high percentage of patients benefit from bariatric procedures in terms of metabolic effect and substantial body mass reduction. These procedures improve glucose metabolism leading to the amelioration or complete resolution of type 2 diabetes, reduction of insulin resistance and alleviation of metabolic syndrome effects. AIM: To assess the impact of laparoscopic sleeve gastrectomy (LSG) on the plasma levels of ghrelin, insulin, glucose, triglycerides, total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions as well as aspartate and alanine transaminases in patients with obesity. MATERIAL AND METHODS: One hundred patients who underwent laparoscopic sleeve gastrectomy in our centre between 2005 and 2009 were included in the study. Among them were 48 males with an average age of 47.93 +/-9.24 years and 52 females with an average age of 44.19 +/-9.33 years. Percentage excess weight loss (%EWL), percentage excess body mass index (BMI) loss (%EBL), ghrelin, insulin, glucose, triglycerides, cholesterol, HDL, LDL, alanine transferase (ALT), and asparagine transferase (AST) were measured preoperatively and on the 7(th) day then 1, 3 and 6 months after the surgery. RESULTS: Statistically significant reduction in postoperative BMI, plasma levels of glucose and insulin as well as the homeostatic model assessment insulin resistance (HOMA IR) score was noted in comparison to the preoperative values. The ghrelin levels decreased. Lipid profile, AST and ALT levels varied depending on the particular time points. CONCLUSIONS: Laparoscopic sleeve gastrectomy reduces body mass and leads to the decrease of concentration of ghrelin in plasma as well as to the improvement of metabolism of insulin, glucose, cholesterol and triglycerides. The above changes alleviated symptoms of metabolic syndrome and obesity related co-morbidities. PMID- 23362425 TI - Surgical treatment options for aldosteronomas. AB - INTRODUCTION: Single access retroperitoneoscopic adrenalectomy (SARA) is the most feasible approach for removing aldosteronomas. AIM: To analyse the advantages and disadvantages of surgical approaches to treating small adrenal tumours. MATERIAL AND METHODS: In the period 2002-2011, 31 patients were operated on at Vilnius University Hospital Santariskiu Clinics for aldosteronomas. Adrenalectomies were performed in the lateral laparoscopic (group A, n = 6), the endoscopic retroperitoneal (group B, n = 20), and the single incision laparoscopic surgery (SILS) and SARA (group C, n = 5) approaches. Seventy five percent of patients were operated on by the same surgeon. The duration of adrenalectomies, and intraoperative and postoperative complications were compared. The possibility of minimally invasive adrenalectomies was evaluated. RESULTS: According to the patients' age, body mass index and tumour size, the groups were equal. The average duration of surgery in group A was shorter than in groups B and C (91 +/ 23 min vs. 118 +/-57 min vs. 144 +/-88 min). Right laparoscopic adrenalectomy was longer than the left (105 +/-26 min vs. 77 +/-6 min), whereas right endoscopic retroperitoneal adrenalectomy was shorter than the left (109 +/-50 min vs. 126 +/ 57 min). The best cosmetic view was in group C. The SARA method was converted into the endoscopic retroperitoneal approach and then into the laparoscopic for one patient. There were no intraoperative or postoperative complications. CONCLUSIONS: Evaluating the minimal invasion of the method, its abilities and simplicity of conversion into another type of endoscopic surgical way, the SARA approach should be the first option for removing aldosteronomas. PMID- 23362426 TI - Total thyroidectomy for non-toxic multinodular goiter with versus without the use of harmonic FOCUS dissecting shears - a prospective randomized study. AB - INTRODUCTION: Thyroidectomy is among the most commonly performed procedures involving the endocrine glands and the development of advanced surgical methods combined with a strife for performing the operation in a manner that is minimally invasive for the patient has considerably increased the need for instruments that would limit surgical trauma. AIM: To compare of the outcomes of total thyroidectomy operations with and without the use of ultrasonic harmonic FOCUS dissecting shears. MATERIAL AND METHODS: Eighty-two patients with a bilateral, non-toxic multinodular goiter were randomized to two groups of 41 patients each. Total thyroidectomy was performed in each patient. In the clip-ligation group (CL G), during thyroidectomy, the superior thyroid vessels were clipped and bipolar coagulation was used to secure smaller vessels, whereas in the harmonic FOCUS group (HF-G), a harmonic device was used to dissect and divide all the thyroid vessels. The statistical analysis included the mean operative time, blood loss, postoperative morbidity and cost-effectiveness. RESULTS: HF-G vs. CL-G operations were shorter (45.4 +/-8.7 min vs. 64.5 +/-14.2 min; p < 0.001), characterized by a lower mean blood loss (29.9 +/-9.8 ml vs. 56.8 +/-11.0 ml; p < 0.001) and appeared to be more cost-effective (666.2 +/-37.5 EUR vs. 718.0 +/-69.2 EUR; p < 0.01). No major complications were observed in both groups. CONCLUSIONS: In total thyroidectomy operations, the harmonic FOCUS is safe and facilitates dissection, allowing for a significant decrease in operative time. Other benefits include lower blood loss and a slightly decreased cost of the procedure. PMID- 23362427 TI - Impact of "non-clamping technique" on intra- and postoperative course after laparoscopic partial nephrectomy. AB - INTRODUCTION: The use of kidney warm ischaemia during laparoscopic partial nephrectomy (LPN) may lead to damage of renal vessels and kidney failure. Laparoscopic partial nephrectomy done without clamping the renal pedicle is feasible and may be beneficial for the postoperative course. AIM: To compare intra- and postoperative course in patients undergoing LPN with and without kidney warm ischaemia. MATERIAL AND METHODS: The material comprises 38 consecutive patients, who underwent LPN in our department during the years 2008 2009. In all cases renal vessels were identified and dissected at first, then resection of the tumour was done. Warm ischaemia was used only in case of difficulties with identification of tumour margin or with the management of bleeding. Out of 38 operations 13 were done without clamping the renal pedicle (group 1) and in the remaining 25 warm ischaemia was applied (group 2). RESULTS: Mean dimension of resected tumours in groups 1 and 2 was 31 mm and 33 mm respectively (p > 0.05), while parameters of intra- and postoperative course differed significantly between the groups: mean blood loss - 135 ml vs. 354 ml (p < 0.05), time of surgery - 72.6 min vs. 132.2 min (p < 0.05), postoperative drain leakage - 290 ml vs. 504 ml (p < 0.05), postoperative hospital stay - 3.1 days vs 5.3 days (p < 0.05). In all patients baseline creatinine levels were normal while after surgery creatinine elevation over the upper limit was found in groups 1 and 2 in one and in 6 patients respectively (p < 0.05). CONCLUSIONS: Laparoscopic resection of kidney tumour without warm ischaemia is feasible and beneficial in pre- and intraoperatively selected cases. Bleeding from renal parenchyma, which requires renal pedicle clamping, may seriously deteriorate intra- and postoperative course in patients undergoing laparoscopic partial nephrectomy. PMID- 23362428 TI - Endoscopic third ventriculostomy in treatment of hydrocephalus. AB - INTRODUCTION: Endoscopic third ventriculostomy (ETV) is a minimally invasive method of treatment of obstructive hydrocephalus (HCP). AIM: To investigate perioperative and intraoperative difficulties, failures and complications of ETV. MATERIAL AND METHODS: Seventy-three procedures of ETV were conducted in our department in the last 5 years on 69 patients with HCP of different etiology. In 4 patients we performed ETV twice. In 4 cases we used neuronavigation. In 6 cases ETV was performed in conjunction with endoscopic biopsy of the tumor. In 6 cases we had to repeat the procedure (4) or implant a ventriculo-peritoneal shunt (2) due to recurrence of symptoms. RESULTS: In our series we had 3 important complications: one thalamic injury and 2 intraventricular hemorrhages. In 4 cases we observed postoperative hyperthermia with the presence of meningeal symptoms. Two cerebrospinal fluid (CSF) leaks were secured with additional stitches and 2 CSF infections were treated with antibiotics. In 1 patient epileptic seizers were observed. Three others complained of nausea and vomiting. The initial success rate of ETV is 70%. CONCLUSIONS: Based on our material we conclude that ETV is a useful and helpful procedure in non-communicating HCP. It carries 4% perioperative risk of serious complications which can be reduced by proper selection of patients, detailed plan and skilful performance of surgery in experienced hands and meticulous postoperative care. PMID- 23362429 TI - The outcomes of SILS cholecystectomy in comparison with classic four-trocar laparoscopic cholecystectomy. AB - INTRODUCTION: General approval of laparoscopy as well as persistent urge to minimize operative trauma with still existing difficulties in putting natural orifice transluminal endoscopic surgery (NOTES) into practice have contributed to the introduction of laparoscopic operations through one incision in the umbilicus named single incision laparoscopic surgery (SILS). AIM: The main aim of this study was to assess the benefits to patients of applying SILS cholecystectomy as a method of gallbladder removal based on the comparison with classic four-port laparoscopic cholecystectomy. MATERIAL AND METHODS: Between 18.03.2009 and 09.12.2009, 100 patients were included in the study and they underwent elective gallbladder removal by applying the laparoscopic technique. All patients were divided into two equal groups: qualified for SILS cholecystectomy (group I) and qualified for classic four-trocar laparoscopic cholecystectomy (group II), whose ASA physical status was I and II. BMI was limited to 35 kg/m(2). Outcome measures included operative time, intensity of postoperative pain and consumption of painkillers, hospital stay, need for conversion, complications, and cosmetic effects. RESULTS: Mean operating time in group I was 66 min and in group II 47.2 min. Intensity of pain evaluated by using the visual analogue scale (VAS) 6 h after the operation in group I was 3.49 and in group II 4.53, whereas 24 h after the operation in group I it was 1.18 and in group II 1.55. The painkiller requirement in group I was smaller than in group II. Mean hospital stay after the operation in group I was 1.33 days and in group II 1.96 days. There were 4 conversions in group I and one conversion in group II. Among the complications in group I there were noted 2 cases of right pneumothorax, 1 case of choleperitonitis and 4 complications connected with wound healing. There was one injury of the duodenum and one wound infection in group II. CONCLUSIONS: Single incision laparoscopic surgery cholecystectomy can be an alternative to classic laparoscopic cholecystectomy, especially with reference to young people with body mass index less than 35 kg/m(2), without serious systemic diseases, operated on electively due to benign gallbladder diseases. PMID- 23362430 TI - Thoracoscopic treatment of benign esophageal tumors. AB - INTRODUCTION: Gastrointestinal stromal tumors are among the most frequent mesenchymal tumors of the gastrointestinal tract; the incidence of these tumors in the esophagus is less than 5%. Prognosis depends on localization, size, mitotic activity and possible invasion of surrounding structures. Minimally invasive surgery may be maximally utilized for removal of these tumors from the esophageal wall. This operation is usually performed thoracoscopically or laparoscopically and using the "rendez-vous" method - with endoscopic navigation. AIM: To evaluate a set of patients with benign tumor of the esophagus who were operated on at the First Department of Surgery from 2006 to 2011. MATERIAL AND METHODS: In the years 2006-2011 a total of 11 patients with benign tumors of the esophagus underwent operation. RESULTS: Of the 11 patients with esophageal tumor, 5 were diagnosed with gastrointestinal stromal tumor, 5 with leiomyoma and in one patient the lesion was described as heterotopy of the pancreas. We used the minimally invasive rendez-vous method with endoscopic navigation in 9 cases. All patients healed primarily and were released from hospital on the 4(th)-7(th) day. These patients are being followed up as outpatients and recurrence of the tumor has not been observed in any of them. CONCLUSIONS: Minimally invasive treatment of benign tumors of the esophageal wall is considered to the method of choice. Due to possible complications and the need for subsequent therapy in some patients, these procedures should be centralized to departments with experience in esophageal, thoracic and minimally invasive surgery. PMID- 23362431 TI - Endoscopic transnasal management of inverted papilloma involving frontal sinuses. AB - Inverted papilloma is a benign locally aggressive tumor of paranasal sinuses which has been traditionally managed with external surgical approaches. Advances in tumor imaging, surgical instrumentation and intraoperative visualization have led to a gradual shift to endonasal attachment-oriented surgery. Involvement of both frontal sinuses by inverted papilloma is rare. There are scant reports in the literature regarding this topic. We present 2 cases of the tumor involving both frontal sinuses removed by median drainage (Draf III procedure) under endoscopic guidance without any additional external approach. The whole cavity of both frontal sinuses was easily inspected at the end of the procedure. No early or late complications were observed. No recurrence was seen in 1-year or 2-year follow-up. Management of frontal sinus inverted papilloma with the endoscopic median drainage approach is feasible and seems to be effective. PMID- 23362432 TI - Laparoscopic single port surgery nephrectomy in a child - initial experience. AB - The aim of the stucdy was to present technical aspects and possible intraoperative complications based on the first single port surgery (SPS) laparoscopic nephrectomy performed in our center. The SPS laparoscopic nephrectomy of the right kidney was performed using a transperitoneal access in a 4-year-old child due to a small nonfunctional kidney complicated by hypertension. The intraoperative course was complicated by rupture of the gall bladder wall after grasper removal without leakage of its contents into the peritoneal cavity. No postoperative complications occurred. The SPS nephrectomy appears to be an advantageous method in children which offers a good cosmetic effect. Other benefits require confirmation in further studies. Fixation of the gall bladder is a very helpful but risky maneuver. PMID- 23362433 TI - Suprapubic transvesical laparoendoscopic single-site surgery for vesicovaginal fistula repair: a case report. AB - Some minimally invasive techniques have been introduced to decrease morbidity related to standard laparoscopic procedures. One such approach is laparoendoscopic single-site surgery (LESS), which can also be applied for transvesical surgery. The aim of the study was to present our initial clinical experience of using this technique for transvesical vesicovaginal fistula (VVF) repair. In August 2011, we carried out the LESS repair of a 3-mm in diameter vesicovaginal fistula on a 72-year-old woman, who failed the conservative treatment with Foley placement. The procedure was performed transvesically (percutaneous intraluminal approach) with a single-port device (4-channel, TriPort+, Olympus Winter&IBE GMBH) via a 1.5-cm incision made 2 cm above the pubic symphysis. A standard 10-mm optic and straight laparoscopic instruments were used. The fistulous tract was dissected and partially excised. The bladder and vaginal wall defects were closed in two layers with running absorbable V-Loc (Covidien, Norwalk, CT, USA) suture. Ureteral catheters were left for 5 days and the Foley catheter for 14 days. The operative time was 170 min. The blood loss was minimal. No complications were observed. The postoperative period was uneventful. During a 6-month follow-up the patient reported no involuntary discharge of urine into the vagina. Diagnostic scans revealed no presence of VVF and laboratory examination results were all within the normal range. Although substantial development of the instruments and skills is needed, the transvesical LESS vesicovaginal fistula repair appeared to be feasible and safe. Nevertheless, further experience and observations are necessary. PMID- 23362434 TI - Strangulation of the stomach and the transverse colon following laparoscopic esophageal hiatal hernia repair. AB - The authors present a 32-year-old male patient with incarceration of a recurrent esophageal hiatal hernia after laparoscopic repair. A life-threatening strangulation of the stomach and the transverse colon occurred within a few days after the operation. Relapse of hiatal hernias amounts to almost half of early complications characteristic for the laparoscopic approach. General recommendations regarding surgical technique as well as perioperative care have been proposed in order to decrease the risk of relapse. Also, routine contrast radiology on the first or second day following the laparoscopic operation facilitates early diagnosis of relapse of hiatal hernia with emergent reoperation. This may result in decreased morbidity and improved overall outcome of the treatment. PMID- 23362436 TI - Impact of the antiproliferative agent ciclopirox olamine treatment on stem cells proteome. AB - AIM: To investigate the proteome changes of stem cells due to ciclopirox olamine (CPX) treatment compared to control and retinoic acid treated cells. METHODS: Stem cells (SCs) are cells, which have the ability to continuously divide and differentiate into various other kinds of cells. Murine embryonic stem cells (ESCs) and multipotent adult germline stem cells (maGSCs) were treated with CPX, which has been shown to have an antiproliferative effect on stem cells, and compared to stem cells treated with retinoic acid (RA), which is known to have a differentiating effect on stem cells. Classical proteomic techniques like 2-D gel electrophoresis and differential in-gel electrophoresis (DIGE) were used to generate 2D protein maps from stem cells treated with RA or CPX as well as from non-treated stem cells. The resulting 2D gels were scanned and the digitalized images were collated with the help of Delta 2D software. The differentially expressed proteins were analyzed by a MALDI-TOF-TOF mass spectrometer, and the identified proteins were investigated and categorized using bioinformatics. RESULTS: Treatment of stem cells with CPX, a synthetic antifungal clinically used to treat superficial mycoses, resulted in an antiproliferative effect in vitro, without impairment of pluripotency. To understand the mechanisms induced by CPX treatments which results in arrest of cell cycle without any marked effect on pluripotency, a comparative proteomics study was conducted. The obtained data revealed that the CPX impact on cell proliferation was accompanied with a significant alteration in stem cell proteome. By peptide mass fingerprinting and tandem mass spectrometry combined with searches of protein sequence databases, a set of 316 proteins was identified, corresponding to a library of 125 non redundant proteins. With proteomic analysis of ESCs and maGSCs treated with CPX and RA, we could identify more than 90 single proteins, which were differently expressed in both cell lines. We could highlight, that CPX treatment of stem cells, with subsequent proliferation inhibition, resulted in an alteration of the expression of 56 proteins compared to non-treated cells, and 54 proteins compared to RA treated cells. Bioinformatics analysis of the regulated proteins demonstrated their involvement in various biological processes. To our interest, a number of proteins have potential roles in the regulation of cell proliferation either directly or indirectly. Furthermore the classification of the altered polypeptides according to their main known/postulated functions revealed that the majority of these proteins are involved in molecular functions like nucleotide binding and metal ion binding, and biological processes like nucleotide biosynthetic processes, gene expression, embryonic development, regulation of transcription, cell cycle processes, RNA and mRNA processing. Proteins, which are involved in nucleotide biosynthetic process and proteolysis, were downregulated in CPX treated cells compared to control, as well as in RA treated cells, which may explain the cell cycle arrest. Moreover, proteins which were involved in cell death, positive regulation of biosynthetic process, response to organic substance, glycolysis, anti-apoptosis, and phosphorylation were downregulated in RA treated cells compared to control and CPX treated cells. CONCLUSION: The CPX treatment of SCs results in downregulation of nucleotide binding proteins and leads to cell cycle stop without impairment of pluripotency. PMID- 23362437 TI - Fetal cardiac mesenchymal stem cells express embryonal markers and exhibit differentiation into cells of all three germ layers. AB - AIM: To study the expression of embryonal markers by fetal cardiac mesenchymal stem cells (fC-MSC) and their differentiation into cells of all the germ layers. METHODS: Ten independent cultures of rat fC-MSC were set up from cells derived from individual or pooled fetal hearts and studies given below were carried out at passages 3, 6, 15 and 21. The phenotypic markers CD29, CD31, CD34, CD45, CD73, CD90, CD105, CD166 and HLA-DR were analyzed by flow cytometry. The expression of embryonal markers Oct-4, Nanog, Sox-2, SSEA-1, SSEA-3, SSEA-4, TRA-1-60 and TRA 1 81 were studied by immunocytochemistry. The fC-MSC treated with specific induction medium were evaluated for their differentiation into (1) adipocytes and osteocytes (mesodermal cells) by Oil Red O and Alizarin Red staining, respectively, as well as by expression of lipoprotein lipase, PPARgamma2 genes in adipocytes and osteopontin and RUNX2 genes in osteocytes by reverse-transcription polymerase chain reaction (RT-PCR); (2) neuronal (ectodermal) cells by expression of neuronal Filament-160 and Glial Fibrillar Acidic Protein by RT-PCR and immunocytochemistry; and (3) hepatocytic (endodermal) cells by expression of albumin by RT-PCR and immunocytochemistry, glycogen deposits by Periodic Acid Schiff staining and excretion of urea into the culture supernatant. RESULTS: The fC-MSC expressed CD29, CD73, CD90, CD105, CD166 but lacked expression of CD31, CD34, CD45 and HLA-DR. They expressed embryonal markers, viz. Oct-4, Nanog, Sox 2, SSEA-1, SSEA-3, SSEA-4, TRA-1-81 but not TRA-1-60. On treatment with specific induction media, they differentiated into adipocytes and osteocytes, neuronal cells and hepatocytic cells. CONCLUSION: Our results together suggest that fC-MSC are primitive stem cell types with a high degree of plasticity and, in addition to their suitability for cardiovascular regenerative therapy, they may have a wide spectrum of therapeutic applications in regenerative medicine. PMID- 23362435 TI - A familiar stranger: CD34 expression and putative functions in SVF cells of adipose tissue. AB - Human adipose tissue obtained by liposuction is easily accessible and an abundant potential source of autologous cells for regenerative medicine applications. After digestion of the tissue and removal of differentiated adipocytes, the so called stromal vascular fraction (SVF) of adipose, a mix of various cell types, is obtained. SVF contains mesenchymal fibroblastic cells, able to adhere to culture plastic and to generate large colonies in vitro, that closely resemble bone marrow-derived colony forming units-fibroblastic, and whose expanded progeny, adipose mesenchymal stem/stromal cells (ASC), show strong similarities with bone marrow mesenchymal stem cells. The sialomucin CD34, which is well known as a hematopoietic stem cell marker, is also expressed by ASC in native adipose tissue but its expression is gradually lost upon standard ASC expansion in vitro. Surprisingly little is known about the functional role of CD34 in the biology and tissue forming capacity of SVF cells and ASC. The present editorial provides a short introduction to the CD34 family of sialomucins and reviews the data from the literature concerning expression and function of these proteins in SVF cells and their in vitro expanded progeny. PMID- 23362438 TI - Immunophenotype and differentiation capacity of bone marrow-derived mesenchymal stem cells from CBA/Ca, ICR and Balb/c mice. AB - AIM: To assess the capacity to isolate and expand mesenchymal stem cells (MSC) from bone marrow of CBA/Ca, ICR and Balb/c mice. METHODS: Bone marrow of tibia and femur were flushed, cultured and maintained in supplemented Dulbecco's modified Eagle's medium. MSC immunophenotype of cultures were tracked along increasing passages for positivity to CD106, Sca-1 and CD44 and negativity to CD45, CD11b and MHC class II. Differentiation capacity of MSC towards osteogenic and adipogenic lineages were also assessed. RESULTS: MSC were successfully cultured from bone marrow of all 3 strains, albeit differences in the temporal expression of certain surface antigens. Their differentiation into osteocytes and adipocytes were also observed. MSC from all 3 mouse strains demonstrated a shift from a haematopoietic phenotype (CD106(-)CD45(+)CD11b(+)Sca-1(low)) to typical MSC phenotype (CD106(+)CD45(-)CD11b(-)Sca-1(high)) with increasing passages. CONCLUSION: Information garnered assists us in the decision of selecting a mouse strain to generate MSC from for downstream experimentation. PMID- 23362439 TI - Wisdom of snake. PMID- 23362441 TI - Does the presence of hypoechoic lesions on transrectal ultrasound suggest a poor prognosis for patients with localized prostate cancer? AB - PURPOSE: The purpose of this study was to investigate the value of hypoechoic lesions on transrectal ultrasound (TRUS) as a prognostic factor for patients with localized prostate cancer. MATERIALS AND METHODS: The patients consisted of 71 patients with pT2N0M0 disease following radical prostatectomy between 2002 and 2008. The group with hypoechoic lesions was labeled group 1, whereas the group without hypoechoic lesions was labeled group 2. The presence of hypoechoic lesions on preoperative TRUS was analyzed as a prognostic factor along with several parameters, including preoperative factors and pathologic factors. The biochemical progression-free survival (BPFS) rate was compared between the two groups according to the presence of hypoechoic lesions on TRUS. RESULTS: A total of 35 patients had hypoechoic lesions on TRUS, whereas 36 had no hypoechoic lesions. Preoperative baseline characteristics were not significantly different between the two groups. In the univariate analysis, BPFS showed significant differences according to the presence of hypoechoic lesions on TRUS and the preoperative prostate-specific antigen level. The BPFS rates over the first 24 months were 97.0% in group 1 and 97.1% in group 2; however, the difference in the BPFS rate over 48 months significantly widened to 75.3% compared with 91.7%, respectively. Despite this finding, no significant independent prognostic factor for BPFS was found on multivariate analysis in this patient cohort. CONCLUSIONS: The presence of hypoechoic lesions on TRUS may suggest worse prognostic characteristics in pT2 prostate cancer. Further studies involving larger subject populations are needed to corroborate the significance of the presence of hypoechoic lesions as a prognostic factor. PMID- 23362442 TI - Impact of prostate volume on oncological and functional outcomes after radical prostatectomy: robot-assisted laparoscopic versus open retropubic. AB - PURPOSE: We compared the impact of prostate volume on oncological and functional outcomes 2 years after robot-assisted laparoscopic prostatectomy (RALP) and open radical retropubic prostatectomy (ORP). MATERIALS AND METHODS: Between 2003 and 2010, 253 consecutive patients who had undergone prostatectomy by a single surgeon were serially followed over 2 years postoperatively. RALP was performed on 77 patients and ORP on 176. The patients were divided into two subgroups according to prostate volume as measured by transrectal ultrasound: less than 40 g and 40 g or larger. Recoveries of potency and continence were checked serially by interview 1, 3, 6, 9, 12, and 24 months postoperatively. RESULTS: RALP was associated with less blood loss (ORP vs. RALP: 910 mL vs. 640 mL, p<0.001) but a longer operation time (150 minutes vs. 220 minutes, p<0.001) than was ORP. No statistically significant differences were found between the two groups for oncological outcomes, such as positive surgical margin (40% vs. 39%, p=0.911) or biochemical recurrence (12% vs. 7%, p=0.155). The overall functional outcomes showed no statistically significant differences at 2 years of follow-up (continence: 97% vs. 94%, p=0.103; potency: 51% vs. 56%, p=0.614). In the results of an inter-subgroup analysis, potency recovery was more rapid in patients who underwent RALP in a small-volume prostate than in those who underwent ORP in a small-volume prostate (3 months: 24% vs. 0%, p=0.005; 6 months: 36% vs. 10%, p=0.024). However, patients who underwent RALP in a large-volume prostate were less likely to recover continence than were patients who underwent ORP in a large volume prostate (97% vs. 88%, p=0.025). CONCLUSIONS: Patients can be expected to recover erectile function more quickly after RALP than after ORP, especially in cases of a small prostate volume. PMID- 23362440 TI - Current management of testicular cancer. AB - Germ cell tumors (GCTs) of the testis are rare, but are the most common cancer in young men. GCTs may consist of one predominant histologic pattern or may represent a mixture of multiple histologic types. For treatment purposes, two broad categories are recognized: 1) pure seminoma and 2) others, which together are termed nonseminomatous GCTs (NSGCTs). In general, seminoma tends to be less aggressive, to be diagnosed at an earlier stage, and to spread predictably along lymphatic channels to the retroperitoneum before spreading hematogenously to the lung or other organs. Compared with NSGCTs, seminoma is exquisitely sensitive to radiation therapy and platinum-based chemotherapy. NSGCTs are usually mixed tumors and teratoma often exists at the sites of metastasis with other GCT elements; cure often requires chemotherapy to kill the chemosensitive-components and surgery to remove the teratomatous components. The main factors contributing to excellent cure rates of GCTs are careful staging at diagnosis; adequate early treatment using chemotherapeutic combinations, with or without radiotherapy and surgery; and very strict follow-up and salvage therapy. We review several clinical studies and summarize the current trends in the management of GCTs. PMID- 23362443 TI - Changes in renal function after laparoscopic partial nephrectomy: comparison with laparoscopic radical nephrectomy. AB - PURPOSE: To evaluate alterations in renal function after laparoscopic radical nephrectomy (LRN) and laparoscopic partial nephrectomy (LPN) for renal tumors. MATERIALS AND METHODS: From March 2008 to August 2011, we performed 175 cases of laparoscopic kidney resection. Among these, we excluded patients who received perioperative immunotherapy or target therapy and also patients with a preoperative estimated glomerular filtration rate (eGFR) <60 mL/min. A total of 32 patients undergoing LPN and 92 patients undergoing LRN were enrolled. We retrospectively reviewed the changes in eGFR (by the modification of diet in renal disease method) at the following time points: preoperative, postoperative 1 week, and postoperative 1, 3, 6, and 12 months. RESULTS: The mean warm ischemia time of the LPN group was 22 minutes (range, 0 to 47 minutes). Mean eGFR values (mL/min/1.73 m(2)) during postoperative week 1 and 1, 3, 6, and 12 months were 70.8, 71.5, 76.7, 76.0, and 75.3 in the LPN group and 52.1, 50.6, 52.8, 53.4, and 52.4 in the LRN group, respectively. One year after the operation, 6.3% (2 patients) of LPN patients and 68.5% (63 patients) of LRN patients had progressed to chronic renal insufficiency (eGFR<60 mL/min/1.73 m(2)). CONCLUSIONS: Renal function recovered slightly after LPN and LRN and was maintained constantly after 3 months. However, renal function showed different patterns of decrease. Despite the concern for warm ischemia, LPN can preserve renal function better than can LRN. LPN should be considered for selected patients to prevent chronic renal insufficiency. PMID- 23362444 TI - Laparoscopic ureteroneocystostomy: modification of current techniques. AB - PURPOSE: To review the feasibility of laparoscopic ureteroneocystostomy with extracorporeal eversion of the ureteral end in various distal ureteral lesions. MATERIALS AND METHODS: We conducted a retrospective review of 5 laparoscopic procedures of ureteroneocystostomy with extracorporeal eversion of the ureteral end. Of these, 4 patients (range, 45 to 54 years) had distal ureter stricture or obstruction after gynecological surgeries for endometriosis or a large uterine myoma. One patient (male, 67 years) had low-grade distal ureter cancer. The laparoscopic procedure was combined with cystoscopic insertion of a ureteral stent and extracorporeal eversion of the ureter through the 10-mm port on the affected side. RESULTS: The laparoscopic ureteral reimplantations with and without a psoas hitch in patients with distal ureteral lesions was successful in all patients. The mean operation time was 137 minutes (range, 104 to 228 minutes). Two patients underwent additional psoas hitch. In all patients, short term success was confirmed by voiding cystourethrography and intravenous pyelography conducted 3 months after the operation. The mean follow-up of the entire group was 12 months (range, 3 to 30 months). We noted no major or minor complications over the follow-up period. CONCLUSIONS: The technique of laparoscopic ureteroneocystostomy for benign or malignant ureteral strictures continues to evolve. Surgeons should be versatile with various options and technical nuances when dealing with these cases. Simple modifications of laparoscopic ureteroneocystostomy with extracorporeal eversion of the ureteral end, nonreflux extravesical anastomosis, and simultaneous cystoscopy will be crucial to the ease of performance and a successful outcome. PMID- 23362445 TI - Risk Factors for Failure of Early Catheter Removal After Greenlight HPS Laser Photoselective Vaporization Prostatectomy in Men With Benign Prostatic Hyperplasia. AB - PURPOSE: To assess the risk factors for developing urinary retention after removal of the urethral catheter on postoperative day 1 in benign prostatic hyperplasia patients who underwent Greenlight HPS laser photoselective vaporization prostatectomy (PVP). MATERIALS AND METHODS: The study included 427 men who underwent Greenlight HPS laser PVP between 2009 and 2012, excluding patients in whom a catheter was maintained for more than 1 day because of urethral procedures. In all patients, a voiding trial was performed on postoperative day 1; if patients were unable to urinate, the urethral catheter was replaced before hospital discharge. The patients were divided into two groups: early catheter removal (postoperative day 1) and late catheter removal (urethral catheter reinsertion). Preoperative and perioperative parameters were compared between the groups. RESULTS: Catheters were successfully removed in 378 (88.6%) patients on postoperative day 1. In 49 patients, the catheters were reinserted and removed a mean of 6.45+/-0.39 days after surgery. In a multivariate analysis, a history of diabetes was the most significant predictor (p=0.028) of failure of early catheter removal, followed by operative time (p=0.039). There were no significant differences in age, prostate volume, International Prostate Symptom Score, or urodynamic parameters between the two groups. CONCLUSIONS: It is feasible, safe, and cost-effective to remove the urethral catheter on postoperative day 1 after Greenlight HPS laser PVP, but the procedure should be done carefully in patients who have history of diabetes or an extended operative time. PMID- 23362446 TI - Effect of photoselective vaporization prostatectomy on lower urinary tract symptoms in benign prostatic hyperplasia with or without intravesical prostatic protrusion. AB - PURPOSE: Intravesical protrusion of the prostate (IPP) can affect voiding. We evaluated the improvement in lower urinary tract symptoms and patient satisfaction after laser prostate photovaporization in benign prostatic hyperplasia (BPH) patients with or without IPP. MATERIALS AND METHODS: This prospective study included 134 patients who underwent GreenLight HPS laser photoselective vaporization prostatectomy (PVP) between January 2010 and July 2011 patient. Preoperative IPP was evaluated by using the retroflexed view from flexible cystoscopy. evaluation included complete medical history, International Prostate Symptom Scores (IPSS), maximum flow rate (Qmax), postvoid residual (PVR), serum prostate-specific antigen (PSA), and transrectal ultrasonogram. Changes from baseline in Qmax, PVR, total IPSS, and IPSS subscores (voiding and storage) were analyzed at postoperative months 1, 3, and 6. RESULTS: The patients' mean age was 66.6+/-7.8 years. Mean serum PSA and prostate volume were 1.7+/-1.5 ng/mL and 42.9+/-16.7 g, respectively. No significant differences existed between the IPP and no IPP groups in preoperative prostate volume, total IPSS, PSA, or lasing time and energy. The mean follow-up duration was 6.2+/-1.9 months. IPP patients showed significant improvements in total IPSS and voiding subscores at months 1 and 3. Improvements in the quality of life score and storage subscore were not significantly different between the groups. Qmax was significantly improved at 6 months postoperatively in the IPP group versus the no IPP group. CONCLUSIONS: Among patients who underwent PVP for BPH, the IPP group showed more symptom improvement, especially in voiding symptoms, than did the no IPP group. Preoperative cystoscopy is helpful for evaluating IPP and for anticipating postoperative outcome. PMID- 23362447 TI - Is concomitant bladder neck reconstruction necessary in neurogenic incontinent patients who undergo augmentation cystoplasty? AB - PURPOSE: In patients with neurogenic bladder due to spinal cord injury or disease who undergo augmentation cystoplasty (AC) for not only bladder dysfunction but also sphincteric incontinence, the need for concomitant bladder neck reconstruction at the time of AC has not yet been established. The aim of this study was to evaluate whether concomitant bladder neck reconstruction is necessary when performing AC. MATERIALS AND METHODS: We retrospectively investigated 35 patients who underwent AC from January 2006 to September 2010. Medical history, preoperative and postoperative fluoroscopic urodynamic study (FUDS) parameters, and responses to an incontinence questionnaire (ICIQ Korean version) were reviewed. RESULTS: A final analysis was performed on 17 patients (9 male, 8 female) who were diagnosed with sphincteric incontinence. Continence status, the number of pads used, and the bother score were significantly improved postoperatively in this subpopulation. Preoperatively, all patients used pads, and the average daily number was 2.2 (median; range 0 to 6). Postoperatively, the number of pads used decreased significantly to 0.9 (median; range 0 to 3) pads a day (p=0.002). Urodynamic parameters including bladder capacity, compliance, involuntary detrusor contraction, and bladder neck incompetence proven by FUDS were also significantly improved. CONCLUSIONS: Our study demonstrated that both objective urodynamic parameters and subjective incontinence symptoms improved significantly after the completion of AC as a single procedure in patients with sphincteric incompetence. This implies that anti-incontinence bladder outlet surgery does not have to be performed simultaneously and can be considered later as a staged operation. PMID- 23362448 TI - A retrospective study of the management of vulvodynia. AB - PURPOSE: Vulvodynia is characterized by chronic vulvar pain caused by sexual intercourse and often results in female sexual dysfunction. Because the causes of vulvodynia are not clear, many patients do not receive optimal treatment. Recently, gabapentin and botulinum toxin A have both been shown to be effective treatments for vulvodynia. In this study, we retrospectively analyzed the clinical outcomes of botulinum toxin A and gabapentin treatment for chronic pain in women with this condition. MATERIALS AND METHODS: Seventy-three women with vulvar pain were administered either gabapentin (n=62) or botulinum toxin A (n=11) injections. Effectiveness was measured by use of a visual analogue scale (VAS). We analyzed the treatment method, treatment duration, success of treatment, and side effects or adverse reactions. RESULTS: Pain levels in both groups significantly decreased after treatment. In the gabapentin group, the VAS score decreased from 8.6 before treatment to 3.2 after treatment (p<0.001). The VAS score in the botulinum toxin A group was reduced from 8.1 to 2.5 (p<0.001). Side effects for both therapies were few and subsided with treatment with general antibiotics and nonsteroidal antiinflammatory drugs. CONCLUSIONS: Gabapentin and botulinum toxin A are safe and effective treatments for vulvodynia. This condition can cause sexual dysfunction and affect quality of life. However, with proper management, satisfactory outcomes for women with vulvodynia can be achieved. PMID- 23362449 TI - Prevalence and associated factors for four sexually transmissible microorganisms in middle-aged men receiving general prostate health checkups: a polymerase chain reaction-based study in Korea. AB - PURPOSE: To investigate the prevalence of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Mycoplasma genitalium (MG), and Ureaplasma urealyticum (UU) in first-voided urine samples and to determine the factors associated with positivity for sexually transmissible microorganisms in healthy, middle-aged Korean men. MATERIALS AND METHODS: Five hundred fifty-one men who came to the hospital for a general prostate health checkup were tested between August 2011 and December 2011. PCR assays for CT, NG, MG, and UU were done with first-voided urine samples and the prevalence of microorganism positivity and association with several clinical parameters were evaluated. RESULTS: The mean age of the men studied was 50.8+/-4.7 years. Among the 551 men, 72 (13.1%) had a positive result for at least one microorganism; one (0.2%) had two different species. The overall prevalence of asymptomatic sexually transmitted infections was 11.1% (61/551). The prevalence rates of CT, NG, MG, and UU infection in the general population were 0.4% (2/551), 0.0% (0/551), 1.0% (6/551), and 11.8% (65/551), respectively. CT-positive patients had a lower mean age than did CT-negative patients. There were no significant differences in symptoms by positivity of each microorganism. CONCLUSIONS: We checked the prevalence rates of four microorganisms, the proportion of symptomatic people, and the association of microbes, age, and symptoms, as the baseline data for Korean middle-aged men. In this population, CT, NG, MG, and UU infections do not seem to be symptomatic. However, the potential role of CT in young men and of UU in middle-aged men with a high rate of detection should be studied continuously as a source of opportunistic infection. PMID- 23362450 TI - Factors that affect nosocomial catheter-associated urinary tract infection in intensive care units: 2-year experience at a single center. AB - PURPOSE: This study took a retrospective approach to investigate patients with catheter-associated urinary tract infection (CAUTI) over 2 years at a single hospital's intensive care unit (ICU) to identify meaningful risk factors and causative organisms. MATERIALS AND METHODS: A retrograde analysis was performed on patients with indwelling catheters between January 2009 and December 2010 in Yeouido St. Mary Hospital medical and surgical ICU. CAUTI was defined as isolated bacterial growth of 100,000 colony-forming units or more either 48 hours after transfer to the ICU if a urinary catheter was placed before the transfer or 48 hours after insertion if the catheter was inserted in the ICU. Only the patients whose culture results were negative before ICU admission were included. RESULTS: There were a total of 1,315 patients with indwelling urinary catheters in our hospital's medical and surgical ICU between January 2009 and December 2010. Of these patients, 241 had positive urine culture results, and 61 had CAUTI. Using multivariate logistic regression analysis, those with diabetes were 4.55 (p<0.001) times as likely to have occurrences of CAUTI than were those without and also had a 1.10-fold (p<0.01) longer duration of an indwelling catheter. Upon urine culture, among the 61 patients with CAUTI, Escherichia coli was the most common bacterium grown; it was identified in 24 patients (38.7%). CONCLUSIONS: The factors and causative organisms contributing to the development of CAUTI in the management of ICU patients must be considered to prevent the occurrence of UTIs in this setting. PMID- 23362451 TI - Brain and skin metastasis from urothelial carcinoma of the bladder. AB - Brain and skin metastasis from urothelial carcinoma of the bladder is rare. There have been few case reports of the clinical course of patients with metastatic urothelial carcinoma of the brain and skin. In the present case, a 60-year-old man had undergone radical cystectomy with an ileal conduit owing to urothelial carcinoma (T1N0M0). The patient developed dizziness 9 years later and a solitary brain tumor was discovered in his left cerebellar hemisphere. The tumor was totally resected and the mass was verified to be metastatic urothelial carcinoma. One year after the metastasectomy of the brain lesion, multiple erythematous nodular lesions developed on his abdominal skin. The skin lesions were excised and verified to be metastatic urothelial carcinoma. This report describes this case of urothelial carcinoma of the bladder that metastasized to the brain and abdominal skin. PMID- 23362452 TI - Metastasis of renal cell carcinoma to the bladder. AB - Renal cell carcinoma is an uncommon source of bladder metastases. Here we report a case of renal cell carcinoma that metastasized to the bladder. A 73-year-old woman complained of gross hematuria. Abdominopelvic computerized tomography showed a bladder mass and a heterogenous enhancing mass in the lower pole of the left kidney with left vein thrombosis. The pathological analysis of the resected bladder specimen revealed metastatic renal cell carcinoma of the clear cell type. PMID- 23362453 TI - Use of medical foods and nutritional approaches in the treatment of Alzheimer's disease. AB - Alzheimer's disease, the most common cause of dementia, has a high global economic impact. To date, there is no curative treatment; therefore, many efforts are directed not only at novel potential disease-modifying treatments and interventions, but also to develop alternative symptomatic and supportive treatments. Examples of these efforts include the medical foods. There are three medical foods that claim to offer symptomatic benefits: Axona((r)), Souvenaid((r)) and CerefolinNAC((r)). Axona supplies ketone bodies as alternative energy source to neurons. Souvenaid provides precursors thought to enhance synaptic function. CerefolinNAC addresses the role of oxidative stress related to memory loss. The current scientific evidence on these medical foods is reviewed in this article. Furthermore, we also review the concept and evidence supporting use of the Mediterranean diet, a possible alternative to medical foods that, if implemented correctly, may have lower costs, fewer side effects and stronger epidemiological health outcomes. PMID- 23362454 TI - Synthesis of ammonia directly from air and water at ambient temperature and pressure. AB - The N=N bond (225 kcal mol-1) in dinitrogen is one of the strongest bonds in chemistry therefore artificial synthesis of ammonia under mild conditions is a significant challenge. Based on current knowledge, only bacteria and some plants can synthesise ammonia from air and water at ambient temperature and pressure. Here, for the first time, we report artificial ammonia synthesis bypassing N2 separation and H2 production stages. A maximum ammonia production rate of 1.14 * 10-5 mol m-2 s-1 has been achieved when a voltage of 1.6 V was applied. Potentially this can provide an alternative route for the mass production of the basic chemical ammonia under mild conditions. Considering climate change and the depletion of fossil fuels used for synthesis of ammonia by conventional methods, this is a renewable and sustainable chemical synthesis process for future. PMID- 23362455 TI - Structural phase transition in IrTe2: a combined study of optical spectroscopy and band structure calculations. AB - Ir(1-x)Pt(x)Te2 is an interesting system showing competing phenomenon between structural instability and superconductivity. Due to the large atomic numbers of Ir and Te, the spin-orbital coupling is expected to be strong in the system which may lead to nonconventional superconductivity. We grew single crystal samples of this system and investigated their electronic properties. In particular, we performed optical spectroscopic measurements, in combination with density function calculations, on the undoped compound IrTe2 in an effort to elucidate the origin of the structural phase transition at 280 K. The measurement revealed a dramatic reconstruction of band structure and a significant reduction of conducting carriers below the phase transition. We elaborate that the transition is not driven by the density wave type instability but caused by the crystal field effect which further splits/separates the energy levels of Te (p(x), p(y)) and Te p(z) bands. PMID- 23362456 TI - PAPTi: a peptide aptamer interference toolkit for perturbation of protein-protein interaction networks. AB - Signaling proteins often form dynamic protein-protein interaction (PPI) complexes to achieve multi-functionality. Methods to abrogate a subset of PPI interfaces without depleting the full-length protein will be valuable for structure-function relationship annotations. Here, we describe the use of Peptide Aptamer Interference (PAPTi) approach for structure-function network studies. We identified peptide aptamers against Dishevelled (Dsh) and beta-catenin (beta-cat) to target the Wnt signaling pathway and demonstrate that these FN3-based MONOBODYs (FNDYs) can be used to perturb protein activities both in vitro and in vivo. Further, to investigate the crosstalk between the Wnt and Notch pathways, we isolated FNDYs against the Notch Ankyrin (ANK) region and demonstrate that perturbing the ANK domain of Notch increases the inhibitory activity of Notch towards Wnt signaling. Altogether, these studies demonstrate the power of the PAPTi approach to dissect specific PPI interactions within signaling networks. PMID- 23362457 TI - In vivo self-bio-imaging of tumors through in situ biosynthesized fluorescent gold nanoclusters. AB - Fluorescence imaging in vivo allows non-invasive tumor diagnostic thus permitting a direct monitoring of cancer therapies progresses. It is established herein that fluorescent gold nanoclusters are spontaneously biosynthesized by cancerous cell (i.e., HepG2, human hepatocarcinoma cell line; K562, leukemia cell line) incubated with micromolar chloroauric acid solutions, a biocompatible molecular Au(III) species. Gold nanoparticles form by Au(III) reduction inside cells cytoplasms and ultimately concentrate around their nucleoli, thus affording precise cell imaging. Importantly, this does not occur in non-cancerous cells, as evidenced with human embryo liver cells (L02) used as controls. This dichotomy is exploited for a new strategy for in vivo self-bio-imaging of tumors. Subcutaneous injections of millimolar chloroauric acid solution near xenograft tumors of the nude mouse model of hepatocellular carcinoma or chronic myeloid leukemia led to efficient biosynthesis of fluorescent gold nanoclusters without significant dissemination to the surrounding normal tissues, hence allowing specific fluorescent self-bio-marking of the tumors. PMID- 23362458 TI - A Weber-like law for perceptual learning. AB - What determines how much an organism can learn? One possibility is that the neural factors that limit sensory performance prior to learning, place an upper limit on the amount of learning that can take place. We tested this idea by comparing learning on a sensory task where performance is limited by cortical mechanisms, at two retinal eccentricities. Prior to learning, visual performance at the two eccentricities was either unmatched or equated in two different ways (through spatial scaling or visual crowding). The magnitude of learning was equivalent when initial levels of performance were matched regardless of how performance was equated. The magnitude of learning was a constant proportion of initial performance. This Weber-like law for perceptual learning demonstrates that it should be possible to predict the degree of perceptual improvement and the final level of performance that can be achieved via sensory training, regardless of what cortical constraint limits performance. PMID- 23362459 TI - Systemic delay propagation in the US airport network. AB - Technologically driven transport systems are characterized by a networked structure connecting operation centers and by a dynamics ruled by pre-established schedules. Schedules impose serious constraints on the timing of the operations, condition the allocation of resources and define a baseline to assess system performance. Here we study the performance of an air transportation system in terms of delays. Technical, operational or meteorological issues affecting some flights give rise to primary delays. When operations continue, such delays can propagate, magnify and eventually involve a significant part of the network. We define metrics able to quantify the level of network congestion and introduce a model that reproduces the delay propagation patterns observed in the U.S. performance data. Our results indicate that there is a non-negligible risk of systemic instability even under normal operating conditions. We also identify passenger and crew connectivity as the most relevant internal factor contributing to delay spreading. PMID- 23362460 TI - Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma. AB - Glioblastoma multiforme (GBM) is a highly invasive and chemoradioresistant brain malignancy. Temozolomide (TMZ), a DNA-alkylating agent, is effective against GBM and has become the standard first-line drug. However, the mechanism by which TMZ regulates the progression of GBM remains elusive. Here, we demonstrate that TMZ targets TAp63, a p53 family member, inducing its expression to suppress the progression of human GBM. High levels of TAp63 expression in GBM tissues after TMZ treatment was an indicator of favourable prognosis. In human GBM cells, TMZ induced TAp63 directly repressed MYC transcription. Activation of this TAp63-MYC pathway by TMZ inhibited human GBM progression both in vitro and in vivo. Furthermore, downregulation of MYC mRNA levels in recurrent GBMs after TMZ treatment correlated with better patient survival. Therefore, our results suggest that the TAp63-mediated transcriptional repression of MYC is a novel pathway regulating TMZ efficacy in GBM. PMID- 23362461 TI - Chaperone-assisted thermostability engineering of a soluble T cell receptor using phage display. AB - We here report a novel phage display selection strategy enabling fast and easy selection of thermostabilized proteins. The approach is illustrated with stabilization of an aggregation-prone soluble single chain T cell receptor (scTCR) characteristic of the murine MOPC315 myeloma model. Random mutation scTCR phage libraries were prepared in E. coli over-expressing the periplasmic chaperone FkpA, and such over-expression during library preparation proved crucial for successful downstream selection. The thermostabilized scTCR(mut) variants selected were produced in high yields and isolated as monomers. Thus, the purified scTCRs could be studied with regard to specificity and equilibrium binding kinetics to pMHC using surface plasmon resonance (SPR). The results demonstrate a difference in affinity for pMHCs that display germ line or tumor specific peptides which explains the tumor-specific reactivity of the TCR. This FkpA-assisted thermostabilization strategy extends the utility of recombinant TCRs and furthermore, may be of general use for efficient evolution of proteins. PMID- 23362462 TI - Quantitative genetic background of the host influences gut microbiomes in chickens. AB - Host genotype and gender are among the factors that influence the composition of gut microbiota. We studied the population structure of gut microbiota in two lines of chickens maintained under the same husbandry and dietary regimes. The lines, which originated from a common founder population, had undergone 54 generations of selection for high (HW) or low (LW) 56-day body weight, and now differ by more than 10-fold in body weight at selection age. Of 190 microbiome species, 68 were affected by genotype (line), gender, and genotype by gender interactions. Fifteen of the 68 species belong to Lactobacillus. Species affected by genotype, gender, and the genotype by gender interaction, were 29, 48, and 12, respectively. Species affected by gender were 30 and 17 in the HW and LW lines, respectively. Thus, under a common diet and husbandry host quantitative genotype and gender influenced gut microbiota composite. PMID- 23362463 TI - Single row rotator cuff repair with modified technique. AB - Rotator cuff tear is a common medical condition. We introduce various suture methods that can be used for arthroscopic rotator cuff repair, review the single row rotator cuff repair method with modified technique, and introduce the Ulsan University (UU) stich. We compare the UU stitch with the modified Mason-Allen (MA) suture method. The UU stitch configuration is a simple alternative to the modified MA suture configuration for rotator cuff repair. PMID- 23362464 TI - Current concepts in management of femoroacetabular impingement. AB - Femoroacetabular impingement (FAI) is an increasingly recognized condition, which is believed to contribute to degenerative changes of the hip. This correlation has led to a great deal of interested in diagnosis and treatment of FAI. FAI can be divided into two groups: cam and pincer type impingement. FAI can lead to chondral and labral pathologies, that if left untreated, can progress rapidly to osteoarthritis. The diagnosis of FAI involves a detailed history, physical exam, and radiographs of the pelvis. Surgical treatment is indicated in anatomic variants known to cause FAI. The primary goal of surgical treatment is to increase joint clearance and decrease destructive forces being transmitted through the joint. Treatment has been evolving rapidly over the past decade and includes three primary techniques: open surgical dislocation, mini-open, and arthroscopic surgery. Open surgical dislocation is a technique for dislocating the femoral head from the acetabulum with a low risk of avascular necrosis in order to reshape the neck or acetabular rim to improve joint clearance. Mini-open treatment is performed using the distal portion of an anterior approach to the hip to visualize and to correct acetabular and femoral head and neck junction deformities. This does not involve frank dislocation. Recently, arthroscopic treatment has gained popularity. This however does have a steep learning curve and is best done by an experienced surgeon. Short- to mid-term results have shown relatively equal success with all techniques in patients with no or only mild evidence of degenerative changes. Additionally, all techniques have demonstrated low rates of complications. PMID- 23362465 TI - Osteoclast fusion and regulation by RANKL-dependent and independent factors. AB - Osteoclasts are the bone resorbing cells essential for bone remodeling. Osteoclasts are formed from hematopoietic progenitors in the monocyte/macrophage lineage. Osteoclastogenesis is composed of several steps including progenitor survival, differentiation to mono-nuclear pre-osteoclasts, fusion to multi nuclear mature osteoclasts, and activation to bone resorbing osteoclasts. The regulation of osteoclastogenesis has been extensively studied, in which the receptor activator of NF-kappaB ligand (RANKL)-mediated signaling pathway and downstream transcription factors play essential roles. However, less is known about osteoclast fusion, which is a property of mature osteoclasts and is required for osteoclasts to resorb bone. Several proteins that affect cell fusion have been identified. Among them, dendritic cell-specific transmembrane protein (DC-STAMP) is directly associated to osteoclast fusion in vivo. Cytokines and factors influence osteoclast fusion through regulation of DC-STAMP. Here we review the recently discovered new factors that regulate osteoclast fusion with specific focus on DC-STAMP. A better understanding of the mechanistic basis of osteoclast fusion will lead to the development of a new therapeutic strategy for bone disorders due to elevated osteoclast bone resorption. Cell-cell fusion is essential for a variety of cellular biological processes. In mammals, there is a limited number of cell types that fuse to form multinucleated cells, such as the fusion of myoblasts for the formation of skeletal muscle and the fusion of cells of the monocyte/macrophage lineage for the formation of multinucleated osteoclasts and giant cells. In most cases, cell-cell fusion is beneficial for cells by enhancing function. Myoblast fusion increases myofiber size and diameter and thereby increases contractile strength. Multinucleated osteoclasts have far more bone resorbing activity than their mono-nuclear counterparts. Multinucleated giant cells are much more efficient in the removal of implanted materials and bacteria due to chronic infection than macrophages. Therefore, they are also called foreign-body giant cells. Cell fusion is a complicated process involving cell migration, chemotaxis, cell-cell recognition and attachment, as well as changes into a fusion-competent status. All of these steps are regulated by multiple factors. In this review, we will discuss osteoclast fusion and regulation. PMID- 23362467 TI - Do osteoporosis-related vertebral fractures precede hip fractures? AB - AIM: To evaluate the relationship between a vertebral fracture and a hip fracture in Saudi Arabians with osteoporosis. METHODS: In this retrospective study, 154 Saudi Arabian patients with osteoporosis-related hip fractures were analyzed for the presence of a vertebral fracture. Radiographs were retrieved from the IPAC (Image Picture Archiving and Computing) System, an imaging retrieval system, and were reviewed independently by two of the authors, Abid Hussain Gullenpet, and Mir Sadat-Ali, and later reviewed jointly. Patients admitted with proximal hip fracture who were >= 50 years and had undergone Thoraco-lumber imaging and a dual energy X-ray absorptiometry (DEXA) scan were included in the study. Patients with a history of significant trauma to the spine and those with a malignancy or connective tissue disorder were excluded from the analysis. RESULTS: Out of 154 patients with hip fractures, 78 had a fracture of the femoral neck while 76 had an intertrochanteric hip fracture. Of the 111 patients who were finally included in the study, after applying inclusion and exclusion criteria, 76 patients with an average age of 67.28 +/- 12 years had no fractures of the spine. Thirty-five patients with an average age of 76.9 +/- 14.5 years (31.53%) had a total of 49 vertebral fractures. Patients with vertebral fractures were significantly older than those without fractures P < 0.001. Overall, 24.7% of these patients had an asymptomatic vertebral fracture. Further analysis showed that 11 males (18.96%) and 24 females (45.28%) had suffered a previous asymptomatic vertebral fracture. Interestingly, all women who participated in this study and who presented with a femoral neck fracture had experienced a prior asymptomatic vertebral fracture. CONCLUSION: We recommend that all elderly patients who go to the radiology department for a chest X-ray also have a DEXA scan and a lateral thoracic spine radiograph. PMID- 23362466 TI - Male osteoporosis: A review. AB - Osteoporosis in men is a heterogeneous disease that has received little attention. However, one third of worldwide hip fractures occur in the male population. This problem is more prevalent in people over 70 years of age. The etiology can be idiopathic or secondary to hypogonadism, vitamin D deficiency and inadequate calcium intake, hormonal treatments for prostate cancer, use of toxic and every disease or drug use that alters bone metabolism.Risk factors such as a previous history of fragility fracture should be assessed for the diagnosis. However, risk factors in men are very heterogeneous. There are significant differences in the pharmacological treatment of osteoporosis between men and women fundamentally due to the level of evidence in published trials supporting each treatment. New treatments will offer new therapeutic prospects. The goal of this work is a revision of the present status knowledge about male osteoporosis. PMID- 23362469 TI - Femoral impaction grafting. AB - Femoral impaction grafting is a reconstruction option applicable to both simple and complex femoral component revisions. It is one of the preferred techniques for reconstructing large femoral defects when the isthmus is non-supportive. The available level of evidence is primarily derived from case series, which shows a mean survivorship of 90.5%, with revision or re-operation as the end-point, with an average follow-up of 11 years. The rate of femoral fracture requiring re operation or revision of the component varies between several large case series, ranging from 2.5% to 9%, with an average of 5.4%. PMID- 23362468 TI - Regulation of bone destruction in rheumatoid arthritis through RANKL-RANK pathways. AB - Recent studies have demonstrated that osteoclasts, the primary cells responsible for bone resorption, are mainly involved in bone and joint destruction in rheumatoid arthritis (RA) patients. Recent progress in bone cell biology has revealed the molecular mechanism of osteoclast differentiation and bone resorption by mature osteoclasts. We highlight here the potential role of the receptor activator of nuclear factor kappaB ligand (RANKL)-RANK pathways in bone destruction in RA and review recent clinical trials treating RA by targeting RANKL. PMID- 23362470 TI - Anterior muscle sparing approach for total hip arthroplasty. AB - The purpose of this review is to examine the validity of positive claims regarding the direct anterior approach (DAA) with a fracture table for total hip arthroplasty. Recent literature regarding the DAA was searched and specific claims investigated including improved early outcomes, speed of recovery, component placement, dislocation rates, and complication rates. Recent literature is positive regarding the effects of total hip arthroplasty with the anterior approach. While the data is not definitive at present, patients receiving the anterior approach for total hip arthroplasty tend to recover more quickly and have improved early outcomes. Component placement with the anterior approach is more often in the "safe zone" than with other approaches. Dislocation rates tend to be less than 1% with the anterior approach. Complication rates vary widely in the published literature. A possible explanation is that the variance is due to surgeon and institutional experience with the anterior approach procedure. Concerns remain regarding the "learning curve" for both surgeons and institutions. In conclusion, it is not a matter of should this approach be used, but how should it be implemented. PMID- 23362471 TI - Access related complications during anterior exposure of the lumbar spine. AB - The new millennium has witnessed the emergence of minimally invasive, non posterior based surgery of the lumbar spine, in particular via lateral based methodologies to discectomy and fusion. In contrast, and perhaps for a variety of reasons, anterior motion preservation (non-fusion) technologies are playing a comparatively lesser, though incompletely defined, role at present. Lateral based motion preservation technologies await definition of their eventual role in the armamentarium of minimally invasive surgical therapies of the lumbar spine. While injury to the major vascular structures remains the most serious and feared complication of the anterior approach, this occurrence has been nearly eliminated by the use of lateral based approaches for discectomy and fusion cephalad to L5 S1. Whether anterior or lateral based, non-posterior approaches to the lumbar spine share certain access related pitfalls and complications, including damage to the urologic and neurologic structures, as well as gastrointestinal and abdominal wall issues. This review will focus on the recognition, management and prevention of these anterior and lateral access related complications. PMID- 23362473 TI - Appreciating the art and science of plastic and reconstructive surgery: a year in review. PMID- 23362472 TI - Finger movement at birth in brachial plexus birth palsy. AB - AIM: To investigate whether the finger movement at birth is a better predictor of the brachial plexus birth injury. METHODS: We conducted a retrospective study reviewing pre-surgical records of 87 patients with residual obstetric brachial plexus palsy in study 1. Posterior subluxation of the humeral head (PHHA), and glenoid retroversion were measured from computed tomography or Magnetic resonance imaging, and correlated with the finger movement at birth. The study 2 consisted of 141 obstetric brachial plexus injury patients, who underwent primary surgeries and/or secondary surgery at the Texas Nerve and Paralysis Institute. Information regarding finger movement was obtained from the patient's parent or guardian during the initial evaluation. RESULTS: Among 87 patients, 9 (10.3%) patients who lacked finger movement at birth had a PHHA > 40%, and glenoid retroversion < -12 degrees , whereas only 1 patient (1.1%) with finger movement had a PHHA > 40%, and retroversion < -8 degrees in study 1. The improvement in glenohumeral deformity (PHHA, 31.8% +/- 14.3%; and glenoid retroversion 22.0 degrees +/- 15.0 degrees ) was significantly higher in patients, who have not had any primary surgeries and had finger movement at birth (group 1), when compared to those patients, who had primary surgeries (nerve and muscle surgeries), and lacked finger movement at birth (group 2), (PHHA 10.7% +/- 15.8%; Version -8.0 degrees +/- 8.4 degrees , P = 0.005 and P = 0.030, respectively) in study 2. No finger movement at birth was observed in 55% of the patients in this study group. CONCLUSION: Posterior subluxation and glenoid retroversion measurements indicated significantly severe shoulder deformities in children with finger movement at birth, in comparison with those lacked finger movement. However, the improvement after triangle tilt surgery was higher in patients who had finger movement at birth. PMID- 23362474 TI - Autologous microvascular breast reconstruction. AB - Autologous microvascular breast reconstruction is widely accepted as a key component of breast cancer treatment. There are two basic donor sites; the anterior abdominal wall and the thigh/buttock region. Each of these regions provides for a number of flaps that are successfully utilised in breast reconstruction. Refinement of surgical technique and the drive towards minimising donor site morbidity whilst maximising flap vascularity in breast reconstruction has seen an evolution towards perforator based flap reconstructions, however myocutaneous flaps are still commonly practiced. We review herein the current methods of autologous microvascular breast reconstruction. PMID- 23362475 TI - Evaluation of an amniotic membrane-collagen dermal substitute in the management of full-thickness skin defects in a pig. AB - BACKGROUND: To minimize the inflammatory reaction and improve healing, a new modified dermal substitute composed of an atelocollagen, chondroitin-6-sulfate, and amniotic membrane (AM) was applied to full-thickness skin defects in a pig. Atelocollagen was extracted from bovine skin, and two modified dermal substitutes were generated according to the cross-linking type. METHODS: The AM-collagen dermal substitutes were characterized and compared with currently used dermal substitutes in a pig skin defect model. There were five experimental groups: dehydrothermal (DHT) cross-linking atelocollagen with the AM on the top (AM-DHT), DHT and chemical cross-linking atelocollagen with the AM on the top (AM DHT/chemical), Terudermis, Integra, and AlloDerm. After 3*3 cm full-thickness skin defects on the back of a pig were created, each dermal substitutes dermal substitutes was randomly grafted on the defects. Two weeks after grafting, autologous partial-thickness skin was over-grafted on the neodermis. The take rate of the dermal substitutes, skin, and histological sections were all assessed at 1, 2, and 4 weeks postoperatively. RESULTS: More rapid healing and a higher take rate were evident in the AM-DHT and Terudermis groups. Histological examination revealed fewer inflammatory cells and more fibroblast hyperplasia in these two groups. Four weeks after surgery, the amount of newly formed collagen was significantly more appropriate in the AM-DHT group. CONCLUSIONS: These observations provide supporting evidence that a newly developed amniotic-collagen dermal substitute may inhibit inflammatory reactions and promote wound healing. PMID- 23362476 TI - Human Acellular Dermis versus Submuscular Tissue Expander Breast Reconstruction: A Multivariate Analysis of Short-Term Complications. AB - BACKGROUND: Acellular dermal matrix (ADM) allografts and their putative benefits have been increasingly described in prosthesis based breast reconstruction. There have been a myriad of analyses outlining ADM complication profiles, but few large scale, multi-institutional studies exploring these outcomes. In this study, complication rates of acellular dermis-assisted tissue expander breast reconstruction were compared with traditional submuscular methods by evaluation of the American College of Surgeon's National Surgical Quality Improvement Program (NSQIP) registry. METHODS: Patients who underwent immediate tissue expander breast reconstruction from 2006-2010 were identified using surgical procedure codes. Two hundred forty tracked variables from over 250 participating sites were extracted for patients undergoing acellular dermis-assisted versus submuscular tissue expander reconstruction. Thirty-day postoperative outcomes and captured risk factors for complications were compared between the two groups. RESULTS: A total of 9,159 patients underwent tissue expander breast reconstruction; 1,717 using acellular dermis and 7,442 with submuscular expander placement. Total complications and reconstruction related complications were similar in both cohorts (5.5% vs. 5.3%, P=0.68 and 4.7% vs. 4.3%, P=0.39, respectively). Multivariate logistic regression revealed body mass index and smoking as independent risk factors for reconstructive complications in both cohorts (P<0.01). CONCLUSIONS: The NSQIP database provides large-scale, multi institutional, independent outcomes for acellular dermis and submuscular breast reconstruction. Both thirty-day complication profiles and risk factors for post operative morbidity are similar between these two reconstructive approaches. PMID- 23362477 TI - Reconstruction of abdominal wall of a chronically infected postoperative wound with a rectus abdominis myofascial splitting flap. AB - BACKGROUND: If a chronically infected abdominal wound develops, complications such as peritonitis and an abdominal wall defect could occur. This could prolong the patient's hospital stay and increase the possibility of re-operation or another infection as well. For this reason, a solution for infection control is necessary. In this study, surgery using a rectus abdominis muscle myofascial splitting flap was performed on an abdominal wall defect. METHODS: From 2009 to 2012, 5 patients who underwent surgery due to ovarian rupture, cesarean section, or uterine myoma were chosen. In each case, during the first week after operation, the wound showed signs of infection. Surgery was chosen because the wounds did not resolve with dressing. Debridement was performed along the previous operation wound and dissection of the skin was performed to separate the skin and subcutaneous tissue from the attenuated rectus muscle and Scarpa's fascial layers. Once the anterior rectus sheath and muscle were adequately mobilized, the fascia and muscle flap were advanced medially so that the skin defect could be covered for reconstruction. RESULTS: Upon 3-week follow-up after a rectus abdominis myofascial splitting flap operation, no major complication occurred. In addition, all of the patients showed satisfaction in terms of function and esthetics at 3 to 6 months post-surgery. CONCLUSIONS: Using a rectus abdominis myofascial splitting flap has many esthetic and functional benefits over previous methods of abdominal defect treatment, and notably, it enabled infection control by reconstruction using muscle. PMID- 23362478 TI - Lower lip reconstruction after wide excision of a malignancy with barrel-shaped excision or the webster modification of the bernard operation. AB - BACKGROUND: Because there are numerous methods for reconstruction of the lower lip, it is not easy to choose the optimal method. In choosing the surgical method for lower lip reconstruction, we obtained acceptable outcomes based on our treatment strategy, which included either a barrel-shaped excision or the Webster modification of the Bernard operation. We report on the surgical outcomes based on our treatment strategy. METHODS: This study included 26 patients who underwent lower lip reconstructive surgery from September 1996 to September 2010. The operation was done using either a barrel-shaped excision or the Webster modification, considering the location of the defect, the size of the defect, and the amount of residual tissue on the lateral side of the vermilion after excision. RESULTS: In our series, 3 patients underwent a single barrel-shaped excision, and nine patients underwent a double barrel-shaped excision. In addition, the unilateral Webster modification was performed on in 6 patients, and there were eight cases of bilateral Webster modification. All of the patients except one were satisfied with the postoperative shape of the lip. In one case both recurrence and dehiscence occurred. One patient had a good postoperative lip shape, but had difficulty wearing a denture, and also underwent commissuroplasty. Furthermore, there were two patients who complained of drooling, and 4 with paresthesia. CONCLUSIONS: A SOFT TISSUE DEFECT RESULTING FROM WIDE EXCISION OF A LOWER LIP MALIGNANCY CAN BE SUCCESSFULLY RECONSTRUCTED USING ONLY ONE OF TWO SURGICAL METHODS: the barrel-shaped excision or the Webster modification of the Bernard operation. PMID- 23362479 TI - Indications, outcomes, and complications of pedicled propeller perforator flaps for upper body defects: a systematic review. AB - BACKGROUND: The aim of this investigation was to systematically review the current literature to provide the best data for indications, outcomes, survival, and complication rates of pedicled propeller perforator flaps for upper body defects. METHODS: A comprehensive literature review for articles published from January 1991 to December 2011 was performed using the PubMed, Medline, and Cochrane Databases. Articles without available full-text, single case reports or papers with excessive missing data were excluded. Papers reporting pedicle perforator (propeller) flaps used for lower extremity reconstruction were excluded from meta-analysis. RESULTS: From the initial 1,736 studies our search yielded, 343 studies qualified for the second stage of selection. Of 117 full text reports screened, 41 studies, met the definitive inclusion and exclusion criteria. Of the selected 41 articles, 26 were case series, original papers or retrospective reviews and were included, whereas 15 were case report papers and therefore were excluded. Two hundred ninety-five propeller flaps were reported to have been used in a total of 283 patients. Indications include repair of trauma induced injuries, post-trauma revision surgery, cancer resection, chronic infection, pressure sores, and chronic ulcers with a major complication rate (3.3%) comparable to that of free flaps. No specific exclusion criteria for the procedure were presented in the studies reviewed. CONCLUSIONS: Pedicled propeller flaps are a versatile and safe reconstructive option that are easy and quick to raise and that provide unlimited clinical solutions because of the theoretical possibility of harvesting them based on any perforator chosen among those classified in the body. PMID- 23362480 TI - Normative measurements of grip and pinch strengths of 21st century korean population. AB - BACKGROUND: Measuring grip and pinch strength is an important part of hand injury evaluation. Currently, there are no standardized values of normal grip and pinch strength among the Korean population, and lack of such data prevents objective evaluation of post-surgical recovery in strength. This study was designed to establish the normal values of grip and pinch strength among the healthy Korean population and to identify any dependent variables affecting grip and pinch strength. METHODS: A cross-sectional study was carried out. The inclusion criterion was being a healthy Korean person without a previous history of hand trauma. The grip strength was measured using a Jamar dynamometer. Pulp and key pinch strength were measured with a hydraulic pinch gauge. Intra-individual and inter-individual variations in these variables were analyzed in a standardized statistical manner. RESULTS: There were a total of 336 healthy participants between 13 and 77 years of age. As would be expected in any given population, the mean grip and pinch strength was greater in the right hand than the left. Male participants (137) showed mean strengths greater than female participants (199) when adjusted for age. Among the male participants, anthropometric variables correlated positively with grip strength, but no such correlations were identifiable in female participants in a statistically significant way. CONCLUSIONS: Objective measurements of hand strength are an important component of hand injury evaluation, and population-specific normative data are essential for clinical and research purposes. This study reports updated normative hand strengths of the South Korean population in the 21st century. PMID- 23362481 TI - Radiofrequency ablation and excision of multiple cutaneous lesions in neurofibromatosis type 1. AB - BACKGROUND: Von Recklinghausen disease or neurofibromatosis type 1 is an autosomal dominant genetic disorder of chromosome 17q11.2. The most common characteristic findings of NF 1 include multiple and recurrent cutaneous neurofibromas associated with psychosocial distress. METHODS: Sixteen patients (9 female, 7 male; average age, 31 years; range, 16 to 67 years) with multiple cutaneous neurofibromas between March 2010 and February 2012 were included in the study. All patients were treated with radiosurgical ablation and excision under general anesthesia. RESULTS: All 16 patients were satisfied with the results, when questioned directly during the outpatient department follow-up. The only complaint from a few patients was minimal scarring, but acceptable results were obtained in the end. CONCLUSIONS: The radiofrequency procedure is almost bloodless and quick, creating a smaller necrotizing zone. Therefore, instead of employing the time consuming traditional surgery, such as laser therapy and electrosurgical excision, that produces uncertain results and can affect normal adjacent tissue, treatment of neurofibromas with radiofrequency ablation and excision can be an alternative choice of treatment for patients with a large number of neurofibromas. PMID- 23362482 TI - A new method for creating a definite philtrum by the flipping of an orbicularis oris muscle flap in a patient with an indistinct philtrum. AB - The philtrum plays a key role in the appearance of the upper lip and nostril sill. Therefore, construction of the philtrum is crucial for attaining a natural appearance of the upper lip. We used a flipping myoplasty of the orbicularis oris muscle on a patient with a flat philtrum in order to effectively reconstruct the philtral dimple and column. A 35-year-old female presented to our department with the complaint of a flat upper lip. A superficial layer of the orbicularis oris muscle on the median aspect of the upper lip was vertically incised and elevated to a thickness of 2 mm. Both sides of the elevated muscle flap were then folded to the lateral sides so that the border could be sutured onto the outer portion of the orbicularis oris muscle. The patient was observed for one year postoperatively. Her philtrum deepened by 1.25 mm, with the central angle of her Cupid's bow improving from a preoperative measurement of 146 degrees to 128 degrees postoperatively. In a patient with an indistinct philtrum, a flipping orbicularis oris myoplasty was performed to attain a definite philtral column and a philtral dimple. Natural upper lip movement was maintained, and an aesthetically and functionally satisfactory reconstruction was achieved. PMID- 23362483 TI - Postoperative monitoring following jaw surgery is essential. PMID- 23362484 TI - Angioleiomyoma of the auricle. PMID- 23362485 TI - Recurrent Auricular Keloids during Pregnancy. PMID- 23362486 TI - Reconstruction of a perineoscrotal defect using bilateral medial thigh fasciocutaneous flaps. PMID- 23362487 TI - Single-Stage Reconstruction of Extensive Defects after Fournier's Gangrene with an Exposed Iliac Crest and Testes. PMID- 23362488 TI - Reconstruction of Unexpected Huge Chest Wall Defect after Recurrent Breast Cancer Excision Using a TRAM Flap Combined with Partial Latissimus Dorsi Muscle Flap. PMID- 23362490 TI - Hungry for glory: team Korea in the world medical football Federation championships. PMID- 23362489 TI - Anomalous extensor indicis proprius muscle. PMID- 23362491 TI - Enzalutamide for the treatment of castration-resistant prostate cancer. AB - Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, given the mechanistic heterogeneity due to a complex signal transduction network. Enzalutamide (MDV-3100), recently approved by the U.S. Food and Drug Administration (FDA) at a dose of 160 mg/day for the treatment of CRPC, blocks androgen signaling by directly binding to the androgen receptor (AR) and inhibiting nuclear translocation and coactivator recruitment of the ligand receptor complex. In preclinical studies, enzalutamide has been shown to block the binding of AR to DNA, resulting in apoptosis and retardation of tumor growth. Clinically, a phase I/II study (N = 140) revealed that enzalutamide had an optimal safety profile and significant antitumor activity in patients with CRPC regardless of prior chemotherapy. In the AFFIRM phase III trial (N = 1,199), oral enzalutamide significantly improved survival in men with metastatic CRPC after chemotherapy. Currently, a phase III trial (PREVAIL) is under way to determine the effectiveness of enzalutamide in patients who have not received prior docetaxel chemotherapy. PMID- 23362492 TI - Ingenol mebutate: a new option for actinic keratosis treatment. AB - Actinic keratosis, one of the most common dermatological pathologies manifests as ultraviolet- or sun-induced macules, papules or plaques, and is considered a biomarker for the risk of skin cancer. Ingenol mebutate (Picato(r)), extracted from the sap of the Euphorbia peplus plant, is a small molecule with a unique mechanism of action involving direct cytotoxicity and immune stimulation. In 2012, ingenol mebutate was approved by the FDA and the EMA for the treatment of actinic keratosis. In phase III trials, ingenol mebutate gel applied topically once daily at 0.015% for 3 days or 0.05% for 2 days, respectively, significantly reduced head and non-head actinic keratosis lesions. Adverse events were mostly mild or moderate. Local skin responses elicited by the treatment, i.e., erythema, flaking/scaling and crusting, were transient, and resolved spontaneously without sequelae. Adherence to the therapy can be facilitated by the short duration of the treatment. PMID- 23362493 TI - Perampanel: a novel antiepileptic for the adjunctive treatment of refractory partial onset seizures. AB - Perampanel is a selective noncompetitive AMPA-type glutamate receptor antagonist which has demonstrated anticonvulsant activity in experimental seizure models and antiepileptic activity in clinical trials. Perampanel has a long mean elimination half-life of 105 hours but this may be reduced in the presence of enzyme-inducing antiepileptic drugs. Adjunctive use of perampanel at 4-12 mg/day in refractory partial-onset seizures reduced seizures by 23-34% in short-term, double-blind, placebo-controlled trials. These reductions were maintained long-term in open label extension studies lasting up to 4 years. Dizziness, somnolence and headache were the most common treatment-emergent adverse events; discontinuation rates due to adverse events approximated 13% in long-term studies. Perampanel's efficacy and tolerability outcomes are broadly comparable with other agents licensed for adjunctive use in refractory partial onset seizures. PMID- 23362494 TI - 2012 in review - part I: the year's new drugs & biologics. AB - Thirty-seven new launches are considered in the first part of this annual review article, including 36 drugs and biologics that reached their first markets worldwide in 2012 and one additional drug that was launched at the end of December 2011. In addition, 26 significant new line extensions (new indications, new formulations and new combinations of existing drugs) that were launched for the first time in 2012 are discussed in this review. Also included are new drugs and biologics and new line extensions that were approved for the first time between January and December 2012, although they were not launched before the end of the year. PMID- 23362495 TI - A report from the American Heart Association Scientific Sessions 2012 (November 3 7 - Los Angeles, California, USA). AB - Highly impacting oral and poster presentations wherein new treatment modalities for coronary artery disease, heart failure and other common cardiovascular diseases were presented throughout the AHA Scientific Sessions 2012, including new developments in the area of lipid-modifying therapies that starred one of the high-impact late-breaking clinical trial sessions during the conference. A summary of the most relevant findings among the over 4,000 abstracts presented during the meeting are reported in the following report. PMID- 23362496 TI - Neural correlates of deficits in pain-related affective meaning construction in patients with chronic pain disorder. AB - OBJECTIVE: Psychological and neural mechanisms of the affective dimension of pain are known to be disturbed in patients with chronic pain disorder. The aim of this functional magnetic resonance imaging study was to assess the neurofunctional and behavioral measures underlying the ability to construct pain-related affective meaning in a painful situation by comparing 21 clinically and psychometrically well-characterized patients with persistent non-nociceptive somatoform pain with 19 healthy controls. METHODS: The functional magnetic resonance imaging task involved viewing pictures depicting human hands and feet in different painful and nonpainful situations. Participants were asked to estimate the perceived pain intensity. These data were correlated with behavioral measures of depression, alexithymia, and general cognitive and emotional empathy. RESULTS: In a hypothesis-driven region-of-interest analysis, the healthy control group exhibited greater activation of the left perigenual anterior cingulate cortex than patients with pain (Montreal Neurological Institute coordinates (x y z)=-8 38 0; cluster extent=54 voxels; T=4.28; p=.006 corrected for multiple comparisons at cluster level). No group differences in the activation of the anterior insular cortex were found. Scores on self-assessment instruments (Beck Depression Inventory I, Interpersonal Reactivity Index, and 20-item Toronto Alexithymia Scale) did not influence neuroimaging results. CONCLUSIONS: Our results suggest that patients with chronic medically unexplained pain have an altered neural pain perception process owing to decreased activation of empathetic-affective networks, which we interpret as a deficit in pain-related affective meaning construction. These findings may lead to a more specific and detailed neurobiological understanding of the clinical impression of disturbed affect in patients with chronic pain disorder. PMID- 23362497 TI - Effects of vitamin and mineral supplementation on stress, mild psychiatric symptoms, and mood in nonclinical samples: a meta-analysis. AB - OBJECTIVE: Biochemical processes in the brain affect mood. Minor dietary inadequacies, which are responsible for a small decline in an enzyme's efficiency, could cumulatively influence mood states. When diet does not provide an optimal intake of micronutrients, supplementation is expected to benefit mood. This meta-analysis evaluated the influence of diet supplementation on mood in nonclinical samples. METHODS: Databases were evaluated and studies were included if they considered aspects of stress, mild psychiatric symptoms, or mood in the general population; were randomized and placebo-controlled; evaluated the influence of multivitamin/mineral supplements for at least 28 days. Eight studies that met the inclusion criteria were integrated using meta-analysis. RESULTS: Supplementation reduced the levels of perceived stress (standard mean difference [SMD]=0.35; 95% confidence interval [CI]=0.47-0.22; p=.001), mild psychiatric symptoms (SMD=0.30; 95% CI=0.43-0.18; p=.001), and anxiety (SMD=0.32; 95% CI=0.48 0.16; p<.001), but not depression (SMD=0.20; 95% CI=0.42-0.030; p<.089). Fatigue (SMD=0.27; 95% CI=0.40-0.146; p<.001) and confusion (SMD=0.225; 95% CI=0.38-0.07; p<.003) were also reduced. CONCLUSIONS: Micronutrient supplementation has a beneficial effect on perceived stress, mild psychiatric symptoms, and aspects of everyday mood in apparently healthy individuals. Supplements containing high doses of B vitamins may be more effective in improving mood states. Questions about optimal levels of micronutrient intake, optimal doses, and active ingredients arise. PMID- 23362498 TI - Bone density characteristics and major depressive disorder in adolescents. AB - OBJECTIVE: Major depressive disorder (MDD) is common during adolescence, a period characterized by rapid bone mineral accrual. MDD has recently been associated with lower bone mineral density (BMD) in adults. Our objective was to determine whether MDD is associated with BMD, bone turnover markers, vitamin D, and gonadal steroids in adolescents. METHODS: Sixty-five adolescents 12 to 18 years of age (32 boys: 16 with MDD and 16 controls; 33 girls: 17 with MDD and 16 controls) were included in a cross-sectional study. BMD and body composition were obtained by dual-energy x-ray absorptiometry. Estradiol, testosterone, 25-hydroxy vitamin D levels, N-terminal propeptide of Type 1 procollagen (a marker of bone formation), and Type I collagen C-telopeptide (a marker of bone resorption) were measured. RESULTS: Boys with MDD had a significantly lower BMD at the hip (mean [standard deviation]=0.99 [0.17] g/cm2 versus 1.04 [0.18] g/cm2, body mass index [BMI] adjusted, p=.005) and femoral neck (0.92 [0.17] g/cm2 versus 0.94 [0.17] g/cm2; BMI adjusted, p=.024) compared with healthy controls after adjusting for BMI. This significant finding was maintained after also adjusting for lean mass and bone age (hip: p=.007; femoral neck: p=.020). In girls, there were no significant differences in BMD between the girls with MDD and the controls after adjusting for BMI (p>.17). CONCLUSIONS: Male adolescents with MDD have a significantly lower BMD as compared with healthy controls after adjusting for body mass and maturity. This association is not observed in girls. PMID- 23362499 TI - Reaction time as a predictor of mortality: the Radiation Effects Research Foundation Adult Health Study. AB - OBJECTIVE: We investigated the association between reaction time (RT) and mortality in middle-aged and older atomic bomb survivors and their unexposed controls over a period of 30 years. METHODS: During 1970-72, 4912 participants of the Adult Health Study cohort in Hiroshima, Japan, underwent biologic tests including RT. Mortality was followed to the end of 2003. RESULTS: In a multivariate-adjusted model, the hazard ratio (HR) for 1-standard deviation increments of RT was 1.08 (95% confidence interval [CI]=1.03-1.13) for men, 1.22 (95% CI=1.16-1.28) for women, and 1.13 (95% CI=1.09-1.16) for all. When the analysis was performed by sex, age, and follow-up period, a consistent increase of mortality with increments of RT was observed. The HR for mortality for the highest RT quintile was higher than that of the lowest quintile in all sex-age groups. A significant positive association between mortality risk and RT was observed even after 20 years of follow-up (p=.03 in men, p<.001 in women). RT and radiation dose were risk factors for mortality independent of conventional risk factors such as smoking, high blood pressure, and diabetes mellitus. Interaction between RT and radiation dose had no significant effect on mortality in men. Although increased radiation dose reduced the HR for mortality per RT increment in women, RT and radiation dose were still significant predictors of mortality. CONCLUSIONS: RT is a consistently strong predictor of mortality. Although mortality risk increased with radiation dose, radiation did not accelerate the relationship between RT and mortality. PMID- 23362500 TI - Sexual orientation and disclosure in relation to psychiatric symptoms, diurnal cortisol, and allostatic load. AB - OBJECTIVES: Lesbian, gay, and bisexual (LGB) individuals-particularly those who have not disclosed their sexual orientation-are believed to experience increased chronic stress in comparison with heterosexuals. This interdisciplinary study assessed whether psychiatric symptoms (self-rated anxiety, depression, and burnout), stress hormone profiles (diurnal cortisol), and physiological dysregulations (allostatic load [AL]) would differ for a) LGBs versus heterosexuals and b) disclosed LGBs versus nondisclosed LGBs. METHODS: The study included 87 healthy participants (mean [SD] age=24.6 [0.6] years; LGB n=46, 43% women; and heterosexual n=41, 49% women). Diurnal cortisol sampled at five time points was averaged for 2 days. AL indices were based on an algorithm incorporating 21 biomarkers representing neuroendocrine, immune/inflammatory, metabolic, and cardiovascular functioning. Psychological measures were assessed with well-validated questionnaires. RESULTS: Between-group results revealed no significant differences in symptoms of anxiety and burnout, nor among diurnal cortisol levels between sexual orientations. By contrast, gay/bisexual men unexpectedly had lower depressive symptoms (p=.003) and AL levels (p=.043) compared with heterosexual men. Within-group results revealed that disclosed LGBs had fewer psychiatric symptoms (p values<0.01) and lower cortisol levels +30 minutes upon awakening (p=.004) compared with nondisclosed LGBs. Disclosure was not significantly related to AL levels. CONCLUSIONS: LGBs did not manifest more stress-related problems than did heterosexuals. Life transitions like disclosing to one's family and friends may be protective against psychopathologies and hyperactive cortisol awakening responses. Our novel findings underline the roles disclosure processes have on positive health and well-being for sexual minorities. PMID- 23362502 TI - Demanding attention: reconsidering the role of attention control groups in behavioral intervention research. AB - Attention control groups play an important but controversial role in randomized controlled trials of behavioral interventions. The study by Pagoto et al. in this issue of Psychosomatic Medicine provides an informative example of some of the problems that attention control conditions can create in psychosomatic and behavioral medicine trials. This article discusses the reasons why these problems occur and provides some practical solutions. It also explains why controlling for attention is unnecessary and counterproductive in some behavioral trials. PMID- 23362501 TI - Social isolation and loneliness: relationships with cognitive function during 4 years of follow-up in the English Longitudinal Study of Ageing. AB - OBJECTIVE: This study aims to evaluate the impact of social isolation and loneliness, individually and simultaneously, on cognitive function in older adults during a 4-year period, using data from the English Longitudinal Study of Ageing, and to evaluate if these associations are moderated by educational level. METHODS: Data on social isolation, loneliness, and cognitive function (verbal fluency, immediate recall, and delayed recall) were obtained at baseline. Follow up measures on cognitive function were obtained 4 years later for 6034 participants (mean age at baseline=65.6 years). Regression analyses were used to evaluate the association between baseline isolation, loneliness, and cognitive function at follow-up. Interactions between social isolation, loneliness, and educational level were also evaluated. RESULTS: Baseline isolation was significantly associated with decreases in all cognitive function measures at follow-up (beta=-.05 to -.03, p<.001), independently of baseline scores, whereas loneliness was associated with poorer immediate recall (beta=-.05, p<.001) and delayed recall (beta=-.03, p=.02). There was a significant interaction between educational level and both isolation (p=.02) and loneliness (p=.01) for delayed recall, such that isolation and loneliness were associated with poorer recall only among those with low levels of education. CONCLUSIONS: Loneliness and isolation are associated with poorer cognitive function among older adults. Interventions to foster social connections may be particularly beneficial for individuals with low levels of education. PMID- 23362503 TI - Prenatal stress and risk of spontaneous abortion. AB - OBJECTIVE: The aim of this study was to evaluate the association between exposure to life-threatening rocket attacks and spontaneous abortions (SAs). STUDY DESIGN: This is a historical cohort study comparing 1345 pregnancies of female residents of a town exposed to rocket attacks with 2143 pregnancies of female residents of an unexposed town. Demographic and medical data were obtained from hospital records and exposure information from official local databases. Intensity of exposure was calculated for preconception and pregnancy periods. RESULTS: Compared with unexposed group, women in the exposed group had higher rates of SA (6.9% versus 4.7%, adjusted odds ratio = 1.59, 95% confidence interval = 1.17 2.2, p = .003). Intensity of preconception and pregnancy exposure were nonlinearly associated with SA risk; both the highest and the lowest quintiles of exposure were associated with increased risk of SA. CONCLUSIONS: Stress during preconception and pregnancy was associated with increased risk of SA. PMID- 23362504 TI - Process evaluation of a tailored multifaceted feedback program to improve the quality of intensive care by using quality indicators. AB - BACKGROUND: In multisite trials evaluating a complex quality improvement (QI) strategy the 'same' intervention may be implemented and adopted in different ways. Therefore, in this study we investigated the exposure to and experiences with a multifaceted intervention aimed at improving the quality of intensive care, and explore potential explanations for why the intervention was effective or not. METHODS: We conducted a process evaluation investigating the effect of a multifaceted improvement intervention including establishment of a local multidisciplinary QI team, educational outreach visits and periodical indicator feedback on performance measures such as intensive care unit length of stay, mechanical ventilation duration and glucose regulation. Data were collected among participants receiving the intervention. We used standardised forms to record time investment and a questionnaire and focus group to collect data on perceived barriers and satisfaction. RESULTS: The monthly time invested per QI team member ranged from 0.6 to 8.1 h. Persistent problems were: not sharing feedback with other staff; lack of normative standards and benchmarks; inadequate case-mix adjustment; lack of knowledge on how to apply the intervention for QI; and insufficient allocated time and staff. The intervention effectively targeted the lack of trust in data quality, and was reported to motivate participants to use indicators for QI activities. CONCLUSIONS: Time and resource constraints, difficulties to translate feedback into effective actions and insufficient involvement of other staff members hampered the impact of the intervention. However, our study suggests that a multifaceted feedback program stimulates clinicians to use indicators as input for QI, and is a promising first step to integrating systematic QI in daily care. PMID- 23362505 TI - Matching identifiers in electronic health records: implications for duplicate records and patient safety. AB - OBJECTIVE: To quantify the percentage of records with matching identifiers as an indicator for duplicate or potentially duplicate patient records in electronic health records in five different healthcare organisations, describe the patient safety issues that may arise, and present solutions for managing duplicate records or records with matching identifiers. METHODS: For each institution, we retrieved deidentified counts of records with an exact match of patient first and last names and dates of birth and determined the number of patient records existing for the top 250 most frequently occurring first and last name pairs. We also identified methods for managing duplicate records or records with matching identifiers, reporting the adoption rate of each across institutions. RESULTS: The occurrence of matching first and last name in two or more individuals ranged from 16.49% to 40.66% of records; inclusion of date of birth reduced the rates to range from 0.16% to 15.47%. The number of records existing for the most frequently occurring name at each site ranged from 41 to 2552. Institutions varied widely in the methods they implemented for preventing, detecting and removing duplicate records, and mitigating resulting errors. CONCLUSIONS: The percentage of records having matching patient identifiers is high in several organisations, indicating that the rate of duplicate records or records may also be high. Further efforts are necessary to improve management of duplicate records or records with matching identifiers and minimise the risk for patient harm. PMID- 23362506 TI - Identifying attributes required by Foundation Year 1 doctors in multidisciplinary teams: a tool for performance evaluation. AB - BACKGROUND: Effective working in multidisciplinary teams (MDTs) is promoted as essential in ensuring good healthcare outcomes, suggesting that an understanding exists of the relationship between outcomes and the attributes needed by individuals to function effectively in the MDT. While the characteristics of effective teamwork have been described, the attributes needed by individual MDT members have not been investigated. To address this, the study focuses on newly qualified Foundation Year 1 (FY1) doctors, creating and testing a tool to evaluate their performance in the MDT. METHODS: Repertory grid technique was used to elicit attributes needed by FY1 doctors to function effectively in the MDT. Study participants (all experienced MDT members) used these to evaluate MDT working by FY1 doctor colleagues. Data on 57 FY1 doctors were collected from 95 MDT members working in five hospitals. Participants also ranked the attributes in terms of importance for effective team functioning and rated an 'Ideal' FY1 doctor. RESULTS: The repertory grid permitted differentiation between groups of FY1 doctors' MDT performance. FY1 doctors who undertook interprofessional training were rated no differently than UK-trained graduates without such training. UK-trained graduates were rated significantly higher on all attributes than non-UK-trained graduates. Overall, FY1 doctors were rated lower than the 'Ideal'. Factor analysis and rankings suggested tensions between clinical attributes needed for good team functioning and more 'social' attributes. CONCLUSIONS: This study demonstrates the potential of repertory grid methodology in eliciting attributes that are important for effective teamworking, and using these to evaluate MDT working by FY1 doctors. PMID- 23362509 TI - Physical activity as an investment in personal and social change: the Human Capital Model. PMID- 23362507 TI - Home-care nurses' perceptions of unmet information needs and communication difficulties of older patients in the immediate post-hospital discharge period. AB - OBJECTIVE: To understand home-care nurses' perceptions of the post hospitalisation information needs and communication problems of older patients, and how these factors might contribute to undesirable outcomes including poor patient reintegration into prior living environments and unplanned hospital readmissions. DESIGN: A ranked list of information needs experienced by patients was developed by two Nominal Group Technique (NGT) sessions from the perspective of home-care nurses. The list was combined with results from previously published work to develop a web-based survey administered to home-care nurses to elicit perceptions of patients' post-hospitalisation information needs. RESULTS: Seventeen nurses participated in the NGT sessions, producing a list of 28 challenges grouped into five themes: medications, disease/condition, non medication care/treatment/safety, functional limitations and communication problems. The survey was sent to 220 home-care nurses, with a 54.1% (119/220) response rate. Respondents identified several frequent, high-impact information and communication needs that have received little attention in readmission literature, including information about medication regimens; the severity of their condition; the hospital discharge management process; non-medication care regimens such as wound care, use of durable medical equipment and home safety; the extent of care needed; and which providers are best suited to provide that care. Responses also identified several communication difficulties that may play a role in readmissions. CONCLUSIONS: Information needs and communication problems identified by home-care nurses expanded upon and reinforced results from prior studies. These results might be used to develop interventions that may improve information sharing among clinicians, patients and caregivers during care transitions to ensure patient reintegration into prior living environments, potentially preventing unplanned hospital readmissions. PMID- 23362511 TI - Cardiovascular measures in children and adolescents with attention deficit/hyperactivity disorder who are new users of methylphenidate and atomoxetine. AB - OBJECTIVE: The purpose of this study was to assess the cardiovascular effects of drugs used for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents treated in community care centers in Italy. METHODS: This study was an open, prospective, observational study of youth with ADHD treated with atomoxetine (ATX) and methylphenidate (MPH). Measurements of blood pressure and heart rate, and electrocardiogram (ECG) assessment were performed at baseline and at regular intervals up to 24 months. RESULTS: By June 2010, 1758 youth were enrolled in the Italian ADHD National Registry. Statistically significant increases were observed in cardiovascular measures: in the MPH group after 6 months in heart rate (+2.01, p = 0.01); in the ATX group after 6 months in diastolic pressure (+1.60, p = 0.01) and in heart rate (+2.93, p = 0.001), and after 12 months in heart rate (+3.26, p = 0.003). Compared with the baseline, 59 patients had an alteration of ECG during the follow-up period. Although at 12 months, the probability of detecting an abnormal ECG was higher in the MPH group than in the ATX group, only 2 out of 30 cases at 6 months with altered ECG were considered to have experienced serious adverse events. One case was treated with ATX and one with MPH, and arrhythmia was the detected abnormality. CONCLUSIONS: Treatment with MPH and ATX in youth appears to have a small but significant impact on the cardiovascular system. The long-term impact of these medications is unknown. Several clinically meaningless ECG alterations were observed mostly in MPH-treated youth. We therefore suggest evaluating cardiovascular risks at baseline. PMID- 23362512 TI - Mitochondrial gene order change in Schistosoma (Platyhelminthes: Digenea: Schistosomatidae). AB - In the flatworm genus Schistosoma, species of which include parasites of biomedical and veterinary importance, mitochondrial gene order is radically different in some species. A PCR-based survey of 19 schistosomatid spp. established which of 14 Schistosoma spp. have the ancestral (plesiomorphic) or derived gene order condition. A phylogeny for Schistosoma was estimated and used to infer the origin of the gene order change which is present in all members of a clade containing Schistosoma incognitum and members of the traditionally recognised Schistosoma indicum, Schistosoma mansoni and Schistosomahaematobium spp. groups. Schistosoma turkestanicum, with the plesiomorphic gene order state, is sister to this clade. Common interval analysis suggests change in gene order, from ancestral to derived, consisted of two sequential transposition events: (a) nad1_nad3 to nad3_nad1 and (b) [atp6,nad2]_[nad3,-nad1,cox1,rrnL,rrnS,cox2,nad6] to [nad3,nad1,cox1,rrnL,rrnS,cox2,nad6]_[atp6,nad2], where gene order offragments within square brackets remain unchanged. Gene order change is rare in parasitic flatworms and is a robust synapomorphy for schistosome spp. that exhibit it. The schistosomatid phylogeny casts some doubt on the origin of Schistosoma (Asian or African), highlights the propensity for species to hosts witch amongst mammalian (definitive) hosts, and indicates the likely importance of snail (intermediate)hosts in determining and defining patterns of schistosome radiation and continental invasion. Mitogenomic sampling of Schistosoma dattai and Schistosoma harinasutai to determine gene order, and within key species, especially S. turkestanicum and S. incognitum, to determine ancestral ranges, may help discover the geographic origins of gene order change in the genus. Samples of S. incognitum from India and Thailand suggest this taxon may include cryptic species. PMID- 23362510 TI - Modeling of lamin A/C mutation premature cardiac aging using patient-specific induced pluripotent stem cells. AB - AIMS: We identified an autosomal dominant non-sense mutation (R225X) in exon 4 of the lamin A/C (LMNA) gene in a Chinese family spanning 3 generations with familial dilated cardiomyopathy (DCM). In present study, we aim to generate induced pluripotent stem cells derived cardiomyocytes (iPSC-CMs) from an affected patient with R225X and another patient bearing LMNA frame-shift mutation for drug screening. METHODS AND RESULTS: Higher prevalence of nuclear bleb formation and micronucleation was present in LMNA(R225X/WT) and LMNA(Framshift/WT) iPSC-CMs. Under field electrical stimulation, percentage of LMNA-mutated iPSC-CMs exhibiting nuclear senescence and cellular apoptosis markedly increased. shRNA knockdown of LMNA replicated those phenotypes of the mutated LMNA field electrical stress. Pharmacological blockade of ERK1/2 pathway with MEK1/2 inhibitors, U0126 and selumetinib (AZD6244) significantly attenuated the pro apoptotic effects of field electric stimulation on the mutated LMNA iPSC-CMs. CONCLUSION: LMNA-related DCM was modeled in-vitro using patient-specific iPSC CMs. Our results demonstrated that haploinsufficiency due to R225X LMNA non-sense mutation was associated with accelerated nuclear senescence and apoptosis of iPSC CMs under electrical stimulation, which can be significantly attenuated by therapeutic blockade of stress-related ERK1/2 pathway. PMID- 23362513 TI - Enhancing learning through an interprofessional project competition. AB - This article describes the process of using an interprofessional team project to address one of the most commonly occurring challenges in health care delivery- medication reconciliation. We describe the planning and execution of the process and the lessons learned from the experience. The intent of this article is to document the significance of each process and the importance of each member involved in the process, and to act as a guideline for institutions planning similar interprofessional team project experiences for students. PMID- 23362514 TI - Developing a sustainable foot care clinic in a homeless shelter within an academic-community partnership. AB - Nursing faculty are confronted with the need to design community learning activities with vulnerable populations to prepare students for nursing practice. The creation of sustainable academic-community partnerships with agencies providing care to underserved populations meets this challenge. This article describes the development and implementation of a foot care clinic in a homeless shelter, created through a model of curricular integration, faculty engagement, and a long-term academic-community partnership. A transformative pedagogical approach based on service-learning was used to facilitate student understanding of social justice through activities that promote citizenship, develop advocacy skills, and increase knowledge and skills related to the role of the public health nurse in the community. The process of designing and developing a community clinical learning activity and the essential components for sustainability are discussed. Student outcomes are addressed. Recommendations for implementing a foot care clinic within an academic-community partnership are outlined. PMID- 23362515 TI - Response to genomic association analysis identifies multiple loci influencing antihypertensive response to an angiotensin II receptor blocker. PMID- 23362516 TI - Epidural corticosteroid injections in the management of sciatica: a systematic review and meta-analysis. AB - BACKGROUND: Existing guidelines and systematic reviews provide inconsistent recommendations on epidural corticosteroid injections for sciatica. Key limitations of existing reviews are the inclusion of trials with active controls of unknown efficacy and failure to provide an estimate of the size of the treatment effect. PURPOSE: To determine the efficacy of epidural corticosteroid injections for sciatica compared with placebo. DATA SOURCES: International Pharmaceutical Abstracts, PsycINFO, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL. STUDY SELECTION: Randomized, placebo-controlled trials assessing the efficacy of epidural corticosteroid injections in participants with sciatica. DATA EXTRACTION: Two independent reviewers extracted data and assessed risk of bias. Leg pain, back pain, and disability were converted to common scales from 0 (no pain or disability) to 100 (worst possible pain or disability). Thresholds for clinically important change in the range of 10 to 30 have been proposed for these outcomes. Effects were calculated for short term (>2 weeks but <=3 months) and long-term (>=12 months) follow-up. DATA SYNTHESIS: Data were pooled with a random-effects model, and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used in summary conclusions. Twenty-five published reports (23 trials) were included. The pooled results showed a significant, although small, effect of epidural corticosteroid injections compared with placebo for leg pain in the short term (mean difference, -6.2 [95% CI, -9.4 to -3.0]) and also for disability in the short term (mean difference, -3.1 [CI, -5.0 to -1.2]). The long-term pooled effects were smaller and not statistically significant. The overall quality of evidence according to the GRADE classification was rated as high. LIMITATION: The review included only English-language trials and could not incorporate dichotomous outcome measures into the analysis. CONCLUSION: The available evidence suggests that epidural corticosteroid injections offer only short-term relief of leg pain and disability for patients with sciatica. The small size of the treatment effects, however, raises questions about the clinical utility of this procedure in the target population. PRIMARY FUNDING SOURCE: None. PMID- 23362517 TI - Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. AB - BACKGROUND: Antibiotic treatment may disturb the resistance of gastrointestinal flora to colonization. This may result in complications, the most serious of which is Clostridium difficile-associated diarrhea (CDAD). PURPOSE: To assess the efficacy and safety of probiotics for the prevention of CDAD in adults and children receiving antibiotics. DATA SOURCES: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, Allied and Complementary Medicine Database, Web of Science, and 12 gray-literature sources. STUDY SELECTION: Randomized, controlled trials including adult or pediatric patients receiving antibiotics that compared any strain or dose of a specified probiotic with placebo or with no treatment control and reported the incidence of CDAD. DATA EXTRACTION: Two reviewers independently screened potentially eligible articles; extracted data on populations, interventions, and outcomes; and assessed risk of bias. The Grading of Recommendations Assessment, Development and Evaluation guidelines were used to independently rate overall confidence in effect estimates for each outcome. DATA SYNTHESIS: Twenty trials including 3818 participants met the eligibility criteria. Probiotics reduced the incidence of CDAD by 66% (pooled relative risk, 0.34 [95% CI, 0.24 to 0.49]; I(2) = 0%). In a population with a 5% incidence of antibiotic-associated CDAD (median control group risk), probiotic prophylaxis would prevent 33 episodes (CI, 25 to 38 episodes) per 1000 persons. Of probiotic-treated patients, 9.3% experienced adverse events, compared with 12.6% of control patients (relative risk, 0.82 [CI, 0.65 to 1.05]; I(2) = 17%). LIMITATIONS: In 13 trials, data on CDAD were missing for 5% to 45% of patients. The results were robust to worst-plausible assumptions regarding event rates in studies with missing outcome data. CONCLUSION: Moderate-quality evidence suggests that probiotic prophylaxis results in a large reduction in CDAD without an increase in clinically important adverse events. PRIMARY FUNDING SOURCE: None. PMID- 23362518 TI - Bjorn Folkow. PMID- 23362519 TI - Summaries for patients. Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. PMID- 23362520 TI - Nurse staffing, quality of care, and quality of life in US nursing homes, 1996 2011: an integrative review. AB - The purpose of this study was to complete an integrated literature review of the relationship between staffing and quality outcomes in nursing homes. The majority of the reviewed studies showed better outcomes with higher nursing staff but depended heavily on cross-sectional observational studies and failed to differentiate RNs from other nursing staff. A total of 28 articles relating nurse staffing and quality outcomes were systematically reviewed and synthesized. However, each study examined different aspects of staffing and different resident or organizational outcomes, making determination of appropriate staffing levels difficult. The reviewed studies have not clearly defined the relationship between differing levels of nurse-staffing skill mix and specific structure, process, outcome, and composite indicators of quality. The inconsistent findings suggest that further research is needed in this area. PMID- 23362521 TI - Human-animal interaction and older adults. PMID- 23362522 TI - Comparison of disseminated intravascular coagulation in trauma with coagulopathy of trauma/acute coagulopathy of trauma-shock. PMID- 23362523 TI - Recommendations for measuring health-related quality of life in children on anticoagulation. PMID- 23362524 TI - Venous thromboembolism in cancer clinical trials: recommendation for standardized reporting and analysis. PMID- 23362525 TI - Incidental venous thromboembolism in oncology patients. PMID- 23362526 TI - Comparison of right ventricular longitudinal strain imaging, tricuspid annular plane systolic excursion, and cardiac biomarkers for early diagnosis of cardiac involvement and risk stratification in primary systematic (AL) amyloidosis: a 5 year cohort study: reply. PMID- 23362528 TI - Reducing incontinence after prolapse repair. PMID- 23362527 TI - Narcotic pain relievers: are you using them correctly? PMID- 23362529 TI - Parkinson's disease: promising strategies to tame symptoms. PMID- 23362530 TI - Calling the shots: vaccines you need. PMID- 23362531 TI - Are you just overtired--or anemic? PMID- 23362532 TI - My low blood pressure occasionally makes me feel faint. How can I avoid passing out? PMID- 23362534 TI - Seasonal sleep-apnea patterns. PMID- 23362533 TI - Is there anything I can do to relieve the chronic dry mouth that my medications cause? PMID- 23362535 TI - Radiation for breast cancer. PMID- 23362536 TI - Radiation for heel spurs. PMID- 23362537 TI - Age affects rate of cognitive decline. PMID- 23362538 TI - Take care of your vision to protect your hips. PMID- 23362539 TI - Researching to make a difference: possibilities for social science research in the age of AIDS. AB - HIV and AIDS is recognized as one of the most devastating pandemics of sub Saharan Africa, and South Africa in particular, with adverse effect on individuals, families, schools, communities and society at large. Research is therefore required to provide a deeper understanding of the complexities of HIV and AIDS in order to mitigate the effect of the pandemic. Much of the excellent research that has been done has been undertaken within a positivist paradigm and has focused on the biomedical aspects of HIV and AIDS, as well as the social aspects of the pandemic. This theoretical position paper draws on various projects in the field of HIV and AIDS education in rural KwaZulu-Natal to argue that more social science research should be framed within a participatory research paradigm, foregrounding participant engagement and process, and which simultaneously has a "research-as-intervention" focus.Such research adheres to the requirement of knowledge production, but also engages the participants as knowledge producers who, through the research process, are enabled to shift towards taking up their own agency. Reflecting on the findings from the various projects suggests that visual participatory methodologies are particularly useful when working with marginalized persons whose voices are seldom heard especially when exploring topics which are difficult to discuss. Furthermore, it brings issues to the fore and opens up debate, while at the same time democratizing research and allowing universities to take up their social responsibility and to contribute towards making a difference in the communities they serve. PMID- 23362540 TI - [The role of online vital statistics: hemoclassification of newborn infants in Bogota, Colombia]. PMID- 23362541 TI - Marburg virus uses a mask to evade immune detection. PMID- 23362542 TI - Pertussis protection diminishes 5 years after fifth dose of DTaP. PMID- 23362543 TI - Study finds children and middle-aged adults are most at risk from variant H3N2 influenza. PMID- 23362544 TI - Can we treat untreatable TB? PMID- 23362545 TI - [Coming soon: the pill for men?]. PMID- 23362546 TI - [White, brown or beige rather?]. PMID- 23362547 TI - [Molecular copies of off-patent biologics that have become biosimilars: a new group recombinant products]. PMID- 23362548 TI - [When two do the same, it is not the same. Requirements for development and quality of biosimilars]. PMID- 23362549 TI - [Comparison of generics and original biopharmaceutical drugs. The clinical development of biosimilars]. PMID- 23362550 TI - [What is exactly alike? High-performance analytics for development of biosimilars]. PMID- 23362551 TI - [Similar but not identical biosimilars: the vision of innovators]. PMID- 23362552 TI - ["Freedom to Operate". Patent Legal Aspects in the preparation of biosimilars]. PMID- 23362553 TI - [Cost-effectiveness advantage? Pharmacoeconomic aspects of biosimilars]. PMID- 23362554 TI - [MRI and PET in Alzheimer's disease]. PMID- 23362555 TI - The oncology acuity tool: a reliable, valid method for measuring patient acuity for nurse assignment decisions. AB - BACKGROUND AND PURPOSE: Matching nurse assignments with patient acuity has critical implications for providing safe, effective, and efficient care. Despite this, we lack well-established methods for accurate assessment of acuity. This study aimed to evaluate the reliability and validity of the Oncology Acuity Tool (OAT), which is used for determining nurse assignments. METHODS: Inter-rater reliability and concurrent validity were assessed via surveys of current users of the tool. Content validity data were collected from expert oncology nurses. Predictive validity was assessed by tracking patients who sustained either of two acute events. RESULTS: Findings included high inter-rater reliability, moderately strong concurrent validity, and moderate content validity. Acuity significantly predicted rapid response team consults but not falls. CONCLUSIONS: The OAT demonstrated sufficient reliability and validity for measuring acuity prospectively in this population. PMID- 23362556 TI - Validity and reliability of the Brief TeamSTEPPS Teamwork Perceptions Questionnaire. AB - BACKGROUND AND PURPOSE: Teamwork is an essential component of hospital nursing quality and safety. The purpose of this study is to test the validity and reliability of the Brief TeamSTEPPS Teamwork Perception Questionnaire (Brief T TPQ). METHODS: The 20-item questionnaire was completed electronically by a sample (N = 456) of hospital bedside nurses and tested for reliability and validity. RESULTS: The survey demonstrated internal consistency reliability of .83-.94 with a total survey reliability of .93. A hierarchical relationship three factor subscale structure was confirmed, explaining 64% of the variance and acceptable factor loadings. A secondary five-factor structure revealed statistically and conceptually coherent skills and behaviors sub-subscales. Discriminant validity was demonstrated with self-esteem and control over practice. CONCLUSIONS: The 20 item Brief T-TPQ is a valid and reliable survey to measure hierarchical teamwork relationships as well as teamwork skills and behaviors. PMID- 23362557 TI - A new faces scale in pain measurement: a test of bias from current mood, trait affectivity, and scale range. AB - BACKGROUND AND PURPOSE: Faces pain rating scales used among children have been criticized to confound affective states with pain when smiling faces are included. This experimental study is an attempt to examine the possible confounding of affective states with pain when smiling faces are used as part of a faces scale. The meaning of the faces was tested to depend on current mood, current pain, trait affectivity, and inclusion versus exclusion of smiling faces. METHODS: Sixty-four participants made 6,720 two-categorical pain judgments on faces with different mouth curvature. RESULTS: In multilevel regression analysis, current level of pain and negative trait affectivity biased faces' meaning only when the smiling faces were excluded from the scale. CONCLUSIONS: In adults, the new full range faces pain scale including a midpoint neutral face and smiling faces was more robust than the restricted scale. The faces scale that was tested in this study is not applicable for patient measurement but it is an interesting tool for psychological research. PMID- 23362558 TI - Development and testing of the Survey of Family Environment (SFE): a novel instrument to measure family functioning and needs for family support. AB - BACKGROUND AND PURPOSE: Hohashi's Concentric Sphere Family Environment Model (CSFEM; Hohashi & Honda, 2011) is a newly proposed family nursing theory for holistically understanding the family environment that acts on family well-being. The purpose of this article is to develop and psychometrically test the Japanese version of the Survey of Family Environment (SFE-J), grounded in the CSFEM, for measuring family's perceived family functioning and family's perceived needs for family support. METHODS: The SFE-J is a 30-item self-administered instrument that assesses five domains (suprasystem, macrosystem, microsystem, family internal environment system, and chronosystem) and has been subjected to rigorous reliability and validity investigations among paired partners in child-rearing families (N of family = 1,990). RESULTS: Internal consistency reliability was high as measured by Cronbach's alpha coefficients. Temporal stability over a 2 week interval was supported by high (substantial or perfect) and significant intraclass correlation coefficients. The total score for the SFE-J was significantly correlated with the Japanese version of the Feetham Family Functioning Survey (FFFS-J), indicating an acceptable concurrent validity. Construct validity was supported by a confirmatory factor analysis that evaluated the five-factor structure to measure the concept of CSFEM. Results also demonstrate that the SFE-J family functioning scores show no significant differences between paired partners. CONCLUSIONS: The SFE-J is a reliable and valid instrument to assess not only intrafamily functioning but also interfamily functioning and, by identifying items/domains with high requirements for family support, serves to facilitate the providing of appropriate support to families. PMID- 23362559 TI - Measurement pilot study of the Meditative Movement Inventory (MMI). AB - BACKGROUND AND PURPOSE: Mind-body practices that blend physical movement or postures with a focus on the breath and a meditative state to achieve deep states of relaxation have recently been characterized as a category of exercise called meditative movement and include practices such as Yoga, Tai Chi, and Qigong. Critical components of such practices have not been adequately assessed in research, leaving the fidelity of interventions in question; however, there is currently no set of relevant instruments. This article describes the development and preliminary validation of two subscales of the meditative movement inventory (MMI). METHODS: Questionnaire items were generated with input from expert practitioners, and tested in the context of an intervention study (N = 87) comparing Qigong/Tai Chi Easy (QG/TCE) to sham Qigong (SQG). RESULTS: Principal components analysis produced three substantively meaningful factors: breath focus (BF; e.g., "I was using my breathing to go into a relaxed state"; five items, alpha = .86), meditative connection (MC; e.g., "I was connected to something greater than myself"; four items, alpha = .90), and flowing motion (FM; e.g., "I moved in relaxed, fluid movements"; two items, alpha = .61, dropped from further analysis). Confirmatory factor analyses of the first two factors (BF and MC) to examine item reliabilities fit the data well providing positive results for construct composition and item reliabilities. CONCLUSIONS: The BF and MC subscales demonstrated initial strong properties for assessing the presence and strength of these factors in meditative movement intervention studies, whereas additional work is needed to further develop the FM subscale. PMID- 23362560 TI - The psychometric properties of the Greek version of Champion's Health Belief Model Scale. AB - BACKGROUND AND PURPOSE: Breast cancer is the leading female type of cancer in Cyprus. Therefore, there is a need for a valid and reliable tool to examine beliefs or practices about breast cancer and breast self-examination (BSE). The objective of this study was to translate the widely used Champion's Health Belief Model Scale into Greek and validate the tool among Cypriot women. METHODS: Data analysis included descriptive statistics, reliability estimates, and confirmatory factor analysis with fit indexes for construct validity. Multiple regression, with dependent variables "frequency of practice of BSE in the previous year" and "intended frequency of BSE," was used to examine predictive validity. Ninety-four women were surveyed. RESULTS: The six-subscale structure (confidence, benefits, susceptibility, barriers, seriousness, motivation) of the Greek version was verified, with a good model fit. Alpha coefficients ranged from .66 to .88, indicating internal consistency reliability of the tool. Regression analysis provided evidence of predictive validity, with barriers and confidence being significant predictors of BSE practice. CONCLUSIONS: The Greek version of Champion's Health Belief Model Scale is a valid and reliable tool for use among Cypriot women that can be used to evaluate their beliefs about breast cancer and BSE and for planning interventions to improve these beliefs. PMID- 23362561 TI - Absolute reliability of the Resilience Scale. PMID- 23362562 TI - Taste preference and psychopathology. AB - OBJECTIVE: Excessive food intake has been linked to many factors including taste preference and the presence of psychopathology. The purpose of this study was to investigate the association between sweet and salty taste preference and psychopathology in patients with severe obesity. METHODS: A consecutive series of patients applying for bariatric surgery was recruited for the study. Taste preference was self-reported. Psychopathology was assessed using the revised version of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). 190 patients were included in the study. RESULTS: In comparison with patients who had salty taste preference, patients with sweet taste preference had significantly higher elevations on the depression (OD: 4.090, p = 0.010) and the hysteria (OD: 2.951, p = 0.026) clinical scales of the MMPI-2. CONCLUSION: The results suggest the presence of an association between taste preference and psychopathology. The findings may be of interest for clinicians who are involved in the treatment of obesity. In particular, they may wish to pay increased attention to patients with sweet taste preference or who have a strong attraction for both sweet and salty foods, in order to detect psychopathology and to adapt the treatment. PMID- 23362563 TI - DTI of the visual pathway in cerebral lesions. AB - Diffusion tensor imaging (DTI) can be used to localise the visual pathway (VP). In the service of the neurosurgery we have been working since the beginning of this year to develop a protocol which is suitable for the every day clinical routine to show the tracts of the white matter. Many lesions of the brain concern the white matter. Up to date it is still difficult to portray the visual pathway. Many centers all around the world are actually trying to localize the visual pathway, yet it is still used for the research. The application of the DTI-data for surgical interventions remains still a rarity. We believe that using this technique it would reduce the intraoperative risk and improve the postoperative outcome. From the beginning of this year we have been able to localize the visual pathway in 14 patients with different illnesses and we performed also postoperative controls. Using this new technique we were able to minimize the intraoperative risk in our patients. PMID- 23362564 TI - Risk factors and disease prevalence in 3331 personal check-ups performed in preventive medicine between 2006 and 2011. cross-sectional and follow-up study. AB - INTRODUCTION: The present data results from a retrospective analysis of 3331 check-ups made in the preventive medicine department of the "ZithaKlinik", named "ZithaGesondheetsZentrum". These check-ups are done for the employee's of several firm's and institutions. According to gender and age, several tests and examinations are performed and the results are given to the person's general practitioner or another doctor of his choice. We will present a global synthesis of all the results but also a follow-up study of persons having performed 2 check ups or more over a 5-year period. POPULATION: In the cross-sectional part, the analysis is done on 3331 individual check-ups (1447 woman, 1884 men). The average age is 50.3 years +/- 11.4. In the follow-up study, 478 persons (191 women, 287 men) had at least 2 (maximum 5) check-ups in the 5-year period of our observation. Initial age was 54.1 +/- 10.9 years for woman and 51.4 +/- 11.4 for men, respectively 56.4 +/- 10.9 and 53.7+/- 11.2 at their last check-up. RESULTS: An alarming number of persons present with a weight or obesity problem (according to age ranging from 22.0% overweight and 7.3% obese from 18-29 years, respectively 37.5% and 11.3% from 30-49 years, finally 44.0% and 20.6% in the range 50-69 years). Associated risk factors and pathologies (Hypertension, Dyslipidemia, NASH, diabetes type 2 and complete metabolic syndromes) are extremely frequent and getting more so with growing age. Furthermore, physical activity is insufficient in grossly 2/3 of the studied population. The only positive point is a tendency of decreasing tobacco use in all age groups. The follow-up study is frustrating because most of the examined criteria get worse in between check-ups instead of getting better with changes in lifestyle in an informed population. CONCLUSIONS: Asymptomatic diseases or risk factors for non communicable diseases are extremely frequent in the population examined. The follow-up data shows that huge parts of this group are not sufficiently conscientious of their problems to act up and change their life-style or seek adapted pharmacological prevention. Absolute number of risk factors (prevalence) or pathologies rise evidently with age but incidence (newly discovered pathologies after a first, second or a record of 21 check-ups with our services) rises less. Life-style changes are rare or insufficient to change the pathological value back to normal or therapeutically range. Even with several biases (retrospective design, selection bias, ...) our study puts similar problems forward in the population as ORISCAV. The astonishing (better than national records) results in tobacco use is probably due to a selection of more health-oriented patients and of a higher socio-educative-economic level. Alcohol abuse was very low but probably due to inadequate screening methods. A better health promotion advocating healthier living must be associated with better communication and new motivational tools. Therapeutical education for patients with chronic non-communicable diseases will be the challenge of the near future as their prevalences increase due to ageing of the population and worse individual lifestyles. In this task, efforts must be made on the personal level (health-team with the individual patient) but also on the national level (legal frame work for patient education by multi-professional teams as they exist already in neighbour states). PMID- 23362565 TI - Transpatellar access for intramedullary stabilisation of the tibia. AB - Postoperative deformities of the knee and sequaelae after intraarticular surgery can interfere with a standard parapetallar approach for intramedullary stabilisation of the tibia. Even the suprapatellar approach can be rendered impossible. For these rare indications we describe the patella osteotomy and transpatellar approach. PMID- 23362566 TI - Investigation of an excess of Salmonella enteritidis phage type 14b and MLVA type 4-7-3-13-10-2-2 in Luxembourg, Belgium and Germany during 2010. AB - We investigated an increase of human cases of Salmonella Enteritidis occurring from August until November 2010 in Belgium, Luxembourg and Germany involving an estimated three hundred laboratory confirmed cases. Molecular typing indicated that the increase in Luxembourg and Belgium was due a particular strain having phage type 14b, MLVA pattern 4-7-3-13-10-2-2 and fully susceptible to the Enternet panel of antibiotics. MLVA and phage typing were found to have similar discriminatory power on a collection of 40 Belgian and Luxembourg strains isolated during 2010. Epidemiological investigations in Luxembourg suggested eggs as a possible source for some cases, although supermarket eggs tested were negative. No other EU countries observed a substantial increase of cases, although three smaller outbreaks in Germany were also due to a strain with the same phage type and MLVA pattern. In 2010 the EU directive banning battery cages came into force in Germany followed by a dioxin food scare incident. Given that the EU Laying Hens Directive will come into force across all Member States in 2012, a closer monitoring of Salmonella contamination of imported eggs at retail and wholesale level is recommended. PMID- 23362567 TI - [Nursing advances!]. PMID- 23362568 TI - [Nursing 2024, what challenges lie ahead?]. PMID- 23362569 TI - [The magnifying mirror to enable patients with diabetes to self-examine their feet]. AB - The treatment of foot wounds is a real public health issue for patients with diabetes. A specific educational tool has been developed for foot self examination: the magnifying mirror. Its use, during nurse consultations and in the patient's home, actively contributes to foot wound prevention messages and actions. PMID- 23362570 TI - [Evidence-based nursing. Support for improving the quality of health care]. PMID- 23362571 TI - [Evidence-based nursing practice]. AB - The growing complexity of nursing situations combined with the availability of scientifically validated knowledge has led to the appearance of the concept of evidence-based nursing. By giving a framework to the clinical decision-making process, Evidence-Based Practice (EBP) is a factor in the improvement of the quality of care. PMID- 23362572 TI - [Integrating nursing care into the Cochrane Collaboration]. AB - The Cochrane Collaboration holds a prominent position in Evidence-Based Practice. Since 2009, this organisation has created a specific area reserved for nursing care. Anyone needing nursing evidence, or wishing to produce some, can obtain useful resources from the Collaboration. PMID- 23362573 TI - [The transfer of scientific knowledge in clinical practice]. AB - The rapid growth of evidence-based practice has been facilitated by the development of theoretical models enabling the components of this concept to be assimilated. The Joanna Briggs Institute is an international organisation which offers a wide range of resources in order to promote this practice in the health sector. PMID- 23362574 TI - [The French Cochrane Center]. PMID- 23362575 TI - [Basing clinical decisions on scientific evidence]. AB - The first three steps of the Evidence-Based Nursing approach are the formulation of the PICO question, ("patient", "intervention", "comparison" and "outcomes"), the search for guidelines and the critical reading of selected recommendations. These can be based on a clinical situation. PMID- 23362576 TI - [Evidence-based nursing, a driver for change in nursing practice]. AB - A urology nursing team examined its perioperative practices in the light of scientific data and implemented updated care practices adapted to this context.This experience favours the development of skills essential for interdisciplinary collaboration drawing on the resources of each profession, to work towards a common goal for the benefit of the patient. PMID- 23362577 TI - [The teaching of evidence-based practice in allied healthcare training in France]. AB - Evidence-Based Practice is a strategy which health professionals can use to guide their clinical decisions. However, the specific skills necessary for its implementation are still insufficiently developed in initial training.A survey of physiotherapy students confirms this observation and suggests that the teaching of Evidence-Based Practice needs to be reinforced. PMID- 23362578 TI - [Evidence-based practice, critical discussions]. AB - The implementation of evidence-based practice provokes critical discussion with regard to its limits, the difficulties encountered in applying it and the potential dangers to which it is associated. Nurses' vigilance is essential as is their knowledge of the methods of this approach. PMID- 23362579 TI - [Integrating evidence-based nursing into nursing education]. PMID- 23362580 TI - [Bibliography. Evidence-based nursing]. PMID- 23362581 TI - [Evaluation of a patient education program]. PMID- 23362582 TI - A prescription for safer care: medication reconciliation. PMID- 23362583 TI - The New England Journal of Medicine publishes pivotal data demonstrating efficacy and safety of oral BG-12 (dimethyl fumarate) in multiple sclerosis. PMID- 23362584 TI - Specialist nursing training in Poland: applications for neuroscience nursing. AB - BACKGROUND: Nurses have a pivotal role in providing facilitating, advocating and promoting the best possible care and outcome for the client. To ensure decisions and actions are based on current standards of practice, nurses must be accountable for participation in ongoing education in their area of practice. AIM: To present a description of the current state of Polish nursing education and specialized model for neurological and neurosurgical nursing that can be utilized for both undergraduate and postgraduate continuing education in Poland. DATA SOURCES: The model of postgraduate training introduced in Poland in 2000 was taken into consideration in developing the framework for neuroscience nursing postgraduate continuing education presented here. The framework for neurological continuing education is also based on a review of the literature and is consistent with Poland's legally binding professional nursing regulations (normative and implementing regulations). CONCLUSION: The model demonstrates the need for the content of pre- and post-undergraduate degree education in neurological nursing to be graduated, based on the frameworks for undergraduate education (acquiring the knowledge and basic skills for performing the work of nurses) and postgraduate education (acquiring knowledge and specialist skills necessary for providing advanced nursing care including medical acts on patients with nervous system diseases). IMPLICATIONS FOR NURSING: New and advanced skills gained in specialization training can be applied to complex functions, roles and professional tasks undertaken by nurses in relation to care of patients with neurological dysfunctions. PMID- 23362585 TI - CNS tuberculosis: a review and illustration from an autopsy case. AB - An estimated one-third of the world's population (2 billion people) is infected with the tubercle bacilli (TB), which is estimated to cause 6% of all deaths worldwide. Despite there being a decline in the incidence of tuberculosis seen in Europe, there are still some countries in the rest of the world where the estimated number of new cases is very high. When a person presents with persistent fever with or without neurological symptoms, the diagnosis of TB cannot be excluded. We present a case report of a 26-year-old male patient, who died of CNS tuberculosis. Such case studies will help keep neuroscience nurses alert to potential medical issues in multiethnic patient populations. PMID- 23362586 TI - Patients' perceptions of their roles in goal setting in a spinal cord injury regional rehabilitation program. AB - Goal setting is a common practice in rehabilitation, yet there is a paucity of literature exploring patients' perceptions of their roles in this process. This study was conducted using a qualitative descriptive methodology to explore patients' perceptions of their roles in setting goals in a spinal cord injury regional rehabilitation program. Imogene King's theory of goal attainment was used to frame the study. Data were collected through interviews and analyzed using a content analysis. The results revealed four themes: Visioning, Redefining, Brainstorming, and Rebuilding Participants (n = 13) envisioned their roles as setting an overarching priority goal, defining detailed rehabilitation goals, sharing knowledge with the team, and rebuilding skills to attain goals. Implications for nursing practice include the need to understand patients' experiences and perceptions, share knowledge, and support effective communication to promote collaborative goal setting. A need to enhance health professionals' education to fully understand factors influencing patients' abilities to set rehabilitation goals, and future research in methods to promote patients' engagement in goal setting was also clearly indicated. PMID- 23362587 TI - Sports-related concussions and the Louisiana Youth Concussion Act. AB - Concussion, also referred to as mild traumatic brain injury (TBI), is defined as a "complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces." Various symptoms may be observed in patients with concussions. All of these might not be evident at the time of the injury and be intermittent in their nature. It is estimated that 300,000 of the yearly TBIs in the United States are sports-related, the second leading cause for TBIs after motor vehicle accidents among people aged 15 to 24 years old. Due to some recently reported high profile injuries and deaths of sports personalities, sports-related concussion has seen increasing media and public interest in the last decade. We review the role of football in youth concussions and analyze the Nationwide Inpatient Sample from 2007 to 2009 to elucidate the outcome and costs associated with sports-related concussions of the youth in the United States. We also review the latest state legislative efforts to decrease the incidence of dangerous sports-related concussions in youth--the Louisiana Youth Concussion Act. PMID- 23362588 TI - Large sacral osteoblastoma: a case report and review of multi-disciplinary management strategies. AB - INTRODUCTION: Osteoblastomas are uncommon primary benign bone tumors. The sacrum is an uncommon site of involvement. We present a case of a large, technically challenging sacral osteoblastoma in a pediatric patient that was managed with en bloc resection and lumbo-sacral reconstruction showing long-term remission. CASE REPORT: A 15-year-old Hispanic male presented to our clinic in May 2006 with low back pain. Imaging revealed a large expansile and erosive mass at the S2 vertebral body. Definitive treatment of the lesion with en-bloc surgical resection was planned after a biopsy that confirmed osteoblastoma. The patient underwent pre-operative embolization and a same-day, two-stage resection of the tumor with lumbosacral instrumentation for pelvic reconstruction. The S1 nerve roots were sacrificed during en-bloc resection of the mass. Post-operatively, the patient developed an areflexic bladder without major motor or sensory impairment. Subsequently, insertion of an artificial urinary sphincter and a colostomy were performed. At the five-year follow up, the patient remains symptom free with no detectable recurrence. CONCLUSION: The sacrum is a known, but rare, location for an osteoblastoma. We present a technically challenging case of a pediatric patient with a large sacral osteoblastoma. We highlight the importance of a multidisciplinary approach to ensure a long-term, disease-free outcome. PMID- 23362589 TI - Sarcoidosis of the thyroid gland and spinal canal: unique localizations. AB - Sarcoid involvement of the thyroid gland and spinal canal are rare individual manifestations of sarcoidosis. In this article, we will describe two concurrent cases of spinal canal and thyroid sarcoid involvement. Diagnostic criteria usually include histologic identification of a non-caseating granuloma, supportive laboratory or imaging tests or both, and a compatible clinical course. Our goal is to discuss the presentations and clinical manifestations of our patients, and we will also review the literature involving sarcoid involvement of the spinal canal and thyroid. Although rare, atypical locations of sarcoid should remain suspected for those patients known to have sarcoid involvement in other organ(s) or found to have granulomatous involvement on pathology. PMID- 23362590 TI - Chemoradiotherapy for unresectable stage IVB head and neck cancer. AB - OBJECTIVE: As the occurrence of unresectable stage IVB head and neck cancer is expected to continue, we present our experience over the last 17 years with chemoradiotherapy management of 14 cases to clarify the effectiveness and safety of this treatment scheme. METHOD: Of the 1,267 individuals who were diagnosed with carcinoma of the upper aerodigestive tract between 1992 to 2008, 14 patients were treated by induction chemotherapy followed by concurrent chemoradiation or simultaneous chemoradiotherapy for stage IVB disease. The median follow-up time was 54.5 months. RESULTS: The complete objective response rate was 79%. Six individuals remained disease-free during a followup period ranging from 24 to 149 months. The disease-free survival rate at five years was 68%. Local, regional, and distant failure rates were 21%,14%, and 7% respectively. Most of the patients (79%) experienced transient mucositis during treatment. Significant late complications consisted of dental caries or osteoradionecrosis (14%) and esophageal stricture (7%). CONCLUSION: Definitive chemoradiotherapy administered for unresectable stage IVB head and neck cancer has the potential of achieving long-term disease-free survival in up to two-thirds of the patients with a low risk of complications. PMID- 23362591 TI - Simultaneous acute appendicitis and pseudomembranous colitis in a pediatric patient. AB - Acute appendicitis is a common cause for pediatric surgery, with an increasing incidence as this population ages. Pseudomembranous colitis (PMC) from Clostridum difficle is being seen more frequently in pediatric patients, especially after treatment with antibiotics and in those with Hirschsprung's disease. Only three prior cases of appendicitis associated with PMC have been described in the literature, and all of them occurred in adult patients. Here, we describe the first documented pediatric case: a 16-year-old female who developed acute appendicitis while concomitantly being treated for suspected pseudomembranous colitis. We concur with previous authors that there may be an association between these two pathologies; furthermore, this association may not always be clinically apparent and may be both under-diagnosed and under-reported. PMID- 23362592 TI - Respiratory syncytial virus-associated hospitalizations in Louisiana. AB - Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia in children under one year of age worldwide. Records indicative of RSV cases were pulled from The Louisiana Inpatient Hospital Discharge Data based on RSV diagnosis codes to describe the burden of RSV infections in Louisiana from 1999 to 2010. Two thousand to three thousand hospitalized RSV cases occurred each year, with rates ranging from 37.2 to 71.4 hospitalizations per 100,000 population and the majority of cases (79%) being diagnosed with bronchiolitis. The vast majority of cases occurred in children under one year of age, and within that group, 44% of the cases occurred in children ages 0 to 3 months. The RSV season was found to occur from November to March, and immunoprophylaxis for high risk infants should be given according to that season. Hospital-acquired versus community-acquired infections were also examined and most (96.1%) cases were community-acquired. PMID- 23362593 TI - Suicide mortality rates in Louisiana, 1999-2010. AB - This report is a descriptive study on suicide deaths in Louisiana occurring in the years 1999 to 2010. Mortality data was collected from death certificates from this 12-year period to describe suicide mortality by year, race, sex, age group, and methods of suicide. Data were also compared to national data. Rates and methods used to commit suicide vary greatly according to sex, race, and age. The highest rates were observed in white males, followed by black males, white females, and black females. Older white males had the highest suicide rates. The influence of age was modulated by the sex and race categories. Firearm was the most common method used in all four categories. Other less common methods were hanging/strangulation/suffocation (HSS) and drugs/alcohol. Although no parish level data were systematically analyzed, a comparison of suicide rates post Katrina versus pre-Katrina was done for Orleans Parish, the rest of the Greater New Orleans area, and a comparison group. It appears that rates observed among whites, particularly males, were higher after Katrina. Data based on mortality do not give a comprehensive picture of the burden of suicide, and their interpretation should be done with caution. PMID- 23362594 TI - Is platelet transfusion necessary prior to a central venous catheter placement in thrombotic thrombocytopenic purpura patients? AB - Due to concern for bleeding from severe thrombocytopenia, some thrombotic thrombocytopenic purpura (TTP) patients receive platelet transfusion prior to central venous catheter placement. However, studies have shown that blood loss associated with this procedure is minimal, and platelet administration is unnecessary. In our study, 11 patients with TTP were identified. Before central line placement, two of the 11 received platelet transfusions, while nine did not. Blood loss in all patients was not significant, supporting the position that platelet transfusion prior to central venous catheter placement in TTP patients is unnecessary. PMID- 23362595 TI - ECG of the month. Electrocardiogram in a man with chronic kidney failure. ECG is abnormal and indicative of heart disease. AB - A 70-year-old man came to the Access to Primary Care Clinic at the Interim LSU Public Hospital because he had been told at another hospital that he needed a kidney doctor. The patient had a history of high blood pressure, type 2 diabetes mellitus, long-standing kidney disease, an above the knee amputation on the left, gout, a possible coronary stent procedure five years ago, and recently poor appetite and inability to care for himself. He had a long history of medical noncompliance and was taking no medications when he came to the hospital. He denied all cardiac symptoms, including chest discomfort. He was admitted to hospital because of a blood pressure of 240/110 mmHg, a serum creatinine of 6.0 mg/dL, and an estimated glomerular filtration rate of 11 mL/min - i.e., chronic kidney disease, stage V. His electrocardiogram was read by the computer as normal (Figure 1). PMID- 23362596 TI - Radiology case of the month. Nausea, vomiting, and diarrhea in a patient with hepatitis C and acquired immunodeficiency syndrome (AIDS). Diffuse, severe gastric-wall thickening, consistent with edema. AB - The patient is a 42-year-old male with a past medical history of HIV/AIDS (his most recent CD4 count, four months before admission, was 19) and hepatitis C who presented to the Emergency Department complaining of one week of persistent nausea, vomiting, and diarrhea. His admit labs were as follows: hemoglobin of 11.8, hematocrit of 35, total protein of 6.0, albumin of 1.6, total bilirubin of 2.3, aspartate aminotransferase (AST) of 141, alkaline phosphatase (ALP) of 146, and alanine aminotransferase (ALT) of 31. Computed tomography (CT) images of the abdomen and pelvis with contrast were obtained (Figures 1 - 4). PMID- 23362597 TI - Clinical case of the month. Idiopathic pulmonary hemosiderosis presenting as a rare cause of iron deficiency anemia in a toddler--a diagnostic challenge. AB - Iron deficiency anemia is the most common cause of anemia in all age groups. Idiopathic pulmonary hemosiderosis is an extremely rare etiology of iron deficiency anemia seen predominantly in the pediatric population. Idiopathic pulmonary hemosiderosis is characterized by the triad of symptoms consisting of iron deficiency anemia, diffuse pulmonary infiltrates, and hemoptysis. The clinical presentation is extremely variable, and all three symptoms may not always be seen. Due to the rarity of the disease and the variability in clinical presentation, diagnosis is usually delayed. Early diagnosis and treatment with corticosteroids prevents further episodes of recurrent alveolar hemorrhage and improves the clinical outcome. Hence, a high index of suspicion is required for the diagnosis of this condition in young patients presenting with severe iron deficiency anemia and diffuse pulmonary infiltrates. We report a toddler with idiopathic pulmonary hemosiderosis whose initial clinical presentation was severe iron deficiency anemia. PMID- 23362598 TI - Submental muscle tissue compliance during relaxation, contraction, and after tone modification interventions. AB - Deviations in muscle tone are presumed to accompany speech motor control deficits in select forms of dysarthria, although there is little confirmation of these associations. For patients experiencing neuromuscular impairments, therapeutic interventions and/or principles have been devised to alleviate tone deviations where they occur and to prevent the development or exacerbation of tone deviations. Potentially therapeutic effects of these interventions on muscle tone in the speech musculature have not been studied empirically. One reason for the paucity of research is that tools for assessing muscle tone in the speech musculature are not generally available. This pilot study explored the feasibility of a commercially available, handheld instrument for measuring submental muscle compliance during relaxed and active conditions in 16 women with normal speech and swallowing. Additionally, the study examined changes in muscle compliance when interventions presumed to impact muscle tone were applied to the submental region. The Myotonometer was sensitive to changes in tissue compliance related to active contraction of the submental musculature. Applying ice or vibration to the submental region resulted in no systematic changes in submental tissue compliance in the relaxed or contracted state. Additional research is needed to validate the use of this instrument to reliably assess muscle tone and other contributors to tissue compliance. If successful, studies should examine the sensitivity of the Myotonometer to assess intervention-induced tissue compliance changes in patient groups with suspected muscle tone impairments. Further study of intervention effects across muscle groups and dosage levels can help inform clinical decisions about the potential usefulness of tone-altering interventions for the orofacial musculature. PMID- 23362600 TI - Speech-language pathology findings in patients with mouth breathing: multidisciplinary diagnosis according to etiology. AB - The purpose of this study was to identify and compare the results of the findings from speech-language pathology evaluations for orofacial function including tongue and lip rest postures, tonus, articulation and speech, voice and language, chewing, and deglutition in children who had a history of mouth breathing. The diagnoses for mouth breathing included: allergic rhinitis, adenoidal hypertrophy, allergic rhinitis with adenoidal hypertrophy; and/or functional mouth breathing. This study was conducted with on 414 subjects of both genders, from 2 to 16-years old. A team consisting of 3 speech-language pathologists, 1 pediatrician, 1 allergist, and 1 otolaryngologist, evaluated the patients. Multidisciplinary clinical examinations were carried out (complete blood counting, X-rays, nasofibroscopy, audiometry). The two most commonly found etiologies were allergic rhinitis, followed by functional mouth breathing. Of the 414 patients in the study, 346 received a speech-language pathology evaluation. The most prevalent finding in this group of 346 subjects was the presence of orofacial myofunctional disorders. The most frequently orofacial myofunctional disorder identified in these subjects who also presented mouth breathing included: habitual open lips rest posture, low and forward tongue rest posture and lack of adequate muscle tone. There were also no statistically significant relationships identified between etiology and speech-language diagnosis. Therefore, the specific type of etiology of mouth breathing does not appear to contribute to the presence, type, or number of speech-language findings which may result from mouth breathing behavior. PMID- 23362599 TI - A lateral cephalometric x-ray study of selected vertical dimensions in children with atypical deglutition. AB - Atypical deglutition (tongue thrust swallowing) has been thought by some to be an etiological factor related to dental malocclusion, especially changes related to excessive increase in vertical facial growth. The purpose of this study was to investigate this possible relationship between atypical deglutition and vertical facial growth by documenting the lower, middle and upper facial areas of children with atypical deglutition. 55 lateral cephalometric radiographs were analyzed and measured in each of two groups of subjects according to standardized facial plane angles between the (I) palatal plane and mandibular plane, (II) palatal plane and occlusal plane, (III) mandibular plane and occlusal plane, (IV) skull base and Frankfurt plane, and (V) mandibular angle. The experimental group was comprised of 55 subjects with atypical deglutition, while 55 subjects with normal swallowing were used as a control group. The linear/angular measurements were subjected to Mann-Whitney statistical test with a significance level of 5%. RESULTS: The average angle of the variables I, II, III and IV are, respectively: 29, 14, 14 and 9 degrees in both groups. There were no significant differences in the variables studied in the normal and atypical swallowing groups. However, for variable V there were 3 degrees of difference between the groups, which was statistically significant. The results of this study suggest that the problem of atypical swallowing may be of functional origin and not associated with anatomical changes seen in vertical growth patterns. PMID- 23362601 TI - Quantitative evaluation of tongue protrusion force. AB - The tongue plays an important role in the functions of speech, mastication, swallowing, and breathing. The tongue helps in the maintenance of proper dental alignment and arch stability. Adequate strength is essential for the tongue to perform these tasks. Recently the Biomechanical Engineering Group from Universidade Federal de Minas Gerais, Brazil, developed a device to improve tongue strength evaluation. The purpose of this study is to describe and compare the main results obtained in tongue protrusion force measurements in different age groups using this new device. Fifteen healthy subjects were given a qualitative evaluation and determined to have normal tongue strength. They were separated by age in three groups: children, adults and elderly. They were then given a quantitative evaluation. Maximum and average forces were analyzed. The time taken to reach maximum force was also assessed. Higher values of maximum and average tongue force were obtained in the adult group, followed by the elderly group and the group of children. Older subjects had greater tongue force when compared to children. However, there were statistically significant differences in the average force and in the maximum force only between children and adults. Time taken to reach maximal isometric force was longer in the elderly group and shorter in the group of children than in the group of adults although no statistically significant difference was found between groups. PMID- 23362602 TI - Confirmational study: a positive-based thumb and finger sucking elimination program. AB - This article emphasizes the critical need for information specifically regarding the topic of retained sucking behaviors. The study aimed to confirm results provided by Van Norman of 723 subjects in 1997. Parent surveys were collected on 441 subjects who received an orofacial myofunctional treatment program provided by one certified orofacial myologist. Results of this study do confirm that retained digit sucking behavior may be addressed successfully and expediently by a program based on positive behavior modification techniques. PMID- 23362603 TI - Meeting the needs of rural and regional families: educating midwives. PMID- 23362604 TI - Interprofessional clinical education: clinicians' views on the importance of leadership. AB - The current shortage of health professionals necessitates new approaches to clinical education that can expand the number of undergraduate students undertaking clinical placements without increasing the burden on clinical staff or placing patients at risk. Interprofessional education has the potential to help increase clinical capacity whilst enriching students' clinical experience. This paper reports on a project which investigated the potential for interprofessional education to increase undergraduate clinical placement capacity in clinical settings. The project utilised an exploratory descriptive methodology to obtain the views of health care professionals about the use of interprofessional education in clinical education at three rural health facilities in Victoria, Australia. Participants (n = 57) had a key role with each health care facility in coordinating and facilitating undergraduate clinical placements. This paper examines the clinicians' views about the central role that leadership plays in actioning interprofessional education in the clinical setting. Whilst interprofessional education was regarded favourably by the majority of participants, data indicated that leadership from education providers, health services, and regulatory authorities was crucial to enable interprofessional education to be implemented and sustained within the clinical learning environment. Without leadership from each of these three spheres of influence, interprofessional education will continue to be difficult to implement for undergraduate students and compromise their exposure to an important aspect of the working life of health care professionals. Such a failure will limit graduates' readiness for collaborative and cross-disciplinary practice. PMID- 23362605 TI - Effective leadership, teamwork and mentoring--essential elements in promoting generational cohesion in the nursing workforce and retaining nurses. AB - Despite recent increases in nurse recruitment in Australia, the current nursing workforce is still below the predicted numbers for the future demands. The combination of an ageing workforce, high nursing staff turnover and an inability to attract and retain nurses is eroding the capacity of the health care sector to appropriately respond to the care needs of the community. Currently, the nursing workforce may have as many as four generations working together. Differences in employment needs and values, work ethics, attitudes towards authority, and professional aspirations, contribute to some of the cross-generational problems that emerge and the turnover of nursing staff. Strategies to improve the retention rates of nurses need to focus on building a cohesive workforce by utilising the strengths and skill sets that characterise different generations of nurses, and creating the conditions in which nurses across all generations feel supported and valued. The aim of this article is to explain how effective leadership, teamwork and mentoring can assist efforts to promote generational cohesion and address the decline in the number of nurses in the workforce. PMID- 23362606 TI - Evaluating and improving a model of nursing care delivery: a process of partnership. AB - INTRODUCTION: Evaluating and improving a model of nursing care is a fundamental part of clinical practice improvement. While Australian nurses are showing increasing interest in improving models of care delivery, more research is needed that addresses and articulates the processes attendant upon evaluating, re designing and implementing improvements to the provision of nursing care. Providing nurses with an open opportunity to plan, act, observe and reflect on their practice promotes successful partnerships between academics and clinicians. AIM: The aim of this study was to evaluate and improve the model of nursing care delivery to patients in a general surgical ward using participatory action research. METHOD: Researchers conducted non-participant observations (n = 9) of two hours duration across the 24 h period. Focus groups (n = 3) were used to share non-participant observation data with staff, providing them with an opportunity to reflect on their practice and explore possible solutions. Data was collected in 2008-2009. RESULTS: Two main problem areas were identified as impeding the nurses' ability to provide care to patients: (i) practices and behaviours of nurses and (ii) infrastructure and physical layout of the ward. An overview of issues within each problem area is presented. CONCLUSION: Shifting the focus of task-centred care towards a more patient-centred care approach, results directly in improvements in resource utilisation, improved cost effectiveness and job satisfaction for nursing staff. New ways of thinking about nursing processes and systems, workflow design and skill allocation will guide hospital administrators and managers in the effective and efficient allocation of nursing work in similar settings. PMID- 23362607 TI - Organisational intervention to reduce occupational stress and turnover in hospital nurses in the Northern Territory, Australia. AB - OBJECTIVE: To evaluate the impact of an organisational intervention aimed to reduce occupational stress and turnover rates of 55% in hospital nurses. DESIGN: The evaluation used a pre- and post-intervention design, triangulating data from surveys and archival information. SETTING: Two public hospitals (H1 and H2) in the Northern Territory (NT) Australia participated in the intervention. SUBJECTS: 484 nurses from the two NT hospitals (H1, Wave 1, N = 103, Wave 2, N = 173; H2, Wave 1, N = 75, Wave 2, N = 133) responded to questionnaires administered in 2008 and in 2010. MEASURES: The intervention included strategies such as the development and implementation of a nursing workload tool to assess nurse workloads, roster audits, increased numbers of nursing personnel to address shortfall, increased access to clinical supervision and support for graduates, increased access to professional development including postgraduate and short courses, and a recruitment campaign for new graduates and continuing employees. We used an extended Job Demand-Resources framework to evaluate the intervention and 17 evaluation indicators canvassing psychological distress, emotional exhaustion, work engagement, job satisfaction, job demands, job resources, and system factors such as psychosocial safety climate. Turnover rates were obtained from archival data. RESULTS: Results demonstrated a significant reduction in psychological distress and emotional exhaustion and a significant improvement in job satisfaction, across both hospitals, and a reduction in turnover in H2 from 2008 and 2010. Evidence suggests that the intervention led to significant improvements in system capacity (adaptability, communication) in combination with a reduction in job demands in both hospitals, and an increase in resources (supervisor and coworker support, and job control) particularly in H1. CONCLUSIONS: The research addresses a gap in the theoretical and intervention literature regarding system/organisation level approaches to occupational stress. The approach was very successful on a range of health, work outcome, and job design indicators with results providing compelling evidence for the success of the system/organisational level intervention. The quasi-experimental design enabled us to conclude that improvements for the nurses and midwives could be attributed to the organisational intervention by the NT Department of Health (DoH). Further research should be undertaken to explore longer-term impacts, and particularly the influence on turnover. Levels of stress in hospital nurses remain high and present important implications for the psychological well-being of staff. PMID- 23362608 TI - Reclaiming caring in nursing leadership: a deconstruction of leadership using a Habermasian lens. AB - Nursing leaders function in an environment of increasing demands coupled with decreasing resources. This paper explores the landscape of nursing leadership from a critical theory perspective, particularly Habermas's theory of communicative action. We not only deconstruct contemporary nursing leadership, discussing the potential negative consequences for those who fulfil roles of both 'nurse' and 'leader', but also offer possibilities for a more positive future. PMID- 23362609 TI - Nursing work directions in Australia: does evidence drive the policy? AB - A significant body of research has shown a relationship between nurse staffing (in particular, skill-mix: the proportion of Registered Nurses [RNs]) and both morbidity and mortality. This relationship is typically investigated by measuring the incidence of Nursing Sensitive Outcomes (NSOs) under different skill-mix levels. Yet whilst the evidence suggests that richer skill-mix is associated with a lower incidence of NSOs, recent Australian policy reforms have proposed the replacement of Registered Nurses with less qualified staff. The present study sought to examine the relationship between staffing, skill-mix, and incidence of NSOs at two hospitals in one Australian state. The study sought to determine the rate of occurrence of several NSOs, the relationship of skill-mix to that rate, and the number of patients affected per annum. It was found that the current rate of NSOs across wards ranged from 0.17% to 1.05%, and that there was an inverse relationship between the proportion of hours worked by RNs and NSO rates: an increase of 10% in the proportion of hours worked by RNs was linked to a decrease in NSO rates by between 11% and 45%. It was estimated that increasing the RN staffing percentage by 10% would mean 160 fewer adverse outcomes for patients per year across these two hospitals. Importantly, increases in nursing hours overall (without increases in skill-mix) had no significant effect on patient outcomes. These findings challenge current policy recommendations, which propose increasing the number of unregistered staff without increasing skill-mix. PMID- 23362610 TI - The role of clinical trial nurses: an Australian perspective. AB - Over the past two decades, the number of clinical trials conducted globally has increased thereby increasing demand for nurses working as Clinical Trial Nurses (CTNs), sometimes known as Clinical Research Nurses. The role and professional issues for these nurses in Australia has not been empirically formulated. Sixty seven clinical trial nurses were surveyed nationally using a modified version of the Clinical Trials Nursing Questionnaire (CTNQ). Findings revealed the complex CTN role can include the coordination of the trials on one or more sites. This involves all domains listed in the questionnaire from protocol development, ethics approval applications, recruitment and consenting of participants in trials, to administering or assisting with treatments within the bounds of their practice code and the evaluation of protocols. Professional issues documented were: being undervalued in the nursing workforce, having no formal educational preparation for the role and minimal recognition in publications emanating from research in which they were involved. These nurses bring their practice knowledge to benefit research outcomes that may contribute to improving patient/client care. PMID- 23362611 TI - Show me the evidence: ways of knowing what works in child welfare. PMID- 23362612 TI - Do evidence-based group parenting programs for high-risk or maltreating parents include content about psychological maltreatment?: a program review. AB - Psychological maltreatment (PM) is a wide-spread form of child maltreatment, both in high-risk and maltreating parents, yet there are no intervention programs that target it directly. In this study, the content of parenting programs for high risk and maltreating parents was assessed to determine whether the program manuals include content on PM. Nine evidence-based group parenting programs for high-risk or maltreating parents (e.g., included in the SAMHSA or a comparable model program registry) were identified. Program manuals were rated for whether they included content on 18 types of psychological maltreatment (PM). Only one type of PM was rated as being included in all nine programs. Not one of the remaining PM types was rated as being included in more than four programs; and many of the PM types were not rated as being included in any program manual. Therefore, existing parenting program manuals do not contain content related to many forms of psychological maltreatment. PMID- 23362613 TI - Strengthening families and communities to prevent child abuse and neglect: lessons from the Los Angeles Prevention Initiative Demonstration Project. AB - The Prevention Initiative Demonstration Project, funded by the Los Angeles County Department of Children and Family Services (DCFS), is a community-specific strategy delivered through eight regional networks designed to address the full spectrum of community-based prevention. This article summarizes a strong and meaningful pattern of improvements found in the second year evaluation for three groups of families--those living in high-risk communities but not involved with DCFS, those being investigated by DCFS for possible child maltreatment, and those with open DCFS cases. PMID- 23362614 TI - Estimating staffing needs for in-home child welfare services with a weighted caseload formula. AB - State child welfare risk and safety assessment data were analyzed to determine three levels of in-home service that correspond to the Child Welfare League of America's (CWLA) national caseload standards and to evaluate the number of staff needed to provide services at each level. The analysis revealed that 50% additional case-carrying in-home services staff were needed to provide appropriate risk- and safety-based services to children in their own homes. Findings from this study were used by the state child welfare services agency to allocate vacant worker positions to local jurisdictions. PMID- 23362615 TI - Understanding the use of psychotropic medications in the child welfare system: causes, consequences, and proposed solutions. AB - Recent studies have highlighted the progressively increasing number of children prescribed psychotropic medication, while findings have illustrated significantly greater usage among child welfare-involved children. These findings have raised serious concerns among mental health and child welfare professionals as well as the general public. To address this issue, the authors explore the factors that may contribute to the higher incidence of psychotropic medication usage among child welfare-involved children and the unintended negative consequences for these children and the public health system. They propose methods to effectively address this problem. PMID- 23362616 TI - Youth and administrator perspectives on transition in Kentucky's state agency schools. AB - Students, a large percentage with disabilities, are at high risk for poor post secondary outcomes in state agency education programs. This mixed-methods study describes the understandings of student transitions in state agency education programs from the perspectives of youth and administrators. Results indicated that: transition is more narrowly defined within alternative education programs; key strengths of transition practice are present in nontraditional schools; and the coordination barriers within this fluid inter-agency transition system are most apparent in students' frequent inter-setting transitions between nontraditional and home schools. PMID- 23362617 TI - Meningococcal vaccine evolution. AB - Neisseria meningitidis is a leading cause of bacterial sepsis and meningitis worldwide. Invasive meningococcal disease (IMD) can develop rapidly and is associated with high mortality and morbidity. Case fatality in developed countries averages 10% and higher rates are reported in less prosperous regions. The incidence of invasive disease due to Neisseria meningitidis is highly variable according to geographical area and serogroup distribution. The major disease burden is in developing countries; in industrialized countries meningococcal disease occurs sporadically and most IMD is caused by serogroups B and C. In the US serogroup Y is a major cause of meningococcal disease, accounting for more than one third of cases. Polysaccharide vaccines against serogroups A, C, W-135, and Y were developed but they were not so effective in protecting infants, who are at particularly high risk from invasive meningococcal infections. Conjugation of bacterial capsular polysaccharide to a carrier protein generates a T cell dependent immune response and immunological memory from infancy. After the introduction of serogroup C meningococcal conjugate vaccines since 1999, the incidence of serogroup C disease fell dramatically in countries in which they have been used. The first quadrivalent meningococcal conjugate vaccine (MenACWY-D) was licensed in the US in 2005. More recently, another tetravalent meningococcal conjugate vaccine (MenACWY-CRM, Menveo) was licensed in Europe and the US. Although polysaccharide and glycoconjugate vaccines have been developed for serogroups A, C, Y and W-135, currently there are no broadly effective vaccines available for the prevention of meningococcal B disease. PMID- 23362619 TI - Surveillance and evidence of contamination in hospital environment from meticillin and vancomycin-resistant microbial agents. AB - INTRODUCTION: Direct contact is undoubtedly the main means of transmission of hospital infections. An investigative study was therefore conducted to assess workplace surfaces at risk from microbial contamination. METHODS: The study was conducted using swabs and contact slides placed on the palms of healthcare workers during their routine patient care and on workplace surfaces (e.g. telephones, computers, medication trolleys, taps) in treatment rooms, operating theatres and wards. Disposable swabs were used for rapid screening and read with a bioluminometer. At the same time, a sample was taken from those testing positive using a contact slide. The samples testing positive for Staphylococci underwent identification to assess resistance to meticillin-resistant Staphylococcus aureus (MRS/MRSA) and to vancomycin (VISA/VRSA). RESULTS: Meticillin-resistant Staphylococcus strains were found on 14.7% (20/136) of samples taken from the hands of workers and 35.7% (15/42) of those from hospital surfaces. An even higher resistance to meticillin and/or vancomycin than that found for S. aureus was identified in nosocomial strains of coagulase negative staphylococci, including S. epidermidis and S. haemolyticus. CONCLUSION: The study concludes that there is thus a need for greater care in complying with procedures designed and support for surveillance to reduce the risk of infection. PMID- 23362618 TI - A phase II, randomised clinical trial to demonstrate the non-inferiority of low dose MF59-adjuvanted pre-pandemic A/H5N1 influenza vaccine in adult and elderly subjects. AB - BACKGROUND: Effective planning and preparedness against a possible future A/H5N1 influenza pandemic is a major global challenge. Because dose sparing strategies are required to meet the global demand for vaccine, efforts have focused on the development of adjuvanted vaccine formulations of relatively lower antigen content. AIM: This study aimed to demonstrate the non-inferiority of a low antigen-dose (3.75 MU) [DOSAGE ERROR CORRECTED] A/H5N1 pre-pandemic vaccine compared with a licensed, higher-dose (7.5 mg) formulation in adult and elderly subjects. Immunogenicity was assessed according to European and U.S. licensure criteria. METHODS: A total of 722 subjects were randomized in equal numbers to receive either the licensed or low-dose formulation. All subjects received two vaccine doses administered three weeks apart. Immunogenicity was assessed three weeks after the administration of each vaccine dose by hemagglutination inhibition (HI), single radial haemolysis (SRH) and microneutralization assays (MN). Local and systemic reactions were assessed over a seven day period post vaccination. Adverse events were recorded throughout. RESULTS: The low-dose vaccine was demonstrated to be non-inferior to the licensed formulation in terms of antibody titres against the vaccine strain. All three European licensure criteria were met by adult subjects in response to the low-dose vaccine; two criteria were met by the elderly age group. Cross-reactive antibodies were detected against the heterologous A/H5N1 antigen strains A/Indonesia/05/05 and A/turkeyTurkey/01/05. Both vaccines were generally well tolerated by both age groups. CONCLUSION: These data demonstrate that a low antigen dose in combination with MF59 adjuvant is adequate for the routine pre-pandemic immunization of adult and elderly subjects. PMID- 23362620 TI - Prevalence and intensity of intestinal helminthiasis in children living in orphanages in Benin City, Nigeria. AB - BACKGROUND: Orphans may be envisaged to have sub-optimal care and may be predisposed to high worm burden. This study was undertaken to determine prevalence and intensity of intestinal helminthiasis in children living in orphanages in Benin City, Nigeria. METHODS: Fresh stool samples from 150 children (0-17 years) living in 10 orphanages in Benin City, were analyzed using the Kato Katz technique for the detection of ova of helminths between January and April, 2011. RESULTS: The subjects consisted of 62 (41.3%) males and 88 (58.7%)females; mean age (+/- standard deviation SD) 7.0 +/- 4.6 years, and mean (+/- SD) years lived in the orphanage was 4.0 +/- 3.7 years. Prevalence of intestinal helminthiasis was 20.7% and this prevalence was highest in children ages 12 17years, children who had lived longer years in the orphanages and in orphanages with poor child/care-giver ratio (orphanage F = 12.0: 1 and orphanage H = 7.3: 1). Mean (+/- SD) age (8.7 +/- 4.5 years) of infected subjects was significantly higher than (6.6 +/- 4.5 years) observed in non-infected subjects (p = 0.023). Ascaris lumbricoides and Trichuris trichiura were the intestinal helminths isolated. Intensity of intestinal helminths was light in 24/31 (77.4%) and moderate in 7/31 (22.6%) infected subjects. Median egg per gram was 999 eggs per gram and range was 48-8000. CONCLUSION: Improved child/care-giver ratio in orphanages will reduce worm burden in orphanages in Benin City. PMID- 23362621 TI - Is Venice an ideal habitat for Legionella pneumophila? AB - INTRODUCTION: Legionella bacterium manifests itself in Legionnaire's disease and Pontiac fever, it is mainly found and transmitted by aerosol produced in cooling towers, water distribution plants and medical equipment, and it affects mainly elder persons in poor health. METHODS: The population of Venice Local Health Unit was divided in two areas of study and the incidence of legionellosis in residents of Venice historical centre (Distretto Sanitario 1) and in residents of the mainland and coastal areas (Distretti Sanitari 2, 3, 4) was calculated. The cases were those notified to the Public Health Unit by law, and the population of residents was that of the eligible for health care in the archives of the Local Health Unit. Only cases of legionellosis in residents who had not travelled in the 10 days previous of the onset of disease, and not related to nosocomial clusters were considered. The standardized incidence ratio was then calculated and confidence interval were defined by Poisson distribution. RESULTS: Given the population of the two areas, 59801 in Distretto Sanitario 1 and 237555 in Distretti 2, 3, 4, the raw incidence of disease is respectively 87 per 100000 and 20 per 100000 in time 2002-2010. The standardized incidence ratio for the population of Distretto Sanitario 1 vs the remaining population is 4.3. DISCUSSION: The difference in risk of getting the disease in this two residential areas geographically very close, is probably related to the different buildings' characteristics, old and difficult to maintain in Venice historical centre. PMID- 23362623 TI - Adherence of Aeromonas hydrophila strains to human enterocyte-like cells pre infected with rotavirus. AB - INTRODUCTION: The interest grown in these years about emerging pathogens in the onset of intestinal disease showed that the pathogenic mechanism is a multifactorial event. Our objective was to evaluate the role of co-infection with rotavirus in the expression of Aeromonas spp adhesiveness. METHODS: The rate of co-infection involves contact of Caco-2 cells with the virus, followed by adsorption for 1 and 2 hours. Aliquots of bacterial suspensions were added to tissue-culture plates. After infection, cell monolayers were lysed; serially diluted lysates were plated to determine the number of bound bacteria by performing colony forming units (CFU) counts. RESULTS: Non-adhesive strains were not subject to variations resulting from co-infection, while those who had medium or high adhesiveness gave rise to an increase of the same. DISCUSSION: Infection with rotavirus promotes the Aeromonas ability to adhere to Caco-2 cells and this effect depends on the duration of infection and on the starting adhesiveness of bacteria strain. PMID- 23362622 TI - Intestinal parasitic infection and nutritional status among school children in Angolela, Ethiopia. AB - INTRODUCTION: Gastrointestinal parasitic infections are most prevalent in populations with low household income, poor handling of personal and environmental sanitation, overcrowding, and limited access to clean water. We conducted this study to estimate the prevalence of parasitic infection and nutritional status, and to evaluate the extent to which the two are associated among schoolchildren in rural Ethiopia. METHODS: This is a cross sectional study of 664 students aged from 6 to 19 years old from Angolela, Ethiopia. Socio demographic information was collected using a structured questionnaire. Anthropometric measurements were taken at the time of interview. Examinations of fecal samples for helminthic and protozoan parasitic infections were performed. Logistic regression procedures were employed to evaluate the association between stunting, underweightedness, and wasting with parasitic infections. RESULTS. One third of the participants were found to have a protozoan infection, while 7.1% were found to have a helminthic infection. Approximately 11% of the students were stunted, 19.6% were wasted, and 20.8% were underweight. Severely underweight boys were 3.88-times as likely as boys of adequate weight (odds ratio OR = 3.88, 95% confidence interval CI: 1.12-13.52) to be diagnosed with protozoan infections. Among girls, those who were severely stunted were approximately 12 times (OR = 11.84, 95%CI: 1.72-81.62) as likely to be infected with a helminthic parasite, than those who were not. Overall, there was a deficit in normal growth patterns as indicated by lower than average anthropometric measures. DISCUSSION AND CONCLUSIONS. There is a high prevalence of intestinal parasitic infections. Stunting, wasting, and underweightedness were also prevalent, and showed patterns of associations with intestinal parasitic infections. Efforts should be made to strengthen and expand school and community-based programs that promote inexpensive, though effective, practices to prevent the spread of parasitic diseases. Initiatives aimed at improving the nutritional status of school children are also needed. PMID- 23362624 TI - High-burden epidemics in Greece in the era of economic crisis. Early signs of a public health tragedy. AB - BACKGROUND: Economic hardships have unleashed epidemics of infectious diseases in many countries in the past. In the era of the current financial crisis in Greece, it is interesting to assess the preliminary evidence concerning outbreaks of infectious diseases. METHODS: Description and evaluation of published surveillance data. RESULTS: Greece has been suffering a high burden of different large-scale epidemics during the last three years. These include the increased mortality of influenza during the pandemic and the first post-pandemic seasons, the emergence and spread of West Nile virus, the appearance of clusters of non imported malaria and the outbreak of Human Immunodeficiency Virus infection among people who inject drugs. CONCLUSION: The economic turmoil in Greece seems to impact the infectious disease dynamics. It is essential to safeguard and even bolster budgetary allocations to the public health sector, in order to alleviate the effects of the economic downturn. PMID- 23362625 TI - Isolation of fungi from housefly (Musca domestica L.) at Slaughter House and Hospital in Sanandaj, Iran. AB - OBJECTIVE: Houseflies have long been regarded as potential carriers of microorganisms especially fungi. Since pathogenic microorganisms are widespread in the hospital environment, there is abundant opportunity for flies to become contaminated and in turn to contaminate the patient environment and residential regions. The aim of this study was to isolate and identify fungi from the slaughter house and the hospital environments. MATERIAL AND METHOD: The flies were captured with a sterile nylon net and transferred to the Entomology Laboratory for identification by standard keys. The flies were captured and rinsed in a solution of 1% sodium hypochlorite for three minutes and twice in sterile distilled water for 1 min then flies was transferred to a 0.85% saline solution. 0.1 ml of this solution was transferred to Sabouraud's dextrose agar (SDA). Isolation of fungi was identified by standard mycological methods. RESULTS: In this study totally 908 Musca domestica (418 flies from the hospital environments and 490 flies from the slaughter house) were collected in Sanandaj, Iran. The main fungi isolated were Aspergillus spp (66%). and another isolated were belong to Penecillium spp. (14%), Fusarium spp. (11.3%), Alternaria spp. (6%) and among the filamentous fungi, 8.6% of the isolates as Microsporum gypseum of dermatophytes was identified. CONCLUSION: The present study supports belief that the house fly is a carrier for fungal spores. Therefore they have to be controlled and density of their population should be reduced undertaken different vector control approaches. PMID- 23362626 TI - Vaccination programmes against invasive disease in Italy, with particular regard to Valle d'Aosta. PMID- 23362627 TI - A journey through disability: a sibling's perspective. PMID- 23362628 TI - Parental self-efficacy and online support among parents of children diagnosed with type 1 diabetes mellitus. AB - Families faced with the challenges of caring for a child newly diagnosed with type 1 diabetes mellitus are often overwhelmed by the regimented demands of diabetes care management. Social support for families has been recognized as an important component to adaptation and has been deemed necessary for helping families develop healthy coping strategies. The purpose of this evidence-based practice (EBP) project was to develop a Web-based platform to enhance social support and increase self-efficacy of parents with a child with type 1 diabetes. The following clinical question guided the project: "Among parents of children diagnosed with type 1 diabetes in a small Midwestern city, what are parents' self reported self-efficacy scores related to diabetic care management pre- and post implementation of a Web-based social support platform?" A one-group pretest/post test descriptive design was used, with parental self-efficacy measured pre- and post-intervention (Web-based platform access) using the Diabetes Empowerment Scale (DES) and Self-Efficacy for Diabetes Scale (SED), and parent satisfaction with the online support platform assessed through parental comments. Project outcomes corroborated the use of online social support as evidenced by improvement in parental self-efficacy scores in both the DES and SED survey measurements. A statistically significant increase (p < 0.05) was found between the pre- and post-implementation scores of the SED survey. Secondary data supported the positive relationship of social support and self-efficacy in raising a child with type 1 diabetes. This online social support platform was found to be an easily adaptable, cost-effective, and innovative means of networking and information sharing among families facing similar challenges in raising a child with type 1 diabetes. PMID- 23362629 TI - A lion in the room: youth living with HIV. AB - This qualitative study conducted in rural and urban Georgia was designed to understand the experience of youth living with HIV who received health care from community-based and AIDS service organizations. The interview guide was developed by the authors within a health improvement context, and data analysis focused on thematic content. Twenty-nine youth, 13 to 24 years of age, volunteered to be interviewed, either in focus groups or independently. The major thematic findings were taking pills, how they look at you, being healthy, keeping it private, a lion next to you, they can help me, and life goes on. Physical and psychosocial benefits were achieved from trusting relationships with professional and personal caregivers, personal control, and self-esteem. This study identified a need for more intense, reliable, and continuous attention to social and family support. PMID- 23362630 TI - The value of qualitative research methods. PMID- 23362631 TI - A framework for exploring adolescent wellness. AB - This article presents and explains a "Framework for Exploring Adolescent Wellness" and outlines a research approach used to explore adolescent wellness specific to the discipline of nursing. The "Framework for Exploring Adolescent Wellness" assessed the concept of wellness through the perceptions of youth and sought to explain the relationship between adolescent well-being and development. A wellness survey was used to collect data from 280 youth, 16 to 20 years old, in two Western Canadian high schools. Their perceptions of wellness meant more to them than regular physical activity and healthy eating. The majority of youth suggested that psychological (89%), social (85%), and physical (80%) development made the most significant contribution to adolescent wellness. Slightly more than half the youth felt that spirituality (53%) contributed to their sense of wellness. These research findings indicate the need for an approach to adolescent nursing care that includes a high priority and greater visibility to the practice and philosophy of wellness. PMID- 23362633 TI - Beyond the medical home: Special Care Family Academy for children and youth. AB - Children and youth with special health care needs require more health care and related services and consequently incur more costs than other individuals. Implementation of the "medical home" concept has benefitted children with special needs, resulting in fewer unmet medical needs and more consistent health care delivery. As advances in health care have enabled an increasingly higher percentage of children with special needs to live far into adulthood, the transition from adolescence to adulthood poses new challenges in obtaining medical care, education, job training, and employment opportunities. A more comprehensive medical home paradigm for children with special needs is composed of three fundamental components: 1) home/community, 2) education, and 3) medical/dental care. These components should be developed equally and in parallel, emphasizing consumer advocacy, care coordination, education, life skills, and career development, to attain independent or minimally dependent living. This new model has been initiated at Hospital for Special Care in New Britain, Connecticut, in its Special Care Family Academy. PMID- 23362632 TI - The psychosocial impact of life-threatening childhood food allergies. AB - The purpose of this integrated literature review was to bring understanding to medical professionals of the psychosocial impact of parenting a child with life threatening food allergies. Prevalence of life-threatening food allergy among children is increasing, and families continue to navigate the effects it can have on all members of a family. A comprehensive literature review was performed related to chronic childhood illnesses and life-threatening food allergies. Commonalities among the conditions exist related to stress, coping, and adaptive responses when parental perceptions and experiences are considered. This information may provide a conceptual context for the adaptation process involved with parenting a young child with life-threatening food allergies, revealing areas where nursing can serve to intervene and support this process. PMID- 23362634 TI - Preventing central line infections in outpatients. PMID- 23362636 TI - The secret of passing tort reform is as simple as one-two-three. PMID- 23362635 TI - Parents of obese children and charges of child abuse: what is our response? PMID- 23362638 TI - What to expect in the 2013 General Assembly. PMID- 23362637 TI - Medicare & Medicaid access to care under the Affordable Care Act. PMID- 23362639 TI - Missouri health care headed for catastrophe without tort reform. PMID- 23362640 TI - Who killed private practice? PMID- 23362641 TI - MSMA advocacy works for all. PMID- 23362642 TI - Principles and strategic plan will guide employed physicians & concentrate on shaping the future of medicine. PMID- 23362643 TI - Doctor pay and social priorities. PMID- 23362644 TI - What I did not learn in medical school or residency. PMID- 23362645 TI - Home health care: healing where the heart is. PMID- 23362646 TI - Adolescent cannabis use: changing minds. PMID- 23362647 TI - Concussions in high school sports: are they worth the risk? Should school football be banned? PMID- 23362648 TI - Qualified spousal trusts. New Missouri law provides financial planning flexibility for married doctors. PMID- 23362649 TI - Alcohol consumption: can we safely toast to our health? AB - Alcohol has been reported to be beneficial in reducing the risk and complications of cardiovascular disease (CVD). This benefit must be balanced with the known risks of alcohol. This review examines the evidence that there is a favorable effect on CVD and attempts to evaluate if the positive effects outweigh the potential pernicious sequellae. PMID- 23362650 TI - Lumbar spinal stenosis: treatment options for an aging population. AB - The fastest growing age group in the United States is the 45 and older population. Due to the nature of the aging lumbar spine, a significant majority of this population will experience low back pain (LBP) and symptoms associated with lumbar spinal stenosis. Accurate diagnosis and appropriate treatment is required if this particular aging group of our population is to maintain an active and productive life into their later years. PMID- 23362651 TI - Mental health access to care in Missouri. AB - Mental illnesses are a significant cause of morbidity and mortality in the United States, affecting, in some estimates, up to one in four adults or 57.7 million people. Severe psychiatric disorders, like schizophrenia, bipolar and major depression occur in one in seventeen Americans. Moreover, serious mental illnesses affect children at rates approaching 10%. Addictive disorders co occurring with other mental illnesses affect over five million adults. The direct cost of these illnesses is high, totaling 16 billion dollars per year; dwarfed by the indirect costs of loss productivity which is four times as much. Individuals diagnosed with mental disorders have significantly higher rates of school dropout, homelessness, incarceration, and suicide. Embedded in these statistics is a concerning fact; access to care for those with psychiatric disorders is poor, with only one-third of adults and half the children diagnosed receiving care in any given year. These numbers are worse if the person is a racial or ethnic minority. This paper hopes to highlight the state of mental health treatment first in the United States and then in our state of Missouri. The news is sobering but there are pockets of good news as well. PMID- 23362652 TI - Mental health care utilization at a free drop-in youth center in St. Louis, Missouri. AB - We review demographic and mental health data from 1,729 youths aged 13 to 24 who attended the SPOT (Supporting Positive Opportunities with Teens), a free multi resource drop-in youth center in St. Louis, within an 18-month period. Logistic regression analysis showed an association of increased mental health utilization and younger age, male gender, unemployment, lower educational attainment, having Medicaid, drug problems, and HIV positive status. Decreased mental health utilization was associated with black or mixed ethnicity, and living with a roommate. PMID- 23362653 TI - Study of secondhand smoke exposure in St. Louis City and County suggests need for comprehensive smoke-free Missouri law adoption. AB - This cross-sectional study provides information about secondhand smoke exposure across the St. Louis metro area and perceptions and attitudes about tobacco and health within the local hospitality industry. Results from this study support the need for passage and implementation of comprehensive smoke-free laws throughout Missouri, particularly in St. Louis City and County where efforts to pass comprehensive smoke-free laws have been unsuccessful. PMID- 23362654 TI - Clinical factors associated with left ventricular ejection fraction disparity in patients with left ventricular dysfunction undergoing multimodality imaging. AB - Drug and device therapy for heart failure is increasingly determined based on left ventricular ejection fraction. Significant disparity frequently exists between echocardiographic and nuclear scintigraphic techniques, even when testing is performed nearly simultaneously in clinically stable patients. In 119 patients with left ventricular dysfunction who underwent both echocardiography and stress testing with nuclear imaging within seven days (but with significant disparity in reported left ventricular ejection fraction), we identified four clinical variables which were associated with left ventricular ejection fraction difference. These clinical variables included atrial fibrillation, left ventricular hypertrophy, severe mitral regurgitation and paced rhythm. PMID- 23362655 TI - Evidence-based nursing practice and oncology care: are we up for the challenge. PMID- 23362656 TI - Counselling and adverse event management for patients with myelodysplastic syndromes undergoing azacitidine therapy: a practice standard for Canadian nurses. AB - Azacitidine (5-azacytidine, VIDAZA) is a disease-modifying agent that improves survival, reduces transfusion dependence, and reduces progression to acute myeloid leukemia in patients with higher risk myelodysplastic syndromes. Azacitidine injection is associated with characteristic adverse events (AEs) that must be managed in order for patients to stay on therapy and achieve optimal therapeutic outcomes. These AEs include injection-site reactions, cytopenias, and gastrointestinal effects. Oncology nurses are uniquely positioned to provide patient support and counselling, thereby helping patients and their families set clear expectations for azacitidine therapy. This article presents a nursing standard designed to support Canadian oncology nurses in the key areas of counselling for patients initiating and continuing azacitidine, as well as nursing strategies for prevention and management of azacitidine-associated AEs. Many of the general principles discussed in this nursing standard can be applied broadly to many diseases and treatments. PMID- 23362657 TI - Priorities, barriers and facilitators for remote support of cancer symptoms: a survey of Canadian oncology nurses. AB - A survey of 368 Canadian oncology nurses revealed that 54% provided remote support to oncology patients. The most common symptoms identified were fatigue, pain, nausea, constipation, and anxiety. Frequent symptoms which nurses felt low confidence in managing were anxiety, neuropathy, depression, anorexia and skin alterations. Most nurses agreed that guidelines were needed that were accessible, and improved continuity of care. Forty-three per cent of respondents felt that existing guidelines were inadequate for complex symptoms. Only 54% of respondents agreed they had received enough symptom management training. Common barriers included time constraints, obtaining accurate patient information via telephone, high workloads and knowledge or training deficits. Facilitating factors for provision of remote support included access to an electronic health record, accessible team members, available technology and ease of documentation. PMID- 23362658 TI - Supportive care needs of Canadian melanoma patients and survivors. AB - The purpose of this study was to determine the supportive care needs of melanoma patients and survivors in Canada. Thirty-one melanoma patients and survivors completed the Supportive Needs Questionnaire--Melanoma Supplementary Module in addition to questions pertaining to information delivery and screening behaviour. Results demonstrated that the majority of patients in the study are having their needs met (61.1% of total participant responses). Unfortunately, a substantial proportion of individuals have unmet needs. Of the examined needs, educational and increased informational resource needs were among the greatest reported, particularly among individuals with less education (high school diploma or less). Although overall it appears the majority of needs are being met, more can be done to improve the care of melanoma patients in Canada. PMID- 23362659 TI - Professional navigation: a comparative study of two Canadian models. AB - For many cancer control programs, cancer navigation has emerged as a specific strategy to improve access to supportive care and the patients' experience of cancer care. This study contributes to a better understanding of professional navigation by comparing two Canadian models: Quebec's Pivot Nurse in Oncology (PNO) and Nova Scotia's Cancer Patient Navigator (CPN). Qualitative interviews were conducted with professional navigators, patients and family members, front line staff, physicians and health administrators (interviews: n = 49; focus groups: n = 10). The two models were analyzed using the professional navigation framework (Fillion et al., 2012). Although the models are different, results show that professional navigators in both programs perform similar functions and face similar challenges. This study highlights the complexity and the value of cancer navigation and recommends relevant actions to optimize its management within the health care system. PMID- 23362660 TI - Evidence-informed protocols to guide oncology nurses providing remote symptom support. PMID- 23362661 TI - The gift of true presence: a nursing story where theory and practice meet. AB - Nursing theories have long existed to guide nursing practice but, in reality, can be challenging to achieve. In this paper the application of Parse's theory on Human Becoming is seen through a nurse's experience with an oncology patient and her family. Her reflection highlights how the concepts and paradoxes of the theory can meet practice. An attitude of true presence enables the nurse to provide quality patient-centred care. Over a period of a year the focus evolves from the perspective of the patient's illness to that of life outside the illness. During that transition, new light is shed on the situation whereby the ultimate meaning changes and transformation occurs for the nurse, the patient and her family. PMID- 23362662 TI - A salute to Dr. Bob. PMID- 23362663 TI - Rule of double effect. PMID- 23362664 TI - Alphavbeta3 suppresses the RhoA-LIMK1 pathway in K1735 melanoma. AB - Mucocutaneous melanoma has a five-year survival rate of less than 10 percent. The alphavbeta3 integrin promotes invasion, which requires actin reorganization by cofilin. The authors previously showed that cofilin and alphavbeta3 promote invasion. K1735 melanoma has several clones, each with different levels of alphavbeta3. The authors found that expression of alphavbeta3 suppresses activation of RhoA thus inhibiting LIMK1 phosphorylation of cofilin. This indicates that alphavbeta3 integrin suppresses the RhoA/ ROCK/LIMK1 pathway. PMID- 23362665 TI - High throughput screening of biologically functional small molecules for modulating the expression of FGFR1OP2/wit3.0 in fibroblasts. AB - Oral wounds heal rapidly without scarring through yet unknown molecular mechanisms. A small cytoskeleton molecule identified in oral wound fibroblasts, FGFR1OP2/wit3.0, has been shown to accelerate wound closure in vitro and in vivo. The objective of this study was to elucidate the transcriptional mechanism of FGFR1OP2/ wit3.0 in fibroblasts using a high throughput drug-screening platform. This pilot study identified chemical compounds that could effectively modulate the FGFR1OP2/wit3.0 expression for future studies on effective wound management. PMID- 23362667 TI - Notion doubts and opinion. PMID- 23362666 TI - Discovery of specific ligands for oral squamous carcinoma to develop anti-cancer drug loaded precise targeting nanotherapeutics. AB - Oral squamous cell carcinoma has a low five-year survival rate, which may be due to late detection and a lack of effective tumor-specific therapies. Using a high throughput drug discovery strategy termed one-bead one-compound combinatorial library, the authors identified six compounds with high binding affinity to different human oral squamous cell carcinoma cell lines but not to normal cells. Current work is under way to develop these ligands to oral squamous cell carcinoma specific imaging probes or therapeutic agents. PMID- 23362668 TI - Attentional selection dilates perceived duration. AB - How do observers judge the passage of time at a short time-scale? Humans are not equipped with a dedicated sensory system for perceiving durations in the same way as they are equipped with systems for perceiving light and sound. Thus, subjective duration depends on the sensory and cognitive processes triggered by sensory input, eg visual or auditory stimuli. Previous studies have demonstrated that the dynamics of this sensory input (eg the rate of stimulus presentation) affect duration judgments. However, it is yet unclear whether automatic or attentive processing of such dynamics accounts for their effect on subjective duration. Automatic and attentive stimulus processing can be distinguished when stimuli are presented in a rapid serial visual presentation (RSVP) paradigm. The second of two targets embedded in an RSVP stream often fails to attract participants' attention and escapes conscious detection, in spite of being automatically processed at a perceptual level. In the present study, we presented RSVP streams and combined a target detection task with a prospective duration judgment task. We demonstrate in three experiments that the number of subjectively perceived target stimuli (and not the number of objectively presented targets) determines subjective duration of the entire RSVP sequence. Target stimuli which escape attentional selection did not affect perceived duration. This finding indicates that attentive rather than automatic processing of stimulus dynamics leads to the subjective time dilation of dynamic stimuli. PMID- 23362669 TI - Wheatstone and the origins of moving stereoscopic images. AB - The recent resurgence of stereoscopic films and television programmes occasions reflection on their origins. Experimental studies of stroboscopic (apparent) motion and stereoscopic vision have their origins in London in the decade from 1825 to 1835. Instruments were devised which simulated motion and depth: sequences of still images could appear to move, and paired pictures (with small horizontal disparities and presented to different eyes) were seen in depth. Until that time, the experience of motion was almost always a consequence of object or observer movement: apparent motion was a novelty. By contrast, stereoscopic vision was the near-universal experience of using two eyes in the natural environment, but its basis remained mysterious. The stereoscope rendered the normal conditions for seeing depth from disparity experimentally tractable. The instruments were called philosophical toys because they fulfilled the dual roles of furthering scientific experiment on the senses and of providing popular amusement. The investigations were initially driven by the need for stimulus control so that the methods of physics could be applied to the study of perceptual phenomena. Many varieties of stroboscopic discs and stereoscopes were devised thereafter and their popularity increased enormously after 1840, when combined with photography. Presenting sequences of stereoscopic photographs in apparent motion was attempted in the 1850s, but proved less successful. The catalyst involved in all these developments was Charles Wheatstone. PMID- 23362670 TI - Age and beauty are in the eye of the beholder. AB - How "old" and "attractive" an individual appears has increasingly become an individual concern leading to the utilisation of various cosmetic surgical procedures aimed at enhancing appearance. Using eyetracking, in the present study we aimed to investigate how individuals perceive age and attractiveness of younger and older faces and what "bottom-up" facial cues are used in this process. One hundred and twenty eight digital images of neutral faces of ages ranging from 20 to 89 years were paired and presented to subjects who judged age and attractiveness levels while having their eye movements recorded. There was an effect of face attractiveness on age-rating accuracy, with attractive faces being rated younger than their true age. Similarly, stimulus age affected attractiveness ratings, with younger faces being perceived as more attractive. Judgments of age and attractiveness were tightly linked to fixations on the eye region, along with the nose and mouth. It is thus likely that cosmetic surgical procedures targeted at the eyes, nose, and mouth may be most efficacious at enhancing one's physical appearance. PMID- 23362671 TI - Horizontal/vertical differences in range and upper/lower visual field differences in the midpoints of sensory fusion limits of oriented lines. AB - O'Shea and Crassini (1982, Perception & Psychophysics 32 195-196) demonstrated that fusion persists for vertical lines with an orientation disparity of 8 degrees, but diplopia is experienced in simultaneously presented horizontal lines with the same disparity. They concluded that the neural fusion process fuses larger horizontal disparities than vertical disparities. Kertesz criticised their demonstration because it did not quantify the possible motor component associated with fusing their counter-rotated images. Krekling and Blika argued that the demonstrated anisotropy is due to a disparity bias in the visual system, owing to the temporalward tilt of corresponding vertical meridians. We addressed these criticisms with a novel stimulus and presentation protocol, that rendered compensatory cyclovergence eye movements unlikely and explored a wide range of orientation disparities. We confirmed O'Shea and Crassini's vertical/horizontal anisotropy in orientation fusion limits. In addition, our measurements of vertical lines showed that the distributions of fused responses as a function of orientation disparity in the upper and lower visual fields were shifted relative to each other. Therefore, the distributions of fusible orientation disparities are wider for vertical lines than horizontal lines and are relatively shifted as predicted if the fusional range is centred around the vertical horopter. PMID- 23362672 TI - The role of movement synchronization with an auditory signal in producing prism adaptation. AB - The prism adaptation procedure is often used to study the plasticity of eye-hand coordination to misalignment of the visual and proprioceptive spatial maps. Misalignment can be resolved by adaptive change in spatial maps of either the eyes or hand or both. In this procedure, pacing pointing movements with a rhythmic auditory signal is usually employed to control movement speed, but the role of the auditory signal itself in producing adaptation has not been examined. The present experiment addressed this issue by testing three conditions: (i) exposure pointing was self-paced without an auditory signal; (ii) exposure pointing was paced by an auditory signal without synchronization; and (iii) exposure pointing was synchronized with the auditory signal. The first condition produced primarily proprioceptive adaptation. The second condition also produced primarily proprioceptive adaptation, but visual adaptation was also present. The third condition produced primarily visual adaptation. Results are discussed in terms of two possible roles for the auditory signal: (i) a rhythmic auditory signal may enhance overall activation of the adaptive neural network; and (ii) movement synchronization with a rhythmic auditory signal may enable multisensory integration, including auditory spatial information that selects the more reliable proprioceptive signal for movement control. Consequently, detection of the misalignment is localized and realignment occurs in the visual system. PMID- 23362673 TI - Moderate movement, more vision: effects of physical exercise on inattentional blindness. AB - Research on inattentional blindness shows that individuals fail to notice unexpected objects or events when attention is focused elsewhere. The majority of previous studies on inattentional blindness have been performed at rest, even though there are several real-life situations that require both physical exercise and focus of attention to accomplish a particular task. A number of different studies have demonstrated that physical exercise influences cognitive performance and attention processes in a variety of ways. Relatively little is known about the effects of physical load on inattentional blindness. The present study was the first attempt to investigate inattentional blindness effects as a function of physical load. Participants were randomly assigned to three groups where they performed two different inattentional blindness tasks: at rest (group 1) and on a bicycle ergometer under moderate (group 2) or high (group 3) physical exercise. The results showed a decrease of inattentional blindness effects from the resting to the moderate exercise condition, and then an increase for the high physical exercise condition, representing an inverted-U plot. Findings support the notion that physical exercise influences individuals' attention performance. We concluded that moderate physical exercise has a positive impact on inattentional blindness, given that people under moderate physical exercise more frequently notice an unexpected object when attention is diverted to another task, and that this evidence should be taken into account when considering certain real-life events. PMID- 23362674 TI - Recognising one's own motor actions through sound: the role of temporal factors. AB - It has been shown that humans are able to recognise their own movement. While visual cues have been amply studied, the contribution of auditory cues is not clear. Our aim was to investigate the role of temporal auditory cues in the identification of one's own or others' performance in a complex movement--a golf swing. We investigated whether golfers are able to discriminate between the sounds associated with their own swings and other golfers' swings, by using the relative timing and the overall duration of the movement. The sounds produced by the participants performing 65 m shots have been recorded and used to create the stimuli. The experimental conditions were: participants' swing sounds and the sounds of other golfers having equal both relative timing and overall duration, equal relative timing but different overall duration, different relative timing but equal overall duration, and both different relative timing and overall duration. The task of the participants was to say whether each sound corresponded or did not correspond to their own swing. Results show that golfers are able to recognise their own movements, but they also recognise as their own the sound produced by other athletes having equal both relative timing and overall duration. PMID- 23362675 TI - Dividing a fixed portion into more pieces leads to larger portion size estimates of JELL-O squares. AB - How visual qualities of a food impact perceptions of the amount of food present and consumed have been studied. Previous research has investigated many factors affecting these perceptions, including the height of a glass, the size of a serving bowl, and other food intake cues. We investigated how the number of pieces a serving is divided into impacts perceptions of the amount of food present and consumed. Results indicate that dividing a fixed portion into a greater number of pieces leads people to perceive a greater amount of food in the serving. PMID- 23362676 TI - Are people adapted to their own glasses? AB - Negative lenses, either in the form of glasses or contact lenses, can correct nearsightedness. Unlike contact lenses, glasses do not only correct, but also induce optic distortions. In the scientific literature, it has often been assumed that people who wear corrective glasses instantaneously account for these distortions when they put their glasses on. We tested this assumption and found that, when people switched between their contact lenses and their glasses, they made the errors that one would predict based on the optics. This shows that people are not immediately adapted to their own glasses when they put them on. PMID- 23362677 TI - Is size misperception of targets simply justification for poor performance? AB - Recent studies show that those who perform poorly on sporting activities involving targets recall the target as smaller than do better performers. Some have attributed the effect to action-specific perception, suggesting perception is influenced directly by how one interacts with an object. We proposed that underestimation of target size may instead serve as a justification for poor performance. We found that inaccurate dart throwers, given an excuse that the darts were of poor quality, were less likely to recall the target as smaller. The findings extend research indicating that perception is influenced by motivational factors, and provide further evidence that size estimates can be distorted by memory errors. PMID- 23362678 TI - Classic debates in selective attention: early vs late, perceptual load vs dilution, mean RT vs measures of capacity. AB - We briefly summarize two important debates regarding selective attention (early vs late selection; perceptual load vs distractor dilution). Also, we report the results of an attempt to replicate Lavie (1995, Journal of Experimental Psychology: Human Perception and Performance 21 451-468). We suggest that measures capable of characterizing the capacity of information processing systems (compared to reporting only mean reaction time) could add great clarity to this literature. PMID- 23362679 TI - The ghost of Helioth and his stereoscope: the return of a phantom. AB - Among the myths surrounding the invention of the stereoscope, that of Helioth stands as a supreme example of shoddy scholarship and its subsequent dissemination. Helioth was said to have made a simple stereoscope before Wheatstone presented his mirror stereoscope to the public in 1838. There is no evidence of Helioth's existence prior to a report in the mid-twentieth century, and despite attempts to dispel his ghost it has recently resurfaced. PMID- 23362680 TI - Hunger enhances vertical vection. AB - Hunger was found to facilitate visually induced illusory upward and downward self motions (vertical vection), but not illusory self-motion in depth (vection in depth). We propose that the origin of this hunger effect lies in the possibility that vertical self-motions (both real and illusory) are more likely to induce changes in visceral state. PMID- 23362681 TI - The FTC's case against the North Carolina Dental Board should not impact the Michigan Board of Medicine. PMID- 23362682 TI - Michigan remains a great place to practice medicine through partnerships such as as physician organizations. PMID- 23362683 TI - Stressed out during the holidays? Try these tips to avoid burnout. PMID- 23362684 TI - Deconstructing MSMS membership. If you think it's only about the pocketbook, think again.... PMID- 23362685 TI - Treating the underserved by training the underserved. PMID- 23362686 TI - The effect of payment reform on physician practices. Part 2. Physicians and health plans prepare for health care's brave new world. AB - In our last installment, we wrote globally about the nature and permanence of trends in physician payment models, particularly the shift from fee-for-service to fee-for-value. In our second communique, we will look specifically at major health plans with which physicians will be working and provide an overview of the payment methods, programs, and demonstrations affecting Michigan physicians and the health care delivery model. PMID- 23362687 TI - After big wins on election night, what do we do now? PMID- 23362688 TI - Think you're done with meaningful use? Think again. PMID- 23362689 TI - Protect vulnerable populations by increasing Michigan's vaccination coverage. PMID- 23362690 TI - Advocacy requires access to policymakers--MDPAC is your ticket. PMID- 23362691 TI - Authentic tolerance: between forbearance and acceptance. AB - Promoting tolerance is seen as a key weapon in battling prejudice in diversity and multicultural training but its meaning has been modified recently. The classical definition of tolerance meant that others are entitled to their opinions and have the right to express them and that even though one may disagree with them, one can live in peace with such differences. In recent years, however, tolerance has come to mean that all ideas and practices must be accepted and affirmed and where appreciation and valuing of differences is the ultimate virtue. Such a neo-classical definition has alienated many who value equality and justice and limits the effectiveness of diversity initiatives that teach the promotion of tolerance. The authors offer authentic tolerance as an alternative, incorporating respect and civility toward others, not necessarily approval of their beliefs and behavior. All persons are equal, but all opinions and conduct are not equal. PMID- 23362692 TI - The effect of yoga on neuroticism in an Indian population varies with socio demographic factors. AB - Neuroticism, or negative affectivity, can influence a person's approach to life. This study examined levels of neuroticism in 249 patients with illnesses known to be related to the mental state. All of them were given a six-day intensive yoga program. Patients showed a decrease in neuroticism measured by the PGI Health Questionnaire. The reduction was maximum for (a) those with ages between 36 and 51 years, (b) females, (c) patients with at least 17 years of education, and (d) those who were self-employed. The results show the importance of socio demographic factors in neuroticism levels and in programs intended to reduce neuroticism. Hence, yoga is a useful intervention to reduce traits of neuroticism, with variations in the degree of change based on social factors. PMID- 23362693 TI - Korean American parents' reconstruction of immigrant parenting in the United States. AB - The aim of this qualitative study was to explore 28 Korean American parents' perceptions of parenting. Interview data were audio taped, transcribed, and analyzed using content analysis. Themes that emerged were: Korean parenting constructed in Korea, European American parenting observed in the United States, and resulting reconstruction of Korean American parenting. The findings indicate that Korean American parents' perceptions of parenting are deeply rooted in the social contexts of where parents were brought up and where parents raise their children. These findings could be used to develop a culturally and linguistically competent parenting program for Korean American parents. PMID- 23362694 TI - Exploration of commonalities and variations in health related beliefs across four Latino subgroups using focus group methodology: implications in care for Latinos with type 2 diabetes. AB - Latinos, now the largest U.S. ethnic minority, have a high risk for type 2 diabetes. The Latino population is a heterogeneous group of individuals from many countries with a variety of beliefs and cultures. The purpose of this study was to explore similarities and differences in beliefs and attitudes related to health and healthcare practices across our Latino subgroups (Mexican, Colombian, Puerto Rican, and Mayan). The study used a qualitative research design employing focus groups and participant questionnaires. Data analysis revealed four themes: 1) View of health; 2) Access to care; 3) Acculturation; and 4) Stress and worry. PMID- 23362695 TI - Complementary and alternative medicine (CAM) use among men with a history of prostate cancer. AB - Complementary and alternative medicine (CAM) has been commonly used among Americans; however, less is known about its use among men with a history of prostate cancer. This study used the 2002 National Health Interview Survey (NHIS) to explore the amount and type of CAM use among 218 Black and White men with a history of prostate cancer. Over 90% of men reported having ever used any form of CAM and most men used biologically-based and mind-body therapies. Nurses are in a unique position to discuss, to assess needs and practices, and perhaps, to act as intermediaries for physicians and other healthcare professionals and prostate cancer survivors who use CAM. PMID- 23362696 TI - A dose of common sense. PMID- 23362697 TI - Overview of current approaches to the evaluation and management of male infertility. AB - Infertility, the inability to conceive after one year of regular, unprotected intercourse, is secondary to male-only factors in 20% and a combination of male and female factors in 30% to 40% of cases. Advances in the identification and management of male factor infertility have provided new and often successful options for paternity. PMID- 23362698 TI - Cleaning urinary drainage bags with vinegar following radical prostatectomy surgery: is it necessary? AB - Following a radical prostatectomy in the authors' institution, patients are sent home with an indwelling urinary catheter. Nurses on the urology unit questioned the standard practice of teaching patients to clean their urinary drainage bags daily with a vinegar solution after discharge and the impact, if any, in reducing catheter-associated urinary tract infections (CAUTI). Using the Mayo Clinic Nursing Framework for Evidence-Based Decision Making (EBDM), the literature was searched and evaluated, and the evidence was compared to current practice. Findings from this literature review did not support the current practice of cleaning the urinary drainage bags with a vinegar solution. This article describes the process taken to make an effective change in the practice at the authors' institution based on the current best evidence. PMID- 23362699 TI - Leakage associated with urinary catheter usage: a design challenge. AB - Indwelling bladder catheter-associated leakage, or catheter bypassing, is a frequently experienced problem, necessitating a carefully planned intervention. Once a bladder catheter is in place, urine may flow intermittently between the catheter shaft and the urethra mucosa, or from around the catheter when inserted suprapubically. A review of the literature identified several reasons for this leakage, including catheter size and anatomical abnormalities. Based on clinical experience, the authors posit that indwelling catheter leakage may also occur as a result of a catheter design flaw. This article provides the theoretical rationale for this hypothesis and a potential solution; formal, rigorous, and appropriate research should be performed to test the hypothesis. PMID- 23362700 TI - Evaluation of the psychometric properties of the Korean language version of the Incontinence Quiz. AB - Psychometric properties of the Korean version of the Incontinence Quiz were evaluated in Korean-American women with urinary incontinence. Findings support the reliability and validity of both versions of the instrument in this population. PMID- 23362701 TI - Adding to the evidence base: evaluation of the psychometric properties of the Korean language version of the Incontinence Quiz. PMID- 23362702 TI - A community-based family intervention program to improve obesity in Hispanic families. AB - INTRODUCTION: The Waukesha County Division of Public Health and Waukesha Memorial Hospital developed a social-ecological approach to diminish the incidence of overweight and obesity in Hispanic families in Waukesha County. PROGRAM DESCRIPTION: A sample of Waukesha County children and their families participated in an 8-week program that promoted awareness of healthy food choices and the importance of physical activity. The program was selected, translated, and adapted for the Hispanic community. Weekly sessions included nutrition classes, physical activity, and a healthy meal for participating families. Biometric data were collected pre- and post-program, including blood pressure, cholesterol, glucose, weight, height, and waist measurement. A pre- and post-program knowledge test regarding nutrition, food labels, and physical activity was administered. RESULTS: A total of 47 Hispanic families participated throughout the course of the program. Biometric measures and tests of nutrition knowledge and attitudes of participants consistently showed improvements. In addition, changes occurred in the community system structure, which positively affected the built environment by improving access to parks, YMCA, and schools for family physical activity. CONCLUSION: The translated curriculum was successful in reducing cardiac and diabetes risk factors in Hispanic adults by increasing knowledge and positive attitudes about healthy behaviors. PMID- 23362703 TI - The effect of prenatal support on birth outcomes in an urban midwestern county. AB - OBJECTIVES: In Dane County, Wisconsin, the black-white infant mortality gap started decreasing from 2000 and was eliminated from 2004 to 2007. Unfortunately, it has reappeared since 2008. This paper examines risk factors and levels of prenatal care to identify key contributors to the dramatic decline and recent increase in black infant mortality and extremely premature birth rates. METHODS: This retrospective cohort study analyzed approximately 100,000 Dane County birth, fetal, and infant death records from 1990 to 2007. Levels of prenatal care received were categorized as "less-than-standard," "standard routine" or "intensive." US Census data analysis identified demographic and socioeconomic changes. Infant mortality rates and extremely premature ( < or = 28 weeks gestation) birth rates were main outcome measures. Contributions to improved outcomes were measured by calculating relative risk, risk difference and population attributable fraction (PAF). Mean income and food stamp use by race were analyzed as indicators of general socioeconomic changes suspected to be responsible for worsening outcomes since 2008. RESULTS: Risk of extremely premature delivery for black women receiving standard routine care and intensive care decreased from 1990-2000 to 2001-2007 by 77.8% (95% CI = 49.9-90.1%) and 57.3% (95% CI = 27.6-74.8%) respectively. Women receiving less-than-standard care showed no significant improvement over time. Racial gaps in mean income and food stamp use narrowed 2002-2007 and widened since 2008. CONCLUSIONS: Prenatal support played an important role in improving black birth outcomes and eliminating the Dane County black-white infant mortality gap. Increasing socioeconomic disparities with worsening US economy since 2008 likely contributed to the gap's reappearance. PMID- 23362704 TI - A review of guidelines for dyslipidemia in children and adolescents. AB - The recent publication of new pediatric lipid screening guidelines represents a change in recommendations regarding lipid screening and management for pediatric patients that will affect all health care professionals who care for children and adolescents. The guidelines differ from the selective screening recommended by the 2007 US Preventive Services Task Force, instead recommending routine lipid screening for children and adolescents at ages 9-11 years and again at 17-21 years. Studies have shown that limiting lipid screening to patients with risk factors fails to identify many patients with genetic or acquired dyslipidemias. Without universal screening, many at-risk children will not be identified. PMID- 23362705 TI - Promoting healthy food consumption: a review of state-level policies to improve access to fruits and vegetables. AB - Research indicates poor nutrition is a leading determinant of the development of chronic disease, and increasing fruit and vegetable consumption is one method for decreasing obesity. Many policies have focused on increasing the demand for fruits and vegetables through price reductions and coupons. However, without ensuring a stable supply, increased demand can continue to raise prices, crowding out individuals who may otherwise have purchased fruits and vegetables and ultimately leading to continued disparities in access. This paper presents a review of selected state-level policy options recently proposed or implemented in states across the United States, and provides an evidence-based lens through which food access policy can be shaped in the Midwest. This review and potential framework uses Wisconsin to illustrate the feasibility of different state-level decisions and their potential impact on particular populations. Future supply side policies to consider include expanding Electronic Benefit Transfer to the Special Supplemental Nutrition Program for Women, Infants and Children (WIC),program and farmers markets, incentivizing the purchase of locally grown produce, assisting local specialty farmers directly, and/or establishing a state level food policy council. This review reveals that a food policy council would create a more sustainable policy analysis process to better ensure future policy adoption is truly comprehensive, encompassing the production, distribution and purchase of locally grown fruits and vegetables. PMID- 23362706 TI - A case of a dermoid cyst compressing the airway. AB - INTRODUCTION: In this report we discuss the etiology, common locations, diagnostic approach, and treatment of a dermoid cyst. CASE PRESENTATION: A 22 year-old man arrived at the emergency department complaining of submental fullness, an increase in snoring, choking, gagging, and difficulty breathing. The patient was taken to the operating room for a complete resection of a large dermoid cyst that was compressing his airway. DISCUSSION: Dermoid cysts are uncommon head and neck tumors mainly presenting in patients aged 15 to 35. The origin of dermoid cysts is thought to be congenital in most cases, but they can also develop from acquired factors such as trauma or surgical implantation that forces epithelial cells into deep tissues. CONCLUSION: Although benign and often asymptomatic, dermoid cysts may cause other associated symptoms due to compression of structures in the head and neck. PMID- 23362707 TI - Smoking and tuberculosis. PMID- 23362708 TI - New strategies of TB control in India: are we on the right track? PMID- 23362709 TI - Relationship between sputum smear grading and smear conversion rate and treatment outcome in the patients of pulmonary tuberculosis undergoing dots--a prospective cohort study. AB - BACKGROUND: The Smear Conversion Rate (SCR) is an operational indicator for the Directly Observed Treatment Short-course (DOTS) strategy of Revised National Tuberculosis Control Programme (RNTCP) in India. The present study was undertaken to determine the relationship between sputum smear grading and smear conversion rate among the Category I smear positive pulmonary tuberculosis patients undergoing DOTS. METHODS: A prospective cohort study was conducted among the Category I smear positive pulmonary tuberculosis patients registered under DOTS at GTB, Karawal Nagar and Shahdara Chest Clinics of Delhi. Sample size for the present study was calculated on the basis of a similar study of a retrospective design conducted at LRS Institute of Tuberculosis and Respiratory diseases New Delhi, India using statistical software Epi Info version 6. Accordingly, a total of 338 sputum smear positive patients with 169 each in the High Positive Cohort (pre-treatment sputum grading 3+) and Low Positive Cohort (pre-treatment sputum grading 2+, 1+ and Scanty) were followed periodically at two months (end of Intensive Phase), at three months (after one month extension of Intensive Phase), at two months of Continuation Phase and then at the end of the treatment to record the sputum AFB result and treatment outcome as per the RNTCP guidelines. Data was analyzed using SPSS Version -15. RESULTS: After two months (end of the intensive phase), SCR was 57.9% (98 of 169) among the High Positive and 71.6% (121 of 169) in the Low positive cohort ( p -0.008). After three months (one month's extension of intensive phase), cumulative SCR was 85.2%( 144 of 169)) in the High Positive and 92.3% (156 of 169) in the Low Positive cohort (p-0.03). Cure rate was 82.8% (140 of 169) in the High Positive and 84.6% (143 of 169) in the Low Positive cohort. Default rate was 3% (five of 169) in the High Positive and 5.3% (nine of 169) in the Low Positive cohort. Failure rate was 11.2% (19 of 169) in the High positive and 6.5% in the Low positive Cohort (11 of 169). Only one patient (0.6%) in each High and Low Positive cohort died during course of treatment (p -0.631). Treatment outcome was further compared among the patients according to their sputum status achieved at two and three months of the treatment after ignoring their initial sputum status. The cure rates for the patients who converted at two months was 90.9% (199 of 219) and for those who did not convert at two months, was 74.3% (84 Of 113) (p -0.000). Similarly, the cure rate for the patients who converted at three months was 84% (68 of 81) and for those who did not convert at three months was 55.2% (16 of 29) (p-0.01). INTERPRETATION: Patients with higher grades of sputum positivity at the beginning of the treatment have significantly lower SCR at the end of intensive phase and even after extending the intensive phase for one month. Hence, they are likely to remain infectious for a longer duration and continue to transmit infection in the community. Therefore, these patients demand to have more stringent self precautionary measures to break the chain of infection in the community. The SCR at two months and three months as an operational indicator should be given more importance rather than being practised only as a documentation and academic exercise. The patient should be investigated for the possible co-morbid conditions and drug resistance which could be a cause for the persistent sputum smear positivity at two and three months and hence poor treatment outcome. PMID- 23362710 TI - Same day sputum smear microscopy approach for the diagnosis of pulmonary tuberculosis in a microscopy centre at Rajahmundry. AB - BACKGROUND: Sputum smear microscopy is the initial and rapid diagnostic technique for tuberculosis. This requires two (spot and morning SM) sputum sample examinations over two days. Collection of two spot samples (SS2) on the same day would reduce the number of visits, time, money and early initiation of treatment. METHODS: We evaluated same day approach (SS2) against standard (SM) for the diagnosis of pulmonary tuberculosis. RESULTS: Out of 658 participants, same day approach could identify 62 cases, whereas standard approach could identify 64 cases. Both the approaches are equally effective (p > 0.05). CONCLUSION: The diagnosis of pulmonary tuberculosis is possible in one day by examining two spot samples. PMID- 23362711 TI - Implementation of RNTCP in a private medical college: five years' experience. AB - BACKGROUND: Revised National Tuberculosis Control Programme (RNTCP) recognizes the need for involvement of all sectors, public and private, to create an epidemiological impact on Tuberculosis control. The private health sector in the country is an important source of care, even with the availability of public health services and Directly Observed Treatment Strategy (DOTS). The data regarding Private-Private mix in our country is lacking. AIM: To evaluate the contribution of {private health sector (Private Medical Colleges and Private practioners (PP)} in TB case-detection, diagnosis and treatment outcomes in Delhi NCR, Ghaziabad, India. METHODOLOGY: We analyzed the TB registers from May 2006 Dec 2010 from our institution and recruited the patients in our study, irrespective of the source. We strengthened the referral by promoting educational intra and inter departmental activities and awareness programme with more stress on retrieval action by contact tracing and counselling. We made a list of PP in our drainage area and regularly met them and tried to understand the barriers in referring cases to DOTS centre. During the study, we tried to maintain the flow of information working as a single window information system. We regularly passed on the information of follow up of patients to private practioners referred to us by them to generate confidence in them. During the study, no incentive was offered to any patient. Various indicators and data were collected annually and analyzed statistically. STATISTICS: Retrospective, Descriptive Analysis. RESULTS: There was a substantial increase of 116.3% in the total patients referred from all sources to Santosh Hospital. The proportion of extra-pulmonary cases was 29.1% to 34.4% of all total cases from the year 2006 to 2010. During subsequent years, we found a significant increase in referral from Private Practioners that was the result of our activities performed in private set up. It was 12.5%, 21.2%, 30.8%, 27.3%, and 29% during 2006, 2007, 2008, 2009 and 2010 respectively. The outcome in our study was in accordance with the outcome at national level under RNTCP. CONCLUSION: Because of extensive educational activities, single window information system and referring the patients back to private sector after completion of treatment increased the confidence amongst the private physicians. These results strengthen the Private-Private Collaboration and show that a stronger link can be developed between medical college and private setup, leading to implementation of successful Private-Private Strategy. PMID- 23362712 TI - Passive smoking, indoor air pollution and childhood tuberculosis: a case control study. AB - BACKGROUND: Passive smoking and biomass fuel use most probably are more harmful to children than adults for two reasons. The first one is children's respiratory and immune systems are not fully developed. Secondly, they spend more time at home and are, therefore, likely to experience more intense and prolonged smoke exposure. AIMS: This study was planned to find out if there is any association between childhood tuberculosis and exposure to passive smoking and biomass fuel. METHODS: A hospital-based case control study was done. All registered consecutive newly diagnosed pediatric tuberculosis cases (0-14 years) from the outpatient department of a tertiary care hospital were recruited as cases. Age and sex matched controls were recruited from a public general hospital of the same locality. A semi-structured, pre-coded interview schedule was administered to parents or legal caregivers of all subjects after obtaining informed written consent. RESULTS: A total of 200 cases and 200 controls were recruited in the study period. The factors which were significantly associated with development of tuberculosis were education of the mother, (OR 1.411, 95% CI 0.888-2.243, p 0.001), a family member having tuberculosis in the last two years and residing in the same house (OR 2.797, 95% CI 1.353-5.789; p-0.004), being a passive smoker (OR 1.725, 95% CI 1.142-2.605; p-0.009). No association between biomass cooking fuel use and development of tuberculosis was found. CONCLUSION: Passive smoking is associated with development of childhood tuberculosis. This requires health education programmes and medical antitobacco advice and services. PMID- 23362713 TI - Inhibitory effect of isoniazid and orlistat combination on mycobacterial ES-31 serine protease in vitro and on the growth of M.tb bacilli in axenic culture. AB - BACKGROUND: Isoniazid and orlistat were reported to have inhibitory effect on mycobacterial ES-31 serine protease in vitro and bacterial cell growth in axenic culture. AIM: To study the cumulative effect and understand drug - drug interaction, if any, when isoniazid and orlistat used in combination. MATERIAL AND METHODS: Inhibition of mycobacterial ES-31 serine protease by different combinations of orlistat and isoniazid together and individually were studied using azocasein assay. Inhibition of secretion of excretory secretory ES-31 antigen in Sautan culture medium was studied under axenic condition and growth of M. tuberculosis H37Ra bacilli by CFU count on LJ-medium. RESULTS: Orlistat and isoniazid both showed inhibitory activity of ES-31 serine protease in in vitro as well as in vivo. Individually, isoniazid showed 90% inhibition at 200 ng/ml while orlistat at 250 ng/ml showed 65% inhibition of mycobacterial ES-31 serine protease in vitro. A combination of orlistat (250 ng/ml) and isoniazid (200 ng/ml) showed 86% inhibition in vitro while 73% inhibition was observed by orlistat (25 ng/ml) and isoniazid (200 ng/ml) on bacterial growth in axenic culture. CONCLUSION: Significant inhibition by orlistat suggests that it could be tried in patients with intolerance to isoniazid or in those already developed isoniazid resistance. It may also be explored in the suspected TB patients as initial medication in place of antibiotics for clinical relief. PMID- 23362714 TI - Fine needle aspiration cytology in breast tuberculosis: diagnostic difficulties- study of eleven cases. AB - BACKGROUND: Incidence of extra-pulmonary tuberculosis is on the rise. Tuberculosis of breast is rare and have multifaceted clinical presentation, often mimicking carcinoma and pyogenic breast abscess. AIM: To study morphologic variations and diagnostic difficulties of breast tuberculosis on fine needle aspiration cytology (FNAC). METHODS: FNAC smears of breast tuberculosis were studied by Leishman's Stain and categorized into four groups. Cytology smears were also studied for presence of Acid Fast Bacilli (AFB) by Ziehl Neelsen (ZN) stain. Histology of excised tissue was studied by Hematoxylin and Eosin stain (H& E). RESULTS: Out of 11 cases, 10 were females and 1 was male. Group 1 (n = 2) showed epithelioid granulomas with necrosis. Group 2 (n = 2) showed epithelioid granulomas without necrosis. Group 3 (n = 3) showed necrosis with a few scattered epithelioid histiocytes. Group 4 (n = 4) showed necrosis with numerous neutrophilic inflammatory cells. In four cases, caseous necrosis could be identified on cytology smears. AFB were found in five cases on FNAC smears. Histology confirmed diagnosis of tuberculosis in all cases. CONCLUSION: In developing countries like India, based on clinical history and other features, FNAC smears showing epithelioid granulomas with or without necrosis should be considered as breast tuberculosis as demonstration of AFB is not mandatory. Identification of caseous necrosis alone is diagnostic of breast tuberculosis in cytology smears. PMID- 23362715 TI - Spinal tuberculosis in an infant associated with maternal urinary tuberculosis. AB - A ten-month-old infant who presented with regression of milestones and seizures was noted to have a gibbus deformity in the upper thoracic region. She was diagnosed to have spine and central nervous system tuberculosis by culture of pus from the paravertebral abcess which showed a growth of Mycobacterium tuberculosis. The mother, who had been having recurrent episodes of Urinary tract infection, was diagnosed to have Urinary TB proven by culture. Spinal tuberculosis, though rare, can be encountered in infancy and should be kept in mind while treating infants presenting with related symptoms. PMID- 23362716 TI - Exaggerated Mantoux reaction in a case of latent tuberculosis infection (LTBI). AB - A 42-year-old female presented with a history of receiving PPD on right forearm intradermally before two days. Patient started having itching and irritation within a few hours and pain, oedema and vesicles formation by next day at the injection site. On examination, the whole right forearm was oedematous with induration of size 50 mm x 50 mm around the site of injection. Tubercular infection was suspected and the patient was subjected to further investigation but nothing, including physical examination, hemogram, fundus examination, chest X-ray, USG abdomen and CT thorax, was found suggestive of tuberculosis, leading to a diagnosis of LTBI. PMID- 23362717 TI - Updates on Revised National TB Control Programme. PMID- 23362718 TI - Stem cells and tuberculosis. PMID- 23362719 TI - Do Yorubas have an origin different from other Africans? PMID- 23362720 TI - Comparison of cardiac autonomic functions among postmenopausal women with and without hormone replacement therapy, and premenopausal women. AB - The aim of present study was comparison of cardiac autonomic status during different phases of reproductive life in women - in premenopausal women between proliferative and secretory phase, in postmenopausal women and in postmenopausal women receiving hormone replacement therapy (HRT). The study included 30 premenopausal women (Group 1) who were assessed in both proliferative (Group 1A) and secretory phase (Group 1B) of menstrual cycle, 30 postmenopausal women (Group 2) and 30 postmenopausal women on HRT (Group 3). Various autonomic function tests were done to assess parasympathetic and sympathetic functions. Results were obtained by ANOVA followed by Tukey test. The postmenopausal women (Group 2) showed increased sympathetic and decreased parasympathetic tone compared to premenopausal women (Group1). The women on HRT (Group 3) showed parasympathetic dominance and decrease in sympathetic activity compared to postmenopausal women (Group 2). Across the menstrual cycle, increased parasympathetic activity was seen in secretory phase while no change was observed in the sympathetic activity in the two phases. PMID- 23362721 TI - Effects of yoga on brain wave coherence in executives. AB - Aim of this study was to assess the effect of Self Management of Excessive Tension (SMET), a yoga based stress management program on brain wave coherence. Brain wave recordings were taken with Brain Master 2 Channel EEG (version-2.0). The subjects for the study were 72 corporate executives, 48.75 +/- 3.86 years of mean age referred from Oil and Natural Gas Corporation Limited. EEG data was recorded on the first and sixth day of 5 days SMET program. A complete statistical and spectral analysis showed 19.31% increase (p=0.03) in delta, 5.04% increase (p=0.65) in theta, 15.40% increase (p=0.09) in alpha, 1.67% decrease (p=0.54) in beta and 18.68% increase (p=0.07) in gamma wave coherence between pre and post intervention measurements. Taken together, these results suggest that participation in a SMET program was associated with improvement in emotional stability and may have implications for 'Executive Efficiency'. Because before and after designs limit inferences about intervention effects, further research is warranted to explore the effects of SMET program for stress management using a larger, randomized controlled trial. PMID- 23362722 TI - Blood pressure responses to steady treadmill exercise in overweight and obese young adults. AB - Overweight and obesity are major risk factors for chronic diseases. There exists an autonomic imbalance in these persons. The blood pressure response to exercise is an useful method to evaluate cardiac status. Hence this project was undertaken to study the blood pressure responses to steady treadmill exercise in overweight and obese persons. The study was carried out on 85 young healthy adults (Normal weight = 30, Overweight = 25 and Obese = 30) in the age group of 18-22 yrs. Steady dynamic exercise test was done on treadmill for 5 mins. Blood pressure and Pulse rate were recorded before, during 3rd min of exercise, immediately after cessation of exercise and after 5 mins of recovery. Statistical analysis was done using one way ANOVA followed by post-hoc tests for between group comparisons. The resting blood pressure was higher in overweight and obese group when compared to normal group. There was increased systolic pressure response to exercise in study groups where as the diastolic pressure decreased during exercise. Heart rate response was also higher in study groups. Over weight and obese young adults had elevated resting blood pressure and showed increased response to steady exercise which could be due to alterations in the autonomic activity in these persons. PMID- 23362723 TI - The effect of posture on esophageal pH in endoscopy normal reflux disease (ENRD) cases. AB - PURPOSE OF THE STUDY: Endoscopy Normal Reflux Disease (ENRD) is a common presentation of reflux disease. These patients are symptomatic but do not have abnormal endoscopy findings. They may have pathological intraesophageal reflux. Lifestyle modifications are the mainstay of management of these patients. Posture plays an important role in their management. It was felt that exact quantification of reflux pattern with different postures in ENRD cases should be studied to include it as a part of management of these cases. BASIC PROCEDURES: Fifteen male patients were studied. 24 h ambulatory pH metry was done for all patients. Half an hour recording was studied for various postures: supine, supine with 30 degrees head end elevated, upright, right and left lateral recumbent position. The data of pH metry for half an hour of each of these postures was studied. RESULTS AND INTERPRETATION: All fifteen patients were ENRD cases and were upright refluxers. None of them had an abnormal supine reflux pattern. The percentage time of reflux and the reflux episode duration was significantly low in supine (P<0.05) and supine with 30 degrees head end elevated (P<0.005). CONCLUSION: In our study of 15 upright refluxers, supine with 30 degrees head end elevated and supine position were the postures associated with least reflux. Posture can help reduce the reflux significantly and can be used as an effective means in management. PMID- 23362724 TI - Association of physical activity and physical fitness with blood pressure profile in Gujarati Indian adolescents. AB - The current study was conducted to determine how physical activity level and physical fitness affects the blood pressure profile of Gujarati Indian adolescents so as to help in developing preventive strategies for the local population as ethnic differences exist in the aetiopathogenesis of hypertension. A cross-sectional study was conducted on 485 Gujarati Indian adolescent boys and girls of age group 16-19 years. Physical activity level was assessed using Johnson Space Center/NASA Physical Activity Rating Scale and VO2 max was used to assess the physical fitness. Body composition was assessed in terms of Body Mass Index, Fat Mass Index and Waist Circumference. Blood Pressure was measured by oscillometry. One-way ANOVA was used to study if any significant differences (P<0.05) existed in the blood pressure profile between the high, moderate and low physical activity groups. Pearson's correlation coefficient was determined to assess the relationship between VO2 max and blood pressure profile. In girls, physical activity level was not found to have a significant effect on the blood pressure profile. In boys, systolic blood pressure and mean arterial pressure were found to be significantly higher in Moderate Physical Activity Group as compared to Low Physical Activity Group. PVO2 max was found to have a significant negative correlationship with SBP, DBP and MAP in girls and a significant negative correlationship with SBP, PP and MAP in boys. It could thus be concluded that a better physical fitness rather than a higher physical activity level could keep the blood pressure in check in the Gujarati Indian adolescents. PMID- 23362725 TI - Effect of yogic package on rheumatoid arthritis. AB - This study aimed at studying the effect of yogic package (YP) with some selected pranayama, cleansing practices and meditation on pain intensity, inflammation, stiffness, pulse rate (PR), blood pressure (BP), lymphocyte count (LC), C reactive protein (CRP) and serum uric acid (UA) level among subjects of rheumatoid arthritis (RA). Randomized control group design was employed to generate pre and post data on participants and controls. Repealed Measure ANOVAs with Bonferroni adjustment were applied to check significant overall difference among pre and post means of participants and controls by using PASW (SPSS Inc. 18th Version). Observed result favored statistically significant positive effect of YP on selected RA parameters and symptoms under study at P<0.05, 0.01 and 0.001 respectively that showed remarkable improvement in RA severity after 40-day practice of YP. It concluded that YP is a significant means to reduce intensity of RA. PMID- 23362726 TI - Assessment of enhanced endothelium-dependent vasodilation by intermittent fasting in Wistar albino rats. AB - Intermittent fasting (IF), a type of feeding regimen where the frequency of eating is reduced enhances cardiovascular stress adaptation and improves cardiovascular risk factors in rats. Data on the effect of IF on the endothelium is not common, so we examined whether IF showed similarity to documented beneficial effects of caloric restriction on endothelium-dependent vasodilatory responses of rat aortic rings. 25 young male Wistar rats had ad libitum (AL) access to food and 25 others were provided with food every other day for 2 months, during which their weight was measured every 2 weeks. Vascular reactivity of abdominal aorta was simultaneously evaluated using dual wire myographs. Weight gain was greater in the AL group (P<0.001) at all weighing intervals. Acetylcholine (ACh; 10(-10)-10(-5)M) produced greater (P<0.05) vasorelaxation in IF rats at the two highest concentrations. IF reduces weight gain in young male rats and improves their aortic endothelium-dependent vasorelaxation. PMID- 23362727 TI - Prevalence of prehypertension and its relationship to cardiovascular disease risk factors in Puducherry. AB - Prehypertension (PHT) leads to hypertension (HT) and cardiovascular (CVD) disease risk. Identification of CVD risk factors in PHT will reduce the burden of HT and CVD in the population. Three hundred staffs of a medical college were screened for prehypertension (PHT). Sixty five PHT and 91 normotensives (NT) were enrolled. Anthropometric measurements and fasting blood glucose and lipid variables were measured. Prevalence of PHT was 22% (males 71%; females 29%). Hip circumference, waist circumference (WC), body mass index (BMI), fasting blood glucose (FBS) and atherogenic lipid indices triglycerides (TG), VLDL cholesterol, TG/HDL and LDL/HDL were increased in PHT. PHT showed significant positive association with BMI, WC, FBS, TG and TG/HDL. Regression analysis revealed BMI, TG and TG/HDL as the independent CVD risk factors in PHT. PHT is predominant in males and BMI, TG are the independent CVD risk factors in Puducherry. PMID- 23362728 TI - Inflammation and oxidative stress in hypothyroids: additive effects on cardiovascular risk. AB - Cardiovascular disease is one of the major complications of hypothyroidism which is one of the most common endocrine disorders in India. In the present study, we have analyzed the link among oxidative stress, C reactive protein which is an inflammatory marker and the cardiovascular lipid risk factors in hypothyroid patients which has not been analyzed before. Sixty seven untreated hypothyroid patients were recruited consecutively for the study. Their ultrasensitive C reactive protein level and oxidative stress profile were measured apart from various lipid risk factors of cardiovascular disease. Ultra sensitive C reactive protein was significantly correlated with increased lipid risk factors of cardiovascular disease, thyroid stimulating hormone level and indices of oxidative stress in these patients. Low grade inflammation in hypothyroidism plausibly acts as the link between higher oxidative stress and the underlying cardiovascular risk among hypothyroid patients. PMID- 23362730 TI - Effect of gender on correlation of anaemia with body mass index in medical students. AB - Nutritional anemia exists globally and cuts across all the sections of the population. Adolescent being formative years in life are more susceptible to nutritional anemia. Considerable changes in growth pattern, lifestyle, dietary habits & behavior are likely to influence the hemoglobin levels among male and females of high income group. Study was done to assess the level of anemia among medical students and it's relation to Body mass index (BMI) among medical students. 200 healthy medical students at the Himalayan Institute of Medical Sciences belonging to both the sexes were taken in the study. Following consent anthropometry was conducted using standard protocol. Body Mass Index of >/= 18.5 kg/m2 is used to define undernutrition. Hemoglobin was estimated in gram %. Statistical analyses was done using mean .Standard deviation, Student's t test, and was studied for effect of gender on correlation of anemia with BMI. 8% of the students of MBBS were found to be anemic (Hb <12 g%) with none of the boys having hemoglobin <12 g% .15.5% under nutrition was observed in the medical students with (25.75%) of girls having a BMI of <18.5 kg/m2. A negative association of hemoglobin was found with nutritional status (BMI) (r = -0.59; P = 0.24) in over weight and obese females students. Nutritional anemia and under nutrition exist among female medical students who are literate, and have free access to the nutritive diet in a good healthy environment. PMID- 23362729 TI - Study of sympathovagal imbalance by spectral analysis of heart rate variability in young prehypertensives. AB - Though prehypertension has recently been considered as a risk factor for cardiovascular accidents, the pathophysiological mechanism that causes the development of prehypertension in normotensive subjects has not been fully elucidated. Therefore, the present study was conducted to assess the sympathovagal imbalance in prehypertensives and normotensives by spectral analysis of heart rate variability (HRV) to understand the nature of change in autonomic balance in this dysfunction. Body mass index (BMI), waist-hip ratio (WHR), basal heart rate (BHR), blood pressure (BP), rate-pressure product (RPP) and spectral indices of HRV such as total power (TP), normalized low frequency power (LFnu), normalized high frequency power (HFnu), ratio of low frequency power to high frequency power (LF-HF ratio), mean heart rate (mean RR), square root of the mean squared differences of successive normal to normal intervals; (RMSSD), the number of interval differences of successive NN intervals greater than 50 ms (NN50) and the proportion derived by dividing NN50 by the total number of NN intervals (pNN50) were assessed in two groups of young subjects: normotensives (n=68) and prehypertensives (n=66). Sympathovagal balance (SVB) was analyzed and correlated with BMI, WHR, BHR, BP and RPP in both the groups. It was observed that autonomic imbalance in prehypertensives was due to increase in both sympathetic activity and vagal inhibition. LF-HF ratio, the sensitive indicator of SVB was significantly correlated with BMI, WHR, BHR, BP and RPP in prehypertensive subjects. It was concluded that vagal inhibition might be important in the critical alteration of sympathovagal balance in the development of prehypertension in young normotensive subjects. PMID- 23362731 TI - Effect of Pranayama on stress and cardiovascular autonomic function. AB - The stress either physical or mental, leads to cardiovascular morbidity. Newly admitted medical students are likely to be exposed to various stresses like change of environment, demanding medical education and different teaching protocol in a medical college. Pranayama is known since ancient times to relieve stress and stabilize autonomic function of the body. Therefore it was decided to study effect of Pranayama on stress and cardiovascular autonomic function. The subjects were first M.B.B.S students and the sample size was 59 consisting of 27 males and 32 females. The group of students thus selected was briefed about the study. After the orientation session, informed written consent was taken, stress questionnaire was put and the autonomic function tests were done. This was followed by practice of Pranayama for 2 months, 1 hour/day for 5 days/week and again stress questionnaire was put and the autonomic function tests were performed on the study group. The above tests were done before and after the practice of Pranayama. The results obtained were analyzed using SPSS software. The stress level has reduced after 2 months of practicing various pranayama as evident by decrease in total stress score which is highly significant. VLF and LF in n.u have reduced significantly after practice of pranayama signifying reduction in sympathetic drive to heart. HF in n.u has increased significantly after practice of pranayama for 2 months showing the increase in parasympathetic output to the heart. LF/ HF ratio reduced significantly after 2 months of practice of pranayama indicating a better sympatho vagal balance with resting balance tilting toward better parasympathetic control. PMID- 23362732 TI - Do blood groups influence our pain perception? PMID- 23362733 TI - Vibration sense impairment in diabetes mellitus. PMID- 23362734 TI - Effects of acute supplementation of Panax ginseng on hydration status during endurance running exercise in a hot and humid environment. PMID- 23362735 TI - Effect of colour and gender on human reaction time. PMID- 23362736 TI - Correlation of BMI with fasting blood glucose in perimenopausal women. PMID- 23362737 TI - Nurses' partnership in IMNCI towards safe childhood. PMID- 23362738 TI - Early ambulation: an ugly phrase for a beautiful idea. AB - The present study was undertaken to assess the effect of scheduled ambulation of selected post-operative outcomes between control and experimental groups in two hospitals of Bangalore; scores of post-operative outcomes of the two groups were also associated with demographic variables. The sample of 60 major abdominal surgery patients admitted in two hospitals was subjected to a rating scale of 14 demographic items and 35 items on parameters of post-operative outcomes like pain, fatigue, urine retention etc. The results showed that scheduled ambulation was effective in reducing the severity of selected post-operative outcomes. PMID- 23362739 TI - Perception of nursing students towards internship. AB - The study, undertaken to assess the perception of students regarding integrated internship in the preparation of staff nurse position among the BSc (N) final year undergraduate students included 43 students (21, 47% female and 22, 53% male) in the hospital setting of Chennai (TN). Majority of students (96%) perceived that there was significant enrichment in preparation in the three aspects: knowledge, skill and attitude and that due to their learning in the internship period, they would confidently function independently in the ward in discharge of their duties. PMID- 23362740 TI - Health problems among menopausal women in Udupi district (Karnataka). AB - Menopause among women, occurring in middle age, brings in its wake, a set of health problems that needs to be handled distinctly by the care givers. A study undertaken to determine the magnitude of health problems in Udupi district of Karnataka included 100 menopausal women in the age group 45-55 years, 50 each from urban and rural pockets. Using demographic proforma, modified socio-economic scale and structured interview schedule as tools, it was concluded that menopausal health problems were more common in women in rural areas than in their urban counterparts: they were also less articulate and less aware about managing or preventing menopausal health problems. PMID- 23362741 TI - Effect of computer-assisted teaching programme on the knowledge of nursing personnel about pre-term labour and low birth weight. AB - Knowledge regarding pre-term labour and low birth weight is directly related to infant mortality, which is sought to be brought down. This study was therefore conducted to assess the knowledge of 50 nursing personnel working in different wards of a selected hospital in J&K, with computer-assisted teaching programme as independent variable; the dependent variable being knowledge of nurses about pre term labour and low birth weight. A 2-part questionnaire was developed to elicit the responses. The study established that computer-assisted programme was quite effective in improving the nurses' knowledge about pre-term labour and low birth weight that could be utilised in routine antenatal care. PMID- 23362742 TI - Infusing nursing research into practice for quality care. PMID- 23362743 TI - Child labour--the ill effects on health. PMID- 23362744 TI - Psycho-social problems of the HIV positive and negative mothers. AB - People affected with HIV face numerous psycho-social problems in their families and work place. The present study attempted to identify various psychosocial problems faced by HIV positive mothers and their comparison was made with those without HIV. In the study, 320 HIV positive and as many negative mothers, attending OPD of Govt Rajaji Hospital and Meenakshi Mission Hospital & Research Centre, Madurai (TN) having children, were included as subjects. All HIV mothers were aware of their HIV status. It was found that majority of HIV positive mothers faced more social problems vis-a-vis HIV negative mothers. PMID- 23362745 TI - Decontamination with chlorhexidine gluconate reduces the incidence of ventilator associated pneumonia. AB - Ventilator-associated pneumonia is a major source of nosocomical infection affecting about 27 percent of all critically ill patients. In this study, an attempt was made to assess the effect of oral decontamination with 0.2% chlorhexidine gluconate solution and hydrogen peroxide solution on the incidence of ventilator-associated pneumonia and oropharyngal colonisation. Seventy patients above 18 years of age admitted in AIIMS, New Delhi were included as subjects. It was concluded that incidence of ventilator-associated pneumonia was higher in patients given oral care with hydrogen peroxide than those on 0.2% chlorhexidine, which was more effective in reducing orophyryngeal colonisation. PMID- 23362746 TI - Development of nursing education in India. PMID- 23362747 TI - Active lecture. PMID- 23362748 TI - Research and clinical findings--a wholistic view. AB - Valuable information is available to clinicians both from research articles, and reports from clinicians. Both sources have limitations. Research, with the exception of longitudinal studies, tends to isolate a variable or two from the whole, limiting its usefulness. Clinical techniques reported are sometimes biased, and perform well for certain therapists in certain settings, and not so well for others. Interrelationships are important among variables such as dentition, anatomy, physiology, oral muscle functions, oral rest postures, eating, and speech. Each affects the others. Equally important are interrelationships among all the specialists who treat patients with orofacial myofunctional disorders. A wholistic approach to the evaluation and treatment of orofacial disorders is advocated. PMID- 23362749 TI - Basic dental information needed for the OFM initial occlusal evaluation. AB - It is incumbent upon the orofacial myologist to evaluate the presenting client's occlusion and detect any behaviors which may be influencing the alignment of the dentition or interfering with the treatment plan of the referral source. In order to accomplish these tasks, it is necessary to share some common terminology and to effectively communicate between all the participants involved in the treatment plan. The purpose of this article is to assist in accomplishing these goals. PMID- 23362750 TI - The "Interdisciplinary Orofacial Examination Protocol for Children and Adolescents": a resource for the interdisciplinary assessment of the stomatognatic system. AB - The Interdisciplinary Orofacial Examination Protocol for Children and Adolescents (Protocolo de exploracion interdisciplinaria orofacial para ninos y adolescents, Barcelona, 2008) is very useful in providing a fast, initial, expedient detection of possible morphological and functional disorders, and to guide the patient toward the appropriate professionals. With this tool it is possible to detect the risk factors which can negatively affect morphological and functional harmony and guide patients toward the necessary treatment as early as possible. This Protocol, developed by 4 orthodontists, 1 ENT and 3 speech language therapists, also contributes to the unification of concepts and nomenclature used by distinct specialists, thus making professional understanding easier and more dynamic. PMID- 23362751 TI - A one-page orofacial myofunctional assessment form: a proposal. AB - The author presents her own proposal of a one-page orofacial myofunctional assessment and for each item on the list a brief rationale is provided. The protocol is an easy but comprehensive form that can be faxed or emailed to referral sources as needed. As science provides more objective assessment and evaluation tools, this one-page form can be easily modified. PMID- 23362752 TI - MBGR protocol of orofacial myofunctional evaluation with scores. AB - The MBGR Protocol with scores was first published in 2009. This protocol was widely administered by speech-language pathologists experienced in orofacial myology in different states from Brazil for four months. From the comments and suggestions of these professionals, the protocol was reviewed and modified. A consistent visual training materials program was prepared, and speech-language pathologists, experienced in orofacial myology from different states of Brazil, Venezuela, Peru, and Colombia were trained with the provided materials. These speech-language pathologists administered the protocol for two years. From the data collected by the speech-language pathologists, modifications were made, and a final version was designed. This final version was administered for two-months by the same speech-language pathologists from Brazil, Venezuela, Peru, and Colombia in order to re-test the final version of MBGR protocol. The aim of this study was to demonstrate the efficiency and effectiveness of the protocol to assess orofacial myofunctional alterations. The final version of the MBGR protocol with scores has proven to be efficient and effective in the identification of individuals experiencing orofacial myofunctional disorders. PMID- 23362753 TI - Sample of a client intake information protocol: a synopsis and rationale. AB - The utilization of standardized comprehensive forms in the field of orofacial myology is crucial as this profession continues to grow and establish assessment and treatment protocols. This article formally presents a comprehensive health history intake form currently in use, and highlights the rationale for each particular question within this form in an effort to explore the evidence-based theory behind each question utilized. Highlighting the importance of obtaining a thorough health history as it pertains to our profession, personally allows the clinician to ultimately best plan a therapeutic strategy and assess the individual criteria necessary for successful orofacial myofunctional habituation. PMID- 23362754 TI - Lingual frenulum protocol with scores for infants. AB - An experimental protocol model for frenulum evaluation was first designed, and administered to ten infants in 2010. After obtaining the data and statistical analysis, the protocol was re-designed and administered to 100 infants. The aim of this study is to present an efficient and effective lingual frenulum protocol with scores for infants. From the experimental protocol model, a new protocol was designed. One speech-language pathologist, and specialist in orofacial myology, administered the new protocol to 100 full-term infants. All steps of the protocol were recorded and photographed. The data collected was sent to two specialists in the area, who evaluated the cases based on the recordings and photographs. The data from the three evaluations were compared. A two-part protocol was designed to evaluate the lingual frenulum in infants. The first part consists of clinical history with specific questions about family history and breastfeeding. The second part consists of clinical examination: anatomo-functional, non-nutritive and nutritive sucking evaluations. A new lingual frenulum protocol with scores for infants was designed, and has proved to be an effective tool for health professionals to assess and diagnose anatomical alterations of the lingual frenulum, and its possible interference with breastfeeding. PMID- 23362755 TI - Aging of secondary organic aerosol from alpha-pinene ozonolysis: roles of hydroxyl and nitrate radicals. AB - This work investigates the oxidative aging of preformed secondary organic aerosol (SOA) derived from alpha-pinene ozonolysis (-100 ppb(v) hydrocarbon [HC(x)] with excess of O3) within the University of California-Riverside Center for Environmental Research and Technology environmental chamber that occurs after introduction of additional hydroxyl (OH) and nitrate (NO3) radicals. Simultaneous measurements of SOA volume concentration, hygroscopicity, particle density, and elemental chemical composition (C:O:H) reveal increased particle wall-loss corrected SOA formation (1.5%, 7.5%, and 15.1%), increase in oxygen-to-carbon ratio (O/C; 15.6%, 8.7%, and 8.7%), and hydrophilicity (4.2%, 7.4%, and 1.4%) after addition of NO (ultraviolet [UV] on), H2O2 (UV(on)), and N2O5 (dark), respectively. The processing observed as an increase in O/C and hydrophilicity is attributed to OH and NO3 reactions with first-generation vapor products and UV photolysis. The rate of increase in O/C appears to be only sufficient to achieve semivolatile oxygenated organic aerosol (SV-OOA) on a day time scale even at the raised chamber radical concentrations. The additional processing with UV irradiation without addition of NO, H2O2, or N2O5 is observed, adding 5.5% wall loss-corrected volume. The photolysis-only processing is attributed to additional OH generated from photolysis of the nitrous acid (HONO) offgasing from chamber walls. This finding indicates that OH and NO3 radicals can further alter the chemical composition of SOA from alpha-pinene ozonolysis, which is proved to consist of first-generation products. IMPLICATIONS: Secondary organic aerosol (SOA) may undergo aging processes once formed in the atmosphere, thereby altering the physicochemical and toxic properties of aerosol. This study discusses SOA aging of a major biogenic volatile organic compound (VOC; alpha-pinene) after it initially forms SOA. Aging of the alpha-pinene ozonolysis system by OH (through NO or H2O2 injection), NO3 (through N2O5 injection), and photolysis is observed. Although the reaction rate appears to be only sufficient to achieve semivolatile oxygenated organic aerosol (SV-OOA) level of oxygenation on a 1-day scale, it is important that SOA aging be considered in ambient air quality models. Aging in this study is attributed to further oxidation of gas-phase oxidation products of alpha-pinene ozonolysis. PMID- 23362756 TI - Measurement of BTEX (benzene, toluene, ethybenzene, and xylene) levels at urban and semirural areas of Algiers City using passive air samplers. AB - The study presents the levels of air pollution by aromatic organic compounds BTEX (benzene, toluene, ethylbenzene, o-, m-, and p-xylenes) in the city of Algiers. The sampling was carried out using Radiello passive sampler. Three sampling campaigns were carried out in roadside, tunnel, urban background, and semirural sites in Algiers. In order to determine the diurnal mean levels of air pollution by BTEX to which people are exposed, a modified passive sampler was used for the first time. In addition, monitoring of pollution inside vehicles was also made. In the spring of 2009, more than 27 samplings were carried out. In the background and road traffic sites the Radiello sampler was exposed for 7 days, whereas the time exposure was reduced to 1 day in the case of the vehicle as well as the tunnel. The results indicate that average benzene concentrations in the roadside and inside vehicle exceed largely the limit value of 5 microg m(-3) established by the European Community (EC). On the other hand, it has been noticed that the concentration levels of other BTEX are relatively high. Also, in order to identify the origin of emission sources, ratios and correlations between the BTEX species have been highlighted. This study shows that road traffic remains the main source of many local emission in Algiers. IMPLICATIONS: The vehicle fleet in Algeria is growing rapidly since the 1990s following economic growth and is responsible for the increasing air pollution in large cities. Because there are no data collection of BTEX carried out by national air quality network, all environmental and transportation policies are based on European emissions standards, but national emission standards are currently not in place. This work will contribute to the analysis of real emissions of BTEX in Algiers, for the development of management and for assessment of population exposure variation depending on the location in the city of Algiers. PMID- 23362758 TI - Preparation, characterization, and phenol adsorption of activated carbons from oxytetracycline bacterial residue. AB - The oxytetracycline bacterial residue-activated carbon (OBR-AC) prepared from oxytetracycline bacterial residue with K2CO3 under chemical activation was studied. The effects of activation temperature, activation time, and activation ratio on the specific surface area (SSA) and methylene blue adsorption (MBA) were studied. Characterization of the optimum OBR-AC was performed by using scanning electron microscopy (SEM), pore structure (PS,) and Fourier-transform infrared spectroscopy (FT-IR). The optimum parameters were as follows: 800 degrees C activation temperature, 3 hr activation time, and 1:3 activation ratio. The SSA and MBA under optimum conditions were 1593.09 m2/g and 117.0 mg/g, respectively. Adsorption equilibrium and kinetics data were determined for the adsorption of phenol from the synthetically prepared phenol solution. The results showed that the Langmuir model gave the best fit for equilibrium isotherm, whereas the kinetics data were well fitted by the pseudo-second order model. IMPLICATIONS: In the past, the bacterial residues have been used for feed additives in China. Unfortunately, doubts of its suitability as a feedstock have been raised because of the small amount of antibiotics, a large number of the fermentation by products and metabolic products and by-products remaining in the bacterial residues. So Oxytetracycline Bacterial Residue (OBR) is one of hazardous wastes in China. In order to solve the problem of OBR, the preparation of OBR-AC is studied, and OBR-AC under optimum operation parameters is characterized by Scanning Eldctron Microscopy (SEM), Pore Structure (PS) and Fourier Transfer Infra Red (FT-IR). Moreover, the phenol adsorption isotherms and kinetics models for OBR-AC under optimum operation parameters are studied. PMID- 23362757 TI - Multiple comparisons of organic, microbial, and fine particulate pollutants in typical indoor environments: diurnal and seasonal variations. AB - This study was performed to investigate the possible sources as well as seasonal and diurnal variations of indoor air pollutants in widely used four different environments (house, office, kindergarten, and primary school) in which people spend most of their time. Bioaerosol levels and species, volatile organic compound (VOC) levels, and PM2.5 (particulate matter with an aerodynamic diameter < or = 2.5 microm) levels were determined in different parts of these environments in parallel with outdoor sampling. Air pollution samplings were carried out in each microenvironment during five subsequent days in both winter and summer in Ankara, Turkey. The results indicated that bioaerosol, VOC, and PM2.5 levels were higher in the winter than in the summer. Moreover PM2.5 and bioaerosol levels showed remarkable daily and diurnal variations, whereas a good correlation was found between the VOC levels measured in the morning and in the afternoon. Bacteria levels were, in general, higher than fungi levels. Among the VOCs, toluene was the most predominant, whereas elevated n-hexane levels were also observed in the kindergarten and the primary school, probably due to the frequent wet cleaning during school days. According to factor analysis, several factors were found to be significantly influencing the indoor air quality (IAQ), and amongst them, VOC-based products used indoors ranked first. The overall results indicate that grab sampling in naturally ventilated places may overestimate or underestimate the IAQ due to the inhomogeneous composition of indoor air caused by irregular exchanges with the outdoor air according to the season and/or occupants' habits. IMPLICATIONS: Seasonal and diurnal variations of VOCs, PM2.5, bioaerosols in house, office, and schools were observed, in which PM2.5 and bioaeorosols showed marked both intra- and interday variability, but VOCs did not. VOC-containing products were the most common source of air pollutants affecting the indoor air quality. External factors affecting the indoor air quality were season and indirectly ventilation. A grab sample cannot be representative in evaluating the air quality of a naturally ventilated environment precisely. PMID- 23362759 TI - A new approach to characterize emission contributions from area sources during optical remote sensing technique testing. AB - In the method termed "Other Test Method-10," the U.S. Environmental Protection Agency has proposed a method to quantify emissions from nonpoint sources by the use of vertical radial plume mapping (VRPM) technique. The surface area of the emitting source and the degree to which the different zones of the emitting source are contributing to the VRPM computed emissions are often unknown. The objective of this study was to investigate and present an approach to quantify the unknown emitting surface area that is contributing to VRPM measured emissions. Currently a preexisting model known as the "multiple linear regression model," which is described in Thoma et al. (2009), is used for quantifying the unknown surface area. The method investigated and presented in this paper utilized tracer tests to collect data and develop a model much like that described in Thoma et al. (2009). However unlike the study used for development of the multiple linear regression model, this study is considered a very limited study due to the low number of pollutant releases performed (seven total releases). It was found through this limited study that the location of an emitting source impacts VRPM computed emissions exponentially, rather than linearly (i.e., the impact that an emitting source has on VRPM measurements decreases exponentially with increasing distances between the emitting source and the VRPM plane). The data from the field tracer tests were used to suggest a multiple exponential regression model. The findings of this study, however, are based on a very small number of tracer tests. More tracer tests performed during all types of climatic conditions, terrain conditions, and different emissions geometries are still needed to better understand the variation of capture efficiency with emitting source location. This study provides a step toward such an objective. IMPLICATIONS: The findings of this study will aid in the advancement of the VRPM technique. In particular, the contribution of this study is to propose a slight improvement in how the area contributing to flux is determined during VRPM campaigns. This will reduce some of the technique's inherent uncertainties when it is employed to estimate emissions from an area source under nonideal conditions. PMID- 23362760 TI - Ozone and its potential control strategy for Chon Buri city, Thailand. AB - This work studies O3 pollution for Chon Buri city in the eastern region of Thailand, where O3 has become an increased and serious concern in the last decade. It includes emission estimation and photochemical box modeling in support of investigating the underlying nature of O3 formation over the city and the roles of precursors emitted from sources. The year 2006 was considered and two single-day episodes (January 29 and February 14) were chosen for simulations. It was found that, in the city, the industrial sector is the largest emissions contributor for every O3 precursor (i.e., NO(x), non-methane volatile organic compounds or NMVOC, and CO), followed by on-road mobile group. Fugitive NMVOC is relatively large, emitted mainly from oil refineries and tank farms. Simulated results acceptably agree with observations for daily maximum O3 level in both episodes and evidently indicate the VOC-sensitive regime for O3 formation. This regime is also substantiated by morning NMVOC/NO(x) ratios observed in the city. The corresponding O3 isopleth diagrams suggest NMVOC control alone to lower elevated O3. In seeking a potential O3 control strategy for the city, a combination of brute-force sensitivity tests, an experimental design, statistical modeling, and cost optimization was employed. A number of emission subgroups were found to significantly contribute to O3 formation, based on the February 14 episode, for example, oil refinery (fugitive), tank farm (fugitive), passenger car (gasoline), and motorcycle (gasoline). But the cost-effective strategy suggests control only on the first two subgroups to meet the standard. The cost of implementing the strategy was estimated and found to be small (only 0.2%) compared to the gross provincial product generated by the entire province where the city is located within. These findings could be useful as a needed guideline to support O3 management for the city. IMPLICATIONS: Elevated O3 in the urban and industrial city of Chon Buri needs better understanding of the problem and technical guidelines for its management. With a city-specific emission inventory and air quality modeling, O3 formation was found to be VOC sensitive, and a cost effective control strategy developed highlights fugitive emissions from the industrial sector to be controlled. PMID- 23362761 TI - Mitigation of odor causing emissions--bench-scale investigation. AB - Emissions of malodors are considered to be the greatest threat to the compost industry. In work presented here, several simple odor mitigation alternatives were investigated for their effectiveness in preventing the release of common odorants, such as terpenes, ammonia, and reduced sulfur compounds. The mitigation methods studied included the use of a blanket of finished compost, compost amendment mixed within the feedstock, odor neutralizing agents (ONAs), and oxygen release compounds (ORCs). Among the mitigation alternatives investigated in this study, the use of finished compost as a blanket and finished compost as an amendment yielded the most conclusive and significant results. Both of these alternatives yielded a substantial emission reduction for terpenes, ammonia, and reduced sulfur compounds. The application of finished compost blanket resulted in up to 95% reduction of terpene and 25% reduction of ammonia emissions. Blending the feedstock with finished compost also provided substantial reduction of terpene emissions ranging from 73.6 to 93.1% at the 24% blending ratio, and up to 85% ammonia reduction a the 35% blending ratio. Use of finished compost also provided 75% lower reduced sulfur compound emissions at the 12% blending ratio. Misting and application of odor neutralizing agents did not result in any consistent reduction in emissions for any of the odorous compounds tested. IMPLICATIONS: The odor emissions from composting are often considered to be the biggest threat to composting facilities. Because most facilities cannot afford enclosures and contained composting vessels, there is a need to inexpensively and effectively control the odor emissions from composting facilities. The findings of this research can lead the way for efforts to control odor easily and cost effectively. In fact, the application of a compost blanket for odor control is already gaining acceptance by the composting industry. PMID- 23362762 TI - A tunnel study to estimate emission factors from mobile sources in Monterrey, Mexico. AB - A six-day tunnel field study was conducted in the city of Monterrey, Mexico, during June 2009 to derive on-road emission factors (EFs)for trace gases and fine particulate matter from the local vehicle fleet. The Loma Larga Tunnel (LLT) is a 532-m-long structure that is mainly used by light-duty gasoline-powered vehicles. It is composed of two independent bores that have a semicircular cross section, 17 m in diameter with a 3.5% slope. During the study, a fleet of 108,569 vehicles with average speeds that ranged from 43 to 76 km/hr was sampled. Ambient air samples were taken inside each bore using 6-L SUMMA-polished canisters and low volume samplers for the quantification of total nonmethane hydrocarbons (TNMHC) and PM2.5, respectively. The effect of road dust resuspension was considered in the computation of PM2.5 EFs. Additional equipment was used to measure real-time levels of CO2 and NO(x); CO EFs were estimated using NO(x) as a surrogate. TNMHC samples and NO(x) levels were obtained for 2-hr time periods, while PM2.5 samples and CO2 levels were obtained using 2.5-hr time periods, which included the time periods of the TNMHC and NO(x) measurements. Estimated EFs for TNMHC, CO, NO(x), and PM2.5 were 1.16 +/- 0.05, 4.83 +/- 2.9, and 0.11 +/- 0.07 g/km-veh (2-hr average) and 17.5 +/- 5.7 mg/veh-km (2.5-hr average), respectively, while CO2 EFs were 182.7 +/- 44 g/km-veh for the 2-hr time periods and 170 +/- 22 g/veh-km for the 2.5-hr time periods. The average fuel economy estimated from the field data was 12.3 +/- 2.3 km/L. The CO2 and TNMHC EFs (on a mass per distance basis) tended to be higher for traffic moving upslope, while the inverse occurred for the PM2.5 EFs. In comparison to other tunnel studies, the CO2 EFs obtained were similar the NO(x) and PM2.5 EFs were lower, and the CO and TNMHC EFs were higher. IMPLICATIONS: Mobile source emission factors (EFs) for Mexican cities other than Mexico City are scarce. In Monterrey, Mexico, one of the three major cities in the country, emissions inventories are constructed based on EFs from other locations. However, it is quite relevant to obtain local information to construct reliable inventories. We present what is, to our knowledge, the first tunnel study conducted in a Mexican city other than Mexico City to estimate fleet average mobile source EFs. This is also the first study that reports PM2.5 EFs derived from a tunnel study in the country. PMID- 23362763 TI - Microwave-induced nanoscale zero-valent iron degradation of perchloroethylene and pentachlorophenol. AB - Microwave (MW) is applied to enhance perchloroethylene (PCE) or pentachlorophenol (PCP) removal using zero-valent iron (ZVI; Fe(0)) as the dielectric medium. ZVI has a much higher dielectric loss factor (39.5) than other media; it is capable of absorbing MW radiation rapidly to speed up the release of electrons, leading to rises of the ZVI particle surface temperature. If the MW power is continued, excessive electricity will accumulated inside ZVI particles, resulting in sparks. The results show that during the initial 5 sec (700 W), the linear aliphatic PCE has a faster decomposing rate than the ringed PCP (82.0% vs. 4.8%) because less energy is required for decomposing the linear-chlorine bond (90 kcal mol(-1)) than ring-chlorine bonds (95 kcal mol(-1)). Later the removal rate for either PCE or PCP remains the same when the exposure time is between 5 and 60 sec. Without MW irradiation, linear PCE molecules have larger surface area to contact ZVI, and hence they have better removal efficiencies than PCP molecules. Using Fe(0) as a microwave dielectric medium to treat PCE or PCP is a new and worthwhile treatment technology; it is environmentally friendly, and its use will eliminate the secondary pollution. IMPLICATIONS: Nanoscale iron particles are characterized by high surface-area-to-volume ratios, high specific surface area, and high surface reactivity. With a much higher dielectric loss factor, it is capable of absorbing MW radiation rapidly to speed up the release of electrons, leading to rise in temperature. The time needed to achieve a satisfactory treatment is also reduced, leading to significant saving of energy consumption to make this method cost effective and also environmentally friendly for the industry to pursuit sustainable development. PMID- 23362764 TI - Co-melting technology in resource recycling of sludge derived from stone processing. AB - Stone processing sludge (SPS) is a by-product of stone-processing wastewater treatment; it is suitable for use as a raw material for making artificial lightweight aggregates (ALWAs). In this study, boric acid was utilized as a flux to lower sintering temperature. The formation of the viscous glassy phase was observed by DTA curve and changes in XRD patterns. Experiments were conducted to find the optimal combination of sintering temperature, sintering time, and boric acid dosage to produce an ALWA of favorable characteristics in terms of water absorption, bulk density, apparent porosity, compressive strength and weight loss to satisfy Taiwan's regulatory requirements for construction and insulation materials. Optimal results gave a sintering temperature of 850 degrees C for 15 min at a boric acid dosage of 15% by weight of SPS. Results for ALWA favorable characteristics were: 0.21% (water absorption), 0.35% (apparent porosity), 1.67 g/cm3 (bulk density), 66.94 MPa (compressive strength), and less than 0.1% (weight loss). PMID- 23362765 TI - [Pharmaceutical agents and medical devices--similar but different]. PMID- 23362767 TI - [Comparison of postoperative pain relief by continuous femoral nerve block and that by epidural block during physiotherapy after minimally invasive surgery of total knee arthroplasty and uni-condylar knee arthroplasty]. AB - BACKGROUND: We compared postoperative pain relief during physiotherapy after minimally invasive surgery (MIS) of total knee arthroplasty (TKA) and unicondylar arthroplasty (UKA). METHODS: Ninety-five patients scheduled for TKA or UKA under spinal anesthesia were divided into continuous femoral nerve block (0.1-0.12% ropivacaine 4 ml x hr(-1)) combined with a single sciatic block (Group CFNB) and epidural block (0.1-0.19% ropivacaine 4 ml x hr(-1)) combined with a single femoral block (Group EP). Visual analogue scale (VAS) at rest, walking, maximal knee flexion, extension, and maximal pain on POD 1 were recorded. Patient's satisfaction of analgesia and supplemental analgesics on POD 1 were recorded. We compared VAS and satisfaction of TKA with UKA during CFNB or EP. RESULTS: VAS at physiotherapy was higher than VAS at rest. VAS at maximal knee flexion was higher than VAS at rest, walking or maximal knee extension in UKA of Group CFNB (n = 29) or EP (n = 19). VAS at flexion and extension were higher than VAS at walk- ing in TKA of Group CFNB (n = 20) or EP (n = 27). VAS, patient's satisfaction and supplemental analgesics on POD 1 were comparable in both groups. CONCLUSIONS: VAS at physiotherapy after TKA or UKA during CFNB or EP was very severe than VAS at rest. PMID- 23362766 TI - [General anesthesia for pediatric cardiac catheterization--effects of anesthetics on blood pressure, heart rate, oxygen saturation, and carbon dioxide]. AB - BACKGROUND: There are limited data about the correlations between amount of anesthetics and variations in vital signs during pediatric cardiac catheterization. METHODS: Data in 80 children with congenital heart disease undergoing cardiac catheterization with/without interventional cardiology in 2004 were examined in this retrospective cohort study. Data on blood pressure, heart rate, oxygen saturation, partial tension in end tidal carbon dioxide (PETCO2), and total amount of anesthetics given during general anesthesia were obtained from anesthetic charts. The correlations between amount of anesthetics and those vital signs were analyzed. RESULTS: Median age of the patients was 14 months and median body weight was 8.8 kg. Median rates of variation in heart rate, blood pressure, oxygen saturation and PET(CO2) were 22.8%, 29.3%, 5.9% and 10.8%, respectively. Although there were no statistical correlations between those vital signs and amounts of anesthetics such as fentanyl, vecuronium and sevoflurane, rates of variation in heart rate was smaller in patients for whom the amount of fentanyl given was more than 4 microg x kg(-1) x hr(-1). CONCLUSIONS: There were no associations between amount of anesthetics and variations in vital signs in pediatric cardiac catheterization. PMID- 23362768 TI - [Effect of ultrasound-guided brachial plexus block on perioperative pain management of total elbow arthroplasty]. AB - BACKGROUND: Ultrasound-guided brachial plexus block (UGBB) makes it possible to block both lateral and medial aspects of the skin overlying the elbow, which are mainly innervated by C5 and T1 roots of brachial plexus, respectively. The effect of UGBB on perioperative pain relief in total elbow arthroplasty (TEA) was evaluated. METHODS: Twenty-one patients scheduled to undergo TEA with general anesthesia from January 2009 to December 2010 were assigned to a group receiving UGBB (Block group, n = 10) and a group receiving general anesthesia alone (General group, n = 11). Perioperative anesthetic dose and postoperative pain intensity were recorded. Statistical analysis was performed with Mann-Whitney's U test, and P < 0.05 was considered to be significant. RESULTS: Median fentanyl doses during the operation in the Block group and General group were 100 microg and 250 microg, respectively (P < 0.05). Numerical rating scale (NRS) in the Block group was significantly lower than that in the General group immediately after the operation (median value: Block group = 0, General group = 4). Although NRS in the two groups was not different from the night of the day of operation, no patient in the Block group needed supplementary opioids. CONCLUSIONS: Ultrasound-guided brachial plexus block in patients undergoing TEA reduces perioperative opioid consumption and wound pain in the early postoperative period. PMID- 23362769 TI - [Use of high frequency oscillatory ventilation in a patient with fulminant fat embolism syndrome]. AB - We report a case of fulminant fat embolism syndrome treated with high frequency oscillatory ventilation (HFOV). A 77-year-old woman sustained a right tibia and fibula fracture and a left open tibia fracture after a traffic accident. She was conscious and her respiratory condition was normal on admission. However, she suddenly progressed to a coma and was intubated for approximately 2 hours after the accident; she developed critical respiratory failure. We used HFOV and were able to maintain her respiratory status. However, her right heart failure deteriorated and she died 95 hours after the accident. It was difficult for her to survive without percutaneous cardiopulmonary support. PMID- 23362770 TI - [A case of severe embolic complications due to warfarin withdrawal]. AB - We report a case of three severe embolic complications due to warfarin withdrawal. An 83-year-old man with hypertension, angina pectoris and atrial fibrillation underwent bladder biopsy under spinal anesthesia after 13 days of warfarin withdrawal. On the second postoperative day, the patient complained of chest pain and was diagnosed as acute myocardial infarction. Embolus was successfully removed by suctioning. Warfarin and heparin therapy was started after that. On the 6th postoperative day, the patient complained of abdominal pain and was diagnosed as superior mesenteric artery embolism. After suctioning of the thrombus and monteplase injection, symptoms disappeared. On the 9th postoperative day, paralysis on the right side of his body and aphasia appeared. Stroke was suspected. Coma advanced day by day and he died due to brain herniation on the 16th postoperative day. In this patient we should have assessed the risk of the thromboembolic complication and planned the appropriate anticoagulation with closer cooperation with his attending physicians. PMID- 23362771 TI - [Hypoxemia caused by retention of irrigation fluid to detect leaks from the lungs during subtotal esophagectomy]. AB - We report a patient who developed hypoxemia caused by retention of irrigation fluid used to detect leaks from the lungs during subtotal esophagectomy. A 58 year-old man developed a sudden onset of hypoxemia with a decrease in tidal volume during subtotal esophagectomy. Chest X-ray revealed a homogeneous opacity of the left lung field, suggesting the presence of fluid in the pleural cavity on the left. The tidal volume and SpO2 increased after drainage of the fluid from the left pleural cavity. The postoperative course was uneventful and the patient was discharged on the 16th postoperative day. PMID- 23362772 TI - [Complementary use of central venous oxygen saturation for fluid management in abdominal surgery patients with severely compromised cardiac function: a report of two cases]. AB - Perioperative fluid management for cases with severely compromised cardiac function undergoing major non-cardiac surgery remains a challenge. Dynamic parameters such as stroke volume variation (SVV) and cardiac index obtained by arterial pulse contour analysis may not be sufficient for fluid optimization because individualized optimal parameter values are difficult to determine in cardiac patients. We report two cases of abdominal surgery with severe pre existing impairment of cardiac function (ejection fraction < 30%) complicated by severe pulmonary and renal dysfunction. In Case 1, because of unreliably high SVV values due to a sudden onset of cardiac arrhythmia, we performed colloid bolus infusion targeting central venous oxygen saturation (ScvO2) above 80%. In Case 2, cardiac index and stroke volume index remained unchanged despite the decrease of SVV after colloid bolus infusion. Infusion of dobutamine was useful for maintaining the ScvO2 above 75% in a rather hypovolemic state (SVV of 10-15%). Our cases suggest that the use of central venous oxygen saturation together with arterial pulse contour analysis may aid decision-making for individualized fluid optimization and use of inotropics in severely compromised cardiac patients undergoing major abdominal surgery. PMID- 23362773 TI - [A case of acute exacerbation of interstitial pneumonia after appendectomy managed with spinal anesthesia]. AB - An 88-year-old woman was admitted with acute appendicitis. She had been treated with prednisolone and home oxygen therapy for interstitial pneumonia. Her respiratory state on admission was Grade 2 of Hugh-Jones' classification, and plasma KL-6 and SP-D levels were high. Seven days after the admission, appendectomy was performed under spinal anesthesia. Spinal anesthesia was initiated by injecting 0.5% hyperbaric bupivacaine 2.0ml into L3-4 interspace, and achieved block level was up to T4. During the operation, her respiratory state was stable, but after the operation, dry cough, increase of body temperature, and dyspnea were observed. Chest roentgenogram revealed severe ground glass appearance and reticular shadows bilaterally. Steroid therapy for acute exacerbation of interstitial pneumonia was initiated, but she died on the 13th POD. This case teaches us to take a lot of care in the management of a patient with high plasma level of KL-6 and SP-D. PMID- 23362774 TI - [Anesthesia for a very elderly patient with aortic stenosis]. AB - Aortic stenosis is a significant risk factor for the development of cardiac complications after noncardiac surgery. Based on this reason, the American College of Cardiology-American Heart Association 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery recommend elective noncardiac surgery should generally be postponed or canceled in patients with symptomatic aortic stenosis. The present report describes the case of a 94-year old male patient with aortic stenosis who underwent emergency abdominal surgery under general anesthesia and orthopedic surgery under spinal anesthesia. Anesthetic management was successful with no complications. In the present case, appropriate choice of anesthetic technique and agent optimized anesthetic management of a very elderly patient with aortic stenosis. PMID- 23362775 TI - [Anesthetic management for a pediatric patient of Klippel-Trenaunay syndrome with giant head by hydrocephalus]. AB - Klippel-Trenaunay syndrome (KTS) is a rare disorder associated with the triad of 1) capillary vascular malformation, 2) varicose veins and/or venous malformation, 3) and soft tissue and/or bony hypertrophy. A six-month old, 6.0-kg-weight male pediatric patient was scheduled for ventriculo-peritoneal shunt operation for hydrocephalus caused by obstructive aqueductus cerebri. At the age of three months, he was diagnosed as KTS by extensive capillary vascular malformation and soft tissue hypertrophy of the right leg. Physical examination showed prominent vascular malformation over his anterior thoracic and abdominal wall, and soft tissue hypertrophy was only on his right leg. Simultaneously, he was complicated with congenital hydrocephalus because of obstructive aqueductus cerebri. His head and skull were enlarged and his head measurement reached 55 cm (chest measurement 32 cm). Anesthetic management of KTS patients should be prepared with blood transfusion against massive hemorrhage and hypovolemic shock. Furthermore, KTS patients should be always considered to have airway difficulty due to the soft tissue hypertrophy, upper and airway hemangiomas. Therefore, we planned safer tracheal intubation following practice guidelines for management of the difficult airway. PMID- 23362776 TI - [Three patients with cervical disc herniation whose severe pain was relieved with oral mini-pulse therapy of betamethasone]. AB - Three patients with severe neck and radicular pain due to cervical disc herniation was not relieved of pain by common drug medication such as NSAIDs and anticonvulsants. Patients underwent oral mini-pulse therapy of betamethasone as the initial dose of 8 mg x day(-1) in the form of 8 tablets of 0.5 mg in a single dose twice a day (after breakfast and after lunch). The daily dose was reduced by half every 4 days, and the therapy was continued for 16 days. In all patients, the pain disappeared completely within the opening 10 days of the therapy, and the pain did not relapse after the therapy. All adverse events of betamethasone including irritation, insomnia and overeating disappeared without medication within several days. PMID- 23362778 TI - [Septic shock after total knee arthroplasty in a patient with Waldenstrom macroglobulinemia]. AB - A 58-year-old man with Waldenstrom macroglobulinemia (WM) was scheduled for total knee arthroplasty for left proximal-end tibial fracture. Before surgery, he took dexamethasone 2 mg orally, and his preoperative IgM level was 2,388 mg x dl(-1). The intraoperative course was favorable. Two days after surgery, he could move to a wheelchair. But, four days after surgery, he fell into septic shock with disseminated intravascular coagulation. Furthermore, cardiac arrest ocurred twice and he finally died. Autopsy revealed the large volume of turbid ascites and petechia of the digestive tract mucosa and the endocardium. However, the infection focus could be not identified. Four days after surgery, the blood culture showed extended-spectrum beta-lactamase-producing Escherichia coli. In patients with WM, abnormalities in immunoglobulins may frequently lead to infection. Decreased cellular immunity by surgical stress, may lead to severe infection. Perioperative management, such as evaluation of the indications for surgery, appropriate administration of prophylactic antibiotics, and proper selection of anesthetic must be considered. PMID- 23362777 TI - [Utility of target controlled infusion technique for deciding the fentanyl infusion rate for post-cholecystectomy pain management in a patient on anticoagulant therapy]. AB - The fentanyl infusion rate was controlled by employing a target controlled infusion (TCI) technique under anticoagulant therapy for postoperative pain management. A 59-year-old woman with atrial fibrillation and mitral stenosis was scheduled for open cholecystectomy. Heparin was continuously infused for anticoagulant therapy. Sevoflurane and remifentanil were used for induction and maintenance of anesthesia. At completion of the operation, her consciousness was checked and the endotracheal tube was then removed under fentanyl TCI (effect site concentration: Ce = 2.0 ng x ml(-1)). In this case, the spontaneous breathing rate was stable (10-12 x min(-1)) under fentanyl TCI. She had no complaints of pain(pain at rest: VAS 20 mm). The breathing rate in this case provided indication for postoperative pain management. The TIVAtrainer simulation makes the exchange from TCI infusion to continuous infusion easy. And the spontaneous breathing monitoring is useful for postoperative pain measurement of laparotomy cases. PMID- 23362779 TI - [Anesthetic management of a parturient with congenital afibrinogenemia undergoing cesarean section]. AB - A 29-year-old parturient with congenital afibrinogenemia was scheduled to receive cesarean section 38 weeks 2 days of gestation. Due to the bleeding ter dency by her abnormality of fibrinogen and afibrinogenemia, general anesthesia was chosen. In addition to routine administration of fibrinogen, perioperative supplementation of fibrinogen with the meticulous evaluation of the coagulation and fibrinolysis status using rotation thromboelastometry (ROTEM) enabled the patient to deliver a healthy baby without any hematological complications. The ROTEM was a useful device to check coagulopathy and fibrinolysis in this patient. PMID- 23362780 TI - [Massive bleeding during and after cesarean section in a patient receiving frozen thawed embryo transfer]. AB - A 30-year-old pregnant woman (151 cm, 49 kg) with twin gestation who had got pregnant with frozen-thawed embryo transfer was scheduled to undergo cesarean section at 37 weeks of gestation. Combined spinal and epidural anesthesia was performed separately at the T12-L1 (epidural) and at the L3-4 interspace (spinal). The sensory anesthesia was extended to T2 and the operation was started. The cesarean delivery was uneventful and healthy 2,370 g and 2,334 g neonates were delivered. Five minutes after the delivery, placenta was removed manually from the uterus. Despite using oxytocin, methylergometrine and prostaglandin F2alpha, uterine contraction was severely impaired and massive bleeding occurred. General anesthesia was not commenced and packed red blood cells, fresh frozen plasma and cryoprecipitate were given. Uterus gradually contracted and the patient was transferred to the ward. However, massive bleeding continued postoperatively, and magnetic resonance imaging indicated retained placenta. Total hysterectomy was performed on the second postoperative day. Atonic bleeding and placental invasion should be the main causes of massive bleeding. Frozen-thawed embryo transfer might be one of the important factors for placental invasion. We have to prepare for massive bleeding during and after the cesarean section in patients receiving frozen-thawed embryo transfer. PMID- 23362781 TI - [Undiagnosed hereditary angioedema in a patient undergoing emergency caesarean section]. AB - Hereditary angioedema (HAE) is characterized by acute, recurrent attacks of localized edema. Surgical procedures, trauma, and infections have been considered as potential triggers of HAE. Although HAE is a rare genetic disorder, approximately 50-60% of all HAE patients are involved with at least one occurrence of upper airway obstruction. The airway trouble is the most life threating complication in HAE patients because HAE-related edema does not respond to typical treatment, such as administration of epinephrine, antihistamines, or glucocorticoids. Indeed, mortality rates of laryngeal attack are estimated around 25% to 40%. Here we describe a case of undiagnosed HAE patient undergoing emergency caesarean section under neuraxial blockade. A 31-year-old woman showed multiple regions at her lip margin during surgery and rapidly developed lip swelling after admission to the ward. Neither respiratory nor hemodynamic instability was found during and after surgery. Immediately, in order to assess whether HAE caused these dermatological manifestations, we measured values of both complement component 4 (C4) and functional activity of C1-esterase inhibitor (C1-inh), a protein of the complement system. These laboratory data showed low levels, which were compatible with HAE definition. After commencement of C1 inhibitor replacement therapy, her lip swelling and erythema gradually disappeared without adverse drug reactions. The patient was finally discharged from our institution 10 days after surgery. PMID- 23362782 TI - [Group A streptococcus-induced toxic shock syndrome in pregnancy: a case report of cesarean section]. AB - Group A streptococcus (GAS)-induced toxic shock syndrome (TSS) in pregnancy is rare, but its clinical course is fulminant. The mortality rates of mother and fetus are reported to be 58 and 66%, respectively. We report a case of GAS-TSS after cesarean section. A 38-year-old pregnant woman of 38 weeks gestation was admitted to our hospital because of vomiting, fever of 39 degrees C, and continuous abdominal pain with scanty genital bleeding. She had complained of sore throat several days before. One hour after admission, external fetal monitoring revealed periodic pulse deceleration to 90 x beats min(-1). The emergent cesarean section was performed under general anesthesia. Approximately 8 hours after the cesarean section, she developed coma, shock and respiratory insufficiency requiring intubation. Streptococcus pyogens were isolated from her blood sample and the patient met criteria for GAS-TSS. She was treated with antibiotics (penicillin and clindamycin), antithrombin III, recomodulin, catecholamins, and continuous hemodialysis with filtration of toxins. Although the patient recovered and was discharged on 63rd day, the infant died on postpartum day 4. Early recognition and intensive treatment for GAS is recommended in a late stage pregnancy with an episode of sore throat, vomiting, high fever, strong labor pain, and DIC signs. PMID- 23362783 TI - [Glidescope performance in tracheal intubation by novice laryngoscopists: a manikin study]. AB - BACKGROUND: The Glidescope is a novel video laryngoscope designed for difficult airway management. It is expected to be a useful device for inexperienced users but published data have been limited. Using a manikin, we compared the performance of the Glidescope with those of the Airway scope and Macintosh laryngoscope in tracheal intubation by inexperienced and experienced operators. METHODS: Seventeen nurses and 17 anesthesiologists were included for the present study. The intubation time, success rate, the pressure exerted on the upper teeth during intubation, visibility of the vocal cord, the most favorable device, and operability of each device (VAS) were recorded. RESULTS: In the inexperienced group, there was no significant difference in the intubation time among the three devices. Visibility and operability of Glidescope and Airwayscope were better than those of Macintosh laryngoscope in the inexperienced group. The pressure on the upper teeth by Glidescope was higher than that by Macintosh laryngoscope, though most inexperienced operators did not feel apprehensive about teeth injury. CONCLUSIONS: The Glidescope was a useful device for the inexperienced operators. However, instructors should notice that inexperienced laryngoscopists tend to push the upper teeth by the Glidescope. PMID- 23362784 TI - Nurse leadership: is it OK to delegate? Revised principles, resources aim to help RNs answer the question. PMID- 23362785 TI - Hurricane Sandy: flooding and fury. Nurses respond to needs during hurricane, suffer losses. PMID- 23362786 TI - Person-centered care--what does it actually mean? PMID- 23362787 TI - Nurse leads the way in reducing falls. PMID- 23362788 TI - Nurses talk, and the public listens. PMID- 23362789 TI - Ask for an advanced practice registered nurse. PMID- 23362790 TI - Broader HIV screening proposed. PMID- 23362791 TI - Improved adhesive strength and toughness of polyvinyl acetate glue on addition of small quantities of graphene. AB - We have prepared composites of polyvinyl acetate (PVAc) reinforced with solution exfoliated graphene. We observe a 50% increase in stiffness and a 100% increase in tensile strength on addition of 0.1 vol % graphene compared to the pristine polymer. As PVAc is commonly used commercially as a glue, we have tested such composites as adhesives. The adhesive strength and toughness of the composites were up to 4 and 7 times higher, respectively, than the pristine polymer. PMID- 23362792 TI - Titanium complexes of tridentate aminebiphenolate ligands containing distinct N alkyls: profound N-substituent effect on ring-opening polymerization catalysis. AB - The synthesis, structural characterization, and reactivity studies of titanium complexes supported by tridentate amine biphenolate ligands of the type [RN(CH(2) 2-O-3,5-C(6)H(2)(tBu)(2))(2)](2-) {[R-ONO](2-); R = tBu (1a), iPr (1b), nPr (1c)} are described. Alcoholysis of Ti(OiPr)(4) with H(2)[1a-1c] in diethyl ether solutions at 25 degrees C generates quantitatively the corresponding [R ONO]Ti(OiPr)(2) (2a-2c) as a yellow crystalline solid. X-ray diffraction studies of 2b and 2c showed them to be five-coordinate, trigonal-bipyramidal species. Ring-opening polymerization of epsilon-caprolactone (epsilon-CL) catalyzed by 2b and 2c proved to be living, as evidenced by the narrow molecular weight distributions of the derived polymers and the linear dependence of number averaged molecular weights on the monomer-to-catalyst ratios or polymerization time. Kinetic studies revealed that the polymerization rates are first-order in the concentration of epsilon-CL and first-order in that of 2b and 2c. The propagation rate of 2c is ca. 15 times faster than that of 2b, highlighting a profound substituent effect of primary versus secondary N-alkyls. In sharp contrast, reactions employing catalytic 2a produce either low-molecular-weight oligomers or polymers characteristic of somewhat wider molecular weight distributions, depending on the polymerization temperatures. PMID- 23362793 TI - Comprehensive genome-wide proteomic analysis of human placental tissue for the Chromosome-Centric Human Proteome Project. AB - As a starting point of the Chromosome-Centric Human Proteome Project (C-HPP), we established strategies of genome-wide proteomic analysis, including protein identification, quantitation of disease-specific proteins, and assessment of post translational modifications, using paired human placental tissues from healthy and preeclampsia patients. This analysis resulted in identification of 4239 unique proteins with high confidence (two or more unique peptides with a false discovery rate less than 1%), covering 21% of approximately 20, 059 (Ensembl v69, Oct 2012) human proteins, among which 28 proteins exhibited differentially expressed preeclampsia-specific proteins. When these proteins are assigned to all human chromosomes, the pattern of the newly identified placental protein population is proportional to that of the gene count distribution of each chromosome. We also identified 219 unique N-linked glycopeptides, 592 unique phosphopeptides, and 66 chromosome 13-specific proteins. In particular, protein evidence of 14 genes previously known to be specifically up-regulated in human placenta was verified by mass spectrometry. With respect to the functional implication of these proteins, 38 proteins were found to be involved in regulatory factor biosynthesis or the immune system in the placenta, but the molecular mechanism of these proteins during pregnancy warrants further investigation. As far as we know, this work produced the highest number of proteins identified in the placenta and will be useful for annotating and mapping all proteins encoded in the human genome. PMID- 23362794 TI - Coexistent childhood renovascular and cerebrovascular disease. PMID- 23362795 TI - A comparison of the in vitro moisture vapour transmission rate and in vivo fluid handling capacity of six adhesive foam dressings to a newly reformulated adhesive foam dressing. AB - This study compared moisture vapour transmission rate (MVTR) and wear time or fluid-handling capacities of six adhesive foam dressings to a reformulated control dressing. Standardised in vitro MVTR methodology and a previously published in vivo artificial wound model (AWM) were used. Mean inverted MVTR for the reformulated dressing was 12 750 g/m(2) /24 hours and was significantly higher than four of the six comparator dressings (P < 0.0001), which ranged from 830 to 11 360 g/m(2) /24 hours. Mean upright MVTR for the reformulated dressing was 980 g/m(2) /24 hours and was significantly different than all of the comparator dressings (P < 0.0001), which ranged from 80 to 1620 g/m(2) /24 hours (three higher/three lower). The reformulated dressing median wear time ranged from 6.1 to >7.0 days, compared with 1.0 to 3.5 days for the comparator dressings (P = 0.0012 to P < 0.0001). The median fluid volume handled ranged from 78.0 to >87 ml compared with 13.0 to 44.5 ml for the comparator dressings (P = 0.0007 to P < 0.001). Interestingly, inverted MVTR did not correspond well to the AWM. These results suggest that marked differences exist between the dressings in terms of both MVTR and wear time or fluid-handling capacity. Furthermore, high inverted MVTR does not necessarily predict longer wear time or fluid-handling capacities of absorbent dressings. PMID- 23362796 TI - Intravitreal bevacizumab for retinal neovascularizations associated with myelinated nerve fibers. AB - PURPOSE: To report the effects of intravitreal bevacizumab injection (IVBI) in a patient affected by retinal neovascularizations (RNVs) associated with myelinated nerve fibers (MNF) and complicated by vitreous hemorrhage. METHODS: A 23-year-old female was referred because of sudden visual acuity deterioration in the left eye. Nine years earlier, the subject underwent retinal laser photocoagulation for recurrent vitreous hemorrhages related to the development of RNV associated with MNF. The ophthalmological evaluation revealed a new recurrence of vitreous hemorrhage associated with fluorescein leakage from RNV. After careful discussion, the patient underwent IVBI. RESULTS: One month after the injection, the best corrected visual acuity (BCVA) improved from 20/400 to 20/100, with a vitreous hemorrhage resolution, and cessation of fluorescein leakage. Over the 24 month follow-up, 2 additional IVBIs were administered due to further vitreous hemorrhage associated with fluorescein leakage from RNV, achieving a final BCVA of 20/80. CONCLUSIONS: IVBI may temporarily counteract the vascular hyperpermeability typical of RNV associated with MNF, leading to the cessation of fluorescein leakage, but does not result in RNV regression. PMID- 23362797 TI - Combined pulmonary fibrosis and emphysema. AB - The advent of computed tomography permitted recognition of the coexistence of pulmonary fibrosis and emphysema (CPFE). Emphysema is usually encountered in the upper lobes preceding fibrosis of the lower lobes, and patients are smokers, predominantly male, with distinct physiologic profile characterized by preserved lung volumes and markedly reduced diffusion capacity. Actually, the term CPFE is reserved for the coexistence of any type and grade of radiological pulmonary emphysema and the idiopathic usual interstitial pneumonia computed tomography pattern as well as any pathologically confirmed case. CPFE is complicated by pulmonary hypertension, lung cancer and acute lung injury and may present different outcome than that of its components. PMID- 23362799 TI - The influence of playing level on the biomechanical demands experienced by rugby union forwards during machine scrummaging. AB - This study investigated machine scrummaging at different playing levels in rugby union and analysed kinetic factors that might influence performance and injury risk. Thirty-four forward packs from six different playing levels scrummaged against an instrumented scrum machine under real environmental conditions. Applied forces were measured in three orthogonal directions. The peak (SD) of the overall compression forces during engagement ranged between 16.5 (1.4) kN (International-Elite) and 8.7 (0.1) kN (Women), while sustained compression forces spanned between 8.3 (1.0) kN (International) and 4.8 (0.5) kN (Women). The peak of the overall vertical force during the initial engagement phase was between -3.9 (0.7) kN (Elite) and -2.0 (1.0) kN (School), and the range of lateral forces was between 1.8 (0.3) kN (International) and 1.1 (0.3) kN (School). Forces measured across all playing levels, particularly during initial engagement, were generally higher than those measured in the most commonly cited previous studies. This increase may be due to a combination of changes in modern scrummaging technique, changes in players' anthropometrics, and experimental conditions that better respect ecological validity. The magnitude of the measured forces is in the range of values that studies on cadaveric specimens have indicated as potentially hazardous for (chronic) spine injuries. PMID- 23362798 TI - Rat injury model under controlled field-relevant primary blast conditions: acute response to a wide range of peak overpressures. AB - We evaluated the acute (up to 24 h) pathophysiological response to primary blast using a rat model and helium driven shock tube. The shock tube generates animal loadings with controlled pure primary blast parameters over a wide range and field-relevant conditions. We studied the biomechanical loading with a set of pressure gauges mounted on the surface of the nose, in the cranial space, and in the thoracic cavity of cadaver rats. Anesthetized rats were exposed to a single blast at precisely controlled five peak overpressures over a wide range (130, 190, 230, 250, and 290 kPa). We observed 0% mortality rates in 130 and 230 kPa groups, and 30%, 24%, and 100% mortality rates in 190, 250, and 290 kPa groups, respectively. The body weight loss was statistically significant in 190 and 250 kPa groups 24 h after exposure. The data analysis showed the magnitude of peak-to peak amplitude of intracranial pressure (ICP) fluctuations correlates well with mortality rates. The ICP oscillations recorded for 190, 250, and 290 kPa are characterized by higher frequency (10-20 kHz) than in other two groups (7-8 kHz). We noted acute bradycardia and lung hemorrhage in all groups of rats subjected to the blast. We established the onset of both corresponds to 110 kPa peak overpressure. The immunostaining against immunoglobulin G (IgG) of brain sections of rats sacrificed 24-h post-exposure indicated the diffuse blood-brain barrier breakdown in the brain parenchyma. At high blast intensities (peak overpressure of 190 kPa or more), the IgG uptake by neurons was evident, but there was no evidence of neurodegeneration after 24 h post-exposure, as indicated by cupric silver staining. We observed that the acute response as well as mortality is a non-linear function over the peak overpressure and impulse ranges explored in this work. PMID- 23362800 TI - Evidence for metal-surface interactions and their role in stabilizing well defined immobilized Ru-NHC alkene metathesis catalysts. AB - Secondary interactions are demonstrated to direct the stability of well-defined Ru-NHC-based heterogeneous alkene metathesis catalysts. By providing key stabilization of the active sites, higher catalytic performance is achieved. Specifically, they can be described as interactions between the metal center (active site) and the surface functionality of the support, and they have been detected by surface-enhanced (1)H-(29)Si NMR spectroscopy of the ligand and (31)P solid-state NMR of the catalyst precursor. They are present only when the metal center is attached to the surface via a flexible linker (a propyl group), which allows the active site to either react with the substrate or relax, reversibly, to the surface, thus providing stability. In contrast, the use of a rigid linker (here mesitylphenyl) leads to a well-defined active site far away from the surface, stabilized only by a phosphine ligand which under reaction conditions leaves probably irreversibly, leading to faster decomposition and deactivation of the catalysts. PMID- 23362801 TI - Edema of the interarytenoid mucosa seen on endoscopy is related to endoscopic positive esophagitis (EE) and is an independent predictor of EE. AB - BACKGROUND: Laryngopharyngeal reflux (LPR) is defined as the retrograde flow of gastric contents up through the esophagus to the larynx and hypopharynx; this is an extra-esophageal manifestation of gastroesophageal reflux disease (GERD). Although both LPR and GERD are caused by reflux of stomach contents, their clinical presentations and treatments differ. PATIENTS AND METHODS: In the present study, we assessed esophago-gastroendoscopic findings related to GERD, specifically endoscopic-positive esophagitis (EE), laryngopharyngeal findings, and GERD symptoms on the 12-question frequency scale for the symptoms of gastroesophageal reflux disease (FSSG). Then, independent predictors of EE were analyzed, and relationships among EE, laryngopharyngeal findings, and patients' symptoms and characteristics were investigated. RESULTS: Hiatal hernia (odds ratio [OR]: 2.70; 95% confidence interval [CI]: 1.17-6.23, P-value 0.019) and edema of theinterarytenoid mucosa (OR, 3.77; 95% CI, 1.26-16.3; P-value 0.035) were significantly related with EE and independent predictors of EE. However, patients' characteristics and the FSSG score had no significant relationship with EE; there was no relationship between patients' characteristics and EE, regardless of its severity. CONCLUSIONS: Although LPR symptoms had no significant relationship with the findings of EE, hiatal hernia and edema of the interarytenoid mucosa were significantly related with EE and were considered to be independent predictors of EE. PMID- 23362803 TI - Microbiology. Editorial. PMID- 23362802 TI - Infectivity of blood products from donors with occult hepatitis B virus infection. AB - BACKGROUND: Occult hepatitis B virus (HBV) infection (OBI) is identified in 1:1000 to 1:50,000 European blood donations. This study intended to determine the infectivity of blood products from OBI donors. STUDY DESIGN AND METHODS: Recipients of previous donations from OBI donors were investigated through lookback (systematic retrieval of recipients) or traceback (triggered by clinical cases). Serologic and genomic studies were undertaken on consenting donors and recipients. Multiple variables potentially affecting infectivity were examined. RESULTS: A total of 45 of 105 (42.9%) donor-recipients pairs carried antibodies to HBV core (anti-HBc) as evidence of previous HBV infection. Subtracting 15% of anti-HBc population background, the adjusted transmission rate was 28%. Anti-HBc prevalence increased to 28 of 44 (63.8%) in unvaccinated recipients receiving anti-HBs-negative OBI blood products. In contrast, four of 26 (15.4%) recipients of anti-HBs-positive products were anti-HBc positive. Transmission with anti-HBs negative products depended on volume of plasma transfused (85%-100% with 200 mL of fresh frozen plasma [FFP], 51% with 50 mL in platelet concentrates [PCs], and 24% with 20 mL in red blood cells [RBCs], p < 0.0001 FFP vs. RBCs). The 50% minimum infectious dose of OBI HBV DNA was estimated at 1049 (117-3441) copies. Donor and recipient strains sequence homology of at least 99% confirmed transfusion-transmitted infection in 10 cases and excluded it in one case. CONCLUSION: Blood products from donors with OBI carry a high risk of HBV transmission by transfusion. This risk is dependent on presence of anti-HBs and viral dose. This may justify safety measures such as anti-HBc and HBV nucleic acid test screening depending on epidemiology. PMID- 23362804 TI - Neurological and intellectual disabilities among adolescents within a custodial institution in South-West Nigeria. AB - A total of 67 adolescents from a juvenile remand home were matched with 67 other adolescents by age and gender, with a view to determine the prevalence and spectrum of neurological and intellectual disabilities. Intelligence quotient (IQ) was estimated using an adapted version of the Slosson's Intelligence Test and a full neurological evaluation was carried out. The mean IQ score for the remand home participants was significantly lower than the controls (77 +/- 11 vs. 99 +/- 14; t = 1.6, P = 0.001). Almost half (46.7%) of the participants in the remand home had intellectual disability of varying degrees, including borderline intellectual functioning, compared with only two (3.3%) of the comparison group (P < 0.001). Epilepsy and neurological deficits were significantly more prevalent among the remand home group, particularly those admitted as victims of neglect, compared with the comparison group (P <= 0.02). These findings and recent literature were used to speculate the possible underlying factors. Policy implications for child social welfare in Nigeria were suggested. PMID- 23362805 TI - The admission CTG: is there any evidence for still using the test? AB - Admission cardiotocography (CTG) was introduced as a screening test for fetal distress in labor in the late 1980s. No systematic assessments of the test were performed before it was taken into widespread use. A screening test is meant to identify individuals with an increased risk for a disease or condition before symptoms occur, to prevent and reduce morbidity or mortality. A screening test should be evaluated according to its effectiveness, prognostic values and reliability. A careful review of the research literature states that routine use of the admission CTG in low-risk women increases the incidence of minor obstetric interventions, may increase the incidence of cesarean sections, but has no impact on other important outcomes. The prognostic values are poor, and the reliability varies from good to poor. There is no evidence showing that the admission CTG is beneficial, and the test should not be offered to low-risk women. PMID- 23362806 TI - Taxonomy of golf putting: do different golf putting techniques exist? AB - This study is a preliminary investigation into the use of cluster analysis to determine if different putting techniques existed in a group of club level golfers. Putting at a hole 4 m away, the performances of 34 experienced golfers (age 55.3 +/- 17.8 years and handicap 15.3 +/- 6.9, range 3-27) were analysed using putter head kinematic and centre of pressure data. Two distinct putting techniques were identified (named as Arm putting and Body putting), this being the first time different putting techniques have been reported in the research literature. These techniques were defined by parameters related solely to movement of the centre of pressure along the line of the putt. Some players (17 of 34) moved between techniques when performing their putting trials. Neither technique produced more accurate putt results (P = 0.783). Putting technique was further analysed after grouping players according to handicap (similar skill level) or accuracy (similar putting performance). The lack of significant findings when players were re-analysed according to handicap or accuracy highlights the importance of the correct methodological approach to detecting technique differences. PMID- 23362807 TI - Children's Memory for Their Mother's Murder: Accuracy, Suggestibility, and Resistance to Suggestion. AB - From its inception, child eyewitness memory research has been guided by dramatic legal cases that turn on the testimony of children. Decades of scientific research reveal that, under many conditions, children can provide veracious accounts of traumatic experiences. Scientific studies also document factors that lead children to make false statements. In this paper we describe a legal case in which children testified about their mother's murder. We discuss factors that may have influenced the accuracy of the children's eyewitness memory. Children's suggestibility and resistance to suggestion are illustrated. Expert testimony, based on scientific research, can aid the trier of fact when children provide crucial evidence in criminal investigations and courtroom trials about tragic events. PMID- 23362808 TI - The relationship between cardiac autonomic function and maximal oxygen uptake response to high-intensity intermittent-exercise training. AB - Major individual differences in the maximal oxygen uptake response to aerobic training have been documented. Vagal influence on the heart has been shown to contribute to changes in aerobic fitness. Whether vagal influence on the heart also predicts maximal oxygen uptake response to interval-sprinting training, however, is undetermined. Thus, the relationship between baseline vagal activity and the maximal oxygen uptake response to interval-sprinting training was examined. Exercisers (n = 16) exercised three times a week for 12 weeks, whereas controls did no exercise (n = 16). Interval-sprinting consisted of 20 min of intermittent sprinting on a cycle ergometer (8 s sprint, 12 s recovery). Maximal oxygen uptake was assessed using open-circuit spirometry. Vagal influence was assessed through frequency analysis of heart rate variability. Participants were aged 22 +/- 4.5 years and had a body mass of 72.7 +/- 18.9 kg, a body mass index of 26.9 +/- 3.9 kg . m(-2), and a maximal oxygen uptake of 28 +/- 7.4 ml . kg(-1) . min(-1). Overall increase in maximal oxygen uptake after the training programme, despite being anaerobic in nature, was 19 +/- 1.2%. Change in maximal oxygen uptake was correlated with initial baseline heart rate variability high frequency power in normalised units (r = 0.58; P < 0.05). Thus, cardiac vagal modulation of heart rate was associated with the aerobic training response after 12 weeks of high-intensity intermittent-exercise. The mechanisms underlying the relationship between the aerobic training response and resting heart rate variability need to be established before practical implications can be identified. PMID- 23362809 TI - Obstructive sleep apnea: should weight loss be prescribed? PMID- 23362810 TI - Severity scores in community-acquired pneumonia: how useful are they? PMID- 23362812 TI - Mepolizumab for severe eosinophilic asthma. AB - In this large (616 patients), double-blind, placebo-controlled, dose-ranging study of mepolizumab (a monoclonal antibody that blocks IL-5 binding to its receptor), patients were given placebo, 75-, 250- or 750-mg mepolizumab by intravenous infusion every 4 weeks for 1 year. Exacerbation rates at all doses were 50% less than those in the placebo group. There were no changes in any other asthma measures (symptoms, quality of life or lung function). This may be a useful advance for a subgroup of severe asthma with frequent exacerbations and persistent eosinophilia, which may be about half of severe asthmatics. More information on patient selection and cost-benefit will be required. PMID- 23362813 TI - Eosinophils as diagnostic tools in chronic lung disease. AB - Chronic lung diseases are very common and form a major threat to large proportions of the population with increased morbidity and mortality. Asthma is one of the most common eosinophilic airway diseases. However, there is growing evidence that eosinophilic inflammation is also important in subgroups of patients with chronic obstructive pulmonary disease, chronic cough and idiopathic pulmonary fibrosis. Several studies have shown that sputum eosinophilia is associated with a favorable response to treatment of corticosteroids in both asthma and chronic obstructive pulmonary disease, and tailored strategies aimed to normalize sputum eosinophils have resulted in a significant reduction in exacerbation rates. In this article, the authors review the role of eosinophilic inflammation in the diagnosis and management of chronic respiratory diseases. PMID- 23362814 TI - The emergence of new therapeutic targets in pulmonary arterial hypertension: from now to the near future. AB - Pulmonary arterial hypertension (PAH) is a vascular remodeling disease that pathologically increases pulmonary vascular resistance. Ultimately, this leads to right ventricular failure and premature death. Current therapeutic strategies are mainly designed to induce relaxation of the pulmonary arteries, but are not directly aimed to improve vascular remodeling that characterize PAH. Although these treatments modestly improve patient symptoms, pulmonary hemodynamics and survival, none of them are curative and approximately 15% of patients die within 1 year of medical follow-up despite treatment. Within the last 5 years, tremendous advances in our understanding of the PAH pathophysiology have arisen. These advances have a high potential for the development of better patient care by providing novel therapeutic targets. The goal of this report is to review the current PAH treatments, as well as novel therapies that will pave the future in this devastating disease. PMID- 23362815 TI - The role of systemic inflammatory biomarkers to predict mortality in chronic obstructive pulmonary disease. AB - The authors discuss the role of inflammatory biomarkers to predict mortality in chronic obstructive pulmonary disease (COPD) in this narrative literature review with expert opinion. The severity of COPD has traditionally been graded using the degree of obstruction as measured by the forced expiratory volume in 1 s because this variable has been predictive of outcomes. However, it is now accepted that COPD is a complex disease with important systemic consequences and that a multidimensional index such as the BMI, obstruction, dyspnea and exercise capacity index is a better predictor of outcome than lung function alone. Because inflammation is thought to play a pivotal role in the genesis of COPD, several serum inflammatory biomarkers have been investigated. Of the ones studied, C reactive protein, IL-6, pulmonary and activation-regulated chemokine and fibronectin:C-reactive protein ratio have been observed to be independently associated with increased risk of death. When added to known clinical variables such as the BMI, obstruction, dyspnea and exercise capacity index, only IL-6 has been shown to further contribute to mortality prediction. It is likely that the use of an integrative approach combining biomarkers investigated through high output technology with clinical parameters, combined with new information from the fields of genomics, transcriptomics, proteomics and metabolomics, will improve the authors capacity to predict mortality in COPD. PMID- 23362816 TI - Effect of inhaled dry powder mannitol on mucus and its clearance. AB - Insufficient hydration at the airway surface can make mucus adherent and poorly cleared. Cough, the major mechanism of mucus clearance in disease, is ineffective when mucus is adhesive. Inhaled mannitol creates an osmotic drive for water to move into the airway lumen. The consequent increased hydration of the airway surface decreases the adherence of mucus to the epithelium, facilitates the coupling of mucus and cilia thereby increasing mucus clearance. Inhaled mannitol also promotes effective coughing and stimulates mucociliary clearance. The beneficial effect of mannitol on mucus and its clearance has been demonstrated in patients with asthma, bronchiectasis and cystic fibrosis. Inhaled dry powder mannitol (BronchitolTM) is promising to be an effective treatment for the clearance of retained airway secretions. PMID- 23362817 TI - Managing an acutely ill patient with pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a progressive disease characterized by a vasculopathy that results in sustained elevation of pulmonary artery pressures, which ultimately leads to right ventricular failure (RVF) and death. Several advances have been made in the treatment of PAH, but it remains a major cause of morbidity and mortality. Managing an acutely ill patient with PAH is especially challenging. The mechanisms of RVF are incompletely understood; these patients do not tolerate fluid shifts well and there are no controlled trials to assess superiority of a certain approach. This article outlines an approach based on current understanding of RVF in PAH and recommends an approach based on the pathophysiology, current evidence and experience. PMID- 23362818 TI - Hemoptysis with diagnostic dilemma. AB - Hemoptysis is a common symptom. Although initial diagnostic workup, including a chest radiograph, often gives a clue to the cause, it provides no diagnostic hints in 3.0-42.2% of episodes of hemoptysis. To describe those cases with no diagnostic hints at initial investigations, experts have used different terms, including unexplained hemoptysis, idiopathic hemoptysis, cryptogenic hemoptysis and hemoptysis with normal chest radiographs. As hemoptysis is a common symptom of bronchogenic carcinoma, there is a concern of having underlying malignancy. Physicians value high-resolution computed tomography and fiberoptic bronchoscopy as the next investigations to establish diagnosis. These investigations however are expensive and nonspecific results are common in those cases of hemoptysis where initial diagnostic workup gives no clues to the cause. As a result, controversies exist with regard to their use. In this article, the author has proposed diagnostic approaches to evaluate those cases of hemoptysis with no diagnostic hints at initial investigation, after extensive review of published articles related to the case scenario. PMID- 23362820 TI - Obituary: Robert S. Schoor, DDS. PMID- 23362822 TI - Effects of carbon and nitrogen plasma immersion ion implantation on in vitro and in vivo biocompatibility of titanium alloy. AB - Growth of bony tissues on titanium biomedical implants can be time-consuming, thereby prolonging recovery and hospitalization after surgery and a method to improve and expedite tissue-implant integration and healing is thus of scientific and clinical interests. In this work, nitrogen and carbon plasma immersion ion implantation (N-PIII and C-PIII) is conducted to modify Ti-6Al-4V to produce a graded surface layer composed of TiN and TiC, respectively. Both PIII processes do not significantly alter the surface hydrophilicity but increase the surface roughness and corrosion resistance. In vitro studies disclose improved cell adhesion and proliferation of MC3T3-E1 preosteoblasts and L929 fibroblasts after PIII. Micro-CT evaluation conducted 1 to 12 weeks after surgery reveals larger average bone volumes and less bone resorption on the N-PIII and C-PIII titanium alloy pins than the unimplanted one at every time point. The enhancements observed from both the in vitro and in vivo studies can be attributed to the good cytocompatibility, roughness, and corrosion resistance of the TiN and TiC structures which stimulate the response of preosteoblasts and fibroblasts and induce early bone formation. Comparing the two PIII processes, N-PIII is more effective and our results suggest a simple and practical means to improve the surface biocompatibility of medical-grade titanium alloy implants. PMID- 23362823 TI - Applicability of the MATRICS Consensus Cognitive Battery in Singapore. AB - The MATRICS Consensus Cognitive Battery (MCCB) was developed to provide a reliable, valid, and standard battery for clinical trials on cognitive enhancers in schizophrenia. In this study we tested the applicability of the MCCB to Singapore's English speakers. Healthy ethnic Chinese, Malay, and Indian English speakers (N = 171) of both genders were recruited within three age groups and three levels of education to match as closely as possible the US norming sample, and were administered the MCCB. Descriptive data, T scores, age, gender, education, and ethnicity effects on performance were explored and compared with the US norming study. Age, education, and ethnicity affected the battery's composite scores, with young and highly educated participants generally outperforming the old, less-educated ones. Male participants outperformed their female counterparts in two out of seven cognitive domains. Although generally lower when compared to the US norming sample, Singaporean scores reflected the same relationship with age, education, and gender, with the exception of a substantially worse performance in the social cognition domain. Differences among the ethnic groups in Singapore-and the poorer performance measured in these groups with respect to the US sample-call for the necessity of an extended norming study in Singapore. PMID- 23362824 TI - Listeria monocytogenes in donated platelets: a potential transfusion-transmitted pathogen intercepted through screening. AB - BACKGROUND: Bacterial contamination of blood components is a potentially life threatening complication of transfusions. In October 2005, the Centers for Disease Control and Prevention (CDC) noted four Listeria monocytogenes (Lm) isolates cultured from four different units of donated apheresis platelets (PLTs) among Lm isolates sent to the CDC National Listeria Reference Laboratory for subtyping as part of routine surveillance activities. STUDY DESIGN AND METHODS: We describe an investigation to determine possible common sources of infection among donors or factors associated with PLT collection or storage and to determine whether human transfusion-associated listeriosis cases had been reported. We also reviewed all isolates with PLTs as a source sent to the CDC National Listeria Reference Laboratory between November 1, 2005, and December 31, 2011. RESULTS: Each PLT donor-associated isolate had a distinct pulsed-field gel electrophoresis pattern combination. Other than these four cases, no other cases of Lm-contaminated PLTs were identified by the American Red Cross or by CDC during 2005. However, two additional cases of Lm isolated from donated PLTs were detected, one in 2008 and one in 2011. CONCLUSION: Although the source of contamination for these PLT units is unclear, and a source common to all units was not identified, this investigation underscores the value of screening for bacterial contaminants of PLTs. PMID- 23362825 TI - Defining and refining the phenotype of PRRT2 mutations. PMID- 23362826 TI - Hybrid feature detection and information accumulation using high-resolution LC-MS metabolomics data. AB - Feature detection is a critical step in the preprocessing of liquid chromatography-mass spectrometry (LC-MS) metabolomics data. Currently, the predominant approach is to detect features using noise filters and peak shape models based on the data at hand alone. Databases of known metabolites and historical data contain information that could help boost the sensitivity of feature detection, especially for low-concentration metabolites. However, utilizing such information in targeted feature detection may cause large number of false positives because of the high levels of noise in LC-MS data. With high resolution mass spectrometry such as liquid chromatograph-Fourier transform mass spectrometry (LC-FTMS), high-confidence matching of peaks to known features is feasible. Here we describe a computational approach that serves two purposes. First it boosts feature detection sensitivity by using a hybrid procedure of both untargeted and targeted peak detection. New algorithms are designed to reduce the chance of false-positives by nonparametric local peak detection and filtering. Second, it can accumulate information on the concentration variation of metabolites over large number of samples, which can help find rare features and/or features with uncommon concentration in future studies. Information can be accumulated on features that are consistently found in real data even before their identities are found. We demonstrate the value of the approach in a proof of-concept study. The method is implemented as part of the R package apLCMS at http://www.sph.emory.edu/apLCMS/ . PMID- 23362827 TI - Are there cognitive and neurobehavioural correlates of hormonal neuroprotection for women after TBI? AB - This study examined possible cognitive correlates of hormonal neuroprotection following traumatic brain injury (TBI) using archival neuropsychological findings for 1563 individuals undergoing acute TBI rehabilitation between 1989 and 2002. Presumed age of menopause was based on the STRAW (Stages of Reproductive Aging) staging system (Soules, 2005; Soules et al., 2001) and general linear model (GLM) analysis of performance on neuropsychological testing by participants across gender and age groups (25-34, 35-44, 45-54, and 55-64) was performed. Hypotheses were (1) women with TBI in the oldest age group would have lower scores on neuropsychological tests and functional outcome measures than women in the younger groups, and (2) men in the oldest age group would have higher scores than women of the same age group. Analyses revealed that oldest females had significantly worse Trails B and SDMT written and oral scores than the youngest females. In addition, oldest females had significantly better Trails B, Rey AVLT and SDMT written scores than the oldest males. Possible cohort exposure to hormone replacement therapy, unknown hormonal status at time of testing, and sample-specific injury characteristics may have contributed to these findings. PMID- 23362828 TI - Physical exercise intervention in depressive disorders: meta-analysis and systematic review. AB - Previous meta-analyses investigating the effect of exercise on depression have included trials where the control condition has been categorized as placebo despite the fact that this particular placebo intervention (e.g., meditation, relaxation) has been recognized as having an antidepressant effect. Because meditation and mindfulness-based interventions are associated with depression reduction, it is impossible to separate the effect of the physical exercise from the meditation-related parts. The present study determined the efficacy of exercise in reducing symptoms of depression compared with no treatment, placebo conditions or usual care among clinically defined depressed adults. Of 89 retrieved studies, 15 passed the inclusion criteria of which 13 studies presented sufficient information for calculating effect sizes. The main result showed a significant large overall effect favoring exercise intervention. The effect size was even larger when only trials that had used no treatment or placebo conditions were analyzed. Nevertheless, effect size was reduced to a moderate level when only studies with high methodological quality were included in the analysis. Exercise may be recommended for people with mild and moderate depression who are willing, motivated, and physically healthy enough to engage in such a program. PMID- 23362829 TI - A fresh perspective on comparing the FDA and the CHMP/EMA: approval of antineoplastic tyrosine kinase inhibitors. AB - We compared and determined the reasons for any differences in the review and approval times of tyrosine kinase inhibitors (TKIs) by the US Food and Drug Administration (FDA) and the European EMA/CHMP. Applications for these novel cancer drugs were submitted to them within a mean of 31.2 days of each other, providing a fair basis for comparison. The FDA had granted priority review to 12 TKIs but the EMA/CHMP did not grant the equivalent accelerated assessment to any. The FDA granted accelerated approvals to six (38%) and CHMP granted (the equivalent) conditional approvals to four (29%) of these agents. On average, the review and approval times were 205.3 days in the US compared with 409.6 days in the European Union (EU). The active review times, however, were comparable (225.4 days in the EU and 205.3 days in the US). Since oncology drug development lasts about 7 years, the 20 days difference in review times between the two agencies is inconsequential. Clock stops during review and the time required to issue an approval had added the extra 184.2 days to review time in the EU. We suggest possible solutions to expedite the EU review and approval processes. However, post-marketing emergence of adverse efficacy and safety data on gefitinib and lapatinib, respectively, indicate potential risks of expedited approvals. We challenge the widely prevalent myth that early approval translates into early access or beneficial impact on public health. Both the agencies collaborate closely but conduct independent assessments and make decisions based on distinct legislation, procedures, precedents and societal expectations. PMID- 23362830 TI - Metformin induces cytotoxicity by down-regulating thymidine phosphorylase and excision repair cross-complementation 1 expression in non-small cell lung cancer cells. AB - Metformin is an antidiabetic drug recently shown to inhibit cancer cell proliferation and growth, although the involved molecular mechanisms have not been elucidated. In many cancer cells, high expression of thymidine phosphorylase (TP) and Excision repair cross-complementation 1 (ERCC1) is associated with poor prognosis. We used A549 and H1975 human non-small cell lung cancer (NSCLC) cell lines to investigate the role of TP and ERCC1 expression in metformin-induced cytotoxicity. Metformin treatment decreased cellular TP and ERCC1 protein and mRNA levels by down-regulating phosphorylated MEK1/2-ERK1/2 protein levels in a dose- and time-dependent manner. The enforced expression of the constitutively active MEK1 (MEK1-CA) vectors significantly restored cellular TP and ERCC1 protein levels and cell viability. Specific inhibition of TP and ERCC1 expression by siRNA enhanced the metformin-induced cytotoxicity and growth inhibition. Arachidin-1, an antioxidant stilbenoid, further decreased TP and ERCC1 expression and augmented metformin's cytotoxic effect, which was abrogated in lung cancer cells transfected with MEK1/2-CA expression vector. In conclusion, metformin induces cytotoxicity by down-regulating TP and ERCC1 expression in NSCLC cells. PMID- 23362831 TI - Differential developmental programming by early protein restriction of rat skeletal muscle according to its fibre-type composition. AB - AIMS: Differences in fibre-type composition of skeletal muscle have been associated with obesity and insulin resistance. As a poor nutrient environment early in life is a predisposing factor for the development of obesity and related metabolic diseases at adulthood, this study aimed at determining the long-term consequences of maternal undernutrition on the structural and metabolic properties of two skeletal muscles characterized by their different fibre-type composition and metabolic properties. METHODS: The fibre-type composition and enzymatic activities of hexokinase (HK), beta-hydroxyacyl-CoA dehydrogenase (beta HAD) and citrate synthase (CS) were measured in soleus and extensor digitorum longus (EDL) muscles from adult rats born to dams fed a control (17% protein) or a low-protein [8% protein (PR)] diet throughout pregnancy and lactation. In addition, the expression levels of several genes regulating glycolysis, fatty acid oxidation and mitochondrial biogenesis were determined by real-time PCR. RESULTS: Protein rats exhibited enhanced density of type II fibres along with decreased rate of fatty acid oxidation and glycolysis in soleus but not EDL. Malnourished rats exhibited also a different gene expression profile in soleus and EDL. Altogether, these alterations correspond to a state of energy deficiency and are present in animals which do not show yet any sign of obesity or glucose intolerance. CONCLUSION: We conclude that maternal protein restriction alters in the long term the structural and enzymatic properties of offspring skeletal muscle in a fibre-type-dependent manner. These alterations might have a causative role in the development of obesity and related metabolic disorders later in life. PMID- 23362832 TI - Repeated-sprint performance and vastus lateralis oxygenation: effect of limited O2 availability. AB - This study examined the influence of muscle deoxygenation and reoxygenation on repeated-sprint performance via manipulation of O2 delivery. Fourteen team-sport players performed 10 10-s sprints (30-s recovery) under normoxic (NM: FI O2 0.21) and acute hypoxic (HY: FI O2 0.13) conditions in a randomized, single-blind fashion and crossover design. Mechanical work was calculated and arterial O2 saturation (Sp O2 ) was estimated via pulse oximetry for every sprint. Muscle deoxyhemoglobin concentration ([HHb]) was monitored continuously by near-infrared spectroscopy. Differences between NM and HY data were analyzed for practical significance using magnitude-based inferences. HY reduced Sp O2 (-10.7 +/- 1.9%, with chances to observe a higher/similar/lower value in HY of 0/0/100%) and mechanical work (-8.2 +/- 2.1%; 0/0/100%). Muscle deoxygenation increased during sprints in both environments, but was almost certainly higher in HY (12.5 +/- 3.1%, 100/0/0%). Between-sprint muscle reoxygenation was likely more attenuated in HY (-11.1 +/- 11.9%; 2/7/91%). The impairment in mechanical work in HY was very largely correlated with HY-induced attenuation in muscle reoxygenation (r = 0.78, 90% confidence limits: 0.49; 0.91). Repeated-sprint performance is related, in part, to muscle reoxygenation capacity during recovery periods. These results extend previous findings that muscle O2 availability is important for prolonged repeated-sprint performance, in particular when the exercise is taken in hypoxia. PMID- 23362834 TI - Three-mode electrochemical sensing of ultralow microRNA levels. AB - MicroRNAs (miRNAs) are an emerging class of biomarkers that are frequently deregulated in cancer cells and have shown great promise for cancer classification and prognosis. In this work, we developed a three-mode electrochemical sensor for detection and quantitation of ultralow levels of miRNAs in a wide dynamic range of measured concentrations. The sensor facilitates three detection modalities based on hybridization (H-SENS), p19 protein binding (P-SENS), and protein displacement (D-SENS). The combined three-mode sensor (HPD SENS) identifies as low as 5 aM or 90 molecules of miRNA per 30 MUL of sample without PCR amplification, and can be operated within the dynamic range from 10 aM to 1 MUM. The HPD sensor is made on a commercially available gold nanoparticles-modified electrode and is suitable for analyzing multiple miRNAs on a single electrode. This three-mode sensor exhibits high selectivity and specificity and was used for sequential analysis of miR-32 and miR-122 on one electrode. In addition, the H-SENS can recognize miRNAs with different A/U and G/C content and distinguish between a fully matched miRNA and a miRNA comprising either a terminal or a middle single base mutation. Furthermore, the H- and P SENS were successfully employed for direct detection and profiling of three endogenous miRNAs, including hsa-miR-21, hsa-miR-32, and hsa-miR-122 in human serum, and the sensor results were validated by qPCR. PMID- 23362833 TI - Immunization with Culex tarsalis mosquito salivary gland extract modulates West Nile virus infection and disease in mice. AB - Mosquito salivary proteins inoculated during blood feeding modulate the host immune response, which can contribute to the pathogenesis of viruses transmitted by mosquito bites. Previous studies with mosquito bite-naive mice indicated that exposure to arthropod salivary proteins resulted in a shift toward a Th2-type immune response in flavivirus-susceptible mice but not flavivirus-resistant animals. In the study presented here, we tested the hypothesis that immunization with high doses of Culex tarsalis salivary gland extracts (SGE) with an adjuvant would prevent Th2 polarization after mosquito bite and enhance resistance to mosquito-transmitted West Nile virus (WNV). Our results indicate that mice immunized with Cx. tarsalis SGE produced increased levels of Th1-type cytokines (IFNgamma and TNFalpha) after challenge with mosquito-transmitted WNV and exhibited both a delay in infection of the central nervous system (CNS) and significantly lower WNV brain titers compared to mock-immunized mice. Moreover, mortality was significantly reduced in the SGE-immunized mice, as none of these mice died, compared to mortality of 37.5% of mock-vaccinated mice by 8 days after infected mosquito bite. These results suggest that development of a mosquito salivary protein vaccine might be a strategy to control arthropod-borne viral pathogens such as WNV. PMID- 23362835 TI - Therapeutic endoscopic retrograde cholangiography using a single-balloon enteroscope in patients with Roux-en-Y anastomosis. AB - BACKGROUND: The aim of the present study was to evaluate the usefulness of a single-balloon enteroscope (SBE) including a newly developed short SBE (SIF Y0004) for therapeutic endoscopic retrograde cholangiography (ERC) in patients with Roux-en-Y (R-Y) anastomosis. PATIENTS AND METHODS: Therapeutic ERC using a SBE was attempted in 19 cases (41 procedures) with R-Y anastomosis after gastrectomy. A standard SBE (working length of 200 cm, working channel of 2.8 mm) was used in 11 cases (Group L), and a short SBE (working length of 152 cm, working channel of 3.2 mm) was used in eight cases (Group S). RESULTS: Insertion of the scope up to the major papilla was achieved in 79% (15/19) of cases. Average insertion time was 37.0 +/- 13.8 min (range, 19-62 min). Bile duct cannulation rate was 79% (11/14) after exclusion of the initial case in which scope exchange was unsuccessful. Average procedure time was78.8 +/- 26.9 min (18 119 min). The scheduled therapeutic procedure was completed in 67% (10/15) of the cases (53% [10/19] on an intention-to-treat basis). Cardiorespiratory suppression due to sedative agents resulting in scope withdrawal developed in one procedure (2.4%; 1/41). Although there was no significant difference in therapeutic results between the two groups, the number of procedures was smaller (1.8 +/- 1.3 vs 3.6 +/- 3.1; P = 0.286) in Group S than in Group L. CONCLUSIONS: Therapeutic ERC using a SBE for patients with R-Y anastomosis is considered to be safe and effective. A short SBE appears to be promising for further improvement in therapeutic results. PMID- 23362836 TI - Change in risk status during labor in a large Norwegian obstetric department: a prospective study. AB - OBJECTIVE: This study aimed to observe risk status on admission to hospital and change in risk status during labor. DESIGN: A prospective observational study allocating all women into low-risk and high-risk groups on admittance to hospital and during labor based on prespecified risk criteria. SETTING: Department of Obstetrics and Gynecology in a district hospital. POPULATION: All 6406 deliveries from 2 May 2004 to 30 September 2006. METHODS: A special form was filled out for all women admitted to the department in labor classifying them as either low or high risk. A change in risk status during labor was also recorded. MAIN OUTCOME MEASURES: Risk status (low and high risk) on admittance to hospital and change in risk status during first stage of labor. RESULTS: On admittance, 67% of women with an intended vaginal delivery were low risk. During the first stage of labor, 41% of the low-risk women changed risk status. Use of epidural anesthesia gave rise to 73% of the risk changes during the first stage of labor and use of oxytocin caused 12%. CONCLUSIONS: Two-thirds of the women were low risk before labor, and 39% of these remained low-risk at the end of the first stage of labor. The main reason for a change of risk status in the obstetric department was the use of epidural anesthesia. PMID- 23362837 TI - Solid-state NMR on bacterial cells: selective cell wall signal enhancement and resolution improvement using dynamic nuclear polarization. AB - Dynamic nuclear polarization (DNP) enhanced solid-state nuclear magnetic resonance (NMR) has recently emerged as a powerful technique for the study of material surfaces. In this study, we demonstrate its potential to investigate cell surface in intact cells. Using Bacillus subtilis bacterial cells as an example, it is shown that the polarizing agent 1-(TEMPO-4-oxy)-3-(TEMPO-4 amino)propan-2-ol (TOTAPOL) has a strong binding affinity to cell wall polymers (peptidoglycan). This particular interaction is thoroughly investigated with a systematic study on extracted cell wall materials, disrupted cells, and entire cells, which proved that TOTAPOL is mainly accumulating in the cell wall. This property is used on one hand to selectively enhance or suppress cell wall signals by controlling radical concentrations and on the other hand to improve spectral resolution by means of a difference spectrum. Comparing DNP-enhanced and conventional solid-state NMR, an absolute sensitivity ratio of 24 was obtained on the entire cell sample. This important increase in sensitivity together with the possibility of enhancing specifically cell wall signals and improving resolution really opens new avenues for the use of DNP-enhanced solid-state NMR as an on cell investigation tool. PMID- 23362838 TI - Intercalation pathway in many-particle LiFePO4 electrode revealed by nanoscale state-of-charge mapping. AB - The intercalation pathway of lithium iron phosphate (LFP) in the positive electrode of a lithium-ion battery was probed at the ~40 nm length scale using oxidation-state-sensitive X-ray microscopy. Combined with morphological observations of the same exact locations using transmission electron microscopy, we quantified the local state-of-charge of approximately 450 individual LFP particles over nearly the entire thickness of the porous electrode. With the electrode charged to 50% state-of-charge in 0.5 h, we observed that the overwhelming majority of particles were either almost completely delithiated or lithiated. Specifically, only ~2% of individual particles were at an intermediate state-of-charge. From this small fraction of particles that were actively undergoing delithiation, we conclude that the time needed to charge a particle is ~1/50 the time needed to charge the entire particle ensemble. Surprisingly, we observed a very weak correlation between the sequence of delithiation and the particle size, contrary to the common expectation that smaller particles delithiate before larger ones. Our quantitative results unambiguously confirm the mosaic (particle-by-particle) pathway of intercalation and suggest that the rate limiting process of charging is initiating the phase transformation by, for example, a nucleation-like event. Therefore, strategies for further enhancing the performance of LFP electrodes should not focus on increasing the phase-boundary velocity but on the rate of phase-transformation initiation. PMID- 23362839 TI - Clearing bowel obstruction and decreasing pain in a terminally ill patient via manual physical therapy. PMID- 23362840 TI - Development of a real-time polymerase chain reaction assay for sensitive detection and quantitation of Babesia microti infection. AB - BACKGROUND: Babesia microti, the most frequently implicated pathogen in transfusion-transmitted babesiosis, is widely endemic in the Northeast and upper Midwestern United States. High seroprevalence in endemic areas limits antibody based donor screening. A high-performance molecular test is needed to identify donors in the preseroconversion window phase as well as to discriminate past serologic exposure with parasite clearance from continued parasitemia. STUDY DESIGN AND METHODS: Frozen Babesia-spiked whole blood was microcentrifuged, and the supernatant transferred and microcentrifuged again to concentrate the parasite. The DNA was extracted and amplified using real-time polymerase chain reaction (PCR) using Babesia-specific primers. The assay was employed in three series of experiments: 1) a validation and optimization spiking experiment, 2) a blinded serial dilution probit analysis to determine the limit of detection, and 3) evaluation of two blinded panels of clinical samples from possible babesiosis cases. RESULTS: At a decreasing inoculum of 445, 44.5, and 4.45 copies/mL, the assay had positive rates of 100, 97.5, and 81%, respectively. The blinded probit analysis demonstrated a detection rate of 95 and 50% at 12.92 and 1.52 parasites/2 mL of whole blood, respectively. Evaluation of clinical samples showed 13 of 21 samples to be positive, with a range of 85 to 4.8 million parasites/mL. There were no positives detected among 48 healthy donors CONCLUSION: We have developed a highly sensitive and specific, quantitative real time PCR-based assay for detection of B. microti that could have a useful role in blood screening. It can also be employed broadly to understand Babesia epidemiology, disease pathogenesis, and host immunology. PMID- 23362841 TI - Cooperative effects of electron donors and acceptors for the stabilization of elusive metal cluster frameworks: synthesis and solid-state structures of [Pt19(CO)24(MU4-AuPPh3)3]- and [Pt19(CO)24{MU4-Au2(PPh3)2}2]. AB - The anionic cluster [Pt(19)(CO)(22)](4-) (1), of pentagonal symmetry, reacts with CO and AuPPh(3)(+) fragments. Upon increasing the Au:Pt(19) molar ratio, different species are sequentially formed, but only the last two members of the series could be characterized by X-ray diffraction, namely, [Pt(19)(CO)(24)(MU(4) AuPPh(3))(3)](-) (2) and [Pt(19)(CO)(24){MU(4)-Au(2)(PPh(3))(2)}(2)] (3). The metallic framework of the starting cluster is completely modified after the addition of CO and AuL(+), and both products display the same platinum core of trigonal symmetry, with closely packed metal atoms. The three AuL(+) units cap three different square faces in 2, whereas four AuL(+) fragments are grouped in two independent bimetallic units in the neutral cluster 3. Electrochemical and spectroelectrochemical studies on 2 showed that its redox ability is comparable with that of the homometallic 1. PMID- 23362842 TI - Energy expenditure and sex differences of golf playing. AB - The purpose of the study was to assess the average physical intensity and energy expenditure during a single round of golf on hilly and flat courses in a heterogeneous group of healthy men and women of varying age and golf handicap. Forty-two males and 24 females completed an incremental cycle-ergometer exercise test to determine exercise performance markers. The heart rate (HR), duration, distance, walking speed, ascent and descent were measured via a global positioning system (GPS)/HR monitor during the game and energy expenditure was calculated. Playing 9 or 18-holes of golf, independent of the golf course design, the average HR was not significantly different between sexes or the subgroups. The intensities were light with respect to the percentage of maximal HR and metabolic equivalents of task (METs). Total energy expenditure of all participants was not significantly different for hilly (834 +/- 344 kcal) vs. flat courses (833 +/- 295 kcal) whereas male players expended significantly greater energy than female players (926 +/- 292 vs. 556 +/- 180 kcal), but did not have significantly greater relative energy expenditure (2.8 +/- 0.8 vs. 2.2 +/- 0.7 METs). As a high volume physical activity, playing golf is suggested to yield health benefits. Since the intensity was well below recommended limits, golf may have health related benefits unrelated to the intensity level of the activity. PMID- 23362843 TI - Integrating virtual reality video games into practice: clinicians' experiences. AB - The Nintendo Wii is a popular virtual reality (VR) video gaming system in rehabilitation practice and research. As evidence emerges related to its effectiveness as a physical therapy training method, clinicians require information about the pragmatics of its use in practice. The purpose of this descriptive qualitative study is to explore observations and insights from a sample of physical therapists (PTs) working with children with acquired brain injury regarding practical implications of using the Wii as a physical therapy intervention. Six PTs employed at a children's rehabilitation center participated in semi-structured interviews, which were transcribed and analyzed using content analysis. Two themes summarize the practical implications of Wii use: 1) technology meets clinical practice; and 2) onus is on the therapist. Therapists described both beneficial and challenging implications arising from the intersection of technology and practice, and reported the personal commitment required to orient oneself to the gaming system and capably implement this intervention. Findings include issues that may be relevant to professional development in a broader rehabilitation context, including suggestions for the content of educational initiatives and the need for institutional support from managers in the form of physical resources for VR implementation. PMID- 23362844 TI - Validation of the Persian version of Functional Index Questionnaire (FIQ) and Modified FIQ in patients with patellofemoral pain syndrome. AB - The aim of this investigation was to culturally translate and validate the Functional Index Questionnaire (FIQ) and Modified FIQ (MFIQ) in patients with patellofemoral pain syndrome (PFPS). A sample of 100 patients with PFPS completed the FIQ and MFIQ, and Short-Form 36 (SF-36) Health Survey in the first session. The FIQ and MFIQ were re-administered to a sample of 47 patients to evaluate test retest reliability. Test-retest reliability and internal consistency were evaluated by the intraclass correlation coefficient (ICC) and Cronbach's alpha coefficient, respectively. Corrected item-total correlations and construct validity were assessed by Spearman's rank correlation. Factor analysis was performed on all items of the Persian FIQ and MFIQ to determine the number of underlying factors and the items which load on each factor. An acceptable level of test-retest reliability (ICC = 0.84, 0.85) and internal consistency (Cronbach's alpha = 0.79, 0.82) was obtained for both the Persian FIQ and MFIQ, respectively. Item-total correlations were greater than 0.40 for all but two questions of the Persian FIQ and all but four questions of the Persian MFIQ. A total of two factors were detected for each questionnaire. There were moderate to low correlations between the Persian FIQ/MFIQ and SF-36. Persian FIQ and MFIQ are two reliable and valid outcome measures of functional limitation and it seems that they are suitable for use in clinical practice of patients with chronic PFPS. PMID- 23362845 TI - Relationship between scores from the Knee Outcome Survey and a single assessment numerical rating in patients with patellofemoral pain. AB - OBJECTIVE: To determine the relationship between patient-reported single numeric ratings and actual scores obtained from a validated instrument, the Knee Outcome Survey (KOS). BACKGROUND: Patient-reported outcome (PRO) measures are an important component of patient management. Information obtained from PRO measures can be used to prioritize goal setting, assist with clinical decision-making, provide evidence for effectiveness of interventions, monitor progress, and assess organizational or clinician performance. METHODS: Scores from the KOS activity of daily living (ADL) and Sports subscales completed at the time of initial examination of patients with patellofemoral pain (n = 29) were retrospectively analyzed and compared to a single assessment numerical rating. RESULTS: Bi variate Pearson product correlation was used to determine association between the KOS-ADL and KOS-Sports with respective single assessment numerical ratings. A high correlation was observed between the KOS-ADL (0.85, p < 0.01) and KOS-Sports (0.88, p < 0.01) with a single assessment numerical rating. CONCLUSIONS: Administration and scoring of standardized outcome measures such as the KOS-ADL and KOS-Sports require several minutes to administer but correlate well with a single assessment numerical ratings. The high correlation of single assessment numerical scores to actual KOS-ADL and KOS-Sports scores may provide support for discretionary use of single numerical ratings during interim patient care visits and/or in instances when time is limited. Additional studies are needed with larger patient populations and specific diagnostic subgroups to determine additional clinical relevance. PMID- 23362846 TI - Association of single nucleotide polymorphisms in CFH, ARMS2 and HTRA1 genes with risk of age-related macular degeneration in Egyptian patients. AB - BACKGROUND: Age-related macular degeneration (AMD) is one of the leading causes of blindness in the elderly worldwide. Several single nucleotide polymorphisms (SNPs) have been linked to the risk of developing AMD. We aimed to examine the association between AMD and SNPs on CFH, ARMS2 and HTRA1 in Egyptians, a previously unstudied population. MATERIALS AND METHODS: Genomic DNA was extracted from 26 AMD patients and 20 controls. Genotyping was performed using PCR followed by allele-specific restriction digestion and direct sequencing. RESULTS: CFH rs1061170 was significantly associated with AMD with the frequency of the risk C allele being 0.53 in patients and 0.17 in controls (p < 0.017). The odds ratio (OR) for the TC genotype was 5.5 (95% CI: 1.1-26.4) and for combined TC + CC genotypes was 8 (95% CI: 1.7-37.1). ARMS2 rs10490924 was also significantly associated with the risk allele T found at a frequency of 0.5 in AMD and 0.15 in controls (p < 0.017, chi(2) test). The OR for the TG genotype was 4.667 (95% CI: 1.2-18.4) and for combined TG + TT genotypes was 7 (95% CI: 1.8-26.5). HTRA1 rs11200638 also was significantly associated, with the risk allele A found at a frequency of 0.44 in patients and 0.17 in controls (p < 0.017, chi(2) test). OR for GA genotype was 5 (95% CI: 1.2-20.9) and for the combined GA + AA genotypes was 6 (95% CI: 1.4-24.7). CONCLUSIONS: Our data demonstrates significant association between AMD and rs1061170 on CFH, rs10490924 on ARMS2 and rs11200638 on HTRA1 in Egyptian patients. These findings are in agreement with previous findings in Caucasians. PMID- 23362847 TI - Severe myopia with unusual retinal anomalies and Dandy-Walker sequence in two sibs. A distinct new neuro-ocular disorder. AB - We have observed a male and a female, sibs of non-consanguineous parents, affected by severe myopia with characteristic retinal defects and Dandy-Walker variant. The peculiarity of the retinopathy consists of pathological myopia with anomalous vitreal fenestrated membranes in the retinal periphery. We suppose that these associations may configure a new genetic syndrome. PMID- 23362848 TI - Molecular genetics of achromatopsia in Newfoundland reveal genetic heterogeneity, founder effects and the first cases of Jalili syndrome in North America. AB - Achromatopsia (ACHM) is a severe retinal disorder characterized by an inability to distinguish colors, impaired visual acuity, photophobia and nystagmus. This rare autosomal recessive disorder of the cone photoreceptors is best known for its increased frequency due to founder effect in the Pingelapese population of the Pacific islands. Sixteen patients from Newfoundland, Canada were sequenced for mutations in the four known achromatopsia genes CNGA3, CNGB3, GNAT2, and PDE6C. The majority (n = 12) of patients were either homozygotes or compound heterozygotes for known achromatopsia alleles, two in CNGB3 (p.T383fsX and p.T296YfsX9) and three in CNGA3 (p.R283Q, p.R427C and p.L527R). Haplotype reconstruction showed that recurrent mutations p.T383fsX and p.L527R were due to a founder effect. Aggregate data from exome sequencing, segregation analysis and archived medical records support a rediagnosis of Jalili syndrome in affected siblings (n = 4) from Family 0094, which to our knowledge is the first family identified with Jalili Syndrome in North America. PMID- 23362849 TI - VKORC1 C1173T and VKORC1 G-1639A gene polymorphisms in Turkish Behcet's patients with ocular and non-ocular involvement. AB - BACKGROUND: Behcet's disease (BD) is a multisystemic vasculitis with unknown etiology. Vitamin K epoxide reductase complex subunit 1 (VKORC1) is the key enzyme in the formation of active vitamin K that is a cofactor of various coagulation factors. Polymorphisms of the VKORC1 may affect the levels of active forms of vitamin K-dependent coagulation proteins and the tendency to thrombosis. The current study aimed to evaluate the role of VKORC1 gene polymorphisms in ocular and non-ocular Behcet's disease. METHODS: VKORC1 C1173T (rs 9934438) and G 1639A (rs 9923231) gene polymorphisms were evaluated by real-time polymerase chain reaction-based DNA analysis. The frequency of alleles and distribution of genotypes were assessed by the chi-squared test. Genotype distribution and Hardy Weinberg equilibrium were tested with the chi(2) test for quality of fit. RESULTS: The distribution of GG, GA and AA and CC, CT, TT genotypes and the frequency of G,A and C,T alleles were not found to be different between patients and controls (p = 0.5651; p = 0.335 respectively), as well as patients with or without eye involvement (p = 0.9267; p = 0.384 respectively). CONCLUSION: VKORC1 polymorphisms seem not to be related with the thrombotic state of systemic and ocular Behcet's disease. PMID- 23362850 TI - Report of a novel mutation in CRB1 in a Lebanese family presenting retinal dystrophy. AB - PURPOSE: To identify the genetic basis of a recessive inheritance form of retinal dystrophy (RD) in a Lebanese family. MATERIALS AND METHODS: Clinical data were recorded for five patients of the 14 family members. Genetic linkage was carried out using Affymetrix 250 K Nspl SNP array followed by sequencing. RESULTS: The patients showed variable phenotypes ranging from Leber Congenital Amaurosis (LCA) to progressive forms of Retinitis Pigmentosa (RP). A 46.1 Mb chromosomal region at chromosome 1q23.3-32.2 was identified by homozygosity mapping. This region contained the Crumbs homologue-1, CRB1, a gene responsible for recessive retinal dystrophies. CRB1 is required for photoreceptor morphogenesis, and it has been associated with RP and LCA. Sequencing of CRB1 revealed two mutations: a novel deletion in exon 6 (c.1772_1775delGCAT; p.C591Sfs*28) and a missense mutation in exon 7 (c.2234C > T; p.T745M). CONCLUSION: We report a novel CRB1 mutation in inherited RD in a Lebanese family, and confirm the considerable phenotype heterogeneity that may exist between individuals sharing the same mutations. PMID- 23362851 TI - The evolution of service-learning: new models and directions. Preface. PMID- 23362852 TI - Intergenerational service-learning: a review of recent literature and directions for the future. AB - This review examines recent studies that have addressed outcomes of intergenerational service-learning courses in gerontology. The history of service learning pedagogy in higher education and its place in today's colleges is also reviewed. Particular attention is given to evaluations of stakeholders: students, older adult participants, agencies and staff, faculty, community residents, colleges, and the community itself. The need for adopting research designs that permit clear conclusions and for utilizing assessments that have psychometrically sound foundations is important in future studies to permit unambiguous comparisons from study to study. The value of the pedagogy for students in particular has been documented over a number of years. Equally important is today's need to assess the impact of the pedagogy on the community. PMID- 23362853 TI - The digital life history project: intergenerational collaborative research. AB - This article describes the Digital Life History Project, a 10-week "lab" linked to a course on aging, in which students and community-dwelling elders work together to create a short digital story honoring the elder's life. After two interview sessions, the pair works together to produce a 3- to 5-minute digital life story narrated by the elder. The resulting multimedia videos are then screened for the community at large at the end of the semester. Students and elders alike report long-term personal, interpersonal, and community-based effects from participating in the Digital Life History Project, including making meaningful relationships, linking biography and history, learning to confront ageism, charting the next chapter, and participating in community-wide education. PMID- 23362854 TI - Students delivering health care to a vulnerable Appalachian population through interprofessional service-learning. AB - Interprofessional student service-learning experiences are integrated into the preventive care of older adult residents of public housing in Appalachia. Receiving a Health Resources and Services Administration grant provided the College of Nursing at East Tennessee State University the opportunity to expand interprofessional clinical experiences for students by partnering with the College of Pharmacy, the College of Clinical & Rehabilitative Health Sciences, and the local public housing authority. Select faculty from each college met and developed a plan to form student teams from all three colleges to conduct in-home comprehensive medical and nutrition assessments and medication chart reviews of high-risk older adults. Following the in-home visit, students and faculty discuss the assessment findings at planned interprofessional meetings. Students present their findings from each discipline's perspective and collaboratively set health priorities and develop intervention strategies and an inclusive follow-up plan. Excerpts from students' reflective narratives discussing the impact of the interprofessional service-learning experiences are shared. PMID- 23362855 TI - Learning by living: life-altering medical education through nursing home-based experiential learning. AB - The University of New England College of Osteopathic Medicine Learning by Living Project (referred to as Learning by Living) was piloted in 2006 as an experiential medical education learning model. Since its inception, medical and other health professions students have been "admitted" into nursing homes to live the life of an older adult nursing home resident for approximately 2 weeks-24 hours a day/7 days a week-complete with a medical diagnosis and "standard" procedures of care. The Learning by Living Project applies qualitative ethnographic/autobiographic research methods to collect students' perspectives and experiences about life lived as an older adult with functional challenges in a residential setting. To date, all students have completed their extended stay successfully and felt that this experiential learning project provided life altering medical education. Longitudinal data reveals that students' maintain patient-centered attitudes and skills such as the use of eye contact, touch, body position, and voice cadence. Barriers to working with older adults are decreased; understanding is gained by "wheeling a mile in an older person's wheelchair." PMID- 23362856 TI - Reflecting on reflection: capitalizing on the learning in intergenerational service-learning. AB - Intergenerational service-learning has become an important practice in gerontology and geriatrics education. Although numerous benefits of service learning have been documented, greater attention to critical reflection, a key component for harvesting the learning in service-learning, is needed to increase our understanding of what students really are learning from intergenerational service-learning and how we may best enhance the positive aspects of that learning. This article examines the elements necessary for effective service learning reflection, as well as reports on the results of a survey of gerontology and geriatric educators (N = 142) regarding their experiences with intergenerational service-learning and their use of specific reflection practices. The findings suggest that the types and implementation of service learning reflection activities used in aging courses vary considerably. The importance of service-learning reflection and its associated benefits and challenges are discussed. PMID- 23362857 TI - Old age is a part of living: student reflections on intergenerational service learning. AB - Analysis of student journals examined the effect intergenerational service learning had upon undergraduate students' attitudes and perceptions of older adults. Students (N = 102) engaged in 12 hours of service-learning with older adults that included writing structured reflection journals. Coding involved open, axial, and selective coding with common themes identified from the journals. Results revealed a positive attitude shift toward older adults over the course of the semester, greater comfort with the idea of aging, and a propensity to describe the experience as being personally and professionally influential in their own lives. Students also reported increased course understanding and a desire to continue volunteering. Implications for intergenerational service learning are discussed. PMID- 23362858 TI - Results of phenol red thread test in clinically normal Syrian hamsters (Mesocricetus auratus). AB - OBJECTIVE: To determine the normal reference range for phenol red thread test (PRTT) values in clinically normal Syrian hamsters (Mesocricetus auratus). ANIMALS: Sixteen healthy adult Syrian hamsters (eight males and eight females) were used in this study. PROCEDURE: Ophthalmic examinations were performed without chemical restraint. PRTT values were evaluated in both eyes of all Syrian hamsters using a commercial PRTT strip of a single lot number. RESULTS: No statistically significant differences between right and left eyes were found for any of the results. The mean +/- SD PRTT values for the study population were 6.8 +/- 2.5 mm/15 s with a range from 3 to 11.5 mm/15 s. Mean PRTTs in male animals were 5.1 +/- 1.2 mm/15 s, whereas mean PRTTs in female hamsters were 8.5 +/- 2.3 mm/15 s. Comparison between mean PRTT values in males and females showed a significant difference (P = 0.004). Mean weights for males and females were 80.9 +/- 4.8 and 90.6 +/- 8.5 g, respectively. No linear relationship between mean PRTT and body weight was found in female (P = 0.46) and male (P = 0.92) hamsters. CONCLUSION: This study provides novel data for normal reference ranges of PRTT values in healthy Syrian hamsters. Results of this study may assist veterinarians in the diagnosis of ocular surface disease and syndromes affecting the tear film in these species. PMID- 23362859 TI - Differences and similarities in the etiology and the incidence of cirrhosis in the Nordic countries. PMID- 23362860 TI - Dynamic electrowetting and dewetting of ionic liquids at a hydrophobic solid liquid interface. AB - The dynamic electrowetting and dewetting of ionic liquids are investigated with high-speed video microscopy. Five imidazolium-based ionic liquids ([BMIM]BF(4), [BMIM]PF(6), [BMIM]NTf(2), [HMIM]NTf(2), and [OMIM]BF(4)) are used as probe liquids. Droplets of ionic liquids are first spread on an insulated electrode by applying an external voltage (electrowetting) and then allowed to retract (dewetting) when the voltage is switched off. The base area of the droplet varies exponentially during both the electrowetting and retraction processes. The characteristic time increases with the viscosity of the ionic liquid. The electrowetting and retraction kinetics (dynamic contact angle vs contact line speed) can be described by the hydrodynamic or the molecular-kinetic model. Energy dissipation occurs by viscous and molecular routes with a larger proportion of energy dissipated at the three-phase contact line when the liquid meniscus retracts from the solid surface. The outcomes from this research have implications for the design and control of electro-optical imaging systems, microfluidics, and fuel cells. PMID- 23362862 TI - A chemical-biological study reveals C9-type iridoids as novel heat shock protein 90 (Hsp90) inhibitors. AB - The potential of heat shock protein 90 (Hsp90) as a therapeutic target for numerous diseases has made the identification and optimization of novel Hsp90 inhibitors an emerging therapeutic strategy. A surface plasmon resonance (SPR) approach was adopted to screen some iridoids for their Hsp90 alpha binding capability. Twenty-four iridoid derivatives, including 13 new natural compounds, were isolated from the leaves of Tabebuia argentea and petioles of Catalpa bignonioides. Their structures were elucidated by NMR, electrospray ionization mass spectrometry, and chemical methods. By means of a panel of chemical and biological approaches, four iridoids were demonstrated to bind Hsp90 alpha. In particular, the dimeric iridoid argenteoside A was shown to efficiently inhibit the chaperone in biochemical and cellular assays. Our results disclose C9-type iridoids as a novel class of Hsp90 inhibitors. PMID- 23362861 TI - The dynamic relationship between social norms and behaviors: the results of an HIV prevention network intervention for injection drug users. AB - AIMS: Social norms are a key source of influence on health behaviors. This study examined changes in social norms and relationships between HIV injection risk behaviors and social norms among injection drug users (IDUs) involved in an experimental intervention. DESIGN: Randomized clinical trial. SETTING: An HIV Prevention Trials Network study, Philadelphia, USA. PARTICIPANTS: IDUs, called indexes, and their social network members, who were drug or sex partners, were recruited for an HIV prevention intervention and followed for up to 30 months (n = 652). Indexes were randomized into a peer education intervention or control condition. MEASUREMENTS: Outcomes of injection-related HIV risk behaviors (sharing needles, sharing cookers, sharing cotton, front-/back-loading) were measured every 6 months and the social norms of these four risk behaviors were assessed every 12 months. FINDINGS: There was a statistically significant intervention effect on all four social norms of injection behaviors, with participants in the intervention reporting less risky social norms compared with controls (changes in mean score: needles, -0.24, P = 0.007; cookers, -0.33, P = .004; cottons, -0.28, P = .0165; front-/back-loading, -0.23, P = .002). There was also a statistically significant bidirectional association with social norms predicting injection risk behaviors at the next assessment and risk behaviors predicting social norms at the subsequent visit. CONCLUSIONS: Through social network interventions it is feasible to change both injection risk behaviors and associated social norms. However, it is critical that social network interventions focus on publically highlighting behavior changes, as changing social norms without awareness of behaviors change may lead to relapse of risk behaviors. PMID- 23362863 TI - Probiotic-mediated competition, exclusion and displacement in biofilm formation by food-borne pathogens. AB - The objective of this study was to examine the inhibitory effect of probiotic strains on pathogenic biofilm formation in terms of competition, exclusion and displacement. Probiotic strains (Lactobacillus acidophilus KACC 12419, Lact. casei KACC 12413, Lact. paracasei KACC 12427 and Lact. rhamnosus KACC 11953) and pathogens (Salmonella Typhimurium KCCM 40253 and Listeria monocytogenes KACC 12671) were used to evaluate the auto-aggregation, hydrophobicity and biofilm formation inhibition. The highest auto-aggregation abilities were observed in Lact. rhamnosus (17.5%), Lact. casei (17.2%) and Lact. acidophilus (15.1%). Salm. Typhimurium had the highest affinity to xylene, showing the hydrophobicity of 53.7%. The numbers of L. monocytogenes biofilm cells during the competition, exclusion and displacement assays were effectively reduced by more than 3 log when co-cultured with Lact. paracasei and Lact. rhamnosus. The results suggest that probiotic strains can be used as alternative way to effectively reduce the biofilm formation in pathogenic bacteria through competition, exclusion and displacement. PMID- 23362864 TI - Identifying the cortical substrates of interictal epileptiform activity in patients with extratemporal epilepsy: An EEG-fMRI sequential analysis and FDG-PET study. AB - PURPOSE: The aim of this study was to apply sequential analysis of electroencephalography-functional magnetic resonance imaging (EEG-fMRI) data to study the cortical substrates related to the generation of the interictal epileptiform activity (IEA) in patients with pharmacoresistant extratemporal epilepsy. METHODS: We analyzed fMRI data from 21 children, adolescents, and young adults patients who showed frequent bursts or runs of spikes on EEG, by using the sequential analysis method. We contrasted consecutive fixed-width blocks of 10 s to obtain the relative variations in cerebral activity along the entire fMRI runs. Significant responses (p < 0.05, family-wise error (FWE) corrected), time related to the IEA recorded on scalp EEG, were considered potential IEA cortical sources. These results were compared with those from the fluorodeoxyglucose positron emission tomography (FDG-PET), intracranial EEG (two patients), and surgery outcome (eight patients). KEY FINDINGS: The typical IEA was recorded in all patients. After the sequential analysis, at least one significant blood oxygen level-dependent (BOLD) response spatially consistent with the presumed epileptogenic zone was found. These IEA-related activation areas coincided when superimposed with the hypometabolism depicted by the FDG-PET. These data were also consistent with the invasive EEG findings. Epileptic seizures were recorded in eight patients. A subset of IEA-associated fMRI activations was consistent the activations at seizure-onset determined by sequential analysis. The inclusion of the IEA-related areas in the resection rendered the patients seizure-free (five of eight operated patients). SIGNIFICANCE: The EEG-fMRI data sequential analysis could noninvasively identify cortical areas involved in the IEA generation. The spatial relationship of these areas with the cortical metabolic abnormalities depicted by the FDG-PET and their intrinsic relationship regarding the ictal onset zone could be useful in epilepsy surgery planning. PMID- 23362866 TI - Expression profiles of cortisol-inactivating enzyme, 11beta-hydroxysteroid dehydrogenase-2, in human epidermal tumors and its role in keratinocyte proliferation. AB - The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) catalyzes the interconversion between hormonally active cortisol and inactive cortisone within cells. There are two isozymes: 11beta-HSD1 activates cortisol from cortisone and 11beta-HSD2 inactivates cortisol to cortisone. 11beta-HSD1 was recently discovered in skin, and we subsequently found that the enzyme negatively regulates keratinocyte proliferation. We verified 11beta-HSD1 and 11beta-HSD2 expression in benign and malignant skin tumors and investigated the role of 11beta-HSD in skin tumor pathogenesis. Randomly selected formalin-fixed sections of skin lesions of seborrheic keratosis (SK), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) were stained with 11beta-HSD1 and 11beta-HSD2 antibodies, and 11beta-HSD expression was also evaluated in murine epidermis in which hyperproliferation was induced by 12-O-tetradecanoylphorbol-13 acetate (TPA). We observed that 11beta-HSD1 expression was decreased in all SK, SCC, and BCC lesions compared with unaffected skin. Conversely, 11beta-HSD2 expression was increased in SK and BCC but not in SCC. Overexpression of 11beta-HSD2 in keratinocytes increased cell proliferation. In the murine model, 11beta-HSD1 expression was decreased in TPA-treated hyperproliferative skin. Our findings suggest that 11beta-HSD1 expression is decreased in keratinocyte proliferative conditions, and 11beta-HSD2 expression is increased in basal cell proliferating conditions, such as BCC and SK. Assessing 11beta-HSD1 and 11beta-HSD2 expression could be a useful tool for diagnosing and characterizing skin tumors. PMID- 23362867 TI - Evidence for a regulatory loop between IFN-gamma and IL-33 in skin inflammation. AB - Interleukin-33 has recently gained much attention due to its role in allergic responses. It has been shown to amplify Th2 responses and to act as a damage associated molecular pattern. IL-33 acts on a broad range of cells and has been proposed to link innate and adaptive features of allergic responses. It was the aim of this study to investigate this property of IL-33 in the inflammatory response characterising atopic dermatitis (AD). We have analysed the response of skin-resident cells derived from patients with AD and healthy donors with regard to the expression of IL-33 and its receptor ST2. The functional impact of IL-33 on CD4+ T cells was investigated. Keratinocytes and dermal fibroblasts clearly differ in their regulation of IL-33. In fibroblasts, the concerted action of TNF alpha and IL-1beta was the strongest inducer, whereas IFN-gamma is clearly the key molecule that upregulates IL-33 in keratinocytes with a more pronounced response of cells derived from patients with AD. Keratinocytes from patients with AD showed a markedly higher constitutive expression level of surface ST2. CD4+ T cells respond to IL-33. Unexpectedly, IL-33 failed to induce a significant secretion of IL-5 or IL-13. By contrast, high amounts of IFN-gamma were detectable if IL-33 was added to the T-cell receptor-stimulated cells or in combination with IL-12. These results suggest that IL-33 and IFN-gamma are closely interlinked in epidermal AD inflammation. IFN-gamma induces IL-33 in keratinocytes and IL-33 acts on activated T cells to further increase the release of IFN-gamma, therefore contributing to drive skin inflammation towards chronic responses. PMID- 23362865 TI - Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). AB - Although knowledge of human renal cytochrome P450 (CYP) and UDP glucuronosyltransferase (UGT) enzymes and their role in xenobiotic and endobiotic metabolism is limited compared with hepatic drug and chemical metabolism, accumulating evidence indicates that human kidney has significant metabolic capacity. Of the drug metabolizing P450s in families 1 to 3, there is definitive evidence for only CYP 2B6 and 3A5 expression in human kidney. CYP 1A1, 1A2, 1B1, 2A6, 2C19, 2D6 and 2E1 are not expressed in human kidney, while data for CYP 2C8, 2C9 and 3A4 expression are equivocal. It is further known that several P450 enzymes involved in the metabolism of arachidonic acid and eicosanoids are expressed in human kidney, CYP 4A11, 4F2, 4F8, 4F11 and 4F12. With the current limited evidence of drug substrates for human renal P450s drug-endobiotic interactions arising from inhibition of renal P450s, particularly effects on arachidonic acid metabolism, appear unlikely. With respect to the UGTs, 1A5, 1A6, 1A7, 1A9, 2B4, 2B7 and 2B17 are expressed in human kidney, whereas UGT 1A1, 1A3, 1A4, 1A8, 1A10, 2B10, 2B11 and 2B15 are not. The most abundantly expressed renal UGTs are 1A9 and 2B7, which play a significant role in the glucuronidation of drugs, arachidonic acid, prostaglandins, leukotrienes and P450 derived arachidonic acid metabolites. Modulation by drug substrates (e.g. NSAIDs) of the intrarenal activity of UGT1A9 and UGT2B7 has the potential to perturb the metabolism of renal mediators including aldosterone, prostaglandins and 20 hydroxyeicosatetraenoic acid, thus disrupting renal homeostasis. PMID- 23362868 TI - HLA-E*0103X is associated with susceptibility to Pemphigus vulgaris. AB - Non-classical human leucocyte antigen-E (HLA-E) mediates natural killer and CD8+ T-cell activity, suggesting a role in the regulation of autoimmunity. HLA E*0103X/*0103X has been associated with Behcet's disease and HLA-E *0101/*0103X with childhood onset diabetes. We investigated HLA-E allele status in 52 Caucasian and Ashkenazi Jewish Pemphigus vulgaris (PV) patients and 51 healthy controls by restriction fragment length polymorphism-polymerase chain reaction and amplification refractory mutation system. Associations were determined via chi-square test, Fisher's exact test and logistical regression analysis. HLA-E outcomes included presumed homozygous *0101/*0101 or *0103X/*0103X genotype status or *0101/*0103X heterozygous status. PV did not significantly associate with either *0101/*0101 or *0101/*0103X genotypes. HLA-E*0103X/*0103X (presumed homozygote) is significantly increased in patients with PV versus controls (P = 0.0146, OR = 3.730, 95%CI = 1.241-11.213). Our data provide the first evidence that HLA-E*0103X is a marker for genetic risk in PV. PMID- 23362869 TI - Ceramides stimulate caspase-14 expression in human keratinocytes. AB - Caspase-14 is an enzyme that is expressed predominantly in cornifying epithelia and catalyses the degradation of profilaggrin. Additionally, caspase-14 plays an important role in the terminal differentiation of keratinocytes. However, how caspase-14 expression is regulated remains largely unknown. Here we demonstrate that ceramides (C(2) -Cer and C(6) -Cer), but not other sphingolipids (C(8) glucosylceramides, sphinganine, sphingosine-1-phosphate or ceramide-1-phosphate), increase caspase-14 expression (mRNA and protein) in cultured human keratinocytes in a dose- and time-dependent manner. Inhibitors of glucosylceramide synthase and ceramidase increase endogenous ceramide levels and also increase caspase-14 expression, indicating an important regulatory role for ceramides and suggesting that the conversion of ceramides to other metabolites is not required. The increase in caspase-14 expression induced by ceramides is first seen at 16 h and requires new protein synthesis, suggesting that the ceramide-induced increase is likely an indirect effect. Furthermore, ceramides increase caspase-14 gene expression primarily by increasing transcription. Blocking de novo synthesis of ceramides does not affect caspase-14 expression, suggesting that basal expression is not dependent on ceramide levels. These studies show that ceramides, an important structural lipid, stimulate caspase-14 expression providing a mechanism for coordinately regulating the formation of lipid lamellar membranes with the formation of corneocytes. PMID- 23362870 TI - The antihistamines clemastine and desloratadine inhibit STAT3 and c-Myc activities and induce apoptosis in cutaneous T-cell lymphoma cell lines. AB - Mycosis fungoides and its leukaemic counterpart Sezary syndrome are the most frequent cutaneous T-cell lymphomas (CTCL), and there is no cure for these diseases. We evaluated the effect of clinically approved antihistamines on the growth of CTCL cell lines. CTCL cell lines as well as blood lymphocytes from patients with Sezary syndrome were cultured with antihistamines, and the cell were analysed for proliferation, apoptosis and expression of programmed death molecules and transcription factors. The two antihistamines clemastine and desloratadine, currently used for symptom alleviation in allergy, induced potent reduction of the activities of the constitutively active transcription factors c Myc, STAT3, STAT5a and STAT5b in mycosis fungoides and Sezary syndrome cell lines. This inhibition was followed by apoptosis and cell death, especially in the Sezary syndrome-derived cell line Hut78 that also showed increased expression of the programmed death-1 (PD-1) after clemastine treatment. In lymphocytes isolated from Sezary syndrome patients, the CD4-positive fraction underwent apoptosis after clemastine treatment, while CD4-negative lymphocytes were little affected. Because both c-Myc and STAT transcription factors are highly expressed in proliferating tumours, their inhibition by clemastine, desloratadine and other inhibitors could complement established chemotherapies not only for cutaneous T cell lymphomas but perhaps also other cancers. PMID- 23362871 TI - Neural nitric oxide synthase participates in pemphigus vulgaris acantholysis through upregulation of Rous sarcoma, mammalian target of rapamycin and focal adhesion kinase. AB - Pemphigus vulgaris (PV) is an autoimmune blistering skin disease characterized by suprabasal acantholysis produced as a consequence of desmoglein (Dsg) and non-Dsg autoantibodies binding to several targeting molecules localized on the membrane of keratinocytes. Nitric oxide (NO) may exert a pathogenic function in several immunological processes. We have previously demonstrated that neural nitric oxide synthase (nNOS) plays part in PV acantholysis. Also, our group has described a relevant role for HER [human epidermal growth factor receptor (EGFR) related] isoforms and several kinases such as Src (Rous sarcoma), mammalian target of rapamycin (mTOR) and focal adhesion kinase (FAK), as well as caspases in PV development. Using a passive transfer mouse model of PV, we aimed to investigate the relationship between the increase in nNOS and EGFR, Src, mTOR and FAK kinase upregulation observed in PV lesions. Our results revealed a new function for nNOS, which contributes to EGFR-mediated PV acantholysis through the upregulation of Src, mTOR and FAK. In addition, we found that nNOS participates actively in PV at least in part by increasing caspase-9 and caspase-3 activities. These findings underline the important issue that in PV acantholysis, caspase activation is a nNOS-linked process downstream of Src, mTOR and FAK kinase upregulation. PMID- 23362872 TI - Arthrophytum scoparium inhibits melanogenesis through the down-regulation of tyrosinase and melanogenic gene expressions in B16 melanoma cells. AB - Melanin performs a crucial role in protecting the skin against harmful ultraviolet light. However, hyperpigmentation may lead to aesthetic problems and disorders such as solar lentigines (SL), melasma, postinflammatory hyperpigmentation and even melanoma. Arthrophytum scoparium grows in the desert in the North African region, and given this type of environment, A. scoparium exhibits adaptations for storing water and produces useful bioactive factors. In this study, the effect of A. scoparium ethanol extract (ASEE) on melanogenesis regulation in B16 murine melanoma cells was investigated. Cells treated with 0.017% (w/v) ASEE showed a significant inhibition of melanin biosynthesis in a time-dependent manner without cytotoxicity. To clarify the mechanism behind the ASEE-treated melanogenesis regulation, the expressions of tyrosinase enzyme and melanogenesis-related genes were determined. Results showed that the expression of tyrosinase enzyme was significantly decreased and Tyr, Trp-1, Mitf and Mc1R mRNA expressions were significantly down-regulated. LC-ESI-TOF-MS analysis of the extract identified the presence of six phenolic compounds: coumaric acid, cinnamic acid, chrysoeriol, cyanidin, catechol and caffeoylquinic acid. The melanogenesis inhibitory effect of ASEE may therefore be attributed to its catechol and tetrahydroisoquinoline derivative content. We report here that ASEE can inhibit melanogenesis in a time-dependent manner by decreasing the tyrosinase protein and Tyr, Trp-1, Mitf and Mc1R mRNA expressions. This is the first report on the antimelanogenesis effect of A. scoparium and on its potential as a whitening agent. PMID- 23362873 TI - In vivo imaging reveals selective PPAR activity in the skin of peroxisome proliferator-activated receptor responsive element-luciferase reporter mice. AB - Peroxisome proliferator-activated receptors (PPARs) have been revealed as key regulators of several skin disorders. This has led to a growing interest in the development of drugs targeting PPARs as therapeutics for skin diseases. To evaluate skin PPAR activity, we developed peroxisome proliferator responsive element-luciferase (PPRE-Luc) mice, a mouse model in which the luciferase gene expression is under the control of a PPAR-inducible promoter in all organs. Our aim was to define and validate experimental conditions to establish PPRE-Luc mice as a valuable tool for in vivo non-invasive evaluation of PPARs activation in the skin. We demonstrated by optical imaging that topical application of 40 mm of Luciferin for 10 min was enough to reveal the optimal luciferase activity in mice skin. The treatment of mice skin with the PPARgamma and PPARalpha agonists, pioglitazone and WY14643, was associated with significant increase in photons emission reaching maximal signalling at 6 h. We have performed dose response studies by testing a large range of pioglitazone and WY14643 concentrations on mouse skin. The specificity of bioluminescence signal induced by pioglitazone and WY14643 was assessed using PPARgamma and PPARalpha antagonists, GW9662 and GW6471, respectively. This approach revealed that the isoform specificity of PPARs agonists decreased when high ligand concentrations were applied on mouse skin. These results were further confirmed by in vitro measurement of luciferase activity in skin extracts. Overall, our results demonstrated that PPRE-Luc mice represent a valuable reporter mouse model for the in vivo pharmacological profiling of drugs targeting PPARs in the skin. PMID- 23362874 TI - Genetic alterations in RAS-regulated pathway in acral lentiginous melanoma. AB - Studies integrating clinicopathological and genetic features have revealed distinct patterns of genomic aberrations in Melanoma. Distributions of BRAF or NRAS mutations and gains of several oncogenes differ among melanoma subgroups, while 9p21 deletions are found in all melanoma subtypes. In the study, status of genes involved in cell cycle progression and apoptosis was evaluated in a panel of 17 frozen primary acral melanomas. NRAS mutations were found in 17% of the tumors. In contrast, BRAF mutations were not found. Gains of AURKA gene (20q13.3) were detected in 37.5% of samples, gains of CCND1 gene (11q13) or TERT gene (5p15.33) in 31.2% and gains of NRAS gene (1p13.2) in 25%. Alterations in 9p21 were identified in 69% of tumors. Gains of 11q13 and 20q13 were mutually exclusive, and 1p13.2 gain was associated with 5p15.33. Our findings showed that alterations in RAS-related pathways are present in 87.5% of acral lentiginous melanomas. PMID- 23362875 TI - Increased expression of glucagon-like peptide-1 receptors in psoriasis plaques. AB - Recent case reports suggest that treatment with glucagon-like peptide-1 (GLP-1) agonists results in clinical improvement of psoriasis. The purpose of this study was to determine whether GLP-1 receptors (GLP-1Rs) are found in the skin of healthy volunteers and psoriasis patients and if so, whether GLP-1Rs are located on keratinocytes or immune cells. Three mm-punch skin biopsies were taken for gene expression analysis from six healthy volunteers and from affected and unaffected skin of six psoriasis patients. In addition, a blood sample was obtained from all participants. Cultured human keratinocytes were either untreated or incubated with tumor necrosis factor- alpha (TNF-alpha), interferon gamma (IFN-gamma) or a combination of TNF-alpha and IFN-gamma for 48 h. Total RNA was extracted from all the samples, reversely transcribed and analysed for the expression of GLP-1R using real-time PCR. Gene expression analysis showed expression of GLP-1Rs in five of six skin biopsies from psoriasis plaques, in one of six biopsies from unaffected psoriatic skin and in one of six biopsies from healthy skin. GLP-1R expression was found in the blood of both healthy volunteers and psoriasis patients. No GLP-1R expression was found in either stimulated or unstimulated cultured human keratinocytes. Our results show increased presence of GLP-1Rs in psoriasis plaques and that this most likely is due to infiltration with immune cells. This offers a possible explanation for the positive effect of treatment with GLP-1R agonists in patients with psoriasis. PMID- 23362876 TI - Staphylococcus aureus skin colonization is promoted by barrier disruption and leads to local inflammation. AB - Experimental mouse models of bacterial skin infections that have been described show that pathogenic microorganisms can readily invade the epidermis and dermis to produce localized infections. We used an epicutaneous mouse skin infection model to determine how the level of barrier disruption by tape-stripping correlates with persistence of Staphylococcus aureus skin colonization, concomitant induction of cutaneous inflammation and infection. Furthermore, we investigated how murine skin responds to S. aureus colonization in a physiologic setting by analysing proinflammatory cytokines and antimicrobial peptides in mouse skin. We show that previous cutaneous damage allows skin inflammation to develop and favours S. aureus persistence leading to cutaneous colonization, suggesting an interdependence of cutaneous bacteria and skin. Our study suggests that skin barrier defects favour S. aureus skin colonization, which is associated with profound cutaneous inflammation. PMID- 23362877 TI - Photoprotective effect of libanoridin isolated from Corydalis heterocarpa on UVB stressed human keratinocyte cells. AB - Ultraviolet-B (UVB) irradiation acts primarily on the epidermal basal cell layer of the skin, inducing harmful biological effects. In this study, we have investigated the effect of libanoridin isolated from Corydalis heterocarpa against UVB-induced damage in human keratinocyte (HaCaT) cells and the molecular mechanism underlying those effects. Treatment with libanoridin inhibited the cell cytotoxicity and LDH induced by UVB exposure at 40 mJ/cm(2). Additionally, expression levels of type IV collagenases (MMP-2, MMP-9) were decreased by libanoridin. Furthermore, MMP tissue inhibitors were enhanced followed by treatment with libanoridin. Moreover, UVB-induced activation of phosphorylation of three MAPKs such as JNK, ERK, p38 and AP-1 transcription factor were decreased by treatment with libanoridin. Our present study demonstrates that libanoridin has the abilities to inhibit UVB-induced cellular damage via ASK1-MAPK and AP-1 signalling pathways. Therefore, libanoridin may be used as an effective natural compound to prevent skin damage due to UVB exposure. PMID- 23362878 TI - Distribution of polyethylene glycol coated quantum dots in mice skin. AB - The distribution of nanoparticles (NP) in an organism is an important issue for developing NP-based drug delivery systems and for general nanotoxicology. The knowledge of NP localisation in the skin is crucial for the optimisation of NP behaviour in vivo. Therefore, we have used semiconductor quantum dots (QD) to investigate their biodistribution in the skin by means of confocal fluorescence microscopy after subcutaneous injection. The results obtained showed that the diffusion of QD in the dermis is limited by basement membrane and dense connective tissue fibres, which resulted in negligible QD penetration into the epidermis, hair follicles, sebaceous and sweat glands, nerves and blood vessels. Low permeation of QD through the tissues results in slow clearance and raises the risks of potential immune, inflammatory and cytotoxic responses. The study reveals the significance of the tissue architecture for the interstitial and intracellular migration patterns of non-functionalised QD. PMID- 23362880 TI - Effects of early oral feeding on relapse and symptoms of upper gastrointestinal bleeding in peptic ulcer disease. AB - BACKGROUND: Peptic ulcer is the most common cause of upper gastrointestinal bleeding (GIB) and nutritional support is a helpful strategy in malnutrition prevention during treatment. As early oral feeding in patients with GIB may shorten hospital stay and decrease costs and risk of infection, the present study was carried out to investigate the effects of early oral feeding on relapse and symptoms of upper GIB. METHODS: The present clinical trial was conducted with the participation of 100 patients with upper GIB due to gastric or duodenum ulcer at Emam Reza University Hospital in Tabriz. Subjects were randomly allocated to two groups (n=50). In one group, patients received oral diet from day 1 and in other group patients were nil by mouth until day 3 and then received oral diet. Endoscopic and clinical findings of patients were recorded from day 1 to 3. RESULTS: The mean age of subjects was 57.6+/-1.7 and 63% were male. Sclerotherapy was used in most cases as a hemostasis treatment. There was no significant difference in laboratory findings and rebleeding between the two groups. In the group with early oral feeding, the time of hospital stay was significantly shorter than in the control group (P<0.001). CONCLUSION: Although early oral feeding had no significant effects on electrolyte balance and treatment outcomes in patients with upper GIB who were treated with endoscopic hemostasis, it could effectively shorten the hospital stay. Consequently, early oral feeding in these patients enables early discharge and reduces the costs of treatment. PMID- 23362881 TI - Genotype-based association analysis using discordant pairs: a penetrance odds ratio approach. AB - Genotypic counts of paired relatives discordant for a complex late-onset disease are often used to test for genetic association. The power of the various statistical test options, when data on covariates are unavailable, has been the focus of recent research. Comparison of the Cochran-Armitage, Bhapkar, and McNemar tests indicates that none is superior to the others in all cases. Using an alternative approach, we found that the theoretical genotypic frequencies of the discordant pairs depend only on the penetrance odds ratios, after conditioning. These odds ratios can be estimated by maximizing a product binomial likelihood and provide insight into the mode of inheritance. We identified cases where exact maximum likelihood (ML) estimates can be explicitly obtained. This approach led us to two tests for association which depend on likelihood ratio (LR) or score statistics. We quantified the power of these tests analytically and examined their performance through simulation. We explored the utility of these tests with an example from the literature-the association between complement factor H (CFH) polymorphisms and age-related macular degeneration. The LR and Score tests serve as simple and effective ways of interpreting paired case control data sets. PMID- 23362882 TI - Noninvasive pH monitoring of platelet concentrates: a large field test. AB - BACKGROUND: Developing new quality control methods for platelet concentrates (PCs) can contribute to increasing transfusion safety and efficiency. The aim of this study was to investigate in a large field test the quality of expired PCs and whether 100% noninvasive pH monitoring can be used to predict PC quality. STUDY DESIGN AND METHODS: The pH of 13,693 PCs produced for transfusion was monitored daily using Blood Storage, Inc.'s pH sterile, automated fluoroscopic evaluation technology. Upon indication of compromised quality or expiration, PCs were returned and in vitro tests were performed. RESULTS: A total of 998 PCs were returned, of which 962 outdated, 26 had a positive BacT/ALERT reaction, seven had aggregates, one was without swirl, one had low pH, and one had high pH. BacT/ALERT was faster in identifying bacterial contamination than pH measurements. The pH at the end of the storage period was significantly lower than at the beginning. In vitro tests indicated that while the PC quality was acceptable upon expiration, it rapidly declined after expiration. CONCLUSION: In this setting where the vast majority of PCs were of good quality and within acceptable pH limits, daily, noninvasive routine pH measurement has limited added value in identifying quality-compromised PCs. PMID- 23362883 TI - Bone mineral density screening among women with a history of breast cancer treated with aromatase inhibitors. AB - BACKGROUND: Understanding adherence to bone mineral density (BMD) screening after breast cancer (BC) treatment with aromatase inhibitors (AI) is an important first step in preventing or treating BC-related osteoporosis. METHODS: This retrospective cohort study assessed receipt and adherence to BMD screening among 342 women diagnosed with BC who were at high risk for osteoporosis after BC treatment with AI between 2004 and 2007. Nonadherence to baseline and annual BMD screening (recommended by 2003 American Society of Clinical Oncology Guidelines) was assessed using descriptive statistics and Poisson regression models accounting for length of AI use and follow-up. RESULTS: In the year before AI initiation, 16% of women received BMD screening. Fifty-six percent had no BMD screening in the 14 months after a minimum of 9 months of continuous AI use, and 75% and 66% failed to have BMD screens during the second (14.1-26 month) and third (26.1-38 month) annual time periods after continuous AI use for at least 23 and 35 months, respectively. Overall, 24% had no BMD screening after 35 months of continuous AI use. Statistically significant predictors of nonadherence included predominant exemestane use, BMD screening before AI initiation, and diabetes mellitus history. Postcollege education, geographic region of primary care clinic, and never smoking were associated with a reduced risk of nonadherence. CONCLUSIONS: A significant proportion of breast cancer patients treated with AI did not receive guideline-recommended BMD screening. Findings should raise awareness of the importance of BMD screening and targeting women at increased risk of screening nonadherence. PMID- 23362884 TI - High and low dose responses of transcriptional biomarkers in ex vivo X-irradiated human blood. AB - PURPOSE: Modifications of gene expression following ionizing radiation (IR) exposure of cells in vitro and in vivo are well documented. However, little is known about the dose-responses of transcriptionally responsive genes, especially at low doses. In this study, we investigated these dose-responses and assessed inter-individual variability. MATERIALS AND METHODS: High dose (0.5-4 Gy) and low dose (5-100 mGy) gene expression responses at 2 h and 24 h using 13 biomarkers transcriptionally regulated through the DNA damage response by the tumor suppressor p53 were investigated. Inter-individual variation was also examined. RESULTS: High dose-response curves were best constructed using a polynomial fit while the low dose-response curves used a linear fit with linear R(2) values of 0.841-0.985. Individual variation was evident in the high and low dose ranges. The FDXR, DDB2 high dose gene combination produced a mean dose estimate of 0.7 Gy for 1 Gy irradiated 'unknown' samples (95% CIs of 0.3-1.1 Gy) and 1.4 Gy for 2 Gy exposure (95% CIs of 0.6-2.1 Gy). The FDXR, DDB2, CCNG1 low dose gene combination estimated 98 mGy (95% CIs of 27-169 mGy) for 100 mGy exposure. CONCLUSIONS: These findings identify genes that fulfill some of the requirements of a good exposure biomarker even at low doses, such as sensitivity, reproducibility and simple proportionality with dose. PMID- 23362885 TI - Frozen blood products: clinically effective and potentially ideal for remote Australia. AB - The development of effective cryopreservation techniques for both red blood cells and platelets, which maintain ex vivo biological activity, in combination with frozen plasma, provides for a unique blood banking strategy. This technology greatly enhances the storage life of these products. The rationale and potential advantages of using cryopreservation techniques for the provision of blood products to remote and military environments have been effectively demonstrated in several conflicts over the last decade. Current haemostatic resuscitation doctrine for the exsanguinating patient supports the use of red blood cells, platelets and frozen plasma early in the resuscitation. We believe an integrated fresh-frozen blood bank inventory could facilitate provision of blood products, not only in the military setting but also in regional Australia, by overcoming many logistic and geographical challenges. The processes involved in production and point of care thawing are sufficiently well developed and achievable to make this technology a viable option. The potential limitations of cryopreservation and subsequent product thawing need to be considered if such a strategy is to be developed. A substantial body of international experience using cryopreserved products in remote settings has already been accrued. This experience provides a template for the possible creation of an Australian integrated fresh-frozen blood bank inventory that could conceivably enhance the care of patients in both regional Australia and in the military setting. PMID- 23362886 TI - Horner's syndrome in patients admitted to the paediatric intensive care unit: epidemiology, diagnosis and clinical practice. AB - Horner's syndrome appears when the three-neuron sympathetic pathway is interrupted anywhere from the posterior-lateral nuclei of the hypothalamus through the spinal cord to the eye. In children, Horner's syndrome can be either congenital or acquired, but overall it is a rare finding. There are several causes of Horner's syndrome, some of iatrogenic. Although uncommon in the paediatric population, prompt recognition of the syndrome and immediate treatment may prevent permanent damage to the neuronal pathway. Awareness of the risk of developing iatrogenic Horner's syndrome and early detection of signs are recommended to minimise future disability. PMID- 23362887 TI - The clinical role of glutamine supplementation in patients with multiple trauma: a narrative review. AB - Glutamine is considered an essential amino acid during stress and critical illness. Parenteral glutamine supplementation in critically ill patients has been shown to improve survival rate and minimise infectious complications, costs and hospital length-of-stay. However, glutamine supplementation in patients receiving enteral nutrition and the best method of administration are still controversial. The purpose of this article is to provide a narrative review of the current evidence and trials of enteral and parenteral glutamine supplementation in multiple trauma patients. A search in PubMed and EMBASE was conducted and relevant papers that investigated the effect of enteral or parenteral glutamine supplementation in patients with multiple trauma were reviewed. Although recent nutritional guidelines recommend that glutamine supplementation should be considered in these patients, further well-designed trials are required to provide a confirmed conclusion. Due to the inconclusive results of enteral glutamine supplementation trials in patients receiving enteral nutrition, future trials should focus on intravenous glutamine supplementation in patients requiring enteral nutrition and on major clinical outcome measures (e.g. mortality rate, infectious complications). PMID- 23362888 TI - Breastfeeding after anaesthesia: a review of the pharmacological impact on children. AB - Post-anaesthetic advice imparted to breastfeeding mothers can vary. This is due in part to the differing information from published data, product information sheets and inevitably from the unhindered flow of opinions available on the internet. This literature review examined the evidence relating to drugs commonly used in the modern anaesthetic setting and their impact on breastfed children. It suggests that special precautions are rarely warranted in the post-anaesthetic care of breastfeeding patients. PMID- 23362889 TI - A prospective randomised comparison of the LMA ProSealTM versus endotracheal tube on the severity of postoperative pain following gynaecological laparoscopy. AB - Pain and postoperative nausea and vomiting (PONV) are common problems after gynaecologic laparoscopy. Two recent studies have shown that morphine requirements and PONV are lower when an LMA ProSealTM is used, rather than an endotracheal tube (ETT), for female patients undergoing breast and gynaecological surgery. We conducted a patient and observer-blinded randomised controlled trial, recruiting non-obese women without gastro-oesophageal reflux undergoing laparoscopic gynaecological surgery. Patients received a standardised relaxant general anaesthetic and then were randomised to receive either an LMA ProSeal or an endotracheal tube. Patients were assessed at two and 24 hours post anaesthesia. The primary outcome was postoperative pain score and secondary endpoints included morphine consumption, postoperative emesis and adverse upper airway symptoms. We recruited 116 patients to the study, 57 patients in the ETT group and 59 patients in the LMA ProSeal group. The patients were similar in demographic and surgical characteristics. At two hours, the ETT group was similar to the LMA ProSeal group in regards to pain scores (Visual Analogue Scale 3.0 vs 3.5, P=0.86), morphine consumption (7.2 vs 7.4 mg, P=0.56) and PONV (47.4 vs 47.5%, P=0.99). After 24 hours, pain scores and PONV rates were also similar. No significant difference in rates of sore throat or dysphagia was observed between the ETT and LMA ProSeal groups. No significant complications were attributable to either airway device. The LMA ProSeal did not decrease pain or PONV in patients undergoing gynaecological laparoscopy when compared to endotracheal intubation. PMID- 23362890 TI - The analgesic effect of intrathecal dexmedetomidine or clonidine, with bupivacaine, in trauma patients undergoing lower limb surgery: a randomised, double-blind study. AB - This randomised, double-blind study was designed to compare the duration of analgesia and adverse effects following intrathecal administration of dexmedetomidine or clonidine, both with bupivacaine, in trauma patients. Ninety adult trauma patients of American Society of Anesthesiologists physical status I II, scheduled for lower limb surgery under subarachnoid block, were randomly allocated to one of three groups. All groups received hyperbaric bupivacaine 0.5% 3 ml, to which was added saline 0.5 ml (Group B): clonidine 50 ug (Group C) or dexmedetomidine 5 ug (Group D). The onset and duration of sensory and motor blockade, severity of postoperative pain, time to first rescue analgesia and total analgesic requirement for 24 hours were noted. There was no significant difference in the onset time of the block but the duration of sensory and motor blockade was prolonged in Groups C and D, compared with Group B. The time to analgesia was significantly prolonged in Group D (824+/-244 minutes) compared with Group C (678+/-178 minutes; P=0.01), the latter being longer than Group B (406+/-119 minutes; P=0.0001). Postoperative pain scores were lower in Groups C and D compared with group b. The requirement for rescue analgesia during the first 24 postoperative hours was significantly less in Groups C and D as compared to Group B (P=0.0001), but comparable between Groups C and D (P=0.203). In conclusion, dexmedetomidine 5 ug added to intrathecal bupivacaine 15 mg produces longer postoperative analgesia than clonidine 50 ug among trauma patients undergoing lower limb surgery. PMID- 23362891 TI - Comparison of physiological responses to spontaneous breathing trials with a T tube and low-level pressure support. AB - Previous studies have shown that spontaneous breathing trials (SBT) with a T-tube or low-level pressure support are comparable. However, low-level pressure support may overestimate the ability of a patient to sustain spontaneous breathing, resulting in premature extubation. Understanding factors contributing to different responses by patients to the two SBT methods aids in clarifying the limitation of using low-level pressure support for SBT. We performed a prospective observational study in 80 consecutive adult patients with mechanical ventilation to identify the factors contributing to different responses of a patient to the two SBT methods. The 80 patients underwent both a T-tube trial and pressure support ventilation of 6 cmH2O (PS-6) on the day of extubation. Stratified analysis was used to evaluate the effects of age, respiratory compliance and resistance, PaO2/FiO2 ratio and underlying disease on post-SBT responses. Comparing the responses to a T-tube trial and PS-6, the patients with old age, poor pulmonary compliance (<=40 ml/cmH2O) and chronic obstructive pulmonary disease had a higher heart rate (difference [95% CI]: 4 [0,8], 5 [2,9], 5 [0,10] beats/minute, respectively) and systolic blood pressure (10 [4,16], 11 [5,16], 7 [0,13] mmHg, respectively) after the T-tube trial. In conclusion, this research shows that old age and impaired respiratory mechanics contribute to different responses to spontaneous breathing trials with a T-tube and low-level pressure support. Further studies are needed to compare the effectiveness of the two SBT methods in predicting successful extubation in such patient groups. PMID- 23362892 TI - The relationship between patient data and pooled clinical management decisions. AB - A strong relationship between patient data and preoperative clinical decisions could potentially be used to support clinical decisions in preoperative management. The aim of this exploratory study was to determine the relationship between key patient data and pooled clinical opinions on management. In a previous study, panels of anaesthetists compared the quality of computer-assisted patient health assessments with outpatient consultations and made decisions on the need for preoperative tests, no preoperative outpatient assessment, possible postoperative intensive care unit/high dependency unit requirements and aspiration prophylaxis. In the current study, the relationship between patient data and these decisions was examined using binomial logistic regression analysis. Backward stepwise regression was used to identify independent predictors of each decision (at P >0.15), which were then incorporated into a predictive model. The number of factors related to each decision varied: blood picture (four factors), biochemistry (six factors), coagulation studies (three factors), electrocardiography (eight factors), chest X-ray (seven factors), preoperative outpatient assessment (17 factors), intensive care unit requirement (eight factors) and aspiration prophylaxis (one factor). The factor types also varied, but included surgical complexity, age, gender, number of medications or comorbidities, body mass index, hypertension, central nervous system condition, heart disease, sleep apnoea, smoking, persistent pain and stroke. Models based on these relationships usually demonstrated good sensitivity and specificity, with receiver operating characteristics in the following areas under curve: blood picture (0.75), biochemistry (0.86), coagulation studies (0.71), electrocardiography (0.90), chest X-ray (0.85), outpatient assessment (0.85), postoperative intensive care unit requirement (0.88) and aspiration prophylaxis (0.85). These initial results suggest modelling of patient data may have utility supporting clinicians' preoperative decisions. PMID- 23362893 TI - Australian paediatric hyperbaric oxygen therapy 1998-2011. AB - For a large number of ischaemic, infective, inflammatory or traumatic conditions, hyperbaric oxygen therapy is either the only treatment or an adjunct that significantly reduces morbidity and mortality. The primary aim of this review is to identify clinical conditions treated in a paediatric population referred to Australian hyperbaric units. Secondary aims are to describe outcomes of treatment and detail any complications occurring during treatment or during transfer between units. This was a retrospective cohort study (January 1998-December 2011) of children treated at four Australian hyperbaric medical units. A total of 112 children underwent 1099 hyperbaric treatments for 14 indications. Ages were not normally distributed with a median age of 14 years (interquartile range 11-16; range 0.25-16 years). Treatments were completed as planned in 81.5% of cases with 25 patients' treatment terminated at the request of physicians, parents or patients. Complications relating to hyperbaric oxygen therapy occurred in 58 treatments (5.3%). Central nervous system oxygen toxicity occurred in 1:366 treatments. Our findings indicate that provision of hyperbaric oxygen therapy to children is feasible in major regional hyperbaric units and is associated with low complication rates. Management of children in an adult hyperbaric facility, however, requires significant cooperation between paediatric, intensive care and hyperbaric consultants, as the need for transfer to another hospital and prolonged transports often impacts on optimal ongoing surgical and intensive care management. PMID- 23362894 TI - Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support. AB - Extracorporeal membrane oxygenation (ECMO) is known to affect pharmacokinetics and hence optimum dosing. The aim of this open label, prospective study was to investigate the pharmacokinetics of oseltamivir (prodrug) and oseltamivir carboxylate (active metabolite) during ECMO. Fourteen adult patients with suspected or confirmed H1N1 influenza were enrolled in the study. Oseltamivir 75 mg was enterally administered twice daily and blood samples for pharmacokinetic assessment were taken on day 1 and 5. A multi-compartmental model to describe the pharmacokinetics of oseltamivir and oseltamivir carboxylate was developed using a non-linear mixed effects modelling approach. The median (range) clearance of oseltamivir carboxylate was 15.8 (4.8-36.6) l/hour, lower than the reported mean value of 21.5 l/hour in healthy adults. The median (range) steady state volume of distribution of oseltamivir carboxylate was 179 (61-436) litres, much greater than healthy adults but similar to previous reports in critically ill patients. Substantial 'between subject' variability in systemic exposure to oseltamivir carboxylate was revealed; median (range) area under the curve and Cmax were 4346 (644-13660) ng/hour/ml and 509 (54-1277) ng/ml, respectively. Both area under the curve and Cmax were significantly correlated with serum creatinine (r2=0.37, P=0.02 and r2=0.29, P=0.02, respectively). Systemic exposure to oseltamivir carboxylate following the administration of enteral oseltamivir 75 mg twice daily in adult ECMO patients is comparable to those in ambulatory patients and far in excess of concentrations required to maximally inhibit neuraminidase activity of the H1N1 virus. Dosage adjustment for ECMO, per se, appears not to be necessary; however, doses should be reduced in patients with renal dysfunction. PMID- 23362895 TI - Epidural anaesthesia with goal-directed administration of ropivacaine improves haemodynamic stability when combined with general anaesthesia in elderly patients undergoing major abdominal surgery. AB - The use of epidural ropivacaine may result in significant haemodynamic fluctuations during combined epidural and general anaesthesia. We designed this study to investigate whether epidural anaesthesia with a goal-directed approach, when combined with general anaesthesia, improved haemodynamic stability in elderly patients undergoing major abdominal surgery. Seventy-five elderly patients undergoing major abdominal surgery were randomly and evenly assigned to one of three groups receiving intraoperative epidural anaesthesia with either ropivacaine 0.1% (Group 1), ropivacaine 0.375% (Group 2) or ropivacaine 0.375% for abdominal wall pain and ropivacaine 0.1% for visceral pain (Group 3). General anaesthesia was induced using a target-controlled infusion of combined propofol and remifentanil. The remifentanil target concentration was adjusted according to the mean arterial pressure and heart rate, and vasoactive agents were administered to maintain stable haemodynamics. The need for vasoactive drug administrations was 1.4 (standard deviation 0.9) in Group 3 (n=24), representing a significantly lower frequency of administration compared with Groups 1 (n=24) and 2 (n=24) (P <0.05 versus Group 1; P <0.01 versus Group 2). The total intraoperative dose of remifentanil was significantly greater in Group 1 (P <0.01 versus Group 2; P <0.05 versus Group 3) but did not differ significantly between Groups 2 and 3. Goal-directed epidural anaesthesia with different ropivacaine concentrations can improve haemodynamic stability when combined with general anaesthesia for elderly patients undergoing major abdominal surgery. PMID- 23362896 TI - The anaesthetic pre-admission clinic is effective in minimising surgical cancellation rates. AB - Pre-admission clinics (PAC) are now well-established in most hospitals. However, there have been few studies examining the efficacy of PACs in minimising day of surgery cancellations due to anaesthetic reasons. A retrospective cross-sectional descriptive study was carried out in a metropolitan tertiary hospital over a four year period to assess reasons for anaesthetic-related day of surgery cancellations in elective surgical patients who attended the PAC. Of 12,537 patients who attended the PAC during the study period, 58 (0.46%) were cancelled on the day of surgery for anaesthetic reasons. The most common cause was non preventable misadventure such as acute respiratory tract infections, seen in 19 patients (33% of all anaesthetic cancellations). The next most common cause was classified as being due to patient or system error (16 patients). This included patients' failure to adhere to fasting or medication guidelines, or a failure to detect and respond to abnormal laboratory results. Clinical disagreement between anaesthetic assessment at the PAC and the attending anaesthetist on the day of surgery was low (12 patients, 21%), and clinical deterioration in a pre-existing condition (six patients, 10%) accounted for the majority of other cancellations. Although patient misadventure constituted the major cause of anaesthetic cancellations, non-adherence to fasting and medication guidelines constituted the next major reason for surgery cancellation due to anaesthetic causes. This is important as such cancellations are potentially preventable and the overall cancellation rate could potentially be improved by instituting relatively simple changes to clinic function. PMID- 23362897 TI - Financial and environmental costs of manual versus automated control of end-tidal gas concentrations. AB - Emerging technologies that reduce the economic and environmental costs of anaesthesia have had limited assessment. We hypothesised that automated control of end-tidal gases, a new feature in anaesthesia machines, will consistently reduce volatile agent consumption cost and greenhouse gas emissions. As part of the planned replacement of anaesthesia machines in a tertiary hospital, we performed a prospective before and after study comparing the cost and greenhouse gas emissions of isoflurane, sevoflurane and desflurane when using manual versus automated control of end-tidal gases. We analysed 3675 general anaesthesia cases with inhalational agents: 1865 using manual control and 1810 using automated control. Volatile agent cost was $18.87/hour using manual control and $13.82/hour using automated control: mean decrease $5.05/hour (95% confidence interval: $0.88 9.22/hour, P=0.0243). The 100-year global warming potential decreased from 23.2 kg/hour of carbon dioxide equivalents to 13.0 kg/hour: mean decrease 10.2 kg/hour (95% confidence interval: 2.7-17.7 kg/hour, P=0.0179). Automated control reduced costs by 27%. Greenhouse gas emissions decreased by 44%, a greater than expected decrease facilitated by a proportional reduction in desflurane use. Automated control of end-tidal gases increases participation in low flow anaesthesia with economic and environmental benefits. PMID- 23362898 TI - A survey of aseptic precautions and needle type for paediatric caudal block in Australia and New Zealand. AB - This cross-sectional survey was designed to evaluate the current practice of anaesthetists in Australia and New Zealand with regard to aseptic technique and needle type during the performance of single-shot caudal blocks. Professional bodies suggest that full aseptic precautions be taken during the administration of caudal or epidural blocks. It has been suggested that using an intravenous cannula or a styletted needle may obviate the occurrence of epidermoid tumours. A total of 202 members of the Society for Paediatric Anaesthesia in New Zealand and Australia were invited to participate in this internet-based survey. Eighty-four responses were received. Most respondents used some form of antiseptic handwash (81%), wore sterile gloves (85.7%), used antiseptic skin preparation (100%) and draped the site (57.1%). When performing caudal blocks, 43.1% used unstyletted needles, 27.2% used styletted spinal needles and 29.6% used intravenous cannulas. However, 11.9% did not wash hands, 10.7% did not wear gloves and 42.9% did not drape the site. Three respondents reported neither handwashing, wearing gloves or draping, instead only using an alcohol swab for skin preparation. The majority of respondents in our region appear to use some level of aseptic precautions, albeit to a variable degree. Published recommendations may either be perceived as overly cautious or as ambiguous in that they do not specify caudal practice as distinct from other epidural blocks. There is a need for clearer professional guidance to support a minimum level of aseptic precaution for single-shot caudal epidural blocks. PMID- 23362899 TI - Early tracheal stenosis causing extubation failure and prolonged ventilator dependency. AB - Postintubation stenosis is the most frequent cause of benign tracheal stenosis and may cause reintubation and delay in weaning of intensive care unit patients. This case study describes typical patients with tracheal stenosis and the management of these patients. Five patients requiring reintubation and mechanical ventilation due to early intubation-related stenosis are discussed. Stridor developed in three cases after extubation. In these cases, bronchoscopy revealed tracheal stenosis. Dilatation and silicone stent placement were performed using rigid bronchoscopy. The other two patients were on ventilators when they were admitted to the intensive care unit and their stenoses were also treated by rigid bronchoscopy. Hypercapnia and hypoxia resolved after intervention in three cases. Of the remaining two patients, one had the tracheostomy closed and in the other patient ventilation was stopped but the tracheostomy was maintained. Tracheal stenosis developing in the subglottic region after extubation, especially after exposure to cuff pressure, may lead to reintubation. A tracheostomy may hinder the diagnosis of progressive stenosis and may lead to unnecessary maintenance of ventilator treatment. Early intubation-related tracheal stenosis should therefore be considered in cases of weaning or extubation failure and prompt appropriate investigation and treatment. PMID- 23362900 TI - Spinal pethidine for elective caesarean section. AB - Pethidine (meperidine) is a unique member of the opioid family. In addition to its analgesic activity, it also has significant local anaesthetic activity. This property enables it to be used as the sole agent for spinal anaesthesia. We describe the successful use of intrathecal pethidine 1 mg/kg for an elective lower segment caesarean section in a patient presumed to be allergic to amide local anaesthetics. There were no significant adverse effects in either the mother or the newborn. PMID- 23362901 TI - Systemic mastocytosis presenting as intraoperative anaphylaxis with atypical features: a report of two cases. AB - Two cases of perioperative cardiovascular collapse are presented that were associated with markedly elevated mast cell tryptase levels shortly after the event, leading to the assumption that an immunoglobin E-mediated, drug-induced anaphylaxis had occurred. However, the clinical picture in both cases was atypical and subsequent skin testing failed to identify a triggering drug. Further blood tests, some weeks later, revealed persistently elevated baseline levels of mast cell tryptase. In both cases bone marrow biopsy and genetic testing confirmed the diagnosis of mastocytosis. We present evidence and speculate that mast cell degranulation was triggered by tourniquet release in the first case and by exposure to peanuts in the second. An atypical presentation of anaphylaxis should alert the anaesthetist to the possibility of previously undiagnosed mastocytosis. PMID- 23362902 TI - Scoring systems for videolaryngoscopes. PMID- 23362904 TI - Use of Cormack and Lehane grading with videolaryngoscopy. PMID- 23362906 TI - Redheads and anaesthesia. PMID- 23362908 TI - The unmeasured ion excess: a follow-up. PMID- 23362909 TI - Delayed recovery from general anaesthesia in a parturient after magnesium toxicity. PMID- 23362910 TI - Frova intubating introducers and double-lumen tubes. PMID- 23362911 TI - Emergency on-pump coronary artery bypass grafting in a patient with hereditary angioedema. PMID- 23362912 TI - Multisystem paradoxical air embolism. PMID- 23362913 TI - The diagnostic role of procalcitonin in quinine-induced disseminated intravascular coagulation. PMID- 23362914 TI - Use of a modified bite-block to facilitate mask ventilation in edentulous elderly patients. PMID- 23362915 TI - A comparison of the effect of meta-analyses and original studies on recommendations from a standard textbook of critical care medicine and altering clinical practice. PMID- 23362916 TI - The Preparation, Properties, and Structure of Tetraphenylarsonium Tetrakis (trifluoroacetato) cobaltate (II). PMID- 23362917 TI - Quantifying the nature of anticipation in professional tennis. AB - We quantify the nature and frequency of anticipation behaviours in professional tennis using video coding of incidents where the time delay between the opponent's stroke and the reaction of the player were recorded. We argue that anticipation is based on uncertain information and should lead in some situations to erroneous decisions. We identified the transition between reaction (with 100% accuracy in the selection of where the ball is played on the court) and anticipation (with less than 100% accuracy) as being 140-160 ms after ball contact. Anticipation behaviours occurred on between 6.14% and 13.42% of the coded situations. These anticipation behaviours appeared almost exclusively in 'unfavourable' situations, where the opponent had a significant tactical advantage, with the type of playing surface having only a limited effect. Moreover, the decrease in accuracy with shorter response times is not monotonic, with an increase in response accuracy being observed for times shorter than 120 ms before ball contact. We propose that very early anticipation behaviours occur when players use significant context-specific information before the opponent's stroke. When such information is not available, players produce anticipation behaviours that are closer to the moment of ball-racket contact using information that is more likely to be based on the opponent's preparation of the stroke. This study opens new directions for research focusing on the testing and training of anticipation in fast ball sports. PMID- 23362918 TI - Resonant antenna probes for tip-enhanced infrared near-field microscopy. AB - We report the development of infrared-resonant antenna probes for tip-enhanced optical microscopy. We employ focused-ion-beam machining to fabricate high-aspect ratio gold cones, which replace the standard tip of a commercial Si-based atomic force microscopy cantilever. Calculations show large field enhancements at the tip apex due to geometrical antenna resonances in the cones, which can be precisely tuned throughout a broad spectral range from visible to terahertz frequencies by adjusting the cone length. Spectroscopic analysis of these probes by electron energy loss spectroscopy, Fourier transform infrared spectroscopy, and Fourier transform infrared near-field spectroscopy corroborates their functionality as resonant antennas and verifies the broad tunability. By employing the novel probes in a scattering-type near-field microscope and imaging a single tobacco mosaic virus (TMV), we experimentally demonstrate high performance mid-infrared nanoimaging of molecular absorption. Our probes offer excellent perspectives for optical nanoimaging and nanospectroscopy, pushing the detection and resolution limits in many applications, including nanoscale infrared mapping of organic, molecular, and biological materials, nanocomposites, or nanodevices. PMID- 23362920 TI - Electrical and physical characterization of bilayer carboxylic acid functionalized molecular layers. AB - We have used flip chip lamination (FCL) to form monolayer and bilayer molecular junctions of carboxylic acid-containing molecules with Cu atom incorporation. Carboxylic acid-terminated monolayers are self-assembled onto ultrasmooth Au by using thiol chemistry and grafted onto n-type Si. Prior to junction formation, monolayers are physically characterized by using polarized infrared absorption spectroscopy, X-ray photoelectron spectroscopy, and near-edge X-ray absorption fine structure spectroscopy, confirming the molecular quality and functional group termination. FCL was used to form monolayer junctions onto H-terminated Si or bilayer junctions of carboxylic acid monolayers on Au and Si. From the electrical measurements, we find that the current through the junction is attenuated as the effective molecular length within the junction increases, indicating that molecules are electrically active within the junction. We find that the electronic transport through the bilayer junction saturates at very thick effective distances possibly because of another electron-transport mechanism that is not nonresonant tunneling as a result of trapped defects or sequential tunneling. In addition, bilayer junctions are fabricated with and without Cu atoms, and we find that the electron transport is not distinguishably different when Cu atoms are within the bilayer. PMID- 23362921 TI - Cardiovascular disease in polycystic ovary syndrome. PMID- 23362919 TI - Protein restriction cycles reduce IGF-1 and phosphorylated Tau, and improve behavioral performance in an Alzheimer's disease mouse model. AB - In laboratory animals, calorie restriction (CR) protects against aging, oxidative stress, and neurodegenerative pathologies. Reduced levels of growth hormone and IGF-1, which mediate some of the protective effects of CR, can also extend longevity and/or protect against age-related diseases in rodents and humans. However, severely restricted diets are difficult to maintain and are associated with chronically low weight and other major side effects. Here we show that 4 months of periodic protein restriction cycles (PRCs) with supplementation of nonessential amino acids in mice already displaying significant cognitive impairment and Alzheimer's disease (AD)-like pathology reduced circulating IGF-1 levels by 30-70% and caused an 8-fold increase in IGFBP-1. Whereas PRCs did not affect the levels of beta amyloid (Abeta), they decreased tau phosphorylation in the hippocampus and alleviated the age-dependent impairment in cognitive performance. These results indicate that periodic protein restriction cycles without CR can promote changes in circulating growth factors and tau phosphorylation associated with protection against age-related neuropathologies. PMID- 23362922 TI - Ligand-mediated self-assembly of hybrid plasmonic and superparamagnetic nanostructures. AB - Hybrid nanostructures with unique optical and magnetic properties have attracted considerable interest as effective mediators for medical imaging and therapy. An aqueous-based, self-assembly approach to synthesizing hybrid plasmonic superparamagnetic nanostructures is presented. The building blocks of the hybrid nanostructure include plasmonic gold nanorods (AuNRs) and superparamagnetic iron oxide nanoparticles (SPIONs). The AuNRs were functionalized via carboxyl-bearing surface ligands, and the SPIONs were kept "bare" after synthesis via a surfactant free thermal decomposition reaction in triethylene glycol. Hybrid SPION-studded AuNR nanostructures were produced upon simple mixing of the components because of the chemisorption of the AuNRs' free carboxyl groups to the SPIONs' surfaces. The reported synthesis strategy is modular in nature and can be expanded to build hybrid nanostructures with a multitude of other plasmonic nanoparticles. With tunable near-infrared absorption peaks and a sufficient number of bound SPIONs, the self-assembled hybrid nanostructures are suitable for biomedical imaging and therapy applications. PMID- 23362923 TI - Biselectivity of isoDGR peptides for fibronectin binding integrin subtypes alpha5beta1 and alphavbeta6: conformational control through flanking amino acids. AB - Integrins are the major class of cell adhesion proteins. Their interaction with different ligands of the extracellular matrix is diverse. To get more insight into these interactions, artificial ligands endowed with a well-defined activity/selectivity profile are necessary. Herein, we present a library of cyclic pentapeptides, based on our previously reported peptide motif c(-phg isoDGR-X-), in which high activity toward fibronectin binding integrins alpha5beta1 and alphavbeta6 and not on vitronectin binding integrins alphavbeta3 and alphavbeta5 has been achieved by changing the flanking amino acids. The structure of the most promising candidates has been determined using a combined approach of NMR, distance geometry, and molecular dynamics simulations, and docking studies have been further used to elucidate the peptide-integrin interactions at the molecular level. The peptides' binding affinity has been characterized by enzyme linked immunosorbent assay experiments, and the results have been verified by cell adhesion experiments on specifically functionalized surfaces. PMID- 23362924 TI - Predators, alternative prey and climate influence annual breeding success of a long-lived sea duck. AB - 1. Perturbations to ecosystems have the potential to directly and indirectly affect species interactions, with subsequent impacts on population dynamics and the vital rates that regulate them. 2. The few long-term studies of common eider breeding ecology indicate that reproductive success is low in most years, interrupted by occasional boom years. However, no study has explicitly examined the drivers of long-term variation in reproductive success. 3. Here, we use encounter history data collected across 41 years to examine the effects of arctic foxes (a terrestrial nest predator), local abundance and spatial distribution of lesser snow geese (an alternative prey source), and spring climate on common eider nest success. 4. Eider nest success declined over the course of the study, but was also highly variable across years. Our results supported the hypothesis that the long-term decline in eider nest success was caused by apparent competition with lesser snow geese, mediated by shared predators. This effect persisted even following a large-scale exodus of nesting geese from the eider colony. Nest success was also lowest in years of low arctic fox index, presumably driven by prey switching in years of low small mammal availability. However, increased snow goose abundance appeared to buffer this effect through prey swamping. The effect of spring climate depended on the stage of the breeding season; cold and wet and warm and dry conditions in early spring were correlated with decreased nest success, whereas warm and wet conditions in late spring increased eider nest success. 5. These results underscore the significance of both trophic interactions and climate in regulating highly variable vital rates, which likely have important consequences for population dynamics and the conservation of long-lived iteroparous species. PMID- 23362925 TI - Endoscopic resection (endoscopic mucosal resection/ endoscopic submucosal dissection) for early gastric cancer. AB - Endoscopic resection of early gastric cancer is a well-established standard therapy in Japan and Korea, and is increasingly used in other countries. Endoscopic resection should be curative for patients, and safe, easy and effective not only for patients, but also for endoscopists. Endoscopic submucosal dissection (ESD) is superior to standard endoscopic mucosal resection (EMR) as it is designed to provide en bloc R0 resection regardless of size and/or location. Correct pathological assessment of en bloc resected specimens is crucial for accurate diagnosis and patient stratification for the risk of metastasis. Outcome studies in Japan and Korea, countries with the highest incidence of gastric cancer, have shown that ESD is efficacious in leading to a good long-term outcome; however, ESD requires an experienced endoscopist with a high skill level. Expanded indications for endoscopic resection have been proposed, especially after large en bloc resection have been accomplished using ESD. The use of ESD could be of huge benefit for the management of gastrointestinal superficial neoplasms. However, for ESD to become a viable therapeutic option, it requires close and supportive working relationships between endoscopists, pathologists and surgeons. PMID- 23362926 TI - Developing consensus on hospital prescribing indicators of potential harms amenable to decision support. AB - AIMS: To develop a list of prescribing indicators specific for the hospital setting that would facilitate the prospective collection of high-severity and/or high-frequency prescribing errors, which are also amenable to electronic clinical decision support. METHODS: A two-stage consensus technique (electronic Delphi) was carried out with 20 experts across England. Participants were asked to score prescribing errors using a five-point Likert scale for their likelihood of occurrence and the severity of the most likely outcome. These were combined to produce risk scores, from which median scores were calculated for each indicator across the participants in the study. The degree of consensus between the participants was defined as the proportion that gave a risk score in the same category as the median. Indicators were included if a consensus of 80% or more was achieved. RESULTS: A total of 80 prescribing errors were identified by consensus as being high or extreme risk. The most common drug classes named within the indicators were antibiotics (n = 13), antidepressants (n = 8), nonsteroidal anti-inflammatory drugs (n = 6) and opioid analgesics (n = 6). The most frequent error type identified as high or extreme risk were those classified as clinical contraindications (n = 29 of 80). CONCLUSIONS: Eighty high-risk prescribing errors in the hospital setting have been identified by an expert panel. These indicators can serve as a standardized, validated tool for the collection of prescribing data in both paper-based and electronic prescribing processes. This can assess the impact of safety improvement initiatives, such as the implementation of electronic clinical decision support. PMID- 23362927 TI - Liposome-quantum dot complexes enable multiplexed detection of attomolar DNAs without target amplification. AB - Sensitive detection of DNA usually relies on target amplification approaches such as polymerase chain reaction and rolling circle amplification. Here we describe a new approach for sensitive detection of low-abundance DNA using liposome-quantum dot (QD) complexes and single-particle detection techniques. This assay allows for detection of single-stranded DNA at attomolar concentrations without the involvement of target amplification. Importantly, this strategy can be employed for simultaneous detection of multiple DNA targets. PMID- 23362929 TI - Combining serology and molecular typing of weak D role in improving D typing strategy in Egypt. AB - BACKGROUND: Rh discrepancies are a problem during routine testing because of partial and weak D phenotypes. Some blood units with weak and partial D expression may escape detection by serology. Limitations of serology can be overcome by molecular typing. The objective of study was to compare currently used serologic methods with molecular analysis to determine the potential application of molecular methods to improve D typing strategies and to estimate the frequency of weak D types among the Arab population. STUDY DESIGN AND METHODS: Fifty blood donor and patient samples with discrepant results of D phenotyping were subjected to routine serology to define the D phenotype including monoclonal anti-D immunoglobulin M and indirect antiglobulin test. Commercially available panels of monoclonal anti-D were used for identification of partial D and weak D phenotypes. Genomic DNA was evaluated using allele specific amplification polymerase chain reaction with sequence-specific primers to define weak D type. RESULTS: Molecular typing confirmed most of the serology results; three samples that were not clear-cut serologically were identified by molecular typing, two samples as weak D Type 4.2 (DAR), and one sample as weak D Type 4.0. Another two samples identified by serologic panel as weak D were unresolved by molecular typing. A sample with partial D Type II by serology revealed a Weak D Type 4.0 by molecular typing. Results interestingly showed the high frequency of weak D Type 4.2 (DAR) in Egypt. CONCLUSION: RHD molecular typing can solve discrepancies during routine testing due to partial and weak D phenotypes for better transfusion outcome. PMID- 23362930 TI - Unsedated transnasal percutaneous endoscopic gastrostomy carried out by a single physician. AB - AIM: The present prospective observational study investigates the safety of transnasal percutaneous endoscopic gastrostomy (T-PEG) carried out by a single physician using an ultrathin endoscope. METHODS: A single endoscopist attempted the unsedated transnasal insertion of a 20-Fr PEG tube using a pull-method in 31 dysphagic patients: 11 females and 20 males aged 76.5+/-10.6(46-96)years, using a 5-mm-diameter endoscope. The indications for PEG, cardiopulmonary function before and after T-PEG, operation time, success or failure, and any immediate adverse events that occurred during each procedure were recorded. Complications, including peristomal infection, systemic infection, tube lifespan, and patient mortality were monitored throughout the post-T-PEG follow-up period. RESULTS: Thirty (96.8%) of the transnasal PEG insertions were successful. The mean operation time was 14.7+/-2.9 (10-20) min, and cardiopulmonary function did not change before and after T-PEG. Complications included three (10%) cases of epistaxis, eight (26.6%) cases of minor Pseudomonas wound infection and two cases of Foley-related urinary tract infection (UTI). No self-extubation was observed, and the mean lifespan of the PEG tubes was 10.7+/-2.2months. Four patients died from pneumonia 10months after T-PEG insertion. CONCLUSION: Unsedated T-PEG insertion carried out by a single physician is a feasible and safe procedure. No major complications or mortality were observed following the procedures; only minor Pseudomonas aeruginosa wound infections were noted. It is an alternative method for dysphagic patients when transoral insertion of endoscopy is impossible. PMID- 23362931 TI - Catalytic asymmetric protonation of silyl ketene imines. AB - An efficient catalytic and highly enantioselective protonation of silyl ketene imines is described. The reaction is catalyzed by the chiral phosphoric acids TRIP or STRIP in the presence of a stoichiometric amount of methanol as the proton source and silyl acceptor. A variety of substituted racemic silyl ketene imines have been transformed into highly enantioenriched nitriles. PMID- 23362932 TI - A minimal set of SNPs for the noninvasive prenatal diagnosis of beta thalassaemia. AB - beta-thalassaemia is one of the commonest autosomal recessive single-gene disorders worldwide. Prenatal tests use invasive methods, posing a risk for the pregnancy itself. Development of a noninvasive prenatal diagnostic method is, therefore, of paramount importance. The aim of the present study is to identify high-heterozygote informative single-nucleotide polymorphisms (SNPs), suitable for the development of noninvasive prenatal diagnosis (NIPD) of beta thalassaemia. SNP genotyping analysis was performed on 75 random samples from the Cypriot population for 140 SNPs across the beta-globin cluster. Shortlisted, highly heterozygous SNPs were then examined in 101 carrier families for their applicability in the noninvasive detection of paternally inherited alleles. Forty nine SNPs displayed more than 6% heterozygosity and were selected for NIPD analysis, revealing 72.28% of the carrier families eligible for qualitative SNP based NIPD, and 92% for quantitative detection. Moreover, inference of haplotypes showed predominant haplotypes and many subhaplotypes with sufficient prevalence for diagnostic exploitation. SNP-based analyses are sensitive and specific for the detection of the paternally inherited allele in maternal plasma. This study provides proof of concept for this approach, highlighting its superiority to NIPD based on single markers and thus providing a blueprint for the general development of noninvasive prenatal diagnostic assays for beta-thalassaemia. PMID- 23362933 TI - Normal weight obesity in Korean adults. AB - BACKGROUND: A better way to define obesity is in terms of the percentage of body fat (BF). Subjects with normal weight, but excess BF are vulnerable to cardiovascular diseases. OBJECTIVE: To evaluate the prevalence and characteristics of subjects having normal weight obesity (NWO) using optimal cut offs of the BF percentage reflecting risk factors for cardiovascular disease (CVD) in Korean adults. DESIGN AND SETTING: The Korea National Health and Nutrition Examination Survey in the Korean population conducted in 2009-2010. PARTICIPANTS: We surveyed 5313 men and 6904 women aged 20 years or older. MEASUREMENTS: We investigated the relations between the BF percentage (measured by dual-energy X-ray absorptiometry) and obesity-related risk factors for CVD (diabetes mellitus, hypertension and dyslipidaemia) in Korean adults. NWO was defined as the combination of a normal body mass index (BMI; 18.5-22.9 kg/m(2) in Asian subjects) and BF percentages above the determined cut-off values. RESULTS: There were strong and graded associations of increasing BF percentages with the prevalence of CVD risk factors. The first cut-off values (defined as being overweight) in men and women were 20.6% and 33.4% BF, respectively, and the second cut-off values (defined as obesity) were 25.7% and 36.0% BF. Thirty-two per cent of normal weight adults had BF percentages greater than or equal to the overweight or obesity cut-offs (NWO). Subjects with NWO had a lower appendicular skeletal muscle mass, a more atherogenic lipid profile and greater insulin resistance. CONCLUSIONS: Obesity can be defined as 26% BF or greater in Korean men and 36% BF or greater in Korean women. There was a high prevalence of clustering of cardiometabolic abnormalities among subjects with NWO. PMID- 23362934 TI - Protective role of ascorbic acid in the decontamination of cow milk casein by gamma-irradiation. AB - PURPOSE: The aim of this work was to investigate the protective role of ascorbic acid on irradiation-induced modification of casein. MATERIALS AND METHODS: Casein stock solutions were irradiated with increasing doses 2-10 kGy using (60)Co Gamma rays at a dose rate D* = 136.73 Gy/min at room temperature. The total viable microorganism content of cow milk casein was evaluated by Plate Count Agar (PCA) incubation for 48 h at 37 degrees C. Sodium dodecylsulfate gel electrophoresis (SDS-PAGE) and Matrix-Assisted Laser Desorption-Ionization Time-of-Flight mass spectrometry (MALDI-TOF-MS) analysis were used to evaluate the effect of gamma irradiation on casein integrity. RESULTS: Gamma irradiation reduced the bacterial contamination of casein solutions at a lower irradiation dose when performed in the presence of ascorbic acid. The irradiation treatment of casein in the absence of ascorbic acid with a dose of 4 kGy could reduce 99% of the original amount of bacterial colonies. However, in the presence of ascorbic acid the irradiation treatment of casein with a dose lower than 2 kGy could reduce 99% of the original amount of bacterial colonies which suggested that the irradiation dose lower than 2 kGy achieved almost the entire decontamination result. SDS-PAGE and MALDI-TOF MS analysis showed that ascorbic acid protected cow milk casein from degradation and subsequent aggregation probably by scavenging oxygen and protein radicals produced by the irradiation. CONCLUSIONS: It is demonstrated that the combination of gamma irradiation and ascorbic acid produce additive effects, providing acceptable hygienic quality of cow milk casein and protects caseins against Reactive Oxygen Species (ROS) generated, during the irradiation process. PMID- 23362936 TI - 18alpha-glycyrrhetinic acid extracted from Glycyrrhiza radix inhibits proliferation and promotes apoptosis of the hepatic stellate cell line. AB - OBJECTIVE: To evaluate the effect of 18alpha-glycyrrhetinic acid (18alpha-GA) on the proliferation and apoptosis of hepatic stellate cells (HSCs) and its underlying mechanisms. METHODS: HSCs (both human and rat HSCs) were pretreated with or without selective peroxisome proliferator-activated receptor-gamma (PPAR gamma) antagonist, GW9662, before 18a-GA treatment. Cell cycle and apoptosis of HSCs were analyzed by flow cytometry, and changes in cell cycle and apoptosis related proteins were analyzed by Western blot. The effect of 18alpha-GA on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) DNA binding activity was measured by ArrayStar transcription factor activity assay. RESULTS: 18alpha-GA markedly reduced LX-2 cell numbers by 14.8% and 31.2% after 48 h and 72 h of treatment, respectively (P < 0.05). 18alpha-GA also significantly increased the percentage of LX-2 cells in phase G0/G1 and decreased it in phase S after treated for 48 h and 72 h compared with the control group. 18alpha-GA increased apoptosis to 6.8% at 48 h, compared with control (2.5%), and at 72 h the percentages of apoptotic cells in control and the treatment groups were 3.1% and 15.6%, respectively, in LX-2 cells (P < 0.01). Similar changes occurred in CCl4-cirrhotic fat-storing cells. Furthermore, 18alpha-GA induced expression of PPAR-gamma and altered some cell cycle and apoptosis-related proteins. 18alpha-GA also inhibited NF-kappaB DNA-binding activity. All these effects were abolished by GW9662. CONCLUSIONS: 18alpha-GA inhibits the proliferation of activated HSCs and induces apoptosis in culture. It also increases PPAR-gamma expression and decreases NF-kappaB DNA-binding activity, which may be involved in these effects. PMID- 23362935 TI - Risk of adverse cardiovascular outcomes and all-cause mortality associated with concomitant use of clopidogrel and proton pump inhibitors in elderly patients. AB - OBJECTIVE: To examine the effect of concomitant use of clopidogrel and PPIs in a national sample of elderly Medicare beneficiaries (age >=65 years). METHODS: A nested case-control design was employed. A cohort of Medicare beneficiaries who initiated clopidogrel and did not have any gap of >=30 days between clopidogrel fills between July 1, 2006 and December 31, 2008 was identified from a 5% national sample of Medicare claims data. Within this cohort, cases (beneficiaries who experienced any major cardiovascular event [MCE] [acute myocardial infarction, stroke, coronary artery bypass graft, or percutaneous coronary intervention] or all-cause mortality) and controls (beneficiaries who did not experience any MCE or all-cause mortality) were identified from inpatient and outpatient claims. Cases and controls were matched on age and the time to first clopidogrel fill. Conditional logistic regression was performed on the matched sample to evaluate the association between concomitant use of clopidogrel and PPIs and adverse health outcomes (MCEs and all-cause mortality). RESULTS: A total of 43,159 clopidogrel users were identified. Among them, 15,415 (35.7%) received clopidogrel and a PPI concomitantly at any time during the study period, 3502 (8.1%) experienced a MCE, 7306 (17.1%) died, and a total of 9908 (22.8%) experienced the primary composite outcome (any MCE or all-cause mortality) during follow-up. The odds ratio (OR) for the primary composite outcome was 1.26 (95% confidence interval [CI]: 1.18-1.35). Secondary analyses indicated that elderly patients using clopidogrel and a PPI concomitantly were more likely to experience all-cause mortality (OR: 1.40; 95% CI: 1.29-1.53) as compared to those receiving clopidogrel only, but not MCEs (OR: 1.06; 95% CI: 0.95-1.18). CONCLUSIONS: Concomitant use of clopidogrel and PPIs was associated with a slightly increased risk of all-cause mortality but not MCEs. PMID- 23362937 TI - Glutamine synthetase expression in activated hepatocyte progenitor cells and loss of hepatocellular expression in congestion and cirrhosis. AB - BACKGROUND & AIMS: In normal human liver, glutamine synthetase (GS) is expressed in a rim of hepatocytes surrounding hepatic veins. GS expression is decreased in cirrhosis and increased in chronic hepatitis, focal nodular hyperplasia, peritumoural hyperplasia and some hepatocellular neoplasms. For the non neoplastic conditions, there is limited information available on histological pattern of altered GS expression and the mechanisms of these changes. METHODS: We examined GS expression in 58 large specimens and 45 needle biopsies with a variety of non-neoplastic human liver conditions and in 12 normal control livers. Expression was correlated with clinical and histological disease states. RESULTS: We identified four patterns of GS expression: (i) Loss of normal perivenular expression was seen in states of chronic congestion, severe cirrhosis and zone 3 necrosis. (ii) Diffuse expression was seen in states with active hepatocellular injury and correlated with Ki-67 expression. (iii) Interface expression was seen in feathery degeneration of chronic cholestasis. (iv) GS expression in activated hepatocyte progenitor cells (HPCs) associated with small ducts and ductules was seen in fulminant hepatic failure and in early and late chronic liver disease and rarely in normal livers. CONCLUSIONS: Glutamine synthetase expression is increased in regenerating hepatocytes and in early HPCs prior to morphological evidence of hepatocellular differentiation. This may be the earliest marker of HPCs yet demonstrated. Loss of expression may be a reflection of disrupted endothelium-hepatocyte contact in hepatic vein walls caused by congestive injury as found in congestive heart failure and advanced cirrhosis. PMID- 23362938 TI - Identification of bacteria-selective threonyl-tRNA synthetase substrate inhibitors by structure-based design. AB - A series of potent and bacteria-selective threonyl-tRNA synthetase (ThrRS) inhibitors have been identified using structure-based drug design. These compounds occupied the substrate binding site of ThrRS and showed excellent binding affinities for all of the bacterial orthologues tested. Some of the compounds displayed greatly improved bacterial selectivity. Key residues responsible for potency and bacteria/human ThrRS selectivity have been identified. Antimicrobial activity has been achieved against wild-type Haemophilus influenzae and efflux-deficient mutants of Escherichia coli and Burkholderia thailandensis. PMID- 23362939 TI - Detection and characterization of early gastric cancer for curative endoscopic submucosal dissection. AB - Because endoscopic submucosal dissection (ESD) of gastric cancer can only be curative if the cancer is detected at an early stage and a precise preoperative diagnosis is made, we reviewed the detection and characterization of early gastric cancer (EGC) using both conventional endoscopy with white-light imaging (C-WLI) and image-enhanced endoscopy (chromoendoscopy [CE] and magnifying narrow band imaging [M-NBI]). Systematic screening of the stomach by C-WLI after ideal preparation of the patient is important for detecting a mucosal lesion, which can then be characterized using CE. However, a limitation of C-WLI with CE is the diagnosis of flat or small gastric cancers. To overcome this, M-NBI together with a comprehensive diagnostic system, termed the 'vessel plus surface classification' system, was developed and has proven very useful. Preoperative assessment for ESD involves determining: (i) histological type; (ii) size; (iii) depth of invasion; (iv) presence or absence of associated ulceration; and (v) horizontal extent of the cancer. A limitation of endoscopic diagnosis using M-NBI is the histologically undifferentiated type of carcinoma, in which case the biopsy specimen is used to make a histopathological diagnosis. PMID- 23362940 TI - Tuning the magnetic properties of metal oxide nanocrystal heterostructures by cation exchange. AB - For three types of colloidal magnetic nanocrystals, we demonstrate that postsynthetic cation exchange enables tuning of the nanocrystal's magnetic properties and achieving characteristics not obtainable by conventional synthetic routes. While the cation exchange procedure, performed in solution phase approach, was restricted so far to chalcogenide based semiconductor nanocrystals, here ferrite-based nanocrystals were subjected to a Fe(2+) to Co(2+) cation exchange procedure. This allows tracing of the compositional modifications by systematic and detailed magnetic characterization. In homogeneous magnetite nanocrystals and in gold/magnetite core shell nanocrystals the cation exchange increases the coercivity field, the remanence magnetization, as well as the superparamagnetic blocking temperature. For core/shell nanoheterostructures a selective doping of either the shell or predominantly of the core with Co(2+) is demonstrated. By applying the cation exchange to FeO/CoFe(2)O(4) core/shell nanocrystals the Neel temperature of the core material is increased and exchange bias effects are enhanced so that vertical shifts of the hysteresis loops are obtained which are superior to those in any other system. PMID- 23362941 TI - Curcumin and genistein coloaded nanostructured lipid carriers: in vitro digestion and antiprostate cancer activity. AB - To increase the oral bioavailability of curcumin and genistein, we fabricated nanostructured lipid carriers (NLCs), and the impact of these carriers on bioaccessibility of curcumin and genistein was studied. Entrapment efficiency was more than 75% for curcumin and/or genistein-loaded NLCs. Solubility of curcumin and/or genistein in simulated intestinal medium (SIM) was >75% after encapsulating within NLCs which otherwise was <20%. Both curcumin and genistein have shown good stability (>=85%) in SIM and simulated gastric medium (SGM) up to 6 h. Coloading of curcumin and genistein had no adverse effect on solubility and stability of each molecule. Instead, coloading increased loading efficiency and the cell growth inhibition in prostate cancer cells. Collectively, these results have shown that coloaded lipid based carriers are promising vehicles for oral delivery of poorly bioaccessible molecules like curcumin and genistein. PMID- 23362942 TI - Chiral selective transmembrane transport of amino acids through artificial channels. AB - Peptide-appended pillar[n]arene (n = 5, 6) derivatives have been synthesized. (1)H NMR and IR studies revealed that the molecules adopt a tubular conformation in solution and lipid bilayer membranes. Kinetic measurements using the fluorescent labeling method with lipid vesicles revealed that these molecules can efficiently mediate the transport of amino acids across lipid membranes at a very low channel-to-lipid ratio (EC(50) = 0.002 mol %). In several cases, chiral selectivity for amino acid enantiomers was achieved, which is one of the key functions of natural amino acid channels. PMID- 23362943 TI - A likelihood ratio test for genome-wide association under genetic heterogeneity. AB - Most existing association tests for genome-wide association studies (GWASs) fail to account for genetic heterogeneity. Zhou and Pan proposed a binomial-mixture model-based association test to account for the possible genetic heterogeneity in case-control studies. The idea is elegant, however, the proposed test requires an expectation-maximization (EM)-type iterative algorithm to identify the penalised maximum likelihood estimates and a permutation method to assess p-values. The intensive computational burden induced by the EM-algorithm and the permutation becomes prohibitive for direct applications to GWASs. This paper develops a likelihood ratio test (LRT) for GWASs under genetic heterogeneity based on a more general alternative mixture model. In particular, a closed-form formula for the LRT statistic is derived to avoid the EM-type iterative numerical evaluation. Moreover, an explicit asymptotic null distribution is also obtained, which avoids using the permutation to obtain p-values. Thus, the proposed LRT is easy to implement for GWASs. Furthermore, numerical studies demonstrate that the LRT has power advantages over the commonly used Armitage trend test and other existing association tests under genetic heterogeneity. A breast cancer GWAS dataset is used to illustrate the newly proposed LRT. PMID- 23362944 TI - Transfusion-transmitted human T-lymphotropic virus Type I infection in a United States military emergency whole blood transfusion recipient in Afghanistan, 2010. AB - BACKGROUND: The United States introduced human T-lymphotropic virus Type I (HTLV I) screening of blood donors in 1988. The US military uses freshly collected blood products for life-threatening injuries when available stored blood components in theater have been exhausted or when these components are unsuccessful for resuscitation. These donors are screened after donation by the Department of Defense (DoD) retrospective testing program. All recipients of blood collected in combat are tested according to policy soon after and at 3, 6, and 12 months after transfusion. CASE REPORT: A 31-year-old US Army soldier tested positive for HTLV-I 44 days after receipt of emergency blood transfusions for severe improvised explosive device blast injuries. One donor's unit tested HTLV-I positive on the DoD-mandated retrospective testing. Both the donor and the recipient tested reactive with enzyme immunoassay and supplemental confirmation by HTLV-I Western blot. The donor and recipient reported no major risk factors for HTLV-I. Phylogenetic analysis of HTLV-I sequences indicated Cosmopolitan subtype, Subgroup B infections. Comparison of long terminal repeat and env sequences revealed molecular genetic linkage of the viruses from the donor and recipient. CONCLUSION: This case is the first report of transfusion transmission of HTLV-I in the US military during combat operations. The emergency fresh whole blood policy enabled both the donor and the recipient to be notified of their HTLV-I infection. While difficult in combat, predonation screening of potential emergency blood donors with Food and Drug Administration-mandated infectious disease testing as stated by the DoD Health Affairs policy should be the goal of every facility engaged with emergency blood collection in theater. PMID- 23362945 TI - High hospital burden in overlap syndrome of asthma and COPD. AB - BACKGROUND: Overlap syndrome of asthma and chronic obstructive pulmonary disease (COPD) is a common condition, which is not well understood. This study describes the characteristics and hospital impact of patients suffering from this condition. METHODS: The data are comprised of the hospital discharge registry data maintained by National Institute for Health and Welfare [Terveyden ja hyvinvoinnin laitos (THL)] between 1972 and 2009 covering the entire Finnish population (5.35 million inhabitants in 2009). In THL, treatment periods for patients with the primary or secondary diagnosis of asthma or COPD were selected. From that data, patients over 34 years and their treatment periods starting and ending 2000-2009 with a principal or secondary diagnosis of asthma [International Classification of Diseases (ICD) 10: J45-J46] or COPD (ICD 10: J41-J44) were picked up. There were 105 122 such patients who had 343 420 treatment periods altogether. RESULTS: Patients with asthma were younger than patients with COPD and overlap syndrome, while COPD and overlap syndrome patients' age distribution was very similar. Patients with both asthma and COPD had 30.4% of all treatment periods, even though the percentage of all patients in this group was only 16.1%. These patients had an increased number of hospitalisation episodes across all age groups. Average number of treatment periods during 2000-2009 was 2.1 in asthma, 3.4 in COPD and 6.0 in overlap syndrome. Hospital impact of the same period in asthma was 939 900 days in COPD 1 517 308 and 1 000 724 days in overlap syndrome. CONCLUSION: Overlap syndrome of asthma and COPD is a common condition with high hospital impact for patients with this condition. PMID- 23362946 TI - Associations of the type of childcare with reported preventive medical and dental care utilization for 1- to 5-year-old children in the United States. AB - OBJECTIVE: Despite that the majority of US children use nonparental childcare (NPC), research examining its effects on children's preventive healthcare utilization is lacking. Our aim was to contrast NPC against parental childcare in terms of preventive medical and dental care utilization. METHODS: Associations of childcare and healthcare utilization were evaluated using the 2007 National Survey of Children's Health, a telephone interview of parent-reported children's health (22,773 children ages 1- to 5-year old). The type of childcare was categorized as parental care, center-based care (CBC), nonrelative home care (NRHC), relative care (RCC), and mixed care (MCC). The outcome measures were preventive medical care (>= 1 physical examination/well child check-up visit) and preventive dental care (>= 1 check-ups/dental cleanings visit) during the past 12 months. RESULTS: Overall, 94.7% of 1- to 5-year-old children received preventive medical care, while only 53.6% received preventive dental care. The highest odds for preventive medical care was for 1- to 2-year-old children utilizing CBC [Odds Ratio (OR) = 2.85, 95% CI = 1.11-7.30] and for 3- to 5-year-old children utilizing MCC (OR = 2.00, 95% CI = 1.23-3.26) followed by CBC (OR = 1.66, 95% CI = 1.13-2.42). Considering preventive dental care, a statistically significant increase occurred for 1- to 2-year-old children with CBC (OR = 1.93, 95% CI = 1.62-2.30), and none occurred for any NPC above the parental childcare rates for 3- to 5-year-old children. CONCLUSIONS: Childcare use, particularly center-based care, may provide a means to raise preventive healthcare utilization for young children. Future regulations, as well as policy and program development, should consider promoting childcare settings as a means to improve preventive health care utilization. PMID- 23362948 TI - Feasibility of a new self-expandable metallic stent for patients with malignant colorectal obstruction. AB - AIM: Stent migration due to peristalsis of the colon is one of the unresolved complications of colonic self-expandable metallic stent (SEMS) placement. Axial force (AF), a recovery force of the stent to a straight position after bending, has been considered a factor influencing the conformability of the digestive tract. An uncovered SEMS (Niti-S Enteral Colonic Uncovered Stent, D-type; Taewoong, Inc., Gimpo, South Korea) with improved conformability is considered to decrease migration. METHODS: Thirty three consecutive patients with symptomatic colorectal obstruction between March 2006 and December 2011 underwent endoscopic stent placement for palliation to estimate the efficacy and safety of Niti-S stents prospectively in four tertiary referral centers. RESULTS: Technical and clinical success rates were 100% and 97%, respectively. Seventeen patients had the following complications: ingrowth (n = 6), overgrowth (n = 1), collapse of the SEMS (n = 1), stool impaction (n = 2), migration (n = 1), bleeding (n = 3), and tenesmus (n = 3). The patient with migration had no recurrent symptoms until death. Of these 17 patients, 10 required re-interventions. Seven patients underwent an additional SEMS implantation. One patient underwent surgery for stoma creation. Two patients had stool impaction, and they underwent endoscopic cleaning. The median duration of patency was 347.0 +/- 65.5 days. The mean survival time after stent insertion was 240.1 +/- 39.9 days. CONCLUSION: The new SEMS effectively relieves malignant colorectal obstruction. Good conformability, according to the very low AF, may contribute to the low incidence of migration. PMID- 23362949 TI - Topical treatment with diclofenac, calcipotriol (vitamin-D3 analog) and difluoromethylornithine (DFMO) does not prevent nonmelanoma skin cancer in mice. AB - Nonmelanoma skin cancer is a common cancer type with increasing incidence. The purpose of this study was to evaluate topical application of diclofenac, calcipotriol, and difluoromethylornithine as chemoprevention in a mouse model of ultraviolet light-induced skin tumors, since these agents have been reported to have tumor inhibiting properties. One hundred twenty eight mice were treated with UVB radiation followed by chemoprevention or placebo. There were no significant effects of the treatments with respect to presence of skin tumors, number of tumors, tumor size, or survival. The investigated drugs were ineffective as chemoprevention in the dose regimens used in this study. PMID- 23362947 TI - 5-HT2A receptor antagonists inhibit hepatic stellate cell activation and facilitate apoptosis. AB - BACKGROUND: 5-hydroxytryptamine (5-HT) receptors are upregulated in activated hepatic stellate cells (HSCs), and are therefore thought to play an important role in their activation. AIM: The aim of this study was to determine whether 5 HT2A receptor antagonists affect the activation or apoptosis of HSCs in vitro and/or in vivo. METHODS: For the in vitro experiments, the viability, apoptosis and wound healing ability of LX-2 cells were examined after treatment with various 5-HT2A receptor antagonists. Levels of HSC activation markers (procollagen type I, alpha-SMA, TGF-beta and Smad 2/3) were measured. For in vivo experiments, rats were divided into three groups: (i) a control group, (ii) a disease group, in which cirrhosis was induced by thioacetamide (iii) a treatment group, in which cirrhosis was induced and a 5-HT2A receptor antagonist (sarpogrelate, 30 mg/kg) was administered. RESULTS: 5-HT2A , but not 5-HT2B receptor mRNA increased with time upon HSC activation. 5-HT2A receptor antagonists (ketanserin and sarpogrelate) inhibited viability and wound healing in LX-2 cells and induced apoptosis. Expression of alpha-SMA and procollagen type I was also inhibited. In the in vivo study, lobular inflammation was reduced in the sarpogrelate-treated group, but there was only slight and statistically insignificant attenuation of periportal fibrosis. Expression of alpha-SMA, TGF beta and Smad 2/3 was also reduced in the treatment group. CONCLUSIONS: 5-HT2A receptor antagonists can reduce inflammation and the activation of HSCs in this cirrhotic model. PMID- 23362950 TI - Bile acids affect the growth of human cholangiocarcinoma via NF-kB pathway. AB - We observed that free bile acids (CA, DCA, and CDCA) inhibited the growth of cholangiocarcinoma cells by promoting cell apoptosis, while the conjugated bile acids (GCA, GDCA, and GCDCA) stimulated cell growth. Consistently, we found that GDCA stimulated tumor growth and CDCA decreased tumor growth in xenografted mice. Further, the phosphorylated IkB was downregulated by free bile acids, and was upregulated by the conjugated bile acids. IL-6 and COX-2 were decreased by the free bile acids and increased by the conjugated bile acids. Collectively, these results suggest that the bile acids regulate the growth of cholangiocarcinoma by modulating NF-kB pathway. PMID- 23362951 TI - The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells. AB - PURPOSE: Severe treatment-related lymphopenia (TRL) occurs in 40% of patients with high grade gliomas (HGG) receiving glucocorticoids, temozolomide, and radiation. This occurs following radiation, persists for months, and is associated with reduced survival. As all three treatment modalities are lymphotoxic, this study was conducted to estimate the radiation dose that lymphocytes receive passing through the radiation field and if this could explain the observed TRL. MATERIALS AND METHODS: A typical glioblastoma plan (8-cm tumor, 60 Gy/30 fractions) was constructed using the PinnacleTM radiation planning system. Radiation doses to circulating cells (DCC) were analyzed using MatLabTM. The primary endpoints were mean DCC and percent of circulating cells receiving >=0.5 Gy. The model was also used to study how changes in target volumes (PTV), dose rates, and delivery techniques affect DCC. RESULTS: The modeling determined that while a single radiation fraction delivered 0.5 Gy to 5% of circulating cells, after 30 fractions 99% of circulating blood had received >=0.5 Gy. The mean DCC was 2.2 Gy and was similar for IMRT, 3D-conformal techniques, and different dose rates. Major changes in PTV size affected mean DCC and percent of circulating cells receiving >=0.5 Gy. CONCLUSIONS: Standard treatment plans for brain tumors deliver potentially lymphotoxic radiation doses to the entire circulating blood pool. Altering dose rates or delivery techniques are unlikely to significantly affect DCC by the end of treatment. Novel approaches are needed to limit radiation to circulating lymphocytes given the association of lymphopenia with poorer survival in patients with HGG. PMID- 23362952 TI - Lysophosphatidic acid aberrancies and hepatocellular carcinoma: studies in the MDR2 gene knockout mouse. AB - Studies show that lysophosphatidic acid (LPA) reprogramming is associated with the development of hepatocellular carcinoma (HCC). This manuscript evaluates the MDR2(-/-) model of HCC as a tool to examine the role of LPA reprogramming in the initiation/progression of HCC and identify novel treatment targets. Hepatic tumors developed in MDR2(-/-) mice between 9-12 m and serum LPA levels were greater in MDR2(-/-) when compared to controls. Blocking LPA biosynthesis/signaling significantly reduced tumor burden. LPA biosynthesis/signaling plays an important role in murine MDR2(-/-) model and is potentially linked to regulation of TNFalpha or other cytokines that are relevant to high-risk patients. PMID- 23362953 TI - Pharmacology 2.0. PMID- 23362954 TI - Comparing radiation toxicities across species: an examination of radiation effects in Mus musculus and Peromyscus leucopus. AB - PURPOSE: Life shortening and pathological complications in similarly irradiated cohorts of the laboratory mouse Mus musculus and the white-footed mouse Peromyscus leucopus were recorded in the course of the Janus studies conducted at Argonne National Laboratory from 1970-1992. This study examines how lifespan, tumor and non-tumor disease incidence, and tumor multiplicity are differentially affected by gamma-rays and neutron radiation exposure in two different animal species. MATERIALS AND METHODS: Survival analyses examined differences in lifespan across species, while decision tree analyses examined statistically significant associations between lifespan, radiation exposure, and specific diseases. Logistic regression models were generated to examine the likelihood of disease incidence in these two species following gamma-ray or neutron radiation exposure. RESULTS: Life shortening in response to radiation was more significant in Peromyscus leucopus than in Mus musculus, irrespective of radiation quality. Many types of tumor and non-tumor diseases were found to be consistently species specific. Tumor multiplicity was observed in both species in response to radiation, although more pronounced in Mus musculus. CONCLUSION: The response to radiation was highly species specific, highlighting the difficulty in extrapolating conclusions from one species to another, irrespective of their phenotypic similarities and ecologic niches. PMID- 23362955 TI - L-citrulline protects against glycerol-induced acute renal failure in rats. AB - There is an increasing evidence that oxidative stress plays an important role in the pathogenesis of rhabdomyolysis-induced acute renal failure (ARF). In this study, protective effects of L-citrulline on glycerol-induced ARF in rats were investigated. Six groups of rats were employed in this study: group 1 served as a control; group 2 was only given glycerol (50%, 10 mL/kg, i.m.); group 3 was given glycerol plus dexamethasone (0.1 mg/kg, i.g.) as positive reference drug, starting at the same time as the glycerol injections; the last three groups were given glycerol plus L-citrulline (300, 600, and 900 mg/kg, i.g.) respectively, starting at the same time as the glycerol injections. The injections of glycerol were only once, and after glycerol injections the i.g. administrations of dexamethasone and L-citrulline were repeated every 24 h for 7 days. After 7 days of glycerol injections, the blood samples and kidney tissues were harvested for future biochemical and pathology analyses. The levels of creatinine (Cr) and urea nitrogen (BUN) in plasma, the content of malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), the activity of total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS), endothelial NO synthase (eNOS), and superoxide dismutase (SOD) were evaluated in kidney tissues. Consequently, administrations of L-citrulline improved an impaired intrarenal oxygenation and kidney function compared with the glycerol group, and prevented the renal oxidative stress damage as well as severe functional and morphological renal deterioration. Therefore, L-citrulline might have potential application in the amelioration of glycerol-induced ARF. PMID- 23362956 TI - New alkylated benzoquinone from Iris nepalensis. AB - Chemical investigation of chloroform extract of rhizomes of Iris nepalensis yielded new alkylated 1,4-benzoquinone derivative (1). The structure of Compound 1 was established by analysis of spectroscopic data. Compound 1 was evaluated for cytotoxic activities against human cancer cell lines A549, HL-60, HCT116 and ZR 75. Compound 1 showed least cytotoxicity against HL-60, HCT116 and ZR-75-30. PMID- 23362957 TI - Cognitive-behavioural physical activity treatment in African-American pre schoolers: effects of age, sex, and BMI. AB - AIM: Prevalence of overweight and obesity in children of 5 years and younger has greatly increased in countries including Australia, Canada, the UK and the USA, with African-Americans most affected in the USA. Low amounts of physical activity may be a primary cause. Interventions intended to increase physical activity during pre-school have had minimal effects. METHODS: A physical activity intervention derived from self-efficacy and social cognitive theory administered by pre-school teachers in the USA (Start For Life) was contrasted with typical care over 8 weeks. The 30-min-per-day treatment incorporated structured gross motor skill physical activities and training in self-management and self regulation skills. The African-American children in the treatment (n = 154, 21 classrooms) and control (n = 121, 11 classrooms) groups ranged in age from 3.5 to 5.6 years. RESULTS: Mixed-model repeated measures analysis of variances indicated significantly (P <= 0.05) greater increases in moderate-to-vigorous physical activity (MVPA) and vigorous physical activity (VPA) in the treatment group when both the children and classrooms were the unit of analysis. Time in sedentary activities was not affected. Together, age, sex and body mass index (BMI) percentile significantly predicted treatment-related changes in MVPA (R(2) = 0.11) and VPA (R(2) = 0.11), with age (beta = -0.22 and beta = -0.23, respectively) and BMI percentile (beta = -0.24 and beta = -0.23, respectively) contributing uniquely to the explained variances indicating greater treatment effects for participants who were younger and had a lower BMI percentile. CONCLUSIONS: The Start For Life treatment was associated with increased MVPA by approximately 1 h per week, with most of that change being in VPA. After sufficient replication, adjustments may be made to maximise treatment effects. PMID- 23362958 TI - Clinical genetics in endoscopy: a two-question diagnosis in a patient with gastrointestinal angiodysplasia. PMID- 23362959 TI - Structure-activity relationship studies of pyrazolo[3,4-d]pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo. AB - We describe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4 d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea (1), which exhibits inhibitory activity but low potency against FLT3 and VEGFR2. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis using cell- and transgenic-zebrafish-based assays led to the discovery of a number of compounds that exhibited both high potency against FLT3-driven human acute myeloid leukemia (AML) MV4-11 cells and a considerable antiangiogenic effect in transgenic-zebrafish-based assays. The compound 1-(4-(1H pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3 (trifluoromethyl)phenyl)urea (33), which exhibited the highest activity in preliminary in vivo anti-AML assays, was chosen for further anti-AML studies. The results demonstrated that compound 33 is a multikinase inhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograft mouse model, a once-daily dose of compound 33 at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analyses were performed to determine the mechanism of action of compound 33. PMID- 23362960 TI - DNA origami nanopillars as standards for three-dimensional superresolution microscopy. AB - Nanopillars are promising nanostructures composed of various materials that bring new functionalities for applications ranging from photovoltaics to analytics. We developed DNA nanopillars with a height of 220 nm and a diameter of ~14 nm using the DNA origami technique. Modifying the base of the nanopillars with biotins allowed selective, upright, and rigid immobilization on solid substrates. With the help of site-selective dye labels, we visualized the structure and determined the orientation of the nanopillars by three-dimensional fluorescence superresolution microscopy. Because of their rigidity and nanometer-precise addressability, DNA origami nanopillars qualify as scaffold for the assembly of plasmonic devices as well as for three-dimensional superresolution standards. PMID- 23362961 TI - Emissions, fate and transport of persistent organic pollutants to the Arctic in a changing global climate. AB - Climate change is expected to alter patterns of human economic activity and the associated emissions of chemicals, and also to affect the transport and fate of persistent organic pollutants (POPs). Here, we use a global-scale multimedia chemical fate model to analyze and quantify the impact of climate change on emissions and fate of POPs, and their transport to the Arctic. First, climate change effects under the SRES-A2 scenario are illustrated using case-studies for two well-characterized POPs, PCB153, and alpha-HCH. Then, we model the combined impact of altered emission patterns and climatic conditions on environmental concentrations of potential future-use substances with a broad range of chemical properties. Starting from base-case generic emission scenarios, we postulate changes in emission patterns that may occur in response to climate change: enhanced usage of industrial chemicals in an ice-free Arctic, and intensified application of agrochemicals due to higher crop production and poleward expansion of potential arable land. We find both increases and decreases in concentrations of POP-like chemicals in the Arctic in the climate change scenario compared to the base-case climate. During the phase of ongoing primary emissions, modeled increases in Arctic contamination are up to a factor of 2 in air and water, and are driven mostly by changes in emission patterns. After phase-out, increases are up to a factor of 2 in air and 4 in water, and are mostly attributable to changes in transport and fate of chemicals under the climate change scenario. PMID- 23362964 TI - Predicting response to anti-TNF-alpha treatment in Hidradenitis suppurativa. PMID- 23362962 TI - Long-term tooth loss in periodontally compromised but treated patients according to the type of prosthodontic treatment. A retrospective study. AB - If prosthodontic treatment is considered after periodontal therapy, the questions arise i) does prosthodontic treatment affect the treatment outcome of the dentition in general and ii) which type of prosthesis is related to best treatment outcome of abutment teeth? Our goal was to compare long-term tooth loss after comprehensive periodontal therapy in patients with or without prosthodontic treatment. Ninety patients' charts with a total of 1937 teeth who had received comprehensive periodontal treatment 5-17 years ago by the same periodontist were retrospectively evaluated. Sixty-five patients received fixed dental prostheses (FDP; n = 29) and/or removable partial dentures anchored with clips (RPDC; n = 25) or double crowns (RPDD; n = 25). Twenty-five patients were also periodontally compromised but treated without prosthodontic treatment and served as a control group. A total of 317 teeth and 70 abutment teeth were lost during 9.7 +/- 4.1 years of observation. Thereof, 273 teeth and 48 abutment teeth were lost due to periodontal reasons. Mean tooth loss amounted to 1.2 +/- 1.5 (controls) and 4.4 +/- 3.4 (partial dentures). Abutment tooth loss was 0.4 +/- 1.1 (FDP), 1.0 +/- 1.2 (RPDC) and 1.3 +/- 1.0 (RPDD). Poisson regressions identified prosthodontic treatment, age, socio-economic status, diabetes mellitus, mean initial bone loss and aggressive periodontitis as factors significantly contributing to tooth loss. Age, diabetes and non-compliance contributed to abutment tooth loss. Not considering biomechanical factors, patients with prosthodontic reconstructions under long-term supportive periodontal therapy were at higher risk for further tooth loss than patients without prostheses. Not only the type of partial denture but also the patient-related risk factors were associated with abutment tooth loss. PMID- 23362965 TI - Atopic dermatitis, filaggrin mutations and irritant contact dermatitis. PMID- 23362966 TI - Atypical erythema multiforme is a prognostic indicator of severe hepatic dysfunction in Dress (Drug Reaction with Eosinophilia and Systemic Symptoms). PMID- 23362967 TI - The effects of pimecrolimus on the innate immune response in atopic dermatitis. PMID- 23362968 TI - Comparison of negative pressure wound therapy and secondary intention healing after excision of acral lentiginous melanoma on the foot. AB - BACKGROUND: Melanoma in dark-skinned individuals often develops in an acral lentiginous fashion on the foot and wide excision usually results in a substantial defect. Various repair methods, including free flap, full-thickness skin graft and secondary intention healing (SIH), are used to repair these defects. Recently, use of negative pressure wound treatment (NPWT) has been shown to accelerate wound healing in different types of wound. OBJECTIVES: To compare the functional and cosmetic results of NPWT and SIH in patients who underwent wide excision of melanomas on the foot. METHODS: The wound defects of 22 patients after wide excision of melanoma on the foot were treated using SIH (n = 13) or NPWT (n = 9). RESULTS: There was no significant difference in time to complete wound healing between the two groups. However, evaluation using the Vancouver Burn Scar Assessment Scale at the time of complete healing showed that the mean score of the NPWT group was significantly lower than that of the SIH group. The NPWT group also had significantly better results than the SIH group in terms of total score, vascularity and height of the scars. As for complications, no wound infection was encountered in the NPWT group, whereas eight of the 13 patients in SIH group had wound infections during the course of treatment despite frequent and meticulous aseptic dressing changes. CONCLUSIONS: These results show that, despite the drawback of rather prolonged healing time, NPWT is an excellent therapeutic option for wounds after wide excision of melanoma on the foot, with acceptable functional and cosmetic outcomes. PMID- 23362970 TI - Allergic rhinitis is often undiagnosed and untreated: results from a general population study of Danish adults. AB - INTRODUCTION: A few earlier studies have indicated that allergic rhinitis (AR) is underdiagnosed and undertreated. OBJECTIVE: To assess awareness, diagnosis and treatment of AR in a general population of Danish adults. METHODS: Between October 2007 and June 2008, a total of 1277 consecutive participants in a Danish general population study of 18- to 69-year olds were skin-prick-tested and asked about respiratory symptoms. AR was defined as a combination of self-reported rhinitis symptoms and skin-prick test reactivity against inhalant allergens. Participants reporting rhinitis symptoms completed an additional questionnaire on medication for rhinitis symptoms. RESULTS: The prevalence of AR was 23.1%. A total of 43.6% (n = 122/280) of persons with AR had not received any treatment in the previous 12 months, and only 56.6% (n = 163/288) had been given a diagnosis of hay fever by a doctor. Both AR and lower airway symptoms indicating more severe AR were reported in 48.5% (n = 143/295). These persons were significantly more likely to having received treatment in previous 12 months and a diagnosis of hay fever. CONCLUSION: Our results support that even in an affluent country like Denmark, AR is often undiagnosed and untreated. There appears to be a need for increased awareness of AR with regard to both diagnosis and treatment. PMID- 23362971 TI - Analysis of 136 pesticides in avocado using a modified QuEChERS method with LC MS/MS and GC-MS/MS. AB - A simple and high-throughput screening method for the analysis of 136 pesticides in avocado ( Persea americana ) by LC-(+)-ESI-MS/MS and GC-MS/MS is presented. A modified QuEChERS sample preparation method was developed to improve the extraction recovery of highly lipophilic pesticides. Extracts from minced avocados after acetonitrile (MeCN) extraction were directly injected to LC-MS/MS, whereas other GC-amenable compounds were treated with the modified QuEChERS procedure for GC-MS/MS analysis. The average recoveries for 79 pesticides quantified by LC-MS/MS at 10, 50, and 200 ng/g fortifying levels were 86.1% or better (with maximum RSD at 9.2%), whereas GC-MS/MS analysis demonstrated 70.2% or better (RSD < 18%) for average recovery from 57 compounds at the same spike levels. The application of LC- and GC-MS/MS combined with the improved extraction procedures led to the current method, which can quantitate these pesticides even if they are present in avocados below the targeted action level by FDA. This method demonstrated the improved recovery of several challenging lipophilic pesticides in highly fat-rich avocados. PMID- 23362969 TI - Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen finding study. AB - BACKGROUND: Interleukin (IL)-17A has major proinflammatory activity in psoriatic lesional skin. OBJECTIVES: To assess the efficacy and safety of secukinumab, a fully human IgG1kappa monoclonal anti-IL-17A antibody, in moderate-to-severe plaque psoriasis in a phase II regimen-finding study. METHODS: A total of 404 patients were randomized to subcutaneous placebo (n = 67) or one of three secukinumab 150 mg induction regimens: single (week 0; n = 66), early (weeks 0, 1, 2, 4; n = 133) and monthly (weeks 0, 4, 8; n = 138 patients). The primary outcome was >= 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75) at week 12. PASI 75 responders from active treatment arms at week 12 were rerandomized to either a fixed-interval (secukinumab 150 mg at weeks 12 and 24; n = 65) or a treatment-at-start-of-relapse maintenance regimen (secukinumab 150 mg at visits at which a start of relapse was observed; n = 67). RESULTS: At week 12, early and monthly induction regimens resulted in higher PASI 75 response rates vs. placebo (54.5% and 42.0% vs. 1.5%; P < 0.001 for both). Among PASI 75 responders at week 12 entering the maintenance period, PASI 75 and PASI 90 achievement at least once from week 20 to week 28 was superior with the fixed-interval regimen [85% (n = 55) and 58% (n = 38), respectively] vs. the start-of-relapse regimen [67% (n = 45), P = 0.020, and 21% (n = 14), respectively]. Fifteen weeks after last study drug administration, < 10% of patients in the fixed-interval and start-of-relapse groups experienced a start of relapse. No immunogenicity was observed, and no injection-site reactions were reported. Reported cases of neutropenia were mild-to-moderate (<= grade 2); none was associated with clinically significant adverse events or resulted in study discontinuation. Due to the brief duration of the safety assessment, no firm conclusions can be drawn regarding long-term safety. CONCLUSIONS: Secukinumab shows efficacy for induction and maintenance treatment of moderate-to-severe plaque psoriasis. PMID- 23362974 TI - The relative influence of team climate, team norms and social network norms on health professionals' implementation of a national recommendation to offer service-users diagnosed with schizophrenia family intervention therapy. AB - Social influence is an important variable influencing health professionals' adoption of clinical recommendations. Different theories conceptualise social influence in different ways. This study operationalised three different forms of social influence--team climate, team norms (descriptive and injunctive) and social network norms (descriptive and injunctive), and compared their ability to predict mental health professionals' self-reported intention to adopt a national, clinical recommendation. A cross-sectional survey was developed, measuring the constructs in relation to intention to offer service-users family an intervention therapy, as part of a larger, theory-based implementation study. The survey was administered to all mental health professionals in one mental health trust. Using multiple regression, descriptive network norms were found to be the only significant predictor of intention. This suggests that behaviour change interventions in this context may benefit from promoting descriptive network norms, for example, emphasising the adoption behaviour of influential peers. Given the high degree of overlap found between network and team members in this study, and the potential challenges of targeting behaviour-change interventions at informal, more difficult to identify networks, future research is needed to evaluate the feasibility of targeting behaviour-change interventions at social networks compared with formal teams. PMID- 23362972 TI - Hydroxyl ion addition to one-electron oxidized thymine: unimolecular interconversion of C5 to C6 OH-adducts. AB - In this work, addition of OH(-) to one-electron oxidized thymidine (dThd) and thymine nucleotides in basic aqueous glasses is investigated. At pHs ca. 9-10 where the thymine base is largely deprotonated at N3, one-electron oxidation of the thymine base by Cl(2)(*-) at ca. 155 K results in formation of a neutral thyminyl radical, T(-H).. Assignment to T(-H). is confirmed by employing (15)N substituted 5'-TMP. At pH >= ca. 11.5, formation of the 5-hydroxythymin-6-yl radical, T(5OH)., is identified as a metastable intermediate produced by OH(-) addition to T(-H). at C5 at ca. 155 K. Upon further annealing to ca. 170 K, T(5OH). readily converts to the 6-hydroxythymin-5-yl radical, T(6OH).. One electron oxidation of N3-methyl-thymidine (N3-Me-dThd) by Cl(2)(*-) at ca. 155 K produces the cation radical (N3-Me-dThd(*+)) for which we find a pH dependent competition between deprotonation from the methyl group at C5 and addition of OH( ) to C5. At pH 7, the 5-methyl deprotonated species is found; however, at pH ca. 9, N3-Me-dThd(*+) produces T(5OH). that on annealing up to 180 K forms T(6OH).. Through use of deuterium substitution at C5' and on the thymine base, that is, specifically employing [5',5"-D,D]-5'-dThd, [5',5"-D,D]-5'-TMP, [CD(3)]-dThd and [CD(3),6D]-dThd, we find unequivocal evidence for T(5OH). formation and its conversion to T(6OH).. The addition of OH(-) to the C5 position in T(-H). and N3 Me-dThd(*+) is governed by spin and charge localization. DFT calculations predict that the conversion of the "reducing" T(5OH). to the "oxidizing" T(6OH). occurs by a unimolecular OH group transfer from C5 to C6 in the thymine base. The T(5OH). to T(6OH). conversion is found to occur more readily for deprotonated dThd and its nucleotides than for N3-Me-dThd. In agreement, calculations predict that the deprotonated thymine base has a lower energy barrier (ca. 6 kcal/mol) for OH transfer than its corresponding N3-protonated thymine base (14 kcal/mol). PMID- 23362973 TI - Presumptive central nervous system cuterebriasis and concurrent protein-losing nephropathy in a dog. AB - OBJECTIVE: To describe the clinical course and successful management of a dog suspected to have central nervous system (CNS) Cuterebra larval migration and concurrent protein-losing nephropathy (PLN). CASE SUMMARY: A 1-year-old castrated male mixed breed dog was diagnosed with presumptive CNS cuterebriasis based on history, progressively deteriorating mentation, seizures, and magnetic resonance images showing a tubular lesion consistent with a migrating Cuterebra tract. Additionally, serum biochemistry and urine analyses revealed the development of a severe PLN. Surgical removal of the Cuterebra was attempted unsuccessfully, and subsequently, the dog was treated with ivermectin, antihistamines, anticonvulsants, and a tapering dose of glucocorticoids. Over several weeks the dog's neurologic status improved and the PLN resolved completely. NEW OR UNIQUE INFORMATION PROVIDED: This case describes successful management of presumptive CNS cuterebriasis in a dog. It is also, to our knowledge, the first report of PLN associated with cuterebriasis in the veterinary literature. PMID- 23362975 TI - Expression of c-Jun and Sox-2 in human schwannomas and traumatic neuromas. AB - AIMS: Schwann cells myelinate axons of the peripheral nervous system. This process of myelination is regulated by various transcription factors. c-Jun and Sox-2 are negative regulators of myelination and control Schwann cell differentiation and plasticity. Schwannoma cells within tumours no longer express myelin markers, and show increased proliferation and decreased apoptosis. We have shown previously that several signalling pathways are activated in schwannoma cells in situ, in particular the c-Jun N-terminal kinase (JNK) pathway. Both in vitro and in vivo we have demonstrated that c-Jun and Sox-2 are co-regulated in Schwann cells and evidence shows that both these proteins regulate myelination negatively. In this study, we aimed to characterize the expression of c-Jun and Sox-2 in schwannoma and traumatic neuroma. METHODS AND RESULTS: Immunohistochemistry using antibodies to c-Jun and Sox-2 was applied to six schwannomas, and the results were compared with those seen in traumatic neuroma and normal nerve. Increased expression of c-Jun and Sox-2 was seen in schwannoma. CONCLUSIONS: We have demonstrated increased expression of c-Jun and Sox-2 in schwannoma compared to traumatic neuroma. There was no expression of c-Jun and Sox-2 in a histologically normal peripheral nerve. PMID- 23362976 TI - Intermittent access ethanol consumption dysregulates CRF function in the hypothalamus and is attenuated by the CRF-R1 antagonist, CP-376395. AB - Corticotrophin-releasing factor (CRF) is a mediator of stress responses and a key modulator of ethanol-mediated behaviors. We report here that the CRF receptor 1 (CRF-R1) antagonist, CP-376395 reduces 20% ethanol consumption in animals trained to consume ethanol on an intermittent, but not a continuous, schedule. Furthermore, using [(35) S]GTPgammaS binding assays, we demonstrate that CRF mediated G-protein signaling in the hypothalamus of the intermittent drinkers is decreased when compared to controls suggesting that the effects of CP-376395 are mediated by extrahypothalamic mechanisms. The present study provides further support for the use of CRF-R1 antagonists for the treatment of alcohol use disorders and suggests that ethanol consumption dysregulates CRF function in the hypothalamus. PMID- 23362977 TI - Efficacy of cryospray ablation for the treatment of chronic radiation proctitis in a pilot study. AB - AIM: Radiation proctitis, a common condition associated with radiotherapy for the treatment of pelvic cancers, is characterized by difficult to manage rectal pain and bleeding. Cryotherapy is a novel technique, previously used in the treatment of vascular ectasias in the upper gastrointestinal tract. The aim of the present study was to determine the efficacy of cryospray application in the treatment of radiation proctitis. METHODS: This is a prospective case-series pilot study. Ten patients with symptomatic chronic radiation proctitis were consecutively enrolled over a 2-year period. Baseline clinical data were collected and an endoscopic score was calculated based on the density of ectasias and circumferential involvement. Subjects underwent up to four cryospray ablation treatment sessions at approximately 4-week intervals or until resolution of the proctitis. The endpoints of the study were endoscopic and clinical improvement in radiation proctitis. RESULTS: Ten patients (nine males and one female) with a mean age of 74 +/- 7 years underwent cryospray treatment; sessions ranged from one to four (six patients had one session, three patients had two sessions, and one patient underwent four sessions). Endoscopic score significantly decreased from a mean of 10.2 +/- 3.0 to 4.0 +/- 2.8 (P = 0.016). Rectal pain significantly decreased from a mean of 3.1 +/- 3.0 to 1.2 +/- 1.7 (P = 0.042) and rectal bleeding improved in 86% (six out of seven) of patients. Nine patients reported improvement in overall well-being. No major complications were encountered. CONCLUSIONS: Cryotherapy is an effective method in the management of chronic radiation proctitis with minimal complications. PMID- 23362978 TI - Uremia and thrombotic microangiopathy: conditions that may havethe same manifestation. AB - In this article, we present the case of a man with uremia. Laboratory testing revealed thrombocytopenia, erythrocyte fragmentation, elevated lactate dehydrogenase, and malignant hypertension, manifestations that are similar to thrombotic microangiopathy (TMA). Thromboasthenia, manifested as a decrease in the platelet aggregation rate, was also noted. Regular hemodialysis (3 times per week) improved the patient's thrombocytopenia and thromboasthenia. This case supports the conclusion that uremic toxin, which can be removed by hemodialysis, inhibits the quantity and quality of platelets. We believe that the platelet aggregation rate can be a useful tool in distinguishing uremia from TMA. PMID- 23362980 TI - The evolving role of plerixafor in hematopoietic progenitor cell mobilization. AB - The introduction of plerixafor as a peripheral blood stem cell mobilization agent has allowed more patients with multiple myeloma, non-Hodgkin's lymphoma, and Hodgkin's disease to mobilize sufficient hematopoietic progenitor cells (HPCs) to proceed to autologous transplantation. Because of the high cost of plerixafor, it is not routinely used in all patients undergoing HPC mobilization. If cost were not an issue, an argument could be made that plerixafor could be added to every mobilization regimen, but cost is an issue so in an attempt to be more cost effective, many centers have limited plerixafor use to patients who have failed or who are predicted to fail collection of adequate numbers of cells by other methods. Additionally, plerixafor is now under investigation both for HPC collection of healthy donors for allogeneic stem cell transplantation and as an adjunct therapy (i.e., chemosensitizing agent) for acute leukemias. This article briefly reviews the role of plerixafor in autologous and allogeneic transplantation as well as its emerging role in the treatment of acute leukemias. Emphasis is placed on the choice of appropriate patients for plerixafor use to assure an adequate stem cell yield while maximizing the cost effectiveness of using plerixafor. The role of prophylactic collections and future areas of research are also presented. PMID- 23362982 TI - Attitude of German women towards hormone therapy: results of a lay survey. AB - OBJECTIVE: Hormone therapy (HT) use has experienced a substantial change since publication of Women's Health Initiative (WHI) controlled trial. We aimed to investigate the attitude towards HT in German women aged 45-60 years. STUDY DESIGN: A questionnaire was sent to 9785 randomly selected women in Germany aged between 45 and 60 years. RESULTS: Response rate was 19.3% (n = 1,893). Of those, 81% experienced climacteric symptoms. Vasomotor symptoms were most frequently reported (71.2%; n = 1332). Of the respondents, 19.7% (n = 369) used HT. The most frequently mentioned benefits of HT were the improvement of climacteric complaints (71.2%; n = 1346), followed by the relief of osteoporosis (37.2%; n = 697) and the "anti-aging" effect (16.3%; n = 305). Breast cancer was stated as the main risk (64.9%; n = 1215), closely followed by weight gain (53.4%; n = 1000) and thromboembolism (48%; n = 898). About 44% of the women who has been advised by gynaecologists choose a HT, whereas this rate dropped down to 14.3% and 11.3% for women who have been advised by friends or media. CONCLUSION: German women were generally aware of the main risks and benefits of HT. "More informed" women appear to be more likely to use HT compared to "less informed" women. The media produces negative impression of HT. PMID- 23362981 TI - Enhanced cellular radiosensitivity induced by cofilin-1 over-expression is associated with reduced DNA repair capacity. AB - PURPOSE: A previous report has indicated that over-expression of cofilin-1 (CFL 1), a member of the actin depolymerizing factor (ADF)/cofilin protein family, enhances cellular radiosensitivity. This study explores the involvement of various DNA damage responses and repair systems in the enhanced cellular radiosensitivity as well as assessing the role of CFL-1 phosphorylation in radiosensitivity. MATERIALS AND METHODS: Human non-small lung cancer H1299 cells harboring a tet-on gene expression system were used to induce exogenous expression of wild-type CFL-1. Colony formation assays were used to determine cell survival after gamma-ray exposure. DNA damage levels were determined by Comet assay. DNA repair capacity was assessed by fluorescence-based DNA repair analysis and antibody detection of various repair proteins. The effects of CFL-1 phosphorylation on radiation responses were explored using two mutant CFL-1 proteins, S3D and S3A. Finally, endogenous CFL-1 phosphorylation levels were investigated using latrunculin A (LA), cytochalasin B (CB) and Y27632. RESULTS: When phosphorylatable CFL-1 was expressed, radiosensitivity was enhanced after exposure to gamma-rays and this was accompanied by DNA damage. Phosphorylated histone H2AX (gamma-H2AX) and p53-binding protein-1 (53BP1) foci, as well as Chk1/2 phosphorylation, were apparently suppressed, although ataxia telangiectasia mutated (ATM) kinase activation was apparently unaffected. In addition, two radiation-induced double-strand break (DSB) repair systems, namely homologous recombination repair (HRR) and non-homologous end joining (NHEJ), were suppressed. Moreover, over-expression of CFL-1 S3D and CFL-1 S3A both enhanced radiosensitivity. However, enhanced radiosensitivity and reduced gamma-H2AX expression were only detected in cells treated with LA which increased endogenous phospho-CFL-1, and not in cells treated with Y27632, which dephosphorylates CFL 1. CONCLUSION: CFL-1 over-expression enhances radiosensitivity and this is associated with reduced DNA repair capacity. Although phosphorylated CFL-1 seems to be involved in radiosensitivity, further studies are required to address the importance of CFL-1 activity to the regulation of radiosensitivity. PMID- 23362983 TI - A soluble bis-chelated gold(I) diphosphine compound with strong anticancer activity and low toxicity. AB - Gold-containing compounds have shown anticancer potential, but their clinical applications have been severely limited by poor stability and high toxicity in vivo. Here, we report a novel soluble bis-chelated gold(I)-diphosphine compound (GC20) with strong anticancer activity and low toxicity. GC20 shows strong antiproliferation potency against a broad spectrum of cancer cell lines including cisplatin-resistant cancer cells (IC50 ~ 0.5 MUM) and significantly reduces tumor growth in several tumor xenografts in mouse models at doses as low as 2 mg/kg. Studies of its mechanism revealed that GC20 specifically inhibits the enzymatic activity of thioredoxin reductase by binding to selenocysteine residue, without targeting other well-known selenol and thiol groups contained in biomolecules. Remarkably, in animal studies GC20 was shown to be well tolerated even at the high dose of 8 mg/kg. Our results strongly suggest that GC20 represents a promising candidate for the development of novel anticancer drugs. PMID- 23362984 TI - The synthetic progestin levonorgestrel is a potent androgen in the three-spined stickleback (Gasterosteus aculeatus). AB - The use of progestins has resulted in contamination of aquatic environments and some progestins have in experimental studies been shown to impair reproduction in fish and amphibians at low ng L(-1) concentrations. The mechanisms underlying their reproductive toxicity are largely unknown. Some progestins, such as levonorgestrel (LNG), exert androgenic effects in mammals by activating the androgen receptor (AR). Male three-spined stickleback (Gasterosteus aculeatus) kidneys produce spiggin, a gluelike glycoprotein used in nest building, and its production is directly governed by androgens. Spiggin is normally absent in females but its production in female kidneys can be induced by AR agonists. Spiggin serves as the best known biomarker for androgens in fish. We exposed adult female sticklebacks to LNG at 5.5, 40, and 358 ng L(-1) for 21 days. Androgenic effects were found at LNG concentrations >=40 ng L(-1) including induction of spiggin transcription, kidney hypertrophy, and suppressed liver vitellogenin transcription. These are the first in vivo quantitative data showing that LNG is a potent androgen in fish supporting the contention that androgenic effects of certain progestins contribute to their reproductive toxicity. PMID- 23362986 TI - Aborted sudden cardiac death due to radiofrequency ablation within the coronary sinus and subsequent total occlusion of the circumflex artery. AB - We report a case of aborted sudden cardiac death and subsequent development of malignant drug-refractory incessant ventricular tachycardia/fibrillation in a patient with acute coronary artery occlusion following radiofrequency ablation within the CS. Catheter ablation is a well-established therapy for treatment of atrial fibrillation (AF). In patients with longstanding persistent AF extensive left atrial ablation and ablation inside the coronary sinus (CS) is frequently performed. Perimitral flutter following AF ablation is the most common form of left atrial macroreentry, especially in patients with previous ablation of complex fractionated electrograms and incomplete linear lesion sets within the left atrium. Successful ablation of this type of tachycardia is generally difficult and in about 60-70% patients requires additional ablation within the CS to achieve termination of tachycardia or/and left atrial isthmus (LAI) block. A limited number of case reports have been published describing acute coronary artery occlusion during or immediately after LAI ablation within the CS. This case exhibits a potential lethal risk of radiofrequency ablation within the CS. PMID- 23362987 TI - Primary clear cell adenocarcinoma arising from rectal endometriosis. PMID- 23362985 TI - Catalytic asymmetric synthesis of cyclic sulfamides from conjugated dienes. AB - This paper describes the catalytic asymmetric diamination of alkyl dienes using N,N'-di-tert-butylthiadiaziridine 1,1-dioxide in the presence of Pd(0) and a chiral phosphoramidite ligand to give cyclic sulfamides in high yield and high ee. The diamination is also amenable to gram scale. PMID- 23362988 TI - Transportin 1 accumulates in FUS inclusions in adult-onset ALS without FUS mutation. PMID- 23362989 TI - Volume estimation in dialysis patients: the concordance of brain-type natriuretic peptide measurements and bioimpedance values. AB - Correct estimation of the dialysis patients' hydration status remains an important clinical challenge. Bioimpedance measurements have been validated by various physiological tests, and the use of brain-type natriuretic peptide (BNP) has been validated by inferior vena cava diameter measurements. This is an observational cohort study that evaluated the correspondence between bioimpedance measured overhydration percentage (OH%) and BNP. We measured predialysis OH% by bioimpedance apparatus (Body Composition Monitor) and BNP by microparticle enzyme linked immunoassay in 41 prevalent stable hemodialysis patients, 19 (46%) women, aged 58.9 +/- 14.5 years. The cohort's average BNP was 2694 +/- 3278 pg/mL and 10 (24.4%) of these 41 patients had BNP < 500 pg/mL (average 260.7 +/- 108.5). The OH% was 8.5 +/- 7.0% among those with a BNP < 500 pg/mL, while the rest of the population had an OH% of 21.4 +/- 8.0%, corresponding to excess volumes of 1.6 +/ 1.3 and 4.4 +/- 3.8 L, respectively. The OH% vs. BNP relationship was best described by the exponential regression of y = 216.4e(0.097x) , predicting a BNP of 216.4 pg/mL at 0% overhydration status (r 0.61). Receiver-operating curves revealed an area under the curve of 0.885 for BNP when the OH% was set >=15% of overhydration and an area under the curve of 0.918 for OH% when the BNP was set >=500 pg/mL for being abnormal. We conclude that in our cohort there was a high degree of correspondence between these two tests with an exponential relationship between the measurements. PMID- 23362990 TI - Direct evidence of memory retrieval as a source of difficulty in non-local dependencies in language. AB - Linguistic dependencies between non-adjacent words have been shown to cause comprehension difficulty, compared with local dependencies. According to one class of sentence comprehension accounts, non-local dependencies are difficult because they require the retrieval of the first dependent from memory when the second dependent is encountered. According to these memory-based accounts, making the first dependent accessible at the time when the second dependent is encountered should help alleviate the difficulty associated with the processing of non-local dependencies. In a dual-task paradigm, participants read sentences that did or did not contain a non-local dependency (i.e., object- and subject extracted cleft constructions) while simultaneously remembering a word. The memory task was aimed at making the word held in memory accessible throughout the sentence. In an object-extracted cleft (e.g., It was Ellen whom John consulted...), the object (Ellen) must be retrieved from memory when consulted is encountered. In the critical manipulation, the memory word was identical to the verb's object (ELLEN). In these conditions, the extraction effect was reduced in the comprehension accuracy data and eliminated in the reading time data. These results add to the body of evidence supporting memory-based accounts of syntactic complexity. PMID- 23362991 TI - Psychotherapeutic intervention in somatisation disorder: results of a controlled study from India. AB - Somatisation disorder is a chronic condition often associated with poor response to treatment, troublesome symptoms, distress, disability and burden. Psychosocial interventions have an important role to play in treatment. However, there is a lack of controlled studies especially from the non-western world. The present study assessed the efficacy of non-pharmacological interventions in somatisation disorder using a case control design. Fifteen patients each diagnosed as somatisation disorder as per ICD DCR criteria received six sessions of a specific psychological intervention (designed specifically for the study) or a non specific psychological intervention along with fluoxetine. The subjects were followed up for 8 weeks. Assessments were carried out at 0, 4 and 8 weeks using structured measures. Mean age of the sample was 33 +/- 7.11 years. Both the groups suffered moderate level of depression, anxiety and disability, and high neuroticism and subjective distress as measured on different instruments. A significant improvement was observed in both the groups in all the measures following the intervention. The group receiving the specific interventions showed more improvement. The study concludes that both specific as well as non specific psychotherapeutic interventions can bring substantial improvement in patients with somatisation disorder, with more improvement seen with specific psychotherapeutic interventions. PMID- 23362993 TI - Steady-state catalytic wave-shapes for 2-electron reversible electrocatalysts and enzymes. AB - Using direct electrochemistry to learn about the mechanism of electrocatalysts and redox enzymes requires that kinetic models be developed. Here we thoroughly discuss the interpretation of electrochemical signals obtained with adsorbed enzymes and molecular catalysts that can reversibly convert their substrate and product. We derive analytical relations between electrochemical observables (overpotentials for catalysis in each direction, positions, and magnitudes of the features of the catalytic wave) and the characteristics of the catalytic cycle (redox properties of the catalytic intermediates, kinetics of intramolecular and interfacial electron transfer, etc.). We discuss whether or not the position of the wave is determined by the redox potential of a redox relay when intramolecular electron transfer is slow. We demonstrate that there is no simple relation between the reduction potential of the active site and the catalytic bias of the enzyme, defined as the ratio of the oxidative and reductive limiting currents; this explains the recent experimental observation that the catalytic bias of NiFe hydrogenase depends on steps of the catalytic cycle that occur far from the active site [Abou Hamdan et al., J. Am. Chem. Soc. 2012, 134, 8368]. On the experimental side, we examine which models can best describe original data obtained with various NiFe and FeFe hydrogenases, and we illustrate how the presence of an intramolecular electron transfer chain affects the voltammetry by comparing the data obtained with the FeFe hydrogenases from Chlamydomonas reinhardtii and Clostridium acetobutylicum, only one of which has a chain of redox relays. The considerations herein will help the interpretation of electrochemical data previously obtained with various other bidirectional oxidoreductases, and, possibly, synthetic inorganic catalysts. PMID- 23362994 TI - Measurements of human herpesvirus 8 viral load in blood before and after leukoreduction filtration. AB - BACKGROUND: Human herpesvirus 8 (HHV-8) is likely transmitted through blood transfusion in high-prevalence areas. The efficacy of leukoreduction filtration for reducing HHV-8 in blood has not been reported. STUDY DESIGN AND METHODS: Blood was drawn from 45 human immunodeficiency virus-positive men either with Kaposi's sarcoma (KS; n=21) or without KS (n=24) and subject to leukoreduction filtration. HHV-8 viral load was measured in plasma and in blood before and after filtration. RESULTS: Twelve subjects, all with KS, had detectable HHV-8 viremia before filtration with viral loads of 10(2) to 10(5) copies/mL (mean, 3 * 10(4) copies/mL). After filtration, seven of 12 subjects no longer had detectable HHV-8 in their blood, and five of 12 subjects had detectable HHV-8 that was 90% reduced on average from prefiltration levels. The presence of HHV-8 in the blood after filtration was strongly associated with prefiltration viral loads greater than 1000 copies/mL and the presence of cell-free virus in plasma. None of the subjects without KS had detectable levels of HHV-8 virus in blood before or after filtration. CONCLUSION: Cell-associated HHV-8 appeared to be effectively removed by leukoreduction filtration. Cell-free HHV-8 was present in 42% of subjects as 1% to 20% of the total virus which was not removed by filtration. PMID- 23362992 TI - Identification of flavone glucuronide isomers by metal complexation and tandem mass spectrometry: regioselectivity of uridine 5'-diphosphate glucuronosyltransferase isozymes in the biotransformation of flavones. AB - Flavone glucuronide isomers of five flavones (chrysin, apigenin, luteolin, baicalein, and scutellarein) were differentiated by collision-induced dissociation of [Co(II) (flavone-H) (4,7-diphenyl-1,10-phenanthroline)(2)](+) complexes. The complexes were generated via postcolumn addition of a metal-ligand solution after separation of the glucuronide products generated upon incubation of each flavone with an array of uridine 5'-diphosphate (UDP) glucuronosyltransferase (UGT) isozymes. Elucidation of the glucuronide isomers allowed a systematic investigation of the regioselectivity of 12 human UGT isozymes, including 8 UGT1A and 4 UGT2B isozymes. Glucuronidation of the 7-OH position was the preferred site for all the flavones except for luteolin, which possessed adjacent hydroxyl groups on the B ring. For all flavones and UGT isozymes, glucuronidation of the 5-OH position was never observed. As confirmed by the metal complexation/MS/MS strategy, glucuronidation of the 6-OH position only occurred for baicalein and scutellarein when incubated with three of the UGT isozymes. PMID- 23362996 TI - DNA-dependent protein kinase and its inhibition in support of radiotherapy. AB - PURPOSE: Radiotherapy has been used as a treatment of almost 50% of all malignant tumors. The aim of this review is to provide a comprehensive overview of the recent knowledge in the field of molecular mechanisms of radiation-induced double stranded breaks (DSB) repair. This paper gives particular emphasis to a key DNA repair enzyme, DNA-dependent protein kinase (DNA-PK), which plays a pivotal role in non-homologous end-joining. Furthermore, we discuss possibilities of DNA-PK inhibition and other molecular approaches employed in order to facilitate radiotherapy. CONCLUSIONS: We have reviewed the recent studies using novel potent and selective small-molecular DNA-PK inhibitors and we conclude that targeted inhibition of DNA repair proteins like DNA-PK in cancer cells, in combination with ionizing radiation, improves the efficacy of cancer therapy while minimizing side-effects of ionizing radiation. Moreover, the recent discovery of short interfering RNA (siRNA) and signal interfering DNA (siDNA)-based therapeutics, or small peptides and RNA, shows a new opportunity of selective and safe application of biological treatment. All of these approaches are believed to contribute to more personalized anti-cancer therapy. PMID- 23362995 TI - Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence. AB - Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared with family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we examined the aggregate impact of multiple single nucleotide polymorphisms (SNPs) on risk prediction. We created genetic sum scores by adding risk alleles associated in discovery samples, and then tested the scores for their ability to discriminate between cases and controls in validation samples. Genetic sum scores were assessed separately for SNPs associated with AD in candidate gene studies and SNPs from GWAS analyses that met varying P-value thresholds. Candidate gene sum scores did not exhibit significant predictive accuracy. Family history was a better classifier of case-control status, with a significant area under the receiver operating characteristic curve (AUC) of 0.686 in COGA and 0.614 in SAGE. SNPs that met less stringent P-value thresholds of 0.01-0.50 in GWAS analyses yielded significant AUC estimates, ranging from mean estimates of 0.549 for SNPs with P < 0.01 to 0.565 for SNPs with P < 0.50. This study suggests that SNPs currently have limited clinical utility, but there is potential for enhanced predictive ability with better understanding of the large number of variants that might contribute to risk. PMID- 23362998 TI - Hydrogen ion (H+) in waste acid as a driver for environmentally sustainable processes: opportunities and challenges. AB - Acid-base neutralization reaction in the aqueous phase is thermodynamically favorable and kinetically fast. Waste acid neutralization is also the most common waste management practice globally. However, waste acid neutralization is yet to be used for any work/energy generation because of the low concentrations of the waste acid and the high heat capacity of aqueous solutions. In this paper, we address potential processes that can effectively take advantage of the high energy inherent in neutralization reactions, in accordance with the goal of sustainable development. PMID- 23362997 TI - Endoscopic diagnosis of gastric mucosal activity and inflammation. AB - AIM: Gastritis is an important pathological state that causes gastric atrophy and cancer. The Sydney System is a well-used classification for histological evaluation for gastritis. However, there is no concordance with endoscopic findings. In the present study, we tried to establish endoscopic criteria and diagnosis for the inflammation activity of gastric mucosa. METHODS: A prospective multicenter study was conducted and 24 facilities participated. Two hundred and seventy patients received endoscopic examinations and 15 endoscopic features were evaluated. Biopsy specimens were taken from five points, and evaluated by a single pathologist for mononuclear cell infiltration and polymorphonuclear cell infiltration. Sensitivity, specificity, positive predictive value, negative predictive value, area under curve of receiver operating characteristics (AUC/ROC) of each endoscopic finding to histological gastritis were calculated. RESULTS: There was no single endoscopic finding that was highly specific for mononuclear cell infiltration and polymorphonuclear cell infiltration. In the corpus, the combination of swelling of areae gastrica by the indigo carmine contrast method (IC method) and lack of a regular arrangement of collecting venules (RAC) in angle for mononuclear cell infiltration (0.887), and the combination of swelling of areae gastrica by the IC method and diffuse redness for polymorphonuclear cell infiltration (0.851) showed the highest AUC/ROC. In the antrum, the combination of diffuse redness and visibility of a vascular pattern for mononuclear cell infiltration (0.780), and the combination of visibility of vascular pattern and swelling of areae gastrica by the IC method for polymorphonuclear cell infiltration (0.795) showed the highest AUC/ROC. CONCLUSION: Combination of endoscopic findings can improve diagnostic accuracy, and sensitivity of examination for inflammation. PMID- 23362999 TI - Development of a peptide antagonist against fsr quorum sensing of Enterococcus faecalis. AB - Enterococcus faecalis fsr quorum sensing (QS) involves an 11-residue cyclic peptide named gelatinase biosynthesis-activating pheromone (GBAP) that autoinduces two pathogenicity-related extracellular proteases in a cell density dependent fashion. To identify anti-pathogenic agents that target fsr QS signaling, peptide antagonists of GBAP were created by our unique drug design approach based on reverse alanine scanning. First of all, a receptor-binding scaffold (RBS), [Ala(4,5,6,8,9,11)]Z-GBAP, was created, in which all amino acids within the ring region of GBAP, except for two essential aromatic residues, were substituted to alanine. Next, the substituted alanine residues were changed back to the original amino acid one by one, permitting selection of those peptide combinations exhibiting increased antagonist activity. After three cycles of this reverse alanine scan, [Ala(5,9,11)]Z-GBAP was obtained as a maximally reverted peptide (MRP) holding the strongest antagonist activity. Then, the fifth residue in MRP, which is one of the critical residues to determine agonist/antagonist activity, was further modified by substituting with different types of amino acids including unnatural amino acids. As a result, [Tyr(Bzl)(5), Ala(9,11)]Z GBAP, named ZBzl-YAA5911, showed the strongest antagonist activity [IC(50) = 26.2 nM and Kd against GBAP receptor (FsrC) = 39.4 nM]. In vivo efficacy of this peptide was assessed with an aphakic rabbit endophthalmitis model. ZBzl-YAA5911 suppressed the translocation of E. faecalis from the aqueous humor into the vitreous cavity by more than 1 order of magnitude and significantly reduced retinal damage. We propose that ZBzl-YAA5911 or its derivatives would be useful as anti-infective agents to attenuate virulence expression in this opportunistic pathogen. PMID- 23363000 TI - Imaging diagnosis-malignant peripheral nerve sheath tumor presenting as an intra axial brain mass in a young dog. AB - A 3-year-old Labrador retriever was presented with acute onset seizures. Magnetic resonance imaging demonstrated an intra-axial mass affecting the right temporal lobe of the brain. Surgical resection and histopathological findings were most consistent with a malignant peripheral nerve sheath tumor. After initial recovery, deterioration 3 months post surgery prompted euthanasia. Post-mortem revealed a mass protruding from the ventral surface of the temporal lobe, encroaching upon the optic chiasm and invading the brain. Histopathology findings were again consistent with malignant peripheral nerve sheath tumor. Although rare, this tumor should be included as a possible differential diagnosis for intra-axial brain masses in dogs. PMID- 23363001 TI - Branching mechanisms in surfactant micellar growth. AB - We present a phase-field model to study the morphological transitions of surfactant micelles in supersaturated dilute solution. Simulations reveal that multiply connected micellar structure can be produced by interface branching instability of a growing micelle at relatively large supersaturation and intermediate spontaneous curvatures. Two branching mechanisms, i.e., a disk-to cylinder shape transition and a tip bifurcation process, are identified for disklike and cylindrical micelles, respectively. We propose that dynamic branching at the micelle growth front provides an important kinetic pathway for the formation of branched wormlike micelles that are observed in many surfactant systems. PMID- 23363002 TI - Role of SALL4 in the progression and metastasis of colorectal cancer. AB - BACKGROUND: Human cancer cells resemble stem cells in expression signatures leading them to share some features, most notably, self-renewal. A complex network of transcription factors and signaling molecules are required for continuance of this trait. SALL4 is a zinc finger transcriptional activator crucial for maintenance of self-renewal in stem cells; however, its expression level has not yet been elucidated in colorectal tumor cells. To determine this level and probable clinicopathological consequences, its expression was analyzed. METHODS: SALL4 expression in fresh tumoral and distant tumor-free tissues from 46 colorectal samples was compared by real-time polymerase chain reaction (PCR). RESULTS: Greater than a two-fold increase in SALL4 expression was detected in 87% of tumors vs. normal related tissues. SALL4 expression was significantly correlated with tumor cell metastasis to lymph nodes, especially in moderately differentiated tumor samples (P < 0.05). Furthermore, higher levels of SALL4 mRNA expression were significantly associated with younger than older patients with tumor cells in stages I and II (P < 0.05). CONCLUSIONS: These results indicate a relationship between SALL4 expression and tumor cell metastasis to lymph nodes and consequent advancement of tumors to advanced stages III and IV. Along with the promising evidence of its role in self-renewal in various cancers, SALL4 may have a role in progression, development and maintenance of colorectal cancers. PMID- 23363004 TI - Evidence for implicit learning in syntactic comprehension. AB - This study provides evidence for implicit learning in syntactic comprehension. By reanalyzing data from a syntactic priming experiment (Thothathiri & Snedeker, 2008), we find that the error signal associated with a syntactic prime influences comprehenders' subsequent syntactic expectations. This follows directly from error-based implicit learning accounts of syntactic priming, but it is unexpected under accounts that consider syntactic priming a consequence of temporary increases in base-level activation. More generally, the results raise questions about the principles underlying the maintenance of implicit statistical knowledge relevant to language processing, and about possible functional motivations for syntactic priming. PMID- 23363003 TI - Development of inhibitors of the PAS-B domain of the HIF-2alpha transcription factor. AB - Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in a variety of pathophysiological settings, including cancer. We describe the first detailed structure-activity relationship study of small molecules designed to inhibit HIF-2alpha-ARNT heterodimerization by binding an internal cavity of the HIF-2alpha PAS-B domain. Through a series of biophysical characterizations of inhibitor-protein interactions (NMR and X-ray crystallography), we have established the structural requirements for artificial inhibitors of the HIF 2alpha-ARNT PAS-B interaction. These results may serve as a foundation for discovering therapeutic agents that function by a novel mode of action. PMID- 23363006 TI - Facile synthesis of 2-arylphenols via palladium-catalyzed cross-coupling of aryl iodides with 6-diazo-2-cyclohexenones. AB - 2-Arylphenols were conveniently synthesized from aryl iodides and 6-diazo-2 cyclohexenones, in moderate to excellent yields, via tandem Pd-catalyzed cross coupling/aromatization. The preliminary results for the corresponding enantioselective version showed that the coupling products could be generated in up to 72% ee. PMID- 23363005 TI - Sensitizing curium luminescence through an antenna protein to investigate biological actinide transport mechanisms. AB - Worldwide stocks of actinides and lanthanide fission products produced through conventional nuclear spent fuel are increasing continuously, resulting in a growing risk of environmental and human exposure to these toxic radioactive metal ions. Understanding the biomolecular pathways involved in mammalian uptake, transport and storage of these f-elements is crucial to the development of new decontamination strategies and could also be beneficial to the design of new containment and separation processes. To start unraveling these pathways, our approach takes advantage of the unique spectroscopic properties of trivalent curium. We clearly show that the human iron transporter transferrin acts as an antenna that sensitizes curium luminescence through intramolecular energy transfer. This behavior has been used to describe the coordination of curium within the two binding sites of the protein and to investigate the recognition of curium-transferrin complexes by the cognate transferrin receptor. In addition to providing the first protein-curium spectroscopic characterization, these studies prove that transferrin receptor-mediated endocytosis is a viable mechanism of intracellular entry for trivalent actinides such as curium and provide a new tool utilizing the specific luminescence of curium for the determination of other biological actinide transport mechanisms. PMID- 23363007 TI - Attrition from an Internet-based treatment program for female sexual dysfunction: who is best treated with this approach? AB - The current study evaluated the attrition from an Internet-based treatment program for female sexual dysfunction (FSD), and determined factors that contribute to this attrition. Of the original, 26 women who were allocated to the treatment group, 12 provided post-intervention data, and of the 27 women who entered the wait list control group, 22 provided post-intervention data. Of 14 control participants who then elected to enter treatment, five provided post intervention data. Therefore, a total of 40 women entered the FSD program and 23 dropped out. Reasons for attrition included: relationship factors, lack of motivation, and time commitment perceived to be excessive. Significant differences were found in levels of relationship satisfaction and intimacy for those who dropped out and those who completed treatment. These findings suggest that participants with high relationship satisfaction and emotional intimacy with their partner are suitable for treatments of this type. PMID- 23363008 TI - Chicoric acid induces apoptosis in 3T3-L1 preadipocytes through ROS-mediated PI3K/Akt and MAPK signaling pathways. AB - Chicoric acid has been reported to possess various bioactivities. However, the antiobesity effects of chicoric acid remain poorly understood. In this study, we investigated the effects of chicoric acid on 3T3-L1 preadipocytes and its molecular mechanisms of apoptosis. Chicoric acid inhibited cell viability and induced apoptosis in 3T3-L1 preadipocytes which was characterized by chromatin condensation and poly ADP-ribose-polymerase (PARP) cleavage. Mitochondrial membrane potential (MMP) loss, Bax/Bcl-2 dysregulation, cytochrome c release, and caspase-3 activation were observed, indicating mitochondria-dependent apoptosis induced by chicoric acid. Furthermore, PI3K/Akt and MAPK (p38 MAPK, JNK, and ERK1/2) signaling pathways were involved in chicoric acid-induced apoptosis. The employment of protein kinase inhibitors LY294002, SB203580, SP600125, and U0126 revealed that PI3K/Akt signaling pathway interplayed with MAPK signaling pathways. Moreover, chicoric acid induced reactive oxygen species (ROS) generation. Pretreatment with the antioxidant N-acetylcysteine (NAC) significantly blocked cell death and changes of Akt and MAPK signalings induced by chicoric acid. In addition, chicoric acid down regulated HO-1 and COX-2 via the PI3K/Akt pathway. PMID- 23363009 TI - The cell survival kinase SGK1 and its targets FOXO3a and NDRG1 in aged human brain. AB - AIMS: Serum- and glucocorticoid-inducible kinase 1 (SGK1) protects neuronal cells from injury stimuli in vitro, and exerts anti-apoptotic effects via downstream targets including the forkhead-like transcription factor FOXO3a. SGK1 is a homolog of Akt, a related survival kinase that is up-regulated in Alzheimer's disease (AD). Here we aimed to examine the expression pattern of SGK1 and FOXO3a in aged human cerebral cortex. METHODS: Cortical tissue from aged donors without brain disease (aged controls, AC, n = 19) and from severe AD patients (Braak stage V-VI; n = 14) were examined by immunohistochemistry and immunoblot analysis. RESULTS: SGK1 was present in all samples (detected by immunohistochemistry and immunoblotting). Large cortical neuronal cells were strongly positive for SGK1, with predominantly nuclear labelling. Some astrocytes and oligodendrocytes were also labelled. SGK1 was not seen in nerve tracts (axons or myelin) and rarely seen in CD68-positive cells (microglia, perivascular macrophages) or vascular cells (myocytes or endothelia). The fraction of large cortical neurones with nuclear FOXO3a was lower in AD cases relative to AC (54%, 70%, respectively, P < 0.001). In immunoblots no difference in SGK1 abundance was detected between AC and AD tissues. Phosphorylation of NDRG1 (an SGK1-specific target) was greater in AD, relative to AC cases (approximately twofold, P = 0.023). CONCLUSIONS: Neuronal expression of SGK1 in aged human brain and its nuclear compartmentalization suggest a possible neuroprotective role. FOXO3a and NDRG1 data suggest augmented SGK1 activity (as reported for Akt) in severe AD. Increased intracellular SGK1 may complement enhanced Akt, with a distinct subcellular localization. PMID- 23363011 TI - Endoscopic ultrasound-guided fine-needle aspiration of omental deposits in undiagnosed ascites. PMID- 23363010 TI - Mephedrone (4-methylmethcathinone) supports intravenous self-administration in Sprague-Dawley and Wistar rats. AB - Recreational use of the drug 4-methylmethcathinone (mephedrone; 4-MMC) became increasingly popular in the United Kingdom in recent years, spurred in part by the fact that it was not criminalized until April 2010. Although several fatalities have been associated with consumption of 4-MMC and cautions for recreational users about its addictive potential have appeared on Internet forums, very little information about abuse liability for this drug is available. This study was conducted to determine if 4-MMC serves as a reinforcer in a traditional intravenous self-administration model. Groups of male Wistar and Sprague-Dawley rats were prepared with intravenous catheters and trained to self administer 4-MMC in 1-hour sessions. Per-infusion doses of 0.5 and 1.0 mg/kg were consistently self-administered, resulting in greater than 80% discrimination for the drug-paired lever and mean intakes of about 2-3 mg/kg/hour. Dose-substitution studies after acquisition demonstrated that the number of responses and/or the total amount of drug self-administered varied as a function of dose. In addition, radiotelemetry devices were used to show that self-administered 4-MMC was capable of increasing locomotor activity (Wistar) and decreasing body temperature (Sprague-Dawley). Pharmacokinetic studies found that the T1/2 of 4-MMC was about 1 hour in vivo in rat plasma and 90 minutes using in vitro liver microsomal assays. This study provides evidence of stimulant-typical abuse liability for 4 MMC in the traditional pre-clinical self-administration model. PMID- 23363013 TI - Nanoscale infrared spectroscopy: improving the spectral range of the photothermal induced resonance technique. AB - Photothermal induced resonance (PTIR) is a new technique which combines the chemical specificity of infrared (IR) spectroscopy with the lateral resolution of atomic force microscopy (AFM). PTIR requires a pulsed tunable laser for sample excitation and an AFM tip to measure the sample expansion induced by light absorption. The limited tunability of commonly available laser sources constrains the application of the PTIR technique to a portion of the IR spectrum. In this work, a broadly tunable pulsed laser relying on a difference frequency generation scheme in a GaSe crystal to emit light tunable from 1.55 MUm to 16 MUm (from 6450 cm(-1) to 625 cm(-1)) was interfaced with a commercial PTIR instrument. The result is a materials characterization platform capable of chemical imaging, in registry with atomic force images, with a spatial resolution that notably surpasses the light diffraction limit throughout the entire mid-IR spectral range. PTIR nanoscale spectra and images allow the identification of compositionally and optically similar yet distinct materials; organic, inorganic, and composite samples can be studied with this nanoscale analog of infrared spectroscopy, suggesting broad applicability. Additionally, we compare the results obtained with the two tunable lasers, which have different pulse lengths, to experimentally assess the recently developed theory of PTIR signal generation. PMID- 23363014 TI - The effect of calyculin A on the dephosphorylation of the histone gamma-H2AX after formation of X-ray-induced DNA double-strand breaks in human blood lymphocytes. AB - PURPOSE: The purpose of this study was to investigate the effect of calyculin A on the number of gamma-H2AX foci (phosphorylated histone variant 2AX) in lymphocytes after in vitro and in vivo irradiation with rather low doses as they are used in diagnostic and interventional radiology. MATERIALS AND METHODS: For in vitro experiments blood samples of 14 healthy volunteers were irradiated with different doses (10, 50, 100 mGy) and incubated with (0.01, 0.1, 1, 10 nM) or without calyculin A for up to 2 hours. Non-irradiated samples with and without calyculin A served as controls. For in vivo evaluation blood samples were collected from seven patients undergoing computed tomography (CT) both with 1 nM calyculin A containing vials and vials without calyculin A. Foci were quantified in isolated lymphocytes using gamma-H2AX immunofluorescence microscopy. RESULTS: 1 nM calyculin A led to a complete inhibition of gamma-H2AX foci loss in irradiated samples whereas no inhibition of p53 binding protein 1 (53 BP1) foci was found. Lower concentrations of the phosphatase inhibitor did not have a sufficient effect on foci decrease. Calyculin A did not affect foci levels in non irradiated samples. If no calyculin A was added into the vial before the blood draws detectable CT-induced foci levels were lower in all patients with a reduction of the medians of 35%. CONCLUSIONS: Using gamma-H2AX immunofluorescence microscopy calyculin A can be a useful tool to mark the induced gamma-H2AX foci after low dose irradiation and to avoid an underestimation of the real deoxyribonucleic acid (DNA) damage in in vitro and in vivo experiments. PMID- 23363012 TI - Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world and its incidence is increasing rapidly. NAFLD is a spectrum ranging from simple steatosis, which is relatively benign hepatically, to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis. Obesity, insulin resistance, type 2 diabetes mellitus, and dyslipidemia are the most important risk factors for NAFLD. Due to heavy enrichment with metabolic risk factors, individuals with NAFLD are at significantly higher risk for cardiovascular disease. Individuals with NAFLD have higher incidence of type 2 diabetes. The diagnosis of NAFLD requires imaging evidence of hepatic steatosis in the absence of competing etiologies including significant alcohol consumption. Liver biopsy remains the gold standard for diagnosing NASH and for determining prognosis. Weight loss remains a cornerstone of treatment. Weight loss of ~5% is believed to improve steatosis, whereas ~10% weight loss is necessary to improve steatohepatitis. A number of pharmacologic therapies have been investigated to treat NASH, and agents such as vitamin E and thiazolidinediones have shown promise in select patient subgroups. PMID- 23363015 TI - Effects of transmembrane hydraulic pressure on performance of forward osmosis membranes. AB - Forward osmosis (FO) is an emerging membrane separation process that continues to be tested and implemented in various industrial water and wastewater treatment applications. The growing interests in the technology have prompted laboratories and manufacturers to adopt standard testing methods to ensure accurate comparison of membrane performance under laboratory-controlled conditions; however, standardized methods might not capture specific operating conditions unique to industrial applications. Experiments with cellulose triacetate (CTA) and polyamide thin-film composite (TFC) FO membranes demonstrated that hydraulic transmembrane pressure (TMP), common in industrial operation of FO membrane elements, could affect membrane performance. Experiments were conducted with three FO membranes and with increasing TMP up to a maximum of 50 psi (3.45 bar). The feed solution was a mixture of salts and the draw solution was either a NaCl solution or concentrated seawater at similar osmotic pressure. Results revealed that TMP minimally affected water flux, reverse salt flux (RSF), and solute rejection of the CTA membrane. However, water flux through TFC membranes might slightly increase with increasing TMP, and RSF substantially declines with increasing TMP. It was observed that rejection of feed constituents was influenced by TMP and RSF. PMID- 23363016 TI - Ultraviolet radiation regulates cortisol activity in a waveband-dependent manner in human skin ex vivo. AB - BACKGROUND: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1), 11beta hydroxysteroid dehydrogenase type 2 (11beta-HSD2), and glucocorticoids (GC) and their receptor (GR) play a key role in tissue-specific regulation of GC action. OBJECTIVES: To determine the expression of genes encoding 11beta-HSD1 (HSD11B1), 11beta-HSD2 (HSD11B2) and GR (GRalpha; also known as NC3R1) and their protein products, and levels of cortisol in human skin explants and/or cocultured keratinocytes/melanocytes after treatment with ultraviolet (UV) A, B or C wavebands. METHODS: Skin from foreskins and/or cocultured human keratinocytes/melanocytes were irradiated with UVA, UVB or UVC (skin) and incubated for 12 and 24 h. Methods of reverse transcription-polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay and immunohistochemistry (IHC) were used to determine expression and localization of corresponding genes or antigens. RESULTS: UVB enhanced the HSD11B1 gene and protein expression in a dose-dependent manner, while UVA had no effect. Similarly, UVC increased 11beta-HSD1 protein product as measured by IHC. UVB and UVC enhanced cortisol production and decreased epidermal GR expression, while UVA had no detectable effects. Although both UVA and UVB stimulated HSD11B2 gene expression, only UVA increased 11beta-HSD2 protein product levels with UVB and UVC having no effect. CONCLUSIONS: We suggest that these differential, waveband dependent effects of UV radiation on the expression of cutaneous HSD11B1, HSD11B2 and GRalpha genes and their corresponding protein products, and cortisol production are to protect and/or restore the epidermal barrier homeostasis against disruption caused by the elevated cortisol level induced by UVB and UVC. PMID- 23363017 TI - Design and development of data glove based on printed polymeric sensors and Zigbee networks for Human-Computer Interface. AB - Current trends in Human-Computer Interface (HCI) have brought on a wave of new consumer devices that can track the motion of our hands. These devices have enabled more natural interfaces with computer applications. Data gloves are commonly used as input devices, equipped with sensors that detect the movements of hands and communication unit that interfaces those movements with a computer. Unfortunately, the high cost of sensor technology inevitably puts some burden to most general users. In this research, we have proposed a low-cost data glove concept based on printed polymeric sensor to make pressure and bending sensors fabricated by a consumer ink-jet printer. These sensors were realized using a conductive polymer (poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) [PEDOT:PSS]) thin film printed on glossy photo paper. Performance of these sensors can be enhanced by addition of dimethyl sulfoxide (DMSO) into the aqueous dispersion of PEDOT:PSS. The concept of surface resistance was successfully adopted for the design and fabrication of sensors. To demonstrate the printed sensors, we constructed a data glove using such sensors and developed software for real time hand tracking. Wireless networks based on low-cost Zigbee technology were used to transfer data from the glove to a computer. To our knowledge, this is the first report on low cost data glove based on paper pressure sensors. This low cost implementation of both sensors and communication network as proposed in this paper should pave the way toward a widespread implementation of data glove for real-time hand tracking applications. PMID- 23363018 TI - Comparison of body segmental kinematic characteristics between children with cerebral palsy performing sit-to-stand with and without a walker. AB - The study investigated how the subjects, 18 children with spastic diplegia aged 7 14 years, attained sit-to-stand (STS). The children were divided into two groups and three STS conditions: 1) those who could attain STS independently (I-STS), 2) those who could not attain STS independently (D-STS), and 3) subjects from the D STS condition who could successfully attain STS with the walker (W-STS). The results showed that I-STS had more mean maximum horizontal location of the upper body and knee than the hip. All body segments of D-STS followed the same model as the I-STS condition, but they moved with less magnitude than I-STS. W-STS presented both pattern and magnitudes relatively similar to I-STS. Furthermore, I STS showed the highest mean maximum horizontal and vertical velocities of body segments, when compared with the other STS conditions. W-STS performed the mean maximum horizontal and vertical linear velocities of all selected segments close to D-STS did. PMID- 23363019 TI - Conformational equilibria of N,N-dimethylsuccinamic acid and its lithium salt as a function of solvent. AB - The conformational preferences of N,N-dimethylsuccinamic acid and its Li(+) salt were estimated by comparing the respective experimental NMR vicinal proton-proton coupling constants to semiempirical coupling constants for each staggered conformer as derived by the Haasnoot-De Leeuw-Altona method. The strong gauche preferences for the Li(+) salts clearly depended more on the solvents' hydrogen bond donating strength (alpha) than on their hydrogen-bond accepting (beta) counterpart, where alpha and beta are the corresponding Kamlet-Taft parameters. PMID- 23363020 TI - Pharmacological chaperones as therapeutics for lysosomal storage diseases. AB - Lysosomal enzymes are responsible for the degradation of a wide variety of glycolipids, oligosaccharides, proteins, and glycoproteins. Inherited mutations in the genes that encode these proteins can lead to reduced stability of newly synthesized lysosomal enzymes. While often catalytically competent, the mutated enzymes are unable to efficiently pass the quality control mechanisms of the endoplasmic reticulum, resulting in reduced lysosomal trafficking, substrate accumulation, and cellular dysfunction. Pharmacological chaperones (PCs) are small molecules that bind and stabilize mutant lysosomal enzymes, thereby allowing proper cellular translocation. Such compounds have been shown to increase enzyme activity and reduce substrate burden in a number of preclinical models and clinical studies. In this Perspective, we review several of the lysosomal diseases for which PCs have been studied and the SAR of the various classes of molecules. PMID- 23363021 TI - Possible antistenotic effect of tranilast in a patient with small bowel tuberculosis to prevent intestinal obstruction due to stenosis progression by antituberculous chemotherapy. AB - Small intestinal tuberculosis is a rare disorder of the small intestine. We report the development of deep small bowel tuberculosis in a rheumatoid arthritis patient who was taking methotrexate. The diagnosis of small bowel tuberculosis was ascertained by typical endoscopic findings and production of interferon gamma in the peripheral blood. The patient was successfully treated with antituberculous chemotherapy combined with an antifibrotic agent, tranilast, to suppress the progression of intestinal stenosis toward symptomatic stricture. PMID- 23363022 TI - Directed evolution of the quorum-sensing regulator EsaR for increased signal sensitivity. AB - The use of cell-cell communication or "quorum sensing (QS)" elements from Gram negative Proteobacteria has enabled synthetic biologists to begin engineering systems composed of multiple interacting organisms. However, additional tools are necessary if we are to progress toward synthetic microbial consortia that exhibit more complex, dynamic behaviors. EsaR from Pantoea stewartii subsp. stewartii is a QS regulator that binds to DNA as an apoprotein and releases the DNA when it binds to its cognate signal molecule, 3-oxohexanoyl-homoserine lactone (3OC6HSL). In the absence of 3OC6HSL, EsaR binds to DNA and can act as either an activator or a repressor of transcription. Gene expression from P(esaR), which is repressed by wild-type EsaR, requires 100- to 1000-fold higher concentrations of signal than commonly used QS activators, such as LuxR and LasR. Here we have identified EsaR variants with increased sensitivity to 3OC6HSL using directed evolution and a dual ON/OFF screening strategy. Although we targeted EsaR-dependent derepression of P(esaR), our EsaR variants also showed increased 3OC6HSL sensitivity at a second promoter, P(esaS), which is activated by EsaR in the absence of 3OC6HSL. Here, the increase in AHL sensitivity led to gene expression being turned off at lower concentrations of 3OC6HSL. Overall, we have increased the signal sensitivity of EsaR more than 70-fold and generated a set of EsaR variants that recognize 3OC6HSL concentrations ranging over 4 orders of magnitude. QS-dependent transcriptional regulators that bind to DNA and are active in the absence of a QS signal represent a new set of tools for engineering cell-cell communication-dependent gene expression. PMID- 23363024 TI - Evidence for cardiolipin binding sites on the membrane-exposed surface of the cytochrome bc1. AB - The respiratory chain is located in the inner membrane of mitochondria and produces the major part of the ATP used by a cell. Cardiolipin (CL), a double charged phospholipid composing ~10-20% of the mitochondrial membrane, plays an important role in the function and supramolecular organization of the respiratory chain complexes. We present an extensive set of coarse-grain molecular dynamics (CGMD) simulations aiming at the determination of the preferential interfaces of CLs on the respiratory chain complex III (cytochrome bc(1), CIII). Six CL binding sites are identified, including the CL binding sites known from earlier structural studies and buried into protein cavities. The simulations revealed the importance of two subunits of CIII (G and K in bovine heart) for the structural integrity of these internal CL binding sites. In addition, new binding sites are found on the membrane-exposed protein surface. The reproducibility of these binding sites over two species (bovine heart and yeast mitochondria) points to an important role for the function of the respiratory chain. Interestingly the membrane-exposed CL binding sites are located on the matrix side of CIII in the inner membrane and thus may provide localized sources of proton ready for uptake by CIII. Furthermore, we found that CLs bound to those membrane-exposed sites bridge the proteins during their assembly into supercomplexes by sharing the binding sites. PMID- 23363023 TI - Functional tooth restoration by allogeneic mesenchymal stem cell-based bio-root regeneration in swine. AB - Our previous proof-of-concept study showed the feasibility of regenerating the dental stem cell-based bioengineered tooth root (bio-root) structure in a large animal model. Here, we used allogeneic dental mesenchymal stem cells to regenerate bio-root, and then installed a crown on the bio-root to restore tooth function. A root shape hydroxyapatite tricalcium phosphate scaffold containing dental pulp stem cells was covered by a Vc-induced periodontal ligament stem cell sheet and implanted into a newly generated jaw bone implant socket. Six months after implantation, a prefabricated porcelain crown was cemented to the implant and subjected to tooth function. Clinical, radiological, histological, ultrastructural, systemic immunological evaluations and mechanical properties were analyzed for dynamic changes in the bio-root structure. The regenerated bio root exhibited characteristics of a normal tooth after 6 months of use, including dentinal tubule-like and functional periodontal ligament-like structures. No immunological response to the bio-roots was observed. We developed a standard stem cell procedure for bio-root regeneration to restore adult tooth function. This study is the first to successfully regenerate a functional bio-root structure for artificial crown restoration by using allogeneic dental stem cells and Vc-induced cell sheet, and assess the recipient immune response in a preclinical model. PMID- 23363025 TI - Determination of light-medium-heavy polycyclic aromatic hydrocarbons in vegetable oils by solid-phase extraction and high-performance liquid chromatography with diode array and fluorescence detection. AB - A new method for determination of 16 polycyclic aromatic hydrocarbons (PAHs) naphthalene, acenaphthylene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, benz[a]anthracene, chrysene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene, dibenz[a,h]anthracene, benzo[g,h,i]perylene, and indeno[1,2,3-cd]pyrene-in vegetable oils was developed. Solid-phase extraction (SPE) prior to high-performance liquid chromatography with fluorescence detection could be used for all those PAHs except acenaphthylene. Acenaphthylene could be detected using a diode array detector at 228 nm. The parameters and variables that affect the extraction were investigated. Under optimum conditions: the extract reagent was centrifuged at 4 degrees C and evaporated. After that a SPE procedure was used for further cleanup. The limits of detection and limits of quantification were in the range of 0.01-2.35 and 0.04-7.00 MUg kg(-1) in vegetable oil, respectively. The relative standard deviations were under 5%. PMID- 23363026 TI - Constructing the health care system in Greece: responsibility and powerlessness. AB - OBJECTIVES: Based on health care professionals' (HPs) and patients' interviews about work demands and quality of care in hospitals, the study explores the way that patients and HPs constructed their identities to describe and construct the health care system in Greece. DESIGN: This is a qualitative study using a focus group (FG) design. METHODS: Seven FGs discussions were conducted: three FGs discussions were conducted for the assessment of job stressors (1 for doctors, 1 for nurses and 1 for residents) and four FGs discussions for the assessment of quality of care (1 for doctors, 1 for nurses, 1 for residents and 1 for patients). The sample consisted of health care professionals working in a teaching hospital in the region of Thessaloniki, Greece, and patients who had at least one experience of any kind in the same hospital. Transcripts of the FGs discussions underwent discourse analysis. RESULTS: The results showed that both HPs and patients construct the health care system based on bipolar constructions of responsibility and powerlessness. In particular, participants use these constructions to allocate the responsibility to different levels of the health care system hierarchy or to the system per se constructing, at the same time, themselves as the 'viewers' of this system. CONCLUSIONS: The study allowed a deeper understanding of issues related to quality of care in hospitals providing context-specific information. Identity in health care organizations was inextricably linked to power and responsibility. The need to deconstruct this responsibility/powerlessness ideology is discussed. PMID- 23363027 TI - Essentialist beliefs about bodily transplants in the United States and India. AB - Psychological essentialism is the belief that some internal, unseen essence or force determines the common outward appearances and behaviors of category members. We investigated whether reasoning about transplants of bodily elements showed evidence of essentialist thinking. Both Americans and Indians endorsed the possibility of transplants conferring donors' personality, behavior, and luck on recipients, consistent with essentialism. Respondents also endorsed essentialist effects even when denying that transplants would change a recipient's category membership (e.g., predicting that a recipient of a pig's heart would act more pig like but denying that the recipient would become a pig). This finding runs counter to predictions from the strongest version of the "minimalist" position (Strevens,2000), an alternative to essentialism. Finally, studies asking about a broader range of donor-to-recipient transfers indicated that Indians essentialized more types of transfers than Americans, but neither sample essentialized monetary transfer. This suggests that results from bodily transplant conditions reflect genuine essentialism rather than broader magical thinking. PMID- 23363028 TI - Ion transport effects in a solid polymer electrolyte due to salt substitution and addition using an ionic liquid. AB - We investigated mass and charge transport in amorphous salt-in-poly(ethylene oxide) (PEO) electrolytes with NaI and/or the ionic liquid (IL) EMImTFSI (1-ethyl 3-methylimizadolium bis(trifluoromethylsulfonyl)imide) as salt component. Combining the results of ion conductivity, pulsed field gradient nuclear magnetic resonance, and radiotracer diffusion measurements, it is found that over wide temperature ranges both the cation and anion diffusion coefficients and the charge diffusivity are distinctly larger in PEO(20)EMImTFSI than in PEO(20)NaI complexes, where the monomer-to-salt mole ratio equals 20. In the mixed-salt complexes PEO(20)NaI(1)EMImTFSI(1) and PEO(20)NaI(0.5)EMImTFSI(0.5), we observe a slowing down of the IL ions EMIm and TFSI along with a diffusivity enhancement of the I anion compared to the single-salt base complexes. For the cation Na, a diffusivity increase is only effected by IL substitution, but because of the concomitant decrease of the Na concentration, it does not predict more effective charge transfer in a battery cell configuration. PMID- 23363029 TI - Outcomes of care in birth centers: demonstration of a durable model. AB - INTRODUCTION: The safety and effectiveness of birth center care have been demonstrated in previous studies, including the National Birth Center Study and the San Diego Birth Center Study. This study examines outcomes of birth center care in the present maternity care environment. METHODS: This was a prospective cohort study of women receiving care in 79 midwifery-led birth centers in 33 US states from 2007 to 2010. Data were entered into the American Association of Birth Centers Uniform Data Set after obtaining informed consent. Analysis was by intention to treat, with descriptive statistics calculated for maternal and neonatal outcomes for all women presenting to birth centers in labor including those requiring transfer to hospital care. RESULTS: Of 15,574 women who planned and were eligible for birth center birth at the onset of labor, 84% gave birth at the birth center. Four percent were transferred to a hospital prior to birth center admission, and 12% were transferred in labor after admission. Regardless of where they gave birth, 93% of women had a spontaneous vaginal birth, 1% an assisted vaginal birth, and 6% a cesarean birth. Of women giving birth in the birth center, 2.4% required transfer postpartum, whereas 2.6% of newborns were transferred after birth. Most transfers were nonemergent, with 1.9% of mothers or newborns requiring emergent transfer during labor or after birth. There were no maternal deaths. The intrapartum fetal mortality rate for women admitted to the birth center in labor was 0.47/1000. The neonatal mortality rate was 0.40/1000 excluding anomalies. DISCUSSION: This study demonstrates the safety of the midwifery-led birth center model of collaborative care as well as continued low obstetric intervention rates, similar to previous studies of birth center care. These findings are particularly remarkable in an era characterized by increases in obstetric intervention and cesarean birth nationwide. PMID- 23363030 TI - Influence of track directions on the biological consequences in cells irradiated with high LET heavy ions. AB - PURPOSE: The impact of the damage distribution to cellular survival and chromosomal aberrations following high Linear Energy Transfer (LET) radiation was investigated. MATERIALS AND METHODS: High LET iron-ions (500 MeV/n, LET 200 keV/MUm) were delivered to G1-phase synchronized Chinese Hamster Ovary (CHO) cells located at a vertical or horizontal angle relative to the ion beam in order to give same dose but different fluence and damage distribution. RESULTS: Horizontal irradiation produced DNA double-strand break (DSB) along each ion track represented as clustered lines, and vertical irradiation produced a greater fluence. The initial damages measured by premature chromosome condensation were equal per dose in both irradiation types. Horizontal irradiation proved to be less effective in cell killing than vertical at doses of more than 3 Gy. Vertical irradiation produced a higher number of metaphase chromosomal aberrations compared to horizontally irradiated samples. In particular, formation of exchange type aberrations was the same, but that of deletion-type aberrations were significantly higher after vertical irradiation than horizontal irradiation. CONCLUSIONS: Therefore, we concluded that high fluence per dose is more effective than low fluence per dose to produce radiation-induced chromosomal aberrations and to kill exposed cells following high LET heavy-ion exposure. PMID- 23363031 TI - Efficacy of endoscopic nasobiliary drainage for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis and cholangitis after repeated clearance of common bile duct stones: experience from a Chinese center. AB - BACKGROUND: The aim of the present study was to investigate whether it is reasonable to insert an endoscopic nasobiliary drainage (ENBD) tube in patients with endoscopic sphincterotomy (EST) and repeated clearance of common bile duct (CBD) stones. PATIENTS AND METHODS: Patients with choledocholithiasis who underwent EST and CBD stone clearance at our center from January 2010 to May 2012 were reviewed. The following parameters were evaluated: (i) serum amylase 2 and 24 h after ERCP; (ii) incidence of endoscopic retrograde cholangiopancreatography (ERCP)-related pancreatitis and cholangitis; (iii) time elapsed to normalization of total serum bilirubin levels for those with jaundice before ERCP; and (iv) length of hospital stay. RESULTS: Compared with the no-ENBD group, the ENBD group presented a significantly lower postoperative serum amylase of 2 and 24 h (81.3 +/- 31.8 U/L vs 90.8 +/- 31.2 U/L, 107.0 +/- 51.1 U/Lvs 132.3 +/- 100.8 U/L, respectively). The incidence of post-ERCP pancreatitis and cholangitis was also lower in the ENBD group, although the differences were not significant (1% vs 4.4%, 0 vs 4.5%, respectively). Time elapsed to normalization of total serum bilirubin levels and length of hospital stay was shorter in the ENBD group (4.3 days +/- 0.6 days vs 4.5 days +/- 0.7 days, P > 0.05; 4.8 days +/- 2.1 days vs 6.3 days +/- 2.8 days, respectively, P < 0.01). CONCLUSIONS: ENBD significantly reduces the incidence of hyperamylasemia and decreases the length of hospital stay in patients with EST and repeated stone extraction. ENBD should be considered for patients with large or multiple CBD stones. PMID- 23363032 TI - Correlative ultrasound anatomy of the feline brachial plexus and major nerves of the thoracic limb. AB - Brachial plexus avulsions commonly occur in cats due to traumatic injuries involving the shoulder. Ultrasound may be an effective method for detecting injured nerves. Additional applications may include characterization of brachial plexus neoplasms and guidance of anesthetic nerve blocks. Aims of this study were to describe ultrasonographic approaches and the normal appearance of this plexus and other major nerves of the thoracic limb in cats. Eight feline cadavers were used to determine anatomic landmarks, obtain cross-sectional anatomic images of the target nerves, and compare these with ultrasound images. An ultrasonographic study was performed in five fresh feline cadavers to assess the brachial plexus and its major components at the levels of the axilla and proximal, middle and distal (lateral and medial approaches) humeral regions. Five healthy adult cats were recruited for an in vivo ultrasonographic study using the same protocol described for the cadaver ultrasonographic study. The roots of the brachial plexus appeared as a cluster of small, round hypoechoic structures surrounded by a hyperechoic rim in the axillary approach. The radialis, medianus, and ulnaris nerves were individually visualized on proximal and middle humeral approaches. The medianus and ulnaris nerves were easily identified on the medial aspect of the humerus in the distal approach. The superficial branch of radialis nerve was seen on the lateral aspect of the distal humerus approach. The nerves appeared as oval-to-round hypoechogenic structures with a hyperechogenic rim. Future studies are needed to compare findings from this study with those in cats with confirmed brachial plexus injuries or other lesions. PMID- 23363034 TI - Sexual concurrency among young African American women. AB - Young African-American women are disproportionately affected by human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) sexually transmitted infections (STI), and engage in greater sexual concurrency than other race/ethnicities. It is important to evaluate behaviors and characteristics associated with the risk of sexual concurrency, so that interventions can target factors most likely to affect positive change. An emphasis on correlates of concurrency beyond individual-level factors has been suggested. The purpose of this study, therefore, was to identify individual- and partner-level characteristics associated with sexual concurrency among high-risk, young African American women. Data were collected from 570 African-American adolescent women (aged 15-21) recruited from a STI clinic, a family planning clinic, and a teen clinic located in Atlanta, GA from March 2002 through August 2004. Logistic regression analysis was conducted in 2012 to evaluate correlates of sexual concurrency. Results show that almost one-quarter of participants reported sexually concurrent partnerships and 28.4% suspected male partner concurrency. Logistic regression results indicated the number of lifetime sexual partners and relationship factors were the primary contributors to engaging in concurrency in this sample. These findings suggest relationship factors may be important contributors to the prevalence of sexual concurrency among young African-American women. Interventions targeted toward sexual health among young African-American women may need to specifically address partner/relationship factors. Through these findings, we hope to better understand sexual risk taking and develop strategies that would overcome barriers to existing interventions aimed at improving the sexual health outcomes of young African-American women. PMID- 23363035 TI - Disturbed sleep in Parkinson's disease: anatomical and pathological correlates. AB - AIMS: Abnormal sleep is a common feature of Parkinson's disease (PD) and prodromal disorders of sleep are frequent (e.g. restless legs syndrome and rapid eye movement sleep behaviour disorder). However, the exact pathological basis of disturbed sleep remains as yet undefined. METHODS: To investigate this further, 32 PD cases were stratified into three groups: (1) PD with disturbed sleep, PD(S); (2) PD with dementia (PDD) and disturbed sleep, PDD(S); and (3) PD without disturbed sleep, PD(nS). The extent of alpha-synuclein (alphaSyn) and Alzheimer disease (AD)-type pathology [amyloid beta peptide (Abeta) and tau] was assessed in 15 regions of the PD brain. RESULTS: The results demonstrate a significant association between disturbed sleep in PD and alphaSyn pathology in specific brainstem [locus coeruleus (P = 0.006) and raphe nuclei (P = 0.02)], hypothalamic [paramammillary nuclei (P = 0.04) and posterior nucleus (P = 0.02)], subcortical/limbic [amygdala (P = 0.03), thalamus (P = 0.01)] and cortical [entorhinal cortex (P = 0.01)] regions. A statistically significant increase of tau pathology was observed in the amygdala (P = 0.03), CA2 sector of the hippocampus (P = 0.01) and entorhinal cortex (P = 0.04) in PD cases with disturbed sleep. CONCLUSIONS: Pathological changes in these structures, residing in the brain circuitry relating to sleep physiology, strongly predict the presence of sleep disturbances in PD. PMID- 23363033 TI - Islet beta cell mass in diabetes and how it relates to function, birth, and death. AB - In type 1 diabetes (T1D) beta cell mass is markedly reduced by autoimmunity. Type 2 diabetes (T2D) results from inadequate beta cell mass and function that can no longer compensate for insulin resistance. The reduction of beta cell mass in T2D may result from increased cell death and/or inadequate birth through replication and neogenesis. Reduction in mass allows glucose levels to rise, which places beta cells in an unfamiliar hyperglycemic environment, leading to marked changes in their phenotype and a dramatic loss of glucose-stimulated insulin secretion (GSIS), which worsens as glucose levels climb. Toxic effects of glucose on beta cells (glucotoxicity) appear to be the culprit. This dysfunctional insulin secretion can be reversed when glucose levels are lowered by treatment, a finding with therapeutic significance. Restoration of beta cell mass in both types of diabetes could be accomplished by either beta cell regeneration or transplantation. Learning more about the relationships between beta cell mass, turnover, and function and finding ways to restore beta cell mass are among the most urgent priorities for diabetes research. PMID- 23363036 TI - Protein post-translational modification analyses using on-chip immunoprobed isoelectric focusing. AB - Post-translational modifications play a critical role in regulating protein function. Increasingly, determination of protein identity, estimation of abundance, and characterization of post-translational modifications are required for analysis of protein-mediated cell signaling networks. As such, we report an integrated and rapid multispectral immunoprobed isoelectric focusing technique for identifying specific proteins bearing post-translational modifications. Immunoprobed isoelectric focusing is composed of isoelectric focusing in a large pore-size polyacrylamide gel to determine protein pI followed by immobilization of pI-resolved proteins. Proteins are immobilized via covalent attachment to a channel-filling benzophenone-functionalized polyacrylamide gel via brief UV exposure (photoblot), followed by multispectral antibody-based detection. The assay correlates observed post-translational modifications to pI shifts relative to the unmodified protein of interest. During the electrokinetically driven antibody probing stage, we observed nonuniform electrophoretic probe mobility along the channel axis. The spatially varying mobility is attributed to nonuniform charge arising from covalent attachment of ampholytes to the benzophenone-functionalized gel matrix during the photoblotting step. Using the multistep microfluidic assay, phosphorylated and acetylated forms of heat shock protein 27 and superoxide dismutase 2 were detected, respectively. The assay reported protein isoforms in immune-purified sample and raw cell lysate in 2 hours with sample volume requirements of 2 MUL. This new assay is well-matched to systems biology frameworks for study of protein post-translational modifications. PMID- 23363037 TI - Household pesticide contamination from indoor pest control applications in urban low-income public housing dwellings: a community-based participatory research. AB - We designed this community-based participatory research (CBPR) project aiming to generate evidence-based research results to encourage residents living in urban low-income public housing dwellings engaging in a community-wide integrated pest management (IPM) program with the intention to improve their health and quality of life, as well as household conditions. We enrolled 20 families and their children in this study in which we utilized environmental exposure assessment (surface wipe and indoor air) tools to quantitatively assessing residential pesticide exposure in young children before the implementation of an IPM program. We analyzed those samples for 19 organophosphate (OP) and pyrethroid pesticides. The most commonly detected pesticides were pyrethroids, particularly permethrin and cypermethrin with average concentrations of 2.47 and 3.87 MUg/m(2), respectively. In many dwellings, we detected OPs, which are no longer available on the market; however, their levels are significantly lower than those of pyrethroids. None of the 20 families was free from pesticide contamination in their households, and pesticides were commonly detected in living room and children's bedroom. The correlation among household hygienic conditions, the sighting of live pests/pest debris, and the degree of indoor pesticide contamination highlights the failure of conventional chemical-based applications for pest controls. The results from the current study, as well as other recent studies, conducted in low-income public housing, child care centers, and randomly selected homes in the U.S. should accentuate the need for alternative pest management programs that incorporate safer and more sustainable protocols for pest controls. PMID- 23363039 TI - Alteration of biophysical activity of pulmonary surfactant by aluminosilicate nanoparticles. AB - The influence of five different types of aluminosilicate nanoparticles (NPs) on the dynamic surface activity of model pulmonary surfactant (PS) (Survanta) was studied experimentally using oscillating bubble tensiometry. Bentonite, halloysite and montmorillonite (MM) NPs, which are used as fillers of polymer composites, were characterized regarding the size distribution, morphology and surface area. Particle doses applied in the studies were estimated based on the inhalation rate and duration, taking into account the expected aerosol concentration and deposition efficiency after penetration of NPs into the alveolar region. The results indicate that aluminosilicate NPs at concentrations in the pulmonary liquid above 0.1 mg cm(-3) are capable of promoting alterations of the original dynamic biophysical activity of the PS. This effect is indicated by deviation of the minimum surface tension, stability index and the size of surface tension hysteresis. Such response is dependent on the type of NPs present in the system and is stronger when particle concentration increases. It is suggested that interactions between NPs and the PS must be related to the surfactant adsorption on the suspended particles, while in the case of surface modified clay NPs the additional washout of surface-active components may be expected. It is speculated that observed changes in surface properties of the surfactant may be associated with undesired health effects following extensive inhalation of aluminosilicate NPs in the workplace. PMID- 23363038 TI - Adverse effects of wood smoke PM(2.5) exposure on macrophage functions. AB - Epidemiological studies have shown a correlation between chronic biomass smoke exposure and increased respiratory infection. Pulmonary macrophages are instrumental in both the innate and the adaptive immune responses to respiratory infection. In the present study, in vitro systems were utilized where alveolar macrophages (AM) and bone marrow-derived macrophages (BMdM) were exposed to concentrated wood smoke-derived particulate matter (WS-PM) and mice were exposed in vivo to either concentrated WS-PM or inhaled WS. In vivo studies demonstrated that WS-exposed mice inoculated with Streptococcus pneumoniae had a higher bacterial load 24 h post-exposure, and corresponding AM were found to have decreased lymphocyte activation activity. Additionally, while classic markers of inflammation (cellular infiltration, total protein, neutrophils) were not affected, there were changes in pulmonary macrophages populations, including significant decreases in macrophages expressing markers of activation in WS exposed mice. The lymphocyte activation activity of WS-PM-exposed AM was significantly suppressed, but the phagocytic activity appeared unchanged. In an effort to determine a pathway for WS-induced suppression, RelB activation, assessed by nuclear translocation, was observed in AM exposed to either inhaled WS or instilled WS-PM. Finally, an analysis of WS-PM fractions determined the presence of 4-5 polycyclic aromatic hydrocarbons (PAHs), and preliminary work suggests a potential role for these PAHs to alter macrophage functions. These studies show a decreased ability of WS-exposed pulmonary macrophages to effectively mount a defense against infection, the effect lasts at least a week post-exposure, and appears to be mediated via RelB activation. PMID- 23363040 TI - Association of Inhalation Toxicologists' (AIT) review of regulatory aspects for inhalation toxicology studies. AB - Regulatory guidelines are intended to provide recommendations on ways to achieve greater harmonization in the interpretation and application of technical procedures and requirements for product registration in order to reduce or obviate replication of the testing carried out during the research and development of new products. The objectives of such harmonization are more economical use of human, animal and material resources; the elimination of unnecessary delay in the global development and availability of new products while maintaining safeguards on quality, safety and efficacy; and the fulfillment of regulatory obligations to protect public health. PMID- 23363041 TI - Acute impact of active and passive electronic cigarette smoking on serum cotinine and lung function. AB - CONTEXT: Electronic cigarettes (e-cigarettes) are becoming increasingly popular yet their effects on health remain unknown. OBJECTIVE: To conduct the first comprehensive and standardized assessment of the acute impact of active and passive e-cigarette smoking on serum cotinine and lung function, as compared to active and passive tobacco cigarette smoking. MATERIALS AND METHODS: Fifteen smokers (>=15 cigarettes/day; seven females; eight males) and 15 never-smokers (seven females; eight males) completed this repeated-measures controlled study. Smokers underwent a control session, an active tobacco cigarette (their favorite brand) smoking session and an active e-cigarette smoking session. Never-smokers underwent a control session, a passive tobacco cigarette smoking session and a passive e-cigarette smoking session. Serum cotinine, lung function, exhaled carbon monoxide and nitric oxide were assessed. The level of significance was set at p <= 0.001 to adjust for multiple comparisons. RESULTS: e-Cigarettes and tobacco cigarettes generated similar (p > 0.001) effects on serum cotinine levels after active (60.6 +/- 34.3 versus 61.3 +/- 36.6 ng/ml) and passive (2.4 +/- 0.9 versus 2.6 +/- 0.6 ng/ml) smoking. Neither a brief session of active e-cigarette smoking (indicative: 3% reduction in FEV1/FVC) nor a 1 h passive e-cigarette smoking (indicative: 2.3% reduction in FEV1/FVC) significantly affected the lung function (p > 0.001). In contrast, active (indicative: 7.2% reduction in FEV1/FVC; p < 0.001) but not passive (indicative: 3.4% reduction in FEV1/FVC; p = 0.005) tobacco cigarette smoking undermined lung function. CONCLUSION: Regarding short-term usage, the studied e-cigarettes generate smaller changes in lung function but similar nicotinergic impact to tobacco cigarettes. Future research should target the health effects of long-term e-cigarette usage, including the effects of nicotine dosage. PMID- 23363042 TI - Carbon monoxide-related deaths in Ankara between 2001 and 2011. AB - OBJECTIVE: The aim of the present study was to describe the epidemiology of unintentional carbon monoxide (CO) poisonings (between 2001 and 2011) in Ankara, Turkey. METHODS: Data were collected from the records of Ankara Branch of Council of Forensic Medicine and the licensed official institutes and hospitals for medico-legal autopsies. A total of 10,720 medico-legal autopsy reports were obtained and reviewed by the authors. RESULTS: Among 622 fatal poisoning cases during the period, 380 deaths were due to unintentional CO poisoning. The mean CO saturation of the groups was 55.4 +/- 13.4 (% saturation). The minimum and maximum levels of CO in blood was 3.6 and 86.5 (% saturation), respectively. Of all the fatal poisonings determined by Ankara Branch of Council of Forensic Medicine, CO poisoning was the most common mortality cause (61.1%). Among the cases, 301 (79.2%) were found to be death in their houses, 43 (11.3%) in hospitals, 15 (3.9%) in their workplaces and 11 (2.9%) in some public places such as park and garden. Most of the cases were from the capital city of Turkey, Ankara (n = 203, 53.4%). When we compared the cities according to their population, it was realized that the highest death rate due to CO poisoning was in Kirikkale (12.3/100,000), followed by Karabuk (8.3/100,000), Cankiri (7.8/100,000) and Kirsehir (5.0/100,000). DISCUSSION AND CONCLUSION: These findings add new data to the pool of knowledge in terms of the need of safety, proper heating system instructions and more education on CO poisoning in Turkey. PMID- 23363043 TI - Evaluation of pulmonary function within a cohort of flavorings workers. AB - OBJECTIVES: We present a re-analysis of a recent Health Hazard Evaluation (HHE) that was performed by the US National Institute for Occupational Safety and Health (NIOSH) regarding the pulmonary status of workers at a flavorings manufacturing facility. This facility has used acetaldehyde, acetoin, benzaldehyde, butyric acid, diacetyl and many other flavoring chemicals for many years. METHODS: Ten years of spirometry testing and job descriptions data on 112 workers were analyzed by the authors and by NIOSH. Using NIOSH's exposure assessment criteria, we compared the prevalence of restrictive findings (as determined by spirometry testing) in production workers to an internal control group that had reduced or no potential for exposure to flavoring chemicals. NIOSH used multiple linear regression to evaluate changes in pulmonary function by the exposure group. After our review of the NIOSH findings, we evaluated associations between longitudinal changes in pulmonary health and workplace exposures through the use of generalized estimating equations. We then compared our results to those obtained by NIOSH. RESULTS: We found that the prevalence of pulmonary restriction was similar in production workers and internal controls. We found no relationship between the magnitude of exposure to flavorings chemicals and observed decrements in pulmonary function. Our findings were contrary to those reported by NIOSH, most likely because of how we accounted for the longitudinal nature of the spirometric data. CONCLUSION: Many years of exposures to flavoring chemicals in this workplace, including diacetyl, were not found to produce an increased risk of abnormal spirometric findings. PMID- 23363044 TI - In vitro study of injury on human bronchial epithelial cells caused by gunpowder smog. AB - Smog inhalation is associated with acute respiratory symptoms in exposed victims. However, despite the evidence from cell injury caused by smog, a stable and practical apparatus used to treat cells with smog is necessary. The aim of this study is to develop a cell research platform of smoke inhalation injury. In the smog-generation device, a wireless electromagnetic heater was used to ignite gunpowder and generate smog. The quality of black powder was checked by the black powder burn rate, and experimental smog was indirectly checked by the amount of cell damage. The temperature and humidity were set at 37 degrees C +/- 1 degrees C and >=95% in the smog-cells reaction chamber, respectively. Factors including gunpowder dosages, smog-exposure time, the cell density, modes of exposure, volumes of smog, test durations, volumes of the cell culture medium and combustion velocity were measured. Coefficient variation of different batches of gunpowder and smog were less than 4% and 9%, respectively. With larger gunpowder dosage and longer exposure time, cell injury appeared to increase. When cells were cultured in 4 * 10(4)/well density in culture medium (1 mL/well), exposed to more than 10 L smog with filter screens above plates, detected after 24 h culture in cell incubator and gunpowder burned out within 5 s, smog had the best effect on cell injury. In conclusion, the experimental device can produce test smog stably and safely. The apparatus treating cells with smog can induce cell injury effectively, and the injury is positively correlated with smog concentration and exposure time. PMID- 23363045 TI - P-directed borylation of phenols. AB - Internal borylation occurs upon activation of aryl di-isopropylphosphinite boranes with HNTf(2) to give heterocyclic intermediates that can be reductively quenched to afford 6 or treated with KHF(2) to give the phenolic potassium aryl trifluoroborate salts 10. The latter salts are useful for Pd-catalyzed coupling with aryl iodides under Molander conditions, provided that precautions are taken to remove the KNTf(2) byproduct from the preceding KHF(2) step. PMID- 23363046 TI - Experimental application of pulsed laser-induced water jet for endoscopic submucosal dissection: mechanical investigation and preliminary experiment in swine. AB - BACKGROUND AND AIM: A current drawback of endoscopic submucosal dissection (ESD) for early-stage gastrointestinal tumors is the lack of instruments that can safely assist with this procedure. We have developed a pulsed jet device that can be incorporated into a gastrointestinal endoscope. Here, we investigated the mechanical profile of the pulsed jet device and demonstrated the usefulness of this instrument in esophageal ESD in swine. METHODS: The device comprises a 5-Fr catheter, a 14-mm long stainless steel tube for generating the pulsed water jet, a nozzle and an optical quartz fiber. The pulsed water jet was generated at pulse rates of 3 Hz by irradiating the physiological saline (4 degrees C) within the stainless steel tube with an holmium-doped yttrium-aluminum-garnet (Ho:YAG) laser at 1.1 J/pulse. Mechanical characteristics were evaluated using a force meter. The device was used only for the part of submucosal dissection in the swine ESD model. Tissues removed using the pulsed jet device and a conventional electrocautery device, and the esophagus, were histologically examined to assess thermal damage. RESULTS: The peak impact force was observed at a stand-off distance of 40 mm (1.1 J/pulse). ESD using the pulsed jet device was successful, as the tissue specimens showed precise dissection of the submucosal layer. The extent of thermal injury was significantly lower in the dissected bed using the pulsed jet device. CONCLUSION: The results showed that the present endoscopic pulsed jet system is a useful alternative for a safe ESD with minimum tissue injury. PMID- 23363048 TI - Preparation and characterization of transparent hydrophilic photocatalytic TiO2/SiO2 thin films on polycarbonate. AB - Transparent hydrophilic photocatalytic TiO2 coatings have been widely applied to endow the surfaces self-cleaning properties. A mixed metal oxide (TiO2/SiO2) can enhance the photocatalytic performance improving the ability of surface adsorption and increasing the amount of hydroxyl surface groups. The present work introduces a systematic study concerning the effect of the SiO2 addition to TiO2 films on the wettability, the photocatalytic activity, the adhesion strength, and the mechanical stability of the films. Transparent hydrophilic photocatalytic TiO2/SiO2 thin films were used to coat the polycarbonate (PC) substrate which was precoated by an intermediate SiO2 layer. The TiO2/SiO2 thin film was prepared employing a bulk TiO2 powder (Sachtleben Hombikat UV 100) and different molar ratios of tetraethoxysilane in acidic ethanol. A dip-coating process was used to deposit the films onto the polycarbonate substrate. The films were characterized by UV/vis spectrophotometry, FTIR spectroscopy, ellipsometry, BET, AFM, XRD, and water contact angle measurements. The mechanical stability and the UV resistance were examined. The photocatalytic activity of the coated surface was calculated from the kinetic analysis of methylene blue photodegradation measurements and compared with the photocatalytic activity of Pilkington Activ sheet glass. The coated surfaces displayed considerable photocatalytic activity and superhydrophilicity after exposure to UV light. The addition of SiO2 results in an improvement of the photocatalytic activity of the TiO2 film reaching the highest value at molar ratio TiO2/SiO2 equal to 1:0.9. The prepared films exhibit a good stability against UV(A) irradiation. PMID- 23363047 TI - The G-quadruplex ligand, SYUIQ-FM05, targets proto-oncogene c-kit transcription and induces apoptosis in K562 cells. AB - CONTEXT: N'-(7-Fluoro-5-N-methyl-10H-indolo[3,2-b]quinolin-5-ium)-N,N dimethylpropane-1,3-diamine iodide (SYUIQ-FM05) is a semi-synthetic derivative of cryptolepine which is from Cryptolepis sanguinolenta (Lindl.) Schlechter (Periplocaeae). This ligand inhibits telomerase activity by stabilizing the G quadruplex structure and induces growth arrest in cancer cells. OBJECTIVE: The anticancer activity of SYUIQ-FM05 via inhibiting c-kit transcription was investigated in leukemic cells. MATERIALS AND METHODS: The cytotoxicity of SYUIQ FM05 in K562 cells was evaluated using a cell viability assay and flow cytometry (FCM) at 0.4, 2.0, 10.0 and 20.0 nM. Under the same concentrations of SYUIQ-FM05 or 100 nM imatinib mesylate (IM), quantitative polymerase chain reaction (Q-PCR) investigated transcription of c-kit and bcl-2, and western blotting analyzed the expression levels of c-Kit, total mitogen-activated protein kinase kinases (MEKs), phospho-MEK (p-MEK), total extracellular regulated protein kinases (ERKs), phospho-ERK (p-ERK), Bcl-2 and Bax. RESULTS: SYUIQ-FM05 inhibited cellular growth with an IC(50) of 10.83 +/- 0.05 nM in K562 cells. c-Kit transcription was suppressed 2.69-, 4.39-, 7.71- and 10.52-fold at 0.4, 2.0, 10.0 and 20.0 nM SYUIQ-FM05, respectively, which produced proportional loss of total c Kit protein except IM. Both SYUIQ-FM05 and IM downregulated p-MEK and p-ERK. Furthermore, bcl-2 transcription was suppressed 1.58- and 1.86-fold at 10.0 and 20.0 nM SYUIQ-FM05, respectively, but 0.4 and 2.0 nM SYUIQ-FM05 had no effect. A decrease in Bcl-2 and an increase in Bax appeared in these treated cells. DISCUSSION AND CONCLUSION: These findings demonstrate that SYUIQ-FM05 could induce apoptosis in a leukemic cell line through inhibiting c-kit transcription, which supports the anticancer potency of SYUIQ-FM05 in c-Kit-positive leukemic cells. PMID- 23363050 TI - Regio- and enantioselective synthesis of pyrrolidines bearing a quaternary center by palladium-catalyzed asymmetric [3 + 2] cycloaddition of trimethylenemethanes. AB - Herein we describe the first use of disubstituted donors in the palladium catalyzed trimethylenemethane (TMM) cycloaddition resulting in an enantioselective synthesis of highly substituted pyrrolidines. These cyanoalkyl donors 1 form all-carbon quaternary centers in a catalytic, asymmetric, and intermolecular manner uniquely using diamidophosphite ligands L2 and L3, generating synthetically important chiral building blocks in good yields and selectivities. PMID- 23363049 TI - Exploring the diffusion of molecular oxygen in the red fluorescent protein mCherry using explicit oxygen molecular dynamics simulations. AB - The development of fluorescent proteins (FPs) has revolutionized cell biology research. The monomeric variants of red fluorescent proteins (RFPs), known as mFruits, have been especially valuable for tagging and tracking cellular processes in vivo. Determining oxygen diffusion pathways in FPs can be important for improving photostability and for understanding maturation of the chromophore. We use molecular dynamics (MD) calculations to investigate the diffusion of molecular oxygen in one of the most useful monomeric RFPs, mCherry. We describe a pathway that allows oxygen molecules to enter from the solvent and travel through the protein barrel to the chromophore. We calculate the free-energy of an oxygen molecule at points along the path. The pathway contains several oxygen hosting pockets, which are identified by the amino acid residues that form the pocket. We also investigate an RFP variant known to be significantly less photostable than mCherry and find much easier oxygen access in this variant. The results provide a better understanding of the mechanism of molecular oxygen access into the fully folded mCherry protein barrel and provide insight into the photobleaching process in these proteins. PMID- 23363051 TI - Laparoscopically harvested gastroepiploic artery for coronary artery bypass grafting. PMID- 23363052 TI - Evaluating ion exchange resin efficiency and oxidative capacity for the separation of uranium(IV) and uranium(VI). AB - BACKGROUND: Previously described methods to separate dissolved U(IV) from dissolved U(VI) under acidic anoxic conditions prior to laboratory analysis were ineffective with materials currently available commercially. Three strong anion exchange resins were examined for their efficiency in separating, recovering, and preserving both redox states during separation. RESULTS: Under oxic conditions, recovery of U(VI) from three exchange resins (Bio-Rad AG(r) 1x8 Poly-Prep(r) prefilled columns, Bio-Rad AG(r) 1x8 powder, and Dowex(r) 1x8 powder) ranged from 72% to 100% depending on the dosed mass, eluent volume, and resin selected. Dowex(r) 1x8 resin was the only resin found to provide 100% recovery of U(VI) with fewer than 5 bed volumes of eluent. Under anoxic conditions, all three resins oxidized U(IV) in aqueous solutions with relatively low U(IV) concentrations (<3x10-6 M). Resin-induced oxidation was observed visually using a leuco dye, safranin-o. Oxidants associated with the resin were irreversibly reduced by the addition of Ti(III). After anoxic resin pre-treatment, a series of U(IV)/U(VI) mixtures at micro-molar levels were prepared and separated using the Dowex(r) 1x8 resin with 100% recovery of both U(IV) and U(VI) with no resin induced changes in oxidation state. CONCLUSIONS: Currently available anion exchange resins with apparently identical physical properties were found to have significantly different recoveries for hexavalent uranium at micro-molar concentrations. A novel qualitative technique was developed to visually assess oxidative capacities of anion exchange resins under acidic anoxic conditions. A protocol was developed for pre-treatment and use of currently available anion exchange resins to achieve quantitative separation of U(IV) and U(VI) in aqueous solutions with low U(IV) concentrations. This method can be applied to future work to quantitatively assess dissolved U(IV) and U(VI) concentrations in both laboratory and field samples. PMID- 23363053 TI - Peptide ligands for pro-survival protein Bfl-1 from computationally guided library screening. AB - Pro-survival members of the Bcl-2 protein family inhibit cell death by binding short helical BH3 motifs in pro-apoptotic proteins. Mammalian pro-survival proteins Bcl-x(L), Bcl-2, Bcl-w, Mcl-1, and Bfl-1 bind with varying affinities and specificities to native BH3 motifs, engineered peptides, and small molecules. Biophysical studies have determined interaction patterns for these proteins, particularly for the most-studied family members Bcl-x(L) and Mcl-1. Bfl-1 is a pro-survival protein implicated in preventing apoptosis in leukemia, lymphoma, and melanoma. Although Bfl-1 is a promising therapeutic target, relatively little is known about its binding preferences. We explored the binding of Bfl-1 to BH3 like peptides by screening a peptide library that was designed to sample a high degree of relevant sequence diversity. Screening using yeast-surface display led to several novel high-affinity Bfl-1 binders and to thousands of putative binders identified through deep sequencing. Further screening for specificity led to identification of a peptide that bound to Bfl-1 with K(d) < 1 nM and very slow dissociation from Bfl-1 compared to other pro-survival Bcl-2 family members. A point mutation in this sequence gave a peptide with ~50 nM affinity for Bfl-1 that was selective for Bfl-1 in equilibrium binding assays. Analysis of engineered Bfl-1 binders deepens our understanding of how the binding profiles of pro-survival proteins differ and may guide the development of targeted Bfl-1 inhibitors. PMID- 23363054 TI - Modulatory role of quercetin against gamma radiation-mediated biochemical and morphological alterations of red blood cells. AB - PURPOSE: The present work was intended to evaluate the radioprotective effect of quercetin against gamma radiation-induced oxidative stress on red blood cells (RBC). MATERIALS AND METHODS: Swiss albino male mice were treated with quercetin (100 mg/kg body wt) for three consecutive days prior to 5 Gy (60)Co-gamma irradiation. RBC was isolated to estimate the level of intracellular reactive oxygen species (ROS), membrane lipid peroxidation (LPO), intracellular reduced glutathione (GSH), mean corpuscular hemoglobin concentration (MCHC), osmotic fragility and morphological alterations by atomic force microscope (AFM). RESULTS: Irradiation increased intracellular ROS and membrane LPO whereas it decreased the intracellular GSH. Quercetin pretreatment ameliorated these alterations. The MCHC value decreased after irradiation whereas quercetin pretreatment restored it. The average osmotic fragility (H50) and the maximum rate of hemolysis (dH/dC)max increased after irradiation. Quercetin pretreatment decreased the H50 and (dH/dC)max. The AFM study showed that irradiation transformed RBC from biconcave to echinocytes, increased their surface roughness and decreased the vertical distance whereas pretreatment of quercetin significantly prevented both the alterations. CONCLUSIONS: Gamma radiation produced ROS and LPO which rendered oxidative stress and ultimately damaged RBC whereas quercetin ameliorated these changes and protected RBC from radiation mediated damage. PMID- 23363055 TI - Involvement of the cholinergic basal forebrain nuclei in spinocerebellar ataxia type 2 (SCA2). AB - AIMS: Spinocerebellar ataxia type 2 (SCA2) belongs to the CAG repeat or polyglutamine diseases. Along with a large variety of motor, behavioural and neuropsychological symptoms the clinical picture of patients suffering from this autosomal dominantly inherited ataxia may also include deficits of attention, impairments of memory, as well as frontal-executive and visuospatial dysfunctions. As the possible morphological correlates of these cognitive SCA2 deficits are unclear we examined the cholinergic basal forebrain nuclei, which are believed to be crucial for several aspects of normal cognition and may contribute to impairments of cognitive functions under pathological conditions. METHODS: We studied pigment-Nissl-stained thick tissue sections through the cholinergic basal forebrain nuclei (that is, medial septal nucleus, nuclei of the diagonal band of Broca, basal nucleus of Meynert) of four clinically diagnosed and genetically confirmed SCA2 patients and of 13 control individuals according to the pathoanatomical approach. The pathoanatomical results were confirmed by additional quantitative investigations of these nuclei in the SCA2 patients and four age- and gender-matched controls. RESULTS: Our study revealed a severe and consistent neuronal loss in all of the cholinergic basal forebrain nuclei (medial septal nucleus: 72%; vertical nucleus of the diagonal band of Broca: 74%; horizontal limb of the diagonal band of Broca: 72%; basal nucleus of Meynert: 86%) of the SCA2 patients studied. Damage to the basal forebrain nuclei was associated with everyday relevant cognitive deficits only in our SCA2 patient with an additional Braak and Braak stage V Alzheimer's disease (AD)-related tau pathology. CONCLUSIONS: The findings of the present study: (1) indicate that the mutation and pathological process underlying SCA2 play a causative role for this severe degeneration of the cholinergic basal forebrain nuclei and (2) may suggest that degeneration of the cholinergic basal forebrain nuclei per se is not sufficient to cause profound and global dementia detrimental to everyday practice and activities of daily living. PMID- 23363056 TI - Optimal number and distribution of points selected on the vertebra for surface matching in CT-based spinal navigation. AB - OBJECTIVE: CT-based spinal navigation systems have widespread clinical applications, and spatial registration is a major source of the application error for these systems. However, the feedback that a surgeon may receive from the system, i.e., the surface registration error (SRE), is misleading, and it is still unclear how to achieve an optimal registration. The objective of this study was to investigate how the number and distribution of the points selected on the posterior surface of the vertebra influence the spatial registration accuracy, and how an optimal distribution can be achieved. MATERIALS AND METHODS: We simulated the spatial registration in the image space to investigate how the number and distribution of points selected on the vertebra influenced the target registration error (TRE). First, we divided the posterior side of the vertebra into five zones and chose 30 points, evenly distributed in different combinations of zones, to simulate the points selected on the vertebra during real navigation. We registered these points to a point cloud representing the surface of the vertebra and calculated the SRE and TRE in the region of interest to determine which combination of zones was optimal. We then chose different numbers of points in the optimal zone combination to study the influence of the number of points on the registration accuracy. RESULTS: The combination including the lamina, both sides of the spinous process, and the four articular processes resulted in a smaller TRE than those combinations including only the lamina or the lamina with one other zone. Further enlarging the area by adding the transverse processes made no difference. In addition, the TRE decreased with the increase in the number of points, while the SRE remained almost unchanged. CONCLUSION: Surgeons should select approximately 30 points distributed evenly across the lamina, both sides of the spinous process, and the four articular processes for surface matching in CT-based spinal navigation. PMID- 23363057 TI - Molecular biomarker-based biokinetic modeling of a PCE-dechlorinating and methanogenic mixed culture. AB - Bioremediation of chlorinated ethenes via anaerobic reductive dechlorination relies upon the activity of specific microbial populations--most notably Dehalococcoides (DHC) strains. In the lab and field Dehalococcoides grow most robustly in mixed communities which usually contain both fermenters and methanogens. Recently, researchers have been developing quantitative molecular biomarkers to aid in field site diagnostics and it is hoped that these biomarkers could aid in the modeling of anaerobic reductive dechlorination. A comprehensive biokinetic model of a community containing Dehalococcoides mccartyi (formerly D. ethenogenes) was updated to describe continuously fed reactors with specific biomass levels based on quantitative PCR (qPCR)-based population data (DNA and RNA). The model was calibrated and validated with subsets of chemical and molecular biological data from various continuous feed experiments (n = 24) with different loading rates of the electron acceptor (1.5 to 482 MUeeq/L-h), types of electron acceptor (PCE, TCE, cis-DCE) and electron donor to electron acceptor ratios. The resulting model predicted the sum of dechlorination products vinyl chloride (VC) and ethene (ETH) well. However, VC alone was under-predicted and ETH was over predicted. Consequently, competitive inhibition among chlorinated ethenes was examined and then added to the model. Additionally, as 16S rRNA gene copy numbers did not provide accurate model fits in all cases, we examined whether an improved fit could be obtained if mRNA levels for key functional enzymes could be used to infer respiration rates. The resulting empirically derived mRNA "adjustment factors" were added to the model for both DHC and the main methanogen in the culture (a Methanosaeta species) to provide a more nuanced prediction of activity. Results of this study suggest that at higher feeding rates competitive inhibition is important and mRNA provides a more accurate indicator of a population's instantaneous activity than 16S rRNA gene copies alone as biomass estimates. PMID- 23363058 TI - Modulation of cytochromes P450 with xanthone-based molecules: from aromatase to aldosterone synthase and steroid 11beta-hydroxylase inhibition. AB - Imidazolylmethylflavones previously reported by us as aromatase inhibitors proved to be able to interact with aldosterone synthase (CYP11B2), a cytochrome P450 enzyme involved in the biosynthesis of the mineralcorticoid hormone aldosterone, and were used to obtain a pharmacophore model for this enzyme. Here, in the search for potential ligands for CYP11B2 and the related CYP11B1, a virtual screening of a small compounds library of our earlier synthesized aromatase inhibitors was performed and, according to the results and the corresponding biological data, led to the design and synthesis of a series of xanthones derivatives carrying an imidazolylmethyl substituent in position 1 and different substituents in position 4. Some very potent inhibitors were obtained; in particular, the 4-chlorine derivative was active in the low nanomolar or subnanomolar range on CYP11B2 and CYP11B1, respectively, proving that xanthone can be considered as an excellent scaffold, whose activity can be directed to different targets when appropriately functionalized. PMID- 23363059 TI - Ultrasonographic assessment of abdominal lymph nodes in puppies. PMID- 23363060 TI - A direct physiological trade-off between personal and social immunity. AB - Recent work shows that organisms possess two strategies of immune response: personal immunity, which defends an individual, and social immunity, which protects other individuals, such as kin. However, it is unclear how individuals divide their limited resources between protecting themselves and protecting others. Here, with experiments on female burying beetles, we challenged the personal immune system and measured subsequent investment in social immunity (antibacterial activity of the anal exudates). Our results show that increased investment in one aspect of personal immunity (wound repair) causes a temporary decrease in one aspect of the social immune response. Our experiments further show that by balancing investment in personal and social immunity in this way during one breeding attempt, females are able to defend their subsequent lifetime reproductive success. We discuss the nature of the physiological trade-off between personal and social immunity in species that differ in the degree of eusociality and coloniality, and suggest that it may also vary within species in relation to age and partner contributions to social immunity. PMID- 23363061 TI - Effect of N-acetylcysteine on pharmacokinetics of acetaminophen in piglets. PMID- 23363062 TI - Control of the graphene-protein interface is required to preserve adsorbed protein function. AB - Graphene's suite of useful properties makes it of interest for use in biosensors. However, graphene interacts strongly with hydrophobic components of biomolecules, potentially altering their conformation and disrupting their biological activity. We have immobilized the protein Concanavalin A onto a self-assembled monolayer of multivalent tripodal molecules on single-layer graphene. We used a quartz crystal microbalance (QCM) to show that tripod-bound Concanavalin A retains its affinity for polysaccharides containing alpha-D-glucopyrannosyl groups as well as for the alpha-D-mannopyranosyl groups located on the cell wall of Bacillus subtilis. QCM measurements on unfunctionalized graphene indicate that adsorption of Concanavalin A onto graphene is accompanied by near-complete loss of these functions, suggesting that interactions with the graphene surface induce deleterious structural changes to the protein. Given that Concanavalin A's tertiary structure is thought to be relatively robust, these results suggest that other proteins might also be denatured upon adsorption onto graphene, such that the graphene-biomolecule interface must be considered carefully. Multivalent tripodal binding groups address this challenge by anchoring proteins without loss of function and without disrupting graphene's desirable electronic structure. PMID- 23363063 TI - An efficient one-pot organocatalyzed synthesis of spiro[chroman-3,6'- furo[2,3 d]pyrimidine]-tetraones. AB - An efficient synthesis of new spiro[chroman-3,6'-furo[2,3-d]pyrimidine]- tetraones by an organocatalyzed three-component condensation reaction of aldehydes, barbituric acids and 3-bromo-4-hydroxy-2H-chromen-2-one in refluxing acetic acid in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is reported. We are hopeful that the products will lead to a wider range pharmacological and physiological activity. PMID- 23363064 TI - Biodegradability of Corexit 9500 and dispersed South Louisiana crude oil at 5 and 25 degrees C. AB - The reported persistence of the dioctyl sodium sulfosuccinate (DOSS) surfactant in Corexit 9500 in the oil plumes formed during the Deepwater Horizon oil spill has contributed to concerns regarding the biodegradability and bioavailability of dispersed oil and dispersants used as an oil spill countermeasure in the Gulf of Mexico. We studied the biodegradation of DOSS and dispersed South Louisiana crude oil (SLC) in laboratory microcosms. Two oil-degrading cultures from the Gulf of Mexico were isolated, one from the surface (meso) and one from close to the area of the Macondo well (cryo). Each was enriched on SLC, the former at 25 degrees C, the latter at 5 degrees C. Results indicated that the meso culture rapidly and completely degraded DOSS, alkanes, and aromatics. The cryo culture metabolized the same compounds but with a lag of 28 d and a remaining residual of iso-alkanes, n-C(30-35), and the 4-ring PAHs. PMID- 23363065 TI - The effect of the endothelin-1 receptor antagonist, bosentan, on patients with poorly controlled asthma: a 17-week, double-blind, placebo-controlled crossover pilot study. AB - OBJECTIVE: To determine the effect of bosentan on subjects with poorly controlled asthma. METHODS: This was a double-blind, placebo-controlled crossover pilot study. Subjects were poorly controlled on anti-inflammatory and long acting beta agonist therapy, and had a baseline forced expiratory volume in 1 second (FEV1) percent of predicted of 40 -70%. Subjects were randomized to receive either bosentan or placebo at the therapeutic dose of 125 mg twice a day for 4 weeks, and then crossed over to the alternate therapy. The asthma control test, asthma symptom scores, rescue albuterol use, and FEV1 were measured at baseline and during the last week of bosentan and placebo. Acute changes in FEV1 were measured after the initial therapeutic bosentan and placebo dose. RESULTS: Seven of eleven randomized subjects completed the protocol. There was no difference in change in FEV1 after the bosentan phase when compared with placebo (+0.08 +/- 0.31 L and +0.23 +/- 0.26 L p = .34). Changes from baseline values in the asthma control test and asthma symptom scores were also similar in bosentan and placebo phases (+1.71 +/- 3.99 and +4.57 +/- 4.39 p = .16) and (+0.14 +/- 9.3 and -0.29 +/- 5.28 p = .93). Rescue beta-agonist use did not change significantly during the last week of the bosentan phase when compared with placebo phase (-5.86 +/- 0.94 puffs and -5.14 +/- 16.85 puffs p = .94). Additionally, there was no difference in the change in FEV1 4 hours after bosentan 125 mg and placebo (-0.08 L +/- 0.07 vs. +0.04 L +/- 0.20 p = .20). CONCLUSIONS: In this pilot study, 4 weeks of bosentan did not improve FEV1, beta-agonist use, asthma symptom score, or asthma control test score in patients with poorly controlled asthma when compared with placebo. PMID- 23363066 TI - Anti-fatigue property of Cordyceps guangdongensis and the underlying mechanisms. AB - CONTEXT: Cordyceps guangdongensis T.H. Li, Q.Y. Lin & B. Song (Cordycipitaceae) is a nontoxic folk medicine and can be cultivated, with noticeable effects of anti-H9N2, life-prolonging and treating chronic renal failure. OBJECTIVE: The anti-fatigue effect of C. guangdongensis, possible mechanism and active constituent were investigated. MATERIALS AND METHODS: Treatment mice were treated with C. guangdongensis powder (0.455, 0.91 and 1.82 g/kg bw daily for low, middle and high doses, respectively); treatment rats were fed, respectively, with ethanol, petroleum ether, ethyl acetate, n-butanol, aqueous phase and hot water extract fractions, for 30 d. Forced swimming time to exhaustion, blood urea nitrogen (BUN) and hepatic glycogen (HG) levels of mice and blood lactic acid (BLC) levels of rats were determined. RESULTS: The swimming times to exhaustion of mice were very significantly (p < 0.01) longer in low-, middle- and high-dose groups (respectively 1.87-, 1.94- and 1.88-times), and significantly (p < 0.05) longer in the n-butanol fraction group (1.52-times), hot water extract group (1.88- times) and refined polysaccharide group (2.66-times) than in blank control; the BLC levels of rats were significantly (p < 0.05) lower in the ethyl alcohol partition group (84.8%), the n-butanol fraction group (84.0%) and the hot water extract group (84.4 %) than in blank. The BUN and HG levels were not significantly different. DISCUSSION AND CONCLUSION: Cordyceps guangdongensis can potently alleviate fatigue through reducing the accumulation of BLC; a functional constituent was the refined polysaccharide. This might become a new functional food for fatigue resistance. PMID- 23363067 TI - Analgesic and anti-inflammatory activity of podophyllotoxin derivatives. AB - CONTEXT: Podophyllotoxin is a natural product that inhibits the polymerization of tubulin and has served as a prototype for the development of diverse antitumor agents in clinical use, such as etoposide, teniposide and etopophos. Reumacon, another semisynthetic derivative, reached its clinical phase for the treatment of rheumatoid arthritis. OBJECTIVE: This study investigated the analgesic and anti inflammatory properties of three compound derivatives from podophyllotoxin. MATERIALS AND METHODS: During a phytochemical study performed on Juniperus thurifera Linne (Cupressaceae) leaves, among other products, several cyclolignans, such as podophyllotoxin, deoxypodophyllotoxin, deoxypicropodophyllotoxin and thuriferic acid were isolated. These compounds, obtained afterwards through semisynthesis, were assayed as analgesic and anti inflammatory agents. Additionally, the cytotoxic activity of thuriferic acid was evaluated in three cancer cell lines, P-388, A-549 and HT-29, and these data were compared with previous cytotoxicity results obtained for the other three compounds. RESULTS: Analgesic activity results showed that deoxypicropodophyllin is as effective as deoxypodophyllotoxin to inhibit nociceptive perception induced by acetic acid in mice (77.8% +/- 4.1% and 71.3% +/- 6.5%, respectively), while its cytotoxicity [1.01 * 10(-7) (GI50 M)] is 100-fold less. Other set of experiments showed that thuriferic acid, a derivative of podophyllotoxin a thousand times less citotoxic [1.21 * 10(-5) (GI50 M)] than deoxypodophyllotoxin, caused significant inhibition of paw edema development in the carrageenan-induced inflammation test (63.4% +/- 3.3%), effect comparable to those of deoxypodophyllotoxin (66.3% +/- 4.4%), and the standard drug indomethacin (61.5% +/- 2.5%). CONCLUSION: We conclude that deoxypicropodophyllotoxin and thuriferic acid are effective in reducing edema formation. However, deoxypicropodophyllin is more related with analgesic activity than anti-inflammatory effect. PMID- 23363068 TI - Anti-obesity effects of galangin, a pancreatic lipase inhibitor in cafeteria diet fed female rats. AB - CONTEXT: Alpinia galanga Willd (Zingiberaceae) (AG) is a rhizomatous herb widely cultivated in shady regions of Malaysia, India, Indochina and Indonesia. It is used in southern India as a domestic remedy for the treatment of rheumatoid arthritis, cough, asthma, obesity, diabetes, etc. It was reported to have anti obesity, hypoglycemic, hypolipidemic and antioxidant properties. OBJECTIVE: A flavonol glycoside, galangin, was isolated from AG rhizomes. Based on its in vitro pancreatic lipase inhibitory effect, the study was further aimed to clarify whether galangin prevented obesity induced in female rats by feeding cafeteria diet (CD) for 6 weeks. MATERIALS AND METHODS: The in vitro pancreatic lipase inhibitory effect of galangin was determined by measuring the release of oleic acid from triolein. For in vivo experiments, female albino rats were fed CD with or without 50 mg/kg galangin for 6 weeks. Body weight and food intake was measured at weekly intervals. On day 42, serum lipids levels were estimated and then the weight of liver and parametrial adipose tissue (PAT) was determined. The liver lipid peroxidation and triglyceride (TG) content was also estimated. RESULTS: The IC50 value of galangin for pancreatic lipase was 48.20 mg/mL. Galangin produced inhibition of increased body weight, energy intake and PAT weight induced by CD. In addition, galangin produced a significant decrease in serum lipids, liver weight, lipid peroxidation and accumulation of hepatic TGs. CONCLUSION: Galangin present in AG rhizomes produces anti-obesity effects in CD fed rats; this may be mediated through its pancreatic lipase inhibitory, hypolipidemic and antioxidant activities. PMID- 23363069 TI - Bioactivity-guided isolation of cytotoxic constituents from three medicinal plants. AB - CONTEXT: The ethanol extracts and their fractions of three Indian medicinal plants, Ervatamia coronaria (Jacq.) Stapf, (Apocynaceae), Mimosa pudica L. (Mimosaceae) and Caesalpinia bonduc (L.) Roxb. (Caesalpiniaceae) were tested for their cytotoxic activity in the brine shrimp lethality (BSL) bioassay and in various cancer cell lines. The plants were selected based on their traditional use in the treatment of cancer/tumors. OBJECTIVES: To investigate the in vitro cytotoxicity of Ervatamia coronaria, Mimosa pudica and Caesalpinia bonduc. MATERIALS AND METHODS: Ethanolic extracts and their fractions of E. coronaria, M. pudica and C. bonduc were subjected to cytotoxicity studies using BSL bioassay method with concentrations of 10, 50, 100, 500 and 1000 ug/ml. The alkaloid fraction of E. coronaria with significant cytotoxicity in BSL bioassay was subjected to in vitro cytotoxicity studies with HT-29, A-549, HepG-2, MCF-7 and L 6 cell lines at concentrations of 12.5, 25, 50, 100 and 200 ug/ml and a DNA fragmentation study using the HT-29 cell line. RESULTS: The alkaloid fractions of E. coronaria and M. pudica showed significant cytotoxicity with LC50 values of 65.83 and 85.10 ug/ml in the BSL bioassay, respectively. The purified alkaloid fraction of E. coronaria exhibited highest cytotoxicity in HT-29, A-549 and MCF-7 cell lines with IC50 values of 32.5, 47.5 and 72.5 ug/ml, respectively, and induced DNA fragmentation in the HT-29 cell line at a concentration of 65 ug/ml. CONCLUSION: The alkaloid fraction of E. coronaria exhibited significant cytotoxicity. Alkaloids such as ervatamine, apparicine and coronaridine that were earlier reported may be responsible for this activity. PMID- 23363070 TI - Antidepressant-like effects of essential oil and asarone, a major essential oil component from the rhizome of Acorus tatarinowii. AB - CONTEXT: Depression is one of the most common psychiatric diseases. Acorus tatarinowii Schott (Araceae) has shown many bioactivities in treatment of senile dementia and epilepsy. However, there is no report on antidepressant-like effects of the essential oil (EO) and its major components on animals under standardized experimental procedures. OBJECTIVE: This study was designed to investigate the antidepressant properties of EO and asarones from the rhizomes of A. tatarinowii. MATERIALS AND METHODS: Gas chromatography-mass spectrometry (GC/MS) was used to determine the composition of EO. The forced swimming test (FST), tail suspension test (TST) and open-field test (OFT) were used to evaluate the antidepressant like effects of EO and asarones. EO [30, 60, 120 or 240 mg/kg, per os (p.o.)], asarones (alpha-asarone and beta-asarone) [5, 10 and 20 mg/kg, intraperitoneal (i.p.)] and imipramine (15 mg/kg, i.p.) were administered at 1 h, 30 min and 30 min before the test, respectively. RESULTS: From the results of GC/MS, it was found that the main components of the EO were alpha-asarone (9.18%) and beta asarone (68.9%). From the results of FST and TST, the immobility time can be reduced to 166 +/- 17 s (p < 0.01) and 146 +/- 15 s (p < 0.05) by EO at the dose of 120 mg/kg. Moreover, significant antidepressant-like effects were shown by alpha-asarone with the immobility time of 178 +/- 15 s (p < 0.05) and 159 +/- 17 s (p < 0.01) in FST, or 147 +/- 12 (p < 0.05) and 134 +/- 12 s (p < 0.01) in TST at the dose of 10 and 20 mg/kg. beta-Asarone also displayed antidepressant-like effects with an immobility time of 179 +/- 18 s (p < 0.05) in FST or 142 +/- 14 (p < 0.05) in TST at 20 mg/kg. However, no change in ambulation was observed in the OFT. CONCLUSION: The results obtained indicate that the EO and asarones from the rhizomes of A. tatarinowii can be considered as a new therapeutic agent for curing depression. PMID- 23363072 TI - Homopolar dihydrogen bonding in alkali metal amidoboranes: crystal engineering of low-dimensional molecular materials. AB - Hydrogen bonding is a predominant interaction in supramolecular chemistry. The absence of a conventional hydrogen bond donor in LiNMe(2)BH(3) and KNMe(2)BH(3) results in the formation of elaborate M...H-B polymeric arrays supported by heteropolar and homopolar H...H bonding, in a unique synergistic combination of unconventional intermolecular interactions. PMID- 23363071 TI - Downregulation of androgen receptor transcription by promoter g-quadruplex stabilization as a potential alternative treatment for castrate-resistant prostate cancer. AB - Androgen receptor (AR) signaling remains an important regulatory pathway in castrate-resistant prostate cancer, and its transcriptional downregulation could provide a new line of therapy. A number of small-molecule ligands have previously demonstrated the ability to stabilize G-quadruplex structures and affect gene transcription for those genes whose promoters contain a quadruplex-forming sequence. Herein, we report the probable formation of new G-quadruplex structure present in the AR promoter in a transcriptionally important location. NMR spectroscopy, circular dichroism, UV spectroscopy, and UV thermal melting experiments for this sequence are consistent with G-quadruplex formation. Fluorescence resonance energy transfer (FRET) melting studies have identified a novel compound, MM45, which appears to stabilize this G-quadruplex at submicromolar concentrations. The effects of MM45 have been investigated in prostate cancer cell lines where it has been shown to inhibit cell growth. A reporter assay intended to isolate the effect of MM45 on the G-quadruplex sequence showed dose-dependent transcriptional repression only when the AR promoter G-quadruplex sequence is present. Dose-dependent transcriptional repression of the AR by MM45 has been demonstrated at both a protein and mRNA level. This proof of concept study paves the route toward a potential alternative treatment pathway in castrate-resistant prostate cancer. PMID- 23363073 TI - Solvent interactions stabilize the polyproline II conformation of glycosylated oligoprolines. AB - In nature, proline residues carry several post-translational modifications (PTMs), including 4R hydroxylation and glycosylation. A recent study synthesized contiguously hydroxylated and glycosylated nonaproline peptides and revealed that both PTMs lead to a significant increase in the thermal stability of PPII relative to the unmodified oligoproline. The increased stability of the hydroxylated peptide can be explained by increased stability of the trans isomer due to stereoelectronic effects. However, the effects of glycosylation cannot be completely explained by stereoelectronics since previous experimental results indicate that 4R-glycosylation does not produce observable changes in the trans preference compared to 4R-hydroxylation. We therefore used sophisticated molecular modeling techniques to determine the reason for the further increase in thermal stability upon glycosylation. Free energy estimates obtained from adaptively biased molecular dynamics calculations in implicit (explicit) solvent are -9 kcal mol(-1) (-20 kcal mol(-1)) for the hydroxylated compound and -9 kcal mol(-1) (-46 kcal mol(-1)) for the glycosylated compound, indicating that direct solvent-peptide interactions are vital for explaining the glycosylation effects on PPII stability. Our data reveals for the first time that interactions between the hydroxyl groups in the glycosylated compound and water act in a complementary fashion with stereoelectronic effects to stabilize the PPII conformation in these substituted oligoproline peptides. PMID- 23363075 TI - Collagenous gastritis. AB - In the present paper, we report a case of rare collagenous gastritis. The patient was a 25-year-old man who had experienced nausea, abdominal distention and epigastralgia since 2005. Esophagogastroduodenoscopy (EGD) carried out at initial examination by the patient's local doctor revealed an extensively discolored depression from the upper gastric body to the lower gastric body, mainly including the greater curvature, accompanied by residual mucosa with multiple islands and nodularity with a cobblestone appearance. Initial biopsies sampled from the nodules and accompanying atrophic mucosa were diagnosed as chronic gastritis. In August, 2011, the patient was referred to Tohoku University Hospital for observation and treatment. EGD at our hospital showed the same findings as those by the patient's local doctor. Pathological findings included a membranous collagen band in the superficial layer area of the gastric mucosa, which led to a diagnosis of collagenous gastritis. Collagenous gastritis is an extremely rare disease, but it is important to recognize its characteristic endoscopic findings to make a diagnosis. PMID- 23363074 TI - 1p/19q testing has no significance in the workup of glioblastomas. AB - AIMS: To determine whether testing for isolated 1p or 19q losses, or as a codeletion, has any significance in the workup of glioblastomas (GBMs). METHODS: Upfront 1p/19q testing by fluorescence in situ hybridization (FISH) and/or polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) was done in 491 gliomas that were histologically diagnosed as GBMs. Outcomes were determined and measured against 1p/19q results. RESULTS: Twenty-eight showed apparent 1p/19q codeletion by either FISH and/or PCR-based LOH, but only 1/26 showed codeletion by both tests. Over 90% of tumours with apparent codeletion by either FISH or LOH also had 10q LOH and/or EGFR amplification, features inversely related to true whole-arm 1p/19q codeletion. Furthermore, only 1/28 tumours demonstrated an R132H IDH1 mutation. Neither 1p/19q codeletion by FISH nor LOH had an impact on GBM survival. Isolated losses of 1p or 19q also had no impact on survival. CONCLUSIONS: These data suggest that (i) 1p/19q testing is not useful on gliomas that are histologically GBMs; (ii) codeletion testing should be reserved only for cases with compatible morphology; and (iii) EGFR, 10q, and IDH1 testing can help act as safeguards against a false-positive 1p/19q result. PMID- 23363076 TI - Effects of tree species richness and composition on moose winter browsing damage and foraging selectivity: an experimental study. AB - The optimal foraging theory, the nutrient balance hypothesis, and the plant association theories predict that foraging decisions and resulting tree damage by large mammalian browsers may be influenced by the species richness and species composition of forest stands. This may lead to either associational susceptibility (increased damage on a focal plant in a mixed stand) or associational resistance (reduced damage in a mixed stand). Better understanding of the mechanisms and the relative importance of tree species richness and composition effects on foraging by mammalian browsers is needed to support sustainable management of forests and mammal populations. However, existing knowledge of forest diversity effects on foraging by large mammalian browsers comes largely from observational studies while experimental evidence is limited. We analysed winter browsing by moose (Alces alces L.) in a long-term, large-scale experiment in Finland, which represents a tree species richness gradient from monocultures to 2-, 3- and 5-species mixtures composed of Scots pine (Pinus sylvestris L.), Norway spruce (Picea abies L.), Siberian larch (Larix sibirica Ledeb.), silver birch (Betula pendula Roth.) and black alder (Alnus glutinosa L.). The intensity of browsing per plot increased with tree species richness while browsing selectivity decreased with tree species being targeted more equally in species-rich mixtures. Tree species composition of a plot was also an important determinant of intensity of browsing. The greatest browsing occurred in plots containing preferred species (pine and birch) while intermediate preference species (larch and alder) experienced associational susceptibility when growing with pine and birch compared with their monocultures or mixtures without pine and birch. In contrast, we found no evidence of associational resistance; the presence of a least preferred species (spruce) in a mixture had no significant effect on moose browsing on other tree species. We demonstrate that the presence of alternative forage species allows moose to spend longer opportunistically foraging in a plot, resulting in increased level of damage in species-rich stands and stands containing preferred tree species. Our results highlight the limitations of the optimal foraging theory in predicting browsing patterns and demonstrate the importance of associational effects within mixed stands. PMID- 23363078 TI - Surfaces with combined microscale and nanoscale structures: a route to mechanically stable superhydrophobic surfaces? AB - Materials with superhydrophobic properties are usually generated by covering the surfaces with hydrophobic nanoscale rough features. A major problem, however, for any practical application of such strongly water-repellent surfaces is the mechanical fragility of the nanostructures. Even moderate forces caused by touching or rubbing the surfaces are frequently strong enough to destroy the nanostructures and lead to the loss of the superhydrophobic properties. In this article, we study the mechanical stability of superhydrophobic surfaces with three different topographies: nano- and microscale features and surfaces carrying a combination of both. The surfaces are generated by silicon etching and subsequent coating with a monolayer of a fluoropolymer (PFA). We perform controlled wear tests on the different surfaces and discuss the impact of wear on the wetting properties of the different surfaces. PMID- 23363077 TI - Fluorinated N,N-dialkylaminostilbenes repress colon cancer by targeting methionine S-adenosyltransferase 2A. AB - Methionine S-adenosyltransferase 2A (MAT2A) is the catalytic subunit for synthesis of S-adenosylmethionine (SAM), the principal methyl donor in many biological processes. MAT2A is up-regulated in many cancers, including liver cancer and colorectal cancer (CRC) and is a potentially important drug target. We developed a family of fluorinated N,N-dialkylaminostilbene agents, called FIDAS agents, that inhibit the proliferation of CRC cells in vitro and in vivo. Using a biotinylated FIDAS analogue, we identified the catalytic subunit of MAT2A as the direct and exclusive binding target of these FIDAS agents. MAT2B, an associated regulatory subunit of MAT2A, binds indirectly to FIDAS agents through its association with MAT2A. FIDAS agents inhibited MAT2A activity in SAM synthesis, and depletion of MAT2A by shRNAs inhibited CRC cell growth. A novel FIDAS agent delivered orally repressed CRC xenografts in athymic nude mice. These findings suggest that FIDAS analogues targeting MAT2A represent a family of novel and potentially useful agents for cancer treatment. PMID- 23363079 TI - Graphene-based photothermal agent for rapid and effective killing of bacteria. AB - Conventional antibiotic therapies are becoming less efficient due to the emergence of antibiotic-resistant bacterial strains. Development of novel antibacterial material to effectively inhibit or kill bacteria is crucial. A graphene-based photothermal agent, magnetic reduced graphene oxide functionalized with glutaraldehyde (MRGOGA), was synthesized for efficient capture and effective killing of both gram-positive Staphylococcus aureus ( S. aureus ) and gram negative Escherichia coli ( E. coli ) bacteria upon near-infrared (NIR) laser irradiation. In the present work, we took advantage of the excellent photothermal properties of reduced graphene oxide upon NIR laser irradiation and glutaraldehyde as an efficient capturing agent toward both bacteria. Its magnetic characteristic allows bacteria to be readily trapped in a small volume by the external magnet. The synergetic effects increase the heating extent by MRGOGA upon NIR laser irradiation and the killing of the captured bacteria. The survival rate and membrane integrity assay demonstrate that 80 ppm MRGOGA solution provided rapid and effective killing of up to 99% of both gram-positive and gram negative bacteria in 10 min upon NIR laser irradiation under batch operation mode. Graphene demonstrated better photothermal antibacterial efficiency than carbon nanotubes. Furthermore, a microfluidic chip system under continuous operation mode demonstrates the reusability of MRGOGA and offers a biocompatible platform for online phothothermal sterilization. PMID- 23363080 TI - Burden of treatment for chronic illness: a concept analysis and review of the literature. AB - CONTEXT: Treatment burden, the burden associated with the treatment and management of chronic illness, has not yet been well articulated. OBJECTIVE: Using Rodgers' (1989, Journal of Advanced Nursing, 14, 330-335) method of concept analysis, this review describes the ways in which treatment burden has been conceptualized to define the concept and to develop a framework for understanding its attributes, antecedents and consequences. METHODS: Leading databases were searched electronically between the years 2002 and 2011. To ensure the review focused on actual observations of the concept of interest, articles that did not measure treatment burden (either qualitatively or quantitatively) were excluded. An inductive approach was used to identify themes related to the concept of treatment burden. MAIN RESULTS: Thirty articles, identified from 1557 abstracts, were included in the review. The attributes of treatment burden include burden as a dynamic process, as a multidimensional concept, and comprising of both subjective and objective elements. Prominent predisposing factors (antecedents) include the person's age and gender, their family circumstances, possible comorbidity, high use of medications, characteristics of treatment and their relationship with their health-care provider. The most dominant consequences are poor health and well-being, non-adherence to treatment, ineffective resource use and burden on significant others. Furthermore, many of these consequences can also become antecedents, reflecting the cyclic and dynamic nature of treatment burden. CONCLUSION: The findings underscore the need for researchers and health care professionals to engage in collaborative discussions and make cooperative efforts to help alleviate treatment burden and tailor treatment regimens to the realities of people's daily lives. PMID- 23363081 TI - Spinal cord stimulation for complex regional pain syndrome type I: a prospective cohort study with long-term follow-up. AB - OBJECTIVES: Spinal cord stimulation (SCS) is an effective treatment for intractable complex regional pain syndrome type I pain. Long-term data are scarce on effectiveness, degree of pain relief, predictors, and complications. MATERIALS AND METHODS: From 1997 to 2008, 84 consecutive patients who received an implanted SCS system after positive test stimulation were included in the prospective study. Treatment effectiveness was assessed annually as measured by mean visual analog scale pain scores and with the Patients Global Impression of Change scale. Treatment success was defined as at least 30% mean pain relief at end point and treatment failure as explantation of the system. A Cox regression determined if baseline factors were associated with both these outcomes. RESULTS: During 11 years, 41% (95% CI: 27-55) of the patients experience at least 30% pain relief at assessment end point. During 12 years of follow-up 63% (95%CI: 41-85) of the implanted patients still use their SCS device at measured end point. Pain relief of at least 50% one week following test stimulation is associated with a higher probability of long-term treatment success. In 51 patients, 122 reinterventions were performed over 12 years; 13 were due to complications, 44 to battery changes, and 65 reinterventions were equipment related. CONCLUSION: SCS provides an effective long-term pain treatment for 63% (95%CI: 41-85) of implanted patients. Forty-one percent (95%CI: 27-55) of SCS treated patients have at least 30% pain reduction at measurement end point. The number of reinterventions after implantation due to equipment-related problems, battery changes, and complications is 122 over 12 years of follow-up. Sixty-one percent (N = 51) of the patients had at least one reintervention. Mean pain relief of at least 50% (visual analog scale) one week after the test stimulation is associated with long term treatment success. PMID- 23363082 TI - The temporal effects of parental divorce on youth substance use. AB - This article examines how the parental divorce process affects youth substance use at various stages relative to the divorce. With child-fixed-effect models and a baseline period that is long before the divorce, the estimates rely on within child changes over time. Youth are more likely to use alcohol 2-4 years before a parental divorce. After the divorce, youth have an increased risk of using alcohol and marijuana, with the effect for marijuana being 12.1 percentage points in the two years right after the divorce (p = .010). The magnitudes of the effects persist as time passes from the divorce. PMID- 23363083 TI - Computationally assisted assignment of kahalalide Y configuration using an NMR constrained conformational search. AB - Assignment of the absolute configuration of cyclic peptides frequently yields challenges, leaving one or more stereogenic centers unassigned due to small quantities of sample and the limited utility of Marfey's or other methods for assigning amino or hydroxy acids. Here, we report isolation of kahalalide Y (1) from Bryopsis pennata for the first time; in addition, the application of a combination of molecular modeling and NOE distance constraint calculations was utilized to determine the conformation of 1 and the absolute configuration of the final stereogenic center of 1. Using the Schrodinger suite, the structure of 1 was sketched in Maestro and minimized using the OPLS2005 force field in Macromodel. A conformational search was performed separately for structures having an R or S configuration at C-3 of the beta-hydroxy fatty acid subunit that completes the cyclic scaffold of 1, after which multiple minimizations for all generated conformers were carried out. The lowest energy conformers of R and S stereoisomers were then subjected to B3LYP geometry optimizations including solvent effects. The S stereoisomer was shown to be in excellent agreement with the NOE-derived distance constraints and hydrogen-bonding stability studies. PMID- 23363084 TI - Simulations of ultrasound propagation in random arrangements of elliptic scatterers: occurrence of two longitudinal waves. AB - Ultrasound propagation in clusters of elliptic (two-dimensional) or ellipsoidal (three-dimensional) scatterers randomly distributed in a fluid is investigated numerically. The essential motivation for the present work is to gain a better understanding of ultrasound propagation in trabecular bone. Bone microstructure exhibits structural anisotropy and multiple wave scattering. Some phenomena remain partially unexplained, such as the propagation of two longitudinal waves. The objective of this study was to shed more light on the occurrence of these two waves, using finite-difference simulations on a model medium simpler than bone. Slabs of anisotropic, scattering media were randomly generated. The coherent wave was obtained through spatial and ensemble-averaging of the transmitted wavefields. When varying relevant medium parameters, four of them appeared to play a significant role for the observation of two waves: (i) the solid fraction, (ii) the direction of propagation relatively to the scatterers orientation, (iii) the ability of scatterers to support shear waves, and (iv) a continuity of the solid matrix along the propagation. These observations are consistent with the hypothesis that fast waves are guided by the locally plate/bar-like solid matrix. If confirmed, this interpretation could significantly help developing approaches for a better understanding of trabecular bone micro-architecture using ultrasound. PMID- 23363085 TI - Shear surface waves in phononic crystals. AB - The existence of shear horizontal (SH) surface waves in two-dimensional periodic phononic crystals with an asymmetric depth-dependent profile is theoretically reported. Examples of dispersion spectra with bandgaps for subsonic and supersonic SH surface waves are demonstrated. The link between the effective (quasistatic) speeds of the SH bulk and surface waves is established. Calculation and analysis is based on the integral form of a projector on the subspace of evanescent modes which means no need for their explicit finding. This method can be extended to the vector waves and the three-dimensional case. PMID- 23363086 TI - Radiation force of an arbitrary acoustic beam on an elastic sphere in a fluid. AB - A theoretical approach is developed to calculate the radiation force of an arbitrary acoustic beam on an elastic sphere in a liquid or gas medium. First, the incident beam is described as a sum of plane waves by employing conventional angular spectrum decomposition. Then, the classical solution for the scattering of a plane wave from an elastic sphere is applied for each plane-wave component of the incident field. The net scattered field is expressed as a superposition of the scattered fields from all angular spectrum components of the incident beam. With this formulation, the incident and scattered waves are superposed in the far field to derive expressions for components of the radiation stress tensor. These expressions are then integrated over a spherical surface to analytically describe the radiation force on an elastic sphere. Limiting cases for particular types of incident beams are presented and are shown to agree with known results. Finally, the analytical expressions are used to calculate radiation forces associated with two specific focusing transducers. PMID- 23363087 TI - In situ estimation of applied biaxial loads with Lamb waves. AB - Spatially distributed arrays of piezoelectric disks are being applied to monitor structural integrity using Lamb waves. Applied loads directly affect waves propagating between array elements because of dimensional changes and the acoustoelastic effect. Resulting changes in phase velocity depend upon the propagation direction as well as the Lamb wave mode and frequency. This paper shows from numerical solutions of the acoustoelastic wave equation for an isotropic plate that it is possible to decouple the effects of a homogeneous biaxial stress into its two principal components. As a consequence of both this decoupling and material isotropy, the acoustoelastic response of a specific mode and frequency is described by only two constants, which can be determined from a uniaxial loading experiment. Using this formulation, a method is developed and verified via simulations to estimate an arbitrary biaxial load from phase velocity changes measured along multiple directions of propagation. Results from uniaxial loading experiments on two different plates further demonstrate the efficacy of the method. It is also shown that opening fatigue cracks may significantly degrade results by interfering with Lamb wave direct arrivals, but that this degradation can be mitigated by using a reduced set of data from unaffected paths of propagation. PMID- 23363088 TI - Doppler-based motion compensation algorithm for focusing the signature of a rotorcraft. AB - A computationally efficient algorithm was developed and tested to compensate for the effects of motion on the acoustic signature of a rotorcraft. For target signatures with large spectral peaks that vary slowly in amplitude and have near constant frequency, the time-varying Doppler shift can be tracked and then removed from the data. The algorithm can be used to preprocess data for classification, tracking, and nulling algorithms. The algorithm was tested on rotorcraft data. The average instantaneous frequency of the first harmonic of a rotorcraft was tracked with a fixed-lag smoother. Then, state space estimates of the frequency were used to calculate a time warping that removed the effect of a time-varying Doppler shift from the data. The algorithm was evaluated by analyzing the increase in the amplitude of the harmonics in the spectrum of a rotorcraft. The results depended upon the frequency of the harmonics and the processing interval duration. Under good conditions, the results for the fundamental frequency of the target (~11 Hz) almost achieved an estimated upper bound. The results for higher frequency harmonics had larger increases in the amplitude of the peaks, but significantly lower than the estimated upper bounds. PMID- 23363089 TI - Aeroacoustics of T-junction merging flow. AB - This paper reports a numerical study of the aeroacoustics of merging flow at T junction. The primary focus is to elucidate the acoustic generation by the flow unsteadiness. The study is conducted by performing direct aeroacoustic simulation approach, which solves the unsteady compressible Navier-Stokes equations and the perfect gas equation of state simultaneously using the conservation element and solution element method. For practical flows, the Reynolds number based on duct width is usually quite high (>10(5)). In order to properly account for the effects of flow turbulence, a large eddy simulation methodology together with a wall modeling derived from the classical logarithm wall law is adopted. The numerical simulations are performed in two dimensions and the acoustic generation physics at different ratios of side-branch to main duct flow velocities VR (=0.5,0.67,1.0,2.0) are studied. Both the levels of unsteady interactions of merging flow structures and the efficiency of acoustic generation are observed to increase with VR. Based on Curle's analogy, the major acoustic source is found to be the fluctuating wall pressure induced by the flow unsteadiness occurred in the downstream branch. A scaling between the wall fluctuating force and the efficiency of the acoustic generation is also derived. PMID- 23363090 TI - Rayleigh scattering of a spherical sound wave. AB - Acoustic Green's functions for a homogeneous medium with an embedded spherical obstacle arise in analyses of scattering by objects on or near an interface, radiation by finite sources, sound attenuation in and scattering from clouds of suspended particles, etc. An exact solution of the problem of diffraction of a monochromatic spherical sound wave on a sphere is given by an infinite series involving products of Bessel functions and Legendre polynomials. In this paper, a simple, closed-form solution is obtained for scattering by a sphere with a radius that is small compared to the wavelength. Soft, hard, impedance, and fluid obstacles are considered. The solution is valid for arbitrary positions of the source and receiver relative to the scatterer. Low-frequency scattering is shown to be rather sensitive to boundary conditions on the surface of the obstacle. Low frequency asymptotics of the scattered acoustic field are extended to transient incident waves. The asymptotic expansions admit an intuitive interpretation in terms of image sources and reduce to classical results in appropriate limiting cases. PMID- 23363091 TI - Determining probability distribution of coherent integration time near 133 Hz and 1346 km in the Pacific Ocean. AB - The hypothesis tested is that internal gravity waves limit the coherent integration time of sound at 1346 km in the Pacific ocean at 133 Hz and a pulse resolution of 0.06 s. Six months of continuous transmissions at about 18 min intervals are examined. The source and receiver are mounted on the bottom of the ocean with timing governed by atomic clocks. Measured variability is only due to fluctuations in the ocean. A model for the propagation of sound through fluctuating internal waves is run without any tuning with data. Excellent resemblance is found between the model and data's probability distributions of integration time up to five hours. PMID- 23363092 TI - Tracking beaked whales with a passive acoustic profiler float. AB - Acoustic methods are frequently used to monitor endangered marine mammal species. Advantages of acoustic methods over visual ones include the ability to detect submerged animals, to work at night, and to work in any weather conditions. A relatively inexpensive and easy-to-use acoustic float, the QUEphone, was developed by converting a commercially available profiler float to a mobile platform, adding acoustic capability, and installing the ERMA cetacean click detection algorithm of Klinck and Mellinger [(2011). J. Acoust. Soc. Am. 129(4), 1807-1812] running on a high-power DSP. The QUEphone was tested at detecting Blainville's beaked whales at the Atlantic Undersea Test and Evaluation Center (AUTEC), a Navy acoustic test range in the Bahamas, in June 2010. Beaked whale were present at AUTEC, and the performance of the QUEphone was compared with the Navy's Marine Mammal Monitoring on Navy Ranges (M3R) system. The field tests provided data useful to evaluate the QUEphone's operational capability as a tool to detect beaked whales and report their presence in near-real time. The range tests demonstrated that the QUEphone's beaked whale detections were comparable to that of M3R's, and that the float is effective at detecting beaked whales. PMID- 23363093 TI - Source levels of fin whale 20 Hz pulses measured in the Northeast Pacific Ocean. AB - Source levels of fin whale calls can be used to determine range to recorded vocalizations and to model maximum communication range between animals. In this study, source levels of fin whale calls were estimated using data collected on a network of eight ocean bottom seismometers in the Northeast Pacific Ocean. The acoustic pressure levels measured at the instruments were adjusted for the propagation path between the calling whales and the instruments using the call location and estimating losses along the acoustic travel path. A total of 1241 calls were used to estimate an average source level of 189 +/- 5.8 dB re 1MUPa at 1 m. This variability is largely attributed to uncertainties in the horizontal and vertical position of the fin whale at the time of each call and the effect of these uncertainties on subsequent calculations. Variability may also arise from station to station differences within the network. For call sequences produced by a single vocalizing whale, no consistent increase or decrease in source level was observed over the duration of a dive. Calls within these sequences that immediately followed gaps of 27 s or longer were classified as backbeat calls and were consistently lower in both frequency and amplitude. PMID- 23363094 TI - A comparison of two methods for phase response calibration of hydrophones in the frequency range 10-400 kHz. AB - A comparison is made of two methods for determining the phase response of hydrophones in the kilohertz frequency range: The three-transducer spherical-wave reciprocity method and the method of optical interferometry. The implementation of the methods and the corresponding experimental systems are described. To facilitate a comparison, the methods are used to determine the phase response of three commercially available measuring hydrophones over the frequency range from 10 to 400 kHz. The results are compared, showing agreement within the estimated uncertainties of the methods. An investigation is conducted into the sources of uncertainties in the methods which increase with frequency. The major sources of uncertainty are residual positioning errors giving rise to phase uncertainties; a significant problem for the reciprocity method is that it requires one hydrophone to be rotated during the measurement procedure. An additional source of uncertainty at higher frequencies may be present if the position of the sensing element is not central within the outer hydrophone boot. PMID- 23363095 TI - Characterization of metal matrix composites by linear ultrasonics and finite element modeling. AB - Titanium metal matrix composites (TiMMCs) offer advantages over traditional materials for aerospace applications due to the increased mechanical strength of the materials. But the non-destructive inspection of these materials, especially with ultrasound, is in an infancy stage. If the manufacturing process of TiMMC is not correctly controlled, then disbonds and voids between the fibers can result. The effective microstructure of the composite makes difficulty to interpret results from traditional ultrasound techniques because of the scattering caused by fibers; the scattering prevents the ultrasound from penetrating far into the composite region and produces a background signal masking any reflections from voids. In this paper, relatively low frequency ultrasound is used to probe the composite region, and the state of the composite (porosity) is inferred from the velocity of the ultrasound traversing the composite. The relationship between the velocity and porosity is complex in this regime, so finite element (FE) analysis is used to model the composite regions and relate the velocity to the porosity. The FE simulated results are validated by ultrasound velocity measurements. PMID- 23363096 TI - Transient wave propagation in the ring stiffened laminated composite cylindrical shells using the method of reverberation ray matrix. AB - The method of reverberation ray matrix is extended to investigate the transient wave propagation and early short time transient responses of the ring stiffened laminated composite cylindrical shells subjected to impact loads. The ring stiffened laminated cylindrical shells are modeled as the continuous coupling systems between the vibration of the un-stiffened laminated cylindrical shell and the motion of the curved beams. The dynamic models of the laminated cylindrical shell and curved beams in the Laplace phase space are established on the basis of the first order shear deformation theory. The reverberation ray matrix can be determined by the boundary and continuous conditions of the ring stiffened laminated cylindrical shell. Using the fast Fourier transform algorithm, the dynamic responses of the ring stiffened laminated cylindrical shells can be computed. Through the numerical simulations, it can be seen that the early short time transient accelerations of the ring stiffened laminated cylindrical shells under impact loads are very large, while the early short time transient shear strains and displacements are very small. Furthermore, the influences of the ring stiffener number and impact load types on the early short time transient responses of the ring stiffened laminated cylindrical shells are also investigated. PMID- 23363097 TI - Analytical approximations for low frequency band gaps in periodic arrays of elastic shells. AB - This paper presents and compares three analytical methods for calculating low frequency band gap boundaries in doubly periodic arrays of resonating thin elastic shells. It is shown that both Foldy-type equations (derived with lattice sum expansions in the vicinity of its poles) and a self-consistent scheme could be used to predict boundaries of low-frequency (below the first Bragg band gap) band gaps due to axisymmetric (n=0) and dipolar (n=1) shell resonances. The accuracy of the former method is limited to low filling fraction arrays, however, as the filling fraction increases the application of the matched asymptotic expansions could significantly improve approximations of the upper boundary of band gap related to axisymmetric resonance. The self-consistent scheme is shown to be very robust and gives reliable results even for dense arrays with filling fractions around 70%. The estimates of band gap boundaries can be used in analyzing the performance of periodic arrays (in terms of the band gap width) without using full semi-analytical and numerical models. The results are used to predict the dependence of the position and width of the low frequency band gap on the properties of shells and their periodic arrays. PMID- 23363098 TI - Retrieval of Green's function in the radiative transfer regime. AB - The field-field correlation function of an imperfectly diffuse acoustic field is shown to equal the (time derivative of) Green's function times the specific intensity of the noise at the position of the pseudo-source directed toward the pseudo-receiver. The identity is established in a high frequency limit in which stations are separated by distances large compared to a wavelength and in which equal-time correlations vary smoothly in space. The specific intensity is governed by a radiative transport equation. This observation permits interpretation of correlation amplitudes and promises to facilitate the retrieval of attenuation, site amplification factors, and scattering strengths from noise correlations. PMID- 23363099 TI - Panel acoustic contribution analysis. AB - Formulations are derived to analyze the relative panel acoustic contributions of a vibrating structure. The essence of this analysis is to correlate the acoustic power flow from each panel to the radiated acoustic pressure at any field point. The acoustic power is obtained by integrating the normal component of the surface acoustic intensity, which is the product of the surface acoustic pressure and normal surface velocity reconstructed by using the Helmholtz equation least squares based nearfield acoustical holography, over each panel. The significance of this methodology is that it enables one to analyze and rank relative acoustic contributions of individual panels of a complex vibrating structure to acoustic radiation anywhere in the field based on a single set of the acoustic pressures measured in the near field. Moreover, this approach is valid for both interior and exterior regions. Examples of using this method to analyze and rank the relative acoustic contributions of a scaled vehicle cabin are demonstrated. PMID- 23363100 TI - An experimental evaluation of the impact of scattering on sound field diffusivity. AB - This work provides a systematic experimental evaluation of the impact of scattering on sound field diffusivity in a proportionate medium-small sized room. A scale model is set up in many ways by increasing the amount of scattering, and detailing measurements of the reverberation time in each case. With the aid of statistical tools, the role of scattering in the process of achieving a diffuse sound field from initially non-diffuse conditions is outlined and a set of reference scattering threshold values is derived. It is found that the same values ensure the validity of the Sabine formula when corrections are adopted in its application. Reverberation time is also predicted in non-diffuse conditions by the Nilsson approach, and its performance is systematically compared with measurements. The Nilsson method was a better predictor of reverberation time under non-diffuse conditions than classical reverberation time formulas. However, for diffuse sound fields, the same method tended to diverge from measured values. An application using more realistic room conditions is developed together with computer simulations. The results outline that there is limited benefit to using computer-aided design models instead of simple formulas to predict reverberation time for non-diffuse sound fields in proportionate medium-small sized rooms. PMID- 23363101 TI - Enhancing rigid frame porous layer absorption with three-dimensional periodic irregularities. AB - This papers reports a three-dimensional (3D) extension of the model proposed by Groby et al. [J. Acoust. Soc. Am. 127, 2865-2874 (2010)]. The acoustic properties of a porous layer backed by a rigid plate with periodic rectangular irregularities are investigated. The Johnson-Champoux-Allard model is used to predict the complex bulk modulus and density of the equivalent fluid in the porous material. The method of variable separation is used together with the radiation conditions and Floquet theorem to derive the analytical expression for the acoustic reflection coefficient from the porous layer with 3D inhomogeneities. Finite element method is also used to validate the proposed analytical solution. The theoretical and numerical predictions agree well with the experimental data obtained from an impedance tube experiment. It is shown that the measured acoustic absorption coefficient spectrum exhibits a quasi-total absorption peak at the predicted frequency of the mode trapped in the porous layer. When more than one irregularity per spatial period is considered, additional absorption peaks are observed. PMID- 23363102 TI - Compact directional acoustic sensor using a multi-fiber optical probe. AB - A compact directional acoustic sensor is described which uses a two-fiber optical probe, a light emitting diode (LED), a photo-diode detector, and a slender cylindrical cantilever to the end of which is attached an optical reflector. Acoustically induced transverse displacement of the cantilever tip modulates the light reflected by it into the collection fiber, which conveys the light to a photo-detector. Directional sensitivity is achieved through the dependence of the collected light on the cosine of the angle between a line through the centers of the two fibers and the cantilever tip displacement (the sound direction). The sensor requires relatively low power, and its LED source has low levels of 1/f noise. These attributes make it a good choice for remote low frequency applications requiring long operating lifetimes. An analytic model of the acoustic response of the cantilever is constructed, which is partially verified using a finite element model and experimentally validated using measurements of the acoustic response in air. The model is used to predict to what extent and over what frequency band that response depends upon the acoustically generated flow (drag) force [Yuan et al., IEEE Sensor J. 8, 1114-1117 (2008)]. PMID- 23363103 TI - Analysis of concert hall acoustics via visualizations of time-frequency and spatiotemporal responses. AB - Acousticians and other practitioners alike often describe acoustic conditions in performance spaces with standard objective parameters. Apart from a few exceptions, the parameters are calculated by integrating the sound energy of the impulse responses over time; this makes them inadequate for researching the acoustics in detail, especially in the early part of the room impulse response. This paper proposes a method based on time-frequency and spatiotemporal presentations to overcome the lack of detail in the standard analysis. In brief, the proposed methods visualize the cumulative development of the sound field as a function of frequency or direction by forward-integrating the energy in the impulse response in short time frames. Analysis on the measurements from six concert halls concentrates particularly on interpreting the results in light of the seat dip effect. Earlier research has concluded that the seat dip effect is reduced by reflection from low overhead surfaces. In contrast, the current results indicate that the seat dip attenuation in the frequency response is corrected the best when the hall provides most lateral reflections. These findings suggest that the proposed analysis is suitable for explaining concert hall acoustics in detail. PMID- 23363104 TI - A free-field method to calibrate bone conduction transducers. AB - Bone conduction communication systems employ a variety of transducers with different physical and electroacoustic properties, and these transducers may be worn at various skull locations. Testing these systems thus requires a reliable means of transducer calibration that can be implemented across different devices, skull locations, and settings. Unfortunately, existing calibration standards do not meet these criteria. Audiometric bone conduction standards focus on only one device model and on limited skull locations. Furthermore, while mechanical couplers may be used for calibration, the general human validity of their results is suspect. To address the need for more flexible, human-centered calibration methods, the authors investigated a procedure for bone transducer calibration, analogous to free-field methods for calibrating air conduction headphones. Participants listened to1s third-octave noise bands (125-12,500 Hz) alternating between a bone transducer and a loudspeaker and adjusted the bone transducer to match the perceived loudness of the loudspeaker at each test frequency. Participants tested two transducer models and two skull locations. Intra- and inter-subject reliability was high, and the resulting data differed by transducer, by location, and from the mechanical coupler. The described procedure is flexible to transducer model and skull location, requires only basic equipment, and directly yields perceptual data. PMID- 23363105 TI - Impulse-noise suppression in speech using the stationary wavelet transform. AB - An approach for detecting and removing impulse noise from speech using the wavelet transform is proposed. The approach utilizes the multi-resolution property of the wavelet transform, which provides finer time resolution at higher frequencies than the short-time Fourier transform to effectively identify and remove impulse noise. The paper then describes how the impulse-detection performance is dependent on certain wavelet features and their relationships with the impulse noise and the underlying speech signal. Performance comparisons carried out with an existing method show that the wavelet approach yields much better features for detecting the impulses. To remove the impulses, an algorithm that uses the stationary wavelet transform has been developed. The algorithm uses a two-step approach where the wavelet coefficients corresponding to the impulses are suppressed in the first step and then substituted by suitable coefficients located within the vicinity of the impulse in the second step. Performance evaluations with an existing method show that the proposed algorithm gives superior results. PMID- 23363106 TI - Multiuser acoustic communications with mobile users. AB - A multiuser receiver is developed that is capable of separating receptions from independent, mobile users whose transmissions overlap in both time and frequency. With respect to any one user's Doppler corrected signal, the other communication signals appear as multiple-access interference distributed across the Doppler dimension. A previously developed receiver composed of an adaptive time-reversal processor embedded within a successive interference cancellation framework is limited to stationary users. This paper extends the receiver to properly remove the interference from moving sources by modeling the effects of Doppler through the interference cancellation receiver. The combined receiver has the ability to remove interference in both the temporal and spatial domains, and this property is shown to be preserved even when users are in motion. When applied to data collected during a recent shallow water experiment (KAM11), the receiver is shown to be capable of separating packets in a two user system where one user is moving while the other is stationary. PMID- 23363107 TI - Dimensional feature weighting utilizing multiple kernel learning for single channel talker location discrimination using the acoustic transfer function. AB - This paper presents a method for discriminating the location of the sound source (talker) using only a single microphone. In a previous work, the single-channel approach for discriminating the location of the sound source was discussed, where the acoustic transfer function from a user's position is estimated by using a hidden Markov model of clean speech in the cepstral domain. In this paper, each cepstral dimension of the acoustic transfer function is newly weighted, in order to obtain the cepstral dimensions having information that is useful for classifying the user's position. Then, this paper proposes a feature-weighting method for the cepstral parameter using multiple kernel learning, defining the base kernels for each cepstral dimension of the acoustic transfer function. The user's position is trained and classified by support vector machine. The effectiveness of this method has been confirmed by sound source (talker) localization experiments performed in different room environments. PMID- 23363108 TI - Extraction of pulse repetition intervals from sperm whale click trains for ocean acoustic data mining. AB - The analysis of acoustic data from the ocean is a valuable tool to study free ranging cetaceans and anthropogenic noise. Due to the typically large volume of acquired data, there is a demand for automated analysis techniques. Many cetaceans produce acoustic pulses (echolocation clicks) with a pulse repetition interval (PRI) remaining nearly constant over several pulses. Analyzing these pulse trains is challenging because they are often interleaved. This article presents an algorithm that estimates a pulse's PRI with respect to neighboring pulses. It includes a deinterleaving step that operates via a spectral dissimilarity metric. The sperm whale (SW) produces trains with PRIs between 0.5 and 2 s. As a validation, the algorithm was used for the PRI-based identification of SW click trains with data from the NEMO-ONDE observatory that contained other pulsed sounds, mainly from ship propellers. Separation of files containing SW clicks with a medium and high signal to noise ratio from files containing other pulsed sounds gave an area under the receiver operating characteristic curve value of 0.96. This study demonstrates that PRI can be used for the automated identification of SW clicks and that deinterleaving via spectral dissimilarity contributes to algorithm performance. PMID- 23363109 TI - Near-field to far-field projection algorithm for free-field or buried scatterer. AB - A near-field to far-field projection algorithm is applied to a structure in the free-field case and generalized to a buried scatterer. The method of superposition is applied where the scattered field produced by the target may be approximated by the field produced by a number of point sources placed near the target. The source strengths are determined by requiring the field they produce to satisfy boundary conditions on the measurement surface. In the free-field case, the expression of the Green's function is simple. In the buried case, the two-domain Green's function may be expressed as an integral over special functions. Once the source strengths are determined, the far-field is computed as a superposition of the fields produced by the individual sources. The algorithm is tested on numerically generated data. PMID- 23363110 TI - Wave motion on the surface of the human tympanic membrane: holographic measurement and modeling analysis. AB - Sound-induced motions of the surface of the tympanic membrane (TM) were measured using stroboscopic holography in cadaveric human temporal bones at frequencies between 0.2 and 18 kHz. The results are consistent with the combination of standing-wave-like modal motions and traveling-wave-like motions on the TM surface. The holographic techniques also quantified sound-induced displacements of the umbo of the malleus, as well as volume velocity of the TM. These measurements were combined with sound-pressure measurements near the TM to compute middle-ear input impedance and power reflectance at the TM. The results are generally consistent with other published data. A phenomenological model that behaved qualitatively like the data was used to quantify the relative magnitude and spatial frequencies of the modal and traveling-wave-like displacement components on the TM surface. This model suggests the modal magnitudes are generally larger than those of the putative traveling waves, and the computed wave speeds are much slower than wave speeds predicted by estimates of middle-ear delay. While the data are inconsistent with simple modal displacements of the TM, an alternate model based on the combination of modal motions in a lossy membrane can also explain these measurements without invoking traveling waves. PMID- 23363111 TI - Maturation of the human medial efferent reflex revisited. AB - Past work applying otoacoustic emissions to gauge maturational status of the medial olivocochlear (MOC) reflex in human newborns has produced mixed results. The present study revisits the question while considering the dual nature of the 2f(1) - f(2) distortion product otoacoustic emission (DPOAE) and expanding measures of medial efferent function. Subjects included premature and term-born neonates, 6-month-old infants and young adults. The MOC reflex was elicited with contralateral acoustic stimulation (CAS) while shifts in amplitude and phase of the DPOAE, and its distortion and reflection components, were monitored. Overall, CAS-elicited reductions in DPOAE level did not differ among age groups. For all ages, the MOC reflex was strongest at frequencies below 1.5 kHz, and the reflection component of the DPOAE was most affected, showing maximally reduced amplitude and shallower phase slope when contralateral noise was presented. Results suggest that the MOC reflex likely reaches maturation prior to full-term birth. However, prematurely born neonates show markedly more episodes of CAS induced DPOAE level enhancement. This may be due to more intrusive component mixing in this age group or disruptions in the formation of the MOC pathway or synapse in the most premature neonates. PMID- 23363112 TI - Suppression tuning of distortion-product otoacoustic emissions: results from cochlear mechanics simulation. AB - This paper presents the results of simulating the acoustic suppression of distortion-product otoacoustic emissions (DPOAEs) from a computer model of cochlear mechanics. A tone suppressor was introduced, causing the DPOAE level to decrease, and the decrement was plotted against an increasing suppressor level. Suppression threshold was estimated from the resulting suppression growth functions (SGFs), and suppression tuning curves (STCs) were obtained by plotting the suppression threshold as a function of suppressor frequency. Results show that the slope of SGFs is generally higher for low-frequency suppressors than high-frequency suppressors, resembling those obtained from normal hearing human ears. By comparing responses of normal (100%) vs reduced (50%) outer-hair-cell sensitivities, the model predicts that the tip-to-tail difference of the STCs correlates well with that of intra-cochlear iso-displacement tuning curves. The correlation is poorer, however, between the sharpness of the STCs and that of the intra-cochlear tuning curves. These results agree qualitatively with what was recently reported from normal-hearing and hearing-impaired human subjects, and examination of intra-cochlear model responses can provide the needed insight regarding the interpretation of DPOAE STCs obtained in individual ears. PMID- 23363114 TI - Reduction of internal noise in auditory perceptual learning. AB - This paper examines what mechanisms underlie auditory perceptual learning. Fifteen normal hearing adults performed two-alternative, forced choice, pure tone frequency discrimination for four sessions. External variability was introduced by adding a zero-mean Gaussian random variable to the frequency of each tone. Measures of internal noise, encoding efficiency, bias, and inattentiveness were derived using four methods (model fit, classification boundary, psychometric function, and double-pass consistency). The four methods gave convergent estimates of internal noise, which was found to decrease from 4.52 to 2.93 Hz with practice. No group-mean changes in encoding efficiency, bias, or inattentiveness were observed. It is concluded that learned improvements in frequency discrimination primarily reflect a reduction in internal noise. Data from highly experienced listeners and neural networks performing the same task are also reported. These results also indicated that auditory learning represents internal noise reduction, potentially through the re-weighting of frequency specific channels. PMID- 23363113 TI - Central masking with bilateral cochlear implants. AB - Across bilateral cochlear implants, contralateral threshold shift has been investigated as a function of electrode difference between the masking and probe electrodes. For contralateral electric masking, maximum threshold elevations occurred when the position of the masker and probe electrode was approximately place-matched across ears. The amount of masking diminished with increasing masker-probe electrode separation. Place-dependent masking occurred in both sequentially implanted ears, and was not affected by the masker intensity or the time delay from the masker onset. When compared to previous contralateral masking results in normal hearing, the similarities between place-dependent central masking patterns suggest comparable mechanisms of overlapping excitation in the central auditory nervous system. PMID- 23363115 TI - Effects of temporal stimulus properties on the perception of across-frequency asynchrony. AB - The role of temporal stimulus parameters in the perception of across-frequency synchrony and asynchrony was investigated using pairs of 500-ms tones consisting of a 250-Hz tone and a tone with a higher frequency of 1, 2, 4, or 6 kHz. Subjective judgments suggested veridical perception of across-frequency synchrony but with greater sensitivity to changes in asynchrony for pairs in which the lower-frequency tone was leading than for pairs in which it was lagging. Consistent with the subjective judgments, thresholds for the detection of asynchrony measured in a three-alternative forced-choice task were lower when the signal interval contained a pair with the low-frequency tone leading than a pair with a high-frequency tone leading. A similar asymmetry was observed for asynchrony discrimination when the standard asynchrony was relatively small (<=20 ms) but not for larger standard asynchronies. Independent manipulation of onset and offset ramp durations indicated a dominant role of onsets in the perception of across-frequency asynchrony. A physiologically inspired model, involving broadly tuned monaural coincidence detectors that receive inputs from frequency selective onset detectors, was able to accurately reproduce the asymmetric distributions of synchrony judgments. The model provides testable predictions for future physiological investigations of responses to broadband stimuli with across frequency delays. PMID- 23363116 TI - The effects of unmodulated carrier fringes on the detection of frequency modulation. AB - Detection thresholds for 100 ms of either 5- or 20-Hz frequency modulation (FM) were measured at various temporal positions within a 600-ms, 4-kHz pure-tone carrier. The results indicated that the temporal position of the signal relative to the fringe influences detection thresholds, including an effect that is reminiscent of auditory backward recognition masking. A task involving frequency increments, rather than sinusoidal FM, yielded similar results. Additional manipulation of total carrier duration indicated that FM detection thresholds improve as the duration of the forward fringe increases, while a backward fringe only degrades performance in the absence of any forward fringe. The results suggest that listeners are insensitive to subtle frequency changes that occur at the onset of a longer stimulus and that the interaction between the opposing effects of the forward and backward fringes is not additive. PMID- 23363117 TI - Linking dynamic-range compression across the ears can improve speech intelligibility in spatially separated noise. AB - Recently introduced hearing devices allow dynamic-range compression to be coordinated at the two ears through a wireless link. This study investigates how linking compression across the ears might improve speech intelligibility in the presence of a spatially separated steady noise. An analysis of the compressors' behavior shows how linked compression can preserve interaural level differences (ILDs) and, compared to compression operating independently at each ear, improve the long-term apparent speech-to-noise ratio (SNR) at the ear with the better SNR. Speech intelligibility for normal-hearing listeners was significantly better with linked than with unlinked compression. The performance with linked compression was similar to that without any compression. The benefit of linked over unlinked compression was the same for binaural listening and for monaural listening to the ear with the better SNR, indicating that the benefit was due to changes to the signal at this ear and not to the preservation of ILDs. Differences in performance across experimental conditions were qualitatively consistent with changes in apparent SNR at the better ear. Predictions made using a speech intelligibility model suggest that linked compression could potentially provide a user of bilateral hearing aids with an improvement in intelligibility of up to approximately ten percentage points. PMID- 23363118 TI - Advantages from bilateral hearing in speech perception in noise with simulated cochlear implants and residual acoustic hearing. AB - Acoustic simulations were used to study the contributions of spatial hearing that may arise from combining a cochlear implant with either a second implant or contralateral residual low-frequency acoustic hearing. Speech reception thresholds (SRTs) were measured in twenty-talker babble. Spatial separation of speech and noise was simulated using a spherical head model. While low-frequency acoustic information contralateral to the implant simulation produced substantially better SRTs there was no effect of spatial cues on SRT, even when interaural differences were artificially enhanced. Simulated bilateral implants showed a significant head shadow effect, but no binaural unmasking based on interaural time differences, and weak, inconsistent overall spatial release from masking. There was also a small but significant non-spatial summation effect. It appears that typical cochlear implant speech processing strategies may substantially reduce the utility of spatial cues, even in the absence of degraded neural processing arising from auditory deprivation. PMID- 23363119 TI - Temporal modulation transfer function for efficient assessment of auditory temporal resolution. AB - Two common measures of auditory temporal resolution are the temporal modulation transfer function (TMTF) and the gap detection threshold (GDT). The current study addresses the lack of efficient psychophysical procedures for collecting TMTFs and the lack of literature on the comparisons of TMTF and GDT. Two procedures for efficient measurements of the TMTF are proposed: (1) A Bayesian procedure that adaptively chooses the stimulus modulation rate and depth to maximize the information gain from each trial and (2) a procedure that reduces the data collection to two adaptive staircase tracks. Results from experiments I and II showed that, for broadband carriers, these approaches provided similar results compared to TMTFs measured using traditional methods despite taking less than 10 min for data collection. Using these efficient procedures, TMTFs were measured from a large number of naive listeners and were compared to the gap detection thresholds collected from the same ears in experiment III. Results showed that the sensitivity parameter estimated from the TMTF measurements correlated well with the GDTs, whereas the cutoff rate is either uncorrelated or positively correlated with the gap detection threshold. These results suggest caution in interpreting a lower GDT as evidence for less sluggish temporal processing. PMID- 23363120 TI - Paralinguistic mechanisms of production in human "beatboxing": a real-time magnetic resonance imaging study. AB - Real-time magnetic resonance imaging (rtMRI) was used to examine mechanisms of sound production by an American male beatbox artist. rtMRI was found to be a useful modality with which to study this form of sound production, providing a global dynamic view of the midsagittal vocal tract at frame rates sufficient to observe the movement and coordination of critical articulators. The subject's repertoire included percussion elements generated using a wide range of articulatory and airstream mechanisms. Many of the same mechanisms observed in human speech production were exploited for musical effect, including patterns of articulation that do not occur in the phonologies of the artist's native languages: ejectives and clicks. The data offer insights into the paralinguistic use of phonetic primitives and the ways in which they are coordinated in this style of musical performance. A unified formalism for describing both musical and phonetic dimensions of human vocal percussion performance is proposed. Audio and video data illustrating production and orchestration of beatboxing sound effects are provided in a companion annotated corpus. PMID- 23363121 TI - Phonovibrographic wavegrams: visualizing vocal fold kinematics. AB - Recently, endoscopic high-speed laryngoscopy has been established for commercial use as a state-of-the-art technique to examine vocal fold kinematics. Since modern cameras provide sampling rates of several thousand frames per second, a high volume of data has to be considered for visual and objective analysis. A method for visualizing endoscopic high speed videos in three-dimensional cycle based graphs combining and extending the approaches of phonovibrograms and electroglottographic wavegrams is presented. To build a phonovibrographic wavegram, individual cycles of a phonovibrogram are segmented, normalized in cycle duration, and concatenated over time. For analyzing purposes, the emerging three-dimensional scalar field is visualized with different rendering techniques providing information of different aspects of vocal fold kinematics. The phonovibrographic wavegram incorporates information about the glottal closure type, size, and location of the amplitudes, symmetry, periodicity, and phase information. The potential of the approach to visualize the characteristics of vocal fold vibration in a compact and intuitive way is demonstrated within two healthy and three pathologic subjects. The phonovibrographic wavegram allows a comprehensive analysis of vocal fold kinematics and reveals information that remains hidden with other visualization techniques. PMID- 23363122 TI - Training listeners to report the acoustic correlate of formant-frequency scaling using synthetic voices. AB - The vocal tract length of a speaker is the primary determinant of the range of formant frequencies (FFs) produced by that speaker. Listeners have demonstrated sensitivity to the average FFs produced by voices, for example, in estimating the relative heights of two speakers based on their speech. However, it is not known whether they can learn to identify voices based on the acoustic characteristic associated with the average FFs produced by a voice (this characteristic will be referred to as FF-scaling). To investigate this, a series of vowels corresponding to voices that differed in their average f0 and/or FF-scaling were synthesized. Listeners (n = 71) were trained to identify these voices using a training procedure where, for each trial, they heard the vowels representing a voice and then had to identify the stimulus voice from among a series of candidate voices that differed in terms of their FF-scaling and/or their f0. Results indicate that listeners can identify voices on the basis of FF-scaling quite accurately and consistently after only a short training session and that, although f0 weakly influences these estimates, they are most strongly determined by the stimulus FFs. PMID- 23363123 TI - Voice quality and tone identification in White Hmong. AB - This study investigates the importance of source spectrum slopes in the perception of phonation by White Hmong listeners. In White Hmong, nonmodal phonation (breathy or creaky voice) accompanies certain lexical tones, but its importance in tonal contrasts is unclear. In this study, native listeners participated in two perceptual tasks, in which they were asked to identify the word they heard. In the first task, participants heard natural stimuli with manipulated F0 and duration (phonation unchanged). Results indicate that phonation is important in identifying the breathy tone, but not the creaky tone. Thus, breathiness can be viewed as contrastive in White Hmong. Next, to understand which parts of the source spectrum listeners use to perceive contrastive breathy phonation, source spectrum slopes were manipulated in the second task to create stimuli ranging from modal to breathy sounding, with F0 held constant. Results indicate that changes in H1-H2 (difference in amplitude between the first and second harmonics) and H2-H4 (difference in amplitude between the second and fourth harmonics) are independently important for distinguishing breathy from modal phonation, consistent with the view that the percept of breathiness is influenced by a steep drop in harmonic energy in the lower frequencies. PMID- 23363124 TI - Single-channel noise reduction using optimal rectangular filtering matrices. AB - This paper studies the problem of single-channel noise reduction in the time domain and presents a block-based approach where a vector of the desired speech signal is recovered by filtering a frame of the noisy signal with a rectangular filtering matrix. With this formulation, the noise reduction problem becomes one of estimating an optimal filtering matrix. To achieve such estimation, a method is introduced to decompose a frame of the clean speech signal into two orthogonal components: One correlated and the other uncorrelated with the current desired speech vector to be estimated. Different optimization cost functions are then formulated from which non-causal optimal filtering matrices are derived. The relationships among these optimal filtering matrices are discussed. In comparison with the classical sample-based technique that uses only forward prediction, the block-based method presented in this paper exploits both the forward and backward prediction as well as the temporal interpolation and, therefore, can improve the noise reduction performance by fully taking advantage of the speech property of self correlation. There is also a side advantage of this block-based method as compared to the sample-based technique, i.e., it is computationally more efficient and, as a result, more suitable for practical implementation. PMID- 23363125 TI - Flow simulations on an organ pipe foot model. AB - The present paper shows numerical simulations of the flow responsible for the sound generation in an organ pipe. Only the foot model of the organ pipe (i.e., with the resonator detached) is investigated by two-dimensional incompressible CFD simulations. It is shown that in spite of the moderately high Reynolds number (Re~2350) no turbulence modeling is necessary. Free jet simulation (foot model without the upper lip) showed that the jet oscillates due to its natural instability. The velocity profile, the centerline and the width of the jet is determined at different heights above the flue. Edge tone simulations (foot model with the upper lip) were carried out having the upper lip at a constant height but at different x positions. It was found that the strongest and most stable edge tone oscillation occurs if the lower left corner of the upper lip is in the centerline of the jet (optimum position). When the upper lip is far from its optimum position the oscillation of the jet is rather due to the natural instability of the jet than the edge tone phenomenon. The results agree well with the experimental results of Aubetaerlechner et al. [J. Acoust. Soc. Am. 126, 878 886 (2009)] and Aubetaerlechner (Ph.D. thesis, Universitat Stuttgart, Stuttgart, Germany) and with former results of the authors [Paal and Vaik, Int. J. Heat Fluid Flow 28, 575-586 (2007); Paal and Vaik, in Conference on Modelling Fluid Flow (CMFF'09), Budapest, Hungary]. PMID- 23363126 TI - Direct numerical simulation of a recorder. AB - The aeroacoustics of a recorder are studied using a direct numerical simulation based on the Navier-Stokes equations in two dimensions. Spatial maps for the air pressure and velocity give a detailed picture of vortex shedding near the labium. Changes in the spectrum as a result of variations in the blowing speed are also investigated. The results are in good semi-quantitative agreement with general results for these phenomena from experiments. PMID- 23363127 TI - Modeling and optimization of an acoustic diode based on micro-bubble nonlinearity. AB - The first acoustic diode (AD), which is composed by integrating a super lattice (SL) with a nonlinear medium (NLM), has recently been proposed to make a one-way street for the acoustic energy flux. This device prohibits the acoustic waves from one direction, but allows the transmission of the second harmonic wave (generated from the NLM) from the other direction. To improve its performance, it is crucial to transfer more acoustic energy from the stop-band of the acoustic filter (i.e., the SL) to its pass-band with the help of the NLM. In this work, a finite difference time domain model is developed to study the dynamic behaviors of the AD, in which a micro-bubble suspension takes the role of the NLM. Based on this model, the method of optimizing the nonlinearity-based AD is investigated by examining its performance with respect to several parameters, such as the periodicity number of the SL, the bubble size distribution, the bubble shell parameters, and the bubble concentration. It is also suggested that, instead of the rectification ratio, it might be more reasonable to characterize the performance of the AD with the energy attenuation coefficients (or transmission loss) for both incident directions. PMID- 23363128 TI - Geographic variability in the acoustic parameters of striped dolphin's (Stenella coeruleoalba) whistles. AB - Geographic variation in the acoustic features of whistles emitted by the striped dolphin (Stenella coeruleoalba) from the Atlantic Ocean (Azores and Canary Islands) and the Mediterranean was investigated. Ten parameters (signal duration, beginning, end, minimum and maximum frequency, the number of inflection points, of steps, of minima and maxima in the contour and the frequency range) were extracted from each whistle. Discriminant function analysis correctly classified 73% of sounds between Atlantic Ocean and Mediterranean Sea. A cline in parameters was apparent from the Azores to the Mediterranean, with a major difference between the Canaries and the Mediterranean than between Azores and Canaries. Signal duration, maximum frequency, and frequency range measured in the Mediterranean sample were significantly lower compared to those measured in the Atlantic. Modulation parameters played a considerable role in area discrimination and were the only parameters contributing to highlight the differences within the Atlantic Ocean. Results suggest that the acoustic features constrained by structural phenotype, such as whistle's frequency parameters, have a major effect on the Atlantic and Mediterranean separation while behavioral context, social, and physical environment may be among the main factors contributing to local distinctiveness of Atlantic areas. These results have potential passive acoustic monitoring applications. PMID- 23363129 TI - Discrimination of phase altered targets by an echolocating Atlantic bottlenose dolphin. AB - Sensitivity of echolocating dolphins to phase changes within echoes may be a vital piece of information when constructing echolocation models. Previous experiments have yielded ambiguous results leaving it unclear what cues might have been used by passively listening dolphins to discriminate between different phase altered signals. This study used a phantom echo generator to produce computer controlled echoes. The dolphin interacted with the system in a real echolocation task to discriminate between simulated targets that were unaltered and those that had a 180 degrees phase shift. The frequency amplitude spectral content between the two targets was the same. There were no temporal differences between the two targets. The only cue that the dolphin could use to discriminate between them was the 180 degrees phase shift. The dolphin preformed at a success level of 40% in discriminating the two echoes. This indicates that the 180 degrees phase shift was not perceived. PMID- 23363130 TI - Characterization of the time-variant behavior of a biomimetic beamforming baffle. AB - Horseshoe bats can actively change the shapes of their noseleaves and outer ears on time scales that are comparable to the duration of the biosonar pulses and echoes. When the shape deformations and the emission or reception of the ultrasonic signals overlap in time, the result is a time-variant diffraction process. Such a dynamic process provides additional flexibility that could potentially be used to enhance the encoding of sensory information. However, such a function remains hypothetical at present. To investigate the time-variant properties of deforming baffles such as the outer ears of horseshoe bats, the acoustic behavior of a biomimetic microphone baffle modeled on these biological structures has been investigated. The methods employed to characterize this device included representations in the time-delay domain as well as in the time frequency domain. It was found that characterization methods which do not employ Fourier transforms revealed even more substantial time-variant effects than were apparent from time-frequency domain characterizations such as beampatterns obtained for different times in the deformation cycle. Furthermore, conspicuous correlates of asymmetries in the time-variant physical shapes were found in some characterizations that could be used to link dynamic baffle geometry with acoustic behavior. PMID- 23363131 TI - Localization and tracking of moving objects in two-dimensional space by echolocation. AB - Bats use frequency-modulated echolocation to identify and capture moving objects in real three-dimensional space. Experimental evidence indicates that bats are capable of locating static objects with a range accuracy of less than 1 MUs. A previously introduced model estimates ranges of multiple, static objects using linear frequency modulation (LFM) sound and Gaussian chirplets with a carrier frequency compatible with bat emission sweep rates. The delay time for a single object was estimated with an accuracy of about 1.3 MUs by measuring the echo at a low signal-to-noise ratio (SNR). The range accuracy was dependent not only on the SNR but also the Doppler shift, which was dependent on the movements. However, it was unclear whether this model could estimate the moving object range at each timepoint. In this study, echoes were measured from the rotating pole at two receiving points by intermittently emitting LFM sounds. The model was shown to localize moving objects in two-dimensional space by accurately estimating the object's range at each timepoint. PMID- 23363132 TI - Nonlinear resonance behavior and linear shell estimates for DefinityTM and MicroMarkerTM assessed with acoustic microbubble spectroscopy. AB - There is a growing interest in microbubble based ultrasound contrast imaging applications in the 5-15 MHz range. In this study, individual microbubbles were insonified at low pressures (<= 25 kPa) using an "acoustic spectroscopy" approach which entailed transmitting a sequence of tone bursts with center frequencies ranging from 4 to 13.5 MHz. The fundamental (transmit) frequency radial excursion amplitude was calculated from the scattered signals to produce a resonance curve for each bubble. For diameters between 2.5 to 4 MUm, 69% of Target-Ready MicroMarkerTM (Bracco, Geneva; Visualsonics, Canada) exhibited asymmetric resonance, characterized by a skewing of the resonance curve and indicative of nonlinear behavior. For DefinityTM (Lantheus Medical Imaging, N. Billerica, MA), these responses were observed for 8% of diameters between 1.7 to 3.1 MUm. For the subset of bubbles exhibiting linear, symmetric resonance curves, resonant frequencies, shell elasticity, and viscosity values were estimated. Between 10 to 12 MHz, for example, Target-Ready MicroMarker between 2.7 to 3.3 MUm in diameter was resonant, where Definity was resonant between 1.7 to 2.6 MUm. From 4 to 13.5 MHz, Target-Ready MicroMarker is characterized by a stiffer shell (3 < chi(0) < 5) N/m than Definity (0.5 < chi(0) < 2.5) N/m, and distinct strain-softening and shear-thinning rheological behavior. For Definity, no clear strain or shear-rate dependence of the shell properties is evident. PMID- 23363133 TI - Transfer function for vital infrasound pressures between the carotid artery and the tympanic membrane. AB - While occupational injury is associated with numerous individual and work-related risk factors, including long working hours and short sleep duration, the complex mechanisms causing such injuries are not yet fully understood. The relationship between the infrasound pressures of the tympanic membrane [ear canal pressure (ECP)], detected using an earplug embedded with a low-frequency microphone, and the carotid artery [carotid artery pressure (CAP)], detected using a stethoscope fitted with the same microphone, can be quantitatively characterized using systems analysis. The transfer functions of 40 normal workers (19 to 57 years old) were characterized, involving the analysis of 446 data points. The ECP waveform exhibits a pulsatile character with a slow respiratory component, which is superimposed on a biphasic recording that is synchronous with the cardiac cycle. The respiratory ECP waveform correlates with the instantaneous heart rate. The results also revealed that various fatigue-related risk factors may affect the mean magnitudes of the measured pressures and the delay transfer functions between CAP and ECP in the study population; these factors include systolic blood pressure, salivary amylase activity, age, sleep duration, postural changes, chronic fatigue, and pulse rate. PMID- 23363189 TI - Coherent processing of shipping noise for ocean monitoring. AB - Ambient noise was recorded on two vertical line arrays (VLAs) separated by 450 m and deployed in shallow water (depth ~150 m) off San Diego, CA continuously for 6 days. Recordings were dominated by non-stationary and non-uniform broadband shipping noise (250 Hz to 1.5 kHz). Stable coherent noise wavefronts were extracted from ambient noise correlations between the VLAs during all 6 days by mitigating the effect of discrete shipping events and using array beamforming with data-derived steering vectors. This procedure allows the tracking of arrival time variations of these coherent wavefronts during 6 days and may help in developing future passive acoustic tomography systems. PMID- 23363188 TI - Mapping procedures can produce non-centered auditory images in bilateral cochlear implantees. AB - Good localization accuracy depends on an auditory spatial map that provides consistent binaural information across frequency and level. This study investigated whether mapping bilateral cochlear implants (CIs) independently contributes to distorted perceptual spatial maps. In a meta-analysis, interaural level differences necessary to perceptually center sound images were calculated for 127 pitch-matched pairs of electrodes; many needed large current adjustments to be perceptually centered. In a separate experiment, lateralization was also found to be inconsistent across levels. These findings suggest that auditory spatial maps are distorted in the mapping process, which likely reduces localization accuracy and target-noise separation in bilateral CIs. PMID- 23363190 TI - Neuromuscular induced phonation in a human ex vivo perfused larynx preparation. AB - Considering differences in laryngeal anatomy, degree of control, and range of voice qualities between animals and humans, investigations of the neuromuscular process of voice control are better conducted using a living human larynx in which parametric stimulation of individual laryngeal muscles is possible. Due to difficulties in access and monitoring of laryngeal muscle activities, such investigations are impossible in living human subject experiments. This study reports the recent success in developing an ex vivo perfused human larynx model, which allows parametric muscle stimulation and observation of its influence on phonation of a virtually living human larynx in a well-controlled laboratory environment. PMID- 23363191 TI - The internal representation of vowel spectra investigated using behavioral response-triggered averaging. AB - Listeners presented with noise were asked to press a key whenever they heard the vowels [a] or [i:]. The noise had a random spectrum, with levels in 60 frequency bins changing every 0.5 s. Reverse correlation was used to average the spectrum of the noise prior to each key press, thus estimating the features of the vowels for which the participants were listening. The formant frequencies of these reverse-correlated vowels were similar to those of their respective whispered vowels. The success of this response-triggered technique suggests that it may prove useful for estimating other internal representations, including perceptual phenomena like tinnitus. PMID- 23363192 TI - Laser enhanced high-intensity focused ultrasound thrombolysis: an in vitro study. AB - Laser-enhanced thrombolysis by high intensity focused ultrasound (HIFU) treatment was studied in vitro with bovine blood clots. To achieve laser-enhanced thrombolysis, laser light was employed to illuminate the sample concurrently with HIFU radiation, and ultrasound and laser parameters were optimized to achieve better thrombolysis efficiency. The results indicated that the thrombolysis efficiency increased when pulse length of HIFU wave, HIFU pressure, or laser fluence increases. Also, with the presence of laser, an enhanced effect of thrombolysis was observed. PMID- 23363193 TI - Can older adults enhance the intelligibility of their speech? AB - Speech understanding difficulties for older adults (OAs) are well documented. Very little is known about whether age-related changes affect their speech production as well. Intelligibility of conversational and clear speech sentences produced by five OA talkers was examined. The results of the sentence-in-noise listening tests revealed that OAs enhanced their intelligibility for young adult (YA) listeners through clear speech modifications. Importantly, though, OAs were less effective at improving their speech to benefit listeners compared to YA talkers [reported in Smiljanic and Bradlow, J. Acoust. Soc. Am. 118(3), 1677-1688 (2005)]. The results suggest that auditory and cognitive changes across lifespan can affect OA's speech patterns and intelligibility. PMID- 23363194 TI - Speech perception in simulated electric hearing exploits information-bearing acoustic change. AB - Stilp and Kluender [(2010). Proc. Natl. Acad. Sci. U.S.A. 107(27), 12387-12392] reported measures of sensory change over time (cochlea-scaled spectral entropy, CSE) reliably predicted sentence intelligibility for normal-hearing listeners. Here, implications for listeners with atypical hearing were explored using noise vocoded speech. CSE was parameterized as Euclidean distances between biologically scaled spectra [measured before sentences were noise vocoded (CSE)] or between channel amplitude profiles in simulated cochlear-implant processing [measured after vocoding (CSE(CI))]. Sentence intelligibility worsened with greater amounts of information replaced by noise; patterns of performance did not differ between CSE and CSE(CI). Results demonstrate the importance of information-bearing change for speech perception in simulated electric hearing. PMID- 23363195 TI - The effect of speakers' sex on voice onset time in Mandarin stops. AB - The goal of the present study is to examine the effect of speakers' gender on voice onset time in Mandarin speakers' stop productions. Word-initial lingual stops were elicited from 10 male and 10 female Mandarin speakers using a word repetition task. The results revealed differentiated voice onset time (VOT) patterns between the two genders for all four lingual stops on raw VOT values. After factoring out speech rate variation, gender-related differences remained for voiced stops only with females' VOTs being shorter than males. The results, together with previous findings from other languages, suggest a sociolinguistic/stylistic account on the relation between gender and VOT that vary in a language-specific manner. PMID- 23363196 TI - Determining the bubble cap film thickness of bursting bubbles from their acoustic emissions. AB - A study of the sound generated by 2.5 mm radius bubbles bursting on the surface of fresh water is presented. The sound pulses are found to be sensitive to the time interval between the bubble reaching the water surface and bursting. Bubbles that burst within a few 10's of milliseconds behave like a Helmholtz resonator and radiate a swept chirp pulse. Bubbles that persist for 100's of milliseconds or more exhibit more complex acoustic behavior. An analysis of the resonator behavior provides an estimate of the film thickness in reasonable agreement with a fluid drainage model. PMID- 23363197 TI - Derivation of a new banded waveguide model topology for sound synthesis. AB - Banded waveguide (BWG) synthesis is an efficient method for real-time physical modeling of dispersive and multidimensional sounding objects, affording simulation of complex interactions, such as bowing. Current implementations, however, use nonphysical design parameters and produce a range of outputs that do not match equivalently designed modal and digital waveguide (DWG) models. This letter proposes a new topology for implementing BWG models without arbitrary parameters. The impulse response of the proposed model is identical to that of equivalent Karplus-Strong type and lumped modal models. Test of a nonlinear bi directional bowed-string model demonstrates improved attack characteristics relative to prior BWG models. PMID- 23363198 TI - Vocal fold vibrations at high soprano fundamental frequencies. AB - Human voice production at very high fundamental frequencies is not yet understood in detail. It was hypothesized that these frequencies are produced by turbulences, vocal tract/vocal fold interactions, or vocal fold oscillations without closure. Hitherto it has been impossible to visually analyze the vocal mechanism due to technical limitations. Latest high-speed technology, which captures 20,000 frames/s, using transnasal endoscopy was applied. Up to 1568 Hz human vocal folds do exhibit oscillations with complete closure. Therefore, the recent results suggest that human voice production at very high F0s up to 1568 Hz is not caused by turbulence, but rather by airflow modulation from vocal fold oscillations. PMID- 23363199 TI - Near-field shock formation in noise propagation from a high-power jet aircraft. AB - Noise measurements near the F-35A Joint Strike Fighter at military power are analyzed via spatial maps of overall and band pressure levels and skewness. Relative constancy of the pressure waveform skewness reveals that waveform asymmetry, characteristic of supersonic jets, is a source phenomenon originating farther upstream than the maximum overall level. Conversely, growth of the skewness of the time derivative with distance indicates that acoustic shocks largely form through the course of near-field propagation and are not generated explicitly by a source mechanism. These results potentially counter previous arguments that jet "crackle" is a source phenomenon. PMID- 23363200 TI - Numerical modeling of wind turbine aerodynamic noise in the time domain. AB - Aerodynamic noise from a wind turbine is numerically modeled in the time domain. An analytic trailing edge noise model is used to determine the unsteady pressure on the blade surface. The far-field noise due to the unsteady pressure is calculated using the acoustic analogy theory. By using a strip theory approach, the two-dimensional noise model is applied to rotating wind turbine blades. The numerical results indicate that, although the operating and atmospheric conditions are identical, the acoustical characteristics of wind turbine noise can be quite different with respect to the distance and direction from the wind turbine. PMID- 23363204 TI - Computational fluid dynamics evaluation of the cross-limb stent graft configuration for endovascular aneurysm repair. AB - The technique of crossing the limbs of bifurcated modular stent grafts for endovascular aneurysm repair (EVAR) is often employed in the face of splayed aortic bifurcations to facilitate cannulation and prevent device kinking. However, little has been reported about the implications of cross-limb EVAR, especially in comparison to conventional EVAR. Previous computational fluid dynamics studies of conventional EVAR grafts have mostly utilized simplified planar stent graft geometries. We herein examined the differences between conventional and cross-limb EVAR by comparing their hemodynamic flow fields (i.e., in the "direct" and "cross" configurations, respectively). We also added a "planar" configuration, which is commonly found in the literature, to identify how well this configuration compares to out-of-plane stent graft configurations from a hemodynamic perspective. A representative patient's cross-limb stent graft geometry was segmented using computed tomography imaging in Mimics software. The cross-limb graft geometry was used to build its direct and planar counterparts in SolidWorks. Physiologic velocity and mass flow boundary conditions and blood properties were implemented for steady-state and pulsatile transient simulations in ANSYS CFX. Displacement forces, wall shear stress (WSS), and oscillatory shear index (OSI) were all comparable between the direct and cross configurations, whereas the planar geometry yielded very different predictions of hemodynamics compared to the out-of-plane stent graft configurations, particularly for displacement forces. This single-patient study suggests that the short-term hemodynamics involved in crossing the limbs is as safe as conventional EVAR. Higher helicity and improved WSS distribution of the cross-limb configuration suggest improved flow-related thrombosis resistance in the short term. However, there may be long-term fatigue implications to stent graft use in the cross configuration when compared to the direct configuration. PMID- 23363203 TI - The simultaneous role of an alveolus as flow mixer and flow feeder for the deposition of inhaled submicron particles. AB - In an effort to understand the fate of inhaled submicron particles in the small sacs, or alveoli, comprising the gas-exchange region of the lung, we calculated the flow in three-dimensional (3D) rhythmically expanding models of alveolated ducts. Since convection toward the alveolar walls is a precursor to particle deposition, it was the goal of this paper to investigate the streamline maps' dependence upon alveoli location along the acinar tree. On the alveolar midplane, the recirculating flow pattern exhibited closed streamlines with a stagnation saddle point. Off the midplane we found no closed streamlines but nested, funnel like, spiral, structures (reminiscent of Russian nesting dolls) that were directed towards the expanding walls in inspiration, and away from the contracting walls in expiration. These nested, funnel-like, structures were surrounded by air that flowed into the cavity from the central channel over inspiration and flowed from the cavity to the central channel over expiration. We also found that fluid particle tracks exhibited similar nested funnel-like spiral structures. We conclude that these unique alveolar flow structures may be of importance in enhancing deposition. In addition, due to inertia, the nested, funnel-like, structures change shape and position slightly during a breathing cycle, resulting in flow mixing. Also, each inspiration feeds a fresh supply of particle-laden air from the central channel to the region surrounding the mixing region. Thus, this combination of flow mixer and flow feeder makes each individual alveolus an effective mixing unit, which is likely to play an important role in determining the overall efficiency of convective mixing in the acinus. PMID- 23363205 TI - Investigation of the in vitro culture process for skeletal-tissue-engineered constructs using computational fluid dynamics and experimental methods. AB - The in vitro culture process via bioreactors is critical to create tissue engineered constructs (TECs) to repair or replace the damaged tissues/organs in various engineered applications. In the past, the TEC culture process was typically treated as a black box and performed on the basis of trial and error. Recently, computational fluid dynamics (CFD) has demonstrated its potential to analyze the fluid flow inside and around the TECs, therefore, being able to provide insight into the culture process, such as information on the velocity field and shear stress distribution that can significantly affect such cellular activities as cell viability and proliferation during the culture process. This paper briefly reviews the CFD and experimental methods used to investigate the in vitro culture process of skeletal-type TECs in bioreactors, where mechanical deformation of the TEC can be ignored. Specifically, this paper presents CFD modeling approaches for the analysis of the velocity and shear stress fields, mass transfer, and cell growth during the culture process and also describes various particle image velocimetry (PIV) based experimental methods to measure the velocity and shear stress in the in vitro culture process. Some key issues and challenges are also identified and discussed along with recommendations for future research. PMID- 23363207 TI - On the importance of modeling stent procedure for predicting arterial mechanics. AB - The stent-artery interactions have been increasingly studied using the finite element method for better understanding of the biomechanical environment changes on the artery and its implications. However, the deployment of balloon-expandable stents was generally simplified without considering the balloon-stent interactions, the initial crimping process of the stent, its overexpansion routinely used in the clinical practice, or its recoil process. In this work, the stenting procedure was mimicked by incorporating all the above-mentioned simplifications. The impact of various simplifications on the stent-induced arterial stresses was systematically investigated. The plastic strain history of stent and its resulted geometrical variations, as well as arterial mechanics were quantified and compared. Results showed the model without considering the stent crimping process underestimating the minimum stent diameter by 17.2%, and overestimating the maximum radial recoil by 144%. It was also suggested that overexpansion resulted in a larger stent diameter, but a greater radial recoil ratio and larger intimal area with high stress were also obtained along with the increase in degree of overexpansion. PMID- 23363206 TI - Quantifying effect of intraplaque hemorrhage on critical plaque wall stress in human atherosclerotic plaques using three-dimensional fluid-structure interaction models. AB - Recent magnetic resonance studies have indicated that intraplaque hemorrhage (IPH) may accelerate plaque progression and play an important role in plaque destabilization. However, the impact of hemorrhage on critical plaque wall stress (CPWS) and strain (CPWSn) has yet to be determined. The objective of this study was to assess the effect of the presence and size of IPH on wall mechanics. The magnetic resonance image (MRI) of one patient with histology-confirmed IPH was used to build eight 3D fluid-structure interaction (FSI) models by altering the dimensions of the existing IPH. As a secondary end point, the combined effect of IPH and fibrous cap thickness (FCT) was assessed. A volume curve fitting method (VCFM) was applied to generate a mesh that would guarantee numerical convergence. Plaque wall stress (PWS), strain (PWSn), and flow shear stress (FSS) were extracted from all nodal points on the lumen surface for analysis. Keeping other conditions unchanged, the presence of intraplaque hemorrhage caused a significant increase (27.5%) in CPWS; reduced FCT caused an increase of 22.6% of CPWS. Similar results were found for CPWSn. Furthermore, combination of IPH presence, reduced FCT, and increased IPH volume caused an 85% and 75% increase in CPWS and CPWSn, respectively. These results show that intraplaque hemorrhage has considerable impact on plaque stress and strain conditions and accurate quantification of IPH could lead to more accurate assessment of plaque vulnerability. Large-scale studies are needed to further validate our findings. PMID- 23363208 TI - Calculation of human femoral vein wall parameters in vivo from clinical data for specific patient. AB - A common problem in the elaboration of biomechanical models is determining the properties and characteristics (measures) of the physical behavior of in vivo tissues in the human body. Correct estimates must be made of the tissue's physical properties and its surroundings. We suggest a method to compute the constitutive modeling of venous tissue, for every specific patient, from clinically registered ultrasounds images. The vein is modeled as a hyperelastic, incompressible, thin-walled cylinder and the membrane stresses are computed using strain energy. The approach is based on a strain-energy function suggested by Holzapfel capturing the characteristic nonlinear anisotropic responses of femoral veins with its collagen fibers. PMID- 23363209 TI - Measuring dynamic in-vivo elbow kinematics: description of technique and estimation of accuracy. AB - BACKGROUND: The objectives of this study were to characterize the translational and rotational accuracy of a model-based tracking technique for quantifying elbow kinematics and to demonstrate its in vivo application. METHOD OF APPROACH: The accuracy of a model-based tracking technique for quantifying elbow kinematics was determined in an in vitro experiment. Biplane X-ray images of a cadaveric elbow were acquired as it was manually moved through flexion-extension. The 3D position and orientation of each bone was determined using model-based tracking. For comparison, the position and orientation of each bone was also determined by tracking the position of implanted beads with dynamic radiostereometric analysis. Translations and rotations were calculated for both the ulnohumeral and radiohumeral joints, and compared between measurement techniques. To demonstrate the in vivo application of this technique, biplane X-ray images were acquired as a human subject extended their elbow from full flexion to full extension. RESULTS: The in vitro validation demonstrated that the model-based tracking technique is capable of accurately measuring elbow motion, with reported errors averaging less than +/-1.0 mm and +/-1.0 deg. For the in vivo application, the carrying angle changed from an 8.3 +/- 0.5 deg varus position in full flexion to an 8.4 +/- 0.5 deg valgus position in full extension. CONCLUSIONS: Model-based tracking is an accurate technique for measuring in vivo, 3D, dynamic elbow motion. It is anticipated that this experimental approach will enhance our understanding of elbow motion under normal and pathologic conditions. PMID- 23363210 TI - Biomechanical measurements of surgical drilling force and torque in human versus artificial femurs. AB - Few experimental studies have examined surgical drilling in human bone, and no studies have inquired into this aspect for a popular commercially-available artificial bone used in biomechanical studies. Sixteen fresh-frozen human femurs and five artificial femurs were obtained. Cortical specimens were mounted into a clamping system equipped with a thrust force and torque transducer. Using a CNC machine, unicortical holes were drilled in each specimen at 1000 rpm, 1250 rpm, and 1500 rpm with a 3.2 mm diameter surgical drill bit. Feed rate was 120 mm/min. Statistical significance was set at p < 0.05. Force at increasing spindle speed (1000 rpm, 1250 rpm, and 1500 rpm), respectively, showed a range for human femurs (198.4 +/- 14.2 N, 180.6 +/- 14.0 N, and 176.3 +/- 11.2 N) and artificial femurs (87.2 +/- 19.3 N, 82.2 +/- 11.2 N, and 75.7 +/- 8.8 N). For human femurs, force at 1000 rpm was greater than at other speeds (p <= 0.018). For artificial femurs, there was no speed effect on force (p >= 0.991). Torque at increasing spindle speed (1000 rpm, 1250 rpm, and 1500 rpm), respectively, showed a range for human femurs (186.3 +/- 16.9 N.mm, 157.8 +/- 16.1 N.mm, and 140.2 +/- 16.4 N.mm) and artificial femurs (67.2 +/- 8.4 N.mm, 61.0 +/- 2.9 N.mm, and 53.3 +/- 2.9 N.mm). For human femurs, torque at 1000 rpm was greater than at other speeds (p < 0.001). For artificial femurs, there was no difference in torque for 1000 rpm versus higher speeds (p >= 0.228), and there was only a borderline difference between the higher speeds (p = 0.046). Concerning human versus artificial femurs, their behavior was different at every speed (force, p <= 0.001; torque, p < 0.001). For human specimens at 1500 rpm, force and torque were linearly correlated with standardized bone mineral density (sBMD) and the T-score used to clinically categorize bone quality (R >= 0.56), but there was poor correlation with age at all speeds (R <= 0.37). These artificial bones fail to replicate force and torque in human cortical bone during surgical drilling. To date, this is the largest series of human long bones biomechanically tested for surgical drilling. PMID- 23363211 TI - Murray's Law in elastin haploinsufficient (Eln+/-) and wild-type (WT) mice. AB - Using either the principle of minimum energy or constant shear stress, a relation can be derived that predicts the diameters of branching vessels at a bifurcation. This relation, known as Murray's Law, has been shown to predict vessel diameters in a variety of cardiovascular systems from adult humans to developing chicks. The goal of this study is to investigate Murray's Law in vessels from mice that are haploinsufficient for the elastin protein (Eln+/-). Elastin is one of the major proteins in the blood vessel wall and is organized in concentric rings, known as lamellae, with smooth muscle cells (SMCs) around the vessel lumen. Eln+/ mice have an increased number of lamellae, as well as smaller, thinner vessels. It is possible that due to decreased amounts of elastin available for vessel wall remodeling during development and in adulthood, Eln+/- vessels would not follow Murray's Law. We examined vessel bifurcations in six different physiologic regions, including the brain, heart, epidermis, ceocum (or cecum), testes, and intestines, in Eln+/- mice and wild-type (WT) littermates. All vessels were between 40 and 300 MUm in diameter. We found that the diameters of both Eln+/- and WT vessels have an average of 13% error from the diameters predicted by Murray's Law, with no significant differences between genotypes or physiologic regions. The data suggest that vessels are optimized to follow Murray's Law, despite limitations on the proteins available for growth and remodeling of the vessel wall. PMID- 23363212 TI - Mechanical compromise of partially lacerated flexor tendons. AB - Tendons function to transmit loads from muscle to move and stabilize joints and absorb impacts. Functionality of lacerated tendons is diminished, however clinical practice often considers surgical repair only after 50% or more of the tendon is lacerated, the "50% rule." Few studies provide mechanical insight into the 50% rule. In this study cyclic and static stress relaxation tests were performed on porcine flexor tendons before and after a 0.5, 1.0, 2.0, or 2.75 mm deep transverse, midsubstance laceration. Elastic and viscoelastic properties, such as maximum stress, change in stress throughout each test, and stiffness, were measured and compared pre- and post-laceration. Nominal stress and stiffness parameters decreased, albeit disproportionately in magnitude, with increasing percent loss of cross-sectional area. Conversely, mean stress at the residual area (determined using remaining intact area at the laceration cross section) exhibited a marked increase in stress concentration beginning at 47.2% laceration using both specified load and constant strain analyses. The marked increase in stress concentration beginning near 50% laceration provides mechanical insight into the 50% rule. Additionally, a drastic decrease in viscoelastic stress parameters after only an 8.2% laceration suggests that time-dependent mechanisms protecting tissues during impact loadings are highly compromised regardless of laceration size. PMID- 23363213 TI - Optimization of a Y-graft design for improved hepatic flow distribution in the fontan circulation. AB - Single ventricle heart defects are among the most serious congenital heart diseases, and are uniformly fatal if left untreated. Typically, a three-staged surgical course, consisting of the Norwood, Glenn, and Fontan surgeries is performed, after which the superior vena cava (SVC) and inferior vena cava (IVC) are directly connected to the pulmonary arteries (PA). In an attempt to improve hemodynamic performance and hepatic flow distribution (HFD) of Fontan patients, a novel Y-shaped graft has recently been proposed to replace the traditional tube shaped extracardiac grafts. Previous studies have demonstrated that the Y-graft is a promising design with the potential to reduce energy loss and improve HFD. However these studies also found suboptimal Y-graft performance in some patient models. The goal of this work is to determine whether performance can be improved in these models through further design optimization. Geometric and hemodynamic factors that influence the HFD have not been sufficiently investigated in previous work, particularly for the Y-graft. In this work, we couple Lagrangian particle tracking to an optimal design framework to study the effects of boundary conditions and geometry on HFD. Specifically, we investigate the potential of using a Y-graft design with unequal branch diameters to improve hepatic distribution under a highly uneven RPA/LPA flow split. As expected, the resulting optimal Y-graft geometry largely depends on the pulmonary flow split for a particular patient. The unequal branch design is demonstrated to be unnecessary under most conditions, as it is possible to achieve the same or better performance with equal-sized branches. Two patient-specific examples show that optimization-derived Y-grafts effectively improve the HFD, compared to initial nonoptimized designs using equal branch diameters. An instance of constrained optimization shows that energy efficiency slightly increases with increasing branch size for the Y-graft, but that a smaller branch size is preferred when a proximal anastomosis is needed to achieve optimal HFD. PMID- 23363214 TI - A numerical study of aortic flow stability and comparison with in vivo flow measurements. AB - The development of an engineering transitional turbulence model and its subsequent evaluation and validation for some diseased cardiovascular flows have been suggestive of its likely utility in normal aortas. The existence of experimental data from human aortas, acquired in the early 1970s with catheter mounted hot film velocimeters, provided the opportunity to compare the performance of the model on such flows. A generic human aorta, derived from magnetic resonance anatomical and velocity images of a young volunteer, was used as the basis for varying both Reynolds number (Re) and Womersley parameter (alpha) to match four experimental data points from human ascending aortas, comprising two with disturbed flow and two with apparently undisturbed flow. Trials were made with three different levels of inflow turbulence intensity (Tu) to find if a single level could represent the four different cases with 4000 < Re < 10,000 and 17 < alpha < 26. A necessary boundary condition includes the inflow "turbulence" level, and convincing results were obtained for all four cases with inflow Tu = 1.0%, providing additional confidence in the application of the transitional model in flows in larger arteries. The Reynolds-averaged Navier Stokes (RANS)-based shear stress transport (SST) transitional model is capable of capturing the correct flow state in the human aorta when low inflow turbulence intensity (1.0%) is specified. PMID- 23363215 TI - The importance of intrinsic damage properties to bone fragility: a finite element study. AB - As the average age of the population has increased, the incidence of age-related bone fracture has also increased. While some of the increase of fracture incidence with age is related to loss of bone mass, a significant part of the risk is unexplained and may be caused by changes in intrinsic material properties of the hard tissue. This investigation focused on understanding how changes to the intrinsic damage properties affect bone fragility. We hypothesized that the intrinsic (MUm) damage properties of bone tissue strongly and nonlinearly affect mechanical behavior at the apparent (whole tissue, cm) level. The importance of intrinsic properties on the apparent level behavior of trabecular bone tissue was investigated using voxel based finite element analysis. Trabecular bone cores from human T12 vertebrae were scanned using microcomputed tomography (MUCT) and the images used to build nonlinear finite element models. Isotropic and initially homogenous material properties were used for all elements. The elastic modulus (E(i)) of individual elements was reduced with a secant damage rule relating only principal tensile tissue strain to modulus damage. Apparent level resistance to fracture as a function of changes in the intrinsic damage properties was measured using the mechanical energy to failure per unit volume (apparent toughness modulus, W(a)) and the apparent yield strength (sigma(ay), calculated using the 0.2% offset). Intrinsic damage properties had a profound nonlinear effect on the apparent tissue level mechanical response. Intrinsic level failure occurs prior to apparent yield strength (sigma(ay)). Apparent yield strength (sigma(ay)) and toughness vary strongly (1200% and 400%, respectively) with relatively small changes in the intrinsic damage behavior. The range of apparent maximum stresses predicted by the models was consistent with those measured experimentally for these trabecular bone cores from the experimental axial compressive loading (experimental: sigma(max) = 3.0-4.3 MPa; modeling: sigma(max) = 2-16 MPa). This finding differs significantly from previous studies based on nondamaging intrinsic material models. Further observations were that this intrinsic damage model reproduced important experimental apparent level behaviors including softening after peak load, microdamage accumulation before apparent yield (0.2% offset), unload softening, and sensitivity of the apparent level mechanical properties to variability of the intrinsic properties. PMID- 23363217 TI - Hyperbolic source location of crack related acoustic emission in bone. AB - Little work has been done on the localization of microcracks in bone using acoustic emission. Microcrack localization is useful to study the fracture process in bone and to prevent fractures in patients. Locating microcracks that occur before fracture allows one to predict where fracture will occur if continued stress is applied to the bone. Two source location algorithms were developed to locate microcracks on rectangular bovine bone samples. The first algorithm uses a constant velocity approach which has some difficulty dealing with the anisotropic nature of bone. However, the second algorithm uses an iterative technique to estimate the correct velocity for the acoustic emission source location being located. In tests with simulated microcracks, the constant velocity algorithm achieves a median error of 1.78 mm (IQR 1.51 mm) and the variable velocity algorithm improves this to a median error of 0.70 mm (IQR 0.79 mm). An experiment in which the bone samples were loaded in a three point bend test until they fractured showed a good correlation between the computed location of detected microcracks and where the final fracture occurred. Microcracks can be located on bovine bone samples using acoustic emission with good accuracy and precision. PMID- 23363216 TI - Incomplete restoration of homeostatic shear stress within arteriovenous fistulae. AB - Arteriovenous fistulae are surgically created to provide adequate access for dialysis patients suffering from end-stage renal disease. It has long been hypothesized that the rapid blood vessel remodeling occurring after fistula creation is, in part, a process to restore the mechanical stresses to some preferred level, i.e., mechanical homeostasis. We present computational hemodynamic simulations in four patient-specific models of mature arteriovenous fistulae reconstructed from 3D ultrasound scans. Our results suggest that these mature fistulae have remodeled to return to ''normal'' shear stresses away from the anastomoses: about 1.0 Pa in the outflow veins and about 2.5 Pa in the inflow arteries. Large parts of the anastomoses were found to be under very high shear stresses >15 Pa, over most of the cardiac cycle. These results suggest that the remodeling process works toward restoring mechanical homeostasis in the fistulae, but that the process is limited or incomplete, even in mature fistulae, as evidenced by the elevated shear at or near the anastomoses. Based on the long term clinical viability of these dialysis accesses, we hypothesize that the elevated nonhomeostatic shear stresses in some portions of the vessels were not detrimental to fistula patency. PMID- 23363218 TI - Predicting sagittal plane biomechanics that minimize the axial knee joint contact force during walking. AB - Both development and progression of knee osteoarthritis have been associated with the loading of the knee joint during walking. We are, therefore, interested in developing strategies for changing walking biomechanics to offload the knee joint without resorting to surgery. In this study, simulations of human walking were performed using a 2D bipedal forward dynamics model. A simulation generated by minimizing the metabolic cost of transport (CoT) resembled data measured from normal human walking. Three simulations targeted at minimizing the peak axial knee joint contact force instead of the CoT reduced the peak force by 12-25% and increased the CoT by 11-14%. The strategies used by the simulations were (1) reduction in gastrocnemius muscle force, (2) avoidance of knee flexion during stance, and (3) reduced stride length. Reduced gastrocnemius force resulted from a combination of changes in activation and changes in the gastrocnemius contractile component kinematics. The simulations that reduced the peak contact force avoided flexing the knee during stance when knee motion was unrestricted and adopted a shorter stride length when the simulated knee motion was penalized if it deviated from the measured human knee motion. A higher metabolic cost in an offloading gait would be detrimental for covering a long distance without fatigue but beneficial for exercise and weight loss. The predicted changes in the peak axial knee joint contact force from the simulations were consistent with estimates of the joint contact force in a human subject who emulated the predicted kinematics. The results demonstrate the potential of using muscle actuated forward dynamics simulations to predict novel joint offloading interventions. PMID- 23363220 TI - Flow-induced deformation of poroelastic tissues and gels: a new perspective on equilibrium pressure-flow-thickness relations. AB - Hydrostatic pressure-driven flows through soft tissues and gels cause deformations of the solid network to occur, due to drag from the flowing fluid. This phenomenon occurs in many contexts including physiological flows and infusions through soft tissues, in mechanically stimulated engineered tissues, and in direct permeation measurements of hydraulic permeability. Existing theoretical descriptions are satisfactory in particular cases, but none provide a description which is easy to generalize for the design and interpretation of permeation experiments involving a range of different boundary conditions and gel properties. Here a theoretical description of flow-induced permeation is developed using a relatively simple approximate constitutive law for strain dependent permeability and an assumed constant elastic modulus, using dimensionless parameters which emerge naturally. Analytical solutions are obtained for relationships between fundamental variables, such as flow rate and pressure drop, which were not previously available. Guidelines are provided for assuring that direct measurements of hydraulic permeability are performed accurately, and suggestions emerge for alternative measurement protocols. Insights obtained may be applied to interpretation of flow-induced deformation and related phenomena in many contexts. PMID- 23363219 TI - A coupled fiber-matrix model demonstrates highly inhomogeneous microstructural interactions in soft tissues under tensile load. AB - A soft tissue's macroscopic behavior is largely determined by its microstructural components (often a collagen fiber network surrounded by a nonfibrillar matrix (NFM)). In the present study, a coupled fiber-matrix model was developed to fully quantify the internal stress field within such a tissue and to explore interactions between the collagen fiber network and nonfibrillar matrix (NFM). Voronoi tessellations (representing collagen networks) were embedded in a continuous three-dimensional NFM. Fibers were represented as one-dimensional nonlinear springs and the NFM, meshed via tetrahedra, was modeled as a compressible neo-Hookean solid. Multidimensional finite element modeling was employed in order to couple the two tissue components and uniaxial tension was applied to the composite representative volume element (RVE). In terms of the overall RVE response (average stress, fiber orientation, and Poisson's ratio), the coupled fiber-matrix model yielded results consistent with those obtained using a previously developed parallel model based upon superposition. The detailed stress field in the composite RVE demonstrated the high degree of inhomogeneity in NFM mechanics, which cannot be addressed by a parallel model. Distributions of maximum/minimum principal stresses in the NFM showed a transition from fiber-dominated to matrix-dominated behavior as the matrix shear modulus increased. The matrix-dominated behavior also included a shift in the fiber kinematics toward the affine limit. We conclude that if only gross averaged parameters are of interest, parallel-type models are suitable. If, however, one is concerned with phenomena, such as individual cell-fiber interactions or tissue failure that could be altered by local variations in the stress field, then the detailed model is necessary in spite of its higher computational cost. PMID- 23363221 TI - Epstein-Barr virus latent membrane protein 1 increases genomic instability through Egr-1-mediated up-regulation of activation-induced cytidine deaminase in B-cell lymphoma. AB - Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP1) is a transmembrane protein essential for EBV-induced immortalization and transformation of B cells. Activation-induced cytidine deaminase (AID) triggers somatic hypermutation and recombination, in turn contributing to lymphomagenesis. Here, we report an intracellular mechanism by which LMP1 contributes to B cell lymphomagenesis via AID expression. In our experiments, LMP1 increased AID mRNA expression and promoter activity. The AID promoter region contains a binding site for Egr-1, a prominent transcription factor that is reported to be up-regulated by LMP1. In promoter activity analysis, Egr-1 enhanced the reporter activity of the wild-type AID promoter, but not that containing a mutated Egr-1 binding site. Egr-1 knockdown abrogated LMP-1-mediated up-regulation of AID promoter reporter activity in EBV-negative BJAB cells and reduced AID promoter reporter activity in EBV-positive SKW6.4 cells. AID induced down-regulation of the nuclear factor kappaB (NFkappaB) inhibitory tumor suppressor Rassf6, suggesting that AID functions as an upstream regulator of the NFkappaB inhibitory Rassf6. Moreover, Egr-1 expression was associated with an increased number of genomic lesions in genome-wide analysis using single nucleotide polymorphism (SNP) microarray and copy number variation (CNV). Collectively, LMP1 induces AID up-regulation and genomic instability via Egr-1. Increased AID expression may, in turn, promote down-regulation of the NFkappaB inhibitor, Rassf6, thereby further increasing the survival of genetically destabilized B-cell lymphoma cells. PMID- 23363222 TI - Masitinib reverses doxorubicin resistance in canine lymphoid cells by inhibiting the function of P-glycoprotein. AB - Overexpression of ABC-transporters including Pgp, MRP1, and BCRP has been associated with multidrug resistance (MDR) in both human and canine oncology. Therapeutic interventions to reverse MDR are limited, but include multidrug protocols and the temporary concomitant use of inhibitors of ABC-transporters. Recently, the use of tyrosine kinase inhibitors has been proposed to overcome MDR in human oncology. One of the tyrosine kinase inhibitors, masitinib, is licensed for veterinary use in the treatment of canine mast cell tumors. Therefore, this study aimed to assess the potential of masitinib to revert MDR in canine malignant lymphoma using an in vitro model with canine lymphoid cell lines. Masitinib had a mild antiproliferative effect on lymphoid cells, inhibited Pgp function at concentrations equal to or exceeding 1 MUm and was able to reverse doxorubicin resistance. The current findings provide the rationale for a combined use of masitinib with doxorubicin in the treatment of dogs with doxorubicin resistant malignant lymphoma but await confirmation in clinical trials. PMID- 23363224 TI - HTQC: a fast quality control toolkit for Illumina sequencing data. AB - BACKGROUND: Illumina sequencing platform is widely used in genome research. Sequence reads quality assessment and control are needed for downstream analysis. However, software that provides efficient quality assessment and versatile filtration methods is still lacking. RESULTS: We have developed a toolkit named HTQC - abbreviation of High-Throughput Quality Control - for sequence reads quality control, which consists of six programs for reads quality assessment, reads filtration and generation of graphic reports. CONCLUSIONS: The HTQC toolkit can generate reads quality assessment faster than existing tools, providing guidance for reads filtration utilities that allow users to choose different strategies to remove low quality reads. PMID- 23363223 TI - In vitro radiosensitization by pentoxifylline does not depend on p53 status. AB - PURPOSE: The mode by which the xanthine derivative, pentoxifylline, induces a radiosensitizing effect in cell cultures is a key and controversial radiobiological issue and requires further elucidation. MATERIALS AND METHODS: Six human glioblastoma cell lines were tested for the effect of pentoxifylline treatment at maximum G2/M block on the basis of cell survival, mitotic activity, and micronucleus formation after exposure to gamma radiation. Cell survival was measured by the colony-forming assay. Micronucleus formation (an indicator of DNA damage) and the proportion of binucleated cells (a representation of mitotic activity) were determined using the cytokinesis-block assay. RESULTS: Remarkably, exposure to a single dose of 4 Gy produced strong G2/M blocks in both p53 mutant and wild-type cells. Addition of pentoxifylline at the peak of radiation-induced G2/M blocks resulted in a p53-independent reduction in cell survival in all cell lines. This radiosensitization was strongly correlated with the magnitude of the radiation-induced G2/M block. The changes observed in mitotic activity and micronucleus yield were also p53-independent. CONCLUSIONS: These results are at variance with the view that pentoxifylline preferentially sensitizes p53 mutant cells, and that sensitization occurs only when cells are irradiated in the presence of the drug. The data suggest that the effectiveness of pentoxifylline as radiosensitizer depends on the proportion of cells that are arrested in the G2/M phase transition following exposure to ionizing radiation. These findings can assist in the identification of cancers that may benefit from therapies using G2/M checkpoint abrogators. PMID- 23363225 TI - Understanding the different types of social support offered by audience to A-list diary-like and informative bloggers. AB - Blogs offer audiences a forum through which they can exchange ideas and provide feedback about the everyday lives and experiences of the bloggers. Such interactions and communication between audiences and bloggers could be regarded as a kind of social support. The present study aims to identify and compare the types of social support offered by audiences to continuous popular diary-like and informative bloggers, and to explore the possible benefits that bloggers may obtain from such social support. Content analysis was used to analyze the 485 and 390 comments provided by the audiences to the A-list diary-like and informative blog posts, respectively. Results reveal that validation, compliment, and encouragement are the most common types of social support given by audiences to A list bloggers. Chi-square test results show that the audiences offer more encouragement-type of social support to diary-like bloggers and more complimentary and informational social support to informative bloggers. Such types of social support may enhance A-list bloggers' self-esteem, boost their confidence, promote their self-understanding, and help them obtain the benefits of social validation, which in turn encourage bloggers to commit continuous self disclosure. PMID- 23363226 TI - The development of video game enjoyment in a role playing game. AB - This study examines the development of video game enjoyment over time. The results of a longitudinal study (N=62) show that enjoyment increases over several sessions. Moreover, results of a multilevel regression model indicate a causal link between the dependent variable video game enjoyment and the predictor variables exploratory behavior, spatial presence, competence, suspense and solution, and simulated experiences of life. These findings are important for video game research because they reveal the antecedents of video game enjoyment in a real-world longitudinal setting. Results are discussed in terms of the dynamics of video game enjoyment under real-world conditions. PMID- 23363227 TI - Impact of virtual training environments on the acquisition and transfer of knowledge. AB - Virtual training environments are appropriate to train complex tasks that require collaboration and interaction among the members of a team, especially if training in reality is not possible, too expensive or too dangerous. The field study reported in this paper compared three training conditions (virtual condition, standard condition, and control condition). The participants were police officers who were being trained in the communication between ground forces and a helicopter crew during an operation. This task (like many other tasks of the police, fire brigade and emergency services) is of high complexity and has no single "correct" solution, is based on specialization of tasks within a team, requires intensive communication among team members, and consists of situations in which human beings are in danger. Learning outcomes and knowledge transfer were measured as dependent variables. The results validate that virtual training was as efficient as standard training with regard to knowledge acquisition, and it was even more efficient with regard to knowledge transfer. With regard to the perceived value of the training, the participants judged standard training to be better than virtual training (except for training satisfaction, where no difference was found between standard and virtual training). These results indicate that virtual training is an effective tool for training in complex tasks that require collaboration and cannot fully be trained for in reality. PMID- 23363228 TI - Show us you are real: the effect of human-versus-organizational presence on online relationship building through social networking sites. AB - This study examined how creating a human presence in organizational online communication affects organization-public relationships and publics' favorable behavioral intentions to engage in word-of-mouth (WOM) and dialogic communications. Four hypotheses were tested in the context of Twitter through a 2*2 (presence: human vs. organizational*organization type: nonprofit vs. for profit) within-subjects design. The results revealed that conversational human voice was perceived to be higher for Twitter pages of organizations with a human presence than for those with an organizational presence. Providing a human presence on social media through the use of social media managers' avatars and names appeared to promote favorable organization-public relationships and positive WOM communication. However, dialogic communication intentions did not significantly differ between organizations incorporating a human presence versus an organizational presence into their Twitter pages. The proposed dynamic role of human presence versus organizational presence adds a new perspective as to how organizations can take better advantage of interpersonal aspects of social media. PMID- 23363229 TI - Cognitive distortions, anxiety, and depression among regular and pathological gambling online poker players. AB - The aims were to assess cognitive distortions and psychological distress (anxiety and depression) among online poker players of different levels of gambling intensity (non-pathological gamblers [NPG], problem gamblers [PbG], and pathological gamblers [PG]), and to examine the relationship between these variables and gambling pathology. Overall, 245 regular online poker players recruited on an Internet forum completed online self-report scales assessing pathological gambling (South Oaks Gambling Screen [SOGS]), psychological distress (Hospital Anxiety and Depression Scale [HADS]) and cognitive distortions (Gambling-Related Cognition Scale). Based on their SOGS scores, poker players were ranked into three groups: NPG (n=146), PbG (n=55), and PG (n=44). All poker players appeared to be more anxious than depressive. PG exhibited higher levels of depression and anxiety than did PbG and NPG. Cognitive distortions also significantly discriminated PG from PbG and NPG. A regression model showed that the perceived inability to stop gambling, the illusion of control, depression (HADS D), and anxiety were good predictors for pathological gambling among poker players. Our results suggest that cognitive distortions play an important role in the development and maintenance of gambling pathology. This study also underlines the role of anxiety and depression in pathological gambling among poker players. It seems relevant to take these elements into account in the research, prevention, and treatment of pathological gambling poker players. PMID- 23363230 TI - Relationship of internet addiction severity with depression, anxiety, and alexithymia, temperament and character in university students. AB - The aim of the study was to investigate the relationship of Internet addiction (IA) severity with alexithymia, temperament, and character dimensions of personality in university students while controlling for the effect of depression and anxiety. A total of 319 university students from two conservative universities in Ankara volunteered for the study. Students were investigated using the Toronto Alexithymia Scale-20, the Temperament and Character Inventory, the Internet Addiction Scale, the Beck Anxiety Inventory, and the Beck Depression Inventory. Of the university students enrolled in the study, 12.2 percent (n=39) were categorized into the moderate/high IA group (IA 7.2 percent, high risk 5.0 percent), 25.7 percent (n=82) were categorized into the mild IA group, and 62.1 percent (n=198) were categorized into the group without IA. Results revealed that the rate of moderate/high IA group membership was higher in men (20.0 percent) than women (9.4 percent). Alexithymia, depression, anxiety, and novelty seeking (NS) scores were higher; whereas self-directedness (SD) and cooperativeness (C) scores were lower in the moderate/high IA group. The severity of IA was positively correlated with alexithymia, whereas it was negatively correlated with SD. The "difficulty in identifying feelings" and "difficulty in describing feelings" factors of alexithymia, the low C and high NS dimensions of personality were associated with the severity of IA. The direction of this relationship between alexithymia and IA, and the factors that may mediate this relationship are unclear. Nevertheless, university students exhibiting high alexithymia and NS scores, along with low character scores (SD and C) should be closely monitored for IA. PMID- 23363231 TI - Plexiform schwannoma of the rectum. AB - Plexiform schwannoma is a benign peripheral nerve sheath tumor composed exclusively of Schwann cells arranged in a plexiform pattern. Most plexiform schwannomas are skin tumors and visceral localization is very rare. To our knowledge, there are six cases localized in visceral organs. We describe herein the first known case of plexiform schwannoma of the rectum resected by endoscopic submucosal dissection (ESD). A 77-year-old woman presented with a short history of anal pain. Sigmoidoscopy demonstrated a submucosal tumor, 20 mm in diameter, of the rectum below the peritoneal reflection (Rb). We resected the tumorby ESD. The tumor consisted of multiple white nodules in the submucosal layer. Microscopic examination revealed that the tumor was composed mainly of Antoni A tissue, compatible with conventional schwannoma. Immunohistochemically, the tumor was positive for S-100, and negative for alpha-smooth muscle actin, c-kit and CD 34. No evidence of recurrence has been found in 2 years of follow up. PMID- 23363232 TI - On the mechanism of action of antipsychotic drugs: a chemical reaction not receptor blockade. AB - Over forty years ago, biochemist Lauro Galzigna conducted an in-vitro experiment showing that the antipsychotic chlorpromazine reacted with the putative psychotogen adrenochrome to form a polymer resembling melanin. The field of psychopharmacology has essentially ignored that simple but illustrative experiment in the intervening time. The present study reproduces principle elements of Galzigna's experiment and expands the scope to include the antipsychotic medications olanzapine and minocycline. The rate of reaction was slow, with maximal yield of black polymer being achieved by 4, 10 and 7 days with chlorpromazine, olanzapine and minocycline, respectively. Changing the pH was most informative for chlorpromazine and minocycline reactions, where yield increased sharply between pH 6.1 and 6.9, and decreased slightly between pH 6.9 and 7.8, consistent with reaction profiles expected for aromatic substitution. Preincubation of olanzapine with iodine doubled the polymer yield, facilitated by the addition of iodine to the aromatic ring and presumably followed by its departure as a "leaving group". Increasing the salt concentration 1.5-fold depressed yields for all three drugs, most likely via ionic shielding of charged functional groups, diminishing reactivity. The results are discussed in regards to the mechanism of action of antipsychotic medications, casting doubt on commonly held theories. The time course of the chemical reactions presented here and the concentrations required, are much more consistent with clinical results than are models concerning receptor-mediated mechanisms. Furthermore, minocycline was effective in this model, but does not appear to have affinity for the primary receptor families thought by many to mediate antipsychotic efficacy. PMID- 23363233 TI - Treatment of lung cancer using nanoparticle drug delivery systems. AB - CONTEXT: One of the leading causes of cancer-associated deaths in most men and women in the Western world is lung cancer. There are various types of treatments depending on the type and the stage of the cancer. A recent type of therapy is targeted gene therapy which aims to target genes that cause lung cancer. However, this therapy has some drawbacks including lack of proper vectors for delivery. These drawbacks can potentially be overcome by using various types of nanoparticles. OBJECTIVE: To review current literature on the treatment of lung cancer with nanoparticles. METHODS: Researchers have attempted to treat lung cancer with a variety of types of nanoparticle matrices including lipid, polylactide-co-glycolide, albumin, poly (omega-pentadecalactone-co-butylene-co succinate), cerium oxide, gold, ultra-small superparamagnetic iron oxide nanoparticles, super paramagnetic iron oxide, lipid-polycation-DNA, N-[1-(2,3- dioleoyloxyl)propyl]-NNN-trimethylammoniummethylsulfate, silica-overcoated magnetic cores, and polyethyleneglycol phosphatidylethanolamine. There are various ways in which nanoparticles enhance drug delivery, and these include encapsulation against immune response, tissue penetration, target selectivity and specificity, delivery monitoring, promoting apoptosis, and blocking pathways for cancer initiation and progression. CONCLUSION: In the past decade, a lot has been said about targeting of NPs for lung and other cancers, but little has been actually successfully delivered to date. Nevertheless, nanoparticles can act as good vectors for delivering drug to the target neoplastic lesions within the lung, increase cellular uptake, increase tissue penetration and help in tracking the drug. In the future, combination therapies may play a key role in the treatment of lung cancer using the existing therapies. PMID- 23363234 TI - Age matching animal models to humans--theoretical considerations. AB - Biomedical animal models predict clinical efficacy with varying degrees of success. An important feature of in vivo modeling is matching the age of the animals used in preclinical research to the age of peak incidence for a disease state in humans. However, growth and development are highly variable between mammalian species, and age matching is always based on assumptions about the nature of development. We propose that researchers commonly make the assumption that developmental sequences are highly conserved between mammalian species--an assumption that we argue is often incorrect. We instead argue that development is often a modular process. Consideration of the modular nature of development highlights the difficulty in matching animal ages to human ages in a one-to-one scalar manner. We illustrate this with a discussion of the problem of age matching rodents to humans for neuroprotection experiments, and argue that researchers should pay deliberate attention to the modularity of developmental processes in order to optimally match ages between species in biomedical research. PMID- 23363235 TI - Fluorescein fluorescence use in the management of intracranial neoplastic and vascular lesions: a review and report of a new technique. AB - The use of fluorescent technologies in neurosurgery has a substantial history with applications to vascular and tumor surgery dating back to the 1940s. This review focuses on the applications of fluorescence imaging to intracranial vascular and neoplastic lesions using sodium fluorescein. The authors performed a literature search for articles about the use of sodium fluorescein in neurosurgery. Fifty-five articles were initially retrieved, and 37 of these were appropriate for this review. The subcategorization of these articles revealed 2 describing the properties of fluorescein, 19 articles relating to applications of fluorescein to tumor, 11 relating to vascular applications, and 5 reporting side effects associated with fluorescein use. Articles related to use of this agent in evaluation of CSF leak were excluded. Sodium fluorescein has been reported to be a useful surgical adjunct in resection of neoplastic lesions based on differential fluorescence between normal and neoplastic tissue. There are many reports on the utility of fluorescein in vascular imaging relating to arteriovenous malformations, aneurysms, and vessel anastomosis; however, these reports do not examine primary outcomes. Sodium fluorescein has been judged as generally safe with few reports of severe complications. Sodium fluorescein has demonstrated promise as a useful surgical adjunct in neurosurgery for vascular and neoplastic lesions. It is well tolerated, but further study is required to determine its full utility. Finally, we will introduce a new practical technology that could potentially improve intraoperative application of sodium fluorescein by improving its fluorescence visualization while using substantially lower doses of this dye. PMID- 23363236 TI - Predicting potent compounds via model-based global optimization. AB - Finding potent compounds for a given target in silico can be viewed as a constraint global optimization problem. This requires the use of an optimization function for which evaluations might be costly. The major task is maximizing the function while minimizing the number of evaluation steps. To solve this problem, we propose a machine learning algorithm, which first builds a statistical QSAR model of the SAR landscape and then uses the model to identify regions in compound space having a high probability to contain a highly potent compound. For this purpose, we devise the so-called expected potency improvement (EI) criterion to rank candidate compounds with respect to their likelihood to exhibit higher potency than the most active compound in the training data. Therefore, this approach significantly differs from a purely prediction-oriented classical QSAR model. The method is superior to a nearest neighbor approach as significantly fewer evaluation steps are needed to identify the most potent compound for the given target. PMID- 23363237 TI - Recurrent wheezing in the first three years of life: short-term prognosis and risk factors. AB - OBJECTIVE: It is difficult to determine if preschool children with recurrent wheezing are suffering from asthma or will suffer from asthma in the future. The aim of this study was to investigate the prognosis and risk factors of recurrent wheezing in children, beginning in the first 3 years of life. METHOD: Children who were referred because of recurrent wheezing episodes during the first 3 years of life were evaluated for the presence of asthma over a 4-year period. A child without any symptoms within the last 12 months was considered to be in remission. RESULTS: The study included 529 (male/female: 2.17) children with a median (inter quartile) age of 0.6 years (0.3-1.0) at symptom onset. The median follow-up and symptom durations were 2.93 years (1.74-4.76) and 4.30 years (2.91-5.97), respectively. Remission/recovery was achieved in 1.7%, 8.0%, and 14.4% of the children within 12, 24, and 36 months, respectively. A negative "stringent asthma predictive index" (API) significantly shortened the time to recovery of wheezing compared to the positive API (p = .036). Maternal smoking during pregnancy (OR = 4.35; 95% CI = 1.29-14.63); p = .018) and the number of emergency room admissions within the first 3 years of life (OR = 1.10; 95% CI = 1.01-1.19); p = .031) were found to be independent risk factors for the persistence of wheezing symptoms. CONCLUSION: Most of the children who were referred with frequent wheezing remain symptomatic 3 years after the initial wheezing episodes. A negative API is related to a shorter wheezing duration. Maternal smoking during pregnancy and the severity of the wheezing episodes appeared to be significant risk factors for the persistence of wheezing symptoms. PMID- 23363238 TI - Stable mercury isotope variation in rice plants (Oryza sativa L.) from the Wanshan mercury mining district, SW China. AB - To study the sources and transformations of Hg in the rice plant ( Oryza sativa L.), stable Hg isotope variations in different tissues (foliage, root, stem, and seed) of rice which were collected from the Wanshan mercury mine (WSMM, Guizhou province, SW China) were investigated by multicollector inductively coupled plasma mass spectrometry (MC-ICP-MS). In comparison, Hg isotope compositions of paddy soil, lichen, and direct ambient air samples in WSMM were also analyzed. We observed that mass dependent fractionation (MDF) of Hg differed by up to ~ 3.00/00 in delta(202)Hg values and that mass independent fractionation (MIF) of Hg isotopes affected the odd Hg isotopes to produce a ~ 0.400/00 range in Delta(199)Hg (and Delta(201)Hg) values in tissues of rice plant. The 1:1 Delta(199)Hg/Delta(201)Hg ratio in tissues of rice supported the hypothesis that a fraction of Hg in tissues of rice plants has undergone a photoreduction process prior to being accumulated by rice plants. We suggest that the variation of MIF represents a mixing between soil Hg and atmospheric Hg in rice plants. The estimated fraction of atmospheric Hg (f) in tissues of rice followed the trend of f leaf > f stem > f seed > f root. Finally, we demonstrated a significant MDF of >1.00/00 in delta(202)Hg during the processes of absorption of atmospheric Hg by leaf tissues and of absorption of soil Hg by roots. Our study demonstrated that Hg isotopes may represent an important contribution both to the study of Hg transportation in plants and to the understanding of sources of Hg contamination to critical food crops. PMID- 23363239 TI - Hysteresis and negative cooperativity in human UDP-glucose dehydrogenase. AB - Human UDP-alpha-d-glucose 6-dehydrogenase (hUGDH) forms a hexamer that catalyzes the NAD(+)-dependent oxidation of UDP-alpha-d-glucose (UDG) to produce UDP-alpha d-glucuronic acid. Mammalian UGDH displays hysteresis (observed as a lag in progress curves), indicating that the enzyme undergoes a slow transition from an inactive to an active state. Here we show that hUGDH is sensitive to product inhibition during the lag. The inhibition results in a systematic decrease in steady-state velocity and makes the lag appear to have a second-order dependence on enzyme concentration. Using transient-state kinetics, we confirm that the lag is in fact due to a substrate and cofactor-induced isomerization of the enzyme. We also show that the cofactor binds to the hUGDH:UDG complex with negative cooperativity. This suggests that the isomerization may be related to the formation of an asymmetric enzyme complex. We propose that the hysteresis in hUGDH is the consequence of a functional adaptation; by slowing the response of hUGDH to sudden increases in the flux of UDG, the other biochemical pathways that use this important metabolite (i.e., glycolysis) will have a competitive edge. PMID- 23363241 TI - Facile large-scale synthesis of monodisperse mesoporous silica nanospheres with tunable pore structure. AB - Mesoporous silica nanoparticles (MSNs) are experiencing rapid development in the biomedical field for imaging and for use in heterogeneous catalysis. Although the synthesis of MSNs with various morphologies and particle sizes has been reported, synthesis of a pore network with monodispersion control below 200 nm is still challenging. We achieved this goal using mild conditions. The reaction occurred at atmospheric pressure with a templating sol-gel technique using cetyltrimethylammonium (CTA(+)) as the templating surfactant and small organic amines (SOAs) as the mineralizing agent. Production of small pore sizes was performed for the first time, using pure and redispersible monodispersed porous nanophases with either stellate (ST) or raspberry-like (RB) channel morphologies. Tosylate (Tos(-)) counterions favored ST and bromide (Br(-)) RB morphologies at ultralow SOA concentrations. Both anions yielded a worm-like (WO) morphology at high SOA concentrations. A three-step formation mechanism based on self-assembly and ion competition at the electrical palisade of micelles is proposed. Facile recovery and redispersion using specific SOAs allowed a high yield production at the kilogram scale. This novel technique has practical applications in industry. PMID- 23363240 TI - Do not forget the professional--the value of the FIRST model for guiding the structural involvement of patients in rheumatology research. AB - BACKGROUND: The FIRST model describes five practical components that enable equal collaboration between patients and professionals in clinical rheumatology research: Facilitate, identify, respect, support and training. OBJECTIVE: To assess the value of this model as a framework for setting up and guiding the structural involvement of people with arthritis in health research. METHOD: The FIRST model was used as a framework during the guidance of a network of patient research partners and clinical rheumatology departments in the Netherlands. A 'monitoring and evaluation' approach was used to study the network over a period of 2 years. Data were collected using mixed methods and subjected to a directed content analysis. The FIRST components structured the data analysis. During monitoring meetings, refined and additional descriptors for each component were formulated and added if new items were found. RESULTS: The FIRST model helps to guide and foster structural partnerships between patients and professionals in health research projects. However, it should be broadened to emphasize the pivotal role of the principal investigator regarding the facilitation and support of patient research partners, to recognize the requirements of professionals for training and coaching and to capture the dynamics of collaboration, mutual learning processes and continuous reflection. CONCLUSION: FIRST is a good model to implement sustainable relationships between patients and researchers. It will benefit from further refinement by acknowledging the dynamics of collaboration and including the concept of reflection and relational empowerment. The reciprocal character of the five components, including training and support of researchers, should be incorporated. PMID- 23363242 TI - Rehabilitation service utilization in children and youth with cerebral palsy. AB - AIM: To describe the pattern of use of rehabilitation services in children and adolescents with cerebral palsy (CP), and to identify factors associated with use. METHODS: In this study, parents of 91 school-age children and 167 adolescents with CP completed a questionnaire regarding educational and rehabilitation resources received within the last 6 months. Rehabilitation services included occupational therapy (OT), physical therapy (PT), speech language pathology (SLP), psychology and special education. Demographic characteristics were documented and developmental and functional status was assessed. Relationships between service utilization and sociodemographic factors, functioning and school setting were determined. RESULTS: Over half of children (53.2%) and adolescents (57.5%) were in regular schools; however, 41% of these required special education resources. The remainder (42.5-46.8%) was in special schools. The majority of children (84.6%) were receiving at least one rehabilitation service although this decreased (68.1%) in adolescence. PT and OT were most common and services were provided predominantly in the school setting. Services were primarily weekly direct interventions at school age, with weekly interventions or consultations most common for adolescents. Younger age was associated with service receipt at school age only. Children with greater motor limitations, lower IQ and greater activity limitations were more likely to receive OT, PT, SLP or special education. Children in segregated schools were significantly more likely to receive rehabilitation services, when compared with children in regular schools. CONCLUSIONS: The majority of children and youth received one or more services. Individuals with greater motor or cognitive challenges were more likely to receive a range of school-based services from rehabilitation specialists. When compared with children of school age, adolescents were less likely to receive services and when provided, services were more likely to be consultative. Services may need to be more optimally organized through childhood to enhance benefits to children with CP across activity limitation profiles. PMID- 23363243 TI - Resveratrol and adipose-derived mesenchymal stem cells are effective in the prevention and treatment of doxorubicin cardiotoxicity in rats. AB - Anthracyclines can cause severe cardiac toxicity leading to heart failure. The aim of this study was to determine the effects of cardioprotective polyphenolic compound resveratrol (RES) and adipose-derived mesenchymal stem cells (ADMSCs) on cardiac tissue of rats treated with doxorubicin (DOX). Forty-two female and three male Wistar-Albino rats were included in the study. The study groups and the control groups were as follows: Group I: DOX; Group II: DOX + RES; Group III: DOX + ADMSCs; Group IV: DOX + RES + ADMSCs; Group V: Sham operation; and Group VI: normal saline. ADMSCs obtained from male rats were defined with stem cell markers [CD11b/c(-), CD45(-), CD90(+), CD44(+), and CD49(+)]. DOX 12 mg/kg intraperitoneally (i.p.) was injected as a single dose in female rats. Resveratrol 100 mg/kg was injected three times i.p. in Groups II and IV. ADMSCs 2 * 10(6) cells/kg/dose were labeled with bromodeoxyuridine (BrdU) and injected i.p. for a total of three times in Groups III and IV. When the study was terminated after 4 weeks, the beating hearts were connected to a Langendorff setup and records were obtained for 30 minutes. Histopathological, immunhistochemical, and immunofluorescent examination with H&E, Troponin I, and BrdU stains were also performed. Also, ADMSCs were demonstrated in the myocardium of transplanted rats. Left ventricle functions and myocardial histology demonstrated significant impairment in DOX only group compared to groups with ADMSCs (P < .05). We suggest that RES and ADMSCs were successful in the prevention and treatment of the doxorubicin cardiomyopathy in rats. The hypothetical mechanisms of regeneration are multiple, including cell differentiation and autocrine/paracrine effects of ADMSCs. PMID- 23363244 TI - Surfactant adsorption and interfacial tension investigations on cyclopentane hydrate. AB - Gas hydrates represent an unconventional methane resource and a production/safety risk to traditional oil and gas flowlines. In both systems, hydrate may share interfaces with both aqueous and hydrocarbon fluids. To accurately model macroscopic properties, such as relative permeability in unconventional systems or dispersion viscosity in traditional systems, knowledge of hydrate interfacial properties is required. This work presents hydrate cohesive force results measured on a micromechanical force apparatus, and complementary water hydrocarbon interfacial tension data. By combining a revised cohesive force model with experimental data, two interfacial properties of cyclopentane hydrate were estimated: hydrate-water and hydrate-cyclopentane interfacial tension values at 0.32 +/- 0.05 mN/m and 47 +/- 5 mN/m, respectively. These fundamental physiochemical properties have not been estimated or measured for cyclopentane hydrate to date. The addition of surfactants in the cyclopentane phase significantly reduced the cyclopentane hydrate cohesive force; we hypothesize this behavior to be the result of surfactant adsorption on the hydrate-oil interface. Surface excess quantities were estimated for hydrate-oil and water-oil interfaces using four carboxylic and sulfonic acids. The results suggest the density of adsorbed surfactant may be 2* larger for the hydrate-oil interface than the water-oil interface. Additionally, hydrate-oil interfacial tension was observed to begin decreasing from the baseline value at significantly lower surfactant concentrations (1-3 orders of magnitude) than those for the water-oil interfacial tension. PMID- 23363245 TI - Female-biased obligate strategies in a partially migratory population. AB - Partial migration occurs when a breeding population consists of seasonal migrants and year-round residents. Although it is common among birds, the basis of individual movement decisions within partially migratory populations is still unresolved. Over 4 years, we used state of the art tracking techniques, a combination of geolocators and radio transmitters, to follow individual European blackbirds Turdus merula year round from a partially migratory population to determine individual strategies and departure and arrival dates. The individual based tracking combined with measures of energetic and hormonal (corticosterone) state enabled us to distinguish between obligate and facultative migration and to test several classical hypotheses of partial migration: the 'Arrival Time'-, 'Dominance'- and 'Thermal Tolerance'-hypotheses. Two distinct periods of departures from the breeding grounds were observed during the study; one in early autumn, and another during the midst of winter. Although blackbirds that migrated in autumn were never observed overwintering within 300 km of the study site, four individuals that departed in the winter were observed within 40 km. Females were significantly more likely to migrate in autumn than males but there was no difference in the age or body size of migrants and non migrants in autumn. Just prior to autumn migration, migrants had higher fat scores than non migrants and tended to have higher concentrations of baseline corticosterone, but similar concentrations of triglycerides. Unlike autumn migrants, we found no difference between the tendencies of males versus females to depart in winter, nor did we find any difference in body size or age of individuals that departed in the winter. Autumn migration was sex biased and resembled obligate migration. Our results provide strong support for the 'Arrival Time' hypothesis for partial migration in the autumn. We found no clear support for the 'Dominance' or 'Thermal Tolerance' hypotheses. By tracking individuals year round, we were able to identify a second period of departures. Overall, these results suggest the co occurrence of obligate autumn migrants, winter movements and sedentary individuals within a single population. PMID- 23363246 TI - Fungal diversity from various marine habitats deduced through culture-independent studies. AB - Studies on the molecular diversity of the micro-eukaryotic community have shown that fungi occupy a central position in a large number of marine habitats. Environmental surveys using molecular tools have shown the presence of fungi from a large number of marine habitats such as deep-sea habitats, pelagic waters, coastal regions, hydrothermal vent ecosystem, anoxic habitats, and ice-cold regions. This is of interest to a variety of research disciplines like ecology, evolution, biogeochemistry, and biotechnology. In this review, we have summarized how molecular tools have helped to broaden our understanding of the fungal diversity in various marine habitats. Majority of the environmental phylotypes could be grouped as novel clades within Ascomycota, Basidiomycota, and Chytridiomycota or as basal fungal lineages. Deep-branching novel environmental clusters could be grouped within Ascomycota as the Pezizomycotina clone group, deep-sea fungal group-I, and soil clone group-I, within Basidiomycota as the hydrothermal and/or anaerobic fungal group, and within Chytridiomycota as Cryptomycota or the Rozella clade. However, a basal true marine environmental cluster is still to be identified as most of the clusters include representatives from terrestrial regions. The challenge for future research is to explore the true marine fungi using molecular techniques. PMID- 23363247 TI - Carbon-nanotube-embedded hydrogel sheets for engineering cardiac constructs and bioactuators. AB - We engineered functional cardiac patches by seeding neonatal rat cardiomyocytes onto carbon nanotube (CNT)-incorporated photo-cross-linkable gelatin methacrylate (GelMA) hydrogels. The resulting cardiac constructs showed excellent mechanical integrity and advanced electrophysiological functions. Specifically, myocardial tissues cultured on 50 MUm thick CNT-GelMA showed 3 times higher spontaneous synchronous beating rates and 85% lower excitation threshold, compared to those cultured on pristine GelMA hydrogels. Our results indicate that the electrically conductive and nanofibrous networks formed by CNTs within a porous gelatin framework are the key characteristics of CNT-GelMA leading to improved cardiac cell adhesion, organization, and cell-cell coupling. Centimeter-scale patches were released from glass substrates to form 3D biohybrid actuators, which showed controllable linear cyclic contraction/extension, pumping, and swimming actuations. In addition, we demonstrate for the first time that cardiac tissues cultured on CNT-GelMA resist damage by a model cardiac inhibitor as well as a cytotoxic compound. Therefore, incorporation of CNTs into gelatin, and potentially other biomaterials, could be useful in creating multifunctional cardiac scaffolds for both therapeutic purposes and in vitro studies. These hybrid materials could also be used for neuron and other muscle cells to create tissue constructs with improved organization, electroactivity, and mechanical integrity. PMID- 23363248 TI - Theoretical study of the protonation of the one-electron-reduced guanine-cytosine base pair by water. AB - Prototropic equilibria in ionized DNA play an important role in charge transport and radiation damage of DNA and, therefore, continue to attract considerable attention. Although it is well-established that electron attachment will induce an interbase proton transfer from N1 of guanine (G) to N3 of cytosine (C), the question of whether the surrounding water in the major and minor grooves can protonate the one-electron-reduced G:C base pair still remains open. In this work, density functional theory (DFT) calculations were employed to investigate the energetics and mechanism for the protonation of the one-electron-reduced G:C base pair by water. Through the calculations of thermochemical cycles, the protonation free energies were estimated to be in the range of 11.6-14.2 kcal/mol. The calculations for the models of C(*-)(H(2)O)(8) and G(-H1)( )(H(2)O)(16), which were used to simulate the detailed processes of protonation by water before and after the interbase proton transfer, respectively, revealed that the protonation proceeds through a concerted double proton transfer involving the water molecules in the first and second hydration shells. Comparing the present results with the rates of interbase proton transfer and charge transfer along DNA suggests that protonation on the C(*-) moiety is not competitive with interbase proton transfer, but the possibility of protonation on the G(-H1)(-) moiety after interbase proton transfer cannot be excluded. Electronic-excited-state calculations were also carried out by the time-dependent DFT approach. This information is valuable for experimental identification in the future. PMID- 23363249 TI - Best treatment practices for pachyonychia congenita. AB - BACKGROUND: Numerous therapeutic modalities have been proposed to treat the manifestations of pachyonychia congenita (PC). While research hopes lie with molecular therapies, patients are in need of answers regarding the efficacy of conventional treatments. AIM OF THE STUDY: To determine patients' experience and preferences regarding conventional treatments for PC. METHODS: The study population included 120 PC patients from 20 countries. The study was based on a patient survey developed by physicians and researchers from the International Pachyonychia Congenita Consortium and conducted via the internet. Using an effectiveness scale of 1 to 5, the patients were asked to grade treatments for different manifestations, including keratoderma, cysts, follicular hyperkeratosis, fingernail and toenail involvement. RESULTS: Patients reported surgical treatments being most effective for cysts and mechanical treatments the most effective conventional therapeutic approach for all other investigated manifestations. The other conventional medical treatments were found to be non effective to only slightly effective. Among patients with keratoderma, older people were more likely to report beneficial effect from mechanical treatments (P = 0.04), topical retinoids (P = 0.04) and topical steroids (P = 0.02). Likewise, females were more inclined to report filing and grinding beneficial than males (P = 0.02). Finally, carriers of KRT16 and KRT6a were more likely to benefit from keratolytics than carriers of mutations in KRT17 (P = 0.04). CONCLUSIONS: None of the currently available therapeutic options for PC are ideal, although they provide some relief, with mechanical/surgical options being preferred over medical therapies. These results emphasize the need for more efficient and targeted therapies. PMID- 23363250 TI - Rechargeable vs. nonrechargeable internal pulse generators in the management of dystonia. AB - OBJECTIVE: To test if deep brain stimulation (DBS) treatment of dystonia was similar in patients before and after implantation of rechargeable internal pulse generators (IPGs). MATERIALS AND METHODS: The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) severity and disability scores were compared in patients before DBS insertion, 24 months after DBS insertion with a nonrechargeable IPG, and after implantation of a rechargeable IPG. RESULTS: No significant differences were observed between dystonia control in patients before and after implantation of a rechargeable IPG. CONCLUSIONS: Rechargeable IPGs should be the IPGs of choice for dystonic patients receiving DBS as IPGs offer similar treatment efficacy to nonrechargeable IPGs with advantages in terms of costs and reductions in reimplantation frequency. PMID- 23363251 TI - Bystander effects in tumor-free and tumor-bearing rat brains following irradiation by synchrotron X-rays. AB - PURPOSE: Synchrotron microbeam radiation therapy (MRT) is a radiosurgery concept in the preclinical stage, developed mainly for brain tumor treatment. Experimental studies suggest that with MRT a better therapeutic index can be obtained than with homogenous field radiotherapy, but the underlying cellular mechanisms need further understanding. The aim of this study was to investigate the dynamics of radiation-induced bystander effects (RIBE) in rats after exposing one brain hemisphere to either MRT or homogenous synchrotron radiation (HSR). MATERIALS AND METHODS: Healthy and tumor-bearing Wistar rats were exposed to doses of 17.5, 35, 70 or 350 Gy, applied either as MRT or HSR to the right cerebral hemisphere. Rats were euthanized at 4, 8 and 12 hours after irradiation to assess the release of bystander signals. Brains and urinary bladders were dissected, and explants for bystander clonogenic reporter assays were set up. RESULTS: Clonogenic survival showed that RIBE occurred in both the non-irradiated brain hemisphere and in bladder of normal and tumor-bearing rats, while the irradiated hemisphere showed the direct effects of radiation. CONCLUSION: The RIBE observed in our reporter cells shows that both MRT and HSR yield a demonstrable abscopal effect after high doses of irradiation; presumably as part of a systemic response. PMID- 23363252 TI - Better association of waist circumference with insulin resistance and some cardiovascular risk factors than body mass index. AB - OBJECTIVE: The aim of the present study was to assess the association of the obesity, measured by body mass index (BMI) or waist circumference (WC), with both insulin resistance (IR) and some cardiovascular disease (CVD) risk factors and to reveal which of these obesity measures maintains stronger association with the IR and CVD risk factors. METHODS: A total of 68 women in the fertile age (32 +/- 6 years) were classified in three groups (normal weight, overweight, and obese) according to BMI, and in two groups (normal and high) according to WC. Systolic (SBP) and diastolic blood pressures (DBP) were measured and fasting insulin (FI), fasting glucose (FG), homeostasis model analysis insulin resistance (HOMA-IR), triglycerides (TGs), low density lipoprotein (LDL-C), and high density lipoprotein (HDL-C) were determined. RESULTS: The values of the FI, FG, HOMA-IR, TGs, LDL-C, SBP, and DBP were significantly higher and HDL-C significantly lower in the obese subjects in comparison with the subjects with normal weight or overweight. By classifying the participants on the basis of their WC, results showed that FI, FG, HOMA-IR, TGs, LDL-C, SBP, and DBP were significantly higher, and HDL-C was significantly lower in the subjects with high WC compared with those having normal WC. Linear regression analysis was done to compare the relationships between these two obesity measures and both the IR and measured CVD risk factors. It was found that both BMI and WC significantly correlate with them, however, WC has a higher r2 (correlation coefficient) than BMI. CONCLUSIONS: The relation between BMI and WC, as two measures of the obesity, which are simple, safe, and inexpensive to obtain as well as HOMA-IR and some CVD risk factors, was established. The original finding of this study is that WC has closer association with CVD risk factors than BMI. Thus, WC can be used to screen for the risk of some health problems as IR, and CVD risk factors in pre menopausal females. PMID- 23363253 TI - Insulin receptor, IRS1, IRS2, INSIG1, INSIG2, RRAD, and BAIAP2 gene expressions in glioma U87 cells with ERN1 loss of function: effect of hypoxia and glutamine or glucose deprivation. AB - OBJECTIVE: The purpose of this study was to examine: 1) the association between the expression of the insulin receptor (INSR), insulin receptor substrate 1 (IRS1) and 2 (IRS2), insulin inducible gene 1 (INSIG1) and 2 (INSIG2), Ras related associated with diabetes (RRAD), and brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) genes in glioma cells and 2) the function of the endoplasmic reticulum stress signaling, mediated by endoplasmic reticulum to nuclei-1 (ERN1) and regulation of these gene expressions by hypoxia and glucose or glutamine deprivation. METHODS: The expression of the INSR, IRS1, IRS2, INSIG1, INSIG2, RRAD, and BAIAP2 genes in the glioma cell line U87 and its subline with ERN1 loss of function was studied by qPCR. The cells were exposed to a mix of 3 % oxygen and 5 % carbon dioxide and glucose or glutamine deprivation. RESULTS: The blockade of the ERN1 signaling enzyme function in glioma cells leads to the gene expression increase in INSR, INSIG2, and IRS2 and decrease in the BAIAP2 and RRAD genes. Hypoxia affected the expression of the INSR, IRS1, IRS2, INSIG1, INSIG2, and BAIAP2 genes with more significant changes in INSIG2 and IRS2 genes. Furthermore, the effect of hypoxia on expression of these genes was mostly dependent on the ERN1 signaling enzyme function. The data also show that glucose or glutamine deprivation may change the expression of the genes studied and that the suppression of the ERN1 enzyme function usually modifies the effect of the glucose or glutamine deprivation. CONCLUSIONS: Results of this study demonstrated the dependence of INSR and related to insulin receptor signaling gene expressions in U87 glioma cells on ERN1 enzyme function indicating its participation in the regulation of metabolic and proliferative processes via endoplasmic reticulum stress which is important component of tumor growth and metabolic diseases. Moreover, hypoxia and glucose or glutamine deprivation are controlled by the expression of insulin receptor and related to insulin signaling genes mostly via ERN1 enzyme signaling. PMID- 23363254 TI - Association of nonalcoholic fatty liver disease (NAFLD) with urolithiasis. AB - OBJECTIVE: The NAFLD is related to metabolic disorders and is negatively associated with kidney function. Renal stone disease (urolithiasis) is an increasing form of a common renal disease that is a multifactorial disorder influenced by both intrinsic and extrinsic, mainly environmental factors. The association between the fatty liver and renal calculi, as a specific underlying risk factor, has received no attention, so far. Therefore, in this study, a possible relationship between fatty liver with renal calculi and urolithiasis is investigated. METHODS: In a cross sectional study, a total of 11245 ultrasonography reports revealing the condition of fatty liver, kidney stones (urolithiasis), or a combination of both of them, were categorized and evaluated statistically. Descriptive statistics determined the number (frequency and percentage) of each condition. The statistical significance of the association between fatty liver and kidney stone, and vice versa, was evaluated using McNemar's test. The Chi Square Test assessed the relationship between genders. Odds ratios and 95% confidence intervals (95% CI) assessed the likelihood of characteristics of urolithiasis for fatty liver patients. RESULTS: We found 8% frequency of urolithiasis among subjects with healthy liver. NAFLD was identified in 30%, while urolithiasis in 11% subjects from all individuals studied. The present study diagnosed urolithiasis in 17% of patients with fatty liver. Its occurrence was more common in men than women. Data revealed more common diagnosis of fatty liver (48%) in patients with urolithiasis, which was also higher in males than females. The higher NAFLD was linked with urolithiasis, indicating a greater chance of their association. Interestingly, the detection frequency of urolithiasis in the patients with NAFLD was also markedly higher (odds ratio: 2.4, 95% CI 2.1-2.7). The NAFLD appears to be an independent variable as a risk factor for stone formation. CONCLUSIONS: The present study indicates that the prevalence of urolithiasis is significantly higher in the NAFLD than healthy subjects. This result suggests that NAFLD may be involved in the mechanism of the onset of the urolithiasis. It is suggested that lipid peroxidation, oxidative stress and changes in the urinary constituents in the NAFLD may be considered as a risk factor in the progression of stone formations. PMID- 23363255 TI - Prevalence of metabolic syndrome, insulin resistance, and microvascular angina pectoris in 500 consecutive patients referred to coronarography. AB - OBJECTIVE: This work was aimed to evaluate the prevalence of insulin resistance (IR) and metabolic syndrome in a large cohort of 40-60 years old patients with cardiovascular symptoms. METHODS: A total of 500 consecutive males and females referred to coronarography and coronary catheterization, because of spontaneous or after load precordial pain plus denivelisation of ST segment by electrocardiography, were included. Besides standard clinical examinations, ergometry, echocardiography, fundamental laboratory tests, and several other laboratory examinations were also performed, including oral glucose toleration test (OGTT), total and high-density lipoprotein (HDL) cholesterol, triglycerides, apoprotein A1 and B, apolipoprotein (a), uric acid, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), cytokines (tumor necrosis factor alpha, TNFalpha, interleukin-1, IL-1, interleukin-6, IL-6), endothelin-1, as well as hormones (insulin, C peptide, leptin, growth hormone, cortisol). RESULTS: In 81.6% of patients, IR syndrome with compensatory hyperinsulinemia was found in a positive correlation with various symptoms of metabolic syndrome, including abdominal obesity, increased body mass index (BMI), dysglycemia, dyslipoproteinemia, coronary stenosis, decreased HDL level, and hypertension. Hirsutism with polycystic ovarian syndrome was found in 52% of examined women with IR. However, a normal coronary angiogram, called as a microvascular form of the angina pectoris (MIV-AP), was found in 14% of predominantly periclimacteric and benign hirsutic females with long-term disorders of menstrual cycle. Since these patients showed the same symptoms as their gender, age, BMI, and degree of coronary stenoses adjusted pairs with the macrovascular form (such as the same levels of several lipids, hormones and obesity measures), our data strongly support the view that MIV-AP might belong to the IR syndrome. CONCLUSIONS: Hyperinsulinemia and high prevalence of various symptoms of metabolic syndrome (MS) were found in high percentage of patients with after load precordial pain who were referred to coronarography. Similarly, in several women, MIV-AP was detected and its affiliation to MS suggested. PMID- 23363257 TI - Can postoperative coffee perk up recovery time after colon surgery? PMID- 23363256 TI - Renin-angiotensin system: upgrade of recent knowledge and perspectives. AB - Although more than 100 years passed from the renin-angiotensin system (RAS) discovery, new knowledge is still ceaselessly accruing in this field. The present review provides brief overview on the history of the RAS investigation, circulating and tissue RAS, and outlines the physiological functions of the RAS major active substance, angiotensin II (ANG II). Circulating ANG II is generated from angiotensin I (ANG I) by carboxypeptidaze angiotensin-converting enzyme (ACE) expressed in the pulmonary endothelial cells. ANG I is formed from angiotensinogen, originating in the liver, by renal peptidase renin secreted by the juxtaglomerular cells. The ANG II effects are mediated mainly via AT1 receptors. Scientific, medical, and pharmacological interests in the RAS relay mainly in its potency to influence the blood pressure and heart hypertrophy. Inhibition of ACE and AT1 receptors has been shown to be very useful in the hypertension management although several unexpected effects of this treatment led to the initiation of new studies. This review also describes other bioactive angiotensins and modifying enzymes identified during the last years, the ways how the RAS activity can be measured and ANG II degraded in the organism. It also indicates the most convenient models for the RAS investigation. Finally, the major mechanisms of the RAS activity regulation are also described. KEYWORDS: angiotensin, angiotensin-converting enzyme, angiotensin-converting enzyme 2, angiotensin AT1 receptors, experimental model. PMID- 23363258 TI - Inducing remission of ulcerative colitis: are clinicians better equipped than ever? PMID- 23363260 TI - Primary sclerosing cholangitis: a review and update on therapeutic developments. AB - Primary sclerosing cholangitis (PSC) is a chronic, cholestatic, idiopathic liver disease characterized by fibro-obliterative inflammation of the hepatic bile ducts. In a clinically significant proportion of patients, PSC progresses to cirrhosis, end-stage liver disease, and in some cases, cholangiocarcinoma. Despite clinical trials of nearly 20 different pharmacotherapies over several decades, safe and effective medical therapy, albeit critically needed, remains to be established. PSC is pathogenically complex, with genetic, immune, enteric microbial, environmental and other factors being potentially involved and, thus, not surprisingly, it manifests as a clinically heterogeneous disease with a relatively unpredictable course. It is likely that this complexity and clinical heterogeneity are responsible for the negative results of clinical trials, but novel insights about and approaches to PSC may shift this trend. The authors herein provide a review of previously tested pharmacologic agents, discuss emerging fundamental concepts and present viewpoints regarding how identifying therapies for PSC may evolve over the next several years. PMID- 23363261 TI - Upper gastrointestinal symptoms in obese patients and their outcomes after bariatric surgery. AB - Obesity is considered an important risk factor for the development of gastrointestinal (GI) disorders, likely through alterations of GI motility. Even though gastroesophageal reflux disease is the condition mainly studied at present, the prevalence of other upper GI symptoms is also augmented in obese patients. Owing to their chronic trend, these disorders have a bearing on public spending and their correct diagnosis would avoid unnecessary cost-consuming investigations. Furthermore, bariatric surgery dramatically changes GI anatomy and physiology, influencing GI symptom outcomes. The aim of this review is to categorize the available results in a pathophysiological framework in an attempt to set up the correct clinical GI management of obese patients before and after bariatric surgery. This would be helpful in tentatively reducing their considerable economic burden on public health services. PMID- 23363262 TI - Diabetic gastroparesis: recent insights into pathophysiology and implications for management. AB - Delayed gastric emptying affects a substantial proportion of patients with long standing diabetes, and when associated with symptoms and/or disordered glycemic control, affects quality of life adversely. Important clinicopathological insights have recently been gained by the systematic analysis of gastric biopsies from patients with severe diabetic gastroparesis, which may stimulate the development of new therapies in the coming decade. Experience with prokinetic therapies and treatments, such as pyloric botulinum toxin injection and gastric electrical stimulation, has established that relief of symptoms does not correlate closely with acceleration of delayed gastric emptying, and that well designed controlled trials are essential to determine the efficacy of emerging therapies. PMID- 23363263 TI - Assessing portal hypertension in liver diseases. AB - Portal hypertension is a common complication of chronic liver diseases and is responsible for most clinical consequences of cirrhosis, which represent the more frequent causes of death and liver transplantation in these patients. This review is aimed at clarifying the state-of-the art assessment of portal hypertension and at discussing recent developments in this field. Particular attention is paid to new noninvasive techniques that will be soon available for potential routine use. PMID- 23363264 TI - Hepatic disease biomarkers and liver transplantation: what is the potential utility of microRNAs? AB - Liver transplantation represents the treatment of choice for acute hepatic failure or chronically induced end stage of liver disease. Molecular characterization of hepatic injury and recovery processes encloses the key for biomarker discovery in the liver transplantation field. Several pathological hepatic processes were demonstrated to be associated with deregulated miRNA profiles. Moreover, abnormal concentration levels of circulating cell-free miRNAs correlate with specific hepatic injury. The high molecular stability and emerging rapid assessment techniques invite further consideration of miRNAs as feasible monitoring and outcome predictive biomarkers for liver disease and liver transplantation. The present review aims to provide an overview of recent achievements in research on the potential applicability of miRNAs as biomarkers in liver disease and liver transplantation. PMID- 23363265 TI - Hepatitis C virus vaccines in the era of new direct-acting antivirals. AB - Hepatitis C virus (HCV) infection is a major global health problem as it has a high propensity for establishing chronicity. Chronic HCV carriers are at risk of developing severe liver disease including fibrosis, cirrhosis and liver cancer. While treatment has considerably improved over the years, therapy is still only partially effective, and is plagued by side effects, which contribute to treatment failure and is expensive to manage. The drug development pipeline contains several compounds that hold promise to achieve the goal of a short and more tolerable therapy, and are also likely to improve treatment response rates. It remains to be seen, however, how potent antiviral drug cocktails will affect the hepatitis C burden worldwide. In resource-poor environments, considerable costs, inadequate infrastructure for medical supervision and distribution may diminish the impact of future therapies. Consequently, development of novel therapeutic and prophylactic strategies is imperative to contain HCV infection globally. PMID- 23363267 TI - Intraluminal duodenal diverticulum with refractory pancreatitis successfully treated by endoscopic diverticulectomy. PMID- 23363268 TI - Serum oxidative-anti-oxidative stress balance is dysregulated in patients with hepatitis C virus-related hepatocellular carcinoma. AB - AIM: Oxidative stress is associated with progression of chronic liver disease (CLD). This association is best established in chronic hepatitis C. However, the anti-oxidative state is not well characterized. The objective of the present study was to investigate the balance of oxidative and anti-oxidative stress in CLD patients. METHODS: We recruited a study population of 208 patients, including healthy volunteers (HV; n = 15), patients with hepatitis B virus (HBV)-related CLD without or with hepatocellular carcinoma (HBV-non-HCC, n = 25, and HBV-HCC, n = 50, respectively), and patients with hepatitis C virus (HCV)-related CLD without or with HCC (HCV-non-HCC, n = 49, and HCV-HCC, n = 69, respectively). Serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY adsorbent test; OXY) were determined, and the balance of these values was used as the oxidative index. Correlations among ROM, OXY, oxidative index and clinical characteristics were investigated. RESULTS: Patients with CLD exhibited elevated ROM and oxidative index compared to HV. Among patients with CLD, HCV positive status correlated with increased ROM. In CLD, HCV-HCC patients exhibited the highest ROM levels. Among HCV-related CLD patients, lower OXY correlated with HCC positive status, but was recovered by eradication of HCC. In HCV-HCC, lower OXY correlated with high PT-INR. CONCLUSION: HCV positive CLD patients displayed higher oxidative stress and HCV-HCC patients displayed lower anti-oxidative state. Anti-oxidative state depression was associated with liver reservoir related data in HCV-HCC and could be reversed with HCC eradication. PMID- 23363269 TI - MYC rearrangements are useful for predicting outcomes following rituximab and chemotherapy: multicenter analysis of Japanese patients with diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and it has several morphologic and clinicopathologic variants. The prognosis of DLBCL can vary according to specific genetic and immunophenotypic abnormalities. The aim of this study was to investigate the prognostic impact of previously identified prognostic factors, such as activated B cell-like immunophenotype, CD5, BCL2 and MYC rearrangement (MYC-R), in patients treated with rituximab. We retrospectively analyzed the prognosis of 100 patients with DLBCL (median age, 66.5 years) treated with rituximab-containing chemotherapy. The 3-year overall survival (OS) and progression-free survival (PFS) were 66% and 62%. Outcomes were significantly worse in patients with MYC-R in 3-year OS (50% vs. 67.8%, p = 0.043) and PFS (30% vs. 57.8%, p = 0.003), and multivariate analysis showed that this finding was independent of the International Prognostic Index (IPI). Immunostaining by Muris algorithm had the highest predictive power among the three algorithms. However, other previously reported prognostic factors, such as BCL2 and CD5, were not good predictors of outcomes in these patients. In conclusion, our data suggest that fluorescence in situ hybridization (FISH) analysis for MYC-R can predict outcomes in response to rituximab containing chemotherapy in Japanese patients with DLBCL. PMID- 23363270 TI - Extranodal marginal zone lymphoma of the cranial dura mater: report of three cases and systematic review of the literature. PMID- 23363271 TI - Recent advances in mantle cell lymphoma: report of the 2012 Mantle Cell Lymphoma Consortium Workshop. AB - Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterized by overexpression of cyclin D1 and the t(11;14)(q13;q32) chromosomal translocation. MCL is biologically and clinically heterogeneous and frequently disseminates to extranodal areas. While a subset of patients have an indolent clinical course, the overall outcome for patients with MCL remains poor. There is no proven curative therapy, and no standard of care has been established for initial or subsequent lines of therapy. Several regimens are highly active in previously untreated patients, and recent research has led to improvements in currently available therapy. Moreover, investigational agents have recently demonstrated promising activity in clinical trials. A workshop was held to review recent data on MCL pathogenesis, novel molecular targets and alternative approaches to immunotherapy, and to discuss recent and ongoing clinical trials in MCL. The presentations are summarized in this article, which is intended to highlight areas of active investigation and identify important avenues for future research. PMID- 23363272 TI - A Bayesian method and its variational approximation for prediction of genomic breeding values in multiple traits. AB - BACKGROUND: Genomic selection is an effective tool for animal and plant breeding, allowing effective individual selection without phenotypic records through the prediction of genomic breeding value (GBV). To date, genomic selection has focused on a single trait. However, actual breeding often targets multiple correlated traits, and, therefore, joint analysis taking into consideration the correlation between traits, which might result in more accurate GBV prediction than analyzing each trait separately, is suitable for multi-trait genomic selection. This would require an extension of the prediction model for single trait GBV to multi-trait case. As the computational burden of multi-trait analysis is even higher than that of single-trait analysis, an effective computational method for constructing a multi-trait prediction model is also needed. RESULTS: We described a Bayesian regression model incorporating variable selection for jointly predicting GBVs of multiple traits and devised both an MCMC iteration and variational approximation for Bayesian estimation of parameters in this multi-trait model. The proposed Bayesian procedures with MCMC iteration and variational approximation were referred to as MCBayes and varBayes, respectively. Using simulated datasets of SNP genotypes and phenotypes for three traits with high and low heritabilities, we compared the accuracy in predicting GBVs between multi-trait and single-trait analyses as well as between MCBayes and varBayes. The results showed that, compared to single-trait analysis, multi-trait analysis enabled much more accurate GBV prediction for low-heritability traits correlated with high-heritability traits, by utilizing the correlation structure between traits, while the prediction accuracy for uncorrelated low-heritability traits was comparable or less with multi-trait analysis in comparison with single-trait analysis depending on the setting for prior probability that a SNP has zero effect. Although the prediction accuracy with varBayes was generally lower than with MCBayes, the loss in accuracy was slight. The computational time was greatly reduced with varBayes. CONCLUSIONS: In genomic selection for multiple correlated traits, multi-trait analysis was more beneficial than single-trait analysis and varBayes was much advantageous over MCBayes in computational time, which would outweigh the loss of prediction accuracy caused by the approximation procedure, and is thus considered a practical method of choice. PMID- 23363274 TI - COE given more time to comply with USDE standards. PMID- 23363275 TI - Lead-based ammunition and fishing tackle. PMID- 23363276 TI - Reactive versus empathic listening: what is the difference? PMID- 23363277 TI - What is your diagnosis? Gastroesophageal intussusception. PMID- 23363278 TI - Pathology in practice. Renal nephroblastoma in a young dog. PMID- 23363279 TI - Pathology in practice. Infectious laryngotracheitis in laying chickens. PMID- 23363280 TI - Current therapeutic approaches to equine protozoal myeloencephalitis. PMID- 23363281 TI - Outcome evaluation of a thoracoscopic pericardial window procedure or subtotal pericardectomy via thoracotomy for the treatment of pericardial effusion in dogs. AB - OBJECTIVE: To evaluate the disease-free interval (DFI) and median survival time (MST) in dogs with idiopathic and neoplastic pericardial effusion surgically treated by a thoracoscopic pericardial window procedure or subtotal pericardectomy via thoracotomy and to compare DFI and MST in dogs with and without a mass on preoperative echocardiography that underwent either surgical technique. DESIGN: Retrospective cohort study. ANIMALS: 58 dogs with pericardial effusion. PROCEDURES: Medical records between 1985 and 2010 were evaluated. Dogs were included in the study if they had confirmed pericardial effusion and underwent a thoracoscopic pericardial window procedure or subtotal pericardectomy via thoracotomy. RESULTS: Clinical signs of dogs at initial evaluation were similar, with the exception of lethargy, between dogs treated by subtotal pericardectomy via thoracotomy or the pericardial window procedure. Dogs with idiopathic pericardial effusion that underwent the thoracoscopic pericardial window procedure had significantly shorter DFI and MST than did those treated by subtotal pericardectomy via thoracotomy. For neoplastic pericardial effusion, DFI and MST were not significantly different between dogs treated with either surgical technique. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs with idiopathic pericardial effusion treated with a subtotal pericardectomy via thoracotomy had a significantly longer DFI and MST, compared with dogs treated by the thoracoscopic pericardial window procedure. This difference in outcome may be related to inaccuracy of the initial diagnosis or ineffectiveness of the pericardial window to palliate the signs of idiopathic pericardial effusion long term. PMID- 23363282 TI - Characterization and treatment of transitional cell carcinoma of the abdominal wall in dogs: 24 cases (1985-2010). AB - OBJECTIVE: To determine uroplakin III expression, potential etiologic factors, biological behavior, and treatment response of transitional cell carcinoma (TCC) in the abdominal wall (ABWTCC) in dogs. DESIGN: Retrospective case series. ANIMALS: 24 dogs with TCC of the urinary tract that also had histopathologic confirmation of ABWTCC. PROCEDURES: Medical records, histologic slides, radiographs, and ultrasonographic images of dogs with ABWTCC between July 1, 1985, and December 31, 2010, were reviewed. In available tissue specimens, immunohistochemistry was used to detect uroplakin III expression in the ABWTCC and in the primary tumor. RESULTS: The ABWTCC lesions ranged from < 2 to > 20 cm in diameter. Uroplakin III was expressed in 19 of 20 primary tumors and 17 of 17 ABWTCCs. Transitional cell carcinoma in the abdominal wall developed significantly more often in dogs that had undergone cystotomy (18/177 [10.2%]) than in those that had not (6/367 [1.6%]). In 1 dog that had not undergone cystotomy, TCC had invaded through the urinary bladder wall and spread down the median ligament to the abdominal wall. None of 18 dogs that received anticancer drugs had remission of the ABWTCC once clinically detected; median survival time after ABWTCC detection was 57 days (range, 0 to 324 days). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that ABWTCC is uncommon, but once TCC becomes established and clinically detectable in the abdominal wall, it carries a poor prognosis. It is crucial to minimize risk of TCC seeding at surgery. Percutaneous sampling of TCC should be avoided. Uroplakin III is commonly expressed in ABWTCC. PMID- 23363283 TI - Preoperative factors associated with postoperative hypocalcemia in dogs with primary hyperparathyroidism that underwent parathyroidectomy: 62 cases (2004 2009). AB - OBJECTIVE: To identify preoperative variables associated with postoperative hypocalcemia in dogs with primary hyperparathyroidism undergoing parathyroidectomy. DESIGN: Retrospective case series. ANIMALS: 62 dogs. PROCEDURES: Medical records of dogs undergoing parathyroidectomy for treatment of primary hyperparathyroidism between January 2004 and January 2009 at 4 institutions were reviewed; data regarding various preoperative variables and postoperative serum total and ionized calcium concentrations were recorded. Preoperative ultrasonographic and surgical findings were compared regarding laterality (right, left, or bilateral) of parathyroid gland lesions. Data were analyzed via ANOVA, simple linear regression, and multiple linear regression to identify associations between preoperative variables and postoperative serum total and ionized calcium nadir concentrations. RESULTS: Preoperative variables significantly associated with low postoperative serum total calcium nadir concentrations included old age, history of weakness, lack of gastrointestinal tract signs, high serum parathyroid hormone concentration, and low serum calcium phosphorus concentration product value. Preoperative variables significantly associated with low postoperative serum ionized calcium nadir concentrations included sexually intact status, low body weight, high serum urea nitrogen concentration, and lack of polyuria and polydipsia in the history. Age, body weight, serum calcium-phosphorus concentration product, and serum concentrations of parathyroid hormone and urea nitrogen were included in the final multiple linear regression model for prediction of postoperative serum calcium concentrations. Ultrasonography was performed in 58 dogs; results for 44 (75.9%) dogs agreed with surgical findings regarding laterality of parathyroid gland lesions. CONCLUSIONS AND CLINICAL RELEVANCE: Prediction of postoperative hypocalcemia in dogs in this study with primary hyperparathyroidism that underwent parathyroidectomy was difficult and depended on multiple (history, physical examination, and clinicopathologic) factors. PMID- 23363284 TI - Anticoagulant rodenticide screening in dogs: 123 cases (1996-2003). AB - OBJECTIVE: To identify dogs with anticoagulant rodenticide (AR) screens submitted, determine whether detected concentrations of the anticoagulants correlated with severity of clinical signs for dogs with positive results on AR screens, and identify the most common disease processes present and the prognosis for those with negative AR screens. DESIGN: Retrospective case series. ANIMALS: 123 dogs. PROCEDURES: History, signalment, clinical signs, physical examination findings, PCV, total solids concentration, prothrombin time, activated partial thromboplastin time, platelet count, AR concentrations, duration of hospitalization, blood products administered, final diagnosis, and outcome were recorded from medical records of dogs that underwent AR toxicology screenings. RESULTS: 75 of 123 (60.9%) dogs tested positive for AR. Dogs tested positive for brodifacoum, diphacinone (also called diphenadione), and chlorophacinone. Dogs with positive AR screenings weighed significantly less, received significantly more fresh frozen plasma, had significantly longer initial prothrombin time, and were significantly more likely to survive, compared with those with negative screens. Anticoagulant rodenticide concentrations ranged from trace amounts to 1,120 parts per billion and were not correlated with any recorded parameter. The most common conditions diagnosed in the 48 dogs with negative screens included neoplasia in 15 (31.3%), immune-mediated disease in 7 (14.6%), and gastrointestinal bleeding in 5 (10.4%) dogs. CONCLUSIONS AND CLINICAL RELEVANCE: AR concentrations were not correlated with severity of clinical signs or the degree of prolongation of coagulation times in this series of patients. Patients with severe coagulopathies but negative results of AR screening had a poor prognosis, with neoplasia as the most common diagnosis. Anticoagulant rodenticide intoxication had the best prognosis, with a survival rate of 98.7% in this study. PMID- 23363285 TI - Diagnosis and treatment of an insulinoma in a guinea pig (Cavia porcellus). AB - CASE DESCRIPTION: A 5-year-old male guinea pig (Cavia porcellus) was examined because of lethargy, weight loss, and episodic neurologic signs, including paddling in lateral recumbency, head tilt, and circling. Prior to initial examination, the animal was treated with corn syrup whenever it appeared lethargic, plus an unknown dosage of sulfadimethoxazole. CLINICAL FINDINGS: The animal was thin, with abdominal distention and subtle torticollis. Chemistry panel results documented hypoglycemia (45 mg/dL). Corn syrup was discontinued in favor of a high-fiber formula fed via a syringe. Measurement of blood insulin concentration demonstrated hyperinsulinemia (> 1,440 pmol/L [> 201 MUU/L]), with concurrent hypoglycemia (0.6 mmol/L [11 mg/dL]). TREATMENT AND OUTCOME: Diazoxide treatment for presumptive insulinoma was started at a dosage of 5 mg/kg (2.3 mg/lb), p.o., every 12 hours. A blood glucose curve demonstrated persistent hypoglycemia, and the diazoxide dosage was gradually increased to 25 mg/kg (11.4 mg/lb), p.o., every 12 hours. A second glucose curve measurement 12 days later confirmed adequate euglycemic control. Three weeks after the initial diazoxide dosage increase, the animal was reexamined for constipation and abdominal distension and died the following day. Histologic analysis confirmed a pancreatic beta-cell tumor (insulinoma). CLINICAL RELEVANCE: To the authors' knowledge, this is the first report of premortem diagnosis and treatment of an insulinoma in a guinea pig. This case demonstrates that diazoxide treatment can help achieve euglycemia in hypoglycemic guinea pigs and is a potential treatment option for guinea pigs with insulinoma. PMID- 23363286 TI - Evaluation of pregnancy and foaling rates after reduction of twin pregnancy via transvaginal ultrasound-guided aspiration in mares. AB - OBJECTIVE: To assess pregnancy and live foaling rates after reduction of twin pregnancy via transvaginal ultrasound-guided aspiration (TUA) in mares and evaluate effects of gestational period, localization of conceptuses, fluid aspiration volume, and combination of TUA with embryonic or fetal puncture on these outcomes. DESIGN: Clinical trial. ANIMALS: 44 mares pregnant with twins (25 to 62 days of gestation). PROCEDURES: TUA was performed in all mares and combined with embryonic or fetal puncture in 13. Follow-up ultrasonographic examinations were performed by referring veterinarians. Effects of gestational period and TUA related variables on pregnancy and foaling rates were assessed. RESULTS: Singleton pregnancy (32/44 [73%]), persistent twin pregnancy (3/44 [7%]), or loss of both conceptuses (9/44 [20%]) was confirmed 5 to 7 days after TUA. Two mares with persistent twin pregnancy underwent another TUA, and 1 underwent prostaglandin F(2alpha)-induced abortion; these were excluded from subsequent analyses. Eighteen of 24 mares reevaluated 3 to 4 weeks after TUA were pregnant with 1 conceptus. Twenty of 41 (49%) mares delivered live singleton foals. Gestational period of TUA did not affect early pregnancy rates. Foaling rate for mares that underwent TUA after day 42 (0/5) was lowest of all groups and was significantly lower than that of mares that underwent TUA between days 31 and 35 (9/14). Three of 13 mares that underwent TUA with embryonic or fetal puncture delivered live foals, compared with 17 of 28 that underwent TUA alone. Effects of other variables were nonsignificant. CONCLUSIONS AND CLINICAL RELEVANCE: TUA was effective for reduction of twin pregnancy in mares, with best results achieved before gestational day 43. PMID- 23363287 TI - Effects of postanesthetic sedation with romifidine or xylazine on quality of recovery from isoflurane anesthesia in horses. AB - OBJECTIVE: To test the hypothesis that postanesthetic sedation with romifidine would dose-dependently improve recovery quality of recovery from isoflurane anesthesia in horses more than postanesthetic sedation with xylazine. DESIGN: Prospective, randomized, blinded clinical trial. ANIMALS: 101 healthy adult horses examined at the University of California-Davis Veterinary Medical Teaching Hospital from 2007 to 2009. PROCEDURES: Horses were sedated with xylazine, and anesthesia was induced with guaifenesin, diazepam, and ketamine via a standardized drug protocol. Anesthesia for surgical or diagnostic procedures was maintained with isoflurane in oxygen for 1 to 4 hours. At the end of anesthesia, horses were moved to a padded stall for recovery. Once the breathing circuit was disconnected and the patient was spontaneously breathing, either xylazine (100 or 200 MUg/kg [45 or 91 MUg/lb]) or romifidine (10 or 20 MUg/kg [4.5 or 9.1 MUg/lb]) was administered i.v.. Objective patient, surgical, and anesthesia data were recorded. Subjective visual analog scale (VAS) scores of recovery quality were assigned by a single individual who was unaware of the treatment received. A stepwise linear regression model was used to correlate patient and procedure factors with the VAS score. RESULTS: Painful procedures, longer anesthesia times, and the Arabian horse breed were associated with poorer VAS scores. Adjustment for these factors revealed an improved VAS recovery score associated with the use of a romifidine dose of 20 MUg/kg. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy adult horses anesthetized with isoflurane for > 1 hour, the results of this study supported the use of 20 MUg of romifidine/kg, i.v., rather than lower romifidine doses or xylazine, for postanesthetic sedation to improve recovery quality. PMID- 23363288 TI - Oleander toxicosis in equids: 30 cases (1995-2010). AB - OBJECTIVE: To determine clinical, laboratory analysis, and necropsy findings for equids with oleander toxicosis and to identify factors associated with outcome. DESIGN: Retrospective case series. ANIMALS: 30 equids. PROCEDURES: Medical records of equids with detectable concentrations of oleandrin in serum, plasma, urine, or gastrointestinal fluid samples and equids that had not received cardiac glycoside drugs but had detectable concentrations of digoxin in serum were identified via a medical records database search. Descriptive statistics were calculated for medical history, physical examination, laboratory analysis, and necropsy variables. Logistic regression analysis was used to identify physical examination and laboratory analysis factors significantly associated with outcome. RESULTS: 3 of 30 (10.0%) equids died before or immediately after arrival at the hospital. Of the other 27 equids, 23 (85.2%) had gastrointestinal tract abnormalities, azotemia was detected for 19 (70.4%), and a cardiac arrhythmia was ausculted for 18 (66.7%). Mortality rate for all equids was 50.0%; mortality rate for hospitalized equids was 44.4%. The most common cause of death was cardiac dysfunction. Odds of survival to discharge from the hospital were lower for equids with cardiac arrhythmias versus those without arrhythmias and decreased with increasing Hct and serum glucose concentrations. Odds of survival increased with increasing serum chloride concentration and duration of hospitalization. CONCLUSIONS AND CLINICAL RELEVANCE: Equids with oleander toxicosis frequently had simultaneous gastrointestinal tract, cardiac, and renal problems. Oleander intoxication should be a differential diagnosis for equids with colic in geographic areas where oleander is found, especially when azotemia or cardiac arrhythmias are detected concurrently. PMID- 23363289 TI - Spectrum of bone marrow failures of myeloid series: new report of neutropenic patients from a referral pediatric center in Iran. AB - Neutropenia is a reduction of the absolute neutrophil count (ANC), which could be seen in different conditions, while its association with a number of primary immunodeficiency diseases has been reported. This study was performed in all neutropenic patients who were admitted in a referral pediatric hospital during a 6-year period (2006-2011). One hundred and forty patients with ANC of below 1500/mm(3) were investigated in this study. The most common causes of neutropenia were severe congenital neutropenia (41%), aplastic anemia (19%), cyclic neutropenia (11%), hyperimmunoglobulin M syndrome (9%), and fanconi anemia (7%). The patients experienced their first manifestation at a median age of 1 year, while the median diagnostic age was 21 months. Parental consanguinity was present in about half of the cases. The most common clinical manifestations of the patients were sinusitis (62 cases), periodontitis (51 cases), acute diarrhea (39 cases), pneumonia (38 cases), abscess (36 cases), skin rashes (35 cases), and otitis media (31 cases). Twenty two patients (16%) died during the study period. Considering the differential diagnosis of neutropenia, making the diagnosis and appropriate treatments are the keys in management of patients with neutropenia to avoid further complications. PMID- 23363290 TI - Influence of replacing Si by Ge in the chalcogenide quaternary sulfides Ag2In2Si(Ge)S6 on the chemical bonding, linear and nonlinear optical susceptibilities, and hyperpolarizability. AB - The linear and nonlinear optical properties of Ag2In2SiS6 and Ag2In2GeS6 are calculated so as to obtain further insight into the electronic properties. The influence of using different exchange correlation potentials and the effect of replacing Si by Ge on the geometry, chemical bonding, and on the optical properties are presented. There is notable increasing in the energy band gap when moving from LDA to GGA, EVGGA then to mBJ. The effect of replacing Si by Ge atom causes a geometric change, which leads to large changes in the linear as well as the nonlinear optical susceptibilities. For the linear optical properties, it causes to increase the amplitude of the left-hand hump of epsilon(2)(average)(omega) as well as a small shift of the main peak to lower energies. We have evaluated epsilon(1)(average)(0) and find that a smaller energy gap yields a larger epsilon1(0) value. From the calculated refractive indices we obtained the birefringence, which is important for second harmonic generation (SHG) and optical parametric oscillation (OPO) as it is defined by the phase matching condition. The second-order nonlinear optical susceptibilities, namely, the SHG are investigated for chi(111)(2)(omega), chi(122)(2)(omega), chi(133)(2)(omega), chi(221)(2)(omega), and chi(331)(2)(omega). We find that chi(111)(2)(omega) is the dominant component. The microscopic second order hyperpolarizability, beta111, for the dominant component chi(111)(2)(omega) was obtained. We should emphasize that replacing Si by Ge enhances the linear and nonlinear optical susceptibilities so that Ag2In2GeS6 shows higher values of the linear and nonlinear optical susceptibilities and beta111 in comparison to Ag2In2SiS6. PMID- 23363291 TI - Melatonin induces autophagy via an mTOR-dependent pathway and enhances clearance of mutant-TGFBIp. AB - The hallmark of granular corneal dystrophy type 2 (GCD2) is the deposit of mutant transforming growth factor-beta (TGF-beta)-induced protein (TGFBIp) in the cornea. We have recently shown that there is a delay in autophagic degradation of mutant-TGFBIp via impaired autophagic flux in GCD2 corneal fibroblasts. We hypothesized that melatonin can specifically induce autophagy and consequently eliminate mutant-TGFBIp in GCD corneal fibroblasts. Our results show that melatonin activates autophagy in both wild-type (WT) and GCD2-homozygous (HO) corneal fibroblast cell lines via the mammalian target of rapamycin (mTOR) dependent pathway. Melatonin treatment also led to increased levels of beclin 1, which is involved in autophagosome formation and maturation. Furthermore, melatonin significantly reduced the amounts of mutant- and WT-TGFBIp. Treatment with melatonin counteracted the autophagy-inhibitory effects of bafilomycin A1, a potent inhibitor of autophagic flux, demonstrating that melatonin enhances activation of autophagy and increases degradation of TGFBIp. Cotreatment with melatonin and rapamycin, an autophagy inducer, had an additive effect on mutant TGFBIp clearance compared to treatment with either drug alone. Treatment with the selective melatonin receptor antagonist luzindole did not block melatonin-induced autophagy. Given its ability to activate autophagy, melatonin is a potential therapeutic agent for GCD2. PMID- 23363293 TI - Margination propensity of vascular-targeted spheres from blood flow in a microfluidic model of human microvessels. AB - Many variants of vascular-targeted carriers (VTCs) have been investigated for therapeutic intervention in several human diseases. However, in order to optimize the functionality of VTC in vivo, carriers' physical properties, such as size and shape, are important considerations for a VTC design that evades the reticuloendothelial system (RES) and successfully interacts with the targeted vessel wall. Nonetheless, little evidence has been presented on the role of size in VTC's interactions with the vascular wall, particularly in the microcirculation. Thus, in this work, we explore how particle size, along with hemodynamics (blood shear rate and vessel size) and hemorheology (blood hematocrit) affect the capacity for spheres to marginate (localize and adhere) to inflamed endothelium in a microfluidic model of human microvessels. Microspheres, particularly the 2 MUm spheres, were found to show disproportionately higher margination than nanospheres in all hemodynamic conditions evaluated due to the poor ability of the latter to localize to the wall region from midstream. This work represents the first evidence that nanospheres may not exhibit "near wall excess" in microvessels, e.g., arterioles and venules, and therefore may not be suitable for imaging and drug delivery applications in cancer and other diseases affecting microvessels. PMID- 23363292 TI - The substrate capture mechanism of Mycobacterium tuberculosis anthranilate phosphoribosyltransferase provides a mode for inhibition. AB - Anthranilate phosphoribosyltransferase (AnPRT, EC 2.4.2.18) is a homodimeric enzyme that catalyzes the reaction between 5'-phosphoribosyl 1'-pyrophosphate (PRPP) and anthranilate, as part of the tryptophan biosynthesis pathway. Here we present the results of the first chemical screen for inhibitors against Mycobacterium tuberculosis AnPRT (Mtb-AnPRT), along with crystal structures of Mtb-AnPRT in complex with PRPP and several inhibitors. Previous work revealed that PRPP is bound at the base of a deep cleft in Mtb-AnPRT and predicted two anthranilate binding sites along the tunnel leading to the PRPP binding site. Unexpectedly, the inhibitors presented here almost exclusively bound at the entrance of the tunnel, in the presumed noncatalytic anthranilate binding site, previously hypothesized to have a role in substrate capture. The potencies of the inhibitors were measured, yielding Ki values of 1.5-119 MUM, with the strongest inhibition displayed by a bianthranilate compound that makes hydrogen bond and salt bridge contacts with Mtb-AnPRT via its carboxyl groups. Our results reveal how the substrate capture mechanism of AnPRT can be exploited to inhibit the enzyme's activity and provide a scaffold for the design of improved Mtb-AnPRT inhibitors that may ultimately form the basis of new antituberculosis drugs with a novel mode of action. PMID- 23363294 TI - Comparing the effects of ultra-high-pressure homogenization and conventional thermal treatments on the microbiological, physical, and chemical quality of almond beverages. AB - The effects of ultra-high-pressure homogenization (UHPH) at 200 and 300 MPa, in combination with different inlet temperatures (55, 65, and 75 degrees C) on almond beverages with lecithin (AML) and without lecithin (AM), were studied. UHPH-treated samples were compared with the base product (untreated), pasteurized (90 degrees C, 90 s), and ultra-high-temperature (UHT, 142 degrees C, 6 s) samples. Microbiological analysis, physical (dispersion stability, particle size distribution, and hydrophobicity), and chemical (hydroperoxide index) parameters of special relevance in almond beverages were studied. Microbiological results showed that pressure and inlet temperature combination had a significant impact on the lethal effect of UHPH treatment. While most UHPH treatments applied produced a higher quality of almond beverage than the pasteurized samples, the combination of 300 MPa and 65 and/or 75 degrees C corresponded to a maximum temperature after high pressure valve of 127.7 +/- 9.7 and 129.3 +/- 12.6 degrees C, respectively. This temperature acted during less than 0.7 s and produced no bacterial growth in almond beverages after incubation at 30 degrees C for 20 d. UHPH treatments of AML samples caused a significant decrease in particle size, resulting in a high physical stability of products compared to conventional heat treatments. UHPH treatment produced higher values of hydroperoxide index at day 1 of production than heat-treated almond beverage. Hydrophobicity increased in AML-UHPH-treated samples compared to AM and conventional treatments. PRACTICAL APPLICATION: Ultra-high-pressure homogenization (UHPH) is an emerging technology, a potential alternative to conventional heat treatments. It is a simple process consisting of single step. When liquid food (almond beverage in this study) passes through the high-pressure valve, a very good stability and reduction of microorganisms is achieved, both effects due to the particle breakdown. Specific UHPH conditions could produce commercial sterilization of almond beverage. PMID- 23363295 TI - Using self-organization to control morphology in molecular photovoltaics. AB - This work explores the formation of well-defined molecular p-n junctions in solution-processed self-assembled heterojunction solar cells using dodecyloxy substituted contorted hexabenzocoronene (12-c-HBC) as a donor material and phenyl C(70)-butyric acid methyl ester (PC(70)BM) as an acceptor. We find that the contorted 12-c-HBC molecules effectively assemble in solution to form a nested structure with the ball-shaped PC(70)BM. The result is a self-assembled molecular scale p-n junction. When this well-defined p-n junction is embedded in active films, we can make efficient self-assembled solar cells with minimal amounts of donor material relative to the acceptor. The power conversion efficiency is drastically enhanced by the mode of donor and acceptor assembly within the film. PMID- 23363296 TI - Alzheimer's disease and diabetes: new insights and unifying therapies. AB - Several research groups have begun to associate the Alzheimer Disease (AD) to Diabetes Mellitus (DM), obesity and cardiovascular disease. This relationship is so close that some authors have defined Alzheimer Disease as Type 3 Diabetes. Numerous studies have shown that people with type 2 diabetes have twice the incidence of sporadic AD. Insulin deficiency or insulin resistance facilitates cerebral beta-amyloidogenesis in murine model of AD, accompanied by a significant elevation in APP (Amyloid Precursor Protein) and BACE1 (beta-site APP Cleaving Enzime 1). Similarly, deposits of Abeta produce a loss of neuronal surface insulin receptors and directly interfere with the insulin signaling pathway. Furthermore, as it is well known, these disorders are both associated to an increased cardiovascular risk and an altered cholesterol metabolism, so we have analyzed several therapies which recently have been suggested as a remedy to treat together AD and DM. The aim of the present review is to better understand the strengths and drawbacks of these therapies. PMID- 23363297 TI - Identifying risk factors for clinically significant diabetic macula edema in patients with type 2 diabetes mellitus. AB - It is known that clinic blood pressure (BP), gender, cigarette smoking, dyslipidemia, anemia and thiazolidenediones (TZD) treatment are predictors for clinically significant diabetic macula edema (CSDME). We examined a most risky factor for CSDME in Japanese patients with type 2 diabetes mellitus (T2DM) and diabetic retinopathy (DR) confirmed using optical coherence tomography by multiple regression analysis (MRA). As the risk factors, wakening-up BP was added to such factors. Seven diabetic Japanese patients with CSDME (group 1) and 124 subjects without CSDME (group 2) assonated with DR using optical coherence tomography were studied. The durations of T2DM in groups 1 and 2 were 15+/-10 years and 20+/-15 years, respectively. There was no statistically difference in means of gender, duration, age, body mass index (BMI), HbA1c, TC, LDL and TC/HDL, serum creatinine, urinary albumin excretion rate, and clinic BP between two groups. Morning systolic home BP (MSHBP), cigarette smoking and foveal thickness were significantly (p<0.001) higher in group 1 than group 2, whereas visual acuity was significantly (p<0.00?) lower in group 1 than in group 2. The patients in both groups had received various kinds of drugs for hyperglycemia, hypertension and others. There were no significant differences in the variables in both groups. MRA revealed that MSHBP, cigarette smoking and pioglitazone as TZD treatment were significantly positive predictors for CSDME, while BMI had a significantly negative predictor. Other variables were not significantly correlated to CSDME. The review summarizes a multiple regression analysis revealed that MSHBP makes an addition to predictive factors for CSDME among risk factors reported previously in patient with T2DM. PMID- 23363298 TI - Thermochemical behavior of lead adjusting formation of chlorinated aromatics in MSW fly ash. AB - In this study, we examined the thermochemical role of Pb in the formation of chlorinated aromatics (aromatic-Cls) in MSW fly ash at 300-400 degrees C, a key temperature window for maximum yield. In the presence of lead oxide alone, aromatic-Cls formation was suppressed. One of the mechanisms of suppression was partial chlorination of PbO by an inorganic chlorine source in the solid phase, based on in situ Pb L3-edge X-ray absorption near-edge structure (XANES) data. In contrast, quantitative GC/MS measurements revealed that PbCl2 promoted aromatic Cls formation to an extent that depends on the Pb concentration, the heating temperature, and the presence of other metal catalysts. We identified two mechanisms of aromatic-Cls formation triggered by PbCl2 in MSW fly ash. First, promotion can occur by the thermochemical partial oxidation of PbCl2. More specifically, real complex solid phase increases the thermochemical oxidation reactivity of PbCl2, based on in situ Pb L3-edge XANES data. Second, Cl K-edge X ray absorption spectroscopy revealed a coexistent effect of PbCl2 with other metal catalysts such as CuCl2 and FeCl3. The presence of PbCl2 influences the balance of the bonding state of chlorine with Cu and Fe atoms at various temperatures. Thus, Pb in real MSW fly ash functions as an "adjuster" in the generation of aromatic-Cls, the nature of which depends on the lead oxide/chloride ratio and the presence of other metal catalysts. PMID- 23363299 TI - Synthesis of superconducting nanocables of FeSe encapsulated in carbonaceous shell. AB - The recent discovery of superconductivity in iron selenide has attracted considerable attention due to the simplicity of composition, unconventional nature of superconductivity, and ease of synthesis. We have synthesized superconducting FeSe nanowires with a simple catalyst-aided vapor transport reaction at 800 degrees C in an inert atmosphere. The precursors were chosen to be elemental Se and iron acetylacetonate [Fe(III)(C5H8O2)3]. These vaporized very easily, thereby facilitating transport, and also contributed to the formation of a carbonaceous shell encapsulating the FeSe nanowires. The superconductivity of these nanocables was confirmed through magnetic measurements and a T(c) of ~8 K was obtained for an ensemble of nanocables. The length of FeSe filling inside the carbon nanofibers could be varied by controlling the reaction conditions while the diameter of nanowires was dependent on the thickness of Au-Pd coating used as a catalyst. Extensive analysis through high-resolution microscopy revealed that there was considerable lattice contraction of FeSe in the nanocable up to about 3.6% along the c-direction leading to a reduced spacing between the (001) lattice planes. Interestingly, this compression was more pronounced near the catalyst FeSe interface and was reduced further along the length of the nanocable. The presence of carbon nanofibers as a shell around the FeSe protected the FeSe nanowires from both atmospheric O2 and moisture attack, as was evident from the very long ambient condition shelf life of these nanocables, and also makes them more stable under e-beam irradiation. PMID- 23363300 TI - Identification of suitable housekeeping genes for normalization of quantitative real-time PCR data during different physiological stages of mammary gland in riverine buffaloes (Bubalus bubalis). AB - Gene expression analysis unravels the complex changes or relations at transcriptomic level. To nullify all type of errors that can be incorporated during any stage of RNA extraction into cDNA synthesis and for reliable results, the data obtained from qPCR have to be normalized using the appropriate/suitable housekeeping genes (HKGs). Unfortunately, till date, no such HKG has been reported for bubaline mammary gland. The objective of the present study was thus to identify and validate the potential HKGs for the gene expression studies in buffalo mammary gland. Mammary tissues from twelve buffaloes during different physiological stages: pre-pubertal (heifer), lactation and involution were obtained for the present study. A total of 16 potential HKGs (GAPDH, beta-actin, UXT, beta2M, A2M, RPl4, RPS9, RPS15A, RPS18, RPS23, HMBS, HPRT1, GTP, EEF1A1, UB1 and RPL22) from different functional classes were evaluated. The analysis revealed that the expression of EEF1A1, RPl4, beta2M and RPS15A was most consistent across different physiological stages of buffalo mammary gland. On the other hand, beta-actin, A2M, RPL22 and GAPDH were the least stable genes making them unsuitable as HKGs. Based on our analysis, we recommend the use of EEF1A1, RPl4, beta2M and RPS15A genes as suitable HKGs for accurate normalization of gene expression data in bubaline mammary gland. PMID- 23363301 TI - Impact of carbon ion irradiation on epidermal growth factor receptor signaling and glioma cell migration in comparison to conventional photon irradiation. AB - PURPOSE: Radiotherapy of malignant gliomas may be limited by an interference of radiation with the migratory potential of tumor cells. Therefore, the influence of conventional photon and modern carbon ion ((12)C) irradiation on glioblastoma cell migration and on epidermal growth factor receptor-related (EGFR) signaling was investigated in vitro. MATERIALS AND METHODS: EGFR overexpressing glioblastoma cell lines U87 EGFR++ and LN229 EGFR++ were irradiated with 0, 2 or 6 Gy photons or (12)C heavy ions. Migration was analyzed 24 h after treatment in a standardized Boyden Chamber assay. At different time points EGFR, protein kinase B (PKB/AKT) and extracellular signal-related kinases (ERK1/2) were analyzed by Western blotting. RESULTS: 2 Gy photon irradiation increased U87 EGFR++ migration and decreased motility of LN229 EGFR++ cells. Heavy ions decreased migration of both cell lines as a function of dose. There was a time dependent increase of phosphorylation of EGFR, AKT and ERK1/2 in U87 EGFR++ after 2 Gy photon irradiation. After heavy ion irradiation EGFR, AKT or ERK1/2 remained unchanged. CONCLUSIONS: Results suggest that the impact of irradiation on tumor cell migration depends on radiation type and cell line. Photons, but not heavy ions, potentially contribute to treatment failure by increasing EGFR-related tumor cell migration. PMID- 23363302 TI - Cytomegalovirus duodenitis associated with acquired immunodeficiency syndrome. PMID- 23363303 TI - Controlled drug-release system based on pH-sensitive chloride-triggerable liposomes. AB - New pH-sensitive lipids were synthesized and utilized in formulations of liposomes suitable for controlled drug release. These liposomes contain various amounts of NaCl in the internal aqueous compartments. The release of the drug model is triggered by an application of HCl cotransporter and exogenous physiologically relevant NaCl solution. HCl cotransporter allows an uptake of HCl by liposomes to the extent of their being proportional to the transmembrane Cl(-) gradient. Therefore, each set of liposomes undergoes internal acidification, which, ultimately, leads to the hydrolysis of the pH-sensitive lipids and content release at the desired time. The developed system releases the drug model in a stepwise fashion, with the release stages separated by periods of low activity. These liposomes were found to be insensitive to physiological concentrations of human serum albumin and to be nontoxic to cells at concentrations exceeding pharmacological relevance. These results render this new drug-release model potentially suitable for in vivo applications. PMID- 23363304 TI - Physicochemical characterization of surfactant incorporating vesicles that incorporate colloidal magnetite. AB - Drug administration through the transdermal route has optimized for the comfort of patients and easy application. However, the main limitation of transdermal drug delivery is the impermeability of the human skin. Recent advances on improvement of drug transport through the skin include elastic liposomes as a penetration enhancer. Entrapment of ferrofluids in the core of liposomes produces magnetoliposomes, which can be driven by a high-gradient magnetic field. The association of both strategies could enhance the penetration of elastic liposomes. This work relies on the preparation and characterization of elastic magnetic liposomes designed to permeate through the skin. The incorporation of colloidal magnetite and the elastic component, octaethylene glycol laurate (PEG-8 L), in the structure of liposomes were evaluated. The capability of the elastic magnetoliposomes for permeation through nanopores of two stacked polycarbonate membranes was compared to conventional and elastic liposomes. Magnetite incorporation was dependent on vesicle diameter and size distribution as well as PEG-8-L incorporation into liposomes, demonstrating the capability of the fluid bilayer to accommodate the surfactant without disruption. On the contrary, PEG-8 L incorporation into magnetoliposomes promoted a decrease of average diameter and a lower PEG-8-L incorporation percentage as a result of reduction on the fluidity of the bilayer imparted by iron incorporation into the lipid structure. Elastic liposomes demonstrated an enhancement of the deformation capability, as compared with conventional liposomes. Conventional and elastic magnetoliposomes presented a reduced capability for deformation and permeation. PMID- 23363305 TI - In vitro studies on 5-florouracil-loaded DTPA-PE containing nanosized pegylated liposomes for diagnosis and treatment of tumor. AB - Theranostic liposomes carry both the therapeutic active ingredients and the contrast agent into one delivery system. Codelivery of imaging contrast agent and chemotherapeutic drugs can provide real-time validation of the targeting strategy, resulting in an another step forward for individual-based therapy. The aim of this study was the incorporation of different drugs used in the diagnosis and treatment of tumors into one delivery system to develop nanosized, polyethylene glycol (PEG)-coated, different charged theranostic liposomes. Different charged liposomes consisting of 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) or Phospholipon((r)) 90G (PL 90G; Phospholipid GmbH, Cologne, Germany), cholesterol, poly(ethylene glycol)2000/phosphatidyl ethanolamine (PEG(2000)-PE), stearylamine (SA) or dicetyl phosphate (DCP), and diethylenetriamine pentaacetate/PE (DTPA-PE) as bilayer ingredients and 5 florouracil (5-FU) as active substance were prepared by the film technique. Characterization, 5-FU in vitro release, cytotoxicity, and physical stability studies were performed. Particle size of all liposomes was 100-150 nm. Difference was not noted between encapsulation efficiency (EE%) of neutral DPPC and PL 90G liposomes containing 5-FU. EE% of charged DPPC liposomes was higher than that of charged PL 90G liposomes. PL 90G containing liposomes had a higher phospholipid amount than the same formulation of DPPC liposomes. DPPC containing different charged liposomes were selected for cytotoxicity studies. Different charged DPPC liposomes had the same antitumoral activity with the free 5-FU solution on MCF-7 cell lines. Liposome dispersions were more stable from the point of particle-size change and 5-FU leakage during storage at refrigerated temperature. The results of this study are very encouraging for the development of theranostic liposome formulations as a targeted delivery system for drugs, such as 5-FU, used both in therapy and imaging. PMID- 23363306 TI - Housing, income inequality and child injury mortality in Europe: a cross sectional study. AB - BACKGROUND: Child poverty rates are compared throughout Europe to monitor how countries are caring for their children. Child poverty reduction measures need to consider the importance of safe living environments for all children. In this study we investigate how European country-level economic disparity and housing conditions relate to one another, and whether they differentially correlate with child injury mortality. METHODS: We used an ecological, cross-sectional study design of 26 European countries of which 20 high-income and 6 upper-middle income. Compositional characteristics of the home and its surroundings were extracted from the 2006 European Union Income Social Inclusion and Living Conditions Database (n = 203,000). Mortality data of children aged 1-14 years were derived from the World Health Organization Mortality Database. The main outcome measure was age standardized cause-specific injury mortality rates analysed by income inequality and housing and neighbourhood conditions. RESULTS: Nine measures of housing and neighbourhood conditions highly differentiating European households at country level were clustered into three dimensions, labelled respectively housing, neighbourhood and economic household strain. Income inequality significantly and positively correlated with housing strain (r = 0.62, P = 0.001) and household economic strain (r = 0.42, P = 0.009) but not significantly with neighbourhood strain (r = 0.34, P = 0.087). Child injury mortality rates correlated strongly with both country-level income inequality and housing strain, with very small age-specific differences. CONCLUSIONS: In the European context housing, neighbourhood and household economic strains worsened with increasing levels of income inequality. Child injury mortality rates are strongly and positively associated with both income inequality and housing strain, suggesting that housing material conditions could play a role in the association between income inequality and child health. PMID- 23363307 TI - Acupuncture and in vitro fertilization: a retrospective chart review. AB - OBJECTIVES: In 2007, Craig et al. reported the results of a randomized controlled trial in which a standardized acupuncture protocol performed on the day of embryo transfer (ET) resulted in lower pregnancy rates after in vitro fertilization (IVF). Between 2005 and 2007, the Craig protocol was used by one of the authors (LHR) at an infertility clinic unaffiliated with the Craig et al. trial. The objective was to retrospectively review clinic records to evaluate the effect of the Craig protocol in both donor and nondonor IVF cycles on four outcomes: (1) live births; (2) biochemical pregnancies; (3) adverse outcomes; and (4) live births in nondonor cycles across age groups established by the Society for Assisted Reproductive Technology. DESIGN: The study design was a retrospective chart review. SETTING: The study was conducted at a private infertility clinic. PATIENT(S): Patients underwent fresh, donor (N=70) or nondonor (N=402) IVF-ET. INTERVENTION(S): The Craig protocol included the following points before ET: GV 20, CV-6, ST-29, SP-8, PC-6, LV-3; Shenmen and Brain on the left ear; and Uterus and Endocrine on the right ear. After transfer the points were LI-4, SP-10, ST 36, SP-6, KI-3; Uterus and Endocrine on the left ear; and Shenmen and Brain on the right ear. MAIN OUTCOME MEASURE(S): Live births (LB) beyond 24 weeks' gestation was the main outcome measure. RESULT(S): In nondonor IVF cycles, there were no differences in LB across age groups (odds ratio [OR]=1.04, 95% confidence interval [CI] 0.68-1.57), biochemical pregnancies (OR=0.60, 95% CI 0.27-1.33), or adverse outcomes (OR=0.63, 95% CI 0.31-1.26). In donor cycles, LB were higher in the acupuncture group (relative risk=1.31, 95% CI 1.02-1.71). CONCLUSIONS: In this observational study, the Craig protocol was not found to lower IVF LB. In fact, the Craig protocol was associated with higher LB in donor cycles. These findings should be considered cautiously because more adequately powered, randomized research is needed. PMID- 23363308 TI - Scalp electrical acupuncture. PMID- 23363309 TI - Thai herbal formulas used for wound treatment: a study of their antibacterial potency, anti-inflammatory, antioxidant, and cytotoxicity effects. AB - AIM: This present work was aimed to investigate wound healing-related biologic activities of traditional herbal formulas used for wound treatment in southern Thailand. METHODS: Water and ethanol extracts of the formulas (THR-SK004, THR SK010, and THR-SK011) were tested for their antibacterial potency against methicillin-resistant Staphylococcus aureus (MRSA) and -susceptible S. aureus. Anti-inflammatory activities of the extracts were assessed by detection of the inhibition of lipopolysaccharide-induced nitric oxide production. Anti-oxidant activities and cytotoxicity of the extracts were also measured. RESULTS: Among the tested formulas, ethanol extract of THR-SK010 consisting of four herbs: Curcuma longa L., Areca catechu L., Oryza sativa L., and Garcinia mangostana L., was found to possess promising antibacterial activities with MIC90 of 4 MUg mL( 1) against MRSA isolates. This ethanol extract offered the highest anti inflammatory activity as well as DPPH and hydroxyl radical scavenging activities. CONCLUSIONS: Remarkable antibacterial, anti-inflammatory, and antioxidant activities as well as low toxicity on Vero cells of THR-SK010 ethanol extract provide scientific information to support the topical use of the formula for wound treatment. This information proposes the potential to develop a new generation of phytopharmaceuticals based on traditional knowledge. PMID- 23363310 TI - European guidelines for prevention and management of influenza in hematopoietic stem cell transplantation and leukemia patients: summary of ECIL-4 (2011), on behalf of ECIL, a joint venture of EBMT, EORTC, ICHS, and ELN. AB - Influenza may cause severe disease and mortality in leukemia patients and in hematopoietic stem cell transplantation recipients. The 4th European Conference of Infections in Leukemia (ECIL-4) has developed evidence-based guidelines for prevention and management of influenza infections in these patients. Real-time reverse-transcription polymerase chain reaction is the diagnostic test of choice, as it is the most sensitive and specific test for influenza. The risks for severe influenza and fatal outcome include lymphopenia, older age, influenza soon after transplantation or chemotherapy, steroid treatment, and lack of early antiviral therapy. Neuraminidase inhibitors (oral oseltamivir or inhalation of zanamivir) are currently the most effective therapeutic agents for influenza. Main preventive measures include annual vaccination of patients, household contacts, and hospital staff. This review summarizes ECIL-4's main recommendations. PMID- 23363312 TI - Fostering successful interprofessional teamwork through an undergraduate student placement in a secondary school. AB - This exploratory case study examined an interprofessional placement of undergraduate students from nutrition, nursing, early childhood education, and child and youth care who collaborated to develop and deliver four healthy-living modules to secondary school students in Canada. An inductive thematic analysis was used to describe the teamwork that occurred between students. Data collected included focus groups with undergraduate students and preceptors, undergraduate students' reflections and secondary school students' evaluations of the modules delivered. Two major themes that emerged from all data sources were "team functioning" and "shift in perspectives". The undergraduate students identified several ways that facilitated their successful and positive teamwork with one another and also expressed how the placement experience improved their interprofessional skills. Findings from this study are discussed in relation to contact theory (Allport, 1954) and self-presentation theory (Goffman, 1963). This study suggests that providing undergraduate students with interprofessional placements in an educational setting can enhance interprofessional teamwork opportunities for students of various disciplines. PMID- 23363311 TI - GxcC connects Rap and Rac signaling during Dictyostelium development. AB - BACKGROUND: Rap proteins belong to the Ras family of small G-proteins. Dictyostelium RapA is essential and implicated in processes throughout the life cycle. In early development and chemotaxis competent cells RapA induces pseudopod formation by activating PI3K and it regulates substrate attachment and myosin disassembly via the serine/threonine kinase Phg2. RapA is also important in late development, however so far little is known about the downstream effectors of RapA that play a role in this process. RESULTS: Here we show that cells expressing constitutively active RapA exhibit a high level of Rac activation. With a pull-down screen coupled to mass spectrometry, we identified the Rac specific guanine nucleotide exchange factor, GxcC, as Rap binding partner. GxcC binds directly and specifically to active RapA and binds to a subset of Dictyostelium Rac proteins. Deletion studies revealed that this pathway is involved in regulating Dictyostelium development. CONCLUSIONS: GxcC provides a novel link between Rap and Rac signalling and is one of the Rap effectors regulating the progression of multicellular development. PMID- 23363313 TI - The role of interprofessional collaboration for intimate partner violence in psychiatric care: a research and development project. AB - In Finland, policy requirements have demanded providers to work collaboratively together with regard to intimate partner violence (IPV). This research and development project seeks to identify efficient tools for stopping IPV. The project included staff training to recognize and respond to IPV, the development of a research-based guideline for use in the care situations of victims and perpetrators and the integration of the guideline into practices and staff development. Networking was developed during the project through interprofessional and multiagency collaboration, whereas appraisal information was collected at different stages of the process. This paper focuses on the issues of interprofessional collaboration, and uses psychiatric care as an example. There is some evidence that interprofessional interventions reduce the cost of patient care and improve the quality of IPV services. That is why it is important to discuss these issues and solve possible problems arising in interprofessional patient care. PMID- 23363314 TI - Cancer incidence and survival in adolescents and young adults in France, 2000 2008. AB - This study aimed to describe cancer incidence (2000-2008) and survival (2000 2004) in France in adolescents and young adults (AYA). All cases of cancer diagnosed in 15-24 years, recorded by all French population-based registries (14% of the French population), over the 2000-2008 period, were included. Incidence change over time was described with the conventional annual percentage change (cAPC). The survival of cases diagnosed (2000-2004) was estimated using Kaplan Meier method. A total of 1022 in adolescents and 1396 in young adults were diagnosed. Overall incidence rates were 219.4/10(6) in 15-19 year olds and 293.1/10(6) in 20-24 year olds. The most frequently diagnosed cancers in male AYA were malignant gonadal germ-cell tumors and Hodgkin's disease, and were melanoma, thyroid carcinoma, and Hodgkin's disease in females. The age-standardized rates appeared stable over time in AYA, with a cAPC of +2.0% (P = 0.68). The 5-year overall survival for all cancers was different between genders and age groups, with 78.8% (95%CI: 75.6-82.0) for males and 85.2% (95%CI: 82.2-88.1) for females (P = 0.01), and 78.5% (95%CI: 75.0-82.1) in 15-19 year olds and 84.3% (95% CI: 81.6-87.0) in 20-24 year olds (P = 0.02). Noteworthy, the frequency and the distribution of tumor types in AYA are unique and different from the observed at any other age group. Survival in French AYA has improved over time. Epidemiological data might reflect major trends in the risk factors and preventive interventions. Thus, further research into etiology of cancers affecting AYA should become key priorities for cancer control among AYA. PMID- 23363315 TI - Delayed first otoacoustic emissions test decreases failure on neonatal hearing screening after caesarean delivery. AB - AIM: Caesarean delivery (CD) was associated with a 3.2-fold higher failure on 1st otoacoustic emissions (OAE) hearing test. We aimed to verify whether postponing 1st OAE beyond 48 h in CD infants decreases hearing screening failure. METHODS: We compared two groups of CD infants as to failure on 1st OAE test: early-1st OAE (n = 560): 1st OAE at 12- to 48-h-olds and late-1st OAE (n = 566): 1st OAE at 48- to 132-h-olds. RESULTS: Compared with early-1st OAE group, the failure rate among late-1st OAE infants was significantly sixfold lower (20.5% vs. 3.4%), with sixfold lower need for repeated tests: 205 vs. 34 tests/1000 CD neonates (p < 0.001). The failure rate decreased with increasing age in both groups (p < 0.001). Univariate analysis: timing of 1st OAE (late vs. early) was significantly associated with failure on 1st OAE. Multivariable analysis: late (48-132 h) 1st OAE test was associated with a 7.7-fold lower risk for failure of 1st OAE, OR (95% CI): 0.13 (0.08-0.21). CONCLUSION: Among CD infants, the risk for failure in late-1st OAE group (>48 h) was 7.7-fold lower, with a sixfold lower need for repeated hearing tests. Delaying 1st OAE in CD infants beyond 48 h of age (preferably between 48 and 132 h) decreases neonatal OAE screening failure. PMID- 23363316 TI - Tuning the dielectric properties of polystyrene/poly(vinylidene fluoride) blends by selectively localizing carbon black nanoparticles. AB - In this work, the dielectric properties of immiscible polystyrene (PS)/poly(vinylidene fluoride) (PVDF) blends are tuned by selectively localizing carbon black (CB) nanoparticles in different phases. The PS/PVDF blends have a wide window of cocontinuity (ca. 30-80 vol % in terms of the volume fraction of PS component (v(PS))). The selective localization of CB nanoparticles is achieved by using the masterbatch process during melt mixing. For the volume ratio PS/PVDF 1/1 and the volume fraction of CB nanoparticles (v(CB)) below but close to the percolation threshold (v(c)(CB)), the selective localization of CB nanoparticles in PVDF phase produces higher dielectric constant (epsilon) than that in PS phase, whereas the epsilon of the ternary mixtures without selective localization of fillers is in the middle. For the volume ratios PS/PVDF 1/2 and 2/1, the selective location of CB nanoparticles in different phases can be used to easily tune the system from conductive to insulating or inverse, which might have potential applications in industry. The fillers are found to be "fixed" in the masterbatch of PS or PVDF component and there is no migration of the fillers to another phase occurring during the further mixing process for the mixing time up to 30 min. Furthermore, the addition of CB nanoparticles to the polymer matrix is found to induce the brittle-ductile transition in the system and increase the compatibility between the immiscible PS and PVDF components, which should benefit the mechanical properties. PMID- 23363318 TI - Selective extraction of N2 from air by diarylimine iron complexes. AB - Treatment of cis-(Me3P)4FeMe2 with ortho-substituted diarylimines afforded 2 equiv of MeH, PMe3, and {mer-kappaC,N,C'-(Ar-2-yl)CH2N?CH(Ar'-2-yl)}Fe(PMe3)3 (Ar = 3,4,6-(F)3-C6H, Ar' = 3,5-(CF3)2-C6H2, 1a; Ar = 3,4,6-(F)3-C6H, Ar' = 3,4,5 (F)3-C6H, 1b; Ar = 4,5,6-(F)3-C6H, Ar' = 3,5-(CF3)2-C6H2, 1c; Ar = C6H4, Ar' = 3 (OMe)-C6H3, 1d; Ar = 4,5,6-(F)3-C6H, Ar' = 3,6-Me2-C6H3, 1e; Ar = C6H4, Ar' = 3,6 Me2-C6H2, 1f). Exposure of 1a-f to O2 caused rapid degradation, but substitution of the unique PMe3 with N2 occurred when 1a-f were exposed to air or N2 (1 atm), yielding {mer-kappaC,N,C'-(Ar-2-yl)CH2N?CH(Ar'-2-yl)}Fe(PMe3)2L (L = N2, 2a-f); CO, CNMe, and N2CPh2 derivatives (L = CO, 3a-d,f; L = CNMe, 8b; L = N2CPh2, 9b) were prepared. Dihydrogen or NH3 binding to {mer-kappaC,N,C'-(3,4,6-(F)3-C6H-2 yl)CH2N?CH-(3,4,5-(F)3-C6H-2-yl)}Fe(PMe3)2 (1b', S = 1 (calc)) to provide 5b (L = H2) or 6b (L = NH3) was found comparable to that of N2, while PMe3 (1b) and pyridine (L = py, 7b) adducts were unfavorable. Protolytic conditions were modeled using HCCR as weak acids, and trans-{kappaC,N-(3,4,5-(F)3 C6H2)CH2N?CH(3,4,6-(F)3-C6H-2-yl)}Fe(PMe3)3(CCR) (R = Me, 4b-Me; R = Ph, 4b-Ph) were generated from 1b. Exposure of 1b to N2O or N3SO2tol generated 2b and Me3PO or Me3P?N(SO2)tol, respectively. Calculations revealed 2b to be thermodynamically and kinetically favored over the calculated Fe(III) superoxide complex, (3)[FeO2], relative to 1b' + N2 + O2. The correlation of 1b' + (3)O2 to (3)[FeO2] is likely to have a relatively high intersystem crossing point (ICP) relative to 1b' + N2 to 2b, thereby explaining the dinitrogen selectivity. PMID- 23363319 TI - Molecularly functionalized silicon substrates for orientation control of the microphase separation of PS-b-PMMA and PS-b-PDMS block copolymer systems. AB - The use of block copolymer (BCP) thin films to generate nanostructured surfaces for device and other applications requires precise control of interfacial energies to achieve the desired domain orientation. Usually, the surface chemistry is engineered through the use of homo- or random copolymer brushes grown or attached to the surface. Herein, we demonstrate a facile, rapid, and tunable approach to surface functionalization using a molecular approach based on ethylene glycol attachment to the surface. The effectiveness of the molecular approach is demonstrated for the microphase separation of PS-b-PMMA and PS-b-PDMS BCPs in thin films and the development of nanoscale features at the substrate. PMID- 23363317 TI - Molecular model of a soluble guanylyl cyclase fragment determined by small-angle X-ray scattering and chemical cross-linking. AB - Soluble guanylyl/guanylate cyclase (sGC) converts GTP to cGMP after binding nitric oxide, leading to smooth muscle relaxation and vasodilation. Impaired sGC activity is common in cardiovascular disease, and sGC stimulatory compounds are vigorously sought. sGC is a 150 kDa heterodimeric protein with two H-NOX domains (one with heme, one without), two PAS domains, a coiled-coil domain, and two cyclase domains. Binding of NO to the sGC heme leads to proximal histidine release and stimulation of catalytic activity. To begin to understand how binding leads to activation, we examined truncated sGC proteins from Manduca sexta (tobacco hornworm) that bind NO, CO, and stimulatory compound YC-1 but lack the cyclase domains. We determined the overall shape of truncated M. sexta sGC using analytical ultracentrifugation and small-angle X-ray scattering (SAXS), revealing an elongated molecule with dimensions of 115 A * 90 A * 75 A. Binding of NO, CO, or YC-1 had little effect on shape. Using chemical cross-linking and tandem mass spectrometry, we identified 20 intermolecular contacts, allowing us to fit homology models of the individual domains into the SAXS-derived molecular envelope. The resulting model displays a central parallel coiled-coil platform upon which the H-NOX and PAS domains are assembled. The beta1 H-NOX and alpha1 PAS domains are in contact and form the core signaling complex, while the alpha1 H-NOX domain can be removed without a significant effect on ligand binding or overall shape. Removal of 21 residues from the C-terminus yields a protein with dramatically increased proximal histidine release rates upon NO binding. PMID- 23363320 TI - Colloidal properties of nanoparticular biogenic selenium govern environmental fate and bioremediation effectiveness. AB - Microbial selenium (Se) bioremediation is based on conversion of water soluble, toxic Se oxyanions to water insoluble, elemental Se. Formed biogenic elemental Se is of nanometer size, hampering straightforward separation from the aqueous phase. This study represents the first systematic investigation on colloidal properties of pure biogenic Se suspensions, linking electrophoretic mobility (zeta-potential) to column settling behavior. It was demonstrated that circumneutral pH, commonly applied in bioremediation, is not appropriate for gravitational separation due to the negative zeta-potential preventing agglomeration. Mono/di/trivalent counter cations and acidity (protons) were used to screen efficiently the intrinsic negative charge of biogenic Se suspensions at circumneutral pH. Fast settling was induced by La(3+) addition in the micromolar range (86.2 +/- 3.5% within 0.5 h), whereas considerably higher concentrations were needed when Ca(2+) or Na(+) was used. Colloidal stability was furthermore studied in different model waters. It was demonstrated that surface waters as such represent a fragile system regarding colloidal stability of biogenic Se suspensions (zeta-potential ~ -30 mV), whereas dissolved organic matter increases colloidal stability. In marine waters, biogenic Se is colloidally destabilized and is thus expected to settle, representing a potential sink for Se during transport in the aquatic environment. PMID- 23363321 TI - The expression of aryl hydrocarbon receptor in porcine ovarian cells. AB - The aryl hydrocarbon receptor (AHR) is an intracellular transcription factor best known for mediating the toxicity of dioxins. The AHR is phylogenetically highly conserved among invertebrates and vertebrates and may play a significant role in the regulation of physiological processes including female reproduction. This study was performed to determine the partial nucleotide sequence of porcine AHR and to evaluate the AHR mRNA (real-time PCR) and AHR protein (Western blot) expression in granulosa and theca interna cells harvested from medium (3-6 mm) and pre-ovulatory (>=8 mm) follicles as well as in luteal cells obtained from corpora lutea collected during the mid-luteal phase (days: 8-10) of the porcine oestrous cycle. In the study, the partial nucleotide sequence of porcine AHR containing 1021 bp (GenBank accession no: HM488957.1) was determined. The AHR transcript and protein were found in all ovarian cells obtained during both phases of the porcine oestrous cycle. The highest AHR transcript level was detected in theca interna cells isolated from pre-ovulatory follicles as well as in luteal cells. Higher AHR protein expression was found in granulosa cells isolated from pre-ovulatory follicles in comparison with all remaining cell types. The presence of AHR in the examined ovarian cells may account for their sensitivity to some environmental pollutants. Moreover, the differences found in AHR mRNA expression between granulosa and theca cells as well as between cells originating from follicles of different size suggest the involvement of AHR in the modulation of reproductive processes in the porcine ovary. PMID- 23363322 TI - Diagnosis of adrenocortical carcinoma via endosonography-assisted fine-needle aspiration of inferior vena cava thrombosis: first case in the literature. PMID- 23363323 TI - Harnessing fluid-driven vesicles to pick up and drop off Janus particles. AB - Using dissipative particle dynamics (DPD) simulations, we model the interaction between nanoscopic lipid vesicles and Janus nanoparticles in the presence of an imposed flow. Both the vesicle and Janus nanoparticles are localized on a hydrophilic substrate and immersed in a hydrophilic solution. The fluid-driven vesicle successfully picks up Janus particles on the substrate and transports these particles as cargo along the surface. The vesicle can carry up to four particles as its payload. Hence, the vesicles can act as nanoscopic "vacuum cleaners", collecting nanoscopic debris localized on the floors of the fluidic devices. Importantly, these studies reveal how an imposed flow can facilitate the incorporation of nanoparticles into nanoscale vesicles. With the introduction of a "sticky" domain on the substrate, the vesicles can also robustly drop off and deposit the particles on the surface. The controlled pickup and delivery of nanoparticles via lipid vesicles can play an important step in the bottom-up assembly of these nanoparticles within small-scale fluidic devices. PMID- 23363324 TI - When grammars collide: Harm reduction, drug detention and the challenges of international policy reform efforts in Vietnam. AB - Throughout the 1990s, a dramatic rise in HIV prevalence rates among drug users in Vietnam attracted the attention of international observers concerned about the prospect of a more generalised epidemic. Vietnam subsequently became the target of extensive funding and advocacy which sought to introduce needle exchange and methadone in a country where drug use was considered a 'social evil', and drug users were subjected to what international observers viewed as draconian incarceration measures. What were the goals of proponents of harm reduction when they came to Vietnam? How did they perceive the state of prevailing approaches to drug users in the context of the Vietnamese HIV epidemic? How did they understand the strategic challenges they faced and the dilemmas they had to confront? Based on in-depth interviews with international harm reduction proponents working in Vietnam, this paper explores the encounter of two grammars of harm reduction, one based on broadly accepted international approaches, the other rooted in Vietnam's own history and politics. From this encounter a set of policies and practices characterised by needle exchange and methadone maintenance emerged, as well as an extensive network of closed centres where tens of thousands of drug users are currently detained. PMID- 23363326 TI - Maternal postnatal mental health and later emotional-behavioural development of children: the mediating role of parenting behaviour. AB - BACKGROUND: Maternal postnatal mental health difficulties have been associated with poor outcomes for children. One mechanism by which parent mental health can impact on children's outcomes is via its effects on parenting behaviour. METHOD: The longitudinal relationships between maternal postnatal distress, parenting warmth, hostility and child well-being at age seven were examined for 2200 families participating in a population-based longitudinal study of Australian children. RESULTS: The relationship between postnatal distress and children's later emotional-behavioural development was mediated by parenting hostility, but not parenting warmth, even after accounting for concurrent maternal mental health. Postnatal distress was more strongly associated with lower parenting warmth for mothers without a past history of depression compared with mothers with a past history of depression. CONCLUSIONS: These findings underscore the contribution of early maternal well-being to later parenting and child outcomes, highlighting the importance of mental health and parenting support in the early parenting years. Implications for policy and practice are discussed. PMID- 23363325 TI - Phoma-like fungi on soybeans. AB - Numerous coelomycetous fungi classified in Ascochyta, Phoma and Phyllosticta, and lately established and/or re-classified genera and species, namely Boeremia and Peyronellaea have been recorded from spots on leaves and pods of soybeans. These rarely observed pathogens are cosmopolitan, ubiquitous species on diseased and dead plant materials, and define frequently as weak or opportunistic parasites. Based on the Genealogical Concordance Phylogenetic Species Recognition, the authors summarize the re-evaluation of the taxonomic status of Phoma sojicola (syn. Ascochyta sojicola) and Phyllosticta sojicola. Inspite of the former delimitation of Ph. sojicola based on small differences in morphological features, it has proved to be identical to Peyronellaea pinodella (syn. Phoma pinodella). Similarly, it was also confirmed that Ph. sojicola was identical to Boeremia exigua var. exigua (syn. Phoma exigua var. exigua). The authors and co workers contributed to the identification of Phoma-like fungi by combined conventional and molecular methods. Protein-encoding genes (TEF1 and beta tubulin) were successfully applied within the Phoma genus to infer phylogenetic relationships. PMID- 23363327 TI - Treatment of post-traumatic stress disorder in patients with severe mental illness: a review. AB - Although the prevalence of post-traumatic stress disorder (PTSD) is high among those with severe mental illness, little is known about the use of interventions to lessen the burden of PTSD in this population. Currently, there are limited data about safe and effective interventions to treat these individuals. This systematic published work review presents the scientific published work reporting studies of psychological treatment approaches for individuals with comorbid PTSD and severe mental illness. A secondary aim of this study was to identify the specific models implemented and tested, and their impact upon patient outcomes. A review of the published work from January 2001 through January 2012 of English language publications retrieved from the Cumulative Index of Nursing and Allied Health Literature (CINAHL), MEDLINE, and the American Psychological Association generated abstracts (PsycINFO) databases was conducted. Six studies met the inclusion criteria for the review. The treatment programs described were cognitive-behavioural therapy, psychoeducation, exposure-based cognitive behavioural therapy, and eye movement desensitization and reprocessing. Evidence of the effectiveness of these programs is examined. Data to support the use of these interventions are limited, indicating the need for further research and efficacy trials. Future areas of research and implications for nursing are discussed. PMID- 23363328 TI - Gauchers disease--a reappraisal of hematopoietic stem cell transplantation. AB - Hematopoietic stem cell transplantation (HSCT), first performed in 1984, was the first treatment approach for Gaucher's disease (GD) which had curative intent. The early successes in HSCT were soon eclipsed by the introduction of a highly effective enzyme replacement therapy (ERT), which has remained the single most widely used treatment. Experience with HSCT is limited to about 50 reported cases, mainly performed in the last century, with an overall survival around 85%. HSCT typically achieves complete correction of visceral and bony changes and can fully stabilize neurological features in otherwise progressive type II and III GD. ERT, in contrast, is completely safe and effective, but is limited by cost, incomplete resolution of visceral, hematological, and bony features in some patients, and lack of neurological correction in type II and III disease. In this review, we summarize and compare HSCT and ERT. With 20 years of experience of ERT, its limitations as well as its advantages are now well delineated. Meanwhile progress in HSCT over the last decade suggests that transplantation would today represent a very safe curative approach for GD offering one time complete correction of the disease, contrasting with the lifelong need for ERT with its associated expense and dependence on sophisticated drug manufacture. Additionally, unlike ERT, HSCT can be beneficial for neurological forms of GD. We conclude that the time has come to re-evaluate HSCT in selected patients with GD where ERT is less likely to fully eradicate symptoms of the disease. PMID- 23363329 TI - Medical costs and healthcare resource use in patients with lupus nephritis and neuropsychiatric lupus in an insured population. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect multiple organ systems, including the kidneys (lupus nephritis) and the central nervous system (neuropsychiatric lupus, or NPSLE). The healthcare costs and resource utilization associated with treating lupus nephritis and NPSLE in a large US managed care plan were studied. METHODS: SLE subjects >=18 years of age and with claims-based evidence of nephritis or neuropsychiatric conditions were identified from a health plan database. An index date was set as a randomly drawn date from all qualifying claims during 2003-2008 for study subjects. Subjects were matched on the basis of demographic and clinical characteristics to unaffected controls. Costs and resource use were determined during a fixed 12 month post-index period. RESULTS: Nine hundred and seven lupus nephritis subjects were matched to controls, and 1062 subjects with NPSLE were matched to controls. Mean overall post-index healthcare costs were significantly higher among subjects with lupus nephritis in comparison to matched controls ($33,472 vs $5347, p < 0.001). Similarly, mean overall post-index healthcare costs were significantly higher among subjects with NPSLE compared to controls ($30,341 vs $4646, p < 0.001). Subjects with lupus nephritis or NPSLE had higher mean post-index numbers of ambulatory visits, specialist visits, emergency department visits and inpatient hospital stays, compared to controls (all p < 0.001). LIMITATIONS: Additional research, such as medical chart review, could provide validation for the claims-based identification of lupus nephritis and NPSLE subjects. Also, indirect costs were not evaluated in this study. CONCLUSION: Subjects with lupus nephritis or NPSLE have high costs and resource use, compared to unaffected controls. PMID- 23363330 TI - Cost, healthcare resource utilization, and adherence of individuals with diabetes using U-500 or U-100 insulin: a retrospective database analysis. AB - OBJECTIVE: To describe costs, healthcare resource utilization, and adherence of US patients receiving human regular U-500 insulin (U-500R), compared to patients receiving high-dose (>200 units/day) U-100 insulins (U-100) by subcutaneous injection for the treatment of diabetes. METHODS: A retrospective analysis of data from Thomson Reuters MarketScan Research Databases (7/1/2008 to 12/31/2010). Difference-in-differences analyses were conducted on cost (medical, pharmacy, and overall costs) and on healthcare resource utilization variables (overall, diabetes-related, and non-diabetes-related medical visits). Adherence rates to the index insulins were assessed by proportion of days covered (PDC). RESULTS: Seven hundred and eleven (19%) patients in the U-500R cohort and 1508 (6%) patients in the U-100 cohort met selection criteria. Propensity score matching resulted in 684 matched pairs. Mean change in annualized pharmacy costs was in favor of the U-500R vs the U-100 cohort (-$1258 vs $3345, a difference of -$4603, p < 0.0001). Mean overall cost increase in the U-500R vs the U-100 cohort was also lower ($1999 vs $9104, a difference of -$7105, p = 0.005). The proportion of patients with at least one coded hypoglycemic event during the 12-month post index period was higher in the U-500R vs the U-100 cohort (17.1% vs 11.7%, p < 0.005), but neither hypoglycemia rate (2.73 vs 2.90 events per person) nor hypoglycemia-specific costs (mean $1669 vs $1543) were significantly different. No significant differences were noted between cohorts for change (post-pre) in any resource utilization category. PDC was greater in the U-500R vs the U-100 cohort (65.2% vs 39.5%, p < 0.0001). LIMITATIONS: Claims data are not as accurate as empirical evaluation by a clinician. Glycemic control data were not available for this analysis. CONCLUSIONS: In patients requiring high-dose insulin, treatment with U-500R vs high-dose U-100 insulins is associated with significant decreases in pharmacy and overall costs, slightly higher hypoglycemia incidence, no difference in hypoglycemia-specific costs or in resource utilization, and better adherence. PMID- 23363331 TI - Myocardial perfusion imaging laboratory efficiency with the use of regadenoson compared to adenosine and dipyridamole. AB - OBJECTIVE: Adenosine, dipyridamole, and regadenoson are pharmacologic stress agents used in myocardial perfusion imaging (MPI), to diagnose and monitor coronary artery disease. Clinical studies suggest that regadenoson has pharmacologic properties that simplify the MPI procedure through availability to a wider range of patients and easier administrative requirements. This study assesses the operational advantages and laboratory efficiency associated with the use of regadenoson compared to adenosine and dipyridamole. METHODS: A web-based survey of 141 nuclear medicine technologists working in US-based cardiovascular imaging laboratories from June-July 2009. MAIN OUTCOME MEASURES: Descriptive statistics measured the adenosine, dipyridamole, and regadenoson cohorts. Bivariate analyses compared the overall and staff-specific time to conduct an MPI test. The site-specific sub-groups were defined by hospital vs non-hospital setting, hours of operation, number of SPECT cameras, and number of full-time equivalent staff, including nurses, nuclear technologists, physicians, and nurse practitioners/physician assistants. RESULTS: The total time to conduct an MPI test was shortest with regadenoson 156 (46) min compared to adenosine and dipyridamole 182 (63) and 191 (61) min, respectively. Time from regadenoson administration to the start of the imaging session, including dose calculation and infusion time, was 14.2 min less than adenosine, and 12.0 min less than dipyridamole. The time to manage adverse events was shortest if it occurred with regadenoson compared to adenosine and dipyridamole, with minor exceptions. Due to the nature of survey implementation, possible recall bias may limit the results. Some differences in procedures times may be attributable to differences in laboratories' protocols. CONCLUSIONS: Overall time savings and time savings stratified by operational ability (number of staff, number of SPECT cameras, hours of operation) translate to a more efficient utilization of laboratory resources when using regadenoson compared to adenosine and dipyridamole. Regadenoson is the most efficient pharmacologic stress agent compared to adenosine and dipyridamole. PMID- 23363333 TI - Is whole-body thermoregulatory function impaired in type 1 diabetes mellitus? AB - During periods of extreme heat individuals with diabetes have greater rates of heat-related morbidity and mortality compared to their non-diabetic counterparts. The reason for this discrepancy is currently unknown. Furthermore, there is a lack of information about whether or not individuals with type 1 diabetes are at a thermoregulatory disadvantage during strenuous physical activity especially when performed in the heat. PURPOSE: This review discusses the current literature pertaining to thermoregulatory responses in individuals with type 1 diabetes. METHODS: We included 14 reviews and 95 original research articles identified by searches of PubMed and Google Scholar and deemed relevant to our subject by three independent readers. RESULTS: Individuals with poorly controlled type 1 diabetes may have impaired heat sensation, and a reduced capacity to dissipate heat due to lower skin blood flow and sweating responses and a greater tendency towards dehydration compared to individuals without diabetes. Impairments may be attenuated or absent in those with good blood glucose control. We found no published studies examining thermoregulatory responses to physical activity in the heat in individuals with type 1 diabetes. CONCLUSIONS: Type 1 diabetes may cause impairments in heat loss resulting in a greater level of thermal strain. Advancement in our understanding about the effects of type 1 diabetes on the heat stress response, especially during different challenges to human heat balance associated with changes in both environmental heat load and metabolic heat production (physical activity), will help us to determine where the risk of heat illness/injury actually exists. PMID- 23363332 TI - New player on an old field; the keap1/Nrf2 pathway as a target for treatment of type 2 diabetes and metabolic syndrome. AB - Nuclear erythroid factor 2 like 2 (Nrf2) has been described as a transcription factor that serves as a master regulator of the adaptive response to exogenous and endogenous oxidative and electrophilic stresses. Evidence of Nrf2 crosstalk with other molecular pathways is increasing; recent publications have proposed a role of Nrf2 in the development of obesity and in the highly regulated process of adipocyte differentiation through its interaction with other transcription factors and receptors implicated in metabolic regulation. In the present review, we discuss the available data on the possible role of Nrf2 in obesity and metabolic syndrome and the feasibility of using Nrf2 as a therapeutic target in the clinical setting. PMID- 23363334 TI - Complete stone clearance using a modified supine position: initial experience and comparison with prone percutaneous nephrolithotomy. AB - BACKGROUND AND PURPOSE: The recently described Galdakao-modified supine Valdivia position for percutaneous nephrolithotomy (PCNL) has become increasingly popular. We have made further modifications to this and describe our recent experience compared with our previous prone cases. PATIENTS AND METHODS: From April 2011, all patients undergoing PCNL have been placed in the modified supine position. A suction beanbag is used to secure the patient and improve renal access. Data on patient age, comorbidities, stone size, operative time, radiation exposure, complications, stone clearance, and length of stay was collected, analyzed, and compared with data from our previous year's prone surgery. RESULTS: Thirty-six patients in each group underwent 41 PCNLs. The groups were well matched for age, sex, and comorbidity. The supine patients tended to have a higher body mass index. Stones in the supine group were larger (32.6 vs 25.7 mm, P=0.0402), and the operative time was shorter (86.2 vs 116.6 min, P=0.003). Radiation time was similar in the two groups, but the dose was higher in the supine group. Stone clearance rates, length of stay (2.5 days), and complications were similar. Nineteen (46%) patients underwent simultaneous lower urinary tract procedures including 4 (10%) with complete staghorn calculi for which ureterorenoscopy was used to fragment ureteral and upper renal pole stones. CONCLUSIONS: The modified supine position for PCNL has a number of advantages for the patient and staff compared with the prone position. Despite a more obese study group with larger stones, we have maintained stone clearance rates and significantly reduced operative time with no increase in complications. The technique has been easy to learn and teach. A major advantage has been simultaneous access to the lower urinary tract for ureteroscopy and stent placement, and this has helped with complete stone clearance. PMID- 23363335 TI - Base-flipping propensities of unmethylated, hemimethylated, and fully methylated CpG sites. AB - Methylation of C5 of cytosines at CpG dinucleotide sites of the DNA is one of the most important factors regulating the expression of genes. The interactions of these CpG sites with proteins are essential for recognition and catalysis and in many cases are characterized by the flipping of either of the cytosine bases out of the DNA helix. In this paper, we present results from molecular dynamics simulations indicating that methylation of CpG sites suppresses spontaneous extra helical conformations of either of the two cytosines. Thus, cytosines in unmethylated sites flip out easier than in hemimethylated sites and the latter flip out easier than in fully methylated sites. The different propensities for base flipping is observed not only between the cytosines that differ in their methylation states but also between the cytosines on the complementary strand. From alchemical mutation calculations, we find that methylation of one of the cytosines increases the free energy of the extra-helical conformation by 10.3 16.5 kJ/mol and this increase is additive with respect to the second methylation. Potential of mean force calculations confirm these results and reveal that cytosines in unmethylated sites favor flipping via the major-groove pathway. We perform several analyses to correlate this behavior with structural changes induced by the different methylation states of the CpG site. However, we demonstrate that the driving force for these propensities is the change in the electronic distribution around the pyrimidine ring upon methylation. In particular, unmethylated cytosine interacts more favorably (primarily via electrostatic forces) with solvent water molecules than methylated cytosine. This is observed for, both, extra-helical cytosines and intra-helical cytosines in which the cytosine on the complementary strand flips out and water molecules enter the DNA double-helix and substitute the hydrogen bonds with the orphan guanine. On the basis of these results of spontaneous base flipping, we conjecture that the mechanism for base flipping observed in complexes between hemimethylated DNAs and proteins is not likely to be passive. PMID- 23363336 TI - Fibroblast growth factor 23 (FGF-23) concentrations in cats with early nonazotemic chronic kidney disease (CKD) and in healthy geriatric cats. AB - BACKGROUND: Fibroblast growth factor (FGF-23) has an important role in phosphate regulation. Its clinical relevance in cats with CKD has not been explored previously. HYPOTHESIS/OBJECTIVES: The study objectives were (1) to determine whether FGF-23 concentrations are increased in nonazotemic cats, cats which developed azotemia within 12 months of screening compared with cats that remained non-azotemic, and (2) to evaluate the relationships between FGF-23 and PTH and FGF-23 and glomerular filtration rate (GFR). ANIMALS: Sixty-two healthy client owned geriatric cats, 14 of which developed azotemia during the 12-month follow up period. METHODS: Healthy nonazotemic cats were recruited prospectively into the study and followed for 12 months. At the study end-point, cats were categorized into 3 groups according to plasma creatinine concentration. PTH, FGF 23, and additional biochemical variables were evaluated at baseline and after 12 months. GFR was measured by a corrected slope-intercept iohexol clearance method. RESULTS: FGF-23 concentrations at baseline were found to be significantly increased in cats that developed azotemia (P = .001) compared with cats that did not develop azotemia. A significant positive relationship was identified between FGF-23 and PTH, whereas the relationship between FGF-23 and GFR was negative. CONCLUSIONS AND CLINICAL IMPORTANCE: FGF-23 concentrations predicted development of azotemia in geriatric cats. Positive relationships between FGF-23 and PTH suggest an association between FGF-23 and renal secondary hyperparathyroidism. PMID- 23363337 TI - Ferromagnetic dinuclear mixed-valence Mn(II)/Mn(III) complexes: building blocks for the higher nuclearity complexes. structure, magnetic properties, and density functional theory calculations. AB - A series of six mixed-valence Mn(II)/Mn(III) dinuclear complexes were synthesized and characterized by X-ray diffraction. The reactivity of the complexes was surveyed, and structures of three additional trinuclear mixed-valence Mn(III)/Mn(II)/Mn(III) species were resolved. The magnetic properties of the complexes were studied in detail both experimentally and theoretically. All dinuclear complexes show ferromagnetic intramolecular interactions, which were justified on the basis of the electronic structures of the Mn(II) and Mn(III) ions. The large Mn(II)-O-Mn(III) bond angle and small distortion of the Mn(II) cation from the ideal square pyramidal geometry were shown to enhance the ferromagnetic interactions since these geometrical conditions seem to favor the orthogonal arrangement of the magnetic orbitals. PMID- 23363338 TI - Involvement of prolactin-releasing peptide in the activation of oxytocin neurones in response to food intake. AB - Food intake activates neurones expressing prolactin-releasing peptide (PrRP) in the medulla oblongata and oxytocin neurones in the hypothalamus. Both PrRP and oxytocin have been shown to have an anorexic action. In the present study, we investigated whether the activation of oxytocin neurones following food intake is mediated by PrRP. We first examined the expression of PrRP receptors (also known as GPR10) in rats. Immunoreactivity of PrRP receptors was observed in oxytocin neurones and in vasopressin neurones in the paraventricular and supraoptic nuclei of the hypothalamus and in the bed nucleus of the stria terminalis. Application of PrRP to isolated supraoptic nuclei facilitated the release of oxytocin and vasopressin. In mice, re-feeding increased the expression of Fos protein in oxytocin neurones of the hypothalamus and bed nucleus of the stria terminalis. The increased expression of Fos protein in oxytocin neurones following re-feeding or i.p. administration of cholecystokinin octapeptide (CCK), a peripheral satiety factor, was impaired in PrRP-deficient mice. CCK-induced oxytocin increase in plasma was also impaired in PrRP-deficient mice. Furthermore, oxytocin receptor deficient mice showed an increased meal size, as reported in PrRP-deficient mice and in CCKA receptor-deficient mice. These findings suggest that PrRP mediates, at least in part, the activation of oxytocin neurones in response to food intake, and that the CCK-PrRP-oxytocin pathway plays an important role in the control of the termination of each meal. PMID- 23363340 TI - Effects of inspired oxygen concentration on ventilation, ventilatory rhythm, and gas exchange in isoflurane-anesthetized horses. AB - OBJECTIVE: To compare the effects of 2 fractions of inspired oxygen, 50% and > 95%, on ventilation, ventilatory rhythm, and gas exchange in isoflurane anesthetized horses. ANIMALS: 8 healthy adult horses. PROCEDURES: In a crossover study design, horses were assigned to undergo each of 2 anesthetic sessions in random order, with 1 week separating the sessions. In each session, horses were sedated with xylazine hydrochloride (1.0 mg/kg, IV) and anesthesia was induced via IV administration of diazepam (0.05 mg/kg) and ketamine (2.2 mg/kg) Anesthesia was subsequently maintained with isoflurane in 50% or > 95% oxygen for 90 minutes. Measurements obtained during anesthesia included inspiratory and expiratory peak flow and duration, tidal volume, respiratory frequency, end-tidal CO(2) concentration, mixed expired partial pressures of CO(2) and O(2), PaO(2), PaCO(2), blood pH, arterial O(2) saturation, heart rate, and arterial blood pressure. Calculated values included the alveolar partial pressure of oxygen, alveolar-to-arterial oxygen tension gradient (PaO(2) - PaO(2)), rate of change of PAO(2) - PaO(2), and physiologic dead space ratio. Ventilatory rhythm, based on respiratory rate and duration of apnea, was continuously observed and recorded. RESULTS: Use of the lower inspired oxygen fraction of 50% resulted in a lower arterial oxygen saturation and PaO(2) than did use of the higher fraction. No significant difference in PaCO(2), rate of change of PAO(2) - PaO(2), ventilatory rhythm, or other measured variables was observed between the 2 sessions. CONCLUSION AND CLINICAL RELEVANCE: Use of 50% inspired oxygen did not improve the ventilatory rhythm or gas exchange and increased the risk of hypoxemia in spontaneously breathing horses during isoflurane anesthesia. Use of both inspired oxygen fractions requires adequate monitoring and the capacity for mechanical ventilation. PMID- 23363341 TI - Pharmacokinetics of long-acting nalbuphine decanoate after intramuscular administration to Hispaniolan Amazon parrots (Amazona ventralis). AB - OBJECTIVE: To evaluate the pharmacokinetics of nalbuphine decanoate after IM administration to Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS: 9 healthy adult Hispaniolan Amazon parrots of unknown sex. PROCEDURES: Nalbuphine decanoate (37.5 mg/kg) was administered IM to all birds. Plasma samples were obtained from blood collected before (time 0) and 0.25, 1, 2, 3, 6, 12, 24, 48, and 96 hours after drug administration. Plasma samples were used for measurement of nalbuphine concentrations via liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated with computer software. RESULTS: Plasma concentrations of nalbuphine increased rapidly after IM administration, with a mean concentration of 46.1 ng/mL at 0.25 hours after administration. Plasma concentrations of nalbuphine remained > 20 ng/mL for at least 24 hours in all birds. The maximum plasma concentration was 109.4 ng/mL at 2.15 hours. The mean terminal half-life was 20.4 hours. CONCLUSIONS AND CLINICAL RELEVANCE: In Hispaniolan Amazon parrots, plasma concentrations of nalbuphine were prolonged after IM administration of nalbuphine decanoate, compared with previously reported results after administration of nalbuphine hydrochloride. Plasma concentrations that could be associated with antinociception were maintained for 24 hours after IM administration of 37.5 mg of nalbuphine decanoate/kg. Safety and analgesic efficacy of nalbuphine treatments in this species require further investigation to determine the potential for clinical use in pain management in psittacine species. PMID- 23363342 TI - Antinociceptive effects of long-acting nalbuphine decanoate after intramuscular administration to Hispaniolan Amazon parrots (Amazona ventralis). AB - OBJECTIVE: To evaluate the thermal antinociceptive effects and duration of action of nalbuphine decanoate after IM administration to Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS: 10 healthy adult Hispaniolan Amazon parrots of unknown sex. PROCEDURES: Nalbuphine decanoate (33.7 mg/kg) or saline (0.9% NaCl) solution was administered IM in a randomized complete crossover experimental design (periods 1 and 2). Foot withdrawal threshold to a noxious thermal stimulus was used to evaluate responses. Baseline thermal withdrawal threshold was recorded 1 hour before drug or saline solution administration, and thermal foot withdrawal threshold measurements were repeated 1, 2, 3, 6, 12, 24, 48, and 72 hours after drug administration. RESULTS: Nalbuphine decanoate administered IM at a dose of 33.7 mg/kg significantly increased thermal foot withdrawal threshold, compared with results after administration of saline solution during period 2, and also caused a significant change in withdrawal threshold for up to 12 hours, compared with baseline values. CONCLUSIONS AND CLINICAL RELEVANCE: Nalbuphine decanoate increased the foot withdrawal threshold to a noxious thermal stimulus in Hispaniolan Amazon parrots for up to 12 hours and provided a longer duration of action than has been reported for other nalbuphine formulations. Further studies with other types of nociceptive stimulation, dosages, and dosing intervals as well as clinical trials are needed to fully evaluate the analgesic effects of nalbuphine decanoate in psittacine birds. PMID- 23363343 TI - Antinociceptive effects of tramadol hydrochloride after intravenous administration to Hispaniolan Amazon parrots (Amazona ventralis). AB - OBJECTIVE: To determine the antinociceptive and sedative effects of tramadol in Hispaniolan Amazon parrots (Amazona ventralis) following IV administration. ANIMALS: 11 healthy Hispaniolan Amazon parrots of unknown sex. PROCEDURES: Tramadol hydrochloride (5 mg/kg, IV) and an equivalent volume (<= 0.34 mL) of saline (0.9% NaCl) solution were administered to parrots in a complete crossover study design. Foot withdrawal response to a thermal stimulus was determined 30 to 60 minutes before (baseline) and 15, 30, 60, 120, and 240 minutes after treatment administration; agitation-sedation scores were determined for parrots at each of those times. RESULTS: The estimated mean changes in temperature from the baseline value that elicited a foot withdrawal response were 1.65 degrees and -1.08 degrees C after administration of tramadol and saline solution, respectively. Temperatures at which a foot withdrawal response was elicited were significantly higher than baseline values at all 5 evaluation times after administration of tramadol and were significantly lower than baseline values at 30, 120, and 240 minutes after administration of saline solution. No sedation, agitation, or other adverse effects were observed in any of the parrots after administration of tramadol. CONCLUSIONS AND CLINICAL RELEVANCE: Tramadol hydrochloride (5 mg/kg, IV) significantly increased the thermal nociception threshold for Hispaniolan Amazon parrots in the present study. Sedation and adverse effects were not observed. These results are consistent with results of other studies in which the antinociceptive effects of tramadol after oral administration to parrots were determined. PMID- 23363344 TI - Flow cytometric detection and procoagulant activity of circulating canine platelet-derived microparticles. AB - OBJECTIVE: To measure platelet membrane-derived microparticle (PMP) content and thrombin-generating capacity of canine plasma subjected to specific processing and storage conditions. ANIMALS: 31 clinically normal dogs (19 males and 12 females). PROCEDURES: Citrate-anticoagulated blood samples obtained from each dog were centrifuged at 2,500 * g to isolate platelet-poor plasma (PPP), then PPP was centrifuged at 21,000 * g to isolate microparticle-free plasma (MPF) and microparticle-enriched plasma (MPEP). Whole blood and paired samples of fresh and frozen-thawed PPP, MPF, and MPEP were dual labeled for flow cytometric detection of membrane CD61 (constitutive platelet antigen) and annexin V (indicating phosphatidylserine externalization). Platelets and PMPs were enumerated with fluorescent, size-calibrated beads. Thrombin generation in fresh and frozen thawed PPP, MPF, and MPEP was measured via kinetic fluorometric assays configured with low tissue factor and low phospholipid concentrations. RESULTS: Initial centrifugation yielded PPP with < 0.5% the platelets of whole blood, with median counts of 413 PMPs/MUL for males and 711 PMPs/MUL for females. Sequential centrifugation resulted in a 10-fold concentration of PMPs in MPEP and virtually depleted PMPs from MPF. Thrombin generation depended on PMP content, with median endogenous thrombin potential of 0, 893, and 3,650 nmol*min for MPF, PPP, and MPEP, respectively. Freeze-thaw cycling caused significant increases in PMP counts and phosphatidylserine externalization. CONCLUSIONS AND CLINICAL RELEVANCE: Canine PMPs were major determinants of thrombin-generating capacity; preanalytic variables influenced plasma PMP content. Processing conditions described here may provide a basis for characterization of PMPs in clinical studies of thrombosis in dogs. PMID- 23363345 TI - Expression of matrix metalloproteinases, their inhibitors, and lysyl oxidase in myocardial samples from dogs with end-stage systemic and cardiac diseases. AB - OBJECTIVE: To compare the degree of mRNA expression for matrix metalloproteinases (MMPs), tissue inhibitors (TIMPs), and lysyl oxidase in myocardial samples from dogs with cardiac and systemic diseases and from healthy control dogs. SAMPLE: Myocardial samples from the atria, ventricles, and septum of 8 control dogs, 6 dogs with systemic diseases, 4 dogs with dilated cardiomyopathy (DCM), and 5 dogs with other cardiac diseases. PROCEDURES: Degrees of mRNA expression for MMP-1, 2, -3, -9, and -13; TIMP-1, -2, -3, and -4; and lysyl oxidase were measured via quantitative real-time PCR assay. Histologic examination of the hearts was performed to identify pathological changes. RESULTS: In myocardial samples from control dogs, only TIMP-3 and TIMP-4 mRNA expression was detected, with a significantly higher degree in male versus female dogs. In dogs with systemic and cardiac diseases, all investigated markers were expressed, with a significantly higher degree of mRNA expression than in control dogs. Furthermore, the degree of expression for MMP-2, TIMP-1, and TIMP-2 was significantly higher in dogs with DCM than in dogs with systemic diseases and cardiac diseases other than DCM. Expression was generally greater in atrial than in ventricular tissue for MMP-2, MMP-13, and lysyl oxidase in samples from dogs with atrial fibrillation. CONCLUSIONS AND CLINICAL RELEVANCE: Degrees of myocardial MMP, TIMP, and lysyl oxidase mRNA expression were higher in dogs with cardiac and systemic diseases than in healthy dogs, suggesting that expression of these markers is a nonspecific consequence of end-stage diseases. Selective differences in the expression of some markers may reflect specific pathogenic mechanisms and may play a role in disease progression, morbidity and mortality rates, and treatment response. PMID- 23363346 TI - Description of technique and lower reference limit for magnetic resonance imaging of hippocampal volumetry in dogs. AB - OBJECTIVE: To evaluate the use of high-resolution MRI for hippocampal volumetry in dogs and to define a lower reference limit for hippocampal formation (HF) volume. ANIMALS: 20 dogs (with no history of seizures and no underlying structural brain disease) that underwent MRI of the brain. PROCEDURES: The MRI protocol included a high-resolution T1-weighted 3-D ultrafast gradient-echo sequence aligned in a dorsal plane perpendicular to the long axis of the HF. Images obtained with MRI were retrospectively analyzed by 2 observers (A and B). Intraobserver and interobserver agreement were calculated with the Lin concordance correlation coefficient. Volume measurements of the HF were adjusted for intracranial volume, and a lower 95% reference limit for adjusted HF volume was calculated. RESULTS: There was substantial intraobserver agreement (Lin concordance correlation coefficient, 0.97 [95% confidence interval {CI}, 0.94 to 0.99]) but poor interobserver agreement (Lin concordance correlation coefficient, 0.63 [95% CI, 0.37 to 0.79]). The lower 95% reference limit for adjusted HF volume was 0.56 cm(3) (90% CI, 0.52 to 0.60 cm(3)) for the right HF and 0.55 cm(3) (90% CI, 0.52 to 0.58 cm(3)) for the left HF. CONCLUSIONS AND CLINICAL RELEVANCE: HF volumes should be adjusted for intracranial volume to account for the large variation in canine skull size. The amount of time required to perform HF volumetry and low interobserver agreement may restrict this technique to research applications, such as the investigation of epileptic patients for hippocampal sclerosis or other cognitive disorders. PMID- 23363347 TI - Comparison of inversion recovery gradient echo with inversion recovery fast spin echo techniques for magnetic resonance imaging detection of navicular bone marrow lesions in horses. AB - OBJECTIVE: To compare navicular bone marrow lesion (BML) conspicuity in the feet of horses as determined via 2 fat-suppressed MRI techniques, including standard short tau inversion recovery (STIR) and inversion recovery gradient echo (IRGE). SAMPLE: Feet (n = 150) of horses with lameness referable to the distal portion of the digit. PROCEDURES: STIR and IRGE sequences were obtained prospectively in all feet with a standing low-field equine MRI system. Presence of a BML was ascertained by identification of a characteristic combination of marrow alterations in T1-weighted, T2*-weighted, T2-weighted, and STIR images. Signal-to noise and contrast-to-noise ratios were calculated on STIR and IRGE sequences in 56 feet with a navicular BML. RESULTS: Signal-to-noise and contrast-to-noise ratios of both sequences correlated linearly (r = 0.87 and r = 0.92, respectively) but were significantly higher for STIR images (mean +/- SD, 22.6 +/ 12.7 and 12.4 +/- 11.4, respectively), compared with IRGE images (13.7 +/- 8.0 and 5.9 +/- 7.2, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that the IRGE sequence revealed BMLs significantly less conspicuously, compared with the standard STIR sequence. The 2 techniques cannot be used interchangeably, and IRGE is therefore not recommended as the sole fat-suppressed sequence for routine equine standing MRI protocols. PMID- 23363348 TI - Incidence of bacteremia following upper gastrointestinal endoscopy and biopsy in healthy dogs before, during, and after treatment with omeprazole. AB - OBJECTIVE: To determine the incidence of bacteremia, as detected by routine methods for bacterial culture of blood samples, following routine endoscopic biopsy of the stomach and duodenum in healthy research dogs and to determine whether treatment with omeprazole administration affected the incidence of bacteremia. ANIMALS: 8 healthy purpose-bred research dogs. PROCEDURES: All dogs underwent gastroduodenoscopy with biopsy at 4 points: twice prior to treatment with omeprazole, once following 15 days of omeprazole treatment (20 mg, PO, q 12 h), and once 14 days after treatment ceased. Dogs had a mean +/- SD body weight of 18.6 +/- 2.0 kg. Blood samples were aseptically obtained at 3 points during each procedure (before, immediately following, and 24 hours after endoscopy), and routine aerobic and anaerobic bacterial culture of blood was performed. RESULTS: 96 cultures were attempted for each culture method, yielding positive results of aerobic culture for 2 dogs at separate time points and no positive results of anaerobic culture. CONCLUSIONS AND CLINICAL RELEVANCE: Routine gastrointestinal endoscopy with biopsy in healthy dogs did not result in a detectable bacteremia in most dogs. Treatment with the gastric acid-suppressing medication omeprazole did not affect the incidence of bacteremia as detected via standard techniques. PMID- 23363349 TI - Evaluation of delivery agents used for introduction of small interfering RNAs into feline corneal cells. AB - OBJECTIVE: To evaluate agents used for delivery of small interfering RNAs (siRNAs) into feline corneal cells, toxicity of the delivery agents, and functionality of anti-feline herpesvirus 1 (FHV-1)-specific siRNA combinations. SAMPLE: Feline primary corneal cells and 19 six-month-old colony-bred cats. PROCEDURES: siRNA delivery into corneal cells via various delivery agents was evaluated via flow cytometric detection of labeled siRNAs. Cellular toxicity was evaluated with a proliferation assay. Functionality was tested via quantitative reverse transcriptase PCR assay, plaque assay, and flow cytometry. In vivo safety was evaluated with an ocular scoring method following topical application of delivery agents containing siRNAs into eyes. Corneal biopsy specimens were used to assess safety and uptake of siRNAs into corneal cells. RESULTS: Use of 3 delivery agents resulted in > 95% transfection of primary corneal cells. Use of a peptide for ocular delivery yielded approximately 82% transfection of cells in vitro. In cultured corneal cells, use of the siRNA combinations resulted in approximately 76% to 89% reduction in FHV-1-specific mRNA, 63% to 67% reduction of FHV-1-specific proteins in treated cells, and 97% to 98% reduction in FHV-1 replication. The agents were nonirritating in eyes, caused no substantial clinical ocular signs, and were nontoxic. Histologically, corneal epithelium and stroma were normal in treated cats. However, none of the agents were effective in delivering siRNAs into the corneal cells in vivo. CONCLUSIONS AND CLINICAL RELEVANCE: The tested anti-FHV-1-specific siRNAs could potentially be used as a treatment for FHV-1 if a successful means of in vivo delivery can be achieved. PMID- 23363350 TI - Evaluation of metaphylactic RNA interference to prevent equine herpesvirus type 1 infection in experimental herpesvirus myeloencephalopathy in horses. AB - OBJECTIVE: To evaluate metaphylactic RNA interference to prevent equine herpesvirus type 1 (EHV-1) infection in experimental herpesvirus myeloencephalopathy in horses and to determine whether horses infected with a neuropathogenic strain of the virus that develop equine herpesvirus myeloencephalopathy (EHM) have differences in viremia. ANIMALS: 13 seronegative horses. PROCEDURES: EHV-1 strain Ab4 was administered intranasally on day 0, and small interfering RNAs (siRNAs [EHV-1 specific siRNAs {n = 7} or an irrelevant siRNA {6}]) were administered intranasally 24 hours before and 12, 24, 36, and 48 hours after infection. Physical and neurologic examinations, nasal swab specimens, and blood samples were collected for virus isolation and quantitative PCR assay. Data from the study were combined with data from a previous study of 14 horses. RESULTS: No significant difference was detected in clinical variables, viremia, or detection of EHV-1 in nasal swab specimens of horses treated with the EHV-1 targeted siRNAs (sigB3-siOri2) versus controls. No significant differences in viremia were detected between horses that developed EHM and those that did not. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of siRNAs targeted against EHV-1 around the time of EHV-1 infection was not protective with this experimental design. Horses infected with the neuropathogenic EHV-1 strain Ab4 that developed EHM did not have a more pronounced viremia. PMID- 23363351 TI - Evaluation of vincristine-associated myelosuppression in Border Collies. AB - OBJECTIVE: To determine whether Border Collies (ATP binding cassette subfamily B1 gene [ABCB1] wildtype) were more likely than other breeds to develop vincristine associated myelosuppression (VAM) and, if so, whether this was caused by a mutation in ABCB1 distinct from ABCB1-1Delta. ANIMALS: Phase 1 comprised 36 dogs with the ABCB1 wildtype, including 26 dogs with lymphoma (5 Border Collies and 21 dogs representing 13 other breeds) treated with vincristine in a previous study; phase 2 comprised 10 additional Border Collies, including 3 that developed VAM and 7 with an unknown phenotype. PROCEDURES: For phase 1, the prevalence of VAM in ABCB1-wildtype Border Collies was compared with that for ABCB1-wildtype dogs of other breeds with data from a previous study. For phase 2, additional Border Collies were included. Hematologic adverse reactions were graded with Veterinary Co-operative Oncology Group criteria. Genomic DNA was used to amplify and sequence all 27 exons of the canine ABCB1. Sequences from affected dogs were compared with those of unaffected dogs and dogs of unknown phenotype. RESULTS: 3 of 5 Border Collies with the ABCB1 wildtype developed VAM; this was significantly higher than the proportion of other dogs that developed VAM (0/21). A causative mutation for VAM in Border Collies was not identified, although 8 single nucleotide polymorphisms in ABCB1 were detected. CONCLUSIONS AND CLINICAL RELEVANCE: Breed-associated sensitivity to vincristine unrelated to ABCB1 was detected in Border Collies. Veterinarians should be aware of this breed predisposition to VAM. Causes for this apparent breed-associated sensitivity should be explored. PMID- 23363352 TI - Effects of oral administration of anti-inflammatory medications on inhibition of paracentesis-induced blood-aqueous barrier breakdown in clinically normal cats. AB - OBJECTIVE: To assess inhibitory effects of orally administered anti-inflammatory medications on paracentesis-induced intraocular inflammation in clinically normal cats. ANIMALS: 30 clinically normal domestic shorthair cats. PROCEDURES: Cats were randomly assigned to a control group and 4 treatment groups. Cats in the treatment groups received an anti-inflammatory medication orally once daily at 7 AM (acetylsalicylic acid [40.5 mg/cat], meloxicam [0.1 mg/kg], prednisone [5 mg/cat], or prednisolone [5 mg/cat]) for 5 days beginning 2 days before paracentesis-induced breakdown of the blood-aqueous barrier (BAB) and continuing until 2 days after paracentesis. Paracentesis of the anterior chamber was performed in 1 randomly selected eye of each cat. Fluorophotometry was performed in both eyes of each cat immediately before (time 0) and 6, 24, and 48 hours after paracentesis. RESULTS: At 24 and 48 hours after paracentesis, fluorescein concentration in the eye subjected to paracentesis in the cats receiving prednisolone was decreased, compared with that in the control cats. At 48 hours, a decrease in the fluorescein concentration was also apparent in the eye subjected to paracentesis in the cats receiving meloxicam, compared with that in the control cats. There was no evidence of treatment effects for acetylsalicylic acid or prednisone. There was no evidence of treatment effects in eyes not subjected to paracentesis. CONCLUSIONS AND CLINICAL RELEVANCE: Orally administered prednisolone and meloxicam significantly decreased intraocular inflammation in clinically normal cats with paracentesis-induced BAB breakdown. Oral administration of prednisolone or meloxicam may be an effective treatment for cats with uveitis. PMID- 23363353 TI - Florfenicol concentrations in ovine tear fluid following intramuscular and subcutaneous administration and comparison with the minimum inhibitory concentrations against mycoplasmal strains potentially involved in infectious keratoconjunctivitis. AB - OBJECTIVE: To measure florfenicol concentrations in ovine tear fluid after IM and SC administration and determine minimum inhibitory concentrations (MICs) of florfenicol against field isolates of Mycoplasma organisms potentially involved in infectious keratoconjunctivitis. ANIMALS: 9 healthy adult Lacaune ewes. PROCEDURES: Animals received an IM and SC administration of florfenicol (20 mg/kg) in a 2-way crossover design. Samples of blood and tear fluid were collected before and for 24 hours after administration. Concentrations of florfenicol in plasma and tear fluid were measured via high-performance liquid chromatography. The MIC of florfenicol for various Mycoplasma strains cultured from sheep and goats was determined via an agar dilution method. RESULTS: Mean florfenicol concentration in tear fluid for the 24-hour period was significantly higher after IM administration (0.70 MUg/mL) than after SC administration (0.22 MUg/mL) and was maintained for a longer duration. The lacrimal fluid-to-plasma concentration ratio was not different between the 2 routes of administration, with mean values of 40.2% and 32.5% after IM and SC administration, respectively. The MIC for Mycoplasma agalactiae, Mycoplasma conjunctivae, and Mycoplasma mycoides isolates ranged from 0.5 to 8 MUg of florfenicol/mL. Two strains of M agalactiae could be considered resistant to florfenicol. CONCLUSIONS AND CLINICAL RELEVANCE: Florfenicol readily penetrated the preocular tear fluid of sheep after IM and SC administration. For both routes of administration, doses > 20 mg/kg would be necessary to achieve tear fluid concentrations of florfenicol greater than the MICs for most strains of Mycoplasma organisms. PMID- 23363354 TI - Effects of a topically applied 2% delta-9-tetrahydrocannabinol ophthalmic solution on intraocular pressure and aqueous humor flow rate in clinically normal dogs. AB - OBJECTIVE: To determine the effects of topically applied 2% delta-9 tetrahydrocannabinol (THC) ophthalmic solution on aqueous humor flow rate (AHFR) and intraocular pressure (IOP) in clinically normal dogs. ANIMALS: 21 clinically normal dogs. PROCEDURES: A randomized longitudinal crossover design was used. Following acquisition of baseline IOP (morning and evening) and AHFR (afternoon only) data, dogs were randomly assigned to 2 treatment groups and received 1 drop of either 2% THC solution or a control treatment (olive oil vehicle) to 1 randomly selected eye every 12 hours for 9 doses. The IOPs and AHFRs were reassessed after the final treatment. Following a washout period of >= 7 days, dogs were administered the alternate treatment in the same eye, and measurements were repeated. RESULTS: Mean +/- SD IOPs in the morning were 15.86 +/- 2.48 mm Hg at baseline, 12.54 +/- 3.18 mm Hg after THC treatment, and 13.88 +/- 3.28 mm Hg after control treatment. Mean +/- SD IOPs in the evening were 13.69 +/- 3.36 mm Hg at baseline, 11.69 +/- 3.94 mm Hg after THC treatment, and 12.13 +/- 2.99 mm Hg after control treatment. Mean IOPs were significantly decreased from baseline after administration of THC solution but not the control treatment. Changes in IOP varied substantially among individual dogs. Mean +/- SD AHFRs were not significantly different from baseline for either treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Topical application of 2% THC ophthalmic solution resulted in moderate reduction of mean IOP in clinically normal dogs. Further research is needed to determine efficacy in dogs with glaucoma. PMID- 23363355 TI - Effects of topical ocular administration of high doses of human recombinant interferon alpha-2b and feline recombinant interferon omega on naturally occurring viral keratoconjunctivitis in cats. AB - OBJECTIVE: To determine whether 14-day topical ocular administration of high doses of feline recombinant interferon omega (FelFN) or human recombinant interferon alpha-2b (HulFN) solution improves clinical disease and decreases virus shedding in cats with naturally acquired viral keratoconjunctivitis. ANIMALS: 36 cats with upper respiratory tract disease and ocular involvement. PROCEDURES: Cats received 1 drop of FelFN solution (1 * 10(6) U/mL), HulFN solution (1 * 10(6) U/mL), or saline (0.9% NaCl) solution (12 cats/group) in each eye twice daily for 14 days (beginning day 1). Oropharyngeal and conjunctival swab samples were collected from each cat before (day 0) and on day 14 of treatment for virus isolation (VI) and real-time quantitative PCR (RT-qPCR) testing to detect feline herpesvirus-1 and feline calicivirus. Subjective clinical scores were recorded on days 0, 3, 7, 10, and 14. RESULTS: The number of cats for which feline herpesvirus-1 was detected via VI or RT-qPCR assay was generally (albeit not always significantly) lower on day 14, compared with day 0 findings; however, findings on days 0 or 14 did not differ among groups. The number of cats for which feline calicivirus was detected via VI or RT-qPCR assay did not differ significantly between days 0 and 14 for any group. Clinical scores significantly decreased over the 14-day period but did not differ among groups. CONCLUSIONS AND CLINICAL RELEVANCE: In cats with naturally occurring viral keratoconjunctivitis, bilateral ocular administration of high doses of FelFN or HulFN twice daily for 14 days did not improve clinical disease or virus shedding, compared with treatment with saline solution. PMID- 23363356 TI - Pharmacokinetics of N-acetylcysteine after oral and intravenous administration to healthy cats. AB - OBJECTIVE: To describe the pharmacokinetics of N-acetylcysteine (NAC) in healthy cats after oral and IV administration. ANIMALS: 6 healthy cats. PROCEDURES: In a crossover study, cats received NAC (100 mg/kg) via IV and oral routes of administration; there was a 4-week washout period between treatments. Plasma samples were obtained at 0, 5, 15, 30, and 45 minutes and 1, 2, 4, 8, 12, 24, 36, and 48 hours after administration, and NAC concentrations were quantified by use of a validated high-performance liquid chromatography-mass spectrometry protocol. Data were analyzed via compartmental and noncompartmental pharmacokinetic analysis. RESULTS: Pharmacokinetics for both routes of administration were best described by a 2-compartment model. Mean +/- SD elimination half-life was 0.78 +/ 0.16 hours and 1.34 +/- 0.24 hours for the IV and oral routes of administration, respectively. Mean bioavailability of NAC after oral administration was 19.3 +/- 4.4%. CONCLUSIONS AND CLINICAL RELEVANCE: The pharmacokinetics of NAC for this small population of healthy cats differed from values reported for humans. Assuming there would be similar pharmacokinetics in diseased cats, dose extrapolations from human medicine may result in underdosing of NAC in cats with acute disease. Despite the low bioavailability, plasma concentrations of NAC after oral administration at 100 mg/kg may be effective in the treatment of chronic diseases. PMID- 23363357 TI - Pharmacokinetics and pharmacodynamics of midazolam after intravenous and intramuscular administration in alpacas. AB - OBJECTIVE: To determine pharmacokinetic and pharmacodynamic properties of midazolam after IV and IM administration in alpacas. ANIMALS: 6 healthy alpacas. PROCEDURES: Midazolam (0.5 mg/kg) was administered IV or IM in a randomized crossover design. Twelve hours prior to administration, catheters were placed in 1 (IM trial) or both (IV trial) jugular veins for drug administration and blood sample collection for determination of serum midazolam concentrations. Blood samples were obtained at intervals up to 24 hours after IM and IV administration. Midazolam concentrations were determined by use of tandem liquid chromatography mass spectrometry. RESULTS: Maximum concentrations after IV administration (median, 1,394 ng/mL [range, 1,150 to 1,503 ng/mL]) and IM administration (411 ng/mL [217 to 675 ng/mL]) were measured at 3 minutes and at 5 to 30 minutes, respectively. Distribution half-life was 18.7 minutes (13 to 47 minutes) after IV administration and 41 minutes (30 to 80 minutes) after IM administration. Elimination half-life was 98 minutes (67 to 373 minutes) and 234 minutes (103 to 320 minutes) after IV and IM administration, respectively. Total clearance after IV administration was 11.3 mL/min/kg (6.7 to 13.9 mL/min/kg), and steady-state volume of distribution was 525 mL/kg (446 to 798 mL/kg). Bioavailability of midazolam after IM administration was 92%. Peak onset of sedation occurred at 0.4 minutes (IV) and 15 minutes (IM). Sedation was significantly greater after IV administration. CONCLUSIONS AND CLINICAL RELEVANCE: Midazolam was well absorbed after IM administration, had a short duration of action, and induced moderate levels of sedation in alpacas. PMID- 23363358 TI - Evaluation of economic and performance outcomes associated with the number of treatments after an initial diagnosis of bovine respiratory disease in commercial feeder cattle. AB - OBJECTIVE: To evaluate associations between economic and performance outcomes with the number of treatments after an initial diagnosis of bovine respiratory disease (BRD) in commercial feedlot cattle. ANIMALS: 212,867 cattle arriving in a Midwestern feedlot between 2001 and 2006. PROCEDURES: An economic model was created to estimate net returns. Generalized linear mixed models were used to determine associations between the frequency of BRD treatments and other demographic variables with economic and performance outcomes. RESULTS: Net returns decreased with increasing number of treatments for BRD. However, the magnitude depended on the season during which cattle arrived at the feedlot, with significantly higher returns for cattle arriving during fall and summer than for cattle arriving during winter and spring. For fall arrivals, there were higher mean net returns for cattle that were never treated ($39.41) than for cattle treated once ($29.49), twice ($16.56), or >= 3 times (-$33.00). For summer arrivals, there were higher least squares mean net returns for cattle that were never treated ($31.83) than for cattle treated once ($20.22), twice ($6.37), or >= 3 times ($-42.56). Carcass traits pertaining to weight and quality grade were deemed responsible for differences in net returns among cattle receiving different numbers of treatments after an initial diagnosis of BRD. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in economic net returns and performance outcomes for feedlot cattle were determined on the basis of number of treatments after an initial diagnosis of BRD; the analysis accounted for the season of arrival, sex, and weight class. PMID- 23363359 TI - Precision and accuracy of clinical illness scores, compared with pulmonary consolidation scores, in Holstein calves with experimentally induced Mycoplasma bovis pneumonia. AB - OBJECTIVE: To determine the precision of a clinical illness score (CIS) system for identification of clinical signs in calves with experimentally induced Mycoplasma bovis pneumonia and to evaluate the accuracy of CISs in relation to pulmonary consolidation scores assigned at necropsy. ANIMALS: 178 Holstein bull calves that were 52 to 91 days of age at the time of pneumonia induction. PROCEDURES: 5 trials involved calves challenged with M bovis and scheduled for euthanasia and necropsy 12 to 24 days afterward. Nine veterinarian observers with various degrees of experience simultaneously assigned CISs to calves within 48 hours before necropsy. The precision of the CIS system among observers was evaluated via the Cohen kappa statistic. The accuracy of each observer's CISs relative to 6 cutoffs (>= 5%, >= 10%, >= 15%, >= 20%, >= 25%, and >= 30%) of percentage pulmonary consolidation was determined by comparing prenecropsy CISs with the gross pulmonary consolidation scores assigned at necropsy. Estimates for sensitivity and specificity were calculated relative to the 6 pulmonary consolidation cutoffs. RESULTS: A slight level of agreement was evident among observers (kappa range, 0.10 to 0.21 for the individual trials) and overall (kappa = 0.16; 95% confidence interval, 0.10 to 0.24). Median sensitivity and specificity changed with pulmonary consolidation score cutoff. Median sensitivity for all observers ranged from 81.7% to 98.9%, and median specificity ranged from 80.8% to 94.9% over all cutoff values. CONCLUSIONS AND CLINICAL RELEVANCE: Agreement among observers assigning CISs to calves was low; the accuracy of the CIS system in relation to that of pulmonary consolidation scoring varied with the severity of consolidation considered to represent bovine respiratory disease. PMID- 23363360 TI - Evaluation of the efficacy and safety of single administration of 4.7-mg deslorelin acetate implants on egg production and plasma sex hormones in Japanese quail (Coturnix coturnix japonica). AB - OBJECTIVE: To evaluate the effects of 4.7-mg deslorelin acetate implants on egg production and plasma concentrations of 17beta-estradiol and androstenedione in Japanese quail (Coturnix coturnix japonica) over 180 days and assess safety of the implants in quail via gross and histologic examination. ANIMALS: 20 female Japanese quail. PROCEDURES: Following a 7-day period of consistent egg laying, quail were anesthetized and received a 4.7-mg deslorelin implant (treatment group; n = 10) or identical placebo implant (control group; 10) SC between the scapulae. Egg production was monitored daily. Plasma concentrations of 17beta estradiol and androstenedione were measured on days 0 (immediately prior to implant injection), 14, 29, 62, 90, 120, 150, and 180 via radioimmunoassay. Birds were weighed periodically and euthanized at day 180 for complete necropsy. RESULTS: Egg production was significantly decreased in the treatment group, compared with the control group, from 2 to 12 weeks after implant injection. Egg production ceased in 6 of 10 quail in the treatment group (mean duration of cessation, 70 days). Plasma androstenedione and 17beta -estradiol concentrations were significantly lower on day 29 in the treatment group than in the control group. On day 180, 17beta -estradiol concentration was lower in control than in treated birds.No clinically relevant lesions were detected in either group at necropsy [corrected]. CONCLUSIONS AND CLINICAL RELEVANCE: 4.7-mg deslorelin acetate implants reversibly decreased egg laying for approximately 70 days in most of the Japanese quail evaluated. Further studies evaluating implants containing different concentrations of the drug are needed in quail and other avian species. PMID- 23363361 TI - Effect of unfocused extracorporeal shock wave therapy on growth factor gene expression in wounds and intact skin of horses. AB - OBJECTIVE: To compare the effect of extracorporeal shock wave therapy (ESWT) on expression of fibroblast growth factor-7 (FGF-7), transforming growth factor beta1 (TGF-beta1), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-A (PDGF), and vascular endothelial growth factor-A (VEGF) in skin with surgically created skin wounds and intact skin in horses. ANIMALS: 14 healthy horses. PROCEDURE: 8 horses were treated with ESWT at 6 locations along the neck at 36, 24, 12, 6, 2, or 1 hour prior to collection of full-thickness biopsy specimens from each location; a control specimen was collected from a sham treated location. In 6 horses, 5 full-thickness wounds were created in each forelimb. Wounds in 1 forelimb/horse received ESWT immediately after creation and subsequently on days 7, 14, and 21; wounds in the contralateral forelimb remained untreated. Biopsy specimens were collected from 1 wound on each forelimb on days 7, 14, 21, 28, and 35. Expression levels of FGF-7, TGF-beta1, IGF-1, PDGF, and VEGF were assessed in tissue samples from the horses' necks and forelimbs. RESULTS: In surgically created wounds, ESWT treatment was associated with reduced TGF-beta1 expression, compared with expression in control wounds, during the entire study period. At 28 days following wound creation, IGF-1 expression was significantly increased for treated and untreated wounds, compared with findings on days 7, 14, 21, and 35. There was no significant effect of treatment on FGF-7, TGF-beta1, IGF-1, PDGF, or VEGF expression in intact skin. CONCLUSIONS AND CLINICAL RELEVANCE: Intervention with ESWT to suppress TGF-beta1 may decrease granulation tissue production, resulting in improved wound healing on the distal portion of horses' limbs. PMID- 23363362 TI - Evaluation of mass spectrometry of urinary proteins and peptides as biomarkers for cats at risk of developing azotemia. AB - OBJECTIVE: To evaluate proteomic delineation of feline urine by mass spectrometry as a method for identifying biomarkers in cats at risk of developing azotemia. SAMPLES: Urine samples from geriatric cats (> 9 years old) with chronic kidney disease and nonazotemic cats that either remained nonazotemic (n = 10) or developed azotemia (10) within 1 year. PROCEDURES: Optimization studies with pooled urine were performed to facilitate the use of surface enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF-MS) for analysis of the urinary proteome of cats. Urine samples from nonazotemic cats at entry to the study were analyzed via SELDI-TOF-MS with weak cation exchange and strong anion exchange arrays. Spectral data were compared to identify biomarkers for development of azotemia. RESULTS: Low protein concentration in feline urine precluded direct application to array surfaces, and a buffer exchange and concentration step was required prior to SELDI-TOF-MS analysis. Three preparation conditions by use of weak cation and strong anion exchange arrays were selected on the basis of optimization studies for detection of biomarkers. Eight potential biomarkers with an m/z of 2,822, 9,886, 10,033, 10,151, 10,234, 11,653, 4,421, and 9,505 were delineated. CONCLUSIONS AND CLINICAL RELEVANCE: SELDI-TOF-MS can be used to detect urinary low-molecular weight peptides and proteins that may represent biomarkers for early detection of renal damage. Further study is required to purify and identify potential biomarkers before their use in a clinical setting. PMID- 23363363 TI - Effect of calf age and administration route of initial multivalent modified-live virus vaccine on humoral and cell-mediated immune responses following subsequent administration of a booster vaccination at weaning in beef calves. AB - OBJECTIVE: To compare immune responses following modified-live virus (MLV) vaccination at weaning after intranasal or SC administration of an MLV vaccine to beef calves at 2 or 70 days of age. ANIMALS: 184 calves. PROCEDURES: Calves were allocated to 1 of 5 groups. The IN2 (n = 37) and IN70 (37) groups received an MLV vaccine containing bovine herpesvirus 1 (BHV1), bovine viral diarrhea virus (BVDV) types 1 and 2, bovine respiratory syncytial virus (BRSV), and parainfluenza 3 virus intranasally and a Mannheimia haemolytica and Pasteurella multocida bacterin SC at median ages of 2 and 70 days, respectively. The SC2 (n = 36) and SC70 (37) groups received a 7-way MLV vaccine containing BHV1, BVDV1, BVDV2, BRSV, parainfluenza 3 virus, M haemolytica, and P multocida SC at median ages of 2 and 70 days, respectively; the control group (37) remained unvaccinated until weaning. All calves received the 7-way MLV vaccine SC at median ages of 217 (weaning) and 231 days. Serum neutralizing antibody (SNA) titers against BHV1, BVDV1, and BRSV and intranasal IgA concentrations were determined at median ages of 2, 70, 140, 217, and 262 days. Cell-mediated immunity (CMI) against BHV1, BRSV, BVDV1, and P multocida was determined for 16 calves/group. RESULTS: At median ages of 140 and 217 days, BVDV1 SNA titers were significantly higher for the SC70 group than those for the other groups. Intranasal IgA concentrations and CMI increased over time for all groups. Vaccination at weaning increased SNA titers and CMI in all groups. CONCLUSIONS AND CLINICAL RELEVANCE: SC administration of an MLV vaccine to 70-day-old calves significantly increased BVDV1 antibody titers before weaning. PMID- 23363364 TI - Prior use of immunomodulatory drugs improves the clinical outcome of endoscopic balloon dilation for intestinal stricture in patients with Crohn's disease. AB - BACKGROUND: Endoscopic balloon dilation is a promising procedure to improve symptoms of intestinal stricture in patients with Crohn's disease (CD). However, the long-term efficacy of endoscopic balloon dilation combined with immunomodulatory drugs remains unclear. The aim of the present study is to investigate whether prior use of immunomodulatory drugs affects the clinical outcome of endoscopic balloon dilation for intestinal stricture in CD. PATIENTS AND METHODS: Between January 2004 and December 2011, 83 dilations were carried out in 25 patients with CD. Median follow-up period was 46 months. Patients were categorized into two groups based on their medications at the first endoscopic balloon dilation: early immunomodulatory drug-induction group (early IM-induction group) in which patients were already treated with immunomodulatory drugs before the dilation; and post-immunomodulatory drug-induction group (post-IM-induction group) in which patients were not yet treated withimmunomodulatory drugs before dilation. We compared the long-term cumulative non-surgical rate and the mean number of dilation procedures per patient between early and post-IM-induction groups to clarify the influence of prior use of immunomodulatory drugs on the clinical outcome of endoscopic balloon dilation. RESULTS: There was a significant difference in the mean number of dilation procedures per patient between the early IM-induction and post-IM-induction groups (P = 0.04), although no significant difference in the cumulative non-surgical rate was observed between the two groups (P = 0.14). CONCLUSION: Prior use of immunomodulatory drugs may improve the clinical outcome of endoscopic balloon dilation for intestinal stricture in CD. PMID- 23363365 TI - Templated nanocrystal assembly on biodynamic artificial microtubule asters. AB - Microtubules (MTs) and the MT-associated proteins (MAPs) are critical cooperative agents involved in complex nanoassembly processes in biological systems. These biological materials and processes serve as important inspiration in developing new strategies for the assembly of synthetic nanomaterials in emerging techologies. Here, we explore a dynamic biofabrication process, modeled after the form and function of natural aster-like MT assemblies such as centrosomes. Specifically, we exploit the cooperative assembly of MTs and MAPs to form artificial microtubule asters and demonstrate that (1) these three-dimensional biomimetic microtubule asters can be controllably, reversibly assembled and (2) they serve as unique, dynamic biotemplates for the organization of secondary nanomaterials. We describe the MAP-mediated assembly and growth of functionalized MTs onto synthetic particles, the dynamic character of the assembled asters, and the application of these structures as templates for three-dimensional nanocrystal organization across multiple length scales. This biomediated nanomaterials assembly strategy illuminates a promising new pathway toward next generation nanocomposite development. PMID- 23363366 TI - Facile preparation route toward speckled colloids via seeded polymerization. AB - A facile method to prepare monodisperse speckled colloids has been developed via one-step seeded polymerization from noncross-linked latex particles. It was found that both cross-linking agents in the added monomer mixture and charged initiation species are essential for the formation of speckles on composite latex particle surface in seeded polymerization. The size and number density of speckles on the surface are tunable by adjusting the concentration of surfactant. A possible mechanism for the formation of such speckled colloids has been proposed based on a series of control experiments. Speckled colloidal particles were used as substrates for the adsorption of tobacco mosaic virus, and a much stronger adsorption was observed compared to smooth particles, implying a potential application of these speckled particles in virus collection and more. PMID- 23363368 TI - DEAD-box proteins, like Leishmania eIF4A, modulate interleukin (IL)-12, IL-10 and tumour necrosis factor-alpha production by human monocytes. AB - Previously we showed that His-tagged, recombinant, Leishmania infantum eukaryotic initiation factor (LeIF) was both an RNA-dependent ATPase and an ATP-dependent RNA helicase in vitro, as described for other members of the DEAD-box helicase family. In addition, we showed that LeIF induces the production of IL-12, IL-10, and TNF-alpha by human monocytes. This study aims to characterize the cytokine inducing activity in human monocytes of several proteins belonging to the DEAD box family from mammals and yeast. All tested proteins contained the 11 conserved motifs (Q, I, Ia, GG Ib, II, III, IV, QxxR, V and VI) characteristic of DEAD-box proteins, but they have different biological functions and different percentages of identities with LeIF. We show that these mammalian or yeast recombinant proteins also are able to induce IL-12, IL-10 and TNF-alpha secretion by monocytes of healthy human subjects. This cytokine-inducing activity is proteinase K sensitive and polymyxin B resistant. Our results show that the induction of cytokines in human monocytes is not unique to the protein LeIF of Leishmania, and it suggests that the activity of certain DEAD-box proteins can be exploited as adjuvant and/or to direct immune responses towards a Th1 profile in vaccination or immunotherapy protocols. PMID- 23363369 TI - Comparative assessment of deferiprone and deferasirox in thalassemia major patients in the first two decades-single centre experience. AB - Iron overload is mainly responsible for the morbidity and mortality in patients with beta thalassemia major (TM). Our aim was to compare treatment outcomes with oral iron chelators, deferiprone (DFP), and deferasirox (DFX) in the first two decades on therapy. Seventy patients with TM (mean age +/- SD, 7.9 +/- 4.2; range 1.5-17 years) attending the pediatric day care unit for regular transfusional support were enrolled in this cross-sectional cohort study. The patients were treated either with DFP at the dose of 75-100 mg/kg/d in three divided doses after food or DFX at the dose of 25-40 mg/kg/d as single dose before food. Mean serum ferritin (+/-SD) was lower in patients below 10 years (n = 44) at 1283 (+/ 600) ng/mL when compared with patients >=10 years (n = 19) at 1546 (+/-589) ng/mL. There was no significant difference in mean serum ferritin (+/-SD) level in patients receiving DFP (1360 +/- 589) versus DFX (1260 +/- 641) in this cohort, P > 0.05. 67% of the patients had Vitamin D deficiency (<50 umol/L). Our results show comparable efficacy of DFP and DFX with regards to iron chelation as estimated by serial serum ferritin levels; however, MRI T2* values were higher in the DFP-treated patients compared to DFX treatment. PMID- 23363371 TI - An investigation of the impact of regular use of the Wii Fit to improve motor and psychosocial outcomes in children with movement difficulties: a pilot study. AB - BACKGROUND: Children with Developmental Co-ordination Disorder (DCD) experience poor motor and psychosocial outcomes. Interventions are often limited within the healthcare system, and little is known about how technology might be used within schools or homes to promote the motor skills and/or psychosocial development of these children. This study aimed to evaluate whether short, regular school-based sessions of movement experience using a commercially available home video game console (Nintendo's Wii Fit) would lead to benefits in both motor and psychosocial domains in children with DCD. METHODS: A randomized crossover controlled trial of children with movement difficulties/DCD was conducted. Children were randomly assigned to an intervention (n = 10) or comparison (n = 8) group. The intervention group spent 10 min thrice weekly for 1 month using Wii Fit during the lunch break, while the comparison group took part in their regular Jump Ahead programme. Pre- and post-intervention assessments considered motor proficiency, self-perceived ability and satisfaction and parental assessment of emotional and behavioural problems. RESULTS: Significant gains were seen in motor proficiency, the child's perception of his/her motor ability and reported emotional well-being for many, but not all children. CONCLUSIONS: This study provides preliminary evidence to support the use of the Wii Fit within therapeutic programmes for children with movement difficulties. This simple, popular intervention represents a plausible method to support children's motor and psychosocial development. It is not possible from our data to say which children are most likely to benefit from such a programme and particularly what the dose and duration should be. Further research is required to inform across these and other questions regarding the implementation of virtual reality technologies in therapeutic services for children with movement difficulties. PMID- 23363370 TI - Differentiation of human embryonic stem cells using size-controlled embryoid bodies and negative cell selection in the production of photoreceptor precursor cells. AB - We proposed to optimize the retinal differentiation protocols for human embryonic stem cells (hESCs) by improving cell handling. To improve efficiency, we first focused on the production of just one retinal precursor cell type (photoreceptor precursor cells [PPCs]) rather than the production of a range of retinal cells. Combining information from a number of previous studies, in particular the use of a feeder-free culture medium and taurine plus triiodothyronine supplements, we then assessed the values of using size-controlled embryoid bodies (EBs) and negative cell selection (to remove residual embryonic antigen-4-positive hESCs). Using size-controlled 1000 cell EBs, significant improvements were made, in that 78% CRX+ve PPCs could be produced in just 17 days. This could be increased to 93% PPCs through the added step of negative cell selection. Improved efficiency of PPC production will help in efforts to undertake shorter and larger preclinical studies as a prelude to future clinical trials. PMID- 23363372 TI - Comparison and contrast of genes and biological pathways responding to Marek's disease virus infection using allele-specific expression and differential expression in broiler and layer chickens. AB - BACKGROUND: Marek's disease (MD) is a commercially important neoplastic disease of chickens caused by the Marek's disease virus (MDV), a naturally occurring oncogenic alphaherpesvirus. Enhancing MD genetic resistance is desirable to augment current vaccines and other MD control measures. High throughput sequencing was used to profile splenic transcriptomes from individual F1 progeny infected with MDV at 4 days of age from both outbred broilers (meat-type) and inbred layer (egg-type) chicken lines that differed in MD genetic resistance. The resulting information was used to identify SNPs, genes, and biological pathways exhibiting allele-specific expression (ASE) in response to MDV infection in each type of chicken. In addition, we compared and contrasted the results of pathway analyses (ASE and differential expression (DE)) between chicken types to help inform on the biological response to MDV infection. RESULTS: With 7 individuals per line and treatment group providing high power, we identified 6,132 single nucleotide polymorphisms (SNPs) in 4,768 genes and 4,528 SNPs in 3,718 genes in broilers and layers, respectively, that exhibited ASE in response to MDV infection. Furthermore, 548 and 434 genes in broilers and layers, respectively, were found to show DE following MDV infection. Comparing the datasets, only 72 SNPs and 850 genes for ASE and 20 genes for DE were common between the two bird types. Although the chicken types used in this study were genetically different, at the pathway level, both TLR receptor and JAK/STAT signaling pathways were enriched as well as exhibiting a high proportion of ASE genes, especially at the beginning of both above mentioned regulatory pathways. CONCLUSIONS: RNA sequencing with adequate biological replicates is a powerful approach to identify high confidence SNPs, genes, and pathways that are associated with transcriptional response to MDV infection. In addition, the SNPs exhibiting ASE in response to MDV infection provide a strong foundation for determining the extent to which variation in expression influences MD incidence plus yield genetic markers for genomic selection. However, given the paucity of overlap among ASE SNP sets (broilers vs. layers), it is likely that separate screens need to be incorporated for each population. Finally, comparison of gene lists obtained between these two diverse chicken types indicate the TLR and JAK/STAT signaling are conserved when responding to MDV infection and may be altered by selection of genes exhibiting ASE found at the start of each pathway. PMID- 23363373 TI - The effect of galactagogue herbal tea on oxidant and anti-oxidant status of human milk. AB - OBJECTIVE: Human milk (HM) has antioxidant constituents which protect newborns against oxidative damage. We aimed to evaluate whether maternal consumption of herbal tea containing fenugreek had any effects on global oxidant and antioxidant capacity of HM. METHODS: Volunteer mothers 18-35 years of age without any antenatal or perinatal risk factors were randomly assigned to receive galactagogue herbal tea (Humana still-tee(r), Herford, Deutschland) 3 cups/d or same amount of water as placebo. The total antioxidant capacity (TAC), total oxidant status (TOS) and the oxidative stress index (OSI) of breast milk samples taken in the 1st day and 7-10 d were compared between groups. RESULTS: Herbal tea (n = 40) and placebo (n = 40) groups had similar TAC, TOS and OSI values in the 1st day samples. TAC, TOS and OSI values in the breast milk samples taken on 7 10th day were also similar. OSI increased significantly in 7-10 day samples compared to 1st day in each group, while TAC and TOS levels did not differ. CONCLUSION: Galactagogue herbal tea containing fenugreek has no detectable effect on global oxidant and antioxidant status of HM. OSI increases in course of lactation compared to colostrums irrespective of galactagogue use. PMID- 23363374 TI - Detailed kinetics and mechanism of the oxidation of thiocyanate ion (SCN-) by peroxomonosulfate ion (HSO5(-)). Formation and subsequent oxidation of hypothiocyanite ion (OSCN-). AB - The haloperoxidase-catalyzed in vivo oxidation of thiocyanate ion (SCN(-)) by H(2)O(2) is important for generation of the antimicrobial hypothiocyanite ion (OSCN(-)), which is also susceptible to oxidation by strong in vivo oxidizing agents (i.e., H(2)O(2), OCl(-), OBr(-)). We report a detailed mechanistic investigation on the multistep oxidation of excess SCN(-) with peroxomonosulfate ion (HSO(5)(-) in the form of Oxone) in the range from pH 6.5 to 13.5. OSCN(-) was detected to be the intermediate of this reaction under the above conditions, and a kinetic model is proposed. Furthermore, by kinetic separation of the consecutive reaction steps, the rate constant of the direct oxidation of OSCN(-) by HSO(5)(-) was determined: k(2) = (1.6 +/- 0.1) * 10(2) M(-1) s(-1) at pH 13.5 and k(2)(H) = (3.3 +/- 0.1) * 10(3) M(-1) s(-1) at pH 6.89. A critical evaluation of the estimated activation parameters of the elementary steps revealed that the oxidations of SCN(-) as well as the consecutive OSCN(-) by HSO(5)(-) are more likely to proceed via 2e(-)-transfer steps rather than 1e(-) transfer. PMID- 23363375 TI - Variation of Kondo peak observed in the assembly of heteroleptic 2,3 naphthalocyaninato phthalocyaninato Tb(III) double-decker complex on Au(111). AB - By using scanning tunneling microscopy (STM), we studied the heteroleptic double decker complex TbNPcPc (NPc = naphthalocyaninato and Pc = phthalocyaninato), where two different planar ligands sandwich a Tb(III) ion and an unpaired pi electron causes Kondo resonance upon adsorption on the Au(111) surface. Kondo resonance is a good conductance control mechanism originating from interactions between conduction electrons and a localized spin. Two types of adsorption geometries appear depending on which side contacts the substrate surface, which we call Pc-up and NPc-up molecules. They make intriguing molecular assemblies by segregation. In addition, different adsorption geometries and molecular assemblies provide a variety of spin and electronic configurations. Pc-up and NPc up molecules both showed the Kondo resonance when they were isolated from other molecules, but their Kondo temperatures were different. A one-dimensional chain composed of only NPc-up molecules was found, in which the dI/dV plot showed a conversion from the Kondo peak to a dip at the Fermi energy. In addition, a two dimensional lattice with an ordering of Pc-up and NPc-up molecules in an alternative manner was observed, in which no Kondo peak was detected in the molecule. The absence of the Kondo peak was accounted for by the change of azimuthal rotational angle of the two ligands of both molecules. The results imply that a molecule design and adsorption configuration tailoring can be used for the spin-mediated control of the electronic conductance of the molecule. PMID- 23363376 TI - Serum insulin-like growth factor 1 and facial ageing: high levels associate with reduced skin wrinkling in a cross-sectional study. AB - BACKGROUND: Insulin-like growth factor (IGF)-1 is a growth factor that can influence fibroblast functioning, with effects including the inhibition of collagenases and the induction of collagen expression. OBJECTIVES: To assess whether serum IGF-1, IGF-binding protein (IGFBP)3 and the ratio between IGF-1 and IGFBP3, as a measure of IGF-1 bioavailability, are associated with facial ageing and skin wrinkling. METHODS: From a random sample comprising 617 subjects from the Leiden Longevity Study, perceived age and skin wrinkling were assessed from facial photographs, and IGF-1 and IGFBP3 were measured in serum. The associations were assessed using linear regression models, adjusted for chronological age, sex, body mass index, smoking and sun exposure. RESULTS: Across tertiles of the ratio of IGF-1 to IGFBP3, and after adjusting for all potential confounding factors, the mean perceived age decreased from 60.6 years in the lowest tertile to 59.5 years in the highest (P = 0.045). Similarly, the mean skin wrinkling grade decreased from 4.8 in the lowest tertile to 4.5 in the highest (P = 0.011). Adding skin wrinkling as a covariate in the analysis between IGF-1 and perceived age diminished this association. CONCLUSIONS: This study demonstrates that a higher ratio of IGF-1 to IGFBP3 associates with a lower perceived age, via its association with reduced skin wrinkling. Whether high IGF-1 levels actually delay the accumulation of skin wrinkling now needs investigating. PMID- 23363377 TI - Genistein, a natural product derived from soybeans, ameliorates polyglutamine mediated motor neuron disease. AB - Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem, and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. AR associated coregulator 70 (ARA70) was the first coregulator of AR to be identified, and it has been shown to interact with AR and increase its protein stability. Here, we report that genistein, an isoflavone found in soy, disrupts the interaction between AR and ARA70 and promotes the degradation of mutant AR in neuronal cells and transgenic mouse models of SBMA. We also demonstrate that dietary genistein ameliorates behavioral abnormalities, improves spinal cord and muscle pathology, and decreases the amounts of monomeric AR and high-molecular weight mutant AR protein aggregates in SBMA transgenic mice. Thus, genistein treatment may be a potential therapeutic approach for alleviating the symptoms of SBMA by disrupting the interactions between AR and ARA70. PMID- 23363378 TI - Examination of the predictive validity of the Dynamic Appraisal of Situational Aggression in two mental health units. AB - Empirically derived structured violence risk assessment instruments are increasingly used by nurses in forensic mental health settings, typically demonstrating stronger predictive validity than unaided clinical risk assessments, and associated with reduced aggression and reduced restrictive practices including seclusion. However, these instruments are less often used in non-forensic mental health settings despite frequent aggression in these settings. This study represents the first test of the Dynamic Appraisal of Situational Aggression (DASA-IV), a structured instrument used to appraise risk for imminent aggression in a non-forensic mental health hospital. Predictive validity of DASA-IV, and unaided clinical and structured clinical judgements made after DASA-IV assessments were compared. Participants included 105 nurses at two mental health inpatient units in rural Victoria, Australia. During the study, 482 DASA-IV assessments and structured clinical judgements were compared with 997 unaided clinical risk judgements. DASA-IV total scores predicted aggression significantly better than unaided clinical risk ratings over the subsequent 24 hours and for the next shift. Nurses' structured clinical judgement ratings were more accurate than unaided clinical appraisals but less accurate than actuarial (DASA-IV derived) scores. The DASA-IV presents as a valid measure for appraising risk of imminent aggression in mainstream mental health inpatient settings. PMID- 23363379 TI - Characterization of extended spectrum beta-lactamase-producing Escherichia coli in community-acquired urinary tract infections in Tunisia. AB - This study was conducted to investigate the molecular epidemiology of extended spectrum beta-lactamase (ESBL)-producing Escherichia coli in community-acquired (urinary tract) infections (CA-UTI) in Tunisia. Between January 2007 and December 2009, 15 E. coli isolates were collected at the laboratory of microbiology of Charles Nicolle Hospital of Tunis. Microbial identification was done with conventional methods. Antibiotic susceptibility was determined by disk diffusion method and ESBL detection was done with double-disk synergy test. ESBL typing was performed by polymerase chain reaction (PCR) and sequencing. Phylogenetic groups, virulence factors, and sequence type (ST)131 were determined by PCR. Genetic relatedness between strains was examined by pulsed-field gel electrophoresis (PFGE) after restriction with XbaI. The prevalence of ESBL-producing E. coli in CA-UTI was 0.046%. The majority of isolates were multidrug resistant. ESBL types were CTX-M-15 (n=13) and SHV-12 (n=2). The most common phylogenetic group was B2 (n=11) and virulence score was greater than or equal to 9 in nine strains. PFGE revealed 12 clusters. The majority of isolates (n=14) belonged to ST131 clone and 11 of them were CTX-M producers. In conclusion, this is the first detailed documentation of CA-ESBLs producing E. coli in Tunisia. Of particular concern is the emergence in our community of the highly diffusing CTX-M-15-B2-ST131 E. coli clone, which requires strengthening surveillance measures to countervail this emergent public health problem. PMID- 23363380 TI - Microbiologic and cytologic assessment of bronchoalveolar lavage fluid from dogs with lower respiratory tract infection: 105 cases (2001-2011). AB - BACKGROUND: Documentation of lower respiratory tract infection has relied on microbiologic and cytologic findings in airway fluid, but there is no gold standard for making a definitive diagnosis. OBJECTIVE: To report cytologic and microbiologic findings in dogs diagnosed with lower respiratory tract infection through evaluation by bronchoscopy and bronchoalveolar lavage. ANIMALS: A total of 105 dogs with spontaneous respiratory disease. METHODS: Retrospective case review of all dogs identified through the electronic medical record database that had bronchoscopy with bronchoalveolar lavage performed between 2001 and 2011. Results of bronchoalveolar lavage cytology and microbiology were evaluated in 510 dogs, and 105 cases with septic, suppurative inflammation or bacterial growth from cultures were examined further. RESULTS: Bacteria were isolated from 89/105 aerobic cultures, 18/104 anaerobic cultures, and 30/99 Mycoplasma spp. cultures. The most common isolate was Mycoplasma spp. followed by Pasteurella sp., Bordetella sp, Enterobacteriaceae, and anaerobes. A single bacterial species was cultured from 44/99 dogs (44%) and multiple bacterial species were isolated from 55/99 dogs (56%). Suppurative inflammation with intracellular bacteria was identified cytologically in 78 of 105 dogs (74%). In 27 dogs that lacked cytologic evidence of sepsis, mixed (n = 18) and neutrophilic (n = 9) inflammation was reported, and Mycoplasma spp. (13/27) or Bordetella spp. (7/27) were most commonly isolated. Most aerobic bacteria were susceptible to routinely used antimicrobial drugs. CONCLUSIONS AND CLINICAL IMPORTANCE: Confirmation of lower respiratory tract infection in dogs is challenging and organisms can be isolated from dogs in which bacteria are not detected on cytologic examination. PMID- 23363381 TI - Relation between bile acid reflux into the stomach and the risk of atrophic gastritis and intestinal metaplasia: a multicenter study of 2283 cases. AB - BACKGROUND: The relationship between bile acid reflux into the stomach and the risk of atrophic gastritis and intestinal metaplasia is still not well understood. Towards obtaining a better understanding, concentrations of bile acids were measured. PATIENTS AND METHODS: This study was carried out with the participation of 14 facilities in Japan, and 2283 samples were collected. The subjects with bile acid concentrations equal to or higher than the limit of detection were divided into four groups of equal size (group A: 0-25%, group B: 26-50%, group C: 51-75%, and group D: 76-100%). Thus, including the control group, there were five groups in total. The odds that the control group would develop atrophic gastritis and intestinal metaplasia was set as 1,and the odds ratios (OR) in groups A, B, C and D were calculated based on the odds in the control group. RESULTS: Regarding the development of atrophic gastritis, no increased risk was observed in either the Helicobacter pylori (H. pylori) positive or -negative cases. The OR for the development of intestinal metaplasia were significantly higher, for both cases with and without H. pylori infection, in group D. CONCLUSION: High concentrations of bile acid seem to be associated with an elevated risk of intestinal metaplasia. PMID- 23363382 TI - On the cellular and molecular regulatory transcriptional mechanisms and responsive putative pathways to inflammatory oxidative stress revisited: current immunological breakthroughs and views at a glance. AB - Responses to oxidative stress are generally regulated by redox-responsive transcription factors (TFs). The abrupt variation in the partial pressure of oxygen (pO2) constitutes a regulatory mechanism. Such TFs forming an integral part of those putative pathways are hypoxia-inducible factor-1alpha(HIF) 1alphaand nuclear factor-kappaB (NF-kappaB), both are sufficiently tuned to govern such a specific response. Reactive species are produced during this transition and the antioxidant defense system controls their production. Oxidative stress occurs when there is imbalance between the production and removal of reactive species. Evidence exists showing that enhancement of the antioxidant defense system can reduce markers of oxidative stress. Recognition of reactive species and redox-mediated modifications as signals may open up a field of cell regulation via targeted control of TFs and hence can providea novel way of controlling diseases. This synopsis summates the major cutting-edge research work in the field of oxidative stress, and surgically identifies common and unique pathways involved with oxidative stress as means of regulatory elements governing TFs. PMID- 23363384 TI - The biology of hair diversity. AB - Hair diversity, its style, colour, shape and growth pattern is one of our most defining characteristics. The natural versus temporary style is influenced by what happens to our hair during our lifetime, such as genetic hair loss, sudden hair shedding, greying and pathological hair loss in the various forms of alopecia because of genetics, illness or medication. Despite the size and global value of the hair care market, our knowledge of what controls the innate and within-lifetime characteristics of hair diversity remains poorly understood. In the last decade, drivers of knowledge have moved into the arena of genetics where hair traits are obvious and measurable and genetic polymorphisms are being found that raise valuable questions about the biology of hair growth. The recent discovery that the gene for trichohyalin contributes to hair shape comes as no surprise to the hair biologists who have believed for 100 years that hair shape is linked to the structure and function of the inner root sheath. Further conundrums awaiting elucidation include the polymorphisms in the androgen receptor (AR) described in male pattern alopecia whose location on the X chromosome places this genetic contributor into the female line. The genetics of female hair loss is less clear with polymorphisms in the AR not associated with female pattern hair loss. Lifestyle choices are also implicated in hair diversity. Greying, which also has a strong genetic component, is often suggested to have a lifestyle (stress) influence and hair follicle melanocytes show declining antioxidant protection with age and lowered resistance to stress. It is likely that hair research will undergo a renaissance on the back of the rising information from genetic studies as well as the latest contributions from the field of epigenetics. PMID- 23363385 TI - Infusion of Life: patient perceptions of expressive therapy during chemotherapy sessions. AB - Through a quanti-qualitative study, we observed the effects of group expressive therapy (ET) sessions on patients' feelings and sense of well-being, as part of the Infusion of Life project. This project is part of a broader programme to improve integral care, developed by an interdisciplinary team headed by a medical doctor who is also an artist and expert in ET. We offered 48 group ET sessions to a total of 253 outpatients with cancer or autoimmune disorders receiving venous infusions in the chemotherapy room of University Hospital Antonio Pedro, Rio de Janeiro, Brazil. The qualitative analysis showed that the programme was a pleasant way to spend time, revived their sense of humour, relieved symptoms, provided meaningful experiences, improved their relationships with staff, enabled expression of their feelings, stimulated them to be creative, improved coping resources and reorganisation of the psyche, and renewed their perspective on life. Family and spirituality were major sources of support. Expressive therapy was shown to be flexible and applicable in small spaces, using recycled materials, even with patients with restrained movements; it can also offer great benefits with relatively small investments if a qualified team is in charge of planning, executing, and auditing the work. PMID- 23363386 TI - Serum thyrotropin levels following levothyroxine administration at breakfast. AB - BACKGROUND: Hypothyroidism is treated with oral levothyroxine. Some patients fail to attain adequate control because of poor compliance. Delaying breakfast to take levothyroxine on an empty stomach can decrease adherence to hypothyroidism treatment. The objective of this study was to evaluate whether administering levothyroxine with breakfast can maintain thyrotropin (TSH) levels in the therapeutic range, without major clinical changes. METHODS: A prospective, randomized, open-label, crossover study was conducted to compare usual levothyroxine administration while in a fasting state with administration during breakfast. From September 2008 to April 2009, 45 patients with primary hypothyroidism who received levothyroxine were recruited. The patients completed 180 days of the protocol and were randomized to 90 days of each levothyroxine administration regimen (while fasting or with breakfast). Clinical and biochemical analyses were performed at baseline and on days 45, 90, 135, and 180. The primary outcome was TSH level. RESULTS: Forty-two patients completed the protocol. The TSH level was higher for levothyroxine administration with breakfast than while fasting (2.89 vs. 1.9 mIU/L, p=0.028). Uncontrolled hypothyroidism (TSH >=3.5 mIU/L) occurred regardless of the type of levothyroxine administration (p=0.26). No risk factors were identified for TSH elevation. CONCLUSIONS: Levothyroxine administration with breakfast could be an alternative regimen for patients who have adherence difficulties due to the need for delaying intake, and is more likely to cause variability in the TSH level, meaning the patient should be followed more closely. For patients in whom a specific serum TSH goal is important, taking levothyroxine while fasting is recommended. PMID- 23363383 TI - Pharmacotherapy of Zollinger-Ellison syndrome. AB - INTRODUCTION: The role of pharmacotherapy in the management of patients with Zollinger-Ellison syndrome (ZES) is often equated with the medical management of acid hypersecretion. However, pharmacotherapy is also increasingly involved in the other management areas of these patients. AREAS COVERED: This paper reviews the role of pharmacotherapy in all aspects of the management of patients with ZES. Newer aspects are emphasized. This includes the difficulty of diagnosing ZES in patients taking proton pump inhibitors. Also covered is the role of pharmacotherapy in controlling acid hypersecretion and other hormonal hypersecretory states these patients may develop, including hyperparathyroidism in patients with multiple endocrine neoplasia type 1 and ZES; tumor localization; and the treatment of advanced metastatic disease. The last includes chemotherapy, liver-directed therapies, biotherapy (somatostatin/interferon), peptide radio receptor therapy and molecular-targeted therapies including the use of mTor inhibitors (everolimus) and tyrosine kinase inhibitors (sunitinib). EXPERT OPINION: Pharmacotherapy is now involved in all aspects of the management of patients with ZES, with the result that ZES has progressed from being considered an entirely surgical disease initially to the present where medical treatment plays a major role in almost all aspects of the management of these patients. PMID- 23363387 TI - Wacker-type oxidation of internal alkenes using Pd(Quinox) and TBHP. AB - The Pd-catalyzed TBHP-mediated Wacker-type oxidation of internal alkenes is reported. The reaction uses 2-(4,5-dihydro-2-oxazolyl)quinoline (Quinox) as ligand and TBHP(aq) as oxidant to deliver single ketone constitutional isomer products in a predictable fashion from electronically biased olefins. This methodology is showcased through its application on an advanced intermediate in the total synthesis of the antimalarial drug artemisinin. PMID- 23363388 TI - Simultaneous single-particle superlocalization and rotational tracking. AB - Superlocalization of single molecules and nanoparticles has become an essential procedure to bring new insights into nanoscale structures and dynamics of biological systems. In the present study, superlocalization is combined with the newly introduced differential interference contrast (DIC) microscopy-based single particle orientation and rotational tracking. The new technique overcomes the difficulty in localization of the antisymmetric DIC point spread function by using a dual-modality microscope configuration for simultaneous rotational tracking and localization of single gold nanorods with nanometer-scale precision. The new imaging setup has been applied to study the steric hindrance induced by relatively large cargos in the microtubule gliding assay and to track nanocargos in the crowded cellular environment. This technique has great potential in the study of biological processes where both localization and rotational information are required. PMID- 23363390 TI - Low-dose mirtazapine added to selective serotonin reuptake inhibitors in pregnant women with major depression or panic disorder including symptoms of severe nausea, insomnia and decreased appetite: three cases. AB - Data on the use of a combination of antidepressants during pregnancy are inadequate. This report presents the beneficial effect of low-dose mirtazapine added onto selective serotonin reuptake inhibitors in the treatment of the symptoms of severe nausea, insomnia and loss of appetite accompanying psychiatric disorders during pregnancy, which is an important problem in clinical practice. The psychiatric diagnoses were determined with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Assessments were performed with the Clinical Global Impression-Improvement Scale and the 17-item Hamilton Rating Scale for Depression. Further studies should be carried out to confirm the positive effects and safety of an additional low-dose mirtazapine in these cases. PMID- 23363389 TI - Differential requirement for Hoxa9 in the development and differentiation of B, NK, and DC-lineage cells from Flt3+ multipotential progenitors. AB - Hoxa9 is a homeodomain transcription factor important for the generation of Flt3+hiIL-7R- lymphoid biased-multipotential progenitors, Flt3+IL-7R+ common lymphoid progenitors (CLPs), and B cell precursors (BCP) in bone marrow (BM). In addition to B-cell, Flt3+IL-7R+ CLPs possess NK and DC developmental potentials, although DCs arise from Flt3+IL-7R- myeloid progenitors as well. In this study, we investigated the requirement for Hoxa9, from Flt3+ or Flt3- progenitor subsets, in the development of NK and DC lineage cells in BM. Flt3+IL-7R+Ly6D- CLPs and their Flt3+IL-7R+Ly6D+ B lineage-restricted progeny (BLP) were significantly reduced in hoxa9-/- mice. Interestingly, the reduction in Flt3+IL 7R+ CLPs in hoxa9-/- mice had no impact on the generation of NK precursor (NKP) subsets, the differentiation of NKP into mature NK cells, or NK homeostasis. Similarly, percentages and numbers of common dendritic progenitors (CDP), as well as their plasmacytoid or conventional dendritic cell progeny in hoxa9-/- mice were comparable to wildtype. These findings reveal distinct requirements for Hoxa9 or Hoxa9/Flt3 molecular circuits in regulation of B versus NK and DC development in BM. PMID- 23363392 TI - 'Everybody just thinks I'm weird': a qualitative exploration of the psychosocial experiences of adolescents with Tourette syndrome. AB - BACKGROUND: Research suggests Tourette syndrome (TS) can have a negative impact on quality of life. To date, little research has examined the perspectives of young people with this condition in depth. METHODS: Six 14- to 16-year-olds with TS took part in semi-structured interviews to explore the perceived impact of this condition on self and on relationships with others. The transcripts were analysed using interpretative phenomenological analysis. RESULTS: The young people felt that TS was a constant presence in their lives, but one they have learnt to cope with well. Most had developed supportive friendships but encountered problems when interacting with the wider peer network. Specific concerns around meeting new people and future employment were voiced. CONCLUSIONS: The adolescents described specific ways in which TS affects quality of life and social interactions, and the effort it can take to cope effectively with this condition. PMID- 23363393 TI - Constructing robust and functional micropatterns on polystyrene surfaces by using deep UV irradiation. AB - We report the preparation of different surface patterns based on the photo-cross linking/degradation kinetics of polystyrene (PS) by using UV light. Upon exposure to UV light, PS can be initially cross-linked, whereas an excess of the exposure time or intensity provokes the degradation of the material. Typically photolithography employs either positive or negative photoresist layers that upon removal of either the exposed or the nonexposed areas transfer the pattern of the mask. Herein, we present a system that can be both negative and positive depending on several aspects, including the irradiation time, intensity, or presence of absorbing active species (photoinitiators) using a general setup. As a result of the optimization of the time of exposure and the use of an appropriate cover or the incorporation of an appropriate amount of photoinitiator (in this particular case IRG 651), different tailor-made surface patterns can be obtained. Moreover, changes of the chemical composition of the polystyrene using, for instance, block copolymers can lead to surface patterns with variable functional groups. In this study we describe the formation of surface patterns using polystyrene-block-poly(2,3,4,5,6-pentafluorostyrene) block copolymers. The introduction of fluorinated moieties clearly modifies the wettability of the films when compared with that of the same structures obtained with PS. As a consequence we present herein a patterning methodology that can simultaneously vary not only the morphology but also the surface chemical composition. PMID- 23363395 TI - Achiral and chiral PNP-pincer ligands with a carbazole backbone: coordination chemistry with d8 transition metals. AB - Two new monoanionic PNP pincer type ligands have been synthesized, the achiral 3,6-di-tert-butyl-1,8-bis((diphenyl-phosphino)methyl)-9H-carbazole CbzdiphosH (5) and the chiral 3,6-di-tert-butyl-1,8-bis(((2R,5R)-2,5-diphenylphospholan-1 yl)methyl)-9H-carbazole CbzdipholH (7), both of which were initially prepared as their borane complexes. The synthesis of CbzdiphosH is based on the reaction between the key intermediate 1,8-bis(bromomethyl)-3,6-di-tert-butyl-9H-carbazole (3) and lithium diphenylphosphide-borane complex. The chiral ligand CbzdipholH was prepared by treating 3 with lithium (2R,5R)-2,5-diphenylphospholanide-borane complex and subsequent deprotection with diethylamine. The complexation of the two ligands with nickel, palladium and rhodium was investigated, for which the conformational behavior of the ligands was found to be different. Although the arrangement of the donor atoms in all crystallographically characterized complexes is approximately square planar, the carbazole plane in Cbzdiphos complexes is inclined relative to the coordination plane. On the other hand, a helical twist is observed in Cbzdiphol complexes. PMID- 23363394 TI - Endoscopic diagnosis of gastric intestinal metaplasia: a prospective multicenter study. AB - BACKGROUND: Intestinal metaplasia (IM) of the gastric mucosa has long attracted attention as a premalignant lesion involved in gastric carcinogenesis. However, endoscopic diagnosis of IM has remained unclear for a long time. In recent years, the methylene blue staining technique and narrow-band imaging (NBI) magnifying endoscopy have facilitated clinical diagnosis of IM, although these methods have some problems due to their complexity. Simple methods for diagnosis of IM using conventional endoscopy and the indigo carmine contrast (IC) method are necessary. PATIENTS AND METHODS: This study was a multicenter, prospective, randomized, comparative study involving 10 facilities. The appearance of IM was examined using conventional and IC methods with an electronic endoscope. RESULTS: Subjects included 163 patients, of whom 87 and 76 underwent conventional and IC methods, respectively. Sensitivity, specificity, and receiver operating characteristic/area under thecurve (ROC/AUC) of conventional and IC methods for the detection of IM in the gastric antrum showed that diagnostic performance of the conventional method was higher, but not significantly, than that of the IC method. Sensitivity, specificity and ROC/AUC of conventional and IC methods for the detection of IM in the gastric body showed that the IC method yielded better (but not significantly better) results than the conventional method. CONCLUSION: The diagnostic performance of the conventional method did not significantly differ from that of the IC method. A villous appearance, whitish mucosa, and rough mucosal surface, as observed by both methods, and areae gastricae pattern, as observed by the IC method, were useful indicators for endoscopic diagnosis of IM. PMID- 23363397 TI - High T(g) bio-based aliphatic polyesters from bicyclic D-mannitol. AB - The carbohydrate-based diol 2,4:3,5-di-O-methylene-d-mannitol (Manx) has been used to obtain aliphatic polyesters. Manx is a symmetric bicyclic compound consisting of two fused 1,3-dioxane rings and bearing two primary hydroxyl groups. In terms of stiffness, it is comparable to the widely known isosorbide, but it affords the additional advantages of being much more reactive in polycondensation and capable of producing stereoregular polymers with fairly high molecular weights. A fully bio-based homopolyester (PManxS) has been synthesized by polycondensation in the melt from dimethyl succinate and Manx. The high thermal stability of PManxS, its relatively high glass transition temperature (Tg = 68 degrees C) and elastic modulus, and its enhanced sensitivity to the action of lipases point to PManxS as a polyester of exceptional interest for those applications where biodegradability and molecular stiffness are priority requirements. In addition, random copolyesters (PBxManxyS) covering a broad range of compositions have been obtained using mixtures of Manx and 1,4-butanediol in the reaction with dimethyl succinate. All PBxManxyS were semicrystalline and displayed Tg values from -29 to +51 degrees C steadily increasing with the content in Manx units. The stress-strain behavior of these copolyesters largely depended on their content in Manx and they were enzymatically degraded faster than PBS. PMID- 23363396 TI - Clinical features of childhood-onset paroxysmal kinesigenic dyskinesia with PRRT2 gene mutations. AB - AIM: To define better the phenotype and genotype of familial and sporadic cases of paroxysmal kinesigenic dyskinesia (PKD) caused by mutations in the PRRT2 gene presenting in the paediatric age group. METHOD: We report the detailed clinical and molecular genetic features of 11 patients (six females, five males) with childhood-onset PRRT2-mutation-positive PKD. RESULTS: Mean age at disease onset was 8 years 7.5 months (range 5-11y), and clinical presentation was characterized by daily short paroxysmal episodes of dystonia/dyskinesia. Most patients also had non-kinesigenic attacks in addition to the classical movement-induced paroxysmal episodes. One family demonstrated great phenotypic variability with PKD, infantile convulsions, and/or hemiplegic migraine affecting different family members with the same mutation. All patients in whom antiepileptics (carbamazepine/phenytoin) were tried showed a dramatic improvement with complete abolition of dyskinetic episodes. INTERPRETATION: Our case series provides a detailed clinical description of patients with PRRT2-PKD, and reports a spectrum of disease-causing mutations, thereby expanding both the clinical phenotype and mutation spectrum of disease. PMID- 23363398 TI - Trauma-informed care in inpatient mental health settings: a review of the literature. AB - Trauma-informed care is an emerging value that is seen as fundamental to effective and contemporary mental health nursing practice. Trauma-informed care, like recovery, leaves mental health nurses struggling to translate these values into day-to-day nursing practice. Many are confused about what individual actions they can take to support these values. To date, the most clearly articulated policy to emerge from the trauma-informed care movement in Australia has been the agreement to reduce, and wherever possible, eliminate the use of seclusion and restraint. Confronted with the constant churn of admissions and readmissions of clients with challenging behaviours, and seemingly intractable mental illness, the elimination of seclusion and restraint is seen to be utopian by many mental health nurses in inpatient settings. Is trauma-informed care solely about eliminating seclusion and restraint, or are there other tangible practices nurses could utilize to effect better health outcomes for mental health clients, especially those with significant abuse histories? This article summarizes the findings from the literature from 2000-2011 in identifying those practices and clinical activities that have been implemented to effect trauma-informed care in inpatient mental health settings. PMID- 23363399 TI - Recent developments of DNA poisons--human DNA topoisomerase IIalpha inhibitors- as anticancer agents. AB - DNA topoisomerases are an important family of enzymes that catalyze the induction of topological changes in the DNA molecule. Their ability to modulate the topology of the DNA makes DNA topoisomerases a key player in several vital cell processes such as replication, transcription, chromosome separation and segregation. Consequently, they already represent an important collection of macromolecular targets for some of the established anticancer drugs on the market as well as serve as templates in the development of novel anticancer drugs especially supported by recent structural advances in the field. The aim of this review is to provide an overview of the recent developments in the field of DNA poisons - a major class of human topoisomerase IIalpha inhibitors - of which several are already in clinical use. Due to frequently experienced occurrence of serious side effects of these molecules during therapy, especially cardiotoxicity issues, further drug design efforts were initiated already yielding novel promising compounds that have overcome this issue and already entered into clinical studies. Some of the presented and discussed chemical classes include intercalators, non-intercalators and redox-dependent poisons of human topoisomerase IIalpha. In particular, this review focuses on the currently available structure-based standpoint of molecular design and on the medicinal chemist's perspective of this field of anticancer drug design. PMID- 23363400 TI - Stratum corneum fatty acids: their critical role in preserving barrier integrity during cleansing. AB - Stratum corneum (SC) bilayer lipids, specifically fatty acids, ceramides and cholesterol, contribute to the permeability barrier function of the skin. Normal skin cleansing is associated with damage to the SC lipids because cleanser surfactants, in addition to providing the desired effect of solubilizing and facilitating the removal of sebum and skin soils, have a propensity to disrupt bilayer lipids by extracting endogenous skin lipids or intercalating into the bilayer. Disrupted SC lipids are associated with a variety of pathological skin conditions, as well as with dry skin induced by harsh cleansing. In an attempt to preserve the barrier and mitigate the damage caused by frequent normal cleansing, the incorporation of physiologically relevant lipids into skin cleansers has become common in leading cleansing products. It has been noted that fatty acids are more susceptible to surfactant-induced removal than other lipids (eg, ceramides), an observation that may form the basis for a critically important strategy for replenishing SC lipids. This review will focus on the role of fatty acids in the structure and function of the SC, and the rationale for incorporation of stearic acid into moisturizing body cleansers to minimize their extraction by surfactants and replenish lost fatty acids to promote skin barrier preservation. PMID- 23363401 TI - Exploring the integration of the biomedical research component in undergraduate medical education. AB - BACKGROUND: A task force of MEDINE (Thematic Network on Medical Education in Europe) organized a survey of European Medical Schools. AIM: To investigate the link between education and biomedical research in the medical curriculum questioning university staff responsible for the curriculum. METHOD: The survey was online between 10/2006 and 3/2007. Answers pertained to the situation in the academic year 2005/06. RESULTS: Ninety-one medical schools/faculties in 26 countries participated, but response rates to some questions were lower due to incomplete responses. In undergraduate programs, 3/4 of the schools offer research courses and in 2/3 students can do research themselves. However, in most schools, fewer than 10% students choose this option. In about half the medical schools writing a thesis is a requirement for graduation, although the term "thesis" is interpreted broadly. Color map analysis revealed the link between medical education and biomedical research: about 25% of the medical schools had little emphasis on research in their undergraduate curriculum. CONCLUSIONS: We identified the curriculum elements most suitable to improve the link between medical education and research for the initial stage (years 1-3) as literature search techniques, statistics and epidemiology, while for the advanced stage (years 4-6), writing a thesis was most relevant. PMID- 23363402 TI - Monoclonal antibodies selective for alpha-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and alpha-synuclein transgenic mice with the disease-causing A30P mutation. AB - Inclusions of intraneuronal alpha-synuclein (alpha-synuclein) can be detected in brains of patients with Parkinson's disease and dementia with Lewy bodies. The aggregation of alpha-synuclein is a central feature of the disease pathogenesis. Among the different alpha-synuclein species, large oligomers/protofibrils have particular neurotoxic properties and should therefore be suitable as both therapeutic and diagnostic targets. Two monoclonal antibodies, mAb38F and mAb38E2, with high affinity and strong selectivity for large alpha-synuclein oligomers were generated. These antibodies, which do not bind amyloid-beta or tau, recognize Lewy body pathology in brains from patients with Parkinson's disease and dementia with Lewy bodies and detect pathology earlier in alpha synuclein transgenic mice than linear epitope antibodies. An oligomer-selective sandwich ELISA, based on mAb38F, was set up to analyze brain extracts of the transgenic mice. The overall levels of alpha-synuclein oligomers/protofibrils were found to increase with age in these mice, although the levels displayed a large interindividual variation. Upon subcellular fractionation, higher levels of alpha-synuclein oligomers/protofibrils could be detected in the endoplasmic reticulum around the age when behavioral disturbances develop. In summary, our novel oligomer-selective alpha-synuclein antibodies recognize relevant pathology and should be important tools to further explore the pathogenic mechanisms in Lewy body disorders. Moreover, they could be potential candidates both for immunotherapy and as reagents in an assay to assess a potential disease biomarker. PMID- 23363403 TI - Hyperammonemic encephalopathy associated with portal vein thrombosis in a thoroughbred foal. PMID- 23363404 TI - Accurate scoring of the apnea-hypopnea index using a simple non-contact breathing sensor. AB - Sleep apnea is a serious condition that afflicts many individuals and is associated with serious health complications. Polysomnography, the gold standard for assessing and diagnosing sleep apnea, uses breathing sensors that are intrusive and can disrupt the patient's sleep during the overnight testing. We investigated the use of breathing signals derived from non-contact force sensors (i.e. load cells) placed under the supports of the bed as an alternative to traditional polysomnography breathing sensors (e.g. nasal pressure, oral-nasal thermistor, chest belt and abdominal belt). The apnea-hypopnea index estimated using the load cells was not different than that estimated using standard polysomnography leads (t44 = 0.37, P = 0.71). Overnight polysomnography sleep studies scored using load cell breathing signals had an intra-class correlation coefficient of 0.97 for the apnea-hypopnea index and an intra-class correlation coefficient of 0.85 for the respiratory disturbance index when compared with scoring using traditional polysomnography breathing sensors following American Academy of Sleep Medicine guidelines. These results demonstrate the feasibility of using unobtrusive load cells installed under the bed to measure the apnea hypopnea index. PMID- 23363406 TI - Semantic remote patient monitoring system. AB - We propose an automated and personalized remote patient monitoring (RPM) system, which is applied to care homes and is dependent on the manipulation of semantics describing situations during patient monitoring in ontological models. Decision making in RPM is based on reasoning performed upon ontologies, which secures the delivery of appropriate e-health services in care homes. Our working experiment shows an example of preventive e-healthcare, but it can be extended to any situation that requires either urgent action from healthcare professionals or a simple recommendation during RPM. We use Semantic Web technology and OWL/SWRL enabled ontologies to illustrate the proposal and feasibility of implementing this RPM system as a software solution in pervasive healthcare. It will be of interest to healthcare professionals, who can directly shape and populate the proposed ontological model, and software engineers, who would consider using OWL/SWRL when creating e-health services in general. PMID- 23363407 TI - Highly luminescent and photostable quantum dot-silica monolith and its application to light-emitting diodes. AB - A highly luminescent and photostable quantum dot-silica monolith (QD-SM) substance was prepared by preliminary surface exchange of the QDs and base catalyzed sol-gel condensation of silica. The SM was heavily doped with 6 mercaptohexanol exchanged QDs up to 12 vol % (26 wt %) without particle aggregation. Propylamine catalyst was important in maintaining the original luminescence of the QDs in the SM during sol-gel condensation. The silica layer was a good barrier against oxygen and moisture, so that the QD-SM maintained its initial luminescence after high-power UV radiation (~1 W) for 200 h and through the 150 degrees C LED encapsulant curing process. Green and red light-emitting QD-SMs were applied as color-converting layers on blue LEDs, and the external quantum efficiency reached up to 89% for the green QD-SM and 63% for the red one. A white LED made with a mixture of green and red QDs in the SM, in which the color coordinate was adjusted at (0.23, 0.21) in CIE1931 color space for a backlight application, showed an efficacy of 47 lm/W, the highest value yet reported. PMID- 23363408 TI - Contextual processing of abstract concepts reveals neural representations of nonlinguistic semantic content. AB - Concepts develop for many aspects of experience, including abstract internal states and abstract social activities that do not refer to concrete entities in the world. The current study assessed the hypothesis that, like concrete concepts, distributed neural patterns of relevant nonlinguistic semantic content represent the meanings of abstract concepts. In a novel neuroimaging paradigm, participants processed two abstract concepts (convince, arithmetic) and two concrete concepts (rolling, red) deeply and repeatedly during a concept-scene matching task that grounded each concept in typical contexts. Using a catch trial design, neural activity associated with each concept word was separated from neural activity associated with subsequent visual scenes to assess activations underlying the detailed semantics of each concept. We predicted that brain regions underlying mentalizing and social cognition (e.g., medial prefrontal cortex, superior temporal sulcus) would become active to represent semantic content central to convince, whereas brain regions underlying numerical cognition (e.g., bilateral intraparietal sulcus) would become active to represent semantic content central to arithmetic. The results supported these predictions, suggesting that the meanings of abstract concepts arise from distributed neural systems that represent concept-specific content. PMID- 23363409 TI - What we think before a voluntary movement. AB - A central feature of voluntary movement is the sense of volition, but when this sense arises in the course of movement formulation and execution is not clear. Many studies have explored how the brain might be actively preparing movement before the sense of volition; however, because the timing of the sense of volition has depended on subjective and retrospective judgments, these findings are still regarded with a degree of scepticism. EEG events such as beta event related desynchronization and movement-related cortical potentials are associated with the brain's programming of movement. Using an optimized EEG signal derived from multiple variables, we were able to make real-time predictions of movements in advance of their occurrence with a low false-positive rate. We asked participants what they were thinking at the time of prediction: Sometimes they were thinking about movement, and other times they were not. Our results indicate that the brain can be preparing to make voluntary movements while participants are thinking about something else. PMID- 23363410 TI - Neural responses to ambiguity involve domain-general and domain-specific emotion processing systems. AB - Extant research has examined the process of decision making under uncertainty, specifically in situations of ambiguity. However, much of this work has been conducted in the context of semantic and low-level visual processing. An open question is whether ambiguity in social signals (e.g., emotional facial expressions) is processed similarly or whether a unique set of processors come on line to resolve ambiguity in a social context. Our work has examined ambiguity using surprised facial expressions, as they have predicted both positive and negative outcomes in the past. Specifically, whereas some people tended to interpret surprise as negatively valenced, others tended toward a more positive interpretation. Here, we examined neural responses to social ambiguity using faces (surprise) and nonface emotional scenes (International Affective Picture System). Moreover, we examined whether these effects are specific to ambiguity resolution (i.e., judgments about the ambiguity) or whether similar effects would be demonstrated for incidental judgments (e.g., nonvalence judgments about ambiguously valenced stimuli). We found that a distinct task control (i.e., cingulo-opercular) network was more active when resolving ambiguity. We also found that activity in the ventral amygdala was greater to faces and scenes that were rated explicitly along the dimension of valence, consistent with findings that the ventral amygdala tracks valence. Taken together, there is a complex neural architecture that supports decision making in the presence of ambiguity: (a) a core set of cortical structures engaged for explicit ambiguity processing across stimulus boundaries and (b) other dedicated circuits for biologically relevant learning situations involving faces. PMID- 23363411 TI - Spatial remapping in the audio-tactile ventriloquism effect: a TMS investigation on the role of the ventral intraparietal area. AB - Previous studies have suggested that the putative human homologue of the ventral intraparietal area (hVIP) is crucially involved in the remapping of tactile information into external spatial coordinates and in the realignment of tactile and visual maps. It is unclear, however, whether hVIP is critical for the remapping process during audio-tactile cross-modal spatial interactions. The audio-tactile ventriloquism effect, where the perceived location of a sound is shifted toward the location of a synchronous but spatially disparate tactile stimulus, was used to probe spatial interactions in audio-tactile processing. Eighteen healthy volunteers were asked to report the perceived location of brief auditory stimuli presented from three different locations (left, center, and right). Auditory stimuli were presented either alone (unimodal stimuli) or concurrently to a spatially discrepant tactile stimulus applied to the left or right index finger (bimodal stimuli), with the hands adopting either an uncrossed or a crossed posture. Single pulses of TMS were delivered over the hVIP or a control site (primary somatosensory cortex, SI) 80 msec after trial onset. TMS to the hVIP, compared with the control SI-TMS, interfered with the remapping of touch into external space, suggesting that hVIP is crucially involved in transforming spatial reference frames across audition and touch. PMID- 23363412 TI - Dopaminergic gene polymorphisms affect long-term forgetting in old age: further support for the magnification hypothesis. AB - Emerging evidence from animal studies suggests that suboptimal dopamine (DA) modulation may be associated with increased forgetting of episodic information. Extending these observations, we investigated the influence of DA-relevant genes on forgetting in samples of younger (n = 433, 20-31 years) and older (n = 690, 59 71 years) adults. The effects of single nucleotide polymorphisms of the DA D2 (DRD2) and D3 (DRD3) receptor genes as well as the DA transporter gene (DAT1; SLC6A3) were examined. Over the course of one week, older adults carrying two or three genotypes associated with higher DA signaling (i.e., higher availability of DA and DA receptors) forgot less pictorial information than older individuals carrying only one or no beneficial genotype. No such genetic effects were found in younger adults. The results are consistent with the view that genetic effects on cognition are magnified in old age. To the best of our knowledge, this is the first report to relate genotypes associated with suboptimal DA modulation to more long-term forgetting in humans. Independent replication studies in other populations are needed to confirm the observed association. PMID- 23363413 TI - The involvement of the thalamus in semantic retrieval: a clinical group study. AB - There is increasing attention about the role of the thalamus in high cognitive functions, including memory. Although the bulk of the evidence refers to episodic memory, it was recently proposed that the mediodorsal (MD) and the centromedian parafascicular (CM-Pf) nuclei of the thalamus may process general operations supporting memory performance, not only episodic memory. This perspective agrees with other recent fMRI findings on semantic retrieval in healthy participants. It can therefore be hypothesized that lesions to the MD and the CM-Pf impair semantic retrieval. In this study, 10 patients with focal ischemic lesions in the medial thalamus and 10 healthy controls matched for age, education, and verbal IQ performed a verbal semantic retrieval task. Patients were assigned to a target clinical group and a control clinical group based on lesion localization. Patients did not suffer from aphasia and performed in the range of controls in a categorization and a semantic association task. However, target patients performed poorer than healthy controls on semantic retrieval. The deficit was not because of higher distractibility but of an increased rate of false recall and, in some patients, of a considerably increased rate of misses. The latter deficit yielded a striking difference between the target and the control clinical groups and is consistent with anomia. Follow-up high-resolution structural scanning session in a subsample of patients revealed that lesions in the CM-Pf and MD were primarily associated with semantic retrieval deficits. We conclude that integrity of the MD and the CM-Pf is required for semantic retrieval, possibly because of their role in the activation of phonological representations. PMID- 23363414 TI - The functional topography and temporal dynamics of overlapping and distinct brain activations for adaptive task control and stable task-set maintenance during performance of an fMRI-adapted clinical continuous performance test. AB - Previous studies have demonstrated that stable and adaptive attention processes are mediated by partly overlapping, but distinct, brain areas. Dorsal medial PFC and anterior insula may form a "core network" for attention control, which is believed to operate on both temporal scales. However, both the existence of such a network as well as the unique functional topography for adaptive and stable attention processes is still highly debated. In this study, 87 healthy participants performed a clinical not-X continuous performance test optimized for use in a mixed block and event-related fMRI design. We observed overlapping activations related to stable and adaptive attention processes in dorsal medial PFC and anterior insula/adjacent cortex as well as in the right inferior parietal lobe and middle temporal gyrus. We also identified areas of activations uniquely related to stable and adaptive attention processes in widespread cortical, cerebellar, and subcortical areas. Interestingly, the functional topography within the PFC indicated a rostro-caudal distribution of adaptive, relative to stable, attention processes. There was also evidence for a time-on-task effect for activations related to stable, but not adaptive, attention processes. Our results provide further evidence for a "core network" for attention control that is accompanied by unique areas of activation involved in domain-specific processes operating on different temporal scales. In addition, our results give new insights into the functional topography of stable and adaptive attention processes and their temporal dynamics in the context of an extensively used clinical attention test. PMID- 23363415 TI - Localization of sesquiterpene formation and emission in maize leaves after herbivore damage. AB - BACKGROUND: Maize (Zea mays L.) leaves damaged by lepidopteran herbivores emit a complex volatile blend that can attract natural enemies of the herbivores and may also have roles in direct defense and inter- or intra-plant signaling. The volatile blend is dominated by sesquiterpenes of which the majority is produced by two herbivore-induced terpene synthases, TPS10 and TPS23. However, little is known about the pattern of volatile emission within maize leaves. RESULTS: In this study, we restricted herbivore feeding to small sections of the maize leaf with the aim of determining the patterns of volatile sesquiterpene emission throughout the damaged leaf and in neighboring leaves. Sesquiterpene volatiles were released at high rates from damaged leaves, but at much lower rates from neighboring leaves. Release was restricted to the site of damage or to leaf sections located apical to the damage, but was not seen in sections basal to the damage or on the other side of the midrib. The emission pattern correlated well with the transcript pattern of the respective sesquiterpene synthase genes, tps10 and tps23, implying that biosynthesis likely occurs at the site of emission. The concentrations of jasmonic acid and its leucine derivative were also elevated in terpene-emitting tissues suggesting a role for jasmonates in propagating the damage signal. CONCLUSIONS: In contrast to other defense reactions which often occur systemically throughout the whole plant, herbivore-induced sesquiterpene production in maize is restricted to the wounding site and distal leaf parts. Since the signal mediating this reaction is directed to the leaf tip and cannot propagate parallel to the leaf axis, it is likely connected to the xylem. The increasing gradient of volatiles from the tip of the leaf towards the damage site might aid herbivore enemies in host or prey finding. PMID- 23363416 TI - A review of mometasone furoate / formoterol in the treatment of asthma. AB - INTRODUCTION: Asthma is a common chronic respiratory disease affecting the airways causing inflammation, airway hyperreactivity (AHR), and respiratory symptoms. Frequently, asthma can be effectively treated with inhaled corticosteroids (ICS) but in more severe cases additional drugs are required, such as long-acting beta2-agonists (LABA). Mometasone furoate (MF) is a synthetic steroid exhibiting a strong affinity for the glucocorticoid receptor as well as a low bioavailability and a high plasma protein binding. In most cases, MF only requires once daily administration. Formoterol fumarate (F) is a full beta2 agonist with a rapid onset and 12 h of duration. AREAS COVERED: The present paper reviews the current knowledge of the novel combination of MF and F for the treatment of asthma. Furthermore, a description of the individual components is included. EXPERT OPINION: At present, only few clinical studies of MF/F are available for review and more studies of MF/F efficacy are needed, especially comparative studies on other ICS/LABA drugs. However, it does not appear from the reviewed literature that MF/F or its individual components are inferior to other equivalent treatments. PMID- 23363417 TI - An optimal polymerization conditions for poly-human placenta hemoglobin with lower mean molecular weight. AB - OBJECTIVES: To reduce the mean molecular weight [Formula: see text] and to increase the effective polymerization ratio (REff) of polymerized human placenta hemoglobin (PolyPHb). METHODS: Three factors of GDA-PolyPHb process such as the approach of feeding GDA (FGDA), hemoglobin concentration ([Hb]) and the molar ratio of GDA, and hemoglobin(RGDA:Hb) were investigated. Finally, the expansion experiments were conducted with optimal conditions. RESULTS: The data showed that the HBOCs with the REff of 67.35% and lower [Formula: see text] of 162.70 kDa were prepared by optimal conditions. CONCLUSION: Compared to original process, the optimal process greatly decreased the [Formula: see text] and increased the REff. PMID- 23363419 TI - Lumbo-pelvic loading during fast bowling in adolescent cricketers: the influence of bowling speed and technique. AB - This study aimed to assess changes in bowling technique and lumbar load over the course of a bowling spell in adolescent fast bowlers, and to investigate the relationship between lumbar loads during fast bowling and kinematic factors which have previously been associated with low back injury. Three-dimensional motion analysis was carried out on forty participants who performed an 8-over bowling spell. There were no significant changes in bowling technique or lumbar loads over the course of the spell. Bowling with a more extended front knee, faster ball release speed and increased shoulder counter-rotation were related to increased lumbo-pelvic loading - in particular peak transverse plane rotation moments and anterior-posterior shear forces. These lumbar loads may be a factor in low back injury aetiology and future studies should investigate the relationship between lumbar loading, injury incidence and other risk factors. PMID- 23363420 TI - Thermally persistent fluorosulfonyl nitrene and unexpected formation of the fluorosulfonyl radical. AB - Thermally persistent triplet sulfonyl nitrene, FSO(2)N, was produced in the gas phase in high yields (up to 66%) by flash vacuum pyrolysis of FSO(2)N(3). Surprisingly, no rearrangement of FSO(2)N was observed, but the long-sought radical FSO(2) (22%) and traces of SO(2) (3%) were identified by IR ((15)N, (18)O, (34)S) spectroscopy. The photoinduced Curtius rearrangement of the nitrene to FNSO(2) was observed in solid noble gas matrices, and reactions of the nitrene with O(2), NO, and CO were studied. PMID- 23363418 TI - UtroUp is a novel six zinc finger artificial transcription factor that recognises 18 base pairs of the utrophin promoter and efficiently drives utrophin upregulation. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common X-linked muscle degenerative disease and it is due to the absence of the cytoskeletal protein dystrophin. Currently there is no effective treatment for DMD. Among the different strategies for achieving a functional recovery of the dystrophic muscle, the upregulation of the dystrophin-related gene utrophin is becoming more and more feasible. RESULTS: We have previously shown that the zinc finger-based artificial transcriptional factor "Jazz" corrects the dystrophic pathology in mdx mice by upregulating utrophin gene expression. Here we describe a novel artificial transcription factor, named "UtroUp", engineered to further improve the DNA-binding specificity. UtroUp has been designed to recognise an extended DNA target sequence on both the human and mouse utrophin gene promoters. The UtroUp DNA-binding domain contains six zinc finger motifs in tandem, which is able to recognise an 18-base-pair DNA target sequence that statistically is present only once in the human genome. To achieve a higher transcriptional activation, we coupled the UtroUp DNA-binding domain with the innovative transcriptional activation domain, which was derived from the multivalent adaptor protein Che-1/AATF. We show that the artificial transcription factor UtroUp, due to its six zinc finger tandem motif, possesses a low dissociation constant that is consistent with a strong affinity/specificity toward its DNA-binding site. When expressed in mammalian cell lines, UtroUp promotes utrophin transcription and efficiently accesses active chromatin promoting accumulation of the acetylated form of histone H3 in the utrophin promoter locus. CONCLUSIONS: This novel artificial molecule may represent an improved platform for the development of future applications in DMD treatment. PMID- 23363421 TI - Regiocontrolled construction of furo[3,2-c]pyran-4-one derivatives by palladium catalyzed cyclization of propargylic carbonates with 4-hydroxy-2-pyrones. AB - The reaction of propargylic carbonates with 4-hydroxy-2-pyrones in the presence of a palladium catalyst is described. By the choice of the reaction temperature, two types of the substituted furo[3,2-c]pyran-4-one derivatives were regioselectively synthesized, respectively. PMID- 23363422 TI - Novel aspects of preoperative chemoradiation therapy improving anti-tumor immunity in pancreatic cancer. AB - Pancreatic cancer is an aggressive cancer with poor prognosis. Little is known about the immune response in the tumor microenvironment after chemotherapy for initially unresectable tumor. The purpose of this study was to investigate the immunological effects of chemoradiation therapy in the tumor microenvironment of pancreatic adenocarcinoma. Seventeen patients with pancreatic adenocarcinoma with and without preoperative chemoradiation therapy were retrospectively analyzed using immunohistochemical methods for HLA class I heavy chain, CD4(+), CD8(+), CD45RO(+) and Foxp3(+) T cell infiltrations. Seven of the 17 study patients received preoperative chemoradiation therapy. There were no statistically significant differences in the number of CD4(+) and CD8(+) T cell infiltrations in the tumor microenvironment. However, the number of Foxp3(+) T cell infiltrations was significantly lower in the neoadjuvant chemoradiation therapy group. The HLA class I expression status was the same between the two groups. In conclusion, preoperative chemoradiation therapy in pancreatic adenocarcinoma is useful for reducing regulatory T cell levels in combination with its direct cytotoxic effects. PMID- 23363423 TI - Objective measures of sleep and dim light melatonin onset in adolescents and young adults with delayed sleep phase disorder compared to healthy controls. AB - Delayed sleep phase disorder is characterized by a delay in the timing of the major sleep period relative to conventional norms. The sleep period itself has traditionally been described as normal. Nevertheless, it is possible that sleep regulatory mechanism disturbances associated with the disorder may affect sleep duration and/or architecture. Polysomnographic data that may shed light on the issue are scarce. Hence, the aim of this study was to examine polysomnographic measures of sleep in adolescents and young adults with delayed sleep phase disorder, and to compare findings to that of healthy controls. A second aim was to estimate dim light melatonin onset as a marker of circadian rhythm and to investigate the phase angle relationship (time interval) between dim light melatonin onset and the sleep period. Data from 54 adolescents and young adults were analysed, 35 diagnosed with delayed sleep phase disorder and 19 healthy controls. Results show delayed timing of sleep in participants with delayed sleep phase disorder, but once sleep was initiated no group differences in sleep parameters were observed. Dim light melatonin onset was delayed in participants with delayed sleep phase disorder, but no difference in phase angle was observed between the groups. In conclusion, both sleep and dim light melatonin onset were delayed in participants with delayed sleep phase disorder. The sleep period appeared to occur at the same circadian phase in both groups, and once sleep was initiated no differences in sleep parameters were observed. PMID- 23363425 TI - Silica precipitation by synthetic minicollagens. AB - Oligomeric Pro-Hyp-Gly- (POG-) peptides, wherein the collagenous triple helix is supported by C-terminal capping, exhibit silica precipitation properties (O, Hyp = (2S,4R)hydroxyproline). As quantified by a molybdate assay, the length of the covalently tethered triple helix (number of POG units) determines the amount of amorphous silica obtained from silicic acid solution. Although lacking charged side chains, the synthetic collagens precipitate large quantities of silicic acid resulting in micrometer-sized spheres of varying surface morphologies as analyzed by scanning electron microscopy. Similar precipitation efficiencies on a fast time scale of less than 10 min were previously described only for biogenic diatom proteins and sponge collagen, respectively, which have a considerably higher structural complexity and limited accessibility. The minicollagens described here provide an unexpected alternative to the widely used precipitation conditions, which generally depend on (poly-)amines in phosphate buffer. Collagen can form intimate connections with inorganic matter. Hence, silica-enclosed collagens have promising perspectives as composite materials. PMID- 23363426 TI - Use of endobronchial valves in persistent air leaks: a case report and review of the literature. AB - Air leaks are observed after lung surgery, but can also occur spontaneously even in a previously normal lung. There are several available methods of management including, among others, chest drainage, Heimlich valves, surgical repair or pleural decortication. However, in some of these patients, surgery may be contraindicated. In this article, the authors report the use of one-way endobronchial valves in the treatment of a compromised patient with bullous emphysema who had previously undergone bullectomy. This approach resulted in improvement of dyspnea and exercise capacity. Use of endobronchial valves is an effective, nonsurgical, minimally invasive intervention for patients with prolonged pulmonary air leaks not suitable for surgical procedures. PMID- 23363424 TI - 3, 4-dihydroxy-L-phenylalanine-derived melanin from Yarrowia lipolytica mediates the synthesis of silver and gold nanostructures. AB - BACKGROUND: Nanobiotechnology applies the capabilities of biological systems in generating a variety of nano-sized structures. Plants, algae, fungi and bacteria are some systems mediating such reactions. In fungi, the synthesis of melanin is an important strategy for cell-survival under metal-stressed conditions. Yarrowia lipolytica, the biotechnologically significant yeast also produces melanin that sequesters heavy metal ions. The content of this cell-associated melanin is often low and precursors such as L-tyrosine or 3, 4-dihydroxy-L-phenylalanine (L-DOPA) can enhance its production. The induced melanin has not been exploited for the synthesis of nanostructures. In this investigation, we have employed L-DOPA melanin for the facile synthesis of silver and gold nanostructures. The former have been used for the development of anti-fungal paints. METHODS: Yarrowia lipolytica NCIM 3590 cells were incubated with L-DOPA for 18 h and the resultant dark pigment was subjected to physical and chemical analysis. This biopolymer was used as a reducing and stabilizing agent for the synthesis of silver and gold nanostructures. These nanoparticles were characterized by UV-Visible spectra, X ray diffraction (XRD) studies, and electron microscopy. Silver nanoparticles were evaluated for anti-fungal activity. RESULTS: The pigment isolated from Y. lipolytica was identified as melanin. The induced pigment reduced silver nitrate and chloroauric acid to silver and gold nanostructures, respectively. The silver nanoparticles were smaller in size (7 nm) and displayed excellent anti-fungal properties towards an Aspergillus sp. isolated from a wall surface. An application of these nanoparticles as effective paint-additives has been demonstrated. CONCLUSION: The yeast mediated enhanced production of the metal-ion reducing pigment, melanin. A simple and rapid method for the extracellular synthesis of nanoparticles with paint-additive-application was developed. PMID- 23363427 TI - Memory, priority encoding, and overcoming high-value proactive interference in younger and older adults. AB - It is often necessary to remember important information while directing attention away from encoding less valuable information. To examine how aging influences the ability to control and update the encoding of high-value information, younger and older adults studied six lists of words that varied in terms of the point values associated with each word. The words were paired with the same high and low point values for three study-test cycles, but on the fourth and subsequent cycles the value-word pairings were switched such that the lowest value pairs became the highest values (and vice versa). For the first three study-test cycles, younger adults outperformed older adults in terms of the number of words recalled and overall point totals, but performance was similar in terms of selectively remembering high-value words. When the values were switched, both groups displayed substantial interference from the previous pairings. Although both groups improved with additional study-test cycles, only younger adults were able to fully recover from the interference effects. A similar, and more pronounced, set of results were obtained when positive and negative point values were paired with the words. The findings are interpreted in a value-directed remembering framework, emphasizing the role of benefits and costs of strategic encoding and age-related differences in the effects of interference on memory. PMID- 23363428 TI - Histological, histomorphometric and microtomographic analyses of retrieval hip resurfacing arthroplasty failed at different times. AB - BACKGROUND: Metal-on-metal hip resurfacing arthroplasty (HR) has been gaining popularity especially for young and active patients. Although different series report good mid-term results, the long-term outcome and failure mechanisms are still concerning. In this consecutive revision case series, 9 retrieved specimens of a failed Birmingham Hip Resurfacing (BHR) were divided according to the time to fracture: 3 specimens failed at less than 6 months (Group 1), 3 failed between 6 months and 3 years (Group 2) and 3 failed later than 3 years (Group 3). The objective of the study was to examine by a specific quantitative histomorphometry and microtomography (micro-CT) method the characteristics of bone quality and its microarchitecture in retrieved metal-on-metal HR. METHODS: A series of 948 BHR were performed between 2001 and 2009. Among these implants 10 failures occurred and nine of these underwent revision surgery and were examined by histomorphometry and micro-CT. RESULTS: Histomorphometry showed a significant increase in trabecular separation (Tb.Sp) in Group 3 in comparison with Group 1 (113%, p < 0.05). In the top region, micro-CT showed that Groups 2 and 3 presented significant lower bone volume (Group 2: 61%, p < 0.005; Group 3: 1%, p < 0.05), trabecular number (Group 2: 53%, p < 0.005; Group 3: 40%, p < 0.05), and higher Tb.Sp (Group: 71%,p < 0.05) when compared to Group 1. Additionally, histomorphometry showed that the top regions in Group 1 had a significantly lower mean percentage of empty osteocyte lacunae than the top regions in both Group 2 and 3 (p < 0.05). CONCLUSIONS: This study showed that the morphometric parameters considered are crucial for a good understanding of mechanical properties of HR and may be of significant importance in the pathogenesis of HR failure particularly in the development of late fractures. PMID- 23363430 TI - Global shifts towards positive species interactions with increasing environmental stress. AB - The study of positive species interactions is a rapidly evolving field in ecology. Despite decades of research, controversy has emerged as to whether positive and negative interactions predictably shift with increasing environmental stress as hypothesised by the stress-gradient hypothesis (SGH). Here, we provide a synthesis of 727 tests of the SGH in plant communities across the globe to examine its generality across a variety of ecological factors. Our results show that plant interactions change with stress through an outright shift to facilitation (survival) or a reduction in competition (growth and reproduction). In a limited number of cases, plant interactions do not respond to stress, but they never shift towards competition with stress. These findings are consistent across stress types, plant growth forms, life histories, origins (invasive vs. native), climates, ecosystems and methodologies, though the magnitude of the shifts towards facilitation with stress is dependent on these factors. We suggest that future studies should employ standardised definitions and protocols to test the SGH, take a multi-factorial approach that considers variables such as plant traits in addition to stress, and apply the SGH to better understand how species and communities will respond to environmental change. PMID- 23363429 TI - Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice. AB - BACKGROUND: Overdosed acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) causes severe liver injury. We examined the effects of ozagrel, a selective thromboxane A2 (TXA2) synthase inhibitor, on liver injury induced by APAP overdose in mice. METHODS: Hepatotoxicity was induced to ICR male mice by an intraperitoneal injection with APAP (330 mg/kg). The effects of ozagrel (200 mg/kg) treatment 30 min after the APAP injection were evaluated with mortality, serum alanine aminotransferase (ALT) levels and hepatic changes, including histopathology, DNA fragmentation, mRNA expression and total glutathione contents. The impact of ozagrel (0.001-1 mg/mL) on cytochrome P450 2E1 (CYP2E1) activity in mouse hepatic microsome was examined. RLC-16 cells, a rat hepatocytes cell line, were exposed to 0.25 mM N-acetyl-p-benzoquinone imine (NAPQI), a hepatotoxic metabolite of APAP. In this model, the cytoprotective effects of ozagrel (1-100 muM) were evaluated by the WST-1 cell viability assay. RESULTS: Ozagel treatment significantly attenuated higher mortality, elevated serum alanine aminotransferase levels, excessive hepatic centrilobular necrosis, hemorrhaging and DNA fragmentation, as well as increase in plasma 2,3-dinor thromboxane B2 levels induced by APAP injection. Ozagrel also inhibited the hepatic expression of cell death-related mRNAs induced by APAP, such as jun oncogene, FBJ osteosarcoma oncogene (fos) and C/EBP homologous protein (chop), but did not suppress B-cell lymphoma 2-like protein11 (bim) expression and hepatic total glutathione depletion. These results show ozagrel can inhibit not all hepatic changes but can reduce the hepatic necrosis. Ozagrel had little impact on CYP2E1 activity involving the NAPQI production. In addition, ozagrel significantly attenuated cell injury induced by NAPQI in RLC-16. CONCLUSIONS: We demonstrate that the TXA2 synthase inhibitor, ozagrel, dramatically alleviates liver injury induced by APAP in mice, and suggest that it is a promising therapeutic candidate for the treatment of APAP-induced liver injury. PMID- 23363431 TI - Prevalence and risk factors for neurological disorders in children aged 6 months to 2 years in northern India. AB - AIM: To study prevalence and risk factors for neurological disorders--epilepsy, global developmental delay, and motor, vision, and hearing defects--in children aged 6 months to 2 years in northern India. METHOD: A two-stage community survey for neurological disorders was conducted in rural and urban areas of Lucknow. After initial screening with a new instrument, the Lucknow Neurodevelopment Screen, screen positives and a random proportion of screen negatives were validated using predefined criteria. Prevalence was calculated by weighted estimates. Demographic, socio-economic, and medical risk factors were compared between validated children who were positive and negative for neurological disorders by univariate and logistic regression analysis. RESULTS: Of 4801 children screened (mean age [SD] 15.32mo [5.96]; 2542 males, 2259 females), 196 were positive; 190 screen positives and 269 screen negatives were validated. Prevalence of neurological disorders was 27.92 per 1000 (weighted 95% confidence interval 12.24-43.60). Significant risk factors (p<=0.01) for neurological disorders were higher age in months (p=0.010), lower mean number of appliances in the household (p=0.001), consanguineous marriage of parents (p=0.010), family history of neurological disorder (p=0.001), and infants born exceptionally small (parental description; p=0.009). On logistic regression, the final model included age (p=0.0193), number of appliances (p=0.0161), delayed cry at birth (p=0.0270), postneonatal meningoencephalitis (p=0.0549), and consanguinity (p=0.0801). INTERPRETATION: Perinatal factors, lower socio-economic status, and consanguinity emerged as predictors of neurological disorders. These factors are largely modifiable. PMID- 23363432 TI - Indolenine meso-substituted dibenzotetraaza[14]annulene and its coordination chemistry toward the transition metal ions Mn(III), Fe(III), Co(II), Ni(II), Cu(II), and Pd(II). AB - A new dibenzotetraaza[14]annulene bearing two 3,3-dimethylindolenine fragments at the meso positions (LH(2)), has been synthesized through a nontemplate method. X ray crystallography shows that the whole molecule is planar. The basicity of the indolenine ring permits the macrocycle to be protonated external to the core and form LH(4)(2+).2Cl(-). Yet another structural modification having strong C-H...pi interactions was found in the chloroform solvate of LH(2). The latter two modifications are accompanied by a degree of nonplanar distortion. The antiaromatic core of the macrocycle can accommodate a number of metal ions, Mn(III), Fe(III), Co(II), Ni(II) and Cu(II), to form complexes of [Mn(L)Br], [Mn(L)Cl], [Fe(LH(2))Cl(2)](+).Cl(-), [Co(L)], [Ni(L)], and [Cu(L)]. In addition, the reaction of LH(2) with the larger Pd(II) ion leads to the formation of [Pd(2)(LH(2))(2)(OAc)(4)] wherein the macrocycle acts as a semiflexible ditopic ligand to coordinate pairs of metal ions via its indolenine N atoms into dinuclear metallocycles. The compounds LH(2), [Co(L)], and [Ni(L)] are isostructural and feature close pi-stacking as well as linear chain arrangements in the case of the metal complexes. Variable temperature magnetic susceptibility measurements showed thermally induced paramagnetism in [Ni(L)]. PMID- 23363433 TI - The pathogenicity of avian metapneumovirus subtype C wild bird isolates in domestic turkeys. AB - BACKGROUND: Avian metapneumovirus subtype C (aMPV/C) causes severe upper respiratory disease in turkeys. Previous report revealed the presence of aMPV/C in wild birds in the southeast regions of the U.S. METHODS: In this study, aMPV/C positive oral swabs from American coots (AC) and Canada geese (CG) were passaged three times in the respiratory tract of specific pathogen free (SPF) turkeys and used as aMPV/C P3 virus isolates in subsequent studies. RESULTS: Wild bird P3 isolates showed similar growth characteristics when compared to virulent aMPV/C in chicken embryo fibroblast ( CEF) cell cultures and their glycoprotein G gene sequence was closely related to the G gene of aMPV/C Colorado reference virus. Three-day-old commercial or SPF turkeys were inoculated oculonasally with wild bird aMPV/C P3 isolates. At 5 and 7 days post-inoculation (DPI), severe clinical signs were observed in both of the AC and CG virus-exposed groups. Viral RNA was detected in tracheal swabs by reverse transcriptase polymerase chain reaction (RT PCR). In addition, immunohistochemistry showed virus replication in the nasal turbinate and trachea. All virus-exposed turkeys developed positive antibody response by 14 DPI. CONCLUSIONS: Our data demonstrate that aMPV/C wild bird isolates induced typical aMPV/C disease in the domestic turkeys. PMID- 23363434 TI - Inflammatory effects of woodsmoke exposure among wildland firefighters working at prescribed burns at the Savannah River Site, SC. AB - Wildland firefighters in the United States are occupationally exposed to high levels of woodsmoke. Results from experimental studies show that exposure to woodsmoke induces inflammation. A study was conducted to investigate the effect of occupational woodsmoke exposure on inflammatory biomarkers in firefighters working at prescribed burns. Twelve U.S. Forest Service wildland firefighters at the Savannah River Site, South Carolina, volunteered to give blood samples during four prescribed burns between February and March 2011. Twenty-four paired (pre- and post-work shift) blood samples were collected using dried blood spot method to facilitate repeated sample collection. Inflammatory biomarker concentrations in blood samples were measured using the Meso Scale Discovery multi-spot assay system. Concurrent personal PM2.5 and CO monitoring of firefighters was conducted. Linear mixed models were used to test whether cross-work shift differences occurred in the following inflammatory biomarkers: IL-1beta, IL-8, CRP, SAA, ICAM-1, and VCAM-1. IL-8 showed a significant cross-work shift difference as indicated by a post/pre-work shift ratio of 1.70 (95% CL: 1.35, 2.13; p = 0.0012). Concentrations of IL-8, CRP, and ICAM-1 increased in >50% of samples across work shift. Firefighters who lighted fires as opposed to other work tasks had the largest cross-work shift increase in IL-8. A significant cross work shift increase in IL-8 in blood samples was observed in healthy wildland firefighters working at prescribed burns. Further research is needed to understand the physiological responses underlying the adverse effects of woodsmoke exposure, and the dose-response relationship between woodsmoke exposure and inflammatory responses. PMID- 23363436 TI - Carbon-layer-protected cuprous oxide nanowire arrays for efficient water reduction. AB - In this work, we propose a solution-based carbon precursor coating and subsequent carbonization strategy to form a thin protective carbon layer on unstable semiconductor nanostructures as a solution to the commonly occurring photocorrosion problem of many semiconductors. A proof-of-concept is provided by using glucose as the carbon precursor to form a protective carbon coating onto cuprous oxide (Cu2O) nanowire arrays which were synthesized from copper mesh. The carbon-layer-protected Cu2O nanowire arrays exhibited remarkably improved photostability as well as considerably enhanced photocurrent density. The Cu2O nanowire arrays coated with a carbon layer of 20 nm thickness were found to give an optimal water splitting performance, producing a photocurrent density of -3.95 mA cm-2 and an optimal photocathode efficiency of 0.56% under illumination of AM 1.5G (100 mW cm-2). This is the highest value ever reported for a Cu2O-based electrode coated with a metal/co-catalyst-free protective layer. The photostability, measured as the percentage of the photocurrent density at the end of 20 min measurement period relative to that at the beginning of the measurement, improved from 12.6% on the bare, nonprotected Cu2O nanowire arrays to 80.7% on the continuous carbon coating protected ones, more than a 6-fold increase. We believe that the facile strategy presented in this work is a general approach that can address the stability issue of many nonstable photoelectrodes and thus has the potential to make a meaningful contribution in the general field of energy conversion. PMID- 23363435 TI - Calmodulin kinase IV-dependent CREB activation is required for neuroprotection via NMDA receptor-PSD95 disruption. AB - NMDA-type glutamate receptors mediate both trophic and excitotoxic signalling in CNS neurons. We have previously shown that blocking NMDAR- post-synaptic density 95 (PSD95) interactions provides significant protection from excitotoxicity and in vivo ischaemia; however, the mechanism of neuroprotection is unclear. Here, we report that blocking PSD-95 interactions with the Tat-NR2B9c peptide enhances a Ca2+-dependent protective pathway converging on cAMP Response Element binding protein (CREB) activation. We provide evidence that Tat-NR2B9c neuroprotection from oxygen glucose deprivation and NMDA toxicity occurs in parallel with the activation of calmodulin kinase signalling and is dependent on a sustained phosphorylation of the CREB transcription factor and its activator CaMKIV. Tat NR2B9c-dependent neuroprotection and CREB phosphorylation are blocked by coapplication of CaM kinase (KN93 and STO-609) or CREB (KG-501) inhibitors, and by siRNA knockdown of CaMKIV. These results are mirrored in vivo in a rat model of permanent focal ischaemia. Tat-NR2B9c application significantly reduces infarct size and causes a selective and sustained elevation in CaMKIV phosphorylation; effects which are blocked by coadministration of KN93. Thus, calcium-dependent nuclear signalling via CaMKIV and CREB is critical for neuroprotection via NMDAR-PSD95 blockade, both in vitro and in vivo. This study highlights the importance of maintaining neuronal function following ischaemic injury. Future stroke research should target neurotrophic and pro-survival signal pathways in the development of novel neuroprotective strategies. PMID- 23363437 TI - A novel non-competitive amperometric immunosensor by using thiourea glutaraldehyde-modified gold electrode for immunoglobulin M detection. AB - A novel non-competitive amperometric immunosensor based on a self-assembled monolayer (SAM) of thiourea modified by a polymeric Schiff's base of glutaraldehyde on gold electrode has been developed for determination of IgM. Alkaline phosphatase (ALP)-conjugated monoclonal anti-mouse immunoglobulin M (IgM) antibody was selectively bound to IgM molecules onto the surface of the electrode. Electrochemical response arising from the catalytic reaction of alkaline phosphatase enzyme. Its reaction with various phosphates such as p aminophenyl phosphate and p-nitrophenyl phosphatase (p-NPP) generates the electrochemically active products p-aminophenol (p-AP) and p-nitrophenol (p-NP), respectively. PMID- 23363438 TI - Identification of differentially expressed proteins of Arthrospira (Spirulina) plantensis-YZ under salt-stress conditions by proteomics and qRT-PCR analysis. AB - Arthrospira (Spirulina) platensis as a representative species of cyanobacteria has been recognized and used worldwide as a source of protein in the food, which possesses some unusual and valuable physiological characteristics, such as alkali and salt tolerance. Based on complete genome sequencing of Arthrospira (Spirulina) plantensis-YZ, we compared the protein expression profiles of this organism under different salt-stress conditions (i.e. 0.02 M, 0.5 M and 1.0 M NaCl, respectively), using 2-D electrophoresis and peptide mass fingerprinting, and retrieved 141 proteins showing significantly differential expression in response to salt-stress. Of the 141 proteins, 114 Arthrospira (Spirulina) plantensis-YZ proteins were found with significant homology to those found in Arthrospira (76 proteins in Arthrospira platensis str. Paraca and 38 in Arthrospira maxima CS-328). The remaining 27 proteins belong to other bacteria. Subsequently, we determined the transcriptional level of 29 genes in vivo in response to NaCl treatments and verified them by qRT-PCR. We found that 12 genes keep consistency at both transcription and protein levels, and transcription of all of them but one were up-regulated. We classified the 141 differentially expressed proteins into 18 types of function categories using COG database, and linked them to their respective KEGG metabolism pathways. These proteins are involved in 31 metabolism pathways, such as photosynthesis, glucose metabolism, cysteine and methionine metabolism, lysine synthesis, fatty acid metabolism, glutathione metabolism. Additionally, the SRPs, heat shock protein and ABC transporter proteins were identified, which probably render Arthrospira (Spirulina) plantensis's resistance against high salt stress. PMID- 23363439 TI - Everolimus-eluting stents versus sirolimus- or paclitaxel-eluting stents: two year results from the Guthrie Health Off-Label Stent (GHOST) registry. AB - OBJECTIVES: We sought to compare the safety and effectiveness of everolimus eluting stents (EES) versus first generation drug-eluting stents (FG-DES; sirolimus-eluting stent [SES] or paclitaxel-eluting stent [PES]). METHODS: In 2,126 patients undergoing percutaneous coronary intervention (PCI), we compared the 2-year incidence of stent thrombosis (ST) and target vessel revascularization (TVR) between the EES versus FG-DES groups. Secondary end-points included all cause death, myocardial infarction (MI), death or MI, and major adverse cardiovascular events (MACE, including death, MI, ST, or TVR). Further, we evaluated these end-points in 2 propensity-matched subgroups: EES versus SES; EES versus PES. RESULTS: Complete 2-year follow-up was available in 1,911 (90%) patients. Compared to FG-DES, implantation of EES was associated with trends towards lower ST (0.9% vs. 2.8%, P = 0.068) and TVR (3.8% vs. 7.2%, P = 0.052), which persisted after adjustment for baseline differences (for ST, adjusted hazard ratio, HR 0.32; 95% confidence interval, 95% CI 0.10-1.02, P = 0.053; for TVR, HR 0.40; 95% CI 0.22-0.75, P = 0.004). Compared to SES, EES implantation was associated with lower TVR and a trend towards lower ST. Compared to PES, EES implantation was associated with less ST and TVR and trends towards lower death/MI and MACE. In the EES group, no ST was seen after the first 3 months. CONCLUSIONS: The use of EES compared to FG-DES appears to be associated with reductions in ST and TVR at 2-year follow-up. Improved outcomes with EES are observed in comparison with SES as well as PES. PMID- 23363440 TI - Substrate-initiated synthesis of cell-penetrating poly(disulfide)s. AB - Lessons from surface-initiated polymerization are applied to grow cell penetrating poly(disulfide)s directly on substrates of free choice. Reductive depolymerization after cellular uptake should then release the native substrates and minimize toxicity. In the presence of thiolated substrates, propagators containing a strained disulfide from asparagusic or, preferably, lipoic acid and a guanidinium cation polymerize into poly(disulfide)s in less than 5 min at room temperature at pH 7. Substrate-initiated polymerization of cationic poly(disulfide)s and their depolymerization with dithiothreitol causes the appearance and disappearance of transport activity in fluorogenic vesicles. The same process is further characterized by gel-permeation chromatography and fluorescence resonance energy transfer. PMID- 23363441 TI - Molecular chaperone ORP150 in ER stress-related diseases. AB - Many disturbances in the normal function of endoplasmic reticulum (ER) cause accumulation of unfolded proteins in the lumen of ER, triggering an evolutionary conserved response, termed the unfolded protein response (UPR). The UPR is the mechanism enabling cells to cope with unfolded proteins, accumulated in ER lumen after the cell has been exposed to various unfavorable conditions. The UPR process has strong prosurvival implications, but switches towards apoptotic cell death when the stress becomes severe and unsolvable. The hallmark of the cytoprotective branch of UPR is stimulation of the expression of ER chaperones, of which ORP150 has gained a great deal of attention. ORP150 has been identified as being overexpressed in the pathology of many diseases and is involved in the cellular response to environmental stress. Although some fragmentary results concerning ORP150 molecular activity have been presented, its exact mode of action still remains unclear. In this paper we focused on the role of ORP150 in the pathogenesis of the main types of ER stress-related diseases: diabetes, neurodegenerative diseases, cardiovascular diseases and cancer. PMID- 23363442 TI - Identification and usage of fluorescent probes as nanoparticle contrast agents in detecting cancer. AB - As advancements in the field of nanoparticle imaging science are made, one of the first benefits will be in open and endoscopic conditions. There is considerable evidence indicating that the use of injected contrast agents can improve the detection of tumor margins and small metastases. New and innovative targeting and contrast agents including small molecules, antibodies and nanoparticles have to be developed for a broad range of tumor types such as breast, brain, pancreatic, and ovarian cancers. At present, a number of organic dye molecules have been approved for human use including (1) indocyanine green (ICG), a near-infrared fluorescent dye; (2) fluorescein, a green fluorescent dye; (3) photofrin, a mixture of fluorescent protoporphyrin oligomers approved for photodynamic therapy, and (4) 5-aminolevulinic acid (ALA), a small molecule that is preferentially taken up by tumor cells leading to biosynthesis and accumulation of protoporphyrin IX, a natural fluorophore with red fluorescence emission. On the other hand, nanoparticles have not received FDA approval for clinical imaging, as this technology needs a lot of development and lot of research is being carried out in this unexplored area. A major task is, therefore to develop biocompatible and nontoxic nanoparticle contrast agents with the potential for FDA approval and human use. Such agents need to show improved sensitivity and specificity for tumor imaging in comparison with small-molecule-dyes. In this regard, it is highly promising to develop smart or activatable nanoparticles with improved pharmacokinetic, tumor targeting and organ clearance properties, based on the use of natural, biodegradable polymers (dextran and heparin). Dextran based particles are sensitive to pH, and can be rapidly broken down under acidic conditions. Under neutral or slightly basic conditions, on the other hand, the dextran nanoparticles are stable and are able to circulate systemically in blood for 14 to 15 hours. In contrast, self-assembled heparin nanoparticles have much shorter blood circulation half-lives (about 60-80 min). For intra-operative use, this short circulation time could be beneficial because the probes will be cleared from the body quickly, so that surgical operations and treatment can start without much delay or waiting. For near-term clinical applications, it is important that both the dextran and heparin particles are able to trap as FDA approved dye (such as indocyanine green), leading to new class of imaging contrast agents with improved bio distribution and photo physical properties. This class of nanoparticle contrast agents could also be conjugated with tumor targeting ligands such as folate, Epidermal Growth Factor (EGF), or RGD (recognition sequence for integrins that contains Arg-Gly-Asp attachment site) for improved sensitivity and specificity in perfect cancer imaging technique agents. This review article actually highlights the new developments occurring in this area of imaging techniques in cancer research and the author himself is using the technique for developing newer fluorescent molecules for molecular imaging using nanotechnology. PMID- 23363443 TI - Integration of in silico and in vitro tools for scaffold optimization during drug discovery: predicting P-glycoprotein efflux. AB - In silico tools are regularly utilized for designing and prioritizing compounds to address challenges related to drug metabolism and pharmacokinetics (DMPK) during the process of drug discovery. P-Glycoprotein (P-gp) is a member of the ATP-binding cassette (ABC) transporters with broad substrate specificity that plays a significant role in absorption and distribution of drugs that are P-gp substrates. As a result, screening for P-gp transport has now become routine in the drug discovery process. Typically, bidirectional permeability assays are employed to assess in vitro P-gp efflux. In this article, we use P-gp as an example to illustrate a well-validated methodology to effectively integrate in silico and in vitro tools to identify and resolve key barriers during the early stages of drug discovery. A detailed account of development and application of in silico tools such as simple guidelines based on physicochemical properties and more complex quantitative structure-activity relationship (QSAR) models is provided. The tools were developed based on structurally diverse data for more than 2000 compounds generated using a robust P-gp substrate assay over the past several years. Analysis of physicochemical properties revealed a significantly lower proportion (<10%) of P-gp substrates among the compounds with topological polar surface area (TPSA) <60 A(2) and the most basic cpKa <8. In contrast, this proportion of substrates was greater than 75% for compounds with TPSA >60 A(2) and the most basic cpKa >8. Among the various QSAR models evaluated to predict P gp efflux, the Bagging model provided optimum prediction performance for prospective validation based on chronological test sets. Four sequential versions of the model were built with increasing numbers of compounds to train the models as new data became available. Except for the first version with the smallest training set, the QSAR models exhibited robust prediction profiles with positive prediction values (PPV) and negative prediction values (NPV) exceeding 80%. The QSAR model demonstrated better concordance with the manual P-gp substrate assay than an automated P-gp substrate screen. The in silico and the in vitro tools have been effectively integrated during early stages of drug discovery to resolve P-gp-related challenges exemplified by several case studies. Key learning based on our experience with P-gp can be widely applicable across other DMPK-related challenges. PMID- 23363444 TI - Hydrolytic and aminolytic kinetic resolution of terminal bis-epoxides. AB - Hydrolytic and aminolytic kinetic resolution of terminal bis-epoxides catalyzed by (salen)Co(III) complexes affords epoxy-diols and N-protected epoxy-amino alcohols with excellent enantio- and diastereoselectivity and good yields. An operationally simple procedure gives instant access to valuable building blocks containing two remote stereocenters in highly enantioenriched form. PMID- 23363445 TI - Norcantharidin inhibits tumor angiogenesis via blocking VEGFR2/MEK/ERK signaling pathways. AB - Norcantharidin (NCTD), the demethylated form of Cantharidin, a reagent isolated from blister beetles, has been shown to be an anti-tumor agent capable of inhibiting proliferation as well as inducing apoptosis in many cancer cell lines. However, little is known about the effect of NCTD in tumor angiogenesis. In this study, we demonstrated that NCTD inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, invasion, and capillary tube formation of primary human umbilical vein endothelial cells (HUVECs) in a dose dependent manner. Furthermore, we showed NCTD inhibited tumor growth and angiogenesis of colon cancer cells (LOVO) in vivo. We then mechanistically described that NCTD specifically abrogated the phosphorylation/activation of vascular endothelial growth factor receptor-2 (VEGFR2)/MEK/ERK pathway kinases, with little effect on the phosphorylation of p38 MAPK and Akt, and on Cox-2 expression. In summary, our results indicate that NCTD is a potential inhibitor of tumor angiogenesis by blocking VEGFR2/MEK/ERK signaling. PMID- 23363446 TI - The impact of reference gene selection in quantification of gene expression levels in guinea pig cervical tissues and cells. AB - BACKGROUND: Accurate measurements of mRNA expression levels in tissues or cells are crucially dependent on the use of relevant reference genes for normalization of data. In this study we used quantitative real-time PCR and two Excel-based applets (geNorm and BestKeeper) to determine the best reference genes for quantification of target gene mRNA in a complex tissue organ such as the guinea pig cervix. RESULTS: Gene expression studies were conducted in cervical epithelium and stroma during pregnancy and parturition and in cultures of primary cells from this tissue. Among 15 reference gene candidates examined, both geNorm and BestKeeper found CLF1 and CLTC to be the most stable in cervical stroma and cervical epithelium, ACTB and PPIB in primary stroma cells, and CLTC and PPIB in primary epithelial cells. The order of stability among the remaining candidate genes was not in such an agreement. Commonly used reference such as GAPDH and B2M demonstrated lower stability. Determination of pairwise variation values for reference gene combinations using geNorm revealed that the geometric mean of the two most stable genes provides sufficient normalization in most cases. However, for cervical stroma tissue in which many reference gene candidates displayed low stability, inclusion of three reference genes in the geometric mean may improve accuracy of target gene expression level analyses. Using the top ranked reference genes we examined the expression levels of target gene PTGS2 in cervical tissue and cultured cervical cells. We compared the results with PTGS2 expression normalized to the least stable gene and found significant differences in gene expression, up to 10-fold in some samples, emphasizing the importance of appropriately selecting reference genes. CONCLUSIONS: We recommend using the geometric mean of CFL1 and CLTC for normalization of qPCR studies in guinea pig cervical tissue studies, ACTB and PPIB in primary stroma cells and CLTC and PPIB in primary epithelial cells from guinea pig. PMID- 23363447 TI - Construction and validation of an ecological version of the Wisconsin Card Sorting Test applied to an elderly population. AB - The goal of this project was to construct and validate an ecological version of the Wisconsin Card Sorting Test (WCST) aimed at the elderly. This was accomplished by replacing the geometric stimuli of the traditional version with stimuli belonging to the semantic category of transport vehicles, and by elimination of the color yellow. The results showed the ecological WCST version was preferred over the traditional version and older people felt less tired during test performance. In the two independent normal elderly groups, all pairs of scores that can be derived from the WCST correlated significantly with each other. Six of 11 outcome measures of the traditional WCST-128 (long) version were significantly influenced by age. By contrast, in the WCST-64 (short) version and in the ecological WCST-54 version only one measure was affected by the age variable. No significant effect of education level or gender emerged from the results in any WCST version. Again, the subjects with cognitive deterioration had lower performance in the ecological WCST-54 version than in the two traditional WCST versions. It seems reasonable to assume that the ecological version of WCST is more discriminating and has more advantages than the traditional versions. Further research on individual differences in the performance on this task will increase understanding of the components of the test, and of the variety of factors and possible deficits that could lead to an impaired performance of the test. PMID- 23363448 TI - Improvement of endocytoscopic findings after per oral endoscopic myotomy (POEM) in esophageal achalasia; does POEM reduce the risk of developing esophageal carcinoma? Per oral endoscopic myotomy, endocytoscopy and carcinogenesis. AB - BACKGROUND: Per oral endoscopic myotomy (POEM) has been reported to be a new therapeutic option for esophageal achalasia. The possibility that POEM could reduce the risk of developing esophageal squamous cell carcinoma was evaluated. METHODS: This was a single-centre, retrospective study. Fifteen consecutive patients with esophageal achalasia who underwent POEM in our institution between August 2010 and January 2012 were enrolled. Ultra-high magnification with endocytoscopy was performed, and both histopathological and immunohistochemical evaluations for Ki-67 and p53 were assessed before and 3 months after POEM. RESULTS: POEM was successfully performed and effectively released the dysphagia symptom in all patients without severe complications. Subjective symptoms (mean Ekcardt score, before 7.4 vs. after 0.5, p<0.05) and manometric pressure studies (mean lower esophageal sphincter pressure), before 82.7 vs. after 22.9 mmHg, p<0.05) showed substantial improvement following POEM. The average numbers of esophageal epithelial nuclei before and after POEM on endocytoscopic images were 128.0 and 78.0, respectively (p<0.05). The mean Ki-67-positive ratio was 26.0 (median 25.4, range, 10.3-33.2) before and 20.7 (median 20.0, 13.1-29.9; p=0.07) after POEM, and the mean p53-positive ratio was 2.35 (median 2.61, 0.32-4.23) before and 0.97 (median 1.49, 0.32-1.56; p<0.05) after POEM. A significant positive correlation was seen between the number of nuclei and the Ki-67-positive ratio (p<0.05). CONCLUSIONS: POEM appears to be an effective and less invasive treatment of choice against achalasia and may reduce the risk of esophageal carcinogenesis. Endocytoscopy can be useful for the assessment of esophageal cellular proliferation. PMID- 23363449 TI - Detection of novel viruses in porcine fecal samples from China. AB - BACKGROUND: Pigs are well known source of human infectious disease. To better understand the spectrum of viruses present in pigs, we utilized the 454 Life Sciences GS-FLX high-throughput sequencing platform to sequence stool samples from healthy pigs. FINDINGS: Total nucleic acid was extracted from stool samples of healthy piglets and randomly amplified. The amplified materials were pooled and processed using a high-throughput pyrosequencing technique. The raw sequences were deconvoluted on the basis of the barcode and then processed through a standardized bioinformatics pipeline. The unique reads (348, 70 and 13) had limited similarity to known astroviruses, bocaviruses and parechoviruses. Specific primers were synthesized to assess the prevalence of the viruses in healthy piglets. Our results indicate extremely high rates of positivity. CONCLUSIONS: Several novel astroviruses, bocaviruses and Ljungan-like viruses were identified in stool samples from healthy pigs. The rates of isolation for the new viruses were high. The high detection rate, diverse sequences and categories indicate that pigs are well-established reservoirs for and likely sources of different enteric viruses. PMID- 23363450 TI - Interpreting one oral health impact profile point. AB - BACKGROUND: Interpretation of scores from oral health-related quality of life (OHRQoL) instruments, such as the Oral Health Impact Profile (OHIP) is challenging. It was the aim of this study to determine how many oral impacts correspond to one point of the 49-item OHIP using a new approach which translates numeric problem counts into the traditionally used ordinal OHIP response categories. METHODS: A sample of 145 consecutively recruited prosthodontic patients seeking treatment or having a routine examination completed the German version of the 49-item OHIP with the original ordinal response format as a self administered questionnaire. In addition, the numerical frequencies of impairment during the previous month were requested in personal interviews. Based on a multilevel mixed-effects linear regression, we estimated the mean difference with 95% confidence interval (CI) in numerical frequency between two adjacent ordinal responses. RESULTS: A numerical frequency of 15.2 (CI: 14.8 - 15.7) impacts per month corresponded to one OHIP point. This translates to approximately one impact every other day in the past month. CONCLUSIONS: The oral problem count per day that corresponds to one OHIP-49 point can be used to interpret this instrument's scores in cross-sectional and longitudinal studies. This number can help to better understand OHRQoL burden for patients, clinicians, and researchers alike. PMID- 23363451 TI - Guiding spatial arrangements of silver nanoparticles by optical binding interactions in shaped light fields. AB - We demonstrate assembly of spheroidal Ag nanoparticle clusters, chains and arrays induced by optical binding. Particles with diameters of 40 nm formed ordered clusters and chains in aqueous solution when illuminated by shaped optical fields with a wavelength of 800 nm; specifically, close-packed clusters were formed in cylindrically symmetric optical traps, and linear chains were formed in line traps. We developed a coupled-dipole model to calculate the optical forces between an arbitrary number of particles and successfully predicted the experimentally observed particle separations and arrangements as well as their dependence on the polarization of the incident light. This demonstrates that the interaction between these small Ag particles and light is well described by approximating the particles as point dipoles, showing that these experiments extend optical binding into the Rayleigh regime. For larger Ag nanoparticles, with diameters of approximately 100 nm, the optical-binding forces become comparable to the largest gradient forces in the optical trap, and the particles can arrange themselves into regular arrays or synthetic photonic lattices. Finally, we discuss the differences between our experimental observations and the point dipole theory and suggest factors that prevent the Ag nanoparticles from aggregating as expected from the theory. PMID- 23363452 TI - Fresh broad (Vicia faba) tissue homogenate-based biosensor for determination of phenolic compounds. AB - In this study, a novel fresh broad (Vicia faba) tissue homogenate-based biosensor for determination of phenolic compounds was developed. The biosensor was constructed by immobilizing tissue homogenate of fresh broad (Vicia faba) on to glassy carbon electrode. For the stability of the biosensor, general immobilization techniques were used to secure the fresh broad tissue homogenate in gelatin-glutaraldehyde cross-linking matrix. In the optimization and characterization studies, the amount of fresh broad tissue homogenate and gelatin, glutaraldehyde percentage, optimum pH, optimum temperature and optimum buffer concentration, thermal stability, interference effects, linear range, storage stability, repeatability and sample applications (Wine, beer, fruit juices) were also investigated. Besides, the detection ranges of thirteen phenolic compounds were obtained with the help of the calibration graphs. A typical calibration curve for the sensor revealed a linear range of 5-60 MUM catechol. In reproducibility studies, variation coefficient (CV) and standard deviation (SD) were calculated as 1.59%, 0.64*10(-3) MUM, respectively. PMID- 23363453 TI - Oxidation of carbene-stabilized diarsenic: diarsene dications and diarsenic radical cations. AB - Oxidation of carbene-stabilized diarsenic, L:As-As:L [L: = :C{N(2,6 (i)Pr(2)C(6)H(3))CH}(2)] (1), with gallium chloride in a 1:4 ratio in toluene affords the dicationic diarsene complex [L:As?As:L](2+)([GaCl(4)](-))(2) (2(2+)[GaCl(4)](2)), while oxidation of 1 with GaCl(3) in a 1:2 ratio in Et(2)O yields the monocationic diarsenic radical complex [L:AsAs:L](*+)[GaCl(4)](-) (2(*+)[GaCl(4)]). Strikingly, complex 2(*+) is the first arsenic radical to be structurally characterized in the solid state. The nature of the bonding in these complexes was probed computationally and spectroscopically. PMID- 23363455 TI - Mineral-water interface reactions of actinides. PMID- 23363454 TI - Illness perceptions in the context of differing work participation outcomes: exploring the influence of significant others in persistent back pain. AB - BACKGROUND: Previous research has demonstrated that the significant others of individuals with persistent back pain may have important influences on work participation outcomes. The aim of this study was to extend previous research by including individuals who have remained in work despite persistent back pain in addition to those who had become incapacitated for work, along with their significant others. The purpose of this research was to explore whether the illness beliefs of significant others differed depending on their relative's working status, and to make some preliminary identification of how significant others may facilitate or hinder work participation for those with persistent back pain. METHODS: Interviews structured around the Illness Perception Questionnaire (chronic pain version) were conducted with back pain patients recruited from a hospital pain management clinic along with their significant others. Some patients had remained in work despite their back pain; others had ceased employment. Data were analysed using template analysis. RESULTS: There were clear differences between beliefs about, and reported responses to, back pain symptoms amongst the significant others of individuals who had remained in employment compared with the significant others of those who had ceased work. Three overarching themes emerged: perceived consequences of back pain, specific nature of employment and the impact of back pain on patient identity. CONCLUSIONS: Significant others of employed individuals with back pain focused on the extent to which activity could still be undertaken despite back pain symptoms. Individuals out of work due to persistent back pain apparently self-limited their activity and were supported in their beliefs and behaviours by their significant others. To justify incapacity due to back pain, this group had seemingly become entrenched in a position whereby it was crucial that the individual with back pain was perceived as completely disabled. We suggest that significant others are clearly important, and potentially detrimental, sources of support to individuals with back pain. The inclusion of significant others in vocational rehabilitation programmes could potentially be a valuable way of mobilising readily accessible resources in a way that supports optimal functioning. PMID- 23363456 TI - BDNF prevents NMDA-induced toxicity in models of Huntington's disease: the effects are genotype specific and adenosine A2A receptor is involved. AB - NMDA receptor-mediated excitotoxicity is thought to play a pivotal role in the pathogenesis of Huntington's disease (HD). The neurotrophin brain-derived neurotrophic factor (BDNF), which is also highly involved in HD and whose effects are modulated by adenosine A2 ARs, influences the activity and expression of striatal NMDA receptors. In electrophysiology experiments, we investigated the role of BDNF toward NMDA-induced effects in HD models, and the possible involvement of A2ARs. In corticostriatal slices from wild-type mice and age matched symptomatic R6/2 mice (a model of HD), NMDA application (75 MUM) induced a transient or a permanent (i.e., toxic) reduction of field potential amplitude, respectively. BDNF (10 ng/mL) potentiated NMDA effects in wild-type, while it protected from NMDA toxicity in R6/2 mice. Both effects of BDNF were prevented by A2 AR blockade. The protective effect of BDNF against NMDA-induced toxicity was reproduced in a cellular model of HD. These findings may have very important implications for the neuroprotective potential of BDNF and A2 AR ligands in HD. PMID- 23363457 TI - A fast approach to global alignment of protein-protein interaction networks. AB - BACKGROUND: Global network alignment has been proposed as an effective tool for computing functional orthology. Commonly used global alignment techniques such as IsoRank rely on a two-step process: the first step is an iterative diffusion based approach for assigning similarity scores to all possible node pairs (matchings); the second step applies a maximum-weight bipartite matching algorithm to this similarity score matrix to identify orthologous node pairs. While demonstrably successful in identifying orthologies beyond those based on sequences, this two-step process is computationally expensive. Recent work on computation of node-pair similarity matrices has demonstrated that the computational cost of the first step can be significantly reduced. The use of these accelerated methods renders the bipartite matching step as the dominant computational cost. This motivates a critical assessment of the tradeoffs of computational cost and solution quality (matching quality, topological matches, and biological significance) associated with the bipartite matching step. In this paper we utilize the state-of-the-art core diffusion-based step in IsoRank for similarity matrix computation, and couple it with two heuristic bipartite matching algorithms - a matrix-based greedy approach, and a tunable, adaptive, auction-based matching algorithm developed by us. We then compare our implementations against the performance and quality characteristics of the solution produced by the reference IsoRank binary, which also implements an optimal matching algorithm. RESULTS: Using heuristic matching algorithms in the IsoRank pipeline exhibits dramatic speedup improvements; typically *30 times faster for the total alignment process in most cases of interest. More surprisingly, these improvements in compute times are typically accompanied by better or comparable topological and biological quality for the network alignments generated. These measures are quantified by the number of conserved edges in the alignment graph, the percentage of enriched components, and the total number of covered Gene Ontology (GO) terms. CONCLUSIONS: We have demonstrated significant reductions in global network alignment computation times by coupling heuristic bipartite matching methods with the similarity scoring step of the IsoRank procedure. Our heuristic matching techniques maintain comparable - if not better - quality in resulting alignments. A consequence of our work is that network-alignment based orthologies can be computed within minutes (as compared to hours) on typical protein interaction networks, enabling a more comprehensive tuning of alignment parameters for refined orthologies. PMID- 23363458 TI - Diabetic gastroparesis. AB - BACKGROUND: Diabetic gastroparesis (DGP) is a gastric complication of diabetes mellitus that causes nausea, vomiting, early satiety, bloating and abdominal pain, in addition to significant morbidity. SOURCES OF DATA: Original and review articles were reviewed through PubMed, including relevant guidelines from the European and American Neurogastroenterology Societies. AREAS OF AGREEMENT: Diagnosis of DGP requires endoscopy and measurement of gastric emptying. Management requires prokinetic therapy, usually in addition to antinausea or other medications. AREAS OF CONTROVERSY: The pathogenesis of DGP is poorly understood. Management strategies are highly variable. Growing points Prokinetic and neuromodulatory medications are in human clinical trials specifically for gastroparesis. AREAS TIMELY FOR DEVELOPING RESEARCH: Further understanding of the molecular pathology leading to DGP is required to potentially arrest the development of this serious diabetic complication. Evaluation of novel agents for use in DGP is sorely needed. PMID- 23363459 TI - Medication adherence and persistence in the treatment of Canadian ulcerative colitis patients: analyses with the RAMQ database. AB - BACKGROUND: Although high non-adherence to medication has been noticed for ulcerative colitis (UC), little is known about adherence to mesalamine treatments and determinants that can predict adherence. The objective of this study was to assess adherence and persistence to mesalamine treatments and their potential determinants in mild to moderate UC patients in a real-life setting in Quebec, Canada. METHODS: A retrospective prescription and medical claims analysis was conducted using a random sample of mesalamine users with UC. For inclusion, patients were required to initiate an oral mesalamine treatment between January 2005 and December 2009. Patients with a diagnosis of Crohn's disease were excluded. Treatment adherence (medication possession ratio [MPR]) and persistence were evaluated over a 1-year period after the index prescription using the Kaplan Meier method with log-rank test and stepwise regression to identify potential determinants. RESULTS: A sample of 1,681 of the new oral mesalamine users (mean age = 55.3) patients was obtained. Overall, the percentage of patients with a MPR of 80% or greater at 12 months was 27.7%, while persistence was 45.5%. Among patients treated with mesalamine delayed/extended-release tablets (Mezavant(r)), adherence and persistence were 40.9% and 71.9%, respectively. Predictors of high adherence included, male gender (OR=1.3; 95% confidence interval [CI]=1.1-1.6), older age (>60 years; OR=1.6; 95% CI=1.3-2.0) and current use of corticosteroids (OR=1.4; 95% CI=1.1-1.8). Predictors of high persistence included male sex (OR=1.4; 95% CI=1.1-1.7), current use of corticosteroids (OR=1.4; 95% CI=1.1-1.7) and presence of hypertension or respiratory diseases (OR=1.2; 95% CI=1.01-1.55). CONCLUSIONS: The majority of patients with UC exhibited low adherence and persistence to mesalamine treatments. Various determinants of improved adherence and persistence were identified. PMID- 23363461 TI - Reflections on twin relationships: twins reared apart and twins of opposite gender. AB - The complexities of twin relationships posed by separate rearing and by opposite sex are considered. Unusual cases may highlight unique social-interactional processes and outcomes occurring in these pairs. Research reviews include recent twin studies on second language acquisition, political behavior, and multiple birth rates. Items of more general interest include twin 'cousins' reared apart, indistinguishable monozygotic quadruplets, a genetic testing dilemma, and a performance about separated twins. PMID- 23363460 TI - The Minnesota Center for Twin and Family Research genome-wide association study. AB - As part of the Genes, Environment and Development Initiative, the Minnesota Center for Twin and Family Research (MCTFR) undertook a genome-wide association study, which we describe here. A total of 8,405 research participants, clustered in four-member families, have been successfully genotyped on 527,829 single nucleotide polymorphism (SNP) markers using lllumina's Human660W-Ouad array. Quality control screening of samples and markers as well as SNP imputation procedures are described. We also describe methods for ancestry control and how the familial clustering of the MCTFR sample can be accounted for in the analysis using a Rapid Feasible Generalized Least Squares algorithm. The rich longitudinal MCTFR assessments provide numerous opportunities for collaboration. PMID- 23363465 TI - Olfactory responses of Drosophila larvae. AB - We studied complete dose-response curves for 53 odorants in the third instar larvae of Drosophila melanogaster. All odorants, except one, elicited an attraction response. Some odorants also elicited a decrease from their peak response at higher concentrations. This concentration-dependent decrease in olfactory response could be due to either desensitization or repulsion, 2 possibilities that we cannot distinguish in our current assay. We observed high variations in factors like slopes, thresholds, and peaks of responses that, in agreement with previous studies, suggest that the responses of different receptors are quite different for the similar change in concentration of various ligands. We also observed that lower attraction thresholds predicted higher peak amplitude. This suggests that if odor responses encompassed wider concentration range than can be covered by the dynamic range of a single receptor, then responses tend to be high in magnitude. PMID- 23363467 TI - Immature DC isolated after co-culture with PUVA-treated peripheral blood mononuclear cells downregulate graft-versus-host reactions in the human skin explant model. AB - Graft-versus-host disease (GvHD) remains the major barrier to successful allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photopheresis (ECP) is a potent immunomodulatory treatment option for GvHD. In contrast to conventional immunosuppressants, ECP is considered not to increase relapse and infection rates resulting from generalised immunosuppression. ECP involves the mechanical separation of 5-10% of patient peripheral blood mononuclear cells, which are then exposed to psoralen and UVA light (PUVA) before they are returned to the patient. ECP has been shown to induce apoptosis in various cell types, in particular lymphocytes. Several studies describe downregulation of pro-inflammatory cytokines as well as promotion of peripheral tolerance through enhanced production of T regulatory cells in the course of ECP treatment. Modulation of antigen-presenting cells such as dendritic cells (DC) by PUVA-treated lymphocytes might be implicated in these regulatory processes. We evaluated the impact of PUVA-treated lymphocytes on immature DC and further demonstrated the functional capacity of such modified DC to modulate GVH reactions using a well-established human skin-explant model of GvHD. Addition of immature DC isolated after co-culture with PUVA-treated but not untreated MLR cells significantly downregulated skin-GvH reactions (p=0.023, Mann-Whitney Test). IFN-gamma levels were non-significantly decreased in MLR and skin supernatants. We observed a non-significant increase in PD-L1 expression in iDC after co-culture with PUVA-treated MLR cells whereas expression levels of IDO and ILT-3 were not affected. We conclude that iDC modulated by PUVA-induced apoptotic cells potently downregulate allogeneic immune responses possibly through PD-L1- dependent signaling. PMID- 23363466 TI - Periodic email prompts to re-use an internet-delivered computer-tailored lifestyle program: influence of prompt content and timing. AB - BACKGROUND: Adherence to Internet-delivered lifestyle interventions using multiple tailoring is suboptimal. Therefore, it is essential to invest in proactive strategies, such as periodic email prompts, to boost re-use of the intervention. OBJECTIVE: This study investigated the influence of content and timing of a single email prompt on re-use of an Internet-delivered computer tailored (CT) lifestyle program. METHODS: A sample of municipality employees was invited to participate in the program. All participants who decided to use the program received an email prompting them to revisit the program. A 2*3 (content * timing) design was used to test manipulations of prompt content and timing. Depending on the study group participants were randomly assigned to, they received either a prompt containing standard content (an invitation to revisit the program), or standard content plus a preview of new content placed on the program website. Participants received this prompt after 2, 4, or 6 weeks. In addition to these 6 experimental conditions, a control condition was included consisting of participants who did not receive an additional email prompt. Clicks on the uniform resource locator (URL) provided in the prompt and log-ins to the CT program were objectively monitored. Logistic regression analyses were conducted to determine whether prompt content and/or prompt timing predicted clicking on the URL and logging in to the CT program. RESULTS: Of all program users (N=240), 206 participants received a subsequent email prompting them to revisit the program. A total of 53 participants (25.7%) who received a prompt reacted to this prompt by clicking on the URL, and 25 participants (12.1%) actually logged in to the program. There was a main effect of prompt timing; participants receiving an email prompt 2 weeks after their first visit clicked on the URL significantly more often compared with participants that received the prompt after 4 weeks (odds ratio [OR] 3.069, 95% CI 1.392-6.765, P=.005) and after 6 weeks (OR 4.471, 95% CI 1.909-10.471, P=.001). Furthermore, participants who received an email prompt 2 weeks after their first visit logged in to the program significantly more often compared to participants receiving the prompt after 6 weeks (OR 16.356, 95% CI 2.071-129.196, P=.008). A trend was observed with regard to prompt content. Participants receiving a prompt with additional content were more likely to log in to the program compared to participants who received a standard prompt. However, this result was not statistically significant (OR 2.286, 95% CI 0.892-5.856, P=.09). CONCLUSIONS: The key findings suggest that boosting revisits to a CT program benefits most from relatively short prompt timing. Furthermore, a preview of new website content may be added to a standard prompt to further increase its effectiveness in persuading people to log in to the program. PMID- 23363468 TI - Injection time-dependent effect of adult human bone marrow stromal cell transplantation in a rat model of severe traumatic brain injury. AB - The object of this study is to evaluate the effects of injecting adult human bone marrow stromal cells (hBMSCs) into rats with severe traumatic brain injury in acute phase and to determine more optimal injection timing between day 1 and day 2 postinjury. The lateral fluid percussion injury model was used. Adult hBMSCs were transplanted into hemisphere to injury sites in the corpus callosum ipsilateral on day 1 (n = 12) or day 7 (n = 8) after injury. A control group (n = 7) underwent only a sham operation without stem cell transplantation. Rats in all groups were analyzed by magnetic resonance spectroscopy (MRS), and by using behavioral, rotarod, and Barnes maze tests on day 1, 7, 14, and 42. Another nine randomly designated rats were sacrificed for immunohistochemical staining. Behavioral test scores increased significantly at all time-points after TBI in the day 7-injected group, compared to the others (p=0.008). GFAP staining was lower on day 42 in day 7-injected rats than in those injected on day 1. But no significant inter- or intra-group differences were observed for other tests. The injection of hBMSCs was found to have limited therapeutic potential with respect to neuroprotection after traumatic brain injury. However, because injection on day 7 after TBI produced greater functional improvements in neurobehavioral tests and more effectively suppressed astroglial activation than an injection on post injury day 1, we cautiously recommend the injection time of day 7 post injury in hBMSCs transplantation in severe TBI, rather than day 1 post injury but further studies on developing hBMSC-based new therapeutic approaches should be warranted for improving neuroprotection in severe TBI. PMID- 23363469 TI - Comparative study on dispersion and interfacial properties of single walled carbon nanotube/polymer composites using Hansen solubility parameters. AB - Dispersion and interfacial strain transfer of single walled carbon nanotubes (SWNTs) are two major challenges for the utilization of SWNTs as reinforcements in polymer composites. Surface modifications could help change the dispersion and interfacial properties. In this study, nanocomposites were fabricated by solution blending 1 wt % SWNTs with various modification (nonmodified, nitric acid functionalized, and amine functionalized SWNTs) and three kinds of polymeric materials (polycarbonate, polyvinylidene fluoride, and epoxy). Chemical compatibilities between SWNTs and solvents or polymers are calculated by the Hansen solubility parameters (HSP) method. The dispersion of the SWNTs in solvents is evaluated by dynamic light scattering. The dispersion of SWNTs in polymers evaluated by a light optical microscope (LOM) generally agrees with the HSP prediction. The strain transfer from the matrix to SWNTs is mainly related to the dispersion, the bundle size, the residual thermal stresses on the sample, and, to lesser degree, the HSP. PMID- 23363470 TI - What to do now? How women with breast cancer make fertility preservation decisions. AB - OBJECTIVES: There has been increased attention paid to cancer-related infertility and fertility preservation. However, how cancer patients decide whether or not to pursue fertility preservation has not been fully examined. METHODS: The data come from 34 interviews with women in the USA diagnosed with breast cancer prior to 40 years of age who contemplated fertility preservation prior to cancer treatment. Fully transcribed interviews were coded through a three-staged inductive process. RESULTS: Three sets of factors that shaped the decision-making process of the respondents regarding fertility preservation treatment options were identified: perceived benefits (e.g. ability to use 'younger' eggs in the future), inhibiting concerns (e.g. success rates) and influential relationships (e.g. physicians, parents and partners). CONCLUSIONS: Respondents saw their main fertility preservation decision as choosing whether or not to pursue egg/embryo banking. The decision-making process was complicated and included both health related and personal considerations, with many respondents reporting a lack of support services for fertility issues. Findings suggest that greater attention needs to be placed on presenting patients with a wider range of options. Those who counsel patients regarding fertility preservation decisions should be aware of the influence of relationship dynamics, broader health care concerns, and fertility histories on these decisions. KEY MESSAGE POINTS: While fertility preservation has garnered greater attention, less is known about how cancer patients make fertility preservation decisions. Despite the range of choices for fertility preservation, respondents identified egg/embryo banking as their primary option. Many factors outside of cancer concerns inhibit and facilitate fertility preservation decisions including fertility history and family relationship dynamics. PMID- 23363471 TI - Hashimoto's thyroiditis in childhood: presentation modes and evolution over time. AB - Aim of this survey is to report the most recent views about Hashimoto's thyroiditis (HT) natural history according to the different presentations. In children presenting with either euthyroidism or subclinical hypothyroidism HT spontaneous course is frequently characterized by a trend towards deterioration of thyroid function, whereas in those presenting with overt hyperthyroidism a definitive resolution of hyperthyroid phase is to be expected. Another possible even though unusual outcome of HT is the conversion to Graves' disease. PMID- 23363472 TI - Clinical reliability of radial forearm free flap in repair of buccal defects. AB - BACKGROUND: The ideal method for buccal defects should provide good outcome of both function and appearance; our goal is to highlight the reliability of radial forearm flap in buccal reconstruction. METHODS: A retrospective study was conducted. From 2005 to 2012, 20 radial forearm flaps were used to repair the defects. We analyzed the superiority and reliability of the flap; in addition, we reviewed some related literature and made a comparison between radial forearm flap and platysma flap. RESULTS: All radial forearm flaps totally survived, but two flaps suffered venous obstruction, hematoma, respectively. Radial forearm flap preserved the original interincisal distance well. In our follow-up, all patients had sufficient mouth-opening width (mean: 4.3 cm). CONCLUSION: Radial forearm flap is a reliable method for buccal defect reconstruction. PMID- 23363473 TI - Brain dopamine-serotonin vesicular transport disease and its treatment. AB - We describe a disease encompassing infantile-onset movement disorder (including severe parkinsonism and nonambulation), mood disturbance, autonomic instability, and developmental delay, and we describe evidence supporting its causation by a mutation in SLC18A2 (which encodes vesicular monoamine transporter 2 [VMAT2]). VMAT2 translocates dopamine and serotonin into synaptic vesicles and is essential for motor control, stable mood, and autonomic function. Treatment with levodopa was associated with worsening, whereas treatment with direct dopamine agonists was followed by immediate ambulation, near-complete correction of the movement disorder, and resumption of development. PMID- 23363474 TI - Use of health IT for higher-value critical care. PMID- 23363475 TI - Molecular analyses of Fusarium isolates recovered from a cluster of invasive mold infections in a Brazilian hospital. AB - BACKGROUND: Invasive fusariosis (IF) is a rare but often fatal fungal infection in immunosuppressed patients. In 2007, cases of IF above the expected epidemiologic baseline were detected in the hematology ward of a hospital in Rio de Janeiro, Brazil. Possible sources of infection were investigated by performing environmental sampling and patient isolate collection, followed by molecular typing. Isolates from dermatology patients with superficial fusariosis were included in the study for comparison to molecular types found in the community. METHODS: Environmental sampling focused on water-related sources in and around the hematology ward. Initially, we characterized 166 clinical and environmental isolates using the Fusarium translation elongation factor 1alpha (EF-1alpha) genetic locus. Isolates included 68 collected from water-related sources in the hospital environment, 55 from 18 hematology patients, and 43 from the skin/nails of 40 outpatients seen at the hospital dermatology clinic. Multi-locus sequence typing was performed on Fusarium solani species complex (FSSC) species 1 and 2 isolates to investigate their relatedness further. RESULTS: Most of the hematology samples were FSSC species 2, with species type FSSC 2-d the most commonly isolated from these patients. Most of the outpatient dermatology samples were also FSSC 2, with type 2-d again predominating. In contrast, environmental isolates from water sources were mostly Fusarium oxysporum species complex (FOSC) and those from air samples mostly Fusarium incarnatum-equiseti species complex (FIESC). A third of the environmental samples were FSSC, with species types FSSC 1-a and FSSC 1-b predominating. CONCLUSIONS: Fusarium isolate species types from hematology patient infections were highly similar to those recovered from dermatology patients in the community. Four species types (FSSC 1-a, 1-b, 2-d and 2-f) were shared between hematology patients and the environment. Limitations in environmental sampling do not allow for nosocomial sources of infection to be ruled out. Future studies will focus on environmental factors that may have influenced the prevalence of FSSC fusariosis in this hematology ward. PMID- 23363476 TI - Lower circulating preptin levels in male patients with osteoporosis are correlated with bone mineral density and bone formation. AB - BACKGROUND: Serum preptin levels among subjects with different bone mineral densities (BMD) were measured and investigated to determine the correlation between BMD and bone-metabolic markers. METHODS: Approximately 52 elderly male patients with osteoporosis, 50 elderly men with osteopaenia, and 31 age-matched normal bone mass controls participated in the study. The serum preptin levels and bone metabolic markers were measured by enzyme-linked immunosorbent assay. The relationships between preptin levels, BMD, and metabolic parameters were also assessed. RESULTS: The serum preptin level was the lowest in the osteoporosis group and positively correlated with BMD. All the bone formation markers in the osteoporosis and osteopaenia groups were significantly reduced compared with those in the normal group. Serum preptin level was positively correlated with all the bone formation markers, whereas no correlation was observed with the bone resorption marker TRACP-5b. CONCLUSIONS: Serum preptin levels are decreased in osteoporosis and osteopaenia patients and positively correlated with BMD. Therefore, preptin is involved in the pathogenesis of osteoporosis, probably through bone formation rather than bone resorption. PMID- 23363477 TI - Light-induced conversion of Trp to Gly and Gly hydroperoxide in IgG1. AB - The exposure of IgG1 in aqueous solution to light with lambda = 254 nm or lambda > 295 nm yields products consistent with Trp radical cation formation followed by (alpha)C-(beta)C cleavage of the Trp side chain. The resulting glycyl radicals either are reduced to Gly or add oxygen prior to reduction to Gly hydroperoxide. Photoirradiation at lambda = 254 nm targets Trp at positions 191 (light chain), 309 and 377 (heavy chain) while photoirradiation at lambda > 295 nm targets Trp at position 309 (heavy chain). Mechanistically, the formation of Trp radical cations likely proceeds via photoinduced electron or hydrogen transfer to disulfide bonds, yielding thiyl radicals and thiols, where thiols may serve as reductants for the intermediary glycyl or glycylperoxyl radicals. PMID- 23363479 TI - Open bite treatment using clear aligners. AB - A 35-year-old female patient with dentoalveolar open bite of 4 mm, molar Class I malocclusion, centered midlines, moderate crowding, and labial inclination of the lower incisor was treated with clear aligners to reduce protrusion and close the anterior open bite. The result showed that clear aligners were an effective method with which to correct this malocclusion. The treatment was complete after 18 months. The patient was satisfied with her new appearance and function. PMID- 23363478 TI - Type III secretion system expression in oxygen-limited Pseudomonas aeruginosa cultures is stimulated by isocitrate lyase activity. AB - Pseudomonas aeruginosa is an opportunistic human pathogen and a common cause of chronic infections in individuals with cystic fibrosis (CF). Oxygen limitation was recently reported to regulate the expression of a major virulence determinant in P. aeruginosa, the type III secretion system (T3SS). Here, we show that expression of the T3SS in oxygen-limited growth conditions is strongly dependent on the glyoxylate shunt enzyme, isocitrate lyase (ICL; encoded by aceA), which was previously shown to be highly expressed in CF isolates. ICL-dependent regulation of the T3SS did not alter the expression level of the master transcriptional regulator, ExsA, but did affect expression of the T3 structural proteins, effectors and regulators (ExsC, ExsD and ExsE). An aceA mutant displayed enhanced biofilm formation during anaerobic growth, which suggested that AceA-dependent modulation of type III secretion might impinge upon the RetS/LadS signalling pathways. Indeed, our data suggest that RetS is able to mediate some of its effects through AceA, as expression of aceA in trans partially restored T3SS expression in a retS mutant. Our findings indicate that AceA is a key player in the metabolic regulation of T3SS expression during oxygen limited growth of P. aeruginosa. To the best of our knowledge, this is the first demonstration that the T3SS can be regulated by factors that do not affect ExsA expression levels. PMID- 23363481 TI - From ozone depletion to agriculture: understanding the role of UV radiation in sustainable crop production. AB - Largely because of concerns regarding global climate change, there is a burgeoning interest in the application of fundamental scientific knowledge in order to better exploit environmental cues in the achievement of desirable endpoints in crop production. Ultraviolet (UV) radiation is an energetic driver of a diverse range of plant responses and, despite historical concerns regarding the damaging consequences of UV-B radiation for global plant productivity as related to stratospheric ozone depletion, current developments representative of a range of organizational scales suggest that key plant responses to UV-B radiation may be exploitable in the context of a sustainable contribution towards the strengthening of global crop production, including alterations in secondary metabolism, enhanced photoprotection, up-regulation of the antioxidative response and modified resistance to pest and disease attack. Here, we discuss the prospect of this paradigm shift in photobiology, and consider the linkages between fundamental plant biology and crop-level outcomes that can be applied to the plant UV-B response, in addition to the consequences for related biota and many other facets of agro-ecosystem processes. PMID- 23363480 TI - Evaluating the effectiveness of reasoning training in military and civilian chronic traumatic brain injury patients: study protocol. AB - BACKGROUND: Individuals who sustain traumatic brain injuries (TBIs) often continue to experience significant impairment of cognitive functions mediated by the prefrontal cortex well into chronic stages of recovery. Traditional brain training programs that focus on improving specific skills fall short of addressing integrative functions that draw upon multiple higher-order processes critical for social and vocational integration. In the current study, we compare the effects of two short-term, intensive, group-based cognitive rehabilitation programs for individuals with chronic TBI. One program emphasizes learning about brain functions and influences on cognition, while the other program adopts a top down approach to improve abstract reasoning abilities that are largely reliant on the prefrontal cortex. These treatment programs are evaluated in civilian and military veteran TBI populations. METHODS/DESIGN: One hundred individuals are being enrolled in this double-blinded clinical trial (all measures and data analyses will be conducted by blinded raters and analysts). Each individual is randomly assigned to one of two treatment conditions, with each condition run in groups of five to seven individuals. The primary anticipated outcomes are improvement in abstract reasoning and everyday life functioning, measured through behavioral tasks and questionnaires, and attention modulation, as measured by functional neuroimaging. Secondary expected outcomes include improvements in the cognitive processes of working memory, attention, and inhibitory control. DISCUSSION: Results of this trial will determine whether cognitive rehabilitation aimed at teaching TBI-relevant information about the brain and cognition versus training in TBI-affected thinking abilities (e.g., memory, attention, and executive functioning) can improve outcomes in chronic military and civilian TBI patient populations. It should shed light on the nature of improvements and the characteristics of patients most likely to benefit. This trial will also provide information about the sustainability of treatment-related improvements 3 months post-training. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01552473. PMID- 23363482 TI - Enhanced photoanodic output at an organic p/n bilayer in the water phase by means of the formation of whiskered phthalocyanine. AB - The photoelectrode characteristics of an organic p/n bilayer in the water phase were studied with respect to film; 3,4,9,10-perylenetetracarboxylic bisbenzimidazole (PTCBI, an n-type semiconductor) was used in combination with 29H,31H-phthalocyanine (H2Pc, a p-type semiconductor). When H2Pc was vapor deposited on top of the PTCBI layer on a heated substrate (cf. degree of pressure, ca. 5.0 * 10-4 Pa; temperature at the substrate, 120 degrees C), a transmission electron microscopic image showed an enhanced contact area of the p/n interface in comparison with that prepared at r.t., due to the formation of a whisker H2Pc. The PTCBI/H2Pc bilayer can work as a photoanode along with photophysical events in its interior. The rate-limiting charge transfer at the H2Pc/water interface was kinetically analyzed assuming the Langmuir adsorption equilibrium at that interface. Kinetic analysis demonstrated that the increased contact area can successfully lead to efficient photoinduced carrier generation; particularly, when a thick whisker of H2Pc was formed, the magnitude of the oxidation kinetics at the H2Pc/water interface was approximately 2.5 times higher than that without thermal treatment. PMID- 23363486 TI - Acupuncture mechanisms in tissue healing: contribution of NO and CGRP. PMID- 23363488 TI - Morphological consequences of lateral outfracture of the inferior turbinate. AB - OBJECTIVE: We report three cases of lateral outfracture of the inferior turbinate, which demonstrate a range of changes in the size, position and shape of the inferior turbinate. METHOD: During a study of the validity of computer modelling of nasal airflow, computed tomography scans of the noses of patients who had undergone lateral outfracture of the inferior turbinate were collected. The pre-operative scan was compared with the post-operative scan six weeks later. RESULTS: In one patient, there was only a small lateral displacement of the inferior turbinate. In the other two cases, appreciable reduction in the volume of one inferior turbinate was noted, in addition to minor changes in the shape. CONCLUSION: Lateral outfracture of the inferior turbinate produces varied and inconsistent changes in morphology which may affect the shape, size and position of the turbinate. PMID- 23363487 TI - Predicting intrinsic clearance for drugs and drug candidates metabolized by aldehyde oxidase. AB - Metabolism by aldehyde oxidase (AO) has been responsible for a number of drug failures in clinical trials. The main reason is the clearance values for drugs metabolized by AO are underestimated by allometric scaling from preclinical species. Furthermore, in vitro human data also underestimates clearance. We have developed the first in silico models to predict both in vitro and in vivo human intrinsic clearance for 8 drugs with just two chemical descriptors. These models explain a large amount of the variance in the data using two computational estimates of the electronic and steric features of the reaction. The in vivo computational models for human metabolism are better than in vitro preclinical animal testing at predicting human intrinsic clearance. Thus, it appears that AO is amenable to computational prediction of rates, which may be used to guide drug discovery, and predict pharmacokinetics for clinical trials. PMID- 23363489 TI - Fast access and early ligation of the renal pedicle significantly facilitates retroperitoneal laparoscopic radical nephrectomy procedures: modified laparoscopic radical nephrectomy. AB - BACKGROUND: The objective of this study was to develop a modified retroperitoneal laparoscopic nephrectomy and compare its results with the previous technique. METHODS: One hundred retroperitoneal laparoscopic nephrectomies were performed from February 2007 to October 2011. The previous technique was performed in 60 cases (Group 1). The modified technique (n = 40) included fast access to the renal pedicle according to several anatomic landmarks and early ligation of renal vessels (Group 2). The mean operation time, mean blood loss, duration of hospital stay conversion rate and complication rate were compared between the groups. RESULTS: No significant differences were detected regarding mean patient age, mean body mass index, and tumor size between the two groups (P >0.05). The mean operation time was 59.5 +/- 20.0 and 39.5 +/- 17.5 minutes, respectively, in Groups 1 and 2 (P <0.001). The mean intraoperative blood loss was 147 +/- 35 and 100 +/- 25 ml, respectively, in Groups 1 and 2 (P <0.001). No significant differences were detected regarding the conversion rate and the complication rate between the two groups (P >0.05). CONCLUSIONS: Early ligature using fast access to the renal vessels during retroperitoneal laparoscopic radical nephrectomy contributed to less operation time and intraoperative blood loss compared with the previous technique. In addition, the modified technique permits the procedure to be performed following the principles of open radical nephrectomy. PMID- 23363490 TI - One hundred years of solitude: integrating single-strain inoculations with community perspectives in the legume-rhizobium symbiosis. PMID- 23363491 TI - Risk factors for father-daughter incest: data from an anonymous computerized survey. AB - Retrospective data from 2,034 female participants, provided anonymously using a computer-assisted self-interview, were used to identify risk factors for father daughter incest (FDI). A total of 51 participants had reported having experienced FDI. The risk factors identified within the nuclear family by the multiple logistic regression analysis included the following: (a) Having parents whose relationship included verbal or physical fighting or brutality increased the likelihood of FDI by approximately 5 times; (b) families accepting father daughter nudity as measured by a scale with values ranging from 0 to 4 increased the likelihood of FDI by approximately 2 times for each unit value increase of 1 above 0; (c) demonstrating maternal affection protected against FDI. The likelihood of being a victim of FDI was highest if the participant's mother never kissed or hugged her; it decreased by 0.44 for a 1-unit increase in affection and by 0.19 times for a 2-unit increase; and (d) being in homes headed by single parent mothers or where divorce or death of the father had resulted in a man other than the biological father living in the home increased the risk of FDI by approximately 3.2 times. The results were consistent with the idea that FDI in many families was the cumulative result of a circular pattern of interactions, a finding that has implications for treatment of the perpetrator, the victim, and the families. The data also suggested it may be possible to design an information program for parents that will result in reducing the risk of FDI in families implementing the program's recommendations. PMID- 23363493 TI - Practical approaches to incurred sample LC-MS/MS reanalysis: confirming unexpected results. AB - Incurred sample reanalysis (ISR) is an important step in assuring the quality of an LC-MS/MS bioanalytical assay and the integrity of bioanalysis conduct. A conventional ISR involves analysis of at least 20 samples taken from an in vivo study a second time using the method that was described in prestudy validation and employed in generating the initial study sample results. However, this practice is sometimes inadequate to confirm bioanalytical results that are unexpected. The present report discusses several additional exploratory activities that were performed to confirm the unexpected plasma concentration time results of NVP-1, an investigational drug candidate, observed in the plasma samples collected from patients in a phase II trial. These approaches include (1) LC-MS/MS reanalysis of the study samples after multiple freeze/thaw cycles followed by a short-term benchtop storage, (2) evaluation of additional MS/MS transitions in LC-MS/MS, (3) employment of a different sample preparation procedure in LC-MS/MS, and (4) study sample dilution using plasma samples from healthy volunteers. These procedures are practical and can be readily implemented in the confirmatory LC-MS/MS bioanalysis of other small molecules. PMID- 23363492 TI - Heparin binding protein in patients with acute respiratory failure treated with granulocyte colony-stimulating factor (filgrastim)--a prospective, placebo controlled, double-blind study. AB - BACKGROUND: Heparin Binding Protein (HBP) is released to blood circulation from activated neutrophils in bacterial infections. It is a potential inducer of vascular leakage and precludes the development of septic shock. Filgrastim induces the production of new neutrophils and modulates their bacterial-killing activity. We evaluated the effect of filgrastim on HBP -concentrations in critically ill patients with acute respiratory failure. METHODS: 59 critically ill patients with acute respiratory failure were included in this randomised, double-blind, placebo-controlled study of filgrastim 300 micrograms/day or corresponding placebo for 7 days. Plasma samples were drawn on baseline, day 4 and day 7. HBP -concentrations, absolute leukocyte and neutrophil counts were measured. RESULTS: The median [IQR] HBP concentrations were 23.6 ng/ml [13.9-43.0 ng/ml], 25.1 ng/ml [17.7-35.5 ng/ml] and 15.9 ng/ml [12.6-20.7 ng/ml] in patients receiving filgrastim on baseline, day 4 and day 7, respectively. The HBP concentrations in placebo group were 21.6 ng/ml [16.9-28.7 ng/ml], 13.9 ng/ml [12.0-19.5 ng/ml] and 17.8 ng/ml [13.6-20.9 ng/ml]. At day 4, the filgrastim group had significantly higher HBP -concentrations when compared to placebo group (p < 0.05). No correlation between HBP-concentrations and absolute neutrophil count or P/F -ratios was found. CONCLUSIONS: Filgrastim treatment is associated with increased circulating HBP levels compared to placebo, but the absolute neutrophil count or the degree of oxygenation failure did not correlate with the observed plasma HBP-concentrations. PMID- 23363494 TI - Pulmonary perfusion with oxygenated blood or custodiol HTK solution during cardiac surgery for postoperative pulmonary function in COPD patients: a trial protocol for the randomized, clinical, parallel group, assessor and data analyst blinded Pulmonary Protection Trial. AB - BACKGROUND: Five to thirty percent of patients undergoing cardiac surgery present with chronic obstructive pulmonary disease (COPD) and have a 2- to 10-fold higher 30-day mortality risk. Cardiopulmonary bypass (CPB) creates a whole body systemic inflammatory response syndrome (SIRS) that could impair pulmonary function. Impaired pulmonary function can, however, be attenuated by pulmonary perfusion with oxygenated blood or custodiol HTK (histidine-tryptophan-ketoglutarate) solution. METHODS/DESIGN: The Pulmonary Protection Trial (PP-Trial) randomizes 90 patients undergoing CPB-dependent cardiac surgery to evaluate whether pulmonary perfusion with oxygenated blood or custodiol HTK solution reduces postoperative pulmonary dysfunction in COPD patients. Further, we aim for a non-randomized evaluation of postoperative pulmonary function after transcatheter aortic-valve implantation (TAVI). The primary outcome measure is the oxygenation index measured from anesthesia induction to the end of surgery and until 24 hours after anesthesia induction for a total of six evaluations. DISCUSSION: Patients with COPD may be impaired by hypoxemia and SIRS. Thus, prolonged recovery and even postoperative complications and death may be reflected by the degree of hypoxemia and SIRS. The limited sample size does not aim for confirmatory conclusions on mortality, cardiovascular complications or risk of pneumonia and sepsis, but the PP-Trial is considered an important feasibility trial paving the road for a multicenter confirmatory trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01614951. PMID- 23363495 TI - Priming after a fractional dose of inactivated poliovirus vaccine. AB - BACKGROUND: To reduce the costs of maintaining a poliovirus immunization base in low-income areas, we assessed the extent of priming immune responses after the administration of inactivated poliovirus vaccine (IPV). METHODS: We compared the immunogenicity and reactogenicity of a fractional dose of IPV (one fifth of a full dose) administered intradermally with a full dose administered intramuscularly in Cuban infants at the ages of 4 and 8 months. Blood was collected from infants at the ages of 4 months, 8 months, 8 months 7 days, and 8 months 30 days to assess single-dose seroconversion, single-dose priming of immune responses, and two-dose seroconversion. Specimens were tested with a neutralization assay. RESULTS: A total of 320 infants underwent randomization, and 310 infants (96.9%) fulfilled the study requirements. In the group receiving the first fractional dose of IPV, seroconversion to poliovirus types 1, 2, and 3 occurred in 16.6%, 47.1%, and 14.7% of participants, respectively, as compared with 46.6%, 62.8%, and 32.0% in the group receiving the first full dose of IPV (P<0.008 for all comparisons). A priming immune response to poliovirus types 1, 2, and 3 occurred in 90.8%, 94.0%, and 89.6% of participants, respectively, in the group receiving the fractional dose as compared with 97.6%, 98.3%, and 98.1% in the group receiving the full dose (P=0.01 for the comparison with type 3). After the administration of the second dose of IPV in the group receiving fractional doses, cumulative two-dose seroconversion to poliovirus types 1, 2, and 3 occurred in 93.6%, 98.1%, and 93.0% of participants, respectively, as compared with 100.0%, 100.0%, and 99.4% in the group receiving the full dose (P<0.006 for the comparisons of types 1 and 3). The group receiving intradermal injections had the greatest number of adverse events, most of which were minor in intensity and none of which had serious consequences. CONCLUSIONS: This evaluation shows that vaccinating infants with a single fractional dose of IPV can induce priming and seroconversion in more than 90% of immunized infants. (Funded by the World Health Organization and the Pan American Health Organization; Australian New Zealand Clinical Trials Registry number, ACTRN12610001046099.). PMID- 23363497 TI - Long-term functional outcomes after treatment for localized prostate cancer. AB - BACKGROUND: The purpose of this analysis was to compare long-term urinary, bowel, and sexual function after radical prostatectomy or external-beam radiation therapy. METHODS: The Prostate Cancer Outcomes Study (PCOS) enrolled 3533 men in whom prostate cancer had been diagnosed in 1994 or 1995. The current cohort comprised 1655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (1164 men) or radiotherapy (491 men). Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis. We used multivariable propensity scoring to compare functional outcomes according to treatment. RESULTS: Patients undergoing prostatectomy were more likely to have urinary incontinence than were those undergoing radiotherapy at 2 years (odds ratio, 6.22; 95% confidence interval [CI], 1.92 to 20.29) and 5 years (odds ratio, 5.10; 95% CI, 2.29 to 11.36). However, no significant between-group difference in the odds of urinary incontinence was noted at 15 years. Similarly, although patients undergoing prostatectomy were more likely to have erectile dysfunction at 2 years (odds ratio, 3.46; 95% CI, 1.93 to 6.17) and 5 years (odds ratio, 1.96; 95% CI, 1.05 to 3.63), no significant between-group difference was noted at 15 years. Patients undergoing prostatectomy were less likely to have bowel urgency at 2 years (odds ratio, 0.39; 95% CI, 0.22 to 0.68) and 5 years (odds ratio, 0.47; 95% CI, 0.26 to 0.84), again with no significant between-group difference in the odds of bowel urgency at 15 years. CONCLUSIONS: At 15 years, no significant relative differences in disease-specific functional outcomes were observed among men undergoing prostatectomy or radiotherapy. Nonetheless, men treated for localized prostate cancer commonly had declines in all functional domains during 15 years of follow-up. (Funded by the National Cancer Institute.). PMID- 23363496 TI - Antibiotics as part of the management of severe acute malnutrition. AB - BACKGROUND: Severe acute malnutrition contributes to 1 million deaths among children annually. Adding routine antibiotic agents to nutritional therapy may increase recovery rates and decrease mortality among children with severe acute malnutrition treated in the community. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned Malawian children, 6 to 59 months of age, with severe acute malnutrition to receive amoxicillin, cefdinir, or placebo for 7 days in addition to ready-to-use therapeutic food for the outpatient treatment of uncomplicated severe acute malnutrition. The primary outcomes were the rate of nutritional recovery and the mortality rate. RESULTS: A total of 2767 children with severe acute malnutrition were enrolled. In the amoxicillin, cefdinir, and placebo groups, 88.7%, 90.9%, and 85.1% of the children recovered, respectively (relative risk of treatment failure with placebo vs. amoxicillin, 1.32; 95% confidence interval [CI], 1.04 to 1.68; relative risk with placebo vs. cefdinir, 1.64; 95% CI, 1.27 to 2.11). The mortality rates for the three groups were 4.8%, 4.1%, and 7.4%, respectively (relative risk of death with placebo vs. amoxicillin, 1.55; 95% CI, 1.07 to 2.24; relative risk with placebo vs. cefdinir, 1.80; 95% CI, 1.22 to 2.64). Among children who recovered, the rate of weight gain was increased among those who received antibiotics. No interaction between type of severe acute malnutrition and intervention group was observed for either the rate of nutritional recovery or the mortality rate. CONCLUSIONS: The addition of antibiotics to therapeutic regimens for uncomplicated severe acute malnutrition was associated with a significant improvement in recovery and mortality rates. (Funded by the Hickey Family Foundation and others; ClinicalTrials.gov number, NCT01000298.). PMID- 23363499 TI - Proteotoxicity and cardiac dysfunction--Alzheimer's disease of the heart? PMID- 23363498 TI - Myths, presumptions, and facts about obesity. AB - BACKGROUND: Many beliefs about obesity persist in the absence of supporting scientific evidence (presumptions); some persist despite contradicting evidence (myths). The promulgation of unsupported beliefs may yield poorly informed policy decisions, inaccurate clinical and public health recommendations, and an unproductive allocation of research resources and may divert attention away from useful, evidence-based information. METHODS: Using Internet searches of popular media and scientific literature, we identified, reviewed, and classified obesity related myths and presumptions. We also examined facts that are well supported by evidence, with an emphasis on those that have practical implications for public health, policy, or clinical recommendations. RESULTS: We identified seven obesity related myths concerning the effects of small sustained increases in energy intake or expenditure, establishment of realistic goals for weight loss, rapid weight loss, weight-loss readiness, physical-education classes, breast-feeding, and energy expended during sexual activity. We also identified six presumptions about the purported effects of regularly eating breakfast, early childhood experiences, eating fruits and vegetables, weight cycling, snacking, and the built (i.e., human-made) environment. Finally, we identified nine evidence supported facts that are relevant for the formulation of sound public health, policy, or clinical recommendations. CONCLUSIONS: False and scientifically unsupported beliefs about obesity are pervasive in both scientific literature and the popular press. (Funded by the National Institutes of Health.). PMID- 23363500 TI - Images in clinical medicine. Lobular panniculitis. PMID- 23363501 TI - Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. PMID- 23363502 TI - Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. PMID- 23363503 TI - Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. PMID- 23363504 TI - Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. PMID- 23363505 TI - Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. PMID- 23363506 TI - Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. PMID- 23363507 TI - Talking with patients about dying. PMID- 23363508 TI - Talking with patients about dying. PMID- 23363509 TI - Talking with patients about dying. PMID- 23363510 TI - Talking with patients about dying. PMID- 23363511 TI - Talking with patients about dying. PMID- 23363512 TI - Deep-brain stimulation for Parkinson's disease. PMID- 23363513 TI - Deep-brain stimulation for Parkinson's disease. PMID- 23363514 TI - Deep-brain stimulation for Parkinson's disease. PMID- 23363515 TI - Deep-brain stimulation for Parkinson's disease. PMID- 23363516 TI - Why doctors prescribe opioids to known opioid abusers. PMID- 23363517 TI - Why doctors prescribe opioids to known opioid abusers. PMID- 23363518 TI - Redefining physicians' role in assisted dying. PMID- 23363519 TI - Redefining physicians' role in assisted dying. PMID- 23363520 TI - Case 33-2012: A woman with altered mental status after childbirth. PMID- 23363521 TI - Case 33-2012: A woman with altered mental status after childbirth. PMID- 23363522 TI - Donor exposures in recipients of pooled platelet concentrates. PMID- 23363525 TI - Images in clinical medicine. Pulmonary sequestration. PMID- 23363526 TI - Impact of a home-based social welfare program on care for palliative patients in the Basque Country (SAIATU Program). AB - BACKGROUND: SAIATU is a program of specially trained in-home social assistance and companionship which, since February 2011, has provided support to end-of-life patients, enabling the delivery of better clinical care by healthcare professionals in Osakidetza (Basque Health Service), in Guipuzcoa (Autonomous Community of the Basque Country).In January 2012, a retrospective observational study was carried out, with the aim of describing the characteristics of the service and determining if the new social service and the associated socio-health co-ordination had produced any effect on the use of healthcare resources by end of-life patients.The results of a comparison of a cohort of cases and controls demonstrated evidence that the program could reduce the use of hospital resources and promote the continuation of living at home, increasing the home-based activity of primary care professionals.The objective of this study is to analyse whether a program of social intervention in palliative care (SAIATU) results in a reduction in the consumption of healthcare resources and cost by end-of-life patients and promotes a shift towards a more community-based model of care. METHOD/DESIGN: Comparative prospective cohort study, with randomised selection of patients, which will systematically measure patient characteristics and their consumption of resources in the last 30 days of life, with and without the intervention of a social support team trained to provide in-home end-of-life care.For a sample of approximately 150 patients, data regarding the consumption of public healthcare resources, SAIATU activity, home hospitalisation teams, and palliative care will be recorded. Such data will also include information dealing with the socio-demographic and clinical characteristics of the patients and attending carers, as well as particular characteristics of patient outcomes (Karnofsky Index), and of the outcomes of palliative care received (Palliative Outcome Scale).Ethical approval for the study was given by the Clinical Research Ethics Committee of Euskadi (CREC-C) on 10 Dec 2012. DISCUSSION: The results of this prospective study will assist in verifying or disproving the hypothesis that the in-home social care offered by SAIATU improves the efficiency of healthcare resource usage by these patients (quality of life, symptom control).This project represents a dramatic advance with respect to other studies conducted to date, and demonstrates how, through the provision of personnel trained to provide social care for patients in the advanced stages of illness, and through strengthening the co-ordination of such social services with existing healthcare system resources, the resulting holistic structure obtains cost savings within the health system and improves the efficiency of the system as a whole. PMID- 23363528 TI - Membrane-active peptides: mechanisms of action. PMID- 23363527 TI - Facile incorporation of aggregation-induced emission materials into mesoporous silica nanoparticles for intracellular imaging and cancer therapy. AB - Aggregation-induced emission (AIE) materials were facilely incorporated into mesoporous silica nanoparticles (MSNs) via one-pot surfactant templated method. Cell imaging and cancer therapy applications of such fluorescent MSNs were further explored. We demonstrated that AIE-MSN nanocomposites showed strong fluorescence and uniform morphology, making them promising for both cell imaging and cancer therapy. PMID- 23363529 TI - Recent advances in computational modeling of alpha-helical membrane-active peptides. AB - Membrane-active peptides (MAPs) represent a broad variety of molecules, and biological functions of most are directly associated with their ability to interact with membranes. Taking into account the effect of MAPs on living cells they can be nominally divided into three major groups - fusion (FPs), antimicrobial/cytolytic (AMPs/CPs) and cell-penetrating (CPPs) peptides. Although spatial structure of different MAPs varies to a great extent, linear alpha helical peptides represent the most studied class. These peptides possess relatively simple structural organization and share a set of similar molecular features, which make them very attractive to both experimental and computational studies. Here, we review different molecular modeling methods in prospective of their applications to study of alpha-helical MAPs. The most sophisticated of them, such as molecular dynamics simulations, give atomistic information about molecular interactions driving peptide binding to the water-lipid interface, cooperative mechanisms of membrane destabilization and thermodynamics of these processes. Significant progress has been achieved in this field during the last few years, resulting in a possibility to observe computationally MAPs action in realistic peptide-to-lipid ratios and over the microsecond timescale. Other relatively simple but powerful approaches allow assessment of important characteristics of MAPs such as alpha-helical propensity, amphiphilicity, total hydrophobicity, and spatial distribution of charge and hydrophobic/hydrophilic properties, etc. Altogether, computational methods provide efficient basis for rational design of MAPs with predefined properties and a spectrum of biological activities. PMID- 23363530 TI - Neurotoxic potential and cellular uptake of T-2 toxin in human astrocytes in primary culture. AB - The trichothecene mycotoxin T-2 toxin, which is produced by fungi of the Fusarium species, is a worldwide occurring contaminant of cereal based food and feed. The cytotoxic properties of T-2 toxin are already well described with apoptosis being a major mechanism of action in various cell lines as well as in primary cells of different origin. However, only few data on neurotoxic properties of T-2 toxin are reported so far, but in vivo studies showed different effects of T-2 toxin on behavior as well as on levels of brain amines in animals. To further investigate the cytotoxic properties of T-2 toxin on cells derived from brain tissue, normal human astrocytes in primary culture (NHA) were used in this study. Besides studies of cytotoxicity, apoptosis (caspase-3-activation, Annexin V) and necrosis (LDH-release), the cellular uptake and metabolism of T-2 toxin in NHA was analyzed and compared to the uptake in an established human cell line (HT-29). The results show that human astrocytes were highly sensitive to the cytotoxic properties of T-2 toxin, and apoptosis, induced at low concentrations, was identified for the first time as the mechanism of toxic action in NHA. Furthermore, a strong accumulation of T-2 toxin in NHA and HT-29 cells was detected, and T-2 toxin was subjected to metabolism leading to HT-2 toxin, a commonly found metabolite after T-2 toxin incubation in both cell types. This formation seems to occur within the cells since incubations of T-2 toxin with cell depleted culture medium did not lead to any degradation of the parent toxin. The results of this study emphasize the neurotoxic potential of T-2 toxin in human astrocytes at low concentrations after short incubation times. PMID- 23363531 TI - Sport participation and subjective well-being: instrumental variable results from German survey data. AB - BACKGROUND: A major policy goal of many ministries of sport and health is increased participation in sport to promote health. A growing literature is emerging about the benefits of sport participation on happiness. A challenge in establishing a link between sport participation and happiness is controlling for endogeneity of sport participation in the happiness equation. METHODS: This study seeks to establish causal evidence of a relationship between sport participation and self reported happiness using instrumental variables (IV). RESULTS: IV estimates based on data from a 2009 population survey living in Rheinberg, Germany indicate that individuals who participate in sport have higher life happiness. The results suggest a U-shaped relationship between age and self reported happiness. Higher income is associated with greater self-reported happiness, males are less happy than females, and single individuals are less happy than nonsingles. CONCLUSIONS: Since the results are IV, this finding is interpreted as a causal relationship between sport participation and subjective well-being (SWB). This broader impact of sport participation on general happiness lends support to the policy priority of many governments to increase sport participation at all levels of the general population. PMID- 23363533 TI - Sulfur doping effects on the electronic and geometric structures of graphitic carbon nitride photocatalyst: insights from first principles. AB - We present here results of our first-principles studies of the sulfur doping effects on the electronic and geometric structures of graphitic carbon nitride (g C(3)N(4)). Using the ab initio thermodynamics approach combined with some kinetic analysis, we reveal the favorable S-doping configurations. By analyzing the valence charge densities of the doped and undoped systems, we find that sulfur partially donates its p(x)- and p(y)- electrons to the system with some back donation to the S p(z)-states. To obtain an accurate description of the excited electronic states, we calculate the electronic structure of the systems using the GW method. The band gap width calculated for g-C(3)N(4) is found to be equal to 2.7 eV, which is in agreement with experiment. We find the S doping causes a significant narrowing of the gap. Furthermore, the electronic states just above the gap become occupied upon doping, making the material a conductor. Analysis of the projected local density of states provides an insight into the mechanism underlying such changes in the electronic structure of g-C(3)N(4) upon S doping. Based on our results, we propose a possible explanation for the S-doping effect on the photocatalytic properties of g-C(3)N(4) observed in experiments. PMID- 23363534 TI - Rhizo-lysimetry: facilities for the simultaneous study of root behaviour and resource use by agricultural crop and pasture systems. AB - BACKGROUND: Rhizo-lysimeters offer unique advantages for the study of plants and their interactions with soils. In this paper, an existing facility at Charles Sturt University in Wagga Wagga Australia is described in detail and its potential to conduct both ecophysiological and ecohydrological research in the study of root interactions of agricultural crops and pastures is quantitatively assessed. This is of significance to future crop research efforts in southern Australia, in light of recent significant long-term drought events, as well as potential impacts of climate change as predicted for the region. The rhizo lysimeter root research facility has recently been expanded to accommodate larger research projects over multiple years and cropping rotations. RESULTS: Lucerne, a widely-grown perennial pasture in southern Australia, developed an expansive root system to a depth of 0.9 m over a twelve month period. Its deeper roots particularly at 2.05 m continued to expand for the duration of the experiment. In succeeding experiments, canola, a commonly grown annual crop, developed a more extensive (approximately 300%) root system than wheat, but exhibited a slower rate of root elongation at rates of 7.47 x 10-3 m day-1 for canola and 1.04 x10-2 m day-1 for wheat. A time domain reflectometry (TDR) network was designed to accurately assess changes in soil water content, and could assess water content change to within 5% of the amount of water applied. CONCLUSIONS: The rhizo lysimetry system provided robust estimates of root growth and soil water change under conditions representative of a field setting. This is currently one of a very limited number of global research facilities able to perform experimentation under field conditions and is the largest root research experimental laboratory in the southern hemisphere. PMID- 23363532 TI - Characterizing the emergence and persistence of drug resistant mutations in HIV-1 subtype C infections using 454 ultra deep pyrosequencing. AB - BACKGROUND: The role of HIV-1 RNA in the emergence of resistance to antiretroviral therapies (ARTs) is well documented while less is known about the role of historical viruses stored in the proviral DNA. The primary focus of this work was to characterize the genetic diversity and evolution of HIV drug resistant variants in an individual's provirus during antiretroviral therapy using next generation sequencing. METHODS: Blood samples were collected prior to antiretroviral therapy exposure and during the course of treatment from five patients in whom drug resistance mutations had previously been identified using consensus sequencing. The spectrum of viral variants present in the provirus at each sampling time-point were characterized using 454 pyrosequencing from multiple combined PCR products. The prevalence of viral variants containing drug resistant mutations (DRMs) was characterized at each time-point. RESULTS: Low abundance drug resistant viruses were identified in 14 of 15 sampling time-points from the five patients. In all individuals DRMs against current therapy were identified at one or more of the sampling time-points. In two of the five individuals studied these DRMs were present prior to treatment exposure and were present at high prevalence within the amplified and sequenced viral population. DRMs to drugs other than those being currently used were identified in four of the five individuals. CONCLUSION: The presence of DRMs in the provirus, regardless of their observed prevalence did not appear to have an effect on clinical outcomes in the short term suggesting that the drug resistant viral variants present in the proviral DNA do not appear to play a role in the short term in facilitating the emergence of drug resistance. PMID- 23363535 TI - Molecular characterization of putative Hepatozoon sp. from the sedge warbler (Acrocephalus schoenobaenus). AB - We characterized partial sequences of 18S rDNA from sedge warblers infected with a parasite described previously as Hepatozoon kabeeni. Prevalence was 47% in sampled birds.We detected 3 parasite haplotypes in 62 sequenced samples from infected animals. In phylogenetic analyses, 2 of the putative Hepatozoon haplotypes closely resembled Lankesterella minima and L. valsainensis. The third haplotype grouped in a wider clade composed of Caryospora and Eimeria. None of the haplotypes showed resemblance to sequences of Hepatozoon from reptiles and mammals. Molecular detection results were consistent with those from microscopy of stained blood smears, confirming that the primers indeed amplified the parasite sequences. Here we provide evidence that the avian Hepatozoon-like parasites are most likely Lankesterella, supporting the suggestion that the systematic position of avian Hepatozoon-like species needs to be revised. PMID- 23363537 TI - Intraindividual neuropsychological test variability in healthy individuals with high average intelligence and educational attainment. AB - Knowledge of patterns of neuropsychological performance among normal, healthy individuals is integral to the practice of clinical neuropsychology, because clinicians may not always account for intraindividual variability (IIV) before coming to diagnostic conclusions. The IIV was assessed among a sample of 46 healthy individuals with high average intelligence and educational attainment, utilizing a battery of neuropsychological tests, including the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) and Wechsler Memory Scale, Fourth Edition (WMS-IV). The data indicated substantial variability in neurocognitive abilities. All participants were found to demonstrate scores considered impaired by at least 2 standard deviations (SDs). Despite adjusting for outliers, no participant produced a "normal" testing profile with an intraindividual maximum discrepancy (MD) of less than 1 SD in either direction. When WAIS-IV Full Scale IQ (FSIQ) was considered, participants generally demonstrated cognitive test scores ranging from 2 SDs less than to 1.5 SDs greater than their FSIQ. Furthermore, after demographic corrections, the majority (59%) of participants demonstrated at least 1 impaired cognitive test score, as defined by being 1 to 1.5 SDs below the mean. Overall, results substantiate the need for clinicians to consider FSIQ and educational attainment in interpretation of neuropsychological testing results, given the relevant commonality of "abnormal" test scores within this population. This may ultimately reduce the likelihood of making false positive conclusions of impairment when educational attainment and intelligence are high, thus improving diagnostic accuracy. PMID- 23363536 TI - Alcohol use disorder-related sick leave and mortality: a cohort study. AB - BACKGROUND: Alcohol use disorders (AUDs) are associated with the highest all cause mortality rates of all mental disorders. The majority of patients with AUDs never receive inpatient treatment for their AUD, and there is lack of data about their mortality risks despite their constituting the majority of those affected. Absenteeism from work (sick leave) due to an AUD likely signals worsening. In this study, we assessed whether AUD-related sick leave was associated with mortality in a cohort of workers in Germany. METHODS: 128,001 workers with health insurance were followed for a mean of 6.4 years. We examined the associations between 1) AUD-related sick leave managed on an outpatient basis and 2) AUD related psychiatric inpatient treatment, and mortality using survival analysis, and Cox proportional hazard regression models (separately by sex) adjusted for age, education, and job code classification. We also stratified analyses by sick leave related to three groups of alcohol-related conditions (all determined by International Classification of Diseases 9th ed. (ICD-9) codes): alcohol abuse and dependence; alcohol-induced mental disorder; and alcohol-induced medical conditions. RESULTS: Outpatient-managed AUD-related sick leave was significantly associated with higher mortality (hazard ratio (HR) 2.90 (95% Confidence interval (CI) 2.24-3.75) for men, HR 5.83 (CI 2.90-11.75) for women). The magnitude of the association was similar for receipt of AUD-related psychiatric inpatient treatment (HR 3.2 (CI 2.76-3.78) for men, HR 6.5 (CI 4.41-9.47) for women). Compared to those without the conditions, higher mortality was observed consistently for outpatients and inpatients across the three groups of alcohol related conditions. Those with alcohol-related medical conditions who had AUD related psychiatric inpatient treatment appeared to have the highest mortality. CONCLUSIONS: Alcohol use disorder-related sick leave as documented in health insurance records is associated with higher mortality. Such sick leave does not necessarily lead to any specific AUD treatment. Therefore, AUD-related sick leave might be used as a trigger for insurers to intervene by offering AUD treatment to patients to try to reduce their risk of death. PMID- 23363538 TI - Effects of organic extracts of six Bangladeshi plants on in vitro thrombolysis and cytotoxicity. AB - BACKGROUND: Thrombus formed in blood vessels lead to atherothrombotic diseases such as myocardial or cerebral infarction. Thrombolytic agents are used to dissolve the already formed clots in the blood vessels; however, these drugs sometimes cause serious and fatal consequences. Herbal preparations have been used since ancient times for the treatment of several diseases although they show little toxicity in some cases. Aqueous extracts of herbs used in thrombolysis have been reported before with cytotoxic data, however, the organic extracts of herbs have not been documented. This study aims to investigate whether organic extracts possess thrombolytic properties with minimal or no toxicity. METHODS: An in vitro thrombolytic model was used to check the clot lysis effect of six Bangladeshi herbal extracts viz., Ageratum conyzoides L., Clausena suffruticosa, Leea indica (Burm.f.) Merr., Leucas aspera Willd., Senna sophera L. Roxb., and Solanum torvum Swartz. using streptokinase as a positive control and water as a negative control. Briefly, venous blood drawn from twenty healthy volunteers was allowed to form clots which were weighed and treated with the test plant materials to disrupt the clots. Weight of clot after and before treatment provided a percentage of clot lysis. Cytotoxicity was screened by brine shrimp lethality bioassay using vincristine sulfate as positive control. RESULTS: Using an in vitro thrombolytic model, Ageratum conyzoides, Clausena suffruticosa, Leea indica, Leucas aspera, Senna sophera and Solanum torvum showed 18.12 +/- 2.34%, 48.9 +/- 2.44%, 39.30 +/- 0.96%, 37.32 +/- 2.00%, 31.61 +/- 2.97% and 31.51 +/- 0.57% and clot lysis respectively. Among the herbs studied Clausena suffruticosa, Leea indica and Leucas aspera showed very significant (p < 0.0001) percentage (%) of clot lysis compared to reference drug streptokinase (75.00 +/- 3.04%). In brine shrimp cytotoxic assay, the extracts Ageratum conyzoides, Clausena suffruticosa, Leea indica, Leucas aspera, Senna sophera and Solanum torvum showed LC50 values 508.86 +/- 6.62,41.16 +/- 1.26, 2.65 +/- 0.16, 181.67 +/- 1.65, 233.37 +/- 7.74 and 478.40 +/- 3.23 MUg/ml, respectively, with reference to vincristine sulfate (LC50 0.76 +/- 0.04). CONCLUSION: Through our study it was found that Clausena suffruticosa, Leea indica and Leucas aspera possessed effective thrombolytic properties whereas Senna sophera and Solanum torvum showed moderate to mild thrombolytic effects while Ageratum conyzoides showed no significant effect. No extract was found cytoxic compared to positive control. Clausena suffruticosa, Leea indica and Leucas aspera could be incorporated as a thrombolytic agent with in vivo effects to improve the atherothrombotic patients. However, Clausena suffruticosa could be the best one to use in this purpose. PMID- 23363539 TI - The prevalence of intimate partner violence in the family: a systematic review of the implications for adolescents in Africa. AB - BACKGROUND: Intimate partner violence (IPV) and its multiple effects are well documented in Western research, but these are not adequately described in Africa. The effects of IPV on adolescent health and well-being are not conclusive. OBJECTIVE: The aim of this review was to systematically appraise prevalence studies conducted on the African continent to establish the prevalence of IPV and the implications of exposure on adolescents in Africa. METHODS: A comprehensive search was conducted in May 2012 for the previous 10 years, using databases such as Ebscohost (Medline, CINAHL, PsyArticles), Directory of Open Access Journals (DOAJ), Project Muse and BioMed Central and also specific journals Lancet, and JSTOR. Two reviewers independently evaluated the methodological quality of the studies reviewed. RESULTS: Seven eligible epidemiological studies were included in this review. Five of the studies were conducted in South Africa, one in Liberia, and another was a multi-country study that included Egypt, Kenya, Malawi, Rwanda and Zambia. The prevalence of IPV in African countries ranged from approximately 26.5% to 48%. All studies reported exposure to family violence during childhood. CONCLUSION: The findings support the global burden of IPV. There is also a need for standardized tools to determine IPV in Africa and a clear definition that can be used in research to allow comparison with future IPV studies. In addition, the studies point to a need for interventions focusing on adolescents exposed to family violence. PMID- 23363540 TI - Diagnosing cancer in the bush: a mixed-methods study of symptom appraisal and help-seeking behaviour in people with cancer from rural Western Australia. AB - BACKGROUND: Previous studies have focused on the treatment received by rural cancer patients and have not examined their diagnostic pathways as reasons for poorer outcomes in rural Australia. OBJECTIVES: To compare and explore symptom appraisal and help-seeking behaviour in patients with breast, lung, prostate or colorectal cancer from rural Western Australia (WA). METHODS: A mixed-methods study of people recently diagnosed with breast, lung, prostate or colorectal cancer from rural WA. The time from first symptom to diagnosis (i.e. total diagnostic interval, TDI) was calculated from interviews and medical records. RESULTS: Sixty-six participants were recruited (24 breast, 20 colorectal, 14 prostate and 8 lung cancer patients). There was a highly significant difference in time from symptom onset to seeking help between cancers (P = 0.006). Geometric mean symptom appraisal for colorectal cancer was significantly longer than that for breast and lung cancers [geometric mean differences: 2.58 (95% confidence interval, CI: 0.64-4.53), P = 0.01; 3.97 (1.63-6.30), P = 0.001, respectively]. There was a significant overall difference in arithmetic mean TDI (P = 0.046); breast cancer TDI was significantly shorter than colorectal or prostate cancer TDI [mean difference : 266.3 days (95% CI: 45.9-486.8), P = 0.019; 277.0 days, (32.1-521.9), P = 0.027, respectively]. These differences were explained by the nature and personal interpretation of symptoms, perceived as well as real problems of access to health care, optimism, stoicism, machismo, fear, embarrassment and competing demands. CONCLUSIONS: Longer symptom appraisal was observed for colorectal cancer. Participants defined core characteristics of rural Australians as optimism, stoicism and machismo. These features, as well as access to health care, contribute to later presentation of cancer. PMID- 23363541 TI - A cross sectional study of HPV type prevalence according to age and cytology. AB - BACKGROUND: A cross sectional study to investigate HPV prevalence according to age and cytology. METHODS: Women presenting to a gynaecological outpatient clinic for a Pap smear test were included in the study (n=3177). All women had cervical cytology and HPV testing. RESULTS: Overall prevalence of any 24 HPV type analysed was 33.1% (95% CI 31.5% to 34.7%) and HPV 16 and HPV 42 were the most frequent (6.7% (95% CI 5.8% to 7.6%), 6.8% (95% CI 5.9% to 7.6%)), in total samples. Multiple HPV infection rate was 12.9% (95% CI 11.8% to 14.1%). High risk HPV (hrHPV) types were present in 27.4% (95% CI 25.8% to 28.9%) of the samples.HPV prevalence was highest among 14 to 19 y.o (46.6% (95% CI 40.7%-52.4%)) and second highest among 30-34 y.o. (39.7%, 95% CI 35.4%-44%). HPV 16 was highest among 20 24 (9.0% (95% CI 6.4%-11.6%)) and second highest among 50 to 54 y.o. (6.3% (95% CI 2.9% to 9.8%).In Low-grade Squamous Intraepithelial Lesions (LgSIL) cytology samples, the most frequently detected hrHPV types were: 16 (14.5% (95% CI 12.1% to 16.9%)), 51 (13.0% (95% CI 10.7% to 15.3%)) and 53 (9.1% (95% CI 7.2% to 11.1%)) and in High-grade Squamous Intraepithelial Lesions (HgSIL) were: HPV 16 (37.2% (95% CI 26.5% to 47.9%)), HPV 51 (17.9% (95% CI 9.4% to 26.5%)) and HPV 18 (12.8% (95% CI 5.4% to 20.2%)). CONCLUSIONS: In the population studied, HPV 16 and 51 were the most frequent detected hrHPV types. HPV positivity, hrHPV and multiple HPV types infections were higher in young women, while HPV prevalence declined with increasing age and presented two peaks a higher (14-19 y.o.) and a lower one (30-34 y.o.) These results may contribute to the creation of a national screening programme. PMID- 23363542 TI - Clinical and pathological features of hepatoid carcinoma of the ovary. AB - Hepatoid carcinoma of the ovary (HCO), a rare invasive malignant tumor composed mainly of epithelioid cells, presented with unilateral or bilateral ovarian masses and elevated serum alpha-fetoprotein (AFP), has been found mainly in post menopausal women. We hereby report on the case of a 53-year-old Chinese woman who presented with abdominal distension and a lower abdominal mass with high serum levels of CA-125 and AFP. She was later diagnosed with bilateral HCO. After surgery and following chemotherapy, the patient had no recurrence of tumor or ascites. The hepatoid cells were positive for AFP, p53 and CK7 by immunohistochemistry. Her serum CA-125 and AFP levels had decreased significantly after surgery. Our results suggest that testing and monitoring of serum levels of AFP and CA-125 are considered as potential biomarkers in the diagnosis and progression of this malignancy, and that tissue immunohistochemical staining for AFP, p53 and CK7, plays an important role in distinguishing HCO from other ovarian tumors. PMID- 23363544 TI - Association of leisure-time physical activity with cardiorespiratory fitness in Indian men. AB - BACKGROUND: The relationship between leisure-time physical activity (LTPA) and cardiorespiratory fitness (CRF) is not clearly understood in Indian men. It is important to elucidate whether the duration or intensity of LTPA is responsible for increasing CRF. This will help in designing better physical activity intervention strategies for improving CRF in Indian men. METHODS: Healthy nondiabetic urban Indian men with no history of coronary heart disease (CHD) were selected (n = 603; aged 22-64 years) and their energy intake and physical activity was determined using a questionnaire. Body fat (percent) was determined by leg-to-leg bioelectrical impedance analysis while CRF was measured on multistage, continuous treadmill test using Bruce protocol. RESULTS: Intensity of physical activity (METs) emerged as the best independent predictor of CRF (beta = 0.217; P < .001). Using univariate General Linear Model, it was found that CRF is more a function of LTPA intensity than LTPA duration, since LTPA duration was not related to CRF when controlled for LTPA intensity. However, LTPA intensity remained significantly associated with CRF even after adjustment for LTPA duration. CONCLUSION: LTPA of preferably higher intensity should be incorporated in the lifestyle to improve CRF and prevent CHD in Indian men. PMID- 23363543 TI - Fenugreek seeds, a hepatoprotector forage crop against chronic AlCl3 toxicity. AB - BACKGROUND: Having considered how bioavailable aluminium (Al) may affect ecological systems and animals living there, especially cattle, and in search for a preventive dietary treatment against Al toxicity, we aimed to test the protective role of fenugreek seeds against chronic liver injury induced by aluminum chloride (AlCl3) in Wistar rats. RESULTS: Five months of AlCl3 oral exposure (500 mg/kg bw i.g for one month then 1600 ppm via drinking water) caused liver atrophy, an inhibition of aspartate transaminase (AST), alanine transaminase (ALT) and glutamyl transpeptidase (GGT), an enhancement of both lipid peroxidation and lactate dehydrogenase (LDH) activity and an increase of total protein level in liver. Moreover, histopathological and histochemical examinations revealed moderate alterations in the hepatic parenchyma in addition to a disrupted iron metabolism. Co-administration of fenugreek seed powder (FSP) at 5% in pellet diet during two months succeeded to antagonize the harmful effects of AlCl3 by restoring all tested parameters. CONCLUSION: This study highlighted the hepatotoxicity of AlCl3 through biochemical and histological parameters in one hand and the hepatoprotective role of fenugreek seeds on the other hand. Thus this work could be a pilot study which will encourage farmers to use fenugreek seeds as a detoxifying diet supplement for domestic animals. PMID- 23363545 TI - Differential emergence of Culicoides (Diptera: Ceratopogonidae) from on-farm breeding substrates in Northern Ireland. AB - Biting midges of the genus Culicoides (Diptera: Ceratopogonidae) are vectors of a number of viral diseases worldwide. Following the unforeseen outbreak of bluetongue in northern Europe (2006-2009) there was a need to clarify on-farm breeding substrates utilized by temperate Culicoides spp. Six substrates (cow dung, cow slurry, horse dung, sheep dung, maize silage and soil) were investigated for Culicoides spp. emergence over a 31-week period. Overall, most Obsoletus group Culicoides emerged from the cow dung and the most Pulicaris group Culicoides emerged from the sheep dung. Furthermore, Culicoides of the Obsoletus group were found to be abundant in cow slurry and sheep dung. Temperature played a significant role in the emergence times of adult Culicoides. The Obsoletus group appear to have undergone 3 generations during the experimental period. The sex ratio of emergent Obsoletus group Culicoides was affected by substrate type, with a greater proportion of males emerging from cow dung and slurry compared with the other substrates. PMID- 23363546 TI - Perspectives of disproportionation driven superconductivity in strongly correlated 3d compounds. AB - Disproportionation in 3d compounds can give rise to an unconventional electron hole Bose liquid with a very rich phase diagram, from a Bose metal, to a charge ordering insulator and an inhomogeneous Bose-superfluid. Optimal conditions for disproportionation driven high-T(c) superconductivity are shown to be realized only for several Jahn-Teller d(n) configurations that permit the formation of well defined local composite bosons. These are the high-spin d(4), low-spin d(7), and d(9) configurations given the octahedral crystal field, and the d(1), high spin d(6) configurations given the tetrahedral crystal field. The disproportionation reaction has a peculiar 'anti-Jahn-Teller' character lifting the bare orbital degeneracy. Superconductivity in the d(4) and d(6) systems at variance with d(1), d(7), and d(9) systems implies unavoidable coexistence of the spin-triplet composite bosons and the magnetic lattice. We argue that unconventional high-T(c) superconductivity, observed in quasi-2d cuprates with tetragonally distorted CuO(6) octahedra and iron-based layered pnictides/chalcogenides with tetrahedrally coordinated Fe(2+) ions presents a key argument to support the fact that the disproportionation scenario is at work in these compounds. PMID- 23363547 TI - Medical school attrition-beyond the statistics a ten year retrospective study. AB - BACKGROUND: Medical school attrition is important--securing a place in medical school is difficult and a high attrition rate can affect the academic reputation of a medical school and staff morale. More important, however, are the personal consequences of dropout for the student. The aims of our study were to examine factors associated with attrition over a ten-year period (2001-2011) and to study the personal effects of dropout on individual students. METHODS: The study included quantitative analysis of completed cohorts and qualitative analysis of ten-year data. Data were collected from individual student files, examination and admission records, exit interviews and staff interviews. Statistical analysis was carried out on five successive completed cohorts. Qualitative data from student files was transcribed and independently analysed by three authors. Data was coded and categorized and key themes were identified. RESULTS: Overall attrition rate was 5.7% (45/779) in 6 completed cohorts when students who transferred to other medical courses were excluded. Students from Kuwait and United Arab Emirates had the highest dropout rate (RR = 5.70, 95% Confidence Intervals 2.65 to 12.27;p < 0.0001) compared to Irish and EU students combined. North American students had a higher dropout rate than Irish and EU students; RR = 2.68 (1.09 to 6.58;p = 0.027) but this was not significant when transfers were excluded (RR = 1.32(0.38, 4.62);p = 0.75). Male students were more likely to dropout than females (RR 1.70, .93 to 3.11) but this was not significant (p = 0.079).Absenteeism was documented in 30% of students, academic difficulty in 55.7%, social isolation in 20%, and psychological morbidity in 40% (higher than other studies). Qualitative analysis revealed recurrent themes of isolation, failure, and despair. Student Welfare services were only accessed by one-third of dropout students. CONCLUSIONS: While dropout is often multifactorial, certain red flag signals may alert us to risk of dropout including non-EU origin, academic struggling, absenteeism, social isolation, depression and leave of absence. Psychological morbidity amongst dropout students is high and Student Welfare services should be actively promoted. Absenteeism should prompt early intervention. Behind every dropout statistic lies a personal story. All medical schools have a duty of care to support students who leave the medical programme. PMID- 23363548 TI - Aminolaevulinic acid synthase of Rhodobacter capsulatus: high-resolution kinetic investigation of the structural basis for substrate binding and catalysis. AB - The first enzyme of haem biosynthesis, ALAS (5-aminolaevulinic acid synthase), catalyses the pyridoxal 5'-phosphate-dependent condensation of glycine and succinyl-CoA to 5-aminolaevulinic acid, CO(2) and CoA. The crystal structure of Rhodobacter capsulatus ALAS provides the first snapshots of the structural basis for substrate binding and catalysis. To elucidate the functional role of single amino acid residues in the active site for substrate discrimination, substrate positioning, catalysis and structural protein rearrangements, multiple ALAS variants were generated. The quinonoid intermediates I and II were visualized in single turnover experiments, indicating the presence of an alpha-amino-beta oxoadipate intermediate. Further evidence was obtained by the pH-dependent formation of quinonoid II from the product 5-aminolaevulinic acid. The function of Arg(21), Thr(83), Asn(85) and Ile(86), all involved in the co-ordination of the succinyl-CoA substrate carboxy group, were analysed kinetically. Arg(21), Thr(83)and Ile(86), all of which are located in the second subunit to the intersubunit active site, were found to be essential. Their location in the second subunit provides the basis for the required structural dynamics during the complex condensation of both substrates. Utilization of L-alanine by the ALAS variant T83S indicated the importance of this residue for the selectiveness of binding with the glycine substrate compared with related amino acids. Asn(85) was found to be solely important for succinyl-CoA substrate recognition and selectiveness of binding. The results of the present study provide a novel dynamic view on the structural basis of ALAS substrate-binding and catalysis. PMID- 23363549 TI - Purification and characterization of mutant miniPlasmin for thrombolytic therapy. AB - BACKGROUND: Previous animal studies by us and others have indicated that catheter administered plasmin or its des-kringle derivatives may be more appropriate alternatives to plasminogen activators for treating thrombolytic diseases, since it has a very short serum half-life and therefore does not result in hemorrhaging. We have previously produced recombinant miniPlasmin (mPlasmin) that was proven suitable for treating peripheral arterial occlusion in animal models. However, our previous results showed that non-specific cleavage at position K698 of mPlasmin during activation hindered the further development of this promising therapeutic candidate. In order to minimize or eliminate the non-specific cleavage problem, we performed saturation mutagenesis at the K698 position to develop a mutant form of mPlasmin for thrombolytic therapy. METHODS: We changed K698 to 16 other amino acids, with preferred E. coli codons. Each of these mutants were expressed in E. coli as inclusion bodies and then refolded, purified, and subsequently characterized by detailed kinetic assays/experiments/studies which identified highly active mutants devoid of non specific cleavage. RESULTS: Activation studies indicated that at those conditions in which the wild type enzyme is cut at the non-specific position K698, the active mutants can be activated without being cleaved at this position. CONCLUSIONS: From the above results, we selected two mutants, K698Q and K698N, as our lead candidates for further thrombolytic drug developments. The selected mutants are potentially better therapeutic candidates for thrombolytic therapy. PMID- 23363550 TI - Recovery post treatment: plans, barriers and motivators. AB - BACKGROUND: The increasing focus on achieving a sustained recovery from substance use brings with it a need to better understand the factors (recovery capital) that contribute to recovery following treatment. This work examined the factors those in recovery perceive to be barriers to (lack of capital) or facilitators of (presence of capital) sustained recovery post treatment. METHODS: A purposive sample of 45 participants was recruited from 11 drug treatment services in northern England. Semi-structured qualitative interviews lasting between 30 and 90 minutes were conducted one to three months after participants completed treatment. Interviews examined key themes identified through previous literature but focused on allowing participants to explore their unique recovery journey. Interviews were transcribed and analysed thematically using a combination of deductive and inductive approaches. RESULTS: Participants generally reported high levels of confidence in maintaining their recovery with most planning to remain abstinent. There were indications of high levels of recovery capital. Aftercare engagement was high, often through self referral, with non substance use related activity felt to be particularly positive. Supported housing was critical and concerns were raised about the ability to afford to live independently with financial stability and welfare availability a key concern in general. Employment, often in the substance use treatment field, was a desire. However, it was a long term goal, with substantial risks associated with pursuing this too early. Positive social support was almost exclusively from within the recovery community although the re-building of relationships with family (children in particular) was a key motivator post treatment. CONCLUSIONS: Addressing internal factors and underlying issues i.e. 'human capital', provided confidence for continued recovery whilst motivators focused on external factors such as family and maintaining aspects of a 'normal' life i.e. 'social and physical capital'. Competing recovery goals and activities can leave people feeling under pressure and at risk of taking on or being pushed to do too much too soon. The breadth of re-integration and future plans at this stage is limited primarily to the recovery community and treatment sector. Services and commissioners should ensure that this does not become a limiting factor in individuals' long term recovery journeys. PMID- 23363551 TI - Omega-3 fatty acids as a putative treatment for traumatic brain injury. AB - Traumatic brain injury (TBI) is a global public health epidemic. In the US alone, more than 3 million people sustain a TBI annually. It is one of the most disabling injuries as it may cause motor and sensory deficits and lead to severe cognitive, emotional, and psychosocial impairment, crippling vital areas of higher functioning. Fueled by the recognition of TBI as the "signature injury" in our wounded soldiers in Iraq and Afghanistan, and its often devastating impact on athletes playing contact sports, interest in TBI and TBI research has increased dramatically. Unfortunately, despite increased awareness of its detrimental consequences, there has been little progress in developing effective TBI interventions. Recent evidence, however, strongly indicates that nutritional intervention may provide a unique opportunity to enhance the neuronal repair process after TBI. To date, two omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have the most promising laboratory evidence for their neuro-restorative capacities in TBI. Although both animal models and human studies of brain injuries suggest they may provide benefits, there has been no clinical trial evaluating the effects of n-3 fatty acids on resilience to, or treatment, of TBI. This article reviews the known functions of n-3 fatty acids in the brain and their specific role in the cellular and biochemical pathways underlying neurotraumatic injury. We also highlight recent studies on the therapeutic impact of enhanced omega 3 intake in vivo, and how this may be a particularly promising approach to improving functional outcome in patients with TBI. PMID- 23363552 TI - The cost-effectiveness of platelet additive solution to prevent allergic transfusion reactions. AB - BACKGROUND: Allergic transfusion reactions (ATRs) are among the most common complications of transfusion. Storage in platelet additive solution (PAS) has been shown to reduce ATRs from apheresis platelets (APs). This study evaluated the cost-effectiveness of using PAS storage as an alternative method to reduce ATRs. STUDY DESIGN AND METHODS: A Markov-based decision tree was constructed to compare ATR rates and associated costs expected from current practice and from alternative strategies of using APs stored in PAS. The potential use of pretransfusion medication was also incorporated. Using a hospital perspective and including direct medical expenses only (US$2012), Monte Carlo microsimulations were run to evaluate outcomes under a base-case analysis. One-way and probabilistic sensitivity analyses were used to assess outcome uncertainty. RESULTS: Under base-case variables, using APs stored in PAS for all patients as an initial transfusion protocol is expected to avert ATRs and associated costs, compared to current practice. Using PAS for all patients along with pretransfusion medication would be cost-saving only when the additional cost of PAS is below $9.14. If PAS storage could eliminate pretransfusion medication use, it is expected to result in cost savings when the additional unit cost of PAS is under $11.90. At a PAS cost of $15, averting one ATR would cost $701.95. Using PAS storage only in response to recurring mild ATRs is associated with cost savings under all costs of PAS evaluated. CONCLUSIONS: Using PAS storage for all AP transfusions to prevent ATRs may be financially and clinically beneficial, compared to current practice. PMID- 23363553 TI - An update of "Cost-effectiveness of rotavirus vaccination in the Netherlands: the results of a Consensus Rotavirus Vaccine model". AB - BACKGROUND: To update a cost-effectiveness analysis of rotavirus vaccination in the Netherlands previously published in 2011. METHODS: The rotavirus burden of disease and the indirect protection of older children and young adults (herd protection) were updated. RESULTS: When updated data was used, routine infant rotavirus vaccination in the Netherlands would potentially become an even more cost-effective strategy than previously estimated with the incremental cost per QALY at only ?3,000-4,000. Break-even total vaccination costs were indicated at ?92-122, depending on the applied threshold. CONCLUSIONS: We concluded that the results on potentially favourable cost-effectiveness in the previous study remained valid, however, the new data suggested that previous results might represent an underestimation of the economic attractiveness of rotavirus vaccination. PMID- 23363555 TI - Nitrogen monoxide inhibits haem synthesis in mouse reticulocytes. AB - AI (anaemia of inflammation) often manifests in patients with chronic immune activation due to cancer, chronic infections, autoimmune disorders, rheumatoid arthritis and other diseases. The pathogenesis of AI is complex and involves cytokine-mediated inhibition of erythropoiesis, insufficient erythropoietin production and diminished sensitivity of erythroid progenitors to this hormone, and retention of iron in haemoglobin-processing macrophages. NO (nitric oxide) is a gaseous molecule produced by activated macrophages that has been identified as having numerous effects on iron metabolism. In the present study, we explore the possibility that NO affects iron metabolism in reticulocytes and our results suggest that NO may also contribute to AI. We treated reticulocytes with the NO donor SNP (sodium nitroprusside). The results indicate that NO inhibits haem synthesis dramatically and rapidly at the level of erythroid-specific 5 aminolaevulinic acid synthase 2, which catalyses the first step of haem synthesis in erythroid cells. We also show that NO leads to the inhibition of iron uptake via the Tf (transferrin)-Tf receptor pathway. In addition, NO also causes an increase in eIF2alpha (eukaryotic initiation factor 2alpha) phosphorylation levels and decreases globin translation. The profound impairment of haem synthesis, iron uptake and globin translation in reticulocytes by NO raises the possibility that this gas may also contribute to AI. PMID- 23363554 TI - Emerging issues in paediatric health research consent forms in Canada: working towards best practices. AB - BACKGROUND: Obtaining a research participant's voluntary and informed consent is the bedrock of sound ethics practice. Greater inclusion of children in research has led to questions about how paediatric consent operates in practice to accord with current and emerging legal and socio-ethical issues, norms, and requirements. METHODS: Employing a qualitative thematic content analysis, we examined paediatric consent forms from major academic centres and public organisations across Canada dated from 2008-2011, which were purposively selected to reflect different types of research ethics boards, participants, and studies. The studies included biobanking, longitudinal studies, and gene-environment studies. Our purpose was to explore the following six emerging issues: (1) whether the scope of parental consent allows for a child's assent, dissent, or future consent; (2) whether the concepts of risk and benefit incorporate the child's psychological and social perspective; (3) whether a child's ability to withdraw is respected and to what extent withdrawal is permitted; (4) whether the return of research results includes individual results and/or incidental findings and the processes involved therein; (5) whether privacy and confidentiality concerns adequately address the child's perspective and whether standard data and/or sample identifiability nomenclature is used; and (6) whether retention of and access to paediatric biological samples and associated medical data are addressed. RESULTS: The review suggests gaps and variability in the consent forms with respect to addressing each of the six issues. Many forms did not discuss the possibility of returning research results, be they individual or general/aggregate results. Forms were also divided in terms of the scope of parental consent (specific versus broad), and none discussed a process for resolving disputes that can arise when either the parents or the child wishes to withdraw from the study. CONCLUSIONS: The analysis provides valuable insight and evidence into how consent forms address current ethical issues. While we do not thoroughly explore the contexts and reasons behind consent form gaps and variability, we do advocate and formulate the development of best practices for drafting paediatric health research consent forms. This can greatly ameliorate current gaps and facilitate harmonised and yet contextualised approaches to paediatric health research ethics. PMID- 23363556 TI - Effects of intervention programs on child and adolescent BMI: A meta-analysis study. AB - BACKGROUND: This meta-analysis study aims to assess the efficacy of school-based and after-school intervention programs on the BMIs of child and adolescents, addressing the correlation between some moderating variables. METHODS: We analyzed 52 studies (N = 28,236) published between 2000-2011. RESULTS: The overall effect size was 0.068 (P < .001), school (r = .069) and after-school intervention (r = .065). Programs conducted with children aged between 15-19 years were the most effective (r = .133). Interventions programs with boys and girls show better effect sizes (r = .110) than programs that included just girls (r = .073). There were no significant differences between the programs implemented in school and after-school (P = .770). The effect size was higher in interventions lasting 1 year (r = .095), with physical activity and nutritional education (r = .148), and that included 3-5 sessions of physical activity per week (r = .080). The effect size also increased as the level of parental involvement increased. CONCLUSIONS: Although of low magnitude (r = .068), the intervention programs had a positive effect in prevention and decreasing obesity in children. This effect seems to be higher in older children's, involving interventions with physical activity and nutritional education combined, with parent's participation and with 1-year duration. School or after-school interventions had a similar effect. PMID- 23363557 TI - Human contact influences the foraging behaviour and parasite community in long tailed macaques. AB - Human-wildlife interactions have reached unprecedented levels, and humans are influencing the earth's ecosystems more rapidly and extensively than ever before. This situation is cause for serious concern, especially since disease interactions between wildlife and humans have been recognized as major conservation threats. In this study, long-tailed macaques, Macaca fascicularis, from 2 forest parks located in north-eastern Thailand were investigated to determine the influence of habitat modification by humans on helminth parasite associations in non-human primates. Macaque populations with contact to anthropogenically modified environments were compared with sylvatic groups in nearby natural environments. In order to test for human-non-human primate transmission of parasites, the local human populations were also examined. Humans were infected with a number of potentially pathogenic parasites, including Opisthorchis viverrini and Strongyloides stercoralis. However, eggs of these helminths were not detected in macaque feces. Thus, no direct parasite transfer from humans to non-human primates could be confirmed. However, macaque groups with more frequent contact with human modified habitats, and a higher portion of human-provided food in their diet, had significantly higher prevalences and intensities of Strongyloides fuelleborni and of an intestinal fluke (probably Haplorchis sp.) than sylvatic groups. Positive correlations were found between the time foraging on the ground and infection with S. fuelleborni, and the amount of human-provided food and intestinal fluke infection. Human alteration of habitat and associated modifications in nonhuman primate behaviour are likely to play a role in determining the occurrence, prevalence and intensity of zoonotic helminth infection of wild non-human primates. PMID- 23363558 TI - Feature-based plan adaptation for fast treatment planning in scanned ion beam therapy. AB - We propose a plan adaptation method for fast treatment plan generation in scanned ion beam therapy. Analysis of optimized treatment plans with carbon ions indicates that the particle number modulation of consecutive rasterspots in depth shows little variation throughout target volumes with convex shape. Thus, we extract a depth-modulation curve (DMC) from existing reference plans and adapt it for creation of new plans in similar treatment situations. The proposed method is tested with seven CT serials of prostate patients and three digital phantom datasets generated with the MATLAB code. Plans are generated with a treatment planning software developed by GSI using single-field uniform dose optimization for all the CT datasets to serve as reference plans and 'gold standard'. The adapted plans are generated based on the DMC derived from the reference plans of the same patient (intra-patient), different patient (inter-patient) and phantoms (phantom-patient). They are compared with the reference plans and a re positioning strategy. Generally, in 1 min on a standard PC, either a physical plan or a biological plan can be generated with the adaptive method provided that the new target contour is available. In all the cases, the V95 values of the adapted plans can achieve 97% for either physical or biological plans. V107 is always 0 indicating no overdosage, and target dose homogeneity is above 0.98 in all cases. The dose received by the organs at risk is comparable to the optimized plans. The plan adaptation method has the potential for on-line adaptation to deal with inter-fractional motion, as well as fast off-line treatment planning, with either the prescribed physical dose or the RBE-weighted dose. PMID- 23363559 TI - Association between IL-1RN VNTR, IL-1beta -511 and IL-6 (-174, -572, -597) gene polymorphisms and urolithiasis. AB - Urolithiasis is a common multifactorial urological disorder that is characterized by stone formation. Interleukin (IL)-1 and IL-6 are pro-inflammatory cytokines that might be linked with urolithiasis. The single nucleotide polymorphisms within the IL-1 and IL-6 cytokine genes altered the cytokine expression levels. Our aim was to investigate the potential of IL-1beta (-511 C>T), IL-6 (-174 G>C, 572 G>C, -597 G>A) and IL-1RN VNTR gene polymorphisms to be a genetic marker for urinary stone disease. The polymorphisms studied in the promoter regions of IL 1beta and IL-6 genes did not reveal a strong association with urolithiasis when compared to the control group (p = 0.293, 0.871, 0.921, 0.536, respectively). However, a significant difference was observed between control and patient groups for IL-1RN VNTR gene polymorphism (chi(2) = 6.131, d.f. = 2, p = 0.047). Our data provide evidence that IL-1RN VNTR gene polymorphism may be involved in the pathogenesis of urinary stone formation, contributing to genetic susceptibility for urolithiasis. PMID- 23363560 TI - Adult-onset immunodeficiency--why is it important in rheumatology? PMID- 23363561 TI - RNAi-mediated knockdown of Xist does not rescue the impaired development of female cloned mouse embryos. AB - In mice, one of the major epigenetic errors associated with somatic cell nuclear transfer (SCNT) is ectopic expression of Xist during the preimplantation period in both sexes. We found that this aberrant Xist expression could be impeded by deletion of Xist from the putative active X chromosome in donor cells. In male clones, it was also found that prior injection of Xist-specific siRNA could significantly improve the postimplantation development of cloned embryos as a result of a significant repression of Xist at the morula stage. In this study, we examined whether the same knockdown strategy could work as well in female SCNT derived embryos. Embryos were reconstructed with cumulus cell nuclei and injected with Xist-specific siRNA at 6-7 h after oocyte activation. RNA FISH analysis revealed that siRNA treatment successfully repressed Xist RNA at the morula stage, as shown by the significant decrease in the number of cloud-type Xist signals in the blastomere nuclei. However, blastomeres with different sizes (from "pinpoint" to "cloud") and numbers of Xist RNA signals remained within single embryos. After implantation, the dysregulated Xist expression was normalized autonomously, as in male clones, to a state of monoallelic expression in both embryonic and extraembryonic tissues. However, at term there was no significant improvement in the survival of the siRNA-injected cloned embryos. Thus, siRNA injection was largely effective in repressing the Xist overexpression in female cloned embryos but failed to rescue them, probably because of an inability to mimic consistent monoallelic Xist expression in these embryos. This could only be achieved in female embryos by applying a gene knockout strategy rather than an siRNA approach. PMID- 23363562 TI - Utilization of a population health survey in policy and practice: a case study. AB - BACKGROUND: There is growing interest by funding bodies and researchers in assessing the impact of research on real world policy and practice. Population health monitoring surveys provide an important source of data on the prevalence and patterns of health problems, but few empirical studies have explored if and how such data is used to influence policy or practice decisions. Here we provide a case study analysis of how the findings from an Australian population monitoring survey series of children's weight and weight-related behaviors (Schools Physical Activity and Nutrition Survey (SPANS)) have been used, and the key facilitators and barriers to their utilization. METHODS: Data collection included semi-structured interviews with the chief investigators (n = 3) and end users (n = 9) of SPANS data to explore if, how and under what circumstances the survey findings had been used, bibliometric analysis and verification using documentary evidence. Data analysis involved thematic coding of interview data and triangulation with other data sources to produce case summaries of policy and practice impacts for each of the three survey years (1997, 2004, 2010). Case summaries were then reviewed and discussed by the authors to distil key themes on if, how and why the SPANS findings had been used to guide policy and practice. RESULTS: We found that the survey findings were used for agenda setting (raising awareness of issues), identifying areas and target groups for interventions, informing new policies, and supporting and justifying existing policies and programs across a range of sectors. Reported factors influencing use of the findings were: i) the perceived credibility of survey findings; ii) dissemination strategies used; and, iii) a range of contextual factors. CONCLUSIONS: Using a novel approach, our case study provides important new insights into how and under what circumstances population health monitoring data can be used to influence real world policy and practice. The findings highlight the importance of population monitoring programs being conducted by independent credible agencies, researchers engaging end-users from the inception of survey programs and utilizing existing policy networks and structures, and using a range of strategies to disseminate the findings that go beyond traditional peer review publications. PMID- 23363564 TI - Scaffold-free cell pellet transplantations can be applied to periodontal regeneration. AB - Cell transplantation has emerged as a novel therapeutic strategy for periodontitis, and the adoption of cell pellet offers advantages by secreting abundant extracellular matrix (ECM) and eliminating the adverse effect of cell carriers. This study aimed to fabricate scaffold-free periodontal ligament stem cell (PDLSC) pellets (MUCPs) and to evaluate their regeneration potential. We constructed monolayer cell pellets (MCPs) by fabricating and culturing multilayered cell sheets (MUCS) and constructed MUCPs from the MUCS. Immunochemistry, scanning electron microscope, real-time PCR, and Western blot analysis showed higher levels of COL-I, COL-III, fibronectin, and laminin in the MUCPs. Furthermore, the massive increase in ECM secretion improved cell adhesion, migration, and proliferation. Finally, upon transplantation into the omentum sac and periodontal defects, all the transplants formed regular aligned cementum/PDL like complex, but the mineral deposit and fiber alignment were more obvious in the MUCPs than in the MCPs. Altogether, our results suggest that MUCPs may be a promising alternative to periodontal repair for future clinical application. PMID- 23363563 TI - Genistein ameliorates adverse cardiac effects induced by arsenic trioxide through preventing cardiomyocytes apoptosis. AB - BACKGROUND/AIMS: Arsenic trioxide (As2O3) is a highly effective agent for treatment of acute promyelocytic leukemia (APL). However, consecutively administered As2O3 induces serious adverse cardiac effects, including long QT syndrome (LQTs) and even sudden cardiac death. Previous studies have shown that genistein (Gen) exerts anti-oxidant, anti-inflammatory, and anti-apoptotic effects. The present study aimed to explore the potential protective effects of Gen on As2O3-induced adverse cardiac effects, and to elucidate the underlying molecular mechanisms. METHODS: A rat model of As2O3-induced QT prolongation was generated by intravenous injection with As2O3. Surface electrocardiogram (ECG) and hemodynamics were employed to assess the LQTs and cardiac function. Intracellular calcium concentration ([Ca(2+)]i) and mitochondrial membrane potential (Deltapsim) were measured by confocal microscopy, and cardiomyocytes apoptosis were assessed by TUNEL assay. Western blot was applied to determine protein levels. RESULTS: We found for the first time that treatment with Gen significantly reversed LQTs and dose-dependently improved As2O3-induced impairment of cardiac function. As2O3 elevated [Ca(2+)]i and Gen mitigated this effect. Meanwhile, Gen significantly reversed As2O3-mediated cardiomyocytes apoptosis. Furthermore, Gen dose-dependently inhibited the phosphorylated JNK and p38-MAPK (pp38-MAPK), and blocked Deltapsim collapse, and further decreased cleaved caspase-3. CONCLUSION: Gen protects against the adverse cardiac effects of As2O3 partly by mitigating cardiomyocytes apoptosis induced by As2O3 through attenuating intracellular calcium overload and downregulating protein expression of p-JNK and pp38-MAPK to ameliorate the damage of Deltapsim leading to suppression of caspase-3 activation. Gen might be used as an adjunction therapy in APL patients receiving As2O3 treatment to avoid, at least to minimize, the adverse cardiac effects of As2O3. PMID- 23363565 TI - Prospective European-wide multicentre study on a blood based real-time PCR for the diagnosis of acute schistosomiasis. AB - BACKGROUND: Acute schistosomiasis constitutes a rare but serious condition in individuals experiencing their first prepatent Schistosoma infection. To circumvent costly and time-consuming diagnostics, an early and rapid diagnosis is required. So far, classic diagnostic tools such as parasite microscopy or serology lack considerable sensitivity at this early stage of Schistosoma infection. To validate the use of a blood based real-time polymerase chain reaction (PCR) test for the detection of Schistosoma DNA in patients with acute schistosomiasis who acquired their infection in various endemic regions we conducted a European-wide prospective study in 11 centres specialized in travel medicine and tropical medicine. METHODS: Patients with a history of recent travelling to schistosomiasis endemic regions and freshwater contacts, an episode of fever (body temperature >=38.5 degrees C) and an absolute or relative eosinophil count of >=700/MUl or 10%, were eligible for participation. PCR testing with DNA extracted from serum was compared with results from serology and microscopy. RESULTS: Of the 38 patients with acute schistosomiasis included into the study, PCR detected Schistosoma DNA in 35 patients at initial presentation (sensitivity 92%). In contrast, sensitivity of serology (enzyme immunoassay and/or immunofluorescence assay) or parasite microscopy was only 70% and 24%, respectively. CONCLUSION: For the early diagnosis of acute schistosomiasis, real time PCR for the detection of schistosoma DNA in serum is more sensitive than classic diagnostic tools such as serology or microscopy, irrespective of the region of infection. Generalization of the results to all Schistosoma species may be difficult as in the study presented here only eggs of S. mansoni were detected by microscopy. A minimum amount of two millilitre of serum is required for sufficient diagnostic accuracy. PMID- 23363567 TI - Mesenchymal stem cell therapy for lung diseases: oasis or mirage? PMID- 23363566 TI - Health communication in primary health care -a case study of ICT development for health promotion. AB - BACKGROUND: Developing Information and Communication Technology (ICT) supported health communication in PHC could contribute to increased health literacy and empowerment, which are foundations for enabling people to increase control over their health, as a way to reduce increasing lifestyle related ill health. However, to increase the likelihood of success of implementing ICT supported health communication, it is essential to conduct a detailed analysis of the setting and context prior to the intervention. The aim of this study was to gain a better understanding of health communication for health promotion in PHC with emphasis on the implications for a planned ICT supported interactive health channel. METHODS: A qualitative case study, with a multi-methods approach was applied. Field notes, document study and focus groups were used for data collection. Data was then analyzed using qualitative content analysis. RESULTS: Health communication is an integral part of health promotion practice in PHC in this case study. However, there was a lack of consensus among health professionals on what a health promotion approach was, causing discrepancy in approaches and practices of health communication. Two themes emerged from the data analysis: Communicating health and environment for health communication. The themes represented individual and organizational factors that affected health communication practice in PHC and thus need to be taken into consideration in the development of the planned health channel. CONCLUSIONS: Health communication practiced in PHC is individual based, preventive and reactive in nature, as opposed to population based, promotive and proactive in line with a health promotion approach. The most significant challenge in developing an ICT supported health communication channel for health promotion identified in this study, is profiling a health promotion approach in PHC. Addressing health promotion values and principles in the design of ICT supported health communication channel could facilitate health communication for promoting health, i.e. 'health promoting communication'. PMID- 23363568 TI - Quality assurance of radiotherapy in the ongoing EORTC 22042-26042 trial for atypical and malignant meningioma: results from the dummy runs and prospective individual case Reviews. AB - BACKGROUND: The ongoing EORTC 22042-26042 trial evaluates the efficacy of high dose radiotherapy (RT) in atypical/malignant meningioma. The results of the Dummy Run (DR) and prospective Individual Case Review (ICR) were analyzed in this Quality Assurance (QA) study. MATERIAL/METHODS: Institutions were requested to submit a protocol compliant treatment plan for the DR and ICR, respectively. DR plans (n=12) and ICR-plans (n=50) were uploaded to the Image-Guided Therapy QA Center of Advanced Technology Consortium server (http://atc.wustl.edu/) and were assessed prospectively. RESULTS: Major deviations were observed in 25% (n=3) of DR-plans while no minor deviations were observed. Major and minor deviations were observed in 22% (n=11) and 10% (n=5) of the ICR-plans, respectively. Eighteen% of ICRs could not be analyzed prospectively, as a result of corrupted or late data submission. CTV to PTV margins were respected in all cases. Deviations were negatively associated with the number of submitted cases per institution (p=0.0013), with a cutoff of 5 patients per institutions. No association (p=0.12) was observed between DR and ICR results, suggesting that DR's results did not predict for an improved QA process in accrued brain tumor patients. CONCLUSIONS: A substantial number of protocol deviations were observed in this prospective QA study. The number of cases accrued per institution was a significant determinant for protocol deviation. These data suggest that successful DR is not a guarantee for protocol compliance for accrued patients. Prospective ICRs should be performed to prevent protocol deviations. PMID- 23363569 TI - Physical activity and mortality among middle-aged and older adults in the United States. AB - BACKGROUND: Physical activity (PA) has been routinely linked to lower all-cause mortality, yet extant research in the United States is primarily based on nonrepresentative samples. Evidence is scant on the relative and independent merits of leisure-time (LTPA) versus non-leisure-time (NLTPA) activities and how the PA-mortality link may vary across racial-ethnic-gender groups. METHODS: Data were from Health and Retirement Study which began in 1992 collecting data on individuals aged 51-61 years who were subsequently surveyed once every 2 years. The current study assessed group-specific effects of LTPA and NLTPA measured in 1992 on mortality that occurred during the 1992-2008 follow-up period. Cox proportional hazard analyses were performed to examine the PA-mortality link. RESULTS: Net of a wide range of controls, both LTPA and NLTPA showed a gradient negative relation with mortality. No gender-PA interaction effects were evident. Some interaction effects of PA with race-ethnicity were found but they were weak and inconsistent. The mortality reduction effects of PA seemed robust across racial-ethnic-gender groups. CONCLUSIONS: Regardless of personal background, PA is a major health promoting factor and should be encouraged in aging populations. More research is needed to assess relative merits of different types and domains of PA. PMID- 23363570 TI - The dosimetric impact of dental implants on head-and-neck volumetric modulated arc therapy. AB - This work aims to investigate the dosimetric impact of dental implants on volumetric modulated arc therapy (VMAT) for head-and-neck patients and to evaluate the effectiveness of using the material's electron-density ratio for the correction. An in-house Monte Carlo (MC) code was utilized for the dose calculation to account for the scattering and attenuation caused by the high-Z implant material. Three different dental implant materials were studied in this work: titanium, Degubond(r)4 and gold. The dose perturbations caused by the dental implant materials were first investigated in a water phantom with a 1 cm(3) insert. The per cent depth dose distributions of a 3 * 3 cm(2) photon field were compared with the insert material as water and the three selected dental implant materials. To evaluate the impact of the dental implant on VMAT patient dose calculation, four head-and-neck cases were selected. For each case, the VMAT plan was designed based on the artifact-corrected patient geometry using a treatment planning system (TPS) that was typically utilized for routine patient treatment. The plans were re-calculated using the MC code for five situations: uncorrected geometry, artifact-corrected geometry and artifact-corrected geometry with one of the three different implant materials. The isodose distributions and the dose-volume histograms were cross-compared with each other. To evaluate the effectiveness of using the material's electron-density ratio for dental implant correction, the implant region was set as water with the material's electron density ratio and the calculated dose was compared with the MC simulation with the real material. The main effect of the dental implant was the severe attenuation in the downstream. The 1 cm(3) dental implant can lower the downstream dose by 10% (Ti) to 51% (Au) for a 3 * 3 cm(2) field. The TPS failed to account for the dose perturbation if the dental implant material was not precisely defined. For the VMAT patient dose calculation, the presence of dental implants degrades the PTV coverage significantly. With the material's electron density ratio applied, the dose calculation accuracy in the water phantom and the VMAT patient was improved to a clinically acceptable level. The effects of the dental implant material can be clinically significant and its impact varies with the density of the dental implant material. We demonstrated that it was effective to use the material's electron-density ratio to account for the dosimetric impact of the dental implant. PMID- 23363571 TI - In vitro isolation from Amblyomma ovale (Acari: Ixodidae) and ecological aspects of the Atlantic rainforest Rickettsia, the causative agent of a novel spotted fever rickettsiosis in Brazil. AB - Recently, a novel human rickettsiosis, namely Atlantic rainforest spotted fever, was described in Brazil. We herein report results of a survey led around the index case in an Atlantic rainforest reserve in Peruibe municipality, southeastern Brazil. A Rickettsia parkeri-like agent (Rickettsia sp. Atlantic rainforest genotype) and Ricketsia bellii were isolated from adult Amblyomma ovale ticks collected from dogs. Molecular evidence of infection with strain Atlantic rainforest was obtained for 30 (12.9%) of 232 A. ovale adult ticks collected from dogs. As many as 88.6% of the 35 examined dogs had anti-Rickettsia antibodies, with endpoint titres at their highest to R. parkeri. High correlation among antibody titres in dogs, A. ovale infestations, and access to rainforest was observed. Amblyomma ovale subadults were found predominantly on a rodent species (Euryoryzomys russatus). From 17 E. russatus tested, 6 (35.3%) displayed anti-Rickettsia antibodies, with endpoint titres highest to R. parkeri. It is concluded that Atlantic rainforest genotype circulates in this Atlantic rainforest area at relatively high levels. Dogs get infected when bitten by A. ovale ticks in the forest, and carry infected ticks to households. The role of E. russatus as an amplifier host of Rickettsia to A. ovale ticks deserves investigation. PMID- 23363572 TI - NDM-1, the ultimate promiscuous enzyme: substrate recognition and catalytic mechanism. AB - The specter of a return to an era in which infectious disease looms as a significant threat to human health is not just hyperbole; there are serious concerns about the widespread overuse and misuse of antibiotics contributing to increased antibiotic resistance in pathogens. The recent discovery of a new enzyme, first identified in Klebsiella pneumoniae from a patient from New Delhi and denoted as NDM-1, represents an example of extreme promiscuity: It hydrolyzes and inactivates nearly all known beta-lactam-based antibiotics with startling efficiency. NDM-1 can utilize different metal cofactors and seems to exploit an alternative mechanism based on the reaction conditions. Here we report the results of a combined experimental and theoretical study that examines the substrate, metal binding, and catalytic mechanism of the enzyme. We utilize structures obtained through X-ray crystallography, biochemical assays, and numerical simulation to construct a model of the enzyme catalytic pathway. The NDM-1 enzyme interacts with the substrate solely through zinc, or other metals, bound in the active site, explaining the observed lack of specificity against a broad range of beta-lactam antibiotic agents. The zinc ions also serve to activate a water molecule that hydrolyzes the beta-lactam ring through a proton shuttle. PMID- 23363573 TI - Calcium-dependent deceleration of the cell cycle in muscle cells by simulated microgravity. AB - Of all our mechanosensitive tissues, skeletal muscle is the most developmentally responsive to physical activity. Conversely, restricted mobility due to injury or disease results in muscle atrophy. Gravitational force is another form of mechanical input with profound developmental consequences. The mechanical unloading resulting from the reduced gravitational force experienced during spaceflight results in oxidative muscle loss. We examined the early stages of myogenesis under conditions of simulated microgravity (SM). C2C12 mouse myoblasts in SM proliferated more slowly (2.23* less) as a result of their being retained longer within the G2/M phase of the cell cycle (2.10* more) relative to control myoblasts at terrestrial gravity. Blocking calcium entry via TRP channels with SKF-96365 (10-20 MUM) accumulated myoblasts within the G2/M phase of the cell cycle and retarded their proliferation. On the genetic level, SM resulted in the reduced expression of TRPC1 and IGF-1 isoforms, transcriptional events regulated by calcium downstream of mechanical input. A decrease in TRPC1-mediated calcium entry thus appears to be a pivotal event in the muscle atrophy brought on by gravitational mechanical unloading. Hence, relieving the constant force of gravity on cells might prove one valid experimental approach to expose the underlying mechanisms modulating mechanically regulated developmental programs. PMID- 23363574 TI - Purification and characterization of glucose 6-phosphate dehydrogenase enzyme from rainbow trout (Oncorhynchus mykiss) liver and investigation of the effects of some metal ions on enzyme activity. AB - Glucose 6-phosphate dehydrogenase (d-glucose 6-phosphate: NADP(+) oxidoreductase, EC 1.1.1.49; G6PD) is a key enzyme that is localized in all mammal tissues, especially in cytoplasmic sections and that catalyzes the first step of pentose phosphate metabolic pathway. In this study, G6PD enzyme was purified 1444-fold with a yield of 77% from rainbow trout liver using 2',5'-ADP-sepharose-4B affinity chromatography. Moreover, a purity check of the enzyme was performed with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Some characteristic features like optimal pH, stable pH, optimal temperature and optimal ionic strength were determined for the purified enzyme. In addition to this, in vitro effects of ions like silver nitrate (Ag(+)), thallium sulphate (TI(+)), cobalt (II) nitrate (Co(2+)) and arsenic (V) oxide (As(5+)) on enzyme activity were researched. Half-maximal inhibitory concentration (IC50) values of Ag(+), Co(2+) and As(5+) metal ions, which showed an inhibitory effect, were found to be 0.0044, 0.084 and 4.058 mM, respectively; and their inhibition constants (K i) were found to be 0.0052 +/- 0.00042, 0.087 +/- 0.015700 and 4.833 +/- 1.753207 mM, respectively. Tl(+) not exhibited inhibitory effect on the enzyme activity. PMID- 23363575 TI - TCDD and corticosterone on testicular steroidogenesis and antioxidant system of epididymal sperm in rats. AB - 2,3,7,8-Tetrachloro dibenzo-p-dioxin (TCDD), an endocrine-disrupting environmental pollutant, has been found to cause male reproductive toxicity. Glucocorticoids have been found to influence the metabolic pathway of TCDD. Stress, which affects the male reproductive function, is marked by an increase in the level and activity of glucocorticoids in the body. The present study was carried out to understand the effect of TCDD on testicular steroidogenesis and sperm antioxidant system under the influence of increased level of corticosterone in the body. Adult male rats were treated with either TCDD (100 ng/kg bw/ day) or corticosterone (3 mg/kg bw/day) or both for 15 days. Treatment with either TCDD or corticosterone was found to suppress the levels of steroidogenic acute regulatory protein and androgen-binding protein and reduce the activities of steroidogenic enzymes in testis while increasing oxidative stress in ventral prostate, seminal vesicles and epididymal sperm. In rats treated with both TCDD and corticosterone, the suppression of testicular steroidogenesis and increase in oxidative stress observed in ventral prostate, seminal vesicles and epididymal sperm were significant as compared to TCDD alone treated rats. The levels of Fas and FasL proteins were also increased in rats subjected to either TCDD or corticosterone treatment. In rats treated with both compounds, the increase observed in testicular levels of Fas and FasL was significant as compared to TCDD alone treated rats. Effect of TCDD on testicular steroidogenesis and antioxidant system of epididymal sperm may get enhanced under increased level of glucocorticoids in the body. PMID- 23363576 TI - Hepatoprotective effect of carob against acute ethanol-induced oxidative stress in rat. AB - The present study was undertaken to determine whether subacute treatment with aqueous extract of carob (Ceratonia siliqua L.) pods (AECPs) protects against ethanol (EtOH)-induced oxidative stress in rat liver. Animals were divided into four groups: control, carob, EtOH and EtOH + carob. Wistar rats were intraperitoneally pretreated with AECP (600 mg/kg body weight (bw)) during 7 days and intoxicated for 6 h by acute oral administration of EtOH (6 g/kg bw) 24 h after the last injection. We found that acute administration of EtOH leads to hepatotoxicity as monitored by the increase in the levels of hepatic marker aspartate aminotransferase and alanine aminotransferase as well as hepatic tissue injury. EtOH also increased the formation of malondialdehyde in the liver, indicating an increase in lipid peroxidation and depletion of antioxidant enzyme activities as superoxide dismutase, catalase and glutathione peroxidase. Subacute carob pretreatment prevented all the alterations induced by EtOH and returned their levels to near normal. Importantly, we showed that acute alcohol increased hepatic and plasmatic hydrogen peroxide and free iron levels. The carob pretreatment reversed EtOH effects to near control levels. These data suggest that carob could have a beneficial effect in inhibiting the oxidative damage induced by acute EtOH administration and that its mode of action may involve an opposite effect on plasma and tissue-free iron accumulation. Indeed, carob can be offered as a food additive to protect against EtOH-induced oxidative damage. PMID- 23363577 TI - Responses of Portulaca oleracea Linn. to selenium exposure. AB - The present study was investigated to evaluate the uptake and accumulation of selenium (Se) by the stem cuttings of Portulaca oleracea L. grown in alfisol amended with various concentrations of Se. P. oleracea accumulated a maximum of 63.4 ug g(-1) dry weight in a short growth period of 42 days. The order of accumulation of Se among the plant parts was leaves (31.5 MUg g(-1)) > stems (16.4 MUg g(-1)) > roots (15.5 MUg g(-1)). The accumulation potential was fourfold higher than the plant available concentration of 15.2 MUg g(-1) of Se g( 1) of soil (diethylenetriaminepentaacetic acid extracted). Although the plant was able to accumulate Se in their tissues, increase in Se concentrations in soil caused a concentration-dependent decrease in the growth rate of plants (regeneration of leaves, number of leaves, number of roots, root length, stem length and biomass). PMID- 23363578 TI - Implications of early aortic stiffening in patients with transposition of the great arteries after arterial switch operation. AB - BACKGROUND: The elastic function of the aorta in patients with transposition of the great arteries after arterial switch operation (ASO) is suspected to be important for long-term prognosis. METHODS AND RESULTS: Fifty-one patients and 34 controls were studied at 3.0 Tesla with MRI. Forty-three patients (12.8+/-6.9 years) underwent 1-stage ASO, 8 patients (23.8+/-6.9 years) had prior pulmonary artery banding (2-stage ASO). Aortic dimensions, distensibility, pulse wave velocity, aortic arch angle, left ventricular (LV) mass, LV systolic function and left atrial (LA) volumes, and LA passive emptying function as marker of LV diastolic function were assessed. Compared with controls, patients had increased aortic root areas (602.6+/-240.5 versus 356.8+/-113.4 mm(2)/m; P<0.01) and reduced distensibility of the thoracic aorta most pronounced at the aortic root (3.2+/-2.0 versus 9.1+/-4.7*10(-3) mm Hg(-1); P<0.01). Aortic distensibility correlated negatively with the aortic areas (P<0.01). Pulse wave velocity was higher in adults after ASO (5.0+/-1.0 versus 3.8+/-1.3 m/s; P<0.01). In contrast to controls pulse wave velocity and distensibility correlated with age in patients (P=0.04 to <0.01), LV mass was higher in patients (P=0.02). LA volumes correlated negatively with aortic root and ascending aortic distensibility and positively with pulse wave velocity (P<0.05). In patients, LA passive emptying function was lower (27.3+/-8.9 versus 41.1+/-6.0; P<0.01) and correlated with aortic root distensibility (P=0.004). CONCLUSIONS: Reduced aortic bioelasticity and aortic root dilatation are present in transposition of the great artery patients post ASO and are likely to contribute to LV diastolic dysfunction. Impaired aortic bioelasticity was strongly associated with age, suggesting the usefulness of follow-up studies for early onset of degenerative cardiovascular disease. PMID- 23363579 TI - Radial strain delay based on segmental timing and strain amplitude predicts left ventricular reverse remodeling and survival after cardiac resynchronization therapy. AB - BACKGROUND: Dyssynchrony assessment based on the timing of regional contraction is inherently independent of underlying myocardial contractility. We tested the hypothesis that patient selection for cardiac resynchronization therapy (CRT) would be enhanced using a parameter derived from the net radial strain delay (RSD) for the 12 basal and mid-left ventricular segments (calculated radial strain delay RSD [RSDc]), based on not only timing but also amplitude of segmental strain. METHODS AND RESULTS: Echocardiographic data were analyzed in 240 patients with symptomatic heart failure undergoing CRT (New York Heart Association class III/IV; QRS >120 milliseconds; ejection fraction, 23+/-7%). RSDc was calculated as the sum of difference between peak radial strain and radial strain at aortic valve closure before CRT implantation. CRT response was defined as >15% reduction in left ventricular end-systolic volume at 6 months. In a derivation group (n=102), RSDc was higher in responders compared with nonresponders (74+/-39% versus 29+/-15%; P<0.001) and related to the change in left ventricular end-systolic volume (r=-0.53; P<0.001). RSDc >40% predicted remodeling (sensitivity, 87%; specificity, 88%). In the validation group (n=108), RSDc similarly predicted response (sensitivity, 89%; specificity, 84%). Survival at long-term follow-up was greater in patients with RSDc >40% (P<0.0001). CONCLUSIONS: RSDc, based on both the timing and the amplitude of segmental strain, has a strong predictive value for CRT remodeling response and long-term survival. PMID- 23363582 TI - Primate-predator interactions. Preface. PMID- 23363580 TI - Comparison of 5% versus 15% sucrose intakes as part of a eucaloric diet in overweight and obese subjects: effects on insulin sensitivity, glucose metabolism, vascular compliance, body composition and lipid profile. A randomised controlled trial. AB - AIMS: The effect of dietary sucrose on insulin resistance and the pathogenesis of diabetes and vascular disease is unclear. We assessed the effect of 5% versus 15% sucrose intakes as part of a weight maintaining, eucaloric diet in overweight/obese subjects. METHODS: Thirteen subjects took part in a randomised controlled crossover study (M:F 9:4, median age 46 years, range 37-56 years, BMI 31.7+/-0.9 kg/m(2)). Subjects completed two 6 week dietary periods separated by 4 week washout. Diets were designed to have identical macronutrient profile. Insulin action was assessed using a two-step hyperinsulinaemic euglycaemic clamp; glucose tolerance, vascular compliance, body composition and lipid profiles were also assessed. RESULTS: There was no change in weight or body composition between diets. There was no difference in peripheral glucose utilization or suppression of endogenous glucose production. Fasting glucose was significantly lower after the 5% diet. There was no demonstrated effect on lipid profiles, blood pressure or vascular compliance. CONCLUSION: A low-sucrose diet had no beneficial effect on insulin resistance as measured by the euglycaemic glucose clamp. However, reductions in fasting glucose, one hour insulin and insulin area under the curve with the low sucrose diet on glucose tolerance testing may indicate a beneficial effect and further work is required to determine if this is the case. Clinical Trial Registration number ISRCTN50808730. PMID- 23363583 TI - Life and dinner under the shared umbrella: patterns in felid and primate communities. AB - Sympatry between primates and felids is potentially relevant to both their behavioural ecology and their conservation. This paper briefly introduces felids and primates, for the purposes of assessing their interrelationships and the patterns in their spatial congruence using IUCN spatial data. First, we review evidence and opportunity for predator-prey interactions between the felids and primates. Second, we analyse the overlap between species of the two taxa to reveal the potential of particular felid species or guilds (unique combinations of 2 or more felids) to act as umbrellas for the conservation of co-occurring primates. Felid guilds vary in terms of their geographical ranges and numbers of members. Some felid species overlap the ranges of many primate species, and the most speciose felid guilds, while geographically limited in distribution, have the potential to act as protective umbrellas to large numbers of primate species. This prompts the hypothesis that threatened primates and felids are facing similar threats and might thus benefit from similar interventions, which is evaluated in a sister paper by Macdonald et al. in this special issue. PMID- 23363584 TI - A problem shared is a problem reduced: seeking efficiency in the conservation of felids and primates. AB - Threats faced by mammalian species can be grouped into one of a handful of categories, such as habitat loss, unsustainable hunting and persecution. Insofar as they face common threats, diverse species may benefit from the same conservation intervention, thereby offering efficiencies in conservation action. We explore this proposition for primates and felids by examining coarse scale overlaps in geographical distributions, using IUCN Red List assessments of the primary threats posed to each species. A global analysis of primates and felids that face common threats reveals the greatest overlap is in Central and South Asia, where up to 14 primates and felids co-occur. More than 80% of the land where at least 1 threatened species of either primate or felid occurs also contains at least one threatened species of the other taxon, yet over 60% of these grid cells containing both threatened primates and felids lie outside Conservation International's hot spots. A review of IUCN Action Plans of the threats to felids and primates strongly supports the hypothesis that they are often the same and occur in the same place. In principle, steps to conserve big cats have the potential to benefit several species of threatened primates, and vice versa. PMID- 23363585 TI - The evolutionary history and palaeo-ecology of primate predation: Macaca sylvanus from Plio-Pleistocene Europe as a case study. AB - In this article we briefly review primate interactions with predators throughout their evolutionary history. Like today, predators of past primates were taxonomically diverse, including crocodilians, aquatic mammals, hyaenids, raptors and other primates. There is strong evidence for felid predation of extinct primates, with most work undertaken on the African Plio-Pleistocene fossil record. Felid predation of Plio-Pleistocene primates from other areas, including Europe, is much less well understood, so we explored co-occurrence and potential interaction between carnivorans (with particular reference to felids) and Macaca sylvanus, which was widespread and present in Europe from the late Miocene to the late Pleistocene. Over its tenure in the fossil record, M. sylvanus co-occurred with a diverse array of carnivorans, including canids and hyaenids, but medium sized felids probably posed the most significant predation risk. It is likely, however, that human predation was a major factor contributing to macaque extinction in Europe. PMID- 23363586 TI - Predation by mammalian carnivores on nocturnal primates: is the lack of evidence support for the effectiveness of nocturnality as an antipredator strategy? AB - The apparent paucity of accounts of predation, particularly by felids, on nocturnal primates is confirmed by a quasi-systematic review of 1,939 publications which revealed just 1 case of a felid eating a nocturnal primate. This instance was amongst only 51 direct reports of predation by vertebrates on nocturnal primates (90% were on Madagascar, where 56% of approx. 110 nocturnal primate species occur), of which 41% were by birds of prey. These findings prompt discussion of two possibilities: (a) nocturnality is, in part, an effective antipredator adaptation, and (b) knowledge of nocturnal primates is so biased by their elusiveness and, for predation, underreporting (e.g. inadequate mechanisms to publish opportunistic observations) that understanding of their biology urgently necessitates both the collation of field observations and innovative research. Interspecific comparisons facilitate deductions about the role of predation in the evolution of primate nocturnality and associated traits, but intraspecific comparisons of changing activity rhythms in response to different levels of predation risk offer the most compelling insights into the functional significance of these adaptations. PMID- 23363587 TI - Why mob? Reassessing the costs and benefits of primate predator harassment. AB - While some primate species attempt to avoid predators by fleeing, hiding or producing alarm calls, others actually approach, harass and sometimes attack potential threats, a behavior known as 'mobbing'. Why individuals risk their safety to mob potential predators remains poorly understood. Here, I review reports of predator harassment by primates to (1) determine the distribution of this behavior across taxa, (2) assess what is known about the costs of mobbing, and (3) evaluate hypotheses about its function. Mobbing is taxonomically widespread and is used against a wide range of predator species. However, inconsistent use of the term 'mobbing' within the primate literature, the lack of systematic studies of primate mobbing, and the likelihood of systematic biases in the existing data pose significant obstacles to understanding this puzzling behavior. Although difficult to quantify, the costs associated with harassing predators appear nontrivial. Many benefits that have been proposed to explain mobbing in birds may also be important in primate systems. There are puzzling aspects of primate mobbing, however, that existing hypotheses cannot explain. Future research should consider the within-group signaling potential of this costly behavior, as well as the ability of behavioral syndromes to explain the distribution of mobbing in primates. PMID- 23363588 TI - Loud calls, startle behaviour, social organisation and predator avoidance in arboreal langurs (Cercopithecidae: Presbytis). AB - Linking predator avoidance and social organisation predicts that large groups are favoured under heavy predation pressure but that small, inconspicuous groups may do equally well by avoiding detection altogether. We explored the relationships between antipredator behaviour (vocalisation, concealment, fleeing), detectability (colouration, group size) and social organisation in arboreal langurs. Three clear antipredation conditions emerged: (1) exemplified by Presbytis melalophos--brightly-coloured species (red, yellow) with contrasting colours, living in large unimale-multifemale groups (>10 individuals), that vocalised frequently and that flee loudly through the canopy; (2) exemplified by P. comata--greyish species (some contrasting colours), living in intermediate, unimale-multifemale or 1-male-1-female groups (approx. 7 individuals), that vocalise infrequently and that flee through the middle forest layers; (3) exemplified by P. frontata--dull-coloured species without contrast, living in small unimale-multifemale or 1-male-1-female groups (<5 individuals), that may freeze upon detection, and that may vocalise mainly during the night. Crypsis as an antipredator strategy is restricted to taxa that occur in 1-male-1-female groups. This wide range of antipredator strategies within a monophyletic taxon living in the same general area with a similar suite of predators facing similar predator pressures appears to be unique among the order Primates. PMID- 23363589 TI - Avoidance of mammalian predators by patas monkeys (Erythrocebus patas) in a risk landscape. AB - Primates and felids often occupy the same landscape, hence evolutionary theory predicts that proximate predator-prey mechanisms will influence both groups' ecology. Erythrocebus patas are potentially vulnerable to a number of predators and exhibit an array of morphological and behavioural predator avoidance strategies. Here, two concurrent studies, one on E. patas and one on the mammalian carnivore assemblage, in the Acacia drepanolobium woodland of Sweetwaters Game Reserve (SGR), Laikipia, Kenya, provided an opportunity to explore interactions between the two taxa, and serve as an example whereby data from different methodologies can be interpreted together. Static interaction models of predation risk due to leopards, lions, black-backed jackals and spotted hyaenas were developed and interpreted with actual and potential dietary information, collected during the study and from the literature, respectively. This amalgamation of field data showed that E. patas in SGR avoided areas with the highest risk of encountering leopards. Furthermore, the patterns of E. patas ranging suggested that males travelling in small bachelor groups were less affected by other predators than females in large social groups. Bachelor males avoided only the most risky areas of the reserve. PMID- 23363590 TI - Sleeping site selection by agile gibbons: the influence of tree stability, fruit availability and predation risk. AB - Primates spend a significant proportion of their lives at sleeping sites: the selection of a secure and stable sleeping tree can be crucial for individual survival and fitness. We measured key characteristics of all tree species in which agile gibbons slept, including exposure of the tree crown, root system, height, species and presence of food. Gibbons most frequently slept in Dipterocarpaceae and Fabaceae trees and preferentially chose trees taller than average, slept above the mean canopy height and showed a preference for liana free trees. These choices could reflect avoidance of competition with other frugivores, but we argue these choices reflect gibbons prioritizing avoidance of predation. The results highlight that gibbons are actively selecting and rejecting sleeping trees based on several characteristics. The importance of the presence of large trees for food is noted and provides insight into gibbon antipredatory behaviour. PMID- 23363591 TI - Non-human predator interactions with wild great apes in Africa and the use of camera traps to study their dynamics. AB - The slow life histories of great apes (hereafter 'apes') combined with a growing inventory of predation incidents suggest that apes may be strongly affected by direct predation, as well as by predation risk. Predation risk may shape and increase behavioural flexibility by forcing individuals to adapt their behaviour to predator patterns. Forest leopards are an apex predator of primates in African rain forests and may represent a significant risk to ape populations. More field data are needed to further elucidate the behavioural modifications of apes in response to predation. We present research methods that combine the use of remote camera traps, capture-mark-recapture statistics and occupancy modelling to study predator-African ape relationships and potential antipredator behaviour through spatial variation in species co-occurrence patterns. PMID- 23363592 TI - Attempted predation by Nigeria-Cameroon chimpanzees (Pan troglodytes ellioti) on Preuss's red colobus (Procolobus preussi) in the Ebo forest, Cameroon. AB - We describe the first observation of a predation attempt by Nigerian-Cameroon chimpanzees (Pan troglodytes ellioti) on Preuss's red colobus (Procolobus preussi) in the Ebo forest, Cameroon. The activity, which was observed for 15 min, primarily involved 1 chimpanzee and 1 red colobus individual, with a further 2 chimpanzees observing the event. Although the behaviour was interrupted when we were detected by the chimpanzees, we believe that this is the first recorded observation of hunting behaviour in Nigeria-Cameroon chimpanzees. PMID- 23363593 TI - Predation as a determinant of minimum group size in baboons. AB - Predation risk places a pressure on animals to adopt mechanisms by which they reduce their individual risk of being preyed on. However, a consensus on methods of determining predation risk has yet to be reached. One of the most widespread ways in which animals respond to predation risk is by living in groups. Minimum permissible group size is the smallest group size that animals are able to live in, given the habitat-specific predation risk they face. We explore ways in which predation risk can be measured and analyse its effect on minimum observed group size in baboons. Using data on predator density, habitat composition and baboon body size, we investigate the impact of the components of predation risk on baboon group size, and derive an equation that best predicts minimum group size. Minimum group size in baboons is related to predator density and female body mass. Both of these elements can, in turn, be estimated from environmental variables. These findings present support for the argument that group living in primates is a response to predation risk and offer potentially new ways of investigating carnivore and primate ecology. PMID- 23363594 TI - Unusually high predation on chacma baboons (Papio ursinus) by female leopards (Panthera pardus) in the Waterberg Mountains, South Africa. AB - Leopards do not preferentially favour baboons as prey, but they are considered the primary predators of baboons across Africa. Even in areas where baboons are abundant, their contribution to leopard diet seldom exceeds 5% of biomass. It is suggested that the extreme aggressiveness of baboons, group vigilance and their high mobility when escaping may limit leopard predation. Male baboons are particularly aggressive, and retaliation often leads to the death of the leopard. However, evidence suggests that leopards may learn to catch and kill certain dangerous prey. This study reports predation on chacma baboons by 3 female leopards on a private game reserve in the Waterberg Mountains of South Africa. Potential leopard feeding sites were identified using global positioning system (GPS) location clusters obtained from GPS collars. Over a 5-month period, we investigated 200 potential leopard feeding sites and located 96 leopard feeding/kill sites. Baboons constituted 18.7% of the leopards' biomass intake. The majority of baboons preyed upon were adults and 70% of the kills were diurnal. In terms of the measured variables, there were no significant differences in the way the leopards preyed upon baboons, compared to the rest of the prey species. PMID- 23363595 TI - Mangrove and peat swamp forests: refuge habitats for primates and felids. AB - Swamp forests may be important refuges for primates and felids where these taxa are threatened with habitat loss. Mangrove and peat swamp forests, impenetrable, wet habitats, inaccessible and uninhabitable for humans, may, in some regions, be the most significant remaining habitats for threatened species. They are nevertheless neglected in field studies compared to relatively species-rich, terrestrial tropical forests probably, in part, because of the difficulties associated with surveying them. As a result, maps of mammal distributions may overlook swamp forests although camera-trapping is gradually rectifying this gap. I have compiled and mapped records of over 60 primate and 20 felid taxa reported to use mangrove and peat swamp forests in Africa and Asia at 47 sites, of which 21 are Afrotropical mangrove, 25 are Indo-Malayan mangrove or peat swamp forest, and 1 is an outlying mangrove site in Japan. Eleven of these are designated Ramsar Sites. I highlight key sites of conservation priority on the basis of primate and felid species richness and composite 'threat scores'. Petit Loango in Gabon and Gunung Palung National Park in Indonesia emerged as top priority sites in Africa and Asia, respectively. Further research on the role of swamp forests in the ecology and persistence of threatened mammals is needed. PMID- 23363596 TI - From cheetahs to chimpanzees: a comparative review of the drivers of human carnivore conflict and human-primate conflict. AB - Human-wildlife conflict is a growing conservation threat, and is increasingly of importance to primate conservationists. Despite this, relatively little work has been done to date on the drivers of human-primate conflict, especially compared to other conflict-causing taxa such as large carnivores. However, the drivers of conflict are often very similar across species, so conflict researchers can learn important lessons from work conducted on other taxa. This paper discusses 8 key factors which are likely to affect how hostile people are towards wildlife and any damage they cause--6 of these are common to both carnivores and primates, while one is much more applicable to carnivores and the other is specific to primates. These conflict drivers involve numerous social and cultural factors, and highlight the importance of truly understanding the local drivers of conflict in order to develop effective mitigation strategies. PMID- 23363598 TI - Intermediate filament-associated cytolinker plectin 1c destabilizes microtubules in keratinocytes. AB - The transition of microtubules (MTs) from an assembled to a disassembled state plays an essential role in several cellular functions. While MT dynamics are often linked to those of actin filaments, little is known about whether intermediate filaments (IFs) have an influence on MT dynamics. We show here that plectin 1c (P1c), one of the multiple isoforms of the IF-associated cytolinker protein plectin, acts as an MT destabilizer. We found that MTs in P1c-deficient (P1c(-/-)) keratinocytes are more resistant toward nocodazole-induced disassembly and display increased acetylation. In addition, live imaging of MTs in P1c(-/-), as well as in plectin-null, cells revealed decreased MT dynamics. Increased MT stability due to P1c deficiency led to changes in cell shape, increased velocity but loss of directionality of migration, smaller-sized focal adhesions, higher glucose uptake, and mitotic spindle aberrations combined with reduced growth rates of cells. On the basis of ex vivo and in vitro experimental approaches, we suggest a mechanism for MT destabilization in which isoform-specific binding of P1c to MTs antagonizes the MT-stabilizing and assembly-promoting function of MT associated proteins through an inhibitory function exerted by plectin's SH3 domain. Our results open new perspectives on cytolinker-coordinated IF-MT interaction and its physiological significance. PMID- 23363599 TI - Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction. AB - Ubiquitin-protein ligases (E3s) that ubiquitinate substrates for proteasomal degradation are often in the position of ubiquitinating themselves due to interactions with a charged ubiquitin-conjugating enzyme (E2). This can mediate the E3's proteasomal degradation. Many E3s have evolved means to avoid autoubiquitination, including protection by partner or substrate binding, preventative modifications, and deubiquitinating enzyme reversal of ubiquitination. Here we describe another adaptation for E3 self-protection discovered while exploring San1, which ubiquitinates misfolded nuclear proteins in yeast for proteasomal degradation. San1 is highly disordered in its substrate binding regions N- and C-terminal to its RING domain. In cis autoubiquitination could occur if these flexible regions come in proximity to the E2. San1 prevents this by containing no lysines in its disordered regions; thus the canonical residue used for ubiquitin attachment has been selectively eliminated. San1's target substrates have lost their native structures and expose hydrophobicity. To avoid in trans autoubiquitination, San1 possesses little concentrated hydrophobicity in its disordered regions, and thus the that feature San1 recognizes in misfolded substrates has also been selectively eliminated. Overall the presence of key residues in San1 have been evolutionarily minimized to avoid self-destruction either in cis or in trans. Our work expands the ways in which E3s protect themselves from autoubiquitination. PMID- 23363597 TI - akirin is required for diakinesis bivalent structure and synaptonemal complex disassembly at meiotic prophase I. AB - During meiosis, evolutionarily conserved mechanisms regulate chromosome remodeling, leading to the formation of a tight bivalent structure. This bivalent, a linked pair of homologous chromosomes, is essential for proper chromosome segregation in meiosis. The formation of a tight bivalent involves chromosome condensation and restructuring around the crossover. The synaptonemal complex (SC), which mediates homologous chromosome association before crossover formation, disassembles concurrently with increased condensation during bivalent remodeling. Both chromosome condensation and SC disassembly are likely critical steps in acquiring functional bivalent structure. The mechanisms controlling SC disassembly, however, remain unclear. Here we identify akir-1 as a gene involved in key events of meiotic prophase I in Caenorhabditis elegans. AKIR-1 is a protein conserved among metazoans that lacks any previously known function in meiosis. We show that akir-1 mutants exhibit severe meiotic defects in late prophase I, including improper disassembly of the SC and aberrant chromosome condensation, independently of the condensin complexes. These late-prophase defects then lead to aberrant reconfiguring of the bivalent. The meiotic divisions are delayed in akir-1 mutants and are accompanied by lagging chromosomes. Our analysis therefore provides evidence for an important role of proper SC disassembly in configuring a functional bivalent structure. PMID- 23363600 TI - Assembly in G1 phase and long-term stability are unique intrinsic features of CENP-A nucleosomes. AB - Centromeres are the site of kinetochore formation during mitosis. Centromere protein A (CENP-A), the centromere-specific histone H3 variant, is essential for the epigenetic maintenance of centromere position. Previously we showed that newly synthesized CENP-A is targeted to centromeres exclusively during early G1 phase and is subsequently maintained across mitotic divisions. Using SNAP-based fluorescent pulse labeling, we now demonstrate that cell cycle-restricted chromatin assembly at centromeres is unique to CENP-A nucleosomes and does not involve assembly of other H3 variants. Strikingly, stable retention is restricted to the CENP-A/H4 core of the nucleosome, which we find to outlast general chromatin across several cell divisions. We further show that cell cycle timing of CENP-A assembly is independent of centromeric DNA sequences and instead is mediated by the CENP-A targeting domain. Unexpectedly, this domain also induces stable transmission of centromeric nucleosomes, independent of the CENP-A deposition factor HJURP. This demonstrates that intrinsic properties of the CENP A protein direct its cell cycle-restricted assembly and induces quantitative mitotic transmission of the CENP-A/H4 nucleosome core, ensuring long-term stability and epigenetic maintenance of centromere position. PMID- 23363602 TI - The ERdj5-Sel1L complex facilitates cholera toxin retrotranslocation. AB - Cholera toxin (CT) traffics from the host cell surface to the endoplasmic reticulum (ER), where the toxin's catalytic CTA1 subunit retrotranslocates to the cytosol to induce toxicity. In the ER, CT is captured by the E3 ubiquitin ligase Hrd1 via an undefined mechanism to prepare for retrotranslocation. Using loss-of function and gain-of-function approaches, we demonstrate that the ER-resident factor ERdj5 promotes CTA1 retrotranslocation, in part, via its J domain. This Hsp70 cochaperone regulates binding between CTA and the ER Hsp70 BiP, a chaperone previously implicated in toxin retrotranslocation. Importantly, ERdj5 interacts with the Hrd1 adaptor Sel1L directly through Sel1L's N-terminal lumenal domain, thereby linking ERdj5 to the Hrd1 complex. Sel1L itself also binds CTA and facilitates toxin retrotranslocation. By contrast, EDEM1 and OS-9, two established Sel1L binding partners, do not play significant roles in CTA1 retrotranslocation. Our results thus identify two ER factors that promote ER-to cytosol transport of CTA1. They also indicate that ERdj5, by binding to Sel1L, triggers BiP-toxin interaction proximal to the Hrd1 complex. We postulate this scenario enables the Hrd1-associated retrotranslocation machinery to capture the toxin efficiently once the toxin is released from BiP. PMID- 23363601 TI - Regulation of apoptosis by Bcl-2 cysteine oxidation in human lung epithelial cells. AB - Hydrogen peroxide is a key mediator of oxidative stress known to be important in various cellular processes, including apoptosis. B-cell lymphoma-2 (Bcl-2) is an oxidative stress-responsive protein and a key regulator of apoptosis; however, the underlying mechanisms of oxidative regulation of Bcl-2 are not well understood. The present study investigates the direct effect of H2O2 on Bcl-2 cysteine oxidation as a potential mechanism of apoptosis regulation. Exposure of human lung epithelial cells to H2O2 induces apoptosis concomitant with cysteine oxidation and down-regulation of Bcl-2. Inhibition of Bcl-2 oxidation by antioxidants or by site-directed mutagenesis of Bcl-2 at Cys-158 and Cys-229 abrogates the effects of H2O2 on Bcl-2 and apoptosis. Immunoprecipitation and confocal microscopic studies show that Bcl-2 interacts with mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2 [ERK1/2]) to suppress apoptosis and that this interaction is modulated by cysteine oxidation of Bcl-2. The H2O2-induced Bcl-2 cysteine oxidation interferes with Bcl-2 and ERK1/2 interaction. Mutation of the cysteine residues inhibits the disruption of Bcl-2 ERK complex, as well as the induction of apoptosis by H2O2. Taken together, these results demonstrate the critical role of Bcl-2 cysteine oxidation in the regulation of apoptosis through ERK signaling. This new finding reveals crucial redox regulatory mechanisms that control the antiapoptotic function of Bcl-2. PMID- 23363603 TI - N-terminal acetylation of the yeast Derlin Der1 is essential for Hrd1 ubiquitin ligase activity toward luminal ER substrates. AB - Two conserved ubiquitin ligases, Hrd1 and Doa10, mediate most endoplasmic reticulum-associated protein degradation (ERAD) in yeast. Degradation signals (degrons) recognized by these ubiquitin ligases remain poorly characterized. Doa10 recognizes the Deg1 degron from the MATalpha2 transcription factor. We previously found that deletion of the gene (NAT3) encoding the catalytic subunit of the NatB N-terminal acetyltransferase weakly stabilized a Deg1-fusion protein. By contrast, a recent analysis of several MATalpha2 derivatives suggested that N terminal acetylation of these proteins by NatB was crucial for recognition by Doa10. We now analyze endogenous MATalpha2 degradation in cells lacking NatB and observe minimal perturbation relative to wild-type cells. However, NatB mutation strongly impairs degradation of ER-luminal Hrd1 substrates. This unexpected defect derives from a failure of Der1, a Hrd1 complex subunit, to be N-terminally acetylated in NatB mutant yeast. We retargeted Der1 to another acetyltransferase to show that it is the only ERAD factor requiring N-terminal acetylation. Preventing Der1 acetylation stimulates its proteolysis via the Hrd1 pathway, at least partially accounting for the ERAD defect observed in the absence of NatB. These results reveal an important role for N-terminal acetylation in controlling Hrd1 ligase activity toward a specific class of ERAD substrates. PMID- 23363604 TI - Rap1 and Canoe/afadin are essential for establishment of apical-basal polarity in the Drosophila embryo. AB - The establishment and maintenance of apical-basal cell polarity is critical for assembling epithelia and maintaining organ architecture. Drosophila embryos provide a superb model. In the current view, apically positioned Bazooka/Par3 is the initial polarity cue as cells form during cellularization. Bazooka then helps to position both adherens junctions and atypical protein kinase C (aPKC). Although a polarized cytoskeleton is critical for Bazooka positioning, proteins mediating this remained unknown. We found that the small GTPase Rap1 and the actin-junctional linker Canoe/afadin are essential for polarity establishment, as both adherens junctions and Bazooka are mispositioned in their absence. Rap1 and Canoe do not simply organize the cytoskeleton, as actin and microtubules become properly polarized in their absence. Canoe can recruit Bazooka when ectopically expressed, but they do not obligatorily colocalize. Rap1 and Canoe play continuing roles in Bazooka localization during gastrulation, but other polarity cues partially restore apical Bazooka in the absence of Rap1 or Canoe. We next tested the current linear model for polarity establishment. Both Bazooka and aPKC regulate Canoe localization despite being "downstream" of Canoe. Further, Rap1, Bazooka, and aPKC, but not Canoe, regulate columnar cell shape. These data reshape our view, suggesting that polarity establishment is regulated by a protein network rather than a linear pathway. PMID- 23363605 TI - TORC1-regulated protein kinase Npr1 phosphorylates Orm to stimulate complex sphingolipid synthesis. AB - The evolutionarily conserved Orm1 and Orm2 proteins mediate sphingolipid homeostasis. However, the homologous Orm proteins and the signaling pathways modulating their phosphorylation and function are incompletely characterized. Here we demonstrate that inhibition of nutrient-sensitive target of rapamycin complex 1 (TORC1) stimulates Orm phosphorylation and synthesis of complex sphingolipids in Saccharomyces cerevisiae. TORC1 inhibition activates the kinase Npr1 that directly phosphorylates and activates the Orm proteins. Npr1 phosphorylated Orm1 and Orm2 stimulate de novo synthesis of complex sphingolipids downstream of serine palmitoyltransferase. Complex sphingolipids in turn stimulate plasma membrane localization and activity of the nutrient scavenging general amino acid permease 1. Thus activation of Orm and complex sphingolipid synthesis upon TORC1 inhibition is a physiological response to starvation. PMID- 23363607 TI - Risk factors for adverse reactions from contrast agents for computed tomography. AB - BACKGROUND: Symptoms of an adverse reaction to contrast agents for computed tomography are diverse ranging, and sometimes serious. The goal of this study is to create a scoring rule to predict adverse reactions to contrast agents used in computed tomography. METHODS: This was a retrospective cohort study of all adult patients undergoing contrast enhanced CT scan for 7 years. The subjects were randomly divided into either a derivation or validation group. Baseline data and clinically relevant factors were collected from the electronic chart. Primary outcome was any acute adverse reactions to contrast media, observed for during 24 hours after administration. All potential candidate predictors were included in a forward stepwise logistic regression model. Prediction scores were assigned based on beta coefficient. A receiver operating characteristic (ROC) curve was drawn, and the area under the curve (AUC) and incidence of acute adverse reactions at each point were obtained. The same process was performed in the validation group. RESULTS: 36,472 patients underwent enhanced CT imaging: 20,000 patients in the derivation group and 16,472 in the validation group. A total of 409 (2.0%, 95% CI:1.9-2.3) and 347 (2.1%, 95% CI:1.9-2.3) acute adverse reactions were seen in the derivation and validation groups. Logistic regression analysis revealed that prior adverse reaction to contrast agents, urticaria, an allergic history to drugs other than contrast agents, contrast agent concentration >70%, age <50 years, and total contrast agent dose >65 g were significant predictors of an acute adverse reaction. AUC was 0.70 (95% CI:0.67-0.73) and 0.67 (95% CI:0.64 0.70) in the derivation and validation groups. CONCLUSIONS: We suggest a prediction model consisting of six predictors for acute adverse reactions to contrast agents used in CT. PMID- 23363606 TI - Phosphorylation on Ser-279 and Ser-282 of connexin43 regulates endocytosis and gap junction assembly in pancreatic cancer cells. AB - The molecular mechanisms regulating the assembly of connexins (Cxs) into gap junctions are poorly understood. Using human pancreatic tumor cell lines BxPC3 and Capan-1, which express Cx26 and Cx43, we show that, upon arrival at the cell surface, the assembly of Cx43 is impaired. Connexin43 fails to assemble, because it is internalized by clathrin-mediated endocytosis. Assembly is restored upon expressing a sorting-motif mutant of Cx43, which does not interact with the AP2 complex, and by expressing mutants that cannot be phosphorylated on Ser-279 and Ser-282. The mutants restore assembly by preventing clathrin-mediated endocytosis of Cx43. Our results also document that the sorting-motif mutant is assembled into gap junctions in cells in which the expression of endogenous Cx43 has been knocked down. Remarkably, Cx43 mutants that cannot be phosphorylated on Ser-279 or Ser-282 are assembled into gap junctions only when connexons are composed of Cx43 forms that can be phosphorylated on these serines and forms in which phosphorylation on these serines is abolished. Based on the subcellular fate of Cx43 in single and contacting cells, our results document that the endocytic itinerary of Cx43 is altered upon cell-cell contact, which causes Cx43 to traffic by EEA1-negative endosomes en route to lysosomes. Our results further show that gap-junctional plaques formed of a sorting motif-deficient mutant of Cx43, which is unable to be internalized by the clathrin-mediated pathway, are predominantly endocytosed in the form of annular junctions. Thus the differential phosphorylation of Cx43 on Ser-279 and Ser-282 is fine-tuned to control Cx43's endocytosis and assembly into gap junctions. PMID- 23363608 TI - Klebsiella pneumoniae liver abscess in diabetic patients: association of glycemic control with the clinical characteristics. AB - BACKGROUND: Klebsiella pneumoniae liver abscess (KPLA) has been reported with increasing frequency in East Asian countries in the past 3 decades, especially in Taiwan and Korea. Diabetes is a well-known risk factor for KPLA and highly associated with septic metastatic complications from KPLA. We investigated the association of glycemic control in diabetic patients with the clinical characteristics of KPLA in Taiwan. METHODS: Adult diabetic patients with KPLA were identified retrospectively in a medical center from January 2007 to January 2012. Clinical characteristics were compared among patients with different levels of current hemoglobin A1c (HbA1c). Risk factors for metastatic infection from KPLA were analyzed. RESULTS: Patients with uncontrolled glycemia (HbA1c >= 7%) were significantly younger than those with controlled glycemia (HbA1c < 7%). Patients with uncontrolled glycemia had the trend to have a higher rate of gas forming liver abscess, cryptogenic liver abscess, and metastatic infection than those with controlled glycemia. Cryptogenic liver abscess and metastatic infection were more common in the poor glycemic control group (HbA1c value >; 10%) after adjustment with age. HbA1c level and abscess < 5 cm were independent risk factors for metastatic complications from KPLA. CONCLUSIONS: Glycemic control in diabetic patients played an essential role in the clinical characteristics of KPLA, especially in metastatic complications from KPLA. PMID- 23363609 TI - Cool and hot executive function in conduct-disordered adolescents with and without co-morbid attention deficit hyperactivity disorder: relationships with externalizing behaviours. AB - BACKGROUND: An understanding of the exact nature of executive function (EF) deficits in conduct disorder (CD) remains elusive because of issues of co morbidity with attention deficit hyperactivity disorder (ADHD). METHOD: Seventy two adolescents with CD, 35 with CD + ADHD and 20 healthy controls (HCs) were assessed on a computerized battery of putative 'cool' and 'hot' EFs. Participants also completed the Child Behaviour Checklist (CBCL). RESULTS: In the cool EF tasks such as planning, the CD + ADHD group in particular showed most notable impairments compared to HCs. This pattern was less evident for set shifting and behavioural inhibition but there were significant correlations between errors scores on these tasks and indices of externalizing behaviours on the CBCL across the sample. For hot EF tasks, all clinical groups performed worse than HCs on delay of gratification and poor performance was correlated with externalizing scores. Although there were no notable group differences on the punishment-based card-playing task, there were significant correlations between ultimate payout and externalizing behaviour across groups. CONCLUSIONS: Overall, our findings highlight the fact that there may be more common than distinguishing neuropsychological underpinnings to these co-morbid disorders and that a dimensional symptom-based approach may be the way forward. PMID- 23363610 TI - Image-based response assessment of liver metastases following stereotactic body radiotherapy with respiratory tracking. AB - OBJECTIVE: To describe post-CyberKnife(r) imaging characteristics of liver metastases as an aid in assessing response to treatment, and a novel set of combined criteria (CC) as an alternative to response according to change in size (RECIST). SUBJECTS AND METHODS: Imaging data and medical records of 28 patients with 40 liver metastases treated with stereotactic body radiotherapy (SBRT) were reviewed. Tumor size, CT attenuation coefficient, and contrast enhancement of lesions were evaluated up to 2 years post SBRT. Rates of local control, progression-free survival, time to progression, and overall survival according to RECIST and CC were estimated. RESULTS: Complete response (CR) was 3.6% (95% CI: 0.1-18%) and 18% (95% CI: 6-37%) according to RECIST and combined criteria, respectively. Two progressive diseases and two partial responses according to RECIST were classified as CR by the combined criteria and one stable response according to RECIST was classified as progressive by CC (Stuart-Maxwell test, p = 0.012). The disease control rate was 60.7% (95% CI: 41-78%) by RECIST and 64% (95% CI: 44%-81%) by CC. CONCLUSION: Use of response criteria based on change in size alone in the interpretation of liver response to SBRT may be inadequate. We propose a simple algorithm with a combination of criteria to better assess tumor response. Further studies are needed to confirm their validity. PMID- 23363611 TI - Daily variations in weather and the relationship with physical activity and sedentary time in European 10- to 12-year-olds: The ENERGY-Project. AB - BACKGROUND: The aim of the study was to examine the association of daily variations in rainfall and temperature with sedentary time (ST) and physical activity (PA) in European children. METHODS: Children were included from 5 countries (Belgium, Greece, Hungary, the Netherlands, Switzerland) as part of the ENERGY-project. We used cross-sectional data from 722 children aged 10-12 years (47% boys). ST and PA were measured by accelerometers for 6 consecutive days, including weekend days. Weather data were collected from online national weather reports. Multilevel regression models were used for data analyses. RESULTS: Maximum temperature was positively associated with light PA (beta = 3.1 min/day; 95% CI = 2.4-3.8), moderate-to-vigorous PA (beta = 0.6 min/day; 95% CI = 0.4 0.8), and average PA [beta = 4.1 counts per minute (cpm); 95% CI = 1.6-6.5, quadratic relationship]. Rainfall was inversely and quadratically associated with light PA (beta = -1.3 min/day; 95% CI = -1.9 to -0.6), moderate-to-vigorous PA (beta = -0.6 min/day; 95% CI = -0.8 to -0.3), and average PA (beta = -1.6 cpm; 95% CI = -2.2 to -0.9). Maximum temperature was not significantly associated with ST (beta = -0.2 min/day; 95% CI = -1.0 to 0.6), while rainfall was positively associated with ST (beta = 0.9 min/day; 95% CI = 0.6-1.3). CONCLUSION: The current study shows that temperature and rainfall are significantly associated with PA and ST in 10- to 12-year-old European children. PMID- 23363612 TI - Systematic assessment of complications and outcome of radical cystectomy undertaken with curative intent in patients with comorbidity and over 75 years of age. AB - OBJECTIVE: To evaluate the complications, survival and oncological outcome of patients >=75 years of age after radical cystectomy for muscle-invasive bladder cancer. PATIENTS AND METHODS: Between April 1993 and August 2010, 765 patients with muscle-invasive bladder cancer underwent radical cystectomy at one high volume center. Of these, 70 patients were >=75 years of age. All 70 patients had at least one severe systemic comorbidity with an American Society of Anesthesiologists score of 3. Primary endpoints of this retrospective study were overall and recurrence-free survival with a mean follow-up of 22 months (1-159). Perioperative parameters such as need for blood transfusions, hospital stay, mortality, short- and long-term complications were also assessed. Complications were graded according to the Clavien-Dindo classification. RESULTS: Perioperative complications occurred in 23/70 patients (33%) with a 30-day mortality rate of 1.4%. 16/70 patients (23%) developed late complications requiring hospitalization. Within 30 days of surgery, according to the Clavien-Dindo grading, 27% had no complications, 3% grade 1, 49% grade 2, 14% grade 3, 6% grade 4 and 1.4% grade 5 complications. Within 31-90 days after surgery, 76% had grade 1 complications, 3% grade 2, 6% grade 3, 9% grade 4 and 6% grade 4 complications. The calculated 5- and 8-year overall survival rates were 30 and 25%, respectively, with a recurrence-free survival rate of 52% at 5 and 42% at 8 years. CONCLUSIONS: Radical cystectomy is an appropriate and effective treatment for comorbid elderly patients. The oncological long-term outcome is the same as in younger patients while overall survival is comparatively lower. Mortality and complication-related morbidity are comparable to those in younger patients with modern perioperative management. PMID- 23363613 TI - SIRT1 regulates the human alveolar epithelial A549 cell apoptosis induced by Pseudomonas aeruginosa lipopolysaccharide. AB - BACKGROUND: Sirtuin1 (SIRT1) is an NAD(+)-dependent deacetylase that plays an inhibitory role in cell apoptosis, which is associated with p53 deacetylation. Lipopolysaccharide (LPS) is a key virulence factor produced by Pseudomonas aeruginosa and plays an important role in mediating the interactions between the bacterium and its host. However, the effect of SIRT1 in the regulation of LPS induced human alveolar epithelial A549 cells apoptosis is unknown. METHODS: Cell viability, apoptosis and reactive oxygen species (ROS) production were first examined in A549 cells that were treated with LPS. Relative cell signaling pathways were further explored by western blot analysis. RESULTS: Exposure of A549 cells to LPS decreased cell viability in a concentration- and time- dependent manner. LPS stimulated cell apoptosis and ROS production while inhibiting the expression of SIRT1 in A549 cells. Activation of SIRT1 by exposure to resveratrol significantly reversed the effects of LPS on A549 cells. In contrast, inhibition of SIRT1 by nicotinamide had the opposite effects enhancing cell apoptosis and ROS production. CONCLUSION: SIRT1 plays an important role in regulating the human alveolar epithelial A549 cell apoptosis process induced by LPS. PMID- 23363615 TI - An examination of the mechanisms by which neural precursors augment recovery following spinal cord injury: a key role for remyelination. AB - The mechanisms by which neural precursor cells (NPCs) enhance functional recovery from spinal cord injury (SCI) remain unclear. Spinal cord injured rats were transplanted with wild-type mouse NPCs, shiverer NPCs unable to produce myelin, dead NPCs, or media. Most animals also received minocycline, cyclosporine, and perilesional infusion of trophins. Motor function was graded according to the BBB scale. H&E/LFB staining was used to assess gray and white matter, cyst, and lesional tissue. Mature oligodendrocytes and ED1(+) inflammatory cells were quantitated. Confocal and electron microscopy were used to assess the relationship between the transplanted cells and axons. Pharmacotherapy and trophin infusion preserved gray matter, white matter, and oligodendrocytes. Trophin infusion also significantly increased cyst and lesional tissue volume as well as inflammatory infiltrate, and functional recovery was reduced. Animals transplanted with wild-type NPCs showed greatest functional recovery; animals transplanted with shiverer NPCs performed the worst. Wild-type NPCs remyelinated host axons. Shiverer NPCs ensheathed axons but did not produce MBP. These results suggest that remyelination by NPCs is an important contribution to functional recovery following SCI. Shiverer NPCs may prevent remyelination by endogenous cells capable of myelin formation. These findings suggest that remyelination is an important therapeutic target following SCI. PMID- 23363614 TI - Characterisation of fibroblast-like synoviocytes from a murine model of joint inflammation. AB - INTRODUCTION: Fibroblast-like synoviocytes (FLS) play a central role in defining the stromal environment in inflammatory joint diseases. Despite a growing use of FLS isolated from murine inflammatory models, a detailed characterisation of these cells has not been performed. METHODS: In this study, FLS were isolated from inflamed joints of mice expressing both the T cell receptor transgene KRN and the MHC class II molecule Ag7 (K/BxN mice) and their purity in culture determined by immunofluorescence and real-time reverse transcription polymerase chain reaction (real-time RT-PCR). Basal expression of proinflammatory genes was determined by real-time RT-PCR. Secreted interleukin 6 (IL-6) was measured by enzyme-linked immunosorbent assay (ELISA), and its regulation by tumor necrosis factor-alpha (TNF-alpha and corticosterone (the major glucocorticoid in rodents) measured relative to other mesenchymal cell populations. RESULTS: Purity of FLS culture was identified by positive expression of fibronectin, prolyl 4 hydroxylase, cluster of differentiation 90.2 (CD90.2) and 248 (CD248) in greater than 98% of the population. Cultured FLS were able to migrate and invade through matrigel, a process enhanced in the presence of TNF-alpha. FLS isolated from K/BxN mice possessed significantly greater basal expression of the inflammatory markers IL-6, chemokine ligand 2 (CCL-2) and vascular cell adhesion molecule 1 (VCAM-1) when compared to FLS isolated from non-inflamed tissue (IL-6, 3.6 fold; CCL-2, 11.2 fold; VCAM-1, 9 fold; P<0.05). This elevated expression was abrogated in the presence of corticosterone at 100 nmol/l. TNF-alpha significantly increased expression of all inflammatory markers to a much greater degree in K/BxN FLS relative to other mesenchymal cell lines (K/BxN; IL-6, 40.8 fold; CCL 2, 1343.2 fold; VCAM-1, 17.8 fold; ICAM-1, 13.8 fold; P<0.05), with secreted IL-6 mirroring these results (K/BxN; con, 169+/-29.7 versus TNF-alpha, 923+/-378.8 pg/ml/1*105 cells; P<0.05). Dose response experiments confirmed effective concentrations between 10 and 100 nmol/l for corticosterone and 1 and 10 ng/ml for TNF-alpha, whilst inflammatory gene expression in FLS was shown to be stable between passages four and seven. CONCLUSIONS: This study has established a well characterised set of key inflammatory genes for in vitro FLS culture, isolated from K/BxN mice and non-inflamed wild-type controls. Their response to both pro- and anti-inflammatory signalling has been assessed and shown to strongly resemble that which is seen in human FLS culture. Additionally, this study provides guidelines for the effective characterisation, duration and treatment of murine FLS culture. PMID- 23363616 TI - Physical activity and nutrition behavioural outcomes of a home-based intervention program for seniors: a randomized controlled trial. AB - BACKGROUND: This intervention aimed to ascertain whether a low-cost, accessible, physical activity and nutrition program could improve physical activity and nutrition behaviours of insufficiently active 60-70 year olds residing in Perth, Australia. METHODS: A 6-month home-based randomised controlled trial was conducted on 478 older adults (intervention, n = 248; control, n = 230) of low to medium socioeconomic status. Both intervention and control groups completed postal questionnaires at baseline and post-program, but only the intervention participants received project materials. A modified fat and fibre questionnaire measured nutritional behaviours, whereas physical activity was measured using the International Physical Activity Questionnaire. Generalised estimating equation models were used to assess the repeated outcomes over both time points. RESULTS: The final sample consisted of 176 intervention participants and 199 controls (response rate 78.5%) with complete data. After controlling for demographic and other confounding factors, the intervention group demonstrated increased participation in strength exercise (p < 0.001), walking (p = 0.029) and vigorous activity (p = 0.015), together with significant reduction in mean sitting time (p < 0.001) relative to controls. Improvements in nutritional behaviours for the intervention group were also evident in terms of fat avoidance (p < 0.001), fat intake (p = 0.021) and prevalence of frequent fruit intake (p = 0.008). CONCLUSIONS: A minimal contact, low-cost and home-based physical activity program can positively influence seniors' physical activity and nutrition behaviours. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12609000735257. PMID- 23363617 TI - First insights into the social organisation of Goodman's mouse lemur (Microcebus lehilahytsara)--testing predictions from socio-ecological hypotheses in the Masoala hall of Zurich Zoo. AB - Following current socio-ecological hypotheses, the social organisation of a species is mainly determined by resource quality and distribution. In the case of Microcebus spp., a taxon-specific socio-ecological model was formulated earlier to explain their variable social organisation. The aim of this study was to test predictions from this model in Goodman's mouse lemur based on a data set from animals living in the semi-free colony of Zurich Zoo. During a 2-month study, we observed 5 females and 5 males using radiotelemetry. We collected data on space use and social behaviour, on sleeping sites and on sleeping group composition. Predictions were only partly confirmed. As expected, Goodman's mouse lemurs were solitary foragers with an increased level of sociality due to crowding effects at the feeding stations. In contrast to the prediction, females and males formed unisexual sleeping groups, which were stable in females and of a fission-fusion type in males. Whereas the formation of sleeping groups by both sexes may be triggered by thermoregulatory benefits, the formation of unisexual sleeping groups may result from divergent interests of the sexes. We conclude that the existing model for the evolution of mouse lemur social organisation needs to be refined. PMID- 23363618 TI - Pathogenic and saprophytic Leptospira species in water and soils from selected urban sites in peninsular Malaysia. AB - Leptospira species were studied in water and soils from selected urban sites in Malaysia. A total of 151 water (n=121) and soil (n=30) samples were collected from 12 recreational lakes and wet markets. All samples were filtered and inoculated into semi-solid Ellinghausen and McCullough modified by Johnson and Harris (EMJH) media supplemented with additional 5-fluorouracil. The cultures were then incubated at 30 degrees C and observed under a dark field microscope with intervals of 10 days. A PCR assay targeting the rrs gene was used to confirm the genus Leptospira among the isolates. Subsequently, the pathogenic status of the isolates was determined using primer sets G1/G2 and Sapro1/Sapro2, which target the secY and rrs genes, respectively. The isolates were identified at serogroup level using the microscopic agglutination test (MAT) while their genetic diversity was assessed by pulsed field gel electrophoresis (PFGE). Based on dark field microscopy, 23.1% (28/121) water and 23.3% (7/30) soil cultures were positive for Leptospira spp. Of the 35 positive cultures, only 8 were pure and confirmed as Leptospira genus by PCR assay. Two out of 8 isolates were confirmed as pathogenic, 5 were saprophytic and one was intermediate. These 8 isolates were negative for the 25 reference hyperimmune rabbit sera tested in the MAT. PFGE showed that all 8 of these environmental Leptospira spp. were genetically diverse. In conclusion, the presence of pathogenic Leptospira spp. in the urban Malaysian environment may indicate and highlight the importance of water screening, especially in recreational lakes, in order to minimize any chance of Leptospira infection. PMID- 23363619 TI - Iron-oxide minerals affect extracellular electron-transfer paths of Geobacter spp. AB - Some bacteria utilize (semi)conductive iron-oxide minerals as conduits for extracellular electron transfer (EET) to distant, insoluble electron acceptors. A previous study demonstrated that microbe/mineral conductive networks are constructed in soil ecosystems, in which Geobacter spp. share dominant populations. In order to examine how (semi)conductive iron-oxide minerals affect EET paths of Geobacter spp., the present study grew five representative Geobacter strains on electrodes as the sole electron acceptors in the absence or presence of (semi)conductive iron oxides. It was found that iron-oxide minerals enhanced current generation by three Geobacter strains, while no effect was observed in another strain. Geobacter sulfurreducens was the only strain that generated substantial amounts of currents both in the presence and absence of the iron oxides. Microscopic, electrochemical and transcriptomic analyses of G. sulfurreducens disclosed that this strain constructed two distinct types of EET path; in the absence of iron-oxide minerals, bacterial biofilms rich in extracellular polymeric substances were constructed, while composite networks made of mineral particles and microbial cells (without polymeric substances) were developed in the presence of iron oxides. It was also found that uncharacterized c-type cytochromes were up-regulated in the presence of iron oxides that were different from those found in conductive biofilms. These results suggest the possibility that natural (semi)conductive minerals confer energetic and ecological advantages on Geobacter, facilitating their growth and survival in the natural environment. PMID- 23363621 TI - Colour removal and carbonyl by-production in high dose ozonation for effluent polishing. AB - Experimental tests have been conducted to investigate the efficiency and the by product generation of high dose ozonation (10-60 mg O3 L(-1)) for complete colour removal from a treated effluent with an important component of textile dyeing wastewater. The effluent is discharged into an effluent-dominated stream where no dilution takes place, and, thus, the quality requirement for the effluents is particularly strict. 30, 60 and 90 min contact times were adopted. Colour was measured as absorbance at 426, 558 and 660 nm wavelengths. pH was monitored throughout the experiments. The experimental work showed that at 50 mg L(-1) colour removal was complete and at 60 mg O3 L(-1) the final aldehyde concentration ranged between 0.72 and 1.02 mg L(-1). Glyoxal and methylglyoxal concentrations were directly related to colour removal, whereas formaldehyde, acetaldehyde, acetone and acrolein were not. Thus, the extent of colour removal can be used to predict the increase in glyoxal and methylglyoxal concentrations. As colour removal can be assessed by a simple absorbance measurement, in contrast to the analysis of specific carbonyl compounds, which is much longer and complex, the possibility of using colour removal as an indicator for predicting the toxic potential of ozone by-products for textile effluents is of great value. PMID- 23363622 TI - Mixed integer programming improves comprehensibility and plan quality in inverse optimization of prostate HDR brachytherapy. AB - Current inverse treatment planning methods that optimize both catheter positions and dwell times in prostate HDR brachytherapy use surrogate linear or quadratic objective functions that have no direct interpretation in terms of dose-volume histogram (DVH) criteria, do not result in an optimum or have long solution times. We decrease the solution time of the existing linear and quadratic dose based programming models (LP and QP, respectively) to allow optimizing over potential catheter positions using mixed integer programming. An additional average speed-up of 75% can be obtained by stopping the solver at an early stage, without deterioration of the plan quality. For a fixed catheter configuration, the dwell time optimization model LP solves to optimality in less than 15 s, which confirms earlier results. We propose an iterative procedure for QP that allows us to prescribe the target dose as an interval, while retaining independence between the solution time and the number of dose calculation points. This iterative procedure is comparable in speed to the LP model and produces better plans than the non-iterative QP. We formulate a new dose-volume-based model that maximizes V(100%) while satisfying pre-set DVH criteria. This model optimizes both catheter positions and dwell times within a few minutes depending on prostate volume and number of catheters, optimizes dwell times within 35 s and gives better DVH statistics than dose-based models. The solutions suggest that the correlation between the objective value and the clinical plan quality is weak in the existing dose-based models. PMID- 23363620 TI - Interspecies interaction between Pseudomonas aeruginosa and other microorganisms. AB - Microbes interact with each other in multicellular communities and this interaction enables certain microorganisms to survive in various environments. Pseudomonas aeruginosa is a highly adaptable bacterium that ubiquitously inhabits diverse environments including soil, marine habitats, plants and animals. Behind this adaptivity, P. aeruginosa has abilities not only to outcompete others but also to communicate with each other to develop a multispecies community. In this review, we focus on how P. aeruginosa interacts with other microorganisms. P. aeruginosa secretes antimicrobial chemicals to compete and signal molecules to cooperate with other organisms. In other cases, it directly conveys antimicrobial enzymes to other bacteria using the Type VI secretion system (T6SS) or membrane vesicles (MVs). Quorum sensing is a central regulatory system used to exert their ability including antimicrobial effects and cooperation with other microbes. At least three quorum sensing systems are found in P. aeruginosa, Las, Rhl and Pseudomonas quinolone signal (PQS) systems. These quorum-sensing systems control the synthesis of extracellular antimicrobial chemicals as well as interaction with other organisms via T6SS or MVs. In addition, we explain the potential of microbial interaction analysis using several micro devices, which would bring fresh sensitivity to the study of interspecies interaction between P. aeruginosa and other organisms. PMID- 23363623 TI - Mechanism of diseases, diagnostic evaluation and treatment strategies. PMID- 23363624 TI - High-throughput sequencing reveals extraordinary fluidity of miRNA, piRNA, and siRNA pathways in nematodes. AB - The nematode Caenorhabditis elegans contains each of the broad classes of eukaryotic small RNAs, including microRNAs (miRNAs), endogenous small-interfering RNAs (endo-siRNAs), and piwi-interacting RNAs (piRNAs). To better understand the evolution of these regulatory RNAs, we deep-sequenced small RNAs from C. elegans and three closely related nematodes: C. briggsae, C. remanei, and C. brenneri. The results reveal a fluid landscape of small RNA pathways with essentially no conservation of individual sequences aside from a subset of miRNAs. We identified 54 miRNA families that are conserved in each of the four species, as well as numerous miRNAs that are species-specific or shared between only two or three species. Despite a lack of conservation of individual piRNAs and siRNAs, many of the features of each pathway are conserved between the different species. We show that the genomic distribution of 26G siRNAs and the tendency for piRNAs to cluster is conserved between C. briggsae and C. elegans. We also show that, in each species, 26G siRNAs trigger stage-specific secondary siRNA formation. piRNAs in each species also trigger secondary siRNA formation from targets containing up to three mismatches. Finally, we show that the production of male- and female specific piRNAs is conserved in all four species, suggesting distinct roles for piRNAs in male and female germlines. PMID- 23363625 TI - Epac2 mediates cardiac beta1-adrenergic-dependent sarcoplasmic reticulum Ca2+ leak and arrhythmia. AB - BACKGROUND: beta-Adrenergic receptor (beta-AR) activation can provoke cardiac arrhythmias mediated by cAMP-dependent alterations of Ca(2+) signaling. However, cAMP can activate both protein kinase A and an exchange protein directly activated by cAMP (Epac), but their functional interaction is unclear. In heart, selective Epac activation can induce potentially arrhythmogenic sarcoplasmic reticulum (SR) Ca(2+) release that involves Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) effects on the ryanodine receptor (RyR). METHODS AND RESULTS: We tested whether physiological beta-AR activation causes Epac-mediated SR Ca(2+) leak and arrhythmias and whether it requires Epac1 versus Epac2, beta(1)-AR versus beta(2)-AR, and CaMKIIdelta-dependent phosphorylation of RyR2-S2814. We used knockout (KO) mice for Epac1, Epac2, or both. All KOs exhibited unaltered basal cardiac function, Ca(2+) handling, and hypertrophy in response to pressure overload. However, SR Ca(2+) leak induced by the specific Epac activator 8-CPT in wild-type mice was abolished in Epac2-KO and double-KO mice but was unaltered in Epac1-KO mice. beta-AR-induced arrhythmias were also less inducible in Epac2-KO versus wild-type mice. beta-AR activation with protein kinase A inhibition mimicked 8-CPT effects on SR Ca(2+) leak and was prevented by blockade of beta(1) AR but not beta(2)-AR. CaMKII inhibition (KN93) and genetic ablation of either CaMKIIdelta or CaMKII phosphorylation on RyR2-S2814 prevented 8-CPT-induced SR Ca(2+) leak. CONCLUSIONS: beta(1)-AR activates Epac2 to induce SR Ca(2+) leak via CaMKIIdelta-dependent phosphorylation of RyR2-S2814. This pathway contributes to beta-AR-induced arrhythmias and reduced cardiac function. PMID- 23363626 TI - Inter-jurisdictional cooperation on pharmaceutical product listing agreements: views from Canadian provinces. AB - BACKGROUND: Confidential product listing agreements (PLAs) negotiated between pharmaceutical manufacturers and individual health care payers may contribute to unwanted price disparities, high administrative costs, and unequal bargaining power within and across jurisdictions. In the context of Canada's decentralized health system, we aimed to document provincial policy makers' perceptions about collaborative PLA negotiations. METHODS: We conducted semi-structured telephone interviews with a senior policy maker from nine of the ten Canadian provinces. We conducted a thematic analysis of interview transcripts to identify benefits, drawbacks, and barriers to routine collaboration on PLA negotiations. RESULTS: Canadian policy makers expressed support for joint negotiations of PLAs in principle, citing benefits of increased bargaining power and reduced inter jurisdictional inequities in drug prices and formulary listings. However, established policy institutions and the politics of individual jurisdictional authority are formidable barriers to routine PLA collaboration. Achieving commitment to a joint process may be difficult to sustain among heterogeneous and autonomous partners. CONCLUSIONS: Though collaboration on PLA negotiation is an extension of collaboration on health technology assessment, it is a very significant next step that requires harmonization of the outcomes of decision making processes. Views of policy makers in Canada suggest that sustaining routine collaborations on PLA negotiations may be difficult unless participating jurisdictions have similar policy institutions, capacities to implement coverage decisions, and local political priorities. PMID- 23363627 TI - Coral-associated micro-organisms and their roles in promoting coral health and thwarting diseases. AB - Over the last decade, significant advances have been made in characterization of the coral microbiota. Shifts in its composition often correlate with the appearance of signs of diseases and/or bleaching, thus suggesting a link between microbes, coral health and stability of reef ecosystems. The understanding of interactions in coral-associated microbiota is informed by the on-going characterization of other microbiomes, which suggest that metabolic pathways and functional capabilities define the 'core' microbiota more accurately than the taxonomic diversity of its members. Consistent with this hypothesis, there does not appear to be a consensus on the specificity in the interactions of corals with microbial commensals, even though recent studies report potentially beneficial functions of the coral-associated bacteria. They cycle sulphur, fix nitrogen, produce antimicrobial compounds, inhibit cell-to-cell signalling and disrupt virulence in opportunistic pathogens. While their beneficial functions have been documented, it is not certain whether or how these microbes are selected by the hosts. Therefore, understanding the role of innate immunity, signal and nutrient exchange in the establishment of coral microbiota and in controlling its functions will probably reveal ancient, evolutionarily conserved mechanisms that dictate the outcomes of host-microbial interactions, and impact the resilience of the host. PMID- 23363628 TI - Early false-belief understanding in traditional non-Western societies. AB - The psychological capacity to recognize that others may hold and act on false beliefs has been proposed to reflect an evolved, species-typical adaptation for social reasoning in humans; however, controversy surrounds the developmental timing and universality of this trait. Cross-cultural studies using elicited response tasks indicate that the age at which children begin to understand false beliefs ranges from 4 to 7 years across societies, whereas studies using spontaneous-response tasks with Western children indicate that false-belief understanding emerges much earlier, consistent with the hypothesis that false belief understanding is a psychological adaptation that is universally present in early childhood. To evaluate this hypothesis, we used three spontaneous-response tasks that have revealed early false-belief understanding in the West to test young children in three traditional, non-Western societies: Salar (China), Shuar/Colono (Ecuador) and Yasawan (Fiji). Results were comparable with those from the West, supporting the hypothesis that false-belief understanding reflects an adaptation that is universally present early in development. PMID- 23363629 TI - Bees diversified in the age of eudicots. AB - Reliable estimates on the ages of the major bee clades are needed to further understand the evolutionary history of bees and their close association with flowering plants. Divergence times have been estimated for a few groups of bees, but no study has yet provided estimates for all major bee lineages. To date the origin of bees and their major clades, we first perform a phylogenetic analysis of bees including representatives from every extant family, subfamily and almost all tribes, using sequence data from seven genes. We then use this phylogeny to place 14 time calibration points based on information from the fossil record for an uncorrelated relaxed clock divergence time analysis taking into account uncertainties in phylogenetic relationships and the fossil record. We explore the effect of placing a hard upper age bound near the root of the tree and the effect of different topologies on our divergence time estimates. We estimate that crown bees originated approximately 123 Ma (million years ago) (113-132 Ma), concurrently with the origin or diversification of the eudicots, a group comprising 75 per cent of angiosperm species. All of the major bee clades are estimated to have originated during the Middle to Late Cretaceous, which is when angiosperms became the dominant group of land plants. PMID- 23363632 TI - The evolutionary origins of modularity. AB - A central biological question is how natural organisms are so evolvable (capable of quickly adapting to new environments). A key driver of evolvability is the widespread modularity of biological networks--their organization as functional, sparsely connected subunits--but there is no consensus regarding why modularity itself evolved. Although most hypotheses assume indirect selection for evolvability, here we demonstrate that the ubiquitous, direct selection pressure to reduce the cost of connections between network nodes causes the emergence of modular networks. Computational evolution experiments with selection pressures to maximize network performance and minimize connection costs yield networks that are significantly more modular and more evolvable than control experiments that only select for performance. These results will catalyse research in numerous disciplines, such as neuroscience and genetics, and enhance our ability to harness evolution for engineering purposes. PMID- 23363630 TI - Cutting through the complexity of cell collectives. AB - Via strength in numbers, groups of cells can influence their environments in ways that individual cells cannot. Large-scale structural patterns and collective functions underpinning virulence, tumour growth and bacterial biofilm formation are emergent properties of coupled physical and biological processes within cell groups. Owing to the abundance of factors influencing cell group behaviour, deriving general principles about them is a daunting challenge. We argue that combining mechanistic theory with theoretical ecology and evolution provides a key strategy for clarifying how cell groups form, how they change in composition over time, and how they interact with their environments. Here, we review concepts that are critical for dissecting the complexity of cell collectives, including dimensionless parameter groups, individual-based modelling and evolutionary theory. We then use this hybrid modelling approach to provide an example analysis of the evolution of cooperative enzyme secretion in bacterial biofilms. PMID- 23363631 TI - To quiver or to shiver: increased melanization benefits thermoregulation, but reduces warning signal efficacy in the wood tiger moth. AB - Melanin production is often considered costly, yet beneficial for thermoregulation. Studies of variation in melanization and the opposing selective forces that underlie its variability contribute greatly to understanding natural selection. We investigated whether melanization benefits are traded off with predation risk to promote observed local and geographical variation in the warning signal of adult male wood tiger moths (Parasemia plantaginis). Warning signal variation is predicted to reduce survival in aposematic species. However, in P. plantaginis, male hindwings are either yellow or white in Europe, and show continuous variation in melanized markings that cover 20 to 90 per cent of the hindwing. We found that the amount of melanization increased from 40 to 59 per cent between Estonia (58 degrees N) and north Finland (67 degrees N), suggesting melanization carries thermoregulatory benefits. Our thermal measurements showed that more melanic individuals warmed up more quickly on average than less melanic individuals, which probably benefits flight in cold temperatures. With extensive field experiments in central Finland and the Alpine region, we found that more melanic individuals suffered increased predation. Together, our data suggest that warning signal efficiency is constrained by thermoregulatory benefits. Differences in relative costs and benefits of melanin probably help to maintain the geographical warning signal differences. PMID- 23363633 TI - Tactic-specific differences in seminal fluid influence sperm performance. AB - Seminal fluid often makes up a large part of an ejaculate, yet most empirical and theoretical studies on sperm competition have focused on how sperm characteristics (number and quality) affect fertilization success. However, seminal fluid influences own sperm performance and may potentially influence the outcome of sperm competition, by also affecting that of rivals. As a consequence males may be expected to allocate their investment in both sperm and seminal fluid in relation to the potential level of competition. Grass goby (Zosterisessor ophiocephalus) is an external fertilizer with guard-sneaker mating tactics, where sperm competition risk varies according to the tactic adopted. Here, we experimentally manipulated grass goby ejaculates by separately combining sperm and seminal fluid from territorial and sneaker males. While sperm of sneaker and territorial males did not differ in their performance when they interacted with their own seminal fluid only, sperm of sneakers increased their velocity and fertilization rate in the presence of territorial males' seminal fluid. By contrast, sneaker males' seminal fluid had a detrimental effect on the performance of territorial males' sperm. Sperm velocity was unaffected by the seminal fluid of males employing the same tactic, suggesting that seminal fluid's effect on rival-tactic sperm is not based on a self/non-self recognition mechanism. Our findings show that cross interactions of sperm and seminal fluid may influence the fertilization success of competing ejaculates with males investing in both sperm and seminal fluid in response to sperm competition risk. PMID- 23363635 TI - Foraging under conditions of short-term exploitative competition: the case of stock traders. AB - Theory purports that animal foraging choices evolve to maximize returns, such as net energy intake. Empirical research in both human and non-human animals reveals that individuals often attend to the foraging choices of their competitors while making their own foraging choices. Owing to the complications of gathering field data or constructing experiments, however, broad facts relating theoretically optimal and empirically realized foraging choices are only now emerging. Here, we analyse foraging choices of a cohort of professional day traders who must choose between trading the same stock multiple times in a row--patch exploitation--or switching to a different stock--patch exploration--with potentially higher returns. We measure the difference between a trader's resource intake and the competitors' expected intake within a short period of time--a difference we call short-term comparative returns. We find that traders' choices can be explained by foraging heuristics that maximize their daily short-term comparative returns. However, we find no one-best relationship between different trading choices and net income intake. This suggests that traders' choices can be short-term win oriented and, paradoxically, maybe maladaptive for absolute market returns. PMID- 23363634 TI - Behavioural changes and the adaptive diversification of pigeons and doves. AB - What factors determine the extent of evolutionary diversification remains a major question in evolutionary biology. Behavioural changes have long been suggested to be a major driver of phenotypic diversification by exposing animals to new selective pressures. Nevertheless, the role of behaviour in evolution remains controversial because behavioural changes can also retard evolutionary change by hiding genetic variation from selection. In the present study, we apply recently implemented Ornstein-Uhlenbeck evolutionary models to show that behavioural changes led to associated evolutionary responses in functionally relevant morphological traits of pigeons and doves (Columbiformes). Specifically, changes from terrestrial to arboreal foraging behaviour reconstructed in a set of phylogenies brought associated shorter tarsi and longer tails, consistent with functional predictions. Interestingly, the transition to arboreality accelerated the rates of evolutionary divergence, leading to an increased morphological specialization that seems to have subsequently constrained reversals to terrestrial foraging. Altogether, our results support the view that behaviour may drive evolutionary diversification, but they also highlight that its evolutionary consequences largely depend on the limits imposed by the functional demands of the adaptive zone. PMID- 23363636 TI - Transcription and redox enzyme activities: comparison of equilibrium and disequilibrium levels in the three-spined stickleback. AB - Evolutionary and acclimatory responses require functional variability, but in contrast with mRNA and protein abundance data, most physiological measurements cannot be obtained in a high-throughput manner. Consequently, one must either rely on high-throughput transcriptomic or proteomic data with only predicted functional information, or accept the limitation that most physiological measurements can give fewer data than those provided by transcriptomics or proteomics. We evaluated how transcriptional and redox enzyme activity data agreed with regard to population differentiation (i.e. a system in steady state in which any time lag between transcription, translation and post-translational effects would be irrelevant) and in response to an acute 6 degrees C increase in temperature (i.e. a disequilibrium state wherein translation could not have caught up with transcription) in the three-spined stickleback (Gasterosteus aculeatus). Transcriptional and enzyme activity data corresponded well with regard to population differentiation, but less so with regard to acute temperature increase. The data thus suggest that transcriptional and functional measurements can lead to similar conclusions when a biological system is in a steady state. The responses to acute changes must, as has been demonstrated earlier, be based on changes in cellular conditions or properties of existing proteins without significant de novo synthesis of new gene products. PMID- 23363637 TI - Stimulation of platelet death by vancomycin. AB - BACKGROUND/AIMS: Side effects of vancomycin, a widely used antibiotic, include thrombocytopenia. The vancomycin-induced thrombocytopenia has been attributed to immune reactions. At least in theory, thrombocytopenia could result in part from the triggering of apoptosis, which results in cell shrinkage and cell membrane scrambling with subsequent phosphatidylserine exposure at the cell surface. The cell membrane scrambling could be initiated by a signaling involving increase of cytosolic Ca(2+) activity, ceramide formation, mitochondrial depolarization and/or caspase activation. Vancomycin has indeed been shown to trigger neutrophil apoptosis. An effect of vancomycin on platelet apoptosis has, however, never been tested. The present study thus explored the effect of vancomycin on platelet activation and apoptosis. METHODS: Human blood platelets were exposed to vancomycin and forward scatter was utilized to estimate cell volume, annexin V binding to quantify phosphatidylserine (PS) exposure, Fluo-3 AM fluorescence to estimate cytosolic Ca(2+) activity ([Ca(2+)]i), antibodies to quantify ceramide formation and immunofluorescence to quantify protein abundance of active caspase 3. RESULTS: A 30 minutes exposure to vancomycin (>=1 ug/ ml) decreased cell volume, triggered annexin V-binding, increased [Ca(2+)]i, activated caspase 3, stimulated ceramide formation, triggered release of thromboxane B2, and upregulated surface expression of CD62P (P-selectin) as well as activated integrin alphallbbeta3. Annexin V-binding and upregulation of CD62P (P-selectin) and integrin alphallbbeta3 was significantly blunted by removal of extracellular Ca(2+). Annexin V-binding was not significantly blunted by pan-caspase inhibitor zVAD-FMK (1 uM). In conclusion, vancomycin results in platelet activation and suicidal platelet death with increase of [Ca(2+)]i, caspase-3 activation, cell membrane scrambling and cell shrinkage. Activation and cell membrane scrambling required the presence of Ca(2+), but not activation of caspases. CONCLUSION: Vancomycin exposure leads to platelet activation and apoptosis. PMID- 23363638 TI - Adrenocortical suppression and recovery after continuous hypnotic infusion: etomidate versus its soft analogue cyclopropyl-methoxycarbonyl metomidate. AB - INTRODUCTION: Etomidate is no longer administered as a continuous infusion for anesthetic maintenance or sedation, because it results in profound and persistent suppression of adrenocortical steroid synthesis with potentially lethal consequences in critically ill patients. We hypothesized that rapidly metabolized soft analogues of etomidate could be developed that do not produce persistent adrenocortical dysfunction even after prolonged continuous infusion. We hope that such agents might also provide more rapid and predictable anesthetic emergence. We have developed the soft etomidate analogue cyclopropyl-methoxycarbonyl etomidate (CPMM). Upon termination of 120-minute continuous infusions, hypnotic and encephalographic recoveries occur in four minutes. The aims of this study were to assess adrenocortical function during and following 120-minute continuous infusion of CPMM and to compare the results with those obtained using etomidate. METHODS: Dexamethasone-suppressed rats were randomized into an etomidate group, CPMM group, or control group. Rats in the etomidate and CPMM groups received 120 minute continuous infusions of etomidate and CPMM, respectively. Rats in the control group received neither hypnotic. In the first study, adrenocortical function during hypnotic infusion was assessed by administering adrenocorticotropic hormone (ACTH) 90 minutes after the start of the hypnotic infusion and measuring plasma corticosterone concentrations at the end of the infusion 30 minutes later. In the second study, adrenocortical recovery following hypnotic infusion was assessed by administering ACTH every 30 minutes after infusion termination and measuring plasma corticosterone concentrations 30 minutes after each ACTH dose. RESULTS: During hypnotic infusion, ACTH-stimulated serum corticosterone concentrations were significantly lower in the CPMM and etomidate groups than in the control group (100 +/- 64 ng/ml and 33 +/- 32 ng/ml versus 615 +/- 265 ng/ml, respectively). After hypnotic infusion, ACTH-stimulated serum corticosterone concentrations recovered to control values within 30 minutes in the CPMM group but remained suppressed relative to those in the control group for more than 3 hours in the etomidate group. CONCLUSIONS: Both CPMM and etomidate suppress adrenocortical function during continuous infusion. However, recovery occurs significantly more rapidly following infusion of CPMM. PMID- 23363639 TI - A "Ciclovia" in San Francisco: Characteristics and physical activity behavior of Sunday Streets participants. AB - BACKGROUND: Temporary parks such as the monthly event, Sunday Streets SF, support public health goals by using existing infrastructure and street closures to provide physical activity in neighborhoods underserved for recreational resources. Sunday Streets creates routes to enhance community connection. METHODS: Six hundred and thirty-nine participants at 3 Sunday Streets events were surveyed using a 36-item instrument of open- and closed-ended questions about overall physical activity behavior, physical activity while at Sunday Streets, experience of the events, and demographic data. RESULTS: Overall, Sunday Streets participants are physically active (79% engage in activity 3-7 days/week) and approximately represent the ethnic minority distribution of the city. There were significant differences between first-time attendees and multiple-event attendees by duration of physical activity at the event (55.83 minutes vs. 75.13 minutes) and by frequency of physical activity bouts per week (3.69 vs. 4.22). Both groups emphasized the positive experience and safe environment as reasons to return to the event; for first-time attendees, the social environment was another reason to return. CONCLUSIONS: Temporary parks like Sunday Streets have the potential to provide healthful, population-wide physical activity using existing streets. The trend toward increased activity by multiple-event attendees suggests the importance of a regular schedule of events. PMID- 23363640 TI - Recovery from chronic fatigue syndrome after treatments given in the PACE trial. AB - BACKGROUND: A multi-centre, four-arm trial (the PACE trial) found that rehabilitative cognitive behaviour therapy (CBT) and graded exercise therapy (GET) were more effective treatments for chronic fatigue syndrome (CFS) than specialist medical care (SMC) alone, when each was added to SMC, and more effective than adaptive pacing therapy (APT) when added to SMC. In this study we compared how many participants recovered after each treatment. METHOD: We defined recovery operationally using multiple criteria, and compared the proportions of participants meeting each individual criterion along with two composite criteria, defined as (a) recovery in the context of the trial and (b) clinical recovery from the current episode of the illness, however defined, 52 weeks after randomization. We used logistic regression modelling to compare treatments. RESULTS: The percentages (number/total) meeting trial criteria for recovery were 22% (32/143) after CBT, 22% (32/143) after GET, 8% (12/149) after APT and 7% (11/150) after SMC. Similar proportions met criteria for clinical recovery. The odds ratio (OR) for trial recovery after CBT was 3.36 [95% confidence interval (CI) 1.64-6.88] and for GET 3.38 (95% CI 1.65-6.93), when compared to APT, and after CBT 3.69 (95% CI 1.77-7.69) and GET 3.71 (95% CI 1.78-7.74), when compared to SMC (p values < or =0.001 for all comparisons). There was no significant difference between APT and SMC. Similar proportions recovered in trial subgroups meeting different definitions of the illness. CONCLUSIONS: This study confirms that recovery from CFS is possible, and that CBT and GET are the therapies most likely to lead to recovery. PMID- 23363643 TI - Pharmacodynamic comparisons for single loading doses of prasugrel (30 mg) and clopidogrel (600 mg) in healthy Korean volunteers. AB - BACKGROUND: Previous studies involving a loading dose (LD) of 60 mg prasugrel have suggested that active metabolite exposure and pharmacodynamic responses may be higher in persons of Asian ethnicity than in Caucasian subjects. The aim of this study was to determine the pharmacodynamic effect of an LD of 30 mg prasugrel and 600 mg clopidogrel in healthy Korean volunteers. METHODS AND RESULTS: Twelve volunteers were randomly assigned to a prasugrel or a clopidogrel group. Following a 2-week washout period, group designations and treatments were switched (6 per group). Platelet function was serially measured via light transmission aggregometry (LTA), VerifyNow and multiple electrode platelet aggregometry (MEA) assays at baseline and 0.5, 2, 6, and 24h after LD. Inhibition of platelet aggregation (IPA) at 0.5-24 h after prasugrel was significantly higher (P<0.001) than that achieved by clopidogrel. The prasugrel peak IPA at 2 h after LD was 93.7% (+/-6.2%) compared to the clopidogrel peak IPA at 6h after LD at 65.8% (+/-17.2%). The VerifyNow and MEA assay yielded results similar to those obtained by LTA. CONCLUSIONS: In healthy Korean subjects, a 30-mg LD of prasugrel yields a more rapid, potent and consistent inhibition of platelet function than a 600-mg LD of clopidogrel. PMID- 23363644 TI - Acute hemodynamic effects of adaptive servo-ventilation in patients with heart failure. AB - BACKGROUND: Adaptive servo-ventilation (ASV) improves cardiac function in patients with heart failure (HF). We compared the hemodynamics of control and HF patients, and identified the predictors for acute effects of ASV in HF. METHODS AND RESULTS: We performed baseline echocardiographic measurements and hemodynamic measurements at baseline and after 15 min of ASV during cardiac catheterization in 11 control and 34 HF patients. Heart rate and blood pressure did not change after ASV in either the control or HF group. Stroke volume index (SVI) decreased from 49.3+/-7.6 to 41.3+/-7.6 ml/m2 in controls (P<0.0001) but did not change in the HF patients (from 34.8+/-11.5 to 32.8+/-8.9 ml/m2, P=0.148). In the univariate analysis, pulmonary capillary wedge pressure (PCWP), mitral regurgitation (MR)/left atrial (LA) area, E/A, E/e', and the sphericity index defined by the ratio between the short-axis and long-axis dimensions of the left ventricle significantly correlated with % change of SVI from baseline during ASV. PCWP and MR/LA area were independent predictors by multivariate analysis. Moreover, responders (15 of 34 HF patients; 44%) categorized by an increase in SVI showed significantly higher PCWP, MR, and sphericity index. CONCLUSIONS: Left ventricular structure and MR, as well as PCWP, could predict acute favorable effects on hemodynamics by ASV therapy in HF patients. PMID- 23363645 TI - Reconsideration of anticoagulant therapy in Japanese patients with atrial fibrillation and moderate renal impairment. PMID- 23363646 TI - Significance of oscillatory breathing on cardiopulmonary exercise testing in chronic heart failure. PMID- 23363647 TI - Periodical assessment of genitourinary and gastrointestinal toxicity in patients who underwent prostate low-dose-rate brachytherapy. AB - BACKGROUND: To compare the periodical incidence rates of genitourinary (GU) and gastrointestinal (GI) toxicity in patients who underwent prostate low-dose-rate brachytherapy between the monotherapy group (seed implantation alone) and the boost group (in combination with external beam radiation therapy (EBRT)). METHODS: A total of 218 patients with a median follow-up of 42.5 months were enrolled. The patients were divided into 2 groups by treatment modality, namely, the monotherapy group (155 patients) and the boost group (63 patients). The periodical incidence rates of GU and GI toxicity were separately evaluated and compared between the monotherapy group and the boost group using the National Cancer Institute - Common Terminology Criteria for Adverse Events, version 3.0. To elucidate an independent factor among clinical and postdosimetric parameters to predict grade 2 or higher GU and GI toxicity in the acute and late phases, univariate and multivariate logistic regression analyses were carried out. RESULTS: Of all patients, 78.0% showed acute GU toxicity, and 7.8% showed acute GI toxicity, while 63.8% showed late GU toxicity, and 21.1% showed late GI toxicity. The incidence rates of late GU and GI toxicity were significantly higher in the boost group. Multivariate analysis showed that the International Prostate Symptom Score (IPSS) before seed implantation was a significant parameter to predict acute GU toxicity, while there were no significant predictive parameters for acute GI toxicity. On the other hand, combination with EBRT was a significant predictive parameter for late GU toxicity, and rectal volume (mL) receiving 100% of the prescribed dose (R100) was a significant predictive parameter for late GI toxicity. CONCLUSIONS: The boost group showed higher incidence rates of both GU and GI toxicity. Higher IPSS before seed implantation, combination with EBRT and a higher R100 were significant predictors for acute GU, late GU and late GI toxicity. PMID- 23363648 TI - Lymphoid follicle colonization by Bcl-2(bright+)CD10(+) B-cells ("follicular lymphoma in situ") at nodal and extranodal sites can be a manifestation of follicular homing of lymphoma. AB - Follicular lymphoma (FL) in situ (FLIS) was first described and proposed as a distinct entity associated with an indolent clinical course in 2002. To gain further insight into the biology of this enigmatic lymphoproliferation, we analyzed morphologic, phenotypic, cytogenetic and molecular features of tissue specimens manifesting a pattern of follicular colonization by Bcl 2(bright+)CD10(+) B-cells and associated lymphomas from 13 adults and evaluated their clinical outcomes. We observed this immunoarchitectural pattern in lymph nodes (n = 8), at extranodal sites (n = 4), or at both locations (n = 1) at diagnosis. All except 3 cases showed concomitant bright CD10 expression. Six (46%) patients had synchronous and 2 (15%) developed metachronous B-cell lymphomas, with 5 representing high-grade lymphomas. The Bcl-2(bright+)CD10(+) B cells colonizing reactive follicles and synchronous lymphomas were clonally related in 4/5 (80%) cases analyzed and 5/6 (83%) displayed BCL2 translocations. Two cases exhibited complex karyotypes in both components; a genetic "triple hit" was detected in one instance and 2 copies of t(14,18) were observed in a lymph node biopsy lacking evidence of lymphoma from an individual with stage 4 disease, suspected on imaging, who subsequently displayed a mantle zone/perifollicular infiltrate of Bcl-2(bright+)CD10(+) B-cells in the adenoids. Our findings suggest that bright Bcl-2, and often bright CD10 expression, by B-cells colonizing reactive follicles might represent a phenomenon related to follicular homing of lymphoma, rather than being an attribute of preneoplastic FL precursors. Furthermore, due to the relatively high frequency of overt lymphomas observed, complete staging workup is recommended for patients exhibiting a Bcl 2(bright+)CD10(+) B-cell follicular colonization pattern on biopsy. PMID- 23363649 TI - Is an individual prediction of maximal work rate by 6-minute walk distance and further measurements reliable in male patients with different lung diseases? AB - BACKGROUND: In patients with chronic lung diseases, the work rate for endurance training is calculated by the maximal work rate (Wmax). Because the assessment bears side effects, a prediction by easier accessible tests would be of practical use. OBJECTIVE: We addressed the reliability of predicting Wmax on the basis of the 6-min walk distance (6MWD) test and a set of further parameters in patients with different lung diseases. METHODS: Baseline data of a longitudinal study including 6MWD, Wmax, peripheral muscle force, lung function, fat-free mass and dyspnea (Modified Medical Research Council score) of 255 men with occupational lung diseases (104 asthma, 69 asbestosis, 42 silicosis, 40 chronic obstructive pulmonary disease) were evaluated. RESULTS: 6MWD correlated with Wmax (r = 0.51, p < 0.05). The product of 6MWD and body weight, in particular fat-free mass, led to an improvement in the correlation of Wmax with 6MWD. Muscle force, lung function and Modified Medical Research Council score correlated moderately but significantly with Wmax (p < 0.05 each). The maximum correlation gained by including 6MWD and further parameters in the prediction equations was r = 0.76 in patients with obstructive lung function impairment and r = 0.61 in asbestosis patients. The residual standard deviations of Wmax predicted by the calculated equations ranged between 20 and 28 W, and the 95% prediction intervals of Wmax ranged between +/-47 and +/-65 W. CONCLUSIONS: A reliable prediction of individual Wmax by 6MWD or related measures and therefore a replacement by other tests is not possible. Nevertheless, it may be useful for the comparison of average values in epidemiological and clinical studies. PMID- 23363650 TI - Should image rotation be addressed during routine cone-beam CT quality assurance? AB - The purpose of this study is to investigate whether quality assurance (QA) for cone-beam computed tomography (CBCT) image rotation is necessary in order to ensure the accuracy of CBCT based image-guided radiation therapy (IGRT) and adaptive radiotherapy (ART). Misregistration of angular coordinates during CBCT acquisition may lead to a rotated reconstructed image. If target localization is performed based on this image, an under- or over-dosage of the target volume (TV) and organs at risk (OARs) may occur. Therefore, patient CT image sets were rotated by 1 degrees up to 3 degrees and the treatment plans were recalculated to quantify changes in dose-volume histograms. A computer code in C++ was written to model the TV displacement and overlap area of an ellipse shape at the target and dose prescription levels corresponding to the image rotation. We investigated clinical scenarios in IGRT and ART in order to study the implications of image rotation on dose distributions for: (1) lateral TV and isocenter (SBRT), (2) central TV and isocenter (IMRT), (3) lateral TV and isocenter (IMRT). Mathematical analysis showed the dose coverage of TV depends on its shape, size, location, and orientation relative to the isocenter. Evaluation of three first scenario for theta = 1 degrees showed variations in TV D95 in the context of IGRT and ART when compared to the original plan were within 2.7 +/- 2.6% and 7.7 +/- 6.9% respectively while variations in the second and third scenarios were less significant (<0.5%) for the angular range evaluated. However a larger degree of variation was found in terms of minimum and maximum doses for target and OARs. The rotation of CBCT image data sets may have significant dosimetric consequences in IGRT and ART. The TV's location relative to isocenter and shape determine the extent of alterations in dose indicators. Our findings suggest that a CBCT QA criterion of 1 degrees would be a reasonable action level to ensure accurate dose delivery. PMID- 23363651 TI - Genomic heterogeneity in acute leukemia. AB - Acquired genetic aberrations are the underlying cause of leukemogenesis in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The karyotypes of AML and ALL cases are generally quite simple as seen by chromosome banding analysis, with few genetic changes and a limited number of subclones. However, investigations using fluorescence in situ hybridization, loss of heterozygosity analysis, single-nucleotide polymorphism arrays, and, most recently, massively parallel sequencing have challenged this view. In particular, comparison of diagnostic and relapse samples, modeling in transgenic mice, and whole-exome and whole-genome sequencing have indicated that widespread genomic heterogeneity, which is masked by a dominant clone, may be present in AML and ALL. In the present review, our current knowledge of genomic heterogeneity in acute leukemia is summarized. PMID- 23363652 TI - Systematic analysis of donor and isolation factor's impact on human islet yield and size distribution. AB - Islet transplantation is a promising therapy for T1DM. Key factors influencing islet yield have been identified with conflicting results. In this study, we analyzed 276 isolations to identify variables for islet yield and, additionally, islet size and size distribution. Pearson correlation analyses demonstrated that BMI had a positive correlation with pancreas size, actual islet count (AIC), and islet equivalent (IEQ)/g (all p <= 0.009), while CIT had a negative correlation with AIC and IEQ/g (all p <= 0.003). In mixed linear regression, BMI also had a positive correlation with islet size but only for shorter digestion times (<=15 min); there was no association between BMI and islet size for longer digestion times (>15 min). CIT was not associated with islet size. Donor age, sex, and preservation solutions were shown to have no correlation with islet yields or size distribution. Pancreas size had a positive correlation with AIC and a negative association with IEQ/g; it also had positive association with islet size but only for females, not males. Overdigestion was positively associated with islet counts; however, there was also a greater proportion of smaller islets when digestion rate was >74% (p = 0.005). Of the three collagenases analyzed, Sigma V had the lowest digestion rate (mean = 65%), approximately 5% or 10% lower than Roche Liberase HI (p = 0.04) and Serva NB1 (p = 0.0003), respectively; however, the Sigma V group showed better islet size preservation. Yet, the enzymes resulted in similar IEQ/g digested tissue. Of the isolated islets, 70.2% were smaller than 150 um and contributed only 20.4% to the total IEQ, while 7.4% of the islets were larger than 250 um but contributed 42.4% to the total IEQ. In summary, BMI, pancreas size, and CIT are useful variables for predicting islet yield, but selection of enzyme and balancing digestion time and rate are also important. PMID- 23363653 TI - Maintenance of "stem cell" features of cartilage cell sub-populations during in vitro propagation. AB - BACKGROUND: The discovery of mesenchymal stem cells (MSCs) or MSC-like cells in cartilage tissue does not tie in well with the established view that MSCs derive from a perivascular niche. The presence of MSCs may raise concerns about specificity and application safety, particularly in terms of the regulatory site. The aim of the present study was to investigate the benefits or possible risks of the MSC-like properties of cells isolated from cartilage in the context of autologous chondrocyte implantation. METHODS: Chondrocytic cells were isolated from cartilage or intervertebral disc tissue. Flow cytometry was used to analyze the expression of cell surface antigens. MSC-like cells were either enriched or depleted by means of magnetic cell sorting (MACS) involving the monoclonal antibodies W5C5/SUSD2 and W8B2/MSCA-1. We addressed the issues of prolonged expansion of such cells as well as the influence of culture medium as a trigger for selecting a single cell type. Established protocols were used to study in vitro differentiation. In addition to histological and biochemical assessment, the acquired phenotypes were also evaluated on the mRNA transcript level. RESULTS: In the studied cells, we found strongly analogous expression of antigens typically expressed on MSCs, including CD49e, CD73, CD90, CD105, CD140b and CD166. The expression of W5C5 and W8B2 antigens in cartilage cell sub-populations did not correlate with multi-potency. We demonstrated that a chondroid precursor, but not a bona fide multipotent mesenchymal, cell type can be obtained under established in vitro culture conditions. The culture media used for expansion influenced the cell phenotype. CONCLUSIONS: The risk of adverse adipose or osseous differentiation is not posed by expanded chondrocyte cultures, even after enrichment of putative MSC-like cell populations by MACS. It is possible that this limited "stemness" in chondrocytes, expanded for use in ACI, may instead be beneficial as it allows re-differentiation under appropriate conditions despite prolonged times in culture. PMID- 23363654 TI - Characteristics of first-time fathers of advanced age: a Norwegian population based study. AB - BACKGROUND: The modern phenomenon of delayed parenthood applies not only to women but also to men, but less is known about what characterises men who are expecting their first child at an advanced age. This study investigates the sociodemographic characteristics, health behaviour, health problems, social relationships and timing of pregnancy in older first-time fathers. METHODS: A cross-sectional study was conducted of 14 832 men who were expecting their first child, based on data from the Norwegian Mother and Child Cohort Study (MoBa) carried out by the Norwegian Institute of Public Health. Data were collected in 2005-2008 by means of a questionnaire in gestational week 17-18 of their partner's pregnancy, and from the Norwegian Medical Birth Register. The distribution of background variables was investigated across the age span of 25 years and above. Men of advanced age (35-39 years) and very advanced age (40 years or more) were compared with men aged 25-34 years by means of bivariate and multivariate logistic regression analyses. RESULTS: The following factors were found to be associated with having the first child at an advanced or very advanced age: being unmarried or non-cohabitant, negative health behaviour (overweight, obesity, smoking, frequent alcohol intake), physical and mental health problems (lower back pain, cardiovascular diseases, high blood pressure, sleeping problems, previous depressive symptoms), few social contacts and dissatisfaction with partner relationship. There were mixed associations for socioeconomic status: several proxy measures of high socioeconomic status (e.g. income >65,000 ?, self-employment) were associated with having the first child at an advanced or very advanced age, as were several other proxy measures of low socioeconomic status (e.g. unemployment, low level of education, immigrant background).The odds of the child being conceived after in vitro fertilisation were threefold in men aged 34-39 and fourfold from 40 years and above. CONCLUSIONS: Men who expect their first baby at an advanced or very advanced age constitute a socioeconomically heterogeneous group with more health problems and more risky health behaviour than younger men. Since older men often have their first child with a woman of advanced age, in whom similar characteristics have been reported, their combined risk of adverse perinatal outcomes needs further attention by clinicians and researchers. PMID- 23363655 TI - Birthplace, culture, self-esteem, and intimate partner violence among community dwelling Hispanic women. AB - The purpose of this study was to explore variations in demographics, culture, self-esteem, and intimate partner violence among Hispanic women according to birthplace, and to identify factors associated with these differences in intimate partner violence (IPV). Baseline data from a randomized control trial testing the efficacy of an HIV prevention program were used. Path analyses identified differences in IPV between Colombian women and women from other Central/South American countries. Self-esteem was the only factor associated with these differences. Interventions addressing the unique needs of Hispanic women from different subgroups are needed. PMID- 23363656 TI - Subjection, subjectivity, and agency: the power, meaning, and practice of mothering among women experiencing intimate partner abuse. AB - Drawing on in-depth interviews with mothers who were abused by intimate partners, we argue that mothering can be a source of empowerment that helps battered women both care for their children and survive and assert themselves. Women in the study sample described a violation of some aspect of their mothering as the reason they left their partners. However, narrative analysis exposed contradictions in participants' stories, revealing multiple factors that shaped their decisions to leave. Although motherhood was significant for the women who participated in the study, it was not their only motivation for ending their relationships with abusive partners. PMID- 23363657 TI - Intimate partner violence and mental health among Italian adolescents: gender similarities and differences. AB - Only a few studies have analyzed the health impact of intimate partner violence (IPV) on male and female adolescents, taking into account other kinds of violence that can affect their health. In this study, 43.7% of female adolescents and 34.8% of males reported IPV; females reported more psychological and sexual IPV, with no differences for physical IPV. Controlling for family and sexual violence and other confounding factors, female adolescents exposed to IPV had significantly higher adjusted odds ratios (AORs) for depression, panic attacks, eating problems, and suicidal ideation. For male adolescents, only the OR of eating problems almost reached statistical significance. PMID- 23363658 TI - Asthmatic response to milk ingestion challenge in adults: a comparison of the open and double-blind challenges. AB - BACKGROUND: Cow's milk allergy can participate in pathophysiological mechanisms underlying bronchial asthma in some adult patients. This role should ultimately be confirmed by means of a milk ingestion challenge. In this study, the diagnostic value of the open food ingestion challenge (OFICH) and the double blind placebo-controlled food challenge (DBPCFC) techniques with milk were compared in adult patients suffering from bronchial asthma with suspected milk allergy. METHODS: In 87 asthmatics with a suspected history and positive skin tests for milk, the 87 OFICHs and DBPCFCs were performed in combination with spirometry and followed up to 72 h after the challenge. RESULTS: Of 87 patients, 74 (85%) developed a positive asthmatic response (AR) (20 immediate, 33 late, 6 dual late and 15 delayed; p < 0.01) and 13 (15%) developed a negative AR (p > 0.1) to OFICH. Seventy-five (86%) developed a positive AR (17 immediate, 35 late, 8 dual late and 15 delayed; p < 0.01) and 12 (14%) developed a negative AR (p > 0.05) to DBPCFC. The correlation between the OFICH and DBPCFC was statistically significant (p < 0.01). All placebo control challenges were negative (p > 0.2). CONCLUSIONS: In some adults with bronchial asthma, involvement of an allergy to cow's milk results in the appearance of various AR types (immediate, late, dual late or delayed). The milk allergy can be confirmed by open or double-blind techniques, combined with spirometry. No significant differences were found between the OFICH and DBPCFC results. OFICH with natural milk combined with spirometry seems, therefore, to be an adequate technique for the detection of milk allergy in asthmatics. The DBPCFC can be performed as an additional check, if necessary. PMID- 23363659 TI - External Qi of Yan Xin Qigong inhibits activation of Akt, Erk1/2 and NF-KB and induces cell cycle arrest and apoptosis in colorectal cancer cells. AB - BACKGROUND/AIMS: Colorectal cancer (CRC) is the second leading cause of cancer death in the Western countries. Novel approaches of treatment are needed for CRC. The purpose of the present study was to investigate cytotoxic effect of external Qi of Yan Xin Qigong (YXQ-EQ) on human colorectal cancer cells. METHODS: The effect of YXQ-EQ on viability, cell cycle progression and apoptosis in colorectal cancer HT-29 cells was investigated. Phosphorylation of Akt and Erk1/2, activation of NF-KB and the expression of proteins involved in regulation of cell cycle and apoptosis were examined by Western blot analysis. RESULTS: YXQ-EQ markedly decreased viability and blocked colony formation of HT-29 cells. YXQ-EQ downregulated cyclin D1 expression and increased accumulation of cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip1), resulting in G1 cell cycle arrest. YXQ EQ induced apoptosis in HT-29 cells in association with decreased expression of antiapoptotic proteins Bcl-xL, XIAP, survivin and Mcl-1 and elevated expression of proapoptotic protein Bax. YXQ-EQ significantly repressed phosphorylation of Akt and Erk1/2 and NF-KB activation in HT-29 cells, suggesting that YXQ-EQ may exert cytotoxic effect through regulating signaling pathways critical for cell proliferation and survival. Furthermore, YXQ-EQ treated PBS and an YXQ-EQ treated plant extract induced apoptosis in HT-29 cells. CONCLUSION: These findings show that YXQ-EQ has potent cytotoxic effect on HT-29 cells and suggest that YXQ-EQ could be potentially used for colorectal cancer treatment either directly or indirectly via carriers. PMID- 23363661 TI - Arch translocation and the intra-arch elephant-trunk technique with collared graft for extended chronic dissecting aortic aneurysm. AB - Management of extensive, chronic, dissecting aortic aneurysms after prior repair of the ascending aorta presents a technical challenge for surgeons. A symptomatic 64-year-old patient was admitted for elective surgical repair of an aortic annular dilatation, causing severe aortic regurgitation, and a Crawford type II extended thoracoabdominal aneurysm, 4 years after he underwent primary repair of an acute aortic dissection. The aorta was diffusely dilated, and there were no sites beyond the distal aortic arch where anastomosis could be performed. We successfully performed total aortic replacement with a 2-stage strategy, using an arch translocation technique and an intra-arch elephant-trunk technique. PMID- 23363660 TI - Health information technology capacity at federally qualified health centers: a mechanism for improving quality of care. AB - BACKGROUND: The adoption of health information technology has been recommended as a viable mechanism for improving quality of care and patient health outcomes. However, the capacity of health information technology (i.e., availability and use of multiple and advanced functionalities), particularly in federally qualified health centers (FQHCs) on improving quality of care is not well understood. We examined associations between health information technology (HIT) capacity at FQHCs and quality of care, measured by the receipt of discharge summary, frequency of patients receiving reminders/notifications for preventive care/follow-up care, and timely appointment for specialty care. METHODS: The analyses used 2009 data from the National Survey of Federally Qualified Health Centers. The study included 776 of the FQHCs that participated in the survey. We examined the extent of HIT use and tested the hypothesis that level of HIT capacity is associated with quality of care. Multivariable logistic regressions, reporting unadjusted and adjusted odds ratios, were used to examine whether 'FQHCs' HIT capacity' is associated with the outcome measures. RESULTS: The results showed a positive association between health information technology capacity and quality of care. FQHCs with higher HIT capacity were significantly more likely to have improved quality of care, measured by the receipt of discharge summaries (OR=1.43; CI=1.01, 2.40), the use of a patient notification system for preventive and follow-up care (OR=1.74; CI=1.23, 2.45), and timely appointment for specialty care (OR=1.77; CI=1.24, 2.53). CONCLUSIONS: Our findings highlight the promise of HIT in improving quality of care, particularly for vulnerable populations who seek care at FQHCs. The results also show that FQHCs may not be maximizing the benefits of HIT. Efforts to implement HIT must include strategies that facilitate the implementation of comprehensive and advanced functionalities, as well as promote meaningful use of these systems. Further examination of the role of health information systems in clinical decision-making and improvements in patient outcomes are needed to better understand the benefits of HIT in improving overall quality of care. PMID- 23363662 TI - Gender differences in the clinical characteristics and outcomes of patients with vasospastic angina--a report from the Japanese Coronary Spasm Association. AB - BACKGROUND: Accumulating evidence has demonstrated the gender differences in the clinical characteristics and outcomes of patients with ischemic heart disease. However, it remains to be elucidated whether it is also the case for vasospastic angina (VSA). METHODS AND RESULTS: We enrolled a total of 1,429 VSA patients (male/female, 1090/339; median age 66 years) in our nationwide multicenter registry by the Japanese Coronary Spasm Association. As compared with male patients, female patients were characterized by older age (median 69 vs. 66 years), lower incidence of smoking (20% vs. 72%) and less significant organic stenosis (9% vs. 16%) (all P=0.001). Multivariate analysis demonstrated that the predictors of major adverse cardiac events (MACE) were considerably different by genders; women were more associated with age and electrical abnormalities, whereas men with structural abnormalities. Overall 5-year MACE-free survival was comparable between both genders. However, when the patients were divided into 3 groups by age [young (<50 years), middle-aged (50-64 years) and elderly (>=65 years)], the survival was significantly lower in the young female group (young 82%, middle-aged 92%, elderly 96%, P<0.01), where a significant interaction was noted between age and smoking. In contrast, the survival was comparable among the 3 age groups of male patients. CONCLUSIONS: These results indicate that there are gender differences in the characteristics and outcomes of VSA patients, suggesting the importance of gender-specific management of the disorder. PMID- 23363663 TI - Improving safety in autologous HSCT for systemic sclerosis. PMID- 23363664 TI - Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis. AB - BACKGROUND: Autologous haemopoietic stem-cell transplantation (HSCT) benefits patients with systemic sclerosis but has been associated with significant treatment-related mortality and failure to improve diffusion capacity of carbon monoxide (DLCO). We aimed to assess efficacy of HSCT and use of rigorous cardiac screening in this group. METHODS: We assessed patients with diffuse systemic sclerosis or limited systemic sclerosis and interstitial lung disease who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL, USA) or the University of Sao Paulo (Ribeirao Preto, Brazil). Unselected peripheral blood stem cells were harvested with cyclophosphamide (2 g/m(2)) and filgrastim. The transplant regimen was a non myeloablative regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4.5-6.5 mg/kg). We followed patients up to 5 years for overall survival, relapse-free survival, modified Rodnan skin score, and pulmonary function tests. FINDINGS: Five (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease. Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival was 70% at 5 years. Compared with baseline, we noted improvements after HSCT in modified Rodnan skin scores at 1 year (58 patients; p<0.0001), 2 years (42 patients; p<0.0001), and 3 years (27 patients; p<0.0001) and forced vital capacity at 1 year (58 patients; p=0.009), 2 years (40 patients; p=0.02), and 3 years (28 patients; p=0.004), but total lung capacity and DLCO were not improved significantly after HSCT. Overall mean DLCO was significantly improved in patients with normal baseline echocardiograms (p=0.005) or electrocardiographs (p=0.05). INTERPRETATION: Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-selected autograft results in sustained improvement in skin thickness and forced vital capacity. DLCO is affected by baseline cardiac function. Guidelines for cardiac screening of patients with systemic sclerosis to assess treatment-related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be reconsidered and updated. FUNDING: None. PMID- 23363665 TI - Rethinking infection prevention research. PMID- 23363668 TI - [Risk factors and coronary angiography characteristics of female patients with acute coronary syndrome]. AB - OBJECTIVE: To assess the risk factors and coronary angiography characteristics of female patients with acute coronary syndrome (ACS). METHODS: A total of consecutive 986 inpatients with ACS who had undergone coronary angiography from March 2009 to August 2010 in our hospital were enrolled in this study. There were 303 female patients and 683 male patients. Clinical data were collected by physicians and the severity of coronary artery stenosis was analyzed via the international Gensini Score system. RESULTS: Incidence of ACS under the age of 60 years [8.6% (26/303) vs. 16.5% (113/683), P < 0.05], family history of coronary artery disease [15.8% (48/303) vs. 23.0% (157/683), P < 0.05], and smokers [19.1% (58/303) vs. 71.7% (490/683), P < 0.001] were significantly less while hypertension [81.5% (247/303) vs. 64.0% (437/536), P < 0.001] and diabetes rate [51.8% (157/303) vs. 44.0% (298/683), P < 0.05] were significantly higher in female patients than in male patients. The comorbidities of dyslipidemia, adiposity, hyper-C-reaction protein and hyperfibrinogenemia were similar between male and female patients (P > 0.05). Unstable angina and non-ST-segment elevation myocardial infarction were more often [86.1% (261/303) vs. 78.5% (536/683)], while ST-segment elevation myocardial infarction was less [13.9% (42/303) vs. 21.5% (147/683), P = 0.005] in female patients than in male patients. There were significantly more incidence of mild coronary artery stenosis [15.0% (47/303) vs. 10.0% (68/683), P = 0.012] and less severely stenotic lesions [84.2% (255/303) vs. 89.8% (613/683), P = 0.013] in female patients than in male patients. Gensini score, percutaneous intervention rate and in-hospital mortality rate were similar between male and female patients with ACS (P > 0.05). CONCLUSIONS: Prevalence rates of diabetes mellitus and hypertension are higher while positive family history on coronary artery disease and smoking rate are lower in female patients with ACS than in male ACS patients. Female ACS patients are often presented with unstable angina or non-ST-segment elevation myocardial infarction and with mild coronary artery stenosis compared to male ACS patients. PMID- 23363666 TI - Daily chlorhexidine bathing to reduce bacteraemia in critically ill children: a multicentre, cluster-randomised, crossover trial. AB - BACKGROUND: Bacteraemia is an important cause of morbidity and mortality in critically ill children. Our objective was to assess whether daily bathing in chlorhexidine gluconate (CHG) compared with standard bathing practices would reduce bacteraemia in critically ill children. METHODS: In an unmasked, cluster randomised, two-period crossover trial, ten paediatric intensive-care units at five hospitals in the USA were randomly assigned a daily bathing routine for admitted patients older than 2 months, either standard bathing practices or using a cloth impregnated with 2% CHG, for a 6-month period. Units switched to the alternative bathing method for a second 6-month period. 6482 admissions were screened for eligibility. The primary outcome was an episode of bacteraemia. We did intention-to-treat (ITT) and per-protocol (PP) analyses. This study is registered with ClinicalTrials.gov (identifier NCT00549393). FINDINGS: 1521 admitted patients were excluded because their length of stay was less than 2 days, and 14 refused to participate. 4947 admissions were eligible for analysis. In the ITT population, a non-significant reduction in incidence of bacteraemia was noted with CHG bathing (3.52 per 1000 days, 95% CI 2.64-4.61) compared with standard practices (4.93 per 1000 days, 3.91-6.15; adjusted incidence rate ratio [aIRR] 0.71, 95% CI 0.42-1.20). In the PP population, incidence of bacteraemia was lower in patients receiving CHG bathing (3.28 per 1000 days, 2.27-4.58) compared with standard practices (4.93 per 1000 days, 3.91-6.15; aIRR 0.64, 0.42 0.98). No serious study-related adverse events were recorded, and the incidence of CHG-associated skin reactions was 1.2 per 1000 days (95% CI 0.60-2.02). INTERPRETATION: Critically ill children receiving daily CHG bathing had a lower incidence of bacteraemia compared with those receiving a standard bathing routine. Furthermore, the treatment was well tolerated. FUNDING: Sage Products, US National Institutes of Health. PMID- 23363667 TI - Variation in human brains may facilitate evolutionary change toward a limited range of phenotypes. AB - Individual variation is the foundation for evolutionary change, but little is known about the nature of normal variation between brains. Phylogenetic variation across mammalian brains is characterized by high intercorrelations in brain region volumes, distinct allometric scaling for each brain region and the relative independence of olfactory and limbic structure volumes from the rest of the brain. Previous work examining brain variation in individuals of some domesticated species showed that these three features of phylogenetic variation were mirrored in individual variation. We extend this analysis to the human brain and 10 of its subdivisions (e.g., isocortex and hippocampus) by using magnetic resonance imaging scans of 90 human brains ranging between 16 and 25 years of age. Human brain variation resembles both the individual variation seen in other species and variation observed across mammalian species, i.e., the relative differences in the slopes of each brain region compared to medulla size within humans and between mammals are concordant, and limbic structures scale with relative independence from other brain regions. This nonrandom pattern of variation suggests that developmental programs channel the variation available for selection. PMID- 23363669 TI - [Analysis of the risk factors of patients with acute coronary syndrome suffering hemorrhage during hospitalization]. AB - OBJECTIVE: To analyze the risk factors related to in-hospital bleeding for patients with acute coronary syndrome (ACS). METHODS: Clinical and therapeutic data of 3807 patients who were registered with acute coronary syndrome in SINO GRACE in China from March 2001 to December 2007 were reviewed. A total of 57 patients were grouped to bleeding group and 234 out of the remaining 3750 patients without bleeding were randomly chosen and served as non-bleeding group. Hemorrhage-related factors were screened and compared between the two groups. Unitary logistic regression analysis was performed to detect the possible factors related to hemorrhage. Factors with P < 0.1 were further analyzed by stepwise regression method and multivariate conditional logistic regression analyses. RESULTS: (1) Age, history of coronary artery bypass graft (CABG), previous hemorrhage, renal failure and heart failure as well incidence of acute coronary syndrome were significantly higher in bleeding group than in non-bleeding group (all P <= 0.05). Patients were more often treated with clopidogrel and glycoprotein (GP) IIb/IIIa receptor antagonist in bleeding group than in non bleeding group. (2) Single factor logistic regression analysis showed that age > 70 years, history of previous bleeding, renal failure, heart failure, clopidogrel and GP IIb/IIIa receptor antagonists use, non-ST-segment elevation myocardial infarction, inferior wall, lateral myocardial infarction, CABG were risk factors for bleeding (all P < 0.05). (3) Multivariate logistic regression analysis showed that history of renal failure (OR = 19.77, 95%CI 4.38 - 89.18, P < 0.01) and clopidogrel (OR = 19.77, 95%CI 4.38 - 89.18, P < 0.01) and GPIIb/IIIa receptor antagonist (OR = 343.57, 95%CI 40.39 - 999.99, P < 0.01) use were the independent risk factors for bleeding. CONCLUSION: Our results show that renal failure history and clopidogrel and GPIIb/IIIa receptor antagonist use are independent risk factors for in-hospital bleeding in patients with acute coronary syndrome. PMID- 23363670 TI - [Clopidogrel metabolism related gene polymorphisms in Chinese patients with acute coronary syndrome]. AB - OBJECTIVE: To detect the single nucleotide polymorphisms of clopidogrel metabolism related genes (CYP2C19, ABCB1 and PON1) in Chinese patients with acute coronary syndrome (ACS) by genotype analysis. METHODS: Genetic analysis was performed in patients admitted to Fuwai Hospital from 2005 to 2008 with ACS within 4 weeks. The detection of polymorphisms was performed by TaqMan real-time PCR method. The alleles genotyped were CYP2C19 *2-*8, *17, ABCB1 C3435T, PON1 Q192R and PON1 L55M. Minor allele frequency (MAF) was calculated. Patients were classified as one of the 5 categories by clopidogrel metabolizer phenotypes as extensive [without any "loss-of-function" (LOF) allele *2-*8 or "gain-of function" (GOF) allele *17], intermediate (with only one LOF allele), Poor (with two or more LOF alleles), ultra (with one or two GOF alleles) or unknown (with one LOF allele and one GOF allele). RESULTS: A total of 2800 ACS patients were enrolled [mean age (59.0 +/- 12.3) years and 2236 males (79.9%)]. There were 74% patients with ST-segment elevation myocardial infarction (STEMI, n = 2072), 22.0% patients with non-ST-segment elevation myocardial infarction (NSTEMI, n = 617) and 4.0% patients with unstable angina (UA, n = 111). The minor allele frequency (MAF) for each genotype of CYP2C19 *2, *3, *4, *17 was 28.7%, 4.6%, 0.1% and 1.2%, respectively. There was no LOF allele *5-*8 in the study population. The MAF for ABCB1 C3435T, PON1 Q192R and PON1 L55M was 39.4%, 37.8% and 4.4%, respectively. Clopidogrel metabolizer groups were defined as extensive in 41.7%, intermediate in 45.6%, poor in 10.3%, ultra in 1.9% and unknown in 0.6% patients, respectively. There were no significant differences for all genotypes between males and females. Total LOF carriers of CYP2C19 were 56.4% and GOF carriers were 2.5%. CONCLUSIONS: Our study demonstrated a high distribution of the LOF allele of CYP2C19 in China ACS population. PMID- 23363671 TI - [Prognostic value of circulating catestatin levels for in-hospital heart failure in patients with acute myocardial infarction]. AB - OBJECTIVE: To determine whether circulating level of catestatin (CST) could provide prognostic information independently of conventional risk markers for the development of in-hospital heart failure in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: The data of 120 STEMI patients (mean age: 61 years, 73% male) were collected from the Second Hospital of Shanxi Medical University and Taiyuan Central Hospital between November 2010 and September 2011.The patients were categorized into 4 groups according to CST (ng/L) quartile: <= 74.72, 74.73-79.67, 79.68 - 84.21 and >= 84.22 ng/L. Clinical features, therapeutic approaches were compared among groups. The patients were also grouped according to Killip class: Killip level I (n = 68), Killip level II (n = 23), Killip level III (n = 18), Killip level IV (n = 11). CST, NE and NT proBNP were compared among groups. The Spearma rank correlation and multivariate logistic regression analysis were applied to determine the association between risk factors and in-hospital heart failure. Receiver-operator characteristic (ROC) curve was performed to evaluate the power of CST and NT-proBNP on predicting in-hospital heart failure. RESULTS: Gender, hospital days, past history of smoking, hypertension, myocardial infarction, CK-MB peak level, TnI peak level, heart rate, blood pressure, blood glucose, blood lipid levels on admission and early reperfusion therapy were similar among groups. Patients with higher CST values were more likely to be older, to have lower body mass index, to have higher white blood cell count, CysC, hs-CRP, NE, NT-proBNP, past history of angina, diabetes mellitus, being diuretic users, and to have a lower ejection fraction (all P < 0.05). Higher CST levels were also associated with increased risk of heart failure (P < 0.05). In proportion with the deterioration of the cardiac function, CST, NE, NT-proBNP concentration gradually increased (all P < 0.05). Spearman rank correlation analysis showed that the CST was negatively correlated with LVEF (r(s) = -0.923, P < 0.001) and positively correlated with NT proBNP (r(s) = 0.884, P < 0.001). After multivariate adjustment, CST remained to be an independent risk factor for the development of in-hospital heart failure (OR = 1.125, 95%CI: 1.056 - 1.198;P < 0.001). The area under the ROC curve of CST and NT-proBNP was 0.777 and 0.874. Using CST = 77.29 ng/L as a cut-off value, the sensitivity was 92.8% and specificity was 70.6% for predicting the development of in-hospital heart failure. CONCLUSION: The plasma CST level is an independent predictor for the development of in-hospital heart failure in patients with STEMI. PMID- 23363672 TI - [Impact of anemia on long-term outcome in elderly patients with acute coronary syndrome undergoing percutaneous coronary interventions]. AB - OBJECTIVE: To assess the impact of pre-procedure anemia on the long-term mortality in elderly patients with acute coronary syndrome (ACS) after percutaneous coronary interventions. METHODS: A total of 1014 ACS patients (>= 60 years of age) with hemoglobin data and without previous treatment with thrombolytic agents and without end-stage renal failure before the interventional procedure were included. Patients were classified as anemia using the definition of World Health Organization: hemoglobin < 130 g/L in men, and < 120 g/L in women. A total of 253 patients were anemia. The clinical features of patients with and without anemia and association of pre-procedure anemia with long-term mortality were analyzed. RESULTS: Incidence of diabetes and serum creatinine level were significantly higher in anemia patients than in non-anemia patients while systolic blood pressure and low-density lipoprotein cholesterol were significantly lower in anemia patients than in non-anemia patients (P < 0.05 or P < 0.01). The patients were followed up for 528 (178 - 675) days. After adjustment for potential co-variants in Cox regression analysis, pre-procedure anemia was associated with a significantly higher long-term mortality (RR: 3.293, 95%CI: 1.431 - 7.578, P < 0.01). CONCLUSION: Pre-procedure anemia is an independent predictor of long-term mortality in elderly patients with acute coronary syndrome after percutaneous coronary interventions. PMID- 23363673 TI - [Clinico-pathological characteristics of infective endocarditis associated with congenital heart disease: an analysis of 74 cases in single center]. AB - OBJECTIVE: To assess the changing profile of infective endocarditis (IE) in patients with congenital heart disease (CHD) from 1998 to 2009 in our hospital. METHODS: Clinical characteristics of IE patients with CHD underwent surgical treatment during 1998 - 2009 in our hospital were evaluated. The coincidence rate between clinical and pathological diagnosis were analyzed. RESULTS: There were 74 IE cases associated with CHD during the 12 years, accounting for 33.6% of all patients with IE receiving surgery during this time period. Mean age was higher for patients treated in 2006 - 2009 than patients treated in 2002 - 2005 [(38.7 +/- 14.6) years vs. (28.4 +/- 12.8) years, P = 0.003].Bicuspid aortic valve (accounting for 52.2%) was the most frequent congenital heart disease and the age of these patients was younger than patients with other congenital heart diseases. IE in CHD affected the left heart structures in 83.8% (62/74) of all cases, 47 in aortic valve (75.8%). Blood cultures were performed in 29.7% of the patients (22/74) and the positive rate was 59.1% (13/22). Streptococci viridans were the most common causative organisms. Echocardiography was performed in all patients and 66.3% echocardiographic records were positive, IE was diagnosed in 53 patients (71.7%) before operation. The operative mortality was 2.7%. CONCLUSION: Congenital heart disease, especially bicuspid aortic valve, is the most common underlying disease for IE. Combined analysis of clinical, echocardiographic and blood culture results are essential for increasing the diagnosis rate of IE. PMID- 23363674 TI - [Distributional characteristics of acylation stimulating protein gene 301T > C polymorphism and association with serum triglyceride in Han and Uighur residents in Xinjiang]. AB - OBJECTIVE: To explore the distributional characteristics of acylation stimulating protein (ASP) gene polymorphism and the association with serum lipid level of Chinese Han and Uighur residents in Xinjiang. METHOD: Genotypes of the ASP gene 301T > C polymorphism was detected by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) in 527 Uighur and 407 Han residents. RESULTS: The frequencies of TT, TC and CC genotype of ASP gene 301T > C were 74.9%, 21.3% and 3.6% in Han group and 47.6, 40.2% and 12.1% in Uighur group (P < 0.05). Serum triglyceride level was significantly higher in C allele carrier (TC + CC genotype) than in TT genotype carrier of both Han and Uighur individuals. After adjusting for age, gender, smoking, drinking, BMI and serum total cholesterol, logistic regression analyses revealed that individuals carrying C allele (TC + CC genotype) faced an increased risk of increased serum triglyceride level than individuals carrying TT genotype in both Han and Uighur individuals (OR = 3.31, 95%CI: 1.31 - 8.36 in Uighur group; OR = 3.98, 95%CI: 1.81 - 8.74 in Han group). CONCLUSION: There is a significant difference on mutational frequencies of the ASP gene 301T > C polymorphism between Uighur and Han residents in Xinjiang and C allele carriers face an increased risk for hypertriglyceridemia in both Uighur and Han residents in Xinjiang. PMID- 23363675 TI - [Value of prospectively electrocardiography-triggered high-pitch computed tomography in the follow-up of patients with previous coronary stent implantation]. AB - OBJECTIVE: To explore the value of prospectively ECG-triggered high-pitch spiral mode CT coronary angiography (CTCA) in the follow-up of patients with prior coronary stent implantation. METHODS: According to the different scan modes, ninety-six patients with heart rate below 75 beat per minute, sinus rhythm and weight below 100 kg and previous coronary stent implantation who underwent 128 slice dual-source Flash spiral CT coronary angiography were randomly divided into two groups according to the randomly numbers in the envelopes: group A(the prospective electrocardiography gated group, 50 cases) and group B(the prospectively ECG-triggered high-pitch spiral mode group, 46 cases). The image quality was evaluated with a four-point grading scale (1 = excellent, 2 = good, 3 = poor, 4 = very poor or non-diagnostic). The total effective dose and the total dose length product between the two groups were recorded respectively. The CTCA enhanced effective dose, dose length product, and the CT volume dosage index (CTDIvol) between the two groups were recorded respectively. RESULTS: A total of 157 stents were implanted, there were 78 stents in group A and 79 stents in group B, and the value of the image quality was (1.3 +/- 0.6) scores in group A and (1.4 +/- 0.6) scores in group B (P > 0.05). The total effective dose [(7.6 +/- 1.8) mSv vs. (1.6 +/- 0.3) mSv] and dose length product [(545.8 +/- 131.5) mGy*cm vs. (111.4 +/- 19.8) mGy*cm]of the entire scan process were significantly higher in group A than in group B (all P < 0.01). The CTCA enhanced effective dose [(6.7 +/- 1.7) mSv vs. (1.2 +/- 0.2) mSv], dose length product [(480.8 +/- 121.9) mGy*cm vs. (84.2 +/- 17.5) mGy*cm] and the CTDIvol [(35.7 +/- 8.6) mGy vs. (4.5 +/- 0.9) mGy] of group A were also significantly higher than those in group B (all P < 0.01). CONCLUSIONS: It is clinically feasible to use the dual-source Flash spiral CT coronary angiography for the follow-up of the patients with previous coronary stent implantation. This new process can substantially reduce the radiation dose while preserving good imaging quality. PMID- 23363676 TI - [Community-based management for chronic heart failure patients under the professional guidance of upper first-class hospital staff]. AB - OBJECTIVE: To establish a community-based management model for heart failure patients under the professional guidance of upper first-class hospital staff. METHODS: Two hundreds heart failure (New York Heart Function II-IV) patients aged from 35 to 85 in two communities of Chengdu city were divided into two groups by cluster randomization: the management group and the control group. The community hospital doctors were trained for the evaluation and management of heart failure according standardized guidelines by upper first-class hospital doctors, and responsible for the management of patients in the management group. Meanwhile, the management group patients also received self-care education. Patients in control group were treated by community doctors without special training. Data including the community hospital doctors' knowledge rate of heart failure, positive diagnosis rate, and the rate for standardized medication for heart failure; the patients' knowledge rate of heart failure, the rate of drug compliance, the rate of standardized drug taken for heart failure, the rate of self-care in daily-life, the quality of life, the incidence of cardiovascular events, hospitalization time and cost were compared between the two groups. RESULTS: The community hospital doctors' knowledge rate of heart failure, the related knowledge for prevention and treatment on the causes of heart failure, the positive diagnosis rate, and the rate for standardized medication for heart failure [beta receptor blocker 77.3% (17/22); angiotensin-converting enzyme inhibitors 63.6% (14/22)] were significantly higher than doctors in the control group (all P < 0.05). There were 96 in the management group and 97 in the control group. Data were similar between the two groups at baseline. After (18.5 +/- 0.5) months, the patient's knowledge rate of heart failure [100% (96/96) vs. 71.1% (69/97)], the rate of drug compliance [78.1% (75/96) vs. 13.4% (13/97)], the rate of standardized drug taken for heart failure[beta receptor blocker: 75.0% (72/96) vs. 8.2% (8/97); angiotensin-converting enzyme inhibitors: 60.4% (58/96)vs. 10.3% (10/97)], and the rate of self-care in daily-life [salt and food restriction:88.5% (85/96) vs. 29.9% (23/97); blood pressure monitoring: 83.3% (80/96) vs. 56.7% (55/97); weight monitoring:78.1% (75/96) vs. 13.4% (13/97)] were all significantly higher in the management group than in control group. For patients with New York Heart Function III-IV, the score of the LiHFe questionnaire (43.7 +/- 9.2 vs. 49.5 +/- 11.3), the incidence of cardiovascular events [63.3% (19/30) vs. 90.3% (28/31)], the days of hospitalization [(8.2 +/- 3.2)days vs. (13.9 +/- 10.9) days], and the cost for hospitalization [(2873.3 +/- 401.6) Yuan vs. (4525.8 +/- 6417.8) Yuan] were all significantly lower in the management group (n = 30) than in the control group (n = 31) (all P < 0.05). CONCLUSIONS: The community-based management model for heart failure patients in the community level is effective to improve the management and outcome in this cohort. PMID- 23363677 TI - [Ischemic preconditioning attenuates myocardial no-reflow and reperfusion injury after revascularization of acute myocardial infarction by reducing myocardial edema via the protein kinase A pathway]. AB - OBJECTIVE: Myocardial edema plays an important role in the development of myocardial no-reflow and reperfusion injury after the revascularization of acute myocardial infarction (AMI). The present study investigated whether the effect of ischemic preconditioning (IPC) against myocardial no-reflow and reperfusion injury was related to the reduction of myocardial edema through the protein kinase A (PKA) pathway. METHODS: Twenty-four minipigs were randomized into sham, AMI, IPC, and IPC + H-89 (PKA inhibitor, 1.0 ug . kg(-1) . min(-1)) groups. The area of no-reflow (ANR), area of necrosis (AN), and water content in left ventricle and ischemic-myocardium and non-ischemic area were determined by pathological studies. Microvascular permeability was determined by FITC-labeled dextran staining. Cardiomyocyte cross-sectional area (CSA) and mitochondria cross sectional area (MSA) were evaluated by histological analysis. Myocardial expression of aquaporins (AQPs) was detected by Western blot. RESULTS: Compared with the MI group, the sizes of no-reflow and infarct were reduced by 31.9% and 46.6% in the IPC group (all P < 0.01), water content was decreased by 5.7% and 4.6% in the reflow and no-reflow myocardium of the IPC group (all P < 0.05), microvascular permeability and cardiomyocytes swelling in the reflow area were inhibited by 29.8% and 21.3% in the IPC group (all P < 0.01), mitochondrial water accumulation in the reflow and no-reflow areas of the IPC group were suppressed by 45.5% and 34.8% respectively (all P < 0.01), and the expression of aquaporin 4, -8, and -9 in the reflow and no-reflow myocardium were blocked in the IPC group. However, these beneficial effects of IPC were partially abolished in the IPC + H-89 group. CONCLUSIONS: The cardioprotective effects of IPC against no reflow and reperfusion injury is partly related to the reduction of myocardial edema by inhibition of microvascular permeability and aquaporins up-regulation via PKA pathway. PMID- 23363678 TI - [The establishment and validation of an endothelial cell senescence model induced by carbamide peroxide]. AB - OBJECTIVE: To establish an in vitro pig iliac artery endothelial cells (PIECs) senescence model using carbamide peroxide (CP). METHODS: MTT assay and DAPI staining were used to define the optimal concentration of CP for inducing to the PIECs senescence model. Cellular morphology, MTT assay, EdU labeling, SA-beta-gal staining and cell scratch test were performed to analyze the cell growth kinetic, proliferative activity, aging ratio and migratory activity difference post CP induction. PI signal staining flow cytometry was used to analyze the cell cycle distribution difference of cells before and after CP induction. RESULTS: The optimal CP concentration was 40 umol/L to induce PIECs senescence. After 1 h treatment with 40 umol/L CP, the PIECs presented typical aging form with lager and more rounded shapes. Compared with control group, the proliferative activity and the migratory distance of CP group were significantly decreased; the SA-beta gal staining positive ratio was significantly increased; the data of mitotic cycle distribution with flow cytometry analysis showed that most cells were arrested at G(1)/G(0) phase. CONCLUSION: CP could efficiently induce pig iliac artery endothelial cell senescence in vitro. PMID- 23363679 TI - [Impact of ideal health behaviors and health factors on the detection rate of the carotid plaques]. AB - OBJECTIVE: To explore the impact of ideal health behaviors and health factors on the detection rate of the carotid plaques. METHODS: Subjects with previous stroke, TIA, myocardial infarction were excluded from the study. A total of 5852 employees (active and retired employers from Tangshan Kailuan company) aged 40 years and over were included through stratified random sampling. Information was obtained from the unified questionnaire, measurements of blood biochemistry and carotid artery ultrasonography. RESULTS: (1) The carotid artery plaque detection rates were 67.0%, 52.3%, 50.5%, 44.3%, 37.2%, 31.9%, 26.1% and 4.2% in the groups with 0, 1, 2, 3, 4, 5, 6 and 7 components of ideal cardiovascular health behaviors and health factors, respectively. (2) The carotid artery plaques total burden score [TBS: M (Q1, Q3)] were 7(7,7), 7(5,7), 7(5,7), 5(3,5), 5(3,5), 5(3,5), 3(3,3), 3(3,3) in the groups with 0, 1, 2, 3, 4, 5, 6 and 7 components of ideal cardiovascular health behaviors and health factors, respectively. (3) Multiple logistic regression analysis showed that 3, 4, 5 and greater than 5 components of ideal cardiovascular health behaviors and health factors were protective factors against carotid plaques compared to less than 2 components of ideal cardiovascular health behaviors and factors (all P < 0.05), the OR (95%CI) values were 0.78 (0.62 - 0.98), 0.53(0.62 - 0.98), 0.52 (0.39 - 0.71) and 0.40 (0.25 - 0.64), respectively. CONCLUSION: Increasing ideal cardiovascular health behaviors and factors are negatively linked with the detection rate and TBS of the carotid plaques. PMID- 23363680 TI - [Again review of research design and statistical methods of Chinese Journal of Cardiology]. AB - OBJECTIVE: To re-evaluate and compare the research design and the use of statistical methods in Chinese Journal of Cardiology. METHOD: Summary the research design and statistical methods in all of the original papers in Chinese Journal of Cardiology all over the year of 2011, and compared the result with the evaluation of 2008. RESULTS: (1) There is no difference in the distribution of the design of researches of between the two volumes. Compared with the early volume, the use of survival regression and non-parameter test are increased, while decreased in the proportion of articles with no statistical analysis. (2) The proportions of articles in the later volume are significant lower than the former, such as 6(4%) with flaws in designs, 5(3%) with flaws in the expressions, 9(5%) with the incomplete of analysis. (3) The rate of correction of variance analysis has been increased, so as the multi-group comparisons and the test of normality. The error rate of usage has been decreased form 17% to 25% without significance in statistics due to the ignorance of the test of homogeneity of variance. CONCLUSION: Many improvements showed in Chinese Journal of Cardiology such as the regulation of the design and statistics. The homogeneity of variance should be paid more attention in the further application. PMID- 23363681 TI - [The long-term follow up outcome of intervention treatment of coronary artery fistula artery fistula: a case report]. PMID- 23363682 TI - [Long-term follow-up results in a patient with coronary spasm induced recurrent acute myocardial infarction]. PMID- 23363683 TI - [Serine protease inhibitor-vaspin and atherosclerosis]. PMID- 23363684 TI - [Research progress of Kruppel-like transcription factor 2 on vascular function]. PMID- 23363685 TI - [Impacts of dyslipidemia on vascular endothelium]. PMID- 23363688 TI - Radiobiological effects of altering dose rate in filter-free photon beams. AB - To validate that altering radiotherapy dose rate through either changing pulse repetition frequency or instantaneous dose rate does not have an effect on cell survival, two human carcinoma and a hamster lung cell line were irradiated with various beam settings. Varian TrueBeam linac with a flattening filter free mode of operation was used for all experiments. The results obtained indicate that either method of changing dose rate has no effect on cell survival in the three cell lines studied. Filtered and filter free modes were also compared in treatments with protracted dose delivery which significantly increases overall treatment time. Cell survival indicated no difference between filter and filter free beam delivery in any of the protraction schemes. An increase in survival was seen in both modes upon protracting dose delivery to 15, 30 or 60 min rather than delivering acutely. Further, analysis of induced DNA double-strand breaks via the gammaH2AX assay showed no difference between filtered and unfiltered beams. The following study suggests that increasing dose rate is an acceptable manner of decreasing radiotherapy treatment time that does not have any detrimental effects on in vitro cell eradication. PMID- 23363687 TI - Familial liability to psychosis is associated with attenuated dopamine stress signaling in ventromedial prefrontal cortex. AB - OBJECTIVE: Patients diagnosed with a psychotic disorder and their first-degree relatives display increased reactivity to stress. Theory predicts that experience of psychosocial stress is associated both with ventromedial prefrontal and mesolimbic dopamine neurotransmission. However, while there is evidence of aberrant striatal dopamine processing in psychotic disorder, the role of the prefrontal cortex remains under-researched. This study aimed at investigating stress-induced in vivo dopamine release in ventromedial prefrontal cortex (vmPFC) of individuals at familial risk for psychosis. METHOD: Fourteen healthy first degree relatives of patients with a diagnosis of psychotic disorder and 10 control subjects underwent a single dynamic positron emission tomography (PET) scanning session after intravenous administration of 183.2 (SD = 7.6) MBq [(18)F]fallypride. Psychosocial stress was initiated at 100 min postinjection using a computerized mental arithmetic task with social evaluative threat components. PET data were analyzed using the linearized simplified reference region model. Regression analyses were performed to compare the spatial extent of task-related ligand displacement between control subjects and relatives and to find how it related to self-rated experiences of psychosocial stress and psychosis. RESULTS: First-degree relatives displayed hyporeactive dopamine signaling in the vmPFC in response to stress. Increased levels of subjectively rated stress were associated with increased intensity of psychotic experiences. This effect was particularly pronounced in first-degree relatives. CONCLUSION: Although previous studies have hypothesized a role for prefrontal dopamine dysfunction in psychosis, this study, to our knowledge, is the first in vivo human imaging study showing attenuated (ie, hyporeactive) dopamine stress neuromodulation in vmPFC of individuals at familial risk for psychosis. PMID- 23363689 TI - A randomised controlled pilot study: the effectiveness of narrative exposure therapy with adult survivors of the Sichuan earthquake. AB - BACKGROUND: Post-Traumatic Stress Disorder (PTSD) is a common psychological reaction after large-scale natural disasters. Given the number of people involved and shortage of resources in any major disaster, brief, pragmatic and easily trainable interventions are needed. The aim of this study is to evaluate the efficacy of Narrative Exposure Therapy (NET) as a short-term treatment for PTSD using Chinese earthquake survivors. METHODS: A randomized waiting-list control pilot study was conducted between December 2009 and March 2010, at the site of the Sichuan earthquake in Beichuan County, China. Adult participants with newly diagnosed Post Traumatic Stress Disorder (PTSD) were randomly allocated to Narrative Exposure Therapy (NET) or a Waiting-List (WL) condition. The latter received NET treatment after a two-week waiting period. To compare the effectiveness of NET in traumatised earthquake survivors, both groups were assessed on PTSD symptoms, general mental health, anxiety and depression, social support, coping style and posttraumatic change before and after treatment and two months post treatment. RESULTS: Adult participants (n=22) were randomly allocated to receive NET (n=11) or WL (n=11). Twenty two participants (11 in NET group, 11 in WL) were included in the analysis of primary outcomes. Compared with WL, NET showed significant reductions in PTSD symptoms, anxiety and depression, general mental stress and increased posttraumatic growth. The WL group later showed similar improvements after treatment. These changes remained stable for a two month follow-up. Measures of social support and coping showed no stable effects. CONCLUSIONS: NET is effective in treating post-earthquake traumatic symptoms in adult Chinese earthquake survivors. The findings help advance current knowledge in the management of PTSD after natural disasters and inform future research. Larger sample sizes are needed to extend the present findings. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-12002473. PMID- 23363690 TI - Increasing mean arterial blood pressure in sepsis: effects on fluid balance, vasopressor load and renal function. AB - INTRODUCTION: The objective of this study was to evaluate the effects of two different mean arterial blood pressure (MAP) targets on needs for resuscitation, organ dysfunction, mitochondrial respiration and inflammatory response in a long term model of fecal peritonitis. METHODS: Twenty-four anesthetized and mechanically ventilated pigs were randomly assigned (n = 8/group) to a septic control group (septic-CG) without resuscitation until death or one of two groups with resuscitation performed after 12 hours of untreated sepsis for 48 hours, targeting MAP 50-60 mmHg (low-MAP) or 75-85 mmHg (high-MAP). RESULTS: MAP at the end of resuscitation was 56 +/- 13 mmHg (mean +/- SD) and 76 +/- 17 mmHg respectively, for low-MAP and high-MAP groups. One animal each in high- and low MAP groups, and all animals in septic-CG died (median survival time: 21.8 hours, inter-quartile range: 16.3-27.5 hours). Norepinephrine was administered to all animals of the high-MAP group (0.38 (0.21-0.56) mcg/kg/min), and to three animals of the low-MAP group (0.00 (0.00-0.25) mcg/kg/min; P = 0.009). The high-MAP group had a more positive fluid balance (3.3 +/- 1.0 mL/kg/h vs. 2.3 +/- 0.7 mL/kg/h; P = 0.001). Inflammatory markers, skeletal muscle ATP content and hemodynamics other than MAP did not differ between low- and high-MAP groups. The incidence of acute kidney injury (AKI) after 12 hours of untreated sepsis was, respectively for low- and high-MAP groups, 50% (4/8) and 38% (3/8), and in the end of the study 57% (4/7) and 0% (P = 0.026). In septic-CG, maximal isolated skeletal muscle mitochondrial Complex I, State 3 respiration increased from 1357 +/- 149 pmol/s/mg to 1822 +/- 385 pmol/s/mg, (P = 0.020). In high- and low-MAP groups, permeabilized skeletal muscle fibers Complex IV-state 3 respiration increased during resuscitation (P = 0.003). CONCLUSIONS: The MAP targets during resuscitation did not alter the inflammatory response, nor affected skeletal muscle ATP content and mitochondrial respiration. While targeting a lower MAP was associated with increased incidence of AKI, targeting a higher MAP resulted in increased net positive fluid balance and vasopressor load during resuscitation. The long-term effects of different MAP targets need to be evaluated in further studies. PMID- 23363691 TI - A combination regimen of bortezomib, cyclophosphamide and betamethasone gives quicker, better and more durable response than VAD/CyBet regimens: results from a Swedish retrospective analysis. AB - BACKGROUND: Induction therapy for multiple myeloma (MM) and remission status before high-dose treatment (HDT) have been shown to be prognostic factors for survival outcome, although the optimal induction therapy is yet to be defined. METHODS: We conducted a retrospective analysis of the impact of induction therapy on survival outcome before and after HDT in MM patients. The study included 236 consecutive patients who underwent HDT. RESULTS: One hundred and forty-two patients (62%) were treated with vincristine, doxorubicin and dexamethasone (VAD) or cyclophosphamide and betamethasone (CyBet) and 94 (38%) were treated with bortezomib, cyclophosphamide and betamethasone (VCB) as induction. Time to first and time to best response was faster in the VCB group than in the VAD/CyBet group, with 42 versus 75 (p < 0.001) and 54 versus 88 days (p < 0.001), respectively. After induction therapy, 49% of the patients in the VCB group and 38% in the VAD/CyBet group achieved a very good partial response or better. Multivariate analysis revealed younger age, lower International Staging System stage and induction treatment with VCB as variables associated with favourable time to progression. CONCLUSIONS: Outcome measured as response and time to progression before and after HDT in MM differs depending on type of induction treatment and suggests that VCB is a highly effective induction regimen that confers a post-HDT advantage. PMID- 23363692 TI - Analytical modeling of trilayer graphene nanoribbon Schottky-barrier FET for high speed switching applications. AB - Recent development of trilayer graphene nanoribbon Schottky-barrier field-effect transistors (FETs) will be governed by transistor electrostatics and quantum effects that impose scaling limits like those of Si metal-oxide-semiconductor field-effect transistors. The current-voltage characteristic of a Schottky barrier FET has been studied as a function of physical parameters such as effective mass, graphene nanoribbon length, gate insulator thickness, and electrical parameters such as Schottky barrier height and applied bias voltage. In this paper, the scaling behaviors of a Schottky-barrier FET using trilayer graphene nanoribbon are studied and analytically modeled. A novel analytical method is also presented for describing a switch in a Schottky-contact double gate trilayer graphene nanoribbon FET. In the proposed model, different stacking arrangements of trilayer graphene nanoribbon are assumed as metal and semiconductor contacts to form a Schottky transistor. Based on this assumption, an analytical model and numerical solution of the junction current-voltage are presented in which the applied bias voltage and channel length dependence characteristics are highlighted. The model is then compared with other types of transistors. The developed model can assist in comprehending experiments involving graphene nanoribbon Schottky-barrier FETs. It is demonstrated that the proposed structure exhibits negligible short-channel effects, an improved on current, realistic threshold voltage, and opposite subthreshold slope and meets the International Technology Roadmap for Semiconductors near-term guidelines. Finally, the results showed that there is a fast transient between on-off states. In other words, the suggested model can be used as a high-speed switch where the value of subthreshold slope is small and thus leads to less power consumption. PMID- 23363693 TI - Management of hepatitis C virus infection: the basics. AB - Chronic hepatitis C virus (HCV) infection affects some 170 million people worldwide, including 3 to 4 million in the United States who are largely unaware of their infection status. HCV has 6 genotypes; genotype 1 is the most common in the United States and genotypes 1 and 4 are less responsive to interferon alfa based therapy than the other genotypes. Treatment with available direct-acting antiviral (DAA) drugs has increased sustained virologic response (SVR) rates in genotype 1 infection and shortened duration of therapy in many patients, but at this time these agents must still be administered with peginterferon alfa and ribavirin to prevent rapid emergence of resistance. Baseline predictors of response to therapy continue to play a role with triple-drug combination therapy including the pharmacogenetic IL28B genotype, which differs in prevalence throughout the world. The stopping/futility rules are different for triple-drug combination therapy, allowing for earlier decision-making. Ultimately, SVR is the goal of HCV treatment because it dramatically reduces likelihood of poor long term outcome, even among patients with histologically advanced disease. This article summarizes a basic review presented by Susanna Naggie, MD, at the IAS-USA live management of HCV continuing medical education program held in Atlanta in October 2012. This article is intended for practitioners who are new to HCV management or who are interested in reviewing the basics of HCV treatments. PMID- 23363694 TI - New and investigational antiretroviral drugs for HIV infection: mechanisms of action and early research findings. AB - Numerous investigational antiretroviral agents are in clinical development. Among them are festinavir (BMS986001), a thymidine analogue similar to stavudine with reduced potential for toxicity; GS-7340, a prodrug of tenofovir that achieves greater intracellular concentrations; MK-1439, a nonnucleoside analogue reverse transcriptase inhibitor (NNRTI) that retains activity against common NNRTI associated resistance mutations; and albuvirtide, a long-acting parenteral fusion inhibitor. Investigational integrase strand transfer inhibitors (InSTIs) include elvitegravir, recently approved by the US Food and Drug Administration (FDA) as part of a once-daily, single-tablet formulation with cobicistat/tenofovir/emtricitabine; dolutegravir, which maintains some activity against raltegravir- and elvitegravir-resistant mutants; and S/GSK1265744, which also maintains some activity against resistance mutations in the integrase gene and is being developed as a long-lasting parenteral agent. Novel 2-(quinolin-3 yl)acetic acid derivatives (LEDGINs), agents that were originally thought to inhibit the interaction of integrase with its cofactor lens epithelium-derived growth factor p75 (LEDGF/p75), be active against InSTI-resistant mutants and to have additive activity when combined with InSTIs. This article summarizes a presentation by Michael S. Saag, MD, at the IAS-USA live Improving the Management of HCV Disease continuing medical education program held in New York in October 2012. PMID- 23363695 TI - Vitamin D, bone, and HIV infection. AB - Vitamin D deficiency has been associated with increased risk for falls and fractures, diabetes and obesity, cardiovascular disease, some malignancies, and tuberculosis. Observational data have suggested benefit of higher vitamin D levels in many of these settings. However, data from randomized trials supporting the benefit of vitamin D supplementation are generally lacking, apart from data showing benefit in preventing falls and fractures in the elderly. HIV-infected persons have a high prevalence of vitamin D deficiency and insufficiency, and some antiretroviral drugs are known to interfere with vitamin D metabolism. However, as in the general population, there are currently few data from clinical trials to identify benefits of vitamin D screening and supplementation in the HIV infected population. A rational approach is to screen at-risk patients (eg, those aged 50 years and older and those with osteoporosis, prior fracture, or high risk for falls); supplementation may be considered in specific subgroups of patients. This article summarizes a presentation by Michael Yin, MD, MS, at the IAS-USA live Improving the Management of HIV Disease continuing medical education program held in New York, New York, in October 2012. PMID- 23363696 TI - Epidermodysplasia verruciformis in an HIV-infected man: a case report and review of the literature. PMID- 23363697 TI - Highlights of the 2012 American Association for the Study of Liver Diseases meeting. AB - The American Association for the Study of Liver Diseases (AASLD) held its annual meeting from November 9, 2012, through November 13, 2012, in Boston, Massachusetts. Hepatitis C virus (HCV) was prominently featured in the meeting, reflecting the rapid pace at which new developments in the field of HCV treatment are being introduced. HCV was the topic of an estimated 451 of the 2051 submitted abstracts (22%), with 148 abstracts (7.2%) focused on investigational drugs; it was also the topic of 1 presidential plenary session (top oral abstracts), 1 symposium, 10 of 37 parallel sessions (oral abstracts), and 1 debriefing session at the close of the meeting. This article will summarize some of the major findings presented at the meeting. PMID- 23363698 TI - Comparative effectiveness research: nursing science and health care delivery. AB - Comparative effectiveness research (CER) is an important foundation in the development of scientific evidence that can assist patients, clinicians, and policy makers in making decisions that improve patient and system outcomes, including cost. CER is a part of what is now called dissemination and implementation science, which focuses on translating knowledge into practice by facilitating stakeholder access to more interpretable findings. CER has evolved from a rich history that aims to compare the effectiveness of select clinical treatments, approaches, or programs. This article describes the development of CER, approaches to designing and analyzing this research, and resources useful in generating such knowledge by nurse scientists. PMID- 23363699 TI - BlaSTorage: a fast package to parse, manage and store BLAST results. AB - BACKGROUND: Large-scale sequence studies requiring BLAST-based analysis produce huge amounts of data to be parsed. BLAST parsers are available, but they are often missing some important features, such as keeping all information from the raw BLAST output, allowing direct access to single results, and performing logical operations over them. FINDINGS: We implemented BlaSTorage, a Python package that parses multi BLAST results and returns them in a purpose-built object-database format. Unlike other BLAST parsers, BlaSTorage retains and stores all parts of BLAST results, including alignments, without loss of information; a complete API allows access to all the data components. CONCLUSIONS: BlaSTorage shows comparable speed of more basic parser written in compiled languages as C++ and can be easily integrated into web applications or software pipelines. PMID- 23363700 TI - Ras activated ERK and PI3K pathways differentially affect directional movement of cultured fibroblasts. AB - BACKGROUND: Cell migration is essential in physiological and pathological processes, such as wound healing and metastasis formation. Ras involvement in these processes has been extensively demonstrated. This work attempts to characterize Ras regulation of the phenomena determining directional cell migration by separately analyzing the role of its principal effector pathways, MAPK and PI3K. METHODS: NIH3T3 and NIHRasV12 fibroblasts were followed in wound healing assays to study, in time and under a directional stimulus, cell migration both under standard conditions and in presence of MAPK and PI3K inhibitors. Several parameters, descriptive of specific aspects of cell motion, were evaluated by coupling dynamic microscopy with quantitative and statistical methods. Quantitative Western Blots coupled with immunofluorescence stainings, were used to evaluate ERK activation. RESULTS: Constitutive RasV12 activation confers to NIH3T3 the ability to close the wound faster. Neither increased cell proliferation nor higher speed explains the accelerated healing, but the increased directional migration drives the wound closure. Inhibition of ERK activation, which occurs immediately after wound, greatly blocks the directional migration, while inhibition of PI3K pathway reduces cell speed but does not prevent wound closure. CONCLUSION: Ras is greatly involved in determining and regulating directionality, ERK is its key effector for starting, driving and regulating directional movement. PMID- 23363701 TI - Immunotherapy with commercial venoms is efficacious for anaphylactic reactions to Vespa orientalis stings. AB - BACKGROUND: Vespa orientalis (VO) stings occasionally induce anaphylaxis. In the absence of commercial VO venom, allergists use commercial venoms for immunotherapy, despite having no indication regarding efficacy. We attempted to examine the effectiveness of immunotherapy with commercial venoms in patients with VO allergy and to identify the venom accountable for this effect. METHODS: Patients who unequivocally identified VO as the culprit insect were administered venom immunotherapy with the commercial venoms available in Israel to which they had positive skin tests. Patients were also skin tested with VO venom sac extracts and, after reaching the maintenance dose, were sting challenged by a live insect. The allergenic components in the venom were determined by immunoblotting. RESULTS: Twelve patients were recruited and, based on their skin test results, all were treated with yellow jacket (YJ) venom, either alone or combined with other venoms. All 8 patients who were sting challenged by VO demonstrated positive skin test responses to VO venom. Six of the stung patients tolerated the sting challenge uneventfully. Two patients developed minimal transient symptoms that resolved spontaneously. SDS-PAGE with patient sera suggested cross-reactivity between VO and YJ venoms at molecular weights of 39-42 kDa. Using phospholipases, antigen 5 and hyaluronidase derived from several Vespa, Dolichovespula and Vespula species, hyaluronidase is possibly accountable for inducing the allergic reaction. CONCLUSION: In the absence of commercial VO venom the practice of treating patients allergic to this insect with available commercial venoms seems to be efficacious and YJ venom is probably responsible for this effect. PMID- 23363703 TI - Stratified cancer screening: the practicalities of implementation. AB - BACKGROUND: Improving understanding of the genetic basis of disease susceptibility enables us to estimate individuals' risk of developing cancer and offer them disease prevention, including screening, stratified to reflect that risk. Little attention has so far been given to the implementation of stratified screening. This article reviews the issues that would arise in delivering such tailored approaches to prevention in practice. RESULTS: Issues analysed include the organisational context within which implementation of stratified prevention would occur, how the offer of screening would be made, making sure consent is adequately informed, how individuals' risk would be assessed, the age at which risk estimation should occur, and the potential use of genetic data for other purposes. The review also considers how management might differ depending on individuals' risk, how their results would be communicated and their follow-up arranged, and the different issues raised by modification of an existing screening programme, such as that for breast cancer, and the establishment of a new one, for example for prostate cancer. CONCLUSION: Stratified screening based on genetic testing is a radically new approach to prevention. Various organisational issues would need to be considered before it could be introduced, and a number of questions require further research. PMID- 23363702 TI - Is antidepressant-associated mania always an evidence of a bipolar spectrum disorder? A case report and review of the literature. AB - OBJECTIVE: The authors consider the clinical implications of characterizing every case of antidepressant-induced mania as evidence of an underlying bipolar diathesis. METHOD: The authors report the case of a 45-year-old man, with no personal or family history of bipolar symptoms, who developed manic symptoms after sertraline initiation for a first lifetime depressive episode. RESULTS: The patient's manic symptoms resolved rapidly with cessation of sertraline. His depressive symptoms responded to mirtazapine, and he had no further mood episodes during 2-year follow-up. DISCUSSION: It may not always be appropriate to identify selective serotonin reuptake inhibitor-induced manic symptoms as pathognomonic for the bipolar diathesis, particularly as the bipolar formulation has distinct implications for future pharmacologic choices. PMID- 23363704 TI - Role of state-dependent learning in the cognitive effects of caffeine in mice. AB - Caffeine is the most widely used psychoactive substance in the world and it is generally believed that it promotes beneficial effects on cognitive performance. However, there is also evidence suggesting that caffeine has inhibitory effects on learning and memory. Considering that caffeine may have anxiogenic effects, thus changing the emotional state of the subjects, state-dependent learning may play a role in caffeine-induced cognitive alterations. Mice were administered 20 mg/kg caffeine before training and/or before testing both in the plus-maze discriminative avoidance task (an animal model that concomitantly evaluates learning, memory, anxiety-like behaviour and general activity) and in the inhibitory avoidance task, a classic paradigm for evaluating memory in rodents. Pre-training caffeine administration did not modify learning, but produced an anxiogenic effect and impaired memory retention. While pre-test administration of caffeine did not modify retrieval on its own, the pre-test administration counteracted the memory deficit induced by the pre-training caffeine injection in both the plus-maze discriminative and inhibitory avoidance tasks. Our data demonstrate that caffeine-induced memory deficits are critically related to state dependent learning, reinforcing the importance of considering the participation of state-dependency on the interpretation of the cognitive effects of caffeine. The possible participation of caffeine-induced anxiety alterations in state dependent memory deficits is discussed. PMID- 23363706 TI - Adherence to tyrosine kinase inhibitor therapy for chronic myeloid leukemia: a Brazilian single-center cohort. AB - The introduction of oral tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes in chronic myeloid leukemia (CML) patients. However, treatment success is directly related to good long-term adherence. Adherence to TKI therapy was evaluated in 137 CML patients over a period of 1 year. Three different methods were used to evaluate adherence: the Morisky questionnaire, a medication diary and the medication possession ratio (MPR). MPR was the most effective method of assessing adherence (median adherence 96.5%; p = 0.0001), duration of TKI treatment was the variable that most impacted adherence (p = 0.03), and the MPR was inversely correlated to the duration of therapy. Additionally, participation in clinical trials, better quality of life as reported by patients and higher socioeconomic status were all related to better compliance (p = 0.02, 0.007 and 0.01, respectively). For patients treated with imatinib for 24-48 months (n = 22), individuals with major molecular response (MMR) had a significantly better MPR than those who failed to achieve MMR (p = 0.04). In this group, the mean MPR was 87% for the population without apparent molecular response and 96% for those achieving MMR; however, only 24% of the patients were completely adherent to TKI treatment. PMID- 23363705 TI - Comparative analysis of tandem repeats from hundreds of species reveals unique insights into centromere evolution. AB - BACKGROUND: Centromeres are essential for chromosome segregation, yet their DNA sequences evolve rapidly. In most animals and plants that have been studied, centromeres contain megabase-scale arrays of tandem repeats. Despite their importance, very little is known about the degree to which centromere tandem repeats share common properties between different species across different phyla. We used bioinformatic methods to identify high-copy tandem repeats from 282 species using publicly available genomic sequence and our own data. RESULTS: Our methods are compatible with all current sequencing technologies. Long Pacific Biosciences sequence reads allowed us to find tandem repeat monomers up to 1,419 bp. We assumed that the most abundant tandem repeat is the centromere DNA, which was true for most species whose centromeres have been previously characterized, suggesting this is a general property of genomes. High-copy centromere tandem repeats were found in almost all animal and plant genomes, but repeat monomers were highly variable in sequence composition and length. Furthermore, phylogenetic analysis of sequence homology showed little evidence of sequence conservation beyond approximately 50 million years of divergence. We find that despite an overall lack of sequence conservation, centromere tandem repeats from diverse species showed similar modes of evolution. CONCLUSIONS: While centromere position in most eukaryotes is epigenetically determined, our results indicate that tandem repeats are highly prevalent at centromeres of both animal and plant genomes. This suggests a functional role for such repeats, perhaps in promoting concerted evolution of centromere DNA across chromosomes. PMID- 23363707 TI - Adiponectin in eutrophic and obese children as a biomarker to predict metabolic syndrome and each of its components. AB - BACKGROUND: Obesity is associated with the rise of noncommunicable diseases worldwide. The pathophysiology behind this disease involves the increase of adipose tissue, being inversely related to adiponectin, but directly related to insulin resistance and metabolic syndrome (MetS). Therefore, this study aimed to determine the relationship between adiponectin levels with each component of MetS in eutrophic and obese Mexican children. METHODS: A cross sectional study was conducted in 190 school-age children classified as obese and 196 classified as eutrophic. Adiponectin, glucose, insulin, high density lipoprotein cholesterol (HDL-C) and triglycerides were determined from a fasting blood sample. Height, weight, waist circumference, systolic and diastolic blood pressures (BP) were measured; MetS was evaluated with the IDF definition. The study groups were divided according to tertiles of adiponectin, using the higher concentration as a reference. Linear regression analysis was used to assess the association between adiponectin and components of the MetS. Finally, stepwise forward multiple logistic regression analysis controlling for age, gender, basal HOMA-IR values and BMI was performed to determine the odds ratio of developing MetS according to adiponectin tertiles. RESULTS: Anthropometric and metabolic measurements were statistically different between eutrophic and obese children with and without MetS (P <0.001). The prevalence of MetS in obese populations was 13%. Adiponectin concentrations were 15.5 +/- 6.1, 12.0 +/- 4.8, 12.4 +/- 4.9 and 9.4 +/- 2.8 MUg/mL for eutrophic and obese subjects, obese without MetS, and obese with MetS, respectively (P <0.001). Obese children with low values of adiponectin exhibited a higher frequency of MetS components: abdominal obesity, 49%; high systolic BP, 3%; high diastolic BP, 2%; impaired fasting glucose, 17%; hypertriglyceridemia, 31%; and low HDL-C values, 42%. Adjusted odds ratio of presenting MetS according to adiponectin categories was 10.9 (95% CI 2.05; 48.16) when the first tertile was compared with the third. CONCLUSION: In this sample of eutrophic and obese Mexican children we found that adiponectin concentrations and MetS components have an inversely proportional relationship, which supports the idea that this hormone could be a biomarker for identifying individuals with risk of developing MetS. PMID- 23363709 TI - [Pay attention to translational medicine in prevention and treatment of myocardial ischemia/reperfusion injury]. PMID- 23363710 TI - [How to screen early repolarization individual with high risk of sudden cardiac death]. PMID- 23363708 TI - Cytoplasmic free Ca2+ is essential for multiple steps in malaria parasite egress from infected erythrocytes. AB - BACKGROUND: Egress of Plasmodium falciparum, from erythrocytes at the end of its asexual cycle and subsequent parasite invasion into new host cells, is responsible for parasite dissemination in the human body. The egress pathway is emerging as a coordinated multistep programme that extends in time for tens of minutes, ending with rapid parasite extrusion from erythrocytes. While the Ca2+ regulation of the invasion of P. falciparum in erythrocytes is well established, the role of Ca2+ in parasite egress is poorly understood. This study analysed the involvement of cytoplasmic free Ca2+ in infected erythrocytes during the multistep egress programme of malaria parasites. METHODS: Live-cell fluorescence microscopy was used to image parasite egress from infected erythrocytes, assessing the effect of drugs modulating Ca2+ homeostasis on the egress programme. RESULTS: A steady increase in cytoplasmic free Ca2+ is found to precede parasite egress. This increase is independent of extracellular Ca2+ for at least the last two hours of the cycle, but is dependent upon Ca2+ release from internal stores. Intracellular BAPTA chelation of Ca2+ within the last 45 minutes of the cycle inhibits egress prior to parasitophorous vacuole swelling and erythrocyte membrane poration, two characteristic morphological transformations preceding parasite egress. Inhibitors of the parasite endoplasmic reticulum (ER) Ca2+-ATPase accelerate parasite egress, indicating that Ca2+ stores within the ER are sufficient in supporting egress. Markedly accelerated egress of apparently viable parasites was achieved in mature schizonts using Ca2+ ionophore A23187. Ionophore treatment overcomes the BAPTA-induced block of parasite egress, confirming that free Ca2+ is essential in egress initiation. Ionophore treatment of immature schizonts had an adverse effect inducing parasitophorous vacuole swelling and killing the parasites within the host cell. CONCLUSIONS: The parasite egress programme requires intracellular free Ca2+ for egress initiation, vacuole swelling, and host cell cytoskeleton digestion. The evidence that parasitophorous vacuole swelling, a stage of unaffected egress, is dependent upon a rise in intracellular Ca2+ suggests a mechanism for ionophore-inducible egress and a new target for Ca2+ in the programme liberating parasites from the host cell. A regulatory pathway for egress that depends upon increases in intracellular free Ca2+ is proposed. PMID- 23363711 TI - [NADPH oxidase inhibitor apocynin attenuates ischemia/reperfusion induced myocardial injury in rats]. AB - OBJECTIVE: To explore the role of NADPH oxidase inhibitor apocynin on ischemia/reperfusion (I/R)-induced myocardial injury. METHODS: Male SD rat hearts were divided into the normal control group; sham group; I/R group (1 h ischemia followed by 3 h reperfusion); I/R + apocynin group (50 mg/kg, administrated at 30 min before reperfusion) and I/R + vehicle group (same volume vehicle administrated at 30 min before reperfusion). At the end of reperfusion, myocardial infarct size, apoptosis, plasma CK activity, myocardial NOX activity, myocardial caspase-3 expression and activity, myocardial mRNA and protein expressions of vascular peroxidase 1 (VPO1) and NOX2 were measured. RESULTS: Infarct size, ratio of cardiomyocyte apoptosis, mRNA and protein expression of VOP1 and NOX2, serum CK, myocardial NOX and caspase-3 activities in the I/R group were all significantly increased compared to those in the sham group (P < 0.01). Above parameters were similar between I/R + vehicle group and I/R group (all P > 0.05). Infarct size, ratio of cardiomyocyte apoptosis, myocardial mRNA and protein expression of VOP1 and NOX2, serum CK, myocardial NOX and caspase-3 activities were significantly lower in I/R + apocynin group compared to those in I/R group (all P < 0.01). CONCLUSIONS: NOX/VPO pathway plays an important role in mediating I/R-induced myocardial oxidative injury. NOX inhibition could reduce I/R-induced myocardial oxidative injury by attenuating myocardial apoptosis in this model. PMID- 23363712 TI - [Poly (ADP-ribose) polymerase inhibition attenuates ischemia/reperfusion induced myocardial injury in rat via reducing myocardial nuclear factor kappaB activity]. AB - OBJECTIVE: To investigate the effect of Poly (ADP-ribose) polymerase (PARP) inhibition on ischemia/reperfusion (I/R) induced myocardial injury in rat and related mechanisms. METHOD: Adult Wistar rats were randomly divided into sham control (n = 18), I/R (60 min ischemia followed by 180 min reperfusion, n = 18) and I/R + PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H) isoquinolinone (DPQ), 10 mg/kg, i.p. injection at 1 h before I/R (n = 18). Myocardial expression of PARP, infarct size, and cardiomyocytes apoptosis were determined. Additionally, myocardial NF-kappaB activity and the myocardial expressions of ICAM-1, COX-2 and MMP-9 at protein and mRNA level were detected. RESULT: (1) Myocardial expression of PARP was significantly upregulated in I/R group compared to sham-control group, which could be significantly reduced by pretreatment with DPQ (P < 0.05 vs. I/R group). (2) Infarct size [(31.45 +/- 5.54)% vs. (45.97 +/- 4.22)%] and cardiomyocytes apoptosis [(23.0 +/- 3.8)% vs. (34.0 +/- 6.2)%] were significantly reduced by pretreatment with DPQ (all P < 0.05 vs. I/R group). (3) Pretreatment with DPQ also significantly decreased the NF-kappaB activity and the myocardial expressions of ICAM-1, COX-2 and MMP-9 at both protein and mRNA level (all P < 0.05). CONCLUSION: The expression of PARP, NF-kappaB activity and the myocardial expressions of ICAM-1, COX-2 and MMP-9 are upregulated in I/R induced myocardial injury. PARP inhibitor DPQ could attenuate I/R induced myocardial injury through reducing NF-kappaB activity and the myocardial expressions of ICAM-1, COX-2 and MMP-9. PMID- 23363713 TI - [Impact of adding folic acid, vitamin B(12) and probucol to standard antihypertensive medication on plasma homocysteine and asymmetric dimethylarginine levels of essential hypertension patients]. AB - OBJECTIVE: To investigate the impact of adding folic acid, vitamin B(12) and probucol to standard antihypertensive medication on plasma homocysteine (Hcy) and asymmetric dimethylarginine (ADMA), serum NO and eNOS of essential hypertensive patients. METHOD: A total of 120 patients with hypertension were randomly divided to three groups (n = 40 each): group 1 (standard medication), group 2 (adding folic acid 5 mg/day and vitamin B(12) 500 ug twice daily) and group 3 (adding folic acid 5 mg/day and vitamin B(12) 500 ug twice daily and probucol 500 mg twice daily). Plasma Hcy and ADMA, serum NO and eNOS levels were observed at baseline, 2 and 12 weeks after various therapy. RESULTS: In group 1, concentrations of plasma Hcy [(23.06 +/- 14.15) umol/L, (23.67 +/- 12.31) umol/L, (23.25 +/- 11.64) umol/L], ADMA [(0.21 +/- 0.12) umol/L, (0.23 +/- 0.13) umol/L, (0.21 +/- 0.09) umol/L] and serum NO [(64.14 +/- 15.07) umol/L, (65.29 +/- 15.04) umol/L, (65.32 +/- 13.58) umol/L], eNOS [(20.02 +/- 4.50) ug/L, (20.79 +/- 4.03) ug/L, (19.82 +/- 5.70) ug/L] remained unchanged during the 12 weeks therapy (all P > 0.05). In group 2, concentrations of plasma Hcy [(12.54 +/- 6.49) umol/L] and ADMA[(0.18 +/- 0.07) umol/L] were significantly decreased after the treatment of 12 weeks than the treatment baseline value [(21.51 +/- 7.82) umol/L, (0.20 +/- 0.12) umol/L] and 2 weeks value[(19.38 +/- 8.14) umol/L, (0.21 +/- 0.12) umol/L], however the concentrations of serum NO and eNOS showed contrary results of the Hcy and ADMA's. (all P < 0.05). In group 3, similar changes occurred at 2 weeks after therapy (P < 0.05 2 weeks vs. baseline and 12 weeks vs. 2 weeks). Plasma ADMA level was positively correlated with Hcy at baseline (r = 0.546, P < 0.05). CONCLUSIONS: Supplementation of folic acid, VitB(12) and/or probucol helps to improve endothelial function and reduce plasma Hcy and ADMA levels in patients with hypertension. PMID- 23363714 TI - [Clinical features of five patients with delayed third degree atrioventricular block after ethanol septal ablation for hypertrophic obstructive cardiomyopathy]. AB - OBJECTIVE: To analyze the clinical features of patients with delayed third degree atrioventricular block after ethanol septal ablation for hypertrophic obstructive cardiomyopathy. METHOD: The clinical data of cases with delayed third degree atrioventricular block after septal ablation for hypertrophic obstructive cardiomyopathy at our hospital from 2000 to 2011 were collected. RESULT: Five out of 235 patients (2.1%) developed delayed third degree atrioventricular block. Delayed third atrioventricular block occurred at 32 h post ablation (28 - 120 h). Their average age is 46 (33 - 64) years old, there are 4 males and 1 female. Left ventricular outflow gradient before ablation was 70 - 100 mm Hg (1 mm Hg = 0.133 kPa). Intraprocedural third degree atrioventricular block occurred in 4 patients. The average injected dose of Ethanol was 1.8 (1.4 - 4.3) ml. Syncope occurred in 3 patients. Temporary pacemaker was reimplanted to all 5 patients and removed after an average of 8 d (3 - 18 d). All 5 patients were in normal sinus rhythms at discharge without the need of implanting permanent pacemaker. There was no syncope in these 5 patients after discharge during the telephone follow up for an average of 9 (1 - 72) months. CONCLUSION: The incidence of delayed third degree atrioventricular block after septal ablation is rare. Prolonged electrocardiography monitoring and prophylactic temporary pacemaker backup post ablation are necessary to detect this event and to prevent syncope related to delayed third degree atrioventricular block after septal ablation. PMID- 23363715 TI - [Clinical and cardiac imaging characteristics of patients with left ventricular apical hypoplasia]. AB - OBJECTIVE: To analyze the clinical and cardiac imaging characteristics of patients with left ventricular apical hypoplasia (LVAH). METHODS: From January 2008 to January 2012, seven patients [3 male/4 female, age: 6 - 44 (19.9 +/- 14.2) years] with LVAH were included in this cohort. Transthoracic echocardiogram was performed in all patients, cardiovascular MRI was performed in 3 patients and cardiovascular CT in another 2 patients. In addition, one LVAH patient underwent cardiac catheterization and angiography examination. RESULTS: Four out of 7 patients complained chest discomfort. Precordial murmur was heard in 3 patients. Atrial fibrillation was evidenced by electrocardiogram in 3 patients. Left ventricular end-diastolic diameter [(57.9 +/- 11.6) mm] increased while left ventricule (LV) longitudinal diameter reduced in all patients. Left ventricular systolic function was reduced in 2 patients and mean LVEF was (47.6 +/- 17.2)%. The interventricular septum bulged towards the right, and the ventricular septum thickness was (7.3 +/- 1.2) mm. The papillary muscles were dominant on the flattened LV anteroapical region. The right ventricle elongated and wrapped around the hypoplastic left ventricular apex, and the dimension of right ventricle was (19.7 +/- 7.6) mm. Focal fat replacement of the left ventricular apical wall was evidenced in 5 patients underwent cardiovascular MRI or CT examinations. CONCLUSIONS: Clinical symptoms are non-specific in LVAH patients. Truncated and spherical LV, abnormal origin of papillary muscles in the flattened LV anterior apex and an elongated right ventricle wrapping around the LV apex as well as focal fat replacement of the left ventricular apical wall are typical imaging characteristics of LVAH. PMID- 23363716 TI - [Impact of attack frequency and therapy strategies on outcome of patients with vasovagal syncope]. AB - OBJECTIVE: To analyze the impact of attack frequency as well as therapy strategies on outcome of patients with vasovagal syncope (VVS). METHODS: A total of 159 patients (aged from 15 - 59 years old) with VVS were included in this study. Patients were divided into low frequency (< 3) group (n = 95) and high (>= 3) frequency group (n = 64) according to the attack frequency in the past 5 years at the primary survey. Patients received one of the three therapies: no treatment, physical therapy, and comprehensive treatment. All cases were followed up with telephone or outpatient visit for 24 months. RESULTS: Incidence of syncope was significantly higher in the high frequency group and in the low frequency group [40.6% (26/64) vs. 11.6% (11/95), P < 0.01]. The overall improvement rate was significantly higher in the low frequency group than that of high frequency group (P < 0.01). Improvement rate was significantly higher in the physical therapy subgroup and the comprehensive treatment subgroup than no treatment subgroup for patients with low attack frequency [81.8% (27/33) vs. 47.1% (8/17), P < 0.05; 82.2% (37/45) vs. 47.1% (8/17), P < 0.05], and in comprehensive treatment subgroup than in physical therapy subgroups observed between and [62.2% (28/45) vs. 31.6% (6/19), P < 0.05] for patients with high attack frequency. CONCLUSION: Outcome is related to previous attack frequency for patients with VVS, physical therapy is effective for reducing the recurrence rate of syncope in VVS patients with low attack frequency while physical therapy combined with pharmacotherapy should be applied for VVS patients with high attack frequency to improve outcome. PMID- 23363717 TI - [One-stop hybrid cardiac surgery for adults with complex heart disease]. AB - OBJECTIVE: To evaluate the efficacy and security of one-stop hybrid cardiac surgery for the treatment of adult patients with complex heart disease. METHODS: From November 2011 to March 2012, a total of 5 patients [4 male, mean age: (58.8 +/- 14.7) years] underwent one-stop hybrid approach in the hybrid operating room. Two patients suffered from multi-coronary lesions, 2 patients were diagnosed with both valvular heart disease and coronary disease, and another 1 patient had valve disease and congenital heart disease (patent ductus arteriosus). Minimally invasive cardiac surgery (coronary artery bypass grafting for the left anterior descending or valvular surgery) and percutaneous intervention were performed in an enhanced operative unit. The efficacy and security of one-stop hybrid cardiac surgery were evaluated after the procedure. RESULTS: The one-stop hybrid procedure was successful in all patients. Left internal mammary artery grafts were unobstructed. A total of 6 non-left anterior descending coronary lesions were treated by percutaneous coronary intervention and 6 drug-eluting stents were implanted. There was no death, perioperative myocardial infarction, heart failure, prosthetic valve dysfunction, respiratory failure, stroke or repeat surgery during the procedure period. All patients remained free from angina, prosthetic valve dysfunction and patent ductus arteriosus recanalisation during the 3.2 months (rang 1 to 5 months) follow-up period. CONCLUSION: One-stop hybrid cardiac surgery provides a reasonable, feasible and safe alternative for treating adult patients with complex heart disease. PMID- 23363718 TI - [Association between genetic polymorphism of the six-transmembrane protein of prostate 2 and obesity in Uygur]. AB - OBJECTIVE: To investigate the association between genetic variations of the six transmembrane protein of prostate 2 (STAMP2) and obesity in Xinjiang Uygur population. METHODS: A total of 2332 Uygur subjects (1455 obesity and 877 non obesity control subjects) were included in this case-control study based on epidemiological survey. Genetic variations of STAMP2 gene functional region were sequenced. The representative variations selected were genotyped by TaqMan-PCR method. RESULTS: Twenty genetic variations, including 14 novel variations, were identified. The genotype distributions of the control group and obesity group were in the Hardy-Weinberg equilibrium (both P > 0.05). The frequency of AA of rs1981529 (67.6% vs. 62.8%, P < 0.05) and the frequency of G-A-G haplotype (62.4% vs. 58.9%, P < 0.05) in obesity group were significantly higher than that in controls while the frequency of A-G-G haplotype was significantly lower in the obesity patients than that in the control group (17% vs. 20%, P < 0.05). After adjusting age, sex, smoking and drinking, logistic regression analysis showed that the AA genotype of rs1981529 (OR: 1.276, 95%CI: 1.049 - 1.552; P < 0.05) and the G-A-G haplotype (OR: 1.356, 95%CI: 1.007 - 1.862, P < 0.05) were the independent risk factors for obesity in this cohort. CONCLUSION: The AA genotype of rs1981529 and G-A-G haplotype are associated with obesity in Uygur population of Xinjiang. PMID- 23363719 TI - [Association between gene polymorphisms of methylenetetrahydrofolate reductase and plasma homocysteine in Uygur patients with venous thromboembolism]. AB - OBJECTIVE: To investigate methylenetetrahydrofolate reductase (MTHFR) gene C677T mutation and plasma homocysteine (Hcy) levels in Uygur patients with venous thromboembolism (VTE) in Xinjiang. METHODS: A total of 222 VTE patients including 74 Uygur and 148 Han ethnic patients were examined, and 86 Uygur ethnic and Han 134 ethnic healthy people were included as controls. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was applied to detect MTHFR gene C677T polymorphism and plasma Hcy levels were measured by fluorescence polarization immunoassay. RESULTS: The MTHFR gene C677T genotypes distribution in Uygur VTE patients and control groups were: TT [28.38% (35/86) vs. 12.79% (11/86), P < 0.05], CT [41.89% (31/74) vs. 52.33% (45/86), P > 0.05]and CC [29.73% (22/74) vs. 34.88% (30/86), P > 0.05], respectively; and in Han VTE patients and control groups were: TT[27.03% (40/148) vs. 14.92% (20/134), P < 0.05], CT [44.59% (66/148) vs. 52.99% (71/134), P > 0.05] and CC [28.38% (42/148) vs. 32.09% (43/134), P > 0.05], respectively. SNP genotyping distribution frequency in Uygur and Han ethnic population was similar between controls and between VTE patients (P > 0.05). Plasma levels of Hcy in MTHFR gene TT genotype were statistically higher than CT and CC genotype (P < 0.05). After adjusting for age, gender, smoking history, hyperlipidemia, hypertension, diabetes, and MTHFR genotype, multifactor logistic regression analysis showed that plasma Hcy level (OR = 1.025, 95%CI 1.003 - 1.046, P = 0.024) and obesity (OR = 4.660, 95%CI 1.417 - 15.324, P = 0.011) were independent risk factors for Uygur ethnic patients with VTE while plasma Hcy level (OR = 1.020, 95%CI 1.006 - 1.034, P = 0.004) and smoking (OR = 2.867, 95%CI 1.062 - 6.586, P = 0.024) were independent risk factors for Han ethnic patients with VTE. CONCLUSION: MTHFR C677T polymorphism (TT genotype carrier) and increased plasma levels of Hcy are risk factors for Uygur and Han ethnic patients with VTE in Xinjiang. PMID- 23363720 TI - [Impact of multifactor intensive intervention on self management, risk factor control and outcome of post percutaneous transluminal coronary intervention patients]. AB - OBJECTIVE: To test the efficacy of multifactor intensive intervention for post percutaneous transluminal coronary intervention (post-PCI) outpatients on self management, risk factor control and outcome. METHODS: A total of 263 patients with coronary heart disease (CAD) discharged from our cardiac center were randomized into usual care (4 CAD lectures focusing on the 2(nd) CAD prevention and patients-oriented outpatient visit) and intensive intervention (4 CAD lectures focusing on the 2(nd) CAD prevention, CAD outpatient visit twice a month, monthly telephone instructions on risk factor control and optimal medication). Patients were followed for 12 months and 250 patients completed follow-up. RESULTS: There were more patients achieved a LDL-C level of less than 2.6 mmol/L in intensive intervention group than in usual care group (71.2% vs. 48.3%, P < 0.01). The percentages of patients taking dietary control (55.3% vs. 26.2%, P < 0.01) and physical exercises (64.4% vs. 39.0%, P < 0.01), receiving beta-adrenergic receptor blocker (75.0% vs. 50.8%, P < 0.01) and statins (72.0% vs. 54.2%, P < 0.01) were significantly higher while cardiovascular event rate (5.9% vs. 0%, P = 0.005)was significantly lower in intensive intervention group than in usual care group. CONCLUSION: Multifactor intensive intervention is helpful on improving the second prevention for post-PCI coronary heart disease patients. PMID- 23363721 TI - [Pharmacokinetics and bioequivalence of domestic trimetazidine formulations]. AB - OBJECTIVE: To compare the pharmacokinetics and bioequivalence between domestic hydrochloric trimetazidine capsules and imported hydrochloric trimetazidine tablets in healthy male Chinese volunteers after single oral administration. METHODS: A single oral dose (test and reference formulations) was given to 24 healthy male Chinese subjects according to an open randomized crossover design. The blood samples were collected before and after administration. Plasma trimetazidine concentration was determined by HPLC-MS/MS. The pharmacokinetic parameters were calculated by WinNonlin Ver 6.2.1 software. RESULTS: The main pharmacokinetic parameters of domestic and imported formulation of trimetazidine were similar: C(max) (70.9 +/- 15.3), (66.4 +/- 13.8) ug/ml; t(max) (1.70 +/- 0.72), (1.85 +/- 0.55) h; t(1/2z) (4.70 +/- 1.75), (4.77 +/- 1.96) h; AUC(0-24 h) (481 +/- 176), (469 +/- 171) ug*h*ml(-1); AUC(0-infinity) (511 +/- 189), (500 +/- 188) ug*h*ml(-1). The estimated 90% CIs for the ratio of C(max) and AUC(0-24 h) were also similar: 101.9% - 112.5% and 99.4% - 104.9%. The relative bioavailability of domestic formulation was (102.2 +/- 8.3)%. CONCLUSION: The results demonstrates that the domestic hydrochloric trimetazidine capsules and imported hydrochloric trimetazidine tablets are bioequivalent. PMID- 23363722 TI - [Mesenchymal stem cells implantation increases the myofibroblasts congregating in infarct region in a rat model of myocardial infarction]. AB - OBJECTIVE: To investigate the modulation effects of mesenchymal stem cells (MSC) implantation on the myofibroblasts congregating in the infarct region after myocardial infarction (MI). METHODS: MI was induced in SD rats by left anterior descending coronary artery ligation, and the experimental animals were assigned randomly into the sham group, MI + PBS group and MI + MSC group (myocardial injection of 0.1 ml 2*10(7)/ml in four locations in the infarct region). Echocardiography, hemodynamic examinations and Masson trichrome staining were performed. Implanted MSC differentiation and myofibroblasts congregating in infarct region were investigated by immunofluorescence staining. TGF-beta(1) Smad2 signaling pathway was examined by real-time RT-PCR and Western blot. RESULTS: (1) Four weeks late, heart-weight/body-weight ratio [(3.04 +/- 0.16) mg/g vs. (3.34 +/- 0.14) mg/g, P < 0.01] and myocardial infarction size [(38.72 +/- 2.38)% vs. (46.36 +/- 2.81)%, P < 0.01] were significantly reduced in MI + MSC group than in MI + PBS group, while scar thickness of infarct region was thicker [(0.93 +/- 0.17) mm vs. (0.65 +/- 0.16) mm, P = 0.01], and LVEF was higher [LVEF: (32.5 +/- 5.9)% vs. (26.5 +/- 4.5)%, P = 0.03] in MI + MSC group than in MI + PBS group. (2) Myofibroblasts congregating in the infarct region was significantly enhanced in MI + MSC group compared with MI + PBS group [(196 +/- 20) cells/mm(2) vs. (89 +/- 25) cells/mm(2), P < 0.01], and part of implanted MSC expressed alpha-SMA(+). (3) TGF-beta(1) expression and the phosphorylating of Smad2 in the infarct region were significantly upregulated in MI + MSC group compared with MI + PBS group (all P < 0.05). CONCLUSIONS: MSC could improve myocardial function and promote myofibroblasts congregating in the infarct region via activating the TGF-beta(1)-Smad2 signaling pathway in this model. PMID- 23363723 TI - [Atorvastatin attenuates parathyroid hormone 1-34 induced cardiomyocytes hypertrophy through downregulating K-Ras-ERK1/2 pathway]. AB - OBJECTIVE: To investigate the effects of atorvastatin on parathyroid hormone 1-34 (PTH1-34) induced neonatal rat cardiomyocytes hypertrophy and on the expression changes of small GTP-binding protein (K-Ras) and extracellular signal regulated protein kinases 1/2 (ERK1/2). METHODS: Neonatal rat cardiomyocytes hypertrophy was established with 10(-7) mol/L rPTH1-34 in the presence or absence of 10(-5) mol/L atorvastatin or 10(-4) mol/L mevalonic acid (MVA). Cardiomyocyte diameter was measured by Motic Images Advanced 3.0 software, the synthetic rate of protein in cardiomyocytes was determined by (3)H-leucine incorporation and single-cell protein content was measured by BCA. The concentration of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were determined by ELISA. Protein expression of ERK1/2, p-ERK1/2 and K-Ras was detected by Western blot. RESULTS: Compared to PTH1-34 group, cellular diameter was decreased 12.07 um, (3)H-leucine incorporation decreased 1622 cpm/well and single-cell protein content decreased 84.34 pg, ANP or BNP concentration reduced 7.13 ug/L or 20.04 ug/L, protein expression of K-Ras, ERK1/2 or p-ERK1/2 downregulated 0.81, 0.19 and 1.44 fold, respectively, in PTH1-34 plus atrovastatin co-treated cardiomyocytes (all P < 0.05). Compared to PTH1-34 plus atrovastatin co-treated group, cardiomyocyte diameter increased 4.95 um, (3)H-leucine incorporation increased 750 cpm/well and single-cell protein content increased 49.08 pg, ANP or BNP increased 3.12 ug/L or 9.35 ug/L and protein expression of K-Ras, ERK1/2 or p ERK1/2 upregulated 0.52, 0.06 and 1.19 fold (all P < 0.05) in MVA, PTH1-34 and atrovastatin co-treated cardiomyocytes. CONCLUSIONS: Atrovastatin attenuates PTH1 34 induced neonatal rat cardiomyocytes hypertrophy through downregulating K-Ras and ERK1/2 pathway. PMID- 23363724 TI - [Interleukin-8 monoclonal antibody attenuates smooth muscle cell proliferation and balloon inflation-induced abdominal aorta stenosis in rabbits]. AB - OBJECTIVE: To observe the effects of interleukin-8 monoclonal antibody on smooth muscle cell proliferation and balloon inflation-induced abdominal aorta stenosis in rabbits. METHODS: Thirty-six New Zealand white rabbits were randomly assigned to balloon inflation group (group A, n = 12), interleukin-8 monoclonal antibody pre-treated rabbits (2 mg/kg for 3 days before balloon inflation, group B, n = 12) and sham-operated control group (group C, n = 12). Peripheral blood was collected before experiment and at 4 h, 1, 3, 7, 14, and 28 days post balloon inflation or sham operation and the levels of IL-8 were measured by enzyme linked immunosorbent assay (ELISA). The ratio of positive and negative masculine cells in the high power microscopic field was determined in proliferating cell nuclear antigen (PCNA) stained slide. Histopathologic examination was performed in abdominal aorta and luminal area, intima and tunica media area were measured. RESULTS: Plasma interleukin-8 began to rise at 4 h and peaked at 1 day and remained increased up to 28 days after balloon inflation in rabbits of group A, plasma interleukin-8 level in group A was significantly higher than in group B and C at 4 h and thereafter post operation. The ratio of positive and negative masculine cells was significantly increased in group A compared to group C and was significantly lower in group B than in group A. Abdominal aorta stenosis, luminal area, intima and tunica media area were significantly reduced in group B than in group A. Correlation analysis indicated that there were positive relations between plasma IL-8 level and intima thickness, area of intima and tunica media, respectively (r = 0.894, 0.783, 0.801, 0.912, all P < 0.01). CONCLUSIONS: Plasma IL-8 level is increased in this abdominal aorta stenosis model and is positively correlated to the severity of abdominal aorta stenosis. IL-8 monoclonal antibody could significantly reduce abdominal aorta stenosis in this abdominal aorta stenosis model. PMID- 23363725 TI - [One case of haemolysis after transcatheter closure of atrial septal defect]. PMID- 23363726 TI - [Research advances in midventricular hypertrophic obstructive cardiomyopathy]. PMID- 23363727 TI - [Progress of liver X receptor research in basic cardiovascular science]. PMID- 23363728 TI - [A case report of anti-thrombotic drug induced acute thrombocytopenia]. PMID- 23363729 TI - Development of a practical ultrasonic approach for simultaneous measurement of the thickness and the sound speed in human skull bones: a laboratory phantom study. AB - The availability of a non-invasive express method for the in vivo measurement of both sound velocity and thickness of the human skull bone would be of great benefit to various transcranial ultrasonic imaging and treatment applications. This paper investigates two ultrasonic methods that measure both parameters and are based on the variable focus technique. All the experiments described in this paper were conducted on specially prepared custom skull bone phantoms, including flat and deformed samples, designed and developed in our laboratory. The first method uses a single immersion 2.25 MHz ultrasonic transducer consecutively focused on the front and back surfaces of the sample. The accuracy and precision of this method are demonstrated via single point measurements on flat samples with and without porosity. The measurement results from a specimen with the randomly curved back surface show the possibility of obtaining the inner profile of the skull bone. The second presented method is a practical modification of the variable focus technique for the linear phased array case. The method was tested on flat and curved skull bone phantoms with and without inner porosity showing higher measurement accuracy and simpler practical realization than its scanning counterpart. PMID- 23363730 TI - New year address on the state of psychosomatic medicine in Japan. PMID- 23363731 TI - Naloxone blocks the deterioration of male sexual behavior induced by alarm pheromone in rats. AB - Previously, we have demonstrated that the alarm pheromone deteriorates sexual behavior in male rats, which was blocked by pretreatment with a corticotrophin releasing hormone (CRH) antagonist. Studies have shown that an opioid antagonist blocked the deterioration of male sexual behavior following intracerebroventricular administration of CRH. Therefore, possibly, the pheromone effects could also be mediated by the opioid system. In this study, we pretreated rats with naloxone, an opioid receptor antagonist, and examined the following sexual behavior modulations in male rats that were exposed to the alarm pheromone. Naloxone blocked the deterioration of sexual behavior in a dose dependent manner. On the basis of these data and the results of the previous study, we conclude that the alarm pheromone activates the CRH system, which then activates the opioid system, to deteriorate male sexual behavior. PMID- 23363732 TI - Incidental genetic findings in randomized clinical trials: recommendations from the Genomics and Randomized Trials Network (GARNET). AB - Recommendations and guidance on how to handle the return of genetic results to patients have offered limited insight into how to approach incidental genetic findings in the context of clinical trials. This paper provides the Genomics and Randomized Trials Network (GARNET) recommendations on incidental genetic findings in the context of clinical trials, and discusses the ethical and practical issues considered in formulating our recommendations. There are arguments in support of as well as against returning incidental genetic findings in clinical trials. For instance, reporting incidental findings in clinical trials may improve the investigator-participant relationship and the satisfaction of participation, but it may also blur the line between clinical care and research. The issues of whether and how to return incidental genetic findings, including the costs of doing so, should be considered when developing clinical trial protocols. Once decided, plans related to sharing individual results from the aim(s) of the trial, as well as incidental findings, should be discussed explicitly in the consent form. Institutional Review Boards (IRBs) and other study-specific governing bodies should be part of the decision as to if, when, and how to return incidental findings, including when plans in this regard are being reconsidered. PMID- 23363733 TI - Breaking Haller's rule: brain-body size isometry in a minute parasitic wasp. AB - Throughout the animal kingdom, Haller's rule holds that smaller individuals have larger brains relative to their body than larger-bodied individuals. Such brain body size allometry is documented for all animals studied to date, ranging from small ants to the largest mammals. However, through experimental induction of natural variation in body size, and 3-D reconstruction of brain and body volume, we here show an isometric brain-body size relationship in adults of one of the smallest insect species on Earth, the parasitic wasp Trichogramma evanescens. The relative brain volume constitutes on average 8.2% of the total body volume. Brain body size isometry may be typical for the smallest species with a rich behavioural and cognitive repertoire: a further increase in expensive brain tissue relative to body size would be too costly in terms of energy expenditure. This novel brain scaling strategy suggests a hitherto unknown flexibility in neuronal architecture and brain modularity. PMID- 23363734 TI - Economic analyses to support decisions about HPV vaccination in low- and middle income countries: a consensus report and guide for analysts. AB - Low- and middle-income countries need to consider economic issues such as cost effectiveness, affordability and sustainability before introducing a program for human papillomavirus (HPV) vaccination. However, many such countries lack the technical capacity and data to conduct their own analyses. Analysts informing policy decisions should address the following questions: 1) Is an economic analysis needed? 2) Should analyses address costs, epidemiological outcomes, or both? 3) If costs are considered, what sort of analysis is needed? 4) If outcomes are considered, what sort of model should be used? 5) How complex should the analysis be? 6) How should uncertainty be captured? 7) How should model results be communicated? Selecting the appropriate analysis is essential to ensure that all the important features of the decision problem are correctly represented, but that the analyses are not more complex than necessary. This report describes the consensus of an expert group convened by the World Health Organization, prioritizing key issues to be addressed when considering economic analyses to support HPV vaccine introduction in these countries. PMID- 23363736 TI - Mild asthma and chronic bronchitis seem to influence functional exercise capacity: a multi-case control study. AB - BACKGROUND: In the Genes Environment Interaction in Respiratory Diseases population-based multi-case control study, we investigated whether asthma, chronic bronchitis (CB) and rhinitis were associated with a reduced 6-minute walk distance (6MWD), and whether the 6MWD determinants were similar for subjects with/without respiratory diseases. METHODS: Cases of asthma (n = 360), CB (n = 120), rhinitis (n = 203) and controls (no respiratory diseases: n = 302) were recruited. The variation in the 6MWD across the groups was analyzed by ANCOVA, adjusting for gender, age, height, weight and comorbidity. The 6MWD determinants were studied by linear regression, and heterogeneity across the cases and controls was investigated. RESULTS: The 6MWD differed across cases and controls (p = 0.01). It was shorter for cases of asthma (-17.1, 95% CI -28.3 to -5.8 m) and CB (-20.7, 95% CI: -36.6 to -4.8 m) than for controls (604 +/- 68 m on average), but not for cases of rhinitis. The negative association between age and the 6MWD was significant for cases of CB, but not for the other groups (p = 0.001). CONCLUSIONS: Even at the level of severity found in the general population, asthma and CB could influence the 6MWD, which seems to reflect the functional exercise level for daily physical activities. The negative association between ageing and the 6MWD was particularly strong in subjects with CB. Our report adds to the mounting evidence that CB is not a trivial condition, especially in the ageing adult population, and it supports the importance of monitoring functional capacity and of physical reconditioning in mild asthma. PMID- 23363737 TI - Management of atmospheric pollutants from waste incineration processes: the case of Bozen. AB - This article presents the case study of a waste incinerator located in a region rich in natural and environmental resources, and close to the city of Bozen, where there are about 100,000 inhabitants. Local authorities paid special attention to the effect of the plant on human health and the surrounding environment. Indeed, among the measures adopted to control the emissions, in 2003 an automatic sampling system was installed specifically to monitor polychlorinated dibenzo-p-dioxin and polychlorinated dibenzofuran (PCDD/F) emissions during the complete operation time of the plant. The continuous sampling system was coupled directly to aerosol spectrometers for the determination of fine and ultra-fine particles in the emissions of the plant. The measurement results suggest that the waste incineration plant of Bozen is not a significant source of PCDD/F, or fine and ultra-fine particles. Immission measurements from other monitoring systems confirmed these results. PMID- 23363738 TI - Combination treatment of epilepsy with ketogenic diet and concurrent pharmacological inhibition of cytochrome P450 2E1. AB - While most epileptic patients respond to treatment with existing antiepileptic drugs, there remains a considerable number of patients in whom these drugs do not suffice. Such patients, particularly children, are often treated using the ketogenic diet. This diet imposes a strict limit on carbohydrates; while providing for adequate protein, most of the calories are supplied as triacylglycerol, much of which is metabolized to ketone bodies. Animal experiments have provided evidence that the anticonvulsant effect of the ketogenic diet is mediated by acetone and correlates with blood acetone levels. Acetone can be converted in vivo to glucose via acetol and pyruvate; the initial conversion to acetol is catalyzed by cytochrome P450 2E1 (CYP2E1). When CYP2E1 knockout mice are subjected to starvation to induce ketogenesis, they develop blood acetone levels much higher than those observed in wild-type mice. Similarly, pharmacological inhibition of CYP2E1 significantly increases blood acetone levels in rat and man. Taken together, these observations suggest that pharmacological inhibition of CYP2E1 has the potential to significantly increase the antiepileptic effect of the ketogenic diet. With patients that respond insufficiently to the diet alone, increased acetone levels may improve response. With patients who respond sufficiently to the diet, CYP2E1 inhibitors might allow a relaxation of the fairly severe diet regimen and so improve compliance and quality of life. An existing inhibitor of CYP2E1 is the drug disulfiram. This drug also inhibits the enzyme aldehyde dehydrogenase, which functions in alcohol degradation, and in this capacity has long been used in the treatment of alcohol addiction. Disulfiram inhibits CYP2E1 at conventional therapeutic dosages and increases blood acetone levels in humans and animals. It should therefore be a viable candidate for the proposed drug/diet combination treatment. PMID- 23363735 TI - Multi-modality: a new approach for the treatment of major depressive disorder. AB - Effective treatment with antidepressants is currently limited by factors that affect treatment compliance, including delay in onset of therapeutic effects and intolerable side-effects. Recent data suggest that use of antidepressant combinations with different mechanisms of action may be a better first-line strategy prior to augmentation with other drug classes. The rationale for this approach is that combining multiple pharmacological actions affecting multiple monoamine targets produces greater efficacy. Several new multi-modal compounds are in development and early results for the most advanced agents indicate shorter onset of therapeutic effects and improved tolerability. By modulating multiple receptors and transmitter systems, it is hoped that these new agents may also treat some of the associated symptoms of major depressive disorder, such as anxiety and cognitive dysfunction. PMID- 23363739 TI - Inhibitory effects and specificity of synthetic sialyldendrimers toward recombinant human cytosolic sialidase 2 (NEU2). AB - Human sialidase 2 (NEU2) is a cytoplasmic sialidase that degrades sialylglycoconjugates, including glycoproteins and gangliosides, via hydrolysis of terminal sialic acids to produce asialo-type molecules. Here, we first report the inhibitory effects of a series of synthetic sialyldendrimers comprising three types [Dumbbell(1)6-S-Neu5Ac(6), Fan(0)3-S-Neu5Ac(3) and Ball(0)4-S-NeuAc(4)] toward recombinant human NEU2 in vitro. Among them, Dumbbell(1)6-S-Neu5Ac(6) exhibited the most potent inhibitory activity (concentration causing 50% inhibition (IC(50)), 0.4 ~ 0.5 mM). In addition, NeuSLac and NeuSCel carrying thiosialyltrisaccharide moieties exhibited more potent inhibitory effects than NeuSGal and NeuSGlc carrying thiosialyldisaccharides. Docking models composed of NEU2 and the thiosialyloligosaccharide suggested that the active pocket of NEU2 prefers the second galactose-beta (Galbeta) to the glucose-beta (Glcbeta) residue in the trisaccharide structure, there being a hydrogen bond between the 4-hydroxy group of the second Galbeta and the side chain of the D46 residue of NEU2. The third Glcbeta residues of NeuSLac and NeuSCel were also predicted to be stabilized by hydrogen bonds with the side chains of the R21, R304, D358 and Y359 residues of NEU2. NEU2 mutants (D358A and Y359A) exhibited reduced affinity for NeuSLac carrying thiosialyltrisaccharide moieties, suggesting the significant roles of D358 and Y359 residues in recognition of thiosialyltrisaccharide moieties of NeuSLac bound in the active pocket of NEU2. Thus, the present sialyldendrimers could be utilized not only as a new class of NEU2 inhibitors but also as molecular probes for evaluating the biological functions of NEU2, including the catalytic activity and mechanism as to natural substrates carrying sialyloligosaccharides. PMID- 23363741 TI - Two methods to generate templates for template-based partial volume effect correction: SPECT phantom experiments. AB - In this paper, we explore the applicability of template-based compensation for the partial volume effect (PVE) for situations where (i) the image has multiple uptake sites (tumors and organs) but only one of them is treated as a region of interest (ROI) with the boundaries available from a high-resolution modality and (ii) no information regarding activities inside or outside this ROI is a priori available. We modeled this situation by performing SPECT acquisitions of phantoms containing 21 containers, which had different shapes and sizes and were filled with different levels of activity. In our analysis, each of these containers was treated as an individual ROI. We compared the performance of two methods of template construction. In method 1, the ROI template value was obtained from a conventionally reconstructed (without PVEC) image. In method 2, the ROI template value was directly (bypassing the PVE-affected conventional image) calculated from projections using region-based reconstruction. Our processing shows that method 1 resulted in consistent (activities for all 21 ROIs were improved) but relatively weak PVE compensation (errors of recovered total activities were equal to or lower than 10% for 5 ROIs only). Application of method 2 resulted in a selective (activities for 19 ROIs were improved) but considerably better compensation when compared to method 1 (errors of recovered total activities were equal to or lower than 10% for 10 ROIs). PMID- 23363740 TI - Advanced mass spectrometry and chemical analyses reveal the presence of terminal disialyl motif on mouse B-cell glycoproteins. AB - The occurrence of a terminal disialyl motif on mammalian O-glycans is increasingly being identified through recent mass spectrometry (MS)-based glycomic profiling. In most cases, it is carried on simple core 1 structures in which both the galactose and N-acetyl galactosamine can be disialylated. In contrast, a disialyl motif on N-glycans is less readily revealed by MS mapping, since additional MS/MS analysis is required to determine the distribution of the various sialic acids on typically multisialylated complex type N-glycans. In our MS-based glycomic screening, we found that a mouse B lymphoma cell line, BCL1, ranks among those that have the highest amount of disialyl motif on its O glycans, including those carried on CD45. More intriguingly, detailed chemical and MS/MS analyses unambiguously showed that the Neu5Gcalpha2-8Neu5Gc disialyl motif is also present on the N-glycans and that it can be carried on the termini of polylactosaminoglycan chains, which can be further sulfated on the proximal GlcNAc, occurring alongside other monosialylated sulfated LacNAc termini. Upon silencing the expression of mouse alpha2,8-sialyltransferase VI (ST8Sia VI), the overall disialyl content decreases significantly, but more so for that on the N glycans than the O-glycans. ST8Sia VI was further shown to be the most significantly upregulated ST8Sia during plasma cell differentiation, which coincides with increasing content of the disialyl motif. Increasing terminal disialylation without leading to polysialylation may thus have important biological consequences awaiting further investigation. Likewise, the expression of mono- and disialylated sulfated LacNAc may constitute novel recognition codes modulating B-cell activation and differentiation. PMID- 23363742 TI - [Study on efficiency and safety of dasatinib in Chinese patients with chronic myelogenous leukemia who are resistant or intolerant to imatinib]. AB - OBJECTIVE: To evaluate the efficiency and safety of dasatinib in Chinese patients (pts) with chronic myelogenous leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast-phase (BP) who are resistant or intolerant to imatinib (IM). METHODS: 119 CML pts received dasatinib 100 mg once daily for pts in CP or 70 mg twice daily for pts in AP/BP. The hematologic/cytogenetic response, progression free-survival (PFS), overall survival (OS) and adverse effects (AE) of the pts were assessed. RESULTS: 59 pts in CP, 25 in AP and 35 in BP received dasatinib treatment. The median duration of dasatinib treatment were 19.32, 20.99 and 3.22 months respectively. Complete hematologic response (CHR), major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were achieved by 91.5%, 50.8% and 42.4% of pts in CP respectively. The median times to achieving MCyR was 12.1 weeks. None of the pts in CP achieved MCyR progressed or died till to last follow-up. CHR and major hematologic response (MaHR) were achieved by 52.0% and 84.0% of pts in AP, respectively. The median time to CHR and MaHR were 16.0 and 12.1 weeks, respectively. 10 pts in AP achieved MCyR and 9 of them were CCyR. The median duration of PFS was 25.7 months for pts in AP. For 35 pts in BP, the rates of CHR and MaHR were 17.1% and 31.4% respectively. Both of the median time to CHR and MaHR were 12.1 weeks and median time of duration of MaHR was 11.2 months. 8 pts in BP achieved MCyR and the median time of duration of MCyR was 13.2 months. The median duration of PFS and OS for the pts in BP were 4.3 and 16.7 months respectively. Grade 3-4 of hematologic AEs related to dasatinib were frequent but manageable by dose interruption/reduction or supportive care. 52.5% and 61.0% of pts in CP experienced grade 3-4 of neutropenia and thrombocytopenia. More than 80% pts in AP/BP occurred grade 3-4 cytopenia. The common non-hematologic AEs related to dasatinib were including grade 1-2 pleural effusion, headache, pneumonia and diarrhea. The frequency of non-hematologic AE was higher in pts with AP/BP than in pts with CP. CONCLUSION: Chinese pts with CML resistant or intolerant to IM treated by dasatinib can achieve relatively sustained hematologic and even cytogenetic remission and are well tolerated. PMID- 23363744 TI - [An epidemiological investigation of adult acute leukemia in Fujian Province in 2010]. AB - OBJECTIVE: To investigate the current incidence of adult acute leukemia (AL) in Fujian Province, and to analyze possible risk factors for adult AL (AAL) in order to provide basic data of preventive intervention for AAL patients of Fujian Province. METHODS: A collaborative group was established and the identical registration forms were filled in by the group of the hospitals. The incidence of newly diagnosed AAL (>= 14-year-old) in 2010 were analyzed retrospectively. RESULTS: (1) 759 new cases of AL were diagnosed in 2010 in Fujian Province. The annual incidence of AL was 2.057/10(5), among which acute myeloid leukemia (AML)?[except acute promyelocytic leukemia (APL)?] was 1.179/10(5), acute lymphoblastic leukemia (ALL) was 0.569/10(5), and APL was 0.309/10(5). The number of patients with AML was higher than that of patients with ALL and APL, with the ratio of AML:ALL:APL being 3.82:1.84:1. (2) There was a male preponderance, the ratio of male/female was 1.24:1. The incidence of AML was slightly higher in men (1.307/10(5)) than in women (1.044/10(5)). There was no significant difference in incidence between men and women in ALL and APL. (3) Most of AAL patients were elderly adult in Fujian Province. (4) There was statistical difference in AAL incidence among different regions of Fujian Province. Infections of Hepatitis B virus might be a risk factor for leukemia. CONCLUSION: The incidence of adult AL in Fujian Province is similar to the previous studies which was carried out by Institute of Hematology, Chinese Academy of Medical Sciences during 1986 and 1988. PMID- 23363743 TI - [Study on expression of PTEN gene and its pseudogene PTENP1 in acute leukemia and correlation between them]. AB - OBJECTIVE: To investigate the expression of PTEN (phosphatase and tension homology deletion on chromosome 10, PTEN) and its pseudogene PTENP1 in acute leukemia (AL) and correlation between them, and to explore the role of PTENP1 on the PTEN expression in AL cells. METHODS: PTEN and PTENP1 mRNA expression were evaluated in bone marrow (BM) samples from 138 newly diagnosed AL patients and 15 healthy controls by quantitative real-time RT-PCR (qRT-PCR). pCDH1-PTENP1 3'UTR GFP lentivirus vectors were constructed. 293T cells were transfected by calcium phosphate precipitation to produce retrovirus. HL-60 cell line was infected with the retroviral vectors expressing pCDH1-GFP and pCDH1-PTENP1 3'UTR-GFP respectively. The flow cell sorter was used to sort the HL-60 with GFP positively expressed. The mRNA expression of PTEN and PTENP1 was detected by qRT-PCR, the expression of PTEN protein by western blot, and the impact of PTENP13'UTR on the proliferation of HL-60 cells by MTT assay. RESULTS: AML patients showed significantly lower PTEN and PTENP1 mRNA expression in BM compared to healthy controls. Correlation analysis showed that the expression of PTEN and PTENP1 mRNA were positively correlated (P < 0.05). The 108 cases of PTENP1(+) AML were classified according to the prognostic classification of 2011 NCCN Clinical Practice Guidelines in AML, there was no difference among different subgroups. HL 60 cell line was infected with the retroviral vectors expressing pCDH1-GFP (control group) and pCDH1-PTENP1 3'UTR-GFP respectively. Compared with the control group, PTENP1 mRNA level of HL-60 infected with the retroviral vectors expressing pCDH1-PTENP1 3'UTR-GFP increased significantly, and PTEN mRNA level also increased. While the PTEN protein level and the cell growth rate of the PTENP1 3'UTR group didn't change significantly. CONCLUSION: PTEN and PTENP1 mRNA expression level of BM cells from AL patients is significantly lower. There is a positive correlation between expression of PTEN and PTENP1 mRNA. PTENP1 may regulate the expression of PTEN in mRNA level. PMID- 23363745 TI - [K562 cell line resistance to nilotinib induced in vitro and preliminary investigation of its mechanisms]. AB - OBJECTIVE: To establish a bcr-abl(+) cell line resistance to nilotinib, and to investigate the possible mechanisms of resistance. METHODS: K562 cells were treated with gradually increasing concentrations of nilotinib to generate resistance cell line K562-RN. The folder of drug-resistance was evaluated by MTT assay. Cells apoptosis rate was detected by flow cytometry, the mRNA level of bcr abl fusion gene by FISH, and the expression of apoptosis relative gene mRNA and protein (such as bcr-abl, HO-1, mdr1, Bcl-2 and caspase-3) by RQ-PCR and western blot. RESULTS: The resistant cell line K562-RN was successfully established, with 2.01 fold resistant to nilotinib compared with K562 cell line ?[the IC(50) value of nilotinib to K562 and K562-RN were (12.320 +/- 1.720) umol/L and (24.742 +/- 2.310) umol/L, respectively?]. It also had the cross resistance to adriamycin, homoharringtonine, etoposide and imatinib. Treated with different concentrations of nilotinib, cell apoptosis rate of K562-RN was significantly lower than that of K562 cells. The rate of bcr-abl gene positive cells was 92% in K562-RN by FISH assay. The mRNA and protein levels of bcr-abl, HO-1 and mdr1 expression up regulated in K562-RN cells, while those of caspase-3 expression down-regulated, being significantly statistical difference when compared with K562 cells (P < 0.05). CONCLUSION: Human leukemic cell line resistance to nilotinib, K562-RN is established successfully by gradually increasing concentrations of drug. The mechanisms of resistance in K562-RN is probably associated with increasing expression of bcr-abl, HO-1, mdr1 and decreasing expression of caspase-3 mRNA and protein levels. PMID- 23363746 TI - [Proliferation-inhibiting and multidrug-resistant reversing effect of bortezomib on human HL-60 cells]. AB - OBJECTIVE: To investigate the proliferation-inhibiting and multidrug-resistant reversing effect of bortezomib on human HL-60 cells, and to explore the mechanism of bortezomib-induced proliferation inhibition in human leukemia cells. METHODS: The multidrug resistant leukemia cell lines HL-60/DNR and HL-60/VCR cells were used as models, and sensitive HL-60 cells as a control. The cytotoxicity of bortezomib on HL-60, HL-60/DNR, HL-60/VCR cells were measured by MTT method, and the non-cytotoxicity dose was determined as reversible dose. The cells were divided into 4 experimental groups: HL-60/DNR + DNR, HL-60/DNR + DNR + bortezomib, HL-60/VCR + VCR, HL-60/VCR + VCR + bortezomib. The bortezomib resistant reversal fold was calculated. The levels of XIAP, cIAP-1, and cIAP-2 mRNA and proteins expression and the activation of NF-kappaB of the HL-60/DNR, HL 60/VCR cells were examined by quantitative real time RT-PCR and western blot respectively after treated with gradually increasing concentrations of bortezomib (10, 40, 80 nmol/L) for 48 hours. RESULTS: Bortezomib inhibited the cell growth of HL-60, HL-60/DNR, and HL-60/VCR in a concentration-dependent manner. The IC(50) values were (28.90 +/- 3.99), (81.19 +/- 9.34), and (73.48 +/- 8.94) nmol/L, respectively. After treated with 10nmol/L bortezomib for 48 hours, the IC(50) value of DNR to HL-60/DNR decreased from (12.90 +/- 1.75) umol/L to (3.54 +/- 0.57) umol/L (P < 0.01), and that of VCR to HL-60/VCR from (33.25 +/- 7.28) umol/L to (9.97 +/- 1.15) umol/L (P < 0.01). The reversal fold (RF) values were 3.32 +/- 0.53 and 2.64 +/- 0.28, respectively. Bortezomib down-regulated the levels of XIAP, cIAP-1, and cIAP-2 mRNA and protein expression and inhibited the NF-kappaB activation in a concentration-dependent manner. CONCLUSION: Bortezomib can inhibit the proliferation of HL-60 cells and reverse multidrug-resistance in the cells. The possible mechanism is associated with down-regulation of IAPs expression. PMID- 23363747 TI - [Hereditary Hemorrhagic Telangiectasia with iron-deficiency anemia: a case report and literature review]. PMID- 23363748 TI - [Outcome of haploidentical hematopoietic stem cell transplantation for refractory/relapsed acute leukemia]. AB - OBJECTIVE: To explore the outcome of human leukocyte antigen (HLA) mismatched/haploidentical hematopoietic stem cell transplantation (HSCT) for refractory/relapsed acute leukemia (AL) patients and its related risk factors. METHODS: 96 refractory/relapsed AL patients who received HLA mismatched/haploidentical HSCT following conditioning regimen comprised of modified busulfan/cyclophosphamide (BU/CY) plus thymoglobulin (ATG) from Jan 2003 to Jun 2011 were analyzed retrospectively. RESULTS: Of the 96 patients, 61 suffered from acute myeloid leukemia (AML), and 35 acute lymphoid leukemia (ALL), all of them in non-remission (NR) or relapse before transplantation. With a median follow-up of 373 (34 - 3157) d, 33 cases (34%) survived, 31 survived without leukemia, and 35 relapsed. The estimated 3-year overall survival (OS) and disease-free survival (DFS) rate was 30.2% and 29.0%, respectively. The 3-year OS rate was significantly higher for AML patients (39.2%) than for ALL patients (15.4%) (P = 0.005). The estimated 3-year OS probabilities for patients with and without prophylactic donor lymphocyte infusion (DLI) were 38.0% and 11.8%, respectively (P = 0.001). Sex, age, conditioning regimen (BU/CY or not, dosage of ATG), the number of HLA mismatches between the donor and recipient, and the number of infused mononuclear cells were not independent factors affecting OS, DFS and relapse. Multivariate analysis showed that DFS rate was significantly higher in patients receiving prophylactic DLI (P = 0.003), in patients with AML (vs with ALL) (P = 0.037) and with chronic GVHD (P = 0.006). CONCLUSIONS: Haploidentical HSCT may prolong DFS in part refractory/relapsed AL patients and even cure them. Prophylactic DLI may reduce relapse and increase survival; for patients with refractory/relapsed ALL, other therapy for prevention and treatment of post-transplant relapse should be explored. PMID- 23363749 TI - [A preliminary study on clinical diagnostic value of plasma elafin in skin acute graft-versus-host disease]. AB - OBJECTIVE: To analyze the specificity, sensitivity and receiver operating characteristic (ROC) curve of plasma elafin for diagnosis of skin acute graft versus-host disease (aGVHD), and to explore its clinical diagnostic value. METHODS: Incidence of skin aGVHD from fifty-three patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) were observed prospectively in Guangdong General Hospital from Apr 2010 to Aug 2011. The plasma concentrations of elafin were detected by enzyme-linked immunosorbent assay (ELISA). Skin biopsies were taken from 28 patients with skin rash, and elafin expression in the skin was detected by immunohistochemistry. Positive expression was defined as significant staining of at 50% of the depth of the epidermis, excluding the granular cell layer and the acrosyringium. RESULTS: Among 28 patients with skin rash, twenty-five were considered as skin aGVHD by clinical diagnosis, seventeen were confirmed as skin aGVHD by pathological biopsy. 11 cases were elafin positive by immunohistochemical staining. Elafin protein was overexpressed in aGVHD skin tissue (P = 0.001). Plasma concentrations of elafin were significantly higher in patients with skin aGVHD (positive) group than in those without skin aGVHD (negative) group (P = 0.005), among which there being no statistically significant difference in plasma elafin level between patients with grade I skin aGVHD group and negative group(P = 0.971), but being statistically significant difference compared patients with grade II-IV skin aGVHD group with those with grade I skin aGVHD group (P = 0.02) and with negative group (P = 0.008). Using the pathological diagnosis as the gold standard, the estimated specificity and the sensitivity of clinical diagnosis criteria were 27.3% and 100%, respectively, and those of tissue elafin protein level were 100% and 64.7%, respectively. The area under the ROC curve was 0.909 (0.797 - 1.021) when plasma concentrations of elafin was used in diagnosis of skin aGVHD. The sensitivity was 82.4% and the specificity was 81.8 % when the critical value was set at 1456.043 ug/L. CONCLUSION: Plasma concentration of elafin is significantly higher at the onset of skin aGVHD. It can be used as biochemical marker of skin aGVHD and has higher value in diagnosis of skin aGVHD. PMID- 23363750 TI - [Study on histone deacetylase inhibitor LBH589 induces apoptosis of multiple myeloma cells and its reversal of drug resistance mechanism]. AB - OBJECTIVE: To explore the impact of a new generation of histone deacetylase inhibitor LBH589 alone or in combination with proteasome inhibitor bortezomib on multiple myeloma (MM) cells proliferation and its mechanism. METHODS: MM cell line U266 and dexamethasone resistant cell line MM1R cells were treated with different concentrations of LBH589 alone or in combination with bortezomib, the inhibition of cells proliferation was detected by MTT, the cell cycle and apoptosis by flow cytometry. The expression level of histone H4 acetylation and PARP, Bcl-X protein was analyzed by western blot, expression level of caspase-3, APAF-1 and TOSO gene by real-time fluorescence quantitative PCR. RESULTS: U266 and MM1R cell proliferation were inhibited by different concentrations of LBH589 (0, 10, 20, 50 nmol/L) alone or 50 nmol/L of LBH589 in combination with bortezomib (10, 20 nmol/L) in a dose- and time-dependent manner. Inhibition effect was significantly higher in all combinative groups than in single agent groups (all P < 0.05). The percentage of G(0)/G(1) phase in MM1R cells were 36.60%, 46.50%, 51.40%, 57.10%, 75.48%, 79.73%, respectively, and the apoptosis rate were 5.27%, 31.41%, 39.78%, 44.07%, 73.60%, 83.27%, respectively. The effects appeared to occur in a dose-dependent manner, and being significantly higher in all combinative groups than in single agent groups (all P < 0.05). The expression of the caspase-3 and APAF-1 gene up-regulated gradually, while TOSO gene expression in MM1R cells down-regulated gradually in a dose- and time dependent manner (all P < 0.05). CONCLUSIONS: LBH589 can inhibit the growth of MM cells, block the cell cycle and induce cell apoptosis, which has anti-resistant effect on multidrug resistant cell. At the same time LBH589 in combination with bortezomib on myeloma cell has a synergistic effect, its mechanism and reversal of drug resistance mechanism involves in multiple changes in gene expression. PMID- 23363751 TI - [The influence of induced autophagy in vitro on proliferation of multiple myeloma cells]. AB - OBJECTIVE: To investigate the influence of autophagy on the survival and proliferation of multiple myeloma (MM) cells. METHODS: Multiple myeloma (MM) cell line U266 cell autophagy was induced by serum-free culture condition, and adding rapamycin or 3-MA respectively. The cells proliferation was observed. U266 cells, lymphoma cell Jurket under normal culture condition, and serum-free cultured Jurket cell were used as control group. The proliferation and apoptosis of cells were determined by CCK8 and flow cytometry, respectively. MDC staining were employed to detect the autophagy. The mRNA expression of Mtor and Beclin1 gene of U266 cells were assayed by RT-PCR. Protein LC3I/LCII and LAMP1 was analyzed by western blot. RESULTS: There was low level of autophagy in U266 cells, sera starvation increased the level of autophagy. Rapamycin upregulated autophagy of the U266 cells and stimulated their proliferation. But the autophagy level of sera starvation and rapamycin group declined when culture for 96h.3-MA had the same effects on U266 cells, although it was on 24 h. But rapamycin and 3-MA could inhibit cell proliferation under normal culture condition. Compared with normal culture condition, apoptosis of U266 cells increased significantly after 24h incubation in medium without sera ?[(1.33 +/- 0.09)% and (17.90 +/- 1.46)%, respectively?] (P < 0.01). Rapamycin and 3-MA could inhibit the serum-free induced apoptosis ?[(6.23 +/- 0.12)% and (6.97 +/- 0.03)%, respectively?](P < 0.01), but cell apoptosis was at the same level after 72 hour incubation ?[(30.37 +/- 0.27)%, (30.13 +/- 1.93)% and (28.57 +/- 2.83)%, respectively?] (P > 0.05). However, apoptosis of U266 cells decreased to 18.7% and 12.6% after removal of rapamycin and 3-MA. CONCLUSION: There is basically level of autophagy in MM cells which is higher than those in the Jurkat cells. Both Rapamycin and 3-MA can inhibit the cells proliferation under normal culture condition. Up-regulated autophagy promotes survival and proliferation of MM cells under sera deletion. Rapamycin strengthens this effect with limited duration. 3-MA has dual effects on cell autophagy. PMID- 23363752 TI - [Effect of baicalein on proliferation and migration in multiple myeloma cell lines RPMI 8226 and U266 cells]. AB - OBJECTIVE: To investigate the effect of baicalein on proliferation and migration of multiple myeloma (MM) cell lines and its molecular mechanism. METHODS: The MM cell line RPMI-8226 and U266 cells were used as the model, and treated with different concentration and time of baicalein the effect of baicalein on the MM cells proliferation was assessed by MTT assay. With or without baicalein or Interleukin-6 (IL-6) treatment, the beta-catenin protein level was analyzed by immunofluorescence assay and western blot assay and mRNA levels of beta-catenin, c-myc, cyclin D1 and integrin 7 gene by RT-PCR. Transwell chamber migration assay was used to detect the cells migration ability with different concentration of baicalein cultured. RESULTS: Baicalein inhibited the MM cell line RPMI 8226 and U266 cell proliferation in a dose- and time-dependent manner. It simultaneously inhibited beta-catenin protein level to resist the effect of IL-6 on inducing MM cell proliferation, and resulted in decrease of beta-catenin, c-myc, cyclinD1 and integrin beta7 mRNA levels. Baicalein also decreased migration ability of MM cells in a dose-dependent manner by SDF-1. CONCLUSION: Baicalein can inhibit MM cells proliferation and migration, and its molecular mechanisms are associated with inhibition of proliferation related genes beta-catenin, c-myc, cyclin D1 and integrin beta7 expression. PMID- 23363753 TI - [Expression of CXCR3 and CCR5 chemokine receptor in spleens of patients with primary immune thrombocytopenia]. AB - OBJECTIVE: To study CXCR3 and CCR5 chemokine receptor expression in spleens of patients with primary immune thrombocytopenia (ITP) and its clinical significance. METHODS: The splenectomy specimens from 10 ITP patients (ITP group) and 8 patients with traumatic splenic rupture (normal control group) were studied. Immunohistochemistry (IHC) was used to study the positive rate of CXCR3 and CCR5. Western blot was performed to detect CXCR3 and CCR5 protein expression, while real-time polymerase chain reaction (RT-PCR) was conducted to analyze their mRNA expression. RESULTS: The positive rate of CXCR3 and CCR5 were both higher in ITP group (90% and 100%, respectively) than those in control group (75% and 87.5%, respectively)(P < 0.05). The differences were statistically significant (P < 0.05). Protein and mRNA level of CXCR3 in ITP group were 3.0 and 3.5 times as high as those in control group, respectively. Those of CCR5 in ITP group were 1.2 and 1.7 times as high as those in control group, respectively. CONCLUSION: High expression of CXCR3 and CCR5 may play a part in the splenic immune disorders in patients with ITP. PMID- 23363754 TI - [Thrombosis of the cerebral veins and sinuses in acute promyelocytic leukemia after all-trans retinoic acid treatment: a case report and literature review]. PMID- 23363755 TI - [Expression of PKCtheta in peripheral blood mononuclear cells of aplastic anemia patients and its effects on Th1 and Tc1 cells]. PMID- 23363756 TI - [Methylation status in promoter region of runx3 gene on cases of children malignant lymphoma and its dynamic]. PMID- 23363757 TI - [Rituximab for the treatment of refractory autoimmune hemolytic anemia and pseudothrombocytopenia in infant: a case report and literature review]. PMID- 23363758 TI - [Analysis of clinical characteristics and JAK2V617F mutation of Tibetan people living at high altitudes with polycythemia]. PMID- 23363760 TI - [Health-related quality of life after allogeneic hematopoietic stem cell transplantation]. PMID- 23363759 TI - [Advances in allogeneic hematopoietic stem cell transplantation for severe aplastic anemia]. PMID- 23363761 TI - [Advances in effect of mitophagy on erythropoiesis]. PMID- 23363762 TI - [Consensus of Chinese experts on diagnosis and treatment of adult primary immune thrombocytopenia (version 2012)]. PMID- 23363763 TI - [Consensus of Chinese experts on diagnosis and treatment of disseminated intravascular coagulation (version 2012)]. PMID- 23363764 TI - [Consensus of Chinese experts on diagnosis and treatment of von Willebrand disease (version 2012)]. PMID- 23363765 TI - [Consensus of Chinese experts on diagnosis of thrombophilia (version 2012)]. PMID- 23363766 TI - [Consensus of Chinese experts on diagnosis and treatment of thrombotic thrombocytopenic purpura (version 2012)]. PMID- 23363767 TI - Mitochondria, obesity and aging. PMID- 23363768 TI - Progress towards malaria elimination in Sabang Municipality, Aceh, Indonesia. AB - BACKGROUND: Indonesia has set 2030 as its deadline for elimination of malaria transmission in the archipelago, with regional deadlines established according to present levels of malaria endemicity and strength of health infrastructure. The Municipality of Sabang which historically had one of the highest levels of malaria in Aceh province aims to achieve elimination by the end of 2013. METHOD: From 2008 to 2010, baseline surveys of malaria interventions, mapping of all confirmed malaria cases, categorization of residual foci of malaria transmission and vector surveys were conducted in Sabang, Aceh, a pilot district for malaria elimination in Indonesia. To inform future elimination efforts, mass screening from the focal areas to measure prevalence of malaria with both microscopy and PCR was conducted. G6PD deficiency prevalence was also measured. RESULT: Despite its small size, a diverse mixture of potential malaria vectors were documented in Sabang, including Anopheles sundaicus, Anopheles minimus, Anopheles aconitus and Anopheles dirus. Over a two-year span, the number of sub-villages with ongoing malaria transmission reduced from 61 to 43. Coverage of malaria diagnosis and treatment, IRS, and LLINs was over 80%. Screening of 16,229 residents detected 19 positive people, for a point prevalence of 0.12%. Of the 19 positive cases, three symptomatic infections and five asymptomatic infections were detected with microscopy and 11 asymptomatic infections were detected with PCR. Of the 19 cases, seven were infected with Plasmodium falciparum, 11 were infected with Plasmodium vivax, and one subject was infected with both species. Analysis of the 937 blood samples for G6PD deficiency revealed two subjects (0.2%) with deficient G6PD. DISCUSSION: The interventions carried out by the government of Sabang have dramatically reduced the burden of malaria over the past seven years. The first phase, carried out between 2005 and 2007, included improved malaria diagnosis, introduction of ACT for treatment, and scale-up of coverage of IRS and LLINs. The second phase, from 2008 to 2010, initiated to eliminate the persistent residual transmission of malaria, consisted of development of a malaria database to ensure rapid case reporting and investigation, stratification of malaria foci to guide interventions, and active case detection to hunt symptomatic and asymptomatic malaria carriers. PMID- 23363769 TI - Full-thickness hysterocystoplasty for management of a large bladder defect: experimental study in goats. AB - The uterine tissue of three healthy nonpregnant goats was evaluated experimentally as a graft for closure of a bladder defect. Goats were subjected to ovariectomy, and then one detubularized uterine horn was used as a graft to close a large defect in the ventral aspect of the bladder. Follow up included monthly radiographic and ultrasonographic examinations and evaluations of kidney function and electrolytes changes for six months. The goats were euthanized after six months, and both the bladder and the graft were examined macroscopically and histologically. The technique required less invasive procedures than those described with alternative techniques of cystoplasty, achieved a high survival rate without life-threatening complications post surgery, was associated with no significant changes in kidney function and electrolytes levels, showed proper healing of the transplanted graft by regeneration rather than repair without scaring or fibrosis and with complete covering of the graft by a healthy urothelium and was associated with no malignant transformation. Hysterocystoplasty is a non-invasive, non-life-threatening technique due to the close position of the bladder to the uterus, and proper healing of the graft reflects absence of pressure on its blood supply. It is an acceptable alternative technique for closure of a large bladder defect and avoids disadvantages of alternative techniques of cystoplasty. It might be accepted by owners of pets, and further studies in clinical cases of dogs are advised. PMID- 23363770 TI - Microbiology. Undernutrition--looking within for answers. PMID- 23363772 TI - Exploring the gap between hand washing knowledge and practices in Bangladesh: a cross-sectional comparative study. AB - BACKGROUND: Hand washing is considered as one of the most effective hygiene promotion activities for public health in developing countries. This study compared hand washing knowledge and practices in BRAC's water; sanitation and hygiene (WASH) programme areas over time. METHODS: This study is a cross sectional comparative study between baseline (2006), midline (2009) and end-line (2011) surveys in 50 sub-districts from the first phase of the programme. Thirty thousand households from 50 sub-districts were selected in two steps: i) 30 villages were selected from each sub-district by cluster sampling, and ii) 20 households were chosen systematically from each village. The matched households were considered (26,404 in each survey) for analysis. Data were collected from households through face-to-face interview using a pre-tested questionnaire. Respondents were the adult female members of the same households, who had knowledge of day-to-day household activities related to water, sanitation and hygiene. RESULTS: A gap between perception and practice of proper hand washing practices with soap was identified in the study areas. Hand washing practice with soap before eating was much lower than after defecation. In baseline data, 8% reported to wash their hands with soap which significantly increased to 22% in end line. Hand washing knowledge and practices before cooking food, before serving food and while handling babies is considerably limited than other critical times. A multivariate analysis shows that socio-economic factors including education of household head and respondent, water availability and access to media have strong positive association with hand washing with soap. CONCLUSION: Gap between knowledge and practice still persists in hand washing practices. Long term and extensive initiatives can aware people about the effectiveness of hand washing. PMID- 23363771 TI - Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. AB - Kwashiorkor, an enigmatic form of severe acute malnutrition, is the consequence of inadequate nutrient intake plus additional environmental insults. To investigate the role of the gut microbiome, we studied 317 Malawian twin pairs during the first 3 years of life. During this time, half of the twin pairs remained well nourished, whereas 43% became discordant, and 7% manifested concordance for acute malnutrition. Both children in twin pairs discordant for kwashiorkor were treated with a peanut-based, ready-to-use therapeutic food (RUTF). Time-series metagenomic studies revealed that RUTF produced a transient maturation of metabolic functions in kwashiorkor gut microbiomes that regressed when administration of RUTF was stopped. Previously frozen fecal communities from several discordant pairs were each transplanted into gnotobiotic mice. The combination of Malawian diet and kwashiorkor microbiome produced marked weight loss in recipient mice, accompanied by perturbations in amino acid, carbohydrate, and intermediary metabolism that were only transiently ameliorated with RUTF. These findings implicate the gut microbiome as a causal factor in kwashiorkor. PMID- 23363773 TI - An unusual cytogenetic rearrangement originating from two different abnormalities in chromosome 6 in a child with acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is usually associated with a favorable outcome, but about 10% of patients tend to relapse. The genetic hallmark of APL is a balanced translocation involving chromosomes 15 and 17, and the PML-RARa gene fusion is found in more than 90% of these cases. Other chromosomal abnormalities are commonly found in APL, but their clinical significance has yet to be determined. Here we report a case of childhood APL that was studied by conventional cytogenetics along with molecular cytogenetic techniques. The patient showed a complex karyotype with an unusual cytogenetic rearrangement originating from two different abnormalities in a single chromosome 6. Our case is an exceptional example of a cryptic cytogenetic anomaly in APL and underscores the importance of detailed genetic characterization. PMID- 23363774 TI - Exocytosis of neutrophil granule subsets and activation of prolyl isomerase 1 are required for respiratory burst priming. AB - This study tested the hypothesis that priming the neutrophil respiratory burst requires both granule exocytosis and activation of the prolyl isomerase Pin1. Fusion proteins containing the TAT cell permeability sequence and either the SNARE domain of syntaxin-4 or the N-terminal SNARE domain of SNAP-23 were used to examine the role of granule subsets in TNF-mediated respiratory burst priming using human neutrophils. Concentration-inhibition curves for exocytosis of individual granule subsets and for priming of fMLF-stimulated superoxide release and phagocytosis-stimulated H2O2 production were generated. Maximal inhibition of priming ranged from 72 to 88%. Linear regression lines for inhibition of priming versus inhibition of exocytosis did not differ from the line of identity for secretory vesicles and gelatinase granules, while the slopes or the y-intercepts were different from the line of identity for specific and azurophilic granules. Inhibition of Pin1 reduced priming by 56%, while exocytosis of secretory vesicles and specific granules was not affected. These findings indicate that exocytosis of secretory vesicles and gelatinase granules and activation of Pin1 are independent events required for TNF-mediated priming of neutrophil respiratory burst. PMID- 23363775 TI - Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been shown to control microglial responses in neuropathic pain. Since adenosine A2A receptors (A2ARs) control neuroinflammation, as well as the production and function of BDNF, we tested to see if A2AR controls the microglia-dependent secretion of BDNF and the proliferation of microglial cells, a crucial event in neuroinflammation. METHODS: Murine N9 microglial cells were challenged with lipopolysaccharide (LPS, 100 ng/mL) in the absence or in the presence of the A2AR antagonist, SCH58261 (50 nM), as well as other modulators of A2AR signaling. The BDNF cellular content and secretion were quantified by Western blotting and ELISA, A2AR density was probed by Western blotting and immunocytochemistry and cell proliferation was assessed by BrdU incorporation. Additionally, the A2AR modulation of LPS-driven cell proliferation was also tested in primary cultures of mouse microglia. RESULTS: LPS induced time-dependent changes of the intra- and extracellular levels of BDNF and increased microglial proliferation. The maximal LPS-induced BDNF release was time-coincident with an LPS-induced increase of the A2AR density. Notably, removing endogenous extracellular adenosine or blocking A2AR prevented the LPS mediated increase of both BDNF secretion and proliferation, as well as exogenous BDNF-induced proliferation. CONCLUSIONS: We conclude that A2AR activation plays a mandatory role controlling the release of BDNF from activated microglia, as well as the autocrine/paracrine proliferative role of BDNF. PMID- 23363776 TI - The influence of vitamin A supplementation on Foxp3 and TGF-beta gene expression in atherosclerotic patients. AB - The aim of this study was to investigate the role of vitamin A in Foxp3 and TGF beta gene expression in atherosclerotic patients. Patients and healthy controls in the vitamin A group received 25,000 IU retinyl palmitate per day, while patients in the placebo group took one capsule of placebo per day for 4 months. Gene expressions of regulatory T cells were studied by real-time PCR. The levels of Foxp3 expression in phytohemagglutinin-activated cells were much higher in the patients who received vitamin A than in placebo-treated patients and healthy controls, while Foxp3 gene expression in oxidized low-density lipoprotein activated cells showed no significant differences between all groups (p=0.357). A significant difference in the expression level of TGF-beta gene in fresh cells was observed between patients and healthy controls (p=0.009). TGF-beta gene expression in oxidized low-density lipoprotein-activated cells increased in all groups; however, these changes were not statistically significant (p=0.65); the changes obtained were 2.8-, 2.2- and 3.9-fold in the vitamin A, placebo, and control groups, respectively. Based on suppressing actions of regulatory T cells on effector T cells and findings that show that vitamin A has the effect of increasing expression of regulatory T cells, it can be concluded that supplementation with vitamin A in atherosclerotic patients may be effective in slowing disease progression. PMID- 23363778 TI - Decreased serum levels of brain-derived neurotrophic factor in adults with attention-deficit hyperactivity disorder. AB - It has been hypothesized that brain-derived neurotrophic factor (BDNF) is involved in the pathogenesis of attention-deficit hyperactivity disorder (ADHD), although experimental data regarding the contribution of BDNF gene polymorphisms to this psychiatric disorder are controversial. Recently, changes in BDNF serum levels have been reported in children with ADHD, but there are no studies about the possible role of this neurotrophin in adults. A total of 54 Caucasoid ADHD adults, including the predominantly inattentive and combined types (aged 33.43 +/ 8.99 yr) and 59 Caucasoid unrelated healthy controls (aged 35.52 +/- 9.37 yr) were included in a study to evaluate BDNF levels in serum. Medical, neurological and psychiatric co-morbidities were excluded. Clinical data concerning ADHD diagnosis and blood samples for patients and controls were collected. BDNF serum levels were significantly lower in adults with ADHD compared to healthy controls (p < 0.0001). Although the combined type of ADHD subgroup displayed lower BDNF serum levels than the inattentive type, the differences did not reach statistical significance. No significant correlations were found between serum BDNF levels and scores on the Conners' Adult ADHD Rating Subscales. These results suggest a role for BDNF in ADHD, at least in those patients whose disorder persists throughout life. Low BDNF levels may contribute to the neurodevelopmental deficits of ADHD and to the persistence of the disorder into adulthood. BDNF differences between ADHD subtypes should be further studied. PMID- 23363777 TI - Visualizing multidimensional cancer genomics data. AB - Cancer genomics projects employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Examples include projects carried out by the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). A crucial step in the extraction of knowledge from the data is the exploration by experts of the different alterations, as well as the multiple relationships between them. To that end, the use of intuitive visualization tools that can integrate different types of alterations with clinical data is essential to the field of cancer genomics. Here, we review effective and common visualization techniques for exploring oncogenomics data and discuss a selection of tools that allow researchers to effectively visualize multidimensional oncogenomics datasets. The review covers visualization methods employed by tools such as Circos, Gitools, the Integrative Genomics Viewer, Cytoscape, Savant Genome Browser, StratomeX and platforms such as cBio Cancer Genomics Portal, IntOGen, the UCSC Cancer Genomics Browser, the Regulome Explorer and the Cancer Genome Workbench. PMID- 23363779 TI - Assessment of left ventricular mass in hypertrophic cardiomyopathy by real-time three-dimensional echocardiography using single-beat capture image. AB - BACKGROUND: Left ventricular (LV) mass is an important prognostic indicator in hypertrophic cardiomyopathy. Although LV mass can be easily calculated using conventional echocardiography, it is based on geometric assumptions and has inherent limitations in asymmetric left ventricles. Real-time three-dimensional echocardiographic (RT3DE) imaging with single-beat capture provides an opportunity for the accurate estimation of LV mass. The aim of this study was to validate this new technique for LV mass measurement in patients with hypertrophic cardiomyopathy. METHODS: Sixty-nine patients with adequate two-dimensional (2D) and three-dimensional echocardiographic image quality underwent cardiac magnetic resonance (CMR) imaging and echocardiography on the same day. Real-time three dimensional echocardiographic images were acquired using an Acuson SC2000 system, and CMR-determined LV mass was considered the reference standard. Left ventricular mass was derived using the formula of the American Society of Echocardiography (M-mode mass), the 2D-based truncated ellipsoid method (2D mass), and the RT3DE technique (RT3DE mass). RESULTS: The mean time for RT3DE analysis was 5.85 +/- 1.81 min. Intraclass correlation analysis showed a close relationship between RT3DE and CMR LV mass (r = 0.86, P < .0001). However, LV mass by the M-mode or 2D technique showed a smaller intraclass correlation coefficient compared with CMR-determined mass (r = 0.48, P = .01, and r = 0.71, P < .001, respectively). Bland-Altman analysis showed reasonable limits of agreement between LV mass by RT3DE imaging and by CMR, with a smaller positive bias (19.5 g [9.1%]) compared with that by the M-mode and 2D methods (-35.1 g [ 20.2%] and 30.6 g [17.6%], respectively). CONCLUSIONS: RT3DE measurement of LV mass using the single-beat capture technique is practical and more accurate than 2D or M-mode LV mass in patients with hypertrophic cardiomyopathy. PMID- 23363780 TI - Defibrillation waveform duration adjustment increases the proportion of acceptable defibrillation thresholds in patients implanted with single-coil defibrillation leads. AB - The aim of this study was to determine whether defibrillation waveform duration adjustment with single-coil defibrillation leads can be used to increase the proportion of patients with satisfactory defibrillation thresholds (DFTs). A retrospective analysis of the DFT levels for 105 patients with implantable cardioverter-defibrillator devices and a single-coil defibrillation lead was performed. Two groups of patients were compared: 34 patients who had undergone waveform tuning (group A) and 71 patients with a fixed-tilt waveform (group B). Additional data including demographics, etiology, New York Heart Association functional class, left ventricular ejection fraction, high-voltage lead impedance and medications were gathered to determine what effect these variables had on the DFT levels. Of the 34 patients who had undergone waveform adjustment (group A), 27 (79%) were found to have satisfactory DFTs, while 41 (58%) of the 71 patients with fixed-tilt devices (group B) had satisfactory DFTs. Waveform duration adjustment was found to significantly increase the proportion of patients with satisfactory DFTs (p = 0.03). PMID- 23363781 TI - On the biological basis for competing macroscopic dose descriptors for kilovoltage dosimetry: cellular dosimetry for brachytherapy and diagnostic radiology. AB - The purpose of this work is to investigate how alternative macroscopic dose descriptors track absorbed dose to biologically relevant subcellular targets via Monte Carlo (MC) analysis of cellular models for a variety of cancerous and normal soft tissues for kilovoltage radiation. The relative mass distributions of water, light inorganic elements, and protein components of nuclear and cytoplasm compartments for various tissues are determined from a literature review. These data are used to develop representative cell models to demonstrate the range of mass elemental compositions of these subcellular structures encountered in the literature from which radiological quantities (energy absorption and attenuation coefficients; stopping powers) are computed. Using representative models of cell clusters, doses to subcellular targets are computed using MC simulation for photon sources of energies between 20 and 370 keV and are compared to bulk medium dose descriptors. It is found that cells contain significant and varying mass fractions of protein and inorganic elements, leading to variations in mass energy absorption coefficients for cytoplasm and nuclear media as large as 10% compared to water for sub-50 keV photons. Doses to subcellular structures vary by as much as 23% compared to doses to the corresponding average bulk medium or to small water cavities embedded in the bulk medium. Relationships between cellular target doses and doses to the bulk medium or to a small water cavity embedded in the bulk medium are sensitive to source energy and cell morphology, particularly for lower energy sources, e.g., low energy brachytherapy (<50 keV). Results suggest that cells in cancerous and normal soft tissues are generally not radiologically equivalent to either water or the corresponding average bulk tissue. For kilovoltage photon sources, neither dose to bulk medium nor dose to water quantitatively tracks energy imparted to biologically relevant subcellular targets for the range of cellular morphologies and tissues considered. PMID- 23363782 TI - Moving the genetics of inflammatory bowel diseases from bench to bedside: first steps towards personalised medicine. PMID- 23363783 TI - Metabolic syndrome risk factors in overweight, obese, and extremely obese Brazilian adolescents. AB - BACKGROUND: Obesity in infancy and adolescence has acquired epidemic dimensions worldwide and is considered a risk factor for a number of disorders that can manifest at an early age, such as Metabolic Syndrome (MS). In this study, we evaluated overweight, obese, and extremely obese adolescents for the presence of MS, and studied the prevalence of single factors of the syndrome in this population. METHODS: A total of 321 adolescents (174 females and 147 males) aged 10 to 16 years, attending the Adolescent Outpatient Clinic of Botucatu School of Medicine, Brazil, between April 2009 and April 2011 were enrolled in this study. Adolescents underwent anthropometric evaluation (weight, height, and abdominal circumference) and Body Mass Index (BMI) was estimated according to age and gender, following Disease Control and Prevention Centers recommendations (CDC, 2000). Blood pressure was measured and individuals with BMI >= 85th percentile were submitted to laboratory evaluation for Total Cholesterol, HDL and LDL Cholesterol, Triglycerides, Fasting Insulinemia, and Fasting Glycemia to identify MS factors, according to the criteria suggested by the International Diabetes Federation. Insulin resistance was calculated by HOMA-IR, Quicki, and Fasting Glycemia/Fasting Insulinemia (FGI). RESULTS AND DISCUSSION: Of the 321 adolescents, 95 (29.6%) were overweight, 129 (40.2%) were obese, and 97 (30.2%) were extremely obese. Around 18% were diagnosed with MS. The most prevalent risk factors were abdominal circumference >=90th percentile (55%), HDL < 40 mg/dL (35.5%), High Pressure >=130/85 mm/Hg (21%), Triglycerides >=150 mg/dL (18.5%), and Fasting Glycemia >=100 mg/dL (2%). Insulin resistance was observed in 65% of the adolescents. CONCLUSION: An increased prevalence of overweight and obesity, together with cardiometabolic risk factors such as dyslipidemia and abnormal blood pressure, were observed in adolescents, contributing to the onset of metabolic syndrome at younger ages. Risk factors for MS were more prevalent in females. PMID- 23363785 TI - Involvement of the autonomic nervous system in diurnal variation of corrected QT intervals in common marmosets. AB - Our previous study has shown that the corrected QT (QTc) interval of the electrocardiogram is longer during the dark period than during the light period in telemetered common marmosets. In the present study, we investigated the involvement of sympathetic and parasympathetic nervous activities in the changes of QTc interval associated with the light-dark cycle.Telemetry transmitters were implanted in six common marmosets to continuously record the electrocardiogram. The QT intervals obtained were corrected for the RR interval by applying individual probabilistic QT-rate correction formulae. Power spectral analysis of heart rate variability was performed to quantify each autonomic nervous function. Changes in QTc intervals and autonomic nervous tones were associated with the light-dark cycle. Parasympathetic nervous activity and QTc intervals significantly increased by approximately 10 ms during the dark period.Atropine, a muscarinic receptor antagonist, suppressed the increased parasympathetic tone and QTc prolongation during the dark period. In contrast, propranolol, a beta adrenoceptor antagonist, decreased the sympathetic activity and increased QTc intervals during the light period. These results suggest that the parasympathetic nerve functions prolong QTc intervals during the dark period, while the sympathetic nerve functions shorten them during the light period in common marmosets. PMID- 23363786 TI - The high rate of de novo graft carcinomas in renal transplant recipients. AB - BACKGROUND: To investigate the incidence, the clinical characteristics and outcomes of renal graft carcinomas in the same renal transplant population. METHODS: From April 1989 to April 2012, 1,037 consecutive renal transplantations were performed in our department. Data were collected prospectively in an extensively maintained database. For all recipients, monitoring consisted of clinical examination and an abdominopelvic CT scan or ultrasonography at least once a year. RESULTS: After 1,037 renal transplantations, 48 men and 14 women (sex ratio 3:4) with a mean age of 54 years (25.1-78.9) were included for urological malignancies. Eight graft carcinomas were identified: 7 renal cell carcinomas (5 papillary carcinomas and 2 clear cell carcinomas of the renal graft) and 1 transitional cell carcinoma of the ureteral graft (incidence 0.78%). Nephron-sparing surgery was chosen for 5 patients with good outcomes. All graft renal cell carcinomas were classified as pT1a and the mean size of tumors was 28.4 mm (range 6-45). The 5-year specific survival rate was 100%. No recurrence was observed with a mean follow-up of 36.8 months (4.1-84.3). CONCLUSION: Thus confirming an increased risk of de novo graft cancer, close monitoring of renal transplant recipients should be discussed with at least an abdominopelvic ultrasonography and PSA measurement once a year. Renal cell graft carcinomas seemed to be mostly small and of papillary type and low grade. PMID- 23363787 TI - [The significance of change of Th22 cells in patients with acute lymphoblastic leukemia]. AB - OBJECTIVE: To investigate the proportion of Th22 cells in peripheral blood of patients with acute lymphoblastic leukemia (ALL) and evaluate its significance. METHODS: The proportions of Th22 cells in peripheral blood of B-ALL and T-ALL patients before therapy (group 1), B-ALL and T-ALL patients in complete remission (ALL-CR, group 2) and healthy donors (group 3) were evaluated by flow cytometry. The cytokines IL-22, TGF-beta, TNF-alpha and IL-6 in peripheral blood of each group were measured by enzyme-linked immunosorbent assay (ELISA). The levels of IL-22 mRNA in peripheral blood mononuclear cells of each group were examined by reverse transcription-PCR (RT-PCR). RESULTS: The percentages of Th22 cells and the levels of IL-22, TNF-alpha, IL-6 and IL-22 mRNA in B-ALL and T-ALL patients before therapy were (0.44 +/- 0.10)%, (10.9 +/- 3.4) ng/L, (110.7 +/- 26.5) ng/L, (60.2 +/- 13.8) ng/L, 0.17 +/- 0.04 and (0.46 +/- 0.11)%, (11.2 +/- 3.5) ng/L, (114.6 +/- 27.0) ng/L, (58.7 +/- 12.4) ng/L, 0.19 +/- 0.04, respectively; Which in B-ALL and T-ALL patients in complete remission were(0.59 +/- 0.15)%, (14.3 +/- 4.1) ng/L, (142.5 +/- 32.7) ng/L, (83.7 +/- 18.9) ng/L, 0.25 +/- 0.06 and(0.60 +/ 0.15)%, (14.6 +/- 4.3) ng/L, (140.4 +/- 31.4) ng/L, (81.4 +/- 18.2) ng/L, 0.26 +/- 0.06, significantly lower than those in healthy donors ?[(1.24 +/- 0.31)%, (19.7 +/- 6.6) ng/L, (238.3 +/- 50.4) ng/L, (138.0 +/- 27.1) ng/L, 0.49 +/- 0.09?] (P < 0.01). The percentages of Th22 cells and the levels of IL-22, TNF alpha, IL-6 and IL-22 mRNA in group l were lower than those in group 2 (P < 0.05), there was not significant difference between B-ALL and T-ALL (P > 0.05). But the levels of TGF-beta in B-ALL and T-ALL patients before therapy ?[(30.6 +/- 8.2) ng/L, (31.4 +/- 8.8) ng/L?] and in complete remission ?[(24.2 +/- 5.8) ng/L, (25.1 +/- 6.1) ng/L?] were significantly higher than those in group 3?[(9.6 +/- 2.8) ng/L?] (P < 0.01). However, the level of TGF-beta in group 1 was higher than that of group 2 (P < 0.05), there was not significant difference between B-ALL and T-ALL (P > 0.05). CONCLUSION: Both the number and function of Th22 cells reduced in ALL patients. Th22 cells might be negatively correlated with ALL progression. The lower levels of TNF-alpha and IL-6, and overexpression of TGF beta in ALL patients might suppress the differentiation of Th22 cells. PMID- 23363784 TI - Potential anti-aging agents suppress the level of constitutive mTOR- and DNA damage- signaling. AB - Two different mechanisms are considered to be the primary cause of aging. Cumulative DNA damage caused by reactive oxygen species (ROS), the by-products of oxidative phosphorylation, is one of these mechanisms (ROS concept). Constitutive stimulation of mitogen- and nutrient-sensing mTOR/S6 signaling is the second mechanism (TOR concept). The flow- and laser scanning- cytometric methods were developed to measure the level of the constitutive DNA damage/ROS- as well as of mTOR/S6- signaling in individual cells. Specifically, persistent activation of ATM and expression of gammaH2AX in untreated cells appears to report constitutive DNA damage induced by endogenous ROS. The level of phosphorylation of Ser235/236 ribosomal protein (RP), of Ser2448-mTOR and of Ser65-4EBP1, informs on constitutive signaling along the mTOR/S6 pathway. Potential gero-suppressive agents rapamycin, metformin, 2-deoxyglucose, berberine, resveratrol, vitamin D3 and aspirin, all decreased the level of constitutive DNA damage signaling as seen by the reduced expression of gammaH2AX in proliferating A549, TK6, WI-38 cells and in mitogenically stimulated human lymphocytes. They all also decreased the level of intracellular ROS and mitochondrial trans-membrane potential DeltaPsim, the marker of mitochondrial energizing as well as reduced phosphorylation of mTOR, RP-S6 and 4EBP1. The most effective was rapamycin. Although the primary target of each on these agents may be different the data are consistent with the downstream mechanism in which the decline in mTOR/S6K signaling and translation rate is coupled with a decrease in oxidative phosphorylation, (revealed by DeltaPsim) that leads to reduction of ROS and oxidative DNA damage. The decreased rate of translation induced by these agents may slow down cells hypertrophy and alleviate other features of cell aging/senescence. Reduction of oxidative DNA damage may lower predisposition to neoplastic transformation which otherwise may result from errors in repair of DNA sites coding for oncogenes or tumor suppressor genes. The data suggest that combined assessment of constitutive gammaH2AX expression, mitochondrial activity (ROS, DeltaPsim) and mTOR signaling provides an adequate gamut of cell responses to evaluate effectiveness of gero suppressive agents. PMID- 23363788 TI - [Role of IFN-gamma + 874 genetic polymorphisms in allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: To explore the impact of IFN-gamma + 874 polymorphisms on the outcome in HLA matched sibling HSCT. METHODS: We used PCR-sequence-specific primer analysis (PCR-SSP) to analyze the polymorphisms of IFN-gamma + 874 T/A in 80 recipient and donor pairs from October 2005 to March 2008. RESULTS: Recipients having donors who possessed IFN-gamma + 874 A/A genotype had significantly earlier neutrophil recovery compared with those having donors with non-A/A genotype (15 (11 - 27) days vs 18 (12 - 30) days, P = 0.029). And IFN-gamma + 874 A/A in both recipients and donors further facilitated neutrophil recovery compared with others (13 (11 - 25) days and 19 (12 - 31) days, P = 0.019). Besides, IFN-gamma + 874 A/A in recipients increased the probability of grade II IV acute graft versus disease (aGVHD) and cytomegalovirus viraemia compared with IFN-gamma + 874 T/A or T/T genotype (20% vs 4% P = 0.041, 43.6% vs 16.0% P = 0.032), which lead to increased 5-year transplant-related mortality (TRM) (33.7% +/- 6.8% vs 12.0% +/- 6.5%, P = 0.050) and decreased 5-year event free survival (EFS) ?[(58.2 +/- 6.7)% vs (84.0 +/- 7.3)%, P = 0.032?] compared with the latter. IFN-gamma + 874 A/A in both recipients and donors also significantly increased the probability of grade II-IV aGVHD and cytomegalovirus viraemia compared with the other (21.7% vs 5.9%, P = 0.050; 45.7% vs 20.6%, P = 0.020), which caused increased 5-year TRM ?[(31.6 +/- 7.5)% vs (13.6 +/- 6.5)%, P = 0.048?] and decreased 5-year EFS ?[(56.8 +/- 7.3)% vs (79.4 +/- 6.9)%, P = 0.037?] compared with the other. CONCLUSION: In HLA-matched sibling HSCT setting, the presence of IFN-gamma + 874 T allele in recipients or in both recipients and donors significantly decreased the risk of grade II-IV aGVHD and CMV infection and increased EFS. While IFN-gamma + 874 A/A in donors or in both recipients and donors was associated with shorter duration to neutrophil recovery. PMID- 23363789 TI - [Epidemiology and antimicrobial resistance of clinical isolates about hospital infection from patients with hematological diseases]. AB - OBJECTIVE: To investigate the epidemiology and antibiotic resistance of isolates from hospitalized patients with hematological disease from 2005 to 2011. METHODS: A total of 1453 bacterial strains were isolated from patients with hematological disease from January 2005 to December 2011. Antimicrobial susceptibility testing was performed by micro-dilution method. RESULTS: (1) The majority of the bacterial strains were respiratory passage examples (57.5%). The portage of blood examples in our division (13.60%) was higher than of whole hospital (6.26%), with lower positive rate of bacterial culture (52.37%) than of whole hospital (60.24%). Chemotherapy-induced agranulocytosis was the main reason for hospital infection. 578 (39.8%) bacterial strains were gram positive, and 875 (60.2%) gram negative bacillus. Staphylococcus epidermidis strains and glucose nonfermenters had a tendency of ascensus. (2) Methicillin resistant staphylococcus aureus (MRSA) accounted for 72.8% antibiotic resistance. Detection rates of ESBLs in Escherichia coli and Klebsiella pneumoniae were 18.9% and 10.4%, respectively. (3) No obvious changes of antimicrobial resistances of Staphylococcus and Enterococcus were observed during these years. The Enterobacteriaceae strains showed lowest resistance rates to Carbapenems, next to Cefoperazone/sulbactam and Piperacillin/tazobactam. But the resistance rates of Escherichia coli to Cefepime and Ceftazidime were gradually increasing during the past years. Pseudomonas aeruginosa and Acinetobacter baumannii of glucose nonfermenters showed lowest resistance rates to Cefoperazone/sulbactam, but the resistance rate of Pseudomonas aeruginosa to Carbapenems increased. CONCLUSIONS: Escherichia coli was the highest in quantity of gram negative bacillus and glucose nonfermenters had a tendency of ascensus. The resistance rates of Escherichia coli to Cefepime and Ceftazidime, Pseudomonas aeruginosa to Carbapenems were gradually increasing in the past years. PMID- 23363790 TI - [Clinical efficacy of immunotherapy of dendritic cell and cytokine-induced killer cell combined with chemotherapy for treatment of multiple myeloma]. AB - OBJECTIVE: This research was aimed to evaluate the immune mechanism and clinical effect of immunotherapy of dendritic cells (DC) and cytokine-induced killer cell (CIK) combined with chemotherapy on multiple myeloma (MM). METHODS: 60 patients with MM were randomly divided into two groups. 30 patients in chemotherapy group were treated by chemotherapy only, 30 patients in joint group were treated by adoptive immunotherapy (DC-CIK) combined with chemotherapy. A variety of immunological indexes (Hsp70, Th1/Th2, TGF-beta) of all patients before and after chemotherapy were recorded; Also the clinical outcomes between two groups were compared. RESULTS: After chemotherapy, the immunological indexes of all patients were better than those of before chemotherapy (P < 0.05); After treatment, quality of life, clinical index and survival in joint group were better than in chemotherapy group (P < 0.05). CONCLUSION: Chemotherapy could break the immunosuppression of MM and improve the anti-tumor response of DC-CIK; Chemotherapy and DC-CIK may have synergistic effect for MM. PMID- 23363791 TI - [The clinical characteristics of 681 patients with diffuse large B-cell lymphoma]. AB - OBJECTIVE: To analyze clinical features and the differences of GCB and non-GCB phenotypes for diffuse large B-cell lymphoma (DLBCL) in different age groups, Ki 67 index and international prognostic index (IPI). METHODS: Clinical data of 681 patients with DLBCL hospitalized in West China Hospital from January 2000 to December 2010 were retrospectively analyzed. RESULTS: Of these DLBCL cases, the median age was 56 years old with a male predominance, 51.4% stage III-IV, 37.6% B symptoms, 30.2% IPI 3-5 scores, 49.8% from extranodal sites, 29.0% gastrointestinal tract infiltration, 38.3% low absolute lymphocyte count (ALC), 56.1% elevated serum lactate dehydrogenase (LDH) level, 83.0% elevated beta(2) microglobulin (beta(2)-MG) level. B symptoms was associated with bone marrow involvement with the odds ratio 5.212 (95%CI 2.821 - 9.632, P = 0.000). Among 268 with DLBCL patients classified by Hans' classification, 28.4% were GCB and 71.6% non-GCB. The proportions of patients with HBsAg-positive, elevated serum LDH level and Bcl-2 positive expression in non-GCB group was higher than those in GCB group (P < 0.05). The differences between GCB and non-GCB DLBCL were not revealed in terms of age subgroups, Ki-67 expression status and IPI subgroups. The high (>= 60%) Ki-67 group included more patients with extranodal site involvement compared with the low (< 60%) Ki-67 group (51.8% vs 38.7%, P = 0.008). The proportion of patents with low ALC in IPI 3-5 scores group was higher than in IPI 0-2 scores group (P = 0.000). The multivariate analysis showed that high IPI had statistically significant negative influence on survival (P = 0.000). CONCLUSIONS: Most patients with DLBCL were middle-aged male from our data. The patients with primary nodal (PN) was almost equal to those with primary extranodal (PEN). The most frequent extranodal site was gastrointestinal tract. The non-GCB phenotype was significantly more common than GCB phenotype in this study, and the non-GCB group included more patients with HBsAg-positive and Bcl-2 positive expression. Low ALC was observed predominantly in the high risk group. IPI score was an independent prognostic indicator for survival. PMID- 23363792 TI - [Significance of microRNA-146b-5p in diffuse large B-cell lymphoma and its relationship with risk assessment]. AB - OBJECTIVE: To study the expression of miR-146b-5p in diffuse large B cell lymphoma (DLBCL), and its relationship with risk assessment. METHODS: 62 cases of nodal DLBCL with follow-up data were collected from Shanxi Cancer Hospital, and were studied by using immunohistochemical EnVision method for CD3, CD10, CD20, Bcl-6 and MUM1. The DLBCLs were classified into germinal center B cell-like (GCB) and non-germinal center B cell-like (non-GCB) subtypes according to Hans'algorithm. Agilent Human miRNA Microarray 16.0 was used to select the miRNAs on paraffin-embedded tissues of 24 DLBCL cases. A TaqMan real-time polymerase chain reaction (RT-PCR) method was performed on 62 nodal DLBCL cases to validate the expression levels of miR-146b-5p.11 cases with reactive lymph node were elected as control. RESULTS: In 62 cases of DLBCL, 35.5% of cases were GCB and 64.5% non-GCB subtypes, the expression of miR-146b-5p in GCB was 3.2 times as much as non-GCB subtypes (P = 0.006). The expression of miR-146b-5p was up regulated in DLBCL, and expression level of miR-146b-5p was 5.4 times as much as reactivated lymph node. In 62 cases of DLBCL, 43.5% cases were recurrence-free and 56.5% recurrence. The expression of miR-146b-5p was remarkably up-regulated in recurrence-free group compared with recurrence group (P = 0.004). Moreover, high expression levels of miR-146b-5p in DLBCL were found to be associated with longer relapse-free survival (P = 0.005), but not for overall survival. Multivariate COX proportional hazard regression analysis revealed that low expression of miR-146b-5p (P = 0.004) and IPI >= 3(P = 0.011) were independent poor prognostic factors in 62 cases of DLBCL. CONCLUSIONS: The expression of miR 146b-5p was up-regulated in recurrence-free group, and its higher expression levels in DLBCL were associated with improved relapse-free survival. Our results suggested that miR-146b-5p might be one of markers for risk assessment. PMID- 23363793 TI - [Relationship of TGF-beta and IL-4R gene polymorphisms with risk of classical Hodgkin lymphoma]. AB - OBJECTIVE: This study was aimed to analyze the relationship between single nucleotide polymorphisms of transforming growth factor-beta1 G-800A and C-509T, interleukin-4 receptor V75I and susceptibility of CHL in adults. METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied to analyze the expressed alleles of the selected SNP loca. The relationship between genomic polymorphisms of TGF-beta1 and IL-4R and susceptibility of CHL were coupled with clinical data. RESULTS: TGF-beta1G-800A and TGF-beta1C-509T had obvious linkage equilibrium (D' = 0.879, r(2) = 0.83, P = 0.020). GT haplotype distribution frequencies in mixed cellularity Hodgkin lymphoma cases and control group were of 53.1% and 34.2%, respectively, with statistically significant (OR = 2.35, P = 0.000); distribution frequencies of mutant gene T/T in disease and control groups were of 38.8% and 15.3%, respectively, also with statistically significant (OR = 3.654, P = 0.000); frequencies of nodular sclerosis CHL patients with IL-4R V75I mutant gene A/A in disease and control groups were of 19.2% and 41.75%, respectively, also with statistically significant (OR = 3.156, P = 0.000). CONCLUSION: Single nucleotide polymorphisms of TGF-beta1 G-800A, C-509T and IL-4R V75I has a significant correlation with Chinese susceptibility to classical Hodgkin lymphoma. PMID- 23363794 TI - [Detection and clinical significance of JAK2 V617F mutation in Chinese and Uyghur patients with chronic myeloproliferative in Xinjiang]. AB - OBJECTIVE: To investigate the frequency of JAK2 V617F gene (hereinafter, the JAK2 gene) mutation in Uyghur patients with chronic myeloproliferative neoplasm (MPN) and its relationship with the clinical characteristics, and further compare differences of mutation rates in Han and Uyghur patients. METHODS: The allele specific polymerase chain reaction (AS-PCR) was used to detect the JAK2 mutation in 55 cases of Uyghur and 79 cases of Han bcr-abl negative MPN patients. RESULTS: (1) JAK2 mutation rate was 73.1% (98/134); The mutation rates of polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis were 84.3% (43/51), 69.7% (46/66) and 52.9% (9/17), respectively (P < 0.05). (2) The difference of mutation rate in Han ?[78.5% (62/79)?] and Uyghur ?[65.5% (36/55)?] patients was not significant (P > 0.05). (3) The patients of JAK2 positive have significantly higher count of blood cells, splenomegaly, thrombosis/bleeding and transformation than those of JAK2 negative ones (P < 0.05), but the clinical features between two ethnic groups were not significant (P > 0.05). CONCLUSION: JAK2 gene mutation occurred in the majority of patients with MPN; the mutation rates, clinical features and the complications between Han and Uyghur patients were not significant, which implicated that MPN patients with JAK2 mutation from different regions and ethnics may have the same molecular pathogenesis. PMID- 23363795 TI - [A case report of primary bone lymphoma with spinal involvement]. PMID- 23363796 TI - [Blockage of Th17 cells differentiation exacerbated mouse acute intestine graft versus-host disease following allogeneic bone marrow transplantation]. AB - OBJECTIVE: To study the role of Th17 cells in acute intestine graft-versus-host disease following allogenetic bone marrow transplantation(allo-BMT). METHODS: Mice were split randomly into five groups: normal control, irradiated, allo-BMT, allo-BMT + DMSO and allo-BMT + Halofuginone (HF) groups. HF was given intraperitoneally at a dose of 5 ug per mouse from -1 d to 10 d after allo-BMT. aGVHD symptoms were followed-up to perform clinical and pathogenic scores. The levels of Th1/Th17, interleukin-17 and interferon-gamma were measured by flow cytometry at day 7 d. mRNA expressions of T-bet, RORgammaT, CXCL9, CXCL10, CXCL11 and CCL20 in intestine were evaluated by real-time PCR. RESULTS: Intestinal damages in allo-BMT-HF mice was more serious than in normal control and allo-BMT groups at day 14 after transplantation. At day 7, Th17 ratio in allo-BMT + HF group was significantly lower than in allo-BMT group. IL-17A was not detected, but Th1 ratio was higher in allo-BMT + HF. There was a similar increment in the relative expressions of T-bet in both allo-BMT and allo-BMT + HF groups. Expressions of CXCL9 and CXCL10 elevated in allo-BMT + HF group, which were significantly higher than those in allo-BMT group (P < 0.01). CCL20 expression significantly increased in allo-BMT group, but it was not detected in allo-BMT + HF group. CONCLUSION: Blockage of th17 cells differentiation exacerbated acute intestine graft versus-host disease. PMID- 23363797 TI - [Impaired interleukin-10 secretion by CD5(+) B cells in patients with primary immune thrombocytopenia]. AB - OBJECTIVE: To investigate the number of peripheral blood CD5(+) B cells and their ability of secreting IL-10 in patients with immune thrombocytopenia (ITP). METHODS: Peripheral blood lymphocytes were isolated from 57 pre-treated, 40 post treated ITP patients and 25 controls using Ficoll-Hypaque density centrifugation and then stained with PE-CD5/FITC-CD19 for flow cytometric analysis. After 24 hour culture, lymphocytes were stained with APC-IL-10 for intracellular cytokine detection. ELISA assay was employed to determine IL-10 concentration in supernatants. RESULTS: The percentage and absolute number of CD5(+) B cells in peripheral blood from pre-treated ITP patients were significantly higher than that from normal controls (3.75 +/- 2.37)% vs (2.10 +/- 1.08)%, P < 0.01; (6.29 +/- 5.77)* 10(7)/L vs (3.06 +/- 1.90)* 10(7)/L, P < 0.01. CD5(+) B cells expressed more intracellular IL-10 than other lymphocyte subsets both in ITP patients and normal controls. The percentages of IL-10(+) cells within CD5(+) B cells in pre-treated ITP patients and normal controls were (29.51 +/- 20.73)% and(15.90 +/- 9.58)%, respectively(P < 0.01). Intracellular mean fluorescence intensity (MFI) of IL-10 in CD5(+) B cells was 27.95 +/- 13.99 in pre-treated patients, which was significantly higher than that in controls (P < 0.01). In contrast, IL-10 concentration in supernatants was (173.05 +/- 102.50) ng/L in pre treated ITP group, which was lower than that (230.61 +/- 76.96) ng/L in controls. In patients who achieved remission, the number of CD5(+) B cells decreased to level comparable to normal controls. While intracellular IL-10 MFI of CD5(+) B cells in post-treated ITP patients remained as high as in pre-treated ones, the IL-10 concentration in supernatants increased to level similar to controls. CONCLUSION: The significantly increased number of CD5(+) B cells and accumulated IL-10 in CD5(+) B cells suggested impaired IL-10 secretion in ITP patients. The number and the ability of secreting IL-10 of CD5(+) B cells could be restored after effective treatments in patients with ITP. PMID- 23363798 TI - [Combination of rituximab with autologous peripheral blood stem cell transplantation for treatment of diffuse large B-cell lymphoma: a single-center experience]. AB - OBJECTIVE: This study was aimed to investigate whether incorporation of rituximab into high-dose chemotherapy with autologous peripheral blood stem cell transplantation (auto-PBSCT)could improve the survival of patients with diffuse large B-cell lymphoma (DLBCL), and evaluate the safety of this regimen. METHODS: Twenty-five patients (age, 17 - 61 yrs) with DLBCL were treated with a sequential chemotherapy for remission induction, intensive chemotherapy for mobilization of stem cells, and high-dose chemotherapy followed by auto-PBSCT. Among 25 patients, 22 cases were at IV Ann Arbor stage, 60% cases with B symptom, and 10 cases with intermediate-high risk and 2 cases with high risk when evaluated by International Prognostic Index (IPI). The high-dose chemotherapy included BEAM regimen for 21 patients, and TBI conditioning regimen for 4 patients. Each patient received infusion of rituximab at a dose of 375 mg/m(2) for 2 times, each at peripheral blood stem cell mobilization and peripheral stem cell infusion. RESULTS: 20 patients achieved complete remission (CR) before transplantation. After high-dose chemotherapy and auto-PBSCT, 92% patients achieved CR. At a median follow-up of 45 months, the estimated 3-year overall survival (OS) and progression-free survival (PFS) were 78.9% and 75.9%, respectively, for all patients; while those were 87.4% and 82.4% for patients achieved CR before auto-PBSCT. Multivariate analysis by Cox regression revealed that failure to achieving CR before auto PBSCT was an independent prognostic factor affecting OS, while factor affecting PFS was IPI scores. Rituximab was generally well tolerated with few side-effects. CONCLUSION: Our results suggested that the addition of rituximab to high-dose chemotherapy followed by auto-PBSCT was effective and safe for patients with DLBCL. PMID- 23363799 TI - [Carrier diagnosis of F9 gross deletion by multiple ligation-dependent probe amplification in hemophilia B]. AB - OBJECTIVE: To investigate the application of multiplex ligation-dependent probe amplification (MLPA) in the gene diagnosis of hemophilia B (HB). METHODS: MLPA and linkage analysis of short tandem repeat (STR) were used for gene diagnoses of two HB families with gross deletions of F9 gene, which were negative by sequencing. RESULTS: The MLPA results indicated the loss of one or two exons in the two patients with the ratio lower than 0.10. Their mothers showed a ratio average of 0.50 +/- 0.05 for the corresponding probes, which revealed she was carrier of large deletions of the F9 gene. The ratios of three sisters of the HB patients were normal, which indicated they were non-carriers. Linkage analysis was consistent with MLPA, but sequencing was not conclusive. CONCLUSION: This report illustrated that MLPA technique represented an efficient method to screen F9 gene gross deletions in sequencing undiagnosed carriers of hemophilia B. PMID- 23363800 TI - [The role of bone marrow pathology in diagnosis and differential diagnosis of refractory cytopenia of children]. AB - OBJECTIVE: To explore the diagnosis and differential diagnosis of refractory cytopenia of children (RCC) according to WHO classification, and discuss the relationship between the cytology reviewed by hematologists and histology reviewed by pathologists. METHODS: We selected 50 non-severe aplastic anemia cases from 2007 - 2010 in our hospital and collected clinical data. Experienced hematologists and pathologists evaluated bone marrow biopsy and smear respectively. RESULTS: Of 50 cases, 23 were male and 27 female (M:F = 1:1.17), the median age at diagnosis was 9 years (ranged from 3 to 14 years). 5 patients had disagreement of diagnosis between hematologists and pathologists. In 3 cases hematologists diagnosed as aplastic anemia (AA) and pathologists as RCC, 2 cases vice versa. The final diagnoses of 50 patients reached consensus between hematologists and pathologists were AA 16 cases, RCC 34 cases including 8 refractory cytopenias with multilineage dysplasia (RCMD) cases. All 16 cases AA showed severe hypocellularity. Only 4 cases (25.00%) RCC showed severe hypocellularity, 19 cases (73.08%) RCC showed mild hypocellularity and 3 cases (11.54%) RCC were normal hypocellularity. CONCLUSION: Our results suggests that RCC was not rare in China. The main feature of RCC was dysplasia because of absence of increased blast. RCC was easily confused with AA. The main points of differential were present dysplastic changes of megakaryocyte best appreciated by the hematologists and morphologists and abnormal location of hematopoietic easily observed by pathologists. Overall, cytology and histology were complementary in the investigation of RCC and AA, because of sometimes one might give information that not be given from the other. PMID- 23363801 TI - [Clinical characteristics of patients with lymphoproliferative disorders after allogeneic hematopoietic stem cell transplant]. PMID- 23363802 TI - [Studies on concentrations and interactions of drugs in patients with administration of high-dose of cytosine arabinoside and methotrexate]. PMID- 23363803 TI - [Expression and clinical significance of neuron-specific enolase in multiple myeloma]. PMID- 23363804 TI - [Update on polymorphism of MICA gene in patients undergone allogeneic hematopoietic stem cell transplant]. PMID- 23363806 TI - Progress in the molecular genetics of hypertrophic cardiomyopathy: a mini-review. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM), which is characterized by unexplained and asymmetric left ventricular hypertrophy in the absence of other cardiac or systemic diseases, is an inherited cardiovascular disease and presents rising penetrance with aging. OBJECTIVE: The purpose of this review is to offer an outline of recent progress in the molecular genetics of HCM and to discuss characteristics of elderly HCM patients. METHODS: Studies were analyzed which included disease genes related to HCM, relationships between genotype and phenotype, potential pathogenesis of HCM, and the features of elderly patients with HCM. RESULTS: HCM is caused by mutations in genes encoding myofilament proteins of the sarcomere, Z-disc proteins, Ca2+ -handling proteins, and other proteins related to the sarcomere. Phenotypic manifestations of HCM are not just determined by these genes; modifying genes and epigenetic factors also contribute to the complexity of the HCM phenotype. The potential pathogenesis of HCM involves dominant negative function, an imbalance of myocardial energetic metabolism, and haploinsufficiency. Late-onset HCM presents its own features in the distribution of causal genes. Mutations in MYBPC3 may be the most common cause of delayed expression of HCM, and the sarcomere gene screen is most likely to be negative in elderly HCM patients. CONCLUSIONS: Despite progress in the identification of genetic causes and pathogenesis of HCM, there are still some questions that need to be better understood. It remains a great challenge to identify the cause of 50% of HCM cases in patients without an identified mutation. The application of a new genetic study technology may completely uncover the genetic background of these cases. In addition, the influences of causal mutations on the function and signaling of cardiocytes are expected to be elucidated further. PMID- 23363807 TI - Publicly funded clinical trials and the future of cancer care. AB - Publicly sponsored trials, conducted primarily by cooperative groups sponsored by the National Cancer Institute, and commercially sponsored trials are necessary to create new knowledge, improve the care of oncology patients, and develop new drugs and devices. Commercial sponsors launch clinical trials that will result in drug approval, label extension, expansion of market share, and an increase in shareholder value. Conversely, publicly sponsored trials seek to optimize therapy for a particular disease, create new knowledge, and improve public health; these trials can also result in label extension of a drug and even in initial drug approval. Publicly sponsored trials may combine and/or compare drugs developed by different commercial sponsors, develop multimodality therapies (e.g., the combination of chemotherapy and radiation), or develop novel treatment schedules or routes of drug administration (e.g., intraperitoneal chemotherapy). Publicly sponsored trials are more likely to focus on therapies for rare diseases and to study survivorship and quality of life; these areas may not be a priority for commercial entities. Screening and prevention strategies have been developed almost exclusively by the public sector given the large sample size and long follow-up period needed to complete the trial and, therefore, the lack of short term commercial gain. Finally, given the public nature of the funding, clinical investigators are expected to publish their results even if the outcomes are unfavorable for the investigational therapy. With the ongoing reorganization of the cooperative groups to form a national clinical trials network, opportunities exist to create a robust platform for biomarker discovery and validation through the expanded collection of well-annotated biospecimens obtained from clinical trial participants. Thus, publicly funded trials are vital to developing and refining new cancer treatments and disseminating results to the medical community and the general public. PMID- 23363805 TI - Hypertension in Northern Angola: prevalence, associated factors, awareness, treatment and control. AB - BACKGROUND: Seventy-five million people are estimated to be hypertensive in sub Saharan Africa. This translates in high morbidity and mortality, as hypertension is now considered to be the number one single risk factor for death worldwide. Accurate data from countries lacking national disease surveillance is needed to guide future evidence-driven health policies. The authors aimed to estimate the prevalence, awareness, management and control of hypertension and associated factors in an adult population of Angola. METHODS: A community-based survey of 1,464 adults, following the World Health Organization's Stepwise Approach to Chronic Disease Risk Factor Surveillance, was conducted to estimate the prevalence of hypertension, awareness, treatment and control in Dande, Northern Angola. Using a demographic surveillance system database, a representative sample of subjects, stratified by sex and age (18-40 and 41-64 years old), was selected. RESULTS: Prevalence of hypertension (systolic blood pressure >=140 mmHg and/or diastolic blood pressure >=90 mmHg and/or hypertensive therapy) was of 23% (95% CI: 21% to 25.2%). A follow-up consultation confirmed the hypertensive status in 82% of the subjects who had a second measurement on average 23 days after the first. Amongst hypertensive individuals, 21.6% (95% CI: 17.0% to 26.9%) were aware of their status. Only 13.9% (95% CI: 5.9% to 29.1%) of the subjects aware of their condition were under pharmacological treatment, of which approximately one-third were controlled. Older age, lower level of education, higher body mass index and abdominal obesity were found to be significantly (p<0.01) associated with hypertension. CONCLUSIONS: Our survey is the first to provide insightful data on hypertension prevalence in Angola. There is an urgent need for strategies to improve prevention, diagnosis and access to adequate treatment in this country, where a massive economic growth and consequent potential impact on lifestyle risk factors could lead to an increase in the prevalence of hypertension and cardiovascular disease. PMID- 23363809 TI - Effect of pyrogallol on the physiology and biochemistry of litchi fruit during storage. AB - BACKGROUND: Litchi (Litchi chinensis Sonn.) fruit are highly perishable and have a very short shelf life, easily turning brown and decaying. This study investigated the efficiency of pyrogallol, a catechin on the physiology and biochemistry in relation to storage life of litchi fruit. RESULTS: Fruit were treated with pyrogallol at 1 mM and then stored at ambient temperature (25 degrees C) or low temperature (4 degrees C). Compared with control, pyrogallol significantly reduced pericarp browning and delayed the rotting of fruit day 4 at 25 degrees C, and on day 30 at 4 degrees C. The chemical treatment reduced respiration rate and the activities of peroxidase (POD) and polyphenol oxidase (PPO), and delayed the loss of membrane permeability. Pyrogallol increased the activity of phenylalanine ammonia-lyase (PAL), delayed the loss of anthocyanin and phenolics, and maintained high 2,2-diphenyl-1-picrlhydrazyl (DPPH) radical scavenging activity and reducing power. High performance liquid chromatograph (HPLC) analysis clearly indicated that treated fruit contained higher concentration of the four phenolic compounds procyanidin B1, (+)-catechin, (-) epicatechin and (-)-epicatechin-3-gallate. CONCLUSIONS: The application of pyrogallol partially reducing pericarp browning and changed quality-related physiological activities and, thus, pyrogallol could have beneficial effects on pericarp browning and fruit decay control, and could be helpful for litchi fruit postharvest storage. PMID- 23363808 TI - A study to evaluate the cause of bone demineralization in gynecological cancer survivors. AB - BACKGROUND: An association between treatment for gynecological cancers and risk of osteoporosis has never been formally evaluated. Women treated for these cancers are now living longer than ever before, and prevention of treatment induced morbidities is important. We aimed to distinguish, in gynecological cancer survivors, whether cancer therapy has additional detrimental effects on bone health above those attributable to hormone withdrawal. METHODS: We performed a retrospective cross-sectional analysis of dual energy x-ray absorptiometry (DEXA) scan results from 105 women; 64 had undergone bilateral salpingo oophorectomy (BSO) followed by chemotherapy or radiotherapy for gynecological malignancies, and 41 age-matched women had undergone BSO for benign etiologies. All were premenopausal prior to surgery. RESULTS: The median age at DEXA scan for the cancer group was 42 years, and 66% had received hormonal replacement therapy (HRT) following their cancer treatment. For the benign group, the median age was 40 years, and 87% had received HRT. Thirty-nine percent of cancer survivors had abnormal DEXA scan results compared to 15% of the control group, with the majority demonstrating osteopenia. The mean lumbar spine and femoral neck bone mineral densities (BMDs) were significantly lower in cancer patients. A history of gynecological cancer treatment was associated with significantly lower BMD in a multivariate logistic regression. CONCLUSIONS: Women treated for gynecological malignancies with surgery and adjuvant chemotherapy have significantly lower BMDs than age-matched women who have undergone oophorectomy for noncancer indications. Prospective evaluation of BMD in gynecological cancer patients is recommended to facilitate interventions that will reduce the risk of subsequent fragility fractures. PMID- 23363810 TI - Prostate disease risk factors among a New Zealand cohort. AB - BACKGROUND: Prostate cancer is a leading public health burden worldwide, and in New Zealand it is the most commonly registered cancer and the third leading cause of cancer deaths among males. Genetic variability and its associations with diet, demographic and lifestyle factors could influence the risk of this disease. METHODS: The single nucleotide polymorphisms (SNPs) within a group of antioxidant genes and related markers were tested between patient and control cohorts, adjusted for significant differences between basic lifestyle and demographic characteristics. RESULTS: Increasing age, smoking and low serum selenium levels were significantly associated with an increased risk for prostate disease. Alcohol consumption increased the glutathione peroxidase (GPx) activity. A significant reduction in alcohol consumption was recorded with prostate disease. Three SNPs, namely GPx1 rs1050450, SEL15 rs5845 and CAT rs1001179, were significantly associated with prostate disease risk. A cumulative risk of prostate cancer was noted with 6 risk alleles. A lower GPx activity was recorded with prostate disease compared to the controls. However, the GPx1 rs1050450 allele T in association with prostate cancer recorded a significantly higher GPx activity compared to the controls. CONCLUSIONS: These data point to a possibility of identifying individuals at risk of prostate cancer for better management purposes. PMID- 23363811 TI - Anti-anhedonic activity of long-term lithium treatment in rats exposed to repeated unavoidable stress. AB - Behavioural and neurochemical responses to palatable food exposure represent an index of hedonic competence. In rats, a palatable meal increases extra-neuronal dopamine levels in the nucleus accumbens shell (NAcS) that confers to it incentive salience and reinforcing value. Repeated stress exposure decreases dopamine output and impairs the NAcS dopaminergic response to palatable food and the competence to acquire a vanilla sugar (VS)-reinforced instrumental behaviour [VS-sustained appetitive behaviour (VAB)]. Moreover, chronic stress exposure disrupts reactivity to aversive stimuli. A 3-wk treatment with lithium, the gold standard treatment in bipolar disorder, tonically reduces NAcS dopamine output and the reactivity to aversive stimuli. However, it does not affect the dopaminergic response to VS and the competence to acquire VAB. This study investigated whether repeated lithium administration is endowed with anti anhedonic activity. The NAcS dopaminergic response to VS and the competence to acquire VAB and sucrose self-administration (SA), in terms of fixed-ratio (FR)1, FR5 and progressive ratio schedules of reinforcement, were studied in saline or lithium-treated groups of non-food-deprived rats exposed or not to repeated unavoidable stress. Chronic stress exposure impaired the NAcS dopaminergic response to VS, acquisition of VAB and sucrose SA, in terms of FR1 and FR5 schedules of reinforcement and breaking point score. Repeated lithium treatment restored these parameters to control group values, even when treatment began in rats already showing an anhedonia-like condition. Since the breaking point defines the reinforcement efficacy of a hedonic stimulus, the present data suggest that lithium treatment is endowed with anti-anhedonic activity in rats. PMID- 23363812 TI - Simultaneous development of Dieterich disease and Freiberg disease. AB - Dieterich disease is an uncommon arthropathy of the hand, with few studies published. This lesion shares a similar etiopathogenesis with Freiberg disease, although the association of both conditions has only been described once. We report a 65-year-old man consulting for inflammatory pain in his right hand of 1 month's duration and also in his right foot of 4 months' duration. The rheumatology department was consulted to rule out systemic disease because the synovitis had occurred simultaneously in 2 different locations. The plain radiography and magnetic resonance imaging findings supported the diagnosis of Dieterich disease and Freiberg disease, although only increased uptake was found on scintigraphy in the affected zones. Few studies have been published about Dieterich disease, most in case report form. To our knowledge, only 1 study has described the association of Dieterich disease and Freiberg disease. Surgical treatment has been described when conservative management is unsuccessful, with multiple techniques used. The present case is the first in which Dieterich disease and Freiberg disease manifested simultaneously in the initial painful inflammatory phase. PMID- 23363813 TI - The immune signature of CD8(+)CCR7(+) T cells in the peripheral circulation associates with disease recurrence in patients with HNSCC. AB - PURPOSE: Patients with cancer have an increased frequency of circulating apoptosis-sensitive CD8(+)CCR7(neg) T cells and few CD8(+)CCR7(+) T cells versus normal controls. The functional and clinical significance of this imbalance was investigated using peripheral blood of patients with squamous cell carcinoma of the head and neck (HNSCC). EXPERIMENTAL DESIGN: The frequency of circulating CD8(+) T cells co-expressing CCR7, CD45RO, CD28, and Annexin V (ANXV) was evaluated in 67 patients and 57 normal controls by flow cytometry. Spearman rank correlations among immunophenotypic profiles were analyzed. Recursive partitioning classified subjects as patients or normal controls based on CD8(+)CCR7(+) T-cell percentages. Kaplan-Meier plots estimated disease-free survival (DFS). RESULTS: The CD8(+)CCR7(+) T-cell frequency was low, whereas that of total CD8(+)CCR7(neg) and ANXV-binding CD8(+)CCR7(neg) T cells was higher in patients with HNSCC than in normal controls (P < 0.001-0.0001). ANXV binding correlated with the absence of CCR7 on CD8(+) T cells (P < 0.001). ANXV binding was negatively correlated with the CD8(+)CD45RO(neg)CCR7(+) (T(N)) cell frequency (P < 0.01) but positively correlated (P < 0.01) with that of CD8(+)CD45RO(+)CCR7(+) (T(CM)) T cells and of the two CCR7(neg) subsets (T(PM) and T(TD)). In recursive partitioning models, the CD8(+)CCR7(+) T-cell frequency of 31% distinguished patients from normal controls with 77% to 88% accuracy after cross-validation. In 25 patients tested before any therapy, the CD8(+)CCR7(+) T cell frequency of less than 28% predicted disease recurrence within 4 years of definitive therapy (P < 0.0115). CONCLUSION: The CD8(+)CCR7(+) T-cell frequency in HNSCC patients' blood tested at diagnosis can discriminate them from normal controls and predicts disease recurrence. PMID- 23363814 TI - A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma. AB - PURPOSE: Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib. EXPERIMENTAL DESIGN: A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two stage Green-Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs. RESULTS: The six month progression-free survival (PFS) rates in phase II (n = 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n = 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib. CONCLUSIONS: The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma. PMID- 23363815 TI - Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas. AB - PURPOSE: Chemokines are involved in cancer-related inflammation and malignant progression. In this study, we evaluated expression of CCR8 and its natural cognate ligand CCL1 in patients with urothelial carcinomas of bladder and renal cell carcinomas. EXPERIMENTAL DESIGN: We examined CCR8 expression in peripheral blood and tumor tissues from patients with bladder and renal carcinomas. CCR8 positive myeloid cells were isolated from cancer tissues with magnetic beads and tested in vitro for cytokine production and ability to modulate T-cell function. RESULTS: We show that monocytic and granulocytic myeloid cell subsets in peripheral blood of patients with cancer with urothelial and renal carcinomas display increased expression of chemokine receptor CCR8. Upregulated expression of CCR8 is also detected within human cancer tissues and primarily limited to tumor-associated macrophages. When isolated, CD11b(+)CCR8(+) cell subset produces the highest levels of proinflammatory and proangiogenic factors among intratumoral CD11b myeloid cells. Tumor-infiltrating CD11b(+)CCR8(+) cells selectively display activated Stat3 and are capable of inducing FoxP3 expression in autologous T lymphocytes. Primary human tumors produce substantial amounts of the natural CCR8 ligand CCL1. CONCLUSIONS: This study provides the first evidence that CCR8(+) myeloid cell subset is expanded in patients with cancer. Elevated secretion of CCL1 by tumors and increased presence of CCR8(+) myeloid cells in peripheral blood and cancer tissues indicate that CCL1/CCR8 axis is a component of cancer-related inflammation and may contribute to immune evasion. Obtained results also implicate that blockade of CCR8 signals may provide an attractive strategy for therapeutic intervention in human urothelial and renal cancers. PMID- 23363816 TI - SHP2 is overexpressed and inhibits pSTAT1-mediated APM component expression, T cell attracting chemokine secretion, and CTL recognition in head and neck cancer cells. AB - PURPOSE: Human leukocyte antigen (HLA) class I antigen processing machinery (APM) component downregulation permits escape of malignant cells from recognition by cytotoxic T lymphocytes (CTL) and correlates with poor prognosis in patients with head and neck cancer (HNC). Activated STAT1 (pSTAT1) is necessary for APM component expression in HNC cells. We investigated whether an overexpressed phosphatase was responsible for basal suppression of pSTAT1 and subsequent APM component-mediated immune escape in HNC cells. EXPERIMENTAL DESIGN: Immunohistochemical staining and reverse transcription PCR of paired HNC tumors was performed for the phosphatases src homology domain-containing phosphatase (SHP)-1 and SHP2. Depletion of phosphatase activity in HNC and STAT1(-/-) tumor cells was achieved by siRNA knockdown. HLA class I-restricted, tumor antigen specific CTL were used in IFN-gamma ELISPOT assays against HNC cells. Chemokine secretion was measured after SHP2 depletion in HNC cells. RESULTS: SHP2, but not SHP1, was significantly upregulated in HNC tissues. In HNC cells, SHP2 depletion significantly upregulated expression of pSTAT1 and HLA class I APM components. Overexpression of SHP2 in nonmalignant keratinocytes inhibited IFN-gamma-mediated STAT1 phosphorylation, and SHP2 depletion in STAT1(-/-) tumor cells did not significantly induce IFN-gamma-mediated APM component expression, verifying STAT1 dependence of SHP2 activity. SHP2 depletion induced recognition of HNC cells by HLA class I-restricted CTL and secretion of inflammatory, T-cell attracting chemokines, RANTES and IP10. CONCLUSION: These findings suggest for the first time an important role for SHP2 in APM-mediated escape of HNC cells from CTL recognition. Targeting SHP2 could enhance T-cell-based cancer immunotherapy. PMID- 23363817 TI - Effective anti-neu-initiated antitumor responses require the complex role of CD4+ T cells. AB - PURPOSE: Targeting oncogenic receptors with antibodies has been thought to suppress tumor growth mainly by interrupting oncogenic signals. Recently, the essential role for adaptive immunity, and CD8(+) T cells in particular, has been established as a major factor for anti-HER2/neu-mediated tumor regression. However, the role of CD4(+) T cells is still being defined. The purpose of this study was to explore whether and to what extent CD4(+) T cells are involved in mediating the effects of anti-HER2/neu therapy. EXPERIMENTAL DESIGN: The role of CD4(+) T cells was examined using a transplant model of the rat HER2/neu overexpressing cell line TUBO. Tumor-bearing mice were treated with anti-neu therapy in conjunction with CD4 depletion or CD40L blockade. The effects of CD4 depletion on the antitumor response were examined by tumor growth analysis and enzyme-linked immunospot (ELISPOT). RESULTS: In addition to CD8(+) T cells, CD4(+) T cells are also essential for anti-neu antibody-mediated tumor regression, but B cells are not required. The role for CD4(+) cells is necessary throughout anti-neu therapy and not limited to helping CD8(+) T cells. Expression of IFN-gamma is necessary for anti-neu therapy and IFN-gamma induces MHC-II expression in TUBO cells promoting direct recognition by CD4(+) T cells. Furthermore, intratumoral depletion of CD4(+) T cells or blockade of the activating cell-surface protein CD40L inhibits the antitumor response. CONCLUSIONS: This study reveals the essential role of CD4(+) T cell for anti-neu mediated tumor regression. PMID- 23363818 TI - A multi-scale cardiovascular system model can account for the load-dependence of the end-systolic pressure-volume relationship. AB - BACKGROUND: The end-systolic pressure-volume relationship is often considered as a load-independent property of the heart and, for this reason, is widely used as an index of ventricular contractility. However, many criticisms have been expressed against this index and the underlying time-varying elastance theory: first, it does not consider the phenomena underlying contraction and second, the end-systolic pressure volume relationship has been experimentally shown to be load-dependent. METHODS: In place of the time-varying elastance theory, a microscopic model of sarcomere contraction is used to infer the pressure generated by the contraction of the left ventricle, considered as a spherical assembling of sarcomere units. The left ventricle model is inserted into a closed loop model of the cardiovascular system. Finally, parameters of the modified cardiovascular system model are identified to reproduce the hemodynamics of a normal dog. RESULTS: Experiments that have proven the limitations of the time varying elastance theory are reproduced with our model: (1) preload reductions, (2) afterload increases, (3) the same experiments with increased ventricular contractility, (4) isovolumic contractions and (5) flow-clamps. All experiments simulated with the model generate different end-systolic pressure-volume relationships, showing that this relationship is actually load-dependent. Furthermore, we show that the results of our simulations are in good agreement with experiments. CONCLUSIONS: We implemented a multi-scale model of the cardiovascular system, in which ventricular contraction is described by a detailed sarcomere model. Using this model, we successfully reproduced a number of experiments that have shown the failing points of the time-varying elastance theory. In particular, the developed multi-scale model of the cardiovascular system can capture the load-dependence of the end-systolic pressure-volume relationship. PMID- 23363819 TI - The value of combining blood culture and SeptiFast data for predicting complicated bloodstream infections caused by Gram-positive bacteria or Candida species. AB - Management of complicated bloodstream infections requires more aggressive treatment than uncomplicated bloodstream infections. We assessed the value of follow-up blood culture in bloodstream infections caused by Staphylococcus aureus, Enterococcus spp., Streptococcus spp., and Candida spp. and studied the value of persistence of DNA in blood (using SeptiFast) for predicting complicated bloodstream infections. Patients with bloodstream infections caused by these microorganisms were enrolled prospectively. After the first positive blood culture, samples were obtained every third day to perform blood culture and SeptiFast analyses simultaneously. Patients were followed to detect complicated bloodstream infection. The study sample comprised 119 patients. One-third of the patients developed complicated bloodstream infections. The values of persistently positive tests to predict complicated bloodstream infections were as follows: SeptiFast positive samples (sensitivity, 56%; specificity, 79.5%; positive predictive value, 54%; negative predictive value, 80.5%; accuracy, 72.3%) and positive blood cultures (sensitivity, 30.5%; specificity, 92.8%; positive predictive value, 64%; negative predictive value, 75.5%; accuracy, 73.9%). Multivariate analysis showed that patients with a positive SeptiFast result between days 3 and 7 had an almost 8-fold-higher risk of developing a complicated bloodstream infection. In S. aureus, the combination of both techniques to exclude endovascular complications was significantly better than the use of blood culture alone. We obtained a score with variables selected by the multivariate model. With a cutoff of 7, the negative predictive value for complicated bloodstream infection was 96.6%. Patients with a positive SeptiFast result between days 3 and 7 after a positive blood culture have an almost 8-fold-higher risk of developing complicated bloodstream infections. A score combining clinical data with the SeptiFast result may improve the exclusion of complicated bloodstream infections. PMID- 23363820 TI - Sequencing-based genotyping of mixed human papillomavirus infections by use of RipSeq software. AB - Sequencing-based pathogen identification directly from clinical specimens requires time-consuming interpretation, especially with mixed chromatograms when multiple microorganisms are detected. We assessed RipSeq Mixed software for human papillomavirus (HPV) genotyping by comparison to the linear array HPV genotyping assay. RipSeq Mixed provided rapid, sequencing-based HPV typing for single-type infections and coinfections with 2 types. PMID- 23363821 TI - Whole-genome mapping: a new paradigm in strain-typing technology. AB - Strain-typing technology in support of outbreak identification and resolution has evolved from phenotypic analysis, such as serology and biotypes, to much-more robust molecular genetic approaches, such as pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing. Whole-genome mapping (WGM) has been recently applied to subtyping analysis, and it bridges the gap between PFGE (~20 bands sorted by size) and whole-genome sequencing. WGM utilizes restriction site analysis but arranges 200 to 500 bands in the order they appear on the chromosome. WGM is able to quickly and cost-effectively generate high-resolution, ordered whole-genome maps of bacteria. PMID- 23363822 TI - Development of a novel PCR restriction analysis of the hsp65 gene as a rapid method to screen for the Mycobacterium tuberculosis complex and nontuberculous mycobacteria in high-burden countries. AB - The limitations of conventional methods of identification of Mycobacterium tuberculosis have led to the development of several nucleic acid amplification techniques which have the advantage of being rapid, sensitive, and specific. However, their expense or the need for technical expertise makes it difficult to use them in regions in which tuberculosis is endemic. A novel PCR restriction analysis (PRA) of the hsp65 gene was therefore developed for rapid screening of clinical isolates to identify Mycobacterium spp. The restriction enzymes NruI and BamHI were selected to obtain a limited number of restriction patterns to further differentiate between Mycobacterium tuberculosis complex (MTBC) and nontuberculous mycobacteria (NTM). Three hundred ten isolates from clinical specimens and 24 reference strains were tested. The assay correctly identified 295 of the 310 culture isolates as MTBC, while the remaining 15 isolates were identified as NTM. Of the isolates tested, 135 MTBC strains and all 15 NTM were also confirmed by PRA using Sau96I and CfoI. Thirty-eight randomly selected MTBC strains and all 15 NTM were further confirmed by sequencing. The NruI/BamHI PRA was simple, as it did not require any elaborate analyses. It was cost-effective, rapid, highly sensitive, and specific and did not require technical expertise. The assay can, therefore, be used as a simple screening test not only to detect Mycobacterium spp. but also to differentiate MTBC from NTM in peripheral laboratories with minimal availability of funds. PMID- 23363823 TI - Detection and genetic diversity of porcine group A rotaviruses in historic (2004) and recent (2011 and 2012) swine fecal samples in Ohio: predominance of the G9P[13] genotype in nursing piglets. AB - Epidemiological surveillance of porcine group A rotavirus (RVA) strains was conducted in five swine herds in Ohio using historical (2004) and recent (2011 to 2012) fecal samples. Of the 371 samples examined, 9.4% (35/371) were positive for RVA. The RVA detection rates increased from 5.9% in 2004 and 8.5% in 2011 to 13.8% in 2012. A total of 23 positive samples were analyzed for RVA G and P genotypes. The dominant G-P combination was G9P[13] found in 60.9% of positive samples. The other combinations were G9P[7] (8.7%), G4P[13] (8.7%), G11P[13] (4.3%), and G11P[7] (4.3%). Sequence analysis of partial VP7 genes of selected strains revealed that the G4 strains were closely related to one another (95%) and, to a lesser extent, to human (82 to 84%) and porcine (84 to 86%) G4 strains. The G11 strains detected shared identical VP7 gene sequences (100%) and were closely related to human (85 to 86%) and other porcine (83%) G11 strains. The G9 strains identified were closely related to one another and to human and other porcine strains (96 to 97%, 89 to 91%, and 89 to 91% nucleotide identities, respectively). The VP4 gene analysis revealed that P[7] strains were closely related to each other and to P[7] strains isolated from porcine, bovine, and panda samples (91 to 99%, 92 to 99% and 92 to 99%, respectively). The P[13] strains showed a higher diversity among themselves and with other porcine P[13] strains, ranging from 83% to 99% and from 82 to 97%, respectively. Our results demonstrate broad genetic heterogeneity of the RVA strains and suggest the possibility of genetic reassortment between different RVA genotypes within these farms. PMID- 23363824 TI - Comparison of Anyplex II RV16 with the xTAG respiratory viral panel and Seeplex RV15 for detection of respiratory viruses. AB - A novel multiplex real-time PCR approach (Anyplex II RV16 [RV16]; Seegene, South Korea) was compared with a multiplex endpoint PCR kit (Seeplex RV15 ACE detection kit [RV15]; Seegene) and a liquid bead-based assay (xTAG respiratory viral panel [xTAG]; Abbott, United States). Of nasopharyngeal swabs or aspirates and bronchoalveolar lavage fluid samples submitted for RV15 testing, 199 retrospectively collected positive specimens and 283 prospectively collected specimens were further tested with RV16 and xTAG. A true-positive result was defined as a positive result from all three methods or RV16 and xTAG or RV15 and xTAG. For specimens with discrepant results, monoplex PCR and sequencing of the target viruses were performed. In total, 300 virus-positive specimens yielded 386 viruses. When the bocavirus results were excluded, the overall sensitivities of RV16, RV15, and xTAG were 95.2%, 93.3%, and 87.2%, respectively (95% confidence intervals, 93.0 to 97.4%, 90.8 to 95.8%, and 83.8 to 90.6%, respectively). RV16 was more sensitive than xTAG for coronavirus OC43/HKU1 (100% versus 26.1%; P < 0.0001) and adenovirus (100% versus 79.5%; P < 0.01) but was less sensitive than xTAG for rhinovirus/enterovirus (89.4% versus 97.9%; P < 0.05). RV16 demonstrated higher sensitivity than RV15 for the detection of adenovirus (100% versus 82.1%; P < 0.05). The specificities of all three methods ranged from 98.6% to 100%. Sequencing analysis of 64 rhinovirus-positive samples revealed that RV16 accurately differentiated between rhinovirus and enterovirus. RV16 most frequently missed rhinovirus C. In conclusion, the overall sensitivity of RV16 was better than that of xTAG. However, improvement of the sensitivity for rhinovirus is required. PMID- 23363825 TI - Direct sequencing and RipSeq interpretation as a tool for identification of polymicrobial infections. AB - In this study, RipSeq Mixed, a software resolving uninterpretable mixed DNA sequencing chromatograms, revealed the bacterial content of 15 polymicrobial samples. Direct sequencing combined with RipSeq Mixed constitutes a valuable supplement to cultivation, particularly when cultivation is negative and direct sequencing is inconclusive despite continued clinical indications of infection. PMID- 23363826 TI - Ciprofloxacin-resistant Aeromonas hydrophila cellulitis following leech therapy. AB - We report a case of surgical site infection with ciprofloxacin-resistant Aeromonas hydrophila following leech therapy. Antimicrobial and genetic analyses of leech and patient isolates demonstrated that the resistant isolates originated from the leech gut microbiota. These data suggest that ciprofloxacin monotherapy as a prophylaxis regimen prior to leech therapy may not be effective in preventing infection. PMID- 23363827 TI - A deceptive case of cellulitis caused by a Gram-negative pathogen. AB - Yokenella regensburgei is a member of the family Enterobacteriaceae that has rarely been implicated in clinical disease. We report here a case of septicemia with a skin and soft tissue source caused by Y. regensburgei in an immunocompromised host. PMID- 23363828 TI - Invasive pulmonary aspergillosis due to Emericella nidulans var. echinulata, successfully cured by voriconazole and micafungin. AB - A 78-year-old male who was undergoing prolonged glucocorticoid treatment experienced cough and expectoration for 2 weeks. Galactomannan antigen analysis and a chest computed tomography (CT) scan suggested a diagnosis of invasive pulmonary aspergillosis. DNA sequencing indicated that Emericella nidulans var. echinulata was the causative agent. A combination of voriconazole and micafungin successfully treated the illness. PMID- 23363829 TI - Evaluation of an algorithmic approach in comparison with the Illumigene assay for laboratory diagnosis of Clostridium difficile infection. AB - The following three diagnostic algorithms were evaluated in comparison with the Illumigene assay as a stand-alone test for Clostridium difficile detection: glutamate dehydrogenase antigen screen (GDH) followed by toxin A/B antigen testing (Tox A/B) with the cell cytotoxicity assay for discordant specimens (algorithm 1), GDH followed by the Illumigene (algorithm 2), and GDH followed by Tox A/B with the Illumigene for discordant specimens (algorithm 3). A total of 428 stool specimens submitted to three clinical microbiology laboratories in Manitoba, Canada, for C. difficile detection between June 2011 and April 2012 were included in the study. The prevalence of C. difficile in the stool specimens was 14.7% (63/428) based on toxigenic culture (microbiologic reference standard). The sensitivity and specificity of the Illumigene for C. difficile detection were 73.0% and 99.7%, respectively. The corresponding sensitivities and specificities were 65.1% and 100.0% for algorithm 1, 68.3% and 100.0% for algorithm 2, and 69.8% and 100.0% for algorithm 3. Using algorithm 1, a cell cytotoxicity assay was required for toxin detection in 37% of positive tests, prolonging turnaround time. However, the predictive value of a positive test based on a clinical reference standard (all tests positive or cytotoxigenic culture positive and clinical disease on chart review) was slightly higher with algorithm 1 than with the Illumigene assay as a stand-alone test or as part of an algorithm (algorithms 2 and 3). Based on a reduction in turnaround time, simplicity, and acceptable sensitivity and specificity, we recommend algorithm 2 (screening with the GDH antigen test and confirmatory testing with the Illumigene). PMID- 23363830 TI - Comparison of (1->3)-beta-D-glucan, mannan/anti-mannan antibodies, and Cand-Tec Candida antigen as serum biomarkers for candidemia. AB - We conducted a case-control study using the Fungitell assay, the novel Platelia Candida Antigen (Ag) Plus and Candida Antibody (Ab) Plus assays, and the Cand-Tec latex agglutination test to evaluate the usefulness of (1->3)-beta-D-glucan (BDG), mannan antigen with/without anti-mannan antibody, and Cand-Tec Candida antigen measurement for the diagnosis of candidemia. A total of 56 patients fulfilled the inclusion criteria and were enrolled. One hundred patients with bacteremia and 100 patients with sterile blood cultures served as negative controls. In the candidemia group, median (1->3)-beta-D-glucan, mannan antigen, and anti-mannan antibody levels were 427 pg/ml, 190 pg/ml, and 18.6 antibody units (AU)/ml, respectively. All three parameters were significantly elevated in patients with candidemia. The sensitivity and specificity were, respectively, 87.5% and 85.5% for (1->3)-beta-D-glucan, 58.9% and 97.5% for mannan antigen, 62.5% and 65.0% for anti-mannan antibody, 89.3% and 63.0% for mannan antigen plus anti-mannan antibody, 89.3% and 85.0% for BDG plus mannan antigen, and 13.0% and 93.9% for Cand-Tec Candida antigen. The low mannan antigen sensitivity was in part caused by Candida parapsilosis and Candida guilliermondii fungemias, which were not detected by the Platelia Candida Ag Plus assay. When the cutoff was lowered from 125 pg/ml to 50 pg/ml, mannan antigen sensitivity increased to 69.6% without severely affecting the specificity (93.5%). Contrary to recently published data, superficial candidiasis was not associated with elevated mannan antigen levels, not even after the cutoff was lowered. Combining procalcitonin (PCT) with (1->3)-beta-D-glucan to increase specificity provided a limited advantage because the benefit of the combination did not outweigh the loss of sensitivity. Our results demonstrate that the Cand-Tec Candida antigen and the mannan antigen plus anti-mannan antibody measurements have unacceptably low sensitivity or specificity. Of the four tests compared, (1->3)-beta-D-glucan and mannan antigen are the superior biomarkers, depending on whether a sensitivity driven or specificity-driven approach is used. PMID- 23363831 TI - Cerebrospinal fluid (1,3)-beta-D-glucan detection as an aid for diagnosis of iatrogenic fungal meningitis. AB - This case series highlights our experience with use of the Fungitell assay for quantifying (1,3)-beta-d-glucan in cerebrospinal fluid during the current U.S. outbreak of fungal meningitis related to contaminated methylprednisolone acetate. This test may prove a useful adjunct in diagnosis and management of exposed patients. PMID- 23363832 TI - Two cases of Ruminococcus gnavus bacteremia associated with diverticulitis. AB - We report two cases of bacteremia with the anaerobic bacterium Ruminococcus gnavus. In both cases, the bacteremia was associated with diverticular disease. Preliminary conventional identification suggested peptostreptococci, and matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis did not produce scores high enough for species identification. Finally, the bacteria were identified by 16S rRNA gene sequencing. PMID- 23363833 TI - Clinical characteristics of Ochrobactrum anthropi bacteremia. AB - The clinical picture of Ochrobactrum anthropi infection is not well described because the infection is rare in humans and identification of the pathogen is difficult. We present a case of O. anthropi bacteremia that was initially misidentified as Ralstonia paucula and later identified by 16S rRNA sequencing and recA analysis. PMID- 23363834 TI - Deciphering genomic virulence traits of a Staphylococcus epidermidis strain causing native-valve endocarditis. AB - We applied real-time genome sequencing to a Staphylococcus epidermidis strain that caused native-aortic-valve endocarditis in a 26-year-old patient. The 2.5-Mb genome from strain CSUR P278 exhibited a unique sequence type among S. epidermidis strains and contained 32 genes previously considered virulence genes in this species. PMID- 23363835 TI - A human papilloma virus testing algorithm comprising a combination of the L1 broad-spectrum SPF10 PCR assay and a novel E6 high-risk multiplex type-specific genotyping PCR assay. AB - Human papillomavirus (HPV) epidemiological and vaccine studies require highly sensitive HPV detection and genotyping systems. To improve HPV detection by PCR, the broad-spectrum L1-based SPF10 PCR DNA enzyme immunoassay (DEIA) LiPA system and a novel E6-based multiplex type-specific system (MPTS123) that uses Luminex xMAP technology were combined into a new testing algorithm. To evaluate this algorithm, cervical swabs (n = 860) and cervical biopsy specimens (n = 355) were tested, with a focus on HPV types detected by the MPTS123 assay (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 6, and 11). Among the HPV positive samples, identifications of individual HPV genotypes were compared. When all MPTS123 targeted genotypes were considered together, good overall agreement was found (kappa = 0.801, 95% confidence interval [CI], 0.784 to 0.818) with identification by SPF10 LiPA, but significantly more genotypes (P < 0.0001) were identified by the MPTS123 PCR Luminex assay, especially for HPV types 16, 35, 39, 45, 58, and 59. An alternative type-specific assay was evaluated that is based on detection of a limited number of HPV genotypes by type-specific PCR and a reverse hybridization assay (MPTS12 RHA). This assay showed results similar to those of the expanded MPTS123 Luminex assay. These results confirm the fact that broad spectrum PCRs are hampered by type competition when multiple HPV genotypes are present in the same sample. Therefore, a testing algorithm combining the broad spectrum PCR and a range of type-specific PCRs can offer a highly accurate method for the analysis of HPV infections and diminish the rate of false-negative results and may be particularly useful for epidemiological and vaccine studies. PMID- 23363836 TI - Identification of endogenous Coccidioides posadasii contamination of commercial primary rhesus monkey kidney cells. AB - Here we describe the identification of endogenous Coccidioides posadasii contamination in commercial rhesus monkey kidney (RhMK) cells and the subsequent nationwide alert that reduced the risk of laboratory exposure. This extraordinary event highlights the necessity for laboratories to remain vigilant in the use of appropriate biosafety procedures, particularly when working with unknown pathogens. PMID- 23363837 TI - Prevalence and characterization of methicillin-resistant Staphylococcus aureus isolates from retail meat and humans in Georgia. AB - There is increasing interest in the presence of Staphylococcus aureus, specifically methicillin-resistant S. aureus (MRSA), on retail meat products. In this study, staphylococci were isolated from retail pork and retail beef in Georgia, and MRSA from the products was compared to human MRSA from the same geographic area using broth microdilution antimicrobial susceptibility testing, multilocus sequence typing (MLST), spa typing, SCCmec typing, and pulsed-field gel electrophoresis (PFGE). S. aureus was isolated from 45% (45/100) of pork products and 63% (63/100) of beef products; mecA was detected in S. aureus from both pork (3/100; 3%) and beef (4/100; 4%). Fifty percent (50/100) of human S. aureus also contained mecA. Multidrug resistance was detected among MRSA from all sources. All MRSA (n = 57) was SCCmec type IV, and nine different spa types were present among the isolates (t002, t008, t012, t024, t179, t337, t548, t681, and t1062). Four sequence types (ST5, ST8, ST9, and ST30) were detected using MLST; the majority of MRSA isolates belonged to ST8, followed by ST5. One retail beef MRSA isolate belonged to ST8, while the remaining three were ST5. In retail pork MRSA, ST5, ST9, and ST30 were observed. The majority of human MRSA isolates belonged to ST8. Thirty-seven MRSA isolates, one of which was a retail beef MRSA isolate, were pvl(+). Using PFGE, MLST, and spa typing, three retail beef MRSA isolates were found to be identical in PFGE pattern, ST, and spa type to two human clonal MRSA isolates (USA100 and USA300). One additional retail beef MRSA isolate had a PFGE pattern similar to that of a human MRSA isolate, whereas none of the retail pork MRSA isolates had PFGE patterns similar to those of human MRSA isolates. These data suggest that the retail beef samples were contaminated by a human source, possibly during processing of the meat, and may present a source of MRSA for consumers and others who handle raw meat. PMID- 23363838 TI - Evaluation of a microarray-based assay for rapid identification of Gram-positive organisms and resistance markers in positive blood cultures. AB - Rapid identification of pathogens directly from positive blood cultures can play a major role in reducing patient mortality rates. We evaluated the performance of the Verigene Gram-Positive Blood Culture (BC-GP) assay (Nanosphere Inc., Northbrook, IL) for detection of commonly isolated Gram-positive organisms as well as associated resistance markers from positive blood cultures. Positive blood cultures (VersaTREK; Trek Diagnostic Systems, Independence, OH) from 203 patients with Gram-positive organism infections were analyzed using the BC-GP assay within 12 h for the detection of 12 different organisms, including staphylococci, streptococci, and enterococci, as well as for the presence of 3 resistance markers (mecA, vanA, and vanB). Results were compared to those of routine laboratory methods for identification and susceptibility testing. For identification of organisms and detection of resistance markers in 178 monomicrobial positive blood cultures, the BC-GP assay showed 94% and 97% concordance, respectively, with routine methods. After 25 polymicrobial cultures were included, the results showed 92% and 96% agreement for identification and resistance markers, respectively, for a total of 203 positive cultures. In 6/25 polymicrobial cultures, at least 1 isolate was not detected. Concordance levels for detection of major pathogens such Staphylococcus aureus (n = 45) and enterococci (n = 19) were 98% and 95%, respectively. Agreement levels for detection of resistance markers such as mecA and vanA/B were 92% and 100%, respectively. The BC-GP assay is capable of providing rapid identification of Gram-positive cocci as well as detection of resistance markers directly from positive blood cultures at least 24 to 48 h earlier than conventional methods. PMID- 23363839 TI - CHROMagar Orientation medium reduces urine culture workload. AB - Microbiology laboratories continually strive to streamline and improve their urine culture algorithms because of the high volumes of urine specimens they receive and the modest numbers of those specimens that are ultimately considered clinically significant. In the current study, we quantitatively measured the impact of the introduction of CHROMagar Orientation (CO) medium into routine use in two hospital laboratories and compared it to conventional culture on blood and MacConkey agars. Based on data extracted from our Laboratory Information System from 2006 to 2011, the use of CO medium resulted in a 28% reduction in workload for additional procedures such as Gram stains, subcultures, identification panels, agglutination tests, and biochemical tests. The average number of workload units (one workload unit equals 1 min of hands-on labor) per urine specimen was significantly reduced (P < 0.0001; 95% confidence interval [CI], 0.5326 to 1.047) from 2.67 in 2006 (preimplementation of CO medium) to 1.88 in 2011 (postimplementation of CO medium). We conclude that the use of CO medium streamlined the urine culture process and increased bench throughput by reducing both workload and turnaround time in our laboratories. PMID- 23363840 TI - CHROMagar Yersinia, a new chromogenic agar for screening of potentially pathogenic Yersinia enterocolitica isolates in stools. AB - CHROMagar Yersinia (CAY) is a new chromogenic medium for the presumptive detection of virulent Yersinia enterocolitica in stools. Based on a comparative analysis of 1,494 consecutive stools from hospitalized patients, CAY was found to be just as sensitive as the reference medium (cefsulodin-irgasan-novobiocin agar) but was significantly more specific and had a very low false-positive rate. CAY reduces the workload (and thus costs) for stool analysis and can therefore be recommended for routine laboratory use. PMID- 23363841 TI - Comparative study of IS6110 restriction fragment length polymorphism and variable number tandem-repeat typing of Mycobacterium tuberculosis isolates in the Netherlands, based on a 5-year nationwide survey. AB - In order to switch from IS6110 and polymorphic GC-rich repetitive sequence (PGRS) restriction fragment length polymorphism (RFLP) to 24-locus variable-number tandem-repeat (VNTR) typing of Mycobacterium tuberculosis complex isolates in the national tuberculosis control program in The Netherlands, a detailed evaluation on discriminatory power and agreement with findings in a cluster investigation was performed on 3,975 tuberculosis cases during the period of 2004 to 2008. The level of discrimination of the two typing methods did not differ substantially: RFLP typing yielded 2,733 distinct patterns compared to 2,607 in VNTR typing. The global concordance, defined as isolates labeled unique or identically distributed in clusters by both methods, amounted to 78.5% (n = 3,123). Of the remaining 855 cases, 12% (n = 479) of the cases were clustered only by VNTR, 7.7% (n = 305) only by RFLP typing, and 1.8% (n = 71) revealed different cluster compositions in the two approaches. A cluster investigation was performed for 87% (n = 1,462) of the cases clustered by RFLP. For the 740 cases with confirmed or presumed epidemiological links, 92% were concordant with VNTR typing. In contrast, only 64% of the 722 cases without an epidemiological link but clustered by RFLP typing were also clustered by VNTR typing. We conclude that VNTR typing has a discriminatory power equal to IS6110 RFLP typing but is in better agreement with findings in a cluster investigation performed on an RFLP-clustering-based cluster investigation. Both aspects make VNTR typing a suitable method for tuberculosis surveillance systems. PMID- 23363842 TI - Indoxyl sulfate enhances p53-TGF-beta1-Smad3 pathway in proximal tubular cells. AB - BACKGROUND/AIM: Indoxyl sulfate-induced activation of nuclear factor (NF)-KB promotes transforming growth factor (TGF)-beta1 in human proximal tubular cells (HK-2 cells). The present study aimed to elucidate the cross talk among indoxyl sulfate, p53 and TGF-beta1-Smad3 signaling in proximal tubular cells. METHODS: The effects of indoxyl sulfate on the expression of TGF-beta1, Smad3, and alpha smooth muscle actin (alpha-SMA) were determined using HK-2 cells. As for in vivo experiments the following animals were used: Dahl salt-resistant normotensive rats (DN) and indoxyl sulfate-administered Dahl salt-resistant normotensive rats (DN+IS). RESULTS: Both indoxyl sulfate and nutlin-3, a specific p53 inducer, stimulated TGF-beta1 expression, which was suppressed by pifithrin-alpha, p nitro, a p53 inhibitor. Further, indoxyl sulfate stimulated TGF-beta1-induced expression of alpha-SMA by enhancing Smad3 expression and TGF-beta1-induced Smad3 phosphorylation. Indoxyl sulfate induced phosphorylation of extracellular signal regulated kinase (ERK). U0126, an inhibitor of ERK pathway, prevented indoxyl sulfate-induced upregulation of Smad3 expression. Immunohistochemistry demonstrated that TGF-beta1 and Smad3 were localized in renal tubular cells, and that indoxyl sulfate increased the TGF-beta1 and Smad3-positive area in the kidney. CONCLUSION: Indoxyl sulfate stimulates p53-induced TGF-beta1 expression and TGF-beta1-induced alpha-SMA expression in proximal tubular cells. Indoxyl sulfate-induced Smad3 accelerates TGF-beta1-induced alpha-SMA expression through ERK activation. Thus, indoxyl sulfate enhances p53-TGF-beta1-Smad3 pathway in proximal tubular cells. PMID- 23363844 TI - [Studies on the title of syndromes in Ben cao gang mu (Compendium of Materia Medica)]. PMID- 23363845 TI - [Approaches to acquire medical prescriptions by the Song intellectuals]. AB - In order to treat disease of oneself or other people, the Song intellectuals were eager to collect medical recipes or compiled medical formularies. Their main approaches in this regard included conversation with medical practitioners, mutual communication among themselves, and reading medical texts. Since the effectiveness of the recipes was emphasized through the first two approaches, the approach of reading medical texts appeared to be insignificant. Even if this last approach was selected, they tended to read those texts with evidences showing its effectiveness of the recipes carried in the texts. PMID- 23363846 TI - [The influence of ZHU Gong's Huo ren shu (A Book for Savings Life)in the Southern Song Dynasty and its Influence on the discipline of Cold Pathogenic Disease]. AB - ZHU Gong's Huo ren shu (A Book for Saving Life) is a famous work in the history of research on Treatise on Cold Damage Diseases. It has great influence on the study of cold pathogenic disease, especially that of the Song dynasty. Many authors reedited or annotated this book to inherit and developed the idea of the Huo ren shu. Thus, a lot of new books, including annotations, revisions, citations, or discussions, appeared. WANG Su's Zeng shi nan yang huo ren shu (Amplified Annotated Huorenshu), for example, is one of them. Those compiled as rhymes or knacks include XU Shu-wei's Shang han bai zheng ge (The Rhymes of Hundred Kinds of Cold Damage Disease), LI Zhi-xian's Huo ren shu kuo (Introduction to Huorenshu), QIAN Wen-li's Shang han bai wen ge (Hundred Questions on Cold Damage Disease), YANG Shi-ying's Shang han lei shu huo ren zong kuo (A General Introduction to Huorenshu, a Classified Book of Cold Damage Disease), and TANG Yin-cai's Shang han jie huo lun (Essay to Answering Suspicions on Cold Damage Disease). Those cited or inherited the book include LI Cheng's Shang han yao zhi (Gist of Cold Damage Disease), GUO Yong's Shang han bu wang lun (Supplements to Cold Damage Disease), SUN Zhi-ning's Shang han jian yao shi shuo (Ten Simple Discourses on Cold Damage Disease), and CHEN Zi-ming's Guan jian da quan liang fang (A Complete Effective Formulary with my Own Opinions). Those differentiating the essentials of the Huorenshu including CHENG Jiong's Huo ren shu bian (Differentiation for Huorenshu), and LU Zu-chang's Ni jin huo ren can tong yu yi (An Elaboration on Huorenshu to be Presented). All the above books indicate the impact of the Huorenshu, and show its influence on later ages as well. PMID- 23363843 TI - Structural and functional association of androgen receptor with telomeres in prostate cancer cells. AB - Telomeres protect the ends of linear chromosomes from being recognized as damaged DNA, and telomere stability is required for genome stability. Here we demonstrate that telomere stability in androgen receptor (AR)-positive LNCaP human prostate cancer cells is dependent on AR and androgen, as AR inactivation by AR antagonist bicalutamide (Casodex), AR-knockdown, or androgen-depletion caused telomere dysfunction, and the effect of androgen-depletion or Casodex was blocked by the addition of androgen. Notably, neither actinomycin D nor cycloheximide blocked the DNA damage response to Casodex, indicating that the role of AR in telomere stability is independent of its role in transcription. We also demonstrate that AR is a component of telomeres, as AR-bound chromatin contains telomeric DNA, and telomeric chromatin contains AR. Importantly, AR inactivation by Casodex caused telomere aberrations, including multiple abnormal telomere signals, remindful of a fragile telomere phenotype that has been described previously to result from defective telomere DNA replication. We suggest that AR plays an important role in telomere stability and replication of telomere DNA in prostate cancer cells, and that AR inactivation-mediated telomere dysfunction may contribute to genomic instability and progression of prostate cancer cells. PMID- 23363847 TI - [Study on carving workers of Chong xiu zheng he jing shi zheng lei bei yong ben cao (Revised Prepared Materia Medica Classified under Syndromes in Zhenghe Period) published by Huiming Xuan (Huiming Sanctum)]. AB - The ancient carving workers have made a great contribution to the xylographic printing art in ancient China, so the studies on them are significant for a survey of ancient Chinese printing history, and for the identification of ancient Chinese books edition. Zheng lei ben cao published by Huiming Xuan (Huiming Sanctum) in the Jin and Yuan dynasties, which is the earliest extant edition of Zhenghe version system of Zheng lei ben cao and has important literature value. Thirty carving workers were involved in its printing process. On the whole, these workers had a relatively high technique and completed a remarkably fine work. In addition to lettering, 28 persons of them also made a total of 536 pages with 900 exquisite engraving illustrations on Chinese materia medica included in this book. Because of the high levels on carving, this precious book has been the representative of Pingshui edition, which has a great reputation but has very few works now. PMID- 23363848 TI - [Compilation of Yan ke zheng zong yuan ji qi wei (Orthodox Ophthalmology: Revealing the Mystery of Eye Disease) and its academic achievements]. AB - As an ophthalmic monograph compiled to systemize and elaborate the Yuan ji qi wei (Revealing the Mystery of Eye Disease) written to explore the gist of the original author, a valuable edition of the original Yuan ji qi wei. SHI Shi-de made reviews and comments to each eye disease included in the first volume of Yuan ji qi wei, followed by the rhymes on the etiology, manifestations, treatment and prescriptions written by his son SHI Guang, and rearranged and systemized the whole text made by his little brother SHI Shi-qi for better memory and popularization. He stressed the significant position of Yuan ji qi wei. The achievements of the Yan ke zheng zong yuan ji qi wei can be summarized into 4 points: the "18 disease" of eye disease is the guidelines for the differential diagnosis of ophthalmic diseases; Shi's annotation developed the essence of Ni's theory; SHI Guang's rhymes facilitated the spread of Ni's theory; the "hints for prescription" being the standards for the treatment of eye disease. PMID- 23363849 TI - [Textual Research on Chiding Disease and Matixiang Herb in Da he wai ke (External Medicine of Da He)]. AB - Recorded in Da he wai ke (The External Medicine of Da He) in the Ming dynasty without a corresponding disease title in contemporary scholarly concepts of Traditional Chinese Medicine (TCM), Chiding disease was described as an acute symptomatic disease with inevitable serious conditions of convulsion-like or mania-like behavior, and as a refractory ailment. It was also considered as an alias of Hongsiding (namely the acute lymphangitis) in few ancient books. Matixiang, a Chinese herb for treatment of Chiding, was regarded as a nonsuch drug by Da he wai ke, and was considered as a take-then-cure drug by Chuang yang jing yan quan shu (Compendium for Experience in Sores Diseases). The present studies about Chiding and Matixiang show that: (1) the name of Chiding was first seen in Zhong zang jing (Master Hua's Classic of the Viscera) ; (2) Chiding was rarely mentioned in medical literature of the Song, Yuan and Qing Dynasty, but mostly seen in the Ming Dynasty; (3) Xinding and Huoyanding were found as synonyms of Chiding ; (4) the distinction between Chiding and Hongsiding (flaming sore) was revealed by comparison analysis of their etiology, affected part(s), symptoms, prognosis and syndromic pictures; (5) Chiding on the tongue is the same as "Tongue Ding" or "Sublingual Ding" in contemporary TCM and as "Sublingual Space Infection" in Western Medicine. Moreover, Chiding on the hands, feet or other skin parts could be classified as "Hands/Feet Ding" in contemporary TCM and as "Furuncle" (i.e., Acute Suppurative Folliculitis and Perifolliculitis or cellulites of the tongue) in Western Medicine; (6) Matixiang is probably deduced as Asarum forbesii Maxim., A. ichangense C. Y. Cheng et C. S. Yang, family Aristolochiaceae, or Valeriana jatamansi Jones., family Valerianaceae. PMID- 23363850 TI - [An analysis on the classification of relics of TCM]. AB - The classification of relics of traditional Chinese medicine (TCM) is an important aspect, a main method of TCM relics research, and a key point for improving the construction of its theory. The general classification in the Cultural Sector could be applied, including relics' location, source, morphological form, time, quality, function, medical type and social character. However, TCM relics reveal high practicality, which should be classified on the basis of their function in order to reflect the meaning, value and their own features different from the relics of other fields. Moreover, this method is easy to operate. Therefore, classification by its function should be paid attention and treated as the key-point in the research on TCM relics. PMID- 23363851 TI - [The development of chemical narcotic and related anesthetic techniques in modern times]. AB - Before the 19(th) century, ether and nitrous oxide were synthesized. However, they were just used as a kind of enjoyable things at night gatherings for their hypnotic and analgesic effect. In the 19(th) century, ether and nitrous oxide came into use in clinical anesthesia. Thereafter, more and more chemical narcotics were synthesized and applied to clinical anesthesia. In 1872, chloroform was injected into man's vein for anesthesia. In the 20(th) century, along with many kinds of barbiturates being synthesized, intravenous anesthesia got much development and application. At the same time, related techniques of anesthesia also improved. In the early 19(th) century, open inhalation anesthesia was often used. In 1900, there came a new anesthesia method by blowing into the windpipe through the cut of throat. Later on, the technique of endotracheal anesthesia and artificial respiration anesthesia (1908), the anesthetic instrument of endotracheal intubation and laryngeal mask and laryngoscope were invented. In the mid 19(th) century, the appearance of injection syringe and cocaine made local anesthesia possible. In 1880, local anesthesia also became successful. Thereafter, a variety of local anesthetic drugs were synthesized and applied, companying with various techniques of local anesthesia such as subarachnoid anesthesia (1900), sacral anesthesia (1901), epidural block (1903), plexus block (1902) and so on. In order to control the depth of anesthesia and respiration effectively, people attempted a lot so that anesthesia machine (1910), improved endotracheal anesthesia (1921), cryogenic technique (1902), controlled hypotension (1940s) and artificial hibernation (1950) came into being. PMID- 23363852 TI - [Version investigation and the author investigation and argumentation of "Zeng Bu Shi Wu Ben Cao Bei Kao"]. AB - "Zeng Bu Shi Wu Ben Cao Bei Kao"is the masterpiece of Guangdong food material medica works Based on the investigation of the existing version. We think the statement that "Chinese ancient books catalogue" record the first version of the book is in ten years of Yong Zheng is wrong. We infer that "Zeng Bu Shi Wu Ben Cao Bei Kao"'s author named He kejian and "Sheng Cao Yao Xing Be Yao"'s author named He Jian is the same person. However, the former book is mainly sorted by He Shengxuan, and it maybe initially carved in 1738. PMID- 23363853 TI - Cell-Free circulating DNA: a new biomarker for the acute coronary syndrome. AB - BACKGROUND: In recent studies, concentrations of cell-free circulating DNA (cf DNA) have been correlated with clinical characteristics and prognosis in several diseases. The relationship between cf-DNA concentrations and the acute coronary syndrome (ACS) remains unknown. Moreover, no data are available for the detection cf-DNA in ACS by a branched DNA (bDNA)-based Alu assay. The aim of the present study was to investigate cf-DNA concentrations in ACS and their relationship with clinical features. METHODS: Plasma cf-DNA concentrations of 137 ACS patients at diagnosis, of 60 healthy individuals and of 13 patients with stable angina (SA) were determined using a bDNA-based Alu assay. RESULTS: ACS patients (median 2,285.0, interquartile range 916.4-4,857.3 ng/ml), especially in ST-segment elevation myocardial infarction patients (median 5,745.4, interquartile range 4,013.5-8,643.9 ng/ml), showed a significant increase in plasma cf-DNA concentrations compared with controls (healthy controls: median 118.3, interquartile range 81.1-221.1 ng/ml; SA patients: median 202.3, interquartile range 112.7-256.1 ng/ml) using a bDNA-based Alu assay. Moreover, we found positive correlations between cf-DNA and Gensini scoring and GRACE (Global Registry of Acute Coronary Events) scoring in ACS. CONCLUSION: cf-DNA may be a valuable marker for diagnosing and predicting the severity of coronary artery lesions and risk stratification in ACS. PMID- 23363854 TI - Polymorphisms in the dopamine transporter gene are associated with visual hallucinations and levodopa equivalent dose in Brazilians with Parkinson's disease. AB - The requirement for dopaminergic drugs in Parkinson's disease (PD) is highly variable. Visual hallucinations are a frequent and serious complication of chronic levodopa therapy. Polymorphisms in the DAT1 gene might affect the reuptake of dopamine in the synaptic cleft, but the influence of this variability on adverse effects or levodopa equivalent dose on PD patients is still poorly investigated. Therefore, the aim of the present study was to investigate DAT1 gene polymorphisms on levodopa equivalent dose and visual hallucination occurrence in PD patients. Altogether, 196 PD patients in treatment with at least 200 mg levodopa equivalent dose for at least 1 yr were included. These patients were genotyped for the -839 C > T and 3' VNTR DAT1 polymorphisms by PCR-based methodologies. Visual hallucinations occurred in 25.5% of the sample. After controlling for confounders, the dopamine transporter (DAT) -839 C allele was associated with visual hallucinations (prevalence ratio 2.5, 95% confidence intervals 1.13-5.5, p = 0.02). Levodopa equivalent dose was lower in carriers of the nine repeat allele of the DAT 3'UTR VNTR (741.2 +/- 355.0 vs. 843.4 +/- 445.7), explaining 21% of dose variability (p = 0.01). Our results support an effect of DAT1 polymorphisms in adverse effects of anti-Parkinsonian drugs and in levodopa equivalent dose usage. PMID- 23363856 TI - [Prevention and control of infectious diseases: basic research and applications]. PMID- 23363855 TI - Vertical equity of healthcare in Taiwan: health services were distributed according to need. AB - INTRODUCTION: To test the hypothesis that the distribution of healthcare services is according to health need can be achieved under a rather open access system. METHODS: The 2001 National Health Interview Survey of Taiwan and National Health Insurance claims data were linked in the study. Health need was defined by self perceived health status. We used Concentration index to measure need-related inequality in healthcare utilization and expenditure. RESULTS: People with greater health need received more healthcare services, indicating a pro-need character of healthcare distribution, conforming to the meaning of vertical equity. For outpatient service, subjects with the highest health need had higher proportion of ever use in a year than those who had the least health need and consumed more outpatient visits and expenditures per person per year. Similar patterns were observed for emergency services and hospitalization. The concentration indices of utilization for outpatient, emergency services, and hospitalization suggest that the distribution of utilization was related to health need, whereas the preventive service was less related to need. CONCLUSIONS: The universal coverage plus healthcare networking system makes it possible for healthcare to be utilized according to need. Taiwan's experience can serve as a reference for health reform. PMID- 23363857 TI - [Review: influenza A and its vaccine]. PMID- 23363858 TI - [Enhance the study of climate change and health, reduce the health risk]. PMID- 23363859 TI - [Analysis of the variation and changes of Yersinia enterocolitica in Ningxia area from 1984 to 2011]. AB - OBJECTIVE: To analyze the genetic evolution and bacterial type changes of Yersinia enterocolitica in the Ningxia area between year 1984 and 2011. METHODS: A total of 296 strains of Yersinia enterocolitica was collected from diarrhea patients, pig, rodents, sheep and dogs between year 1984 and 2011. The serotype, biotype, ail, ystA, ystB, yadA, virF and other toxic genes were detected. The PFGE subtypes of serotype O:3 and O:9 strains and the cluster features were analyzed. RESULTS: Out of 296 Yersinia enterocolitica strains, pig was the main host, accounting for 65.20% (193/296), followed by rodents, accounting for 32.43% (96/296). Serotype and biotype had their own respective dominant types in different periods. During 1984 and 1985, 2 strains of serotype O:3 and 3 strains of serotype O:9 were isolated, all belonged to biotype 3. Because of lack of strains, there were no obvious dominant types found. Between 1997 and 1999, 177 strains of serotype O:9 Yersinia enterocolitica were isolated as the dominant strain; and there were 178 strains of biotype 2 Yersinia enterocolitica were found. During 2007 and 2011, 54 strains of serotype O:3 Yersinia enterocolitica were isolated as dominant strain; followed by 26 strains of serotype O:5. There were separately 44 and 59 strains of biotype 1A and biotype 3. The PCR test divided the 248 strains into 4 types, including pathogenic strains as type I (ail(+), ystA(+), ystB(-), yadA(+), virF(+)). The PFGE divided the serotype O:3 into 12 types, in which K6GN11C30021 and K6GN11C30012 were the dominant types, accounting for 63.64% (42/66). The serotype O:9 were divided into 14 types, in which K6GN11C90010, K6GN11C90008, K6GN11C30018 and K6GN11C90003 were the dominant types, accounting for 89.01% (162/182). CONCLUSION: The different serotypes of isolated strains in Ningxia district showed different dominant bacteria in different periods; while the biotypes also changed with serotypes. The Yersinia enterocolitica isolated from different years showed great variation. PMID- 23363860 TI - [Etiology surveillance of hand-foot-mouth disease in Henan province between 2008 and 2011]. AB - OBJECTIVE: To understand etiological types and distribution features of hand-foot mouth disease (HFMD) in Henan province between 2008 and 2011. METHODS: A total of 30 486 specimens of feces, rectal swabs or throat swabs from HFMD patients were collected by each Municipal CDC in Henan from 2008 to 2011. The enterovirus 71 (EV71), coxsackie virus A16 (CA16) and other enterovirus (EV) were detected by RT PCR or real time RT-PCR. The VP1 gene of EV71 was amplified and the sequences were analyzed by bioinformatics software. A genetic evolution tree of the sequence was constructed as well. RESULTS: The positive rates of EV71, CA16 and other EV were 62.70% (11 209/17 876), 12.03% (2150/17 876), 25.27% (4517/17 876) in 17 876 laboratory diagnosed cases, respectively. The differences were statistically significant (chi(2) = 157.17, P < 0.05). The positive rates of EV71, CA16 and other EV were 63.40% (7370/11 624), 11.58% (1346/11 624) and 25.02% (2908/11 624) in male patients and 61.40% (3839/6252), 12.86% (804/6252) and 25.74% (1609/6252) in female patients, respectively. The differences were statistically significant (chi(2) = 4.06, P < 0.05). The children under 5 years old were high-risk population of HFMD, accounting to 97.67% (17 459/17 876) of the laboratory-diagnosed patients.86.92% (15 537/17 876) cases were children between 1 to 3 years old. Constituent ratio of EV71 changed seasonally during a year, there was a high infection ratio of EV71 between April and June, especially in May, the infection ratio reached 69.34% (2384/3438). The positive rates of EV71, CA16 and other EV were 82.48% (5715/6929), 1.76% (122/6929) and 15.76% (1092/6929) among the 6929 laboratory-diagnosed severe cases, respectively. The positive rates of EV71 was higher than CA16 and other EV (chi(2) = 9259.17, 6170.81, P < 0.05, respectively). There were 117 deaths because of severe HFMD, 55 (47.01%) of which were laboratory confirmed. 50 death cases were infected by EV71, and according to the genetic evolution analysis, the VP1 gene of EV71 strain was belonged to subtype C4 of gene C. CONCLUSION: The EV71 and CA16 were the main pathogens which caused HFMD in Henan province, and EV71 virus was the dominant strain, belonging to C4 subtype of gene C. PMID- 23363861 TI - [Epidemic characteristics and viral antibody level among healthy people of Japanese B encephalitis in Henan province in 2010]. AB - OBJECTIVE: To understand the epidemic characteristics and viral antibody level among healthy people of Japanese B encephalitis (JE) in Henan province in 2010. METHODS: A total of 433 selected JE cases in Henan province in 2010 were analyzed by descriptive epidemiological method. Xinyang and Luoyang were selected as survey sites in 2010.12 administrative villages were randomly selected from both cities. As the investigation objects, 519 healthy people from the two cities were randomly selected by eight age groups:less than one year old, 1 - 2 years old, 3 4 years old, 5 - 6 years old, 7 - 14 years old, 15 - 19 years old, 20 - 59 years old, and above 60 years old. A total of 1008 samples of blood specimens were collected both in May and November, and JE viral antibody was detected by micro cytopathic effect neutralization test. RESULTS: The incidence rate of JE was 0.46/100 000 (433/94 130 434) in Henan province in 2010.97.69% (423/433) of the patients were found between July and September, and 81.06% (351/433) were distributed in Nanyang, Xinyang, Luoyang, Zhumadian and Zhoukou city. Children aged 0 to 14 years were the primarily affected group (82.22%, 356/433), the people above 15 years old accounted for 17.78% (77/433) of whole cases in Henan province, but the same group accounted for 65.79% (50/76) of whole cases in Luoyang city, which obviously higher than the percentage in Henan province (chi(2) = 79.57, P < 0.05). Most patients were scattered children in Henan province, accounting for 58.89% (255/433). In Luoyang city, most patients were peasants, accounting for 44.74% (34/76). The antibody positive rate of JE among health people above 15 years old in Luoyang city was 48.94% (46/94), which was lower than it in Xinyang city at 97.78% (88/90). The difference showed statistical significance (chi(2) = 55.42, P < 0.05). The antibody positive rate among healthy people under vaccination was 50.41% (61/121), which was obviously higher than that among people without vaccination, at 16.67% (6/36) in Luoyang city. The difference showed statistical significance (chi(2) = 12.92, P < 0.05). The antibody positive rate among healthy people under vaccination was 67.11% (51/76) in Xinyang city, which was obviously higher than that among people without vaccination, at 46.39% (45/97). The difference showed statistical significance (chi(2) = 7.40, P < 0.05). CONCLUSION: The incidence of JE showed seasonal and regional characteristics, there were differences among ages and occupations. The difference was consistent with the difference in viral antibody level among health people in Henan province and Luoyang city. PMID- 23363862 TI - [Time-series analysis on the malaria morbidity affected by meteorological factors in Guangdong province]. AB - OBJECTIVE: To evaluate the associations between malaria risk and meteorological factors. METHODS: A negative binomial distribution regression analysis was built between the temperature, relative humidity, rainfall capacity and the monthly incidence of malaria, based on the temperature information provided by Guangdong Meteorological Department and the malaria incidence information provided by Guangdong Center of Disease Prevention and Control during year 1980 to 2004, adopting the time-series analysis method and by distributed lag non-linear model, in order to analyze the immediate factors. RESULTS: The number of monthly malaria cases in Guangdong province reached 4010 between year 1984 and 2004, while the monthly maximal temperature, minimal temperature, average temperature, relative humidity and average rainfall capacity was separately 26.3 degrees C, 18.8 degrees C, 21.9 degrees C, 88.0% and 5.6 mm. The immediate effect of monthly maximal temperature on malaria incidence showed non-linear relationships. When the temperature reached 32.3 degrees C, the risk was highest, the relative risk (RR) was 2.51 (95%CI: 1.99 - 3.16); when the relative humidity was 60.0%, the relative risk of malaria was highest as 1.19 (95%CI: 0.66 - 2.11) and then decreased gradually; and when the relative humidity was 86.6%, the risk of malaria was lowest at 0.51 (95%CI: 0.34 - 0.76). The risk of malaria increased while the rainfall capacity was 14.5 mm, the risk of malaria was the highest at 1.29 (95%CI: 0.87 - 1.93). Strongest delayed effects on malaria incidence was observed when the monthly maximal temperature reached 31.5 degrees C at lagged 2 months, with the value of RR at 1.81 (95%CI: 1.02 - 3.22). When the monthly rainfall capacity was over 15.2 mm, the delayed effects was strong but short. When the monthly maximal temperature of 33.7 degrees C, the excess risk of malaria was comparatively high, the excess risk was 92.2% (95%CI: 30.5% - 183.2%) when lagging one month. When the relative humidity was low, the delayed effect of malaria lasted for a long time, and the cumulative effect was huge. When the relative humidity reached 87.0%, the excess risk lagging 3 months was only -66.6% (95%CI: -86.4% - -17.7%). When the rainfall capacity was 15.5 mm, the cumulative effect on malaria reached the peak after 3 months, while the excess risk was 40.7% (95%CI: -30.0% - -182.6%); afterwards the cumulative effect gradually weakened. Positive and negative interaction effects were significant between malaria risk and maximal temperature and monthly rainfall capacity, and monthly rainfall capacity and relative humidity at lagged 2 months, respectively. CONCLUSION: High temperature and large rainfall capacity might be the risk factors of malaria in Guangdong province, and there was an obvious interaction between the two factors. PMID- 23363863 TI - [Analysis of the spatial and temporal characteristics of measles patients younger than 1 year old in Shandong province]. AB - OBJECTIVE: To explore the spatial and temporal characteristics of measles patients younger than 1 year old in Shandong province. METHODS: A total of 5309 cases of measles, whose patients were younger than 1 year old in Shandong province between year 1999 and 2008 were collected. The epidemic features of measles were described, and the annual infant incidence was calculated. Software ArcGIS9.3 was applied to draw the spatial map of the disease, and the software GeoDa0.95i-beta was adopted to analyze the spatial autocorrelation. RESULTS: The incidence among infants younger than 1 year old reported in Shandong province rose from 23.45/100 000 (206 cases) in 1999 to 269.60/100 000 (2791 cases) in 2008.5309 cases covered all month-aged infants under 1 year old, except 12 months old. Most patients (3494 cases) aged between 6 - 9 months old; especially the infants around 8 months old, accounting for 20.7% (1100/5309). The epidemic peak was between March and May, accounting for 45.5% (2414/5309). The spatial and temporal distribution features showed an up and down temporal trend and an increase from east to west in spatial trend. The global Moran's I values of measles incidence among infants in Shandong province were 0.346, 0.150, 0.396, 0.213, 0.477, 0.354 and 0.331 in year 1999, 2001 - 2002, 2005 - 2008 (P < 0.01) and 0.076 in year 2004 (P < 0.05). The local spatial autocorrelation analysis showed that southwest and northwest districts of Shandong were highly clustered districts of measles. CONCLUSION: In Shandong, the measles incidence among infants younger than 1 year old rose obviously; especially the infants aged between 6-9 months age. The epidemic peak was between March and May. A positive spatial correlation was found, the disease showed a distinct regional distribution feature, and a cluster district was found. PMID- 23363864 TI - [Spatial distribution and risk factors of tuberculosis in Songjiang district, Shanghai during 2006 and 2009]. AB - OBJECTIVE: To identify spatial distribution and risk factors among tuberculosis (TB) cases in Songjiang district, Shanghai, 2006 - 2009. METHODS: All active TB cases and all bacteriologically confirmed TB cases diagnosed during the period from 2006 to 2009 were recruited into the study. Spatial scan statistics were used to identify spatial clusters. Using logistic regression, we compared the demographic and clinical characteristics of TB cases in spatial clusters versus TB cases not in spatial clusters. RESULTS: A total of 1815 active TB cases and 730 bacteriologically confirmed TB cases were recruited during 2006 - 2009. Chedun township and Xinqiao township was detected to be a spatial cluste (RR = 1.38, LLR = 16.78, P < 0.01), which was the location of the municipal industrial zone. No spatial cluster was found during 2006 - 2007, while during 2008 - 2009 Chedun township was detected to be a spatial cluster (RR = 1.70, LLR = 15.06, P < 0.01). Among resident population, the spatial cluster of TB cases was located in the southwestern part of Songjiang district, which included five townships Xinbang, Shihudang, Xiaokunshan, Maogang and Yongfeng (RR = 1.49, LLR = 10.52, P < 0.01); while among migrant population, the spatial cluster of TB cases was located in Chedun township (RR = 1.55, LLR = 15.64, P < 0.01). There were higher proportions of resident TB cases who were farmers (AOR = 4.9, 95%CI: 1.9 - 12.3) or had other occupations (AOR = 2.6, 95%CI: 1.1 - 5.9) in the spatial cluster. There were higher proportions of migrant TB cases who lived here for less than 5 years (< 1 year: AOR = 5.9, 95%CI: 1.8 - 19.5; 1 - 5 years: AOR = 3.2, 95%CI: 1.0 - 9.9) or worked at other occupations (AOR = 2.8, 95%CI: 1.5 - 5.1) and lower proportions of migrant TB cases who came from Eastern region (AOR = 0.3, 95%CI: 0.1 - 0.8) or Middle region (AOR = 0.5, 95%CI: 0.3 - 0.9) in the spatial cluster. CONCLUSION: In Songjiang district there was a spatial cluster in TB cases, which was Chedun township. Local residents with TB who were farmers or had other occupations were more likely to be in the spatial cluster. Migrants with TB who lived here for less than 5 years or came from Western region were more likely to be in the spatial cluster. PMID- 23363865 TI - [Study on comprehensive monitoring of mouse and effect of hemorrhagic fever with renal syndrome vaccine in high prevalence areas of natural focus infectious disease of Zhejiang province in 1994--2010]. AB - OBJECTIVE: To study the comprehensive monitoring mechanism of mouse and the effect of hemorrhagic fever with renal syndrome (HFRS) vaccine in the high prevalence areas of natural focus infectious disease of Zhejiang province in 1994 - 2010. METHODS: The night trapping method was used to monitor the population proportion, density and the rate of hantavirus (HV) carriers in mice in Xikou township Longyou county in August and September from 1994 to 2010. The healthy residents in Xikou township aged 16 to 60 years were recruited. The subjects were randomly selected as vaccination group and control group according to age, sex, occupational distribution (10 178 in intervention group and 16 159 in control group). Intervention group was given purified and inactivated vaccine from suckling mouse brain, while the control group received no intervention. The prevention effect was evaluated by protective rate of vaccine. RESULTS: The mouse population was stable in the sixteen years and the apodemus agrarius was the main type (76.5% (564/737)). The average density of mouse was 4.73% (1170/24 727). The average rate of virus carrier of mouse was 3.87% (41/1033). In 1994 - 1995, the density of mouse was 22.82% (186/815) and the rate of virus carrier was 7.0% (10/143). In 2009 - 2010, the density of mouse decreased to 2.75% (119/4330) and the rate of virus carrier was 5.5% (13/237). The average antibody positive rate of mouse from 2005 to 2010 was 4.8% (35/728) and the rate was 4.4% (6/138), 0.0% (0/113), 11.8% (16/136), 1.0% (1/104), 3.7% (4/109) and 6.3% (8/128) in each year (P < 0.01). The protective rate of HFRS vaccine was 96.2% (1 case in intervention group and 41 cases in control group). CONCLUSION: The density of mouse decreased significantly in Zhejiang province. The rate of virus carrier of mouse is stable. The vaccine is effective. PMID- 23363866 TI - [Association between human beta defensin-1 single nucleotide polymorphisms and susceptibility to pulmonary tuberculosis]. AB - OBJECTIVE: To investigate the possible association between the SNP in the 5' untranslated region (5' UTR) of the human beta defensin 1 (DEFB1) gene and the susceptibility to pulmonary tuberculosis (PTB) in Chinese Han population. METHODS: In this case-control study, venous blood was collected from 102 patients with PTB and 148 healthful persons. Genomic DNA was extracted using whole blood DNA extraction kit. The -52A/G, -44C/G and -20A/G SNP were genotyped by PCR directed sequencing. The genotypes and allele frequency were analyzed using the chi(2) test. The linkage disequilibrium and haplotype were analyzed by SHEsis software. RESULTS: A total of 102 patients with PTB (69 males and 33 females, (53.42 +/- 20.22) years old) and 148 healthy control cases (95 males and 53 females, (50.67 +/- 14.53) years old) were enrolled, with no difference in gender and age (all P values > 0.05). DEFB1 -44 CC genotype was significantly more frequently found in PTB patients than in control group (81.4% (83/102) vs 66.9% (99/148), chi(2) = 5.114, P < 0.05, OR = 2.096, 95%CI: 1.095 - 4.011), so was 44C allele (89.2% (182/204) vs 80.4% (238/296), chi(2) = 6.975, P < 0.05, OR = 1.576, 95%CI: 1.086 - 2.286). No difference in -52 A/G and -20 A/G SNP was observed between the two groups. The proportion of the GGG (-52/-44/-20) haplotype was lower in PTB patients than in the control group (0.030 vs 0.081, chi(2) = 5.629, P < 0.05, OR = 0.348, 95%CI: 0.140 - 0.863). No linkage disequilibrium was found among the SNP of the three sites (D' values were 0.132, 0.064, 0.088; r(2) values were 0.003, 0.002, 0.003; all P values > 0.05). CONCLUSION: These results suggest that the SNP of DEFB1 5' UTR is associated with susceptibility to PTB in Chinese Han population. -44 C->G SNP and the related haplotype (GGG) might play a protective role in the pathogenesis of PTB. PMID- 23363867 TI - [Gene-gene interactions among the peroxisome proliferator-activated receptor polymorphisms for hypertriglyceridemia]. AB - OBJECTIVE: To investigate the association of ten SNP at peroxisome proliferator activated receptors (PPARalpha, delta, gamma) with hypertriglyceridemia and the gene-gene interaction. METHODS: Participants were recruited from the Prevention of MetS and Multi-metabolic Disorders in Jiangsu province of China Study (PMMJS). A total of 820 subjects were selected from the 4083 participants who had received follow-up examination, by using simple random sampling. Participants in baseline and follow-up study surveys were both collected blood samples 11 ml in the morning after at least 8 hours of fasting. Blood samples which collected at the baseline were subjected to PPARalpha, PPARdelta and PPARgamma genotype analyses. Blood samples which collected at the follow-up were used to measure serum triglyceride levels. The logistic regression model was used to analyze the association between different SNP and hypertriglyceridemia, and the generalized multifactor dimensionality reduction (GMDR) was applied to explore the gene-gene interaction. RESULTS: The samples included 474 in the non-hypertriglyceridemia group and 346 in the hypertriglyceridemia group. The genotype frequencies of rs1800206 in the hypertriglyceridemia group were 211 (61.0%) for LL, 132 (38.2%) for LV and 3 (0.9%) for VV, and in the non-hypertriglyceridemia group were 411 (86.7%) for LL, 59 (12.4%) for LV and 4(0.8%) for VV (chi(2) = 74.18, P < 0.01). V allele frequencies of rs1800206 in the hypertriglyceridemia group was 138(19.9%), and in the non-hypertriglyceridemia group was 67 (7.1%) (chi(2) = 60.62, P < 0.01). The genotype frequencies of rs2016520 in the hypertriglyceridemia group were 177 (51.2%) for TT, 154 (44.5%) for TC and 15 (4.3%) for CC, and in the non-hypertriglyceridemia group were 211 (44.5%) for TT, 212 (44.7%) for TC and 51 (10.8%) for CC(chi(2) = 15.93, P < 0.01). C allele frequencies of rs2016520 in the hypertriglyceridemia group was 184(26.6%), and in the non-hypertriglyceridemia group was 314 (33.1%) (chi(2) = 8.07, P < 0.01). The genotype frequencies of rs3856806 in the hypertriglyceridemia group were 149 (43.1%) for CC, 156 (45.1%) for CT and 41 (11.8%) for TT, and in the non hypertriglyceridemia group were 269 (56.8%) for CC, 170 (35.9%) for CT and 35 (7.4%) for TT (chi(2) = 15.93, P < 0.01). T allele frequencies of rs3856806 in the hypertriglyceridemia group was 238(34.4%), and was 240 (25.3%) in the non hypertriglyceridemia group (chi(2) = 15.96, P < 0.01). The genotype frequencies of rs1805192 in the hypertriglyceridemia group were 145 (41.9%) for PP, 158(45.7%) for PA and 43(12.4%) for AA, and in the non-hypertriglyceridemia group were 314 (66.2%) for PP, 137(28.9%) for PA and 23(4.9%) for AA (chi(2) = 50.92, P < 0.01). A allele frequencies of rs1805192 in the hypertriglyceridemia group was 244(35.2%), and was 183 (19.3%) in the non-hypertriglyceridemia group(chi(2) = 52.89, P < 0.01). After adjusting age, gender, smoking, alcohol consumption, high fat diet, low -fiber diet and occupational physical activity factors, rs1800206, rs2016520, rs3856806 and rs1805192 were significantly associated with hypertriglyceride, while the OR (95%CI) was 3.88 (2.69 - 5.60), 0.71 (0.52 - 0.96), 1.40 (1.03 - 1.90) and 2.56 (1.88 - 3.49), respectively (P < 0.05). GMDR model analysis showed that the second-order model (rs1800206 and rs1805192) was the best model when quality traits of triglyceride was chosen as outcome (P < 0.01); while third-order model (rs1800206, rs1805192 and rs2016520) was the best model when quantitative traits of triglyceride was chosen as outcome (P < 0.01). CONCLUSION: The rs1800206, rs2016520, rs3856806 and rs1805192 were significantly associated with hypertriglyceridemia. There was a gene-gene interaction between multiple SNP. PMID- 23363868 TI - [Current status of diabetes, hypertension and dyslipidemia among older Chinese adults in 2010]. AB - OBJECTIVE: To investigate the distribution of hypertension, diabetes and dyslipidemia among elderly population in China in 2010. METHODS: In 2010, The 3rd Chronic Non-communicable Disease & Risk Factor Surveillance in China was conducted in 31 provinces and Xinjiang Production & Construction Corps. A stratified multi-stage cluster sampling was used from 162 National Disease Surveillance Points (DSPs). A total of 19 981 residents aged >= 60 years received a set of standardized questionnaire interview, physical examinations and laboratory test for lipid & glucose levels in blood. After complex weighting of the sample, the prevalence of hypertension, diabetes and dyslipidemia were compared for different gender, age groups and regions. RESULTS: After complex weighting, among elderly, the overall prevalence of hypertension was 66.9%, and the rates were greater in the eastern areas (67.9%) than in the western areas (62.5%) (P < 0.05), there was no significant difference between urban areas and rural areas (P > 0.05); the prevalence of diabetes was 19.6%, the rates were greater in the eastern areas (21.5%) than in the western areas (17.7%) (P < 0.05), and greater in the urban areas (25.0%) than in the rural areas (17.0%) (P < 0.05) ; the prevalence of high triglycerides, high blood cholesterol and high low-density lipoprotein were all higher in the urban areas (12.4%, 6.4% and 5.2%) than in the rural areas (10.1%, 4.2% and 2.8%) (all P values < 0.05), and also higher for women (12.9%, 6.9% and 4.7%) than for men (8.7%, 2.9% and 2.4%) (all P values < 0.05); the prevalence of hypertension in people with abnormal blood lipids (74.3%) was higher than those with normal blood lipids (65.7%) (P < 0.05); the prevalence of hypertension and dyslipidemia in people with diabetes (77.3%, 23.2%) were both greater than the prevalence in non-diabetic group (64.5%, 12.6%) (both P values < 0.05). CONCLUSION: The present study showed high prevalence of hypertension, diabetes and dyslipidemia among elderly people in China. The rates were greater in the eastern than in the western and higher for women than for men. The rates of diabetes and dyslipidemia were significantly higher in the urban areas than in the rural areas. Comprehensive prevention and control of hypertension, diabetes and dyslipidemia among the elderly should be enhanced. PMID- 23363869 TI - [Status quo of lifestyle among women of five occupations in six provinces of China]. AB - OBJECTIVE: To learn the status quo of lifestyle among women of five occupations in six provinces of China. METHODS: A questionnaire was administered among 7416 women from five occupations (civil servants, teachers of elementary and high schools, technical staff, enterprise managers and physical laborers) in Beijing, Hebei, Jilin, Hubei, Ningxia and Gansu of China. The sample was selected by multi stage stratified cluster random sampling method from December 2009 to June 2010. The questionnaire information included demographic characteristics, diet, sleep habit, smoking, physical exercise. The chi(2) test was used to analyze the different in life style of different occupations. RESULTS: There were 7416 valid questionnaires received, and the valid rate of the questionnaires was 97.58% (7416/7682). About 38.00% (2818/7416) respondents preferred to bland diet and 28.44% (2109/7416) preferred to salty and oily food and 33.56% (2489/7416) had no preference. The proportion of sleep time between seven and eight hours per day was highest (accounting for 56.23%, 4154/7416), 25.27% (1867/7416) with sleep time less than seven hours. Among the population who had the sleep time less seven hours, teacher that had the highest rate accounted for 33.19% (531/1607) and technical staff had the lowest rate accounted for 21.05% (301/1401) (P < 0.01). Most of respondents were non-smokers, accounting for 93.10% (6869/7416). 22.73% (1671/7416) respondents passively smoked. The proportion of always passive smoking was highest among civil servants and lowest among teachers, accounting for 26.60% (404/1531) and 18.71% (298/1607), respectively. The proportion of having no physical exercises was highest, accounting for 62.87% (4637/7416). The proportion of having three times physical exercises per week was 12.68% (935/7416). The proportion of having no physical exercises among physical laborers (66.42%, 912/1386), enterprise managers (66.64%, 987/1491) and teachers (62.40%, 999/1607) were higher than others and the proportion of having physical exercises per week among technical staff was 40.83% (569/1401), higher than others (P < 0.01). The proportion of person who worked in sitting quietly beyond six hours per day was 42.62% (3146/7416). The technical staff had the higher rate than other occupational populations (P < 0.01), accounting for 57.83% (809/1401). CONCLUSION: The female occupational population had some unhealthy lifestyles, such as taking in high salt food, lacking of sleep, smoking and passive smoking, lacking of physical exercises and working in sitting quietly. Different occupational populations had different unhealthy lifestyles. PMID- 23363870 TI - [Analysis on growth and malnutrition status of Tibetan children aged 0 to 35 months in rural Lhasa in 2010]. AB - OBJECTIVE: To understand the growth and malnutrition status of Tibetan children aged 0 to 35 months in rural Lhasa in 2010. METHODS: Cross-sectional study and multistage sampling design were used to randomly select sampling units. A total of 640 children were studied. Height and weight were measured and nutritional status was evaluated with WHO reference in 2006 using Z-scores. Z-scores of weight-for-age (WAZ), Z-scores of height-for-age (HAZ) and Z-scores of weight-for height (WHZ) were analyzed. RESULTS: At the age of 18 - 35 months, the children in rural Lhasa were 3.0 cm shorter as compared to the China national length reference. At the age of 6 - 11, 12 - 17 months, weight ((8.84 +/- 1.23) and (10.20 +/- 1.08) kg) and length ((70.45 +/- 4.46) and (76.73 +/- 4.78) cm) of boys were significantly higher than girls (weight: (8.42 +/- 1.30) and (9.59 +/- 1.26) kg; length: (67.61 +/- 3.98) and (74.25 +/- 4.50) cm) (all P values < 0.05). WAZ and HAZ were -0.17 +/- 1.11 and -1.11 +/- 1.46, respectively. The HAZ of 18 - 23 months children (-1.51 +/- 1.24) was significantly different from the HAZ of 0 - 5, 6 - 11, 12 - 17 months children (HAZ: -0.75 +/- 1.50, -0.83 +/- 1.72, -1.07 +/- 1.55, respectively) (all P values < 0.05), comparison with the HAZ of 24 - 29, 30 - 35 months children (HAZ: -1.41 +/- 1.25, -1.24 +/- 1.05), the results showed that there were no significant difference (all P values > 0.05), HAZ of 18 - 23 months children was the lowest. The prevalence of stunting, underweight, and wasting were 24.6% (155/630), 5.4% (33/616) and 1.0% (6/608), respectively. The malnutrition of boys was more serious than that of girls, the stunting of 18 - 23 and 24 - 29 months children had reached 35.0% (36/103) and 29.1% (25/86), respectively. CONCLUSION: The growth and development status of children in rural Lhasa under 3 years old was poor, and the malnutrition of local children should not be ignored with variations by gender and months of age. PMID- 23363871 TI - [Development of an in vitro digestion model for assessing the bioaccessibility of aflatoxin B group in foods]. AB - OBJECTIVE: To develop and validate an in vitro digestion model for assessing the bioaccessibilities of some important mycotoxins of aflatoxin B group (aflatoxin B(1) and aflatoxin B(2), AFB(1) and AFB(2)). METHODS: Using simulating gastrointestinal physiological digestion process, the effects of digestion time (long, medium and short), the fasting and feeding status (fasting, between fasting and semi-feeding, semi-feeding, between semi-feeding and feeding, feeding states), the volume and pH (high, medium and low) of digestive solution, as well as other food ingredients ingested along with aflatoxin B group from mixed foods on bioaccessiblities of AFB(1) and AFB(2) in the mouth, stomach and small intestine were studied. The optimal technical parameters of the model were identified and the model was validated with mycotoxin adsorbents. RESULTS: The optimal conditions of AFB(1) releasing from the ingested foods at the highest concentration in gastrointestinal tract were as follows: digestion time of 6 min, 1.5 h and 2.5 h in mouth, stomach and duodenum, respectively; the optimal pH values of 1.1 and 7.5 for gastric juice and duodenal fluid; the volume of 7, 13, 12 and 6 ml for saliva, gastric juice, intestinal fluid and bile, respectively; the optimal conditions of AFB(2) releasing from the ingested foods at the highest concentration in gastrointestinal tract were as follows: digestion time of 6 min, 2.5 h and 2.5 h in mouth, stomach and duodenum, respectively; the optimal pH values of 1.1 and 7.8 for gastric juice and duodenal fluid; the volume of 5, 12, 13 and 6 ml for saliva, gastric juice, intestinal fluid and bile, respectively. The bioaccessibilities of both AFB(1) and AFB(2) were highest at the fasting state (83.1% and 89.3% respectively). The bioaccessibilities decreased with the increasing of stomach contents, but the changes in bioaccessibility were not significant when the stomach contents reached the semi-feeding state or more. From semi-feeding to feeding state, the biocessibilities of AFB(1) decreased from 72.8% to 71.5% and AFB(2) decreased from 78.3% to 76.9%. Chlorophyll and activated charcoal were the strongest absorbent in reducing the bioaccessibilities of AFB(1) and AFB(2), and the bioaccessibilities decreased to 0.8% and 1.3% respectively. CONCLUSION: The in vitro digestion model developed in the present study is stable and reproducible, and meets the requirements for assessing the bioaccessibilities of AFB(1) and AFB(2) in foods. PMID- 23363872 TI - [Rapid identification of Beijing measles vaccine virus and wild virus by multiplex real-time fluorescent PCR]. AB - OBJECTIVE: To identify wild measles virus and vaccine virus by detection nucleic acid of clinical samples from measles patients with immunization history circulating in Beijing through multiplex real-time fluorescent PCR technology. METHODS: From July 2011 to February 2012, 10 throat swabs and 15 urine specimens were collected from 16 suspected measles patients who were 8 - 9 months old infants with immunization history in Beijing. The specificity of multiplex real time fluorescent PCR was firstly tested by measles vaccine virus, wild virus and other respiratory virus. Then the vaccine virus and wild virus were titrated and diluted to test the sensitivity of the PCR method. The result was then compared with it analyzed by PCR-RFLP method. Meanwhile, the clinical sample of the measles patients were tested and confirmed by sequencing method. RESULTS: The primer-probe sets of Fam, Joe and Cy5 showed great specificity of measles virus, and could distinguish the measles vaccine virus and wild virus well. The sensitivity of this method to detect measles vaccine virus reached 0.1 CCID(50)/0.1 ml; and the sensitivity to wild virus reached 0.006 CCID(50)/0.1 ml; which were both higher than the sensitivity of PCR-RFLP method. Out of the 16 measles patients with vaccination history, 3 were negative and the other 13 all belonged to measles virus genotype A, and were confirmed to be vaccine virus by sequencing method. CONCLUSION: Multiplex real-time PCR method is accurate, rapid and sensitive to identify measles vaccine virus and wild virus. The method could greatly help us to find measles patients and to identify the vaccine-related cases. PMID- 23363873 TI - [What temperature index is the best predictor for the impact of temperature on mortality]. AB - OBJECTIVE: To explore the suitable temperature index to establish temperature mortality model. METHODS: The mortality and meteorological information of Guangzhou between year 2006 and 2010 were collected to explore the association between sendible temperature, heat index and deaths by adopting distributed lag non-linear model to fit the daily maximum, mean and minimum temperature with and without humidity. Q-Q plots based on the standardized residuals of each model were used to qualitatively access the goodness of fitting. The minimum Akaike information criterion (AIC) and residual sum of squares (RSS) value were used to explore the most suitable temperature index for model establishment, and to further analyze the fittest temperature index for different diseases, ages and cold and hot effect. RESULTS: Guangzhou features a subtropical monsoon climate, with an annual average temperature at 22.9 degrees C and daily average relative humidity of 71%. The standardized residuals of all models followed normal distribution. For all death, death from circulation system diseases, the 65-84 years old aging groups and cold effect models, the daily average temperature fit better, whose AIC (RSS) values were the smallest as 11 537 (1897), 9527 (1928), 10 595 (2018) and 11 523 (1899), respectively. However, for death from respiratory system disease, groups aging under 65 years old or over 85 years old and hot effect models, the daily average sendible temperature fit better, whose AIC (RSS) values were the smallest as 8265(1854), 675 (1739), 8550 (1871) and 11 687 (1938), respectively. In comparison with the model controlling both temperature and relative humidity, different diseases, aging groups and cold and hot effect models fitted by sendible temperature index showed smaller AIC (RSS) values. The relative risk (RR) value of the cold effect lagging 0 - 3 days fitting by daily maximal temperature was < 1, and the RR value of it fitting by daily minimum temperature was > 1.04. The RR value of the hot effect lagging 0 - 1 days fitting by daily maximal temperature was < 1.16, and the RR values of it fitting by daily minimum temperature and daily average temperature were > 1.16. CONCLUSION: There were no best temperature indicators for different diseases, ages and cold and hot effect. The model using sendible temperature index better fit the model including relative humidity as a covariable. PMID- 23363874 TI - Epilepsy in Asia: a Cambodian experience. AB - Epilepsy is particularly challenging for resource-poor countries and in turn for Asia which is likely to have greater challenges in terms of treatment cost and deficit, premature mortality, health transitions, population and poverty size, etc. Here we present an example of working in one of the resource-poor 'least talked-about' populations to demonstrate that finding financial means and achieving cross-country cooperation over a long period of time is possible even in countries with currently limited resources. Conducting such cooperation could be a model for other initiatives. Scientific, capacity-building, and political tools should be employed to generate local representative data and influence government policies. These measures can be of immediate benefit for patients in these countries. PMID- 23363875 TI - Family size preference and factors affecting the fertility rate in Hyogo, Japan. AB - BACKGROUND: Japan has consistently shown a low fertility rate, which has been lower than the replacement level since 1974, and represents one of the least fertile countries in the world. This study was designed to determine the family size preference of and its effect on Japanese women. METHODS: We conducted a questionnaire survey among women who visited the obstetrics and gynecology department of 18 hospitals and clinics in the Hyogo Prefecture, Japan, between October 2011 and February 2012. All the women were categorized according to age group and area of residence, and the survey results were statistically analyzed using a t test. RESULTS: A total of 1616 women were included in this study. There was no significant difference between the mean desired and actual marital ages (26.70 and 26.67 years, respectively). The mean desired number of children was 2.55, which was significantly more than the mean actual number of children (1.77) in all generations. The mean desired and actual numbers of children were more in the rural areas (2.73 and 2.09, respectively) than in the urban (2.54 and 1.70, respectively) and semi-urban areas (2.49 and 1.60, respectively). The mean number of family members was significantly greater in the rural areas (3.84) than in the urban (3.25) and semi-urban areas (3.05).The most important concern among women who had never delivered a baby was childbearing itself, followed by the expenses related to pregnancy and childbearing. CONCLUSIONS: The family size preference of the women in our study was higher than the actual numbers of children. The fertility intentions were low among the younger women but high among those living in rural areas with larger families. PMID- 23363876 TI - Interplay between population dynamics and drug tolerance of Staphylococcus aureus persister cells. AB - Population dynamics parameters of Staphylococcus aureus strain SA113 were quantified based on growth and killing experiments with batch culture cells in rich medium. Eradication kinetics and the concomitant isolation of a subpopulation of drug-tolerant SA113 persisters upon treatment with super-minimal inhibitory concentrations of antibiotics such as ciprofloxacin, daptomycin, and tobramycin served as a basis for mathematical analyses. According to a two-state model for stochastic phenotype switching, levels of persister cells and their eradication rates were influenced by the antibiotics used for isolation, clearly indicating a heterogeneous pool of S. aureus persisters. Judging from time dependent experiments, the persisters' degree of drug tolerance correlated with the duration of antibiotic challenge. Moreover, cross-tolerance experiments with cells consecutively treated with two different antibiotics revealed that multi drug tolerance is not a necessary trait of S. aureus persisters isolated by antibiotic challenge. In some cases, the results depended on the order of the two antibiotic treatments, suggesting that antibiotic tolerance may be achieved by a combination of preexisting persisters and an adaptive response to drug exposure. Counts of live cells which had endured drug treatment increased only after lag phases of at least 3 h after the shift to non-selective conditions. Thus, this study provides quantitative insights into population dynamics of S. aureus persisters with regard to antibiotic challenge. PMID- 23363877 TI - Absence of association between the incidence of BK virus and sporadic Creutzfeldt Jakob disease. AB - BACKGROUND: Many studies suggest that the virus-like particles are required for the infection of Creutzfeldt-Jakob disease (CJD). OBJECTIVE: To determine the relationship between BK polyomavirus (BKV) and sporadic CJD. MATERIALS AND METHODS: We investigated the prevalence of BKV in urine samples from 94 sporadic CJD patients and 54 other neurological disease (OND) patients using polymerase chain reaction. RESULTS: BKV DNA was detected in 16 (17%) and 9 (16.7%) urine samples from sporadic CJD and OND patients, respectively. There was no significant difference in the incidence of BKV infection between Korean sporadic CJD and OND patients (p = 0.9558). In order to investigate the genotypes of BKV, we analyzed 22 BKV isolates obtained from Korean patients by DNA sequencing and nucleotide sequence analysis. Three distinct subtypes, namely I, III, and IV, were found in 66.7, 22.2, and 11.1% of 9 BKV isolates from OND patients, whereas subtypes I and IV were detected in 76.9 and 23.1% of 13 BKV isolates from sporadic CJD patients. Interestingly, subtype III was not detected in sporadic CJD patients. Significant differences in the frequency of BKV genotypes were not observed between sporadic CJD and OND patients. CONCLUSIONS: These results indicate that BKV may not play an important role in the pathogenesis of prion diseases. PMID- 23363878 TI - Intramolecular H-bonding interaction in angular 3-pi-EWG substituted imidazo[1,2 a]pyridines contributes to conformational preference. AB - BACKGROUND: The proton at position 5 of imidazo[1,2-a]pyridines substituted with an angular electron withdrawing group (EWG) at position 3, shows an unusual downfield chemical shift, which is usually explained in terms of a peri effect. However usage of this term is sometimes confusing. In this investigation, it is proposed that the aforementioned shift is in fact a combination of several factors: Anisotropy, long-distance mesomerism and an attractive intramolecular interaction of the electrostatic hydrogen bond type. RESULTS: Theoretical calculations were performed aimed to obtain evidence of the existence of an intramolecular non-bonding interaction between H-5 and the oxygen atom of the EWG. Results derived from conformational and vibrational analysis at the DFT B3LYP/6-311++G(d,p) level of theory, the determination of Bond Critical Points derived from AIM theory, and the measurement of some geometrical parameters, support the hypothesis that the higher stability of the prevailing conformation in these molecules (that in which the oxygen of the EWG is oriented towards H-5) has its origin in an intramolecular interaction. CONCLUSION: Computational calculations predicted correctly the conformational preferences in angular 3-pi EWG-substituted imidazo[1,2-a]pyridines. The existence of an electrostatic hydrogen bond between H-5 and the oxygen atom of the pi-EWG was supported by several parameters, including X-ray crystallography. The existence of such structural array evidently impacts the H-5 chemical shift. PMID- 23363879 TI - Oral sodium thiosulfate as maintenance therapy for calcific uremic arteriolopathy: a case series. AB - BACKGROUND: Calcific uremic arteriolopathy (CUA) is a rare but serious disorder affecting 4% of dialysis patients. Intravenous sodium thiosulfate (IV STS) has been shown as an effective treatment. In Canada, the average cost of IV STS is about CAD 12,000 per month, while the cost of compounded oral STS is CAD 45 per month. METHODS: Prospective cohort where all patients diagnosed with CUA during the year 2011 were included. They were treated initially with IV STS. Afterwards, each patient had a baseline bone scan and was started on oral STS for a total of 6 months followed by a repeat bone scan. A single radiologist, blinded to the dates of both scans for a given patient, read all scans. RESULTS: Four patients were studied. The intravenous dose used was 25 g three times a week for an average duration of 131 days. After the maintenance therapy, 2 patients developed further regression of the lesions, 1 had stable lesions, and 1 got worse; however, nonadherence to the drug was confirmed. The oral medication was well tolerated with no reported side effects. CONCLUSION: Oral STS, after IV STS, seems to stabilize, or even improve CUA lesions, and therefore could be useful as maintenance therapy, especially since its cost is much more reasonable than IV STS and due to the ongoing shortage of the IV formulation. PMID- 23363880 TI - The first 180 days. PMID- 23363881 TI - Prediction of visual outcomes after open globe injury in children: a 17-year Canadian experience. AB - PURPOSE: To analyze the predictive value of ocular trauma scoring systems for open globe injury in children, to determine risk factors for poor visual outcome, and to assess circumstances under which trauma occurs. METHODS: The medical records of patients <18 years of age who presented with open globe injuries from January 1992 to December 2009 were examined retrospectively. Information recorded included demographic profile; date, time, and place of injury; cause and extent of injury; complications; and final best-corrected visual acuity. Injuries were classified by Ocular Trauma Classification Group guidelines. RESULTS: A total of 131 patients were included. Final best-corrected visual acuity was >=20/40 in 74 patients (56.5%) after mean follow-up of 24.8 months. Injuries occurred more commonly in boys (98/131), and 45% of injuries occurred in children aged <=5 years (P = 0.001). Injuries were more common indoors (P = 0.003), in the afternoon (P < 0.001), and on Saturdays and Mondays (P = 0.004). Multiple regression analysis identified risk factors for final best-corrected visual acuity <20/40: age <5 years, injuries with retrolimbal involvement, wound length >5 mm, globe rupture, vitreous hemorrhage, and retinal detachment (P < 0.05). CONCLUSIONS: Visual outcomes after pediatric open globe injury in this study compare favorably to results reported previously. Knowledge of weekly fluctuations in occurrence may help guide development of prevention strategies. Age <5 years is an independent risk factor for a poorer outcome. The ocular trauma score is useful in assessing prognosis after pediatric open globe injury. PMID- 23363882 TI - Newborn retinal hemorrhages: a systematic review. AB - PURPOSE: To systematically review the characteristics, prevalence, evolution, and obstetric associations of retinal hemorrhages (RH) in newborns. METHODS: A systematic review, searching 10 databases (1970-2011), identified 45 studies, which underwent two independent reviews via the use of standardized critical appraisal. Studies meeting the following criteria were included: examination by an ophthalmologist, use indirect ophthalmoscopy, and first examination conducted within 96 hours of birth and before hospital discharge. RESULTS: Thirteen studies were included, representing 1,777 infants. The studies revealed that 25.6% of newborns born via spontaneous vaginal deliveries had RH. In contrast, infants delivered by vacuum extraction had a 42.6% rate of RH (OR, 2.75; 95% CI, 1.32 5.70), and infants delivered by double-instrument deliveries (forceps and vacuum) had a 52% rate of RH (OR, 3.27; 95% CI, 1.68-6.36). The hemorrhages are commonly bilateral (59%), of varying severity, from "mild" (22%-56%) to "severe" (18% 37%), and predominantly intraretinal and in the posterior pole. The majority of RH (83%) resolved within 10 days; isolated cases persisted to 58 days. CONCLUSIONS: Birth-related RH in infants occurs in one-quarter of normal deliveries and are far more common after instrumental deliveries. Commonly bilateral, they were predominantly intraretinal, posterior, resolved rapidly, and very rarely persisted beyond 6 weeks. PMID- 23363884 TI - Immunization coverage in young children: a study nested into a health and demographic surveillance system in Burkina Faso. AB - BACKGROUND: Reliable estimates of immunization coverage are the basis for rational policy making, program implementation and evaluation. Vaccination coverage is usually measured using administrative data or surveys, both having a number of methodological problems. METHODS: We estimated vaccination coverage using a data set of 11 906 children aged <5 years from an existing Health and Demographic Surveillance System (HDSS) in north-western Burkina Faso. Data were collected from September 2008 to December 2009. RESULTS: Vaccination coverage based on information from existing vaccination cards ranged from 80% (measles) to 94% (OPV1). When taking into consideration all information available (including BCG scars in children with and without vaccination card), full coverage in children aged 12-23 months was around 75%, with a significantly higher coverage in rural compared with urban areas. There were no differences in vaccination coverage between boys and girls. CONCLUSION: The study supports other studies that found vaccination coverage improvement in Burkina Faso recently. In addition, our study found slightly better vaccination coverage in rural compared with urban areas, which needs further consideration. PMID- 23363883 TI - Congenital glaucoma with acquired peripheral circumferential iris degeneration. AB - Iris anomalies associated with congenital or early-childhood glaucoma include stable primary developmental abnormalities such as those associated with the Axenfeld-Rieger spectrum and aniridia. Secondary generalized iris atrophy from uncontrolled intraocular pressure is another potential iris finding in pediatric glaucoma. We document an unusual pattern of acquired peripheral circumferential iris degeneration in 2 unrelated children with otherwise-controlled congenital glaucoma. Genetic testing revealed a common homozygous CYP1B1 mutation in one (p.Gly61Glu) and a novel heterozygous FOXC1 deletion in the other (p.Tyr81_Pro95del). PMID- 23363886 TI - Prevalence of cerebral palsy in Quebec: alternative approaches. AB - AIM: To provide an estimate of the period prevalence of cerebral palsy (CP) in the province of Quebec. METHODS: Children with CP were identified from three consecutive birth cohorts (1999-2001) from the Quebec CP Registry, covering 6 of the 17 administrative health regions of the province. Two inferential approaches were applied for period prevalence estimation, frequentist and bayesian. RESULTS: 228 children were identified with CP. Using a frequentist approach, the overall prevalence of CP was 1.84 per 1,000 children aged 9-11 years living in those areas in 2010 (95% CI 1.60-2.08). Using a bayesian approach taking into account the uncertainty about the registry's sensitivity in capturing all cases, the overall prevalence is higher at 2.30 per 1,000 children with a 95% CI (1.99 2.65). CONCLUSION: Using a bayesian approach to adjust for the registry's known high specificity and lower sensitivity, the prevalence estimate is in concordance with worldwide estimates and estimates using administrative databases in western Canadian provinces. Future studies are needed to validate the diagnosis of CP within administrative databases and to evaluate possible regional trends across Canada in both prevalence and health service utilization, which may highlight disparities in healthcare delivery. PMID- 23363887 TI - Changes in the MEG background activity in patients with positive symptoms of schizophrenia: spectral analysis and impact of age. AB - The frequency spectrum of the magnetoencephalogram (MEG) background activity was analysed in 15 schizophrenia (SCH) patients with predominant positive symptoms and 17 age-matched healthy control subjects using the following variables: median frequency (MF), spectral entropy (SpecEn) and relative power in delta (RPdelta), theta (RPtheta), lower alpha (RPalpha1), upper alpha (RPalpha2), beta (RPbeta) and gamma (RPgamma) bands. We found significant differences between the two subject groups in the average level of MF and RPgamma in some regions of the scalp. Additionally, the MF, SpecEn, RPbeta and RPgamma values of SCH patients with positive symptoms had a different dependence on age as compared with the results of control subjects, suggesting that SCH affects the way in which the brain activity evolves with age. Moreover, we also classified the MEG signals by means of a cross-validated feature selection process followed by a logistic regression. The subjects were classified with 71.3% accuracy and an area under the ROC curve of 0.741. Thus, the spectral and classification analysis of the MEG in SCH may provide insights into how this condition affects the brain activity and may help in its early detection. PMID- 23363888 TI - A novel mutation of IGSF1 in a Japanese patient of congenital central hypothyroidism without macroorchidism. AB - Congenital central hypothyroidism (C-CH) is a rare disease known to be caused by mutations of the genes encoding TSH beta or the TRH receptor gene, although the cause of the disease in a number of patients has not yet been clarified. Recently, mutations and deletions of the immunoglobulin superfamily member 1 (IGSF1) gene have been reported to be the cause of C-CH. Here we report a Japanese male patient with C-CH due to a novel IGSF1 mutation. He was detected by neonatal mass screening of simultaneous TSH and free T4 measurements and levothyroxine was initiated. At 6 years of age he underwent 123I scintigraphy after levothyroxine treatment had been discontinued for one month and his thyroid and pituitary function were evaluated. Since TSH and PRL responses after TRH stimulation were low, his diagnosis of C-CH was confirmed. During follow up, whereas onset of his puberty was delayed, his secondary sex characterization completed at 17 years old. In this patient we analyzed IGSF1 and TRHR. As results, we identified a novel insertion mutation in IGSF1 (c.3528-3529insC), resulting in a premature stop codon (p.Pro1082Trpfs39X). In conclusion, we identified a novel mutation of IGSF1 in a Japanese male patient with C-CH. PMID- 23363889 TI - Dermoscopy of desmoplastic trichoepithelioma reveals other criteria to distinguish it from basal cell carcinoma. AB - BACKGROUND: Desmoplastic trichoepithelioma (DT) is a rare benign adnexal neoplasm considered to have follicular differentiation. It usually presents as an asymptomatic, firm, annular plaque with a raised border. The diagnosis of DT is based on clinical and histological features which can be similar to those of morpheiform basal cell carcinoma. Taking this into consideration, the use of another diagnostic technique would be very useful. Dermoscopy is a noninvasive diagnostic technique allowing a more accurate diagnosis. OBJECTIVES: To differentiate DT and morpheiform basal cell carcinoma by means of dermoscopy. METHODS: Here, we describe the dermoscopic features of a case of DT, and make a direct clinicopathological correlation by using the horizontally cut slides provided by Mohs micrographic surgery. RESULTS: On dermoscopy, DT shows well defined borders and an ivory-white color, as well as prominent arborizing telangiectasias in the central area and on the right side. There are no leaf-like structures and no ovoid nests. This observation confirms and completes the first dermoscopic analysis of DT reported in the literature so far. PMID- 23363890 TI - Mineralisation of developmentally hypomineralised human enamel in vitro. AB - Molar-incisor hypomineralisation (MIH) is a problematic and costly condition. Caries remineralising agents are often recommended for MIH management despite the lack of evidence that these lesions have the capacity for increasing their mineral content. Following surface layer removal +/- NaOCl pre-treatment and 14 day exposure to a CPP-ACFP solution at pH 5.5, MIH lesions were analysed using transverse microradiography and polarised light microscopy. Lesions were highly variable but treatment with the remineralising solution increased mineral content (1,828 +/- 461 vol% min . um, %R = 17.7 +/- 5.7) and porosity decreased demonstrating the proof of concept that the mineral content of developmentally hypomineralised enamel can be improved after eruption. PMID- 23363891 TI - Gene polymorphisms of interleukin-10 and tumor necrosis factor-alpha are associated with contrast-induced nephropathy. AB - BACKGROUND/AIMS: Contrast-induced nephropathy (CIN) is the third most common cause of hospital-acquired acute renal failure. However, the pathogenesis of CIN remains unclear. This study evaluated the role of anti-inflammatory cytokine interleukin-10 (IL-10) and pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) gene polymorphisms as CIN susceptibility markers after percutaneous coronary intervention (PCI). METHODS: Four IL-10 tag SNPs (rs1554286, rs3021094, rs3790622, rs1800896) and three TNF-alpha tag SNPs (rs1799964, rs1800630, rs1800629) were analyzed by MALDI-TOF mass spectrometry in 53 CIN patients and 455 control subjects. Serum IL-10 and TNF-alpha were detected using ELISA. RESULTS: When compared to controls, the CIN patients showed increased frequencies of CC (rs1554286) and AG+GG (rs1800896) genotypes in IL-10 and GA+AA (rs1800629) genotype in TNF-alpha (OR = 2.24 (1.13-4.44), p = 0.018; OR = 2.61 (1.30-5.26), p = 0.005, and OR = 2.11 (1.08-4.09), p = 0.025, respectively). Baseline serum IL 10 levels in CIN patients were significantly lower (1.02 +/- 1.14 vs. 2.78 +/- 4.73 pg/ml, p = 0.008). Patients with CIN had a higher rate of decline in renal function than those without CIN (0.89 +/- 1.67 vs. 0.30 +/- 0.95 ml/min/1.73 m(2) per month, p = 0.002). Significantly higher rates of decline in creatinine clearance were noted in patients with TNF-alpha (rs1800629) GA+AA than GG genotype (0.88 +/- 1.83 vs. 0.36 +/- 0.70, p = 0.03), and with IL-10 (rs1800896) AG+GG than AA genotype (1.28 +/- 2.14 vs. 0.33 +/- 0.90, p < 0.001). CONCLUSIONS: Gene polymorphisms of IL-10 and TNF-alpha are associated with CIN risk and long term renal outcome after PCI. More prospective studies are needed to confirm our results. PMID- 23363892 TI - [The evaluation of hypertensive patients who are supposedly under control according to office blood pressure measurements with ambulatuar blood pressure monitoring: an observational prospective study in three big cities (AKB3IL study)]. AB - OBJECTIVES: The aim of the study is to evaluate hypertensive patients who are supposedly under control according to office blood pressure measurements with 24 hour ambulatuar blood pressure monitoring for determining their actual controlled hypertension rate. In addition, we investigate the adherence ratio of blood pressure measurements to current guidelines. STUDY DESIGN: Nine hundred-forty hypertensive patients supposedly under control according to office blood pressure measurements were enrolled in the study. Twenty-four hour ambulatuar blood pressure monitoring was performed on all of them. RESULTS: Actual controlled hypertension was determined in 617 (65.6%) patients whereas 323 (34.4%) patients had uncontrolled hypertension. The blood pressure measurements that were over threshold values were seen mostly at night and in the early morning during ambulatuar blood pressure monitoring. Nocturnal and early morning hypertension was determined in most of the patients who were supposedly under control according to office blood pressure measurements. This was especially true in patients with high cardiovascular risk such as diabetes mellitus, chronic kidney failure, and metabolic syndrome. CONCLUSION: Efficacy of antihypertensive therapy during 24 hour and the early morning period is essential for optimal risk modification. PMID- 23363893 TI - [Beyond blood pressure measurement in the office setting]. PMID- 23363894 TI - Appropriateness of the current guidelines on reperfusion treatment for patients applying to our hospital with ST-segment elevation acute myocardial infarction. AB - OBJECTIVES: This study investigated the appropriateness of treatment for patients admitted with ST-segment elevation myocardial infarction (STEMI) according to the current guidelines. We also aimed to determine in-patient and out-patient factors affecting optimal reperfusion therapy. STUDY DESIGN: The reperfusion therapy of 176 patients with STEMI was determined. The time period from first contact with a healthcare provider to the time of balloon inflation (door to balloon time), and from the time period of first contact with a healthcare provider to the time of initiation of a thrombolytic (door to needle time) were calculated. Similarly, the time from admission at the emergency service (ES) of our hospital after referral to the moment of balloon inflation (ES to balloon time) and the period from admission to ES at our hospital to the moment of initiation of a thrombolytic (ES to needle time) were calculated. In order to determine the amount of in-hospital delay, the time from ES admission to the call to the cardiology department and the time for the cardiologist to evaluate the patient and transfer time were recorded. Whether the referring physician was a cardiologist and the effect of work hours on the reperfusion period was also recorded. RESULTS: The door to balloon time in the referred patient group was calculated as an average of 228 minutes, while the time for patients directly admitted to ES was calculated as an average of 98 minutes. Patients referred for the mechanical reperfusion period compared to American Heart Association (AHA) guidelines consisted of only 6% of the eligible patients, while according to the European Society of Cardiology (ESC) guidelines 13% of patients were appropriate. Patients who were directly admitted to ES, experienced rates according to AHA guidelines and 73% experienced these rates according to ESC guidelines. We also found no significant effect of working hours or referring physician's specialty (cardiologist or other) on reperfusion time. CONCLUSION: Compliance rates of reperfusion therapy for patients presenting with STEMI was very low. We realized, when taking into consideration the reasons for delay in terms of both health community and the policy of the country, it is obvious that we have to take strict measures. PMID- 23363895 TI - Relation of inflammatory and oxidative markers to the occurrence and recurrence of persistent atrial fibrillation. AB - OBJECTIVES: There is increasing evidence linking inflammation and oxidative stress to atrial fibrillation (AF). In this study, we tested the hypothesis that C-reactive protein (CRP) and oxidative stress markers can predict the recurrence of persistent AF after successful pharmacological cardioversion. A possible relationship with AF occurrence was also investigated. STUDY DESIGN: Using a case control study design, CRP, catalase, superoxide dismutase (SOD), and malondialdehyde (MDA) levels of 42 patients (23 female, 19 male; mean age 58.4+/ 13.6 years) with documented persistent AF episodes were compared with 21 controls (9 female; 12 male; mean age 58.1+/-6.9 years). RESULTS: Overall AF patients were followed for 6 months, and 17 showed recurrence. Then, they were divided into two groups (recurrence and no recurrence) and compared with each other. CRP, SOD, and MDA levels were significantly higher in AF patients compared with controls. However, only CRP levels were significantly higher in patients with AF recurrence compared to those without recurrence. CONCLUSION: Increased markers of inflammation and oxidative stress are found in patients with persistent AF, suggesting that inflammation and oxidative stress may be associated with the presence of arrhythmia. PMID- 23363896 TI - [Evaluation of serum adiponectin levels in patients with obstructive sleep apnea syndrome]. AB - OBJECTIVES: Serum adiponectin levels have been found to be lower in patients with obesity, hypertension, and coronary artery diseases. In this study, we aimed to evaluate serum adiponectin levels in patients with obstructive sleep apnea syndrome (OSAS) and to correlate these levels with the severity of OSAS. STUDY DESIGN: In 62 OSAS patients (39 males, 23 females) and 32 controls (23 males, 9 females) determined by polisomnography, serum adiponectin levels were analyzed by the ELISA method. Patients were classified as having either mild (apnea hypopnea index, AHI: 5-14), moderate (AHI: 15-29) or severe (AHI >=30) OSAS, and controls were defined as AHI <5. Plasma fasting glucose, total cholesterol (TC), triglyceride (TG), and high (HDL-C) and low (LDL-C) density lipoprotein cholesterols were analyzed, and the results were compared between the groups. RESULTS: There was no significant difference in mean age (51.6+/-10.7 years for patients, 48.3+/-10.8 years for controls) or body mass index (32.9+/-6.0 kg/m2 for patients, 31.3+/-5.6 kg/m2 for controls, p>0.05) in our study population. There was no significant difference in the number of hypertensive, diabetics, or smokers between the patients and controls. While serum TC, TG, and HDL cholesterol levels were not significantly different between two groups, the serum adiponectin levels of patients (3.0+/-3.4 ug/dl) were significantly lower than those of the controls (5.2+/-5.2 ug/dl, p=0.01). While serum adiponectin levels showed a significantly negative correlation with AHI (r=-0.221, p=0.03), there was a significantly positive correlation with minimum and mean oxygen saturations (r=0.213, p=0.04 and r=0.205, p=0.05). CONCLUSION: Serum adiponectin levels were significantly lower in patients with OSAS, especially for those in the severe OSAS group. Serum adiponectin levels are related to the severity of OSAS and arterial oxygen saturation. PMID- 23363897 TI - [Reshaping the left Judkins catheter for a right coronary angiogram in the anomalous aortic origin of the right coronary: killing two birds with one left Judkins]. AB - OBJECTIVES: Selective cannulation of the right coronary artery (RCA) in the anomalous aortic origin of the RCA is technically difficult and challenging. In this study, we tested the success of RCA cannulation with a reshaped left Judkins catheter in cases of difficult selective cannulation. STUDY DESIGN: The study population consisted of 837 consecutive patients (456 male, 381 female) that were admitted to our hospital with stable angina pectoris and acute coronary syndrome between October 1 and December 31, 2011. In cases where RCA cannulation was difficult, the 10 centimeter section of the left Judkins proximal to the secondary curve was reshaped by hand to form an inward slope. The secondary curve angle was increased to approximately 100 degrees and the primary curve angle was adjusted to 120 degrees. Then, we attempted to perform selective RCA cannulation. RESULTS: In 49 of the 837 patients, selective RCA cannulation was unsuccessful with the right Judkins catheter. In 42 of these 49 (86%) cases, the RCA was cannulated with the reshaped left Judkins. We failed to cannulate the right coronary in two cases with downward angulation, one with upward angulation, one with high take-off origin, and one with anterior origin. A multipurpose, internal mammary artery, left Amplatz 1, and right Amplatz 1 catheter were used for cannulation in these cases, respectively. There was no angina, nor were there electrocardiographic or hemodynamic changes during the procedure. CONCLUSION: In cases where the selective cannulation of the RCA is difficult, using a reshaped left Judkins may be a successful and cost-effective method of selective cannulation. PMID- 23363898 TI - Evaluation of endothelial functions in patients with Behcet's disease without overt vascular involvement. AB - OBJECTIVES: Behcet's disease (BD) is a chronic inflammatory disease characterized by recurrent oral and genital ulcerations and ocular lesions. This multisystemic disorder primarily affects the vascular system. In the present study, we aimed to evaluate vascular endothelial function in patients with Behcet' s disease without vascular involvement. STUDY DESIGN: We studied 40 patients with BD (44.9+/-5.4 years) and 20 healthy controls (45.4+/-8.2 years). Brachial artery Doppler ultrasonography (USG) and bilateral carotid artery intima-media thickness measurements were performed. RESULTS: Basal diameter of the brachial artery were similar between the two groups. However, flow-mediated dilation was markedly impaired in patients with Behcet' s disease (p=0.03). Nitrate-induced dilation values were similar between the two groups (p=0.16). Carotid artery intima-media thickness was slightly increased in the patient group compared to the control group, but the difference did not reach statistical significance (0.69+/-0.15 to 0.59+/-0.09 respectively; p=0.06). CONCLUSION: Vascular endothelial function is impaired in BD. Brachial artery Doppler USG is a reliable and reproducible method to establish changes in vascular functions. PMID- 23363899 TI - Prinzmetal angina or coronary spasm related to anaphylactoid reaction? AB - Prinzmetal's angina is a challenging diagnostic of spontaneous brief episodes of chest pain. Anaphylactoid reactions to radiocontrast media are immediate hypersensitivity responses that can mediate coronary artery spasm. Herein, we report the case of a 61-year-old man who underwent a coronary angiography for angina. The right coronary artery (RCA) was first visualized as normal, but during the left coronary system injections, he developed ST segment elevation and cardiogenic shock. No iatrogenic dissection of the left coronary system, which was initially normal, was displayed, but surprisingly, a retrograde supply to the RCA was visualized. Thus, we re-catheterized the RCA, which indicated a total occlusion of its second segment. Nitrate injections completely relieved the spasm and the clinical condition of the patient normalized. The possible related mechanisms are also discussed. PMID- 23363900 TI - [Significant reduction in mitral regurgitation after transcatheter aortic valve implantation in a patient with severe degenerative aortic valve disease, moderate to severe mitral regurgitation, and normal ejection fraction]. AB - The best treatment modalities in severe aortic valve disease are surgery and, in selected patients, transcatheter aortic valve implantation (TAVI). At the present time, transcatheter aortic valve implantation performed in inoperable patients or in patients with high surgical risk not only treats the aortic valve stenosis but also treats the low ejection fraction and mitral regurgitation that result from it. An 83-year-old female patient presented with shortness of breath and class 3 angina. Transthoracic and transesophageal echocardiography revealed severe AS, moderate-to-severe MR, and normal ejection fraction. The patient was considered at high risk for aortic valve replacement (Logistic Euroscore 20, STS score 15). A dramatic decrease in the degree of mitral regurgitation was detected after the successful TAVI. PMID- 23363901 TI - Acute pericarditis during 5-fluorouracil, docetaxel and cisplatin therapy. AB - DCF chemotherapy regimen includes docetaxel, cisplatin, and 5-fluorouracil (5 FU). Cardiotoxicity is one of the well-known side effects of 5-FU, docetaxel, and cisplatin. In addition, the complications and side effects are more apparent when these three agents are given in combination. For the first time we describe a case of acute pericarditis associated with DCF regimen in a male patient. A 55 year-old man recently diagnosed with syncrone nasopharenx and non-small cell lung carcinoma was admitted to the oncology unit for chemotherapy. On the fourth day of infusion therapy with DCF he developed a central chest pain that was in pleuritic character and aggravated by recumbence. On electrocardiography (ECG), there was ST elevation on V2-6, D1, D2, and AVL. The patient was immediately transported to the cardiac catheterization laboratory for primary percutaneous coronary intervention. On coronary angiography, coronary arteries were normal. There was no segmentary wall motion abnormality on left ventricle in transthoracic echocardiography. The patient was diagnosed with acute pericarditis and the DCF regimen was discontinued. After 3 days, chest pain disappeared and ECG was normalized. According to the present case, the management of DCF-induced pericarditis includes stopping the drug and administering supportive treatment. The best method to prevent recurrent pericarditis induced by DCF is to use an alternate chemotherapeutic regimen. PMID- 23363902 TI - Does sildenafil contribute to acute coronary thrombosis? AB - Sildenafil was the first oral compound to be approved for the treatment of erectile dysfunction. It is a selective inhibitor of isoform 5 of phosphodiesterase, which is the enzyme responsible for the breakdown of 3', 5' cyclic guanosine mono-phosphate. Sildenafil-associated myocardial infarction (MI) is rarely seen in patients without previous history of coronary artery disease. A 43-year-old man presented with sudden onset of chest pain. It was determined that his chest pain started after sildenafil intake. Findings consistent with acute anterior MI were observed on electrocardiography. Coronary angiography showed total occlusion of left anterior descending artery with thrombosis. Coronary angioplasty and stenting was successfully performed. PMID- 23363903 TI - Successful catheter ablation of accessory pathway from noncoronary cusp of aorta: an alternative approach. AB - Anteroseptal accessory pathways are relatively rare. Because of the close proximity of the atrioventricular (AV) node, ablation of these accessory pathways has the potential to result in AV block. The anteroseptal region is adjacent to the noncoronary cusp, allowing anteroseptal accessory pathways to be ablated from the noncoronary cusp. A 34 year-old male patient with recurrent episodes of palpitation for approximately ten years was admitted to our department. Twelve lead-ECG was consistent with anteroseptal accessory pathway. Intracardiac recordings were also consistent with anteroseptal accessory pathway. In this case, we found an excellent AV relation while mapping the noncoronary cusp. Radiofrequency (RF) ablation was applied to this region. Pre-excitation was immediately disappeared during RF application. After RF ablation, there was no pre-excitation detectable by ECG. In this report, we present a case of anteroseptal accessory pathway that was successfully ablated from the noncoronary cusp. PMID- 23363904 TI - [Double aortic arch with dominant left arch: case report]. AB - A vascular ring is defined as an anomaly of the great arteries (aortic arch and its branches) that compresses the trachea or esophagus. Double aortic arch is the most common vascular ring. Double aortic arch is very rare and typically becomes symptomatic in infancy or early childhood. We present a 7-year-old girl admitted to our clinic for evaluation of recurrent respiratory infection with dysphagia. Double aortic arch was suspected from echocardiography and diagnosed with cardiac computed tomography. Left aortic arcus was larger than the right at computed tomography and cardiac catheterisation. After surgery the symptoms improved strikingly. We conclude that vascular ring should be considered in the patients presenting with recurrent pulmonary infections and dysphagia. Early diagnosis and treatment may prevent chronic, irreversible complications. PMID- 23363905 TI - [Perioperative management in patients receiving newer oral anticoagulant and antiaggregant agents]. AB - It is anticipated that an increasing number of patients undergoing surgical procedures will be taking new anticoagulants and antiaggregants. Currently, only a small amount of data (which were derived from subgroup analyses of undedicated studies) exist regarding the optimal strategy in these patients. Clinical studies are urgently required to establish safe surgical procedures for this high risk patient population. Unlike warfarin, dabigatran and rivaroxaban have predictable and consistent anticoagulant effects with a rapid onset of action, short half life, and consequently no need for routine laboratory testing. The pharmacologic profiles of these drugs represent an advantage for patients on chronic oral anticoagulant treatment who are undergoing invasive procedures. These drugs may minimize patient time spent without the antithrombotic effects of oral anticoagulants during the perioperative period, potentially eliminating the need for bridging therapy altogether. PMID- 23363906 TI - [Differential diagnosis of wide QRS complex tachycardias by ECG]. PMID- 23363907 TI - Case images: A very rare case: Ebstein anomaly, biventricular noncompaction and pre-excitation in the same patient. PMID- 23363908 TI - Case images: Biventricular hypertrophic cardiomyopathy in a baby diagnosed with Pompe disease. PMID- 23363909 TI - Case images: Budd-Chiari syndrome and multiple coronary fistulae in a patient with Behcet's disease. PMID- 23363910 TI - Case images: Hypertrophic cardiomyopathy associated with mid-ventricular obstruction and apical aneurysm. PMID- 23363911 TI - Case images: Transthoracic echocardiographic and angiographic view of a coronary to-left ventricular fistula. PMID- 23363912 TI - [Targets and entry points of the Twelfth Five Year Action Plan For HIV/AIDS Prevention and Control in China]. PMID- 23363913 TI - [The application of National AIDS spending assessment in a county of Dehong prefecture, Yunnan province, China]. AB - OBJECTIVE: To calculate the actual expenditures in a county of Dehong prefecture, Yunnan province, China by using the method of National AIDS Spending Assessment (NASA) in 2010. METHODS: Data were collected through NASA data collection form based on adapted NASA classification in the county of Dehong prefecture from October to December, 2011, and complemented by semi-structured interview with 16 well trained programmatic and financial representatives in 8 spending units. Data were entered in Resource Tracking Software (RTS) V 2009.3.0, and SPSS 13.0 was used for data processing and analysis. RESULTS: The NASA estimations showed that the county spent a total of Y16 235 954 on HIV/AIDS in 2010. Public funds constituted 96.3% of the total expenditure (Y15 630 937), followed by Global Fund which accounted for 3.0% (Y484 585) and private sources which accounted for 0.7% (Y120 432). Findings based on NASA categories showed that AIDS spendings were mainly on 4 areas, and expenditure on Care & Treatment was Y12 401 382 (76.4% of total expenditure), followed by Prevention which accounted for 14.3% (Y2 325 707), Program Management & Administration which accounted for 7.8% (Y1 268 523) and human resources which accounted for 1.5% (Y240 342). The most beneficial population group was People Living with HIV (PLHIV), accounting for 84.7% of total expenditure. (Y13 753 428), followed by 4.8% for high risk population, including female sex workers and their partners (Y297 333), injection drug users and their partners (Y293 143), men having sex with men and their partners (Y185 136) and 1.5% (Y241 429) for the general population. CONCLUSION: The local funds for HIV/AIDS in this county was insufficient. The local government should increase corresponding funds based on central government funding. Care and treatment was the first spending priority in the county and the investment of prevention services needs to be increased. Prevention and treatment and care should be combined to ensure the effectiveness of comprehensive prevention and treatment of AIDS. PMID- 23363914 TI - [Analysis of expenditure cost of intervention among men who have sex with men in certain city]. AB - OBJECTIVES: To learn the use of fund investment and actual expenditure cost among men who have sex with man (MSM) intervention in the city, in order to provide related evidences for carrying out the intervention effectively MSM. METHODS: Financial records were used to collect the information about the fund source and allocation of the resource invested for the MSM intervention between 2006 and 2009. Key staff was interviewed to get related information. The activity-based costing method was adopted to analyze the actual expenditure of MSM intervention in different sites, and the allocation of the total cost to each activity, the intervention times in different sites and the unit cost in actual HIV testing person-times promoted by MSM intervention was then calculated. RESULTS: Interventions through internet and in bar and bathhouse were conducted in the certain city. Total funds for MSM intervention between 2006 and 2009 were 4.441 million, 56.7% (Y2.530 million) of which were from international cooperation programs, whose direct cost covered 50.5% (Y2.243 million) of the total cost. The actual expenditure in interventions through Internet was Y750 656 (16.9%), including direct expenditure Y317 088 and indirect expenditure Y433 568. The actual expenditure in interventions in bar was Y2 061 846 (46.4%), including direct expenditure Y1 114 423 and indirect expenditure Y947 423. The actual expenditure in interventions in bathhouse was Y1 628 751 (36.7%), including direct expenditure Y811 474 and indirect expenditure Y817 277. The person-times of receiving MSM intervention and the unit cost for promoting HIV test through the above 3 access all decreased. The average cost for one person-time intervention through internet and in bar and bathhouse decreased from Y68.7 (1011 person-times), Y67.3 (3282 person-times), Y67.9 (3140 person-times) in 2006 to Y40.9 (25 523 person-times), Y30.2 (28 121 person-times), Y17.5 (28 381 person times) in 2009 respectively, and the cost for promoting one person-time HIV test decreased from Y1789.2 (58 person-times), Y1175.6 (188 person-times), Y574.2 (312 person-times)per person time to Y676.9 (394 person-times), Y556.5 (1637 person times), Y316.5 (2237 person-times) respectively. CONCLUSION: The unit cost of MSM intervention through internet and in bar and bathhouse decreased, as well as the cost for HIV test promotion per person-time in the city. Meanwhile, the intervention covered more and more people annually. PMID- 23363915 TI - [The unprotected sexual behaviors and its influencing factors among HIV-infected men who have sex with men in Shanghai, China]. AB - OBJECTIVE: To investigate the sexual partners and sexual behaviors among HIV infected men who have sex with men (MSM) and to examine the factors related with high risky sexual behaviors. METHODS: A total of 200 HIV-positive MSM participants were recruited using "snowballing" sampling from June to December in 2010 in Shanghai. Participants completed the questionnaire which included social demographic characteristics, sexual behaviors with male and female sexual partners in the past 6 months, alcohol consumption, alkyl nitrite use, illegal substances use and depression and anxiety symptoms, etc. RESULTS: Of the 200 HIV positive MSM participants, 45.0% (90/200) of participants' ages ranged from 26 to 35, and 30.0% (60/200) of the respondents were married. Participants living with a male partner and living with a female partner accounted for 17.0% (34/200) and 9.0% (18/200), respectively. A total of 57.5% (115/200) had anal sex with male and 13.5% (27/200) had sex with female in the past 6 months. The percentage of participants who had 2 or more male anal sexual partners was 36.5% (73/200). During last six months, participants who didn't use condom consistently during anal sexes with men and vaginal sexes with women accounted for 16.0% (32/200) and 3.5% (7/200), respectively. The rate of risky sexual behaviors (any unprotected sex with male or female) during past 6 months was 17.5% (35/200). Factors associated with risky sexual behaviors included getting drunk before last sex (OR = 4.270, 90%CI: 1.676 - 10.881), using alkyl nitrite (OR = 3.397, 90%CI: 1.564 - 7.377) and having casual male partners (OR = 2.951, 90%CI: 1.278 - 5.252) during past six months, getting HIV infection diagnosis in half year (OR = 4.181, 90%CI: 1.939 - 9.013). CONCLUSION: There were high rates of unprotected anal sex with men and vaginal sex with women among HIV positive MSM and alcohol and substance use before sex could increase the risk of having unprotected sex. PMID- 23363916 TI - [Mutation of drug resistant gene in HIV/AIDS patients with antiretroviral therapy in Shandong province in 2011]. AB - OBJECTIVE: To investigate drug resistance status in patients with highly active antiretroviral therapy (HAART) in Shandong province. METHODS: A total of 758 patients were separated from the anticoagulatory whole blood during May and October in 2011. The entire protease gene and part of the reverse transcriptase gene were amplified by RT-PCR and nest-PCR in the samples with viral load larger than 1000 copies/ml, then sequenced the gene fragments. Mutation of drug resistant gene and drug susceptibility was analyzed by the online tool HIV db program developed by Stanford University. RESULTS: The rate of virologic failure in patients was 9.1% (69/758). A total of 53 gene sequences that acquired were used for genotypic resistance analysis. A total of 23 patients were indicated drug resistance with the total of 3.1% (23/742). Drug resistance rates of nucleotide reverse transcriptase inhibitor (NRTI) and non-NRTI(NNRTI) were 2.4% (18/742) and 3.0% (22/742), respectively, and the primary mutation types of drug resistance were M184V and Y181C for NRTI and NNRTI, with no resistance to protease inhibitor (PI). In the 23 patients indicated drug resistance, 78.3% (18/23) were NRTI resistance, 95.7% (22/23) were NNRTI resistance and 73.9% (17/23) dual NRTI and NNRTI resistance. CONCLUSION: The presence of drug resistant gene in HIV strains among AIDS patients with HAART in Shandong province was at low level, but mutation diversity was found in drug resistant gene. PMID- 23363917 TI - [Molecular characteristics of HIV-1 CRF01_AE strains in Zhejiang province in 2009]. AB - OBJECTIVE: To analyze the molecular epidemiological characteristics of HIV-1 subtype CRF01_AE strains being prevailed among HIV/AIDS in Zhejiang province in 2009. METHODS: A total of 303 subjects were identified by stratified random sampling among HIV infected individuals in Zhejiang province in 2009. Gag fragments of the HIV-1 strains were amplified by nested polymerase chain reaction from the DNA extracted from whole blood of HIV-1 infected individuals. PCR products were sequenced and analyzed by phylogenetic method. RESULTS: A total of 132 HIV-1 subtype CRF01_AE sequences were identified from the 225 samples that sequenced successfully, accounting for 58.67% (132/225). A total of 90.91% (120/132) CRF01_AE strains infected HIV/AIDS were transmitted mainly by sexual contacts. A total of 65.91% (87/132) of the cases infected by heterosexual route and 25.00% (33/132) by homosexual route. There were three main clusters in the phylogenetic tree. Pairwise DNA distance within three groups was 0.037 +/- 0.011, 0.034 +/- 0.008 and 0.047 +/- 0.010, which has statistical significance (P < 0.05). Distribution of the sequence of homosexual behavior infected individuals was relatively concentrated in clusters one (96.97%, 32/33), and crossed with heterosexual behavior infectors, and presented the close relations with strains from Jiangsu province, Zhengzhou of Henan province, Liaoning province, Shijiazhuang of Hebei province. CONCLUSION: The CRF01_AE strains were the dominant subtypes among HIV infected individuals. The majority of the CRF01_AE infected cases had high risk sexual behavior. The heterosexual infected cases were more than homosexual cases. The circulating status of CRF01_AE strains in homosexual population was relatively independent, but also had evidence of transmission from man who have sex with man to heterosexual population. PMID- 23363918 TI - [The primary HIV drug resistance in partial region of Henan province]. AB - OBJECTIVE: To study the prevalence of primary HIV drug resistance in antiretroviral therapy (ART) areas of Henan province. METHODS: A total of 121 drug-naive long-term infected individuals and 154 patients with newly diagnosed from January 2011 to March 2012 were recruited, the questionnaires were surveyed and whole blood were collected to analyze the CD4(+)T cell counts and viral load. In-house method for genotypic resistance test was determined in those with viral load > 1000 copies/ml samples, the differences of demographic characteristics, immunological parameters and primary drug resistance were compared between the two groups. RESULTS: A total of 121 cases of long-term individuals who had infected (12.50 +/- 3.21) years were mainly previous paid blood donors, and the age was (46.61 +/- 9.32) years old. The infection route of the newly diagnosed were diversity, including blood, sexual transmission and others, the cases were 73, 73, 8, respectively, the confirmatory year was (0.91 +/- 0.28) years, and average age was (22.21 +/- 3.11) years old. The difference were statistically significant in the route of transmission, age and infection time from demographic analysis of the two groups (P < 0.05). The absolute M(P(25)-P(75)) counts of CD4(+)T lymphocytes of long-term group was 322 (217 - 422) cell/ul, which was lower than the newly diagnosed was 434(308 - 578) cell/ul (P < 0.05), and viral load was 4.0 (2.96 - 4.64) copies/ml, 3.77 (2.94 - 4.53) copies/ml, the difference was not significant (P > 0.05). The prevalence of primary drug resistance in long-term group and newly diagnosed was 5.79% (7/121), 9.09% (14/154), respectively, and the difference was statistically different (P < 0.05), and one PI-resistant strain was found in the newly diagnosed group. CONCLUSION: The primary drug resistant strains in untreated patients were found in Henan province of ART areas, and there was difference in degree of resistance between long-term infected individuals and newly diagnosed. PMID- 23363919 TI - [Characteristics and associated factors of long-term retention for methadone maintenance treatment patients]. AB - OBJECTIVE: To describe the characteristics and factors associated with long-term retention for methadone maintenance treatment (MMT) patients. METHODS: This study was conducted in eight MMT clinics located in Sichuan, Yunnan, Guangxi, Guizhou and Zhejiang provinces. Five hundred and thirty-nine MMT patients who enrolled in MMT clinics in 2004 and retained in treatment by June 2010 were selected as study subjects. Chi-square tests were used to compare the demographics and drug abuse history at enrollment and treatment characteristics during the follow-up period between continuous treatment patients and discontinuous treatment patients. RESULTS: Of the 539 patients, 110 (20.4%) were continuous treatment patients whereas 429 (79.6%) were discontinuous treatment patients. Of these 429 discontinuous treatment patients, 84.1% (361/429) had 2-4 treatment episodes whereas 15.9% (68/429) had 5 or more episodes during follow-up period. When continuous treatment patients were compared with discontinuous treatment patients, living with family members or friends (88.2% (97/110), 78.5% (337/429)), age of first drug use under 25 (61.8% (68/110), 71.3% (306/429)), low urine morphine positive test results (67.3% (74/110), 38.2% (164/429)) and living within 5 kilometers of the MMT clinic (72.7% (80/110), 61.3% (263/429)) were positively associated with higher possibility of continuous treat retention (P < 0.05). Demographics and drug abuse characteristics at enrollment, including gender, age, employment status, family relationship, injection, needle sharing, criminal behavior, contacts with drug users, MMT daily dosage and family members receiving MMT were not significantly associated with treatment retention (P > 0.05). CONCLUSION: Illicit drug use during the treatment and longer distance travelling to MMT clinic might have negative impact on patients' continuous treatment retention. Mobile MMT vehicles and expanded MMT service sites could be introduced to improve compliance of treatment retention of MMT patients. PMID- 23363920 TI - [Effectiveness of intervention services provided by social workers in methadone maintenance treatment clinics]. AB - OBJECTIVE: To investigate the effectiveness of psychosocial services provided by social workers in reducing dropout rate and increasing treatment dosage in methadone maintenance treatment (MMT) users. METHODS: From May in 2009 to April in 2010, 300 MMT users were recruited from three MMT clinics in Guangzhou, and were randomly allocated into the intervention group and the control groups. The control group (152 cases) received standard MMT services while the intervention group (148 cases) received additional services provided by social workers. Methadone dosage, dropout rate, perceptions toward MMT etc. were compared between the two groups. RESULTS: The 1-month dropout rate of the control and intervention groups were 19.7% (30/152) and 6.8% (10/148) (P < 0.05) respectively; the 6-month dropout rate of the control and intervention groups were 75.5% (115/152) and 50.7% (75/148) (P < 0.05) respectively. The intervention group had higher average treatment dosage than the control group ((56.0 +/- 21.2) vs (64.4 +/- 23.1) ml/d, (58.0 +/- 24.0) vs (66.1 +/- 26.6) ml/d, P < 0.05). At 1-month and 6-month, the intervention group had higher scores of MMT-related perception ((1.26 +/- 0.68) vs (1.84 +/- 0.95), (1.55 +/- 0.83) vs (2.44 +/- 1.23), P < 0.05), self-efficacy of maintenance ((3.68 +/- 1.33) vs (4.20 +/- 1.05), (3.80 +/- 1.38) vs (4.43 +/- 0.79), P < 0.05) and satisfaction toward MMT((4.08 +/- 0.54) vs (4.15 +/- 0.60), (4.01 +/- 0.67) vs (4.31 +/- 0.64), P < 0.05) as compared to the control group. The reverse was true for the score of negative experiences ((1.05 +/- 0.86) vs (0.96 +/- 0.92), (1.46 +/- 0.87) vs (1.11 +/- 1.07), P < 0.05). CONCLUSION: The psychosocial interventions provided by social workers were effective in reducing dropout rate, increasing treatment dosage and improving cognitions of MMT users. PMID- 23363921 TI - [Analysis on late diagnosis reasons of newly diagnosed HIV/AIDS patients]. AB - OBJECTIVE: To understand the characteristics of HIV/AIDS patients with late diagnosis and find the factors associated with late HIV detection. METHODS: HIV late diagnosed patients and early diagnosed patients, which were identified and classified by definition in advance, were selected from the case reporting database of HIV/AIDS Comprehensive Response Information Management System in eight counties of four provinces (Zhumadian, Nanyang, and Zhoukou of Hennan province; Liuzhou and Lingshan county of Guangxi autonomous region; Guangzhou and Shenzhen of Guangdong province; Dehong of Yunnan province) between January 1, 2009 and June 30, 2010. A total of 3912 eligible patients were investigated, including 2496 late diagnosis and 1416 early diagnosis. The structured questionnaires were used to obtain information on behaviors, HIV detection history and reason of late detection for all eligible HIV/AIDS patients. Late diagnosed patients were defined by CD4 T-cell counts less than 200 cells/mm(3) or diagnosis as AIDS within the reported year after the first HIV positive test. The univariate and multivariate logistic regression methods were used to analyze the characteristics of HIV/AIDS late diagnosed patients. RESULTS: Only 14.2% (350/2469) of them have ever had the awareness of "to go for HIV testing", 68.8% (150/218)of which did not put it into practice within one month because of discrimination and stigma. Among those HIV late diagnosed patients without the awareness of "to go for HIV testing", the proportions of "never worried about HIV infection" or "never heard of AIDS" were 69.7% (1476/2116) and 18.1% (383/2116), respectively. When those HIV late diagnosed patients visited health settings because of AIDS related symptoms, only 40.0% (590/1475) of them received the HIV testing service. Furthermore, 54.5% (322/590) of those received HIV testing were not informed the results. Compared with early diagnosed patients, patients with late diagnosis were over 50 years old (OR = 4.14, 95%CI: 3.09 - 5.55), primary school education (OR = 1.29, 95%CI: 1.10 - 1.52) and illiteracy (OR = 2.15, 95%CI: 1.25 - 2.82), Routes of transmission from former illegal blood or plasma (OR = 2.91, 95%CI: 2.27 - 3.74) and transfusion of blood/blood products (OR = 2.79, 95%CI: 2.11 - 3.68). Late diagnosed patients were identified mainly from voluntary counseling and testing (45.4%, 1130/1528) and medical institutions (38.3%, 954/1469). CONCLUSION: The main reasons for late diagnosis of HIV infection are low initiative of HIV testing and discrimination and stigma. Furthermore, the low awareness of medical institutions to actively provide HIV testing affects the early diagnosis of HIV infections. PMID- 23363922 TI - [The incidence and mortality trends of female breast cancer in Beijing, China: between 2004 and 2008]. AB - OBJECTIVE: To analyze the incidence and mortality trends of female breast cancer in urban and rural areas of Beijing from 2004 to 2008. METHODS: The incidence and mortality data of female breast cancer from 2004 to 2008 were sorted from Beijing Cancer Registry Database, including 15 527 new diagnosed cases and 3219 deceased cases in total, covering population 29 351 258 person years; among which 11 065 new cases and 2378 deceased cases were from urban areas, covering 17 877 128 person years and 4462 new diagnosed cases and 841 deceased cases were from rural areas, covering 11 474 130 person years. The incidence cases aged 25 and above were divided into 13 age groups by 5 years. The cases under 49 years (<= 49) and over 49 years (> 49) were separately defined as premenopausal group and postmenopausal group. Incidence and mortality rates in each year, age-specific incidence and mortality rates in urban and rural areas in Beijing were calculated. The annual standard incidence and mortality rates were adjusted by world population constitution; and the incidence rates ratio in different years related to the place of residence, urban or rural were calculated. JoinPoint software was applied to analyze the incidence trend and calculated the annual percentage of changing (APC). RESULTS: The age of female breast cancer patients in urban Beijing in 2004 was (55.83 +/- 13.01), while it changed to (56.10 +/- 12.80) in 2008, increasing by 0.27 years old. The proportion of the patients who were under 49 years declined from 38.32% (732/1910) in 2004 to 34.02% (894/2628) in 2008. While the average age of the patients in rural areas have improved 0.21 year old, from (52.15 +/- 11.33) years old in 2004 to (52.36 +/- 11.59) years old in 2008; and the proportion of the patients under 49 years also declined from 45.44% (314/691) in 2004 to 43.40% (454/1046) in 2008. From 2004 to 2008, the incidence and mortality rate of female breast cancer in urban areas of Beijing separately rose from 55.43/100 000 (1910/3 445 812) and 10.65/100 000 (367/3 445 812) to 70.70/100 000 (2628/3 717 436) and 15.01/100 000 (558/3 717 436). And in rural areas, those rates separately rose from 30.60/100 000 (691/2 257 953) and 5.54/100 000 (125/2 257 953) in 2004 to 44.78/100 000 (1046/2 336 040) and 7.49/100 000 (175/2 336 040) in 2008. After adjusting by world population constitution, the difference showed no statistical significance in mortality trend of female breast cancer in rural areas of Beijing (P > 0.05). In year 2004, the female breast cancer incidence rate ratio of urban to rural areas in Beijing fluctuated between 1.34 and 4.47, with the average ratio value at 1.81. In year 2008, the ratio value fluctuated between 1.15 and 2.37, with the average ratio value at 1.57. During 2004 and 2008, the peak age group of the female breast cancer incidence in urban areas was in 60 - 64 years old group, with the rate of 126.92/100 000 (998/786 300) whereas the mortality rate was increasing within aging. In rural areas the peak age groups of the incidence and mortality were separately in 50 - 54 and 80 - 84 years old groups, with the rate of 80.63/100 000 (793/983 516) and 29.17/100 000 (40/137 132) respectively. CONCLUSION: The incidence and mortality of breast cancer in urban areas in Beijing, as well as the incidence of breast cancer in rural areas in Beijing showed increasing trend annually. The gap in breast cancer incidence between rural and urban areas in Beijing was narrowing, while the incidence rate among different aging groups and the peak mortality rate showed significant difference between urban and rural areas in Beijing. PMID- 23363923 TI - [Analysis of the lag-effects of temperature on the five cities' mortality in China]. AB - OBJECTIVE: To study the characteristics of the effect of different temperatures on mortality of different cities through analyzing the relationship between mortality and meteorology of five Chinese cities. METHODS: We get the demography and climate data of Beijing, Tianjin, Shanghai, Nanjing and Changsha cities from National Center of Disease Control and Prevention and Climate net respectively. Then we applied the R software and Distributed Lag Non-linear Models (DLNM) package to analyze our data and find the nonlinear and lag effects on mortality using DLNM. RESULTS: The city of Beijing and Tianjin are located in the temperate zone. And the climate of Shanghai, Nanjing, Changsha belong to subtropical monsoon climate. When the daily mean temperature arrived 30 degrees C and on lag 0 day, the values of relative risk of effect of high mean temperature on mortality in Nanjing (1.31, 95%CI: 1.21 - 1.41) and Changsha (1.25, 95%CI: 1.13 - 1.39) are larger than that in Beijing (1.18, 95%CI: 1.12 - 1.25), Tianjin (1.18, 95%CI: 1.10 - 1.26) and Shanghai(1.15, 95%CI: 1.06 - 1.24). While the relative risk of effect of low mean temperature on mortality is lower and lasts for a longer lag time. During the whole lag time, the relative risk of effect of the lowest daily mean temperature of each city on mortality in Tianjin, Changsha, Beijing, Nanjing, and Shanghai is 3.41, 95%CI: 1.60 - 7.27, 2.15, 95%CI: 1.11 - 4.15, 2.24, 95%CI: 1.12 - 4.48, 2.80, 95%CI: 1.75 - 4.48, 1.53, 95%CI: 1.12 - 2.03, respectively. The cumulative effect of mean temperature on mortality appears like a U-shape. When on lag 0-1 day, the value of relative risk of effect of extremely high temperature and the highest mean temperature on mortality is larger than 1. While the effect of low temperature on mortality becomes obvious after lag 2 days. CONCLUSION: Depending on this research, extremely low temperature and the lowest mean temperature has a more obvious impact on mortality in the northern area than in the south. Extremely high temperature and the highest daily mean temperature is on the contrary. Meanwhile, different temperatures have different impacts on mortality in the same city: high temperature has an acute impact while there is a longer lag time in low temperature. PMID- 23363924 TI - [The assessment of vulnerability to floods in Guangdong province at district level]. AB - OBJECTIVE: To evaluate the vulnerability to floods in Guangdong province at district level. METHODS: Data were collected from the sixth census, the 2010 Statistical Yearbook of Guangdong, the 2010 Health Statistics Yearbook of Guangdong and China Disease Prevention and Control information systems, etc. The weight of each indicator was determined based on subjective method and objective method respectively; and finally the results of the two methods were compared. RESULTS: 13 indicators were selected for the assessment of vulnerability to floods, including 6 sensitivity indicators, 5 adaptability indicators and 2 exposure indicators. Indicators with large weight (subjective weight/objective weight) were the proportion of population older than 65 years old (0.31/0.30), the proportion of population older than 65 years old (0.16/0.23), infant mortality rate (0.18/0.20), the total Gross Domestic Product (GDP) per capita (0.33/0.21), the proportion of illiterate in the population older than 15 years old (0.19/0.28), history frequency of floods (0.75/0.75). The mean vulnerability index (VI) calculated by subjective method was 0.35 with the standard deviation of 0.10; the mean vulnerability index calculated by objective method was 0.31 with the standard deviation of 0.08. The two weighting methods showed consistent results of vulnerability index (ICC = 0.975, P < 0.01). VI of most districts dropped in the interval of 0.30 - 0.39. Districts with subjective VI > 0.50 or objective VI > 0.40 should pay more attention to floods, including parts of the coastal areas, Beijiang River Basin, the eastern tributary area of Dongjiang River and the northern part of Pearl River Delta. Dapu district of Meizhou (0.55/0.45), Dianbai district and Maogang district of Maoming (0.54/0.48) were most vulnerable. Districts of Heyuan, Dongguan, Zhaoqing and Huizhou were less vulnerable, Yuancheng district of Heyuan showed least vulnerable to floods (0.15/0.12) followed by Dongguan (0.18/0.16), Duanzhou district (0.18/0.16) and Guangning (0.17/0.15) district of Zhaoqing. The score of indicators differed among different level of vulnerability (P < 0.05). CONCLUSION: Different regions of Guangdong province showed different vulnerability to floods, vulnerable areas should be priority in the prevention and control of floods. PMID- 23363925 TI - [Prediction of heat-related mortality impacts under climate change scenarios in Shanghai]. AB - OBJECTIVE: To project the future impacts of climate change on heat-related mortality in shanghai. METHODS: The statistical downscaling techniques were applied to simulate the daily mean temperatures of Shanghai in the middle and farther future under the changing climate. Based on the published exposure reaction relationship of temperature and mortality in Shanghai, we projected the heat-related mortality in the middle and farther future under the circumstance of high speed increase of carbon e mission (A2) and low speed increase of carbon emission (B2). The data of 1961 to 1990 was used to establish the model, and the data of 1991 - 2001 was used to testify the model, and then the daily mean temperature from 2030 to 2059 and from 2070 to 2099 were simulated and the heat related mortality was projected. The data resources were from U.S. National Climatic Data Center (NCDC), U.S. National Centers for Environmental Prediction Reanalysis Data in SDSM Website and UK Hadley Centre Coupled Model Data in SDSM Website. RESULTS: The explained variance and the standard error of the established model was separately 98.1% and 1.24 degrees C. The R(2) value of the simulated trend line equaled to 0.978 in Shanghai, as testified by the model. Therefore, the temperature prediction model simulated daily mean temperatures well. Under A2 scenario, the daily mean temperature in 2030 - 2059 and 2070 - 2099 were projected to be 17.9 degrees C and 20.4 degrees C, respectively, increasing by 1.1 degrees C and 3.6 degrees C when compared to baseline period (16.8 degrees C). Under B2 scenario, the daily mean temperature in 2030 - 2059 and 2070 - 2099 were projected to be 17.8 degrees C and 19.1 degrees C, respectively, increasing by 1.0 degrees C and 2.3 degrees C when compared to baseline period (16.8 degrees C). Under A2 scenario, annual average heat-related mortality were projected to be 516 cases and 1191 cases in 2030 - 2059 and 2070 - 2099, respectively, increasing 53.6% and 254.5% when compared with baseline period (336 cases). Under B2 scenario, annual average heat-related mortality were projected to be 498 cases and 832 cases in 2030 - 2059 and 2070 - 2099, respectively, increasing 48.2% and 147.6% when compared with baseline period (336 cases). CONCLUSION: Under the changing climate, heat-related mortality is projected to increase in the future;and the increase will be more obvious in year 2070 - 2099 than in year 2030 - 2059. PMID- 23363926 TI - Epidemiological study of adult-onset myasthenia gravis in the area of Belgrade (Serbia) in the period 1979-2008. AB - BACKGROUND: The aim of this study was to analyze the prevalence and incidence of adult-onset myasthenia gravis (MG) in the Belgrade population from 1979 to 2008. METHODS: Data on the number of MG patients and their basic demographic and clinical characteristics were collected from hospital records (1979-1992) and the Belgrade MG Registry (1993-2008). Incidence and prevalence were standardized by the direct method (using the world standard population). A time-trend analysis of MG incidence was performed using a linear regression model. RESULTS: During the study period 562 cases (316 women, 246 men) were registered. On December 31st, 2008, the standardized prevalence (according to the world standard population) was 188.3/1,000,000 (women: 237.8/1,000,000; men: 139.4/1,000,000). The average annual standardized incidence rate was 13.3/1,000,000 (women: 14.1/1,000,000; men: 12.2/1,000,000). The incidence rates tended to increase significantly in both sexes during the study period (y = 3.299 + 14.363x, p = 0.002). Age-specific incidence rates for women demonstrated a bimodal pattern, with the first peak in the 20- to 29-year age group and the second one in the >=70-year group. For both genders, an increase in age-specific incidence rates was registered for all age groups, although this was significant (p = 0.001) only for an MG onset of >=60 years of age. CONCLUSIONS: The study confirms an increase in the incidence of MG in the area of Belgrade during the study period, especially for those with MG onset after 60 years of age. PMID- 23363927 TI - The carbohydrate-binding module of xylanase from Nonomuraea flexuosa decreases its non-productive adsorption on lignin. AB - BACKGROUND: The enzymatic hydrolysis step converting lignocellulosic materials into fermentable sugars is recognized as one of the major limiting steps in biomass-to-ethanol process due to the low efficiency of enzymes and their cost. Xylanases have been found to be important in the improvement of the hydrolysis of cellulose due to the close interaction of cellulose and xylan. In this work, the effects of carbohydrate-binding module (CBM family II) of the xylanase 11 from Nonomuraea flexuosa (Nf Xyn11) on the adsorption and hydrolytic efficiency toward isolated xylan and lignocellulosic materials were investigated. RESULTS: The intact family 11 xylanase of N. flexuosa clearly adsorbed on wheat straw and lignin, following the Langmuir-type isotherm. The presence of the CBM in the xylanase increased the adsorption and hydrolytic efficiency on insoluble oat spelt xylan. But the presence of the CBM did not increase adsorption on pretreated wheat straw or isolated lignin. On the contrary, the CBM decreased the adsorption of the core protein to lignin containing substrates, indicating that the CBM of N. flexuosa xylanase did not contribute to the non-productive adsorption. CONCLUSION: The CBM of the N. flexuosa xylanase was shown to be a xylan-binding module, which had low affinity on cellulose. The CBM of the N. flexuosa xylanase reduced the non-specific adsorption of the core protein to lignin and showed potential for improving the hydrolysis of lignocellulosic materials to platform sugars. PMID- 23363929 TI - Vascular research using human pluripotent stem cells and humoral factors. AB - Embryonic stem (ES) cells are pluripotent cells collected from the inner cell mass of blastocysts. Induced pluripotent stem cells exhibit characteristics and pluripotency similar to ES cells, even though they were generated from adult somatic cells. We have been investigating the vascular differentiation kinetics of human pluripotent stem cells (PSCs) and their application to human vascular research and clinical medicine. In this review, we present an overview of recent vascular research using human PSCs, focusing on the role of humoral factors and their receptors. We also discuss possible future application of human PSCs to translational research on human vascular disorders. PMID- 23363928 TI - Hamstring and psoas length of crouch gait in cerebral palsy: a comparison with induced crouch gait in age- and sex-matched controls. AB - BACKGROUND: Previous studies have shown that hamstring lengths are often not short in patients with cerebral palsy, which raises concerns over the benefits of distal hamstring lengthening in patients with crouch gait. In this study, the authors measured lengths of hamstrings and psoas muscles in normal subjects mimicking crouch gait and compared these with lengths in cerebral palsy patients with crouch gait. METHODS: Thirty-six patients with cerebral palsy and crouch gait were included in this study, and in addition, 36 age- and sex-matched normal controls were recruited. Hamstring and psoas muscle lengths in patients were evaluated using gait analysis and interactive musculoskeletal modeling software. Muscle lengths were also measured in the normal control group during normal gait and while mimicking crouch gait, and these were compared with those of cerebral palsy patient with crouch gait. RESULTS: No significant differences were observed between maximum hamstring (p=0.810) and maximum psoas (p=0.456) lengths of patients and controls mimicking crouch gait. However, patients showed significantly shorter excursions of hamstring (p=0.022) and psoas (p=0.036) muscles than controls, whereas no significant excursion differences were observed between controls during normal gait and mimicking crouch gait. CONCLUSIONS: Normal controls mimicking crouch gait and cerebral palsy patients with crouch gait demonstrate similar muscle length patterns. However, mimicked crouch gait did not reproduce the excursion pattern shown by patients with crouch gait, which suggests that reduced hamstring and psoas excursion is an innate characteristic of pathologic crouch gait. PMID- 23363930 TI - Burning sensation in oral submucous fibrosis and its possible association with mucin secreted by affected minor salivary glands. PMID- 23363931 TI - Tissue engineering of blood vessels in cardiovascular disease: moving towards clinical translation. AB - Tissue engineering focuses on the construction of three-dimensional neotissues from their cellular components. Neotissue can be used to repair or replace tissues that are missing, damaged, or diseased. Despite its relative youth, the field has undergone significant growth. Vascular tissue engineering is at the forefront in the translation of this technology, as tissue engineered vascular grafts have already been successfully implanted in children with congenital heart disease. The purpose of this report is to review the advances in the understanding of tissue engineered vascular grafts as the technology moves to clinical translation. PMID- 23363932 TI - Predicting age of onset in familial essential tremor: how much does age of onset run in families? AB - BACKGROUND: The extent to which age of onset of essential tremor (ET) aggregates in families is unknown; hence, it is unclear whether information about the age of onset in one family member can be used to predict the age of onset in others. METHODS: ET probands and relatives were enrolled in a genetic study at Columbia University. RESULTS: Data from 26 probands and 52 relatives were analyzed. The probands' age of onset correlated significantly with their relatives' age of onset (r = 0.50, p = 0.001). In 57.7% of cases, the relative's age of onset was within 10 years of the proband's onset (i.e. a 20-year age range). The proportion of affected relatives with age at onset <20 years was 64.7% in the families of probands with onset younger than 20 years, but only 7.7% in the families of probands with onset >=20 years (p < 0.001). There was little evidence for genetic anticipation; 9/18 (50.0%) children reported a younger age of onset than the proband. CONCLUSIONS: In families containing multiple individuals with ET, the age at onset of probands and relatives was significantly correlated. Age of onset may be most tightly linked in families in which the proband had a young age of onset. PMID- 23363933 TI - On the feasibility of self-mixing interferometer sensing for detection of the surface electrocardiographic signal using a customized electro-optic phase modulator. AB - Optical sensing offers an attractive option for detection of surface biopotentials in human subjects where electromagnetically noisy environments exist or safety requirements dictate a high degree of galvanic isolation. Such circumstances may be found in modern magnetic resonance imaging systems for example. The low signal amplitude and high source impedance of typical biopotentials have made optical transduction an uncommon sensing approach. We propose a solution consisting of an electro-optic phase modulator as a transducer, coupled to a vertical-cavity surface-emitting laser and the self mixing signal detected via a photodiode. This configuration is physically evaluated with respect to synthesized surface electrocardiographic (EKG) signals of varying amplitudes and using differing optical feedback regimes. Optically detected EKG signals using strong optical feedback show the feasibility of this approach and indicate directions for optimization of the electro-optic transducer for improved signal-to-noise ratios. This may provide a new means of biopotential detection suited for environments characterized by harsh electromagnetic interference. PMID- 23363934 TI - [18F]fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography imaging in oncology: initial staging and evaluation of cancer therapy. AB - Positron emission tomography (PET) with [18F]fluoro-2-deoxy-D-glucose (FDG) has proven to be a valuable diagnostic modality in various diseases. Its accuracy has been improved with the hybrid PET/computed tomography (CT) technique because of precise anatomic location of areas of abnormal FDG accumulation. This integrated PET/CT modality has been widely adopted, particularly in oncology. This paper reviews the role of FDG-PET/CT imaging in breast cancer, non-small-cell lung cancer, colorectal cancer, head and neck cancer as well as lymphoma on the basis of recent key articles. Special attention is paid to preoperative diagnostic workup, evaluation of treatment response and survival prognosis. Experience from specialized centers indicates that there is strong evidence for the clinical effectiveness of FDG-PET/CT in staging, restaging and the prediction of response to therapy in the above-mentioned malignancies. It is concluded that this imaging modality contributes considerably to improved patient management and paves the way to personalize cancer treatment in a cost-effective way. PMID- 23363936 TI - Incidence and prevalence of multiple sclerosis in the Americas: a systematic review. AB - BACKGROUND: The incidence and prevalence of multiple sclerosis (MS) varies considerably around the world. No previous study has performed a comprehensive review examining the incidence and prevalence of MS across the Americas. The purpose of this study was to systematically review and assess the quality of studies estimating the incidence and/or prevalence of MS in North, Central and South American regions. METHODS: A comprehensive literature search was performed using MEDLINE and EMBASE from January 1985 to January 2011. Search terms included 'multiple sclerosis', 'incidence', 'prevalence' and 'epidemiology'. Only full text articles published in English or French were included. Study quality was assessed using an assessment tool based on recognized guidelines and designed specifically for this study. RESULTS: A total of 3,925 studies were initially identified, with 31 meeting the inclusion criteria. The majority of studies examined North American regions (n = 25). Heterogeneity was high among all studies, even when stratified by country. Only half of the studies reported standardized rates, making comparisons difficult. Quality scores ranged from 3/8 to 8/8. CONCLUSION: This review highlights the gaps that still exist in the epidemiological knowledge of MS in the Americas, and the inconsistencies in methodologies and quality among the published studies. There is a need for future studies of MS prevalence and incidence to include uniform case definitions, employ comparable methods of ascertainment, report standardized results, and be performed on a national level. Other factors such as sex distribution, ethnic make-up and population lifestyle habits should also be considered. PMID- 23363935 TI - Fine-mapping of 5q12.1-13.3 unveils new genetic contributors to caries. AB - Caries is a multifactorial disease and little is still known about the host genetic factors influencing susceptibility. Our previous genome-wide linkage scan has identified the interval 5q12.1-5q13.3 as linked to low caries susceptibility in Filipino families. Here we fine-mapped this region in order to identify genetic contributors to caries susceptibility. Four hundred and seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. DMFT scores and genotype data of 75 single-nucleotide polymorphisms were evaluated in the Filipino families with the Family-Based Association Test. For replication purposes, a total 1,467 independent subjects from five different populations were analyzed in a case-control format. In the Filipino cohort, statistically significant and borderline associations were found between low caries experience and four genes spanning 13 million base pairs (PART1, ZSWIM6, CCNB1, and BTF3). We were able to replicate these results in some of the populations studied. We detected PART1 and BTF3 expression in whole saliva, and the expression of BTF3 was associated with caries experience. Our results suggest BTF3 may have a functional role in protecting against caries. PMID- 23363937 TI - Interaction between interferon-stimulated gene 56 and melanoma differentiation associated gene 5 in Toll-like receptor 3 signaling in normal human mesangial cells. AB - BACKGROUND/AIMS: Toll-like receptor 3 (TLR3) is a pathogen recognition receptor against viral double-stranded RNA. TLR3 signaling is important in antiviral responses, but inappropriate TLR3 signaling may be related with inflammatory renal diseases. Interferon (IFN)-stimulated gene 56 (ISG56) is an IFN-inducible gene that encodes a multifunctional protein with 6 tetratricopeptide motifs and is thought to be involved in antiviral reactions, but the role of ISG56 in TLR3 signaling in mesangial cells is not known well. METHODS: Normal human mesangial cells were cultured and treated with a synthetic TLR3 ligand polyinosinic polycytidylic acid, and the expression of ISG56 was analyzed using real-time RT PCR and Western blot analyses. Using an RNA-interfering technique, involvement of TLR3, IFN-beta, melanoma differentiation-associated gene 5 (MDA5) or retinoic acid-inducible gene-I (RIG-I) in ISG56 expression, and of ISG56 in the expression of MDA5, RIG-I, CXCL10 and CCL5 was examined. RESULTS: Treatment of cells with polyinosinic-polycytidylic acid induced ISG56. ISG56 induction was inhibited by knockdown of TLR3 or IFN-beta, and knockdown of ISG56 resulted in the decreased expression of MDA5, RIG-I, CXCL10 and CCL5. RNA interference against MDA5 decreased ISG56 expression. CONCLUSION: ISG56 was induced by TLR3 signaling via newly synthesized IFN-beta. ISG56 is involved in the expression of MDA5, RIG-I, CXCL10 and CCL5, and ISG56 and MDA5 may constitute a positive-feedback loop. ISG56 may play a role in immune and inflammatory reactions induced by TLR3 signaling in human mesangial cells. PMID- 23363938 TI - [Primary percutaneous coronary intervention for acute myocardial infarction in elderly aged 75 years and over: in-hospital mortality and clinical outcome]. AB - OBJECTIVES: We aimed to determine the in-hospital mortality and clinical outcome of patients older than 75 years who were admitted to our high-volume tertiary center with ST-elevation myocardial infarction (STEMI) and treated with primary percutaneous intervention (PCI). STUDY DESIGN: Our study included patients over 75 years old who were admitted with STEMI and underwent primary PCI at our center between January 2008 and September 2011. We retrospectively collected data from our hospital records for 1165 patients with STEMI. We found 186 patients that were eligible for our study. We defined major adverse cardiovascular events (MACE) as in-hospital mortality, repeated target vessel revascularization, and reinfarction. RESULTS: The mean age of the patients was 79.7+/-4.4 years and the mean pain-balloon inflation time was 4.7+/-2.3 hours. The procedure success rate was 71.5%. In-hospital mortality and MACE occurred in 20.4% and 25.8% of patients, respectively. Twenty patients had cardiogenic shock at admission. Patients with cardiogenic shock had significantly more MACE than the rest of the study population (76.5% vs. 17.5%, p<0.0001). Independent predictors of MACE included Killip class at admission (OR 4.98, 95% CI 1.25-19.8, p=0.02), white blood cell counting (OR 1.15, 95% CI 1.0-1.3, p=0.04), development of in-hospital heart failure (OR 3.34, 95% CI 1.07-10.58, p=0.04), the presence of atrioventricular block in the hospital (OR 3.98, 95% CI 1.09-14.5, p=0.04), and the TIMI flow rate after primary PCI (OR 3.42, 95% CI 1.19-10.76, p=0.04). CONCLUSION: Our study revealed a high rate of MACE in patients older than 75 years admitted with STEMI regardless of undergoing primary PCI. PMID- 23363939 TI - Determination of subclinical atherosclerosis in plaque type psoriasis patients without traditional risk factors for atherosclerosis. AB - OBJECTIVES: Systemic inflammation plays an important role in the pathogenesis of atherosclerosis in psoriasis patients. Therefore, persistent skin inflammation in psoriasis patients may contribute to the development of premature atherosclerosis, as it occurs in rheumatoid arthritis and systemic lupus erythematosus. We aimed to evaluate the relationship between subclinical atherosclerosis and psoriasis by using pulse wave velocity (PWV) and the measurement of carotid intima media thickness (CIMT) in psoriatic patients. STUDY DESIGN: Fifty-seven plaque-type psoriasis patients (31 males, 26 females; mean age 41+/-10.8 years) and 60 healthy individuals (32 males, 28 females; mean age 40+/-9.4 years) were included. Atherosclerotic risk factors were excluded in both of the groups. Demographic, bio-chemical data, psoriasis area and severity index (PASI) score of the psoriasis group, and disease duration were recorded. Carotid femoral artery PWV and CIMT values were compared. RESULTS: PWV, and the maximum and average CIMT values of psoriasis patients were higher than those of the healthy group (PWV: 7.04+/-1.1 m/sn vs. 6.03+/-0.61 m/sn, p<0.001; maximum CIMT: 0.86+/-0.09 mm vs. 0.77+/-0.06 mm, p<0.001; mean CIMT: 0.73+/-0.09 mm vs. 0.66+/ 0.06 mm p<0.001, respectively). Although there was no difference in the lipid levels of the groups, total/HDL cholesterol (4.40+/-1.26 vs. 3.88+/-1.18, p=0.02, respectively), and LDL/HDL cholesterol ratios (2.78+/-0.98 vs. 2.32+/-0.92, p=0.01, respectively) of the psoriasis group were higher than those of the healthy group. A positive correlation was observed between PASI and the PWV (r=0.417, p=0.001). CONCLUSION: Despite the nonexistence of atherosclerotic risk factors, the risk of development of atherosclerosis is higher in psoriasis patients compared to healthy individuals. In addition to damage of the artery wall caused by systemic inflammation, lipid metabolism disorders may contribute to the development of atherosclerosis in these patients. PMID- 23363940 TI - Factors affecting left ventricular synchronicity in hypertensive patients: are arterial stiffness and central blood pressures influential? AB - OBJECTIVES: Left ventricular (LV) dyssynchrony is a common finding in patients with hypertension and is associated with LV hypertrophy. Arterial stiffness (AS) and central (aortic) blood pressures play a significant role in end-organ damage such as LV hypertrophy caused by hypertension. The objective of this study was to investigate the relationship between AS, central blood pressures (BP) and LV dyssynchrony. STUDY DESIGN: Thirty-five newly diagnosed hypertensive patients and 40 controls were enrolled in the study. The entire study population underwent a comprehensive echocardiographic study including tissue synchrony imaging. The 12 segmental model was used to measure the time to regional peak systolic tissue velocity (Ts) in the LV and two dyssynchrony indices were computed. Parameters of AS including pulse wave velocity (PWV), augmentation index (AIx@75), and central systolic and diastolic BP were evaluated by applanation tonometry. RESULTS: The baseline clinical and echocardiographic parameters of both groups were similar except for their BPs. Dyssynchrony indices were prolonged in patients with hypertension as compared to the controls. The standart deviation of Ts of 12 LV segments in patients with hypertension and the controls were 48.7+/-18.8 vs. 25.8+/-13.1, respectively (p<0.001), and the maximal difference in Ts between any 2 of 12 LV segments was 143.9+/-52.2 for hypertension patients vs. 83.8+/-39.4 for controls (p<0.001). PWV (11.9+/-2.5 vs. 9.5+/-1.4, p<0.001), AIx@75 (27.4+/ 8.3 vs. 18.3+/-9, p=0.009), and central systolic (147.6+/-20.8 vs. 105.4+/-11, p<0.001) and diastolic (99.8+/-14.4 vs. 72.8+/-9.5, p<0.001) pressures were higher in patients with hypertension than in the controls, respectively. In multivariable analysis, central systolic BP (beta=0.496, p=0.03), LV mass index (beta=0.232, p=0.027), and body mass index (beta=0.308, p=0.002) were found to be independently related to dyssynchrony. CONCLUSION: Central systolic BP is an independent predictor of LV dyssynchrony, but Aix@75 did not have an independent effect on LV synchronicity in patients with newly-diagnosed hypertension. PMID- 23363941 TI - [The relationship between serum parathormone levels and the severity of coronary artery disease]. AB - OBJECTIVES: It has been reported that increased parathormone (PTH) levels have unfavorable effects on the cardiovascular system. PTH produces unfavorable effects via either PTH receptors or the renin angiotensin aldosterone system. Data shows that there is a relationship between PTH and coronary artery disease (CAD), although this relationship is still being debated. In this study, we evaluate the relationship between serum PTH levels and CAD. STUDY DESIGN: The study included 260 patients (125 males, 135 females, mean age 56.01+/-11.9 years) who underwent coronary angiography with a prediagnosis of CAD. Venous blood samples were taken 6 hours before the coronary angiography for the measurement of serum PTH levels. The extent of CAD was evaluated by calculation of Gensini scores. RESULTS: The Gensini score was 0 in 99 of the patients. Mild atherosclerosis and severe atherosclerosis were determined in 67 and 94 patients, respectively. According to the Gensini score, serum PTH levels were 5.17+/-2.07 pmol/l, 4.88+/-2.40 pmol/l and 4.98+/-3.04 pmol/l, respectively. PTH levels were similar in patients with mild atherosclerosis and with normal coronary arteries (Gensini score 0) (p=0.55). There was no difference in PTH levels between patients with mild and severe atherosclerosis (p=0.77). In addition, no significant difference in PTH levels were detected between those with normal coronary arteries and those with severe atherosclerosis (p=0.78). CONCLUSION: Serum PTH level does not determine the extensity of CAD. PMID- 23363942 TI - [Is there any relationship between serum parathormone levels and severity of coronary artery disease in patients without renal failure?]. PMID- 23363943 TI - Assessment of left ventricular systolic and diastolic function with conventional and tissue Doppler echocardiography imaging techniques in patients administered tyrosine kinase inhibitor. AB - OBJECTIVES: The aim of this study was to use echocardiographic techniques to determine the possible cardiotoxic effects of low molecular weight tyrosine kinase inhibitors (TKI) in patients receiving the therapy for the first time. STUDY DESIGN: Thirty patients (17 females; 13 males; mean age 49+/-16; range 22 to 76 years) who met the exclusion criteria and were diagnosed as having malignancy were enrolled. All patients underwent conventional echocardiography and tissue Doppler imaging (TDI) prior to the treatment. The conventional echocardiogram was repeated 2 months later as the patients were concurrently receiving therapy. Myocardial Performance Index was obtained by conventional echocardiography and by TDI techniques to evaluate left ventricular systolic and diastolic function. RESULTS: Statistically significant increase occurred in mean left ventricle (LV) end-systolic volume. However, there was significant decrease in both mean LV ejection fraction and LV stroke volume values (64+/-3, 62+/-4, p=0.000 and 67+/-13, 61+/-13, p=0.000, respectively). Anterior wall Em/Am ratio measured by using the TDI technique was significantly decreased at the end of two months (0.99+/-0.49, 0.90+/-0.41, p=0.03). In addition, decreases were determined in Sm values obtained from all of four LV walls and also in mean Sm value, but this decrease was significant only for the lateral wall Sm measurement (12.8+/ 2.9, 11.6+/-2.3, p=0.004). CONCLUSION: Tyrosine-kinase inhibitors therapy can be administered safely to patients without predisposing factors for cardiotoxicity in short treatment intervals, and low molecular TKIs may cause subtle or clinically significant cardiotoxicity following the treatment period even in patients without predisposing factors for cardiotoxicity, so clinicians should consider this possibility. PMID- 23363944 TI - Aortic knob calcification and coronary artery lesion complexity in non-ST-segment elevation acute coronary syndrome patients. AB - OBJECTIVES: Coronary artery lesion complexity is important for risk stratification of acute coronary syndrome (ACS) patients undergoing cardiac catheterization. SYNTAX score is a pure angiographic measure of anatomic coronary complexity. Chest radiography is a routine examination for evaluating patients with chest pain. There have been no studies to date exploring the relation between aortic knob calcification (AKC) and coronary lesion complexity assessed by SYNTAX score. STUDY DESIGN: 135 consecutive patients with first time diagnosis of non-ST segment elevation ACS were enrolled. SYNTAX score was calculated by dedicated computer software. Aortic calcification was assessed visually. RESULTS: Patients with AKC had higher SYNTAX score compared to those without AKC (16+/-6 vs. 11+/-7, p=0.019). Also, patients with AKC had higher TIMI risk score and were more elderly. Linear regression analysis demonstrated AKC (95% confidence interval [CI] 1.7-6.9, p=0.002), diabetes (95% CI, 1.1-5.7, p=0.005), and smoking (95% CI, 1.2-13.5, p=0.004) as independent determinants of SYNTAX score. CONCLUSION: Aortic calcification detected on chest X-ray is an independent predictor of complex coronary artery lesions in patients with ACS. PMID- 23363945 TI - Shone's complex with dextrocardia and situs inversus totalis: a case report. AB - Parachute mitral valve complex is an unusual congenital anomaly that has been described by Shone et al. It is characterized by a parachute deformity of the mitral valve associated with additional forms of left heart anomalies, such as aortic valvular stenosis and coarctation of the aorta. A 21-year-old female who was referred to our department because of progressive dyspnea on effort and at rest and minimal cyanosis is presented in this case report. On cardiac auscultation, the patient had a grade III/VI pansystolic murmur best heard at the lower left sternal border. The chest X-ray demonstrated dextrocardia and mild cardiomegaly. Echocardiographic evaluation revealed Shone's complex, including parachute mitral valve anomaly. PMID- 23363946 TI - [A case of acute coronary syndrome following the use of parenteral penicillin: Kounis syndrome]. AB - Kounis syndrome refers to the concurrence of acute coronary events and allergic or hypersensitivity reactions. In this report, we describe the case of a male patient, in whom acute ST-segment elevation and myocardial infarction developed immediately after injection of depot penicillin, and we discuss the Kounis syndrome. A 52-year-old male patient had chest pain, hypotension and ST-elevation on leads DI and aVL of electrocardiography 30 minutes after intramuscular penicillin injection due to cryptic tonsillitis. Kounis syndrome was considered as a possible diagnosis according to the presentation. Histamine and tryptase levels were not studied due to the delay on arrival to the emergency department. The patient promptly underwent coronary angiography, which revealed only diffuse plaques in all main coronary arteries without any obstructive lesion. We found only increased immunoglobulin (Ig) E, which is associated with the syndrome. With this report, we remind clinicians to consider Kounis syndrome in patients who are subjected to allergenic substances and demonstrate acute chest pain. PMID- 23363947 TI - Late stent thrombosis after wasp sting. AB - Myocardial infarction (MI) following a bee sting is a highly unusual reaction. A 65-year-old man allergic to honeybee venom was admitted to the emergency department suffering from a wasp sting with urticaria. The patient had a history of bare metal stent (BMS) 9 months previously with regular drug use. He experienced chest pain after the sting and electrocardiography revealed ST segment elevation in the chest leads. Subsequently, the patient developed ventricular tachycardia disrupting hemodynamics. Sinus rhythm was obtained by cardioversion. Coronary angiogram revealed total stent thrombosis (ST) in the midportion of the left anterior descending coronary artery. Primary coronary intervention was successfully performed. Presence of shared pathways in allergic reaction and MI pathogenesis may be responsible for de novo or ST. To our knowledge, this is the first case of total occlusive late ST in BMS following a wasp sting. PMID- 23363948 TI - Successful transcatheter closure of a Fontan fenestration with a bioabsorbable Biostar occluder. AB - We report the successful closure of an extracardiac Fontan fenestration with a bio-absorbable device, which may be refenestrated by a transcatheter route when needed, in a 10-year-old boy. The patient presented with cyanosis two years after an extracardiac Fontan operation. Echocardiography revealed a moderate shunt from the Fontan circulation into the systemic circulation with a mean pressure gradient of 3-4 mmHg. Treadmill testing revealed a significant decrease in oxygen saturation (down to the low 50's from a baseline level of 80-85%). Cardiac catheterization revealed normal pressure in the Fontan circuit. A temporary balloon occlusion test showed that the defect was suitable for permanent occlusion. The fenestration was then occluded by a bio-absorbable Biostar (NMT medical, Boston, USA) atrial septal occluder device. The oxygen saturation on room air increased up to 95% after closure. PMID- 23363949 TI - Alternative method for accessing the target coronary artery in patients with difficult coronary anatomy: exchanging the diagnostic catheter with a guiding catheter. AB - We report a method of the placement of the guiding catheter in two cases in which the diagnostic catheter could be easily engaged to the target coronary arteries but not a guiding catheter, due to a distorted aortic sinus and an osteal subtotal occlusion, respectively. After engaging to the target coronary artery with a diagnostic catheter, a coronary guidewire was advanced through the diagnostic catheter, and exchanged with a guiding catheter over the guidewires. The procedures were completed with success. PMID- 23363950 TI - Percutaneous closure of paravalvular mitral regurgitation with Vascular Plug III under the guidance of real-time three-dimensional transesophageal echocardiography. AB - Transcatheter closure of mitral prosthetic paravalvular leak (PVL) has been hampered by technical challenges and the lack of closure devices specifically designed for this purpose. The oblong cross-sectional shape of the Amplatzer Vascular Plug III device (AVP) may be a more appropriate choice to be deployed for mitral PVL's. Real-time three-dimensional transesophageal echocardiography (RT-3D TEE) has emerged as an efficient tool that provides essential information concerning leakage size, location, and shape as well as navigation of catheters and wires. We assessed the feasibility and short, mid, and long-term efficacy of transcatheter mitral PVL closure using AVP-III under the guidance of RT-3D TEE. Three patients with severe symptomatic mitral PVL at high risk for repeat surgery underwent transcatheter leak closure with AVP III. Transfemoral approaches were used under RT-3D TEE guidance. Transcatheter closure of mitral PVLs was performed successfully in 3 patients using 5 devices. The first patient with 2 devices deployed had residual mitral regurgitation resulting in re-operation at the sixth month. The second patient had improved normally with a functioning prosthesis after the deployment of two devices, but had progressively worsening mitral regurgitation for which re-operation at the sixteenth month of follow-up was necessary. The third patient had no residual leak, with normal prosthetic function. At 24 months follow-up, all patients were in satisfactory clinical status. Although RT-3D TEE plays an essential role in guidance of transcatheter closure of mitral PVLs with AVP III, the absence of a specific closure device limits mid and long-term success rates. PMID- 23363951 TI - [Carotid endarterectomy versus stenting: where do we stand today?]. AB - Carotid artery stenosis is the major cause of the stroke associated with ischemic origin and carries increased mortality and morbidity. Since carotid artery endarterectomy (CEA) was first performed in 1950, in conjunction with the advanced technology and increased experience under the guidance of randomized controlled trials, balloon angioplasty and carotid artery stenting, which have similar mortality and morbidity, have become comparable with CEA. Determining the optimal treatment option for each patient is the most important issue in carotid artery stenosis. Today, there have been improvements in technology and recent advances in the cardiovascular sciences. Moreover, there is increased experience, increased attention to patient selection, and a team approach to find the most suitable treatment for the patient. In this review, we briefly discuss the current treatment approaches for carotid artery stenosis under the guidance of the modern studies. PMID- 23363952 TI - Case images: myocardial noncompaction accompanied by mitral valve prolapse. PMID- 23363953 TI - Case images: volume measurement of a cardiac myxomatous lesion with three dimensional echocardiography. PMID- 23363954 TI - Case images: the value of three dimensional echocardiography in the detection of prosthetic mitral valve dehiscence. PMID- 23363955 TI - Case images: real-time three dimensional versus two dimensional transesophageal echocardiography for visualization of thoracic aortic atheroma. PMID- 23363956 TI - Case images: squamous cell lung cancer metastasis in the left atrium: an interesting case with cardiac images. PMID- 23363957 TI - New insights into how HBV manipulates the innate immune response to establish acute and persistent infection. AB - The mechanisms by which HBV establishes and maintains chronic infection are poorly understood. Although adult acquired HBV is generally cleared by a robust immune response, most individuals infected at childbirth or in very early childhood develop lifelong chronic infection. In addition, acute infections are unresolved in approximately 5% of individuals infected in adulthood. The host cell mechanisms that ensure establishment and resolution of acute infection and persistent infection remain unclear. Currently, two schools of thought suggest that either HBV is a 'stealth' virus, which initially establishes infection by avoiding host innate immune responses, or that HBV facilitates initial infection and progression to persistence by actively manipulating the host innate immune response to its advantage. There is increasing evidence that activation of innate host cell signalling pathways plays a major role in limiting adult acquired HBV infection and that, in turn, HBV has evolved numerous strategies to counteract these defence mechanisms. In this review, we summarize current knowledge regarding innate immune responses to HBV infection and discuss how HBV regulates cell signalling pathways to its advantage, particularly in the setting of chronic HBV infection. In turn, we show how an intimate knowledge of innate immune responses is driving development of novel therapeutic agents to treat chronic HBV infection. PMID- 23363958 TI - [Report and response of cases infected with a novel coronavirus]. PMID- 23363959 TI - [Practice and prospect of translational toxicology]. PMID- 23363960 TI - [Trend of energy intake among Chinese children and adolescents in nine provinces from 1989 to 2009]. AB - OBJECTIVE: To examine the trends of energy intake among Chinese children and adolescents in nine provinces from 1989 to 2009. METHOD: Stratified multi-stage cluster sampling method was used to recruit 488, 2807, 2802, 2580, 2520, 1604, 1305 and 1159 children and adolescents aged 6 - 17 years in each year of 1989, 1991, 1993, 1997, 2000, 2004, 2006 and 2009 in 9 provinces. The descriptive analyses were carried out for three days 24-h dietary recall data to compare energy intake by year and demographic characteristics. RESULTS: The median of dietary energy intake among Chinese children and adolescents aged 6 - 17 years in 1989, 1991, 1993, 1997, 2000, 2004, 2006 and 2009 were 6645.7, 8314.8, 7849.3, 8115.0, 7970.5, 7598.0, 7345.0 and 7051.9 kJ/d (chi(2) = 239.75, P < 0.01), respectively. In 2009, children and adolescents from city (7820.4 kJ/d) and county (7356.0 kJ/d) consumed more energy than that from suburb (7168.2 kJ/d) and village (6863.5 kJ/d) (chi(2) = 8.00, P < 0.05). Cereal was the main food source of energy intake. In 2009, the percentage of energy intake from cereal was 44.0%, 45.6%, 52.9% and 61.0% (chi(2) = 36.75, P < 0.01)for city, suburb, county and village respectively. The percentage of population with > 30% of energy intake from dietary fat increased yearly and that with more than 60% of energy from carbohydrate decreased, from 25.4% (124/488) and 54.1% (264/488) in 1989 to 58.1% (637/1159) and 15.9% (184/1159) (chi(2) values were 811.24, 919.35 respectively;both P values < 0.05) in 2009. The percentage of children and adolescents whose energy intake was more than 80% recommended nutrient intake (RNI) declined from 60.2% (294/488) in 1989 to 47.8% (554/1159) in 2009(chi(2) = 227.66, P < 0.05). CONCLUSION: The current study demonstrated that energy intake of Chinese children and adolescents increased at early stage and then declined in the recent years. Average energy intake was higher in city and county than suburb and village. PMID- 23363961 TI - [Trend in dietary vitamin C intake among Chinese children and adolescents between 1991 and 2009]. AB - OBJECTIVE: To examine status and trend in dietary vitamin C intake between 1991 and 2009 in Chinese children and adolescents aged 6 to 17 years. METHODS: A stratified multistage, random cluster sampling process was used to investigate 2716, 2691, 2507, 2358, 1490, 1218 and 1073 children and adolescents aged 6 - 17 years in 1991, 1993, 1997, 2000, 2004, 2006 and 2009 respectively in 9 provinces. Their consecutive 3 d 24 h dietary recall data were analyzed to compare vitamin C intake in children and adolescents with different characteristics and different years. RESULTS: The median of dietary vitamin C intake in Chinese children and adolescents decreased from 69.7 mg/d in 1991 to 53.4 mg/d in 2009 (chi(2) = 188.1, P < 0.01). Vitamin C intake of rural children and adolescents decreased from 73.7 mg/d in 1991 to 52.5 mg/d in 2009 (chi(2) = 96.7, P < 0.01); vitamin C intake of children and adolescents in the low-income household decreased from 74.3 mg/d in 1991 to 47.5 mg/d in 2009 (chi(2) = 172.9, P < 0.01). The percentage of children and adolescents whose vitamin C intake equal or higher than recommended nutrient intake of vitamin C decreased from 35.9% (974/2716) in 1991 to 18.5% (198/1073) in 2009 (chi(2) = 284.7, P < 0.01). CONCLUSION: There was a decreased trend in dietary vitamin C in Chinese children and adolescents during the past two decades. The children and adolescents of low-income household in rural areas may pose a higher risk of inadequate vitamin C intake. PMID- 23363962 TI - [Effects of systolic blood pressure and low density lipoprotein on carotid plaques]. AB - OBJECTIVE: To explore the different effects of systolic blood pressure (SBP) and low density lipoprotein on carotid plaques (LDL-C). METHODS: A total of 101 510 serving and retired workers of a company who participated in the health examination in 2006-2009, 5852 participants were selected as study subjects by stratified random sampling according to the age and sex ratio. These subjects took their health examination in 2010-2011 including the carotid ultrasound. Finally, 5361 eligible participants with complete data were included in the analysis. The detection and weighted rates of carotid plaques were calculated for four groups: normal SBP and LDL-C group (3524 subjects), normal SBP and high LDL C group (356 subjects), elevated SBP and normal LDL-C group (1308 subjects) and elevated SBP and high LDL-C group (173 subjects). The effects of different baseline SBP and LDL-C on detection rates of the carotid artery plaques were analyzed by logistic regression. RESULTS: The detection rate of carotid plaques in normal SBP and LDL-C group, normal SBP and high LDL-C group, elevated SBP and normal LDL-C group, elevated SBP and high LDL-C group was 33.7% (1186/3524), 41.3% (147/356), 64.8% (847/1308), 68.8% (119/173) (chi(2) = 425.75, P < 0.05) and the weighted detection rate was 36.0%, 42.0%, 64.5% and 68.3% respectively. For men, the detection rate was 44.2% (877/1985), 51.1% (97/190), 70.6% (657/930), 71.3% (82/115) (chi(2) = 194.02, P < 0.05) and the weighted detection rate was 31.2%, 36.1%, 49.8% and 50.3% respectively. For women, the detection rate was 20.1% (309/1539), 30.1% (50/166), 50.3% (190/378), 63.8% (37/58) (chi(2) = 180.17, P < 0.05) and the weighted detection rate was 30.9%, 46.3%, 70.3%, and 88.1% respectively. After adjusted for other risk factors, the OR (95%CI) value was 1.37 (1.05 - 1.78), 2.05 (1.74 - 2.43) and 2.12 (1.45 - 3.12) for normal SBP and high LDL-C group, elevated SBP and normal LDL-C group and elevated SBP and high LDL-C group respectively compared with normal SBP and LDL-C group. CONCLUSION: Elevated SBP and high LDL-C were risk factors of the carotid artery plaques. Compared with high LDL-C, elevated SBP may add a higher risk for carotid plaques. PMID- 23363963 TI - [Investigation of subjective well-being and influence factors among residents living in old districts in Wuhan, China]. AB - OBJECTIVE: To investigate the subjective well-being and its influence factors among residents living in old districts in Wuhan. METHODS: In June, 2011, a total of 500 residents living in Shanghai Street in Wuhan were recruited as subjects for this study by two-stage stratified random sampling method. The information of demographic features, health status, spare time, family status, interpersonal relationship and social environment were collected by self-made questionnaires naming "survey of satisfaction of residents living in old districts". The results were analyzed by single-factor and multi-factors analysis method. RESULTS: In this study, 448 samples of questionnaire were answered qualified (89.6%, 448/500). The subjects aged (51.3 +/- 16.1) years old. The single-factor analysis showed that male and female influence the subjective happiness got 5.43 +/- 1.66, 5.77 +/- 1.65 (U = -2.32, P < 0.05);the age of 0 - 45, 46 - 59, 60 and above group got 5.12 +/- 1.68, 5.47 +/- 1.81, 6.29 +/- 1.23, respectively (H = 43.07, P < 0.01); the unmarried, married, divorced, loss of spouse and remarriage groups got 5.18 +/- 1.94, 5.74 +/- 1.54, 4.00 +/- 2.04, 5.68 +/- 1.91, 6.63 +/- 0.92, respectively (H = 17.41, P < 0.01); education background were primary school and blow, junior middle school, senior high school, bachelor degree, master degree and above got 6.30 +/- 1.42, 5.55 +/- 1.82, 5.90 +/- 1.46, 5.07 +/- 1.74, 4.75 +/ 2.22 (H = 26.99, P < 0.01); monthly household income was Y0 - 2000, Y2001 - 4000, Y4001 - 8000, Y8001 - 10 000, Y10 000 and above got 5.34 +/- 1.87, 5.68 +/- 1.53, 6.20 +/- 1.07, 7.33 +/- 0.58, 6.00 +/- 0.00, respectively (H = 13.85, P < 0.01). The subjective satisfaction of social environment ranked from high to low were: city public security (56.0%, 248/448), traffic environment (44.9%, 199/448), community environment (14.9%, 66/448), housing conditions (13.8%, 61/448) and medical environment (8.2%, 36/448). Multiple regression model suggested that the determinant coefficient was 0.53(P < 0.01), with a good degree of fitting. The model showed that the factors influencing the residents' happiness were ranked: social environment (beta' = 0.34), family status (beta' = 0.32), health status (beta' = 0.21), education background (beta'(0-6) school year = 0.00, beta'(7-9) school year = -0.12, beta'(9-12) school year = 0.04, beta'(>12) school year = -0.14), monthly household income (beta' = 0.07) and marital status (beta'(unmarried) = 0.00, beta'(married) = 0.03, beta'(divorced) = -0.03, beta'(widowed) = 0.01, beta'(remarried) = 0.02). CONCLUSION: The factors that social environment, family status, health status, education background, monthly household income and marital status could influence the subjective happiness of residents living in old districts in Wuhan. A perfect social security system could improve the subjective happiness of residents in old districts in Wuhan. PMID- 23363964 TI - [Economic burden of disease studies in patients with epilepsy]. AB - OBJECTIVE: To analyze the various factors affecting the economic burden of disease in patients with epilepsy. METHODS: This research used a multi-stage random sampling method, comprehensive intervention and without intervention of the epilepsy project group conducted a field survey of health examination among patients with epilepsy of 874 (422 cases in intervention group and 452 cases in control group) in Mengzhou, Xiuwu, Yancheng, Yuanhui, Wuyang, Linying, Shaoling, Xinye and Fangcheng. DALY indicators combined with human capital approach was used to measure the economic burden of disease in patients from two aspects of the direct economic burden and indirect economic burden. RESULTS: The age of comprehensive intervention group was (43.7 +/- 8.5) years old, and it was (44.4 +/- 7.2) years old in no intervention control group. The age difference was not statistically significant (P = 0.365). The direct economic burden per capita of the survey was 1019.6 yuan per year, while epilepsy drugs 434.2 yuan per year, 485.2 and 66.4 yuan per year in the intervention group, while 1518.5 and 777.5 yuan per year in the control group. Each object in this study lost (16.67 +/- 10.01) DALY, with 8.58 DALY in intervention group and 24.23 DALY in no intervention control group. The per capita indirect economic burden of the intervention and control groups were 68 115.2, 401 036.5 yuan, the per capita total economic burden of disease were 68 600.5, 408 755.0 yuan. Multivariate logistic regression analysis showed that disease duration year of >= 37, 30 - 36, 20 - 29, 10 - 19, OR (95%CI) were 4.44 (2.37 - 8.33), 3.32 (1.85 - 5.94), 3.25 (1.90 - 5.56), 2.53 (1.46 - 4.41). If patients with longer duration, the more serious the patient's disease burden. Medication compliance (in order to comply with a good group control) OR (95%CI) was 3.37 (2.34 - 4.83), medication in the single form (serving multi-drug groups for control) OR (95%CI) 0.41 (0.29 - 0.59). Serving a single agent and good compliance of economic burden of disease were lighter. CONCLUSION: Epilepsy caused serious economic damage. Longer duration, medication adherence poor and serving more than medicine by heavier economic burden of disease; comprehensive intervention could reduce the economic burden of disease of patients with epilepsy. PMID- 23363965 TI - [Interaction of folate deficiency and aberrant profile of DNA methyltransferase 1 in the progression of cervix carcinogenesis]. AB - OBJECTIVE: To explore the interaction of folate deficiency and aberration of DNA methyltransferase 1 (DNMT1) in the progression of cervix carcinogenesis. METHODS: All clinical samples were collected from 80 patients with cervix squamous cell carcinoma (SCC), 105 patients with cervical intraepithelial neoplasm (CINI, n = 52; CINII/III, n = 53) and 53 patients with cervix inflammation (CI). The participants were diagnosed by histology at Shanxi Province Tumor Hospital and Second Hospital of Shanxi Medical University during the period of September 2009 to May 2010. Meanwhile, cervical cancer cell lines Caski and C33A were treated with different concentration of folate. Radioimmunoassay (RIA), Western blotting and real-time PCR were used to detect the levels of serum folate, the expression of DNMT1 protein and mRNA, respectively. The data were analyzed by Student t test, ANOVA, chi-square test and Spearman correlation using SPSS statistical package. The correlation strength between factors and cervical canceration was calculated by OR and 95%CI value. Interaction effect was evaluated by the application of additive effect model. RESULTS: The levels of serum folate (median inter-quartile range) were (2.66 +/- 1.82), (2.83 +/- 2.23), (3.17 +/- 1.91) and (3.21 +/- 1.74) ng/ml, the levels of DNMT1 protein (x(-) +/- s) were 2.28 +/- 0.55, 1.84 +/- 0.37, 1.33 +/- 0.38 and 0.92 +/- 0.29, the Ct-ratio (Ct value of DNMT1/Ct value of beta-actin) of DNMT1 mRNA (x(-) +/- s) were 1.26 +/- 0.13, 1.27 +/- 0.12, 1.27 +/- 0.12 and 1.33 +/- 0.11 in the group of SCC, CINII/III, CINIand CI, respectively. The results showed that the serum folate levels were descended, and the expression levels of DNMT1 protein (chi(2)(tend) = 50.80, P < 0.05) and mRNA (chi(2)(tend) = 17.63, P < 0.05) were increased steadily with the severity of the cervix lesions. Moreover, our results revealed that there was an additive interaction between folate deficiency and high-expression of DNMT1 protein related to the risk of CIN and SCC. And it showed that the relative excess risk of interaction (RERI), attributable proportion of interaction (API) and synergy index(S) was 0.27, 0.14 and 1.40 in CINI group, 0.47, 0.19, 1.46 in CINII/III group, 1.60, 0.31, 1.61 in SCC group, respectively. It was found that folate was able to reduce the proliferation of Caski and C33A cells (r values were 0.954 and 0.969, all P values < 0.05), with 11.4% and 13.6% of growth inhibition at the concentration of 10 ug/ml, 64.8% and 49.4% at 1000 ug/ml in Caski and C33A cells, respectively. The result showed there was an inverse correlation between the levels of folate and DNMT1 protein (r values were -0.859 and -0.914, all P values < 0.05), with 1.96 and 1.92 of expression levels at the concentration of 10 ug/ml, and 1.60 and 1.38 at 1000 ug/ml in Caski and C33A cells, respectively. At folate concentration of 1000 ug/ml, the expression of DNMT1 protein or mRNA was higher in Caski cell than in C33A cell (t values were -4.22 and 3.50, all P values < 0.05). CONCLUSION: Our finding indicated that the low levels of serum folate and high-expression of DNMT1 protein or mRNA seemed to be associated with high risk of cervical cancer and cervix precancerous lesion. Sufficient folate is able to effectively inhibit the growth of cervical cancer cells in vitro, and would counteract transcriptional and posttranscriptional aberration of DNMT1. It suggested that there might be a synergistic action between folate deficiency and aberration of DNMT1 in the progression of cervix carcinogenesis. PMID- 23363966 TI - [Key quality indicators of the China Comprehensive AIDS Response 2008 - 2011 Program]. AB - OBJECTIVE: To analyze the key indicators of China Comprehensive AIDS Response Program (China CARES) and the effects of this program during 2008 and 2011. METHODS: Data were obtained from National AIDS Comprehensive Prevention and Control Information System. The general population HIV test rate and spouse of people living with HIV or AIDS (PLWHA) HIV test rate were chosen as the indicators for HIV testing expansion; anti-retroviral therapy (ART) coverage and PLWHA CD4 test rate during the past 6 months as the indicators for treatment expansion; femal sex worker (FSW) intervention coverage and injection drug users (IDU) intervention coverage as the Indicators for behavior intervention expansion. The Key working quality indicators of 309 program sites were calculated and the results were compared. RESULTS: During 2008 and 2011, for China CARES, the Median of general population HIV test rate were 1.8%, 2.5%, 3.2% and 5.5%, the Median of spouse of PLWHA HIV test rate were 80.9%, 85.7%, 91.8% and 100.0%, the Median of ART coverage were 60.0%, 66.7%, 76.1% and 92.0%, the Median of PLWHA CD4 test rate during the past 6 months were 27.7%, 45.4%, 58.6% and 75.3%, the Median of FSW intervention coverage were 43.8%, 67.8%, 73.3% and 90.9%, the Median of IDU intervention coverage were 18.2%, 24.0%, 34.0% and 72.4%. The indicators of China CARES increased steadily from 2008 to 2011 in HIV testing expansion, treatment expansion and behavior intervention expansion; Compared to 2008, the percentage of the China CARES which had great progress of the 6 indicators were 98.4% (304/309), 98.3% (286/291), 94.0% (281/299), 93.5% (288/308), 91.8% (279/304) and 90.0% (223/247). in 2008, 3 indicators which were ART coverage, PLWHA CD4 test rate during the past 6 months and FSW intervention coverage were lower than national average (6.9%, 17.9% and 30.9%), the general population HIV test rate, spouse of PLWHA HIV test rate and IDU intervention coverage were higher than national average (3.4%, 64.3% and 22.8%), with the China CARES project going on, in 2011, key indicators which were general population HIV test rate, spouse of PLWHA HIV test rate, ART coverage, PLWHA CD4 test rate during the past 6 months, FSW intervention coverage and IDU intervention coverage were all higher than national average (6.5%, 80.6%, 81.9% and 55.9%).the proportions of China CARES sites whose 6 indicators were higher than national average in 2008 were 32.7% (101/309), 60.6% (149/246), 37.4% (99/265), 61.1% (181/296), 64.0% (174/270) and 45.3% (73/161), and the proportions increase annually to 2011 were 44.0% (136/309), 89.3% (260/291), 76.6% (229/299), 77.9% (240/308), 91.4% (278/304) and 64.8% (160/247). CONCLUSION: An obvious achievements have been made in the areas of HIV/AIDS prevention and control among China CARES sites during 2008 and 2011 than the national average. PMID- 23363967 TI - [Analysis on epidemiology and the main clinical symptoms of viral encephalitis in Gansu, 2009-2011]. AB - OBJECTIVE: To understand the epidemiological characteristics and the main clinical symptoms of viral encephalitis in Gansu. METHODS: A total of 322 viral encephalitis patients were recruited from province sentinel hospitals in Gansu province from 2009 to 2011, and their basic information were collected as well as their serum samples and cerebrospinal fluid samples. 296 out of the 322 cases were qualified for our study. Based on the patients' epidemiological characteristics and clinical features, we determined the detection of the virus types (at least one kind of virus detection was carried out for each case). ELISA was applied to test the IgM antibody of Japanese encephalitis (JE) virus (JEV), enterovirus (EV: including Coxsackie virus, echovirus, enterovirus 71), mumps virus and herpes simplex virus (HSV) in cerebrospinal fluid and serum specimen. The difference of positive detected rate between types of virus, among patients from different regions, time, or at different ages, as well as the different clinical symptoms between JE patients and other viral encephalitis patients, were analyzed and compared. RESULTS: The positive detected rate of virus in the 296 patients was 27.03% (80/296); the positive rate of JEV, EV, mumps virus, HSV detected was separately 7.53% (22/292), 8.75% (23/263), 13.84% (22/159) and 15.09% (40/265), and the difference was statistically significant (chi(2) = 10.849, P < 0.05). 90.91% (20/22) of the JEV positive cases were distributed in Tianshui, Longnan and Pingliang, and 95.45% (21/22) patients were infected from July to September. All the 23 EV detected positive patients were infected from April to December, while the ages of patients ranged from 1 to 44 years old. Mumps virus, HSV testing positive cases had onset every month. Logistic regression analysis showed that the patients who had the symptoms as disturbance of consciousness (OR = 15.487, 95%CI: 2.266 - 105.852), somnolence (OR = 11.659, 95%CI: 1.783 - 76.242), convulsions (OR = 11.062, 95%CI: 1.687 - 72.530) were more likely to infect JEV. CONCLUSION: HSV was the principal pathogen of viral encephalitis in Gansu. An obvious central tendency in the regional and time distribution was found in JEV infection; and the clinical symptoms of JE patients were more severe. PMID- 23363968 TI - [Study of molecular subtypes of biotype 1A Yersinia enterocolitica in Shandong province from 2008 to 2009]. AB - OBJECTIVE: To investigate the molecular subtypes of 73 strains of Yersinia enterocolitica biotype 1A isolated in Shandong province by PFGE, and thereby to analyze the relationship between PFGE typing and biological characteristics. METHODS: Seventy-three strains of Yersinia enterocolitica biotype 1A were isolated from animal feces and meat products in Gaomi city and Wulian county in Shandong province from 2008 to 2009. Motility test, serum agglutination and virulent genes detection by PCR were used to learn the biological characteristics of the isolated strains. The molecular subtypes were determined by PFGE, whose relationships with motility, serotypes and virulent genotypes were also analyzed. RESULTS: Out of the 73 strains of Yersinia enterocolitica, 5 showed medium-active motility while the other 68 showed well-active motility. The dominated serotypes were O:5(17/73) and O:8(14/73), followed by O:9(5/73) and O:7, 8(1/73), and there was no O:3 serotype found. Meanwhile, 36 strains couldn't be serotyped. All the strains were negative with the gene ail, ystA, yadA and virF, yet the positive rate of ystB gene was 72.6% (53/73). The 73 strains of Yersinia enterocolitica isolated could be subtyped into 54 PFGE patterns (K6GN11SD0001-K6GN11SD0054), most of which only had 1 or 2 isolated strains, and no pattern was dominant. The strains in the same or similar cluster were from different hosts; each serotype and toxic genotype scattered in the clustering trees, without specific correlation with PFGE subtypes. 4 out of 5 strains, which showed medium-active motility, belonged to one branch, with the similarity coefficient at 80.9% - 100.0%; while all the toxic genotype belonged to type B. CONCLUSION: Biotype 1A Yersinia enterocolitica has many clones, whose PFGE types had relations with motility, but no relations with virulent genotype and host. PMID- 23363969 TI - [Study on types of M protein gene in group A streptococcus isolated from children in Beijing, 2011]. AB - OBJECTIVE: To explore the distribution characteristics of the types of M protein gene (emm) in group A streptococcus (GAS) isolated from children in Beijing in the year 2011. METHODS: During May to July in 2011, a total of 3315 patients who were diagnosed scarlet fever or pharyngeal infection by doctors in pediatric outpatient and emergency units of 36 hospitals, were selected as subjects. Their throat swab samples were collected and isolated the strains of GAS. Gene emm was then amplified and sequenced by PCR method, and the differences in types of gene emm between different populations and diseases were compared. RESULTS: A total of 633 strains of GAS were isolated from the 3315 throat swab samples, 610 strains out of which were gene emm positive and were recruited in the study. Out of the 610 recruited strains, 448 (73.4%) were isolated from scarlet fever patients, the other 162 (26.6%) were isolated from pharyngeal infection patients; 397 (65.1%) were from urban, the other 213 (34.9%) were from suburb; 240 (39.4%) were from patients aging between 1 - 5 years old, the other 369(60.6%) were from patients aging 6 - 18 years old. A total of 8 types of gene emm (scarlet fever: 6 types, pharyngeal infection: 4 types) and 21 subtypes of gene emn (scarlet fever: 16 subtypes, pharyngeal infection: 10 subtypes) were identified. Three new subtypes were found in the study, naming emm1.63, emm12.62 and st5144.20. Among them, emm1.63 was found both in scarlet fever and pharyngeal infection patients, while emm12.62 and st5144. 20 were only found in pharyngeal infection patients. Among all the types of gene-emm, emm12 accounted for the highest percentage as 80.5% (491/610) and then followed by emm1 (18.0% (110/610)). Among all the subtypes, the dominant subtype was emm12.00, accounting for 69.0% (421/610), following by emm1.00 (16.9% (103/610)) and emm12.19 (6.1% (37/610)). All the above types and subtypes of gene emm were the most prevalent strains in scarlet fever patients and pharyngeal infection patients. Significant differences in the distribution of prevalent strains were observed among various aging patients and regions. The constituent ratios of emm1, emm1.00 and emm12.19 were higher in patients from suburb (emm1: 22.1% (47/213), emm1.00: 19.2% (40/213), emm12.19: 8.0% (17/213)) than those in urban areas (emm1: 15.9% (63/397), emm1.00: 15.6% (62/397), emm12.19: 5.0% (20/397)). The difference showed statistical significance (P < 0.05). The constituent ratio of emm1.00 was higher among patients aging 6-18 years old (19.2% (71/369)) than those aging 1 - 5 years old (13.3% (32/240)). The difference also showed statistical significance (chi(2) = 8.45, P < 0.05). CONCLUSION: Among the types of gene emm in GAS isolated from children in Beijing in year 2011, the most prevalent two were emm12 and emm1, and the most prevalent emm subtypes were emm12.00, emm1.00 and emm12.19. A significant difference in their distribution between various aging patients and isolated places can be obviously found. PMID- 23363970 TI - [Meta-analysis of effect of n-3 long-chain polyunsaturated fatty acid supplementation of pregnant women on head circumference of newborn infants]. AB - OBJECTIVE: To evaluate systematically the effect of n-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA) supplementation of pregnant women on head circumference of newborn infants. METHODS: A thorough literature search was done for full texts which studied the effect of n-3 LC-PUFA supplementation of pregnant women on head circumference of newborn infants among PubMed, Cochrane Library, Chinese periodical full text database and Wanfang database using the mesh terms as n-3, long chain polyunsaturated fatty acids, DHA, EPA, docosahexaenoic acid, eicosapentaenoic acid, fish oil, pregnancy, infant. Only randomized controlled trials were chosen for analysis. A total of 74 relevant articles were selected. RevMan 5.0 software was used to perform the Meta analysis on those valid studies. Weighted mean difference was calculated with inverse variance method. The sensitivity analysis was also performed. RESULTS: Eight articles met the inclusion criteria, among which 6 literatures were from developing countries and the other 2 from developed countries. All of them were written in English. These studies were reported from 2001 to 2011. Intervention group included 871 objects with n-3 LC-PUFA supplementation, whereas control group included 894 objects with placebo or no supplementation. Supplementation was associated with significantly greater head circumference of the infants in the intervention group than that of the control group (weighted mean difference was 0.17 cm, 95%confidence interval (CI) was 0.01 - 0.32 cm, P < 0.05). But the difference was no long significant according to the sensitivity analysis (weighted mean difference was 0.16 cm, 95%CI was -0.01 - 0.34 cm, P = 0.07). The funnel plot was symmetrical, indicating there was no publication bias between the eight studies. CONCLUSION: It can't be confirmed whether supplementation with n-3 LC-PUFA of pregnant women can increase the infants' head circumference at birth from present data acquired. PMID- 23363971 TI - [Detection of monoamine neurotransmitters and its metabolites by high performance liquid chromatograph after pre-column derivatization of dansyl chloride column]. AB - OBJECTIVE: To develop a high performance liquid chromatography (HPLC) for detection of monoamine neurotransmitters and its metabolites after pre-column derivatization with dansyl chloride. METHODS: The C(18) chromatograph column (150 mm*4.6 mm*5 um) was selected for detection, and derived by dansyl chloride (10 mg/ml) under the condition of 50 degrees C water bath by pH11 buffer solution. 20 ul acetic acid acetone solution (1.0 mol/L) was then mixed in for termination of the reaction. Then the solution was cooling to room temperature, 0.1 mol/L acetic acid zinc-acetonitrile-tetrahydrofuran solution was adopted for mobile phrase, with the volume ratio at 62:35:3. The flow rate was 1.0 ml/min between 0-10 min, 2.0 ml/min between 10-35 min. The ultraviolet detection wavelength was 286 nm. The above method separately detected monoamine neurotransmitters and its metabolites and evaluated the limit of detection, accurate degree and accuracy degree. RESULTS: The linear relations between each component was good in the range of 1 - 20 ug/ml (r = 0.999). The lowest detection limit of norepinephrine, dopamine, 5-hydroxytryptamine and the metabolites 3-methoxy-4-benzoglycols, homovanillic acid and 5-heteroauxin were separately 0.60, 0.80, 0.41, 0.21, 0.19 and 0.1 ug/ml; while the average recovery rates were between 78.5% - 95.9%, and the relative standard deviation (RSD) was 6.62%, 7.64%, 2.98%, 3.60%, 5.09% and 3.09%, respectively. In the process of selection and optimization of the chromatographic conditions, we observed the importance of metal ions to discretion, and discussed the temperature, pH of the buffer solution and dosage of dansyl chloride in derivation. Under the above conditions, the reaction was perfect, and the baseline of the detected materials thoroughly separated. CONCLUSION: The method to detect monoamine neurotransmitters and its metabolites by HPLC and pre-column derivatization with dansyl chloride was established; and this method could provide reference for the detection of polyamine by HPLC. PMID- 23363972 TI - The psychometric properties of the Vanderbilt attention-deficit hyperactivity disorder diagnostic parent rating scale in a community population. AB - OBJECTIVE: To examine the psychometric properties of the Vanderbilt ADHD Diagnostic Parent Rating Scale (VADPRS) using a community-based sample of primarily elementary and middle school-aged children. METHOD: Participants were initially recruited from 41 elementary schools in 5 Oklahoma school districts including urban, suburban, and rural students. Vanderbilt rating scales were obtained from all teachers (n = 601) and sampled parents (n = 587) of the participating children. Construct validity was assessed by confirmatory factor analysis of the 45 items that made up the 4 scales of inattention, hyperactivity, conduct/oppositional problems, and anxiety/depression problems. Reliability was evaluated from internal consistency, test-retest, and interrater agreement perspectives. Criterion validity was evaluated via comparisons to a structured psychiatric interview with the parents using the Diagnostic Interview Schedule for Children-IV. RESULTS: A 4-factor model (inattention, hyperactivity, conduct/oppositional problems, and anxiety/depression problems) fit the data well once discarding conduct items that were infrequently endorsed. The estimates of coefficient alpha ranged from .91 to .94 and the analogous KR20 coefficient for a binary item version of the scale ranged from .88 to .91. Test-retest reliability exceeded .80 for all summed scale scores. The VADPRS produced a sensitivity of .80, specificity of .75, positive predictive value of .19, and negative predictive value of .98 when predicting an attention-deficit hyperactivity disorder (ADHD) case definition that combined teacher's Vanderbilt ADHD Diagnostic Teacher Rating Scale and parent diagnostic interview responses. CONCLUSION: The confirmation of the construct and concurrent criterion validities found in this study further support the utility of the VADPRS as a diagnostic rating scale for ADHD. PMID- 23363973 TI - The psychometric properties of the Vanderbilt attention-deficit hyperactivity disorder diagnostic teacher rating scale in a community population. AB - OBJECTIVE: This study examined the psychometric properties of the Vanderbilt AD/HD Diagnostic Teacher Rating Scale (VADTRS). METHODS: Information was collected from teachers and parents in 5 school districts (urban, suburban, and rural). All teachers in participating schools were asked to complete the VADTRS on all their students. Construct validity was evaluated through an exploratory factor analysis investigation of the 35 items that made up the 4 scales of inattention, hyperactivity, conduct/oppositional problems, and anxiety/depression problems. Convergent validity was assessed among a subsample of participants whose teachers completed the Strengths and Difficulties Questionnaire (SDQ). Finally, predictive validity was examined for another subsample of high- and low risk children whose parents completed a structured psychiatric interview, the Diagnostic Interview Schedule for Children-IV. RESULTS: For construct validity, a 4-factor model (inattention, hyperactivity, conduct/oppositional, and anxiety/depression problems) fits the data well. The estimates of the KR20 coefficient for a binary item version of the scale ranged from .85 to .94. Convergent validity with the SDQ was high (Pearson's correlations > .72) for these 4 factors. For predictive validity, the VADTRS produced a sensitivity of .69, specificity of .84, positive predictive value of .32, and negative predictive value of .96 when predicting future case definitions among children whose parents completed a diagnostic interview. CONCLUSION: The confirmation of the construct and convergent validity and acceptable scale reliabilities found in this study further supports the utility of the VADTRS as a diagnostic rating scale for attention-deficit hyperactivity disorder. The low predictive validity further demonstrates the need for multiple observers in establishing the diagnosis. PMID- 23363974 TI - Special education and later academic achievement. AB - OBJECTIVES: To determine whether grade at entry to special education is associated with improved reading achievement in children with reading disorders (RD) and whether the effect of grade at entry to special education differs by socioeconomic status (SES). METHODS: The authors conducted a secondary data analysis using data from the Early Childhood Longitudinal Study-Kindergarten Cohort (ECLS-K), a nationally representative cohort of children followed longitudinally from kindergarten through eighth grade (1998-2007). Using data from the fifth grade wave of ECLS-K, the authors identified children with RD (n = 290). The outcome of interest was change in score on the reading achievement test, which was developed by ECLS-K staff, between first and fifth grade. Using multiple linear regression, the authors modeled outcome as a function of a child's grade at entry to special education, controlling for several covariates. RESULTS: Early entry to special education (by first grade vs second or third grade) was associated with larger gains in reading achievement between first and fifth grade (p < .0001). Children who entered special education by first grade versus second grade gained 4.5 more points on the reading achievement test (p < .0001). Children who entered special education by first grade versus third grade gained 1.7 more points on the reading achievement test (p < .0001). There was no difference in the magnitude of gains associated with early entry to special education between children from families of low and higher SES. CONCLUSION: For children with RD, early entry to special education is associated with improved reading achievement during elementary school. PMID- 23363976 TI - Insulin resistance from binge drinking: it's all in your head. AB - Binge alcohol exposure impairs hepatic insulin action by blunting insulin receptor signaling in the brain and enables the identification of a therapeutic target that may help treat alcohol-induced insulin resistance (Lindtner et al., this issue). PMID- 23363975 TI - Self-triggered assistive stimulus training improves step initiation in persons with Parkinson's disease. AB - BACKGROUND: Prior studies demonstrated that hesitation-prone persons with Parkinson's disease (PDs) acutely improve step initiation using a novel self triggered stimulus that enhances lateral weight shift prior to step onset. PDs showed reduced anticipatory postural adjustment (APA) durations, earlier step onsets, and faster 1st step speed immediately following stimulus exposure. OBJECTIVE: This study investigated the effects of long-term stimulus exposure. METHODS: Two groups of hesitation-prone subjects with Parkinson's disease (PD) participated in a 6-week step-initiation training program involving one of two stimulus conditions: 1) Drop. The stance-side support surface was lowered quickly (1.5 cm); 2) Vibration. A short vibration (100 ms) was applied beneath the stance side support surface. Stimuli were self-triggered by a 5% reduction in vertical force under the stance foot during the APA. Testing was at baseline, immediately post-training, and 6 weeks post-training. Measurements included timing and magnitude of ground reaction forces, and step speed and length. RESULTS: Both groups improved their APA force modulation after training. Contrary to previous results, neither group showed reduced APA durations or earlier step onset times. The vibration group showed 55% increase in step speed and a 39% increase in step length which were retained 6 weeks post-training. The drop group showed no stepping-performance improvements. CONCLUSIONS: The acute sensitivity to the quickness-enhancing effects of stimulus exposure demonstrated in previous studies was supplanted by improved force modulation following prolonged stimulus exposure. The results suggest a potential approach to reduce the severity of start hesitation in PDs, but further study is needed to understand the relationship between short- and long-term effects of stimulus exposure. PMID- 23363977 TI - CD271(+) bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) can persist in hostile intracellular microenvironments evading immune cells and drug treatment. However, the protective cellular niches where Mtb persists remain unclear. We report that Mtb may maintain long-term intracellular viability in a human bone marrow (BM) derived CD271(+)/CD45(-) mesenchymal stem cell (BM-MSC) population in vitro. We also report that Mtb resides in an equivalent population of BM-MSCs in a mouse model of dormant tuberculosis infection. Viable Mtb was detected in CD271(+)/CD45(-) BM-MSCs isolated from individuals who had successfully completed months of anti-Mtb drug treatment. These results suggest that CD271(+) BM-MSCs may provide a long-term protective intracellular niche in the host in which dormant Mtb can reside. PMID- 23363978 TI - Binge drinking induces whole-body insulin resistance by impairing hypothalamic insulin action. AB - Individuals with a history of binge drinking have an increased risk of developing the metabolic syndrome and type 2 diabetes. Whether binge drinking impairs glucose homeostasis and insulin action is unknown. To test this, we treated Sprague-Dawley rats daily with alcohol (3 g/kg) for three consecutive days to simulate human binge drinking and found that these rats developed and exhibited insulin resistance even after blood alcohol concentrations had become undetectable. The animals were resistant to insulin for up to 54 hours after the last dose of ethanol, chiefly a result of impaired hepatic and adipose tissue insulin action. Because insulin regulates hepatic glucose production and white adipose tissue lipolysis, in part through signaling in the central nervous system, we tested whether binge drinking impaired brain control of nutrient partitioning. Rats that had consumed alcohol exhibited impaired hypothalamic insulin action, defined as the ability of insulin infused into the mediobasal hypothalamus to suppress hepatic glucose production and white adipose tissue lipolysis. Insulin signaling in the hypothalamus, as assessed by insulin receptor and AKT phosphorylation, decreased after binge drinking. Quantitative polymerase chain reaction showed increased hypothalamic inflammation and expression of protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signaling. Intracerebroventricular infusion of CPT-157633, a small-molecule inhibitor of PTP1B, prevented binge drinking-induced glucose intolerance. These results show that, in rats, binge drinking induces systemic insulin resistance by impairing hypothalamic insulin action and that this effect can be prevented by inhibition of brain PTP1B. PMID- 23363979 TI - In active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive T(regs) involves IL-6-mediated signaling. AB - Patients with multiple sclerosis (MS) manifest demyelination and neurodegeneration mediated in part by CD4(+) T cells that have escaped regulation. Resistance of pathogenic effector T cells (T(effs)) to suppression by regulatory T cells (T(regs)) has been demonstrated in several autoimmune diseases. Although impairment in T(reg) number and function has been observed in relapsing-remitting MS (RRMS), T(eff) resistance has not been well studied in this disease. To determine whether T(eff) resistance contributes to failed tolerance in RRMS, we performed T(reg) suppression assays with T(effs) from either RRMS patients not on immunomodulatory therapy or healthy individuals. T(eff) resistance was present in the T(effs) of RRMS patients with active disease but not from patients with inactive disease. Interleukin-6 (IL-6) and phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) promote T(eff) resistance to T(regs), and we found an increase in IL-6 receptor alpha (IL-6Ralpha) expression and elevated IL-6 signaling as measured by pSTAT3 in our RRMS subjects. Further, the impaired suppression in RRMS subjects correlated with an increase in IL-6Ralpha surface expression on CD4(+) T cells and an increase in pSTAT3 in response to IL-6. To address whether the enhanced pSTAT3 contributed to T(eff) resistance in active RRMS patients, we blocked STAT3 phosphorylation and found that impaired suppression was reversed. Therefore, enhanced IL-6R signaling through pSTAT3, in some cases through increased IL 6Ralpha expression, contributed to T(eff) resistance in active RRMS. These markers may aid in determining disease activity and responsiveness to immunomodulatory therapies in RRMS. PMID- 23363981 TI - Probucol suppresses initiation of chronic hemodialysis therapy and renal dysfunction-related death in diabetic nephropathy patients: Sakura study. AB - AIM: Probucol has antioxidant as well as cholesterol-lowering effects. We examined the effect of probucol on the progression of diabetic nephropathy. We named this study 'Sakura Study' after our hospital and city. METHODS: We performed a randomized, open trial on 162 type 2 diabetic patients with clinical albuminuria (urinary albumin excretion >300 mg/g creatinine). Eighty patients were assigned to probucol treatment (500 mg/day) and 82 patients to no probucol treatment. All patients were followed for five years. The primary outcome was the time to renal dysfunction events, defined as the initiation of chronic hemodialysis therapy and renal dysfunction-related death. RESULTS: Probucol decreased total cholesterol, HDL-cholesterol, and LDL-cholesterol compared to the control group. The serum creatinine increase rate was significantly lower (p= 0.015) in the probucol group (0.066 mg/dL/month) than in the non-probucol group (0.116 mg/dL/month). Renal dysfunction events occurred in 72 patients during this study. The 69 patients who were initiated on chronic hemodialysis comprised 42 in the non-probucol group and 27 in the probucol group. Three patients in the non probucol group, but no patients in the probucol group died of renal dysfunction. The renal dysfunction event-free survival rate was significantly higher (log rank: p= 0.02) in the probucol group than in the non-probucol group. CONCLUSION: Probucol suppressed the progression of diabetic nephropathy and renal dysfunction events. PMID- 23363982 TI - Carotid artery plaque and LDL-to-HDL cholesterol ratio predict atherosclerotic status in coronary arteries in asymptomatic patients with type 2 diabetes mellitus. AB - AIMS: To investigate the clinical predictors of coronary atherosclerosis and to assess the utility of maximum-IMT for predicting coronary atherosclerosis in asymptomatic type 2 diabetic patients. METHODS: One hundred one Japanese patients with type 2 diabetes underwent computed tomography coronary angiography. Definitions of coronary artery stenosis and vulnerable coronary plaque were luminal narrowing of >=50% and any coronary plaque with positive vessel remodeling and low attenuation, respectively. Carotid intima-media thickness (IMT) was assessed using B-mode ultrasound. RESULTS: Of the 101 patients, 40 had coronary artery stenosis without vulnerable coronary plaque, 7 had vulnerable coronary plaque without coronary artery stenosis, and 23 had coronary artery stenosis with vulnerable coronary plaque. Male sex (p=0.031), duration of diabetes (p=0.024), systolic blood pressure (SBP) (p=0.039), and the LDL/HDL ratio (LDL/HDL) (p=0.013) were independent predictors of coronary artery stenosis and the LDL/HDL (p=0.042) independently predicted vulnerable coronary plaque by logistic regression analyses. Areas under the curves in receiver operating characteristic curve analysis of the maximum-IMT, LDL/HDL, and these two parameters combined were 0.711 (95% CI 0.601-0.820), 0.618 (0.508-0.728), and 0.732 (0.632-0.831), respectively, for predicting coronary artery stenosis and 0.655 (0.537-0.773), 0.629 (0.504-0.754), and 0.710 (0.601-0.818), respectively, for predicting vulnerable coronary plaque. CONCLUSIONS: Male sex, duration of diabetes, elevated SBP, and LDL/HDL were independent predictors of coronary artery stenosis. LDL/HDL was an independent predictor of vulnerable coronary plaque. Maximum-IMT predicted both coronary stenosis and vulnerable coronary plaque. Adding LDL/HDL improved the prediction of coronary artery stenosis and vulnerable coronary plaque. PMID- 23363980 TI - TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. AB - Innate lymphoid cells (ILCs) are a recently identified family of heterogeneous immune cells that can be divided into three groups based on their differential developmental requirements and expression of effector cytokines. Among these, group 2 ILCs produce the type 2 cytokines interleukin-5 (IL-5) and IL-13 and promote type 2 inflammation in the lung and intestine. However, whether group 2 ILCs reside in the skin and contribute to skin inflammation has not been characterized. We identify a population of skin-resident group 2 ILCs present in healthy human skin that are enriched in lesional human skin from atopic dermatitis (AD) patients. Group 2 ILCs were also found in normal murine skin and were critical for the development of inflammation in a murine model of AD-like disease. Remarkably, in contrast to group 2 ILC responses in the intestine and lung, which are critically regulated by IL-33 and IL-25, group 2 ILC responses in the skin and skin-draining lymph nodes were independent of these canonical cytokines but were critically dependent on thymic stromal lymphopoietin (TSLP). Collectively, these results demonstrate an essential role for IL-33- and IL-25 independent group 2 ILCs in promoting skin inflammation. PMID- 23363983 TI - Biomechanical factors in coronary vulnerable plaque risk of rupture: intravascular ultrasound-based patient-specific fluid-structure interaction studies. AB - OBJECTIVES: The aim of this study was to elucidate the mechanisms and underlying biomechanical factors that may play a role in the risk of rupture of vulnerable plaques (VPs) by studying patient-based geometries of coronary arteries reconstructed from intravascular ultrasound (IVUS) imaging utilizing fluid structure interaction (FSI) numerical simulations. BACKGROUND: According to recent estimates, coronary artery disease is responsible for one in six deaths in the USA, and causes about one million heart attacks each year. Among these, the rupture of coronary VPs followed by luminal blockage is widely recognized as a major cause of sudden heart attacks; most importantly, the patients may appear as asymptomatic under routine screening before the occurrence of the index event. MATERIALS AND METHODS: FSI simulations of patient-based geometries of coronary arteries reconstructed from IVUS imaging were performed to establish the dependence of the risk of rupture of coronary VP on biomechanical factors, such as the fibrous cap thickness, presence of microcalcification in the fibrous cap, arterial anisotropy, and hypertension. RESULTS: Parametric FSI simulations indicated that mechanical stresses (von Mises stresses) increase exponentially with the thinning of the fibrous cap as well as with increasing levels of hypertension. The inclusion of a microcalcification in the fibrous cap considerably increases the risk of rupture of VP , with an ~two-fold stress increase in the VP stress burden. Furthermore, the stress-driven reorientation and biochemical degradation of the collagen fibers in the vessel wall because of atherosclerosis (studied with an anisotropic fibrous cap 65 degrees fiber reorientation angle) results in a 30% increase in the stress levels as compared with simulations with isotropic material models, clearly indicating that the latter, which are commonly used in such studies, underestimate the risk of rupture of VP. CONCLUSION: The results indicate that IVUS-based patient-specific FSI simulations for mapping the wall stresses, followed by analysis of the biomechanical risk factors, may be used as an additional diagnostic tool for clinicians to estimate the plaque burden and determine the proper treatment and intervention. PMID- 23363984 TI - Difference in neointimal appearance between early and late restenosis after sirolimus-eluting stent implantation assessed by optical coherence tomography. AB - OBJECTIVES: Late in-stent restenosis (ISR) is an important clinical issue in the drug-eluting stent era. Autopsy studies have reported different underlying mechanisms between early ISR and late ISR. The aim of the present study was to compare the neointimal tissue appearance between early ISR (<1 year) and late ISR (>1 year) after sirolimus-eluting stent (SES) implantation using optical coherence tomography (OCT). MATERIALS AND METHODS: We examined the neointimal tissue appearance in 48 ISR lesions after SES implantation [30 early ISR lesions (8+/-1 months after stenting) and 18 late ISR lesions (34+/-14 months after stenting)] by OCT. ISR was defined as percent diameter stenosis more than 50% within the stented segment in angiography. Lipid-rich neointima was characterized by signal-poor regions with diffuse borders. Thin-cap fibroatheroma (TCFA)-like neointima was defined by lipid-rich neointima with cap thickness 65 MUm or less. RESULTS: In the OCT findings, heterogeneous neointima was more often observed in the late ISR group compared with the early ISR group (89 vs. 43%, P=0.002). Although the frequency of intraluminal thrombus was not different between the two groups (P=0.085), the frequency of lipid-rich neointima (83 vs. 27%, P<0.001), TCFA-like neointima (39 vs. 10%, P=0.028), microchannels within neointima (67 vs. 27%, P=0.007), and neointimal disruption (33 vs. 3%, P=0.008) was significantly higher in the late ISR group. CONCLUSION: In the present OCT study, it was found that atherosclerotic progression of neointima, such as lipid-rich neointima, TCFA like neointima, microchannels, and neointimal disruption, was more often observed in late ISR lesions after SES implantation compared with early ISR ones. PMID- 23363985 TI - Diagnostic performance of computed tomographic coronary angiography in patients with end-stage renal disease. AB - BACKGROUND: End-stage renal disease (ESRD) is characterized by a very high rate of cardiovascular events that warrants thorough screening for coronary atherosclerosis, especially in patients undergoing a kidney transplant. Therefore, we assessed the diagnostic performance of 64-slice multidetector coronary computed tomographic angiography (CCTA) in patients with ESRD. METHODS: We included patients who had been referred for a CCTA and an invasive coronary angiography (diagnostic standard) within 6 months, either as part of clinical work-up in two urban medical centers or as part of the multicenter ACCURACY trial. RESULTS: Thirty-one ESRD patients were included and compared with 588 non ESRD patients undergoing CCTA and invasive coronary angiography. On a patient based model, the sensitivity, specificity, and positive and negative predictive values to detect at least 50% and at least 70% stenosis were 100, 78, 92, and 100% and 100, 91, 95, and 100%, respectively, for ESRD patients and 97, 83, 87, and 96% and 94, 87, 85, and 95%, respectively, for non-ESRD controls. There were no statistically significant differences between ESRD and non-ESRD participants in diagnostic performance measures. CONCLUSION: Results show 64-row multidetector CCTA is highly sensitive and specific in the detection of coronary artery stenosis irrespective of ESRD. Our findings suggest that CCTA is a promising diagnostic tool for the timely detection and/or exclusion of coronary atherosclerosis in patients undergoing pretransplant cardiovascular surveillance. PMID- 23363986 TI - SYNTAX score is a predictor of angiographic no-reflow in patients with ST elevation myocardial infarction treated with a primary percutaneous coronary intervention. AB - OBJECTIVES: The no-reflow phenomenon has a negative prognostic value in patients with acute ST-elevation myocardial infarction (STEMI). The SYNTAX score (SS) quantifies the extent and complexity of angiographic disease and predicts long term mortality and morbidity in STEMI. We aimed to assess the no-reflow and its possible relationships with SS and clinical characteristics in patients with STEMI treated with a primary percutaneous coronary intervention (PPCI). MATERIALS AND METHODS: In this study, 880 patients with STEMI treated with PPCI were included prospectively (646 men and 234 women, mean age 58.5+/-12.4 years). The SS, thrombolysis in myocardial infarction (TIMI) flow grade score, and TIMI myocardial blush grade score were determined in all patients. No-reflow was defined as TIMI grade 0, 1 and 2 flows or TIMI grade 3 with myocardial blush grade 0 and 1. The patients were divided into two groups: a normal flow group and a no-reflow group. RESULTS: No-reflow was observed in 32.8% of patients. The mean SS of the no-reflow group was higher than that of the normal flow group (19.2+/ 6.8/12.9+/-6.1, P<0.001). On multivariate logistic regression analysis, SS [beta=0.872, 95% confidence interval (CI)=0.845-0.899, P<0.001], diabetes (beta=0.767, 95% CI=0.128-4.597, P=0.004), anterior myocardial infarction (beta=5.421, 95% CI=1.369-21.469, P=0.025), and thrombus grade after wiring (beta=2.537, 95% CI=1.506-4.273, P<0.001) were found to be independent predictors of no-reflow. The cutoff value of SS obtained by the receiver-operator characteristic curve analysis was 19.75 for the prediction of no-reflow (sensitivity: 70.6%, specificity: 69.4%). CONCLUSION: The SS is a predictor of no reflow in patients with STEMI treated with PPCI. PMID- 23363988 TI - Microenvironment: an accommodating host. PMID- 23363987 TI - Short-term and long-term mortality associated with ventricular arrhythmia in patients hospitalized with acute coronary syndrome: findings from the Gulf RACE registry-2. AB - OBJECTIVES: Ventricular arrhythmia (VA) in the setting of acute coronary syndrome (ACS) carries an ominous prognosis; however, long-term prognosis associated with VA in ACS in the Middle East is unknown. Accordingly, we sought to assess the incidence, in-hospital outcomes, and 1-year mortality of in-hospital VA in patients with ACS. METHODS AND RESULTS: The Second Gulf Registry of Acute Coronary Events (Gulf RACE-2) is a multinational observational study of patients with ACS, which enrolled 7930 patients. Of these, 333 (4.2%) developed VA during hospitalization. Patients with VA were significantly older (mean age 58.3 vs. 56.8 years), and had a significantly higher rate of prior stroke/transient ischemic attack (7.5 vs. 4.2%), smoking (36.6 vs. 35.6%), congestive heart failure (11.0 vs. 6.5%), and peripheral artery disease (6.5 vs. 1.7%), compared with patients without VA. They had significantly less diabetes mellitus (35.4 vs. 40.3%), hypertension (43.2 vs. 47.9%), percutaneous coronary intervention (6.1 vs. 9.4%), and dyslipidemia (22.4 vs. 38.2%). The adjusted odds ratios for in hospital, 30-day, and 1-year mortality in VA complicating all ACS were 25.8, 11.1, and 7.3; ST-elevation myocardial infarctions were 18.3, 11.7, and 6.3; and unstable angina and non-ST elevation myocardial infarctions were 47.4, 10.3, and 18.7, respectively (all P<0.001). CONCLUSION: In-hospital VA in patients with ACS with and without ST elevation was associated with significantly higher in hospital, 30-day, and 1-year mortality. Noticeably higher long-term mortality among Middle Eastern patients with ACS having VA compared with other reports requires further study and warrants immediate attention. PMID- 23363990 TI - Ubiquitylation: Mediation by degradation. PMID- 23363989 TI - Prostate cancer: is it time to expand the research focus to early-life exposures? AB - Although the contribution of lifestyle and environment (non-genetic factors) to prostate carcinogenesis is indicated by international variation in prostate cancer occurrence and migration studies, no conclusive modifiable risk factors have yet been identified. One possible reason for this may be the dearth of epidemiological research on exposures experienced early in life, when the immature prostate may be more susceptible to carcinogenic exposures. In this Opinion article, we summarize the rationale for studying early-life exposures, describe the small body of early-life research and its associated challenges, and point to solutions for future research. PMID- 23363991 TI - Changes in dairy food and nutrient intakes in Australian adolescents. AB - Dairy nutrients, such as calcium, are particularly important in adolescence, a critical time for growth and development. There are limited Australian data following individuals through adolescence, evaluating changes in dairy nutrient and dairy product consumption. We used a validated food frequency questionnaire to investigate consumption in adolescents participating in both the 14 and 17 year follow-ups of the Western Australian Pregnancy Cohort (Raine) Study. Most adolescents did not reach age and gender specific recommended daily intakes for calcium or magnesium at 14 years, and this decreased as they aged to 17 years (from 33.0% to 29.2% meeting for calcium, P < 0.05, and from 33.6% to 20.5% meeting for magnesium, P < 0.01). Mean intakes of calcium, potassium, riboflavin and vitamin A also decreased with age (P < 0.01). Mean dairy intake decreased from 536 +/- 343 g/day to 464 +/- 339 g/day (P < 0.01), due mostly to a decrease in regular milk, although flavoured milk consumption increased in boys. Cheese and butter were the only products to show a significantly increased consumption over the period. Girls decreased from 2.2 to 1.9 serves/day of dairy, while boys remained relatively steady at 2.9 to 2.8 serves/day. Our findings suggest that dairy product consumption decreases over adolescence. This may have implications for bone mass, development and later health. PMID- 23363992 TI - Retinal spectral domain optical coherence tomography in early atrophic age related macular degeneration (AMD) and a new metric for objective evaluation of the efficacy of ocular nutrition. AB - PURPOSE: A challenge in ocular preventive medicine is identification of patients with early pathological retinal damage that might benefit from nutritional intervention. The purpose of this study is to evaluate retinal thinning (RT) in early atrophic age-related macular degeneration (AMD) against visual function data from the Zeaxanthin and Visual Function (ZVF) randomized double masked placebo controlled clinical trial (FDA IND #78973). METHODS: Retrospective, observational case series of medical center veterans with minimal visible AMD retinopathy (AREDS Report #18 simplified grading 1.4/4.0 bilateral retinopathy). Foveal and extra-foveal four quadrant SDOCT RT measurements were evaluated in n = 54 clinical and ZVF AMD patients. RT by age was determined and compared to the OptoVue SD OCT normative database. RT by quadrant in a subset of n = 29 ZVF patients was correlated with contrast sensitivity and parafoveal blue cone increment thresholds. RESULTS: Foveal RT in AMD patients and non-AMD patients was preserved with age. Extrafoveal regions, however, showed significant slope differences between AMD patients and non-AMD patients, with the superior and nasal quadrants most vulnerable to retinal thinning (sup quad: -5.5 MUm/decade thinning vs. Non-AMD: -1.1 MUm/decade, P < 0.02; nasal quad: -5.0 MUm/decade thinning vs. Non-AMD: -1.0 MUm/decade, P < 0.04). Two measures of extrafoveal visual deterioration were correlated: A significant inverse correlation between % RT and contrast sensitivity (r = -0.33, P = 0.01, 2 Tailed Paired T) and an elevated extrafoveal increment blue cone threshold (r = +0.34, P = 0.01, 2 Tailed T). Additional SD OCT RT data for the non-AMD oldest age group (ages 82-91) is needed to fully substantiate the model. CONCLUSION: A simple new SD OCT clinical metric called "% extra-foveal RT" correlates well with functional visual loss in early AMD patients having minimal visible retinopathy. This metric can be used to follow the effect of repleting ocular nutrients, such as zinc, antioxidants, carotenoids, n-3 essential fats, resveratrol and vitamin D. PMID- 23363994 TI - Dose and latency effects of leucine supplementation in modulating glucose homeostasis: opposite effects in healthy and glucocorticoid-induced insulin resistance states. AB - Dexamethasone (DEXA) is a potent immunosupressant and anti-inflammatory agent whose main side effects are muscle atrophy and insulin resistance in skeletal muscles. In this context, leucine supplementation may represent a way to limit the DEXA side effects. In this study, we have investigated the effects of a low and a high dose of leucine supplementation (via a bolus) on glucose homeostasis, muscle mass and muscle strength in energy-restricted and DEXA-treated rats. Since the leucine response may also be linked to the administration of this amino acid, we performed a second set of experiments with leucine given in bolus (via gavage) versus leucine given via drinking water. Leucine supplementation was found to produce positive effects (e.g., reduced insulin levels) only when administrated in low dosage, both via the bolus or via drinking water. However, under DEXA treatment, leucine administration was found to significantly influence this response, since leucine supplementation via drinking water clearly induced a diabetic state, whereas the same effect was not observed when supplied via the gavage. PMID- 23363993 TI - The use of fish oil lipid emulsion in the treatment of intestinal failure associated liver disease (IFALD). AB - Since 2004, fish oil based lipid emulsions have been used in the treatment of intestinal failure associated liver disease, with a noticeable impact on decreasing the incidence of morbidity and mortality of this often fatal condition. With this new therapy, however, different approaches have emerged as well as concerns about potential risks with using fish oil as a monotherapy. This review will discuss the experience to date with this lipid emulsion along with the rational for its use, controversies and concerns. PMID- 23363995 TI - Dietary regulation of histone acetylases and deacetylases for the prevention of metabolic diseases. AB - Age-related diseases such as type 2 diabetes, cardiovascular disease, and cancer involve epigenetic modifications, where accumulation of minute changes in the epigenome over time leads to disease manifestation. Epigenetic changes are influenced by life style and diets. This represents an avenue whereby dietary components could accelerate or prevent age-related diseases through their effects on epigenetic modifications. Histone acetylation is an epigenetic modification that is regulated through the opposing action of histone acetylases (HATs) and deacetylases (HDACs). These two families of enzymes play critical roles in metabolic processes and their dysregulation is associated with pathogenesis of several diseases. Dietary components, such as butyrate, sulforaphane, and curcumin, have been shown to affect HAT and HDAC activity, and their health benefits are attributed, at least in part, to epigenetic modifications. Given the decades that it takes to accumulate epigenetic changes, it is unlikely that pharmaceuticals could undo epigenetic changes without side effects. Therefore, long term consumption of dietary components that can alter the epigenome could be an attractive means of disease prevention. The goal of this review is to highlight the roles of diets and food components in epigenetic modifications through the regulation of HATs and HDACs for disease prevention. PMID- 23363996 TI - Monounsaturated fatty acids and risk of cardiovascular disease: synopsis of the evidence available from systematic reviews and meta-analyses. AB - No dietary recommendations for monounsaturated fatty acids (MUFA) are given by the National Institute of Medicine, the United States Department of Agriculture, European Food and Safety Authority and the American Diabetes Association. In contrast, the Academy of Nutrition and Dietetics, and the Canadian Dietetic Association both promote <25% MUFA of daily total energy consumption, while the American Heart Association sets a limit of 20% MUFA in their respective guidelines. The present review summarizes systematic reviews and meta-analyses of randomized controlled trials and cohort studies investigating the effects of MUFA on cardiovascular and diabetic risk factors, cardiovascular events and cardiovascular death. Electronic database Medline was searched for systematic reviews and meta-analyses using "monounsaturated fatty acids", "monounsaturated fat", and "dietary fat" as search terms with no restriction to calendar date or language. Reference lists and clinical guidelines were searched as well. Sixteen relevant papers were identified. Several studies indicated an increase of HDL cholesterol and a corresponding decrease in triacylglycerols following a MUFA rich diet. The effects on total and LDL-cholesterol appeared not consistent, but no detrimental effects on blood lipids were observed. Values for systolic and diastolic blood pressure were found to be reduced both during short- and long term protocols using high amounts of MUFA as compared to low-MUFA diets. In type 2 diabetic subjects, MUFA exerted a hypoglycemic effect and reduced glycosylated hemoglobin in the long term. Data from meta-analyses exploring evidence from long term prospective cohort studies provide ambiguous results with respect to the effects of MUFA on risk of coronary heart disease (CHD). One meta-analysis reported an increase in CHD events, however, most meta-analyses observed a lesser number of cases in participants subjected to a high-MUFA protocol. Although no detrimental side effects of MUFA-rich diets were reported in the literature, there still is no unanimous rationale for MUFA recommendations in a therapeutic regimen. Additional long-term intervention studies are required to characterized efficacy and effectiveness of recommending MUFA-rich diet among general and clinical populations. PMID- 23363997 TI - Breastfeeding duration and residential isolation amid aboriginal children in Western Australia. AB - OBJECTIVES: To examine factors that impact on breastfeeding duration among Western Australian Aboriginal children. We hypothesised that Aboriginal children living in remote locations in Western Australia were breastfed for longer than those living in metropolitan locations. METHODS: A population-based cross sectional survey was conducted from 2000 to 2002 in urban, rural and remote settings across Western Australia. Cross-tabulations and multivariate logistic regression analyses were performed, using survey weights to produce unbiased estimates for the population of Aboriginal children. Data on demographic, maternal and infant characteristics were collected from 3932 Aboriginal birth mothers about their children aged 0-17 years (representing 22,100 Aboriginal children in Western Australia). RESULTS: 71% of Aboriginal children were breastfed for three months or more. Accounting for other factors, there was a strong gradient for breastfeeding duration by remoteness, with Aboriginal children living in areas of moderate isolation being 3.2 times more likely to be breastfed for three months or more (p < 0.001) compared to children in metropolitan Perth. Those in areas of extreme isolation were 8.6 times more likely to be breastfed for three months or longer (p < 0.001). CONCLUSIONS: Greater residential isolation a protective factor linked to longer breastfeeding duration for Aboriginal children in our West Australian cohort. PMID- 23363999 TI - Food sources of energy and nutrients among adults in the US: NHANES 2003-2006. AB - Identification of current food sources of energy and nutrients among US adults is needed to help with public health efforts to implement feasible and appropriate dietary recommendations. To determine the food sources of energy and 26 nutrients consumed by US adults the 2003-2006 National Health and Nutrition Examination Survey (NHANES) 24-h recall (Day 1) dietary intake data from a nationally representative sample of adults 19+ years of age (y) (n = 9490) were analyzed. An updated USDA Dietary Source Nutrient Database was developed for NHANES 2003-2006 using current food composition databases. Food grouping included ingredients from disaggregated mixtures. Mean energy and nutrient intakes from food sources were sample-weighted. Percentages of total dietary intake contributed from food sources were ranked. The highest ranked sources of energy and nutrients among adults more than 19 years old were: energy - yeast bread/rolls (7.2%) and cake/cookies/quick bread/pastry/pie (7.2%); protein-poultry (14.4%) and beef (14.0%); total fat - other fats and oils (9.8%); saturated fatty acids - cheese (16.5%) and beef (9.1%); carbohydrate - soft drinks/soda (11.4%) and yeast breads/rolls (10.9%); dietary fiber - yeast breads/rolls (10.9%) and fruit (10.2%); calcium - milk (22.5%) and cheese (21.6%); vitamin D - milk (45.1%) and fish/shellfish (14.4%); and potassium - milk (9.6%) and coffee/tea/other non alcoholic beverages (8.4%). Knowledge of primary food sources of energy and nutrients can help health professionals design effective strategies to reduce excess energy consumed by US adults and increase the nutrient adequacy of their diets. PMID- 23364000 TI - Continuous noninvasive monitoring of lung recruitment during high-frequency oscillatory ventilation by electrical impedance measurement: an animal study. AB - BACKGROUND: Ventilatory pressures should target the range between the upper and lower inflection point of the pressure volume curve in order to avoid atelecto- and volutrauma. During high-frequency oscillatory ventilation (HFOV), this range is difficult to determine. Quadrant impedance measurement (QIM) has recently been shown to allow accurate and precise measurement of lung volume changes during conventional mechanical ventilation. OBJECTIVES: To investigate if QIM can be used to determine a static pressure-residual impedance curve during a recruitment derecruitment manoeuvre on HFOV and to monitor the time course of alveolar recruitment after changing mean airway pressure (MAP). METHODS: An incremental and decremental MAP trial (6 cm H2O to 27 cm H2O) was conducted in five surfactant-depleted newborn piglets during HFOV. Ventilatory, gas exchange and haemodynamic parameters were recorded. Continuous measurement of thoracic impedance change was performed. RESULTS: Mean residual impedance (RI) increased with each stepwise increase of MAP resulting in a total mean increase of +26.5% (+/-4.0) at the highest MAP (27 cm H2O) compared to baseline ventilation at 6 cm H2O. Upon decreasing MAP levels, RI fell more slowly compared to its ascent; 83.4% (+/-19.1) and 84.8% (+/-16.4) of impedance changes occurred in the first 5 min after an increase or decrease in airway pressure, respectively. CONCLUSIONS: QIM could be used for continuous monitoring of thoracic impedance and determination of the pressure-RI curve during HFOV. The method could prove to be a promising bedside method for the monitoring of lung recruitment during HFOV in the future. PMID- 23363998 TI - Retina, retinol, retinal and the natural history of vitamin A as a light sensor. AB - Light is both the ultimate energy source for most organisms and a rich information source. Vitamin A-based chromophore was initially used in harvesting light energy, but has become the most widely used light sensor throughout evolution from unicellular to multicellular organisms. Vitamin A-based photoreceptor proteins are called opsins and have been used for billions of years for sensing light for vision or the equivalent of vision. All vitamin A-based light sensors for vision in the animal kingdom are G-protein coupled receptors, while those in unicellular organisms are light-gated channels. This first major switch in evolution was followed by two other major changes: the switch from bistable to monostable pigments for vision and the expansion of vitamin A's biological functions. Vitamin A's new functions such as regulating cell growth and differentiation from embryogenesis to adult are associated with increased toxicity with its random diffusion. In contrast to bistable pigments which can be regenerated by light, monostable pigments depend on complex enzymatic cycles for regeneration after every photoisomerization event. Here we discuss vitamin A functions and transport in the context of the natural history of vitamin A-based light sensors and propose that the expanding functions of vitamin A and the choice of monostable pigments are the likely evolutionary driving forces for precise, efficient, and sustained vitamin A transport. PMID- 23364001 TI - Associations between body composition and gait-speed decline: results from the Health, Aging, and Body Composition study. AB - BACKGROUND: In older adults, every 0.1-m/s slower gait speed is associated with a 12% higher mortality. However, little research has identified risk factors for gait-speed decline. OBJECTIVE: We assessed the association between several measures of body composition and age-related decline in gait speed. DESIGN: Data were from 2306 older adults who were participating in the Health, Aging, and Body Composition cohort and were followed for 4 y (50% women; 38% black). Usual walking speed (m/s) over 20 m was measured in years 2 through 6, and the baseline and changes in several measures of body composition were included in mixed effects models. RESULTS: Gait speed declined by 0.06 +/- 0.00 m/s over the 4-y period. Baseline thigh intermuscular fat predicted the annual gait-speed decline (+/-SE) in both men and women (-0.01 +/- 0.00 and -0.02 +/- 0.00 m/s per 0.57 cm(2), respectively; P < 0.01). In men, but not in women, this relation was independent of total body adiposity. In longitudinal analyses, changes in thigh intermuscular fat and total thigh muscle were the only body-composition measures that predicted gait-speed decline in men and women combined. When modeled together, every 5.75-cm(2) increase in thigh intermuscular fat was associated with a 0.01 +/- 0.00-m/s decrease in gait speed, whereas every 16.92-cm(2) decrease in thigh muscle was associated with a 0.01 +/- 0.00-m/s decrease in gait speed. CONCLUSIONS: High and increasing thigh intermuscular fat are important predictors of gait-speed decline, implying that fat infiltration into muscle contributes to a loss of mobility with age. Conversely, a decreasing thigh muscle area is also predictive of a decline in gait speed. PMID- 23364002 TI - Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes. AB - BACKGROUND: There is evidence that reducing blood glucose concentrations, inducing weight loss, and improving the lipid profile reduces cardiovascular risk in people with type 2 diabetes. OBJECTIVE: We assessed the effect of various diets on glycemic control, lipids, and weight loss. DESIGN: We conducted searches of PubMed, Embase, and Google Scholar to August 2011. We included randomized controlled trials (RCTs) with interventions that lasted >=6 mo that compared low carbohydrate, vegetarian, vegan, low-glycemic index (GI), high-fiber, Mediterranean, and high-protein diets with control diets including low-fat, high GI, American Diabetes Association, European Association for the Study of Diabetes, and low-protein diets. RESULTS: A total of 20 RCTs were included (n = 3073 included in final analyses across 3460 randomly assigned individuals). The low-carbohydrate, low-GI, Mediterranean, and high-protein diets all led to a greater improvement in glycemic control [glycated hemoglobin reductions of -0.12% (P = 0.04), -0.14% (P = 0.008), -0.47% (P < 0.00001), and -0.28% (P < 0.00001), respectively] compared with their respective control diets, with the largest effect size seen in the Mediterranean diet. Low-carbohydrate and Mediterranean diets led to greater weight loss [-0.69 kg (P = 0.21) and -1.84 kg (P < 0.00001), respectively], with an increase in HDL seen in all diets except the high-protein diet. CONCLUSION: Low-carbohydrate, low-GI, Mediterranean, and high-protein diets are effective in improving various markers of cardiovascular risk in people with diabetes and should be considered in the overall strategy of diabetes management. PMID- 23364003 TI - Earlier introduction of aguitas is associated with higher risk of stunting in infants and toddlers in the Western Highlands of Guatemala. AB - BACKGROUND: In many cultures, simple herbal infusions, thin gruels, or sweetened water (aguitas in Guatemalan parlance) are given to infants and toddlers. Formative research has shown that the use of aguitas in early child feeding is deeply embedded in Guatemalan culture. OBJECTIVE: We examined the prevalence and timing of the introduction of aguitas during early life in a low-income population of metropolitan Quetzaltenango in relation to stunting in children. DESIGN: Responses from 456 mothers of children aged 5-23 mo were analyzed by using logistic regression to explore relations between linear growth (stunting), diarrhea, and age at the first introduction of aguitas. RESULTS: A total of 358 of 456 infants (79%) were aguita users independent of sex or ethnicity. Of infants given aguitas, one-fourth of subjects were introduced to aguitas within the first 2.9 wk of age, and one-half of subjects were introduced to aguitas within the first 9 wk of age. Subjects introduced to aguitas before 2.9 wk of age were 1.8 times more likely to be stunted (95% CI: 1.1, 2.8; P = 0.03) irrespective of ethnicity. Children who had ever been given aguitas were twice as likely to have also had diarrhea (OR: 2.1; 95% CI: 1.3, 3.3) and more likely to have needed medical attention for diarrhea (OR: 2.1; 95% CI: 1.1, 4.2), but diarrheal experience was independent of stunting. CONCLUSION: Because of the early introduction of aguitas and the high prevalence of stunting in Guatemala, longitudinal studies are urgently needed to clarify the causal relations. This trial was registered at Nederlands Trial register as NTR3273 for 5-mo-olds and Nederlands Trial register as NTR3292 for infants >=6 mo. PMID- 23364005 TI - Randomized controlled trial of oral omega-3 PUFA in solar-simulated radiation induced suppression of human cutaneous immune responses. AB - BACKGROUND: Skin cancer is a major public health concern, and the majority of cases are caused by solar ultraviolet radiation (UVR) exposure, which suppresses skin immunity. Omega-3 (n-3) PUFAs protect against photoimmunosuppression and skin cancer in mice, but the impact in humans is unknown. OBJECTIVES: We hypothesized that EPA-rich n-3 PUFA would abrogate photoimmunosuppression in humans. Therefore, a nutritional study was performed to assess the effect on UVR suppression of cutaneous cell-mediated immunity (CMI) reflected by nickel contact hypersensitivity (CHS). DESIGN: In a double-blind, randomized controlled study, 79 volunteers (nickel-allergic women, 22-60 y old, with phototype I or II) took 5 g n-3 PUFA-containing lipid (70% EPA plus 10% DHA) or a control lipid daily for 3 mo. After supplementation, nickel was applied to 3 skin sites preexposed on 3 consecutive days to 1.9, 3.8, or 7.6 J/cm(2) of solar-simulated radiation (SSR) and to 3 unexposed control sites. Nickel CHS responses were quantified after 72 h and the percentage of immunosuppression by SSR was calculated. Erythrocyte [red blood cell (RBC)] EPA was measured by using gas chromatography. RESULTS: SSR dose related suppression of the nickel CHS response was observed in both groups. Photoimmunosuppression appeared less in the n-3 PUFA group than in the control group (not statistically significant [mean difference (95% CI): 6.9% (-2.1%, 15.9%)]). The difference was greatest at 3.8 J/cm(2) SSR [mean difference: 11% (95% CI: 0.5%, 21.4%)]. Postsupplementation RBC EPA was 4-fold higher in the n-3 PUFA group than in the control group (mean difference: 2.69% (95% CI: 2.23%, 3.14%), which confirmed the EPA bioavailability. CONCLUSION: Oral n-3 PUFAs appear to abrogate photoimmunosuppression in human skin, providing additional support for their chemopreventive role; verification of study findings is required. This trial was registered at clinicaltrials.gov as NCT01032343. PMID- 23364006 TI - The effect of maternal omega-3 (n-3) LCPUFA supplementation during pregnancy on early childhood cognitive and visual development: a systematic review and meta analysis of randomized controlled trials. AB - BACKGROUND: Maternal fish consumption during pregnancy has been positively associated with cognitive and visual abilities in the offspring, leading to the hypothesis that maternal omega-3 (n-3) long-chain PUFA (LCPUFA) supplementation improves children's neurologic and visual development. OBJECTIVE: The objective was to evaluate the effect of maternal omega-3 LCPUFA supplementation in pregnancy on neurologic and visual development in the offspring. DESIGN: Five electronic databases were searched. Human randomized controlled trials that supplemented the maternal diet with omega-3 LCPUFAs during pregnancy, or pregnancy and lactation, and that assessed either neurologic or visual development of the offspring were included. Trial quality was assessed, and the results of eligible trials were compared in meta-analyses. RESULTS: Eleven RCTs involving 5272 participants were included in the review. Most trials had methodologic limitations. No differences in standardized psychometric test scores for cognitive, language, or motor development were observed between the LCPUFA supplemented and control groups, except for cognitive scores in 2-5-y-old children, in whom supplementation resulted in higher Developmental Standard Scores (mean difference: 3.92; 95% CI: 0.77, 7.08; n = 156; P = 0.01). However, this effect was from 2 trials with a high risk of bias. Because of the variety of visual assessments and age ranges, it was not possible to combine studies with visual outcomes in a meta-analysis, although 6 of the 8 assessments in 5 trials reported no difference between the supplemented and control groups. CONCLUSION: The evidence does not conclusively support or refute that omega-3 LCPUFA supplementation in pregnancy improves cognitive or visual development. PMID- 23364004 TI - Vitamin D supplementation and calcium absorption during caloric restriction: a randomized double-blind trial. AB - BACKGROUND: Weight loss (WL) is associated with a decrease in calcium absorption and may be one mechanism that induces bone loss with weight reduction. OBJECTIVE: Because vitamin D supplementation has been shown to increase true fractional calcium absorption (TFCA), the goal of this study was to examine the effect of vitamin D during WL or weight maintenance (WM). DESIGN: A randomized, placebo controlled, double-blind 6-wk study was conducted in 82 postmenopausal women [BMI (in kg/m(2); +/-SD): 30.2 +/- 3.7] with 25-hydroxyvitamin D [25(OH)D] concentrations <70 nmol/L during either WL or WM. All women were given 10 MUg vitamin D(3)/d and 1.2 g Ca/d and either weekly vitamin D(3) (375 MUg) or a placebo equivalent to 63 MUg (2500 IU)/d and 10 MUg (400 IU)/d, respectively. We measured TFCA with the use of dual-stable isotopes, 25(OH)D, parathyroid hormone, estradiol, calcitriol, and urinary calcium at baseline and 6 wk in weight loss and vitamin D(3)-supplementation (WL-D; n = 19), weight maintenance and vitamin D(3)-supplementation (WM-D; n = 20), weight loss and placebo (n = 22), and weight maintenance and placebo (n = 21) groups. RESULTS: WL groups lost 3.8 +/- 1.1% of weight with no difference between vitamin D(3) supplementation and the placebo. The rise in serum 25(OH)D was greatest in the WL-D group (19.8 +/- 14.5 nmol/L) compared with in WM-D (9.1 +/- 10.3 nmol/L) and placebo groups (1.5 +/- 10.9 nmol/L). TFCA increased with vitamin D(3) supplementation compared with placebo treatment (P < 0.01) and decreased during WL compared with WM. Serum 25(OH)D or 1,25-dihyroxyvitamin D did not correlate with TFCA. CONCLUSION: These data show that vitamin D supplementation increases TFCA and that WL decreases TFCA and suggest that, when calcium intake is 1.2 g/d, either 10 or 63 MUg vitamin D/d is sufficient to maintain the calcium balance. This trial was registered at clinicaltrials.gov as NCT00473031. PMID- 23364007 TI - Risk of hospitalization or death from ischemic heart disease among British vegetarians and nonvegetarians: results from the EPIC-Oxford cohort study. AB - BACKGROUND: Few previous prospective studies have examined differences in incident ischemic heart disease (IHD) risk between vegetarians and nonvegetarians. OBJECTIVE: The objective was to examine the association of a vegetarian diet with risk of incident (nonfatal and fatal) IHD. DESIGN: A total of 44,561 men and women living in England and Scotland who were enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Oxford study, of whom 34% consumed a vegetarian diet at baseline, were part of the analysis. Incident cases of IHD were identified through linkage with hospital records and death certificates. Serum lipids and blood pressure measurements were available for 1519 non cases, who were matched to IHD cases by sex and age. IHD risk by vegetarian status was estimated by using multivariate Cox proportional hazards models. RESULTS: After an average follow-up of 11.6 y, there were 1235 IHD cases (1066 hospital admissions and 169 deaths). Compared with nonvegetarians, vegetarians had a lower mean BMI [in kg/m(2); -1.2 (95% CI: -1.3, -1.1)], non-HDL cholesterol concentration [-0.45 (95% CI: -0.60, -0.30) mmol/L], and systolic blood pressure [-3.3 (95% CI: -5.9, -0.7) mm Hg]. Vegetarians had a 32% lower risk (HR: 0.68; 95% CI: 0.58, 0.81) of IHD than did nonvegetarians, which was only slightly attenuated after adjustment for BMI and did not differ materially by sex, age, BMI, smoking, or the presence of IHD risk factors. CONCLUSION: Consuming a vegetarian diet was associated with lower IHD risk, a finding that is probably mediated by differences in non-HDL cholesterol, and systolic blood pressure. PMID- 23364008 TI - Improved 4-compartment body-composition model for a clinically accessible measure of total body protein. AB - BACKGROUND: Muscle wasting is a consequence of many primary conditions including sarcopenia, cachexia, osteoporosis, HIV/AIDS, and chronic kidney disease. Unfortunately, there is not a clinically accessible method to measure total body protein, which is the functional mass of muscle. OBJECTIVE: We sought to derive a simple method to measure total body protein by using dual-energy X-ray absorptiometry (DXA) and bioimpedance analysis (BIA). DESIGN: We retrospectively analyzed a clinical convenience sample of individuals with numerous metabolic conditions from the Monash Medical Centre, Melbourne, Australia, who had a concurrent protein measure by using neutron activation analysis-derived protein (NAA-TBPro), water measure by using BIA, and whole-body DXA scan. The study was split into calibration and validation data sets by using simple random sampling stratified by sex, BMI category, and age decade. We generated a protein estimate direct-calibration protein (DC-TBPro) derived from BIA water, bone mass, and body volume. We compared NAA-TBPro with DC-TBPro and 2 protein estimates from the literature, one that used the DC-TBPro equation with fixed coefficients [4 compartment Lohman method for analysis of total body protein (4CL-TBPro)] and another that used fat-free mass, age, and sex [Wang equation-derived protein (W TBPro)]. RESULTS: A total of 187 participants [119 women; mean (+/-SD) age: 37.0 +/- 15.4 y; mean (+/-SD) BMI (in kg/m(2)) 24.5 +/- 7.7] were included. When plotted against NAA-TBPro, DC-TBPro had the highest correlation [coefficient of determination (R(2)) = 0.87], lowest root mean squared error (RMSE; 0.87 kg), and fewest outliers compared with 4CL-TBPro (R(2) = 0.75; RMSE = 1.22 kg) and W-TBPro (R(2) = 0.80; RMSE = 1.10 kg). CONCLUSIONS: A simple method to measure total body protein by using a DXA system and BIA unit was developed and compared with NAA as proof of principle. With additional validation, this method could provide a clinically useful way to monitor muscle-wasting conditions. PMID- 23364009 TI - Common variants at 12q24 are associated with drinking behavior in Han Chinese. AB - BACKGROUND: Alcohol consumption is heritable, but genetic susceptibility to drinking behavior has not been investigated widely in genome-wide association studies. OBJECTIVE: We aimed to identify susceptibility loci for drinking behavior (drinkers compared with nondrinkers) in Han Chinese. DESIGN: We performed 2 genome-wide association studies including 1420 drinkers and 3590 nondrinkers in discovery, followed by a de novo replication analysis comprising 4896 drinkers and 13,293 nondrinkers. DNA samples of the subjects were collected for genotyping. RESULTS: The association results of drinking behavior (drinkers or nondrinkers) showed a cluster of single nucleotide polymorphisms at 12q24 in discovery (P < 5 * 10(-8)), with the strongest association for rs11066280 near C12orf51 (P-combined = 3.26 * 10(-215)). Moreover, we observed the association with drinking behavior for a functional variant in ALDH2 at 12q24 (rs671, P discovery = 5.17 * 10(-35)). We also identified the association between rs11066280 and daily alcohol intake among drinkers (P-combined = 4.01 * 10(-21)). CONCLUSION: Our data indicate that common variants at 12q24 may contribute to the susceptibility of drinking behavior in Han Chinese. PMID- 23364012 TI - High nutritional quality is not associated with low greenhouse gas emissions in self-selected diets of French adults. AB - BACKGROUND: Healthy diets are supposed to be more environmentally friendly because they rely mainly on plant-based foods, which have lower greenhouse gas emissions (GHGEs) per unit weight than do animal-based foods. OBJECTIVES: The objectives were to estimate the GHGEs associated with the consumption of self selected diets in France and to analyze their relation with the nutritional quality of diets. DESIGN: For each adult in the national dietary Individual and National Survey on Food Consumption (n = 1918), the GHGEs of his or her diet were estimated based on the GHGEs of 391 foods. Highest-nutritional-quality diets were defined as those having simultaneously 1) an energy density below the median, 2) a mean adequacy ratio (MAR) above the median, and 3) a mean excess ratio (MER, percentage of maximum recommended values for nutrients for which intake should be limited) below the median. RESULTS: MAR was positively correlated and MER was negatively correlated with diet-related GHGEs. High-nutritional-quality diets contained more plant-based foods, notably fruit and vegetables, and fewer sweets and salted snacks than did low-quality diets. After adjustment for age, sex, and energy intake, the consumption of sweets and salted snacks was negatively correlated with diet-related GHGEs, whereas the consumption of animal products and of fruit and vegetables was positively associated with them. After adjustment for energy intake, high-nutritional-quality diets had significantly higher GHGEs (+9% and +22% for men and women, respectively) than did low-nutritional-quality diets. CONCLUSION: Despite containing large amounts of plant-based foods, self selected diets of the highest nutritional quality are currently not those with the lowest diet-related GHGEs. PMID- 23364011 TI - Association of vitamin D deficiency with incidence of type 2 diabetes in high risk Asian subjects. AB - BACKGROUND: Recent studies suggest an association between 25-hydroxyvitamin D [25(OH)D] and type 2 diabetes (T2D) risk. However, prospective studies investigating the relation between vitamin D inadequacy and incidence of T2D incorporating obesity and dynamic measures of insulin resistance (IR) and pancreatic beta cell function are limited. OBJECTIVE: We tested the hypothesis that baseline 25(OH)D is associated with the incidence of T2D in high-risk subjects for up to 5 y of follow-up, independently of obesity, baseline IR, and beta cell function. DESIGN: We recruited 1080 nondiabetic Korean subjects [mean +/- SD age: 49.5 +/- 11.4 y] based on the presence of one or more risk factors for T2D, including obesity, hypertension, dyslipidemia, and/or family history of T2D. We measured anthropometric and biochemical indicators, HOMA2-IR, and the insulinogenic index (IGI; calculated as change in insulin at 30 min/change in glucose at 30 min) from a 75-g oral-glucose-tolerance test. RESULTS: Of the participants, 10.5% had a serum 25(OH)D deficiency (<10 ng/mL), 51.6% had an insufficiency (10.0-19.9 ng/mL), and 38.0% had a sufficiency (>=20 ng/mL), and the incidence of T2D at 32.3 +/- 15.6 mo (+/-SD) declined accordingly: 15.9%, 10.2%, and 5.4%, respectively (P < 0.001). After adjustment for age, sex, blood pressure, lifestyles, family history, season, parathyroid hormone, and high sensitivity C-reactive protein, the participants with 25(OH)D deficiency had an increased risk of T2D independently of BMI, HOMA2-IR, and IGI; the HRs were 2.06 (95% CI: 1.22, 3.49) for 25(OH)D 10-19.9 ng/mL compared with >=20 ng/mL and 3.23 (95% CI: 1.66, 6.30) for 25(OH)D <10 ng/mL compared with >=20 ng/mL. CONCLUSION: The current prospective study suggests that vitamin D metabolism may play a role in T2D pathogenesis independently of known risk factors. This trial was registered at clinicaltrials.gov as NCT01508481. PMID- 23364010 TI - Clinical utility of visceral adipose tissue for the identification of cardiometabolic risk in white and African American adults. AB - BACKGROUND: Visceral adipose tissue (VAT) has been identified as a harmful fat depot, and sex and race differences in VAT have been reported in white and African Americans. OBJECTIVES: We determined the clinical utility of VAT in the identification of individuals at elevated cardiometabolic risk in white and African American adults and compared the clinical utility with measures obtained by using dual-energy X-ray absorptiometry (DXA) and anthropometric measures. DESIGN: The sample included 429 white women, 311 African American women, 406 white men, and 100 African American men who were 18-74 y of age. VAT was measured by using computed tomography, fat mass (FM) and percentage of body fat were measured by using DXA, and waist circumference (WC) and BMI were assessed. Receiver operating characteristic curves were used to compare the utility of measures in the identification of participants in the upper quintile of a continuous score derived from principal components analysis of fasting glucose, HDL cholesterol, triglycerides, and blood pressure. RESULTS: The clinical utility of measures varied across sex-by-race groups. In the overall sample, the areas under the curve were significantly higher for VAT and WC in comparison with the other indicators. Identified VAT thresholds were higher in white men (140 cm(2)) and women (141 cm(2)) than in African American men (82 cm(2)) and women (97 cm(2)). CONCLUSIONS: VAT and WC showed greater clinical utility than did other obesity measures. Because of the complexity of measuring VAT, the use of WC is recommended for the identification of adults with elevated cardiometabolic risk factors. The Pennington Center Longitudinal Study was registered at clinicaltrials.gov as NCT00959270. PMID- 23364013 TI - The importance of behavioral anchoring in neuroimaging studies of obesity. PMID- 23364014 TI - Physical activity and sedentary leisure time and their associations with BMI, waist circumference, and percentage body fat in 0.5 million adults: the China Kadoorie Biobank study. AB - BACKGROUND: Few large studies in China have investigated total physical activity and sedentary leisure time and their associations with adiposity. OBJECTIVE: We investigated determinants of physical activity and sedentary leisure time and their associations with adiposity in China. DESIGN: A total of 466,605 generally healthy participants (age: 30-79 y, 60% female) in the China Kadoorie Biobank were included in this cross-sectional analysis. Self-reported information on a range of activities was collected by interviewer-administered questionnaire. Physical activity was calculated as metabolic equivalent task hours per day (MET h/d) spent on work, transportation, housework, and nonsedentary recreation. Sedentary leisure time was quantified as hours per day. Adiposity measures included BMI, waist circumference, and percentage body fat (by bioimpedance analysis). Associations were estimated by linear and logistic regression. RESULTS: The mean physical activity was 22 MET-h/d, and the mean sedentary leisure time was 3.0 h/d. For each sex, physical activity was about one-third lower among professionals/administrators than among factory workers, with intermediate levels for other occupational categories. A 1-SD (14 MET-h/d) greater physical activity was associated with a 0.15-unit (95% CI: 0.14, 0.16) lower BMI (in kg/m(2)), a 0.58-cm (95% CI: 0.55, 0.61) smaller waist circumference, and 0.48 (95% CI: 0.45, 0.50) percentage points less body fat. In contrast, a 1-SD (1.5 h/d) greater sedentary leisure time was associated with a 0.19-unit higher BMI (95% CI: 0.18, 0.20), a 0.57-cm larger waist circumference (95% CI: 0.54, 0.59), and 0.44 (95% CI: 0.42, 0.46) percentage points more body fat. For any given physical activity level, greater sedentary leisure time was associated with a greater prevalence of increased BMI, as was lower physical activity for any given sedentary leisure time. CONCLUSIONS: In adult Chinese, physical activity varies substantially by occupation, and lack of physical activity and excess sedentary leisure time are independently and jointly associated with greater adiposity. PMID- 23364016 TI - Increased sensitivity to food cues in the fasted state and decreased inhibitory control in the satiated state in the overweight. AB - BACKGROUND: Flexibility of food reward-related brain signaling (FRS) between food and nonfood stimuli may differ between overweight and normal-weight subjects and depend on a fasted or satiated state. OBJECTIVE: The objective was to assess this flexibility in response to visual food and nonfood cues. DESIGN: Twenty normal weight [mean +/- SEM BMI (in kg/m(2)) = 22.7 +/- 0.2; mean +/- SEM age = 22.4 +/- 0.4 y] and 20 overweight (BMI = 28.1 +/- 0.3; age = 24.0 +/- 0.7 y) participants completed 2 fMRI scans. Subjects arrived in a fasted state and consumed a breakfast consisting of 20% of subject-specific energy requirements between 2 successive scans. A block paradigm and a food > nonfood contrast was used to determine FRS. RESULTS: An overall stimulus * condition * subject group effect was observed in the anterior cingulate cortex (ACC) (P < 0.006, F((1,38)) = 9.12) and right putamen (P < 0.006, F((1,38)) = 9.27). In all participants, FRS decreased from the fasted to the satiated state in the cingulate (P < 0.005, t((39)) = 3.15) and right prefrontal cortex (PFC) (P < 0.006, t((39)) = 3.00). In the fasted state, they showed FRS in the PFC (P < 0.004, t((39)) = 3.17), left insula (P < 0.009, t((39)) = 2.95), right insula (P < 0.005, t((39)) = 3.12), cingulate cortex (P < 0.004, t((39)) = 3.21), and thalamus (P < 0.006, t((39)) = 2.96). In the satiated state, FRS was limited to the left insula (P < 0.005, t((39)) = 3.21), right insula (P < 0.006, t((39)) = 3.04), and cingulate cortex (P < 0.005, t((39)) = 3.15). Regarding subject group, in the fasted state, FRS in the ACC was more pronounced in overweight than in normal-weight subjects (P < 0.005, F((1,38)) = 9.71), whereas in the satiated state, FRS was less pronounced in overweight than in normal-weight subjects in the ACC (P < 0.006, F((1,38)) = 9.18) and PFC (P < 0.006, F((1,38)) = 8.86), which suggests lower inhibitory control in the overweight. CONCLUSION: FRS was higher in the overweight in the satiated state; however, when sufficiently satiated, the overweight showed decreased inhibitory control signalling, which facilitates overeating. This trial was registered in the Dutch clinical trial register as NTR2174. PMID- 23364017 TI - Consumption of artificially and sugar-sweetened beverages and incident type 2 diabetes in the Etude Epidemiologique aupres des femmes de la Mutuelle Generale de l'Education Nationale-European Prospective Investigation into Cancer and Nutrition cohort. AB - BACKGROUND: It has been extensively shown, mainly in US populations, that sugar sweetened beverages (SSBs) are associated with increased risk of type 2 diabetes (T2D), but less is known about the effects of artificially sweetened beverages (ASBs). OBJECTIVE: We evaluated the association between self-reported SSB, ASB, and 100% fruit juice consumption and T2D risk over 14 y of follow-up in the French prospective Etude Epidemiologique aupres des femmes de la Mutuelle Generale de l'Education Nationale-European Prospective Investigation into Cancer and Nutrition cohort. DESIGN: A total of 66,118 women were followed from 1993, and 1369 incident cases of T2D were diagnosed during the follow-up. Cox regression models were used to estimate HRs and 95% CIs for T2D risk. RESULTS: The average consumption of sweetened beverages in consumers was 328 and 568 mL/wk for SSBs and ASBs, respectively. Compared with nonconsumers, women in the highest quartiles of SSB and ASB consumers were at increased risk of T2D with HRs (95% CIs) of 1.34 (1.05, 1.71) and 2.21 (1.56, 3.14) for women who consumed >359 and >603 mL/wk of SSBs and ASBs, respectively. Strong positive trends in T2D risk were also observed across quartiles of consumption for both types of beverage (P = 0.0088 and P < 0.0001, respectively). In sensitivity analyses, associations were partly mediated by BMI, although there was still a strong significant independent effect. No association was observed for 100% fruit juice consumption. CONCLUSIONS: Both SSB consumption and ASB consumption were associated with increased T2D risk. We cannot rule out that factors other than ASB consumption that we did not control for are responsible for the association with diabetes, and randomized trials are required to prove a causal link between ASB consumption and T2D. PMID- 23364015 TI - Does diet-beverage intake affect dietary consumption patterns? Results from the Choose Healthy Options Consciously Everyday (CHOICE) randomized clinical trial. AB - BACKGROUND: Little is understood about the effect of increased consumption of low calorie sweeteners in diet beverages on dietary patterns and energy intake. OBJECTIVE: We investigated whether energy intakes and dietary patterns were different in subjects who were randomly assigned to substitute caloric beverages with either water or diet beverages (DBs). DESIGN: Participants from the Choose Healthy Options Consciously Everyday randomized clinical trial (a 6-mo, 3-arm study) were included in the analysis [water groups: n = 106 (94% women); DB group: n = 104 (82% women)]. For energy, macronutrient, and food and beverage intakes, we investigated the main effects of time, treatment, and the treatment by-time interaction by using mixed models. RESULTS: Overall, the macronutrient composition changed in both groups without significant differences between groups over time. Both groups reduced absolute intakes of total daily energy, carbohydrates, fat, protein, saturated fat, total sugar, added sugar, and other carbohydrates. The DB group decreased energy from all beverages more than the water group did only at month 3 (P-group-by-time < 0.05). Although the water group had a greater reduction in grain intake at month 3 and a greater increase in fruit and vegetable intake at month 6 (P-group-by-time < 0.05), the DB group had a greater reduction in dessert intake than the water group did at month 6 (P group-by-time < 0.05). CONCLUSIONS: Participants in both intervention groups showed positive changes in energy intakes and dietary patterns. The DB group showed decreases in most caloric beverages and specifically reduced more desserts than the water group did. Our study does not provide evidence to suggest that a short-term consumption of DBs, compared with water, increases preferences for sweet foods and beverages. This trial was registered at clinicaltrials.gov as NCT01017783. PMID- 23364019 TI - Liking compared with wanting for high- and low-calorie foods in anorexia nervosa: aberrant food reward even after weight restoration. AB - BACKGROUND: Recent frameworks for understanding food rewards recognize the role of separable affective and motivational processes (liking and wanting) in driving human eating behavior. Separate assessments of liking and wanting may aid in understanding the complex eating-related behaviors seen in anorexia nervosa (AN). OBJECTIVE: The aim of this study was to examine separately liking and wanting for foods of different energy densities in women at different stages of AN and in healthy volunteers at both an implicit and an explicit level. DESIGN: Explicit liking and wanting responses to high- and low-calorie foods were derived from analog ratings, whereas an implicit "wanting" measure was identified by using reaction time in a forced-choice procedure. Explicit and implicit processes were compared across 3 groups of AN participants (current AN, weight-restored AN, and recovered AN) and healthy volunteers. RESULTS: Currently underweight AN participants explicitly wanted high-calorie foods less than did the other groups. Both current and weight-restored AN groups demonstrated significantly less implicit "wanting" for high-calorie foods and more implicit "wanting" for low calorie foods-an inverted pattern to never-ill participants. CONCLUSIONS: The aberrant responses to food that characterize AN may be driven more by altered motivational salience ("wanting") than by explicit liking responses. This pattern of aberrant food reward appears to be independent of weight status. Examining the processes that motivate approach or avoidance of low- and high-calorie foods in AN may aid the development of targeted strategies to augment existing interventions. PMID- 23364018 TI - Energy-containing beverages: reproductive hormones and ovarian function in the BioCycle Study. AB - BACKGROUND: Energy-containing beverages are widely consumed among premenopausal women, but their association with reproductive hormones is not well understood. OBJECTIVE: The objective was to assess the association of energy-containing beverages, added sugars, and total fructose intake with reproductive hormones among ovulatory cycles and sporadic anovulation in healthy premenopausal women. DESIGN: Women (n = 259) in the BioCycle Study were followed for up to 2 menstrual cycles; they provided fasting blood specimens during up to 8 visits/cycle and four 24-h dietary recalls/cycle. RESULTS: Women who consumed >=1 cup (1 cup = 237 mL) sweetened soda/d had 16.3% higher estradiol concentrations compared with women who consumed less sweetened soda (86.5 pg/mL compared with 74.4 pg/mL, P = 0.01) after adjustment for age, BMI, race, dietary factors, and physical activity. Similarly elevated estradiol concentrations were found for >=1 cup cola/d and noncola soda intake. Neither artificially sweetened soda nor fruit juice intake >=1 cup/d was significantly associated with reproductive hormones. Added sugar above the average US woman's intake (>=73.2 g/d) or above the 66th percentile in total fructose intake (>=41.5 g/d) was associated with significantly elevated estradiol but not consistently across all models. No associations were found between beverages, added sugars, or total fructose intake and anovulation after multivariate adjustment. CONCLUSIONS: Even at moderate consumption amounts, sweetened soda is associated with elevated follicular estradiol concentrations among premenopausal women but does not appear to affect ovulatory function. Further research into the mechanism driving the association between energy-containing beverages and reproductive hormones, and its potential implications for women's health, is warranted. PMID- 23364020 TI - Diet and diabetes revisited, yet again. PMID- 23364021 TI - Is there a dose-response relation of dietary glycemic load to risk of type 2 diabetes? Meta-analysis of prospective cohort studies. AB - BACKGROUND: Although much is known about the association between dietary glycemic load (GL) and type 2 diabetes (T2D), prospective cohort studies have not consistently shown a positive dose-response relation. OBJECTIVE: We performed a comprehensive examination of evidence on the dose response that links GL to T2D and sources of heterogeneity among all prospective cohort studies on healthy adults available in the literature. DESIGN: We conducted a systematic review of all prospective cohort studies and meta-analyses to quantify the GL-T2D relation both without and with adjustment for covariates. RESULTS: Among 24 prospective cohort studies identified by August 2012, the GL ranged from ~60 to ~280 g per daily intake of 2000 kcal (8.4 MJ). In a fully adjusted meta-analysis model, the GL was positively associated with RR of T2D of 1.45 (95% CI: 1.31, 1.61) for a 100-g increment in GL (P < 0.001; n = 24 studies; 7.5 million person-years of follow-up). Sex (P = 0.03), dietary instrument validity (P < 0.001), and ethnicity (European American compared with other; P = 0.04) together explained 97% of the heterogeneity among studies. After adjustment for heterogeneities, we used both funnel and trim-and-fill analyses to identify a negligible publication bias. Multiple influence, cumulative, and forecast analyses indicated that the GL T2D relation tended to have reached stability and to have been underestimated. The relation was apparent at all doses of GL investigated, although it was statistically significant only at >95 g GL/2000 kcal. CONCLUSION: After we accounted for several sources of heterogeneity, findings from prospective cohort studies that related the GL to T2D appear robust and consistently indicate strong and significantly lower T2D risk in persons who consume lower-GL diets. This review was registered at http://www.crd.york.ac.uk/PROSPERO as CRD42011001810. PMID- 23364022 TI - 11beta Hydroxysteroid dehydrogenase type 2 and dietary acid load are independently associated with blood pressure in healthy children and adolescents. AB - BACKGROUND: The reduced activity of 11beta hydroxysteroid dehydrogenase type 2 (11betaHSD2) contributes to elevated blood pressure (BP) in clinical syndromes, but its effect on BP in the physiologic range is unclear. OBJECTIVES: We examined the association of 11betaHSD2 activity with BP in healthy children independent of known BP-related dietary and other factors and determined whether the diet dependent acid load may constitute a dietary factor related to BP. DESIGN: We conducted a cross-sectional analysis in 267 healthy children (age range: 4-14 y) who provided a 24-h urine sample, a parallel 3-d weighed dietary record, and 1-3 BP measurements +/-1.5 y around the urine collection. The ratio of urinary free cortisone to cortisol measured by using a radioimmunoassay was used as an index for 11betaHSD2. Urinary net acid excretion and the urinary and dietary potential renal acid load (PRAL) were used to predict the diet-dependent acid load. The PRAL was calculated as the sum of major mineral nonbicarbonate anions minus the sum of mineral cations. Sex-, age- and height-independent SD scores (SDSs) of systolic and diastolic BP were used as outcomes in linear regression analyses. RESULTS: 11betaHSD2 was inversely associated with systolic BP SDSs in basic models and in analyses adjusted for body size, maternal BP, breastfeeding, and dietary intakes of total energy, salt, and fruit and vegetables (P = 0.03). In models that included indexes of dietary acid load instead of fruit and vegetables, all 3 acid-load biomarkers were significantly (P = 0.006-0.02) directly related to systolic BP. CONCLUSION: A lower 11betaHSD2 activity and higher dietary acid load may independently contribute to higher systolic BP in healthy children. PMID- 23364023 TI - Measurement of RBC agglutination with microscopic cell image analysis in a microchannel chip. AB - Since Landsteiner's discovery of ABO blood groups, RBC agglutination has been one of the most important immunohematologic techniques for ABO and RhD blood groupings. The conventional RBC agglutination grading system for RhD blood typings relies on macroscopic reading, followed by the assignment of a grade ranging from (-) to (4+) to the degree of red blood cells clumping. However, with the new scoring method introduced in this report, microscopically captured cell images of agglutinated RBCs, placed in a microchannel chip, are used for analysis. Indeed, the cell images' pixel number first allows the differentiation of agglutinated and non-agglutinated red blood cells. Finally, the ratio of agglutinated RBCs per total RBC counts (CRAT) from 90 captured images is then calculated. During the trial, it was observed that the agglutinated group's CRAT was significantly higher (3.77-0.003) than that of the normal control (0). Based on these facts, it was established that the microchannel method was more suitable for the discrimination between agglutinated RBCs and non-agglutinated RhD negative, and thus more reliable for the grading of RBCs agglutination than the conventional method. PMID- 23364024 TI - Effects of various drugs (flunixin, pentoxifylline, enoxaparin) modulating micro rheological changes in cerulein-induced acute pancreatitis in the rat. AB - Previously we have investigated the cerulein-induced acute pancreatitis and provided data on its micro-rheological impact in the rat. We hypothesized that non-steroid anti-inflammatory agent flunixin, the xanthine-derivate pentoxifylline and the low molecular weight heparin enoxaparin may have various beneficial effects improving microcirculatory and rheological parameters. In female rats, under general anesthesia, 10 MUg/kg cerulein s.c. was administered and 2 hours afterwards microcirculation was tested by laser Doppler flowmetry on the tongue and after performing laparotomy on the small intestine, liver and pancreas prior to terminal blood sampling. From blood samples hematological parameters, blood pH, lactate concentration, erythrocyte deformability, osmoscan parameters and erythrocyte aggregation were tested. Compared to normal control in acute pancreatitis group we found severe deterioration in tissue microcirculation together with impaired erythrocyte deformability and enhanced aggregation, accompanied by acidic pH and increasing lactate concentration. Improvement was found when using flunixin (s.c.), pentoxifylline (i.p.) or enoxaparin (s.c.). These drugs could partly improve the blood flux on the surface of the investigated organs, and the flunixin had the most expressed improving effects on micro-rheological parameters. Surprisingly, the improving effect of pentoxifylline on micro-rheological parameters was not obvious (red blood cell deformability did not improved better than in the other treated groups), however, microcirculatory parameters improved. PMID- 23364025 TI - Industry influence in evidence production. PMID- 23364027 TI - The association between recreational parks, facilities and childhood obesity: a cross-sectional study of the 2007 National Survey of Children's Health. AB - BACKGROUND: Despite the rising childhood obesity rates, few studies have examined the association between access to recreational parks and facilities and obesity. METHODS: A cross-sectional study was performed among 42 278 US children who participated in the 2007 National Survey of Children's Health. Access to parks and recreational facilities was self-reported by parents, and body mass index was calculated from parents' self-report of the child's height and weight. Logistic regression was used to obtain ORs and 95% CIs. Since obesity was not a rare occurrence, an OR correction method was used to provide a more reliable estimate of the prevalence ratio (PR). RESULTS: Children with access to parks and facilities had decreased prevalence of obesity as compared to children without access (PR=0.79, 95% CI 0.69 to 0.91). After adjustment for covariates, the magnitude of the association remained unchanged; however, results were no longer statistically significant (PR=0.77, 95% CI 0.55 to 1.07). Race/ethnicity was an effect modifier of the access-obesity relationship (p<0.0001). Among Non-Hispanic White children, there was no strong association (PR=0.89, 95% CI 0.64 to 1.23). However, among Non-Hispanic Black children, those who had access to recreational parks and facilities had 0.40 times the prevalence of obesity as compared to those without access, and this result was statistically significant (95% CI 0.17 to 0.90). CONCLUSIONS: This research highlights potential health disparities in childhood obesity due to limited access to recreational parks and facilities. Additional studies are needed to further investigate this association. If confirmed, providing safe, accessible parks and facilities may be one way to combat childhood obesity, particularly among minority children. PMID- 23364026 TI - Prescribing for weight loss in primary care: evidence from a population based study. AB - BACKGROUND: Taking antiobesity medication can be a cost effective way to lose weight. Uptake is determined in part by a General Practitioner's decision to prescribe weight loss medication and, in part, by patient preference. It is probable that the latter may indicate a patient's readiness to lose weight. METHODS: Analysis of cross-sectional data (from February 2003 to March 2011) from a population based prescribing database (~1.75 million people) using an adjusted Poisson regression. RESULTS: The number of antiobesity medications increased from 23.4 per 1000 population in 2004 to 30.7 per 1000 population in 2010 and was three times higher in female than in male subjects. Against this background, a marked seasonal variation in the number of antiobesity medications dispensed was evident (p<0.001), peaking in June/July with a trough in December/January (+/ 8.0% peak to trough). The seasonal component was stronger in female subjects, +/ 11.2% peak to trough, compared with +/-3.5% for male subjects. CONCLUSIONS: Obese patients, particularly women, increase their uptake of weight loss medication in the months leading up to the summer holiday period. The period prior to the summer may represent a time that health professionals could promote increased participation of obese patients in weight loss programmes. PMID- 23364028 TI - Socioeconomic development and girl child survival in rural North India: solution or problem? AB - BACKGROUND: Socioeconomic development has been considered as a solution to the problem of sex differentials at birth and under-five mortality. This paper analyses longitudinal data from the Ballabgarh Health and Demographic Surveillance System (HDSS) site in north India to check its veracity. METHODS: A cohort of children born between 1 January 2006 and 31 December 2011 at Ballabgarh HDSS were followed till death, emigration, 3 years of age or end of the study. Socioeconomic status (SES) was measured by caste, parental combined years of schooling and wealth index and divided into low, mid and high strata for each of them. Sex ratio at birth (SRB) was reported as the number of girls per 1000 boys. The Kaplan-Meier survival curves were drawn and a Cox Proportional HR of girls over boys was estimated. RESULTS: A total of 12 517 native born children (25 797 child years) were enrolled of which 710 died (death rate of 56.7/1000-live births and 27.5/1000 child-years. Socioeconomically advantaged children had significantly lower death rates. The SRB (10-16% lower) and neonatal death rate were consistently adverse for girls in the advantaged groups by all the three indicators of SES. The first month survival rates were better for girls in the lower SES categories (significant only in caste (HR 0.58; 0.37 to 0.91). High SES categories consistently showed adverse survival rates for girls (HR of 1.22 to 1.59). CONCLUSIONS: Better socioeconomic situation worsened the sex differentials, especially at birth. Therefore, specific interventions targeting gender issues are required, at least as a short-term measure. PMID- 23364030 TI - Diabetes mellitus and elevated copeptin levels in middle age predict low cognitive speed after long-term follow-up. AB - BACKGROUND/AIMS: We examined the potential impact of vascular risk factors including copeptin - a robust surrogate marker of arginine vasopressin associated with the metabolic syndrome and diabetes risk - on future cognitive abilities in a population-based cohort. METHODS: Participants (n = 933) were investigated using baseline data, including copeptin levels, and data collected 16 years later using the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT). RESULTS: Logistic regression showed that diabetes (OR, 1.86; p < 0.05) and higher copeptin levels (OR, 1.19; p < 0.05) were independently associated with an increased risk of low AQT performance. CONCLUSION: Prevalence of diabetes mellitus and elevated copeptin levels in middle age predict lower cognitive speed after long-term follow-up. PMID- 23364032 TI - [Effects of case-based small group learning about care of infected children for daycare center teachers]. AB - PURPOSE: This study was conducted to develop and implement a case-based small group learning program on the care of children with infectious disease, and to examine its effects on knowledge, attitude and preventive practice behaviors of daycare center teachers compared to a control group. METHODS: Based on the need assessment, the case-based learning program for the management of infectious children was developed. For this quasi-experimental study, 69 teachers were recruited from 14 child daycare centers in a city located in J province. Thirty four teachers were assigned to experimental group and participated in the case based small group learning once a week for 5 weeks. Data were analyzed using the SPSS 18.0 program to perform chi2-test and t-tests. Analysis of covariance was used to treat the covariate of the number of assigned children between experimental and control groups. RESULTS: The experimental group showed significantly higher posttest scores in knowledge, attitude and preventive practice behaviors than those of control group (p<.001). CONCLUSION: These findings indicate that case-based small group learning is an effective educational strategy for daycare center teachers to learn infection management through the emphasis of self-reflection and discussion. PMID- 23364031 TI - Apolipoprotein E and change in episodic memory in blacks and whites. AB - BACKGROUND: Apolipoprotein E (APOE) epsilon4 is related to faster decline in episodic memory in Whites, but the relation is unknown in Blacks. The purpose of this study was to determine whether epsilon4 has a selective effect on decline in episodic memory in Blacks. METHODS: Data are from two cohort studies with similar design. The sample consisted of 1,211 participants [28.4% Blacks, mean age = 78.6 years (SD = 7.4), education = 14.7 years (SD = 3.1)] without dementia at baseline, who underwent annual clinical evaluations for up to 6 years. Summary measures of 5 cognitive abilities were derived from 18 neuropsychological tests. RESULTS: In mixed models that controlled for age, sex, education, and race, possession of epsilon4 (present in 32.9% of Blacks and 21.0% of Whites, p < 0.001) was related to faster decline in episodic memory and 4 other cognitive abilities (all p values <0.01). In separate models that examined the interaction of race and epsilon4 on decline, there was no significant difference between Blacks and Whites in the effect of epsilon4 on decline in episodic memory, perceptual speed, or visuospatial ability. By contrast, the effect of epsilon4 differed for semantic memory and working memory. Results were similar after adjusting for vascular conditions. CONCLUSIONS: The results suggest that APOE epsilon4 is related to a faster rate of decline in episodic memory in Blacks similar to Whites. In addition, there were racial differences in the effect of epsilon4 in other cognitive abilities such that the epsilon4 allele was related to faster decline in semantic memory and working memory for Whites but not for Blacks. PMID- 23364033 TI - [Effects of passive upper arm exercise on range of motion, muscle strength, and muscle spasticity in hemiplegic patients with cerebral vascular disease]. AB - PURPOSE: The purpose of this study was to investigate the effects of passive upper arm exercise on range of motion, muscle strength, and muscle spasticity in hemiplegic patients with cerebral vascular disease. METHODS: A quasi-experimental design with nonequivalent control group was utilized. According to inclusion criteria, 25 patients were assigned to the control group with routine care, followed by 25 to the intervention group with passive exercise for 30 minutes per session, twice a day for 2 weeks. Eighteen patients in the intervention group and 17 in the control group completed the posttest measurement, including range of motion for upper arm joints, manual muscle test, and Modified Ashworth Scale for muscle spasticity. RESULTS: The intervention group had a significantly improved range of motion in the shoulder and wrist joints. No interaction effect was found for the elbow joint. No significant differences were found in muscle strength or muscle spasticity between the groups. CONCLUSION: Results of the study indicate that passive exercise safely applied for two weeks improves range of motion in joints of the upper arm in these patients. Further study with long-term follow-up is needed to verify the role of passive exercise in preventing muscle spasticity in this population. PMID- 23364035 TI - [Effects of individualized nutritional education programs on the level of nutrient intake and nutritional status of colorectal cancer patients undergoing palliative chemotherapy]. AB - PURPOSE: The purpose of this study was to examine the effects of an individualized nutritional education programs on nutrient intake and nutritional status of patients with colorectal cancer who are undergoing palliative chemotherapy. METHODS: Forty patients with colorectal cancer (19 experimental and 21 control patients) were recruited from a chemotherapy ward at S University Hospital in Seoul, Korea. The experimental group received two individualized nutritional counseling sessions and two telephone counseling sessions over 6 weeks. The control group received nutritional counseling after completion of data collection. Nutritional education included general guidelines for food intake while receiving chemotherapy, dietary guidelines for patients with colorectal cancer, daily meal schedules to overcome cancer, and dietary guideline for each chemotherapy side effect. Data were analyzed using chi2-test and t-test with the SPSS program 17.0. RESULTS: Two group comparison revealed that the experimental group had significantly improved calorie (p=.038) and total protein intake (p=.001), and serum albumin percentage change (p=.040). Body weight did not increase but remained the same as the baseline in both groups. CONCLUSION: Study results indicate that this individualized nutritional education programs are effective in enhancing nutrient intake and nutritional status of patients with colorectal cancer who are undergoing palliative chemotherapy. PMID- 23364036 TI - [Fall prediction model for community-dwelling elders based on gender]. AB - PURPOSE: This study was done to explore factors relating to number of falls among community-dwelling elders, based on gender. METHODS: Participants were 403 older community dwellers (male=206, female=197) aged 60 or above. In this study, 8 variables were identified as predictive factors that can result in an elderly person falling and as such, supports previous studies. The 8 variables were categorized as, exogenous variables; perceived health status, somatization, depression, physical performance, and cognitive state, and endogenous variables; fear of falling, ADL & IADL and frequency of falls. RESULTS: For men, ability to perform ADL & IADL (beta(32)=1.84, p<.001) accounted for 16% of the variance in the number of falls. For women, fear of falling (beta(31)=0.14, p<.05) and ability to perform ADL & IADL (beta(32)=1.01, p<.001) significantly contributed to the number of falls, accounting for 15% of the variance in the number of falls. CONCLUSION: The findings from this study confirm the gender-based fall prediction model as comprehensive in relation to community-dwelling elders. The fall prediction model can effectively contribute to future studies in developing fall prediction and intervention programs. PMID- 23364034 TI - [Effects of normal saline for maintenance of arterial lines of surgical patients]. AB - PURPOSE: The purpose of this study was to analyze the effectiveness of saline solution vs. heparinized-saline for maintenance of arterial lines and to detect changes in platelet and aPTT as physiological indexes. METHODS: In this nonequivalent control group, non-synchronized, double-blind study the effects of heparinized and saline solution on the maintenance of arterial lines were compared. Fifty five patients received the heparinized solution and fifty nine patients received the saline solution. All patients who had surgery in K university hospital between September and December 2011 were eligible for participation in the study. RESULTS: There was no statistically significant difference between the saline and the heparin group in the maintenance time of the arterial lines or the number of irrigations. There was no statistically significant difference between the groups in changes in the number of platelets and aPTT for interaction between the groups and time intervals. CONCLUSION: The results indicate that saline solution can be used as an irrigation solution for the maintenance of arterial lines of adult surgical patients, rather than heparinized-saline, in view of potential risk factors in the use of heparin. PMID- 23364037 TI - [Risk factors influencing probability and severity of elder abuse in community dwelling older adults: applying zero-inflated negative binomial modeling of abuse count data]. AB - PURPOSE: This study was conducted to identify risk factors that influence the probability and severity of elder abuse in community-dwelling older adults. METHODS: This study was a cross-sectional descriptive study. Self-report questionnaires were used to collect data from community-dwelling Koreans, 65 and older (N=416). Logistic regression, negative binomial regression and zero inflated negative binomial regression model for abuse count data were utilized to determine risk factors for elder abuse. RESULTS: The rate of older adults who experienced any one category of abuse was 32.5%. By zero-inflated negative binomial regression analysis, the experience of verbal-psychological abuse was associated with marital status and family support, while the experience of physical abuse was associated with self-esteem, perceived economic stress and family support. Family support was found to be a salient risk factor of probability of abuse in both verbal-psychological and physical abuse. Self-esteem was found to be a salient risk factor of probability and severity of abuse in physical abuse alone. CONCLUSION: The findings suggest that tailored prevention and intervention considering both types of elder abuse and target populations might be beneficial for preventative efficiency of elder abuse. PMID- 23364029 TI - Comparison of disease clusters in two elderly populations hospitalized in 2008 and 2010. AB - BACKGROUND: As chronicity represents one of the major challenges in the healthcare of aging populations, the understanding of how chronic diseases distribute and co-occur in this part of the population is needed. OBJECTIVES: The aims of this study were to evaluate and compare patterns of diseases identified with cluster analysis in two samples of hospitalized elderly. METHODS: Data were obtained from the multicenter 'Registry Politerapie SIMI (REPOSI)' that included people aged 65 or older hospitalized in internal medicine and geriatric wards in Italy during 2008 and 2010. The study sample from the first wave included 1,411 subjects enrolled in 38 hospitals wards, whereas the second wave included 1,380 subjects in 66 wards located in different regions of Italy. To analyze patterns of multimorbidity, a cluster analysis was performed including the same diseases (19 chronic conditions with a prevalence >5%) collected at hospital discharge during the two waves of the registry. RESULTS: Eight clusters of diseases were identified in the first wave of the REPOSI registry and six in the second wave. Several diseases were included in similar clusters in the two waves, such as malignancy and liver cirrhosis; anemia, gastric and intestinal diseases; diabetes and coronary heart disease; chronic obstructive pulmonary disease and prostate hypertrophy. CONCLUSION: These findings strengthened the idea of an association other than by chance of diseases in the elderly population. PMID- 23364039 TI - [Effects of a recreational combination gymnastics program for old-old women]. AB - PURPOSE: In this study a recreational combination gymnastics program was provided for women 75 years of age or older and the effects on physical fitness (grip strength, static balance, ability to do complex movement), depression, cognitive function and quality of life were examined. METHODS: A quasi-experimental study employing a nonequivalent control group, pre-post design was conducted. Participants included 53 women elders whose cognitive function was within the normal range. The women were assigned to an experimental group (27) or a control group (26). The intervention was conducted twice a week for a period of 12 weeks. Chi-square test, t-test, paired t-test, Wilcoxon rank sum test and Wilcoxon signed rank test were used for data analysis. RESULTS: Following completion of the program, left grip strength (t=2.17, p=.035), right grip strength (t=2.04, p=.046), static balance (t=-2.18, p=.030), depression (z=-2.88, p=.004), cognitive function (t=3.96, p<.001), and quality of life (t=-3.19, p=.002) were significantly better in the experimental group. CONCLUSION: Findings from this study indicate that recreational combination gymnastics programs are effective in enhancing physical fitness, cognitive function, and quality of life and in decreasing depression for female elders and could therefore be regarded as positive programs for promotion of physical and mental health for older women. PMID- 23364038 TI - [Meta-analysis of spiritual intervention studies on biological, psychological, and spiritual outcomes]. AB - PURPOSE: The purpose of this study was to evaluate the effectiveness of spiritual intervention studies by examining biological, psychological, and spiritual outcomes. METHODS: From electronic databases 2522 studies were retrieved, of which 21 studies met the inclusion criteria. These studies had 1411 participants. Two authors independently extracted data from the selected studies and assessed the methodological quality. The data were analyzed using the RevMan 5.1 program of the Cochrane library. RESULTS: Overall effect size of spiritual intervention on spiritual and psychological (depression and anxiety) outcomes were moderate (d=-0.65 to d=-0.76, p<.001). The effects on biological outcomes (pain and functional status) ranged from -0.51 to -0.39, respectively. No publication bias was detected as evaluated by a funnel plot. Spiritual intervention had a moderate effect on psychological and spiritual outcomes and a smaller effect on biological outcomes. CONCLUSION: The results of this study suggest that spiritual intervention can relieve depression and anxiety. Further randomized controlled trials studies are needed to evaluate the effects of spiritual intervention on biological outcomes. PMID- 23364040 TI - [Psychometric properties of Korean Minimal Insomnia Screening Scale]. AB - PURPOSE: The purposes of this study were to develop a Minimal Insomnia Screening Scale for Korean adults (KMISS) and to evaluate psychometric properties and discriminant ability of the developed scale. METHODS: Data from a cross-sectional survey of 959 Korean adults were analyzed to develop the summated insomnia scale, which was evaluated in terms of reliability, validity, and discriminant ability by receiver operating characteristics (ROC) curve analysis. RESULTS: Item-total correlations ranged between .71-.79 and Cronbach's alpha was .87. Adequate validity was also evident. ROC-curve analysis showed area under ROC was .87 (95% CI: .84-.90) and identified the optimal cut-off score as <= 20 (sensitivity, .83; specificity, .75; positive/negative predictive values, .40/.95). Using this cut off score, the prevalence of insomnia in the study sample was 26.3% and most frequent among women and the oldest group. CONCLUSION: Data supports the psychometric properties of KMISS as a possible insomnia screening instrument. KMISS also shows promise as a convenient ultra-short screening measure of insomnia for adults and epidemiological studies in community health care settings. PMID- 23364041 TI - [Development of a scale to measure life transition process in parents of children with autism]. AB - PURPOSE: The purpose of this research was to develop a scale to measure the life transition process of parents of children with autism, against the backdrop of a lack of research on this topic. METHODS: Seventy preliminary items were drawn from previous qualitative research, and content validity was tested by three professors as well as three parents of children with autism. A questionnaire survey was also done between August 2011 and February 2012. Data were collected from 207 parents of children with autism and analyzed using descriptive statistics, item analysis, Cronbach's alpha, Pearson correlation coefficients, and factor analysis with the SPSS Win 15.0 program. RESULTS: Twenty-nine items were selected to constitute the appropriate measuring scale and categorized into 5 factors explaining 63.2% of the total variance. The 5 factors were named; stages of denial (5 items), wandering (6 items), devotion (7 items), frustration (3 items), and finally acceptance (8 items). Cronbach's alpha for the 29 items was .80. CONCLUSION: The results of this study not only suggest assessment criteria for the life transition process of parents who have children with autism but also provide basic directions for program development to provide differentiated support and care at each stage. PMID- 23364042 TI - [Effects of compassion satisfaction and social support in the relationship between compassion fatigue and burnout in hospital nurses]. AB - PURPOSE: The purpose of this study was to identify the effects of compassion satisfaction and social support in the relationship between compassion fatigue and burnout among hospital nurses. METHODS: The participants were 430 nurses working in general hospitals. Data were collected with self-administrated questionnaires and analyzed by hierarchical multiple regression. RESULTS: (a) Compassion fatigue had a significant positive effect on burnout; (b) social support and compassion satisfaction had negative effects on burnout, and (c) social support and compassion satisfaction did not moderate the effects of compassion fatigue on burnout. CONCLUSION: These findings provide strong empirical evidence for the importance of compassion fatigue, compassion satisfaction and social support in explaining burnout of nurses. Also, it would be of great value to further define compassion fatigue and compassion satisfaction even though these concepts are not accepted in the realities of health care. PMID- 23364043 TI - [Effects of Korean proficiency and parent-child cohesion on self-esteem and acculturation among children from multicultural families]. AB - PURPOSE: There is evidence that parent-child cohesion is a potentially influential factor in children's self-esteem and acculturation. However, no research to date has examined cohesion with parents as a potential pathway between Korean proficiency and self-esteem or acculturation among children from multicultural families. This study was done to address these limitations by examining whether and to what extent cohesion with parents mediated the effect of Korean proficiency on self-esteem and acculturation among children from multicultural families. METHODS: Data were collected from a sample of 138 mothers and their children living in Seoul, Daegu, Kyungi province, and Kyungpook province. Multiple regression analysis was used to examine the relationships between the variables of interest. Mediation effects of cohesion with parents were tested by following the procedure recommended by Baron and Kenny (1986). RESULTS: Cohesion with parents partially mediated the relationship between Korean proficiency and self-esteem. For children's acculturation, the effect of Korean proficiency was partially mediated through father-child cohesion. Mother-child cohesion completely mediated the relationship between Korean proficiency and acculturation. CONCLUSION: These findings suggest that to help children from multicultural families experiencing difficulties with self-esteem or acculturation, it might be useful to develop programs that are aimed at strengthen cohesion with parents. PMID- 23364045 TI - [Effects on salivation, xerostomia and halitosis in elders after oral function improvement exercises]. AB - PURPOSE: The purpose of this study was to investigate effects of Oral Function Improvement Exercises on salivation, xerostomia and halitosis in elderly people. METHODS: The participants in the study were 48 female community-dwelling elders in D city. The Oral Function Improvement Exercises were given 3 times a week, for a total of 24 times from August to October 2011. Spitting method, Visual Analogue Scale, and halimeter (mBA-21) were used to evaluate the effects of Oral Function Improvement Exercises on salivation, xerostomia, and halitosis. The data were analyzed using chi2-test and t-test with the SPSS program. RESULTS: The experimental group had significantly better salivation, and less xerostomia and halitosis than the control group. CONCLUSION: The results indicate that Oral Function Improvement Exercises were effective for salivation, xerostomia and halitosis in the elders. Therefore, it was suggested that Oral Function Improvement Exercise are applicable in a community nursing intervention program to improve the quality of life for elders. PMID- 23364044 TI - [Evaluation and application of the Korean version of the sexuality attitudes and beliefs survey for nurses]. AB - PURPOSE: This study was conducted to evaluate the validity and reliability of the Korean version of the Sexuality Attitudes and Beliefs Survey (SABS) and to assess SABS for Korean nurses. METHODS: The Korean version of SABS was developed through forward-backward translation techniques. Internal consistency reliability and construct validity using confirmatory factor analysis were conducted using PASW+ PC Win (18.0) and AMOS (18.0). Data were collected from 567 nurses who worked in one of six general hospitals across the country. RESULTS: The Korean version of SABS showed a reliable internal consistency with Cronbach's alpha of subscales ranging from .59 to .73. Factor loadings of the 10 items of three subscales ranged from .38 to .83. The three subscales model were validated by confirmatory factor analysis (GFI>.97, RMSEA<.05). Sexuality attitudes and beliefs for Korean nurses were more negative than that of European or American nurses. The SABS scores for Korean nurses were significantly different according to age, marriage, education, clinical experiences, and feeling about sexuality. CONCLUSION: The Korean version of SABS has satisfactory construct validity and reliability to measure Korean nurses' attitudes and belief toward sexuality. Education is essential to enhance importance and self-efficacy and to relieve barriers to addressing patients' sexuality. PMID- 23364046 TI - [Posttraumatic growth of patients with breast cancer]. AB - PURPOSE: A diagnosis of breast cancer is one of the most traumatic events that threatens a woman's life, but while women adapt to and overcome these threats, they not only experience negative aspects, but also growth. The purpose of this study was to identify the many factors that affect growth, and to provide fundamental information for nursing interventions, which can help the women in their growth. METHODS: The participants in this study were 131 married women patients with breast cancer, who were on medical treatment in one of two university hospitals, in Seoul and Chungnam. Data were collected for posttraumatic growth, self-esteem, cancer coping questionnaire, marital intimacy, and body image. The data were analyzed using the SPSS 19.0 program (IBM). RESULTS: Interpersonal cancer coping, intrapersonal cancer coping (planning) and self-esteem accounted for 29.0% of posttraumatic growth. CONCLUSION: These findings indicate that in order to help the women's growth after the trauma of breast cancer, it is necessary to enhance their self-esteem, and to develop psycho-social nursing supportive programs. PMID- 23364047 TI - Statics and dynamics of electroactuation with single-charge-carrier ionomers. AB - A simple theory of electromechanical transduction for single-charge-carrier double-layer electroactuators is developed, in which the ion distribution and curvature are mutually coupled. The obtained expressions for the dependence of the curvature and charge accumulation on the applied voltage, as well as the electroactuation dynamics, are compared with literature data. The mechanical or sensor performance of such electroactuators appears to be determined by just three cumulative parameters, with all of their constituents measurable, permitting a scaling approach to their design. PMID- 23364049 TI - Hdac6 deletion delays disease progression in the SOD1G93A mouse model of ALS. AB - Defects in axonal transport are thought to contribute to the pathogenesis of neurodegenerative disease. Because alpha-tubulin acetylation facilitates axonal transport, inhibition of the alpha-tubulin deacetylating enzymes, histone deacetylase 6 (Hdac6) and silent information regulator 2 (Sirt2), is thought to be an interesting therapeutic strategy for these conditions. Amyotrophic lateral sclerosis (ALS) is a one such rapidly progressive and fatal neurodegenerative disorder, in which axonal transport defects have been found in vitro and in vivo. To establish whether the inhibition of Hdac6 or Sirt2 may be of interest for ALS treatment, we investigated whether deleting Hdac6 or Sirt2 from the superoxide dismutase 1, SOD1(G93A) mouse affects the motor neuron degeneration in this ALS model. Deletion of Hdac6 significantly extended the survival of SOD1(G93A) mice without affecting disease onset, and maintained motor axon integrity. This protective effect was associated with increased alpha-tubulin acetylation. Deletion of Sirt2 failed to affect the disease course, but also did not modify alpha-tubulin acetylation. These findings show that Hdac6, rather than Sirt2, is a therapeutic target for the treatment of ALS. Moreover, Sirt2 appears not to be a major alpha-tubulin deacetylase in the nervous system. PMID- 23364051 TI - Investigating urinary tract infections in children. PMID- 23364050 TI - Tuning the electrocatalytic hydrogen evolution reaction promoted by [Mo2O2S2] based molybdenum cycles in aqueous medium. AB - We report the syntheses and characterizations, in the solid state and in solution, of three new cyclic polyoxothiomolybdates self-assembled around 2,5 dimethylterephthalate (DMT) and 2,5-bis(trifluoromethyl)terephthalate (DFMT) ligands, namely [Mo12DMT](2-), [Mo12DFMT](2-) and [Mo16DFMT](2-). A series of these two Mo12-compounds completed by the two Mo12-compounds obtained with 2,3,5,6-tetramethylterephthalate and trimesate ligands offer the opportunity to compare their electro-catalytic properties for reduction of protons into hydrogen. The ability of these compounds to promote the reduction of protons into hydrogen in aqueous medium is evidenced and the influence of the embedded ligand is highlighted, thus allowing proposal of a mechanism for the hydrogen evolution reaction catalyzed by these clusters. PMID- 23364048 TI - The genome-defence gene Tex19.1 suppresses LINE-1 retrotransposons in the placenta and prevents intra-uterine growth retardation in mice. AB - DNA methylation plays an important role in suppressing retrotransposon activity in mammalian genomes, yet there are stages of mammalian development where global hypomethylation puts the genome at risk of retrotransposition-mediated genetic instability. Hypomethylated primordial germ cells appear to limit this risk by expressing a cohort of retrotransposon-suppressing genome-defence genes whose silencing depends on promoter DNA methylation. Here, we investigate whether similar mechanisms operate in hypomethylated trophectoderm-derived components of the mammalian placenta to couple expression of genome-defence genes to the potential for retrotransposon activity. We show that the hypomethylated state of the mouse placenta results in activation of only one of the hypomethylation sensitive germline genome-defence genes: Tex19.1. Tex19.1 appears to play an important role in placenta function as Tex19.1(-/-) mouse embryos exhibit intra uterine growth retardation and have small placentas due to a reduction in the number of spongiotrophoblast, glycogen trophoblast and sinusoidal trophoblast giant cells. Furthermore, we show that retrotransposon mRNAs are derepressed in Tex19.1(-/-) placentas and that protein encoded by the LINE-1 retrotransposon is upregulated in hypomethylated trophectoderm-derived cells that normally express Tex19.1. This study suggests that post-transcriptional genome-defence mechanisms are operating in the placenta to protect the hypomethylated cells in this tissue from retrotransposons and suggests that imbalances between retrotransposon activity and genome-defence mechanisms could contribute to placenta dysfunction and disease. PMID- 23364052 TI - Contaminated ink might be responsible for Mycobacterium chelonae infection after tattooing. PMID- 23364053 TI - The GMC, as usual, wastes our money. PMID- 23364054 TI - Lumbar puncture in adult bacterial meningitis: time to reconsider guidelines? PMID- 23364055 TI - Children could miss out on treatment with proposed linkage of data. PMID- 23364056 TI - Proposed Child Protection Information System seems to run counter to best evidence. PMID- 23364057 TI - Proposed model of early dementia screening cannot be valid. PMID- 23364058 TI - Drugs for bipolar disorder while breast feeding. PMID- 23364059 TI - Self or partnership management of bipolar disorder. PMID- 23364060 TI - Confusion is everywhere. PMID- 23364061 TI - Diagnosis of Klinefelter's syndrome is confounded by obesity. PMID- 23364062 TI - Klinefelter's syndrome does not cause delayed puberty. PMID- 23364063 TI - More temples than toilets? PMID- 23364064 TI - Bad medicine: food intolerance. PMID- 23364065 TI - "Women who smoke like men, die like men". PMID- 23364066 TI - Preoperative transfusions for patients with sickle cell disease? PMID- 23364067 TI - No evidence of cancer risk from folate supplements. PMID- 23364068 TI - Deactivating cardioverter defibrillators near the end of life. PMID- 23364069 TI - How the message from mortality figures was missed at Mid Staffs. PMID- 23364070 TI - Imagine all the people. PMID- 23364071 TI - After aid: the NHS can also learn from India and China. PMID- 23364072 TI - Measuring hospital clinical outcomes. PMID- 23364073 TI - NHS consults on new strategy to reduce carbon emissions. PMID- 23364074 TI - Local authorities must have suicide prevention plans, says parliamentary report. PMID- 23364075 TI - Health, wellbeing, and disability among older people infected or affected by HIV in Uganda and South Africa. AB - OBJECTIVE: To describe and compare the health status, emotional wellbeing, and functional status of older people in Uganda and South Africa who are HIV infected or affected by HIV in their families. METHODS: Data came from the general population cohort and Entebbe cohort of the Medical Research Council/Uganda Virus Research Institute, and from the Africa Centre Demographic Information System through cross-sectional surveys in 2009/10 using instruments adapted from the World Health Organization (WHO) Study on Global Ageing and Adult Health (SAGE). Analysis was based on 932 people aged 50 years or older (510 Uganda, 422 South Africa). RESULTS: Participants in South Africa were slightly younger (median age 60 years in South Africa, 63 in Uganda), and more were currently married, had no formal education, were not working, and were residing in a rural area. Adjusting for socio-demographic factors, older people in South Africa were significantly less likely to have good functional ability [adjusted odds ratio (aOR) 0.72, 95% CI 0.53-0.98] than those in Uganda, but were more likely to be in good subjective wellbeing (aOR 2.15, 95% CI 1.60-2.90). South Africans were more likely to be obese (aOR 5.26, 95% CI 3.46-8.00) or to be diagnosed with hypertension (aOR 2.77, 95% CI 2.06-3.73). DISCUSSION AND CONCLUSIONS: While older people's health problems are similar in the two countries, marked socio-demographic differences influence the extent to which older people are affected by poorer health. It is therefore imperative when designing policies to improve the health and wellbeing of older people in sub-Saharan Africa that the region is not treated as a homogenous entity. PMID- 23364076 TI - Hot spot detection and spatio-temporal dispersion of dengue fever in Hanoi, Vietnam. AB - INTRODUCTION: Dengue fever (DF) in Vietnam remains a serious emerging arboviral disease, which generates significant concerns among international health authorities. Incidence rates of DF have increased significantly during the last few years in many provinces and cities, especially Hanoi. The purpose of this study was to detect DF hot spots and identify the disease dynamics dispersion of DF over the period between 2004 and 2009 in Hanoi, Vietnam. METHODS: Daily data on DF cases and population data for each postcode area of Hanoi between January 1998 and December 2009 were obtained from the Hanoi Center for Preventive Health and the General Statistic Office of Vietnam. Moran's I statistic was used to assess the spatial autocorrelation of reported DF. Spatial scan statistics and logistic regression were used to identify space-time clusters and dispersion of DF. RESULTS: The study revealed a clear trend of geographic expansion of DF transmission in Hanoi through the study periods (OR 1.17, 95% CI 1.02-1.34). The spatial scan statistics showed that 6/14 (42.9%) districts in Hanoi had significant cluster patterns, which lasted 29 days and were limited to a radius of 1,000 m. The study also demonstrated that most DF cases occurred between June and November, during which the rainfall and temperatures are highest. CONCLUSIONS: There is evidence for the existence of statistically significant clusters of DF in Hanoi, and that the geographical distribution of DF has expanded over recent years. This finding provides a foundation for further investigation into the social and environmental factors responsible for changing disease patterns, and provides data to inform program planning for DF control. PMID- 23364078 TI - Convergence in fertility of South Africans and Mozambicans in rural South Africa, 1993-2009. AB - BACKGROUND: Although there are significant numbers of people displaced by war in Africa, very little is known about long-term changes in the fertility of refugees. Refugees of the Mozambican civil war (1977-1992) settled in many neighbouring countries, including South Africa. A large number of Mozambican refugees settled within the Agincourt sub-district, underpinned by a Health and Socio-demographic Surveillance Site (AHDSS), established in 1992, and have remained there. The AHDSS data provide a unique opportunity to study changes in fertility over time and the role that the fertility of self-settled refugee populations plays in the overall fertility level of the host community, a highly relevant factor in many areas of sub-Saharan Africa. OBJECTIVES: To examine the change in fertility of former Mozambican self-settled refugees over a period of 16 years and to compare the overall fertility and fertility patterns of Mozambicans to host South Africans. METHODS: Prospective data from the AHDSS on births from 1993 to 2009 were used to compare fertility trends and patterns and to examine socio-economic factors that may be associated with fertility change. RESULTS: There has been a sharp decline in fertility in the Mozambican population and convergence in fertility patterns of Mozambican and local South African women. The convergence of fertility patterns coincides with a convergence in other socio-economic factors. CONCLUSION: The fertility of Mozambicans has decreased significantly and Mozambicans are adopting the childbearing patterns of South African women. The decline in Mozambican fertility has occurred alongside socio-economic gains. There remains, however, high unemployment and endemic poverty in the area and fertility is not likely to decrease further without increased delivery of family planning to adolescents and increased education and job opportunities for women. PMID- 23364077 TI - Estimating the extent of household contact misclassification with index cases of disease in longitudinal studies using a stochastic simulation model. AB - BACKGROUND: Household contact with an index case of an infectious disease is a known risk factor for infection transmission. However, such contact may be underestimated due to the dynamic nature of households, particularly in longitudinal studies. Such studies generally begin with contact defined at a single point in time ('snap-shot'), leading to contact misclassification for some individuals who actually experienced contact before and after the snapshot. OBJECTIVE: To quantify contact misclassification with index cases of disease in households. METHODS: Historical data of 112,026 individuals from 17,889 households from an epidemiological study on leprosy in northern Malawi were used. Individuals were interviewed in the early 1980s and followed up over 5 years. It was possible to trace whether individuals died, changed household within the area, or moved out of the area between the two surveys.Using a 10% sample of households as the starting population and parameters for demographic and household changes over 5 years, the extent of contact misclassification was estimated through a simulation model of household dynamics, which traced contact with index cases in households over time. The model thereafter compared initial contact status and 'true' contact status generated from simulations. RESULTS: The starting population had 11,401 individuals, 52% female, and 224 (2%) leprosy index cases. Eleven percent of the households had at least one index case resident and 10% (1, 177) of non-case individuals were initial contacts. Sensitivity of initial contact status ranged from 0.52 to 0.74 and varied by age and sex. Sensitivity was low in those aged 20-29 and under 5 years but high in 5- to 14-year-olds. By gender, there were no differences among those aged under 5; females had lower sensitivity among those aged under 20 and higher for those above 30, respectively. Sensitivity was also low in simulations of long incubation periods. CONCLUSION: This work demonstrates the implications of changes in households on household contact-associated disease spread, particularly for long durations of follow-up and infections with long incubation periods where earlier unobserved contact is critical. PMID- 23364079 TI - Developing a new mid-level health worker: lessons from South Africa's experience with clinical associates. AB - BACKGROUND: Mid-level medical workers play an important role in health systems and hold great potential for addressing the human resource shortage, especially in low- and middle-income countries. South Africa began the production of its first mid-level medical workers - known as clinical associates - in small numbers in 2008. OBJECTIVE: We describe the way in which scopes of practice and course design were negotiated and assess progress during the early years. We derive lessons for other countries wishing to introduce new types of mid-level worker. METHODS: We conducted a rapid assessment in 2010 consisting of a review of 19 documents and 11 semi-structured interviews with a variety of stakeholders. A thematic analysis was performed. RESULTS: Central to the success of the clinical associate training programme was a clear definition and understanding of the interests of various stakeholders. Stakeholder sensitivities were taken into account in the conceptualisation of the role and scope of practice of the clinical associate. This was achieved by dealing with quality of care concerns through service-based training and doctor supervision, and using a national curriculum framework to set uniform standards. CONCLUSIONS: This new mid-level medical worker can contribute to the quality of district hospital care and address human resource shortages. However, a number of significant challenges lie ahead. To sustain and expand on early achievements, clinical associates must be produced in greater numbers and the required funding, training capacity, public sector posts, and supervision must be made available. Retaining the new cadre will depend on the public system becoming an employer of choice. Nonetheless, the South African experience yields positive lessons that could be of use to other countries contemplating similar initiatives. PMID- 23364080 TI - Compensation for environmental asbestos-related diseases in South Africa: a neglected issue. AB - BACKGROUND: Environmentally acquired asbestos-related diseases (ARDs) are of concern globally. In South Africa, there is widespread contamination of the environment due to historical asbestos mining operations that were poorly regulated. Although the law makes provision for the compensation of occupationally acquired ARDs, compensation for environmentally acquired ARDs is only available through the Asbestos Relief Trust (ART) and Kgalagadi Relief Trust, both of which are administered by the ART. This study assessed ARDs and compensation outcomes of environmental claims submitted to the Trusts. METHODS: The personal details, medical diagnoses, and exposure information of all environmental claims considered by the Trusts from their inception in 2003 to April 2010 were used to calculate the numbers and proportions of ARDs and compensation awards. RESULTS: There were 146 environmental claimants of whom 35 (23.9%) had fibrotic pleural disease, 1 (0.7%) had lung cancer, and 77 (52.7%) had malignant mesothelioma. 53 (36.3%) claimants were compensated: 20 with fibrotic pleural disease and 33 with mesothelioma. Of the 93 (63.7%) claimants who were not compensated, 33 had no ARDs, 18 had fibrotic pleural disease, 1 had lung cancer, and 44 had mesothelioma. In addition to having ARDs, those that were compensated had qualifying domestic (33; 62.2%) or neighbourhood (20; 37.8%) exposures to asbestos. Most of the claimants who were not compensated had ARDs but their exposures did not meet the Trusts' exposure criteria. CONCLUSIONS: This study demonstrates the environmental impact of asbestos mining on the burden of ARDs. Mesothelioma was the most common disease diagnosed, but most cases were not compensated. This highlights that there is little redress for individuals with environmentally acquired ARDs in South Africa. To stop this ARD epidemic, there is a need for the rehabilitation of abandoned asbestos mines and the environment. These issues may not be unique to South Africa as many countries continue to mine and use asbestos. PMID- 23364081 TI - Building consensus on key priorities for rural health care in South Africa using the Delphi technique. AB - BACKGROUND: South Africa is currently undergoing major health system restructuring in an attempt to improve health outcomes and reduce inequities in access. Such inequities exist between private and public health care and within the public health system itself. Experience shows that rural health care can be disadvantaged in policy formulation despite good intentions. The objective of this study was to identify the major challenges and priority interventions for rural health care provision in South Africa thereby contributing to pro-rural health policy dialogue. METHODS: The Delphi technique was used to develop consensus on a list of statements that was generated through interviews and literature review. A panel of rural health practitioners and other stakeholders was asked to indicate their level of agreement with these statements and to rank the top challenges in and interventions required for rural health care. RESULTS: Response rates ranged from 83% in the first round (n=44) to 64% in the final round (n=34). The top five priorities were aligned to three of the WHO health system building blocks: human resources for health (HRH), governance, and finance. Specifically, the panel identified a need to focus on recruitment and support of rural health professionals, the employment of managers with sufficient and appropriate skills, a rural-friendly national HRH plan, and equitable funding formulae. CONCLUSION: Specific policies and strategies are required to address the greatest rural health care challenges and to ensure improved access to quality health care in rural South Africa. In addition, a change in organisational climate and a concerted effort to make a career in rural health appealing to health care workers and adequate funding for rural health care provision are essential. PMID- 23364082 TI - Exploring the paradox: double burden of malnutrition in rural South Africa. AB - BACKGROUND: This article is a review of the PhD thesis by Elizabeth Kimani-Murage that explores the double burden of malnutrition in rural South Africa. This is in the context of a worryingly rapid increase in obesity and obesity-related diseases in low- and middle-income countries (LMICs) including South Africa, and in the wake of on-going nutrition transition and lifestyle changes in these countries. OBJECTIVE: To understand the profiles of malnutrition among children and adolescents in a poor, high HIV prevalent, transitional society in a middle income country. METHODS: A cross-sectional growth survey was conducted in 2007 targeting 4,000 children and adolescents aged 1-20 years. In addition, HIV testing was carried out on children aged 1-5 years and Tanner pubertal assessment among adolescents aged 9-20 years. RESULTS: The study shows stunting at an early age and adolescent obesity, particularly among girls, that co-exists in the same socio-geographic population. The study also shows that HIV is an independent modifiable risk factor for poor nutritional outcomes in children and makes a significant contribution to nutritional outcomes at the individual level. Significant predictors of undernutrition at an early age, documented at individual, household, and community levels, include child's HIV status, age and birth weight, maternal age, age of household head, and area of residence. Significant predictors of overweight/obesity and risk for metabolic disease during adolescence, documented at individual and household levels include child's age, sex, and pubertal development, household-level food security, socio-economic status, and household head's highest education level. CONCLUSIONS: The combination of early stunting and adolescent obesity raises critical concerns in the wake of the rising public health importance of metabolic diseases in LMICs. This is because, both paediatric obesity and adult short stature are risk factors for metabolic syndrome and metabolic diseases in adulthood. Clearly, policies and interventions to address malnutrition in this and other transitional societies need to be double-pronged and gender-sensitive. PMID- 23364083 TI - Relationship between household socio-economic status and under-five mortality in Rufiji DSS, Tanzania. AB - BACKGROUND: Disparities in health outcomes between the poor and the better off are increasingly attracting attention from researchers and policy makers. However, policies aimed at reducing inequity need to be based on evidence of their nature, magnitude, and determinants. OBJECTIVES: The study aims to investigate the relationship between household socio-economic status (SES) and under-five mortality, and to measure health inequality by comparing poorest/least poor quintile mortality rate ratio and the use of a mortality concentration index. It also aims to describe the risk factors associated with under-five mortality at Rufiji Demographic Surveillance Site (RDSS), Tanzania. METHODS: This analytical cross sectional study included 11,189 children under-five residing in 7,298 households in RDSS in 2005. Principal component analysis was used to construct household SES. Kaplan-Meier survival incidence estimates were used for mortality rates. Health inequality was measured by calculating and comparing mortality rates between the poorest and least poor wealth quintile. We also computed a mortality concentration index. Risk factors of child mortality were assessed using Poisson regression taking into account potential confounders. RESULTS: Under-five mortality was 26.9 per 1,000 person-years [95% confidence interval (CI) (23.7-30.4)]. The poorest were 2.4 times more likely to die compared to the least poor. Our mortality concentration index [-0.16; 95% CI ( 0.24, -0.08)] indicated considerable health inequality. Least poor households had a 52% reduced mortality risk [incidence rate ratio (IRR) = 0.48; 95% CI 0.30 0.80]. Furthermore, children with mothers who had attained secondary education had a 70% reduced risk of dying compared to mothers with no education [IRR = 0.30; 95% CI (0.22-0.88)]. CONCLUSION: Household socio-economic inequality and maternal education were associated with under-five mortality in the RDSS. Targeted interventions to address these factors may contribute towards accelerating the reduction of child mortality in rural Tanzania. PMID- 23364084 TI - Alcohol use in early and late adolescence among the birth to twenty cohort in Soweto, South Africa. AB - BACKGROUND: Alcohol is a risk factor for the leading causes of mortality and morbidity among young people Globally. Youth drinking, initiated in early adolescence and continued into early adulthood, is influenced by maternal socio demographic factors and maternal education. Limited prospective data exists in South Africa on the prevalence of alcohol use during adolescence and adolescent and maternal socio-demographic correlates. OBJECTIVE: To examine the prevalence of lifetime alcohol use during early (13 years) and late (18 years) adolescence in Soweto, South Africa, and its association with child and maternal socio demographic factors. METHODS: Data on alcohol use in early adolescence (age 13 years) and late adolescence (age 18 years) were collected using self-completed pen and paper and self-completed computer-based questionnaires, respectively. Univariate analyses were conducted on child (gender and number of school years repeated by grade 7), maternal socio-demographic correlates (education, marital status, and age), and household socioeconomic status (SES). Bivariate logistic regression analyses examined associations between alcohol use and all child and maternal socio-demographic factors. Multivariate logistic regression analyses were conducted on all the variables found to be significantly (pB0.10) associated with alcohol use to examine the predictive value on alcohol use at early and late adolescence. RESULTS: Lifetime alcohol use increased from 22% at early adolescence to 66% at late adolescence. In multivariate analyses, gender, maternal education, and SES predicted lifetime alcohol use at early adolescence, while gender, maternal education, marital status, and SES were predictive of the same at late adolescence. CONCLUSION: This study aids researchers and practitioners to identify maternal and child socio-demographic risk profiles for alcohol use to inform policies and programmes. PMID- 23364085 TI - Policy implementation and financial incentives for nurses in South Africa: a case study on the occupation-specific dispensation. AB - BACKGROUND: In 2007, the South African government introduced the occupation specific dispensation (OSD), a financial incentive strategy, to attract, motivate, and retain health professionals in the public sector. Implementation commenced with the nursing sector, but there have been unintended negative consequences. OBJECTIVE: First, to examine implementation of the OSD for nurses using Hogwood and Gunn's framework that outlines 'perfect implementation' pre conditions. Second, to highlight the conditions for the successful implementation of financial incentives. METHODS: A qualitative case study design using a combination of a document review and in-depth interviews with 42 key informants. RESULTS: The study found that there were several implementation weaknesses. Only a few of the pre-conditions were met for OSD policy implementation. The information systems required for successful policy implementation, such as the public sector human resource data base and the South African Nursing Council register of specialised nurses were incomplete and inaccurate, thus undermining the process. Insufficient attention was paid to time and resources, dependency relationships, task specification, and communication and coordination. CONCLUSION: The implementation of financial incentives requires careful planning and management in order to avoid loss of morale and staff grievances. PMID- 23364086 TI - A rapid assessment of a community health worker pilot programme to improve the management of hypertension and diabetes in Emfuleni sub-district of Gauteng Province, South Africa. AB - BACKGROUND: Non-communicable diseases (NCD) and infectious chronic illnesses are recognised as significant contributing factors to the burden of disease globally, specifically in South Africa, yet clinical management is often poor. The involvement of community health workers (CHWs) in TB and HIV care in South Africa, and other low- and middle-income settings, suggests that they could make an important contribution in the management of NCDs. OBJECTIVES: Using a rapid assessment, this study examines the outcomes of a pilot CHW programme to improve the management of hypertension and diabetes in Gauteng province, South Africa. METHODS: A record review compared outcomes of patients receiving home visits (n56) with a control group (n168) attending the clinic, matched, as far as possible, on age, gender, and condition. Focus group discussions and semi structured interviews with CHWs, patients, district, clinic, and NGO staff were used to obtain descriptions of the functioning of the programme and patient experiences. RESULTS: Despite the greater age and co-morbidity among those in the pilot programme, the findings suggest that control of hypertension was improved by CHW home visits in comparison to usual clinic care. However, too few doctor visits, insufficient monitoring of patient outcomes by clinic staff, and a poor procurement process for supplies required by the CHWs hampered the programme's activities. CONCLUSION: The role of CHWs in the management of hypertension should be given greater consideration, with larger studies being conducted to provide more robust evidence. Adequate training, supervision, and operational support will be required to ensure success of any CHW programme. PMID- 23364087 TI - Self-reported health and health care use in an ageing population in the Agincourt sub-district of rural South Africa. AB - BACKGROUND: South Africa is experiencing a demographic and epidemiological transition with an increase in population aged 50 years and older and rising prevalence of non-communicable diseases. This, coupled with high HIV and tuberculosis prevalence, puts an already weak health service under greater strain. OBJECTIVE: To measure self-reported chronic health conditions and chronic disease risk factors, including smoking and alcohol use, and to establish their association with health care use in a rural South African population aged 50 years or older. METHODS: The Study on Global Ageing and Adult Health (SAGE), in collaboration with the INDEPTH Network and the World Health Organization, was implemented in the Agincourt sub-district in rural northeast South Africa where there is a long-standing health and socio-demographic surveillance system. Household-based interviews were conducted in a random sample of people aged 50 years and older. The interview included questions on self-reported health and health care use, and some physical measurements, including blood pressure and anthropometry. RESULTS: Four hundred and twenty-five individuals aged 50 years or older participated in the study. Musculoskeletal pain was the most prevalent self reported condition (41.7%; 95% Confidence Interval [CI] 37.0-46.6) followed by hypertension (31.2%; 95% CI 26.8-35.9) and diabetes (6.1%; 95% CI 4.1-8.9). All self-reported conditions were significantly associated with low self-reported functionality and quality of life, 57% of participants had hypertension, including 44% of those who reported normal blood pressure. A large waist circumference and current alcohol consumption were associated with high risk of hypertension in men, whereas in women, old age, high waist-hip ratio, and less than 6 years of formal education were associated with high risk of hypertension. Only 45% of all participants reported accessing health care in the last 12 months. Those who reported higher use of the health facilities also reported lower levels of functioning and quality of life. CONCLUSIONS: Self-reported chronic health conditions, especially hypertension, had a high prevalence in this population and were strongly associated with higher levels of health care use. The primary health care system in South Africa will need to provide care for people with non-communicable diseases. PMID- 23364088 TI - "Even if I were to consent, my family will never agree": exploring autopsy services for posthumous occupational lung disease compensation among mineworkers in South Africa. AB - CONTEXT: In the South African mining sector, cardiorespiratory-specific autopsies are conducted under the Occupational Diseases in Mines and Works Act (ODMWA) on deceased mineworkers to determine eligibility for compensation. However, low levels of autopsy utilisation undermine the value of the service. OBJECTIVE: To explore enablers and barriers to consent that impact on ODMWA autopsy utilisation for posthumous monetary compensation. METHODS: In-depth interviews were conducted with mineworkers, widows and relatives of deceased mineworkers as well as traditional healers and mine occupational health practitioners. RESULTS: A range of socio-cultural barriers to consent for an autopsy was identified. These barriers were largely related to gendered power relations, traditional and religious beliefs, and communication and trust. Understanding these barriers presents opportunities to intervene so as to increase autopsy utilisation. CONCLUSIONS: Effective interventions could include engagement with healthy mine workers and their families and re-evaluating the permanent removal of organs. The study adds to our understanding of utilisation of the autopsy services. PMID- 23364089 TI - The non-fatal disease burden caused by type 2 diabetes in South Africa, 2009. AB - BACKGROUND: Increasing urbanisation and rising unhealthy lifestyle risk factors are contributing to a growing diabetes epidemic in South Africa. In 2000, a study estimated diabetes prevalence to be 5.5% in those aged over 30. Accurate, up-to date information on the epidemiology and burden of disease due to diabetes and its sequelae is essential in the planning of health services for diabetes management. OBJECTIVE: To calculate the non-fatal burden of disease in Years Lost due to Disability (YLD) due to diabetes and selected sequelae in South Africa in 2009. YLD measures the equivalent loss of life due to ill-health. METHODS: A series of systematic literature reviews identified data on the epidemiology of diabetes and its sequelae in South Africa. The data identified were then applied to Global Burden of Disease (GBD) methodology to calculate the burden attributable to diabetes. RESULTS: Prevalence of type 2 diabetes in South Africa in 2009 is estimated at 9.0% in people aged 30 and older, representing approximately 2 million cases of diabetes. We modelled 8,000 new cases of blindness and 2,000 new amputations annually caused by diabetes. There are 78,900 YLD attributed to diabetes, with 64% coming from diabetes alone, 24% from retinopathy, 6% from amputations, 9% from attributable stroke disability, and 7% from attributable ischemic heart disease disability. CONCLUSIONS: We estimate that the prevalence of diabetes is increasing in South Africa. Significant disability associated with diabetes is demonstrated. Some of the attributed burden can be prevented through early detection and treatment. PMID- 23364090 TI - Comparing the job satisfaction and intention to leave of different categories of health workers in Tanzania, Malawi, and South Africa. AB - BACKGROUND: Job satisfaction is an important determinant of health worker motivation, retention, and performance, all of which are critical to improving the functioning of health systems in low- and middle-income countries. A number of small-scale surveys have measured the job satisfaction and intention to leave of individual health worker cadres in different settings, but there are few multi country and multi-cadre comparative studies. OBJECTIVE: The objective of this study was to compare the job satisfaction and intention to leave of different categories of health workers in Tanzania, Malawi, and South Africa. METHODS: We undertook a cross-sectional survey of a stratified cluster sample of 2,220 health workers, 564 from Tanzania, 939 from Malawi, and 717 from South Africa. Participants completed a self-administered questionnaire, which included demographic information, a 10-item job satisfaction scale, and one question on intention to leave. Multiple regression was used to identify significant predictors of job satisfaction and intention to leave. RESULTS: There were statistically significant differences in job satisfaction and intention to leave between the three countries. Approximately 52.1% of health workers in South Africa were satisfied with their jobs compared to 71% from Malawi and 82.6% from Tanzania (chi2=140.3, p<0.001). 18.8% of health workers in Tanzania and 26.5% in Malawi indicated that they were actively seeking employment elsewhere, compared to 41.4% in South Africa (chi2=83.5, p<0.001). The country differences were confirmed by multiple regression. The study also confirmed that job satisfaction is statistically related to intention to leave. CONCLUSIONS: We have shown differences in the levels of job satisfaction and intention to leave between different groups of health workers from Tanzania, Malawi, and South Africa. Our results caution against generalising about the effectiveness of interventions in different contexts and highlight the need for less standardised and more targeted HRH strategies than has been practised to date. PMID- 23364091 TI - Analysing post-apartheid gender and racial transformation in medical education in a South African province. AB - INTRODUCTION: In light of global concerns about insufficient numbers of doctors, midwives, and nurses, the World Health Organization (WHO) has identified the scale-up of the production of medical professionals who are competent and responsive to community needs as urgent and necessary. Coincident with this imperative, South African medical schools have also had to consider redressing apartheid-era inequities in access to medical education and changing the racial and gender profile of medical graduates to be representative of the population. In this article, we explore progress and challenges with regard to transformation, defined as intentional and planned changes aimed at addressing historical disadvantages, in the Gauteng Province of South Africa. METHODS: A cross-sectional, descriptive analysis was conducted using data on medical school admissions and graduations from the Health and Education Departments for the period 1999-2011. Admission and graduation statistics of 1999, 2005, 2008, and 2011 were analysed according to race and gender. RESULTS: The results show that there has been progress in transforming the race and gender composition of medical students and graduates, in line with the transformation strategies of the South African government. In 1999, black African enrolments and graduates were conspicuously low in two of the three medical schools in the Gauteng province. By 2011, an almost six-fold increase in black African student enrolments was seen in one medical school that was previously designated as a white institution. In contrast, at the historically black medical school, whites only represented 0.40% of enrolments in 1999 and 7.4% in 2011. Since 1999, the number and proportion of female medical enrolments and graduates has also increased substantially. CONCLUSION: While there has been progress with redressing historical disparities and inequities in terms of race and gender, further efforts are needed to ensure that student intakes and graduations are in line with the South African population profile. PMID- 23364092 TI - Administrative integration of vertical HIV monitoring and evaluation into health systems: a case study from South Africa. AB - BACKGROUND: In light of an increasing global focus on health system strengthening and integration of vertical programmes within health systems, methods and tools are required to examine whether general health service managers exercise administrative authority over vertical programmes. OBJECTIVE: To measure the extent to which general health service (horizontal) managers, exercise authority over the HIV programme's monitoring and evaluation (M&E) function, and to explore factors that may influence this exercise of authority. METHODS: This cross sectional survey involved interviews with 51 managers. We drew ideas from the concept of 'exercised decision-space' - traditionally used to measure local level managers' exercise of authority over health system functions following decentralisation. Our main outcome measure was the degree of exercised authority classified as 'low', 'medium' or 'high' - over four M&E domains (HIV data collection, collation, analysis, and use). We applied ordinal logistic regression to assess whether actor type (horizontal or vertical) was predictive of a higher degree of exercised authority, independent of management capacity (training and experience), and M&E knowledge. RESULTS: Relative to vertical managers, horizontal managers had lower HIV M&E knowledge, were more likely to exercise a higher degree of authority over HIV data collation (OR 7.26; CI: 1.9, 27.4), and less likely to do so over HIV data use (OR 0.19; CI: 0.05, 0.84). A higher HIV M&E knowledge score was predictive of a higher exercised authority over HIV data use (OR 1.22; CI: 0.99, 1.49). There was no association between management capacity and degree of authority. CONCLUSIONS: This study demonstrates a HIV M&E model that is neither fully vertical nor integrated. The HIV M&E is characterised by horizontal managers producing HIV information while vertical managers use it. This may undermine policies to strengthen integrated health system planning and management under the leadership of horizontal managers. PMID- 23364093 TI - Moving towards universal coverage in South Africa? Lessons from a voluntary government insurance scheme. AB - BACKGROUND: In 2005, the South African government introduced a voluntary, subsidised health insurance scheme for civil servants. In light of the global emphasis on universal coverage, empirical evidence is needed to understand the relationship between new health financing strategies and health care access thereby improving global understanding of these issues. OBJECTIVES: This study analysed coverage of the South African government health insurance scheme, the population groups with low uptake, and the individual-level factors, as well as characteristics of the scheme, that influenced enrolment. METHODS: Multi-stage random sampling was used to select 1,329 civil servants from the health and education sectors in four of South Africa's nine provinces. They were interviewed to determine factors associated with enrolment in the scheme. The analysis included both descriptive statistics and multivariate logistic regression. RESULTS: Notwithstanding the availability of a non-contributory option within the insurance scheme and access to privately-provided primary care, a considerable portion of socio-economically vulnerable groups remained uninsured (57.7% of the lowest salary category). Non-insurance was highest among men, black African or coloured ethnic groups, less educated and lower-income employees, and those living in informal-housing. The relatively poor uptake of the contributory and non-contributory insurance options was mostly attributed to insufficient information, perceived administrative challenges of taking up membership, and payment costs. CONCLUSION: Barriers to enrolment include insufficient information, unaffordability of payments and perceived administrative complexity. Achieving universal coverage requires good physical access to service providers and appropriate benefit options within pre-payment health financing mechanisms. PMID- 23364094 TI - Modelling determinants, impact, and space-time risk of age-specific mortality in rural South Africa: integrating methods to enhance policy relevance. AB - BACKGROUND: There is a lack of reliable data in developing countries to inform policy and optimise resource allocation. Health and socio-demographic surveillance sites (HDSS) have the potential to address this gap. Mortality levels and trends have previously been documented in rural South Africa. However, complex space-time clustering of mortality, determinants, and their impact has not been fully examined. OBJECTIVES: To integrate advanced methods enhance the understanding of the dynamics of mortality in space-time, to identify mortality risk factors and population attributable impact, to relate disparities in risk factor distributions to spatial mortality risk, and thus, to improve policy planning and resource allocation. METHODS: Agincourt HDSS supplied data for the period 1992-2008. Advanced spatial techniques were used to identify significant age-specific mortality 'hotspots' in space-time. Multivariable Bayesian models were used to assess the effects of the most significant covariates on mortality. Disparities in risk factor profiles in identified hotspots were assessed. RESULTS: Increasing HIV-related mortality and a subsequent decrease possibly attributable to antiretroviral therapy introduction are evident in this rural population. Distinct space-time clustering and variation (even in a small geographic area) of mortality were observed. Several known and novel risk factors were identified, and population impact was quantified. Significant differences in the risk factor profiles of the identified 'hotspots' included ethnicity; maternal, partner, and household deaths; household head demographics; migrancy; education; and poverty. CONCLUSIONS: A complex interaction of highly attributable multilevel factors continues to demonstrate differential space-time influences on mortality risk (especially for HIV). High-risk households and villages displayed differential risk factor profiles. This integrated approach could prove valuable to decision makers. Tailored interventions for specific child and adult high-risk mortality areas are needed, such as preventing vertical transmission, ensuring maternal survival, and improving water and sanitation infrastructure. This framework can be applied in other settings within the region. PMID- 23364095 TI - The contribution of spatial analysis to understanding HIV/TB mortality in children: a structural equation modelling approach. AB - BACKGROUND: South Africa accounts for more than a sixth of the global population of people infected with HIV and TB, ranking her highest in HIV/TB co-infection worldwide. Remote areas often bear the greatest burden of morbidity and mortality, yet there are spatial differences within rural settings. OBJECTIVES: The primary aim was to investigate HIV/TB mortality determinants and their spatial distribution in the rural Agincourt sub-district for children aged 1-5 years in 2004. Our secondary aim was to model how the associated factors were interrelated as either underlying or proximate factors of child mortality using pathway analysis based on a Mosley-Chen conceptual framework. METHODS: We conducted a secondary data analysis based on cross-sectional data collected in 2004 from the Agincourt sub-district in rural northeast South Africa. Child HIV/TB death was the outcome measure derived from physician assessed verbal autopsy. Modelling used multiple logit regression models with and without spatial household random effects. Structural equation models were used in modelling the complex relationships between multiple exposures and the outcome (child HIV/TB mortality) as relayed on a conceptual framework. RESULTS: Fifty-four of 6,692 children aged 1-5 years died of HIV/TB, from a total of 5,084 households. Maternal death had the greatest effect on child HIV/TB mortality (adjusted odds ratio=4.00; 95% confidence interval=1.01-15.80). A protective effect was found in households with better socio-economic status and when the child was older. Spatial models disclosed that the areas which experienced the greatest child HIV/TB mortality were those without any health facility. CONCLUSION: Low socio economic status and maternal deaths impacted indirectly and directly on child mortality, respectively. These factors are major concerns locally and should be used in formulating interventions to reduce child mortality. Spatial prediction maps can guide policy makers to target interventions where they are most needed. PMID- 23364096 TI - A South African university-practitioner partnership to strengthen capacity in social and behaviour change communication. AB - Globally, communication plays an integral role in public health strategies, from infectious diseases to diseases related to lifestyles. The evolution of the field of social and behaviour change communication (SBCC), combined with the need for evidence based practice and multi-level interventions to promote health, and human resource gaps in sub-Saharan Africa have led to the imperative to standardise and formalise the field. Moreover, current practitioners come from different disciplinary backgrounds underlining the need to define common core skills and competencies. This paper describes the partnership between the Wits School of Public Health and the Soul City Institute for Health and Development Communication and how the partners responded to this need. It highlights the factors influencing sustainable institutional capacity to provide quality assured, accredited training. We describe an unexpected positive response from a number of practitioner organisations that have chosen to send multiple staff members for training, specifically to build a critical mass within their organisations. Finally, we note the interest from (mostly) southern-based academic institutions in setting up similar programmes and postulate that south south collaborations can contribute to building sustainable context specific and evidence-informed SBCC programmes in the global south. PMID- 23364097 TI - Occupational respiratory diseases in the South African mining industry. AB - BACKGROUND: Crystalline silica and asbestos are common minerals that occur throughout South Africa, exposure to either causes respiratory disease. Most studies on silicosis in South Africa have been cross-sectional and long-term trends have not been reported. Although much research has been conducted on the health effects of silica dust and asbestos fibre in the gold-mining and asbestos mining sectors, little is known about their health effects in other mining sectors. OBJECTIVE: The aims of this thesis were to describe silicosis trends in gold miners over three decades, and to explore the potential for diamond mine workers to develop asbestos-related diseases and platinum mine workers to develop silicosis. METHODS: Mine workers for the three sub-studies were identified from a mine worker autopsy database at the National Institute for Occupational Health. RESULTS: From 1975 to 2007, the proportions of white and black gold mine workers with silicosis increased from 18 to 22% and from 3 to 32% respectively. Cases of diamond and platinum mine workers with asbestos-related diseases and silicosis, respectively, were also identified. CONCLUSION: The trends in silicosis in gold miners at autopsy clearly demonstrate the failure of the gold mines to adequately control dust and prevent occupational respiratory disease. The two case series of diamond and platinum mine workers contribute to the evidence for the risk of asbestos-related diseases in diamond mine workers and silicosis in platinum mine workers, respectively. The absence of reliable environmental dust measurements and incomplete work history records impedes occupational health research in South Africa because it is difficult to identify and/or validate sources of dust exposure that may be associated with occupational respiratory disease. PMID- 23364098 TI - Predictors of loss to follow-up among children in the first and second years of antiretroviral treatment in Johannesburg, South Africa. AB - BACKGROUND: Ninety percent of the world's 2.1 million HIV-infected children live in sub-Saharan Africa, and 2.5% of South African children live with HIV. As HIV care and treatment programmes are scaled-up, a rise in loss to follow-up (LTFU) has been observed. OBJECTIVE: The aim of the study was to determine the rate of LTFU in children receiving antiretroviral treatment (ART) and to identify baseline characteristics associated with LTFU in the first year of treatment. We also explored the effect of patient characteristics at 12 months treatment on LTFU in the second year. METHODS: The study is an analysis of prospectively collected routine data of HIV-infected children at the Harriet Shezi Children's Clinic (HSCC) in Soweto, Johannesburg. Cox proportional hazards models were fitted to investigate associations between baseline characteristics and 12-month characteristics with LTFU in the first and second year on ART, respectively. RESULTS: The cumulative probability of LTFU at 12 months was 7.3% (95% CI 7.1 8.8). In the first 12 months on ART, independent predictors of LTFU were age <1 year at initiation, recent year of ART start, mother as a primary caregiver, and being underweight (WAZ <= -2). Among children still on treatment at 1 year from ART initiation, characteristics that predicted LTFU within the second year were recent year of ART start, mother as a primary caregiver, being underweight (WAZ <= -2), and low CD4 cell percentage. CONCLUSIONS: There are similarities between the known predictors of death and the predictors of LTFU in the first and second years of ART. Knowing the vital status of children is important to determine LTFU. Although HIV-positive children cared for by their mothers appear to be at greater risk of becoming LTFU, further research is needed to explore the challenges faced by mothers and other caregivers and their impact on long-term HIV care. There is also a need to investigate the effects of differential access to ART between mothers and children and its impact on ART outcomes in children. PMID- 23364099 TI - Alcohol consumption and household expenditure on alcohol in a rural district in Vietnam. AB - INTRODUCTION: Alcohol use and alcohol-related problems are on the rise in low- and middle-income countries. Expenditure on alcohol is an important problem for families and communities and needs to be assessed. AIM: This study examines level of alcohol consumption and expenditure on alcohol in a district in Vietnam. METHODS: A cross-sectional survey was conducted in a rural district in northern Vietnam. Multi-stage sampling was employed to randomly select participants from 20 communities and a town in the same district. One thousand five hundred and sixty-four adults (765 males and 799 females) aged 18-60 years were interviewed. Information about alcohol use as well as expenditure on alcohol consumption four weeks prior to the interview was gathered. Non-parametric tests and log-linear regression were employed to compare expenditure on alcohol consumption across socioeconomic groups. RESULTS: The prevalence of alcohol use one month prior to interview was 35% (66% among men and 5% among women). The median alcohol consumption among those who reported use of alcohol in the week prior to the interview was 7.9 standard drinks. Excessive drinking (more than 14 standard drinks per week for men and more than seven standard drinks per week for women) occurred among 35% of those who used alcohol. Median expenditure for alcohol consumption during one month by those who drank alcohol was USD 3.5, accounting for 4.6% of household food expenditure, 2.7% of total household expenditure, and 1.8% of household income. The differences in alcohol consumption and expenditure between sexes and between socioeconomic groups are also presented. CONCLUSION: Our study confirms that alcohol consumption and alcohol-related problems are common among men in Vietnam. The share of alcohol expenditure in total household expenditure is substantial, especially among poor households. This should be considered an important public health issue, which needs to be taken into account in the alcohol policy debate. PMID- 23364100 TI - Urban-rural and gender differences in tobacco and alcohol use, diet and physical activity among young black South Africans between 1998 and 2003. AB - BACKGROUND: Non-communicable chronic diseases (NCDs) have increased in South Africa over the past 15 years. While these usually manifest during mid-to-late adulthood, the development of modifiable risk factors that contribute to NCDs are usually adopted early in life. OBJECTIVE: To describe the urban-rural and gender patterns of NCD risk factors in black adolescents and young adults (15- to 24 year-olds) from two South African Demographic and Health Surveys conducted 5 years apart. DESIGN: An observational study based on interviews and measurements from two cross-sectional national household surveys. Changes in tobacco and alcohol use, dietary intake, physical inactivity, and overweight/ obesity among 15- to 24-year-olds as well as urban-rural and gender differences were analysed using logistic regression. The 'Surveyset' option in Stata statistical software was used to allow for the sampling weight in the analysis. RESULTS: Data from 3,186 and 2,066 black 15- to 24-year-old participants in 1998 and 2003, respectively, were analysed. In males, the prevalence of smoking (1998: 21.6%, 2003: 19.1%) and problem drinking (1998: 17.2%, 2003: 15.2%) were high and increased with age, but in females were much lower (smoking - 1998: 1.0%, 2003: 2.1%; problem drinking - 1998: 4.2%, 2003: 5.8%). The predominant risk factors in females were overweight/obesity (1998: 29.9%, 2003: 31.1%) and physical inactivity (2003: 46%). Urban youth, compared to their rural counterparts, were more likely to smoke (odds ratio (OR): 1.39, 95% confidence interval (CI): 1.09 1.75), have high salt intake (OR: 1.75, 95% CI: 1.12-2.78), be overweight/obese (OR: 1.39, 95% CI: 1.14-1.69), or be physically inactive (OR: 1.45, 95% CI: 1.12 1.89). However, they had lower odds of inadequate micronutrient intake (OR: 0.46, 95% CI 0.34-0.62), and there was no overall significant urban- rural difference in the odds for problem drinking but among females the odds were higher in urban compared to rural females. CONCLUSION: Considering that the prevalence of modifiable NCD risk factors was high in this population, and that these may persist into adulthood, innovative measures are required to prevent the uptake of unhealthy behaviours, and regular surveillance is needed. PMID- 23364101 TI - Outreach services to improve access to health care in South Africa: lessons from three community health worker programmes. AB - INTRODUCTION: In South Africa, there are renewed efforts to strengthen primary health care and community health worker (CHW) programmes. This article examines three South African CHW programmes, a small local non-governmental organisation (NGO), a local satellite of a national NGO, and a government-initiated service, that provide a range of services from home-based care, childcare, and health promotion to assist clients in overcoming poverty-related barriers to health care. METHODS: The comparative case studies, located in Eastern Cape and Gauteng, were investigated using qualitative methods. Thematic analysis was used to identify factors that constrain and enable outreach services to improve access to care. RESULTS: The local satellite (of a national NGO), successful in addressing multi-dimensional barriers to care, provided CHWs with continuous training focused on the social determinants of ill-health, regular context-related supervision, and resources such as travel and cell-phone allowances. These workers engaged with, and linked their clients to, agencies in a wide range of sectors. Relationships with participatory structures at community level stimulated coordinated responses from service providers. In contrast, an absence of these elements curtailed the ability of CHWs in the small NGO and government initiated service to provide effective outreach services or to improve access to care. CONCLUSION: Significant investment in resources, training, and support can enable CHWs to address barriers to care by negotiating with poorly functioning government services and community participation structures. PMID- 23364102 TI - Longitudinal measurements of oxygen consumption in growing infants during the first weeks after birth: old data revisited. AB - BACKGROUND: In a study conducted in 1966-1969, longitudinal measurements were made of the metabolic rate in growing infants. Statistical methods for analyzing longitudinal data weren't readily accessible at that time. OBJECTIVES: To measure minimal rates of oxygen consumption (V.O2, ml/min) in growing infants during the first postnatal weeks and to determine the relationships between postnatal increases in V.O2, body size and postnatal age. METHODS: We studied 61 infants of any birth weight or gestational age, including 19 of very low birth weight. The infants, nursed in incubators, were clinically well and without need of oxygen supplementation or respiratory assistance. Serial measures of V.O2 using a closed circuit method were obtained at approximately weekly intervals. V.O2 was measured under thermoneutral conditions with the infant asleep or resting quietly. Data were analyzed using mixed-effects models. RESULTS: During early postnatal growth, V.O2 rises as surface area (m(2))(1.94) (standard error, SE 0.054) or body weight (kg)(1.24) (SE 0.033). Multivariate analyses show statistically significant effects of both size and age. Reference intervals (RIs) for V.O2 for fixed values of body weight and postnatal age are presented. As V.O2 rises with increasing size and age, there is an increase in the skin-operative environmental temperature gradient (T skin-op) required for heat loss. Required T skin-op can be predicted from surface area and heat loss (heat production minus heat storage). CONCLUSIONS: Generation of RIs for minimal rates of V.O2 in growing infants from the 1960s was enabled by application of mixed-effects statistical models for analyses of longitudinal data. Results apply to the precaffeine era of neonatal care. PMID- 23364103 TI - Profiling the medical admissions of the homeless. AB - AIM: to describe the characteristics and outcomes of homeless people admitted to our Internal Medicine service in St. James's Hospital, Dublin (Ireland), between 2002 and 2011. METHODS: we interrogated an anonymized in-patient database. RESULTS: there were 1,460 homeless admissions (623 unique patients; 39% admitted more than once). Most patients were young, male, and had low comorbidity levels. Thirty-seven percent of the admissions were alcohol-related and 27% substance abuse-related. Thirteen percent had an active psychiatric illness. Their in patient mortality rate was 5%. Seventy-two percent were discharged without the residential arrangement being explicitly documented, 15% self-discharged or absconded, and 8% were discharged to a residential facility. CONCLUSION: results are novel in our context and will be relevant for local policy and practice. PMID- 23364104 TI - Shared experiences of consultant delivered care - a toolkit for those responsible for configuring consultant delivered care in Acute Medicine. AB - BACKGROUND: NHS London released commissioning standards for Adult emergency services in September 2011. The Pan- London Acute Medicine Network (PLAN) agreed to survey its members regarding these standards. METHOD: A web-based survey asked PLAN members to comment on the standards which were most relevant to Consultant delivered care in Acute Medicine. The self-reported rate of compliance with each standard was calculated. The free text comments were grouped by thematic analysis. RESULTS: 23 responses were received. The compliance with each standard was variable between 9% and 91%. DISCUSSION: A series of themes are discussed and presented as tips to be considered by those responsible for providing Consultant delivered care to patients on an AMU. CONCLUSION: There is still enormous variation between trusts in how acute medical services are supported by Consultant physicians. The demands on each service and the resources available to trusts differ hugely, therefore the solutions to providing a Consultant-led service need to be tailor made for each AMU. PMID- 23364105 TI - Euglycemic ketoacidosis as a cause of a metabolic acidosis in the Intensive Care Unit. AB - Euglycaemic ketoacidosis is a rare endocrine emergency, which can have disastrous consequences if left undiagnosed. We present the case of a 57 year old man with type 2 diabetes who developed ketoacidosis (DKA) following a myocardial infarction, despite being normoglycaemic, following discontinuation of his insulin infusion in an intensive care setting. The case highlights the importance of capillary ketone body testing in this scenario as well as the dangers of an over reliance on blood glucose values in the diagnosis of ketoacidosis. The notion that DKA can occur in both type 1 and type 2 diabetes is reaffirmed and the value of adequate insulin therapy in euglycaemic ketoacidosis is emphasized. PMID- 23364106 TI - Non-Convulsive Status Epilepticus as a cause for prolonged delirium: an under diagnosed phenomenon? AB - Delirium is a common cause for acute hospital admissions. There are many potential causes for this presentation, including infection, polypharmacy and metabolic disorders. We present the case of a patient with hyponatraemia and prolonged delirium, in whom the diagnosis of non-convulsive status epilepticus (NCSE) was made following electroencephalography (EEG). PMID- 23364107 TI - Intra-abdominal abscess in older patients: two atypical presentations to the Acute Medical Unit. AB - An abscess is a localised collection of necrotic tissue, white cells and bacteria, collectively forming pus. Intra-abdominal abscesses can occur viscerally (e.g. hepatic abscess), retroperitoneally (e.g. psoas abscess) or intraperitoneally (e.g. subphrenic abscess).(1, 2) Clinical presentation is variable and largely depends on the site of abscess. Fever and abdominal pain are the classic symptoms although in older people presentation can be non-specific. Prompt diagnosis and early intervention are vital for good outcomes.(3) We present two cases of older women whose presentation with atypical symptoms resulted in a delay in diagnosis. PMID- 23364108 TI - Exertional syncope as a presenting feature in Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is an acute demyelinating disorder of the peripheral nervous system that results in motor weakness, absent reflexes and autonomic nervous system dysfunction. Autonomic failure is reported in approximately 65 % of patients with GBS and usually follows extensive motor involvement. In this case our patient presented with syncope and other signs of autonomic failure before the motor weakness developed. Few cases in the literature have reported features of autonomic failure before established weakness in GBS; to our knowledge, syncope has not been described previously as a presenting feature of GBS. PMID- 23364109 TI - Sepsis- what is the role for acute medicine? PMID- 23364110 TI - Problem based review: the patient with dizziness on the AMU. AB - Unsteadiness, balance disturbance, and ,dizziness, are common presenting complaints on the Acute Medical Unit. This article outlines key components in the evaluation of these problems and describes the most common clinical patterns of dizziness. A case history is used to highlight some key learning points. PMID- 23364111 TI - The febrile patient with neutropenia. AB - Fever in a neutropenic patient is an acute medical emergency. This article considers the diagnosis, investigation and management of neutropenic sepsis, along with the clinical challenges that an acute physician may face when treating patients presenting with this condition. PMID- 23364112 TI - Problem-based review: A patient with metabolic acidosis. AB - Metabolic acidosis is a common metabolic derangement present in the acute medical patient. A thorough and structured investigative approach is required as there are many causes and management is reliant on identifying these. In particular calculation of the anion gap with correction for albumin level and use of the delta ratio can be helpful in complex cases especially in patients where a combination of metabolic derangements may be present. PMID- 23364113 TI - Borderline personality disorder. PMID- 23364114 TI - Disclosures of conflicts of interest in psychiatric review articles. AB - To characterize disclosures of conflicts of interest in review articles in psychiatry, we identified 285 reviews from 10 high-impact journals in psychiatry and 2 in general medicine. Disclosures were reliably coded as biotechnology/pharmaceutical/other material interests, nonprofit/government, communication companies, or other. The authors in both types of journals frequently reported industry ties. However, the reviews in the psychiatric journals were significantly less likely to include industry-related disclosures (32% of the reviews; 18% of the authors) compared with the general medical journals (64% of the articles; 40% of the authors). The most common types of industry-related disclosures were for consulting, research support, and speaking fees. Disclosures seemed to be of limited utility in helping readers assess possible biases because the nature and the extent of the relationships being disclosed were often unclear. Efforts to screen out authors with significant financial relationships pertaining to the topic under review may be more effective than are disclosures in protecting the integrity of the medical literature. PMID- 23364115 TI - Developing conceptualization of borderline personality disorder. PMID- 23364116 TI - Patterns of interpersonal problems in borderline personality disorder. AB - Borderline personality disorder (BPD) is characterized by a wide variety of interpersonal problems. We examined whether there are different characteristic interpersonal patterns in BPD and how these patterns are related to symptom distress and therapeutic alliance. In 228 inpatients with diagnoses of BPD, interpersonal subtypes based on the Inventory of Interpersonal Problems (Horowitz et al., Inventar zur Erfassung Interpersonaler Probleme, 2000) were examined through cluster analyses. The global symptom severity and therapeutic alliance were also assessed. We identified five characteristic interpersonal patterns, which we labeled as follows: Cluster 1, "Vindictive"; Cluster 2, "Moderate Submissive"; Cluster 3, "Nonassertive"; Cluster 4, "Exploitable"; and Cluster 5, "Socially Avoidant." The clusters differed significantly in terms of interpersonal distress, interpersonal differentiation, and severity of global symptoms. The ratings of the therapeutic alliance by therapists during treatment significantly differed between the interpersonal subtypes, and the lowest ratings for patients were in the "Socially Avoidant" cluster. Our results stress the impact of interpersonal style on the appearance and treatment of BPD. PMID- 23364117 TI - Borderline personality disorder and emotional intelligence. AB - The present study investigated emotional intelligence (EI) in borderline personality disorder (BPD). It was hypothesized that patients with BPD (n = 61) compared with patients with other personality disorders (PDs; n = 69) and nonpatients (n = 248) would show higher scores on the ability to perceive emotions and impairments in the ability to regulate emotions. EI was assessed with the Mayer-Salovey-Caruso Emotional Intelligence Test (Mayer, Salovey, and Caruso [New York: MHS, 2002]). As compared with the PD group and the nonpatient group, the patients with BPD displayed the anticipated deficits in their ability to understand, whereas no differences emerged with respect to their ability to perceive, use, and regulate emotions. In addition, a negative relationship was found between the severity of BPD and total EI score. However, this relationship disappeared when intelligence quotient was partialled out. These results suggest that BPD is associated with emotion understanding deficits, whereas temporary severity of BPD is associated with emotion regulation deficits. PMID- 23364118 TI - Altered state and trait disgust in borderline personality disorder. AB - Clinical experience suggests that the emotion disgust plays an important role in borderline personality disorder (BPD). We investigated 30 female patients with BPD and 30 healthy women who answered different measures of trait disgust, specifically disgust proneness, disgust sensitivity, and self-disgust. Moreover, all participants rated affective facial expressions as well as affective scenes according to perceived or elicited basic emotions. The patients with BPD reported elevated trait disgust, especially for the area of self-disgust. They also rated facial expressions of disgust as more intense than did the healthy women but only when the person who displayed this emotion was male. This sex-specific disgust bias was independent of depression and experienced sexual/physical abuse in the clinical group. Altogether, the patients with BPD showed a broad spectrum of altered disgust processes, which was positively correlated with disorder severity. Consequently, the assessment of disgust reactivity should be introduced as a diagnostic tool for this disorder. PMID- 23364119 TI - Temperamental patterns in female adolescents with borderline personality disorder. AB - A specific composition of temperament traits with high novelty seeking (NS), high harm avoidance (HA), and low reward dependence (RD) has been attributed to adult patients with borderline personality disorder (BPD). This study examined whether an analogue personality profile is specifically associated with adolescent BPD. The female study sample comprised 33 adolescents with BPD, 35 clinical controls (CCs), and 31 healthy controls (HCs). Dimensions of temperament and character were measured according to Cloninger's biopsychosocial model of personality. Significantly higher means of NS and HA but lower means of RD could be determined in the adolescents with BPD compared with the CCs and the HCs. The comparable findings of this specific temperament constellation in adolescents and adult patients with BPD suggest that heritable factors such as temperamental traits may contribute to the vulnerability for developing BPD. Early identification of a "borderline temperament" may facilitate early intervention and lower the risk for developing BPD. PMID- 23364120 TI - Impulsivity in relation to stress in patients with borderline personality disorder with and without co-occurring attention-deficit/hyperactivity disorder: an exploratory study. AB - Impulsivity is regarded as a key feature in borderline personality disorder (BPD). However, discrepancies in previous research indicate that the role of impulsivity in BPD is not yet fully understood. For example, state-dependent impulsivity in individuals with BPD may be related to co-occurring psychiatric conditions such as attention-deficit/hyperactivity disorder (ADHD) and to emotional states. We assessed self-reports of trait and state impulsivity and response inhibition before and after an experimental stress induction in 15 patients with BPD without ADHD, 15 patients with BPD and ADHD, 15 patients with ADHD, and 15 healthy participants. The patients in both BPD subgroups reported a stress-dependent increase of state impulsivity, which was not observed in the other groups. Response inhibition was impaired in the patients with BPD and ADHD but not in those without ADHD compared with the healthy participants. We suggest that stress levels and co-occurring ADHD should receive attention in future studies on impulsivity in BPD. PMID- 23364121 TI - Systems Training for Emotional Predictability and Problem Solving (STEPPS) group treatment for offenders with borderline personality disorder. AB - Systems Training for Emotional Predictability and Problem Solving (STEPPS) is a manual-based group treatment of persons with borderline personality disorder (BPD). We report results from a study of offenders supervised by the Iowa Department of Corrections. Seventy-seven offenders participated in STEPPS groups. The offenders experienced clinically significant improvement in BPD-related symptoms (d = 1.30), mood, and negative affectivity. Suicidal behaviors and disciplinary infractions were reduced. Baseline severity was inversely associated with improvement. The offenders indicated satisfaction with STEPPS. We conclude that STEPPS can be successfully integrated into the care of offenders with BPD in prison and community corrections settings. PMID- 23364122 TI - The effects of borderline personality disorder and panic disorder on suicide attempts and the associated influence of affective dysregulation in the general population. AB - Previous studies have demonstrated individual associations between borderline personality disorder (BPD), panic attacks (PAs), and panic disorder (PD) in relation to suicide attempts (SAs). This study examined the comorbid effects of these variables. Data from wave 2 of the National Epidemiologic Survey of Alcohol and Related Conditions (N = 34,653) were used to examine using logistic regression the relationship between individuals with BPD (n = 562), PA (n = 253), PD (n = 255), comorbid BPD and PD (n = 146), and co-occurring BPD and PA (n = 119) who had attempted suicide. It was found that BPD, PD, and PA are associated with SAs. Comorbid PD and BPD, or PA and BPD, only slightly increased the association of BPD alone with SA. Associations were greatly decreased after controlling for affective dysregulation. These findings emphasize the importance of affective dysregulation in individuals with BPD in relation to suicide attempts. PMID- 23364124 TI - Expanding the scope of treatment for borderline personality disorder. PMID- 23364123 TI - Improving access in borderline therapy for difficult-to-engage patients: a clinical description. AB - Debate about suitability or clinicians' low expectations has led to patients with personality disorders being labeled as difficult and being socially excluded from pathways of care. Traditional psychotherapeutic treatments in borderline personality disorder demand too much of these patients' fractured ego structures for meaningful (long-term) therapeutic engagement. However, these patients cause clinicians anxiety and are a burden in health care systems. This article describes the challenge for clinical care teams working in partnership arrangements-psychotherapy and psychiatry services-to provide a containing framework of care. Early access to a pragmatic psychoanalytically oriented group treatment in borderline personality disorder is aimed at offering these patients an opportunity to make transitions in borderline treatment and thus alter the trajectory of their (self-) destructive pathway. A clinical and theoretical case is made for clinicians and health strategists to re-engage in the process of making meaningful early contact with borderline vulnerability. The group-based treatment model in borderline disturbance described in this article has helped forge partnerships between psychotherapy and psychiatric teams in providing in depth diagnostic and prognostic information early in the patients' journey. PMID- 23364125 TI - The factorial invariance across gender of three well-supported models: further evidence for a five-factor model of posttraumatic stress disorder. AB - Three well-supported latent models of posttraumatic stress disorder (PTSD; i.e., Emotional Numbing, Dysphoria, and Dysphoric Arousal [DA] models) were examined using factorial invariance across gender. There is a notable lack of studies that have investigated the factorial invariance of the PTSD models across gender, and, to date, no study has assessed the factorial invariance of the DA model across gender. The current sample consisted of 571 children and adolescent earthquake survivors (297 male and 274 female participants) from China. The results indicated that the 17 symptoms of PTSD have equivalent factor loadings between the male and female participants. Furthermore, the female participants evidenced more severe manifestations of PTSD. Moreover, the newly proposed five-factor DA model provided superior fit to the data compared with the Emotional Numbing and Dysphoria models. The implication of these results is discussed. PMID- 23364126 TI - Psychological trauma symptom improvement in veterans using emotional freedom techniques: a randomized controlled trial. AB - This study examined the effect of Emotional Freedom Techniques (EFT), a brief exposure therapy combining cognitive and somatic elements, on posttraumatic stress disorder (PTSD) and psychological distress symptoms in veterans receiving mental health services. Veterans meeting the clinical criteria for PTSD were randomized to EFT (n = 30) or standard of care wait list (SOC/WL; n = 29). The EFT intervention consisted of 6-hour-long EFT coaching sessions concurrent with standard care. The SOC/WL and EFT groups were compared before and after the intervention (at 1 month for the SOC/WL group and after six sessions for the EFT group). The EFT subjects had significantly reduced psychological distress (p < 0.0012) and PTSD symptom levels (p < 0.0001) after the test. In addition, 90% of the EFT group no longer met PTSD clinical criteria, compared with 4% in the SOC/WL group. After the wait period, the SOC/WL subjects received EFT. In a within-subjects longitudinal analysis, 60% no longer met the PTSD clinical criteria after three sessions. This increased to 86% after six sessions for the 49 subjects who ultimately received EFT and remained at 86% at 3 months and at 80% at 6 months. The results are consistent with that of other published reports showing EFT's efficacy in treating PTSD and comorbid symptoms and its long-term effects. PMID- 23364127 TI - Preexisting mental illness and risk for developing a new disorder after hurricane Katrina. AB - To investigate predisaster mental illness as a risk factor of poor postdisaster mental health outcomes, veterans with (n = 249) and without (n = 250) preexisting mental illness residing in the Gulf Coast during Hurricane Katrina were surveyed after Katrina and screened for posttraumatic stress disorder (PTSD), depression, generalized anxiety disorder, and panic. Logistic regression examined the association between preexisting mental disorders and positive screens after the hurricane, adjusting for demographics and exposure to hurricane-related stressors. The odds of screening positive for any new mental disorder were 6.8 times greater for those with preexisting mental illness compared with those without preexisting mental illness. Among those with preexisting PTSD, the odds of screening positive for any new mental illness were 11.9 times greater; among those with schizophrenia, 9.1 times greater; and among those with affective disorders, 4.4 times greater. Persons with preexisting mental illnesses, particularly PTSD, should be considered a high-risk group for poor outcomes after a disaster. PMID- 23364128 TI - Where did I put my keys? - a 'we' intervention to promote memory in healthy older adults: a controlled pilot study. AB - BACKGROUND: Numerous behavioural studies have shown that older adults have more difficulty in binding things together and have underlined the corresponding importance of this function in everyday memory tasks. OBJECTIVE: This study was designed to test a new brief inter-dependent self-knowledge intervention on memory functions in aging. METHODS: Before engaging in a working memory task based on binding objects and their locations, half of the participants read a series of paragraphs that focused on the individual self and were written in the first person singular 'I' (in-dependent self-knowledge), whereas the other half read paragraphs that focused on the relational self and were written in the first person plural 'We' (inter-dependent self-knowledge). RESULTS: Results showed that older adults who were trained with 'We' passages were more successful in remembering objects and their location compared to the group of participants who were trained with 'I' passages. CONCLUSION: These findings are discussed in terms of the role that social factors may have in favouring memory functions in aging and delineate a new cognitive clinical protocol based on an inter-dependent self knowledge approach. PMID- 23364129 TI - Prevalence of dementia in elderly clients of a private health care plan: a study of the FIBRA-RJ, Brazil. AB - AIMS: To describe the overall prevalence of dementia syndrome and its major subtypes among elderly clients of a private health care plan and to ascertain the association between this syndrome and socioeconomic characteristics. METHODS: A survey was organized in two stages: screening for cognitive impairment and diagnostic evaluation. The study population comprised 683 elderly subjects (aged >67 years), an expanded sample of 7,486 individuals, of the database of the FIBRA RJ, which evaluated clients of a private health care plan residing in northern districts of the municipality of Rio de Janeiro, Brazil. The diagnosis of dementia was obtained according to DSM-IV criteria. RESULTS: A total of 115 individuals were diagnosed with dementia, resulting in a prevalence of 16.9% (95% CI = 14.4-19.8). The association was strongest among older age groups, i.e. 85-89 years old (prevalence ratio = 8.85; 95% CI = 2.11-37.11) and 90 or more years old (prevalence ratio = 8.85; 95% CI = 2.11-37.11), and among illiterate people (prevalence ratio = 2.77; 95% CI = 1.07-7.19). Sex, personal income and marital status displayed no association with dementia. CONCLUSION: The prevalence of dementia was higher than found by population-based studies. These findings point to a possibility of a high demand for specialized services among older adults served by the private health care sector. PMID- 23364131 TI - Food safety attitudes in college students: a structural equation modeling analysis of a conceptual model. AB - College students are one of the most at-risk population groups for food poisoning, due to risky food safety behaviors. Using the Likert Scale, undergraduate students were asked to participate in a Food Safety Survey which was completed by 499 students ages 18-25. Data was analyzed using SPSS and AMOS statistical software. Four conceptual definitions regarding food safety were defined as: general food safety, bacterial food safety, produce food safety, and politics associated with food safety. Knowledge seems to be an important factor in shaping students attitudes regarding general and bacterial safety. Ethnicity plays a role in how people view the politics of food safety, and the safety of organic foods. PMID- 23364132 TI - Effect of hypoxic-ischemic insults on the composition of fatty acids in the brain of neonatal rats. AB - BACKGROUND: Long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA; 22:6 n-3), comprise a major component of brain membrane phospholipids. The effect of neonatal hypoxic-ischemic insults on brain fatty acid composition is not completely understood. The aim of this study was to investigate alterations in brain fatty acid composition during development and in response to hypoxic-ischemic insults in neonatal rats. METHODS: Postnatal day 7 pups were randomly assigned to two experimental groups: a control group or a hypoxic ischemic group in which hypoxia-ischemia was produced by left common carotid artery occlusion and exposure to 8% oxygen for 1.5 h. Various brain fatty acids were measured on postnatal days 8, 10 and 14. RESULTS: On postnatal day 14, the ratio of DHA to total fatty acids increased in the control group, but not in the hypoxic-ischemic group (p < 0.05). We observed no significant differences in arachidonic acid content in the brain between the two groups. CONCLUSIONS: These results suggest that hypoxic-ischemic insults interfere with accumulation of brain DHA in developing rats. DHA supplementation may be beneficial for treating neonatal hypoxic-ischemic encephalopathy. PMID- 23364133 TI - Do patients with non-arteritic ischemic optic neuritis have increased risk for cardiovascular and cerebrovascular events? AB - OBJECTIVES: To compare the incidence of cardiac and cerebrovascular events following non-arteritic anterior ischemic optic neuropathy (NAION) compared to published control data using the Framingham, United Kingdom Prospective Diabetes Study (UKPDS) and the National Vascular Disease Prevention Alliance (NVDPA) data. METHODS: A retrospective study of all consecutive cases of NAION between 1990 and 2005. Patients were stratified into those with or without prior ischemic events and into diabetics and non-diabetics. Outcome measures included cardiovascular morbidity, cerebrovascular events and the Framingham, UKPDS and NVDPA scores for each patient. RESULTS: According to the NVDPA, the average absolute 5-year risk for cardiovascular disease (CVD) was 8.98, compared to 9 CVD events in our study. In the diabetic patients, 5 (17%) had a cardiac event and 2 (8%) had a cerebral vascular accident (CVA). Based on the UKPDS risk calculator, the average 10-year risk for cardiac events is 21.6%, CVA -6.8%. In the non-diabetics, there were 3 cases (7.5%) of myocardial infarction, compared to the average 10-year Framingham risk for myocardial infarction or coronary death of 11% (+/-8 SD). CONCLUSIONS: Following NAION, the incidence of cardiovascular or cerebrovascular events in patients taking aspirin is not in major excess from that expected in risk-factor age-matched controls. PMID- 23364134 TI - Realization of on-tissue protein identification by highly efficient in situ digestion with graphene-immobilized trypsin for MALDI imaging analysis. AB - A novel implementation of in situ protein digestion supported by a graphene oxide immobilized enzyme reactor (GO-IMER) in the MALDI imaging mass spectrometry (IMS) workflow is reported, which enables the simultaneous diagnostic identity and distribution attributes of the proteome on tissue. PMID- 23364135 TI - Formation and properties of graphane superstructures. AB - Hydrogenated graphene, also known as graphane, is a wide band gap semiconductor in its various possible conformations. Here we show with first-principles calculations that application of uniaxial pressure can give rise to stripes of the so-called washboard conformation between segments of the most stable chair geometry. Compressed washboard-chair superlattices follow distinct zigzag patterns with interchanging chair and washboard parts. Hybrid systems of this type could be employed in various applications, such as in the templated growth of nanosystems, or as parts of nanomechanical systems. PMID- 23364136 TI - Associations between magnetic resonance imaging measures and neuropsychological impairment in early and late onset alzheimer's disease. AB - AIM: To assess the associations of global atrophy and white matter hyperintensities (WMH) with neuropsychological function in early and late onset Alzheimer's disease (AD). METHODS: We included 107 patients with sporadic AD (21 early onset and 86 late onset) from our memory clinic. Tests for (working) memory, language, executive function, mental speed, and attention were administered. Global atrophy and global and lobar WMH were measured using 1 Tesla MRI. Linear regression analyses with terms for MRI measures, neuropsychological test results, age, gender, education, and the interaction between separate brain measures and age of onset were performed. RESULTS: Global atrophy was associated with more severely impaired global cognition, working memory, mental speed, and executive function (p < 0.05). Significant interactions between global atrophy and age at onset showed that these associations were mostly attributable to patients with early onset AD. By contrast, an association between global atrophy and memory was found, which was specifically attributable to late onset AD patients. No associations between global WMH and cognitive function were found. Subsequently we analyzed regional WMH and found that temporal WMH was associated with impaired memory, and frontal WMH was associated with slower mental speed. CONCLUSION: Cortical atrophy, a key feature of AD, is linked to a wide range of cognitive functions, specifically in early onset AD patients. For WMH, there were no interactions with age at onset, but we found specific associations between temporal WMH and memory and frontal WMH and mental speed. PMID- 23364137 TI - Differential cholinergic pathway involvement in Alzheimer's disease and subcortical ischemic vascular dementia. AB - BACKGROUND: This study aimed to evaluate the relationship between loss of white matter cholinergic pathways, atrophy of the nucleus basalis of Meynert (NBM), and cognitive function in patients with subcortical ischemic vascular dementia (SIVD) or Alzheimer's disease (AD). METHODS: The participants included 26 SIVD, 17 probable AD with or without white-matter changes, and 20 age-matched healthy controls. Thin-section coronal T2-weighted images were acquired using 3.0 T MR. The extent of white matter hyperintensities within cholinergic pathways were assessed using the cholinergic pathways hyperintensities scale (CHIPS). NBM atrophy was assessed from the thickness of the substantia innominata (SI) at the level of the crossing of the anterior commissure. Cognitive impairment was measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Correlations between CHIPSs, SI thickness, and cognitive impairment were evaluated using the Spearman ranked correlation test. RESULTS: In AD, MMSE scores and CDR were correlated with SI thickness (rho = 0.450, p = 0.006 and rho = -0.520, p = 0.030, respectively) but not with CHIPS scores (rho = -0.160, p = 0.530 and rho = 0.270, p = 0.292, respectively). By contrast, aggravated MMSE score and CDR in SIVD had a tendency to correlate with elevated CHIPS scores (rho = -0.344, p = 0.127 and rho = 0.521, p = 0.021, respectively) but not with SI thickness (rho = -0.210, p = 0.480 and rho = 0.080, p = 0.736, respectively). CONCLUSIONS: Loss of cholinergic pathways correlates with cognitive dysfunction in both AD and SIVD. The mechanisms appear to differ: NBM atrophy is likely to be the predominant contributor to cognitive impairments in AD, whereas, the cognitive dysfunction of SIVD was associated with compromised subcortical cholinergic fibers not with nucleus itself. PMID- 23364138 TI - Age-related changes in brain extracellular space affect processing of amyloid beta peptides in Alzheimer's disease. AB - Alzheimer's disease is a neurodegenerative disease in which aging is not only a major risk factor but a major determinant of onset, course, and pathogenesis. The synthesis of amyloid-beta (Abeta) peptides by neurons and their excretion into the extracellular space (ECS) is a core feature of AD that begins more than two decades before the onset of clinical symptoms. The ECS resembles a syncytium with the appearance in electron micrographs of continuous channels and lakes separating the outer membranes of the neurons, neuroglia, and vascular elements embedded in it. It consists primarily of a proteoglycan matrix through which circulates an interstitial fluid, derived in part from cerebrospinal fluid (CSF). The process by which Abeta accumulates in the ECS includes decreased production of CSF, matrix proteoglycans, and ECS volume, all of which become more severe with advancing age and lead to an age-related increase in the Abeta pool. Although the relationship between Abeta and the appearance of cognitive symptoms is uncertain, available data support a strong relationship between the toxicity of Abeta for neurons and the total Abeta burden, including the soluble and fibrillar Abeta, the Abeta42/Abeta40 ratio, and Abeta-proteoglycan reactivity. Proteoglycans have been shown to foster the formation of neurotoxic fibrillar Abeta42 and neuritic plaques that enhance neuronal and synaptic damage and eventual loss culminating in the onset and progression of dementia. As this process depends upon age-related events, it suggests that the successful control of AD lies in finding effective means of prevention. PMID- 23364139 TI - Amyloid pathology influences abeta1-42 cerebrospinal fluid levels in dementia with lewy bodies. AB - A significant proportion of patients with dementia with Lewy bodies (DLB) show Alzheimer's disease (AD) pathology like senile plaques and neurofibrillary tangles. Biomarkers in cerebrospinal fluid (CSF), such as amyloid-beta1-42 (Abeta1-42), total tau (T-tau), and hyperphosphorylated tau (P-tau181P), are linked to the different pathological hallmarks of AD. We set up a study to investigate the influence of AD co-pathology on CSF biomarker concentrations and profiles in autopsy-confirmed DLB. DLB patients with senile plaques showed significantly lower CSF Abeta1-42 concentrations than DLB patients without senile plaques, but not compared to the AD patients. There were no significant differences in CSF T-tau or P-tau181P concentrations between DLB patients with and without neurofibrillary tangles. A correlation was found between the number of APOE epsilon4 alleles and Abeta1-42 CSF levels in DLB patients with senile plaques. Although the CSF biomarkers Abeta1-42, T-tau, and P-tau181P have an added diagnostic value for the differential dementia diagnosis, concomitant amyloid pathology in DLB limits the use of CSF Abeta1-42 for the differential diagnosis of AD versus DLB. PMID- 23364141 TI - Impaired transcription in Alzheimer's disease: key role in mitochondrial dysfunction and oxidative stress. AB - Alzheimer's disease (AD) is the major cause of dementia in the world. Abnormal extracellular accumulation of amyloid-beta (Abeta) peptide and tau hyperphosphorylation, forming neurofibrillary tangles in the brain, are hallmarks of the disease. Oxidative stress, neuroinflammation, and mitochondrial and synaptic dysfunction are also observed in AD and often correlated to intracellular Abeta. This peptide results from the cleavage of the amyloid-beta protein precursor by beta- and gamma-secretases and tends to be secreted after its production. However, secreted Abeta can be internalized by the interaction with membrane receptors, namely N-methyl-D-aspartate receptors, advanced glycation end products receptors, and/or alpha 7 nicotinic acetylcholine receptors. Inside the cell, Abeta interacts with several organelles, including mitochondria and nucleus, and there is growing evidence pointing to a possible role of Abeta in the regulation of gene transcription. Accordingly, transcriptional deregulation was observed in several AD models and human samples from AD patients through modified expression, phosphorylation levels, function, and subcellular localization of some transcription factors, resulting in the suppression of neuroprotective transcription both in the nucleus and the mitochondria. In this review we focus on key transcription regulators related with mitochondrial biogenesis and antioxidant defenses that seem to be altered in AD models and also on the role of intranuclear Abeta in the pathogenesis of the disease. PMID- 23364140 TI - Aftins increase amyloid-beta42, lower amyloid-beta38, and do not alter amyloid beta40 extracellular production in vitro: toward a chemical model of Alzheimer's disease? AB - Increased production of amyloid-beta (Abeta)42 peptide, derived from the amyloid beta protein precursor, and its subsequent aggregation into oligomers and plaques constitutes a hallmark of Alzheimer's disease (AD). We here report on a family of low molecular weight molecules, the Aftins (Amyloid-beta Forty-Two Inducers), which, in cultured cells, dramatically affect the production of extracellular/secreted amyloid peptides. Aftins trigger beta-secretase inhibitor and gamma-secretase inhibitors (GSIs) sensitive, robust upregulation of Abeta42, and parallel down-regulation of Abeta38, while Abeta40 levels remain stable. In contrast, intracellular levels of these amyloids appear to remain stable. In terms of their effects on Abeta38/Abeta40/Abeta42 relative abundance, Aftins act opposite to gamma-secretase modulators (GSMs). Abeta42 upregulation induced by Aftin-5 is unlikely to originate from reduced proteolytic degradation or diminished autophagy. Aftin-5 has little effects on mitochondrial functional parameters (swelling, transmembrane potential loss, cytochrome c release, oxygen consumption) but reversibly alters the ultrastructure of mitochondria. Aftins thus alter the Abeta levels in a fashion similar to that described in the brain of AD patients. Aftins therefore constitute new pharmacological tools to investigate this essential aspect of AD, in cell cultures, allowing (1) the detection of inhibitors of Aftin induced action (potential 'anti-AD compounds', including GSIs and GSMs) but also (2) the identification, in the human chemical exposome, of compounds that, like Aftins, might trigger sustained Abeta42 production and Abeta38 down-regulation (potential 'pro-AD compounds'). PMID- 23364142 TI - High serum YKL-40 level in patients with COPD is related to hypoxemia and disease severity. AB - Chronic obstructive pulmonary disease (COPD) is a major health problem with increasing morbidity and mortality throughout the world. YKL-40 is a chitin binding glycoprotein consisting of 383 amino acids, with a molecular mass of 40 kDa, and its serum level is elevated in inflammatory diseases. YKL-40 is a newly recognized biomarker of inflammation and has not been thoroughly investigated in COPD. The aim of the study is to investigate the relationship between serum YKL 40 levels and severity of COPD. The study population consisted of 52 patients with COPD with the mean age of 60.2 +/- 10.1 years. The serum YKL-40 level increased significantly with increasing age (p = 0.022, r = 0.346). In COPD patients, high serum YKL-40 level is correlated to low forced expiratory volume at 1 second (FEV1, percent of predicted) (r = -0.277, p = 0.047). Moreover, high serum YKL-40 level is correlated to low arterial oxygen pressure (PaO2, mmHg) (r = -0.387, p = 0.005). The mean serum YKL-40 level was found as 243.1 +/- 129.2 ng/ml in COPD patients with desaturation during 6-minute walk test (6MWT) and this value was higher than the mean serum YKL-40 level (155.8 +/- 59.1 ng/ml) of COPD patients without desaturation during 6MWT (p = 0.004). This study demonstrated that high serum YKL-40 levels were correlated to severity of COPD. We propose that circulating YKL-40 levels could be a biomarker for hypoxemia and decline in lung function. PMID- 23364143 TI - Subcutaneous methotrexate, ulcers, and doses. PMID- 23364145 TI - Lyme borreliosis: an update for Canadian dermatologists. AB - BACKGROUND: Lyme borreliosis is a multisystemic tick-borne spirochetosis, which may result in dermatologic, musculoskeletal, cardiovascular, and neurologic manifestations. OBJECTIVE: Patients with suspected acute Lyme borreliosis infection may be referred for urgent dermatologic review. Canadian dermatologists should be aware of the latest information regarding the diagnosis and management of Lyme borreliosis. METHODS: This review is based on a PubMed database search combining the word "Lyme" with variations of the word "Canada." Data sources included articles from the fields of ecology, epidemiology, laboratory diagnostics, and clinical management. CONCLUSION: In this review, the ecological basis of spirochete transmission by tick vectors is described. The latest available Canadian epidemiologic data are summarized. North American clinical manifestations of Lyme borreliosis are contrasted with European presentations. The Canadian Public Health Laboratory Network's diagnostic guidelines are summarized. Finally, treatment recommendations are outlined. PMID- 23364144 TI - Phototherapy in psoriasis: a review of mechanisms of action. AB - BACKGROUND: Phototherapy is one of the most efficacious treatment options for psoriasis. New, emerging studies are beginning to define the biologic mechanisms by which phototherapy improves psoriasis. METHODS: To provide an overview of the mechanisms thought to be responsible for the therapeutic effects of phototherapy, a review was performed on all relevant published studies in the Medline database from January 1, 1985, to August 15, 2011. FINDINGS: Four categories of action were proposed in the literature to describe the effects of phototherapy in psoriasis: (1) alteration of the cytokine profile, (2) induction of apoptosis, (3) promotion of immunosuppression, and (4) all other mechanisms. CONCLUSIONS: Phototherapy acts through a combination of pathways to confer therapeutic benefits in psoriasis, and these different modalities may help explain its particular usefulness in treating this cutaneous disease. PMID- 23364146 TI - Degree of histologic inflammation in lupus erythematosus and direct immunofluorescence results: red and inflamed lesions do not increase the chances of getting a bright band. AB - BACKGROUND: In the diagnostic work-up of lupus erythematosus (LE), direct immunofluorescence (DIF) examination could be helpful. Classically, clinically red lesions are targeted by clinicians in the hope of yielding an informative DIF result. However, the investigative correlation between the degree of inflammation and DIF positivity has never been published in the literature. OBJECTIVE: In this study, we sought to discover if histologically inflamed lesions correlated with DIF positivity results. METHOD: We studied 112 lesions histologically consistent with LE and correlated the degree of histologic inflammation on the DIF hematoxylin and eosin-stained biopsy with DIF positivity. The degree and location of the inflammation, as well as the involvement of the dermoepidermal interface, were documented. RESULTS: A positive lupus band test was defined as the presence of either (1) granular IgG alone +/- other immunoglobulins and/or C3 or (2) granular IgM or Ig A plus other immunoglobulins +/- C3. Fifty-four of 112 (48%) cases had positive DIF (DIF+) results, 26 of 112 (23%) had negative DIF (DIF-) results, and 32 of 112 (29%) had nonspecific DIF patterns. Of the DIF+ cases, 41 of 54 (76%) showed some degree of inflammation, whereas 25 of 26 (96%) DIF- cases had inflammation (p = .60). Most of the biopsies in the study (85%) were inflamed, but the degree and location of the inflammation had no influence on DIF+ results. The intensity of the DIF+ band further failed to show any relationship with the degree of inflammation. CONCLUSION: The level of inflammatory activity in a clinical lesion fails to correlate with DIF positivity. Furthermore, other common histopathologic findings of LE are not predictive of DIF results. PMID- 23364147 TI - Factors related to delay in the diagnosis of basal cell carcinoma. AB - BACKGROUND: There is often a delay between the clinical emergence of a basal cell carcinoma (BCC) and the point in time at which the patient presents for definitive diagnosis and treatment. Previously published studies on delays regarding skin cancer have focused on melanoma rather than BCC. We conducted a study aimed at identifying factors associated with the detection of BCC and reasons for the delay in diagnosis. METHOD: A monocentric study was performed. Patients with a primary BCC diagnosed in 2010 were included in the study. They were asked about factors concerning BCC awareness and detection, tumor characteristics, previous history of nonmelanoma cutaneous cancer, family history of nonmelanoma cutaneous cancer, and the presence of comorbidities. Data were analyzed using SPSS software. RESULTS: The mean diagnostic delay for BCC in our hospital setting was estimated at 19.79 +/- 14.71 months. Delayed diagnosis was significantly associated with patients over 65 years, those without a previous history of BCC, those without a family history of BCC, those with BCC located elsewhere than the head or neck, and those with lesions not associated with itching or bleeding. CONCLUSION: This study revealed considerable delay in the diagnosis of BCC. The main reason for delay in the diagnosis seems to be the initial decision of the patient to seek medical advice. These data suggest a need for greater information for the general public on the symptoms and signs that should prompt suspicion of a BCC. PMID- 23364148 TI - In vivo reflectance confocal microscopy of halo nevus. AB - BACKGROUND: RCM (reflectance confocal microscopy) is a noninvasive, high resolution technology that has been proven to improve the diagnostic accuracy over clinical examination in several skin diseases. OBJECTIVE: The aim of this article is to describe the morphologic features of halo nevi (HN) observed with RCM and correlate them with their dermoscopic characteristics. METHOD: Nine patients with the clinical diagnosis of HN were assessed with RCM. A second assessment was performed up to 12 months later. Dermoscopic global patterns were obtained and correlated with the RCM findings. RESULTS: In five (55.6%) cases, pagetoid cells were observed. Nonedged dermal papilla and junctional thickening were found in three (33%) cases. Nucleated cells in the dermal papillae and plump bright cells were observed in seven (77.8%) and six (66.7%) cases, respectively. CONCLUSION: Our study shows that HN observed by RCM can show atypical features that overlap with those observed on atypical melanocytic lesions and malignant melanoma. PMID- 23364149 TI - Teaching dermatology to internal medicine residents: needs assessment survey and possible directions. AB - BACKGROUND: Internal medicine trainees receive limited teaching and training in dermatology and may feel inadequately prepared to assess and manage patients with dermatologic complaints. No study to date has assessed the needs of internal medicine trainees in Canada with regard to dermatology teaching. OBJECTIVE: To determine internal medicine residents' comfort in assessing and managing dermatologic issues and their educational needs in dermatology. METHODS: An electronic survey was conducted of first-, second-, and third-year internal medicine residents at the University of Toronto. RESULTS: Fifty-four of 186 internal medicine trainees responded to our survey (response rate = 29%). Each respondent did not answer every question. Residents were generally uncomfortable or very uncomfortable assessing and managing dermatologic issues in the emergency department (40 of 47, 85%), ward or intensive care unit (39 of 47, 83%), and ambulatory clinic (40 of 47, 85%). Residents thought that various clinical and didactic dermatology exposures would be useful to their training as internists. Case-based teaching and ambulatory clinical rotations were felt to be particularly valuable. Additionally, 38 of 46 (83%) respondents wanted to learn how to perform punch biopsies. CONCLUSIONS: An effort should be made to increase the availability of relevant dermatology teaching and clinical exposures for internal medicine residents. PMID- 23364150 TI - Examining the relationship between alopecia areata, androgenetic alopecia, and emotional intelligence. AB - BACKGROUND: Emotional stress has been associated with the development of alopecia areata (AA) and androgenetic alopecia (AGA). Emotional intelligence (EI), a component of general intelligence, is thought to govern the recognition, expression, and control of stress and other emotions. People with low EI are unable to adequately control stress in everyday life. OBJECTIVE: To investigate EI differences between AA and AGA patients and a control population. METHODS: Thirty-five AGA patients and 42 AA patients, with patchy (n = 28), ophiasis (n = 5), totalis (n = 5), and universalis (n = 4) distribution of hair loss, completed a 133-item Emotional Quotient-Inventory (EQ-I ) psychometric assessment. Scores were compared between AA, AGA, and 77 control subjects obtained from the North American normative population sample on which the psychometric instrument was normed. RESULTS: Statistically significant differences were found in EI between AA patients and controls with the EQ-I Stress Tolerance scale (p = .005). AGA patients also differed significantly from the controls but to a lesser degree compared toAA patients. In overall EI, there were no apparent differences between AGA and AA patients. CONCLUSIONS: AA and AGA patients exhibit a mild depressive reaction to their condition, with AA patients demonstrating a significantly stronger deficiency in coping with stress than AGA patients. The data support a psychosomatic contribution to AA. Referral of patients for EI assessment and psychosocial counseling could help reduce stress. PMID- 23364151 TI - Treatment of mycosis fungoides with bexarotene results in remission of diffuse plane xanthomas. AB - BACKGROUND: Cutaneous xanthomas develop as a result of intracellular and dermal deposition of lipids in either hyper- or normolipidemic patients. Plane xanthomas may signal the presence of an underlying monoclonal gammopathy, chronic myelomonocytic leukemia, or cutaneous T-cell lymphoma. Investigators have suggested that xanthomatized T cells may result in induction of plane xanthomas. METHODS: We report the case of a patient with mycosis fungoides (MF) and plane xanthomas who was treated with bexarotene for his MF. RESULTS: Significant improvement in the clinical signs of MF was observed within 3 months. We also observed a substantial regression of the xanthomas after 5 months of treatment. Complete clinical remission of both the MF and xanthomas was obtained after 6 months. The patient was still free of xanthomas after 3 years of follow-up. CONCLUSION: Bexarotene led to the clearing of the cutaneous lesions of cutaneous T-cell lymphoma and plane xanthomas. This may be due to an effect of bexarotene on the aberrant T cells that may cause xanthomatization. PMID- 23364152 TI - Radiation- and chemotherapy-induced permanent alopecia: case series. AB - BACKGROUND: Radiation- and chemotherapy-induced alopecia is mostly temporary. However, permanent scalp alopecia is reported, albeit infrequently. OBJECTIVE: The objective of this observational case series was to determine the kind and doses of chemotherapeutic agents and radiation in inducing permanent alopecia of the scalp. METHODS AND RESULTS: Eleven patients referred to our department over a period of 3 years for permanent alopecia after chemotherapy/radiotherapy or combination therapy were included. A detailed medical and therapeutic history was obtained from each patient and from medical records. Photography was done, and the scalp biopsies were taken. Patients were divided into three groups according to the type of therapy. The first group received conditioning chemotherapy prior to bone marrow transplantation. The second group had radiation for brain tumors, and the third group received both. CONCLUSION: A comprehensive multicenter and multidisciplinary study is required to determine the definite causative agents, doses, and other cofactors that induce permanent alopecia following chemotherapy/radiotherapy, as well as the means to avoid this distressing outcome in surviving patients. PMID- 23364153 TI - Dynaclose tape: a practical alternative to punch biopsy site closure. AB - BACKGROUND: A punch biopsy is a common therapeutic and diagnostic procedure that is routinely performed by dermatologists. A thin cylinder of tissue is removed with a biopsy punch, which creates a full-thickness wound. Sutures are used for primary closure as part of standard practice and are removed in follow-up 5 to 14 days later. The biopsy site heals with a small linear scar. In the past, punch biopsies were often left to heal by secondary intention, but given the extended healing time, this has fallen out of practice among dermatologists. OBJECTIVE: The purpose of this case report is to introduce a new quick and cost-effective approach to accelerate secondary intention healing following punch biopsies in busy dermatology clinics. RESULTS/CONCLUSION: We present a case where Dynaclose tape (Canica Design Inc, Almonte, ON) was used as an alternative to sutures for biopsy site closure. Dynaclose tape is a strip with adhesive ends and a clear center composed of silicone elastomer. The silicone elastomer promotes wound closure by pulling the opposing margins together. The tape maintains excellent adhesion and follows the natural shape of the skin to maximize patient comfort and mobility. PMID- 23364154 TI - Atypical presentation of congenital yellow nail syndrome in a 2-year-old female. AB - BACKGROUND: Yellow nail syndrome (YNS) is a rare clinical entity of unknown etiology that is characterized by a triad of yellow nails, respiratory manifestations, and lymphedema. The condition appears in the mid- to later years of life and only rarely in childhood. We describe a rare case of YNS with an atypical clinical presentation consisting of only yellow and dystrophic nails in a 2-year-old female since birth. OBJECTIVE: A case of congenital YNS with only dystrophic and yellow nails is reported. METHODS AND RESULTS: A 2-year-old female presented with yellow nails since birth. There was no positive family history. Physical examination revealed 20 thickened, dystrophic, yellow nails with onycholysis. There was no evidence of respiratory manifestations or lymphedema. CONCLUSION: Although rare, YNS can present as a congenital clinical entity and persist after birth. Pediatric patients with YNS show different clinical manifestations than the classic adult patient. The presence of yellow and dystrophic nails in the absence of respiratory and lymphatic manifestations may be the only sign of pathology and warrants close monitoring as progression to more serious complications can occur. PMID- 23364155 TI - Successful intravenous immunoglobulin treatment of atypical lichen myxedematosus associated with hypothyroidism and central nervous system involvement: case report and discussion of the literature. AB - BACKGROUND: Lichen myxedematosus (LM) is a rare idiopathic disorder characterized by papules, plaques, and/or nodules in the skin secondary to mucin deposition and variable dermal fibrosis in the absence of thyroid disease. Case reports are the predominant literature on LM due to its rarity, and the data are limited regarding the disease. No standard treatment regimen exists, and the response to treatment varies. OBJECTIVE: This report adds to the limited literature on atypical LM associated with thyroid dysfunction and contributes to the growing body of evidence supporting intravenous immunoglobulin (IVIg) as effective therapy for extensive cases. METHODS AND RESULTS: We report an unusual case of atypical LM associated with hypothyroidism, central nervous system (CNS) disturbances, and atrial fibrillation in a 64-year-old male. The patient experienced remarkable improvement within 3 months of beginning IVIg treatment; however, he required repeat therapy due to the recurrence of CNS symptoms 3 months after treatment. CONCLUSION: We agree with previous authors that thyroid dysfunction alone should not preclude a diagnosis of LM. Additionally, we contribute to the increasing evidence of IVIg being an effective treatment, particularly in the setting of systemic complications or acute worsening of LM. PMID- 23364156 TI - Photo-responsive block copolymer micelles: design and behavior. AB - Stimuli-responsive block copolymer micelles are the topic of intense research since they are able to show sharp and eventually reversible responses to various environmental changes and find applications in various fields including controlled drug delivery. Among all the available stimuli, light has recently attracted much attention since it can be localized in time and space, and it can also be triggered from outside of the system. In this tutorial review, we highlight the progress realized in recent years. More precisely, we provide some guidelines towards the rational design of photo-responsive block copolymers and we present the different photo-responsive moieties that have been used so far. We also discuss the different types of irreversible and reversible responses encountered by photo-responsive block copolymer micelles. Finally, we suggest possible future developments including the design of biocompatible systems operating at excitation wavelengths compatible for biomedical applications. PMID- 23364157 TI - Efficient sensitized emission in Yb(III) pentachlorotropolonate complexes. AB - New Yb(III) complexes based on the pentachlorotropolonate (pctrop) ligand show enhanced infrared emission when excited in the orange organic chromophore. Yb(pctrop)(3)(DMF-d(7))(2) presents the highest reported quantum yield for a nonfluorinated infrared-emitting organolanthanide complex. PMID- 23364158 TI - Growing wealth has resulted in greater spending on health, report argues. PMID- 23364159 TI - Assessing inter-rater agreement of environmental audit data in a matched case control study on bicycling injuries. AB - BACKGROUND: Environmental audit tools must be reliable in order to accurately estimate the association between built environmental characteristics and bicycling injury risk. OBJECTIVE: To examine the inter-rater agreement of a built environment audit tool within a case-control study on the environmental determinants of bicycling injuries. METHODS: Auditor pairs visited locations where bicycling injuries occurred and independently recorded location characteristics using the Systematic Pedestrian and Cyclist Environmental Scan (SPACES). Two case groups were defined: (1) where a bicyclist was struck by a motor-vehicle (MV) and (2) where the bicyclist's injuries required hospitalisation. The two corresponding control groups were (1) where non-MV bicycle-related injuries occurred and (2) where minor bicycle-related injuries occurred. Inter-rater reliability of each item on the tool was assessed using observed agreement and kappa with 95% CI. RESULTS: Ninety-seven locations were audited. Inter-observer agreement was generally high (>=95%); most items had a 1 2% difference in responses. Items with >=5% differences between raters included path condition, slope and obstructions. For land use, path and roadway characteristics, kappa ranged from 0.3 for presence of offices and cleanliness to 0.9 for schools and number of lanes; overall, 78% of items had at least substantial agreement (kappa>=0.61). For bicyclists struck by a MV the proportion of items with substantial agreement was 60%, compared with 73% for non-MV related injuries. For hospitalisations and minor bicycle-related injuries, 76% of items had substantial agreement. CONCLUSIONS: Agreement was substantial for most, but not all SPACES items. The SPACES provides reliable quantitative descriptions of built environmental characteristics at bicycling injury locations. PMID- 23364160 TI - Thrombophilia in Patients With Lower Limb Deep Veins Thrombosis (LDVT) Results of a Monocentric Survey on 103 Consecutive Outpatients. AB - A debate concerns the utility of large screening for acquired or inherited thrombophilia. The study concerns relationship between inherited thrombophilic status and lower limb deep vein thrombosis (LDVT) and highlights the possible use of extensive thrombophilia screening to determine an emerging risk of LDVT. From January 2010 to January 2012, 103 consecutive patients with LDVT were considered. In all, 57 (55.3%) patients with LDVT showed inherited thrombophilia. The most frequent trombophilic alterations were deficiency of protein S (33 patients, 32.0%), methylentethrafolate reductase (MTHFR) gene C677T variant (22 patients, 21.4%), protrombin gene G20210A alteration (50, 14.6%), and deficiency of protein C (12, 11.6%). Age and MTHFR variant were found related to LDVT and thrombophilia was related to distal LDVT. A high frequency of thrombophylic factor was found in patients with LDVT, but we believe that a generic genetic screening should not be suggested for these patients. PMID- 23364161 TI - The risk factors for thrombosis in children with acute lymphoblastic leukemia. AB - We aimed to scrutinize the risk factors for thrombosis in children with acute lymphoblastic leukemia treated with the Berlin-Frankfurt-Munster 95 protocol. The study population was 82 children younger than 16 years of age. The children were followed up for 10 years until January 2007. Thrombosis occurred in 10 (12%) of 82 patients during the treatment course, mainly after the M protocol. The most common risk factor was factor V Leiden (FVL; 15.6%). This was followed by methyleneterahydrofolate reductase (MTHFR; 9.3%), elevated lipoprotein (1.5%), and prothrombin (PT) 20210A (1.5%) in descending order. The risk of thrombosis was found to be significantly high in patients with FVL mutation (odds ratio = 7.1, 95% confidence interval = 1.6-30.5). The risk of thrombosis was not significant in patients with MTHFR and PT20210A mutation (P = .2). Age, catheter usage, FVL mutation, and prednisolone treatment are significant risk factors for thromboemboli occurrence. PMID- 23364162 TI - Portal vein thrombosis: a clinician-oriented and practical review. AB - With advances in modern imaging techniques, portal vein thrombosis (PVT) is being increasingly diagnosed. It has a wide ranging clinical spectrum from being an asymptomatic state to a potentially life-threatening situation. It is not unusual to find it as an incidental finding in the abdominal imagings done for other reasons. It is commonly associated with cirrhosis and abdominal malignancies and also has a strong association with prothrombotic disorders. It is often difficult for the clinicians to decide whether PVT is acute or chronic. This poses great challenges to its management strategies that include anticoagulants, thrombolysis, and surgical options. Timely diagnosis and appropriate management have great bearings on its outcomes of morbidity and mortality. In this clinician oriented review, we have provided a concise review of clinical aspects of PVT and discussed various management strategies while addressing the common questions that come to a physician's mind dealing with such a patient. PMID- 23364163 TI - A tango for four: deciding on growth hormone therapy in idiopathic short stature. PMID- 23364168 TI - Four square step test performance in people with Parkinson disease. AB - BACKGROUND AND PURPOSE: The Four Square Step Test (4SST), a quick and simple test of multidirectional stepping, may be useful in predicting falls in people with Parkinson disease (PD). We studied the reliability of the 4SST and its ability to discriminate between freezers and nonfreezers, between fallers and nonfallers, and factors predictive of 4SST performance in people with PD. METHODS: Fifty three individuals with idiopathic PD completed the full protocol, including the 4SST as well as measures of balance, walking, and disease severity on anti-PD medication. RESULTS: Interrater (intraclass correlation coefficient [ICC] = 0.99) and test-retest reliability were high (ICC = 0.78). The median 4SST performance was 9.52 seconds. There was a significant difference between 4SST time on medication versus off (P = 0.03), while differences between fallers and nonfallers (P = 0.06) and between freezers and nonfreezers (P = 0.08) did not reach significance. All outcome measures were significantly related to 4SST time. In an exploratory, simultaneous regression analysis, 56% of the variance in 4SST performance could be accounted for by 3 measures: Mini-Balance Evaluation Systems Test (Mini-BESTest), Five Time Sit to Stand, and Nine Hole Peg Test. The 4SST cutoff score for distinguishing fallers from nonfallers was 9.68 seconds (Area under curve = 0.65, sensitivity = 0.73, specificity = 0.57). The posttest probability of an individual with a score greater than the cutoff being a faller was 31% (pretest probability = 21%). DISCUSSION AND CONCLUSIONS: The 4SST is a reliable, quick test that can distinguish between on-and off-medication conditions in PD but is not as good as other tests (eg, Mini-BESTest) for distinguishing between fallers and nonfallers. Video Abstract available (see the Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A31) for more insights from the authors. PMID- 23364169 TI - Dual-task training for balance and mobility in a person with severe traumatic brain injury: a case study. AB - BACKGROUND AND PURPOSE: Attentional impairments following severe traumatic brain injury (TBI) are common and can lead to decreased functional mobility and balance, as well as deficits in previously automatic movements such as walking and stair climbing. The purpose of this case study was to determine the feasibility and potential value of incorporating a cognitive-motor dual-task training program into physical therapy for a patient with a severe TBI. CASE DESCRIPTION: The patient was a 26-year-old woman who sustained a severe TBI during a motor vehicle accident 46 days prior to physical therapy evaluation. On the 8-level Rancho Los Amigos Cognitive Function Scale, her functioning was classified as level IV. She had impairments in attention, functional mobility, and balance, all of which limited her ability to participate in activities of daily living. INTERVENTION: : Physical therapy was provided over 26 days within the inpatient rehabilitation setting. Interventions included mobility tasks such as walking, balancing, and stair climbing. Mobility training was paired with specific secondary cognitive and motor tasks. OUTCOMES: Dual-task training may have contributed to improvements on outcome measures designed to test divided attention including the Walking While Talking Test and Trail Making Test and a greater rate of improvement in walking speed and time to descend stairs when compared to the baseline phase. DISCUSSION: Addition of cognitive-motor dual-task training to standard physical therapy in the inpatient rehabilitation setting appears to be feasible and may have value for improving function in individuals with severe TBI. VIDEO ABSTRACT AVAILABLE: (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A41) for more insights from the authors. PMID- 23364170 TI - Personality traits and behavioural and psychological symptoms in patients with mild cognitive impairment. AB - BACKGROUND AND AIMS: Both personality changes and behavioural and psychological symptoms (BPS) may be associated with mild cognitive impairment (MCI) in later life and help identify incipient dementia. We wished to investigate the links between personality and BPS in MCI. METHOD: We studied premorbid personality traits as estimated 5 years back and their changes in 83 control subjects and 52 MCI patients using the revised NEO Personality Inventory for the Five-Factor Model completed by a proxy. Information on BPS was obtained using the Neuropsychiatric Inventory (NPI). Analyses were controlled for current depression and anxiety. RESULTS: Premorbid neuroticism and openness to experience were associated with the total NPI score. The changes in neuroticism, extraversion, openness to experiences, and conscientiousness were associated with apathy and affective symptoms. CONCLUSIONS: Personality changes and BPS occur in MCI. The occurrence of affective BPS and apathy is associated with both premorbid personality traits and their changes. PMID- 23364171 TI - Two-hit model of brain damage in the very preterm newborn: small for gestational age and postnatal systemic inflammation. AB - BACKGROUND: We sought to disentangle the contributions of perinatal systemic inflammation and being small for gestational age (SGA) to the occurrence of low Bayley Mental Development Indices (MDIs) at the age of 2 y. METHODS: We measured the concentration of 25 inflammation-related proteins in blood obtained during the first two postnatal weeks from 805 infants who were born before the 28th wk of gestation and who had MDI measurements at the age of 2 y and were able to walk independently. RESULTS: SGA newborns who did not have systemic inflammation (a concentration of an inflammation-related protein in the top quartile for gestational age on two days a week apart) were at a greater risk of an MDI <55, but not 55-69, than their peers who had neither SGA nor systemic inflammation. SGA infants who had elevated blood concentrations of interleukin (IL)-1beta, tumor necrosis factor-alpha, or IL-8 during the first 2 postnatal weeks were at even higher risk of an MDI <55 than their SGA peers without systemic inflammation and their non-SGA peers with systemic inflammation. CONCLUSION: SGA appears to place very preterm newborns at an increased risk of a very low MDI. Systemic inflammation adds considerably to the increased risk. PMID- 23364172 TI - Microglia activation in the extremely preterm human brain. AB - BACKGROUND: The periventricular white matter (PVWM) of the immature preterm brain is selectively vulnerable to a spectrum of injury. Although essential for normal brain development, the presence of resident microglia may exacerbate PVWM injury. METHODS: We used immunohistochemistry to investigate microglia profile in human preterm noninjured control brains and in brains with evidence of germinal matrix hemorrhage/intraventricular hemorrhage (GMH/IVH), with median gestational age (GA) of 24.1 and 25.4 wk, respectively. RESULTS: The number of microglia in the PVWM was higher than the other brain regions in both the control and GMH/IVH groups. Microglial density increased further in the PVWM of GMH/IVH brains, regardless of hemorrhage severity and despite normal macroscopic and imaging appearances to the PVWM. This was due to an increase in activated Iba1/CD68- and not Iba/CD45-immunopositive microglia. However, there were very few CD68/Ki67 colocalized cells, suggesting that the source of this increase may be due to a quick transformation of CD45-immunopositive hematopoietic microglia into CD68 immunopositive microglia. There was also increased apoptosis in the PVWM of all cases of GMH/IVH, with axonal injury and increased tumor necrosis factor-alpha (TNF-alpha) expression evident in the most severe cases. CONCLUSION: Isolated GMH/IVH may influence ongoing brain development, with a significant role played by microglial activation. PMID- 23364173 TI - Hyperglycemia increases the risk of death in extremely preterm baboons. AB - BACKGROUND: Transient neonatal hyperglycemia (HG) has been reported in up to 80% of extremely preterm human infants. We hypothesize that severe HG is associated with increased morbidity and mortality in preterm baboons. METHODS: Sixty-six baboons born at 67% of gestation were studied. HG was defined as serum glucose level >=150 mg/dl during the first week of life. Animals were stratified into two groups: severe HG (>=8 events) and nonsevere HG (<8 events). RESULTS: HG developed in 65 of the 66 (98%) baboons that were included. A total of 3,386 glucose measurements were obtained. The mean serum glucose level was 159 +/- 69 mg/dl for the severe HG group and 130 +/- 48 mg/dl for the nonsevere HG group during the first week of life. No differences were found in gender, birth weight, sepsis, patent ductus arteriosus, or oxygenation/ventilation indexes between groups. Severe HG was associated with early death even after controlling for sepsis, postnatal steroid exposure, and catecholamine utilization. CONCLUSION: HG is common in preterm baboons and is not associated with short-term morbidity. Severe HG occurring in the first week of life is associated with early death in preterm baboons. PMID- 23364181 TI - Feasibility study of semiconductor sequencing for noninvasive prenatal detection of fetal aneuploidy. AB - BACKGROUND: Noninvasive prenatal detection of common fetal aneuploidies with cell free DNA from maternal plasma has been achieved with high-throughput next generation sequencing platforms. Turnaround times for previously tested platforms are still unsatisfactory for clinical applications, however, because of the time spent on sequencing. The development of semiconductor sequencing technology has provided a way to shorten overall run times. We studied the feasibility of using semiconductor sequencing technology for the noninvasive detection of fetal aneuploidy. METHODS: Maternal plasma DNA from 13 pregnant women, corresponding to 4 euploid, 6 trisomy 21 (T21), 2 trisomy 18 (T18), and 1 trisomy 13 (T13) pregnancies, were sequenced on the Ion Torrent Personal Genome Machine sequencer platform with 318 chips. The data were analyzed with the T statistic method after correcting for GC bias, and the T value was calculated as an indicator of fetal aneuploidy. RESULTS: We obtained a mean of 3 524 401 high-quality reads per sample, with an efficiency rate of 77.9%. All of the T21, T13, and T18 fetuses could be clearly distinguished from euploid fetuses, and the time spent on library preparation and sequencing was 24 h. CONCLUSIONS: Semiconductor sequencing represents a suitable technology for the noninvasive prenatal detection of fetal aneuploidy. With this platform, sequencing times can be substantially reduced; however, a further larger-scale study is needed to determine the imprecision of noninvasive fetal aneuploidy detection with this system. PMID- 23364182 TI - Lateral flow assay with near-infrared dye for multiplex detection. AB - BACKGROUND: Lateral flow assays (LFAs) are popular point-of-care diagnostic tools because they are rapid and easy to use. Nevertheless, they often lack analytical sensitivity and quantitative output and may be difficult to multiplex, limiting their usefulness in biomarker measurement. As a proof-of-concept study, we detail the design of a quantitative, multiplex LFA with readily available near-infrared (NIR) detection to improve analytical sensitivity. METHODS: NIR dye was conjugated to selected antibodies and incorporated into LFAs. We used singleplex, optimized NIR-LFAs to measure interleukin (IL)-6 from 0 to 200 pg/mL and developed duplex assays to simultaneously measure IL-6 from 0 to 100 pg/mL (0 to 4.5 pmol/L) and C-reactive protein (CRP) from 50 to 2500 ng/mL (0.4 to 20 nmol/L) on a single test strip. Assays were tested on 60 different spiked samples and compared to ELISA results. RESULTS: NIR-LFAs detected IL-6 in a 10% plasma matrix with a limit of detection of 4 pg/mL (182 fmol/L) and a CV <7%. Duplex NIR-LFAs quantitatively measured IL-6 and CRP concentrations simultaneously. Values strongly correlated to ELISA measurements, with R(2) values of 0.9825 and 0.9711 for IL-6 and CRP, respectively. CONCLUSIONS: NIR-LFAs exhibit quantitative measurement at pg/mL concentrations owing to a high signal-to-background ratio and robust detection antibody clearance through the test strip. Moreover, NIR LFAs are able to detect molecules present at vastly different concentrations in multiplex format and compare favorably to ELISAs. LFAs with direct NIR detection may be a valuable tool for biomarker evaluation in the point-of-care setting. PMID- 23364183 TI - Relapsing neuromas: a therapeutic challenge? PMID- 23364184 TI - Microspectroscopic SERS detection of interleukin-6 with rationally designed gold/silver nanoshells. AB - Rationally designed gold/silver nanoshells (Au/Ag-NS) with plasmon resonances optimized for red laser excitation in order to minimize autofluorescence from clinical samples exhibit scattering cross-sections, which are ca. one order of magnitude larger compared with solid quasi-spherical gold nanoparticles (Au-NPs) of the same size. Hydrophilic stabilization and sterical accessibility for subsequent bioconjugation of Au/Ag-NS is achieved by coating their surface with a self-assembled monolayer (SAM) of rationally designed Raman reporter molecules comprising terminal mono- and tri-ethylene glycol (EG) spacers, respectively. The stability of the hydrophilically stabilized metal colloid was tested under different conditions. In contrast to metal colloids coated with a SAM without terminal EG spacers, the hydrophilically stabilized SERS particles do not aggregate under physiologically relevant conditions, i.e., buffer solutions with high ionic strength. Using these rationally designed SERS particles in conjunction with a microspectroscopic acquisition scheme, a sandwich immunoassay for the sensitive detection of interleukin-6 (IL-6) was developed. Several control experiments demonstrate the high specificity of the assay towards IL-6, with a lowest detectable concentration of ca. 1 pg mL(-1). The signal strength of the Au/Ag-NS is at least one order of magnitude higher compared with hydrophilically stabilized, non-aggregated solid quasi-spherical Au-NPs of the same size. PMID- 23364185 TI - Use of ion-mobility mass spectrometry (IMS-MS) to map polyoxometalate Keplerate clusters and their supramolecular assemblies. AB - We present the high-resolution (HRES-MS) and ion-mobility (IMS-MS) mass spectrometry studies of icosahedral nanoscale polyoxometalate-based {L(30)}{(Mo)Mo(5)} Keplerate clusters, and demonstrate the use of IMS-MS to resolve and map intact nanoclusters, and its potential for the discovery of new structures, in this case the first gas phase observation of 'proto-clustering' of higher order Keplerate supramolecular aggregates. PMID- 23364186 TI - Tetrabenzoporphyrins: synthetic developments and applications. AB - Tetrabenzoporphyrins have attracted considerable worldwide attention over the last few decades. Since the discovery of these pigments, chemists, biologists, medical professionals and material scientists have devoted pronounced efforts in order to develop synthetic methods and discover useful applications for these compounds. Nowadays, tetrabenzoporphyrins occupy a prominent position in porphyrin chemistry, and this review is intended to cover the main synthetic methods and applications of these compounds. PMID- 23364188 TI - Low levels of foot-and-mouth disease virus 3C protease expression are required to achieve optimal capsid protein expression and processing in mammalian cells. AB - The foot-and-mouth disease virus (FMDV) capsid protein precursor (P1-2A) is processed by the virus-encoded 3C protease (3C(pro)) to produce VP0, VP3, VP1 and 2A. Within the virus-encoded polyprotein, the P1-2A and 3C(pro) can be expected to be produced at equivalent concentrations. However, using transient-expression assays, within mammalian cells, it is possible to modify the relative amounts of the substrate and protease. It has now been shown that optimal production of the processed capsid proteins from P1-2A is achieved with reduced levels of 3C(pro) expression, relative to the P1-2A, compared with that achieved with a single P1 2A-3C polyprotein. Expression of the FMDV 3C(pro) is poorly tolerated by mammalian cells and higher levels of the 3C(pro) greatly inhibit protein expression. In addition, it is demonstrated that both the intact P1-2A precursor and the processed capsid proteins can be efficiently detected by FMDV antigen detection assays. Furthermore, the P1-2A and the processed forms each bind to the integrin alphavbeta6, the major FMDV receptor. These results contribute to the development of systems which efficiently express the components of empty capsid particles and may represent the basis for safer production of diagnostic reagents and improved vaccines against foot-and-mouth disease. PMID- 23364187 TI - A novel mosquito-borne Orbivirus species found in South-east Asia. AB - The genus Orbivirus of the family Reoviridae includes a genetically diverse group of dsRNA arthropod-borne viruses that infect a wide variety of animal species. Here, we report the complete genome and phylogenetic analysis of a novel orbivirus (IAn-66411 or Sathuvachari virus, SVIV) isolated in 1963 from starlings (Brahminy myna) collected in Vellore, Tamil Nadu, India. Comparative genetic analysis of the SVIV polymerase (VP1 protein), core protein (VP3) and outer core protein (VP7) confirmed that SVIV is most closely related to the mosquito-borne orbiviruses, but that it is equally divergent from all known species. Therefore, SVIV should be tentatively considered as the prototype of a novel mosquito associated Orbivirus species. These findings will aid in the development of molecular reagents that can identify genetically similar orbiviruses and help elucidate their geographical distribution, epidemiology, species tropism and possible disease association. PMID- 23364189 TI - A mutation 'hot spot' in the Schmallenberg virus M segment. AB - In the autumn of 2011, Schmallenberg virus (SBV), a novel orthobunyavirus of the Simbu serogroup, was identified by metagenomic analysis in Germany. SBV has since been detected in ruminants all over Europe, and investigations on phylogenetic relationships, clinical signs and epidemiology have been conducted. However, until now, only comparative sequence analysis of SBV genome segments with other species of the Simbu serogroup have been performed, and detailed data on the S and M segments, relevant for virus-host-cell interaction, have been missing. In this study, we investigated the S- and M-segment sequences obtained from 24 SBV positive field samples from sheep, cattle and a goat collected from all over Germany. The results obtained indicated that the overall genome variability of SBV is neither regionally nor host species dependent. Nevertheless, we characterized for the first time a region of high sequence variability (a mutation 'hot spot') within the glycoprotein Gc encoded by the M segment. PMID- 23364190 TI - In vivo and in vitro identification of a hypervariable region in Schmallenberg virus. AB - Detected for the first time in 2011, Schmallenberg virus (SBV) is an orthobunyavirus of the Simbu serogroup that caused a large outbreak in European ruminants. In a tight time frame, data have been obtained on SBV epidemiology and the clinical pictures associated with this new viral infection, but little information is available on the molecular biology of SBV. In this study, SBV sequence variability was characterized from the central nervous system of two stillborn lambs in a naturally infected herd. A hypervariable region (HVR) was detected in the N-terminal region of the SBV Gc glycoprotein through sequencing and analysis of the two full-length genomes representative of intra-herd SBV dissemination. In vitro growth assays coupled with full-length genome sequencing were performed on the two isolates after successive cellular passages, showing an in vitro adaptation of SBV and mutation accumulation inside the HVR in the absence of immune selective pressure. PMID- 23364192 TI - Novel ssDNA virus recovered from estuarine Mollusc (Amphibola crenata) whose replication associated protein (Rep) shares similarities with Rep-like sequences of bacterial origin. AB - Over the past couple of years highly diverse novel ssDNA viruses have been discovered. Here, we present the first ssDNA virus, Gastropod-associated circular ssDNA virus (GaCSV), recovered from a mollusc Amphibola crenata Martyn 1784, which is a deposit feeder that grazes micro-organisms and organic detritus on the surface of tidal mudflats. The GaCSV (2351 nt) genome contains two large bidirectionally transcribed ORFs. The smaller ORF (874 nt) has similarities to viral replication-associated protein (Rep) sequences of some bacteria and circoviruses, whereas the larger ORF (955 nt) does not relate to any sequences in public databases and we presume it potentially encodes the capsid protein. Phylogenetic analysis shows that the GaCSV Rep clusters with Rep-like sequences of bacterial origin, highlighting the role of ssDNA viruses in horizontal gene transfer. The occurrence of previously unknown viruses in organisms associated with human pollution is a relatively unexplored field. PMID- 23364191 TI - Coronaviruses in bats from Mexico. AB - Bats are reservoirs for a wide range of human pathogens including Nipah, Hendra, rabies, Ebola, Marburg and severe acute respiratory syndrome coronavirus (CoV). The recent implication of a novel beta (beta)-CoV as the cause of fatal respiratory disease in the Middle East emphasizes the importance of surveillance for CoVs that have potential to move from bats into the human population. In a screen of 606 bats from 42 different species in Campeche, Chiapas and Mexico City we identified 13 distinct CoVs. Nine were alpha (alpha)-CoVs; four were beta CoVs. Twelve were novel. Analyses of these viruses in the context of their hosts and ecological habitat indicated that host species is a strong selective driver in CoV evolution, even in allopatric populations separated by significant geographical distance; and that a single species/genus of bat can contain multiple CoVs. A beta-CoV with 96.5 % amino acid identity to the beta-CoV associated with human disease in the Middle East was found in a Nyctinomops laticaudatus bat, suggesting that efforts to identify the viral reservoir should include surveillance of the bat families Molossidae/Vespertilionidae, or the closely related Nycteridae/Emballonuridae. While it is important to investigate unknown viral diversity in bats, it is also important to remember that the majority of viruses they carry will not pose any clinical risk, and bats should not be stigmatized ubiquitously as significant threats to public health. PMID- 23364193 TI - Identification of a movement protein of Mirafiori lettuce big-vein ophiovirus. AB - Mirafiori lettuce big-vein virus (MiLBVV) is a member of the genus Ophiovirus, which is a segmented negative-stranded RNA virus. In microprojectile bombardment experiments to identify a movement protein (MP) gene of ophioviruses that can trans-complement intercellular movement of an MP-deficient heterologous virus, a plasmid containing an infectious clone of a tomato mosaic virus (ToMV) derivative expressing the GFP was co-bombarded with plasmids containing one of three genes from MiLBVV RNAs 1, 2 and 4 onto Nicotiana benthamiana. Intercellular movement of the movement-defective ToMV was restored by co-expression of the 55 kDa protein gene, but not with the two other genes. Transient expression in epidermal cells of N. benthamiana and onion showed that the 55 kDa protein with GFP was localized on the plasmodesmata. The 55 kDa protein encoded in the MiLBVV RNA2 can function as an MP of the virus. This report is the first to describe an ophiovirus MP. PMID- 23364194 TI - Arenavirus reverse genetics for vaccine development. AB - Arenaviruses are important human pathogens with no Food and Drug Administration (FDA)-licensed vaccines available and current antiviral therapy being limited to an off-label use of the nucleoside analogue ribavirin of limited prophylactic efficacy. The development of reverse genetics systems represented a major breakthrough in arenavirus research. However, rescue of recombinant arenaviruses using current reverse genetics systems has been restricted to rodent cells. In this study, we describe the rescue of recombinant arenaviruses from human 293T cells and Vero cells, an FDA-approved line for vaccine development. We also describe the generation of novel vectors that mediate synthesis of both negative sense genome RNA and positive-sense mRNA species of lymphocytic choriomeningitis virus (LCMV) directed by the human RNA polymerases I and II, respectively, within the same plasmid. This approach reduces by half the number of vectors required for arenavirus rescue, which could facilitate virus rescue in cell lines approved for human vaccine production but that cannot be transfected at high efficiencies. We have shown the feasibility of this approach by rescuing both the Old World prototypic arenavirus LCMV and the live-attenuated vaccine Candid#1 strain of the New World arenavirus Junin. Moreover, we show the feasibility of using these novel strategies for efficient rescue of recombinant tri-segmented both LCMV and Candid#1. PMID- 23364196 TI - On the design of a bioacoustic sensor for the early detection of the red palm weevil. AB - During the last two decades Red Palm Weevil (RPW, Rynchophorus Ferrugineus) has become one of the most dangerous threats to palm trees in many parts of the World. Its early detection is difficult, since palm trees do not show visual evidence of infection until it is too late for them to recover. For this reason the development of efficient early detection mechanisms is a critical element of RPW pest management systems. One of the early detection mechanisms proposed in the literature is based on acoustic monitoring, as the activity of RPW larvae inside the palm trunk is audible for human operators under acceptable environmental noise levels (rural areas, night periods, etc.). In this work we propose the design of an autonomous bioacoustic sensor that can be installed in every palm tree under study and is able to analyze the captured audio signal during large periods of time. The results of the audio analysis would be reported wirelessly to a control station, to be subsequently processed and conveniently stored. That control station is to be accessible via the Internet. It is programmed to send warning messages when predefined alarm thresholds are reached, thereby allowing supervisors to check on-line the status and evolution of the palm tree orchards. We have developed a bioacoustic sensor prototype and performed an extensive set of experiments to measure its detection capability, achieving average detection rates over 90%. PMID- 23364197 TI - Hybrid modeling method for a DEP based particle manipulation. AB - In this paper, a new modeling approach for Dielectrophoresis (DEP) based particle manipulation is presented. The proposed method fulfills missing links in finite element modeling between the multiphysic simulation and the biological behavior. This technique is amongst the first steps to develop a more complex platform covering several types of manipulations such as magnetophoresis and optics. The modeling approach is based on a hybrid interface using both ANSYS and MATLAB to link the propagation of the electrical field in the micro-channel to the particle motion. ANSYS is used to simulate the electrical propagation while MATLAB interprets the results to calculate cell displacement and send the new information to ANSYS for another turn. The beta version of the proposed technique takes into account particle shape, weight and its electrical properties. First obtained results are coherent with experimental results. PMID- 23364198 TI - Enhancement of NH3 gas sensitivity at room temperature by carbon nanotube-based sensor coated with Co nanoparticles. AB - Multi-walled carbon nanotube (MWCNT) film has been fabricated onto Pt-patterned alumina substrates using the chemical vapor deposition method for NH(3) gas sensing applications. The MWCNT-based sensor is sensitive to NH(3) gas at room temperature. Nanoclusters of Co catalysts have been sputtered on the surface of the MWCNT film to enhance gas sensitivity with respect to unfunctionalized CNT films. The gas sensitivity of Co-functionalized MWCNT-based gas sensors is thus significantly improved. The sensor exhibits good repeatability and high selectivity towards NH(3), compared with alcohol and LPG. PMID- 23364195 TI - Recent developments in human immunodeficiency virus-1 latency research. AB - Almost 30 years after its initial discovery, infection with the human immunodeficiency virus-1 (HIV-1) remains incurable and the virus persists due to reservoirs of latently infected CD4(+) memory T-cells and sanctuary sites within the infected individual where drug penetration is poor. Reactivating latent viruses has been a key strategy to completely eliminate the virus from the host, but many difficulties and unanswered questions remain. In this review, the latest developments in HIV-persistence and latency research are presented. PMID- 23364199 TI - Recent advances in bacteriophage based biosensors for food-borne pathogen detection. AB - Foodborne diseases are a major health concern that can have severe impact on society and can add tremendous financial burden to our health care systems. Rapid early detection of food contamination is therefore relevant for the containment of food-borne pathogens. Conventional pathogen detection methods, such as microbiological and biochemical identification are time-consuming and laborious, while immunological or nucleic acid-based techniques require extensive sample preparation and are not amenable to miniaturization for on-site detection. Biosensors have shown tremendous promise to overcome these limitations and are being aggressively studied to provide rapid, reliable and sensitive detection platforms for such applications. Novel biological recognition elements are studied to improve the selectivity and facilitate integration on the transduction platform for sensitive detection. Bacteriophages are one such unique biological entity that show excellent host selectivity and have been actively used as recognition probes for pathogen detection. This review summarizes the extensive literature search on the application of bacteriophages (and recently their receptor binding proteins) as probes for sensitive and selective detection of foodborne pathogens, and critically outlines their advantages and disadvantages over other recognition elements. PMID- 23364201 TI - Adsorption behavior and electronic properties of Pdn (n <= 10) clusters on silicon carbide nanotubes: a first-principles study. AB - First-principles calculations have been carried out to investigate the adsorption of Pd(n) (n <= 10) clusters on the single-walled (8, 0) and (5, 5) SiC nanotubes (SiCNTs). We find that the Pd(n) clusters can be stably adsorbed on the outer surfaces of both SiCNTs through an exothermic adsorption process. The adsorption energies of the Pd(n) clusters on the (8, 0) SiCNT are generally larger than those of clusters on the (5, 5) SiCNT. The number of bonds between the Pd(n) clusters and the SiCNTs increases with increasing cluster size. The Pd atoms adjacent to the SiCNTs adsorb preferentially on the bridge sites over an axial Si C bond. The adsorption leads to elongation of the Pd-Pd bond lengths and structural reconstruction for the Pd(n) clusters. Moreover, the adsorbed Pd(n) clusters show two-layered structures at the cluster size n >= 4. We also find that the adsorbed Pd(n) clusters induce some impurity states within the band gap of the pristine SiCNTs and the strong pd hybridization near the Fermi level, thereby reducing the band gap. The charge transfer from the SiCNTs to the Pd atoms that occurs is observed for all the systems considered. Due to the strong interactions between the Pd(n) clusters and the SiCNTs, most adsorbed Pd(n) clusters exhibit zero magnetic moment. PMID- 23364202 TI - Warning about warnings: weighing risk and benefit when information is in a state of flux. AB - In 2010, new data about the safety of recombinant human growth hormone (rhGH) resulted in warnings and subsequent pronouncements by the US Food and Drug Administration (FDA) and its European counterpart [the European Medicines Agency (EMA)] regarding its use in children and adolescents as an elective treatment for short stature. However, opinions about these new data are divergent: the FDA did not change the label of the drug and experts have argued for further research on the safety of rhGH. In this situation of an evolving scientific controversy, it is unclear how questions about benefit and risk are communicated to patients and their parents. Social biases and misperceptions about the deleterious effects of short stature and the benefits of added height influence decisions to prescribe rhGH and may affect discussions of the warnings by regulators. Fully supporting a model of shared decision-making involving children and adolescents requires sharing risk-benefit information, including evolving information from drug regulators, with patients and parents. PMID- 23364203 TI - Effects of physical activity programmes in the workplace (PAPW) on the perception and intensity of musculoskeletal pain experienced by garment workers. AB - OBJECTIVE: The physical activity programmes in the workplace (PAPW) are applied to minimize the prevalence, incidence and intensity of pain. This study evaluated the perception of pain and quantifies its intensity among garment workers before and after performing a PAPW. PARTICIPANTS: We included 61 workers of a clothing company, who were classified randomly into experimental group (n = 44) 28.7 +/- 8.8 years old and a control group (n = 17) 27.8 +/- 7.4 years (20-43 years). METHODS: The Trigger Points test questionnaire was used to assess pain perception and quantify its intensity. The PAPW was conducted in 15-minute sessions per day, consisting of stretching exercises (40%), muscular endurance (40%), self-massage relaxation and massage techniques (10%), and group dynamics (10%). RESULTS: The garment workers who participated in the PAPW showed a significant reduction of pain felt in the neck and wrists, and also a reduction in pain intensity in shoulders, arms, fingers and wrists that are most often strained during sewing. CONCLUSIONS: Our findings suggest that PAPW that target muscle groups that are more tense in sewing tasks, may be considered by companies for supporting adaptation to the work environment and improving health by reducing muscle and joint pain. PMID- 23364204 TI - The financial impact of employment decisions for individuals with HIV. AB - OBJECTIVE: Individuals living with HIV face challenging employment decisions that have personal, financial, and health impacts. The decision to stay or to leave the work force is much more complicated for an individual with HIV because the financial choices related to potential health benefits are not clearly understood. To assist in the decision-making process for an individual with HIV, we propose to develop a decision model that compares the potential costs and benefits of staying in or leaving the work force. PARTICIPANTS: A hypothetical cohort of HIV-infected individuals was simulated in our decision model. Characteristics of these individuals over a one-year period were extracted from the medical literature and publicly available national surveys. Men and women between the ages of 18 and 59 were included in our simulated cohort. METHODS: A decision tree model was created to estimate the financial impact of an individual's decision on employment. The outcomes were presented as the cost savings associated with the following employment statuses over a one-year period: 1) staying full-time, 2) switching from full-to part-time, 3) transitioning from full-time to unemployment, and 4) staying unemployed. CD4 T cell counts and employment statuses were stratified by earned income. Employment probabilities were calculated from national databases on employment trends in the United States. Sensitivity analyses were conducted to test the robustness of the effects of the variables on the outcomes. RESULTS: Overall, the decision outcome that resulted in the least financial loss for individuals with HIV was to remain at work. For an individual with CD4 T cell count > 350, the cost difference between staying employed full-time and switching from full-time to part-time status was a maximum of $2,970. For an individual with a CD4 T cell count between 200 and 350, the cost difference was as low as $126 and as great as $2,492. For an individual with a CD4 T cell count < 200, the minimum cost difference was $375 and the maximum cost difference was $2,253. CONCLUSIONS: Based on our simulated model, we recommend an individual with CD4 T cell count > 350 to stay employed full-time because it resulted in the least financial loss. On the other hand, for an individual with a CD4 T cell < 350, the financial cost loss was much more variable. Our model provides an objective decision-making guide for individuals with HIV to weigh the costs and benefits of employment decisions. PMID- 23364205 TI - Dietary spices as beneficial modulators of lipid profile in conditions of metabolic disorders and diseases. AB - Spices are valued for their medicinal properties besides their use as food adjuncts to enhance the sensory quality of food. Dietary garlic, onion, fenugreek, red pepper, turmeric, and ginger have been proven to be effective hypocholesterolemics in experimentally induced hypercholesterolemia. The hypolipidemic potential of fenugreek in diabetic subjects and of garlic and onion in humans with induced lipemia has been demonstrated. Capsaicin and curcumin - the bioactive compounds of red pepper and turmeric - are documented to be efficacious at doses comparable to usual human intake. Capsaicin and curcumin have been shown to be hypotriglyceridemic, thus preventing accumulation of fat in the liver under adverse situations by enhancing triglyceride transport out of the liver. Capsaicin, curcumin, fenugreek, ginger, and onion enhance secretion of bile acids into bile. These hypocholesterolemic spices/spice principles reduce blood and liver cholesterol by enhancing cholesterol conversion to bile acids through activation of hepatic cholesterol-7alpha-hydroxylase. Many human trials have been carried out with garlic, onion, and fenugreek. The mechanism underlying the hypocholesterolemic and hypotriglyceridemic influence of spices is fairly well understood. Health implications of the hypocholesterolemic effect of spices experimentally documented are cardio-protection, protection of the structural integrity of erythrocytes by restoration of membrane cholesterol/phospholipid profile and prevention of cholesterol gallstones by modulation of the cholesterol saturation index in bile. PMID- 23364206 TI - Advanced native kidney renal cell carcinoma in renal transplant recipients: role of sirolimus as dual anti-cancer and anti-rejection agent. AB - The incidence of native kidney renal cell carcinoma (RCC) in renal transplant recipients is 15 times higher than the general population. These tumors are often found incidentally when imaging is performed for another indication. At that stage tumors are usually small and asymptomatic but it is possible that they may escape detection until a more advanced stage. Early stage RCC can be treated with radical nephrectomy but the treatment of advanced RCC may be more complicated and is associated with a poorer prognosis. RCC in context of renal transplant presents a special therapeutic challenge; balancing treatment of a potentially lethal malignancy in a redundant organ whilst maintaining good allograft function.We describe 2 cases of advanced renal cell carcinoma of native kidneys in renal transplant recipients and present our experience with sirolimus as a dual immunosuppressive and anti-tumor agent. PMID- 23364207 TI - A case of IgA nephropathy associated with mycosis fungoides that developed into rapidly progressive glomerulonephritis. AB - A 53-year-old Japanese male was diagnosed with atopic dermatitis and initiated treatment with a local dermatologist in February 2001. A routine medical check-up revealed proteinuria, microscopic hematuria and slight elevation of serum creatinine level in spring 2006. He was referred to our hospital for nephrology consultation and followup.In December 2009, he developed a sudden high fever of greater than 39 degrees C with sore throat. In addition, his serum creatinine level greatly increased to 4.6 mg/dl. His prevalent renal illness was thought to be rapidly progressive glomerulonephritis (RPGN). Soon after admission, kidney and skin biopsies were performed. The kidney specimens showed that the glomeruli had proliferative mesangial cells strongly positive for anti-IgA antibody, 75% of which manifested fibrocellular crescentic formation surrounding the Bowman's capsules. His skin disease was pathologically proven to be mycosis fungoides(MF). It is likely that his kidney disease was exacerbated by the upper respiratory tract infection and converted to RPGN. Ash is kidney function rapidly declined, hemodialysis therapy was initiated and he remains on chronic dialysis therapy. This is a serious case of IgA nephropathy associated with MF,which developed into RPGN and subsequent end-stage renal disease. PMID- 23364208 TI - Factitious proteinuria - the most dominant feature in a young female patient with Munchausen syndrome. AB - Munchausen syndrome is a factitious disorder with predominantly physical signs and symptoms, resulting from the patient's high motivation for assuming a sick role, without any external incentives or boundaries. We report the case of a young female patient with factitious proteinuria in the nephrotic range and a fairly eventful medical history. After performing many expensive and unnecessary investigations and procedures,the real origin of the proteinuria was determined;it was found to be caused by the patient carefully adding calibrated egg albumin to her urine samples. This discovery roused suspicions about multiple, non-corroborated conditions from her history (e.g., multiple miscarriages, breast cancer, and thyroid disorders).The diversity of diseases presented by a single Munchausen patient tends to be bizarre,and thus is a challenge for health care providers to diagnose the condition. Teamwork is therefore of the utmost necessity to diagnose Munchausen syndrome. PMID- 23364210 TI - The combination of work organizational climate and individual work commitment predicts return to work in women but not in men. AB - OBJECTIVE: To analyze if the combination of organizational climate and work commitment can predict return to work (RTW). METHODS: This prospective Swedish study was based on 2285 participants, 19 to 64 years old, consecutively selected from the employed population, newly sick-listed for more than 14 days. Data were collected in 2008 through postal questionnaire and from register data. RESULTS: Among women, the combination of good organizational climate and fair work commitment predicted an early RTW with an adjusted relative risk of 2.05 (1.32 to 3.18). Among men, none of the adjusted variables or combinations of variables was found significantly to predict RTW. CONCLUSIONS: This study demonstrated the importance of integrative effects of organizational climate and individual work commitment on RTW among women. These factors did not predict RTW in men. More research is needed to understand the RTW process among men. PMID- 23364211 TI - Work-related productivity losses in an era of ageing populations: the case of colorectal cancer. AB - OBJECTIVE: We investigated patterns and costs of lost productivity due to colorectal cancer in Ireland and examined how rising pension ages affect these costs. METHODS: Data from a postal survey of colorectal cancer survivors (6 to 30 months after diagnosis; n = 159), taken from March 2010 to January 2011, were combined with population-level survival estimates and national wage data to calculate temporary and permanent disability, and premature mortality, costs using the human capital approach. RESULTS: Almost 40% of respondents left the workforce permanently after diagnosis and 90% took temporary time off work. Total costs of lost productivity per person were 205,847 in 2008 assuming retirement at the age of 65. When the retirement age was raised to 70, productivity costs increased by almost a half. CONCLUSIONS: Our study demonstrated the considerable productivity costs associated with colorectal cancer and highlighted the effect of rising retirement ages on costs. PMID- 23364212 TI - Psychosocial work factors and sick leave, occupational accident, and disability pension: a cohort study of civil servants. AB - OBJECTIVE: To study associations between psychosocial work factors (PWF) and sick leave, occupational accident, and disability pension. METHODS: A random population of 967 civil servants participated in a survey on PWF and health. The median follow-up time was 7 years. RESULTS: Frequent feedback from supervisor, good opportunities for mental growth, good team climate, and high appreciation were associated with a decrease in the risk of sickness absences and shift/period work, monotonous movements, and crowdedness of workplace were associated with an increase in the risk of sickness absences. Good communication at work was associated with a decrease in client violence and high work pressure was associated with an increased risk of occupational accidents. High work control and good team climate were associated with a decreased and shift/period work and client violence was associated with an increased risk of disability pensions. CONCLUSIONS: Psychosocial work factors can predict health outcomes with economic impact. PMID- 23364209 TI - The general population cohort in rural south-western Uganda: a platform for communicable and non-communicable disease studies. AB - The General Population Cohort (GPC) was set up in 1989 to examine trends in HIV prevalence and incidence, and their determinants in rural south-western Uganda. Recently, the research questions have included the epidemiology and genetics of communicable and non-communicable diseases (NCDs) to address the limited data on the burden and risk factors for NCDs in sub-Saharan Africa. The cohort comprises all residents (52% aged >=13years, men and women in equal proportions) within one half of a rural sub-county, residing in scattered houses, and largely farmers of three major ethnic groups. Data collected through annual surveys include; mapping for spatial analysis and participant location; census for individual socio demographic and household socioeconomic status assessment; and a medical survey for health, lifestyle and biophysical and blood measurements to ascertain disease outcomes and risk factors for selected participants. This cohort offers a rich platform to investigate the interplay between communicable diseases and NCDs. There is robust infrastructure for data management, sample processing and storage, and diverse expertise in epidemiology, social and basic sciences. For any data access enquiries you may contact the director, MRC/UVRI, Uganda Research Unit on AIDS by email to mrc@mrcuganda.org or the corresponding author. PMID- 23364213 TI - Prognosis of acute coronary events is worse in patients living alone: the FINAMI myocardial infarction register. AB - BACKGROUND: Single living has been associated with a worse prognosis of acute coronary syndrome (ACS). We aimed to study the relation of sociodemographic characteristics to the morbidity, mortality, and case fatality (CF) of ACS in a large population-based ACS register. METHODS: The population-based FINAMI myocardial infarction register recorded 15,330 cases of ACS among persons aged 35 99 years in Finland in 1993-2002. Record linkage with the files of Statistics Finland provided information on sociodemographic characteristics (marital status, household size). RESULTS: ACS incidence and 28-day mortality rate were higher in unmarried men and women in all age groups. The prehospital CF of incident ACS was higher in single living and/or unmarried 35-64-year-old people. The 28-day CF was 26% (95% confidence interval, CI, 24-29%) in married men, 42% (95% CI 37-47%) in men who had previously been married, and 51% (95% CI 46-57%) in never-married men. Among women, the corresponding figures were 20% (95% CI 15-24%), 32% (95% CI 25-39%), and 43% (95% CI 31-56%). Most of these CF differences were apparent already at the prehospital phase. The only difference in treatment was that middle-aged men living alone or unmarried received thrombolysis less often. The disparities in ACS morbidity and mortality by marital status tended to widen during the study period. CONCLUSIONS: Single living and/or being unmarried increases the risk of having a heart attack and worsens its prognosis both in men and women regardless of age. Most of the excess mortality appears already before the hospital admission and seems not to be related to differences in treatment of ACS. PMID- 23364214 TI - Neuropathic pain components are common in patients with painful cervical radiculopathy, but not in patients with nonspecific neck-arm pain. AB - OBJECTIVES: The aim of this study was to investigate, using quantitative sensory testing (QST) parameters and the painDETECT (PD-Q) screening questionnaire, the presence of neuropathic pain (NeP) in patients with unilateral painful cervical radiculopathy (CxRAD) and in patients with unilateral nonspecific neck-arm pain associated with heightened nerve mechanosensitivity (NSNAP). METHODS: All patients completed the PD-Q before QST. QST was performed bilaterally in the maximal pain area and the affected dermatome in 23 patients with painful C6 or C7 radiculopathy and in 8 patients with NSNAP following a C6/7 dermatomal pain distribution. RESULTS: Patients with CxRAD demonstrated a significant loss of sensory function in mechanical (P<=0.021) and vibration sense (P<=0.003) on the symptomatic side compared with the asymptomatic side in both tested body regions and in the dermatome reduced cold detection (P=0.021) and pressure pain sensitivity (P=0.005), findings consistent with nerve root damage. These sensory alterations in the maximal pain area/symptomatic side are confirmative for the presence of NeP. In contrast to these QST data, only 30% of patients with CxRAD demonstrated a NeP component according to the PD-Q score. In patients with NSNAP, a significant side-to-side difference was demonstrated for warm detection threshold in the dermatome (P=0.030). The PD-Q score indicated that NeP components were unlikely in this group. DISCUSSION: QST data suggest that NeP is likely to be observed in patients with painful CxRAD, but not in patients with NSNAP. PMID- 23364216 TI - Mixed-linker MOFs with CAU-10 structure: synthesis and gas sorption characteristics. AB - The metal-organic framework compound [Al(OH)(BDC-Br)] (1) (BDC-Br2- = 5-bromo-1,3 benzenedicarboxylate) denoted CAU-10-Br was synthesised under solvothermal reaction conditions. Its structure was successfully refined by Rietveld methods. The framework is based on the connection of infinite helical chains of cis-corner sharing AlO6-polyhedra via BDC-Br2- ions. Thus non-intersecting parallel channels are formed, each periodically varying in diameter between 1.1 and 6.6 A. Nevertheless 1 adsorbs CO2 at 298 K, while it is non-porous towards H2 and N2 at 77 K. Employing high-throughput (HT) methods we identified synthesis conditions that lead to the formation of mixed-linker MOFs with CAU-10 topology. Starting with a molar ratio H2BDC:H2BDC-Br = 3:1 we established a synthesis procedure for the partially bromo-functionalised mixed-linker-MOF [Al(OH)(BDC)0.8(BDC-Br)0.2] (2) denoted as CAU-10-H/Br. Starting with a molar ratio H2BDC-NH2:H2BDC-NO2 = 1:1 the partially NO2- and NH2-functionalised mixed-linker MOF [Al(OH)(BDC NO2)0.55(BDC-NH2)0.23(BDC-NHCHO)0.22] (3) denoted as CAU-10-NO2/NH2 was synthesised, in which the NH2-groups were found to be partially formylated. The partial bromo-functionalisation in CAU-10-H/Br (2) leads to a lower sorption capacity in comparison with the parent structure CAU-10-H, while the pore accessibility is comparable. The incorporation of NO2-, NH2- and NHCHO-groups in CAU-10-NO2/NH2 (3) does not only affect the accessibility of the pores for N2, but results also in an increased capacity for H2 and CO2 in comparison with the parent structure CAU-10-NO2. The reproducibility of the synthesis procedures was tested regarding the composition of the MOFs and the resulting gas sorption properties. In 2 a molar fraction of (BDC)2- = 80 +/- 2% is found, while in 3 a molar fraction of (BDC-NO2)2- = 55 +/- 2% is observed. Starting from the molar ratio H2BDC:H2BDC-CH3 = 1:1 mixed linker MOFs denoted as CAU-10-H/CH3 (4) were also obtained. In contrast to 2 and 3 the molar ratios of BDC2-/BDC-CH32- and especially the sorption properties differ substantially for every batch. The compounds were further characterised by X-ray powder diffraction, thermogravimetric/elemental analysis, NMR/Vis/IR-spectroscopy, and gas sorption measurements. PMID- 23364218 TI - Predictors of physical activity 6 months postintervention in the active for life initiative. AB - BACKGROUND: Understanding who is most and least likely to remain active after the completion of physical activity (PA) interventions can assist in developing more targeted and effective programs to enhance prolonged behavior change. The purpose of this study was to examine predictors of meeting PA recommendations 6 months postintervention in participants enrolled in Active for Life. METHODS: Participants from 2 behavioral PA programs [158 Active Choices (AC); 1025 Active Living Every Day (ALED)] completed surveys 6 months after completion of the active intervention. Analyses examined predictors of meeting PA recommendations at follow-up. RESULTS: The following were significant predictors: In ALED: self report health status, satisfaction with body function, and self-efficacy at baseline; PA status at posttest; changes in self-efficacy, perceived stress, and satisfaction with body function and appearance from baseline to posttest. In AC: PA status at post-test. CONCLUSIONS: The ultimate goal of health promotion programs is to teach the behavioral skills necessary to sustain behavior change once an active intervention is complete. The findings from this study suggest that predicting PA behavior after cessation of PA interventions may not be straightforward, and predictor variables may operate differently in different intervention approaches. PMID- 23364217 TI - Optimal dose period for indisetron tablets for preventing chemotherapy-induced nausea and vomiting with modified FOLFOX6: a randomized pilot study. AB - BACKGROUND: Indisetron is a serotonin (5-hydroxytryptamine type 3) receptor antagonist that also antagonizes 5-hydroxytryptamine type 4 receptors. We designed a pilot study in order to explore the optimal dosing period for indisetron during modified FOLFOX6 (mFOLFOX6). PATIENTS AND METHODS: Forty-two chemotherapy-naive patients with advanced colorectal cancer scheduled to receive mFOLFOX6 were randomly assigned to either a 1- or 3-day indisetron regimen arm. The primary endpoint was complete protection from vomiting. RESULTS: Proportions of patients with complete protection from vomiting were 85.7% [95% confidence interval (CI) 63.7-97.0] with the 3-day regimen and 81.0% (95% CI 58.1-94.6) with the 1-day regimen. Proportions of patients with complete protection from nausea were 47.6% in each arm (95% CI 25.7-70.2). No rescue therapy rates were 66.7% (95% CI 43.0-85.4) versus 57.1% (95% CI 34.0-78.2). No severe adverse events were observed in either arm. CONCLUSION: Both 1- and 3-day indisetron regimens were feasible for preventing nausea and vomiting induced by mFOLFOX6. PMID- 23364219 TI - Patient selection for therapy reduction after long-term daily proton pump inhibitor treatment for gastro-oesophageal reflux disease: trial and error. AB - BACKGROUND: Proton pump inhibitor (PPI) therapy reduction after long-term daily treatment for gastro-oesophageal reflux disease (GORD) symptomatology proves difficult in primary care practice. We aimed to identify patient and/or disease characteristics in long-term daily PPI users predicting a successful switch to less than daily therapy. METHODS: GORD patients who after long-term continuous treatment were able to use less than a daily PPI dose in a placebo-controlled trial were compared to patients who persisted in a daily dosage with respect to general, lifestyle and quality of life characteristics (SF-36 Health Survey) as well as psychological factors (Symptom Check List 90), symptom control on daily PPI (Quality of Life in Reflux and Dyspepsia questionnaire), disease and medication history. RESULTS: Adequate symptom control on daily PPI use and female gender were determinants of successful therapy reduction. A prediction rule including the Quality of Life in Reflux and Dyspepsia vitality dimension and gender correctly predicted 64% of patients to both less than daily and sustained daily treatment (area under the receiver operating characteristic curve = 0.69). CONCLUSION: In the heterogeneous population of PPI users for GORD in primary care, no clinically useful, easily obtainable combination of patient characteristics was able to adequately predict eligibility for therapy reduction. Switching to less than daily therapy remains a process of trial and error in which motivation of the patient and support by the physician will be important factors for success. PMID- 23364221 TI - The prevalence, impact and economic implications of atrial fibrillation in stroke: what progress has been made? AB - Atrial fibrillation (AF) is a major risk factor for stroke, especially in the elderly. Increased life expectancies mean that AF-related stroke is a growing global public health concern. Improvements in the detection, treatment and prevention of the consequences of AF have occurred in recent years. However, the extent to which these improvements have impacted on the prevalence of AF, the risk of AF-related stroke and subsequent economic costs are unknown. This review provides a contemporary assessment of the epidemiological data on AF-related stroke aimed at assessing the effectiveness of primary prevention strategies and associated economic implications with reductions in stroke incidence. A systematic review of the literature was performed. Appropriately designed studies were identified and retrieved. Evidence on changes in the prevalence of AF, the risk of stroke associated with AF and the excess cost of AF-related stroke over the last 30 years was summarised. The results provide evidence that the age adjusted prevalence of AF and the relative risk of stroke associated with AF has remained relatively constant. Unless action is taken to improve detection of AF and reduce its consequences, a considerable increase in the social and economic burden associated with AF-related stroke is likely. PMID- 23364222 TI - Huge solitary fibrous tumor of the pleura with hypoglycemia and hypokalemia: a case report. AB - The occurrence of hypoglycemia with an intrathoracic tumor is referred to as Doege- Potter syndrome (DPS). However, the association between hypokalemia and DPS is rare. We report a case of a solitary fibrous tumor of the pleura with refractory hypoglycemia and hypokalemia. A 57-year-old male was admitted to our hospital for unconsciousness. His serum glucose and potassium levels were low. Radiological findings revealed a large tumor occupying the left hemithorax. Despite being treated with glucose and potassium replacement therapy, the patient still suffered from repetitive fasting hypoglycemic and hypokalemia episodes. After the tumor was completely resected, his serum levels of glucose and potassium returned to normal level. PMID- 23364220 TI - Disruption of the putative vascular leak peptide sequence in the stabilized ricin vaccine candidate RTA1-33/44-198. AB - Vitetta and colleagues identified and characterized a putative vascular leak peptide (VLP) consensus sequence in recombinant ricin toxin A-chain (RTA) that contributed to dose-limiting human toxicity when RTA was administered intravenously in large quantities during chemotherapy. We disrupted this potentially toxic site within the more stable RTA1-33/44-198 vaccine immunogen and determined the impact of these mutations on protein stability, structure and protective immunogenicity using an experimental intranasal ricin challenge model in BALB/c mice to determine if the mutations were compatible. Single amino acid substitutions at the positions corresponding with RTA D75 (to A, or N) and V76 (to I, or M) had minor effects on the apparent protein melting temperature of RTA1-33/44-198 but all four variants retained greater apparent stability than the parent RTA. Moreover, each VLP(-) variant tested provided protection comparable with that of RTA1-33/44-198 against supralethal intranasal ricin challenge as judged by animal survival and several biomarkers. To understand better how VLP substitutions and mutations near the VLP site impact epitope structure, we introduced a previously described thermal stabilizing disulfide bond (R48C/T77C) along with the D75N or V76I substitutions in RTA1-33/44-198. The D75N mutation was compatible with the adjacent stabilizing R48C/T77C disulfide bond and the T(m) was unaffected, whereas the V76I mutation was less compatible with the adjacent disulfide bond involving C77. A crystal structure of the RTA1-33/44-198 R48C/T77C/D75N variant showed that the structural integrity of the immunogen was largely conserved and that a stable immunogen could be produced from E. coli. We conclude that it is feasible to disrupt the VLP site in RTA1-33/44-198 with little or no impact on apparent protein stability or protective efficacy in mice and such variants can be stabilized further by introduction of a disulfide bond. PMID- 23364223 TI - Pulmonary and pleural metastases from benign meningeal meningioma: a case report. AB - Meningiomas are generally benign tumors, but rarely metastasize outside of the central nervous system. A 25-year-old female was admitted to our institute because of an abnormal shadow on her chest x-ray. A computed tomography (CT) scan showed a 3-cm, well- circumscribed mass in the right lower lobe of the lung. We performed thoracotomy and resected three pulmonary tumors at the right lung and diaphragm. Histological examination revealed a benign meningothelial meningioma. Six months later, she complained of heaviness of her head and a head CT scan revealed an intracranial mass. A craniotomy was performed and a brain tumor was found to be histologically identical to the lung tumors. During the 21 years since the first operation, we performed three times of pulmonary and pleural metastasectomies and two times of resection of intracranial local recurrences. All of those tumors were meningothelial meningioma without malignant change. The patient is alive without metastasis after the last resection of metastatic tumors. PMID- 23364224 TI - Partial anomalous pulmonary venous connection associated with lung cancer in the same lobe: report of a case. AB - A 64-year-old man with primary lung cancer (cT1aN0M0) was diagnosed as having partial anomalous pulmonary venous connection (PAPVC) in the same lobe by preoperative chest computed tomography (CT). The anomalous vein originated from left upper lobe pulmonary vein and flowed into the left brachiocephalic vein. Although the patient was asymptomatic, cardiac catheterization revealed that pulmonary-systemic blood flow ratio (Qp/Qs ratio) was 2.0, and his pulmonary arterial pressure was marginally elevated (60/18 mmHg). We performed left upper lobectomy as the definitive treatment for both lung cancer and PAPVC. His pulmonary arterial pressure decreased after lobectomy (33/16 mmHg). He is living well without relapse of lung cancer 56 months after surgery. Although PAPVC is detectable on computed tomography, out of 7 previous reports of PAPVC associated with lung cancer, only 2 cases were diagnosed preoperatively. The presence of PAPVC should be kept in mind before major lung resections. PMID- 23364225 TI - Ectopic cervical thymoma accompanied by Good's syndrome. AB - Ectopic cervical thymoma (ECT) is a rare tumor that is frequently misdiagnosed as a thyroid tumor or other malignancy. A 34-year-old male with a right palpable neck mass had been mistakenly diagnosed with T-cell lymphoblastic lymphoma even after an open biopsy. The atypical clinical course, including hypogammaglobulinemia, led us to the correct diagnosis; ECT accompanied by Good's syndrome (GS). After the intravenous infusion of gammaglobulin, tumor resection and a subsequent video-assisted thoracoscopic extended thymectomy were performed. The final diagnosis was type AB thymoma, Masaoka stage I. This report is, to the best of our knowledge, the first description of this extremely rare combination. PMID- 23364226 TI - Coronary artery bypass grafting in a patient with unstable angina pectoris and bronchiectasis. AB - Bronchiectasis is characterized by the abnormal and permanent dilatation of bronchi. Clinical manifestations of bronchiectasis include persistent or recurrent cough, purulent sputum, hemosputum, and hemoptysis. A 75-year-old man with bronchiectasis required coronary bypass grafting for unstable angina pectoris with severe stenosis of the left main trunk. Computed tomography showed fistulae between the dilated bronchial arteries and the left pulmonary artery. Cardiac catheter examination showed significant left-right shunt and left ventricular dilatation. To avoid perioperative massive hemoptysis, embolizations of 2 bronchial arteries and an inferior phrenic artery were performed preceding the coronary artery bypass grafting. Both transcatheter embolization and coronary artery bypass grafting were successfully performed without any complications. Herein, we illustrate a very rare case of bronchiectasis in a patient with unstable angina pectoris who underwent transcatheter embolization for a systemic pulmonary shunt preceding coronary artery bypass grafting with cardiopulmonary bypass. PMID- 23364227 TI - A resectable pancreatic metastasis from pulmonary adenocarcinoma. AB - A 67-year-old man, diagnosed as primary pulmonary adenocarcinoma by intraoperative fine-needle aspiration biopsy cytology, underwent right lower lobectomy with radical lymphadenectomy. The pathological stage was Stage IIA (pT1bN1M0, N-reason: 12L positive). After surgery, nodular shadows without intrathoracic lymph node or distant metastasis were demonstrated metachronously three times by follow-up CT. Wedge resection was performed for each of the tumors, and the pathological diagnosis in each case was primary pulmonary adenocarcinoma, Stage IA (T1b), IA (T1a) and IA (T1a), respectively. Five years after the initial pulmonary resection, a follow-up abdominal CT revealed a20-mm nodular shadow. We suspected that this pancreatic tumor might be a primary rather than metastatic one, therefore, pancreatoduodenectomy was performed. Pathological examination revealed adenocarcinoma that was positive for thyroid transcription factor (TTF)-1, allowing a final diagnosis of metastatic pulmonary adenocarcinoma.This case is very rare, because most cases of pancreatic metastasis from lung cancer have already widespread disease at the time of diagnosis.This case illustrates that pancreatic metastasis from pulmonary adenocarcinoma should be borne in mind, even if the pancreatic tumor is a solitary lesion without additional organ metastasis. PMID- 23364228 TI - A rare, combined cardiac and hepatic crossbow injury. AB - A 32-year-old man presented to our hospital after a failed suicide attempt using a crossbow. The patient had shot himself in close range with a double-barreled crossbow, simultaneously two arrows, in the chest. In spite of his life threatening injuries, the man survived. The lodged arrows helped to avoid tremendous loss of blood. After his arrival in the hospital, the surgical removal of the arrows proceeded under direct visualization with corresponding sutures on the heart and liver. The patient's postoperative course was uneventful. PMID- 23364229 TI - Cerebroprotective effect of preoperative dual antiplatelet therapy in patients undergoing coronary bypass surgery. AB - OBJECTIVES: Reduction of cognitive function is a possible side effect after coronary artery surgery using cardiopulmonary bypass (CPB). We investigated the effect of single versus dual antiplatelet therapy on cognitive performance in patients undergoing coronary artery bypass grafting (CABG) with CPB. METHODS: 50 consecutive CABG patients with preoperative intake of aspirin were compared to 49 consecutive patients with aspirin and clopidogrel. Six neuropsychological subtests from the Syndrom Kurz Test and the Alzheimer's Disease Assessment Scale were performed preoperatively and on the third postoperative day. To assess the overall cognitive function and the degree of cognitive decline across all tests after surgery we combined the six test-scores by principal component analysis. RESULTS: Patients had a mean age of 66.1 +/- 9.3 years, received a mean of 2.8 +/ 1.0 bypasses within an average of 87 +/- 31 minutes on cardiopulmonary bypass. These parameters as well as the preoperative combined neurocognitive score were not significantly different between the groups. After the operation there was a significant deterioration of the combined neuropsychological score in both groups (single: preop -0.2 +/- 1.5 vs. postop -1.8 +/- 1.7, p = 0.000 and dual: preop 0.2 +/- 1.5 vs. postop -0.5 +/- 2.1, p = 0.004). However, the patients operated under dual antiplatelet therapy showed a significant less decline of overall cognitive function compared to the single antiplatelet therapy patients (dual: 0.7 +/- 1.5 vs single: 1.6 +/- 1.6, p = 0.004). CONCLUSION: Dual antiplatelet therapy has a cerebroprotective effect in patients undergoing coronary artery bypass surgery. Compared to single antiplatelet therapy it reduces an early postoperative substantial decline of neuropsychological abilities. PMID- 23364230 TI - Effect of tadalafil on neointimal hyperplasia in a rabbit carotid artery anastomosis model. AB - PURPOSE: Intimal thickening, which results from the response to arterial damage caused by therapeutic interventions or other reasons, is usually called as neointima. Neointimal hyperplasia is a main step in the pathogenesis of late-term restenosis, which is developed after vascular interventions. Reduction in nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling plays a substantial role in the pathogenesis of neointima formation. Phosphodiesterase V is detected in the peripheral coronary and pulmonary vascular smooth muscle cells and in the cardiac tissue. Based on the effects of phosphodiesterase V inhibitors on vascular smooth muscle cells, in the present study, the effect of tadalafil, a new member of phosphodiesterase V inhibitors, on neointimal hyperplasia was investigated in the rabbit carotid artery anastomosis model. MATERIAL AND METHOD: Fourteen male New Zealand white rabbits weighing between 2.5-3 kg, were used. The rabbits were randomly divided into two equal groups; tadalafil group received oral tadalafil (2 mg/kg/day), and PBS group received sterile PBS solution (normal saline; 2 mg/kg/day) for 28 days after the surgery. The right carotid arteries of all rabbits were anastomosed in an end-to-end fashion using 8/0 polypropylene suture. The rabbits were sacrificed at the end of the postoperative period of 28 days. After sacrificing, firstly anastomosis segment on the right carotid artery and secondly a part of the left carotid artery (as control) of each rabbit were removed. Morphometric examination of tissue sections was performed under a light microscope connected to an image capture system. RESULTS: There was a significant difference between the right and left carotid arteries in terms of intimal area and intima/media ratio both in tadalafil and PBS groups (p <0.001 for each). Intimal area and intima/media ratio were increased in the right carotid arteries compared to the left carotid arteries (p <0.001 for each). Besides, when the right carotid arteries of both groups were compared using covariance analysis, it was observed that intimal area and intima/media ratio in the anastomosis site were significantly reduced with tadalafil treatment (p <0.001). CONCLUSION: The present study was promising in terms of tadalafil use as a new agent for the prevention of neointimal hyperplasia, which is the leading cause of late-term graft failure in vascular surgery. PMID- 23364231 TI - Relationship between arteriosclerosis obliterans and the ratio of serum eicosapentaenoic acid to arachidonic acid. AB - PURPOSE: A low ratio of serum eicosapentaenoic acid to arachidonic acid (EPA/AA) has been associated with coronary artery disease. We retrospectively examined serum concentrations of polyunsaturated fatty acids in patients with arteriosclerosis obliterans (ASO) and in non-atherosclerotic patients. METHODS: From April 2011 to March 2012, serum EPA/AA was retrospectively examined in 33 consecutive outpatients with ASO complicated by intermittent claudication and 21 outpatients with hypercholesterolemia without ASO as controls. The Student's t test was used for continuous variables and Chi-square test for categorical variables, with analysis of covariance adjusting for age, sex, body mass index, smoking, alcohol, and diabetes. RESULTS: The ASO group were significantly different with regard to mean age (71.5 vs. 63.9 year-old, p = 0.03), body mass index (21.3 vs. 24.1 kg/m(2), p = 0.002) and morbidity of diabetes mellitus (51.5 vs. 4.8%, p = 0.0004). Serum EPA/AA was significantly decreased in ASO (0.36 vs. 0.61, p = 0.03), when adjusted for age, sex, body mass index, smoking status and alcohol drinking, but was not statistically significant when adjusted for diabetes. CONCLUSION: Patients with ASO were more likely to have a low EPA/AA ratio and non- diabetic patients with ASO had a significantly reduced EPA/AA. PMID- 23364232 TI - Relationship between lung adenocarcinoma histological subtype and patient prognosis. AB - PURPOSE: Lung adenocarcinoma (AC) demonstrates various histological subtypes within the tumour tissue. A panel established jointly by the IASLC, ATS and ERS classified invasive lung ACs based on the predominant histological subtype. We examined the distribution of tumours in lung AC patients according to histological subtype and analysed the effects of this classification on survival. METHODS: The records of patients who had pulmonary resection for lung cancer between January 2000 and December 2009 were reviewed and 226 lung AC patients who fulfilled the inclusion criteria were identified. Histological subtypes of the ACs and their ratios in the tumour tissue were determined. Tumours were classified according to the predominant histological subtype and subsequently graded. The relationship between the predominant histological subtype, grade and survival were analysed. RESULTS: Tumours were predominantly acinar in 99 cases (43.8%), solid in 89 (39.3%), lepidic in 20 (8.8%), and papillary in 11 (4.8%), whereas 7 tumours (3%) were variants of AC. Stage significantly affected survival (p = 0.001); however, the predominant histological subtype had no significant effect. The 5-year survival rate for patients with histologically grade II tumours was 48.6%, whereas that in patients with grade III tumours was 56%. (p = 0.69). CONCLUSION: Invasive lung ACs may be defined by their predominant histological subtype. However, it is not yet possible to conclude that this classification is related to survival. PMID- 23364233 TI - Mid-term outcomes of acute type B aortic dissection in Japan single center. AB - PURPOSE: To study mid-term outcomes in patients admitted to receive treatment for acute type B aortic dissection. METHODS: The study group comprised 229 patients with acute type B aortic dissection treated between January 2000 and July 2010. 128 patients had a thrombosed false lumen, and 101 had a patent false lumen. RESULTS: In the thrombosed group, 6 had rupture, 4 had malperfusion, and 118 had no complications. There were 5 early deaths (3.9%). In the patent group, 12 had rupture, 19 had malperfusion, and 70 had no complications. There were 6 early deaths (5.9%). Overall survival rates in the thrombosed group and the patent group were 94.7 +/- 2.2% and 90.2 +/- 3.2% at 1 year, and 84.3 +/- 4.6% and 85.9 +/- 4.3% at 5 years (p = 0.892), respectively. Aorta-related event-free rates were 85.6 +/- 3.4% and 48.3 +/- 5.5% at 1 year, and 76.0 +/- 5.1% and 35.2 +/- 7.2% at 5 years (p <0.001), respectively. CONCLUSIONS: The incidences of rupture and malperfusion during the acute phase were higher in the patent group compared with the thrombosed group. At the late period, although the aorta-related event rate was higher in the patent group, the survival rate did not differ between two groups. Close follow-up and aggressive intervention strategy of the patent group may result comparable outcomes with the thrombosed group. PMID- 23364234 TI - Three dimensional computed tomography lung modeling is useful in simulation and navigation of lung cancer surgery. AB - The number of minimally invasive operations, such as video-assisted thoracoscopic surgery (VATS) lobectomy or segmentectomy, has enormously increased in recent years. These operations require extreme knowledge of the anatomy of pulmonary vessels and bronchi in each patient, and surgeons must carefully dissect the branches of pulmonary vessels during operation. Thus, foreknowledge of the anatomy of each patient would greatly contribute to the safety and accuracy of the operation. The development of multi-detector computed tomography (MDCT) has promoted three dimensional (3D) images of lung structures. It is possible to see the vascular and bronchial structures from the view of the operator; therefore, it is employed for preoperative simulation as well as navigation during operation. Due to advances in software, even small vessels can be accurately imaged, which is useful in performing segmentectomy. Surgical simulation and navigation systems based on high quality 3D lung modeling, including vascular and bronchial structures, can be used routinely to enhance the safety operation, education of junior staff, as well as providing a greater sense of security to the operators. PMID- 23364235 TI - Successful use of mediastinal repositioning employing PTFE sheet for right-sided post-pneumonectomy syndrome. AB - Post-pneumonectomy syndrome (PPS) is a rare late complication of pneumonectomy, and diverse treatments have been employed. We herein present a useful technique for right-sided PPS. The patient was a 53-year-old female who underwent a right pneumonectomy for locally advanced squamous cell lung cancer (pT2N2M0). Mild dyspnea and stridor developed and progressed 1 year after surgery. A chest roentgenogram and computed tomography (CT) scan showed a right-sided mediastinal shift. Under local anesthesia, a chest tube with a balloon was inserted into the right thoracic cavity, and the balloon was inflated with air. Dyspnea and stridor improved and disappeared as the balloon expanded. Then, mediastinal fixation was performed under general anesthesia. Mediastinal fixation involved a PTFE (polytetrafluoroethylene) sheet which was sewn on the sternum and costal cartilage anteriorly, on the vertebra posteriorly, and covered the azygos vein level superiorly and two thirds of the pericardium inferiorly using nonabsorbable sutures. A post-operative chest roentgenogram and CT scan showed improvement of the right-sided mediastinal shift. The post-operative course was uneventful, and dyspnea and stridor were improved and became stable. In conclusion, the presented method is a useful procedure for right-sided PPS. PMID- 23364236 TI - Emergency coronary artery bypass grafting after substernal gastric tube interposition for esophageal cancer. AB - A 67-year-old man who had undergone substernal gastric tube interposition due to esophageal cancer showed ST changes on electrocardiography. Diagnosis was severe stenosis of the left anterior descending branch that required emergency coronary artery bypass grafting. Preoperative computed tomography (CT) showed the feeding arteries of the gastric tube were in contact with the left internal mammary artery. Therefore, we felt harvesting this artery could be dangerous and decided to perform a median sternotomy, approaching from the right side of the gastric tube. The pericardium was easily and safely reached. We undertook on-pump cardiac arrest single coronary artery bypass grafting of the left anterior descending artery with a saphenous vein graft. The postoperative course was uneventful without mediastinitis. Cardiac surgery after esophageal cancer is often performed from a left thoracotomy. But, we recommend a median sternotomy be performed as an option. Preoperative contrast-enhanced CT should be considered as it may indicate the need for a significant revision such as a median sternotomy. PMID- 23364237 TI - Prospective study of sarpogrelate hydrochloride on patients with arteriosclerosis obliterans. AB - OBJECTIVE: To evaluate the effect of sarpogrelate for patients with atherosclerotic obliterans (ASO). PATIENTS AND METHODS: Patients with ASO were randomly divided into sarpogrelate group (n = 92) and control group (n = 84). The patients in sarpogrelate group received sarpogrelate (100 mg, tid), whereas in control group aspirin (100 mg, qd) was administered orally. The patients were followed up monthly to observe any side effect of medication. Clinical manifestation, painless walking distance, Rutherford type and ankle brachial Index (ABI) were studied. RESULTS: In comparison with control group, the severity of pain, Rutherford type 0 and 1 were improved with statistic significance. Incidence of patients with intermittent claudication decreased from 56.6% before treatment to 28.3% after treatment; the painless walking distance was prolonged (116.3 +/- 72.3m vs. 243.5 +/- 175.3m, P <0.001); ABI values were increased (0.74 +/- 0.17 vs. 0.86 +/- 0.18; p <0.001). No side effect of medication was observed. CONCLUSION: Sarpogrelate has a therapeutic effect on patients with atherosclerotic obliterans. PMID- 23364238 TI - A 5-year-old boy with a large hereditary multiple exostoses lump grown into thoracic cavity. AB - Multiple exostosis is associated with the autosomal dominant disorder and hereditary multiple exostoses (HMEs), are rarely growing around the ribs and the formation of a large lump into the thoracic cavity. It's generally agreed that when there are no symptoms present, a HME patient could either avoid any treatment or postpone the operation until adolescence. We present a 5-year-old boy with 4 cm * 3.5 cm HMEs lump invasion into the thoracic cavity, with symptoms of chest distress and right chest pain. This patient received video-assisted thoracoscopic surgery (VATS) and a the lump and 1 cm rib involved was resected. During a 2 years follow-up, the patient remained in good condition without recurrence and complications. PMID- 23364239 TI - Which type of secondary tricuspid regurgitation accompanying mitral valve disease should be surgically treated? AB - PURPOSE: The purpose of this study was to examine changes in severity of secondary tricuspid regurgitation (TR) accompanying mitral valve disease, and to identify factors predicting failure of improvement in TR after mitral valve surgery. METHODS: We studied 99 patients who had TR of grade >=2+ preoperatively, 47 with tricuspid annuloplasty (TAP Group) performed concurrently, and 52 with mitral surgery alone (nTAP Group). Predictors of failure of improvement in TR in the nTAP Group were analyzed. RESULTS: The mean follow-up period was 4.6 +/- 2.7 years. There was a significant difference between the TAP and nTAP Groups in TR improvement (93.6% vs. 67.3% respectively, p <0.001) and in change of TR grade ( 2.1 +/- 1.0 vs. -0.9 +/- 1.0 respectively, p <0.001). Univariate analysis in the nTAP Group identified rheumatic etiology, atrial fibrillation, mitral stenosis (MS), and large left atrium prior to surgery as risk factors for failure of improvement. In multivariate analysis atrial fibrillation was identified as a predictor of failure of improvement (p = 0.004). CONCLUSION: Our results suggest that TAP should be performed concurrently with mitral valve surgery in patients with secondary TR of grade >=2+, especially those having atrial fibrillation, even if TR is not severe. PMID- 23364240 TI - A case of rapidly growing osteosarcoma of the rib. AB - A 37-year-old woman noticed a right anterior chest mass and pain. The mass had been rapidly growing and she visited our hospital. The mass was hard and 8 * 7 cm in size. It was detected in the upper inner quadrant of her anterior chest wall. A computed tomography (CT) examination and magnetic resonance imaging (MRI) of the chest revealed a large heterogeneously enhanced mass arising from the right chest wall with lytic destruction of the rib and coarse calcification. An image diagnosis of osteogenic sarcoma originating from a rib was made. She underwent surgical excision of the tumor and chest wall reconstruction. Microscopic examination of the resected tumor showed multiple neoplastic cells accompanied by osteoid formation within the tumor. The tumor was diagnosed as high-grade malignant osteosarcoma of the rib. Primary osteosarcoma commonly originates in the long bone in children and adolescents, but it occurs very rarely in the ribs in adults. Surgical resection plays an important role in the treatment for this disease. We report a case of primary osteosarcoma that originated in the rib of a young woman and was treated successfully by surgery. PMID- 23364241 TI - Electronic properties of pure and p-type doped hexagonal sheets and zigzag nanoribbons of InP. AB - Unlike graphene, a hexagonal InP sheet (HInPS) cannot be obtained by mechanical exfoliation from the native bulk InP, which crystallizes in the zinc blende structure under ambient conditions. However, by ab initio density functional theory calculations we found that a slightly buckled HInPS is stable both in pristine form and when doped with Zn atoms; the same occurred for hydrogen passivated zigzag InP nanoribbons (ZInPNRs), quasi-one-dimensional versions of the quasi-two-dimensional material. We investigated the electronic properties of both nanostructures, in the latter case also in the presence of an external transverse electric field, and the results are compared with those of hypothetical planar HInPS and ZInPNRs. The band gaps of planar ZInPNRs were found to be tunable by the choice of strength of this field, and to show an asymmetric behavior under weak electric fields, by which the gap can either be increased or decreased depending on their direction; however, this effect is absent from slightly buckled ZInPNRs. The binding energies of the acceptor impurity states of Zn-doped HInPS and ZInPNRs were found to be similar and much larger than that of Zn-doped bulk InP. These latter findings show that the reduction of the dimensionality of these materials limits the presence of free carriers. PMID- 23364242 TI - Effect of the BCL2 gene polymorphism on survival in advanced-stage non-small cell lung cancer patients who received chemotherapy. AB - INTRODUCTION: This study aimed to evaluate the association between BCL2 single nucleotide polymorphisms and survival outcome in advanced non-small cell lung cancer (NSCLC). METHODS: One hundred and sixty-eight patients with advanced NSCLC who were treated with anti-cancer drugs and could be evaluated for therapeutic response between April 2005 and March 2010 at Kyoto University Hospital were enrolled. DNA was extracted from peripheral blood samples. The BCL2 polymorphisms -938 C->A (rs2279115) and +21 A->G (rs1801018) were genotyped using the 5' nuclease assay. The univariate relationship between each independent clinicopathologic variable and BCL2 genotype was examined using Fisher's exact test. To evaluate risk factors associated with prognosis, a Cox proportional hazards regression model with a step-down procedure was used. RESULTS: The median survival time of patients with the -938 AA and AC genotypes were significantly shorter than those with the -938 CC genotype (p = 0.027 by log-rank test). Based on multivariate analysis, poor performance status [hazard ratio (HR) 2.424, 95% confidence interval (CI) 1.727-3.262; p < 0.0001], non-adenocarcinoma histology (HR 1.512, 95% CI 1.167-1.938; p = 0.0048) and the BCL2 -938 AA + AC genotype (HR 1.219, 95% CI, 1.024-1.456; p = 0.0256) were significant independent prognostic factors for survival. CONCLUSIONS: Polymorphisms in BCL2 may be associated with survival in advanced-stage NSCLC patients who received chemotherapy. PMID- 23364243 TI - 22q11.2 Microduplication with thyroid hemiagenesis. AB - BACKGROUND: Chromosome 22q11.2 microduplications are extremely rarely detected; in comparison, the deletion of same region, known as the DiGeorge/velocardiofacial syndrome, occurs more frequently. Thyroid anomalies commonly occur in patients with 22q11.2 deletion syndrome, however few reports of thyroid anomalies associated with 22q11.2 microduplication have been published thus far. CASE REPORT: We present a case of a male infant who was prenatally diagnosed with 22q11.2 microduplication and was found to have congenital hypothyroidism due to thyroid hemiagenesis after birth. Moreover, the baby had bilateral hearing impairment, bilateral cryptorchidism, and a rotated penis. At the age of 2 years, the infant was euthyroid with levothyroxine replacement, but he showed significant developmental delay. CONCLUSIONS: To our knowledge, this is the first case of congenital hypothyroidism with thyroid hemiagenesis in a patient showing 22q11.2 microduplication. Thyroid dysgenesis could be an additional clinical feature shared by the 22q11.2 microduplication and deletion syndrome, suggesting that the duplication and deletion of a gene may result in a common phenotype. Thyroid dysgenesis should be considered in the evaluation and management of patients with this genomic disorder. PMID- 23364245 TI - Is pouch surgery safe in children with ulcerative colitis who are treated with preoperative immunosuppressive medications? PMID- 23364244 TI - Premature delivery reduces intestinal cytoskeleton, metabolism, and stress response proteins in newborn formula-fed pigs. AB - OBJECTIVE: Preterm infants often show intolerance to the first enteral feeds, and the structural and functional basis of this intolerance remains unclear. We hypothesized that preterm and term neonates show similar gut trophic responses to feeding but different expression of intestinal functional proteins, thus helping to explain why preterm neonates are more susceptible to feeding-induced disorders such as necrotizing enterocolitis (NEC). METHODS: Incidence of feeding-induced NEC, intestinal mass, and brush border enzyme activities, and the intestinal proteome in preterm cesarean-delivered pigs were compared with the corresponding values in pigs delivered spontaneously at term. RESULTS: For both preterm and term pigs, mucosal mass and maltase activity increased (50%-100%), whereas lactase decreased (-50%), relative to values at birth. Only preterm pigs were highly NEC sensitive (30% vs 0% in term pigs, P < 0.05). By gel-based proteomics, 36 identified proteins differed in expression, with most proteins showing downregulation in preterm pigs, including proteins related to intestinal structure and actin filaments, stress response, protein processing, and nutrient metabolism. CONCLUSIONS: Despite that enteral feeding induces rapid gut tropic response in both term and preterm neonates, the expression level of cellular proteins related to mucosal integrity, metabolism, and stress response differed markedly (including complement 3, prohibitin, ornithine carbamoyltransferase, and arginosuccinate synthetase). These proteins may play a role in the development of functional gut disorders and NEC in preterm neonates. PMID- 23364246 TI - Authors' response. PMID- 23364247 TI - Economics of vaccines revisited. AB - Performing a total health economic analysis of a vaccine newly introduced into the market today is a challenge when using the conventional cost-effectiveness analysis we normally apply on pharmaceutical products. There are many reasons for that, such as: the uncertainty in the total benefit (direct and indirect) to be measured in a population when using a cohort model; (1) appropriate rules about discounting the long-term impact of vaccines are absent jeopardizing therefore their value at the initial investment; (2) the presence of opposite contexts when introducing the vaccine in developed vs. the developing world with high benefits, low initial health care investment for the latter vs. marginal benefit and high cost for the former; with a corresponding paradox for the vaccine becoming very cost-effective in low income countries but rather medium in middle low to high middle income countries; (3) and the type of trial assessment for the newer vaccines is now often performed with immunogenicity reaction instead of clinical endpoints which still leaves questions on their real impact and their head-to head comparison. (4.) PMID- 23364253 TI - Understanding intermolecular C-F bond activation by a transient titanium neopentylidyne: experimental and theoretical studies on the competition between 1,2-CF bond addition and [2 + 2]-cycloaddition/beta-fluoride elimination. AB - Complex (PNP)Ti=CH(t)Bu(CH(2)(t)Bu) (PNP(-) = N[2-P(CHMe(2))(2)-4 methylphenyl](2)) eliminates H(3)C(t)Bu to form transient (PNP)Ti=C(t)Bu, which activates the C-F bond of ortho-difluoropyridine and ortho-fluoropyridine to form the alkylidene-fluoride complexes, (PNP)Ti=C[(t)Bu(NC(5)H(3)F)](F) (1) and (PNP)Ti=C[(t)Bu(NC(5)H(4))](F) (2), respectively. When (PNP)Ti=CH(t)Bu(CH(2)(t)Bu) is treated with meta-fluoropyridine, the ring-opened product (PNP)Ti(C((t)Bu)CC(4)H(3)-3-FNH) (3) is the only recognizable titanium metal complex formed. Theoretical studies reveal that pyridine binding disfavors 1,2-CF bond addition across the alkylidyne ligand in the case of ortho-fluoride pyridines, while sequential [2 + 2]-cycloaddition/beta-fluoride elimination is a lower energy pathway. In the case of meta-fluoropyridine, [2 + 2]-cycloaddition and subsequent ring-opening metathesis is favored as opposed to C-H bond addition or sequential [2 + 2]-cycloaddition/beta-hydride elimination. In all cases, C-H bond addition of ortho-fluoropyridines or meta-fluoropyridine is discouraged because such substrate must bind to titanium via its C-H bond, which is rather weak compared to the titanium-pyridine binding. PMID- 23364254 TI - Enantioselective total synthesis of virosaine A and bubbialidine. AB - The first enantioselective total syntheses of virosaine A and bubbialidine are described. Key transformations include the formation of a tetracyclic intermediate via an intramolecular aza-Michael addition, generation of a N hydroxy-pyrrolidine through a Cope elimination and an intramolecular [1,3] dipolar cycloaddition to generate a complex 7-oxa-1-azabicyclo[3.2.1]octane ring system. PMID- 23364255 TI - Effect of a single high loading dose of rosuvastatin on percutaneous coronary intervention for acute coronary syndromes. AB - OBJECTIVES: A high loading dose of atorvastatin has been confirmed to reduce postprocedural events in patients undergoing percutaneous coronary intervention (PCI). In this study, we sought to investigate the protective effects of rosuvastatin in patients with acute coronary syndromes (ACS) undergoing PCI and to determine the effect of rosuvastatin pretreatment on the postprocedural levels of high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and monocyte chemotactic protein 1 (MCP-1). METHODS: A total of 125 patients with non ST-segment elevation ACS were randomized to pretreatment with rosuvastatin (20 mg 2-4 hours before PCI [n = 62]) or placebo (n = 63). All the patients received subsequent long-term rosuvastatin treatment (10 mg/d). The main end point of the trial was the 30-day incidence of major adverse cardiac events (death, myocardial infarction, or unplanned revascularization). Plasma levels of hs-CRP, IL-6, and MCP-1 were detected before PCI and 6 hours, 24 hours, and 3 days after PCI. RESULTS: The primary end point occurred in 8.1% of the patients in the rosuvastatin arm and 22.2% in the placebo arm (P < .01); this difference was entirely attributed to a reduced incidence of myocardial infarction (8.1% vs 22.2%; P < .01). The postprocedural elevation in creatine kinase-MB and troponin I was also significantly lower in the rosuvastatin group at 6 hours, 24 hours, and 3 days. Plasma levels of hs-CRP, IL-6, and MCP-1 increased significantly after PCI in both the rosuvastatin and control groups; however, the postprocedural elevations in hs-CRP and IL-6 levels were significantly lower in the rosuvastatin group than the control group. CONCLUSIONS: A single, high dose (20 mg) of rosuvastatin prior to PCI reduces postprocedural myocardial injury in patients with ACS, with a concomitant attenuation of the postprocedural increase in hs-CRP and IL-6 levels. PMID- 23364256 TI - Independent and combined associations of cardiorespiratory fitness and fatness with cardiovascular risk factors in Brazilian youth. AB - BACKGROUND: The purpose of this study was to examine the independent and combined influence of cardiorespiratory fitness (CRF), body mass index (BMI) and percentage of fat (% fat) on total cholesterol (TC) and blood pressure (BP) in male and female youth. METHODS: 1442 (721 girls) children and adolescents aged 7 12 years were randomly selected. CRF, BMI, % fat (predictor variables), TC, systolic (SBP) and diastolic blood pressure (DBP; outcome variables) were measured. Using standardized cut-off points, we created categories for each variable. Bivariate and multivariable analyses were used to test the independent influence of predictors on outcomes. RESULTS: The prevalence of increased TC, SBP, and DBP were 34.4% (95% CI 31.9-37.0), 9.1% (95% CI 7.5-10.6), and 15.5% (95% CI 13.5-17.4), respectively. In multivariable analyses, CRF was a significant predictor of all outcome variables (P < .05). BMI was associated with SBP and DBP (P < .05) and % fat was associated only with SBP (P < .05). CRF had stronger associations with TC than BMI, whereas the opposite was observed for SBP and DBP. CONCLUSIONS: CRF and BMI are independently associated to TC and BP in male and female youth, and individuals unfit/overweight have greater likelihood of presenting these risk factors. PMID- 23364257 TI - Chemotherapy and radiotherapy downregulate the activity and expression of DNA methyltransferase and enhance Bcl-2/E1B-19-kDa interacting protein-3-induced apoptosis in human colorectal cancer cells. AB - Bcl-2/E1B 19-kDa interacting protein 3 (BNIP3) is a proapoptotic protein whose expression level is often low in colorectal cancer (CRC) cells due to the BNIP3 gene promoter DNA methylation by DNA methyltransferase (DNMT). It is known that chemotherapy and radiotherapy suppress CRC through inducing tumor apoptosis. However, the molecular mechanisms underlying chemotherapy and radiotherapy induced apoptosis of CRC cells are not well defined. In this study, we observed that the expression level of BNIP3 in colon cancer cells was significantly increased by treatment with therapeutic agents and radiation in vitro. The BNIP3 protein level in CRC tissues from patients who received preoperative concurrent chemotherapy was significantly higher than in those who received surgery alone. Furthermore, treatment with chemotherapeutic agents and radiation significantly decreased the DNMT1 expression level and enzymatic activity. Both expression level and activity of DNMT1 were inversely correlated with the expression level of BNIP3 in colon carcinoma cells after treatment with chemotherapeutic agents and radiation. Consistent with increased BNIP3 expression, chemotherapeutic agents and radiation induced colon carcinoma cell apoptosis in a dose-dependent manner. Based on these observations, we conclude that chemotherapy and radiotherapy inhibit DNMT1 expression to upregulate BNIP3 expression to promote CRC cell apoptosis. And, BNIP3 may play a role in the caspase-dependent apoptosis pathways, mainly during treatment with chemotherapy and radiotherapy. PMID- 23364258 TI - Active eosinophilic esophagitis is associated with impaired elimination of budesonide by cytochrome P450 3A enzymes. AB - BACKGROUND/AIMS: Topically administered glucocorticoids such as budesonide have the potential of being established as first-line medical treatment of eosinophilic esophagitis (EoE). Safety of budesonide is based on high elimination by cytochrome P450 3A (CYP3A) enzymes. We aimed to investigate systemic absorption and elimination of a new budesonide formulation in patients with active EoE in comparison with healthy controls. METHODS: After single and multiple doses of orodispersible budesonide (4 mg/day) the parent drug, its CYP3A dependent metabolites, and endogenous cortisol were determined in 12 adult patients with active EoE and 12 healthy controls. An approved ileal-release formulation of budesonide was taken for reference. Molar ratios of metabolite formation in plasma were used as indices of CYP3A metabolic function. RESULTS: CYP3A-dependent metabolite formation was significantly reduced in patients with active EoE as compared to healthy controls. Impaired biotransformation was reflected by a significantly higher extent of budesonide absorption and elongated elimination half-life in EoE patients. Comparison of morning serum cortisol levels at baseline with those after 1 week of treatment with budesonide revealed a significant decrease in EoE patients but not in healthy subjects. CONCLUSION: Active EoE is associated with reduced elimination of budesonide via CYP3A, the major subfamily of drug-metabolizing enzymes in humans. PMID- 23364259 TI - Use of percutaneous coronary intervention to treat heart attack continues to rise in UK, audit shows. PMID- 23364260 TI - Ongoing cuts to sexual health services will cost UK economy billions, says report. PMID- 23364262 TI - Avatars of adipose tissue: the saga of transformation of white fat, the villain into brown fat, the protector. Focus on "Inflammation induced by RAW macrophages suppresses the UCP1 mRNA induction via ERK activation in 10T1/2 adipocytes". PMID- 23364261 TI - Curcumin abates hypoxia-induced oxidative stress based-ER stress-mediated cell death in mouse hippocampal cells (HT22) by controlling Prdx6 and NF-kappaB regulation. AB - Oxidative stress and endoplasmic reticulum (ER) stress are emerging as crucial events in the etiopathology of many neurodegenerative diseases. While the neuroprotective contributions of the dietary compound curcumin has been recognized, the molecular mechanisms underlying curcumin's neuroprotection under oxidative and ER stresses remains elusive. Herein, we show that curcumin protects HT22 from oxidative and ER stresses evoked by the hypoxia (1% O(2) or CoCl(2) treatment) by enhancing peroxiredoxin 6 (Prdx6) expression. Cells exposed to CoCl(2) displayed reduced expression of Prdx6 with higher reactive oxygen species (ROS) expression and activation of NF-kappaB with IkappaB phosphorylation. When NF-kappaB activity was blocked by using SN50, an inhibitor of NF-kappaB, or cells treated with curcumin, the repression of Prdx6 expression was restored, suggesting the involvement of NF-kappaB in modulating Prdx6 expression. These cells were enriched with an accumulation of ER stress proteins, C/EBP homologous protein (CHOP), GRP/78, and calreticulin, and had activated states of caspases 12, 9, and 3. Reinforced expression of Prdx6 in HT22 cells by curcumin reestablished survival signaling by reducing propagation of ROS and blunting ER stress signaling. Intriguingly, knockdown of Prdx6 by antisense revealed that loss of Prdx6 contributed to cell death by sustaining enhanced levels of ER stress-responsive proapoptotic proteins, which was due to elevated ROS production, suggesting that Prdx6 deficiency is a cause of initiation of ROS mediated ER stress-induced apoptosis. We propose that using curcumin to reinforce the naturally occurring Prdx6 expression and attenuate ROS-based ER stress and NF kappaB-mediated aberrant signaling improves cell survival and may provide an avenue to treat and/or postpone diseases associated with ROS or ER stress. PMID- 23364263 TI - Cyclic AMP-mediated pleiotropic effects of glucagon-like peptide-1 receptor activation. Focus on "Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a". PMID- 23364264 TI - Diversity of lipid mediators in human adipose tissue depots. AB - Adipose tissue is a heterogeneous organ with remarkable variations in fat cell metabolism depending on the anatomical location. However, the pattern and distribution of bioactive lipid mediators between different fat depots and their relationships in complex diseases have not been investigated. Using LC-MS/MS based metabolo-lipidomics, here we report that human subcutaneous (SC) adipose tissues possess a range of specialized proresolving mediators (SPM) including resolvin (Rv) D1, RvD2, protectin (PD) 1, lipoxin (LX) A4, and the monohydroxy biosynthetic pathway markers of RvD1 and PD1 (17-HDHA), RvE1 (18-HEPE), and maresin 1 (14-HDHA). The "classic" eicosanoids prostaglandin (PG) E2, PGD2, PGF2alpha, leukotriene (LT) B4, 5-hydroxyeicosatetraenoic acid (5-HETE), 12-HETE, and 15-HETE were also identified in SC fat. SC fat from patients with peripheral vascular disease (PVD) exhibited a marked deficit in PD1 and 17-HDHA levels. Compared with SC, perivascular adipose tissue displayed higher SPM levels, suggesting an enhanced resolution capacity in this fat depot. In addition, augmented levels of eicosanoids and SPM were observed in SC fat surrounding foot wounds. Notably, the profile of SC PGF2alpha differed significantly when patients were grouped by body mass index (BMI). In the case of peri-wound SC fat, BMI negatively correlated with PGE2. In this tissue, proresolving mediators RvD2 and LXA4 were identified in lower levels than the proinflammatory LTB4. Collectively, these findings demonstrate a diverse distribution of bioactive lipid mediators depending on the localization of human fat depots and uncover a specific SPM pattern closely associated with PVD. PMID- 23364266 TI - Effective contractile response to voltage-gated Na+ channels revealed by a channel activator. AB - This study investigated the molecular identity and impact of enhancing voltage gated Na(+) (Na(V)) channels in the control of vascular tone. In rat isolated mesenteric and femoral arteries mounted for isometric tension recording, the vascular actions of the Na(V) channel activator veratridine were examined. Na(V) channel expression was probed by molecular techniques and immunocytochemistry. In mesenteric arteries, veratridine induced potent contractions (pEC(50) = 5.19 +/- 0.20, E(max) = 12.0 +/- 2.7 mN), which were inhibited by 1 MUM TTX (a blocker of all Na(V) channel isoforms, except Na(V)1.5, Na(V)1.8, and Na(V)1.9), but not by selective blockers of Na(V)1.7 (ProTx-II, 10 nM) or Na(V)1.8 (A-80347, 1 MUM) channels. The responses were insensitive to endothelium removal but were partly (~60%) reduced by chemical destruction of sympathetic nerves by 6-hydroxydopamine (2 mM) or antagonism at the alpha1-adrenoceptor by prazosin (1 MUM). KB-R7943, a blocker of the reverse mode of the Na(+)/Ca(2+) exchanger (3 MUM), inhibited veratridine contractions in the absence or presence of prazosin. T16A(inh)-A01, a Ca(2+)-activated Cl(-) channel blocker (10 MUM), also inhibited the prazosin resistant contraction to veratridine. Na(V) channel immunoreactivity was detected in freshly isolated mesenteric myocytes, with apparent colocalization with the Na(+)/Ca(2+) exchanger. Veratridine induced similar contractile effects in the femoral artery, and mRNA transcripts for Na(V)1.2 and Na(V)1.3 channels were evident in both vessel types. We conclude that, in addition to sympathetic nerves, NaV channels are expressed in vascular myocytes, where they are functionally coupled to the reverse mode of Na(+)/Ca(2+) exchanger and subsequent activation of Ca(2+)-activated Cl(-) channels, causing contraction. The TTX sensitive Na(V)1.2 and Na(V)1.3 channels are likely involved in vascular control. PMID- 23364268 TI - Purinergic regulation of CFTR and Ca(2+)-activated Cl(-) channels and K(+) channels in human pancreatic duct epithelium. AB - Purinergic agonists have been considered for the treatment of respiratory epithelia in cystic fibrosis (CF) patients. The pancreas, one of the most seriously affected organs in CF, expresses various purinergic receptors. Studies on the rodent pancreas show that purinergic signaling regulates pancreatic secretion. In the present study we aim to identify Cl(-) and K(+) channels in human pancreatic ducts and their regulation by purinergic receptors. Human pancreatic duct epithelia formed by Capan-1 or CFPAC-1 cells were studied in open circuit Ussing chambers. In Capan-1 cells, ATP/UTP effects were dependent on intracellular Ca(2+). Apically applied ATP/UTP stimulated CF transmembrane conductance regulator (CFTR) and Ca(2+)-activated Cl(-) (CaCC) channels, which were inhibited by CFTRinh-172 and niflumic acid, respectively. The basolaterally applied ATP stimulated CFTR. In CFPAC-1 cells, which have mutated CFTR, basolateral ATP and UTP had negligible effects. In addition to Cl(-) transport in Capan-1 cells, the effects of 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2 one (DC-EBIO) and clotrimazole indicated functional expression of the intermediate conductance K(+) channels (IK, KCa3.1). The apical effects of ATP/UTP were greatly potentiated by the IK channel opener DC-EBIO. Determination of RNA and protein levels revealed that Capan-1 cells have high expression of TMEM16A (ANO1), a likely CaCC candidate. We conclude that in human pancreatic duct cells ATP/UTP regulates via purinergic receptors both Cl(-) channels (TMEM16A/ANO1 and CFTR) and K(+) channels (IK). The K(+) channels provide the driving force for Cl(-)-channel-dependent secretion, and luminal ATP provided locally or secreted from acini may potentiate secretory processes. Future strategies in augmenting pancreatic duct function should consider sidedness of purinergic signaling and the essential role of K(+) channels. PMID- 23364265 TI - The world pandemic of vitamin D deficiency could possibly be explained by cellular inflammatory response activity induced by the renin-angiotensin system. AB - This review attempts to show that there may be a relationship between inflammatory processes induced by chronic overstimulation of the renin angiotensin system (RAS) and the worldwide deficiency of vitamin D (VitD) and that both disorders are probably associated with environmental factors. Low VitD levels represent a risk factor for several apparently different diseases, such as infectious, autoimmune, neurodegenerative, and cardiovascular diseases, as well as diabetes, osteoporosis, and cancer. Moreover, VitD insufficiency seems to predispose to hypertension, metabolic syndrome, left ventricular hypertrophy, heart failure, and chronic vascular inflammation. On the other hand, inappropriate stimulation of the RAS has also been associated with the pathogenesis of hypertension, heart attack, stroke, and hypertrophy of the left ventricle and vascular smooth muscle cells. Because VitD receptors (VDRs) and RAS receptors are almost distributed in the same tissues, a possible link between VitD and the RAS is even more plausible. Furthermore, from an evolutionary point of view, both systems were developed simultaneously, actively participating in the regulation of inflammatory and immunological mechanisms. Changes in RAS activity and activation of the VDR seem to be inversely related; thus any changes in one of these systems would have a completely opposite effect on the other, making it possible to speculate that the two systems could have a feedback relationship. In fact, the pandemic of VitD deficiency could be the other face of increased RAS activity, which probably causes lower activity or lower levels of VitD. Finally, from a therapeutic point of view, the combination of RAS blockade and VDR stimulation appears to be more effective than either RAS blockade or VDR stimulation individually. PMID- 23364267 TI - The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility. AB - The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop. Bmal1 encodes a core molecular clock transcription factor. Germline Bmal1 knockout mice show a loss of circadian variation in heart rate and blood pressure, and they develop dilated cardiomyopathy. We tested the role of the molecular clock in adult cardiomyocytes by generating mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCSDeltaBmal1). ECG telemetry showed that cardiomyocyte-specific deletion of Bmal1 (iCSDeltaBmal1(-/-)) in adult mice slowed heart rate, prolonged RR and QRS intervals, and increased episodes of arrhythmia. Moreover, isolated iCSDeltaBmal1(-/-) hearts were more susceptible to arrhythmia during electromechanical stimulation. Examination of candidate cardiac ion channel genes showed that Scn5a, which encodes the principle cardiac voltage-gated Na(+) channel (Na(V)1.5), was circadianly expressed in control mouse and rat hearts but not in iCSDeltaBmal1(-/-) hearts. In vitro studies confirmed circadian expression of a human Scn5a promoter-luciferase reporter construct and determined that overexpression of clock factors transactivated the Scn5a promoter. Loss of Scn5a circadian expression in iCSDeltaBmal1(-/-) hearts was associated with decreased levels of Na(V)1.5 and Na(+) current in ventricular myocytes. We conclude that disruption of the molecular clock in the adult heart slows heart rate, increases arrhythmias, and decreases the functional expression of Scn5a. These findings suggest a potential link between environmental factors that alter the cardiomyocyte molecular clock and factors that influence arrhythmia susceptibility in humans. PMID- 23364269 TI - The morbidity rate of chronic disease among Chinese rural residents: results from Liuyang cohort. AB - OBJECTIVE: To study the health status and explore the putative risk factors of chronic diseases among a Chinese rural population. SUBJECTS AND METHODS: Face-to face interviews were carried out to collect the information of social characteristics, health status and related risk factors of 11,909 families comprised of 49,383 subjects in the rural area of Liuyang, Hunan province during 2007. Chronic disease was diagnosed according to the diagnosis certification from the town clinic or superior level hospital. RESULTS: The morbidity rate of chronic disease among Liuyang rural residents in 2007 was 19.22%. The prevalence of the top 10 chronic disorders was as follows: hypertension: 3.65%; urolithiasis: 1.03%; chronic obstructive pulmonary disease: 0.92%; ischemic heart disease: 0.92%; chronic gastritis: 0.91%; cerebrovascular disease: 0.71%; lumbar disk disease: 0.61%; chronic viral hepatitis: 0.55%; gallstones: 0.54%, and diabetes: 0.54%. Age, gender, educational level, occupation, marital status, type of housing, source of drinking water, smoking, underweight and overweight were factors associated with chronic disease. We also noticed that 14.2% of the residents were underweight and 29.7% are still using unsafe sources of drinking water. CONCLUSIONS: The prevalence of chronic disease in Liuyang area was severe both in communicable and noncommunicable chronic disease. Unhealthy lifestyles such as tobacco usage and overweight partially contributed to the high prevalence of chronic disease. PMID- 23364270 TI - Differences in relative hippocampus volume and number of hippocampus neurons among five corvid species. AB - The relative size of the avian hippocampus (Hp) has been shown to be related to spatial memory and food storing in two avian families, the parids and corvids. Basil et al. [Brain Behav Evol 1996;47:156-164] examined North American food storing birds in the corvid family and found that Clark's nutcrackers had a larger relative Hp than pinyon jays and Western scrub jays. These results correlated with the nutcracker's better performance on most spatial memory tasks and their strong reliance on stored food in the wild. However, Pravosudov and de Kort [Brain Behav Evol 2006;67:1-9] raised questions about the methodology used in the 1996 study, specifically the use of paraffin as an embedding material and recalculation for shrinkage. Therefore, we measured relative Hp volume using gelatin as the embedding material in four North American species of food-storing corvids (Clark's nutcrackers, pinyon jays, Western scrub jays and blue jays) and one Eurasian corvid that stores little to no food (azure-winged magpies). Although there was a significant overall effect of species on relative Hp volume among the five species, subsequent tests found only one pairwise difference, blue jays having a larger Hp than the azure-winged magpies. We also examined the relative size of the septum in the five species. Although Shiflett et al. [J Neurobiol 2002;51:215-222] found a difference in relative septum volume amongst three species of parids that correlated with storing food, we did not find significant differences amongst the five species in relative septum. Finally, we calculated the number of neurons in the Hp relative to body mass in the five species and found statistically significant differences, some of which are in accord with the adaptive specialization hypothesis and some are not. PMID- 23364272 TI - Noninfluenza vaccination coverage among adults - United States, 2011. AB - Vaccinations are recommended throughout life to prevent vaccine-preventable diseases and their sequelae. Adult vaccination coverage, however, remains low for most routinely recommended vaccines and well below Healthy People 2020 targets. In October 2012, the Advisory Committee on Immunization Practices (ACIP) approved the adult immunization schedule for 2013. Apart from influenza vaccination, which is now recommended for all adults, other vaccines recommended for adults target different populations based on age, certain medical conditions, behavioral risk factors (e.g., injection drug use), occupation, travel, and other indications. To assess adult (aged >=19 years) vaccination coverage for select vaccines, CDC analyzed data from the 2011 National Health Interview Survey (NHIS). This report summarizes the results of that analysis for pneumococcal vaccine, tetanus toxoid containing vaccines (including tetanus and diphtheria toxoid [Td] with acellular pertussis vaccine [Tdap]), and hepatitis A, hepatitis B, herpes zoster (shingles), and human papillomavirus (HPV) vaccines, by selected characteristics (age, race/ethnicity,? and vaccination target criteria). Influenza vaccination coverage estimates for the 2011-12 influenza season have been published separately. Compared with 2010, the data indicate modest increases in Tdap vaccination among persons aged 19-64 years and HPV vaccination among women, but only little improvement in coverage for the other vaccines among adults in the United States. Coverage for tetanus vaccination (with any tetanus toxoid containing vaccine) during the past 10 years was unchanged. Substantial increases in vaccination coverage are needed to reduce the occurrence of vaccine preventable diseases among adults. The Community Preventive Services Task Force and other authorities have recommended that health-care providers incorporate vaccination needs assessment, recommendation, and offer of vaccination into routine clinical practice for adult patients. PMID- 23364271 TI - Ciguatera fish poisoning - New York City, 2010-2011. AB - During August 2010-July 2011, the New York City Department of Health and Mental Hygiene (DOHMH) received reports of six outbreaks and one single case of ciguatera fish poisoning (CFP), involving a total of 28 persons. CFP results from consumption of certain large, predatory, tropical reef fish that have bioaccumulated ciguatoxins (CTX). CFP is characterized by various gastrointestinal, cardiovascular, and neurologic symptoms. A prolonged period of acute illness can result, and the neurologic symptoms can last months, with variable asymptomatic and symptomatic periods. The first two outbreaks and the single case, involving 13 persons, were reported during August 6-September 13, 2010. DOHMH distributed a health alert in November 2010 requesting health-care providers be alert for CFP signs and symptoms. The health alert resulted in identification of 11 more cases that month and an additional two outbreaks involving four persons in July 2011. In comparison, only four CFP outbreaks, involving 21 persons total, had been reported in New York City (NYC) during the preceding 10 years (2000-2009). DOHMH's investigation revealed that 13 persons became ill after eating barracuda, and 15 became ill after eating grouper. Although specific and highly sensitive laboratory analyses can detect and confirm CTX in fish, no practical field tests are available for fish monitoring programs. CFP prevention depends on educating the public, seafood suppliers, and distributors about known CFP endemic areas and high-risk fish species. Traceback investigations of fish associated with outbreaks provide valuable information regarding fishing areas associated with CFP. Not all fish from CFP endemic areas are ciguatoxic, but persons who eat fish from endemic regions are at higher risk for CFP. If an illness is suspected to be CFP, public health authorities should be notified and informed of the case history for possible investigation and intervention measures. PMID- 23364273 TI - Notes from the field: Multistate outbreak of human Salmonella typhimurium infections linked to contact with pet hedgehogs - United States, 2011-2013. AB - CDC is collaborating with the U.S. Department of Agriculture's Animal and Plant Health Inspection Service (USDA-APHIS) and state health departments to investigate an outbreak of human Salmonella Typhimurium infections with an indistinguishable pulsed-field gel electrophoresis pattern linked to contact with pet hedgehogs. This outbreak strain is historically rare, with only one to two cases reported via PulseNet (the national molecular subtyping network for foodborne disease surveillance) annually since 2002. Since 2011, an increasing number of cases have been detected. PulseNet identified 14 human isolates in 2011, 18 in 2012, and two in 2013. PMID- 23364274 TI - Guidelines for the mapping of cancer registry data: results from a breast cancer expert panel study. AB - CONTEXT: Small area (eg, subcounty) cancer mapping is one of the analytic services most commonly requested of cancer registries and local public health agencies, and difficulties in providing it have been noted to undermine public confidence. Although a great many statistical protocols have been published to enable this practice, none of them are in common use to generate information for the general public. OBJECTIVES: To evaluate the utility of subcounty breast cancer mapping and articulate guidelines and a possible protocol for its implementation by cancer registries and local public health agencies. METHODS: We convened an Expert Advisory Group of breast cancer stakeholders from around California to elicit values, priorities, and preferred characteristics of protocols for proactive subcounty breast cancer mapping. Upon formulating a protocol, we applied it to 9 years of data (2000-2008) describing invasive breast cancer in California for evaluation by the Expert Advisory Group. RESULTS: Maps with subcounty resolution were seen to provide important information with a wide range of applications. Priorities included the avoidance of false-positive findings, scientific credibility, and the provision of information elucidating social and environmental characteristics. A protocol using Kulldorff's Scan Statistic along with postanalytic steps for refining results was elaborated; when applied to the data, 4 discrete regions with elevated rates of invasive breast cancer were identified and described. CONCLUSIONS: Expert Advisory Group priorities were readily translatable into a scientifically rigorous protocol that protected confidentiality and avoided statistically unstable rate estimates. The resulting maps enabled participants to visualize geographically defined populations falling within and crossing county boundaries. These findings support the enactment of policies for the routine and proactive analysis of breast cancer surveillance data to provide subcounty information. PMID- 23364275 TI - Correlation between Ki67 and breast cancer prognosis. AB - BACKGROUND: Ki67 is an immunohistochemical proliferation marker in many types of cancer and has been widely studied among breast cancer patients mostly through retrospective studies. METHODS: The MEDLINE/PubMed database was searched for publications with the medical subject heading 'Ki 67' and the key words 'breast', 'cancer', and 'prognosis'. We restricted our search to articles published until 2012. RESULTS: In this review, we included 78 articles and abstracts that were accessible and available in English. An effort to further explain the role of Ki67 in the prognosis of breast cancer has been made. CONCLUSIONS: The debate on the prognostic role of Ki67 in breast cancer is still open, although most of the studies have established a relation between Ki67 and overall and disease-free survival. Further research should be made in order to establish Ki67 as a standard prognostic marker in breast cancer. PMID- 23364276 TI - Disruption of components of vascular endothelial growth factor angiogenic signalling system in metabolic syndrome. Findings from a study conducted in rural Bangladeshi women. AB - Metabolic syndrome (MetS) is associated with impaired angiogenesis, a process that is chiefly regulated by vascular endothelial growth factor (VEGF) upon binding to its specific receptors, VEGF-R1 and VEGF-R2. The purpose of the present study was to assess trends or patterns in plasma levels of VEGF and its soluble receptors in subjects with (MetS) or without (non-MetS) MetS; and further examine their association with clinical or metabolic parameters using a subpopulation of South Asian country. A total of 1,802 rural Bangladeshi women aged >=15 years were studied using a population-based cross-sectional survey. Plasma levels of VEGF were found to be significantly increased (MetS vs. non MetS: 483.9 vs. 386.9, p<0.001), whereas, the soluble forms of VEGF receptors, sVEGF-R1 and sVEGF-R2, were significantly decreased in subjects with Mets (sVEGF R1, MetS vs. non-MetS: 512.5 vs. 631.3, p<0.001; sVEGF-R2, MetS vs. non-MetS: 9,302.8 vs. 9,787.4, p=0.004). After adjustment for age and all potential variables, multiple regression analysis revealed that plasma levels of VEGF had significant positive association with blood glucose (p = 0.019) and body mass index (p = 0.007). We also found that mean plasma levels of VEGF increased in direct proportion to levels of MetS components. The present study is the first ever to demonstrate a positive association between trends in levels of plasma VEGF and MetS using a large sample size from South Asia. The association between plasma VEGF and MetS needs further investigations in order to clearly decipher the clinical predictive value and accuracy of plasma VEGF in MetS. PMID- 23364278 TI - Refinement of Swedish administrative registers to monitor stroke events on the national level. AB - BACKGROUND: Routinely collected databases are kept for administrative purposes. We have refined the analyses of the Swedish National Patient Register and the Cause of Death Register and explored their validity to monitor stroke at the population level. METHODS: First-ever strokes (incident cases) and all stroke events were measured by combining the two administrative registers and adding refinements. The administrative registers were validated against the Northern Sweden MONICA, a well-validated population-based epidemiological stroke register. Positive predictive values (PPVs) and sensitivity were calculated. RESULTS: After refinements (restriction to first-ever strokes and additional minor delineations), the PPV of the two administrative registers combined was 94% and sensitivity 92% when compared with all MONICA stroke categories together. For stroke attacks (first and recurrent events together), the PPV in the administrative registers was 85% and sensitivity 91%. The PPV was higher in women than in men, whereas the sensitivity was similar. The PPV was lower but sensitivity higher in people below compared with those above 75 years of age. Both PPV and sensitivity were lower among fatal cases than among cases that survived 28 days. CONCLUSIONS: After refinement, Swedish national administrative registers may, with some caveats, be used as a low-resource-consuming alternative to crudely monitor stroke incidence rates at the national level. If further accuracy is strived for, high-quality conventional epidemiological registers are required. PMID- 23364279 TI - Compound coverage enhancement of electrospray ionization mass spectrometry through the addition of a homemade needle. AB - The response of many previously low-detectable or undetectable compounds in electrospray ionization mass spectrometry (ESI-MS) has been enhanced by the addition of a simple, homemade needle into the traditional ESI interface. The needle located between the ESI emitter and the ion sweep cone (inlet of the detector) would ionize those neutral gaseous compounds, formed during electrospray, by a corona discharge process. The mobile phases, ESI parameters and positions of the needle were investigated and optimized. Several groups of compounds and herbal extracts were tested using the homemade set-up. Both the results of the flow injection and the hyphenated MS analyses showed significant enhancement effects of our homemade needle. The advantages of the proposed method include low cost, simplicity and practicality. PMID- 23364277 TI - Epigenetic regulation of estrogen signaling in breast cancer. AB - Estrogen signaling is mediated by ERalpha and ERbeta in hormone dependent, breast cancer (BC). Over the last decade the implication of epigenetic pathways in BC tumorigenesis has emerged: cancer-related epigenetic modifications are implicated in both gene expression regulation, and chromosomal instability. In this review, the epigenetic-mediated estrogen signaling, controlling both ER level and ER targeted gene expression in BC, are discussed: (1) ER silencing is frequently observed in BC and is often associated with epigenetic regulations while chemical epigenetic modulators restore ER expression and increase response to treatment;(2) ER-targeted gene expression is tightly regulated by co-recruitment of ER and both coactivators/corepressors including HATs, HDACs, HMTs, Dnmts and Polycomb proteins. PMID- 23364280 TI - Investigating the effects of ABC transporter-based acquired drug resistance mechanisms at the cellular and tissue scale. AB - In this paper we systematically investigate the effects of acquired drug resistance at the cellular and tissue scale, with a specific focus on ATP-binding cassette (ABC) transporter-based mechanisms and contrast this with other representative intracellular resistance mechanisms. This is done by developing in silico models wherein the drug resistance mechanism is overlaid on a coarse grained description of apoptosis; these cellular models are coupled with interstitial drug transport, allowing for a transparent examination of the effect of acquired drug resistances at the tissue level. While ABC transporter-mediated resistance mechanisms counteract drug effect at the cellular level, its tissue level effect is more complicated, revealing unexpected trends in tissue response as drug stimuli are systematically varied. Qualitatively different behaviour is observed in other drug resistance mechanisms. Overall the paper (i) provides insight into the tissue level functioning of a particular resistance mechanism, (ii) shows that this is very different from other resistance mechanisms of an apparently similar type, and (iii) demonstrates a concrete instance of how the functioning of a negative feedback based cellular adaptive mechanism can have unexpected higher scale effects. PMID- 23364281 TI - Treatment of adolescents with early-onset schizophrenia spectrum disorders: in search of a rational, evidence-informed approach. AB - PURPOSE OF REVIEW: We aimed to review literature on the efficacy and tolerability of psychosocial and psychopharmacological interventions in youth with early-onset schizophrenia spectrum disorders (EOS). A rationale for pragmatic psychopharmacology in EOS, including dosing, switching and adverse effect monitoring and management, is provided. RECENT FINDINGS: Three randomized controlled trials (RCTs) over the last 8 years demonstrated benefits of psychosocial interventions (i.e. psychoeducation, cognitive remediation, cognitive behavioural therapy) for EOS without clear advantages of one psychosocial treatment over another. Six large, placebo-controlled, short-term RCTs over the last 4 years demonstrated that aripiprazole, olanzapine, paliperidone, quetiapine and risperidone, but not ziprasidone, were superior to placebo. Except for clozapine's superiority in treatment-refractory EOS, efficacy appeared similar across studied first-generation and second-generation antipsychotics, but tolerability varied greatly across individual agents. SUMMARY: Antipsychotics are efficacious in the treatment of EOS. Given the lack of efficacy differences between antipsychotics (except for clozapine for treatment-refractory EOS), we propose that tolerability considerations need to guide choice of antipsychotics. Further and longer-term efficacy and effectiveness studies are urgently needed that should also explore pharmacologic and nonpharmacologic augmentation strategies. PMID- 23364282 TI - Current world literature. PMID- 23364284 TI - Measuring presenteeism: which questionnaire to use in physical activity research? AB - BACKGROUND: An emerging area of interest in workplace health is presenteeism; the measurable extent to which physical or psychosocial symptoms, conditions and disease adversely affect the work productivity of those who choose to remain at work. Given established links between presenteeism and health, and health and physical activity, presenteeism could be an important outcome in workplace physical activity research. This study provides a narrative review of questionnaires for use in such research. METHODS: Eight self-report measures of presenteeism were identified. Information regarding development, constructs measured and psychometric properties was extracted from relevant articles. RESULTS: Questionnaires were largely self-administered, had 4-44 items, and recall periods ranging from 1 week to 1 year. Items were identified as assessing work performance, physical tolerance, psychological well-being and social or role functioning. Samples used to test questionnaires were predominantly American male employees, with an age range of 30-59 years. All instruments had undergone psychometric assessment, most commonly discriminant and construct validity. CONCLUSION: Based on instrument characteristics, the range of conceptual foci covered and acceptable measurement properties, the Health and Work Questionnaire, Work Ability Index, and Work Limitations Questionnaire are suggested as most suitable for further exploring the relationship between physical activity and presenteeism. PMID- 23364285 TI - Comparison of short-term surgical outcomes after single-incision laparoscopic versus multiport laparoscopic right colectomy: a two-center, prospective case controlled study of 100 patients. AB - BACKGROUND: Recent case studies have demonstrated the feasibility of single incision laparoscopic colectomy (SILC). Few comparative studies for SILC and multiport laparoscopic colectomy (MLC) have been conducted. The aim of this case controlled study was to compare the short-term surgical outcomes between SILC and MLC for right-sided colectomies. METHODS: Between January 2010 and February 2012, data from the first 50 consecutive patients that underwent right SILS at one of the two institutions were compared with a group of 50 consecutive patients that underwent right MLC in the same period. RESULTS: Median operative time was significantly shorter in SILC (97 vs. 112 min; p < 0.001). Between both groups, no statistically significant differences were found regarding number and nature of short-term complications, number of reoperations [4 (8%) vs. 6 (12%)], and mortality rate [1 (2%) vs. 2 (4%)]. Median postoperative hospital stay was 6 days for both groups. CONCLUSION: SILC is a safe and feasible procedure when performed by experienced laparoscopic surgeons. Length of hospital stay and overall complication rates are comparable with MLC. Until today, no clear advantages of SILC over MLC have been demonstrated. However, due to its smaller incisional trauma, SILC could be a major step in improving cosmetic outcomes. PMID- 23364286 TI - Stem cell treatment for chronic lung diseases. AB - Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or chronic obstructive pulmonary disease and asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal and financial burden. In view of the current disappointing status of available pharmaceutical agents, there is an urgent need for alternative more effective therapeutic approaches that will not only help to relieve patient symptoms but will also affect the natural course of the respective disease. Regenerative medicine represents a promising option with several fruitful therapeutic applications in patients suffering from chronic lung diseases. Nevertheless, despite relative enthusiasm arising from experimental data, application of stem cell therapy in the clinical setting has been severely hampered by several safety concerns arising from the major lack of knowledge on the fate of exogenously administered stem cells within chronically injured lung as well as the mechanisms regulating the activation of resident progenitor cells. On the other hand, salient data arising from few 'brave' pilot investigations of the safety of stem cell treatment in chronic lung diseases seem promising. The main scope of this review article is to summarize the current state of knowledge regarding the application status of stem cell treatment in chronic lung diseases, address important safety and efficacy issues and present future challenges and perspectives. In this review, we argue in favor of large multicenter clinical trials setting realistic goals to assess treatment efficacy. We propose the use of biomarkers that reflect clinically inconspicuous alterations of the disease molecular phenotype before rigid conclusions can be safely drawn. PMID- 23364287 TI - Salvage external beam radiotherapy for recurrent prostate adenocarcinoma after high-intensity focused ultrasound as primary treatment. AB - INTRODUCTION: The main objective was to evaluate feasibility, toxicity and biochemical control rates of salvage external beam radiotherapy (EBRT) in recurrent localized prostate cancer after high-intensity focused ultrasound (HIFU) as primary therapy. PATIENTS AND METHODS: A total of 24 patients who underwent salvage EBRT after 1 or 2 HIFU sessions and with a minimum post treatment follow-up of 24 months were retrospectively evaluated. Primary endpoints were toxicity and biochemical disease-free survival (bDFS, defined according to the ASTRO Phoenix definition). RESULTS: Median follow-up was 40.3 months. Gastrointestinal toxicity was low. Acute genitourinary (GU) toxicity grade <=II rate was 45.8%, with only few patients presenting grade III (8.3%) and grade IV (4.2%) toxicity. Late grade >=III GU toxicity was registered in 16.7% of patients. The 3-year bDFS rate was 77.8%. Patients achieving a nadir prostate specific antigen (nPSA) of <=0.35 ng/ml after EBRT had significantly higher bDFS (3-year bDFS: 87.7 vs. 50%, respectively; p = 0.001). Achieving nPSA <=0.35 ng/ml was the only factor independently associated to long-term bDFS both on univariate (p = 0.01) and multivariate analysis (HR 7.06, p = 0.039). CONCLUSIONS: Salvage EBRT after HIFU failure is feasible and allows to obtain satisfactory biochemical control rates, especially in patients attaining a nPSA <=0.35 ng/ml after EBRT. PMID- 23364288 TI - Patients' and providers' perceptions of the impact of health literacy on communication in pulmonary rehabilitation. AB - Chronic obstructive pulmonary disease (COPD) is the most prevalent form of chronic respiratory diseases worldwide. Pulmonary rehabilitation, including self management education, highlights the importance of good patient-provider communication in establishing optimal care. There is a growing awareness of the potential impact of health literacy (HL) on the patients' access to and understanding of medical information. This study was designed to explore the patients' and health care professionals' (HCPs) perceptions of the role of HL in health communication. Semi-structured interviews and focus groups were conducted with 12 patients and 20 HCPs at a Pulmonary Rehabilitation Center in Metropolitan Toronto. Although the term health literacy was not familiar to many patients, the contribution of knowledge to patient well-being was consistently identified by patients and HCPs. Barriers to communication included provider time constraints and the use of medical jargon. For providers they also included patient characteristics, language, culture and awareness of health resources. Approaches that might improve communication incorporated family support, peer support, better print and visual teaching material and a trusting empathic patient provider relationship. The findings provide an increased understanding of patients' and providers' perceptions of HL as a barrier to effective communication of medical information to patients with COPD as well as approaches that might improve this communication. PMID- 23364289 TI - Sonochemically produced polydopamine nanocapsules with selective antimicrobial activity. AB - A facile, versatile, and one-pot sonochemical synthesis of polydopamine (PDA) nanocapsules from dopamine is reported. The nanocapsules (227 +/- 25 nm) can encapsulate hydrophobic substances while retaining the reactivity of PDA toward nucleophilic reactions, enabling facile surface modification for different applications. PDA nanocapsules are nontoxic to mammalian cells while Cu containing PDA capsules demonstrate strong (99.9%) and rapid (15 min) bactericidal activity. PMID- 23364290 TI - Manipulation of micro-particles through optical interference patterns generated by integrated photonic devices. AB - Micro-particle transport and switch governed by guided-wave optical interference are presented. The optical interference, occurring in a directional coupler and a multi-mode interferometer made by inverted rib waveguides, results in a specific evanescent field dependent on wavelength. Through a detailed theoretical analysis, the field of induced optical force shows a correlative pattern associated with the evanescent field. Experimental results demonstrate that 10 MUm polystyrene beads are propelled with a trajectory subject to the interference pattern accordingly. By launching different wavelengths, the polystyrene beads can be delivered to different output waveguide ports. Massive micro-particle manipulation is applicable. PMID- 23364291 TI - BRCA1 and BRCA2 mutations in the ovarian cancer population across race and ethnicity: special reference to Asia. AB - OBJECTIVE: To evaluate the prevalence and spectrum of BRCA mutations among ovarian carcinoma patients of different races and ethnicity with special reference to Asia. METHODS: A systematic review of the literature was undertaken to evaluate the prevalence of BRCA mutations among people belonging to different races. The electronic search strategy was developed specifically for the different databases concerned and via cross-referencing. RESULTS: The frequency of BRCA1 and BRCA2 mutations ranged from 1.1 to 39.7 and from 0 to 13.9, respectively. BRCA1 mutations are more common among ovarian cancer cases than BRCA2 mutations, although the ratio of BRCA1 to BRCA2 varies between populations. The Swedish and Indian populations showed 12 and 7 times as many BRCA1 as BRCA2 mutations, respectively, whilst in a study from Iceland the ratio was 0.5:1. These wide-ranging estimates of the mutation prevalence suggest genetic heterogeneity between different populations. CONCLUSION: The ability to identify BRCA1/2 mutations was found to be successful in the clinical management of ovarian cancer. Given the implications for clinical care and for advances in cancer prevention, identifying racial difference in genetic or lifestyle factors, which may modify the cancer risk due to BRCA1/2 mutations, is a high priority for future research. PMID- 23364292 TI - Exercise and blood flow restriction. AB - A growing body of research has demonstrated the effectiveness of exercise (low intensity resistance training, walking, cycling) combined with blood flow restriction (BFR) for increased muscular strength and hypertrophy. The BFR is achieved via the application of external pressure over the proximal portion of the upper or lower extremities. The external pressure applied is sufficient to maintain arterial inflow while occluding venous outflow of blood distal to the occlusion site. With specific reference to low-intensity resistance training, the ability to significantly increase muscle strength and hypertrophy when combined with BFR is different from the traditional paradigm, which suggests that lifting only higher intensity loads increases such characteristics. The purpose of this review was to discuss the relevant literature with regard to the type and magnitude of acute responses and chronic adaptations associated with BFR exercise protocols vs. traditional non-BFR exercise protocols. Furthermore, the mechanisms that stimulate such responses and adaptations will be discussed in the context of neural, endocrine, and metabolic pathways. Finally, recommendations will be discussed for the practitioner in the prescription of exercise with BFR. PMID- 23364293 TI - Heart rate variability reflects training load and psychophysiological status in young elite gymnasts. AB - In gymnastics, monitoring of the training load and assessment of the psychophysiological status of elite athletes is important for training planning and to avoid overtraining, consequently reducing the risk of injures. The aim of this study was to examine whether heart rate variability (HRV) is a valuable tool to determine training load and psychophysiological status in young elite gymnasts. Six young male elite gymnasts took part in a 10-week observational study. During this period, beat-to-beat heart rate intervals were measured every training day in weeks 1, 3, 5, 7, and 9. Balance, agility, upper limb maximal strength, lower limb explosive, and elastic power were monitored during weeks 2, 4, 6, 8, and 10. Training load of each training session of all 10 weeks was assessed by session rating of perceived exertion (RPE) and psychophysiological status by Foster's index. Morning supine HRV (HF% and LF%/HF%) correlated with the training load of the previous day (r = 0.232, r = -0.279, p < 0.05 ). Morning supine to sitting HRV difference (mean R wave to R wave interval (RR), mean heart rate, HF%, SD1) correlated with session RPE of the previous day (r = -0.320, r = 0.301, p < 0.01; r = 0.265, r = -0.270, p < 0.05) but not with Foster's index. Training day/reference day HRV difference (mean RR, SD1) showed the best correlations with session RPE of the previous day (r = -0.384, r = -0.332, p < 0.01) and Foster's index (r = -0.227, r = -0.260, p < 0.05). In conclusion, HRV, and in particular training day/reference day mean RR difference or SD1 difference, could be useful in monitoring training load and psychophysiological status in young male elite gymnasts. PMID- 23364294 TI - The effects of multiple daily applications of ice to the hamstrings on biochemical measures, signs, and symptoms associated with exercise-induced muscle damage. AB - There is inconclusive evidence for the effectiveness of cryotherapy for the treatment of exercised-induced muscle damage (EIMD). Small sample sizes and treatment applications that did not correspond to evidence-based practice are limitations in previous studies that may have contributed to these equivocal findings. The purpose of this study was to examine the effectiveness of daily multiple applications of ice on EIMD throughout the 72-hour recovery period, an icing protocol that more closely resembles current clinical practice. Thirty three subjects were assigned to either the cryotherapy group (n = 23) or control group (n = 10). The EIMD was induced through repeated isokinetic eccentric contractions of the right hamstring muscle group. The experimental group received ice immediately after induction of EIMD and continued to ice thrice a day for 20 minutes throughout the 72 hours; the control group received no intervention. Isometric torque, hamstring length, pain, and biochemical markers (creatine kinase [CK], alanine aminotransferase, and aspartate aminotransferase [AST]) were assessed at baseline, 24, 48, and 72 hours. Both groups demonstrated a significant change (p < 0.05) in all dependent variables compared with that at baseline, but there was no difference between groups except for pain. The cryotherapy group had significantly (p = 0.048) less pain (3.0 +/- 2.1 cm) compared with the control (5.35 +/- 2.5 cm) at 48 hours. Although not statistically significant, the cryotherapy group had a greater range of motion and lower CK and AST means at 72 hours compared with that of the control group. Repeated applications of ice can decrease the pain associated with EIMD significantly at 48 hours post EIMD. Although the results may not be unique, the methodology in this study was distinctive in that we used a larger sample size and an icing protocol similar to current recommended treatment practice. PMID- 23364295 TI - Allometric scaling of Wingate anaerobic power test scores in men. AB - This study examined the appropriate magnitude of allometric scaling of the Wingate anaerobic test (WAnT) power data for body mass (BM) and established normative data for the WAnT for adult men. Eighty-three men completed a standard WAnT using 0.1 kg.kg(-1) BM resistance. Allometric exponents and percentile ranks for 1-second peak power (PP), 5-second PP, and mean power (MP) were established. The Predicted Residual Sum of Squares (PRESS) procedure was used to assess external validity while avoiding data splitting. The mean 1-second PP, 5-second PP, and MP were 1,049.1 +/- 168.8 W, 1,013.4 +/- 158.6 W, and 777.9 +/- 105.0 W, respectively. Allometric exponents for 1-second PP, 5-second PP, and MP scaled for BM were b = 0.89, 0.88, and 0.86, respectively. Correlations between allometrically scaled 1-second PP, 5-second PP, and MP, and BM were r = -0.03, 0.03, and -0.02, respectively, suggesting that the allometric exponents derived were effective in partialling out the effect of BM on WAnT values. The PRESS procedure values resulted in small decreases in R2 (0.03, 0.04, and 0.02 for 1 second PP, 5-second PP, and MP, respectively) suggesting acceptable levels of external validity when applied to independent samples. The allometric exponents and normative values provide a useful tool for comparing WAnT scores in college aged females without the confounding effect of BM. It is suggested that exponents of b = 0.89 (1-second PP), b = 0.88 (5-second PP), and b = 0.86 (MP) be used for allometrically scaling WAnT power values in healthy adult men and that the confidence limits for these allometric exponents be considered as 0.66-1.0 for PP and 0.69-1.0 for MP. The use of these exponents in allometric scaling of male WAnT power values provide coaches and practitioners with valid means for comparing power production between individuals without the confounding influence of BM. PMID- 23364296 TI - Comparison of integrated and isolated training on performance measures and neuromuscular control. AB - Traditional weight training programs use an exercise prescription strategy that emphasizes improving muscle strength through resistance exercises. Other factors, such as stability, endurance, movement quality, power, flexibility, speed, and agility are also essential elements to improving overall functional performance. Therefore, exercises that incorporate these additional elements may be beneficial additions to traditional resistance training programs. The purpose of the study was to compare the effects of an isolated resistance training program (ISO) and an integrated training program (INT) on movement quality, vertical jump height, agility, muscle strength and endurance, and flexibility. The ISO program consisted of primarily upper and lower extremity progressive resistance exercises. The INT program involved progressive resistance exercises, and core stability, power, and agility exercises. Thirty subjects were cluster randomized to either the ISO (n = 15) or INT (n = 15) training program. Each training group performed their respective programs 2 times per week for 8 weeks. The subjects were assessed before (pretest) and after (posttest) the intervention period using the following assessments: a jump-landing task graded using the Landing Error Scoring System (LESS), vertical jump height, T-test time, push-up and sit-up performance, and the sit-and-reach test. The INT group performed better on the LESS test (pretest: 3.90 +/- 1.02, posttest: 3.03 +/- 1.02; p = 0.02), faster on the T-test (pretest: 10.35 +/- 1.20 seconds, posttest: 9.58 +/- 1.02 seconds; p = 0.01), and completed more sit-ups (pretest: 40.20 +/- 15.01, posttest: 46.73 +/- 14.03; p = 0.045) and push-ups (pretest: 40.67 +/- 13.85, posttest: 48.93 +/- 15.17; p = 0.05) at posttest compared with pretest, and compared with the ISO group at posttest. Both groups performed more push-ups (p = 0.002), jumped higher (p < 0.001), and reached further (p = 0.008) at posttest compared with that at pretest. Performance enhancement programs should use an integrated approach to exercise selection to optimize performance and movement technique benefits. PMID- 23364297 TI - The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance. AB - Obesity is characterised by a chronic state of low-grade inflammation in different tissues including the vasculature. There is a causal link between adipose tissue (AT) inflammation and obesity-related metabolic complications, such as the development of insulin resistance and subsequently of type 2 diabetes. Intense efforts in the recent years have aimed at dissecting the pathophysiology of AT inflammation. The role of both innate and adaptive immune cells, such as macrophages or cytotoxic T cells in AT inflammation has been demonstrated. Besides these cells, more leukocyte subpopulations have been recently implicated in obesity, including neutrophils and eosinophils, mast cells, natural killer cells or dendritic cells. The involvement of multiple leukocyte subpopulations underlines the complexity of obesity-associated AT inflammation. In this review, we discuss the role of innate immune cells in AT inflammation, obesity and related metabolic disorders. PMID- 23364298 TI - Update on interventions focused on symptom clusters: what has been tried and what have we learned? AB - PURPOSE OF REVIEW: Although clinicians and researchers acknowledge symptom clusters, the focus has been on relieving a single symptom. This review summarizes the recent literature on interventions that focus on relief of symptom clusters in patients with cancer. RECENT FINDINGS: Twelve intervention studies meeting inclusion criteria were published in 2011-2012. The timeframe was expanded to 2009-2012 and 24 studies met the criteria: 18 in early stage and 6 in advanced-stage cancer patients. Several cognitive behavioral therapy, complementary therapy, and exercise interventions demonstrated positive outcomes in relieving a variety of symptom clusters in several cancer types. Most psychoeducational interventions using traditional formats or those combined with automated clinician alerts demonstrated effectiveness in reducing a variety of clusters. Clusters that included fatigue and anxiety or depression were reduced by exercise in early stage patients and by methylphenidate in advanced-stage patients. Current NIH R01 funded studies verified the trends in the types of interventions being tested. SUMMARY: Few interventions have been tested and found to be effective in relieving the specific symptom clusters in early and advanced stage cancer patients. Future research needs to expand our understanding of the mechanisms that initiate co-occurring symptoms. Mechanism-targeted interventions need to be identified and tested in homogeneous samples with specific symptom clusters. Interventions need to be replicated before guidelines can be established. PMID- 23364299 TI - Current world literature. PMID- 23364301 TI - Advisory Committee on Immunization Practices (ACIP) recommended immunization schedules for persons aged 0 through 18 years and adults aged 19 years and older- United States, 2013. PMID- 23364302 TI - Advisory Committee on Immunization Practices (ACIP) recommended immunization schedule for persons aged 0 through 18 years--United States, 2013. PMID- 23364303 TI - Advisory Committee on Immunization Practices (ACIP) recommended immunization schedule for adults aged 19 years and older--United States, 2013. PMID- 23364304 TI - Pandemic influenza vaccination during pregnancy: an investigation of vaccine uptake during the 2009/10 pandemic vaccination campaign in Great Britain. AB - BACKGROUND: Pregnant women in Great Britain were recommended to receive influenza A(H1N1)pdm09 vaccines during the 2009/10 influenza pandemic, however uptake of the vaccines by pregnant women was reported to have been very low. AIM: We sought to estimate uptake of influenza A(H1N1)pdm09 vaccines and to investigate predictors of vaccine uptake in pregnant women in Great Britain during the 2009/10 pandemic. RESULTS: Uptake of influenza A(H1N1)pdm09 vaccines by pregnant women was 21.6%. Pregnant women with an underlying health condition increasing the risk of influenza-related complications had a higher vaccination rate than pregnant women without such conditions. The hazard ratio comparing these two groups decreased logarithmically throughout pregnancy from 9.3 in the first week to 1.3 by the end of pregnancy. Increasing maternal age (HR 1.01, CI 95 1.01 1.01), having a previous delivery recorded (HR 1.21, CI95 1.16-1.27) and living in Scotland (HR 2.58, CI95 2.34-2.85) or Wales (HR 1.37, CI95 1.20-1.57) as opposed to England were all also associated with an increase in vaccination uptake rates throughout pregnancy. DISCUSSION: Uptake of influenza A(H1N1)pdm09 vaccines by pregnant women was low. None of the potential predictors evaluated in this study were strong enough to account for this, however information on health beliefs and GP recommendation were not available. If the low rates reported here are to be improved new strategies to increase uptake of influenza vaccine in pregnant women need to be identified, evaluated and implemented. METHODS: Uptake rates were calculated using data from the UK General Practice Research Database (GPRD). Predictors of vaccination were identified using a Cox proportional hazards model. PMID- 23364305 TI - National policy on physical activity: the development of a policy audit tool. AB - BACKGROUND: Physical inactivity is a leading risk factor for noncommunicable disease worldwide. Increasing physical activity requires large scale actions and relevant, supportive national policy across multiple sectors. METHODS: The policy audit tool (PAT) was developed to provide a standardized instrument to assess national policy approaches to physical activity. A draft tool, based on earlier work, was developed and pilot-tested in 7 countries. RESULTS: After several rounds of revisions, the final PAT comprises 27 items and collects information on 1) government structure, 2) development and content of identified key policies across multiple sectors, 3) the experience of policy implementation at both the national and local level, and 4) a summary of the PAT completion process. CONCLUSIONS: PAT provides a standardized instrument for assessing progress of national policy on physical activity. Engaging a diverse international group of countries in the development helped ensure PAT has applicability across a wide range of countries and contexts. Experiences from the development of the PAT suggests that undertaking an audit of health enhancing physical activity (HEPA) policy can stimulate greater awareness of current policy opportunities and gaps, promote critical debate across sectors, and provide a catalyst for collaboration on policy level actions. The final tool is available online. PMID- 23364306 TI - Poor decision making is associated with an increased risk of mortality among community-dwelling older persons without dementia. AB - BACKGROUND: Decision making is thought to be an important determinant of health and well-being across the lifespan, but little is known about the association of decision making with mortality. METHODS: Participants were 675 older persons without dementia from the Rush Memory and Aging Project, a longitudinal cohort study of aging. Baseline assessments of decision making were used to predict the risk of mortality during up to 4 years of follow-up. RESULTS: The mean score on the decision making measure at baseline was 7.1 (SD = 2.9, range: 0-12), with lower scores indicating poorer decision making. During up to 4 years of follow-up (mean = 1.7 years), 40 (6% of 675) persons died. In a proportional hazards model adjusted for age, sex and education, the risk of mortality increased by about 20% for each additional decision making error (HR = 1.19, 95% CI = 1.07-1.32, p = 0.002). Thus, a person who performed poorly on the measure of decision making (score = 3, 10th percentile) was about 4 times more likely to die compared to a person who performed well (score = 11, 90th percentile). Further, the association of decision making with mortality persisted after adjustment for the level of cognitive function. CONCLUSION: Poor decision making is associated with an increased risk of mortality in old age even after accounting for cognitive function. PMID- 23364307 TI - Serum levels of anti-apolipoprotein A-1 auto-antibodies and myeloperoxidase as predictors of major adverse cardiovascular events after carotid endarterectomy. AB - We aimed at challenging the prognostic accuracies of myeloperoxidase (MPO) and antibodies anti-apolipoprotein A-1 (anti-apoA-1 IgG), alone or in combination, for major adverse cardiovascular events (MACE) prediction, one year after carotid endarterectomy (CEA). In this prospective single centre study, 178 patients undergoing elective CEA were included. Serum anti-apoA-1 IgG and MPO were assessed by enzyme-linked immunosorbent assay prior to the surgery. Post-hoc determination of the MPO cut-off was performed by receiver operating characteristics (ROC) analyses. MACE was defined by the occurrence of fatal or non-fatal acute coronary syndromes or stroke during one year follow-up. Prognostic accuracy of anti-apoA-1 IgG was assessed by ROC curve analyses, survival analyses and reclassification statistics. During follow-up, 5% (9/178) of patients presented a MACE, and 29% (52/178) were positive for anti-apoA-1 IgG. Patients with MACE had higher median MPO and anti-apoA-1 IgG levels at admission (p=0.01), but no difference for the 10-year global Framingham risk score (FRS) was observed (p=0.22). ROC analyses indicated that both MPO and anti-apoA-1 IgG were significant predictors of subsequent MACE (area under the curve [AUC]: 0.75, 95% confidence interval [95%CI]: 0.61-0.89, p=0.01; and 0.74, 95%CI: 0.59-90; p=0.01), but combining anti-apoA-1 IgG positivity and MPO>857 ng/ml displayed the best predictive accuracy (AUC: 0.78, 95%CI: 0.65-0.91; p=0.007). It was associated with a poorer MACE-free survival (98.2% vs. 57.1%; p<0.001, LogRank), with a positive likelihood ratio of 13.67, and provided incremental predictive ability over FRS. In conclusion, combining the assessment of anti-apoA-1 IgG and MPO appears as a promising risk stratification tool in patients with severe carotid stenosis. PMID- 23364308 TI - Effect of intravitreal bevacizumab injection before Ahmed glaucoma valve implantation in neovascular glaucoma. AB - PURPOSE: To assess the efficacy of preoperative intravitreal bevacizumab injection (IVB) before Ahmed glaucoma valve (AGV) implantation in the treatment of neovascular glaucoma (NVG). METHODS: This retrospective, comparative and consecutive case series study included 41 eyes from 41 patients who underwent AGV implantation for treatment of NVG. The study group was composed of 19 patients (19 eyes) to whom IVB was administered before surgery, while the control group was composed of 22 patients (22 eyes) to whom IVB was not administered before AGV implantation. Findings such as intraocular pressures measured before and after surgery, surgical success rates, and postoperative complications were compared between the groups. RESULTS: There were no significant differences in preoperative data between groups. The surgical success rate in the study group (79%) was better than in the control group (64%), but this difference was not statistically significant (p = 0.28). Early postoperative complications such as fibrinous reaction in the anterior chamber as well as hyphema were less frequently observed in the study group. CONCLUSIONS: Intravitreal bevacizumab is a useful preparatory step to safely and effectively implant an aqueous shunting tube in eyes with severe NVG and intractable intraocular pressure. PMID- 23364309 TI - EVICR. PMID- 23364310 TI - Diffusion tensor imaging findings of optic radiation in patients with putaminal hemorrhage. AB - OBJECTIVES: Little is known about optic radiation (OR) injury in intracerebral hemorrhage (ICH). We attempted to investigate OR injury in patients with ICH by diffusion tensor imaging (DTI). METHODS: Forty-three consecutive patients with putaminal hemorrhage and 40 normal healthy control subjects were recruited. DTI data were acquired at the beginning of rehabilitation (average 34 days after onset). DTI-Studio software was used to reconstruct the OR. Fractional anisotropies (FA) and fiber numbers of the ORs were measured. FA values and fiber numbers of affected ORs were described as abnormal when they were more than 2.5 SD lower than those of normal controls. RESULTS: Thirty (70%) of the 43 patients showed an OR abnormality in the affected hemisphere. In 13 (30%) patients, the affected OR was disrupted or nonreconstructable. On the other hand, of the 20 patients with preserved OR integrity, 14 (33%) had a low FA value and 3 (7%) a low FA and fiber number. The other 13 (30%) of the 43 patients had no abnormal OR findings. CONCLUSION: Seventy percent of patients showed any abnormality of OR in the affected hemisphere on DTI. This result suggests that patients with putaminal hemorrhage are at high risk of OR injury. PMID- 23364311 TI - Competitive stem cell recruitment by multiple cytotactic cues. AB - A multitude of cytotactic cues direct cell migration in development, cancer metastasis and wound healing. However, our understanding of cell motility remains fragmented partially because current migration devices only allow the study of independent factors. We developed a cell motility assay that allows competitive recruitment of a given cell population simultaneously by gradients of multiple cytotactic cues, observable under real-time imaging. Well-defined uniform gradients of cytotactic cues can be independently generated and sustained in each channel. As a case study, bone marrow mesenchymal stem/stromal cells (MSCs) were exposed to 15 cytokines that are commonly present in arthritis. Cytokines that induced robust recruitment of MSCs in multiple groups were selected to 'compete' in a final round to yield the most chemotactic factor(s) based on cell migration numbers, distances, migration indices and motility over time. The potency of a given cytokine in competition frequently differed from its individual action, substantiating the need to test multiple cytokines concurrently due to synergistic or antagonistic effects. This new device has the rare capacity to screen molecules that induce cell migration in cancer therapy, drug development and tissue regeneration. PMID- 23364312 TI - Sidestepping questions of legitimacy: how community representatives manoeuvre to effect change in a health service. AB - Empirical studies of community participation in health services commonly tie effectiveness to the perceived legitimacy of community representatives among health staff. This article examines the underlying assumption that legitimacy is the major pathway to influence for community representatives. It takes a different vantage point from previous research in its examination of data (primarily through 34 in-depth interviews, observation and recording of 26 meetings and other interactions documented in field notes) from a 3-year study of community representatives' action in a large health region in Australia. The analysis primarily deploys Michel de Certeau's ideas of Strategy and Tactic to understand the action and effects of the generally 'weaker players' in the spaces and places dominated by powerful institutions. Through this lens, we can see the points where community representatives are active participants following their own agenda, tactically capitalising on cracks in the armour of the health service to seize opportunities that present themselves in time to effect change. Being able to see community representatives as active producers of change, not simply passengers following the path of the health service, challenges how we view the success of community participation in health. PMID- 23364314 TI - No tumour-initiating risk associated with scAAV transduction in newborn rat liver. AB - Delivery of recombinant adeno-associated virus (rAAV) vectors to the newborn liver is followed by a rapid loss of episomal vector copies because of hepatocyte proliferation. In selected hepatocytes, integration of rAAV genomes can lead to a sustained expression of the transgene. The safety of in vivo gene therapy with single-stranded AAV vectors has been questioned in a study reporting a high incidence of hepatocellular carcinoma, associated with provirus integration events in mice that receive an single-stranded AAV injection at birth. To investigate the tumour-initiating potential of the newly established self complementary AAV (scAAV) vectors in the liver, groups of newborn rats received intravenous injection of a scAAV vector encoding the green fluorescent protein (GFP), or were injected with phosphate-buffered saline (PBS) or diethylnitrosamine (DEN), a well-known liver tumour initiator. The rats were fed on a diet containing 2-acetylaminofluorene, a potent liver tumour-promoting agent to accelerate the carcinogenic process. After 2 months, the animals were killed and their livers analysed. Preneoplastic nodules were identified by glutathion S transferase-p (GSTp) staining, and GFP expression was detected by immunohistochemistry. Vector genome integration events were analysed. The numbers of GSTp-positive foci were comparable in the PBS and the scAAV-GFP groups and significantly higher in the DEN group. The proportion of GSTp-positive foci that also expressed GFP was low and in the range expected for random occurrence. No specific integration hot spots were detected by linear amplification-mediated-PCR in transduced liver. In conclusion, scAAV transduction of newborn rat liver does not trigger preneoplastic lesions suggesting an absence of liver tumourigenesis. PMID- 23364313 TI - Combinatorial anti-HIV gene therapy: using a multipronged approach to reach beyond HAART. AB - The 'Berlin Patient', who maintains suppressed levels of HIV viremia in the absence of antiretroviral therapy, continues to be a standard bearer in HIV eradication research. However, the unique circumstances surrounding his functional cure are not applicable to most HIV(+) patients. To achieve a functional or sterilizing cure in a greater number of infected individuals worldwide, combinatorial treatments, targeting multiple stages of the viral life cycle, will be essential. Several anti-HIV gene therapy approaches have been explored recently, including disruption of the C-C chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) coreceptor loci in CD4(+) T cells and CD34(+) hematopoietic stem cells. However, less is known about the efficacy of these strategies in patients and more relevant HIV model systems such as non human primates (NHPs). Combinatorial approaches, including genetic disruption of integrated provirus, functional enhancement of endogenous restriction factors and/or the use of pharmacological adjuvants, could amplify the anti-HIV effects of CCR5/CXCR4 gene disruption. Importantly, delivering gene disruption molecules to genetic sites of interest will likely require optimization on a cell type-by cell type basis. In this review, we highlight the most promising gene therapy approaches to combat HIV infection, methods to deliver these therapies to hematopoietic cells and emphasize the need to target viral replication pre- and post-entry to mount a suitably robust defense against spreading infection. PMID- 23364315 TI - Engineering a serum-resistant and thermostable vesicular stomatitis virus G glycoprotein for pseudotyping retroviral and lentiviral vectors. AB - Vesicular stomatitis virus G glycoprotein (VSV-G) is the most widely used envelope protein for retroviral and lentiviral vector pseudotyping; however, serum inactivation of VSV-G pseudotyped vectors is a significant challenge for in vivo gene delivery. To address this problem, we conducted directed evolution of VSV-G to increase its resistance to human serum neutralization. After six selection cycles, numerous common mutations were present. On the basis of their location within VSV-G, we analyzed whether substitutions in several surface exposed residues could endow viral vectors with higher resistance to serum. S162T, T230N and T368A mutations enhanced serum resistance, and additionally K66T, T368A and E380K substitutions increased the thermostability of VSV-G pseudotyped retroviral vectors, an advantageous byproduct of the selection strategy. Analysis of a number of combined mutants revealed that VSV-G harboring T230N+T368A or K66T+S162T+T230N+T368A mutations exhibited both higher in vitro resistance to human serum and higher thermostability, as well as enhanced resistance to rabbit and mouse serum. Finally, lentiviral vectors pseudotyped with these variants were more resistant to human serum in a murine model. These serum-resistant and thermostable VSV-G variants may aid the application of retroviral and lentiviral vectors to gene therapy. PMID- 23364317 TI - Multi-cistronic vector encoding optimized safety switch for adoptive therapy with T-cell receptor-modified T cells. AB - T-cell receptor (TCR) gene transfer is an attractive strategy to equip T cells with defined antigen-specific TCRs using short-term in vitro procedures to target both hematological malignancies and solid tumors. TCR gene transfer poses different safety issues that might warrant the inclusion of a suicide gene. High affinity TCRs may result in on-target toxicity, and off-target reactivity directed against healthy tissue can be observed due to mixed TCR dimers. Inclusion of a suicide gene as a safety switch may abrogate these unwanted toxicities. Human CD20 has been proposed as a nonimmunogenic suicide gene targeted by widely used clinical-grade anti-CD20 antibodies that can additionally function as a selection marker. However, transduction of T cells with a multi cistronic vector encoding both TCR and CD20 resulted in poor coexpression. In this study, we demonstrated that codon optimization of TCR and CD20 resulted in profound coexpression of both the preferentially expressed antigen in melanoma (PRAME)-TCR and CD20, allowing selective as well as efficient elimination of these engineered T cells in vitro. These results demonstrate the great potential of codon optimized CD20 to be broadly used in clinical trials as a safety switch. PMID- 23364316 TI - Suppression of breast tumor growth by DNA vaccination against phosphatase of regenerating liver 3. AB - Phosphatase of regenerating liver (PRL)-3 is highly expressed in multiple cancers and has important roles in cancer development. Some small-molecule inhibitors and antibodies targeting PRL-3 have been recently reported to inhibit tumor growth effectively. To determine whether PRL-3-targeted DNA vaccination can induce immune response to prevent or inhibit the tumor growth, we established mouse D2F2 breast cancer cells expressing PRL-3 (D2F2/PRL-3) and control cells (D2F2/NC) with lentivirus, and constructed pVAX1-Igkappa-PRL-3 plasmid (named as K-P3) as DNA vaccine to immunize BALB/c mice. We found that the K-P3 vaccine delivered by gene gun significantly prevented the growth of D2F2/PRL-3 compared with pVAX1 vector (P<0.01), but not of D2F2/NC, and improved the survival of D2F2/PRL-3 innoculated mice. Both PRL-3-targeted cytotoxic T lymphocytes (CTLs) and T-helper type 1 cell immune response (production of high levels of interferon-gamma and tumor necrosis factor-alpha) were found to be involved in the preventive effect. Furthermore, PRL-3-targeted DNA immunization inhibited tumor growth of D2F2/PRL-3 cells in mice. We also evaluated the potential of immunization with PRL-3 protein, but no significant therapeutic or preventive effect was obtained on tumor growth. To enhance the immunity of PRL-3, we incorporated different molecular adjuvants, such as Mycobacterium tuberculosis heat-shock protein, CTL antigen 4 and M. tuberculosis T-cell stimulatory epitope (MT), into K-P3 vaccine for expressing the fusion proteins. We found that these adjuvant molecules did not significantly improve the antitumor activity of PRL-3 vaccine, but enhanced the production of PRL-3 antibodies in immunized mice. Summarily, our findings demonstrate that PRL-3-targeted DNA vaccine can generate significantly preventive and therapeutic effects on the growth of breast cancer expressing PRL-3 through the induction of cellular immune responses to PRL-3. PMID- 23364318 TI - Changes in physical activity and sedentary behavior in a randomized trial of an internet-based versus workbook-based family intervention study. AB - BACKGROUND: The America on the Move (AOM) Family Intervention Program has been shown to prevent excess weight gain in overweight children. Providing intervention materials via the internet would have the potential to reach more families but may increase sedentary behavior. The purpose was to evaluate whether delivering the AOM Family Intervention via the internet versus printed workbook would have a similar impact on sedentary behaviors in children. METHODS: 131 children (age 8-12) were randomized to receive the AOM Family Intervention via the internet or workbook for 12 weeks. Changes in objectively measured sedentary time and moderate-to vigorous physical activity (MVPA) as well as self-reported screen time were compared between groups. RESULTS: There were no significant differences between groups in screen time, sedentary time, or MVPA at the end of the 12 week intervention. Families receiving the intervention via the internet were more likely to remain in the study (98% vs. 82%, P = .016). CONCLUSIONS: Using the internet to deliver the lifestyle intervention did not increase sedentary behavior in children. Attrition rates were lower when the program was delivered by internet versus via printed materials. These results provide support for using the internet to deliver healthy lifestyle programs for children. PMID- 23364319 TI - Vancomycin Ophthalmic Ointment 1% for methicillin-resistant Staphylococcus aureus or methicillin-resistant Staphylococcus epidermidis infections: a case series. AB - OBJECTIVES: To investigate the efficacy and safety of Vancomycin Ophthalmic Ointment 1% (Toa Pharmaceutical Co., Ltd, Toyama, Japan) in patients with external ocular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE). DESIGN: A case series. SETTING: This study was a multicentre, open-label, uncontrolled study in Japan approved as orphan drug status. PARTICIPANTS: Patients with MRSA or MRSE external ocular infections unresponsive to the treatment of fluoroquinolone eye drops. INTERVENTIONS: Vancomycin Ophthalmic Ointment 1% was administered four times daily. PRIMARY AND SECONDARY OUTCOME MEASURES: The subjective and objective clinical scores and bacterial cultures were collected at days 0 (baseline), 3, 7 and 14. The primary outcome was clinical response evaluation (efficacy rate) determined as complete response, partial response, no response and worsening. Secondary outcome was the eradication of the bacteria. Safety was assessed by adverse events including cases in which neither MRSA nor MRSE was detected. RESULTS: Twenty-five cases with MRSA (20) or MRSE (5) infections were enrolled. Of these 25 cases, 4 discontinued the treatment due to the negative results for bacterial culture during screening or at baseline. Of the 21 cases with conjunctivitis (14), blepharitis (3), meibomitis (1), dacryocystitis (2) or keratitis (1), 14 (66.7%) cases were evaluated as being excellently (complete response, 2 cases) or well (partial response, 12 cases) treated. The eradication rates were 68.4% in MRSA (13 of 19 cases) and 100% in MRSE (2 of 2 cases). Ten adverse events occurred in 7 (28.0%) of 25 cases at the local administration site. CONCLUSIONS: Vancomycin Ophthalmic Ointment 1% was considered to be useful for the treatment of intractable ocular MRSA/MRSE infections. PMID- 23364321 TI - Testing for new oral anticoagulants with LA-resistant Russells viper venom reagents. An in vitro study. PMID- 23364320 TI - Methodology of a large prospective, randomised, open, blinded endpoint streamlined safety study of celecoxib versus traditional non-steroidal anti inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis: protocol of the standard care versus celecoxib outcome trial (SCOT). AB - INTRODUCTION: Cyclooxygenase 2 (COX-2) inhibitors have less upper gastrointestinal toxicity than traditional non-steroidal anti-inflammatory drugs (NSAIDs). However, both COX-2 inhibitors and traditional NSAIDs may be associated with adverse cardiovascular side effects. Data from randomised and observational studies suggest that celecoxib has similar cardiovascular toxicity to traditional NSAIDs. The overall safety balance of a strategy of celecoxib therapy versus traditional NSAID therapy is unknown. The European Medicines Agency requested studies of the cardiovascular safety of celecoxib within Europe. The Standard care versus Celecoxib Outcome Trial (SCOT) compares the cardiovascular safety of celecoxib with traditional NSAID therapy in the setting of the European Union healthcare system. METHODS AND ANALYSIS: SCOT is a large streamlined safety study conducted in Scotland, England, Denmark and the Netherlands using the Prospective Randomised Open Blinded Endpoint design. Patients aged over 60 years with osteoarthritis or rheumatoid arthritis, free from established cardiovascular disease and requiring chronic NSAID therapy, are randomised to celecoxib or their previous traditional NSAID. They are then followed up for events by record linkage within their normal healthcare setting. The hypothesis is non-inferiority with a confidence limit of 1.4. The primary endpoint is the first occurrence of hospitalisation or death for the Anti-Platelet Trialists' Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are (1) first hospitalisation or death for upper gastrointestinal ulcer complications (bleeding, perforation or obstruction); (2) first occurrence of hospitalised upper gastrointestinal ulcer complications or APTC endpoint; (3) first hospitalisation for heart failure; (4) first hospitalisation for APTC endpoint plus heart failure; (5) all-cause mortality and (6) first hospitalisation for new or worsening renal failure. ETHICS AND DISSEMINATION: SCOT has been approved by the relevant ethics committees. The trial results will be published in a peer-reviewed scientific journal. CLINICAL TRIALS REGISTRATION NUMBER: Clinicaltrials.gov (NCT00447759). PMID- 23364322 TI - Interleukin 6 plasma concentration associates with cognitive decline: the northern Manhattan study. AB - BACKGROUND: Interleukin 6 (IL-6) is an inflammatory cytokine that has been associated with vascular disease and cognitive impairment, but few studies have examined these relationships in population-based studies that include Hispanic and Black people who often have a greater prevalence of vascular risk factors and are at an elevated risk of dementia than Whites. We examined relative elevations of plasma IL-6 concentrations in relation to cognitive decline in a stroke-free racially/ethnically diverse community-based sample from Northern Manhattan. METHODS: We used mixed effects models to measure the effect of IL-6 on change in performance on the modified Telephone Interview for Cognitive Status (TICS-m) measured annually in our cohort, adjusting for sociodemographic and vascular risk factors. RESULTS: There were 1,224 participants with IL-6 levels (median 1.5 pg/ml, interquartile range 0.83-2.57 pg/ml) and TICS-m data available (mean = 31.6 points, SD 6.5). The mean age was 71 (SD 9.3; 64% women, 59% Hispanic, 19% Black, 19% White) with 3,406 person-years and a median 3.0 years of follow-up (interquartile range 1.1-4.0 years). Participants with IL-6 levels above the median showed greater cognitive decline on the TICS-m compared to those with levels below the median, adjusting for sociodemographic and vascular factors (beta = -0.17 points/year, p = 0.02). Decline on the TICS-m among participants with IL-6 above the median differed by age (p for interaction <0.001). There was no interaction by race/ethnicity, vascular risk factors, C-reactive protein, apolipoprotein epsilon4 allele status, or the metabolic syndrome among nondiabetics. CONCLUSIONS: IL-6 associated with cognitive decline among older participants in this racially/ethnically diverse sample independent of other vascular risk factors and C-reactive protein. PMID- 23364323 TI - The evolution of male-female sexual dimorphism predates the gender-based divergence of the mating locus gene MAT3/RB. AB - The molecular bases for the evolution of male-female sexual dimorphism are possible to study in volvocine algae because they encompass the entire range of reproductive morphologies from isogamy to oogamy. In 1978, Charlesworth suggested the model of a gamete size gene becoming linked to the sex-determining or mating type locus (MT) as a mechanism for the evolution of anisogamy. Here, we carried out the first comprehensive study of a candidate MT-linked oogamy gene, MAT3/RB, across the volvocine lineage. We found that evolution of anisogamy/oogamy predates the extremely high male-female divergence of MAT3 that characterizes the Volvox carteri lineage. These data demonstrate very little sex-linked sequence divergence of MAT3 between the two sexes in other volvocine groups, though linkage between MAT3 and the mating locus appears to be conserved. These data implicate genetic determinants other than or in addition to MAT3 in the evolution of anisogamy in volvocine algae. PMID- 23364324 TI - Maximum likelihood estimation of frequencies of known haplotypes from pooled sequence data. AB - DNA samples are often pooled, either by experimental design or because the sample itself is a mixture. For example, when population allele frequencies are of primary interest, individual samples may be pooled together to lower the cost of sequencing. Alternatively, the sample itself may be a mixture of multiple species or strains (e.g., bacterial species comprising a microbiome or pathogen strains in a blood sample). We present an expectation-maximization algorithm for estimating haplotype frequencies in a pooled sample directly from mapped sequence reads, in the case where the possible haplotypes are known. This method is relevant to the analysis of pooled sequencing data from selection experiments, as well as the calculation of proportions of different species within a metagenomics sample. Our method outperforms existing methods based on single-site allele frequencies, as well as simple approaches using sequence read data. We have implemented the method in a freely available open-source software tool. PMID- 23364325 TI - Intravitreal bevacizumab for type 2 idiopathic macular telangiectasia. AB - BACKGROUND/AIMS: The aim of this paper is to report the treatment of type 2 nonproliferative idiopathic macular telangiectasia (IMT) with intravitreal bevacizumab (IVB). METHODS: Retrospective case series of 10 eyes of 5 patients with type 2 IMT. All patients received 3 monthly IVB injections. Visual acuity (VA), fluorescein angiography (FA) and optical coherence tomography (OCT) were performed at baseline and 4 weeks after each injection. RESULTS: Four weeks after the third IVB injection, VA remained stable for all patients. All eyes showed some decrease in fluorescein leakage, and there was a mild decrease in central macular thickness. One year later, VA, OCT and FA findings returned to the baseline levels. CONCLUSION: IVB did not improve VA in cases of type 2 IMT. PMID- 23364326 TI - The transcription factor Otx2 regulates choroid plexus development and function. AB - The choroid plexuses (ChPs) are the main regulators of cerebrospinal fluid (CSF) composition and thereby also control the composition of a principal source of signaling molecules that is in direct contact with neural stem cells in the developing brain. The regulators of ChP development mediating the acquisition of a fate that differs from the neighboring neuroepithelial cells are poorly understood. Here, we demonstrate in mice a crucial role for the transcription factor Otx2 in the development and maintenance of ChP cells. Deletion of Otx2 by the Otx2-CreERT2 driver line at E9 resulted in a lack of all ChPs, whereas deletion by the Gdf7-Cre driver line affected predominately the hindbrain ChP, which was reduced in size, primarily owing to an increase in apoptosis upon Otx2 deletion. Strikingly, Otx2 was still required for the maintenance of hindbrain ChP cells at later stages when Otx2 deletion was induced at E15, demonstrating a central role of Otx2 in ChP development and maintenance. Moreover, the predominant defects in the hindbrain ChP mediated by Gdf7-Cre deletion of Otx2 revealed its key role in regulating early CSF composition, which was altered in protein content, including the levels of Wnt4 and the Wnt modulator Tgm2. Accordingly, proliferation and Wnt signaling levels were increased in the distant cerebral cortex, suggesting a role of the hindbrain ChP in regulating CSF composition, including key signaling molecules. Thus, Otx2 acts as a master regulator of ChP development, thereby influencing one of the principal sources of signaling in the developing brain, the CSF. PMID- 23364327 TI - The transcription factor Vox represses endoderm development by interacting with Casanova and Pou2. AB - Endoderm and mesoderm are both formed upon activation of Nodal signaling but how endoderm differentiates from mesoderm is still poorly explored. The sox-related gene casanova (sox32) acts downstream of the Nodal signal, is essential for endoderm development and requires the co-factor Pou2 (Pou5f1, Oct3, Oct4) in this process. Conversely, BMP signals have been shown to inhibit endoderm development by an as yet unexplained mechanism. In a search for Casanova regulators in zebrafish, we identified two of its binding partners as the transcription factors Pou2 and Vox, a member of the Vent group of proteins also involved in the patterning of the gastrula. In overexpression studies we show that vox and/or Vent group genes inhibit the capacity of Casanova to induce endoderm, even in the presence of its co-factor Pou2, and that Vox acts as a repressor in this process. We further show that vox, but not other members of the Vent group, is essential for defining the proper endodermal domain size at gastrulation. In this process, vox acts downstream of BMPs. Cell fate analysis further shows that Vox plays a key role downstream of BMP signals in regulating the capacity of Nodal to induce endoderm versus mesoderm by modulating the activity of the Casanova/Pou2 regulatory system. PMID- 23364329 TI - On the embryonic origin of adult melanophores: the role of ErbB and Kit signalling in establishing melanophore stem cells in zebrafish. AB - Pigment cells in vertebrates are derived from the neural crest (NC), a pluripotent and migratory embryonic cell population. In fishes, larval melanophores develop during embryogenesis directly from NC cells migrating along dorsolateral and ventromedial paths. The embryonic origin of the melanophores that emerge during juvenile development in the skin to contribute to the striking colour patterns of adult fishes remains elusive. We have identified a small set of melanophore progenitor cells (MPs) in the zebrafish (Danio rerio, Cyprinidae) that is established within the first 2 days of embryonic development in close association with the segmentally reiterated dorsal root ganglia (DRGs). Lineage analysis and 4D in vivo imaging indicate that progeny of these embryonic MPs spread segmentally, giving rise to the melanophores that create the adult melanophore stripes. Upon depletion of larval melanophores by morpholino knockdown of Mitfa, the embryonic MPs are prematurely activated; their progeny migrate along the spinal nerves restoring the larval pattern and giving rise to postembryonic MPs associated with the spinal nerves. Mutational or chemical inhibition of ErbB receptors blocks all early NC migration along the ventromedial path, causing a loss of DRGs and embryonic MPs. We show that the sparse like (slk) mutant lacks larval and metamorphic melanophores and identify kit ligand a (kitlga) as the underlying gene. Our data suggest that kitlga is required for the establishment or survival of embryonic MPs. We propose a model in which DRGs provide a niche for the stem cells of adult melanophores. PMID- 23364330 TI - Eaf1 and Eaf2 negatively regulate canonical Wnt/beta-catenin signaling. AB - Eaf factors play a crucial role in tumor suppression and embryogenesis. To investigate the potential mechanism of Eaf activity, we performed loss- and gain of-function assays in zebrafish using morpholino and mRNA injections, respectively. We found that eaf1 and eaf2 inhibit Wnt/beta-catenin signaling, thereby modulating mesodermal and neural patterning in the embryo. Moreover, ectopic expression of eaf1 and eaf2 in embryos and cultured cells blocked beta catenin reporter activity. By immunoprecipitation, we also observed that Eaf1 and Eaf2 bound to the Armadillo repeat region and C-terminus of beta-catenin, as well as to other beta-catenin transcription complex proteins, such as c-Jun, Tcf and Axin, suggesting the formation of a novel complex. In addition, the N-terminus of Eaf1 and Eaf2 bound to beta-catenin and exhibited dominant-negative activity, whereas the C-terminus appeared to either harbor a suppression domain or to recruit a repressor. Both the N- and C-terminus must be intact for Eaf1 and Eaf2 suppressive activity. Lastly, we demonstrate a conservation of biological activities for Eaf family proteins across species. In summary, our evidence points to a novel role for Eaf1 and Eaf2 in inhibiting canonical Wnt/beta-catenin signaling, which might form the mechanistic basis for Eaf1 and Eaf2 tumor suppressor activity. PMID- 23364328 TI - The Frizzled-dependent planar polarity pathway locally promotes E-cadherin turnover via recruitment of RhoGEF2. AB - Polarised tissue elongation during morphogenesis involves cells within epithelial sheets or tubes making and breaking intercellular contacts in an oriented manner. Growing evidence suggests that cell adhesion can be modulated by endocytic trafficking of E-cadherin (E-cad), but how this process can be polarised within individual cells is poorly understood. The Frizzled (Fz)-dependent core planar polarity pathway is a major regulator of polarised cell rearrangements in processes such as gastrulation, and has also been implicated in regulation of cell adhesion through trafficking of E-cad; however, it is not known how these functions are integrated. We report a novel role for the core planar polarity pathway in promoting cell intercalation during tracheal tube morphogenesis in Drosophila embryogenesis, and present evidence that this is due to regulation of turnover and levels of junctional E-cad by the guanine exchange factor RhoGEF2. Furthermore, we show that core pathway activity leads to planar-polarised recruitment of RhoGEF2 and E-cad turnover in the epidermis of both the embryonic germband and the pupal wing. We thus reveal a general mechanism by which the core planar polarity pathway can promote polarised cell rearrangements. PMID- 23364331 TI - Kit signaling is involved in melanocyte stem cell fate decisions in zebrafish embryos. AB - Adult stem cells are crucial for growth, homeostasis and repair of adult animals. The melanocyte stem cell (MSC) and melanocyte regeneration is an attractive model for studying regulation of adult stem cells. The process of melanocyte regeneration can be divided into establishment of the MSC, recruitment of the MSC to produce committed daughter cells, and the proliferation, differentiation and survival of these daughter cells. Reduction of Kit signaling results in dose dependent reduction of melanocytes during larval regeneration. Here, we use clonal analysis techniques to develop assays to distinguish roles for these processes during zebrafish larval melanocyte regeneration. We use these clonal assays to investigate which processes are affected by the reduction in Kit signaling. We show that the regeneration defect in kita mutants is not due to defects in MSC recruitment or in the proliferation, differentiation or survival of the daughter cells, but is instead due to a defect in stem cell establishment. Our analysis suggests that the kit MSC establishment defect results from inappropriate differentiation of the MSC lineage. PMID- 23364333 TI - Stages of change in adults with acquired hearing impairment seeking help for the first time: application of the transtheoretical model in audiologic rehabilitation. AB - OBJECTIVES: This study investigated the application of the transtheoretical (stages-of-change) model in audiologic rehabilitation. More specifically, it described the University of Rhode Island Change Assessment (URICA) scores of adults with acquired hearing impairment. It reported the psychometric properties (construct, concurrent, and predictive validity) of the stages-of-change model in this population. DESIGN: At baseline, 153 adults with acquired hearing impairment seeking help for the first time completed the URICA as well as measures of degree of hearing impairment, self-reported hearing disability, and years since hearing impairment onset. Participants were subsequently offered intervention options: hearing aids, communication programs, and no intervention. Their intervention uptake and adherence were assessed 6 months later and their intervention outcomes were assessed 3 months after intervention completion. First, the stages-of-change construct validity was evaluated by investigating the URICA factor structure (principal component analysis), internal consistency, and correlations between stage scores. The URICA scores were reported in terms of the scores for each stage of change, composite scores, stages with highest scores, and stage clusters (cluster analysis). Second, the concurrent validity was assessed by examining associations between stages of change and degree of hearing impairment, self reported hearing disability, and years since hearing impairment onset. Third, the predictive validity was evaluated by investigating associations between stages of change and intervention uptake, adherence, and outcomes. RESULTS: First, in terms of construct validity, the principal component analysis identified four instead of three stages (precontemplation, contemplation, preparation, and action) for which the internal consistency was good. Most of the sample was in the action stage. Correlations between stage scores supported the model. Cluster analysis identified four stages-of-change clusters, which the authors named active change, initiation, disengagement, and ambivalence. In terms of concurrent validity, participants who reported a more advanced stage of change had a more severe hearing impairment, reported greater hearing disability, and had a hearing impairment for a longer period of time. In terms of predictive validity, participants who reported a more advanced stage of change were more likely to take up an intervention and to report successful intervention outcomes. However, stages of change did not predict intervention adherence. CONCLUSIONS: The majority of the sample was in the action stage. The construct, concurrent, and predictive validity of the stages-of-change model were good. The stages-of-change model has some validity in the rehabilitation of adults with hearing impairment. The data support that change might be better represented on a continuum rather than by movement from one step to the next. Of all the measures, the precontemplation stage score had the best concurrent and predictive validity. Therefore, further research should focus on addressing the precontemplation stage with a measure suitable for clinical use. PMID- 23364332 TI - Histone demethylase dUTX antagonizes JAK-STAT signaling to maintain proper gene expression and architecture of the Drosophila testis niche. AB - Adult stem cells reside in microenvironments called niches, where they are regulated by both extrinsic cues, such as signaling from neighboring cells, and intrinsic factors, such as chromatin structure. Here we report that in the Drosophila testis niche an H3K27me3-specific histone demethylase encoded by Ubiquitously transcribed tetratricopeptide repeat gene on the X chromosome (dUTX) maintains active transcription of the Suppressor of cytokine signaling at 36E (Socs36E) gene by removing the repressive H3K27me3 modification near its transcription start site. Socs36E encodes an inhibitor of the Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway. Whereas much is known about niche-to-stem cell signaling, such as the JAK-STAT signaling that is crucial for stem cell identity and activity, comparatively little is known about signaling from stem cells to the niche. Our results reveal that stem cells send feedback to niche cells to maintain the proper gene expression and architecture of the niche. We found that dUTX acts in cyst stem cells to maintain gene expression in hub cells through activating Socs36E transcription and preventing hyperactivation of JAK-STAT signaling. dUTX also acts in germline stem cells to maintain hub structure through regulating DE-Cadherin levels. Therefore, our findings provide new insights into how an epigenetic factor regulates crosstalk among different cell types within an endogenous stem cell niche, and shed light on the biological functions of a histone demethylase in vivo. PMID- 23364334 TI - Dose-response of women's health-related quality of life (HRQoL) and life satisfaction to physical activity. AB - BACKGROUND: To examine the dose-response relationship between health related quality of life (HRQoL) and life satisfaction (outcomes) and duration of recreational physical activity (exposure). Further, to explore whether these relationships depend on type of physical activity (PA). METHODS: 793 Australian rural-living women self-reported on duration of recreational PA; HRQoL via SF-36 Mental Component Summary (MCS) and Physical Component Summary (PCS); and a life satisfaction scale. ANOVAs and ANCOVAs investigated differences in outcomes (MCS, PCS, and life satisfaction) between tertiles of exposure to recreational PA, and types of PA (club sport, gymnasium, walking), with adjustment for potential confounders. RESULTS: A significant positive dose-response relationship was found between PCS and level of PA. Furthermore, this relationship depended on type of PA, with club-sport participants recording higher PCS than non-club-sport participants in all but the highest tertile of exposure. Life satisfaction and MCS were not significantly related to level of PA. CONCLUSION: Physical health was positively associated with level of recreational PA, with club sport participation contributing greater benefits at low to moderate exposures than participation in gymnasium or walking activities. PMID- 23364335 TI - Effect of IR laser on myoblasts: a proteomic study. AB - Laser therapy is used in physical medicine and rehabilitation to accelerate muscle recovery and in sports medicine to prevent damages produced by metabolic disturbances and inflammatory reactions after heavy exercise. The aim of this research was to get insight into possible benefits deriving from the application of an advanced IR laser system to counteract deficits of muscle energy metabolism and stimulate the recovery of hypotrophic tissue. We studied the effect of IR laser treatment on proliferation, differentiation, cytoskeleton organization and global protein expression in C2C12 myoblasts. We found that laser treatment induced a decrease in the cell proliferation rate without affecting cell viability, while leading to cytoskeletal rearrangement and expression of the early differentiation marker MyoD. The differential proteome analysis revealed the up-regulation and/or modulation of many proteins known to be involved in cell cycle regulation, cytoskeleton organization and differentiation. PMID- 23364336 TI - Early regression of left ventricular hypertrophy after treatment with esmolol in an experimental rat model of primary hypertension. AB - Certain beta-adrenergic blockers have proven useful in the regression of ventricular remodeling when administered as long-term treatment. However, early regression of left ventricular hypertrophy (LVH) has not been reported, following short-term administration of these drugs. We tested the hypothesis that short term administration of the cardioselective beta-blocker esmolol induces early regression of LVH in spontaneously hypertensive rats (SHR). Fourteen-month-old male SHRs were treated i.v. with vehicle (SHR) or esmolol (SHR-E) (300 MUg kg(-1) min(-1)). Age-matched vehicle-treated male Wistar-Kyoto (WKY) rats served as controls. After 48 h, left ventricular morphology and function were assessed using M-mode echocardiograms (left ventricular mass index (LVMI), ejection fraction and transmitral Doppler (early-to-atrial filling velocity ratio (E/A), E wave deceleration time (Edec time)). The standardized uptake value (SUV) was applied to evaluate FDG (2-deoxy-2[18F]fluoro-D-glucose) uptake by the heart using PET/CT. Left ventricular subendocardial and subepicardial biopsies were taken to analyze changes in cross-sectional area (CSA) of left ventricular cardiomyocytes and the fibrosis was expressed as collagen volume fraction (CVF). LVMI was lower in SHR-E with respect to SHR (P=0.009). There were no significant differences in EF, E/A ratio or Edec time in SHR-E compared with SHR (P=0.17, 0.55 and P=0.80, respectively). PET acquisitions in SHR-E showed lower (18)F-FDG uptake than SHR (P=0.003). Interestingly, there were no significant differences in SUV in either SHR-E or WKY (P=0.63). CSA in subendocardial and subepicardial regions was minor in SHR-E with respect to SHR (P<0.001), and there were no significant differences in CVF between both groups. Esmolol reverses early LVH in the SHR model of stable compensated ventricular hypertrophy. This is the first study to associate early regression of LVH with administration of a short-term beta-blocker. PMID- 23364337 TI - Carbonyl stress induces hypertension and cardio-renal vascular injury in Dahl salt-sensitive rats. AB - One major precursor of carbonyl stress, methylglyoxal (MG), is elevated in the plasma of chronic kidney disease (CKD) patients, and this precursor contributes to the progression of vascular injury, hypertension and renal injury in diabetic nephropathy patients. This molecule induces salt-sensitive hypertension via a reactive oxygen species-mediated pathway. We examined the role of MG in the pathogenesis of hypertension and cardio-renal injury in Dahl salt-sensitive (Dahl S) rats, which is a rat model of CKD. Nine-week-old Dahl S rats were fed a 1% NaCl diet, and 1% MG was added to their drinking water for up to 12 weeks. Blood pressure and cardio-renal injuries were compared with rats treated with tap water alone. The angiotensin II receptor blocker (ARB), candesartan (10 mg kg(-1) day( 1)), was administered to MG Dahl S rats to determine the impact of this drug on the pathogenesis of MG-induced CKD. A progressive increase in systolic blood pressure was observed (123+/-1-148+/-5 mm Hg) after 12 weeks of MG administration. MG administration significantly increased urinary albumin excretion, glomerular sclerosis, tubular injury, myocardial collagen content and cardiac perivascular fibrosis. MG also enhanced the renal expression of NE carboxyethyl-lysine (an advanced glycation end product), 8-hydroxydeoxyguanosine (a marker of oxidative stress), macrophage (ED-1) positive cells (a marker of inflammation) and nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activity. Candesartan treatment for 4 weeks significantly reduced these parameters. These results suggest that MG-induced hypertension and cardio-renal injury and increased inflammation and carbonyl and oxidative stress, which were partially preventable by an ARB. PMID- 23364338 TI - Aldosterone is synthesized in and activates bulbospinal neurons through mineralocorticoid receptors and ENaCs in the RVLM. AB - The effects of aldosterone and mineralocorticoid receptor (MR) blockers on presympathetic neurons in the rostral ventrolateral medulla (RVLM) are well studied. To directly investigate whether aldosterone, eplerenone (an MR blocker), FAD286 (an aldosterone synthase inhibitor) and benzamil (an epithelial sodium channel (ENaC) blocker) affect RVLM neurons, we examined changes in the membrane potentials (MPs) of bulbospinal RVLM neurons using the whole-cell patch-clamp technique during superfusion with these drugs to brainstem-spinal cord preparations. Aldosterone superfusion (0.1 MUmol/l) depolarized the RVLM neurons. In contrast, eplerenone superfusion (1 MUmol/l) hyperpolarized them. To evaluate the existence of aldosterone, FAD286 superfusion (10 MUmol/l) was performed, and the RVLM neurons became hyperpolarized during FAD superfusion. These data suggest that MRs exist and that aldosterone is synthesized in the brainstem. Benzamil superfusion (1 MUmol/l) hyperpolarized the RVLM neurons. To clarify whether aldosterone, eplerenone, FAD286 and benzamil acted directly on the RVLM neurons, a low-Ca(2+), high-Mg(2+) solution was used to block the synaptic input to the RVLM neurons, and the above-mentioned drugs were added during the low-Ca(2+) superfusion. During the aldosterone superfusion, the RVLM neurons became depolarized, and they became hyperpolarized during eplerenone, FAD286 or benzamil superfusion. Importantly, when aldosterone was superfused after the benzamil solution, the MPs of the RVLM neurons did not depolarize. These results suggest that MRs are present in the RVLM neurons and that aldosterone is synthesized in the RVLM. The RVLM neurons themselves possess ENaCs, and ENaCs are the underlying mechanism by which aldosterone activates RVLM neurons. PMID- 23364339 TI - Role of hypothalamic angiotensin type 1 receptors in pressure overload-induced mineralocorticoid receptor activation and salt-induced sympathoexcitation. AB - Pressure overload enhances salt-induced sympathoexcitation through hypothalamic mineralocorticoid receptor (MR)-epithelial Na channel activation. Pressure overload also increases hypothalamic angiotensin type 1 receptors (AT1R). However, the role of AT1R in pressure overload-induced MR activation and salt induced sympathoexcitation remains unknown. Therefore, the aim of the present study was to address this question. We performed aortic banding (AB) on mice from the Institute of Cancer Research. The expression of hypothalamic MR, serum/glucocorticoid-induced protein kinase-1 (SGK-1) and AT1R increased independently of plasma renin activity at 2 or 4 weeks after AB. Next, we performed AB in AT1aR-knockout (KO) mice and c57BL6/J wild-type (WT) mice. Sham operated (Sham) mice were used as a control. Four weeks after AB (AB-KO or AB WT), the expression of hypothalamic MR and SGK-1 increased in both AB-WT and AB KO compared with Sham-WT and Sham-KO, respectively. The expression of AT1R was also greater in AB-WT than in Sham-WT. In addition, mice were fed a high-salt (8%) diet for an additional 4 weeks (ABH-KO and ABH-WT). High salt loading increased the urinary excretion of norepinephrine, a marker of sympathetic activity in ABH-WT, concomitant with hypothalamic MR activation, but not in ABH KO. These results indicate that pressure overload activated hypothalamic MR independently of AT1R. After salt intake, however, AT1R was necessary to maintain hypothalamic MR activation and salt-induced sympathoexcitation. PMID- 23364340 TI - Acute effects of third generation beta-blockers on short-term and beat-to-beat blood pressure variability in sinoaortic-denervated rats. AB - An increase in blood pressure variability (BPV) contributes to the development of target organ damage associated with hypertension. Treatment with conventional beta-blockers, such as atenolol, has been associated with an increase in BPV; however, the extrapolation of these results to third generation beta-blockers with pleiotropic effects seems to be inappropriate. The cardiovascular effects of third generation beta-blockers, carvedilol and nebivolol, were assessed in sinoaortic-denervated rats (SAD) and compared with the second generation beta blocker atenolol and the calcium channel blocker verapamil, with a special focus on short-term BPV. Male SAD rats were acutely treated with carvedilol, nebivolol, atenolol or verapamil at two different doses, and the effects on blood pressure and BPV were recorded. Short-term BPV was assessed by the s.d. of BP recordings. Beat-to-beat BPV was studied using spectral analysis to assess the vascular sympatholytic activity of carvedilol and nebivolol by estimating the effects of these drugs on the ratio of low frequency (LF) to high frequency (HF) BPV (LF/HF ratio). Nebivolol, carvedilol and the calcium channel blocker verapamil significantly attenuated short-term BPV at both doses in SAD animals, and there were no differences between the drugs. Conversely, atenolol did not modify baseline s.d. values at either dose. Carvedilol and nebivolol significantly reduced the LF/HF ratio in SAD rats compared with the effects of atenolol and verapamil, suggesting the ability of the third generation beta-blockers to reduce vascular sympathetic activity. In conclusion, third generation beta-blockers induce a marked reduction in short-term BPV in SAD rats compared to atenolol. Moreover, the ability of carvedilol and nebivolol to reduce short-term BPV in SAD rats is equivalent to that of verapamil, suggesting that these beta-blockers may have an additional beneficial effect through their control of short-term variability to a similar extent to calcium channel blockers. PMID- 23364342 TI - Fetal aortic wall thickness: a marker of hypertension in IUGR children? AB - Fetuses with intrauterine growth restriction (IUGR) have significant aortic intima-media thickening (aIMT), which suggests that preclinical atherosclerosis might predispose the infants to hypertension. However, the natural course of aIMT in babies with IUGR remains an open question.The study enrolled 77 pregnant women between January 2007 and August 2009. The fetuses were classified as AGA (appropriate for gestational age) or IUGR, if the estimated fetal weight was between the 10th and 90th percentile or below the 10th percentile (with umbilical artery pulsatility index (PI) >2s.d.), respectively. Anthropometric parameters and aIMT were detected in each IUGR and AGA fetus at a mean gestational age of 32 weeks. The follow-up was performed in 25 IUGR and 25 AGA infants at a mean postnatal age of 18 months; the previous measurements were repeated, and blood pressure measurements were taken. The maximum aIMT was significantly higher in the IUGR fetuses and infants compared with the AGA infants, both in utero (2.05+/ 0.43 vs. 1.05+/-0.19 mm, P<0.001) and at the follow-up (2.3+/-0.8 vs. 1.06+/-0.18 mm, P<0.0001), the resulting values significantly correlated (P=0.018) with one another. The systolic blood pressure was significantly increased in the IUGR subjects (123+/-16 vs. 104+/-8.5 mm Hg, P<0.0004), and it correlated with the prenatal and postnatal aIMT values (P<0.0156 and P<0.0054, respectively). The aortic wall thickening progression in IUGR fetuses and infants differed from AGA, which may predispose the infants to hypertension early in life and cardiovascular risk later in life. PMID- 23364341 TI - Role of STAT3 in angiotensin II-induced hypertension and cardiac remodeling revealed by mice lacking STAT3 serine 727 phosphorylation. AB - STAT3 is involved in protection of the heart provided by ischemic preconditioning. However, the role of this transcription factor in the heart in chronic stresses such as hypertension has not been defined. We assessed whether STAT3 is important in hypertension-induced cardiac remodeling using mice with reduced STAT3 activity due to a S727A mutation (SA/SA). Wild type (WT) and SA/SA mice received angiotensin (ANG) II or saline for 17 days. ANG II increased mean arterial and systolic pressure in SA/SA and WT mice, but cardiac levels of cytokines associated with heart failure were increased less in SA/SA mice. Unlike WT mice, hearts of SA/SA mice showed signs of developing systolic dysfunction as evidenced by reduction in ejection fraction and fractional shortening. In the left ventricle of both WT and SA/SA mice, ANG II induced fibrosis. However, fibrosis in SA/SA mice appeared more extensive and was associated with loss of myocytes. Cardiac hypertrophy as indexed by heart to body weight ratio and left ventricular anterior wall dimension during diastole was greater in WT mice. In WT+ANG II mice there was an increase in the mass of individual myofibrils. In contrast, cardiac myocytes of SA/SA+ANG II mice showed a loss in myofibrils and myofibrillar mass density was decreased during ANG II infusion. Our findings reveal that STAT3 transcriptional activity is important for normal cardiac myocyte myofibril morphology. Loss of STAT3 may impair cardiac function in the hypertensive heart due to defective myofibrillar structure and remodeling that may lead to heart failure. PMID- 23364343 TI - Back to the future: our health history begins long before birth. PMID- 23364344 TI - Severe hypovitaminosis D in chronic kidney disease: association with blood pressure and coronary artery calcification. AB - Hypovitaminosis D occurs early in the course of chronic kidney disease (CKD), and its association with cardiovascular morbidity and mortality is well known. In this study, we aimed to evaluate whether the degree of hypovitaminosis D may differently affect blood pressure (BP) and coronary artery calcification (CAC) in nondialyzed CKD patients. This study included 80 CKD patients with a creatinine clearance between 15 and 60 ml/min/1.73 m(2) and serum 25 hydroxivitamin D [25(OH)D] level <30 ng/ml. Patients underwent 24-h ambulatory BP monitoring, evaluation of CAC (multi-slice computed tomography), and laboratory evaluation. Two groups, based on the degree of hypovitaminosis D, were defined according to the median 25(OH)D value. Patients with severe hypovitaminosis D [25(OH)D <17.2 ng/ml; S-group) exhibited a higher systolic BP at all time periods (24-h, nighttime, daytime) when compared to patients with mild hypovitaminosis D [25(OH)D >17.2 ng/ml; M-group]. No differences were found between the S and M group in terms of diastolic BP and the presence of coronary calcification. In the multiple linear regression analysis, severe hypovitaminosis D was a predictor of 24-h, daytime and nighttime BP after controlling for a number of confounders. The severity of hypovitaminosis D was associated with increased BP in nondialyzed CKD patients. The degree of hypovitaminosis D was not related to CAC, which was equally elevated in both the severe and mild hypovitaminosis D groups. PMID- 23364345 TI - Magnet removal and reinsertion in a cochlear implant recipient undergoing brain MRI. AB - BACKGROUND: Recent advances in cochlear implants (CIs) and in magnetic resonance imaging (MRI) techniques have led to increasing numbers of implanted patients who have undergone brain MRIs for various reasons. This paper first describes the surgical procedure for removing the magnet before an MRI and its subsequent reinsertion immediately afterwards in a CI recipient. METHOD: After the administration of local anesthesia, the magnet was removed by a surgical incision made along the posterior margin of the receiver-stimulator. The flap was elevated and the capsule over the implant was incised. The magnet was removed, maintained under sterile conditions and reinserted immediately after the completion of the 1.5-Tesla MRI. RESULTS: The patient was able to wear her device immediately after surgery. Large CI-associated artifacts were observed on the MRIs irrespective of sequences. The function of the device was not altered by either the MRI or the surgical procedure. CONCLUSION: The proposed surgical incision that follows the posterior margins of the receiver-stimulator allows the wearing of the device immediately after the surgical procedure. An MRI has limited diagnostic value for lesions located on the implanted side due to unavoidable artifacts, even after the magnet has been removed. PMID- 23364346 TI - Venous thromboembolism in adults treated for acute lymphoblastic leukaemia: Effect of fresh frozen plasma supplementation. AB - Treatment of acute lymphoblastic leukaemia (ALL) is frequently complicated by venous thromboembolism (VTE). The efficacy and optimal approach of VTE prevention are unclear, particularly in adult patients. We assessed the effect of thromboprophylaxis on symptomatic VTE incidence in cycle 1 of ALL treatment in adult patients. Secondly, we explored potential etiologic factors for VTE and the clinical impact of VTE on ALL outcome. We retrospectively assessed symptomatic VTE incidence and use of thromboprophylaxis in 240 adults treated for newly diagnosed ALL in the Dutch-Belgian HOVON-37 multicentre study (1999-2005). Potential etiologic factors were explored by analysis of patient and disease characteristics, impact of VTE on ALL outcome by analysis of complete remission and overall survival rates. Symptomatic VTE was observed in 24 of 240 patients (10%). Thromboprophylaxis differed by centre (prophylactic fresh frozen plasma (FFP) supplementation or no thromboprophylaxis) and was applied only during L asparaginase in cycle 1. VTE incidence was significantly lower with FFP supplementation than without FFP (6% vs. 19%; adjusted odds ratio [OR] 0.28; 95% confidence interval [CI] 0.10-0.73). FFP did not influence antithrombin or fibrinogen plasma levels. Patients with VTE in cycle 1 had a significantly poorer complete remission rate (adjusted OR 0.18; 95% CI 0.07-0.50), particularly patients with cerebral venous thrombosis (adjusted OR 0.17; 95% CI 0.04-0.65). Our study suggests that prophylactic FFP supplementation effectively reduces symptomatic VTE incidence during ALL treatment in adults. This should be confirmed in a randomised controlled trial. PMID- 23364348 TI - Exercise and hematopoietic stem and progenitor cells: protection, quantity, and function. AB - The effects of exercise on mature cells of the hematopoietic lineage have been well characterized; however, the effects of exercise on the more primitive cells of the hematopoietic system are unknown. Here, we propose that the benefits of exercise apply to hematopoietic progenitors and that exercise increases hematopoietic stem cell quantity primarily mediated via adaptations in the stem cell niche. PMID- 23364347 TI - Task-dependent postural control throughout the lifespan. AB - Routine activities performed while standing and walking require the ability to appropriately and continuously modulate postural movements as a function of a concurrent task. Changes in task-dependent postural control contribute to the emergence, maturation, and decline of complex motor skills and stability throughout the lifespan. PMID- 23364350 TI - Mass spectrometry: towards in vivo analysis of biological systems. AB - In vivo analysis is of paramount importance in monitoring physiological processes that take place in living organisms. Mass spectrometry, an analytical technique with high speed, sensitivity and specificity, is indispensable in biochemical studies nowadays. However, traditional mass spectrometric techniques are of limited applicability in direct analysis of living organisms due to various constraints, e.g., the necessity of ionization of analytes under vacuum and perturbation of physiological functions of living organisms during analysis. Recent development of mass spectrometry, particularly the development of ambient ionization techniques, has opened the door for direct analysis of living organisms. These new mass spectrometric techniques have the features that the ionization processes take place under atmospheric pressure and no or only little sample preparation is required, thus are well suited for analysis of living specimens without significantly perturbing their physiological states. The role of these mass spectrometric techniques in in vivo analysis has been increasingly important in recent years and is expected to be further expanded in the future. In this review, the use of various mass spectrometric techniques in in vivo analysis of biological systems is summarized and the prospects are discussed. PMID- 23364349 TI - Effects of ready for recess, an environmental intervention, on physical activity in third- through sixth-grade children. AB - BACKGROUND: The purpose of this study was to determine the effectiveness of Ready for Recess, an elementary school recess intervention targeting staff training (ST) or providing recreational equipment (EQ) separately, and the combination (EQ+ST) on physical activity (PA). METHODS: Participants were children attending 1 of 12 elementary schools (grades 3rd-6th) included in the study. Separate analytical models were used to evaluate the effects of the intervention conditions on children's accelerometry and direct observation derived PA measures. RESULTS: Boys and girls were measured using accelerometry (n = 667). Boys in EQ+ST increased their MVPA by 14.1% while ST decreased their MVPA by 13.5%. Girls in ST decreased their MVPA by -11.4%. Neither boys nor girls in EQ increased their time spent in MVPA. A total of 523 (boys) and 559 (girls) observations were collected. For boys' and girls' sedentary and vigorous activity there were no significant main effects for treatment condition, time, or treatment condition-by-time effects. CONCLUSIONS: Environmental modifications are only as strong as the staff that implements them. Supervision, if not interactive, may be detrimental to PA participation, especially in girls. Research related to staff training for encouragement and promotion of PA coupled with appropriate use of equipment during recess is warranted. PMID- 23364351 TI - Epigenetic transcriptional activation of monocyte chemotactic protein 3 contributes to long-lasting neuropathic pain. AB - A multiplex analysis for profiling the expression of candidate genes along with epigenetic modification may lead to a better understanding of the complex machinery of neuropathic pain. In the present study, we found that partial sciatic nerve ligation most remarkably increased the expression of monocyte chemotactic protein 3 (MCP-3, known as CCL7) a total of 33 541 genes in the spinal cord, which lasted for 4 weeks. This increase in MCP-3 gene transcription was accompanied by the decreased trimethylation of histone H3 at Lys27 at the MCP 3 promoter. The increased MCP-3 expression associated with its epigenetic modification observed in the spinal cord was almost abolished in interleukin 6 knockout mice with partial sciatic nerve ligation. Consistent with these findings, a single intrathecal injection of recombinant proteins of interleukin 6 significantly increased MCP-3 messenger RNA with a decrease in the level of Lys27 trimethylation of histone H3 at the MCP-3 promoter in the spinal cord of mice. Furthermore, deletion of the C-C chemokine receptor type 2 (CCR2) gene, which encodes a receptor for MCP-3, failed to affect the acceleration of MCP-3 expression in the spinal cord after partial sciatic nerve ligation. A robust increase in MCP-3 protein, which lasted for up to 2 weeks after surgery, in the dorsal horn of the spinal cord of mice with partial sciatic nerve ligation was seen mostly in astrocytes, but not microglia or neurons. On the other hand, the increases in both microglia and astrocytes in the spinal cord by partial sciatic nerve ligation were mostly abolished in interleukin 6 knockout mice. Moreover, this increase in microglia was almost abolished by CCR2 gene deletion, whereas the increase in astrocytes was not affected in nerve-ligated mice that lacked the CCR2 gene. We also found that either in vivo or in vitro treatment with MCP-3 caused robust microglia activation. Under these conditions, intrathecal administration of MCP-3 antibody suppressed the increase in microglia within the mouse spinal cord and neuropathic pain-like behaviours after nerve injury. With the use of a functional magnetic resonance imaging analysis, we demonstrated that a single intrathecal injection of MCP-3 induced dramatic increases in signal intensity in pain-related brain regions. These findings suggest that increased MCP-3 expression associated with interleukin 6 dependent epigenetic modification at the MCP-3 promoter after nerve injury, mostly in spinal astrocytes, may serve to facilitate astrocyte-microglia interaction in the spinal cord and could play a critical role in the neuropathic pain-like state. PMID- 23364352 TI - New roles for microRNAs in cross-species communication. AB - Communication between cells ensures coordinated behavior. In prokaryotes, this signaling is typically referred to as quorum sensing, whereas in eukaryotic cells, communication occurs through hormones. In recent years, reports have shown that small noncoding RNAs, called microRNAs (miRNAs), can be transmitted from one species to another, inducing signal interference in distant species, even in a cross-kingdom manner. This new mode of cross-species communication might mediate symbiotic and pathogenic relationships between various organisms (e.g., microorganisms and their hosts). Here, we discuss several recent studies concerning miRNA-mediated cross-species gene regulation. PMID- 23364353 TI - Speedy speciation in a bacterial microcosm: new species can arise as frequently as adaptations within a species. AB - Microbiologists are challenged to explain the origins of enormous numbers of bacterial species worldwide. Contributing to this extreme diversity may be a simpler process of speciation in bacteria than in animals and plants, requiring neither sexual nor geographical isolation between nascent species. Here, we propose and test a novel hypothesis for the extreme diversity of bacterial species-that splitting of one population into multiple ecologically distinct populations (cladogenesis) may be as frequent as adaptive improvements within a single population's lineage (anagenesis). We employed a set of experimental microcosms to address the relative rates of adaptive cladogenesis and anagenesis among the descendants of a Bacillus subtilis clone, in the absence of competing species. Analysis of the evolutionary trajectories of genetic markers indicated that in at least 7 of 10 replicate microcosm communities, the original population founded one or more new, ecologically distinct populations (ecotypes) before a single anagenetic event occurred within the original population. We were able to support this inference by identifying putative ecotypes formed in these communities through differences in genetic marker association, colony morphology and microhabitat association; we then confirmed the ecological distinctness of these putative ecotypes in competition experiments. Adaptive mutations leading to new ecotypes appeared to be about as common as those improving fitness within an existing ecotype. These results suggest near parity of anagenesis and cladogenesis rates in natural populations that are depauperate of bacterial diversity. PMID- 23364355 TI - Colloidal synthesis and characterizations of wittichenite copper bismuth sulphide nanocrystals. AB - Wittichenite (Cu(3)BiS(3)) nanocrystals have been synthesized utilizing a hot injection method. They have been characterized in detail. Cu(3)BiS(3) nanocrystals possessed a band gap of 1.56 eV, and the corresponding nanocrystal film shows a clear photoresponse in I-V measurements. Our work illustrates that Cu(3)BiS(3) nanocrystals have potential in the application of solar cells. PMID- 23364354 TI - A global perspective on marine photosynthetic picoeukaryote community structure. AB - A central goal in ecology is to understand the factors affecting the temporal dynamics and spatial distribution of microorganisms and the underlying processes causing differences in community structure and composition. However, little is known in this respect for photosynthetic picoeukaryotes (PPEs), algae that are now recognised as major players in marine CO2 fixation. Here, we analysed dot blot hybridisation and cloning-sequencing data, using the plastid-encoded 16S rRNA gene, from seven research cruises that encompassed all four ocean biomes. We provide insights into global abundance, alpha- and beta-diversity distribution and the environmental factors shaping PPE community structure and composition. At the class level, the most commonly encountered PPEs were Prymnesiophyceae and Chrysophyceae. These taxa displayed complementary distribution patterns, with peak abundances of Prymnesiophyceae and Chrysophyceae in waters of high (25:1) or low (12:1) nitrogen:phosphorus (N:P) ratio, respectively. Significant differences in phylogenetic composition of PPEs were demonstrated for higher taxonomic levels between ocean basins, using Unifrac analyses of clone library sequence data. Differences in composition were generally greater between basins (interbasins) than within a basin (intrabasin). These differences were primarily linked to taxonomic variation in the composition of Prymnesiophyceae and Prasinophyceae whereas Chrysophyceae were phylogenetically similar in all libraries. These data provide better knowledge of PPE community structure across the world ocean and are crucial in assessing their evolution and contribution to CO2 fixation, especially in the context of global climate change. PMID- 23364356 TI - The aging eye: common degenerative mechanisms between the Alzheimer's brain and retinal disease. AB - Alzheimer's disease (AD) is a common, incurable, and progressive dementia, characterized by loss of learning and memory and the neuropathologic accumulation of amyloid plaques and neurofibrillary tangles in the brain. A number of similarities between AD pathology and several distinct retinal degenerations have been described, particularly with respect to either glaucoma or age-related macular degeneration (AMD), each a leading cause of vision loss and blindness worldwide. Although comparisons between these diseases may provide important new insights into their pathogenic mechanisms, glaucoma and AMD result in markedly different degenerations. Therefore, analyses of the differences and the similarities between these conditions may prove equally productive. Common mechanisms that appear to underlie all three diseases are explored here, as well as potential use of the retina as a biomarker for AD diagnosis and progression. Based on this comparison, past and current efforts to transfer therapeutic strategies between diseases are discussed. PMID- 23364357 TI - Extreme signet ring cell change in a large B-cell lymphoma of follicular origin. AB - We report a large B-cell lymphoma of follicular origin with extreme signet ring cell differentiation. Initially classified as follicular lymphoma on a fine needle core biopsy, the presence of cohesive sheets of extrafollicular signet ring cells triggered an excisional biopsy for further characterization. The excised lymph node revealed focal follicular hyperplasia, follicular lymphoma, and a neoplasm composed of vague nodules and sheets of large atypical cells, all of which virtually exhibited large clear intracytoplasmic vacuoles with peripheral displacement of nuclei. The tumor cells were negative for mucin and lacked immunoreactivity with pancytokeratin, but were strongly immunoreactive with CD20, BCL-2, BCL-6, and CD10 antibodies. Electron microscopy studies revealed electron-lucent vacuoles with no particular internal structure. This case is unique in that extreme signet ring cell differentiation somewhat obscured the true cytological identity of the interfollicular lymphoma and suggested alternative diagnoses. PMID- 23364358 TI - Multifocal capillary hemangioma-like vascular proliferation of the kidney associated with clear cell renal cell carcinoma: a case report and review of the literature. AB - We report the case of a 69-year-old man who underwent a radical left nephrectomy for a renal mass. Microscopically, the features were those of a clear cell-type renal cell carcinoma associated with 2 foci of capillary hemangioma-like vascular proliferation in the adjacent renal parenchyma. The main differential diagnosis and the possible pathogenesis of this vascular lesion are discussed. PMID- 23364360 TI - A new year and a new way of doing things. PMID- 23364359 TI - Microsatellite markers as a rapid approach for autozygosity mapping in Hermansky Pudlak syndrome: identification of the second HPS7 mutation in a patient presenting late in life. PMID- 23364361 TI - Gender differences when using sedative music during colonoscopy. AB - Colonoscopy is a procedure often experienced as uncomfortable and worrying. Music has been reported to reduce discomfort during colonoscopy; however, no study in a Swedish setting has been found. The purpose of this randomized controlled trial was to analyze the effects of sedative music on patients' experience of anxiety, pain, relaxation, and well-being during colonoscopy. Prior to colonoscopy, adult patients (n = 120), aged 18-80 years, were randomly assigned to either an intervention group (n = 60) who listened to sedative instrumental music with 60 80 beats per minute during the colonoscopy or a control group. After the colonoscopy, both groups completed a questionnaire on anxiety, the State Trait Anxiety Inventory, and an anxiety Visual Analogue Scale. Pain, relaxation, and well-being were also measured with Visual Analogue Scales. Women in the intervention group had a lower level of anxiety during the colonoscopy than those in the control group (p = .007) and well-being was significantly higher in the intervention group, especially among men, than in the controls (p = .006 and p = .025, respectively). Men in the intervention group were more relaxed during the colonoscopy than those in the control group (p = .065). Listening to sedative music decreased anxiety among women and increased well-being among men during colonoscopy. PMID- 23364363 TI - At the ethical crossroads: how a gastroenterology procedure unit negotiated a solution for a reoccurring ethical dilemma. AB - The gastroenterology procedures environment has proven to be fertile ground for the realization of moral distress as it relates to the practice of nursing. Specifically, nurses are expected to fulfill their duty as advocates for their clients at all times and within all contexts; however, their ability to discharge this essential function has been complicated by such influential factors as sedating medications, competing ethical motivations, discordant conclusions of moral reasoning and action, as well as competing institutional factors. This article begins with a fictional case study to introduce readers to the contextual essence of the moral distress that a group of gastroenterology nurses was collectively experiencing. Subsequently, the aim of this article was to explicate how one department, with the aid of an ethics committee, negotiated a process similar to the case study to develop a pragmatic policy and identify an educational primer that encourages nurses to reexamine and value the tangible realities inherent and expected of an advocate in the dynamically complex environment that characterizes all gastroenterology procedure environments where gastroenterology nurses practice. PMID- 23364362 TI - Fire in the belly and the professionalization of nurses: a historical analysis of Crohn disease care. AB - Today, professional nurses around the world are stepping up to meet the needs of individuals with Crohn disease, using their specialized knowledge and skills that demonstrate areas of expertise that have not always existed. The gastrointestinal specific knowledge being used by these 21st-century nurses exists today because progressive efforts of nurses in previous decades moved the profession of nursing forward. The purpose of this article was to describe and analyze the development of the role of nurses in responding to new challenges patients with Crohn disease face since the emergence of the disease in the early 20th century. The authors used traditional historic research methods to conduct the study. Primary sources include nursing journals and textbooks published in the 20th and 21st centuries and documents archived at The Mount Sinai Hospital in New York City, where Burrill B. Crohn conducted his seminal work. The significance of the findings is that the changing role of nurses in caring for patients with Crohn disease mirrors the professionalization of nursing during the 20th and early 21st centuries. PMID- 23364364 TI - Open or laparoscopic surgery for colorectal cancer: a retrospective comparative study. AB - Laparoscopic surgery for colorectal cancer has been used with success since 1991. During the last decade, many studies have compared laparoscopic surgery with open colectomy. The aim of this retrospective study was to present the advantages and disadvantages of laparoscopic and open colectomy for cancer, focusing on the postoperative care of patients. Eighty-eight consecutive patients suffering from cancer of the colon and rectum, surgically treated, were studied. They were divided into 2 groups: Group A patients (n = 48) underwent laparoscopic colectomy, and Group B patients (n = 40) were treated with an open procedure. For postoperative care of the patients, analgesia, median hospital stay, overall cost, and complications between the 2 groups were studied and statistically compared. Laparoscopic colectomy was associated with a shorter average hospital stay, fewer complications, earlier start of a normal diet, and better control of postoperative pain. Nonetheless, the cost of surgical instruments used in laparoscopic operation is higher. Laparoscopic surgery, despite its higher cost, seems to add significant advantages in the postoperative recovery of patients suffering from colorectal cancer. PMID- 23364365 TI - Clostridium difficile infection and fecal bacteriotherapy. AB - Clostridium difficile, also called "C. diff," is a gram-positive bacillus associated with nosocomial infections involving diarrhea, most often seen in developing countries. The severity of C. diff-associated diarrhea varies tremendously from mild and self-limiting to fulminant and life-threatening. C. diff has become an extremely important pathogen in community health but can be minimized with attention to proper hygiene. This article presents a case study regarding the treatment and management options of C. diff infection using a recent update of clinical guidelines for patient management. PMID- 23364367 TI - Adherence and completion in hepatitis C management: a systematic review. AB - The complexity and challenge of Hepatitis C virus (HCV) medication therapy call for a comprehensive and integrated approach in management. This article includes an appraisal of the current state of the science in HCV management and the various models that support treatment completion and adherence. The patient undergoing HCV therapy may experience a wide range of symptoms such as anemia, depression, fatigue, and flu-like symptoms. These can constantly confront the patient's adherence and compliance with treatment. The article includes an analysis of the strengths, weaknesses, and limitations of the evidence. Future directions in research were also identified. PMID- 23364368 TI - Aortobronchial fistula. PMID- 23364370 TI - Tips and tactics for using and interpreting capnography. PMID- 23364369 TI - Famous colonoscopy quotes. PMID- 23364371 TI - Periorbital ecchymosis following an upper gastrointestinal endoscopy. PMID- 23364373 TI - Ketamine and atropine for pediatric sedation: a prospective double-blind randomized controlled trial. AB - INTRODUCTION: Sedation in children can be a challenge for emergency physicians, which demands for selecting an effective medication with few complications and good analgesic effects. This study has been performed to evaluate the adverse effects of ketamine while using either atropine or placebo in emergency departments. METHODS: This is a prospective randomized controlled trial involving 200 patients with age ranging between 2 and 15 years, who need a painful procedure. Participants randomly were divided into 2 groups both treated by ketamine (1 mg/kg intravenously administered); group 1 received excessive intravenous atropine (0.01 mg/kg), whereas distilled water was given to group 2 as placebo. Adverse effects and duration of the treatments were recorded. RESULTS: From March to September 2010, 200 of 218 eligible patients were enrolled. The mean (SD) age of patients in the intervention group was 7.0 (3.6) years that showed no statistical difference with the control group (age range, 2 15 years; mean, 7.1 [3.8] years). The mean procedure and sedation time between the intervention and placebo groups were not significantly different (P = 0.919 and 0.783, respectively). Several differences between the intervention and placebo groups were noted including nausea and vomiting, but only the difference in hypersalivation was statistically significant (12% vs 28%). Low oxygen saturation was reported only in 2% of the participants, whereas none of the children experienced apnea or laryngospasm during the sedation process. CONCLUSIONS: Atropine added to ketamine significantly reduces hypersalivation without producing any adverse effects on the procedure duration or success rate. PMID- 23364374 TI - Comparison of the incidence, etiology, and management of anaphylaxis over time. AB - BACKGROUND: Failure to promptly recognize and treat anaphylaxis can result in death. Understanding the incidence, etiology, and management is imperative. A previous pediatric study identified latex as the most common anaphylaxis allergen. We aim to describe the incidence, etiology, and management of anaphylaxis prelatex and postlatex-precaution implementation. METHODS: Retrospective review of inpatient and emergency department (ED) records of pediatric anaphylaxis patients seen at 1 institution between 1986 and 1990 or 2002 and 2006 was performed. Patients with 2 systemic symptoms (gastrointestinal, respiratory, hypotension/syncope, oropharyngeal, altered mental status) or 1 systemic symptom plus 1 cutaneous symptom (urticaria, edema, or flushing) were included. RESULTS: Fifty-three episodes were included from 1986 to 1990. A total of 117 episodes were included from 2002 to 2006. Approximately 80% of cases presented to the ED. From 1986 to 1990, we noted 30.5 cases per 100,000 ED visits versus 38 cases per 100,000 ED visits from 2002 to 2006. Food allergens were most common in both groups (43%). Latex accounted for only 1.9% of cases in 1986 to 1990 versus 1.7% postlatex precautions. Prehospital epinephrine use was poor. Patients in 2002 to 2006 were more likely to receive steroids, H2-blockers, epinephrine autoinjectors, and allergist referrals but less likely to receive epinephrine. CONCLUSIONS: The etiology of pediatric anaphylaxis has not significantly changed over time but seems to differ across regions because latex was not a significant allergen at this institution in either period. The incidence of anaphylaxis has increased slightly. Anaphylaxis remains underdiagnosed and undertreated. Improved education of patients/caregivers and health care providers is needed. PMID- 23364372 TI - Creating an infrastructure for safety event reporting and analysis in a multicenter pediatric emergency department network. AB - OBJECTIVE: Hospital incident reporting is widely used but has had limited effectiveness for improving patient safety nationally. We describe the process of establishing a multi-institutional safety event reporting system. METHODS: A descriptive study in The Pediatric Emergency Care Applied Research Network of 22 hospital emergency departments was performed. An extensive legal analysis addressed investigators' concerns about sharing confidential incident reports (IRs): (1) the ability to identify sites and (2) potential loss of peer review statute protection. Of the 22 Pediatric Emergency Care Applied Research Network sites, 19 received institutional approval to submit deidentified IRs to the data center. Incident reports were randomly assigned to independent review; discordance was resolved by consensus. Incident reports were categorized by type, subtype, severity, staff involved, and contributing factors. RESULTS: A total of 3,106 IRs were submitted by 18 sites in the first year. Reporting rates ranged more than 50-fold from 0.12 to 6.13 per 1000 patients. Data were sufficient to determine type of error (90% of IRs), severity (79%), staff involved (82%), and contributing factors (82%). However, contributing factors were clearly identified in only 44% of IRs and required extrapolation by investigators in 38%. The most common incidents were related to laboratory specimens (25.5%), medication administration (19.3%), and process variance, such as delays in care (14.4%). CONCLUSIONS: Incident reporting provides qualitative data concerning safety events. Perceived legal barriers to sharing confidential data can be addressed. Large variability in reporting rates and low rates of providing contributing factors suggest a need for standardization and improvement of safety event reporting. PMID- 23364375 TI - Abscess volume and ultrasound characteristics of community-associated methicillin resistant Staphylococcus aureus infection. AB - BACKGROUND: Skin abscesses may vary in volume and inflammation based on organism, although this has not been evaluated using emergency ultrasonography (EUS). OBJECTIVE: The objective of this study was to examine the utility of EUS in discerning skin abscess volume and inflammation by infecting organism. METHODS: This was a secondary analysis of prospectively enrolled subjects 2 months to 19 years presenting for a skin abscess. Subjects with a prior drainage procedure, multiple lesions, incomplete EUS measurements, or lack of an abscess culture were excluded. Abscess cavity dimensions in the x, y, and z planes and signs of local inflammation (cobblestoning, hyperechoic, or thickened dermis) were determined. Abscess volume was calculated using the ellipsoid formula: 4/3 pi . (rx) . (ry) . (rz). RESULTS: One hundred eighty-eight subjects met the inclusion criteria. Mean age was 7.7 +/- 6.2 years; 39.9% were male. The gluteal region was most commonly involved (33.0%), and lesions were present for a mean 4.2 days (95% confidence interval [CI], 3.8-4.6 days). Methicillin-resistant Staphylococcus aureus (MRSA) was isolated from 125 (66.5%); methicillin-sensitive S. aureus (21.8%) was most common among non-MRSA lesions. Abscess volume was smaller in MRSA (1.12 cm3) compared with non-MRSA (2.46 cm3) lesions (mean difference, -1.33 cm; 95% CI, 2.21 to -0.47 cm3). No differences between MRSA and non-MRSA lesions were present for EUS signs of inflammation. When adjusting for age, duration of lesion, and spontaneous drainage, smaller abscess volumes were associated with MRSA infection (odds ratio, 0.83; 95% CI, 0.71-0.97). Using an optimal threshold value of 1.32 cm3, sensitivity and specificity for non-MRSA lesion were 50.8% and 81.5%, respectively. CONCLUSIONS: Methicillin-resistant S. aureus infection is statistically negatively associated with abscess volume, although of limited predictive ability. Findings using EUS suggest that MRSA does not differ from other organisms with respect to size and inflammation. Clinicians should not consider unique treatment for the presence of MRSA abscess based on these EUS findings. PMID- 23364376 TI - Effectiveness of a pediatric verbal lead exposure screening protocol in emergency department patients. AB - PURPOSE: The population demographics found in many urban emergency departments (EDs) often mirrors those of children at risk for elevated serum lead levels. We evaluated the effectiveness of a verbal lead screening program for screening high risk children presenting to the ED. METHODS: A prospective observational cohort study was conducted of children aged 9 months to 6 years, living in 2 target counties and presenting to an urban, academic, Midwestern ED. Those with a prior lead level, enrolled in a program requiring lead testing, or with an unstable medical condition were excluded. A 6-question validated verbal survey was administered to all parents of eligible children, and the results recorded in the patient's electronic medical record. Children who screened positive were referred to their local health department for blood lead testing. Health department records were reviewed for follow-up visits and blood lead levels. RESULTS: During the study period, 3513 children were eligible (mean age, 2.6 years; 53.3% male), with 815 patients screened and 209 (25.6%) screening positive. Most positively screened patients (71.8%) documented only 1 affirmative question, most often indicating they lived in a home built before 1978. Of those children who screened positive, 14.8% (31/209) had a blood lead level performed within 6 months. Of those tested, 4 children had an elevated lead level (>10 ug/dL). CONCLUSIONS: Use of an ED verbal lead exposure screening tool identified children requiring additional follow-up testing. However, health department-referred children had poor follow-up, and few children were ultimately documented with elevated lead levels. PMID- 23364377 TI - Adolescent synthetic cathinone exposures reported to Texas poison centers. AB - OBJECTIVES: This study describes the pattern of adolescent synthetic cathinone exposures reported to a large, statewide poison center system. METHODS: Synthetic cathinone exposures among patients younger than 20 years reported to Texas poison centers during 2010 to 2011 were identified. The distribution of exposures by various demographic and clinical factors was determined. RESULTS: For 51 adolescent exposures, the mean age was 17.5 years (range, 12-19 years). The exposure was by inhalation in 66.7% of the cases and 60.8% involved male patients. The exposure site was the patient's own or another residence in 58.8% of the cases. The patient was already at or en route to a health care facility in 76.5% of the cases, and the medical outcome was known or suspected to be serious in 74.5%. The most frequently reported adverse clinical effects were agitation/irritability (43.1%), tachycardia (37.3%), drowsiness/lethargy (13.7%), hallucinations (9.8%), fever (9.8%), vomiting (9.8%), and hypertension (7.8%). CONCLUSIONS: Adolescent synthetic cathinone exposures reported to Texas poison centers were more likely to have occurred by inhalation. The adolescents were more likely to be male. The exposures more often occurred at the patient's own residence and were managed at a health care facility with a serious outcome. This pattern of exposures was similar to that observed among adults. PMID- 23364378 TI - Comparison of 2-view abdominal radiographs with ultrasound in children with suspected intussusception. AB - BACKGROUND: The clinical presentation of intussusception is variable; therefore, screening with either abdominal radiography (AXR) or abdominal ultrasound (US) is often used, although the optimal method is not known. PURPOSE: This study aimed to compare the utility of AXR with that of the US in children with suspected intussusception. METHODS: Retrospective cohort of children age 3 months to 3 years presenting to a pediatric emergency department (ED) between 2007 and 2009. Inclusion criteria were as follows: (1) presentation to the ED for suspected intussusception and (2) both 2-view AXR and US performed during the ED visit. An AXR was deemed negative for intussusception if air was visualized in the ascending colon on 2 views and transverse colon on the supine view; US results were obtained from the radiologist report at the time of presentation. Criterion standard measures for intussusception were contrast enema, operative report, or follow-up. RESULTS: A total of 286 children were included, with mean (SD) age 16.1 (9.1) months; 62.2% were male, and 43.7% were African American. Intussusception was present in 61 subjects (21.3%). Abdominal radiography had sensitivity of 62.3% (95% confidence interval [CI], 50.1%-74.5%) and specificity of 86.7% (95% CI, 82.2%-91.1%), whereas US had a sensitivity of 98.4% (95% CI, 95.2%-100.0%) and specificity of 96.4% (95% CI, 94.0%-98.9%). Ultrasound had a greater negative predictive value (99.5%; 95% CI, 98.6%-100.4%) compared with AXR (89.4%; 95% CI, 85.4%-93.5%). Abdominal radiography had a greater false-positive rate (13.3% vs 3.6%) and greater false-negative rate (37.8% vs 1.6%), compared with US. CONCLUSIONS: Ultrasound is superior to AXR as a screening method for establishing and excluding the diagnosis of intussusception. The poor test characteristics of 2-view AXR suggest that it should not be used as a primary screening method in cases of suspected intussusception. PMID- 23364379 TI - Assessment of the reliability of active radiofrequency identification technology for patient tracking in the pediatric emergency department. AB - INTRODUCTION: Radiofrequency identification (RFID) technology has been used in other emergency department settings but has not been assessed in a pediatric emergency department setting for its reliability in its application as a patient tracking system. The goal of this study was to assess the accuracy, precision, and reliability of the technology in a simulated pediatric emergency department setting to collect patient tracking information. METHODS: A simulated pediatric emergency department clinical assessment room was developed to serve as a test room to collect patient tracking information. This information included the interaction times between simulated patients, parents, physicians, and nurses. Direct observation of these interaction times were recorded by an observer. A patient tracking system based on active RFID technology recorded interaction times between models wearing RFID devices and recorded this information in a computerized data log. Comparison between the direct observation record and the data log was used to determine accuracy, precision, and reliability. RESULTS: A total of 152 directly observed interactions were recorded. Data extraction from the data log yielded 152 sensor-recorded interactions, resulting in a reliability of 1.0. Data pair comparison on all events resulted in a mean difference of 2.88 seconds. CONCLUSIONS: Active RFID-based patient tracking systems are a precise and reliable means of recording patient interaction events in the pediatric emergency department. PMID- 23364380 TI - Maternal somatic symptoms, psychosocial correlates, and subsequent pediatric emergency department use. AB - BACKGROUND: Somatization is associated with increased health care use in adults. Whether mothers with somatic symptoms use more health care resources for their children has not been investigated. OBJECTIVE: This study aimed to explore the association of maternal somatic symptoms and emergency department (ED) use. DESIGN/METHODS: Mothers from a cohort of 319 mother-child dyads were screened for somatic symptoms using the Patient Health Questionnaire 15. Dyads were followed up for 3 years after the initial ED visit to record ED use. The outcome variable was ED use (lower ED use, 0-3 visits, higher ED use, 4+ visits). The primary independent variable was somatization, with a dichotomous variable analyzing the Patient Health Questionnaire 15 symptom count of less than 7 symptoms (lower somatization) and 7 or more symptoms (higher somatization [HISOM]). Secondary independent variables included demographic data, maternal major depression, and maternal difficulty in taking care of the child or themselves. Statistical analysis included bivariate and multivariate analyses. RESULTS: Mothers with HISOM symptoms did not demonstrate an increased use of the ED in bivariate analysis. Higher somatization mothers did show an increased (1) endorsement of maternal major depression symptoms and (2) maternal perception of difficulty in taking care of the child and themselves. When adjusted for these and other covariates, HISOM mothers were more likely to be in the higher ED use group (1.83; 95% confidence interval, 0.99-3.38) P = 0.055). CONCLUSIONS: Mothers with higher somatic symptom loads were more likely to screen positive for depression and to report difficulty caring for their child and for themselves. A trend toward higher use of the pediatric ED warrants further study. PMID- 23364381 TI - Disk battery ingestion: case series with assessment of clinical and financial impact of a preventable disease. AB - BACKGROUND: Commonly, foreign objects are incidentally ingested and pass harmlessly through the gastrointestinal tract; however, disk batteries present exceptional risk. In 2009, the American Association of Poison Control Centers listed disk batteries as the number 1 cause of fatal ingestions in children younger than 5 years. Lithium batteries are the most dangerous, and they are rapidly rising in use by manufacturers. Paralleling that rise, there has been a 6.7-fold increase in major or fatal outcomes between 1985 and 2009. This study describes the variability in patient presentations, the courses of patients' evaluations, and the clinical and financial consequences of disk battery ingestion. METHODS: In this retrospective study, cases from 2001 to 2011 were reviewed for details of care for disk battery ingestions including presentation and management details. Cost of care information from our patients' records was compared with that of national averages on esophageal foreign bodies using the Healthcare Cost and Utilization Project's Kids' Inpatient Database. RESULTS: Six cases are presented. The patients' age averaged 1.85 years. Presentations varied with respect to symptoms, time course, and steps in treatment. Mean length of stay was 9.0 days, and mean cost was $14,994. CONCLUSIONS: Emergency medicine physicians, otolaryngologists, radiologists, gastroenterologists, and pediatric surgeons may be able to mitigate, albeit not entirely prevent, potential serious complications in patients with disk battery ingestions by proper diagnosis and timely treatment. Recommendations for management are presented, which highlight the need for emergent removal of any battery that is lodged and close follow-up of these patients once they are out of the hospital. PMID- 23364382 TI - Asthma vital signs at triage: home or admission (ASTHmA). AB - OBJECTIVES: Commonly used acute asthma scoring systems assess severity of symptoms, whereas other clinical models aim to predict hospitalization; all rely on a measure of response to treatment and use the same criteria across age ranges. This may not reflect a child's changing physiology and response to illness as he or she grows older.This study aimed to find age-specific objective predictors of hospitalization readily known at triage. The goal is to identify rapidly those who will likely need admission regardless of treatment administered or response to aggressive treatment in the emergency department (ED). METHODS: Children between 1 and 18 years of age with a final primary ED International Classification of Diseases, Ninth Revision, diagnosis of asthma or asthma-related spectrum of disease were studied using data from the National Hospital Ambulatory Medical Care Survey. The primary outcome was hospital admission (observation unit, ward, monitored, or pediatric intensive care unit).Triage vital signs, mode of arrival, recent visits, emergency severity index score, as well as demographic and socioeconomic factors were incorporated into age-specific forward-selection multiple logistic regression models. RESULTS: In 2,454,983 ED visits for asthma or reactive airway disease among children 1 to 18 years of age, patterns of vital sign predictors for admission varied by age group. Across all ages, diastolic hypotension at triage was an early, consistent, independent predictor of admission, especially in 1- to 3-year-olds (odds ratio, 6.27; 95% confidence interval, 6.01-6.54) and 3- to 6-year-olds (odds ratio, 17.95; 95% confidence interval, 16.80-19.17). CONCLUSIONS: Age-specific assessment is important in the evaluation of acute asthma or reactive airway exacerbation. Diastolic hypotension may serve as an early warning indicator of severity of disease and need for hospitalization. Variability by age group in vital sign predictor for admission calls for further development or refinement of age-specific asthma assessment tools. PMID- 23364384 TI - Factors associated with prolonged stay in a pediatric emergency observation unit of an urban tertiary children's hospital in China. AB - OBJECTIVES: This study aimed to examine the factors associated with increased length of stay (LOS > 24 hours) in the pediatric emergency observation unit (OU) of an urban tertiary children's hospital in China. METHODS: This study was a retrospective cohort study. We retrieved and examined all the records of patients (age, 0-16 years) who were admitted to the OU (n = 10,852) during July 1, 2008, to June 30, 2009. The primary outcome was LOS and prolonged stay (LOS > 24 hours). We also performed a sensitivity analysis by using LOS of 3 days or greater and LOS of 6 days or greater as dependent variables in logistic regression and compared with LOS of greater than 24 hours regression to examine the robustness of the associations. RESULTS: The overall mean (SD) LOS was 24.0 (24.4) hours; 31.3% had LOS of greater than 24 hours, of which the mean (SD) LOS was 50.2 (28.6) hours. The following factors were associated with LOS of greater than 24 hours: age, 28 days to 3 months (odds ratio, [OR], 1.87; 95% confidence interval, 1.36-2.59) and older than 3 months to 12 months (OR, 1.83; 95% CI, 1.35 2.50) compared with age 0 to 28 days; neurologic diseases (OR, 1.50; 95% CI, 1.31 1.72), infectious diseases (OR, 2.00; 95% CI, 1.61-2.49), and visits for non respiratory-related signs and symptoms (OR, 2.00; 95% CI, 1.61-2.49); acuity level of emergent (OR, 1.79; 95% CI, 1.57-2.04); procedures (OR, 7.09; 95% CI, 4.16-12.10); emergency transfusions (OR, 1.33; 95% CI, 1.01-1.75); staffed by residents (OR, 1.12; 95% CI, 1.01-1.24); and patients living in low-annual gross domestic product districts (OR, 1.14; 95% CI, 1.01-1.29). Arrival at evening (OR, 0.54; 95% CI, 0.49-0.60) and overnight (OR, 0.43; 95% CI, 0.38-0.49) were less likely to have LOS of greater than 24 hours than arrival during day shifts. CONCLUSIONS: We identified some risk factors for prolonged stay in an OU. These factors are the starting points in understanding issues related to prolonged stay and are needed to assess efficiency and quality of care in pediatric emergency department and OU. Our results have provided information basis for making improvements in the system and may be important considerations for similar institutions, which encounter similar challenges. PMID- 23364383 TI - Evaluation of a high-dose continuous albuterol protocol for treatment of pediatric asthma in the emergency department. AB - OBJECTIVES: This study aimed to assess the safety and efficacy of a high-dose continuous nebulized albuterol (CNA) protocol for treatment of asthma in the pediatric emergency department (ED). A secondary objective included a cost benefit analysis of protocol use. METHODS: In this retrospective chart review, we compared cohorts of patients treated in our ED for acute asthma exacerbation before and after implementation of a CNA protocol. Patients between the ages of 2 and 21 years seen between March 1 and May 31, 2008 (preprotocol, n = 393), and March 1 to May 31, 2009 (postprotocol, n = 373), were included. Safety data included medication-related adverse effects as well as serum potassium and glucose levels. Efficacy data included ED length of stay, disposition, return visits, time to first albuterol treatment, and corticosteroid administration. Cost analysis included the cost of medications and respiratory therapy time. RESULTS: Postprotocol patients more often received CNA (57.9% vs 25.2%, P < 0.01). No significant adverse effects, including tachyarrhythmia and symptomatic hypokalemia, were found in either group. Serum potassium levels were higher in the postprotocol group (3.9 mEq/L [n = 34] vs 3.5 mEq/L [n = 28], P < 0.01). Emergency department stay was longer in the postprotocol group (217.8 minutes vs 187.2 minutes, P < 0.01). Emergency department disposition was similar in both groups. The mean cost per patient was higher in the postprotocol group ($327.21 vs $277.95, P < 0.01). CONCLUSIONS: We found the CNA protocol to be safe. Superior efficacy to a traditional treatment approach was not demonstrated. The mean cost of treatment was higher in the postprotocol group. Further prospective studies should be conducted to confirm the findings of this retrospective, observational study. PMID- 23364385 TI - Galinstan thermometer is more accurate than digital for the measurement of body temperature in children. AB - BACKGROUND: The mercury thermometer (MT) was considered the reference standard for the evaluation of body temperature; however, since April 2009, it has no longer been available in Italy. OBJECTIVE: This study aimed to evaluate the accuracy of digital thermometer (DT) and galinstan thermometer (GT) in comparison with the MT. METHODS: We prospectively recruited 284 children (age, 1 month to 17 years; mean, 8.5 years) seen in the emergency department of a tertiary pediatric hospital between November and December 2010. For each patient, body temperature was measured sequentially in the right axilla in a randomized fashion using DT, GT, and MT. Fever was defined as an axillary temperature of 37.5 degrees C or greater. The temperature readings with DT and GT were compared statistically with those of MT (reference standard). RESULTS: No statistically significant difference in mean temperature was found between MT and GT in pairwise comparison (P = 0.06), whereas significant differences were found between MT and DT (P < 0.001) and between GT and DT (P < 0.001). Sensitivity and specificity of DT were 67.5% and 98.0%, respectively. When considering children with a temperature of 39 degrees C or higher, the false-negative rate was 65.4% with DT and 30.8% with GT. CONCLUSIONS: Although both DT and GT had good specificity and positive predictive value compared with MT, GT had higher sensitivity and a lower rate of false negative rates. Galinstan thermometer is more accurate in the measurement of body temperature compared with DT or MT. PMID- 23364386 TI - Draining ears and tympanostomy tubes: a survey of pediatric otolaryngologists and pediatric emergency medicine physicians. AB - INTRODUCTION: Posttympanostomy tube otorrhea also known as acute otitis media with tympanostomy tubes (AOMT) occurs in 15% to 80% of children with tympanostomy tubes. Its management is fairly standardized among pediatric ear, nose, and throat (ENT) physicians owing to recommendations published by the American Academy of Otolaryngology-Head and Neck Surgery. Pediatric emergency medicine (EM) physicians have no such guidelines. OBJECTIVE: This study aimed to compare management of AOMT by pediatric ENT and EM physicians. METHODS: A 27-question online survey was disseminated via SurveyMonkey.com using e-mail addresses of ENT and EM physicians via organization directories and professional listserves. RESULTS: A total of 175 and 174 responses were received from EM and ENT physicians, respectively. Higher proportion of EM physicians used oral antibiotics to treat AOMT (54% [n = 94] vs 9% [n = 16], P < 0.001). Virtually all ENT physicians used topical antibiotics, compared with 87% of EM physicians. Only 6% (n = 10) of EM physicians used suction to clean ear canals (aural toilet) before instilling topical antibiotics, compared with 81% (n = 138) of ENT physicians. Most ENT physicians (80% [n = 138]) instructed patients to keep the treated ear up for 10 to 60 seconds after instilling the drops and to use the tragal pump technique to direct the medication down the ear canal and through the tube (92% [n = 157]). Only 56% (n = 98) and 24% (n = 41) of EM physicians did the same. CONCLUSIONS: There are large differences between ENT and EM physicians with respect to: the use of systemic antibiotics, techniques of using ototopical antibiotics, methods of aural toilet in treating AOMT, and directions given to patients. PMID- 23364387 TI - Dedicated pediatric behavioral health unit: serving the unique and individual needs of children in behavioral health crisis. AB - Pediatric mental health emergencies are an increasing part of emergency medical practice because emergency departments have become the safety net for a fragmented mental health infrastructure that is experiencing critical shortages in services in all sectors. The emergency services for behavioral health unit at Akron Children's Hospital is an innovative model for delivering care to pediatric patients with mental health emergencies. A multidisciplinary team using the expertise of emergency services, psychiatry, social work, parent advisory counsel, security services, and engineering/architecture developed the emergency services for behavioral health unit blueprint, process, and staffing model. PMID- 23364388 TI - Mild cognitive impairment in moderate to severe COPD: a preliminary study. AB - BACKGROUND: Cognitive impairment is a frequent feature of COPD. However, the proportion of patients with COPD with mild cognitive impairment (MCI) is still unknown, and no screening test has been validated to date for detecting MCI in this population. The goal of this study was to determine the frequency and subtypes of MCI in patients with COPD and to assess the validity of two cognitive screening tests, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), in detecting MCI in patients with COPD. METHODS: Forty-five patients with moderate to severe COPD and 50 healthy control subjects underwent a comprehensive neuropsychologic assessment using standard MCI criteria. Receiver operating characteristic curves were obtained to assess the validity of the MMSE and the MoCA to detect MCI in patients with COPD. RESULTS: MCI was found in 36% of patients with COPD compared with 12% of healthy subjects. Patients with COPD with MCI had mainly the nonamnestic MCI single domain subtype with predominant attention and executive dysfunctions. The optimal MoCA screening cutoff was 26 (<= 25 indicates impairment, with 81% sensitivity, 72% specificity, and 76% correctly diagnosed). No MMSE cutoff had acceptable validity. CONCLUSIONS: In this preliminary study, a substantial proportion of patients with COPD were found to have MCI, a known risk factor for dementia. Longitudinal follow-up on these patients is needed to determine the risk of developing more severe cognitive and functional impairments. Moreover, the MoCA is superior to the MMSE in detecting MCI in patients with COPD. PMID- 23364389 TI - Tumor-associated macrophage promotes tumor progression via STAT3 signaling in hepatocellular carcinoma. AB - OBJECTIVE: Signal transducer and activator of transcription 3 (STAT3) is activated in hepatocellular carcinoma (HCC), and tumor-associated macrophage plays an important role in tumor progression. Therefore, we examined STAT3 activation, cytokine expression and infiltration of tumor-associated macrophages in resected HCCs as well as the alteration of cell growth and migration by cytokine stimulation in HCC cell lines. METHODS: Immunohistochemical staining of phosphorylated STAT3 (pSTAT3), CD163, interleukin (IL)-6, Ki-67 and Bcl-XL was performed for 101 cases of resected HCC, and correlations between pSTAT3 staining and clinicopathological findings were analyzed. In HCC cell lines (PLC/PRF/5 and Huh7), cell proliferation and migration by IL-6 stimulation and S3I-201 (STAT3 inhibitor) treatment were analyzed. RESULTS: In HCC specimens, the pSTAT3 positive group showed high levels of alpha-fetoprotein (p = 0.0276), large tumor size (p = 0.0092), frequent intrahepatic metastasis (p = 0.0214), high Ki-67 (p = 0.0002) and Bcl-XL (p = 0.0001), poor prognosis (p = 0.0234), and high recurrence rate (p = 0.0003). CD163-positive cells were frequently observed in the pSTAT3 positive group (p = 0.0013). In two HCC cell lines, IL-6 stimulation promoted cell proliferation and migration via the STAT3 phosphorylation, and S3I-201 inhibited this activation. CONCLUSIONS: STAT3 activation was correlated with aggressive behavior of HCC and may be mediated via tumor-associated macrophage. We expect that STAT3 signaling and tumor-associated macrophages can be attractive therapeutic targets in HCC patients. PMID- 23364390 TI - Inhaled corticosteroid dose response using domiciliary exhaled nitric oxide in persistent asthma: the FENOtype trial. AB - BACKGROUND: International guidelines advocate a standard approach to asthma management for all, despite its heterogeneity. "Personalized" treatment of inflammatory asthma phenotypes confers superior benefits. We wished to evaluate dose response to inhaled corticosteroids (ICSs) in patients with asthma with an elevated fractional exhaled nitric oxide (Feno) phenotype using domiciliary measurements. METHODS: We performed a randomized, crossover trial in 21 patients with mild to moderate persistent asthma receiving ICSs with elevated Feno (>30 parts per billion [ppb]) that increased further (>10 ppb) after ICS washout. Patients were randomized to 2 weeks of either fluticasone propionate 50 MUg bid (FP100) or 250 MUg bid (FP500). The primary outcome was response in diurnal domiciliary Feno levels. Secondary outcomes included mannitol challenge, serum eosinophilic cationic protein (ECP), blood eosinophil count, and asthma control questionnaire. RESULTS: We found significant dose-related reductions of diurnal Feno compared with baseline - morning Feno: baseline = 71 ppb (95% CI, 61-83 ppb); FP100 = 34 ppb (95% CI, 29-40 ppb), P < .001; FP500 = 27 ppb (95% CI, 22-33 ppb), P < .001; and significant dose separation for morning, P < .05, and evening, P < .001. Time-series Feno displayed exponential decay: FP100 R2 = 0.913, half-life = 69 h (95% CI, 50-114 h); FP500 R2 = 0.966, half-life = 55 h (95% CI, 45-69 h), as well as diurnal variation. The Asthma Control Questionnaire showed significant improvements exceeding the minimal important difference (>0.5) with values in keeping with controlled asthma (<0.75) after each dose: FP100 = 0.48 (95% CI, 0.24-0.71), P = .004; FP500 = 0.37 (95% CI, 0.18-0.57), P = .001. All other secondary inflammatory related outcomes (mannitol, ECP, and eosinophils) showed significant improvements from baseline but no dose separation. CONCLUSIONS: There is a significant dose response of diurnal Feno to ICS in patients with asthma with an elevated Feno phenotype, which translates into well-controlled asthma. Further interventional studies are warranted using domiciliary Feno in this specific phenotype. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00995657; URL: clinicaltrials.gov. PMID- 23364391 TI - Follow-up study of 22 Chinese children with Alexander disease and analysis of parental origin of de novo GFAP mutations. AB - To delineate the phenotype and genotype in Chinese children with type I Alexander disease (AxD) and the parental origin of de novo glial fibrillary acidic protein (GFAP) mutations. Twenty-two children with clinically diagnosed type I AxD were followed up for 1.66-6.62 years. Allele-specific PCR was used for the analysis of parental origin of the allele harboring the de novo mutation. Phenotype of these patients were consistent with type I AxD described in other population, with developmental delay (motor delay in 81.82%, cognitive delay in 63.64%), macrocephaly (100%), seizures (95.45%), paroxysmal deterioration (27.27%) and typical brain magnetic resonance imaging (100%). Progression was slower than reported. At 8.55 years of age (5.29-13.25), all patients who underwent the second follow-up were alive. Eleven heterozygous missense mutations of GFAP were identified in 21 patients, with three novel mutations. Reported hot spot mutations, p.R79, p.R239 and p.R88, were also identified in Chinese patients. Mutations were de novo in all but one case. The mother of a proband was demonstrated to be a presymptomatic patient with type II AxD with a p.R79H mutation. Ninety percent of de novo mutations were on the paternal allele demonstrated by allele-specific PCR. This is the largest follow-up study on Chinese children with AxD. The phenotypes of these patients are consistent with reports in other populations. GFAP mutations were identified in 95.46% of Chinese children with clinically diagnosed type I AxD. Our data suggested a male germ line transmission. PMID- 23364392 TI - Advanced maternal age at childbirth and the development of uniparental disomy. A commentary on the proportion of uniparental disomy is increased in Prader-Willi syndrome due to an advanced maternal childbearing age in Korea. PMID- 23364393 TI - DRD2 haplotype associated with negative symptoms and sustained attention deficits in Han Chinese with schizophrenia in Taiwan. AB - Previous studies have reported significant associations between schizophrenia and the dopamine receptor D2 gene (DRD2) variants. The relationships between DRD2 and clinical phenotypes are of particular interest because DRD2 has been shown to associate with treatment response and prefrontal dopamine transmission. Glatt et al. reported significant associations between schizophrenia and DRD2 variants (two single-nucleotide polymorphisms (SNPs) rs1079727 and rs2283265, and two haplotypes, block 3 (rs1079727(A)-rs2440390(C)-rs2283265(G)) and block 4 (rs1801028(G)-rs1110977(A)-rs1124492(C)-rs2734841 (T))) in 2408 Han Chinese individuals in Taiwan. To further investigate the relationships between the SNPs/haplotypes of DRD2 and clinical symptoms and neuropsychological function, we compared the quantitative phenotypes in patients with risk alleles/haplotypes and those without. The results showed that the A allele of rs1079727, G allele of rs2283265, A allele of rs1124492 and the risk haplotype (A-C-G) of block 3 were associated with more severe negative symptoms. With regard to neuropsychological performance, the risk haplotype (G-A-C-T) of block 4 was associated with poorer performance in the sustained attention task. Our results imply that the genetic variants of DRD2 might not only have a role in susceptibility to schizophrenia, but also influence the phenotypes of negative symptoms and sustained attention in schizophrenia. This association warrants further validation. PMID- 23364394 TI - A genome-wide association study of a coronary artery disease risk variant. AB - Although over 30 common genetic susceptibility loci have been identified to be independently associated with coronary artery disease (CAD) risk through genome wide association studies (GWAS), genetic risk variants reported to date explain only a small fraction of heritability. To identify novel susceptibility variants for CAD and confirm those previously identified in European population, GWAS and a replication study were performed in the Koreans and Japanese. In the discovery stage, we genotyped 2123 cases and 3591 controls with 521 786 SNPs using the Affymetrix SNP Array 6.0 chips in Korean. In the replication, direct genotyping was performed using 3052 cases and 4976 controls from the KItaNagoya Genome study of Japan with 14 selected SNPs. To maximize the coverage of the genome, imputation was performed based on 1000 Genome JPT+CHB and 5.1 million SNPs were retained. CAD association was replicated for three GWAS-identified loci (1p13.3/SORT1 (rs599839), 9p21.3/CDKN2A/2B (rs4977574), and 11q22.3/ PDGFD (rs974819)) in Koreans. From GWAS and a replication, SNP rs3782889 showed a strong association (combined P=3.95 * 10(-14)), although the association of SNP rs3782889 doesn't remain statistically significant after adjusting for SNP rs11066015 (proxy SNP with BRAP (r(2)=1)). But new possible CAD-associated variant was observed for rs9508025 (FLT1), even though its statistical significance did marginally reach at the genome-wide a significance level (combined P=6.07 * 10(-7)). This study shows that three CAD susceptibility loci, which were previously identified in European can be directly replicated in Koreans and also provides additional evidences implicating suggestive loci as risk variants for CAD in East Asian. PMID- 23364395 TI - Exome sequencing identifies novel rheumatoid arthritis-susceptible variants in the BTNL2. AB - The butyrophilin-like protein 2 gene (BTNL2) within the class III region of the major histocompatibility complex genomic region was identified as a rheumatoid arthritis (RA) susceptibility gene by exome sequencing (19 RA cases) with stepwise filtering analysis, and then validated by Sanger sequencing and association analysis using 432 cases and 432 controls. Logistic regression of the Sanger-sequenced single-nucleotide variants in an association study of 432 cases and 432 controls showed that 12 non-synonymous single-nucleotide polymorphisms (SNPs) in BTNL2 were significantly associated with RA. The lowest P-values were obtained from three SNPs, rs41521946, rs28362677 and rs28362678, which were in absolute linkage disequilibrium: P=4.55E-09, odds ratio=1.88, 95% confidence interval=1.52-2.33. The BTNL2 locates on chromosome 6 between HLA-DRB1 and NOTCH4, and is 170 kb apart from these two genes. Although DRB1 and NOTCH4 were reported to be RA-susceptible, the three BTNL2 SNPs retained significant association with RA when evaluated by the logistic regression with the adjustment for RA-susceptible HLA-DRB1 alleles in Japanese or rs2071282-T in NOTCH4: P=0.0156 and P=0.00368, respectively. These results suggest that the three non synonymous SNPs in BTNL2 confer RA risk independently from HLA-DRB1 and NOTCH4. PMID- 23364396 TI - A microRNA-520 mirSNP at the MMP2 gene influences susceptibility to endometriosis in Chinese women. AB - The MMP2 gene has been implicated in the pathogenesis of endometriosis. We investigated the role and function of single-nucleotide polymorphisms (SNP) of MMP2 in relation to endometriosis. First a case-control study was conducted and 17 SNPs were examined in 211 patients and 344 controls. Regression analysis was used to evaluate the genetic effect. We used reporter assay to validate the functional consequences of the significant SNP. Two SNPs (rs243832 and rs7201) had P-values <0.05 and they are in strong linkage disequilibrium (D'=0.96 and r(2)=0.47). Further analysis showed that rs7201 but not rs246832 was an independent risk factor and the risk C allele of rs7201 had an odds ratio (OR) of 1.88 (P=0.004). SNP rs7201 is located at the 3'-untranslated region and is predicted to be within the microRNA-520g binding site. The reporter assay for rs7201 showed that the risk C allele had a higher expression level than the A allele (P=0.027). Using microRNA-520g mimic and inhibitor, the results indicated that the A allele but not the risk C allele can be regulated by microRNA-520g. The C allele of SNP rs7201 increases a risk for endometriosis because of out of regulation by microRNA-520g. PMID- 23364397 TI - Exome sequencing reveals SCO2 mutations in a family presented with fatal infantile hyperthermia. AB - We applied whole-exome sequencing (WES) for identification of an underlying genetic cause of a disease in a family presented with fatal infantile hyperthermia. Analysis of WES results revealed novel, deleterious compound missense mutations, Val160Ala and Pro233Thr, in the synthesis of cytochrome C oxidase 2 gene (SCO2) encoding a mitochondrial protein, Sco2, which is important for cytochrome C oxidase (COX) synthesis. Autosomal recessive mutations in SCO2 are known to be associated with COX deficiency recognized as fatal infantile cardio-encephalomyopathy (604272, OMIM). The Val160Ala and Pro233Thr mutations occurred in the conserved thioredoxin domain of Sco2 and predicted to disrupt protein folding and interaction of Sco2 with other proteins. Our results show applicability of WES in identification of disease-causing mutations and in establishing molecular diagnosis of severe, infantile onset disorder with a challenging diagnosis. PMID- 23364399 TI - Achieving prescriptive authority for clinical nurse specialists. PMID- 23364398 TI - Preparation of non-aggregated fluorescent nanodiamonds (FNDs) by non-covalent coating with a block copolymer and proteins for enhancement of intracellular uptake. AB - Fluorescent nanodiamonds (FNDs) are very promising fluorophores for use in biosystems due to their high biocompatibility and photostability. To overcome their tendency to aggregate in physiological solutions, which severely limits the biological applications of FNDs, we developed a new non-covalent coating method using a block copolymer, PEG-b-P(DMAEMA-co-BMA), or proteins such as BSA and HSA. By simple mixing of the block copolymer with FNDs, the cationic DMAEMA and hydrophobic BMA moieties can strongly interact with the anionic and hydrophobic moieties on the FND surface, while the PEG block can form a shell to prevent the direct contact between FNDs. The polymer-coated FNDs, along with BSA- and HSA coated FNDs, showed non-aggregation characteristics and maintained their size at the physiological salt concentration. The well-dispersed, polymer- or protein coated FNDs in physiological solutions showed enhanced intracellular uptake, which was confirmed by CLSM. In addition, the biocompatibility of the coated FNDs was expressly supported by a cytotoxicity assay. Our simple non-covalent coating with the block copolymer, which can be easily modified by various chemical methods, projects a very promising outlook for future biomedical applications, especially in comparison with covalent coating or protein-based coating. PMID- 23364400 TI - What is known about outcomes of patients with low back pain? AB - Review of recent evidence with translation to practice for the role of advanced practice registered nurses is presented using a case study module for the following: "What is known about Outcomes of Patients with Low Back Pain? The study results showed that patients with low back pain may have substantial continuing pain and functional limitations. The implications and clinical relevance of these findings for advanced practice nurses are discussed highlighting best evidence. PMID- 23364401 TI - Fractures of the distal radius. AB - Distal radius fractures represent 1 of every 6 fractures treated in emergency departments (EDs) each year. This injury has a peak incidence within both the 5- to 24-year-old age group and the elderly female population aged 65 years and older. An understanding of the functional anatomy of the wrist fracture will greatly aid the practitioner in proper treatment and referral for these injuries. After obtaining wrist radiographs, a thorough examination must be performed. Once anesthesia is achieved (via hematoma block, sedation, or Bier block), the first line of treatment of distal radius fractures is to reduce the fracture and stabilize the bone alignment, even if it is expected that the patient will require surgical intervention. Up to 50% of patients are at risk of losing reduction, and 20%-50% of distal radius fractures will eventually require surgical fixation. Referral to an orthopedist can be made during the ED visit or done on an outpatient status. PMID- 23364402 TI - Rapid sequence intubation medication therapies: a review in light of recent drug shortages. AB - Rapid sequence intubation is a stepwise process developed to assist health care providers in placing emergent artificial airways for patients requiring assisted ventilation. This practice includes routine administration of sedative and neuromuscular blocking agent (NMBA) medications for patient comfort during endotracheal tube placement. Members of the multidisciplinary team should be well educated about the various medications used during this process to ensure safe medication practices in an emergent situation. Recent drug shortages have forced many health care professionals to use alternative medications with which they are less familiar. The intent of this review is to familiarize health care providers with the pharmacology and adverse effect profiles of alternative sedative and NMBA medications used in emergent airway placement in light of recent drug shortages. PMID- 23364405 TI - The legal and ethical implications of social media in the emergency department. AB - Social media is a growing and popular means of communication. It is understandable that health care providers may not share identifying information on patients through these sources. Challenges arise when patients and family members wish to record the care provided in the emergency department. The health care provider may be faced with an ethical and possibly legal dilemma when social media is present in the emergency department. This article seeks to discuss the legal and ethical principles surrounding social media in the emergency department. PMID- 23364404 TI - Acute aortic emergencies--part 2: aortic dissections. AB - Patients with aortic disease are some of the highest acuity patients that emergency clinicians encounter. Dissection is the most common aortic catastrophe and involves separation of the aortic layers in a longitudinal fashion leading to diminished perfusion and systemic ischemia. Characteristics of pain, branch vessel involvement, and incidence lead to an understanding of patient presentation, morbidity, and mortality. Diagnosis, selection of diagnostic studies, the degree of preoperative ischemia, and risk of operative mortality can be accomplished using validated clinical decision tools. Emergency interventions are guided by the type of dissection according to the Stanford classification system. Medical management includes pain control and anti-impulse, antihypertensive therapy through vasodilatation and blockage of the sympathetic beta-response. The patient may then be evaluated for open surgical intervention, aortic fenestration, endovascularly placed stent grafts, or a combination possibly in a staged approach. Morbidity includes rupture, stroke, paraplegia, acute renal failure, bowel ischemia, and peripheral ischemia. PMID- 23364406 TI - Development and implementation of the Memorial Emergency Department Fall Risk Assessment Tool. AB - The purpose of this study was to determine the validity and reliability of an evidence-based, emergency department (ED) fall risk assessment tool as a sensitive predictor for falls in the ED population. The overarching goal of the project was to improve patient safety and eliminate patient falls resulting in serious injury in the ED. An ED-specific tool was designed on the basis of the risk factors consistently identified in the literature: prior fall history, impaired mobility, altered mental status, altered elimination, and the use of sedative medication. The Memorial ED Fall Risk Assessment Tool was validated in two EDs (North campus and Central campus) located within a large urban health care system in Colorado Springs, Colorado. The two EDs have a combined 140,000 annual patient visits. The Memorial ED Fall Risk Assessment Tool appears to be a valid tool for this two-ED hospital system. PMID- 23364407 TI - EMLA application exceeding two hours improves pediatric emergency department venipuncture success. AB - The purpose of this study was to determine whether placing Eutectic Mixture of Local Anesthetics (EMLA) at emergency department (ED) triage improves venipuncture success. Emergency department triage nurses prospectively identified patients aged 0-18 years assessed to have 50% or greater chance of needing venipuncture while in the emergency department. Identified patients received EMLA or no intervention according to randomized 24-h blocks. Data were collected on need for venipuncture, venipuncture success (defined as obtaining access in one attempt), and duration and success of EMLA application (defined as EMLA occluded between 1 and 5 h). Parents' satisfaction and perception of pain were assessed with a 5-item scale. Consent was obtained from 267 out of 287 patients, in whom 111 of 154 venipunctures were successful (72%). EMLA (n = 100) and no intervention (n = 167) groups did not differ by age or dehydration-related illnesses. Nurses flagged patients more often on days when EMLA was not applied (chi(2) = 37.8, df2, p < 0.0001), but with lower specificity of needing venipuncture (48.5% no-intervention venipuncture rate vs. 73% venipuncture rate with EMLA (chi(2) = 14.4, df2, p = 0.0001). Of the 73 EMLA patients undergoing venipuncture, 2 removed EMLA at unknown times; 2 had application duration longer than 5 h, and nurses chose non-EMLA venipuncture sites for 8. Punctures through EMLA sites with appropriate duration were successful in 51/61 (84%) versus 58/89 (65%) in untreated skin (p = 0.01, odds ratio (OR) = 2.8; 95% confidence interval (CI) [1.3, 6.2]). Success in intention-to-treat groups did not differ (OR = 1.8, 95% CI [0.87, 3.7]). Improved venipuncture success was seen linearly with increased application duration (p = 0.018). Parents perceived less pain with punctures through EMLA sites (p = 0.006). Venipuncture through an EMLA site reduced pain and improved success. Rates improved with increasing application duration. Barriers to triage EMLA placement should be evaluated. Application longer than 2 h should be studied further as a means to improve success. EMLA was supplied as a part of the Investigator-sponsored study program of AstraZeneca. PMID- 23364408 TI - Pediatric emergency department provider perceptions of universal sexually transmitted infection screening. AB - The purpose of this study was to describe the perceptions of pediatric emergency care providers in relation to implementing a universal sexually transmitted infection screening process for adolescent female patients in a pediatric emergency department. A descriptive qualitative design was used with a convenience sample of pediatric emergency physicians and nurses working in a large urban, pediatric teaching hospital. Participants were individually interviewed using a standard interview guide. Verbatim transcripts were analyzed using a modified constant comparative analysis method. Three overriding themes were identified that describe the perceptions of providers in relation to a universal screening process in a pediatric emergency department: Attitudes, Barriers, and Solutions. Universal sexually transmitted infection screening is one strategy that may help with early identification and treatment of adolescent female patients with undiagnosed sexually transmitted infections, and the pediatric emergency department is a potential site for such screening. PMID- 23364409 TI - Simultaneous profiling of multiple gene-methylation loci by electrochemical methylation-specific ligase detection reaction. AB - A novel method of electrochemical methylation-specific ligation detection reaction is first presented for simultaneous evaluation of multiple gene methylation loci in a single-tube experiment without PCR amplification or restriction enzyme reaction. PMID- 23364410 TI - Comparing quality-adjusted life expectancy at different levels of physical activity. AB - BACKGROUND: Physical activity is a determinant of health which has been shown to impact both morbidity and mortality. This study compares quality-adjusted life expectancy (QALE) according to different levels of physical activity. METHODS: This study estimated health-related quality of life from the 2001-2009 Behavioral Risk Factor Surveillance System and then applied these estimates to the life tables to calculate QALE for individuals who engaged in 4 categories of physical activity-vigorous, moderate only, leisure-time only, and inactive. RESULTS: The QALE at 18 years old was 58.4, 54.0, 54.2, and 47.0 years for individuals who reported vigorous activity, moderate activity, leisure-time activity, and inactivity, respectively. The QALE for inactive white females was 9.2 years less than the QALE for white females who engaged in some physical activity, the most among the 4 sex-by-race groups; this was followed by white males (7.8 years), Black females (6.7 years), and Black males (6.0 years). CONCLUSIONS: This study demonstrates the incremental improvement of individuals' life expectancy and QALE with increases in physical activity. These findings could be of assistance to clinicians in motivating patients to become more active and public health officials and policymakers evaluating intervention programs designed to promote physical activity. PMID- 23364411 TI - From the editor. What's in a name? PMID- 23364412 TI - Bringing knowledge to action in the context of a major organizational transition. AB - In the context of organizational transitions in health care institutions, the decisions taken by leaders and clinicians are informed by multiple sources and by a multitude of actors at all levels of the organization. A study was conducted in the context of a major organizational transition at the McGill University Health Centre in Montreal, Quebec, Canada. The purpose was to examine the body of literature around the notions of "evidence" in decision-making processes in health care. Key informants who had a strategic decision-making role linked to the transition activities were interviewed to explore their perceptions of the types of evidence used to support changes in the organization. Results revealed that managers and clinicians relied on multiple sources of evidence and shared similar concerns about reliability and validity of scant evidence. PMID- 23364413 TI - In a niche of time: do specialty hospitals outperform general services hospitals? AB - Niche hospitals represent a growing segment in the health care industry. Niche facilities are primarily engaged in the treatment of cardiac or orthopedic conditions. The effectiveness of this strategy is of interest because niche hospitals focus on only the most profitable services. The purpose of this research was to assess the financial effectiveness of the niche strategy. We theorize that firm and market-level factors concomitantly with the strategy of the hospital-niche versus traditional-are associated with financial performance. This research used 2 data sources, the 2003 Medicare Cost Report and the 2003 Area Resource File. The sample was limited to only for-profit, urban, nongovernmental hospitals (n = 995). The data were analyzed using hierarchical least squares regression. Financial performance was operationalized using the hospital's return on assets. The principal finding of this project is that niche hospitals had significantly higher performance than traditional facilities. From the organizational perspective, the niche strategy leads to better financial performance. From a societal perspective, the niche strategy provides increased focus and efficiencies through repetition. Despite the limited focus of this strategy, patients who can access these providers may experience better outcomes than patients in more traditional hospitals. PMID- 23364414 TI - A new costing model in hospital management: time-driven activity-based costing system. AB - Traditional cost systems cause cost distortions because they cannot meet the requirements of today's businesses. Therefore, a new and more effective cost system is needed. Consequently, time-driven activity-based costing system has emerged. The unit cost of supplying capacity and the time needed to perform an activity are the only 2 factors considered by the system. Furthermore, this system determines unused capacity by considering practical capacity. The purpose of this article is to emphasize the efficiency of the time-driven activity-based costing system and to display how it can be applied in a health care institution. A case study was conducted in a private hospital in Cyprus. Interviews and direct observations were used to collect the data. The case study revealed that the cost of unused capacity is allocated to both open and laparoscopic (closed) surgeries. Thus, by using the time-driven activity-based costing system, managers should eliminate the cost of unused capacity so as to obtain better results. Based on the results of the study, hospital management is better able to understand the costs of different surgeries. In addition, managers can easily notice the cost of unused capacity and decide how many employees to be dismissed or directed to other productive areas. PMID- 23364415 TI - Redesigning medical education to improve health care delivery and outcomes. AB - The need to improve the health of individuals and populations by providing high quality health care has become a priority and has led to the implementation of various quality indicators to measure performance and outcomes. However, significant disparities exist in the health care delivery and outcomes among individuals that can only intensify, considering the future projections for an aging and increasingly diverse population. This article provides the authors' perspectives on how these issues can be addressed and overcome by redesigning medical education so the future generations of physicians have the necessary knowledge, skills, and attitudes to provide high-quality, patient-centered, and culturally sensitive care. PMID- 23364416 TI - Solve the puzzle of electronic health record implementation budgeting. AB - Health care organizations need to adopt an electronic health record (EHR) system for compliance with the Health Information Technology for Economic and Clinical Health Act. How to budget the EHR implementation is a challenging issue to the chief financial officers in health care organizations. This article uses a mock hospital to illustrate how to prepare an EHR implementation budget step by step in a hospital setting. After the project budget baseline is set, the budgeting steps are as follows: (1) estimating the cost for each project element, (2) aggregating all costs, and (3) revising budget to meet the budget baseline. Several budgeting techniques are discussed, including analogue, parametric, and unit cost based on effort. The budgeting methodology can also be applied to a physician/clinic EHR implementation budget. PMID- 23364419 TI - Health care mergers and acquisitions: implications of robbers cave realistic conflict theory and prisoner's dilemma game theory. AB - Many health care mergers and acquisitions have proven highly successful because of the geographic proximity of the institutions, coalignment strategies, complementary services, and improved financial performance. Other health care mergers and acquisitions, however, have been dismal failures. This article seeks to explain a primary cause of less successful mergers or acquisitions through the prism of a multiscale, iterative prisoner's dilemma that occurs between department managers. Aspects of "Coping Theory," "Resource (Conservation) Theory," and "Social Comparison Theory" are used to analyze the experience of employees charged with making mergers or acquisitions successful. Lastly, this article suggests possible culture clash remedies drawn from the realistic conflict experiment conducted by Muzafer Sherif near Robbers Cave State Park in Oklahoma. PMID- 23364418 TI - Framing, agenda setting, and disease phobia of AIDS-related coverage in the South Korean mass media. AB - There has been little research on the concrete role of the press in discourses on AIDS. This study investigated the AIDS discourses created by the major media. In particular, from the perspective of the agenda-setting theory, it examines differences in the framing of AIDS-related news depending on the political orientation and news sources of the press. This study analyzed the thematic frames and news sources implied by AIDS-related coverage. The 2 major media representing conservatism and progressivism were selected as the objects of analysis. As for the search engine for content analysis, the Korean Integrated Newspaper Database System was used, and 151 articles containing "AIDS" or "HIV" over 5 years from January 2005 to December 2010 were analyzed. According to the results of the analysis, there were the 6 following frames: aid/support, accident, human rights, risk, prevention, and biomedicine. Whereas the conservative press in South Korea continued to frame AIDS in the traditional way, the progressive press tended relatively more often to attempt new agenda setting, from the perspective of human rights and inequality. However, both newspaper companies tended mostly to select experts as the sources of AIDS news, thus continuing to exclude infectees and civil and society organizations. PMID- 23364420 TI - Chief executive officers in US hospitals: a reexamination of workforce demographics and educational issues. AB - The US Bureau of Labor Statistics reports the "employment of medical and health services managers is expected to grow by 22% from 2010 to 2020" (http://www.bls.gov.ooh/management/medical-and-health-services-managers.htm#tab 6). The US Bureau of Labor Statistics notes this is substantially faster than the national average for other occupations. Information from this report finds its way into popular media, news shows, and other information outlets, which increases the number of prospective applicants to college and university health care management programs. (For the purposes of this article, no differentiation is made between various programs geared toward preparing health care managers; this includes, but is not limited to, degrees in hospital administration, hospital services administration, health care management, etc.) In 2007, the authors conducted a survey of chief executive officers in US hospitals that sought to identify educational and demographic information of individuals holding top management positions in US health care institutions. The survey was repeated in 2012, at the 5-year interval, to determine if chief executive officer information had changed. PMID- 23364421 TI - Impact of community capacity on the health status of residents: understanding with the contextual multilevel model. AB - There has been little conceptual understanding as to how community capacity works, although it allows for an important, population-based health promotional strategy. In this study, the mechanism of community capacity was studied through literature reviews to suggest a comprehensive conceptual model. The research results found that the key to community capacity prevailed in how actively the capacities of individuals and their communities are able to interact with one another. Under active interactions, community-based organizations, which are a type of voluntary association, were created within the community, and cohesion among residents was enhanced. In addition, people were more willing to address community issues. During the process, many services were initiated to meet the people's health needs and strengthen their social and psychological ties. The characteristics of community capacity were named as the contextual multilevel effects. Because an increase in community capacity contributes to a boosted health status, encourages health behaviors, and eventually leads to the overall prosperity of the community, more public health-related attention is required. PMID- 23364422 TI - Does the Planetree patient-centered approach to care pay off?: a cost-benefit analysis. AB - Although the Planetree patient-centered approach to care is being implemented in many institutions around the world, its impact is still the subject of some debate. On the one hand, it is viewed as the most cost-effective way to provide care and create a positive work environment that reduces staff burnout. On the other hand, it is argued that it requires higher staffing ratios and a substantial infusion of financial resources and is time consuming, which in turn results in more work. The present study addresses the economic agenda of the Planetree patient-centered approach to care and has been designed to answer the following question: do the advantages of the Planetree patient-centered approach outweigh its costs? This question is of considerable interest for health care administrators and managers because the relevant authorities the world over have limited resources to allocate to health care organizations. Using a trend analysis approach to cost-benefit in a rehabilitation center, this study shows that the revenues the model generates are greater than the costs of implementing it. Fewer grievances and vacant positions, an improved employee retention rate, a better working atmosphere, and a high level of employee satisfaction (higher than in similar establishments) were also noted. PMID- 23364424 TI - Self-assembled dual in-plane gate thin-film transistors gated by nanogranular SiO2 proton conductors for logic applications. AB - Phosphorus (P)-doped nanogranular SiO(2) films are deposited by plasma-enhanced chemical vapor deposition at room temperature, and a high proton conductivity of ~5.6 * 10(-4) S cm(-1) is measured at room temperature with a relative humidity of 70%. The accumulation of protons at the SiO(2)/indium-zinc-oxide (IZO) interface induces a large electric-double-layer (EDL) capacitance. Thin-film transistors (TFTs) with two in-plane gates are self-assembled on transparent conducting glass substrates. The large EDL capacitance can effectively modulate the IZO channel with a current ON/OFF ratio of >10(7). Such TFTs calculate dual input signals at the gate level coupled with a floating gate, analogous to that of neuron MOS (vMOS). AND logic is demonstrated on the neuron TFTs. Such neuron TFTs gated by P-doped nanogranular SiO(2) shows an effective electrostatic modulation on conductivities of oxide semiconductors, which is meaningful for portable chemical-biological sensing applications. PMID- 23364423 TI - The functional exchangeability of pk- and k-turns in RNA structure. AB - Ribonuclease P RNA requires a sharply kinked RNA helix to make a loop-receptor interaction that creates the binding site for the substrate. In some forms of the ribozyme, this is accomplished by a k-turn, while others have a different element called the pk-turn. The structure of the pk-turn in RNase P of Thermotoga maritima is globally very similar to a k-turn, but lacks all the standard features of that structure, including long-range hydrogen bonds between the two helical arms. We show here that in an isolated RNA duplex, the pk-turn fails to adopt a tightly kinked structure, but rather is a flexible element. This suggests that the tertiary contacts of RNase P assist its folding into the required kinked structure. We find that we can replace the k-turn of the SAM-I riboswitch with the pk-turn, such that the resulting RNA retains its ability to bind SAM, although with lower affinity. We also find that we can replace the pk-turn of T. maritima RNase P with a standard k-turn (in either orientation) with retention of ribozyme activity. Thus, although the pk-turn cannot intrinsically fold into the kinked structure, it can be induced to fold correctly in context. And the pk-turn and k-turns can substitute functionally for one another. PMID- 23364425 TI - Rattus model utilizing selective pulmonary ischemia induces bronchiolitis obliterans organizing pneumonia. AB - Bronchiolitis obliterans organizing pneumonia (BOOP), a morbid condition when associated with lung transplant and chronic lung disease, is believed to be a complication of ischemia. Our goal was to develop a simple and reliable model of lung ischemia in the Sprague-Dawley rat that would produce BOOP. Unilateral ischemia without airway occlusion was produced by an occlusive slipknot placed around the left main pulmonary artery. Studies were performed 7 days later. Relative pulmonary and systemic flow to each lung was measured by injection of technetium Tc 99m macroaggregated albumin. Histological sections were examined for structure and necrosis and scored for BOOP. Apoptosis was detected by immunohistochemistry with an antibody against cleaved caspase 3. Pulmonary artery blood flow to left lungs was less than 0.1% of the cardiac output, and bronchial artery circulation was ~2% of aortic artery flow. Histological sections from ischemic left lungs consistently showed Masson bodies, inflammation, and young fibroblasts filling the distal airways and alveoli, consistent with BOOP. In quantitative evaluation of BOOP using epithelial changes, inflammation and fibrosis were higher in ischemic left lungs than right or sham-operated left lungs. Apoptosis was increased in areas exhibiting histological BOOP, but there was no histological evidence of necrosis. Toll-like receptor 4 expression was increased in ischemic left lungs over right. An occlusive slipknot around the main left pulmonary artery in rats produces BOOP, providing direct evidence that ischemia without immunomodulation or coinfection is sufficient to initiate this injury. It also affords an excellent model to study signaling and genetic mechanisms underlying BOOP. PMID- 23364426 TI - Role of pulmonary artery reactivity and nitric oxide in injury and inflammation following lung contusion. AB - The mechanisms contributing to hypoxia in lung contusion (LC) remain unclear and not temporally associated with the peak onset of acute inflammation. We investigated the role of oxidative stress in alteration of pulmonary arterial (PA) reactivity following LC. In addition, the role of antioxidants in reversing this process was examined. PaO2 and PA reactivity were measured in rats subjected to bilateral LC. Rings were pretreated with a nitric oxide synthase (NOS) inhibitor, L-nitro arginine (10(-3) M), or PEG-superoxide dismutase (SOD) and PEG catalase (CAT), or both (L-nitro arginine + SOD/CAT). Rings were constricted with norepinephrine and relaxed with an NOS agonist (A23187) or NO donor (SNAP [S nitrosyl amino penicillamine]). Immunochemical and mass spectrometric quantification for nitrotyrosine was performed. Rats were hypoxemic at 4 h after contusion compared with controls, but recovered by 24 h (PaO(2)/FIO(2) ratio: baseline, 443 +/- 28; 4 h, 288 +/- 46; and 24 h, 417 +/- 23). Pulmonary arterial constriction to NOS inhibition and relaxation to A23187 were impaired 4 h after LC. Pulmonary arterial relaxation to SNAP was decreased at 4 and 24 h after LC. These alterations in PA reactivity were reversed by SOD/CAT pretreatment. SOD1 and 2 mRNA were upregulated, and soluble guanylyl cyclase mRNA was downregulated 24 h after LC. Immunohistochemistry and mass spectrometry revealed that levels of 3-nitrotyrosine were increased markedly at 4 h following LC consistent with superoxide generation and formation of peroxynitrite. Collectively, these data suggest that consumption of NO due to excess superoxide resulting in peroxynitrite formation leads to diminished vascular reactivity following LC. PMID- 23364427 TI - Inhibition of neutrophil exocytosis ameliorates acute lung injury in rats. AB - Exocytosis of neutrophil granules contributes to acute lung injury (ALI) induced by infection or inflammation, suggesting that inhibition of neutrophil exocytosis in vivo could be a viable therapeutic strategy. This study was conducted to determine the effect of a cell-permeable fusion protein that inhibits neutrophil exocytosis (TAT-SNAP-23) on ALI using an immune complex deposition model in rats. The effect of inhibition of neutrophil exocytosis by intravenous administration of TAT-SNAP-23 on ALI was assessed by albumin leakage, neutrophil infiltration, lung histology, and proteomic analysis of bronchoalveolar lavage fluid (BALF). Administration of TAT-SNAP-23, but not TAT-control, significantly reduced albumin leakage, total protein levels in the BALF, and intra-alveolar edema and hemorrhage. Evidence that TAT-SNAP-23 inhibits neutrophil exocytosis included a reduction in plasma membrane CD18 expression by BALF neutrophils and a decrease in neutrophil granule proteins in BALF. Similar degree of neutrophil accumulation in the lungs and/or BALF suggests that TAT-SNAP-23 did not alter vascular endothelial cell function. Proteomic analysis of BALF revealed that components of the complement and coagulation pathways were significantly reduced in BALF from TAT-SNAP-23-treated animals. Our results indicate that administration of a TAT fusion protein that inhibits neutrophil exocytosis reduces in vivo ALI. Targeting neutrophil exocytosis is a potential therapeutic strategy to ameliorate ALI. PMID- 23364428 TI - Isolated mitochondria infusion mitigates ischemia-reperfusion injury of the liver in rats. AB - A recent study showed that the injection of mitochondria isolated from a nonischemic region mitigated myocardial injury. We tested the protective effects of infusing isolated mitochondria on the reperfusion injury in the liver of rats. A partial liver ischemia-reperfusion (I/R) model in male Wistar rats was used. At the 45th minute of liver ischemia, the recipient's spleen was infused with vehicle (I/R-vehicle group) or vehicle containing isolated mitochondria (7.7 * 10 +/- 1.5 * 10/mL, I/R-mito group). After a 240-min reperfusion, the serum and livers were collected to assess tissue injury. Our results show that the elevation of serum alanine aminotransferase (414.3 +/- 67.1 vs. 208.8 +/- 30.2 U/L), the necrosis of hepatocytes on hematoxylin-eosin staining, increase in positive counts in TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining (59.5% +/- 4.4% vs. 24.6% +/- 9.1%), the expression of cytosolic cytochrome c, cleaved caspase 9, and 4-hydroxynonenal were all reduced in the I/R-mito group, compared with the I/R-vehicle group. The membrane potential of the isolated mitochondria measured by JC-1 fluorescence remained high, and the infused mitochondria were distributed in the liver parenchyma at 240 min after reperfusion. These results demonstrate that an intrasplenic infusion of viable mitochondria isolated from the donor before reperfusion significantly reduced I/R injury in the liver. PMID- 23364429 TI - Salvianolic acid B protects from pulmonary microcirculation disturbance induced by lipopolysaccharide in rat. AB - The aim of the present study was to examine the effect and possible mechanism of salvianolic acid B (SalB) on pulmonary microcirculation disturbance induced by lipopolysaccharide (LPS) in rat. Male Sprague-Dawley rats were subjected to thoracotomy under continuous anesthesia and mechanical ventilation. Albumin leakage from pulmonary capillary and the numbers of leukocytes adherent to the pulmonary capillary wall were determined for 60 min by an upright microscope upon LPS (2 mg . kg(-1) . h(-1)) infusion with or without administration of SalB (5 mg . kg(-1) . h(-1)). Pulmonary tissue wet-to-dry weight ratio, tumor necrosis factor alpha, and interleukin 8 in plasma and bronchoalveolar lavage fluid were measured. In addition, the expressions of E-selectin, intercellular adhesion molecule 1, and myeloperoxidase in pulmonary tissue were assessed by immunohistochemistry. The expressions of aquaporin 1 (AQP-1), AQP-5, metalloproteinase 2 (MMP-2), and MMP-9 were assessed by Western blot assay. Pretreatment with SalB significantly attenuated LPS-induced pulmonary microcirculatory disturbance, including the increase in leukocyte adhesion and albumin leakage. In addition, LPS increased pulmonary tissue wet-to-dry weight ratio and tumor necrosis factor alpha and interleukin 8 levels in plasma and bronchoalveolar lavage fluid enhanced the expression of E-selectin, intercellular adhesion molecule 1, myeloperoxidase, MMP-2, and MMP-9, whereas it decreased the expression of AQP-1 and AQP-5 in pulmonary tissue, all of which were attenuated by SalB pretreatment. Salvianolic acid B pretreatment improves pulmonary microcirculation disturbance and lung injury on LPS exposure. More studies are required to evaluate the potential of SalB as an option for protecting lung from endotoxemia. PMID- 23364430 TI - A novel model of burn-blast combined injury and its phasic changes of blood coagulation in rats. AB - Burn-blast combined injury has a complex pathological process that may cause adverse complications and difficulties in treatment. This study aims to establish a standard animal model of severe burn-blast combined injury in rats and also to investigate early phasic changes of blood coagulation. By using 54 Wistar rats, distance from explosion source (Hexogen) and size of burned body surface area were determined to induce severe burn-blast combined injury. Thereafter, 256 rats were randomly divided into four groups (n = 64): blast injury group, burn injury group, burn-blast combined injury group, and sham injury group. Gross anatomy and pathological changes in lungs were investigated at 3, 24, 72, and 168 h, respectively. Blood was also collected for analyzing coagulation parameters as prothrombin time, activated partial thromboplastin time, and plasma levels of fibrinogen, D-dimer, antithrombin III, and alpha2-antiplasmin from 0 to 168 h after injury. Severe burn-blast combined injury was induced by inflicting rats with a moderate blast injury when placing rats 75 cm away from explosion source and a full-thickness burn injury of 25% total body surface area. The rats with burn-blast combined injury had more severe lung injuries when compared with the other three groups. Pathological examination in the BBL group showed diffused alveolar hemorrhage, fluid filling, alveolar atelectasis, rupture and hyperplasia of partial alveolar septum, emphysema-like change, reduced capillary bed, and infiltration of extensive polymorphonuclear cells after injury. The blood of combined injured rats was in a hypercoagulable state within 24 h, shortly restored from 24 to 48 h, and rehypercoagulated from 48 to 72 h after injury. A secondary excessively fibrinolytic function was also found thereafter. The rat model of burn-blast combined injury was successfully established by simulating real explosion characteristics. Rats with burn-blast combined injuries suffered from more severe lung injuries and abnormal coagulation and fibrinolytic function than those induced by a burn injury or a blast injury component. Hence, a time dependent treatment strategy on coagulation function should be emphasized in clinical therapy of burn-blast combined injury. PMID- 23364431 TI - Geranylgeranyl transferase regulates streptococcal M1 protein-induced CXC chemokine formation and neutrophil recruitment in the lung. AB - Streptococcal toxic shock syndrome is most frequently associated with Streptococcus pyogenes of the M1 serotype. Simvastatin protects against M1 protein-induced acute lung damage, although downstream mechanisms remain elusive. Herein, we hypothesized that geranylgeranylation might regulate proinflammatory effects in M1 protein-induced lung injury. Male C57BL/6 mice received the geranylgeranyl transferase inhibitor, GGTI-2133, before M1 protein injection. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema, and CXC chemokine formation. Mac-1 expression on neutrophils was quantified by use of flow cytometry. Quantitative reverse transcriptase-polymerase chain reaction was used to determine gene expression of CXC chemokines in alveolar macrophages. GGTI-2133 reduced M1 protein-provoked infiltration of neutrophils, edema, and tissue injury in the lung. Inhibition of geranylgeranyl transferase had no effect on M1 protein-evoked upregulation of Mac 1 on neutrophils. However, geranylgeranyl transferase inhibition completely inhibited pulmonary formation of CXC chemokines in mice exposed to M1 protein. Notably, GGTI-2133 abolished M1 protein-induced gene expression of CXC chemokines in alveolar macrophages. These novel findings indicate that geranylgeranyl transferase is an important regulator of neutrophil recruitment and CXC chemokine production in the lung. Thus, targeting geranylgeranyl transferase might be a potent way to ameliorate streptococcal M1 protein-triggered acute lung injury. PMID- 23364432 TI - Sepsis-induced hypercytokinemia and lymphocyte apoptosis in aging-accelerated Klotho knockout mice. AB - Sepsis is primarily a disease of the aged, with 65% of sepsis cases reported in patients older than 65 years and 80% of deaths due to sepsis occurring in this age group. Klotho knockout mice (Klotho mice) are a mouse model of accelerated aging and shortened life span. The purpose of the study was to elucidate the immunological changes occurring in Klotho mice during sepsis. Five-week-old homozygous female Klotho knockout (Klotho) and wild-type (WT) mice were subjected to 1 * 27-gauge cecal ligation and puncture (CLP), and survival was compared after 4 days. Another set of mice was killed at 8 h after CLP or sham surgery, and the spleen, thymus, and serum were harvested. Apoptosis was measured by flow cytometry by using caspase 3. Serum cytokines and bacterial colony count in peritoneal lavage were also analyzed. Klotho septic mice started to die at 8 to 12 h after CLP, and the final survival of Klotho mice was significantly lower than that of WT mice (0% vs. 100%, P < 0.01). Increased bacterial count in the peritoneal cavity and decreased recruitment of neutrophils and macrophages to the peripheral cavity were observed in Klotho-CLP mice. Both flow cytometric and immunohistological analyses showed a dramatic increase in caspase 3-positive cells in the thymus and spleen of Klotho-CLP mice (P < 0.01). Serum concentrations of interleukin 6, tumor necrosis factor alpha, and interleukin 10 were higher in Klotho-CLP mice than in WT-CLP mice. Hypercytokinemia with impaired bacterial clearance and increased apoptosis of lymphocytes may be related to poor survival in Klotho-septic mice. PMID- 23364433 TI - Hypoxic postconditioning inhibits endoplasmic reticulum stress-mediated cardiomyocyte apoptosis by targeting PUMA. AB - Postconditioning prevents cardiomyocytes from ischemia/reperfusion-induced apoptosis. However, little is known about the molecular mechanisms that mediate the cardioprotective effect of postconditioning. Here, we hypothesized that postconditioning targeted p53 upregulated modulator of apoptosis (PUMA) to protect cardiomyocytes against endoplasmic reticulum stress-mediated apoptosis. Our results demonstrated that postconditioning could inhibit GRP78 (78-kDa glucose-regulated protein) expression, caspase-12 activation, and cardiomyocyte apoptosis by regulating PUMA expression. In addition, p53 is involved in the regulatory role of postconditioning in PUMA expression. Our data reveal a cardioprotective pathway of postconditioning in which it represses PUMA. PMID- 23364435 TI - Induced pluripotent stem cells mediate the release of interferon gamma-induced protein 10 and alleviate bleomycin-induced lung inflammation and fibrosis. AB - Chronic lung diseases cause serious morbidity and mortality, and effective treatments are limited. Induced pluripotent stem cells (iPSCs) lacking the reprogramming factor c-Myc (3-gene iPSCs) can be used as ideal tools for cell based therapy because of their low level of tumorigenicity. In this study, we investigated whether 3-gene iPSC transplantation could rescue bleomycin-induced pulmonary fibrosis. After the induction of pulmonary inflammation and fibrosis via intratracheal delivery of bleomycin sulfate, mice were i.v. injected with 3 gene iPSCs or conditioned medium (iPSC-CM) at 24 h after bleomycin treatment. Administration of either 3-gene iPSCs or iPSC-CM significantly attenuated collagen content and myeloperoxidase activity, diminished neutrophil accumulation, and rescued pulmonary function and recipient survival after bleomycin treatment. Notably, both treatments reduced the levels of inflammatory cytokines and chemokines, including interleukin 1 (IL-1), IL-2, IL-10, tumor necrosis factor-alpha, and monocyte chemotactic protein 1 yet increased the production of the antifibrotic chemokine interferon-gamma-induced protein 10 (IP 10) in bleomycin-injured lungs. Furthermore, IP-10 neutralization via treatment with IP-10-neutralizing antibodies ameliorated the reparative effect of either 3 gene iPSCs or iPSC-CM on collagen content, neutrophil and monocyte accumulation, pulmonary fibrosis, and recipient survival. Intravenous delivery of 3-gene iPSCs/iPSC-CM alleviated the severity of histopathologic and physiologic impairment in bleomycin-induced lung fibrosis. The protective mechanism was partially mediated by the early moderation of inflammation, reduced levels of cytokines and chemokines that mediate inflammation and fibrosis, and an increased production of antifibrotic IP-10 in the injured lungs. PMID- 23364436 TI - Outcomes in critically ill cancer patients with septic shock of pulmonary origin. AB - Increased therapeutic intensity has translated into better survival at a price of infectious and toxic life-threatening complications, chiefly affecting the lungs. Yet, no study specifically evaluated outcomes in cancer patients admitted to the intensive care unit (ICU) for septic shock of pulmonary origin. This is a multicenter cohort study of cancer patients admitted to the ICU for septic shock and pneumonia between 1998 and 2008. Independent determinants of hospital mortality were assessed using a multivariate logistic regression model. Prognostic impact of persistence or acquisition of organ failures was evaluated by survival conditional probabilities. During the 10-year study period, 218 patients were included. Hematologic malignancy (mostly non-Hodgkin lymphoma and acute leukemia) affected 84%, and solid tumors (mostly lung cancer) affected 16% of patients. Chemotherapy was recently administered in 89% of patients, and 24.5% of patients were recipients of hematopoietic stem cell transplantation (35 autologous, 18 allogeneic). At the time of ICU admission, 60% of patients were in partial or complete remission. All patients received vasopressors; invasive mechanical ventilation (MV) was needed in 78.4% and dialysis in 30% of patients. Intensive care unit and hospital mortality rates were 56.4% and 62.4%, respectively. Independent risk factors for hospital mortality were age older than 60 years, time between first symptoms and ICU admission, use of invasive MV, need for invasive MV after use of noninvasive ventilation, and coma. Analysis of survival probability showed that there was no temporal threshold after which persistence or gain of organ dysfunction indicated no hope for survival. Survival in cancer patients with septic shock from pulmonary origin is substantial, even when organ dysfunctions are not rapidly reversible. Delayed ICU management is an independent predictor of death. Studies assessing survival benefits from early ICU management are warranted. PMID- 23364437 TI - Genetic predisposition to acute respiratory distress syndrome in patients with severe sepsis. AB - OBJECTIVE: The objective of this study was to analyze the association between candidate gene polymorphisms and susceptibility to acute respiratory distress syndrome (ARDS) in patients with severe sepsis. METHODS: Patients older than 18 years admitted to the intensive care unit (ICU) with the diagnosis of severe sepsis were prospectively included. A blood sample was drawn on the first day of ICU admission, and DNA was extracted. We genotyped the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene (polymerase chain reaction) and the following single-nucleotide polymorphisms (TaqMan SNP genotyping assay): tumor necrosis factor alpha -376 G/A, -308 G/A, and -238 G/A; interleukin 8 -251 T/A; pre-B cell colony-enhancing factor -1001 G/T; and vascular endothelial growth factor +405 C/G and +936 C/T. Polymorphisms were selected based on reports on their association with ARDS. Variables associated in univariate analysis (P < 0.1) with the diagnosis of ARDS were included in a multiple logistic regression analysis. RESULTS: We studied 149 patients, of whom 35 presented ARDS. Variables included in the maximal multivariate model were male sex, chronic alcoholism, use of ACE inhibitors or angiotensin-receptor blockers, Simplified Acute Physiology Score II score, serum glucose concentration at ICU admission, and the presence of the allele D of the ACE gene. After adjustment for those variables, the presence of the allele D of the ACE gene (odds ratio, 4.75; 95% confidence interval, 1.02-22.20; P = 0.048) was significantly associated with the diagnosis of ARDS. CONCLUSION: The presence of the allele D of the ACE gene is associated with ARDS in patients with severe sepsis. PMID- 23364438 TI - Fluid resuscitation guided by sublingual partial pressure of carbon dioxide during hemorrhagic shock in a porcine model. AB - To avoid aggressive fluid resuscitation during hemorrhagic shock, fluid resuscitation is best guided by a specific measurement of tissue perfusion. We investigated whether fluid resuscitation guided by sublingual PCO2 would reduce the amount of resuscitation fluid without compromising the outcomes of hemorrhagic shock. Ten male domestic pigs weighing between 34 and 37 kg were used. Forty-five percent of estimated blood volume was removed during an interval of 1 h. The animals were then randomized to receive fluid resuscitation based on either sublingual PCO2 or blood pressure (BP). In the sublingual PCO2-guided group, resuscitation was initiated when sublingual PCO2 exceeded 70 Torr and stopped when it decreased to 50 Torr. In the BP-guided group, resuscitation was initiated when mean aortic pressure decreased to 60 mmHg and stopped when it increased to 90 mmHg. First, Ringer's lactate solution (RLS) of 30 mL kg was administered; subsequently, the shed blood was transfused if sublingual PCO2 remained greater than 50 Torr in the sublingual PCO2-guided group or mean aortic pressure was less than 90 mmHg in the BP-guided group. All the animals were monitored for 4 h and observed for an additional 68 h. In the sublingual PCO2 guided group, fluid resuscitation was required in only 40% of the animals. In addition, a significantly lower volume of RLS (170 +/- 239 mL, P = 0.005 vs. BP guided group) was administered without the need for blood infusion in this group. However, in the BP-guided group, all the animals required a significantly larger volume of fluid (955 +/- 381 mL), including both RLS and blood. There were no differences in postresuscitation tissue microcirculation, myocardial and neurologic function, and 72-h survival between groups. During hemorrhagic shock, fluid resuscitation guided by sublingual PCO2 significantly reduced the amount of resuscitation fluid without compromising the outcomes of hemorrhagic shock. PMID- 23364440 TI - Involvement of the nitric oxide/cyclic guanylate monophosphate pathway in the pilocarpine-induced seizure model in mice. AB - The present study was designed to investigate the involvement of the nitric oxide (NO)/cyclic guanylate monophosphate pathway in pilocarpine-induced seizures in mice. Male Swiss mice (26-32 g) were used as the in vivo model. The following pharmacological tools were utilized: the non-selective NO synthase (NOS) inhibitor L-NAME (10 mg/kg, i.p.), a preferential inducible NOS (iNOS) inhibitor aminoguanidine (25 mg/kg, i.p.), a highly specific iNOS inhibitor 1400W (2.5 mg/kg, i.p.), the NO donor L-arginine (150 mg/kg, i.p.), and the soluble guanylyl cyclase inhibitor ODQ (10 mg/kg, i.p.). The animals were divided into groups (n = 8) and pretreated for 30 min before receiving pilocarpine (400 mg/kg, i.p.), while the control group received only pilocarpine. They were observed for 60 min to measure initial seizure latency, latency till death, and mortality. An administration of L-NAME or ODQ delayed the onset of initial seizure, increased latency till death, and produced a 25% survival rate. Aminoguanidine increased the initial seizure and latency until death, and administration of 1400W did not have an effect. Incremental increases of NO by L-arginine were capable of decreasing the seizure and death latency. These results support the idea that the constitutive NOS, probably neuronal NOS, followed by soluble guanylyl cyclase activation is involved in the convulsive responses caused by pilocarpine administration. PMID- 23364441 TI - Isotype-switched immunoglobulin G antibodies to HIV Gag proteins may provide alternative or additional immune responses to 'protective' human leukocyte antigen-B alleles in HIV controllers. AB - BACKGROUND: Natural control of HIV infection is associated with CD8 T-cell responses to Gag-encoded antigens of the HIV core and carriage of 'protective' human leukocyte antigen (HLA)-B alleles, but some HIV controllers do not possess these attributes. As slower HIV disease progression is associated with high levels of antibodies to HIV Gag proteins, we have examined antibodies to HIV proteins in controllers with and without 'protective' HLA-B alleles. METHODS: Plasma from 32 HIV controllers and 21 noncontrollers was examined for immunoglobulin G1 (IgG1) and IgG2 antibodies to HIV proteins in virus lysates by western blot assay and to recombinant (r) p55 and gp140 by ELISA. Natural killer (NK) cell-activating antibodies and FcgammaRIIa-binding immune complexes were also assessed. RESULTS: Plasma levels of IgG1 antibodies to HIV Gag (p18, p24, rp55) and Pol-encoded (p32, p51, p66) proteins were higher in HIV controllers. In contrast, IgG1 antibodies to Env proteins were less discriminatory, with only antigp120 levels being higher in controllers. High-level IgG2 antibodies to any Gag protein were most common in HIV controllers not carrying a 'protective' HLA-B allele, particularly HLA-B*57 (P = 0.016). HIV controllers without 'protective' HLA-B alleles also had higher plasma levels of IgG1 antip32 (P = 0.04). NK cell activating antibodies to gp140 Env protein were higher in elite controllers but did not differentiate HIV controllers with or without 'protective' HLA-B alleles. IgG1 was increased in FcgammaRIIa-binding immune complexes from noncontrollers. CONCLUSION: We hypothesize that isotype-switched (IgG2+) antibodies to HIV Gag proteins and possibly IgG1 antip32 may provide alternative or additional immune control mechanisms to HLA-restricted CD8 T-cell responses in HIV controllers. PMID- 23364439 TI - Hyperosmolarity attenuates TNF-alpha-mediated proinflammatory activation of human pulmonary microvascular endothelial cells. AB - Firm neutrophil (PMN)-endothelial (EC) adhesion is crucial to the PMN-mediated hyperinflammation observed in acute lung injury. Hypertonic saline (HTS) used for resuscitation of hemorrhagic shock has been associated with a decreased incidence of PMN-mediated lung injury/acute respiratory distress syndrome. We hypothesize that physiologically accessible hypertonic incubation (170 vs. 140 mM, osmolarity ranging from 360 to 300 mOsm/L) inhibits proinflammatory activation of human pulmonary microvascular endothelial cells (HMVECs). Proinflammatory activation of HMVECs was investigated in response to tumor necrosis factor-alpha (TNF-alpha), including interleukin 8 (IL-8) release, intercellular adhesion molecule 1 (ICAM 1) surface expression, PMN adhesion, and signaling mechanisms under both isotonic (control) and hypertonic conditions. Hyperosmolarity alone had no effect on either basal IL-8 release or ICAM-1 surface expression but did lead to concentration-dependent decreases in TNF-alpha-induced IL-8 release, ICAM-1 surface expression, and PMN-HMVEC adhesion. Conversely, HTS activated p38 mitogen activated protein kinase (MAPK) and enhanced TNF-alpha activation of p38 MAPK. Despite this basal activation, hyperosmolar incubation attenuated TNF-alpha stimulated IL-8 release and ICAM-1 surface expression and subsequent PMN adherence, while p38 MAPK inhibition did not further influence the effects of hyperosmolar conditions on ICAM-1 surface expression. In addition, TNF-alpha induced nuclear factor-kappaB DNA binding, but HTS conditions attenuated this by 31% (P < 0.01). In conclusion, HTS reduces PMN-HMVEC adhesion and TNF-alpha induced proinflammatory activation of primary HMVECs via attenuation of nuclear factor-kappaB signaling. PMID- 23364442 TI - Provider-initiated testing and counselling programmes in sub-Saharan Africa: a systematic review of their operational implementation. AB - OBJECTIVE: The routine offer of an HIV test during patient-provider encounters is gaining momentum within HIV treatment and prevention programmes. This review examined the operational implementation of provider-initiated testing and counselling (PITC) programmes in sub-Saharan Africa. DESIGN AND METHODS: PUBMED, EMBASE, Global Health, COCHRANE Library and JSTOR databases were searched systematically for articles published in English between January 2000 and November 2010. Grey literature was explored through the websites of international and nongovernmental organizations. Eligibility of studies was based on predetermined criteria applied during independent screening by two researchers. RESULTS: We retained 44 studies out of 5088 references screened. PITC polices have been effective at identifying large numbers of previously undiagnosed individuals. However, the translation of policy guidance into practice has had mixed results, and in several studies of routine programmes the proportion of patients offered an HIV test was disappointingly low. There were wide variations in the rates of acceptance of the test and poor linkage of those testing positive to follow-up assessments and antiretroviral treatment. The challenges encountered encompass a range of areas from logistics, to data systems, human resources and management, reflecting some of the weaknesses of health systems in the region. CONCLUSIONS: The widespread adoption of PITC provides an unprecedented opportunity for identifying HIV-positive individuals who are already in contact with health services and should be accompanied by measures aimed at strengthening health systems and fostering the normalization of HIV at community level. The resources and effort needed to do this successfully should not be underestimated. PMID- 23364443 TI - Treatment of anal intraepithelial neoplasia: has it come of age? PMID- 23364444 TI - Polymorphic LEDGF/p75 variants support efficient HIV-1 infection ex vivo. PMID- 23364445 TI - Sexually transmitted infection with an immune-escape mutant hepatitis B virus in an hepatitis B virus-vaccinated individual with acute HIV-hepatitis C virus infection. PMID- 23364446 TI - Intracranial hypertension following highly active antiretroviral therapy interruption in an HIV-infected woman: case report and review of the literature. PMID- 23364447 TI - Modifiable behaviors help to explain the inequalities in perceived health associated with deprivation and social class: evidence from a national sample. AB - BACKGROUND: The association between health and deprivation is of serious concern to many health promotion agencies. The purpose of the current study was to assess whether modifiable behaviors of physical activity (PA), sports participation, diet, smoking and body mass index (BMI) can help to explain these inequalities in a sample of 4653 respondents from Northern Ireland. METHODS: The study is based on a cross-sectional survey of Northern Irish adults. Responses to a self-rated health question were dichotomized and binary logistic regression was used to identify the health inequalities between areas of high, middle or low deprivation. These differences were further adjusted for other sociodemographic factors and subsequently for various modifiable behaviors of PA, sports participation, diet, smoking, and BMI. RESULTS: Respondents from high and middle areas of deprivation are more likely to report poorer health. As soon as sociodemographic factors and other modifiable behaviors were included, these inequalities either disappeared or were greatly reduced. CONCLUSION: Many inequalities in health in NI can be explained by the respondents' sociodemographic characteristics that can be further explained by introducing information about respondents who meet the recommended PA guidelines, play sport, eat 5 portions of fruit and vegetables, and maintain an optimal BMI. PMID- 23364448 TI - Implant microdesigns and their impact on osseointegration. AB - Researchers are in constant search for the ideal implant surface condition in an attempt to improve osseointegration of the implant and to increase bone-to implant contact. Although introduction of rough surfaces was able to overcome a lot of limitations that presented with machined surfaces, they are still incapable of ensuring predictable results and guaranteed success. Various techniques in implant surface modifications have been proposed, all aimed at improving bone formation around dental implants. Understanding how surface modification of dental implants can impact osseointegration might help the clinician to maximize the success rate of implants and diminish the complications that can be encountered after their placement. In view of that, this article is aimed at assessing the different surface conditioning techniques available and will present a review of the literature that focuses on the influence of microdesign of dental implants on their osseointegration. PMID- 23364449 TI - Electrogenerated chemiluminescence and interfacial charge transfer dynamics of poly(3-hexylthiophene-2,5-diyl) (P3HT)-TiO2 nanoparticle thin film. AB - We present electrogenerated chemiluminescence (ECL) and photoluminescence (PL) characteristics of poly(3-hexylthiophene-2,5-diyl) (P3HT) thin films incorporated with monodisperse TiO(2) nanoparticles prepared using a hydrothermal reaction in the presence of oleylamine and oleic acid. The ECL turn-on potential decreases in the presence of TiO(2) nanocrystals, accompanied with an increase in ECL intensity. Only a minor ECL quantum efficiency decrease is obtained in the presence of <40 wt% TiO(2), indicating the formation of an effective interpenetrating network of TiO(2) and disordering of polymer packing to allow the ECL coreactant to transport through the film for efficient electroluminescence. In contrast, PL quenching increases with the weight percentage of TiO(2) and significant PL quenching is obtained when the P3HT film contains up to 80 wt% TiO(2) due to charge transfer. Polaron absorption after the photoinduced charge separation in the presence of 80 wt% TiO(2) nanoparticles is significantly enhanced with longer-lived lifetimes of >1000 ps in contrast to the neat P3HT film. The absorption of polarons created at the P3HT-TiO(2) interface is found to increase with the P3HT-TiO(2) interfacial area per unit volume. PMID- 23364450 TI - Supramolecular polymerization in water harnessing both hydrophobic effects and hydrogen bond formation. AB - The formation of supramolecular polymers in water through rational design of a benzene-1,3,5-tricarboxamide (BTA) motif is presented. Intermolecular hydrogen bonding and hydrophobic effects cooperate in the self-assembly into long fibrillar aggregates. Minimal changes in molecular structure significantly affect the internal packing of the aggregates. PMID- 23364451 TI - Endoplasmic reticulum stress plays a key role in the pathogenesis of diabetic peripheral neuropathy. AB - Endoplasmic reticulum stress resulting from abnormal folding of newly synthesized proteins impairs metabolism, transcriptional regulation, and gene expression, and it is a key mechanism of cell injury. Endoplasmic reticulum stress plays an important role in cardiovascular and neurodegenerative diseases, cancer, and diabetes. We evaluated the role for this phenomenon in diabetic peripheral neuropathy. Endoplasmic reticulum stress manifest in upregulation of multiple components of unfolded protein response was identified in neural tissues (sciatic nerve, spinal cord) of streptozotocin diabetic rats and mice. A chemical chaperone, trimethylamine oxide, administered for 12 weeks after induction of diabetes (110 mg.kg-1.d-1, a prevention paradigm) attenuated endoplasmic reticulum stress, peripheral nerve dysfunction, intraepidermal nerve fiber loss, and sciatic nerve and spinal cord oxidative-nitrative stress in streptozotocin diabetic rats. Similar effects on diabetes-induced endoplasmic reticulum stress and peripheral nerve dysfunction were observed with a structurally unrelated chemical chaperone, 4-phenylbutyric acid (100 mg.kg-1.d-1, intraperitoneal). CCAAT/enhancer-binding protein homologous protein (CHOP)(-/-) mice made diabetic with streptozotocin displayed less severe sciatic nerve oxidative-nitrative stress and peripheral neuropathy than the wild-type (C57Bl6/J) mice. Neither chemical chaperones nor CHOP gene deficiency reduced diabetic hyperglycemia. Our findings reveal an important role of endoplasmic reticulum stress in the development of diabetic peripheral neuropathy and identify a potential new therapeutic target. PMID- 23364452 TI - The protective effects of CD39 overexpression in multiple low-dose streptozotocin induced diabetes in mice. AB - Islet allograft survival limits the long-term success of islet transplantation as a potential curative therapy for type 1 diabetes. A number of factors compromise islet survival, including recurrent diabetes. We investigated whether CD39, an ectonucleotidase that promotes the generation of extracellular adenosine, would mitigate diabetes in the T cell-mediated multiple low-dose streptozotocin (MLDS) model. Mice null for CD39 (CD39KO), wild-type mice (WT), and mice overexpressing CD39 (CD39TG) were subjected to MLDS. Adoptive transfer experiments were performed to delineate the efficacy of tissue-restricted overexpression of CD39. The role of adenosine signaling was examined using mutant mice and pharmacological inhibition. The susceptibility to MLDS-induced diabetes was influenced by the level of expression of CD39. CD39KO mice developed diabetes more rapidly and with higher frequency than WT mice. In contrast, CD39TG mice were protected. CD39 overexpression conferred protection through the activation of adenosine 2A receptor and adenosine 2B receptor. Adoptive transfer experiments indicated that tissue-restricted overexpression of CD39 conferred robust protection, suggesting that this may be a useful strategy to protect islet grafts from T cell-mediated injury. PMID- 23364454 TI - Blood pressure and chronic kidney disease progression in a multi-racial cohort: the Multi-Ethnic Study of Atherosclerosis. PMID- 23364455 TI - The charge-flipping algorithm in crystallography. AB - The charge-flipping algorithm (CFA) is a member of the diverse family of dual space iterative phasing algorithms. These algorithms use alternating modifications in direct and reciprocal space to find a solution to the phase problem. The current state-of-the-art CFA is reviewed and it is put in the context of related dual-space algorithms with relevance for crystallography. The CFA has found applications in many crystallographic problems. The principal applications in various fields are described with sections devoted to routine structure solution, the solution of complex structures from powder diffraction data, the solution of incommensurately modulated crystals and quasicrystals, macromolecular crystallography and single-particle imaging. PMID- 23364456 TI - The role of the coordination defect (CD) in the structures of anion-deficient, fluorite-related compounds. AB - The various superstructure phases that occur with the anion-deficient compositions of binary oxides MO(2-x) with the fluorite structure as parent are explored here in terms of the original 'coordination defect' (or CD) concept in which each vacant oxygen site, ?, is 'coordinated' by six O atoms thereby creating the octahedral 'structure-determining' entity [M(3.5)?O(6)]. It emerges that the structure and composition of each anion-deficient (polymorph) phase can be described in terms of crystallographic 'motifs' which comprise sets of parallel coplanar polygons based on 1/2<210>(F) and 1/2<111>(F) CD linkages. PMID- 23364457 TI - Structural transformations in the low-temperature grown GaAs with superlattices of Sb and P delta-layers. AB - The structure of low-temperature grown GaAs with equidistant delta-layers of Sb and P was studied by analysis of the X-ray curves, which was supported by optical absorption measurements and transmission electron microscopy. The simultaneous fitting of the X-ray reflectivity curve and diffraction ones for GaAs (004) and GaAs (115) crystallographic planes provided reliable information about the period of delta-layer superlattice, thickness of the Sb and P delta-layers, and amount of excess As. Variation of these parameters was documented when excess As precipitated into As nanoinclusions upon annealing. The Sb and P delta-layers impact differently on the As precipitation processes in low-temperature grown GaAs. The combination of Sb and P delta-layers appears to be an effective tool for spatial patterning of the nanoinclusion array and prevention of the defect formation under annealing. PMID- 23364453 TI - Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism. AB - Impaired cardiac microvascular function contributes to cardiovascular complications in diabetes. Glucagon-like peptide-1 (GLP-1) exhibits potential cardioprotective properties in addition to its glucose-lowering effect. This study was designed to evaluate the impact of GLP-1 on cardiac microvascular injury in diabetes and the underlying mechanism involved. Experimental diabetes was induced using streptozotocin in rats. Cohorts of diabetic rats received a 12 week treatment of vildagliptin (dipeptidyl peptidase-4 inhibitor) or exenatide (GLP-1 analog). Experimental diabetes attenuated cardiac function, glucose uptake, and microvascular barrier function, which were significantly improved by vildagliptin or exenatide treatment. Cardiac microvascular endothelial cells (CMECs) were isolated and cultured in normal or high glucose medium with or without GLP-1. GLP-1 decreased high-glucose-induced reactive oxygen species production and apoptotic index, as well as the levels of NADPH oxidase such as p47(phox) and gp91(phox). Furthermore, cAMP/PKA (cAMP-dependent protein kinase activity) was increased and Rho-expression was decreased in high-glucose-induced CMECs after GLP-1 treatment. In conclusion, GLP-1 could protect the cardiac microvessels against oxidative stress, apoptosis, and the resultant microvascular barrier dysfunction in diabetes, which may contribute to the improvement of cardiac function and cardiac glucose metabolism in diabetes. The protective effects of GLP-1 are dependent on downstream inhibition of Rho through a cAMP/PKA mediated pathway. PMID- 23364458 TI - Electronic influence of beta-diketonato-type ligands on the coordination of 1,5 cyclooctadiene to palladium(II) as defined by 'Venus fly trap' geometric parameters. AB - A range of single-crystal structures of the type [Pd(cod)(LL'-Bid)]A, where LL' Bid = acetylacetonato (acac), thenoyltrifluoroactetonato (thtfac) and hexafluoroacetylacetonato (hfacac), and A = tetrafluoroborate (BF(4)(-)) and hexafluorophosphate (PF(6)(-)), are reported. The complexes [Pd(cod)(acac)]PF(6) (I), [Pd(cod)(thtfac)]PF(6) (III), [Pd(cod)(thtfac)]BF(4) (IV) and [Pd(cod)(hfacac)]PF(6) (V) are isostructural in the monoclinic space group P2(1)/c. The influence of the variation of the beta-diketonato-type ligands on the coordination geometry of cis,cis-1,5-cycloocta-1,5-diene (cod) was investigated and found that no significant changes to the Pd-C and C=C bond distances were observed. The 'Venus fly trap' parameters vary by 7.8 degrees for the 'jaw' angle (psi), while the 'bite' angle (chi) remains virtually constant. PMID- 23364459 TI - Weak intermolecular hydrogen and halogen interactions in an isomorphous halogen series of pseudoterpyridine Zn(II) complexes. AB - The synthesis and characterization of a series of halogen-substituted pseudoterpyridine Zn(II) homoleptic mononuclear complexes, based on ligands L(11) L(44) [2,6-pyridinedicarboxaldehydebis(p-R-phenylimines), R = F, Cl, Br, I] are reported. Neither of the structures contain relatively strong classical hydrogen bonds (OH...O, NH...O, OH...N, NH...N) and the structure packing is thus determined by a subtle interplay of weaker interactions. Isostructurality of the four halogen analogues is very rare, and in this study -Br, -Cl and -F are found to be isostructural in different degrees, whereas -I is not. Interestingly, although it is closely isostructural to the -Cl and -Br compounds, the F analogue is shown not to form F...O bonds, while the Cl and the Br analogues do form Hal...O bonds. This raises an important question on the role of Hal...O bonds in the structuration of the crystal packing, particularly the stabilization effect. Similarly, while the CH...Hal interaction seems to give one-dimensional cohesion in the -Cl and -Br analogues, this feature is absent in the -F analogue, despite its close isostructurality. CH...O interactions appear to dominate to a first degree the cohesion between the anionic trifluoromethanesulfonate network and the cationic Zn-pyridinedicarboxaldehydebis(p-R-phenylimines) network. The analysis of these interactions is corroborated by reduced density gradient calculations based on promolecular densities. PMID- 23364460 TI - Structural and electronic aspects of hydrogen bonding in two polymorphs of butylene-N,N'-bis(O,O'-diarylphosphoramidate). AB - The bisphosphoramidate (C(6)H(5)O)(2)P(O)NH(CH(2))(4)NHP(O)(OC(6)H(5))(2) crystallizes in two polymorphs, one (ndl) with a needle habit from tetrahydrofuran (THF)/ethanol and another (prm) which forms prisms from H(2)O/ethanol. The molecules in the two forms differ from each other in some torsion angles and the orientation of the diaminobutane bridge, although the differences between the similar bond lengths are not significant for the two polymorphs. The geometry optimizations at the B3LYP/6-31+G* level for isolated molecules show that the two conformers which exist in the crystalline state also represent local gas-phase energy minima. The decrease in the N-H distance from the optimized to the crystal structures has been described in terms of the decrease in electron density (rho) at the bond-critical point (b.c.p.) of the N-H bond path when the molecule participates in hydrogen bonding, comparing the results of atoms-in-molecules (AIM) and natural bond orbital (NBO) analyses for fully optimized structures ndl and prm with their hydrogen-bonded model clusters. PMID- 23364461 TI - Entry point into new trimeric and tetrameric imide-based macrocyclic esters derived from isophthaloyl dichloride and methyl 6-aminonicotinate. AB - The one-step reaction of isophthaloyl dichloride with the 2-aminopyridine derivative (methyl 6-aminonicotinate) yields (i) a trimer-based macrocycle (EsIO)(3) and (ii) a tetramer-based macrocycle (EsIO)(4) in modest isolated synthetic yields (total of 25%), together with (iii) longer open-chain oligomers. The macrocyclization relies on the semi-flexible imide hinge formed by reaction of the 2-amino(pyridine) functional group with two acyl chloride functional groups. The determining factors in macrocycle synthesis are: (a) imide formation using the heteroaromatic ortho-N functionality; (b) the inherent ability of the imide to twist by 85-115 degrees from planarity (as measured by the CO...CO imide torsion angles), thereby providing a hinge for macrocyclic ring closure or potentially (non)helical assembly in oligomer/polymer formation; (c) the conformational flexibility of the isophthaloyl group with meta-related carbonyl groups to twist and adopt either syn or anti conformations, although the syn conformation is observed structurally for all isophthaloyl groups in both (EsIO)(3) (trezimide) and (EsIO)(4) (tennimide) macrocycles. PMID- 23364462 TI - Thermodynamic and structural relationships between the two polymorphs of 1,3 dimethylurea. AB - The title compound exists as polymorph (I), Fdd2 with Z = 8 [Perez-Folch et al. (1997). J. Chem. Cryst. 27, 367-369; Marsh (2004). Acta Cryst. B60, 252-253], and as polymorph (II), P2(1)2(1)2 with Z = 2 [Martins et al. (2009). J. Phys. Chem. A, 113, 5998-6003]. We have redetermined both structures at somewhat lower temperatures [(I) at 180 K rather than room temperature; (II) at 100 K rather than 150 K]. For polymorph (I) the space group Fdd2 is confirmed rather than the original choice of Cc. The molecular structures of both polymorphs are essentially identical, with exact crystallographic twofold symmetry, approximate C(2v) symmetry, and a trans orientation of the H-N-C=O moiety. In both polymorphs the molecules associate into chains of rings with graph set C(4)[R(2)(1)(6)] via bifurcated hydrogen-bond systems C(N-H)(2)...O=C. In the polar structure (I) the chains are necessarily all parallel, whereas in (II) equal numbers of parallel and antiparallel chains are present. Further physical investigations [differential scanning calorimetry (DSC), powder investigations, solvent-induced phase conversions] were undertaken: these showed: (i) that the commercially available compound consists predominantly of polymorph (II), which on heating transforms into polymorph (I) by an endothermic reaction, so that both polymorphs are related by enantiotropism; (ii) that polymorph (I) represents the more stable modification at room temperature, where polymorph (II) is metastable, with the thermodynamic transition temperature lying somewhere between 253 K and room temperature. An apparent third polymorph, consisting of fibrous needles, was shown by powder diffraction to consist of a mixture of polymorphs (I) and (II). PMID- 23364463 TI - A high-pressure polymorph of chlorpropamide formed on hydrostatic compression of the alpha-form in saturated ethanol solution. AB - The crystal structure of the high-pressure polymorph (alpha') of an antidiabetic drug, chlorpropamide [4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, C(10)H(13)ClN(2)O(3)S], which is formed at ~2.8 GPa from the alpha-polymorph (P2(1)2(1)2(1)) on hydrostatic compression in saturated ethanol solution, has been determined. As a result of the phase transition, the a, c and alpha parameters change jumpwise, whereas the changes in b parameter are continuous through the phase transition point. The high-pressure form is monoclinic (P2(1)11) and has Z' equal to 2, the two independent molecules differing in their conformations. The hydrogen bonds expand slightly in the high-pressure polymorph after the transition, and this expansion is interrelated with the changes in molecular conformations enabling a denser packing. The transition is reversible, but the crystal quality deteriorates as a result of multiple compression decompression cycles, and a pseudomerohedral twinning accompanies the transformation. PMID- 23364464 TI - On the shortest B(III)-O bonds. AB - For the crystal structures of oxoborates, the value of ~1.2 A can be regarded as the lower physical limit for B(III)-O bond lengths. The oxoborate crystal structures with B(III)-O bond lengths shorter than ~1.2 A have been found to be either doubtful or clearly erroneous. PMID- 23364465 TI - A dispersive scattering centers-based strategy for dramatically enhancing the photocatalytic efficiency of photocatalysts in liquid-phase photochemical processes: a case of Ag nanosheets. AB - A dispersive scattering centers-based strategy was proposed to enhance the photocatalytic efficiency of photocatalysts in liquid-phase photochemical processes. Photocatalytic efficiencies of the photocatalyst, Degussa P25, in water splitting and photodegradation were markedly enhanced by using Ag nanosheets as dispersive scattering centers. PMID- 23364467 TI - 1,3,5-Trisubstituted benzenes as fluorescent photoaffinity probes for human carbonic anhydrase II capture. AB - The synthesis of small molecule based 1,3,5-trisubstituted benzenes for photo mediated capture of human carbonic anhydrase II with visualisation by fluorescence is described. PMID- 23364466 TI - Loss-of-function ferrochelatase and gain-of-function erythroid-specific 5 aminolevulinate synthase mutations causing erythropoietic protoporphyria and x linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria. AB - Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inborn errors of heme biosynthesis with the same phenotype but resulting from autosomal recessive loss-of-function mutations in the ferrochelatase (FECH) gene and gain of-function mutations in the X-linked erythroid-specific 5-aminolevulinate synthase (ALAS2) gene, respectively. The EPP phenotype is characterized by acute, painful, cutaneous photosensitivity and elevated erythrocyte protoporphyrin levels. We report the FECH and ALAS2 mutations in 155 unrelated North American patients with the EPP phenotype. FECH sequencing and dosage analyses identified 140 patients with EPP: 134 with one loss-of-function allele and the common IVS3 48T>C low expression allele, three with two loss-of-function mutations and three with one loss-of-function mutation and two low expression alleles. There were 48 previously reported and 23 novel FECH mutations. The remaining 15 probands had ALAS2 gain-of-function mutations causing XLP: 13 with the previously reported deletion, c.1706_1709delAGTG, and two with novel mutations, c.1734delG and c.1642C>T(p.Q548X). Notably, XLP represented ~10% of EPP phenotype patients in North America, two to five times more than in Western Europe. XLP males had twofold higher erythrocyte protoporphyrin levels than EPP patients, predisposing to more severe photosensitivity and liver disease. Identification of XLP patients permits accurate diagnosis and counseling of at-risk relatives and asymptomatic heterozygotes. PMID- 23364468 TI - Swinging heart in acute pancreatitis. AB - Pleural effusions and ascites are not uncommon in acute pancreatitis; however, pericardial effusions complicated by cardiac tamponade are extremely rare and definite treatment has yet to be established. This case report illustrates the findings in a 57-year-old patient, who was diagnosed of an acute alcoholic pancreatitis. The clinical course was complicated by recurrent episodes of acute pancreatitis, and eventually, the patient developed acute circulatory failure that was caused by cardiac tamponade. The patient was successfully treated by an emergency pericardiocentesis; however, although the patient was treated with intrapericardial triamcinolone and octreotide, pericardial effusion reoccurred. Eventually, a pancreaticopericardial fistula was diagnosed by endoscopic retrograde cholangiopancreaticography, and after successful stent placement in a disrupted pancreatic duct, the clinical recovery was uneventful. To the best of the authors' knowledge, this is the first case of a successful endoscopic treatment of a pancreaticopericardial fistula complicated by cardiac tamponade in a patient with acute pancreatitis. PMID- 23364470 TI - Cadence, energy expenditure, and gait symmetry during music-prompted and self regulated walking in adults with unilateral transtibial amputation. AB - BACKGROUND: Walking cadence has shown promise for estimating walking intensity in healthy adults. Auditory cues have been shown to improve gait symmetry in populations with movement disorders. We investigated the walking cadence-energy expenditure relationship in unilateral transtibial amputees (TTAs), and the potential of music cues for regulating walking cadence and improving gait symmetry. METHODS: Seventeen unilateral TTAs performed 2 5-min treadmill walking trials, followed by 2 5-min overground walking trials (self-regulated "brisk" intensity, and while attempting to match a moderate-tempo digital music cue). RESULTS: Walking cadence significantly (P < .001) and accurately (R(2) = .55, SEE = 0.50 METs) predicted energy expenditure, and a cadence of 86 steps.min(-1) was equivalent to a 3-MET intensity. Although most participants were able to match cadence to prescribed music tempo, gait symmetry was not improved during the music-guided condition, compared with the self-regulated condition. CONCLUSIONS: This is the first study to investigate the utility of walking cadence for monitoring and regulating walking intensity in adults with lower limb prosthesis. Cadence has similar or superior accuracy as an indicator of walking intensity in this population, compared with the general population, and adults with a unilateral TTA are capable of walking at moderate intensity and above for meaningful bouts of time. PMID- 23364469 TI - Spinal cord neurosarcoidosis. AB - BACKGROUND: Spinal cord neurosarcoidosis (SN) is problematic to diagnose because it mimics other inflammatory neurologic diseases. The authors report the clinical features of 29 SN cases. METHODS: They retrospectively reviewed the medical records of 29 histologically proven sarcoidosis patients with spinal cord involvement seen at 3 university medical centers. They collected clinical data including laboratory and radiological findings. Clinical outcomes were assessed retrospectively using the modified Rankin scale. RESULTS: The cohort included high number of African Americans (16/29, 55%). The lung and intrathoracic lymph nodes were the most common confirmatory biopsy sites (18/29, 62%), whereas the spinal cord was a relatively uncommon one (4/29, 14%). The most common presenting symptoms were lower extremity weakness and paresthesias. Thoracic segment was most frequently involved (21/27, 78%). Lesions were mostly intramedullary (22/27, 81%), although nearly half involved the leptomeninges (13/27, 48%). The average size of a lesion spanned 3.9 spine segments (range, 1-9); 17 of 22 (77%) intramedullary patients had >=3 spine segments involved. Angiotensin-converting enzyme levels in cerebrospinal fluid were elevated in only 2 of 11 (18%) patients. All patients received glucocorticosteroids. Additional immune modulating agents were used in 24 of 29 (83%) patients. Scores on the modified Rankin scale at the final follow-up visit were improved. CONCLUSIONS: Most SN cases were diagnosed indirectly based on extraneural tissue biopsy. Extended spinal cord lesion (>=3 spine segments) may be useful to distinguish SN from multiple sclerosis. Cerebrospinal fluid analysis was of limited value. Most patients experienced clinical improvement with immunosuppressive treatment, but many required combination therapy. PMID- 23364471 TI - Effects of imidazoline and non-imidazoline alpha-adrenergic agents on rabbit platelet aggregation. AB - BACKGROUND/AIMS: Imidazoline alpha2-adrenergic agents exert complex effects on mammalian platelet aggregation. Although non-adrenergic, imidazoline (I) receptors have been revealed in human platelets, there is limited information about imidazoline's action on platelet aggregation. This study aimed to investigate aggregatory and anti-aggregatory effects of various imidazoline or non-imidazoline alpha-adrenergic agents on rabbit platelets. METHODS: Aggregatory responses of agents on rabbit platelets were examined by turbidimetric method. Radioligand binding assay to platelet I1 and I2 receptors was performed using [(3)H]-clonidine and [(3)H]-idazoxan, respectively. RESULTS: Aggregation was not induced by alpha-adrenoceptor agonists alone. Adrenaline and noradrenaline produced dose-dependent potentiation of ADP- or collagen-induced aggregation. Imidazoline adrenoceptor agonists clonidine and p-aminoclonidine also potentiated ADP-induced platelet aggregation. The alpha2-adrenoceptor antagonists and/or certain imidazoline adrenergic agents inhibited adrenaline-potentiated aggregation in a dose-dependent manner, whereas alpha1-adrenoceptor antagonists and non-imidazoline alpha-adrenergic agents were either ineffective or less effective in inhibiting adrenaline-potentiated aggregation. Rabbit platelets did not have I1 receptors, but had I2 receptors, indicating that adrenaline potentiated platelet aggregation was inhibited by idazoxan, but not by imidazoline compounds clonidine and oxymetazoline. CONCLUSIONS/IMPLICATIONS: These results demonstrated that alpha2-adrenoceptor-blocking agents and/or imidazoline alpha-adrenergic agents effectively inhibit adrenaline-potentiated platelet aggregation. It is proposed that imidazoline structure in part plays a role in the inhibition of adrenaline-potentiated aggregation. PMID- 23364472 TI - 17DD yellow fever vaccine: a double blind, randomized clinical trial of immunogenicity and safety on a dose-response study. AB - OBJECTIVE: To verify if the Bio-Manguinhos 17DD yellow fever vaccine (17DD-YFV) used in lower doses is as immunogenic and safe as the current formulation. RESULTS: Doses from 27,476 IU to 587 IU induced similar seroconversion rates and neutralizing antibodies geometric mean titers (GMTs). Immunity of those who seroconverted to YF was maintained for 10 mo. Reactogenicity was low for all groups. METHODS: Young and healthy adult males (n = 900) were recruited and randomized into 6 groups, to receive de-escalating doses of 17DD-YFV, from 27,476 IU to 31 IU. Blood samples were collected before vaccination (for neutralization tests to yellow fever, serology for dengue and clinical chemistry), 3 to 7 d after vaccination (for viremia and clinical chemistry) and 30 d after vaccination (for new yellow fever serology and clinical chemistry). Adverse events diaries were filled out by volunteers during 10 d after vaccination. Volunteers were retested for yellow fever and dengue antibodies 10 mo later. Seropositivity for dengue was found in 87.6% of volunteers before vaccination, but this had no significant influence on conclusions. CONCLUSION: In young healthy adults Bio Manguinhos/Fiocruz yellow fever vaccine can be used in much lower doses than usual. INTERNATIONAL REGISTER: ISRCTN 38082350. PMID- 23364473 TI - Mechanochemical reactions and syntheses of oxides. AB - Technological and scientific challenges coupled with environmental considerations have prompted a search for simple and energy-efficient syntheses and processing routes of materials. This tutorial review provides an overview of recent research efforts in non-conventional reactions and syntheses of oxides induced by mechanical action. It starts with a brief account of the history of mechanochemistry. Ensuing discussions will review the progress in homogeneous and heterogeneous mechanochemical reactions in oxides of various structures. The review demonstrates that the event of mechanically induced reactions provides novel opportunities for the non-thermal manipulation of materials and for the tailoring of their properties. PMID- 23364474 TI - An olefin isomerization/asymmetric Pictet-Spengler cascade via sequential catalysis of ruthenium alkylidene and chiral phosphoric acid. AB - Chiral phosphoric acid works together with Hoveyda-Grubbs II catalyst enabling highly efficient synthesis of enantioenriched tetrahydro-beta-carboline (up to 95% yield, 90% ee) through an olefin isomerization/Pictet-Spengler cascade reaction via sequential catalysis. PMID- 23364476 TI - Exome sequencing identifies SLC24A5 as a candidate gene for nonsyndromic oculocutaneous albinism. AB - Oculocutaneous albinism (OCA) is a heterogeneous and autosomal recessive disorder with hypopigmentation in the eye, hair, and skin color. Four genes, TYR, OCA2, TYRP1, and SLC45A2, have been identified as causative genes for nonsyndromic OCA1 4, respectively. The genetic identity of OCA5 locus on 4q24 is unknown. Additional unknown OCA genes may exist as at least 5% of OCA patients have not been characterized during mutational screening in several populations. We used exome sequencing with a family-based recessive mutation model to determine that SLC24A5 is a previously unreported candidate gene for nonsyndromic OCA, which we designate as OCA6. Two deleterious mutations in this patient, c.591G>A and c.1361insT, were identified. We found apparent increase of immature melanosomes and less mature melanosomes in the patient's skin melanocytes. However, no defects in the platelet dense granules were observed, excluding typical Hermansky Pudlak syndrome (HPS), a well-known syndromic OCA. Moreover, the SLC24A5 protein was reduced in steady-state levels in mouse HPS mutants with deficiencies in BLOC 1 and BLOC-2. Our results suggest that SLC24A5 is a previously unreported nonsyndromic OCA candidate gene and that the SLC24A5 transporter is transported into mature melanosomes by HPS protein complexes. PMID- 23364475 TI - Pharmacokinetic profile and safety of 150 mg of maraviroc dosed with 800/100 mg of darunavir/ritonavir all once daily, with and without nucleoside analogues, in HIV-infected subjects. AB - BACKGROUND: Once-daily nucleoside-sparing combination antiretroviral therapy regimens are attractive options for the treatment of HIV infection. However, the pharmacokinetic profiles of such regimens are often not established. METHODS: HIV infected subjects receiving 245/200 mg of tenofovir/emtricitabine plus 800/100 mg of darunavir/ritonavir once daily with plasma HIV RNA <50 copies/mL were eligible. On day 1 (period 1), 150 mg of maraviroc daily was added and on day 11 (period 2), tenofovir/emtricitabine discontinued. At steady-state (days 10 and 20), intensive pharmacokinetic sampling was undertaken. We assessed (i) the number of subjects with trough (C(trough)) and average (C(avg)) maraviroc concentrations <25 and <75 ng/mL, respectively; (ii) geometric mean (GM) ratios for pharmacokinetic parameters for period 2 versus period 1; and (iii) factors associated with total maraviroc exposure. RESULTS: Eleven subjects completed the study procedures (mean age 49 years; range 35-59 years). In three subjects, maraviroc C(trough) and C(avg) were <25 and <75 ng/mL, respectively (C(avg), 68 ng/mL and C(trough), 14 and 21 ng/mL). Although not statistically significant, a trend was observed towards lower maraviroc, darunavir and ritonavir concentrations in period 2 versus period 1; total maraviroc exposure was 3579 ng. h/mL (95% CI: 2983-4294) and 2996 ng. h/mL (95% CI: 2374-3782) in periods 1 and 2, respectively, and the GM ratio was 0.84 (95% CI: 0.67-1.05). Only total ritonavir exposure was significantly associated with total maraviroc exposure (P=0.049; 95% CI: 0.01-0.91). No clinical safety concerns were observed. CONCLUSIONS: Within this novel nucleoside-sparing regimen, maraviroc exposure is dependent on ritonavir exposure, which was slightly reduced in the absence of tenofovir/emtricitabine. PMID- 23364477 TI - Targeted disruption of glutathione peroxidase 4 in mouse skin epithelial cells impairs postnatal hair follicle morphogenesis that is partially rescued through inhibition of COX-2. AB - Selenoproteins are essential molecules for the mammalian antioxidant network. We previously demonstrated that targeted loss of all selenoproteins in mouse epidermis disrupted skin and hair development, and caused premature death. In the current study, we targeted specific selenoproteins for epidermal deletion to determine whether similar phenotypes developed. Keratinocyte-specific knockout mice lacking either the glutathione peroxidase 4 (GPx4) or thioredoxin reductase 1 (TR1) gene were generated by cre-lox technology using K14-cre. TR1 knockout mice had a normal phenotype in resting skin, whereas GPx4 loss in the epidermis caused epidermal hyperplasia, dermal inflammatory infiltrate, dysmorphic hair follicles, and alopecia in perinatal mice. Unlike epidermal ablation of all selenoproteins, mice ablated for GPx4 recovered after 5 weeks and had a normal life span. GPx1 and TR1 were upregulated in the skin and keratinocytes of GPx4 knockout mice. GPx4 deletion reduces keratinocyte adhesion in culture and increases lipid peroxidation and cyclooxygenase-2 (COX-2) levels in cultured keratinocytes and whole skin. Feeding a COX-2 inhibitor to nursing mothers partially prevents development of the abnormal skin phenotype in knockout pups. These data link the activity of cutaneous GPx4 to the regulation of COX-2 and hair follicle morphogenesis, and provide insight into the function of individual selenoprotein activity in maintaining cutaneous homeostasis. PMID- 23364478 TI - Adrenomedullin haploinsufficiency predisposes to secondary lymphedema. AB - Secondary lymphedema is a debilitating condition, and genetic factors predisposing to its development remain largely unknown. Adrenomedullin (AM) is peptide encoded, together with proadrenomedullin N-terminal peptide (PAMP), by the Adm gene (adrenomedullin gene). AM and its putative receptor calcitonin receptor-like receptor (CLR) are implicated in angiogenesis and lymphangiogenesis during embryogenesis and wound healing, suggesting their possible involvement in secondary lymphedema. To investigate whether AM deficiency predisposes to secondary lymphedema, we used heterozygous adult mice with Adm gene-knockin stop mutation, which selectively abrogated AM, but preserved PAMP, expression (Adm(AM+/Delta) animals). After hind limb skin incision, Adm messenger RNA expression was upregulated in wounded tissue of both Adm(AM+/+) and Adm(AM+/Delta) mice. However, only Adm(AM+/Delta) animals developed limb swelling and histopathological lymphedematous changes, including epidermal thickening, elevated collagen fiber density, and increased microvessel diameter. Secondary lymphedema was prevented when circulating AM levels in Adm(AM+/Delta) mice were restored by systemic peptide delivery. In human skin, CLR was expressed in tissue components affected by lymphedema, including epidermis, lymphatics, and blood vessels. Our study identified a previously unrecognized role for endogenous AM as a key factor in secondary lymphedema pathogenesis and provided experimental in vivo evidence of an underlying germ-line genetic predisposition to developing this disorder. PMID- 23364480 TI - Exercise training in solid organ transplant recipients: a systematic review and meta-analysis. AB - BACKGROUND: Exercise training is effective in improving the cardiovascular risk profiles of nontransplanted patients, but the health benefits and potential harms of routine exercise training after solid organ transplantation are unclear. This study aims to assess the health benefits and harms of supervised exercise training programs in solid organ recipients. METHODS: We systematically reviewed all randomized controlled trials (RCTs) comparing the outcomes of exercise training programs in solid organ recipients against standard care. MEDLINE, EMBASE, the Transplant Library from the Centre for Evidence in Transplantation, and the Cochrane Central Register of Controlled Trials were searched to June 2012. RESULTS: In total, 15 eligible RCTs involving 643 patients (9 cardiac transplants [n=250 patients], 2 kidney transplants [n=164 patients], 3 lung transplants [n=110 patients], and 1 liver transplant [n=119 patients]) were included. Cardiac transplant recipients who engaged in an exercise program after transplantation showed significant improvement in maximal oxygen uptake (standardized mean difference, 0.77; 95% confidence interval, 0.10-1.45) but no improvement in the overall serum lipid profile, blood pressure, and glycemic control compared with standard care. Among other solid organ transplant recipients, no significant improvements in exercise capacity or cardiovascular risk factors such as incidence of new-onset diabetes after transplantation were observed, but all effect estimates were very imprecise. CONCLUSIONS: Exercise training is a promising but unproven intervention for improving the cardiovascular outcomes of solid organ transplant recipients. Existing trials are small, of relatively short duration, and focused on surrogate outcomes. Large scale RCTs are urgently required if resources are to be directed toward exercise programs. PMID- 23364479 TI - The hematopoietic stem cell regulatory gene latexin has tumor-suppressive properties in malignant melanoma. AB - Despite recent advancements in therapy, melanoma remains a highly lethal skin cancer. A better understanding of the genetic and epigenetic changes responsible for melanoma formation and progression could result in the development of more effective treatments. Advanced melanomas are known to exhibit widespread promoter region CpG island methylation leading to the inactivation of key tumor suppressor genes. Meta-analyses of relevant microarray data sets revealed the hematopoietic stem cell regulator gene latexin (LXN) to be commonly downregulated in approximately 50% of melanomas. The CpG island in the promoter region of LXN was almost universally hypermethylated in melanoma cell lines and tumors, and treatment of the cell lines with the demethylating drug 5-aza-2'-deoxycytidine resulted in increased LXN expression. In this paper, we demonstrate that the exogenous expression of LXN in melanoma cell lines results in a significant inhibition of tumor cell proliferation. In addition, we show that the increased expression of LXN in these lines correlates with reduction in the expression levels of stem cell transcription factors OCT4, NANOG, SOX2, KLF4, and MYCN, indicating that LXN may exert its tumor-suppressive function by altering the stem cell-like properties of melanoma cells. PMID- 23364481 TI - Endothelial dysfunction is associated with graft loss in renal transplant recipients. AB - BACKGROUND: Endothelial dysfunction is prevalent in renal transplant recipients, but it is uncertain if there is an association with graft loss or mortality. METHODS: Since 1997, we have measured endothelial function noninvasively by forearm laser Doppler flowmetry in several small trials. These tests were pooled for the current analysis. We used Cox proportional hazard models to adjust for patient and graft characteristics. Due to significant heterogeneity between tests conducted before or after day 90 after transplantation, these were examined separately. RESULTS: In the 175 patients examined after day 90 after transplantation, an endothelial function score below the median predicted graft loss (hazard ratio [HR], 1.85 [1.09-3.16]; P=0.02) and death-censored graft loss (HR, 2.63 [1.18-5.84]; P=0.02) but not all-cause mortality (HR, 1.20 [0.62-2.30]; P=0.58). In 140 patients examined before day 90 after transplantation, no association was found. CONCLUSION: Endothelial dysfunction identified more than 90 days after transplantation was associated with renal graft loss. PMID- 23364482 TI - Effect of cytomegalovirus immunoglobulin on the incidence of lymphoproliferative disease after lung transplantation: single-center experience with 1157 patients. AB - BACKGROUND: Posttransplantation lymphoproliferative disorder (PTLD), a complication of lung transplantation with an incidence ranging from as much as 20%, is mainly associated with Epstein-Barr virus (EBV) infection. In renal transplantation, the use of immunoglobulin (Ig) cytomegalovirus (CMV) prophylaxis, which contains anti-EBV antibodies, resulted in a significant lower incidence of PTLD. In this study, we report our experience with PTLD in lung transplantation with CMV Ig prophylaxis. METHODS: One-thousand one-hundred fifty seven consecutive patients who underwent lung transplantation at the Medical University of Vienna between November 1989 and December 2011 were included in this retrospective analysis on PTLD. CMV prophylaxis consisted in all patients of antiviral drugs (ganciclovir/valganciclovir) combined with anti-CMV Ig for 4 weeks. RESULTS: A total of 18 patients (1.5%) developed PTLD of B cell origin. Fifteen patients were diagnosed in the first posttransplantation year, and three patients, beyond 1 year. One- and three-year survival after diagnosis of PTLD was 50% and 38%, respectively. CONCLUSION: The incidence of PTLD in our center is extremely low when compared with the scientific literature. We hypothesize that CMV Ig prophylaxis also protects from EBV-associated PTLD. PMID- 23364483 TI - CYP3A and ABCB1 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of tacrolimus and its metabolites (M-I and M-III). AB - BACKGROUND: We prospectively studied renal transplant recipients receiving tacrolimus to determine the relationship between the CYP3A4, CYP3A5, and ABCB1 genetic polymorphisms and the pharmacokinetics (PK) and pharmacodynamics (PD) of tacrolimus and its metabolites. METHODS: Renal transplant recipients receiving tacrolimus were genotyped for CYP3A4*4, CYP3A4*5, CYP3A4*18, CYP3A5*3, ABCB1 c.1236C->T, ABCB1 c.2677G->A/T, and ABCB1 c.3435C->T. Dose-adjusted trough concentration (C0) of tacrolimus and its metabolites (M-I and M-III) and PK and PD (T-cell and monocyte subsets) were determined on transplantation days -2, 5, 30, and 90 and correlated with the corresponding genotypes. RESULTS: The dose adjusted C0 of tacrolimus and its metabolites and AUC0-12 were significantly higher and the mean fluorescence intensity (MFI) of HLA/DR in monocytes was significantly lower in patients with CYP3A5*3/*3 than in patients with CYP3A5*1/*1 or CYP3A5*1/*3. However, there was no significant difference in the dose-adjusted C0 of tacrolimus and its metabolites, PK and PD among the ABCB1 genotypes. The MFI of HLA/DR in monocytes showed a significant negative correlation with dose-adjusted C0 of tacrolimus and its metabolites and AUC0-12. In a multiple regression analysis, the presence of the CYP3A5*3/*3 genotype was a significant independent variable determining the dose-adjusted C0 of tacrolimus and its metabolites, AUC0-12, and the MFI of HLA/DR in monocytes. CONCLUSIONS: This study demonstrates that the CYP3A5 genetic polymorphisms are associated with the individual differences in PK and PD as well as in C0 of tacrolimus and its metabolites. The MFI of HLA/DR in monocytes might be considered to be a significant tool for monitoring tacrolimus efficacy. PMID- 23364484 TI - Combined heart and liver transplant attenuates cardiac allograft vasculopathy compared with isolated heart transplantation. AB - BACKGROUND: We evaluated whether combined heart and liver transplant (H+LTx) can protect the heart graft from the development of cardiac allograft vasculopathy using coronary three-dimensional (3D) volumetric intravascular ultrasound (IVUS). METHODS: From 2004 to 2009, we identified 24 isolated heart transplant (HTx) and 10 H+LTx recipients in whom two coronary 3D IVUS studies were performed 1 year apart. Baseline 3D IVUS was performed at 0.22 (0.17-1.16) years after transplantation, with follow-up 3D IVUS exams performed after baseline exam (0.96 [0.83-1.08]). RESULTS: Rate of plaque volume and plaque index (plaque volume/vessel volume) progression was attenuated in the H+LTx group (0.3+/-1.1 vs. 1.5+/-2.9 mm/mm; P=0.08 and 0.01+/-0.03 vs. 0.1+/-0.1; P=0.004, respectively). Rejection burden was much lower in the H+LTx patients. Outcome analysis in 66 consecutive patients (56 HTx and 10 H+LTx) was performed irrespective of performance of second coronary IVUS. H+LTx was associated with reduced rate of cardiac events (P=0.04), which remained significant when adjusted for the difference in the primary etiology for heart disease (P=0.05). CONCLUSIONS: Our preliminary serial 3D coronary IVUS data show that H+LTx attenuates cardiac allograft vasculopathy by decreasing the rate of plaque volume and plaque index progression and improves coronary-related outcomes. Because of the small numbers and the differences in etiology of heart disease, our data should be interpreted cautiously, and larger clinical trials would be required to recommend H+LTx for improved coronary remodeling. PMID- 23364485 TI - Insulin-Like growth factor-II (IGF-II) prevents proinflammatory cytokine-induced apoptosis and significantly improves islet survival after transplantation. AB - BACKGROUND: The early loss of functional islet mass (50-70%) due to apoptosis after clinical transplantation contributes to islet allograft failure. Insulin like growth factor (IGF)-II is an antiapoptotic protein that is highly expressed in beta-cells during development but rapidly decreases in postnatal life. METHODS: We used an adenoviral (Ad) vector to overexpress IGF-II in isolated rat islets and investigated its antiapoptotic action against exogenous cytokines interleukin-1beta- and interferon-gamma-induced islet cell death in vitro. Using an immunocompromised marginal mass islet transplant model, the ability of Ad-IGF II-transduced rat islets to restore euglycemia in nonobese diabetic/severe combined immunodeficient diabetic recipients was assessed. RESULTS: Ad-IGF-II transduction did not affect islet viability or function. Ad-IGF-II cytokine treated islets exhibited decreased cell death (40% +/- 2.8%) versus Ad-GFP and untransduced control islets (63.2% +/- 2.5% and 53.6% +/- 2.3%, respectively). Ad IGF-II overexpression during cytokine treatment resulted in a marked reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells (8.3% +/- 1.4%) versus Ad-GFP control (41% +/- 4.2%) and untransduced control islets (46.5% +/- 6.2%). Western blot analysis confirmed that IGF-II inhibits apoptosis via activation of the phosphatidylinositol 3 kinase/Akt signaling pathway. Transplantation of IGF-II overexpressing islets under the kidney capsule of diabetic mice restored euglycemia in 77.8% of recipients compared with 18.2% and 47.5% of Ad-GFP and untransduced control islet recipients, respectively (P<0.05, log-rank [Mantel-Cox] test). CONCLUSIONS: Antiapoptotic IGF-II decreases apoptosis in vitro and significantly improved islet transplant outcomes in vivo. Antiapoptotic gene transfer is a potentially powerful tool to improve islet survival after transplantation. PMID- 23364486 TI - The influence of renal function on vitamin D metabolism in the very elderly. AB - OBJECTIVES: Hypovitaminosis D and chronic kidney disease (CKD) are highly prevalent in older adults. The factors correlating with 25-OH-vitamin D and PTH levels were analyzed in older adults with and without CKD. DESIGN: We performed a cross-sectional analysis embedded within the BELFRAIL study. SETTING: A population-based prospective cohort study of the very elderly in Belgium. PARTICIPANTS: 325 participants, all aged 80 or older. MEASURMENTS: Time of year and LAPAQ score were used as proxies for sunshine exposure. Vitamin D3 supplementation, gender, institutionalisation, age, level of education, and serum calcium and phosphorus level were examined as possible confounders in the analyses. RESULTS: There was no correlation between the presence of CKD and low 25-OH-vitamin D levels, but there was a significant (p<0.01) correlation between CKD and high PTH levels. Among the participants with a normal eGFR, the LAPACQ score, vitamin D supplementation, season, log PTH value and eGFR were correlated with log 25-OH-vitamin D levels. Among the participants with CKD, only vitamin D supplementation, log PTH levels and serum calcium levels were correlated with log 25-OH-vitamin D levels. Gender, log 25-OH-vitamin D values, serum calcium and phosphorus levels and eGFR were correlated with log PTH values in the patients with normal eGFR. Log 25-OH-vitamin D values, serum phosphorus levels, vitamin D supplementation (p=0.07), season (p=0.10) and eGFR were correlated with log PTH values in the patients with CKD. CONCLUSION: Exposure to sunshine and an active lifestyle were correlated with higher 25-OH-vitamin D levels in older adults without CKD. The PTH level in patients with CKD may be influenced by the season. PMID- 23364487 TI - Under-reporting of energy intake in elderly Australian women is associated with a higher body mass index. AB - OBJECTIVES: Identify the extent of under-reporting of energy intake and the characteristics associated with implausible intakes in elderly women. DESIGN: Dietary intake was assessed using a 3-day weighed food record. Protein intake was validated by 24-hour urinary nitrogen. To examine under-reporting, participants were grouped according to their energy intake and compared to the Goldberg cut off equation. Logistic regression was performed to assess the influence of body mass index (BMI) and social-demographic factors on under-reporting. SETTING: Community dwelling elderly women from Perth, Western Australia. PARTICIPANTS: 217 elderly women aged 70-80 years. RESULTS: Under-reporters had a higher physical activity level (p<0.001) compared with acceptable-reporters. The under-reporters also had a higher body weight (p=0.006), body mass index (BMI) (p=0.001), waist (p=0.011), hip circumference (p<0.001), whole body fat mass (p<0.001) and percentage body fat (p<0.001) than acceptable-reporters. Under-reporters had a significantly lower intakes of protein, fat, carbohydrate and alcohol (p<0.001) and fewer reported food items, compared with acceptable reporters. However, 24 hour urinary nitrogen was only marginally different between the two groups (p=0.053). Participants with a higher BMI were more likely to under-report their energy intake (BMI=25-29.9: odds ratio=2.98[95% CI=1.46-6.09]; BMI>=30: 5.84[2.41 14.14]). CONCLUSION: Under-reporting energy intake in elderly women was associated with a higher BMI, body fat and higher self-reported physical activity levels. A higher BMI (>=25) appears to be most significant factor in determining if elderly women will underreport their food intake and may be related to body image. These results have implications for undertaking surveys of food intake in elderly women. PMID- 23364488 TI - Dietary vitamin D intake and muscle mass in older women. Results from a cross sectional analysis of the EPIDOS study. AB - OBJECTIVES: Vitamin D intake may prevent physical performance decline through prevention of muscle mass loss. Our objective was to determine whether low dietary intakes were associated with low muscle mass (MM). DESIGN AND PARTICIPANTS: Cross-sectional analysis of 1989 community-dwelling women (mean age 80.5+/-3.8years) from the EPIDemiologie de l'OSteoporose (EPIDOS) study were assessed at baseline. MEASUREMENTS: Low intakes of vitamin D (<70ug/week) were estimated from the weekly dietary vitamin D intakes (self-administered food frequency questionnaire). Low MM was defined according to the appendicular skeletal muscle mass index assessed using Dual Energy X-ray Absorptiometry, divided by square height of less than 5.45 kg/m2. Usual gait speed defined physical performance. Age, sun exposure, co-morbidities, education level, living arrangements, recreational physical activity, dietary protein and calcium intakes, bone mineral density, handgrip strength, and body mass index were considered as potential confounders. Multivariate logistic regression analyses assessed the association between low vitamin D intakes and low MM. RESULTS: Two hundred and nine (10.5%) women with low MM were compared to 1,780 women with normal MM. In final model, obesity/overweight (Adjusted Odds Ratios, aOR=0.09; 95%CI [0.05-0.17]), malnutrition (aOR=3.90; 95%CI [2.74-5.54]) and low handgrip strength (aOR=2.33; 95%CI [1.44-3.77]; p<0.001) were statistically associated with a low MM status. CONCLUSION: No association with low MM has been reported regarding low dietary intakes of vitamin D. PMID- 23364490 TI - Food preferences of middle aged and elderly subjects in a Brazilian city. AB - OBJECTIVES: The objectives of this study were to assess data on the consumption frequency of some food items and the places they are purchased, especially by adults and elderly subjects, and finally to determine their food preference using cluster and correspondence analyses as a diagnosis and prevention factor. DESIGN: Cross-sectional study. SETTING: Town of Serranopolis do Iguacu, State of Parana, Brazil, city with 4,854 inhabitants of which 22% are over 50 years old. PARTICIPANTS: Two hundred and ninety five randomly selected subjects (96 men and 199 women), between 51 and 91 years old. MEASUREMENTS: A socio-demographic and food frequency questionnaire was applied via home visits including questions on socioeconomic, anthopometric and health characteristics concerning the consumption frequency of 45 food items and the places they were purchased, using a five point category scale to obtain consumption data as well. The body mass index (BMI) was calculated using the Quetelet Index and compared with the World Health Organization Report Consultation on obesity. The cluster and correspondence statistical analysis were used to determine their food preference. RESULTS: From the correspondence mapping (which explained 89.1 % of the variance), it was possible to determine aspects regarding the non-consumption of instant soups, frozen vegetables, cookies, crystallized fruits, canned fruit, distilled drinks and beer. CONCLUSIONS: The dimensional representation structure demonstrated that the population of Serranopolis, who were 62 % overweight, preferred high fat content products, suggesting a reevaluation of their eating habits in the expectation of preventing non transmissible chronic diseases. The value given to farm production in Serranopolis do Iguacu was also observed. PMID- 23364489 TI - Older Australians' perceptions and practices in relation to a healthy diet for old age: a qualitative study. AB - OBJECTIVE: To explore older independently-living Australians' perceptions and practices about what constitutes a healthy diet for older people. DESIGN: Qualitative methodology, focus groups. SETTING: Independently-living retirees in Northern NSW, Australia. PARTICIPANTS: A total of 29 participants in five focus groups, ranging in age from 60-93 years, with a mean age of 73.3 +/- 8.8years; the majority (79%) were women. RESULTS: Thematic analysis of the focus group interviews revealed four themes that best represent older people's perceptions and practices in relation to healthy eating for old age. These included: 1) healthy foods - participants believed in a hierarchy of perceived healthfulness or importance of foods; 2) quantity - participants believed that ageing was associated with a reduced dietary intake and less need for meat; 3) personal circumstances - participants acknowledged that food costs, social situations and health conditions influenced their food choices; and 4) good intention - participants acknowledged that the desire to regain or maintain wellbeing and to preserve health positively influenced their food choices. Participants were unaware of the national nutrient targets for older Australians. CONCLUSION: The trend towards reduced dietary intake of meat and the indifference to dairy products expressed by many participants in this study suggests that they are at risk of not achieving the requirements for protein and calcium in particular. Failure to meet these age-adjusted nutrient targets has important implications for the health and functional capacity of older people. PMID- 23364491 TI - Multidisciplinary team meetings (MDTM) in detection of Alzheimer's disease: data from the IDEM study. AB - INTRODUCTION: The National Institute for Health and Clinical Excellence (NICE) in the United Kingdom, the Institut fur Qualitat und Wirtschaftlichkeit im Gesundheitswesen (IQWIG) in Germany and the Haute Autorite de Sante (HAS) in France have recently set out guidelines on prescription of anti-dementia medication. The HAS proposes in particular that continuation of these drugs for longer than one year should be decided in multidisciplinary team meetings (MDTM). OBJECTIVE: To assess the feasibility of MDTM and the satisfaction of coordinating physicians from institutions for the dependent elderly (nursing home, NH) and expert physicians from memory clinics who have participated in the meetings. METHODS: Survey carried out among physicians who had participated in the MDTM held as part of the IDEM study (Interest of systematic tracking of dementia cases in NH: analysing the contribution of MDTM in Alzheimer's disease and related diseases; PHRC National 2009, Code 0910701). The survey evaluated the organization of MDTM and the physicians' opinion of these meetings. RESULTS: The cases of 574 patients were discussed in MDTM involving 133 healthcare professionals (32 coordinating physicians, 48 expert physicians, 4 general practitioners and 49 other health professionals). The mean number of participants was 4.2+/-1.6. About 16 minutes were spent discussing the case of each resident. About 90% of physicians considered that the meetings were useful. Overall assessment of their efficacy was 11.5/20 for the coordinating physicians and 14.1/20 for the expert physicians. The benefits of MDTM in relation to the work entailed were considered important by 60% of expert physicians and 33% of coordinating physicians. CONCLUSIONS: Our survey confirmed the feasibility of MDTM in the field of Alzheimer's disease. The overall benefit/workload ratio of the meetings was considered to be favorable for the expert physicians. The benefits of MDTM were turned out to be less appreciated by the coordinating physicians according to high workload involved. PMID- 23364492 TI - Challenges in managing the diet of older adults with early-stage Alzheimer dementia: a caregiver perspective. AB - Caregivers (CG) of older adults suffering from Alzheimer disease (AD) are confronted by many challenges when caring for their family member; these include dietary management. OBJECTIVES: To identify difficulties in dietary management encountered by CG taking part in the Nutrition Intervention Study (NIS), and to gather their opinions on the intervention. DESIGN, SETTING AND PARTICIPANTS: Thirty-three CG of individuals with AD from the NIS intervention group were contacted. Individual interviews were conducted and analyzed using qualitative data analysis, and themes around challenges related to dietary practices experienced by CG were identified. RESULTS: Twenty-four CG were interviewed; 58% were aged 70 and older and 58% were the patient's spouse. Three major thematic categories emerged: 1. Dietary challenges and coping strategies used by CG; 2. CGs' opinion about the NIS; 3. CG interest in participating in a nutrition education support service. Changes in food habits and increasing dependency on the CG were the major themes related to dietary challenges. CONCLUSION: A better understanding of the CG's experience is essential for the development of nutrition interventions adapted to the needs of older adults with AD and their CG. PMID- 23364493 TI - Nutritional status in Parkinson's disease patients undergoing deep brain stimulation surgery: a pilot study. AB - OBJECTIVES: People with Parkinson's disease (PD) are at higher risk of malnutrition due to PD symptoms and pharmacotherapy side effects. When pharmacotherapy is no longer effective for symptom control, deep-brain stimulation (DBS) surgery may be considered. The aim of this study was to assess the nutritional status of people with PD who may be at higher risk of malnutrition related to unsatisfactory symptom management with optimised medical therapy. DESIGN: This was an observational study using a convenience sample. SETTING: Participants were seen during their hospital admission for their deep brain stimulation surgery. PARTICIPANTS: People with PD scheduled for DBS surgery were recruited from a Brisbane neurological clinic (n=15). MEASUREMENTS: The Patient-Generated Subjective Global Assessment (PG-SGA), weight, height and body composition were assessed to determine nutritional status. RESULTS: Six participants (40%) were classified as moderately malnourished (SGA-B). Eight participants (53%) reported previous unintentional weight loss (average loss of 13%). On average, participants classified as well-nourished (SGA-A) were younger, had shorter disease durations, lower PG-SGA scores, higher body mass (BMI) and fat free mass indices (FFMI) when compared to malnourished participants (SGA-B). Five participants had previously received dietetic advice but only one in relation to unintentional weight loss. CONCLUSION: Malnutrition remains unrecognised and untreated in this group despite unintentional weight loss and presence of nutrition impact symptoms. Improving nutritional status prior to surgery may improve surgical outcomes. PMID- 23364494 TI - Association of depressive symptoms with recurrent falls: a cross-sectional elderly population based study and a systematic review. AB - BACKGROUND: Screening of depressive symptoms is recommended in recurrent fallers. Compared to the 30-item and 15-item Geriatric Depression Scales (GDS), the 4-item GDS is easier to administer and quicker to perform. The association between abnormal 4-item GDS score and recurrent falls has not yet been examined. In addition, while depressive symptoms-related gait instability is well known, the association with recurrent falls has been few studied. OBJECTIVE: 1) To examine the association between abnormal 4-item GDS score and recurrent falls in community-dwelling older adults using original data from health examination centers (HEC) of French health insurance of Lyon, and 2) to perform a systematic review of studies that examined the association of depressive symptoms with recurrent falls among older adults. METHODS: Firstly, based on a cross-sectional design, 2,594 community-dwellers (mean age 72.1+/-5.4years; 49.8% women) were recruited in HEC of Lyon, France. The 4-item GDS score (abnormal if score>=1) and recurrent falls (i.e., 2 or more falls in the past year) were used as main outcomes. Secondly, a systematic English and French Medline literature search was conducted on May 28, 2012 with no limit of date using the following Medical Subject Heading (MeSH) terms "Aged OR aged, 80 and over", "Accidental falls", "Depressive disorder" and "Reccurence". The search also included the reference lists of the retrieved articles. RESULTS: A total of 19.0% (n=494) participants were recurrent fallers in the cross-sectional study. Abnormal 4-item GDS score was more prevalent among recurrent fallers compared to non-recurrent fallers (44.7% versus 25.0%, with P<0.001), and was significantly associated with recurrent falls (Odd ratio (OR)=1.82 with P<0.001 for full model; OR=1.86 with P<0.001 for stepwise backward model). In addition to the current study, the systematic review found only four other studies on this topic, three of them examining the association of depressive symptoms with recurrent falls using 30 item or 15-item GDS. All studies showed a significant association of depressive symptoms with recurrent falls. CONCLUSIONS: The current cross-sectional study shows an association between abnormal 4-item GDS score and recurrent falls. This association of depressive symptoms with recurrent falls was confirmed by the systematic review. Based on these results, we suggest that recurrent falls risk assessment should involve a systematic screening of depressive symptoms using the 4-item GDS. PMID- 23364495 TI - Evaluation of vitamin D medicines and dietary supplements and the physicochemical analysis of selected formulations. AB - CONTEXT: Vitamin D is purported to offer wide ranging and numerous health benefits leading to increased interest from manufacturers of medicines and dietary supplements. Elderly patients frequently require vitamin D supplementation due to reduced sun exposure and dietary intake. There are ever increasing numbers of vitamin D formulations in the global market. However, due to a lack of regulatory restrictions for some of these products the quality of these dosage forms can be of some concern. OBJECTIVES: To study vitamin D formulations available in the global market and evaluate physic-chemical properties of selected formulations from the New Zealand market. METHOD: The first component of this study consisted of a search for different vitamin D formulations available in selected countries. The second component of the study involved assaying selected vitamin D formulations available in New Zealand. Vitamin D was extracted from capsule, tablet and emulsion formulations and quantified using a validated High Performance Liquid Chromatography (HPLC) method. RESULTS: Of the 14 analysed formulations, only 60% were within 100+/-10 % of the label claim. The two registered, prescription formulations available exhibited vitamin D levels of 90+/-4% and 97+/-2% of the labeled amount, while non-registered, non-prescription dietary supplements had vitamin D levels ranging from 8+/-2% to 201+/-29% of the labeled amount. CONCLUSIONS: Dietary supplements do not require strict regulation and showed a large variation in the percentage label claim of vitamin D. Prescription formulations which are more strictly regulated gave content values within standard acceptance ranges. Vitamin D has proven health benefits and also the potential to cause harm, therefore there is a need for tougher regulations of dietary supplements to ensure acceptable quality. PMID- 23364496 TI - Percutaneous endoscopic gastrostomy (PEG) tube feeding of nursing home residents is not associated with improved body composition parameters. AB - OBJECTIVES: To study differences in nutritional status and body composition, by feeding modality, among disabled nursing home residents. DESIGN: A retrospective chart-review study. SETTING: A nursing wing of a public urban geriatric center. PARTICIPANTS: Three groups of patients: non-dysphagic, orally-fed dysphagic and percutaneous endoscopic gastrostomy -fed dysphagic patients. INTERVENTION: Standard nursing care. MEASUREMENTS: Basal metabolic rate, total energy expenditure and nitrogen balance under oral or percutaneous endoscopic gastrostomy feeding. Dietary intake was assessed during a 3-days period by daily food intake protocols and a 24-hours urinary creatinine excretion to detect nitrogen balance and calculate body composition parameters. RESULTS: Data of 117 patients (55.5% females), mean age 84.6+/-7.5 (range 66-98 years) was analyzed. Dysphagic patients (60) differed from non-dysphagic patients (57) by lower body mass index (p=0.020), fat mass index (p=0.017), daily protein intake (p<0.0001), daily energy intake (p<0.001), protein related energy intake (p<0.001) and a negative nitrogen balance (p<0.001). In regression analyses, dysphagia was associated with increased risk of having a body mass index lower than 22.0kg/m2 (OR=2.60, 95% CI 1.135-5.943), a negative nitrogen balance (OR=2.33, 95% CI 1.063 4.669), a low fat mass index (OR=2.53, 95% CI 1.066-6.007), and low daily protein and energy intakes per body weight (OR=2.87, 95% CI 1.316-6.268 and OR=2.99, 95% CI 1.297-6.880). Compared with orally-fed dysphagic patients (21pts.), percutaneous endoscopic gastrostomy -fed patients (39pts.) received an additional mean energy intake of 30.5% kcal per day and mean protein intake of 26.0%. This additional intake was not associated with improved body composition parameters (such as fat free mass, skeletal mass or body mass index). CONCLUSION: Dysphagic nursing home residents are characterized by worse nutritional, metabolic and body composition parameters, compared with non-dysphagic residents. Body composition parameters did not differ between orally-fed and percutaneous endoscopic gastrostomy-fed dysphagic patients, despite significantly better nutritional and metabolic parameters in PEG-fed patients. Other approaches (perhaps physical training, pharmacological etc.) should be sought to improve body composition of such patients. PMID- 23364497 TI - A probiotics-containing biscuit modulates the intestinal microbiota in the elderly. AB - OBJECTIVES: Evaluation of the impact of a biscuit containing the probiotics Bifidobacterium longum Bar33 and Lactobacillus helveticus Bar13 on the intestinal microbiota in the elderly. DESIGN: Randomized double-blind placebo-controlled trial. PARTICIPANTS: Thirty-two elderly volunteers living in Italy. The group was composed of 19 women and 13 men aged between 71 and 88 years (mean 76). INTERVENTION: Subjects were randomized in two groups consuming one dose of the probiotics-containing biscuit or placebo once a day for 30 days. MEASUREMENTS: For each subject the intestinal microbiota was characterized using the phylogenetic microarray platform HTF-Microbi.Array before and after intervention. RESULTS: Our data demonstrated that one-month consumption of a probiotics containing biscuit was effective in redressing some of the age-related dysbioses of the intestinal microbiota. In particular, the probiotic treatment reverted the age-related increase of the opportunistic pathogens Clostridium cluster XI, Clostridium difficile, Clostridium perfringens, Enterococcus faecium and the enteropathogenic genus Campylobacter. CONCLUSION: The present study opens the way to the development of elderly-tailored probiotic-based functional foods to counteract the age-related dysbioses of the intestinal microbiota. PMID- 23364498 TI - A multicentric individually-tailored controlled trial of education and professional support to nursing home staff: research protocol and baseline data of the IQUARE study. AB - BACKGROUND: Whilst the number of people living in nursing homes (NH) is expected to rise, research on NH quality is scarce. The purpose of this article is to describe the research protocol of the IQUARE study and to present its baseline data. METHODS AND DESIGN: IQUARE is a 18-month multicentric individually-tailored controlled trial of education and professional support to NH staff. The main purposes of IQUARE are to improve the quality of the health care provided in NHs and to reduce the risk of functional decline among residents. Data on internal organisation and residents' health for the 175 participating NHs were recorded by NH staff at baseline. NHs were allocated to either a light intervention group (LIG, n = 90 NHs, totalising 3 258 participants) or a strong intervention group (SIG, n = 85 NHs, totalising 3 017 participants). Intervention for LIG consisted at delivering to NH staff descriptive statistics on indicators of quality regarding their NH and the NHs from their sub-region of health and region; whereas for SIG, NH staff received the same information that LIG, but quality indicators were discussed by a cooperative work (two half-day meetings) between a hospital geriatrician and NH staff. Strategies for overcoming NH's weaknesses were then traced; the efficacy of strategies is evaluated at a 6-month period. RESULTS: Baseline data showed high levels of dependence, comorbidities, psychological disturbances and medication's consumption among NH residents. Large discrepancies among NHs were observed. CONCLUSIONS: IQUARE is one of the largest controlled trials in NHs developed in France. Results from IQUARE may constitute the basis for the development of new work modalities within the French health system, and serve as a model of a feasible research approach in NHs. PMID- 23364499 TI - Parathyroid hormone response to severe vitamin D deficiency is sex associated: an observational study of 571 hip fracture inpatients. AB - OBJECTIVES: To investigate the association between sex and parathyroid hormone response to severe vitamin D deficiency after hip fracture. DESIGN: Cross sectional study. SETTING: Rehabilitation hospital in Italy. PARTICIPANTS: 571 consecutive inpatients with hip fracture and severe vitamin D deficiency (serum 25-hydroxyvitamin D < 12ng/ml), without hypercalcemia or estimated glomerular filtration rate (GFR) < 15ml/min. MEASUREMENTS: In each patient we assessed PTH (by two-site chemiluminescent enzyme-labelled immunometric assay), 25 hydroxyvitamin D (by immunoenzymatic assay), albumin-adjusted total calcium, phosphate, magnesium, and creatinine 21.3 +/- 6.1 (mean +/- SD) days after fracture occurrence. Functional level was assessed using the Barthel index. PTH response to vitamin D deficiency was classified as either secondary hyperparathyroidism (serum PTH >75pg/ml) or functional hypoparathyroidism, i.e., inappropriate normal levels of PTH (<=75pg/ml). RESULTS: Among the 571 patients, 336 (59%) had functional hypoparathyroidism, whereas 235 (41%) had secondary hyperparathyroidism. PTH status was significantly different between sexes (p=0.003): we found functional hypoparathyroidism in 61% of women and 43% of men (secondary hyperparathyroidism in 39% of women and 57% of men). The significance of the between-sex difference was maintained after adjustment for age, estimated GFR, phosphate, albumin-adjusted total calcium, albumin, Barthel index scores, 25 hydroxyvitamin D, and hip fracture type (either cervical or trochanteric). The adjusted odds ratio was 1.85 (95%CI from 1.09 to 3.13; p=0.023). CONCLUSIONS: Data shows that PTH response to vitamin D deficiency was sex-associated following a fracture of the hip. The higher prevalence of secondary hyperparathyroidism may play a role in the known prognostic disadvantage found in hip-fracture men. PMID- 23364500 TI - Poor nutritional status is associated with urinary tract infection among older people living in residential care facilities. AB - AIM: To investigate factors associated with poor nutritional status in older people living in residential care facilities. METHODS: 188 residents (136 women, 52 men) with physical and cognitive impairments participated. Mean age was 84.7 y (range 65-100). The Mini Nutritional Assessment (MNA), Barthel ADL Index, Mini Mental State Examination (MMSE), and Geriatric Depression Scale were used to evaluate nutritional status, activities of daily living, cognitive status and depressive symptoms. Medical conditions, clinical characteristics and prescribed drugs were recorded. Univariate and multivariate regressions were used to investigate associations with MNA scores. RESULTS: The mean MNA score was 20.5 +/ 3.7 (range 5.5-27) and the median was 21 (interquartile range (IQR) 18.8-23.0). Fifteen per cent of participants were classified as malnourished and 66% at risk of malnutrition. Lower MNA scores were independently associated with urinary tract infection (UTI) during the preceding year (beta = - 0.21, P = 0.006), lower MMSE scores (beta = 0.16, P = 0.030), and dependent in feeding (beta = - 0.14, P = 0.040). CONCLUSION: The majority of participants were at risk of or suffering from malnutrition. Urinary tract infection during the preceding year was independently associated with poor nutritional status. Dependence in feeding was also associated with poor nutritional status as were low MMSE scores for women. Prospective observations and randomized controlled trials are necessary to gain an understanding of a causal association between malnutrition and UTI. PMID- 23364501 TI - A survey of physicians who care for older persons in Southwest China. AB - OBJECTIVE: The aim of this survey is to determine the main barriers of geriatric health care from the physicians' point of view and compare the improvement before and after the Continue Medical Education (CME) provided by International Association of Gerontology and Geriatrics (IAGG). DESIGN: Cross-sectional survey. SETTING AND PARTICIPANTS: Five hundred samples were generated using systematic random sampling from the address lists of physicians in Southwest China who had received the IAGG CME or been trained in Sichuan Association of Geriatrics (SAG) CME. MEASUREMENTS: The interview instrument examined demographics and information on geriatric education. RESULTS: Of the 500 physician sampled, 461(92.2 percent) responded. 34.3 percent of the respondents reported that over 70 percent of their patients were older persons. 76.8 percent of the respondents felt that they lacked geriatric knowledge. Only 15.6 percent of the respondents had geriatric curriculum before graduation, and 26.0 percent received geriatric trainings after graduation. Most physicians felt that "Language barrier" and "Insufficient geriatric education in undergraduate medical school and postgraduate education" were the main challenges in practicing geriatric medicine. Geriatric training and knowledge are inadequate due to the lack of geriatric curriculums in medical schools and CME for physicians who practice geriatrics. With the help of IAGG, CME in Southwest China provided more workshops on geriatric progress in year 2011 than in year 2007-2010. Eighty percent of the physicians acknowledged that the IAGG CME was helpful for their clinical practice. The physicians paid more attention to geriatric syndromes rather than age-related pathophysiology alone. CONCLUSION: CME provided by geriatric associations is helpful. Collaboration between different geriatric societies such as IAGG and SAG may be a good model for spreading geriatric knowledge and should be considered by medical educational administration. PMID- 23364502 TI - Merckel cell carcinoma: the impact of multidisciplinary management. AB - Merkel cell carcinoma (MMC) is a rare primary neuroendocrine skin tumor associated with a poor prognosis. MMC is histologically similar to small cell lung carcinoma. The incidence of MCC is increasing with a median age of discovery of approximately 70 years old. Treatment of MCC, which usually occurs in sun exposed skin, includes surgery with reconstruction associated with radiotherapy and/or chemotherapy for advanced stages including widespread metastases. We report two cases of Merkel cell carcinoma in 76 and 84 year old patients and describe the natural history of this cancer and management in geriatric patients. Merkel cell carcinoma (MCC) is a rare cancer with high malignant potential that mainly affects people over the age of 65. It must be diagnosed early to improve the prognosis. The survival rate at 5 years for local or regional invasion is 65%. The median survival for metastasized stages is 10 months. The therapeutic regimen recommended for the treatment of MCC is influenced by the geriatric status of patients, and a multidisciplinary oncogeriatric approach could be of interest. PMID- 23364504 TI - Effect of multimodality chest physiotherapy on the rate of recovery and prevention of complications in patients with mechanical ventilation: a prospective study in medical and surgical intensive care units. AB - BACKGROUND: Mechanically ventilated patients have an increased risk of complications leading to ventilation weaning more difficult resulting in excessive morbidity and mortality. Chest physiotherapy plays an important role in management of ventilated patients. However, these techniques have been studied on patients as a single entity or with combination of two techniques. The present study was designed to evaluate the effect of multimodality chest physiotherapy on the rate of recovery and prevention of complications in adult ventilated patients. MATERIALS AND METHODS: Out of 173 patients who were randomly allocated to two groups, 86 patients received MH and suctioning in control group and 87 patients were treated with multimodality chest physiotherapy in the study group twice daily till they were extubated. All patients were followed up for the global outcomes and complications during mechanical ventilation. RESULTS: There were significant improvements in terms of rate of recovery in study group compared to the control group (P = 0.000). Complication rates were higher with 61.6% in the control group as compared to 26.4% in the study group. Duration of hospitalization was longer in the study group (16 +/- 9.40 days) as compared to the control group (12.8 +/- 6.12 days). Successful weaning from mechanical ventilation was noted in 58 patients in the study group and 24 patients in the control group which was statistically significant. CONCLUSIONS: Multi-modality chest physiotherapy protocol has shown to prevent ventilator-associated pneumonia and enhance the clinical outcome in ventilated patients and may be recommended as a treatment option in ICU. It has also shown to enhance the weaning process and proved to be safe. PMID- 23364503 TI - Characteristics of patients who stop falling after a risk-based multidisciplinary intervention initiated in a geriatric day hospital. AB - BACKGROUND: Multidisciplinary interventions for fallers have provided conflicting results in part due to the diversity of fallers' profiles. OBJECTIVES: to determine the characteristics of the subgroup of patients with a positive response to a multidisciplinary fall prevention program initiated in a geriatric day hospital. DESIGN: Prospective observational study in day hospital. METHODS: Patients > 75 years referred for falls during the last 3 months benefited from a multidisciplinary assessment to record their characteristics at baseline and to tailor a risk-based multidisciplinary intervention for fall prevention. Patients free from falls at the 3rd or 6th month were compared to persistent fallers for baseline characteristics. RESULTS: Sixty-nine patients were assessed at baseline (mean age 85.2 y (SD=0.6)), 44 at the 3rd month and 21 at the 6th month. Baseline characteristics of the patients free from falls at the 3rd month were the lower number of previous non-serious falls (p=0.013), living in nursing home (p=0.045), a higher Berg balance score (p=0.02) and a better mental health-related quality of life (M HQol, p=0.045). On multivariate analysis restricted to home-dwelling patients, the positive predictive factors were less isolation at home (OR=0.028, 95%CI [0-0.813], p=0.037), a lower number of non-serious previous falls (OR= 0.526 [0.309- 0.894], p=0.018), a better M HQol (OR=1.205 [1.000-1.452], p=0.050) and a trend for younger age (OR= 0.662, [0.426-1.027], p=0.066). CONCLUSION: Being able to call upon a support person (familial or institutional) to apply advice and a less serious risk of falling may be preliminary conditions for success in a multidisciplinary intervention initiated in a day hospital. PMID- 23364505 TI - Are we ignoring diabetic disability: a cross sectional study of diabetic myopathy. AB - BACKGROUND: The complications associated with type 2 Diabetes Mellitus (DM) may cause functional impairment in older people. Recently it has been proved that motor dysfunction in the form of skeletal muscle dysfunction does occur in type II DM. However very few studies have assessed the upper limb skeletal muscle dysfunction. OBJECTIVES: The study was aimed to assess the hand grip strength, endurance in type 2 DM patients and compare the same with age matched healthy controls. We also correlated glycosylated Hb and duration of illness with the hand grip strength and endurance in the patients. MATERIALS AND METHODS: Hand grip dynamometer was used to measure the hand grip strength and endurance in sixty diagnosed patients of type II DM. Similar tests were performed in age matched healthy controls. Blood samples were collected for blood glucose fasting, postprandial levels and Hb1AC in both the groups. Comparisons between patients and controls, and correlations were done by applying suitable tests. RESULTS: The hand grip muscle strength and endurance in type II DM patients were significantly lower as compared to the normal controls (P < 0.05, P < 0.001). There was no correlation between the hand grip muscle strength and endurance with HbA1c and the duration of the disease in the patients of type II DM (P > 0.05). CONCLUSIONS: The present study shows that type II DM patients suffer from skeletal muscle dysfunction in the form of reduced hand grip strength and endurance. Hence the treating Physician should not be ignorant about these disabilities. In addition to the strict measures to control the blood glucose levels, interventions to improve the muscle mass and strength in these patients should be undertaken. PMID- 23364506 TI - Imaging in adult patients with acute febrile encephalopathy: what is better computerized tomography or magnetic resonance imaging. AB - CONTEXT: Imaging techniques are commonly used by emergency physicians in a febrile comatose patient. Their utility requires judicious use of the available resources. In this study, we have compared the efficacy of cranial imaging techniques in adult patients with acute febrile encephalopathy. MATERIALS AND METHODS: This prospective observational study enrolled 101 patients presenting to the emergency with fever of less than 15 days duration and altered sensorium. All the patients were subjected to routine investigations, detailed cerebrospinal fluid analysis, computerized tomograms (noncontrast followed by contrast enhanced), and magnetic resonance imaging of the brain. Final diagnosis was reached after considering the clinical, biochemical findings, imaging results, and response to therapy. The positive yield of radiological investigations was compared against the final diagnosis. RESULTS: The patients were divided into three groups. Forty-eight had evidence of meningoencephalitis, 22 patients had pyogenic meningitis, and 20 were combined together in other group. In 12 patients, a definitive diagnosis could not be made. Only 37% patients were detected to have abnormal computerized tomograms and the most common abnormality was diffuse edema, which failed to point to an etiological diagnosis. Magnetic resonance imaging was abnormal in 62.75% cases and was able to suggest an etiological diagnosis in 100% cases of cerebral venous thrombosis, tubercular meningitis, 95% cases of meningoencephalitis, and 45% patients with meningitis. CONCLUSIONS: We can conclude that magnetic resonance imaging provides better information than computerized tomography in adult patients with acute febrile encephalopathy. PMID- 23364507 TI - Nondrug noninvasive treatment in the management of patellofemoral osteoarthritis. AB - BACKGROUND: Patellofemoral osteoarthritis is a chronic joint disease affecting one-third of elderly people. The disease impacts upon activities of daily living (e.g. walking, stair-climbing, and housekeeping), ultimately leading to a loss of functional independence and quality of life. PURPOSE: The main purpose of this study was to assess the results of nondrug noninvasive treatment in the management of patellofemoral osteoarthritis. MATERIALS AND METHODS: This study was conducted in the department of Orthopaedics in M. M. Medical College, Mullana, Ambala, Haryana, India from June 2005 to June 2010. Two hundred fifty one out patients of patellofemoral arthritis with a mean age of 45 years were studied. They were managed with noninvasive treatment and were followed for 24 months. RESULTS: At 30 to 40 years of age it was good to excellent, respectively. More than 40 years it was good. The patients global evaluation of condition were found very good up to the age of 30 years at 2 years of follow up, good to very good between 30 to 40 years, respectively, and over the age of 40 years it was good. CONCLUSION: Nondrug noninvasive interventions can reduce pain and improve function in patellofemoral osteoarthritis. PMID- 23364508 TI - Prevalence and relationship of human papilloma virus type 16 and type 18 with oral squamous cell carcinoma and oral leukoplakia in fresh scrappings: a PCR study. AB - INTRODUCTION: It has been always an area of diffuse clarity when you study malignancy and its pathogenesis. Recently, it has invited lot of interest among the researchers about the possibility of role of viruses in the initiation of carcinogenesis. Recent advances in the field of molecular biology and biotechnology have solved some problems with regard to pathogenesis. Human papilloma virus (HPV) and its role in the initiation of malignancy in the cervix is proven almost beyond doubt. OBJECTIVES: The present study is aimed at the role of two types of HPV 16 and 18 in the initiation of oral premalignant and squamous cell carcinoma. The study also aims at using polymerase chain reaction (PCR) in finding out the prevalence of these types diagnosed histologically as oral leukoplakia and oral squamous cell carcinoma and prevalence of its association with the habit of tobacco use. MATERIALS AND METHODS: In the present study, 45 patients having histopathologically confirmed oral squamous cell carcinoma in the age range of 32-85 years were selected along with 20 histopathologically confirmed oral leukoplakia in the age range 22-66 years. All the samples were subjected to polymerase chain reaction. The PCR reaction was carried out in PTC 200 thermo-cycler [MJ Research Inc, Watertown, MA, USA]. RESULTS: The site prevalence and co-infection rate of these two types of viruses are being analyzed using very simple non-invasive scrapings obtained from fresh scrapings and found to be really high. It was also observed that 73.3% (33/45) of the oral squamous cell carcinoma patients were positive for oral HPV type 16 while 71.1% (32/45) were positive for HPV type 18 infection and 57.7% (26/45) were found to have both HPV type 16 and HPV type 18 infections. CONCLUSIONS: HPV type 16, 18, and co infection of both types showed high prevalence in oral squamous cell carcinoma.The prevalence of HPV type 18 was found to be higher than HPV type 16 and co-infection in oral leukoplakia. It was observed that the tongue and palate lesions in the oral squamous cell carcinoma patients showed high prevalence of HPV type 16, type 18, and co-infection compared with other sites. PMID- 23364509 TI - Predicting metabolic clearance for drugs that are actively transported into hepatocytes: incubational binding as a consequence of in vitro hepatocyte concentration is a key factor. AB - Incubational binding or the fraction of drug unbound in an in vitro incubation, fuinc, is an important parameter to predict or measure in the pursuit of accurate clearance predictions from in vitro data. Here we describe a method for fuinc determination directly in the hepatocyte intrinsic clearance (CLint) assay with emphasis on compounds that are actively transported into hepatocytes, hypothesizing that for such compounds the typical protocol of 1 million hepatocytes/ml systematically underestimates the maximum attainable unbound intracellular drug concentration. Using the transporter substrate atorvastatin as a test compound, incubations were performed and a mathematical model applied to describe metabolism, distribution, and binding at different hepatocyte concentrations. From these investigations it was evident that, since binding is more extensive intracellularly than in the medium, increased partitioning into the cellular volume, due to active uptake, increases the total amount of atorvastatin bound in the incubation. Consequently, a significant lowering of the hepatocyte concentration impacts the free drug concentration in the incubation and increases the observed rate of metabolism and therefore observed CLint (that is, when viewed from the media drug concentration). The applicability of the findings was tested for a series of 11 actively transported zwitterions for which standard rat hepatocyte metabolic CLint data (1 million cells/ml incubation) poorly predicted in vivo clearance (average fold error of 5.4). Using metabolic CLint determined at a lower hepatocyte concentration (0.125 million cells/ml) considerably improved clearance predictions (average fold error of 2.3). PMID- 23364510 TI - Bitemporal intractable epilepsy: could it be surgically treatable?. AB - BACKGROUND: The goal of this study is to retrieve the attention to the treatment opportunities for this cohort of intractable bitemporal epilepsy patients who in most cases are not considered optimal candidates for surgery. OBJECTIVES: The purpose of this study is to demonstrate that electrophysiologically guided precise surgeries on both temporal lobes can have a beneficial effect on seizures without additional cognitive decline. METHODS: Twenty-one intractable bitemporal epilepsy patients [13 men, 8 women, mean age 21 years (range 6-43), mean duration of illness 17 years (range 3-31), frequency of seizures 6-55 per month] underwent stereotactic cryosurgery on both temporal lobes guided by chronic and intraoperative depth electrode studies. RESULTS: Class I ('free of disabling seizures') outcome was achieved for 11/21 (52%), class II ('rare seizures') for 6/21 (29%), and class IV ('no worthwhile improvement') for 4/21 (19%) patients. No worsening of seizure or clinically significant cognitive or memory impairments were observed in this cohort of patients (follow-up 5-10 years). CONCLUSIONS: The minimally invasive precise surgeries on both temporal lobes confined to the removal/lesion of just the brain tissue that exhibited epileptic activity can have a beneficial effect on seizure frequency and severity without additional devastating declines in intelligence, learning and memory. PMID- 23364511 TI - Routine inpatient provider-initiated HIV testing in Malawi, compared with client initiated community-based testing, identifies younger children at higher risk of early mortality. AB - OBJECTIVE: To determine how routine inpatient provider-initiated HIV testing differs from traditional community-based client-initiated testing with respect to clinical characteristics of children identified and outcomes of outpatient HIV care. DESIGN: Prospective observational cohort. METHODS: Routine clinical data were collected from children identified as HIV-infected by either testing modality in Lilongwe, Malawi, in 2008. After 1 year of outpatient HIV care at the Baylor College of Medicine Clinical Center of Excellence, outcomes were assessed. RESULTS: Of 742 newly identified HIV-infected children enrolling into outpatient HIV care, 20.9% were identified by routine inpatient HIV testing. Compared with community-identified children, hospital-identified patients were younger (median 25.0 vs 53.5 months), with more severe disease (22.2% vs 7.8% WHO stage IV). Of 466 children with known outcomes, 15.0% died within the first year of HIV care; median time to death was 15.0 weeks for community-identified children vs 6.0 weeks for hospital-identified children. The strongest predictors of early mortality were severe malnutrition (hazard ratio, 4.3; 95% confidence interval, 2.2-8.3), moderate malnutrition (hazard ratio, 3.2; confidence interval, 1.6 6.6), age < 12 months (hazard ratio, 3.2; 95% confidence interval, 1.4-7.2), age 12 to 24 months (hazard ratio, 2.5; 95% confidence interval, 1.1-5.7), and WHO stage IV (hazard ratio, 2.2; 95% confidence interval, 1.1-4.6). After controlling for other variables, hospital identification did not independently predict mortality. CONCLUSIONS: Routine inpatient HIV testing identifies a subset of younger HIV-infected children with more severe, rapidly progressing disease that traditional community-based testing modalities are currently missing. PMID- 23364512 TI - Social network-based recruitment successfully reveals HIV-1 transmission networks among high-risk individuals in El Salvador. AB - OBJECTIVE: HIV in Central America is concentrated among certain groups such as men who have sex with men (MSM) and female sex workers (FSWs). We compared social recruitment chains and HIV transmission clusters from 699 MSM and 787 FSWs to better understand factors contributing to ongoing HIV transmission in El Salvador. METHODS: Phylogenies were reconstructed using pol sequences from 119 HIV-positive individuals recruited by respondent-driven sampling (RDS) and compared with RDS chains in 3 cities in El Salvador. Transmission clusters with a mean pairwise genetic distance <= 0.015 and Bayesian posterior probabilities =1 were identified. Factors associated with cluster membership were evaluated among MSM. RESULTS: Sequences from 34 (43%) MSM and 4 (10%) FSW grouped in 14 transmission clusters. Clusters were defined by risk group (12 MSM clusters) and geographic residence (only 1 spanned separate cities). In 4 MSM clusters (all n = 2), individuals were also members of the same RDS chain, but only 2 had members directly linked through recruitment. All large clusters (n >= 3) spanned >1 RDS chain. Among MSM, factors independently associated with cluster membership included recent infection by BED assay (P = 0.02), sex with stable male partners (P = 0.02), and sex with >= 3 male partners in the past year (P = 0.04). CONCLUSIONS: We found few HIV transmissions corresponding directly with the social recruitment. However, we identified clustering in nearly one-half of MSM suggesting that RDS recruitment was indirectly but successfully uncovering transmission networks, particularly among recent infections. Interrogating RDS chains with phylogenetic analyses may help refine methods for identifying transmission clusters. PMID- 23364513 TI - Immune recovery after starting ART in HIV-infected patients presenting and not presenting with tuberculosis in South Africa. AB - We studied the immune response after starting antiretroviral treatment (ART) in 15,646 HIV-infected patients with or without tuberculosis (TB) at presentation in 3 ART programs in South Africa between 2003 and 2010. Patients presenting with TB had similar increases in CD4 cells compared with all other patients (adjusted difference 4.9 cells/uL per 6 months, 95% confidence interval: 0.2 to 9.7). Younger age, advanced clinical stage, female sex, and lower CD4 cell count at ART start were all associated with steeper CD4 slopes. In South Africa, HIV-infected patients presenting with TB experience immune recovery after starting ART that is no worse than in other patients. PMID- 23364514 TI - Using human pluripotent stem cell-derived dopaminergic neurons to evaluate candidate Parkinson's disease therapeutic agents in MPP+ and rotenone models. AB - To begin to develop a high-throughput assay system to evaluate potential small molecule therapy for Parkinson's disease (PD), we have performed a low-throughput assay with a small number of compounds using human pluripotent stem cell-derived dopaminergic neurons. We first evaluated the role of 44 compounds known to work in rodent systems in a 1-methyl-4-phenylpyridinium (MPP(+)) assay in a 96-well format using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay as a readout for neuroprotection. Glial cell-derived neurotrophic factor was used as a positive control because of its well-documented neuroprotective effect on dopaminergic neurons, and two concentrations of each drug were tested. Of 44 compounds screened, 16 showed a neuroprotective effect at one or both dosages tested. A dose-response curve of a subset of the 16 positives was established in the MPP(+) model. In addition, we validated neuroprotective effects of these compounds in a rotenone-induced dopaminergic neuronal cell death, another established model for PD. Our human primary dopaminergic neuron based assays provide a platform for rapid screening and/or validation of potential neuroprotective agents in PD treatment using patient-specific cells and show the importance of using human cells for such assays. PMID- 23364515 TI - Identification of a small-molecule inhibitor of bacterial AraC family activators. AB - Protein members of the AraC family of bacterial transcriptional activators have great promise as targets for the development of novel antibacterial agents. Here, we describe an in vivo high-throughput screen to identify inhibitors of the AraC family activator protein RhaS. The screen used two Escherichia coli reporter fusions: one to identify potential RhaS inhibitors and a second to eliminate nonspecific inhibitors from consideration. One compound with excellent selectivity, OSSL_051168, was chosen for further study. OSSL_051168 inhibited in vivo transcription activation by the RhaS DNA-binding domain to the same extent as the full-length protein, indicating that this domain was the target of its inhibition. Growth curves showed that OSSL_051168 did not affect bacterial cell growth at the concentrations used in this study. In vitro DNA-binding assays with purified protein suggest that OSSL_051168 inhibits DNA binding by RhaS. In addition, we found that it inhibits DNA binding by a second AraC family protein, RhaR, which shares 30% amino acid identity with RhaS. OSSL_051168 did not have a significant impact on DNA binding by the non-AraC family proteins CRP and LacI, suggesting that the inhibition is likely specific for RhaS, RhaR, and possibly additional AraC family activator proteins. PMID- 23364516 TI - Assay development for identifying inhibitors of the mycobacterial FadD32 activity. AB - FadD32, a fatty acyl-AMP ligase (FAAL32) involved in the biosynthesis of mycolic acids, major and specific lipid components of the mycobacterial cell envelope, is essential for the survival of Mycobacterium tuberculosis, the causative agent of tuberculosis. The protein catalyzes the conversion of fatty acid to acyl adenylate (acyl-AMP) in the presence of adenosine triphosphate and is conserved in all the mycobacterial species sequenced so far, thus representing a promising target for the development of novel antituberculous drugs. Here, we describe the optimization of the protein purification procedure and the development of a high throughput screening assay for FadD32 activity. This spectrophotometric assay measuring the release of inorganic phosphate was optimized using the Mycobacterium smegmatis FadD32 as a surrogate enzyme. We describe the use of T m (melting temperature) shift assay, which measures the modulation of FadD32 thermal stability, as a tool for the identification of potential ligands and for validation of compounds as inhibitors. Screening of a selected library of compounds led to the identification of five novel classes of inhibitors. PMID- 23364517 TI - Dichlorination of olefins with NCS/Ph(3)P. AB - A 2 : 1 mixture of NCS and Ph(3)P successfully promoted the anti-dichlorination of olefins to provide corresponding dichlorides, serving as a molecular chlorine surrogate generated in situ. PMID- 23364518 TI - Glomerular diseases seen with cancer and chemotherapy: a narrative review. AB - Glomerular lesions have been recognized in a number of malignant diseases. Membranous nephropathy is the most common glomerular pathology associated with solid tumors. In Hodgkin's disease, the most common lesion is minimal change disease, reflecting possibly an anomaly of T-cell function. On the other hand, in patients with chronic lymphocytic leukemia, a large proportion of glomerular lesions fall into the category of membranoproliferative glomerulonephritis. Membranous nephropathy is also the most common glomerular disease seen following stem cell transplantation, suggesting a possible immune-mediated mechanism. Chemotherapy agents such as interferon, anti-vascular endothelial growth factor agents, tyrosine kinase inhibitors, and bisphosphonates have also been associated with various glomerular diseases and thrombotic microangiopathy. Failure to recognize certain paraneoplastic glomerular diseases can lead to potentially unnecessary therapies. This review describes the association of glomerular diseases with solid tumors, hematological malignancies, stem cell transplantation, and chemotherapeutic agents. We also describe the pitfalls in diagnosis and the dilemma in treating these entities. PMID- 23364519 TI - Parathyroid hormone-related protein protects renal tubuloepithelial cells from apoptosis by activating transcription factor Runx2. AB - Runx2 is a key transcription factor in bone development regulating several processes, including osteoblast apoptosis. The antiapoptotic effects of parathyroid hormone (PTH) in osteoblasts depend on Runx2-mediated transcription of prosurvival genes. In the kidney, PTH-related protein (PTHrP) promotes tubulointerstitial cell survival by activating the PTH/PTHrP type 1 receptor. We found that Runx2 is expressed in renal tubuloepithelial MCT and HK2 cell lines in vitro and in the mouse kidney tubuloepithelium in vivo. The 1-36 amino-acid fragment of PTHrP was found to increase the expression and nuclear translocation of Runx2 in both cell lines in a dose- and time-dependent manner. PTHrP(1-36) protected renal tubuloepithelial cells from folic acid toxicity and serum deprivation, an effect inhibited by a dominant-negative Runx2 construct or a Runx2 siRNA. Furthermore, PTHrP(1-36) upregulated the antiapoptotic proteins Bcl 2 and osteopontin, and these effects were abolished by Runx2 siRNA. Runx2, osteopontin, and Bcl-2 were increased in tubuloepithelial cells from transgenic mice with PTHrP overexpression and in wild-type mice with acute or chronic renal failure. Thus, PTHrP regulates renal tubuloepithelial cell survival via Runx2 in the mammalian kidney. PMID- 23364520 TI - Phosphate-induced autophagy counteracts vascular calcification by reducing matrix vesicle release. AB - Autophagy is a dynamic and highly regulated process of self-digestion responsible for cell survival and reaction to oxidative stress. As oxidative stress is increased in uremia and is associated with vascular calcification, we studied the role of autophagy in vascular calcification induced by phosphate. In an in vitro phosphate-induced calcification model of vascular smooth muscle cells (VSMCs) and in an in vivo model of chronic renal failure, autophagy was inhibited by the superoxide dismutase mimic MnTMPyP, superoxide dismutase-2 overexpression, and by knockdown of the sodium-dependent phosphate cotransporter Pit1. Although phosphate-induced VSMC apoptosis was reduced by an inhibitor of autophagy (3 methyladenine) and knockdown of autophagy protein 5, calcium deposition in VSMCs was increased during inhibition of autophagy, even with the apoptosis inhibitor Z VAD-FMK. An inducer of autophagy, valproic acid, decreased calcification. Furthermore, 3-methyladenine significantly promoted phosphate-induced matrix vesicle release with increased alkaline phosphatase activity. Thus, autophagy may be an endogenous protective mechanism counteracting phosphate-induced vascular calcification by reducing matrix vesicle release. Therapeutic agents influencing the autophagic response may be of benefit to treat aging or disease-related vascular calcification and osteoporosis. PMID- 23364521 TI - Molecular fingerprinting of the podocyte reveals novel gene and protein regulatory networks. AB - A thorough characterization of the transcriptome and proteome of endogenous podocytes has been hampered by low cell yields during isolation. Here we describe a double fluorescent reporter mouse model combined with an optimized bead perfusion protocol and efficient single cell dissociation to yield more than 500,000 podocytes per mouse allowing for global, unbiased downstream applications. Combining mRNA and miRNA transcriptional profiling with quantitative proteomic analyses revealed programs of highly specific gene regulation tightly controlling cytoskeleton, cell differentiation, endosomal transport, and peroxisome function in podocytes. Strikingly, the analyses further predict that these podocyte-specific gene regulatory networks are accompanied by alternative splicing of respective genes. Thus, our 'omics' approach will facilitate the discovery and integration of novel gene, protein, and organelle regulatory networks that deepen our systematic understanding of podocyte biology. PMID- 23364522 TI - Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy. AB - Antibodies to the phospholipase A2 receptor 1 (PLA2R1) have been reported in 70% of cases of idiopathic membranous nephropathy (IMN). The genetic susceptibility of IMN has been accounted for by HLA DQA1 and PLA2R1 genes. Here we retrospectively quantified PLA2R antibodies by ELISA, and genotyped DQ alleles and PLA2R1 single-nucleotide polymorphisms for association with clinical criteria for disease activity at the time of first sample and with outcome over a median total follow-up of 90 months. In 90 prevalent patients with biopsy-proven IMN, anti-PLA2R antibodies were present in 75% of patients with IMN with active disease and were significantly higher than in patients in partial or complete remission at the time of antibody measurement. There was a differential IgG subclass response (4>2>3>1) at an early stage, i.e., within 6 months of biopsy. Levels of PLA2R antibodies were significantly linked to DQA1*05:01 and DQB1*02:01. Survival analysis of patients with IMN showed that PLA2R antibodies are significantly linked with outcome. Thus, high levels of PLA2R antibodies are linked with active disease and a higher risk of declining renal function during follow-up. Future therapeutic trials in IMN should monitor anti-PLA2R, as patients with a high antibody burden may benefit from earlier therapeutic intervention. PMID- 23364523 TI - Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage. AB - Hypertension and renal damage in Dahl SS rats are associated with increased infiltrating immune cells in the kidney. To examine the role of infiltrating immune cells in this disease process, a zinc finger nuclease targeting bases 672 706 of recombination-activating gene 1 (Rag1) was injected into the pronucleus of Dahl SS (SS/JrHsdMcwi) strain embryos and implanted in pseudopregnant females. This strategy yielded a rat strain with a 13-base frame-shift mutation in the target region of Rag1 and a deletion of immunoreactive Rag1 protein in the thymus. Flow cytometry demonstrated that the Rag1-null mutant rats have a significant reduction in T and B lymphocytes in the circulation and spleen. Studies were performed on SS and Rag1-null rats fed a 4.0% NaCl diet for 3 wk. The infiltration of T cells into the kidney following high-salt intake was significantly blunted in the Rag1-null rats (1.7 +/- 0.6 * 10(5) cells/kidney) compared with the Dahl SS (5.6 +/- 0.9 * 10(5) cells/kidney). Accompanying the reduction in infiltration of immune cells in the kidney, mean arterial blood pressure and urinary albumin excretion rate were significantly lower in Rag1-null mutants (158 +/- 3 mmHg and 60 +/- 16 mg/day, respectively) than in SS rats (180 +/- 11 mmHg and 251 +/- 37 mg/day). Finally, a histological analysis revealed that the glomerular and tubular damage in the kidneys of the SS rats fed a high salt diet was also attenuated in the Rag1 mutants. These studies demonstrate the importance of renal infiltration of immune cells in the pathogenesis of hypertension and renal damage in Dahl SS rats. PMID- 23364525 TI - Brief light stimulation during the mouse nocturnal activity phase simultaneously induces a decline in core temperature and locomotor activity followed by EEG determined sleep. AB - Light exerts a variety of effects on mammals. Unexpectedly, one of these effects is the cessation of nocturnal locomotion and the induction of behavioral sleep (photosomnolence). Here, we extend the initial observations in several ways, including the fundamental demonstration that core body temperature (T(c)) drops substantially (about 1.5 degrees C) in response to the light stimulation at CT15 or CT18 in a manner suggesting that the change is a direct response to light rather than simply a result of the locomotor suppression. The results show that 1) the decline of locomotion and T(c) begin soon after nocturnal light stimulation; 2) the variability in the magnitude and onset of light-induced locomotor suppression is very large, whereas the variability in T(c) is very small; 3) T(c) recovers from the light-induced decline in advance of the recovery of locomotion; 4) under entrained and freerunning conditions, the daily late afternoon T(c) increase occurs in advance of the corresponding increase in wheel running; and 5) toward the end of the subjective night, the nocturnally elevated T(c) persists longer than does locomotor activity. Finally, EEG measurements confirm light-induced sleep and, when T(c) or locomotion was measured, show their temporal association with sleep onset. Both EEG- and immobility-based sleep detection methods confirm rapid induction of light-induced sleep. The similarities between light-induced loss of locomotion and drop in T(c) suggest a common cause for parallel responses. The photosomnolence response may be contingent upon both the absence of locomotion and a simultaneous low T(c). PMID- 23364524 TI - Reduced c-Fos expression in medullary catecholaminergic neurons in rats 20 h after exposure to chronic intermittent hypoxia. AB - Persons affected by obstructive sleep apnea (OSA) have increased arterial blood pressure and elevated activity in upper airway muscles. Many cardiorespiratory features of OSA have been reproduced in rodents subjected to chronic-intermittent hypoxia (CIH). We previously reported that, following exposure to CIH, rats have increased noradrenergic terminal density in brain stem sensory and motor nuclei and upregulated expression of the excitatory alpha(1)-adrenergic receptors in the hypoglossal motor nucleus. This suggested that CIH may enhance central catecholaminergic transmission. We now quantified c-Fos expression in different groups of pontomedullary catecholaminergic neurons as an indirect way of assessing their baseline activity in rats subjected to CIH or sham treatment (7 AM-5 PM daily for 35 days). One day after the last CIH exposure, the rats were gently kept awake for 2.5 h and then were anesthetized and perfused, and their pontomedullary brain sections were subjected to dopamine beta-hydroxylase (DBH) and c-Fos immunohistochemistry. DBH-positive cells were counted in the A1/C1, A2/C2, A5, subcoeruleus (sub-C) and A7 groups of catecholaminergic neurons, and the percentages of those expressing c-Fos were determined. We found that fewer DBH cells expressed c-Fos in CIH- than in sham-treated rats in the medulla (significant in the A1 group). In the pons (rostral A5, sub-C, and A7), c-Fos expression did not differ between the CIH- and sham-treated animals. We suggest that, when measured 20 h after the last CIH exposure, catecholaminergic transmission is enhanced through terminal sprouting and receptor upregulation rather than through increased baseline activity in pontomedullary catecholaminergic neurons. PMID- 23364526 TI - Reduced carbohydrate availability enhances exercise-induced p53 signaling in human skeletal muscle: implications for mitochondrial biogenesis. AB - The mechanisms that regulate the enhanced skeletal muscle oxidative capacity observed when training with reduced carbohydrate (CHO) availability are currently unknown. The aim of the present study was to test the hypothesis that reduced CHO availability enhances p53 signaling and expression of genes associated with regulation of mitochondrial biogenesis and substrate utilization in human skeletal muscle. In a repeated-measures design, muscle biopsies (vastus lateralis) were obtained from eight active males before and after performing an acute bout of high-intensity interval running with either high (HIGH) or low CHO availability (LOW). Resting muscle glycogen (HIGH, 467 +/- 19; LOW, 103 +/- 9 mmol/kg dry wt) was greater in HIGH compared with LOW (P < 0.05). Phosphorylation (P-) of ACC(Ser79) (HIGH, 1.4 +/- 0.4; LOW, 2.9 +/- 0.9) and p53(Ser15) (HIGH, 0.9 +/- 0.4; LOW, 2.6 +/- 0.8) was higher in LOW immediately postexercise and 3 h postexercise, respectively (P < 0.05). Before and 3 h postexercise, mRNA content of pyruvate dehydrogenase kinase 4, mitochondrial transcription factor A, cytochrome-c oxidase IV, and PGC-1alpha were greater in LOW compared with HIGH (P < 0.05), whereas carnitine palmitoyltransferase-1 showed a trend toward significance (P = 0.09). However, only PGC-1alpha expression was increased by exercise (P < 0.05), where three-fold increases occurred independently of CHO availability. We conclude that the exercise-induced increase in p53 phosphorylation is enhanced in conditions of reduced CHO availability, which may be related to upstream signaling through AMPK. Given the emergence of p53 as a molecular regulator of mitochondrial biogenesis, such nutritional modulation of contraction-induced p53 activation has implications for both athletic and clinical populations. PMID- 23364528 TI - Inhibitory mechanism of the nucleus of the solitary tract involved in the control of cardiovascular, dipsogenic, hormonal, and renal responses to hyperosmolality. AB - The nucleus of the solitary tract (NTS) is the primary site of visceral afferents to the central nervous system. In the present study, we investigated the effects of lesions in the commissural portion of the NTS (commNTS) on the activity of vasopressinergic neurons in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, plasma vasopressin, arterial pressure, water intake, and sodium excretion in rats with plasma hyperosmolality produced by intragastric 2 M NaCl (2 ml/rat). Male Holtzman rats with 15-20 days of sham or electrolytic lesion (1 mA; 10 s) of the commNTS were used. CommNTS lesions enhanced a 2 M NaCl intragastrically induced increase in the number of vasopressinergic neurons expressing c-Fos in the PVN (28 +/- 1, vs. sham: 22 +/- 2 c-Fos/AVP cells) and SON (26 +/- 4, vs. sham: 11 +/- 1 c-Fos/AVP cells), plasma vasopressin levels (21 +/- 8, vs. sham: 6.6 +/- 1.3 pg/ml), pressor responses (25 +/- 7 mmHg, vs. sham: 7 +/- 2 mmHg), water intake (17.5 +/- 0.8, vs. sham: 11.2 +/- 1.8 ml/2 h), and natriuresis (4.9 +/- 0.8, vs. sham: 1.4 +/- 0.3 meq/1 h). The pretreatment with vasopressin antagonist abolished the pressor response to intragastric 2 M NaCl in commNTS-lesioned rats (8 +/- 2.4 mmHg at 10 min), suggesting that this response is dependent on vasopressin secretion. The results suggest that inhibitory mechanisms dependent on commNTS act to limit or counterbalance behavioral, hormonal, cardiovascular, and renal responses to an acute increase in plasma osmolality. PMID- 23364529 TI - Role of cardiac natriuretic peptides in seawater adaptation of medaka embryos as revealed by loss-of-function analysis. AB - Cardiac natriuretic peptides (atrial natriuretic peptide, ANP; b-type natriuretic peptide, BNP; ventricular natriuretic peptide, VNP) and their direct ancestor C type natriuretic peptide 3 (CNP3) exert potent osmoregulatory actions in fish. However, very little is known about their roles in embryonic osmoregulation. In this study, we performed loss-of-function analysis using euryhaline medaka (Oryzias latipes), which has lost ANP and VNP during evolution and thus possesses only BNP and CNP3. We found that the maintenance of whole-body osmolality in seawater embryos was impaired by the knockdown of BNP+OLGC7 (BNP receptor) or CNP3 alone from 1 day postfertilization, and the CNP3 knockdown was accompanied by greater water loss. The impaired osmoregulation in the knockdown embryos was not due to the suppressed expression of major transporters for NaCl excretion via ionocytes or of key enzyme genes for metabolic water production, but to the impaired blood circulation to the yolk-sac membrane caused by abnormal heart development. We detected a strong positive correlation between impaired blood circulation and increased body fluid osmolality and pharmacological blockade of blood flow increased body fluid osmolality in seawater embryos. We also found that the exaggerated water loss in CNP3 knockdown embryos is related to the failure to suppress aquaporin (AQP3, AQP4, and AQP9) gene expression. These results show that CNP3 decrease water permeability of body surfaces and that both BNP and CNP3 ensure sufficient blood flow to the yolk-sac membrane for efficient salt excretion by ionocytes and sufficient water production by yolk metabolism to promote seawater adaptation during early development in medaka. PMID- 23364527 TI - Mitochondrial morphology transitions and functions: implications for retrograde signaling? AB - In response to cellular and environmental stresses, mitochondria undergo morphology transitions regulated by dynamic processes of membrane fusion and fission. These events of mitochondrial dynamics are central regulators of cellular activity, but the mechanisms linking mitochondrial shape to cell function remain unclear. One possibility evaluated in this review is that mitochondrial morphological transitions (from elongated to fragmented, and vice versa) directly modify canonical aspects of the organelle's function, including susceptibility to mitochondrial permeability transition, respiratory properties of the electron transport chain, and reactive oxygen species production. Because outputs derived from mitochondrial metabolism are linked to defined cellular signaling pathways, fusion/fission morphology transitions could regulate mitochondrial function and retrograde signaling. This is hypothesized to provide a dynamic interface between the cell, its genome, and the fluctuating metabolic environment. PMID- 23364531 TI - The tight junction protein claudin-b regulates epithelial permeability and sodium handling in larval zebrafish, Danio rerio. AB - The functional role of the tight junction protein claudin-b in larval zebrafish (Danio rerio) was investigated. We showed that claudin-b protein is expressed at epithelial cell-cell contacts on the skin. Translational gene knockdown of claudin-b protein expression caused developmental defects, including edema in the pericardial cavity and yolk sac. Claudin-b morphants exhibited an increase in epithelial permeability to the paracellular marker polyethylene glycol (PEG-4000) and fluorescein isothiocyanate-dextran (FD-4). Accumulation of FD-4 was confined mainly to the yolk sac and pericardial cavity in the claudin-b morphants, suggesting these regions became particularly leaky in the absence of claudin-b expression. Additionally, Na(+) efflux was substantially increased in the claudin b morphants, which contributed to a significant reduction in whole-body Na(+) levels. These results indicate that claudin-b normally acts as a paracellular barrier to Na(+). Nevertheless, the elevated loss of Na(+) in the morphants was compensated by an increase in Na(+) uptake. Notably, we observed that the increased Na(+) uptake in the morphants was attenuated in the presence of the selective Na(+)/Cl(-)-cotransporter (NCC) inhibitor metolazone, or during exposure to Cl(-)-free water. These results suggested that the increased Na(+) uptake in the morphants was, at least in part, mediated by NCC. Furthermore, treatment with an H(+)-ATPase inhibitor bafilomycin A1 was found to reduce Na(+) uptake in the morphants, suggesting that H(+)-ATPase activity was essential to provide a driving force for Na(+) uptake. Overall, the results suggest that claudin-b plays an important role in regulating epithelial permeability and Na(+) handling in zebrafish. PMID- 23364530 TI - Comparative physiology and architecture associated with the mammalian urine concentrating mechanism: role of inner medullary water and urea transport pathways in the rodent medulla. AB - Comparative studies of renal structure and function have potential to provide insights into the urine-concentrating mechanism of the mammalian kidney. This review focuses on the tubular transport pathways for water and urea that play key roles in fluid and solute movements between various compartments of the rodent renal inner medulla. Information on aquaporin water channel and urea transporter expression has increased our understanding of functional segmentation of medullary thin limbs of Henle's loops, collecting ducts, and vasa recta. A more complete understanding of membrane transporters and medullary architecture has identified new and potentially significant interactions between these structures and the interstitium. These interactions are now being introduced into our concept of how the inner medullary urine-concentrating mechanism works. A variety of regulatory pathways lead directly or indirectly to variable patterns of fluid and solute movements among the interstitial and tissue compartments. Animals with the ability to produce highly concentrated urine, such as desert species, are considered to exemplify tubular structure and function that optimize urine concentration. These species may provide unique insights into the urine concentrating process.(1) PMID- 23364532 TI - Inhibition of TWIST1 leads to activation of oncogene-induced senescence in oncogene-driven non-small cell lung cancer. AB - A large fraction of non-small cell lung cancers (NSCLC) are dependent on defined oncogenic driver mutations. Although targeted agents exist for EGFR- and EML4-ALK driven NSCLCs, no therapies target the most frequently found driver mutation, KRAS. Furthermore, acquired resistance to the currently targetable driver mutations is nearly universally observed. Clearly a novel therapeutic approach is needed to target oncogene-driven NSCLCs. We recently showed that the basic helix loop-helix transcription factor Twist1 cooperates with mutant Kras to induce lung adenocarcinoma in transgenic mouse models and that inhibition of Twist1 in these models led to Kras-induced senescence. In the current study, we examine the role of TWIST1 in oncogene-driven human NSCLCs. Silencing of TWIST1 in KRAS-mutant human NSCLC cell lines resulted in dramatic growth inhibition and either activation of a latent oncogene-induced senescence program or, in some cases, apoptosis. Similar effects were observed in EGFR mutation-driven and c-Met amplified NSCLC cell lines. Growth inhibition by silencing of TWIST1 was independent of p53 or p16 mutational status and did not require previously defined mediators of senescence, p21 and p27, nor could this phenotype be rescued by overexpression of SKP2. In xenograft models, silencing of TWIST1 resulted in significant growth inhibition of KRAS-mutant, EGFR-mutant, and c-Met-amplified NSCLCs. Remarkably, inducible silencing of TWIST1 resulted in significant growth inhibition of established KRAS-mutant tumors. Together these findings suggest that silencing of TWIST1 in oncogene driver-dependent NSCLCs represents a novel and promising therapeutic strategy. PMID- 23364533 TI - Diminished origin-licensing capacity specifically sensitizes tumor cells to replication stress. AB - Previous studies have shown that dormant licensed replication origins can be exploited to enhance recovery from replication stress. Since tumor cells express high levels of origin-licensing proteins, we examined whether depletion of such factors might specifically sensitize tumor versus nontumor cells. Consistent with previous findings, we observed that three tumor-derived cell lines overexpress ORC1, a licensing component, compared with four nontumor cell lines and that a greater level of ORC1 was required to maintain viability in the tumor cells. We determined siRNA-mediated knockdown conditions for each line that maximally reduced ORC1 but did not impact upon viability, which we considered would optimally deplete dormant origins. ORC1 depletion hypersensitized the tumor derived cells to hydroxyurea and H202 but did not affect the sensitivity of the nontumor lines. Similar results were observed following depletion of ORC6 or CDC6. Furthermore, codepletion of p53 and ORC1 modestly impaired viability of 1BR3hTERT nontumor fibroblasts and more dramatically caused hypersensitivity to hydroxyurea. Finally, overexpression of the c-Myc oncogene combined with ORC1 depletion in nontumor BJhTERT cells diminished viability. Collectively, these findings suggest that tumor cells may have a reliance on origin-licensing capacity, suggesting that licensing factors could represent a target for drug based cancer therapy. PMID- 23364535 TI - Significance of divergent expression of prostaglandin EP4 and EP3 receptors in human prostate cancer. AB - PGE2 has been implicated in prostate cancer tumorigenesis. We hypothesized that abnormal prostaglandin receptor (EPR) expression may contribute to prostate cancer growth. Twenty-six archived radical prostatectomy specimens were evaluated by immunohistochemistry (IHC) and Western blotting for the expression of EP1, EP2, EP3, and EP4. As a corollary, EPR expression in one normal (PZ-HPV7) and four prostate cancer cell lines (CA-HPV10, LNCaP, PC3, and Du145) were assessed by Western blotting. Prostate cancer and normal cell growth were compared in vitro after EPR blockade, siRNA EPR knockdown, or overexpression. EP1, EP2, EP3, and EP4 receptors were detected by IHC in all areas of benign tissue within the clinical prostate cancer specimens. In areas of prostate cancer, EP4 and EP2 were overexpressed in 85% (22 of 26) and 75% (18 of 24) and EP3 expression was reduced in all (26 of 26, 100%) specimens (P < 0.05 vs. benign tissue). EP1 showed no specific differential expression pattern. Increased EP4 and reduced EP3 was confirmed by Western blotting in fresh clinical specimens and in prostate cancer cell lines (CA-HPV10, LNCaP, PC3, and Du145) compared with the normal prostate cell line (PZ-HPV7). EP2 and EP4 siRNA knockdown resulted in reduced in vitro growth and metastasis-related gene expression (MMP9 and Runx2) of prostate cancer lines, and in vitro migration was inhibited by EP4 antagonists. As a corollary, EP3-overexpressing PC3 cells displayed impaired growth in vitro. Human prostate cancer is associated with EP4 and EP2 overexpression and reduced EP3 expression. These data suggest that targeting specific EPR may represent a novel therapeutic approach for prostate cancer. PMID- 23364534 TI - Alpha-CaMKII plays a critical role in determining the aggressive behavior of human osteosarcoma. AB - Osteosarcoma is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. Despite improvements in osteosarcoma treatment, more specific molecular targets are needed as potential therapeutic options. One target of interest is alpha-Ca(2+)/calmodulin-dependent protein kinase II (alpha-CaMKII), a ubiquitous mediator of Ca(2+)-linked signaling, which has been shown to regulate tumor cell proliferation and differentiation. Here, we investigate the role of alpha-CaMKII in the growth and tumorigenicity of human osteosarcoma. We show that alpha-CaMKII is highly expressed in primary osteosarcoma tissue derived from 114 patients, and is expressed in varying levels in different human osteosarcoma (OS) cell lines [MG 63, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)/HOS, and 143B). To examine whether alpha-CaMKII regulates osteosarcoma tumorigenic properties, we genetically inhibited alpha-CaMKII in two osteosarcoma cell lines using two different alpha-CaMKII shRNAs delivered by lentiviral vectors and overexpressed alpha-CaMKII by retrovirus. The genetic deletion of alpha-CaMKII by short hairpin RNA (shRNA) in MG-63 and 143B cells resulted in decreased proliferation (50% and 41%), migration (22% and 25%), and invasion (95% and 90%), respectively. The overexpression of alpha-CaMKII in HOS cells resulted in increased proliferation (240%), migration (640%), and invasion (10,000%). Furthermore, alpha-CaMKII deletion in MG-63 cells significantly reduced tumor burden in vivo (65%), whereas alpha-CaMKII overexpression resulted in tumor formation in a previously nontumor forming osteosarcoma cell line (HOS). Our results suggest that alpha-CaMKII plays a critical role in determining the aggressive phenotype of osteosarcoma, and its inhibition could be an attractive therapeutic target to combat this devastating adolescent disease. PMID- 23364536 TI - SNF5 reexpression in malignant rhabdoid tumors regulates transcription of target genes by recruitment of SWI/SNF complexes and RNAPII to the transcription start site of their promoters. AB - Malignant rhabdoid tumor (MRT), a highly aggressive cancer of young children, displays inactivation or loss of the hSNF5/INI1/SMARCB1 gene, a core subunit of the SWI/SNF chromatin-remodeling complex, in primary tumors and cell lines. We have previously reported that reexpression of hSNF5 in some MRT cell lines causes a G1 arrest via p21(CIP1/WAF1) (p21) mRNA induction in a p53-independent manner. However, the mechanism(s) by which hSNF5 reexpression activates gene transcription remains unclear. We initially searched for other hSNF5 target genes by asking whether hSNF5 loss altered regulation of other consensus p53 target genes. Our studies show that hSNF5 regulates only a subset of p53 target genes, including p21 and NOXA, in MRT cell lines. We also show that hSNF5 reexpression modulates SWI/SNF complex levels at the transcription start site (TSS) at both loci and leads to activation of transcription initiation through recruitment of RNA polymerase II (RNAPII) accompanied by H3K4 and H3K36 modifications. Furthermore, our results show lower NOXA expression in MRT cell lines compared with other human tumor cell lines, suggesting that hSNF5 loss may alter the expression of this important apoptotic gene. Thus, one mechanism for MRT development after hSNF5 loss may rely on reduced chromatin-remodeling activity of the SWI/SNF complex at the TSS of critical gene promoters. Furthermore, because we observe growth inhibition after NOXA expression in MRT cells, the NOXA pathway may provide a novel target with clinical relevancy for treatment of this aggressive disease. PMID- 23364538 TI - Childhood mortality due to unintentional injuries in Japan, 2000–2009. AB - This study examined deaths due to unintentional injuries among children in Japan to identify the age groups and sexes at most risk, and the types of injuries, so that effective forms of targeted intervention can be devised. Among children aged 0-14 years, deaths whose underlying causes had been classified under code V01-X59 of the ICD-10 were defined as deaths of children caused by unintentional injuries. Using data from the Vital Statistics 2000-2009 for analysis, we examined the changes in mortality and trends in terms of sex, age, and cause of death. Mortality decreased by 46.2%, from 933 in 2000 to 502 in 2009. The mortality rate among children aged 1-4 years decreased by almost half. The total number of deaths during this decade was 7,362 (boys: 4,690, girls: 2,672). Among the causes of death, the majority were due to "transport accidents", followed by "other accidental threats to breathing", and "accidental drowning and submersion". The characteristics observed in terms of sex, age, and cause of death--that is, deaths from suffocation among infants aged less than 1 year, drowning deaths among boys, and transport accidents involving pedestrians and cyclists--must be addressed as targets for future intervention. PMID- 23364537 TI - Effects of simultaneous knockdown of HER2 and PTK6 on malignancy and tumor progression in human breast cancer cells. AB - Breast cancer is the most common malignancy in women of the Western world. One prominent feature of breast cancer is the co- and overexpression of HER2 and protein tyrosine kinase 6 (PTK6). According to the current clinical cancer therapy guidelines, HER2-overexpressing tumors are routinely treated with trastuzumab, a humanized monoclonal antibody targeting HER2. Approximately, 30% of HER2-overexpressing breast tumors at least initially respond to the anti-HER2 therapy, but a subgroup of these tumors develops resistance shortly after the administration of trastuzumab. A PTK6-targeted therapy does not yet exist. Here, we show for the first time that the simultaneous knockdown in vitro, compared with the single knockdown of HER2 and PTK6, in particular in the trastuzumab resistant JIMT-1 cells, leads to a significantly decreased phosphorylation of crucial signaling proteins: mitogen-activated protein kinase 1/3 (MAPK 1/3, ERK 1/2) and p38 MAPK, and (phosphatase and tensin homologue deleted on chromosome ten) PTEN that are involved in tumorigenesis. In addition, dual knockdown strongly reduced the migration and invasion of the JIMT-1 cells. Moreover, the downregulation of HER2 and PTK6 led to an induction of p27, and the dual knockdown significantly diminished cell proliferation in JIMT-1 and T47D cells. In vivo experiments showed significantly reduced levels of tumor growth following HER2 or PTK6 knockdown. Our results indicate a novel strategy also for the treatment of trastuzumab resistance in tumors. Thus, the inhibition of these two signaling proteins may lead to a more effective control of breast cancer. PMID- 23364539 TI - [The expression and modulatory role of reprogramming markers on the in vivo regeneration of dental pulp and periodontal ligament tissue after injury]. AB - PURPOSE: The purpose of this study was to investigate the expression of reprogramming markers including Oct-4, Sox2 and c-Myc in rat dental pulp and periodontal ligament tissues undergoing tissue regeneration after injury. METHODS: Lewis rat model with dental pulp and periodontal ligament injury was created. HE staining was applied to investigate the structure of newly formed dentin-pulp complex and periodontium. The distribution of Oct-4, Sox2 and c-Myc was determined by immunofluorescent staining. RESULTS: HE staining showed that newly formed dentin-pulp complex and periodontium was constructed 4 weeks after injury. Immunofluorescent staining revealed Oct-4, Sox2 and c-Myc signal was activated in the newly formed dental pulp and periodontal ligament tissue after injury compared with the normal ones. Oct-4 and Sox2 showed similar expression pattern. CONCLUSIONS: Oct-4, Sox2 and c-Myc signaling may play an important modulatory role in the dental tissue regeneration after injury. Oct-4 and Sox2 may have operative interaction whereas c-Myc may play independent role during this process. PMID- 23364540 TI - [The change of calcitonin gene- related peptide in periodontal tissue during orthodontic tooth movement]. AB - PURPOSE: To establish a Sprague-Dawley rat model of tooth movement, detect the expression of calcitonin gene-related peptide (calcitonin gene related peptide, CGRP) in Sprague-Dawley rats' periodontal tissues during tooth movement and explore the role of the peripheral mechanisms of pain in orthodontics. METHODS: 60 Sprague-Dawley rats were randomly divided into experimental group (n=54) and control group (n=6). Force was applied on right maxillary first molar in rats and the changes of CGRP expression were detected by real-time PCR 4 h, 8 h, 1 d, 3 d, 5 d, 7 d, 14 d after tooth movement. SPSS 13.0 software package was selected and one-way ANOVA (least significant difference, LSD) was used for statistics analysis. RESULTS: Experimental tooth movement led to an increase in the expression of CGRP. In addition, following experimental tooth movement, the expression of CGRP in periodontal tissues was significantly up-regulated from 4 h, with a peak on 1d and returned to the control level at 2-week. 1 d after experimental tooth movement, the application of different forces to rats induced a significant increase in CGRP expression. CONCLUSION: The regular change of CGRP expression in periodontal tissues indicates that CGRP may play an important role in peripheral mechanism of orthodontic pain. PMID- 23364541 TI - [Inhibitory effect of VEGF antisense phosphorothioate oligodeoxynucleotides on the growth of human salivary adenoid cystic carcinoma xenografts in nude mice]. AB - PURPOSE: To investigate the inhibitory effect of VEGF antisense phosphorothioate oligodeoxynucleoiides on the growth of human salivary adenoid cystic carcinoma (SACC) xenografts in nude mice. METHODS: The VEGF-ASODN was synthesised artificially. After the model of human SACC xenografts in nude mice was established, they were random1y divided into three groups: antisense group, scrambled group and normal saline group. A control group without cancer was also established. Antisense(66 MUg), scrambled sequence(66 MUg) and normal saline(once every 3 days and 7 times in all) were injected in three experimental groups, respectively. Two days after therapy, the mice were sacrificed. Serums were used for detection of VEGF protein. All tumors were measured and weighted. The quantity of VEGF mRNA and protein and PLI, MVD was detected by hybridization in situ and immunohistochemistry. SPSS13.0 software package was used for statistical analysis. RESULTS: The VEGF-ASODN could suppress the expression of VEGF in human SACC xenografts in nude mice and reduce VEGF protein in serum of nude mice significantly. It cou1d also reduce the volume and weight of xenografts and could reduce the expression of VEGF mRNA and its protein, PCNA and CD34. CONCLUSION: By inhibiting the expression of VEGF, VEGF-ASODN can inhabit proliferation of human SACC xenografts in nude mice. PMID- 23364542 TI - [Detection of reactive oxygen species of human dental pulp cells by flow cytometry]. AB - PURPOSE: To establish a method for detection of reactive oxygen species(ROS) of human dental pulp cells(HDPCs) by flow cytometry. METHODS: HDPCs were obtained using tissue explant technique in vitro. The subcultured cells were exposed to peroxide oxygen(H2O2) of different concentrations from 50 MUmol/L to 400 MUmol/L for 30 minutes, then incubated with two different concentrations of 2',7' dichlorofluorescein diacetate (DCFH-DA), which were 10 MUmol/L and 20 MUmol/L for 20 minutes at 37 degrees centigrade in dark. The fluorescence intensities of intracellular dichlorofluorescein(DCF) were detected by flow cytometry. Statistical analysis was carried out by SPSS 13.0 software software. RESULTS: The positive rate varied with different concentrations of detectors. The fluorescence intensities remained insignificant difference among samples incubated with the same concentration of detector and H(2)O(2),and increased by rising of the incubating concentration of H(2)O(2). CONCLUSIONS: The detector with concentration of 20 MUmol/L shows higher detector loading rate(positive rate). The intracellular ROS level changes as the H(2)O(2) treatment concentration rising from 50 to 400 MUmol/L. The application of flow cytometry to measure the ROS in HDPCs is simple, reliable and stable. PMID- 23364543 TI - [Ectopic osteogenesis of SGDs in goat's muscle pouch]. AB - PURPOSE: To investigate ectopic osteogenesis of composites SGDs with porous calcium phosphate cement(pCPC) in goat's muscle pouch. METHODS: SGDs were cultivated with modified tissue culture techniques, then were induced into osteoblasts in the third passage, the osteogenic-induced SGDs were combined with pCPC and transplanted into the goat left dorsal muscle pouch, the pCPC without cells was transplanted into the right dorsal muscle pouch as negative controls. The transplants were harvested at 2-,4-,6-,8- week and prepared for histological examination. The morphologic quantitative analysis was made by SPSS 16.0 software package. RESULTS: Bone formation was not detected in pCPC without cells by histological examination. 2,4,6,8 weeks after transplantation in SGDs-pCPC group, the percentages of bone formation were (1.24+/-0.25)%,(1.59+/-0.23)%,(4.12+/ 0.39)% and (5.68+/-0.58)%,respectively.There was no significant difference in bone formation at 2 and 4 weeks after transplantation (P>0.05). At 8- week, the percentages of bone formation were higher than that at 6- week in SGDs-pCPC group, and both significantly higher than that at 2- and 4- week(P<0.05). CONCLUSION: SGDs combined with pCPC have the ability of ectopic osteogenesis. PMID- 23364544 TI - [Study of oral precancerous lesion and oral cancer by using micro PET/CT]. AB - PURPOSE: To study oral precancerous lesion and oral cancer by using micro PET/CT. METHODS: Thirty-nine SD rats were divided into experimental group and control group. 33 of them were raised with a 4-nitroquinoline-1-oxide (4NQO) solution with the concentration of 0.002% during the first 13 weeks, and then changed to normal water. The other 6 rats drank normal water all the time. During 25th to 30th week of the experiment, 2-Deoxy-2-[F-18]fluoro-D-glucose (FDG)-PET/CT was performed for these rats. One day after imaging, pathological examination was performed. SUVmax and T/NT were investigated according to pathological results. SAS6.0 software package was used for statistical analysis. RESULTS: There was no significant difference in SUVmax among the normal group, precancerous group and cancerous group (P>0.05). There was significant difference in T/NT(muscle, brain) between the normal group and the cancerous group (P<0.05). But there was no significant difference between the normal group and the precancerous group (P>0.05); and no significant difference between the precancerous group and the cancerous group (P>0.05). The T/NT (muscle, brain) ratios increased along with the increase of the pathologic grade of the lesions. There was no significant difference in T/NT(thyroid) among the three groups and no correlation between the T/NT(thyroid) ratios and the pathologic grade. CONCLUSIONS: Micro PET/CT, as a non-invasive technology, may contribute to the dynamic studies of the process of carcinogenesis. T/NT(muscle, brain) ratios could show the degree of lesions of rat's tongue during carcinogenesis. PMID- 23364545 TI - [Cytocompatibility of chitosan-based thermosensitive hydrogel to human periodontal ligament cell]. AB - PURPOSE: The aim of this investigation was to evaluate the cytocompatibility of an in situ chitosan-quaternized chitosan/alpha, beta-glycerophosphate (CS HTCC/GP) thermosensitive hydrogel in vitro. METHODS: The primary cells were isolated from human periodontal ligament and cultured. The role of different concentrations of CS-HTCC/GP extract to HPDLCs was evaluated by MTT assay and alkaline phosphatase (ALP) activity. Also, the ultra-architecture of HPDLCs was determined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) respectively. SPSS13.0 software package was used for statistical analysis. RESULTS: By immunocytochemical method, the cells were stained positively to antibodies against vimentin, and negatively to antibodies against cytokeratin, which indicated that they were external embryo mesenchymal cell without epithelial cell mixure. CS-HTCC/GP thermosensitive hydrogel promoted proliferation of HPDLCs,especially at 3d and 5d, the results was significantly different (P<0.001). ALP activity was significantly greater in group 2 and 3 than in group 4 after 5d (P<0.001). Also, no negative influence to ultrastructure of HPDLCs was found through SEM and TEM. CONCLUSIONS: The results indicate that CS HTCC/GP thermosensitive hydrogel exhibits excellent cytocompatibility and has potential to be used as an in situ injectable local periodontal drug delivery vehicle and a tissue-engineering scaffold for periodontal disease therapy. PMID- 23364546 TI - [An anticaries experimental study of SD rat immunized by recombinant plasmid pEGFP-N1-Srv+ encoding the V-region of surface protein of Streptococcus mutans]. AB - PURPOSE: An anticaries DNA vaccine pEGFP-N1-Srv+ was used to immunize rats by different immune pathways. The expression of recombinant plasmid in different tissues in vivo and the specific immune response and protection effects against dental caries were observed. METHODS: 20 SD rats were divided into 4 groups, immunized with the recombinant plasmid pEGFP-N1-SrV+ by submandibular gland target injection(TSG), and intramuscular injection,respectively; then the expression of recombinant plasmid in different tissues were detected by immunohistochemistry technique. 24 SD rats were divided into 4 groups, immunized with recombinant plasmid pEGFP-N1-SrV+ of 100 MUg, then boosted once after two weeks, through the same routes as above;then indirect ELISA technique was used to detect the specific antibodies. Keyes caries scores were used to evaluate the anticaries effects. The data was analyzed by using SPSS17.0 software package. RESULTS: (1)Recombinant plasmid was positively expressed in the muscle fibers and submandibular glands.(2)The specific salivary anti-SR IgA and serum IgG were detected, and the peak time of the antibodies level appeared 4 weeks after initial . At the 4th week, the levels of specific anti-SR antibodies were higher in the experimental group than that in the negative control group. The levels of salivary specific anti-SR IgA were significantly higher in TSG immunization group than that in the intramuscular injection group. (3)Keyes caries scores were not significantly different between the experimental groups and negative control groups. recombinant plasmid pEGFP-N1-Srv+ expressed in vivo and effectively increased specific salivary anti-SR IgA and serum IgG, and TSG immunization route significantly increased the specific salivary anti-SR IgA compared with the intramuscular immunization route;however, the recombinant plasmid pEGFP-N1-Srv+ alone can not protect the rats from dental caries. CONCLUSIONS: The recombinant plasmid pEGFP-N1-SrV+ expressed in vivo and effectively increased specific salivary anti-SR IgA and serum IgC, and TSG immunization route significantly increased the specific salivary anti-SR IgA compared with the intramuscular immunization route; however, the recombinant plasmid pEGFP-N1-Srv+ alone can not protect the rats from dental caries. PMID- 23364547 TI - [Effect of compound Chinese traditional medicine on periapical periodontitis in dogs and cytotoxic assay]. AB - PURPOSE: To assess the efficacy of compound Chinese traditional medicine(CTM), which is composed of gallic acid, magnolol and polysaccharide of Bletilla, against apical periodontitis in dogs and cytotoxic assay. METHODS: A animal model of apical periodontitis was built, CTM was then used to disinfect the root canal. The effect of the restoration of periapical bone in dogs was investigated after regular root canal filling. SAS6.12 software package was used for statistical analysis, and MTT was used to test cell toxicity of CTM. RESULTS: CTM can cure inflammation effectively, and CTM had no cytotoxic effect on periodontal ligament cells at 5-week. CONCLUSIONS: The compound Chinese traditional medicine may be an effective disinfecting drug for root canal disinfection. PMID- 23364548 TI - [The effect of different retention pin on the shear force of anterior base plate]. AB - PURPOSE: The purpose of this study was to compare the effect of enhancement by different shape retention nails on the anterior region resin denture base through shear strength measurements. METHODS: 24 specimens with the same size and thickness were divided into 4 groups by the shape of retention nails. Three experimental groups of the resin denture base specimen were placed a retention nail with different shape, Deltatype, V type and I type. Another group of 6 specimens without nail was used as control. All the samples' shear forces were tested by universal mechanical testing machine, and the data was statistically analyzed by SPSS 10.1 software package. RESULTS: The shear forces of Deltatype group, V type group, the I type group and control group, were respectively (326.80+/-64.17) N, (225.07+/-31.76) N, (182.85+/-15.18) N, and (116.67soil 4.35) N. According to the statistical results, the difference of shear forces had no significant difference (P>0.05) between I type and V type, although the shear forces of these two groups were significantly greater than the control group (P<0.05). The shear forces of Delta type group were significantly greater than the other three groups (P<0.05). CONCLUSIONS: The retention nail of Delta shape can significantly enhance the anti-shear ability of resin denture base. PMID- 23364549 TI - [Use of digital image correlation method to measure polymerization shrinkage dynamics of light cured composite resin]. AB - PURPOSE: To evaluate the role of digital image correlation method in measuring the initiation and propagation of polymerization shrinkage of light cured composite resin. METHODS: Six freshly extracted complete molars were collected and divided into 2 groups randomly. The proximal surface was sliced to plane and proximal-occlusal cavity were prepared with 2.0 mm*2.0 mm*2.0 mm in size, then the tissue surface was treated with etch and bond. The cavity samples in the first group were filled with 3M Z350, and the samples in the second group were filled with material 3M Valux Plus, the proximal surfaces were dealt with random speckle, then fixed to micro tensile framework. As light curing proceeded for 40 seconds, all the speckled images were collected by digital camera in real-time simultaneously. The digital image correlation analysis software was used to deal these images and achieve the displacement and strains in both horizontal and vertical direction on all pixel points, at last the linear shrinkage ratios were counted and the displacement at free surface of the two materials at the 20th second were analyzed with SPSS 12.01 software package for Student's t test. RESULTS: The results showed displacement and strain distribution were accurately achieved and their correlation ratios (R) were bigger than 0.98. The shrinkage represented anisotropy with different direction and unequal value in 40 seconds. The linear shrinkage values of the two materials were 0.439%-0.75%, 0.526%-0.834% in horizontal direction and 0.253%-1.34%, 0.355%-1.51% in vertical direction,respectively. Considering the displacement at the 20th second, shrinkage of Z350 was lower than V. P's both in horizontal and vertical directions (P<0.05). CONCLUSIONS: This study indicates that digital image correlation method can be used to study the polymerization shrinkage of light cured composites kinematically and effectively, and calculate displacement and strain continually in full fields. Also this method is much closer to clinic application, and can give more theoretical and experimental evidence for clinic use. PMID- 23364550 TI - [The effect of disinfectant soaking on dental gypsum model size]. AB - PURPOSE: To study the influence of disinfectant soaking on the dimensional stability of three kinds of dental gypsum model. METHODS: Three commonly used gypsums ( type III,IV,Vtype) in clinic were used to make 24 specimens for 50 mm*15 mm*10 mm in size. One hour after release, the specimens were placed for 24 h. A digital caliper was used to measure the size of the gypsum model. Distilled water immersion was as used control, glutaraldehyde disinfectant and Metrix CaviCide disinfectant soaking were used for the experimental group. After soaking for 0.5h, the gypsum models were removed and placed for 0.5 h, 1 h, 2 h, 24 h. The size of the models was measured again using the same method. The data was analyzed with SPSS10.0 software package. RESULTS: The initial gypsum model length was (50.07+/-0.017) mm, (50.048+/-0.015) mm and (50.027+/-0.015) mm. After soaking for different times, the size of the model changed little, and the dimensions changed less than 0.01%. CONCLUSION: The results show that disinfectant soaking has no significant effect on dental model dimensions. PMID- 23364551 TI - [Association of variants in chromosome 9p21.3 and chronic periodontitis in the Han Chinese population]. AB - PURPOSE: To investigate the association of the single nucleotide polymorphism (SNP) in chromosome 9p21.3 and chronic periodontitis in the Han Chinese population. METHODS: rs2891168,rs1333048 and rs1333042 genotypes of randomly grouped 172 healthy control subjects and 221 patients with chronic periodontitis(CP) were genotyped by TaqMan probe real-time fluorescent quantitative PCR. Statistical analysis of Chi-square test was performed using SPSS16.0 software package. RESULTS: Rs2891168 was closely associated with chronic periodontitis(P=0.003), and the frequency of G allele was higher in the patients compared with the control(48.36% vs 40.00%, OR=1.209, 95% CI: 1.001-1.461, P=0.045). Rs1333048 and rs1333042 were not associated with chronic periodontitis. CONCLUSIONS: There is SNP correlated with chronic periodontitis in chromosome 9p21.3, which indicates that the 9p21.3 locus may be the susceptible region. However, the mechanism remains unclear. PMID- 23364552 TI - [Condylar position and condylar symmetry in patients with temporomandibular disorders]. AB - PURPOSE: To investigate condylar position and condylar symmetry in patients with temporomandibular disorders (TMD) as well as malocclusion. METHODS: Fifteen patients with TMD and malocclusion were selected for the experiment, 15 asymptomatic patients served as controls. The bilateral temporomandibular joints of all subjects were evaluated by computed tomography (CT) imaging. Both the joint spaces and the condylar symmetry were determined, based on the axial CT images properly chose. All statistical analysis were performed using SPSS17.0 software package. RESULTS: The condyle of the patients in the experimental group were seated more posteriorly, while slight anterior condylar position were found in the control group. In the experimental group, the horizontal angle of the condyle in the symptomatic side was larger than that in the asymptomatic side (P<0.05), while the vertical angle was just opposite (P<0.05). No statistically significant asymmetries were found in the mediolateral diameter,the anteroposterior diameter, the angle of condylar axis, the distance between condylar center to midsagittal plane and anteroposterior difference of condyle center. CONCLUSION: Obvious posterior condylar position and vertical asymmetry exist in patients with temporomandibular disorders. PMID- 23364553 TI - [Investigation on facial profile preferences of orthodontic patients]. AB - PURPOSE: To investigate facial profile preferences of orthodontic patients and determine whether the patient's age and sex were influential factors in the esthetic perception for providing reference for clinical practice. METHODS: Profile digital photographs of each patient were used. Changes in facial convexity were established by altering the position of mandible incrementally with Photoshop 7.0. Thus profile images of various degrees of mandiblular anteroposterior discrepancy for each patient was generated. Then an electronic questionnaire was designed and administered to investigate tolerable boundary values for mandibular retrognathism, tolerable boundary values for mandibular prognathism and most pleasing profiles of 203 subjects (average age 19.2+/-6.0 years; 70 males, 133 females). Differences between male and female profiles in the esthetic perception of patients were analyzed by Wilcoxon matched-pairs signed ranks test. Comparison of esthetics perception for male and female profiles regarding patient's sex and age was made by Wilcoxon rank sum test of two independent samples. All statistical analysis was performed using SPSS 17.0 software package. RESULTS: The zone of acceptability of facial convexity was 168 degrees -180 degrees for male model and 160 degrees -172 degrees for female model. The most pleasing profile was 172 degrees for male and 168 degrees for female. There was no significant difference between male and female patients in facial profile preferences (P>0.05). The differences in facial profile preferences between adult group and immature group were statistically significant (P<0.05). In the comparison of age groups, the adult group preferred bigger facial convexity angles than immature group for male and female retrognathia profile, male prognathia profile and male most pleasing profile. CONCLUSIONS: The zone of acceptability of facial convexity and the most pleasing profile exist in patients' esthetic perception of profile. There is difference between male and female profiles in the esthetic perception. The facial profile preferences of orthodontic patients are influenced by age, not by sex. PMID- 23364554 TI - [The expression of EGFR in oral lichen planus, squamous cell papilloma and squamous cell carcinoma]. AB - PURPOSE: To study the role of EGFR in the genesis of squamous cell by means of observation on its expression in oral lichen planus(OLP), squamous cell papilloma (SCP)and squamous cell carcinoma(SCC). METHODS: EGFR expression was observed in 20 OLPs, 20 SCPs,20 SCCs and 5 normal oral mucosa specimen by immunohistochemistry. The number of positive cells was counted by Fromowitz method and COX-2 expression was analyzed with SPSS11.5 software package. RESULTS: The expression of EGFR was weak in OLP without erosive and ulcerative lesion. The strongly positive rates of EGFR in OLP with erosive and ulcerative lesion group, SCP group and SCC group were 20%, 25% and 60%, respectively .There were significant differences between the OLP with erosive and ulcerative lesion and OLP without erosive and ulcerative lesion. The expression of EGFR increased significantly from OLP, SCP to SCC (P<0.05). CONCLUSIONS: The expression of EGFR is important in the progression of OLP, SCP and SCC. It can be an important target for chemical prevention and therapy. PMID- 23364555 TI - [Study of the relationship between patients' personality traits and satisfaction after fixed denture restorations]. AB - PURPOSE: To investigate 98 fixed denture patients' personality traits and the relationship between patients' personality traits and satisfaction with fixed denture restoration. METHODS: 16PF questionnaire and satisfaction questionnaire were used to study 98 fixed denture patients' personality traits and the relationship between personality traits and general satisfaction and specific satisfaction. The data was analyzed with SPSS17.0 software package. RESULTS: There were significant differences between 98 fixed denture patients' personality traits and those of health adult in factor B(reasoning), C(emotional stability), E(dominance), F(liveliness), H(social Boldness), I(sensitivity), L(vigilance), N(privateness), O(apprehension), Q(1)(openness to change) and Q(2)(self reliance). The regression analysis demonstrated that Q4(tension), G(rule consciousness), L(vigilance), Q(3)(perfectionism), Q(1)(openness to change), N(privateness), A(warmth) and M(abstractedness)in 16PF were correlated with the general satisfaction of patients after fixed denture restorations (F=20.566' P=0.000, R2=0.649), Q(4), L, Q(3), N and M were negatively correlated with their general satisfaction; however G, Q(1) and A were positively correlated with it. Except the sense of stability and avoid of food impaction,L,C, Q(4) and Q(3) were negatively correlated with their satisfaction on aesthetic effectiveness, while A, G, I and E were positively correlated with it. L, Q(4), N and Q(3) were negatively correlated with their mastication satisfaction, while G and Q(1) were positively correlated with it. O and Q(4) were negatively correlated with their comfortable satisfaction, while C was positively correlated with it. CONCLUSIONS: There is significant difference in personality traits between fixed denture patients and Chinese normal adults. There is close relationship between the personality traits of fixed denture patients and their satisfaction. Meanwhile, the general and specific satisfaction are influenced by different personality traits. It is important to pay more attention to fixed denture patients' personality traits in clinical practice. PMID- 23364556 TI - [The influential factors of patients' compliance with supportive periodontal therapy]. AB - PURPOSE: To discuss the influential factors of patients' compliance with chronic periodontitis during supportive periodontal therapy (SPT) period and the counter measures. METHODS: Chronic periodontal patients completing intial non-surgical therapy with SPT were investigated with a self-designed questionnaire after 2 years by outpatient follow-up and telephone interviews to obtain information for analysis. RESULTS: One hundred and one effective scales were collected. Factors influenced patients' compliance including disease awareness, health care quality, age, education level, economic status and so on. CONCLUSIONS: There are many factors influencing patients' compliance, and the key to improve patient compliance is that doctors should instruct the patients appropriately, follow up annually, and improve the quality of medical services. PMID- 23364557 TI - [Expression and significance of pericytes and TGF-beta in infantile parotid hemangioma]. AB - PURPOSE: To study the expression and significance of pericytes and TGF-beta in infantile parotid hemangioma. METHODS: The expressions of pericytes and TGF-beta at protein level were examined in 76 cases of infant parotid hemangioma by strep avidin-biotin complex (SABC) immunohistochemical technique. All statistical analysis were performed using SPSS 13.0 statistical package. The relationship between the expression of pericytes and TGF-beta and clinical phase of hemangioma was analyzed by using Chi-square test. Kappa test was used to determine the relationship between pericytes and TGF-beta expression. RESULTS: The rates of positive expression of pericytes were 86.7%(13/15), 45.5%(10/22) and 51.3%(20/39) in early, middle and advanced stage of hemangioma, respectively. The rates of positive expression of TGF-beta were 33.3%(5/15), 40.9%(9/22) and 76.9%(30/39) in early, middle and advanced stage of hemangioma, respectively. There was significantly close correlation between the level of pericytes and clinical phase of hemangioma, as well as between TGF-beta expression and clinical phase of hemangioma(P<0.05). CONCLUSION: Pericytes and TGF-beta may significantly contribute to the proliferation of infantile parotid hemangioma. PMID- 23364558 TI - [The prefabricated post and composite resin core technique used in restoring residual crown of posterior tooth]. AB - PURPOSE: To investigate the clinical effect of repairing posterior residual crown using titanium alloy post combined with composite resin core technique. METHODS: Twenty-one patients (26 residual crown) with perfect root canal therapy were selected. Modern bonding technique was used to build up the core with titanium alloy post and flow composite resin together for crown restoration. RESULTS: After ten years of clinical observation, only 4 cases among the 21 patients failed in restoration. The rate of success was 85%. X-ray showed that the periapical alveolar bone density was enhanced after restoration. CONCLUSIONS: Standard root canal therapy and effective post-core strengthening can restore the function of the residual crown and retain the tooth. PMID- 23364559 TI - [Clinical study of large mandibular odontogenic keratocystic tumours in adolescents treated by decompression]. AB - PUPPOSE: To evaluate the effect of decompression for large mandibular odontogenic keratocystic tumours in adolescents. METHODS: Fifteen cases of large odontogenic keratocystic tumours in mandible underwent decompression from Feb.2005 to Feb.2011, the average age of the patients was 19.3 years. Patients were follow-up by X-ray every 2-3 months, and every 6-12 months by CT. Subsequent curettage was given when the remaining tumours were less than 2cm in diameter. RESULTS: The decompression period lasted from 12 to 18 months, with an average time of 13.6 months. After decompression, bone regeneration was noticed on radiographs, the average decrement percentage of the tumour size was 41.5% at 6-month, 61.5% at 12 month and 81.8% at 18-month after operation. All patients were followed up for 1 5 years after secondary surgical curettage, no recurrence was observed. CONCLUSION: Decompression is a preferred treatment for large mandibular odontogenic keratocystic tumours in adolescents. PMID- 23364560 TI - [Removable appliance and closed of central incisors: report of 48 cases]. AB - PURPOSE: To evaluate the treatment effect of orthodontic traction on embedded and inverted maxillary bending central incisors. METHODS: Fifty-two embedded and inverted maxillary central incisors without-eruption ability in 48 cases were treated by combined orthodontic traction with surgical treatment after spiral CT positioning and expanding the space, the eruption situation, gingival-breaking time and teeth pulp vitality after treatment were recorded, and the treatment effect was evaluated. RESULTS: Forty-eight cases with 52 impacted upper central incisors were treated with surgical and closed orthodontic traction, successful results were achieved in 36 cases, accounting for 69.23%; 15 cases had improvement, accounting for 28.85%; 1 case failed, accounting for 1.9%. Pulp vitality tests were all normal and there was no root absorption and ankylosis. CONCLUSIONS: Selecting appropriate cases, precise positioning with spiral CT, proper space expanding and rational application of removable traction appliance are the keys to successful treatment of impacted and inverted maxillary bending central incisors of children in mixed dentition. PMID- 23364561 TI - [Clinical observation of Foley pressurized bladders in treating 32 cases of maxillary comminuted fractures]. AB - PURPOSE: To discuss the application of Foley pressurized bladders with rigid internal fixation in treating 32 cases of maxillary comminuted fractures and analyze the clinical advantages. METHODS: All the 32 cases of maxillary comminuted fractures were approached with maxillary vestibular or coronary incision. The infraorbital border and maxillary forehead were replaced and fixed with titanium plate. Foley pressure bladders was placed through opening into the inferior meatus. Balloon dilatation was used to reposition the maxillary anterior, medial wall and orbital floor fracture. RESULTS: Thirty-two cases of maxillary comminuted fractures were treated with Foley pressurized bladders. The overall curative rate was 97.2%. Patients had less pain and bleeding with slight reaction after surgery. The facial swelling time was shorter and the recovery of the contour was good. CONCLUSIONS: Use of Foley pressurized bladders in maxillary fractures is simple, economical and practical. The result is satisfactory and the indication is wide. PMID- 23364562 TI - [Meta analysis of the comparison between cast metal posts' and fiber posts' clinical results]. AB - PURPOSE: This study was designed to use meta analysis to compare the success rate between cast metal posts and fiber posts after root canal therapy. METHODS: The Chinese literatures published between 2001 and 2011 about the differences between the success rate of cast metal posts and fiber posts were collected. The criteria for inclusion and exclusion was established according to evidence-based medicine method. Meta-analysis was performed with Review Manager 4.2 (RevMan 4.2). RESULTS: Eight literatures were eligible for inclusion in this meta analysis, 929 patients were involved. The RR(relative risk) and 95% CI(confidence interval) were 0.92, 0.89-0.95, respectively. CONCLUION: Fiber post has a higher success rate when used in the restoration of endodontically treated teeth. PMID- 23364563 TI - [Effect of clinical experience on the shade matching accuracy]. AB - PURPOSE: To evaluate the effect of clinical experience on the shade matching accuracy. METHODS: Thirty-seven dental students (group A) who had 1 to 2 years of clinical experience and 57 dental students (group B) who didn't have clinical experience took part in this experiment. Participants were divided into two groups (TTB group and TT group) and used the Toothguide Training (TT) and Toothguide Training Box (TTB) respectively. All participants received training session once a week for 3 weeks. Before training and each time after finished training all participants were asked to identify ten unlabeled tabs which had been randomly chosen from Vita 3D-master shadeguide. SPSS 16.0 software package was used for Wilcoxon signed rank test. RESULTS: Before training, the accuracy rate of group A and group B was (65.67+/-20.4)% and (70.17+/-17.57)% respectively. After training, the accuracy rate of group A and group B was (78.91+/-22.82)% and (80.17+/-17.77)% respectively. No significant difference was found between group A and B, but significant difference was found between before and after training. CONCLUSIONS: This study shows clinical experience is not found to be a significant factor to the teeth shade matching. The training can improve the accuracy of shade matching. PMID- 23364564 TI - [Exploration of basic restorative dental materials teaching in the field of dental technology]. AB - This study was to compare the difference of the existing course materials of basic restorative dental with the past materials, found out the weakness of teaching mode before the reform, and explored the reform in education through teaching content, method and evaluation, in order to improve the teaching quality. PMID- 23364566 TI - Practice guidelines for management of the difficult airway: an updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. PMID- 23364567 TI - Practice guidelines for postanesthetic care: an updated report by the American Society of Anesthesiologists Task Force on Postanesthetic Care. PMID- 23364568 TI - A single-nucleotide polymorphism in SCN9A may decrease postoperative pain sensitivity in the general population. AB - BACKGROUND: This study aimed to explore the role of a nonsynonymous single nucleotide polymorphism, 3312G>T, in SCN9A, which was identified in probands with congenital indifference to pain, but which is also present in normal controls, in the prediction of individual baseline pain perception, and postoperative pain sensitivity in the general population. METHODS: Preoperative pressure pain thresholds and tolerance were measured in 200 patients undergoing pancreatectomy, and the postoperative pain sensitivity and analgesic demand were recorded. These variables were compared according to the SCN9A 3312G>T alleles. Logistic regression analysis was used to test the role of preoperative variables in the prediction of postoperative inadequate analgesia. RESULTS: The 3312Tallele was present in 22 individuals, and the 3312Tallele frequency was 5.5% (22/200). The average patient-controlled analgesia pressing frequency and opioid consumption in 3312G patients was significantly higher than those in 3312T patients (2.70 [SD: 0.84] vs. 2.05 [SD: 0.43], P < 0.001; 100.8 [SD: 40.7] vs. 74.8 [SD: 20.8] ml, P = 0.006). The incidence of inadequate analgesia in 3312G patients was significantly higher than that of patients carrying the 3312Tallele (29.2% vs. 4.5%; P = 0.013). Carrying the 3312Tallele and having a higher pressure pain threshold predicted a lower risk of postoperative inadequate analgesia, with an odds ratio of 0.10 (95% CI: 0.01 to 0.76, P = 0.026) and 0.32 (95% CI: 0.13 to 0.82, P = 0.018), respectively. CONCLUSION: Patients carrying the SCN9A 3312Tallele presented with lower postoperative pain sensitivity in the presence of a similar surgical pain stimulus, and had a lower likelihood of developing inadequate analgesia than those carrying the 3312Gallele. PMID- 23364570 TI - Waking to drink: rates of evaporative water loss determine arousal frequency in hibernating bats. AB - Bats hibernate to cope with low ambient temperatures (T(a)) and low food availability during winter. However, hibernation is frequently interrupted by arousals, when bats increase body temperature (T(b)) and metabolic rate (MR) to normothermic levels. Arousals account for more than 85% of a bat's winter energy expenditure. This has been associated with variation in T(b), T(a) or both, leading to a single testable prediction, i.e. that torpor bout length (TBL) is negatively correlated with T(a) and T(b). T(a) and T(b) were both found to be correlated with TBL, but correlations alone cannot establish a causal link between arousal and T(b) or T(a). Because hydration state has also been implicated in arousals from hibernation, we hypothesized that water loss during hibernation creates the need in bats to arouse to drink. We measured TBL of bats (Pipistrellus kuhlii) at the same T(a) but under different conditions of humidity, and found an inverse relationship between TBL and total evaporative water loss, independent of metabolic rate, which directly supports the hypothesis that hydration state is a cue to arousal in bats. PMID- 23364571 TI - Cardioacceleratory function of the neurohormone CCAP in the mosquito Anopheles gambiae. AB - Crustacean cardioactive peptide (CCAP) is a highly conserved arthropod neurohormone that is involved in ecdysis, hormone release and the modulation of muscle contractions. Here, we determined the CCAP gene structure in the malaria mosquito Anopheles gambiae, assessed the developmental expression of CCAP and its receptor and determined the role that CCAP plays in regulating mosquito cardiac function. RACE sequencing revealed that the A. gambiae CCAP gene encodes a neuropeptide that shares 100% amino acid identity with all sequenced CCAP peptides, with the exception of Daphnia pulex. Quantitative RT-PCR showed that expression of CCAP and the CCAP receptor displays a bimodal distribution, with peak mRNA levels in second instar larvae and pupae. Injection of CCAP revealed that augmenting hemocoelic CCAP levels in adult mosquitoes increases the anterograde and retrograde heart contraction rates by up to 28%, and increases intracardiac hemolymph flow velocities by up to 33%. Partial CCAP knockdown by RNAi had the opposite effect, decreasing the mosquito heart rate by 6%. Quantitative RT-PCR experiments showed that CCAP mRNA is enriched in the head region, and immunohistochemical experiments in newly eclosed mosquitoes detected CCAP in abdominal neurons and projections, some of which innervated the heart, but failed to detect CCAP in the abdomens of older mosquitoes. Instead, in older mosquitoes CCAP was detected in the pars lateralis, the subesophageal ganglion and the corpora cardiaca. In conclusion, CCAP has a potent effect on mosquito circulatory physiology, and thus heart physiology in this dipteran insect is under partial neuronal control. PMID- 23364572 TI - Collision-avoidance behaviors of minimally restrained flying locusts to looming stimuli. AB - Visually guided collision avoidance is of paramount importance in flight, for instance to allow escape from potential predators. Yet, little is known about the types of collision-avoidance behaviors that may be generated by flying animals in response to an impending visual threat. We studied the behavior of minimally restrained locusts flying in a wind tunnel as they were subjected to looming stimuli presented to the side of the animal, simulating the approach of an object on a collision course. Using high-speed movie recordings, we observed a wide variety of collision-avoidance behaviors including climbs and dives away from - but also towards - the stimulus. In a more restrained setting, we were able to relate kinematic parameters of the flapping wings with yaw changes in the trajectory of the animal. Asymmetric wing flapping was most strongly correlated with changes in yaw, but we also observed a substantial effect of wing deformations. Additionally, the effect of wing deformations on yaw was relatively independent of that of wing asymmetries. Thus, flying locusts exhibit a rich range of collision-avoidance behaviors that depend on several distinct aerodynamic characteristics of wing flapping flight. PMID- 23364573 TI - Atmospheric propagation modeling indicates homing pigeons use loft-specific infrasonic 'map' cues. AB - Results from an acoustic ray-tracing program using daily meteorological profiles are presented to explain 'release-site biases' for homing pigeons at three experimental sites in upstate New York where W. T. Keeton and his co-workers at Cornell University conducted extensive releases between 1968 and 1987 in their investigations of the avian navigational 'map'. The sites are the Jersey Hill and Castor Hill fire towers, and another near Weedsport, where control pigeons from the Cornell loft vanished in random directions, in directions consistently >50 deg clockwise and in directions ~15 deg clockwise from the homeward bearing, respectively. Because Cornell pigeons were disoriented at Jersey Hill whereas birds from other lofts were not, it is inferred that Jersey Hill lies within an acoustic 'shadow' zone relative to infrasonic signals originating from the Cornell loft's vicinity. Such signals could arise from ground-to-air coupling of near-continuous microseisms, or from scattering of direct microbaroms off terrain features, both of which are initially generated by wave-wave interactions in the deep ocean. HARPA runs show that little or no infrasound from the loft area arrived at Jersey Hill on days when Cornell pigeons were disoriented there, and that homeward infrasonic signals could have arrived at all three sites from directions consistent with pigeon departure bearings, especially on days when these bearings were unusual. The general stability of release-site biases might be due to influences of terrain on transmission of the homeward signals under prevailing weather patterns, whereas short-term changes in biases might be caused by rapid shifts in atmospheric conditions. PMID- 23364574 TI - Reducing cardiovascular risk in women with lupus: perception of risk and predictors of risk-reducing behaviors. AB - BACKGROUND: Women with systemic lupus erythematosus (SLE) display a 7- to 10-fold increased risk for cardiovascular disease (CVD) compared with non-SLE controls, yet many are unaware of this risk despite years spent in the healthcare system. It is not clear why they lack awareness of increased CVD risk or which factors influence awareness. OBJECTIVE: The purpose of this study was to assess in women with SLE their perceived CVD risk, the association between clinically identified and perceived CVD risk factors, and factors that influenced CVD risk awareness and adoption of risk-reducing behaviors. METHODS: Questionnaires, face-to-face meetings, and clinical assessments were used to collect data on demographics, perceived CVD risk, perceived CVD risk factors, actual CVD risk factors, risk reducing behaviors, and healthcare provider counseling from 60 women with SLE. Regression analyses identified factors that influenced risk awareness and adoption of risk-reducing behaviors. RESULTS: Two-thirds of the participants perceived themselves at increased CVD risk when compared with women without SLE, but the same number did not perceive an increase in their absolute CVD risk. Age was a significant predictor (P = .05) for awareness of increased absolute risk; younger age correlated with increased awareness. Most women received information about heart disease from public media. On average, participants had 4 CVD risk factors but perceived that they had only 2. Age (P = .001) and the number of perceived risk factors (P = .004) predicted adoption of risk-reducing behaviors (P = .03). CONCLUSION: Participants underestimated their CVD risk factors and did not personalize their increased CVD risk. Healthcare providers' identification and discussion of CVD risk factors in women with SLE may enhance their CVD risk awareness and the adoption of risk-reducing behaviors. PMID- 23364575 TI - Hyperglycemia is associated with corrected QT prolongation and mortality in acutely ill patients. AB - BACKGROUND: The QT interval on an electrocardiogram represents ventricular repolarization time. Increased length of this interval, known as corrected QT (QTc) prolongation, can be a precursor to torsade de pointes, a potentially life threatening ventricular dysrhythmia. An association exists between blood glucose and QTc interval in ambulatory populations. Because both hyperglycemia and QTc prolongation are common in critically ill patients, we sought to examine the relationship between blood glucose, QTc interval prolongation, and all-cause mortality in critically ill patients. METHODS: We studied adult patients admitted to cardiac monitoring units. Blood glucose and other clinical variables were abstracted from the medical record. Corrected QT measurements were automatically derived from continuous bedside cardiac monitoring systems. RESULTS: Twenty-five percent (233/940) of the patients had QTc prolongation, and 53% had elevated blood glucose (>140 mg/dL) during hospitalization. Adjusted odds for QTc prolongation were 2.1 (95% confidence interval, 1.5-3.1) for moderately elevated blood glucose (140-180 mg/dL) and 3.7 (95% confidence interval, 2.5-5.4) for severely elevated blood glucose (>180 mg/dL). Mortality rate was highest (16%) in patients experiencing both severely elevated blood glucose (>180 mg/dL) and QTc interval prolongation. CONCLUSIONS: Hyperglycemia is linked with QTc prolongation, and both are associated with increased odds of mortality in critically ill patients. Further studies are needed to extrapolate the relationship between glucose and ventricular repolarization, as well as appropriate glucose control parameters and QTc interval monitoring in critical care units. PMID- 23364576 TI - Highly efficient visible-light-induced aerobic oxidative C-C, C-P coupling from C H bonds catalyzed by a gold(III)-complex. AB - A novel and highly efficient gold(III)-complex catalyzed aerobic oxidative alpha C-H functionalization of amines has been developed. The tertiary amines can be directly coupled with various nucleophiles using air as a sustainable oxidant. PMID- 23364578 TI - Water overload as a biomarker for heart failure and acute renal failure. AB - Heart failure (HF) and acute renal failure (ARF) are two very prevalent entities in our environment which impact directly and synergistically in the morbidity and mortality of our patients. ARF, when oligoanuric, often leads to water overload. It represents the precipitating core of the mechanism of acute decompensation of the HF and is associated with the worsening of symptoms, hospitalisation and death. Determining the water balance in HF can be complex and depends, largely, on the underlying pathophysiology. New biomarkers and new technologies are proving to be useful for the detection and identification of risk of acutely decompensated HF that may allow early intervention and reversal of the ARF that translates into better clinical outcomes. PMID- 23364577 TI - Gene capture coupled to high-throughput sequencing as a strategy for targeted metagenome exploration. AB - Next-generation sequencing (NGS) allows faster acquisition of metagenomic data, but complete exploration of complex ecosystems is hindered by the extraordinary diversity of microorganisms. To reduce the environmental complexity, we created an innovative solution hybrid selection (SHS) method that is combined with NGS to characterize large DNA fragments harbouring biomarkers of interest. The quality of enrichment was evaluated after fragments containing the methyl coenzyme M reductase subunit A gene (mcrA), the biomarker of methanogenesis, were captured from a Methanosarcina strain and a metagenomic sample from a meromictic lake. The methanogen diversity was compared with direct metagenome and mcrA-based amplicon pyrosequencing strategies. The SHS approach resulted in the capture of DNA fragments up to 2.5 kb with an enrichment efficiency between 41 and 100%, depending on the sample complexity. Compared with direct metagenome and amplicons sequencing, SHS detected broader mcrA diversity, and it allowed efficient sampling of the rare biosphere and unknown sequences. In contrast to amplicon based strategies, SHS is less biased and GC independent, and it recovered complete biomarker sequences in addition to conserved regions. Because this method can also isolate the regions flanking the target sequences, it could facilitate operon reconstructions. PMID- 23364579 TI - Treatment with adalimumab in amyloidosis secondary to rheumatoid arthritis: two case reports. AB - Rheumatological diseases and, firstly, rheumatoid arthritis (RA) remain a major cause of secondary amyloidosis. The emergence of biological agents such as adalimumab in the early treatment of RA can be an effective alternative to stop the development and progression of secondary amyloidosis. Not all patients will respond the same way to treatment; we must consider associated comorbidity, the poor prognosis factors for predicting therapeutic response and possible adverse effects. In the adverse effects of biological therapies, there has been an increase in the rate of lethal infections and congestive heart failure. We present two cases with renal amyloidosis secondary to RA who had a different clinical course: our 1st case had a good response to Adalimumab while the 2nd case evolved unfavourably after treatment, and died from cardiovascular complications. PMID- 23364580 TI - Improvement of therapeutic compliance in haemodialysis patients with poor phosphorus control and adherence to treatment with binders: COMQUELFOS study. AB - BACKGROUND: The effectiveness of phosphate binders in daily practice is directly related to therapeutic compliance (TC) by the patient. The goal of this study was to analyse the TC of haemodialysis patients with hyperphosphatemia and its influence on serum phosphorus for 6 months follow up. METHODS: 181 patients were included, who had mean initial phosphate levels (P) >5mg/dl. TC with different phosphate binders was evaluated, considering non-adherent patients those who had <75% of TC, SMAQ scale score of "non-adherent"(Table 1), and P>5mg/dl. Patients who were adherent at baseline visit (BV) left the study, the rest continued to V5 (6 months). TC at baseline and during the follow up (V1-V5) was analysed. Phosphate binders and the evolution of phosphataemia based on treatment were assessed. RESULTS: 103 male and 78 female patients were evaluated, with a mean age of 59.9 (21-86) years. Of these, 39.2% (n=71) were adherent in the BV. Patients older than 60 years of age were more adherent than younger ones (P=.019).Table 6 specifies the causes of non-compliance. The remaining 60.8% of patients (n=110), were non-adherent and continued through to the end of the study. An average of 27.2% of these patients became adherent during the course of the study. Table 7 shows the relative levels of P with TC over successive visits. At the end of the study, mean P levels had decreased by 1.26mg/dl (P<.0001). CONCLUSION: Among HD patients with poor P level control, there is a low level of adherence with phosphorus binder treatment, at 39.2%. Compliance and phosphataemia are improved with different strategies. The decrease of P is higher in adherent patients than in non-adherent patients. PMID- 23364583 TI - 'Shedding' light on mechanisms of hyperphosphatemic vascular dysfunction. AB - Cardiovascular disease is prevalent in chronic kidney disease (CKD) populations. Vascular dysfunction characterized by endothelial-cell damage, inflammation, and impaired angiogenesis is described in CKD, and hyperphosphatemia has been associated with vascular disease in CKD and general populations. We discuss the findings of elegant studies by Di Marco et al., linking hyperphosphatemia to downregulation of annexin II, an important protein implicated in fibrinolysis, cell adhesion, signal transduction, and angiogenesis. PMID- 23364584 TI - Prediction of renal end points in chronic kidney disease. AB - Estimated glomerular filtration rate and albuminuria are dominant clinical predictors of renal outcomes in chronic kidney disease. Wong and collaborators report that BMP-7 and transforming growth factor-beta1 improve risk discrimination for renal end points in type 2 diabetes. However, to develop predictive models, clearly defined, clinically meaningful, validated end points must be used. End-stage renal disease and kidney transplantation remain the most definitive renal end points, whereas doubling of serum creatinine and death from renal disease lack rigor. PMID- 23364585 TI - Mannan binding lectin: a two-faced regulator of renal allograft injury? AB - Complement activation plays an important role in the pathogenesis of renal allograft injury after kidney transplantation. There are three known pathways of complement activation, namely, classical, alternative, and lectin pathways. In renal allograft injury, contradictory results were reported about the role of the lectin pathway activated via mannan binding lectin (MBL). This Commentary discusses the findings by Bay et al. (this issue), who demonstrated a protective role for circulating MBL in the recipient, particularly in non-HLA immunized recipients. PMID- 23364586 TI - Evidence for inheritance of medullary sponge kidney. AB - Medullary sponge kidney (MSK) is associated with recurrent calcium stones. Gambaro's group evaluated the relatives of probands with MSK. When prior imaging was not available, they performed renal ultrasounds. They demonstrated familial clustering, providing the best evidence yet that MSK is a heritable disorder. Although a small proportion of MSK cases are associated with variants of glial cell-derived neurotrophic factor (GDNF), the genetic basis for most instances of MSK is not known. PMID- 23364587 TI - Family-based studies to the rescue of genome-wide association studies in renal function. AB - Contrary to the apparent impossibility of replicating linkage results across studies on renal outcomes, and denying the general difficulty of identifying meaningful association signals under previously identified linkage peaks, a new study on an isolated Mongolian population could replicate two previously reported linkage peaks and corroborate them by significant associations at multiple single nucleotide polymorphisms. Although the two genetic loci are not novel, the study sheds light on key aspects of the genetic analysis of kidney function in the general population. PMID- 23364588 TI - Shining light on vitamin D trials in chronic kidney disease. AB - Vitamin D compounds may have extraskeletal functions. Chronic kidney disease (CKD) offers an opportunity to investigate these actions, as vitamin D deficiency is prevalent in this population and actions of vitamin D such as those on the heart and glucose metabolism are highly relevant. However, recent randomized controlled trials have tempered enthusiasm. We appraise a trial by de Boer et al. that addresses effects of paricalcitol on glucose metabolism in CKD, and offer perspectives on future trials. PMID- 23364589 TI - Redefining C3 glomerulopathy: 'C3 only' is a bridge too far. PMID- 23364590 TI - On 'Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations'. PMID- 23364591 TI - The author replys:. PMID- 23364592 TI - The authors reply:. PMID- 23364594 TI - Physical finding of nutcracker phenomenon. PMID- 23364595 TI - The Case | Bilateral kidney tumors and lung cysts. PMID- 23364596 TI - The expanding genetic toolkit for exploring mechanisms of general anesthesia. PMID- 23364597 TI - Anesthetics interfere with axon guidance in developing mouse neocortical neurons in vitro via a gamma-aminobutyric acid type A receptor mechanism. AB - BACKGROUND: The finding that exposure to general anesthetics (GAs) in childhood may increase rates of learning disabilities has raised a concern that anesthetics may interfere with brain development. The generation of neuronal circuits, a complex process in which axons follow guidance cues to dendritic targets, is an unexplored potential target for this type of toxicity. METHODS: GA exposures were conducted in developing neocortical neurons in culture and in early postnatal neocortical slices overlaid with fluorescently labeled neurons. Axon targeting, growth cone collapse, and axon branching were measured using quantitative fluorescence microscopy. RESULTS: Isoflurane exposure causes errors in Semaphorin 3A-dependent axon targeting (n = 77 axons) and a disruption of the response of axonal growth cones to Semaphorin-3A (n = 2,358 growth cones). This effect occurs at clinically relevant anesthetic doses of numerous GAs with allosteric activity at gamma-aminobutyric acid type A receptors, and it was reproduced with a selective agonist. Isoflurane also inhibits growth cone collapse induced by Netrin-1, but does not interfere branch induction by Netrin-1. Insensitivity to guidance cues caused by isoflurane is seen acutely in growth cones in dissociated culture, and errors in axon targeting in brain slice culture occur at the earliest point at which correct targeting is observed in controls. CONCLUSIONS: These results demonstrate a generalized inhibitory effect of GAs on repulsive growth cone guidance in the developing neocortex that may occur via a gamma aminobutyric acid type A receptor mechanism. The finding that GAs interfere with axon guidance, and thus potentially with circuit formation, represents a novel form of anesthesia neurotoxicity in brain development. PMID- 23364598 TI - Activation of triggering receptor expressed on myeloid cells-1 protects monocyte from apoptosis through regulation of myeloid cell leukemia-1. AB - BACKGROUND: Triggering receptor expressed on myeloid cells-1 (TREM-1) can amplify the proinflammatory response and may contribute to the pathogenesis of inflammatory disease such as sepsis. However, the role of TREM-1 in monocyte fate and the detailed molecular mechanisms evoked by TREM-1 are unknown. METHODS: Adenoviruses overexpressing TREM-1 were constructed and transfected into a monocytic cell line. After activation of TREM-1 by agonist antibody with or without lipopolysaccharide, apoptosis was induced and assayed using flow cytometry. The signaling pathways downstream of TREM-1 were illustrated by inhibitory experiments. Proapoptotic/antiapoptotic protein levels were measured using immunoblot. In addition, the relationship between the expression levels of TREM-1 in monocytes and the magnitude of monocyte apoptosis were analyzed in septic patients. RESULTS: Activation of TREM-1 protected monocytes from staurosporine-induced apoptosis. This characteristic was also obtained under lipopolysaccharide stimulation. The protection of TREM-1 against monocyte apoptosis was abrogated after inhibition of extracellular signal-regulated kinase or v-akt murine thymoma viral oncogene homologue signaling. Cross-linking of TREM 1 remarkably up-regulated myeloid cell leukemia-1 protein level, and inhibition of extracellular signal-regulated kinase or v-akt murine thymoma viral oncogene homologue resulted in the reduction of myeloid cell leukemia-1 expression. Inhibition of myeloid cell leukemia-1 abolished the antiapoptotic effect of TREM 1. Furthermore, in septic patients, TREM-1 levels were inversely correlated to the magnitude of apoptosis in monocyte. CONCLUSIONS: TREM-1 played an important role in apoptosis in monocytes. Activation of TREM-1 protected monocytic cells from apoptosis through activation of both extracellular signal-regulated kinase and v-akt murine thymoma viral oncogene homologue pathways and increased expression of myeloid cell leukemia-1 protein. These findings provide a novel additional mechanism for TREM-1-mediated hyperinflammatory response in monocytes. PMID- 23364599 TI - Xenon and isoflurane reduce left ventricular remodeling after myocardial infarction in the rat. AB - BACKGROUND: Xenon and isoflurane are known to have cardioprotective properties. We tested the hypothesis that these anesthetics positively influence myocardial remodeling 28 days after experimental perioperative myocardial infarction and compared their effects. METHODS: A total of 60 male Sprague-Dawley rats were subjected to 60 min of coronary artery occlusion and 120 min of reperfusion. Prior to ischemia, the animals were randomized for the different narcotic regimes (0.6 vol% isoflurane, 70 vol% xenon, or intraperitoneal injection of s-ketamine). Acute injury was quantified by echocardiography and troponin I. After 4 weeks, left ventricular function was assessed by conductance catheter to quantify hemodynamic compromise. Cardiac remodeling was characterized by quantification of dilatation, hypertrophy, fibrosis, capillary density, apoptosis, and expression of fetal genes (alpha/beta myosin heavy chains, alpha-skeletal actin, periostin, and sarco/endoplasmic reticulum Ca2+-ATPase). RESULTS: Whereas xenon and isoflurane impeded the acute effects of ischemia-reperfusion on hemodynamics and myocardial injury at a comparable level, differences were found after 4 weeks. Xenon in contrast to isoflurane or ketamine anesthetized animals demonstrated a lower remodeling index (0.7 +/- 0.1 vs. 0.9 +/- 0.3 and 1.0 +/- 0.3g/ml), better ejection fraction (62 +/- 9 vs. 49 +/- 7 and 35 +/- 6%), and reduced expression of beta-myosin heavy chain and periostin. The effects on hypertrophy, fibrosis, capillary density, and apoptosis were comparable. CONCLUSIONS: Compared to isoflurane and s-ketamine, xenon limited progressive adverse cardiac remodeling and contractile dysfunction 28 days after perioperative myocardial infarction. PMID- 23364600 TI - Estimated glomerular filtration rate: more bang for the buck. PMID- 23364602 TI - Lanthanide coordination polymers based on 5-(2'-carboxylphenyl) nicotinate: syntheses, structure diversity, dehydration/hydration, luminescence and magnetic properties. AB - Twelve lanthanide coordination polymers associated with the organic ligand 5-(2' carboxylphenyl) nicotinic acid (H2cpna): {[Ln(Hcpna)(cpna)(phen)].H2O}n (Ln = Sm (1), Tb (2), Ho (3), phen = 1,10-phenanthroline), {[Sm(Hcpna)(cpna)(phen)].2H2O}n (4), {[Ln2(cpna)3(H2O)3].4H2O}n (Ln = Y (5), Tb(6), Dy (7), Ho (8)), [Lu2(cpna)3(H2O)2]n (9), {[Y2(cpna)3(phen)2(H2O)].H2O}n (10), and [Ln(cpna)(phen)(NO3)]n (Ln = Tm (11), Lu (12)) have been prepared by hydrothermal methods and structurally characterized. The structure analyses reveal that complexes 1-3 are isostructural and possess unique three-dimensional (3D) frameworks based on the dodecanuclear Sm/Tb/Ho macrocycles. Complex 4 exhibits a one-dimensional (1D) wheel-chain structure, which further builds three dimensional (3D) supramolecular architecture via O-HN hydrogen-bonding interactions. Complexes 5-8 are also isostructural and display three-dimensional (3D) open frameworks, which possess two types of channels along the a- and b axis, respectively. Complexes 9 and 10 feature three-dimensional (3D) frameworks and are created from tetranuclear and dinuclear units, respectively. Complexes 11 and 12 are isostructural and demonstrate one-dimensional (1D) double chain structures, which further build three-dimensional (3D) supramolecular architecture via C-H...O hydrogen-bonding. The results show that the pH value of the reaction system, anion, auxiliary ligand and lanthanide contraction play a significant role in determining the structures of the complexes. In addition, the results of luminescent measurements for compounds 2 and 6 in the solid state at room temperature indicate that the different types of structures have a dissimilar influence on their characteristic luminescence. The magnetic properties of compounds 1, 3, 4, 7 and 11 have been investigated. Furthermore, thermal stabilities for 1-12 and the dehydration/hydration properties of compound 6 have also been studied. PMID- 23364605 TI - Role of endothelial nitric oxide synthase and vagal activity in the endothelial protection of atorvastatin in ischemia/reperfusion injury. AB - Vascular endothelial dysfunction plays a pivotal role in the development and maintenance of ischemia/reperfusion (I/R) injury. Statins, developed as lipid lowering drugs, partially restore vagal activity and exhibit pleiotropic effects. This study was aimed at determining the effect of atorvastatin (ATV) on endothelial dysfunction in peripheral resistance arteries after I/R injury. After pretreatment with ATV (10 mg.kg.d) or its vehicle for 3 days, the superior mesenteric artery was occluded for 60 minutes and reperfusion for 90 minutes or the rats were anesthetized without being subjected to ischemia. In the ATV treated I/R group, the increased contractions to KCl and 5-hydroxytryptamine induced by I/R were ameliorated, and attenuated endothelium-dependent relaxations to acetylcholine (ACh) were normalized. The restored relaxation to ACh was abolished by N-nitro-L-arginine methyl ester. ATV prevented the structural damage of vascular endothelial cells. Furthermore, the activities of phosphatidylinositol-3-kinase, Akt, and endothelial nitric oxide synthase were elevated in mesenteric arteries after ATV treatment. In addition, I/R-induced increment of endothelial cells apoptosis was also attenuated by ATV. Intriguingly, ATV also increased baroreflex sensitivity and serum ACh content after I/R. In conclusion, the endothelial protective effect of ATV in peripheral arteries is associated with the activated phosphatidylinositol-3 kinase/Akt/endothelial nitric oxide synthase pathway and restored vagal activity. PMID- 23364606 TI - Transient receptor potential canonical type 3 channels--their evolving role in hypertension and its related complications. AB - : Recent studies indicate that transient receptor potential canonical type 3 (TRPC3) channels contribute to the regulation of blood pressure and vascular and renal function. Several studies show that TRPC3 dysfunction is associated with hypertension, atherosclerosis, cardiac hypertrophy, and cerebrovascular events. In this review, we summarize the role of TRPC3 channels in the cardiovascular system, and we focus on their pathophysiological role in hypertension and related target organ damages. We provide new insight into the involvement of TRPC3 channels in the development of hypertension and its related complications. PMID- 23364607 TI - Differential effects of the peroxynitrite donor, SIN-1, on atrial and ventricular myocyte electrophysiology. AB - Oxidative stress has been implicated in the pathogenesis of heart failure and atrial fibrillation and can result in increased peroxynitrite production in the myocardium. Atrial and ventricular canine cardiac myocytes were superfused with 3 morpholinosydnonimine-N-ethylcarbamide (SIN-1), a peroxynitrite donor, to evaluate the acute electrophysiologic effects of peroxynitrite. Perforated whole cell patch clamp techniques were used to record action potentials. SIN-1 (200 uM) increased the action potential duration (APD) in atrial and ventricular myocytes; however, in the atria, APD prolongation was rate independent, whereas in the ventricle APD, prolongation was rate dependent. In addition to prolongation of the action potential, beat-to-beat variability of repolarization was significantly increased in ventricular but not in atrial myocytes. We examined the contribution of intracellular calcium cycling to the effects of SIN-1 by treating myocytes with the SERCA blocker, thapsigargin (5-10 uM). Inhibition of calcium cycling prevented APD prolongation in the atrial and ventricular myocytes, and prevented the SIN-1-induced increase in ventricular beat-to-beat APD variability. Collectively, these data demonstrate that peroxynitrite affects atrial and ventricular electrophysiology differentially. A detailed understanding of oxidative modulation of electrophysiology in specific chambers is critical to optimize therapeutic approaches for cardiac diseases. PMID- 23364608 TI - Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor. AB - The human electrophysiological and pharmacological properties of XEN-D0101 were evaluated to assess its usefulness for treating atrial fibrillation (AF). XEN D0101 inhibited Kv1.5 with an IC50 of 241 nM and is selective over non-target cardiac ion channels (IC50 Kv4.3, 4.2 MUM; hERG, 13 MUM; activated Nav1.5, >100 MUM; inactivated Nav1.5, 34 MUM; Kir3.1/3.4, 17 MUM; Kir2.1, >>100 MUM). In atrial myocytes from patients in sinus rhythm (SR) and chronic AF, XEN-D0101 inhibited non-inactivating outward currents (Ilate) with IC50 of 410 and 280 nM, respectively, and peak outward currents (Ipeak) with IC50 of 806 and 240 nM, respectively. Whereas Ilate is mainly composed of IKur, Ipeak consists of IKur and Ito. Therefore, the effects on Ito alone were estimated from a double-pulse protocol where IKur was inactivated (3.5 uM IC50 in SR and 1 uM in AF). Thus, inhibition of Ipeak is because of IKur reduction and not Ito. XEN-D0101 significantly prolonged the atrial action potential duration at 20%, 50%, and 90% of repolarization (AF tissue only) and significantly elevated the atrial action potential plateau phase and increased contractility (SR and AF tissues) while having no effect on human ventricular action potentials. In healthy volunteers, XEN-D0101 did not significantly increase baseline- and placebo-adjusted QTc up to a maximum oral dose of 300 mg. XEN-D0101 is a Kv1.5/IKur inhibitor with an attractive atrial-selective profile. PMID- 23364609 TI - Activation of autophagy in ischemic postconditioning contributes to cardioprotective effects against ischemia/reperfusion injury in rat hearts. AB - We tested the hypothesis that ischemic postconditioning (IPost) induces autophagy and the activation of autophagy contributes to the cardioprotective effects against ischemia/reperfusion injury in rat hearts. Rats were subjected to IPost established by 3 cycles of 10-second reperfusion followed by 10-second ischemia at the end of 30-minute ischemia. The activation of autophagy was assessed by the morphological and biochemical examinations after 120-minute reperfusion in ventricular tissue. To investigate the contribution of autophagy to IPost, the rats were pretreated with the autophagy inhibitor 3-methyl-adenine (3-MA). We found that IPost increased the formation of autophagic vacuoles, the autophagic related protein levels of LC3-II, Beclin1, lysosome-associated membrane protein 2, and cathepsin D, and the mRNA level of LC3 and Beclin1 in the risk zone of the postconditioned hearts. Furthermore, 3-MA treatment significantly reversed the reduction effect of IPost on infarct volume, and in the meantime, inhibited the induction of LC3 and Beclin1. In addition, 3-MA treatment inhibited the antiapoptotic-related protein levels of Bcl-2 and increased the apoptotic-related protein levels of Bad. Taken together, these results indicate that the protective effects of IPost are associated with the activation of autophagy in rat hearts. PMID- 23364610 TI - Bovine milk-derived lactoferrin exerts proangiogenic effects in an Src-Akt-eNOS dependent manner in response to ischemia. AB - Lactoferrin (LF) exerts a variety of biological effects, including the promotion of angiogenesis by increasing the expression of angiogenesis-related genes and reducing blood pressure via a nitric oxide-dependent mechanism. In this study, we investigated the effects of LF on angiogenesis using C57BL/6J mice that received daily unilateral treatment with or without bovine milk-derived LF (bLF) after unilateral hindlimb surgery. The analysis of laser speckle blood flow showed that bLF treatment promoted blood flow recovery in response to ischemic hindlimb. The capillary density of ischemic adductor muscles and the phosphorylation of Src, Akt, and endothelial nitric oxide synthase (eNOS) were also significantly higher in bLF-treated mice than in vehicle-treated mice. Furthermore, bLF increased the phosphorylation levels of Src, Akt, and eNOS in in vitro experiments using human aortic endothelial cells. The action of bLF on eNOS phosphorylation was abolished by both LY294002, a phosphatidylinositol 3-kinase inhibitor, and 4-amino-5-(4 chlorophenyl)-7-(dimethylethyl)pyrazolo [3,4-d]pyrimidine (PP2), an Src inhibitor. Similarly, bLF-induced acceleration of tube formation, cell proliferation, and cell migration in human aortic endothelial cells were inhibited by LY294002 or PP2. Thus, bLF promotes vascular endothelial cell function via an Src Akt eNOS-dependent pathway, thereby contributing to revascularization in response to ischemia. PMID- 23364611 TI - Optimization of beta-glucosidase, beta-xylosidase and xylanase production by Colletotrichum graminicola under solid-state fermentation and application in raw sugarcane trash saccharification. AB - Efficient, low-cost enzymatic hydrolysis of lignocellulosic residues is essential for cost-effective production of bioethanol. The production of beta-glucosidase, beta-xylosidase and xylanase by Colletotrichum graminicola was optimized using Response Surface Methodology (RSM). Maximal production occurred in wheat bran. Sugarcane trash, peanut hulls and corncob enhanced beta-glucosidase, beta xylosidase and xylanase production, respectively. Maximal levels after optimization reached 159.3 +/- 12.7 U g-1, 128.1 +/- 6.4 U g-1 and 378.1 +/- 23.3 U g-1, respectively, but the enzymes were produced simultaneously at good levels under culture conditions optimized for each one of them. Optima of pH and temperature were 5.0 and 65 degrees C for the three enzymes, which maintained full activity for 72 h at 50 degrees C and for 120 min at 60 degrees C (beta glucosidase) or 65 degrees C (beta-xylosidase and xylanase). Mixed with Trichoderma reesei cellulases, C. graminicola crude extract hydrolyzed raw sugarcane trash with glucose yield of 33.1% after 48 h, demonstrating good potential to compose efficient cocktails for lignocellulosic materials hydrolysis. PMID- 23364612 TI - Green approach—multicomponent production of boron—containing hantzsch and biginelli esters. AB - Multicomponent reactions are excellent methods that meet the requirements of green chemistry, by reducing the number of steps, and consequently reducing purification requirements. Accordingly, in this work, 11 novel hybrid-boron containing molecules, namely eight 1,4-dihydropyridines and three 3,4 dihydropyrimidinones, derived from formylphenylboronic acids (ortho, meta and para), were obtained using a green approach, involving H-4CR and B-3CR practices, in the presence of ethanol, which is a green solvent, and using three comparatively different modes of activation (mantle heating, yield 3%-7% in 24 h, Infrared Radiation (IR) irradiation, yield 12%-17% in 12 h, and microwave irradiation, yield 18%-80%, requiring very low reaction times of 0.25-0.33 h). In addition, as a green-approach is offered, a convenient analysis, of the 12 green chemistry principles for the overall procedure was performed. Finally, since all the products are new, characterizations were carried out using common analytic procedures (1H, 11B, and 13C NMR, FAB+MS, HRMS, and IR). The accurate mass data of unexpected ions related to interactions between thioglycerol and the expected products, in the FAB+-mode, enabled unequivocal characterization of the target molecules. PMID- 23364613 TI - Oxidative folding in the mitochondrial intermembrane space in human health and disease. AB - Oxidative folding in the mitochondrial intermembrane space (IMS) is a key cellular event associated with the folding and import of a large and still undetermined number of proteins. This process is catalyzed by an oxidoreductase, Mia40 that is able to recognize substrates with apparently little or no homology. Following substrate oxidation, Mia40 is reduced and must be reoxidized by Erv1/Alr1 that consequently transfers the electrons to the mitochondrial respiratory chain. Although our understanding of the physiological relevance of this process is still limited, an increasing number of pathologies are being associated with the impairment of this pathway; especially because oxidative folding is fundamental for several of the proteins involved in defense against oxidative stress. Here we review these aspects and discuss recent findings suggesting that oxidative folding in the IMS is modulated by the redox state of the cell. PMID- 23364614 TI - Antioxidant, Analgesic, Anti-Inflammatory, and Hepatoprotective Effects of the Ethanol Extract of Mahonia oiwakensis Stem. AB - The aim of this study was to evaluate pharmacological properties of ethanol extracted from Mahonia oiwakensis Hayata stems (MOS(EtOH)). The pharmacological properties included antioxidant, analgesic, anti-inflammatory and hepatoprotective effects. The protoberberine alkaloid content of the MOS(EtOH) was analyzed by high-performance liquid chromatography (HPLC). The results revealed that three alkaloids, berberine, palmatine and jatrorrhizine, could be identified. Moreover, the MOS(EtOH) exhibited antioxidative activity using the DPPH assay (IC(50), 0.743 mg/mL). The DPPH radical scavenging activity of MOS(EtOH) was five times higher that that of vitamin C. MOS(EtOH) was also found to inhibit pain induced by acetic acid, formalin, and carrageenan inflammation. Treatment with MOS(EtOH) (100 and 500 mg/kg) or silymarin (200 mg/kg) decreased the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with the CCl(4)-treated group. Histological evaluation showed that MOS(EtOH) reduced the degree of liver injury, including vacuolization, inflammation and necrosis of hepatocytes. The anti-inflammatory and hepatoprotective effect of MOS(EtOH) were found to be related to the modulation of antioxidant enzyme activity in the liver and decreases in malondialdehyde (MDA) level and nitric oxide (NO) contents. Our findings suggest that MOS(EtOH) has analgesic, anti-inflammatory and hepatoprotective effects. These effects support the use of MOS(EtOH) for relieving pain and inflammation in folk medicine. PMID- 23364615 TI - Adsorption and Self-Assembly of Large Polycyclic Molecules on the Surfaces of TiO2 Single Crystals. AB - Titanium dioxide is one of the most frequently studied metal oxides, and its (110) rutile surface serves as a prototypical model for the surface science of such materials. Recent studies have also shown that the (011) surface is relatively easy for preparation in ultra-high vacuum (UHV) and that both the (110) and (011) surfaces could be precisely characterized using scanning tunneling microscopy (STM). The supramolecular self-assembly of organic molecules on the surfaces of titanium dioxide plays an important role in nanofabrication, and it can control the formation and properties of nanostructures, leading to wide range of applications covering the fields of catalysis, coatings and fabrication of sensors and extends to the optoelectronic industry and medical usage. Although the majority of experiments and theoretical calculations are focused on the adsorption of relatively small organic species, in recent years, there has been increasing interest in the properties of larger molecules that have several aromatic rings in which functional units could also be observed. The purpose of this review is to summarize the achievements in the study of single polycyclic molecules and thin layers adsorbed onto the surfaces of single crystalline titanium dioxide over the past decade. PMID- 23364616 TI - Synthesis and antimicrobial evaluation of some novel bis-alpha,beta-unsaturated ketones, nicotinonitrile, 1,2-dihydropyridine-3-carbonitrile, fused thieno[2,3 b]pyridine and pyrazolo[3,4-b]pyridine derivatives. AB - The title compounds were prepared by reaction of 1,1'-(5-methyl-1-phenyl-1H pyrazole-3,4-diyl)diethanone (1) with different aromatic aldehydes 2a-c, namely Furfural (2a), 4-chlorobenzaldehyde (2b) and 4-methoxybenzaldhyde (2c) to yield the corresponding alpha,beta-unsaturated ketones 3a-c. Compound 3 was reacted with malononitrile, 2-cyanoacetamide or 2-cyanothioacetamide yielded the corresponding bis[2-amino-6-(aryl)nicotinonitrile] 4a-c, bis[6-(2-aryl)-2-oxo 1,2-dihydropyridine-3-carbonitrile] 5a-c or bis[6-(2-aryl)-2-thioxo-1,2 dihydropyridine-3-carbonitrile] 6a,b, respectively. The reaction of compound 6a with each of 2-chloro-N-(4-bromophenyl) acetamide (7a), chloroacetamide (7b) in ethanolic sodium ethoxide solution at room temperature to give the corresponding 4,4'-(5-methyl-1-phenyl-1H-pyrazole-3,4-diyl)bis-6-(2-furyl)thieno[2,3-b]pyridine 2-carboxamide] derivatives 9a,b. While compound 6a reacted with hydrazine hydrate yielded the 4,4'-(5-methyl-1-phenyl-1H-pyrazole-3,4-diyl)bis[6-(2-furyl)-1H pyrazolo[3,4-b]pyridin-3-amine] 11. The structures of the products were elucidated based on their spectral properties, elemental analyses and, wherever possible, by alternate synthesis. Antimicrobial evaluation of the products was carried out. PMID- 23364617 TI - Effectiveness of HPV 16 viral load and the E2/E6 ratio for the prediction of cervical cancer risk among Chinese women. AB - The effectiveness of the E2/E6 ratio, the state of viral genome integration and the viral load of human papillomavirus 16 (HPV 16) in predicting the risk of cervical cancer among Chinese women was investigated. Quantitative PCRs for the E2/E6 ratio and the viral load were performed on 85 cervical cancer samples and 55 HPV 16 positive healthy controls. The integrated form of the viral genome was found in 10.9% control samples and in 26.4% cervical cancer samples (P = 0.02). The majority of the cervical cancer (63.2%) and control samples (60%) were mixed forms. The E2/E6 ratio was associated with a high risk of cervical cancer (OR = 7.29, P = 9.55E-6). The integrated form (OR = 6.54, P = 0.005) and mixed form (OR = 2.93, P = 0.042) increased the risk of cervical cancer. The mean viral load in cervical cancer samples (37,371 +/- 227,135) was higher than that in the controls (4,619 +/- 27,079; P = 0.011). Additionally, the viral load increased along with the cervical cancer progression from the International Federation of Gynecology and Obstetrics (FIGO) stage I (12,337 +/- 25,604) to stage II (67,453 +/- 319,821). Compared with the state of viral genome integration (area under the receiver operating characteristic curve (AUC) = 0.743) or the viral load (AUC = 0.694), the E2/E6 ratio improved the effectiveness of the risk prediction of cervical cancer (AUC = 0.777), with the sensitivity (specificity) 81.2% (71.7%). The state of viral genome integration and the viral load of HPV 16 were important factors for the risk prediction of cervical cancer among Chinese women, and the E2/E6 ratio had a better cervical cancer risk prediction with age adjustment. PMID- 23364618 TI - Synthesis and spectroscopic properties of fluorescent 5-benzimidazolyl-2' deoxyuridines 5-fdU probes obtained from o-phenylenediamine derivatives. AB - Fluorescent nucleosides (dU(bmz)) with desirable fluorescence quantum yield (Phi) are synthesized from almost non-fluorescent 5-fdU and o-phenylenediamine derivatives. The fluorescence of these nucleosides is quite sensitive to pH and organic solvents. 4-Methoxybenzene-1,2-diamine was used for the detection of 5 fdU among natural nucleosides. PMID- 23364619 TI - Investigation of the toxicokinetics of petroleum hydrocarbon distillates with the earthworm Eisenia andrei. AB - The Canada-wide standards for petroleum hydrocarbons in soils regulate petroleum hydrocarbons based on four distillate ranges: F1 (C6-C10), F2 (>C10-C16), F3 (>C16-C34), and F4 (>C34). Previous toxicity tests with earthworms and F2, as well as two subfractions of F3, F3a (>C16-C23) and F3a (>C23-C34), indicate that test durations might not be sufficiently long to reach threshold effect concentrations, likely because of the differing toxicokinetics for each distillate. A study was conducted to determine the toxicokinetics of both aliphatic and aromatic fractions of F2, F3a, and F3b with the earthworm Eisenia andrei. Peak accumulation curves were observed for F2 aliphatics and aromatics and F3a aromatics, likely as a result of changes in exposure concentration over the test duration via loss or a decrease in the bioavailable fraction. Biota-soil accumulation factors were >1 for total F2 aliphatics and aromatics and F3a aromatics as well as for several individual polyaromatic hydrocarbons for each distillate. Aromatics were disproportionately accumulated over aliphatics and were the main contributors to toxicity; therefore, aromatics and aliphatics should be regulated separately. The toxicokinetics were used to interpret previous toxicity data. Higher molecular weight distillates need longer-than standard test durations to determine toxicity, so toxicity test results from fixed, standard-duration tests are not strictly comparable for these petroleum distillates. PMID- 23364620 TI - Wavelength-dependent ultraviolet induction of cyclobutane pyrimidine dimers in the human cornea. AB - Exposition to ultraviolet (UV) light is involved in the initiation and the progression of skin cancer. The genotoxicity of UV light is mainly attributed to the induction of cyclobutane pyrimidine dimers (CPDs), the most abundant DNA damage generated by all UV types (UVA, B and C). The human cornea is also exposed to the harmful UV radiations, but no UV-related neoplasm has been reported in this ocular structure. The probability that a specific DNA damage leads to a mutation and eventually to cellular transformation is influenced by its formation frequency. To shed light on the genotoxic effect of sunlight in the human eye, we have analyzed CPD induction in the cornea and the iris following irradiation of ex vivo human eyes with UVA, B or C. The extent of CPD induction was used to establish the penetrance of the different UV types in the human cornea. We show that UVB- and UVC-induced CPDs are concentrated in the corneal epithelium and do not penetrate deeply beyond this corneal layer. On the other hand, UVA wavelengths penetrate deeper and induce CPDs in the entire cornea and in the first layers of the iris. Taken together, our results are undoubtedly an important step towards better understanding the consequences of UV exposure to the human eye. PMID- 23364622 TI - Are the K/DOQI objectives for bone mineral alterations in stage 3-5 chronic kidney disease patients unreachable or inadequate? PMID- 23364621 TI - Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. AB - This phase 2 study assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of carfilzomib, a selective proteasome inhibitor, in patients with multiple myeloma and varying degrees of renal impairment, including patients on chronic hemodialysis. Patients were grouped by creatinine clearance: >80 ml/min, 50-80 ml/min, 30-49 ml/min, <30 ml/min and chronic hemodialysis. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 in 28-day cycles: 15 mg/m(2) (Cycle 1), 20 mg/m(2) (Cycle 2) and 27 mg/m(2) (Cycles 3+). There were no differences in carfilzomib clearance or exposure among patients with normal renal function and any group with renal impairment. Grade 3/4 adverse events (AEs) included anemia (28.0%), thrombocytopenia (20.0%), lymphopenia (18.0%) and fatigue (14.0%). AEs were similar among groups. At 15 mg/m(2), proteasome inhibition up to 85% was observed and did not differ among groups. Although nearly 50% of patients were refractory to both bortezomib and lenalidomide, end of study partial response or better (overall response rate) was 25.5% with 7.9 months median duration of response. In conclusion, the pharmacokinetics and safety of carfilzomib were not influenced by the degree of baseline renal impairment, including in patients on dialysis, and carfilzomib was well tolerated and demonstrated promising efficacy. PMID- 23364623 TI - Cytomegalovirus and paediatric renal transplants: is this a current issue? AB - OBJECTIVE: An observational retrospective multicentre study of kidney transplants in paediatric patients was performed to evaluate the current situation of cytomegalovirus (CMV) in this population, before our participation in an international clinical trial of prophylaxis for 6 months. MATERIAL AND METHOD: Our study included 239 patients aged <19 years, from 5 Spanish centres between 2005-2009, with 1 year of follow-up. RESULTS: Pretransplant CMV serology was negative in 54% of recipients and 34.7% of donors. Sixty patients (25.1%) were considered at high risk (D+/R-) for CMV infection. Prophylaxis was used in 80.8% of recipients, including all high-risk patients, for an average time of 65.5 days. CMV viraemia occurred in 24.26% (58 cases among 239 patients), and disease in 6.7%. CMV infection was associated with serological status (D/R) (P<.001), positive serology of the donor (P<.001) and duration of prophylaxis <20 days (P<.05). There were no cases of patient or graft loss secondary to infection, nor resistance to treatment. CONCLUSIONS: The main preventative strategy against CMV in paediatric renal transplantation in our country is chemical prophylaxis (81%), with an incidence of infection and disease of 24% and 6.7%, respectively. There were no serious direct or indirect effects in the first year post-transplant. The incidence is mainly linked with serological D/R and positive donor status. PMID- 23364624 TI - Has the survival of the graft improved after renal transplantation in the era of modern immunosuppression? AB - The introduction of new immunosuppressant drugs in recent years has allowed for a reduction in acute rejection rates along with highly significant improvements in short-term kidney transplantation results. Nonetheless, this improvement has not translated into such significant changes in long-term results. In this manner, late graft failure continues to be a frequent cause of readmission onto dialysis programmes and re-entry onto the waiting list. Multiple entities of immunological and non-immunological origin act together and lead to chronic allograft dysfunction. The characteristics of the transplanted organ are a greater determinant of graft survival, and although various algorithms have been designed as a way of understanding the risk of the transplant organ and assigning the most adequate recipient accordingly. They are applied in the clinical setting only under exceptional circumstances. Characterising, for each patient, the immune factors (clinical and subclinical rejection, reactivation of dormant viral infections, adherence to treatment) and non-immune factors (hypertension, diabetes, anaemia, dyslipidaemia) that contribute to chronic allograft dysfunction could allow us to intervene more effectively as a way of delaying the progress of such processes. Therefore, identifying the causes of graft failure and its risk factors, applying predictive models, and intervening in causal factors could constitute strategies for improving kidney transplantation results in terms of survival. This review analyses some of the evidences conditioning graft failure as well as related therapeutic and prognostic aspects: 1) magnitude of the problem and causes of graft failure; 2) identification of graft failure risk factors; 3) therapeutic strategies for reducing graft failure, and; 4) graft failure prediction. PMID- 23364625 TI - An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document. AB - Haemolytic uraemic syndrome (HUS) is a clinical entity defined as the triad of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). Atypical HUS (aHUS) is a sub-type of HUS in which the TMA phenomena are the consequence of decreased regulation of the alternative complement pathway on cell surfaces due to a genetic cause. aHUS is an extremely rare disease that, despite the administration of standard treatment with plasma therapy, often progresses to terminal chronic renal failure with a high associated rate of mortality. In recent years, research has established the key role that the complement system plays in the induction of endothelial damage in patients with aHUS, through the characterisation of multiple mutations and polymorphisms in the genes that code for certain complement factors. Eculizumab is a monoclonal antibody that inhibits the terminal fraction of the complement protein, blocking the formation of a cell membrane attack complex. In prospective studies in patients with aHUS, administering eculizumab produces a rapid and sustained interruption in the TMA process, with significant improvements in long-term renal function and an important decrease in the need for dialysis or plasma therapy. In this document, we review and bring up to date the important aspects of this disease, with special emphasis on how recent advancements in diagnostic and therapeutic processes can modify the treatment of patients with aHUS. PMID- 23364627 TI - The influence of clinical situation on health-related quality of life in paediatric chronic kidney disease patients. AB - BACKGROUND: Studies examining health-related quality of life (HRQOL) in adults with chronic kidney disease (CKD) have demonstrated that certain clinical situations such as number of hospitalisations and anaemia can affect patient quality of life. Very few such studies have been carried out in children. OBJECTIVE: To analyse the impact of laboratory variables and various clinical situations on HRQOL of paediatric CKD patients. PATIENTS AND METHOD: We carried out a cross-sectional study using the TECAVNER questionnaire in 71 children with CKD and their parents (33 transplanted patients, 11 on peritoneal dialysis, 5 on haemodialysis, and 22 on conservative treatment). We analysed laboratory variables (blood urea nitrogen, creatinine, haematocrit, and albumin), clinical situation (short stature, arterial hypertension, and bone deformities), number of hospitalisations, and days spent in the hospital in the previous 6 months, as well as number of drugs administered and fluids/diet restrictions. RESULTS: The factor that most heavily affected the quality of life of our patients was water restrictions. In addition, hypertension affected cognitive function in these children. A haematocrit value >35% improved physical activity and functionality. We observed no association between albumin and HRQOL. CONCLUSIONS: These results confirm previous hypotheses and contribute to the validity of the TECAVNER questionnaire. PMID- 23364626 TI - Characteristics of bone mineral metabolism in patients with stage 3-5 chronic kidney disease not on dialysis: results of the OSERCE study. AB - OSERCE is a multi-centre and cross-sectional study with the aim of analysing the biochemical, clinical, and management characteristics of bone mineral metabolism alterations and the level of compliance with K/DOQI guideline recommendations in patients with chronic kidney disease (CKD) not on dialysis. The study included a total of 634 patients from 32 different Spanish nephrology units, all with CKD, estimated glomerular filtration rates <60 ml/min/1.73 m(2), and not on dialysis (K/DOQI stage: 33% stage 3, 46% stage 4, and 21% stage 5). In 409 of these patients, laboratory parameters were also measured in a centralised laboratory, including creatinine, calcium, phosphorous, intact parathyroid hormone (PTH), 25 OH-vitamin D, and 1,25-OH2-Vitamin D levels. The rates of non-compliance with the K/DOQI objectives for calcium, phosphorous, intact PTH, and calcium x phosphate product among these patients were 45%, 22%, 70%, and 4%, respectively. Of the 70% of patients with intact PTH levels outside of the target range established by the K/DOQI guidelines, 55.5% had values above the upper limit and 14.5% had values below the lower limit. Of the 45% of patients with calcium levels outside of the target range, 40% had values above the upper limit and 5% had values below the lower limit. Of the 22% of patients with phosphorous levels outside of the target range, 19% had values above the upper limit, and 3% had values below the lower limit. Finally, 4% of patients also had values for the calcium x phosphate product that were outside of the recommended range. Only 1.8% of patients complied with all four K/DOQI objectives. The values detected in centralised laboratory analyses were not significantly different from those measured in the laboratories at each institution. In addition, 81.5% of patients had a deficiency of calcidiol (25-OH-D3) (<30 ng/ml); of these, 35% had moderate-severe deficiency (<15 ng/ml) and 47% had mild deficiency (15-30 ng/ml). Calcitriol (1,25-OH2-D3) levels were deficient in 64.7% of patients. Whereas the calcidiol deficiency was not correlated with the CKD stage, calcitriol deficit were more pronounced at more advanced stages of CKD. The results of the OSERCE study confirm the difficulty in reaching the target values recommended by the K/DOQI guidelines in patients with CKD not on dialysis, in particular in the form of poor control of secondary hyperparathyroidism and vitamin D deficiency. With this in mind, we must review strategies for treating bone mineral metabolism alterations in these patients, and perhaps revise the target parameters set by current guidelines. PMID- 23364628 TI - Paricalcitol reduces proteinuria but does not modify peritoneal protein loss in patients on peritoneal dialysis. AB - INTRODUCTION: Paricalcitol, a selective activator of Vitamin D receptors, is successfully used as a treatment of hyperparathyroidism secondary to chronic kidney disease (CKD). In addition, it has been proposed for reducing proteinuria in patients with CKD. Nonetheless, little is known about its effect on peritoneal protein loss in patients on peritoneal dialysis (PD). OBJECTIVES: To analyse the efficiency of oral paricalcitol in secondary hyperparathyroidism control in PD patients and to verify its effect on urinary and peritoneal effluent protein loss. MATERIAL AND METHOD: Prospective study with a 12-month follow-up on a cohort of PD patients. Invention consisted of the introduction of paricalcitol for the treatment of secondary hyperparathyroidism. Paricalcitol was dosed according to parathyroid hormone (PTH): 1mg/day for patients with PTH < 500 pg/ml, and 2mg/day for those with higher PTH levels. Epidemiological, clinical and analytical data were analysed. RESULTS: 38 patients (56 +/- 19 years, 55% women, 16% diabetics, technique time (14 +/- 10 months) were included in the study. Thirty-three of them received 1mg/day of paricalcitol; the rest received 2mg/day. The use of paricalcitol was associated with a PTH decrease of 30.7 +/- 6.8% (P<.001) after 12 months of treatment with no changes in calcium (8.82 +/- 0.96 vs. 9.02 +/- 0.91; P = .153) and phosphate levels (4.78 +/- 0.63 vs. 4.93 +/ 0.77; P = .693). Patients did not modify treatment concurrent with phosphate binders over the study period, nor did they change the cinacalcet dosage. However, fewer patients needed it by the end of the study. The PTH baseline levels were independent indicators of its decrease (b = 0.689, P = .018), and the rest of the analysed parameters were not affected. Over the study period there was a proteinuria decrease (0.79 +/- 0.41 vs. 0.64 +/- 0.36 g/day, P = .034) with no changes in renal function (7.2 +/- 1.1 vs. 6.3 +/- 0.9 ml/min, P =.104). Similarly, no differences were found in in the percentages of patients taking renin-angiotensin system inhibitors (71 vs. 68 %, P = .472) or the doses needed. There was no significant change in peritoneal protein loss (5.8 +/- 1.9 vs. 6.0 +/- 2.2g/24h, P = .731) nor in serum albumin levels (3.7 +/- 1.1 vs. 3.7 +/- 1.2g/dl, P = .697). CONCLUSIONS: The use of oral paricalcitol reduces PTH levels safely and substantially in patients on PD. Their use is associated with a proteinuria decrease and is not linked to a decrease of glomerular filtration rate or changes in the medication that could modify it. We have found no modification in the amount of peritoneal protein loss. PMID- 23364629 TI - Double treatment with paricalcitol-associated calcifediol and cardiovascular risk biomarkers in haemodialysis. AB - BACKGROUND: The deficit of 25-hydroxyvitamin D (25OHD) associated with secondary hyperparathyroidism (SHPT) is a frequent finding in chronic kidney disease (CKD) patients on haemodialysis (HD). These events are associated with increased morbidity and mortality rates of cardiovascular (CV) origin. Adequate 25OHD serum levels as well as the use of selective vitamin D receptor activators (VDRA) have been shown to have beneficial and independent effects on bone mineral metabolism and cardiovascular risk. Currently, there is still controversy regarding the type of supplementation needed by CKD patients on HD. OBJECTIVE: The aim of our study was to evaluate whether there is a benefit of combination therapy with 25OHD, calcifediol and a VDRA, oral paricalcitol, on bone-mineral metabolism and inflammatory markers, compared to single treatment with each of these in a group of patients on HD. MATERIAL AND METHOD: We performed a prospective study of 6 months, involving 26 patients in our HD unit. We randomised patients into two groups: group 1 (G1) received oral paricalcitol treatment at doses of 1 mcg/day. Group 2 (G2) was treated with 1 ampoule calcifediol/wk (0.266 mg/wk=16 000U) orally. After 3 months of treatment, calcifediol and paricalcitol were added to the G1 and G2 respectively at the same doses, keeping these treatments together for 3 months to complete the 6 months of follow-up. Laboratory tests were performed at months 0, 3 and 6, measuring in all patients serum markers of 25OHD, calcium (Ca), phosphorus (P) and PTH. Bone turnover markers measured were: alkaline phosphatase (AP), aminoterminal propeptide of procollagen type 1 (Pinp1) and carboxyl-terminal telopeptide of type I collagen (CrossLaps), and inflammatory markers: IL-8. We also collected data on levels of insulin, glucose, haemoglobin, erythropoiesis-stimulating agents (ESAs) and rates of resistance to EPO and HOMA (homeostasis model assessment). RESULTS: We detected a deficit of 25 hydroxyvitamin D in all patients studied, with a mean of 13.67 +/- 4.81 ng/ml. Supplementation with oral calcifediol significantly corrects this deficit without evidence of toxicity (35.36 +/- 33.68 ng/ml in G1 at 6 months and 59.21 +/- 26.50 ng/ml in G2 at 3 months). Paricalcitol treatment significantly reduces PTH levels in G1 at 3 months (P<.039). We also noted a decrease in bone marker Pinp1 with paricalcitol, pointing to a possible direct effect on bone cells (P<.001). Both treatment with paricalcitol and with calcifediol produced a significant decrease in levels of IL-8 (P<.001), a known inflammatory marker, drawing attention to a trend towards better response to erythropoiesis-stimulating agents (ESAs), possibly related to the decrease in inflammation. The HOMA index did not change significantly. CONCLUSION: Based on our results, we cannot conclude that the association of calcifediol and paricalcitol produces advantages over the effect of each drug separately. In addition, Paricalcitol by itself appears to have a direct effect on cellular bone remodelling. PMID- 23364630 TI - Repeated analysis of estimated insulin resistance using the HOMAIR index in nondiabetic patients on peritoneal dialysis and its relationship with cardiovascular disease and mortality. AB - Terminal chronic renal failure patients show early insulin resistance (IR), characterised by alterations in the hydrocarbon metabolism and hyperinsulinaemia generally associated with dyslipidaemia and a proinflammatory condition. Cardiovascular disease (CVD) is the main cause of mortality in patients on dialysis. There is a strong association between IR, hyperinsulinism and CV disease. The objective of this study was to evaluate the effect of peritoneal dialysis (PD) on IR and its effects on the subsequent CVD morbidity and mortality in nondiabetic uraemic patients. It involved 69 nondiabetic patients on PD, 35 incident patients (<= 3 months on PD) and 34 prevalent patients (>3 months on PD), with 2 estimated insulin resistance measurements 12 months apart using the insulin resistance index (HOMAIR). The mean HOMAIR value in incident patients was 1.8 +/- 1.3 and 2.2 +/- 2.1 at baseline situation and at 12 months respectively (not significant [NS]). In prevalent patients these values were 2.3 +/- 1.3 and 2.5 +/- 2.2 (NS). In our study, the mean glucose, insulin and IR concentrations measured by the HOMAIR and QUICKI indexes (the latter being a quantitative control for insulin sensitivity control) were similar at baseline situation and the following year, in both incident and prevalent patients. We did not find any significant differences in relation to CVD comorbidity, ischaemic heart disease, heart failure or cerebrovascular or peripheral comorbidity neither in the HOMAIR index or insulin levels. To conclude, nondiabetic patients on PD do not display a significant increase in HOMAIR levels and this remains the case over time when on dialysis. This, in turn, suggests that PD is not an IR risk factor. The fact that the IR indexes are not associated with CVD morbidity or mortality seems to suggest that this is a less significant factor in the field of PD. PMID- 23364631 TI - Advancing in the management of chronic kidney disease: the results of implementing a quick resolution consultation. AB - BACKGROUND: Currently, chronic kidney disease (CKD) is understood as global important public health problem, a situation that requires a new approach. OBJECTIVES: To show the results obtained after implementing a quick resolution consultation for CKD management. METHODS: Results were analysed during 6 month time period. RESULTS: A total of 9.61% of received proposals were referred to primary care without in-person visits. In addition, 28.05% of patients were initially evaluated through high resolution clinics and 62.33% were directly referred to other clinics. From the initial 28.05% mentioned, once evaluated, treatment adjusted and informed about the disease, 70% were referred over to primary care for monitoring and the remaining 30% were given specialist appointments. As a consequence, 70.65% of patients were selected for monitoring by nephrology from all proposals received, and 29.35% for primary care monitoring. We observed a significant decrease in the delay until the first medical appointment. CONCLUSIONS: Quick resolution consultations demonstrated to be an efficient tool for CKD management. Its implementation allowed both low consumption of health care resources, selected patients with high risk of progressive cardiovascular disease for long term monitoring, and offered not only an initial evaluation and adjustment of treatment with information provided to those who would be monitored by primary care, but also diminished primary care delays significantly. PMID- 23364632 TI - CKD-EPI is the most reliable equation to estimate renal function in patients with systemic lupus erythematosus. AB - BACKGROUND: No study has determined the best equation for estimating renal function in patients with systemic lupus erythematosus (SLE), starting from a gold standard test. OBJECTIVE: To evaluate the performance of cistatin/creatinine based equations for estimating renal function in patients with SLE. METHODS: We conducted two phases: the first phase included 14 patients in which iothalamate clearance was used to determine the glomerular filtration rate (GFR) and compared with different equations based on cystatin C and/or creatinine. In the second phase, we used the best equation (a cystatin and creatinine-based equation) as "reference standard" to compare 5 creatinine-based equations in 55 patients with SLE. RESULTS: In the first phase the equation developed by Stevens and colleagues (based on creatinine and cystatin C), was the best equation. In phase 2, the CKD EPI (Chronic Kidney Disease Epidemiology Collaboration) equation was the best equation with bias of -2. 1 ml/min/1.73, accuracy (P30) of 94.5% and precision (interquartile range of differences) of -2.1 ml/min/1.73. CONCLUSIONS: Our data suggest that CKD-EPI is the best creatinine-based equation to estimate GFR in patients with SLE. PMID- 23364633 TI - The impact of darbepoetin alfa in early post-transplant anaemia management: retrospective exploratory study. AB - BACKGROUND AND OBJECTIVES: The use of darbepoetin alfa in the first week of post renal transplant (RT). METHODS: Retrospective observational study carried out in four hospitals, which included all adult patients that underwent RT for 9 months with haemoglobin data during the first 6 months of post-transplant (n=129). Darbepoetin alfa was administered in accordance with the clinical practice. RESULTS: Darbepoetin alfa was administered in the first week to 60 individuals (46.5%), who had a mean baseline Hb (+/- standard deviation) of 12.7 g/dl +/- 1.6g/dl. Anaemia incidence (Hb<11 g/dl) during the first month was higher in patients who did not receive darbepoetin alfa (40.6% vs. 25.0% in patients treated with darbepoetin alfa, P=.045). No anaemia incidence differences were observed during months +2 to +6. There was a tendency towards transfusion decrease in patients who received darbepoetin alfa (13.3% vs. 20.3%, P=.295). Renal recovery time was similar but in the subgroup which received grafts from donors with asystole there was a tendency towards a faster recovery with darbepoetin alfa (15.1 +/- 7.7 vs. 20.1 +/- 8.8 days, P=.157). The creatinine clearance rate at 3 and 6 months was similar. Fourteen patients (10.9%) suffered from cardiovascular events with no relation to darbepoetin alfa (P=.772). CONCLUSIONS: Administering darbepoetin alfa in the first week following renal transplant reduces anaemia incidence during the first month without increase cardiovascular events. PMID- 23364634 TI - Protective effect of alpha tocopherol on contrast-induced nephropathy in rats. AB - BACKGROUND: Contrast-induced nephropathy (CIN) is a prominent cause of in hospital acute kidney injury occurring after the administration of intravenous radiocontrast medium. Oxidative stress has been proposed as one of the more important mechanisms in the pathogenesis of CIN. The aim of the present study has been to determine the effect of alpha tocopherol on the reduction of renal damage in a rat model of CIN. METHODS: Male Sprague Dawley rats were subjected into six groups pretreated with alpha-tocopherol (250 or 500 mg/kg/day) or the vehicle tweeen80 for 5 days before the induction of CIN. Renal function and oxidative stress markers; level of malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD) activity were determined. Kidney tissues were sectioned for pathohistological examination. RESULTS: In the contrast media (CM) group, an increase in serum urea and creatinine was found. Tubular necrosis and peritubular capillary congestion were demonstrated in this group. Also, an imbalance of oxidative stress markers; an increase in MDA and a decreased SOD activity in kidney were shown. On the contrary, in CIN-induced rats administrated with alpha-tocopherol group, a significant reduction of renal function and renal MDA, together with a significant increase of renal SOD, were observed. Interestingly, a reduction in MDA and an increase of TAC in serum, along with prevention of tubular injury, were demonstrated in this group, as compared to the CM group. CONCLUSION: This present study demonstrated that alpha tocopherol showed protective effect on the rat renal damage induced CIN. Therefore, this vitamin could be used as an antioxidant to attenuate the radiocontrast oxidative damage. PMID- 23364635 TI - Serology for hepatitis B and C, HIV and syphilis in the initial evaluation of diabetes patients referred for an external nephrology consultation. AB - INTRODUCTION: Information is available regarding the prevalence and incidence of positive microbiological serology results both in the general population and in patients on haemodialysis in Spain. Nevertheless, little information is known regarding patients with diabetes attended in external nephrology consultations. OBJECTIVE: To evaluate the percentage of patients with positive serology results for hepatitis B and C, Human Immunodeficiency Virus (HIV), and syphilis in the initial assessment of patients referred to diabetic nephropathy external consultations. PATIENTS AND METHOD: Retrospective study of 500 patients assessed over the course of 5 years with the diagnosis of diabetic nephropathy originating in external consultations and for which hepatitis B, C, HIV, and syphilis serology had been requested. RESULTS: With regard to hepatitis B virus, 0.4% of patients had chronic hepatitis B, 10.2% had overcome the hepatitis and were in recovery, and 4.2% had received the hepatitis B vaccine. As for hepatitis C, 2.4% of the patients studied had antibodies against hepatitis C. With regard to syphilis, 0.8% of patients had positive serological results. No patients had positive HIV serology results. CONCLUSIONS: Despite major methodological limitations, this would be the first study to evaluate the microbiological serology of diabetic nephropathy patients treated in external consultations. PMID- 23364636 TI - Chagas' disease and kidney donation. AB - Due to current trends in human population movements, there has been an increase in the number of individuals with Chagas’ disease (CD) living in non endemic regions; as such, there is a high probability that we will face an increase in cases of CD, both in patients requiring renal replacement therapy and in potential donors. We present the case of an organ donor with positive serology for Trypanosoma cruzi, whose kidneys were implanted into two different recipients. Prophylaxis was administered with benznidazole for 3 weeks. Over the course of two years of serological and clinical follow-up, no evidence of Chagas’ transmission or infection was observed. This positive evolution suggests that renal transplants derived from donors with positive serology results and no signs of acute or chronic disease may be acceptable. We also provide a review of the evidence supporting this conclusion and the available recommendations in the medical literature. PMID- 23364637 TI - Protein/creatinine ratio in spot urine versus 24-hour urine protein. PMID- 23364638 TI - Correlation versus agreement; protein/creatinine ratio in spot urine and 24-hour urine protein. PMID- 23364639 TI - Comment on "membranous glomerulonephritis associated with mieloperoxidase antineutrophil cytoplasmic antibody-associated glomerulonephritis". PMID- 23364640 TI - Response to "Comment on 'Membranous glomerulonephritis associated with mieloperoxidase antineutrophil cytoplasmic antibody-associated glomerulonephritis'". PMID- 23364641 TI - Laparoscopy as an effective technique for peritoneal catheter placement. PMID- 23364642 TI - Nurse-psychologist interdisciplinary approach for advanced chronic kidney disease consultations: objectives and protocol. PMID- 23364643 TI - Implementation of clinical guidelines and compliance with target haemoglobin levels in peritoneal dialysis. PMID- 23364644 TI - Law on advance directives in Mexico. PMID- 23364645 TI - Delayed introduction of tacrolimus in sub-optimal kidneys. A short-term follow-up study in the University Hospital of Salamanca. PMID- 23364646 TI - Terminal chronic kidney disease in Gambia. A one-year study. PMID- 23364647 TI - Mycophenolate mofetil induced severe, life threatening lower gastrointestinal bleeding - case report. PMID- 23364648 TI - A long-term follow-up of an Imerslund-Grasbeck syndrome patient with proteinuria. PMID- 23364649 TI - Emphysematous cystitis. PMID- 23364650 TI - De novo tacrolimus- associated hemolytic uremic syndrome after renal transplantation - case report. PMID- 23364651 TI - Recurrent cutaneous necrosis of a multifactorial origin in a patient on haemodialysis. PMID- 23364652 TI - Adverse reaction to intravenous iron: hypersensitivity or secondary side effect? PMID- 23364653 TI - Pediatric Pseudotumor Cerebri Associated With Low Serum Levels of Vitamin A. AB - The aim of this study was to describe the association between pediatric pseudotumor cerebri and low serum vitamin A levels. We retrospectively reviewed the charts of 6 children (5 boys, 1 girl; mean age 8 years) with increased intracranial pressure and low serum vitamin A levels (mean 16.0 +/- 8.8 ug/dL). The etiology of the vitamin A deficiency was a restricted diet (2 children), intestinal malabsorption caused by celiac disease (2 children), and undetermined cause (2 children). Only 1 child had ocular signs of xerosis. Poor visual acuity at presentation and lower serum vitamin A levels were associated with a poor visual outcome and development of optic atrophy. In conclusion, pseudotumor cerebri in children can be associated with vitamin A deficiency even when other manifestations of xerophthalmia do not exist. Early recognition of this condition and appropriate therapy can prevent blindness. PMID- 23364654 TI - Prospective Study of the Emfit Movement Monitor. AB - Sudden unexplained death in epilepsy (SUDEP) is associated with generalized tonic clonic seizures and occurs most often when patients are in bed. There are several seizure detection monitors on the market, but little data are available on the sensitivity and specificity of these devices. We recently tested 2 models of seizure detection alarms with disappointing results. Here we tested the Emfit movement monitor on children with various seizure types who also had standard video electroencephalography (EEG), cardiopulmonary, and nursing monitoring. Video EEG records were reviewed to detect any seizures. In 45 patients, 78 seizures were recorded by video EEG. The Emfit movement monitor captured 23 seizure events (30%) in total, and 15 of the 28 (54%) that occurred during sleep. Most importantly, the alarm was activated with 11 of the 13 (85%) generalized tonic-clonic seizures that occurred in sleeping children. The Emfit movement monitor performed very well in comparison to previously tested devices. PMID- 23364655 TI - Childhood chronic inflammatory demyelinating polyneuropathy: an overview of 10 cases in the modern era. AB - Chronic inflammatory demyelinating polyneuropathy is a rare condition in children. In this article, we report our experience in the management of 10 cases of childhood chronic inflammatory demyelinating polyneuropathy in a single center, in the era of contrast-enhanced magnetic resonance imaging (MRI), genetic microarray, and chronic inflammatory demyelinating polyneuropathy disease activity status. Robust neurophysiologic abnormalities were present in all cases and both MRI and lumbar puncture were useful adjuncts in diagnosis. Genetic microarray is a simple technique useful in excluding the most common hereditary demyelinating neuropathy. Intravenous immunoglobulin was an effective first-line therapy in most cases, with refractory cases responding to corticosteroids and rituximab. We found the chronic inflammatory demyelinating polyneuropathy disease activity status useful for assessing outcome at final follow-up, whereas the modified Rankin score was better for assessing peak motor disability. PMID- 23364656 TI - SMART syndrome (stroke-like migraine attacks after radiation therapy) in adult and pediatric patients. AB - SMART syndrome (stroke-like migraine attacks after radiation therapy) is a rare condition that involves complex migraines with focal neurologic findings in patients following cranial irradiation for central nervous system malignancies. Little is known about the mechanisms behind the disorder, making successful treatment challenging. We report 2 new cases of SMART syndrome in pediatric patients as well as review all documented cases of the syndrome. Each of our 2 pediatric patients suffered multiple episodes. Attacks were characterized by severe headache, visual disturbance, aphasia, and weakness. Recovery occurred over several days to weeks. The data from all documented reports of SMART syndrome indicate a greater prevalence for male gender. An age-dependent pattern of onset was also observed, with a greater variability of syndrome onset in patients who received cranial irradiation at a younger age. SMART appears to be a reversible, recurrent long-term complication of radiation therapy with possible age- and gender-related influences. PMID- 23364657 TI - Preparation of coordination polymers with 8-hydroxyquinoline azo benzensulfonic acid as a planar multidentate ligand and the study of their photochemical and photo-stability properties. AB - The combination of ditopic ligand 4-(8-hydroxyquinoline-5-azo)-benzensulfonic acid (H2QBS) with metal ions (M = Na(+), Pb(2+), Zn(2+), Mn(2+), Cd(2+)) leads to five different coordination polymers (CPs): [Na2(QBS)(H2O)2]n (1 , 3D framework), {[Pb(QBS)(DMSO)].2((i)PrOH)}n (2.2(i)PrOH, 2D layer), {[Zn(QBS)(DMSO)].2DMSO}n (3.2DMSO, 1D chain), [Mn(QBS)((i)PrOH)(DMSO)]n (4, 1D ladder), and [Cd2(QBS)2(DMSO)2(H2O)4]n (5, 1D chain). All compounds were characterized by FT IR, elemental analysis and TG analysis, and their structures were determined by single crystal X-ray diffraction. As expected, H2QBS acted as a multimode ligand and the azo bond in the trans-form existed in all compounds. Their photo stability was also studied using irradiation from different light sources (450 nm, 365 nm and 254 nm). Under blue light (450 nm) and lower energy UV light (365 nm), the colors of all compounds were well preserved and the absorption spectra show slight changes. However, when irradiated using higher energy UV light (254 nm), the coordination interaction between the metal ions and the ligand was disassociated and the color faded. PMID- 23364658 TI - Chylous ascites and chylothorax as presentation of a systemic progression of discoid lupus. AB - We describe a patient with a history of discoid lupus erythematosus who presented with chylous ascites and chylothorax. Analysis of peritoneal and pleural fluid showed a high level of triglycerides and the presence of antinuclear antibody and anti-dsDNA antibody. Further study revealed other diagnostic criteria for systemic lupus erythematosus and serologic markers of disease activity. The patient was successfully treated with methylprednisolone pulse therapy and high doses of prednisone, followed by immunosuppressants. PMID- 23364659 TI - Remission induction in a case of refractory Behcet disease with alemtuzumab. PMID- 23364660 TI - Lupus enteritis: an uncommon manifestation of systemic lupus erythematosus. AB - We report the case of a 25-year-old Iraqi woman who had multiple hospitalizations at an outside hospital for abdominal pain, nausea, and diarrhea without any evidence of systemic lupus erythematosus. Laboratory investigations finally showed a positive antinuclear antibody (1280), positive anti-dsDNA, anti-beta2 glycoprotein I, low complement, positive Coombs tests, and leukopenia. A kidney biopsy showed ISN class II lupus nephritis. An ileal biopsy and angiogram were unremarkable. A computed tomography showed marked and dramatic bowel edema involving the small and large bowel ("target sign"), dilatation of intestinal segments, engorgement of mesenteric vessels ("comb sign"), and increased attenuation of mesenteric fat. These cardinal signs on computed tomography scan led to the correct diagnosis of lupus enteritis. Treatment was commenced with high-dose corticosteroids followed by mycophenolate mofetil, hydroxychloroquine, and then oral cyclophosphamide, but failed. The patient was eventually treated with the Euro-Lupus intravenous cyclophosphamide regimen, which resulted in significant clinical and radiological resolution. PMID- 23364661 TI - Rheumatology practice profiles in teaching and community settings in Puerto Rico: implications to subspecialty training. AB - BACKGROUND: University-based fellowship training programs may not always provide the required experience to manage common and less complex medical conditions usually seen at the community setting. Few studies have addressed this concern. OBJECTIVE: The purpose of this study was to compare the demographic features, diagnoses, and rheumatologic procedures in patients seen at the University of Puerto Rico Medical Sciences Campus Adult Rheumatology Training Program practice and 3 community-based rheumatology practices in Puerto Rico. METHODS: Claim forms submitted to health care insurance companies in 2007 from the university and community practices were evaluated. Demographic parameters, primary diagnoses (per International Classification of Diseases, Ninth Revision), medical visits, and rheumatologic procedures (per Current Procedural Terminology 4) were examined. Variables were analyzed by chi and Student t tests. RESULTS: A total of 11,373 claim forms were reviewed: 1952 from the university setting and 9421 from the community-based practices. Younger age and female sex were more common in visits from the university-based setting. Autoimmune diseases were reported more commonly at the university setting (65.3% vs 37.6%, P < 0.001). Conversely, osteoarthritis (24.4% vs 9.8%, P < 0.001), fibromyalgia syndrome (7.4% vs 1.9, P < 0.001), and regional rheumatic pain syndromes (7.2% vs 1.4%, P < 0.001) were seen more frequently at community practices. Hospital/emergency room visits (11.8% vs 0.3%, P < 0.001) were more frequent at the university setting, whereas joint (13.3% vs 2.9%, P < 0.001) and periarticular injections (6.2% vs 1.7%, P < 0.001) were performed more frequently at the community practices. CONCLUSIONS: Several differences were found in the profile of demographic parameters, diagnoses, medical visits, and rheumatologic procedures between patients seen at the University of Puerto Rico Medical Sciences Campus rheumatology practice and 3 community-based practices. Efforts may be required to diversify and increase the exposure of rheumatology fellows to patients with conditions commonly seen at the community setting. PMID- 23364662 TI - Etanercept-induced Henoch-Schonlein purpura in a patient with ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a chronic inflammatory disease that primarily affects the axial skeleton. Extra-articular manifestations are less common relative to other rheumatic diseases, and vasculitic complications typically involve the ascending aorta and aortic valve. The use of tumor necrosis factor inhibitors is efficacious in the treatment of patients with AS. Since their routine use, however, tumor necrosis factor inhibitors have been associated with the development of drug-induced complications including the induction of lupus and both cutaneous and systemic vasculitis. In this report, we describe a patient with severe longstanding AS, who developed Henoch-Schonlein purpura after commencing therapy with etanercept. Tumor necrosis factor inhibitor-induced Henoch-Schonlein purpura has been very rarely reported and has been mostly recognized in patients with rheumatoid arthritis. PMID- 23364663 TI - Primary meningococcal arthritis requiring surgical drainage. AB - Primary meningococcal arthritis (PMA) is a relatively rare diagnosis where the role of early surgical intervention for its treatment is not well defined. We report a case of PMA in a young otherwise healthy patient who developed polyarticular joint pain secondary to Niessieria meningitidis without systemic symptoms of meningitis or meningococcemia. He underwent a prolonged course of intravenous antibiotics and serial aspirations of his shoulder. However, symptoms in his shoulder did not improve and he later underwent surgical irrigation and debridement.Intraoperatively, the patient had no signs of articular damage to his right shoulder despite prolonged clinically symptomatic disease. Six weeks after surgery, he has regained normal strength and full range of motion without any deficits.Nonoperative management of PMA is frequently, but not invariably, successful. We report a patient with this diagnosis who ultimately needed surgical evacuation of his shoulder joint to achieve resolution of his symptoms. PMID- 23364664 TI - Clinical features and outcomes of 37 Argentinean patients with severe granulomatosis with polyangiitis (wegener granulomatosis). AB - BACKGROUND: Most epidemiologic studies involving severe granulomatosis with polyangiitis (SGPA) patients have investigated populations from the northern hemisphere, whereas few studies have been conducted in South America. None of the South American studies have differentiated between localized GPA and SGPA. PURPOSE: The present study was designed to describe a cohort of Argentinean patients who were diagnosed with SGPA and to compare this cohort with previously well-described cohorts. METHODS: We performed a retrospective study that included 37 consecutive SGPA patients who were seen at 2 tertiary centers in Buenos Aires. RESULTS: Nineteen patients (51.3%) were male, and 18 patients (49.7%) were female. The mean age at the onset of symptoms was 48.5 +/- 12.01 years. Antineutrophil cytoplasmic antibody (ANCA) was detected in 34 patients (91.89%): 32 patients (86.48%) had a cytoplasmic staining pattern, whereas 2 patients (5.40%) had a perinuclear pattern. Three patients were ANCA-negative. Twenty-four patients (64%) achieved remission, and 7 patients (19%) had response as defined by at least 50% reduction in the disease activity score. Nineteen relapses were observed in 12 patients, and 2 of the relapses were fatal. Overall, there were 14 deaths (37.83%). CONCLUSIONS: The present series demonstrated that Argentinean patients have similar demographics, clinical manifestations, and outcomes as the cohorts from the northern hemisphere. There was less granulomatous organ involvement (ear/nose/throat, lung granulomas) in the present cohort compared with other series. PMID- 23364665 TI - Chronic opioid use in fibromyalgia syndrome: a clinical review. AB - Chronic opioid therapy in the treatment of chronic nonmalignant pain has increased drastically over the past decade. This is a worrisome trend in general, but specifically, given pathophysiologic characteristics seen in fibromyalgia (FM) syndrome patients, the use of this class of medication deserves special scrutiny. We first describe the current understanding of the etiology and pathophysiology of FM, including the role of genetic and environmental factors in the development of this syndrome. We then discuss the biologic effects of opioid use. Next, we review the pharmaceutical treatment options for FM, including 3 Food and Drug Administration-approved medications, and the evolution of treatment guidelines since 2004. We then highlight the various consequences associated with the mechanism of action of opioids and the specific concerns for FM patients.Finally, summarizing the existing literature, we make the case that chronic opioid use is inappropriate in the treatment of FM because of the interaction of unique pathophysiologic characteristics of the patients and effects associated with chronic opioid use. PMID- 23364666 TI - Potential pitfalls in the diagnosis of crystal-induced arthritis and in the sonographic measurement of hyaline cartilage due to the presence of joint effusion. PMID- 23364668 TI - Panniculectomy and abdominoplasty in patients undergoing gynecologic surgery: a single center case series of 15 combined procedures. AB - The current obesity epidemic poses significant challenges to surgical specialists striving to safely and effectively deliver medical care. In the United States, approximately 33.3% of men and 35.3% of women are classified as obese. Pelvic surgery, especially in patients with gynecological malignancies and those who require complex surgical procedures carries additional risk because of the increased technical difficulty posed by excess abdominal wall tissues and increased difficulty in providing and maintaining exposure of the appropriate pelvic anatomy. Simultaneous panniculectomy or abdominoplasty in selected patients may provide better access and visualization of the surgical field, reduce operative difficulty, and decrease perioperative morbidity. We retrospectively reviewed our experience in 15 patients undergoing panniculectomy or abdominoplasty in conjunction with gynecologic surgery. This review was conducted after approval by the local institutional review board. Complications were analyzed, and 2 (13%) of the 15 patients were found to have major complications. The only statistically significant finding for prediction of a negative outcome was an association of hypertension and advanced age with increased risk of postoperative transfusion (P < 0.02). PMID- 23364669 TI - Reciprocal dominance of the anterolateral and anteromedial thigh flap perforator anatomy. AB - BACKGROUND: When anterolateral thigh (ALT) perforators are inadequate, exploration of the contralateral thigh may be required. If anteromedial thigh (AMT) perforators were useable in these instances, harvest could proceed from a single donor site. METHODS: A prospective cohort study was performed examining 100 consecutive thighs. Anterolateral and anteromedial thigh skin territories were surgically explored, and perforator size and number were documented. The relationship between ALT and AMT size and number was examined using Fisher exact test, logistic regression, and linear regression. RESULTS: Patients with small or no ALT perforators usually had a large AMT perforator. Patients with large or medium ALT perforators usually had medium or small AMT perforators (P = 0.029). Patients with small or no ALT perforators had a 6-fold increased chance of large/medium AMT perforators (odds ratio, 6.18; 95% confidence interval [CI], 1.23-30.91; P = 0.026). Patients without ALT perforators usually had 1 or more AMT perforators. Patients with 3 ALT perforators usually had no AMT perforators (P < 0.001). Patients with 1 or fewer ALT perforators had a 4-fold increased chance of an AMT perforator (odds ratio, 3.77; 95% CI, 1.34-10.65; P = 0.012). After assigning numeric values to perforators based on size, the total scores for ALT and AMT regions were analyzed using a linear regression model. Lower ALT perforator scores were significantly related to higher AMT scores (slope, -0.33; 95% CI, -0.46 to -0.20; P < 0.001). The Spearman test showed a similar relationship (rho = -0.43, P < 0.001). CONCLUSIONS: There is an inverse relationship between size and number of ALT and AMT perforators, that is, when ALT perforators are inadequate, AMT perforators are typically useable. PMID- 23364670 TI - A new technique for correction of simple congenital earlobe clefts: diametric hinge flaps method. AB - BACKGROUND: The earlobe plays an important part in the aesthetic appearance of the auricle. Congenital cleft earlobe may vary considerably in severity from a simple notching to extensive tissue deficiency. Most patients with cleft earlobe require surgical correction because of abnormal appearance. In this article, a new surgical technique for correcting congenital simple cleft earlobe using diametric hinge flaps is introduced. METHODS OR DESIGN: We retrospectively reviewed 4 patients diagnosed with congenital cleft earlobe between 2008 and 2010. All of them received this new surgical method. The patients were followed up from 3 to 6 months. All patients attained relatively full bodied earlobes with smooth contours, inconspicuous scars, and found their reconstructed earlobes to be aesthetically satisfactory. One patient experienced hypoesthesia in the area operated on, but recovered 3 months later. No other complications were noted. CONCLUSIONS: This simple method not only makes full use of the surrounding tissues to reconstruct full bodied earlobes but also avoids small notch formation caused by the linear scar contraction sometimes seen when using more traditional methods. PMID- 23364671 TI - Reconstruction of large dorsal digital defects with arterialized venous flaps: our experience and comprehensive review of literature. AB - Coverage of the dorsal aspect of the fingers is difficult, especially when the defect is large and multiple digits are involved with composite tissue loss and very few conventional flaps are suitable in dealing with such situation. The purpose of this study was to present our experience of reconstruction of the large dorsal digital defects with the arterialized venous flap (AVF) and evaluate its merits and demerits in this clinical setting with a comprehensive review of literature. From August 2008 to December 2010, 7 composite palmaris longus venous flaps and 5 AVFs were used in the reconstruction of extensive dorsal digital injuries in 8 patients, and a comprehensive review of literature regarding the reconstruction of dorsal digital defects with AVFs was carried out. All the flaps survived completely. The outcomes were very satisfactory for functional recovery, aesthetic appearance, and sensation restoration at an average follow-up of 11.8 months; the literature review also revealed the similar results. On the basis of our experience and literature review, AVFs are reliable and good candidates for resurfacing large dorsal digital defects when local flaps are not available or insufficient for coverage. Composite AVF with palmaris longus tendon is an optimal choice for 1-stage reconstruction of dorsal composite finger injuries. PMID- 23364673 TI - Visualizing the vascular history of nonmelanoma skin tumors: an in vivo human study. AB - INTRODUCTION: The formation of cutaneous carcinoma has been shown to rely on neovascularization, with angiogenesis being implicated in the invasive process of skin malignancy and metastasis. To date, studies of angiogenesis have generally been limited to in vitro, animal (often murine), or postexcision histopathologic models. METHODS: To demonstrate the angiogenic progression of human tumors in vivo, this study has used the Spectrophotometric Intracutaneous Analyser (SIAscope; Biocompatibles, Surrey, United Kingdom) to produce parametric images of 250 nonmelanoma skin cancers and 13 actinic keratoses. This provides a history, in images, of the vascular basis of skin cancer formation. RESULTS AND CONCLUSIONS: While displaying that the in vitro findings of angiogenesis are indeed occurring in vivo in humans, this technique also suggests a practical means to allow accurate application and monitoring of antiangiogenic therapy. In addition, it raises the possibility of differentiating superficial from nonsuperficial nonmelanoma skin cancers in an office-based setting, thus allowing accurate usage of surgical or nonsurgical treatment methods. PMID- 23364674 TI - Preaxial polydactyly of the upper limb viewed as a spectrum of severity of embryonic events. AB - Preaxial polydactyly (PPD) is a common congenital abnormality and its classification varies among geneticists and hand surgeons. For example, the triphalangeal thumb, preaxial polysyndactyly, and the mirror hand deformity are considered as forms of PPD only in the genetics literature. Preaxial polydactyly is an error in the anteroposterior axis of the development of the upper limb. In this paper, the development of this axis is detailed and all molecular events that are known to lead to PPD are reviewed. Finally, based on the review, PPD is viewed as a spectrum of severity of embryonic events. PMID- 23364675 TI - Propeller flaps in the closure of free fibula flap donor site skin defects. AB - The free fibula is a versatile and commonly used free flap in microvascular reconstruction. It allows for reconstruction of both bone and soft tissue defects. In head and neck reconstruction, the skin paddle harvested along with the flap allows for the reconstruction of skin or oral mucosal defects. After skin paddle harvest, the donor site can be closed primarily or with skin grafts. Grafting the donor area is the common method used. However, this could lead to delayed healing because of the poor graft over the area of peroneal tendons. Propeller flaps have been extensively reported for closure of leg skin defects. We report a series of 10 patients in whom we used a local propeller flap for the closure of the fibula flap skin donor site. The donor defects could be satisfactorily closed without the need of a skin graft in 9 patients. This method is simple, reliable, and suitable for closing small to medium defects. PMID- 23364676 TI - The course of the intercostobrachial nerve in the axillary region and as it is related to transaxillary breast augmentation. AB - PURPOSE: The aim of this study was to precisely determine the course of the intercostobrachial nerve (ICBN) in the axillary region and as it is related to bony landmarks, and all of this might be of use for transaxillary breast augmentation. METHODS: Thirty hemithoraxes of 15 fresh cadavers of Korean adults were dissected. After removal of the skin, the ICBN from its origin was identified. The point of emergence (EP) and the branching point (BP) were marked on translucent paper. RESULTS: The ICBN appeared at the second intercostal space approximately (mean +/- SD; 33.4 +/- 12.7) mm lateral to the midclavicular line and 9.8 +/- 6.4 mm medial to the lateral border of the pectoralis minor (P minor) muscle. The mean (SD) distance from the lower border of the second rib to the EP was 5.2 +/- 2.0 mm. The mean +/- SD distance from the upper border of the third rib to the EP was 12.7 +/- 3.3 mm. It traveled inferolaterally (mean +/- SD) 15.1 +/- 10.4 degrees from the horizontal plane) 39.4 +/- 19.2 mm to reach to the BP. The BP was located at the second intercostal space approximately (mean +/- SD) 59.4 +/- 21.2 mm lateral to the midclavicular line and 28.5 +/- 18.2 mm lateral to the lateral border of the P minor muscle. The mean +/- SD distance from the lower border of the second rib to the BP was 11.3 +/- 5.4 mm. The mean +/- SD distance from the upper border of the third rib to the BP was 6.3 +/- 7.1 mm. At the BP, the ICBN gave off a medial brachial cutaneous nerve, and this coursed superolaterally [mean (mean +/- SD, 50.7 +/- 15.1 degrees from the horizontal plane) toward the medial surface of the upper arm. The mean +/- SD depth of the ICBN from the superficial surface of the pectoralis major and P minor was 22.7 +/ 5.7 mm and 15.0 +/- 5.2 mm, respectively. CONCLUSION: When performing mammary augmentation, care should be taken not to dissect the undersurface of the P minor at the second intercostal space to avoid injury to the ICBN. PMID- 23364677 TI - Analysis of DNA repair-related genes in breast cancer reveals CUL4A ubiquitin ligase as a novel biomarker of trabectedin response. AB - Trabectedin is more active in nucleotide excision repair (NER)-efficient and homologous recombination repair (HRR)-deficient cells. As up to 25% of sporadic breast tumors present somatic inactivation of the HRR pathway (BRCAness phenotype), we sought to characterize trabectedin effect in BRCA1-proficient and BRCA1-null breast cancer cell lines. We evaluated whether HRR and NER gene expression correlates with trabectedin sensitivity and explored the response predictive value of the CUL4A ubiquitin ligase, which ubiquitinates NER pathway members. We characterized trabectedin cytotoxicity, cell-cycle effects, and BRCA1, BRCA2, XRCC3, XPG, ERCC1, and CUL4A expression in 10 breast cancer cell lines. Gene expression and trabectedin sensitivity association were determined in cell lines. Survival assays after trabectedin treatment were conducted in CUL4A silenced BRCA1-proficient and -deficient cells. Because of limited phase II clinical trials evaluating trabectedin efficacy in patients with breast cancer, we assessed CUL4A immunohistochemical staining in a retrospective series of 118 sarcomas from trabectedin-treated patients to validate in vivo our in vitro observations. In cell lines, greater trabectedin sensitivity was associated with higher CUL4A expression and lower BRCA1/ERCC5, BRCA1/CUL4A, and XRCC3/CUL4A expression ratios. In agreement, BRCA1-deficient CUL4A-knockdown cells presented higher cell survival after trabectedin exposure than did scramble control cells. Lack of effect in BRCA1-proficient cells suggests that HRR impairment is key in CUL4A-mediated trabectedin sensitivity. High CUL4A expression in nontranslocation related patients with sarcoma predicted improved progression-free survival [PFS; HR, 0.37; 95% confidence interval (CI), 0.20-0.68, P = 0.001] and overall survival (OS; HR, 0.44; 95% CI, 0.21-0.93, P = 0.026). Our observations support the notion of greater trabectedin activity in tumors exhibiting BRCAness and reveal CUL4A as a potential biomarker for definition of trabectedin target patients. PMID- 23364678 TI - Poly(beta-amino ester) nanoparticle delivery of TP53 has activity against small cell lung cancer in vitro and in vivo. AB - Small cell lung cancer (SCLC) is an aggressive disease with one of the highest case-fatality rates among cancer. The recommended therapy for SCLCs has not changed significantly over the past 30 years; new therapeutic approaches are a critical need. TP53 is mutated in the majority of SCLC cases and its loss is required in transgenic mouse models of the disease. We synthesized an array of biodegradable poly(beta-amino ester) (PBAE) polymers that self-assemble with DNA and assayed for transfection efficiency in the p53-mutant H446 SCLC cell line using high-throughput methodologies. Two of the top candidates were selected for further characterization and TP53 delivery in vitro and in vivo. Nanoparticle delivery of TP53 resulted in expression of exogenous p53, induction of p21, induction of apoptosis, and accumulation of cells in sub-G1 consistent with functional p53 activity. Intratumoral injection of subcutaneous H446 xenografts with polymers carrying TP53 caused marked tumor growth inhibition. This is the first demonstration of TP53 gene therapy in SCLC using nonviral polymeric nanoparticles. This technology may have general applicability as a novel anticancer strategy based on restoration of tumor suppressor gene function. PMID- 23364680 TI - Diaphragm muscle thinning in patients who are mechanically ventilated. AB - BACKGROUND: Approximately 40% of patients in medical ICUs require mechanical ventilation (MV). Approximately 20% to 25% of these patients will encounter difficulties in discontinuing MV. Multiple studies have suggested that MV has an unloading effect on the respiratory muscles that leads to diaphragmatic atrophy and dysfunction, a process called ventilator-induced diaphragmatic dysfunction (VIDD). VIDD may be an important factor affecting when and if MV can be discontinued. A sensitive and specific diagnostic test for VIDD could provide the physician with valuable information that might influence decisions regarding extubation or tracheostomy. The purpose of this study was to quantify, using daily sonographic assessments, the rate and degree of diaphragm thinning during MV. METHODS: Seven intubated patients receiving MV during acute care were included. Using sonography, diaphragm muscle thickness was measured daily from the day of intubation until the patient underwent extubation or tracheostomy or died. We analyzed our data using standard descriptive statistics, linear regression, and mixed-model effects. RESULTS: The overall rate of decrease in the diaphragm thickness of all seven patients over time averaged 6% per day of MV, which differed significantly from zero. Similarly, the diaphragm thickness decreased for each patient over time. CONCLUSION: Sonographic assessment of the diaphragm provides noninvasive measurement of diaphragmatic thickness and the degree of diaphragm thinning in patients receiving MV. Our data show that diaphragm muscle thinning starts within 48 h after initiation of MV. However, it is unclear if diaphragmatic thinning correlates with diaphragmatic atrophy or pulmonary function. The relationship between diaphragm thinning and diaphragm strength remains to be elucidated. PMID- 23364679 TI - Potential of pretreatment neural activity in the visual cortex during emotional processing to predict treatment response to scopolamine in major depressive disorder. AB - CONTEXT: The need for improved treatment options for patients with major depressive disorder (MDD) is critical. Faster-acting antidepressants and biomarkers that predict clinical response will facilitate treatment. Scopolamine produces rapid antidepressant effects and thus offers the opportunity to characterize potential biomarkers of treatment response within short periods. OBJECTIVE: To determine if baseline brain activity when processing emotional information can predict treatment response to scopolamine in MDD. DESIGN: A double-blind, placebo-controlled, crossover study together with repeated functional magnetic resonance imaging, acquired as participants performed face identity and face-emotion working memory tasks. SETTING: National Institute of Mental Health Division of Intramural Research Programs. PARTICIPANTS: Fifteen currently depressed outpatients meeting DSM-IV criteria for recurrent MDD and 21 healthy participants, between 18 and 55 years of age. MAIN OUTCOME MEASURE: The magnitude of treatment response to scopolamine (percentage of change in the Montgomery-Asberg Depression Rating Scale score between study end and baseline) was correlated with blood oxygen level-dependent (BOLD) signal associated with each working memory component (encode, maintenance, and test) for both identity and emotion tasks. Treatment response also was correlated with change in BOLD response (scopolamine vs baseline). Baseline activity was compared between healthy and MDD groups. RESULTS: Baseline BOLD response in the bilateral middle occipital cortex, selectively during the stimulus-processing components of the emotion working memory task (no correlation during the identity task), correlated with treatment response magnitude. Change in BOLD response following scopolamine administration in overlapping areas in the middle occipital cortex while performing the same task conditions also correlated with clinical response. Healthy controls showed higher activity in the same visual regions than patients with MDD during baseline. CONCLUSION: These results implicate cholinergic and visual processing dysfunction in the pathophysiology of MDD and suggest that neural response in the visual cortex, selectively to emotional stimuli, may provide a useful biomarker for identifying patients who will respond favorably to scopolamine. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00055575. PMID- 23364682 TI - Iodinin (1,6-dihydroxyphenazine 5,10-dioxide) from Streptosporangium sp. induces apoptosis selectively in myeloid leukemia cell lines and patient cells. AB - Despite recent improvement in therapy, acute myeloid leukemia (AML) is still associated with high lethality. In the presented study, we analyzed the bioactive compound iodinin (1,6-dihydroxyphenazine 5,10-dioxide) from a marine actinomycetes bacterium for the ability to induce cell death in a range of cell types. Iodinin showed selective toxicity to AML and acute promyelocytic (APL) leukemia cells, with EC50 values for cell death up to 40 times lower for leukemia cells when compared with normal cells. Iodinin also successfully induced cell death in patient-derived leukemia cells or cell lines with features associated with poor prognostic such as FLT3 internal tandem duplications or mutated/deficient p53. The cell death had typical apoptotic morphology, and activation of apoptotic signaling proteins like caspase-3. Molecular modeling suggested that iodinin could intercalate between bases in the DNA in a way similar to the anti-cancer drug daunorubicin (DNR), causing DNA-strand breaks. Iodinin induced apoptosis in several therapy-resistant AML-patient blasts, but to a low degree in peripheral blood leukocytes, and in contrast to DNR, not in rat cardiomyoblasts. The low activity towards normal cell types that are usually affected by anti-leukemia therapy suggests that iodinin and related compounds represent promising structures in the development of anti-cancer therapy. PMID- 23364683 TI - HPN, a synthetic analogue of bromophenol from red alga Rhodomela confervoides: synthesis and anti-diabetic effects in C57BL/KsJ-db/db mice. AB - 3,4-Dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol (HPN) is a synthetic analogue of 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6 (ethoxymethyl)benzyl)benzene-1,2-diol (BPN), which is isolated from marine red alga Rhodomela confervoides with potent protein tyrosine phosphatase 1B (PTP1B) inhibition (IC(50) = 0.84 MUmol/L). The in vitro assay showed that HPN exhibited enhanced inhibitory activity against PTP1B with IC(50) 0.63 MUmol/L and high selectivity against other PTPs (T cell protein tyrosine phosphatase (TCPTP), leucocyte antigen-related tyrosine phosphatase (LAR), Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2). The results of antihyperglycemic activity using db/db mouse model demonstrated that HPN significantly decreased plasma glucose (P < 0.01) after eight weeks treatment period. HPN lowered serum triglycerides and total cholesterol concentration in a dose-dependent manner. Besides, both of the high and medium dose groups of HPN remarkably decreased HbA1c levels (P < 0.05). HPN in the high dose group markedly lowered the insulin level compared to the model group (P < 0.05), whereas the effects were less potent than the positive drug rosiglitazone. Western blotting results showed that HPN decreased PTP1B levels in pancreatic tissue. Last but not least, the results of an intraperitoneal glucose tolerance test in Sprague-Dawley rats indicate that HPN have a similar antihyperglycemic activity as rosiglitazone. HPN therefore have potential for development as treatments for Type 2 diabetes. PMID- 23364684 TI - The Oklahoma Thrombotic Thrombocytopenic Purpura-haemolytic Uraemic Syndrome Registry. A model for clinical research, education and patient care. AB - The Oklahoma Thrombotic Thrombocytopenic Purpura-Haemolytic Uraemic Syndrome (TTP HUS) Registry has a 24 year record of success for collaborative clinical research, education, and patient care. This article tells the story of how the Registry began and it describes the Registry's structure and function. The Registry provides a model for using a cohort of consecutive patients to investigate a rare disorder. Collaboration between Oklahoma, United States and Bern, Switzerland has been the basis for successful interpretation of Registry data. Registry data have provided new insights into the evaluation and management of TTP. Because recovery from acute episodes of TTP has been assumed to be complete, the increased prevalence of hypertension, diabetes, depression, and death documented by long-term follow-up was unexpected. Registry data have provided opportunities for projects for students and trainees, education of physicians and nurses, and also for patients themselves. During our follow-up, patients have also educated Registry investigators about problems that persist after recovery from an acute episode of TTP. Most important, Registry data have resulted in important improvements for patient care. PMID- 23364685 TI - Cell biology: Beneficial lessons from viruses. PMID- 23364687 TI - Magnetic-field-controlled reconfigurable semiconductor logic. AB - Logic devices based on magnetism show promise for increasing computational efficiency while decreasing consumed power. They offer zero quiescent power and yet combine novel functions such as programmable logic operation and non-volatile built-in memory. However, practical efforts to adapt a magnetic device to logic suffer from a low signal-to-noise ratio and other performance attributes that are not adequate for logic gates. Rather than exploiting magnetoresistive effects that result from spin-dependent transport of carriers, we have approached the development of a magnetic logic device in a different way: we use the phenomenon of large magnetoresistance found in non-magnetic semiconductors in high electric fields. Here we report a device showing a strong diode characteristic that is highly sensitive to both the sign and the magnitude of an external magnetic field, offering a reversible change between two different characteristic states by the application of a magnetic field. This feature results from magnetic control of carrier generation and recombination in an InSb p-n bilayer channel. Simple circuits combining such elementary devices are fabricated and tested, and Boolean logic functions including AND, OR, NAND and NOR are performed. They are programmed dynamically by external electric or magnetic signals, demonstrating magnetic-field-controlled semiconductor reconfigurable logic at room temperature. This magnetic technology permits a new kind of spintronic device, characterized as a current switch rather than a voltage switch, and provides a simple and compact platform for non-volatile reconfigurable logic devices. PMID- 23364688 TI - Neuroscience: Salty sensations. PMID- 23364689 TI - Dicalcium nitride as a two-dimensional electride with an anionic electron layer. AB - Recent studies suggest that electrides--ionic crystals in which electrons serve as anions--are not exceptional materials but rather a generalized form, particularly under high pressure. The topology of the cavities confining anionic electrons determines their physical properties. At present, reported confining sites consist only of zero-dimensional cavities or weakly linked channels. Here we report a layered-structure electride of dicalcium nitride, Ca(2)N, which possesses two-dimensionally confined anionic electrons whose concentration agrees well with that for the chemical formula of [Ca(2)N](+).e(-). Two-dimensional transport characteristics are demonstrated by a high electron mobility (520 cm(2) V(-1) s(-1)) and long mean scattering time (0.6 picoseconds) with a mean free path of 0.12 micrometres. The quadratic temperature dependence of the resistivity up to 120 Kelvin indicates the presence of an electron-electron interaction. A striking anisotropic magnetoresistance behaviour with respect to the direction of magnetic field (negative for the field perpendicular to the conducting plane and positive for the field parallel to it) is observed, confirming diffusive two dimensional transport in dense electron layers. Additionally, band calculations support confinement of anionic electrons within the interlayer space, and photoemission measurements confirm anisotropic low work functions of 3.5 and 2.6 electronvolts, revealing the loosely bound nature of the anionic electrons. We conclude that Ca(2)N is a two-dimensional electride in terms of [Ca(2)N](+).e(-). PMID- 23364690 TI - A black-hole mass measurement from molecular gas kinematics in NGC4526. AB - The masses of the supermassive black holes found in galaxy bulges are correlated with a multitude of galaxy properties, leading to suggestions that galaxies and black holes may evolve together. The number of reliably measured black-hole masses is small, and the number of methods for measuring them is limited, holding back attempts to understand this co-evolution. Directly measuring black-hole masses is currently possible with stellar kinematics (in early-type galaxies), ionized-gas kinematics (in some spiral and early-type galaxies) and in rare objects that have central maser emission. Here we report that by modelling the effect of a black hole on the kinematics of molecular gas it is possible to fit interferometric observations of CO emission and thereby accurately estimate black hole masses. We study the dynamics of the gas in the early-type galaxy NGC 4526, and obtain a best fit that requires the presence of a central dark object of 4.5(+4.2)(-3.1) * 10(8) solar masses (3sigma confidence limit). With the next generation millimetre-wavelength interferometers these observations could be reproduced in galaxies out to 75 megaparsecs in less than 5 hours of observing time. The use of molecular gas as a kinematic tracer should thus allow one to estimate black-hole masses in hundreds of galaxies in the local Universe, many more than are accessible with current techniques. PMID- 23364691 TI - Solid-state physics: A new spin on spintronics. PMID- 23364693 TI - Fungal biology: Multiple mating strategies. PMID- 23364694 TI - tmc-1 encodes a sodium-sensitive channel required for salt chemosensation in C. elegans. AB - Transmembrane channel-like (TMC) genes encode a broadly conserved family of multipass integral membrane proteins in animals. Human TMC1 and TMC2 genes are linked to human deafness and required for hair-cell mechanotransduction; however, the molecular functions of these and other TMC proteins have not been determined. Here we show that the Caenorhabditis elegans tmc-1 gene encodes a sodium sensor that functions specifically in salt taste chemosensation. tmc-1 is expressed in the ASH polymodal avoidance neurons, where it is required for salt-evoked neuronal activity and behavioural avoidance of high concentrations of NaCl. However, tmc-1 has no effect on responses to other stimuli sensed by the ASH neurons including high osmolarity and chemical repellents, indicating a specific role in salt sensation. When expressed in mammalian cell culture, C. elegans TMC 1 generates a predominantly cationic conductance activated by high extracellular sodium but not by other cations or uncharged small molecules. Thus, TMC-1 is both necessary for salt sensation in vivo and sufficient to generate a sodium sensitive channel in vitro, identifying it as a probable ionotropic sensory receptor. PMID- 23364695 TI - The 'obligate diploid' Candida albicans forms mating-competent haploids. AB - Candida albicans, the most prevalent human fungal pathogen, is considered to be an obligate diploid that carries recessive lethal mutations throughout the genome. Here we demonstrate that C. albicans has a viable haploid state that can be derived from diploid cells under in vitro and in vivo conditions, and that seems to arise through a concerted chromosome loss mechanism. Haploids undergo morphogenetic changes like those of diploids, including the yeast-hyphal transition, chlamydospore formation and a white-opaque switch that facilitates mating. Haploid opaque cells of opposite mating type mate efficiently to regenerate the diploid form, restoring heterozygosity and fitness. Homozygous diploids arise spontaneously by auto-diploidization, and both haploids and auto diploids show a similar reduction in fitness, in vitro and in vivo, relative to heterozygous diploids, indicating that homozygous cell types are transient in mixed populations. Finally, we constructed stable haploid strains with multiple auxotrophies that will facilitate molecular and genetic analyses of this important pathogen. PMID- 23364699 TI - Preoperative histological subtype classification of intraductal papillary mucinous neoplasms (IPMN) by pancreatic juice cytology with MUC stain. AB - OBJECTIVE: To prospectively evaluate the diagnostic value of preoperative histological subtyping of intraductal papillary mucinous neoplasms (IPMNs) by pancreatic juice cytology (PJC) with mucin (MUC) stain. BACKGROUND: IPMNs are classified into four subtypes based on their histomorphology and mucin phenotype, and varied degrees of malignant nature and prognosis among these subtypes have been shown. METHODS: The subjects were 36 patients with surgically confirmed IPMNs, who underwent PJC preoperatively by endoscopic retrograde cholangiopancreatography. Histological subtyping of cytological samples with or without MUC stain (MUC1, MUC2, and MUC5AC) was compared with that of resected specimens. RESULTS: Histologically, low-grade dysplasia was found in 4 patients, intermediate in 10, high grade in 11, and invasive carcinoma in 11. Gastric, intestinal, pancreatobiliary, and oncocytic subtypes corresponded to 16, 14, 5, and 1 patient, respectively. The rate of high-grade dysplasia (HGD) and/or invasive IPMNs was 25% for gastric subtype, 85.7% for intestinal subtype, and 100% for both pancreatobiliary and oncocytic subtypes, showing a significant correlation between histological subtype and rate of HGD and/or invasive IPMN (P < 0.01 for gastric vs nongastric).Histological subtype was successfully diagnosed by PJC in 42% (15/36) without MUC stain, and the rate was significantly improved to 89% (32/36) with MUC stain (P < 0.01). The sensitivity, specificity, and overall accuracy of PJC with MUC stain were 86%, 100%, and 94% for intestinal subtype, respectively. When cytological grade was combined with MUC stain, the diagnosis of HGD/invasive IPMN showed 77.2% sensitivity, 85.7% specificity, and 80.5% accuracy. CONCLUSIONS: Preoperative PJC with MUC stain proved to be highly reliable for identifying the histological subtype of IPMN and may provide useful information for deciding surgical indication. PMID- 23364700 TI - The choice of primary repair or mesh repair for paraesophageal hernia: a decision analysis based on utility scores. AB - BACKGROUND: Controversy exists on the use of mesh in the repair of paraesophageal hernias (PEH). This debate centers around the type of mesh used, its value in preventing recurrence, its short- and long-term complications, and the consequences of those complications compared with primary repair. Decision analysis is a method to account for the important aspects of a clinical decision. The purpose of this study was to determine whether or not the addition of mesh would be superior in PEH repair. METHODS: A decision analysis model of the choice between primary repair and mesh repair of a PEH was constructed. The essential features of the decision were the rate of perioperative complications, PEH recurrence rate, reoperation rate after recurrence, rate of symptomatic recurrence, and type of outcome after reoperation. The literature was reviewed to obtain data for the decision analysis and the average rates used in the baseline analysis. A utility score was used as the outcome measure, with a perfect outcome receiving a score of 100 and death 0. Sensitivity analysis was used to determine if changing the rates of recurrence or reoperation changed the dominant treatment. RESULTS: Using the baseline analysis, mesh repair was slightly superior to primary repair (utility score 99.59 vs 99.12, respectively). However, if recurrence rates were similar, primary repair would be slightly superior; whereas if reoperation rates were similar, mesh repair would be superior. Using sensitivity analysis, there are combinations of recurrence rates and reoperation rates that would make one repair superior to the other. However, these differences are relatively small. CONCLUSIONS: Depending on what the decision maker accepts as the recurrence and reoperation rates for these types of repair, either mesh or primary repair may be the treatment of choice. However, the differences between the two are small, and, perhaps, clinically inconsequential. PMID- 23364696 TI - Identification of a candidate therapeutic autophagy-inducing peptide. AB - The lysosomal degradation pathway of autophagy has a crucial role in defence against infection, neurodegenerative disorders, cancer and ageing. Accordingly, agents that induce autophagy may have broad therapeutic applications. One approach to developing such agents is to exploit autophagy manipulation strategies used by microbial virulence factors. Here we show that a peptide, Tat beclin 1-derived from a region of the autophagy protein, beclin 1, which binds human immunodeficiency virus (HIV)-1 Nef-is a potent inducer of autophagy, and interacts with a newly identified negative regulator of autophagy, GAPR-1 (also called GLIPR2). Tat-beclin 1 decreases the accumulation of polyglutamine expansion protein aggregates and the replication of several pathogens (including HIV-1) in vitro, and reduces mortality in mice infected with chikungunya or West Nile virus. Thus, through the characterization of a domain of beclin 1 that interacts with HIV-1 Nef, we have developed an autophagy-inducing peptide that has potential efficacy in the treatment of human diseases. PMID- 23364701 TI - Assessing the impact of a sacral resection on morbidity and survival after extended radical surgery for locally recurrent rectal cancer. AB - OBJECTIVES: To describe the experience of sacrectomy with extended radical resection in the treatment of locally recurrent rectal cancer. BACKGROUND: Resections of the bony pelvis, especially the sacrum, are becoming more common as part of extended radical exenterations for patients with recurrent rectal cancer. However, sacrectomy has been shown to carry a significant decrease in survival. Morbidity rates have been associated with the level of the sacrectomy (ie, >S3 junction). METHODS: An analysis was conducted using prospective data from patients with recurrent rectal cancer who underwent pelvic exenteration involving sacrectomy from July 1998 until June 2011. The impact of the proximal level of sacrectomy [low (<=S3) vs high (>=S2-S3 disc)] was compared. RESULTS: Of 240 exenteration patients, 79 underwent sacrectomy, with 49 for recurrent rectal cancer. An R0 margin was achieved in 36 (74%) patients. Achievement of clear operative margins (R0) conferred a large and significant benefit for disease-free survival compared with R1 and R2 resections (median 45 months vs 19 and 8 months, respectively; P = 0.045). Complications were reported in 40 (82%) patients, with major and minor complications in 19 (39%) and 38 (78%) patients, respectively. The proximal level of the sacrectomy (high vs low) did not significantly impair the ability to achieve a clear margin and was not associated with an increase in major or minor complications. CONCLUSIONS: This large, single-center series has demonstrated that extended pelvic exenteration involving sacrectomy has excellent R0 margins and survival rates for recurrent rectal cancer. A high sacrectomy has comparable results with a more distal abdominosacral resection. PMID- 23364703 TI - Scottish science is ready to go it alone. PMID- 23364702 TI - Identification of small RNA pathway genes using patterns of phylogenetic conservation and divergence. AB - Genetic and biochemical analyses of RNA interference (RNAi) and microRNA (miRNA) pathways have revealed proteins such as Argonaute and Dicer as essential cofactors that process and present small RNAs to their targets. Well-validated small RNA pathway cofactors such as these show distinctive patterns of conservation or divergence in particular animal, plant, fungal and protist species. We compared 86 divergent eukaryotic genome sequences to discern sets of proteins that show similar phylogenetic profiles with known small RNA cofactors. A large set of additional candidate small RNA cofactors have emerged from functional genomic screens for defects in miRNA- or short interfering RNA (siRNA) mediated repression in Caenorhabditis elegans and Drosophila melanogaster, and from proteomic analyses of proteins co-purifying with validated small RNA pathway proteins. The phylogenetic profiles of many of these candidate small RNA pathway proteins are similar to those of known small RNA cofactor proteins. We used a Bayesian approach to integrate the phylogenetic profile analysis with predictions from diverse transcriptional coregulation and proteome interaction data sets to assign a probability for each protein for a role in a small RNA pathway. Testing high-confidence candidates from this analysis for defects in RNAi silencing, we found that about one-half of the predicted small RNA cofactors are required for RNAi silencing. Many of the newly identified small RNA pathway proteins are orthologues of proteins implicated in RNA splicing. In support of a deep connection between the mechanism of RNA splicing and small-RNA-mediated gene silencing, the presence of the Argonaute proteins and other small RNA components in the many species analysed strongly correlates with the number of introns in those species. PMID- 23364715 TI - Research prize boost for Europe. PMID- 23364716 TI - UK research councils could face mergers. PMID- 23364717 TI - Coffee rust regains foothold. PMID- 23364718 TI - Funding agencies urged to check for duplicate grants. PMID- 23364719 TI - Magnetic logic makes for mutable chips. PMID- 23364720 TI - Obama rekindles climate hopes. PMID- 23364722 TI - Planetary science: Caught in the act. PMID- 23364723 TI - Ocean conservation: A big fight over little fish. PMID- 23364724 TI - Research funding: Same work, twice the money? PMID- 23364725 TI - After Einstein: Scientific genius is extinct. PMID- 23364730 TI - Conservation: Mauritius threatens its own biodiversity. PMID- 23364731 TI - Revived species: where will they live? PMID- 23364732 TI - Revived species: how would they survive? PMID- 23364733 TI - Nuclear stockpile: Concern over US nuclear stewardship. PMID- 23364734 TI - Latin: Dead language still alive for botanists. PMID- 23364735 TI - Sustainability: Sustain the future by doing more with less. PMID- 23364736 TI - Carl Woese (1928-2012). PMID- 23364737 TI - Solar physics: The planetary hypothesis revived. PMID- 23364738 TI - Biogeochemistry: The depths of nitrogen cycling. PMID- 23364739 TI - Condensed-matter physics: Hidden is more. PMID- 23364741 TI - Hastatic order in the heavy-fermion compound URu2Si2. AB - The development of collective long-range order by means of phase transitions occurs by the spontaneous breaking of fundamental symmetries. Magnetism is a consequence of broken time-reversal symmetry, whereas superfluidity results from broken gauge invariance. The broken symmetry that develops below 17.5 kelvin in the heavy-fermion compound URu(2)Si(2) has long eluded such identification. Here we show that the recent observation of Ising quasiparticles in URu(2)Si(2) results from a spinor order parameter that breaks double time-reversal symmetry, mixing states of integer and half-integer spin. Such 'hastatic' order hybridizes uranium-atom conduction electrons with Ising 5f(2) states to produce Ising quasiparticles; it accounts for the large entropy of condensation and the magnetic anomaly observed in torque magnetometry. Hastatic order predicts a tiny transverse moment in the conduction-electron 'sea', a colossal Ising anisotropy in the nonlinear susceptibility anomaly and a resonant, energy-dependent nematicity in the tunnelling density of states. PMID- 23364742 TI - An old disk still capable of forming a planetary system. AB - From the masses of the planets orbiting the Sun, and the abundance of elements relative to hydrogen, it is estimated that when the Solar System formed, the circumstellar disk must have had a minimum mass of around 0.01 solar masses within about 100 astronomical units of the star. (One astronomical unit is the Earth-Sun distance.) The main constituent of the disk, gaseous molecular hydrogen, does not efficiently emit radiation from the disk mass reservoir, and so the most common measure of the disk mass is dust thermal emission and lines of gaseous carbon monoxide. Carbon monoxide emission generally indicates properties of the disk surface, and the conversion from dust emission to gas mass requires knowledge of the grain properties and the gas-to-dust mass ratio, which probably differ from their interstellar values. As a result, mass estimates vary by orders of magnitude, as exemplified by the relatively old (3-10 million years) star TW Hydrae, for which the range is 0.0005-0.06 solar masses. Here we report the detection of the fundamental rotational transition of hydrogen deuteride from the direction of TW Hydrae. Hydrogen deuteride is a good tracer of disk gas because it follows the distribution of molecular hydrogen and its emission is sensitive to the total mass. The detection of hydrogen deuteride, combined with existing observations and detailed models, implies a disk mass of more than 0.05 solar masses, which is enough to form a planetary system like our own. PMID- 23364743 TI - Magnetic ratchet for three-dimensional spintronic memory and logic. AB - One of the key challenges for future electronic memory and logic devices is finding viable ways of moving from today's two-dimensional structures, which hold data in an x-y mesh of cells, to three-dimensional structures in which data are stored in an x-y-z lattice of cells. This could allow a many-fold increase in performance. A suggested solution is the shift register--a digital building block that passes data from cell to cell along a chain. In conventional digital microelectronics, two-dimensional shift registers are routinely constructed from a number of connected transistors. However, for three-dimensional devices the added process complexity and space needed for such transistors would largely cancel out the benefits of moving into the third dimension. 'Physical' shift registers, in which an intrinsic physical phenomenon is used to move data near atomic distances, without requiring conventional transistors, are therefore much preferred. Here we demonstrate a way of implementing a spintronic unidirectional vertical shift register between perpendicularly magnetized ferromagnets of subnanometre thickness, similar to the layers used in non-volatile magnetic random-access memory. By carefully controlling the thickness of each magnetic layer and the exchange coupling between the layers, we form a ratchet that allows information in the form of a sharp magnetic kink soliton to be unidirectionally pumped (or 'shifted') from one magnetic layer to another. This simple and efficient shift-register concept suggests a route to the creation of three dimensional microchips for memory and logic applications. PMID- 23364744 TI - Divergent global precipitation changes induced by natural versus anthropogenic forcing. AB - As a result of global warming, precipitation is likely to increase in high latitudes and the tropics and to decrease in already dry subtropical regions. The absolute magnitude and regional details of such changes, however, remain intensely debated. As is well known from El Nino studies, sea-surface-temperature gradients across the tropical Pacific Ocean can strongly influence global rainfall. Palaeoproxy evidence indicates that the difference between the warm west Pacific and the colder east Pacific increased in past periods when the Earth warmed as a result of increased solar radiation. In contrast, in most model projections of future greenhouse warming this gradient weakens. It has not been clear how to reconcile these two findings. Here we show in climate model simulations that the tropical Pacific sea-surface-temperature gradient increases when the warming is due to increased solar radiation and decreases when it is due to increased greenhouse-gas forcing. For the same global surface temperature increase the latter pattern produces less rainfall, notably over tropical land, which explains why in the model the late twentieth century is warmer than in the Medieval Warm Period (around AD 1000-1250) but precipitation is less. This difference is consistent with the global tropospheric energy budget, which requires a balance between the latent heat released in precipitation and radiative cooling. The tropospheric cooling is less for increased greenhouse gases, which add radiative absorbers to the troposphere, than for increased solar heating, which is concentrated at the Earth's surface. Thus warming due to increased greenhouse gases produces a climate signature different from that of warming due to solar radiation changes. PMID- 23364745 TI - Deep instability of deforested tropical peatlands revealed by fluvial organic carbon fluxes. AB - Tropical peatlands contain one of the largest pools of terrestrial organic carbon, amounting to about 89,000 teragrams (1 Tg is a billion kilograms). Approximately 65 per cent of this carbon store is in Indonesia, where extensive anthropogenic degradation in the form of deforestation, drainage and fire are converting it into a globally significant source of atmospheric carbon dioxide. Here we quantify the annual export of fluvial organic carbon from both intact peat swamp forest and peat swamp forest subject to past anthropogenic disturbance. We find that the total fluvial organic carbon flux from disturbed peat swamp forest is about 50 per cent larger than that from intact peat swamp forest. By carbon-14 dating of dissolved organic carbon (which makes up over 91 per cent of total organic carbon), we find that leaching of dissolved organic carbon from intact peat swamp forest is derived mainly from recent primary production (plant growth). In contrast, dissolved organic carbon from disturbed peat swamp forest consists mostly of much older (centuries to millennia) carbon from deep within the peat column. When we include the fluvial carbon loss term, which is often ignored, in the peatland carbon budget, we find that it increases the estimate of total carbon lost from the disturbed peatlands in our study by 22 per cent. We further estimate that since 1990 peatland disturbance has resulted in a 32 per cent increase in fluvial organic carbon flux from southeast Asia--an increase that is more than half of the entire annual fluvial organic carbon flux from all European peatlands. Our findings emphasize the need to quantify fluvial carbon losses in order to improve estimates of the impact of deforestation and drainage on tropical peatland carbon balances. PMID- 23364746 TI - Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo. AB - Stroking of the skin produces pleasant sensations that can occur during social interactions with conspecifics, such as grooming. Despite numerous physiological studies (reviewed in ref. 2), molecularly defined sensory neurons that detect pleasant stroking of hairy skin in vivo have not been reported. Previously, we identified a rare population of unmyelinated sensory neurons in mice that express the G-protein-coupled receptor MRGPRB4 (refs 5, 6). These neurons exclusively innervate hairy skin with large terminal arborizations that resemble the receptive fields of C-tactile (CT) afferents in humans. Unlike other molecularly defined mechanosensory C-fibre subtypes, MRGPRB4(+) neurons could not be detectably activated by sensory stimulation of the skin ex vivo. Therefore, we developed a preparation for calcium imaging in the spinal projections of these neurons during stimulation of the periphery in intact mice. Here we show that MRGPRB4(+) neurons are activated by massage-like stroking of hairy skin, but not by noxious punctate mechanical stimulation. By contrast, a different population of C fibres expressing MRGPRD was activated by pinching but not by stroking, consistent with previous physiological and behavioural data. Pharmacogenetic activation of Mrgprb4-expressing neurons in freely behaving mice promoted conditioned place preference, indicating that such activation is positively reinforcing and/or anxiolytic. These data open the way to understanding the function of MRGPRB4 neurons during natural behaviours, and provide a general approach to the functional characterization of genetically identified subsets of somatosensory neurons in vivo. PMID- 23364748 TI - Does consumption rate scale superlinearly? AB - Arising from S. Pawar, A. I. Dell & V. M. Savage 486, 485-489 10.1038/nature11131(2012)A recent paper by Pawar and colleagues has provided important insights into the consequences of foraging behaviour for food-web dynamics. One notable pattern predicted by their analysis is that consumption rate (c) scales superlinearly (cm(1.16)) with consumer body mass (m) in three dimensional (3D), but not two-dimensional (2D), foraging spaces. Although we feel that the authors should be applauded for this interesting contribution, we argue that their result is not consistent with established life-history theory. To resolve this contradiction, progress in both fields is probably required, including new empirical studies in which consumption rate, metabolism and dimensionality are examined directly under natural conditions. PMID- 23364750 TI - Improvement of ylang-ylang essential oil characterization by GC*GC-TOFMS. AB - A single fraction of essential oil can often contain hundreds of compounds. Despite of the technical improvements and the enhanced selectivity currently offered by the state-of-the-art gas chromatography (GC) and mass spectrometry (MS) instruments, the complexity of essential oils is frequently underestimated. Comprehensive two-dimensional GC coupled to time-of-flight MS (GC*GC-TOFMS) was used to improve the chemical characterization of ylang-ylang essential oil fractions recently reported in a previous one-dimensional (1D) GC study. Based on both, the enhanced chromatographic separation and the mass spectral deconvolution, 161 individual compounds were identified and labeled as potentially characteristic analytes found in both low and high boiling fractions issued from distillation of mature ylang-ylang flowers. Compared to the most recent full GC-MS characterization, this represents 75 new compounds, essentially consisting of terpenes, terpenoid esters, and alcohols. PMID- 23364751 TI - Radical scavenging capacity of methanolic Phillyrea latifolia L. extract: anthocyanin and phenolic acids composition of fruits. AB - Radical scavenging capacity of a crude methanolic extract from the fruits of Phillyrea latifolia L., commonly known as green olive tree or mock privet, was investigated with reference to anthocyanin standards, as flavonoids, and phenolic acid standards, as phenylpropanoids. Characterization with high performance liquid chromatography-diode array detection (HPLC-DAD) indicated the presence of keracyanin, kuromanin, cyanidin, ferulic acid, caffeic acid and rosmarinic acid at amounts of 289.1, 90.4, 191.4, 225.2, 221.2 and 190.1 mg/100 g fresh weight (FW) of fruits, respectively. Chlorogenic and p-coumaric acids were found to exist in lower amounts. Trolox equivalent antioxidant capacity (TEAC) and IC(50) values of the plant extract were found to be 1.8 mM Trolox equivalents (TE)/g FW of fruits and 69.4 ug/mL, respectively, indicating the close radical scavenging activity of the extract to those of keracyanin and p-coumaric acid. The crude methanolic P. latifolia L. fruit extract was seen to be fairly potent in radical scavenging. Total phenolic content (TPC) of the plant extract was found to be 1652.9 mg gallic acid equivalent (GAE)/100 g FW of fruits. PMID- 23364752 TI - Study of total antioxidant activity of human serum blood in the pathology of alcoholism. AB - The total antioxidant activity (TAA) of human serum blood of patients suffering from alcoholism was tested by cathode voltammetry with a model process of oxygen electroreduction. A known spectrophotometrical method was used for comparison. As results the total antioxidant activity of serum blood of patients with alcoholism was estimated by voltammetry during therapy in hospital. It was shown the TAA of serum blood of patients in pathology before and after treatment is lower than that one of healthy people. However, during the process of 10 days of alcoholism treatment the TAA coefficient increases. The relationship between the coefficient of total antioxidant activity of human serum blood and the stage of treatment was detected. PMID- 23364753 TI - Recent progress in graphene-based nanomaterials as advanced electrocatalysts towards oxygen reduction reaction. AB - Development of state-of-the-art electrocatalysts with inexpensive and commercially available materials to facilitate sluggish cathodic oxygen reduction reaction (ORR) is a key issue in the development of fuel cells and other electrochemical energy devices. Although great progress has been achieved in this area of research and development, there are still some challenges in both their ORR activity and stability. The emergence of graphene (GN) provides an excellent alternative to electrode materials and great efforts have been made to utilize GN based nanomaterials as promising electrode materials for ORR due to the high electrical conductivity, large specific surface area, profuse interlayer structure and abounding functional groups involved. It should be noted that rational design of these GN-based nanomaterials with well-defined morphology also plays an important role in their electrochemical performance for ORR. Considerable attempts were achieved to construct a variety of heteroatom doped GN nanomaterials or GN-based nanocomposites, aiming at fully using their excellent properties in their application in ORR. In this critical review, in line with the material design and engineering, some recent advancements in the development of GN-based electrocatalysts for ORR in electrochemical energy devices (fuel cells and batteries) are then highlighted, including heteroatom-doped GN nanomaterials, GN-based nonprecious hybrid nanocomposites (GN/metal oxides, GN/N-M, GN/carbon nitride, etc.) and GN/noble metal nanocomposites. PMID- 23364754 TI - Survey of laboratory tests used in the diagnosis and evaluation of haemophilia A. AB - Although the incidence of haemophilia A is reportedly uniform across ethnic groups, the prevalence varies in different countries. This suggests variability in the effectiveness of diagnostic strategies which is of particular importance in the recognition of milder forms of the disease. To assess the different laboratory tests that are used in the diagnosis and subsequent management of haemophilia A we carried out a web-based survey of established haemophilia centres. This was sent to 13 haemophilia physicians from haemophilia-treatment centres in Germany, Italy, Spain, South Africa, Taiwan, Norway, Canada, UK and the USA. The survey asked for details of clotting tests, the use of genetic analysis and the use of global haemostatic assays in haemophilia A cases. The results show considerable variation in the laboratory methods used for the screening, diagnosis and monitoring of haemophilia A. There is variability in the techniques used even for long-standing, standardised assays such as the one-stage factor assay. There is marked regional variability in the use of molecular diagnosis. Assessment of haemophilia A requires accurate and sensitive assays. Some laboratories continue to rely on a single-factor assay in the diagnosis of non-severe disease, although cases with assay discrepancy may be missed by this strategy. Global assays are becoming important in the evaluation and management of patients. However, standardisation and the correlation with clinical outcomes require further study. Genetic diagnosis in patients with haemophilia remains underutilised in USA, possibly because of a lack of funding. PMID- 23364755 TI - Acute myocardial infarction and diagnosis-related groups: patient classification and hospital reimbursement in 11 European countries. AB - AIMS: As part of the diagnosis related groups in Europe (EuroDRG) project, researchers from 11 countries (i.e. Austria, England, Estonia, Finland, France, Germany, Ireland, Netherlands, Poland, Spain, and Sweden) compared how their DRG systems deal with patients admitted to hospital for acute myocardial infarction (AMI). The study aims to assist cardiologists and national authorities to optimize their DRG systems. METHODS AND RESULTS: National or regional databases were used to identify hospital cases with a primary diagnosis of AMI. Diagnosis related group classification algorithms and indicators of resource consumption were compared for those DRGs that individually contained at least 1% of cases. Six standardized case vignettes were defined, and quasi prices according to national DRG-based hospital payment systems were ascertained. European DRG systems vary widely: they classify AMI patients according to different sets of variables into diverging numbers of DRGs (between 4 DRGs in Estonia and 16 DRGs in France). The most complex DRG is valued 11 times more resource intensive than an index case in Estonia but only 1.38 times more resource intensive than an index case in England. Comparisons of quasi prices for the case vignettes show that hypothetical payments for the index case amount to only ?420 in Poland but to ?7930 in Ireland. CONCLUSIONS: Large variation exists in the classification of AMI patients across Europe. Cardiologists and national DRG authorities should consider how other countries' DRG systems classify AMI patients in order to identify potential scope for improvement and to ensure fair and appropriate reimbursement. PMID- 23364757 TI - Interaction of CO2 with oxygen adatoms on rutile TiO2(110). AB - The interactions of CO2 with oxygen adatoms (Oa's) on rutile TiO2(110) surfaces have been studied using scanning tunneling microscopy. At 50 K CO2 is found to adsorb preferentially on five-coordinated Ti sites (Ti5c's) next to Oa's rather than on oxygen vacancies (VO's) (the most stable adsorption sites on reduced TiO2(110)). Temperature dependent studies show that after annealing to 100-160 K, VO's become preferentially populated indicating the presence of a kinetic barrier for CO2 adsorption onto the VO's. The difference between the CO2 binding energy on VO's and Ti5c sites next to the Oa's is found to be only 0.009-0.025 eV. The barrier for CO2 diffusion away from Oa's is estimated to be ~0.17 eV. Crescent like features of the images of CO2 adsorbed on Ti5c's next to Oa's are interpreted as a time average of terminally bound CO2 molecules switching between the configurations that are tilted towards Oa and/or towards one of the two neighbouring bridging oxygen (Ob) rows. In the presence of VO defects, the Ti5c bound CO2 is found to tilt preferentially away from the VO containing Ob row. If another CO2 is present on the neighbouring Ti5c row, both CO2 molecules tilt towards the common Ob row that separates them. PMID- 23364756 TI - Hepatitis E virus isolated from rabbits is genetically heterogeneous but with very similar antigenicity to human HEV. AB - Rabbit hepatitis E virus (HEV) in China may represent a novel HEV genotype, although no consensus has been reached. It is unclear whether the ORF2 capsid protein containing the immunodominant epitopes from rabbit HEV differs from those of human HEV. In this study, 661 bile samples collected from domestic rabbits in Jiangsu province, eastern China were amplified by RT-nPCR using a set of HEV universal ORF2 primers. All 42 (6.4%) positive PCR products were sequenced. Phylogenetic analysis using the ORF2 sequences of 557 bp in length showed the Jiangsu isolates were separate from HEV genotypes 1, 2, 3, 4, avian HEV and rat HEV, and clustered together with rabbit HEV sequences. These 42 isolates were divided into five branches including two newly identified in the present study. Comparison with rabbit HEV sequences from China available in GenBank, using a 298 bp ORF2 segment, showed these sequences clustered together into a unique rabbit HEV clade, and were divided into eight sub-branches with high genetic heterogeneity. In addition, 267 serum samples collected from domestic rabbits, serial serum samples from two rhesus monkeys experimentally infected with HEV genotype 1 or 4, and serial serum samples from two New-Zealand rabbits infected experimentally with rabbit HEV were tested simultaneously by EIA using recombinant truncated ORF2 capsid proteins derived from rabbit and human HEV. The virtually identical results obtained suggest that rabbit and human HEV ORF2 antigens contain very similar immunodominant epitopes. All these data are helpful to identify the biological characteristics of the newly identified rabbit HEV. PMID- 23364758 TI - Camellia sinensis (green tea) extract attenuate acrylamide induced testicular damage in albino rats. AB - Acrylamide is a proved toxin for testicular function, found in food when heated for long period of time. Green tea (Camellia sinensis) is a potent antioxidant; the aim of this study was to investigate the protective effect of green tea extract against the toxic effects of acrylamide in rat testes. METHODS: acrylamide was administered orally to rats in different doses and also the extract of green tea was administered orally to different groups of animals in combination with the acrylamide. The weight of animals, testosterone hormone level and histopathological effect upon testicles were evaluated. RESULTS: Testosterone hormone level in serum, and histopathological findings were significantly improved with the co-administration of green tea extract with the acrylamide. Green tea extract reversed all the toxic effects of acrylamide even in high dose for long period (90 days). CONCLUSION: Green tea extract is a potent antioxidant antidote for the acrylamide toxic effects upon testicular function. PMID- 23364759 TI - Accelerated MRI by SPEED with generalized sampling schemes. AB - PURPOSE: To enhance the fast imaging technique of skipped phase encoding (PE) and edge deghosting (SPEED) for more general sampling options, and thus more flexibility in implementations and applications. METHODS: SPEED uses skipped PE steps to accelerate MRI scan. Previously, the PE skip size was chosen from prime numbers only. This restriction has been relaxed in this study to allow choice of any integers rather than merely prime numbers. Various sampling patterns were studied under all possible combinations of PE skip size and PE shifts. A criterion based on the rank values of ghost phasor matrices was introduced to evaluate SPEED reconstruction. RESULTS: The reconstruction quality was found to correlate with the rank value of the ghost phasor matrix and the skipped PE size N. A low-rank value indicates a singular matrix that causes failure of the SPEED reconstruction. Composite numbers combined with appropriately chosen PE shifts yielded satisfactory reconstruction results. CONCLUSION: With properly chosen PE shifts, it was found that any integers, including both prime numbers and composite numbers, could be used as PE skip size for SPEED. This finding allows much more flexible data acquisition options that may lead to more freedom in practical implementations and applications. PMID- 23364760 TI - Synthesis of aryl ethers from benzoates through carboxylate-directed C-H activating alkoxylation with concomitant protodecarboxylation. PMID- 23364761 TI - Chromenoquinoline-based thiol probes: a study on the quencher position for controlling fluorescent Off-On characteristics. AB - The design, synthesis and thiol sensing ability of chromenoquinoline-based fluorescent probes 4, 5 and 6 and are reported here. The relative position of the maleimide moiety was varied along the chromenoquinoline fluorophore to decrease the background fluorescence. Lower background fluorescence in probes 4 and 6 was rationalized by the smaller k(r)/k(nr) values compared to that of probe 5. An intramolecular charge transfer (ICT) mechanism was proposed for quenching and the extent was dependent on the position of the maleimide quencher. Fluorescent Off On characteristics were evaluated by theoretical calculations. All probes were selective only towards thiol containing amino acids. Thiol sensing by probes 4 and 6 were much better compared to 5. Probe 4 displayed a better fluorescence response for less hindered thiol (185-, 223- and 156-fold for Hcy, Cys and GSH, respectively), while for probe 6, a higher enhancement in fluorescence was observed with more hindered thiols (180-, 205- and 245-fold for Hcy, Cys and GSH, respectively). The better response to bulkier thiol, GSH by probe 6 was attributed to the steric crowding at the C-4 position and bulkiness of the GSH group which force the succinimide unit to be in a nearly orthogonal conformation. This spatial arrangement was important in reducing the fluorescence quenching ability of the succinimide moiety. The application of probes 4, 5 and 6 was demonstrated by naked eye detection thiols using a 96-well plate system as well as by live-cell imaging. PMID- 23364762 TI - Single cell membrane poration by bubble-induced microjets in a microfluidic chip. AB - This paper demonstrates membrane poration of a single suspension cell due to a fast liquid microjet. The jet is formed during the collapse of a laser induced bubble created at a variable stand-off distance from the target cell. The cell is trapped by a converging structure within a microfluidic chip. The asymmetrical growth and collapse of the cavitation bubble next to the cell lead to the microjetting, which deforms and porates the cell membrane. In the experiments, the membrane porations of myeloma cells are probed with the uptake of trypan blue. Time-resolved studies of the diffusion of trypan blue show a marked dependency on the bubble dynamics, i.e. the stand-off distance. The penetration length of the dye increases with shorter distances. Numerical simulations of the diffusion process agree with larger pores formed on the cell membrane. This method allows for a fast, repeatable, and localized rupture of membranes of individual cells in suspension. PMID- 23364763 TI - Heart health. PMID- 23364764 TI - Pathology: At the heart of the problem. PMID- 23364765 TI - Physiology: Beating stroke. PMID- 23364766 TI - Drugs: Blood battles. PMID- 23364767 TI - Psychology: Mind over myocardium. PMID- 23364768 TI - Cardiovascular disease: Biochemistry to behaviour. PMID- 23364769 TI - Public planning: Designs fit for purpose. PMID- 23364770 TI - Perspective: The power of disease prevention. PMID- 23364771 TI - Diagnostics: The new risk predictors. PMID- 23364772 TI - Perspective: A tale of two receptors. PMID- 23364773 TI - Design of chemical glycosyl donors: does changing ring conformation influence selectivity/reactivity? AB - This tutorial review focuses on the design of glycosyl donors, especially on attempts to control selectivity/reactivity by employing bulky substituents, cyclic protecting groups, or bridged structures. These structural modifications are performed to change the conformational distributions of pyranoside/furanoside rings. We also briefly discuss this issue with regard to studies on furanosides and enzymatic glycosylation reactions. Readers will find that some of the designed glycosyl donors have been used to achieve total syntheses of natural products. PMID- 23364774 TI - Osteogenic capacity of human BM-MSCs, AT-MSCs and their co-cultures using HUVECs in FBS and PL supplemented media. AB - Human bone marrow-derived mesenchymal stem cells (BM-MSCs) and human adipose tissue-derived mesenchymal stem cells (AT-MSCs) are the most frequently used stem cells in tissue engineering. Due to major clinical demands, it is necessary to find an optimally safe and efficient way for large-scale expansion of these cells. Considering the nutritional source in the culture medium and method, this study aimed to analyze the effects of FBS- and PL-supplemented media on osteogenesis in stem cell mono- and co-cultures with human umbilical vein endothelial cells (HUVECs). Results showed that cell metabolic activity and proliferation increased in PL- compared to FBS-supplemented media in mono- and co cultures for both BM-MSCs and AT-MSCs. In addition, calcium deposition was cell type dependent and decreased for BM-MSCs but increased for AT-MSCs in PL supplemented medium in both mono- and co-cultures. Based on the effects of co cultures, BM-MSCs/HUVECs enhanced osteogenesis compared to BM-MSCs monocultures in both FBS- and PL-supplemented media whereas AT-MSCs/HUVECs showed similar results compared to AT-MSCs monocultures. PMID- 23364775 TI - Cardiovascular risk among patients on clopidogrel anti-platelet therapy after placement of drug-eluting stents is modified by genetic variants in both the CYP2C19 and ABCB1 genes. AB - Long-term (at least one year) dual anti-platelet therapy incorporating aspirin and clopidogrel is currently recommended following percutaneous coronary intervention with placement of a drug-eluting stent (DES). Genetic variants in both the ABCB1 and CYP2C19 genes have been associated with cardiovascular events among patients on clopidogrel. We examined the concurrent contribution of the CYP2C19 *2 and *17 alleles and the ABCB1 3435 alleles to one-year clinical risk among patients (n=1,034 on clopidogrel therapy following the placement of a DES. For CYP2C19*2, event rates were 8.4%, 10.9% and 44.4% for patients with 0, 1 and 2 *2 alleles, respectively (p=0.016). ABCB1 3435 was not associated with events in univariate analysis. However, 72% of patients with a *2 variant also possessed the ABCB1 3435 C allele; among these patients (*2/C genotype) the event rate for myocardial infarction (MI) was 14.2% vs. 6.9% for those lacking both *2 and C alleles (p=0.027) and for MI/death, 16.9% vs. 9.6% (p=0.046). Overall for all genotypes, the presence of the gain-of-function (protective) *17 allele significantly reduced the one-year rate of MI from 11.1% to 7.0% (p=0.045) and trended to reduce the combined rate of MI/death from 13.8% to 10.5% (p=0.182). In conclusion, the ABCB1 3435 locus and the *2 allele combine to impart a significant trend toward increased risk. This trend was largely reversed by the simultaneous carriage of one or two *17 alleles. These findings suggest that assessment of a combined genotype may improve risk assessment. PMID- 23364776 TI - The characteristics and subtypes of headache in relation to age and gender in a rural community in Eastern Turkey. AB - OBJECTIVES: Headache is a frequent and widespread symptom constituting a major health problem for all age groups, though vast differences are present according to age and gender, as well as population characteristics. In this hospital-based study, we investigated the characteristics and subtypes of headache in relation to age and gender in a rural community in the eastern part of Turkey. METHODS: A total of 11549 subjects were evaluated, and 4951 patients (42.8%) reported headaches. The 1-year headache prevalence was 38.6% in children, 47.0% in adults, and 23.3% in the elderly (p<0.001). The female to male ratio was higher in adults (p<0.001) and elderly headache patients (p<0.001), but not in children (p=0.654). RESULTS: The most common diagnosis was frequent episodic tension-type headache in all age groups. Headaches attributed to epileptic seizure and rhinosinusitis were about three times more common in children, while chronic tension-type headache was about three times more common in adults and the elderly. While 60% of patients with migraine were male among the group of children, about 80% of patients were females among the adults. CONCLUSION: The understanding of the epidemiology of headache and subtypes is important as it constitutes a major health problem due to its high prevalence in all age groups. PMID- 23364777 TI - [The role of pericranial muscles in the succesful management of episodic tension type headache]. AB - OBJECTIVES: Peripheral and central nociceptive mechanisms are responsible for the development of Tension Type Headache (TTH). Analgesics are frequently used in the treatment of acute TTH. Antidepressants are used in prevention. In this study, the therapeutic efficacy of local application of lidocaine was investigated in Episodic Tension Type Headache (ETTH) patients. METHODS: ETTH patients with pericranial tenderness (n=20, Group 1) and without pericranial tenderness (n=20, Group 2) were included in our study. Three sessions of local injection of 1% lidocaine were performed in both groups. Two-sided intramuscular injections of 1 mL were applied for each patient. The muscles treated were the frontal, temporal, masseter, sternokloidomastoid, semispinalis capitis, splenius capitis and trapezius muscles. Patients were evaluated in 1st, 2nd, and 3rd months. The number of painful days per month and pain intensities were recorded according to Visual Analog Scale (VAS) before and after the treatment. RESULTS: 11 male and 29 female patients were included in the study. The mean ages of Group 1 and Group 2 were 35.95 +/- 9.85 (18-53) and 34.85 +/- 10.04 (20-54) years, respectively. There was no difference between the groups in terms of age, gender, pain frequency and pain intensity (p>0.05). The frequency and severity of pain was significantly lower in pericranial-sensitive ETTH patients at the 1st, 2nd, and 3rd months after local lidocaine injections compared to ETTH patients having pericranial tenderness (p<0.05). CONCLUSION: Local lidocaine application can be used as an effective method in the treatment of ETTH patients with pericranial tenderness. PMID- 23364778 TI - [Comparison of ultrasound-guided supraclavicular and infraclavicular approaches for brachial plexus blockade]. AB - OBJECTIVES: Ultrasound-guided supraclavicular and infraclavicular blocks are commonly used for upper extremity surgery. The primary aims of our study were to compare block success, block onset times and performance times; secondary aims were to compare the number of needle advancements, and incidence of adverse events of ultrasound-guided supraclavicular or infraclavicular blocks. METHODS: 110 patients were randomized into two groups: supraclavicular (Group S) and infraclavicular (Group I). All the patients were given a mixture of 20 ml 0.5% levobupivacaine and 10 ml 2% lidocaine as local anesthetics. The sensory score of the seven terminal nerves was assessed every 10 min for 30 min. RESULTS: Block success (Group I: 92.7%; Group S: 83.6%) and block onset time (Group I: 12.5 +/- 4.8; Group S: 11.6 +/- 3.9 min) were similar between the groups. Block performance time was shorter in Group I, than Group S (194.4 +/- 65; 226.3 +/- 59 sec, P<0.05). The number of needle advancements were lower in Group I than Group S (p<0.05). The Group I patients had a significantly improved block of the median and ulnar nerves than Group S, and Group S patients had a better block of the medial cutaneous nerve, than Group I (p<0.05). Horner syndrome was observed in 9 patients (16.3%) and paresthesia in one patient (1.8%) in Group S. CONCLUSION: Similar block features were observed with infraclavicular and supraclavicular approaches, but infraclavicular block may be preferable to supraclavicular block due to the lower incidence of transient adverse events. PMID- 23364779 TI - [Risk factors associated with lower back pain in the Polyclinic of Algology]. AB - OBJECTIVES: To study the risk factors associated with lower back pain such as age, gender, marital status, occupation, education level, smoking and alcohol consumption among patients who presented to the Algology Polyclinic. METHODS: The patients' age, gender, occupation, marital status, education, economic level, smoking and alcohol consumption were evaluated and recorded on a "Pain Assessment Form". The highest level of education level was asked and when economic level was questioned, the answers of patients were considered without restricrion between limits. RESULTS: Out of 772 patients, 200 had mechanical lower back pain. 23.5% had hernia nucleous pulposus, 20% had facet joint degeneration, 18.5% had a narrow spinal channel, 7.5% had sakroiliac joint degeneration, 20.1% had more than one pathology, and 10.5% had other pathologies. Lower back pain did not differ according to age and gender. Students had significantly lower pain, whereas workers had significantly higher lower back pain (p=0.005). Of the patients with lower back pain, 170 of them were married and 30 were widowed or single (p=0.059). With higher education, pain was significantly decreased (p=0.001). More pain was reported among individuals with low socioeconomic level (p=0.042). There was a correlation between lower back pain and smoking (p=0030), but there was no correlation between lower back pain and alcohol consumption (p=0.638). CONCLUSION: Lower education, lower economic level, labor intensive jobs and smoking were correlated with lower back pain. It was concluded that by taking precautions that lower risk factors, incidence of lower back pain can be decreased. PMID- 23364780 TI - [Pediatric nurse views regarding parental presence during a child's painful procedures]. AB - OBJECTIVES: Family- centered care is one of the basic principles of pediatric nursing and allows pediatric patients to have parental support during invasive procedures. But health care professionals often hesitate regarding parental presence during pediatric invasive procedure. The aim of this descriptive study is to determine the views of nurses regarding parental presence invasive procedures in children. METHODS: This study was conducted between the dates 15th March and 15th July 2009 in a university hospital in Ankara which permitted parental stay. A total of 43 (57%) nurses accepted our invitation to participate in this research. A demographic data form with open and closed ended interview questionnaires was used in the study. RESULTS: The majority of nurses reported that parents should not be present with the child during the painful procedure. The disadvantages of parental presence during a painful procedure commonly expressed by the nurses were increased anxiety in the child (77.1%), increased health professional anxiety (60.0%), and a detrimental effect of parental presence on the success of the procedure (60.0%). The nurses' recommendations to make the painful procedures less traumatic for both children and their parents are explaining the procedure to the children and parents (83.7%), use of local anesthesia or sedation before the procedure (37.2%), and performing painful procedures with specialized teams (20.9%). CONCLUSION: The nurses in the study population tended to prefer parents not to be present during painfull procedures. The findings of the study indicate the need for development of written polices and guidelines on the practice of painfull procedures. Recommendations for future research are presented. PMID- 23364781 TI - Levobupivacaine for postoperative pain management in circumcision: caudal blocks or dorsal penile nerve block. AB - OBJECTIVES: In this study, we evaluated the analgesic efficacy and adverse effect profile of levobupivacaine in caudal and DPNB in postcircumcision pediatric patients. METHODS: Sixty boys between 2-10 years of age undergoing circumcision were enrolled. The patients were divided into two groups: Group C (n=30) and Group P (n=30) were applied caudal block or dorsal penile nerve block (DPNB), respectively. Blocks were performed before surgery as a supplement to general anesthesia with 1 mL kg(-1) 0.25% levobupivacaine. Postoperative pain and sedation scores were assessed on the 10th and 30th minutes, and hours 1-6. The number of pain free patients in the first 6 hours, the duration of analgesia, time to first analgesic administration, walking, micturition, and total paracetamol demands, and length of stay were recorded. RESULTS: Demographic data were similar between groups. The number of children who spent the first 6 hours pain-free was larger in Group C than Group P (p=0.0001). The time to first analgesic (p=0.000033) and walking (p=0.004) were longer in Group C. There were 14 patients with motor block in Group C (p=0.00007). In view of AUC, FPRS, OPS and MPOPS were significantly better in Group C on the first postoperative 6 hours. CONCLUSION: Caudal block done using levobupivacaine for postoperative pain management in circumcision is more successful than penile block, however there is a significant delay in time to first walking and as might be expected there is an increased risk of motor block. PMID- 23364782 TI - [Convulsion due to application of low dose meperidine: a case report]. AB - Meperidine is an opiod analgesic used in a variety of clinical situations. The active metabolite, normeperidine, is a central nervous system excitatory agent and has the ability to cause irritability, hyperreflexia, tremor, myoclonus and seizures. Previously identified risk factors for the development of meperidine related seizures include renal failure, high meperidine dosages, and co adminestration of hepatic enzyme inducing medications or phenothiazines which decreases seizure treshold. Patients with normal renal function rarely manifest seizure activity when given meperidine. Here we report a 10 year old boy with a femur fraction who had normal renal function. We used low dose meperidine due to post operative pains. PMID- 23364783 TI - Ultrasound guided TAP block for the treatment of postoperative prolonged pain - an alternative approach. AB - Transversus abdominis plane (TAP) block is a relatively new regional anesthesia technique in which T7-12 intercostal nerves, ilioinguinal and iliohypogastric nerves, and cutaneous branches of L1-3 nerves are blocked between the internal oblique and transversus abdominis muscles. This technique is mostly used for the treatment of acute postoperative pain following abdominal surgery. In this case report, we evaluate the usage of TAP block in prolonged pain following upper abdominal surgery. PMID- 23364784 TI - [A brachial plexus variation identified during ultrasound-guided interscalene block]. PMID- 23364785 TI - Evaluation of etravirine resistance in clinical samples by a simple phenotypic test. AB - Drug resistance testing is an important tool in the management of HIV-1 infection. As access to genotypic resistance assays is limited in low- and middle income settings, alternatives are warranted. The aim of the study was to adapt a phenotypic drug susceptibility assay, ExaVir Drug, for detection of resistance to the second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (ETR). Five NNRTI resistant mutant forms of RT were produced (L100I, K103N, L100I/K103N, Y181C, V179D) in order to validate the assay for ETR. Furthermore, HIV-1 RT was purified from plasma samples (n = 28) obtained from treatment naive and experienced HIV-1 infected patients, and ETR drug susceptibility (IC(50)) was estimated. The direct sequencing of the pol gene was performed. The recombinant RT mutants had the expected changes in drug sensitivity patterns. The RTs isolated from plasma of therapy naive individuals showed low IC(50) for ETR. In the plasma virus from treatment experienced patients with Y181C, A98G, V108I, and/or K101E mutations in the pol gene, higher IC(50) values were found in line with reduced susceptibility data for ETR. This study demonstrates that ExaVir(r) Drug, a simple enzymatic phenotypic assay, can be used for detection of ETR resistance, including cross-resistance to other NNRTIs, in clinical samples. A further evaluation is needed to define clinical cut-offs; however the assay is an alternative to more costly HIV drug resistance tests, especially in low-income countries. PMID- 23364786 TI - Differential phosphorylation, desensitization, and internalization of alpha1A adrenoceptors activated by norepinephrine and oxymetazoline. AB - Loss of response on repetitive drug exposure (i.e., tachyphylaxis) is a particular problem for the vasoconstrictor effects of medications containing oxymetazoline (OXY), an alpha1-adrenoceptor (AR) agonist of the imidazoline class. One cause of tachyphylaxis is receptor desensitization, usually accompanied by phosphorylation and internalization. It is well established that alpha1A-ARs are less phosphorylated, desensitized, and internalized on exposure to the phenethylamines norepinephrine (NE), epinephrine, or phenylephrine (PE) than are the alpha1B and alpha1D subtypes. However, here we show in human embryonic kidney-293 cells that the low-efficacy agonist OXY induces G protein coupled receptor kinase 2-dependent alpha1A-AR phosphorylation, followed by rapid desensitization and internalization (~40% internalization after 5 minutes of stimulation), whereas phosphorylation of alpha1A-ARs exposed to NE depends to a large extent on protein kinase C activity and is not followed by desensitization, and the receptors undergo delayed internalization (~35% after 60 minutes of stimulation). Native alpha1A-ARs from rat tail artery and vas deferens are also desensitized by OXY, but not by NE or PE, indicating that this property of OXY is not limited to recombinant receptors expressed in cell systems. The results of the present study are clearly indicative of agonist-directed alpha1A-AR regulation. OXY shows functional selectivity relative to NE and PE at alpha1A ARs, leading to significant receptor desensitization and internalization, which is important in view of the therapeutic vasoconstrictor effects of this drug and the varied biologic process regulated by alpha1A-ARs. PMID- 23364787 TI - Demographic and personal factors associated with metabolic control and self-care in youth with type 1 diabetes: a systematic review. AB - Optimal use of recent technological advances in insulin delivery and glucose monitoring remain limited by the impact of behaviour on self-care. In recent years, there has been a resurgence of interest in psychosocial methods of optimizing care in youth with type 1 diabetes. We therefore sought to examine the literature for demographic, interpersonal and intrapersonal correlates of self care and/or metabolic control. Studies for this systematic review were obtained via an electronic search of Medline, Embase, Cumulative Index to Nursing and Allied Health Literature and PsycINFO databases. Seventy studies fulfilled the inclusion criteria. These studies have indicated that identifiable individual characteristics in each domain are robustly associated with metabolic control and/or self-care in children and adolescents. We present these characteristics and propose a theoretical model of their interactions and effect on diabetes outcomes. There is currently no consensus regarding patient selection for insulin pump therapy. In this era of scarce healthcare resources, it may be prudent to identify youth requiring increased psychosocial support prior to regimen intensification. The importance of this review lies in its potential to create a framework for rationally utilizing resources by stratifying costly therapeutic options to those who, in the first instance, will be most likely to benefit from them. PMID- 23364788 TI - Nuclear calcium signaling regulates nuclear export of a subset of class IIa histone deacetylases following synaptic activity. AB - In neurons, dynamic changes in the subcellular localization of histone deacetylases (HDACs) are thought to contribute to signal-regulated gene expression. Here we show that in mouse hippocampal neurons, synaptic activity dependent nucleo-cytoplasmic shuttling is a common feature of all members of class IIa HDACs, which distinguishes them from other classes of HDACs. Nuclear calcium, a key regulator in neuronal gene expression, is required for the nuclear export of a subset of class IIa HDACs. We found that inhibition of nuclear calcium signaling using CaMBP4 or increasing the nuclear calcium buffering capacity by means of expression of a nuclear targeted version of parvalbumin (PV.NLS-mC) led to a build-up of HDAC4 and HDAC5 in the cell nucleus, which in the case of PV.NLS-mC can be reversed by nuclear calcium transients triggered by bursts of action potential firing. A similar nuclear accumulation of HDAC4 and HDAC5 was observed in vivo in the mouse hippocampus following stereotaxic delivery of recombinant adeno-associated viruses expressing either CaMBP4 or PV.NLS-mC. The modulation of HDAC4 activity either by RNA interference-mediated reduction of HDAC4 protein levels or by expression of a constitutively nuclear localized mutant of HDAC4 leads to changes in the mRNA levels of several nuclear calcium-regulated genes with known functions in acquired neuroprotection (atf3, serpinb2), memory consolidation (homer1, arc), and the development of chronic pain (ptgs2, c1qc). These results identify nuclear calcium as a regulator of nuclear export of HDAC4 and HDAC5. The reduction of nuclear localized HDACs represents a novel transcription-promoting pathway stimulated by nuclear calcium. PMID- 23364789 TI - Activation of a PGC-1-related coactivator (PRC)-dependent inflammatory stress program linked to apoptosis and premature senescence. AB - PGC-1-related coactivator (PRC), a growth-regulated member of the PGC-1 coactivator family, contributes to the expression of the mitochondrial respiratory apparatus. PRC also orchestrates a robust response to metabolic stress by promoting the expression of multiple genes specifying inflammation, proliferation, and metabolic reprogramming. Here, we demonstrate that this PRC dependent stress program is activated during apoptosis and senescence, two major protective mechanisms against cellular dysfunction. Both PRC and its targets (IL1alpha, SPRR2D, and SPRR2F) were rapidly induced by menadione, an agent that promotes apoptosis through the generation of intracellular oxidants. Menadione induced apoptosis and the PRC stress program were blocked by the antioxidant N acetylcysteine. The PRC stress response was also activated by the topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN-38), an inducer of premature senescence in tumor cells. Cells treated with SN-38 displayed morphological characteristics of senescence and express senescence-associated beta galactosidase activity. In contrast to menadione, the SN-38 induction of the PRC program occurred over an extended time course and was antioxidant-insensitive. The potential adaptive function of the PRC stress response was investigated by treating cells with meclizine, a drug that promotes glycolytic energy metabolism and has been linked to cardio- and neuroprotection against ischemia-reperfusion injury. Meclizine increased lactate production and was a potent inducer of the PRC stress program, suggesting that PRC may contribute to the protective effects of meclizine. Finally, c-MYC and PRC were coordinately induced under all conditions tested, implicating c-MYC in the biological response to metabolic stress. The results suggest a general role for PRC in the adaptive response to cellular dysfunction. PMID- 23364790 TI - Enhanced aggregation of androgen receptor in induced pluripotent stem cell derived neurons from spinal and bulbar muscular atrophy. AB - Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. Ligand dependent nuclear accumulation of mutant AR protein is a critical characteristic of the pathogenesis of SBMA. SBMA has been modeled in AR-overexpressing animals, but precisely how the polyglutamine (polyQ) expansion leads to neurodegeneration is unclear. Induced pluripotent stem cells (iPSCs) are a new technology that can be used to model human diseases, study pathogenic mechanisms, and develop novel drugs. We established SBMA patient-derived iPSCs, investigated their cellular biochemical characteristics, and found that SBMA-iPSCs can differentiate into motor neurons. The CAG repeat numbers in the AR gene of SBMA-iPSCs and also in the atrophin-1 gene of iPSCs derived from another polyQ disease, dentato-rubro pallido-luysian atrophy (DRPLA), remain unchanged during reprogramming, long term passage, and differentiation, indicating that polyQ disease-associated CAG repeats are stable during maintenance of iPSCs. The level of AR expression is up regulated by neuronal differentiation and treatment with the AR ligand dihydrotestosterone. Filter retardation assays indicated that aggregation of ARs following dihydrotestosterone treatment in neurons derived from SBMA-iPSCs increases significantly compared with neurological control iPSCs, easily recapitulating the pathological feature of mutant ARs in SBMA-iPSCs. This phenomenon was not observed in iPSCs and fibroblasts, thereby showing the neuron dominant phenotype of this disease. Furthermore, the HSP90 inhibitor 17 allylaminogeldanamycin sharply decreased the level of aggregated AR in neurons derived from SBMA-iPSCs, indicating a potential for discovery and validation of candidate drugs. We found that SBMA-iPSCs possess disease-specific biochemical features and could thus open new avenues of research into not only SBMA, but also other polyglutamine diseases. PMID- 23364791 TI - Secreted progranulin is a homodimer and is not a component of high density lipoproteins (HDL). AB - Progranulin is a secreted glycoprotein, and the GRN gene is mutated in some cases of frontotemporal dementia. Progranulin has also been implicated in cell growth, wound healing, inflammation, and cancer. We investigated the molecular nature of secreted progranulin and provide evidence that progranulin exists as a homodimer. Although recombinant progranulin has a molecular mass of ~85 kDa by SDS-PAGE, it elutes in fractions corresponding to ~170-180 kDa by gel-filtration chromatography. Additionally, recombinant progranulin can be intermolecularly cross-linked, yielding a complex corresponding to a dimer (~180 kDa), and progranulins containing different epitope tags physically interact. In plasma, progranulin similarly forms complexes of ~180-190 kDa. Although progranulin partially co-fractionated with high density lipoproteins (HDL) by gel-filtration chromatography, we found no evidence that progranulin in mouse or human plasma is a component of HDL either by ultracentrifugation or by lipid binding assays. We conclude that circulating progranulin exists as a dimer and is not likely a component of HDL. PMID- 23364792 TI - Multisite binding of a general anesthetic to the prokaryotic pentameric Erwinia chrysanthemi ligand-gated ion channel (ELIC). AB - Pentameric ligand-gated ion channels (pLGICs), such as nicotinic acetylcholine, glycine, gamma-aminobutyric acid GABA(A/C) receptors, and the Gloeobacter violaceus ligand-gated ion channel (GLIC), are receptors that contain multiple allosteric binding sites for a variety of therapeutics, including general anesthetics. Here, we report the x-ray crystal structure of the Erwinia chrysanthemi ligand-gated ion channel (ELIC) in complex with a derivative of chloroform, which reveals important features of anesthetic recognition, involving multiple binding at three different sites. One site is located in the channel pore and equates with a noncompetitive inhibitor site found in many pLGICs. A second transmembrane site is novel and is located in the lower part of the transmembrane domain, at an interface formed between adjacent subunits. A third site is also novel and is located in the extracellular domain in a hydrophobic pocket between the beta7-beta10 strands. Together, these results extend our understanding of pLGIC modulation and reveal several specific binding interactions that may contribute to modulator recognition, further substantiating a multisite model of allosteric modulation in this family of ion channels. PMID- 23364793 TI - The near-iron transporter (NEAT) domains of the anthrax hemophore IsdX2 require a critical glutamine to extract heme from methemoglobin. AB - Several gram-positive pathogenic bacteria employ near-iron transporter (NEAT) domains to acquire heme from hemoglobin during infection. However, the structural requirements and mechanism of action for NEAT-mediated heme extraction remains unknown. Bacillus anthracis exhibits a rapid growth rate during systemic infection, suggesting that the bacterium expresses efficient iron acquisition systems. To understand how B. anthracis acquires iron from heme sources, which account for 80% of mammalian iron stores, we investigated the properties of the five-NEAT domain hemophore IsdX2. Using a combination of bioinformatics and site directed mutagenesis, we determined that the heme extraction properties of IsdX2 are dependent on an amino acid with an amide side chain within the 310-helix of the NEAT domain. Additionally, we used a spectroscopic analysis to show that IsdX2 NEAT domains only scavenge heme from methemoglobin (metHb) and that autoxidation of oxyhemoglobin to metHb must occur prior to extraction. We also report the crystal structures of NEAT5 wild type and a Q29T mutant and present surface plasmon resonance data that indicate that the loss of this amide side chain reduces the affinity of the NEAT domain for metHb. We propose a model whereby the amide side chain is first required to drive an interaction with metHb that destabilizes heme, which is subsequently extracted and coordinated in the aliphatic heme-binding environment of the NEAT domain. Because an amino acid with an amide side chain in this position is observed in NEAT domains of several genera of gram-positive pathogenic bacteria, these results suggest that specific targeting of this or nearby residues may be an entry point for inhibitor development aimed at blocking bacterial iron acquisition during infection. PMID- 23364794 TI - Nuclease activity of the human SAMHD1 protein implicated in the Aicardi-Goutieres syndrome and HIV-1 restriction. AB - The human HD domain protein SAMHD1 is implicated in the Aicardi-Goutieres autoimmune syndrome and in the restriction of HIV-1 replication in myeloid cells. Recently, this protein has been shown to possess dNTP triphosphatase activity, which is proposed to inhibit HIV-1 replication and the autoimmune response by hydrolyzing cellular dNTPs. Here, we show that the purified full-length human SAMHD1 protein also possesses metal-dependent 3'->5' exonuclease activity against single-stranded DNAs and RNAs in vitro. In double-stranded substrates, this protein preferentially cleaved 3'-overhangs and RNA in blunt-ended DNA/RNA duplexes. Full-length SAMHD1 also exhibited strong DNA and RNA binding to substrates with complex secondary structures. Both nuclease and dNTP triphosphatase activities of SAMHD1 are associated with its HD domain, but the SAM domain is required for maximal activity and nucleic acid binding. The nuclease activity of SAMHD1 could represent an additional mechanism contributing to HIV-1 restriction and suppression of the autoimmune response through direct cleavage of viral and endogenous nucleic acids. In addition, we demonstrated the presence of dGTP triphosphohydrolase and nuclease activities in several microbial HD domain proteins, suggesting that these proteins might contribute to antiviral defense in prokaryotes. PMID- 23364795 TI - MicroRNA-31 sensitizes human breast cells to apoptosis by direct targeting of protein kinase C epsilon (PKCepsilon). AB - MicroRNAs post-transcriptionally regulate gene expression and thereby contribute to the modulation of numerous complex and disease-relevant cellular phenotypes, including cell proliferation, cell motility, apoptosis, and stress response. In breast cancer cell systems, miR-31 has been shown to inhibit cell migration, invasion, and metastasis. Here, we link enhanced expression of miR-31 to the inhibition of the oncogenic NF-kappaB pathway, thus supporting the tumor suppressive function of this microRNA. We identified protein kinase C epsilon (PKCepsilon encoded by the PRKCE gene) as a novel direct target of miR-31 and show that down-regulation of PKCepsilon results in impaired NF-kappaB signaling, enhanced apoptosis, and increased sensitivity of MCF10A breast epithelial and MDA MB-231 triple-negative breast cancer cells toward ionizing radiation as well as treatment with chemotherapeutics. Mechanistically, we attribute this sensitization to anti-cancer treatments to the PRKCE-mediated down-regulation of the anti-apoptotic factor BCL2. In clinical breast cancer samples, high BCL2 expression was associated with poor prognosis. Furthermore, we found an inverse correlation between miR-31 and BCL2 expression, highlighting the functional relevance of the indirect down-regulation of BCL2 via direct targeting of PRKCE by miR-31. PMID- 23364796 TI - The presence of HIV-1 Tat protein second exon delays fas protein-mediated apoptosis in CD4+ T lymphocytes: a potential mechanism for persistent viral production. AB - HIV-1 replication is efficiently controlled by the regulator protein Tat (101 amino acids) and codified by two exons, although the first exon (1-72 amino acids) is sufficient for this process. Tat can be released to the extracellular medium, acting as a soluble pro-apoptotic factor in neighboring cells. However, HIV-1-infected CD4(+) T lymphocytes show a higher resistance to apoptosis. We observed that the intracellular expression of Tat delayed FasL-mediated apoptosis in both peripheral blood lymphocytes and Jurkat cells, as it is an essential pathway to control T cell homeostasis during immune activation. Jurkat-Tat cells showed impairment in the activation of caspase-8, deficient release of mitochondrial cytochrome c, and delayed activation of both caspase-9 and -3. This protection was due to a profound deregulation of proteins that stabilized the mitochondrial membrane integrity, such as heat shock proteins, prohibitin, or nucleophosmin, as well as to the up-regulation of NF-kappaB-dependent anti apoptotic proteins, such as BCL2, c-FLIPS, XIAP, and C-IAP2. These effects were observed in Jurkat expressing full-length Tat (Jurkat-Tat101) but not in Jurkat expressing the first exon of Tat (Jurkat-Tat72), proving that the second exon, and particularly the NF-kappaB-related motif ESKKKVE, was necessary for Tat mediated protection against FasL apoptosis. Accordingly, the protection exerted by Tat was independent of its function as a regulator of both viral transcription and elongation. Moreover, these data proved that HIV-1 could have developed strategies to delay FasL-mediated apoptosis in infected CD4(+) T lymphocytes through the expression of Tat, thus favoring the persistent replication of HIV-1 in infected T cells. PMID- 23364797 TI - Myogenin recruits the histone chaperone facilitates chromatin transcription (FACT) to promote nucleosome disassembly at muscle-specific genes. AB - Facilitates chromatin transcription (FACT) functions to reorganize nucleosomes by acting as a histone chaperone that destabilizes and restores nucleosomal structure. The FACT complex is composed of two subunits: SSRP1 and SPT16. We have discovered that myogenin interacts with the FACT complex. Transfection of FACT subunits with myogenin is highly stimulatory for endogenous muscle gene expression in 10T1/2 cells. We have also found that FACT subunits do not associate with differentiation-specific genes while C2C12 cells are proliferating but are recruited to muscle-specific genes as differentiation initiates and then dissociate as differentiation proceeds. The recruitment is dependent on myogenin, as knockdowns of myogenin show no recruitment of the FACT complex. These data suggest that FACT is involved in the early steps of gene activation through its histone chaperone activities that serve to open the chromatin structure and facilitate transcription. Consistent with this hypothesis, we find that nucleosomes are depleted at muscle-specific promoters upon differentiation and that this activity is dependent on the presence of FACT. Our results show that the FACT complex promotes myogenin-dependent transcription and suggest that FACT plays an important role in the establishment of the appropriate transcription profile in a differentiated muscle cell. PMID- 23364799 TI - A conformational NMR analysis of methymycin aglycones: complete and unambiguous assignments of stereochemically diverse glycosylated methymycin analogs by 1D and 2D NMR techniques and molecular modeling. AB - The (1)H and (13)C NMR spectra of 10-deoxymethynolide (1), 8.9-dihydro-10 deoxymethynolide (2) and its glycosylated derivatives (3-9) were analyzed using gradient-selected NMR techniques, including 1D TOCSY, gCOSY, 1D NOESY (DPFGSENOE), NOESY, gHMBC, gHSQC and gHSQC-TOCSY. The NMR spectral parameters (chemical shifts and coupling constants) of 1-9 were determined by iterative analysis. For the first time, complete and unambiguous assignment of the (1)H NMR spectrum of 10-deoxymethynolide (1) has been achieved in CDCl(3), CD(3)OD and C(6)D(6) solvents. The (1)H NMR spectrum of 8,9-dihydro-10-deoxymethynolide (2) was recorded in CDCl(3), (CD(3))(2)CO and CD(3)OD solutions to determine the conformation. NMR-based conformational analysis of 1 and 2 in conjugation with molecular modeling concluded that the 12-membered ring of the macrolactones may predominantly exist in a single stable conformation in all solvents examined. In all cases, a change in solvent caused only small changes in chemical shifts and coupling constants, suggesting that all glycosylated methymycin analogs exist with similar conformations of the aglycone ring in solution. PMID- 23364798 TI - Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. AB - Perisynaptic astrocytes express important glutamate transporters, especially excitatory amino acid transporter 2 (EAAT2, rodent analog GLT1) to regulate extracellular glutamate levels and modulate synaptic activation. In this study, we investigated an exciting new pathway, the exosome-mediated transfer of microRNA (in particular, miR-124a), in neuron-to-astrocyte signaling. Exosomes isolated from neuron-conditioned medium contain abundant microRNAs and small RNAs. These exosomes can be directly internalized into astrocytes and increase astrocyte miR-124a and GLT1 protein levels. Direct miR-124a transfection also significantly and selectively increases protein (but not mRNA) expression levels of GLT1 in cultured astrocytes. Consistent with our in vitro findings, intrastriatal injection of specific antisense against miR-124a into adult mice dramatically reduces GLT1 protein expression and glutamate uptake levels in striatum without reducing GLT1 mRNA levels. MiR-124a-mediated regulation of GLT1 expression appears to be indirect and is not mediated by its suppression of the putative GLT1 inhibitory ligand ephrinA3. Moreover, miR-124a is selectively reduced in the spinal cord tissue of end-stage SOD1 G93A mice, the mouse model of ALS. Subsequent exogenous delivery of miR-124a in vivo through stereotaxic injection significantly prevents further pathological loss of GLT1 proteins, as determined by GLT1 immunoreactivity in SOD1 G93A mice. Together, our study characterized a new neuron-to-astrocyte communication pathway and identified miRNAs that modulate GLT1 protein expression in astrocytes in vitro and in vivo. PMID- 23364800 TI - Gender differences control the susceptibility to ER stress-induced acute kidney injury. AB - Endoplasmic reticulum (ER) stress contributes to acute kidney injury induced by several causes. Kidney dysfunction was shown to be influenced by gender differences. In this study we observed differences in the severity of kidney injury between male and female mice in response to tunicamycin, an ER stress agent. Tunicamycin-treated male mice showed a severe decline in kidney function and extensive kidney damage of proximal tubules in the kidney outer cortex (S1 and S2 segments). Interestingly, female tunicamycin-treated mice did not show a decline in kidney function, and their kidneys showed damage localized primarily to proximal tubules in the inner cortex (S3 segment). Protein markers of ER stress, glucose-regulated protein, and X-box binding protein 1 were also more elevated in male mice. Similarly, the induction of apoptosis was higher in tunicamycin-treated male mice, as measured by the activation of Bax and caspase 3. Testosterone administered to female mice before tunicamycin resulted in a phenotype similar to male mice with a comparable decline in renal function, tissue morphology, and induction of ER stress markers. We conclude that kidneys of male mice are much more susceptible to ER stress-induced acute kidney injury than those of females. Moreover, this sexual dimorphism could provide an interesting model to study the relation between kidney function and injury to a specific nephron segment. PMID- 23364801 TI - Inherited secondary nephrogenic diabetes insipidus: concentrating on humans. AB - The study of human physiology is paramount to understanding disease and developing rational and targeted treatments. Conversely, the study of human disease can teach us a lot about physiology. Investigations into primary inherited nephrogenic diabetes insipidus (NDI) have contributed enormously to our understanding of the mechanisms of urinary concentration and identified the vasopressin receptor AVPR2, as well as the water channel aquaporin-2 (AQP2), as key players in water reabsorption in the collecting duct. Yet, there are also secondary forms of NDI, for instance as a complication of lithium treatment. The focus of this review is secondary NDI associated with inherited human diseases, such as Bartter syndrome or apparent mineralocorticoid excess. Currently, the underlying pathophysiology of this inherited secondary NDI is unclear, but there appears to be true AQP2 deficiency. To better understand the underlying mechanism(s), collaboration between clinical and experimental physiologists is essential to further investigate these observations in appropriate experimental models. PMID- 23364802 TI - Aging and hemoglobin-induced acute kidney injury. PMID- 23364803 TI - Role of guanine-nucleotide exchange factor Epac in renal physiology and pathophysiology. AB - Exchange proteins directly activated by cAMP [Epac(s)] were discovered more than a decade ago as new sensors for the second messenger cAMP. The Epac family members, including Epac1 and Epac2, are guanine nucleotide exchange factors for the Ras-like small GTPases Rap1 and Rap2, and they function independently of protein kinase A. Given the importance of cAMP in kidney homeostasis, several molecular and cellular studies using specific Epac agonists have analyzed the role and regulation of Epac proteins in renal physiology and pathophysiology. The specificity of the functions of Epac proteins may depend upon their expression and localization in the kidney as well as their abundance in the microcellular environment. This review discusses recent literature data concerning the involvement of Epac in renal tubular transport physiology and renal glomerular cells where various signaling pathways are known to be operative. In addition, the potential role of Epac in kidney disorders, such as diabetic kidney disease and ischemic kidney injury, is discussed. PMID- 23364804 TI - Impaired pressure natriuresis resulting in salt-sensitive hypertension is caused by tubulointerstitial immune cell infiltration in the kidney. AB - Immune cell infiltration of the kidney is a constant feature in salt-sensitive hypertension (SSHTN). We evaluated the relationship between the renal inflammation and pressure natriuresis in the model of SSHTN that results from transient oral administration of N(omega)-nitro-L-arginine methyl ester (L-NAME). Pressure natriuresis was determined in Wistar rats that received 4 wk of a high salt (4% NaCl) diet, starting 1 wk after stopping L-NAME, which was administered alone (SSHTN group, n = 17) or in association with mycophenolate mofetil (MMF; MMF group, n = 15). The administration of MMF in association with L-NAME is known to prevent the subsequent development of SSHTN. Control groups received a high (n = 12)- and normal (0.4%)-salt diet (n = 20). Rats with SSHTN had increased expression of inflammatory cytokines and oxidative stress. The severity of hypertension correlated directly (P < 0.0001) with the number of tubulointerstitial immune cells and angiotensin II-expressing cells. Pressure natriuresis was studied at renal arterial pressures (RAPs) of 90, 110, 130, and 150 mmHg. Glomerular filtration rate was similar and stable in all groups, and renal blood flow was decreased in the SSHTN group. Significantly decreased natriuresis (P < 0.05) was found in the SSHTN group at RAPs of 130 and 150 mmHg, and there was an inverse correlation (P < 0.01) between the urinary sodium excretion and the number of tubulointerstitial inflammatory cells (lymphocytes and macrophages) and cells expressing angiotensin II. We conclude that tubulointerstitial inflammation plays a key role in the impairment of pressure natriuresis that results in salt-dependent hypertension in this experimental model. PMID- 23364806 TI - Phosphodiesterase-5 inhibition attenuates early renal ischemia-reperfusion induced acute kidney injury: assessment by quantitative measurement of urinary NGAL and KIM-1. AB - Acute kidney injury (AKI) is a common clinical problem that still lacks effective treatment. Phosphodiesterase-5 (PDE5) inhibitors possess anti-apoptotic and anti oxidant properties, making it a promising therapy for ischemia-reperfusion (I/R) injury of various organs. The present study evaluated the early nephroprotective effects of Tadalafil, a PDE5 inhibitor, in an experimental model of renal I/R. Sprague-Dawley rats were divided into two groups: vehicle-treated I/R (n = 10), and Tadalafil (10 mg/kg po)-treated I/R group (n = 11). After removal of the right kidney and collection of two baseline urine samples, the left renal artery was clamped for 45 min followed by reperfusion for 60, 120, 180, and 240 min. Functional and histological parameters of the kidneys from the various groups were determined. In the vehicle-treated I/R group, glomerular filtration rate was significantly reduced compared with that in normal kidneys. In addition, the ischemic kidney showed remarkable cast formation, necrosis, and congestion, a consistent pattern of acute tubular necrosis. Furthermore, urinary excretion of NGAL and KIM-1, two novel biomarkers of kidney injury, substantially increased following I/R insult. In contrast, Tadalafil treatment resulted in a significant improvement in kidney function and amelioration of the adverse histological alterations of the ischemic kidney. Noteworthy, the urinary excretion of NGAL and KIM-1 markedly decreased in the Tadalafil-treated I/R group. These findings demonstrate that Tadalafil possesses early nephroprotective effects in rat kidneys subjected to I/R insult. This approach may suggest a prophylactic therapy for patients with ischemic AKI. PMID- 23364805 TI - Inhibition of p38 MAPK attenuates renal atrophy and fibrosis in a murine renal artery stenosis model. AB - Renal artery stenosis (RAS) is an important cause of chronic renal dysfunction. Recent studies have underscored a critical role for CCL2 (MCP-1)-mediated inflammation in the progression of chronic renal damage in RAS and other chronic renal diseases. In vitro studies have implicated p38 MAPK as a critical intermediate for the production of CCL2. However, a potential role of p38 signaling in the development and progression of chronic renal disease in RAS has not been previously defined. We sought to test the hypothesis that inhibition of p38 MAPK ameliorates chronic renal injury in mice with RAS. We established a murine RAS model by placing a cuff on the right renal artery and treated mice with the p38 inhibitor SB203580 or vehicle for 2 wk. In mice treated with vehicle, the cuffed kidney developed interstitial fibrosis, tubular atrophy, and interstitial inflammation. In mice treated with SB203580, the RAS-induced renal atrophy was reduced (70% vs. 39%, P < 0.05). SB203580 also reduced interstitial inflammation and extracellular matrix deposition but had no effect on the development of hypertension. SB203580 partially blocked the induction of CCL2, CCL7 (MCP-3), CC chemokine receptor 2 (CCR2), and collagen 4 mRNA expression in the cuffed kidneys. In vitro, blockade of p38 hindered both TNF-alpha and TGF beta-induced CCL2 upregulation. Based on these observations, we conclude that p38 MAPK plays a critical role in the induction of CCL2/CCL7/CCR2 system and the development of interstitial inflammation in RAS. PMID- 23364808 TI - Catalytic reduction of CO(2) to CO by using zinc(II) and in situ generated carbodiphosphoranes. AB - Playing it 'CO'ol: CO(2) is catalytically reduced to CO with concurrent oxidation of phosphine to phosphineoxide by using an in situ generated catalyst derived from a carbodiphosphorane and zinc(II). PMID- 23364807 TI - Nanostructured alpha-Fe2O3 platform for the electrochemical sensing of folic acid. AB - alpha-Fe(2)O(3) nanofibers are synthesized by a simple and efficient electrospinning method and the selective determination of folic acid (FA) is demonstrated in the presence of an important physiological interferent, ascorbic acid (AA), using the alpha-Fe(2)O(3) nanofiber modified glassy carbon (GC) electrode at physiological pH. Bare GC electrode fails to determine the concentration of FA in the presence of a higher concentration of AA due to the surface fouling caused by the oxidized products of AA and FA. However, modification with alpha-Fe(2)O(3) nanofibers not only separates the voltammetric signals of AA and FA by 420 mV between AA and FA, but also enhances higher oxidation current. The amperometric current response is linearly dependent on FA concentration in the range of 60-60,000 nM, and the alpha-Fe(2)O(3) nanofiber modified electrode displayed an excellent sensitivity for FA detection with an experimental detection limit of 60 nM (1.12 * 10(-10) M (S/N = 3)). Furthermore, the alpha-Fe(2)O(3) nanofiber modified electrode showed an admirable selectivity towards the determination of FA even in the presence of a 1000-fold excess of AA and other common interferents. This modified electrode has been successfully applied for determination of FA in human blood serum samples. PMID- 23364809 TI - The action of all-trans-retinoic acid (ATRA) and synthetic retinoid analogues (EC19 and EC23) on human pluripotent stem cells differentiation investigated using single cell infrared microspectroscopy. AB - All trans-retinoic acid (ATRA) is widely used to direct the differentiation of cultured stem cells. When exposed to the pluripotent human embryonal carcinoma (EC) stem cell line, TERA2.cl.SP12, ATRA induces ectoderm differentiation and the formation of neuronal cell types. We have previously generated synthetic analogues of retinoic acid (EC23 and EC19) which also induce the differentiation of EC cells. Even though EC23 and EC19 have similar chemical structures, they have differing biochemical effects in terms of EC cell differentiation. EC23 induces neuronal differentiation in a manner similar to ATRA, whereas EC19 directs the cells to form epithelial-like derivatives. Previous MALDI-TOF MS analysis examined the response of TERA2.cl.SP12 cells after exposure to ATRA, EC23 and EC19 and further demonstrated the similarly in the effect of ATRA and EC23 activity whilst responses to EC19 were very different. In this study, we show that Fourier Transform Infrared Micro-Spectroscopy (FT-IRMS) coupled with appropriate scatter correction and multivariate analysis can be used as an effective tool to further investigate the differentiation of human pluripotent stem cells and monitor the alternative affects different retinoid compounds have on the induction of differentiation. FT-IRMS detected differences between cell populations as early as 3 days of compound treatment. Populations of cells treated with different retinoid compounds could easily be distinguished from one another during the early stages of cell differentiation. These data demonstrate that FT-IRMS technology can be used as a sensitive screening technique to monitor the status of the stem cell phenotype and progression of differentiation along alternative pathways in response to different compounds. PMID- 23364810 TI - In vitro and in vivo enhancement of osteogenic capacity in a synthetic BMP-2 derived peptide-coated mineralized collagen composite. AB - Enhancement of osteogenic capacity was achieved in a mineralized collagen composite, nano-hydroxyapatite/collagen (nHAC), by loading with synthetic peptides derived from BMP-2 residues 32-48 (P17-BMP-2). Rabbit marrow stromal cells (MSCs) were used in vitro to study cell biocompatibility, attachment and differentiation on the mineralized collagen composite by a cell counting kit, scanning electron microscopy (SEM) and real-time reversed transcriptase polymerase chain reaction analysis (RT-PCR). Optimal peptide dosage (1.0 ug/mL) was obtained by RT-PCR analysis in vitro. In addition, the relative expression level of OPN and OCN was significantly upregulated on P17-BMP-2/nHAC compared with nHAC. In vitro results of P17-BMP-2 release kinetics demonstrated that nHAC released P17-BMP-2 in a controlled and sustained manner. In the rabbit mandibular box-shaped bone defect model, osteogenic capacity of three groups (nHAC, P17-BMP 2/nHAC, rhBMP-2/nHAC) was evaluated. Compared to the nHAC group, bone repair responses in both P17-BMP-2/nHAC and rhBMP-2/nHAC group implants were significantly improved based on histological analysis. The osteogenic response of the P17-BMP-2/nHAC group was similar to that of the rhBMP-2/nHAC group. PMID- 23364811 TI - Rapid molecular diagnosis of measles virus infection in an epidemic setting. AB - During the 2011 measles outbreak in Paris (France), patients with clinical suspicion of measles were tested for virological confirmation of measles virus (MV) infection. To assess the practical value of molecular diagnosis in an epidemic setting, 171 oral fluid samples and 235 serum samples collected from 270 patients were tested prospectively for MV-RNA using a novel one-step real-time RT PCR assay including an internal control. Serum samples were also tested for MV specific IgG and IgM antibodies. MV infection was confirmed by detection of MV RNA and/or MV-IgM for 229 of the 270 patients. The results for the 102 cases with both serum and oral fluid samples available were used to compare the techniques. The detection rate of MV-RNA by RT-PCR was 98% (100/102) for oral fluid and 95% (97/102) for serum samples. The detection rate of MV-IgM was 85% (87/102). Negative MV-IgM results were observed mostly for serum samples collected early after the onset of the rash. A MV-RNA standard of known concentration obtained by in vitro transcription was used to quantify MV-RNA in samples. MV-RNA copy numbers were significantly higher in oral fluid than in serum samples, but did not correlate with time of sampling (within 1 week after the onset of the rash), patient age, or vaccination status. During the early stage of infection, the MV RNA viral load in serum was lower in patients positive than in those negative for MV-IgG. In conclusion, the one-step real-time RT-PCR assay is a simple and sensitive tool suitable for MV diagnosis within hours. PMID- 23364812 TI - The role of the metabolic syndrome in patients with provoked venous thromboembolic events. PMID- 23364814 TI - Cocoa polyphenols enhance positive mood states but not cognitive performance: a randomized, placebo-controlled trial. AB - This study aimed to examine the acute and sub-chronic effects of cocoa polyphenols on cognition and mood. In a randomized, double-blind study, healthy middle-aged participants received a dark chocolate drink mix standardized to contain 500 mg, 250 mg or 0 mg of polyphenols (placebo) in a parallel-groups design. Participants consumed their assigned treatment once daily for 30 days. Cognition was measured with the Cognitive Drug Research system and self-rated mood with the Bond-Lader Visual Analogue Scale. Participants were tested at baseline, at 1, 2.5 and 4 h after a single acute dose and again after receiving 30 days of treatment. In total, 72 participants completed the trial. After 30 days, the high dose of treatment significantly increased self-rated calmness and contentedness relative to placebo. Mood was unchanged by treatment acutely while cognition was unaffected by treatment at all time points. This randomized controlled trial is perhaps the first to demonstrate the positive effects of cocoa polyphenols on mood in healthy participants. This provides a rationale for exploring whether cocoa polyphenols can ameliorate the symptoms associated with clinical anxiety or depression. PMID- 23364815 TI - Opiate agonists and antagonists modulate taste perception in opiate-maintained and recently detoxified subjects. AB - Heroin addicts consume large quantities of refined sugars. This study investigated the effect of opiate use and antagonism on sweet taste in opiate maintained drug users and detoxified former chronic opiate users, using a within subject design. Seven opiate users received methadone and seven buprenorphine maintenance. Six detoxified subjects received naltrexone. Sucrose recognition thresholds and measurements of pleasantness and intensity were determined before and four hours after 1) a single dose of methadone or buprenorphine or 2) naltrexone. Control data were taken from a cohort of healthy volunteers including smokers. All measures of sweet and salt taste perception were significantly greater in opiate users and recently detoxified subjects compared to control subjects, with the exception of sweet pleasantness, which returned to control level after detoxification. Acute methadone administration reduced salt thresholds and unpleasantness to control levels. Increased sweet thresholds and salt unpleasantness in detoxified subjects were reversed by acute opioid antagonism, returning to control levels. These results suggest that opiate use and antagonism alters taste perception. Some of the alterations reverse on detoxification (sweet pleasantness), and others can be reversed by opioid antagonism (sweet threshold, salt unpleasantness). Changes in taste perception may underlie altered consumption of refined sugars in opiate users. PMID- 23364816 TI - [Patient safety in anaesthesiology: implementation of the Declaration of Helsinki]. PMID- 23364817 TI - [Letter to Kunz T et al. Puncture tracheotomy in intensive care - Update 2012. Anasthesiol Intensivmed Notfallmed Schmerzther 2012; 47(10): 598-604. ]. PMID- 23364819 TI - [Modification of perioperative psychiatric drug therapy]. AB - Apart from cardiovascular, pulmonary and metabolic drugs, many patients scheduled for surgery are taking antidepressive or antipsychotic drugs. Some of these psychiatric drugs may interfere with anesthetics. The anesthesiologist has to decide whether or not to continue the psychiatric medication during the perioperative period. Since the discontinuation of psychiatric drugs may lead to withdrawal syndromes, the decision should be made in accordance with the attending psychiatrist. Should the discontinuation of any psychiatric drug be recommended, it may be prudent to involve the attending surgeon in order to postpone the procedure, since the modification of psychiatric drugs may take several days.Prospective randomized data about the perioperative modification of psychiatric drugs are scarce. Thus, recommendations in this regard must rely on physiological and pharmacological principles, case reports and published expert opinions. In this article we use the available data to answer the question of a journal reader regarding the perioperative modification of Opipramol therapy for a 59-year-old patient scheduled for elective shoulder surgery. PMID- 23364820 TI - [Surgical therapy and critical care medicine in severely burned patients - Part 2: the basics in definite care]. AB - Critical care medicine in severely burned patients should be adapted to the different pathophysiological phases. Accordingly, surgical and non-surgical therapy must be coordinated adequately. Initial stabilization of the burn victim during the first 24 hours (Surgical therapy and critical care medicine in severely burned patients - Part 1: the first 24 ours, AINS 9/12) is followed by a long lasting reconstructive period. During this time calculated fluid replacement to compensate evaporative losses by large bourn wounds is as essential as reconstruction of the integrity of the skin and the modulation of metabolic consequences following severe burn injury. Special attention has to be paid to local and systemic infections. PMID- 23364821 TI - [Air embolism after removal of central venous catheter]. AB - Placement and removal of central venous catheters (CVC) are routine procedures in anesthesiology and on the intensive care unit. There are numerous possible complications associated with those interventions. Here, we report on a patient who developed respiratory failure immediately after removal of a CVC. The proof of air bubbles in echocardiography confirmed the diagnosis of air embolism. In this article we describe causes, symptoms and therapy of air embolism. PMID- 23364822 TI - [Helsinki Declaration on Patient Safety in Anaesthesiology -- SOP for local anesthetics intoxication]. PMID- 23364823 TI - [Air conditioning units and warm air blankets in the operating room]. AB - Nowadays almost all operating rooms are equipped with air conditioning (AC units). Their main purpose is climatization, like ventilation, moisturizing, cooling and also the warming of the room in large buildings. In operating rooms they have an additional function in the prevention of infections, especially the avoidance of postoperative wound infections. This is achieved by special filtration systems and by the creation of specific air currents. Since hypothermia is known to be an unambiguous factor for the development of postoperative wound infections, patients are often actively warmed intraoperatively using warm air blankets (forced-air warming units). In such cases it is frequently discussed whether such warm air blankets affect the performance of AC units by changing the air currents or whether, in contrast, have exactly the opposite effect. However, it has been demonstrated in numerous studies that warm air blankets do not have any relevant effect on the functioning of AC units. Also there are no indications that their use increases the rate of postoperative wound infections. By preventing the patient from experiencing hypothermia, the rate of postoperative wound infections can even be decreased thereby. PMID- 23364824 TI - [Awareness -- even today, a problem?]. PMID- 23364825 TI - [Neuromonitoring and awareness]. AB - Awareness is a rare but in some cases severe complication of general anesthesia. In clinical practice vegetative signs such as sweating, lacrimation, tachycardia and hypertension are used to assess the anesthetic depth. Awareness however may also occur without any of these signs. Different systems based on the electroencephalogram (EEG) have been developed to monitor hypnosis. Some studies have shown that the use of EEG based monitor systems can reduce the incidence of awareness in patients of high risk. A similar reduction of the incidence was reached in studies using protocols based on concentrations of volatile anesthetics. Other systems to monitor anesthetic depth have been developed, but their influence on awareness has not yet been investigated sufficiently. Further studies are needed to clarify their impact concerning the incidence of awareness. PMID- 23364826 TI - [Awareness - clinical relevance]. AB - Awareness is a rare but typical complication during general anesthesia, with a reported incidence of 0.1- 0.2% to 1% (high risk patients) in adults and probably much higher in children with 0.2 -1.2%. Awareness is defined as consciousness during general anesthesia with explicit (conscious) recall of memories.Wakefulness during anesthesia can meet DSM-IV criteria of trauma. Significant long-term psychological sequelae (e.g. post-traumatic stress disorder) may occur.Recommendations of the German Society of Anesthesiologists have been developed according to the ASA Task Force for intraoperative awareness and brain function monitoring.The article focuses on risk factors and sequelae of awareness, explains the options for detection of intraoperative wakefulness and postoperative memories and makes recommendations for prevention and handling of awareness. PMID- 23364827 TI - [Awareness - medico legal aspects]. AB - In general there are 3 significant malpractice risks for anaesthesiologists: insufficient supervision especially in case of patients, who have a known awareness risk, technical mistakes in the preparation or controlling of anaesthesia and no or insufficient therapeutic reaction if awareness has occurred. As long as awareness cannot be avoided during anaesthesia this risk should be explained to the patient. But the information should be given by the physician very subtly and carefully.Until today there have been only 3 court decisions in Germany concerning awareness. In all cases the claims have been dismissed. There is no Federal Court decision dealing with informed consent in case of awareness. PMID- 23364830 TI - Isolation and characterization of luciferase from Indian firefly, Luciola praeusta. AB - Luciferase from Indian firefly Luciola praeusta (Coleoptera: Lampyridae: Luciolinae) was isolated and the properties compared with that of the North American firefly, Photinus pyralis. Luciola praeusta luciferase was purified using acetone extraction, gel-filtration column chromatography, ammonium sulfate precipitation and anion exchange chromatography. Sodium dodecyl sulfate polyacrylamide gel electrophoresis indicates a homogeneous preparation and the molecular mass was slightly higher than that of Photinus pyralis. The effect of pH, buffer composition and metal ions on the spectral characteristics was studied. The maximum bioluminescence activity of luciferase was observed in ACES buffer at pH 6.5. The emission maximum of 562 nm (in crude extract) was red shifted to 570 nm in Tricine buffer at pH 7.8. In addition, the effect of bovine serum albumin on the storage stability of the protein was investigated. Based on the unique spectral characteristics observed, we propose that Luciola praeusta luciferase in the native form is suitable for the assay of biochemical metabolites in acidic pH. PMID- 23364831 TI - Characterization of sodium dodecylsulphate and dodecylphosphocholine mixed micelles through NMR and dynamic light scattering. AB - The complexity of biological membranes leads to the use of extremely simplified models in biophysical investigations of membrane-bound proteins and peptides. Liposomes are probably the most widely used membrane models due, especially, to their versatility in terms of electric charge and size. However, liquid-state NMR suffers the lack of such a model, because even the smallest liposomes slowly tumble in solution, resulting in a dramatic signals broadening. Micelles are typically used as good substitutes, with sodium dodecylsulphate (SDS) and dodecylphosphocholine (DPC) being the most widely employed surfactants. However, they are always used separately to mimic prokaryotic and eukaryotic membranes, respectively, and accurate investigations as a function of surface charge cannot be performed. In this work, the critical micelle concentration (CMC) of binary mixtures with different SDS/DPC ratios has been determined by following the chemical shift variation of selected (1)H and (31)P NMR signals as a function of total surfactant concentration. The regular solution theory and the Motomura's formalism have been applied to characterize the micellization both in water and in phosphate buffer saline, and results were compared with those obtained directly from the experimental NMR chemical shift. The zeta-potential and size distribution of the mixed micelles have been estimated with dynamic light scattering measurements. Results showed that SDS and DPC are synergic and can be used together to prepare mixed micelles with different negative/zwitterionic surfactants molar ratio. PMID- 23364832 TI - 31P NMR chemical shifts of carbene-phosphinidene adducts as an indicator of the pi-accepting properties of carbenes. PMID- 23364833 TI - Trends in the incidence of cancer in the black population of Harare, Zimbabwe 1991-2010. AB - Incidence rates of different cancers have been calculated for the black population of Harare, Zimbabwe for a 20-year period (1991-2010) coinciding with continuing social and lifestyle changes, and the peak, and subsequent wane, of the HIV-AIDS epidemic. The overall risk of cancer increased during the period in both sexes, with rates of cervix and prostate cancers showing particularly dramatic increases (3.3% and 6.4% annually, respectively). By 2004, prostate cancer had become the most common cancer of men. The incidence of cancer of the esophagus, formerly the most common cancer of men, has remained relatively constant, whereas rates of breast and cervix cancers, the most common malignancies of women, have shown significant increases (4.9% and 3.3% annually, respectively). The incidence of Kaposi sarcoma increased to a maximum around 1998 2000 and then declined in all age groups, and in both sexes The incidence of squamous cell cancers of the conjunctiva is relatively high, with temporal trends similar to those of Kaposi sarcoma. Non-Hodgkin lymphoma, the fifth most common cancer of men and fourth of women, showed a steady increase in incidence throughout the period (6.7-6.9% annually), although rates in young adults (15-39) have decreased since 2001. Cancer control in Zimbabwe, as elsewhere in sub Saharan Africa, involves meeting the challenge of emerging cancers associated with westernization of lifestyles (large bowel, breast and prostate), while the incidence of cancers associated with poverty and infection (liver, cervix and esophagus) shows little decline, and the residual burden of the AIDS-associated cancers remains significant. PMID- 23364834 TI - Diagnostic and prognostic value of Ischemia-modified albumin in patients with Crimean-Congo hemorrhagic fever. AB - The aim of this study was to determine the diagnostic and prognostic significance of ischemia modified albumin (IMA) levels in patients with Crimean-Congo hemorrhagic fever (CCHF). This retrospective study was conducted with patients with CCHF. IMA levels in patients with CCHF were determined using the rapid colorimetric method. IMA levels of CCHF patients were significantly higher compared with the control group (P = 0.0001). At an IMA cut-off point of 0.555 ABSU (absorbance units), sensitivity was 65.1%, specificity 82.5%, positive predictive values (PPV) 82.5%, and negative predictive values (NPV) 65.1%. IMA levels of patients with hemorrhage were significantly higher compared with patients without hemorrhage (P = 0.005). IMA has been validated as both a new and sensitive ischemia and oxidative stress biomarker. In addition to its diagnostic significance, IMA investigated in CCHF patients at time of arrival may be an important marker with its prognostic role in determining in the early stage whether the disease will follow a hemorrhagic course. PMID- 23364835 TI - Protein interaction and cellular localization of human CDC45. AB - CDC45, which plays a role in eukaryotic DNA replication, is a member of the CMG (CDC45/MCM2-7/GINS) complex that is thought to function as a replicative DNA helicase. However, the biochemical properties of CDC45 are not fully understood. We systematically examined the interactions of human CDC45 with MCM2-7, GINS and other replication proteins by immunoprecipitation. We found that CDC45 can directly interact with all MCM2-7 proteins; with PSF2, PSF3 and SLD5 in GINS subunits; and with replication protein A2 (RPA2), AND-1 and topoisomerase 2 binding protein 1. These results are consistent with the notion that CDC45 plays a role in progression of DNA replication forks. Experiments using antibodies against CDC45 show that the level of CDC45 recovered from the Triton-insoluble chromatin-containing fraction is peaked at middle of S phase in synchronized HeLa cells. However, incubation of the Triton-insoluble fraction with nucleases resulted in recovery of less than half the amount of CDC45 in the nuclease sensitive fraction; this result is in contrast with RPA1 and proliferating cell nuclear antigen distribution. These results indicate that a considerable portion of CDC45 localizes in a region other than the DNA replication forks in nuclei or it localizes on the replication forks but it is not fractionated with the fork proteins owing to its tight association with presumably nuclear scaffolds. PMID- 23364836 TI - A simple and rapid spectrofluorimetric method for determining the pharmacokinetics and metabolism of rhaponticin in rat plasma, feces and urine using a cerium probe. AB - Rhaponticin (RH) demonstrates a variety of pharmacological activities, including antitumor, antithrombotic and antioxidant effects. It is essential to establish a simple, rapid and reliable analytical method for determining the pharmacokinetics of RH. A simple cerium ion (Ce(3+)) probe method was developed and validated to determine RH in rat plasma, feces and urine. The fluorescence intensities of the cerium ion (Ce(3+)) were quenched by addition of RH, along with a remarkable red shift. Spectral data revealed that fluorescence quenching of Ce(3+) by RH was due to the formation of a Ce(3+)-RH complex. Using to the Stern-Volmer equation, the binding parameters for interactions between Ce(3+) and RH were obtained. Based on these, a rapid and simple spectrofluorimetric method was developed to determine the metabolism and pharmacokinetics of RH using a Ce(3+) probe. The assay was linear over the concentration range of 0.11-9.52, 0.25-8.87 and 0.18-9.10 MUM for plasma, feces and urine, respectively and RH recoveries were found to be 98.24 +/ 0.8, 97.78 +/- 1.2 and 97.54 +/- 0.8% for plasma, feces and urine, respectively. The relative standard deviations were < 9.5%. The spectrofluorimetric method was simple and rapid for quantitative determination of RH and its metabolism, and was affordable for most laboratories because of the fluorescence spectroscopy and low equipment cost. These pharmacokinetic, bioavailability and metabolism studies of RH will provide helpful information for the development of suitable dosage forms and clinical references on rational administration. PMID- 23364839 TI - In vivo molecular imaging of gastric cancer by targeting MG7 antigen with confocal laser endomicroscopy. AB - BACKGROUND AND STUDY AIMS: In vivo molecular imaging represents a powerful tool for the immediate diagnosis of gastric cancer. In this study, the monoclonal antibody MG7, which is a specific molecular marker against gastric cancer, was labeled with fluorescent agents to enable in vivo real-time imaging by confocal laser endomicroscopy (CLE). PATIENTS AND METHODS: In vivo molecular imaging was performed in tumor-bearing mice from two kinds of human gastric cancer cell lines. Xenograft tumors were visualized in vivo first with a whole-body fluorescent imaging device and then by CLE using fluorescently labeled MG7 antibody. Gastric cancerous tissue and noncancerous mucosa from human biopsies or surgical specimens were also examined ex vivo by CLE. RESULTS: Intravital imaging of xenograft tumors revealed a specific cellular signal, whereas no specific signal was observed in control tissue or in mice injected with irrelevant antibodies. An ex vivo experiment on human specimens using a rigid confocal probe showed positive fluorescent staining in 22/23 samples diagnosed as gastric cancer and weak signals in 5/23 noncancerous tissue samples. CLE evaluation correlated well with immunohistochemical findings. CONCLUSIONS: Screening tumors in vivo by CLE may help to detect MG7-Ag-positive tissues, decrease the sampling error by screening the large tumor surface not routinely screened by biopsy or conventional immunohistochemistry, and facilitate early detection of gastric carcinoma. PMID- 23364837 TI - Regulation of protein-protein binding by coupling between phosphorylation and intrinsic disorder: analysis of human protein complexes. AB - Phosphorylation offers a dynamic way to regulate protein activity, subcellular localization, and stability. The majority of signaling pathways involve an extensive set of protein-protein interactions, and phosphorylation is widely used to regulate protein-protein binding by affecting the stability, kinetics and specificity of interactions. Previously it was found that phosphorylation sites tend to be located on protein-protein binding interfaces and may orthosterically modulate the strength of interactions. Here we studied the effect of phosphorylation on protein binding in relation to intrinsic disorder for different types of human protein complexes with known structure of the binding interface. Our results suggest that the processes of phosphorylation, binding and disorder-order transitions are coupled to each other, with about one quarter of all disordered interface Ser/Thr/Tyr sites being phosphorylated. Namely, residue site disorder and interfacial states significantly affect the phosphorylation of serine and to a lesser extent of threonine. Tyrosine phosphorylation might not be directly associated with binding through disorder, and is often observed in ordered interface regions which are not predicted to be disordered in the unbound state. We analyze possible mechanisms of how phosphorylation might regulate protein-protein binding via intrinsic disorder, and specifically focus on how phosphorylation could prevent disorder-order transitions upon binding. PMID- 23364840 TI - Endoscopic resection in the duodenum: current limitations and future directions. AB - Duodenal lesions that should be considered for endoscopic resection comprise a heterogeneous group of disorders. Most are adenomas, primarily located in the descending duodenum. In comparison to lesions of a similar size elsewhere in the gastrointestinal tract, the risk of major complications from endoscopic resection of duodenal lesions is magnified. The unique anatomical features of the duodenum are largely responsible for this, but despite this we continue to apply conventional endoscopic therapies when a more sophisticated approach is required. Many other important clinical questions in relation to duodenal adenomas remain unanswered. This review aims to identify the gaps in the knowledge base and therapeutic approach and propose some solutions and directions for future research. PMID- 23364841 TI - Endoscopic submucosal dissection for sessile, nonampullary duodenal adenomas. AB - Although endoscopic submucosal dissection (ESD) is increasingly utilized to treat early neoplasms of the gastrointestinal tract, its use for duodenal neoplasms is limited by the thin wall and narrow lumen of the duodenum. We have reviewed cases where ESD was used to treat sessile, nonampullary duodenal neoplasms. To do this, we retrospectively reviewed the medical records of patients treated with ESD for adenomas of the duodenum from January 2001 to December 2010, assessing the curative outcomes and complication rates. A total of 14 cases were reviewed. Mean patient age was 56.4 years. The mean size of tumors and mean size of the specimens were 17.1 mm and 26.4 mm, respectively. The en bloc resection rate with ESD was 78.6%, and the complete (R0) resection rate was 85.7%. No patient in the study experienced major bleeding. However, second-look endoscopy revealed minor bleeding requiring endoscopic homeostasis in one case (7.1%). Perforations were observed in five cases (35.7%). Two of the five patients with perforation underwent surgery. The ESD methods yielded acceptable curative resection rates for duodenal adenomas, although ESD was associated with a higher rate of perforation. Therefore, duodenal ESD should be performed with care and only in selected patients to avoid serious complications. PMID- 23364842 TI - Barrett's esophagus as a marker for increased risk for esophageal cancer and cardiorespiratory disease. PMID- 23364843 TI - Reply to Schoppman et al. PMID- 23364844 TI - Residual biliary stones: do we need peroral cholangioscopy? PMID- 23364845 TI - Reply to Peng & Chow. PMID- 23364846 TI - ESGE newsletter. Definition of "endoscope families" as used in EN ISO 15883-4. PMID- 23364847 TI - Exploratory study on association of genetic variation in TBC1D1 with antipsychotic-induced weight gain. AB - BACKGROUND: Previous studies have shown that antipsychotics with high propensity for antipsychotic-induced weight gain (AIWG) influence glucose transporter type 4 (GLUT4) mediated glucose intake. Variation in the gene encoding TBC1 domain family member 1 (TBC1D1), a Rab-GTPase activating protein regulating GLUT4 trafficking, has been associated with obesity. Therefore, we investigated the impact of TBC1D1 polymorphisms on AIWG. METHODS: We analyzed rs9852 and rs35859249 in TBC1D1 in 195 schizophrenia subjects treated mostly with clozapine or olanzapine for up to 14 weeks. Association was tested using analysis of variance and analysis of covariance with change (%) from baseline weight as the dependent variable. RESULTS: Analysis of covariance showed a non-significant trend for lower weight gain in carriers of the T-allele of rs9852 than in C allele homozygotes (p = 0.063). This effect was more pronounced in the subgroup of patients treated with clozapine or olanzapine (p = 0.024). For rs35859249, no significant association with AIWG could be detected. CONCLUSIONS: This is the first study examining the association between TBC1D1 and AIWG. The moderate association of rs9852, located in the 3'UTR near a miRNA binding site, indicates an influence of TBC1D1 on AIWG. Further investigations remain necessary to elucidate the role of this gene in AIWG. PMID- 23364848 TI - ProEx C as an adjunct marker to improve cytological detection of urothelial carcinoma in urinary specimens. AB - BACKGROUND: ProEx C is an antibody cocktail targeting the expression of topoisomerase IIalpha and minichromosome maintenance protein-2. ProEx C staining is being used to assist in diagnoses of the gynecological specimens. This study was designed to determine the utility of ProEx C in urine cytology samples for improving the detection of urothelial carcinomas where a significant number of urine cytology specimens are diagnosed as "atypia." METHODS: Sixty urinary specimens (12 negative, 13 positive, and 35 atypical cases) were stained with ProEx C, and ProEx C results were recorded as positive when nuclear staining was only seen in at least one morphologically atypical urothelial cell. RESULTS: All 12 benign cytology samples showed negative staining with ProEx C. Twelve of 13 cases that had a malignant cytologic diagnosis showed a positive nuclear staining of the malignant cells. Eighteen of 35 cases with atypical cytologic diagnoses showed positive nuclear staining. Of the 35 cases with "atypia," 17 had a malignant histopathologic follow-up. In this study, ProEx C stain had an overall sensitivity of 78.4%, specificity of 95.7%%, positive predictive value of 96.7%, and negative predictive value of 73.3% for the detection of urothelial carcinoma. CONCLUSIONS: ProEx C stain is a useful adjunct test to urine cytologic analysis, even in specimens with limited cellularity. In urinary smears, this test is most useful in stratification of the "atypical" diagnoses into benign and malignant subsets. To the authors' knowledge, this is the first study of ProEx C application in urine cytology as an adjunct marker for detection of urothelial carcinoma. PMID- 23364850 TI - Physical activity and health outcomes: evidence from Canada. AB - Health production models include participation in physical activity as an input. We investigate the relationship between participation in physical activity and health using a bivariate probit model. Participation is identified with an exclusion restriction on a variable reflecting sense of belonging to the community. Estimates based on data from Cycle 3.1 of the Canadian Community Health Survey indicate that participation in physical activity reduces the reported incidence of diabetes, high blood pressure, heart disease, asthma, and arthritis as well as being in fair or poor health. Increasing the intensity above the moderate level and frequency of participation in physical activity appears to have a diminishing marginal impact on adverse health outcomes. Our results provide support for guidelines about engaging in exercise regularly to achieve health benefits. PMID- 23364849 TI - Ovarian cancer risk factors by tumor dominance, a surrogate for cell of origin. AB - Differentiating ovarian tumors based on developmental pathway may further enhance our understanding of the disease. Traditionally, ovarian cancers were thought to arise from the ovarian surface epithelium; however, recent evidence suggests that some tumors originate in the fallopian tube. We classified cases in a population based case-control study (New England Case-Control [NECC] Study) and two cohort studies (Nurses' Health Study [NHS]/Nurses' Health Study II [NHSII]) by tumor dominance, a proxy for tissue of origin. Dominant tumors (likely ovarian origin) are restricted to one ovary or are at least twice as large on one ovary compared to the other. Ovarian cancer risk factors were evaluated in relation to dominant and nondominant tumors (likely tubal origin) using polytomous logistic regression (NECC) or competing risks Cox models (NHS/NHSII). Results were combined using random-effects meta-analyses. Among 1,771 invasive epithelial ovarian cancer cases, we observed 1,089 tumors with a dominant mass and 682 with no dominant mass. Dominant tumors were more likely to be mucinous, endometrioid or clear cell, whereas nondominant tumors were more likely to be serous. Tubal ligation, two or more births, endometriosis and age were more strongly associated with dominant tumors (rate ratio [RR] = 0.60, 0.83, 1.58 and 1.37, respectively) than nondominant tumors (RR = 1.03, 0.93, 0.84 and 1.14, respectively; p-difference = 0.0001, 0.01, 0.0003 and 0.01, respectively). These data suggest that risk factors for tumors putatively arising from ovarian versus fallopian tube sites may differ; in particular, reproductive factors may be more important for ovarian derived tumors. As this is the first study to evaluate ovarian cancer risk factors by tumor dominance, these results need to be validated by other studies. PMID- 23364852 TI - Small-angle neutron scattering for in situ probing of ion adsorption inside micropores. AB - Confined ions: The high penetrating power and sensitivity of neutron scattering to isotope substitution are harnessed to observe changes in the ion concentration in a porous carbon material as a function of the applied potential and the pore size. Depending on the solvent properties and the solvent-pore-wall interactions, either enhanced or reduced ion electroadsorption may take place. PMID- 23364851 TI - Applying active learning to supervised word sense disambiguation in MEDLINE. AB - OBJECTIVES: This study was to assess whether active learning strategies can be integrated with supervised word sense disambiguation (WSD) methods, thus reducing the number of annotated samples, while keeping or improving the quality of disambiguation models. METHODS: We developed support vector machine (SVM) classifiers to disambiguate 197 ambiguous terms and abbreviations in the MSH WSD collection. Three different uncertainty sampling-based active learning algorithms were implemented with the SVM classifiers and were compared with a passive learner (PL) based on random sampling. For each ambiguous term and each learning algorithm, a learning curve that plots the accuracy computed from the test set as a function of the number of annotated samples used in the model was generated. The area under the learning curve (ALC) was used as the primary metric for evaluation. RESULTS: Our experiments demonstrated that active learners (ALs) significantly outperformed the PL, showing better performance for 177 out of 197 (89.8%) WSD tasks. Further analysis showed that to achieve an average accuracy of 90%, the PL needed 38 annotated samples, while the ALs needed only 24, a 37% reduction in annotation effort. Moreover, we analyzed cases where active learning algorithms did not achieve superior performance and identified three causes: (1) poor models in the early learning stage; (2) easy WSD cases; and (3) difficult WSD cases, which provide useful insight for future improvements. CONCLUSIONS: This study demonstrated that integrating active learning strategies with supervised WSD methods could effectively reduce annotation cost and improve the disambiguation models. PMID- 23364853 TI - Implantable left ventricular assist devices as initial therapy for refractory postmyocardial infarction cardiogenic shock. AB - OBJECTIVES: Recently, the initial therapy for refractory cardiogenic shock has largely been based on use of short-term mechanical devices with later conversion to durable options. The premise is that such patients cannot tolerate cardiopulmonary bypass and the extended surgery needed for implantable left ventricular assist device (LVAD) placement. We have adopted an alternative strategy to implant long-term LVADs as the initial device therapy in such patients. METHODS: Over a 3 year period, we used implantable LVADs (Jarvik 2000, one; Ventrassist, one; Heartmate XVE, two; and Heartmate II, nine) in 13 patients (11 men and two women; mean age 54 years) with postmyocardial infarction shock without prior use of a short-term LVAD. The median time interval from myocardial infarction to LVAD implantation was 3.5 days. Eight patients were on a ventilator, two had unknown neurological status and four had suffered cardiac arrest in the preceding 24 h. Two had prior coronary artery bypass graft. Nine had received dual antiplatelet therapy postmyocardial infarction. The mean laboratory value of creatinine was 1.5 mg/dl, alanine aminotransferase 748 U/l, international normalized ratio 1.5 and lactate 3.2 mmol/l. One procedure was carried out off pump; for the others, the mean cardiopulmonary bypass time was 72 min. Right ventricular assist devices were used in two cases and were later explanted. RESULTS: One patient died of progressive multiorgan failure. All others survived to hospital discharge. There were no re-explorations for bleeding or major infectious complications; two patients had perioperative stroke. The median duration of mechanical ventilation, intensive care unit stay and hospital stay was 3, 9 and 18 days, respectively. At 1 year, of the 12 survivors, eight have since had heart transplant, one patient underwent device explant, two remained alive on support and one died 7 months post-LVAD. CONCLUSIONS: Our data challenge the notion that patients in refractory cardiogenic shock are too ill to tolerate immediate placement of implantable LVADs. Despite the surgical challenges, a one-stop implantable LVAD approach for cardiogenic shock is feasible and may offer unique advantages over the bridge-to-bridge approach because it avoids the incremental costs, hospitalization and morbidity associated with repeated interventions. PMID- 23364854 TI - Reply to Ugur et al. PMID- 23364855 TI - Editorial comment: Acute myocardial infarction and refractory cardiogenic shock: the simpler, the better? PMID- 23364856 TI - Aortic valve replacement in a single coronary artery arising from the right Valsalva sinus. PMID- 23364857 TI - High risk of cardiovascular diseases after diagnosis of multiple sclerosis. AB - BACKGROUND: Studies of the risk of cardiovascular diseases (CVDs) in patients with multiple sclerosis (MS) have the potential to improve our understanding of the etiology of and the heterogeneity of prognosis and outcomes. OBJECTIVES: To investigate the risk of myocardial infarction (MI), stroke, heart failure (HF), and atrial fibrillation (AF) or Flutter in MS patients with different ethnicity, both female and male. METHODS: Using Poisson regression, we performed a nationwide study in Sweden to investigate the association between the diagnosis of MS and the risk of MI, stroke, HF, or AF/Flutter in 8281 patients who were hospitalized due to MS from 1987 through 2009, plus 76,640 matched control individuals. We performed stratified analyses by sex, age at follow-up and country of birth. RESULTS: Among MS patients, the incidence rate ratio for MI was 1.85 (95% confidence interval (CI) 1.59 to 2.15), for stroke was 1.71 (95% CI 1.46 to 2.00), for HF was 1.97 (95% CI 1.52 to 2.56) and for AF/Flutter was 0.63 (95% CI 0.46 to 0.87), as compared with individuals without MS. The increased risks were particularly prominent for women. These associations remained after stratification by sex, age and country of birth. CONCLUSION: We recommend careful surveillance and preventive CVDs measures among MS patients, particularly among the women. PMID- 23364858 TI - Prevalence and associated clinical characteristics of hepatitis B, C, and HIV infections among injecting drug users in Korea. AB - Injecting drug use is associated with an increased risk of blood-borne viral infections, such as hepatitis B and C viruses (HBV and HCV, respectively) and human immunodeficiency virus (HIV). However, their prevalence, virological characteristics, and associated factors are not clear among the injecting drug users in Korea. The aim of this study was to determine the prevalence of HBV, HCV, and HIV infection, as well as their virological and clinical characteristics of injecting drug users in South Korea. Between 2007 and 2010, 318 injecting drug users (89.3% male; mean +/- age 41.9 +/- 8.15 years) were participated. While HIV infection was not found, the seroprevalence of anti-HCV and HBV surface antigen (HBsAg) was 48.4% (n = 154) and 6.6% (n = 21), respectively. HBV/HCV co-infection was found in 4.1% (n = 13). Occult HBV infection was suggested in 5.0% (n = 16). Among the HCV genotypes, 1b (37.7%) and 2a/2c (35.7%) were mostly often detected. HCV RNA was detected in 98.1% (n = 151/154) and high-level viremia (HCV RNA level, >=400,000 IU/ml) were observed in 59.6% (n = 90/151). In multiple logistic regression analysis, old age (OR 1.18 per year, 95% CI = 1.09-1.27) and ever sharing injecting equipment (OR 4.17, 95% CI = 1.39-12.45) independently predicted HCV mono-infection. The prevalence of HBV and HCV infection were high but largely undiagnosed in the present sample of Korean injecting drug users. Strategic prevention, screening, and treatment are needed to reduce further transmission and morbidity. PMID- 23364859 TI - Sample size determination for testing equality in Poisson frequency data under an AB/BA crossover trial. AB - Assuming that the frequency of occurrence follows the Poisson distribution, we develop sample size calculation procedures for testing equality based on an exact test procedure and an asymptotic test procedure under an AB/BA crossover design. We employ Monte Carlo simulation to demonstrate the use of these sample size formulae and evaluate the accuracy of sample size calculation formula derived from the asymptotic test procedure with respect to power in a variety of situations. We note that when both the relative treatment effect of interest and the underlying intraclass correlation between frequencies within patients are large, the sample size calculation based on the asymptotic test procedure can lose accuracy. In this case, the sample size calculation procedure based on the exact test is recommended. On the other hand, if the relative treatment effect of interest is small, the minimum required number of patients per group will be large, and the asymptotic test procedure will be valid for use. In this case, we may consider use of the sample size calculation formula derived from the asymptotic test procedure to reduce the number of patients needed for the exact test procedure. We include an example regarding a double-blind randomized crossover trial comparing salmeterol with a placebo in exacerbations of asthma to illustrate the practical use of these sample size formulae. PMID- 23364860 TI - Cytologic and cystoscopic predictors of recurrence and progression in patients with low-grade urothelial carcinoma. AB - BACKGROUND: Patients with low-grade urothelial carcinoma (LGUC) are at risk of recurrence and must undergo lifelong surveillance. To date, cytology and cystoscopy are the gold standard for the detection of de novo and recurrent LGUC. The objective of the current study was is to further characterize the role of cytology and cystoscopy in determining the risk of recurrence and progression in these patients. METHODS: The authors retrospectively identified patients with LGUC who had urine cytology within 2 months of biopsy, and data were abstracted from their electronic charts. Electronic medical records were reviewed for cystoscopic findings and histologic and cytologic follow-up data over a 5-year period. Statistical analysis was performed with chi-square tests. RESULTS: In total, 76 patients were identified who had histologic follow-up material available, and 49% of those patients demonstrated progression or recurrence of urothelial carcinoma. The initial presence of multiple lesions on cystoscopy was associated with any recurrence or progression (67.7% vs 31%; P = .002), tumor size >2 cm was associated with initial positive or suspicious urine cytology (23.8% vs 3.7%; P = .076), and positive or suspicious initial cytology was associated with high-grade recurrence (58.3% vs 19.4%; P = .009). CONCLUSIONS: Cystoscopic findings, such as the presence of multiple lesions, together with concurrent positive or suspicious urine cytology, were associated with recurrence or progression of LGUC. These findings may help to identify high-risk patients. PMID- 23364861 TI - ["Sudden dyspnea: case report of a important differential diagnosis in ENT surgery"]. PMID- 23364862 TI - [Current practice of tumour endoscopy in German ENT-clinics]. AB - BACKGROUND: Second primary carcinomas (SPC) essentially influence therapy and the outcome in head and neck cancer. This study presents the current status of tumour endoscopy in German ENT-clinics. MATERIAL AND METHODS: A standardised questionnaire regarding indication, time of event, examined anatomical region and technique of tumour endoscopy was compiled, sent to all German ENT-clinics (n=159) and subsequently analysed. RESULTS: In 94-100% of the clinics, tumour endoscopy is being conducted when primary carcinoma lies within oral cavity, pharynx, larynx or is a CUP-syndrome. In 80%, 2-stage surgical procedure is preferred. Nasal cavity and tracheobronchial system (47%, 74%) are often not included in the examination. When primary cancer is seen, in 7% of the clinics a standardised biopsy of unsuspicious anatomic areas is conducted. In CUP-syndrome, unsuspicious surfaces within the pharynx do not undergo routine biopsy in 10-20% of the clinics. In tracheobronchoscopy (63.0%) and esophagoscopy (93.3%) rigid scopes are mainly used. 65% of the clinics conduct endoscopy as follow-up care. CONCLUSION: Practice of tumour endoscopy in German ENT-clinics is widespread but does not follow standardised mechanisms. Current international literature shows that there is no common consensus on value and techniques of tumour endoscopy, however, due to highly developed radiological diagnostics, risks of rigid endoscopies and unknown incidence of second primary tumours it is discussed more and more negative. To establish future guidelines, controlled studies or analysis of large populations seem to be necessary. PMID- 23364863 TI - [Development of an ICF-based clinical practice guideline for the assessment of function in head and neck cancer]. AB - BACKGROUND: Functional outcome following head and neck cancer is not regularly assessed in a standardized way in clinical practice. Clinical trials assessing functional outcome apply many different instruments. Therefore, results are not always comparable and have limited clinical implications. Aim of this study was the identification, interdisciplinary evaluation, and recommendation of functional outcome instruments for use in clinical practice and clinical trials in patients with HNC. MATERIAL: Preparatory studies came up with a shortlist of outcome instruments on the basis of previously determined criteria. An interdisciplinary expert group evaluated these instruments and decided on which ones can be recommended for use in 3 application areas: screening, therapy evaluation/planning, and clinical trials. Decision making health professionals included physicians (ENT and maxillofacial surgeons, radiotherapists, oncologists), medical psychologists, speech and language therapists, physiotherapists, and social workers. RESULTS: 98 instruments were presented at the consensus conference. Altogether 21 participants recommended for each of the 3 application areas a basic set of measures for the evaluation of impairment in 6 functional domains: follow-up therapy monitoring, pain, ingestion, voice/speaking, other organic problems, and psychosocial problems. CONCLUSION: A multi-professional expert's pool discussed and adopted recommendations for the use of functional outcome instruments in clinical praxis and/or in research. The re-commended instruments are now available for use in clinical routine. PMID- 23364864 TI - [Additional qualification in health economics--a pre-condition for ENT leadership positions?]. AB - BACKGROUND: The increasing medical-technical progress as well as the dramatic demographic changes cause problems with regard to rapid enlargement of medical service offers, allocation of resources and a financing shortfall in the German public health system. The economization in the German Health System can also be perceived in ENT departments. MATERIAL AND METHODS: After performing an internet search about the rapidly growing market for qualifications measures in health economics, we hence conducted an anonymous survey for ENT senior doctors and directors of the 34 German University Departments to evaluate their attitude towards, as well as their expectation of such an add-on qualification. RESULTS: Since the German government finalized the health care reform in the year 2000 such qualification measures rapidly developed: amongst others, 26 postgraduate, extra-occupational master programs have been inaugurated. The anonymous survey was answered by 105 ENT doctors (63 senior doctors, 27 vice professors and 15 directors). 63% out of these 105 colleagues considered such an add-on qualification to be mandatory. 41% of the colleagues were already "add-on qualified" in that field, only 10 of them by means of a study program. 71 of 105 colleagues (68%) considered the add-on qualification to be advantageous for their future personal career. With regard to the designated contents of the study program, "Staff Management" was even prioritized to "Hospital Financing" and "Cost Accounting". CONCLUSION: Aspects of management and a (health-) economical basic knowledge became an integral part of the daily routine for "first-line management doctors" also in (University) ENT-departments. PMID- 23364865 TI - Highly pure solid-state white-light emission from solution-processable soft hybrids. AB - Highly pure and solution processable white-light-emitting hybrids are presented. These soft-hybrids are designed by an organic-inorganic supramolecular co assembly in water. White-light emission is achieved by partial energy transfer (ET) between donor and acceptor molecules anchored on the inorganic component. The unique and remarkable processability feature of these hybrids is demonstrated by painting/writing onto large glass and flexible plastic substrates. PMID- 23364866 TI - Sensitivity of endoscopic screening for gastric cancer by the incidence method. AB - Although radiographic screening for gastric cancer has been conducted in Japan, it is anticipated that endoscopy will become a new screening method because of its high detection rate. The sensitivities of endoscopic and radiographic screening were calculated by the detection method and the incidence method based on the results of community-based screening in Japan. There were 56,676 screenings for gastric cancer using endoscopy and radiography from April 2002 to March 2007 in Yonago, Japan. The target age group was from 40 to 79 years. Screen detected and interval cancers were investigated based on a screening database linked to the Tottori Cancer Registry. All gastric cancers diagnosed within 1 year after a negative screen were considered interval cancers. Based on the screening history, these were divided into prevalence screening and incidence screening. Prevalence screenings included 7,388 for endoscopic screening and 5,410 for radiographic screening, whereas incidence screenings included 18,021 for endoscopic screening and 11,417 for radiographic screening. The sensitivity of prevalence screening calculated by the incidence method was 0.886 (95% confidence interval [CI] = 0.698-0.976) for endoscopic screening and 0.831 (95% CI = 0.586-0.964) for radiographic screening; however, the difference was not significant (p = 0.626). The sensitivity of incidence screening calculated by the incidence method was 0.954 (95% CI = 0.842-0.994) for endoscopic screening and 0.855 (95% CI = 0.637-0.970) for radiographic screening (p = 0.177). Endoscopic screening for gastric cancer had a higher sensitivity than radiographic screening by the incidence method in both screening rounds. However, further study is needed to evaluate mortality reduction and to estimate overdiagnosis with endoscopic screening for gastric cancer. PMID- 23364867 TI - Measurement of entropy production in living cells under an alternating electric field. AB - Entropy is a thermodynamic property toward equilibrium based on the dissipation of energy. Cells constitute such a thermodynamic system, in which entropy production is both inevitable and highly significant. Although the experimental measurement of entropy production in a cell is very difficult, a new method to accomplish this in living cells is reported herein. Through heating the sample by alternating electric fields and recording the heat flow from cells, the entropy production in two normal cell lines, MCF10A and HL-7702, and two cancerous cell lines, MDA-MB-231 and SMMC-7721, was measured and compared. The scaled electroinduced entropy production rate (SEEP) of cancer cells monotonically increases with electric field strength at 5-40 V/cm, while that of normal cells changes nonmonotonically with electric field strength, reaching a peak at 5-30 V/cm. For all cell lines, the cancerous-to-normal ratio of field-induced entropy production is clearly <1 in a large range of field strength from 5 to 25 V/cm. Therefore, this work presents an easy and effective strategy for experimentally investigating the thermodynamic properties of the cell, and gives deeper insight into the physical differences between normal and cancerous cells exposed to electric fields. PMID- 23364868 TI - Responding to the outbreak of invasive fungal infections: the value of public health to Americans. PMID- 23364869 TI - A carbone-stabilized two-coordinate phosphorus(III)-centered dication. PMID- 23364870 TI - Latent viral infections in young patients with inflammatory diseases treated with biological agents: prevalence of JC virus genotype 2. AB - Treatment with biological drugs is associated with increased susceptibility to viral infections. Reactivation of JC virus (JCV) and human cytomegalovirus (HCMV) in adults after therapy has been documented. The long-term effects of biological and conventional therapy on human herpesviruses and polyomaviruses infections in young patients were assessed. One hundred eighty-six samples [urine, serum, and blood cells (PBMCs)] from 62 patients (15.8 +/- 6.2 years old) with Crohn's disease, ulcerative rectocolitis or juvenile rheumatoid arthritis treated with immunotherapy or conventional therapy for over 12 months were tested by real time PCR. One hundred twenty-four samples (urine and blood) from 62 matched healthy volunteers (13.8 +/- 8.6 years old) were included as controls. Sequencing of the JCV viral protein 1 (VP1) and transcriptional control region (TCR) was performed. Herpes simplex virus 1/2 and varicella zoster virus genomes were not detected in any patients, whereas Epstein-Barr virus, HCMV, and human herpesvirus-6 genomes were detected in 4.8%, 3.2%, and 1.6% of the patients, respectively. JCV was detected in 22.6% (14/62) of urine samples from patients and in 8% (5/62) from controls, in 50% (7/14) of sera from patients shedding JCV, and in 71.4% (5/7) of matched PBMCs. There was a significant association between infliximab treatment and excretion of JCV genotype 2. Subclinical infection/reactivation of JCV genotype 2 in young patients during infliximab therapy was demonstrated. Conversely, increased susceptibility to herpesviruses infection was not shown. Future studies are warranted to investigate the effects of JCV reactivation on the health of young patients treated with infliximab. PMID- 23364871 TI - Restrictive right ventricular physiology after tetralogy of Fallot repair is associated with fibrosis of the right ventricular outflow tract visualized on cardiac magnetic resonance imaging. AB - AIMS: To determine whether the restrictive physiology seen in Tetralogy of Fallot (TOF) patients can be explained by fibrosis of the right ventricular (RV) outflow tract. The aetiology for restrictive RV physiology after TOF repair is not known. METHODS AND RESULTS: TOF patients (n = 31, 13 girls, 10.2 years +/- 2.8) were included 9.2 +/- 2.9 years after total correction and examined with cardiac magnetic resonance (CMR) and Doppler echocardiography. Cine, flow, and late gadolinium contrast enhanced (LGE) CMR imaging were performed to quantify RV volumes, pulmonary flow and regurgitation (PR), and fibrosis. Healthy children (n = 12) were investigated with CMR of the pulmonary flow. Forward flow during atrial contraction above mean + 2 SD of healthy subjects was set as a marker of restrictive physiology. Four patients were excluded due to suboptimal LGE-CMR. Fisher's exact test was used to determine the association between restrictive physiology and fibrosis. Sixteen patients showed fibrosis in the right ventricular outflow tract (RVOT) on LGE-CMR and 14 of them showed restrictive physiology on CMR. Of the 11 patients without fibrosis in the RVOT, 1 showed restrictive physiology. The odds ratio for RVOT fibrosis in patients with restrictive RV physiology was 70.0 (CI: 5.6-882.7, P < 0.001). The transannular patch repair did not differ between the groups (P = 0.37). The degree of RVOT fibrosis correlated positively with PR (r(2) = 0.38, P < 0.001) and RV volumes (r(2) = 0.51 for end-diastolic volume and r(2) = 0.47 for end-systolic volume, P < 0.001). CONCLUSION: There is a strong association between the restrictive RV physiology detected on CMR and fibrosis of the RVOT in children after TOF repair. PMID- 23364872 TI - Dopamine-modulated aversive emotion processing fails in alcohol-dependent patients. AB - Negative mood states after alcohol detoxification may enhance the relapse risk. As recently shown in healthy volunteers, dopamine storage capacity (V d) in the left amygdala was positively correlated with functional activation in the left amygdala and anterior cingulate cortex (ACC) during an emotional task; high functional connectivity between the amygdala and the ACC, a region important for emotion regulation, was associated with low trait anxiety. Based on these findings, we now tested whether detoxified alcohol-dependent patients have a disrupted modulation of the anterior cingulate cortex activation in response to aversive stimuli by amygdala dopamine. Furthermore, we asked whether disrupted functional coupling between amygdala and ACC during aversive processing is related to trait anxiety.We used combined 6-[18F]-fluoro-l-DOPA positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and Spielberger's state-trait anxiety questionnaire (STAI) in 11 male detoxified alcohol-dependent patients compared to 13 matched healthy controls.Unlike healthy controls, patients showed no significant correlation between our PET metric for dopamine storage capacity (FDOPA V d), in left amygdala and activation in left ACC. Moreover, the functional connectivity between amygdala and ACC during processing of aversive emotional stimuli was reduced in patients. Voxel-based morphometry did not reveal any discernible group differences in amygdala volume.These results suggest that dopamine-modulated corticolimbic circuit function is important for responding to emotional information such that apparent functional deficits in this neuromodulatory circuitry may contribute to trait anxiety in alcohol dependent patients. PMID- 23364873 TI - Parental perceived benefits of OROS-methylphenidate treatment for the child with attention-deficit/hyperactivity disorder and for parents themselves. AB - Given the shortage of studies on parental perceived benefits of OROS methylphenidate treatment in Asian populations, we assessed parental response to OROS-methylphenidate treatment of Korean children with attention deficit/hyperactivity disorder (ADHD), in relation to children's academic performance and behavioral symptoms as well as parental rearing stress and depressive symptoms.We enrolled 132 medication-naive children with ADHD into a multicenter, open-label, 12-week trial of OROS-MPH. The outcome measures were the ADHD rating scale-IV (ADHD-RS), the comprehensive attention test and academic performance rating scale, and the clinical global impression (CGI) severity/improvement instrument (for the children) and Beck depression inventory and parenting stress index (for their parents).We found parent-perceived improvements in children's ADHD-related behavioral symptoms and academic function and their parents' depressive symptoms and parenting stress. Investigator-rated ADHD symptoms and subjects' neuropsychological function were also improved (p<0.001).Parents of Korean children with ADHD perceive that OROS-methylphenidate treatment improves their children's academic function and behavior as well as their own child-rearing stress and emotional state. These findings must be interpreted with caution, due to a non-comparative open-label trial. PMID- 23364874 TI - Comparative study of epidermal growth factor receptor mutation analysis on cytology smears and surgical pathology specimens from primary and metastatic lung carcinomas. AB - BACKGROUND: The detection of epidermal growth factor receptor (EGFR) mutations on small biopsy or fine-needle aspiration samples is required to guide therapy in nonsmall cell lung cancer (NSCLC). In this study, the authors compared results from EGFR mutation testing on both cytologic smears and surgical specimens and also compared the performance of platforms using 2 different technologies (pyrosequencing and real-time polymerase chain reaction) for both specimen types. METHODS: Specimens from 114 patients were divided into 2 subsets. The first subset had 60 paired cytology smears and surgical specimens, including 37 paired specimens from the same site and 23 paired specimens from different sites. The second subset consisted of nonpaired cytology smears and formalin-fixed, paraffin embedded (FFPE) tissues (including 8 cell blocks), which were compared on the pyrosequencing and real-time polymerase chain reaction platforms. Laser-capture microscopy was used to enrich tumor in the FFPE specimens before DNA extraction. RESULTS: All cytology smears that were used in the study were adequate for analysis on both platforms. Comparison between smears and concurrent FFPE tissues from the same anatomic site had a concordance rate of 97%. The concordance rate between the pyrosequencing platform and the real-time polymerase chain reaction platform was 84% and 85% for FFPE tissues and cytology smears, respectively. CONCLUSIONS: The current results indicated that direct extraction and analysis of EGFR mutations from cytology smears can be performed successfully on both a pyrosequencing platform and a real-time polymerase chain reaction platform with results comparable to those achieved in matched surgical specimens. In fine needle aspiration/endobronchial ultrasound samples with limited tissue, cytology smears can be important for molecular analysis. Cancer (Cancer Cytopathol) 2013;121:361-369. (c) 2012 American Cancer Society. PMID- 23364875 TI - Pharmacological doses of melatonin induce alterations in mitochondrial mass and potential, bcl-2 levels and K+ currents in UVB-exposed U937 cells. AB - Apoptosis is observed in 'actively' dying cells after the exposure to cell stressors such as ultraviolet light irradiation. Since melatonin has been proposed to act under stressful conditions as cell protection factor, in this study we examined the potential of this molecule when used at pharmacological concentrations to control mitochondrial damage and apoptotic signalling of UVB irradiated U937 human leukaemic cells. Moreover, the effect of melatonin treatment on electrophysiological properties and membrane K(+) currents of irradiated U937 cells was investigated as functional aspects relevant to the anti apoptotic role of melatonin. The general effect is associated with the restoration of mass, number and membrane potential of mitochondria, with a lower caspase activation and bcl-2 upregulation. In the presence of the caspase inhibitor ZVAD-Fmk, melatonin seems to drive UVB stressed cells to follow the mitochondrial intrinsic pathway, interfering just at the mitochondrial level. Moreover, treatment with melatonin, as well as ZVAD-Fmk, prevented the K(+) current reduction observed late following the UVB insult application, by sparing cells from death; this result also indicates that the decrease of K(+) leakage currents could represent a functional feature of apoptotic process in UV-exposed U937 cells. PMID- 23364876 TI - Telomerase inhibitors from cyanobacteria: isolation and synthesis of sulfoquinovosyl diacylglycerols from Microcystis aeruguinosa PCC 7806. AB - By using the Telospot assay, 27 different extracts of cyanobacteria were evaluated for telomerase inhibition. All extracts showed varying, but significant activity. We selected Microcystis aeruguinosa PCC 7806 to identify the active compound and a bioassay guided fractionation led us to isolate mixtures of sulfoquinovosyl diacylglycerols (SQDGs), which were identified by 2D NMR and MS/MS experiments. Pure SQDG derivatives were then synthesized. The IC(50) values of pure synthetic sulfoquinovosyl dipalmitoylglycerol and the monopalmitoylated derivative against telomerase were determined to be 17 and 40 MUM, respectively. A structure-activity relationship study allowed the identification of compounds with modified lipophilic acyl groups that display improved activity. PMID- 23364877 TI - Summary of the HESI consortium studies exploring circulating inhibin B as a potential biomarker of testis damage in the rat. AB - The Developmental and Reproductive Toxicity Technical Committee of the Health and Environmental Sciences Institute hosted a working consortium of companies to evaluate a new commercially available analytic assay for Inhibin B in rat serum or plasma. After demonstrating that the kit was stable and robust, the group performed a series of independent pathogenesis studies (23 different compound/investigator combinations) designed to examine the correlation between the appearance of lesions in the testis and changes in circulating levels of Inhibin B. These studies were reported individually in the previous articles in this series (this issue), and are discussed in this paper. For roughly half of these exposures, lesions appeared well before Inhibin B changed. A few of the studies showed a good correlation between seminiferous tubule damage and reduced circulating Inhibin B levels, while for seven exposures, circulating Inhibin B was reduced with no detectable alteration in testis histology. Whether this indicates a prodromal response or a false-positive signal will require further investigation. These exceptions could plausibly suggest some value of circulating Inhibin B as a useful biomarker in some circumstances. However, for roughly half of these exposures, Inhibin B appeared to be a lagging biomarker, requiring significant damage to the seminiferous tubules before a consistent and credible reduction in circulating levels of Inhibin B was observed. PMID- 23364878 TI - Optimal recall period for caregiver-reported illness in risk factor and intervention studies: a multicountry study. AB - Many community-based studies of acute child illness rely on cases reported by caregivers. In prior investigations, researchers noted a reporting bias when longer illness recall periods were used. The use of recall periods longer than 2 3 days has been discouraged to minimize this reporting bias. In the present study, we sought to determine the optimal recall period for illness measurement when accounting for both bias and variance. Using data from 12,191 children less than 24 months of age collected in 2008-2009 from Himachal Pradesh in India, Madhya Pradesh in India, Indonesia, Peru, and Senegal, we calculated bias, variance, and mean squared error for estimates of the prevalence ratio between groups defined by anemia, stunting, and underweight status to identify optimal recall periods for caregiver-reported diarrhea, cough, and fever. There was little bias in the prevalence ratio when a 7-day recall period was used (<10% in 35 of 45 scenarios), and the mean squared error was usually minimized with recall periods of 6 or more days. Shortening the recall period from 7 days to 2 days required sample-size increases of 52%-92% for diarrhea, 47%-61% for cough, and 102%-206% for fever. In contrast to the current practice of using 2-day recall periods, this work suggests that studies should measure caregiver-reported illness with a 7-day recall period. PMID- 23364879 TI - Mortality risk score prediction in an elderly population using machine learning. AB - Standard practice for prediction often relies on parametric regression methods. Interesting new methods from the machine learning literature have been introduced in epidemiologic studies, such as random forest and neural networks. However, a priori, an investigator will not know which algorithm to select and may wish to try several. Here I apply the super learner, an ensembling machine learning approach that combines multiple algorithms into a single algorithm and returns a prediction function with the best cross-validated mean squared error. Super learning is a generalization of stacking methods. I used super learning in the Study of Physical Performance and Age-Related Changes in Sonomans (SPPARCS) to predict death among 2,066 residents of Sonoma, California, aged 54 years or more during the period 1993-1999. The super learner for predicting death (risk score) improved upon all single algorithms in the collection of algorithms, although its performance was similar to that of several algorithms. Super learner outperformed the worst algorithm (neural networks) by 44% with respect to estimated cross validated mean squared error and had an R2 value of 0.201. The improvement of super learner over random forest with respect to R2 was approximately 2-fold. Alternatives for risk score prediction include the super learner, which can provide improved performance. PMID- 23364880 TI - Second trimester fetal death caused by varicella-zoster virus infection. AB - A 31-year-old woman contracted acute varicella at 13 weeks of gestation. Severe hydrops fetalis, hepatomegaly, and intrauterine fetal death were detected at 16 weeks of gestation by ultrasound examinations. An examination at autopsy, histopathology, and polymerase chain reaction (PCR) provided evidence of varicella-zoster virus (VZV) infection of the fetus. Second trimester intrauterine fetal death caused by mother to fetus infection of VZV is extremely rare. PMID- 23364881 TI - Intercellular adhesion molecule-1 (ICAM-1) expression correlates with oral cancer progression and induces macrophage/cancer cell adhesion. AB - Intercellular adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein in the immunoglobulin superfamily, which plays an important role in cell adhesion and signal transduction. Although ICAM-1 is believed to play a role in several malignancies, it is still uncertain whether or not ICAM-1 expression contributes to cancer progression. In this study, we performed clinicopathological and cell biological analyses of ICAM-1 expression in oral squamous cell carcinoma (SCC). First, we examined the ICAM-1 expression in tongue SCC immunohistochemically, and revealed that ICAM-1 was expressed predominantly at the invasive front area of tongue SCC. ICAM-1 expression at the invasive front area was correlated with invasion, lymph node metastasis and increased blood and lymphatic vessel density of the tongue SCC. The relationship between ICAM-1 expression and clinicopathological factors were consistent with the increased proliferation, invasion and cytokine-production activities of ICAM-1-transfected SCC cells. Second, we analyzed the relationship between macrophages and ICAM-1-expressing tongue SCC cells because ICAM-1 is known to act as a ligand for adhesion of immune cells. Increased ICAM-1 expression in tongue SCC was correlated with increased macrophage infiltration within SCC nests. Moreover, macrophage/SCC-cell adhesion through ICAM-1 molecule was revealed using an in vitro cell adhesion and blockade assay. These findings indicate that ICAM-1 plays an important role in tongue SCC progression, which may result from the SCC-cell activity, angiogenic activity, lymphangiogenic activity and macrophage/SCC-cell adhesion. PMID- 23364882 TI - Can a gene-expression classifier with high negative predictive value solve the indeterminate thyroid fine-needle aspiration dilemma? AB - The recent study by Alexander et al validates the effectiveness of the Afirma test, and suggests a potential ancillary role for this unique test when appropriately applied in the evaluation of thyroid nodules classified by fine needle aspiration as indeterminate. PMID- 23364883 TI - Ferrocene and pentaphosphaferrocene: a comparative study regarding redox chemistry. PMID- 23364884 TI - Anti-inflammatory activity of Bromelia hieronymi: comparison with bromelain. AB - Some plant proteases (e. g., papain, bromelain, ficin) have been used as anti inflammatory agents for some years, and especially bromelain is still being used as alternative and/or complementary therapy to glucocorticoids, nonsteroidal antirheumatics, and immunomodulators. Bromelain is an extract rich in cysteine endopeptidases obtained from Ananas comosus. In this study the anti-inflammatory action of a partially purified extract of Bromelia hieronymi fruits, whose main components are cysteine endopeptidases, is presented. Different doses of a partially purified extract of B. hieronymi were assayed on carrageenan-induced and serotonine-induced rat paw edema, as well as in cotton pellet granuloma model. Doses with equal proteolytic activity of the partially purified extract and bromelain showed significantly similar anti-inflammatory responses. Treatment of the partially purified extract and bromelain with E-64 provoked loss of anti inflammatory activity on carrageenan-induced paw edema, a fact which is consistent with the hypothesis that the proteolytic activity would be responsible for the anti-inflammatory action. PMID- 23364885 TI - Single oral dose pharmacokinetics of decursin, decursinol angelate, and decursinol in rats. AB - Decursin and decursinol angelate are the major components in the alcoholic extract of the root of Angelica gigas Nakai. Our previous work convincingly demonstrated that both decursin and decursinol angelate were rapidly converted to decursinol in mice after administration by either oral gavage or i. p. injection. In the current study, we compared for the first time the plasma profiles of decursinol, when equal moles of decursin/decursinol angelate or decursinol were given to rats by oral gavage, and investigated the effect of different formulas and other chemicals in Angelica gigas extract on the bioavailability of decursinol. Our results show that gavage of decursinol led to a faster attainment of plasma decursinol peak (Tmax ~ 0.7 h) and much higher peak levels than an equal molar amount administered as decursin/decursinol angelate mixture or as Angelica gigas ethanol extract, resulting in 2-3 fold higher bioavailability as estimated by the area under the curve of the respective regimens (65 012 vs. 27 033 h . ng/mL for decursinol and decursin/decursinol angelate treatment groups, respectively). Compared to a formula based on ethanol-PEG400-Tween80, carboxyl methyl cellulose was a less optimized vehicle. In addition, we detected peak levels of decursin and decursinol angelate in the plasma of rats administered with decursin/decursinol angelate or Angelica gigas extract in the nM range (Tmax ~ 0.5 h) with a newly established sensitive UHPLC-MS/MS method. Furthermore, our data support the liver, instead of intestine, as a major organ site where decursin and decursinol angelate were hydrolyzed to decursinol with a S9 microsomal in vitro metabolism assay. Taken together, our study provided important PK, LC-MS/MS methodology, formulation and metabolism insights in a rodent model for the rational design of in vivo efficacy studies of the corresponding chemicals in the future. PMID- 23364886 TI - Heracleifolinosides A-F, new triterpene glycosides from Cimicifuga heracleifolia, and their inhibitory activities against hypoxia and reoxygenation. AB - Six new 9,19-cycloartane triterpene glycosides, heracleifolinosides A-F (1-6), and one new chromone, norkhelloside (7), were isolated from the rhizome of Cimicifuga heracleifolia, together with 15 known compounds (8-22). The structures of the new compounds were elucidated by means of spectroscopic methods including 2D NMR and mass spectrometry. The extracts of C. heracleifolia and all the isolated compounds were tested for activities against hypoxia and reoxygenation injury in human umbilical vein endothelial cells. Heracleifolinoside B (2) is effectively resistant to hypoxia and reoxygenation-induced human umbilical vein endothelial cell injury, with cell viabilities of 61.95 +/- 2.04 %, 77.04 +/- 4.44 %, and 83.65 +/- 3.29 % at concentrations of 1, 10, and 100 uM, respectively. PMID- 23364887 TI - Evidence of chondrocyte turnover in lung cartilage, with the probable participation of nestin-positive cells. AB - Healthy adult cartilage is thought to have little or no capacity to renewal, and cell turnover has not been reported in lung cartilage. We report that chondrocyte turnover occurs in lung cartilage, found in an unrelated study. Lung specimens from CD1 mice of 2, 6, 12, 18 or 24 months were fixed in 10% neutral-buffered formalin and paraffin-embedded. Apoptosis was analysed by in situ end-labelling of fragmented DNA. Proliferating cell nuclear antigen (PCNA) and nestin were examined by immunohistochemistry. Apoptosis and PCNA were detected in lung chondrocytes. Serial section analysis showed that cells in apoptosis were different from PCNA-positive cells, indicating that turnover was occurring. Chondrocytes were negative for nestin. Nestin-positive cells were present in connective tissue associated with cartilage, in some specimens in close proximity of it and in perivascular cells. Thus cell turnover in lung cartilage is possible, which may be mediated by nestin-positive cells. PMID- 23364888 TI - Assessment of inhibin B as a biomarker of testicular injury following administration of carbendazim, cetrorelix, or 1,2-dibromo-3-chloropropane in Wistar han rats. AB - Although histopathology is considered the gold standard for assessing testicular toxicity in the nonclinical setting, identification of noninvasive biomarkers for testicular injury are desirable to improve safety monitoring capabilities for clinical trials. Inhibin B has been investigated as a noninvasive biomarker for testicular toxicity. This study investigates the correlation of Inhibin B in Wistar Han rats with the onset and reversibility of testicular histopathology from classical testicular toxicants carbendazim, cetrorelix acetate (CTX), and 1,2-dibromo-3-chloropropane (DBCP). The dose regimen included Interim (day 8), Drug (day 29), and nondosing Recovery (day 58) Phases. Inhibin B was not effective at predicting the onset of carbendazim- or CTX-mediated testicular pathology in rats. Inhibin B was reduced by DBCP administration at the end of the Drug Phase only, acting as a leading indicator of the onset of testicular toxicity before the onset of germ cell depletion. However, since Inhibin B was only decreased at the end of the Dosing Phase and not at the Recovery Phase, when the onset of testicular pathology occurred, it is unclear if monitoring Inhibin B would provide sufficient advanced warning for the onset of testicular pathology. Furthermore, follicle stimulating hormone was decreased following CTX and DBCP administration in the Interim Phase and CTX in the Drug Phase. Inhibin B has limited predictive capacity as a leading testicular biomarker in rats. PMID- 23364889 TI - An automatic molecular dispenser of chloride. AB - The combined activity of the 1.1.1-cryptand and of a dicopper(II) bistren cryptate complex including chloride makes the Cl(-) ion be continuously and slowly delivered to the solution, without any external intervention. The 1.1.1 cryptand slowly releases OH(-) ions, according to a defined kinetics, and each OH(-) ion displaces a Cl(-) ion from the cryptate. Chloride displacement induces a sharp colour change from bright yellow to aquamarine and can be conveniently monitored spectrophotometrically, even in diluted solutions. The 1.1.1-cryptand is the motor of a molecular dispenser (the dicopper(II) cryptate) delivering chloride ion automatically, from the inside of the solution. PMID- 23364890 TI - Influence of gait training and prosthetic foot category on external work symmetry during unilateral transtibial amputee gait. AB - BACKGROUND: Prosthetic foot prescription guidelines lack scientific evidence and are concurrent with an amputee's concurrent with an amputee's Medicare Functional Classification Level (K-Level) and categorization of prosthetic feet. OBJECTIVE: To evaluate the influence of gait training and four categories of prosthetic feet (K1, K2, K3, and microprocessor ankle/foot) on Symmetry in External Work for K Level-2 and K-Level-3 unilateral transtibial amputees. DESIGN: Randomized repeated-measures trial. METHODS: Five K-Level-2 and five K-Level-3 subjects were tested in their existing prosthesis during Session 1 and again in Session 2, following 2 weeks of standardized gait training. In Sessions 3-6, subjects were tested using a study socket and one of four randomized test feet. There was an accommodation period of 10-14 days with each foot. Symmetry in External Work for positive and negative work was calculated at each session to determine symmetry of gait dynamics between limbs at self-selected walking speeds. RESULTS: K-Level 2 subjects had significantly higher negative work symmetry with the K3 foot, compared to K1/K2 feet. For both subject groups, gait training had a greater impact on positive work symmetry than test feet. CONCLUSION: Higher work symmetry is possible for K-Level-2 amputees who are trained to take advantage of K3 prosthetic feet designs. There exists a need for an objective determinant for categorizing and prescribing prosthetic feet. PMID- 23364891 TI - Comparison of human first and third trimester placental mesenchymal stem cell. AB - Placenta mesenchymal stem cells (PMSCs) have the characteristic features of stem cells including renewability in vitro, surface expression, differentiation potency and ability to adhere to the culture surface. PMSCs expressed genes are normally found in the embryonic tissues before the onset of gastrulation, indicating multipotency. However, the stemness can depend on the stages of the placenta from which the cells were isolated. PMSCs were isolated from two different stages of placenta for comparison, that is the first and third trimesters. Both sets had very similar patterns of surface expression as CD44, CD73, CD90 and CD105, and of self renewability in vitro. Expressions of pluripotency-coupled genes were also confirmed in both sets of cells; however, there was a significant difference in the expression levels: fPMSC (mesenchymal stem cells isolated from the first trimester human placenta) being 2-11-fold higher than tPMSC (mesenchymal stem cells isolated from the third trimester human placenta). Possibly due to the difference in the expression levels of the pluripotency-related genes, induction of genes specific to the ectodermal tissues were more prominent in fPMSC than tPMSC after induced differentiation. PMID- 23364892 TI - Reactions of arynes with nitrosoarenes--an approach to substituted carbazoles. PMID- 23364893 TI - EBV counteracts IL-21-induced apoptosis in an EBV-positive diffuse large B-cell lymphoma cell line. AB - Previously, interleukin (IL)-21 has been found to induce apoptosis by activating the signal transducer and activator of transcription 3 (STAT3) and concomitant upregulation of c-Myc in diffuse large B-cell lymphoma (DLBCL) lines with unknown Epstein-Barr virus (EBV) status. Here, as a first approach toward the characterization of the role of EBV in DLCBL, the EBV gene expression and the IL 21 sensitivity of the EBV-positive DLBCL line, Farage, have been examined. It was found that, surprisingly, despite c-Myc upregulation, IL-21 induced cell proliferation rather than apoptosis in Farage. Expression of a dominant-negative EBNA1 mutant and the consecutive downregulation of EBV gene expression antagonized the IL-21-induced proliferation of Farage and increased apoptosis. These findings reveal a previously unknown role of EBV in DLBCL that is of possible relevance for the current attempt to use IL-21 in therapy. PMID- 23364894 TI - Virtual microscopy is a superior and reputable pedagogical tool for histology learning: response to Xu. PMID- 23364895 TI - NF-KB activity functions in primary pericytes in a cell- and non-cell-autonomous manner to affect myotube formation. AB - INTRODUCTION: Skeletal muscle regeneration following damage relies on proliferation and differentiation of muscle precursor cells (MPCs). We recently observed increased NF-kB activity in vascular-associated muscle resident pericytes following muscle damage in humans. We determined how altered NF-kB activity in human primary pericytes (HPPs) affects their myogenic differentiation (cell-autonomous effects), as well as proliferation and differentiation of co cultured MPCs (non-cell-autonomous effects). METHODS: HPPs were transfected with vectors that increased or decreased NF-kB activity. Transfected HPPs were co cultured with C2 C12 myoblasts under differentiation conditions, and HPP fusion to myotubes was measured. We also co-cultured HPPs with C2 C12 myoblasts and measured proliferation and myotube formation. RESULTS: Inhibition of NF-kB activity increased HPP fusion to C2 C12 myotubes. Moreover, enhanced NF-kB activity in HPPs suppressed differentiation and enhanced proliferation of co cultured myoblasts. CONCLUSIONS: NF-kB activity acts cell-autonomously to inhibit HPP myogenic differentiation and non-cell-autonomously to promote MPC proliferation and suppress MPC differentiation in vitro. PMID- 23364896 TI - Incorporation of bioactive glass in calcium phosphate cement: material characterization and in vitro degradation. AB - Calcium phosphate cements (CPCs) have been widely used as an alternative to biological grafts due to their excellent osteoconductive properties. Although degradation has been improved by using poly(D,L-lactic-co-glycolic) acid (PLGA) microspheres as porogens, the biological performance of CPC/PLGA composites is insufficient to stimulate bone healing in large bone defects. In this context, the aim of this study was to investigate the effect of incorporating osteopromotive bioactive glass (BG; up to 50 wt %) on setting properties, in vitro degradation behavior and morphological characteristics of CPC/BG and CPC/PLGA/BG. The results revealed that the initial and final setting time of the composites increased with increasing amounts of incorporated BG. The degradation test showed a BG-dependent increasing effect on pH of CPC/BG and CPC/PLGA/BG pre set scaffolds immersed in PBS compared to CPC and CPC/PLGA equivalents. Whereas no effects on mass loss were observed for CPC and CPC/BG pre-set scaffolds, CPC/PLGA/BG pre-set scaffolds showed an accelerated mass loss compared with CPC/PLGA equivalents. Morphologically, no changes were observed for CPC and CPC/BG pre-set scaffolds. In contrast, CPC/PLGA and CPC/PLGA/BG showed apparent degradation of PLGA microspheres and faster loss of integrity for CPC/PLGA/BG pre set scaffolds compared with CPC/PLGA equivalents. Based on the present in vitro results, it can be concluded that BG can be successfully introduced into CPC and CPC/PLGA without exceeding the setting time beyond clinically acceptable values. All injectable composites containing BG had suitable handling properties and specifically CPC/PLGA/BG showed an increased rate of mass loss. Future investigations should focus on translating these findings to in vivo applications. PMID- 23364897 TI - Is magnetic resonance imaging reliable in predicting clinical outcome after articular cartilage repair of the knee? A systematic review and meta-analysis. AB - BACKGROUND: While MRI can provide a detailed morphological evaluation after articular cartilage repair, its additional value in determining clinical outcome has yet to be determined. PURPOSE: To evaluate the correlation between MRI and clinical outcome after cartilage repair and to identify parameters that are most important in determining clinical outcome. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A systematic search was performed in Embase, MEDLINE, and the Cochrane Collaboration. Articles were screened for relevance and appraised for quality. Guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) Statement were used. Chi-square tests were performed to find variables that could determine correlation between clinical and radiological parameters. RESULTS: A total of 32 articles (total number of patients, 1019) were included. A majority (81%) were case series or cohort studies that used similar standardized MRI techniques. The mean Coleman score was 63 (range, 42-96). For the majority of MRI parameters, limited or no correlation was found. Nine studies (28%) found a correlation between clinical outcome and the composite magnetic resonance observation of cartilage repair tissue (MOCART) or Henderson score and 7 (22%) with defect fill. In 5 studies, a weak to moderate correlation was found between clinical outcome and the T2 index (mean Pearson coefficient r = .53). CONCLUSION: Strong evidence to determine whether morphological MRI is reliable in predicting clinical outcome after cartilage repair is lacking. Future research aiming specifically at clinical sensitivity of advanced morphological and biochemical MRI techniques after articular cartilage repair could be of great importance to the field. PMID- 23364898 TI - Elevated nuclear S100P expression is associated with poor survival in early breast cancer patients. AB - S100P - low molecular weight acidic protein has been shown to be involved in processes of proliferation, survival, angiogenesis, multidrug resistance and metastasis in various human malignancies. In breast cancer, S100P expression is associated with immortalization of neoplastic cells and aggressive tumour behaviour, indicating that this protein may have adverse prognostic value. We analyzed nuclear and cytoplasmic expression of S100P in 85 stage II breast cancer patients with a median follow up of 17 years. Immunohistochemical reactions were performed on paraffin sections of primary tumours, using monoclonal antibodies against S100P. We also studied prognostic value of S100P mRNA expression using the KM plotter which assessed the effect of 22,277 genes on survival in 2422 breast cancer patients. Moreover, the relationship was examined between expression of S100P in cells of four breast cancer cell lines and their sensitivity to the 11 most frequently applied cytotoxic drugs. Univariate and multivariate analyses showed that higher expression of nuclear S100P (S100Pn) was typical for cases of a shorter overall survival and disease-free time. KM plotter analysis showed that elevated S100P expression was specific for cases of a relapse-free survival and distant metastases-free survival. No relationship could be documented between expression of S100P and sensitivity of breast cancer cells to cytostatic drugs. We demonstrated that a high S100Pn expression level was associated with poor survival in early stage breast cancer patients. Since preliminary data indicated that expression of S100P was up-regulated by activation of glucocorticoid receptor and several agents manifested potential to activate or inhibit S100P promoter activity, this protein might become a therapy target and warrants further studies with respect to its prognostic, predictive and potentially therapeutic value. PMID- 23364899 TI - On the mechanism of the dehydroaromatization of hexane to benzene by an iridium pincer catalyst. AB - The developments in the area of transition-metal pincer complexes have opened up new avenues for conversion of saturated hydrocarbons to more useful aromatic compounds under homogeneous reaction conditions. In the backdrop of an interesting series of conversions of unbranched alkanes to benzene, toluene, and xylene (known as the BTX family aromatics) reported by Goldman and co-workers (Nature Chem. 2011, 3, 167), we herein present a comprehensive mechanistic picture obtained by using density functional computations. The reaction involves an iridium-PCP-pincer-catalyzed dehydroaromatization of hexane to benzene (in which PCP=eta(3) -C6 H3 (iPrP)2 -1,3) by using tert-butylethylene (TBE) as a sacrificial acceptor. The most energetically preferred pathway for a sequence of dehydrogenations is identified to begin with a terminal C?H bond activation of n hexane leading to the formation of hex-1-ene. Although the initial dehydrogenation of n-hexane was found to be endergonic, the accompanying exoergic hydrogenation of TBE to tert-butylethane (TBA) compensates the energetics to keep the catalytic cycle efficient. Subsequent dehydrogenations provide a hexa-1,3 diene and then a hexa-1,3,5-triene. The pincer bound triene is identified to undergo cyclization to furnish cyclohexadiene. Eventually, dehydrogenation of cyclohexa-1,3-diene offers benzene. In the most preferred pathway, the Gibbs free energy barrier for cyclization leading to the formation of cyclohexa-1,3-diene is found to exhibit the highest barrier (21.7 kcal mol(-1) ). PMID- 23364901 TI - Enantioselective copper-catalyzed intramolecular phenolic O-H bond insertion: synthesis of chiral 2-carboxy dihydrobenzofurans, dihydrobenzopyrans, and tetrahydrobenzooxepines. AB - Efficient: A copper-catalyzed enantioselective intramolecular insertion of carbenoids into phenolic O-H bonds has been developed. This method can be used for the synthesis of the title compounds in high yields and excellent enantioselectivities under mild and neutral conditions. NaBAr(F)=sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. PMID- 23364900 TI - Concordant hypermethylation of intergenic microRNA genes in human hepatocellular carcinoma as new diagnostic and prognostic marker. AB - Epigenetic inactivation by aberrant DNA methylation has been reported for many microRNA genes in various human malignancies. However, relatively little is known about microRNA gene methylation in hepatocellular carcinoma (HCC). Therefore, a systematic screen for identification of aberrantly hypermethylated microRNA genes in HCC was initiated. The methylation status of 39 intergenic CpG island associated microRNA genes was analyzed in HCC cell lines (n = 7), immortalized hepatocytes (n = 2) and normal liver samples (n = 5). Subsequently, 13 differentially methylated microRNA genes were analyzed in primary human HCC samples (n = 40), benign liver tumors (n = 15) and the adjacent liver tissues employing pyrosequencing. Expression of microRNA genes was measured using quantitative real-time polymerase chain reaction (RT-PCR). In addition, DNA methylation and expression of microRNA genes were measured after DNMT1 knockdown or DNMT inhibition. Aberrant hypermethylation and concomitant reduction in expression of intergenic microRNA genes is a frequent event in human HCC: hsa-mir 9-2 (23%), hsa-mir-9-3 (50 %), hsa-mir-124-1 (20%), hsa-mir-124-2 (13%), hsa-mir 124-3 (43%), hsa-mir-129-2 (58%), hsa-mir-596 (28%) and hsa-mir-1247 (38%). Altogether, it affects 90% of the HCC specimens under study. MicroRNA gene methylation is not found in hepatocellular adenoma (n = 10) and focal nodular hyperplasia (n = 5). DNMT1 knockdown or DNMT inhibition reduced microRNA gene methylation and stimulated expression. In primary human HCC specimens hypermethylation and expression of microRNA genes showed an inverse correlation. Concordant hypermethylation of three or more microRNA genes is a highly specific marker for the detection of HCC and for poor prognosis. PMID- 23364902 TI - Mesenchymal stem cells of human placenta and umbilical cord suppress T-cell proliferation at G0 phase of cell cycle. AB - Mesenchymal stem cells (MSC) generated from human umbilical cord (UC-MSC) and placenta (PLC-MSC) were assessed and compared for their immunomodulatory function on T cells proliferation by analysis of the cell cycle. Mitogen stimulated or resting T cells were co-cultured in the presence or absence of MSC. T-cell proliferation was assessed by tritiated thymidine ((3) H-TdR) assay and the mechanism of inhibition was examined bycell cycle and apoptosis assay. Both UC MSC and PLC-MSC profoundly inhibited the proliferation of T-cell, mainly via cell to-cell contact. MSC-mediated anti-proliferation does not lead to apoptosis,but prevented T cells from entering S phase and they therefore accumulated in the G(0) /G(1) phases. The anti-proliferative activity of MSC was related to this cell cycle arrest of T-cell. UC-MSC produced a greater inhibition than PLC-MSC in all measured parameters. PMID- 23364903 TI - A specialist, second-tier response to out-of-hospital cardiac arrest: setting up TOPCAT2. AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is the most common, immediately life-threatening, medical emergency faced by ambulance crews. Survival from OHCA is largely dependent on quality of prehospital resuscitation. Non-technical skills, including resuscitation team leadership, communication and clinical decision-making are important in providing high quality prehospital resuscitation. We describe a pilot study (TOPCAT2, TC2) to establish a second tier, expert paramedic response to OHCA in Edinburgh, Scotland. METHODS: Eight paramedics were selected to undergo advanced training in resuscitation and non technical skills. Simulation and video feedback was used during training. The designated TC2 paramedic manned a regular ambulance service response car and attended emergency calls in the usual manner. Emergency medical dispatch centre dispatchers were instructed to call the TC2 paramedic directly on receipt of a possible OHCA call. Call and dispatch timings, quality of cardiopulmonary resuscitation and return-of-spontaneous circulation were all measured prospectively. RESULTS: Establishing a specialist, second-tier paramedic response was feasible. There was no overall impact on ambulance response times. From the first 40 activations, the TC2 paramedic was activated in a median of 3.2 min (IQR 1.6-5.8) and on-scene in a median of 10.8 min (8.0-17.9). Bimonthly team debrief, case review and training sessions were successfully established. OHCA attended by TC2 showed an additional trend towards improved outcome with a rate of return of spontaneous circulation of 22.5%, compared with a national average of 16%. CONCLUSIONS: Establishing a specialist, second-tier response to OHCA is feasible, without impacting on overall ambulance response times. Improving non-technical skills, including prehospital resuscitation team leadership, has the potential to save lives and further research on the impact of the TOPCAT2 pilot programme is warranted. PMID- 23364904 TI - A woman with sudden-onset facial oedema. PMID- 23364905 TI - The development and assessment of an online microscopic anatomy laboratory course. AB - Increasing enrollment in post-secondary institutions across North America, along with an increase in popularity of and demand for distance education is pressuring institutions to offer a greater number and variety of courses online. A fully online laboratory course in microscopic anatomy (histology) which can be taught simultaneously with a face-to-face (F2F) version of the same course has been developed. This full year course was offered in the Fall/Winter (FW) terms in both F2F and online formats. To ensure that the online course was of the same quality as the F2F format, a number of performance indicators were evaluated. The same course, offered exclusively online during the summer with a compressed time frame, was also evaluated. Senior undergraduate students self-selected which version of the course they would enroll in. Course assessment outcomes were compared while incoming grades were used as a predictor for course performance. There were no significant differences between the incoming grades for the F2F FW and Online FW courses; similarly, there were no significant differences between outcomes for these formats. There were significant differences between the incoming grades of the F2F FW and Summer Online students. However, there were no significant differences among any of the outcomes for any of the formats offered. Incoming grades were strong, significant predictors of course performance for both formats. These results indicate that an online laboratory course in microscopic anatomy is an effective format for delivering histology course content, therefore giving students greater options for course selections. PMID- 23364906 TI - Autoimmune neuromyotonia following human papilloma virus vaccination. PMID- 23364907 TI - Anthropometrics, body shape over 12 years and risk of cancer events in pre- and post-menopausal women. AB - Studies of anthropometry and cancer have focused on body mass index (BMI). Relations between weight, waist (WC) and hip circumferences (HC), birth length and adult height with cancer are less well studied. Women from the French E3N study, born between 1925 and 1950, were followed biennially from 1995 until 2008. Body shape was classed into four groups based on median WC and HC at baseline. Hazard ratios (HRs) were estimated by Cox proportional hazards regression models. Over the 12 years of follow-up, 7,247 of 63,798 women developed cancer. As WC increased, we found a trend for decreasing cancer risk in pre-menopausal women, which reversed to an increasing risk in post-menopausal women. This remained unchanged after further adjustment for HC /or height [HR: 0.72 (0.52-1.00) before menopause and 1.17 (1.04-1.31) in the 5th vs. 1st quintile of HC], and were similar after exclusion of breast cancer. We showed that large body shape decreased cancer risk before menopause and increased it after [HR: 0.87 (0.73 1.02) and 1.11 (1.04-1.17), respectively, in women with large waist and hips compared to small waist and hips]. Adult height was associated with an non significant increase in cancer in pre-menopause and a significant cancer risk in menopause, independent of other anthropometric characteristics [5th vs. 1st quintile [HR: 1.24 (0.98-1.56) and 1.20 (1.10-1.30)], respectively as was long birth length in post-menopausal women [HR: 1.18 (1.07-1.30) compared to medium birth length]. These results suggest independent roles of height and WC on cancer risk, through different pathways. PMID- 23364908 TI - Templating irreversible covalent macrocyclization by using anions. AB - Inorganic anions were used as templates in the reaction between a diamine and an activated diacid to form macrocyclic amides. The reaction conditions were found to perform the macrocyclization sufficiently slow to observe a template effect. A number of analytical methods were used to clarify the reaction mechanisms and to show that the structure of the intermediate plays a decisive role in determining the product distribution. For the macrocyclization under kinetic control, it was shown that the amount of a template, the conformational rigidity of building blocks, and the anion affinities of reaction components and intermediates are important parameters that one should take into consideration to achieve high yields. PMID- 23364909 TI - Graft copolymer polyelectrolyte complexes for delivery of cationic antimicrobial peptides. AB - Peptides have enormous potential as therapeutic agents for the treatment of infection, in immunomodulation and for other medical applications, but their hydrolytic degradation in biological fluids is a serious limitation to their in vivo performance. Here we demonstrate the potential utility of polyelectrolyte nanoparticle complexes of novel self-assembling anionic graft copolymers for protecting peptides from degradation in human plasma. The anionic graft copolymers are synthesized by covalently attaching pendent polyetheramine chains to poly(alkylacrylic acid) backbones by carbodiimide coupling. The peptide:copolymer nanocomplexes' particle size, zeta-potential, peptide binding, and controlled release of the peptide are shown to be dependent upon the pendent chain graft density, polymer backbone alkyl groups (propyl vs. methyl), and the nanocomplexes' electrostatic charge ratio. The nanocomplexes can provide substantial protection to the bound peptides from degradation in human plasma for at least 24 h and, in standard microbiological assays are shown to retain some or all of the peptide's antimicrobial activity against a clinically relevant strain of Staphylococcus aureus. PMID- 23364911 TI - Direct selective oxidative cross-coupling of simple alkanes with heteroarenes. PMID- 23364910 TI - Gut hormone activity of children born to women with and without gestational diabetes. AB - What is already known about this subject Children born to women with gestational diabetes have greater risk for obesity. Obesity in adults and children is associated with blunted postprandial gut hormone responses. What this study adds Children of women with gestational diabetes have a blunted postprandial response of GLP-1. Children of women with gestational diabetes have high fasting PYY concentrations. BACKGROUND: Intrauterine exposure to gestational diabetes mellitus (GDM) increases risk for obesity. Obesity is associated with a blunted postprandial gut hormone response, which may impair satiety and thereby contribute to weight gain. The postprandial response of gut hormones among children of women with GDM has not previously been investigated. OBJECTIVE: To examine whether children of women with GDM have suppressed peptide-tyrosine tyrosine (PYY) and glucagon-like-peptide-1 (GLP-1), and higher concentrations of ghrelin, following a meal challenge. A secondary objective was to investigate associations of these hormones with children's free-living energy intake. METHODS: Children (n = 42) aged 5-10 years were stratified into two groups: offspring of GDM mothers (OGD) and of non-diabetic mothers (CTRL). Body composition was measured by dual-energy X-ray absorptiometry, and circulating PYY, GLP-1 and total ghrelin were measured during a liquid meal challenge. Energy intake was assessed by three 24-h diet recalls. RESULTS: Between-groups analyses of fasting and incremental area under the curve (AUC) found no differences in ghrelin. Incremental AUC for GLP-1 was greater among the CTRL vs. OGD (P < 0.05), and fasting PYY, but not incremental AUC, was higher among OGD vs. CTRL (P < 0.01). Associations of fasting and incremental AUC for each gut hormone with children's usual energy intake did not differ significantly by group. CONCLUSIONS: Further research is needed to more fully examine the potential role of postprandial GLP-1 suppression and high-fasting PYY concentrations on the feeding behaviour and risk for obesity among children exposed to GDM in utero. PMID- 23364912 TI - Detection and comparison of cut-off values for total AgNOR area/nuclear area and AgNOR number/nucleus in benign thyroid nodules and normal thyroid tissue. AB - Argyrophilic nucleolar organising region associated proteins (AgNORs) are of interest in a variety of diseases including thyroid disorders. We have investigated the cut-off values for AgNOR count and with a new approach, Total AgNOR area/nuclear area (TNORa/Na) proportions to discriminate thyrocytes obtained from benign thyroid nodules and normal thyroid tissue. Thirty patients whose fine needle aspiration (FNA) materials were compatible with a benign lesion (named as goiter group) and 30 controls (subjects with normal thyroid tissue) were included. In the control group, biopsy material was obtained from histologically normal thyroid gland operated on because FNA material was compatible with papillary thyroid carcinoma (PTC). These samples were stained for AgNOR and 100 nuclei per individual were examined. Both AgNOR values for individual cells and cut-off values were detected for each group. Patients with goiter had significantly (P<0.001) higher AgNOR count (2.1 +/- 0.6%) and TNORa/Na (6.1 +/- 1.5%) than the control groups (1.4 +/- 0.2 and 3.0 +/- 0.4, respectively). The cut-off values were <1.5 for AgNOR count and <3.8 for TNORa/Na in thyrocytes of the controls. This modified method is an easy and reliable method for discriminating various thyroid disorders, including the differentiation of benign thyroid nodules from malignant ones. It also helps to discriminate thyrocytes obtained from benign nodules from normal thyroid tissue, aiding accurate localisation of sampling in FNA material. PMID- 23364914 TI - Impact of complications on long-term survival after resection of colorectal liver metastases. AB - BACKGROUND: Postoperative complications may have an adverse effect not only on short-term but also long-term outcome among patients having surgery for cancer. A retrospective series of patients who had surgery for colorectal liver metastases (CLM) was used to assess this association. METHODS: Patients who had surgery with curative intent for CLM from 2000 to 2009 were included. The impact of postoperative complications, patient characteristics, disease stage and treatment on long-term survival was analysed using multivariable Cox regression models. RESULTS: A total of 251 patients were included. The median age was 58 (interquartile range 51-68) years and there were 87 women (34.7 per cent). A minor or major postoperative complication developed in 41 and 14 patients respectively, and five patients (2.0 per cent) died after surgery. The 5-year recurrence-free (RFS) and overall survival rates were 19.5 and 41.9 per cent respectively. Multivariable analysis revealed that postoperative complications independently predicted shorter RFS (hazard ratio (HR) 2.36, 95 per cent confidence interval 1.56 to 3.58) and overall survival (HR 2.34, 1.46 to 3.74). Other independent predictors of shorter RFS and overall survival included lymph node metastasis, concomitant extrahepatic disease, a serum carcinoembryonic antigen level of at least 100 ng/dl, and the use of radiofrequency ablation (RFS only). The severity of complications also correlated with RFS (P = 0.006) and overall survival (P = 0.001). CONCLUSION: Postoperative complications were independently associated with decreased long-term survival after surgery for CLM with curative intent. The prevention and management of postoperative adverse events may be important oncologically. PMID- 23364913 TI - Optimizing the 6-min walk test as a measure of exercise capacity in COPD. AB - BACKGROUND: It is uncertain whether the effort and expense of performing a second walk for the 6-min walk test improves test performance. Hence, we attempted to quantify the improvement in 6-min walk distance if an additional walk were to be performed. METHODS: We studied patients consecutively enrolled into the National Emphysema Treatment Trial who prior to randomization and after 6 to 10 weeks of pulmonary rehabilitation performed two 6-min walks on consecutive days (N = 396). Patients also performed two 6-min walks at 6-month follow-up after randomization to lung volume reduction surgery (n = 74) or optimal medical therapy (n = 64). We compared change in the first walk distance to change in the second, average-of two, and best-of-two walk distances. RESULTS: Compared with the change in the first walk distance, change in the average-of-two and best-of-two walk distances had better validity and precision. Specifically, 6 months after randomization to lung volume reduction surgery, changes in the average-of-two (r = 0.66 vs r = 0.58, P = .01) and best-of-two walk distances (r = 0.67 vs r = 0.58, P = .04) better correlated with the change in maximal exercise capacity (ie, better validity). Additionally, the variance of change was 14% to 25% less for the average-of-two walk distances and 14% to 33% less for the best-of-two walk distances than the variance of change in the single walk distance, indicating better precision. CONCLUSIONS: Adding a second walk to the 6-min walk test significantly improves its performance in measuring response to a therapeutic intervention, improves the validity of COPD clinical trials, and would result in a 14% to 33% reduction in sample size requirements. Hence, it should be strongly considered by clinicians and researchers as an outcome measure for therapeutic interventions in patients with COPD. PMID- 23364916 TI - MRI of carriers of the apolipoprotein E e4 allele-evidence for structural differences in normal-appearing brain tissue in e4+ relative to e4- young adults. AB - Apolipoprotein E is a protein involved in cholesterol and lipid transport. The gene coding for this protein has three different alleles: e2, e3 and e4. The e4 allele is recognised as a significant risk factor for the development of Alzheimer's disease in later life. Paradoxically, behavioural and functional evidence has demonstrated that the e4 allele may confer a cognitive advantage to the carrier in youth. In this article, a range of sophisticated and novel structural imaging techniques were used to identify subtle differences in the brain tissue of groups of young e4 and homozygous e3 carriers that might support this paradox. Using voxel-based morphometry of high-resolution structural MR images, we identified a higher white matter volume ratio in e4 relative to homozygous e3 carriers. Furthermore, diffusion tensor imaging and tract-based spatial statistics studies identified increases in axial diffusivity and mode of anisotropy in carriers of the e4 allele. In addition, quantitative magnetisation transfer data were analysed using tract-based spatial statistics. Evidence of a trend towards an increased transverse relaxation time of the bound proton pool was detected in e4 carriers, indicative of altered white matter composition. These changes were found to correlate with indices of cognitive performance across the two groups, supporting the notion that such subtle differences in white matter integrity may confer neural advantages that contribute to cognitive outcomes and, potentially, to performance differences, such as observed here in a test of verbal fluency and reported previously by other researchers. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 23364915 TI - Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. AB - Certain chemotherapeutic regimens trigger cancer cell death while inducing dendritic cell maturation and subsequent immune responses. However, chemotherapy induced immunogenic cell death (ICD) has thus far been restricted to select agents. In contrast, several chemotherapeutic drugs modulate antitumor immune responses, despite not inducing classic ICD. In addition, in many cases tumor cells do not die after treatment. Here, using docetaxel, one of the most widely used cancer chemotherapeutic agents, as a model, we examined phenotypic and functional consequences of tumor cells that do not die from ICD. Docetaxel treatment of tumor cells did not induce ATP or high-mobility group box 1 (HMGB1) secretion, or cell death. However, calreticulin (CRT) exposure was observed in all cell lines examined after chemotherapy treatment. Killing by carcinoembryonic antigen (CEA), MUC-1, or PSA-specific CD8(+) CTLs was significantly enhanced after docetaxel treatment. This killing was associated with increases in components of antigen-processing machinery, and mediated largely by CRT membrane translocation, as determined by functional knockdown of CRT, PERK, or CRT blocking peptide. A docetaxel-resistant cell line was selected (MDR-1(+), CD133(+)) by continuous exposure to docetaxel. These cells, while resistant to direct cytostatic effects of docetaxel, were not resistant to the chemomodulatory effects that resulted in enhancement of CTL killing. Here, we provide an operational definition of "immunogenic modulation," where exposure of tumor cells to nonlethal/sublethal doses of chemotherapy alters tumor phenotype to render the tumor more sensitive to CTL killing. These observations are distinct and complementary to ICD and highlight a mechanism whereby chemotherapy can be used in combination with immunotherapy. PMID- 23364917 TI - SnO2 tube-in-tube nanostructures: Cu@C nanocable templated synthesis and their mutual interferences between heavy metal ions revealed by stripping voltammetry. AB - SnO2 tube-in-tube nanostructures are synthesized using Cu@C nanocables as effective sacrificial templates. It is revealed by stripping voltammetry that SnO2 tube-in-tube nanostructures show excellent performances in the determination of heavy metal ions, which might be related to the extraordinary adsorbing capacities of the hollow structure to metal ions, i.e., metal ions could diffuse into the interior of tubular structure. PMID- 23364920 TI - Maximizing coordinative and electronic unsaturation: three-coordinate dicationic platinum complexes. PMID- 23364918 TI - Food insecurity, food assistance and weight status in US youth: new evidence from NHANES 2007-08. AB - OBJECTIVE: To investigate food assistance participation as a risk factor for overweight and obesity in youth, and food insecurity as an effect modifier. METHODS: The sample included youth ages 4-17, in families <=200% of the federal poverty line in the 2007-2008 National Health and Nutrition Examination Survey (n = 1321). Food insecurity was measured with the US Department of Agriculture survey module. Food assistance participation was assessed for Supplemental Nutrition Assistance Program, Special Supplemental Nutrition Program for Women, Infants and Children and school meals. Body size was classified by age- and sex specific body mass index (BMI) percentile, BMI z-score and waist circumference percentile. Regression models with direct covariate adjustment and programme specific propensity scores, stratified by food insecurity, estimated associations between food assistance participation and body size. RESULTS: Food assistance participation was not associated with increased body size among food-insecure youth in models with direct covariate adjustment or propensity scores. Compared with low-income, food-secure youth not participating in food assistance, BMI z scores were higher among participants in models with direct covariate adjustment (0.27-0.38 SD and 0.41-0.47 SD, for boys and girls, respectively). Using propensity scores, results were similar for boys, but less so for girls. CONCLUSIONS: Food assistance programme participation is associated with increased body size in food-secure youth, but not food-insecure youth. Using both direct covariate adjustment and a propensity score approach, self-selection bias may explain some, but not all, of the associations. Providing healthy food assistance that improves diet quality without contributing to excessive intake remains an important public health goal. PMID- 23364919 TI - c-Myc suppressed E-cadherin through miR-9 at the post-transcriptional level. AB - c-Myc oncoprotein is overexpressed in most human cancers and regulates different genes and pathways in different cell types. E-cadherin expression is repressed by MYC through a post-transcriptional mechanism, but the exact mechanism remains elusive. Since E-cadherin is a direct target of miR-9 and miR-9 can be activated by MYC and MYCN, this suggests that c-Myc negatively modulates E-cadherin through a microRNA pathway. We have established a c-Myc-inducible expression system in which the protein level and transcriptional activity of c-Myc is significantly upregulated upon doxycycline induction. Overexpressed c-Myc led to an EMT-like conversion in the T-REx-293 cells and resulted in a significant decrease in E cadherin and an increase in Vimentin. Stem-loop RT-PCR showed elevated expression of miR-9 when c-Myc was induced to be overexpressed. Regarding the relationship of c-Myc, miR-9 and E-cadherin, the expression of miR-9 was curtailed by using antagomir-9 in induced overexpressing c-Myc. Restoration of E-cadherin expression became much stronger in the presence of c-Myc. Thus c-Myc represses E-cadherin at the post-transcriptional level through miR-9. PMID- 23364921 TI - Developmental changes in the composition of five anthraquinones from Rheum palmatum as quantified by (1) H-NMR. AB - INTRODUCTION: Rheum palmatum is an important traditional Chinese medicine featuring anthraquinones with several activities. Generally, rhein, emodin, aloe emodin, physcion and chrysophanol are used as chemical markers for the quality control of rhubarb products. OBJECTIVE: To develop a simple protocol for the quantification of rhein, emodin, aloe-emodin, physcion and chrysophanol in R. palmatum collected at different developmental stages. METHODS: (1) H-NMR spectra were measured on samples dissolved in acetone-d6 , quantification was carried out using the signals of H-4 of rhein (deltaH 8.36), H-7 of emodin (deltaH 6.68), CH2 OH of aloe-emodin (deltaH 4.81), OCH3 of physcion (deltaH 4.02) and CH3 of chrysophanol (deltaH 2.50), which were well separated from other signals. Quantitative analysis was based on the relative ratio of the intensity of each compound to the known amount of internal standard maleic acid. RESULTS: The quantitative (1) H-NMR (qHNMR) method developed showed good precision, trueness, linearity, repeatability and stability for the quantification of rhein, emodin, aloe-emodin, physcion and chrysophanol. This method was applied successfully to explore the seasonal variations of the five major anthraquinones in R. palmatum, and provided quantitative results in reasonable agreement with those obtained by the HPLC-UV method. CONCLUSION: Compared with the conventional HPLC-based methods, the qHNMR analysis is rapid, reference-free and convenient with less sample pre-treatment. This technique should be a feasible choice for the quality control of R. palmatum. PMID- 23364922 TI - Increased expression of metadherin protein predicts worse disease-free and overall survival in laryngeal squamous cell carcinoma. AB - Metadherin (MTDH) is involved in tumourigenesis and cancer progression in multiple human malignancies. However, the MTDH protein has rarely been reported in laryngeal squamous cell carcinoma (LSCC). The expression pattern of the MTDH protein in 176 primary archival LSCC and 27 corresponding adjacent noncarcinoma specimens was detected by immunohistochemistry and further correlated with clinicopathological parameters. The results demonstrated that 161 (91.48%) primary LSCC samples stained positive for MTDH; however, staining was barely detectable in all adjacent noncarcinoma samples. Moreover, the expression of the MTDH protein was significantly associated with the primary tumour site (p = 0.021), T classification (p = 0.002), clinical stage (I + II/III + IV; p < 0.001), lymph node metastasis (p < 0.001) and postoperational recurrence (p < 0.001). Kaplan-Meier analysis revealed that MTDH expression was significantly associated with worse disease-free survival (DFS) and overall survival (OS) rates in patients with LSCC (both p < 0.001). When lymph node metastasis and MTDH expression were considered together, patients with lymph node metastasis and high MTDH expression had both poorer DFS and OS rates than others (both p < 0.001). Finally, multivariate analysis demonstrated that MTDH expression was an independent prognostic factor for both DFS and OS rates in patients with LSCC. Strong MTDH expression was negatively correlated with a canonical epithelial mesenchymal transition molecule E-cadherin (p < 0.001) and positively associated with proangiogenic protein vascular endothelial growth factor (p < 0.001). MTDH overexpression was tightly associated with more aggressive tumour behaviour and a poor prognosis, indicating that MTDH is a valuable molecular biomarker for LSCC progression. PMID- 23364923 TI - Role of HMGB1 in propofol protection of rat intestinal epithelial cells injured by heat shock. AB - Gut-derived endotoxin and pathogenic bacteria may be important causative factors of morbidity and death during heat stroke. However, as the key component of intestinal mucosal barrier, the molecular mechanism of how intestinal epithelial cells are injured by heat shock is remains unclear. After rat intestinal epithelial cells (IEC-6) had been exposed to heat shock, their viability was measured. Propofol, which plays an important role in anti-inflammation and organ protection, was investigated to see how it affected viability under this stress. Changes of high mobility group box 1 (HMGB1) in IEC-6 cells were measured with RT PCR and Western blot assay at transcription and translational levels, respectively. Ethyl pyruvate (EP), a specific inhibitor of HMGB1 that can inhibit the release of HMGB1 without affecting its intracellular synthesis, was also investigated. Heat shock significantly reduced the intracellular level of HMGB1, and propofol inhibit its reduction. Propofol protected the heat shock-injured cells, at least partly through inhibiting the release of intracellular HMGB1 to reduce the direct or indirect cell damage caused by HMGB1. Pretreatment with high concentrations of EP also attenuated heat-shock injury. PMID- 23364924 TI - Precision biopolymers from protein precursors for biomedical applications. AB - The synthesis of biohybrid materials with tailored functional properties represents a topic of emerging interest. Combining proteins as natural, macromolecular building blocks, and synthetic polymers opens access to giant brush-like biopolymers of high structural definition. The properties of these precision polypeptide copolymers can be tailored through various chemical modifications along their polypeptide backbone, which expands the repertoire of known protein-based materials to address biomedical applications. In this article, the synthetic strategies for the design of precision biopolymers from proteins through amino acid specific conjugation reagents are highlighted and the different functionalization strategies, their characterization, and applications are discussed. PMID- 23364925 TI - Purification of long helical capsid of newcastle disease virus from Escherichia coli using anion exchange chromatography. AB - NP(Deltac375) is a truncated version of the nucleocapsid protein of Newcastle disease virus (NDV) which self-assembles into a long helical structure. A packed bed anion exchange chromatography (PB-AEC), SepFastTM Supor Q pre-packed column, was used to purify NP(Deltac375) from clarified feedstock. This PB-AEC column adsorbed 76.2% of NP(Deltac375) from the clarified feedstock. About 67.5% of the adsorbed NP(Deltac375) was successfully eluted from the column by applying 50 mM Tris-HCl elution buffer supplemented with 0.5 M NaCl at pH 7. Thus, a recovery yield of 51.4% with a purity of 76.7% which corresponds to a purification factor of 6.5 was achieved in this PB-AEC operation. Electron microscopic analysis revealed that the helical structure of the NP(Deltac375) purified by SepFast(TM) Supor Q pre-packed column was as long as 490 nm and 22-24 nm in diameter. The antigenicity of the purified NP(Deltac375) was confirmed by enzyme-linked immunosorbent assay. PMID- 23364926 TI - High-resolution CT scan findings in familial interstitial pneumonia do not conform to those of idiopathic interstitial pneumonia. AB - BACKGROUND: The aim of this study was to describe the high-resolution CT (HRCT) scan features that characterize familial interstitial pneumonia (FIP). METHODS: FIP was defined by the presence of two or more cases of probable or definite idiopathic interstitial pneumonia (IIP) in individuals related within three degrees. The cases were collected consecutively from three centers. We identified 371 individuals with potential FIP from 289 families, including 340 individuals who had HRCT scans. Two chest radiologists independently reviewed the HRCT scans, scoring the extent and distribution of HRCT scan findings, and assessed the overall radiologic diagnosis. RESULTS: HRCT scan abnormalities suggestive of IIP were present in 85% (289 of 340 subjects). The most frequent findings were reticular pattern (n = 238, 82%) and ground-glass opacity (GGO) associated with reticular abnormality (n = 231, 80%). Other changes included GGO in 116 (40%), honeycombing in 92 (32%), and micronodules in 65 (22%). In the 289 cases with evidence of IIP, the findings were diffusely distributed in the craniocaudal plane in 186 (64%), and the lower lung zones were predominantly involved in 89 (31%). In the axial plane, 194 (67%) had a subpleural distribution; 88 (30%) were diffuse. The imaging pattern was classified as definite or probable usual interstitial pneumonia (UIP) in only 62 subjects (22%) and definite or probable nonspecific interstitial pneumonia (NSIP) in 35 subjects (12%). In 160 subjects (55%), the imaging findings did not conform to previously described UIP or NSIP patterns. CONCLUSIONS: Reticulation and a mixed GGO/reticular pattern are the most common HRCT scan findings in FIP. The parenchymal abnormalities are most often diffuse in the craniocaudal dimension and have a predominantly peripheral distribution in the axial dimension. Although a radiologic UIP pattern is not uncommon, most cases do not conform to typical UIP or NSIP patterns. PMID- 23364927 TI - Protecting-group-free diastereoselective C-C coupling of 1,3-glycols and allyl acetate through site-selective primary alcohol dehydrogenation. PMID- 23364928 TI - Decreased muscle concentrations of ATP and PCR in the quadriceps muscle of fibromyalgia patients--a 31P-MRS study. AB - BACKGROUND AND METHODS: Fibromyalgia (FMS) has a prevalence of approximately 2% in the population. Central alterations have been described in FMS, but there is not consensus with respect to the role of peripheral factors for the maintenance of FMS. 31P magnetic resonance spectroscopy (31P-MRS) has been used to investigate the metabolism of phosphagens in muscles of FMS patients, but the results in the literature are not in consensus. The aim was to investigate the quantitative content of phosphagens and pH in resting quadriceps muscle of patients with FMS (n = 19) and in healthy controls (CONTROLS; n = 14) using (31) P-MRS. It was also investigated whether the concentrations of these substances correlated with measures of pain and/or physical capacity. RESULTS: Significantly lower concentrations of adenosine triphosphate (ATP) and phosphocreatinine (PCr; 28-29% lower) were found in FMS. No significant group differences existed with respect to inorganic phosphate (Pi), Pi/PCr and pH. The quadriceps muscle fat content was significantly higher in FMS than in CONTROLS [FMS: 9.0 +/- 0.5% vs. CONTROLS: 6.6 +/- 0.6%; (mean +/- standard error); P = 0.005]. FMS had significantly lower hand and leg capacity according to specific physical test, but there were no group differences in body mass index, subjective activity level and in aerobic fitness. In FMS, the specific physical capacity in the leg and the hand correlated positively with the concentrations of ATP and PCr; no significant correlations were found with pain intensities. CONCLUSIONS: Alterations in intramuscular ATP, PCr and fat content in FMS probably reflect a combination of inactivity related to pain and dysfunction of muscle mitochondria. PMID- 23364929 TI - Water-soluble fluorescent probes based on dendronized polyfluorenes for cell imaging. AB - Novel water-soluble dendronized fluorescent polyfluorenes (DFPFs) are prepared from hydrophilic monomers and hydrophobic comonomers. Incomplete energy transfer is found to result in a two-color emission of the DFPFs at around 410 and 650 nm. The incomplete energy transfer can be attributed to the poor compatibility between the fluorene and benzothiadiazole units. Polyethylene oxide (PEO) encapsulation of the DFPFs shows over 90% cell viability, indicating good biocompatibility. These DFPFs show differential cellular uptake. P1 with fewer PEO chains exhibits limited cellular membrane uptake and low brightness in cells. By contrast, P3 with more PEO chains is efficiently internalized by cells and accumulated in the cytoplasm. A strong fluorescence from whole cells is also observed. PMID- 23364930 TI - In reference to late complications of nickel-titanium alloy stent in tracheal stenosis. PMID- 23364931 TI - Rhodium(III)-catalyzed C-C coupling between arenes and aziridines by C-H activation. AB - Making C-C from C-H: [{RhCp*Cl(2)}(2)]/AgSbF(6) (Cp*=pentamethylcyclopentadienyl) can regioselectively catalyze the C-C coupling of arenes with aziridines by a C-H activation pathway. An eight-membered rhodacyclic intermediate resulting from the insertion of the Rh-C bond into the aziridine was isolated. PMID- 23364932 TI - Nasal nitric oxide levels do not allow for discrimination between olfactory loss due to various etiologies. AB - OBJECTIVES/HYPOTHESIS: Nasal nitric oxide (NO) and olfactory function are decreased in patients with chronic inflammatory sinonasal disease, suggesting a link between these two parameters. The aim of the study was to investigate nasal NO levels in patients with olfactory dysfunction due to different causes. STUDY DESIGN: Prospective study in a university clinic setting (tertiary referral center). METHODS: Posttraumatic (n = 11), idiopathic (n = 13), and sinonasal related olfactory-impaired patients (n = 55) were compared with healthy subjects (n = 11). Nasal NO levels, olfactory testing (Sniffin' Sticks), and rhinosinusitis questionnaires (Short-Form 36, Sinonasal Outcome Test 22, Rhinosinusitis Disability Index) were obtained. RESULTS: No significant difference in nasal NO levels were found between the different olfactory dysfunction causes. Nasal NO correlated negatively with age and positively with overall olfactory function, olfactory discrimination, and identification but not with olfactory thresholds. The more nasal symptoms prevailed in the Rhinosinusitis Disability Index, the lower the nasal NO. CONCLUSIONS: Nasal NO levels do not allow for discrimination between olfactory loss due to various etiologies based on the present data. Nasal NO production seems to decrease with age and also seems to be associated to overall olfactory function and in particular to central nervous system tasks such as olfactory discrimination and identification but not to olfactory thresholds. These findings raise questions about the link and interaction between olfactory function and nasal NO. PMID- 23364933 TI - Biology-oriented synthesis of a tetrahydroisoquinoline-based compound collection targeting microtubule polymerization. AB - In the third place: Inspired by the tetrahydroisoquinoline (THIQ) alkaloid noscapine, inhibitors of tubulin polymerization that bind to a site different from the colchicine and the vinca alkaloid binding sites have been synthesized. One compound is more potent than noscapine in HeLa cells and can overcome resistance to chemotherapeutics. PMID- 23364934 TI - Molecular characterization of norovirus GII strains identified in Albania. AB - Noroviruses (NoVs) are considered as the leading cause of diarrheal diseases in all groups of age. In the last decade the number of NoV outbreaks worldwide is increasing. Data published by the systems of NoV surveillance show the GII.4 strain as the human predominant genotype circulating worldwide and new genetic variants of GII.4 were associated with epidemic events. In Albania the economy transformation has damaged significantly the environment and a large circulation of enteric viruses was reported in the past with the presence of NoV among the genotyped strains. This study aimed to characterize, by molecular analysis, the NoV GII strains detected in Albania during two time periods: in 2010 from the outbreak occurred in Ballsh and in 2002-2003 from sporadic cases of diarrhoea. A total of 21 Nov GII strains were characterized. The NoV GII.4 was genotyped more frequently and it was related closely to the pandemic variants recorded in GenBank. During 2002-2003, six NoV GII recombinant strains have been characterized. PMID- 23364935 TI - Model for conformational relaxation of flexible conjugated polymers: application to p-phenylenevinylene trimers in nonpolar solvents. AB - Photoexcitation of flexible conjugated polymers is invariably followed by a fast conformational/torsional relaxation towards a configuration favouring coplanarity of the conjugated segments. In general, the experimental relaxation rate constant (k(CR)) depends on the solvent viscosity (eta) and temperature (T), and is not proportional to T/eta. A theory capable of explaining the observed dependence of k(CR) on T and eta over a wide range of these variables is not available. This gap is filled here by presenting a stochastic model that includes the participation of the oligomer side chain in storing and dissipating the stresses induced by photoexcitation. The model is able to account for the softening of solute-solvent interactions and its predictions are found to be in excellent agreement with the observed relaxation rate constants of a series of substituted p-phenylenevinylene trimers [ChemPhysChem 2009, 10, 448-454] on T, eta and the size of the side-chains. PMID- 23364936 TI - Genetics and genomics of flower initiation and development in roses. AB - Roses hold high symbolic value and great cultural importance in different societies throughout human history. They are widely used as garden ornamental plants, as cut flowers, and for the production of essential oils for the perfume and cosmetic industries. Domestication of roses has a long and complex history, and the rose species have been hybridized across vast geographic areas such as Europe, Asia, and the Middle East. The domestication processes selected several flower characters affecting floral quality, such as recurrent flowering, double flowers, petal colours, and fragrance. The molecular and genetic events that determine some of these flower characters cannot be studied using model species such as Arabidopsis thaliana, or at least only in a limited manner. In this review, we comment on the recent development of genetic, genomic, and transcriptomic tools for roses, and then focus on recent advances that have helped unravel the molecular mechanisms underlying several rose floral traits. PMID- 23364937 TI - Application of glutathione to roots selectively inhibits cadmium transport from roots to shoots in oilseed rape. AB - Glutathione is a tripeptide involved in various aspects of plant metabolism. This study investigated the effects of the reduced form of glutathione (GSH) applied to specific organs (source leaves, sink leaves, and roots) on cadmium (Cd) distribution and behaviour in the roots of oilseed rape plants (Brassica napus) cultured hydroponically. The translocation ratio of Cd from roots to shoots was significantly lower in plants that had root treatment of GSH than in control plants. GSH applied to roots reduced the Cd concentration in the symplast sap of root cells and inhibited root-to-shoot Cd translocation via xylem vessels significantly. GSH applied to roots also activated Cd efflux from root cells to the hydroponic solution. Inhibition of root-to-shoot translocation of Cd was visualized, and the activation of Cd efflux from root cells was also shown by using a positron-emitting tracer imaging system (PETIS). This study investigated a similar inhibitory effect on root-to-shoot translocation of Cd by the oxidized form of glutathione, GSSG. Inhibition of Cd accumulation by GSH was abolished by a low-temperature treatment. Root cells of plants exposed to GSH in the root zone had less Cd available for xylem loading by actively excluding Cd from the roots. Consequently, root-to-shoot translocation of Cd was suppressed and Cd accumulation in the shoot decreased. PMID- 23364938 TI - Metabolic profiling reveals coordinated switches in primary carbohydrate metabolism in grape berry (Vitis vinifera L.), a non-climacteric fleshy fruit. AB - Changes in carbohydrate metabolism during grape berry development play a central role in shaping the final composition of the fruit. The present work aimed to identify metabolic switches during grape development and to provide insights into the timing of developmental regulation of carbohydrate metabolism. Metabolites from central carbon metabolism were measured using high-pressure anion-exchange chromatography coupled to tandem mass spectrometry and enzymatic assays during the development of grape berries from either field-grown vines or fruiting cuttings grown in the greenhouse. Principal component analysis readily discriminated the various stages of berry development, with similar trajectories for field-grown and greenhouse samples. This showed that each stage of fruit development had a characteristic metabolic profile and provided compelling evidence that the fruit-bearing cuttings are a useful model system to investigate regulation of central carbon metabolism in grape berry. The metabolites measured showed tight coordination within their respective pathways, clustering into sugars and sugar-phosphate metabolism, glycolysis, and the tricarboxylic acid cycle. In addition, there was a pronounced shift in metabolism around veraison, characterized by rapidly increasing sugar levels and decreasing organic acids. In contrast, glycolytic intermediates and sugar phosphates declined before veraison but remained fairly stable post-veraison. In summary, these detailed and comprehensive metabolite analyses revealed the timing of important switches in primary carbohydrate metabolism, which could be related to transcriptional and developmental changes within the berry to achieve an integrated understanding of grape berry development. The results are discussed in a meta-analysis comparing metabolic changes in climacteric versus non-climacteric fleshy fruits. PMID- 23364939 TI - Regulation of guard cell photosynthetic electron transport by nitric oxide. AB - Nitric oxide (NO) is one of the key elements in the complex signalling pathway leading to stomatal closure by inducing reversible protein phosphorylation and Ca(2+) release from intracellular stores. As photosynthesis in guard cells also contributes to stomatal function, the aim of this study was to explore the potential role of NO as a photosynthetic regulator. This work provides the first description of the reversible inhibition of the effect of NO on guard cell photosynthetic electron transport. Pulse amplitude modulation (PAM) chlorophyll fluorescence measurements on individual stomata of peeled abaxial epidermal strips indicated that exogenously applied 450nM NO rapidly increases the relative fluorescence yield, followed by a slow and constant decline. It was found that NO instantly decreases photochemical fluorescence quenching coefficients (qP and qL), the operating quantum efficiency of photosystem II (PhiPSII), and non photochemical quenching (NPQ) to close to zero with different kinetics. NO caused a decrease in NPQ, which is followed by a slow and continuous rise. The removal of NO from the medium surrounding the epidermal strips using a rapid liquid perfusion system showed that the effect of NO on qP and PhiPSII, and thus on the linear electron transport rate through PSII (ETR), is reversible, and the constant rise in NPQ disappears, resulting in a near steady-state value. The reversible inhibition by NO of the ETR could be restored by bicarbonate, a compound known to compete with NO for one of the two coordination sites of the non-haem iron (II) in the QAFe(2+)QB complex. PMID- 23364940 TI - Virus-induced gene silencing of Arabidopsis thaliana gene homologues in wheat identifies genes conferring improved drought tolerance. AB - In a non-model staple crop like wheat (Triticum aestivumI L.), functional validation of potential drought stress responsive genes identified in Arabidopsis could provide gene targets for breeding. Virus-induced gene silencing (VIGS) of genes of interest can overcome the inherent problems of polyploidy and limited transformation potential that hamper functional validation studies in wheat. In this study, three potential candidate genes shown to be involved in abiotic stress response pathways in Arabidopsis thaliana were selected for VIGS experiments in wheat. These include Era1 (enhanced response to abscisic acid), Cyp707a (ABA 8'-hydroxylase), and Sal1 (inositol polyphosphate 1-phosphatase). Gene homologues for these three genes were identified in wheat and cloned in the viral vector barley stripe mosaic virus (BSMV) in the antisense direction, followed by rub inoculation of BSMV viral RNA transcripts onto wheat plants. Quantitative real-time PCR showed that VIGS-treated wheat plants had significant reductions in target gene transcripts. When VIGS-treated plants generated for Era1 and Sal1 were subjected to limiting water conditions, they showed increased relative water content, improved water use efficiency, reduced gas exchange, and better vigour compared to water-stressed control plants inoculated with RNA from the empty viral vector (BSMV0). In comparison, the Cyp707a-silenced plants showed no improvement over BSMV0-inoculated plants under limited water condition. These results indicate that Era1 and Sal1 play important roles in conferring drought tolerance in wheat. Other traits affected by Era1 silencing were also studied. Delayed seed germination in Era1-silenced plants suggests this gene may be a useful target for developing resistance to pre-harvest sprouting. PMID- 23364941 TI - Increased levels of IAA are required for system 2 ethylene synthesis causing fruit softening in peach (Prunus persica L. Batsch). AB - The fruit of melting-flesh peach (Prunus persica L. Batsch) cultivars produce high levels of ethylene caused by high expression of PpACS1 (an isogene of 1 aminocyclopropane-1-carboxylic acid synthase), resulting in rapid fruit softening at the late-ripening stage. In contrast, the fruit of stony hard peach cultivars do not soften and produce little ethylene due to low expression of PpACS1. To elucidate the mechanism for suppressing PpACS1 expression in stony hard peaches, a microarray analysis was performed. Several genes that displayed similar expression patterns as PpACS1 were identified and shown to be indole-3-acetic acid (IAA)-inducible genes (Aux/IAA, SAUR). That is, expression of IAA-inducible genes increased at the late-ripening stage in melting flesh peaches; however, these transcripts were low in mature fruit of stony hard peaches. The IAA concentration increased suddenly just before harvest time in melting flesh peaches exactly coinciding with system 2 ethylene production. In contrast, the IAA concentration did not increase in stony hard peaches. Application of 1 naphthalene acetic acid, a synthetic auxin, to stony hard peaches induced a high level of PpACS1 expression, a large amount of ethylene production and softening. Application of an anti-auxin, alpha-(phenylethyl-2-one)-IAA, to melting flesh peaches reduced levels of PpACS1 expression and ethylene production. These observations indicate that suppression of PpACS1 expression at the late-ripening stage of stony hard peach may result from a low level of IAA and that a high concentration of IAA is required to generate a large amount of system 2 ethylene in peaches. PMID- 23364942 TI - Understanding the electronic structures of graphene quantum dot physisorption and chemisorption onto the TiO2 (110) surface: a first-principles calculation. AB - We investigated the interfacial electronic structure and charge transfer properties of graphene quantum dot (GQD) physisorption and chemisorption on the TiO(2) (110) surface from density functional theory calculations. The simulations show that a slight charge transfer occurs in physisorption case while a significant charge transfer takes place in chemisorption configuration. We present a detailed comparison of the similarities and differences between the electronic structures. The similarities originate from the positive work function difference in both the physisorption and chemisorption configurations, which is able to drive electron transfer from GQD into TiO(2), leading to charge separation across the GQD-TiO(2) interface. The differences stem from the interaction between the GQD and TiO(2) substrate. For example, GQD bounds to TiO(2) surface through van der Waals interactions in the case of physisorption. In the chemisorption configuration, however, there exists strong covalent bonding between them. This leads to much more efficient charge separation for chemisorption than for physisorption. Furthermore, the GQD-TiO(2) composites show large band-gap narrowing that could extend the optical absorption edge into the visible-light region. This should imply that chemisorbed GQDs produce a composite with better photocatalytic and photovoltaic performance than composites formed through physisorption. PMID- 23364943 TI - Effects of chlorpyrifos on reproductive toxicology of male rats. AB - The aim of this study is to investigate the effects of subchronic exposure to chlorpyrifos on reproductive toxicology of male rats. Forty healthy male rats were divided into four groups: three exposure groups and a control group. Chlorpyrifos was administered orally to male rats at 0, 2.7, 5.4, and 12.8 mg/kg for 90 days to evaluate the toxic alterations in testicular histology, testicular marker enzyme activities and related genes expression levels, sperm dynamics, and testosterone levels. The body weight and the testis weight of animals did not show any significant changes. Chlorpyrifos brought about marked reduction in testicular sperm counts, sperm motility, and significant growth of sperm malformation rate in exposed males. Histopathological examination of testes showed mild to severe degenerative changes in seminiferous tubules at various dose levels. The levels of testosterone (T) showed a decreasing tendency, and there was a statistical difference between the 5.4, 12.8 mg/kg groups, and the control group. The levels of follicle stimulating hormone (FSH) were significantly increased in 5.4 and 12.8 mg/kg groups, but there were no obvious effects on the levels of luteinizing hormone (LH) and estradiol (E2 ). A significant increase in the activities of LDH and LDH-x was observed in chlorpyrifos exposed rats in 5.4 and 12.8 mg/kg groups, but the expression levels of related genes had no significant differences between chlorpyrifos exposure groups and the control group. These results suggest that chlorpyrifos has adverse effects on reproductive system of male rats. PMID- 23364944 TI - Comparative toxicity of pyrethroid insecticides to two estuarine crustacean species, Americamysis bahia and Palaemonetes pugio. AB - Pyrethroid insecticides are widely used on agricultural crops, as well as for nurseries, golf courses, urban structural and landscaping sites, residential home and garden pest control, and mosquito abatement. Evaluation of sensitive marine and estuarine species is essential for the development of toxicity testing and risk-assessment protocols. Two estuarine crustacean species, Americamysis bahia (mysids) and Palaemonetes pugio (grass shrimp), were tested with the commonly used pyrethroid compounds, lambda-cyhalothrin, permethrin, cypermethrin, deltamethrin, and phenothrin. Sensitivities of adult and larval grass shrimp and 7-day-old mysids were compared using standard 96-h LC50 bioassay protocols. Adult and larval grass shrimp were more sensitive than the mysids to all the pyrethroids tested. Larval grass shrimp were approximately 18-fold more sensitive to lambda-cyhalothrin than the mysids. Larval grass shrimp were similar in sensitivity to adult grass shrimp for cypermethrin, deltamethrin, and phenothrin, but larvae were approximately twice as sensitive to lambda-cyhalothrin and permethrin as adult shrimp. Acute toxicity to estuarine crustaceans occurred at low nanogram per liter concentrations of some pyrethroids, illustrating the need for careful regulation of the use of pyrethroid compounds in the coastal zone. PMID- 23364945 TI - Inspiration closure reflex: the effect of respiration on intrinsic sphincters. AB - INTRODUCTION: The functions of the lower esophageal sphincter (LES) and internal urethral sphincter (IUS) have not been reported during voluntary and involuntary respiratory maneuvers. METHODS: In this study we performed a prospective barium videofluoroscopy study (BSV) of the LES on 4 healthy adult men during voluntary cough (VC), laryngeal expiration reflex (LER), breath-hold maneuvers, and normal inspiration. One subject had fiber-optic pressure catheters placed in the LES and IUS, and electromyographic recording of the right T7-8 intercostals during respiration. RESULTS: BSV showed closure and relaxation of the LES corresponding to the inspiration and expiration of VC. The LES was patent during the LER. There was closure of the LES during the deep inspiration/breath-hold event. Pressure catheters in the LES and IUS showed increased pressure during inspiration. CONCLUSIONS: These observations suggest that pulmonary inspiration afferents elicit a patterned reflex motor response in the LES and IUS, referred to as the inspiration closure reflex (ICR). PMID- 23364946 TI - Toxicity evaluation of beta-diketone antibiotics on the development of embryo larval zebrafish (Danio rerio). AB - This study evaluated the effects of beta-diketone antibiotics (DKAs) on the development of embryo-larval zebrafish (Danio rerio). When exposure to DKAs, developmental malformations, such as hatching delay, curved body axis, pericardial edema, uninflated swim bladder and yolk sac edema, were observed at 120 h postfertilization (hpf). The estimated 120 hpf nominal concentrations of no observed effect concentration and lowest observed effect concentration for DKAs were 18.75 and 37.50 mg/L, respectively, suggesting that DKAs have much lower toxicity than other persistent pollutants. Following DKA exposure, embryonic heart rates were significantly reduced as compared to the controls at 48 and 60 hpf. The peak bending motion frequency appeared 1 h earlier than in control embryos. The 2.34 and 9.38-mg/L treatment groups had a higher basal swim rate than control groups at 120 hpf in both light and light-to-dark photoperiod experiments. The occurrence of high speed swim rates was enhanced approximately threefold to sevenfold in the 2.34 and 9.38 mg/L treatments compared to the control. Glutathione (GSH) concentrations in the 2.34 and 9.38-mg/L treatments were significantly higher than the control at 72 hpf, suggesting that GSH production was induced at the end of the hatching period. When exposed to DKAs, zebrafish superoxide dismutase enzyme (SOD) activities were significantly inhibited in the early embryonic period, demonstrating that the clearing ability in zebrafish was lower than the generation rate of free radicals. In summary, the combined DKAs were developmentally toxic to zebrafish in their early life stages and had the ability to impair individual behaviors that are of great importance in the assessment of their ecological fitness. PMID- 23364947 TI - Topographic and ultrastructural variations in isthmus segment of oviduct during oestrous cycle in Caprines. AB - In the present study, the morphological variations in the isthmus segment of goat (Capra hircus) oviduct were studied using scanning and ultrastructural techniques during luteal and follicular phases of oestrous cycle. Topographic analysis of the isthmus epithelium in the follicular phase demonstrated irregular distribution of ciliated cells on the epithelium. A few secretory cells possessed bulbous apical processes which were concealed by the cilia. Cyclic changes were noticed in the secretory cells of isthmus. Under electron microscopy the isthmus region of the oviduct during the follicular phase revealed presence of almost blunt processes at their apical surfaces. The secretory cells were attached to the basal lamina and were characterized by the presence of secretory granules, numerous ribosomes, extensive smooth endoplasmic reticulum, well-developed golgi zones in the cytoplasm, and a microvillus luminal surface. The parallel use of these two methods in isthmus segment of the oviduct has enabled us to analyze the marked cyclic variations in the topography and fine structure during follicular and luteal phases of the oestrous cycle. The results of the present investigation on topography and ultrastructure will be of great help in explaining different bottlenecks of gamete interaction, maturation, fertilization, and early embryo development. PMID- 23364949 TI - Role of the endothelial-derived endogenous anti-inflammatory factor Del-1 in inflammation-mediated adrenal gland dysfunction. AB - Inflammation in the course of systemic inflammatory response syndrome (SIRS) or sepsis often results in dysregulation of the hypothalamic-pituitary-adrenal axis; however, the underlying mechanisms are not well understood. The adrenal gland is highly vascularized; thus, we hypothesized that endothelial dysfunction may actively participate in inflammation-related adrenal insufficiency. To address this hypothesis, we used the properties of developmental endothelial locus-1 (Del 1), which is an endothelial-derived anti-inflammatory factor that antagonizes integrin-dependent leukocyte adhesion. Here we identified that Del-1 is expressed in the adrenal gland and that its expression was down-regulated upon SIRS induction by systemic lipopolysaccharide administration. Furthermore, we observed increased leukocyte accumulation, inflammation, and higher apoptosis in the adrenal glands of Del-1-deficient mice as compared with wild-type mice. Strikingly, Del-1 deficiency was also associated with reduced corticosterone and ACTH levels 24 hours after lipopolysaccharide administration. Together, these data suggest that Del-1 may act as a gatekeeper of adrenal gland inflammation and may regulate the integrity of the hypothalamic-pituitary-adrenal axis stress response, thereby modulating adrenal (dys)function in the course of SIRS. PMID- 23364948 TI - Cellular mechanism by which estradiol protects female ovariectomized mice from high-fat diet-induced hepatic and muscle insulin resistance. AB - Estrogen replacement therapy reduces the incidence of type 2 diabetes in postmenopausal women; however, the mechanism is unknown. Therefore, the aim of this study was to evaluate the metabolic effects of estrogen replacement therapy in an experimental model of menopause. At 8 weeks of age, female mice were ovariectomized (OVX) or sham (SHAM) operated, and OVX mice were treated with vehicle (OVX) or estradiol (E2) (OVX+E2). After 4 weeks of high-fat diet feeding, OVX mice had increased body weight and fat mass compared with SHAM and OVX+E2 mice. OVX mice displayed reduced whole-body energy expenditure, as well as impaired glucose tolerance and whole-body insulin resistance. Differences in whole-body insulin sensitivity in OVX compared with SHAM mice were accounted for by impaired muscle insulin sensitivity, whereas both hepatic and muscle insulin sensitivity were impaired in OVX compared with OVX+E2 mice. Muscle diacylglycerol (DAG), content in OVX mice was increased relative to SHAM and OVX+E2 mice. In contrast, E2 treatment prevented the increase in hepatic DAG content observed in both SHAM and OVX mice. Increases in tissue DAG content were associated with increased protein kinase Cepsilon activation in liver of SHAM and OVX mice compared with OVX+E2 and protein kinase Ctheta activation in skeletal muscle of OVX mice compared with SHAM and OVX+E2. Taken together, these data demonstrate that E2 plays a pivotal role in the regulation of whole-body energy homeostasis, increasing O(2) consumption and energy expenditure in OVX mice, and in turn preventing diet-induced ectopic lipid (DAG) deposition and hepatic and muscle insulin resistance. PMID- 23364950 TI - Single file reciprocating technique using conventional nickel-titanium rotary endodontic files. AB - This study was aimed to evaluate the applicability of a reciprocating movement technique with conventional nickel-titanium files for root canal preparation. Forty-four simulated canals in resin blocks were used in this study and divided as following four groups according to the instruments used and preparation methods. Group CP (n = 12) and CR (n = 12) were instrumented with continuous rotation using four files of ProFile and RaCe, respectively. Group RP (n = 10) and RR (n = 10) were instrumented with a reciprocation movement by using a single ProFile and RaCe file, respectively. The resin blocks were scanned before and after instrumentation, and the images were superimposed. To compare the efficiency of canal shaping, the preparation time, and centering ratio were calculated. Morphologic changes of tested files were examined by scanning electron microscopy (SEM). Data were analyzed by ANOVA and Duncan's post hoc test at p < 0.05. The preparation time was markedly shorter in Groups RP and RR than in Groups CP and CR. No significant difference in the centering ratio was noted between groups. Although the files used for Groups CP and CR showed no distortion under the SEM evaluation, the files used for Groups RP and RR had considerable torsional distortion. This study suggests that the reciprocating instrumentation technique using conventional nickel-titanium rotary file systems might have a comparable efficacy for the root canal shaping with reduced shaping time. Although the reciprocating technique seems to be an effective alternative to the conventional rotation technique, the risk of torsional distortion and fracture should be considered before clinical application. PMID- 23364951 TI - Different mandibular first molar shapes according to groove and cusp configuration in relation to suggested bracket position. AB - The aim of this study was to explore the shape differences in the mandibular first molars through orthographic measurements using three-dimensional (3D) virtual models, and study the possibility of new morphologic categories that require more than subjective visual inspection. A total of 164 mandibular first molars with five cusps were selected for classification. Using 3D laser scanning and reconstruction software, virtual casts were constructed. After several linear and angular measurements on the virtual occlusal plane, the teeth were clustered using the partitioning around medoids methods-an unsupervised classification. The cluster analysis presented two clusters that showed statistically significant differences in the measurements over the cusp locations and groove configurations. However, gender differences were not shown in the angular groove and cusp configurations. Two clusters were found in the population of the present study, and this result suggested the existence of a diverse morphologic trait in the mandibular molar even in the same origin and could be considered in positioning orthodontic brackets that have built-in prescriptions. PMID- 23364952 TI - Combinations of parabens at concentrations measured in human breast tissue can increase proliferation of MCF-7 human breast cancer cells. AB - The alkyl esters of p-hydroxybenzoic acid (parabens), which are used as preservatives in consumer products, possess oestrogenic activity and have been measured in human breast tissue. This has raised concerns for a potential involvement in the development of human breast cancer. In this paper, we have investigated the extent to which proliferation of MCF-7 human breast cancer cells can be increased by exposure to the five parabens either alone or in combination at concentrations as recently measured in 160 human breast tissue samples. Determination of no-observed-effect concentrations (NOEC), lowest-observed-effect concentrations (LOEC), EC50 and EC100 values for stimulation of proliferation of MCF-7 cells by five parabens revealed that 43/160 (27%) of the human breast tissue samples contained at least one paraben at a concentration >= LOEC and 64/160 (40%) > NOEC. Proliferation of MCF-7 cells could be increased by combining all five parabens at concentrations down to the 50(th) percentile (median) values measured in the tissues. For the 22 tissue samples taken at the site of ER + PR + primary cancers, 12 contained a sufficient concentration of one or more paraben to stimulate proliferation of MCF-7 cells. This demonstrates that parabens, either alone or in combination, are present in human breast tissue at concentrations sufficient to stimulate the proliferation of MCF-7 cells in vitro, and that functional consequences of the presence of paraben in human breast tissue should be assessed on the basis of all five parabens and not single parabens individually. PMID- 23364953 TI - Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis B with high baseline viral load. AB - We evaluated the antiviral response of patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as having hepatitis B virus (HBV) DNA >= 9 log10 copies/mL, after 240 weeks of tenofovir disoproxil fumarate (TDF) treatment. A total of 641 hepatitis B e antigen (HBeAg)-negative and HBeAg positive patients (129 with HVL) received 48 weeks of TDF 300 mg (HVL n = 82) or adefovir dipivoxil (ADV) 10 mg (HVL n = 47), followed by open-label TDF for an additional 192 weeks. Patients with confirmed HBV DNA >= 400 copies/mL on or after week 72 had the option of adding emtricitabine (FTC). By week 240, 98.3% of HVL and 99.2% of non-HVL patients on treatment achieved HBV DNA <400 copies/mL. Both groups had similar rates of histologic regression between baseline and week 240. Patients with HVL generally took longer to achieve HBV DNA <400 copies/mL than non-HVL patients, but by week 96, the percentages of patients with HBV DNA <400 copies/mL were similar in both groups. Among HVL patients, time to achieving HBV DNA <400 copies/mL was shorter among those initially receiving TDF, compared to ADV. No patient with baseline HVL had persistent viremia at week 240 or amino acid substitutions associated with TDF resistance. CONCLUSION: CHB patients with HVL can achieve HBV DNA negativity with long-term TDF treatment, although time to HBV DNA <400 copies/mL may be longer, relative to patients with non-HVL. PMID- 23364954 TI - A note on the catch-up time method for estimating lead or sojourn time in prostate cancer screening. AB - Models of cancer screening assume that cancers are detectable by screening before being diagnosed clinically through symptoms. The duration of this preclinical phase is called sojourn time, and it determines how much diagnosis might be advanced in time by the screening test (lead time). In the catch-up time method, mean sojourn time or lead time are estimated as the time needed for cumulative incidence in an unscreened population to catch up with the detection rate (prevalence) at a first screening test. The method has been proposed as a substitute of the prevalence/incidence ratio in the case of prostate cancer where incidence cannot be treated as a constant. A model is proposed to justify this estimator. It is shown that this model is different from classic Markov-type models developed for breast cancer screening. In both models, the catch-up time method results in biased estimates of mean sojourn time. PMID- 23364955 TI - SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating beta catenin. AB - Mesenchymal stem cells (MSCs) are multi-potent cells that can differentiate into osteoblasts, adipocytes, chondrocytes and myocytes. This potential declines with aging. We investigated whether the sirtuin SIRT1 had a function in MSCs by creating MSC specific SIRT1 knock-out (MSCKO) mice. Aged MSCKO mice (2.2 years old) showed defects in tissues derived from MSCs; i.e. a reduction in subcutaneous fat, cortical bone thickness and trabecular volume. Young mice showed related but less pronounced effects. MSCs isolated from MSCKO mice showed reduced differentiation towards osteoblasts and chondrocytes in vitro, but no difference in proliferation or apoptosis. Expression of beta-catenin targets important for differentiation was reduced in MSCKO cells. Moreover, while beta catenin itself (T41A mutant resistant to cytosolic turnover) accumulated in the nuclei of wild-type MSCs, it was unable to do so in MSCKO cells. However, mutating K49R or K345R in beta-catenin to mimic deacetylation restored nuclear localization and differentiation potential in MSCKO cells. We conclude that SIRT1 deacetylates beta-catenin to promote its accumulation in the nucleus leading to transcription of genes for MSC differentiation. PMID- 23364957 TI - Metabolic syndrome with hyperglycemia and the risk of ischemic stroke. AB - PURPOSE: The association of ischemic stroke and metabolic syndrome (MetSyn) with or without diabetes mellitus (DM) is not clear. The present study aimed to identify the impact of diabetes or hyperglycemia on the risk of MetSyn-associated ischemic stroke. MATERIALS AND METHODS: This study comprised an Asian population of 576 patients with acute nonembolic cerebral infarction and 500 controls. MetSyn was defined according to the criteria of the International Diabetes Federation. MetSyn patients were further subgrouped according to their glucose levels: MetSyn with DM, MetSyn with impaired fasting glucose (IFG) and MetSyn with normal glucose tolerance (NGT). The impact of MetSyn on cerebral infarction was then evaluated. RESULTS: At baseline, the prevalence of MetSyn in patients with cerebral infarction was higher than that of the controls (57.29% vs. 10.00%, p<0.01). In the stroke group, the prevalences of MetSyn with DM, IFG, and NGT were 25.69%, 8.85% and 22.74%, respectively, all of which were higher than that of the controls (all p-values<0.05). By multiple logistic regression analysis, we discovered that MetSyn was associated with an increased risk of cerebral infarction (odds ratio: 5.73, p<0.01). After adjustment for all the components of MetSyn, the odds ratios of MetSyn with DM, IFG, and NGT were 5.70, 2.24 and 2.19 (all p-values <0.05), respectively. CONCLUSION: In Asian population, patients with MetSyn accompanied by T2DM are at the greatest risk for acute non-embolic stroke. Additionally, IFG was not observed to be associated with an increased risk for MetSyn-related ischemic stroke. PMID- 23364956 TI - Cross-protective immune responses elicited by live attenuated influenza vaccines. AB - The desired effect of vaccination is to elicit protective immune responses against infection with pathogenic agents. An inactivated influenza vaccine is able to induce the neutralizing antibodies directed primarily against two surface antigens, hemagglutinin and neuraminidase. These two antigens undergo frequent antigenic drift and hence necessitate the annual update of a new vaccine strain. Besides the antigenic drift, the unpredictable emergence of the pandemic influenza strain, as seen in the 2009 pandemic H1N1, underscores the development of a new influenza vaccine that elicits broadly protective immunity against the diverse influenza strains. Cold-adapted live attenuated influenza vaccines (CAIVs) are advocated as a more appropriate strategy for cross-protection than inactivated vaccines and extensive studies have been conducted to address the issues in animal models. Here, we briefly describe experimental and clinical evidence for cross-protection by the CAIVs against antigenically distant strains and discuss possible explanations for cross-protective immune responses afforded by CAIVs. Potential barriers to the achievement of a universal influenza vaccine are also discussed, which will provide useful guidelines for future research on designing an ideal influenza vaccine with broad protection without causing pathogenic effects such as autoimmunity or attrition of protective immunity against homologous infection. PMID- 23364958 TI - The influence of anti-platelet resistance on the development of cerebral ischemic lesion after carotid artery stenting. AB - PURPOSE: Cerebral ischemic lesions are frequently observed after carotid artery stenting (CAS), and anti-platelet agents are used to prevent stent thrombosis and peri-procedural complications. However, despite the premedication, cerebral ischemic lesions are observed, suggesting that they may rather be related to anti platelet resistance. We, therefore, investigated the effects of anti-platelet resistance on the development of cerebral ischemic lesions after CAS. MATERIALS AND METHODS: We retrospectively reviewed patients who received CAS and selected patients for whom brain MRI was performed within 24 hours after CAS and for whom anti-platelet resistance was checked. Anti-platelet resistance was examined by the VerifyNow system. We analyzed the correlation between anti-platelet resistance and cerebral ischemic lesions detected on follow-up MRI. RESULTS: Among 76 patients, 45 (59.2%) developed new ischemic lesions after CAS. Twelve (15.8%) patients showed aspirin resistance and 50 (65.8%) patients showed clopidogrel resistance. Patients with a new ischemic lesion demonstrated a significantly greater frequency of clopidogrel resistance than those who had no new ischemic lesion (82.2% versus 41.9%, p=0.001). The frequency of aspirin resistance was not significantly different between the groups of patients with and without new ischemic lesions (20.0% versus 9.7%, p=0.340). In multivariate analysis, clopidogrel resistance was a significant risk factor for post procedural cerebral ischemia. CONCLUSION: Anti-platelet resistance can be used to predict new ischemic lesions after CAS. Anti-platelet resistance should be evaluated in all patients prior to CAS to prevent ischemic complications related to CAS. PMID- 23364959 TI - Hemodynamic instability during carotid angioplasty and stenting-relationship of calcified plaque and its characteristics. AB - PURPOSE: During carotid angioplasty and stenting (CAS), hemodynamic instability (HDI) can occur, possibly causing post-procedural ischemic complications. The goal of this study was to investigate the risk factors of HDI focusing on characteristics of plaque. MATERIALS AND METHODS: Thirty nine CAS patients were retrospectively evaluated for HDI. Prolonged HDI that lasted over 30 minutes was analyzed in relation to characteristics of calcified plaque. RESULTS: Nineteen (48.7%) patients had HDI. Ten of the 19 had both bradycardia and hypotension, and nine had only bradycardia. All bradycardia was treated well with a transcutaneous temporary cardiac pacemaker. But eight patients presented with prolonged hypotension in spite of recovery of bradycardia. Calcified plaque was a related factor associated with HDI (odds ratio, 8.571; 95% confidence interval, 1.321 55.62; p=0.024). Extensive and eccentric type calcified plaques were associated with prolonged hypotension (p=0.04, and p=0.028, respectively). CONCLUSION: The calcification of plaque is a predictable factor of HDI during CAS, and its extensive and eccentric calcified plaques may be related to prolonged HDI. PMID- 23364960 TI - Beneficial effects of stroke-unit care in stroke patients with atrial fibrillation. AB - PURPOSE: Continuous cardiac monitoring in a stroke unit (SU) may improve detection of atrial fibrillation (AF), and SU care may improve the rate of anticoagulation by better adherence to a standardized treatment protocol in patients with AF. We investigated the effects of the SU on the detection of AF and the rate of warfarin therapy in patients with AF. MATERIALS AND METHODS: Acute stroke patients who had been admitted before or after the opening of the SU were included in our study. SU patients were monitored continuously with electrocardiography. Rates of AF and warfarin therapy were compared between patients admitted to the SU (SU group) and those admitted to the general ward (GW) prior to the opening of the SU (GW group). RESULTS: Total 951 patients had been admitted to the GW prior to the opening of the SU (from January 2000 to November 2002), and 2349 patients to the SU (from January 2003 to December 2008). AF was found in 149 patients (15.7%) in the GW group and in 487 (20.7%) in the SU group. Most of AF detected during admission was paroxysmal AF (84.8%). The frequency of newly detected AF was higher in the SU group than the GW group (2.5% vs. 0.7%, p=0.001). The rate of anticoagulation consideration was also higher in the SU group. CONCLUSION: SU care improved the detection of AF and the rate of anticoagulation consideration in acute stroke patients. Our findings support the benefits of continuous cardiac monitoring in the SU for stroke patients. PMID- 23364961 TI - Health-related quality of life and cognitive functioning at on- and off-treatment periods in children aged between 6-13 years old with brain tumors: a prospective longitudinal study. AB - PURPOSE: Our study aimed to examine the relationship between intelligence and health-related quality of life (HRQOL) in children (6-13 years old) diagnosed as having a brain tumor. MATERIALS AND METHODS: We administered a Korean version of the Wechsler Intelligence Scale for Children-III, the Pediatric Quality of Life Inventory, version 4.0 (PedsQL), the Korean version of the Parenting Stress Index Short Form, and the Korean Version of the Parenting Sense of Competence (K-PSOC) scale before or after initial radiotherapy (T1) and after treatment termination (T2). In total, 13 patients completed both the T1 and T2 interviews. RESULTS: Scores significantly declined between T1 and T2 on the full-scale intelligence quotients (FIQ), verbal intelligence quotients (VIQ), performance intelligence quotients (PIQ), similarity and coding tests, as well as the K-PSOC, which measures parental anxiety. FIQ scores at T1 were correlated with the self reported PedsQL total scores (r=0.739) and the parent proxy-report PedsQL scores for school functioning (r=0.706) at T2. Also, the FIQ scores at T2 were correlated with the self-reported PedsQL total scores (r=0.748) and scores for physical health (r=0.728) at T2. CONCLUSION: The cognitive ability and intelligence level of the patients significantly declined between on and off treatment periods, and higher intelligence functioning at both on and off treatment was correlated with long-term higher HRQOL. Further investigations that monitor intelligence, HRQOL and parenting stress over a longer period, using a greater number of participants, are needed. PMID- 23364962 TI - Precommissural fornix in the human brain: a diffusion tensor tractography study. AB - PURPOSE: Other than a single case report, no diffusion tensor tractography (DTT) studies of the precommissural fornix in the human brain have been conducted. In the current study, we attempted to visualize the precommissural fornix in the human brain using DTT. MATERIALS AND METHODS: We recruited 36 healthy volunteers for this study. Diffusion tensor images were scanned using a 1.5-T scanner, and the precommissural fornix was analyzed using Functional Magnetic Resonance Imaging of the Brain (FMRIB) software. Values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume of the precommissural fornix were measured. RESULTS: The precommissural fornix originated from the hippocampal formation on each hemisphere as a crus; both crura were then joined to the body of the fornix. The body of the fornix continued anteriorly to the level just superior to the anterior commissure, where it divided into each column of the precommissural fornix. Each column descended anteriorly to the anterior commissure and terminated in the septal nuclei. Values of FA, MD, and tract volumes of the precommissural fornix did not differ between the right and left hemispheres (p>0.05). CONCLUSION: We believe that the methodology and results of this study would be helpful to future research on the precommissural fornix and in the elucidation of the pathology of diseases involving the precommissural fornix. PMID- 23364963 TI - Intrathecal lamotrigine attenuates mechanical allodynia and suppresses microglial and astrocytic activation in a rat model of spinal nerve ligation. AB - PURPOSE: Lamotrigine, a novel anticonvulsant, is a sodium channel blocker that is efficacious in certain forms of neuropathic pain. Recently, microglial and astrocytic activation has been implicated in the development of nerve injury induced neuropathic pain. We have assessed the effects of continuous intrathecal administration of lamotrigine on the development of neuropathic pain and glial activation induced by L5/6 spinal-nerve ligation in rats. MATERIALS AND METHODS: Following left L5/6 spinal nerve ligation (SNL), Sprague-Dawley male rats were intrathecally administered lamotrigine (24, 72, or 240 MUg/day) or saline continuously for 7 days. Mechanical allodynia of the left hind paw to von Frey filament stimuli was determined before surgery (baseline) and once daily for 7 days postoperatively. On day 7, spinal activation of microglia and astrocytes was evaluated immunohistochemically, using antibodies to the microglial marker OX-42 and the astrocyte marker glial fibrillary acidic protein (GFAP). RESULTS: Spinal nerve ligation induced mechanical allodynia in saline-treated rats, with OX-42 and GFAP immunoreactivity being significantly increased on the ipsilateral side of the spinal cord. Continuously administered intrathecal lamotrigine (240 MUg/day) prevented the development of mechanical allodynia, and lower dose of lamotrigine (72 MUg/day) ameliorated allodynia. Intrathecal lamotrigine (72 and 240 MUg/day) inhibited nerve ligation-induced microglial and astrocytic activation, as evidenced by reduced numbers of cells positive for OX-42 and GFAP. CONCLUSION: Continuously administered intrathecal lamotrigine blocked the development of mechanical allodynia induced by SNL with suppression of microglial and astrocytic activation. Continuous intrathecal administration of lamotrigine may be a promising therapeutic intervention to prevent neuropathy. PMID- 23364964 TI - Anti-allodynic effects of levodopa in neuropathic rats. AB - PURPOSE: Levodopa is the most effective anti-Parkinsonian agent. It has also been known to exhibit analgesic properties in laboratory and clinical settings. However, studies evaluating its effects on neuropathic pain are limited. The aim of the present study was to examine the anti-allodynic effects of levodopa in neuropathic rats. MATERIALS AND METHODS: Sprague-Dawley male rats underwent the surgical procedure for L5 and L6 spinal nerves ligation. Sixty neuropathic rats were randomly divided into 6 groups for the oral administration of distilled water and levodopa at 10, 30, 50, 70, and 100 mg/kg, respectively. We co administered carbidopa with levodopa to prevent peripheral synthesis of dopamine from levodopa, and observed tactile, cold, and heat allodynia pre-administration, and at 15, 30, 60, 90, 120, 150, 180, and 240 min after drug administration. We also measured locomotor function of neuropathic rats using rotarod test to examine whether levodopa caused side effects or not. RESULTS: Distilled water group didn't show any difference in all allodynia. For the levodopa groups (10 100 mg/kg), tactile and heat withdrawal thresholds were increased, and cold withdrawal frequency was decreased dose-dependently (p<0.01). In addition, levodopa induced biphasic analgesia. Different dosage of levodopa did not impact on the rotarod time (p>0.05). CONCLUSION: Levodopa reversed tactile, cold and heat allodynia in neuropathic rat without any side effects. PMID- 23364965 TI - Early differential changes in coronary plaque composition according to plaque stability following statin initiation in acute coronary syndrome: classification and analysis by intravascular ultrasound-virtual histology. AB - PURPOSE: The aim of this study was to demonstrate the early effects of statin treatment on plaque composition according to plaque stability on Intravascular Ultrasound- Virtual Histology at 6 months after a coronary event. Previous trials have demonstrated that lipid lowering therapy with statins decreases plaque volume and increases plaque echogenicity in patients with coronary artery disease. MATERIALS AND METHODS: Fifty-four patients (54 lesions) with acute coronary syndrome were prospectively enrolled. We classified and analyzed the target plaques into two types according to plaque stability: thin-cap fibroatheroma (TCFA, n=14) and non-TCFA (n=40). The primary end point was change in percent necrotic core in the 10-mm subsegment with the most disease. RESULTS: After 6 months of statin therapy, no change was demonstrated in the mean percentage of necrotic core (18.7+/-8.5% to 20.0+/-11.0%, p=0.38). There was a significant reduction in necrotic core percentage in patients with TCFA (21.3+/ 7.2% to 14.4+/-8.9%, p=0.017), but not in patients with non-TCFA. Moreover, change in percent necrotic core was significantly correlated with change in high sensitivity C-reactive protein levels (r=0.4, p=0.003). Changes in low-density lipoprotein cholesterol levels and lipid core percentage demonstrated no significant associations. CONCLUSION: A clear reduction of lipid core was observed only for the TCFA plaque type, suggesting that changes in plaque composition following statin therapy might occur earlier in vulnerable plaque than in stable plaque; the effect may be related to the anti-inflammatory effects of statins. PMID- 23364966 TI - Improvement of glycemic control after re-emphasis of lifestyle modification in type 2 diabetic patients reluctant to additional medication. AB - PURPOSE: The aim of this study is to observe glycemic changes after emphasizing the importance of lifestyle modification in patients with mild or moderately uncontrolled type 2 diabetes. MATERIALS AND METHODS: We examined 51 type 2 diabetic patients with 7.0-9.0% hemoglobin A1c (HbA1c) who preferred to change their lifestyle rather than followed the recommendation of medication change. At the enrollment, the study subjects completed questionnaires about diet and exercise. After 3 months, HbA1c levels were determined and questionnaires on the change of lifestyle were accomplished. We divided the study subjects into 3 groups: improved (more than 0.3% decrease of HbA1c), aggravated (more than 0.3% increase of HbA1c) and not changed (-0.3% 0.05). There was also no significant difference in biochemical recurrence rate between the two groups at the last follow-up, although Group 2 tended to have a lower PCa recurrence rate than Group 1 and the initial prostate-specific antigen (PSA) level was significantly higher in Group 2 than Group 1 (p=0.0496). CONCLUSION: The present single-surgeon case series study revealed a trend toward a lower rate of PCa recurrence in NHT+RRP treated patients compared to those treated with RRP alone, but this did not reach statistical significance, despite the fact that NHT+RRP patients exhibited higher serum PSA levels preoperatively. Prospective studies with a longer duration of observation and a greater number of patients would be helpful in evaluating NHT more definitively. PMID- 23364976 TI - Long-term (postnatal day 70) outcome and safety of intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells in neonatal hyperoxic lung injury. AB - PURPOSE: This study was performed to evaluate the long-term effects and safety of intratracheal (IT) transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in neonatal hyperoxic lung injury at postnatal day (P)70 in a rat model. MATERIALS AND METHODS: Newborn Sprague Dawley rat pups were subjected to 14 days of hyperoxia (90% oxygen) within 10 hours after birth and allowed to recover at room air until sacrificed at P70. In the transplantation groups, hUCB-MSCs (5*105) were administered intratracheally at P5. At P70, various organs including the heart, lung, liver, and spleen were histologically examined, and the harvested lungs were assessed for morphometric analyses of alveolarization. ED-1, von Willebrand factor, and human-specific nuclear mitotic apparatus protein (NuMA) staining in the lungs and the hematologic profile of blood were evaluated. RESULTS: Impaired alveolar and vascular growth, which evidenced by an increased mean linear intercept and decreased amount of von Willebrand factor, respectively, and the hyperoxia induced inflammatory responses, as evidenced by inflammatory foci and ED-1 positive alveolar macrophages, were attenuated in the P70 rat lungs by IT transplantation of hUCB-MSCs. Although rare, donor cells with human specific NuMA staining were persistently present in the P70 rat lungs. There were no gross or microscopic abnormal findings in the heart, liver, or spleen, related to the MSCs transplantation. CONCLUSION: The protective and beneficial effects of IT transplantation of hUCB-MSCs in neonatal hyperoxic lung injuries were sustained for a prolonged recovery period without any long-term adverse effects up to P70. PMID- 23364977 TI - External validation of the Acute Physiology and Chronic Health Evaluation II in Korean intensive care units. AB - PURPOSE: This study was designed to validate the usefulness of the Acute Physiology and Chronic Health Evaluation (APACHE) II for predicting hospital mortality of critically ill Korean patients. MATERIALS AND METHODS: We analyzed data on 826 patients who had been admitted to nine intensive care units and were included in the Fever and Antipyretics in Critical Illness Evaluation study cohort. RESULTS: Among the patients enrolled, 62% (512/826) were medical and 38% (314/826) were surgical patients. The median APACHE II score was 17 (11 to 23 interquartile range), and the hospital mortality rate was 19.5%. Age, underlying diseases, medical patients, mechanical ventilation, and renal replacement therapy were independently associated with hospital mortality. The calibration of APACHE II was poor (H=57.54, p<0.0001; C=55.99, p<0.0001), and the discrimination was modest [area under the receiver operating characteristic (aROC)=0.729]. Calibration was poor for both medical and surgical patients (H=63.56, p<0.0001; C=73.83, p<0.0001, and H=33.92, p<0.0001; C=33.34, p=0.0001, respectively), while discrimination was poor for medical patients (aROC=0.651) and modest for surgical patients (aROC=0.704). At the predicted risk of 50%, APACHE II had a sensitivity of 36.6% and a specificity of 87.4% for hospital mortality. CONCLUSION: For Koreans, the APACHE II exhibits poor calibration and modest discrimination for hospital mortality. Therefore, a new model is needed to accurately predict mortality in critically ill Korean patients. PMID- 23364978 TI - Feasibility and early outcomes of intensivist-led critical care after major trauma in the Korean ICU. AB - PURPOSE: Substantial evidence supports the benefits of an intensivist model of critical care delivery. However, currently, this mode of critical care delivery has not been widely adopted in Korea. We hypothesized that intensivist-led critical care is feasible and would improve ICU mortality after major trauma. MATERIALS AND METHODS: A trauma registry from May 2009 to April 2011 was reviewed retrospectively. We evaluated the relationship between modes of ICU care (open vs. intensivist) and in-hospital mortality following severe injury [Injury Severity Score (ISS)>15]. An intensivist-model was defined as ICU care delivered by a board-certified physician who had no other clinical responsibilities outside the ICU and who is primarily available to the critically ill or injured patients. ISS and Revised Trauma Score were used as measure of injury severity. The Trauma and Injury Severity Score methodology was used to calculate each individual patient's probability of survival. RESULTS: Of the 251 patients, 57 patients were treated by an intensivist [intensivist group (IG)] while 194 patients were not [non-intensivist group (NIG)]. The ISS of IG was significantly higher than that for NIG (26.5 vs. 22.3, p=0.023). The hospital mortality rate for IG was significantly lower than that for NIG (15.8% and 27.8%, p<0.001). CONCLUSION: The intensivist model of critical care is feasible, and there is room for improvement in the care of major trauma patients. Although trauma systems take time to mature, future studies are needed to evaluate the best model of critical care delivery for severely injured patients in Korea. PMID- 23364979 TI - Rapamycin inhibits transforming growth factor beta1-induced fibrogenesis in primary human lung fibroblasts. AB - PURPOSE: The present study was designed to determine whether rapamycin could inhibit transforming growth factor beta1 (TGF-beta1)-induced fibrogenesis in primary lung fibroblasts, and whether the effect of inhibition would occur through the mammalian target of rapamycin (mTOR) and its downstream p70S6K pathway. MATERIALS AND METHODS: Primary normal human lung fibroblasts were obtained from histological normal lung tissue of 3 patients with primary spontaneous pneumothorax. Growth arrested, synchronized fibroblasts were treated with TGF-beta1 (10 ng/mL) and different concentrations of rapamycin (0.01, 0.1, 1, 10 ng/mL) for 24 h. We assessed m-TOR, p-mTOR, S6K1, p-S6K1 by Western blot analysis, detected type III collagen and fibronectin secreting by ELISA assay, and determined type III collagen and fibronectin mRNA levels by real-time PCR assay. RESULTS: Rapamycin significantly reduced TGF-beta1-induced type III collagen and fibronectin levels, as well as type III collagen and fibronectin mRNA levels. Furthermore, we also found that TGF-beta1-induced mTOR and p70S6K phosphorylation were significantly down-regulated by rapamycin. The mTOR/p70S6K pathway was activated through the TGF-beta1-mediated fibrogenic response in primary human lung fibroblasts. CONCLUSION: These results indicate that rapamycin effectively suppresses TGF-beta1-induced type III collagen and fibronectin levels in primary human lung fibroblasts partly through the mTOR/p70S6K pathway. Rapamycin has a potential value in the treatment of pulmonary fibrosis. PMID- 23364980 TI - Interleukin-10 down-regulates cathepsin B expression in fetal rat alveolar type II cells exposed to hyperoxia. AB - PURPOSE: Hyperoxia has the chief biological effect of cell death. We have previously reported that cathepsin B (CB) is related to fetal alveolar type II cell (FATIIC) death and pretreatment of recombinant IL-10 (rIL-10) attenuates type II cell death during 65%-hyperoixa. In this study, we investigated what kinds of changes of CB expression are induced in FATIICs at different concentrations of hyperoxia (65%- and 85%-hyperoxia) and whether pretreatment with rIL-10 reduces the expression of CB in FATIICs during hyperoxia. MATERIALS AND METHODS: Isolated embryonic day 19 fetal rat alveolar type II cells were cultured and exposed to 65%- and 85%-hyperoxia for 12 h and 24 h. Cells in room air were used as controls. Cytotoxicity was assessed by lactate dehydrogenase (LDH) released into the supernatant. Expression of CB was analyzed by fluorescence-based assay upon cell lysis and western blotting, and LDH-release was re-analyzed after preincubation of cathepsin B-inhibitor (CBI). IL-10 production was analyzed by ELISA, and LDH-release was re-assessed after preincubation with rIL-10 and CB expression was re-analyzed by western blotting and real-time PCR. RESULTS: LDH-release and CB expression in FATIICs were enhanced significantly in an oxygen-concentration-dependent manner during hyperoxia, whereas caspase-3 was not activated. Preincubation of FATIICs with CBI significantly reduced LDH-release during hyperoxia. IL-10-release decreased in an oxygen-concentration-dependent fashion, and preincubation of the cells with rIL 10 significantly reduced cellular necrosis and expression of CB in FATIICs which were exposed to 65%- and 85%-hyperoxia. CONCLUSION: Our study suggests that CB is enhanced in an oxygen- concentration-dependent manner, and IL-10 has an inhibitory effect on CB expression in FATIICs during hyperoxia. PMID- 23364981 TI - Rapid decrease of intact parathyroid hormone could be a predictor of better response to cinacalcet in hemodialysis patients. AB - PURPOSE: Cinacalcet is effective for treating refractory secondary hyperparathyroidism (SHPT), but little is known about the response rates and clinical factors influencing the response. MATERIALS AND METHODS: A prospective, single-arm, multi-center study was performed for 24 weeks. Cinacalcet was administered to patients with intact parathyroid hormone (iPTH) level greater than 300 pg/mL. Cinacalcet was started at a dose of 25 mg daily and titrated until 100 mg to achieve a serum iPTH level<300 pg/mL (primary end point). Early response to cinacalcet was defined as a decrease of iPTH more than 50% within one month. RESULTS: Fifty-seven patients were examined. Based on the magnitude of iPTH decrease, patients were divided into responder (n=47, 82.5%) and non responder (n=10, 17.5%) groups. Among the responders, 38 achieved the primary end point, whereas 9 patients showed a reduction in serum iPTH of 30% or more, but did not reach the primary end point. Compared to non-responders, responders were significantly older (p=0.026), female (p=0.041), and diabetics (p<0.001). Additionally, early response was observed more frequently in the responders (30/47, 63.8%), of whom the majority (27/30, 90.0%) achieved the primary end point. Multivariate analysis showed that lower baseline iPTH levels [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.93-0.99], the presence of diabetes (OR 46.45, CI 1.92-1125.6) and early response (OR 21.54, CI 2.94-157.7) were significant clinical factors affecting achievement of iPTH target. CONCLUSION: Cinacalcet was effective in most hemodialysis patients with refractory SHPT. The presence of an early response was closely associated with the achievement of target levels of iPTH. PMID- 23364982 TI - Easily removable ureteral catheters for internal drainage in children: a preliminary report. AB - PURPOSE: We review our experience using a new and easily removable ureteral catheter in patients who underwent complicated ureteral reimplantation. Our goal was to shorten hospital stay and lower anxiety during catheter removal without fear of postoperative ureteral obstruction. MATERIALS AND METHODS: Between April 2009 and September 2010, nine patients who underwent our new method of catheter removal after ureteral reimplantation were enrolled. Patients who underwent simple ureteral reimplantation were excluded from the study. Following ureteral reimplantation, a combined drainage system consisting of a suprapubic cystostomy catheter and a ureteral catheter was installed. Proximal external tubing was clamped with a Hem-o-lok clamp and the rest of the external tubing was eliminated. Data concerning the age and sex of each patient, reason for operation, method of ureteral reimplantation, and postoperative parameters such as length of hospital stay and complications were recorded. RESULTS: Of the nine patients, four had refluxing megaureter, four had a solitary or non-functional contralateral kidney and one had ureteral stricture due to a previous anti-reflux operation. The catheter was removed at postoperative week one. The mean postoperative hospital stay was 2.4 days (range 1-4 days), and the mean follow-up was 9.8 months. None of the patients had postoperative ureteral obstructions, and there were no cases of migration or dislodgement of the catheter. CONCLUSION: Our new method for removing the ureteral catheter would shorten hospital stays and lower levels of anxiety when removing ureteral catheters in patients with a high risk of postoperative ureteral obstruction. PMID- 23364983 TI - Outpatient-based pneumococcal vaccine campaign and survey of perceptions about pneumococcal vaccination in patients and doctors. AB - PURPOSE: Despite the ready availability of pneumococcal vaccine, vaccination rates are quite low in South Korea. This study was designed to assess perceptions and awareness about pneumococcal vaccines among subjects at risk and find strategies to increases vaccine coverage rates. MATERIALS AND METHODS: A cross sectional, community-based survey was conducted to assess perceptions about the pneumococcal vaccine at a local public health center. In a tertiary hospital, an outpatient- based pneumococcal vaccine campaign was carried out for the elderly and individuals with chronic co-morbidities from May to July of 2007. RESULTS: Based on the survey, only 7.6% were ever informed about pneumococcal vaccination. The coverage rates of the pneumococcal vaccine before and after the hospital campaign showed an increased annual rate from 3.39% to 5.91%. The most common reason for vaccination was "doctor's advice" (53.3%). As for the reasons for not receiving vaccination, about 75% of high risk patients were not aware of the pneumococcal vaccine, which was the most important barrier to vaccination. Negative clinician's attitude was the second most common cause of non vaccination. CONCLUSION: Annual outpatient-based campaigns early in the influenza season may improve pneumococcal vaccine coverage rates. Doctor's advice was the most important encouraging factor for vaccination. PMID- 23364984 TI - Evaluation of a rapid detection influenza virus a antigens kit using paired serum antibody test. AB - PURPOSE: To evaluate the feasibility for gold immunochromatographic assay (GICA) in rapid detection of influenza virus A infection. MATERIALS AND METHODS: Seventy three patients were enrolled. All patients contributed nasopharyngeal secretions and paired serum samples. Nasopharyngeal secretions was used for colloidal gold immunochromatographic rapid assay for influenza A virus immediately after the collection of specimen. Paired serum samples were used for the hemagglutination inhibition assay at the Centers for Disease Control and Prevention influenza network laboratory in Beijing. RESULTS: Compare GICA test to hemagglutination inhibition (HI) assay, the Kappa value was 0.402 and the p value in the paired chi2 test was higher than 0.05. Therefore, the difference was not statistically significant. The sensitivity of GICA was 50.0% and the specificity was 90.2%, and the negative predictive value was 90.2%. CONCLUSION: The sensitivity for Influenza A antigen detection by using GICA is relatively low, the specificity is relatively satisfactory. PMID- 23364985 TI - Causes of death of prisoners of war during the Korean War (1950-1953). AB - PURPOSE: This study aimed at analyzing the causes of death of prisoners of war (POWs) during the Korean War (1950-1953) who fought for the Communist side (North Korea and the People's Republic of China). In 1998, the United States Department of Defense released new information about the prisoners including, 7,614 deaths of the POW during the Korean War. The data on the causes of death of the POWs during the Korean War provides valuable information on the both the public health and history of the conflict. MATERIALS AND METHODS: To analyze the causes of death of the POWs, we classified the clinical diagnosis and findings on 7,614 deaths into 22 chapters, as outlined in the International Statistical Classification of Diseases and Related Health Problems-10th Revision (ICD-10). Second, we traced changes in the monthly death totals of POWs as well as deaths caused by common infectious diseases and external causes of death including injury over time from August 1950 to September 1953. RESULTS: The most common category of causes of deaths of POWs was infectious disease, 5,013 (65.8%) out of 7,614 deaths, followed by external causes including injury, 817 (10.7%). Overall, tuberculosis and dysentery/diarrhea were the most common causes of death. Deaths caused by acute and chronic infection, or external causes showed different patterns of increases and decline over time during the Korean War. CONCLUSION: The information and data on POWs' deaths during the Korean War reflects the critical impact of the POWs' living conditions and the effect of public health measures implemented in POW camps during the war. PMID- 23364986 TI - Preventive effects of Lactobacillus mixture on experimental E. coli urinary tract infection in infant rats. AB - PURPOSE: Urinary tract infection (UTI) is an ascending infection of fecal uropathogens, urogenital lactobacilli are suggested to play a role in the prevention of UTI. This study was to investigate whether lactobacillus mixture (LM) could prevent the experimental infantile UTI. MATERIALS AND METHODS: The LM were composed of three lactobacillus strains (L. gasseri, L. rhamnosus, and L. reuteri). Mother rats were grouped as lactobacillus (LB) group I (LB I, n=22), II (LB II, n=24) and control (n=20). LB I and LB II were fed with LM (1 mL/day) and control with phosphate-buffered saline (PBS) from late pregnancy through lactation. All newborn rats were breast-fed and their urine and stool were collected at the end of the 3rd week to compare lactobacillus colony. Then, infant rats from LB II were treated with intravesical instillation of LM. Infant rats from LB I and control were instilled with PBS. Twenty-four hours later, experimental UTI was introduced by intravesical instillation of standard E. coli strain. After 72 hours later, the infant rats were sacrificed for histologic examination. RESULTS: Lactobacilli colonies in urine and stool were not statistically different among the three groups. The incidence of pyelonephritis in the LB II was 16.7% (4/24), LB I 72.7% (16.22) and control 75.0% (15/20) (p=0.015). The incidence of cystitis was not significantly different among the three groups. CONCLUSION: The intravesically instilled LM significantly prevented experimental pyelonephritis in infant rats, however, LM administered orally to the pregnant and lactating mother rats did not. PMID- 23364987 TI - Expression and localization of COMMD1 proteins in human placentas from women with preeclampsia. AB - PURPOSE: Recently, COMMD1 has been identified as a novel interactor and regulator of hypoxia-inducible factor-1 and nuclear factor kappa B transcriptional activity. The goal of this study was to determine the difference of COMMD1 expression in the placentas of women with normal and preeclamptic (PE) pregnancies. MATERIALS AND METHODS: Immnoperoxidase and immunofluorescent staining for COMMD1 was performed on nine normal and nine severe PE placental tissues, and COMMD1 mRNA expression was quantified by quantitative reverse transcription polymerase chain reaction. RESULTS: The expression of mRNA of COMMD1 was significantly higher in the study group than in the control group. The immunoreactivity was higher especially in the syncytiotrophoblast of PE placentas than in the control group. CONCLUSION: This study demonstrated increased placental COMMD1 expression in women with severe preeclampsia compared to that found in women with normal pregnancies, and this finding might contribute to a better understanding of the pathophysiology of preeclampsia. PMID- 23364988 TI - Analysis of single nucleotide polymorphism in adolescent idiopathic scoliosis in Korea: for personalized treatment. AB - PURPOSE: The incidence of adolescent idiopathic scoliosis (AIS) has rapidly increased, and with it, physician consultations and expenditures (about one and a half times) in the last 5 years. Recent etiological studies reveal that AIS is a complex genetic disorder that results from the interaction of multiple gene loci and the environment. For personalized treatment of AIS, a tool that can accurately measure the progression of Cobb's angle would be of great use. Gene analysis utilizing single nucleotide polymorphism (SNP) has been developed as a diagnostic tool for use in Caucasians but not Koreans. Therefore, we attempted to reveal AIS-related genes and their relevance in Koreans, exploring the potential use of gene analysis as a diagnostic tool for personalized treatment of AIS therein. MATERIALS AND METHODS: A total of 68 Korean AIS and 35 age- and sex matched, healthy adolescents were enrolled in this study and were examined for 10 candidate scoliosis gene SNPs. RESULTS: This study revealed that the SNPs of rs2449539 in lysosomal-associated transmembrane protein 4 beta (LAPTM4B) and rs5742612 in upstream and insulin-like growth factor 1 (IGF1) were associated with both susceptibility to and curve severity in AIS. The results suggested that both LAPTM4B and IGF1 genes were important in AIS predisposition and progression. CONCLUSION: Thus, on the basis of this study, if more SNPs or candidate genes are studied in a larger population in Korea, personalized treatment of Korean AIS patients might become a possibility. PMID- 23364989 TI - Clinical results of auto-iliac cancellous bone grafts combined with implantation of autologous bone marrow cells for osteonecrosis of the femoral head: a minimum 5-year follow-up. AB - PURPOSE: There are no reports about bone graft and cell therapy for the osteonecrosis of femoral head (ONFH). We prospectively evaluated the clinical results of auto-iliac cancellous bone grafts combined with implantation of autologous bone marrow cells for ONFH. MATERIALS AND METHODS: Sixty-one hips in 52 patients with ONFH treated with bone graft and cell therapy were enrolled, and the average follow-up of the patients was 68 (60-88) months. Necrotic lesions were classified according to their size by the Steinberg method and location of necrosis. RESULTS: At the last follow-up, the percentage of excellent or good results was 80% (12/15 hips) in the small lesion group, 65% (17/26 hips) in the medium size group, and 28% (6/20 hips) in the large size group. The procedures were a clinical success in 4 of 5 hips (80%) of stage I, 23 of 35 hips (65.7%) of stage II, 7 of 18 hips (38.9%) of stage III, and 1 of 3 hips (33.3%) of stage IV grade, according to the Association Research Circulation Osseous grading system. Among the 20 cases with large sized necrotic lesions, 17 cases were laterally located and this group showed the worst outcomes, with 13 hips (76.5%) having bad or failed clinical results. CONCLUSION: The results of the present study suggested that patients who have a large sized lesion or medium sized laterally located lesion would not be good candidates for the head preserving procedure. However, for medium sized lesions, this procedure generated clinical results comparable to those of other head preserving procedures. PMID- 23364990 TI - Relation among the gross motor function, manual performance and upper limb functional measures in children with spastic cerebral palsy. AB - PURPOSE: The objective of this study was to describe hand function in relation with gross motor function and subtype of spastic cerebral palsy and to investigate the relationships among gross motor function, bimanual performance, unimanual capacity and upper limb functional measures in children with spastic cerebral palsy (CP). MATERIALS AND METHODS: We collected upper extremity data of 140 children with spastic CP. The Gross Motor Functional Classification System (GMFCS) was used to assess gross motor function, Manual Ability Classification System (MACS) for bimanual performance, and Modified House Functional Classification (MHC) for the best capacity of each hand. Upper limb functions were evaluated by using the Upper Limb Physician's Rating Scale and Upper Extremity Rating Scale. RESULTS: There was a good correlation between GMFCS and MACS in children with bilateral CP, but the correlation was not strong in children with unilateral CP. No significant difference between GMFCS and MACS was found in children with bilateral CP, but children with unilateral CP scored higher on GMFCS than on MACS. A strong correlation was observed between MACS and MHC in children with bilateral CP, but not in children with unilateral CP. The upper limb functional measures in each hand were highly related with MACS and MHC in bilateral CP, but not in unilateral CP. CONCLUSION: Gross motor function, bimanual performance and the best capacity of each hand are closely related with each other in children with bilateral CP, but not in children with unilateral CP. PMID- 23364991 TI - Acute modulations in stratum corneum permeability barrier function affect claudin expression and epidermal tight junction function via changes of epidermal calcium gradient. AB - Tight junction (TJ) is recognized as a second barrier of the skin. Altered expression of TJ proteins in various skin diseases characterized by the abnormal permeability barrier such as psoriasis suggests that TJ could be affected by stratum corneum (SC) barrier status. However, the physiological relationship between SC and TJ barrier remains to be investigated. Therefore, we examined the effect of SC barrier disruption on the expression of TJ proteins, claudin (Cldn) 1 and Cldn-4, and TJ barrier function in hairless mouse skin. We also investigated whether the alterations in epidermal Ca2+ affected TJ proteins expression in vivo. Repeated tape-stripping induced a sequential change of the expression and function of TJ. As early as 15-30 minutes after tape-stripping, downregulation of Cldn-1 and Cldn-4 immunoreactivity and protein level without change in mRNA level was found. This was accompanied by the abnormal leakage of lanthanum. However, by 1 hour Cldn-1 and Cldn-4 immunolocalization recovered along with normalized lanthanum permeation pattern. Moreover, the mRNA and protein levels of Cldn-1 and Cldn-4 were increased by 1 to 6 hours after tape stripping. Inhibition of calcium loss by immersion of barrier-disrupted skin into a high Ca2+ solution prevented the dislocation of Cldn-1 and Cldn-4. Occlusion of barrier-disrupted skin delayed the restoration of Cldn-1 and Cldn-4. Our results suggest that the alteration of epidermal Ca2+ gradient caused by SC barrier perturbation affects the TJ structure and function and the faster recovery of TJ as compared to the SC barrier may imply the protective homeostatic mechanism of skin barrier. PMID- 23364992 TI - A case of Long QT syndrome type 3 aggravated by beta-blockers and alleviated by mexiletine: the role of epinephrine provocation test. AB - Long QT syndrome (LQTs) is an uncommon genetic disease causing sudden cardiac death with Torsade de Pointes (TdP). The first line drug treatment has been known to be beta-blocker. We encountered a 15-year-old female student with LQTs who had prolonged QTc and multiple episodes of syncope or agonal respiration during sleep. Although her T wave morphology in surface electrocardiography resembled LQTs type 1, her clinical presentation was unusual. During the epinephrine test, TdP was aggravated during beta-blocker medication, but alleviated by sodium channel blocker (mexiletine). Therefore, she underwent implantable cardioverter defibrillator implantation. PMID- 23364993 TI - Dorsal-plantar loop technique using chronic total occlusion devices via anterior tibial artery. AB - The effectiveness of below-the-knee (BTK) percutaneous transluminal angioplasty to obtain successful revascularization in patients with critical limb ischemia has been well established, and many of these patients with chronic lower extremity disease have been treated by endovascular intervention as the firstline treatment. Dorsal-plantaer loop technique is one of the new BTK interventional techiniques, and includes recanalization of both pedal and plantar arteries and their anatomical anastomoses. This method generally needs two approaches simultaneously, including antegrade and retrograde. In this report, however, we describe a case in which dorsal-plantar loop technique with only one antegrade approach, using chronic total occlusion devices via anterior tibial artery, was used to successfully recanalize BTK arteries. We think that this new technique, which may represent a safe and feasible endovascular option to avoid more invasive, time-consuming, and riskier surgical procedures, especially in end stage renal disease and diabetes, should be considered whenever the foot is at risk, and results of above-the-ankle percutaneous transluminal angioplasty remain unsatisfactory or insufficient to achieve limb salvage. PMID- 23364994 TI - A 47,X,+t(X;X)(p22.3;p22.3)del(X)(p11.23q11.2),Y Klinefelter variant with morbid obesity. AB - Klinefelter syndrome is the most common type of genetic cause of hypogonadism. This syndrome is characterized by the presence of 1 or more extra X chromosomes. Phenotype manifestations of this syndrome are small testes, fibrosis of the seminiferous tubules, inability to produce sperm, gynecomastia, tall stature, decrease of serum testosterone and increases of luteinizing hormone and follicle stimulating hormone. Most patients with Klinefelter syndrome are tall, with slender body compositions, and reports of obesity are rare. We report the case of a 35-yr-old man with hypogonadism and morbid obesity and diabetes mellitus. He had gynecomastia, small testes and penis, very sparse body hair and his body mass index was 44.85. He did not report experiencing broken voice and was able to have erections. We conducted a chromosome study. His genotype was 47,X,+t(X;X)(p22.3;p22.3)del(X)(p11.23q11.2). In this case, the patient was diagnosed as Klinefelter syndrome. He showed rare phenotypes like morbid obesity and average height and the phenotype may be caused by the karyotype and the excess number of X chromosome. Further studies of the relationship between chromosomes and phenotype are warranted. PMID- 23364995 TI - Can we accurately assess liver fibrosis with Fibroscan(r) using fewer valid measurements? PMID- 23364998 TI - Selective fluorescence quenching in cationic fluorene-thiophene diblock copolymers for ratiometric sensing of anions. AB - The cationic, all-conjugated AB diblock copolymer poly[9,9-bis(2 ethylhexyl)fluorene]-b-poly[3-(6-trimethylammoniumhexyl) thiophene] bromide (PF2/6-b-P3TMAHT) shows dual fluorescence from the poly(fluorene) (PF) and poly(thiophene) (PT) blocks. A comparison of fluorescence quenching of the cationic PT block fluorescence with unquenched PF block provides a sensitive ratiometric method for anion sensing. The application to analysis of halide ions, single- and double-stranded DNA is demonstrated. High selectivity is observed with halide ions, with the strongest quenching being seen with iodide. The quenching with DNA can be used for nucleic acid quantification at sub-MUM concentrations. PMID- 23364999 TI - The power to conquer adversity. PMID- 23364997 TI - Irritable mood in adult major depressive disorder: results from the world mental health surveys. AB - BACKGROUND: Although irritability is a core symptom of DSM-IV major depressive disorder (MDD) for youth but not adults, clinical studies find comparable rates of irritability between nonbipolar depressed adults and youth. Including irritability as a core symptom of adult MDD would allow detection of depression equivalent syndromes with primary irritability hypothesized to be more common among males than females. We carried out a preliminary examination of this issue using cross-national community-based survey data from 21 countries in the World Mental Health (WMH) Surveys (n = 110,729). METHODS: The assessment of MDD in the WHO Composite International Diagnostic Interview includes one question about persistent irritability. We examined two expansions of the definition of MDD involving this question: (1) cases with dysphoria and/or anhedonia and exactly four of nine Criterion A symptoms plus irritability; and (2) cases with two or more weeks of irritability plus four or more other Criterion A MDD symptoms in the absence of dysphoria or anhedonia. RESULTS: Adding irritability as a tenth Criterion A symptom increased lifetime prevalence by 0.4% (from 11.2 to 11.6%). Adding episodes of persistent irritability increased prevalence by an additional 0.2%. Proportional prevalence increases were significantly higher, but nonetheless small, among males compared to females. Rates of severe role impairment were significantly lower among respondents with this irritable depression who did not meet conventional DSM-IV criteria than those with DSM-IV MDD. CONCLUSION: Although limited by the superficial assessment in this single question on irritability, results do not support expanding adult MDD criteria to include irritable mood. PMID- 23365000 TI - Sleep hygiene program implementation in patients with traumatic brain injury. AB - PURPOSE: Traumatic brain injury (TBI) is a serious public health problem. The impact of TBI on the individual is multifaceted and includes neurocognitive, behavioral, and psychiatric disturbances as well as greater predisposition for dementia. A common but significant problem reported by patients after TBI is sleep disturbance. The purpose of this manuscript is twofold: (1) to describe our experience with implementation of the newly developed sleep hygiene guidelines; and (2) to report our preliminary results of implementation of the sleep hygiene guidelines on TBI patient outcomes. METHODS: A mixed methods approach was used to assess implementation of sleep hygiene guidelines and to gather preliminary data on outcomes. RESULTS: Although not statistically significant, the average self reported sleep duration of these TBI patients was slightly higher in 2010 than 2009, with a FIM score that was similar for both time points. In 2009, the mean change in functional independence measure (FIM) score (n = 34) was 1.44. In 2010, the mean change in FIM score (n = 33) was 1.42. In 2009, most patients (n = 13) admitted to the hospital continued to take medications and were discharged with a sleep aid. In 2010, most patients reported a change in their sleep medication prescriptions (on medications at admission and none at discharge) or had continued to take their prescribed sleep medications from admission to discharge (n = 12). CONCLUSION: Sleep disorders have a major impact on health outcomes in patients with TBI. To optimize rehabilitation and ultimately improve functional outcomes of patients with TBI, implementation of evidence-based clinical guidelines for sleep is imperative. We report our initial experience with implementation of sleep guidelines. PMID- 23365001 TI - Study of older adults' use of self-regulation for COPD self-management informs an evidence-based patient teaching plan. AB - PURPOSE: People with chronic obstructive pulmonary disease (COPD) have frequent hospitalizations and emergency department visits, often due to COPD exacerbations which worsen disease status. Recognizing exacerbations is challenging; patients must distinguish between day-to-day COPD symptom variations and exacerbation symptoms. Self-regulation theory (Bandura, 1999) is useful for understanding symptom recognition, interpretation, and response. In this article a qualitative study of self-regulation use by 28 older adults with COPD (Brandt, 2005) is summarized. METHODS: Twenty-eight community-dwelling older adults were interviewed. Data were analyzed using the interpretive description method. RESULTS AND DISCUSSION: Informants used self-regulation behaviors in varying degrees. Most attended primarily to their breathing, comparing their usual degree of breathlessness and intensifying their everyday self-management practices if breathlessness worsened. CLINICAL RELEVANCE: A theory- and evidence-based COPD teaching plan for use by rehabilitation nurses is presented that includes attention to exacerbation recognition. PMID- 23365002 TI - Eliciting patient and caregiver perspectives to improve the public reporting of rehabilitation quality measures. AB - PURPOSE: To evaluate patients' and caregivers' abilities to comprehend information on rehabilitation quality measures, and select high-quality rehabilitation facility. DESIGN: We used exploratory, qualitative study using cognitive interviewing. SETTING: Three Outpatient rehabilitation facilities in metropolitan Chicago, Illinois, USA. PARTICIPANTS: The study participants included 27 patients or three caregivers, 63% female; 36.7% white, 43.3% African American, 10% Asian, 10% missing/other; health literacy: 59% at the 8th grade level or lower; age range: 33-94. MAIN OUTCOME MEASURE(S): Patient and caregiver comprehension of quality measures. RESULTS: Respondents understood some rehabilitation quality terms, but had difficulty with medical terminology; linking quality measures to hospital quality; explaining choice of "better" quality facility; and reading tables. The research team simplified terminology, definitions, layout, and design; added an introduction to provide a framework for understanding quality. CONCLUSIONS: Quality measure information can be difficult to understand and use. When reporting quality measures, use plain language, avoid medical jargon, follow logically sequenced content, easy-to-read layout, provide framework for understanding quality, and solicit consumer feedback. CLINICAL IMPLICATIONS: Not applicable. PMID- 23365003 TI - Preferences for rehabilitation services among women with major limb amputations. AB - PURPOSE: We present five cases of adult females with major limb amputations, their concerns and preferences for services across the life span. DESIGN: A convenience sample of five veteran and nonveteran women aged 19-58 with major limb amputations participating in a regional VA Prosthetics Conference in 2010 took part in a panel interview. FINDINGS: The concerns identified by these women as high priorities included independence and participation in a full range of life activities, limitations in access, patient decision-making and body image concerns, and preferences for selected services. Maximizing function and quality of life for women amputees requires identifying patient preferences for rehabilitation and prosthetic services. Lessons learned could inform development of clinic-based rehabilitation care, prosthetic services, and studies of women with major limb amputations. CONCLUSIONS: As the current conflicts in Iraq and Afghanistan wind down, the number of women veterans seeking rehabilitation and prosthetic services will increase. With this information, rehabilitation and prosthetic service providers and organizations will be uniquely positioned to provide prevention and treatment of amputations for this growing population of women veterans in national care delivery systems and in communities. CLINICAL RELEVANCE: An open-ended facilitated discussion among a panel of women with major limb amputations provided insights for providers and organizations with respect to needs, concerns, and preferences for rehabilitation and prosthetic services. PMID- 23365004 TI - A long-term physical activity training program increases strength and flexibility, and improves balance in older adults. AB - PURPOSE: Physical activity training programs in older adults have recognized health benefits. Evidence suggests that training should include a combination of progressive resistance, balance, and functional training. Our aim was to assess the effects of a simple physical activity program working on strength, flexibility, cardiovascular fitness, and balance in older adults, as well as the effects of a detraining period, at various different ages. METHODS: This was longitudinal prospective study, including a convenience sample of 227 independent older adults (54 men, 173 women) who completed a simple 9-month training program and 3-month detraining follow-up. The subjects were categorized into two age groups (65-74 [n = 180], and >74 years [n = 47]). At the beginning of the study (baseline), the end of the training period, and 3 months later (postdetraining), body mass index, body fat percentage, triceps skinfold thickness, hand grip strength, lower limb and trunk flexibility, resting heart rate, heart rate after exercise, and balance were measured, while VO(2 max) was estimated using the Rockport fitness test and/or measured directly. RESULTS: Significant improvements in strength (p < .0001), flexibility (p < .0001), heart rate after exercise (p < .0001), and balance (p < .0001) were observed at the end of the training program. Flexibility and balance (p < .0001) improvements were maintained at the end of the detraining. CONCLUSION: A simple long-term physical activity training program increases strength in both sexes, improves flexibility in women, and improves balance in older adults. The results also indicate the importance of beginning early in old age and maintaining long-term training. PMID- 23365005 TI - Impact of exercise on lower activity levels in children with acute lymphoblastic leukemia: a randomized controlled trial from Turkey. AB - This randomized, controlled experimental study was carried out to determine the effects of an exercise program on both physical parameters and the quality of life of children with acute lymphoblastic leukemia (ALL). A total of 41 children with ALL (20 trial and 21 control cases) at two university hospitals were accepted into the study. Due to the demise of one of the children in the trial group, the study was completed with 19 trial and 21 control patients, a total of 40 children and their parents. Regular and systematic exercise regimens implemented by children with ALL have resulted in improved testing results, enhanced physical performance, and better laboratory results compared with a control group and to children's scores before the initiation of such a program. PMID- 23365006 TI - Non-linear optical microscopy of kidney tumours. AB - The unregulated cancer cell growth leads to strong alterations in morphology and composition of the tissue. The combination of coherent anti-Stokes Raman scattering, two-photon excited fluorescence and second harmonic generation enables a high resolution imaging with strong information on tissue composition and can then provide useful information for tumour diagnosis. Here we present the potential of multimodal non-linear microscopy for imaging of renal tumours. Using cryosections of human oncocytoma and carcinoma, the method gave a detailed insight in cancer morphology and composition, enabling to discern between normal kidney tissue, tumour and necrosis. Several features significant for the diagnosis were clearly visualised without use of any staining. Translation of this method in clinical pathology will greatly improve speed and quality of the analyses. PMID- 23365007 TI - Maize seed coatings and seedling sprayings with chitosan and hydrogen peroxide: their influence on some phenological and biochemical behaviors. AB - OBJECTIVE: To evaluate the effect of chitosan (CH) and hydrogen peroxide (H(2)O(2)) seed coatings and seedling sprinklings on two different maize varieties by measuring their phenology, the H(2)O(2) presence, the catalase (CAT) activity, and the protein quantity. METHODS: Seven groups of ten seeds for each maize variety were treated with CH (2% (20 g/L) and 0.2% (2 g/L)) or H(2)O(2) (8 mmol/L) by coating, sprinkling, or both. Germination and seedling growth were measured. One month after germination, the presence of H(2)O(2) in seedlings in the coated seed treatments was evaluated. Protein content and CAT activity were determined under all treatments. RESULTS: H(2)O(2) seed coating enhanced the germination rate and increased seedling and stem length in the quality protein maize (QPM) variety. Seedlings had a higher emergence velocity under this treatment in both varieties. CH and H(2)O(2) sprinklings did not have an effect on seedling phenology. Exogenous application of H(2)O(2) promoted an increase of endogenous H(2)O(2). CH and H(2)O(2) seedling sprinkling increased the protein content in both maize varieties, while there was no significant effect on the CAT activity of treated seeds and seedlings. CONCLUSIONS: CH and H(2)O(2) enhance some phenological and biochemical features of maize depending on their method of application. PMID- 23365008 TI - Protective effect of oat bran extracts on human dermal fibroblast injury induced by hydrogen peroxide. AB - Oat contains different components that possess antioxidant properties; no study to date has addressed the antioxidant effect of the extract of oat bran on the cellular level. Therefore, the present study focuses on the investigation of the protective effect of oat bran extract by enzymatic hydrolysates on human dermal fibroblast injury induced by hydrogen peroxide (H(2)O(2)). Kjeldahl determination, phenol-sulfuric acid method, and high-performance liquid chromatography (HPLC) analysis indicated that the enzymatic products of oat bran contain a protein amount of 71.93%, of which 97.43% are peptides with a molecular range from 438.56 to 1301.01 Da. Assays for 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity indicate that oat peptide-rich extract has a direct and concentration-dependent antioxidant activity. 3-(4,5-Dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay and the TdT-mediated digoxigenin-dUTP nick-end labeling (TUNEL) assay for apoptosis showed that administration of H(2)O(2) in human dermal fibroblasts caused cell damage and apoptosis. Pre-incubation of human dermal fibroblasts with the Oatp for 24 h markedly inhibited human dermal fibroblast injury induced by H(2)O(2), but application oat peptides with H(2)O(2) at same time did not. Pre-treatment of human dermal fibroblasts with Oatp significantly reversed the H(2)O(2)-induced decrease of superoxide dismutase (SOD) and the inhibition of malondialdehyde (MDA). The results demonstrate that oat peptides possess antioxidant activity and are effective against H(2)O(2)-induced human dermal fibroblast injury by the enhanced activity of SOD and decrease in MDA level. Our results suggest that oat bran will have the potential to be further explored as an antioxidant functional food in the prevention of aging-related skin injury. PMID- 23365009 TI - Improved cadmium uptake and accumulation in the hyperaccumulator Sedum alfredii: the impact of citric acid and tartaric acid. AB - The elucidation of a natural strategy for metal hyperaccumulation enables the rational design of technologies for the clean-up of metal-contaminated soils. Organic acid has been suggested to be involved in toxic metallic element tolerance, translocation, and accumulation in plants. The impact of exogenous organic acids on cadmium (Cd) uptake and translocation in the zinc (Zn)/Cd co hyperaccumulator Sedum alfredii was investigated in the present study. By the addition of organic acids, short-term (2 h) root uptake of (109)Cd increased significantly, and higher (109)Cd contents in roots and shoots were noted 24 h after uptake, when compared to controls. About 85% of the (109)Cd taken up was distributed to the shoots in plants with citric acid (CA) treatments, as compared with 75% within controls. No such effect was observed for tartaric acid (TA). Reduced growth under Cd stress was significantly alleviated by low CA. Long-term application of the two organic acids both resulted in elevated Cd in plants, but the effects varied with exposure time and levels. The results imply that CA may be involved in the processes of Cd uptake, translocation and tolerance in S. alfredii, whereas the impact of TA is mainly on the root uptake of Cd. PMID- 23365010 TI - Conjugated linoleic acid isomers and their precursor fatty acids regulate peroxisome proliferator-activated receptor subtypes and major peroxisome proliferator responsive element-bearing target genes in HepG2 cell model. AB - The purpose of this study was to examine the induction profiles (as judged by quantitative reverse transcription polymerase chain reaction (qRT-PCR)) of peroxisome proliferator-activated receptor (PPAR) alpha, beta, gamma subtypes and major PPAR-target genes bearing a functional peroxisome proliferator responsive element (PPRE) in HepG2 cell model upon feeding with cis-9,trans-11 octadecadienoic acid (9-CLA) or trans-10,cis-12-octadecadienoic acid (10-CLA) or their precursor fatty acids (FAs). HepG2 cells were treated with 100 MUmol/L 9 CLA or 10-CLA or their precursor FAs, viz., oleic, linoleic, and trans-11 vaccenic acids against bezafibrate control to evaluate the induction/expression profiles of PPAR alpha, beta, gamma subtypes and major PPAR-target genes bearing a functional PPRE, i.e., fatty acid transporter (FAT), glucose transporter-2 (GLUT-2), liver-type FA binding protein (L-FABP), acyl CoA oxidase-1 (ACOX-1), and peroxisomal bifunctional enzyme (PBE) with reference to beta-actin as house keeping gene. Of the three housekeeping genes (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), beta-actin, and ubiquitin), beta-actin was found to be stable. Dimethyl sulfoxide (DMSO), the common solubilizer of agonists, showed a significantly higher induction of genes analyzed. qRT-PCR profiles of CLAs and their precursor FAs clearly showed upregulation of FAT, GLUT-2, and L-FABP (~0.5 2.0-fold). Compared to 10-CLA, 9-CLA decreased the induction of the FA metabolizing gene ACOX-1 less than did PBE, while 10-CLA decreased the induction of PBE less than did ACOX-1. Both CLAs and precursor FAs upregulated PPRE-bearing genes, but with comparatively less or marginal activation of PPAR subtypes. This indicates that the binding of CLAs and their precursor FAs to PPAR subtypes results in PPAR activation, thereby induction of the target transporter genes coupled with downstream lipid metabolising genes such as ACOX-1 and PBE. To sum up, the expression profiles of these candidate genes showed that CLAs and their precursor FAs are involved in lipid signalling by modulating the PPAR alpha, beta, or gamma subtype for the indirect activation of the PPAR-target genes, which may in turn be responsible for the supposed health effects of CLA, and that care should be taken while calculating the actual fold induction values of candidate genes with reference to housekeeping gene and DMSO as they may impart false positive results. PMID- 23365011 TI - Effect of NaCl treatments on glucosinolate metabolism in broccoli sprouts. AB - To understand the regulation mechanism of NaCl on glucosinolate metabolism in broccoli sprouts, the germination rate, fresh weight, contents of glucosinolates and sulforaphane, as well as myrosinase activity of broccoli sprouts germinated under 0, 20, 40, 60, 80, and 100 mmol/L of NaCl were investigated in our experiment. The results showed that glucoerucin, glucobrassicin, and 4-hydroxy glucobrassicin in 7-d-old broccoli sprouts were significantly enhanced and the activity of myrosinase was inhibited by 100 mmol/L of NaCl. However, the total glucosinolate content in 7-d-old broccoli sprouts was markedly decreased although the fresh weight was significantly increased after treatment with NaCl at relatively low concentrations (20, 40, and 60 mmol/L). NaCl treatment at the concentration of 60 mmol/L for 5 d maintained higher biomass and comparatively higher content of glucosinolates in sprouts of broccoli with decreased myrosinase activity. A relatively high level of NaCl treatment (100 mmol/L) significantly increased the content of sulforaphane in 7-d-old broccoli sprouts compared with the control. These results indicate that broccoli sprouts grown under a suitable concentration of NaCl could be desirable for human nutrition. PMID- 23365012 TI - Optimization of biotransformation from phytosterol to androstenedione by a mutant Mycobacterium neoaurum ZJUVN-08. AB - Biotransformation of phytosterol (PS) by a newly isolated mutant Mycobacterium neoaurum ZJUVN-08 to produce androstenedione has been investigated in this paper. The parameters of the biotransformation process were optimized using fractional factorial design and response surface methodology. Androstenedione was the sole product in the fermentation broth catalyzed by the mutant M. neoaurum ZJUVN-08 strain. Results showed that molar ratio of hydroxypropyl-beta-cyclodextrin (HP beta-CD) to PS and substrate concentrations were the two most significant factors affecting androstenedione production. By analyzing the statistical model of three dimensional surface plot, the optimal process conditions were observed at 0.1 g/L inducer, pH 7.0, molar ratio of HP-beta-CD to PS 1.92:1, 8.98 g/L PS, and at 120 h of incubation time. Under these conditions, the maximum androstenedione yield was 5.96 g/L and nearly the same with the non-optimized (5.99 g/L), while the maximum PS conversion rate was 94.69% which increased by 10.66% compared with the non-optimized (84.03%). The predicted optimum conditions from the mathematical model were in agreement with the verification experimental results. It is considered that response surface methodology was a powerful and efficient method to optimize the parameters of PS biotransformation process. PMID- 23365013 TI - Spatio-temporal reconstruction of air temperature maps and their application to estimate rice growing season heat accumulation using multi-temporal MODIS data. AB - The accumulation of thermal time usually represents the local heat resources to drive crop growth. Maps of temperature-based agro-meteorological indices are commonly generated by the spatial interpolation of data collected from meteorological stations with coarse geographic continuity. To solve the critical problems of estimating air temperature (T(a)) and filling in missing pixels due to cloudy and low-quality images in growing degree days (GDDs) calculation from remotely sensed data, a novel spatio-temporal algorithm for T(a) estimation from Terra and Aqua moderate resolution imaging spectroradiometer (MODIS) data was proposed. This is a preliminary study to calculate heat accumulation, expressed in accumulative growing degree days (AGDDs) above 10 degrees C, from reconstructed T(a) based on MODIS land surface temperature (LST) data. The verification results of maximum T(a), minimum T(a), GDD, and AGDD from MODIS derived data to meteorological calculation were all satisfied with high correlations over 0.01 significant levels. Overall, MODIS-derived AGDD was slightly underestimated with almost 10% relative error. However, the feasibility of employing AGDD anomaly maps to characterize the 2001-2010 spatio-temporal variability of heat accumulation and estimating the 2011 heat accumulation distribution using only MODIS data was finally demonstrated in the current paper. Our study may supply a novel way to calculate AGDD in heat-related study concerning crop growth monitoring, agricultural climatic regionalization, and agro-meteorological disaster detection at the regional scale. PMID- 23365014 TI - Effect of the scale of quantitative trait data on the representativeness of a cotton germplasm sub-core collection. AB - A cotton germplasm collection with data for 20 quantitative traits was used to investigate the effect of the scale of quantitative trait data on the representativeness of plant sub-core collections. The relationship between the representativeness of a sub-core collection and two influencing factors, the number of traits and the sampling percentage, was studied. A mixed linear model approach was used to eliminate environmental errors and predict genotypic values of accessions. Sub-core collections were constructed using a least distance stepwise sampling (LDSS) method combining standardized Euclidean distance and an unweighted pair-group method with arithmetic means (UPGMA) cluster method. The mean difference percentage (MD), variance difference percentage (VD), coincidence rate of range (CR), and variable rate of coefficient of variation (VR) served as evaluation parameters. Monte Carlo simulation was conducted to study the relationship among the number of traits, the sampling percentage, and the four evaluation parameters. The results showed that the representativeness of a sub core collection was affected greatly by the number of traits and the sampling percentage, and that these two influencing factors were closely connected. Increasing the number of traits improved the representativeness of a sub-core collection when the data of genotypic values were used. The change in the genetic diversity of sub-core collections with different sampling percentages showed a linear tendency when the number of traits was small, and a logarithmic tendency when the number of traits was large. However, the change in the genetic diversity of sub-core collections with different numbers of traits always showed a strong logarithmic tendency when the sampling percentage was changing. A CR threshold method based on Monte Carlo simulation is proposed to determine the rational number of traits for a relevant sampling percentage of a sub-core collection. PMID- 23365015 TI - Modular establishment of a diketopyrrolopyrrole-based polymer library via Pd catalyzed direct C-H (Hetero)arylation: a highly efficient approach to discover low-bandgap polymers. AB - A concise, highly efficient palladium-catalyzed direct C-H (hetero)arylation is developed to modularly assemble a diketopyrrolopyrrole (DTDPP)-based polymer library to screen low-bandgap and near-infrared (NIR) absorbing materials. The DTDPP-based copolymers P1 and P2 with an alternating donor-acceptor-donor acceptor (D-A-D-A) sequence and the homopolymer P9 exhibit planarity and excellent pi-conjugation, which lead to low bandgaps (down to 1.22 eV) as well as strong and broad NIR absorption bands (up to 1000 nm). PMID- 23365016 TI - Formaldehyde in the ambient atmosphere: from an indoor pollutant to an outdoor pollutant? AB - Formaldehyde has been discussed as a typical indoor pollutant for decades. Legal requirements and ever-lower limits for formaldehyde in indoor air have led to a continual reduction in the amount of formaldehyde released from furniture, building materials, and household products over many years. Slowly, and without much attention from research on indoor air, a change of paradigm is taking place, however. Today, the formaldehyde concentrations in outdoor air, particularly in polluted urban areas, sometimes already reach indoor levels. This is largely a result of photochemical processes and the use of biofuels. In the medium term, this development might have consequences for the way buildings are ventilated and lead to a change in the way we evaluate human exposure. PMID- 23365017 TI - A method to predict and understand fish survival under dynamic chemical stress using standard ecotoxicity data. AB - The authors present a method to predict fish survival under exposure to fluctuating concentrations and repeated pulses of a chemical stressor. The method is based on toxicokinetic-toxicodynamic modeling using the general unified threshold model of survival (GUTS) and calibrated using raw data from standard fish acute toxicity tests. The model was validated by predicting fry survival in a fish early life stage test. Application of the model was demonstrated by using Forum for Co-ordination of Pesticide Fate Models and Their Use surface water (FOCUS-SW) exposure patterns as model input and predicting the survival of fish over 485 d. Exposure patterns were also multiplied by factors of five and 10 to achieve higher exposure concentrations for fish survival predictions. Furthermore, the authors quantified how far the exposure profiles were below the onset of mortality by finding the corresponding exposure multiplication factor for each scenario. The authors calculated organism recovery times as additional characteristic of toxicity as well as number of peaks, interval length between peaks, and mean duration as additional characteristics of the exposure pattern. The authors also calculated which of the exposure patterns had the smallest and largest inherent potential toxicity. Sensitivity of the model to parameter changes depends on the exposure pattern and differs between GUTS individual tolerance and GUTS stochastic death. Possible uses of the additional information gained from modeling to inform risk assessment are discussed. PMID- 23365018 TI - Regeneration of dental pulp/dentine complex with a three-dimensional and scaffold free stem-cell sheet-derived pellet. AB - Dental pulp/dentine complex regeneration is indispensable to the construction of biotissue-engineered tooth roots and represents a promising approach to therapy for irreversible pulpitis. We used a tissue-engineering method based on odontogenic stem cells to design a three-dimensional (3D) and scaffold-free stem cell sheet-derived pellet (CSDP) with the necessary physical and biological properties. Stem cells were isolated and identified and stem cells from root apical papilla (SCAPs)-based CSDPs were then fabricated and examined. Compact cell aggregates containing a high proportion of extracellular matrix (ECM) components were observed, and the CSDP culture time was prolonged. The expression of alkaline phosphatase (ALP), dentine sialoprotein (DSPP), bone sialoprotein (BSP) and runt-related gene 2 (RUNX2) mRNA was higher in CSDPs than in cell sheets (CSs), indicating that CSDPs have greater odonto/osteogenic potential. To further investigate this hypothesis, CSDPs and CSs were inserted into human treated dentine matrix fragments (hTDMFs) and transplanted into the subcutaneous space in the backs of immunodeficient mice, where they were cultured in vivo for 6 weeks. The root space with CSDPs was filled entirely with a dental pulp-like tissue with well-established vascularity, and a continuous layer of dentine-like tissue was deposited onto the existing dentine. A layer of odontoblast-like cells was found to express DSPP, ALP and BSP, and human mitochondria lined the surface of the newly formed dentine-like tissue. These results clearly indicate that SCAP CSDPs with a mount of endogenous ECM have a strong capacity to form a heterotopic dental pulp/dentine complex in empty root canals; this method can be used in the fabrication of bioengineered dental roots and also provides an alternative treatment approach for pulp disease. PMID- 23365019 TI - What the guru showed me. PMID- 23365020 TI - Hand disorders in musicians: the orthopaedic surgeon's role. AB - Like athletes, musicians are vulnerable to musculoskeletal injuries that can be career ending or have a severe negative financial impact. All ages are affected, with a peak incidence in the third and fourth decades. Women are slightly more likely to be affected than men. It is incumbent upon orthopaedic surgeons to be able to complete a thorough physical assessment, be aware of the risk factors associated with musculoskeletal symptoms in musicians, and have a detailed knowledge of the specific syndromes they suffer and their appropriate treatment. In this paper we review the common hand injuries that afflict musicians and discuss their treatment. PMID- 23365021 TI - Fractures of the radial head. AB - Most fractures of the radial head are stable undisplaced or minimally displaced partial fractures without an associated fracture of the elbow or forearm or ligament injury, where stiffness following non-operative management is the primary concern. Displaced unstable fractures of the radial head are usually associated with other fractures or ligament injuries, and restoration of radiocapitellar contact by reconstruction or prosthetic replacement of the fractured head is necessary to prevent subluxation or dislocation of the elbow and forearm. In fractures with three or fewer fragments (two articular fragments and the neck) and little or no metaphyseal comminution, open reduction and internal fixation may give good results. However, fragmented unstable fractures of the radial head are prone to early failure of fixation and nonunion when fixed. Excision of the radial head is associated with good long-term results, but in patients with instability of the elbow or forearm, prosthetic replacement is preferred. This review considers the characteristics of stable and unstable fractures of the radial head, as well as discussing the debatable aspects of management, in light of the current best evidence. PMID- 23365022 TI - The incidence of noise generation arising from the large-diameter Delta Motion ceramic total hip bearing. AB - Noise generation has been reported with ceramic-on-ceramic articulations in total hip replacement (THR). This study evaluated 208 consecutive Delta Motion THRs at a mean follow-up of 21 months (12 to 35). There were 141 women and 67 men with a mean age of 59 years (22 to 84). Patients were reviewed clinically and radiologically, and the incidence of noise was determined using a newly described assessment method. Noise production was examined against range of movement, ligamentous laxity, patient-reported outcome scores, activity level and orientation of the acetabular component. There were 143 silent hips (69%), 22 (11%) with noises other than squeaking, 17 (8%) with unreproducible squeaking and 26 (13%) with reproducible squeaking. Hips with reproducible squeaking had a greater mean range of movement (p < 0.001) and mean ligament laxity (p = 0.004), smaller median head size (p = 0.01) and decreased mean acetabular component inclination (p = 0.02) and anteversion angle (p = 0.02) compared with the other groups. There was no relationship between squeaking and age (p = 0.13), height (p = 0.263), weight (p = 0.333), body mass index (p = 0.643), gender (p = 0.07) or patient outcome score (p = 0.422). There were no revisions during follow-up. Despite the surprisingly high incidence of squeaking, all patients remain satisfied with their hip replacement. PMID- 23365023 TI - Combined trabecular metal acetabular shell and augment for acetabular revision with substantial bone loss: a mid-term review. AB - Trabecular metal (TM) augments are a relatively new option for reconstructing segmental bone loss during acetabular revision. We studied 34 failed hip replacements in 34 patients that were revised between October 2003 and March 2010 using a TM acetabular shell and one or two augments. The mean age of the patients at the time of surgery was 69.3 years (46 to 86) and the mean follow-up was 64.5 months (27 to 107). In all, 18 patients had a minor column defect, 14 had a major column defect, and two were associated with pelvic discontinuity. The hip centre of rotation was restored in 27 patients (79.4%). The Oxford hip score increased from a mean of 15.4 points (6 to 25) before revision to a mean of 37.7 (29 to 47) at the final follow-up. There were three aseptic loosenings of the construct, two of them in the patients with pelvic discontinuity. One septic loosening also occurred in a patient who had previously had an infected hip replacement. The augments remained stable in two of the failed hips. Whenever there was a loose acetabular component in contact with a stable augment, progressive metal debris shedding was evident on the serial radiographs. Complications included another deep infection treated without revision surgery. Good clinical and radiological results can be expected for bone-deficient acetabula treated by a TM cup and augment, but for pelvic discontinuities this might not be a reliable option. PMID- 23365024 TI - Surface finish of the Exeter Trauma Stem: a cause for concern? AB - Recent guidance recommends the use of a well-proven cemented femoral stem for hemiarthroplasty in the management of fractures of the femoral neck, and the Exeter Trauma Stem (ETS) has been suggested as an example of such an implant. The design of this stem was based on the well-proven Exeter Total Hip Replacement stem (ETHRS). This study assessed the surface finish of the ETS in comparison with the ETHRS. Two ETSs and two ETHRSs were examined using a profilometer with a precision of 1 nm and compared with an explanted Exeter Matt stem. The mean roughness average (RA) of the ETSs was approximately ten times higher than that of the ETHRSs (0.235 MUm (0.095 to 0.452) versus 0.025 MUm (0.011 to 0.059); p < 0.001). The historical Exeter Matt stem roughness measured a mean RA of 0.973 MUm (0.658 to 1.159). The change of the polished Exeter stem to a matt surface finish in 1976 resulted in a high stem failure rate. We do not yet know whether the surface differences between ETS and ETHRS will be clinically significant. We propose the inclusion of hemiarthroplasty stems in national joint registries. PMID- 23365025 TI - Ten-year results of the Press Fit Condylar Sigma total knee replacement. AB - We report ten-year clinical and radiological follow-up data for the Sigma Press Fit Condylar total knee replacement system (Sigma PFC TKR). Between October 1998 and October 1999 a total of 235 consecutive PFC Sigma TKRs were carried out in 203 patients. Patients were seen at a specialist nurse-led clinic seven to ten days before admission and at six and 18 months, three, five and eight to ten years after surgery. Data were recorded prospectively at each clinic visit. Radiographs were obtained at the five- and eight- to ten-year follow-up appointments. Of the 203 patients, 147 (171 knees) were alive at ten years and 12 were lost to follow-up. A total of eight knees (3.4%) were revised, five for infection and three to change the polyethylene insert. The survival at ten years with an endpoint of revision for any reason was 95.9%, and with an endpoint of revision for aseptic failure was 98.7%. The mean American Knee Society Score (AKSS) was 79 (10 to 99) at eight to ten years, compared with 31 (2 to 62) pre operatively. Of 109 knee with radiographs reviewed, 47 knees had radiolucent lines but none showed evidence of loosening. PMID- 23365026 TI - Cementless fixation in Oxford unicompartmental knee replacement: a multicentre study of 1000 knees. AB - The Cementless Oxford Unicompartmental Knee Replacement (OUKR) was developed to address problems related to cementation, and has been demonstrated in a randomised study to have similar clinical outcomes with fewer radiolucencies than observed with the cemented device. However, before its widespread use it is necessary to clarify contraindications and assess the complications. This requires a larger study than any previously published. We present a prospective multicentre series of 1000 cementless OUKRs in 881 patients at a minimum follow up of one year. All patients had radiological assessment aligned to the bone implant interfaces and clinical scores. Analysis was performed at a mean of 38.2 months (19 to 88) following surgery. A total of 17 patients died (comprising 19 knees (1.9%)), none as a result of surgery; there were no tibial or femoral loosenings. A total of 19 knees (1.9%) had significant implant-related complications or required revision. Implant survival at six years was 97.2%, and there was a partial radiolucency at the bone-implant interface in 72 knees (8.9%), with no complete radiolucencies. There was no significant increase in complication rate compared with cemented fixation (p = 0.87), and no specific contraindications to cementless fixation were identified. Cementless OUKR appears to be safe and reproducible in patients with end-stage anteromedial osteoarthritis of the knee, with radiological evidence of improved fixation compared with previous reports using cemented fixation. PMID- 23365027 TI - Proprioceptive changes in the contralateral knee joint following anterior cruciate injury. AB - Loss of proprioception following an anterior cruciate ligament (ACL) injury has been well documented. We evaluated proprioception in both the injured and the uninjured limb in 25 patients with ACL injury and in 25 healthy controls, as assessed by joint position sense (JPS), the threshold for the detection of passive movement (TDPM) and postural sway during single-limb stance on a force plate. There were significant proprioceptive deficits in both ACL-deficient and uninjured knees compared with control knees, as assessed by the angle reproduction test (on JPS) and postural sway on single limb stance. The degree of loss of proprioception in the ACL-deficient knee and the unaffected contralateral knee joint in the same patient was similar. The TDPM in the injured knee was significantly higher than that of controls at 30 degrees and 70 degrees of flexion. The TDPM of the contralateral knee joint was not significantly different from that in controls. Based on these findings, the effect of proprioceptive training of the contralateral uninjured knee should be explored. PMID- 23365028 TI - Long-term follow-up of Van Nes rotationplasty in patients with congenital proximal focal femoral deficiency. AB - Van Nes rotationplasty may be used for patients with congenital proximal focal femoral deficiency (PFFD). The lower limb is rotated to use the ankle and foot as a functional knee joint within a prosthesis. A small series of cases was investigated to determine the long-term outcome. At a mean of 21.5 years (11 to 45) after their rotationplasty, a total of 12 prosthetic patients completed the Short-Form (SF)-36, Faces Pain Scale-Revised, Harris hip score, Oswestry back pain score and Prosthetic Evaluation Questionnaires, as did 12 age- and gender matched normal control participants. A physical examination and gait analysis, computerised dynamic posturography (CDP), and timed 'Up & Go' testing was also completed. Wilcoxon Signed rank test was used to compare each PFFD patient with a matched control participant with false discovery rate of 5%. There were no differences between the groups in overall health and well-being on the SF-36. Significant differences were seen in gait parameters in the PFFD group. Using CDP, the PFFD group had reduced symmetry in stance, and reduced end point and maximum excursions. Patients who had undergone Van Nes rotationplasty had a high level of function and quality of life at long-term follow-up, but presented with significant differences in gait and posture compared with the control group. PMID- 23365029 TI - Rotator cuff repair in patients over 70 years of age: early outcomes and risk factors associated with re-tear. AB - This study reports the clinical and sonographic outcome of arthroscopic rotator cuff repair in patients aged >= 70 years and aimed to determine factors associated with re-tear. A total of 69 consecutive repairs were performed in 68 patients with a mean age of 77 years (70 to 86). Constant-Murley scores were collected pre-operatively and at one year post-operatively. The integrity of the repair was assessed using ultrasound. Re-tear was detected in 20 of 62 patients (32%) assessed with ultrasound. Age at operation was significantly associated with re-tear free survival (p = 0.016). The mean pre-operative Constant score was 23 (sd 14), which increased to 58 (sd 20) at one year post-operatively (paired t test, p < 0.001). Male gender was significantly associated with a higher score at one year (p = 0.019). We conclude that arthroscopic rotator cuff repair in patients aged >= 70 years is a successful procedure. The gender and age of the patient are important factors to consider when planning management. PMID- 23365030 TI - A new mechanism of injury in ankylosing spondylitis: non-traumatic hyperextension causing atlantoaxial subluxation. AB - Ankylosing spondylitis (AS) is a progressive multisystem chronic inflammatory disorder. The hallmark of this pathological process is a progressive fusion of the zygapophyseal joints and disc spaces of the axial skeleton, leading to a rigid kyphotic deformity and positive sagittal balance. The ankylosed spine is unable to accommodate normal mechanical forces, rendering it brittle and susceptible to injury. Traumatic hyperextension injury of the cervical spine leading to atlantoaxial subluxation (AAS) in AS patients can often be fatal. We report a non-traumatic mechanism of injury in AS progressing to AAS attributable to persistent hyperextension, which resulted in fatal migration of C2 through the foramen magnum. PMID- 23365031 TI - The Oswestry Risk Index: an aid in the treatment of metastatic disease of the spine. AB - The revised Tokuhashi, Tomita and modified Bauer scores are commonly used to make difficult decisions in the management of patients presenting with spinal metastases. A prospective cohort study of 199 consecutive patients presenting with spinal metastases, treated with either surgery and/or radiotherapy, was used to compare the three systems. Cox regression, Nagelkerke's R(2) and Harrell's concordance were used to compare the systems and find their best predictive items. The three systems were equally good in terms of overall prognostic performance. Their most predictive items were used to develop the Oswestry Spinal Risk Index (OSRI), which has a similar concordance, but a larger coefficient of determination than any of these three scores. A bootstrap procedure was used to internally validate this score and determine its prediction optimism. The OSRI is a simple summation of two elements: primary tumour pathology (PTP) and general condition (GC): OSRI = PTP + (2 - GC). This simple score can predict life expectancy accurately in patients presenting with spinal metastases. It will be helpful in making difficult clinical decisions without the delay of extensive investigations. PMID- 23365032 TI - Evaluation of the efficacy of Escherichia coli-derived recombinant human bone morphogenetic protein-2 in a mini-pig spinal anterior interbody fusion model. AB - We evaluated the efficacy of Escherichia coli-derived recombinant human bone morphogenetic protein-2 (E-BMP-2) in a mini-pig model of spinal anterior interbody fusion. A total of 14 male mini-pigs underwent three-level anterior lumbar interbody fusion using polyether etherketone (PEEK) cages containing porous hydroxyapatite (HA). Four groups of cages were prepared: 1) control (n = 10 segments); 2) 50 MUg E-BMP-2 (n = 9); 3) 200 MUg E-BMP-2 (n = 10); and 4) 800 MUg E-BMP-2 (n = 9). At eight weeks after surgery the mini-pigs were killed and the specimens were evaluated by gross inspection and manual palpation, radiological evaluation including plain radiographs and micro-CT scans, and histological analysis. Rates of fusion within PEEK cages and overall union rates were calculated, and bone formation outside vertebrae was evaluated. One animal died post-operatively and was excluded, and one section was lost and also excluded, leaving 38 sites for assessment. This rate of fusion within cages was 30.0% (three of ten) in the control group, 44.4% (four of nine) in the 50 MUg E BMP-2 group, 60.0% (six of ten) in the 200 MUg E-BMP-2 group, and 77.8% (seven of nine) in the 800 MUg E-BMP-2 group. Fusion rate was significantly increased by the addition of E-BMP-2 and with increasing E-BMP-2 dose (p = 0.046). In a mini pig spinal anterior interbody fusion model using porous HA as a carrier, the implantation of E-BMP-2-loaded PEEK cages improved the fusion rate compared with PEEK cages alone, an effect that was significantly increased with increasing E BMP-2 dosage. PMID- 23365033 TI - Unilateral lower limb loss following combat injury: medium-term outcomes in British military amputees. AB - This is a case series of prospectively gathered data characterising the injuries, surgical treatment and outcomes of consecutive British service personnel who underwent a unilateral lower limb amputation following combat injury. Patients with primary, unilateral loss of the lower limb sustained between March 2004 and March 2010 were identified from the United Kingdom Military Trauma Registry. Patients were asked to complete a Short-Form (SF)-36 questionnaire. A total of 48 patients were identified: 21 had a trans-tibial amputation, nine had a knee disarticulation and 18 had an amputation at the trans-femoral level. The median New Injury Severity Score was 24 (mean 27.4 (9 to 75)) and the median number of procedures per residual limb was 4 (mean 5 (2 to 11)). Minimum two-year SF-36 scores were completed by 39 patients (81%) at a mean follow-up of 40 months (25 to 75). The physical component of the SF-36 varied significantly between different levels of amputation (p = 0.01). Mental component scores did not vary between amputation levels (p = 0.114). Pain (p = 0.332), use of prosthesis (p = 0.503), rate of re-admission (p = 0.228) and mobility (p = 0.087) did not vary between amputation levels. These findings illustrate the significant impact of these injuries and the considerable surgical burden associated with their treatment. Quality of life is improved with a longer residual limb, and these results support surgical attempts to maximise residual limb length. PMID- 23365034 TI - Acetabular fractures with marginal impaction: mid-term results. AB - Over a five-year period, adult patients with marginal impaction of acetabular fractures were identified from a registry of patients who underwent acetabular reconstruction in two tertiary referral centres. Fractures were classified according to the system of Judet and Letournel. A topographic classification to describe the extent of articular impaction was used, dividing the joint surface into superior, middle and inferior thirds. Demographic information, hospitalisation and surgery-related complications, functional (EuroQol 5-D) and radiological outcome according to Matta's criteria were recorded and analysed. In all, 60 patients (57 men, three women) with a mean age of 41 years (18 to 72) were available at a mean follow-up of 48 months (24 to 206). The quality of the reduction was 'anatomical' in 44 hips (73.3%) and 'imperfect' in 16 (26.7%). The originally achieved anatomical reduction was lost in12 patients (25.8%). Radiologically, 33 hips (55%) were graded as 'excellent', 11 (18.3%) as 'good', one (1.7%) as 'fair' and 15 (25%) as 'poor'. A total of 11 further operations were required in 11 cases, of which six were total hip replacements. Univariate linear regression analysis of the functional outcome showed that factors associated with worse pain were increasing age and an inferior location of the impaction. Elevation of the articular impaction leads to joint preservation with satisfactory overall medium-term functional results, but secondary collapse is likely to occur in some patients. PMID- 23365035 TI - Using the patient's perspective to develop function short forms specific to total hip and knee replacement based on WOMAC function items. AB - Although the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index was originally developed for the assessment of non-operative treatment, it is commonly used to evaluate patients undergoing either total hip (THR) or total knee replacement (TKR). We assessed the importance of the 17 WOMAC function items from the perspective of 1198 patients who underwent either THR (n = 704) or TKR (n = 494) in order to develop joint-specific short forms. After these patients were administered the WOMAC pre-operatively and at three, six, 12 and 24 months' follow-up, they were asked to nominate an item of the function scale that was most important to them. The items chosen were significantly different between patients undergoing THR and those undergoing TKR (p < 0.001), and there was a shift in the priorities after surgery in both groups. Setting a threshold for prioritised items of >= 5% across all follow-up, eight items were selected for THR and seven for TKR, of which six items were common to both. The items comprising specific WOMAC-THR and TKR function short forms were found to be equally responsive compared with the original WOMAC function form. PMID- 23365036 TI - Implant sonication increases the diagnostic accuracy of infection in patients with delayed, but not early, orthopaedic implant failure. AB - The purpose of this study was to compare the diagnostic accuracy for the detection of infection between the culture of fluid obtained by sonication (SFC) and the culture of peri-implant tissues (PITC) in patients with early and delayed implant failure, and those with unsuspected and suspected septic failure. It was hypothesised that SFC increases the diagnostic accuracy for infection in delayed, but not early, implant failure, and in unsuspected septic failure. The diagnostic accuracy for infection of all consecutive implants (hardware or prostheses) that were removed for failure was compared between SFC and PITC. This prospective study included 317 patients with a mean age of 62.7 years (9 to 97). The sensitivity for detection of infection using SFC was higher than using PITC in an overall comparison (89.9% versus 67%, respectively; p < 0.001), in unsuspected septic failure (100% versus 48.5%, respectively; p < 0.001), and in delayed implant failure (88% versus 58%, respectively; p < 0.001). PITC sensitivity dropped significantly in unsuspected compared with suspected septic failure (p = 0.007), and in delayed compared with early failure (p = 0.013). There were no differences in specificity. Sonication is mainly recommended when there is implant failure with no clear signs of infection and in patients with delayed implant failure. In early failure, SFC is not superior to PITC for the diagnosis of infection and, therefore, is not recommended as a routine diagnostic test in these patients. PMID- 23365037 TI - Identification of the biopsy track in musculoskeletal tumour surgery: a novel technique using India ink. AB - Local recurrence along the biopsy track is a known complication of percutaneous needle biopsy of malignant musculoskeletal tumours. In order to completely excise the track with the tumour its identification is essential, but this becomes increasingly difficult over time. In an initial prospective study, 22 of 45 patients (48.8%) identified over a three-month period, treated by resection of a musculoskeletal tumour, had an unidentifiable biopsy site at operation, with identification statistically more difficult after 50 days. We therefore introduced the practice of marking the biopsy site with India ink. In all 55 patients undergoing this procedure, the biopsy track was identified pre operatively (100%); this difference was statistically significant. We recommend this technique as a safe, easy and accurate means of ensuring adequate excision of the biopsy track. PMID- 23365038 TI - Risk factors for overgrowth after flexible intramedullary nailing for fractures of the femoral shaft in children. AB - We analysed retrospectively the risk factors leading to femoral overgrowth after flexible intramedullary nailing in 43 children (mean age 7.1 years (3.6 to 12.0)) with fractures of the shaft of the femur. We reviewed their demographic data, mechanism of injury, associated injuries, the type and location of the fractures, the nail-canal diameter (NCD) ratios and femoral overgrowth at a mean follow-up of 40.7 months (25.2 to 92.7). At that time, the children were divided into two groups, those with femoral overgrowth of < 1 cm (Group 1), and those with overgrowth of >= 1 cm (Group 2). The mean femoral overgrowth of all patients was 0.6 cm at final follow-up. Overgrowth of >= 1 cm was noted in 11 children (25.6%). The NCD ratio was significantly lower in Group 2 than in Group 1, with an odds ratio of 30.0 (p = 0.003). We believe that a low NCD ratio is an indicator of an unstable configuration with flexible intramedullary nailing, and have identified an association between a low NCD ratio and femoral overgrowth resulting in leg-length discrepancy after flexible intramedullary nailing in paediatric femoral shaft fractures. PMID- 23365039 TI - Long-term outcome of reconstruction of the hip in young children with cerebral palsy. AB - We reviewed the long-term radiological outcome, complications and revision operations in 19 children with quadriplegic cerebral palsy and hip dysplasia who underwent combined peri-iliac osteotomy and femoral varus derotation osteotomy. They had a mean age of 7.5 years (1.6 to 10.9) and comprised 22 hip dislocations and subluxations. We also studied the outcome for the contralateral hip. At a mean follow-up of 11.7 years (10 to 15.1) the Melbourne cerebral palsy (CP) hip classification was grade 2 in 16 hips, grade 3 in five, and grade 5 in one. There were five complications seen in four hips (21%, four patients), including one dislocation, one subluxation, one coxa vara with adduction deformity, one subtrochanteric fracture and one infection. A recurrent soft-tissue contracture occurred in five hips and ten required revision surgery. In pre-adolescent children with quadriplegic cerebral palsy good long-term outcomes can be achieved after reconstruction of the hip; regular follow-up is required. PMID- 23365041 TI - Outpatient taping in the treatment of idiopathic congenital talipes equinovarus. AB - The Ponseti and French taping methods have reduced the incidence of major surgery in congenital idiopathic clubfoot but incur a significant burden of care, including heel-cord tenotomy. We developed a non-operative regime to reduce treatment intensity without affecting outcome. We treated 402 primary idiopathic clubfeet in patients aged < three months who presented between September 1991 and August 2008. Their Harrold and Walker grades were 6.0% mild, 25.6% moderate and 68.4% severe. All underwent a dynamic outpatient taping regime over five weeks based on Ponseti manipulation, modified Jones strapping and home exercises. Feet with residual equinus (six feet, 1.5%) or relapse within six months (83 feet, 20.9%) underwent one to three additional tapings. Correction was maintained with below-knee splints, exercises and shoes. The clinical outcome at three years of age (385 feet, 95.8% follow-up) showed that taping alone corrected 357 feet (92.7%, 'good'). Late relapses or failure of taping required limited posterior release in 20 feet (5.2%, 'fair') or posteromedial release in eight feet (2.1%, 'poor'). The long-term (> 10 years) outcomes in 44 feet (23.8% follow-up) were assessed by the Laaveg-Ponseti method as excellent (23 feet, 52.3%), good (17 feet, 38.6%), fair (three feet, 6.8%) or poor (one foot, 2.3%). These compare favourably with published long-term results of the Ponseti or French methods. This dynamic taping regime is a simple non-operative method that delivers improved medium-term and promising long-term results. PMID- 23365040 TI - The effect of gestational age on sonographic screening of the hip in term infants. AB - Several authors have suggested that the final five weeks of gestation are a critical period for the development of the hip. In order to test the hypothesis that gestational age at birth may influence the development of the hip joint, we analysed the sonographic findings in 1992 hips (in 996 term newborns) with no risk factor for developmental dysplasia of the hip. The 996 infants were born at a mean gestational age of 39 weeks (37 to 41). The mean bony roof angle (alpha), cartilage roof angle (beta) and the distribution of the type of hip were compared between the 37th, 38th, 39th, 40th and 41st birth week groups. There was a significant difference in the distribution of type of hip between the different birth week groups (p < 0.001), but no significant difference between the alpha angles of all groups (p = 0.32). There was no correlation between birth week and roof angle (p = 0.407 and p = 0.291, respectively) and no significant correlation between birth weight and roof angle (p = 0.735 and p = 0.132, respectively). The maturity of the infant hip, as assessed sonographically, does not appear to be affected by gestational age, and the fetal development of the acetabular roof appears to plateau from 37 weeks. PMID- 23365042 TI - Prevalence of radiographic findings associated with hip dysplasia in a population based cohort of 2081 19-year-old Norwegians. AB - In Norway total joint replacement after hip dysplasia is reported more commonly than in neighbouring countries, implying a higher prevalence of the condition. We report on the prevalence of radiological features associated with hip dysplasia in a population of 2081 19-year-old Norwegians. The radiological measurements used to define hip dysplasia were Wiberg's centre-edge (CE) angle at thresholds of < 20 degrees and < 25 degrees , femoral head extrusion index < 75%, Sharp's angle > 45 degrees , an acetabular depth to width ratio < 250 and the sourcil shape assessed subjectively. The whole cohort underwent clinical examination of their range of hip movement, body mass index (BMI), and Beighton hypermobility score, and were asked to complete the EuroQol (EQ-5D) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The prevalence of hip dysplasia in the cohort varied from 1.7% to 20% depending on the radiological marker used. A Wiberg's CE angle < 20 degrees was seen in 3.3% of the cohort: 4.3% in women and 2.4% in men. We found no association between subjects with multiple radiological signs indicative of dysplasia and BMI, Beighton score, EQ 5D or WOMAC. Although there appears to be a high prevalence of hip dysplasia among 19-year-old Norwegians, this is dependent on the radiological parameters applied. PMID- 23365045 TI - Controlling the pore sizes and related properties of inverse opal scaffolds for tissue engineering applications. AB - Inverse opal scaffolds are finding widespread use in tissue engineering and regenerative medicine. Herein, the way in which the pore sizes and related physical properties of poly(D,L-lactide-co-glycolide) inverse opal scaffolds are affected by the fabrication conditions is systematically investigated. It is found that the window size of an inverse opal scaffold is mainly determined by the annealing temperature rather than the duration of time, and the surface pore size is largely determined by the concentration of the infiltration solution. Although scaffolds with larger pore or window sizes facilitate faster migration of cells, they show slightly lower compressive moduli than scaffolds with smaller pore or window sizes. PMID- 23365047 TI - Quantitative interpretation of diffusion-ordered NMR spectra: can we rationalize small molecule diffusion coefficients? PMID- 23365046 TI - Angiogenic gene-modified myoblasts promote vascularization during repair of skeletal muscle defects. AB - Vascularization is thought to be a principle obstacle in the reconstruction of skeletal muscle defects. Long-term survival of reconstructed skeletal muscle is dependent on good vascularization. In this study, we upregulated angiogenic gene expression in myoblasts in an attempt to promote vascularization during repair of skeletal muscle defects. Skeletal myoblasts were isolated and expanded from newborn male Sprague-Dawley (SD) rats. The cells were transfected with human vascular endothelial growth factor 165 (VEGF-165) or human stromal cell-derived factor 1 (SDF-1), using LipofectamineTM 2000 transfection reagent, prior to seeding onto calf collagen scaffolds. Gene and protein overexpression was verified by ELISA, RT-PCR and western blot analysis. Cell-seeded scaffolds were transplanted into back muscle defects in female SD rats. At weeks 2, 4 and 8 after transplantation, Y chromosome detection was used to observe the survival of growth factor-producing cells within the scaffolds in vivo. Capillary density was investigated using microvessel density detection, haematoxylin and eosin (H&E) staining and immunohistochemical staining. We found that vascularization was enhanced by transfected myoblasts compared with non-transfected myoblasts. In addition, VEGF-165 and SDF-1 had a synergistic effect on vascularization during repair of skeletal muscle defects in vivo. In conclusion, we have combined myoblast-seeded collagen sponge with gene therapy, resulting in a promising approach for the construction of well-vascularized skeletal muscle. PMID- 23365048 TI - Vascular tissue engineering of small-diameter blood vessels: reviewing the electrospinning approach. AB - Vascular tissue engineering is a relevant research field aimed at elaborating and proposing innovative solutions to overcome the drawbacks related to the use of conventional blood vessel substitutes, especially referring to small-diameter grafts. For this aim, electrospinning can be regarded as a valuable technique to produce novel scaffolds with several functional characteristics that can be usefully tailored for the application discussed here. The reproduction of the natural extracellular matrix obtained by processing bioresorbable polymers, either functionalized or not, is driving the biomedical research towards technical solutions that can lead to an actual therapeutic improvement. In this context, this paper reviews those studies focused on the selection of suitable biomaterials for vascular applications, their microstructure, the cell response to polymeric fibres and the strategies considered so far to modify and therefore enhance the performance of final electrospun scaffolds. PMID- 23365049 TI - Radio-frequency ionization of organic compounds for mass spectrometry analysis. AB - A new ionization technique: A radio-frequency signal was used to ionize neutral organic molecules in the ultrahigh-vacuum region of a Fourier transform ion cyclotron resonance mass spectrometer. Radio-frequency ionization (RFI) yielded signal/noise (S/N) ratios roughly six times higher than those generated by conventional 70 eV electron impact ionization (EI). PMID- 23365050 TI - Dopaminergic treatment and nonmotor features of Parkinson disease: the horse lives. PMID- 23365051 TI - Spinal ischemic stroke following dialysis: clinical and radiologic findings. PMID- 23365052 TI - DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss. AB - BACKGROUND: Mutations in DNA methyltransferase 1 (DNMT1) have been identified in 2 autosomal dominant syndromes: 1) hereditary sensory autonomic neuropathy with dementia and hearing loss (HSAN1E); and 2) cerebellar ataxia, deafness, and narcolepsy. Both syndromes have mutations in targeting sequence (TS) domain (exons 20-21), which is important in mediating DNA substrate binding to the DNMT1 catalytic domain. Frontal lobe hypometabolism has been documented in an HSAN1E family, but memory loss has been the primary cognitive complaint. The chromosomal location of the DNMT1 gene at 19p13.2 has been linked to familial late-onset Alzheimer disease. METHODS: We sequenced 41 exons of DNMT1 and their flanking regions in 1) 2 kindreds with HSAN1E; 2) 48 patients with HSAN1 alone without dementia and hearing loss; and 3) 5 probands of familial frontotemporal dementia (FTD) kindreds. We also sequenced exon 20 and 21 in 364 autopsy-confirmed late onset Alzheimer disease cases. RESULTS: Mutations in DNMT1 were specific to 2 HSAN1E kindreds with dementia and hearing loss (no narcolepsy). One family carried previously identified mutation Tyr495Cys; the other carried a novel Tyr495His, both in the TS domain. The symptoms of these patients include prominent personality, psychiatric manifestations, and seizures in one and the onset time is later than the previously reported cases. CONCLUSION: Clinicians should consider DNMT1 mutations in patients presenting with FTD or primary memory decline who also have sensory neuropathy and hearing loss. Amino acid Tyr495 is a hot spot for HSAN1E, distinct from exon 21 mutations associated with narcolepsy. PMID- 23365053 TI - A randomized controlled trial of intranasal ketamine in migraine with prolonged aura. AB - OBJECTIVE: The aim of our study was to test the hypothesis that ketamine would affect aura in a randomized controlled double-blind trial, and thus to provide direct evidence for the role of glutamatergic transmission in human aura. METHODS: We performed a double-blinded, randomized parallel-group controlled study investigating the effect of 25 mg intranasal ketamine on migraine with prolonged aura in 30 migraineurs using 2 mg intranasal midazolam as an active control. Each subject recorded data from 3 episodes of migraine. RESULTS: Eighteen subjects completed the study. Ketamine reduced the severity (p = 0.032) but not duration of aura in this group, whereas midazolam had no effect. CONCLUSIONS: These data provide translational evidence for the potential importance of glutamatergic mechanisms in migraine aura and offer a pharmacologic parallel between animal experimental work on cortical spreading depression and the clinical problem. CLASSIFICATION OF EVIDENCE: This study provides class III evidence that intranasal ketamine is effective in reducing aura severity in patients with migraine with prolonged aura. PMID- 23365054 TI - Nonmotor fluctuations in Parkinson disease: severity and correlation with motor complications. AB - OBJECTIVE: To evaluate frequency, severity, and correlation of nonmotor symptoms (NMS) with motor complications in fluctuating Parkinson disease (PD). METHODS: The Multicenter NonMotor Fluctuations in PD cross-sectional study used clinical examination of 10 NMS (dysphagia, anxiety, depression, fatigue, excessive sweating, inner restlessness, pain, concentration/attention, dizziness, bladder urgency) quantified using a visual analogue scale (VAS) in motor-defined on (NMS(On)) and off state (NMS(Off)) combined with motor assessments and self ratings at home in 100 patients with advanced PD. RESULTS: All NMS except dysphagia, excessive sweating, and bladder urgency fluctuated in conjunction to motor fluctuations with more frequent and severe symptoms in off compared to on state. The proportions of patients experiencing autonomic/sensory NMS in both motor states were similar to those with these NMS exclusively in off state (ratios 0.4-1.3), while for mental/psychic NMS the proportions with exclusive manifestation in off state were higher (ratios 1.8-3.1). Demographic and clinical characteristics correlated neither with NMS frequency patterns and severities nor with DeltaNMS(On/Off) severities (defined as the differences of VAS scores between on and off). Severities of NMS(on), NMS(Off), and DeltaNMS(On/Off) did not correlate with motor function. Presence of anxiety, depression, fatigue, and pain had negative impact on health-related quality of life (HRQOL) measured by Parkinson's Disease Questionnaire-8 scoring independent of their occurrence with respect to motor state. Fluctuations of these NMS but not of fatigue deteriorated HRQOL. CONCLUSION: Patterns of NMS fluctuations are heterogeneous and complex, but psychic NMS fluctuate more frequently and severely. Demographic parameters and motor function do not correlate with NMS or nonmotor fluctuation severities in fluctuating PD. PMID- 23365055 TI - Disparities among Asians and native Hawaiians and Pacific Islanders with ischemic stroke. AB - OBJECTIVES: To evaluate disparities in cardiovascular risk factors among Asians and Native Hawaiians and other Pacific Islanders (NHPI) in Hawaii who are hospitalized with ischemic stroke. METHODS: We performed a retrospective study on consecutive patients hospitalized for ischemic stroke at a single tertiary center in Honolulu between 2004 and 2010. The prevalence of cardiovascular risk factors was compared for NHPI, Asians, and whites who were hospitalized for ischemic stroke. RESULTS: A total of 1,921 patients hospitalized for ischemic stroke were studied. NHPI were less likely to be older (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.94-0.96), more likely to be female (OR 1.55, 95% CI 1.07-2.24), and more likely to have diabetes (OR 2.74, 95% CI 1.87-4.00), hypertension (OR 1.98, 95% CI 1.27-3.10), and obesity (OR 1.82, 95% CI 1.25-2.65) than whites. NHPI had higher low-density lipoprotein levels (114 +/- 50 mg/dL vs 103 +/- 45 mg/dL, p = 0.001) and lower high-density lipoprotein levels (38 +/- 11 mg/dL vs 45 +/- 15 mg/dL, p < 0.0001) than whites. Compared with Asians, NHPI were less likely to be older (OR 0.95, 95% CI 0.94-0.97) and more likely to have diabetes (OR 1.88, 95% CI 1.35-2.61), previous stroke or TIA (OR 1.57, 95% CI 1.09-2.25), and obesity (OR 6.05, 95% CI 4.31-8.48). CONCLUSIONS: Asians, NHPI, and whites with ischemic stroke have substantially different cardiovascular risk factors. Targeted secondary prevention will be important in reducing disparities among these racial groups. PMID- 23365056 TI - alpha-Synuclein pathology is related to postoperative delirium in patients undergoing gastrectomy. AB - OBJECTIVE: The clinical characteristics of postoperative delirium are similar to core features of alpha-synuclein-related cognitive disorders, such as dementia with Lewy bodies or Parkinson disease dementia. We therefore investigated the alpha-synuclein pathology in patients who experienced postoperative delirium after gastrectomy for stomach cancer. METHOD: Patients with and without postoperative delirium were selected among patients undergoing total gastrectomy for primary gastric cancer from 2007 to 2011 (each n = 16) at the university hospital. Immunohistochemical staining for alpha-synuclein of both normal and phosphorylated form was performed in the myenteric plexus. A logistic regression analysis was applied to identify independent predictors of postoperative delirium. RESULTS: No significant differences were observed for age, sex, operation time, or onset of delirium after total gastrectomy between patients with and without postoperative delirium. Patients with postoperative delirium had a higher frequency of intensive care unit admissions (43.8 vs 6.3%, p = 0.037) and alpha-synuclein-positive pathologies of normal (56.3 vs 12.5%, p = 0.023) and phosphorylated form (43.8 vs 6.3%, p = 0.037) compared with those without postoperative delirium. A logistic regression analysis revealed that immunoreactivity for normal alpha-synuclein (odds ratio [OR] 9.20) and intensive care unit admission (OR 11.97) were independently associated with postoperative delirium. CONCLUSION: These results suggest that underlying alpha-synuclein pathologies in the stomach are associated with postoperative delirium, implying that postoperative delirium represents a preclinical stage of alpha-synuclein related to cognitive disorders. PMID- 23365057 TI - Microvascular brain pathology and late-life motor impairment. AB - OBJECTIVE: To test the hypothesis that microvascular brain pathology is associated with late-life motor impairment. METHODS: More than 2,500 persons participating in the Religious Orders Study or the Memory and Aging Project agreed to annual motor assessment and autopsy. Brains from 850 deceased participants were assessed for microvascular pathology including microinfarcts, cerebral amyloid angiopathy, and arteriolosclerosis, and we examined their association with global motor scores proximate to death. RESULTS: Mean age at death was 88.5 years. More than 60% of cases had evidence of 1 or more microvascular pathologies and of these more than half did not have observed macroinfarcts. In separate regression models adjusted for age, sex, and education, microinfarcts and arteriolosclerosis were associated with level of motor function proximate to death (arteriolosclerosis, estimate, -0.027, SE 0.005, p < 0.001; microinfarcts, estimate, -0.017, SE 0.008, p = 0.026). These associations were not attenuated when controlling for vascular risk factors and diseases, postmortem interval, or interval from last clinical examination, and did not vary with level of cognition or presence of dementia proximate to death. When the 3 microvascular pathologies, macroinfarcts, and atherosclerosis were considered together in a single model, more severe arteriolosclerosis (estimate, 0.021, SE 0.005, p < 0.001) and macroinfarcts (estimate, -0.019, SE 0.006, p < 0.001) showed separate effects with the level of motor function proximate to death. CONCLUSIONS: Microvascular brain pathology is common in older adults and may represent an under-recognized, independent cause of late-life motor impairment. PMID- 23365058 TI - Sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy. AB - OBJECTIVE: To investigate whether sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy (FSHD). METHODS: Sarcomeric function was evaluated by contractile studies on demembranated single muscle fibers obtained from quadriceps muscle biopsies of 4 patients with FSHD and 4 healthy controls. The sarcomere length dependency of force was determined together with measurements of thin filament length using immunofluorescence confocal scanning laser microscopy. X-ray diffraction techniques were used to study myofilament lattice spacing. RESULTS: FSHD muscle fibers produced only 70% of active force compared to healthy controls, a reduction which was exclusive to type II muscle fibers. Changes in force were not due to changes in thin filament length or sarcomere length. Passive force was increased 5- to 12-fold in both fiber types, with increased calcium sensitivity of force generation and decreased myofilament lattice spacing, indicating compensation by the sarcomeric protein titin. CONCLUSIONS: We have demonstrated a reduction in sarcomeric force in type II FSHD muscle fibers, and suggest compensatory mechanisms through titin stiffening. Based on these findings, we propose that sarcomeric dysfunction plays a critical role in the development of muscle weakness in FSHD. PMID- 23365059 TI - Peripheral neuropathy due to dinitrophenol used for weight loss: something old, something new. PMID- 23365060 TI - Blood-brain barrier disruption is associated with increased mortality after endovascular therapy. AB - OBJECTIVE: To evaluate the incidence, baseline characteristics, and clinical prognosis of blood-brain barrier (BBB) disruption after endovascular therapy in acute ischemic stroke patients. METHODS: A total of 220 patients treated with endovascular therapy between April 2007 and October 2011 were identified from a prospective, clinical, thrombolysis registry. All patients underwent a nonenhanced CT scan immediately after treatment. CT scan or MRI was systematically realized at 24 hours to assess intracranial hemorrhage complications. BBB disruption was defined as a hyperdense lesion on the posttreatment CT scan. RESULTS: BBB disruption was found in 128 patients (58.2%; 95% confidence interval [CI], 51.4%-64.9%). Cardioembolic etiology, high admission NIH Stroke Scale score, high blood glucose level, internal carotid artery occlusion, and use of combined endovascular therapy (chemical and mechanical revascularization) were independently associated with BBB disruption. Patients with BBB disruption had lower rates of early major neurologic improvement (8.6% vs 31.5%, p < 0.001), favorable outcome (39.8% vs 61.8%, p = 0.002), and higher rates of 90-day mortality (34.4% vs 14.6%, p = 0.001) and hemorrhagic complications (42.2% vs 8.7%, p < 0.001) than those without BBB disruption. By multivariable analysis, patients with BBB disruption remained with a lower rate of early neurologic improvement (adjusted odds ratio [OR], 0.28; 95% CI, 0.11-0.70) and with a higher rate of mortality (adjusted OR, 2.37; 95% CI, 1.06-5.32) and hemorrhagic complications (adjusted OR, 6.38; 95% CI, 2.66-15.28). CONCLUSION: BBB disruption has a detrimental effect on outcome and is independently associated with mortality after endovascular therapy. BBB disruption assessment may have a role in prognosis staging in these patients. PMID- 23365062 TI - Trigeminal stimulation: a superhighway to the brain? PMID- 23365061 TI - Pallidal somatotopy suggested by deep brain stimulation in a patient with dystonia. PMID- 23365063 TI - Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. AB - OBJECTIVE: To determine whether childhood obesity is a risk factor for developing pediatric multiple sclerosis (MS) or clinically isolated syndrome (CIS). METHODS: Cases were identified through the Kaiser Permanente Southern California (KPSC) pediatric acquired demyelinating diseases cohort between 2004 and 2010. For cases, body mass index (BMI) was obtained prior to symptom onset, for the underlying cohort BMI was obtained through the KPSC Children's health study (n = 913,097). Weight classes of normal weight, overweight, moderate obesity, and extreme obesity were assigned based on BMI specific for age and sex. RESULTS: We identified 75 newly diagnosed pediatric cases of MS or CIS, the majority of which were in girls (n = 41, 55%), age 11-18 (n = 54, 72%). Obesity was associated with a significantly increased risk of MS/CIS in girls (p = 0.005 for trend) but not in boys (p = 0.93). The adjusted odds ratio and 95% confidence intervals for CIS/MS among girls was 1.58 (0.71-3.50) for overweight compared to normal weight (reference category), 1.78 (0.70-4.49) for moderately obese, and 3.76 (1.54-9.16) for extremely obese. Moderately and extremely obese cases were more likely to present with transverse myelitis compared with normal/overweight children (p = 0.003). CONCLUSION: Our findings suggest the childhood obesity epidemic is likely to lead to increased morbidity from MS/CIS, particularly in adolescent girls. PMID- 23365065 TI - Microvascular disease and motoric dysfunction. PMID- 23365064 TI - Sex differences and hemoglobin levels in relation to stroke outcomes. AB - OBJECTIVE: Women have worse outcomes after stroke compared to men. Since women have lower hemoglobin values, we examined whether hemoglobin levels may associate with worse stroke outcomes in women. METHODS: We retrospectively studied 274 patients enrolled in a prospective multicenter study. We explored the relationship of hemoglobin with clinical outcome at 6 months, as measured by the modified Rankin Scale (mRS). Ordinal logistic regression was used to evaluate the independent effect of hemoglobin on clinical outcome, and to explore the influence of sex on that association. RESULTS: Women had a lower mean hemoglobin level (11.7 +/- 1.8 g/dL) compared to men (13.3 +/- 1.7 g/dL). Low hemoglobin was associated with worse 6-month mRS outcomes in univariate analysis (p < 0.001). Lower hemoglobin remained independently associated with poor outcome after adjustment for comorbid disease, stroke severity, age, and sex. The inclusion of hemoglobin in the model attenuated the independent effect of sex on outcome. CONCLUSIONS: Sex differences in stroke outcome are linked to lower hemoglobin level, which is more prevalent in women. Further examination of this potentially modifiable predictor is warranted. PMID- 23365066 TI - Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy. AB - OBJECTIVE: To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial. METHODS: This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters. RESULTS: At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as >50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p = 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59-0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA). CONCLUSIONS: This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial. CLASSIFICATION OF EVIDENCE: This phase II study provides Class II evidence that trigeminal nerve stimulation may be safe and effective in reducing seizures in people with DRE. PMID- 23365067 TI - Radiofrequency and cryoenergy endo-epicardical catheter and surgical approach for a case of incessant ventricular tachycardia ablation. PMID- 23365068 TI - Reply--About methodology of pre-/post-studies. PMID- 23365069 TI - Absolute risk reduction in total mortality with implantable cardioverter defibrillators: analysis of primary and secondary prevention trial data to aid risk/benefit analysis. AB - AIMS: Absolute risk reduction (ARR) and number needed to treat (NNT) are considered by many to be the most appropriate figures to use for the informed consent process, yet the results of published implantable cardioverter defibrillators (ICD) trials are frequently presented as relative risk reduction or odds ratio. The period over which risk reduction is calculated also varies between trials, making comparison difficult. METHODS AND RESULTS: Published ICD trials used to formulate national and international guidelines were examined for 1, 2, and 3 year total mortality in ICD and medically treated patients. The number of patients enrolled and at risk at these time points were also sought. Where the raw data were not included in the original text, estimates were taken from published Kaplan-Meier graphs. Eight primary prevention (PP) trials, three secondary prevention (SP) trials, and one SP meta-analyses were included. For PP, ARR at 3-year follow-up ranged from 0 (no benefit) to 24.6% (NNT = 4). For SP, ARR at 3-year follow up ranged from 3.7% (NNT = 27) to 11.3% (NNT = 9). Absolute risk reduction increased with follow-up in PP trials, whereas there was considerable variation in SP trials. Overall, very few trial patients received 3 year follow-up, giving wide confidence intervals (CIs). CONCLUSION: Absolute risk reduction from ICD trials varies significantly depending upon trial entry criteria, subgroup characteristics, and duration of follow-up. The relatively small number of patients followed for 2 or more years leads to wide CIs. Despite these limitations, the standardized ARR and NNT data presented may give a more individualized estimate of risk/benefit that could potentially aid an informed consent process. PMID- 23365070 TI - Epicardially originating ventricular tachycardia: an unusual presentation of bronchiectasis. PMID- 23365071 TI - Alcohol-induced ventricular fibrillation in a case of Brugada syndrome. PMID- 23365072 TI - An atrial fibrillation suppression algorithm encourages angina. PMID- 23365073 TI - Therapeutic potential of perivascular cells from human pluripotent stem cells. AB - Vascularization of injured tissues or artificial grafts is a major challenge in tissue engineering, stimulating a continued search for alternative sources for vasculogenic cells and the development of therapeutic strategies. Human pluripotent stem cells (hPSCs), either embryonic or induced, offer a plentiful platform for the derivation of large numbers of vasculogenic cells, as required for clinical transplantations. Various protocols for generation of vasculogenic smooth muscle cells (SMCs) from hPSCs have been described with considerably different SMC derivatives. In addition, we recently identified hPSC-derived pericytes, which are similar to their physiological counterparts, exhibiting unique features of blood vessel-residing perivascular cells, as well as multipotent mesenchymal precursors with therapeutic angiogenic potential. In this review we refer to methodologies for the development of a variety of perivascular cells from hPSCs with respect to developmental induction, differentiation capabilities, potency and their dual function as mesenchymal precursors. The therapeutic effect of hPSC-derived perivascular cells in experimental models of tissue engineering and regenerative medicine are described and compared to those of their native physiological counterparts. PMID- 23365074 TI - Analysis of APC types involved in CD4 tolerance and regulatory T cell generation using reaggregated thymic organ cultures. AB - Tolerance to self-Ags is generated in the thymus. Both epithelial and hematopoietic thymic stromal cells play an active and essential role in this process. However, the role of each of the various stromal cell types remains unresolved. To our knowledge, we describe the first comparative analysis of several types of thymic hematopoietic stromal cells (THSCs) for their ability to induce CD4 tolerance to self, in parallel with the thymic epithelium. The THSCs- two types of conventional dendritic cells (cDCs), plasmacytoid dendritic cells, macrophages (MPhis), B lymphocytes, and eosinophils--were first characterized and quantified in adult mouse thymus. They were then examined in reaggregated thymic organ cultures containing mixtures of monoclonal and polyclonal thymocytes. This thymocyte mixture allows for the analysis of Ag-specific events while avoiding the extreme skewing frequently seen in purely monoclonal systems. Our data indicate that thymic epithelium alone is capable of promoting self-tolerance by eliminating autoreactive CD4 single-positive thymocytes and by supporting regulatory T cell (Treg) development. We also show that both non-Treg CD4 single positive thymocytes and Tregs are efficiently deleted by the two populations of cDCs present in the thymus, as well as to a lesser extent by MPhis. Plasmacytoid dendritic cells, B lymphocytes, and eosinophils were not able to do so. Finally, cDCs were also the most efficient THSCs at supporting Treg development in the thymus, suggesting that although they may share some characteristics required for negative selection with MPhis, they do not share those required for the support of Treg development, making cDCs a unique cell subset in the thymus. PMID- 23365075 TI - IFN-gamma Production by amyloid beta-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by the presence of amyloid-beta (Abeta) containing plaques, neurofibrillary tangles, and neuronal loss in the brain. Inflammatory changes, typified by activated microglia, particularly adjacent to Abeta plaques, are also a characteristic of the disease, but it is unclear whether these contribute to the pathogenesis of AD or are a consequence of the progressive neurodegenerative processes. Furthermore, the factors that drive the inflammation and neurodegeneration remain poorly understood. CNS-infiltrating T cells play a pivotal role in the pathogenesis of multiple sclerosis, but their role in the progression of AD is still unclear. In this study, we examined the role of Abeta-specific T cells on Abeta accumulation in transgenic mice that overexpress amyloid precursor protein and presenilin 1 (APP/PS1). We found significant infiltration of T cells in the brains of APP/PS1 mice, and a proportion of these cells secreted IFN-gamma or IL-17. Abeta-specific CD4 T cells generated by immunization with Abeta and a TLR agonist and polarized in vitro to Th1-, Th2-, or IL-17-producing CD4(+) T cells, were adoptively transferred to APP/PS1 mice at 6 to 7 mo of age. Assessment of animals 5 wk later revealed that Th1 cells, but not Th2 or IL-17-producing CD4(+) T cells, increased microglial activation and Abeta deposition, and that these changes were associated with impaired cognitive function. The effects of Th1 cells were attenuated by treatment of the APP/PS1 mice with an anti-IFN-gamma Ab. Our study suggests that release of IFN-gamma from infiltrating Th1 cells significantly accelerates markers of diseases in an animal model of AD. PMID- 23365076 TI - Constitutive lymphocyte transmigration across the basal lamina of high endothelial venules is regulated by the autotaxin/lysophosphatidic acid axis. AB - Lymphocyte extravasation from the high endothelial venules (HEVs) of lymph nodes is crucial for the maintenance of immune homeostasis, but its molecular mechanism remains largely unknown. In this article, we report that lymphocyte transmigration across the basal lamina of the HEVs is regulated, at least in part, by autotaxin (ATX) and its end-product, lysophosphatidic acid (LPA). ATX is an HEV-associated ectoenzyme that produces LPA from lysophosphatidylcholine (LPC), which is abundant in the systemic circulation. In agreement with selective expression of ATX in HEVs, LPA was constitutively and specifically detected on HEVs. In vivo, inhibition of ATX impaired the lymphocyte extravasation from HEVs, inducing lymphocyte accumulation within the endothelial cells (ECs) and sub-EC compartment; this impairment was abrogated by LPA. In vitro, both LPA and LPC induced a marked increase in the motility of HEV ECs; LPC's effect was abrogated by ATX inhibition, whereas LPA's effect was abrogated by ATX/LPA receptor inhibition. In an in vitro transmigration assay, ATX inhibition impaired the release of lymphocytes that had migrated underneath HEV ECs, and these defects were abrogated by LPA. This effect of LPA was dependent on myosin II activity in the HEV ECs. Collectively, these results strongly suggest that HEV-associated ATX generates LPA locally; LPA, in turn, acts on HEV ECs to increase their motility, promoting dynamic lymphocyte-HEV interactions and subsequent lymphocyte transmigration across the basal lamina of HEVs at steady state. PMID- 23365077 TI - Targeting macrophage activation for the prevention and treatment of Staphylococcus aureus biofilm infections. AB - Biofilm infections often lead to significant morbidity due to their chronicity and recalcitrance to antibiotics. We have demonstrated that methicillin-resistant Staphylococcus aureus (MRSA) biofilms can evade macrophage (MPhi) antibacterial effector mechanisms by skewing MPhis toward an alternatively activated M2 phenotype. To overcome this immune evasion, we have used two complementary approaches. In the first, a proinflammatory milieu was elicited by local administration of classically activated M1 MPhis and in the second by treatment with the C5a receptor (CD88) agonist EP67, which invokes MPhi proinflammatory activity. Early administration of M1-activated MPhis or EP67 significantly attenuated biofilm formation in a mouse model of MRSA catheter-associated infection. Several proinflammatory mediators were significantly elevated in biofilm-infected tissues from MPhi- and EP67-treated animals, revealing effective reprogramming of the biofilm environment to a proinflammatory milieu. A requirement for MPhi proinflammatory activity was demonstrated by the fact that transfer of MyD88-deficient MPhis had minimal impact on biofilm growth. Likewise, neutrophil administration had no effect on biofilm formation. Treatment of established biofilm infections with M1-activated MPhis also significantly reduced catheter-associated biofilm burdens compared with antibiotic treatment. Collectively, these results demonstrate that targeting MPhi proinflammatory activity can overcome the local immune inhibitory environment created during biofilm infections and represents a novel therapeutic strategy. PMID- 23365078 TI - Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions. AB - Complement factor H (CFH) regulates complement activation in host tissues through its recognition of polyanions, which mediate CFH binding to host cell surfaces and extracellular matrix, promoting the deactivation of deposited C3b. These polyanions include heparan sulfate (HS), a glycosaminoglycan with a highly diverse range of structures, for which two regions of CFH (CCP6-8 and CCP19-20) have been implicated in HS binding. Mutations/polymorphisms within these glycosaminoglycan-binding sites have been associated with age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome. In this study, we demonstrate that CFH has tissue-specific binding properties mediated through its two HS-binding regions. Our data show that the CCP6-8 region of CFH binds more strongly to heparin (a highly sulfated form of HS) than CCP19-20, and that their sulfate specificities are different. Furthermore, the HS binding site in CCP6-8, which is affected by the AMD-associated Y402H polymorphism, plays the principal role in host tissue recognition in the human eye, whereas the CCP19-20 region makes the major contribution to the binding of CFH in the human kidney. This helps provide a biochemical explanation for the genetic basis of tissue-specific diseases such as AMD and atypical hemolytic uremic syndrome, and leads to a better understanding of the pathogenic mechanisms for these diseases of complement dysregulation. PMID- 23365080 TI - T cell Ig mucin-3 promotes homeostasis of sepsis by negatively regulating the TLR response. AB - Sepsis is an excessive inflammatory condition with a high mortality rate and limited prediction and therapeutic options. In this study, for the first time, to our knowledge, we found that downregulation and/or blockade of T cell Ig and mucin domain protein 3 (Tim-3), a negative immune regulator, correlated with severity of sepsis, suggesting that Tim-3 plays important roles in maintaining the homeostasis of sepsis in both humans and a mouse model. Blockade and/or downregulation of Tim-3 led to increased macrophage activation, which contributed to the systemic inflammatory response in sepsis, whereas Tim-3 overexpression in macrophages significantly suppressed TLR-mediated proinflammatory cytokine production, indicating that Tim-3 is a negative regulator of TLR-mediated immune responses. Cross-talk between the Tim-3 and TLR4 pathways makes TLR4 an important contributor to Tim-3-mediated negative regulation of the innate immune response. Tim-3 signaling inhibited LPS-TLR4-mediated NF-kappaB activation by increasing PI3K-AKT phosphorylation and A20 activity. This negative regulatory role of Tim-3 reflects a new adaptive compensatory and protective mechanism in sepsis victims, a finding of potential importance for modulating innate responses in these patients. PMID- 23365079 TI - Rheumatoid factor B cell memory leads to rapid, switched antibody-forming cell responses. AB - B cells are critical in the initiation and maintenance of lupus. Autoreactive B cells clonally expand, isotype switch, and mutate--properties associated with memory B cells (MBCs), which are typically generated via germinal centers. The development and functions of autoreactive MBCs in lupus are poorly understood. Moreover, mounting evidence implicates the extrafollicular (EF) response in the generation of switched and mutated autoantibodies that are driven by BCR and TLR corecognition, raising the question of whether MBCs are generated in this context. In this study, we investigated autoreactive MBC generation associated with this type of response. We transferred B cells from AM14 site-directed BCR transgenic mice into nontransgenic normal recipients and elicited an EF response with anti-chromatin Ab, as in prior studies. By following the fate of the stimulated cells at late time points, we found that AM14 B cells persisted at increased frequency for up to 7 wk. Furthermore, these cells had divided in response to Ag but were subsequently quiescent, with a subset expressing the memory marker CD73. These cells engendered rapid, isotype-switched secondary plasmablast responses upon restimulation. Both memory and rapid secondary responses required T cell help to develop, emphasizing the need for T-B collaboration for long-term self-reactivity. Thus, using this model system, we show that the EF response generated persistent and functional MBCs that share some, but not all, of the characteristics of traditional MBCs. Such cells could play a role in chronic or flaring autoimmune disease. PMID- 23365081 TI - Activation of invariant NK T cells in periodontitis lesions. AB - Periodontitis is one of the most prevalent human inflammatory diseases. The major clinical phenotypes of this polymicrobial, biofilm-mediated disease are chronic and aggressive periodontitis, the latter being characterized by a rapid course of destruction that is generally attributed to an altered immune-inflammatory response against periodontal pathogens. Still, the biological basis for the pathophysiological distinction of the two disease categories has not been well documented yet. Type I NKT cells are a lymphocyte subset with important roles in regulating immune responses to either tolerance or immunity, including immune responses against bacterial pathogens. In this study, we delineate the mechanisms of NKT cell activation in periodontal infections. We show an infiltration of type I NKT cells in aggressive, but not chronic, periodontitis lesions in vivo. Murine dendritic cells infected with aggressive periodontitis-associated Aggregatibacter actinomycetemcomitans triggered a type I IFN response followed by type I NKT cell activation. In contrast, infection with Porphyromonas gingivalis, a principal pathogen in chronic periodontitis, did not induce NKT cell activation. This difference could be explained by the absence of a type I IFN response to P. gingivalis infection. We found these IFNs to be critical for NKT cell activation. Our study provides a conceivable biological distinction between the two periodontitis subforms and identifies factors required for the activation of the immune system in response to periodontal bacteria. PMID- 23365082 TI - Immunopathology of immune reconstitution inflammatory syndrome in Whipple's disease. AB - During antimicrobial treatment of classic Whipple's disease (CWD), the chronic systemic infection with Tropheryma whipplei, immune reconstitution inflammatory syndrome (IRIS), is a serious complication. The aim of our study was to characterize the immunological processes underlying IRIS in CWD. Following the definition of IRIS, we describe histological features of IRIS and immunological parameters of 24 CWD IRIS patients, 189 CWD patients without IRIS, and 89 healthy individuals. T cell reconstitution, Th1 reactivity, and the phenotype of T cells were described in the peripheral blood, and infiltration of CD4(+) T cells and regulatory T cells in the duodenal mucosa was determined. During IRIS, tissues were heavily infiltrated by CD3(+), predominantly CD45RO(+)CD4(+) T cells. In the periphery, initial reduction of CD4(+) cell counts and their reconstitution on treatment was more pronounced in CWD patients with IRIS than in those without IRIS. The ratio of activated and regulatory CD4(+) T cells, nonspecific Th1 reactivity, and the proportion of naive among CD4(+) T cells was high, whereas serum IL-10 was low during IRIS. T. whipplei-specific Th1 reactivity remained suppressed before and after emergence of IRIS. The findings that IRIS in CWD mainly are mediated by nonspecific activation of CD4(+) T cells and that it is not sufficiently counterbalanced by regulatory T cells indicate that flare-up of pathogen-specific immunoreactivity is not instrumental in the pathogenesis of IRIS in CWD. PMID- 23365083 TI - Antagonizing the alpha4beta1 integrin, but not alpha4beta7, inhibits leukocytic infiltration of the central nervous system in rhesus monkey experimental autoimmune encephalomyelitis. AB - The immune system is characterized by the preferential migration of lymphocytes through specific tissues (i.e., tissue tropism). Tissue tropism is mediated, in part, by the alpha(4) integrins expressed by T lymphocytes. The alpha(4)beta(1) integrin mediates migration of memory T lymphocytes into the CNS, whereas the alpha(4)beta(7) integrin mediates migration preferentially into gastrointestinal tissue. This paradigm was established primarily from investigations in rodents; thus, the objective of this investigation was to determine if blocking the alpha(4)beta(7) integrin exclusively would affect migration of T lymphocytes into the CNS of primates. The effects of the dual alpha(4)beta(1) and alpha(4)beta(7) antagonist natalizumab were compared with those of the alpha(4)beta(7) antagonist vedolizumab on experimental autoimmune encephalomyelitis in the rhesus monkey. Animals received an initial i.v. bolus of placebo, natalizumab (30 mg/kg), or vedolizumab (30 mg/kg) before intracutaneous immunization with recombinant human myelin oligodendrocyte glycoprotein and then Ab once weekly thereafter. Natalizumab prevented CNS inflammation and demyelination significantly (p < 0.05), compared with time-matched placebo control animals, whereas vedolizumab did not inhibit these effects, despite saturating the alpha(4)beta(7) integrin in each animal for the duration of the investigation. These results demonstrate that blocking alpha(4)beta(7) exclusively does not inhibit immune surveillance of the CNS in primates. PMID- 23365084 TI - NFATc1 induction in peripheral T and B lymphocytes. AB - NFAT transcription factors control the proliferation and survival of peripheral lymphocytes. We have reported previously that the short isoform NFATc1/alphaA whose generation is induced by immune receptor stimulation supports the proliferation and inhibits the activation-induced cell death of peripheral T and B cells. We will show in this study that in novel bacterial artificial chromosome transgenic mice that express EGFP under the control of entire Nfatc1 locus the Nfatc1/Egfp transgene is expressed as early as in double-negative thymocytes and in nonstimulated peripheral T and B cells. Upon immune receptor stimulation, Nfatc1/Egfp expression is elevated in B, Th1, and Th2 cells, but only weakly in T regulatory, Th9, and Th17 cells in vitro whose generation is affected by TGFbeta. In naive lymphocytes, persistent immune receptor signals led to a 3-5 increase in NFATc1/alphaA RNA levels during primary and secondary stimulation, but a much stronger induction was observed at the protein level. Whereas anti-CD3(+)CD28 stimulation of primary T cells induces both NFATc1/alphaA and their proliferation and survival, anti-IgM stimulation of B cells induces NFATc1/alphaA and proliferation, but activation-induced cell death after 3-d incubation in vitro. The anti-IgM-mediated activation-induced cell death induction of B cells in vitro is suppressed by anti-CD40-, LPS-, and CpG-mediated signals. In addition to inducing NF-kappaB factors, together with anti-IgM, these signals also support the generation of NFATc1/alphaA. According to these data and the architecture of its promoter region, the Nfatc1 gene resembles a primary response gene whose induction is affected at the posttranscriptional level. PMID- 23365085 TI - Addition of glycosylation to influenza A virus hemagglutinin modulates antibody mediated recognition of H1N1 2009 pandemic viruses. AB - Seasonal influenza A viruses (IAV) originate from pandemic IAV and have undergone changes in antigenic structure, including addition of glycans to the viral hemagglutinin (HA). Glycans on the head of HA promote virus survival by shielding antigenic sites, but highly glycosylated seasonal IAV are inactivated by soluble lectins of the innate immune system. In 2009, human strains of pandemic H1N1 [A(H1N1)pdm] expressed a single glycosylation site (Asn(104)) on the head of HA. Since then, variants with additional glycosylation sites have been detected, and the location of these sites has been distinct to those of recent seasonal H1N1 strains. We have compared wild-type and reverse-engineered A(H1N1)pdm IAV with differing potential glycosylation sites on HA for sensitivity to collectins and to neutralizing Abs. Addition of a glycan (Asn(136)) to A(H1N1)pdm HA was associated with resistance to neutralizing Abs but did not increase sensitivity to collectins. Moreover, variants expressing Asn(136) showed enhanced growth in A(H1N1)pdm-vaccinated mice, consistent with evasion of Ab-mediated immunity in vivo. Thus, a fine balance exists regarding the optimal pattern of HA glycosylation to facilitate evasion of Ab-mediated immunity while maintaining resistance to lectin-mediated defenses of the innate immune system. PMID- 23365086 TI - A bacterial artificial chromosome transgene with polymorphic Cd72 inhibits the development of glomerulonephritis and vasculitis in MRL-Faslpr lupus mice. AB - Systemic lupus erythematosus is considered to be under the control of polygenic inheritance, developing according to the cumulative effects of susceptibility genes with polymorphic alleles; however, the mechanisms underlying the roles of polygenes based on functional and pathological genomics remain uncharacterized. In this study, we substantiate that a CD72 polymorphism in the membrane-distal extracellular domain impacts on both the development of glomerulonephritis and vasculitis in a lupus model strain of mice, MRL/MpJ-Fas(lpr), and the reactivity of BCR signal stimulation. We generated mice carrying a bacterial artificial chromosome transgene originating from C57BL/6 (B6) mice that contains the Cd72(b) locus (Cd72(B6) transgenic [tg]) or the modified Cd72(b) locus with an MRL derived Cd72(c) allele at the polymorphic region corresponding to the membrane distal extracellular domain (Cd72(B6/MRL) tg). Cd72(B6) tg mice, but not Cd72(B6/MRL) tg mice, showed a significant reduction in mortality following a marked improvement of disease associated with decreased serum levels of IgG3 and anti-dsDNA Abs. The number of splenic CD4(-)CD8(-) T cells in Cd72(B6) tg mice was decreased significantly in association with a reduced response to B cell receptor signaling. These results indicate that the Cd72 polymorphism affects susceptibility to lupus phenotypes and that novel functional rescue by a bacterial artificial chromosome transgenesis is an efficient approach with wide applications for conducting a genomic analysis of polygene diseases. PMID- 23365087 TI - TRIF-mediated TLR3 and TLR4 signaling is negatively regulated by ADAM15. AB - TLRs are a group of pattern-recognition receptors that play a crucial role in danger recognition and induction of the innate immune response against bacterial and viral infections. The TLR adaptor molecule, Toll/IL-1R domain-containing adaptor inducing IFN (TRIF), facilitates TLR3 and TLR4 signaling and concomitant activation of the transcription factors, NF-kappaB and IFN regulatory factor 3, leading to proinflammatory cytokine production. Whereas numerous studies have been undertaken toward understanding the role of TRIF in TLR signaling, little is known about the signaling components that regulate TRIF-dependent TLR signaling. To this end, TRIF-interacting partners were identified by immunoprecipitation of the TRIF signaling complex, followed by protein identification using liquid chromatography mass spectrometry. Following stimulation of cells with a TLR3 or TLR4 ligand, we identified a disintegrin and metalloprotease (ADAM)15 as a novel TRIF-interacting partner. Toward the functional characterization of the TRIF:ADAM15 interaction, we show that ADAM15 acts as a negative regulator of TRIF mediated NF-kappaB and IFN-beta reporter gene activity. Also, suppression of ADAM15 expression enhanced polyriboinosinic polyribocytidylic acid and LPS mediated proinflammatory cytokine production via TRIF. In addition, suppression of ADAM15 expression enhanced rhinovirus 16 and vesicular stomatitis virus mediated proinflammatory cytokine production. Interestingly, ADAM15 mediated the proteolytic cleavage of TRIF. Thus, ADAM15 serves to curtail TRIF-dependent TLR3 and TLR4 signaling and, in doing so, protects the host from excessive production of proinflammatory cytokines and matrix metalloproteinases. In conclusion, to our knowledge, our study clearly shows for the first time that ADAM15 plays an unexpected role in TLR signaling, acting as an anti-inflammatory molecule through impairment of TRIF-mediated TLR signaling. PMID- 23365088 TI - Brain. Editorial. PMID- 23365089 TI - Neuroinflammation and the dynamic lesion in traumatic brain injury. PMID- 23365090 TI - This limb is mine but I do not want it: from anatomy to body ownership. PMID- 23365091 TI - A single strand that links multiple neuropathologies in human disease. AB - The development of the human central nervous system is a complex process involving highly coordinated periods of neuronal proliferation, migration and differentiation. Disruptions in these neurodevelopmental processes can result in microcephaly, a neuropathological disorder characterized by a reduction in skull circumference and total brain volume, whereas a failure to maintain neuronal health in the adult brain can lead to progressive neurodegeneration. Defects in the cellular pathways that detect and repair DNA damage are a common cause of both these neuropathologies and are associated with a growing number of hereditary human disorders. In particular, defects in the repair of DNA single strand breaks, one of the most commonly occurring types of DNA lesion, have been associated with three neuropathological diseases: ataxia oculomotor apraxia 1, spinocerebellar ataxia with neuronal neuropathy 1 and microcephaly, early-onset, intractable seizures and developmental delay. A striking similarity between these three human diseases is that they are all caused by mutations in DNA end processing factors, suggesting that a particularly crucial stage of DNA single strand break repair is the repair of breaks with 'damaged' termini. Additionally all three disorders lack any extraneurological symptoms, such as immunodeficiency and cancer predisposition, which are typically found in other human diseases associated with defective DNA repair. However despite these similarities, two of these disorders present with progressive cerebellar degeneration, whereas the third presents with severe microcephaly. This review discusses the molecular defects behind these disorders and presents several hypotheses based on current literature on a number of important questions, in particular, how do mutations in different end processing factors within the same DNA repair pathway lead to such different neuropathologies? PMID- 23365093 TI - Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. AB - Neurodegeneration is the main cause for permanent disability in multiple sclerosis. The effect of current immunomodulatory treatments on neurodegeneration is insufficient. Therefore, direct neuroprotection and myeloprotection remain an important therapeutic goal. Targeting acid-sensing ion channel 1 (encoded by the ASIC1 gene), which contributes to the excessive intracellular accumulation of injurious Na(+) and Ca(2+) and is over-expressed in acute multiple sclerosis lesions, appears to be a viable strategy to limit cellular injury that is the substrate of neurodegeneration. While blockade of ASIC1 through amiloride, a potassium sparing diuretic that is currently licensed for hypertension and congestive cardiac failure, showed neuroprotective and myeloprotective effects in experimental models of multiple sclerosis, this strategy remains untested in patients with multiple sclerosis. In this translational study, we tested the neuroprotective effects of amiloride in patients with primary progressive multiple sclerosis. First, we assessed ASIC1 expression in chronic brain lesions from post-mortem of patients with progressive multiple sclerosis to identify the target process for neuroprotection. Second, we tested the neuroprotective effect of amiloride in a cohort of 14 patients with primary progressive multiple sclerosis using magnetic resonance imaging markers of neurodegeneration as outcome measures of neuroprotection. Patients with primary progressive multiple sclerosis underwent serial magnetic resonance imaging scans before (pretreatment phase) and during (treatment phase) amiloride treatment for a period of 3 years. Whole-brain volume and tissue integrity were measured with high-resolution T(1) weighted and diffusion tensor imaging. In chronic brain lesions of patients with progressive multiple sclerosis, we demonstrate an increased expression of ASIC1 in axons and an association with injury markers within chronic inactive lesions. In patients with primary progressive multiple sclerosis, we observed a significant reduction in normalized annual rate of whole-brain volume during the treatment phase, compared with the pretreatment phase (P = 0.018, corrected). Consistent with this reduction, we showed that changes in diffusion indices of tissue damage within major clinically relevant white matter (corpus callosum and corticospinal tract) and deep grey matter (thalamus) structures were significantly reduced during the treatment phase (P = 0.02, corrected). Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis. PMID- 23365092 TI - Inflammation and white matter degeneration persist for years after a single traumatic brain injury. AB - A single traumatic brain injury is associated with an increased risk of dementia and, in a proportion of patients surviving a year or more from injury, the development of hallmark Alzheimer's disease-like pathologies. However, the pathological processes linking traumatic brain injury and neurodegenerative disease remain poorly understood. Growing evidence supports a role for neuroinflammation in the development of Alzheimer's disease. In contrast, little is known about the neuroinflammatory response to brain injury and, in particular, its temporal dynamics and any potential role in neurodegeneration. Cases of traumatic brain injury with survivals ranging from 10 h to 47 years post injury (n = 52) and age-matched, uninjured control subjects (n = 44) were selected from the Glasgow Traumatic Brain Injury archive. From these, sections of the corpus callosum and adjacent parasaggital cortex were examined for microglial density and morphology, and for indices of white matter pathology and integrity. With survival of >=3 months from injury, cases with traumatic brain injury frequently displayed extensive, densely packed, reactive microglia (CR3/43- and/or CD68 immunoreactive), a pathology not seen in control subjects or acutely injured cases. Of particular note, these reactive microglia were present in 28% of cases with survival of >1 year and up to 18 years post-trauma. In cases displaying this inflammatory pathology, evidence of ongoing white matter degradation could also be observed. Moreover, there was a 25% reduction in the corpus callosum thickness with survival >1 year post-injury. These data present striking evidence of persistent inflammation and ongoing white matter degeneration for many years after just a single traumatic brain injury in humans. Future studies to determine whether inflammation occurs in response to or, conversely, promotes white matter degeneration will be important. These findings may provide parallels for studying neurodegenerative disease, with traumatic brain injury patients serving as a model for longitudinal investigations, in particular with a view to identifying potential therapeutic interventions. PMID- 23365094 TI - Fibronectin aggregation in multiple sclerosis lesions impairs remyelination. AB - Remyelination following central nervous system demyelination is essential to prevent axon degeneration. However, remyelination ultimately fails in demyelinating diseases such as multiple sclerosis. This failure of remyelination is likely mediated by many factors, including changes in the extracellular signalling environment. Here, we examined the expression of the extracellular matrix molecule fibronectin on demyelinating injury and how this affects remyelination by oligodendrocytes progenitors. In toxin-induced lesions undergoing efficient remyelination, fibronectin expression was transiently increased within demyelinated areas and declined as remyelination proceeded. Fibronectin levels increased both by leakage from the blood circulation and by production from central nervous system resident cells. In chronically demyelinated multiple sclerosis lesions, fibronectin expression persisted in the form of aggregates, which may render fibronectin resistant to degradation. Aggregation of fibronectin was similarly observed at the relapse phase of chronic experimental autoimmune encephalitis, but not on toxin-induced demyelination, suggesting that fibronectin aggregation is mediated by inflammation-induced demyelination. Indeed, the inflammatory mediator lipopolysaccharide induced fibronectin aggregation by astrocytes. Most intriguingly, injection of astrocyte derived fibronectin aggregates in toxin-induced demyelinated lesions inhibited oligodendrocyte differentiation and remyelination, and fibronectin aggregates are barely expressed in remyelinated multiple sclerosis lesions. Therefore, these findings suggest that fibronectin aggregates within multiple sclerosis lesions contribute to remyelination failure. Hence, the inhibitory signals induced by fibronectin aggregates or factors that affect fibronectin aggregation could be potential therapeutic targets for promoting remyelination. PMID- 23365096 TI - Assessing prenatal white matter connectivity in commissural agenesis. AB - Complete or partial agenesis of the corpus callosum are rather common developmental abnormalities, resulting in a wide spectrum of clinical neurodevelopmental deficits. Currently, a significant number of these cases are detected by prenatal sonography during second trimester screening examinations. However, major uncertainties about a detailed morphological diagnosis and the clinical significance do not allow accurate prenatal counselling. Here, we were able to demonstrate the 3D connectivity of aberrant commissural tracts in 16 cases with complete and four cases with partial callosal agenesis using the foetal magnetic resonance imaging techniques of diffusion tensor imaging and tractography in utero and in vivo between gestational weeks 20 and 37. The 'misguided' pre-myelinated callosal axons that represent the bundle of Probst were non-invasively visualized, and they showed a degree of structural integrity similar to that of the callosal pathways of age-matched foetuses without cerebral pathologies. In two foetuses, we were able to prove, by post-mortem histology, that diffusion tensor imaging allows the depiction of the bundle of Probst, even during early stages of pre-myelination at 20 and 22 gestational weeks. In cases with partial callosal agenesis, an aberrant sigmoid-shaped bundle was prenatally depicted, confirming the findings of heterotopic interhemispheric connectivity in adults with partial callosal agenesis. In addition to the corpus callosum, other white matter pathways were also involved, including somatosensory and motor pathways that showed significantly higher fractional anisotropy values in cases with callosal agenesis compared with control subjects. A detailed prenatal assessment of abnormal white matter connectivity in cases of midline anomalies will help to explain and understand the clinical heterogeneity in these cases, taking future foetal neurological counselling strategies to a new level. PMID- 23365095 TI - The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination. AB - Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens. Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery. After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5alpha-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells. Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic testosterone analogue 7alpha-methyl-19 nortestosterone, which has been developed for long-term male contraception and androgen replacement therapy in hypogonadal males and does not stimulate prostate growth, also efficiently promoted myelin repair. These data establish the efficacy of androgens as remyelinating agents and qualify the brain androgen receptor as a promising drug target for remyelination therapy, thus providing the preclinical rationale for a novel therapeutic use of androgens in males with multiple sclerosis. PMID- 23365098 TI - Hyaluronan accumulation and arrested oligodendrocyte progenitor maturation in vanishing white matter disease. AB - Vanishing white matter disease is a genetic leukoencephalopathy caused by mutations in eukaryotic translation initiation factor 2B. Patients experience a slowly progressive neurological deterioration with episodes of rapid clinical worsening triggered by stress. The disease may occur at any age and leads to early death. Characteristic neuropathological findings include cystic degeneration of the white matter with feeble, if any, reactive gliosis, dysmorphic astrocytes and paucity of myelin despite an increase in oligodendrocytic density. These features have been linked to a maturation defect of astrocytes and oligodendrocytes. However, the nature of the link between glial immaturity and the observed neuropathological features is unclear. We hypothesized that the defects in maturation and function of astrocytes and oligodendrocytes are related. Brain tissue of seven patients with genetically proven vanishing white matter disease was investigated using immunohistochemistry, western blotting, quantitative polymerase chain reaction and size exclusion chromatography. The results were compared with those obtained from normal brain tissue of age-matched controls, from chronic demyelinated multiple sclerosis lesions and from other genetic and acquired white matter disorders. We found that the white matter of patients with vanishing white matter disease is enriched in CD44-expressing astrocyte precursor cells and accumulates the glycosaminoglycan hyaluronan. Hyaluronan is a major component of the extracellular matrix, and CD44 is a hyaluronan receptor. We found that a high molecular weight form of hyaluronan is overabundant, especially in the most severely affected areas. Comparison between the more severely affected frontal white matter and the relatively spared cerebellum confirms that high molecular weight hyaluronan accumulation is more pronounced in the frontal white matter than in the cerebellum. High molecular weight hyaluronan is known to inhibit astrocyte and oligodendrocyte precursor maturation and can explain the arrested glial progenitor maturation observed in vanishing white matter disease. In conclusion, high molecular weight species of hyaluronan accumulate in the white matter of patients with vanishing white matter disease, and by inhibiting glial maturation and proper function, they may be a major determinant of the white matter pathology and lack of repair. PMID- 23365097 TI - Auditory analysis of xeroderma pigmentosum 1971-2012: hearing function, sun sensitivity and DNA repair predict neurological degeneration. AB - To assess the role of DNA repair in maintenance of hearing function and neurological integrity, we examined hearing status, neurological function, DNA repair complementation group and history of acute burning on minimal sun exposure in all patients with xeroderma pigmentosum, who had at least one complete audiogram, examined at the National Institutes of Health from 1971 to 2012. Seventy-nine patients, aged 1-61 years, were diagnosed with xeroderma pigmentosum (n = 77) or xeroderma pigmentosum/Cockayne syndrome (n = 2). A total of 178 audiograms were included. Clinically significant hearing loss (>20 dB) was present in 23 (29%) of 79 patients. Of the 17 patients with xeroderma pigmentosum type neurological degeneration, 13 (76%) developed hearing loss, and all 17 were in complementation groups xeroderma pigmentosum type A or type D and reported acute burning on minimal sun exposure. Acute burning on minimal sun exposure without xeroderma pigmentosum-type neurological degeneration was present in 18% of the patients (10/55). Temporal bone histology in a patient with severe xeroderma pigmentosum-type neurological degeneration revealed marked atrophy of the cochlear sensory epithelium and neurons. The 19-year mean age of detection of clinically significant hearing loss in the patients with xeroderma pigmentosum with xeroderma pigmentosum-type neurological degeneration was 54 years younger than that predicted by international norms. The four frequency (0.5/1/2/4 kHz) pure-tone average correlated with degree of neurodegeneration (P < 0.001). In patients with xeroderma pigmentosum, aged 4-30 years, a four-frequency pure-tone average >=10 dB hearing loss was associated with a 39-fold increased risk (P = 0.002) of having xeroderma pigmentosum-type neurological degeneration. Severity of hearing loss parallels neurological decline in patients with xeroderma pigmentosum-type neurological degeneration. Audiometric findings, complementation group, acute burning on minimal sun exposure and age were important predictors of xeroderma pigmentosum-type neurological degeneration. These results provide evidence that DNA repair is critical in maintaining neurological integrity of the auditory system. PMID- 23365100 TI - Chronic exposure of astrocytes to interferon-alpha reveals molecular changes related to Aicardi-Goutieres syndrome. AB - Aicardi-Goutieres syndrome is a genetically determined infantile encephalopathy, manifesting as progressive microcephaly, psychomotor retardation, and in ~25% of patients, death in early childhood. Aicardi-Goutieres syndrome is caused by mutations in any of the genes encoding TREX1, RNASEH2-A, -B, -C and SAMHD1, with protein dysfunction hypothesized to result in the accumulation of nucleic acids within the cell, thus triggering an autoinflammatory response with increased interferon-alpha production. Astrocytes have been identified as a major source of interferon-alpha production in the brains of patients with Aicardi-Goutieres syndrome. Here, we study the effect of interferon-alpha treatment on astrocytes derived from immortalized human neural stem cells. Chronic interferon-alpha treatment promoted astrocyte activation and a reduction in cell proliferation. Moreover, chronic exposure resulted in an alteration of genes and proteins involved in the stability of white matter (ATF4, eIF2Balpha, cathepsin D, cystatin F), an increase of antigen-presenting genes (human leukocyte antigen class I) and downregulation of pro-angiogenic factors and other cytokines (vascular endothelial growth factor and IL-1). Interestingly, withdrawal of interferon-alpha for 7 days barely reversed these cellular alterations, demonstrating that the interferon-alpha mediated effects persist over time. We confirmed our in vitro findings using brain samples from patients with Aicardi Goutieres syndrome. Our results support the idea of interferon-alpha as a key factor in the pathogenesis of Aicardi-Goutieres syndrome relating to the observed leukodystrophy and microangiopathy. Because of the sustained interferon-alpha effect, even after withdrawal, therapeutic targets for Aicardi-Goutieres syndrome, and other interferon-alpha-mediated encephalopathies, may include downstream interferon-alpha signalling cascade effectors rather than interferon alpha alone. PMID- 23365101 TI - Rating disease progression of Friedreich's ataxia by the International Cooperative Ataxia Rating Scale: analysis of a 603-patient database. AB - The aim of this cross-sectional study was to analyse disease progression in Friedreich's ataxia as measured by the International Cooperative Ataxia Rating Scale. Single ratings from 603 patients with Friedreich's ataxia were analysed as a function of disease duration, age of onset and GAA repeat lengths. The relative contribution of items and subscales to the total score was studied as a function of disease progression. In addition, the scaling properties were assessed using standard statistical measures. Average total scale progression per year depends on the age of disease onset, the time since diagnosis and the GAA repeat length. The age of onset inversely correlates with increased GAA repeat length. For patients with an age of onset <=14 years associated with a longer repeat length, the average yearly rate of decline was 2.5 +/- 0.18 points in the total International Cooperative Ataxia Rating Scale for the first 20 years of disease duration, whereas patients with a later onset progress more slowly (1.8 +/- 0.27 points/year). Ceiling effects in posture, gait and lower limb scale items lead to a reduced sensitivity of the scale in the severely affected population with a total score of >60 points. Psychometric scaling analysis shows generally favourable properties for the total scale, but the subscale grouping could be improved. This cross-sectional study provides a detailed characterization of the International Cooperative Ataxia Rating Scale. The analysis further provides rates of change separated for patients with early and late disease onset, which is driven by the GAA repeat length. Differences in the subscale dynamics merit consideration in the design of future clinical trials applying this scale as a neurological assessment instrument in Friedreich's ataxia. PMID- 23365099 TI - New insights into genotype-phenotype correlations for the doublecortin-related lissencephaly spectrum. AB - X-linked isolated lissencephaly sequence and subcortical band heterotopia are allelic human disorders associated with mutations of doublecortin (DCX), giving both familial and sporadic forms. DCX encodes a microtubule-associated protein involved in neuronal migration during brain development. Structural data show that mutations can fall either in surface residues, likely to impair partner interactions, or in buried residues, likely to impair protein stability. Despite the progress in understanding the molecular basis of these disorders, the prognosis value of the location and impact of individual DCX mutations has largely remained unclear. To clarify this point, we investigated a cohort of 180 patients who were referred with the agyria-pachygyria subcortical band heterotopia spectrum. DCX mutations were identified in 136 individuals. Analysis of the parents' DNA revealed the de novo occurrence of DCX mutations in 76 cases [62 of 70 females screened (88.5%) and 14 of 60 males screened (23%)], whereas in the remaining cases, mutations were inherited from asymptomatic (n = 14) or symptomatic mothers (n = 11). This represents 100% of families screened. Female patients with DCX mutation demonstrated three degrees of clinical-radiological severity: a severe form with a thick band (n = 54), a milder form (n = 24) with either an anterior thin or an intermediate thickness band and asymptomatic carrier females (n = 14) with normal magnetic resonance imaging results. A higher proportion of nonsense and frameshift mutations were identified in patients with de novo mutations. An analysis of predicted effects of missense mutations showed that those destabilizing the structure of the protein were often associated with more severe phenotypes. We identified several severe- and mild-effect mutations affecting surface residues and observed that the substituted amino acid is also critical in determining severity. Recurrent mutations representing 34.5% of all DCX mutations often lead to similar phenotypes, for example, either severe in sporadic subcortical band heterotopia owing to Arg186 mutations or milder in familial cases owing to Arg196 mutations. Taken as a whole, these observations demonstrate that DCX-related disorders are clinically heterogeneous, with severe sporadic and milder familial subcortical band heterotopia, each associated with specific DCX mutations. There is a clear influence of the individual mutated residue and the substituted amino acid in determining phenotype severity. PMID- 23365102 TI - Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy. AB - A cardioskeletal myopathy with onset and death in infancy, morphological features of muscle type I hypotrophy with myofibrillar disorganization and dilated cardiomyopathy was previously reported in three Dutch families. Here we report the genetic cause of this disorder. Multipoint parametric linkage analysis of six Dutch patients identified a homozygous region of 2.1 Mb on chromosome 12, which was shared between all Dutch patients, with a log of odds score of 10.82. Sequence analysis of the entire linkage region resulted in the identification of a homozygous mutation in the last acceptor splice site of the myosin regulatory light chain 2 gene (MYL2) as the genetic cause. MYL2 encodes a myosin regulatory light chain (MLC-2V). The myosin regulatory light chains bind, together with the essential light chains, to the flexible neck region of the myosin heavy chain in the hexameric myosin complex and have a structural and regulatory role in muscle contraction. The MYL2 mutation results in use of a cryptic splice site upstream of the last exon causing a frameshift and replacement of the last 32 codons by 20 different codons. Whole exome sequencing of an Italian patient with similar clinical features showed compound heterozygosity for two other mutations affecting the same exon of MYL2, also resulting in mutant proteins with altered C terminal tails. As a consequence of these mutations, the second EF-hand domain is disrupted. EF-hands, assumed to function as calcium sensors, can undergo a conformational change upon binding of calcium that is critical for interactions with downstream targets. Immunohistochemical staining of skeletal muscle tissue of the Dutch patients showed a diffuse and weak expression of the mutant protein without clear fibre specificity, while normal protein was absent. Heterozygous missense mutations in MYL2 are known to cause dominant hypertrophic cardiomyopathy; however, none of the parents showed signs of cardiomyopathy. In conclusion, the mutations in the last exon of MYL2 are responsible for a novel autosomal recessive lethal myosinopathy due to defects changing the C-terminal tail of the ventricular form of the myosin regulatory light chain. We propose 'light chain myopathy' as a name for this MYL2-associated myopathy. PMID- 23365103 TI - SGCE mutations cause psychiatric disorders: clinical and genetic characterization. AB - Myoclonus dystonia syndrome is a childhood onset hyperkinetic movement disorder characterized by predominant alcohol responsive upper body myoclonus and dystonia. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. Previous studies have suggested that patients with SGCE mutations may have an increased rate of psychiatric disorders. We established a cohort of patients with myoclonus dystonia syndrome and SGCE mutations to determine the extent to which psychiatric disorders form part of the disease phenotype. In all, 89 patients with clinically suspected myoclonus dystonia syndrome were recruited from the UK and Ireland. SGCE was analysed using direct sequencing and for copy number variants. In those patients where no mutation was found TOR1A (GAG deletion), GCH1, THAP1 and NKX2-1 were also sequenced. SGCE mutation positive cases were systematically assessed using standardized psychiatric interviews and questionnaires and compared with a disability-matched control group of patients with alcohol responsive tremor. Nineteen (21%) probands had a SGCE mutation, five of which were novel. Recruitment of family members increased the affected SGCE mutation positive group to 27 of whom 21 (77%) had psychiatric symptoms. Obsessive-compulsive disorder was eight times more likely (P < 0.001) in mutation positive cases, compulsivity being the predominant feature (P < 0.001). Generalized anxiety disorder (P = 0.003) and alcohol dependence (P = 0.02) were five times more likely in mutation positive cases than tremor controls. SGCE mutations are associated with a specific psychiatric phenotype consisting of compulsivity, anxiety and alcoholism in addition to the characteristic motor phenotype. SGCE mutations are likely to have a pleiotropic effect in causing both motor and specific psychiatric symptoms. PMID- 23365104 TI - Neuronal activity correlated with checking behaviour in the subthalamic nucleus of patients with obsessive-compulsive disorder. AB - Doubt, and its behavioural correlate, checking, is a normal phenomenon of human cognition that is dramatically exacerbated in obsessive-compulsive disorder. We recently showed that deep brain stimulation in the associative-limbic area of the subthalamic nucleus, a central core of the basal ganglia, improved obsessive compulsive disorder. To understand the physiological bases of symptoms in such patients, we recorded the activity of individual neurons in the therapeutic target during surgery while subjects performed a cognitive task that gave them the possibility of unrestricted repetitive checking after they had made a choice. We postulated that the activity of neurons in this region could be influenced by doubt and checking behaviour. Among the 63/87 task-related neurons recorded in 10 patients, 60% responded to various combinations of instructions, delay, movement or feedback, thus highlighting their role in the integration of different types of information. In addition, task-related activity directed towards decision making increased during trials with checking in comparison with those without checking. These results suggest that the associative-limbic subthalamic nucleus plays a role in doubt-related repetitive thoughts. Overall, our results not only provide new insight into the role of the subthalamic nucleus in human cognition but also support the fact that subthalamic nucleus modulation by deep brain stimulation reduced compulsive behaviour in patients with obsessive-compulsive disorder. PMID- 23365106 TI - Supplementation with n3 fatty acid ethyl esters increases large and small artery elasticity in obese adults on a weight loss diet. AB - Increased arterial stiffness is associated with enhanced risk of cardiovascular disease in obese individuals. Whether n3 fatty acid ethyl ester (FAEE) supplementation improves arterial stiffness in obese participants on a weight loss diet has not yet been investigated. The objective of the study was to carry out a 12-wk randomized, single-blind trial to test the effect of a 25% energy deficit weight loss diet alone (WL) (n = 12) or WL plus 4 g/d Omacor (46% EPA and 38% DHA) supplementation (WL+FAEE) (n = 13) on arterial elasticity in obese adults. Large (C1) and small artery elasticity (C2) were measured by pulse contour analysis of the radial artery. WL alone reduced (P < 0.05 in all) body weight (-3%), waist circumference (-4%), systolic (-3%) and diastolic (-3%) blood pressures, cardiac output (-4%), plasma TG concentration (-25%), and the homeostasis model assessment (HOMA) score (-12%) and increased plasma HDL cholesterol (+9%) and adiponectin (+18%) concentrations. However, WL alone did not alter C1 and C2. The WL+FAEE intervention significantly reduced body weight ( 4%), waist circumference (-4%), systolic (-8%) and diastolic (-5%) blood pressures, pulse pressure (-5%), heart rate (-8%), plasma TG concentration ( 36%), and HOMA score (-12%) and increased stroke volume (+3%), plasma HDL cholesterol (+6%) and adiponectin concentrations (+28%), and C1 (+20%) and C2 (+22%) artery elasticity. The changes in systolic blood pressure, heart rate, plasma TGs, C1, and C2 were significantly greater in the WL+FAEE group than in the WL group. Supplementation with n3 FAEEs improves C1 and C2 independently of weight loss in obese adults. PMID- 23365105 TI - Long-term adherence to the Mediterranean diet is associated with overall cognitive status, but not cognitive decline, in women. AB - In this large-scale prospective epidemiological study, we examined associations of long-term adherence to the Mediterranean diet (MeDi) and subsequent cognitive function and decline. We included 16,058 women from the Nurses' Health Study, aged >=70 y, who underwent cognitive testing by telephone 4 times during 6 y, beginning in 1995-2001, and provided repeated information on diet between 1984 and the first cognitive exam. Primary outcomes were the Telephone Interview for Cognitive Status (TICS) and composite scores of verbal memory and global cognition. MeDi adherence was based on intakes of: vegetables, fruits, legumes, whole grains, nuts, fish, red and processed meats, moderate alcohol, and the ratio of monounsaturated:saturated fat. Long-term MeDi exposure was estimated by averaging all repeated measures of diet (>13 y, on average). In primary analyses of cognitive change, the MeDi was not associated with decline in global cognition or verbal memory. In a secondary approach examining cognitive status in older age, determined by averaging all 4 repeated measures of cognition, each higher quintile of long-term MeDi score was linearly associated with better multivariable-adjusted mean cognitive scores [differences in mean Z-scores between extreme quintiles of MeDi = 0.06 (95% CI: 0.01, 0.11); = 0.05 (95% CI: 0.01, 0.08); and = 0.06 (95% CI: 0.03, 0.10) standard units; P-trends = 0.004, 0.002, and <0.001 for TICS, global cognition, and verbal memory, respectively]. These associations were similar to those observed in women 1-1.5 y apart in age. In summary, long-term MeDi adherence was related to moderately better cognition but not with cognitive change in this very large cohort of older women. PMID- 23365107 TI - Dietary supplement use and folate status during pregnancy in the United States. AB - Adequate folate and iron intake during pregnancy is critical for maternal and fetal health. No previous studies to our knowledge have reported dietary supplement use and folate status among pregnant women sampled in NHANES, a nationally representative, cross-sectional survey. We analyzed data on 1296 pregnant women who participated in NHANES from 1999 to 2006 to characterize overall supplement use, iron and folic acid use, and RBC folate status. The majority of pregnant women (77%) reported use of a supplement in the previous 30 d, most frequently a multivitamin/-mineral containing folic acid (mean 817 MUg/d) and iron (48 mg/d). Approximately 55-60% of women in their first trimester reported taking a folic acid- or iron-containing supplement compared with 76-78% in their second trimester and 89% in their third trimester. RBC folate was lowest in the first trimester and differed by supplement use across all trimesters. Median RBC folate was 1628 nmol/L among users and 1041 nmol/L among nonusers. Among all pregnant women, median RBC folate increased with trimester (1256 nmol/L in the first, 1527 nmol/L in the second, and 1773 nmol/L in the third). Given the role of folic acid in the prevention of neural tube defects, it is notable that supplement use and median RBC folate was lowest in the first trimester of pregnancy, with 55% of women taking a supplement containing folic acid. Future research is needed to determine the reasons for low compliance with supplement recommendations, particularly folic acid, in early pregnancy. PMID- 23365108 TI - Berries reduce postprandial insulin responses to wheat and rye breads in healthy women. AB - Starch in white wheat bread (WB) induces high postprandial glucose and insulin responses. For rye bread (RB), the glucose response is similar, whereas the insulin response is lower. In vitro studies suggest that polyphenol-rich berries may reduce digestion and absorption of starch and thereby suppress postprandial glycemia, but the evidence in humans is limited. We investigated the effects of berries consumed with WB or RB on postprandial glucose and insulin responses. Healthy females (n = 13-20) participated in 3 randomized, controlled, crossover, 2-h meal studies. They consumed WB or RB, both equal to 50 g available starch, with 150 g whole-berry puree or the same amount of bread without berries as reference. In study 1, WB was served with strawberries, bilberries, or lingonberries and in study 2 with raspberries, cloudberries, or chokeberries. In study 3, WB or RB was served with a mixture of berries consisting of equal amounts of strawberries, bilberries, cranberries, and blackcurrants. Strawberries, bilberries, lingonberries, and chokeberries consumed with WB and the berry mixture consumed with WB or RB significantly reduced the postprandial insulin response. Only strawberries (36%) and the berry mixture (with WB, 38%; with RB, 19%) significantly improved the glycemic profile of the breads. These results suggest than when WB is consumed with berries, less insulin is needed for maintenance of normal or slightly improved postprandial glucose metabolism. The lower insulin response to RB compared with WB can also be further reduced by berries. PMID- 23365109 TI - Role of patient characteristics for fast-track hip and knee arthroplasty. AB - BACKGROUND: Patient age and comorbidity have been found to increase the length of hospital stay (LOS), readmissions, and mortality after surgery, including in elective primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). Whether the same applies in fast-track THA and TKA with early mobilization and an LOS aim of 2-4 days remains unanswered. METHOD: A prospective study on patient characteristics and comorbidity in consecutive unselected patients undergoing fast-track THA and TKA was cross-referenced with the Danish National Health Registry and medical charts allowing complete 90 days follow-up. RESULTS: A total of 3112 THA/TKAs were performed in 3020 patients. The mean age was 67 (range 18 97) years. The median LOS was 3 (inter-quartile range: 1) and the mean 3.0 days (range 1-34), with 91% having LOS <=4 days. Age 76-80 [odds ratio (OR): 1.57; 95% confidence interval (CI): 0.99-2.47], 81-85 (OR: 2.40; 1.45-4.00), and >85 yr (OR: 4.10; 2.15-7.82), preoperative cardiopulmonary disease (CPD) (OR: 1.40; 1.03 1.91), preoperative use of a mobility aid (OR: 1.95; 1.46-2.54), and living conditions (OR: 1.92; 1.44-2.54) were related to LOS >4 days. However, more than 75% of those aged over 80 yr or with these conditions had an LOS <=4 days. Mortality and readmission rate were 0.22% and 6.6%, respectively, at 30 days and 0.42% and 9.3% at 90 days. Readmissions were similarly related to older age, CPD, and use of mobility aids. CONCLUSIONS: Fast-track THA and TKA with LOS of <=4 days and discharge to home is feasible and safe, including in elderly patients with comorbidities. PMID- 23365110 TI - Hematogenous metastatic patterns of curatively resected colon cancer were different from those of stage IV and autopsy cases. AB - The hematogenous metastases of colon cancer have primarily been explained by the cascade hypothesis based on the cadaveric study. However, we experienced several cases with isolated lung metastasis. The metastatic patterns of a total of 982 patients with colon cancer who underwent surgery were reviewed. The incidence of single-site metastasis in curatively resected cases was significantly higher than in Stage IV cases (P = 0.002). The frequency of liver metastasis was significantly lower in curatively resected cases than in Stage IV cases (P < 0.0001). The frequencies of liver metastasis in Stage IV cases and in autopsy cases reported previously were almost the same (84%, 85%). The frequency of metastasis after curatively resection that did not include the liver was 39%, and cases of isolated lung metastases accounted for 19%. The patterns of hematogenous metastases that are inconsistent with the cascade hypothesis are more common than previously thought in clinical cases, especially in curatively resected cases. PMID- 23365111 TI - Cancer articles in weekly magazines: useful media to deliver cancer information to the public? AB - OBJECTIVE: Japanese weekly magazines, which have a circulation of over 2 700 000, play important roles in communicating with the public. They offer a wide range of information, entertainment, gossip, politics and economics, and often include articles on cancer. However, cancer articles in magazines have not been systematically analyzed. METHODS: We investigated cancer-related articles and advertisements in six major Japanese weekly magazines to demonstrate trends in public interest regarding cancer. RESULTS: The total number of articles assessed from July 2009 to December 2010 was 36 914, of which 696 (1.9%) were cancer articles. The total number of advertisements was 21 718, of which 340 (1.6%) were related to cancer. The number of cancer articles demonstrated an upward trend during the study period. Articles focused on lung (n = 145) and urogenital cancer (n = 122). The most common content comprised therapies and diagnosis (n = 340) and case reports on individual patients (n = 160). After a famous Japanese comedian revealed his prostate cancer diagnosis, the number of articles on prostate cancer increased from 2.0 to 6.6 per month. Immunotherapy including some dubious folk therapies was the most frequently reported cancer therapy in articles and advertisements (30.4%). A small group of oncologists were repeatedly referred to in comment sources; 35.6% of comments were presented by only five doctors. CONCLUSIONS: Cancer articles in weekly magazines are common paper media for providing cancer information to the public. However, the information provided might place emphasis on unestablished treatments or biased opinions. PMID- 23365112 TI - Oncology nurses' recognition of supportive care needs and symptoms of their patients undergoing chemotherapy. AB - OBJECTIVE: To assess the accuracy of oncology nurses' recognition of supportive care needs and symptoms of their patients undergoing chemotherapy. METHODS: The participants comprised randomly selected cancer outpatients receiving chemotherapy in an ambulatory setting and 17 oncology nurses working in two chemotherapy units in Japan. For assessment of the patients' supportive care needs and symptoms, the patients were asked to respond to a validated self administered questionnaire. The oncology nurses completed a survey in which they indicated their perception of the level of the same set of needs or symptoms. The two data sets obtained from the patients and nurses were compared statistically to assess the accuracy of the oncology nurses' recognition of their patients' needs and symptoms. RESULTS: Complete data sets were available for 439 patients. The most common primary cancers were breast cancer (36.0%), followed by colorectal (24.4%) and lung (12.3%) cancers. Nurses' awareness of their patients' supportive care needs and physical and psychological symptoms were less than optimal in routine care. In particular, psychological symptoms and support needs for these symptoms were markedly under-recognized. Physical symptoms associated with chemotherapy, such as hair loss, appetite loss and fatigue, were better recognized than symptoms not specific to chemotherapy, such as constipation, insomnia, dyspnea and pain. CONCLUSIONS: Oncology nurses' recognition may not accurately reflect their patients' supportive care needs and symptoms in routine practice. In clinical practice, it may be beneficial to conduct routine screening of patients' perceived needs and symptoms comprehensively using self-administered questionnaires. PMID- 23365113 TI - Effect of Daikenchuto (TJ-100) on postoperative bowel motility and on prevention of paralytic ileus after pancreaticoduodenectomy: a multicenter, randomized, placebo-controlled phase II trial (the JAPAN-PD study). AB - We conducted a multicenter, randomized, controlled trial in patients with pancreaticoduodenectomy to investigate the efficacy of Daikenchuto (TJ-100), which is a Kampo medicine (traditional Japanese herbal medicine), for its effect on postoperative bowel motility and for prevention of postoperative paralytic ileus. This clinical trial primarily evaluates the co-primary endpoints: (i) the incidence rate of postoperative paralytic ileus lasting over 72 h after surgery and (ii) time to having the first postoperative passage of flatus. The secondary endpoints are the incidence of postoperative paralytic ileus in cases that combined with/without enteral alimentation, QOL assessment by the Gastrointestinal Symptom Rating Scale (GSRS) Score (Japanese Version) and visual analogue scale, the change ratio of abdominal circumference, the incidence of postoperative complication, the number of postoperative hospital days, the incidence of surgical site infection and the incidence of postoperative small bowel obstruction within 2 years after surgery. Two hundred and twenty patients are required in the study (110 patients per group). PMID- 23365114 TI - Effects on employees of controlling working hours and working schedules. AB - BACKGROUND: High levels of control over working time and low variability in working hours have been associated with improved health-related outcomes. The potential mechanisms for this association remain unclear. AIMS: To examine how work-time control and variability of working times are associated with fatigue recovery, sleep quality, work-life balance, and 'near misses' at work. METHODS: Manufacturing sector employees completed a questionnaire that assessed work-time control, work-time variability, fatigue recovery, sleep quality, work-life balance and the frequency of near misses in the past 6 months. Mixed model analysis of covariance and multiple logistic regression analysis tested the main effects of work-time control and variability and their interaction, while adjusting for age, sex, work schedules, and overtime work in the past month. Subscales of work-time control were also investigated (control over daily working hours and over days off). RESULTS: One thousand three hundred and seventy-two completed questionnaires were returned, a response rate of 69%. A significantly higher quality of sleep and better work-life balance were found in the 'high control with low variability' reference group than in the other groups. Significantly better recovery of fatigue was also observed in the group having control over days off with low variability. While near misses were more frequent in the group with high control over daily working hours coupled with high variability compared with the reference group this was not significant. CONCLUSIONS: High work-time control and low variability were associated with favourable outcomes of health and work-life balance. This combined effect was not observed for the safety outcome addressed here. PMID- 23365115 TI - Job satisfaction and intention to quit the job. AB - BACKGROUND: Negative psychosocial work conditions may influence the motivation of employees to adhere to their job. AIMS: To elucidate the perception of psychosocial work conditions among Danish hospital employees who would quit their job if economically possible and those who would not. METHODS: A cross-sectional questionnaire study of hospital employees. The questionnaire gave information on elements of the psychosocial work environment (job demands, job influence, job support, management quality, exposure to bullying), general health status, sick leave during the preceding year, life style (leisure time physical activity, alcohol intake and smoking habits), age, sex and profession. RESULTS: There were 1809 participants with a response rate of 65%. About a quarter (26%) reported that they would quit their job if economically possible; this rose to 40% among the 17% who considered their health mediocre or bad. In a final logistic regression model, six factors were identified as independently associated with the wish to quit or not: self-assessed health status, meaningfulness of the job, quality of collaboration among colleagues, age, trustworthiness of closest superior(s) and exposure to bullying. Based on these factors it was possible to identify groups with fewer than 15% wishing to quit, and similarly, groups where 50% or more would quit if this was economically possible. CONCLUSIONS: Psychosocial work conditions, in particular meaningfulness of the job, were independently associated with intention to quit the job if economically possible and relevant within different job categories. PMID- 23365116 TI - Evaluation of a case management service to reduce sickness absence. AB - BACKGROUND: It is unclear whether and to what extent intensive case management is more effective than standard occupational health services in reducing sickness absence in the health care sector. AIMS: To evaluate a new return to work service at an English hospital trust. METHODS: The new service entailed intensive case management for staff who had been absent sick for longer than 4 weeks, aiming to restore function through a goal-directed and enabling approach based on a bio psycho-social model. Assessment of the intervention was by controlled before and after comparison with a neighbouring hospital trust at which there were no major changes in the management of sickness absence. Data on outcome measures were abstracted from electronic databases held by the two trusts. RESULTS: At the intervention trust, the proportion of 4-week absences that continued beyond 8 weeks fell from 51.7% in 2008 to 49.1% in 2009 and 45.9% in 2010. The reduction from 2008 to 2010 contrasted with an increase at the control trust from 51.2% to 56.1%-a difference in change of 10.7% (95% CI 1.5-20.0%). There was also a differential improvement in mean days of absence beyond 4 weeks, but this was not statistically significant (1.6 days per absence; 95% CI -7.2 to 10.3 days). CONCLUSIONS: Our findings suggest that the intervention was effective, and calculations based on an annual running cost of L57 000 suggest that it was also cost-effective. A similar intervention should now be evaluated at a larger number of hospital trusts. PMID- 23365117 TI - Risk factors for sickness absence among Estonian employees. AB - BACKGROUND: During the last decade, sickness absence rates in Estonia have reached the level of Nordic countries. This places Estonia in a group of countries with the highest absence rate in the European Union. Unlike Nordic countries, factors associated with sickness absence have not been studied in Estonia. AIMS: To investigate which work-related, individual and health factors, other than current illness, influence sickness absence among Estonian paid employees. METHODS: The study population consisted of 2941 employees who completed an Estonian Health Interview Survey conducted in 2006. Multiple logistic regression analysis was performed to explore associations between individual, health and work-related factors and recent sickness absence. RESULTS: Sickness absence was significantly associated with poor self-rated general health (OR = 1.82; 95% CI = 1.34-2.48), presence of chronic disease (OR = 1.66; 95% CI = 1.21-2.27), lower education (OR = 1.59; 95% CI = 1.20-2.12) and job dissatisfaction (OR = 1.74, 95% CI = 1.23-2.26) in the final multivariate model after adjustment for age and gender conclusions: Most sickness absence risk factors revealed by previous studies were only moderately associated with sickness absence in the Estonian working population. In contrast to Nordic countries, there was no gender difference or age gradient. Among workplace risk factors, job dissatisfaction was most strongly associated with sickness absence. PMID- 23365118 TI - Equality Act 2010: knowledge, perceptions and practices of occupational physicians. AB - BACKGROUND: Historically, many prospective employees in Great Britain have undergone pre-employment health screening (PEHS) assessments before a job offer. Section 60 of the Equality Act 2010 stipulates that PEHS assessments before a job offer may contravene the disability provisions of the Act except under specific circumstances. PEHS assessments in the current format may not fully comply with the provisions of the legislation. AIMS: To describe the knowledge, perceptions and practices of occupational health physicians in UK following implementation of the Equality Act 2010. METHODS: Data were collected through an anonymous online survey of occupational health physicians (OHPs) actively reporting to the Occupational Physicians Reporting Activity (OPRA) at the Centre for Occupational and Environmental Health, the University of Manchester. RESULTS: There were 126 responses available for analysis (response rate 43%). Most participants (81%) were accredited occupational health specialists providing occupational health advice to various industry sectors; 96% reported involvement in PEHS assessments; 81% reported awareness of section 60 of the Equality Act 2010. Further analysis of these participants revealed varying knowledge levels and practices relating to specific requirements of section 60. Changes in professional practice resulting from the Act were reported by 38%, while 46% reported no change. CONCLUSIONS: There have been minimal immediate changes to PEHS practices by OHPs in response to section 60 of the Act. Some OHPs displayed inadequate knowledge of specific requirements of section 60 of the Act. OHPs could benefit from further training on specific requirements of this legislation. PMID- 23365119 TI - Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas. AB - The RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. Thyroid cancer cells are also comparatively refractory to RAF inhibitors. In contrast to melanomas, inhibition of mitogen-activated protein kinase (MAPK) signaling by PLX4032 is transient in thyroid and colorectal cancer cells. The rebound in extracellular signal-regulated kinase (ERK) in thyroid cells is accompanied by increased HER3 signaling caused by induction of ERBB3 (HER3) transcription through decreased promoter occupancy by the transcriptional repressors C-terminal binding protein 1 and 2 and by autocrine secretion of neuregulin-1 (NRG1). The HER kinase inhibitor lapatinib prevents MAPK rebound and sensitizes BRAF-mutant thyroid cancer cells to RAF or MAP-ERK kinase inhibitors. This provides a rationale for combining ERK pathway antagonists with inhibitors of feedback-reactivated HER signaling in this disease. The determinants of primary resistance to MAPK inhibitors vary between cancer types, due to preferential upregulation of specific receptor tyrosine kinases, and the abundance of their respective ligands. PMID- 23365121 TI - Excess mortality in patients diagnosed with hypothyroidism: a nationwide cohort study of singletons and twins. AB - BACKGROUND: Although hypothyroidism is associated with increased morbidity, an association with increased mortality is still debated. Our objective was to investigate, at a nationwide level, whether a diagnosis of hypothyroidism influences mortality. METHODS: In an observational cohort study from January 1, 1978 until December 31, 2008 using record-linkage data from nationwide Danish health registers, 3587 singletons and 682 twins diagnosed with hypothyroidism were identified. Hypothyroid individuals were matched 1:4 with nonhypothyroid controls with respect to age and gender and followed over a mean period of 5.6 years (range 0-30 years). The hazard ratio (HR) for mortality was calculated using Cox regression analyses. Comorbidity was evaluated using the Charlson score (CS). RESULTS: In singletons with hypothyroidism, the mortality risk was increased (HR 1.52; 95% confidence interval [CI]: 1.41-1.65). Although the effect attenuated, hypothyroidism remained associated with increased mortality when evaluating subjects with a CS = 0 (HR 1.23; 95% CI: 1.05-1.44). In twin pairs discordant for hypothyroidism, the hypothyroid twin had excess mortality compared with the corresponding euthyroid cotwin (HR 1.40; 95% CI 0.95-2.05). However, after stratifying for zygosity, hypothyroidism was associated with excess mortality in dizygotic twin pairs (HR 1.61; 95% CI 1.00-2.58), whereas the association attenuated in monozygotic pairs (HR 1.06; 95% CI 0.55-2.05). CONCLUSIONS: Hypothyroidism is associated with an excess mortality of around 50%, which to some degree is explained by comorbidity. In addition, the finding of an association between hypothyroidism and mortality within disease discordant dizygotic but not monozygotic twin pairs indicates that the association between hypothyroidism and mortality is also influenced by genetic confounding. PMID- 23365122 TI - First-born children have reduced insulin sensitivity and higher daytime blood pressure compared to later-born children. AB - BACKGROUND: Evidence suggests that first-born children and adults are phenotypically different to later-born children. Therefore, we aimed to assess whether birth order would be associated with changes in metabolism in childhood. METHODS: We studied 85 healthy prepubertal children aged 4 to 11 years, born 38 to 40 weeks' gestation, and birth weight appropriate for gestational age: 32 first-born and 53 later-born children. Clinical assessments included measurement of children's height, weight, fasting lipid and hormonal profiles, and dual energy x-ray absorptiometry-derived body composition. Children also underwent 24 hour ambulatory blood pressure monitoring, and frequently sampled intravenous glucose tests with Bergman's minimal model. RESULTS: First-born children were approximately 3 cm taller (height SD scores 0.88 vs 0.39; P = .009) and were slimmer (body mass index SD scores -0.05 vs 0.39; P = .048) than later-born children. Consistent with their taller stature, first-born children also had a 27% increase in IGF-I concentrations (227 vs 173 ng/mL; P = .002). Insulin sensitivity was reduced by 21% among first-borns compared to later-borns (8.4 vs 10.6 * 10(-4)/min/[mU/L]; P = .019). Further, 24-hour ambulatory blood pressure monitoring showed that first-borns had higher daytime systolic (+5 mm Hg; P = .032) and diastolic (+4 mm Hg; P = .029) blood pressure. Blood lipids were unaffected by birth order. CONCLUSIONS: Although first-borns were taller and slimmer, these children had reduced insulin sensitivity and increased daytime blood pressure compared to later-borns. Thus, first-borns may be at a greater risk of metabolic and cardiovascular diseases in adult life. This finding may have important public health implications, in light of a worldwide trend toward smaller families. PMID- 23365120 TI - Prenatal diagnosis of congenital adrenal hyperplasia caused by P450 oxidoreductase deficiency. AB - CONTEXT: Mutations in the electron donor enzyme P450 oxidoreductase (POR) result in congenital adrenal hyperplasia with apparent combined 17alpha hydroxylase/17,20 lyase and 21-hydroxylase deficiencies, also termed P450 oxidoreductase deficiency (PORD). Major clinical features present in PORD are disordered sex development in affected individuals of both sexes, glucocorticoid deficiency, and multiple skeletal malformations. OBJECTIVE: The objective of the study was to establish a noninvasive approach to prenatal diagnosis of PORD including assessment of malformation severity to facilitate optimized prenatal diagnosis and timely treatment. DESIGN: We analyzed 20 pregnancies with children homozygous or compound heterozygous for disease-causing POR mutations and 1 pregnancy with a child carrying a heterozygous POR mutation by recording clinical and biochemical presentations and fetal ultrasound findings. In 4 of the pregnancies (3 homozygous and 1 heterozygous for disease-causing POR mutations), prenatal analysis of steroid metabolite excretion in maternal urine was carried out by gas chromatography/mass spectrometry during gestational weeks 11-23. RESULTS: Pregnancy complications in our cohort included maternal virilization (6 of 20) with onset in the second trimester. Seven pregnant women presented with low unconjugated estriol at prenatal screening (triple or quadruple antenatal screening test). Overt dysmorphic features were noted in 19 of the 20 babies at birth but observed in only 5 by prenatal ultrasound. These 5 had the most severe malformation phenotypes and poor outcome, whereas the other babies showed normal development. Steroid profiling of maternal urine revealed significantly increased steroids of fetal origin, namely the pregnenolone metabolite epiallopregnanediol and the androgen metabolite androsterone, with concomitant low values for estriol. Diagnostic steroid ratios conclusively indicated PORD as early as gestational week 12. In the heterozygous pregnancy, steroid ratios were only slightly elevated and estriol excretion was normal. CONCLUSION: Prenatal diagnosis in PORD is readily established via urinary steroid metabolite analysis of maternal urine. Visible malformations at prenatal ultrasound predict a severe malformation phenotype. PMID- 23365124 TI - Bromocriptine-induced brainstem angulation in a patient with invasive prolactinoma. PMID- 23365123 TI - DNA mismatch repair protein (MSH6) correlated with the responses of atypical pituitary adenomas and pituitary carcinomas to temozolomide: the national cooperative study by the Japan Society for Hypothalamic and Pituitary Tumors. AB - CONTEXT: Temozolomide (TMZ) is an alkylating agent and was a first-line chemotherapeutic agent for malignant gliomas. Recently, TMZ has been documented to be effective against atypical pituitary adenomas (APAs) and pituitary carcinomas (PCs). OBJECTIVE: The clinical and pathological characteristics of APAs and PCs treated with TMZ in Japan were surveyed and analyzed retrospectively. DESIGN: Members of the Japan Society of Hypothalamic and Pituitary Tumors were surveyed regarding the clinical characteristics of APAs and PCs treated with TMZ. Stored tumor samples were gathered from the responders and were assessed by the immunohistochemistry of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, p53, MSH6, and anterior pituitary hormones. Responses to TMZ treatment were defined as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) according to RECIST (Response Evaluation Criteria in Solid Tumors) version 2.0. SUBJECTS: Three samples from 3 subjects with APA and 11 samples from 10 subjects with PC were available. RESULTS: The 13 subjects had APAs and PCs consisting of 5 prolactin-producing tumors, 5 ACTH-producing tumors, and 3 null cell adenomas. The clinical response to TMZ treatment was as follows: 4 cases of CR and PR (31%), 2 cases of SD (15%), 6 cases of recurrence after CR and PR (46%), and 1 case of PD (8%). However, considerable subjects had recurrent disease after a response to TMZ. The immunohistochemical findings of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, and p53 did not show any significant correlation with the efficacy of TMZ. However, the immunopositivity of MSH6 was positively correlated with TMZ response (P = .015, Fisher's exact test). CONCLUSIONS: This study showed that preserving MSH6 function was contributory to the effectiveness of TMZ in malignant pituitary neoplasms. It is necessary to survey more cases and evaluate multifactor analyses. PMID- 23365125 TI - Unilateral and bilateral adrenalectomy for pheochromocytoma requires adjustment of urinary and plasma metanephrine reference ranges. AB - CONTEXT: Follow-up after adrenalectomy for pheochromocytoma is recommended because of a recurrence risk. During follow-up, plasma and/or urinary metanephrine (MN) and normetanephrine (NMN) are interpreted using reference ranges obtained in healthy subjects. OBJECTIVE: Because adrenalectomy may decrease epinephrine production, we compared MN and NMN concentrations in patients after adrenalectomy to concentrations in a healthy reference population. DESIGN: A single-center cohort study was performed in pheochromocytoma patients after adrenalectomy between 1980 and 2011. SUBJECTS: Seventy patients after unilateral and 24 after bilateral adrenalectomy were included. MAIN OUTCOME MEASURES: Plasma-free and urinary-deconjugated MN and NMN determined at 3 to 6 months and annually until 5 years after adrenalectomy were compared with concentrations in a reference population. Data are presented in median (interquartile range). RESULTS: Urinary and plasma MN concentrations 3 to 6 months after unilateral adrenalectomy were lower compared with the reference population (39 [31-53] MUmol/mol creatinine and 0.14 [0.09-0.18] nmol/L vs 61 [49 74] MUmol/mol creatinine and 0.18 [0.13-0.23] nmol/L, respectively, both P < .05). Urinary MN after bilateral adrenalectomy was reduced even further (7 [1-22] MUmol/mol creatinine; P < .05). Urinary and plasma NMN were higher after unilateral adrenalectomy (151 [117-189] MUmol/mol creatinine and 0.78 [0.59-1.00] nmol/L vs 114 [98-176] MUmol/mol creatinine and 0.53 [0.41-0.70] nmol/L; both P < .05). Urinary NMN after bilateral adrenalectomy was higher (177 [106-238] MUmol/mol creatinine; P < .05). Changes in urinary and plasma MNs persisted during follow-up. CONCLUSION: Concentrations of MN are decreased, whereas NMN concentrations are increased after unilateral and bilateral adrenalectomy. Adjusted reference values for MN and NMN are needed in the postsurgical follow-up of pheochromocytoma patients. PMID- 23365126 TI - Breast-feeding vs formula-feeding for infants born small-for-gestational-age: divergent effects on fat mass and on circulating IGF-I and high-molecular-weight adiponectin in late infancy. AB - CONTEXT: Fetal growth restraint, if followed by rapid weight gain, confers risk for adult disease including diabetes. How breast-feeding may lower such risk is poorly understood. OBJECTIVE, STUDY PARTICIPANTS, INTERVENTION, OUTCOMES: In infants born small-for-gestational-age (SGA), we studied the effects of nutrition in early infancy (breast-feeding vs formula-feeding; BRF vs FOF) on weight partitioning and endocrine markers in late infancy. Body composition (by absorptiometry), fasting glycemia, insulin, IGF-I, and high-molecular-weight (HMW) adiponectin were assessed at 4 and 12 months in BRF controls born appropriate-for-GA (N = 31) and in SGA infants receiving BRF (N = 48) or FOF (N = 51), the latter being randomized to receive a standard formula (FOF1) or a protein-rich formula (FOF2). SETTING: The study was conducted in a University Hospital. RESULTS: SGA-BRF infants maintained a low fat mass and normal levels of IGF-I and HMW adiponectin. In contrast, SGA-FOF infants normalized their body composition by gaining more fat; this normalization was accompanied by a marked fall in HMW adiponectinemia and, in FOF2 infants, by elevated IGF-I levels. In late infancy, SGA-BRF infants were most sensitive to insulin, even more sensitive than appropriate-for-GA-BRF controls. CONCLUSIONS: Because the health perspectives are better for SGA-BRF than for SGA-FOF infants, the present results suggest that FOF for SGA infants should aim at maintaining normal IGF-I and HMW adiponectin levels rather than at normalizing body composition. Nutriceutical research for SGA infants may thus have to be redirected. PMID- 23365127 TI - The changing clinical patterns of primary hyperparathyroidism in Chinese patients: data from 2000 to 2010 in a single clinical center. AB - CONTEXT: In Western countries, most patients with primary hyperparathyroidism (PHPT) are asymptomatic. The incidence of parathyroid cancer is as low as 1% but is trending upward. The clinical outlook for Chinese patients with PHPT is unclear. OBJECTIVE: Our objective was to describe the changing clinical patterns of benign and malignant PHPT in Chinese patients from 2000 to 2010. DESIGN AND SETTING: This was a cross-sectional study. SUBJECTS: A total of 249 patients with PHPT were studied. MAIN OUTCOME MEASURES: The clinical manifestations and biochemical abnormalities of PHPT were analyzed. RESULTS: Of our patients with PHPT, 61.4% were symptomatic, but asymptomatic PHPT has increased from <21% in 2000-2006 to 42.4% to 52.5% in 2007-2010. Of asymptomatic patients, 48.9% came to our center because of elevation of serum calcium levels, and another 46.9% came because of parathyroid nodule(s) incidentally discovered by thyroid ultrasonography, with a steady increase from 18.3% before 2007 to 35.7% in 2007 2008 and 61.5% in 2009-2010. Serum calcium and PTH concentrations greater than 2.77 mmol/L (area under the curve, 0.995; P < .001) and 316.3 pg/dL (area under the curve, 0.842; P < .001), respectively, are responsible for symptom development. The occurrence of parathyroid carcinoma was as high as 5.96%, but a trend downward from 10.53% to 4.44% was observed. CONCLUSIONS: The overall clinical and biochemical features of PHPT in Chinese patients are still classic, but the disease is now evolving into a more asymptomatic type. The incidental parathyroid lesion captured by routine neck ultrasonography was the leading cause for such a dramatic change. The high incidence of parathyroid carcinoma is now decreasing. PMID- 23365128 TI - All-cause and disease-specific mortality and morbidity in patients with congenital hypothyroidism treated since the neonatal period: a national population-based study. AB - CONTEXT: Little is known about the long-term health of patients treated for congenital hypothyroidism since the neonatal period. OBJECTIVE: To evaluate the causes of mortality and comorbidity in a population-based registry of young adult patients. DESIGN, SETTING, AND PARTICIPANTS: All 1772 eligible patients diagnosed during the first decade after the introduction of neonatal screening in France participated in the study. Follow-up data on vital status were available, in May 2010, for 99.5% of the patients. Completed questionnaires were obtained from 1202 of the selected patients. MAIN OUTCOME MEASURES: All-cause and cause-specific mortality and comorbidity. RESULTS: All-cause mortality in the congenital hypothyroidism (CH) patients was slightly higher than expected on the basis of year, age, and sex (standardized mortality ratio [SMR] 1.24, 95% CI: 0.81-1.82). SMRs for each category of underlying cause of death showed mortality due to diseases of the central nervous system (SMR 5.22, 95% CI: 1.68-12.17) and congenital malformations (SMR 3.15, 95% CI: 1.86-6.49) to be significantly higher than expected in the CH patients. The risk of developing an associated chronic disease in the 1202 patients who completed the questionnaire was twice that for the reference population (odds ratio 2.0 [1.32-3.03]). Neurologic or mental diseases and congenital malformations were the most frequent (odds ratios 2.54 [1.12-5.86], 4.18 [1.27-13.76], and 4.36 [1.24-15.34], respectively). Overall, mortality and morbidity were not affected by sex, disease severity, cause of CH, or adequacy of treatment. CONCLUSION: Prognosis has improved considerably, but a few patients diagnosed during the first 10 years of screening in France nonetheless displayed comorbidity and mortality due to various neurodevelopmental disorders and associated malformations. These results reveal a continuing need for improvements in care and studies to provide knowledge about the full spectrum of the disease and the mechanisms underlying these developmental abnormalities. PMID- 23365129 TI - Calcium-mediated parathyroid hormone suppression to assess progression of secondary hyperparathyroidism during treatment among incident dialysis patients. AB - CONTEXT: Parathyroid gland function is affected adversely by tissue hyperplasia and gland enlargement in hyperparathyroidism. OBJECTIVE: We examined the effects of 2 treatment strategies on the progression of secondary hyperparathyroidism using measurements of the nonsuppressible component of calcium-regulated PTH secretion as an index of parathyroid mass. DESIGN, SUBJECTS, AND INTERVENTION: In this randomized, open-label study, subjects managed with hemodialysis for >3 but <12 months before entering the trial (mean, 7.2 months) who had baseline plasma PTH levels >300 pg/mL received cinacalcet and low-dose vitamin D sterols (Cin-D, n = 153) or larger, varying doses of calcitriol, or other vitamin D analogs (Flex D, n = 151). Study drug doses were adjusted periodically based on PTH and serum total calcium determinations. MAIN OUTCOME MEASURES: The exploratory endpoint was calcium-regulated PTH release, assessed using a standardized PTH suppression test before and after 52 weeks of treatment and 4 weeks after withdrawing treatment. PTH and serum total calcium were measured before hemodialysis using high-calcium (3.5 mEq/L or 1.75 mmol/L) dialysate and after 150 and 180 minutes. RESULTS: Mean (95% confidence interval) nonsuppressible calcium-regulated PTH release at baseline did not differ between Cin-D, 33.4% (25.9%, 40.9%), and Flex-D, 28.1% (23.2%, 32.9%). Corresponding values after 52 weeks of treatment were 34.3% (29.7%, 38.9%) and 42.0% (32.7%, 51.3%), not significant, and did not change measurably in either group when reevaluated 4 weeks after treatments were withdrawn. CONCLUSION: Disease progression over 12 months was not documented using a PTH suppression test in this population. Calcium-mediated PTH suppression was maintained fully, however, in Cin-D despite reductions in serum total calcium concentration, whereas values did not increase in Flex-D despite substantial increases in serum calcium. PMID- 23365130 TI - Tryptophan hydroxylase autoantibodies as markers of a distinct autoimmune gastrointestinal component of autoimmune polyendocrine syndrome type 1. AB - BACKGROUND: Autoantibodies to tryptophan hydroxylase (TPHAbs) directed against serotonin-producing enterochromaffin cells (EC) have been reported in autoimmune polyendocrine-syndrome type 1 (APS-1) patients with gastrointestinal dysfunction (GID). Serotonin plays a critical role in enteric function and its peripheral blood levels reflect serotonin release from the gastrointestinal tract. AIMS: We test the hypothesis that TPHAbs mark a distinct autoimmune component of APS-1 characterized by an autoimmune attack toward EC, which results in clinical GID. METHODS: TPHAbs were measured in 64 APS-1 patients. Endoscopy with gastric (antrum/body) and duodenal biopsy was carried in 16 TPHAbs+ patients (8 with and 8 without GID) and in 2 TPHAbs- patients (without GID). Immunohistochemistry of biopsy specimens was carried out using antibodies to serotonin, chromogranin-A, CD3, CD4, CD8, and CD20. Serotonin serum levels were measured in TPHAbs+ and TPHAbs- patients who had endoscopy. RESULTS: Thirty-seven of 64 patients were TPHAbs+ (11/12 with GID and 26/52 without GID; P < .001). Gastric and duodenal biopsies in all 8 TPHAb+ patients with GID showed lymphocytic infiltration with increased CD3+CD8+ intraepithelial lymphocytes and absence of EC. Furthermore, mean serotonin serum levels were below the normal range in TPHAb+ patients with GID (P < .01). In 8 TPHAb+ patients without GID gastric and duodenal biopsies showed different grades of inflammatory infiltration and reduced number of EC. Mean serotonin serum levels were near the lower limit of the normal range. In all TPHAbs+ patients the biopsies showed a reduced number of chromogranin-A positive cells consistent with enteroendocrine cells depletion. TPHAbs- patients without GID showed normal gastrointestinal mucosa and serotonin serum levels. CONCLUSIONS: TPHAbs appear to be markers of a distinct autoimmune component of APS-1. Progressive involvement of the gastrointestinal EC leads to the transition from preclinical to clinical disease, characterized by GID and reduced serotonin serum levels. PMID- 23365131 TI - Virilizing sclerosing-stromal tumor of the ovary in a young woman with McCune Albright syndrome: clinical, pathological, and immunohistochemical studies. AB - CONTEXT: McCune-Albright syndrome (MAS) is characterized by polyostotic fibrous dysplasia, cafe-au-lait skin pigmentations, and gonadotropin-independent sexual precocious puberty, resulting from a somatic postzygotic activating mutation of the GNAS1 gene. SETTING: We report a virilizing sclerosing-stromal tumor of the ovary in a young female with MAS. PATIENT: She presented polyostotic fibrous dysplasia of the left upper and lower limbs and a cafe-au-lait skin spot in the posterior area of the neck. She had a history of precocious puberty, diagnosed at the age of 6 years and treated with cyproterone acetate until the age of 10 years; then she developed central puberty with severe oligomenorrhea. At the age of 23 years, she was hospitalized for a virilization syndrome including hirsutism, acne, deepening of the voice, amenorrhea, and clitoromegaly. Serum levels of T were dramatically increased (1293 ng/dl; normal range, 10-80). The abdominal computed tomography scan revealed a solid mass located on the left ovary. INTERVENTION: An ovariectomy was performed, and histological examination revealed a sclerosing-stromal tumor with pseudolobular pattern. RESULTS: Immunohistochemical studies revealed that the tumor cells expressed all steroidogenic enzymes involved in androgen synthesis. Molecular analysis revealed that ovarian tumor cells harbored the Arg 201 activating mutation in the GNAS1 gene. After surgery, T levels returned to normal, the patient retrieved a normal gonadal function, and she was able to become pregnant. CONCLUSION: This observation extends the clinical spectrum of ovarian pathology of women with MAS. However, the mechanisms causing this ovarian tumor remain unclear, even if the gsp oncogene has been implicated in the pathogenesis of some gonadal tumors. PMID- 23365132 TI - Disease resistance gene-induced growth inhibition is enhanced by rcd1 independent of defense activation in Arabidopsis. AB - Activation of plant immune responses is often associated with an inhibition of plant growth. The molecular mechanisms underlying this fitness cost are unknown. Here, we utilize the autoimmune response mutant suppressor of npr1, constitutive1 (snc1) resulting from an activated form of the Disease Resistance (R) gene to dissect the genetic component mediating growth inhibition in Arabidopsis (Arabidopsis thaliana). The radical-induced cell death1 (rcd1) mutant defective in responses to reactive oxygen species (ROS) was isolated as an enhancer of the snc1 mutant in growth inhibition but not in defense response activation. Similarly, the vitamin C2 (vtc2) and vtc3 mutants defective in ROS detoxification enhanced the growth defects of snc1. Thus, perturbation of ROS status by R gene activation is responsible for the growth inhibition, and this effect is independent of defense response activation. This was further supported by the partial rescue of growth defects of rcd1 snc1 by the respiratory burst oxidase homolog D (rbohD) and rbohF mutations compromising the generation of ROS burst. Collectively, these findings indicate that perturbation of ROS homeostasis contributes to the fitness cost independent of defense activation. PMID- 23365133 TI - Defining the role of histone deacetylases in the inhibition of mammary carcinogenesis by dietary energy restriction (DER): effects of suberoylanilide hydroxamic acid (SAHA) and DER in a rat model. AB - Dietary energy restriction (DER) inhibits experimentally induced mammary cancer, an effect accompanied by elevated levels of silent information regulator 2 (SIRT1), a class III histone deacetylase (HDAC). However, the effect of DER on targets of other classes of HDACs has not been reported, a highly relevant issue given evidence that HDAC induction favors the development of cancer and tumor growth. Experiments were carried out to determine whether suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor with broad activity, would affect the anti-cancer activity of DER. Female Sprague Dawley rats (n = 30/group) were injected with 1-methyl-1-nitrosourea (50 mg/kg) at 21 days of age and 7 days thereafter were randomized to groups fed: (i) control diet (AIN-93G), (ii) 0.1% SAHA (w/w), (iii) 40% DER, or (iv) 0.1% SAHA + 40% DER. An additional group was fed 0.1% SAHA + 40%DER for 5 weeks and released to control diet for 3 weeks. DER significantly reduced mammary cancer incidence, multiplicity, and cancer burden and prolonged cancer latency (P < 0.01). Cancer inhibition was maintained in SAHA + DER, despite evidence that histone (H2A(Lys9), H2B(Lys5), and H4(Lys5/8/12/16), but not H3(Lys9); P < 0.001) and non-histone protein deacetylation (p53(Lys373) and p53(Lys382); P < 0.001) induced by DER was reversed by SAHA. This indicates that the inhibition of DER of cancer is not dependent on HDAC induction. After releasing rats from DER + SAHA, cancer multiplicity remained lower than control (P < 0.05), consistent with apoptosis mediated cell deletion. These findings support further investigation of the hypothesis that HDAC induction by DER blunts its anti-carcinogenic impact. PMID- 23365134 TI - TGF-beta mediates homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells. AB - Although studies have suggested that bone marrow human mesenchymal stem cells (BM hMSC) may be used as delivery vehicles for cancer therapy, it remains unclear whether BM-hMSCs are capable of targeting cancer stem cells, including glioma stem cells (GSC), which are the tumor-initiating cells responsible for treatment failures. Using standard glioma models, we identify TGF-beta as a tumor factor that attracts BM-hMSCs via TGF-beta receptors (TGFbetaR) on BM-hMSCs. Using human and rat GSCs, we then show for the first time that intravascularly administered BM-hMSCs home to GSC-xenografts that express TGF-beta. In therapeutic studies, we show that BM-hMSCs carrying the oncolytic adenovirus Delta-24-RGD prolonged the survival of TGF-beta-secreting GSC xenografts and that the efficacy of this strategy can be abrogated by inhibition of TGFbetaR on BM-hMSCs. These findings reveal the TGF-beta/TGFbetaR axis as a mediator of the tropism of BM-hMSCs for GSCs and suggest that TGF-beta predicts patients in whom BM-hMSC delivery will be effective. PMID- 23365135 TI - CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma. AB - Sustained activation of the stress-regulated transcription factor NRF2 (NFE2L2) is a prominent feature of many types of cancer, implying that mutations driving NRF2 may be important to tumor progression. In hereditary type 2 papillary renal cell carcinoma (PRCC2, also known as hereditary leiomyomatosis and renal cell cancer), NRF2 activation is a direct consequence of the accumulation of intracellular fumarate, a result of fumarate hydratase (FH) inactivation, but it is not clear how NRF2 may be activated in sporadic forms of PRCC2. Here we show that somatic mutations in NRF2, CUL3, and SIRT1 are responsible for driving the NRF2 activation phenotype in sporadic PRCC2. Transcriptome sequencing revealed the expression pattern of mutant alleles of NRF2, CUL3, and SIRT1 and also confirmed NRF2 activation in clinical specimens. Our results show a convergence in somatic mutations in sporadic PRCC2 with FH mutation in hereditary PRCC2. PMID- 23365137 TI - PNAS introduces new magazine section. PMID- 23365136 TI - Anti-CD20 antibody promotes cancer escape via enrichment of tumor-evoked regulatory B cells expressing low levels of CD20 and CD137L. AB - The possible therapeutic benefits of B-cell depletion in combating tumoral immune escape have been debated. In support of this concept, metastasis of highly aggressive 4T1 breast cancer cells in mice can be abrogated by inactivation of tumor-evoked regulatory B cells (tBreg). Here, we report the unexpected finding that B-cell depletion by CD20 antibody will greatly enhance cancer progression and metastasis. Both murine and human tBregs express low levels of CD20 and, as such, anti-CD20 mostly enriches for these cells. In the 4T1 model of murine breast cancer, this effect of enriching for tBregs suggests that B-cell depletion by anti-CD20 may not be beneficial at all in some cancers. In contrast, we show that in vivo-targeted stimulation of B cells with CXCL13-coupled CpG oligonucleotides (CpG-ODN) can block cancer metastasis by inhibiting CD20(Low) tBregs. Mechanistic investigations suggested that CpG-ODN upregulates low surface levels of 4-1BBL on tBregs to elicit granzyme B-expressing cytolytic CD8(+) T cells, offering some explanative power for the effect. These findings underscore the immunotherapeutic importance of tBreg inactivation as a strategy to enhance cancer therapy by targeting both the regulatory and activating arms of the immune system in vivo. PMID- 23365140 TI - Statistical process control charts for attribute data involving very large sample sizes: a review of problems and solutions. AB - The use of statistical process control (SPC) charts in healthcare is increasing. The primary purpose of SPC is to distinguish between common-cause variation which is attributable to the underlying process, and special-cause variation which is extrinsic to the underlying process. This is important because improvement under common-cause variation requires action on the process, whereas special-cause variation merits an investigation to first find the cause. Nonetheless, when dealing with attribute or count data (eg, number of emergency admissions) involving very large sample sizes, traditional SPC charts often produce tight control limits with most of the data points appearing outside the control limits. This can give a false impression of common and special-cause variation, and potentially misguide the user into taking the wrong actions. Given the growing availability of large datasets from routinely collected databases in healthcare, there is a need to present a review of this problem (which arises because traditional attribute charts only consider within-subgroup variation) and its solutions (which consider within and between-subgroup variation), which involve the use of the well-established measurements chart and the more recently developed attribute charts based on Laney's innovative approach. We close by making some suggestions for practice. PMID- 23365138 TI - Photosynthetic reaction center as a quantum heat engine. AB - Two seemingly unrelated effects attributed to quantum coherence have been reported recently in natural and artificial light-harvesting systems. First, an enhanced solar cell efficiency was predicted and second, population oscillations were measured in photosynthetic antennae excited by sequences of coherent ultrashort laser pulses. Because both systems operate as quantum heat engines (QHEs) that convert the solar photon energy to useful work (electric currents or chemical energy, respectively), the question arises whether coherence could also enhance the photosynthetic yield. Here, we show that both effects arise from the same population-coherence coupling term which is induced by noise, does not require coherent light, and will therefore work for incoherent excitation under natural conditions of solar excitation. Charge separation in light-harvesting complexes occurs in a pair of tightly coupled chlorophylls (the special pair) at the heart of photosynthetic reaction centers of both plants and bacteria. We show the analogy between the energy level schemes of the special pair and of the laser/photocell QHEs, and that both population oscillations and enhanced yield have a common origin and are expected to coexist for typical parameters. We predict an enhanced yield of 27% in a QHE motivated by the reaction center. This suggests nature-mimicking architectures for artificial solar energy devices. PMID- 23365139 TI - Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes. AB - Aggregation of misfolded proteins is characteristic of a number of neurodegenerative diseases, including Huntington disease (HD). The CCT/TRiC (chaperonin containing TCP-1/TCP-1 ring) chaperonin complex can inhibit aggregation and cellular toxicity induced by expanded repeat Huntingtin (mHtt) fragments. The substrate-binding apical domain of CCT/TRiC subunit CCT1, ApiCCT1, is sufficient to inhibit aggregation of expanded repeat mHtt fragments in vitro, providing therapeutic promise for HD. However, a key hurdle in considering ApiCCT1 as a potential treatment is in delivery. Because ApiCCT1 has a region of similarity to the HIV Tat protein cell-transduction domain, we tested whether recombinant ApiCCT1 (ApiCCT1(r)) protein could enter cells following exogenous delivery and modulate an established panel of mHtt-mediated cell-based phenotypes. Cell fractionation studies demonstrate that exogenous ApiCCT1(r) can penetrate cell membranes and can localize to the nucleus, consistent with a strategy that can target both cytosolic and nuclear pathogenic events in HD. ApiCCT1(r) application does indeed modulate HD cellular phenotypes by decreasing formation of visible inclusions, fibrillar oligomers, and insoluble mHtt derived from expression of a truncated mHtt exon 1 fragment. ApiCCT1(r) also delays the onset of inclusion body formation as visualized via live imaging. ApiCCT1(r) reduces mHtt-mediated toxicity in immortalized striatal cells derived from full length knock-in HD mice, suggesting that therapeutic benefit may extend beyond effects on aggregation. These studies provide the basis for a potentially robust and unique therapeutic strategy to target mHtt-mediated protein pathogenesis. PMID- 23365141 TI - Non-tuberculous mycobacterial pulmonary infection in the immunocompetent host. AB - Throughout much of the world, the incidence of non-tuberculous mycobacterial pulmonary infections in immunocompetent hosts is on the rise. These organisms are widespread in the natural environment; the explanation for what appears to be an increased susceptibility among human hosts is uncertain. Among more than 120 known species, the most common pathogenic isolate in the USA is Mycobacterium avium complex. The diagnosis of pulmonary disease caused by M. avium complex requires a compatible history, suggestive radiographic findings (on chest computed tomography) and microbiologic confirmation on culture of respiratory samples (sputum or direct lung sampling). Treatment options have improved with inclusion of macrolide antibiotics in a multi-drug regimen, but failure rates remain high (20-40%) even after a prolonged course of therapy. Newer, less toxic and more effective anti-mycobacterial agents are greatly needed for treatment of this increasingly common respiratory disease. PMID- 23365142 TI - Acute flaccid paraparesis secondary to bilateral ischaemic lumbosacral plexopathy. PMID- 23365143 TI - Abdominal tuberculosis: a retrospective review of cases presenting to a UK district hospital. AB - INTRODUCTION: Peterborough has one of the highest rates of tuberculosis in the East of England; ~40% of TB treated locally is extra-pulmonary. AIM AND METHODS: All adults diagnosed with abdominal tuberculosis (ATB) between January 2008 and September 2011 in Peterborough Hospitals were retrospectively evaluated with regard to their clinical history, investigation, management and outcomes. RESULTS: In total, 17 patients diagnosed with ATB were reviewed. All the patients were from (or descended from) high-risk ethnic groups. Four had co-existing pulmonary TB. Intestinal and peritoneal TB were the most common findings. The most common clinical manifestations included abdominal pain (71%), weight loss (59%), diarrhoea (47%) and pyrexia (41%). Fifteen patients had samples sent for microbiological investigation; 1 (6%) was smear positive and 9 (53%) were culture positive. Two (12%) were isoniazid resistant. No rifampicin resistance was detected. Anti-tuberculous therapy was given for 6-12 months. In total, 16 (94%) patients completed the treatment; 1 patient died prior to regime completion (crude mortality: 6%). There was one reported case of pyrazinamide intolerance and two episodes of isoniazid intolerance. DISCUSSION: ATB is a diagnostic challenge, especially in absence of lung involvement. It mimics other diseases and clinical presentation is usually non-specific, which may lead to diagnostic delay and development of complications. Extreme vigilance should be used when dealing with unexplained abdominal symptoms to ensure timely diagnosis of ATB. Early diagnosis with early anti-tuberculous therapy and surgical treatment are essential to ensure as positive an outcome as possible. PMID- 23365144 TI - Left main coronary artery aneurysm. PMID- 23365145 TI - A case of pancreatic invasive ductal adenocarcinoma with malignant peritoneal cystic components. PMID- 23365146 TI - Burden of cancer in Asia extrapolated from the WHO mortality database. PMID- 23365147 TI - Predictors for the 5-year risk of serious infections in patients with rheumatoid arthritis treated with anti-tumour necrosis factor therapy: a cohort study in the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. AB - OBJECTIVE: The use of TNF inhibitors leads to an increased risk of serious infections in RA. Predicting this risk would facilitate the prevention of serious infections. The objective of this study was to identify which factors are predictive of the increased risk of serious infections in RA patients treated with TNF inhibiting therapy. METHODS: Data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry of 2044 patients with RA were used for the analyses. Data were censored at stopping TNF inhibitors or end of observation time up to 5 years. Univariate and multivariate analysis of baseline variables was performed using Cox regression with time to the first serious infection as dependent variable. RESULTS: During a follow-up time of 5 years, 128 of 2044 (6.3%) patients developed a first serious infection with a total of 141 serious infections. The incidence rate in the first year after start of TNF inhibiting therapy was 4.57 first serious infections per 100 patient-years and 2.91 per 100 patient-years over 5 years. Age, corticosteroid use, visual analogue scale (VAS) pain, HAQ, tender joint count 28 joints (TJC28) and the presence of comorbidities were significant predictors for developing a serious infection during TNF inhibiting therapy in the multivariate model. CONCLUSION: Age, corticosteroid use, VAS pain, HAQ, TJC28 and the presence of comorbidities all at baseline were significant predictors for developing a serious infection during TNF inhibiting therapy in RA patients. PMID- 23365148 TI - Ayurvedic medicine offers a good alternative to glucosamine and celecoxib in the treatment of symptomatic knee osteoarthritis: a randomized, double-blind, controlled equivalence drug trial. AB - OBJECTIVE: To demonstrate clinical equivalence between two standardized Ayurveda (India) formulations (SGCG and SGC), glucosamine and celecoxib (NSAID). METHODS: Ayurvedic formulations (extracts of Tinospora cordifolia, Zingiber officinale, Emblica officinalis, Boswellia serrata), glucosamine sulphate (2 g daily) and celecoxib (200 mg daily) were evaluated in a randomized, double-blind, parallel efficacy, four-arm, multicentre equivalence drug trial of 24 weeks duration. A total of 440 eligible patients suffering from symptomatic knee OA were enrolled and monitored as per protocol. Primary efficacy variables were active body weight bearing pain (visual analogue scale) and modified WOMAC pain and functional difficulty Likert score (for knee and hip); the corresponding a priori equivalence ranges were +/-1.5 cm, +/-2.5 and +/-8.5. RESULTS: Differences between the intervention arms for mean changes in primary efficacy variables were within the equivalence range by intent-to-treat and per protocol analysis. Twenty six patients showed asymptomatic increased serum glutamic pyruvic transaminase (SGPT) with otherwise normal liver function; seven patients (Ayurvedic intervention) were withdrawn and SGPT normalized after stopping the drug. Other adverse events were mild and did not differ by intervention. Overall, 28% of patients withdrew from the study. CONCLUSION: In this 6-month controlled study of knee OA, Ayurvedic formulations (especially SGCG) significantly reduced knee pain and improved knee function and were equivalent to glucosamine and celecoxib. The unexpected SGPT rise requires further safety assessment. TRIAL REGISTRATION: Clinical Drug Trial Registry-India, www.ctri.nic.in, CTRI/2008/091/000063. PMID- 23365149 TI - Effect on bone turnover markers of once-yearly intravenous infusion of zoledronic acid versus daily oral risedronate in patients treated with glucocorticoids. AB - OBJECTIVE: Long-term glucocorticoid use is accompanied by rapid bone loss; however, early treatment with bisphosphonates prevents bone loss and reduces fracture risk. The aim of this study was to examine the effects of two bisphosphonates, i.v. zoledronic acid (ZOL) versus oral risedronate (RIS), on bone turnover markers (BTMs) in subjects with glucocorticoid-induced osteoporosis (GIO). METHODS: Patients were randomly stratified according to the duration of pre-study glucocorticoid therapy [prevention subpopulation (ZOL, n = 144; RIS, n = 144) <=3 months, treatment subpopulation (ZOL, n = 272; RIS, n = 273) >3 months]. Changes in beta-C-terminal telopeptides of type 1 collagen (beta-CTx), N terminal telopeptide of type I collagen (NTx), procollagen type 1 N-terminal propeptide (P1NP) and bone-specific alkaline phosphatase (BSAP) from baseline were measured on day 10 and months 3, 6 and 12. RESULTS: At most time points, there were significantly greater reductions (P < 0.05) in the concentrations of serum beta-CTx, P1NP and BSAP and urine NTx in subjects on ZOL compared with RIS in both males and females of the treatment and prevention subpopulations. In pre- and post-menopausal women, there were significantly greater reductions in the concentrations of BTMs with ZOL compared with RIS. At 12 months, ZOL had significantly greater reductions compared with RIS (P < 0.05) for beta-CTx, P1NP, BSAP and NTx levels, independent of glucocorticoid dose. CONCLUSIONS: Once-yearly i.v. infusion of ZOL 5 mg was well tolerated in different subgroups of GIO patients. ZOL was non-inferior to RIS and even superior to RIS in the response of BTMs in GIO patients. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00100620. PMID- 23365150 TI - Simulation of triacylglycerol ion profiles: bioinformatics for interpretation of triacylglycerol biosynthesis. AB - Although the synthesis pathways of intracellular triacylglycerol (TAG) species have been well elucidated, assessment of the contribution of an individual pathway to TAG pools in different mammalian organs, particularly under pathophysiological conditions, is difficult, although not impossible. Herein, we developed and validated a novel bioinformatic approach to assess the differential contributions of the known pathways to TAG pools through simulation of TAG ion profiles determined by shotgun lipidomics. This powerful approach was applied to determine such contributions in mouse heart, liver, and skeletal muscle and to examine the changes of these pathways in mouse liver induced after treatment with a high-fat diet. It was clearly demonstrated that assessment of the altered TAG biosynthesis pathways under pathophysiological conditions can be readily achieved through simulation of lipidomics data. Collectively, this new development should greatly facilitate our understanding of the biochemical mechanisms underpinning TAG accumulation at the states of obesity and lipotoxicity. PMID- 23365151 TI - Ecological consequences of body size decline in harvested fish species: positive feedback loops in trophic interactions amplify human impact. AB - Humans are changing marine ecosystems worldwide, both directly through fishing and indirectly through climate change. One of the little explored outcomes of human-induced change involves the decreasing body sizes of fishes. We use a marine ecosystem model to explore how a slow (less than 0.1% per year) decrease in the length of five harvested species could affect species interactions, biomasses and yields. We find that even small decreases in fish sizes are amplified by positive feedback loops in the ecosystem and can lead to major changes in natural mortality. For some species, a total of 4 per cent decrease in length-at-age over 50 years resulted in 50 per cent increase in predation mortality. However, the magnitude and direction in predation mortality changes differed among species and one shrinking species even experienced reduced predation pressure. Nevertheless, 50 years of gradual decrease in body size resulted in 1-35% decrease in biomasses and catches of all shrinking species. Therefore, fisheries management practices that ignore contemporary life-history changes are likely to overestimate long-term yields and can lead to overfishing. PMID- 23365154 TI - Bilateral optic perineuritis as the presenting feature of giant cell arteritis. AB - Optic perineuritis (OPN) is an uncommon inflammatory disorder of the optic nerve sheath. Most cases are idiopathic, though OPN can rarely occur as a manifestation of vasculitic diseases. We describe the case of a 74-year-old Caucasian man presenting with diplopia and bilateral visual loss. A brain MRI showed bilateral OPN without involvement of other structures. All the tests performed to investigate OPN's aetiology showed negative results. Considering clinical presentation and neuroimaging findings, a diagnosis of bilateral idiopathic OPN was made. Treatment with intravenous high-dose steroid was administered. Four weeks after admission, the steroid therapy was interrupted because of Listeria monocytogenes invasive infection. After steroid treatment withdrawal, the patient developed jaw claudication and bilateral skin necrosis of the temporal region, clinical features that are highly specific for giant cell arteritis (GCA). On this basis, a diagnosis of bilateral OPN secondary to GCA was made. PMID- 23365157 TI - Follicular dendritic cell sarcoma of the tonsil. AB - Follicular dendritic cell sarcoma (FDCS) is an uncommon tumour within the spectrum of histiocytic and dendritic cell neoplasms that can occur at nodal and extra-nodal sites. Besides being rare, these tumours are difficult to diagnose. A 72-year-old man with a painless mass in the right tonsil was admitted to the Mersin University Hospital. Tonsillectomy was performed. Microscopically, the tumour consisted of spindle-shaped cells with large oval to polygonal nuclei. Lymphocytes were scattered among the tumour cells. Immunohistochemically, the cells were positive for CD23 and vimentin. The tumour was diagnosed as FDCS with histological and immunohistochemical findings. Recognition of extranodal FDCS requires knowledge of this entity and to consider it during the diagnosis. Confirmatory immunohistochemical staining is essential for diagnosis. Correct characterisation of this neoplasm is important because of its potential for recurrence and metastasis. PMID- 23365159 TI - A tale of two pelvises. AB - Two female doctors who were undergoing officer training at the Royal Military Academy Sandhurst sustained pubic ramus stress fractures. This report looks at the reasons why these medical officers may have sustained these fractures and how they may be prevented in future. PMID- 23365158 TI - Syphilis: an ancient foe with multiple faces. AB - Syphilis can have a multitude of different ophthalmological presentations. The authors present a case of a 59-year-old man, with complaints of bilateral blurred vision starting 6 months before. His best-corrected visual acuity was 20/20 in both eyes. Ophthalmological examination revealed bilateral superotemporal retinal oedema, extending to the superior macular region, with a white stippled discolouration of the corresponding retinal pigment epithelium. Laboratory work up confirmed the diagnosis of syphilis. The patient was treated with penicillin G benzathine-2.4 million IU intramuscular weekly for 3 weeks. After treatment, a clinical improvement of the fundus lesions was observed along with a subjective improvement in visual function. Over a 12 month follow-up period, no recurrences have occurred. PMID- 23365160 TI - Osteosarcoma arising on a background of Paget's disease report of an unusual case. AB - One of the serious complications of Paget's disease (PD) is a significant increase in the risk of developing osteosarcoma. Approximately 1% of the patients with PD develop osteosarcoma. This contributes significantly to the mortality and morbidity of the patients with PD. We present the case of an elderly person, who developed osteosarcoma 1 year after being diagnosed to have PD. The patient had been diagnosed to have lymphoma 8 years prior to the diagnosis of PD. The association between PD and follicular lymphoma is discussed. PMID- 23365161 TI - Home deliveries in Chandigarh, the beautiful city of India: a tug of war between culture and science. AB - There have been various commitments made in the international front to reduce maternal mortality ratio, and India has set its target at <100 maternal deaths/100,000 live-births. One of the strategies is to have 80% of the deliveries take place at healthcare institutions. However, health-related behaviour and decision-making is affected by many factors beyond the availability of health services. We report the case of a fourth gravida, belonging to the Sansi tribe, with son-preference in urban northern India, who delivered her fourth female child at home. We attempt to understand beliefs, norms and practices involved in deciding place of delivery in the context of theory of reasoned action and health belief model so that cultural appropriateness can be ensured in healthcare delivery. The study emphasises that there is need for improvement in cultural appropriateness of healthcare services delivered to the community. PMID- 23365162 TI - A not very NICE case of endocarditis. AB - A 69-year-old man, previously independent and with a pre-existing metallic aortic valve, presented with a history of fevers, confusion and malaise and was diagnosed with prosthetic valve endocarditis. Blood cultures taken on presentation grew Streptococcus sanguinis and vegetations were confirmed on transoesophageal echocardiogram. He had had a dental procedure 10 days before presentation but had not received prophylactic antibiotics; he had been receiving antibiotic prophylaxis for dental treatment up until the change in NICE guidelines in 2008. He was treated with high dose antibiotics and was referred for cardiothoracic surgery, but developed a cerebrovascular event, thought to be embolic, and deteriorated and died. Given that the patient had a metallic aortic valve and poor dentition, and therefore was at increased risk of infective endocarditis, should the new guidelines have been followed so rigidly, particularly as American and European guidelines still recommend the use of antibiotic prophylaxis in this patient group? PMID- 23365163 TI - Short-term surviving sirenomelia neonate followed by a complex mesodermal malformation in a sibling. PMID- 23365164 TI - An unusual cause of severe persistent neutropenia in a child with nephrotic syndrome. AB - A 5-year-old boy presented with neutropenia 9 weeks following the administration of rituximab for management of his steroid-dependent nephrotic syndrome. Extensive investigations failed to identify any underlying cause. In keeping with adult reports, rituximab was thought to be the likely cause for this 'late-onset' neutropenia (LOP). He was treated successfully with granulocyte-colony stimulating factor. Patients treated with rituximab need to be carefully monitored for LOP. PMID- 23365165 TI - Delayed diagnosis of cryptococcal meningoencephalitis due to negative cryptococcal antigen test. AB - Cryptococcus spp. commonly causes infection in immunocompromised hosts. Clinical presentation of cryptococcal meningoencephalitis (CM) is variable, but headache, fever and a high intracranial pressure should suggest the diagnosis. The cryptococcal antigen test is a specific and sensitive rapid test that can be performed on blood or cerebrospinal fluid. We report a case of CM in a patient with previously undetected lymphocytopenia. Because cryptococcal antigen test results were negative, diagnosis and treatment were delayed. PMID- 23365166 TI - Hypoadrenal syndrome in a patient with amyloidosis secondary to familial Mediterranean fever. AB - Amyloidosis is a common complication of poorly controlled familial Mediterranean fever (FMF). A variety of organs including kidneys, heart, liver, thyroid and adrenal glands may be clinically affected. However, involvement of adrenal glands leading to significant inefficiency is rarely seen in FMF patients with amyloidosis. The impairment of neuroendocrine immune system in FMF together with proteinuria in renal amyloidosis is a challenge while interpreting adrenal function tests. Here we present a case report of a 42-year-old man with FMF and renal failure due to amyloidosis whose disease course was complicated by adrenal insufficiency. PMID- 23365167 TI - Creutzfeldt-Jakob disease presenting with visual symptoms: a case of the 'Heidenhain variant'. AB - Creutzfeldt-Jakob disease (CJD) belongs to a group of prion diseases that may be caused by the abnormal folding of proteins called prion proteins. The 'Heidenhain variant' is a subclass of patients with CJD, who present with isolated visual symptoms at the onset without any cognitive decline. Here we report such a case of an elderly man presenting with progressive diminution of vision, forgetfulness, abnormal behaviour, myoclonic jerks and akinetic mutism since the last 5 months. On clinical examination, lead pipe rigidity was present in all four limbs, and plantars were bilateral extensors. In view of rapidly progressive dementia associated with myoclonus, a possibility of CJD was entertained. As visual symptoms preceded dementia, hence the Heidenhain variant was strongly suspected. MRI of the brain revealed cortical ribboning, and EEG showed periodic triphasic waveforms with background slowing. The patient succumbed to the illness within 1 month of hospitalisation. PMID- 23365168 TI - Diagnostic dilemma: Kikuchi's disease or tuberculosis? AB - Any patient from a tuberculosis (TB) endemic area such as India with classical clinical features of fever, weight loss and lymphadenopathy, making a diagnosis of Kikuchi's disease (KD) prior to waiting for the 6-week culture is not appropriate. KD or histiocytic necrotising lymphadenitis is a rare self-limiting cervical lymphadenitis, often a diagnosis of exclusion. One needs to exclude TB, sarcodosis, lymphoma and autoimmune diseases to make such a diagnosis. The patient here with classical clinical presentation of TB with lymph node biopsy mimicking KD (biopsy and immunohistochemistry) posed a big diagnostic dilemma. However, culture of the biopsied lymphatic tissue was confirmed to be mycobacterium TB after the 6th week of incubation. The patient was treated with antitubercular drugs initially, and later, steroid was added in view of his persistent symptoms and he responded. One should wait for the tissue culture report to confirm or exclude the diagnosis of TB. Exclusion should not be based only on laboratory criteria. Histopathogically, TB can mimic any other granulomatous disorder. PMID- 23365169 TI - Paradoxical response to dexamethasone and spontaneous hypocortisolism in Cushing's disease. AB - Paradoxical response to dexamethasone and spontaneous development of hypocortisolism are rare features of Cushing's disease. We report a 13-year-old boy with Cushing's disease owing to a pituitary macroadenoma. On initial evaluation, he had partial suppression of serum cortisol by dexamethasone. He developed transient hypocortisolism after first adenomectomy, but the disease recurred after 1 year. Repeat evaluation showed recurrent hypercortisolism and paradoxical response to dexamethasone. He underwent second surgery and, postoperatively, hypercostisolism persisted even after 2 years of surgery. Repeat evaluations after 8 years of second surgery revealed persistent hypocortisolism despite residual tumour of same size and similar plasma adrenocorticotropic hormone (ACTH) levels. We have also shown that the paradoxical increase in serum cortisol was preceded by a paradoxical increase in ACTH. The paradoxical response persisted despite hypocortisolism. This patient with Cushing's disease had two very rare features: paradoxical response to dexamethasone and spontaneous development of hypocortisolism. PMID- 23365170 TI - Radiographical appearance of osteitis fibrosa cystica in primary hyperparathyroidism before and after parathyroidectomy. PMID- 23365171 TI - Disseminated tuberculosis in a patient with antinuclear antibody-negative systemic lupus erythematosus: a rare association. AB - Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with diverse manifestations. Tuberculosis is known to induce and exacerbate SLE and it becomes quite difficult to diagnose tuberculosis in this setting, owing to a similar, overlapping presentation of tuberculosis and SLE. We report a case of disseminated tuberculosis in a patient with antinuclear antibody-negative SLE. Treatment was started with antitubercular drugs together with hydroxychloroquine and steroid. After 6 months of follow-up the patient recovered with treatment. PMID- 23365172 TI - Anomalous ovarian artery vascularisation of a large uterine fibroid: successful embolisation. PMID- 23365173 TI - Extraocular sebaceous carcinoma mimicking benign sebaceous cyst. AB - Extraocular sebaceous carcinoma (SC) is an exceptionally rare neoplasm and has been confused in the past with basal cell carcinoma showing sebaceous differentiation. However, in contrast to the latter tumour, SC can be an aggressive cancer. We describe the case of a 55-year-old man with a 3-year history of a 5 * 2 cm lesion on the posterior thoracic wall. It had increased in size during this period but was otherwise asymptomatic. There was no significant past medical history or lymphadenopathy. Nor was there a family history of malignancy. The lesion was totally excised. The histopathological report revealed SC. As this neoplasm may be associated with Muir-Torre syndrome, the patient was screened for underlying internal neoplasia. All haematological, biochemical and tumour markers, imaging and endoscopic examinations were normal. Since SC may appear before the development of internal malignancy, our patient was scheduled for follow-up visits every 3 months. PMID- 23365174 TI - Black oesophagus. AB - Acute oesophageal necrosis, also known as 'Black Oesophagus', is a rare endoscopic finding since its first description by Goldenberg in 1990. In endoscopic studies, the frequency ranged from 0.01% to 0.2%. The aetiology is undefined and is probably multifactorial. A 62-year-old woman, with chronic alcoholism, was admitted to the internal medicine department for dehydration and marked malnutrition problems. Melaena was detected, and oesophagogastroduodenoscopy showed black mucosa of the lower two-thirds of the oesophagus and candidiasis. The patient gradually recovered after conservative treatments (intravenous proton pump inhibitor and total parental nutrition) and fluconazole. Oesophagus stricture was developed after 1 month, and balloon dilatation was performed successfully. PMID- 23365175 TI - Malaria and the conducting system of the heart. AB - We report the case of an adult male patient who was admitted to our hospital with a diagnosis of vivax malaria complicated with renal insufficiency and acute respiratory distress syndrome (ARDS). The patient was treated with intravenous artesunate. He was intubated and mechanically ventilated and taken up for haemodialysis in view of worsening renal parameters. He developed tachycardia a few hours later. ECG showed sinus tachycardia. Tachycardia persisted though the blood pressure was normal, there was no evidence of bleeding, and the heart was clinically normal. We tried to control the heart rate with diltiazem, adenosine and metoprolol but the tachycardia persisted. The heart rate was finally controlled with amiodarone. The patient improved, was weaned off from the ventilator and extubated. His renal functions gradually improved. Oral amiodarone was continued and there was no recurrence of tachycardia. We present this case to highlight the interesting association of vivax malaria with persistent, difficult to treat tachycardia. PMID- 23365176 TI - Congenital familial myasthenic syndromes: disease and course in an affected dizygotic twin pair. AB - The present report describes clinical variability in an affected dizygotic twin pair. Twin 1 showed classical features of the congenital myasthenic syndromes (CMS), that is, ptosis, dysphonia, asthenia and hypotonia. In twin 2, these clinical signs were less pronounced, but subtle resulting in severe lumbar hyperlordosis. Molecular analysis, performed for both twins, revealed the presence of three polymorphisms in the heterozygous form in RAPSN gene. The present report highlights the clinical variability of the CMS. PMID- 23365177 TI - Electrical tuning and transduction in short hair cells of the chicken auditory papilla. AB - The avian auditory papilla contains two classes of sensory receptor, tall hair cells (THCs) and short hair cells (SHCs), the latter analogous to mammalian outer hair cells with large efferent but sparse afferent innervation. Little is known about the tuning, transduction, or electrical properties of SHCs. To address this problem, we made patch-clamp recordings from hair cells in an isolated chicken basilar papilla preparation at 33 degrees C. We found that SHCs are electrically tuned by a Ca(2+)-activated K(+) current, their resonant frequency varying along the papilla in tandem with that of the THCs, which also exhibit electrical tuning. The tonotopic map for THCs was similar to maps previously described from auditory nerve fiber measurements. SHCs also possess an A-type K(+) current, but electrical tuning was observed only at resting potentials positive to -45 mV, where the A current is inactivated. We predict that the resting potential in vivo is approximately -40 mV, depolarized by a standing inward current through mechanotransducer (MT) channels having a resting open probability of ~0.26. The resting open probability stems from a low endolymphatic Ca(2+) concentration (0.24 mM) and a high intracellular mobile Ca(2+) buffer concentration, estimated from perforated-patch recordings as equivalent to 0.5 mM BAPTA. The high buffer concentration was confirmed by quantifying parvalbumin-3 and calbindin D-28K with calibrated postembedding immunogold labeling, demonstrating >1 mM calcium-binding sites. Both proteins displayed an apex-to-base gradient matching that in the MT current amplitude, which increased exponentially along the papilla. Stereociliary bundles also labeled heavily with antibodies against the Ca(2+) pump isoform PMCA2a. PMID- 23365179 TI - Mechanisms of responsibility assignment during redundant reaching movements. AB - When the two hands act together to achieve a goal, the redundancy of the system makes it necessary to distribute the responsibility for error corrections across the two hands. In an experiment in which participants control a single cursor with the movements of both hands, we show that right-handed individuals correct for movement errors more with their nondominant left hand than with their right hand, even though the dominant right hand corrects the same errors more quickly and efficiently when each hand acts in isolation. By measuring the responses to rapid cursor and target displacements using force channels, we demonstrate that this shift is due to a modulation of the feedback gains of each hand rather than to a shift in the onset of the corrective response. We also show that the shift toward left-hand corrections is more pronounced for errors that lead to adaptation (cursor displacements) than for perturbations that do not (target displacements). This finding provides some support for the idea that the motor system assigns the correction to the most likely source of the error to induce learning and to optimize future performance. Finally, we find that the relative strength of the feedback corrections in the redundant task correlates positively with those found for the nonredundant tasks. Thus the process of responsibility assignment modulates the processes that normally determine the gains of feedback correction rather than completely overwriting them. PMID- 23365180 TI - Deficits in anticipatory inhibition of postural muscle activity associated with load release while standing in individuals with spastic diplegic cerebral palsy. AB - This study aimed to determine whether individuals with spastic diplegic cerebral palsy (SDCP) have deficits in anticipatory inhibition of postural muscle activity. Nine individuals with SDCP (SDCP group, 3 female and 6 male, 13-24 yr of age) and nine age- and sex-matched individuals without disability (control group) participated in this study. Participants stood on a force platform, which was used to measure the position of the center of pressure (CoP), while holding a light or heavy load in front of their bodies. They then released the load by abducting both shoulders. Surface electromyograms were recorded from the rectus abdominis, erector spinae (ES), rectus femoris (RF), medial hamstring (MH), tibialis anterior (TA), and gastrocnemius (GcM) muscles. In the control group, anticipatory inhibition before load release and load-related modulation of the inhibition were observed in all the dorsal muscles recorded (ES, MH, and GcM). In the SDCP group, similar results were obtained in the trunk muscle (ES) but not in the lower limb muscles (MH and GcM), although individual differences were seen, especially in MH. Anticipatory activation of the ventral lower limb muscles (RF and TA) and load-related modulation of the activation were observed in both participant groups. CoP path length during load release was longer in the SDCP group than in the control group. The present findings suggest that individuals with SDCP exhibit deficits in anticipatory inhibition of postural muscles at the dorsal part of the lower limbs, which is likely to result in a larger disturbance of postural equilibrium. PMID- 23365178 TI - Neural dynamics in response to binary taste mixtures. AB - Taste stimuli encountered in the natural environment are usually combinations of multiple tastants. Although a great deal is known about how neurons in the taste system respond to single taste stimuli in isolation, less is known about how the brain deals with such mixture stimuli. Here, we probe the responses of single neurons in primary gustatory cortex (GC) of awake rats to an array of taste stimuli including 100% citric acid (100 mM), 100% sodium chloride (100 mM), 100% sucrose (100 mM), and a range of binary mixtures (90/10, 70/30, 50/50, 30/70, and 10/90%). We tested for the presence of three different hypothetical response patterns: 1) responses varying monotonically as a function of concentration of sucrose (or acid) in the mixture (the "monotonic" pattern); 2) responses increasing or decreasing as a function of degree of mixture of the stimulus (the "mixture" pattern); and 3) responses that change abruptly from being similar to one pure taste to being similar the other (the "categorical" pattern). Our results demonstrate the presence of both monotonic and mixture patterns within responses of GC neurons. Specifically, further analysis (that included the presentation of 50 mM sucrose and citric acid) made it clear that mixture suppression reliably precedes a palatability-related pattern. The temporal dynamics of the emergence of the palatability-related pattern parallel the temporal dynamics of the emergence of preference behavior for the same mixtures as measured by a brief access test. We saw no evidence of categorical coding. PMID- 23365181 TI - Removal of supraspinal input reveals a difference in the flexor and extensor monosynaptic reflex response to quipazine independent of motoneuron excitation. AB - The purpose of this study was to determine if quipazine, a serotonergic agonist, differentially modulates flexor and extensor motor output. This was achieved by examining the monosynaptic reflex (MSR) of the tibial (extensor) and peroneal (flexor) nerves, by determining the basic and rhythmic properties of extensor and flexor motoneurons, and by recording extracellular Ia field potentials of the tibial and peroneal nerves in the in vivo adult decerebrate rat in both spinal intact and acute spinalized preparations. In the spinal intact preparation, the tibial and peroneal MSR amplitude significantly increased compared with baseline in response to quipazine, with no difference between nerves (P < 0.05). In the spinalized preparation, the MSR was significantly increased in both the tibial and peroneal nerves with the latter increasing more than the former (5.7 vs. 3.6 times; P < 0.05). Intracellular motoneuron experiments demonstrated that rheobase decreased, while input resistance, afterhyperpolarization amplitude, and the firing rate at a given current injection increased in motoneurons following quipazine administration with no differences between extensor and flexor motoneurons. Both the tibial and peroneal nerve extracellular Ia field potentials increased with the peroneal demonstrating a significantly greater increase (7 vs. 38%; P < 0.05) following quipazine. It is concluded that in the spinal intact preparation quipazine does not have a differential effect on flexor or extensor motor output. However, in the acute spinalized preparation, quipazine preferentially affects the flexor MSR compared with the extensor MSR, likely due to the removal of a descending tonic inhibition on flexor Ia afferents. PMID- 23365182 TI - Delay activity of saccade-related neurons in the caudal dentate nucleus of the macaque cerebellum. AB - The caudal dentate nucleus (DN) in lateral cerebellum is connected with two visual/oculomotor areas of the cerebrum: the frontal eye field and lateral intraparietal cortex. Many neurons in frontal eye field and lateral intraparietal cortex produce "delay activity" between stimulus and response that correlates with processes such as motor planning. Our hypothesis was that caudal DN neurons would have prominent delay activity as well. From lesion studies, we predicted that this activity would be related to self-timing, i.e., the triggering of saccades based on the internal monitoring of time. We recorded from neurons in the caudal DN of monkeys (Macaca mulatta) that made delayed saccades with or without a self-timing requirement. Most (84%) of the caudal DN neurons had delay activity. These neurons conveyed at least three types of information. First, their activity was often correlated, trial by trial, with saccade initiation. Correlations were found more frequently in a task that required self-timing of saccades (53% of neurons) than in a task that did not (27% of neurons). Second, the delay activity was often tuned for saccade direction (in 65% of neurons). This tuning emerged continuously during a trial. Third, the time course of delay activity associated with self-timed saccades differed significantly from that associated with visually guided saccades (in 71% of neurons). A minority of neurons had sensory-related activity. None had presaccadic bursts, in contrast to DN neurons recorded more rostrally. We conclude that caudal DN neurons convey saccade-related delay activity that may contribute to the motor preparation of when and where to move. PMID- 23365184 TI - Limb motion dictates how motor learning arises from arbitrary environmental dynamics. AB - A key idea in motor learning is that internal models of environmental dynamics are internally represented as functions of spatial variables including position, velocity, and acceleration of body motion. We refer to such a representation as motion dependent. The evidence for a motion-dependent representation is, however, primarily based on examination of the adaptation to motion-dependent dynamic environments. To more rigorously test this idea, we examined the adaptive response to perturbations that cannot be well approximated by motion-state: force impulses--brief, high-amplitude pulses of force. The induced adaptation characterizes the impulse response of the system--a widely used technique for probing system dynamics in engineering systems identification. Here we examined the adaptive responses to two different force-impulse perturbations during human voluntary reaching movements. We found that although neither could be well approximated by motion-state (R(2) < 0.18 in both cases), both perturbations induced single-trial adaptive responses that were (R(2) > 0.87). Moreover, these responses were similar in shape to those induced by low-fidelity motion-based approximations of the force-impulses (r > 0.88). Remarkably, we found that the motion dependence of the adaptive responses to force-impulses persisted, even after prolonged exposure (R(2) > 0.95). During a 300-trial training period, trial to-trial fluctuations in the position, velocity, and acceleration of motion accurately predicted trial-to-trial fluctuations in the adaptive response, and the adaptation gradually became more specific to the perturbation, but only via reorganization of the structure of the motion-dependent representation. These results indicate that internal models of environmental dynamics represent these dynamics in a motion-dependent manner, regardless of the nature of the dynamics encountered. PMID- 23365183 TI - Common mechanisms regulating dark noise and quantum bump amplification in Drosophila photoreceptors. AB - Absolute visual thresholds are limited by "dark noise," which in Drosophila photoreceptors is dominated by brief (~10 ms), small (~2 pA) inward current events, occurring at ~2/s, believed to reflect spontaneous G protein activations. These dark events were increased in rate and amplitude by a point mutation in myosin III (NINAC), which disrupts its interaction with the scaffolding protein, INAD. This phenotype mimics that previously described in null mutants of ninaC (no inactivation no afterpotential; encoding myosin III) and an associated protein, retinophilin (rtp). Dark noise was similarly increased in heterozygote mutants of diacylglycerol kinase (rdgA/+). Dark noise in ninaC, rtp, and rdgA/+ mutants was greatly suppressed by mutations of the Gq alpha-subunit (Galphaq) and the major light-sensitive channel (trp) but not rhodopsin. ninaC, rtp, and rdgA/+ mutations also all facilitated residual light responses in Galphaq and PLC hypomorphs. Raising cytosolic Ca(2+) in the submicromolar range increased dark noise, facilitated activation of transient receptor potential (TRP) channels by exogenous agonist, and again facilitated light responses in Galphaq hypomorphs. Our results indicate that RTP, NINAC, INAD, and diacylglycerol kinase, together with a Ca(2+)-dependent threshold, share common roles in suppressing dark noise and regulating quantum bump generation; consequently, most spontaneous G protein activations fail to generate dark events under normal conditions. By contrast, quantum bump generation is reliable but delayed until sufficient G proteins and PLC are activated to overcome threshold, thereby ensuring generation of full-size bumps with high quantum efficiency. PMID- 23365185 TI - Predictive encoding of moving target trajectory by neurons in the parabigeminal nucleus. AB - Intercepting momentarily invisible moving objects requires internally generated estimations of target trajectory. We demonstrate here that the parabigeminal nucleus (PBN) encodes such estimations, combining sensory representations of target location, extrapolated positions of briefly obscured targets, and eye position information. Cui and Malpeli (Cui H, Malpeli JG. J Neurophysiol 89: 3128 3142, 2003) reported that PBN activity for continuously visible tracked targets is determined by retinotopic target position. Here we show that when cats tracked moving, blinking targets the relationship between activity and target position was similar for ON and OFF phases (400 ms for each phase). The dynamic range of activity evoked by virtual targets was 94% of that of real targets for the first 200 ms after target offset and 64% for the next 200 ms. Activity peaked at about the same best target position for both real and virtual targets. PBN encoding of target position takes into account changes in eye position resulting from saccades, even without visual feedback. Since PBN response fields are retinotopically organized, our results suggest that activity foci associated with real and virtual targets at a given target position lie in the same physical location in the PBN, i.e., a retinotopic as well as a rate encoding of virtual target position. We also confirm that PBN activity is specific to the intended target of a saccade and is predictive of which target will be chosen if two are offered. A Bayesian predictor-corrector model is presented that conceptually explains the differences in the dynamic ranges of PBN neuronal activity evoked during tracking of real and virtual targets. PMID- 23365187 TI - Kinetic adaptation during locomotion on a split-belt treadmill. AB - It has been suggested that a feedforward control mechanism drives the adaptation of the spatial and temporal interlimb locomotion variables. However, the internal representation of limb kinetics during split-belt locomotion has not yet been studied. In hand movements, it has been suggested that kinetic and kinematic parameters are controlled by separate neural processes; therefore, it is possible that separate neural processes are responsible for kinetic and kinematic locomotion parameters. In the present study, we assessed the adaptation of the limb kinetics by analyzing the ground reaction forces (GRFs) as well as the center of pressure (COP) during adaptation to speed perturbation, using a split belt treadmill with an integrated force plate. We found that both the GRF of each leg at initial contact and the COP changed gradually and showed motor aftereffects during early postadaptation, suggesting the use of a feedforward predictive mechanism. However, the GRF of each leg in the single-support period used a feedback control mechanism. It changed rapidly during the adaptation phase and showed no motor aftereffect when the speed perturbation was removed. Finally, we found that the motor adaptation of the GRF and the COP are mediated by a dual rate process. Our results suggest two important contributions to neural control of locomotion. First, different control mechanisms are responsible for forces at single- and double-support periods, as previously reported for kinematic variables. Second, our results suggest that motor adaptation during split-belt locomotion is mediated by fast and slow adaptation processes. PMID- 23365186 TI - Transient shifts in frontal and parietal circuits scale with enhanced visual feedback and changes in force variability and error. AB - When subjects perform a learned motor task with increased visual gain, error and variability are reduced. Neuroimaging studies have identified a corresponding increase in activity in parietal cortex, premotor cortex, primary motor cortex, and extrastriate visual cortex. Much less is understood about the neural processes that underlie the immediate transition from low to high visual gain within a trial. This study used 128-channel electroencephalography to measure cortical activity during a visually guided precision grip task, in which the gain of the visual display was changed during the task. Force variability during the transition from low to high visual gain was characterized by an inverted U-shape, whereas force error decreased from low to high gain. Source analysis identified cortical activity in the same structures previously identified using functional magnetic resonance imaging. Source analysis also identified a time-varying shift in the strongest source activity. Superior regions of the motor and parietal cortex had stronger source activity from 300 to 600 ms after the transition, whereas inferior regions of the extrastriate visual cortex had stronger source activity from 500 to 700 ms after the transition. Force variability and electrical activity were linearly related, with a positive relation in the parietal cortex and a negative relation in the frontal cortex. Force error was nonlinearly related to electrical activity in the parietal cortex and frontal cortex by a quadratic function. This is the first evidence that force variability and force error are systematically related to a time-varying shift in cortical activity in frontal and parietal cortex in response to enhanced visual gain. PMID- 23365188 TI - Parameterized phase response curves for characterizing neuronal behaviors under transient conditions. AB - Phase response curves (PRCs) are a simple model of how a neuron's spike time is affected by synaptic inputs. PRCs are useful in predicting how networks of neurons behave when connected. One challenge in estimating a neuron's PRCs experimentally is that many neurons do not have stationary firing rates. In this article we introduce a new method to estimate PRCs as a function of firing rate of the neuron. We call the resulting model a parameterized PRC (pPRC). Experimentally, we perturb the neuron applying a current with two parts: 1) a current held constant between spikes but changed at the onset of a spike, used to make the neuron fire at different rates, and 2) a pulse to emulate a synaptic input. A model of the applied constant current and the history is made to predict the interspike interval (ISI). A second model is then made to fit the modulation of the spike time from the expected ISI by the pulsatile stimulus. A polynomial with two independent variables, the stimulus phase and the expected ISI, is used to model the pPRC. The pPRC is validated in a computational model and applied to pyramidal neurons from the CA1 region of the hippocampal slices from rat. The pPRC can be used to model the effect of changing firing rates on network synchrony. It can also be used to characterize the effects of neuromodulators and genetic mutations (among other manipulations) on network synchrony. It can also easily be extended to account for more variables. PMID- 23365189 TI - A fluid-structure interaction model to characterize bone cell stimulation in parallel-plate flow chamber systems. AB - Bone continuously adapts its internal structure to accommodate the functional demands of its mechanical environment and strain-induced flow of interstitial fluid is believed to be the primary mediator of mechanical stimuli to bone cells in vivo. In vitro investigations have shown that bone cells produce important biochemical signals in response to fluid flow applied using parallel-plate flow chamber (PPFC) systems. However, the exact mechanical stimulus experienced by the cells within these systems remains unclear. To fully understand this behaviour represents a most challenging multi-physics problem involving the interaction between deformable cellular structures and adjacent fluid flows. In this study, we use a fluid-structure interaction computational approach to investigate the nature of the mechanical stimulus being applied to a single osteoblast cell under fluid flow within a PPFC system. The analysis decouples the contribution of pressure and shear stress on cellular deformation and for the first time highlights that cell strain under flow is dominated by the pressure in the PPFC system rather than the applied shear stress. Furthermore, it was found that strains imparted on the cell membrane were relatively low whereas significant strain amplification occurred at the cell-substrate interface. These results suggest that strain transfer through focal attachments at the base of the cell are the primary mediators of mechanical signals to the cell under flow in a PPFC system. Such information is vital in order to correctly interpret biological responses of bone cells under in vitro stimulation and elucidate the mechanisms associated with mechanotransduction in vivo. PMID- 23365190 TI - Mechanics of plant fruit hooks. AB - Hook-like surface structures, observed in some plant species, play an important role in the process of plant growth and seed dispersal. In this study, we developed an elastic model and further used it to investigate the mechanical behaviour of fruit hooks in four plant species, previously measured in an experimental study. Based on Euler-Bernoulli beam theory, the force-displacement relationship is derived, and its Young's modulus is obtained. The result agrees well with the experimental data. The model aids in understanding the mechanics of hooks, and could be used in the development of new bioinspired Velcro-like materials. PMID- 23365192 TI - Walking, running, and resting under time, distance, and average speed constraints: optimality of walk-run-rest mixtures. AB - On a treadmill, humans switch from walking to running beyond a characteristic transition speed. Here, we study human choice between walking and running in a more ecological (non-treadmill) setting. We asked subjects to travel a given distance overground in a given allowed time duration. During this task, the subjects carried, and could look at, a stopwatch that counted down to zero. As expected, if the total time available were large, humans walk the whole distance. If the time available were small, humans mostly run. For an intermediate total time, humans often use a mixture of walking at a slow speed and running at a higher speed. With analytical and computational optimization, we show that using a walk-run mixture at intermediate speeds and a walk-rest mixture at the lowest average speeds is predicted by metabolic energy minimization, even with costs for transients-a consequence of non-convex energy curves. Thus, sometimes, steady locomotion may not be energy optimal, and not preferred, even in the absence of fatigue. Assuming similar non-convex energy curves, we conjecture that similar walk-run mixtures may be energetically beneficial to children following a parent and animals on long leashes. Humans and other animals might also benefit energetically from alternating between moving forward and standing still on a slow and sufficiently long treadmill. PMID- 23365191 TI - Comparison of in vitro human endothelial cell response to self-expanding stent deployment in a straight and curved peripheral artery simulator. AB - Haemodynamic forces have a synergistic effect on endothelial cell (EC) morphology, proliferation, differentiation and biochemical expression profiles. Alterations to haemodynamic force levels have been observed at curved regions and bifurcations of arteries but also around struts of stented arteries, and are also known to be associated with various vascular pathologies. Therefore, curvature in combination with stenting might create a pro-atherosclerotic environment compared with stenting in a straight vessel, but this has never been investigated. The goal of this study was to compare EC morphology, proliferation and differentiation within in vitro models of curved stented peripheral vessel models with those of straight and unstented vessels. These models were generated using both static conditions and also subjected to 24 h of stimulation in a peripheral artery bioreactor. Medical-grade silicone tubes were seeded with human umbilical vein endothelial cells to produce pseudovessels that were then stented and subjected to 24 h of physiological levels of pulsatile pressure, radial distention and shear stress. Changes in cell number, orientation and nitric oxide (NO) production were assessed in straight, curved, non-stented and stented pseudovessels. We report that curved pseudovessels lead to higher EC numbers with random orientation and lower NO production per cell compared with straight pseudovessels after 24 h of biomechanical stimulation. Both stented curved and stented straight pseudovessels had lower NO production per cell than corresponding unstented pseudovessels. However, in contrast to straight stented pseudovessels, curved stented pseudovessels had fewer viable cells. The results of this study show, for the first time, that the response of the vascular endothelium is dependent on both curvature and stenting combined, and highlight the necessity for future investigations of the effects of curvature in combination with stenting to fully understand effects on the endothelial layer. PMID- 23365193 TI - From natural to artificial photosynthesis. AB - Demand for energy is projected to increase at least twofold by mid-century relative to the present global consumption because of predicted population and economic growth. This demand could be met, in principle, from fossil energy resources, particularly coal. However, the cumulative nature of carbon dioxide (CO(2)) emissions demands that stabilizing the atmospheric CO(2) levels to just twice their pre-anthropogenic values by mid-century will be extremely challenging, requiring invention, development and deployment of schemes for carbon-neutral energy production on a scale commensurate with, or larger than, the entire present-day energy supply from all sources combined. Among renewable and exploitable energy resources, nuclear fusion energy or solar energy are by far the largest. However, in both cases, technological breakthroughs are required with nuclear fusion being very difficult, if not impossible on the scale required. On the other hand, 1 h of sunlight falling on our planet is equivalent to all the energy consumed by humans in an entire year. If solar energy is to be a major primary energy source, then it must be stored and despatched on demand to the end user. An especially attractive approach is to store solar energy in the form of chemical bonds as occurs in natural photosynthesis. However, a technology is needed which has a year-round average conversion efficiency significantly higher than currently available by natural photosynthesis so as to reduce land area requirements and to be independent of food production. Therefore, the scientific challenge is to construct an 'artificial leaf' able to efficiently capture and convert solar energy and then store it in the form of chemical bonds of a high-energy density fuel such as hydrogen while at the same time producing oxygen from water. Realistically, the efficiency target for such a technology must be 10 per cent or better. Here, we review the molecular details of the energy capturing reactions of natural photosynthesis, particularly the water splitting reaction of photosystem II and the hydrogen-generating reaction of hydrogenases. We then follow on to describe how these two reactions are being mimicked in physico-chemical-based catalytic or electrocatalytic systems with the challenge of creating a large-scale robust and efficient artificial leaf technology. PMID- 23365194 TI - Response kinetics in the complex chemotaxis signalling pathway of Rhodobacter sphaeroides. AB - Chemotaxis is one of the best-characterized signalling systems in biology. It is the mechanism by which bacteria move towards optimal environments and is implicated in biofilm formation, pathogenesis and symbiosis. The properties of the bacterial chemosensory response have been described in detail for the single chemosensory pathway of Escherichia coli. We have characterized the properties of the chemosensory response of Rhodobacter sphaeroides, an alpha-proteobacterium with multiple chemotaxis pathways, under two growth conditions allowing the effects of protein expression levels and cell architecture to be investigated. Using tethered cell assays, we measured the responses of the system to step changes in concentration of the attractant propionate and show that, independently of the growth conditions, R. sphaeroides is chemotactic over at least five orders of magnitude and has a sensing profile following Weber's Law. Mathematical modelling also shows that, as E. coli, R. sphaeroides is capable of showing fold-change detection (FCD). Our results indicate that general features of bacterial chemotaxis such as the range and sensitivity of detection, adaptation times, adherence to Weber's Law and the presence of FCD may be integral features of chemotaxis systems in general, regardless of network complexity, protein expression levels and cellular architecture across different species. PMID- 23365195 TI - Plasticity facilitates sustainable growth in the commons. AB - In the commons, communities whose growth depends on public good, individuals often rely on surprisingly simple strategies, or heuristics, to decide whether to contribute to the shared resource (at risk of exploitation by free-riders). Although this appears a limitation, we show here how four heuristics lead to sustainable growth when coupled to specific ecological constraints. The two simplest ones-contribute permanently or switch stochastically between contributing or not-are first shown to bring sustainability when the public good efficiently promotes growth. If efficiency declines and the commons is structured in small groups, the most effective strategy resides in contributing only when a majority of individuals are also contributors. In contrast, when group size becomes large, the most effective behaviour follows a minimal-effort rule: contribute only when it is strictly necessary. Both plastic strategies are observed in natural scenarios across scales that present them as relevant social motifs for the sustainable management of public goods. PMID- 23365196 TI - Negative feedback in ants: crowding results in less trail pheromone deposition. AB - Crowding in human transport networks reduces efficiency. Efficiency can be increased by appropriate control mechanisms, which are often imposed externally. Ant colonies also have distribution networks to feeding sites outside the nest and can experience crowding. However, ants do not have external controllers or leaders. Here, we report a self-organized negative feedback mechanism, based on local information, which downregulates the production of recruitment signals in crowded parts of a network by Lasius niger ants. We controlled crowding by manipulating trail width and the number of ants on a trail, and observed a 5.6 fold reduction in the number of ants depositing trail pheromone from least to most crowded conditions. We also simulated crowding by placing glass beads covered in nest-mate cuticular hydrocarbons on the trail. After 10 bead encounters over 20 cm, forager ants were 45 per cent less likely to deposit pheromone. The mechanism of negative feedback reported here is unusual in that it acts by downregulating the production of a positive feedback signal, rather than by direct inhibition or the production of an inhibitory signal. PMID- 23365197 TI - Computed tomography-based diagnosis of diffuse compensatory enlargement of coronary arteries using scaling power laws. AB - Glagov's positive remodelling in the early stages of coronary atherosclerosis often results in plaque rupture and acute events. Because positive remodelling is generally diffused along the epicardial coronary arterial tree, it is difficult to diagnose non-invasively. Hence, the objective of the study is to assess the use of scaling power law for the diagnosis of positive remodelling of coronary arteries based on computed tomography (CT) images. Epicardial coronary arterial trees were reconstructed from CT scans of six Ossabaw pigs fed on a high-fat, high-cholesterol, atherogenic diet for eight months as well as the same number of body-weight-matched farm pigs fed on a lean chow (101.9+/-16.1 versus 91.5+/-13.1 kg). The high-fat diet Ossabaw pig model showed diffuse positive remodelling of epicardial coronary arteries. Good fit of measured coronary data to the length volume scaling power law ( where L(c) and V(c) are crown length and volume) were found for both the high-fat and control groups (R(2) = 0.95+/-0.04 and 0.99+/ 0.01, respectively). The coefficient, K(LV), decreased significantly in the high fat diet group when compared with the control (14.6+/-2.6 versus 40.9+/-5.6). The flow-length scaling power law, however, was nearly unaffected by the positive remodelling. The length-volume and flow-length scaling power laws were preserved in epicardial coronary arterial trees after positive remodelling. K(LV) < 18 in the length-volume scaling relation is a good index of positive remodelling of coronary arteries. These findings provide a clinical rationale for simple, accurate and non-invasive diagnosis of positive remodelling of coronary arteries, using conventional CT scans. PMID- 23365199 TI - Editorial. PMID- 23365198 TI - Magnetoreception in laboratory mice: sensitivity to extremely low-frequency fields exceeds 33 nT at 30 Hz. AB - Magnetoreception in the animal kingdom has focused primarily on behavioural responses to the static geomagnetic field and the slow changes in its magnitude and direction as animals navigate/migrate. There has been relatively little attention given to the possibility that weak extremely low-frequency magnetic fields (wELFMF) may affect animal behaviour. Previously, we showed that changes in nociception under an ambient magnetic field-shielded environment may be a good alternative biological endpoint to orientation measurements for investigations into magnetoreception. Here we show that nociception in mice is altered by a 30 Hz field with a peak amplitude more than 1000 times weaker than the static component of the geomagnetic field. When mice are exposed to an ambient magnetic field-shielded environment 1 h a day for five consecutive days, a strong analgesic (i.e. antinociception) response is induced by day 5. Introduction of a static field with an average magnitude of 44 uT (spatial variability of +/-3 uT) marginally affects this response, whereas introduction of a 30 Hz time-varying field as weak as 33 nT has a strong effect, reducing the analgesic effect by 60 per cent. Such sensitivity is surprisingly high. Any purported detection mechanisms being considered will need to explain effects at such wELFMF. PMID- 23365200 TI - Angiographic warning of hemorrhagic transformation after stent retriever thrombectomy procedure. AB - This study reports cerebral angiographic findings observed after stent retriever thrombectomy that is suggestive of a higher risk of hemorrhagic transformation (HT). A woman aged 65-75 presented with a right middle cerebral artery syndrome confirmed by non-contrast CT brain scan. Endovascular revascularization using the Solitaire device was placed across the thromboembolic occlusion and thromboembolectomy was performed. Angiography showed complete recanalization of the left internal carotid artery, anterior and middle cerebral artery branches. Twelve hours following the procedure the patient had a hemorrhagic conversion of the ischemic infarct with significant mass effect causing herniation. Despite surgical intervention (hemicraniectomy) the patient died. The angiographic features following revascularization of the vessels distal to the occlusion showed subtle dilations which were visualized at the branch points of the vessels. This may be a warning sign of increased risk of HT. PMID- 23365202 TI - Serotype sensitivity of a lateral flow immunoassay for cryptococcal antigen. AB - To meet the needs of a global community, an immunoassay for cryptococcal antigen (CrAg) must have high sensitivity for CrAg of all major serotypes. A new immunoassay for CrAg in lateral flow format was evaluated and found to have a high sensitivity for detection of serotypes A, B, C, and D. PMID- 23365201 TI - The role of miR-18b in MDM2-p53 pathway signaling and melanoma progression. AB - BACKGROUND: Although p53 is inactivated by point mutations in many tumors, melanomas infrequently harbor mutations in the p53 gene. Here we investigate the biological role of microRNA-18b (miR-18b) in melanoma by targeting the MDM2-p53 pathway. METHODS: Expression of miR-18b was examined in nevi (n = 48) and melanoma (n = 92) samples and in melanoma cell lines and normal melanocytes. Immunoblotting was performed to determine the expression of various proteins regulated by miR-18b. The effects of miR-18b overexpression in melanoma cell lines were investigated using assays of colony formation, cell viability, migration, invasion, and cell cycle and in a xenograft model (n = 10 mice per group). Chromatin immunoprecipitation and methylation assays were performed to determine the mechanism of microRNA silencing. RESULTS: Expression of miR-18b was substantially reduced in melanoma specimens and cell lines by virtue of hypermethylation and was reinduced (by 1.5- to 5.3-fold) in melanoma cell lines after 5-AZA-deoxycytidine treatment. MDM2 was identified as a target of miR-18b action, and overexpression of miR-18b in melanoma cells was accompanied by 75% reduced MDM2 expression and 2.5-fold upregulation of p53, resulting in 70% suppression of melanoma cell colony formation. The effects of miR-18b overexpression on the p53 pathway and on melanoma cell growth were reversed by MDM2 overexpression. Stable overexpression of miR-18b produced potent tumor suppressor activity, as evidenced by suppressed melanoma cell viability, induction of apoptosis, and reduced tumor growth in vivo. miR-18b overexpression suppressed melanoma cell migration and invasiveness and reversed epithelial-to mesenchymal transition. CONCLUSIONS: Our results demonstrate a novel role for miR 18b as a tumor suppressor in melanoma, identify the MDM2-p53 pathway as a target of miR-18b action, and suggest miR-18b overexpression as a novel strategy to reactivate the p53 pathway in human tumors. PMID- 23365203 TI - Assessment of a protein cocktail-based skin test for bovine tuberculosis in a double-blind field test in cattle. AB - Bovine tuberculosis (bTB) is a worldwide zoonosis caused mainly by Mycobacterium bovis. The traditional diagnostic method used often is the tuberculin skin test, which uses bovine purified protein derivatives (PPD-B). However, it is difficult to maintain uniformity of PPD-B from batch to batch, and it shares common antigens with nonpathogenic environmental mycobacteria. To overcome these problems, M. bovis-specific antigens that showed good T cell stimulation, such as CFP-10, ESAT-6, Rv3615c, etc., have been used in the skin test, but there have been no large-scale clinical studies on these antigens. In this study, two combinations (CFP-10/ESAT-6/TB10.4 protein cocktail and CFP-10/ESAT 6/Rv3872/MPT63 protein cocktail) were developed and used as stimuli in the skin test. Cattle were double-blind tested to assess the efficiency of the protein cocktail-based skin tests. The results showed that the CFP-10/ESAT-6/TB10.4 protein cocktail-based skin test can differentiate TB-infected cattle from Mycobacterium avium-infected ones and that it shows a high degree of agreement with the traditional tuberculin skin test (kappa = 0.8536) and gamma interferon (IFN-gamma) release assay (kappa = 0.8154). Compared to the tuberculin skin test, the relative sensitivity and relative specificity of the CFP-10/ESAT-6/TB10.4 based skin test were 87% and 97%, respectively., The relative sensitivity and relative specificity of the CFP-10/ESAT-6/TB10.4-based skin test were 93% and 92%, respectively, on comparison with the IFN-gamma release assay. The correlation between the increases in skin thickness observed after the inoculation of stimuli was high (PPD-B versus CFP-10/ESAT-6/TB10.4, Spearman r of 0.8435). The correlation between the optical density at 450 nm (OD450) obtained after blood stimulation with PPD-B and the increase in skin thickness observed after inoculation of the CFP-10/ESAT-6/TB10.4 protein cocktail was high (Spearman r = 0.7335). Therefore, the CFP-10/ESAT-6/TB10.4-based skin test responses correlate to traditional measures of bovine TB evaluation, including skin test and gamma interferon release assay. PMID- 23365204 TI - Outer surface protein C peptide derived from Borrelia burgdorferi sensu stricto as a target for serodiagnosis of early lyme disease. AB - Current serodiagnostic assays for Lyme disease are inadequate at detecting early infection due to poor sensitivity and nonspecificity that arise from the use of whole bacteria or bacterial proteins as assay targets; both targets contain epitopes that are cross-reactive with epitopes found in antigens of other bacterial species. Tests utilizing peptides that contain individual epitopes highly specific for Borrelia burgdorferi as diagnostic targets are an attractive alternative to current assays. Using an overlapping peptide library, we mapped linear epitopes in OspC, a critical virulence factor of B. burgdorferi required for mammalian infection, and confirmed the results by enzyme-linked immunosorbent assay (ELISA). We identified a highly conserved 20-amino-acid peptide epitope, OspC1. Via ELISA, OspC1 detected specific IgM and/or IgG in 60 of 98 serum samples (62.1%) obtained from patients with erythema migrans (early Lyme disease) at the time of their initial presentation. By comparison, the commercially available OspC peptide PepC10 detected antibody in only 48 of 98 serum samples (49.0%). In addition, OspC1 generated fewer false-positive results among negative healthy and diseased (rheumatoid arthritis and positive Rapid Plasma Reagin [RPR+] test result) control populations than did PepC10. Both highly specific and more sensitive than currently available OspC peptides, OspC1 could have value as a component of a multipeptide Lyme disease serological assay with significantly improved capabilities for the diagnosis of early infection. PMID- 23365205 TI - A single electroporation delivery of a DNA vaccine containing the hemagglutinin gene of Asian H5N1 avian influenza virus generated a protective antibody response in chickens against a North American virus strain. AB - Protection against the avian influenza (AI) H5N1 virus is suspected to be mainly conferred by the presence of antibodies directed against the hemagglutinin (HA) protein of the virus. A single electroporation delivery of 100 or 250 MUg of a DNA vaccine construct, pCAG-HA, carrying the HA gene of strain A/Hanoi/30408/2005 (H5N1), in chickens led to the development of anti-HA antibody response in 16 of 17 immunized birds, as measured by a hemagglutination inhibition (HI) test, competitive enzyme-linked immunosorbent assay (cELISA), and an indirect ELISA. Birds vaccinated by electroporation (n = 11) were protected from experimental AI challenge with strain A/chicken/Pennsylvania/1370/1/1983 (H5N2) as judged by low viral load, absence of clinical symptoms, and absence of mortality (n = 11). In contrast, only two out of 10 birds vaccinated with the same vaccine dose (100 or 250 MUg) but without electroporation developed antibodies. These birds showed high viral loads and significant morbidity and mortality after the challenge. Seroconversion was reduced in birds electroporated with a low vaccine dose (10 MUg), but the antibody-positive birds were protected against virus challenge. Nonelectroporation delivery of a low-dose vaccine did not result in seroconversion, and the birds were as susceptible as those in the control groups that received the control pCAG vector. Electroporation delivery of the DNA vaccine led to enhanced antibody responses and to protection against the AI virus challenge. The HI test, cELISA, or indirect ELISA for anti-H5 antibodies might serve as a good predictor of the potency and efficacy of a DNA immunization strategy against AI in chickens. PMID- 23365206 TI - Long-term immunogenicity of the pandemic influenza A/H1N1 2009 vaccine among health care workers: influence of prior seasonal influenza vaccination. AB - Health care workers (HCWs) are at great risk of influenza infection and transmission. Vaccination for seasonal influenza is routinely recommended, but this strategy should be reconsidered in a pandemic situation. Between October 2009 and September 2010, a multicenter study was conducted to assess the long term immunogenicity of the A/H1N1 2009 monovalent influenza vaccine among HCWs compared to non-health care workers (NHCWs). The influence of prior seasonal influenza vaccination was also assessed with respect to the immunogenicity of pandemic H1N1 influenza vaccine. Serum hemagglutinin inhibition titers were determined prevaccination and then at 1, 6, and 10 months after vaccination. Of the 360 enrolled HCW subjects, 289 participated in the study up to 10 months after H1N1 monovalent influenza vaccination, while 60 of 65 NHCW subjects were followed up. Seroprotection rates, seroconversion rates, and geometric mean titer (GMT) ratios fulfilled the European Union's licensure criteria for influenza A/California/7/2009 (H1N1) at 1 month after vaccination in both the HCWs and NHCWs, without any significant difference. At 6 months after vaccination, the seroprotection rate was more significantly lowered among the NHCWs than among the HCWs (P < 0.01). Overall, postvaccination (1, 6, and 10 months after vaccination) GMTs for A/California/7/2009 (H1N1) were significantly lower among the seasonal influenza vaccine recipients than among the nonrecipients (P < 0.05). In conclusion, HCWs should be encouraged to receive an annual influenza vaccination, considering the risk of repeated exposure. However, prior reception of seasonal influenza vaccine showed a negative influence on immunogenicity for the pandemic A/H1N1 2009 influenza vaccine. PMID- 23365207 TI - Identification of allergenic component Tyr p 8 from Tyrophagus putrescentiae and cross-reactivity with Der p 8. AB - Group 8 mite allergens exhibit sequence homology to glutathione S-transferases (GSTs), such as that from Dermatophagoides pteronyssinus (Der p 8). GSTs have been identified as important allergens in studies of allergens from house dust mites, cockroaches, and fungi. Our objective was to purify the native group 8 allergen from Tyrophagus putrescentiae (nTyr p 8) and generate recombinant Tyr p 8 (rTyr p 8) for immunological characterization. The allergenicity was determined by antibody recognition, IgE inhibition, and triggering of the basophil sensitized release of histamine, using T. putrescentiae hypersensitivity sera. The results showed that the mRNA transcript of nTyr p 8 is 657 bp long, contains 218 amino acids with a molecular mass of 26 kDa, and exhibits 83% sequence homology to Der p 8. Serum samples from the allergic patients with an IgE positive response to T. putrescentiae were analyzed to determine their IgE response to rTyr p 8. The results showed that the sera of 48 subjects (45.3%) had specific IgE against rTyr p 8. However, sera of only 19 subjects (17.9%) had specific IgE against rTyr p 8 after D. pteronyssinus absorption. Histamine release was observed from T. putrescentiae-allergic subjects in the presence of rTyr p 8. Both the nTyr p 8 and T. putrescentiae crude extract had been demonstrated to possess GST enzymatic activity. Although the specific binding of serum IgE to rTyr p 8 was only 17.9%, which indicates that rTyr p 8 was not a major allergen, the positive response to rTyr p 8 was due to the cross-reactivity with Der p 8. The group 8 mite allergen might be of use in the design of a suitable allergen for diagnosis and for the development of novel immunotherapies. PMID- 23365208 TI - IgG4 detection of Echinococcus granulosus paramyosin is a useful diagnostic test for human hydatidosis. AB - Hydatidosis is a public health problem in many parts of the world, and improvement in diagnosis of the disease is still being pursued. Protoscoleces of Echinococcus granulosus were isolated from hydatid cysts collected from naturally infected sheep slaughtered in abattoirs in Iran. Sonicated extract of protoscolex was subjected to two-dimensional gel electrophoresis and Western blot analysis. Primary antibodies were from serum samples from 130 hydatidosis patients, 38 individuals infected with other parasitic infections, and 30 healthy people, whereas peroxidase (HRP)-conjugated anti-human IgG and IgG4 were used as secondary antibodies. The recombinant form of the identified protein was produced and tested for its sensitivity and specificity for the detection of human hydatidosis. An antigenic band of ~60 kDa was found to be sensitive (82%) and specific (100%) for the detection of hydatidosis when probed with anti-human IgG4 HRP, while the sensitivity and specificity were 33 and 100%, respectively, with anti-human IgG-HRP. By mass spectrometry, the band was identified as protoscolex tegument paramyosin. The sensitivity and specificity of full-length paramyosin recombinant protein in IgG4 blots were found to be 86 and 98%, respectively. In conclusion, IgG4 detection of Echinococcus granulosus paramyosin was found to be useful for the diagnosis of human hydatidosis. PMID- 23365209 TI - Testing for antireticulin antibodies in patients with celiac disease is obsolete: a review of recommendations for serologic screening and the literature. AB - Celiac disease (CD) is an autoimmune disorder that occurs in genetically susceptible individuals of all ages and is triggered by immune response to gluten and related proteins. The disease is characterized by the presence of HLA-DQ2 and/or -DQ8 haplotypes, diverse clinical manifestations, gluten-sensitive enteropathy, and production of several autoantibodies of which endomysial, tissue transglutaminase, and deamidated gliadin peptide antibodies are considered specific. Although antireticulin antibodies (ARA) have historically been used in the evaluation of CD, these assays lack optimal sensitivities and specificities for routine diagnostic use. This minireview highlights the advances in CD specific serologic testing and the rationale for eliminating ARA from CD evaluation consistent with recommendations for diagnosis. PMID- 23365211 TI - Neural correlates of face detection. AB - Although face detection likely played an essential adaptive role in our evolutionary past and in contemporary social interactions, there have been few rigorous studies investigating its neural correlates. MJH, a prosopagnosic with bilateral lesions to the ventral temporal-occipital cortices encompassing the posterior face areas (fusiform and occipital face areas), expresses no subjective difficulty in face detection, suggesting that these posterior face areas do not mediate face detection exclusively. Despite his normal contrast sensitivity and visual acuity in foveal vision, the present study nevertheless revealed significant face detection deficits in MJH. Compared with controls, MJH showed a lower tolerance to noise in the phase spectrum for faces (vs. cars), reflected in his higher detection threshold for faces. MJH's lesions in bilateral occipito temporal cortices thus appear to have produced a deficit not only in face individuation, but also in face detection. PMID- 23365210 TI - Natural killer cells and antifungal host response. AB - As a result of improved experimental methodologies and a better understanding of the immune system, there is increasing insight into the antifungal activity of natural killer (NK) cells. Murine and human NK cells are able to damage fungi of different genera and species in vitro, and they exert both direct and indirect antifungal activity through cytotoxic molecules such as perforin and through cytokines and interferons, respectively. On the other hand, recent data suggest that fungi exhibit immunosuppressive effects on NK cells. Whereas clear in vivo data are lacking in humans, the importance of NK cells in the host response against fungi has been demonstrated in animal models. Further knowledge of the interaction of NK cells with fungi might help to better understand the pathogenesis of invasive fungal infections and to improve treatment strategies. PMID- 23365212 TI - Electrophysiological correlates of competitor activation predict retrieval induced forgetting. AB - The very act of retrieval modifies the accessibility of memory for knowledge and past events and can also cause forgetting. A prominent theory of such retrieval induced forgetting (RIF) holds that retrieval recruits inhibition to overcome interference from competing memories, rendering these memories inaccessible. The present study tested a fundamental tenet of the inhibitory-control account: The competition-dependence assumption. Event-related potentials (ERPs) were recorded while participants engaged in a competitive retrieval task. Competition levels were manipulated within the retrieval task by varying the cue-item associative strength of competing items. In order to temporally separate ERP correlates of competitor activation and target retrieval, memory was probed with the sequential presentation of 2 cues: A category cue, to reactivate competitors, and a target cue. As predicted by the inhibitory-control account, competitors with strong compared with weak cue-competitor association were more susceptible to forgetting. Furthermore, competition-sensitive ERP modulations, elicited by the category cue, were observed over anterior regions and reflected individual differences in ensuing forgetting. The present study demonstrates ERP correlates of the reactivation of tightly bound associated memories (the competitors) and provides support for the inhibitory-control account of RIF. PMID- 23365213 TI - Three-dimensional spatial distribution of synapses in the neocortex: a dual-beam electron microscopy study. AB - In the cerebral cortex, most synapses are found in the neuropil, but relatively little is known about their 3-dimensional organization. Using an automated dual beam electron microscope that combines focused ion beam milling and scanning electron microscopy, we have been able to obtain 10 three-dimensional samples with an average volume of 180 um(3) from the neuropil of layer III of the young rat somatosensory cortex (hindlimb representation). We have used specific software tools to fully reconstruct 1695 synaptic junctions present in these samples and to accurately quantify the number of synapses per unit volume. These tools also allowed us to determine synapse position and to analyze their spatial distribution using spatial statistical methods. Our results indicate that the distribution of synaptic junctions in the neuropil is nearly random, only constrained by the fact that synapses cannot overlap in space. A theoretical model based on random sequential absorption, which closely reproduces the actual distribution of synapses, is also presented. PMID- 23365214 TI - Is GABA co-released with glutamate from hippocampal mossy fiber terminals? PMID- 23365215 TI - Exploring the neural basis of consciousness through anesthesia. PMID- 23365216 TI - Sonic Hedgehog signaling is a positive oligodendrocyte regulator during demyelination. AB - The morphogen Sonic Hedgehog (Shh) controls the generation of oligodendrocyte (OLs) during embryonic development and regulates OL production in adulthood in the cortex and corpus callosum. The roles of Shh in CNS repair following lesions associated with demyelinating diseases are still unresolved. Here, we address this issue by using a model of focal demyelination induced by lysolecithin in the corpus callosum of adult mice. Shh transcripts and protein were not detected in control animals but were upregulated in a time-dependent manner in the oligodendroglial lineage within the lesion. We report an increased transcription of Shh target genes suggesting a broad reactivation of the Shh pathway. We show that the adenovirus-mediated transfer of Shh into the lesioned brain results in the attenuation of the lesion extent with the increase of OL progenitor cells (OPCs) and mature myelinating OL numbers due to survival, proliferation, and differentiation activities as well as the decrease of astrogliosis and macrophage infiltration. Furthermore, the blocking of Shh signaling during the lesion, using its physiological antagonist, Hedgehog interacting protein, results in a decrease of OPC proliferation and differentiation, preventing repair. Together, our findings identify Shh as a necessary factor playing a positive role during demyelination and indicate that its signaling activation stands as a potential therapeutic approach for myelin diseases. PMID- 23365217 TI - Top-down modulation of lateral interactions in visual cortex. AB - The primary visual cortex (V1) changes its computation according to the perceptual task being performed. We propose that this cognitive modulation results from gating of V1 intrinsic connections. To test this idea, using behavioral paradigms that engage top-down modulation of V1 contextual interactions, we recorded from chronically implanted electrode arrays in macaques. We observed task-dependent changes in interactions between V1 sites measured both by correlation between spike trains and by coherence between local field potentials (LFP-LFP coherence). The direction of the changes in aggregate activity, as measured by LFPs, depended on perceptual strategy: perceptual grouping increased LFP coherence between sites crucial for the task, whereas perceptual segregation lowered the LFP coherence. Using spiking activity as a measure, we found that the behaviorally driven changes in correlation structure between neurons dramatically increased the stimulus-related information that they convey; this additional increase in encoded information at the level of neuronal ensembles equals that obtained from task-driven reconfigurations of neural tuning curves. The improvements in information encoding were strongest for stimuli with greatest discrimination difficulty. PMID- 23365218 TI - Distinct modes of dopamine and GABA release in a dual transmitter neuron. AB - We now know of a surprising number of cases where single neurons contain multiple neurotransmitters. Neurons that contain a fast-acting neurotransmitter, such as glutamate or GABA, and a modulatory transmitter, such as dopamine, are a particularly interesting case because they presumably serve dual signaling functions. The olfactory bulb contains a large population of GABA- and dopamine containing neurons that have been implicated in normal olfaction as well as in Parkinson's disease. Yet, they have been classified as nonexocytotic catecholamine neurons because of the apparent lack of vesicular monoamine transporters. Thus, we examined how dopamine is stored and released from tyrosine hydroxylase-positive GFP (TH(+)-GFP) mouse periglomerular neurons in vitro. TH(+) cells expressed both VMAT2 (vesicular monoamine transporter 2) and VGAT (vesicular GABA transporter), consistent with vesicular storage of both dopamine and GABA. Carbon fiber amperometry revealed that release of dopamine was quantal and calcium-dependent, but quantal size was much less than expected for large dense core vesicles, suggesting that release originated from small clear vesicles identified by electron microscopy. A single action potential in a TH(+) neuron evoked a brief GABA-mediated synaptic current, whereas evoked dopamine release was asynchronous, lasting for tens of seconds. Our data suggest that dopamine and GABA serve temporally distinct roles in these dual transmitter neurons. PMID- 23365219 TI - Adolescent cocaine exposure causes enduring macroscale changes in mouse brain structure. AB - Cocaine dependence is associated with abnormalities in brain structure in humans. However, it is unclear whether these differences in brain structure predispose an individual to drug use or are a result of cocaine's action on the brain. This study investigates the impact of chronic cocaine exposure on brain structure and drug-related behavior in mice. Specifically, mice received daily cocaine or saline injections for 20 d during two developmental time periods: adolescence (27 46 d old) and young adulthood (60-79 d old). Following 30 d of abstinence, either fixed brain T2 weighted magnetic resonance images were acquired on a 7 T scanner at 32 MUm isotropic voxel dimensions or mice were assessed for sensitization to the locomotor stimulant effects of cocaine. Three automated techniques (deformation-based morphometry, striatum shape analysis, and cortical thickness assessment) were used to identify population differences in brain structure in cocaine-exposed versus saline-exposed mice. We found that cocaine induced changes in brain structure, and these were most pronounced in mice exposed to cocaine during adolescence. Many of these changes occurred in brain regions previously implicated in addiction including the nucleus accumbens, striatum, insular cortex, orbitofrontal cortex, and medial forebrain bundle. Furthermore, exposure to the same cocaine regimen caused sensitization to the locomotor stimulant effects of cocaine, and these effects were again more pronounced in mice exposed to cocaine during adolescence. These results suggest that altered brain structure following 1 month of abstinence may contribute to these persistent drug-related behaviors, and identify cocaine exposure as the cause of these morphological changes. PMID- 23365220 TI - Rod photoreceptors protect from cone degeneration-induced retinal remodeling and restore visual responses in zebrafish. AB - Humans are largely dependent upon cone-mediated vision. However, death or dysfunction of rods, the predominant photoreceptor subtype, results in secondary loss of cones, remodeling of retinal circuitry, and blindness. The changes in circuitry may contribute to the vision deficit and undermine attempts at restoring sight. We exploit zebrafish larvae as a genetic model to specifically characterize changes associated with photoreceptor degenerations in a cone dominated retina. Photoreceptors form synapses with two types of second-order neurons, bipolar cells, and horizontal cells. Using cell-specific reporter gene expression and immunolabeling for postsynaptic glutamate receptors, significant remodeling is observed following cone degeneration in the pde6c(w59) larval retina but not rod degeneration in the Xops:mCFP(q13) line. In adults, rods and cones are present in approximately equal numbers, and in pde6c(w59) mutants glutamate receptor expression and synaptic structures in the outer plexiform layer are preserved, and visual responses are gained in these once blind fish. We propose that the abundance of rods in the adult protects the retina from cone degeneration-induced remodeling. We test this hypothesis by genetically manipulating the number of rods in larvae. We show that an increased number and uniform distribution of rods in lor/tbx2b(p25bbtl) or six7 morpholino-injected larvae protect from pde6c(w59)-induced secondary changes. The observations that remodeling is a common consequence of photoreceptor death across species, and that in zebrafish a small number of surviving photoreceptors afford protection from degeneration-induced changes, provides a model for systematic analysis of factors that slow or even prevent the secondary deteriorations associated with neural degenerative disease. PMID- 23365221 TI - Thalamic contribution to cortical processing of taste and expectation. AB - Taste-related information reaches the gustatory cortex (GC) through two routes: a thalamic and a limbic pathway. While evidence is accumulating on limbic-cortical interactions in taste, very little information is available on the function of the gustatory thalamus in shaping GC activity. Here we rely on behavioral electrophysiological techniques to study taste-evoked activity in GC before and after inactivation of the parvicellular portion of the ventroposteromedial nucleus of thalamus (VPMpc; i.e., the gustatory thalamus). Gustatory stimuli were presented to rats either alone or preceded by an anticipatory cue. The reliance on two different behavioral contexts allowed us to investigate how the VPMpc mediates GC responses to uncued tastants, cued tastants, and anticipatory cues. Inactivation of the thalamus resulted in a dramatic reduction of taste processing in GC. However, responses to anticipatory cues were unaffected by this manipulation. The use of a cue-taste association paradigm also allowed for the identification of two subpopulations of taste-specific neurons: those that responded to gustatory stimulation and to the cue (i.e., cue-and-taste) and those that responded to tastants only (i.e., taste-only). Analyses of these two populations revealed differences in response dynamics and connectivity with the VPMpc. The results provide novel evidence for the role of VPMpc in shaping GC activity and demonstrate a previously unknown association between responsiveness to behavioral events, temporal dynamics, and thalamic connectivity in GC. PMID- 23365222 TI - Acid-sensing ion channel-1a is not required for normal hippocampal LTP and spatial memory. AB - Acid-sensing ion channel-1a (ASIC1a) is localized in brain regions with high synaptic density and is thought to contribute to synaptic plasticity, learning, and memory. A prominent hypothesis is that activation of postsynaptic ASICs promotes depolarization, thereby augmenting N-methyl-d-aspartate receptor function and contributing to the induction of long-term potentiation (LTP). However, evidence for activation of postsynaptic ASICs during neurotransmission has not been established. Here, we re-examined the role of ASIC1a in LTP in the hippocampus using pharmacological and genetic approaches. Our results showed that a tarantula peptide psalmotoxin, which profoundly blocked ASIC currents in the hippocampal neurons, had no effect on LTP. Similarly, normal LTP was robustly generated in ASIC1a-null mice. A further behavioral analysis showed that mice lacking ASIC1a had normal performance in hippocampus-dependent spatial memory. In summary, our results indicate that ASIC1a is not required for hippocampal LTP and spatial memory. We therefore propose that the role of ASIC1a in LTP and spatial learning should be reassessed. PMID- 23365223 TI - Interaction between orbital prefrontal and rhinal cortex is required for normal estimates of expected value. AB - Predicting and valuing potential rewards requires integrating sensory, associative, and contextual information with subjective reward preferences. Previous work has identified regions in the prefrontal cortex and medial temporal lobe believed to be important for each of these functions. For example, activity in the orbital prefrontal cortex (PFo) encodes the specific sensory properties of and preferences for rewards, while activity in the rhinal cortex (Rh) encodes stimulus-stimulus and stimulus-reward associations. Lesions of either structure impair the ability to use visual cues or the history of previous reinforcement to value expected rewards. These areas are linked via reciprocal connections, suggesting it might be their interaction that is critical for estimating expected value. To test this hypothesis, we interrupted direct, intra-hemispheric PFo-Rh interaction in monkeys by performing crossed unilateral ablations of these regions (functional disconnection). We asked whether this circuit is crucial primarily for cue-reward association or for estimating expected value per se, by testing these monkeys, as well as intact controls, on tasks in which expected value was either visually cued or had to be inferred from block-wise changes in reward size in uncued trials. Functional disconnection significantly affected performance in both tasks. Specifically, monkeys with functional disconnection showed less of a difference in error rates and reaction times across reward sizes, in some cases behaving as if they expected rewards to be of equal magnitude. These results support a model whereby information about rewards signaled in PFo is combined with associative and contextual information signaled within Rh to estimate expected value. PMID- 23365225 TI - Tuning in to sound: frequency-selective attentional filter in human primary auditory cortex. AB - Cocktail parties, busy streets, and other noisy environments pose a difficult challenge to the auditory system: how to focus attention on selected sounds while ignoring others? Neurons of primary auditory cortex, many of which are sharply tuned to sound frequency, could help solve this problem by filtering selected sound information based on frequency-content. To investigate whether this occurs, we used high-resolution fMRI at 7 tesla to map the fine-scale frequency-tuning (1.5 mm isotropic resolution) of primary auditory areas A1 and R in six human participants. Then, in a selective attention experiment, participants heard low (250 Hz)- and high (4000 Hz)-frequency streams of tones presented at the same time (dual-stream) and were instructed to focus attention onto one stream versus the other, switching back and forth every 30 s. Attention to low-frequency tones enhanced neural responses within low-frequency-tuned voxels relative to high, and when attention switched the pattern quickly reversed. Thus, like a radio, human primary auditory cortex is able to tune into attended frequency channels and can switch channels on demand. PMID- 23365226 TI - Choice coding in frontal cortex during stimulus-guided or action-guided decision making. AB - To optimally obtain desirable outcomes, organisms must track outcomes predicted by stimuli in the environment (stimulus-outcome or SO associations) and outcomes predicted by their own actions (action-outcome or AO associations). Anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) are implicated in tracking outcomes, but anatomical and functional studies suggest a dissociation, with ACC and OFC responsible for encoding AO and SO associations, respectively. To examine whether this dissociation held at the single neuron level, we trained two subjects to perform choice tasks that required using AO or SO associations. OFC and ACC neurons encoded the action that the subject used to indicate its choice, but this encoding was stronger in OFC during the SO task and stronger in ACC during the AO task. These results are consistent with a division of labor between the two areas in terms of using rewards associated with either stimuli or actions to guide decision-making. PMID- 23365227 TI - Selective regulation of GluA subunit synthesis and AMPA receptor-mediated synaptic function and plasticity by the translation repressor 4E-BP2 in hippocampal pyramidal cells. AB - The eukaryotic initiation factor 4E-binding protein-2 (4E-BP2) is a repressor of cap-dependent mRNA translation and a major downstream effector of the mammalian target of rapamycin (mTOR) implicated in hippocampal long-term synaptic plasticity and memory. Yet, synaptic mechanisms regulated by 4E-BP2 translational repression remain unknown. Combining knock-out mice, whole-cell recordings, spine analysis, and translation profiling, we found that 4E-BP2 deletion selectively upregulated synthesis of glutamate receptor subunits GluA1 and GluA2, facilitating AMPA receptor (AMPAR)-mediated synaptic transmission and affecting translation-dependent chemically induced late long-term potentiation (cL-LTP). In 4E-BP2 knock-out (4E-BP2(-/-)) mice, evoked and miniature EPSCs were increased, an effect mimicked by short-hairpin RNA knockdown of 4E-BP2 in wild-type mice, indicating that 4E-BP2 level regulates basal transmission at mature hippocampal AMPAR-containing synapses. Remarkably, in 4E-BP2(-/-) mice, the AMPA to NMDA receptor (NMDAR) EPSC ratio was increased, without affecting NMDAR-mediated EPSCs. The enhanced AMPAR function concurred with increased spine density and decreased length resulting from greater proportion of regular spines and less filopodia in 4E-BP2(-/-) mice. Polysome profiling revealed that translation of GluA1 and GluA2 subunits, but not GluN1 or GluN2A/B, was selectively increased in 4E-BP2(-/-) hippocampi, consistent with unaltered I-V relation of EPSCs mediated by GluA1/GluA2 heteromers. Finally, translation-dependent cL-LTP of unitary EPSCs was also affected in 4E-BP2(-/-) mice, lowering induction threshold and removing mTOR signaling requirement while impairing induction by normal stimulation. Thus, translational control through 4E-BP2 represents a unique mechanism for selective regulation of AMPAR synthesis, synaptic function, and long-term plasticity, important for hippocampal-dependent memory processes. PMID- 23365224 TI - Abl2/Arg controls dendritic spine and dendrite arbor stability via distinct cytoskeletal control pathways. AB - Rho family GTPases coordinate cytoskeletal rearrangements in neurons, and mutations in their regulators are associated with mental retardation and other neurodevelopmental disorders (Billuart et al., 1998; Kutsche et al., 2000; Newey et al., 2005; Benarroch, 2007). Chromosomal microdeletions encompassing p190RhoGAP or its upstream regulator, the Abl2/Arg tyrosine kinase, have been observed in cases of mental retardation associated with developmental defects (Scarbrough et al., 1988; James et al., 1996; Takano et al., 1997; Chaabouni et al., 2006; Leal et al., 2009). Genetic knock-out of Arg in mice leads to synapse, dendritic spine, and dendrite arbor loss accompanied by behavioral deficits (Moresco et al., 2005; Sfakianos et al., 2007). To elucidate the cell-autonomous mechanisms by which Arg regulates neuronal stability, we knocked down Arg in mouse hippocampal neuronal cultures. We find that Arg knockdown significantly destabilizes dendrite arbors and reduces dendritic spine density by compromising dendritic spine stability. Inhibiting RhoA prevents dendrite arbor loss following Arg knockdown in neurons, but does not block spine loss. Interestingly, Arg deficient neurons exhibit increased miniature EPSC amplitudes, and their remaining spines exhibit larger heads deficient in the actin stabilizing protein cortactin. Spine destabilization in Arg knockdown neurons is prevented by blocking NMDA receptor-dependent relocalization of cortactin from spines, or by forcing cortactin into spines via fusion to an actin-binding region of Arg. Thus, Arg employs distinct mechanisms to selectively regulate spine and dendrite stability: Arg dampens activity-dependent disruption of cortactin localization to stabilize spines and attenuates Rho activity to stabilize dendrite arbors. PMID- 23365228 TI - Synaptic mechanisms of temporal diversity in the lateral geniculate nucleus of the thalamus. AB - The lateral geniculate nucleus (LGN) contains a unique and numerous class of cells called lagged cells, which introduce a time delay into the neural signal provided to cortex. Previous studies have shown that this delay is dependent on GABA(A) receptors within the LGN. Furthermore, lagged cells have distinct integrative properties with a slower rising, more sustained, and overall lower firing rates than nonlagged cells. We have recorded intracellularly from lagged cells in the cat LGN and found a unique property of their retinal inputs that underlies both their temporal and integrative visual response properties. Lagged cell EPSPs, which often derive from a single retinal input, have smaller amplitudes, repolarize more quickly, and are followed by a Cl(-)-dependent hyperpolarization compared with nonlagged cells. The Cl(-)-dependent hyperpolarization sums early in the visual response generating a powerful synaptic inhibition that coincides with the peak frequency of retinal input and delays the spike response in lagged cells. The hyperpolarization subsides rapidly over ~20-40 ms allowing for slow summation of the retinal input leading to the visual spike response. Given the tight association of single retinal EPSPs and the following inhibition, we propose that both functional properties result from the triadic circuitry prevalent in the LGN and particularly prominent in lagged X cells. Thus, our results show for the first time a dynamic interaction of retinal excitation and fast feedforward inhibition that determines the integrative properties and the delay in firing of lagged cells. PMID- 23365229 TI - Anatomical coupling between distinct metacognitive systems for memory and visual perception. AB - A recent study found that, across individuals, gray matter volume in the frontal polar region was correlated with visual metacognition capacity (i.e., how well one's confidence ratings distinguish between correct and incorrect judgments). A question arises as to whether the putative metacognitive mechanisms in this region are also used in other metacognitive tasks involving, for example, memory. A novel psychophysical measure allowed us to assess metacognitive efficiency separately in a visual and a memory task, while taking variations in basic task performance capacity into account. We found that, across individuals, metacognitive efficiencies positively correlated between the two tasks. However, voxel-based morphometry analysis revealed distinct brain structures for the two kinds of metacognition. Replicating a previous finding, variation in visual metacognitive efficiency was correlated with volume of frontal polar regions. However, variation in memory metacognitive efficiency was correlated with volume of the precuneus. There was also a weak correlation between visual metacognitive efficiency and precuneus volume, which may account for the behavioral correlation between visual and memory metacognition (i.e., the precuneus may contain common mechanisms for both types of metacognition). However, we also found that gray matter volumes of the frontal polar and precuneus regions themselves correlated across individuals, and a formal model comparison analysis suggested that this structural covariation was sufficient to account for the behavioral correlation of metacognition in the two tasks. These results highlight the importance of the precuneus in higher-order memory processing and suggest that there may be functionally distinct metacognitive systems in the human brain. PMID- 23365230 TI - Dense and overlapping innervation of pyramidal neurons by chandelier cells. AB - Chandelier (or axo-axonic) cells are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells and thus could have an important role controlling the activity of cortical circuits. To understand their connectivity, we labeled upper layers chandelier cells (ChCs) from mouse neocortex with a genetic strategy and studied how their axons contact local populations of pyramidal neurons, using immunohistochemical detection of axon initial segments. We studied ChCs located in the border of layers 1 and 2 from primary somatosensory cortex and found that practically all ChC axon terminals contact axon initial segments, with an average of three to five boutons per cartridge. By measuring the number of putative GABAergic synapses in initial segments, we estimate that each pyramidal neuron is innervated, on average, by four ChCs. Additionally, each individual ChC contacts 35-50% of pyramidal neurons within the areas traversed by its axonal arbor, with pockets of very high innervation density. Finally, ChCs have similar innervation patterns at different postnatal ages (P18-P90), with only relatively small lateral expansions of their arbor and increases in the total number of their cartridges during the developmental period analyzed. We conclude that ChCs innervate neighboring pyramidal neurons in a dense and overlapping manner, a connectivity pattern that could enable ChCs to exert a widespread influence on their local circuits. PMID- 23365231 TI - Dysregulation of hypoxia-inducible factor by presenilin/gamma-secretase loss-of function mutations. AB - Presenilin (PSEN) 1 and 2 are the catalytic components of the gamma-secretase complex, which cleaves a variety of proteins, including the amyloid precursor protein (APP). Proteolysis of APP leads to the formation of the APP intracellular domain (AICD) and amyloid beta that is crucially involved in the pathogenesis of Alzheimer's disease. Prolyl-4-hydroxylase-domain (PHD) proteins regulate the hypoxia-inducible factors (HIFs), the master regulators of the hypoxic response. We previously identified the FK506 binding protein 38 (FKBP38) as a negative regulator of PHD2. Genetic ablation of PSEN1/2 has been shown to increase FKBP38 protein levels. Therefore, we investigated the role of PSEN1/2 in the oxygen sensing pathway using a variety of genetically modified cell and mouse lines. Increased FKBP38 protein levels and decreased PHD2 protein levels were found in PSEN1/2-deficient mouse embryonic fibroblasts and in the cortex of forebrain specific PSEN1/2 conditional double knock-out mice. Hypoxic HIF-1alpha protein accumulation and transcriptional activity were decreased, despite reduced PHD2 protein levels. Proteolytic gamma-secretase function of PSEN1/2 was needed for proper HIF activation. Intriguingly, PSEN1/2 mutations identified in Alzheimer patients differentially affected the hypoxic response, involving the generation of AICD. Together, our results suggest a direct role for PSEN in the regulation of the oxygen sensing pathway via the APP/AICD cleavage cascade. PMID- 23365233 TI - Short-term memory in networks of dissociated cortical neurons. AB - Short-term memory refers to the ability to store small amounts of stimulus specific information for a short period of time. It is supported by both fading and hidden memory processes. Fading memory relies on recurrent activity patterns in a neuronal network, whereas hidden memory is encoded using synaptic mechanisms, such as facilitation, which persist even when neurons fall silent. We have used a novel computational and optogenetic approach to investigate whether these same memory processes hypothesized to support pattern recognition and short term memory in vivo, exist in vitro. Electrophysiological activity was recorded from primary cultures of dissociated rat cortical neurons plated on multielectrode arrays. Cultures were transfected with ChannelRhodopsin-2 and optically stimulated using random dot stimuli. The pattern of neuronal activity resulting from this stimulation was analyzed using classification algorithms that enabled the identification of stimulus-specific memories. Fading memories for different stimuli, encoded in ongoing neural activity, persisted and could be distinguished from each other for as long as 1 s after stimulation was terminated. Hidden memories were detected by altered responses of neurons to additional stimulation, and this effect persisted longer than 1 s. Interestingly, network bursts seem to eliminate hidden memories. These results are similar to those that have been reported from similar experiments in vivo and demonstrate that mechanisms of information processing and short-term memory can be studied using cultured neuronal networks, thereby setting the stage for therapeutic applications using this platform. PMID- 23365234 TI - HDAC inhibition facilitates the switch between memory systems in young but not aged mice. AB - Chromatin modifications, especially histone acetylation, are critically involved in gene regulation required for long-term memory processes. Increasing histone acetylation via administration of histone deacetylase inhibitors before or after a learning experience enhances memory consolidation for hippocampus-dependent tasks and rescues age-related memory impairments. Whether acutely and locally enhancing histone acetylation during early consolidation processes can operate as a switch between multiple memory systems is less clear. This study examined the short- and long-term behavioral consequences of acute intra-CA1 administration of the histone deacetylase inhibitor Trichostatin A (TSA) on cue versus place learning strategy selection after a cue-guided water maze task and competition testing performed 1 or 24 h later in mice. Here, we show that intra-CA1 TSA infusion administrated immediately post-training biased young mice away from striatum-dependent cue strategy toward hippocampus-dependent place strategy under training condition that normally promotes cue strategy in vehicle controls. However, concomitant infusions of TSA with either PKA inhibitor, Rp-cAMPS, into CA1 or cAMP analog, 8Br-cAMP, into dorsal striatum failed to bias young mice to place strategy use. Behavioral and immunohistochemical analyses further indicated that post-training TSA infusion in aged mice rescued aging-associated deregulation of H4 acetylation in the CA1 but failed to reverse phosphorylated CREB deficits and to produce strategy bias on the 24 h probe test. These findings suggest that post-training intra-CA1 TSA infusion promotes dynamic shift from striatum toward the hippocampal system in young but not aged animals, and support the possibility of a role for CREB in the TSA-mediated switch between these two memory systems. PMID- 23365232 TI - The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. AB - We have previously shown that myelin abnormalities characterize the normal aging process of the brain and that an age-associated reduction in Klotho is conserved across species. Predominantly generated in brain and kidney, Klotho overexpression extends life span, whereas loss of Klotho accelerates the development of aging-like phenotypes. Although the function of Klotho in brain is unknown, loss of Klotho expression leads to cognitive deficits. We found significant effects of Klotho on oligodendrocyte functions, including induced maturation of rat primary oligodendrocytic progenitor cells (OPCs) in vitro and myelination. Phosphoprotein analysis indicated that Klotho's downstream effects involve Akt and ERK signal pathways. Klotho increased OPC maturation, and inhibition of Akt or ERK function blocked this effect on OPCs. In vivo studies of Klotho knock-out mice and control littermates revealed that knock-out mice have a significant reduction in major myelin protein and gene expression. By immunohistochemistry, the number of total and mature oligodendrocytes was significantly lower in Klotho knock-out mice. Strikingly, at the ultrastructural level, Klotho knock-out mice exhibited significantly impaired myelination of the optic nerve and corpus callosum. These mice also displayed severe abnormalities at the nodes of Ranvier. To decipher the mechanisms by which Klotho affects oligodendrocytes, we used luciferase pathway reporters to identify the transcription factors involved. Together, these studies provide novel evidence for Klotho as a key player in myelin biology, which may thus be a useful therapeutic target in efforts to protect brain myelin against age-dependent changes and promote repair in multiple sclerosis. PMID- 23365235 TI - Remapping of border ownership in the visual cortex. AB - We see objects as having continuity although the retinal image changes frequently. How such continuity is achieved is hard to understand, because neurons in the visual cortex have small receptive fields that are fixed on the retina, which means that a different set of neurons is activated every time the eyes move. Neurons in areas V1 and V2 of the visual cortex signal the local features that are currently in their receptive fields and do not show "remapping" when the image moves. However, subsets of neurons in these areas also carry information about global aspects, such as figure-ground organization. Here we performed experiments to find out whether figure-ground organization is remapped. We recorded single neurons in macaque V1 and V2 in which figure-ground organization is represented by assignment of contours to regions (border ownership). We found previously that border-ownership signals persist when a figure edge is switched to an ambiguous edge by removing the context. We now used this paradigm to see whether border ownership transfers when the ambiguous edge is moved across the retina. In the new position, the edge activated a different set of neurons at a different location in cortex. We found that border ownership was transferred to the newly activated neurons. The transfer occurred whether the edge was moved by a saccade or by moving the visual display. Thus, although the contours are coded in retinal coordinates, their assignment to objects is maintained across movements of the retinal image. PMID- 23365236 TI - Calcium, calpain, and calcineurin in low-frequency depression of transmitter release. AB - Low-frequency depression (LFD) of transmitter release occurs at phasic synapses with stimulation at 0.2 Hz in both isolated crayfish (Procambarus clarkii) neuromuscular junction (NMJ) preparations and in intact animals. LFD is regulated by presynaptic activity of the Ca(2+)-dependent phosphatase calcineurin (Silverman-Gavrila and Charlton, 2009). Since the fast Ca(2+) chelator BAPTA-AM inhibits LFD but the slow chelator EGTA-AM does not, the Ca(2+) sensor for LFD may be close to a Ca(2+) source at active zones. Calcineurin can be activated by the Ca(2+)-activated protease calpain, and immunostaining showed that both proteins are present at nerve terminals. Three calpain inhibitors, calpain inhibitor I, MDL-28170, and PD150606, but not the control compound PD145305, inhibit LFD both in the intact animal as shown by electromyograms and by intracellular recordings at neuromuscular junctions. Analysis of mini-EPSPs indicated that these inhibitors had minimal postsynaptic effects. Proteolytic activity in CNS extract, detected by a fluorescent calpain substrate, was modulated by Ca(2+) and calpain inhibitors. Western blot analysis of CNS extract showed that proteolysis of calcineurin to a fragment consistent with the constitutively active form required Ca(2+) and was blocked by calpain inhibitors. Inhibition of LFD by calpain inhibition blocks the reduction in phosphoactin and the depolymerization of tubulin that normally occurs in LFD, probably by blocking the dephosphorylation of cytoskeletal proteins by calcineurin. In contrast, high frequency depression does not involve protein phosphorylation- or calpain dependent mechanisms. LFD may involve a specific pathway in which local Ca(2+) signaling activates presynaptic calpain and calcineurin at active zones and causes changes of tubulin cytoskeleton. PMID- 23365237 TI - Where one hand meets the other: limb-specific and action-dependent movement plans decoded from preparatory signals in single human frontoparietal brain areas. AB - Planning object-directed hand actions requires successful integration of the movement goal with the acting limb. Exactly where and how this sensorimotor integration occurs in the brain has been studied extensively with neurophysiological recordings in nonhuman primates, yet to date, because of limitations of non-invasive methodologies, the ability to examine the same types of planning-related signals in humans has been challenging. Here we show, using a multivoxel pattern analysis of functional MRI (fMRI) data, that the preparatory activity patterns in several frontoparietal brain regions can be used to predict both the limb used and hand action performed in an upcoming movement. Participants performed an event-related delayed movement task whereby they planned and executed grasp or reach actions with either their left or right hand toward a single target object. We found that, although the majority of frontoparietal areas represented hand actions (grasping vs reaching) for the contralateral limb, several areas additionally coded hand actions for the ipsilateral limb. Notable among these were subregions within the posterior parietal cortex (PPC), dorsal premotor cortex (PMd), ventral premotor cortex, dorsolateral prefrontal cortex, presupplementary motor area, and motor cortex, a region more traditionally implicated in contralateral movement generation. Additional analyses suggest that hand actions are represented independently of the intended limb in PPC and PMd. In addition to providing a unique mapping of limb-specific and action-dependent intention-related signals across the human cortical motor system, these findings uncover a much stronger representation of the ipsilateral limb than expected from previous fMRI findings. PMID- 23365238 TI - Ablation of neurons expressing melanin-concentrating hormone (MCH) in adult mice improves glucose tolerance independent of MCH signaling. AB - Melanin-concentrating hormone (MCH)-expressing neurons have been ascribed many roles based on studies of MCH-deficient mice. However, MCH neurons express other neurotransmitters, including GABA, nesfatin, and cocaine-amphetamine-regulated transcript. The importance of these other signaling molecules made by MCH neurons remains incompletely characterized. To determine the roles of MCH neurons in vivo, we targeted expression of the human diphtheria toxin receptor (DTR) to the gene for MCH (Pmch). Within 2 weeks of diphtheria toxin injection, heterozygous Pmch(DTR/+) mice lost 98% of their MCH neurons. These mice became lean but ate normally and were hyperactive, especially during a fast. They also responded abnormally to psychostimulants. For these phenotypes, ablation of MCH neurons recapitulated knock-out of MCH, so MCH appears to be the critical neuromodulator released by these neurons. In contrast, MCH-neuron-ablated mice showed improved glucose tolerance when compared with MCH-deficient mutant mice and wild-type mice. We conclude that MCH neurons regulate glucose tolerance through signaling molecules other than MCH. PMID- 23365239 TI - alpha2 Adrenergic receptor-mediated inhibition of thermogenesis. AB - alpha2 adrenergic receptor (alpha2-AR) agonists have been used as antihypertensive agents, in the management of drug withdrawal, and as sedative analgesics. Since alpha2-AR agonists also influence the regulation of body temperature, we explored their potential as antipyretic agents. This study delineates the central neural substrate for the inhibition of rat brown adipose tissue (BAT) and shivering thermogenesis by alpha2-AR agonists. Nanoinjection of the alpha2-AR agonist clonidine (1.2 nmol) into the rostral raphe pallidus area (rRPa) inhibited BAT sympathetic nerve activity (SNA) and BAT thermogenesis. Subsequent nanoinjection of the alpha2-AR antagonist idazoxan (6 nmol) into the rRPa reversed the clonidine-evoked inhibition of BAT SNA and BAT thermogenesis. Systemic administration of the alpha2-AR agonists dexmedetomidine (25 MUg/kg, i.v.) and clonidine (100 MUg/kg, i.v.) inhibited shivering EMGs, BAT SNA, and BAT thermogenesis, effects that were reversed by nanoinjection of idazoxan (6 nmol) into the rRPa. Dexmedetomidine (100 MUg/kg, i.p.) prevented and reversed lipopolysaccharide-evoked (10 MUg/kg, i.p.) thermogenesis in free-behaving rats. Cholera toxin subunit b retrograde tracing from rRPa and pseudorabies virus transynaptic retrograde tracing from BAT combined with immunohistochemistry for catecholaminergic biosynthetic enzymes revealed the ventrolateral medulla as the source of catecholaminergic input to the rRPa and demonstrated that these catecholaminergic neurons are synaptically connected to BAT. Photostimulation of ventrolateral medulla neurons expressing the PRSx8-ChR2-mCherry lentiviral vector inhibited BAT SNA via activation of alpha2-ARs in the rRPa. These results indicate a potent inhibition of BAT and shivering thermogenesis by alpha2-AR activation in the rRPa, and suggest a therapeutic potential of alpha2-AR agonists for reducing potentially lethal elevations in body temperature during excessive fever. PMID- 23365240 TI - High-learners present larger mid-frontal theta power and connectivity in response to incorrect performance feedback. AB - A crucial aspect of cognitive control and learning is the ability to integrate feedback, that is, to evaluate action outcomes and their deviations from the intended goals and to adjust behavior accordingly. However, how high-learners differ from low-learners in relation to feedback processing has not been characterized. Further, little is known about the underlying brain connectivity patterns during feedback processing. This study aimed to fill these gaps by analyzing electrical brain responses from healthy adult human participants while they performed a time estimation task with correct and incorrect feedback. As compared with low-learners, high-learners presented larger mid-frontal theta (4-8 Hz) oscillations and lower sensorimotor beta (17-24 Hz) oscillations in response to incorrect feedback. Further, high-learners showed larger theta connectivity from left central, associated with motor activity, to mid-frontal, associated with performance monitoring, immediately after feedback (0-0.3 s), followed by (from 0.3 to 0.6 s after feedback) a flux from mid-frontal to prefrontal, associated with executive functioning. We suggest that these results reflect two cognitive processes related to successful feedback processing: first, the obtained feedback is compared with the expected one, and second, the feedback history is updated based on this information. Our results also indicate that high and low-learners differ not only on how they react to incorrect feedback, but also in relation to how their distant brain areas interact while processing both correct and incorrect feedback. This study demonstrates the neural underpinnings of individual differences in goal-directed adaptive behavior. PMID- 23365241 TI - Bayesian prediction and evaluation in the anterior cingulate cortex. AB - The dorsal anterior cingulate cortex (dACC) has been implicated in a variety of cognitive control functions, among them the monitoring of conflict, error, and volatility, error anticipation, reward learning, and reward prediction errors. In this work, we used a Bayesian ideal observer model, which predicts trial-by-trial probabilistic expectation of stop trials and response errors in the stop-signal task, to differentiate these proposed functions quantitatively. We found that dACC hemodynamic response, as measured by functional magnetic resonance imaging, encodes both the absolute prediction error between stimulus expectation and outcome, and the signed prediction error related to response outcome. After accounting for these factors, dACC has no residual correlation with conflict or error likelihood in the stop-signal task. Consistent with recent monkey neural recording studies, and in contrast with other neuroimaging studies, our work demonstrates that dACC reports at least two different types of prediction errors, and beyond contexts that are limited to reward processing. PMID- 23365242 TI - Biphasic cholinergic synaptic transmission controls action potential activity in thalamic reticular nucleus neurons. AB - Cholinergic neurons in the basal forebrain and the brainstem form extensive projections to a number of thalamic nuclei. Activation of cholinergic afferents during distinct behavioral states can regulate neuronal firing, transmitter release at glutamatergic and GABAergic synapses, and synchrony in thalamic networks, thereby controlling the flow of sensory information. These effects are thought to be mediated by slow and persistent increases in extracellular ACh levels, resulting in the modulation of populations of thalamic neurons over large temporal and spatial scales. However, the synaptic mechanisms underlying cholinergic signaling in the thalamus are not well understood. Here, we demonstrate highly reliable cholinergic transmission in the mouse thalamic reticular nucleus (TRN), a brain structure essential for sensory processing, arousal, and attention. We find that ACh release evoked by low-frequency stimulation leads to biphasic excitatory-inhibitory (E-I) postsynaptic responses, mediated by the activation of postsynaptic alpha4beta2 nicotinic ACh receptors (nAChRs) and M2 muscarinic ACh receptors (mAChRs), respectively. In addition, ACh can bind to mAChRs expressed near cholinergic release sites, resulting in autoinhibition of release. We show that the activation of postsynaptic nAChRs by transmitter release from only a small number of individual axons is sufficient to trigger action potentials in TRN neurons. Furthermore, short trains of cholinergic synaptic inputs can powerfully entrain ongoing TRN neuronal activity. Our study demonstrates fast and precise synaptic E-I signaling mediated by ACh, suggesting novel computational mechanisms for the cholinergic control of neuronal activity in thalamic circuits. PMID- 23365243 TI - Neurturin overexpression in skin enhances expression of TRPM8 in cutaneous sensory neurons and leads to behavioral sensitivity to cool and menthol. AB - Neurturin (NRTN) is a member of the glial cell line-derived neurotrophic factor family of ligands that exerts its actions via Ret tyrosine kinase and GFRalpha2. Expression of the Ret-GFRalpha2 coreceptor complex is primarily restricted to the peripheral nervous system and is selectively expressed by sensory neurons that bind the isolectin B(4) (IB(4)). To determine how target-derived NRTN affects sensory neuron properties, transgenic mice that overexpress NRTN in keratinocytes (NRTN-OE mice) were analyzed. Overexpression of NRTN increased the density of PGP9.5-positive, but not calcitonin gene-related peptide-positive, free nerve endings in footpad epidermis. GFRalpha2-immunopositive somata were hypertrophied in NRTN-OE mice. Electron microscopic analysis further revealed hypertrophy of unmyelinated sensory axons and a subset of myelinated axons. Overexpression of NRTN increased the relative level of mRNAs encoding GFRalpha2 and Ret, the ATP receptor P2X(3) (found in IB(4)-positive, GFRalpha2-expressing sensory neurons), the acid-sensing ion channel 2a, and transient receptor potential cation channel subfamily member M8 (TRPM8) in sensory ganglia. Behavioral testing of NRTN-OE mice revealed an increased sensitivity to mechanical stimuli in glabrous skin of the hindpaw. NRTN-OE mice also displayed increased behavioral sensitivity to cool temperature (17 degrees C-20 degrees C) and oral sensitivity to menthol. The increase in cool and menthol sensitivity correlated with a significant increase in TRPM8 expression and the percentage of menthol-responsive cutaneous sensory neurons. These data indicate that the expression level of NRTN in the skin modulates gene expression in cutaneous sensory afferents and behavioral sensitivity to thermal, chemical, and mechanical stimuli. PMID- 23365246 TI - Complex movement topography and extrinsic space representation in the rat forelimb motor cortex as defined by long-duration intracortical microstimulation. AB - Electrical stimulation of the motor cortex in the rat can evoke complex forelimb multi-joint movements, including movement of limb and paw. In this study, these movements have been quantified in terms of 3D displacement and kinematic variables of two markers positioned on the wrist and middle digits (limb and paw movement, respectively). Electrical microstimulation was applied to the motor cortex using a pulse train of 500 ms duration. Movements were measured using a high-resolution 3D optical system. Five classes of limb movements (abduction, adduction, extension, retraction, elevation) and four classes of paw movements (opening, closure, opening/closure sequence, supination) were described according to their kinematics. A consistent topography of these classes of movements was presented across the motor cortex together with a topography of spatial locations to which the paw was directed. In about one-half of cortical sites, a specific pattern of limb-paw movement combination did exist. Four categories of limb-paw movements resembling behavioral repertoire were identified: reach-shaping, reach grasp sequence, bring-to-body, and hold-like movement. Overall, the forelimb motor region included: (1) a large caudal forelimb area dominated by reach shaping movement representation; (2) a small rostral area containing reach-grasp sequence and bring-to-body movement representation; and (3) a more lateral portion where hold-like movement was represented. These results support the view that, in rats, the motor cortex controls forelimb movements at a relatively complex level and suggest that the orderly representation of complex movements and their dynamics/kinematics emerge from the principles of forelimb motor cortex organization. PMID- 23365245 TI - Chronic inactivation of a neural circuit enhances LTP by inducing silent synapse formation. AB - Chronic inactivation of a neural network is known to induce homeostatic upregulation of synaptic strength, a form of synaptic plasticity that differs from Hebbian-type synaptic plasticity in that it is not input-specific, but involves all synapses of an individual neuron. However, it is unclear how homeostatic and Hebbian synaptic plasticity interact in the same neuron. Here we show that long-term potentiation (LTP) at Schaffer collateral-CA1 synapses is greatly enhanced in cultured mouse hippocampal slices after chronic (60 h) network-activity blockade with tetrodotoxin (TTX). This increase in LTP is not due to an altered synaptic NMDA receptor composition or presynaptic function. Instead, we found that silencing neural network activity not only increases the abundance of both AMPA and NMDA receptors at existing synapses as previously described, but also promotes the presence of new glutamatergic synapses that contain only NMDA receptors-a class of synapses that are functionally silent due to the absence of AMPA receptors. Induction of LTP in TTX-treated neurons leads to insertion of AMPA receptors into the silent synapses, thereby "switching on" these silent synapses, which produces the observed enhancement of LTP magnitude. Our findings suggest that homeostatic synaptic plasticity manifests not only in the adjustment of the strength of existing synapses, but also in the modulation of new synapse formation/maintenance. Moreover, presence of new but functionally silent synapses enables more robust LTP to occur through rapid conversion of silent synapses to active synapses, resulting in a stronger input-specific modulation of synapses following prolonged network silencing. PMID- 23365247 TI - Adaptation improves neural coding efficiency despite increasing correlations in variability. AB - Exposure of cortical cells to sustained sensory stimuli results in changes in the neuronal response function. This phenomenon, known as adaptation, is a common feature across sensory modalities. Here, we quantified the functional effect of adaptation on the ensemble activity of cortical neurons in the rat whisker-barrel system. A multishank array of electrodes was used to allow simultaneous sampling of neuronal activity. We characterized the response of neurons to sinusoidal whisker vibrations of varying amplitude in three states of adaptation. The adaptors produced a systematic rightward shift in the neuronal response function. Consistently, mutual information revealed that peak discrimination performance was not aligned to the adaptor but to test amplitudes 3-9 MUm higher. Stimulus presentation reduced single neuron trial-to-trial response variability (captured by Fano factor) and correlations in the population response variability (noise correlation). We found that these two types of variability were inversely proportional to the average firing rate regardless of the adaptation state. Adaptation transferred the neuronal operating regime to lower rates with higher Fano factor and noise correlations. Noise correlations were positive and in the direction of signal, and thus detrimental to coding efficiency. Interestingly, across all population sizes, the net effect of adaptation was to increase the total information despite increasing the noise correlation between neurons. PMID- 23365244 TI - Properties of ribbon and non-ribbon release from rod photoreceptors revealed by visualizing individual synaptic vesicles. AB - Vesicle release from rod photoreceptors is regulated by Ca(2+) entry through L type channels located near synaptic ribbons. We characterized sites and kinetics of vesicle release in salamander rods by using total internal reflection fluorescence microscopy to visualize fusion of individual synaptic vesicles. A small number of vesicles were loaded by brief incubation with FM1-43 or a dextran conjugated, pH-sensitive form of rhodamine, pHrodo. Labeled organelles matched the diffraction-limited size of fluorescent microspheres and disappeared rapidly during stimulation. Consistent with fusion, depolarization-evoked vesicle disappearance paralleled electrophysiological release kinetics and was blocked by inhibiting Ca(2+) influx. Rods maintained tonic release at resting membrane potentials near those in darkness, causing depletion of membrane-associated vesicles unless Ca(2+) entry was inhibited. This depletion of release sites implies that sustained release may be rate limited by vesicle delivery. During depolarizing stimulation, newly appearing vesicles approached the membrane at ~800 nm/s, where they paused for ~60 ms before fusion. With fusion, vesicles advanced ~18 nm closer to the membrane. Release events were concentrated near ribbons, but lengthy depolarization also triggered release from more distant non ribbon sites. Consistent with greater contributions from non-ribbon sites during lengthier depolarization, damaging the ribbon by fluorophore-assisted laser inactivation (FALI) of Ribeye caused only weak inhibition of exocytotic capacitance increases evoked by 200-ms depolarizing test steps, whereas FALI more strongly inhibited capacitance increases evoked by 25 ms steps. Amplifying release by use of non-ribbon sites when rods are depolarized in darkness may improve detection of decrements in release when they hyperpolarize to light. PMID- 23365248 TI - How embodied is perceptual decision making? Evidence for separate processing of perceptual and motor decisions. AB - The extent to which different cognitive processes are "embodied" is widely debated. Previous studies have implicated sensorimotor regions such as lateral intraparietal (LIP) area in perceptual decision making. This has led to the view that perceptual decisions are embodied in the same sensorimotor networks that guide body movements. We use event-related fMRI and effective connectivity analysis to investigate whether the human sensorimotor system implements perceptual decisions. We show that when eye and hand motor preparation is disentangled from perceptual decisions, sensorimotor areas are not involved in accumulating sensory evidence toward a perceptual decision. Instead, inferior frontal cortex increases its effective connectivity with sensory regions representing the evidence, is modulated by the amount of evidence, and shows greater task-positive BOLD responses during the perceptual decision stage. Once eye movement planning can begin, however, an intraparietal sulcus (IPS) area, putative LIP, participates in motor decisions. Moreover, sensory evidence levels modulate decision and motor preparation stages differently in different IPS regions, suggesting functional heterogeneity of the IPS. This suggests that different systems implement perceptual versus motor decisions, using different neural signatures. PMID- 23365249 TI - Neural correlates of reinforcement learning and social preferences in competitive bidding. AB - In competitive social environments, people often deviate from what rational choice theory prescribes, resulting in losses or suboptimal monetary gains. We investigate how competition affects learning and decision-making in a common value auction task. During the experiment, groups of five human participants were simultaneously scanned using MRI while playing the auction task. We first demonstrate that bidding is well characterized by reinforcement learning with biased reward representations dependent on social preferences. Indicative of reinforcement learning, we found that estimated trial-by-trial prediction errors correlated with activity in the striatum and ventromedial prefrontal cortex. Additionally, we found that individual differences in social preferences were related to activity in the temporal-parietal junction and anterior insula. Connectivity analyses suggest that monetary and social value signals are integrated in the ventromedial prefrontal cortex and striatum. Based on these results, we argue for a novel mechanistic account for the integration of reinforcement history and social preferences in competitive decision-making. PMID- 23365250 TI - Brain microstructure reveals early abnormalities more than two years prior to clinical progression from mild cognitive impairment to Alzheimer's disease. AB - Diffusion imaging is a promising marker of microstructural damage in neurodegenerative disorders, but interpretation of its relationship with underlying neuropathology can be complex. Here, we examined both volumetric and brain microstructure abnormalities in 13 amnestic patients with mild cognitive impairment (MCI), who progressed to probable Alzheimer's disease (AD) no earlier than 2 years after baseline scanning, in order to focus on early, and hence more sensitive, imaging markers. We compared them to 22 stable amnestic MCI patients with similar cognitive performance and episodic memory impairment but who did not show progression of symptoms for at least 3 years. Significant group differences were mainly found in the volume and microstructure of the left hippocampus, while white matter group differences were also found in the body of the fornix, left fimbria, and superior longitudinal fasciculus (SLF). Diffusion index abnormalities in the SLF were the sign of a subtle microstructural injury not detected by standard atrophy measures in the corresponding gray matter regions. The microstructural measure obtained in the left hippocampus using diffusion imaging showed the most substantial differences between the two groups and was the best single predictor of future progression to AD. An optimal prediction model (91% accuracy, 85% sensitivity, 96% specificity) was obtained by combining MRI measures and CSF protein biomarkers. These results highlight the benefit of using the information of brain microstructural damage, in addition to traditional gray matter volume, to detect early, subtle abnormalities in MCI prior to clinical progression to probable AD and, in combination with CSF markers, to accurately predict such progression. PMID- 23365251 TI - Functional impact of dendritic branch-point morphology. AB - Cortical pyramidal cells store multiple features of complex synaptic input in individual dendritic branches and independently regulate the coupling between dendritic and somatic spikes. Branch points in apical trees exhibit wide ranges of sizes and shapes, and the large diameter ratio between trunk and oblique dendrites exacerbates impedance mismatch. The morphological diversity of dendritic bifurcations could thus locally tune neuronal excitability and signal integration. However, these aspects have never been investigated. Here, we first quantified the morphological variability of branch points from two-photon images of rat CA1 pyramidal neurons. We then investigated the geometrical features affecting spike initiation, propagation, and timing with a computational model validated by glutamate uncaging experiments. The results suggest that even subtle membrane readjustments at branch points could drastically alter the ability of synaptic input to generate, propagate, and time action potentials. PMID- 23365252 TI - Dopaminergic neurons encode a distributed, asymmetric representation of temperature in Drosophila. AB - Dopaminergic circuits modulate a wide variety of innate and learned behaviors in animals, including olfactory associative learning, arousal, and temperature preference behavior. It is not known whether distinct or overlapping sets of dopaminergic neurons modulate these behaviors. Here, I have functionally characterized the dopaminergic circuits innervating the Drosophila mushroom body with in vivo calcium imaging and conditional silencing of genetically defined subsets of neurons. Distinct subsets of PPL1 dopaminergic neurons innervating the vertical lobes of the mushroom body responded to decreases in temperature, but not increases, with rapidly adapting bursts of activity. PAM neurons innervating the horizontal lobes did not respond to temperature shifts. Ablation of the antennae and maxillary palps reduced, but did not eliminate, the responses. Genetic silencing of dopaminergic neurons innervating the vertical mushroom body lobes substantially reduced behavioral cold avoidance, but silencing smaller subsets of these neurons had no effect. These data demonstrate that overlapping dopaminergic circuits encode a broadly distributed, asymmetric representation of temperature that overlays regions implicated previously in learning, memory, and forgetting. Thus, diverse behaviors engage overlapping sets of dopaminergic neurons that encode multimodal stimuli and innervate a single anatomical target, the mushroom body. PMID- 23365253 TI - Notum homolog plays a novel role in primary motor innervation. AB - To form complex neuronal networks, growth cones use intermediate targets as guideposts on the path to more distant targets. In the developing zebrafish (Danio rerio), the muscle pioneers (MPs) are intermediate targets for primary motor neurons (PMNs) that innervate the trunk musculature. The mechanisms regulating PMN axon guidance at the MPs are not fully understood. We have identified a new member of the Notum family in zebrafish, Notum 2, which is expressed exclusively in the MPs during primary motor innervation. While homologs of Notum, including zebrafish Notum 1a, negatively regulate the Wnt/beta-catenin signaling pathway, we discovered a novel function of Notum 2 in regulating motor axon guidance. Knockdown of Notum 2 resulted in a failure of caudal primary (CaP) axons to migrate beyond the MPs, despite the proper specification of the intermediate target. In contrast, mosaic Notum 2 overexpression induced branching of PMN axons. This effect is specific to Notum 2, as overexpression of Notum 1a does not affect PMN axon trajectory. Ectopic expression of Notum 2 by cells contacting the growing CaP axon induced the highest frequency of branching, suggesting that localized Notum 2 expression affects axon behavior. We propose a model where Notum 2 expression at the MPs provides a cue to release CaP motor axons from their intermediate targets, allowing growth cones to proceed to secondary targets in the ventral muscle. This work demonstrates an unexpected role for a Notum homolog in regulating growth cone migration, separate from the well established functions of other Notum homologs in Wnt signaling. PMID- 23365255 TI - Attention to bright surfaces enhances the pupillary light reflex. AB - One longstanding question is how early in the visual system attention exerts its influence. Here we show that an effect of attention can be measured at the earliest possible stage of visual information processing, as a change in the optics of the eye. We tested human subjects and found that covertly attending to bright surfaces results in an enhanced pupillary light reflex (PLR)-the pupillary constriction that occurs in response to light increments. The PLR optimizes the optical quality of the retinal image across illumination conditions, increasing sensitivity by modulating retinal illumination, and improving acuity by reducing spherical aberrations. The attentional modulation of the PLR that we describe constitutes a new mechanism through which vision is affected by attention; we discuss three alternatives for the neural substrates of this effect, including the possibility that attention might act indirectly, via its well established effects in early visual cortex. PMID- 23365254 TI - Retinotopic patterns of correlated fluctuations in visual cortex reflect the dynamics of spontaneous perceptual suppression. AB - While viewing certain stimuli, perception changes spontaneously in the face of constant input. For example, during "motion-induced blindness" (MIB), a small salient target spontaneously disappears and reappears when surrounded by a moving mask. Models of such bistable perceptual phenomena posit spontaneous fluctuations in neuronal activity throughout multiple stages of the visual cortical hierarchy. We used fMRI to link correlated activity fluctuations across human visual cortical areas V1 through V4 to the dynamics (rate and duration) of MIB target disappearance. We computed the correlations between the time series of fMRI activity in multiple retinotopic subregions corresponding to MIB target and mask. Linear decomposition of the matrix of temporal correlations revealed spatial patterns of activity fluctuations, regardless of whether or not these were time locked to behavioral reports of target disappearance. The spatial pattern that dominated the activity fluctuations during MIB was spatially nonspecific, shared by all subregions, but did not reflect the dynamics of perception. By contrast, the fluctuations associated with the rate of MIB disappearance were retinotopically specific for the target subregion in V4, and the fluctuations associated with the duration of MIB disappearance states were target-specific in V1. Target-specific fluctuations in V1 have not previously been identified by averaging activity time-locked to behavioral reports of MIB disappearance. Our results suggest that different levels of the visual cortical hierarchy shape the dynamics of perception via distinct mechanisms, which are evident in distinct spatial patterns of spontaneous cortical activity fluctuations. PMID- 23365256 TI - ASPP1/2 regulate p53-dependent death of retinal ganglion cells through PUMA and Fas/CD95 activation in vivo. AB - The transcription factor p53 mediates neuronal death in a variety of stress related and neurodegenerative conditions. The proapoptotic activity of p53 is tightly regulated by the apoptosis-stimulating proteins of p53 (ASPP) family members: ASPP1 and ASPP2. However, whether ASPP1/2 play a role in the regulation of p53-dependent neuronal death in the CNS is currently unknown. To address this, we asked whether ASPP1/2 contribute to the death of retinal ganglion cells (RGCs) using in vivo models of acute optic nerve damage in mice and rats. Here, we show that p53 is activated in RGCs soon after injury and that axotomy-induced RGC death is attenuated in p53 heterozygote and null mice. We demonstrate that ASPP1/2 proteins are abundantly expressed by injured RGCs, and that short interfering (si)RNA-based ASPP1 or ASPP2 knockdown promotes robust RGC survival. Comparative gene expression analysis revealed that siASPP-mediated downregulation of p53-upregulated-modulator-of-apoptosis (PUMA), Fas/CD95, and Noxa depends on p53 transcriptional activity. Furthermore, siRNA against PUMA or Fas/CD95 confers neuroprotection, demonstrating a functional role for these p53 targets in RGC death. Our study demonstrates a novel role for ASPP1 and ASPP2 in the death of RGCs and provides evidence that blockade of the ASPP-p53 pathway is beneficial for central neuron survival after axonal injury. PMID- 23365257 TI - The location of feedback-related activity in the midcingulate cortex is predicted by local morphology. AB - Information processing in the medial frontal cortex is often said to be modulated in pathological conditions or by individual traits. This has been observed in neuroimaging and event-related potential studies centered in particular on midcingulate cortex (MCC) functions. This region of the brain is characterized by considerable intersubject morphological variability. Whereas in a subset of hemispheres only a single cingulate sulcus (cgs) is present, a majority of hemispheres exhibit an additional sulcus referred to as the paracingulate sulcus (pcgs). The present functional magnetic resonance imaging study defined the relationship between the local morphology of the cingulate/paracingulate sulcal complex and feedback-related activity. Human subjects performed a trial-and-error learning task in which they had to discover which one of a set of abstract stimuli was the best option. Feedback was provided by means of fruit juice, as in studies with monkeys. A subject-by-subject analysis revealed that the feedback related activity during exploration was systematically located in the cgs when no pcgs was observed, but in the pcgs when the latter sulcus was present. The activations had the same functional signature when located in either the cgs or in the pcgs, confirming that both regions were homologues. Together, the results show that the location of feedback-related MCC activity can be predicted from morphological features of the cingulate/paracingulate complex. PMID- 23365258 TI - Separate contributions of kinematic and kinetic errors to trajectory and grip force adaptation when transporting novel hand-held loads. AB - Numerous studies of motor learning have examined the adaptation of hand trajectories and grip forces when moving grasped objects with novel dynamics. Such objects initially result in both kinematic and kinetic errors; i.e., mismatches between predicted and actual trajectories and between predicted and actual load forces. Here we investigated the contribution of these errors to both trajectory and grip force adaptation. Participants grasped an object with novel dynamics using a precision grip and moved it between two targets. Kinematic errors could be effectively removed using a force channel to constrain hand motion to a straight line. When moving in the channel, participants learned to modulate grip force in synchrony with load force and this learning generalized when movement speed in the channel was doubled. When the channel was removed, these participants continued to effectively modulate grip force but exhibited substantial kinematic errors, equivalent to those seen in participants who did not previously experience the object in the channel. We also found that the rate of grip force adaptation did not depend on whether the object was initially moved with or without a channel. These results indicate that kinematic errors are necessary for trajectory but not grip force adaptation, and that kinetic errors are sufficient for grip force but not trajectory adaptation. Thus, participants can learn a component of the object's dynamics, used to control grip force, based solely on kinetic errors. However, this knowledge is apparently not accessible or usable for controlling the movement trajectory when the channel is removed. PMID- 23365259 TI - Effect of reconstruction parameters in high-definition PET/CT on assessment of lymph node metastases in head and neck squamous cell carcinoma. AB - Therapy outcome and overall survival in patients with head and neck squamous cell carcinoma (HNSCC) is influenced by precise localization of the primary tumor and detection of lymph node metastasis involvement at the time of initial diagnosis. Only accurate preoperative staging can improve primary tumor response and avoid early locoregional recurrence with lymph node metastases. The purpose of this study was the optimization of reconstruction parameters in high-definition PET/CT for the improved diagnostic assessment of lymph node metastases. METHODS: In the experimental study, image contrast and signal-to-noise ratio were evaluated using a Jaszczak phantom. In the clinical study, 54 patients underwent head and neck imaging on a PET/CT scanner. Diagnostic findings were correlated with postoperative histopathology. For the 54 patients, 123 lymph nodes were evaluated on PET and histologically correlated with the neck dissection specimen. Forty-one lymph nodes were benign, and 82 findings were confirmed as being malignant. Both experimental and clinical studies were reconstructed into a 200 * 200 matrix using a 3-dimensional iterative reconstruction algorithm (ordered-subset expectation maximization [OSEM], 3 iterative steps, 24 subsets). Postfiltering with a 3-dimensional gaussian filter was applied. To study the effect of smoothing filter strength on the diagnostic accuracy of lymph node metastasis detection, 3 different cutoffs-1, 3, and 6 mm in full width at half maximum-were used to perform reconstructions. RESULTS: Phantom studies showed that images reconstructed with 3-mm gaussian postfiltering gained a higher image quality and signal-to-noise ratio. Overall sensitivities for correctly diagnosed lymph nodes were best in 3-mm postfiltered images. Best results for true-positive lymph node findings were achieved with 3-mm postfiltering. With 1-mm postfiltering, accurate lesion detection was not improved, because increasing sensitivity (95% true positive) correlated with decreasing specificity (12% false-positive). CONCLUSION: For lymph node assessment on a high-resolution PET/CT scanner, we consider the OSEM algorithm with 3 iterations and 24 subsets, combined with 3 dimensional 3-mm gaussian postfiltering, to be optimal. The continuous application of presently established PET protocols in patients with HNSCC will prove whether current acquisition and reconstruction methods are valuable and should be maintained. PMID- 23365260 TI - Adiponectin enhances calcium dependency of mouse bladder contraction mediated by protein kinase Calpha expression. AB - Adiponectin is an adipose tissue-secreted protein and is a multifunctional adipocytokine. However, the association of adiponectin with bladder contraction has not been investigated. In this study, the adiponectin-sense transgenic mouse (Adip-Sen mouse; age, 16-24 weeks; male) and age-matched controls (C57Bl mouse) were studied. The Adip-Sen mouse showed a significant increase in plasma adiponectin levels (56.2%; P < 0.01), compared with those in the C57Bl mouse, without affecting other lipid parameters. Isometric force development in bladder smooth muscle tissues were detected using an organ-bath system. Although carbachol (CCh)-induced (0.1-100 uM) time- and dose-dependent contractions in Adip-Sen mouse bladder were slightly enhanced, compared with those in the C57Bl mouse during a low range (0.3-1.0 uM) of CCh, differences could not be detected with other CCh concentrations. However, the reduction in contraction under Ca(2+) replaced conditions was significantly different between Adip-Sen and C57Bl mice (94.1 and 66.3% of normal contraction, respectively; n = 5). A parameter of Ca(2+) sensitivity, the relation between intracellular Ca(2+) concentration and contraction, was increased in the Adip-Sen mouse, compared with that in the C57B1 mouse. This Ca(2+) dependency in the Adip-Sen mouse was reduced by a protein kinase C (PKC) inhibitor, but not by a Rho kinase inhibitor. Expression of the calcium-dependent isoform of PKC, PKCalpha, was increased in the Adip-Sen mouse bladder, and CCh-induced phosphorylation of PKCalpha was also enhanced, compared with those in the C57Bl mouse. In conclusion, adiponectin is associated with bladder smooth muscle contraction, which involves an increase in Ca(2+) dependency of contraction mediated by PKCalpha expression. PMID- 23365261 TI - A qualitative investigation of the motivations, experiences and views of female sunbed users under the age of 18 in England. AB - OBJECTIVE: To explore the motivations, experiences and views of female regular sunbed users aged 15-17 and consider the implications of legislation seeking to restrict sunbed use among the under-18s. Design Qualitative study of 12 focus groups. METHOD: Participants were recruited opportunistically through community and social networks, around tanning salons, leisure and educational facilities in six English towns and cities. Interviews were transcribed, a thematic framework generated and a validation exercise conducted. Setting Urban communities in England. Participants Sixty-nine female regular sunbed users aged 15-18. RESULTS: Respondents consistently valued tanning and attached considerable personal and social importance to it. They showed an awareness of the risks of sunbed use that they accepted, downplayed and/or ignored. While experiences and responses to supervision varied, respondents were resistant to any measures that restricted their use and expressed willingness to find ways around such restrictions. CONCLUSIONS: The sunbed users interviewed in this study attached considerable significance to tanning, rationalized the risks of sunbed use and expressed their determination to continue using them. The impact of legislation to limit sunbed access may be weakened without requirements to ensure supervision of salons. PMID- 23365262 TI - Midwives' influenza vaccine uptake and their views on vaccination of pregnant women. AB - BACKGROUND: Pregnant women in England are now offered seasonal influenza vaccine. Midwives could be influential in promoting this, but specific information on their views on the policy and their role in its implementation is lacking. METHODS: London midwives were surveyed for their views on the new policy and their own vaccine uptake, using an anonymously self-completed semi-structured online survey via a convenience sampling approach. RESULTS: In total, 266 midwives responded. Sixty-nine percent agreed with the policy of vaccinating all pregnant women. Seventy-six percent agreed that midwives should routinely advise pregnant women on vaccination, but only 25% felt adequately prepared for this role. Just 28% wished to be vaccinators, due to concerns about increased workload and inadequate training. Forty-three percent received seasonal influenza vaccine themselves. Major reasons for non-uptake were doubts about vaccine necessity (34%), safety (25%) and effectiveness (10%); and poor arrangements for vaccination (11%). Suggested strategies for improving their own uptake included better access to evidence of effectiveness (67%) and improved work-based vaccination (45%). CONCLUSIONS: London midwives support influenza vaccination of pregnant women, but are more willing to give advice on, than to administer, the vaccine. Midwives' own influenza vaccine uptake could improve with more information and easier access to vaccination in their workplace. PMID- 23365263 TI - Prospective pilot evaluation of the effectiveness and cost-utility of a 'health first' case management service for long-term Incapacity Benefit recipients. AB - BACKGROUND: In line with the NICE guidance, an NHS-commissioned case management intervention was provided for individuals receiving Incapacity Benefit payments for >=3 years in the North East of England. The intervention aimed to improve the health of the participants. METHODS: A total of 131 participants receiving the intervention were compared over 9 months with a (non-equivalent) comparison group of 229 receiving Incapacity Benefit payments and usual care. Health was measured using EQ-5D, EQ-VAS, SF-8, HADS and the Nordic Musculoskeletal questionnaire. Socio-demographic and health behaviour data were also collected. Fixed-effects linear models with correlated errors were used to compare health changes between groups over time. A preliminary cost-utility analysis was also conducted. RESULTS: The comparison group measures of health were stable over time. Starting from comparatively poor initial levels, case-management group generic (EQ5D, EQ VAS) and mental health (HADS-A, HADS-D and SF8-MCS) measures improved within 6 months to similar levels found in the comparison group. Musculoskeletal (Nordic 2) and health behaviours did not improve. Tentative estimates of cost-utility suggest an intervention cost in the region of L16 700-L23 500 per QALY. CONCLUSIONS: Case management interventions may improve the health of Incapacity Benefit recipients. Further research is required to help confirm these pilot findings. PMID- 23365264 TI - External beam boost irradiation for clinically positive pelvic nodes in patients with uterine cervical cancer. AB - The purpose of this study was to retrospectively analyze the treatment results of boost external beam radiotherapy (EBRT) to clinically positive pelvic nodes in patients with uterine cervical cancer. The study population comprised 174 patients with FIGO stages 1B1-4A cervical cancer who were treated with definitive radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) and high-dose-rate intracavitary brachytherapy (HDR-ICBT). Patients with positive para-aortic or common iliac nodes (>=10 mm in the shortest diameter, as evaluated by CT/MRI) were ineligible for the study. Fifty-seven patients (33%) had clinically positive pelvic nodes. The median maximum diameter of the nodes was 15 mm (range, 10-60 mm) and the median number of positive lymph nodes was two (range, one to four). Fifty-two of 57 patients (91%) with positive nodes were treated with boost EBRT (6-10 Gy in three to five fractions). The median prescribed dose of EBRT for nodes was 56 Gy. The median follow-up time for all patients was 66 months (range, 3-142 months). The 5-year overall survival rate, disease-free survival rate and pelvic control rate for patients with positive and negative nodes were 73% and 92% (P = 0.001), 58% and 84% (P < 0.001), and 83% and 92% (P = 0.082), respectively. Five of 57 node-positive patients (9%) developed pelvic node recurrences. All five patients with nodal failure had concomitant cervical failure and/or distant metastases. No significant difference was observed with respect to the incidence or severity of late complications by application of boost EBRT. The current retrospective study demonstrated that boost EBRT to positive pelvic nodes achieves favorable nodal control without increasing late complications. PMID- 23365265 TI - Interactions of Saccharomyces cerevisiae fermentation product and in-feed antibiotic on gastrointestinal and immunological responses in piglets challenged with Escherichia coli K88+. AB - Interactive effects between in-feed antibiotics (PC; 0.04% chlortetracycline + 0.004% Denagard) and a Saccharomyces cerevisiae fermentation product (XPC) were investigated. Five pens of 3 pigs/pen were randomly allotted to one of six diets consisting of control (NC; no additives), XPC alone (0.2%), PC alone, or PC plus one of three levels of XPC (0.1, 0.2, or 0.4%). On day 7, all pigs were bled for baseline serum and then orally inoculated with a 6-mL dose of 2 x 10(9) cfu/mL of ciprofloxacin-resistant Escherichia coli K88(+) (ETEC). Severity of diarrhea, using fecal score (FS), was assessed on days 8, 9, and 10. On day 10, pigs were bled and 1 pig/pen was killed to obtain gastrointestinal (GIT) samples. Remaining pigs were monitored for another 4 d and then killed to obtain GIT samples. Pigs fed PC and XPC in combination of PC had a lower (P = 0.02) FS than NC. The PC pigs had lower (P = 0.02) serum interleukin-6 and XPC pigs had higher (P < 0.01) serum tumor necrosis factor-alpha than NC pigs. Ileal mucosal ETEC count was lower on day 10 (P = 0.04) and day 14 (P < 0.01) when additives were fed in combination. Microbiome analysis of day 10 digesta using pyrosequencing showed that pigs fed the PC with XPC had enriched (P = 0.01) Streptococcaceae family than PC fed alone. On day 10, pigs fed PC alone and in combination with XPC at a lower dose had shallower (P = 0.01) crypt depth than those fed higher doses of XPC, XPC alone, or NC. Pigs fed XPC had a thicker colon wall on day 10 (P < 0.01) compared to those fed non-XPC diets. Ileal and colonic digesta NH(3) concentration was lower (P < 0.05) for pigs fed additives-containing diets on days 10 and 14. Feeding PC or XPC reduced diarrhea and the number of ETEC attached to the ileal mucosa; however, responses suggest independent and interactive effects that might be associated with the nature of these additives. PMID- 23365266 TI - Epidermal growth factor-expressing Lactococcus lactis enhances growth performance of early-weaned pigs fed diets devoid of blood plasma. AB - The effect of supplementing Lactococcus lactis (L. lactis) that was engineered to express epidermal growth factor (EGF-LL) to early-weaned pigs fed diets with typical levels of blood plasma (5%) or diets without blood plasma [blood plasma was substituted with soybean (Glycine max) meal and fish meal, based on amino acid supply] was examined. A total of 108 weaned piglets (19-26 d of age; mean initial BW 6.58 kg; 9 pigs per pen) were fed ad libitum according to a 2-phase feeding program without growth promoters. Three pens were assigned to each of 4 treatments: i) blood plasma-containing diet with blank bacterial growth medium (BP-Con), ii) blood plasma-containing diet with fermented EGF-LL (BP-EGF), iii) blood plasma-free diet with blank bacterial growth medium (BPF-Con), and iv) blood plasma-free diet with fermented EGF-LL (BPF-EGF). The amount of epidermal growth factor (EGF) was determined in the fermentation product and pigs were allotted 60 MUg EGF/kg BW/d for 3 wk postweaning. There were no differences in overall growth performance between BP-Con and BP-EGF pigs and no differences in overall growth performance between LoCon and BPF-EGF pigs. Pigs fed BPF-EGF showed increased daily BW gain (410 vs. 260 g/d; P < 0.01) and gain:feed (0.67 vs. 0.58; P < 0.05) compared to BPF-Con pigs in wk 3 postweaning; this was comparable to values for the BP-Con group (400 g/d and 0.64). These results indicate that supplementation with EGF-LL can be effective in enhancing the performance of early-weaned piglets fed a low complexity diet and reduces the need for feeding high-quality animal proteins and antibiotics. PMID- 23365267 TI - Effect of feeding piglets with different extruded and nonextruded cereals on the gut mucosa and microbiota during the first postweaning week. AB - Two trials were conducted to evaluate the effect of different cereals in piglet diets on the jejunal mucosa and the ileal and cecal microbiota during the first postweaning days. In Trial 1, 48 newly weaned pigs (7.95 kg BW; 26 d of age) were individually housed and distributed among 3 experimental diets containing white rice (Oryza sativa), naked oats (Avena sativa), or barley (Hordeum vulgare) as the cereal source. At the start of the trial (weaning; day 0), 12 piglets were slaughtered and sampled to obtain initial reference values for histology and microbiology determinations. Additionally, 4 pigs per treatment per day were slaughtered and sampled at days 1, 2, and 6 postweaning. Villus height (VH), crypt depth (CD), and intraepithelial lymphocytes (IEL) in jejunal mucosa were measured, and microbiota in ileal and cecal digesta were evaluated by RFLP. The Manhattan distances between RFLP profiles were calculated and, for each treatment and sampling day, intragroup similarities (IGS) were estimated. In Trial 2, an additional 48 piglets were used (7.56 kg BW; 26 d of age), and the same experimental procedures were performed except that the 3 experimental diets contained extruded white rice, extruded naked oats, or extruded barley as the cereal source. A reduction in VH was observed in both trials from day 0 to 6 (P < 0.05). In Trial 1 (raw cereals), more IEL and deeper crypts were observed for the barley than for the naked oats based diets (P < 0.05). In Trial 2, no differences among extruded cereals were observed for the histological parameters. In Trial 1, feeding naked oats resulted in lower IGS (increased heterogeneity) of the microbiota in the ileum and in the cecum compared to rice and barley (P < 0.05). In Trial 2, the pigs fed extruded barley had lower IGS in the ileum than those fed extruded naked oats and extruded rice whereas in the cecum, both extruded barley and extruded rice resulted in lower IGS than extruded naked oats (P < 0.05). It is concluded that cereal nature affects the composition of the microbiota and the morphology of the gut mucosa in newly weaned pigs. PMID- 23365268 TI - G protein-coupled receptor120 (GPR120) transcription in intestinal epithelial cells is significantly affected by bacteria belonging to the Bacteroides, Proteobacteria, and Firmicutes phyla. AB - Free fatty acids (FFA) are produced in the intestine by microbial fermentation. Recently, a family of G protein-coupled receptors (GPR) acting as FFA transporters has been reported including GPR120, which is expressed by intestinal epithelial cells. The GPR120 has been reported to affect the expression of glucagon-like peptide (GLP)-1 as well as function as a control point for anti inflammatory effects. The aim of the present study was to evaluate whether 12 selected intestinal bacteria, representing the 4 major phyla present in the intestine, affect intestinal epithelial cell GPR120 and GLP-1 mRNA abundance. Supernatants of the 12 bacteria were added to differentiated Caco-2 intestinal epithelial cells cultured on filter inserts in concentrations corresponding to a cell:bacteria ratio of 1:200. After 4 h of incubation, changes in cellular mRNA of GLP-1 and GPR120 by bacterial supernatant were examined using real-time reverse transcriptase polymerase chain reaction. The abundance of GLP-1 mRNA decreased when cells were exposed to 4 of the 12 supernatants (P <= 0.05) compared with cells without bacteria added. Supernatants from 8 of the 12 bacteria analyzed increased the mRNA level of GPR120 (P <= 0.05) compared with cells without bacteria added. The alteration in cellular GPR120 mRNA was observed with bacteria categorized as either probiotics or bacteria capable of inducing an anti-inflammatory effect. The beneficial effect of these bacteria may very well be mediated by regulation of GPR120. The regulation of GPR120 by intestinal microbiota represents a direct signaling pathway for gut bacteria to affect host health and metabolism. PMID- 23365269 TI - Effect of wheat distillers dried grains with solubles or sugar beet pulp on prevalence of Salmonella enterica Typhimurium in weaned pigs. AB - Salmonella enterica Typhimurium (ST) is of concern in the swine industry with relevance for animal health and consumer safety. Nutritional strategies might help to reduce ST infection and transmission. This study examined the potential of wheat (Triticum aestivum) distillers dried grains with solubles (DDGS) and sugar beet (Beta vulgaris) pulp (SBP) to alter intestinal microbial communities and ST shedding using a Trojan model. Weaned pigs (n = 105; 28.5 +/- 3.5 d of age) were separated into 3 treatment groups (7 pigs/pen) and fed a wheat-based control diet or the control diet formulated with 15% wheat DDGS or 6% SBP inclusion. Following 12 d of diet adaptation, 2 pigs/pen were inoculated with 2 x 10(9) cfu ST, resistant to novobiocin and nalidixic acid. Fecal swabs were taken from infected pigs and pen-mates (contact pigs) for 9 d following challenge, enriched in nutrient broth for 24 h, and plated on selective media to determine prevalence of ST. The ranges of prevalence of ST in feces were from 90 to 100% in challenged pigs and 74 to 78% in contact pigs. No influence of treatment on rectal temperature and prevalence of ST in contact pigs were observed. Fifteen contact pigs were euthanized per treatment group on 9 and 10 d postchallenge to enumerate in intestinal contents (ileum, cecum, and proximal colon), Lactobacillus spp., Enterobacteriaceae, and Clostridium clusters I, VI, and XVIa by quantitative PCR (qPCR) and to determine ST prevalence by selective culture. No significant effects of diet were observed with respect to ST prevalence in feces, ileum, cecum, colon, and lymph nodes of contact pigs. Compared with the control diet, DGGS and SBP diets showed a trend towards increased (P < 0.1) number of Lactobacillus species in the cecum and colon. Although both wheat DGGS and SBP tended to increase the Lactobacillus spp. neither of the feed ingredients affected ST prevalence. PMID- 23365270 TI - The influence of grinding intensity and compaction of diets on the microbial community in the gastrointestinal tract of young pigs. AB - Sixty weaned piglets (33 d, 7.96 +/- 1.09 kg BW) were divided into 4 groups with 15 pigs each and fed identical diets in which meal was coarsely ground (CM), coarsely ground and pelleted (CP), finely ground and pelleted (FP), or coarsely ground and extruded (CE) for 4 wk. At the end of the trial the pigs were killed and samples of the digesta were taken from the stomach, the end of the small intestine, and the cecum for microbiological, DM, pH, and lactic acid analyses. Differences (P < 0.05) regarding the counts of bacteria were mainly found between the CM and the FP group, but the CP and the CE diet mostly resulted in intermediate values. Pigs fed the CM diet had the highest numbers of lactobacilli in the stomach content (P < 0.01) and the cecal digesta (P < 0.05). Perhaps due to a more efficient stomach barrier, characterized by high lactobacilli counts and a marked pH gradient in the stomach content (cardia, 5.15 +/- 0.475; pylorus, 2.83 +/- 1.06; P < 0.01), the lowest counts of coliform bacteria were found in the distal part of the small intestine in pigs fed the CM diet (P < 0.05). PMID- 23365271 TI - Effect of feeding level on the composition of the intestinal microbiota in weaned piglets. AB - In piglets, the development and composition of intestinal microbiota is influenced by dietary factors. A considerable reduction in feed intake during the transition from liquid to solid feed is often accompanied by postweaning diarrhea. Therefore, it is hypothesized that variations in feeding level during weaning may affect intestinal microbial composition. Forty-eight piglets fitted with simple ileal T-cannulas were used to examine the effects of a high (60 g/kg BW) and a low (30 g/kg BW) feeding level on the composition of the ileal and fecal microbiota. The assay diets contained graded inclusion levels of soybean (Glycine max) meal or casein. Bacterial cell numbers of total eubacteria, Lactobacillus spp., and the mainly proteolytic Clostridium leptum, Clostridium coccoides, Enterobacteriaceae, and Bacteroides-Prevotella-Porphyromonas group (Bacteroides group) of feces and ileal digesta were determined by use of real time PCR. There were no interactions between feeding level and protein source except for the Bacteroides group in ileal digesta. Ileal cell numbers of lactobacilli were increased (P < 0.001) at the higher feeding level. In contrast, ileal cell numbers of Clostridium coccoides were lower (P < 0.001) at the higher feeding level. There were no differences of bacterial cell numbers in feces. Results indicate that feeding level affects microbial composition in the small intestine. Also, sufficient feed intake during weaning encourages proliferation of beneficial bacteria, thereby contributing to improved gut health. PMID- 23365272 TI - Assessment of RNA integrity in the postmortem pig colonic tissue ex vivo. AB - Surgical removal of porcine intestinal tissue followed by an ex vivo challenge is an alternative technique of testing the anti-inflammatory effect of bioactive compounds in the intestine of live pigs. We investigated the effects of ex vivo incubation of porcine colonic tissue on the quantity and quality of total RNA over a 12-h time period. Colonic tissue of pig (n = 6) was surgically removed immediately postslaughter and incubated for 0, 3, 6, and 12 h in a humidified cell culture incubator with 5% CO(2) at 37 degrees C. Tissue samples were processed for RNA extraction. The quantity and quality of total RNA were assessed on a NanoDrop Spectrophotometer and an Agilent 2100 Bioanalyzer, respectively. Ex vivo incubation had an effect on both the quantity (P < 0.001) and quality (P < 0.001) of total RNA. Relative to the RNA yield at 0 h (505.0 +/- 48.64 MUg/mg), the yield was significantly reduced after 6 h (227.6 +/- 25.52 MUg/mg; P < 0.001) and 12 h (159.3 +/- 24.19 MUg/mg; P < 0.001) of incubation. The 28S and 18S rRNA bands were visibly intact after 0, 3, and 6 h of incubation. However, after 12 h of incubation, a degraded RNA profile was evident. The RNA integrity number (RIN) values for the 0, 3, 6, and 12 h of incubation were 9.4 +/- 0.10, 9.0 +/- 0.10, 6.7 +/- 0.17 (P < 0.001), and 3.3 +/- 0.24 (P < 0.001), respectively. The transcript abundances of 4 constitutively expressed genes glyceraldehyde 3 phosphate dehydrogenase (GAPDH), beta actin (ACTB), beta 2-microglobulin (B2M), and peptidylprolyl isomerase A (PPIA) were reduced at both 6 and 12 h of incubation. It is concluded that ex vivo incubation of porcine colonic tissue up to 3 h postmortem generates good quality total RNA suitable for gene expression studies. PMID- 23365273 TI - Expression of heat shock protein 27 in gut tissue of growing pigs fed diets without and with inclusion of chicory fiber. AB - The physiological expression of cytoprotective heat shock protein 27 (Hsp27) in the gut was investigated in eighteen 7-wk-old pigs fed one of 3 fiber-rich diets for 18 d. The diets were a cereal-based control diet and a cereal-based diet with inclusion of either 80 g/kg chicory forage (CF80) or chicory root (CR80). Immunohistochemical staining showed that Hsp27 was expressed in all the samples from ileum and colon. The expression was most intensive in the apical intestinal epitheliums in close contact with luminal contents and lighter in crypt cells. The ileal Peyer's patches showed a strong expression of Hsp27, which was highly correlated with Hsp27 expression in the ileal epithelial cells (P = 0.003). The frequency of ileal Hsp27 expression with the most intensive staining was distributed higher in pigs fed chicory forage diet (CF80, 25%) followed by chicory root diet (CR80, 16.7%) and the control (11.1%). In proximal colon, the frequency of expression showed a similar pattern for the different diets. The intestinal microbiota profile was characterized with the intention to find correlations to heat shock protein (Hsp) expression in pig gastrointestinal (GI) tract and showed that the distal ileum and proximal colon encompass its own unique microbial profile. However, no significant relationship was found between gut microbiota diversity and Hsp27 expression. These indicate that Hsp27 expression in the porcine gut could be associated with specific dietary fiber components but not the overall microbiota diversity. PMID- 23365274 TI - The microbiological and immunomodulatory effects of spray-dried versus wet dietary supplementation of seaweed extract in the pig gastrointestinal tract. AB - Seaweeds and seaweed extract (SWE) possess antimicrobial, anti-inflammatory, prebiotic, and growth-promoting properties. Extracts can be prepared in different ways including wet, spray-dried, and freeze-dried forms. The aim of this study was to determine if spray drying of laminarin and fucoidan derived from Laminaria digitata had an effect on the microbiological and cytokine profile of the gastrointestinal tract (GIT) compared to the wet SWE in newly weaned pigs. No differences in cytokine expression were observed between wet and spray dried SWE formulation in either the ileum or colon. Bifidobacteria counts were greater (P < 0.05) in the wet SWE formulation relative to both spray dried SWE and the basal diet in the ileum. In conclusion, neither of the SWE formulations had significant effects on the cytokine profile in the ileum or colon. However, a prebiotic effect observed in the ileum of piglets in response to the wet SWE formulation was lost following spray drying of the SWE. PMID- 23365275 TI - Effect of feeding different cereal-based diets on the performance and gut health of weaned piglets with or without previous access to creep feed during lactation. AB - A trial was conducted to evaluate the effect of different cereals on the performance, gut mucosa, and microbiota of weanling pigs with or without previous access to creep feed during lactation. A total of 108 newly weaned pigs (7.4 kg BW; 26 d of age; half with and half without creep feed) were used. Piglets were distributed by BW into 36 pens according to a 2 * 6 factorial arrangement of treatments with previous access to creep feed (with or without) and cereal source in the experimental diet [barley (Hordeum vulgare), rice (Oryza sativa)-wheat (Triticum aestivum) bran, corn (Zea mays), naked oats (Avena sativa), oats, or rice] as main factors. Pigs were offered the experimental diets for 21 d and performance was monitored. At day 21, 4 piglets from each treatment were killed and sampled for the histological evaluation of jejunal mucosa and the study of ileal and cecal microbiota by RFLP. The Manhattan distances between RFLP profiles were calculated and intragroup similarities (IGS) were estimated for each treatment. An interaction between cereal source and previous creep feeding was observed for ADFI (P < 0.05), indicating that whereas creep feeding increased ADFI for the rice-wheat bran diet it reduced it for naked oats. No differences in mucosal morphology were observed except for deeper crypts in pigs that did not have previous access to creep feed (P < 0.05). Cereal source had a significant effect on IGS of ileal and cecal microbiota (P < 0.01). In the ileum oats and corn had the highest IGS (i.e., lowest heterogeneity of the microbiota) followed by rice, naked oats, barley, and rice-wheat bran whereas in the cecum, IGS was highest for rice and oats followed by corn, barley, rice-wheat bran, and naked oats. An interaction between creep feeding and cereal was also observed for the IGS of the cecal microbiota at day 21 (P < 0.05). Access to creep feed reduced IGS in the piglets fed oats or barley but no differences were observed for the other cereal sources. It is concluded that the effect of creep feeding during lactation on the performance and the microbiota of piglets after weaning is dependent on the nature of the cereal in the postweaning diet. PMID- 23365276 TI - Influence of fermentable carbohydrates or protein on large intestinal and urinary metabolomic profiles in piglets. AB - It was recently shown that variations in the ratio of dietary fermentable carbohydrates (fCHO) and fermentable protein (fCP) differentially affect large intestinal microbial ecology and the mucosal response. Here we investigated the use of mass spectrometry to profile changes in metabolite composition in colon and urine associated with variation in dietary fCHO and fCP composition and mucosal physiology. Thirty-two weaned piglets were fed 4 diets in a 2 * 2 factorial design with low fCP and low fCHO, low fCP and high fCHO, high fCP and low fCHO, and high fCP and high fCHO. After 21 to 23 d, all pigs were euthanized and colon digesta and urine metabolite profiles were obtained by mass spectrometry. Analysis of mass spectra by partial least squares approach indicated a clustering of both colonic and urinary profiles for each pig by feeding group. Metabolite identification and annotation using the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways revealed increased abundance of metabolites associated with arachidonic acid metabolism in colon of pigs fed a high concentration of fCP irrespective of dietary fCHO. Urinary metabolites did not show as clear patterns. Mass spectrometry can effectively differentiate metabolite profiles in colon contents and urine associated with changes in dietary composition. Whether metabolite profiling is an effective tool to identify specific metabolites (biomarkers) or metabolite profiles associated with gut function and integrity needs further elucidation. PMID- 23365277 TI - Soybean oligosaccharides alter colon short-chain fatty acid production and microbial population in vitro. AB - This study was conducted to the determine fermentation characteristics of soybean oligosaccharides (SBOS) in an in vitro system. Digesta collected from the colon of Huanjiang mini-pigs was used as inoculums, and SBOS (0.2 g per 10 mL fermentation broth) was used as substrate during the in vitro fermentation. The inoculum or inoculum + glucose (0.2 g) was used as negative or positive control, respectively. The slurry was fermented in an anaerobic chamber and gas production (GP) recording was taken after 48 h of incubation by referring to the moving scale on the plunger of the glass syringes, and then GP parameters, pH value, NH(3)-N content, short chain fatty acid (SCFA) levels, and microbial community in the fermentation broth were determined. For gas production parameters, pH, and fermentation product determination after 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 42, and 48 h of incubation, SBOS and glucose demonstrated similar responses compared to control including increase maximal gas production, decreased lag time, decreased pH, and accumulation of NH(3) and increased SCFA. The exception was rate of GP, which was higher (P < 0.05) for SBOS compared with glucose. Incubation with SBOS increased (P < 0.05) the microbial diversity and population of Bifidobacterium and Lactobacillus but decreased (P < 0.05) Escherichia and Streptococcus when compared with incubation with glucose. These findings suggested that the SBOS can improve the gut microbiota balance in colon and modulate its metabolism. PMID- 23365278 TI - Effects of dietary beta-glucans supplementation on cytokine expression in porcine liver. AB - As dietary supplementation with beta-glucans can stimulate the innate immune response in the porcine gastrointestinal system (GIT), the aim of this study was to determine if the effects of beta-glucan supplementation extend beyond the GIT to systemic levels. Hence, the effects of dietary supplementation of beta-glucans derived from Laminara digitata, Laminara hyperborea, and Sacharomyces cerevisiae on cytokine expression in the porcine liver with or without ex vivo lipopolysaccharide (LPS) challenge were examined. No significant differences in gene expression were observed in the unchallenged liver tissue, but differences were observed in all supplementation groups in the LPS challenged tissue. Relative to the basal diet, IL-6 (P < 0.05) was less expressed in the S. cerevisiae supplementation group, IL-6 (P < 0.05) and TLR-4 (P < 0.05) were less expressed in the L. digitata supplementation group, and IL-10 (P = 0.06) and IL 1alpha (P = 0.02) were more expressed in the L. hyperborea supplementation group. There was a ~ 3-fold increase in both IL-10 and IL-1alpha in the liver samples of L. hyperborea relative to the L. digitata supplementation groups (P < 0.01). The results indicate that supplementation with beta-glucans from both yeast and seaweed sources have systemic effects evidenced by changes in cytokine expression in the liver in response to LPS challenge; however, the cytokines affected varied according to the source of the beta-glucan. PMID- 23365279 TI - Escherichia coli challenge in newborn pigs. AB - Escherichia coli F18 is a common porcine enteric pathogen causing diarrhea and edema in weaned pigs. An essential step in the pathogenesis of this enteric colibacillosis is a fimbria-receptor interaction in the small intestine, involving the alpha(1,2)-fucosyltransferase gene (FUT1) enzyme for bacterial receptor binding to the epithelium. Enzyme expression is genetically determined and increases after weaning at 3 to5 wk, probably due to age- and/or diet-related intestinal maturation. We hypothesized that artificially reared piglets, deprived of sow's milk from birth, show susceptibility to F18 already in the neonatal period. First we verified the intestinal expression of FUT1 in preterm, term, and weaned pigs by quantitative real-time polymerase chain reaction. Then age-related F18 susceptibility (degree of diarrhea) was evaluated in 3-, 10-, and 20-d-old pigs after inoculation of 10(10) cfu E. coli F18 per day for 12 d. Finally, F18 susceptibility was evaluated in caesarean-delivered 0- to 7-d-old piglets inoculated daily with F18 as above. For all pigs, their sows were genotyped to ensure expression of the FUT1 enzyme. FUT1 expression was detected in the proximal and distal small intestine with no apparent differences in levels among preterm, term, and weaned pigs. No consistent F18-induced diarrhea was detected in any of the 3 groups of 3- to 20-d-old pigs. In contrast, 0- to 7-d-old caesarean-delivered pigs showed a higher score of diarrhea in pigs inoculated with F18 compared with controls (2.4 +/- 0.1 vs. 1.8 +/- 0.1 respectively; P < 0.001). Caesarean-delivered piglets deprived of sow milk are highly susceptible to diarrhea induced by E. coli F18. Lack of the protective effects of birth colonization and sow milk may contribute to high intestinal F18 sensitivity. The newborn pig may be a useful model to investigate factors in maternal milk that protect against F18 diarrhea. PMID- 23365280 TI - Extracts of brown seaweeds can attenuate the bacterial lipopolysaccharide-induced pro-inflammatory response in the porcine colon ex vivo. AB - Bioactive compound-rich brown seaweeds are demonstrated to have numerous health benefits including anti-microbial and immunomodulatory bioactivities in the pig intestine. In this study, the immunomodulating effects of extracts of brown seaweed (Ascophyllum nodosum and Fucus serratus) were evaluated on the porcine colon using a bacterial lipopolysaccharide (LPS) ex vivo model. Approximately 1.5 * 1.5 cm of pig colon (n = 6) was stripped of its overlying muscle layer and incubated in 1 mL Dulbecco's Modified Eagle Medium containing bacterial LPS (10 MUg) and seaweed extracts (1 mg). Gene expression of interleukin-8 (IL-8) and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFA) were measured using quantitative real time PCR. In contrast to the low level of expression of IL-8, IL-6, and TNFA genes in the colonic tissue at 0 h, LPS treatment increased (P < 0.05) the expression of IL-8, IL-6, and TNFA genes to 2.38 +/- 0.86, 1.90 +/- 0.66, and 1.90 +/- 0.57 fold, respectively. This pro-inflammatory response induced by the LPS was suppressed by the extracts of Ascophyllum. Ascophyllum extract reduced (P < 0.05) the expression of IL-8, IL-6, and TNFA genes to 0.99 +/- 0.53, 0.75 +/- 0.33, and 1.01 +/- 0.17 fold, and Fucus extract reduced (P < 0.05) the expression of the corresponding genes to 0.70 +/- 0.32, 0.69 +/- 0.38, and 1.15 +/- 0.25 fold, respectively. It is concluded that the extracts of Ascophyllum and Fucus seaweeds have potential to suppress the pro-inflammatory response induced by the bacterial LPS in the pig colon. PMID- 23365281 TI - Starch and fiber properties affect their kinetics of digestion and thereby digestive physiology in pigs. AB - Traditionally in swine nutrition, analyses of starch and fiber have focused on assessing quantity; however, both have a wide range of functional properties making them underappreciated nutrients. Starch ranging from low to high amylose changes from rapidly digestible in the upper gut to poorly digestible but fermentable in the lower gut thereby changing from a source of glucose to VFA source. Likewise, fibers ranging from low to high viscosity affect digesta flow and from slowly to rapidly fermentable alter production of VFA serving as energy for the gut or whole body. Our hypothesis is that total extent, kinetics, and site of digestion or fermentation of starch and fiber are important for whole body nutrient use and intestinal health. To elucidate their effects, we developed in vitro, lab-based methodologies to describe kinetics of digestion and fermentation and linked these with in vivo models including i) ileum cannulation to collect digesta, ii) portal-vein catheterization to sequentially sample blood, iii) slaughter method to collect site-specific intestinal tissue and digesta, and iv) indirect calorimetry. Using these methods, kinetics of nutrient absorption was associated with pancreatic and intestinal hormones released into the portal vein, intestinal microbiota, and gene expression in intestinal tissue and microbiota. These studies confirmed that slowly digestible starch is partially degraded in the distal small and large intestine and fermented into VFA including butyrate (10-fold increase in net portal appearance), which reduces insulin responses by 60% and whole body energy use. Starch entering the distal intestine altered mRNA abundance of nutrient transporters and was bifidogenic. Extremely viscous purified fiber dampened glycemic responses and reduced digesta passage rate by 50% thereby increasing ileal digestion of dietary nutrients whereas increased fiber in feed grains reduced nutrient digestibility. Fermentable fiber increased butyrate and insulin production. These methods will therefore support elucidation of mechanisms that link starch and fiber properties to whole body nutrient use and intestinal health. PMID- 23365282 TI - Modeling digestibility of dietary phosphorus in growing and finish pigs. AB - Low P digestibility combined with intensive pig production can lead to water pollution. The aim of this paper was to develop a model able to represent P digestion in pigs across diets and contribute towards the reduction of P excretion. Phosphorus in plant feedstuffs includes some nonphytate P (NPP) that is readily digested but is mostly as organic phytate P (oP) that is indigestible unless it is dephosphorylated. The ability of pigs to dephosphorylate oP using endogenous phytase enzymes is limited and is a function of Ca intake. The effect of Ca (g/kg diet) on the proportion of oP dephosphorylated (kg/kg) in the small intestine (SI) and large intestine (LI) was determined as 0.26 - (0.015 * dietary Ca) and 0.69 - (0.059 * dietary Ca), respectively. The dephosphorylated oP in the LI was assumed to be indigestible and was excreted. Proportion of oP dephosphosphorylation (kg/kg) by microbial and plant phytase activity (FTU) in the stomach was estimated to be 0.56 * [1 - exp(-0.001 * FTU)] and 0.38 * [1 - exp(-0.002 * FTU)], respectively. Phosphorus digestibility (kg/kg) of NPP and dephosphorylated oP in the SI was assumed to be constant at 0.8. The model was used to predict P digestibility in 2 experiments by Stein et al. (2011) and Poulsen et al. (2010) and compare the predictions with experimental outcomes. The model successfully predicted the P digestibility to a range of dietary Ca concentrations and for 2 levels of supplementation with microbial phytase. However, the predictions overestimated P digestion systematically but always within a 10% margin of the observed values. The model could be a useful tool for formulating strategies to improve the efficiency of P digestion and reduce soluble P excretion in pigs. PMID- 23365283 TI - The impact of lower gut nitrogen supply on nitrogen balance and urea kinetics in growing pigs fed a valine-limiting diet. AB - An N-balance and isotope dilution study was performed to determine the effect of lower gut N supply on N retention and CO(NH(2))(2) kinetics in growing pigs. Nine cecally cannulated and jugular-catheterized barrows (initial BW 22.4 +/- 1.2 kg) were randomly assigned to 1 of 3 cecal N infusion treatments: saline, casein, or CO(NH(2))(2); the latter 2 treatments were infused at a rate of 40% of daily N intake. All pigs were fed a Val-limiting corn (Zea mays) starch and soybean (Glycine max) meal-based diet. Cecal N infusions did not affect apparent total tract digestibility of N (P > 0.05). The efficiency of using N [% of apparent ileal digestible intake; 72.9 +/- 1.9, 84.9 +/- 1.9, and 85.6 +/- 2.3% (P = 0.01) for saline, casein, and CO(NH(2))(2), respectively] and Val (76.9 +/- 1.9, 86.5 +/- 1.9, and 86.5 +/- 2.4; P = 0.02) for whole body protein and Val retention increased for casein and CO(NH(2))(2). Urea flux and urinary N excretion increased (P < 0.05) similarly for both N infusions, but this increase did not fully account for lower gut N disappearance. Lower gut N disappearance is in the form of NPN, which can be used for microbial AA production in the upper gut and should be considered when determining N and AA supply and requirements. PMID- 23365284 TI - Molecular weight distribution of soluble fiber fractions and short chain fatty acids in ileal digesta of growing pigs. AB - The effect of dietary fiber source on molecular weight (MW) distribution of soluble fiber fractions and short chain fatty acids (SCFA) in ileal digesta of 7 post valve T-cecum (PVTC) cannulated growing pigs was studied. Pigs were fed semisynthetic diets with sugar beet (Beta vulgaris) pulp (SBP) or chicory (Cichorium intybus) forage (CFO) as fiber sources of which the soluble nonstarch polysaccharide (NSP) fraction originated mainly from pectin. Three MW intervals were selected-large MW (MWL): 10,000,000 to 1,000,000 g/mol, medium MW (MWM): 1,000,000 to 200,000 g/mol, and small MW (MWS): 200,000 to 10,000 g/mol-and the relative distribution (% of total) of molecules in each interval was calculated. The MWM fraction was higher (P < 0.05) in ileal digesta of pigs fed diet SBP and the MWS fraction was higher (P < 0.05) in ileal digesta of pigs fed diet CFO. The mole/100 mole of propionic acid (HPr) was higher (P < 0.010) in pigs fed diet SBP whereas pigs fed diet CFO had higher (P < 0.010) mole/100 mole of acetic acid (HAc). The proportion of the MWL and MWM fractions in ileal digesta were negatively correlated to HAc (r = -0.52, P = 0.05, and r = -0.62, P = 0.02, respectively). The proportion of MWM in ileal digesta was positively correlated to HPr (r = 0.83; P = 0.001) whereas MWS and HPr were negatively correlated (r = 0.76; P = 0.002). In conclusion, the bacterial degradation of the soluble NSP fraction is selective and MW distribution may explain differences in SCFA production. PMID- 23365285 TI - The contribution of portal drained viscera to circadian homocysteinemia in pigs. AB - Homocysteine (Hcy) is an intermediary S-containing amino acid produced by the methylation process within all cells. It is known as a powerful pro-oxidant with multiple deleterious effects on immune and physiological functions. Blood plasma total Hcy (tHcy), the most common indicator of Hcy status, can be reduced by dietary folates or vitamin B(12) in pigs as in most mammalians. In humans, homocysteinemia is routinely assessed after an overnight fast (>= 12 h) although information is not available on circadian tHcy changes. Using a subgroup of pigs from a study on portal appearance of vitamin B(12) after a single meal containing 0, 25 or 250 MUg of cyanocobalamin, the present study aimed to report the circadian profile of postmeal blood plasma tHcy and estimate the contribution of portal drained viscera (PDV) to the systemic tHcy. Four pigs (39.7 +/- 1.1 kg BW) were surgically equipped at 101.0 +/- 8.2 d of age with catheters in the portal vein and carotid artery; an ultrasonic flow probe was also fitted around the portal vein for blood flow recordings. Blood samples were collected simultaneously from the 2 catheters once before meal and at least every hour during 24 h after ingestion of 1.2 kg of a vitamin-free semipurified diet. Arterial tHcy changed considerably during the 24-h postmeal period (P < 0.001; SE = 0.8). In fact, from 12.3 MUM 10 min before meal, tHcy gradually reached a maximum of 23.4 MUM 13 h postmeal and returned to 15.5 MUM 23 h after the meal. Net fluxes of tHcy across PDV were not influenced by levels of dietary vitamin B(12), postprandial time, or their interaction (P > 0.25); average net flux did not differ from zero (P > 0.08). These results suggest that systemic Hcy following a meal originates from metabolic pools other than PDV. It appears that an overnight fast of 12 h will reflect the peak rather than the basal value for tHcy. The duration of the fasting period is therefore a critical factor for a reliable interpretation of tHcy homeostasis in pigs. Such information may be also relevant for human health and nutrition because pig is recognized as a reliable model for Hcy metabolism. PMID- 23365286 TI - Dietary energy density affects the preference for protein or carbohydrate solutions and piglet performance after weaning. AB - Physiological state or dietary nutrient content can be determinants of the sensory perception with consequences for feed preferences. The aim of the present study was to assess whether the preference for protein or carbohydrate of piglets is affected by dietary energy density. In total, 240 weanling piglets (28 d old; initial BW 7.2 +/- 1.1 kg) were allocated to 24 pens (10 pigs/pen) according to BW. Piglets were split up into 2 groups and had ad libitum access to a high energy (HE; 3.90 Mcal DE/kg; crude fat 129 g/kg) or a low energy (LE; 3.35 Mcal DE/kg; crude fat 60 g/kg) diet with similar CP content (190 g/kg). Piglet performance and preference for protein [porcine digestible peptides (PDP; Palbio 62SP, Bioiberica, Palafolls, Spain) 20 g/L] or carbohydrate (sucrose 20 g/L) solutions were measured on days 14 and 21 after weaning using a double-choice test (DCHT). The LE diet promoted a higher (P < 0.05) ADFI and ADG than the HE diet. Final BW on day 21 was higher (P < 0.001) for piglets fed the LE diet than piglets fed the HE diet (12.8 vs. 11.5 kg). Preference (P > 0.05) was not observed for protein or carbohydrate solutions on day 14 or 21 in piglets fed the LE diet. On the other hand, piglets fed the HE diet had higher (75% on day 14 and 65% on day 21; P < 0.01) preference for the sucrose solution. Dietary energy level and consequent nutrient imbalances, such as dietary protein-to-energy ratio, may affect feed preference for protein or carbohydrate solutions in piglets. PMID- 23365287 TI - Supplementation of barley-based diets with beta-glucanase for pigs: energy and amino acid digestibility response. AB - An experiment was conducted to determine the effect of graded levels of beta glucanase supplementation to barley (Hordeum vulgare)-based diets on the digestibility of DM, GE, N, and AA for growing-finishing pigs. Eight pigs (initial BW: 53.3 +/- 3.2 kg) were each fitted with a simple T-cannula at the distal ileum and allotted to a replicated 4 * 4 Latin square design with 4 diets and 4 periods in each square. Diets were based on a barley-soybean (Glycine max) meal (SBM) basal diet (BD) containing 199 g CP and 3286 kcal DE per kilogram of diet. Treatments consisted of the BD and the BD supplemented with 10,000 (10K), 20,000 (20K), or 30,000 (30K) units of beta-glucanase per kilogram at the expense of corn (Zea mays). Chromic oxide (0.5%) was included as an indigestible marker. Each experimental period consisted of 4 d of adaptation, 1 d of feces collection, and 2 d of ileal digesta collection. Apparent total tract digestibility (ATTD) of DM ranged from 81.0 to 82.5% and was not affected by beta-glucanase supplementation. In the BD, ATTD of GE and N was 83.1 and 83.3%, respectively, and was not different in the BD supplemented with up to 30K units of beta glucanase per kilogram at 83.4 and 83%, respectively. Increasing levels of beta glucanase supplementation to the barley-SBM-based diet did not affect the ATTD of any criteria measured. Apparent ileal digestibility (AID) for DM, GE, and N ranged from 60.6, 65.4, and 70.8% (10K) to 66.4, 71.0, and 74.9% (20K), respectively. For indispensable AA, AID for Lys (79.9%) and Met (78.1%) was lowest in the BD supplemented with 20K and 10K units of beta-glucanase per kilogram, respectively, and was not different from the digestibility of Lys and Met in the diet with added 30K units of beta-glucanase per kilogram at 80.8 and 80.4%, respectively. There were neither significant linear nor quadratic effects of beta-glucanase supplementation to barley-SBM-based diets on the AID of DM, GE, N, and AA. In conclusion, beta-glucanase supplementation did not affect apparent ileal and total tract nutrient digestibility in grow-finish pigs fed a barley-SBM based diet. PMID- 23365288 TI - The supplementation of low-P diets with microbial 6-phytase expressed in Aspergillus oryzae increases P and Ca digestibility in growing pigs. AB - A trial was conducted to evaluate the dose response of a novel microbial 6 phytase expressed in Aspergillus oryzae (Ronozyme HiPhos; DSM Nutritional Products, Basel, Switzerland) in pigs. Forty-eight individually housed pigs (Landrace * Pietrain; 52 kg BW; 24 males and 24 females) were distributed among 6 experimental treatments consisting of a low-P diet (3.5 g P/kg; 1.1 g digestible P/kg), which was supplemented with 500, 1000, 2000, or 4000 units of phytase activity/kg, and a standard-P diet (4.5 g P/kg; 1.8 g digestible P/kg) that was supplemented with CaHPO(4). After 17 d, fresh feces were sampled from all pigs and the apparent total tract digestibility of DM, OM, ash, P, and Ca was measured using TiO(2) as indigestible marker. Blood samples were also obtained from each pig and serum was analyzed for P and Ca concentrations. The nonsupplemented low-P diet increased Ca and reduced P blood serum concentrations (P < 0.05) relative to the standard-P diet (10.8 vs. 10.2 and 6.7 vs. 7.7 mg/dL, respectively). Phytase supplementation of the low-P diet reduced Ca (from 10.8 to 9.9 mg/dL; linear, P < 0.001) and increased P concentrations (from 6.7 to 8.0 mg/dL; linear and quadratic, P < 0.001) in serum and reduced P concentration in feces (from 13.7 to 7.6 g/kg DM; linear and quadratic, P < 0.001). Phytase improved the total tract digestibility of P (from 29.0 to 62.3%; linear and quadratic, P < 0.001 and P < 0.05), Ca (from 54.0 to 75.7%; quadratic, P < 0.01), and ash (from 46.2 to 57.7%; quadratic, P < 0.01). In conclusion, the microbial 6-phytase tested improves the apparent total tract digestibility of P in growing pigs and reduces P excretion in feces in a dose-dependent manner. PMID- 23365289 TI - Slowly digestible starch influences mRNA abundance of glucose and short-chain fatty acid transporters in the porcine distal intestinal tract. AB - The relationship between starch chemistry and intestinal nutrient transporters is not well characterized. We hypothesized that inclusion of slowly instead of rapidly digestible starch in pig diets will decrease glucose and increase short chain fatty acid (SCFA) transporter expression in the distal gut. Weaned barrows (n = 32) were fed 4 diets containing 70% starch [ranging from 0 to 63% amylose and from 1.06 (rapidly) to 0.22%/min (slowly) rate of in vitro digestion] at 3 * maintenance energy requirement in a complete randomized block design. Ileal and colon mucosa was collected on day 21 to quantify mRNA abundance of Na(+) dependent glucose transporter 1 (SGLT1), monocarboxylic acid transporter 1 (MCT1), and Na(+)-coupled monocarboxylate transporter (SMCT). Messenger RNA was extracted and cDNA manufactured prior to relative quantitative reverse transcription PCR. Data were analyzed using the 2(-Delta DeltaC)(T) method, with beta-actin and glyceraldehyde-3-phosphate dehydrogenase as reference genes, and regression analysis was performed. As in vitro rate of digestion decreased, SGLT1 linearly increased (P < 0.05) in the ileum. Contrary to SGLT1, MCT1 tended to linearly decrease (P = 0.08) in the ileum and increased quadratically (P < 0.001) in the colon with decreasing rate of digestion. Starch digestion rate did not affect SMCT in the ileum; however, colonic SMCT quadratically decreased (P < 0.01) with decreasing rate of digestion. In conclusion, in contrast to our hypothesis, slowly digestible starch increased ileal glucose and decreased ileal SCFA transporter mRNA abundance, possibly due to an increased glucose in the luminal ileum. Effects of starch on colonic SCFA transporter mRNA abundance were inconsistent. PMID- 23365290 TI - Prececal digestibility of various sources of starch in minipigs with or without experimentally induced exocrine pancreatic insufficiency. AB - Low prececal digestibility of starch leads to a higher starch flux into the hindgut, causing a forced microbial fermentation, energy losses, and meteorism. For exocrine pancreatic insufficiency (EPI), lack of pancreatic amylase can be compensated mostly by hindgut fermentation of starch. Even in pigs with complete loss of pancreatic secretion, starch digestibility over the entire tract is reaching levels of controls. To optimize diets for human patients with EPI, the proportion of starch that is digested by the ileum is important. Minipigs were fitted with an ileocecal reentrant fistula (n = 8) to determine prececal digestibility of starch. In 5 minipigs the pancreatic duct was ligated (PL) to induce EPI; 3 minipigs served as controls (Con). Various starch sources were tested in a 1-d screening test; therefore, disappearance rate (DR) instead of digestibility was used. Test meals consisted of 169 g DM of a basal diet plus 67.5 g DM of the starch (without thermal treatment; purified; starch content of 89 to 94.5%) and Cr(2)O(3). The test meal contained (% of DM) starch, 67; crude fat, 1.69; CP, 15; crude fiber, 2.0; and Cr(2)O(3), 0.25. In PL, prececal DR of starch was lower than in Con (P < 0.05) for all starch sources. In Con, prececal DR of starch was almost complete (>90%) but was lower (P < 0.05) for potato (Solanum tuberosum) starch (75.4%). In PL, prececal DR of starch was higher (P < 0.05) for wheat (Triticum aestivum) starch (61.2%) than corn (Zea mays) starch (43.0%) and rice (Oryza sativa) starch (29.2%) and intermediate for potato and field pea (Pisum sativum) starch. For patients with EPI, wheat starch seems favorable due to the higher prececal digestibility whereas raw corn and rice starch should be avoided. PMID- 23365291 TI - Ileal digestibility of amino acids in coproducts of corn processing into ethanol for pigs. AB - Five barrows with an average initial BW of 45 kg and fitted with a T-cannula at the distal ileum were fed 5 diets to determine the standardized ileal digestibility (SID) of AA in corn (Zea mays) distillers' dried grains (DDG), DDG with solubles (DDGS), high-protein DDG (HPDDG) and high-protein DDGS (HPDDGS). On a DM basis, the test ingredients contained 33.7% CP, 19.2% ADF, and 53.1% NDF for DDG; 30.3% CP, 11.8% ADF, and 40.6% NDF for DDGS; 62.5% CP, 28.4% ADF, and 45.1% NDF for HPDDG; and 52.4% CP, 17.4% ADF, and 30.4% NDF for HPDDGS. The 5 diets consisted of a N-free diet (NFD) and 4 semipurified diets, in which the test ingredient was the sole protein source with chromic oxide added at 5 g/kg as an indigestible marker, and fed for each of 5 periods. The NFD was used to determine basal endogenous AA losses. Each period consisted of a 5-d adjustment period and 2 d of ileal digesta collection for 10 h on each of day 6 and day 7. Amino acids in the test ingredients were well digested by pigs and SID of Lys for DDG, DDGS, HPDDG, and HPDDGS were 88.6, 79.9, 94.6, and 85.8%, respectively. Corresponding values for were Met 93.9, 92.8, 97.1, and 94.6%. The SID of Lys was greater (P < 0.05) in HPDDG than DDGS. In general, digestibility of AA in the high-protein coproduct of the dry grind processing of corn into ethanol was 2 to 8 percentage units more than in the regular coproduct and 2 to 9 percentage units less in the coproduct with added solubles. PMID- 23365292 TI - Effect of L-valine supplementation to a wheat-based diet with leucine excess on performance, gene expression, and serum concentration of amino acids. AB - Excess Leu in the diet reduces the expression of the cationic AA transporter b(0,+), absorption of Lys and Arg, feed intake, and ADG of pigs. Because Val competes with Leu for absorption, surplus Val may correct some of these effects. An experiment was conducted to analyze the effect of surplus Val in a basal wheat (Triticum aestivum) diet fortified with free Lys, Thr, and Met and containing excess Leu and Ile on performance, expression of genes encoding b(0,+), and serum concentrations of AA. Sixteen pigs (30.3 +/- 2.1 kg BW) were used. Treatments were wheat based with excess Leu and Ile (T1) and T1 plus 0.44% L-Val (T2). At the end of the 21-d study, 12 pigs were euthanized; jugular blood was collected to analyze serum AA and jejunal mucosa to measure expression of b(0,+). Surplus Val increased (P < 0.05) ADG and G:F and serum Val, Lys, and Arg but did not affect (P > 0.10) b(0,+) expression. Although analyzed Val content in the basal diet was lower than calculated, the increased serum Lys and improved pig performance may suggest that excess Leu limits Val availability and that surplus Val could correct some of the negative effects of excess Leu. PMID- 23365293 TI - Growth performance and nutrient digestibilities in nursery pigs receiving varying doses of xylanase and beta-glucanase blend in pelleted wheat- and barley-based diets. AB - In 2 experiments, dose response efficacy of a xylanase and beta-glucanase blend (XB) on growth performance and ileal nutrient digestibility was investigated in nursery pigs fed pelleted wheat (Triticum aestivum)- and barley (Hordeum vulgare) based diets. A basal diet (meeting NRC [1998] specifications for 6 to 30 kg BW, except for 5% lower DE) was supplemented with XB to give 4 diets (0, 50, 100, and 200 g/t). The xylanase and beta-glucanase blend was formulated to contain guaranteed activity of 12,200 and 1520 units/g, respectively. In Exp.1, 192 nursery pigs (initial BW of 6.5 kg) were randomly assigned to 4 diets to give 12 pens (4 pigs/pen) per diet to study growth performance for 42 d. In Exp. 2, apparent ileal digestibility (AID) of energy and AA was evaluated in 4 individually housed ileal-cannulated barrows (21 kg BW) according to a 4 * 4 Latin square design. In Exp. 1, XB linearly and quadratically increased (P < 0.05) G:F compared with control. Adding 200 g/t increased overall G:F by 20% compared with control. In Exp. 2, XB linearly increased (P < 0.05) AID of DM, CP, energy, and AA. In conclusion, supplemental xylanase and beta-glucanase in nursery pelleted wheat- and barley-based diets deficient in DE increased energy and nutrient use, resulting in better G:F. In conclusion, an enzyme product containing a combination of xylanase and beta-glucanase allowed young pigs to derive more nutrients and energy in a wheat- and barley-based diet deficient in energy. PMID- 23365294 TI - Comparative effects of three phytases on the phosphorus and calcium use in the weaned piglet. AB - The addition of phytase to swine diets has generally increased P digestibility and consequently reduced fecal excretion of P. The comparative effects on P and Ca digestibility of dietary inclusion of 5 different phytases were evaluated in the weaned piglet. RONOZYME HiPhos is a microbial 6-phytase produced by synthetic genes, mimicking a gene from Citrobacter braakii, and was compared to the Escherichia coli-derived phytases Phyzyme and OptiPhos. In total, 112 weaned piglets (28 d old) were allocated to 8 equal groups of 14 animals. Pigs were fed for 29 d a vegetable-based diet without addition of mineral P [Co(-)] or this diet supplemented with 12 g/kg feed of CaHPO(4) [Co(+)] or with HiPhos at 1000 units/kg (H1000) or 1500 units/kg (H1500), Phyzyme at 500 units/kg (P500) or 750 units/kg (P750), or OptiPhos at 500 units/kg (O500) or 750 units/kg (O750). All phytases reduced (P < 0.05) fecal P concentration and excretion and increased (P < 0.05) P digestibility and apparent P absorption. The digestible P equivalences of H1000, H1500, P500, P750, O500, and O750 were 0.94, 1.50, 0.67, 0.92, 0.58, and 1.11 g of full available P/kg of feed, respectively. Calcium digestibility was increased (P < 0.05) and Ca excretion reduced (P < 0.05) by the phytases. The 3 phytase preparations increased digestibility and apparent absorption of P and Ca in weaned piglets fed a diet containing P exclusively from plant origin. PMID- 23365295 TI - True total-tract digestibility of phosphorus in monocalcium phosphate for 15-kg pigs. AB - The objective of this study was to determine the true total-tract digestibility (TTTD) of P in Ca(H(2)PO(4))(2) for 15-kg pigs using the regression technique. Forty-eight pigs (15.7 +/- 1.53 kg initial BW) were used in a randomized complete block design. There were 8 dietary treatments with 6 replicates per treatment. The dietary treatments included a negative control (3.30 g/kg total P) and 7 additional dietary treatments with incremental addition of 0.74 g/kg P through Ca(H(2)PO(4))(2) resulting in a range of 3.30 to 8.45 g/kg total P in the dietary treatments. The ingredient composition of the negative control was 600 g/kg corn (Zea mays), 300 g/kg soybean (Glycine max) meal, 64.85 g/kg cornstarch, 20 g/kg soybean oil, 3.3 g/kg salt, 6.05 g/kg limestone, 3.0 g/kg vitamin + mineral premix, and 2.8 g/kg pure AA. Limestone was used to keep the Ca:P ratio constant at 1.25 across all dietary treatments and cornstarch was used to fill the slack. After a 5-d adaptation, total feces were collected for 5 d and were initiated and ended with the appearance of Fe(2)O(3)-marked feces. Daily feed allowance was set at between 3.5 and 4.0% of the BW of pigs to guarantee that the feed waste was minimized. Water was supplied separately at an allowance of 2 times the amount of feed. Dietary P intake, fecal P output, and digested P increased linearly (P < 0.001) with the increasing P level whereas the apparent total-tract P digestibility in diets increased both linearly (P < 0.001) and quadratically (P = 0.007). The regression of daily digested P against daily P intake gave an estimated TTTD of 67.5% for P in Ca(H(2)PO(4))(2) and the endogenous P losses were 494 mg/d. The R(2) with this linear regression was 0.93. In conclusion, a strong linear relationship was obtained between digested P and P intake; the TTTD of P in Ca(H(2)PO(4))(2) was 67.5% for 15-kg pigs. PMID- 23365296 TI - Total tract digestibility of nitrogen in pigs exposed to high environmental temperatures. AB - The effect of environmental heat stress on N metabolism was studied using 7 gilts (50.5 +/- 1.7 kg initial BW). Pigs were housed in metabolism cages in a climate controlled room. After a 4-d adaptation, two 14-d experimental periods followed during which the animals were exposed to thermo-neutral temperature (NT; 20.61 +/ 0.1 degrees C) or high environmental temperature (HT; 30.41 +/- 0.4 degrees C). In each experimental period, two 24-h balance periods were carried out to collect feces and urine (via bladder catheters) for N analysis. Based on N intake and N excretion, N balance was calculated. At HT conditions, N intake was lower (P = 0.028), urinary N excretion increased (P = 0.040), and N retention decreased (P = 0.001) in comparison with NT conditions. Exposure of pigs to HT tended to reduce (P = 0.070) digestibility of N as compared to NT conditions. When pigs are exposed long term to continuous HT, N retention decreases presumably due to decreased use of ME during respiration. PMID- 23365297 TI - The supplementation of low-P diets with microbial 6-phytase expressed in Aspergillus oryzae improves P digestibility in sows. AB - Two trials were conducted to evaluate a novel microbial 6-phytase expressed in Aspergillus oryzae (Ronozyme HiPhos; DSM Nutritional Products, Basel, Switzerland) in gestating and lactating sows. In the first trial, 24 sows (Duroc * Landrace; 223 kg BW) were offered, at 16 d of gestation, a low-P control diet (formulated to provide 4.0 g total P/kg; 1.5 g digestible P/kg) supplemented with 0, 500, or 1000 phytase activity (FYT)/kg of phytase. Two weeks later, fresh feces were sampled from all sows and the apparent total tract digestibility of P was measured using TiO(2) as indigestible marker. Phytase supplementation did not (P > 0.10) affect the total tract digestibility of P but reduced (P < 0.05) P concentration in feces (from 14.5 to 12.0 and 12.0 g/kg DM). In the second trial, 32 lactating sows (Duroc * Landrace; 282 kg BW) were used. They were offered, at 7 d of lactation, a low-P control diet (formulated to provide 6.1 g total P/kg; 3 g digestible P/kg) or the same diet supplemented with 500 FYT/kg of phytase. After 2 wk, fresh feces were sampled from all sows and the apparent total tract digestibility of P was measured using TiO(2) as indigestible marker. Phytase supplementation improved (P < 0.001) the apparent total tract digestibility of P from 27.5 to 38.7% and reduced (P < 0.001) P concentration in feces (from 27.5 to 21.4 g/kg DM). In conclusion, the microbial 6-phytase tested increased the apparent total tract digestibility of P in sows and reduced P excretion in feces. PMID- 23365298 TI - Comparison of standardized ileal amino acid digestibilities in protein supplements and cereal grains for weaned pigs. AB - Standardized ileal digestibility (SID) of AA in protein ingredients and grains was determined in weaned piglets (5 kg initial BW) using the difference method. Animals were fitted with a simple ileal T-cannula on day 24 or 25 of age. A synthetic diet based on corn (Zea mays) starch and casein was either supplemented with an extruded soybean (Glycine max) meal (ESM), rice (Oryza sativa) protein concentrate (RPC), full fat heat-treated soybeans (SB), corn, barley (Hordeum vulgare), or wheat (Triticum aestivum). The contribution of CP and AA from casein and from the assay feed ingredients to the assay diet averaged 50% each. Each diet was fed to 6 animals according to a row-column design with 3 periods. Apparent ileal digestibility was corrected for basal ileal endogenous losses of AA to obtain SID values. Between RPC and soy products, differences (P < 0.05) in SID of most AA such as Lys, Met, and Thr were greater than within soybean products (ESM and SB). The SID of indispensable AA did not differ (P > 0.05) between barley and wheat, except for Met (P < 0.05). Furthermore, SID of Arg, His, Ile, Phe, and Trp was lower (P < 0.05) in corn than wheat. In conclusion, SID of most AA in the present study with piglets was lower than tabulated SID values determined in studies with grower-finisher pigs. Furthermore, the use of RPC, despite its high CP content, in diets for weaned piglets is limited due to its low SID of AA. PMID- 23365299 TI - Differences in portal appearance of lysine and methionine in Iberian and Landrace pigs. AB - Compared to modern breeds, Iberian pigs have lower rates of muscle protein deposition and greater viscera weight. Factors that limit growth performance of Iberian pigs are unknown. We hypothesized that differences in net portal appearance of the essential AA Lys and Met might partially explain the lower growth rate reported in Iberian pigs compared to modern breeds. Net portal appearance of AA was measured in 6 Iberian and 6 Landrace gilts (28 kg BW) fitted with chronic catheters in the portal vein, carotid artery, and mesenteric vein. Blood samples were taken for 6 h after feeding 2 isoenergetic diets (14.0 to 14.5 MJ ME/kg DM) with low CP (LCP) and high CP (HCP) (13 vs. 16%, respectively) in a crossover design after a 1-wk adaptation. Net portal appearance of Lys was greater (P < 0.05) when pigs consumed the HCP than LCP diet (23 vs. 15 MUmol/min); breeds did not differ. Net portal appearance of Met tended to be higher (P = 0.076) for pigs fed HCP than LCP diet (4.4 vs. 3.6 MUmol/min); breeds did not differ. In conclusion, differences in portal appearance of Lys and Met did not exist between Iberian and Landrace pigs fed barley (Hordeum vulgare) soybean (Glycine max) diets with low and high protein concentration. PMID- 23365300 TI - Lower gut nitrogen supply does not affect apparent ileal digestibility of nitrogen or amino acids in growing pigs. AB - An implicit assumption in measures of ileal digestibility (ID) to estimate bioavailability of AA and N is that ID is not influenced by lower gut N metabolism. The absorption of nitrogenous compounds from the lower gut, derived from fermentative AA catabolism, may have an impact on N metabolism and microbial AA synthesis in the upper gut as a result of CO(NH(2))(2) recycling. The objective of this trial was to determine the apparent ID of N and AA in growing pigs fed a corn (Zea mays) starch and soybean (Glycine max) meal-based diet and receiving an infusion of N into the caecum at 40% of N intake. Eight pigs (initial BW of 23.3 +/- 0.55 kg) were fitted with simple T-cannulas in the ileum and cecum and randomly assigned to 1 of 3 continuous cecal infusion treatments [saline, sodium caseinate, or CO(NH(2))(2)] according to a crossover design with 3 periods. Digesta samples were collected and pooled per pig for each 2-d period, freeze-dried, ground, and analyzed for DM, OM, total N, and AA. Lower gut N supply did not affect apparent ID of DM, OM, total N (85.4, 83.4, and 82.7 +/- 1.74%; P = 0.31), or any AA (e.g., 90.1, 89.0, and 89.9 +/- 1.08% for Lys; P = 0.70) for saline, casein, and CO(NH(2))(2) treatments, respectively. Apparent ID may be an insufficiently sensitive measure to determine effects of lower gut N metabolism on N absorption from the lower gut and subsequent recycling into the upper gut. PMID- 23365301 TI - The effects of supplementation of a novel bacterial 6-phytase on mineral digestibility and plasma minerals in lactating sows. AB - Pigs digest P in plant feedstuffs poorly because pigs do not produce sufficient endogenous phytase to hydrolyze P from phytate (inositol hexaphosphate). Supplementation of phytase to diets of piglets and grower-finisher pigs increased digestibility of minerals including P and Ca; however, data on phytase efficacy in lactating sows are scarce. Therefore, effects of adding a bacterial 6-phytase expressed in a strain of Aspergillus oryzae (Ronozyme HiPhos; DSM Nutritional Products, Basel, Switzerland) on apparent total tract digestibility (ATTD) of P and Ca was assessed in 45 lactating sows. Three diets were prepared: (i) positive control (PC; 0.52% available P), a regular sow diet containing inorganic P, (ii) negative control (NC; 0.20% available P) without inorganic P, and (iii) NC + 500 units of phytase/kg diet. Each diet was fed randomly to 15 sows for 21 d (from 5 d prior to farrowing to 15 d after farrowing). At day 15 after farrowing, ATTD of P did not differ between PC and NC. Phytase supplementation to NC increased (P < 0.05) ATTD of P from 34 to 46% compared to NC but did not affect (P > 0.05) ATTD of CP and Ca. On day 1 after farrowing, plasma P was 0.66 mmol/L lower (P < 0.05) in sows fed NC than PC. Phytase supplementation to NC increased (P < 0.05) plasma P by 0.40 mmol/L on day 1 but not on day 15 after farrowing. In conclusion, phytase supplementation increased P bioavailability in lactating sows. PMID- 23365302 TI - Effect of particle size and heat treatment of soybean meal on standardized ileal digestibility of amino acids in growing pigs. AB - A study with growing barrows was conducted to evaluate of variations in particle size and degree of heat treatment during processing on standardized ileal digestibility (SID) of AA in soybean (Glycine max) meal (SBM). A commercial SBM batch was visually identified as being overtoasted due to its brownish color and was separated into small and large particles using a 1-mm sieve. In addition, 3 SBM were produced from 1 batch of soybean and exposed to different processing conditions (temperature and direct steam contact) referred to as mild (105 degrees C; 34 min), medium (115 degrees C; 45 min), and strong (139 degrees C; 7 min). In total, 5 SBM-corn (Zea mays) starch-based diets were formulated to contain SBM as the sole protein source. This experiment was conducted according to a 6 * 6 Latin square design using 6 barrows (23 kg initial BW) fitted with a T cannula at the distal ileum. With increasing particle size, SID of His and some dispensable AA increased (P < 0.05). Lower SID values in small compared to large SBM particles indicate more pronounced heat damage possibly due to increased surface area. The SID of CP and AA was lowest in the mild, intermediate in the strong, and highest in the medium toasted SBM (P < 0.001). These differences in SID are reflected in varying contents of trypsin inhibitors, Lys, reactive Lys, and NDF. In conclusion, both differences in particles size and variations in thermal processing conditions of SBM may affect SID of CP and AA. PMID- 23365303 TI - Nutritional characteristics of by-products originating from the Central European ethanol fuel industry for pigs. AB - Chemical composition and nutrient and energy digestibilities were determined in 4 samples of dried distillers grains with solubles (DDGS) and 1 sample of wet distillers grains (WDG) from 4 ethanol fuel manufacturers. The cereal sources used for ethanol production were wheat (Triticum aestivum; 1 sample), wheat + barley (Hordeum vulgare; 2 samples), and maize (Zea mays; 2 samples). The nutrient contents (expressed as % of DM) were variable, ranging from 30.5 to 39.5 CP, 4.4 to 12.3 fat, 7.5 to 12.9 crude fiber, 2.7 to 7.8 ash, and 0.4 to 0.9 total P. The concentration of Lys ranged from 2.05 to 5.20 g/kg DM. The diets were fed to 6 gilts (39.9 +/- 1.9 kg BW) fitted with ileal T-cannulas using a 5 * 6 Youden square. Each experimental period comprised a 5-d adaptation followed by a 2-d collection of urine and feces and 1-d (24 h) collection of ileal digesta. Using acid-insoluble ash as a marker, apparent ileal digestibility (AID) and apparent total tract digestibility (ATTD) of nutrients and energy and AID of AA were calculated. The ATTD of N ranged from 55.7 to 83.7%. The N retention expressed as percentage of N intake ranged from 10.2 to 32.0. Except for wheat based DDGS, the AID of N was 66.8%. The ATTD and AID values of NDF were 52.8 and 24.4%, respectively. The concentration of total P in WDG was half of values in DDGS, which likely caused its very low ATTD (1.4%). The ATTD and AID of energy ranged from 58.8 to 73.9% and from 40.6 to 54.1%, respectively. The AID of AA was greatest (P < 0.001) in WDG (71.8%) and lowest (P < 0.001) in DDGS from wheat (44.8%). In conclusion, nutrient variability among DDGS samples varies greatly, and source of origin is an important determinant of quality. PMID- 23365304 TI - Lactose in diet influences the degradation of mixed linked beta(1-3;1-4)-D-glucan in the small intestine of pigs. AB - The objective was to study the cause of variation in digestibility of mixed linked beta(1-3;1-4)-D-glucan (beta-glucan) in the small intestine of growing pigs. The beta-glucan is an important cell wall [dietary fiber (DF)] component of the endosperm of barley (Hordeum vulgare) and oats (Avena sativa). The digestibility of beta-glucan in the small intestine from both cereals is among the highest of all DF components, but in 1 study with oat-based diets it was lower (P < 0.001) than in other studies. In this study, whey protein containing lactose was used as protein supplement. Lactose is slowly digestible in the small intestine. To investigate if lactose might cause the lower digestibility of beta glucan in the study with whey protein, the lactose in diets was analyzed together with lactose and organic acids (lactic acids and short-chain fatty acids) in digesta samples from the small intestine (the small intestine was by length divided in 3 equal segments: SI(1), SI(2), and SI(3)) and ileal digesta. Diets containing lactose were based on oat goats, oat flour, and oat bran (12 to 38 g lactose/kg DM) whereas the reference diets were based on rolled oats, rolled oats and oat bran, wheat (Triticum aestivum) flour with added oat bran, and wheat flour with added beta-glucan (0 to 1 g lactose/kg DM). Lactose was identified in digesta up to SI(2) but disappeared in digesta from SI(3) and ileum. Digestibility of beta-glucan did not differ among diets up to SI(3) (18% average) whereas digestibility in ileum was 64% in diets without lactose and 27% in diets containing lactose (P < 0.001). The beta-glucan was virtually completely digested in the cecum (96% average) in all diets. The concentration of organic acids did not differ between diets either in SI(3), ileum, or cecum. In conclusion, slowly digestible lactose was the most likely cause of the reduced digestibility of beta glucan in oat diets containing lactose. PMID- 23365305 TI - Assessment of the presence of chemosensing receptors based on bitter and fat taste in the gastrointestinal tract of young pig. AB - Knowledge on porcine bitter and fat taste receptors and on their expression in gastrointestinal tract of pigs is scarce. We searched for the presence of porcine homologous sequences for 13 human transcripts of bitter and fat taste receptors in ENSEMBL and National Center for Biotechnology Information databases. For taste 2 receptor (TAS2R) 8, alignment was not observed; for TAS2R13 and TAS2R46 the porcine predicted sequence aligned with several other human bitter genes. For 7 genes for bitter taste (TAS2R1, TAS2R3, TAS2R7, TAS2R9, TAS2R10, TAS2R16, and TAS2R38) and for 3 genes for fat taste (GPR40, GPR43, and GPR120), a full homology for exon sequences was found and primers were designed by Primer3. These 7 genes were amplified with real-time PCR and verified on agarose gel in 5 gastrointestinal segments of weaned pigs: oxyntic (ST1), pyloric (ST2), and cardiac to oxyntic transition mucosa (ST3), jejunum (JEJ), and colon (COL). Suitability of mRNA was verified by amplifying RPL4 and HMBS2 genes. Each bitter taste gene was detectable on agarose gel in at least 1 subject of all the gastrointestinal segments except for TAS2R3 and TAS2R38 that were never detected in ST1 and COL, respectively. The inspection of bitter taste genes amplification curve indicated that the expression was in general very low. GPR43 and GPR120 were present in all segments from all pigs. Expression was not detected for GPR40. Data also indicate that colon is the preeminent tract where fat detection by GPR120 takes place (P < 0.001). The presence of gene expression for several chemosensing receptors for bitter and fat taste in different compartments of the stomach confirms that this organ should be considered a player for the early detection of bolus composition. PMID- 23365306 TI - Ileal and total tract digestibility of wet and dried wheat distillers grain products in growing pigs. AB - The apparent ileal digestibility (AID) and apparent total tract digestibility (ATTD) of nutrients were evaluated in 2 commercially available products: wheat (Triticum aestivum) wet distillers grain with solubles (WDGS) and wheat dried distillers grain with solubles (DDGS). Two diets included (DM basis) 50% basal diet with either 50% WDGS (W) or 50% DDGS (D). The basal diet included corn (Zea mays) starch, sugar, vitamins, and minerals. Seven castrated male pigs with post valve T-cecum cannulas were fed the diets according to a changeover design during two 14-d periods. In a pre- and postperiod, casein was given as the only protein source with the basal diet to estimate endogenous losses of N and AA for calculation of standardized ileal digestibility (SID). The AID of OM did not differ between diets, but ATTD of OM was higher (P < 0.05) for diet W. The AID (76.2 vs. 68.9%), SID, and ATTD of CP was higher (P < 0.05) in diet W than diet D. The SID for Lys (75.7 vs. 51.8%) and Met (75.8 vs. 70.1%) was higher (P < 0.01) in WDGS than DDGS. In conclusion, drying of wheat distillers grain products can markedly lower ileal digestibility of Lys and Met whereas negative effects on energy value are small. PMID- 23365307 TI - Meta-analysis of effects of microbial phytase on digestibility and bioavailability of copper and zinc in growing pigs. AB - A meta-analysis was conducted to determine the effect of microbial phytase in pig diets on digestibility and bioavailability of Cu and Zn. Studies (n = 22) into effects of microbial phytase on digestibility and plasma levels of Cu and Zn were included in a dataset and regression analysis was performed to quantify the effect of Aspergillus niger derived 3-phytase in studies (n = 14) with a maximum dietary Zn content of 100 mg/kg and a maximum Cu addition of 20 mg/kg. Phytase inclusion increased digestibility of Zn (P = 0.003) and plasma Zn content (P < 0.001) without affecting digestibility and plasma level of Cu. Based on a comparison with dose-response studies with Zn, we estimated 500 phytase units (FTU) of microbial phytase is equivalent to 27 mg of Zn from ZnSO(4). PMID- 23365308 TI - Prediction of apparent, standardized, and true ileal digestible total and reactive lysine contents in heat-damaged soybean meal samples. AB - Forty-two individually housed entire male pigs weighing 37.5 +/- 0.15 kg (mean +/ SEM) were used in a randomized block design having 7 dietary treatments (n = 6). The dietary treatments were 5 semisynthetic diets containing 350 g/kg of soybean (Glycine max) meal (SBM) with variable heat treatments (0, 7, 14, 21, and 28 min autoclaved at 135 degrees C), a protein free (N-free) diet, and an enzymatically hydrolyzed casein (EHC) diet. Heat treatment linearly decreased (P < 0.001) total Lys content from 27.5 to 19.2 g/kg and reactive Lys content from 23.4 to 11.7 g/kg. Apparent, standardized, and true ileal digestible total and reactive Lys contents linearly decreased (P < 0.001) with increasing severity of heat treatment and were accurately predictable (P < 0.001) from total and reactive Lys content in heat-damaged SBM. These data indicate that excessive heat processing of SBM reduced both the content (P < 0.001) and digestibility (P < 0.001) of total and reactive Lys in SBM. PMID- 23365309 TI - Digestible and metabolizable energy concentrations in copra meal, palm kernel meal, and cassava root fed to growing pigs. AB - An experiment was conducted to measure DE and ME in copra (Cocos nucifera) meal (CM), palm kernel meal (PKM), and cassava (Manihot esculenta) root (CR) in growing pigs. Eight boars with an initial BW of 67.3 +/- 5.8 kg were individually housed in metabolism crates that were equipped with a feeder and a nipple drinker. A replicated 4 * 4 Latin square design was used with 4 dietary treatments, 4 periods, and 8 animals. A basal diet mainly contained corn (Zea mays) and soybean (Glycine max) meal. Three additional diets were formulated to contain 30% of CM, PKM, and CR. All diets contained the same proportion of corn:soybean meal ratio at 4.14:1. The apparent total tract digestibility of energy was 89.5, 84.1, 82.4, and 87.9% (P < 0.001) in the basal, CM, PKM, and CR diets, respectively. The DE in CM and PKM were greater (P < 0.05) than in CR (3440 and 3238 vs. 2966 kcal/kg as-fed). The ME in CM was greater (P < 0.05) than in CR (3340 vs. 2935 kcal/kg as-fed) but not different from the ME in PKM (3168 kcal/kg as-fed). In conclusion, CM and PKM have a higher DE value than CR, and CM has a higher ME value than CR. PMID- 23365310 TI - Performance and apparent total tract phosphorus and calcium digestibility in grower-finisher pigs fed diets with and without phytase. AB - The efficacy of a thermotolerant 6-phytase on performance and apparent total tract digestibility (ATTD) of P and Ca was evaluated in 96 crossbred barrows (8 replicates with 3 pigs each) fed 4 diets. Diets based on corn (Zea mays), a heat treated grain mix, and soybean (Glycine max) meal with recommended [positive control (PC)] or reduced [negative control (NC)] P and Ca levels were fed from 25 to 115 kg BW. The PC diets contained 0.61% P and 0.72% Ca from 25 to 45 kg, 0.59% P and 0.66% Ca from 45 to 70 kg, and 0.48% P and 0.51% Ca from 70 kg to final BW. The NC diets were reduced in digestible P by 2.0, 2.0, and 1.1 g/kg and in Ca by 1.4, 1.0, and 0.8 g/kg, respectively, for the 3 phases. Phytase was added at 0, 250, and 500 phytase units (FTU)/kg to the NC diet. Performance was measured at the end of each feeding period and ATTD of P and Ca evaluated for a 3-d collection following a 7-d adaptation at an average BW of 45, 70, and 116 kg. Final BW of NC pigs (111.9 kg) was increased (P < 0.05) by P addition (120.3 kg; PC) and by phytase inclusion at both rates (116.5 and 117.6 kg, respectively). The ADG of NC pigs (781 g) was increased (P < 0.05) by both phytase levels (5.5 and 6.6%); pigs fed 500 FTU/kg achieved similar ADG as PC pigs (833 and 858 g, respectively). The G:F was reduced (P < 0.05) in NC pigs (0.308) compared to pigs fed the PC diet (0.328) or diets with 250 or 500 FTU phytase/kg (0.324 and 0.330, respectively). The ATTD of P was lowest in all periods for pigs fed NC diets (35.5% in starter, 32.2% in grower, and 32.1% in finisher period). Phytase increased (P < 0.05) ATTD of P in all periods at both application rates. Pigs fed 500 FTU/kg diet had a higher (P < 0.05) ATTD of P than pigs fed 250 FTU/kg and an ATTD of P at least similar to pigs fed PC. Similar but less pronounced effects were observed for ATTD of Ca. The phytase added to grower-finisher diets with reduced P and Ca nearly restored performance to the level of pigs fed diets with adequate P and Ca. PMID- 23365312 TI - The degradation of arabinoxylan-rich cell walls in digesta obtained from piglets fed wheat-based diets varies depending on digesta collection site, type of cereal, and source of exogenous xylanase. AB - The objective of the present study was to compare the ability of experimental and commercial xylanases to degrade, in vitro, the arabinoxylan (AX) fraction in digesta from 28-d-old piglets fed a wheat (Triticum aestivum)-based diet (49% wheat). Pigs were euthanized at 1, 2, 3, or 4 h after feeding; stomach and ileum contents were isolated and frozen and later used for the in vitro studies. Xylan solubilization provided information regarding the ability of the enzymes to degrade AX during the harsh in vivo conditions prevailing in the gastrointestinal tract. The hydrolytic capacity of a commercial xylanase was compared with that of an experimental xylanase using stomach digesta (pH 1.8) obtained at 4 h after feeding. Relative to the control, both enzymes increased (P < 0.001) xylan solubilization 3-fold. In the ileal digesta (1 h), xylan solubilization was increased by 36% (P < 0.001). Inclusion of arabinofuranosidases (Ara f) with xylanases increased xylan solubilization in stomach samples (P = 0. 007 and P = 0. 030) but not in ileal samples (P = 0.873 and P = 0.997). Our results illustrate clearly the importance of using different conditions and substrates when enzyme performance is studied in vitro as a prescreening tool for setting up in vivo trials. PMID- 23365311 TI - Effects of beta-hydroxy beta-methyl butyrate supplementation to sows in late gestation on absorption and hepatic metabolism of glucose and amino acids during transition. AB - A multicatheter sow model was established to study the effects of dietary beta hydroxy beta-methyl butyrate (HMB) supplementation on net portal flux (NPF) and net hepatic flux (NHF) of HMB, glucose, and the AA Ala, Gly, Ile, Leu, Phe, Tyr, and Val. Eight second parity sows were fitted with permanent indwelling catheters in an artery and in the portal, hepatic, and mesenteric veins. Eight hourly sets of blood samples were taken starting 30 min before the morning meal on day -3 and day 3 relative to parturition. Four control (CON) sows were fed a standard lactation diet from day -15 and throughout the experiment, and 4 HMB sows were fed the control diet supplemented with 15 mg Ca(HMB)(2)/kg BW mixed in one third of the morning meal from day -10 until parturition. Net portal flux of HMB was affected by treatment (Trt; P < 0.01) and peaked in the HMB sows at 6.9 mmol/h 30 min after the morning meal and then decreased towards preprandial level (0.0 mmol/h) 3.5 h after the meal, revealing that dietary HMB was rapidly absorbed from the intestine. The NHF of HMB tended to be affected by Trt (P = 0.06) showing a small hepatic uptake of HMB (1.1 mmol/h) in HMB sows. Net portal flux of glucose and all measured AA, except for Gly and Tyr, were affected the Trt * time interaction (P < 0.01). The NPF was positive for all nutrients, indicating absorption from the intestine to the portal blood. Absorption rates appeared to be more stable for HMB than for CON sows. Net hepatic flux of glucose was not affected by Trt. It was negative from 1.5 to 2.5 h after the meal, indicating hepatic uptake, but positive before and after, indicating net hepatic release of glucose. Net hepatic fluxes of AA were negative and were not affected by Trt (P > 0.10), except for Phe (P < 0.05). In conclusion, HMB reduced the variation in net portal flux of glucose and AA during 8 h of blood sampling and suggest that the improved sow productivity observed by others may be due to a more uniform nutrient absorption pattern into portal blood. PMID- 23365313 TI - Effects of dietary supplementation with a protease on the apparent ileal digestibility of the weaned piglet. AB - The effects of an acid-stable protease (RONOZYME ProAct) supplemented to a corn (Zea mays)-soybean (Glycine max) meal-based diet on apparent ileal digestibility (AID) of nutrients were evaluated in 120 weaned piglets (28 d old; 8.17 +/- 0.90 kg). Pigs were divided into 2 equal groups and had free access to mash diet containing 0.4% Cr(2)O(3) as indigestible marker [basal diet (Std)] or this diet supplemented with RONOZYME ProAct at 15,000 PROT [the amount of enzyme that releases 1 MUmol of pnitroaniline from 1 MUM of substrate (Suc-Ala-Ala-Pro-Phe-p nitroaniline) per min at pH 9.0 and 37 degrees C)/kg (ProA). The ileal content was collected for the digestibility determination after euthanasia of 35 piglets of each group after 14 d of study and 25 piglets of each group after 29 d. Compared to group Std, AID of CP was increased (P < 0.05) after 29 d of treatment in group ProA. The AID of the indispensable AA, Met + Cys, and branched-chain AA was increased (P < 0.05) at the end of the study. In the protease supplemented pigs, the AID of the individual AA was not improved after 14 d of treatment whereas it was increased (P < 0.05) at the end of the experiment for Arg, Asp + Asn, Glu + Gln, His, Ile, Lys, Phe, Thr, Tyr ,and Val. In conclusion, dietary protease supplementation increased AID of AA in piglets. PMID- 23365314 TI - Comparative evaluation of standardized ileal amino acid digestibility in protein supplements for piglets. AB - Standardized ileal digestibility (SID) of AA was determined in 6 protein ingredients for piglets. A basal diet based on corn (Zea mays) starch and casein was supplemented with fluid-bed-dried porcine intestinal mucosa hydrolysate, spray-dried porcine intestinal mucosa hydrolysate, soy (Glycine max) protein concentrate, 2 batches of soy protein, or full-fat soybeans. The SID of AA did not differ between the 4 soybean products (P > 0.05). Compared to most SID values in the 4 soybean products, SID of AA were lower in the 2 porcine intestinal mucosa hydrolysates (P <= 0.05). In conclusion, although the initial trypsin inhibitor contents in the raw soybeans have not been determined, high SID values in the 4 soybean products indicate that the different processing procedures used to manufacture these products were efficient to inactivate trypsin inhibitors. For most AA in the 2 porcine intestinal mucosa hydrolysates, drying procedure did not affect SID of AA, but SID values were generally lower compared to the 4 soybean products. PMID- 23365315 TI - Effect of dietary fiber and crude protein content in feed on nitrogen retention in pigs. AB - Eight gilts (29.9 +/- 1.7 kg initial BW) were used to evaluate effects of dietary (crude) fiber on N excretion via feces and urine at 2 levels of dietary CP. Pigs were fed 4 dietary treatments according to a double 4 * 4 Latin square. Treatments were low (14%) CP and low (3.25%) (crude) fiber (LPAA), low CP and high (4.46%) fiber (LPAABP), high (18.8%) CP and low fiber (HP), and high CP and high fiber (HPBP). Diets were based on soybean (Glycine max) meal, wheat (Triticum aestivum), and maize (Zea mays) and were supplemented with crystalline AA. High fiber diets contained 15% dried beet (Beta vulgaris) pulp. Pigs were housed in metabolic cages and fed 2 equal meals at 0700 and 1700 h at a daily rate of 90 g/kg BW(0.75). Water was offered ad libitum. Each experimental period consisted of a 6-d adaptation followed by a 4-d collection of feces and urine (bladder catheters). Data were analyzed using ANOVA. Differences between means (P < 0.05) were assessed using Fisher's LSD procedure. The N intake, fecal N excretion and absorption, and N retention increased (P < 0.05) in pigs fed high CP diets with added fiber (HP vs. HPBR). With added fiber, urinary N excretion (g/d) was reduced (P < 0.02) only for the low-CP diet. Urinary N as a percentage of N intake was reduced (P < 0.01) in both groups fed high-fiber diets irrespective of dietary CP content. Dietary fiber level did not affect DMI. Fecal DM excretion (g/d) was higher (P < 0.02) in pigs fed diets with high CP and high fiber content than in pigs fed diets with high CP and low fiber content. In conclusion, beet pulp fiber added to diets increased fecal N and reduced urinary N and in diets with higher CP content increased overall N retention. PMID- 23365316 TI - Effects of faba bean and faba bean hulls on expression of selected genes in the small intestine of piglets. AB - In a small intestinal segment perfusion (SISP) study in pigs, effects were studied of intestinal perfusion of ground faba beans (Vicia faba), faba bean hulls, or saline on intestinal net fluid absorption in intestinal segments either challenged or not with an enterotoxigenic Escherichia coli (ETEC). After an 8-h perfusion, piglets were euthanized and small intestinal mucosa samples were collected for analysis of expression level of a selected set of genes (APOC3, TIMP1, AQP8, MMP1, MUC13, and PAP) using real-time quantitative PCR (qPCR). Perfusion with ground faba beans and faba bean hulls and challenge with ETEC affected (P < 0.05) expression of several of genes in the intestinal mucosa. Expression of APOC3, TIMP1, AQP8, MMP1, and PAP was correlated with net fluid absorption in the small intestine of pigs. PMID- 23365317 TI - Improved nutrient digestibility and retention partially explains feed efficiency gains in pigs selected for low residual feed intake. AB - Residual feed intake (RFI) is a unique measure of feed efficiency (FE) and an alternative to traditional measures. The RFI is defined as the difference between the actual feed intake of a pig and its expected feed intake based on a given amount of growth and backfat. Therefore, selecting pigs with a low RFI (LRFI) results in a more feed-efficient animal for a given rate of growth. Our objective was to determine the extent to which apparent total tract digestibility of nutrients and energy use and retention may explain FE differences between pigs divergently selected for LRFI or high RFI (HRFI). After 7 generations of selection, 12 HRFI and 12 LRFI pigs (62 +/- 3 kg BW) were randomly assigned to metabolism crates. Pigs had free access to a standard diet based on corn (Zea mays) and soybean (Glycine max) meal containing 0.4% TiO(2), an exogenous digestibility marker. After a 7-d acclimation, total urine and feces were collected for 72 h. Nutrient and energy digestibility, P digestibility, and N balance were then measured and calculated to determine differences between the RFI lines. As expected, ADFI was lower (2.0 vs. 2.6 kg; P < 0.01), ADG did not differ, and FE was higher in the LRFI (P < 0.001) compared to the HRFI pigs. The digestibility values for DM (87.3 vs. 85.9%), N (88.3 vs. 86.1%), and GE (86.9 vs. 85.4%) were higher (P <= 0.003) in the LRFI vs. HRFI pigs, respectively. The DE (16.59 vs. 16.32 MJ/kg DM) and ME (15.98 vs. 15.72 MJ/kg DM) values were also greater (P < 0.001) in LRFI pigs. When correcting for ADFI, P digestibility did not differ between the lines. However, the LRFI pigs tended to have improved N retention (P = 0.08) compared to HRFI pigs (36.9 vs. 32.1 g/d). In conclusion, the higher energy and nutrient digestibility, use, and retention may partially explain the superior FE seen in pigs selected for LRFI. PMID- 23365318 TI - Dietary protein excess does not influence calcium and phosphorus absorption and retention in Iberian pigs growing from 50 to 100 kg body weight. AB - Effects of apparent total tract digestible dietary protein [expressed as apparent ileal digestible (AID) Lys in parentheses] from excessive to marginally deficient [110 (7.9), 92 (6.6), 73 (5.3) and 54 (3.8) g/kg DM] and feeding level (FL; 0.80 and 0.95 * ad libitum) upon fractional absorption and retention of Ca and P was studied in 48 purebred Iberian barrows from 50 to 100 kg BW to investigate possible detrimental effects of protein over supply on Ca and P metabolism. The diets were prepared by diluting a high-protein diet, formulated according to the ideal protein concept, with a protein-free mixture. The diets provided (per kg DM) 11.6 to 10.7 g Ca, 6.67 to 6.25 g total P, and 13.9 to 14.8 MJ ME. Intake levels with free access to feed were calculated according to individual BW and were adjusted weekly. A digestibility and balance trial was performed at 75 kg BW. The ADFI was 3104 and 2643 g for 0.95 and 0.80 * ad libitum FL. The ADG reached a maximum at 854 g (18.87 g/MJ ME intake) with the diet containing 5.3 g AID Lys/kg DM. Dietary AID Lys content did not alter Ca and P fractional apparent absorption, which attained average values of 0.417 +/- 0.0109 and 0.545 +/- 0.0106. The Ca and P retention as a fraction of intake remained unaffected at 0.403 +/- 0.0114 and 0.403 +/- 0.0120. The Ca urinary losses were not elevated by excess of dietary protein supply, remaining at 0.260 +/- 0.0212 g/d. High feeding level increased (P < 0.05) the flow of absorbed Ca and P. In conclusion, long term, high-protein (Lys) intake did not affect Ca intestinal absorption and renal excretion in the pig. PMID- 23365319 TI - Nutrient digestibility of degermed, dehulled corn, citrus pulp, and soy protein concentrate by barrows. AB - This study was carried out to determine apparent ileal digestibility (AID) and apparent total tract digestibility (ATTD) of DM, CP, GE, and their respective digestible content of degermed dehulled corn (Zea mays), citrus pulp, and soy (Glycine max) protein concentrate by pigs using the difference method. Thirty-two barrows (28.1 +/- 1.6 kg of BW) were fed a corn-soybean meal basal diet or 1 of 3 diets formulated by replacing 30% of the basal diet with 30% of 1 of the test feedstuffs for 11 d. Chromic oxide (0.3%) was included in the diets. Feces were collected from days 7 to 11 by grab sampling and ileal digesta were collected after pigs were slaughtered on day 12. The AID of DM and AID and ATTD of GE of degermed corn (77.4, 88.7, and 77.7%) were greater (P < 0.05) than those observed in citrus pulp (50.3, 86.5, and 55.8%) and in soy protein concentrate (63.5, 85.1, and 59.4%), which did not differ (P > 0.05). The ATTD of CP, total digestible CP, and total DE of soy protein concentrate (87.5%, 500 g/kg, and 3739 kcal/kg) were higher (P < 0.05) than the values in degermed corn (81.7%, 57.5 g/kg, and 3330 kcal/kg), which were greater (P < 0.05) than those in citrus pulp (60.5%, 39.5 g/kg, and 3223 kcal/kg). Total and ileal digestible DM, AID of CP, and ileal DE of degermed corn (782 g/kg, 673 g/kg, 70.7%, and 2913 kcal/kg) and soy protein concentrate (778 g/kg, 570 g/kg, 78.7%, and 2878 kcal/kg) were similar (P > 0.05) and greater (P < 0.05) than those in citrus pulp (737 g/kg, 436 g/kg, 50.6%, and 2081 kcal/kg). Ileal digestible CP of degermed corn (49.8 g/kg) and citrus pulp (33.0 g/kg) did not differ (P > 0.05) but were smaller (P < 0.05) than the value found in soy protein concentrate (434 g/kg). The DM and energy from degermed corn are more efficiently digested by the pig than those from soy protein concentrate and citrus pulp. Soy protein concentrate was the best protein source evaluated in this study. PMID- 23365320 TI - Degradation and fermentation characteristics of wheat coproducts from flour milling in the pig intestine studied in vitro. AB - Use of wheat (Triticum aestivum) flour milling coproducts (WFM) in pig diets may ameliorate high feed cost. However, digestibility of WFM is lower than feed grains, and limited information exists about their fermentation characteristics. In vitro degradation and fermentation characteristics of 6 WFM samples (2 Shorts, 2 Millrun, middlings, and bran) with varying fiber and protein contents were studied. After a pepsin-pancreatin hydrolysis, WFM were incubated in a buffer solution with minerals and fresh pig feces as inoculum. Accumulated gas production was measured for 72 h and modeled. The VFA concentration was measured in the fermented solutions. The DM degradability during fermentation ranged from 31 to 52% and correlated negatively with ADF (r = -0.65; P < 0.01) and positively with CP (r = 0.50; P < 0.01) content of WFM. Total gas production ranged from 101 to 148 mL/g DM incubated and was negatively correlated with ADF and crude fiber (r = -0.70 and -0.59, respectively; P < 0.01). The VFA production ranged from 2.0 to 3.0 mmol/g and the fractional rate of degradation ranged from 0.08 to 0.11/h. In conclusion, fiber components were associated with degradability and fermentability of WFM. Therefore, treatments targeted to reduce the impact of fiber and protein may increase the digestibility and fermentability of wheat coproducts from flour milling. PMID- 23365321 TI - Influence of forage inclusion in the diet on ileal and total tract digestibility. AB - The present investigation aimed to study the ileal and total tract digestibility of 3 forages (clover-grass, clover-grass silage, and field pea (Pisum sativum) barley (Hordeum vulgare) silage) supplemented to a basal diet. A total of 24 pigs, adapted to eating forages by supplementing a basal feed with clover-grass silage from weaning, were fitted with a T-cannula at the terminal ileum at approximate 30 kg BW. For each of the 3 types of forage, 2 balance trials with a 4 wk interval were carried out. Two pigs in each test were fed the basal diet and 6 others were fed the basal diet plus forage throughout the whole experiment. The intake of forages was low and quite variable and on average accounted for only 10 to 12% of the DMI. Ileal digestibility of protein estimated by collection from the T-cannula was higher (P = 0.031) than the digestibility estimated by the slaughter technique indicating some separation of the digesta collected from the T-cannula. The forages had, as expected, a lower total tract DM and energy digestibility than the basal diet (P < 0.05). The fresh clover-grass had a higher energy digestibility than the 2 silages (60 vs. 48%; P < 0.05). Inclusion of 10% of GE in the diet as forage reduced (P < 0.05) the energy digestibility of the ration by 2.2% for clover-grass, 3.4% for clover-grass silage, and 5.0% for pea barley silage. In organic slaughter pig production, the overall energy supply from these forages is limited, but they may play an important role in satiety and rooting behavior. PMID- 23365322 TI - Short-term effect of dietary yeast nucleotide supplementation on total and diurnal variation of small intestinal enzyme activities in piglets. AB - A study was carried out to investigate, whether short-term supplementation of dietary yeast nucleotides affects total and diurnal variation of enzyme activities in the small intestine of weaned piglets. Twelve barrows, weaned at 18 d of age (5 kg initial BW), were fitted with a simple T-cannula at the distal ileum. Twice daily (0730 and 1930 h), 6 piglets each received a cereal-soybean (Glycine max) meal-based diet with or without supplementation of 1 g/kg of a yeast nucleotide product in 2 consecutive periods. In each period, digesta samples were collected 6 times at given intervals during 24 h digesta collection. Dietary supplementation with yeast nucleotides did not affect (P > 0.05) total enzyme activities for alpha-amylase, leucine aminopeptidase (LAP), maltase, and lactase in ileal digesta. Therefore, data of both treatments were pooled to determine diurnal variations in enzyme activities. For alpha-amylase, a diurnal variation in enzyme activity could be observed (P < 0.05). Variations in diurnal activities of LAP, maltase, and lactase were not observed (P > 0.05). In conclusion, yeast nucleotides do not affect total small intestinal enzyme activities. Independent of diet composition, alpha-amylase activities may vary over time, with peak flow at 6 h postprandially. PMID- 23365324 TI - Bioavailability of zinc from different sources in pigs. AB - In contrast to inorganic Zn, organic Zn sources are absorbed via peptide or AA transport systems resulting in a higher digestibility and availability. Bioavailability of organically bound Zn seems also to be influenced by the type of complex being used. Forty-two gilts (Large white * Landrace) with initial BW of 24 +/- 1.4 kg were allotted to 6 treatments of 7 pigs each. Pigs were fed diets based on corn (Zea mays), barley (Hordeum vulgare), and soybean (Glycine max) meal containing either low or high Zn supplementation with ZnO, Zn-Met 1:2 complex, Zn-Gly, Zn proteinate (Zn-Prot), or Zn-yeast. Diets were fed during a 10 d adaptation followed by a 4-d quantitative collection. Daily feed allowance was restricted to 1400 g/pig. Pigs were weighed at the start and end of adaptation and collection and feed consumption was monitored daily. Dietary Zn addition was 10 and 100 mg/kg feed for ZnO and 10 mg/kg feed for other Zn sources. Corresponding ADG ranged from 437 to 587 g with the lowest (P < 0.05) ADG for 10 ppm ZnO. Only Zn-Met addition increased (P < 0.02) Zn digestibility and retention (P < 0.05). Organically bound Zn, in particular Zn from Zn-Met 1:2 and Zn-yeast, can replace higher dosages of ZnO due to better bioavailability indicating that type of chelate is important for Zn retention. Organically bound Zn may reduce Zn excretion, which consequently may lower the environmental impact. PMID- 23365323 TI - Effects of a 6-phytase on the apparent ileal digestibility of minerals and amino acids in ileorectal anastomosed pigs fed on a corn-soybean meal-barley diet. AB - Phosphorus of plant-based feedstuffs for monogastric animals is mainly in the form of phytic P, which has a very low bioavailability. The nondigested phytic P may contribute to P pollution. Furthermore, phytic acid may reduce digestibility of other minerals and protein. This study evaluated effects of the microbial 6 phytase RONOZYME HiPhos on apparent ileal digestibility of P, phytic acid, Ca, CP, energy, and AA in six 60-d-old ileorectal anastomosed pigs. In a duplicated 3 * 3 Latin square design, pigs had free access to alternatively a corn (Zea mays) soybean (Glycine max) meal-barley (Hordeum vulgare)-based diet or this diet supplemented with RONOZYME HiPhos at either 500 units/kg (RH500) or 1000 units/kg (RH1000). Pigs fed diets supplemented with RH500 or RH1000 increased (P < 0.05) digestibility of P, Ca, and Lys. Pigs fed diet RH1000 increased (P < 0.05) digestibility of CP, total AA, indispensable AA, Glu + Gln, His, Gly, Ala, Tyr, Leu, Phe, and Met. Similar to growth trials with increased total tract digestibility of P and Ca, phytase increased apparent ileal digestibility of these indispensable minerals and phytate. The phytase increased digestibility of CP and indispensable AA indicating a better availability of plant-based proteins. PMID- 23365325 TI - Effect of soybean meal origin on standardized ileal amino acid digestibility in piglets. AB - The present study with piglets was conducted to estimate standardized ileal digestibility (SID) of AA in European Union soybean (Glycine max) meal (SBM) imports sourced from Argentina, Brazil, and the United States. Twelve piglets with an average initial BW of 9 kg (47 d of age) were fitted with a simple ileal T-cannula to determine SID of AA in 4 batches of SBM originating either from Argentina (n = 1), Brazil (n = 1), or the United States (n = 2; US1 and US2). A semisynthetic diet based on corn (Zea mays) starch and casein (125 g casein/kg as fed) was supplemented with 1 of 4 batches SBM at an inclusion rate of 235 g SBM/kg (as-fed) each. The chemical composition did not differ largely, with CP contents ranging from 458 in Argentinean to 461 g/kg (as-fed) in US1 SBM. The SID of indispensable AA ranged from 80% in US2 SBM to 83% in Argentinean SBM and from 74% for Trp in US2 and Brazilian SBM to 91% for Arg in US2, Brazilian, and Argentinean SBM. Most SID values did not differ among the SBM batches (P > 0.05). In conclusion, European SBM imports from Brazil, Argentina, or the United Sates were similar in their chemical composition. For most AA, high and uniform SID values were obtained independent from their source of origin. PMID- 23365326 TI - An increased ratio of dietary tryptophan to lysine improves feed efficiency and elevates plasma tryptophan and kynurenine in the absence of antimicrobials and regardless of infection with enterotoxigenic Escherichia coli in weaned pigs. AB - This experiment examined if a higher ratio of dietary Trp:Lys in the absence of antimicrobials improves production indices and modulates diarrhea in weaned pigs infected with enterotoxigenic Escherichia coli (ETEC). Effects of the Trp:Lys ratio on plasma levels of Trp and its metabolite kynurenine (Kyn) were also examined. Individually housed mixed-sex pigs (n = 72) weaned at 21 d of age (Landrace * Large White; initial BW of 6.3 +/- 0.32 kg) were stratified into 1 of 6 treatments (n = 12) according to a 2 * 3 factorial arrangement of (i) infection or without infection with ETEC and (ii) 3 dietary standardized ileal digestible (SID) Trp:Lys ratios of 0.17, 0.21, or 0.26 in a randomized complete block design. Pigs were fed diets (10.4 MJ NE; 1.24% SID Lys; 19.5% CP) ad libitum for 3 wk after weaning. Pigs were infected with ETEC (O149:K98:K88) at 72, 96, and 120 h after weaning and then bled on day 11. A Trp:Lys ratio of 0.26 improved (P = 0.021) G:F over the study period compared to other ratios, without an infection effect (P > 0.05). Treatments did not affect ADG or ADFI (P > 0.05). Infection increased (P = 0.039) the diarrhea index and increased fecal consistency scores (P = 0.010). Plasma Trp and Kyn were lower (P < 0.001) in pigs fed 0.17 Trp:Lys than those fed ratios of 0.21 and 0.26 and were not affected (P > 0.05) by infection. In conclusion, in the absence of antimicrobials, increasing the dietary Trp:Lys ratio to 0.26 improved G:F after weaning and increased plasma levels of Trp and Kyn. PMID- 23365327 TI - Phytase improves apparent total tract digestibility of phosphorus and calcium in piglets fed diets with adequate or reduced phosphorus content. AB - The effect of a thermotolerant 6-phytase produced by Trichoderma reesei on performance and apparent total tract digestibility (ATTD) of P and Ca was evaluated in 192 weaned piglets (randomized block design; 16 replicates; 2 piglets each). Diets based on wheat (Triticum aestivum), barley (Hordeum vulgare), oat (Avena sativa), soybean (Glycine max) meal, and whey protein with adequate [positive control (PC)] or reduced [negative control (NC)] Ca and P levels were fed for 46 d after weaning. The PC and NC diets contained 8.0 and 6.4 g/kg Ca and 2.9 and 1.9 g/kg digestible P, respectively. Pelleted diets contained 0, 500, or 1000 phytase units (FTU)/kg. Growth performance and G:F were measured during starter (25 d) and weaner pig (21 d) periods. The ATTD of Ca and P was determined by spot sampling at the end of the weaner pig period (8 pens per treatment over 5 consecutive d). Data were analyzed using a mixed model with random block effect and fixed effect of dietary P and phytase level and their interaction. Dietary P level did not affect ADG or G:F of piglets over the entire feeding period (P > 0.10) whereas phytase increased G:F (P < 0.05). During the starter period, phytase linearly enhanced (P < 0.05) ADG (258, 266, and 292 g) and G:F (639, 677, and 664 g gain/kg feed DM) without further increase in the weaner pig period (P > 0.10). A P * phytase interaction (P < 0.05) was observed for ATTD of P, more so for NC (48, 61, and 68%, respectively) than PC diets (52, 62, and 61%). The ATTD of Ca was higher (P < 0.05) for PC than NC diets (68 vs. 58%) and increased quadratically by phytase (61, 65, and 63%). In conclusion, the phytase tested enhanced piglet performance during the postweaning period and increased ATTD of P and Ca. PMID- 23365328 TI - Phytase inclusion in pig diets improves zinc status but its effect on copper availability is inconsistent. AB - Complexation of dietary phytate with cations is a major cause of reduced bioavailability of Zn and possibly Cu in pig diets. We conducted 2 studies with 2 treatments in young growing pigs (8 to 40 kg) to estimate potential contributions of phytase to availability and supply of Zn and Cu, respectively. Each treatment comprised 10 pens with 8 pigs each as experimental units. In Exp. 1, 500 phytase units (FTU)/kg of microbial phytase (Natuphos 5000G; BASF) was added to a diet containing 15 mg Zn from ZnSO(4) and 160 mg/kg Cu from CuSO(4) in addition to Cu and Zn from feed ingredients. In Exp. 2, 500 FTU/kg was added to a diet containing 45 mg Zn from ZnSO(4) without added CuSO(4). Feces were collected to determine nutrient digestibility, blood was collected, and pigs were killed to determine Cu and Zn in the liver. In both experiments, phytase inclusion increased (P < 0.001) Zn digestibility by on average 10% units, serum Zn level (P < 0.001) by 0.4 mg/L, and liver Zn content (P < 0.001) by 129 mg/kg DM. In Exp. 1 phytase increased (P = 0.03) Cu digestibility by 6% units but reduced (P = 0.04) liver Cu content by 35 mg/kg DM. In Exp. 2 phytase reduced (P < 0.001) Cu digestibility by 16% units without affecting liver Cu content. Results indicate that the effect of phytase on Cu availability depends on dietary Cu and Zn content and the response variable studied. In conclusion, the consistent effects of phytase on indices of Zn status allow a reduction of Zn inclusion in phytase supplemented diets. PMID- 23365329 TI - Metabolic profiling of plasma from sows before parturition and during lactation using a liquid chromatography-mass spectrometry-based approach. AB - During transition from late gestation to lactation, the sow undergoes large and sudden metabolic changes to adapt from anabolic to catabolic metabolism. Little is known about changes in nutrient uptake and intermediary metabolism of transition sows. This study was undertaken to screen the metabolic profile for qualitative changes in nutrient uptake and metabolism during transition. Four sows were fitted with permanent catheters in artery femoralis (AF), portal vein (PV), and hepatic vein (HV) (sampling sites). Sows were fed a standard lactation diet from 15 d prior to 28 d after parturition. Blood samples were taken 1.5 h after feeding on days -10, -3, 3, and 17 relative to parturition and plasma metabolites were analyzed by a liquid chromatography-mass spectrometry-based approach. Principal components analysis was performed to visualize the metabolic profiles and to screen for intermediary metabolites altered during the transition period. The metabolic profile of sows on day 3 after parturition was distinct from other days. Plasma betaine, Pro, and some unidentified lipid compounds contributed to the separation on day 3; betaine and Pro were lowered by 30% at day 3 compared to day -10 and day -3 (P < 0.001). Plasma choline, Pro, creatine, and unidentified lipid compounds contributed to the separation due to sampling sites. Plasma choline was lowest in HV, intermediate in AF, and highest in PV (P < 0.001) plasma, indicating net absorption from the gastrointestinal tract (PV vs. AF) and liver metabolism (HV vs. PV). The majority of unidentified metabolites found using the loadings plots that were affected by day or sampling site or both were revealed as lipid compounds, that is, bile acid, cholesterol, glycerol, phosphatidyl, sphingomyelin, or acylglycerol derivatives. In conclusion, the intermediary metabolism of sows, especially for fat, changed during transition, and a deeper understanding and detection of involved metabolites are needed to optimize sow feeding during transition. PMID- 23365330 TI - Ileal digestibility of sunflower meal, pea, rapeseed cake, and lupine in pigs. AB - The standardized ileal digestibility (SID) of CP and AA was evaluated in soybean (Glycine max) meal, sunflower (Helianthus annuus) meal, rapeseed cake, and field pea (Pisum sativum) using 10 pigs and in lupine (Lupinus angustifolius) using 7 pigs. Pigs were fitted with either a T-cannula or a steered ileocecal valve cannula. Diets contained 170 to 186 g CP/kg DM. Endogenous losses of CP and AA were estimated by feeding a N-free diet. The SID was calculated using the average of Cr(2)O(3) and TiO(2) as indigestible markers and corrected for type of cannula. The SID of CP was greater (P < 0.05) for soybean meal and pea compared to sunflower meal, rapeseed cake, and lupine. The SID of Lys and His were lowest (P < 0.05) in sunflower meal, and the SID of Met and Val were lowest (P < 0.05) in lupine. These results imply soybean meal and pea to be a high-digestible protein source relative to sunflower meal, rapeseed cake, and especially lupine, although all tested feedstuffs seem appropriate for inclusion in diets for organic pigs. PMID- 23365331 TI - Effect of microbial phytase on phosphorus digestibility in non-heat-treated and heat-treated wheat-barley pig diets. AB - The objective was to evaluate effects of microbial phytase on apparent total tract digestibility (ATTD) of P in a non-heat-treated and a heat-treated wheat (Triticum aestivum)-barley (Hordeum vulgare) diet fed without inorganic P in a 2 * 3 factorial arrangement. The basal diet was ground and half of the batch was steam pelleted at 81 degrees C and crumbled. Phytase was added at 0, 250, and 500 phytase units (FTU)/kg as-fed (Aspergillus niger). The study comprised 36 pigs from 6 litters. Pigs were housed in metabolism crates and fed 1 of 6 diets for 12 d: 5 d for adaptation and 7 d for total collection of feces. The ATTD of P was highest (P < 0.01) for the non-heat-treated diets and highest (P < 0.01) for the phytase-supplemented diets. Heat treatment reduced plant phytase activity by 25% whereby the ATTD of P decreased (P < 0.01) from 57 to 49%. Microbial phytase increased the ATTD of P to a maximum of 64 and 61% in the non-heat-treated and heat-treated diets corresponding to an increase of 7 and 12%-units. Responses for ATTD of P did not differ between 250 vs. 500 FTU/kg as-fed. In conclusion, processing of feed (meal or pellets) containing plant phytase should be considered to avoid over- or underestimation of effects of microbial phytase. PMID- 23365332 TI - Digestible energy values of feed ingredients with or without addition of enzymes complex in growing pigs. AB - The DE values and digestible nutrients content of 6 diets were measured in 60-kg male growing pigs fed restricted amount of feed. Diets were prepared from 5 ingredients [wheat (Triticum aestivum), corn (Zea mays), barley (Hordeum vulgare), wheat bran, and soybean (Glycine max) meal; inclusion levels of ingredients were not correlated] with or without carbohydrose enzyme (Rovabio Excel AP; 3300 endo-beta-1,4-xylanase visco units and 300 endo-1,3(4)-beta glucanase units/kg of feed; 150 g/t of feed) according to a 6 * 2 factorial arrangement; dietary NDF ranged from 10.6 to 20.1% of DM. Pigs (5 per treatment) were placed in metabolism cages that allowed total collections of feces and urine for 10 d after a 11-d adaptation. Samples of feed, urine, and feces were analyzed for GE, ash, and N. Digestibility of GE, N, and OM were calculated. The effects of diet and enzyme (Enz) were evaluated by ANOVA. In addition, the DE and digestible nutrient contents of ingredients were calculated by regression of nutritive values of diets on level of ingredient inclusions. Apparent total tract digestibility of OM, N, and GE of diets were associated with dietary NDF content (r = -0.97; P < 0.001) and were increased (P < 0.05) by Enz addition by 0.4, 1.6, and 0.5%-units (a difference between two percentage values) for OM, N, and GE digestibility, respectively. Improvement in DE value due to Enz averaged 0.09 MJ/kg DM (15.11 vs. 15.02 MJ/kg DM; P < 0.05). The ADG (891 vs. 850 g/d; P < 0.05) was also increased by Enz addition. The calculated DE content without Enz addition averaged 16.3, 16.4, 14.9, 10.5, and 17.2 MJ/kg DM for wheat, corn, barley, wheat bran, and soybean meal, respectively. The Enz addition increased the DE value of ingredients similarly, but the best response was observed for wheat (0.33 MJ/kg DM). PMID- 23365333 TI - Effects of formic acid and phytase supplementation on digestibility and use of phosphorus and zinc in growing pigs. AB - Two studies, arranged according to a 4 * 4 Latin square design, were conducted to assess effects of dietary acidification on fungal 3-phytase (PHY) efficacy in growing pigs. In Exp. 1, effects of supplementing 500 units/kg feed of PHY and 4.7 g/kg HCOOH either alone or in combination on the use of P and Zn in growing pigs fed a pelleted diet based on wheat (Triticum aestivum), barley (Hordeum vulgare), and soybean (Glycine max) meal were investigated. In Exp. 2 the same dietary treatments were fed except that PHY supplementation was increased to 1000 units/kg. In both experiments, PHY supplementation increased (P < 0.05) P digestibility and retention. A PHY * HCOOH supplementation interaction on P balance was observed (P < 0.05), indicating that the combination of the additives may increase P digestibility and retention. Effects of HCOOH and PHY on Zn use followed a similar pattern. Supplementation of 1000 units/kg of PHY further increased P and Zn retention compared to supplementation of 500 units/kg. In conclusion, the present study indicated that HCOOH supplementation to diets with microbial PHY may increase PHY efficacy. PMID- 23365334 TI - Effect of supplementing different ratios of laminarin and fucoidan in the diet of the weanling piglet on performance, nutrient digestibility, and fecal scoring. AB - A 3 * 2 factorial experiment was conducted to investigate the effects of different ratios of dietary laminarin (LAM) and fucoidan (FUC) on growth performance and nutrient digestibility in newly weaned piglets. At weaning, 168 piglets (24 d of age; 6.8 kg live weight) were assigned to 1 of 6 dietary treatments (n = 14/treatment): (i) basal diet, (ii) basal diet + 240 mg/kg FUC, (iii) basal diet + 150 mg/kg LAM, (iv) basal diet + 150 mg/kg LAM and 240 mg/kg FUC, (v) basal diet + 300 mg/kg LAM, and (vi) basal diet + 300 mg/kg LAM and 240 mg/kg FUC. Pigs offered 300 mg/kg LAM-supplemented diets had a higher ADG (P < 0.05) throughout the entire experimental period (days 0-35) compared with pigs offered diets with 0 and 150 mg/kg LAM supplementation. There was a significant interaction between LAM and FUC supplementation on G:F (P < 0.05) during the entire experimental period. Pigs offered the 300 mg/kg LAM-supplemented diet had a higher G:F than pigs offered the basal diet. However, there was no effect of the high level LAM on G:F when combined with FUC. There was a significant interaction between LAM and FUC supplementation on the apparent total tract digestibility (ATTD) of GE (P < 0.05). Pigs offered the 150 and 300 mg/kg LAM diet had an increased ATTD of GE compared with pigs offered the basal diet. However, there was no effect of LAM on ATTD of GE when combined with FUC. Pigs offered the 150 and 300 mg/kg LAM-supplemented diets had an improved fecal consistency (P < 0.05) from day 7 to day 14 compared to pigs offered diets without LAM supplementation. In conclusion, the inclusion of LAM improved growth performance of pigs after weaning partially due to an increased ATTD of GE. PMID- 23365335 TI - Digestibility energy and amino acids of canola meal from two species (Brassica juncea and Brassica napus) fed to distal ileum cannulated grower pigs. AB - Yellow-seeded Brassica juncea is a novel canola species targeted to grow in the southern Canadian prairies where thermotolerance, disease resistance, and adaptation to dry agronomic conditions are required. The support of its cultivation needs nutritional evaluation of its coproduct. The B. juncea canola meal (CM) contains less fiber than conventional, dark-seeded Brassica napus CM but also slightly less Lys. In a 6 * 6 Latin square, 6 distal ileum cannulated pigs (47 kg BW) were fed 6 diets to determine the apparent ileal digestibility (AID) and standardized ileal digestibility (SID) of CP and AA, AID and apparent total tract digestibility (ATTD) of energy, and VFA content in digesta and feces. Pigs were fed 6 diets: basal [46% wheat (Triticum aestivum) and corn (Zea mays) starch], 4 diets with 46% wheat and either B. juncea or B. napus CM at 25 or 50%, and a N-free diet based on corn starch. The B. juncea CM had higher (P < 0.05) ATTD of energy than B. napus CM (68.6 vs. 60.3%) likely due to its lower fiber content. Ileal total VFA was lower (P < 0.001) in pigs fed B. juncea than B. napus CM diets. In pigs fed B. juncea CM, the molar ratio in digesta was lower (P < 0.001) for acetate and butyrate whereas the propionate ratio was lower (P < 0.001) in feces than in pigs fed B. napus CM diets. The CM species did not affect the AID of energy, SID of AA, and feces VFA content. The DE value was higher (P < 0.05) and content of SID Lys was lower (P < 0.05) for B. juncea than B. napus CM. In conclusion, availability of B. juncea CM, a coproduct of a canola species grown in Canadian prairie land, will increase flexibility in swine feed formulation. PMID- 23365336 TI - Prediction of gross energy and digestible energy in copra meal, palm kernel meal, and cassava root fed to pigs. AB - Many of the available prediction equations for feed energy value may not be applicable for ingredients such as copra (Cocos nucifera) meal (CM), palm kernel meal (PKM), and cassava (Manihot esculenta) root (CR). Therefore, we developed novel equations for estimating GE and DE concentrations in CM, PKM, CR, and diets containing these ingredients. Data for GE and DE concentrations were obtained from previous experiments in which the chemical composition in the ingredients and diets were determined. In addition, in vitro DM digestibility (IVDMD) values in 3 samples of ingredients including CM, PKM, and CR and 4 samples of diets including a corn (Zea mays)-soybean (Glycine max) meal-based diet and 3 diets containing CM, PKM, and CR were determined. Based on the model R(2), conceptual predictive criterion, and the P-value of the equation, the best equation for GE concentration (kcal/kg) was GE = 3313 + (24.81 * CP) + (9.83 * NDF) with R(2) = 0.93, root mean square error = 102, and P = 0.005 (CP and NDF values are percentages). Regression analysis was conducted between the DE:GE ratio and IVDMD (%). The DE:GE ratio was 0.81, 0.73, 0.83, 0.89, 0.84, 0.82, and 0.88 in CM, PKM, CR, a corn-soybean meal-based diet, and diets containing CM, PKM, or CR, respectively. The values for IVDMD were 70.3, 42.6, 88.2, 93.4, 86.7, 75.5, and 91.3%, respectively. The DE:GE ratio may be calculated by (0.0030 * IVDMD) + 0.5986 (R(2) = 0.91; P = 0.001). Using the estimated GE concentration and IVDMD, the prediction equation for DE concentration (kcal/kg) was DE = -1965 + (1.02 * GE) + (15.33 * IVDMD) with R(2) = 0.88 and P = 0.007. In conclusion, IVDMD values are useful in estimating energy digestibility in CM, PKM, CR, and diets containing these ingredients. PMID- 23365337 TI - The effect of seaweed extract as an alternative to zinc oxide diets on growth performance, nutrient digestibility, and fecal score of weaned piglets. AB - This study investigated if supplementing the diet with seaweed extracts (SWE) containing laminarin and fucoidan would promote growth performance, nutrient digestibility, and fecal consistency in newly weaned piglets during 2 growth phases as compared with ZnO. The experiment was designed as a 2 * 2 factorial with 2 levels of SWE (0 or 300 mg/kg laminarin + 240 mg/kg fucoidan) and 2 levels of ZnO [0 or added (3.1 g/kg for the starter diet and 2.5 g/kg for the transition diet)]. Dietary treatments were (i) basal diet, (ii) basal diet + ZnO, (iii) basal diet + SWE, and (iv) basal diet + ZnO + SWE. Newly weaned 6.5-kg pigs (n = 12; 4 pigs per pen) were offered supplements in a starter diet from weaning (day 0) to day 21 and in a transition diet from day 22 to day 40. There was an interaction (P = 0.005) between SWE and ZnO on G:F whereby pigs supplemented with SWE and ZnO individually had improved G:F when compared with the combination diet. There was an interaction between SWE and ZnO interaction on digestibility of DM (P < 0.01), N (P < 0.01), and NDF (P < 0.01). Pigs offered the SWE diets alone had a higher digestibility of DM, N, and NDF compared with pigs offered the basal diet. In summary, SWE induced a comparable growth performance pattern as obtained with ZnO inclusion. However, this was negated when supplements were offered in combination. Improvements in growth performance of pigs consuming SWE alone may reflect improvements in nutrient digestibility. PMID- 23365338 TI - Evaluation of different protections of butyric acid aiming for release in the last part of the gastrointestinal tract of piglets. AB - Three tests, 2 in vivo and 1 in vitro, were conducted to compare how 2 forms of protection of butyric acid (BA) affect its liberation along the gastrointestinal tract (GIT) of piglets. The 2 forms of BA were vegetable fat-encapsulated sodium butyrate (SBE) and monoglyceride of butyric acid (MB). In the first trial, 528 piglets were weaned at 21 d of age and assigned to 3 diets in 8 replicate pens of 22 piglets per pen for 39 d. The 3 diets were (i) prestarter and starters I and II (Con), (ii) C + SBE (6 kg/t in both prestarter and starter feeds), and (iii) C + MB (2.5 kg/t in the prestarter feed, 2 kg/t in the starter feed I, and 0 kg/t in the starter feed II). Piglets receiving C and SBE feeds tended to show higher BW (18.74, 18.66, and 17.82 kg; P < 0.1) and ADG (331.2, 330.5, and 308.9 g/d; P < 0.1) than MB piglets; no significant differences were observed in feed intake or FCR. In the second trial, 8 pens of 4 piglets each (4 pens per treatment), weaned at 21 d, were given either a standard postweaning program with SBE (2 kg/t) or with MB (2 kg/t) and received the same amount of BA. Body weight, feed intake, and FCR were evaluated at days 14 and 28 of trial. At the end of the trial, 1 animal per pen was euthanized and the concentration of BA and VFA in duodenum, jejunum, ileum, colon, and cecum were quantified with HPLC. There were no statistical differences in growth, feed intake, or FCR. However, SBE-fed animals had higher concentration of VFA in colon than MB-fed animals. There were relevant numerical differences in the rest of the GIT sections but they were not statistically significant. The in vitro digestion of the products confirmed that BA can be released more easily from SBE (157.2 g of BA/kg of product after 7 h) than from MB (56.4 g of BA/kg of product after 7 h). It is concluded that the addition of SBE allows more BA to reach the distal sections of the GIT than MB. PMID- 23365339 TI - Cocoa husks in diets of Italian heavy pigs. AB - The aim of the present study was to evaluate the effect of cocoa husks feeding on liver composition of the Italian heavy pig. Cocoa husks are by-products derived from chocolate production and have a high content of proteins, lipids, and NDF. Cocoa husks are also rich in antioxidants, polyphenols in particular. Eight finishing pigs were divided into 2 groups: control group fed a traditional diet, based on cereals, and treatment group fed a diet obtained by substitution of 10% of the control diet with coarsely ground cocoa husks. The trial was conducted during the hot season and lasted 6 wk, at the end of which all the pigs were slaughtered. Cocoa husks diet reduced dry matter intake (P < 0.01) and energy intake (P < 0.01) but neither body weight nor backfat thickness was affected by cocoa husks diet. Treatment did not influence carcass weight and hot dressing percentage but reduced liver weight (P < 0.05), liver dry matter percentage (P < 0.01), DNA (P = 0.01), and glycogen content (P = 0.01). By contrast, cocoa husks increased liver ether extract (P = 0.05) without affecting cholesterol content. Liver weight loss, reduction of protein synthesis, and a shift toward glycogen use instead of fat oxidation are considered metabolic strategies to reduce heat production under hot conditions. It is possible, therefore, that cocoa husks feeding promoted the process of acclimation because pigs needed less feeding to reach similar body and carcass weight as control pigs. PMID- 23365340 TI - Effect of immune system stimulation and divergent selection for residual feed intake on digestive capacity of the small intestine in growing pigs. AB - Little is known of the consequences of divergent selection for residual feed intake (RFI) on intestinal digestion capacity, particularly during immune system stimulation (ISS). Our objective was to evaluate the impact of ISS and divergent selection for RFI on apparent ileal digestibility (AID) and apparent fecal digestibility (AFD) of nutrients and intestinal nutrient active transport and barrier function. Twenty-eight gilts (63 +/- 4 kg BW) from low RFI (LRFI; n = 14) and high RFI (HRFI; n = 14) Yorkshire lines were randomly selected from the Iowa State University RFI herd. Following adaptation, 8 pigs in each line were injected intramuscularly and every 48 h for 7 d with increasing amounts of Escherichia coli lipopolysaccharide (ISS+). Remaining pigs were injected with saline (ISS-). Pigs were then euthanized and ileal digesta was collected for measuring AID of nutrients. Fecal samples were collected on a daily basis and pooled for measuring AFD of nutrients. A segment of ileum was used to measure nutrient transport and transepithelial resistance (TER) and/or barrier integrity by Ussing chambers. No effects of line or its interaction with ISS on AID of CP (N * 6.25) and OM, TER, and active nutrients transport were observed. However, ISS decreased (P < 0.05) and tended to (P < 0.1) decrease AID of CP and OM, respectively. Decrease in AFD of CP as result of ISS was greater in the LRFI line compared to the HRFI line (P < 0.05). Relative to ISS-, active glucose and P transport was greater in ISS+ pigs (P < 0.05). Genetic selection for LRFI increases the AFD but has no effect on AID of nutrients. It also reduces the total tract digestive capacity of growing pigs during ISS. Immune system stimulation affects both AID and AFD of dietary CP. PMID- 23365341 TI - Dynamic changes in digestive capability may contribute to compensatory growth following a nutritional insult in newly weaned pigs. AB - We have previously demonstrated that feeding low complexity diets (LOW) compromises growth performance of pigs during the first 3 wk after weaning and induces compensatory growth and improved feed efficiency thereafter. A study was undertaken to explore physiological mechanisms involved in compensatory growth following a nutritional insult. Fifty-six pigs were weaned at 21 +/- 2 d of age and fed high complexity diets (HIGH) for 6 wk. All pigs received the same grower diet thereafter. Pigs were killed at weeks 2, 4, and 8 after weaning and proximal jejunum and distal ileum were sampled for evaluation of histology and enzyme activity. In the proximal jejunum, villus height was lower (P = 0.03) at week 2 in pigs on LOW than HIGH but not different at week 4. There was no effect of diet on crypt depth; villus height:crypt depth ratio increased (P = 0.02) from week 2 to week 4 in pigs on LOW but was not changed in pigs on HIGH. Diet did not impact gut morphology at the distal ileum. Enzyme activity was lowest (P < 0.05) at week 2 for sucrase and aminopeptidase N (APN) and lowest (P < 0.06) at week 8 for lactase. Sucrase activity was numerically higher at week 4 in pigs fed LOW but numerically higher at week 8 in pigs fed HIGH. Lactase and APN activity were not affected by diet. Compensatory growth observed in pigs following a nutritional insult after weaning may be due in part to improved digestive capability. PMID- 23365342 TI - Standardized ileal amino acid digestibility in egg from hyperimmunized hens fed to weaned pigs. AB - The study was conducted to determine the apparent ileal digestibility (AID) and standardized ileal digestibility (SID) of AA in egg from hens hyperimmunized with Escherichia coli K88 antigens (EGG) fed to weaned pigs. Spray dried porcine plasma (SDPP) was included for comparison. Eight barrows (Yorkshire-Landrace * Duroc; initial BW of 17 +/- 1 kg) were fitted with a T-cannula at the distal ileum and fed 2 diets in a completely randomized design to give 4 replicates per diet. The diets were corn (Zea mays) starch based with either EGG or SDPP as the sole source of protein and were formulated to contain 130 g/kg CP. At the end of the study, a 50 g/kg casein diet was fed to all pigs (n = 8) to quantify endogenous N and AA losses to determine SID. Titanium dioxide (3 g/kg) was included in the diets as an indigestible maker. Each period lasted for 7 d. Pigs were adapted to their respective diets for 5 d followed by 12 h of continuous ileal digesta collection on days 6 and 7. Daily feed allowance was set at 4% BW at the beginning of each period and offered in 2 equal portions at 0800 and 1600 h as a dry mash. Pigs had unlimited access to water via low pressure nipple drinkers. The AID (%) of CP and indispensable AA were lower (P < 0.05) in EGG compared with SDPP. The SID (%) of CP (82 vs. 96) and indispensable AA were lower (P < 0.05) in pigs fed EGG compared with SDPP. In conclusion, the average AID and SID of N and indispensable AA in EGG are lower than in SDPP when fed at high levels. PMID- 23365343 TI - High-moisture air-tight storage of barley and wheat improves nutrient digestibility. AB - Barley (Hordeum vulgare) and wheat (Triticum aestivum) are often stored dry with 14% or less moisture, which during rainy periods may require that grains are dried after harvest. The hypothesis is that air-tight storage of high-moisture barley and wheat will increase nutrient digestibility due to chemical conversions prior to feeding. The objective was to evaluate the effect of high moisture compared to dry storage of barley and wheat on digestibility of P and CP. The crops were grown on 1 field keeping other factors constant. Half of the grains was harvested in the morning after a rainy day and stored in air-tight silos (DM, %: barley, 85.2; wheat, 82.8) and the other half was harvested later the same day (windy and sunny) and stored dry (DM, %: barley, 89.8; wheat, 88.3). After 6 mo of storage, 1 low- and 1 high-moisture diet were prepared with a barley:wheat ratio of 1:1 mixed with soybean (Glycine max) meal and rapeseed cake to produce a compound diet without inorganic P and microbial phytase. Sixteen 45-kg pigs housed in metabolism crates were fed either the low- or the high-moisture diet for 5 d for adaptation and 7 d for total collection of feces. Digestibility of P was 12% higher (P < 0.01) and of CP was 4% higher (P = 0.08) in the high-moisture diet. Phytase activity of dry-stored grain was lower (P < 0.01) and phytate P was 4% higher in the high-moisture stored grain vs. the grains stored dry. Overall, high-moisture storage increased digestibility of P and CP when the grain was fed to finishing pigs. Therefore, high-moisture air-tight storage saved energy (without drying) and at the same time enhanced P digestibility and increased the nutritional value of grain probably through enzymatic activity during storage. PMID- 23365344 TI - Dose response of a new phytase on dry matter, calcium, and phosphorus digestibility in weaned piglets. AB - The present study evaluated the dose response of Buttiauxella phytase on apparent total tract digestibility (ATTD) of DM, Ca, and P in weaned pigs at 2 locations. Experimental diets fed to weaned pigs were a positive control (PC), a negative control (NC), and NC supplemented with increasing levels of Buttiauxella phytase. In Trial A, ATTD of P was 57.2% for PC, 32.5% for NC, and 59.4, 62.0, 63.8, 66.0, and 67.3% for 250, 500, 750, 1000, and 2000 phytase units (FTU) added to NC, respectively. In Trial B, ATTD of P was 45.2% for PC, 28.4% for NC, and 58.7, 64.1, 67.9, and 70.9% for 250, 500, 1000, and 2000 FTU added to NC, respectively. In both studies, the reduction in P in the NC diets reduced (P < 0.01) ATTD of P when compared with the PC diets. Phytase supplementation linearly and quadratically increased (P < 0.01) ATTD of P at all inclusion levels to the NC diet. In conclusion, the average digestible P increase from Buttiauxella phytase (vs. the NC diet) was 1.3, 1.5, 1.6, and 1.7 g digestible P/kg feed for 250, 500, 1000, and 2000 FTU/kg, respectively. PMID- 23365345 TI - Evolution of zinc, iron, and copper concentrations along the gastrointestinal tract of piglets weaned with or without in-feed high doses of zinc oxide compared to unweaned littermates. AB - High doses of ZnO are used to treat diarrhea in weaning pigs but are also an environmental concern. The mechanism of action of Zn against diarrhea is still not well understood. The amount of solubilized Zn, the relation of Zn with Fe and Cu, and the concentration of these elements in the gastrointestinal tract (GIT) are key data to understanding its mechanism of action and optimize its use. Therefore, we studied the Zn, Fe, and Cu concentrations in the GIT content of unweaned, weaned, and ZnO-treated pigs. Eight litters were used and 3 piglets were selected within each litter. Two piglets from each litter were weaned at 21 d of age and fed a commercial control diet (WCt) or WCt + 2000 mg/kg of Zn as ZnO (WZn). The third pig was kept unweaned (Uw) with the sow. All 24 pigs were killed at 28 d of age, GIT contents were sampled, soluble and insoluble fractions of the content were separated, and Zn, Fe, and Cu concentrations were analyzed. Concentration of Zn increased 3 to 5 fold along the GIT (2 to 10 fold in the soluble fraction) for weaned pigs on WZn compared to WCt and Uw pigs (P < 0.01 in all cases). The proportion of total Zn that was present in the soluble fraction was 4 to 10 folds higher in jejunum, ileum, and cecum of Uw pigs than in those weaned (P < 0.01 in all cases) but was not affected by ZnO treatment. Concentration of Fe in the soluble fraction was higher for Uw pigs compared to weaned pigs along the GIT (P < 0.05 in all cases) even when concentration in total content was lower for Uw pigs in stomach (P = 0.001) and jejunum (P = 0.029). Concentrations of Cu were lower in Uw pigs than in weaned pigs along the GIT (P < 0.05 in all cases). Surprisingly, animals on WZn showed a 5 to 10 fold increase of Cu solubilized in distal parts of the GIT (cecum and colon; P < 0.001) compared to other groups. Differences in Zn, Fe, and Cu concentrations found among treatments will be useful in future studies for understanding mechanism of action of ZnO and optimizing its use in order to avoid environmental concerns. PMID- 23365346 TI - Evaluation of energy digestibility of canola coproducts by in vitro analyses and characterization of fat digestion using spectroscopy. AB - In vitro methods did not accurately predict in vivo apparent total tract digestibility of energy for canola coproducts (r = -0.81; P = 0.002). We scanned 153 samples of digesta, feces, and in vitro digestion residues (ivR) on a Fourier transform midinfrared instrument with a single-reflection attenuated total reflectance attachment. The second derivative spectral net intensities of the carbonyl ester peak at 1745 cm(-1) and olefinic hydrocarbon (=C-H) peak at 3008 cm(-1) were both higher in ivR than in feces (3.83 * 10(-04) vs. 3.46 * 10(-05) and 7.92 * 10(-05) vs. 5.17 * 10(-06), respectively; P < 0.001), indicating poor enzymatic digestion of unsaturated fat. In conclusion, fat digestion of in vitro procedure for canola coproducts requires improvement to adequately mimic in vivo digestion in pigs. PMID- 23365347 TI - Effects of dietary true digestible calcium to phosphorus ratio on growth performance and efficiency of calcium and phosphorus use in growing pigs fed corn and soybean meal-based diets. AB - Objectives of this study were to determine effects of dietary true fecal digestible Ca to true digestible P ratio on growth performance and efficiency of Ca and P use in growing pigs fed corn (Triticum aestivum)-soybean (Glycine max) meal (SBM)-based diets. Experiment 1 was carried out to measure true fecal digestibility of Ca and P as well as the fecal endogenous outputs of these nutrients associated with a corn and SBM-based diet in 12 Yorkshire growing pigs with an average initial BW of 23.2 +/- 0.6 kg by the substitution method. True fecal digestibility values (%; n = 6) of Ca (53.6 +/- 12.7) and P (43.8 +/- 16.7) as well as the fecal endogenous outputs (g/kg DMI; n = 12) of Ca (0.91 +/- 0.20) and P (1.31 +/- 0.15) associated with the diets were determined. Experiment 2 was conducted with 36 Yorkshire barrows of an average initial BW of 24.2 +/- 0.6 kg and the pigs were fed 6 diets according to a completely randomized block design. The 6 diets were corn and SBM based with diet 1 containing 0.2% true digestible Ca and 0.3% true digestible P and were formulated to contain 6 total Ca to total P ratios based on analyzed dietary Ca and P contents (diet 1, 0.6:1; diet 2, 0.7:1; diet 3, 0.8:1; diet 4, 1.3:1; diet 5, 1.0:1; and diet 6, 1.3:1) by supplementing gradient levels of limestone with a constant dietary P content for meeting the recommended requirement. Changes in the dietary Ca to P ratio had no effects (P > 0.05) on ADG. No differences (P > 0.05) in ADFI were observed between the other diets except the lower ADFI (P < 0.05) in diet 3 compared with diet 2. However, G:F was higher (P < 0.05) in diet 2 compared with diets 5 and 6. Changes in the dietary Ca to P ratio had consistent effects on true fecal P digestibility and retention with much lower values (P < 0.05) observed in diet 5 in comparison with the other diets. In summary, true fecal digestible Ca to P ratios of 0.9:1 to 1.0:1 were associated with optimal responses in both G:F as well as true fecal P digestibility and retention in growing pigs fed corn and SBM based diets. PMID- 23365348 TI - Heat stress reduces barrier function and alters intestinal metabolism in growing pigs. AB - High ambient temperature exposure can cause major reductions in intestinal function, pig performance, and, if severe enough, mortality. Therefore, our objective was to examine how acute heat stress (HS) alters growing pig intestinal integrity and metabolism. Individually penned crossbred gilts and barrows (46 +/- 6 kg BW) were exposed to either thermal neutral (TN; 21 degrees C; 35 to 50% humidity; n = 8) or HS conditions (35 degrees C; 24 to 43% humidity; n = 8) for 24 h. All pigs had ad libitum access to feed and water. Rectal temperature (Tr), respiration rates (RR), BW, and feed intake (FI) were measured. Pigs were killed after 24 h of environmental exposure and freshly isolated ileum and colon samples were mounted into modified Ussing chambers. Segments were analyzed for glucose and glutamine nutrient transport and barrier integrity [transepithelial electrical resistance (TER) and fluorescein isothiocyanate-labeled dextran transport]. As expected, pigs exposed to HS had an increase in Tr (39.3 vs. 40.9 degrees C; P < 0.01) and RR (52 vs. 119 breaths per minute; P < 0.05). Heat stress decreased FI (53%; P < 0.05) and BW (-2.2 kg; P < 0.05) compared to TN pigs. Compared to TN pigs, mucosal heat shock protein 70 increased (101%; P < 0.05) whereas intestinal integrity was compromised in the HS pigs (ileum and colon TER decreased 52 and 24%, respectively; P < 0.05). Furthermore, serum endotoxin concentrations increased 200% due to HS (P = 0.05). Intestinal glucose transport and blood glucose were elevated due to HS (P < 0.05). However, ileal sucrase and maltase activities decreased in HS pigs (30 and 24%, respectively; P < 0.05). Altogether, these data indicate that high ambient heat loads reduce intestinal integrity and increase circulating endotoxin and stress in pigs. Furthermore, glucose transport and digestive capacity are altered during acute HS. PMID- 23365349 TI - The influence of dietary locust bean gum and live yeast on some digestive immunological parameters of piglets experimentally challenged with Escherichia coli. AB - Gums and yeast cells are natural mannose-rich products that can be used as subtracts for adhesion of gram-negative bacteria. The aim of the study was to investigate the role of dietary locust bean gum (LBG; Salmosan, ITPSA, Spain) or live yeast (Saccharomyces cerevisiae Sc47; Actisaf, Lesaffre, France) as immunological enhancers of the intestinal function of piglets. Treatments included a noninfected group fed with a control diet and 4 other groups orally challenged with 1x10(8) cfu of Escherichia coli K88. The challenged groups were fed the control or the control diet supplemented with colistin, LBG, or yeast. Twenty-five Landrace * Duroc piglets weaned at 4 wk were used. The animals were group housed, challenged on day 14, and euthanized 2 d later. Blood, bile, ileum, and mesenteric lymph node (MLN) samples were obtained for analysis of C-reactive protein (CRP), secretory immunoglobulin A (sIgA), and Toll-like receptors 2 (TLR2) and 4 (TLR4). Challenge increased the level of CRP of piglets fed the control diet, but this did not happen in the piglets fed the supplemented diets (P < 0.001). Challenge upregulated TLR2 in MLN and TLR4 in ileum and MLN (P < 0.05). This was prevented by yeast supplementation for the TLR2 in MLN and TLR4 in ileum. Pigs fed colistin and LBG diets showed intermediate but nonsignificant responses. In conclusion, the results suggest that colistin, live yeast, and LBG reduce the levels of CRP in blood of piglets challenged with E. coli, and yeast reduces the expression of Toll-like receptors in the intestine. PMID- 23365350 TI - Effects of dietary supplementation with Laminaria hyperborea, Laminaria digitata, and Saccharomyces cerevisiae on the IL-17 pathway in the porcine colon. AB - An unregulated T(h)17 inflammatory response has been highlighted as a major contributor to the underlying pathology of inflammatory bowel diseases (IBD) whereas regulatory T (T(REG)) cells) have been highlighted as pivotal in suppressing autoimmune and inflammatory responses in the gut. Following dietary supplementation, beta-glucans have been shown to reduce the T(h)17 signature molecule IL-17a in the porcine colon. To expand this observation we examined the effects of supplementing feeds with beta-glucans derived from seaweeds Laminaria hyperborea and Laminaria digitata and the yeast Saccharomyces cerevisiae on gene expression of a range of cytokines, receptors, and signal transducing molecules relevant to the T(h)17 and T(REG) pathways in the porcine colon. All sources of beta-glucans significantly decreased the expression of T(h)17-related cytokines (IL-17a, IL-17F, and IL-22), receptor IL23R, and IL-6. There was no alteration to the T(REG)-related target, Foxp3, or to TGF-beta, although a significant reduction in IL-10 was observed in the L. digitata supplementation group. PMID- 23365351 TI - Butyrate promotes the recovering of intestinal wound healing through its positive effect on the tight junctions. AB - Postweaning diarrhea is one of the most common causes of morbidity and mortality in weanling piglets. Feeding sodium butyrate to weanling piglets decreased the incidence of diarrhea, but the mechanism has not been fully elucidated. The present study was to evaluate the effect of sodium butyrate on diarrhea in relation to wound healing of intestinal barrier using IPEC-J2 cell model. Cultured cells were scratched to induce wound and then were treated with 4 mM sodium butyrate. The results showed that supplementation of the cells with sodium butyrate significantly promoted the process of wound healing, indicating the protective effects of butyrate on the intestinal mucosa. Butyrate treatment enhanced mRNA expression of the intestinal mucosal tight junction proteins occludin and zonula occluden protein-1 (P < 0.05), which suggested that the promotion of wound healing by butyrate is related to the maintenance of the function of the intestinal barrier. In addition, in the butyrate-treated group, intestinal total superoxide dismutase and glutathione peroxidase (P < 0.05), two of the main antioxidant enzymes, as well as glutathione (P < 0.05), one of the nonenzymatic antioxidant components, were enhanced whereas the malondialdehyde level, a marker of free radical mediated lipid peroxidation injury, was decreased (P < 0.05) compared with the control group. Collectively, these results indicate that dietary sodium butyrate might, at least partly, play an important role in recovering the intestinal tight junctions having a positive effect on maintaining the gut integrity. PMID- 23365352 TI - The effect of a mixture of dairy-based feed ingredients, vegetable fats, and yeast cell walls on performance and innate immunity of weaned piglets. AB - Positive effects of yeast concentrate on immunity and performance of weaned piglets have been reported. However, the effects on innate immunity were not examined. Natural antibodies (NAb) are part of innate immunity and have been related to health and survival in fish, poultry, rodents, and man. Yeast cell walls may also affect innate immunity of weaned piglets. We studied the effect of Nuklospray ProHealth containing a spray dried blend of dairy-based feed ingredients, vegetable fats, and processed yeast cell walls as protein source on NAb levels and performance of weaned piglets. A total of 120 piglets weaned at 28 d of age were assigned 2 treatments comprising a control diet and an experimental diet with the test product. Piglets were housed in groups of 6 during the first 4 weeks after weaning. Blood samples of 20 healthy nonmedicated piglets per treatment were taken at days 0, 14, and 28 after weaning and analyzed for NAb levels binding keyhole limpet hemocyanin by an indirect ELISA procedure. Performance parameters also were determined. Overall, the experimental diet tended to improve feed intake (574 vs. 522 g/d; P < 0.1), ADG (449 vs. 412 g/d; P < 0.1), and final BW (21.4 vs. 20.3 kg; P = 0.08) compared to the control diet. No differences were found in feed conversion ratio or fecal score. At day 0, no differences in NAb levels were found, but on day 14 after weaning, NAb levels of piglets fed the experimental diet were significantly higher than of piglets fed the control diet (2.05 vs. 1.70; P < 0.05). On day 28 after weaning no differences were found. These results indicate that day 14 postweaning levels of NAb as a parameter of innate immunity were improved and indicate a tendency for improvement of postweaning performance of piglets fed diets supplemented with Nuklospray ProHealth. PMID- 23365353 TI - Effect of grinding intensity and feed physical form on in vitro adhesion of Salmonella Typhimurium and mannose residues in intestinal mucus receptors for salmonellae. AB - The hypothesis of this study was that feeding a fine, pelleted diet (FP) compared to a coarse meal diet (CM) results in a higher mannose content in the intestinal mucus of pigs and therefore an increased in vitro adhesion of Salmonella Typhimurium DT104 L to the mucus. The 2 diets were fed to a total of 24 weaned pigs for 6 wk after which mannose content in the mucus was evaluated histochemically using the alpha1-3-d-mannose-specific lectin Galanthus nivalis agglutinin. The crypt width was determined as an indirect measure for the amount of secreted mucus. Ileal and cecal tissue samples were incubated with approximately 7.77 * 10(7) cfu Salmonella Typhimurium and numbers of salmonellae adhering to the mucus and/or mucosa were determined by culture techniques. There was no effect of feed physical form on the in vitro adhesion of S. Typhimurium either in the ileum (7.1 +/- 0.19 log(10) cfu/g tissue) or in the cecum (6.8 +/- 0.26 log(10) cfu/g). The mannose content of the mucus also did not differ between the treatment groups. The crypts of the duodenum, jejunum, and cecum were wider (P < 0.05) after feeding the CM diet. This might be an indication for a higher mucus production in these pigs. PMID- 23365354 TI - In vitro test on the ability of a yeast cell wall based product to inhibit the Escherichia coli F4ac adhesion on the brush border of porcine intestinal villi. AB - The ability of a yeast cell wall (YCW)-based product (SENTIGUARD C; Nutriad) to inhibit the enterotoxigenic Escherichia coli F4ac (ETEC) adhesion on the brush border of porcine intestinal villi was tested. The ETEC suspensions were preincubated with 2 batches of the product (A and B) at different concentrations (10, 5, and 0.5%, wt/vol) or with their filtrates (AF and BF) and then with intestinal villi susceptible to ETEC adhesion. In all the trials, ETEC suspensions were also preincubated with egg yolk (E) immunized against ETEC to assess the maximum inhibition of the adhesiveness or directly with the villi [control group (Con)] to verify the maximum adhesiveness of the pathogen. For each treatment, 20 different villi were observed, brush border measured, and the adherent pathogens counted. A scanning electron microscope analysis was used to confirm the ability of ETEC to adhere on the YCW. The E treatment significantly reduced the pathogen adhesion on the villi compared with the C group in all the trials (P < 0.001). Both batches of SENTIGUARD C significantly reduced the pathogen adhesion on the villi compared with the C group at the concentration of 10 and 5% (P < 0.001) but not at the concentration of 0.5%. The BF did not significantly reduce the ETEC adhesion whereas the AF significantly increased bacterial adhesion (P = 0.015). The microscopy results confirm the ability of ETEC to adhere on YCW. Taken together, our results indicate the ability of the SENTIGUARD C to contain the intestinal infection from ETEC in young pigs with the affinity of ETEC to YCW. PMID- 23365355 TI - Consumption of guar gum and retrograded high-amylose corn resistant starch increases IL-10 abundance without affecting pro-inflammatory cytokines in the colon of pigs fed a high-fat diet. AB - Increases in dietary intake of viscous and nonviscous soluble fiber are reported to improve bowel health. However, related biological mechanisms are not very clear. This study was conducted to examine if colonic inflammation would occur in a typical Western diet model and determine if consumption of soluble fiber components would attenuate potential detrimental effects by differentially affecting colonic abundances of anti-inflammatory cytokine IL-10 and 2 pro inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and IL-6 in pigs fed a high-fat basal diet supplemented, respectively, with 15% viscous soluble fiber guar gum (GG) and 15% nonviscous soluble fiber, that is, retrograded high amylose corn (Zea mays) resistant starch (RS). A total of 24 Yorkshire growing barrows were assigned into a standard corn and soybean (Glycine max) meal (SBM) based grower diet as a positive control (PC), an animal protein-based high-fat basal diet as the negative control (NC), and 2 NC basal diets supplemented with 15% GG and 15% RS, respectively, according to a completely randomized block design for 4 wk. Abundance of these cytokines in homogenized and extracted colonic tissue supernatant samples was measured by ELISA. Although colonic IL-10 abundance was lower (P < 0.05) in the corn and SBM-based PC group than that in the high-fat basal NC group, there were no differences (P > 0.05) in colonic abundances of TNF-alpha and IL-6 between NC and PC groups and among all of the treatment groups. Compared with the NC group, consumption of GG and RS at 15% increased (P < 0.05) colonic IL-10 abundance. Moreover, there was no difference (P > 0.05) in colonic IL-10 abundance between the 15% GG and the 15% RS groups. Thus, consumption of a typical high-fat Western diet did not induce colonic inflammation. Diets supplemented with 15% GG or 15% RS may protect the colon from developing inflammation by enhancing IL-10 abundance. PMID- 23365356 TI - Diarrhea-like condition and intestinal mucosal responses in susceptible homozygous and heterozygous F4R+ pigs challenged with enterotoxigenic Escherichia coli. AB - Enterotoxigenic Escherichia coli (ETEC) F4 is a major cause of diarrhea in both neonatal and young pigs. Indeed, only pigs having F4 receptors are susceptible. Among the susceptible pigs, it is yet unknown if spontaneous E. coli postweaning diarrhea (PWD) occurrence and intestinal mucosal responses to ETEC differ between genotypes. This study investigated a diarrhea-like condition and intestinal mucosal responses in F4 homo- and heterozygous susceptible weaner pigs. Sixteen weaned pigs (28 d of age) were used in a 2 * 2 factorial study with genotype (homo- or heterozygous F4R(+)) and inoculation with E. coli F4 or not as the 2 factors. Within genotype, 4 pigs were inoculated with E. coli F4 and the other 4 pigs received saline buffer on days 7 and 8 after weaning. Fecal score and DM and bacterial counts were conducted from days 7 to 12 after weaning. Blood was obtained on days 3 and 10 after weaning and at the time of killing. Four pigs were killed per day on days 14, 15, 16, and 17. Small intestine (SI) was divided into 3 parts of equal length for measurement of intestinal weight and the amount of mucosa. Lymphocyte subsets in jejunal Peyer's patches (jejPP) were analyzed using flow cytometry. Escherichia coli reduced (P = 0.05) total percentage of intestinal mucosa (on a dry basis) and had an impact on metabolomics profile of the plasma. No effect of genotype was seen on fecal score and DM, fecal shedding of hemolytic E. coli, mucosal responses, metabolomics profile, antibody responses, and lymphocyte subsets counts. This study suggests that both F4 homo- and heterozygous susceptible pigs have similar functional receptors for E. coli F4, which facilitate the adhesion of F4 to the intestinal tissue. PMID- 23365357 TI - Effects of supplementing dietary laminarin and fucoidan on intestinal morphology and the immune gene expression in the weaned pig. AB - Previous studies have shown the benefit of combining seaweed extracts laminarin (LAM) and fucoidan (FUC) on improving growth in piglets' performance after weaning. A 2 * 2 factorial experiment was conducted to investigate the interaction between FUC (0 and 240 mg/kg) and LAM (0 and 300 mg/kg) levels on gut morphology and colonic cytokine gene expression in the weaned pig. Twenty-eight piglets (6.9 kg BW) were assigned to 1 of 4 dietary treatments for 8 d after weaning and then sacrificed. The dietary treatments were as follows: (i) basal diet, (ii) basal diet + 240 mg/kg FUC, (iii) basal diet + 300 mg/kg LAM, and (iv) basal diet + 300 mg/kg LAM and 240 mg/kg FUC. There was an interaction (P < 0.01) between LAM and FUC supplementation on duodenal villous height and the villus height to crypt depth ratio. Pigs offered the LAM or FUC diet singularly had an increased villus height and villus height to crypt depth ratio compared with pigs offered the basal diet. However, there was no effect of the LAM and FUC combination diet on morphology. Pigs offered the LAM-supplemented diets had a lower IL-6 (P < 0.05), IL-17 (P < 0.001), and IL-1beta (P < 0.001) mRNA expression in the colon compared with pigs offered diets without LAM supplementation. In conclusion, the enhancement in intestinal structure and downregulation of inflammatory cytokine gene expression obtained suggest that LAM may provide a dietary means to improve gut health in weaned pigs. PMID- 23365359 TI - Prenatal gastrointestinal development in the pig and responses after preterm birth. AB - Despite clinical research and medical advances, care of the preterm infant remains a clinical challenge, with the immature gastrointestinal (GI) system limiting the types and amounts of nutrients that can be provided enterally to meet energy and nutrient requirements. Progress in understanding the relationship between dietary inputs and the developing GI system after preterm birth has been limited by ethical constraints of using preterm infants as experimental subjects and a lack of relevant animal models. We review development of the GI system of the pig during gestation, the similarities shared with human fetuses, and the responses to dietary stimuli. The GI systems of pigs and humans develop early in gestation, with growth and maturation accelerating during the final weeks prior to birth. As a consequence, deficits in GI digestive capacities are directly related to how early in gestation an infant or pig is delivered, thereby complicating attempts to provide adequate enteral nutrients for growth and development. Pigs differ from humans by being born with low activities of the brush border membrane carbohydrases necessary for hydrolysis of nonlactose carbohydrates. Fetuses of both species have impaired lipid digestion coinciding with lipid malabsorption after preterm birth. Protease activity, although present, may not be adequate and may limit growth potential. Undigested enteral inputs are available to the resident bacteria and the production of metabolites can influence health and nutrition. The preterm pig represents a relevant and translational animal model for understanding GI development and for identifying diet and regulatory factors that stimulate GI growth and maturation after preterm birth and thereby accelerate the transition from parenteral nutrition to full enteral nutrition. PMID- 23365358 TI - The small intestinal apical hydrolase activities are decreased in the piglet with bowel inflammation induced by dextran sodium sulfate. AB - Inflammatory bowel disease (IBD) is characterized by cramping, abdominal pain, bloating, constipation, and diarrhea. We tested the hypothesis that compromised activities of the major small intestinal apical hydrolases contribute to the symptoms of IBD. Changes in hydrolytic kinetics, target protein abundances, and mRNA expression of intestinal alkaline phosphatase (IAP), lactase, maltase, sucrase-isomaltase (SI), maltase-glucoamylase (MGA), and aminopeptidase N (APN) in piglets with colonic inflammation chemically induced by dextran sodium sulfate (DSS) were investigated. Yorkshire piglets at 5 d of age, with an average initial BW of about 3 kg, were fitted with intragastric catheters and were divided into control (CON; n = 6) and treatment groups (DSS; n = 5). Both groups were infused with an equal volume of either saline or 1.25 g of DSS . kg BW(-1) . d(-1) in saline, respectively, for 10 d. Enzyme kinetic experiments for IAP, lactase, maltase, SI, MGA, and APN were measured at 37 degrees C with isolated proximal jejunal apical membrane. Target hydrolase protein abundances in the apical membrane were analyzed by Western blotting and their mRNA abundances in the jejunum were measured by quantitative real-time reverse transcription (RT-) PCR with beta-actin as the housekeeping gene. Expressed as percentage of the CON, DSS treatment decreased (P < 0.05) the maximal specific activities of IAP (53%), lactase (78%), maltase (56%), SI (72%), MGA (29%), and APN (22%) as well as the target hydrolase protein abundances of IAP (39%), lactase (35%), SI (36%), and APN (54%), respectively. Decreases (P < 0.05) in the mRNA abundances (% of the CON) for lactase (25%), SI (52%), MGA (75%), and APN (39%) were observed in the DSS group. However, DSS treatment increased (P < 0.05) the jejunal IAP mRNA abundance by 3.5 fold. We conclude that decreases in the small intestinal apical activities of these examined hydrolases likely contribute to overgrowth of pathogenic bacterial populations in the distal small intestine and the colon, leading to the pathogenesis of IBD. PMID- 23365360 TI - Evaluation of immunoglobulin G absorption from colostrum supplements gavaged to newborn piglets. AB - Absorption of energy and IgG at birth from colostrum may improve survival and immune competency of newborn piglets. Adequate intake of colostrum may be difficult for piglets due to low birth weight, birth order, or viability. This study was designed to evaluate orally fed colostrum supplements with different energy sources and IgG from porcine plasma on piglet serum IgG content and absorption of IgG compared to pooled sow colostrum. Ninety-six newborn piglets from 12 sows with an average birth weight of 1,288 g were used. Eight piglets were removed from each sow immediately at birth, prior to suckling, and randomly allotted to receive either pooled sow colostrum or 1 of 3 colostrum supplements (A, B, and C) fed at 2 dosing schemes. Piglets received their allotted treatment as either one 30-mL dose at 0 h or three 10-mL doses at 0, 2, and 4 h. Piglets received ad libitum access to water at 2-h intervals after receiving their last treatment dose. Twelve hours after the first dose, piglets were weighed and 4 mL of blood was collected. Plasma IgG content, apparent efficiency of absorption, hematocrit, protein, and glucose were determined. Birth weight and final BW did not differ between treatments; however, pigs fed sow colostrum lost more weight ( 72 g) than pigs fed colostrum supplements (-40 g; P < 0.001). Differences in hematocrit or serum glucose were not detected. Serum protein was higher (P < 0.05) in piglets fed colostrum supplements than in pigs fed sow colostrum. Serum IgG content did not differ among treatments. Apparent efficiency of IgG absorption was greatest for sow colostrum followed by colostrum supplements B, A, and C (28.5, 27.6, 25.5, and 24.7%, respectively). The single and multiple dose regimes delivered comparable serum IgG whereas the single dose yielded better piglet hydration as noted by less weight loss. In conclusion, all colostrum supplements were comparable in delivering absorbable IgG to the neonatal piglet. PMID- 23365361 TI - Chenodeoxycholic acid reduces intestinal permeability in newly weaned piglets. AB - Piglets are highly susceptible to gut health-related problems. Intravenously administered chenodeoxycholic acid (CDCA) affects gut health mediated through glucagon-like peptide 2 (GLP-2). To test whether CDCA is a suitable feed additive for improving gut health, a trial was performed with newly weaned (21 d) piglets offered a diet with or without 60 mg CDCA/kg feed (n = 24/treatment). Upon weaning, piglets were fasted for 16 h and then intragastrically dosed with 20 g test feed in 40 g water. Subsequently, a jugular blood sample was taken on 45, 90, 135, or 180 min for analysis of GLP-2, peptide YY (PYY), and glucose. Afterwards, piglets were offered the experimental diets ad libitum. On days 3.5, 7.5, and 10.5 after weaning, serum responses to an intragastric dose of lactulose and Co-EDTA were tested at 2 h after dosing in 8 piglets per treatment. Immediately thereafter, piglets were euthanized, intestines were harvested, and permeability was measured ex vivo using the everted gut sac technique with 4 kDa fluorescein isothiocyanato (FITC)-dextran as marker at 25, 50, and 75% of the length of the small intestine. Dietary CDCA did not affect (P > 0.05) ADFI, ADG, G:F, blood glucose, and plasma GLP-2 and PYY. Serum cobalt and lactulose at day 10.5 tended to be lower in CDCA pigs compared with control pigs. Serum cobalt and lactulose concentrations were positively correlated (r = 0.67; P < 0.01). In conclusion, CDCA tended to reduce intestinal permeability at 10.5 d after weaning when fed to newly weaned piglets, implying that CDCA deserves further study as a means for improving intestinal health. The positive correlation found between Co EDTA and lactulose indicates that both marker molecules measure similar change in permeability. PMID- 23365362 TI - Perinatal growth restriction is not related to higher intestinal distribution and increased serum levels of 5-hydroxytryptamin in piglets. AB - Serotonin [5-hydroxytryptamin (5-HT)] is abundantly present in intestinal enteroendocrine cells and neurons and plays a crucial role in gastrointestinal functions (i.e., motility and mucosal secretion). Increased concentrations of 5 HT and its precursor l-Trp are present in plasma and brain tissues in case of intrauterine growth retardation (IUGR). Therefore, 5-HT might be involved in the impaired gastrointestinal function associated with IUGR. Small-for-gestational age (SGA) piglets have been widely used as animal model for IUGR. Hence, the density of intestinal 5-HT cells in fetal and neonatal SGA piglets was compared with serotonergic cell density in normal weight (NW) littermates. Furthermore, 5 HT serum concentrations of the neonatal piglets were analyzed. Stereological analysis showed that fetal piglets have higher (P < 0.01) volume densities of 5 HT enteroendocrine cells compared to 3-d-old piglets irrespective of BW. Serum concentrations did not differ in relation to postnatal age (P = 0.637) and BW (P = 0.892). These results contrast with serum and brain 5-HT and l-Trp levels in human and guinea pig SGA individuals and seemingly contest the fact that 5-HT plays an important role in gut impairment in SGA. PMID- 23365363 TI - Half-life of porcine antibodies absorbed from a colostrum supplement containing porcine immunoglobulins. AB - Absorption of immunoglobulins (Ig) at birth from colostrum is essential for piglet survival. The objective was to evaluate the half-life of antibodies absorbed in the bloodstream of newborn piglets orally fed a colostrum supplement (CS) containing energy (fat and carbohydrates) and IgG from porcine plasma. Viable piglets (n = 23; 900 to 1,800 g BW) from 6 sows were colostrum deprived and blood sampled and within the next 2 h of life randomly allocated to either control group (n = 9) providing 30 mL of Ig-free milk replacer or a group (n = 14) receiving 30 mL of CS by oral gavage. Piglets were transported to a Biosafety Level 3 facility (Centre de Recerca en Sanitat Animal, Spain) and fed Ig-free milk replacer every 3 to 4 h for 15 d. Survival, weight, plasma IgG content by radial immunodiffusion (RID), and antibodies against porcine circovirus type 2 (PCV2), porcine parvovirus (PPV), porcine reproductive and respiratory syndrome (PRRS), Mycoplasma hyopneumoniae (Mhy), and swine influenza virus (SIV) were determined by specific ELISA before treatment administration, at 24 h, and weekly for 56 d. Clinical symptoms were not observed for either group. Mortality index was lower (17 vs. 38%; P < 0.02) and BW higher (17.7 vs. 15.3 kg; P = 0.035) for pigs supplemented with CS than piglets in the control group. At 24 h postadministration, the CS group had a plasma IgG mean of 7.6 +/- 0.06 vs. 0.14 +/- 0.03 mg/mL for the control group. The IgG levels in the CS group decayed until day 21 when de novo synthesis of IgG was detected in 25% of piglets. Half life of antibody concentration (HLAC) by RID was 6.2 d. In the CS group, efficiency of PCV2 and PPV antibody transfer was high. For PCV2, all animals remained positive by day 56 and the calculated HLAC was 17.7 d. For PPV, 72.7% of piglets were ELISA positive by day 35 and HLAC was 12.0 d. For PRRS, all piglets remained positive by day 14 and the calculated HLAC was 11.9 d. For Mhy and SIV the calculated HLAC were 8.4 and 3.0 d. In summary, half-life of antibodies derived from blood plasma in the bloodstream of newborn piglets varied from 3.0 to 17.7 d. The study also confirm that antibodies derived from porcine plasma were well absorbed and can be an useful tool for providing protection against several or specific pathogens and can be a good alternative to formulate CS for newborn piglets. PMID- 23365364 TI - Stimulating effect of pancreatic-like enzymes on the development of the gastrointestinal tract in piglets. AB - Use of nutritional components from the milk and eventually from the solid feed relates to the growth and development of gastrointestinal tract (GIT). We studied the effect of pancreatic-like enzymes [porcine pancreatic enzymes (Creon) or microbial-derived amylase, protease, and lipase] on GIT morphology and lipid absorption in suckling piglets. Both enzyme preparations, in low or high dose, were fed via a stomach tube twice a day for 7 d starting at 8 d of age and controls received vehicle, n = 6. The day after treatments ended, lipid absorption was tested after which pigs were euthanized and GIT was examined. Enzyme cocktails, irrespective of their origin, increased (P < 0.001) triglyceride level in blood. Enzyme preparation affected (P < 0.001) small intestinal mucosal thickness, villi length, and crypt depth and (P < 0.01) mitotic division of enterocytes. In addition, the external administration of pancreatic enzymes stimulated pancreatic growth as observed by increased (P < 0.05) mitotic division of pancreatic cells. The study revealed that pancreatic or pancreatic-like enzymes of microbial origin administrated in the early postperinatal period enhance GIT development and may be used to better prepare the GIT of piglets for milk use and weaning. PMID- 23365365 TI - Increased intestinal barrier function in the small intestine of formula-fed neonatal piglets. AB - Within-litter birth weight variation is adversely correlated to piglet survival and postnatal growth. A less efficient epithelial barrier function in light piglets may partly explain this inverse relationship between birth weight and zootechnical performance. A compromised epithelial barrier increases paracellular permeability; consequently, toxins, allergenic compounds, or bacteria may enter systemic circulation and induce inflammatory responses. Dietary effects on function of gut epithelium of piglet are largely unknown. This study investigated epithelial barrier function of the small intestine of normal birth weight (NBW) piglets (1.46 +/- 0.10 kg) and low birth weight (LBW) piglets (<1 kg at birth) in relation to their diet. Sixteen pairs of 3-d-old LBW and NBW piglets were randomly assigned to 3 groups: a sow-fed control group euthanized at day 3 of age (SOW3), piglets sow fed until day 10 (SOW10), and formula-fed piglets fed formula from day 3 until day 10 (FOR10). To measure gut permeability, piglets were dosed intragastrically with 0.75 g lactulose/kg BW and 0.3 g mannitol/kg BW 4 h before euthanasia. Urinary sugar excretion was measured using enzymatic spectrophotometry. Irrespective of birth weight, lactulose levels of FOR10 (4.4 +/- 2.3 mmol/L) tended to be lower (P = 0.07) than SOW10 (26.4 +/- 10.2 mmol/L) indicating a reduced paracellular intestinal permeability in FOR10. This reduction was associated with a 6-fold elevated (P < 0.01) protein expression of occludin, an important tight junction protein, in FOR10 compared to SOW10. Mannitol levels in FOR10 (31.0 +/- 18.2 mmol/L) did not differ (P = 0.28) from SOW10 (61.1 +/- 10.2 mmol/L). However, shorter villi (P < 0.01) in FOR10 indicated a reduced absorptive capacity. In conclusion, formula feeding caused minor symptoms of gastrointestinal dysfunction compared to sow-fed piglets irrespective of their birth weight. PMID- 23365366 TI - Insoluble nonstarch polysaccharides in diets for weaned piglets. AB - To examine the effect of inclusion insoluble nonstarch polysaccharides (iNSP) in weaned diets on postweaning piglet performance, intestinal activity, and microbial composition 2 experiments were designed. In Exp. 1, 180 piglets were weaned at 28 d of age and divided over 3 treatments: positive control (PC; highly digestible protein), negative control (NC; standard cereal-based diet), and an experimental diet {iNSP; standard + 15% iNSP [wheat straw and oat (Avena sativa) hull]}. Diets were fed during 14 d after weaning. The ADFI, ADG, and G:F were determined. The inclusion of iNSP increased (P < 0.001) ADFI and G:F during days 0 to 14 after weaning and increased the ADG (P = 0.008) during days 0 to 7 after weaning compared with the NC diet. In Exp. 2, 36 piglets were fed the same diets as in Exp. 1. On days 5 and 14 after weaning, 18 piglets were euthanized to determine enzyme activity, intestinal morphology, and microbial population in the ileum and colon and organ weight. The iNSP diet reduced the concentration of Escherichia coli bacteria in the ileum (P = 0.021) and in the colon (P = 0.002) digesta and tended to increase (P = 0.060) the amylase activity. The iNSP diet stimulated the physical adaptation of the gastrointestinal tract because stomach weight as percentage of BW was heavier (P = 0.004) than for the NC diet. In conclusion, the consumption of diets with higher iNSP content in the early weaning period affects the microbial colonization without reducing enzyme activity or animal performance compared with a standard weaned pig diet. PMID- 23365367 TI - The growing pancreatic duct ligated pig as a model for exocrine pancreatic insufficiency in children: investigations to achieve sufficient vitamin A and vitamin E supply. AB - Human patients suffering from exocrine pancreatic insufficiency (EPI) are susceptible to deficiencies in fat-soluble vitamins. In children with cystic fibrosis, EPI is common and aspects of sufficient vitamin supply are of special interest. The aim of this study was to determine the best application form to maintain vitamin A and E levels in the physiological range in growing pigs with EPI (induced by pancreatic duct ligation) as a model for children. The pancreatic duct was ligated (PL) in twelve 8-wk-old pigs; 4 sham-operated pigs served as controls (Con). Pigs (n = 16) were individually housed and fed a diet containing 13,393 IU vitamin A and 122 mg vitamin E/kg DM. The PL pigs (n = 12) were divided into 3 groups (n = 4) 2 wk after surgery: PL-0, without extra vitamin supply; PL+ORAL, 90,000 IU vitamin A and 600 mg vitamin E/kg of DM plus emulsifier E 484 added to the diet; and PL+IM, intramuscular injection of vitamin A (5,250 IU) and vitamin E [aqueous; 3.15 mg/(kg BW . wk)] plus 700 mg vitamin E (oily)/(animal . wk). All PL pigs were supplemented with the pancrelipase Creon (19.8 g = 1,048,727 IU lipase/kg feed) beginning 2 wk after ligation of the pancreatic duct. Pigs were euthanized at 16 wk of age. Tocopherol levels (mg/kg DM) in liver were reduced (P <= 0.005) in PL-0 and PL+IM (6.91 and 8.61, respectively) whereas PL+ORAL did not differ from Con (27.4 and 25.8, respectively; P >= 0.77). Compared to control pigs (241 +/- 14.1 mg vitamin A/kg DM of liver), the concentration of vitamin A (mg/kg DM) in liver was lower (P < 0.003) in PL-0 (136 +/- 18.5) but higher (P < 0.003) in PL+ORAL (375 +/- 50.0). In the group PL+IM a high individual variation was observed (288 +/- 142 mg vitamin A/kg DM of liver). Extra dietary supply of high doses of vitamin A and E with an efficient emulsifier was adequate to maintain vitamin A and E in liver tissue within reference values. The present data underline the need for extra supplementation of vitamin A and E in juvenile patients with EPI and indicate that oral application is suitable. PMID- 23365368 TI - Exogenous pancreatic-like enzymes are recovered in the gut and improve growth of exocrine pancreatic insufficient pigs. AB - The exocrine pancreatic insufficient (EPI) pigs grow less due to different disturbances in feed digestion, absorption, and retention. Use of pancreatic-like enzymes of microbial origin in pigs may improve feed use and performance in slow growing pigs. The aim was to study gut recovery and effectiveness of pancreatic like enzymes of microbial origin supplementation on pig performance. Six male pigs 10 to 12 kg BW underwent pancreatic duct ligation surgery to induce total exocrine pancreatic insufficiency (EPI). Three cannulas to access the gastrointestinal tract content were installed in stomach, duodenum, and ileum in EPI pigs and in 3 control (healthy) pigs. One month after surgery, enzymes were given before feeding and digesta samples were collected for analyses. The BW of EPI pigs did not increase during 1 mo following surgery (11.7 vs. 11.6 kg BW); however, BW increased after 1 wk of enzyme supplementation (12.1 kg BW). Coefficient of fat and N absorption increased (P < 0.05) in EPI pigs after enzyme supplementation. Activity of amylase, lipase, and protease in chyme samples of EPI pigs was very low compared to controls. In EPI pigs after enzyme supplementation, amylase activity increased from 5.32 to 72.9 units/mL but remained lower than that of healthy pigs (162.7 units/mL). Lipase activity increased from 79.1 to 421.6 units/mL, which was similar to that of controls (507.3 units/mL). Proteolytic activity increased from 7.8 to 69.7 units/mL but still did not reach control pigs (164.3 units/mL). In conclusion, exogenous microbial enzymes mimic endogenous pancreatic enzymes being recovered along the lumen of the gastrointestinal tract. These enzymes might be a useful tool to stimulate growth of slower-growing pigs after the weaning period. PMID- 23365370 TI - Effects of processing technologies combined with cell wall degrading enzymes on in vitro degradability of barley. AB - Effects of processing technologies and cell wall degrading enzymes on in vitro degradation of barley were tested in a 5 * 2 factorial arrangement: 5 technologies (unprocessed, wet-milling, extrusion, autoclaving, and acid autoclaving), with or without enzymes. Upper gastrointestinal tract digestion (Boisen incubation) and large intestinal fermentation (gas production technique) were simulated in duplicate. All technologies increased digestion of DM (13 to 43% units) and starch (22 to 51% units) during Boisen incubation, compared with the unprocessed control (P < 0.01). Wet-milling, extrusion, and acid-autoclaving increased CP digestion by 29 to 33% units (P < 0.01). Xylanase and beta-glucanase addition increased digestion of DM (~ 20% units), starch (~ 20% units), and CP (~ 10% units) in unprocessed and autoclaved barley (P < 0.01). Wet-milling, extrusion, and acid-autoclaving, reduced the extent (50%) and maximum rate (60 to 75%) of fermentation (P < 0.01), which appeared to reflect the reduced amount of starch present in the Boisen residues. In conclusion, wet-milling, extrusion, and acid-autoclaving improved in vitro starch and CP digestion in barley, which is related to the cell wall matrix disruption. Addition of xylanases and beta glucanases improved in vitro starch and CP digestion only in unprocessed barley or barley poorly affected by processing. PMID- 23365369 TI - Effect of feeding colostrum versus exogenous immunoglobulin G on gastrointestinal structure and enteric nervous system in newborn pigs. AB - Colostrum is an indispensable source of antibodies (IgG) protecting the newborn pig against infection. We studied the effect of feeding colostrum and purified IgG on early structure and development of the gastrointestinal tract (GIT). Newborn littermate pigs were fed either colostrum, an elemental diet (ED), or an ED supplemented with purified serum IgG (ED + IgG) for 24 h or then only ED up to 72 h. Afterwards, pigs were slaughtered. Colostrum-fed pigs or ED supplemented with IgG (ED + IgG) increased thickness (P < 0.001) of stomach mucosa and muscularis (P < 0.05) compared to the ED group not receiving IgG. Feeding an ED supplemented with IgG improved morphology of the GIT towards that of colostrum fed piglets and indicates a beneficial effect of IgG on GIT development in neonatal pigs. Immunohistochemical studies indicate that ED feeding may influence the expression of nitric oxide synthase in jejunal myenteric (but not submucous) neurons of newborn pigs. PMID- 23365371 TI - Inhibitory action of two zinc oxide sources on the ex vivo growth of porcine small intestine bacteria. AB - Pharmacological dosage of zinc oxide in piglet weaning diets is a common practice to improve growth performance and gut health. However, high zinc excretion in animal wastes poses environmental challenges. Alternatives to current practice are studied. In this study, the inhibitory action of 2 zinc oxide sources on the ex vivo growth of small intestinal bacteria from weaned piglets was studied. Lag time was higher (P < 0.05) in media supplemented with a new zinc oxide preparation in stomach samples, but not in jejunum samples. Bacterial growth reduction (P < 0.05) was more drastic and more rapid in media supplemented with the new zinc oxide preparation. PMID- 23365373 TI - Dietary conjugated linoleic acid modify gene expression in liver, muscles, and fat tissues of finishing pigs. AB - The aim of this study was to investigate underlying mechanisms of dietary conjugated linoleic acid (CLA) on lipid metabolism in various tissues of pigs. Sixteen gilts (73 +/- 3 kg) were fed a control (containing sunflower oil) or an experimental diet in which 4% of sunflower oil was replaced by CLA, and slaughtered at an average BW of 117 +/- 4.9 kg. Transcription of peroxisome proliferator-activated receptor alpha (PPARalpha), peroxisome proliferator activated receptor gamma (PPARgamma), fatty acid synthase (FAS), sterol regulatory element binding protein (SREBP1), acetyl-CoA carboxylase (ACC), lipoprotein lipase (LPL), delta-6-desaturase (D6D), and stearoyl CoA desaturase (SCD) were determined by real-time PCR in longissimus thoracis (LT) and semimembranosus (SM) muscles, LT subcutaneous and SM intermuscular fat, and in the liver. Fatty acid (FA) composition was analyzed using gas chromatography in these tissues, except for SM intermuscular fat. Dietary CLA increased PPARgamma in LT muscle (P < 0.05), whereas CLA reduced PPARalpha transcription in all tissues studied (P < 0.05) with the exception of intermuscular fat. Transcription of genes related to FA synthesis was reduced by CLA in SM muscle and liver (SREBP1, both P < 0.1; ACC, P < 0.01 in SM; and FAS, P < 0.01 in liver), whereas CLA reduced (P < 0.05) LPL and D6D transcriptions in SM muscle and reduced (P < 0.05) SCD in liver but increased (P < 0.05) SCD in LT muscle and intermuscular fat. Saturated FA were increased in all studied tissues (P < 0.01), while monosaturated and polyunsaturated FA were reduced in a tissue-specific way by CLA. It was concluded that dietary CLA affected transcription of genes and fat metabolism in a tissue-specific manner. PMID- 23365372 TI - Effects of oral supplementation with glutamate or combination of glutamate and N carbamylglutamate on intestinal mucosa morphology and epithelium cell proliferation in weanling piglets. AB - To evaluate the effects of glutamate (Glu) or combination of Glu and N carbamylglutamate (NCG) on intestinal mucosa morphology and epithelium cell proliferation, 18 piglets weaned at 21 d (BW 5.56 +/- 0.51 kg) were grouped into 3 treatments and fed one of the following diets for 20 d: a standard diet (SD), SD+Glu(1%), or SD+Glu(1%)+NCG(0.05%). All the piglets were killed for intestinal mucosa collection, and real-time PCR was used to detect mRNA abundance of proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), and beta-catenin. The results showed that compared with the control group, adding Glu or Glu+NCG to the diet resulted in a higher villus height and mucosal thickness (P < 0.05) in the jejunum. However, the villus height/crypt depth ratio was unaltered. The RT-PCR results showed that Glu+NCG significantly increased PCNA mRNA abundance in both jejunum and ileum (P < 0.05), while they also significantly increased beta-catenin and VEGF mRNA abundance in ileum (P < 0.05). Only Glu increased PCNA mRNA abundance in the jejunum (P < 0.05) and beta catenin mRNA in the jejunum (P < 0.05). These results indicated that oral supply of Glu improved intestinal mucosa morphology, and combined Glu and NCG may have favorable effects on intestinal epithelium cell proliferation than Glu alone. PMID- 23365374 TI - Effect of diet grinding and pelleting fed either dry or liquid feed on dry matter and pH in the stomach of pigs and the development of gastric ulcers. AB - The physical form of diets has a marked impact on the development of gastric ulcers in pigs. Earlier studies showed effects of fine grinding and pelleting on the integrity of gastric mucosa as well as on local intragastric milieu. This study was conducted to evaluate the effects of dry or liquid feeding on intragastric milieu (DM and pH) in pigs. The 23 piglets were housed individually and fed with test diets and water ad lib for 6 wk. Both experimental diets [coarsely ground diet fed as mash (CM) vs. finely ground pelleted diet (FP)] were identical in ingredients (39.5% wheat, 34% barley, 20% soybean meal) and chemical composition and were either offered dry or in liquid (25% DM) form. At the end of the trial the animals were slaughtered; the stomach was removed and samples were taken from different localizations. Feeding diets dry or liquid had no effect on the pH (P > 0.05). The diet noticeably affected the gastric content. The FP diets resulted in a more liquid chyme (P < 0.05), and the intragastric pH did not differ between regions. Feeding CM caused marked effects of localization regarding pH (highest values: pars nonglandularis; lowest values: fundus). None of the pigs fed CM showed signs of gastric ulcers, but the score was markedly higher (P < 0.05) when pigs were fed FP. Therefore the predominant factor for development of gastric ulcers seems to be the structure (particle size) of the diet. PMID- 23365375 TI - Effects of dietary supplementation with two potassium formate sources on performance of 8- to 22-kg pigs. AB - Dietary inclusion of salts of organic acids may modulate intestinal microbiota and enhance performance of pigs. Published data on the effects of potassium formate (KF; pH 6.0-8.5) on pig performance are scarce compared with that of potassium diformate (KDF; pH 4.1-4.5). Therefore, the objective was to evaluate the effects of KDF or KF supplementation on performance of 8- to 22-kg pigs. A 35 d growth trial was conducted with 144 PIC pigs (initial BW of 7.9 +/- 0.69 kg) with 6 pigs (3 gilts and 3 barrows) per pen and 8 pens per treatment. Pigs were assigned to 3 diets based on corn (Zea mays), wheat (Triticum aestivum), and soybean (Glycine max) meal for each of the prestarter (days 1-14) and starter phases (days 15-35). The basal diet was supplemented with KDF at 1.20% or KF at 1.56% replacing corn starch to create diets 2 and 3, respectively, to provide a constant formate content. The ADG and feed conversion ratio (FCR) were not affected by the addition of KDF or KF during the prestarter phase. Addition of KDF or KF to the basal diet increased (P < 0.01) ADG and final BW and improved FCR (P < 0.05) during the starter and the overall 35-d period. The ADFI was not affected by the treatments. Performance of pigs fed diets supplemented with KF and KDF were similar. Diarrhea incidences were observed during week 1 but no differences were observed (P > 0.05) among treatments in term of the number of antibiotic treatments or fecal consistency scores. Overall, the supplementation of 1.56% KF or 1.20% KF improved performance of weaned pigs. PMID- 23365377 TI - Use of a colon simulation technique to assess the effect of live yeast on fermentation parameters and microbiota of the colon of pig. AB - The impact of 2 doses of a Saccharomyces cerevisiae were evaluated, 5 * 10(10) cfu/kg of feed (L1) and 5 * 10(11) cfu/kg of feed (L2) against a control (CON) with no added yeast, using an in vitro model [colon simulation technique (Cositec)] to mimic digestion in the pig colon. The L2 (but not L1) dose significantly improved DM digestibility compared to CON (61 v 58%) and increased NH(3) concentrations (+15%). Volatile fatty acid concentrations increased with L2 compared to CON--isobutyrate (+13.5%), propionate (+8.5%), isovalerate (+17.8%), and valerate (+25%)--but only valerate was increased with L1 (+14.2%). The analysis of microbiota from the liquid associated bacteria (LAB) and solid associated bacteria (SAB) revealed an interaction between the fraction and treatment (P < 0.05). Indeed, L2 had a significant impact on SAB and LAB (P < 0.01) whereas L1 only tended to change the structure of the population in the SAB (P < 0.1). Overall, this study showed that a live yeast probiotic could improve digestion in a colonic simulation model but only at the higher dose used and this effect was associated with a shift in the bacterial population therein. PMID- 23365376 TI - Comparison of four feed proteases for improvement of nutritive value of poultry feather meal. AB - Feed industries are seeking new ways to cope with increased raw material costs, and one approach is to apply enzymatic treatment in the production of feed ingredients from animal by-products. Keratinases, a group of proteases, are capable of hydrolyzing keratin-rich material and have been applied in the production of cost-effective feather by-products for use as feed and fertilizers. The current study examined 4 commercial feed proteases from Bacillus subtilis, Bacillus licheniformis PWD-1, Aspergillus niger, and Serratia proteamaculans HY-3 used to hydrolyze chicken feather under different conditions. The degree of keratinolysis was monitored by measuring the release of NH(2) groups using o phthalaldehyde (OPA) and by scanning electron microscopy. All 4 feed proteases were able to degrade feather at pH 5.5 and 7.0. The degree of hydrolysis was stimulated by the addition of reducing reagents such as dithiothreitol (DTT) and Na(2)SO(3). In general, the protease from B. subtilis was more efficient in degrading feather keratin compared to the other 3 feed proteases at both pH 5.5 and 7.0. For commercial production, the application of protease from B. subtilis is even more advantageous considering the lower cost-in-use. PMID- 23365379 TI - Changes in the pig small intestinal mucosal glutathione kinetics after weaning. AB - Glutathione (GSH) serves as a major endogenous antioxidant and its kinetics have been poorly described in the weaned pig. This study was to assess the effect of birth weight, sex, and days postweaning on the small intestine (SI) mucosal GSH kinetics. At weaning (18.8 +/- 0.44 d) 34 pairs of intrauterine growth restricted (IUGR) and normal birth weight sex-matched littermates were selected and fed a starter diet ad libitum until 1 h before sampling at 0, 2, 5, 12 and 28 d postweaning. Mucosa was collected from 2 SI sites, at 5% and at 75% of total length, to determine GSH and glutathione disulfide (GSSG), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA), and plasm GSH-Px and MDA. At both 5 and 75% of total length, the GSH-Px activity and GSH concentrations increased gradually with increasing days postweaning to peak at day 12 (P < 0.05). The GSH-Px activity and GSH concentrations at 5% of SI length were consistently higher as compared to 75% of SI length (e.g., at day 12, 43.2 and 28.9 units/mg protein and 21.5 and 15.4 MUmol/g protein, respectively). The GSSG:GSH ratio at 5% of total length was 2-fold higher at day 5 compared to all other days (P < 0.05), possibly indicating that the mucosal redox balance was disturbed in that time window. The higher GSH-Px activity, GSH content, and GSSG:GSH ratio in the proximal SI might illustrate the higher need for antioxidant action at that site. Plasma MDA and GSH-Px activity followed a comparable pattern as in the small intestine. PMID- 23365378 TI - Responses of dietary ileal amino acid digestibility to consumption of different cultivars of potatoes and conventional fibers in grower pigs fed a high-fat basal diet. AB - Whereas dietary fibers are well recognized for nutritional management of human health issues, fiber is also known to be one of the dietary factors potentially affecting digestive use of dietary proteins. As a staple food, potato (Solanum tuberosum) may be a significant dietary fiber source. The objective of this study was to examine effects of dietary supplementation of six potato cultivar-genotype samples that differ in soluble fiber content and two conventional fiber components (i.e., cellulose and guar gum) on the apparent ileal AA digestibility in pigs fed a high-fat basal diet. The basal diet was formulated as a zero-fiber negative control (NC) to contain 41.5% poultry meal, 4% casein, 15% animal fat oil blend, 2.8% sucrose, 31% corn (Zea mays) starch, 0.50% salt, and 0.40% trace mineral-vitamin supplement with fat contributing to 47% of the dietary GE. The two fiber diets were formulated by respectively diluting the basal diet with 10% guar gum and 10% cellulose at the expense of corn starch. Six other test diets were formulated by including 8.5% guar gum and further diluting the basal diet with 25.1% one of the six cultivar-genotype samples of dehydrated potato tuber powder to contain about 10% total dietary fiber at the expense of corn starch. Eighty-one 25-kg barrows were fitted with a simple T-cannula at the distal ileum and fed the diets according to a completely randomized block design with each block lasting 28 d. Compared with the NC, the ileal digestibility of Ala, Gly, and Pro were decreased (P < 0.05) by 10% guar gum whereas the digestibility of Gly was reduced (P < 0.05) by 10% cellulose. The ileal digestibility of several AA was decreased (P < 0.05) by the test potatoes plus 8.5% guar gum compared with the NC. Our results suggest that dietary inclusion of fiber at 10% from guar gum and cellulose and contributed by potatoes may adversely affect digestive use of dietary protein. PMID- 23365380 TI - Whole body protein deposition and plasma amino acid profiles in growing and/or finishing pigs fed increasing levels of sulfur amino acids with and without Escherichia coli lipopolysaccharide challenge. AB - A split plot experiment with 72 male pigs weighing 52.9 +/- 0.39 kg (mean +/- SEM) was conducted to examine AA partitioning and body protein deposition (PD) in response to increasing dietary sulfur amino acids (SAA) with or without immune system (IS) activation. The main plot was with and without IS activation, and 4 diets containing different amounts of standardized ileal digestible (SID) SAA (SAA to Lys ratios of 0.45, 0.55, 0.65 and 0.75) were the subplots. Activation of IS was achieved by intramuscular injection of Escherichia coli lipopolysaccharides (LPS; serotype 055:B5, Sigma; 30 MUg/kg BW) every Monday and Thursday, with control pigs injected with sterile saline. Maximum body PD, measured by dual-energy X-ray absorptiometry (DXA), and minimum plasma urea content were achieved at SID SAA:Lys ratio of 0.55 in saline-injected pigs but were achieved at a SID SAA:Lys ratio of 0.75 in IS-activated pigs. Immune system activation increased rectal temperature (P < 0.05), plasma haptoglobin (1.1 vs. 2.0 mg/mL; P < 0.001), and the proportion of neutrophils (0.39 vs. 0.42; P < 0.05) and decreased serum albumin content (38.4 vs. 36.8 g/L; P < 0.01). Increasing dietary SAA had no effects on these variables. Immune system-activated pigs had lower levels of homocysteine (Hcy; P < 0.001) and a lower Ser content (P < 0.05). Results showed that increasing dietary SAA as DL-methionine in growing and/or finishing pigs altered plasma AA contents, and that use efficiency of the AA was improved when greater levels of SAA were supplemented in IS-activated pigs. PMID- 23365381 TI - Colostrum and milk production of sows is affected by dietary conjugated linoleic acid. AB - The present experiment was conducted to investigate dietary effects of conjugated linoleic acid (CLA) on sow traits related to piglet survival and growth performance. A total of 23 gestating sows were fed either a standard lactation diet (control diet [CON]) or the CON supplemented with 1.3% CLA (cis-9, trans-11 and trans-10, cis-12) from day 108 of gestation until weaning (4 wk after parturition) to evaluate whether dietary CLA affects the yield and composition of colostrum, time for initiation of milk production, and sow milk yield. Sows fed CLA tended to produce more colostral fat (6.3 vs. 5.2%, respectively; P = 0.10) than CON sows whereas contents of lactose, protein, and dry matter were similar in the two groups. Sows fed CLA tended to produce less colostrum than CON sows (409 vs. 463 g/piglet, respectively; P = 0.07) as predicted by the piglet rate of gain from 0 to 24 h (58 vs. 97 g/piglet, respectively; P = 0.07). The piglet mortality during the first week of lactation tended to be higher for sows fed CLA than for CON sows (6.8 vs. 2.3%, respectively; P = 0.10), and the number of piglets that died or were moved to others sows to ensure survival during the first week was more than double in the CLA group (17.6 vs. 7.8%, respectively; P = 0.04). Copious milk production was initiated 33 h (CLA) and 34 h (CON) after parturition and was not affected by dietary treatments (P = 0.41). Sow milk yield was improved by the CLA treatment from days 7 to 14 of lactation (P = 0.03). Weight at birth (1.40 kg for both groups; P = 0.98) and at weaning [8.2 kg (CLA) and 8.0 kg (CON); P = 0.52] was not statistically different. In conclusion, colostrum yield was inhibited but milk yield was stimulated by dietary inclusion of cis-9, trans-11 and trans-10, cis-12 CLA and indicates that sow productivity may be improved by using different fatty acids for transition and lactating sows. PMID- 23365382 TI - The effect of protease and nonstarch polysaccharide enzymes on manure odor and ammonia emissions from finisher pigs. AB - A 2 * 2 factorial experiment was conducted to investigate the effect of dietary protease (0 and 200 mg/kg) and xylanase (0 and 200mg/kg) in reducing manure odor and NH(3) from finisher pigs. Sixteen pigs were assigned to 1 of 4 dietary treatments, (i) basal diet, (ii) basal diet + xylanase, (iii) basal diet + protease, or (iv) basal diet + xylanase + protease, for 24 d. The manure samples from pigs offered diets containing protease showed increased (P < 0.05) molar proportions of isobutyric acid, isovaleric acid, valeric acid, and branched-chain fatty acids in contrast to pigs offered diets without protease supplementation. The pigs offered diets with xylanase inclusion had reduced (P < 0.05) manure odor emissions compared to pigs offered diets without xylanase supplementation [598 vs. 1306 European odor units (OuE)/m(3)]. Pigs offered protease-supplemented diets alone had significantly higher NH(3) emissions compared to basal fed pigs. However, NH(3) emissions were reduced when protease was combined with xylanase. In summary, this study indicates that protease supplementation increased protein derived VFA in manure and also increased manure NH(3) emissions when offered singularly. Consumption of diets containing xylanase reduced manure odor emissions. PMID- 23365383 TI - Effect of beta-hydroxy beta-methyl butyrate supplementation of sows in late gestation and lactation on sow production of colostrum and milk and piglet performance. AB - This trial was conducted to investigate whether beta-hydroxy beta-methyl butyrate (HMB) supplementation during late gestation and throughout lactation would influence colostrum and milk production of sows and neonatal piglet survival (0 to 24 h). Control sows (CON; n = 8) were fed a standard lactation diet from day 108 of gestation and until 28 d after parturition (weaning). Sows fed HMB (n = 8) were fed the CON diet topdressed with 2.5 g Ca(HMB)(2) equally divided at each 2 daily meals throughout the experiment. Litters were standardized to 12 piglets per sow within experimental group on day 1, and both groups weaned on average 11.3 piglets per sow. Blood samples were taken from the sows by jugular vein puncture on days -3, 1, 10, 17, and 28 relative to parturition. Piglets were weighed at birth, after 24 h, and repeatedly throughout lactation to estimate the colostrum and milk yield of the sows. Samples of colostrum and milk were collected and analyzed. Sows fed HMB had a higher colostrum yield (512 vs. 434 +/ 30 g/piglet; P = 0.05) estimated based on the piglet weight gain during the colostrum period (132 vs. 76 +/- 21 g/piglet; P = 0.05) and the mortality rate of HMB piglets were lower during the colostrum period (0.0 vs. 4.8%, P < 0.05). The HMB supplementation did not affect colostrum composition (P > 0.10). Supplementation with HMB increased milk content of fat (7.40 vs. 6.47 +/- 0.30%; P < 0.05), dry matter (19.0 vs. 18.2 +/- 0.26; P < 0.05), and energy (4.81 vs. 4.47 +/- 0.12 kJ/g; P < 0.05) and reduced the sow backfat at weaning (11.4 vs. 14.5 +/- 1.0 mm; P < 0.05). The HMB piglets weighed less at weaning than the control piglets (7.48 vs. 8.30 +/- 0.20 kg; P < 0.01), although the milk yield was not reduced. Plasma acetate was higher in HMB sows [202 (175; 233) vs. 158 (141; 179) MUM; P < 0.05] whereas plasma 3-hydroxy butyrate was reduced in HMB sows during lactation. In conclusion, HMB supplemented to sows improved the colostrum production but inhibited piglet growth at peak lactation. PMID- 23365384 TI - The effect of protease and xylanase enzymes on growth performance and nutrient digestibility in finisher pigs. AB - Two 2 * 2 factorial experiments were conducted to investigate the interaction between xylanase (0 vs. 200 mg/kg) and protease (0 vs. 200 mg/kg) enzyme supplementation on growth performance (Exp. 1) and coefficient of ileal and total tract apparent digestibility in grower-finisher pigs (Exp. 2). One hundred and twenty-eight individual fed pigs (BW = 34.2 kg; n = 32) were assigned to 1 of 4 dietary treatments: basal diet (T1), T1 + xylanase enzyme (T2), T1 + protease enzyme (T3), or T1 + xylanase + protease enzymes (T4). The pigs offered diets containing protease enzymes had reduced daily gain (0.795 vs. 0.840 kg/d; P < 0.05) and final body weight (96.4 vs. 99.1 kg; P < 0.05) compared to pigs offered diets without protease enzymes. Pigs offered xylanase-supplemented diets had reduced daily gain (0.787 vs. 0.848 kg/d; P < 0.05) compared to pigs offered diets without xylanase enzymes. In Exp. 2, the nutrient digestibility experiment consisted of 24 intact male pigs (n = 6; BW = 78 kg), offered identical diets to that offered in Exp. 1. Following the fecal collections, the pigs were slaughtered and digesta samples were taken from the ileum in order to measure apparent ileal N and GE digestibilities. Pigs offered diets supplemented with protease had increased coefficients of ileal digestibility of N compared to pigs offered diets without protease supplementation (0.583 vs. 0.449; P < 0.05). There was a xylanase * protease interaction (P < 0.05) on the apparent ileal digestibility of GE. Pigs offered diets containing protease only had increased apparent ileal digestibility of GE compared to basal fed pigs; however, the ileal digestibility of GE decreased when protease was combined with xylanase. Neither xylanase nor protease enzymes had any effect on total tract digestibility of GE or N. In conclusion, xylanase and protease enzyme supplementation had no positive effects on grower-finisher pig performance. PMID- 23365385 TI - Casein addition to a whey-based formula has limited effects on gut function in preterm pigs. AB - Preterm infants are susceptible to necrotizing enterocolitis (NEC). Using preterm pigs, we determined whether a whey-casein-based formula would be superior to a formula based on whey protein alone. Twenty cesarean-derived preterm pigs (92% gestation) were given total parenteral nutrition for 36 h followed by 30 h of enteral feeding with whey [protein fraction of milk formula based on whey (WHEY); n = 11] or casein and/or whey [protein fraction of milk formula based on a combination of casein and whey (CASEIN); n = 9]-based formulas. Sugar absorptive function was investigated at 6 and 30 h after initiation of enteral feeding using bolus feedings with galactose and mannitol. Pigs were killed after the last in vivo sugar absorption test and evaluated for NEC and the mid intestine was used for ex vivo measurements of hexose absorption. Microbiota profile and short chain fatty acid (SCFA) levels were studied in gut contents. Severity of NEC lesions was similar between diet groups but galactose absorption was markedly higher in CASEIN than in WHEY (P < 0.01) although only 6 h after the start of the enteral feeding period. There were no differences in ex vivo (14)C-D-glucose uptake, digestive enzymes, microbiota profile, or SCFA concentration. Casein may transiently stimulate intestinal sugar absorption but has limited effects on gut structure, microbiota, and NEC in preterm pigs. PMID- 23365386 TI - Flavor preferences conditioned by postingestive effect of sucrose and porcine digestive peptides in postweaning pigs. AB - Pigs can learn to prefer a flavor if it has been previously associated to positive consequences. The aim of this experiment was to study flavor preferences conditioned by the postingestive effect of nutrients in pigs. In total, 240 weanling piglets were allocated in 24 pens (10 piglets/pen) and distributed to 2 groups of animals (12 pens per group). Pigs in Group 1 (G1) were trained during 8 d with one flavor [positive conditioned stimulus (CS+)] into a protein solution [4% porcine digestible peptides (PDP)] on odd days and another flavor [negative conditioned stimulus (CS-)] into 100 mM of monosodium glutamate (MSG) solution on even days (5-L bottle for 24 h). In the second group of pigs [Group 2 (G2)], CS+ was mixed into a 4% sucrose solution in odd days and CS- into 1% sucrose + 0.08% saccharine on even days. Therefore, treatments were defined as CS+, the flavor associated with PDP or sucrose, on odd days, which were assumed to have a higher postingestive effect than MSG or saccharine + sucrose, the ingredients associated to CS-. Concentration of ingredients in the solutions were chosen to ensure that hedonic attraction for PDP and MSG solutions and for sucrose and saccharine + sucrose were similar (checked in previous double-choice studies). The amount of solution offered during training period was prepared to be totally consumed each day to equalize flavors intake. Flavors (0.0375% anise or garlic) were counterbalanced across replicates to act as CS+ or CS-. Double-choice test between flavors dissolved in water (CS+ and CS-) were performed by selecting 2 pigs/pen on days 1, 6, and 8 after the training period. Solution intake was measured after 30 min. Piglets showed higher intakes for CS+ than CS- in G2 [212 vs. 76 mL and 168 vs. 86 mL (P < 0.05) and 195 vs. 78 mL (P = 0.15)] on days 1, 6, and 8, respectively. Differences between CS+ and CS- consumption were observed in G1 on day 8 (231 vs. 130 mL; P < 0.05). In conclusion, weanling pigs can acquire flavor preferences through associative learning between a flavor and postingestive effects of some nutrients. PMID- 23365387 TI - Evaluation of two external markers for measurement of ileal and total tract digestibility of pigs fed human-type diets. AB - External markers for determination of nutrient digestibility have often been evaluated in conventional dry feeds but less often in conventional feeds such as human-type diets used in animal model studies. In the present study, 5 ileal cannulated pigs were fed 5 types of soft bread-based diets supplemented with Cr(2)O(3) and AIA as digestibility markers for 1 wk in a Latin square design. Ileal contents were collected twice for 5 h and a fecal grab sample was obtained once per week. Ileal and total tract digestibility of OM and nonstarch polysaccharides (NSP) based on the 2 markers were compared by linear regression. Across dietary treatments and site of collection, high correlation existed between digestibility values obtained with Cr(2)O(3) and AIA, resulting in a R(2) > 0.77 (P < 0.001) and a linear relation close to unity. For ileal samples, the correlation was poor, particularly for NSP, which had R(2) = 0.09 (P = 0.14) whereas OM had an R(2) = 0.52 (P <0.001). On the other hand, fecal grab samples led to R(2) > 0.92 (P < 0.001) for both OM and NSP. However, AIA gave higher values than Cr(2)O(3), particularly in samples with lower digestibility. The discrepancy is presumably caused by analytical difficulties due to a high fecal ash contents or interference with other components in the human-type diets. PMID- 23365388 TI - Use of medium without reducing agent for in vitro fermentation studies by bacteria isolated from pig intestine. AB - Over the past decade, several in vitro methods have been developed to study intestinal fermentation in pigs and its influence on health. In these methods, samples are fermented by a bacterial inoculum diluted in a mineral buffer solution. Generally, a reducing agent such as Na(2)S or cysteine HCl generates the required anaerobic environment by release of H(2)S inducing an imbalance among bacterial species by the production of toxic metabolites. Therefore, an experiment was conducted to study the impact of reducing agent on fermentation patterns. Protein (soybean protein and/or casein) and carbohydrate (potato starch and/or cellulose) ingredients were fermented in vitro by pig intestinal bacteria from fresh feces obtained from 3 sows fed an antibiotic-free commercial diet in 3 incubation media differing in reducing agent: (i) Na(2)S, (ii) cysteine HCl, or (iii) without reducing agent. Gas fermentation kinetics were monitored over 72 h (pressure was measured every 2 min). Short-chain fatty acid (SCFA) production after 24 and 72 h were compared among ingredient and reducing agents (n = 2). Gas production was higher (P < 0.05) when fermenting carbohydrate than protein ingredients. Except for soybean protein, total SCFA production after 24 and 72 h was similar (P > 0.05) for each ingredient regardless the incubation medium. The SCFA molar ratios did not differ (P > 0.05) between Na(2)S and without reducing agent. In conclusion, saturation of incubation media with CO(2) seems sufficient to generate an anaerobic environment. So incubation media could be simplified by omitting the reducing agent without influencing the fermentation kinetics and SCFA production. PMID- 23365389 TI - Direct and regression methods do not give different estimates of digestible and metabolizable energy of wheat for pigs. AB - Digestible and metabolizable energy contents of feed ingredients for pigs can be determined by direct or indirect methods. There are situations when only the indirect approach is suitable and the regression method is a robust indirect approach. This study was conducted to compare the direct and regression methods for determining the energy value of wheat for pigs. Twenty-four barrows with an average initial BW of 31 kg were assigned to 4 diets in a randomized complete block design. The 4 diets consisted of 969 g wheat/kg plus minerals and vitamins (sole wheat) for the direct method, corn (Zea mays)-soybean (Glycine max) meal reference diet (RD), RD + 300 g wheat/kg, and RD + 600 g wheat/kg. The 3 corn soybean meal diets were used for the regression method and wheat replaced the energy-yielding ingredients, corn and soybean meal, so that the same ratio of corn and soybean meal across the experimental diets was maintained. The wheat used was analyzed to contain 883 g DM, 15.2 g N, and 3.94 Mcal GE/kg. Each diet was fed to 6 barrows in individual metabolism crates for a 5-d acclimation followed by a 5-d total but separate collection of feces and urine. The DE and ME for the sole wheat diet were 3.83 and 3.77 Mcal/kg DM, respectively. Because the sole wheat diet contained 969 g wheat/kg, these translate to 3.95 Mcal DE/kg DM and 3.89 Mcal ME/kg DM. The RD used for the regression approach yielded 4.00 Mcal DE and 3.91 Mcal ME/kg DM diet. Increasing levels of wheat in the RD linearly reduced (P < 0.05) DE and ME to 3.88 and 3.79 Mcal/kg DM diet, respectively. The regressions of wheat contribution to DE and ME in megacalories against the quantity of wheat DM intake in kilograms generated 3.96 Mcal DE and 3.88 Mcal ME/kg DM. In conclusion, values obtained for the DE and ME of wheat using the direct method (3.95 and 3.89 Mcal/kg DM) did not differ (0.78 < P < 0.89) from those obtained using the regression method (3.96 and 3.88 Mcal/kg DM). PMID- 23365391 TI - Development of an ex vivo model for investigating the bacterial association to the gut epithelium of pigs. AB - To study enterotoxigenic Escherichia coli (ETEC) association to the gut of pigs, a simple and reproducible experimental model would be helpful. The aim of this experiment was to establish a model for studying the association of ETEC to the gut epithelium of pigs. Intestinal segments were prepared from 4 weaned pigs, which were tested susceptible to E. coli O149:F4 (homo- and heterozygotic; 2 pigs each) and O138:F18 (all homozygotic). Five segments were taken from 50% of the intestinal length measured from duodenum [mid small intestine (SI)], and 5 segments were taken from 90% distal to the duodenum (distal SI). The segments were immersed in Dulbecco's Modified Eagle Medium (DMEM) and kept on ice. Polyethylene tubing was inserted into either end of the segment and tied. The tissue was washed with 50 mL of PBS. The other end of segment was tied, 10 mL of DMEM alone or DMEM containing either E. coli F4 or F18 was inoculated, and the segment was sealed with Teflon plug. The segment was immersed in DMEM in a 300-mL infusion bottle in a shaking water bath at 37 degrees C. After 1 h the segment was removed, tissue was washed with 50 mL of PBS, weighed, and homogenized in PBS. Final dilution of 10(-6) was prepared from the content and homogenate. The E. coli was enumerated on MacConkey agar. Data were analyzed according to a 2 * 3 * 2 parametric model including the effects of intestinal segment, E. coli strain, and site of SI with GLM procedure in SAS. A t-test was used to analyze the effect of genotype in F4-inoculated segment. The binding of E. coli on the tissue was 10 times higher (P < 0.001) for F4 than F18. The E. coli F18 was highest (P < 0.05) in mid SI whereas differences were not observed (P > 0.05) between sites of SI for F4. Fewer (P < 0.001) bacteria bound in the control and they associated more (P = 0.10) at distal than mid SI. The E. coli did not differ (P > 0.05) between genotypes in F4-inoculated segment. In conclusion, the ex vivo model may be feasible to investigate the ETEC association to the gut epithelium of pigs. PMID- 23365390 TI - Discrepancies in microbiota composition along the pig gastrointestinal tract between in vivo observations and an in vitro batch fermentation model. AB - In vitro fermentation models are increasingly used to assess prebiotic potential of novel indigestible carbohydrates (CHO). A trial was performed to assess the validity of such approaches by comparing the influence of fermentation of inulin and cellulose on microbiota in vivo and in vitro. Two semipurified diets based on 5% inulin or 5% cellulose were fed to 2 groups of four 25-kg pigs. After 3 wk, the pigs were slaughtered and digesta was sampled from jejunum, ileum, cecum, and 3 parts of the colon to measure pH and microbiota population. An in vitro gas fermentation test was also performed on inulin and cellulose using fresh feces of the experimental pigs as bacterial inoculum. The gas production kinetics were modeled and fermentation broth sampled after 5, 8, 12, 24, and 72 h. Bacterial DNA was extracted and quantitative PCR was performed to quantify total bacteria, lactobacilli, bifidobacteria, Bacteroides, Clostridium cluster I, and Escherichia coli. Total bacteria quantification was similar between both systems. In vivo, total bacteria increased (P < 0.001) along the gut until the second part of the colon (from 10.5(7) to 10(10) cfu/mg) and then decreased (P < 0.05) to 10(9) cfu whereas in vitro, it increased (P < 0.05) until 12 to 24 h of fermentation (from 10(9) to 10.5(9) cfu/mL) and then decreased (P < 0.05) to initial level (10(9) cfu/mL). This evolution was consistent with fermentation kinetics. In both models, inulin increased (P < 0.05) the ratio of bifidobacteria and E. coli populations in the total microflora compared to cellulose. However, in vivo this was observed only in the first parts of the gut whereas in vitro the effect lasted for 72 h. Inulin also increased (P < 0.001) Bacteroides genus in vitro but not in vivo where the evolutions of Bacteroides were similar (P > 0.05) for both CHO. Evolutions of lactobacilli and Clostridium populations in both systems were also not consistent. This can be ascribed to specific bacterial properties as, for example, adhesive properties or sensitivity to sulfur reducing agent used in the in vitro model. As is, the in vitro model does not reflect properly changes in microbiota along the digestive tract induced by specific feed ingredients compared to in vivo observations. PMID- 23365393 TI - Effect of milk hydrolysates on inflammation markers and drug-induced transcriptional alterations in cell-based models. AB - Nonsteroidal anti-inflammatory drugs (NSAID) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue. Earlier studies in our laboratory have found that specific casein hydrolysates (CH) might be useful in the treatment of gastrointestinal wounds. The underlying mechanisms that support inflammation and wound healing are not completely understood, but transcriptional alterations may be used as markers for inflammation and wound healing. The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin (60 min) followed by corolase (0, 10, or 60 min) were investigated in intestinal epithelial cells treated with the NSAID indomethacin. The bioactivity was evaluated as transcriptional alterations of transforming growth factor-beta1 (TGF-beta1), cyclooxygenase-2 (COX-2), peroxisome proliferator-activated receptor gamma (PPAR-gamma) and nuclear factor kappaB (NFkappaB) by real-time PCR. Furthermore, the effect of CH on lipopolysaccharide-induced inflammation was evaluated in macrophages by measuring PG E(2) levels. Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF-beta1 and NFkappaB (P < 0.05) compared with the hydrolysate treated with pepsin only. Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of COX-2 (P < 0.05) compared with hydrolysate treated with corolase for only 10 min whereas transcription of PPAR gamma was not affected (P > 0.05). Additionally, the hydrolysate prepared by pepsin treatment only (0 min corolase) had a pro-inflammatory effect on macrophages via PG E(2) stimulation (P < 0.05). In conclusion, CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF-beta1, COX-2, and NFkappaB. PMID- 23365392 TI - The porcine gut microbial metagenomic library for mining novel cellulases established from growing pigs fed cellulose-supplemented high-fat diets. AB - The porcine gut microbiome is a novel genomic resource for screening cellulose degrading enzymes. A plasmid metagenomic expression library was constructed from the hindgut microbiota of 6 Yorkshire growing pigs (25 to 40 kg) fed a high-fat basal diet supplemented with 10% Solka-Floc for 28 d. Fresh cecal and colonic digesta samples were collected, flash-frozen in liquid N, and stored under -80 degrees C. Metagenomic DNA was extracted, mechanically sheared, and cleaned to remove small DNA fragments (<1.0 kb). The resulting DNA fragments were subjected to blunt-end polishing, fractionation, and purification by using commercial kits. The end-modified DNA fragments were ligated to pCR4Blunt-TOPO vector and transformed into competent Escherichia coli TOPO10 cells. Metagenomic plasmid libraries were screened for carboxymethyl cellulolytic activities by using lysogeny broth agar plates. The average insert size of the resulting library was approximately 4.2 kb. Screening for the ability to hydrolyze carboxymethyl cellulose yielded 14 positive colonies, giving an estimated 430 Mb of metagenomic DNA in the approximately 102,000 E. coli clones with an overall hit rate of 0.14%. The 11 assembled insert sequences included 4 function-related gene clusters, and a total of 18 putative carbohydrate active enzyme genes were identified. This included genes encoding 11 cellulases, 4 hemicellulases, 1 polygalacturonas, 1 glycoside hydrolase family 26 mannanase-family 5 cellulase chimeric enzyme gene, and 1 cellobiose phosphorylase. In conclusion, the coupling of functional metagenomic mining with biochemical characterization of fiber degrading enzymes is a powerful strategy for exploring the enzymological underpinnings of the anaerobic fermentation of dietary fiber in the complex animal gut environment. PMID- 23365394 TI - Growth performance and preference studies to evaluate solvent-extracted Brassica napus or Brassica juncea canola meal fed to weaned pigs. AB - Inclusion of conventional dark-seeded (Brassica napus) and novel yellow-seeded (Brassica juncea) canola meal (CM) can potentially replace soybean (Glycine max) meal (SBM) in pig diets. Our objective was to examine the preference of weaned pigs fed diets containing SBM or B. napus or B. juncea CM and to compare it against previously reported growth performance data (Exp. 1 and 2). In Exp. 1 and 2, growth performance was evaluated using 220 and 240 weaned pigs, respectively, by replacing dietary SBM with up to 20% B. napus (Exp. 1) or 24% B. juncea CM (Exp. 2). Feeding up to 20% B. napus CM to pigs did not affect growth performance, but increasing inclusion of B. juncea CM linearly reduced (P < 0.001) ADFI, ADG, and G:F most likely due to the higher content of glucosinolates, particularly gluconapin in B. juncea CM as confirmed by principle component analysis. In Exp. 3 and 4, SBM and B. napus and B. juncea CM fed at 20% dietary inclusion were evaluated in 2 preference studies using 216 and 144 pigs of 35 d of age, respectively. Pens equipped with 2 feeders housed 8 or 4 pigs per pen, in Exp. 3 and 4, respectively. Diets formulated to equal NE and standardized ileal digestible AA were offered in a paired choice as mash (Exp. 3) or pellets (Exp. 4) for 3 consecutive 7-d periods (3 d nontest and 4 d preference test). The 3 treatments offered were (i) SBM vs. B. napus CM, (ii) SBM vs. B. juncea CM, and (iii) B. napus vs. B. juncea CM. Pigs preferred SBM (P < 0.001) over B. napus and B. juncea CM diets, and pigs preferred B. napus (P < 0.001) over B. juncea CM diet. High content of the glucosinolate gluconapin likely reduced feed preference in B. juncea more than in B. napus CM. In conclusion, the contrast between preference and performance studies feeding CM to pigs indicates that preference studies should be interpreted cautiously until validated by growth performance data. PMID- 23365395 TI - Redox potential of cecum content of growing pigs and its relation with pH and VFA concentration. AB - Digestive microflora is partly responsible for physiological gut conditions. Measurements of redox potential (Eh) and pH of digesta may give a basis for understanding microbial activity and dynamics of fermentation. However, few studies have assessed the Eh of the gastrointestinal tract of pigs. Twenty-four pigs of 30 kg BW were slaughtered to measure Eh and pH of cecum content in situ and to obtain samples of ileum, cecum, and colon contents for VFA determinations. Pigs had previously been fed with a nonmedicated starter feed for 5 wk. Measurements of Eh and pH were recorded first at 2 min and then at 5-min intervals for 35 min to estimate kinetics and the delay to reach stabilization of the Eh value. Cecum Eh rapidly decreased (P < 0.001) from -115 to -180 mV after 15 min of insertion of the electrodes and then slowly decreased until -185 mV at 35 min. Cecal pH started at 5.74 and decreased (P < 0.01) slowly afterwards until 5.53 after 35 min. The Eh value after stabilization was negatively correlated (r = -0.64; P < 0.001) with final pH. Acetic, propionic, and butyric acids accounted for 58.7, 24.0, and 12.8%, respectively, of total VFA production of cecum content. The VFA production of ileal content was lower (P < 0.001) when compared to cecum or colon (50.8, 142.1, and 130.8 MUmol/g, respectively) and a higher proportion of formic and lactic acids was detected (32.3 and 27.0%, respectively). Proportions of acetic and propionic acids were negatively (r = 0.53; P < 0.01) and positively (r = 0.66; P < 0.001) correlated with Eh, respectively. In conclusion, Eh measured after stabilization seemed to be a meaningful predictor of hindgut fermentative activity. PMID- 23365396 TI - Blood sampling and hemolysis affect concentration of plasma metabolites. AB - Two experiments were carried out to reveal and quantify plasma metabolites that are sensitive to hemolysis and animal stress due to the blood sampling procedure (vein puncture vs. catheter). In Exp. 1, 48 sows were fed 4 diets either once (0800 h) or twice daily (0800 h and 1500 h) in a crossover design and blood was collected after restraint via vein puncture 1, 4, 11, and 23 h after morning feeding. Plasma samples were categorized as without or with minor or major hemolysis [clear (n = 218), yellow (n = 97), or red (n = 37)] upon centrifugation. Plasma NEFA (P < 0.001) was lower in hemolyzed samples but plasma propionate, caproate, isovalerate (P < 0.001), and isobutyrate (P < 0.05) were higher in hemolyzed samples. Plasma glucose and lactate were the only metabolites that were not affected by hemolysis. Interactions with hemolysis and other fixed effects were not found (P > 0.05). In Exp. 2, a subset of samples from 24 sows fed twice daily in Exp. 1 was combined with data obtained from 30 sows sampled using jugular vein catheters. All sows in Exp. 2 were fed twice daily (0800 h and 1500 h) and blood samples collected repeatedly 1, 4, 11, and 23 h after morning feeding (other conditions were similar as in Exp. 1). Plasma isobutyrate (P < 0.001), NEFA (P < 0.01), and acetate (P < 0.05) were lowered and plasma caproate (P < 0.001), glucose (P < 0.01), lactate, and isovalerate (P < 0.05) were elevated in samples obtained via vein puncture as compared to via vein catheters. Plasma insulin, propionate, and butyrate were not sensitive to the blood sampling procedure. In conclusion, blood sampling procedure and hemolysis affect the measured metabolite concentrations and should be considered or accounted for when comparing results within and between experiments. PMID- 23365397 TI - Development and validation of a spectroscopic method to predict wheat protein digestibility. AB - The CP digestibility is traditionally measured by chemical analyses of CP and marker concentration in digesta and diets. Potentially, CP digestibility can also be predicted by marker concentrations and spectral analyses of digesta and diet. Spectroscopy is a rapid, nondestructive method to ascertain qualitative and quantitative chemical information. Based on Beer's law, a spectroscopic method was developed to predict in vivo CP digestibility. To validate, samples of digesta and diet of wheat grain with predetermined apparent ileal digestibility (AID) of CP were scanned on a Fourier transform midinfrared (FTIR) instrument with a single-reflection attenuated total reflectance attachment. The AID of CP was calculated from peak intensities of spectra and measured marker concentrations in digesta and diet and then compared with in vivo AID of CP. The AID of CP of a wheat-based diet was predicted accurately with a deviation of 0.68 +/- 0.86% from in vivo AID of CP ranging from 60.4 to 87.8%. Functional group digestibility based on the peak at 1,643 cm(-1) or the Amide I region was strongly correlated (r >= 0.99; P < 0.001) with in vivo AID of CP. In conclusion, instead of predictions based on calibrations, CP digestibility can also be potentially predicted directly from FTIR spectra. PMID- 23365399 TI - Long term effects of pre- and early postnatal nutrition and environment on the gut. AB - The Developmental Origins of Health and Disease hypothesis formulated in the early 1990 s has stimulated research on long-term effects of early nutrition and environment over the last decades. Long-term is understood in this review as physiologically relevant periods such as after weaning, around sexual maturity, and in adulthood, as opposed to early developmental periods. The small and large intestines as targets for the study of long-term effects have received little attention until recent years and the stomach has been considered very rarely. Data have accumulated for laboratory animal models but they are still scarce in the swine species. Following the epidemics of metabolic diseases and obesity in western countries, experimental evidence has been published showing that nutritional factors, including energy, fat and fatty acids, protein, and micronutrients impact various facets of gut function. These include alterations in intestinal digestive, absorptive, secretory, barrier, and defense systems, often in a way potentially detrimental to the host. Environmental factors with long-term influence include stress (e.g., maternal deprivation, neonatal gut irritation), chemical pollutants (e.g., bisphenol A), and gut microbiota disturbances (e.g., by antibiotics). Examples of such long-term effects on the gut are provided in both laboratory animals and pigs together with underlying physiological mechanisms whenever available. Experimental evidence for the involvement of underlying epigenetic modifications (e.g., genomic DNA methylation) in long-term studies has just started to emerge with regard to the gastrointestinal tract. Also, interactions between the microbiota and the host are being considered pivotal in the early programming of gut functions. Finally, suggestions for future research are provided in order to better understand and then control early programming as an attempt to optimize vital functions of the gastrointestinal tract throughout adult life. PMID- 23365398 TI - The in vivo infusion of hydrogen peroxide induces oxidative stress and differentially affects the activities of small intestinal carbohydrate digestive enzymes in the neonatal pig. AB - Chronic fatigue syndrome (CFS) is characterized by persistent and relapsing fatigue that involves oxidative stress in its pathogenesis. We tested the hypothesis that a decrease in key carbohydrate-digesting enzyme activity in the gut is one of the major biological mechanisms of developing CFS in liquid formula fed neonatal pigs with in vivo infusion of H(2)O(2). Piglets at 7 to 10 d of age were fitted with an intraperitoneal catheter, allowed a 3-d post surgical recovery, and infused with either H(2)O(2) at 5 mmol/kg BW (PER; n = 8) or the same volume of saline (CON; n = 8) in six 20-ml doses daily for a period of 10 d. During this period, animal behavior was monitored, blood samples collected, and jejunal enzyme activity kinetic experiments for lactase, sucrase, maltase, and maltase-glucoamylase were conducted. Plasma concentration of reduced glutathione remained similar (P > 0.05) to the pre-infusion level over the study duration in the CON group whereas this was 65% lower (P < 0.05) than the pre-infusion level in the PER group. Piglets experiencing oxidative stress had an overall lower (P < 0.05) physical mobility and the maximal jejunal specific activities [MUmol/(mg protein . min)] for lactase (PER, 6.54 +/- 0.68 vs. CON, 12.65 +/- 0.69) and maltase (PER, 57.39 +/- 1.02 vs. CON, 75.60 +/- 1.04), respectively. However, differences were not observed (P > 0.05) in the maximal specific activities [MUmol/(mg protein . min)] of sucrase (PER, 10.50 +/- 1.37 vs. CON, 12.40 +/- 1.55) and maltase-glucoamylase (PER, 0.71 +/- 0.08 vs. CON, 0.70 +/- 0.07) between the 2 groups. In conclusion, infusion of a suitable dose of H(2)O(2) induced CFS in the neonatal pigs. Oxidative stress in vivo differentially affected the maximal activities of important small intestinal carbohydrate digesting enzymes in neonatal pigs fed a dairy milk-based liquid formula. PMID- 23365400 TI - Butyrate supplementation to gestating sows and piglets induces muscle and adipose tissue oxidative genes and improves growth performance. AB - Weaned pigs often experience growth reduction immediately after weaning due to multiple stress factors associated with weaning. We tested the effect of prenatal and postnatal butyrate supplementation on growth performance of piglets. In study 1, piglets were orally gavaged with 0.3% butyrate from day 4 after birth to weaning (day 21). Butyrate increased ADG by 13% compared to saline treated control. Expression of peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1alpha) was higher in muscle, adipose tissue, and ileum of butyrate-supplemented animals. Also, peroxisome proliferator activated receptor alpha (PPARalpha) was induced (P < 0.05) in the subcutaneous adipose tissue (SCAT) and muscle (longissimus dorsi [LD]) of butyrate-supplemented piglets. In vitro, butyrate increased (P < 0.05) fatty acid oxidation in primary adipocytes and suppressed basal lipolysis by 62% compared to untreated cells. Butyrate suppressed (P < 0.05) lipogenesis ((14)C-glucose incorporation into lipids) in adipocytes. This was accompanied by an approximately 30% reduction in the mRNA expression of fatty acid synthase (P < 0.05) in butyrate-treated cells vs. controls. Piglets born to sows that were supplemented with 0.3% butyrate during the last trimester of gestation had a 15% higher (P < 0.05) body weight at 12 wk than controls. In summary, butyrate supplementation to gestating sows and piglets enhanced postweaning growth performance, which may be mediated by increased substrate oxidation in butyrate treated animals. PMID- 23365401 TI - Effects of a simple or a complex starter microbiota on intestinal microbiota composition in caesarean derived piglets. AB - The present study was designed to develop a model in piglets that allows the investigation of the effects of postnatal association with a simple or a complex microbiota on gut health and development. Thirty piglets from 2 sows were obtained by caesarean delivery (day 0) and were equally divided over 2 treatment groups housed in separate clean, nonsterile rooms. All piglets received orally a simple microbiota consisting of Lactobacillus amylovorus, Clostridium glycolicum, and Parabacteroides spp. on days 1, 2, and 3 after birth. On day 3 and 4 the piglets received either a complex microbiota by providing them with a fecal inoculant of an adult sow [complex association (CA)] or a placebo inoculant [simple association (SA)]. Fecal microbiota composition, as determined by denaturing gradient gel electrophoresis and by pig intestinal tract chip (PITChip) analysis of 16S rRNA genes (days 3, 5, 7, 14, and 28), was less diverse in the SA group compared to the CA group. A difference in fecal microbiota composition between treatments persisted until the end of the study. It was concluded that the composition of microbiota in feces of cesarean delivery derived piglets is influenced by bacterial association in the first days after birth. Differences in fecal microbiota composition between piglets exposed to a simple or complex inoculum at early age persisted for at least 3 wk. PMID- 23365402 TI - Zinc oxide at low supplementation level improves productive performance and health status of piglets. AB - Use of ZnO at high doses (3000 ppm) for diarrhea prophylaxis in piglets is widely extended in postweaning Spanish diets, in compliance with the national veterinary regulation. However, European feed legislation limits total dietary Zn to a maximum of 150 mg/kg of complete feed. The objective of this study was to compare a new potentiated form of ZnO, HiZox (Animine), at nutritional level (150 ppm) with pharmacological dosage (3000 ppm) of regular ZnO in starter diets on the productive performance and health status of piglets in a medium-low health status farm. A total of 144 pigs at weaning (28 d of age) were distributed in 6 piglets/pen and 12 pens/treatment. In the prestarter phase (28 to 42 d of age), all pigs received the same commercial feed, including 3000 ppm ZnO. In the starter phase (42 to 63 d of age) (T1) included 3000 ppm of regular ZnO (2500 ppm Zn), and (T2) was supplemented with 110 ppm Zn from potentiated ZnO (HiZox). Average daily feed intake, ADG, G:F, and pig-MAP serum concentration, an acute phase protein commonly used as unspecific biomarker of disease or other acute phase reactions, were measured at 42 and 63 d of life. Pen of 6 piglets was the experimental unit and data were analyzed using the GLM procedure of SAS version 9.0. Piglets fed with T2-HiZox had improved ADG and G:F (P < 0.001) compared to piglets fed with T1-ZnO. In addition, at 63 d of age, the T2 group had a lower pig-MAP serum concentration than T1 group (1.71 vs. 0.95 MUg/mL; P < 0.05) indicating higher health status in the T2 group. In conclusion, in low-medium sanitary conditions and in compliance with European regulation, HiZox significantly increased piglet growth compared to pharmacological dosage of regular ZnO in the starter phase. This can be explained by a better health of pigs expressed by a lower level of inflammatory protein pig-MAP. PMID- 23365403 TI - Behavioral changes in response to feeding pancreatic-like enzymes to exocrine pancreatic insufficiency pigs. AB - Behavioral changes during pancreatic enzyme therapy have never been studied. The present study investigated behavioral changes in exocrine pancreatic insufficiency (EPI) pigs when their feed was supplemented with pancreatic-like enzymes of microbial origin. A crossover design study was used to test the effect of enzyme supplementation in 2 * 4 EPI pigs that underwent pancreatic duct ligation (PDL). After 40 d of adaptation, the study commenced, comprising 2 control and 2 enzyme feeding periods of 10 d each in sequence. On days 7 and 10 of each experimental period, behavior was monitored for 24 h and feed consumption and BW were recorded. Behavioral observations focused on the pigs' activity-- lying down or passive, or sitting, or standing or active--and were expressed as percentage activity for 24 h. During the adaptation period, BW gain was completely inhibited after PDL whereas for the entire study period, the body weight increased from 10.5 +/- 1.1 to 14.0 +/- 1.4 kg (P < 0.01). Exocrine pancreatic insufficiency pigs were more active when fed the enzymes (21 vs. 18% per 24 h; P < 0.01). Microbial enzyme supplementation not only improved the growth of the EPI pigs but it also increased their activity. This behavior change contradicts the generally accepted norm that satiety evokes by digestion and subsequent nutrients absorption reduces human or animal motility. PMID- 23365404 TI - Body composition of piglets from sows fed the leucine metabolite beta-hydroxy beta-methyl butyrate in late gestation. AB - Supplementation of the leucine metabolite beta-hydroxy beta-methyl butyrate (HMB) to sows during late gestation or lactation has been shown to improve piglet health, survival, and growth. This study aimed to investigate long-term effects of HMB supplementation to late-gestating sows on body characteristics of piglets at weaning. Sows were fed a standard lactation diet from day -15 relative to parturition and throughout the experiment and a diet supplemented with (HMB; n = 2) or without [control (CON); n = 3] 15 mg Ca(HMB)(2)/kg BW in morning meals from day -10 until parturition. Fifty-six suckling piglets were weighed at day 28 and water content was assessed by deuterium oxide dilution. Piglets were euthanized, organ weights and lengths were recorded, the empty carcass was analyzed for dry matter, ash, and crude protein content, and body fat content was calculated. Two litters were treated for diarrhea, which was included in the statistical model. Weight at birth and at day 28 was not affected by maternal HMB supplementation. The total weight of the small intestine in HMB piglets was 15% lighter (P < 0.01) and the caecum of HMB piglets were 16% longer and 22% heavier (P < 0.01) than in CON piglets, and the large intestine was not affected by treatment. Diarrhea increased the length and weight of small and large intestine (P < 0.01) and weight of the kidneys (P < 0.01). The weight of the liver was increased by 8% in the HMB piglets (P < 0.01) compared with CON piglets, and the spleen was 31% heavier in HMB piglets (P < 0.01). The weight of the kidneys was increased for the HMB piglets (P < 0.01) whereas the weights of stomach and heart were not affected by HMB supplementation. The carcasses of HMB piglets had a lower DM and fat content (P < 0.05) and increased CP content (P < 0.01) compared with CON piglets. In conclusion, the study showed that maternal HMB supplementation in late gestation had long-lasting effects on characteristics of the piglets. PMID- 23365405 TI - Impact of Pichia guilliermondii on sow, litter, and weaned pig immune performance. AB - Three groups of gestating gilts and sows (Exp. 1; n = 98) were used to determine the effects of Pichia guilliermondii (Pg), a whole yeast product (CitriStim, ADM Alliance Nutrition), on dam and litter immune parameters. At breeding, gilts and sows were allotted to 1 of 3 treatments maintained through lactation: sow control (SC) diet or SC supplemented with 0.1 (S1) or 0.2% (S2) Pg. Pigs from groups 1 (Exp. 2) and 2 (Exp. 3) were weaned (21 d) and allotted in a 3 (SC, S1, or S2) * 2 [nursery with Pg (NPg) or without Pg (NC)] factorial arrangement in a randomized complete block design. In Exp. 2 blood samples were collected on days 5 and 28 postweaning for analysis. In Exp. 3, 36 pigs were individually penned and challenged with lipopolysaccharide (25 MUg/kg BW intramuscular; 0 h). Individual BW, ADFI, and rectal temperature (RT) were collected at -48, -24, 0, 24, and 48 h and blood samples were collected at 0, 5, and 24 h for analysis. In Exp. 1, total neutrophil count (NEU) and neutrophil:lymphocyte ratio (NLR) were greater on day 110 of gestation (P < 0.05) in S1 than SC. At weaning there was a liner increase (P < 0.05) in NEU, NLR, and percentage of total leukocytes (PTL) that were NEU as level of Pg increased in sow diets. In Exp. 2, pigs from S1 had increased (P < 0.05) overall IgG than SC. The PTL that were eosinophils was greater in pigs from S2 fed NPg on day 5 than NC (P < 0.05) and increased in all pigs from S2 on day 28 (sow linear, P < 0.1). On day 28, total leukocytes and eosinophils were increased in pigs from SC [quadratic response (Q), P < 0.05]. In Exp. 3, a linear increase (P < 0.05) in ADFI was observed at -24 to 0 h, -48 to 0 h, and 24 to 48 h as the level of Pg increased in sow diets. There was a linear increase in RT at -48, -24, 0, and 5 h with increasing Pg inclusion in sow diets (P < 0.05). However, RT decreased more from 5 to 24 h in pigs from sows receiving Pg. The number of monocytes and PTL that were monocytes were higher in S2 compared to SC and S1 (P < 0.05). Also, NEU were reduced at 5 h in S1 (P < 0.05), NLR was lower in S2 at 0 h and S1 at 5 h, IL-1beta concentration was greater in SC at 0 h and S1 at 5 h, and IL-6 concentration was greater in S2 at 0 h and S1 at 5 h (P < 0.05). Furthermore, blood urea N (BUN) was higher in NC at 0 and 5 h than NPg (P < 0.05). In conclusion, Pg appears to impact immune response criteria of sows and weaned pigs. PMID- 23365406 TI - Ileal mucosa-associated--but not ileal digesta--bacterial profiles in grower pigs are influenced by nutrition and use of antibiotics for weaner pigs. AB - A longitudinal study was conducted in pigs to evaluate the effect of nutrition and use of antibiotics for weaner pigs on ileal bacterial microbiota. Forty-eight pigs were weaned at 21 +/- 2 d of age and fed a high complexity diet (High) or low complexity diet (Low) with chlortetracycline (A+) or without chlortetracycline (A-) for 6 wk. All pigs received the same grower diet thereafter. Pigs were killed at week 2, 4, and 8 and ileal digesta as well as a 40-cm section of the distal ileum were taken for extraction of digesta and mucosa associated bacteria, respectively. Total DNA was extracted using a commercially available kit and PCR amplicons were generated using HDA1-GC and HDA2 primers against the V3 region of the 16S rRNA gene. Denaturing gradient gel electrophoresis (DGGE) of PCR amplicons was used for separation of distinct bacteria communities. Similarities of PCR-DGGE profiles were analyzed with Bionumerics software and the degree of similarity represented by a similarity coefficient. The DNA bands were compared using a positional tolerance of 0.5%. In the digesta, HighA-, LowA+, and LowA- were 47.6, 63.6, and 58.8% similar, respectively, at week 2 and 64.0, 69.2, and 66.7% similar, respectively, at week 4. Digesta bacteria were 90.9 (HighA-) and 85.7% (LowA-) similar to HighA+ at week 8 but due to a smiling edge of the DGGE gel, the profile for LowA+ was deemed inappropriate for similarity analysis. In the mucosa, HighA-, LowA+, and LowA- were 58.8, 80.0 and 44.4% similar, respectively, compared to HighA+ at week 2; 81.5, 75.0, and 88.9% similar, respectively, at week 4; and 81.8, 76.2, and 78.3% similar, respectively, at week 8. The bacterial profile was more similar between weeks 2 and 4 in the digesta than in the mucosa but more similar between weeks 4 and 8 in the mucosa than in the digesta. Postweaning nutrition may have a long-term effect on ileal mucosa-associated--but not ileal digesta--microbiota profiles. PMID- 23365407 TI - Extreme divergence in floral scent among woodland star species (Lithophragma spp.) pollinated by floral parasites. AB - BACKGROUNDS AND AIMS: A current challenge in coevolutionary biology is to understand how suites of traits vary as coevolving lineages diverge. Floral scent is often a complex, variable trait that attracts a suite of generalized pollinators, but may be highly specific in plants specialized on attracting coevolved pollinating floral parasites. In this study, floral scent variation was investigated in four species of woodland stars (Lithophragma spp.) that share the same major pollinator (the moth Greya politella, a floral parasite). Three specific hypotheses were tested: (1) sharing the same specific major pollinator favours conservation of floral scent among close relatives; (2) selection favours 'private channels' of rare compounds particularly aimed at the specialist pollinator; or (3) selection from rare, less-specialized co-pollinators mitigates the conservation of floral scent and occurrence of private channels. METHODS: Dynamic headspace sampling and solid-phase microextraction were applied to greenhouse-grown plants from a common garden as well as to field samples from natural populations in a series of experiments aiming to disentangle the genetic and environmental basis of floral scent variation. KEY RESULTS: Striking floral scent divergence was discovered among species. Only one of 69 compounds was shared among all four species. Scent variation was largely genetically based, because it was consistent across field and greenhouse treatments, and was not affected by visits from the pollinating floral parasite. CONCLUSIONS: The strong divergence in floral scents among Lithophragma species contrasts with the pattern of conserved floral scent composition found in other plant genera involved in mutualisms with pollinating floral parasites. Unlike some of these other obligate pollination mutualisms, Lithophragma plants in some populations are occasionally visited by generalist pollinators from other insect taxa. This additional complexity may contribute to the diversification in floral scent found among the Lithophragma species pollinated by Greya moths. PMID- 23365408 TI - Inferring microRNA-mRNA causal regulatory relationships from expression data. AB - MOTIVATION: microRNAs (miRNAs) are known to play an essential role in the post transcriptional gene regulation in plants and animals. Currently, several computational approaches have been developed with a shared aim to elucidate miRNA mRNA regulatory relationships. Although these existing computational methods discover the statistical relationships, such as correlations and associations between miRNAs and mRNAs at data level, such statistical relationships are not necessarily the real causal regulatory relationships that would ultimately provide useful insights into the causes of gene regulations. The standard method for determining causal relationships is randomized controlled perturbation experiments. In practice, however, such experiments are expensive and time consuming. Our motivation for this study is to discover the miRNA-mRNA causal regulatory relationships from observational data. RESULTS: We present a causality discovery-based method to uncover the causal regulatory relationship between miRNAs and mRNAs, using expression profiles of miRNAs and mRNAs without taking into consideration the previous target information. We apply this method to the epithelial-to-mesenchymal transition (EMT) datasets and validate the computational discoveries by a controlled biological experiment for the miR-200 family. A significant portion of the regulatory relationships discovered in data is consistent with those identified by experiments. In addition, the top genes that are causally regulated by miRNAs are highly relevant to the biological conditions of the datasets. The results indicate that the causal discovery method effectively discovers miRNA regulatory relationships in data. Although computational predictions may not completely replace intervention experiments, the accurate and reliable discoveries in data are cost effective for the design of miRNA experiments and the understanding of miRNA-mRNA regulatory relationships. PMID- 23365409 TI - Bayesian parentage analysis with systematic accountability of genotyping error, missing data and false matching. AB - MOTIVATION: The goal of any parentage analysis is to identify as many parent offspring relationships as possible, while minimizing incorrect assignments. Existing methods can achieve these ends, but they require additional information in the form of demographic data, thousands of markers and/or estimates of genotyping error rates. For many non-model systems, it is simply not practical, cost-effective or logistically feasible to obtain this information. Here, we develop a Bayesian parentage method that only requires the sampled genotypes to account for genotyping error, missing data and false matches. RESULTS: Extensive testing with microsatellite and SNP datasets reveals that our Bayesian parentage method reliably controls for the number of false assignments, irrespective of the genotyping error rate. When the number of loci is limiting, our approach maximizes the number of correct assignments by accounting for the frequencies of shared alleles. Comparisons with exclusion and likelihood-based methods on an empirical salmon dataset revealed that our Bayesian method had the highest ratio of correct to incorrect assignments. PMID- 23365410 TI - MosaicFinder: identification of fused gene families in sequence similarity networks. AB - MOTIVATION: Gene fusion is an important evolutionary process. It can yield valuable information to infer the interactions and functions of proteins. Fused genes have been identified as non-transitive patterns of similarity in triplets of genes. To be computationally tractable, this approach usually imposes an a priori distinction between a dataset in which fused genes are searched for, and a dataset that may have provided genetic material for fusion. This reduces the 'genetic space' in which fusion can be discovered, as only a subset of triplets of genes is investigated. Moreover, this approach may have a high-false-positive rate, and it does not identify gene families descending from a common fusion event. RESULTS: We represent similarities between sequences as a network. This leads to an efficient formulation of previous methods of fused gene identification, which we implemented in the Python program FusedTriplets. Furthermore, we propose a new characterization of families of fused genes, as clique minimal separators of the sequence similarity network. This well-studied graph topology provides a robust and fast method of detection, well suited for automatic analyses of big datasets. We implemented this method in the C++ program MosaicFinder, which additionally uses local alignments to discard false-positive candidates and indicates potential fusion points. The grouping into families will help distinguish sequencing or prediction errors from real biological fusions, and it will yield additional insight into the function and history of fused genes. AVAILABILITY: FusedTriplets and MosaicFinder are published under the GPL license and are freely available with their source code at this address: http://sourceforge.net/projects/mosaicfinder. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23365411 TI - MSMExplorer: visualizing Markov state models for biomolecule folding simulations. AB - SUMMARY: Markov state models (MSMs) for the study of biomolecule folding simulations have emerged as a powerful tool for computational study of folding dynamics. MSMExplorer is a visualization application purpose-built to visualize these MSMs with an aim to increase the efficacy and reach of MSM science. AVAILABILITY: MSMExplorer is available for download from https://simtk.org/home/msmexplorer. The source code is made available under the GNU Lesser General Public License at https://github.com/SimTk/msmexplorer. PMID- 23365413 TI - Kisspeptin receptor, GPR54, as a candidate for the regulation of testicular activity in the frog Rana esculenta. AB - Kisspeptins, acting via GPR54, are new players in the control of reproductive axis. They have the ability to communicate with GnRH neurons sending environmental, metabolic, and gonadal signals, with the induction of GnRH and LH secretion as final effect. At present, the physiological significance of kisspeptin signaling in the gonad is poorly investigated. We cloned GPR54 receptor from the anuran amphibian Rana esculenta testis and investigated its expression in several tissues (brain, spinal cord, ovary, muscle, and kidney). In particular, the expression analysis was carried out in pituitary and testis during the annual sexual cycle. Pituitary and testicular GPR54 mRNA increased at the end of the winter stasis (February) and reached high levels during the breeding season (April). The analysis of GPR54 expression in testis was reinforced by in situ hybridization that revealed GPR54 presence in the interstitial compartment and in proliferating germ cells. Testicular GPR54 expression in February and in June was indicated to be estradiol dependent. Furthermore, in February, kisspeptin-10 (Kp-10) induced the testicular expression of both GPR54 and estrogen receptor alpha (ERalpha) in a dose-dependent manner. Conversely, in March, Kp-10 had a biphasic effect on the expression of ERalpha, being inhibitory at short (1 h) and stimulatory at longer (4 h) incubation time. In conclusion, our results demonstrate that frog testis expresses GPR54 in an estradiol-dependent manner and that Kp-10 modulates the testicular expression of ERalpha; thus, the kisspeptin/GPR54 system might be locally involved in the regulation of estrogen-dependent testicular functions such as germ cell proliferation and steroidogenesis. PMID- 23365412 TI - Gestational protein restriction increases angiotensin II production in rat lung. AB - Gestational protein restriction (PR) alters the renin-angiotensin system in uterine arteries and placentas and elevates plasma levels of angiotensin II in pregnant rats. To date, how PR increases maternal plasma levels of angiotensin II remains unknown. In this study, we hypothesize that the expression and/or the activity of angiotensin I converting enzyme (peptidyl-dipeptidase A) 1 (ACE) in lungs, but not kidneys and blood, largely contribute to elevated plasma angiotensin II levels in pregnant rats subject to gestational PR. Time-scheduled pregnant Sprague-Dawley rats were fed a normal or low-protein diet from Day 3 of pregnancy until euthanized at Day 19 or 22. Expressions of Ace and Ace2 (angiotens in I converting enzyme [peptidyl-dipeptidase A] 2) in lungs and kidneys from pregnant rats by quantitative real-time PCR and Western blotting, and the activities of these proteins in lungs, kidneys, and plasma, were measured. The mRNA levels of Ace and Ace2 in lungs were elevated by PR at both Days 19 and 22 of pregnancy. The abundance of ACE protein in lungs was increased, but ACE2 protein was decreased, by PR. The activities of ACE, but not ACE2, in lungs were increased by PR. PR did not change expressions of Ace and Ace2, the activities of both ACE and ACE2 in kidneys, and the abundance and activity of plasma ACE. These findings suggest that maternal lungs contribute to the elevated plasma levels of angiotensin II by increasing both the expression and the activity of ACE in response to gestational PR. PMID- 23365414 TI - Evidence for a luteotropic role of peroxisome proliferator-activated receptor gamma: expression and in vitro effects on enzymatic and hormonal activities in corpora lutea of pseudopregnant rabbits. AB - The expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and its role in corpora lutea (CL) function were studied in pseudopregnant rabbits. Corpora lutea were collected at an early stage (Day 4), midstage (Day 9), and late stage (Day 13) of pseudopregnancy. Immunohistochemistry found evidence for the presence of PPARgamma in the perinuclear cytoplasm and nucleus of all the luteal cells; immunoreactivity decreased from the early to the late stage, with immunonegativity of the nuclei of late stage CL. PPARgamma mRNA transcript was expressed in all the luteal stages with the lowest level in the late stage. In CL cultured in vitro, the PPARgamma agonist (15-deoxy delta12,14 prostaglandin J2 [15d-PGJ2], 200 nM) increased and the antagonist (T0070907, 50 nM) decreased progesterone secretion at early and midluteal stages, whereas 15d PGJ2 reduced and T0070907 increased PGF2alpha at the same stages. Prostaglandin endoperoxide synthase 2 (PTGS2) activity was reduced by 15d-PGJ2 and increased by T0070907 in CL of early and midluteal stages. Conversely, 15d-PGJ2 increased and T0070907 reduced 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity in early and midluteal stage CL. PGE2 in vitro secretion as well as PTGS1 and 20alpha-HSD enzymatic activities were not affected by 15d-PGJ2 and T0070907 in any CL types. These results indicate that PPARgamma plays a luteotropic role in pseudopregnant rabbits, through PTGS2 down-regulation and 3beta-HSD up-regulation, with a consequent PGF2alpha decrease and progesterone increase. PMID- 23365415 TI - Melatonin prevents postovulatory oocyte aging in the mouse and extends the window for optimal fertilization in vitro. AB - The quality of metaphase II oocytes deteriorates rapidly following ovulation as the result of an aging process associated with impaired fertilizing potential, disrupted developmental competence, and increased likelihood of embryonic resorption. Because oxidative stress accelerates the onset of apoptosis in oocytes and influences their capacity for fertilization, this study aimed to characterize the significance of such stress in the postovulatory aging of mouse oocytes in vitro. We investigated the ability of the potent antioxidant melatonin to arrest the aging process when used to supplement oocyte culture medium. This study demonstrated that oxidative stress may occur in oocytes after as little as 8 h in culture and coincides with the appearance of early apoptotic markers such as phosphatidylserine externalization, followed 16 h later by caspase activation (P < 0.05) and morphological evidence of oocyte senescence. Importantly, supplementation of oocyte culture medium with 1 mM melatonin was able to significantly relieve the time-dependent appearance of oxidative stress in oocytes (P < 0.05) and, as a result, significantly delay the onset of apoptosis (P < 0.05). Furthermore, melatonin supplementation extended the optimal window for fertilization of oocytes aged for 8 and 16 h in vitro (P < 0.05) and significantly improved the quality of the resulting embryos (P < 0.01). We conclude that melatonin may be a useful tool in a clinical setting to prevent the time-dependent deterioration of oocyte quality following prolonged culture in vitro. PMID- 23365416 TI - Flexible marginalized models for bivariate longitudinal ordinal data. AB - Random effects models are commonly used to analyze longitudinal categorical data. Marginalized random effects models are a class of models that permit direct estimation of marginal mean parameters and characterize serial correlation for longitudinal categorical data via random effects (Heagerty, 1999). Marginally specified logistic-normal models for longitudinal binary data. Biometrics 55, 688 698; Lee and Daniels, 2008. Marginalized models for longitudinal ordinal data with application to quality of life studies. Statistics in Medicine 27, 4359 4380). In this paper, we propose a Kronecker product (KP) covariance structure to capture the correlation between processes at a given time and the correlation within a process over time (serial correlation) for bivariate longitudinal ordinal data. For the latter, we consider a more general class of models than standard (first-order) autoregressive correlation models, by re-parameterizing the correlation matrix using partial autocorrelations (Daniels and Pourahmadi, 2009). Modeling covariance matrices via partial autocorrelations. Journal of Multivariate Analysis 100, 2352-2363). We assess the reasonableness of the KP structure with a score test. A maximum marginal likelihood estimation method is proposed utilizing a quasi-Newton algorithm with quasi-Monte Carlo integration of the random effects. We examine the effects of demographic factors on metabolic syndrome and C-reactive protein using the proposed models. PMID- 23365417 TI - Effect of pelvic floor muscle training during pregnancy and after childbirth on prevention and treatment of urinary incontinence: a systematic review. AB - BACKGROUND: Urinary incontinence (UI) is a common condition in women causing reduced quality of life and withdrawal from fitness and exercise activities. Pregnancy and childbirth are established risk factors. Current guidelines for exercise during pregnancy have no or limited focus on the evidence for the effect of pelvic floor muscle training (PFMT) in the prevention and treatment of UI. AIMS: Systematic review to address the effect of PFMT during pregnancy and after delivery in the prevention and treatment of UI. DATA SOURCES: PubMed, CENTRAL, Cochrane Library, EMBASE and PEDro databases and hand search of available reference lists and conference abstracts (June 2012). METHODS: STUDY ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) and quasiexperimental trials published in the English language. PARTICIPANTS: Primiparous or multiparous pregnant or postpartum women. INTERVENTIONS: PFMT with or without biofeedback, vaginal cones or electrical stimulation. STUDY APPRAISAL AND SYNTHESIS METHODS: Both authors independently reviewed, grouped and qualitatively synthesised the trials. RESULTS: 22 randomised or quasiexperimental trials were found. There is a very large heterogeneity in the populations studied, inclusion and exclusion criteria, outcome measures and content of PFMT interventions. Based on the studies with relevant sample size, high adherence to a strength-training protocol and close follow-up, we found that PFMT during pregnancy and after delivery can prevent and treat UI. A supervised training protocol following strength-training principles, emphasising close to maximum contractions and lasting at least 8 weeks is recommended. CONCLUSIONS: PFMT is effective when supervised training is conducted. Further high-quality RCTs are needed especially after delivery. Given the prevalence of female UI and its impact on exercise participation, PFMT should be incorporated as a routine part of women's exercise programmes in general. PMID- 23365418 TI - Exercise during pregnancy and gestational diabetes-related adverse effects: a randomised controlled trial. AB - OBJECTIVE: To examine the effect of regular moderate-intensity exercise (three training sessions/week) on the incidence of gestational diabetes mellitus (GDM, primary outcome). We also examined if the exercise intervention modifies the association between GDM and birth weight and risk of macrosomia, gestational age, risk of caesarean delivery and maternal weight gain (secondary outcomes). METHODS: We randomly assigned 510 healthy gravida to either an exercise intervention or a usual care (control) group (n=255 each). The exercise programme focused on moderate-intensity resistance and aerobic exercises (three times/week, 50-55 min/session). GDM diabetes was diagnosed according to the WHO criteria and the International Association for Diabetes in Pregnancy Study Group (IADPSG). RESULTS: The intervention did not reduce the risk of developing GDM (OR 0.84, 95% CI 0.50 to 1.40) when using the WHO criteria. We observed that the intervention reduced by 58% the GDM-related risk (WHO criteria) of having a newborn with macrosomia (OR 1.76, 95% CI 0.04 to 78.90 vs 4.22, 95% CI 1.35 to 13.19) in exercise and control groups, respectively), and by 34% the GDM-related risk of having acute and elective caesarean delivery (OR 1.30, 95% CI 0.44 to 3.84 vs 1.99, 95% CI 0.98 to 4.06 in exercise and control groups, respectively). Gestational age was similar across the treatment groups (control, exercise) and GDM category (GDM or non-GDM), and maternal weight gain was ~12% lower in the exercise group independent of whether women developed GDM. The results were similar when the IADPSG criteria were used instead. CONCLUSIONS: Regular moderate intensity exercise performed over the second-third trimesters of pregnancy can be used to attenuate important GDM-related adverse outcomes. PMID- 23365419 TI - The development of healthy tennis clubs in the Netherlands. AB - OBJECTIVES: To explore the factors that facilitate or hinder the development of healthy tennis clubs in the Netherlands and to identify suitable interventions that would help clubs to reach 'healthy club' status. METHODS: A maximum variation, purposive sampling strategy was used to identify and recruit board members (n=16) from 10 Dutch tennis clubs. Data were collected using in-depth interviews based on an interview guide. The interviews explored what steps the clubs had taken to create a healthy tennis club, and what the respondents perceived to be the barriers to reaching healthy club status. The data were analysed using thematic content analysis. An ecological model was used to frame the interpretation of the themes and guide the development of the interventions. RESULTS: Four emerging themes were identified: provision of healthy foods, injury prevention and health services, social health and safety around the club. The main facilitators were found to be support from club management, having appropriate policies in place and having appointed officers. The main barriers were identified as a lack of policy templates, inadequate knowledge of coaches on injury prevention and injury management and fragmented access to relevant information. CONCLUSIONS: Guided by an ecological model, this study demonstrates the many factors that influence tennis clubs and the individual members of a healthy tennis club. Using this model, a multilevel intervention framework has been created that could be used by the Royal Netherlands Lawn Tennis Association to increase the number of healthy tennis clubs in the Netherlands. PMID- 23365420 TI - Frequent and variable cytotoxic-T-lymphocyte escape-associated fitness costs in the human immunodeficiency virus type 1 subtype B Gag proteins. AB - Cytotoxic-T-lymphocyte (CTL) escape mutations undermine the durability of effective human immunodeficiency virus type 1 (HIV-1)-specific CD8(+) T cell responses. The rate of CTL escape from a given response is largely governed by the net of all escape-associated viral fitness costs and benefits. The observation that CTL escape mutations can carry an associated fitness cost in terms of reduced virus replication capacity (RC) suggests a fitness cost-benefit trade-off that could delay CTL escape and thereby prolong CD8 response effectiveness. However, our understanding of this potential fitness trade-off is limited by the small number of CTL escape mutations for which a fitness cost has been quantified. Here, we quantified the fitness cost of the 29 most common HIV 1B Gag CTL escape mutations using an in vitro RC assay. The majority (20/29) of mutations reduced RC by more than the benchmark M184V antiretroviral drug resistance mutation, with impacts ranging from 8% to 69%. Notably, the reduction in RC was significantly greater for CTL escape mutations associated with protective HLA class I alleles than for those associated with nonprotective alleles. To speed the future evaluation of CTL escape costs, we also developed an in silico approach for inferring the relative impact of a mutation on RC based on its computed impact on protein thermodynamic stability. These data illustrate that the magnitude of CTL escape-associated fitness costs, and thus the barrier to CTL escape, varies widely even in the conserved Gag proteins and suggest that differential escape costs may contribute to the relative efficacy of CD8 responses. PMID- 23365421 TI - An adjuvanted herpes simplex virus 2 subunit vaccine elicits a T cell response in mice and is an effective therapeutic vaccine in Guinea pigs. AB - Immunotherapeutic herpes simplex virus 2 (HSV-2) vaccine efficacy depends upon the promotion of antigen-specific immune responses that inhibit reactivation or reactivated virus, thus controlling both recurrent lesions and viral shedding. In the present study, a candidate subunit vaccine, GEN-003/MM-2, was evaluated for its ability to induce a broad-spectrum immune response in mice and therapeutic efficacy in HSV-2-infected guinea pigs. GEN-003 is comprised of HSV-2 glycoprotein D2 (gD2DeltaTMR340-363) and a truncated form of infected cell polypeptide 4 (ICP4383-766), formulated with Matrix M-2 (MM-2) adjuvant (GEN 003/MM-2). In addition to eliciting humoral immune responses, CD4(+) and CD8(+) T cells characterized by the secretion of multiple cytokines and cytolytic antigen specific T cell responses that were able to be recalled at least 44 days after the last immunization were induced in immunized mice. Furthermore, vaccination with either GEN-003 or GEN-003/MM-2 led to significant reductions in both the prevalence and severity of lesions in HSV-2-infected guinea pigs compared to those of phosphate-buffered saline (PBS) control-vaccinated animals. While vaccination with MM-2 adjuvant alone decreased recurrent disease symptoms compared to the PBS control group, the difference was not statistically significant. Importantly, the frequency of recurrent viral shedding was considerably reduced in GEN-003/MM-2-vaccinated animals but not in GEN-003- or MM 2-vaccinated animals. These findings suggest a possible role for immunotherapeutic GEN-003/MM-2 vaccination as a viable alternative to chronic antiviral drugs in the treatment and control of genital herpes disease. PMID- 23365422 TI - Release of severe acute respiratory syndrome coronavirus nuclear import block enhances host transcription in human lung cells. AB - The severe acute respiratory syndrome coronavirus accessory protein ORF6 antagonizes interferon signaling by blocking karyopherin-mediated nuclear import processes. Viral nuclear import antagonists, expressed by several highly pathogenic RNA viruses, likely mediate pleiotropic effects on host gene expression, presumably interfering with transcription factors, cytokines, hormones, and/or signaling cascades that occur in response to infection. By bioinformatic and systems biology approaches, we evaluated the impact of nuclear import antagonism on host expression networks by using human lung epithelial cells infected with either wild-type virus or a mutant that does not express ORF6 protein. Microarray analysis revealed significant changes in differential gene expression, with approximately twice as many upregulated genes in the mutant virus samples by 48 h postinfection, despite identical viral titers. Our data demonstrated that ORF6 protein expression attenuates the activity of numerous karyopherin-dependent host transcription factors (VDR, CREB1, SMAD4, p53, EpasI, and Oct3/4) that are critical for establishing antiviral responses and regulating key host responses during virus infection. Results were confirmed by proteomic and chromatin immunoprecipitation assay analyses and in parallel microarray studies using infected primary human airway epithelial cell cultures. The data strongly support the hypothesis that viral antagonists of nuclear import actively manipulate host responses in specific hierarchical patterns, contributing to the viral pathogenic potential in vivo. Importantly, these studies and modeling approaches not only provide templates for evaluating virus antagonism of nuclear import processes but also can reveal candidate cellular genes and pathways that may significantly influence disease outcomes following severe acute respiratory syndrome coronavirus infection in vivo. PMID- 23365423 TI - Human papillomavirus episome stability is reduced by aphidicolin and controlled by DNA damage response pathways. AB - A highly reproducible quantitative PCR (Q-PCR) assay was used to study the stability of human papillomavirus (HPV) in undifferentiated keratinocytes that maintain viral episomes. The term "stability" refers to the ability of episomes to persist with little copy number variation in cells. In investigating the mechanism of action of PA25, a previously published compound that destabilizes HPV episomes, aphidicolin was also found to markedly decrease episome levels, but via a different pathway from that of PA25. Since aphidicolin is known to activate DNA damage response (DDR) pathways, effects of inhibitors and small interfering RNAs (siRNAs) acting within DDR pathways were investigated. Inhibitors of Chk1 and siRNA directed against ataxia-telangiectasia mutated (ATM) and ataxia telangiectasia Rad3-related (ATR) pathways significantly reduced viral episomes, suggesting that these pathways play a role in maintaining HPV episome stability. Inhibitors of Chk2 and DNA-PK had no effect on episome levels. Pharmacological inhibition of ATM proteins had no effect on episome levels, but ATM knockdown by siRNA significantly reduced episome levels, suggesting that ATM proteins are playing an important role in HPV episome stability that does not require kinase activity. These results outline two pathways that trigger episome loss from cells and suggest the existence of a little-understood mechanism that mediates viral DNA elimination. Together, our results also indicate that HPV episomes have a stability profile that is remarkably similar to that of fragile sites; these similarities are outlined and discussed. This close correspondence may influence the preference of HPV for integration into fragile sites. PMID- 23365425 TI - Structural analysis of the evolutionary origins of influenza virus hemagglutinin and other viral lectins. AB - Influenza virus and other viruses use host cell surface sugars as receptors. Here we show that the sugar-binding domains in influenza virus hemagglutinin and other viral lectins share the same structural fold as human galectins (host lectins). Unlike the easily accessible sugar-binding sites in human galectins, the sugar binding sites in viral lectins are hidden in cavities. We propose that these viral lectins originated from host lectins but have evolved to use hidden sugar binding sites to evade host immune attacks. PMID- 23365424 TI - RNA transfer from poliovirus 135S particles across membranes is mediated by long umbilical connectors. AB - During infection, the binding of poliovirus to its cell surface receptor at 37 degrees C triggers an expansion of the virus in which internal polypeptides that bind to membranes are externalized. Subsequently, in a poorly understood process, the viral RNA genome is transferred directly across an endosomal membrane, and into the host cell cytoplasm, to initiate infection. Here, cryoelectron tomography demonstrates the results of 37 degrees C warming of a poliovirus receptor-liposome model complex that was produced using Ni-nitrilotriacetic acid lipids and His-tagged receptor ectodomains. In total, 651 subtomographic volumes were aligned, classified, and averaged to obtain detailed pictures, showing both the conversion of virus into its expanded form and the passage of RNA into intact liposomes. Unexpectedly, the virus and membrane surfaces were located ~50 A apart, with the 5-fold axis tilted away from the perpendicular, and the solvent spaces between them were spanned by either one or two long "umbilical" density features that lie at an angle to the virus and membrane. The thinner connector, which sometimes appears alone, is 28 to 30 A in diameter and has a footprint on the virus surface located close to either a 5-fold or a 3-fold axis. The broader connector has a footprint near the quasi-3-fold hole that opens upon virus expansion and is hypothesized to include RNA, shielded from enzymatic degradation by polypeptides that include the N-terminal extension of VP1 and capsid protein VP4. The implications of these observations for the mechanism of RNase-protected RNA transfer in picornaviruses are discussed. PMID- 23365426 TI - Structural and functional analysis of coxsackievirus A9 integrin alphavbeta6 binding and uncoating. AB - Coxsackievirus A9 (CVA9) is an important pathogen of the Picornaviridae family. It utilizes cellular receptors from the integrin alphav family for binding to its host cells prior to entry and genome release. Among the integrins tested, it has the highest affinity for alphavbeta6, which recognizes the arginine-glycine aspartic acid (RGD) loop present on the C terminus of viral capsid protein, VP1. As the atomic model of CVA9 lacks the RGD loop, we used surface plasmon resonance, electron cryo-microscopy, and image reconstruction to characterize the capsid-integrin interactions and the conformational changes on genome release. We show that the integrin binds to the capsid with nanomolar affinity and that the binding of integrin to the virion does not induce uncoating, thereby implying that further steps are required for release of the genome. Electron cryo tomography and single-particle image reconstruction revealed variation in the number and conformation of the integrins bound to the capsid, with the integrin footprint mapping close to the predicted site for the exposed RGD loop on VP1. Comparison of empty and RNA-filled capsid reconstructions showed that the capsid undergoes conformational changes when the genome is released, so that the RNA capsid interactions in the N termini of VP1 and VP4 are lost, VP4 is removed, and the capsid becomes more porous, as has been reported for poliovirus 1, human rhinovirus 2, enterovirus 71, and coxsackievirus A7. These results are important for understanding the structural basis of integrin binding to CVA9 and the molecular events leading to CVA9 cell entry and uncoating. PMID- 23365427 TI - Inhibition of the host translation shutoff response by herpes simplex virus 1 triggers nuclear envelope-derived autophagy. AB - Macroautophagy is a cellular pathway that degrades intracellular pathogens and contributes to antigen presentation. Herpes simplex virus 1 (HSV-1) infection triggers both macroautophagy and an additional form of autophagy that uses the nuclear envelope as a source of membrane. The present study constitutes the first in-depth analysis of nuclear envelope-derived autophagy (NEDA). We established LC3a as a marker that allowed us to distinguish between NEDA and macroautophagy in both immunofluorescence and flow cytometry. NEDA was observed in many different cell types, indicating that it is a general response to HSV-1 infection. This autophagic pathway is known to depend on the viral protein gamma34.5, which can inhibit macroautophagy via binding to beclin-1. Using mutant viruses, we were able to show that binding of beclin-1 by gamma34.5 had no effect on NEDA, demonstrating that NEDA is regulated differently than macroautophagy. Instead, NEDA was triggered in response to gamma34.5 binding to protein phosphatase 1alpha, an interaction used by the virus to prevent host cells from shutting off protein translation. NEDA was not triggered when late viral protein production was inhibited with acyclovir or hippuristanol, indicating that the accumulation of these proteins might stress infected cells. Interestingly, expression of the late viral protein gH was sufficient to rescue NEDA in the context of infection with a virus that otherwise does not support strong late viral protein expression. We argue that NEDA is a cellular stress response triggered late during HSV-1 infection and might compensate for the viral alteration of the macroautophagic response. PMID- 23365428 TI - Targeting IkappaB proteins for HIV latency activation: the role of individual IkappaB and NF-kappaB proteins. AB - Latently infected cell reservoirs represent the main barrier to HIV eradication. Combination antiretroviral therapy (cART) effectively blocks viral replication but cannot purge latent provirus. One approach to HIV eradication could include cART to block new infections plus an agent to activate latent provirus. NF-kappaB activation induces HIV expression, ending latency. Before activation, IkappaB proteins sequester NF-kappaB dimers in the cytoplasm. Three canonical IkappaBs, IkappaBalpha, IkappaBbeta, and IkappaBepsilon, exist, but the IkappaB proteins' role in HIV activation regulation is not fully understood. We studied the effects on HIV activation of targeting IkappaBs by single and pairwise small interfering RNA (siRNA) knockdown. After determining the relative abundance of the IkappaBs, the relative abundance of NF-kappaB subunits held by the IkappaBs, and the kinetics of IkappaB degradation and resynthesis following knockdown, we studied HIV activation by IkappaB knockdown, in comparison with those of known HIV activators, tumor necrosis factor alpha (TNF-alpha), tetradecanoyl phorbol acetate (TPA), and trichostatin A (TSA), in U1 monocytic and J-Lat 10.6 lymphocytic latently infected cells. We found that IkappaBalpha knockdown activated HIV in both U1 and J-Lat 10.6 cells, IkappaBbeta knockdown did not activate HIV, and, surprisingly, IkappaBepsilon knockdown produced the most HIV activation, comparable to TSA activation. Our data show that HIV reactivation can be triggered by targeting two different IkappaB proteins and that IkappaBepsilon may be an effective target for HIV latency reactivation in T-cell and macrophage lineages. IkappaBepsilon knockdown may offer attractive therapeutic advantages for HIV activation because it is not essential for mammalian growth and development and because new siRNA delivery strategies may target siRNAs to HIV latently infected cells. PMID- 23365429 TI - Epstein-Barr virus deubiquitinase downregulates TRAF6-mediated NF-kappaB signaling during productive replication. AB - Epstein-Barr virus (EBV), a human oncogenic herpesvirus that establishes a lifelong latent infection in the host, occasionally enters lytic infection to produce progeny viruses. The EBV oncogene latent membrane protein 1 (LMP1), which is expressed in both latent and lytic infection, constitutively activates the canonical NF-kappaB (p65) pathway. Such LMP1-mediated NF-kappaB activation is necessary for proliferation of latently infected cells and inhibition of viral lytic cycle progression. Actually, canonical NF-kappaB target gene expression was suppressed upon the onset of lytic infection. TRAF6, which is activated by conjugation of polyubiquitin chains, associates with LMP1 to mediate NF-kappaB signal transduction. We have found that EBV-encoded BPLF1 interacts with and deubiquitinates TRAF6 to inhibit NF-kappaB signaling during lytic infection. HEK293 cells with BPLF1-deficient recombinant EBV exhibited poor viral DNA replication compared with the wild type. Furthermore, exogenous expression of BPLF1 or p65 knockdown in cells restored DNA replication of BPLF1-deficient viruses, indicating that EBV BPLF1 deubiquitinates TRAF6 to inhibit NF-kappaB signal transduction, leading to promotion of viral lytic DNA replication. PMID- 23365430 TI - Chromatin immunoprecipitation and microarray analysis suggest functional cooperation between Kaposi's Sarcoma-associated herpesvirus ORF57 and K-bZIP. AB - The Kaposi's sarcoma-associated herpesvirus (KSHV) open reading frame 57 (ORF57) encoded protein (Mta) is a multifunctional regulator of viral gene expression. ORF57 is essential for viral replication, so elucidation of its molecular mechanisms is important for understanding KSHV infection. ORF57 has been implicated in nearly every aspect of viral gene expression, including transcription, RNA stability, splicing, export, and translation. Here we demonstrate that ORF57 interacts with the KSHV K-bZIP protein in vitro and in cell extracts from lytically reactivated infected cells. To further test the biological relevance of the interaction, we performed a chromatin immunoprecipitation and microarray (ChIP-chip) analysis using anti-ORF57 antibodies and a KSHV tiling array. The results revealed four specific areas of enrichment, including the ORF4 and K8 (K-bZIP) promoters, as well as oriLyt, all of which interact with K-bZIP. In addition, ORF57 associated with DNA corresponding to the PAN RNA transcribed region, a known posttranscriptional target of ORF57. All of the peaks were RNase insensitive, demonstrating that ORF57 association with the viral genome is unlikely to be mediated exclusively by an RNA tether. Our data demonstrate that ORF57 associates with the viral genome by using at least two modes of recruitment, and they suggest that ORF57 and K bZIP coregulate viral gene expression during lytic infection. PMID- 23365431 TI - Crystal structure of a poxvirus-like zalpha domain from cyprinid herpesvirus 3. AB - Zalpha domains are a subfamily of the winged helix-turn-helix domains sharing the unique ability to recognize CpG repeats in the left-handed Z-DNA conformation. In vertebrates, domains of this family are found exclusively in proteins that detect foreign nucleic acids and activate components of the antiviral interferon response. Moreover, poxviruses encode the Zalpha domain-containing protein E3L, a well-studied and potent inhibitor of interferon response. Here we describe a herpesvirus Zalpha-domain-containing protein (ORF112) from cyprinid herpesvirus 3. We demonstrate that ORF112 also binds CpG repeats in the left-handed conformation, and moreover, its structure at 1.75 A reveals the Zalpha fold found in ADAR1, DAI, PKZ, and E3L. Unlike other Zalpha domains, however, ORF112 forms a dimer through a unique domain-swapping mechanism. Thus, ORF112 may be considered a new member of the Z-domain family having DNA binding properties similar to those of the poxvirus E3L inhibitor of interferon response. PMID- 23365432 TI - Emergence in Japan of an HIV-1 variant associated with transmission among men who have sex with men (MSM) in China: first indication of the International Dissemination of the Chinese MSM lineage. AB - A survey of HIV-1 strains circulating in the Tokyo-Kanagawa metropolitan area of Japan during 2004 to 2011 (n = 477) identified six Japanese males (patients 1 to 6), who harbored viruses with genome segments derived from a distinct CRF01_AE variant uniquely found among men who have sex with men (MSM) in China (designated CN.MSM.01-1). These six HIV infections were diagnosed in 2010 and 2011 among MSM (3 of 75) and men with unknown risk factors (3 of 63) and differed from the vast majority of HIV infections among MSM in Japan, which are overwhelmingly characterized by subtype B (239 of 246 [97.2%]). Approximately one-third (91 of 239 [38.1%]) of subtype B strains from MSM in Japan belong to a large monophyletic cluster (designated JP.MSM.B-1). In addition, we identified a smaller subtype B cluster (n = 8) (designated JP.MSM.B-2) that also contains strains from two Chinese MSM living in Japan. Interestingly, patients 5 and 6 were found to be coinfected with CRF01_AE (CN.MSM.01-1) and subtype B (JP.MSM.B-2 or JP.MSM.B-1) variants that are unique to the HIV-1 epidemics among MSM in China and Japan, respectively. Our study demonstrates for the first time the effect of the expanding HIV epidemic among MSM in China on transmission in neighboring countries and shows the ongoing mixing of CRF01_AE and subtype B lineages unique to HIV-1 that cocirculate in MSM populations in East Asia. This finding highlights the importance of strengthening epidemiological surveillance in the region and the need for effective measures to limit transmission among MSM in East Asia. PMID- 23365433 TI - Alphaherpesviral US3 kinase induces cofilin dephosphorylation to reorganize the actin cytoskeleton. AB - The conserved alphaherpesviral serine/threonine kinase US3 causes dramatic actin rearrangements, associated with increased viral spread. Here, we show that US3 of pseudorabies virus (PRV) leads to activation (dephosphorylation) of the central actin regulator cofilin. A mutation that impairs US3 kinase activity and the group I p21-activated kinase inhibitor IPA-3 inhibited US3-mediated cofilin activation. Additionally, expression of phosphomimetic S3D cofilin significantly suppressed the ability of US3 to cause cell projections and cell rounding. In conclusion, the US3 kinase of PRV leads to activation (dephosphorylation) of cofilin, and cofilin contributes to US3-mediated actin rearrangements. PMID- 23365434 TI - SMC1-mediated intra-S-phase arrest facilitates bocavirus DNA replication. AB - Activation of a host DNA damage response (DDR) is essential for DNA replication of minute virus of canines (MVC), a member of the genus Bocavirus of the Parvoviridae family; however, the mechanism by which DDR contributes to viral DNA replication is unknown. In the current study, we demonstrate that MVC infection triggers the intra-S-phase arrest to slow down host cellular DNA replication and to recruit cellular DNA replication factors for viral DNA replication. The intra S-phase arrest is regulated by ATM (ataxia telangiectasia-mutated kinase) signaling in a p53-independent manner. Moreover, we demonstrate that SMC1 (structural maintenance of chromosomes 1) is the key regulator of the intra-S phase arrest induced during infection. Either knockdown of SMC1 or complementation with a dominant negative SMC1 mutant blocks both the intra-S phase arrest and viral DNA replication. Finally, we show that the intra-S-phase arrest induced during MVC infection was caused neither by damaged host cellular DNA nor by viral proteins but by replicating viral genomes physically associated with the DNA damage sensor, the Mre11-Rad50-Nbs1 (MRN) complex. In conclusion, the feedback loop between MVC DNA replication and the intra-S-phase arrest is mediated by ATM-SMC1 signaling and plays a critical role in MVC DNA replication. Thus, our findings unravel the mechanism underlying DDR signaling-facilitated MVC DNA replication and demonstrate a novel strategy of DNA virus-host interaction. PMID- 23365435 TI - Measles virus infection of epithelial cells in the macaque upper respiratory tract is mediated by subepithelial immune cells. AB - Measles virus (MV), one of the most contagious viruses infecting humans, causes a systemic infection leading to fever, immune suppression, and a characteristic maculopapular rash. However, the specific mechanism or mechanisms responsible for the spread of MV into the respiratory epithelium in the late stages of the disease are unknown. Here we show the crucial role of PVRL4 in mediating the spread of MV from immune to epithelial cells by generating a PVRL4 "blind" recombinant wild-type MV and developing a novel in vitro coculture model of B cells with primary differentiated normal human bronchial epithelial cells. We utilized the macaque model of measles to analyze virus distribution in the respiratory tract prior to and at the peak of MV replication. Expression of PVRL4 was widespread in both the lower and upper respiratory tract (URT) of macaques, indicating MV transmission can be facilitated by more than only epithelial cells of the trachea. Analysis of tissues collected at early time points after experimental MV infection demonstrated the presence of MV-infected lymphoid and myeloid cells contacting respiratory tract epithelium in the absence of infected epithelial cells, suggesting that these immune cells seed the infection in vivo. Thereafter, lateral cell-to-cell spread of MV led to the formation of large foci of infected cells in the trachea and high levels of MV infection in the URT, particularly in the nasal cavity. These novel findings have important implications for our understanding of the high transmissibility of measles. PMID- 23365436 TI - Interactions of the Kaposi's Sarcoma-associated herpesvirus nuclear egress complex: ORF69 is a potent factor for remodeling cellular membranes. AB - All herpesviruses encode a complex of two proteins, referred to as the nuclear egress complex (NEC), which together facilitate the exit of assembled capsids from the nucleus. Previously, we showed that the Kaposi's sarcoma-associated herpesvirus (KSHV) NEC specified by the ORF67 and ORF69 genes when expressed in insect cells using baculoviruses for protein expression forms a complex at the nuclear membrane and remodels these membranes to generate nuclear membrane derived vesicles. In this study, we have analyzed the functional domains of the KSHV NEC proteins and their interactions. Site-directed mutagenesis of gammaherpesvirus conserved residues revealed functional domains of these two proteins, which in many cases abolish the formation of the NEC and remodeling of nuclear membranes. Small in-frame deletions within ORF67 in all cases result in loss of the ability of the mutant protein to induce cellular membrane proliferation as well as to interact with ORF69. Truncation of the C terminus of ORF67 that resides in the perinuclear space does not impair the functions of ORF67; however, deletion of the transmembrane domain of ORF67 produces a protein that cannot induce membrane proliferation but can still interact with ORF69 in the nucleus and can be tethered to the nuclear membrane by virtue of its interaction with the wild-type-membrane-anchored ORF67. In-frame deletions in ORF69 have varied effects on NEC formation, but all abolish remodeling of nuclear membranes into circular structures. One mutant interacts with ORF67 as well as the wild-type protein but cannot function in membrane curvature and fission events that generate circular vesicles. These studies genetically confirm that ORF67 is required for cellular membrane proliferation and that ORF69 is the factor required to remodel these duplicated membranes into circular-virion-size vesicles. Furthermore, we also investigated the NEC encoded by Epstein-Barr virus (EBV). The EBV complex comprised of BFRF1 and BFLF2 was visualized at the nuclear membrane using autofluorescent protein fusions. BFRF1 is a potent inducer of membrane proliferation; however, BFLF2 cannot remodel these membranes into circular structures. What was evident is the superior remodeling activity of ORF69, which could convert the host membrane proliferations induced by BFRF1 into circular structures. PMID- 23365437 TI - The myeloid transcription factor GATA-2 regulates the viral UL144 gene during human cytomegalovirus latency in an isolate-specific manner. AB - It is generally accepted that, following primary infection, human cytomegalovirus (HCMV) establishes lifelong latency in CD34(+) progenitor cells and other derivative cells of the myeloid lineage. In this study, we show that the viral UL144 gene is expressed during latent infection in two cell types of the myeloid lineage, CD34(+) and CD14(+) monocytes, and that the UL144 protein is functional in latently infected monocytes. However, this latency-associated expression of UL144 occurs only in certain isolates of HCMV and depends on the presence of functional GATA-2 transcription factor binding sites in the UL144 promoter, in contrast to the viral latency-associated gene LUNA, which we also show is regulated by GATA-2 but expressed uniformly during latent infection independent of the virus isolate. Taken together, these data suggest that the HCMV latency associated transcriptome may be virus isolate specific and dependent on the repertoire of transcription factor binding sites in the promoters of latency associated genes. PMID- 23365438 TI - Venezuelan equine encephalitis virus nsP2 protein regulates packaging of the viral genome into infectious virions. AB - Alphaviruses are one of the most geographically widespread and yet often neglected group of human and animal pathogens. They are capable of replicating in a wide variety of cells of both vertebrate and insect origin and are widely used for the expression of heterologous genetic information both in vivo and in vitro. In spite of their use in a range of research applications and their recognition as a public health threat, the biology of alphaviruses is insufficiently understood. In this study, we examined the evolution process of one of the alphaviruses, Venezuelan equine encephalitis virus (VEEV), to understand its adaptation mechanism to the inefficient packaging of the viral genome in response to serial mutations introduced into the capsid protein. The new data derived from this study suggest that strong alterations in the ability of capsid protein to package the viral genome leads to accumulation of adaptive mutations, not only in the capsid-specific helix I but also in the nonstructural protein nsP2. The nsP2 specific mutations were detected in the protease domain and in the amino terminus of the protein, which was previously proposed to function as a protease cofactor. These mutations increased infectious virus titers, demonstrated a strong positive impact on viral RNA replication, mediated the development of a more cytopathic phenotype, and made viruses capable of developing a spreading infection. The results suggest not only that packaging of the alphavirus genome is determined by the presence of packaging signals in the RNA and positively charged amino acids in the capsid protein but also that nsP2 is either directly or indirectly involved in the RNA encapsidation process. PMID- 23365439 TI - Recruitment of Brd4 to the human papillomavirus type 16 DNA replication complex is essential for replication of viral DNA. AB - Replication of the human papillomavirus (HPV) DNA genome relies on viral factors E1 and E2 and the cellular replication machinery. Bromodomain-containing protein 4 (Brd4) interacts with viral E2 protein to mediate papillomavirus (PV) genome maintenance and viral transcription. However, the functional role of Brd4 in the HPV life cycle remains to be clearly defined. In this study, we provide the first look into the E2-Brd4 interaction in the presence of other important viral factors, such as the HPV16 E1 protein and the viral genome. We show that Brd4 is recruited to actively replicating HPV16 origin foci together with HPV16 E1, E2, and a number of the cellular replication factors: replication protein A70 (RPA70), replication factor C1 (RFC1), and DNA polymerase delta. Mutagenesis disrupting the E2-Brd4 interaction abolishes the formation of the HPV16 replication complex and impairs HPV16 DNA replication in cells. Brd4 was further demonstrated to be necessary for HPV16 viral DNA replication using a cell-free replication system in which depletion of Brd4 by small interfering RNA (siRNA) silencing leads to impaired HPV16 viral DNA replication and recombinant Brd4 protein is able to rescue viral DNA replication. In addition, releasing endogenous Brd4 from cellular chromatin by using the bromodomain inhibitor JQ1(+) enhances HPV16 DNA replication, demonstrating that the role of Brd4 in HPV DNA replication could be uncoupled from its function in chromatin-associated transcriptional regulation and cell cycle control. Our study reveals a new role for Brd4 in HPV genome replication, providing novel insights into understanding the life cycle of this oncogenic DNA virus. PMID- 23365440 TI - Modeling the acute and chronic phases of Theiler murine encephalomyelitis virus infection. AB - Theiler murine encephalomyelitis virus (TMEV) infection of a mouse's central nervous system is biphasic: first the virus infects motor neurons (acute phase), and this is followed by a chronic phase in which the virus infects glial cells (primarily microglia and macrophages [M]) of the spinal cord white matter, leading to inflammation and demyelination. As such, TMEV-induced demyelinating disease in mice provides a highly relevant experimental animal model for multiple sclerosis. Mathematical models have proven valuable in understanding the in vivo dynamics of persistent virus infections, such as HIV-1, hepatitis B virus, and hepatitis C virus infections. However, viral dynamic modeling has not been used for understanding TMEV infection. We constructed the first mathematical model of TMEV-host kinetics during acute and early chronic infections in mice and fit measured viral kinetic data with the model. The data fitting allowed us to estimate several unknown parameters, including the following: the rate of infection of neurons, 0.5 * 10(-8) to 5.6 * 10(-8) day(-1); the percent reduction of the infection rate due to the presence of virus-specific antibodies, which reaches 98.5 to 99.9% after day 15 postinfection (p.i.); the half-life of infected neurons, 0.1 to 1.2 days; and a cytokine-enhanced macrophage source rate of 25 to 350 M/day into the spinal cord starting at 10.9 to 12.9 days p.i. The model presented here is a first step toward building a comprehensive model for TMEV-induced demyelinating disease. Moreover, the model can serve as an important tool in understanding TMEV infectious mechanisms and may prove useful in evaluating antivirals and/or therapeutic modalities to prevent or inhibit demyelination. PMID- 23365441 TI - Antigenicity and immunogenicity of transmitted/founder, consensus, and chronic envelope glycoproteins of human immunodeficiency virus type 1. AB - Human immunodeficiency virus type 1 (HIV-1) vaccine development requires selection of appropriate envelope (Env) immunogens. Twenty HIV-1 Env glycoproteins were examined for their ability to bind human anti-HIV-1 monoclonal antibodies (MAbs) and then used as immunogens in guinea pigs to identify promising immunogens. These included five Envs derived from chronically infected individuals, each representing one of five common clades and eight consensus Envs based on these five clades, as well as the consensus of the entire HIV-1 M group, and seven transmitted/founder (T/F) Envs from clades B and C. Sera from immunized guinea pigs were tested for neutralizing activity using 36 HIV-1 Env-pseudotyped viruses. All Envs bound to CD4 binding site, membrane-proximal, and V1/V2 MAbs with similar apparent affinities, although the T/F Envs bound with higher affinity to the MAb 17b, a CCR5 coreceptor binding site antibody. However, the various Envs differed in their ability to induce neutralizing antibodies. Consensus Envs elicited the most potent responses, but neutralized only a subset of viruses, including mostly easy-to-neutralize tier 1 and some more-difficult-to neutralize tier 2 viruses. T/F Envs elicited fewer potent neutralizing antibodies but exhibited greater breadth than chronic or consensus Envs. Finally, chronic Envs elicited the lowest level and most limited breadth of neutralizing antibodies overall. Thus, each group of Env immunogens elicited a different antibody response profile. The complementary benefits of consensus and T/F Env immunogens raise the possibility that vaccines utilizing a combination of consensus and T/F Envs may be able to induce neutralizing responses with greater breadth and potency than single Env immunogens. PMID- 23365442 TI - HLA-B*57 versus HLA-B*81 in HIV-1 infection: slow and steady wins the race? AB - Two human leukocyte antigen (HLA) variants, HLA-B*57 and -B*81, are consistently known as favorable host factors in human immunodeficiency virus type 1 (HIV-1) infected Africans and African-Americans. In our analyses of prospective data from 538 recent HIV-1 seroconverters and cross-sectional data from 292 subjects with unknown duration of infection, HLA-B*57 (mostly B*57:03) and -B*81 (exclusively B*81:01) had mostly discordant associations with virologic and immunologic manifestations before antiretroviral therapy. Specifically, relatively low viral load (VL) in HLA-B*57-positive subjects (P <= 0.03 in various models) did not translate to early advantage in CD4(+) T-cell (CD4) counts (P >= 0.37). In contrast, individuals with HLA-B*81 showed little deviation from the normal set point VL (P > 0.18) while maintaining high CD4 count during early and chronic infection (P = 0.01). These observations suggest that discordance between VL and CD4 count can occur in the presence of certain HLA alleles and that effective control of HIV-1 viremia is not always a prerequisite for favorable prognosis (delayed immunodeficiency). Of note, steady CD4 count associated with HLA-B*81 in HIV-1-infected Africans may depend on the country of origin, as observations differed slightly between subgroups enrolled in southern Africa (Zambia) and eastern Africa (Kenya, Rwanda, and Uganda). PMID- 23365443 TI - Reassortment complements spontaneous mutation in influenza A virus NP and M1 genes to accelerate adaptation to a new host. AB - Influenza A virus (IAV) infects a remarkably wide variety of avian and mammalian hosts. Evolution finely hones IAV genes to optimally infect and be transmitted in a particular host species. Sporadically, IAV manages to jump between species, introducing novel antigenic strains into the new host population that wreak havoc until herd immunity develops. IAV adaptation to new hosts typically involves reassortment of IAV gene segments from coinfecting virus strains adapted to different hosts in conjunction with multiple adaptive mutations in the various IAV genes. To better understand host adaptation between mammalian species in real time, we passaged mouse-adapted A/PR8/34 (PR8) in guinea pigs. Guinea pigs, unlike mice, support spontaneous and robust IAV transmission. For some IAV strains, including PR8, adaptation is required for a virus to attain transmissibility, providing an opportunity to understand the evolution of transmissibility in guinea pigs. Multiple guinea pig-adapted PR8 mutants generated by serial nasal wash passaging in independent lines replicated more efficiently and were transmitted by cocaging. All transmissible variants possessed one of two nonsynonymous mutations in M1, either alone or in combination with mutations in PB2, HA, NP, or NA. Rapid reassortment between independently selected variants combined beneficial mutations in NP and M1 to form the fittest virus capable of being transmitted. These findings provide further insight into genetic determinants in NP and M1 involved in PR8 IAV adaptation to be transmitted in a new host and clearly show the benefit of a segmented genome in rapidly generating optimal combinations of mutations in IAV evolution. PMID- 23365444 TI - Infection of the upper respiratory tract with seasonal influenza A(H3N2) virus induces protective immunity in ferrets against infection with A(H1N1)pdm09 virus after intranasal, but not intratracheal, inoculation. AB - The clinical symptoms caused by infection with influenza A virus vary widely and depend on the strain causing the infection, the dose and route of inoculation, and the presence of preexisting immunity. In most cases, seasonal influenza A viruses cause relatively mild upper respiratory tract disease, while sometimes patients develop an acute severe pneumonia. Heterosubtypic immunity induced by previous infections with influenza A viruses may dampen the development of clinical symptoms caused by infection with influenza A viruses of another subtype, as is the case during influenza pandemics. Here we show that ferrets acquire protective immunity after infection of the upper respiratory tract with a seasonal influenza A(H3N2) virus against subsequent infection with influenza A(H1N1)pdm09 virus inoculated by the intranasal route. However, protective heterosubtypic immunity was afforded locally, since the prior infection with the A(H3N2) virus did not provide protection against the development of pneumonia induced after intratracheal inoculation with the A(H1N1)pdm09 virus. Interestingly, some of these animals developed more severe disease than that observed in naive control animals. These findings are of interest in light of the development of so-called universal influenza vaccines that aim at the induction of cross-reactive T cell responses. PMID- 23365445 TI - Oxysterol-binding protein family I is the target of minor enviroxime-like compounds. AB - Enviroxime is an antipicornavirus compound that targets host phosphatidylinositol 4-kinase III beta (PI4KB) activity for its antipicornavirus activity. To date, several antipoliovirus (PV) compounds similar to enviroxime that are associated with a common resistance mutation in viral protein 3A (a G5318A [3A-Ala70Thr] mutation in PV) have been identified. Most of these compounds have a direct inhibitory effect on PI4KB activity, as well as enviroxime (designated major enviroxime-like compounds). However, one of the compounds, AN-12-H5, showed no inhibitory effect on PI4KB and was considered to belong to another group of enviroxime-like compounds (designated minor enviroxime-like compounds). In the present study, we performed a small interfering RNA (siRNA) sensitization assay targeting PI4KB-related genes and identified oxysterol-binding protein (OSBP) as a target of minor enviroxime-like compounds. Knockdown of OSBP and OSBP2 increased the anti-PV activities of AN-12-H5 and a newly identified minor enviroxime-like compound, T-00127-HEV2, and also to T-00127-HEV1 to a minor extent, in the cells. A ligand of OSBP, 25-hydroxycholesterol (25-HC), acted as a minor enviroxime-like compound. Minor enviroxime-like compounds induced relocalization of OSBP to the Golgi apparatus in cells. Treatment of the cells with major or minor enviroxime-like compounds suppressed the expression of genes (HMGCS1 and SQLE) in the SREBP/SCAP regulatory pathway and diminished endogenous phosphatidylinositol 4-phosphate (PI4P) at the Golgi apparatus. Our results suggested that minor enviroxime-like compounds are phenotypically identical to 25 HC and that major and minor enviroxime-like compounds suppress the production and/or accumulation of PI4P in PV-infected cells by targeting PI4KB and OSBP family I activities, respectively. PMID- 23365446 TI - Structural and thermodynamic basis of amprenavir/darunavir and atazanavir resistance in HIV-1 protease with mutations at residue 50. AB - Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I50V/L substitutions emerge in patients, compromising drug susceptibility and leading to treatment failure. The I50V substitution is often associated with amprenavir (APV) and darunavir (DRV) resistance, while the I50L substitution is observed in patients failing atazanavir (ATV) therapy. To explain how APV, DRV, and ATV susceptibility are influenced by mutations at residue 50 in HIV-1 protease, structural and binding thermodynamics studies were carried out on I50V/L-substituted protease variants in the compensatory mutation A71V background. Reduced affinity to both I50V/A71V and I50L/A71V double mutants is largely due to decreased binding entropy, which is compensated for by enhanced enthalpy for ATV binding to I50V variants and APV binding to I50L variants, leading to hypersusceptibility in these two cases. Analysis of the crystal structures showed that the substitutions at residue 50 affect how APV, DRV, and ATV bind the protease with altered van der Waals interactions and that the selection of I50V versus I50L is greatly influenced by the chemical moieties at the P1 position for APV/DRV and the P2 position for ATV. Thus, the varied inhibitor susceptibilities of I50V/L protease variants are largely a direct consequence of the interdependent changes in protease inhibitor interactions. PMID- 23365447 TI - Matriptase proteolytically activates influenza virus and promotes multicycle replication in the human airway epithelium. AB - Influenza viruses do not encode any proteases and must rely on host proteases for the proteolytic activation of their surface hemagglutinin proteins in order to fuse with the infected host cells. Recent progress in the understanding of human proteases responsible for influenza virus hemagglutinin activation has led to the identification of members of the type II transmembrane serine proteases TMPRSS2 and TMPRSS4 and human airway trypsin-like protease; however, none has proved to be the sole enzyme responsible for hemagglutinin cleavage. In this study, we identify and characterize matriptase as an influenza virus-activating protease capable of supporting multicycle viral replication in the human respiratory epithelium. Using confocal microscopy, we found matriptase to colocalize with hemagglutinin at the apical surface of human epithelial cells and within endosomes, and we showed that the soluble form of the protease was able to specifically cleave hemagglutinins from H1 virus, but not from H2 and H3 viruses, in a broad pH range. We showed that small interfering RNA (siRNA) knockdown of matriptase in human bronchial epithelial cells significantly blocked influenza virus replication in these cells. Lastly, we provide a selective, slow, tight binding inhibitor of matriptase that significantly reduces viral replication (by 1.5 log) of H1N1 influenza virus, including the 2009 pandemic virus. Our study establishes a three-pronged model for the action of matriptase: activation of incoming viruses in the extracellular space in its shed form, upon viral attachment or exit in its membrane-bound and/or shed forms at the apical surface of epithelial cells, and within endosomes by its membrane-bound form where viral fusion takes place. PMID- 23365448 TI - Ribosomal protein P0 promotes Potato virus A infection and functions in viral translation together with VPg and eIF(iso)4E. AB - We report here that the acidic ribosomal protein P0 is a component of the membrane-associated Potato virus A (PVA) ribonucleoprotein complex. As a constituent of the ribosomal stalk, P0 functions in translation. Although the ribosomal stalk proteins P0, P1, P2, and P3 are all important for PVA infection, P0 appears to have a distinct role from those of the other stalk proteins in infection. Our results indicate that P0 also regulates viral RNA functions as an extraribosomal protein. We reported previously that PVA RNA can be targeted by VPg to a specific gene expression pathway that protects the viral RNA from degradation and facilitates its translation. Here, we show that P0 is essential for this activity of VPg, similar to eIF4E/eIF(iso)4E. We also demonstrate that VPg, P0, and eIF(iso)4E synergistically enhance viral translation. Interestingly, the positive effects of VPg and P0 on viral translation were negatively correlated with the cell-to-cell spread of infection, suggesting that these processes may compete for viral RNA. PMID- 23365449 TI - An antiviral role for antimicrobial peptides during the arthropod response to alphavirus replication. AB - Alphaviruses establish a persistent infection in arthropod vectors which is essential for the effective transmission of the virus to vertebrate hosts. The development of persistence in insects is not well understood, although it is thought to involve the innate immune response. Using a transgenic fly system expressing a self-replicating viral RNA genome analog, we have previously demonstrated antiviral roles of the Drosophila Imd (immune deficiency) and Jak STAT innate immunity pathways in response to alphavirus replication. In the present study, comparative microarray analysis of flies harboring an alphavirus replicon and control green fluorescent protein flies identified 95 SINrep sensitive genes. Furthermore, a subset of these genes is regulated by Rel or STAT transcription factors of the Imd and Jak-STAT pathways, respectively. We identified two antimicrobial peptide genes, attC and dptB, which are SINrep sensitive and regulated by STAT and Rel, respectively. SINrep flies heterozygous for attC had an increased viral RNA level, while knocking down dptB in SINrep flies resulted in impaired development. When injected with whole virus, the double-stranded RNA knockdowns of either attC or dptB showed a significant increase in virus titers. Our data demonstrate an antiviral response involving the Imd and Jak-STAT mediated expression of dptB and attC. PMID- 23365450 TI - Tyrosine phosphorylation of the triple gene block protein 3 regulates cell-to cell movement and protein interactions of Potato mop-top virus. AB - Functions of viral proteins can be regulated through phosphorylation by serine/threonine kinases in plants, but little is known about the involvement of tyrosine kinases in plant virus infection. In this study, TGBp3, one of the three movement proteins encoded by a triple gene block (TGB) of Potato mop-top virus (PMTV), was detected for the first time in PMTV-infected plants and found to be tyrosine phosphorylated. Phosphorylation sites (Tyr(87-89) and Tyr(120)) were located in two amino acid motifs conserved in the TGB-containing, rod-shaped plant viruses. Substitution of these tyrosine residues in both motifs was needed to abolish tyrosine phosphorylation of TGBp3. Substitution of Tyr(87-89) with alanine residues enhanced the interaction between TGBp3 and TGBp2 and inhibited cell-to-cell movement of PMTV. On the other hand, substitution of Tyr(120) with alanine resulted in no alteration in the interaction of TGBp3 with TGBp2, but the mutant virus was not infectious. The results suggest that tyrosine phosphorylation is a mechanism regulating the functions of plant virus movement proteins. PMID- 23365451 TI - Contrasting roles of mitogen-activated protein kinases in cellular entry and replication of hepatitis C virus: MKNK1 facilitates cell entry. AB - The human kinome comprises over 800 individual kinases. These contribute in multiple ways to regulation of cellular metabolism and may have direct and indirect effects on virus replication. Kinases are tempting therapeutic targets for drug development, but achieving sufficient specificity is often a challenge for chemical inhibitors. While using inhibitors to assess whether c-Jun N terminal (JNK) kinases regulate hepatitis C virus (HCV) replication, we encountered unexpected off-target effects that led us to discover a role for a mitogen-activated protein kinase (MAPK)-related kinase, MAPK interacting serine/threonine kinase 1 (MKNK1), in viral entry. Two JNK inhibitors, AS601245 and SP600125, as well as RNA interference (RNAi)-mediated knockdown of JNK1 and JNK2, enhanced replication of HCV replicon RNAs as well as infectious genome length RNA transfected into Huh-7 cells. JNK knockdown also enhanced replication following infection with cell-free virus, suggesting that JNK actively restricts HCV replication. Despite this, AS601245 and SP600125 both inhibited viral entry. Screening of a panel of inhibitors targeting kinases that may be modulated by off target effects of AS601245 and SP600125 led us to identify MKNK1 as a host factor involved in HCV entry. Chemical inhibition or siRNA knockdown of MKNK1 significantly impaired entry of genotype 1a HCV and HCV-pseudotyped lentiviral particles (HCVpp) in Huh-7 cells but had only minimal impact on viral RNA replication or cell proliferation and viability. We propose a model by which MKNK1 acts to facilitate viral entry downstream of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK), both of which have been implicated in the entry process. PMID- 23365452 TI - The human papillomavirus type 8 E6 protein interferes with NOTCH activation during keratinocyte differentiation. AB - Cutaneous beta-human papillomavirus (beta-HPV) E6 proteins inhibit NOTCH signaling by associating with the transcriptional coactivator MAML1. NOTCH has tumor suppressor activities in epithelial cells and is activated during keratinocyte differentiation. Here we report that HPV type 8 (HPV8) E6 subverts NOTCH activation during keratinocyte differentiation by inhibiting RBPJ/MAML1 transcriptional activator complexes at NOTCH target DNA. NOTCH inhibition impairs epithelial differentiation and may thus contribute to beta-HPV replication and viral oncogenesis. PMID- 23365453 TI - Comprehensive in vitro analysis of simian retrovirus type 4 susceptibility to antiretroviral agents. AB - Simian retrovirus type 4 (SRV-4), a simian type D retrovirus, naturally infects cynomolgus monkeys, usually without apparent symptoms. However, some infected monkeys presented with an immunosuppressive syndrome resembling that induced by simian immunodeficiency virus infection. Antiretrovirals with inhibitory activity against SRV-4 are considered to be promising agents to combat SRV-4 infection. However, although some antiretrovirals have been reported to have inhibitory activity against SRV-1 and SRV-2, inhibitors with anti-SRV-4 activity have not yet been studied. In this study, we identified antiretroviral agents with anti SRV-4 activity from a panel of anti-human immunodeficiency virus (HIV) drugs using a robust in vitro luciferase reporter assay. Among these, two HIV reverse transcriptase inhibitors, zidovudine (AZT) and tenofovir disoproxil fumarate (TDF), potently inhibited SRV-4 infection within a submicromolar to nanomolar range, which was similar to or higher than the activities against HIV-1, Moloney murine leukemia virus, and feline immunodeficiency virus. In contrast, nonnucleoside reverse transcriptase inhibitors and protease inhibitors did not exhibit any activities against SRV-4. Although both AZT and TDF effectively inhibited cell-free SRV-4 transmission, they exhibited only partial inhibitory activities against cell-to-cell transmission. Importantly, one HIV integrase strand transfer inhibitor, raltegravir (RAL), potently inhibited single-round infection as well as cell-free and cell-to-cell SRV-4 transmission. These findings indicate that viral expansion routes impact the inhibitory activity of antiretrovirals against SRV-4, while only RAL is effective in suppressing both the initial SRV-4 infection and subsequent SRV-4 replication. PMID- 23365454 TI - Structural basis of substrate specificity and protease inhibition in Norwalk virus. AB - Norwalk virus (NV), the prototype human calicivirus, is the leading cause of nonbacterial acute gastroenteritis. The NV protease cleaves the polyprotein encoded by open reading frame 1 of the viral genome at five nonhomologous sites, releasing six nonstructural proteins that are essential for viral replication. The structural details of how NV protease recognizes multiple substrates are unclear. In our X-ray structure of an NV protease construct, we observed that the C-terminal tail, representing the native substrate positions P5 to P1, is inserted into the active site cleft of the neighboring protease molecule, providing atomic details of how NV protease recognizes a substrate. The crystallographic structure of NV protease with the C-terminal tail redesigned to mimic P4 to P1 of another substrate site provided further structural details on how the active site accommodates sequence variations in the substrates. Based on these structural analyses, substrate-based aldehyde inhibitors were synthesized and screened for inhibition potency. Crystallographic structures of the protease in complex with each of the three most potent inhibitors were determined. These structures showed concerted conformational changes in the S4 and S2 pockets of the protease to accommodate variations in the P4 and P2 residues of the substrate/inhibitor, which could be a mechanism for how the NV protease recognizes multiple sites in the polyprotein with differential affinities during virus replication. These structures further indicate that the mechanism of inhibition by these inhibitors involves covalent bond formation with the side chain of the conserved cysteine in the active site by nucleophilic addition, and such substrate-based aldehydes could be effective protease inhibitors. PMID- 23365455 TI - SCE1, the SUMO-conjugating enzyme in plants that interacts with NIb, the RNA dependent RNA polymerase of Turnip mosaic virus, is required for viral infection. AB - SUMOylation, which is catalyzed by small ubiquitin-like modifier (SUMO) enzymes, is a transient, reversible posttranslational protein modification that regulates diverse cellular processes. Potyviruses, the largest group of known plant viruses, comprise many agriculturally important viruses, such as Turnip mosaic virus (TuMV). The potyviral genome encodes 11 mature proteins. To investigate if SUMOylation plays a role in potyvirus infection, a yeast two-hybrid screen was performed to examine possible interactions of each of the 11 viral proteins of TuMV with AtSCE1, the only SUMO-conjugating enzyme in Arabidopsis thaliana homologous to the key SUMO-conjugating enzyme E2 in mammalian cells or Ubc9 in yeast. A positive reaction was found between AtSCE1 and NIb, the potyviral RNA dependent RNA polymerase. Further bimolecular fluorescence complementation (BiFC) and fluorescence resonance energy transfer (FRET) assays revealed that the NIb and AtSCE1 interaction occurred in both the cytoplasm and nuclei of epidermal cells of Nicotiana benthamiana. The interaction motif was mapped to a region encompassing NIb amino acids 171 to 300 which contains a potential negatively charged amino acid-dependent SUMOylation motif (NDSM). An Escherichia coli SUMOylation assay showed that NIb can be SUMOylated and that the lysine residue (K172) in the motif is a potent SUMOylation site. A TuMV infectious clone with an arginine (R) substitution mutation at K172 compromised TuMV infectivity in plants. In comparison with wild-type Arabidopsis plants, sce1 knockdown plants exhibited increased resistance to TuMV as well as a nonrelated RNA virus. To the best of our knowledge, this is the first report showing that the host SUMO modification system plays an essential role in infection by plant RNA viruses. PMID- 23365456 TI - Developments in the identification of glycan biomarkers for the detection of cancer. AB - Changes in glycosylation readily occur in cancer and other disease states. Thanks to recent advances in the development of analytical techniques and instrumentation, especially in mass spectrometry, it is now possible to identify blood-derived glycan-based biomarkers using glycomics strategies. This review is an overview of the developments made in the search for glycan-based cancer biomarkers and the technologies currently in use. It is anticipated that the progressing instrumental and bioinformatics developments will allow the identification of relevant glycan biomarkers for the diagnosis, early detection, and monitoring of cancer treatment with sufficient sensitivity and specificity for clinical use. PMID- 23365457 TI - Viral latency locus augments B-cell response in vivo to induce chronic marginal zone enlargement, plasma cell hyperplasia, and lymphoma. AB - Kaposi sarcoma (KS) is associated with KS-associated herpesvirus (KSHV). This virus also causes B-cell lymphoma and B-cell hyperplasia. There exists no in vivo model for KSHV-associated B-cell malignancies or premalignant persistence in B cells. We generated a transgenic mouse that expresses multiple viral latent genes, including LANA, vFLIP, vCYC, all viral micro RNAs, and kaposin under the transcriptional control of their natural regulatory region. This promoter is B cell specific, though it is a weak promoter. Mature B cells were chronically activated, leading to hyperglobulinemia triggered by increased plasma cell frequency and marginal zone (MZ) B-cell hyperplasia. The mice had an augmented response to T-dependent antigen as well as the TLR4 ligand LPS, leading to exacerbated MZ and germinal center responses and increased CD138(+) plasma cells. It is the first model to assess the viral micro RNA function in vivo. These data support a potentially novel mechanism of viral persistence in which virally infected B cells become hyper-responsive to coincident, but unrelated, pathogen exposure, leading to preferential expansion and ultimately lymphoma in a small subset of cases. PMID- 23365458 TI - Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56(bright) subset. AB - Mutations in the transcription factor GATA2 underlie the syndrome of monocytopenia and B- and natural killer (NK)-cell lymphopenia associated with opportunistic infections and cancers. In addition, patients have recurrent and severe viral infections. NK cells play a critical role in mediating antiviral immunity. Human NK cells are thought to mature in a linear fashion, with the CD56(bright) stage preceding terminal maturation to the CD56(dim) stage, considered the most enabled for cytotoxicity. Here we report an NK cell functional defect in GATA2-deficient patients and extend this genetic lesion to what is considered to be the original NK cell-deficient patient. In most cases, GATA2 deficiency is accompanied by a severe reduction in peripheral blood NK cells and marked functional impairment. The NK cells detected in peripheral blood of some GATA2-deficient patients are exclusively of the CD56(dim) subset, which is recapitulated on in vitro NK cell differentiation. In vivo, interferon alpha treatment increased NK cell number and partially restored function but did not correct the paucity of CD56(bright) cells. Thus, GATA2 is required for the maturation of human NK cells and the maintenance of the CD56(bright) pool in the periphery. Defects in GATA2 are a novel cause of profound NK cell dysfunction. PMID- 23365460 TI - The histone demethylase UTX regulates stem cell migration and hematopoiesis. AB - Regulated migration of hematopoietic stem cells is fundamental for hematopoiesis. The molecular mechanisms underlying stem cell trafficking are poorly defined. Based on a short hairpin RNA library and stromal cell-derived factor-1 (SDF-1) migration screening assay, we identified the histone 3 lysine 27 demethylase UTX (Kdm6a) as a novel regulator for hematopoietic cell migration. Using hematopoietic stem and progenitor cells from our conditional UTX knockout (KO) mice, we were able to confirm the regulatory function of UTX on cell migration. Moreover, adult female conditional UTX KO mice displayed myelodysplasia and splenic erythropoiesis, whereas UTX KO males showed no phenotype. During development, all UTX KO female and a portion of UTX KO male embryos developed a cardiac defect, cranioschisis, and died in utero. Therefore, UTY, the male homolog of UTX, can compensate for UTX in adults and partially during development. Additionally, we found that UTX knockdown in zebrafish significantly impairs SDF-1/CXCR4-dependent migration of primordial germ cells. Our data suggest that UTX is a critical regulator for stem cell migration and hematopoiesis. PMID- 23365459 TI - Neurokinin-1 receptor agonists bias therapeutic dendritic cells to induce type 1 immunity by licensing host dendritic cells to produce IL-12. AB - Substance-P and hemokinin-1 are proinflammatory neuropeptides with potential to promote type 1 immunity through agonistic binding to neurokinin-1 receptor (NK1R). Dendritic cells (DCs) are professional antigen-presenting cells that initiate and regulate the outcome of innate and adaptive immune responses. Immunostimulatory DCs are highly desired for the development of positive immunization techniques. DCs express functional NK1R; however, regardless of their potential DC-stimulatory function, the ability of NK1R agonists to promote immunostimulatory DCs remains unexplored. Here, we demonstrate that NK1R signaling activates therapeutic DCs capable of biasing type 1 immunity by inhibition of interleukin-10 (IL-10) synthesis and secretion, without affecting their low levels of IL-12 production. The potent type 1 effector immune response observed following cutaneous administration of NK1R-signaled DCs required their homing in skin-draining lymph nodes (sDLNs) where they induced inflammation and licensed endogenous-conventional sDLN-resident and -recruited inflammatory DCs to secrete IL-12. Our data demonstrate that NK1R signaling promotes immunostimulatory DCs, and provide relevant insight into the mechanisms used by neuromediators to regulate innate and adaptive immune responses. PMID- 23365461 TI - Cooperating gene mutations in childhood acute myeloid leukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2, and DNMT3A. AB - Gene mutations involving epigenetic regulators recently have been described in adult acute myeloid leukemia (AML). Similar studies are limited in children. We analyzed gene mutations and cooperation in pediatric AML with special reference on mutated epigenetic regulators. Nineteen gene mutations, including 8 class I genes, 4 class II genes, WT1 and TP53 (class III), and 5 epigenetic regulator genes (class IV), were analyzed in 206 children with de novo AML. Mutational analysis was performed with polymerase chain reaction-based assay followed by direct sequencing. One hundred seventeen of 206 patients (56.8%) had at least one mutation: 51% class I, 13% class II, 6.8% class III, and 5.6% class IV. FLT3 internal tandem duplication was most frequent, and 29% of patients had more than one gene mutation. Two patients carried ASXL1 mutations, both with t(8;21), 2 had DNMT3A mutations, 2 had IDH1 mutations, 1 had IDH2 mutation, and 3 had TET2 mutations. Both patients with IDH1 mutations had AML-M0 subtype and MLL-partial tandem duplication. Cooperating mutations with mutated epigenetic regulators were observed in 8 of 10 patients. We conclude that mutated epigenetic regulators were much less than those in adult AML but with frequent cooperating mutations. ASXL1, TET2, and IDH1 mutations were associated with specific genetic subtypes. PMID- 23365462 TI - Differential control of Helios(+/-) Treg development by monocyte subsets through disparate inflammatory cytokines. AB - Foxp3(+) regulatory T cells (Tregs) play a pivotal role in control of autoimmunity and pathological immune responses. Helios, the Ikarus family transcription factor, binds to the Foxp3 promoter, stabilizing its expression, and is expressed in 70% of peripheral Tregs of healthy individuals. This frequency is altered during malignancy, infection, and autoimmunity, although the mechanisms that control proliferation and relative numbers of Helios(+/-) Tregs remain largely unknown. Using a T-cell-monocyte in vitro stimulation assay, we now show that proliferation of Helios(+) Tregs is inhibited by CD16(+) monocyte subset. Antibody blocking with anti-interleukin (IL)-12 reversed this inhibition, whereas addition of IL-12 suppressed Helios(+) Treg expansion, indicating that CD16(+) monocyte control of Helios(+) Treg numbers is mediated through IL-12. In contrast, proliferation of Helios(-) Tregs, which express higher levels of tumor necrosis factor receptor II (TNFRII), was suppressed by TNF-alpha, whereas anti TNF-alpha and anti-TNFRII reversed the inhibition. CD16(-) monocyte subset was mainly responsible for TNF-alpha-mediated control of Helios(-) Treg expansion. Altogether, these data suggest a differential role for monocyte subsets in control of Helios(+/-) Treg development that is mediated by distinct inflammatory cytokines. These data may have important implications for understanding the pathogenesis as well as control of chronic inflammatory and autoimmune diseases. PMID- 23365464 TI - Time from diagnosis to intensive chemotherapy initiation does not adversely impact the outcome of patients with acute myeloid leukemia. AB - In acute myeloid leukemia (AML), new strategies assess the potential benefit of genetically targeted therapy at diagnosis. This implies waiting for laboratory tests and therefore a delay in initiation of chemotherapy. We studied the impact of time from diagnosis to treatment (TDT) on overall survival, early death, and response rate in a retrospective series of 599 newly diagnosed AML patients treated by induction chemotherapy between 2000 and 2009. The effect of TDT was assessed using multivariate analysis. TDT was analyzed as a continuous variable using a specific polynomial function to model the shape and form of the relationship. The median TDT was 8 days (interquartile range, 4-16) and was significantly longer in patients with a white blood cell count (WBC) <50 Giga per liter (G/L) (P < .0001) and in older patients (P = .0004). In multivariate analysis, TDT had no impact on overall survival (P = .4095) compared with age >60 years, secondary AML, WBC >50 G/L, European LeukemiaNet risk groups, and Eastern Cooperative Oncology Group performance status. Furthermore, TDT was not associated with response rate and early death. Thus, waiting a short period of time for laboratory tests to characterize leukemias better and design adapted therapeutic strategies at diagnosis seems possible. PMID- 23365465 TI - The fox and the grapes: an Anglo-Irish perspective on conscientious objection to the supply of emergency hormonal contraception without prescription. AB - Emergency hormonal contraception (EHC) has been available from pharmacies in the UK without prescription for 11 years. In the Republic of Ireland this service was made available in 2011. In both jurisdictions the respective regulators have included 'conscience clauses', which allow pharmacists to opt out of providing EHC on religious or moral grounds providing certain criteria are met. In effect, conscientious objectors must refer patients to other providers who are willing to supply these medicines. Inclusion of such clauses leads to a cycle of cognitive dissonance on behalf of both parties. Objectors convince themselves of the existence of a moral difference between supply of EHC and referral to another supplier, while the regulators must feign satisfaction that a form of regulation lacking universality will not lead to adverse consequences in the long term. We contend that whichever of these two parties truly believes in that which they purport to must act to end this unsatisfactory status quo. Either the regulators must compel all pharmacists to dispense emergency contraception to all suitable patients who request it, or a pharmacist must refuse either to supply EHC or to refer the patient to an alternative supplier and challenge any subsequent sanctions imposed by their regulator. PMID- 23365463 TI - Robo4 is an effective tumor endothelial marker for antibody-drug conjugates based on the rapid isolation of the anti-Robo4 cell-internalizing antibody. AB - Monoclonal antibodies (mAbs) that are internalized into cells are a current focus in the development of antibody-drug conjugates (ADCs). We describe a phage display-based high-throughput screening system to rapidly isolate cell internalizing mAbs. We simultaneously examined the cell-internalizing activities of several hundred independent mAbs and successfully isolated cell-internalizing mAbs against the tumor endothelial markers Roundabout homolog 4 (Robo4) and vascular endothelial growth factor receptor 2 (VEGFR2). Tumor accumulation of mAbs with high cell-internalizing activity was significantly higher than that of mAbs with low cell-internalizing activity. Furthermore, the antitumor effects of ADCs of mAbs with high cell-internalizing activity were significantly stronger than those of mAbs with low cell-internalizing activity. Although anti-VEGFR2 therapy caused a significant loss of body weight, anti-Robo4 therapy did not. These findings indicate that cell-internalizing activity plays an important role in the biodistribution and therapeutic effects of ADCs. Further, Robo4 can be an effective marker for tumor vascular targeting. PMID- 23365466 TI - Conscientious objection by Muslim students startling. PMID- 23365467 TI - Attitudes towards euthanasia in Iran: the role of altruism. AB - OBJECTIVE: Altruism is arguably the quintessential moral trait, involving willingness to benefit others and unwillingness to harm them. In this study, I explored how altruism and other personality variables relate to acceptance of euthanasia. In addition, I investigated the role of culture in attitudes to subcategorical distinctions of euthanasia. METHODS: 190 Iranian students completed the Attitude Towards Euthanasia scale, the HEXACO Personality Inventory Revised, and an interest in religion measure. RESULTS: Higher scores on altruism, Honesty-Humility, Agreeableness, Conscientiousness and religiousness were associated with viewing euthanasia as unacceptable. As expected, altruism explained unique variance in euthanasia attitude beyond gender, religiosity and broad personality factors. CONCLUSIONS: Cultural and individual differences should be taken into consideration in moral psychology research and end-of-life decision-making. PMID- 23365468 TI - The child's right to an open future: is the principle applicable to non therapeutic circumcision? AB - The principle of the child's right to an open future was first proposed by the legal philosopher Joel Feinberg and developed further by bioethicist Dena Davis. The principle holds that children possess a unique class of rights called rights in trust-rights that they cannot yet exercise, but which they will be able to exercise when they reach maturity. Parents should not, therefore, take actions that permanently foreclose on or pre-empt the future options of their children, but leave them the greatest possible scope for exercising personal life choices in adulthood. Davis particularly applies the principle to genetic counselling, arguing that parents should not take deliberate steps to create physically abnormal children, and to religion, arguing that while parents are entitled to bring their children up in accordance with their own values, they are not entitled to inflict physical or mental harm, neither by omission nor commission. In this paper, I aim to elucidate the open future principle, and consider whether it is applicable to non-therapeutic circumcision of boys, whether performed for cultural/religious or for prophylactic/health reasons. I argue that the principle is highly applicable to non-therapeutic circumcision, and conclude that non therapeutic circumcision would be a violation of the child's right to an open future, and thus objectionable from both an ethical and a human rights perspective. PMID- 23365469 TI - Genetic improvement of bread wheat yield and associated traits in Spain during the 20th century. AB - A collection of 26 wheat genotypes widely grown in Spain during the 20th century was evaluated in eight contrasting environments in order to quantify breeding achievements in yield and associated traits. From 1930 to 2000, yield increased at a rate of 35.1 kg/ha/yr or 0.88%/yr, but estimations of relative genetic gain (RGG) were environment-dependent. RGG estimated for yield were positively associated with the average minimum daily temperatures from sowing to heading in the testing environments (R(2) = 0.81; P < 0.01). The number of grains/spike and the number of spikes/m(2) increased at a rate of 0.60%/yr and 0.30%/yr, respectively, while grain weight remained unchanged. The present study detected two main episodes of yield improvement during the century. The first one coincided with the introduction, during the 1950s, of the first improved cultivars derived from intra-specific crosses, which increased the yield of landraces by 30% due to an increase of c. 58% in the number of grains/spike, accompanied by a 16% reduction in grain weight. These initial cultivars (termed 'old-bred' in a previous study by Sanchez-Garcia et al. 2012) exhibited a higher harvest index (HI), increased from 0.25 to 0.40, but maintained the same aboveground biomass at maturity as the landraces (despite reducing both plant height and the number of tillers/plant) due to increases in the proportion of tillers bearing spikes. The second yield gain occurred after the introduction, in the early 1970s, of semi-dwarf germplasm from CIMMYT (International Maize and Wheat Improvement Centre) and some French cultivars. This new germplasm further reduced plant height, improved HI up to 0.45 and increased the number of tillers/plant while maintaining their rate of fertility, thus resulting in a yield gain of c. 37%. The cultivars released during the last decade of the century did not contribute to significant yield improvements. PMID- 23365470 TI - Bedside teaching in undergraduate medical education: issues, strategies, and new models for better preparation of new generation doctors. AB - Bedside teaching is a vital component of medical education. It is applicable to any situation where teaching is imparted in the presence of patients. In teaching in the patients' presence, learners have the opportunities to use all of their senses and learn the humanistic aspect of medicine such as role modeling, which is vital but difficult to communicate in words. Unfortunately, bedside teaching has been on the decline. To investigate the reasons for the decline in bedside teaching, its importance and its revival, a review of literature was carried out using PubMed and other data bases. The review revealed that the major concerns of bedside teaching were time constraint, false preceptors' concern about patients' comfort, short stay of patients in hospitals, learner distraction by technology, lack of experience and unrealistic faculty expectation. Whatsoever the reasons, bedside teaching cannot be replaced with anything else. There are newer approaches of effective bedside teaching, and the core focus of all such approaches is educational process. A bedside teacher must learn how to involve patients and learners in the educational processes. Moreover, bedside teaching is the process through which learners acquire the skills of communication by asking patients' permission, establishing ground rules, setting time limit, introducing the team, diagnosing learner, diagnosing patient, conducting focused teaching, using simple language, asking patient if there is any question, closing with encouraging thanks, and giving feedback privately. It is most important to ensure a comfortable environment for all participants, the learner, the patient and the bedside teacher. Ongoing faculty development programs on educational processes and realistic faculty expectations may overcome the problems. PMID- 23365471 TI - Gonioscopic features in patients with acute and chronic angle-closure glaucoma. AB - BACKGROUND: A number of ocular biometric parameters, iris hiotologic and anatomic characters have been suggested as inciting factors for converting patients with narrow angle to angle-closure glaucoma. This study was conducted to determine if there was any goniscopic difference between patients with acute angle-closure glaucoma (AACG) and chronic angle-closure glaucoma (CACG). METHODS: The study is a retrospective analysis of the charts of 97 patients with asymmetric CACG and 15 patients with unilateral AACG. The age, sex, type of glaucoma, gonioscopic findings and optic nerve head cup/disc ratio were recorded for all patients. Dynamic gonioscopy and Spaeth's convention were used to grade the drainage angle. The eyes with AACG or more optic nerve damage in CACG groups were considered as involved eye, and the contralateral eyes in the AACG and CACG groups were considered as noninvolved and less-involved, respectively. RESULTS: There was no significant difference between patients with AACG and CACG in terms of age, gender, refraction, and laterality of the involved eyes. In intragroup analysis, no significant difference was observed for distribution of iris attachment, irido corneal angle, iris configuration, or trabecular pigmentation. In intergroup analysis, the superior iris was attached more anterior in the involved eyes of AACG compared to that in CACG (P=0.007). Moreover, the iris root attachment was also more anterior in both the superior (P=0.001) and inferior (P=0.002) angles of the noninvolved eyes of AACG vs. than those in the less-involved eyes of CACG group. CONCLUSION: The findings of the study indicate that there is no significant difference between the eyes with AACG or CACG in terms of goniscopic findings. However, the superior iris attachment was located more anterior in eyes with AACG compared to that in eyes with CACG. PMID- 23365472 TI - Vascular injuries caused by tear gas shells: surgical challenge and outcome. AB - BACKGROUND: Tear gas shells are used to disperse the mob during any type of street protests. Vascular injuries due to tear gas shells have not been reported. The present study was undertaken to analyse the pattern, presentation, management and outcome of vascular injury due to tear gas shells. METHODS: Eighteen patients with vascular injury caused by tear gas shells from 1(st) Jan. 2008 to 31(st) Dec 2009 were studied. Patients with vascular injuries caused by causes other than tear gas shells were excluded from the study. RESULTS: All patients were treated with reverse saphenous vein graft as segmental loss was less than 2.5 cm. Wound infection was the most common complication, followed by graft occlusion. Amputation rate was 16.66%. Associated nerve injury occurred in 44.44% of the patients. CONCLUSION: Tear gas shell injuries should not be taken lightly. They can cause injuries as serious as vascular injuries. Vascular injuries cased by tear gas shells require prompt revascularisation to improve limb salvage. Despite proper revascularisation, patients have significant morbidity and need proper rehabilitation in the follow ups. PMID- 23365473 TI - The correlation of brody high resolution computed tomography scoring system with clinical status and pulmonary function test in patients with cystic fibrosis. AB - BACKGROUND: To reduce the mortality and morbidity rates of cystic fibrosis (CF) patients, and to have an effective clinical management, it is important to monitor the progression of the disease. The aim of this study was to evaluate the progression of lung disease in CF patients by means of assessing the correlation of the CT scoring system with clinical status and pulmonary function test at the Pediatric Pulmonary Ward of Masih Daneshvari Hospital in 2008. METHODS: Pulmonary high resolution computed tomography (HRCT) was performed in 23 CF patients using the Brody's scoring system. Morphologic signs as well as the extent and severity of each sign were scored, and the total score was calculated. The correlation of HRCT scores (total score as well as the score for each parameter) with Shwachman Kuczycki scoring system and pulmonary function test were examined. RESULTS: The study included 9 female and 14 male patients with an age range of 5-23 years (mean: 13.42 years). Bronchiectasis (100%) and peribronchial wall thickening (100%) were the most frequent CT abnormalities. Mucus plugging, air trapping and parenchymal involvements were respectively seen in 95.7%, 91.3% and 47.8% of patients. The overall CT score for all patients was 57.6+/-24.2 (means+/-SD). The results of pulmonary function test showed a restrictive pattern; however, in 5.3% of the patients PFT was normal. The overall Shwachman-Kulczycki score was 53.48+/ 13.8. There was a significantly (P=0.015) negative correlation between the total CT score and Shwachman-Kulczycki score; however, there was no significant correlation between total CT score and the results of PFT (P=0.481)CONCLUSION: The Brody's scoring system for high resolution computed tomography seems to be a sensitive and efficient method to evaluate the progression of CF, and can be more reliable when we combine the CT scores with clinical parameters. PMID- 23365474 TI - The Antimicrobial Activities of Extract and Compounds Isolated from Brillantaisia lamium. AB - BACKGROUND: Brillantaisia lamium is an erect branched herb, which grows to a height of 1.50 m in moist tropical areas, both in full sun and partial shade. In , the aerial part of this plant is used in the treatment of various microbial infections such as skin diseases and infections of urinary tract. The aim of this study was to evaluate the antimicrobial activities of CH(2)Cl(2): MeOH (1:1) extract, fractions and compounds from the aerial part of B. lamium. METHODS: The plant was dried and extracted by maceration in CH(2)Cl(2): MeOH (1:1 v/v). Structures of the compounds from the CH(2)Cl(2): MeOH (1:1) soluble fraction were determined by spectroscopic methods and compared with published data. The broth micro dilution method was used to evaluate the antimicrobial activities against bacteria and fungal species. RESULTS: Four known compounds: aurantiamide acetate (1), lupeol (2), lespedin (3), sitosterol 3-O-beta-D-glucopyranoside (4) and a mixture of sterols: campesterol (5), stigmasterol (6) and beta-sitosterol (7) were isolated from CH(2)Cl(2): MeOH (1:1) extract of B. lamium aerial parts. The crude extract, fractions and isolated compounds exhibited both antibacterial and antifungal activities that varied with microorganism (MIC=6.25 - 1000 ug/ml). Compound 3 was the most active (MIC=6.25 - 100 ug/ml) while Staphylococcus aureus, Enterococcus faecalis, Candida tropicalis and Cryptococcus neoformans were the most sensitive to all the tested compounds. CONCLUSION: The overall results of this study indicate that the CH(2)Cl(2): MeOH (1:1) extract and some of isolated compounds have interesting antimicrobial properties and can be used for the treatment of fungal and bacterial infections. PMID- 23365475 TI - A comparison of interposition and femoropopliteal bypass grafts in the management of popliteal artery trauma. AB - BACKGROUND: Peripheral vascular injury associated with lower limb trauma is a well-known emergency. The experience for the management of popliteal artery trauma have mainly come from managing the traumas of military personnels during Iran-Iraq war. The present study compared the effects of two currently-used surgical techniques in the management of popliteal trauma, namley femoropopliteal bypass graft and interposition vein graft on limb salvage. METHODS: A retrospective review of 40 patients with popliteal artery trauma admitted to the trauma unit of a university teaching hospital during 2003 to 2008. The patients had undergone femoropopliteal bypass graft (n=26) or interposition vein graft (n=14) for the management of popliteal trauma. RESULTS: The amputation rate among patients managed by femoropopliteal bypass or interposition vein graft was 35.7% and 61.5%, respectively. Knee stability among patients managed by interposition graft group was 57.7% and in those managed by femoropopliteal bypass graft was 85.7%. CONCLUSION: The rates of knee stability achieved by the employed techniques indicate that femoropopliteal bypass vein graft is superior, and therefore, preferable to the interposition vein graft in the management of popliteal artery trauma. PMID- 23365476 TI - The Neurological Manifestations of H1N1 Influenza Infection; Diagnostic Challenges and Recommendations. AB - BACKGROUND: World Health Organization declared pandemic phase of human infection with novel influenza A (H1N1) in April 2009. There are very few reports about the neurological complications of H1N1 virus infection in the literature. Occasionally, these complications are severe and even fatal in some individuals. The aims of this study were to report neurological complaints and/or complications associated with H1N1 virus infection. METHODS: The medical files of all patients with H1N1 influenza infection admitted to a specified hospital in the city of , from October through November 2009 were reviewed. More information about the patients were obtained by phone calls to the patients or their care givers. All patients had confirmed H1N1 virus infection with real-time PCR assay. RESULTS: Fifty-five patients with H1N1 infection were studied. Twenty-three patients had neurological signs and/or symptoms. Mild neurological complaints may be reported in up to 42% of patients infected by H1N1 virus. Severe neurological complications occurred in 9% of the patients. The most common neurological manifestations were headache, numbness and paresthesia, drowsiness and coma. One patient had a Guillain-Barre syndrome-like illness, and died in a few days. Another patient had focal status epilepticus and encephalopathy. CONCLUSIONS: The H1N1 infection seems to have been quite mild with a self-limited course in much of the world, yet there appears to be a subset, which is severely affected. We recommend performing diagnostic tests for H1N1influenza virus in all patients with respiratory illness and neurological signs/symptoms. We also recommend initiating treatment with appropriate antiviral drugs as soon as possible in those with any significant neurological presentation accompanied with respiratory illness and flu-like symptoms. PMID- 23365477 TI - Molecular Characterization of Cosenza Mutation among Patients with Glucose-6 Phosphate Dehydrogenase Deficiency in huzestan Province, Southwest Iran. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common hereditary enzymatic disorders in human, increases the vulnerability of erythrocytes to oxidative stress. It is also characterized by remarkable molecular and biochemical heterogeneity. According to previous investigations, G6PD Cosenza (G1376C) is a common G6PD mutation in some parts of . Therefore in the present study we have characterized mutation among G6PD deficient individuals in Khuzestan province. In order to identify G6PD Cosenza, we analyzed the G6PD gene in 64 samples out of 231 deficient individuals who had not G6PD Mediterranean mutation, using PCR- restriction fragment length polymorphism (RFLP) method. G6PD Cosenza mutation was found in 6 males of 231 samples, resulting in the relative rate of 2.6% and allele frequency of 0.023 among Khuzestanian G6PD deficient subjects. A comparison of these results with previous findings in some parts of suggests that G6PD Cosenza is a common mutation in Khuzestanian G6PD deficient individuals. PMID- 23365478 TI - Leukocytosis as an alarming sign for mortality in patients hospitalized in general wards. AB - There is some evidence that leukocytosis without infection is associated with increased hospital mortality, but data in this regard are very incomplete. This study was designed to investigate the relationship between leukocytosis at the time of admission and mortality among patients hospitalized in general wards. During July to Nov 2004, all deceased patients who had a white blood cell (WBC) count record for the first 24 hours of admission were selected as cases. Among survivors, twice the number of cases was selected as controls. Different levels of WBC counts were compared between cases and controls. Totally 1650 patients, including 550 deceased (cases) and 1100 survivors (controls) were analyzed. Of these, 876 (53%) were males and 774 (47%) females, and 42 (3%) were admitted to ICU, 1426 (86%) to medical and 182 (11%) to surgical wards. There was a significant difference between the mean age of deceased patients (78.0 years) and survivors (53.0 years) (P<0.0001). The median WBC for deceased and surviving patients was 9.4 and 11.4*10(9)/l, respectively. Patients with a WBC >10*10(9)/l accounted for 804, among which 335 (42%) were deceased. Leukocytosis and leukopoenia were more frequent among the deceased patients compared to the survivors. The likelihood ratio for leukocytosis and leukopenia among the cases and controls was 1.4 and 2.3, respectively. Leukocytosis was identified as an alarming sign for mortality among patients admitted to general hospital wards at early stages of admission. A quick medical intervention for amendment of the causes related to leukocytosis should consequently reduce hospital mortality. PMID- 23365479 TI - Survival after In-Hospital Cardiopulmonary Resuscitation in a Major Referral Center during 2001-2008. AB - Despite efforts to save more people suffering from in-hospital cardiac arrest, rates of survival after in-hospital cardiopulmonary resuscitation (CPR) are no better today than they were more than a decade ago. This study was undertaken to assess the demographics, clinical parameters and outcomes of patients undergoing CPR by the code blue team at our center during 2001 to 2008. Data were collected retrospectively from adult patients (n=2262) who underwent CPR. Clinical outcomes of interest were survival at the end of CPR and survival at discharge from the hospital. Factors associated with survival were evaluated using binomial and tests. Of the patients included (n=2262), 741 patients (32.8%) had successful CPR. The number of male patients requiring CPR was more than females in need of the procedure. The majority of patients requiring CPR were older than 60 years (56.4+/-17.9). The number of successful CPR cases in long-day shift (7:00 to 19:00) was more than that in the night shift (19:00 to 7:00). Furthermore, 413 (18.4%) cases were resuscitated on holidays and 1849 (81.7%) on the working days. The duration of CPR was 10 min or less in 710 (31.4%) cases. Cardiopulmonary resuscitations which lasted less than 10 minutes were associated with better outcomes. The findings of the present study indicate that some manageable factors including the duration of CPR, working shift, working day (holiday or non holiday) could affect the CPR outcomes. The findings might also be taken as evidence to suggest that the allocation of more personnel in each shift especially in night shifts and holidays, planning to increase the personnel's CPR skills, and decreasing the waste time would result in the improvement of CPR outcome. PMID- 23365480 TI - The application of a new cyanoacrylate glue in pediatric surgery for fistula closure. AB - Surgical glues have been used in pediatric surgery because of the fragility of tissue, and to prevent major surgeries. The present report describes our experience with using a new cyanoacrylate Glubran 2 (Viareggio, Italy) in the treatment of five cases of tracheoesophageal atresia with fistula (one fistula protection, three recurrent fistula, and one unstable patients), two cases of hypospadias, one case of vesicutanouse fistula after bladder extrophy, and one case of cloacal extrophy from January-December 2008. Three cases of recurrent tracheoesophageal atresia with fistula were treated by bronchoscpic glue injection. The other two cases benefited from glue through its ability to plug the fistula and to act as a protecting layer on anastomosis. In two cases with hypospadias excessive use of the glue caused skin necrosis, which was repaired. The wounds of cloacal extrophy were protected from nearby colostomy contamination and infection, and the vesicocutanouse fistula was closed by deepithelialization and sealing with glue. Based on the outcomes of the cases, it may be possible to suggest that Glubran 2 may be used safely in Pediatric Surgery as a sealant for the prevention and treatment of fistulas. PMID- 23365481 TI - Disseminated peritoneal leiomyomatosis. AB - Leiomyomatosis peritonealis disseminata is a very rare condition characterized by the development of multiple smooth muscle-like nodules in the peritoneal cavity. It is associated with increased serum levels of gonadal steroids. The present report describes a 29-year-old patient underwent transabdominal hysterectomy and Bilateral Salpingo oophorectomy six years ago because of leiomyomatosis peritonealis disseminata. After six years she referred to us again because of retroperitoneal fibroma, another rare entity, during hormone replacement therapy inspite of lack of uterus and previous castration. PMID- 23365482 TI - Vasovagal syncope treated as epilepsy for 16 years. AB - The differentiation of vasovagal syncope and epileptic seizure is sometimes problematic, since vasovagal syncope may mimic epileptic seizures in many ways. The present report describes a patient who had been diagnosed and treated as having epilepsy with medically-refractory seizures for 16 years. Often, unlike epileptic seizures, tonic-clonic convulsions and postictal confusion are uncommon features of vasovagal syncope, but these may occur. Our patient was subjected to subcutaneous injection of one ml normal saline, which caused asystole leading to hypoxia and consequently a typical tonic-clonic convulsion. This patient was proved to have vasovagal syncope. The findings in the present case suggest that the possibility of vasovagal syncope should always be taken into consideration when evaluating patients with medically-refractory or unusual pattern of seizures. In such a circumstance, simultaneous video electroencephalogram/electocardiogram monitoring may help achieve the correct diagnosis. PMID- 23365483 TI - The use of citric Acid for the treatment of chronic non-healing sinus. PMID- 23365484 TI - Association of methylmalonic acidemia and erythema nodosum. PMID- 23365485 TI - Board task performance: An exploration of micro- and macro-level determinants of board effectiveness. AB - This paper addresses recent calls to narrow the micro-macro gap in management research (Bamberger, 2008), by incorporating a macro-level context variable (country) in exploring micro-level determinants of board effectiveness. Following the integrated model proposed by Forbes and Milliken (1999), we identify three board processes as micro-level determinants of board effectiveness. Specifically, we focus on effort norms, cognitive conflicts and the use of knowledge and skills as determinants of board control and advisory task performance. Further, we consider how two different institutional settings influence board tasks, and how the context moderates the relationship between processes and tasks. Our hypotheses are tested on a survey-based dataset of 535 medium-sized and large industrial firms in Italy and Norway, which are considered to substantially differ along legal and cultural dimensions. The findings show that: (i) Board processes have a larger potential than demographic variables to explain board task performance; (ii) board task performance differs significantly between boards operating in different contexts; and (iii) national context moderates the relationships between board processes and board task performance. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 23365486 TI - Suppression of dextran sulfate sodium-induced colitis in mice by radon inhalation. AB - The enhanced release of reactive oxygen species from activated neutrophils plays important role in the pathogenesis of inflammatory bowel disease. We previously reported that radon inhalation activates antioxidative functions in various organs of mice. In this study, we examined the protective effects of radon inhalation on dextran sulfate sodium- (DSS) induced colitis in mice which were subjected to DSS for 7 days. Mice were continuously treated with air only (sham) or radon at a concentration of 2000 Bq/m3 from a day before DSS administration to the end of colitis induction. In the results, radon inhalation suppressed the elevation of the disease activity index score and histological damage score induced by DSS. Based on the changes in tumor necrosis factor-alpha in plasma and myeloperoxidase activity in the colon, it was shown that radon inhalation suppressed DSS-induced colonic inflammation. Moreover, radon inhalation suppressed lipid peroxidation of the colon induced by DSS. The antioxidant level (superoxide dismutase and total glutathione) in the colon after DSS administration was significantly higher in mice treated with radon than with the sham. These results suggested that radon inhalation suppressed DSS-induced colitis through the enhancement of antioxidative functions in the colon. PMID- 23365487 TI - Role of mitogen-activated protein kinase pathways in multifactorial adverse cardiac remodeling associated with metabolic syndrome. AB - Metabolic syndrome has been widely associated with an increased risk for acute cardiovascular events. Emerging evidence supports metabolic syndrome as a condition favoring an adverse cardiac remodeling, which might evolve towards heart dysfunction and failure. This pathological remodeling has been described to result from the cardiac adaptive response to clinical mechanical conditions (such as hypertension, dyslipidemia, and hyperglycemia), soluble inflammatory molecules (such as cytokines and chemokines), as well as hormones (such as insulin), characterizing the pathophysiology of metabolic syndrome. Moreover, these cardiac processes (resulting in cardiac hypertrophy and fibrosis) are also associated with the modulation of intracellular signalling pathways within cardiomyocytes. Amongst the different intracellular kinases, mitogen-activated protein kinases (MAPKs) were shown to be involved in heart damage in metabolic syndrome. However, their role remains controversial. In this paper, we will discuss and update evidence on MAPK-mediated mechanisms underlying cardiac adverse remodeling associated with metabolic syndrome. PMID- 23365488 TI - An emerging role of glucagon-like peptide-1 in preventing advanced-glycation-end product-mediated damages in diabetes. AB - Glucagon-like peptide-1 (GLP-1) is a gut hormone produced in the intestinal epithelial endocrine L cells by differential processing of the proglucagon gene. Released in response to the nutrient ingestion, GLP-1 plays an important role in maintaining glucose homeostasis. GLP-1 has been shown to regulate blood glucose levels by stimulating glucose-dependent insulin secretion and inhibiting glucagon secretion, gastric emptying, and food intake. These antidiabetic activities highlight GLP-1 as a potential therapeutic molecule in the clinical management of type 2 diabetes, (a disease characterized by progressive decline of beta-cell function and mass, increased insulin resistance, and final hyperglycemia). Since chronic hyperglycemia contributed to the acceleration of the formation of Advanced Glycation End-Products (AGEs, a heterogeneous group of compounds derived from the nonenzymatic reaction of reducing sugars with free amino groups of proteins implicated in vascular diabetic complications), the administration of GLP-1 might directly counteract diabetes pathophysiological processes (such as pancreatic beta-cell dysfunction). This paper outlines evidence on the protective role of GLP-1 in preventing the deleterious effects mediated by AGEs in type 2 diabetes. PMID- 23365489 TI - Role of matrix metalloproteinase-8 in atherosclerosis. AB - Plaque rupture is the main cause of acute myocardial infarction and stroke. Atherosclerotic plaques have been described to be vulnerable and more prone to rupture when they are characterized by thin, highly inflamed, and collagen-poor fibrous caps and contain elevated levels of proteases, including metalloproteinases (MMPs). Initiation of collagen breakdown in plaques requires interstitial collagenases, a MMP subfamily consisting of MMP-1, MMP-8, and MMP 13. Previous reports demonstrated that MMP-1 and MMP-13 might be overexpressed in both human and experimental atherosclerosis. Since neutrophils have been only recently reported in atherosclerotic plaques, the role of MMP-8 (formerly known as "neutrophil collagenase") was only marginally evaluated. In this paper, we will update and comment on evidence of the most relevant regulatory pathways and activities mediated by MMP-8 in atherogenesis. PMID- 23365491 TI - CD8+CXCR5+ T cells regulate pathology in the genital tract. AB - We have identified a CD8+CXCR5+ T cell that prevents the development of oviduct dilation following C. muridarum genital infection. Phenotypic studies show that CD8+CXCR5+ cells express markers of T regulatory cells (FoxP3, CD25, and GITR) but do not express a necessary component of cytotoxic cells (perforin). Cxcr5-/- mice have significantly lower numbers of CD8+ cells and lack the CD8+CXCR5+ population while the total number of CD4+ cells is equivalent between mouse strains. The transfer of CD8+ splenocytes from WT mice reduces the oviduct dilation seen in Cxcr5-/- mice following C. muridarum infection. Future studies will investigate the mechanism by which this cell type regulates genital tract pathology. PMID- 23365492 TI - Endoscopic Ultrasound-Guided Celiac Plexus Neurolysis in Pancreatic Cancer: A Prospective Pilot Study of Safety Using 10 mL versus 20 mL Alcohol. AB - Background. The dose of alcohol used in EUS-CPN is not standardized. The objective was to compare the safety of 20 mL alcohol versus 10 mL alcohol during EUS-CPN for patients with pancreatic cancer-related pain. Methods. 20 patients were selected to receive 10 mL or 20 mL of alcohol during EUS-CPN. Followup was done at baseline, 24 hours, and weekly. Health-related quality of life (HRQoL) was assessed at baseline, week 2, week 4, and every 4 weeks thereafter until pain returned. Results. There were no major complications in both groups. Minor self limited adverse effects were seen in 6 (30%) subjects and included lightheadedness in 1 (5%), transient diarrhea in 2 (10%), and transient nausea and vomiting in 3. Pain relief was similar in both groups: 80% in the 10 mL group and 100% in the 20 mL group (P = 0.21). The mean (+/- SD) duration of pain relief in the 10 mL and 20 mL groups was 7.9 +/- 10.8 and 8.4 +/- 9.2 weeks, respectively. 30% of patients in each group had complete pain relief. Conclusions. EUS-CPN using 20 mL of alcohol is safe. Similar clinical outcomes were seen in both groups. Further investigations to confirm these findings are warranted. PMID- 23365493 TI - Disordered Attention: Implications for Understanding and Treating Internalizing and Externalizing Disorders in Childhood. AB - In this article, we present evidence that disorders of attention are present in wide range of psychological disorders, and that the appropriate assessment and treatment of these attention difficulties can be an important adjunct to traditional therapeutic approaches. We review approaches to attention training in some detail and discuss how attention-focused treatment might be implemented in clinical practice. PMID- 23365494 TI - Medical schools : the supply and availability of qualified human resources - challenges and opportunities. PMID- 23365490 TI - Vitreous mediators in retinal hypoxic diseases. AB - The causes of retinal hypoxia are many and varied. Under hypoxic conditions, a variety of soluble factors are secreted into the vitreous cavity including growth factors, cytokines, and chemokines. Cytokines, which usually serve as signals between neighboring cells, are involved in essentially every important biological process, including cell proliferation, inflammation, immunity, migration, fibrosis, tissue repair, and angiogenesis. Cytokines and chemokines are multifunctional mediators that can direct the recruitment of leukocytes to sites of inflammation, promote the process, enhance immune responses, and promote stem cell survival, development, and homeostasis. The modern particle-based flow cytometric analysis is more direct, stable and sensitive than the colorimetric readout of the conventional ELISA but, similar to ELISA, is influenced by vitreous hemorrhage, disruption of the blood-retina barrier, and high serum levels of a specific protein. Finding patterns in the expression of inflammatory cytokines specific to a particular disease can substantially contribute to the understanding of its basic mechanism and to the development of a targeted therapy. PMID- 23365495 TI - An overview on the development of newcastle disease virus as an anti-cancer therapy. AB - Newcastle disease virus (NDV) is one of the most economically important avian virus which affects the poultry industry worldwide. Although NDV is being very actively studied in Malaysia, there are still no studies on its potential as an anticancer agent, a new approach to treating cancer known as virotherapy. Currently, a collaborative research is being undertaken between Universiti Putra Malaysia (UPM), Universiti Sains Malaysia (USM) and Majlis Kanser Nasional (MAKNA) in characterising various local NDV isolates as anticancer agent. This paper describes an overview of the research that have been carried out worldwide in the use of NDV for cancer treatment and also some of our findings in characterising local NDVs with oncolytic properties. PMID- 23365496 TI - Cancer of the cervix - from bleak past to bright future; a review, with an emphasis on cancer of the cervix in malaysia. AB - Cancer of the cervix has the potential to be eradicated since the initiating cause is known. There was not much known about this cancer until the time of the Renaissance. In Malaysia, it is the second most common cancer among females after breast cancer. The strategies on prevention in this country are still not optimal. This article highlights the problems and also discusses the pathogenesis of this disease. The key to prevention is screening and the future is the era of molecular pap smear. PMID- 23365498 TI - Comparison Between 3D TOF Magnetic Resonance Angiography and Intraarterial Digital Subtraction Angiography in Imaging the Circle of Willis. AB - This study was done compare the accuracy of non-contrast enhanced 3D time of flight magnetic resonance angiography (3D TOF MRA) with intraarterial digital subtraction angiography (IADSA) in depicting the arterial segments of the circle of Willis. 398 arterial segments were analysed from 38 patients who underwent both non-contrast enhanced 3D TOF MRA and IADSA examinations in Hospital Universiti Sains Malaysia from November 1998 to December 2000. Two observers performed blinded retrospective analysis of the IADSA images and Maximum Intensity Projection display of the 3D TOF MRA of the circle of Willis on separate sessions. Non-contrast enhanced 3D TOF MRA was sensitive and specific in depicting the A1, A2, M1, P1 and Anterior Communicating segments of the circle of Willis with a sensitivity ranging from 94.5% to 100% and specificity ranging from 90.5% to 100%. However it was poor in depicting the Posterior Communicating segments with a sensitivity of 21.4%. MIP display of the non-contrast enhanced 3D TOF MRA is sensitive in depicting the anatomy of the circle of Willis except for the PCOM segment. It is thus a reliable method for screening of this arterial circle. PMID- 23365497 TI - Permeability of dentine. AB - This is an update on the present integrated knowledge regarding dentine permeability that assumed a role in dentine sensitivity and contribute clinically to the effective bonding properties of restorative dental materials. This paper will attempt to refer to in vivo and in vitro studies of dentine permeability and the various interrelated factors governing it. PMID- 23365499 TI - Toxic effects of 5-Fluorouracil on sperm count in wistar rats. AB - The antimetabolite, 5-fluorouracil is widely used in the treatment of cancers. Although its toxic effects on testis causing germinal epithelial sloughing, tubular atrophy and generation of multinucleated cells were reported, its effect on spermatogenesis has not been studied. Hence the present study was conducted to evaluate the effects of 5-fluorouracil on epididymal sperm count. Male Wistar rats were employed in the study (n=5 per group). The animals were injected (i.p) with five consecutive doses of 5-fluorouracil (10, 20, 30mg/kg b.w) at an interval of 24h and the control with 0.1ml-distilled water. Samples were obtained at 14, 35, 42 and 70 days after injection. Rats were sacrificed, a laparatomy was performed and epididymes were collected in 1ml phosphate buffered saline (pH 7.2), minced, filtered and stained with 1% aqueous eosin Y. An aliquot was taken in leucocyte pipette, diluted with phosphate buffered saline and sperm count was done as per the standard procedure. Data were analyzed by Mann Whitney U test. The results of this study revealed that 5 - fluorouracil significantly decreased the sperm count in a dose- and time-dependent manner. PMID- 23365500 TI - Test ordering pattern at the chemical pathology laboratory, hospital universiti sains malaysia. AB - The utilization of the chemical laboratory resources at the Hospital Sains Malaysia was evaluated. More than 100,000 test requests received and performed over a 12-month period, were analyzed retrospectively. The analysis conducted included the abnormal results obtained, the degree of duplication of tests, and the extent of test-panel ordering. It was found that a relatively moderate degree of over-ordering was evident. The findings suggested that the main reasons for over-ordering were the use of panel tests of ordering, in addition to a small, yet significant degree of duplication. Strategies for cutting down the test ordering have been reviewed and discussed. PMID- 23365501 TI - An immunohistochemical study of retinoblastoma gene product in normal, premalignant and malignant tissues of the uterine cervix. AB - The retinoblastoma gene was the first tumour suppressor gene identified that was altered not only in retinoblastomas but has been described in a wide variety of human neoplasms. The retinoblastoma gene encodes a nuclear phosphoprotein that in its hypophosphorylated state plays an important role in regulating the cell cycle, thus preventing from tumour formation. Expression of retinoblastoma gene protein product (pRB) was investigated in 118 formalin-fixed, paraffin-embedded cervical tissues by immunohistochemistry using commercially available antibody directed against RB protein. Ten normal ectocervical epithelium, 16 cervical intraepithelial neoplasia (CIN) I, 13 CIN II, 14 CIN III, 53 invasive squamous cell carcinoma, 11 adenocarcinoma and 1 small cell carcinoma were selected for this study. The proportions of pRB-positive cells as well as the extent of pRB expression in ectocervical squamous epithelium were assessed and compared among the lesions. The pRB expression was observed in 100% of normal ectocervical epithelium (n=10), 100% of CIN lesions (n=43) and 98.5% of invasive carcinoma of the uterine cervix (n=65) and were statistically significant when CIN or CIN/invasive were compared to normal cases (P < 0.01, P < 0.05 respectively). While in invasive squamous cell carcinoma (SCC), 81.8% (9/11) pRB-positive cells were found in much higher percentages in well differentiated SCC compared to 64.3% (18/28) of moderately differentiated cases and only 7.1% (1/14) of poorly differentiated SCC (P < 0.01, respectively). The results of this study suggest that loss of RB protein expression is rare in carcinoma of the uterine cervix and this protein may be important in the pathogenesis of cervical carcinoma. PMID- 23365502 TI - Tuberculosis in AIDS patients. AB - Tuberculosis is the top agenda among opportunistic diseases and the most leading cause of death in HIV/AIDS patients. A total of 406 AIDS patients were recruited in this retrospective and descriptive study. 123/406 (30.3%) were diagnosed as AIDS-related tuberculosis (TB). Their age range from 17 to 69 years with a mean (+/-SD) of 37.2 (+/-9.51. There were significant association between occupation, or mode of HIV transmission and tuberculosis infection (p< 0.05). Pulmonary tuberculosis 104/123 (84.6%) was the most common disease location among TB patients. We found the significant association between the clinical presentations i.e. fever, cough, sputum or hemoptysis and TB patients (p<0.05), moreover, the level of CD4 cell count plays a significant role in association with the disease (p<0.05) in this study. PMID- 23365503 TI - The effect of propranolol in malay patients with liver cirrhosis - a pharmacodynamic evaluation. AB - The pharmacodynamics of propranolol were studied in 12 cirrhotic Malay patients. Fifteen healthy Malay volunteers were selected and several clinical parameters were obtained. The effects of three doses of propranolol in reducing the heart rate (HR) of these patients were observed to be significantly different. These differences were seen at dosing of 10 mg vs 20 mg and 10 mg vs 30 mg (P<0.001 and P<0.01, respectively). However, no significant difference was seen for doses between 20 mg vs 30 mg. At 20 mg the reduction in HR is more pronounced than the effect seen with the other two doses. The effects of propranolol in reducing V(max) and V(mean) of portal vein blood flow were found to be not significant at doses of 10 mg vs 30 mg, but between 10 mg vs 20 mg and 20 mg vs 30 mg there was significant difference (P<0.05 and P<0.01, respectively). Reduction of V(max) of more than 10% of baseline was achieved at doses of 10 mg and 20 mg. However, at a dose of 20 mg a more significant reduction was observed than at a dose of 10 mg. Dose-concentration-effect relationship was seen to be significantly different between HR reduction and propranolol concentration of the three steady-state levels (P<0.001). Similar results were obtained with V(max) and V(mean). The V(max) was found to be a reliable parameter for the assessment of therapeutic effect of the drugs in conferring changes in portal haemodynamics of liver cirrhotic patients. Further, Child-Pugh score is thought to be an important supporting factor in evaluating prognosis. The results of this pharmacodynamics studies suggest that the optimal dose of propranolol may be 20 mg propranolol thrice daily for cirrhotic Malay patients. PMID- 23365504 TI - Suitability of Parkinson's patients for surgery in the north East coast of peninsular malaysia: a prospective analysis. AB - There is no report in the English literature on the criteria for neuroablation or neuroaugmentation for the treatment of Parkinson's disease in a developing country like Malaysia. A prospective study of patients with Parkinson's disease from the north-eastern peninsular Malaysia was done to assess their suitability of surgery. Age, race, duration of illness and dementia were considered important factors towards the success of such surgical procedures. A mathematical model is suggested for future cases deemed to be suitable for neuroaugmentative or ablative surgery. PMID- 23365505 TI - Effects of a herbal drink on cycling endurance performance. AB - In this study, we examined the effects of acute ingestion of a herbal drink (H) or a coloured water placebo (P) on physiological responses and performance during cycling exercise. Eight healthy and trained male young cyclists (age: 16.0+/ 0.5years) exercised on a cycle ergometer at 72.0+/-0.8% of the maximal oxygen consumption (VO(2max)) until exhaustion in a room maintained at 23.9+/-0.2 degrees C and 64.2+/-1.6% relative humidity on two occasions, 1-week apart. During each exercise bout, subjects received 3ml.kg(-1) body weight of H or P every 20 minutes in a double-blind randomised study design. There was no significant difference between H and P trials in the total work time to exhaustion (84.5+/-5.1 and 82.3+/-5.6 min respectively). Changes in heart rate, oxygen consumption, plasma glucose concentrations, plasma lactate concentrations, rectal temperature, respiratory exchange ratio and energy expenditure were similar with both type of drinks. Loss of plasma volume was also similar with both drinks. Herbal drink elicited similar physiological responses, thermoregularity responses and exercise performances during endurance cycling when compared to the placebo ingestion. Thus, it can be concluded that the ingredient in the herbal drink did not provide any added advantage to cycling endurance performance. PMID- 23365506 TI - Reoperative thyroid surgery in hospital universiti sains malaysia. AB - From 1996 to 2001, 393 thyroidectomies were performed and 25 (6.4%) patients underwent reoperative thyroid surgery at Hospital Universiti Sains Malaysia. All reoperated patients had undergone one prior thyroid operation. All were females with an average age of 39.1 years (18-61 years). The most frequent indication for reoperation was cancer in resected specimen of an originally misdiagnosed carcinoma treated by partial thyroid resection. Final histological diagnosis of 25 reoperations showed thyroid carcinoma in 22 (88%) cases and multinodular goiter in 3 cases. The overall interval between the initial and the reoperative procedures ranged from 3 weeks to 15 years. There was no post-operative mortality after reoperation. Post-operative complications were discovered in 5 patients, as 3 (12%) of whom had transient hypocalcaemia, one (4%) had wound breakdown and one (4%) had permanent recurrent laryngeal nerve palsy. Reoperative thyroid surgery is an uncommon operation with high complication rate. PMID- 23365507 TI - Heterophoria in young adults with emmetropia and myopia. AB - The purpose of this study was to investigate the relationship between heterophoria and refractive error. Thirty-six subjects (11 myopes, 25 emmetropes) participated in this study. Heterophoria was measured with the Free-Space Phoria Card at five different viewing distances (25cm, 33cm, 50cm, 100cm and 300cm). Regardless of the types of heterophoria, the amount of heterophoria reduced towards orthophoric position with increasing viewing distance. Emmetropes and myopes did not show any significant difference in the degree of heterophoria at different viewing distances (F = 0.30, p>0.05) or in the type of heterophoria (chi(2) = 2, p>0.05). PMID- 23365508 TI - Unilateral exophthalmos caused by an extramedullary plasmacytoma: a case report. AB - Solitary plasmacytoma of the head and neck is a rare disease entity. Its description in the literature consist of some case reports. Solitary plasmacytoma presenting with exophthalmos are rare. We report a case of intracranial solitary plasmacytoma in an elderly lady with involvement of the right orbitocranial region presenting with severe exophthalmos. The tumour was debulked and radiotherapy was given. PMID- 23365509 TI - Molecular tools for the detection of nitrogen cycling Archaea. AB - Archaea are widespread in extreme and temperate environments, and cultured representatives cover a broad spectrum of metabolic capacities, which sets them up for potentially major roles in the biogeochemistry of their ecosystems. The detection, characterization, and quantification of archaeal functions in mixed communities require Archaea-specific primers or probes for the corresponding metabolic genes. Five pairs of degenerate primers were designed to target archaeal genes encoding key enzymes of nitrogen cycling: nitrite reductases NirA and NirB, nitrous oxide reductase (NosZ), nitrogenase reductase (NifH), and nitrate reductases NapA/NarG. Sensitivity towards their archaeal target gene, phylogenetic specificity, and gene specificity were evaluated in silico and in vitro. Owing to their moderate sensitivity/coverage, the novel nirB-targeted primers are suitable for pure culture studies only. The nirA-targeted primers showed sufficient sensitivity and phylogenetic specificity, but poor gene specificity. The primers designed for amplification of archaeal nosZ performed well in all 3 criteria; their discrimination against bacterial homologs appears to be weakened when Archaea are strongly outnumbered by bacteria in a mixed community. The novel nifH-targeted primers showed high sensitivity and gene specificity, but failed to discriminate against bacterial homologs. Despite limitations, 4 of the new primer pairs are suitable tools in several molecular methods applied in archaeal ecology. PMID- 23365511 TI - Levels, distribution, and health risks of polycyclic aromatic hydrocarbons in four freshwater edible fish species from the Beijing market. AB - We first estimated the content of polycyclic aromatic hydrocarbons (PAHs) in the brain, liver, bladder, roe, and muscle of four species of edible freshwater fish from the Beijing market. The distribution characteristics of PAHs in these tissues and organs were analyzed to determine their health risks to humans. The results showed that the residual levels of wet weight and lipid-normalized weight ?PAHs in various tissues of these fish ranged from 0.51 ng.g(-1) to 28.78 ng.g( 1) and from 93.62 ng.g(-1) to 8203.43 ng.g(-1), respectively. The wet weight contents of ?PAHs were relatively higher in the brain and lower in the liver and muscle. But the differences were not significant. And the differences of lipid normalized weight PAHs were significant, which in the bighead carp were found significantly the highest, followed in crucian carp, and the lowest in grass carp and carp. The contents of ?PAHs were the highest in the liver and the lowest in the brain. In the tissues with a higher lipid content, higher residual levels of PAHs were found. The carcinogenic risks for humans from residual ?PAHs in the various fish tissues were far below 10(-5). PMID- 23365512 TI - Design and control of glycerol-tert-butyl alcohol etherification process. AB - Design, economics, and plantwide control of a glycerol-tert-butyl alcohol (TBA) etherification plant are presented. The reaction takes place in liquid phase, in a plug flow reactor, using Amberlyst 15 as a catalyst. The products' separation is achieved by two distillation columns where high-purity ethers are obtained and a section involving extractive distillation with 1,4-butanediol as solvent, which separates TBA from the TBA/water azeotrope. Details of design performed in AspenPlus and an economic evaluation of the process are given. Three plantwide control structures are examined using a mass balance model of the plant. The preferred control structure fixes the fresh glycerol flow rate and the ratio glycerol + monoether : TBA at reactor-inlet. The stability and robustness in the operation are checked by rigorous dynamic simulation in AspenDynamics. PMID- 23365514 TI - Does the panoramic radiography have the power to identify the gonial angle in orthodontics? AB - PURPOSE: The objective of this study was to assess gonial angle under the angle classification by comparing panoramic radiograph and lateral cephalometric radiograph. MATERIALS AND METHODS: 49 patients (25 males, 24 females) with an age range of 12-29 years participated in the present study. Subjects were retrospectively selected among those categorised as skeletal and dental Class I, II, and III malocclusion group. Using lateral cephalometric radiograph, mandibular and ramal planes were drawn and based on these planes. Gonial angle was determined from two tangents which were drawn from the inferior border of the mandible and posterior borders of the condyle and ramus of both sides in the panoramic radiographs. Multiple comparison tests (ANOVA) were used to determine differences between the three angle groups. RESULTS: There were no significant differences between Class I, II, and III malocclusion group values of gonial angles determined by lateral cephalometric radiograph and panoramic radiographs (P > 0.05). CONCLUSION: Panoramic radiograph results were shown to be as reliable as lateral cephalometric radiograph in all angle classifications. Panoramic radiography can be used as an alternative radiographic technique to detect gonial angle in orthodontic patients. PMID- 23365513 TI - Exhaled breath condensate: a promising source for biomarkers of lung disease. AB - Exhaled breath condensate (EBC) has been increasingly studied as a noninvasive research method for sampling the alveolar and airway space and is recognized as a promising source of biomarkers of lung diseases. Substances measured in EBC include oxidative stress and inflammatory mediators, such as arachidonic acid derivatives, reactive oxygen/nitrogen species, reduced and oxidized glutathione, and inflammatory cytokines. Although EBC has great potential as a source of biomarkers in many lung diseases, the low concentrations of compounds within the EBC present challenges in sample collection and analysis. Although EBC is viewed as a noninvasive method for sampling airway lining fluid (ALF), validation is necessary to confirm that EBC truly represents the ALF. Likewise, a dilution factor for the EBC is needed in order to compare across subjects and determine changes in the ALF. The aims of this paper are to address the characteristics of EBC; strategies to standardize EBC sample collection and review available analytical techniques for EBC analysis. PMID- 23365515 TI - Preparation of PEO/clay nanocomposites using organoclay produced via micellar adsorption of CTAB. AB - The aim of this study was the preparation of polyethylene oxide (PEO)/clay nanocomposites using organoclay produced via micellar adsorption of cethyltrimethyl ammonium bromide (CTAB) and their characterisation by X-ray diffraction (XRD), and Fourier transform infrared (FT-IR) spectra, and the investigation of certain mechanical properties of the composites. The results show that the basal distance between the layers increased with the increasing CTAB/clay ratio as parallel with the zeta potential values of particles. By considering the aggregation number of CTAB micelles and interlayer distances of organo-clay, it could be suggested that the predominant micelle geometry at lower CTAB/clay ratios is an ellipsoidal oblate, whereas, at higher CTAB/clay ratios, sphere-ellipsoid transition occurs. The increasing tendency of the exfoliation degree with an increase in clay content may be attributed to easier diffusion of PEO chains to interlayer regions. FT-IR spectra show that the intensity of Si-O stretching vibrations of the organoclays (1050 cm(-1)) increased, especially in the ratios of 1.0 g/g clay and 1.5 g/g clay with the increasing CTAB content. It was observed that the mechanical properties of the composites are dependent on both the CTAB/clay ratios and clay content of the composites. PMID- 23365516 TI - Ecological network analysis for a low-carbon and high-tech industrial park. AB - Industrial sector is one of the indispensable contributors in global warming. Even if the occurrence of ecoindustrial parks (EIPs) seems to be a good improvement in saving ecological crises, there is still a lack of definitional clarity and in-depth researches on low-carbon industrial parks. In order to reveal the processes of carbon metabolism in a low-carbon high-tech industrial park, we selected Beijing Development Area (BDA) International Business Park in Beijing, China as case study, establishing a seven-compartment- model low-carbon metabolic network based on the methodology of Ecological Network Analysis (ENA). Integrating the Network Utility Analysis (NUA), Network Control Analysis (NCA), and system-wide indicators, we compartmentalized system sectors into ecological structure and analyzed dependence and control degree based on carbon metabolism. The results suggest that indirect flows reveal more mutuality and exploitation relation between system compartments and they are prone to positive sides for the stability of the whole system. The ecological structure develops well as an approximate pyramidal structure, and the carbon metabolism of BDA proves self mutualistic and sustainable. Construction and waste management were found to be two active sectors impacting carbon metabolism, which was mainly regulated by internal and external environment. PMID- 23365517 TI - Industry efficiency and total factor productivity growth under resources and environmental constraint in China. AB - The growth of China's industry has been seriously depending on energy and environment. This paper attempts to apply the directional distance function and the Luenberger productivity index to measure the environmental efficiency, environmental total factor productivity, and its components at the level of subindustry in China over the period from 1999 to 2009 while considering energy consumption and emission of pollutants. This paper also empirically examines the determinants of efficiency and productivity change. The major findings are as follows. Firstly, the main sources of environmental inefficiency of China's industry are the inefficiency of gross industrial output value, the excessive energy consumption, and pollutant emissions. Secondly, the highest growth rate of environmental total factor productivity among the three industrial categories is manufacturing, followed by mining, and production and supply of electricity, gas, and water. Thirdly, foreign direct investment, capital-labor ratio, ownership structure, energy consumption structure, and environmental regulation have varying degrees of effects on the environmental efficiency and environmental total factor productivity. PMID- 23365518 TI - A bat algorithm with mutation for UCAV path planning. AB - Path planning for uninhabited combat air vehicle (UCAV) is a complicated high dimension optimization problem, which mainly centralizes on optimizing the flight route considering the different kinds of constrains under complicated battle field environments. Original bat algorithm (BA) is used to solve the UCAV path planning problem. Furthermore, a new bat algorithm with mutation (BAM) is proposed to solve the UCAV path planning problem, and a modification is applied to mutate between bats during the process of the new solutions updating. Then, the UCAV can find the safe path by connecting the chosen nodes of the coordinates while avoiding the threat areas and costing minimum fuel. This new approach can accelerate the global convergence speed while preserving the strong robustness of the basic BA. The realization procedure for original BA and this improved metaheuristic approach BAM is also presented. To prove the performance of this proposed metaheuristic method, BAM is compared with BA and other population-based optimization methods, such as ACO, BBO, DE, ES, GA, PBIL, PSO, and SGA. The experiment shows that the proposed approach is more effective and feasible in UCAV path planning than the other models. PMID- 23365519 TI - A review of integration strategies to support gene regulatory network construction. AB - Gene regulatory network (GRN) construction is a central task of systems biology. Integration of different data sources to infer and construct GRNs is an important consideration for the success of this effort. In this paper, we will discuss distinctive strategies of data integration for GRN construction. Basically, the process of integration of different data sources is divided into two phases: the first phase is collection of the required data and the second phase is data processing with advanced algorithms to infer the GRNs. In this paper these two phases are called "structural integration" and "analytic integration," respectively. Compared with the nonintegration strategies, the integration strategies perform quite well and have better agreement with the experimental evidence. PMID- 23365520 TI - An integrated fuzzy approach for strategic alliance partner selection in third party logistics. AB - Outsourcing some of the logistic activities is a useful strategy for companies in recent years. This makes it possible for firms to concentrate on their main issues and processes and presents facility to improve logistics performance, to reduce costs, and to improve quality. Therefore provider selection and evaluation in third-party logistics become important activities for companies. Making a strategic decision like this is significantly hard and crucial. In this study we proposed a fuzzy multicriteria decision making (MCDM) approach to effectively select the most appropriate provider. First we identify the provider selection criteria and build the hierarchical structure of decision model. After building the hierarchical structure we determined the selection criteria weights by using fuzzy analytical hierarchy process (AHP) technique. Then we applied fuzzy technique for order preference by similarity to ideal solution (TOPSIS) to obtain final rankings for providers. And finally an illustrative example is also given to demonstrate the effectiveness of the proposed model. PMID- 23365522 TI - Cooperative scheduling of imaging observation tasks for high-altitude airships based on propagation algorithm. AB - The cooperative scheduling problem on high-altitude airships for imaging observation tasks is discussed. A constraint programming model is established by analyzing the main constraints, which takes the maximum task benefit and the minimum cruising distance as two optimization objectives. The cooperative scheduling problem of high-altitude airships is converted into a main problem and a subproblem by adopting hierarchy architecture. The solution to the main problem can construct the preliminary matching between tasks and observation resource in order to reduce the search space of the original problem. Furthermore, the solution to the sub-problem can detect the key nodes that each airship needs to fly through in sequence, so as to get the cruising path. Firstly, the task set is divided by using k-core neighborhood growth cluster algorithm (K-NGCA). Then, a novel swarm intelligence algorithm named propagation algorithm (PA) is combined with the key node search algorithm (KNSA) to optimize the cruising path of each airship and determine the execution time interval of each task. Meanwhile, this paper also provides the realization approach of the above algorithm and especially makes a detailed introduction on the encoding rules, search models, and propagation mechanism of the PA. Finally, the application results and comparison analysis show the proposed models and algorithms are effective and feasible. PMID- 23365521 TI - The effects of whole-body vibration on the cross-transfer of strength. AB - This study investigated whether the use of superimposed whole-body vibration (WBV) during cross-education strength training would optimise strength transfer compared to conventional cross-education strength training. Twenty-one healthy, dominant right leg volunteers (21 +/- 3 years) were allocated to a strength training (ST, m = 3, f = 4), a strength training with WBV (ST + V, m = 3, f = 4), or a control group (no training, m = 3, f = 4). Training groups performed 9 sessions over 3 weeks, involving unilateral squats for the right leg, with or without WBV (35 Hz; 2.5 mm amplitude). All groups underwent dynamic single leg maximum strength testing (1RM) and single and paired pulse transcranial magnetic stimulation (TMS) prior to and following training. Strength increased in the trained limb for the ST (41%; ES = 1.14) and ST + V (55%; ES = 1.03) groups, which resulted in a 35% (ES = 0.99) strength transfer to the untrained left leg for the ST group and a 52% (ES = 0.97) strength transfer to the untrained leg for the ST + V group, when compared to the control group. No differences in strength transfer between training groups were observed (P = 0.15). For the untrained leg, no differences in the peak height of recruitment curves or SICI were observed between ST and ST + V groups (P = 1.00). Strength training with WBV does not appear to modulate the cross-transfer of strength to a greater magnitude when compared to conventional cross-education strength training. PMID- 23365524 TI - Assessment for fuel consumption and exhaust emissions of China's vehicles: future trends and policy implications. AB - In the recent years, China's auto industry develops rapidly, thus bringing a series of burdens to society and environment. This paper uses Logistic model to simulate the future trend of China's vehicle population and finds that China's auto industry would come into high speed development time during 2020-2050. Moreover, this paper predicts vehicles' fuel consumption and exhaust emissions (CO, HC, NO(x), and PM) and quantificationally evaluates related industry policies. It can be concluded that (1) by 2020, China should develop at least 47 million medium/heavy hybrid cars to prevent the growth of vehicle fuel consumption; (2) China should take the more stringent vehicle emission standard V over 2017-2021 to hold back the growth of exhaust emissions; (3) developing new energy vehicles is the most effective measure to ease the pressure brought by auto industry. PMID- 23365523 TI - In silico evolution of gene cooption in pattern-forming gene networks. AB - Gene recruitment or cooption occurs when a gene, which may be part of an existing gene regulatory network (GRN), comes under the control of a new regulatory system. Such re-arrangement of pre-existing networks is likely more common for increasing genomic complexity than the creation of new genes. Using evolutionary computations (EC), we investigate how cooption affects the evolvability, outgrowth and robustness of GRNs. We use a data-driven model of insect segmentation, for the fruit fly Drosophila, and evaluate fitness by robustness to maternal variability-a major constraint in biological development. We compare two mechanisms of gene cooption: a simpler one with gene Introduction and Withdrawal operators; and one in which GRN elements can be altered by transposon infection. Starting from a minimal 2-gene network, insufficient for fitting the Drosophila gene expression patterns, we find a general trend of coopting available genes into the GRN, in order to better fit the data. With the transposon mechanism, we find co-evolutionary oscillations between genes and their transposons. These oscillations may offer a new technique in EC for overcoming premature convergence. Finally, we comment on how a differential equations (in contrast to Boolean) approach is necessary for addressing realistic continuous variation in biochemical parameters. PMID- 23365525 TI - Material flow analysis of fossil fuels in China during 2000-2010. AB - Since the relationship between the supply and demand of fossil fuels is on edge in the long run, the contradiction between the economic growth and limited resources will hinder the sustainable development of the Chinese society. This paper aims to analyze the input of fossil fuels in China during 2000-2010 via the material flow analysis (MFA) that takes hidden flows into account. With coal, oil, and natural gas quantified by MFA, three indexes, consumption and supply ratio (C/S ratio), resource consumption intensity (RCI), and fossil fuels productivity (FFP), are proposed to reflect the interactions between population, GDP, and fossil fuels. The results indicated that in the past 11 years, China's requirement for fossil fuels has been increasing continuously because of the growing mine productivity in domestic areas, which also leads to a single energy consumption structure as well as excessive dependence on the domestic exploitation. It is advisable to control the fossil fuels consumption by energy recycling and new energy facilities' popularization in order to lead a sustainable access to nonrenewable resources and decrease the soaring carbon emissions. PMID- 23365526 TI - Distribution and bioconcentration of polycyclic aromatic hydrocarbons in surface water and fishes. AB - To examine spatial distribution and bioconcentration of PAHs, water and fish samples were collected from Pearl River Delta in summer and spring, respectively. Particulate organic carbon, dissolved organic carbon, biodegradable DOC (BDOC), and chlorophyll a were measured. PAHs were dominated by 2- and 3-ring compounds in the water and SPM samples. Aqueous and solid-phase PAHs, respectively, showed significant correlations with total organic matter (TOC) in SPM or dissolved organic matter (DOC) in the water. The in-situ partitioning coefficients (logK(oc), mL/g) for the samples were observed to be related to logK(ow), implying that the hydrophobicity of PAHs is a critical factor in their distribution. It was also observed that BCF increased with the increasing K(ow) in the viscera of tilapia (logBCF = 0.507logK(ow) - 1.368, r = 0.883). However, most of the observed log BCF values in other different fish tissues at first increased with the increasing of log K(ow), then reached a maximum value when logK(ow) is between 5 and 7, and then decreased when logK(ow) is higher than 7, indicating that the value of BCF may vary due to the diversity of fish species. PMID- 23365527 TI - Simulation of the fate and seasonal variations of alpha-hexachlorocyclohexane in Lake Chaohu using a dynamic fugacity model. AB - Fate and seasonal variations of alpha-hexachlorocyclohexane (alpha-HCH) were simulated using a dynamic fugacity model in Lake Chaohu, China. Sensitivity analyses were performed to identify influential parameters and Monte Carlo simulation was conducted to assess model uncertainty. The calculated and measured values of the model were in good agreement except for suspended solids, which might be due to disregarding the plankton in water. The major source of alpha-HCH was an input from atmospheric advection, while the major environmental outputs were atmospheric advection and sediment degradation. The net annual input and output of alpha-HCH were approximately 0.294 t and 0.412 t, respectively. Sediment was an important sink for alpha-HCH. Seasonal patterns in various media were successfully modeled and factors leading to this seasonality were discussed. Sensitivity analysis found that parameters of source and degradation were more important than the other parameters. The sediment was influenced more by various parameters than air and water were. Temperature variation had a greater impact on the dynamics of the model output than other dynamic parameters. Uncertainty analysis showed that the model uncertainty was relatively low but significantly increased in the second half of the simulation period due to the increase in the gas-water diffusion flux variability. PMID- 23365528 TI - Gene expression network reconstruction by LEP method using microarray data. AB - Gene expression network reconstruction using microarray data is widely studied aiming to investigate the behavior of a gene cluster simultaneously. Under the Gaussian assumption, the conditional dependence between genes in the network is fully described by the partial correlation coefficient matrix. Due to the high dimensionality and sparsity, we utilize the LEP method to estimate it in this paper. Compared to the existing methods, the LEP reaches the highest PPV with the sensitivity controlled at the satisfactory level. A set of gene expression data from the HapMap project is analyzed for illustration. PMID- 23365529 TI - Mental health recovery: evaluation of a recovery-oriented training program. AB - AIM: This study investigates the effectiveness of a recovery-oriented training program on knowledge and attitudes of mental health care professionals towards recovery of people with serious mental illness. METHODS: Using data from a longitudinal study of recovery, changes in knowledge and attitudes of 210 mental health care professionals towards recovery were explored using the Recovery Attitude Questionnaire and the Recovery Knowledge Inventory. The study uses a two group multiple intervention interrupted time-series design which is a variant of the stepped-wedge trial design. A total of six measurements occasions took place. RESULTS: This study shows that professionals' attitudes towards recovery from mental illness can improve with training. After two intensive recovery-oriented training sessions, mental health care professionals have a more positive attitude towards recovery in clinical practice. CONCLUSION: A recovery-oriented training program can change attitudes of mental health care professionals towards recovery of serious mental illness. PMID- 23365530 TI - Enhanced growth of multipurpose Calliandra (Calliandra calothyrsus) using arbuscular mycorrhiza fungi in Uganda. AB - This study was conducted to compare the effect of selected arbuscular mycorrhiza fungi genera and their application rates for enhanced Calliandra growth in Uganda. The performance of Calliandra under different types and rates of arbuscular mycorrhiza fungi inoculation was assessed in the greenhouse using sterilized Mabira soils. Four dominant genera were isolated from the rhizosphere of sorghum in the laboratory. Calliandra seeds were grown in pots and the seed coating method of application was used at concentrations of 0 spores, 30 spores and 50 spores. Each treatment was replicated three times. All Calliandra inoculated seedlings showed improved seedling growth (in terms of height and shoot dry matter weight) compared to the control (P < 0.05) except with the arbuscular mycorrhiza fungi mixture treated Calliandra at 50 spores rate. Glomus sp. and Acaulospora sp. had significant influence on the height of Calliandra, while AMF mixture performed best in terms of shoot dry weight (P < 0.05). This study provides a good scope for commercially utilizing the efficient strains of arbuscular mycorrhiza fungi for beneficial effects in the primary establishment of slow growing seedlings ensuring better survival and improved growth. PMID- 23365531 TI - An assessment of Japanese carbon tax reform using the E3MG econometric model. AB - This paper analyses the potential economic and environmental effects of carbon taxation in Japan using the E3MG model, a global macroeconometric model constructed by the University of Cambridge and Cambridge Econometrics. The paper approaches the issues by considering first the impacts of the carbon tax in Japan introduced in 2012 and then the measures necessary to reduce Japan's emissions in line with its Copenhagen pledge of -25% compared to 1990 levels. The results from the model suggest that FY2012 Tax Reform has only a small impact on emission levels and no significant impact on GDP and employment. The potential costs of reducing emissions to meet the 25% reduction target for 2020 are quite modest, but noticeable. GDP falls by around 1.2% compared to the baseline and employment by 0.4% compared to the baseline. But this could be offset, with some potential economic benefits, if revenues are recycled efficiently. This paper considers two revenue recycling scenarios. The most positive outcome is if revenues are used both to reduce income tax rates and to increase investment in energy efficiency. This paper shows there could be double dividend effects, if Carbon Tax Reform is properly designed. PMID- 23365532 TI - Case study on incentive mechanism of energy efficiency retrofit in coal-fueled power plant in China. AB - An ordinary steam turbine retrofit project is selected as a case study; through the retrofit, the project activities will generate emission reductions within the power grid for about 92,463 tCO(2)e per annum. The internal rate of return (IRR) of the project is only -0.41% without the revenue of carbon credits, for example, CERs, which is much lower than the benchmark value of 8%. Only when the unit price of carbon credit reaches 125 CNY/tCO(2), the IRR could reach the benchmark and an effective carbon tax needs to increase the price of carbon to 243 CNY/tce in order to make the project financially feasible. Design of incentive mechanism will help these low efficiency enterprises improve efficiency and reduce CO(2) emissions, which can provide the power plants sufficient incentive to implement energy efficiency retrofit project in existing coal-fuel power generation-units, and we hope it will make a good demonstration for the other low efficiency coal fueled power generation units in China. PMID- 23365533 TI - Antimicrobial activity and phytochemical screening of Buchenavia tetraphylla (Aubl.) R. A. Howard (Combretaceae: Combretoideae). AB - This study evaluated the antimicrobial and hemolytic activities and phytochemical constituents of hydroalcoholic extract and its fractions from Buchenavia tetraphylla leaves. Cyclohexane (BTCF), ethyl acetate (BTEF), and n-butanol soluble (BTSBF) and non-soluble (BTNBF) fractions were obtained from a liquid liquid partition of hydroalcoholic extract (BTHE) from B. tetraphylla leaves. The hemolytic activity of active fractions was checked. The BTHE inhibited the growth of Micrococcus luteus (MIC: 0.10 mg/mL), Pseudomonas aeruginosa (MIC: 0.20 mg/mL), Mycobacterium smegmatis (MIC: 0.39 mg/mL), Proteus vulgaris, and Staphylococcus aureus (MIC: 0.78 mg/mL for both). The more active fractions were BTCF and BTBSF. BTCF showed better potential to inhibit M. luteus (0.10 mg/mL), P. aeruginosa (0.20 mg/mL), S. enteritidis (0.39 mg/mL), and S. aureus (1.56 mg/mL). BTBSF showed the best results for M. luteus (0.10 mg/mL), M. smegmatis, B. subtilis (0.39 mg/mL for both), and P. vulgaris (0.10 mg/mL). The HC50 were greater than observed MIC: 20.30, 4.70 and 2.53 mg/mL, respectively, to BTBF, BTHE and BTCF, which. The phytochemical analysis detected the presence of flavanoids, triterpene, carbohydrate, and tannin. Our work showed for the first time the broad-spread antimicrobial activity of B. tetraphylla, which has nonhemolytic action, creating a new perspective on the interesting association of traditional and scientific knowledge. PMID- 23365534 TI - Embodied energy use in China's infrastructure investment from 1992 to 2007: calculation and policy implications. AB - Infrastructure has become an important topic in a variety of areas of the policy debate, including energy saving and climate change. In this paper, we use an energy input-output model to evaluate the amounts of China's embodied energy use in infrastructure investment from 1992 to 2007. We also use the structure decomposition model to analyze the factors impacting the embodied energy use in infrastructure investment for the same time period. The results show that embodied energy use in infrastructure investment accounted for a significant proportion of China's total energy use with an increasing trend and reflect that improper infrastructure investment represents inefficient use of energy and other resources. Some quantitative information is provided for further determining the low carbon development potentials of China's economy. PMID- 23365535 TI - Biofilm formation and adherence characteristics of Listeria ivanovii strains isolated from ready-to-eat foods in Alice, South Africa. AB - The present study was carried out to investigate the potential of Listeria ivanovii isolates to exist as biofilm structures. The ability of Listeria ivanovii isolates to adhere to a surface was determined using a microtiter plate adherence assay whereas the role of cell surface properties in biofilm formation was assessed using the coaggregation and autoaggregation assays. Seven reference bacterial strains were used for the coaggregation assay. The degree of coaggregation and autoaggregation was determined. The architecture of the biofilms was examined under SEM. A total of 44 (88%) strains adhered to the wells of the microtiter plate while 6 (12%) did not adhere. The coaggregation index ranged from 12 to 77% while the autoaggregation index varied from 11 to 55%. The partner strains of S. aureus, S. pyogenes, P. shigelloides, and S. sonnei displayed coaggregation indices of 75% each, while S. Typhimurium, A. hydrophila, and P. aeruginosa registered coaggregation indices of 67%, 58%, and 50%, respectively. The ability of L. ivanovii isolates to form single and multispecies biofilms at 25 degrees C is of great concern to the food industry where these organisms may adhere to kitchen utensils and other environments leading to cross contamination of food processed in these areas. PMID- 23365536 TI - A high voltage ratio and low ripple interleaved DC-DC converter for fuel cell applications. AB - This paper proposes a high voltage ratio and low ripple interleaved boost DC-DC converter, which can be used to reduce the output voltage ripple. This converter transfers the low DC voltage of fuel cell to high DC voltage in DC link. The structure of the converter is parallel with two voltage-doubler boost converters by interleaving their output voltages to reduce the voltage ripple ratio. Besides, it can lower the current stress for the switches and inductors in the system. First, the PSIM software was used to establish a proton exchange membrane fuel cell and a converter circuit model. The simulated and measured results of the fuel cell output characteristic curve are made to verify the correctness of the established simulation model. In addition, some experimental results are made to validate the effectiveness in improving output voltage ripple of the proposed high voltage ratio interleaved boost DC-DC converters. PMID- 23365537 TI - Evaluating ecological and economic benefits of a low-carbon industrial park based on millennium ecosystem assessment framework. AB - The Millennium Ecosystem Assessment (MA) framework was modified with a special focus on ecosystem service values. A case study of a typical low-carbon industrial park in Beijing was conducted to assess the ecological and economic benefits. The total economic value of this industrial park per year is estimated to be 1.37 * 10(8) RMB yuan, where the accommodating and social cultural services are the largest two contributors. Due to the construction of small grasslands or green roofs, considerable environmental regulation services are also provided by the park. However, compared with an ecoindustrial park, carbon mitigation is the most prominent service for the low-carbon industrial park. It can be concluded that low-carbon industrial park construction is an efficacious way to achieve coordinated development of society, economy, and environment, and a promising approach to achieving energy saving and carbon reduction. PMID- 23365538 TI - Passivity-based adaptive hybrid synchronization of a new hyperchaotic system with uncertain parameters. AB - We investigate the adaptive hybrid synchronization problem for a new hyperchaotic system with uncertain parameters. Based on the passivity theory and the adaptive control theory, corresponding controllers and parameter estimation update laws are proposed to achieve hybrid synchronization between two identical uncertain hyperchaotic systems with different initial values, respectively. Numerical simulation indicates that the presented methods work effectively. PMID- 23365539 TI - Large scale association analysis for drug addiction: results from SNP to gene. AB - Many genetic association studies used single nucleotide polymorphisms (SNPs) data to identify genetic variants for complex diseases. Although SNP-based associations are most common in genome-wide association studies (GWAS), gene based association analysis has received increasing attention in understanding genetic etiologies for complex diseases. While both methods have been used to analyze the same data, few genome-wide association studies compare the results or observe the connection between them. We performed a comprehensive analysis of the data from the Study of Addiction: Genetics and Environment (SAGE) and compared the results from the SNP-based and gene-based analyses. Our results suggest that the gene-based method complements the individual SNP-based analysis, and conceptually they are closely related. In terms of gene findings, our results validate many genes that were either reported from the analysis of the same dataset or based on animal studies for substance dependence. PMID- 23365540 TI - Development of methane and nitrous oxide emission factors for the biomass fired circulating fluidized bed combustion power plant. AB - This study makes use of this distinction to analyze the exhaust gas concentration and fuel of the circulating fluidized bed (CFB) boiler that mainly uses wood biomass, and to develop the emission factors of Methane (CH(4)), Nitrous oxide (N(2)O). The fuels used as energy sources in the subject working sites are Wood Chip Fuel (WCF), RDF and Refused Plastic Fuel (RPF) of which heating values are 11.9 TJ/Gg, 17.1 TJ/Gg, and 31.2 TJ/Gg, respectively. The average concentrations of CH(4) and N(2)O were measured to be 2.78 ppm and 7.68 ppm, respectively. The analyzed values and data collected from the field survey were used to calculate the emission factor of CH(4) and N(2)O exhausted from the CFB boiler. As a result, the emission factors of CH(4) and N(2)O are 1.4 kg/TJ (0.9-1.9 kg/TJ) and 4.0 kg/TJ (2.9-5.3 kg/TJ) within a 95% confidence interval. Biomass combined with the combustion technology for the CFB boiler proved to be more effective in reducing the N(2)O emission, compared to the emission factor of the CFB boiler using fossil fuel. PMID- 23365541 TI - Robust microarray meta-analysis identifies differentially expressed genes for clinical prediction. AB - Combining multiple microarray datasets increases sample size and leads to improved reproducibility in identification of informative genes and subsequent clinical prediction. Although microarrays have increased the rate of genomic data collection, sample size is still a major issue when identifying informative genetic biomarkers. Because of this, feature selection methods often suffer from false discoveries, resulting in poorly performing predictive models. We develop a simple meta-analysis-based feature selection method that captures the knowledge in each individual dataset and combines the results using a simple rank average. In a comprehensive study that measures robustness in terms of clinical application (i.e., breast, renal, and pancreatic cancer), microarray platform heterogeneity, and classifier (i.e., logistic regression, diagonal LDA, and linear SVM), we compare the rank average meta-analysis method to five other meta analysis methods. Results indicate that rank average meta-analysis consistently performs well compared to five other meta-analysis methods. PMID- 23365542 TI - Experience of wellness recovery action planning in self-help and mutual support groups for people with lived experience of mental health difficulties. AB - The main aim of this research was to assess the relevance and impact of wellness recovery action planning (WRAP) as a tool for self-management and wellness planning by individuals with mental health problems from pre-existing and newly formed groups, where the possibilities for continued mutual support in the development of WRAPs could be explored. Interviews and focus groups were conducted and pre-post recovery outcome measures completed (Recovery Assessment Scale and Warwick Edinburgh Mental Well Being Scale). 21 WRAP group participants took part in the research. The WRAP approach, used in groups and delivered by trained facilitators who could also share their lived experience, was very relevant and appeared to have a positive impact on many of the participants. The impact on participants varied from learning more about recovery and developing improved self-awareness to integrating a WRAP approach into daily life. The apparent positive impact of WRAP delivered in the context of mutual support groups indicates that it should be given serious consideration as a unique and worthwhile option for improving mental health. WRAP groups could make a significant contribution to the range of self-management options that are available for improving mental health and well-being. PMID- 23365543 TI - Recent advances in the surgical treatment of differentiated thyroid cancer: a comprehensive review. AB - Differentiated thyroid cancers have become one of the fastest growing malignancies in the world. While surgery has remained the cornerstone of management of these tumors, the surgical approach has seen numerous innovations over the past few decades. The use of video-assistance and robotics has revolutionized thyroid surgery. This paper provides a comprehensive evaluation of the different approaches to thyroid surgery, the utility of prophylactic and therapeutic lymph node dissection, and evidence-based guidelines in the treatment of differentiated thyroid cancers. Minimally invasive video-ssisted thyroidectomy is both safe and effective in the hands of the trained surgeon and, in selected patient populations, has comparative perioperative morbidity and better cosmesis as compared to conventional open thyroidectomy. It is universally accepted that therapeutic central lymph node dissection should be performed when metastatic lymph nodes are identified on physical exam, ultrasound, or intraoperatively. In the absence of overt nodal metastasis, the role of elective prophylactic central lymph node dissection remains a matter of debate and prospective, randomized studies are warranted to evaluate the utility of this procedure. PMID- 23365544 TI - Prophylactic nailing of incomplete atypical femoral fractures. AB - INTRODUCTION: Recent reports have described the occurrence of low-energy subtrochanteric and femoral shaft fractures associated with long-term bisphosphonate use. Although information regarding the surgical treatment of these atypical femoral fractures is increasing, it is unclear if the preventive operation is useful in incomplete fractures. This study examined the results of preventive intramedullary nailing for incomplete atypical femoral fractures. MATERIAL AND METHODS: A retrospective search was conducted for patients older than 50 years receiving bisphosphonate therapy, with incomplete, nondisplaced fractures in either the subtrochanteric or diaphyseal area of the femur. Seventeen patients with a total of 20 incomplete, non-displaced lesions were included. The mean duration of bisphosphonate use was 50.5 months. Eleven of the 17 (64.7%) patients had complete or incomplete fractures on the contralateral femur. All were treated with prophylactic fixation of an intramedullary (IM) nail. The minimum followup was 12 months. RESULTS: All cases healed with a mean period of 14.3 weeks. Nineteen of the 20 cases healed with the dissolution of incomplete fractures of the lateral aspect. A complete fracture developed at the time of nailing in one patient, but it healed with callus bridging. CONCLUSION: IM nailing appears to be a reliable way of preventing the progress of incomplete atypical femoral fractures. PMID- 23365545 TI - Goblet cell carcinoids of the appendix. AB - Goblet cell carcinoid (GCC) tumors are a rare subgroup of neuroendocrine tumors almost exclusively originating in the appendix. The tumor most often presents in the fifth or sixth decade with a clinical picture of appendicitis or in advanced cases an abdominal mass associated with abdominal pain. Histologically tumors are most often positive for chromogranin A and synaptophysin, however, less homogenous than for classic appendix carcinoids. The malignant potential is higher than that for the classic appendix carcinoids due to local spread and distant metastases at diagnosis and the proliferation markers (Ki67 index) may determine prognosis. Octreotide receptor scintigraphy is usually negative while CT/MRI scans may be useful. Chromogranin A is usually negative and other biomarkers related to the mucinous component or the tumor (CEA, CA-19-9, and CA 125) may be used. Surgery is the main treatment with appendectomy and right hemicolectomy while patients with disseminated disease should be treated with chemotherapy. Overall 5-year survival is approximately 75%. The diagnosis and treatment of GCC tumors should be restricted to high volume NET centers in order to accumulate knowledge and improve survival in GCC NET patients. The aim of this paper is to update on epidemiology, clinical presentation, and diagnostic markers including Ki67 index, treatment, and survival. PMID- 23365546 TI - The Bristol hip view: its role in the diagnosis and surgical planning and occult fracture diagnosis for proximal femoral fractures. AB - AIM: To evaluate whether a modified radiographic view of the femoral neck improves the diagnosis of occult proximal femoral. MATERIALS AND METHODS: Prospective study of patients presenting with clinically suspected proximal femoral fractures or who underwent traditional plain radiographic views and the Bristol hip view (a 30-degree angled projection). Six blinded independent observers assessed the images for presence of a fracture, anatomical level, and displacement. RESULTS: 166 consecutive patients presenting with the clinical diagnosis of a proximal femoral fracture, of which 61 sustained a fracture. Six of these were deemed occult due to negative plain and had proven fractures on subsequent cross-sectional imaging. The Bristol hip view demonstrated five of these six fractures. It performed better than the traditional lateral hip view to identify the injury. The Bristol hip view predicted correctly the fracture type and displacement in all cases and missed only one of the occult fractures. CONCLUSION: The Bristol hip view is more sensitive and clearer than a lateral projection for patients. It adds useful diagnostic information and performs better than the traditional views in occult fractures. Its use may prevent the need for further cross sectional imaging and subsequent surgical delay. PMID- 23365547 TI - Experimental research of dynamic instabilities in the presence of coiled wire inserts on two-phase flow. AB - The aim of this study is to experimentally investigate the effect of the coiled wire insertions on dynamic instabilities and to compare the results with the smooth tube for forced convection boiling. The experiments were conducted in a circular tube, and water was used as the working fluid. Two different pitch ratios (H/D = 2.77 and 5.55) of coiled wire with circular cross-sections were utilised. The constant heat flux boundary condition was applied to the outer side of the test tube, and the constant exit restriction was used at the tube outlet. The mass flow rate changed from 110 to 20 g/s in order to obtain a detailed idea about the density wave and pressure drop oscillations, and the range of the inlet temperature was 15-35 degrees C. The changes in pressure drop, inlet temperature, amplitude, and the period with mass flow rate are presented. For each configuration, it is seen that density wave and pressure drop oscillations occur at all inlet temperatures. Analyses show that the decrease in the mass flow rate and inlet temperature causes the amplitude and the period of the density wave and the pressure drop oscillations to decrease separately. PMID- 23365548 TI - Computational and bioinformatics frameworks for next-generation whole exome and genome sequencing. AB - It has become increasingly apparent that one of the major hurdles in the genomic age will be the bioinformatics challenges of next-generation sequencing. We provide an overview of a general framework of bioinformatics analysis. For each of the three stages of (1) alignment, (2) variant calling, and (3) filtering and annotation, we describe the analysis required and survey the different software packages that are used. Furthermore, we discuss possible future developments as data sources grow and highlight opportunities for new bioinformatics tools to be developed. PMID- 23365549 TI - Effect of electronic acceptor segments on photophysical properties of low-band gap ambipolar polymers. AB - Stimulated by a recent experimental report, charge transfer and photophysical properties of donor-acceptor ambipolar polymer were studied with the quantum chemistry calculation and the developed 3D charge difference density method. The effects of electronic acceptor strength on the structure, energy levels, electron density distribution, ionization potentials, and electron affinities were also obtained to estimate the transporting ability of hole and electron. With the developed 3D charge difference density, one visualizes the charge transfer process, distinguishes the role of molecular units, and finds the relationship between the role of DPP and excitation energy for the three polymers during photo excitation. PMID- 23365551 TI - Significance analysis of prognostic signatures. AB - A major goal in translational cancer research is to identify biological signatures driving cancer progression and metastasis. A common technique applied in genomics research is to cluster patients using gene expression data from a candidate prognostic gene set, and if the resulting clusters show statistically significant outcome stratification, to associate the gene set with prognosis, suggesting its biological and clinical importance. Recent work has questioned the validity of this approach by showing in several breast cancer data sets that "random" gene sets tend to cluster patients into prognostically variable subgroups. This work suggests that new rigorous statistical methods are needed to identify biologically informative prognostic gene sets. To address this problem, we developed Significance Analysis of Prognostic Signatures (SAPS) which integrates standard prognostic tests with a new prognostic significance test based on stratifying patients into prognostic subtypes with random gene sets. SAPS ensures that a significant gene set is not only able to stratify patients into prognostically variable groups, but is also enriched for genes showing strong univariate associations with patient prognosis, and performs significantly better than random gene sets. We use SAPS to perform a large meta-analysis (the largest completed to date) of prognostic pathways in breast and ovarian cancer and their molecular subtypes. Our analyses show that only a small subset of the gene sets found statistically significant using standard measures achieve significance by SAPS. We identify new prognostic signatures in breast and ovarian cancer and their corresponding molecular subtypes, and we show that prognostic signatures in ER negative breast cancer are more similar to prognostic signatures in ovarian cancer than to prognostic signatures in ER positive breast cancer. SAPS is a powerful new method for deriving robust prognostic biological signatures from clinically annotated genomic datasets. PMID- 23365552 TI - Fast and Analytical EAP Approximation from a 4th-Order Tensor. AB - Generalized diffusion tensor imaging (GDTI) was developed to model complex apparent diffusivity coefficient (ADC) using higher-order tensors (HOTs) and to overcome the inherent single-peak shortcoming of DTI. However, the geometry of a complex ADC profile does not correspond to the underlying structure of fibers. This tissue geometry can be inferred from the shape of the ensemble average propagator (EAP). Though interesting methods for estimating a positive ADC using 4th-order diffusion tensors were developed, GDTI in general was overtaken by other approaches, for example, the orientation distribution function (ODF), since it is considerably difficult to recuperate the EAP from a HOT model of the ADC in GDTI. In this paper, we present a novel closed-form approximation of the EAP using Hermite polynomials from a modified HOT model of the original GDTI-ADC. Since the solution is analytical, it is fast, differentiable, and the approximation converges well to the true EAP. This method also makes the effort of computing a positive ADC worthwhile, since now both the ADC and the EAP can be used and have closed forms. We demonstrate our approach with 4th-order tensors on synthetic data and in vivo human data. PMID- 23365553 TI - Compressed sensing photoacoustic imaging based on fast alternating direction algorithm. AB - Photoacoustic imaging (PAI) has been employed to reconstruct endogenous optical contrast present in tissues. At the cost of longer calculations, a compressive sensing reconstruction scheme can achieve artifact-free imaging with fewer measurements. In this paper, an effective acceleration framework using the alternating direction method (ADM) was proposed for recovering images from limited-view and noisy observations. Results of the simulation demonstrated that the proposed algorithm could perform favorably in comparison to two recently introduced algorithms in computational efficiency and data fidelity. In particular, it ran considerably faster than these two methods. PAI with ADM can improve convergence speed with fewer ultrasonic transducers, enabling a high performance and cost-effective PAI system for biomedical applications. PMID- 23365550 TI - Fluctuating roles of matrix metalloproteinase-9 in oral squamous cell carcinoma. AB - One hallmark of cancer is the degradation of the extracellular matrix (ECM), which is caused by proteinases. In oral cancers, matrix metalloproteinases (MMPs), especially MMP-9, are associated with this degradation. MMPs break down the ECM allowing cancer to spread; they also release various factors from their cryptic sites, including cytokines. These factors modulate cell behavior and enhance cancer progression by regulating angiogenesis, migration, proliferation, and invasion. The development of early metastases is typical for oral cancer, and increased MMP-9 expression is associated with a poor disease prognosis. However, many studies fail to relate MMP-9 expression with metastasis formation. Contrary to earlier models, recent studies show that MMP-9 plays a protective role in oral cancers. Therefore, the role of MMP-9 is complicated and may fluctuate throughout the different types and stages of oral cancers. PMID- 23365554 TI - Modeling Airflow Using Subject-Specific 4DCT-Based Deformable Volumetric Lung Models. AB - Lung radiotherapy is greatly benefitted when the tumor motion caused by breathing can be modeled. The aim of this paper is to present the importance of using anisotropic and subject-specific tissue elasticity for simulating the airflow inside the lungs. A computational-fluid-dynamics (CFD) based approach is presented to simulate airflow inside a subject-specific deformable lung for modeling lung tumor motion and the motion of the surrounding tissues during radiotherapy. A flow-structure interaction technique is employed that simultaneously models airflow and lung deformation. The lung is modeled as a poroelastic medium with subject-specific anisotropic poroelastic properties on a geometry, which was reconstructed from four-dimensional computed tomography (4DCT) scan datasets of humans with lung cancer. The results include the 3D anisotropic lung deformation for known airflow pattern inside the lungs. The effects of anisotropy are also presented on both the spatiotemporal volumetric lung displacement and the regional lung hysteresis. PMID- 23365555 TI - The smoothing artifact of spatially constrained canonical correlation analysis in functional MRI. AB - A wide range of studies show the capacity of multivariate statistical methods for fMRI to improve mapping of brain activations in a noisy environment. An advanced method uses local canonical correlation analysis (CCA) to encompass a group of neighboring voxels instead of looking at the single voxel time course. The value of a suitable test statistic is used as a measure of activation. It is customary to assign the value to the center voxel; however, this is a choice of convenience and without constraints introduces artifacts, especially in regions of strong localized activation. To compensate for these deficiencies, different spatial constraints in CCA have been introduced to enforce dominance of the center voxel. However, even if the dominance condition for the center voxel is satisfied, constrained CCA can still lead to a smoothing artifact, often called the "bleeding artifact of CCA", in fMRI activation patterns. In this paper a new method is introduced to measure and correct for the smoothing artifact for constrained CCA methods. It is shown that constrained CCA methods corrected for the smoothing artifact lead to more plausible activation patterns in fMRI as shown using data from a motor task and a memory task. PMID- 23365556 TI - A New GLLD Operator for Mass Detection in Digital Mammograms. AB - During the last decade, several works have dealt with computer automatic diagnosis (CAD) of masses in digital mammograms. Generally, the main difficulty remains the detection of masses. This work proposes an efficient methodology for mass detection based on a new local feature extraction. Local binary pattern (LBP) operator and its variants proposed by Ojala are a powerful tool for textures classification. However, it has been proved that such operators are not able to model at their own texture masses. We propose in this paper a new local pattern model named gray level and local difference (GLLD) where we take into consideration absolute gray level values as well as local difference as local binary features. Artificial neural networks (ANNs), support vector machine (SVM), and k-nearest neighbors (kNNs) are, then, used for classifying masses from nonmasses, illustrating better performance of ANN classifier. We have used 1000 regions of interest (ROIs) obtained from the Digital Database for Screening Mammography (DDSM). The area under the curve of the corresponding approach has been found to be A(z) = 0.95 for the mass detection step. A comparative study with previous approaches proves that our approach offers the best performances. PMID- 23365558 TI - Emergent central pattern generator behavior in gap-junction-coupled Hodgkin Huxley style neuron model. AB - Most models of central pattern generators (CPGs) involve two distinct nuclei mutually inhibiting one another via synapses. Here, we present a single-nucleus model of biologically realistic Hodgkin-Huxley neurons with random gap junction coupling. Despite no explicit division of neurons into two groups, we observe a spontaneous division of neurons into two distinct firing groups. In addition, we also demonstrate this phenomenon in a simplified version of the model, highlighting the importance of afterhyperpolarization currents (I(AHP)) to CPGs utilizing gap junction coupling. The properties of these CPGs also appear sensitive to gap junction conductance, probability of gap junction coupling between cells, topology of gap junction coupling, and, to a lesser extent, input current into our simulated nucleus. PMID- 23365559 TI - A Gabor-block-based kernel discriminative common vector approach using cosine kernels for human face recognition. AB - In this paper a nonlinear Gabor Wavelet Transform (GWT) discriminant feature extraction approach for enhanced face recognition is proposed. Firstly, the low energized blocks from Gabor wavelet transformed images are extracted. Secondly, the nonlinear discriminating features are analyzed and extracted from the selected low-energized blocks by the generalized Kernel Discriminative Common Vector (KDCV) method. The KDCV method is extended to include cosine kernel function in the discriminating method. The KDCV with the cosine kernels is then applied on the extracted low-energized discriminating feature vectors to obtain the real component of a complex quantity for face recognition. In order to derive positive kernel discriminative vectors, we apply only those kernel discriminative eigenvectors that are associated with nonzero eigenvalues. The feasibility of the low-energized Gabor-block-based generalized KDCV method with cosine kernel function models has been successfully tested for classification using the L(1), L(2) distance measures; and the cosine similarity measure on both frontal and pose-angled face recognition. Experimental results on the FRAV2D and the FERET database demonstrate the effectiveness of this new approach. PMID- 23365557 TI - Impact of GLP-1 receptor agonists on major gastrointestinal disorders for type 2 diabetes mellitus: a mixed treatment comparison meta-analysis. AB - AIM: We aimed to integrate evidence from all randomized controlled trials (RCTs) and assess the impact of different doses of exenatide or liraglutide on major gastrointestinal adverse events (GIAEs) in type 2 diabetes (T2DM). METHODS: RCTs evaluating different doses of exenatide and liraglutide against placebo or an active comparator with treatment duration >=4 weeks were searched and reviewed. A total of 35, 32 and 28 RCTs met the selection criteria evaluated for nausea, vomiting, and diarrhea, respectively. Pairwise random-effects meta-analyses and mixed treatment comparisons (MTC) of all RCTs were performed. RESULTS: All GLP-1 dose groups significantly increased the probability of nausea, vomiting and diarrhea relative to placebo and conventional treatment. MTC meta-analysis showed that there was 99.2% and 85.0% probability, respectively, that people with exenatide 10 MUg twice daily (EX10BID) was more vulnerable to nausea and vomiting than those with other treatments. There was a 78.90% probability that liraglutide 1.2 mg once daily (LIR1.2) has a higher risk of diarrhea than other groups. A dose-dependent relationship of exenatide and liraglutide on GIAEs was observed. CONCLUSIONS: Our MTC meta-analysis suggests that patients should be warned about these GIAEs in early stage of treatment by GLP-1s, especially by EX10BID and LIR1.2, to promote treatment compliance. PMID- 23365560 TI - Analyzing the effects of gap junction blockade on neural synchrony via a motoneuron network computational model. AB - In specific regions of the central nervous system (CNS), gap junctions have been shown to participate in neuronal synchrony. Amongst the CNS regions identified, some populations of brainstem motoneurons are known to be coupled by gap junctions. The application of various gap junction blockers to these motoneuron populations, however, has led to mixed results regarding their synchronous firing behavior, with some studies reporting a decrease in synchrony while others surprisingly find an increase in synchrony. To address this discrepancy, we employ a neuronal network model of Hodgkin-Huxley-style motoneurons connected by gap junctions. Using this model, we implement a series of simulations and rigorously analyze their outcome, including the calculation of a measure of neuronal synchrony. Our simulations demonstrate that under specific conditions, uncoupling of gap junctions is capable of producing either a decrease or an increase in neuronal synchrony. Subsequently, these simulations provide mechanistic insight into these different outcomes. PMID- 23365561 TI - l(p)-Norm multikernel learning approach for stock market price forecasting. AB - Linear multiple kernel learning model has been used for predicting financial time series. However, l(1)-norm multiple support vector regression is rarely observed to outperform trivial baselines in practical applications. To allow for robust kernel mixtures that generalize well, we adopt l(p)-norm multiple kernel support vector regression (1 <= p < infinity) as a stock price prediction model. The optimization problem is decomposed into smaller subproblems, and the interleaved optimization strategy is employed to solve the regression model. The model is evaluated on forecasting the daily stock closing prices of Shanghai Stock Index in China. Experimental results show that our proposed model performs better than l(1)-norm multiple support vector regression model. PMID- 23365562 TI - Age-specific mechanisms in an SSVEP-based BCI scenario: evidences from spontaneous rhythms and neuronal oscillators. AB - Utilizing changes in steady-state visual evoked potentials (SSVEPs) is an established approach to operate a brain-computer interface (BCI). The present study elucidates to what extent development-specific changes in the background EEG influence the ability to proper handle a stimulus-driven BCI. Therefore we investigated the effects of a wide range of photic driving on children between six and ten years in comparison to an adult control group. The results show differences in the driving profiles apparently in close communication with the specific type of intermittent stimulation. The factor age gains influence with decreasing stimulation frequency, whereby the superior performance of the adults seems to be determined to a great extent by elaborated driving responses at 10 and 11 Hz, matching the dominant resonance frequency of the respective background EEG. This functional interplay was only partially obtained in higher frequency ranges and absent in the induced driving between 30 and 40 Hz, indicating distinctions in the operating principles and developmental changes of the underlying neuronal oscillators. PMID- 23365563 TI - Spike-Timing-dependent plasticity and short-term plasticity jointly control the excitation of Hebbian plasticity without weight constraints in neural networks. AB - Hebbian plasticity precisely describes how synapses increase their synaptic strengths according to the correlated activities between two neurons; however, it fails to explain how these activities dilute the strength of the same synapses. Recent literature has proposed spike-timing-dependent plasticity and short-term plasticity on multiple dynamic stochastic synapses that can control synaptic excitation and remove many user-defined constraints. Under this hypothesis, a network model was implemented giving more computational power to receptors, and the behavior at a synapse was defined by the collective dynamic activities of stochastic receptors. An experiment was conducted to analyze can spike-timing dependent plasticity interplay with short-term plasticity to balance the excitation of the Hebbian neurons without weight constraints? If so what underline mechanisms help neurons to maintain such excitation in computational environment? According to our results both plasticity mechanisms work together to balance the excitation of the neural network as our neurons stabilized its weights for Poisson inputs with mean firing rates from 10 Hz to 40 Hz. The behavior generated by the two neurons was similar to the behavior discussed under synaptic redistribution, so that synaptic weights were stabilized while there was a continuous increase of presynaptic probability of release and higher turnover rate of postsynaptic receptors. PMID- 23365564 TI - Endoscopic ultrasound. PMID- 23365565 TI - Methanolic Root Extract of Rauwolfia serpentina Benth Improves the Glycemic, Antiatherogenic, and Cardioprotective Indices in Alloxan-Induced Diabetic Mice. AB - The aim of the study was to evaluate the phytochemistry and the effect of methanolic root extract (MREt) of Rauwolfia serpentina on alloxan-induced diabetic Wister male mice. Mice were divided in control (distilled water at 1 mL/kg) and alloxan-induced diabetic mice which subdivided into diabetic (distilled water at 1 mL/kg), negative (0.05% dimethyl sulfoxide at 1 mL/kg), positive (glibenclamide at 5 mg/kg) controls, and three test groups (MREt at 10, 30, and 60 mg/kg). All treatments were given orally for 14 days. Qualitatively MREt showed the presence of alkaloids, carbohydrates, flavonoids, glycosides, cardiac glycosides, phlobatannins, resins, saponins, steroids, tannins, and triterpenoids, while quantitatively extract was rich in total phenols. The flavonoids, saponins and alkaloids were also determined in root powder. MREt found effective in improving the body weights, glucose and insulin levels, insulin/glucose ratio, glycosylated and total hemoglobin in test groups as compared to diabetic control. Similarly, significantly decreased levels of total cholesterol, triglycerides, low-density lipoprotein (LDL-c), and very low-density lipoprotein (VLDL-c) cholesterols were found in test groups. Significant lipolysis with improved glycogenesis was also found in liver tissues of all test groups. ALT levels were found normal in all groups. Thus, MREt improves the glycemic, antiatherogenic, coronary risk, and cardioprotective indices in alloxan induced diabetic mice. PMID- 23365566 TI - Inhibition of Growth and Induction of Apoptosis in Fibrosarcoma Cell Lines by Echinophora platyloba DC: In Vitro Analysis. AB - Echinophora platyloba DC plant (Khousharizeh) is one of the indigenous medicinal plants which is used as a food seasoning and medicine in Iran. The objective of this study was to examine the in vitro cytotoxic activity and the mechanism of cell death of crude methanolic extracts prepared from Echinophora platyloba DC, on mouse fibrosarcoma cell line (WEHI-164). Cytotoxicity and viability of methanolic extract was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and dye exclusion assay. Cell death ELISA was employed to quantify the nucleosome production result from nuclear DNA fragmentation during apoptosis and determine whether the mechanism involves induction of apoptosis or necrosis. The cell death was identified as apoptosis using terminal deoxynucleotidyl transferase- (TdT-) mediated dUTP nick end labeling (TUNEL) assay. Our results demonstrated that the extract decreased cell viability, suppressed cell proliferation, and induced cell death in a time- and dose-dependent manner in WEHI-164 cells (IC50 = 196.673 +/- 12.4 MUg/mL) when compared with a chemotherapeutic anticancer drug, Toxol. Observation proved that apoptosis was the major mechanism of cell death. So the Echinophora platyloba DC extract was found to time- and dose-dependently inhibit the proliferation of fibrosarcoma cell possibly via an apoptosis-dependent pathway. PMID- 23365567 TI - Technological approaches to remote monitoring of elderly people in cardiology: a usability perspective. AB - Moving from the experience gained in home telemonitoring of elderly patients with Congestive Heart Failure, that confirmed a reduction of the rehospitalization rate and an improved monitoring of drugs assumption by the patients, this paper extends the evaluation of technological approaches for remote health monitoring of older adults. Focus of the evaluation is on telemedicine effectiveness and usability, either from a patient's or a medical operator's perspective. The evaluation has been performed by testing three remote health platforms designed according to different technological approaches, in a realistic scenario involving older adults and medical operators (doctors and nurses). The aim of the testing activity was not to benchmark a specific solution with respect to the others, but to evaluate the main positive and negative issues related to the system and service design philosophy each solution was built upon. Though preliminary, the results discussed in the paper can be used as a set of guidelines in the selection of proper technological equipments for services targeted to elderly users, from a usability perspective. These results need to be complemented with more focused discussions of the ethical, medical, and legal aspects of the use of technology in remote healthcare. PMID- 23365568 TI - Real-time ultrasound-guided spinal anaesthesia: a prospective observational study of a new approach. AB - Identification of the subarachnoid space has traditionally been achieved by either a blind landmark-guided approach or using prepuncture ultrasound assistance. To assess the feasibility of performing spinal anaesthesia under real time ultrasound guidance in routine clinical practice we conducted a single center prospective observational study among patients undergoing lower limb orthopaedic surgery. A spinal needle was inserted unassisted within the ultrasound transducer imaging plane using a paramedian approach (i.e., the operator held the transducer in one hand and the spinal needle in the other). The primary outcome measure was the success rate of CSF acquisition under real-time ultrasound guidance with CSF being located in 97 out of 100 consecutive patients within median three needle passes (IQR 1-6). CSF was not acquired in three patients. Subsequent attempts combining landmark palpation and pre-puncture ultrasound scanning resulted in successful spinal anaesthesia in two of these patients with the third patient requiring general anaesthesia. Median time from spinal needle insertion until intrathecal injection completion was 1.2 minutes (IQR 0.83-4.1) demonstrating the feasibility of this technique in routine clinical practice. PMID- 23365570 TI - Literature mining solutions for life science research. PMID- 23365569 TI - Serological Evidence of Exposure to Leptospira spp. in Veterinary Students and Other University Students in Trinidad and Tobago. AB - The study compared the serological evidence of leptospirosis in 212 students in four schools (veterinary, dental, advanced nursing education and pharmacy) of the University of the West Indies (UWI), by testing for IgG immunoglobulins to Leptospira spp. using the enzyme-linked immunosorbent assay (ELISA) and the microscopic agglutination test (MAT). Overall, of 212 students tested by the ELISA, 12 (5.7%) and 31 (14.6%) were positive and borderline, respectively. Amongst the 113 veterinary students 11 (9.7%) and 19 (16.8%) were seropositive and borderline respectively compared with nonveterinary students with corresponding values of 1 (1.0%) and 12 (12.1%). The frequency of serological evidence of leptospirosis by the ELISA was statistically significantly (P < 0.05; chi(2)) higher in veterinary students, 26.5% (30 of 113) than in nonveterinary students, 13.1% (13 of 99). By the MAT, the seropositivity for leptospirosis was similar for veterinary students, 7.1% (8 of 113) and nonveterinary students, 7.1% (7 of 99). For veterinary students, the prevalent infecting serovar was Icterohaemorrhagiae Copenhageni while amongst nonveterinary students, the prevalent serovar was Australis Rachmati. Being a veterinary student was the only risk factor that was significantly associated with Leptospira infection indicating that veterinary students need to be cognizant and to practise preventive measures for leptospirosis. PMID- 23365571 TI - Analysis of Pregnancy Outcomes Using the New IADPSG Recommendation Compared with the Carpenter and Coustan Criteria in an Area with a Low Prevalence of Gestational Diabetes. AB - Aims. This paper aims to evaluate characteristics and pregnancy outcomes in women prior classified normal by Carpenter and Coustan criteria (old criteria) and now gestational diabetes (GDM) by the IADPSG criteria. Methods. Retrospective analysis of 6727 pregnancies is used. Using the old criteria, 222 had GDM (old GDM). Using the IADPSG criteria, 382 had GDM of which 160 had a normal glucose tolerance with the old criteria (new GDM). We compared the new GDM group with the old GDM group and women with normal glucose tolerance with both criteria (NGT group, 6345). Results. New GDM women were younger (31.6 +/- 4.7 versus 33.3 +/- 7.2 years, P = 0.010) than old GDM women. Caesarean section was performed in 30.5% of new GDM, in 32.4% of old GDM (P = 0.706), and in 23.3% of NGT women (P = 0.001). Large for gestational age occurred in 10.8% of new GDM, in 13.8% of old GDM (P = 0.473), and in 9.0% of NGT women (P = 0.099). Shoulder dystocia occurred in 3.9% of new GDM, in 3.2% of old GDM (P = 0.736), and in 1.4% of NGT women (P = 0.007). Conclusion. Using the IADPSG criteria, more women are identified as having GDM, and these women carry an increased risk for adverse gestational outcome compared to women without GDM. PMID- 23365572 TI - Effects of Age and Sex on Estimated Diabetes Prevalence Using Different Diagnostic Criteria: The Tromso OGTT Study. AB - HbA(1c) 6.5% has recently been recommended as an alternative diagnostic criterion for diabetes. The aims of the study were to evaluate the effects of age, sex, and other factors on prevalence of diabetes and to compare risk profiles of subjects with diabetes when defined by HbA(1c) and glucose criteria. Subjects were recruited among participants in the longitudinal population-based Tromso Study. HbA(1c), fasting plasma glucose, and 2-hour plasma glucose were measured in 3,476 subjects. In total, 294 subjects met one or more of the diagnostic criteria for diabetes; 95 met the HbA(1c) criterion only, 130 met the glucose criteria only, and 69 met both. Among subjects with diabetes detected by glucose criteria (regardless of HbA(1c)), isolated raised 2-hour plasma glucose was more common in subjects aged >= 60 years as compared to younger subjects and in elderly women as compared to elderly men. Subjects with diabetes detected by glucose criteria only had worse cardiometabolic risk profiles than those detected by HbA(1c) only. In conclusion, the current HbA(1c) and glucose criteria defined different subjects with diabetes with only modest overlap. Among a substantial proportion of elderly subjects, and especially elderly women, the 2-hour plasma glucose was the only abnormal value. PMID- 23365573 TI - Undertreated breast cancer in the elderly. AB - The effect of undertreatment with adjuvant hormonal therapy, chemotherapy, or radiation was studied in elderly women with breast cancer. A prospectively maintained database was used to identify women undergoing potentially curative surgery between 1978 and 2012. The presentation, pathologic findings, treatment, and outcomes of 382 women over 70 were compared to the findings in 2065 younger patients. Subsequently, conventionally treated and undertreated elderly patients were identified and their characteristics and outcomes were compared. Both young and old patients presented most frequently with mammographic findings, but older patients presented more frequently with mammographic masses while younger patients presented more frequently with mammographic calcifications. Cancers of older patients were significantly more favorable than cancers in younger patients: smaller, with more infiltrating lobular, fewer ductal carcinoma in situ, and more frequently estrogen receptor positive and fewer were poorly differentiated. Elderly patients had less axillary sampling, fewer mastectomies, less adjuvant radiation therapy, and more hormonal therapy. Fifty-one percent of the 382 elderly patients were undertreated by conventional criteria. Undertreated patients were more frequently in situ, better differentiated, smaller, and more often estrogen receptor positive. Forty-four percent of the undertreated patients died during followup without disease recurrence. Despite undertreatment, local and distant disease-free survival was comparable to patients who were not undertreated. PMID- 23365574 TI - Influenza a virus entry: implications in virulence and future therapeutics. AB - Influenza A viruses have broad host tropism, being able to infect a range of hosts from wild fowl to swine to humans. This broad tropism makes highly pathogenic influenza A strains, such as H5N1, potentially dangerous to humans if they gain the ability to jump from an animal reservoir to humans. How influenza A viruses are able to jump the species barrier is incompletely understood due to the complex genetic nature of the viral surface glycoprotein, hemagglutinin, which mediates entry, combined with the virus's ability to use various receptor linkages. Current therapeutics against influenza A include those that target the uncoating process after entry as well as those that prevent viral budding. While there are therapeutics in development that target entry, currently there are none clinically available. We review here the genetics of influenza A viruses that contribute to entry tropism, how these genetic alterations may contribute to receptor usage and species tropism, as well as how novel therapeutics can be developed that target the major surface glycoprotein, hemagglutinin. PMID- 23365576 TI - Porphyromonas gingivalis Outer Membrane Vesicles Mediate Coaggregation and Piggybacking of Treponema denticola and Lachnoanaerobaculum saburreum. AB - Porphyromonas gingivalis sheds outer membrane vesicles that contain several virulence factors, including adhesins. In this study, we investigated the ability of P. gingivalis outer membrane vesicles to mediate the coaggregation and piggybacking of Treponema denticola and Lachnoanaerobaculum saburreum. Marked coaggregation between T. denticola and L. saburreum occurred in the presence of P. gingivalis outer membrane vesicles. Sucrose was an effective chemoattractant for the motile species T. denticola. The addition of outer membrane vesicles to a mixture of T. denticola and L. saburreum significantly increased the number of nonmotile bacteria that migrated into a sucrose-filled capillary tube immersed in the bacterial mixture. Under optimal conditions, the number of nonmotile L. saburreum in the capillary tube increased approximately 5-fold, whereas no increase occurred when boiled vesicles were used. This study showed that P. gingivalis outer membrane vesicles mediate coaggregation between T. denticola and L. saburreum and that nonmotile bacteria can be translocated by piggybacking on spirochetes. PMID- 23365575 TI - Cellular factors implicated in filovirus entry. AB - Although filoviral infections are still occurring in different parts of the world, there are no effective preventive or treatment strategies currently available against them. Not only do filoviruses cause a deadly infection, but they also have the potential of being used as biological weapons. This makes it imperative to comprehensively study these viruses in order to devise effective strategies to prevent the occurrence of these infections. Entry is the foremost step in the filoviral replication cycle and different studies have reported the involvement of a myriad of cellular factors including plasma membrane components, cytoskeletal proteins, endosomal components, and cytosolic factors in this process. Signaling molecules such as the TAM family of receptor tyrosine kinases comprising of Tyro3, Axl, and Mer have also been implicated as putative entry factors. Additionally, filoviruses are suggested to bind to a common receptor and recent studies have proposed T-cell immunoglobulin and mucin domain 1 (TIM-1) and Niemann-Pick C1 (NPC1) as potential receptor candidates. This paper summarizes the existing literature on filoviral entry with a special focus on cellular factors involved in this process and also highlights some fundamental questions. Future research aimed at answering these questions could be very useful in designing novel antiviral therapeutics. PMID- 23365577 TI - Nanomechanical Characterization of Canine Femur Bone for Strain Rate Sensitivity in the Quasistatic Range under Dry versus Wet Conditions. AB - As a strain rate-dependent material, bone has a different mechanical response to various loads. Our aim was to evaluate the effect of water and different loading/unloading rates on the nanomechanical properties of canine femur cortical bone. Six cross-sections were cut from the diaphysis of six dog femurs and were nanoindented in their cortical area. Both dry and wet conditions were taken into account for three quasistatic trapezoid profiles with a maximum force of 2000 MUN (holding time = 30 s) at loading/unloading rates of 10, 100, and 1000 MUN/s, respectively. For each specimen, 254 +/- 9 (mean +/- SD) indentations were performed under different loading conditions. Significant differences were found for the elastic modulus and hardness between wet and dry conditions (P < 0.001). No influence of the loading/unloading rates was observed between groups except for the elastic modulus measured at 1000 MUN/s rate under dry conditions (P < 0.001) and for the hardness measured at a rate of 10 MUN/s under wet conditions (P < 0.001). Therefore, for a quasistatic test with peak load of 2000 MUN held for 30 s, it is recommended to nanoindent under wet conditions at a loading/unloading rate of 100-1000 MUN/s, so the reduced creep effect allows for a more accurate computation of mechanical properties. PMID- 23365578 TI - Plasma treatment maintains surface energy of the implant surface and enhances osseointegration. AB - The surface energy of the implant surface has an impact on osseointegration. In this study, 2 surfaces: nonwashed resorbable blasting media (NWRBM; control) and Ar-based nonthermal plasma 30 days (Plasma 30 days; experimental), were investigated with a focus on the surface energy. The surface energy was characterized by the Owens-Wendt-Rabel-Kaelble method and the chemistry by X-ray photoelectron spectroscopy (XPS). Five adult beagle dogs received 8 implants (n = 2 per surface, per tibia). After 2 weeks, the animals were euthanized, and half of the implants (n = 20) were removal torqued and the other half were histologically processed (n = 20). The bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO) were evaluated on the histologic sections. The XPS analysis showed peaks of C, Ca, O, and P for the control and experimental surfaces. While no significant difference was observed for BIC parameter (P > 0.75), a higher level for torque (P < 0.02) and BAFO parameter (P < 0.01) was observed for the experimental group. The surface elemental chemistry was modified by the plasma and lasted for 30 days after treatment resulting in improved biomechanical fixation and bone formation at 2 weeks compared to the control group. PMID- 23365579 TI - The bone marrow microenvironment as niche retreats for hematopoietic and leukemic stem cells. AB - Leukemia poses a serious challenge to current therapeutic strategies. This has been attributed to leukemia stem cells (LSCs), which occupy endosteal and sinusoidal niches in the bone marrow similar to those of hematopoietic stem cells (HSCs). The signals from these niches provide a viable setting for the maintenance, survival, and fate specifications of these stem cells. Advancements in genetic engineering and microscopy have enabled us to critically deconstruct and analyze the anatomic and functional characteristics of these niches to reveal a wealth of new knowledge in HSC biology, which is quite ahead of LSC biology. In this paper, we examine the present understanding of the regulatory mechanisms governing HSC niches, with the goals of providing a framework for understanding the mechanisms of LSC regulation and suggesting future strategies for their elimination. PMID- 23365580 TI - Changes of CD4(+) CD25(+) Regulatory T Cells, FoxP3 in Adjuvant Arthritis Rats with Damage of Pulmonary Function and Effects of Tripterygium Glycosides Tablet. AB - Objective. To observe the effects of tripterygium glycosides tablet (TPT) on swelling degree, arthritis index (AI), pulmonary function, cytokines, the expression of regulatory T cells (Treg), and Foxp3 in rats of adjuvant arthritis. Methods. Rats were averagely divided into normal control (NC) group, model control (MC) group, methotrexate (MTX) group, and tripterygium glycosides tablet (TPT) group. Except for the rats of normal group, the others were intracutaneously injected with 0.1 mL of Freund's complete adjuvant in the right hindlimb. NC group and MC group were treated with physiological saline. MTX group and TPT group were treated with MTX, TPT, respectively. Results. The levels of swelling degree, AI, the alveolar inflammation integral, TNF alpha (TNF-alpha), and endothelium-1 (ET-1 ) in MC group were significantly increased (P < 0.01), and the levels of forced vital capacity (FVC), 25% vital capacity of the peak expiratory flow (FEF(25)), 50% vital capacity of the peak expiratory flow (FEF(50)), 75% vital capacity of the peak expiratory flow (FEF(75)), maximum midexpiratory flow (MMF), peak expiratory flow (PEF), interleukin-10 (IL-10), CD4(+) CD25(+) Treg, and Foxp3 were decreased (P < 0.01). The scores of alveolitis and ET-1 were decreased with treatment of TPT. The levels of FVC, FEF(25), FEF(50), FEF(75), MMF, PEF, IL-10, and CD4(+) CD25(+) Treg in peripheral blood were increased. The expressions of Foxp3 protein and mRNA in lung tissue were also increased in TPT group. Conclusions. The paw swelling can be inhibited by TPT, and the inflammatory response in lung tissue was also decreased, which is a significant improvement in pulmonary function. The mechanism is probably associated with upregulating the expression of IL-10, Foxp3, and downregulating the level of TNF-alpha. PMID- 23365581 TI - Optical, spectroscopic, and Doppler evaluation of "normal" and "abnormal" reflexology areas in lumbar vertebral pathology: a case study. AB - Scientific validation of reflexology requires an in-depth and noninvasive evaluation of "reflexology/reflex areas" in health and disease. The present paper reports the differential properties of "normal" and "abnormal" reflexology areas related to the lumbar vertebrae in a subject suffering from low back pain. The pathology is supported by radiological evidence. The reflexology target regions were clinically assessed with respect to colour and tenderness in response to finger pressure. Grey scale luminosity and pain intensity, as assessed by visual analogue scale scores, differentiated "normal" from "abnormal" skin. Skin swept source-optical coherence tomography recorded their structural differences. Infrared thermography revealed temperature variations. A laser Doppler study using a combined microcirculation and transcutaneous oxygen monitoring system indicated alterations in blood flow and oxygen perfusion. Raman spectroscopy showed differences in chemical signatures between these areas. The present findings may indicate a potential correlation between the reflexology areas and subsurface pathological changes, showing an association with the healthy or unhealthy status of the lumbar vertebrae. PMID- 23365582 TI - Omega-3 polyunsaturated Fatty acids enhance neuronal differentiation in cultured rat neural stem cells. AB - Polyunsaturated fatty acids (PUFAs) can induce neurogenesis and recovery from brain diseases. However, the exact mechanisms of the beneficial effects of PUFAs have not been conclusively described. We recently reported that docosahexaenoic acid (DHA) induced neuronal differentiation by decreasing Hes1 expression and increasing p27(kip1) expression, which causes cell cycle arrest in neural stem cells (NSCs). In the present study, we examined the effect of eicosapentaenoic acid (EPA) and arachidonic acid (AA) on differentiation, expression of basic helix-loop-helix transcription factors (Hes1, Hes6, and NeuroD), and the cell cycle of cultured NSCs. EPA also increased mRNA levels of Hes1, an inhibitor of neuronal differentiation, Hes6, an inhibitor of Hes1, NeuroD, and Map2 mRNA and Tuj-1-positive cells (a neuronal marker), indicating that EPA induced neuronal differentiation. EPA increased the mRNA levels of p21(cip1) and p27(kip1), a cyclin-dependent kinase inhibitor, which indicated that EPA induced cell cycle arrest. Treatment with AA decreased Hes1 mRNA but did not affect NeuroD and Map2 mRNA levels. Furthermore, AA did not affect the number of Tuj-1-positive cells or cell cycle progression. These results indicated that EPA could be involved in neuronal differentiation by mechanisms alternative to those of DHA, whereas AA did not affect neuronal differentiation in NSCs. PMID- 23365583 TI - Microcirculatory changes in term newborns with suspected infection: an observational prospective study. AB - Background. In adults severely disturbed microcirculatory flow can be observed by Orthogonal Polarized Spectral (OPS) imaging techniques during sepsis. Therefore we set out to assess for microcirculatory changes in term newborns with suspected early onset infection using OPS. Methods. OPS images were obtained prospectively from the vascular bed of the ear conch and upper arm of 47 newborns on their 1st, 2nd, and 3rd day of life. OPS sequences were analyzed semiquantitatively offline and blinded to clinical status of the infant. Flow in vessels was classified as continuous or noncontinuous flow and given as proportion of total vessels per image as in the studies in adults. Results. The proportion of vessels with continuous flow was significantly lower in the infants with infection (69% [56 81] versus 90% [87-94] (P = 0.0003)). None of the infants with infection was in shock or severely septic. Conclusion. In term neonates the microcirculatory flow is impaired in a large proportion of vessels even in mild to moderate infection. These changes can be observed at the onset of disease at the external ear, an optimal site for microcirculatory measurements in term infants. PMID- 23365585 TI - Peptide-Modulated Activity Enhancement of Acidic Protease Cathepsin E at Neutral pH. AB - Enzymes are regulated by their activation and inhibition. Enzyme activators can often be effective tools for scientific and medical purposes, although they are more difficult to obtain than inhibitors. Here, using the paired peptide method, we report on protease-cathepsin-E-activating peptides that are obtained at neutral pH. These selected peptides also underwent molecular evolution, after which their cathepsin E activation capability improved. Thus, the activators we obtained could enhance cathepsin-E-induced cancer cell apoptosis, which indicated their potential as cancer drug precursors. PMID- 23365584 TI - What do we know of childhood exposures to metals (arsenic, cadmium, lead, and mercury) in emerging market countries? AB - Arsenic, cadmium, lead, and mercury present potential health risks to children who are exposed through inhalation or ingestion. Emerging Market countries experience rapid industrial development that may coincide with the increased release of these metals into the environment. A literature review was conducted for English language articles from the 21st century on pediatric exposures to arsenic, cadmium, lead, and mercury in the International Monetary Fund's (IMF) top 10 Emerging Market countries: Brazil, China, India, Indonesia, Mexico, Poland, Russia, South Korea, Taiwan, and Turkey. Seventy-six peer-reviewed, published studies on pediatric exposure to metals met the inclusion criteria. The reported concentrations of metals in blood and urine from these studies were generally higher than US reference values, and many studies identified adverse health effects associated with metals exposure. Evidence of exposure to metals in the pediatric population of these Emerging Market countries demonstrates a need for interventions to reduce exposure and efforts to establish country-specific reference values through surveillance or biomonitoring. The findings from review of these 10 countries also suggest the need for country-specific public health policies and clinician education in Emerging Markets. PMID- 23365586 TI - Respiratory health effects associated with restoration work in post-Hurricane Katrina New Orleans. AB - BACKGROUND: This study examines prevalence of respiratory conditions in New Orleans-area restoration workers after Hurricane Katrina. METHODS: Between 2007 and 2010, spirometry and respiratory health and occupational questionnaire were administered to 791 New Orleans-area adults who mostly worked in the building construction and maintenance trades or custodial services. The associations between restoration work hours and lung function and prevalence of respiratory symptoms were examined by multiple linear regression, chi2, or multiple logistic regression. RESULTS: 74% of participants performed post-Katrina restoration work (median time: 620 hours). Symptoms reported include episodes of transient fever/cough (29%), sinus symptoms (48%), pneumonia (3.7%), and new onset asthma (4.5%). Prevalence rate ratios for post-Katrina sinus symptoms (PRR = 1.3; CI: 1.1, 1.7) and fever and cough (PRR = 1.7; CI: 1.3, 2.4) were significantly elevated overall for those who did restoration work and prevalence increased with restoration work hours. Prevalence rate ratios with restoration work were also elevated for new onset asthma (PRR = 2.2; CI: 0.8, 6.2) and pneumonia (PRR = 1.3; CI: 0.5, 3.2) but were not statistically significant. Overall, lung function was slightly depressed but was not significantly different between those with and without restoration work exposure. CONCLUSIONS: Post-Katrina restoration work is associated with moderate adverse effects on respiratory health, including sinusitis and toxic pneumonitis. PMID- 23365587 TI - Bacteriological and physicochemical studies on Tigris River near the water purification stations within Baghdad Province. AB - We studied the physical, chemical, and microbiological factors that influence drinking water quality processed from River Tigris, and of the three main drinking water purification stations located at different parts of Tigris River, along with evaluation of drinking water of Al-Shula region in Baghdad city. Water samples were taken monthly from December 2009 to September 2010. Physical and chemical analyses of water included determination of temperature, pH, turbidity, electrical conductivity, total dissolved solids, salinity, dissolved oxygen, and biological oxygen demand. The results of water before and after purification indicated values within the international allowable levels. Microbial analyses included estimation of the number of total viable microbial counts, total coliform, total fecal E. coli and Pseudomonas aeruginosa, and other pathogenic bacteria that might be present in the water of the three stations and of the Tigris River, and also the tap water from Al-Shula houses. The results indicated that the types and proportions of various bacterial species isolated from different water sources were almost similar. This indicates inefficient purification procedures in all the stations studied, which exceeded the internationally allowable level of pathogens in potable water. Also, this explains the high incidence rate of children diarrheal reported in Al-Shula region. PMID- 23365588 TI - Impact of blood sample collection and processing methods on glucose levels in community outreach studies. AB - Glucose obtained from unprocessed blood samples can decrease by 5%-7% per hour due to glycolysis. This study compared the impact of glucose degradation on measured glucose values by examining two different collection methods. For the first method, blood samples were collected in tubes containing sodium fluoride (NaF), a glycolysis inhibitor. For the second method, blood samples were collected in tubes containing a clot activator and serum gel separator and were centrifuged to separate the serum and plasma 20 minutes after sample collection. The samples used in the two methods were collected during the same blood draw and were assayed by the clinical laboratory 2-4 hours after the samples were obtained. A total of 256 pairs of samples were analyzed. The average glucose reading for the centrifuged tubes was significantly higher than the NaF tubes by 0.196 +/- 0.159 mmol/L (P < 0.01) or 4.2%. This study demonstrates the important role collection methods play in accurately assessing glucose levels of blood samples collected in the field, where working environment may be suboptimal. Therefore, blood samples collected in the field should be promptly centrifuged before being transported to clinical labs to ensure accurate glucose level measurements. PMID- 23365590 TI - Triple active antiretroviral regimen including enfuvirtide via the Biojector is effective and safe. AB - For full HIV virological suppression, three fully active antiretroviral agents are required. New drug classes should be included to ensure that agents are fully active. The addition of enfuvirtide and efavirenz to the present patient's new antiretroviral regimen ensured that two fully active agents were in use in the setting of a moderate degree of nucleoside resistance and a high level of protease resistance, and where non-nucleoside reverse transcriptase inhibitors were still fully active. Both viral load and CD4 count responded favourably to this regimen. The patient received support from physicians and clinic staff in the introduction and use of enfuvirtide. To reduce injection site reactions, a needle-free injection system (Biojector) proved effective. PMID- 23365591 TI - Patient care and support measures overcome reluctance to initiate new regimen containing enfuvirtide. AB - Patients can be resistant to initiation of enfuvirtide therapy because of concerns about self-injection and related issues. Because the introduction of a new drug class can substantially enhance the efficacy of an antiretroviral regimen, supporting the patient in the introduction of enfuvirtide, a safe and efficacious agent in a new class, offers therapeutic benefits. In the present patient, who showed resistance to all three of the major antiretroviral drug classes, enfuvirtide was successfully introduced with clinic and peer support group assistance. The patient's acceptance was enhanced by the use of a needle free injection system (Biojector), with minimal side effects and significantly improved virological and immunological control. PMID- 23365592 TI - The clinical cost of delays in switching therapy. AB - Management of the HIV patient with treatment experience continues to improve and evolve. New guidelines suggest that the goal of therapy should be maximal virological suppression. This is best achieved by using combinations of agents to which the virus is most likely to have some susceptibility and, where possible, by using agents within a new therapeutic class. The cases discussed demonstrate how the use of a potent regimen as salvage therapy can have good clinical, immunological and virological outcomes. However, if the salvage regimen selected is not potent enough to achieve these goals, the durability of the response is limited. The key lesson is that these strategies should be built on potency and agents should not be held back in case the strategy fails. PMID- 23365593 TI - Treatment strategy: Role of enfuvirtide in managing treatment-limiting side effects. AB - Side effects can limit the options available to physicians for the treatment of HIV infection. Management of these side effects is essential, to avoid cessation of treatment. The entry inhibitor enfuvirtide can be useful as one of three active agents in an HIV treatment regimen as a way to both reduce treatment limiting side effects and provide an efficacious agent for viral control. In the present case, the patient had a problematic and lengthy treatment history, with numerous concomitant conditions. His latest regimen, which includes an agent in a new drug class (enfuvirtide), has maintained HIV suppression while minimizing toxicity. PMID- 23365589 TI - Guidelines for the prevention and management of community-associated methicillin resistant Staphylococcus aureus: A perspective for Canadian health care practitioners. PMID- 23365594 TI - Challenges in initiating antiretroviral therapy in 2010. AB - Many clinical trials have shown that initiating antiretroviral therapy (ART) at higher rather than lower CD4 T cell-positive counts results in survival benefit. Early treatment can help prevent end-organ damage associated with HIV replication and can decrease infectivity. The mainstay of treatment is either a non nucleoside reverse transcriptase inhibitor or a ritonavir-boosted protease inhibitor in combination with two nucleoside reverse transcriptase inhibitors. While effective at combating HIV, ART can produce adverse alterations of lipid parameters, with some studies suggesting a relationship between some anti retroviral agents and cardiovascular disease. As the HIV-positive population ages, issues such as hypertension and diabetes must be taken into account when initiating ART. Adhering to ART can be difficult; however, nonoptimal adherence to ART can result in the development of resistance; thus, drug characteristics and the patient's preparedness to begin therapy must be considered. Reducing the pill burden through the use of fixed-dose antiretroviral drug combinations can facilitate adherence. PMID- 23365595 TI - The Inhibition of Spinal Astrocytic JAK2-STAT3 Pathway Activation Correlates with the Analgesic Effects of Triptolide in the Rat Neuropathic Pain Model. AB - Neuropathic pain (NP) is an intractable clinical problem without satisfactory treatments. However, certain natural products have been revealed as effective therapeutic agents for the management of pain states. In this study, we used the spinal nerve ligation (SNL) pain model to investigate the antinociceptive effect of triptolide (T10), a major active component of the traditional Chinese herb Tripterygium wilfordii Hook F. Intrathecal T10 inhibited the mechanical nociceptive response induced by SNL without interfering with motor performance. Additionally, the anti-nociceptive effect of T10 was associated with the inhibition of the activation of spinal astrocytes. Furthermore, intrathecal administration of T10 attenuated SNL-induced janus kinase (JAK) signal transducers and activators of transcription 3 (STAT3) signalling pathway activation and inhibited the upregulation of proinflammatory cytokines, such as interleukin-6, interleukin-1 beta, and tumour necrosis factor-alpha, in dorsal horn astrocytes. Moreover, NR2B-containing spinal N-methyl D-aspartate receptor (NMDAR) was subsequently inhibited. Above all, T10 can alleviate SNL-induced NP via inhibiting the neuroinflammation in the spinal dorsal horn. The anti inflammation effect of T10 may be related with the suppression of spinal astrocytic JAK-STAT3 activation. Our results suggest that T10 may be a promising drug for the treatment of NP. PMID- 23365597 TI - Gastroprotective Activity of Polygonum chinense Aqueous Leaf Extract on Ethanol Induced Hemorrhagic Mucosal Lesions in Rats. AB - Polygonum chinense is a Malaysian ethnic plant with various healing effects. This study was to determine preventive effect of aqueous leaf extract of P. chinense against ethanol-induced gastric mucosal injury in rats. Sprague Dawley rats were divided into seven groups. The normal and ulcer control groups were orally administered with distilled water. The reference group was orally administered with 20 mg/kg omeprazole. The experimental groups received the extracts 62.5, 125, 250, and 500 mg/kg, accordingly. After sixty minutes, distilled water and absolute ethanol were given (5 mL/kg) to the normal control and the others, respectively. In addition to histology, immunohistochemical and periodic acid schiff (PAS) stains, levels of lipid peroxidation, malondialdehyde (MDA), antioxidant enzymes, and superoxide dismutase (SOD) were measured. The ulcer group exhibited severe mucosal damages. The experimental groups significantly reduced gastric lesions and MDA levels and increased SOD level. Immunohistochemistry of the experimental groups showed upregulation and downregulation of Hsp70 and Bax proteins, respectively. PAS staining in these groups exhibited intense staining as compared to the ulcer group. Acute toxicity study revealed the nontoxic nature of the extract. Our data provide first evidence that P. chinense extract could significantly prevent gastric ulcer. PMID- 23365598 TI - Syringic Acid Extracted from Herba dendrobii Prevents Diabetic Cataract Pathogenesis by Inhibiting Aldose Reductase Activity. AB - Objective. Effects of Syringic acid (SA) extracted from dendrobii on diabetic cataract (DC) pathogenesis were explored. Methods. Both in vitro and in vivo DC lens models were established using D-gal, and proliferation of HLEC exposed to SA was determined by MMT assay. After 60-day treatment with SA, rat lens transparency was observed by anatomical microscopy using a slit lamp. SA protein targets were extracted and isolated using 2-DE and MALDI TOF/TOF. AR gene expression was investigated using qRT-PCR. Interaction sites and binding characteristics were determined by molecule-docking techniques and dynamic models. Results. Targeting AR, SA provided protection from D-gal-induced damage by consistently maintaining lens transparency and delaying lens turbidity development. Inhibition of AR gene expression by SA was confirmed by qRT-PCR. IC(50) of SA for inhibition of AR activity was 213.17 MUg/mL. AR-SA binding sites were Trp111, His110, Tyr48, Trp20, Trp79, Leu300, and Phe122. The main binding modes involved hydrophobic interactions and hydrogen bonding. The stoichiometric ratio of non-covalent bonding between SA and AR was 1.0 to 13.3. Conclusion. SA acts to prevent DC in rat lenses by inhibiting AR activity and gene expression, which has potential to be developed into a novel drug for therapeutic management of DC. PMID- 23365599 TI - Efficacy and side effects of chinese herbal medicine for menopausal symptoms: a critical review. AB - This study evaluates 23 (9 Chinese and 14 non-Chinese) randomized controlled trials for efficacy and side effects of Chinese herbal medicine on menopausal symptoms. Menopause was diagnosed according to western medicine criteria in all studies while seven Chinese studies and one non-Chinese study further stratified the participants using traditional Chinese medical diagnosis "Zheng differentiation." Efficacy was reported by all 9 Chinese and 9/14 non-Chinese papers. Side effects and adverse events were generally mild and infrequent. Only ten severe adverse events were reported, two with possible association with the therapy. CHM did not increase the endometrial thickness, a common side effect of hormone therapy. None of the studies investigated long-term side effects. Critical analysis revealed that (1) high-quality studies on efficacy of Chinese herbal medicine for menopausal syndrome are rare and have the drawback of lacking traditional Chinese medicine diagnosis (Zheng-differentiation). (2) Chinese herbal medicine may be effective for at least some menopausal symptoms while side effects are likely less than hormone therapy. (3) All these findings need to be confirmed in further well-designed comprehensive studies meeting the standard of evidence-based medicine and including Zheng-differentiation of traditional Chinese medicine. PMID- 23365596 TI - Potential antiosteoporotic agents from plants: a comprehensive review. AB - Osteoporosis is a major health hazard and is a disease of old age; it is a silent epidemic affecting more than 200 million people worldwide in recent years. Based on a large number of chemical and pharmacological research many plants and their compounds have been shown to possess antiosteoporosis activity. This paper reviews the medicinal plants displaying antiosteoporosis properties including their origin, active constituents, and pharmacological data. The plants reported here are the ones which are commonly used in traditional medical systems and have demonstrated clinical effectiveness against osteoporosis. Although many plants have the potential to prevent and treat osteoporosis, so far, only a fraction of these plants have been thoroughly investigated for their physiological and pharmacological properties including their mechanism of action. An attempt should be made to highlight plant species with possible antiosteoporosis properties and they should be investigated further to help with future drug development for treating this disease. PMID- 23365601 TI - Interstitial fluid flow: the mechanical environment of cells and foundation of meridians. AB - Using information from the deep dissection, microobservation, and measurement of acupoints in the upper and lower limbs of the human body, we developed a three dimensional porous medium model to simulate the flow field using FLUENT software and to study the shear stress on the surface of interstitial cells (mast cells) caused by interstitial fluid flow. The numerical simulation results show the following: (i) the parallel nature of capillaries will lead to directional interstitial fluid flow, which may explain the long interstitial tissue channels or meridians observed in some experiments; (ii) when the distribution of capillaries is staggered, increases in the velocity alternate, and the velocity tends to be uniform, which is beneficial for substance exchange; (iii) interstitial fluid flow induces a shear stress, with magnitude of several Pa, on interstitial cell membranes, which will activate cells and lead to a biological response; (iv) capillary and interstitial parameters, such as capillary density, blood pressure, capillary permeability, interstitial pressure, and interstitial porosity, affect the shear stress on cell surfaces. The numerical simulation results suggest that in vivo interstitial fluid flow constitutes the mechanical environment of cells and plays a key role in guiding cell activities, which may explain the meridian phenomena and the acupuncture effects observed in experiments. PMID- 23365600 TI - Inhibition of Activity of GABA Transporter GAT1 by delta-Opioid Receptor. AB - Analgesia is a well-documented effect of acupuncture. A critical role in pain sensation plays the nervous system, including the GABAergic system and opioid receptor (OR) activation. Here we investigated regulation of GABA transporter GAT1 by deltaOR in rats and in Xenopus oocytes. Synaptosomes of brain from rats chronically exposed to opiates exhibited reduced GABA uptake, indicating that GABA transport might be regulated by opioid receptors. For further investigation we have expressed GAT1 of mouse brain together with mouse deltaOR and MUOR in Xenopus oocytes. The function of GAT1 was analyzed in terms of Na(+)-dependent [(3)H]GABA uptake as well as GAT1-mediated currents. Coexpression of deltaOR led to reduced number of fully functional GAT1 transporters, reduced substrate translocation, and GAT1-mediated current. Activation of deltaOR further reduced the rate of GABA uptake as well as GAT1-mediated current. Coexpression of MUOR, as well as MUOR activation, affected neither the number of transporters, nor rate of GABA uptake, nor GAT1-mediated current. Inhibition of GAT1-mediated current by activation of deltaOR was confirmed in whole-cell patch-clamp experiments on rat brain slices of periaqueductal gray. We conclude that inhibition of GAT1 function will strengthen the inhibitory action of the GABAergic system and hence may contribute to acupuncture-induced analgesia. PMID- 23365602 TI - Stimulation of TRPV1 by Green Laser Light. AB - Low-level laser irradiation of visible light had been introduced as a medical treatment already more than 40 years ago, but its medical application still remains controversial. Laser stimulation of acupuncture points has also been introduced, and mast-cells degranulation has been suggested. Activation of TRPV ion channels may be involved in the degranulation. Here, we investigated whether TRPV1 could serve as candidate for laser-induced mast cell activation. Activation of TRPV1 by capsaicin resulted in degranulation. To investigate the effect of laser irradiation on TRPV1, we used the Xenopus oocyte as expression and model system. We show that TRPV1 can functionally be expressed in the oocyte by (a) activation by capsaicin (K(1/2) = 1.1 MUM), (b) activation by temperatures exceeding 42 degrees C, (c) activation by reduced pH (from 7.4 to 6.2), and (d) inhibition by ruthenium red. Red (637 nm) as well as blue (406 nm) light neither affected membrane currents in oocytes nor did it modulate capsaicin-induced current. In contrast, green laser light (532 nm) produced power-dependent activation of TRPV1. In conclusion, we could show that green light is effective at the cellular level to activate TRPV1. To which extend green light is of medical relevance needs further investigation. PMID- 23365603 TI - Inhibitory Activities of Cudrania tricuspidata Leaves on Pancreatic Lipase In Vitro and Lipolysis In Vivo. AB - To identify effective herb to treat obesity, we screened 115 herbal extracts for inhibition of porcine pancreatic lipase (triacylg-ycerol acylhydrolase, EC 3.1.1.3) activity in vitro. Of the extracts tested, Cudrania tricuspidata leaves exhibited the most pronounced inhibitory effect on lipase activity with an IC(50) value of 9.91 MUg/mL. Antilipid absorption effects of C. tricuspidata leaves were examined in rats after oral administration of lipid emulsions containing 50 or 250 mg C. tricuspidata/kg body weight. Plasma triacylglycerol levels 2 h after the oral administration of emulsions containing C. tricuspidata were significantly reduced compared to the untreated group (P < 0.05). These results suggest that C. tricuspidata leaves may be useful for the treatment of obesity. PMID- 23365604 TI - In Vivo and In Vitro Antinociceptive Effect of Fagopyrum cymosum (Trev.) Meisn Extracts: A Possible Action by Recovering Intestinal Barrier Dysfunction. AB - Fagopyrum cymosum (Trev.) Meisn (Fag) is a herb rhizome which has been widely used to treat diseases. To investigate the effects and mechanisms of the Fag on irritable bowel syndrome (IBS), in vivo neonatal pups maternal separation (NMS) combined with intracolonic infusion of acetic acid (AA) was employed to establish IBS rat models. Fag reduced their visceral hyperalgesia and the whole gut permeability, ameliorated colonic mucosa inflammation and injury, and upregulated the expression of decreased tight junction proteins (TJs) of claudin-1, occludin, and ZO-1 (except ZO-2) in colonic epithelium. Caco-2 monolayer cells were incubated with TNF-alpha and IFN-gamma in vitro to establish an epithelial barrier dysfunction model whose transepithelial electrical resistance (TER) depended more on dose of Fag than that of the controls, and whose TJs levels were lower than those of the controls. Fag upregulated the NP-40 insoluble and soluble components of the four TJs markedly in a dose-dependent manner. These data suggest that Fag alleviated the hyperalgesia of IBS rats by reducing intestinal inflammation and enhancing mucosal epithelial function after regulating the structure and function of TJs. PMID- 23365605 TI - Does propolis help to maintain oral health? AB - Propolis, known also as bee glue, is a wax-cum-resin substance which is created out of a mix of buds from some trees with the substance secreted from bee's glands. Its diverse chemical content is responsible for its many precious salubrious properties. It was used in medicine already in ancient Egypt. Its multiple applications during the centuries have been studied and described in details. The purpose of this study is to present the possible use of propolis in treatment of various diseases of oral cavity in their dental aspect. The paper presents properties and possible applications of bee glue depending on dental specialities. An overview of publications which appeared during the recent years will allow the reader to follow all the possibilities to apply propolis in contemporary dentistry. PMID- 23365606 TI - The Effect of Elephantopus scaber L. on Liver Regeneration after Partial Hepatectomy. AB - Liver regeneration after partial hepatectomy (PHx) is a physiological response for maintaining homeostasis. The aim of this study is to investigate effects of Elephantopus scaber L.- (ESL-) induced liver regeneration on growth factors (HGF and IGF-1), cell cycle regulation, and apoptosis suppressed. In this study, we fed five Chinese medicinal herbs (1 g/kg/day), Codonopsis pilosula (CP, Dangshen), Salvia miltiorrhiza Bunge (SMB, Danshen,), Bupleurum kasi (BK, Chaihu), Elephantopus scaber L. (ESL, Teng-Khia-U), and Silymarin (Sm, 25 mg/kg) for 7 days to male Spraue-Dawley rats. Then surgical 2/3 PHx was conducted and liver regeneration mechanisms were estimated on the following 24 hrs and 72 hrs. The activities of growth factors (HGF and IGF-I) and cell cycle proteins were measured by Western blot and RT-PCR. Histological analysis and apoptosis were detected by H&E stain and TUNEL. The results showed that extraction of Elephantopus scaber L. (ESL) and Silymarin (Sm, positive control) were increased protein expression levels of HGF and IGF-1 which leads into cell cycle. These results suggest that the ESL plays a crucial role in cell cycle-induced liver regeneration and apoptosis. These results suggested that the ESL plays a crucial role in cell cycle-induced liver regeneration and suppressed hepatocytes apoptosis. PMID- 23365607 TI - Antimicrobial Potential and Chemical Characterization of Serbian Liverwort (Porella arboris-vitae): SEM and TEM Observations. AB - The chemical composition of Porella arboris-vitae extracts was determined by solid phase microextraction, gas chromatography-mass spectrometry (SPME GC-MS), and 66 constituents were identified. The dominant compounds in methanol extract of P. arboris-vitae were beta-caryophyllene (14.7%), alpha-gurjunene (10.9%), alpha-selinene (10.8%), beta-elemene (5.6%), gamma-muurolene (4.6%), and allo aromadendrene (4.3%) and in ethanol extract, beta-caryophyllene (11.8%), alpha selinene (9.6%), alpha-gurjunene (9.4%), isopentyl alcohol (8.8%), 2-hexanol (3.7%), beta-elemene (3.7%), allo-aromadendrene (3.7%), and gamma-muurolene (3.3%) were the major components. In ethyl acetate extract of P. arboris-vitae, undecane (11.3%), beta-caryophyllene (8.4%), dodecane (6.4%), alpha-gurjunene (6%), 2-methyldecane (5.1%), hemimellitene (4.9%), and D-limonene (3.9%) were major components. The antimicrobial activity of different P. arboris-vitae extracts was evaluated against selected food spoilage microorganisms using microbroth dilution method. The Minimal Inhibitory Concentration (MIC) varied from 0.5 to 1.5 mg/mL and 1.25 to 2 mg/mL for yeast and bacterial strains, respectively. Significant morphological and ultrastructural alterations due to the effect of methanolic and ethanolic P. arboris-vitae extracts on S. Enteritidis have also been observed by scanning electron microscope and transmission electron microscope, respectively. The results provide the evidence of antimicrobial potential of P. arboris-vitae extracts and suggest its potential as natural antimicrobial agents for food preservation. PMID- 23365608 TI - Objectifying specific and nonspecific effects of acupuncture: a double-blinded randomised trial in osteoarthritis of the knee. AB - Introduction. Acupuncture was recently shown to be effective in the treatment of knee osteoarthritis. However, controversy persists whether the observed effects are specific to acupuncture or merely nonspecific consequences of needling. Therefore, the objective of this study is to determine the efficacy of different acupuncture treatment modalities. Materials and Methods. We compared between three different forms of acupuncture in a prospective randomised trial with a novel double-blinded study design. One-hundred and sixteen patients aged from 35 to 82 with osteoarthritis of the knee were enrolled in three study centres. Interventions were individualised classical/ modern semistandardised acupuncture and non-specific needling. Blinded outcome assessment comprised knee flexibility and changes in pain according to the WOMAC score. Results and Discussion. Improvement in knee flexibility was significantly higher after classical Chinese acupuncture (10.3 degrees; 95% CI 8.9 to 11.7) as compared to modern acupuncture (4.7 degrees; 3.6 to 5.8). All methods achieved pain relief, with a patient response rate of 48 percent for non-specific needling, 64 percent for modern acupuncture, and 73 percent for classical acupuncture. Conclusion. This trial establishes a novel study design enabling double blinding in acupuncture studies. The data suggest a specific effect of acupuncture in knee mobility and both non specific and specific effects of needling in pain relief. PMID- 23365609 TI - Antiobesity Effects of the Ethanol Extract of Laminaria japonica Areshoung in High-Fat-Diet-Induced Obese Rat. AB - Laminaria japonica Areshoung, a widely consumed marine vegetable, has traditionally been used in Korean maternal health. The present study investigated the antiobesity effects of Laminaria japonica Areshoung ethanol extract (LE) and its molecular mechanism in high-fat-diet-induced obese rats. Six-week-old Sprague Dawley male rats were separately fed a normal diet or a high-calorie high-fat diet for 6 weeks; then they were treated with LE or tea catechin for another 6 weeks. LE administration significantly decreased the body weight gain, fat-pad weights, and serum and hepatic lipid levels in HD-induced obese rats. The histological analysis revealed that LE-treated group showed a significantly decreased number of lipid droplets and size of adipocytes compared to the HD group. To elucidate the mechanism of action of LE, the levels of genes and proteins involved in obesity were measured in the liver and skeletal muscle. LE treatment resulted in an increased expression of fatty acid oxidation and thermogenesis-related genes in obese rats. Conversely, the expression of the fat intake-related gene (ACC2) and lipogenesis-related genes was reduced by LE treatment. Additionally, LE treatment increased the phosphorylation of AMP activated protein kinase and its direct downstream protein, acetyl coenzyme A carboxylase, which is one of the rate-limiting enzymes in fatty acid synthesis pathway. These findings demonstrate that LE treatment has a protective effect against a high-fat-diet-induced obesity in rats through regulation of expression of genes and proteins involved in lipolysis and lipogenesis. PMID- 23365610 TI - Acetonic and Methanolic Extracts of Heterotheca inuloides, and Quercetin, Decrease CCl(4)-Oxidative Stress in Several Rat Tissues. AB - The present study was designed to test the hypothesis that the acetonic and methanolic extracts of H. inuloides prevent carbon tetrachloride-(CCl(4)) induced oxidative stress in vital tissues. Pretreatment with both H. inuloides extracts or quercetin attenuated the increase in serum activity of alkaline phosphatase (ALP), total bilirubin (BB), creatinine (CRE), and creatine kinase (CK), and impeded the decrease of gamma-globulin (gamma-GLOB) and albumin (ALB) observed in CCl(4)-induced tissue injury. The protective effect was confirmed by histological analysis with hematoxylin-eosin and periodic acid/Schiff's reagent. Level of lipid peroxidation was higher in the organs of rats exposed to CCl(4) than in those of the animals treated with Heterohteca extracts or quercetin, and these showed levels similar to the untreated group. Pretreatment of animals with either of the extracts or quercetin also prevented the increase of 4-hydroxynonenal and 3-nitrotyrosine. Pretreatment with the plant extracts or quercetin attenuated CCl(4) toxic effects on the activity of several antioxidant enzymes. The present results strongly suggest that the chemopreventive effect of the extracts used and quercetin, against CCl(4) toxicity, is associated with their antioxidant properties and corroborated previous results obtained in liver tissue. PMID- 23365611 TI - Antidepressive-Like Property of Dichloromethane Fraction of Pimenta pseudocaryophyllus and Relevance of Monoamine Metabolic Enzymes. AB - Pimenta pseudocaryophyllus popularly referred to as craveiro is considered as a calming agent in different local preparations. The present study attempted to examine antidepressant-like effect of dichloromethane fraction (DF) and role of monoamine oxidase (MAO), tryptophan, and tyrosine hydroxylase. Based on the research focus, tail suspension (TS), forced swimming (FS), and open field (OF) tests were conducted after oral administration of DF (125, 250, or 500 mg/Kg). Ex vivo assay of MAO was also conducted to evaluate inhibitory effect of DF (250 mg/Kg). Administration of DF elicits antidepressant-like response in the TS and FS. However, DF 500 mg/Kg did not alter mice performance in these models. The data obtained in the OF showed a reduction in total crossing and rearing activity; these effects suggest motor interference in TS and FS performance. Mice pretreatment with p-chlorophenylalanine methyl ester (PCPA) (100 mg/kg, i.p. serotonin biosynthesis inhibitor) for 4 consecutive days or acute administration of alpha-methyl-p-tyrosine (AMPT) (100 mg/kg, i.p.-catecholamine synthesis inhibitor) blocked anti-immobility effect of DF in the FS. In ex vivo assay of MAO, DF did not inhibit catabolic activity of MAO. Our findings support antidepressant-like activity of DF and suggest an effect that depends on monoamine biosynthesis. PMID- 23365612 TI - Add-on effect of chinese herbal medicine on mortality in myocardial infarction: systematic review and meta-analysis of randomized controlled trials. AB - In China, Chinese herbal medicine (CHM) is widely used as an adjunct to biomedicine (BM) in treating myocardial infarction (MI). This meta-analysis of RCTs evaluated the efficacy of combined CHM-BM in the treatment of MI, compared to BM alone. Sixty-five RCTs (12,022 patients) of moderate quality were identified. 6,036 patients were given CHM plus BM, and 5,986 patients used BM only. Combined results showed clear additional effect of CHM-BM treatment in reducing all-cause mortality (relative risk reduction (RRR) = 37%, 95% CI = 28% 45%, I(2) = 0.0%) and mortality of cardiac origin (RRR = 39%, 95% CI = 22%-52%, I(2) = 22.8). Benefits remained after random-effect trim and fill adjustment for publication bias (adjusted RRR for all-cause mortality = 29%, 95% CI = 16%-40%; adjusted RRR for cardiac death = 32%, 95% CI = 15%-46%). CHM is also found to be efficacious in lowering the risk of fatal and nonfatal cardiogenic shock, cardiac arrhythmia, myocardial reinfarction, heart failure, angina, and occurrence of total heart events. In conclusion, addition of CHM is very likely to be able to improve survival of MI patients who are already receiving BM. Further confirmatory evaluation via large blinded randomized trials is warranted. PMID- 23365613 TI - Antitumor Effect of Periplocin in TRAIL-Resistant Human Hepatocellular Carcinoma Cells through Downregulation of IAPs. AB - Cortex periplocae is the dried root bark of Periploca sepium Bge., a traditional Chinese herb medicine. It contains high amounts of cardiac glycosides. Several cardiac glycosides have been reported to inhibit tumor growth or induce tumor cell apoptosis. We extracted and purified cortex periplocae and identified periplocin as the active ingredient that inhibited the growth of TNF-related apoptosis-inducing ligand-(TRAIL-) resistant hepatocellular carcinoma cells. The antitumor activity of periplocin was further increased by TRAIL cotreatment. Periplocin sensitized TRAIL-resistant HCC through the following two mechanisms. First, periplocin induced the expression of DR4 and FADD. Second, the cotreatment of TRAIL and periplocin suppressed several inhibitors of apoptosis (IAPs). Both mechanisms resulted in the activation of caspase 3, 8, and 9 and led to cell apoptosis. In addition, intraperitoneal injection (IP) of periplocin repressed the growth of hepatocellular carcinoma (HCC) in xenograft tumor model in mice. In summary, periplocin sensitized TRAIL-resistant HCC cells to TRAIL treatment and resulted in tumor cell apoptosis and the repression of tumor growth in vivo. PMID- 23365614 TI - Oat Attenuation of Hyperglycemia-Induced Retinal Oxidative Stress and NF-kappaB Activation in Streptozotocin-Induced Diabetic Rats. AB - The overproduction of reactive oxygen species (ROS) plays a central role in the pathogenesis of endothelial damage in diabetes. To assess the effect of oat on experimental diabetic retinopathy, five groups of Albino rats were studied: nondiabetic control, untreated diabetic, and diabetic rats treated with 5%, 10%, and 20% (W/W) oat of the diet for 12 weeks. Novel data were obtained in this study indicating a protective role of oat against oxidative stress and diabetic retinopathy. The effects of oat on parameters of oxidative stress, AGE, and nuclear factor kappa B (NF-kappaB) were assessed by ELISA and NF-kappaB activation by electrophoretic mobility shift assay. Tumor necrosis factor alpha (TNFalpha) and vascular endothelial growth factor (VEGF) were also determined. After 12 weeks of diabetes, oat treatment reduced blood glucose levels, HbA1c, all oxidative stress markers, CML, normalized NF-kappaB activation and TNFalpha expression. Furthermore it reduced VEGF in the diabetic retina by 43% (P < 0.001). In conclusion, oat modulates microvascular damage through normalized pathways downstream of ROS overproduction and reduction of NF-kappaB and its controlled genes activation, which may provide additional endothelial protection. PMID- 23365615 TI - Self-adaptive image reconstruction inspired by insect compound eye mechanism. AB - Inspired by the mechanism of imaging and adaptation to luminosity in insect compound eyes (ICE), we propose an ICE-based adaptive reconstruction method (ARM ICE), which can adjust the sampling vision field of image according to the environment light intensity. The target scene can be compressive, sampled independently with multichannel through ARM-ICE. Meanwhile, ARM-ICE can regulate the visual field of sampling to control imaging according to the environment light intensity. Based on the compressed sensing joint sparse model (JSM-1), we establish an information processing system of ARM-ICE. The simulation of a four channel ARM-ICE system shows that the new method improves the peak signal-to noise ratio (PSNR) and resolution of the reconstructed target scene under two different cases of light intensity. Furthermore, there is no distinct block effect in the result, and the edge of the reconstructed image is smoother than that obtained by the other two reconstruction methods in this work. PMID- 23365616 TI - Assessing the effects of estrogen on the dynamics of breast cancer. AB - Worldwide, breast cancer has become the second most common cancer in women. The disease has currently been named the most deadly cancer in women but little is known on what causes the disease. We present the effects of estrogen as a risk factor on the dynamics of breast cancer. We develop a deterministic mathematical model showing general dynamics of breast cancer with immune response. This is a four-population model that includes tumor cells, host cells, immune cells, and estrogen. The effects of estrogen are then incorporated in the model. The results show that the presence of extra estrogen increases the risk of developing breast cancer. PMID- 23365617 TI - A 3D visualization method for bladder filling examination based on EIT. AB - As the researches of electric impedance tomography (EIT) applications in medical examinations deepen, we attempt to produce the visualization of 3D images of human bladder. In this paper, a planar electrode array system will be introduced as the measuring platform and a series of feasible methods are proposed to evaluate the simulated volume of bladder to avoid overfilling. The combined regularization algorithm enhances the spatial resolution and presents distinguishable sketch of disturbances from the background, which provides us with reliable data from inverse problem to carry on to the three-dimensional reconstruction. By detecting the edge elements and tracking down the lost information, we extract quantitative morphological features of the object from the noises and background. Preliminary measurements were conducted and the results showed that the proposed algorithm overcomes the defects of holes, protrusions, and debris in reconstruction. In addition, the targets' location in space and roughly volume could be calculated according to the grid of finite element of the model, and this feature was never achievable for the previous 2D imaging. PMID- 23365618 TI - Locomotor development prediction based on statistical model parameters identification. AB - This paper introduces an approach for parameters identification of a statistical predicting model with the use of the available individual data. Unknown parameters are separated into two groups: the ones specifying the average trend over large set of individuals and the ones describing the details of a concrete person. In order to calculate the vector of unknown parameters, a multidimensional constrained optimization problem is solved minimizing the discrepancy between real data and the model prediction over the set of feasible solutions. Both the individual retrospective data and factors influencing the individual dynamics are taken into account. The application of the method for predicting the movement of a patient with congenital motility disorders is considered. PMID- 23365619 TI - Bayes clustering and structural support vector machines for segmentation of carotid artery plaques in multicontrast MRI. AB - Accurate segmentation of carotid artery plaque in MR images is not only a key part but also an essential step for in vivo plaque analysis. Due to the indistinct MR images, it is very difficult to implement the automatic segmentation. Two kinds of classification models, that is, Bayes clustering and SSVM, are introduced in this paper to segment the internal lumen wall of carotid artery. The comparative experimental results show the segmentation performance of SSVM is better than Bayes. PMID- 23365620 TI - Modeling innate immune response to early Mycobacterium infection. AB - In the study of complex patterns in biology, mathematical and computational models are emerging as important tools. In addition to experimental approaches, these modeling tools have recently been applied to address open questions regarding host-pathogen interaction dynamics, including the immune response to mycobacterial infection and tuberculous granuloma formation. We present an approach in which a computational model represents the interaction of the Mycobacterium infection with the innate immune system in zebrafish at a high level of abstraction. We use the Petri Net formalism to model the interaction between the key host elements involved in granuloma formation and infection dissemination. We define a qualitative model for the understanding and description of causal relations in this dynamic process. Complex processes involving cell-cell or cell-bacteria communication can be modeled at smaller scales and incorporated hierarchically into this main model; these are to be included in later elaborations. With the infection mechanism being defined on a higher level, lower-level processes influencing the host-pathogen interaction can be identified, modeled, and tested both quantitatively and qualitatively. This systems biology framework incorporates modeling to generate and test hypotheses, to perform virtual experiments, and to make experimentally verifiable predictions. Thereby it supports the unraveling of the mechanisms of tuberculosis infection. PMID- 23365621 TI - Application of seemingly unrelated regression in medical data with intermittently observed time-dependent covariates. AB - BACKGROUND. In many studies with longitudinal data, time-dependent covariates can only be measured intermittently (not at all observation times), and this presents difficulties for standard statistical analyses. This situation is common in medical studies, and methods that deal with this challenge would be useful. METHODS. In this study, we performed the seemingly unrelated regression (SUR) based models, with respect to each observation time in longitudinal data with intermittently observed time-dependent covariates and further compared these models with mixed-effect regression models (MRMs) under three classic imputation procedures. Simulation studies were performed to compare the sample size properties of the estimated coefficients for different modeling choices. RESULTS. In general, the proposed models in the presence of intermittently observed time dependent covariates showed a good performance. However, when we considered only the observed values of the covariate without any imputations, the resulted biases were greater. The performances of the proposed SUR-based models in comparison with MRM using classic imputation methods were nearly similar with approximately equal amounts of bias and MSE. CONCLUSION. The simulation study suggests that the SUR-based models work as efficiently as MRM in the case of intermittently observed time-dependent covariates. Thus, it can be used as an alternative to MRM. PMID- 23365622 TI - The value of private patient information in the physician-patient relationship: a game-theoretic account. AB - This paper presents a game-theoretical model of the physician-patient relationship. There is a conflict of interests between physician and patient, in that the physician prefers the patient to always obtain a particular treatment, even if the patient would not consider this treatment in his interest. The patient obtains imperfect cues of whether or not he needs the treatment. The effect of an increase in the quality of the patient's private information is studied, in the form of an improvement in the quality of his cues. It is shown that when the patient's information improves in this sense, he may either become better off or worse off. The precise circumstances under which either result is obtained are derived. PMID- 23365623 TI - Two-dimensional matrix algorithm using detrended fluctuation analysis to distinguish Burkitt and diffuse large B-cell lymphoma. AB - A detrended fluctuation analysis (DFA) method is applied to image analysis. The 2 dimensional (2D) DFA algorithms is proposed for recharacterizing images of lymph sections. Due to Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), there is a significant different 5-year survival rates after multiagent chemotherapy. Therefore, distinguishing the difference between BL and DLBCL is very important. In this study, eighteen BL images were classified as group A, which have one to five cytogenetic changes. Ten BL images were classified as group B, which have more than five cytogenetic changes. Both groups A and B BLs are aggressive lymphomas, which grow very fast and require more intensive chemotherapy. Finally, ten DLBCL images were classified as group C. The short term correlation exponent alpha1 values of DFA of groups A, B, and C were 0.370 +/- 0.033, 0.382 +/- 0.022, and 0.435 +/- 0.053, respectively. It was found that alpha1 value of BL image was significantly lower (P < 0.05) than DLBCL. However, there is no difference between the groups A and B BLs. Hence, it can be concluded that alpha1 value based on DFA statistics concept can clearly distinguish BL and DLBCL image. PMID- 23365624 TI - A modified amino acid network model contains similar and dissimilar weight. AB - For a more detailed description of the interaction between residues, this paper proposes an amino acid network model, which contains two types of weight--similar weight and dissimilar weight. The weight of the link is based on a self consistent statistical contact potential between different types of amino acids. In this model, we can get a more reasonable representation of the distance between residues. Furthermore, with the network parameter, average shortest path length, we can get a more accurate reflection of the molecular size. This amino acid network is a "small-world" network, and the network parameter is sensitive to the conformation change of protein. For some disease-related proteins, the highly central residues of the amino acid network are highly correlated with the hot spots. In the compound with the related drug, these residues either interacted directly with the drug or with the residue which is in contact with the drug. PMID- 23365626 TI - S-Fluorenylmethyl protection of the cysteine side chain upon N(alpha)-Fmoc deprotection. AB - Deprotection of an N(alpha)-Fmoc-protected glycocysteine derivative 7 with an excess of morpholine unexpectedly led to the fluorenylmethyl-protected thioether 8 in high yield. The suggested mechanism for this reaction comprises the addition of the cysteine thiolate on the exocyclic double bond of dibenzofulvene, which is formed during Fmoc deprotection. The influence of base concentration on this transprotection reaction was studied. PMID- 23365625 TI - Efficient identification of transcription factor binding sites with a graph theoretic approach. AB - Identifying transcription factor binding sites with experimental methods is often expensive and time consuming. Although many computational approaches and tools have been developed for this problem, the prediction accuracy is not satisfactory. In this paper, we develop a new computational approach that can model the relationships among all short sequence segments in the promoter regions with a graph theoretic model. Based on this model, finding the locations of transcription factor binding site is reduced to computing maximum weighted cliques in a graph with weighted edges. We have implemented this approach and used it to predict the binding sites in two organisms, Caenorhabditis elegans and mus musculus. We compared the prediction accuracy with that of the Gibbs Motif Sampler. We found that the accuracy of our approach is higher than or comparable with that of the Gibbs Motif Sampler for most of tested data and can accurately identify binding sites in cases where the Gibbs Motif Sampler has difficulty to predict their locations. PMID- 23365627 TI - Hydrophobic analogues of rhodamine B and rhodamine 101: potent fluorescent probes of mitochondria in living C. elegans. AB - Mitochondria undergo dynamic fusion and fission events that affect the structure and function of these critical energy-producing cellular organelles. Defects in these dynamic processes have been implicated in a wide range of human diseases including ischemia, neurodegeneration, metabolic disease, and cancer. To provide new tools for imaging of mitochondria in vivo, we synthesized novel hydrophobic analogues of the red fluorescent dyes rhodamine B and rhodamine 101 that replace the carboxylate with a methyl group. Compared to the parent compounds, methyl analogues termed HRB and HR101 exhibit slightly red-shifted absorbance and emission spectra (5-9 nm), modest reductions in molar extinction coefficent and quantum yield, and enhanced partitioning into octanol compared with aqueous buffer of 10-fold or more. Comparison of living C. elegans (nematode roundworm) animals treated with the classic fluorescent mitochondrial stains rhodamine 123, rhodamine 6G, and rhodamine B, as well as the structurally related fluorophores rhodamine 101, and basic violet 11, revealed that HRB and HR101 are the most potent mitochondrial probes, enabling imaging of mitochondrial motility, fusion, and fission in the germline and other tissues by confocal laser scanning microscopy after treatment for 2 h at concentrations as low as 100 picomolar. Because transgenes are poorly expressed in the germline of these animals, these small molecules represent superior tools for labeling dynamic mitochondria in this tissue compared with the expression of mitochondria-targeted fluorescent proteins. The high bioavailabilty of these novel fluorescent probes may facilitate the identification of agents and factors that affect diverse aspects of mitochondrial biology in vivo. PMID- 23365628 TI - Reactions of salicylaldehyde and enolates or their equivalents: versatile synthetic routes to chromane derivatives. AB - The reported methodologies for the synthesis of chromane derivatives through the reaction of salicylaldehyde and enolates are discussed. The enolates and their equivalents involved in the reactions discussed in this article were derived from ketones, nitroalkanes, malononitrile and alpha,beta-unsaturated compounds. PMID- 23365629 TI - Theoretical study on beta-cyclodextrin inclusion complexes with propiconazole and protonated propiconazole. AB - The synthesis of the beta-cyclodextrin/propiconazole nitrate inclusion complex and the advantages of the encapsulation of this drug were recently reported, but the experimental data only partially revealed the structure of the supramolecular complex due to the limitations in understanding the intermolecular association mechanism. The present work describes the equilibrium molecular geometries of beta-cyclodextrin/propiconazole and beta-cyclodextrin/protonated propiconazole, established by the AM1 and PM3 semi-empirical methods. The affinity between different parts of the guest molecule and the cyclodextrin cavity was studied considering that propiconazole possesses three residues able to be included into the host cavity through primary or secondary hydroxyl rims. The results have revealed that the most stable complex is formed when the azole residue of the propiconazole enters the cavity of the cyclodextrin through the narrow hydroxyl's rim. PMID- 23365630 TI - Stereoselective synthesis of tetrasubstituted alkenes via a sequential carbocupration and a new sulfur-lithium exchange. AB - We have designed a new sequential carbocupration and sulfur-lithium exchange that leads stereo- and regioselectively to trisubstituted alkenyllithiums. Subsequent trapping with various electrophiles yields tetrasubstituted olefins with good control of the double-bond geometry (E/Z ratio up to 99:1). The novel sulfur lithium exchange could be extended to the stereoselective preparation of Z-styryl lithium derivatives with almost complete retention of the double-bond geometry. PMID- 23365631 TI - Highly stereocontrolled synthesis of trans-enediynes via carbocupration of fluoroalkylated diynes. AB - Treatment of readily prepared (Z)-6-benzyloxy-1,1,1,2-tetrafluoro-6-methyl-2 hepten-4-yne with 1.5 equiv of LHMDS in -78 degrees C for 1 h gave the corresponding trifluoromethylated diyne in an excellent yield. This diyne was found to be a good substrate for the carbocupration with various higher-ordered cyanocuprates to give the corresponding vinylcuprates in a highly regio- and stereoselective manner. The in situ generated vinylcuprates could react very smoothly with an excess amount of iodine, the vinyl iodides being obtained in high yields. Thus-obtained iodides underwent a very smooth Sonogashira cross coupling reaction to afford various trans-enediynes in high yields. PMID- 23365632 TI - Intramolecular carbolithiation of N-allyl-ynamides: an efficient entry to 1,4 dihydropyridines and pyridines - application to a formal synthesis of sarizotan. AB - We have developed a general synthesis of polysubstituted 1,4-dihydropyridines and pyridines based on a highly regioselective lithiation/6-endo-dig intramolecular carbolithiation from readily available N-allyl-ynamides. This reaction, which has been successfully applied to the formal synthesis of the anti-dyskinesia agent sarizotan, further extends the use of ynamides in organic synthesis and further demonstrates the synthetic efficiency of carbometallation reactions. PMID- 23365633 TI - Dipyrazolo[1,5-a:4',3'-c]pyridines - a new heterocyclic system accessed via multicomponent reaction. AB - The synthesis of dipyrazolo[1,5-a:4',3'-c]pyridines is described. Easily obtainable 5-alkynylpyrazole-4-carbaldehydes, p-toluenesulfonyl hydrazide, and an aldehyde or ketone containing an alpha-hydrogen atom were reacted in a silver triflate catalyzed multicomponent reaction affording new tricyclic compounds with a dipyrazolo[1,5-a:4',3'-c]pyridine core. Detailed NMR spectroscopic investigations ((1)H, (13)C and (15)N) were undertaken with all obtained compounds. PMID- 23365634 TI - Genistein sensitizes bladder cancer cells to HCPT treatment in vitro and in vivo via ATM/NF-kappaB/IKK pathway-induced apoptosis. AB - Bladder cancer is the most common malignant urological disease in China. Hydroxycamptothecin (HCPT) is a DNA topoisomerase I inhibitor, which has been utilized in chemotherapy for bladder cancer for nearly 40 years. Previous research has demonstrated that the isoflavone, genistein, can sensitize multiple cancer cell lines to HCPT treatment, such as prostate and cervical cancer. In this study, we investigated whether genistein could sensitize bladder cancer cell lines and bladder epithelial cell BDEC cells to HCPT treatment, and investigated the possible underlying molecular mechanisms. Genistein could significantly and dose-dependently sensitize multiple bladder cancer cell lines and BDEC cells to HCPT-induced apoptosis both in vitro and in vivo. Genistein and HCPT synergistically inhibited bladder cell growth and proliferation, and induced G2/M phase cell cycle arrest and apoptosis in TCCSUP bladder cancer cell and BDEC cell. Pretreatment with genistein sensitized BDEC and bladder cancer cell lines to HCPT-induced DNA damage by the synergistic activation of ataxia telangiectasia mutated (ATM) kinase. Genistein significantly attenuated the ability of HCPT to induce activation of the anti-apoptotic NF-kappaB pathway both in vitro and in vivo in a bladder cancer xenograft model, and thus counteracted the anti apoptotic effect of the NF-kappaB pathway. This study indicates that genistein could act as a promising non-toxic agent to improve efficacy of HCPT bladder cancer chemotherapy. PMID- 23365635 TI - Pediatric invasive pneumococcal disease caused by vaccine serotypes following the introduction of conjugate vaccination in Denmark. AB - A seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the Danish childhood immunization program (2+1 schedule) in October 2007, followed by PCV13 starting from April 2010. The nationwide incidence of IPD among children younger than 5 years nearly halved after the introduction of PCV7 in the program, mainly due to a decline in IPD caused by PCV7-serotypes. We report the results from a nationwide population-based cohort study of laboratory confirmed IPD cases in children younger than 5 years during October 1, 2007 to December 31, 2010 and describe the characteristics of children suspected to present with a vaccine failure. The period between April 19 and December 31, 2010 was considered a PCV7/PCV13 transitional period, where both vaccines were offered. We identified 45 episodes of IPD caused by a PCV7 serotype (23% of the total number) and 105 (55%) caused by one of the 6 additional serotypes in PCV13. Ten children had received at least one PCV7 dose before the onset of IPD caused by a PCV7 serotype. Seven children were considered to be incompletely vaccinated before IPD, but only three cases fulfilled the criteria of vaccine failure (caused by serotypes 14, 19F and 23F). One case of vaccine failure was observed in a severely immunosuppressed child following three PCV7 doses, and two cases were observed in immunocompetent children following two infant doses before they were eligible for their booster. None of the IPD cases caused by the additional PCV13 serotypes had been vaccinated by PCV13 and there were therefore no PCV13-vaccine failures in the first 8-months after PCV13 introduction in Denmark. PMID- 23365636 TI - Direct immunochemiluminescent assay for proBNP and total BNP in human plasma proBNP and total BNP levels in normal and heart failure. AB - BACKGROUND: Recent studies have shown that in addition to brain (or B-type) natriuretic peptide (BNP) and the N-terminal proBNP fragment, levels of intact proBNP are also increased in heart failure. Moreover, present BNP immunoassays also measure proBNP, as the anti-BNP antibody cross-reacts with proBNP. It is important to know the exact levels of proBNP in heart failure, because elevation of the low-activity proBNP may be associated with the development of heart failure. METHODOLOGY/PRINCIPAL FINDINGS: We therefore established a two-step immunochemiluminescent assay for total BNP (BNP+proBNP) and proBNP using monoclonal antibodies and glycosylated proBNP as a standard. The assay enables measurement of plasma total BNP and proBNP within only 7 h, without prior extraction of the plasma. The detection limit was 0.4 pmol/L for a 50-ul plasma sample. Within-run CVs ranged from 5.2%-8.0% in proBNP assay and from 7.0%-8.4% in total BNP assay, and between-run CVs ranged from 5.3-7.4% in proBNP assay and from 2.9%-9.5% in total BNP assay, respectively. The dilution curves for plasma samples showed good linearity (correlation coefficients = 0.998-1.00), and analytical recovery was 90-101%. The mean total BNP and proBNP in plasma from 116 healthy subjects were 1.4 +/- 1.2 pM and 1.0 +/- 0.7 pM, respectively, and were 80 +/- 129 pM and 42 +/- 70 pM in 32 heart failure patients. Plasma proBNP levels significantly correlate with age in normal subjects. CONCLUSIONS/SIGNIFICANCE: Our immunochemiluminescent assay is sufficiently rapid and precise for routine determination of total BNP and proBNP in human plasma. PMID- 23365637 TI - Transcriptome exploration in Leymus chinensis under saline-alkaline treatment using 454 pyrosequencing. AB - BACKGROUND: Leymus chinensis (Trin.) Tzvel. is a high saline-alkaline tolerant forage grass genus of the tribe Gramineae family, which also plays an important role in protection of natural environment. To date, little is known about the saline-alkaline tolerance of L. chinensis on the molecular level. To better understand the molecular mechanism of saline-alkaline tolerance in L. chinensis, 454 pyrosequencing was used for the transcriptome study. RESULTS: We used Roche 454 massive parallel pyrosequencing technology to sequence two different cDNA libraries that were built from the two samples of control and under saline alkaline treatment (optimal stress concentration-Hoagland solution with 100 mM NaCl and 200 mM NaHCO(3)). A total of 363,734 reads in control group and 526,267 reads in treatment group with an average length of 489 bp and 493 bp were obtained, respectively. The reads were assembled into 104,105 unigenes with MIRA sequence assemable software, among which, 73,665 unigenes were in control group, 88,016 unigenes in treatment group and 57,576 unigenes in both groups. According to the comparative expression analysis between the two groups with the threshold of "log2 Ratio >=1", there were 36,497 up-regulated unegenes and 18,218 down regulated unigenes predicted to be the differentially expressed genes. After gene annotation and pathway enrichment analysis, most of them were involved in stress and tolerant function, signal transduction, energy production and conversion, and inorganic ion transport. Furthermore, 16 of these differentially expressed genes were selected for real-time PCR validation, and they were successfully confirmed with the results of 454 pyrosequencing. CONCLUSIONS: This work is the first time to study the transcriptome of L. chinensis under saline-alkaline treatment based on the 454-FLX massively parallel DNA sequencing platform. It also deepened studies on molecular mechanisms of saline-alkaline in L. chinensis, and constituted a database for future studies. PMID- 23365638 TI - Polymer uncrossing and knotting in protein folding, and their role in minimal folding pathways. AB - We introduce a method for calculating the extent to which chain non-crossing is important in the most efficient, optimal trajectories or pathways for a protein to fold. This involves recording all unphysical crossing events of a ghost chain, and calculating the minimal uncrossing cost that would have been required to avoid such events. A depth-first tree search algorithm is applied to find minimal transformations to fold [Formula: see text], [Formula: see text], [Formula: see text], and knotted proteins. In all cases, the extra uncrossing/non-crossing distance is a small fraction of the total distance travelled by a ghost chain. Different structural classes may be distinguished by the amount of extra uncrossing distance, and the effectiveness of such discrimination is compared with other order parameters. It was seen that non-crossing distance over chain length provided the best discrimination between structural and kinetic classes. The scaling of non-crossing distance with chain length implies an inevitable crossover to entanglement-dominated folding mechanisms for sufficiently long chains. We further quantify the minimal folding pathways by collecting the sequence of uncrossing moves, which generally involve leg, loop, and elbow-like uncrossing moves, and rendering the collection of these moves over the unfolded ensemble as a multiple-transformation "alignment". The consensus minimal pathway is constructed and shown schematically for representative cases of an [Formula: see text], [Formula: see text], and knotted protein. An overlap parameter is defined between pathways; we find that [Formula: see text] proteins have minimal overlap indicating diverse folding pathways, knotted proteins are highly constrained to follow a dominant pathway, and [Formula: see text] proteins are somewhere in between. Thus we have shown how topological chain constraints can induce dominant pathway mechanisms in protein folding. PMID- 23365639 TI - A mathematical model for microRNA in lung cancer. AB - Lung cancer is the leading cause of cancer-related deaths worldwide. Lack of early detection and limited options for targeted therapies are both contributing factors to the dismal statistics observed in lung cancer. Thus, advances in both of these areas are likely to lead to improved outcomes. MicroRNAs (miRs or miRNAs) represent a class of non-coding RNAs that have the capacity for gene regulation and may serve as both diagnostic and prognostic biomarkers in lung cancer. Abnormal expression patterns for several miRNAs have been identified in lung cancers. Specifically, let-7 and miR-9 are deregulated in both lung cancers and other solid malignancies. In this paper, we construct a mathematical model that integrates let-7 and miR-9 expression into a signaling pathway to generate an in silico model for the process of epithelial mesenchymal transition (EMT). Simulations of the model demonstrate that EGFR and Ras mutations in non-small cell lung cancers (NSCLC), which lead to the process of EMT, result in miR-9 upregulation and let-7 suppression, and this process is somewhat robust against random input into miR-9 and more strongly robust against random input into let-7. We elected to validate our model in vitro by testing the effects of EGFR inhibition on downstream MYC, miR-9 and let-7a expression. Interestingly, in an EGFR mutated lung cancer cell line, treatment with an EGFR inhibitor (Gefitinib) resulted in a concentration specific reduction in c-MYC and miR-9 expression while not changing let-7a expression. Our mathematical model explains the signaling link among EGFR, MYC, and miR-9, but not let-7. However, very little is presently known about factors that regulate let-7. It is quite possible that when such regulating factors become known and integrated into our model, they will further support our mathematical model. PMID- 23365640 TI - FANC pathway promotes UV-induced stalled replication forks recovery by acting both upstream and downstream Poleta and Rev1. AB - To cope with ultraviolet C (UVC)-stalled replication forks and restart DNA synthesis, cells either undergo DNA translesion synthesis (TLS) by specialised DNA polymerases or tolerate the lesions using homologous recombination (HR)-based mechanisms. To gain insight into how cells manage UVC-induced stalled replication forks, we analysed the molecular crosstalk between the TLS DNA polymerases Poleta and Rev1, the double-strand break repair (DSB)-associated protein MDC1 and the FANC pathway. We describe three novel functional interactions that occur in response to UVC-induced DNA lesions. First, Poleta and Rev1, whose optimal expression and/or relocalisation depend on the FANC core complex, act upstream of FANCD2 and are required for the proper relocalisation of monoubiquitinylated FANCD2 (Ub-FANCD2) to subnuclear foci. Second, during S-phase, Ub-FANCD2 and MDC1 relocalise to UVC-damaged nuclear areas or foci simultaneously but independently of each other. Third, Ub-FANCD2 and MDC1 are independently required for optimal BRCA1 relocalisation. While RPA32 phosphorylation (p-RPA32) and RPA foci formation were reduced in parallel with increasing levels of H2AX phosphorylation and MDC1 foci in UVC-irradiated FANC pathway-depleted cells, MDC1 depletion was associated with increased UVC-induced Ub-FANCD2 and FANCD2 foci as well as p RPA32 levels and p-RPA32 foci. On the basis of the previous observations, we propose that the FANC pathway participates in the rescue of UVC-stalled replication forks in association with TLS by maintaining the integrity of ssDNA regions and by preserving genome stability and preventing the formation of DSBs, the resolution of which would require the intervention of MDC1. PMID- 23365641 TI - Significant association of Glutathione S-transferase T1 null genotype with prostate cancer risk: a meta-analysis of 26,393 subjects. AB - BACKGROUND: Recent studies on the association between Glutathione S-transferase T1 (GSTT1) polymorphism and risk of prostate cancer showed inconclusive results. To clarify this possible association, we conducted a meta-analysis of published studies. METHODS: DATA WERE COLLECTED FROM THE FOLLOWING ELECTRONIC DATABASES: Pubmed, Embase, and Chinese Biomedical Database (CBM). The odds ratio (OR) and its 95% confidence interval (95%CI) was used to assess the strength of the association. We summarized the data on the association between GSTT1 null genotype and risk of prostate cancer in the overall population, and performed subgroup analyses by ethnicity, adjusted ORs, and types of controls. RESULTS: Ultimately, a total of 43 studies with a total of 26,393 subjects (9,934 cases and 16,459 controls) were eligible for meta-analysis. Overall, there was a significant association between GSTT1 null genotype and increased risk of prostate cancer (OR = 1.14, 95%CI 1.01-1.29, P = 0.034). Meta-analysis of adjusted ORs also showed a significant association between GSTT1 null genotype and increased risk of prostate cancer (OR= 1.34, 95%CI 1.09-1.64, P = 0.006). Similar results were found in the subgroup analyses by ethnicity and types of controls. CONCLUSION: This meta-analysis demonstrates that GSTT1 null genotype is associated with prostate cancer susceptibility, and GSTT1 null genotype contributes to increased risk of prostate cancer. PMID- 23365642 TI - Stromal cells induce Th17 during Helicobacter pylori infection and in the gastric tumor microenvironment. AB - Gastric cancer is associated with chronic inflammation and Helicobacter pylori infection. Th17 cells are CD4(+) T cells associated with infections and inflammation; but their role and mechanism of induction during carcinogenesis is not understood. Gastric myofibroblasts/fibroblasts (GMF) are abundant class II MHC expressing cells that act as novel antigen presenting cells. Here we have demonstrated the accumulation of Th17 in H. pylori-infected human tissues and in the gastric tumor microenvironment. GMF isolated from human gastric cancer and H. pylori infected tissues co-cultured with CD4(+) T cells induced substantially higher levels of Th17 than GMF from normal tissues in an IL-6, TGF-beta, and IL 21 dependent manner. Th17 required interaction with class II MHC on GMF for activation and proliferation. These studies suggest that Th17 are induced during both H. pylori infection and gastric cancer in the inflammatory milieu of gastric stroma and may be an important link between inflammation and carcinogenesis. PMID- 23365643 TI - Challenges to evaluating respiratory syncytial virus mortality in Bangladesh, 2004-2008. AB - BACKGROUND: Acute lower respiratory illness is the most common cause of death among children, globally. Data are not available to make accurate estimates on the global mortality from respiratory syncytial virus (RSV), specifically. METHODS: Respiratory samples collected from children under 5 years of age during 2004 to 2008 as part of population-based respiratory disease surveillance in an urban community in Dhaka, Bangladesh were tested for RSV, human metapneumovirus (HMPV), human parainfluenza virus (PIV) types 1, 2, and 3, influenza and adenovirus by RT-PCR. Verbal autopsy data were used to identify children who died from respiratory illness in a nearby rural community. Significance of the correlation between detections and community respiratory deaths was determined using Spearman's coefficient. RESULTS: RSV activity occurred during defined periods lasting approximately three months but with no clear seasonal pattern. There was no significant correlation between respiratory deaths and detection of any of the respiratory viruses studied. CONCLUSION: Outbreaks of respiratory viruses may not be associated with deaths in children in the study site; however, the few respiratory deaths observed and community-to-community variation in the timing of outbreaks may have obscured an association. An accurate assessment of respiratory virus-associated deaths will require detections and death data to come from the same location and a larger study population. PMID- 23365644 TI - Characterization of genetic diversity and linkage disequilibrium of ZmLOX4 and ZmLOX5 loci in maize. AB - Maize (Zea mays L.) lipoxygenases (ZmLOXs) are well recognized as important players in plant defense against pathogens, especially in cross kingdom lipid communication with pathogenic fungi. This study is among the first to investigate genetic diversity at important gene paralogs ZmLOX4 and ZmLOX5. Sequencing of these genes in 400 diverse maize lines showed little genetic diversity and low linkage disequilibrium in the two genes. Importantly, we identified one inbred line in which ZmLOX5 has a disrupted open reading frame, a line missing ZmLOX5, and five lines with a duplication of ZmLOX5. Tajima's D test suggests that both ZmLOX4 and ZmLOX5 have been under neutral selection. Further investigation of haplotype data revealed that within the ZmLOX family members only ZmLOX12, a monocot specific ZmLOX, showed strong linkage disequilibrium that extends further than expected in maize. Linkage disequilibrium patterns at these loci of interest are crucial for future candidate gene association mapping studies. ZmLOX4 and ZmLOX5 mutations and copy number variants are under further investigation for crop improvement. PMID- 23365645 TI - Insulin-like growth factor 1 receptor (IGF1R) expression and survival in operable squamous-cell laryngeal cancer. AB - INTRODUCTION: Prognosis of patients with operable laryngeal cancer is highly variable and therefore potent prognostic biomarkers are warranted. The insulin like growth factor receptor (IGFR) signaling pathway plays a critical role in laryngeal carcinogenesis and progression. PATIENTS AND METHODS: We identified all patients with localized TNM stage I-III laryngeal cancer managed with potentially curative surgery between 1985 and 2008. Immunohistochemical (IHC) expression of IGF1R-alpha, IGF1R-beta and IGF2R was evaluated using the immunoreactive score (IRS) and mRNA levels of important effectors of the IGFR pathway were assessed, including IGF1R, IGF-binding protein 3 (IGFBP3), suppressor of cytokine signaling 2 (SOCS2) and members of the MAP-kinase (MAP2K1, MAPK9) and phosphatidyl-inositol 3 kinase (PIK3CA, PIK3R1) families. Cox-regression models were applied to assess the predictive value of biomarkers on disease-free survival (DFS) and overall survival (OS). RESULTS: Among 289 eligible patients, 95.2% were current or ex smokers, 75.4% were alcohol abusers, 15.6% had node-positive disease and 32.2% had received post-operative irradiation. After a median follow-up of 74.5 months, median DFS was 94.5 months and median OS was 106.3 months. Using the median IRS as the pre-defined cut-off, patients whose tumors had increased IGF1R-alpha cytoplasm or membrane expression experienced marginally shorter DFS and significantly shorter OS compared to those whose tumors had low IGF1R-alpha expression (91.1 vs 106.2 months, p = 0.0538 and 100.3 vs 118.6 months, p = 0.0157, respectively). Increased mRNA levels of MAPK9 were associated with prolonged DFS (p = 0.0655) and OS (p = 0.0344). In multivariate analysis, IGF1R alpha overexpression was associated with a 46.6% increase in the probability for relapse (p = 0.0374). Independent predictors for poor OS included node-positive disease (HR = 2.569, p<0.0001), subglottic/transglottic localization (HR = 1.756, p = 0.0438) and IGF1R-alpha protein overexpression (HR = 1.475, p = 0.0504). CONCLUSION: IGF1R-alpha protein overexpression may serve as an independent predictor of relapse and survival in operable laryngeal cancer. Prospective evaluation of the IGF1R-alpha prognostic utility is warranted. PMID- 23365646 TI - Fatty acid binding proteins FABP9 and FABP10 participate in antibacterial responses in Chinese mitten crab, Eriocheir sinensis. AB - Invertebrates rely solely on the innate immune system for defense against pathogens and other stimuli. Fatty acid binding proteins (FABP), members of the lipid binding proteins superfamily, play a crucial role in fatty acid transport and lipid metabolism and are also involved in gene expression induced by fatty acids. In the vertebrate immune system, FABP is involved in inflammation regulated by fatty acids through its interaction with peroxidase proliferator activate receptors (PPARs). However, the immune functions of FABP in invertebrates are not well characterized. For this reason, we investigated the immune functionality of two fatty acid binding proteins, Es-FABP9 and Es-FABP10, following lipopolysaccharide (LPS) challenge in the Chinese mitten crab (Eriocheir sinensis). An obvious variation in the expression of Es-FABP9 and Es FABP10 mRNA in E. sinensis was observed in hepatopancreas, gills, and hemocytes post-LPS challenge. Recombinant proteins rEs-FABP9 and rEs-FABP10 exhibited distinct bacterial binding activity and bacterial agglutination activity against Escherichia coli and Staphylococcus aureus. Furthermore, bacterial growth inhibition assays demonstrated that rEs-FABP9 responds positively to the growth inhibition of Vibrio parahaemolyticuss and S. aureus, while rEs-FABP10 responds positively to the growth inhibition of Aeromonas hydrophila and Bacillus subtilis. Coating of agarose beads with recombinant rEs-FABP9 and rEs-FABP10 dramatically enhanced encapsulation of the beads by crab hemocytes in vitro. In conclusion, the data presented here demonstrate the participation of these two lipid metabolism-related proteins in the innate immune system of E. sinensis. PMID- 23365647 TI - BatSLAM: Simultaneous localization and mapping using biomimetic sonar. AB - We propose to combine a biomimetic navigation model which solves a simultaneous localization and mapping task with a biomimetic sonar mounted on a mobile robot to address two related questions. First, can robotic sonar sensing lead to intelligent interactions with complex environments? Second, can we model sonar based spatial orientation and the construction of spatial maps by bats? To address these questions we adapt the mapping module of RatSLAM, a previously published navigation system based on computational models of the rodent hippocampus. We analyze the performance of the proposed robotic implementation operating in the real world. We conclude that the biomimetic navigation model operating on the information from the biomimetic sonar allows an autonomous agent to map unmodified (office) environments efficiently and consistently. Furthermore, these results also show that successful navigation does not require the readings of the biomimetic sonar to be interpreted in terms of individual objects/landmarks in the environment. We argue that the system has applications in robotics as well as in the field of biology as a simple, first order, model for sonar based spatial orientation and map building. PMID- 23365648 TI - Recognizing sights, smells, and sounds with gnostic fields. AB - Mammals rely on vision, audition, and olfaction to remotely sense stimuli in their environment. Determining how the mammalian brain uses this sensory information to recognize objects has been one of the major goals of psychology and neuroscience. Likewise, researchers in computer vision, machine audition, and machine olfaction have endeavored to discover good algorithms for stimulus classification. Almost 50 years ago, the neuroscientist Jerzy Konorski proposed a theoretical model in his final monograph in which competing sets of "gnostic" neurons sitting atop sensory processing hierarchies enabled stimuli to be robustly categorized, despite variations in their presentation. Much of what Konorski hypothesized has been remarkably accurate, and neurons with gnostic-like properties have been discovered in visual, aural, and olfactory brain regions. Surprisingly, there have not been any attempts to directly transform his theoretical model into a computational one. Here, I describe the first computational implementation of Konorski's theory. The model is not domain specific, and it surpasses the best machine learning algorithms on challenging image, music, and olfactory classification tasks, while also being simpler. My results suggest that criticisms of exemplar-based models of object recognition as being computationally intractable due to limited neural resources are unfounded. PMID- 23365649 TI - The functional DRD3 Ser9Gly polymorphism (rs6280) is pleiotropic, affecting reward as well as movement. AB - Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [(11)C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis. PMID- 23365650 TI - Characterization and expression patterns of microRNAs involved in rice grain filling. AB - MicroRNAs (miRNAs) are upstream gene regulators of plant development and hormone homeostasis through their directed cleavage or translational repression of the target mRNAs, which may play crucial roles in rice grain filling and determining the final grain weight and yield. In this study, high-throughput sequencing was performed to survey the dynamic expressions of miRNAs and their corresponding target genes at five distinct developmental stages of grain filling. In total, 445 known miRNAs and 45 novel miRNAs were detected with most of them expressed in a developmental stage dependent manner, and the majority of known miRNAs, which increased gradually with rice grain filling, showed negatively related to the grain filling rate. Detailed expressional comparisons revealed a clear negative correlation between most miRNAs and their target genes. It was found that specific miRNA cohorts are expressed in a developmental stage dependent manner during grain filling and the known functions of these miRNAs are involved in plant hormone homeostasis and starch accumulation, indicating that the expression dynamics of these miRNAs might play key roles in regulating rice grain filling. PMID- 23365652 TI - Sexual segregation and flexible mating patterns in temperate bats. AB - Social structure evolves from a trade-off between the costs and benefits of group living, which are in turn dependent upon the distribution of key resources such as food and shelter. Males and females, or juveniles and adults, may have different priorities when selecting habitat due to differences in physiological or behavioural imperatives, leading to complex patterns in group composition. We studied social structure and mating behaviour in the insectivorous bat Myotis daubentonii along an altitudinal gradient, combining field studies with molecular genetics. With increasing altitude the proportion of males in summer roosts increased and only males were present in the highest roosts. With increasing altitude environmental temperature decreased, nightly variation in temperature increased, and bat foraging activity decreased, supporting the hypothesis that the harsher, high elevation sites cannot support breeding females. We found that offspring in female-dominated lowland roosts had a very high probability of being fathered by bats caught during autumn swarming at hibernation sites, in contrast to those in intermediate roosts, which had a high probability of being fathered by males sharing the nursery roost with the females. Whilst females normally appear to exclude males from nursery colonies, for those in marginal habitats, one explanation for the presence of males is that the thermoregulatory benefits to the females may outweigh disadvantages, such as competition for food, and give some males an opportunity to increase their breeding success. We suggest that the environment, and its effects on resource distribution, thus determine social structure, which in turn determines the mating pattern that has evolved. PMID- 23365651 TI - Vasopressin effectively suppresses male fertility. AB - Arginine vasopressin (VP) is neurohypophysial hormone has been implicated in stimulating contractile activity of the male reproductive tract in the testis. Higher levels of VP decrease sperm count and motility. However, very little is known about the involvement of VP in controlling mammalian reproductive process. The goal of this study was to confirm that effect of VP receptor (AVPR2) on sperm function in capacitation condition. Deamino [Cys 1, D-ArgS] vasopressin (dDAVP), an AVPR2 agonist that operates only on AVPR2, was used. Also, Mouse spermatozoa were incubated with various concentrations of dDAVP (10(-11)-10(-5) M) and sperm motility, capacitation status, Protein Kinase A activity (PKA), tyrosine phosphorylation, fertilization, and embryo development were assessed using computer-assisted sperm analysis, Combined Hoechst 33258/chlortetracycline fluorescence, Western blotting, and in vitro fertilization, respectively. AVPR2 was placed on the acrosome region and mid-piece in cauda epididymal spermatozoa, but the caput epididymal spermatozoa was mid-piece only. The high dDAVP treatment (10(-8) and 10(-5) M) significantly decreased sperm motility, intracellular pH and PKA substrates (approximately 55 and 22 kDa) and increased Ca(2+) concentration. The highest concentration treatment significantly decreased PKA substrate (approximately 23 kDa) and tyrosine phosphorylation (approximately 30 kDa). VP detrimentally affected capacitation, acrosome reaction, and embryo development. Treatment with the lowest concentration (10(-11) M) was not significantly different. Our data have shown that VP stimulates ion transport across sperm membrane through interactions with AVPR2. VP has a detrimental effect in sperm function, fertilization, and embryonic development, suggesting its critical role in the acquisition of fertilizing ability of mouse spermatozoa. These research findings will enable further study to determine molecular mechanism associated with fertility in capacitation and fertilization. It is also an important pivotal precondition to the progress of diagnostic test to identify infertility and to apply male contraception. PMID- 23365653 TI - Phylogenetic and temporal dynamics of human immunodeficiency virus type 1 CRF01_AE in China. AB - To explore the epidemic history of HIV-1 CRF01_AE in China, 408 fragments of gag gene sequences of CRF01_AE sampled in 2002-2010 were determined from different geographical regions and risk populations in China. Phylogenetic analysis indicates that the CRF01_AE sequences can be grouped into four clusters, suggesting that at least four genetically independent CRF01_AE descendants are circulating in China, of which two were closely related to the isolates from Thailand and Vietnam. Cluster 1 has the most extensive distribution in China. In North China, cluster 1 and cluster 4 were mainly transmitted through homosexuality.The real substance of the recent HIV-1 epidemic in men who have sex with men(MSM) of North China is a rapid spread of CRF01_AE, or rather two distinctive natives CRF01_AE.The time of the most recent common ancestor (tMRCA) of four CRF01_AE clusters ranged from the years 1990.9 to 2003.8 in different regions of China. This is the first phylogenetic and temporal dynamics study of HIV-1 CRF01_AE in China. PMID- 23365654 TI - Associations between UCP1 -3826A/G, UCP2 -866G/A, Ala55Val and Ins/Del, and UCP3 55C/T polymorphisms and susceptibility to type 2 diabetes mellitus: case-control study and meta-analysis. AB - BACKGROUND: Some studies have reported associations between five uncoupling protein (UCP) 1-3 polymorphisms and type 2 diabetes mellitus (T2DM). However, other studies have failed to confirm the associations. This paper describes a case-control study and a meta-analysis conducted to attempt to determine whether the following polymorphisms are associated with T2DM: -3826A/G (UCP1); -866G/A, Ala55Val and Ins/Del (UCP2) and -55C/T (UCP3). METHODS: The case-control study enrolled 981 T2DM patients and 534 nondiabetic subjects, all of European ancestry. A literature search was run to identify all studies that investigated associations between UCP1-3 polymorphisms and T2DM. Pooled odds ratios (OR) were calculated for allele contrast, additive, recessive, dominant and co-dominant inheritance models. Sensitivity analyses were performed after stratification by ethnicity. RESULTS: In the case-control study the frequencies of the UCP polymorphisms did not differ significantly between T2DM and nondiabetic groups (P>0.05). Twenty-three studies were eligible for the meta-analysis. Meta-analysis results showed that the Ala55Val polymorphism was associated with T2DM under a dominant model (OR = 1.27, 95% CI 1.03-1.57); while the -55C/T polymorphism was associated with this disease in almost all genetic models: allele contrast (OR = 1.17, 95% CI 1.02-1.34), additive (OR = 1.32, 95% CI 1.01-1.72) and dominant (OR = 1.18, 95% CI 1.02-1.37). However, after stratification by ethnicity, the UCP2 55Val and UCP3 -55C/T alleles remained associated with T2DM only in Asians (OR = 1.25, 95% CI 1.02-1.51 and OR = 1.22, 95% CI 1.04-1.44, respectively; allele contrast model). No significant association of the -3826A/G, -866G/A and Ins/Del polymorphisms with T2DM was observed. CONCLUSIONS: In our case-control study of people with European ancestry we were not able to demonstrate any association between the UCP polymorphisms and T2DM; however, our meta-analysis detected a significant association between the UCP2 Ala55Val and UCP3 -55C/T polymorphisms and increased susceptibility for T2DM in Asians. PMID- 23365655 TI - Dynamics of coral reef benthic assemblages of the Abrolhos Bank, eastern Brazil: inferences on natural and anthropogenic drivers. AB - The Abrolhos Bank (eastern Brazil) encompasses the largest and richest coral reefs of the South Atlantic. Coral reef benthic assemblages of the region were monitored from 2003 to 2008. Two habitats (pinnacles' tops and walls) were sampled per site with 3-10 sites sampled within different reef areas. Different methodologies were applied in two distinct sampling periods: 2003-2005 and 2006 2008. Spatial coverage and taxonomic resolution were lower in the former than in the latter period. Benthic assemblages differed markedly in the smallest spatial scale, with greater differences recorded between habitats. Management regimes and biomass of fish functional groups (roving and territorial herbivores) had minor influences on benthic assemblages. These results suggest that local environmental factors such as light, depth and substrate inclination exert a stronger influence on the structure of benthic assemblages than protection from fishing. Reef walls of unprotected coastal reefs showed highest coral cover values, with a major contribution of Montastraea cavernosa (a sediment resistant species that may benefit from low light levels). An overall negative relationship between fleshy macroalgae and slow-growing reef-building organisms (i.e. scleractinians and crustose calcareous algae) was recorded, suggesting competition between these organisms. The opposite trend (i.e. positive relationships) was recorded for turf algae and the two reef-building organisms, suggesting beneficial interactions and/or co-occurrence mediated by unexplored factors. Turf algae cover increased across the region between 2006 and 2008, while scleractinian cover showed no change. The need of a continued and standardized monitoring program, aimed at understanding drivers of change in community patterns, as well as to subsidize sound adaptive conservation and management measures, is highlighted. PMID- 23365656 TI - Screening of a specific peptide binding to VPAC1 receptor from a phage display peptide library. AB - BACKGROUND/PURPOSE: The VPAC1 receptor, a member of the vasoactive intestinal peptide receptors (VIPRs), is overexpressed in the most frequently occurring malignant tumors and plays a major role in the progression and angiogenesis of a number of malignancies. Recently, phage display has become widely used for many applications, including ligand generation for targeted imaging, drug delivery and therapy. In this work, we developed a panning procedure using a phage display peptide library to select a peptide that specifically binds to the VPAC1 receptor to develop a novel targeted probe for molecular imaging and therapy. METHODS: CHO K1 cells stably expressing VPAC1 receptors (CHO-K1/VPAC1 cells) were used to select a VPAC1-binding peptide from a 12-mer phage peptide library. DNA sequencing and homologous analysis of the randomly selected phage clones were performed. A cellular ELISA was used to determine the most selectively binding peptide for further investigation. Binding specificity to the VPAC1 receptor was analyzed by competitive inhibition ELISA and flow cytometry. The binding ability of the selected peptide to CHO-K1/VPAC1 cells and colorectal cancer (CRC) cell lines was confirmed using fluorescence microscopy and flow cytometry. RESULTS: A significant enrichment of phages that specifically bound to CHO-K1/VPAC1 cells was obtained after four rounds of panning. Of the selected phage clones, 16 out of 60 shared the same peptide sequence, GFRFGALHEYNS, which we termed the VP2 peptide. VP2 and vasoactive intestinal peptide (VIP) competitively bound to the VPAC1 receptor. More importantly, we confirmed that VP2 specifically bound to CHO K1/VPAC1 cells and several CRC cell lines. CONCLUSION: Our results demonstrate that the VP2 peptide could specifically bind to VPAC1 receptor and several CRC cell lines. And VP2 peptide may be a potential candidate to be developed as a useful diagnostic molecular imaging probe for early detection of CRC. PMID- 23365657 TI - Stability of zinc finger nuclease protein is enhanced by the proteasome inhibitor MG132. AB - BACKGROUND: Zinc finger nucleases (ZFNs) are powerful tools for gene therapy and genetic engineering. The characterization of ZFN protein stability and the development of simple methods to improve ZFN function would facilitate the application of this promising technology. However, the factors that affect ZFN protein stability and function are not yet clear. Here, we determined the stability and half-life of two ZFN proteins and examined the effect of MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal-Hl), a proteasome inhibitor, on ZFN mediated gene modifications. METHODOLOGY/PRINCIPAL FINDINGS: ZFN proteins were expressed in 293T cells after transfection of ZFN-encoding plasmids. We studied two ZFN pairs: Z-224, which targets the CCR5 gene, and K-230, which targets a region 230 kbp upstream of CCR5. Western blotting after treatment with cycloheximide showed that the half-life of these ZFN proteins was around two hours. An immunoprecipitation assay revealed that the ZFN interacts with ubiquitin molecules and undergoes polyubiquitination in vivo. Western blotting showed that the addition of MG132, a proteasomal inhibitor, increased ZFN protein levels. Finally, a surrogate reporter assay and a T7E1 assay revealed that MG132 treatment enhanced ZFN-directed gene editing. CONCLUSIONS: To our knowledge, this is the first study to investigate ZFN protein stability and to show that a small molecule can increase ZFN activity. Our protein stability study should lay the foundation for further improvement of ZFN technology; as a first step, the use of the small molecule MG132 can enhance the efficiency of ZFN-mediated gene editing. PMID- 23365658 TI - Evolution of a pathogen: a comparative genomics analysis identifies a genetic pathway to pathogenesis in Acinetobacter. AB - Acinetobacter baumannii is an emergent and global nosocomial pathogen. In addition to A. baumannii, other Acinetobacter species, especially those in the Acinetobacter calcoaceticus-baumannii (Acb) complex, have also been associated with serious human infection. Although mechanisms of attachment, persistence on abiotic surfaces, and pathogenesis in A. baumannii have been identified, the genetic mechanisms that explain the emergence of A. baumannii as the most widespread and virulent Acinetobacter species are not fully understood. Recent whole genome sequencing has provided insight into the phylogenetic structure of the genus Acinetobacter. However, a global comparison of genomic features between Acinetobacter spp. has not been described in the literature. In this study, 136 Acinetobacter genomes, including 67 sequenced in this study, were compared to identify the acquisition and loss of genes in the expansion of the Acinetobacter genus. A whole genome phylogeny confirmed that A. baumannii is a monophyletic clade and that the larger Acb complex is also a well-supported monophyletic group. The whole genome phylogeny provided the framework for a global genomic comparison based on a blast score ratio (BSR) analysis. The BSR analysis demonstrated that specific genes have been both lost and acquired in the evolution of A. baumannii. In addition, several genes associated with A. baumannii pathogenesis were found to be more conserved in the Acb complex, and especially in A. baumannii, than in other Acinetobacter genomes; until recently, a global analysis of the distribution and conservation of virulence factors across the genus was not possible. The results demonstrate that the acquisition of specific virulence factors has likely contributed to the widespread persistence and virulence of A. baumannii. The identification of novel features associated with transcriptional regulation and acquired by clades in the Acb complex presents targets for better understanding the evolution of pathogenesis and virulence in the expansion of the genus. PMID- 23365659 TI - IRGM variants and susceptibility to inflammatory bowel disease in the German population. AB - BACKGROUND & AIMS: Genome-wide association studies identified the autophagy gene IRGM to be strongly associated with Crohn's disease (CD) but its impact in ulcerative colitis (UC), its phenotypic effects and potential epistatic interactions with other IBD susceptibility genes are less clear which we therefore analyzed in this study. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2060 individuals including 817 CD patients, 283 UC patients, and 961 healthy, unrelated controls (all of Caucasian origin) was analyzed for six IRGM single nucleotide polymorphisms (SNPs) (rs13371189, rs10065172 = p.Leu105Leu, rs4958847, rs1000113, rs11747270, rs931058). In all patients, a detailed genotype phenotype analysis and testing for epistasis with the three major CD susceptibility genes NOD2, IL23R and ATG16L1 were performed. Our analysis revealed an association of the IRGM SNPs rs13371189 (p = 0.02, OR 1.31 [95% CI 1.05-1.65]), rs10065172 = p.Leu105Leu (p = 0.016, OR 1.33 [95% CI 1.06-1.66]) and rs1000113 (p = 0.047, OR 1.27 [95% CI 1.01-1.61]) with CD susceptibility. There was linkage disequilibrium between these three IRGM SNPs. In UC, several IRGM haplotypes were weakly associated with UC susceptibility (p<0.05). Genotype phenotype analysis revealed no significant associations with a specific IBD phenotype or ileal CD involvement. There was evidence for weak gene-gene interaction between several SNPs of the autophagy genes IRGM and ATG16L1 (p<0.05), which, however, did not remain significant after Bonferroni correction. CONCLUSIONS/SIGNIFICANCE: Our results confirm IRGM as susceptibility gene for CD in the German population, supporting a role for the autophagy genes IRGM and ATG16L1 in the pathogenesis of CD. PMID- 23365660 TI - Mitochondrial DNA variants mediate energy production and expression levels for CFH, C3 and EFEMP1 genes: implications for age-related macular degeneration. AB - BACKGROUND: Mitochondrial dysfunction is associated with the development and progression of age-related macular degeneration (AMD). Recent studies using populations from the United States and Australia have demonstrated that AMD is associated with mitochondrial (mt) DNA haplogroups (as defined by combinations of mtDNA polymorphisms) that represent Northern European Caucasians. The aim of this study was to use the cytoplasmic hybrid (cybrid) model to investigate the molecular and biological functional consequences that occur when comparing the mtDNA H haplogroup (protective for AMD) versus J haplogroup (high risk for AMD). METHODOLOGY/PRINCIPAL FINDINGS: Cybrids were created by introducing mitochondria from individuals with either H or J haplogroups into a human retinal epithelial cell line (ARPE-19) that was devoid of mitochondrial DNA (Rho0). In cybrid lines, all of the cells carry the same nuclear genes but vary in mtDNA content. The J cybrids had significantly lower levels of ATP and reactive oxygen/nitrogen species production, but increased lactate levels and rates of growth. Q-PCR analyses showed J cybrids had decreased expressions for CFH, C3, and EFEMP1 genes, high risk genes for AMD, and higher expression for MYO7A, a gene associated with retinal degeneration in Usher type IB syndrome. The H and J cybrids also have comparatively altered expression of nuclear genes involved in pathways for cell signaling, inflammation, and metabolism. CONCLUSION/SIGNIFICANCE: Our findings demonstrate that mtDNA haplogroup variants mediate not only energy production and cell growth, but also cell signaling for major molecular pathways. These data support the hypothesis that mtDNA variants play important roles in numerous cellular functions and disease processes, including AMD. PMID- 23365661 TI - Species' life-history traits explain interspecific variation in reservoir competence: a possible mechanism underlying the dilution effect. AB - Hosts species for multi-host pathogens show considerable variation in the species' reservoir competence, which is usually used to measure species' potential to maintain and transmit these pathogens. Although accumulating research has proposed a trade-off between life-history strategies and immune defences, only a few studies extended this to host species' reservoir competence. Using a phylogenetic comparative approach, we studied the relationships between some species' life-history traits and reservoir competence in three emerging infectious vector-borne disease systems, namely Lyme disease, West Nile Encephalitis (WNE) and Eastern Equine Encephalitis (EEE). The results showed that interspecific variation in reservoir competence could be partly explained by the species' life histories. Species with larger body mass (for hosts of Lyme disease and WNE) or smaller clutch size (for hosts of EEE) had a lower reservoir competence [corrected]. Given that both larger body mass and smaller clutch size were linked to higher extinction risk of local populations, our study suggests that with decreasing biodiversity, species with a higher reservoir competence are more likely to remain in the community, and thereby increase the risk of transmitting these pathogens, which might be a possible mechanism underlying the dilution effect. PMID- 23365662 TI - Corneal wound healing is compromised by immunoproteasome deficiency. AB - Recent studies have revealed roles for immunoproteasome in regulating cell processes essential for maintaining homeostasis and in responding to stress and injury. The current study investigates how the absence of immunoproteasome affects the corneal epithelium under normal and stressed conditions by comparing corneas from wildtype (WT) mice and those deficient in two immunoproteasome catalytic subunits (lmp7(-/-)/mecl-1(-/-), L7M1). Immunoproteasome expression was confirmed in WT epithelial cells and in cells of the immune system that were present in the cornea. More apoptotic cells were found in both corneal explant cultures and uninjured corneas of L7M1 compared to WT mice. Following mechanical debridement, L7M1 corneas displayed delayed wound healing, including delayed re epithelialization and re-establishment of the epithelial barrier, as well as altered inflammatory cytokine production compared to WT mice. These results suggest that immunoproteasome plays an important role in corneal homeostasis and wound healing. PMID- 23365663 TI - Real-time bladder lesion registration and navigation: a phantom study. AB - BACKGROUND: Bladder cancer is the fourth most common malignancy in men, with a recurrence rate of 33-64%. Tumor documentation during cystoscopy of the bladder is suboptimal and might play a role in these high recurrence rates. OBJECTIVE: In this project, a bladder registration and navigation system was developed to improve bladder tumor documentation and consequently increase reproducibility of the cystoscopy. MATERIALS/METHODS: The bladder registration and navigation system consists of a stereo-tracker that tracks the location of a newly developed target, which is attached to the endoscope during cystoscopy. With this information the urology registration and navigation software is able to register the 3D position of a lesion of interest. Simultaneously, the endoscopic image is captured in order to combine it with this 3D position. To enable navigation, navigational cues are displayed on the monitor, which subsequently direct the cystoscopist to the previously registered lesion. To test the system, a rigid and a flexible bladder phantom was developed. The system's robustness was tested by measuring the accuracy of registering and navigating the lesions. Different calibration procedures were compared. It was also tested whether system accuracy is limited by using a previously saved calibration, to avoid surgical delay due to calibration. Urological application was tested by comparing a rotational camera (fixed to the rotating endoscope) to a non-rotational camera (dangling by gravity) used in standard urologic practice. Finally, the influence of volume differences on registering and navigating was tested. RESULTS/CONCLUSION: The bladder registration and navigation system has an acceptable accuracy for bladder lesion registration and navigation. Limitations for patient determinants included changes in bladder volume and bladder deformation. In vivo studies are required to measure the effect of these limitations and functionality in urological practice as a tool to increase reproducibility of the cystoscopy. PMID- 23365664 TI - Tolerance to high temperature extremes in an invasive lace bug, Corythucha ciliata (Hemiptera: Tingidae), in subtropical China. AB - Biological invasions are predicted to be more frequent as climate change is increasing its positive impact on the prevalence of invasive exotic species. Success of insect invaders in different temperature zones is closely related to their tolerance to temperature extremes. In this study, we used an exotic lace bug (Corythucha ciliata) as the study organism to address the hypotheses that an insect species invading a subtropical zone from temperate regions has a high capacity to survive and adapt to high temperatures, and that its thermal tolerance plays an important role in determining its seasonal abundance and geographic distribution. To test these hypotheses, the effects of heat shock on the survival and reproduction of C. ciliata adults were assessed in the laboratory. Adults were exposed to 26 (control), 35, 37, 39, 41, 43, and 45 degrees C for 2 h, and then were transferred to 26 degrees C. Heat-shock temperatures ranging from 35 to 41 degrees C did not significantly affect survival pattern, longevity, and fecundity of adults, but heat shock at 43 and 45 degrees C significantly reduced these traits. Exposing parent females to heat shock treatments from 35 to 41 degrees C did not significantly affect the hatching rate of their eggs, survival of the nymphs, and the proportion of female F(1) progeny, while no progeny were produced with treatments of 43 and 45 degrees C. The results indicate that C. ciliata can tolerate high temperatures less than 41 degrees C, which may contribute to its expansion into the lower latitudes in China where its hosts (Platanus trees) are widely planted. Our findings have important implications for predicting seasonal abundance and understanding invasion mechanisms of this important urban invader under climate change. PMID- 23365665 TI - Combinatorial signaling through TLR-2 and CD86 augments activation and differentiation of resting B cells. AB - B cells are an integral component in mounting humoral immune responses and they are also crucial in programming T cell mediated immunity. Usually, B cell activation is initiated by recognition of antigen through B cell receptor (BCR), followed by its processing and presentation to T cells. But very little is known about BCR independent activation of B cells. Now, there is an increasing body of evidence indicating the combinatorial effect of innate and adaptive immune components in modulating the functions of B cells. In this study, we demonstrate the activation of resting B cells (RB) by simultaneous involvement of Toll like Receptor-2 (TLR-2) and costimulatory molecule, CD86. Interestingly, these B cells exhibited significant level of activation and proliferation. Furthermore, this process of activation leads to the differentiation of RB cells, preferably into marginal zone precursors (CD19(+)IgD(hi)IgM(hi)CD21/35(hi)CD23(hi)) in a shorter time window and showed increased secretion of IgG isotype. These RB cells also showed enhanced antigen uptake capacity. These observations were also substantiated by microarray gene expression results, which strengthen the notion that combinatorial signaling through innate and adaptive immune components enhances B cell mediated immune response. Thus, the present study elucidates a novel BCR independent B cell activation mechanism that links TLR-2 and CD86. Hence signaling of TLRs in conjunction with costimulatory molecules will substantially help in bolstering humoral immune response, which can be extrapolated to formulate vaccination strategies for diseases involving B cell mediated immunity. PMID- 23365666 TI - Extracellular dGMP enhances Deinococcus radiodurans tolerance to oxidative stress. AB - Free extracellular DNA provides nutrition to bacteria and promotes bacterial evolution by inducing excessive mutagenesis of the genome. To understand the influence of extracellular DNA fragments on D. radiodurans, we investigated cell growth and survival after extracellular DNA or dNMPs treatment. The results showed that the extracellular DNA fragments inhibited the growth of D. radiodurans. Interestingly, dGMP, a DNA component, enhanced D. radiodurans tolerance to H(2)O(2) and gamma-radiation significantly. Further experiments indicated that extracellular dGMP stimulated the activity of one catalase (KatA, DR1998), and induced gene transcription including the extracellular nuclease (drb0067). When this only extracellular nuclease gene (drb0067) in D. radiodurans was deleted, the mutant strain showed more sensitive to H(2)O(2) and gamma radiation than the wild type strain. These results suggest that DRB0067 plays an important role in oxidative stress resistance. Taken together, we proposed a new anti-oxidation mechanism in D. radiodurans. This mechanism acts to increase expression levels of DRB0067 which then secretes active nuclease to degrade extracellular DNA fragments. The extracellular nuclease has a two-fold benefit, creating more free dNTPs for further cell protection and the removal of extracellular DNA fragments. PMID- 23365667 TI - Random parameter sampling of a generic three-tier MAPK cascade model reveals major factors affecting its versatile dynamics. AB - The mitogen-activated protein kinase (MAPK) pathway is considered to be a central block in many biological signaling networks. Despite the common core cascade structure, the activation of MAPK in different biological systems can exhibit different types of dynamic behaviors. Computer modeling may help to reveal the mechanisms underlying such variations. However, so far most computational models of the MAPK cascade have been system-specific, or to reflect a particular type among the wide spectrum of possible dynamics. To obtain a general and integrated view of the relationship between the dynamics of MAPK activation and the structures and parameters of the MAPK cascade, we constructed a generic model by comparing previous models covering different specific biological systems. We assumed that reliable qualitative results could be predicted through a qualitative model with pseudo parameters. We used randomly sampled parameters instead of a specific set of "best-fit" parameters to avoid biases towards any particular systems. A range of dynamics behaviors for MAPK activation, including ultrasensitivity, bistability, transient activation and oscillation, were successfully predicted by the generic model. The results indicated that the steady state dynamics (ultrasensitivity and bistability) was jointly determined by the three-tiered structure of the MAPK cascade and the competitive substrate binding in the dual-phosphorylation processes of the central components, while the temporal dynamics (transient activation and oscillation) was mainly affected by the upstream signaling pathway and feedbacks. Moreover, MAPK kinase (MAPKK) played more important roles than the other two components in determining the dynamics of MAPK activation. We hypothesize that this is an important and advantageous property for the regulation and for the functional diversity of MAPK pathways in real cells. Finally, to assist developing generic models for signaling motifs through model comparisons, we proposed a reaction-based database to make the model data more flexible and interoperable. PMID- 23365668 TI - Pentosan polysulfate: a novel therapy for the mucopolysaccharidoses. AB - BACKGROUND: Pentosan polysulfate (PPS) is an FDA-approved, oral medication with anti-inflammatory and pro-chondrogenic properties. We have previously shown that animal models of the mucopolysaccharidoses (MPS) exhibit significant inflammatory disease, contributing to cartilage degeneration. Enzyme replacement therapy (ERT) only partly reduced inflammation, and anti-TNF-alpha antibody therapy significantly enhanced clinical and pathological outcomes. Here we describe the use of PPS for the treatment of MPS type VI rats. METHODOLOGY/PRINCIPAL FINDINGS: Treatment began during prenatal development and at 1 and 6 months of age. All animals were treated until they were 9 months old. Significant reductions in the serum and tissue levels of several inflammatory markers (e.g., TNF-alpha, MIP 1alpha and RANTES/CCL5) were observed, as was reduced expression of inflammatory markers in cultured articular chondrocytes. ADAMTS-5/aggrecanase-2 levels also were reduced in chondrocytes, consistent with an elevation of serum tissue inhibitor of metalloproteinase 1. Marked improvements in motility and grooming behavior occurred, along with a reduction in eye and nasal secretions and a lessening of the tracheal deformities. MicroCT and radiographic analyses further revealed that the treated MPS skulls were longer and thinner, and that the teeth malocclusions, misalignments and mineral densities were improved. MicroCT analysis of the femurs and vertebrae revealed improvements in trabecular bone mineral densities, number and spacing in a subset of treated MPS animals. Biomechanical assessments of PPS-treated spines showed partially restored torsional behaviors, suggesting increased spinal stability. No improvements were observed in cortical bone or femur length. The positive changes in the PPS treated MPS VI rats occurred despite glycosaminoglycan accumulation in their tissues. CONCLUSIONS: Based on these findings we conclude that PPS could be a simple and effective therapy for MPS that might provide significant clinical benefits alone and in combination with other therapies. PMID- 23365669 TI - Arginase treatment prevents the recovery of canine lymphoma and osteosarcoma cells resistant to the toxic effects of prolonged arginine deprivation. AB - Rapidly growing tumor cells require a nutrient-rich environment in order to thrive, therefore, restricting access to certain key amino acids, such as arginine, often results in the death of malignant cells, which frequently display defective cell cycle check-point control. Healthy cells, by contrast, become quiescent and remain viable under arginine restriction, displaying full recovery upon return to arginine-rich conditions. The use of arginase therapy to restrict available arginine for selectively targeting malignant cells is currently under investigation in human clinical trials. However, the suitability of this approach for veterinary uses is unexplored. As a prelude to in vivo studies in canine malignancies, we examined the in vitro effects of arginine-deprivation on canine lymphoid and osteosarcoma cell lines. Two lymphoid and 2 osteosarcoma cell lines were unable to recover following 6 days of arginine deprivation, but all remaining cell lines displayed full recovery upon return to arginine-rich culture conditions. These remaining cell lines all proved susceptible to cell death following the addition of arginase to the cultures. The lymphoid lines were particularly sensitive to arginase, becoming unrecoverable after just 3 days of treatment. Two of the osteosarcoma lines were also susceptible over this time frame; however the other 3 lines required 6-8 days of arginase treatment to prevent recovery. In contrast, adult progenitor cells from the bone marrow of a healthy dog were able to recover fully following 9 days of culture in arginase. Over 3 days in culture, arginase was more effective than asparaginase in inducing the death of lymphoid lines. These results strongly suggest that short-term arginase treatment warrants further investigation as a therapy for lymphoid malignancies and osteosarcomas in dogs. PMID- 23365670 TI - Green tea phenolic epicatechins inhibit hepatitis C virus replication via cycloxygenase-2 and attenuate virus-induced inflammation. AB - Chronic hepatitis C virus (HCV) infection is the leading risk factor for hepatocellular carcinoma (HCC) and chronic liver disease worldwide. Green tea, in addition to being consumed as a healthy beverage, contains phenolic catechins that have been used as medicinal substances. In the present study, we illustrated that the epicatechin isomers (+)-epicatechin and (-)-epicatechin concentration dependently inhibited HCV replication at nontoxic concentrations by using in vitro cell-based HCV replicon and JFH-1 infectious systems. In addition to significantly suppressing virus-induced cyclooxygenase-2 (COX-2) expression, our results revealed that the anti-HCV activity of the epicatechin isomers occurred through the down-regulation of COX-2. Furthermore, both the epicatechin isomers additively inhibited HCV replication in combination with either interferon-alpha or viral enzyme inhibitors [2'-C-methylcytidine (NM-107) or telaprevir]. They also had prominent anti-inflammatory effects by inhibiting the gene expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and inducible nitrite oxide synthase as well as the COX-2 in viral protein-expressing hepatoma Huh-7 cells. Collectively, (+)-epicatechin and (-)-epicatechin may serve as therapeutic supplements for treating HCV-related diseases. PMID- 23365671 TI - Thrips tabaci population genetic structure and polyploidy in relation to competency as a vector of tomato spotted wilt virus. AB - Knowledge of population-level genetic differences can help explain variation among populations of insect vectors in their role in the epidemiology of specific viruses. Variation in competency to transmit Tomato spotted wilt virus (TSWV) that exists among populations of Thrips tabaci has been associated with the presence of cryptic species that exhibit different modes of reproduction and host ranges. However, recent findings suggest that vector competency of T. tabaci at any given location depends on the thrips and virus populations that are present. This study characterizes the population genetic structure of T. tabaci collected from four locations in North Carolina and examines the relationship between population genetic structure and variation in TSWV transmission by T. tabaci. Mitochondrial COI sequence analysis revealed the presence of two genetically distinct groups with one characterized by thelytokous, parthenogenetic reproduction and the other by arrhenotokous, sexual reproduction. Using a set of 11 microsatellite markers that we developed to investigate T. tabaci population genetic structure, we identified 17 clonal groups and found significant genetic structuring among the four NC populations that corresponded to the geographic locations where the populations were collected. Application of microsatellite markers also led to the discovery of polyploidy in this species. All four populations contained tetraploid individuals, and three contained both diploid and tetraploid individuals. Analysis of variation in transmission ofTSWV among isofemale lines initiated with individuals used in this study revealed that 'clone assignment,' 'virus isolate' and their interaction significantly influenced vector competency. These results highlight the importance of interactions between specific T. tabaci clonal types and specific TSWV isolates underlying transmission of TSWV by T. tabaci. PMID- 23365672 TI - Circulating protein fragments of cartilage and connective tissue degradation are diagnostic and prognostic markers of rheumatoid arthritis and ankylosing spondylitis. AB - Inflammation driven connective tissue turnover is key in rheumatic diseases, such as ankylosing spondylitis (AS). Few biomarkers are available for measuring disease prognosis or the efficacy of interventions applied in these tissue related conditions. Type II collagen is the primary structural protein of cartilage and type III collagen of connective tissues, and obvious targets for the collagenalytic, which increase during tissue inflammation. The objective of the study was to investigate the diagnostic and prognostic utility of cartilage, C2M, and synovial, C3M, turnover biomarkers in AS. Serum samples were retrieved from patients suffering from AS (n = 103), RA (n = 47) and healthy controls (n = 56). AS progressors were defined as having new vertebral syndesmophytes or more that 3 unit change in mSASSS over a two-year period. Type II collagen degradation markers in serum were measured by the C2M ELISA, and type III collagen degradation by the C3M ELISA. Logistic regression and dichotomized decision tree were used to analyze the prognostic value of the markers individually or in combination. Both C2M and C3M levels were significantly higher in RA patients than in healthy controls (p<0.0001). Diagnostic utility was analyzed by ROC and areas under the curve (AUCs) were 72% and 89% for C2M and C3M, respectively. Both C2M and C3M, were significantly higher in serum samples from AS patient than from healthy controls (p<0.0001). The AUCs of C2M and C3M, respectively, were 70% and 81% for AS. A combination of C2M and C3M, dichotomized according to best cut-offs for individual markers, could correctly identify 80% of the progressors and 61% of the non-progressors. The present study is the first to show that specific biomarkers of cartilage and connective tissue degradation facilitate both diagnosis and prediction of progression of RA and AS. PMID- 23365673 TI - FOXM1 is an oncogenic mediator in Ewing Sarcoma. AB - Ewing Family Tumors (Ewing Sarcoma and peripheral Primitive Neuroectodermal Tumor) are common bone and soft tissue malignancies of childhood, adolescence and young adulthood. Chromosomal translocation in these tumors produces fusion oncogenes of the EWS/ETS class, with EWS/FLI1 being by far the most common. EWS/ETS chimera are the only well established driver mutations in these tumors and they function as aberrant transcription factors. Understanding the downstream genes whose expression is modified has been a central approach to the study of these tumors. FOXM1 is a proliferation associated transcription factor which has increasingly been found to play a role in the pathogenesis of a wide range of human cancers. Here we demonstrate that FOXM1 is expressed in Ewing primary tumors and cell lines. Reduction in FOXM1 expression in Ewing cell lines results in diminished potential for anchorage independent growth. FOXM1 expression is enhanced by EWS/FLI1, though, unlike other tumor systems, it is not driven by expression of the EWS/FLI1 target GLI1. Thiostrepton is a compound known to inhibit FOXM1 by direct binding. We show that Thiostrepton diminishes FOXM1 expression in Ewing cell lines and this reduction reduces cell viability through an apoptotic mechanism. FOXM1 is involved in Ewing tumor pathogenesis and may prove to be a useful therapeutic target in Ewing tumors. PMID- 23365674 TI - Sputum microbiota in tuberculosis as revealed by 16S rRNA pyrosequencing. AB - BACKGROUND: Tuberculosis (TB) remains a global threat in the 21st century. Traditional studies of the disease are focused on the single pathogen Mycobacterium tuberculosis. Recent studies have revealed associations of some diseases with an imbalance in the microbial community. Characterization of the TB microbiota could allow a better understanding of the disease. METHODOLOGY/PRINCIPAL FINDINGS: Here, the sputum microbiota in TB infection was examined by using 16S rRNA pyrosequencing. A total of 829,873 high-quality sequencing reads were generated from 22 TB and 14 control sputum samples. Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, and Fusobacteria were the five major bacterial phyla recovered, which together composed over 98% of the microbial community. Proteobacteria and Bacteroidetes were more represented in the TB samples and Firmicutes was more predominant in the controls. Sixteen major bacterial genera were recovered. Streptococcus, Neisseria and Prevotella were the most predominant genera, which were dominated by several operational taxonomic units grouped at a 97% similarity level. Actinomyces, Fusobacterium, Leptotrichia, Prevotella, Streptococcus, and Veillonella were found in all TB samples, possibly representing the core genera in TB sputum microbiota. The less represented genera Mogibacterium, Moryella and Oribacterium were enriched statistically in the TB samples, while a genus belonging to the unclassified Lactobacillales was enriched in the controls. The diversity of microbiota was similar in the TB and control samples. CONCLUSIONS/SIGNIFICANCE: The composition and diversity of sputum microbiota in TB infection was characterized for the first time by using high-throughput pyrosequencing. It lays the framework for examination of potential roles played by the diverse microbiota in TB pathogenesis and progression, and could ultimately facilitate advances in TB treatment. PMID- 23365675 TI - Persistence of aquatic insects across managed landscapes: effects of landscape permeability on re-colonization and population recovery. AB - Human practices in managed landscapes may often adversely affect aquatic biota, such as aquatic insects. Dispersal is often the limiting factor for successful re colonization and recovery of stressed habitats. Therefore, in this study, we evaluated the effects of landscape permeability, assuming a combination of riparian vegetation (edge permeability) and other vegetation (landscape matrix permeability), and distance between waterbodies on the colonization and recovery potential of weakly flying insects. For this purpose, we developed two models, a movement and a population model of the non-biting midge, Chironomus riparius, an aquatic insect with weak flying abilities. With the movement model we predicted the outcome of dispersal in a landscape with several linear water bodies (ditches) under different assumptions regarding landscape-dependent movement. Output from the movement model constituted the probabilities of encountering another ditch and of staying in the natal ditch or perishing in the landscape matrix, and was used in the second model. With this individual-based model of midge populations, we assessed the implications for population persistence and for recovery potential after an extreme stress event. We showed that a combination of landscape attributes from the movement model determines the fate of dispersing individuals and, once extrapolated to the population level, has a big impact on the persistence and recovery of populations. Population persistence benefited from low edge permeability as it reduced the dispersal mortality which was the main factor determining population persistence and viability. However, population recovery benefited from higher edge permeability, but this was conditional on the low effective distance that ensured fewer losses in the landscape matrix. We discuss these findings with respect to possible landscape management scenarios. PMID- 23365676 TI - Oblique bile duct predisposes to the recurrence of bile duct stones. AB - BACKGROUND AND STUDY AIMS: Bile stones represent a highly prevalent condition and abnormalities of the biliary tree predispose to stone recurrence due to development of biliary stasis. In our study, we assessed the importance of an altered bile duct course for stone formation. PATIENTS AND METHODS: 1,307 patients with choledocholithiasis in the absence of any associated hepatobiliary disease who underwent endoscopic retrograde cholangiopancreatography (ERCP) between 2002 and 2009 were analysed. The angle enclosed between the horizontal portion of the common bile duct (CBD) and the horizontal plane was measured (angle alpha). Oblique common bile duct (OCBD) was defined as a CBD with angle alpha < 45 degrees . RESULTS: 103 patients (7.9%) were found to harbour OCBD and these were compared to 104 randomly selected control subjects. Compared to controls, OCBD patients were (i) significantly older (72 +/- 13 vs. 67 +/- 13, p<0.00001); (ii) more frequently underwent a cholecystectomy (p = 0.02) and biliary surgery (p = 0.003) prior to the diagnosis and (iii) more often developed chronic pancreatitis (p = 0.04) as well as biliary fistulae (p = 0.03). Prior to and after ERCP, OCBD subjects displayed significantly elevated cholestatic parameters and angle alpha negatively correlated with common bile duct diameter (r = -0.29, p = 0.003). OCBD subjects more often required multiple back-to-back ERCP sessions to remove bile stones (p = 0.005) as well as more ERCPs later on due to recurrent stone formation (p<0.05). CONCLUSION: OCBD defines a novel variant of the biliary tree, which is associated with chronic cholestasis, hampers an efficient stone removal and predisposes to recurrence of bile duct stones. PMID- 23365677 TI - Baculovirus superinfection: a probable restriction factor on the surface display of proteins for library screening. AB - In addition to the expression of recombinant proteins, baculoviruses have been developed as a platform for the display of complex eukaryotic proteins on the surface of virus particles or infected insect cells. Surface display has been used extensively for antigen presentation and targeted gene delivery but is also a candidate for the display of protein libraries for molecular screening. However, although baculovirus gene libraries can be efficiently expressed and displayed on the surface of insect cells, target gene selection is inefficient probably due to super-infection which gives rise to cells expressing more than one protein. In this report baculovirus superinfection of Sf9 cells has been investigated by the use of two recombinant multiple nucleopolyhedrovirus carrying green or red fluorescent proteins under the control of both early and late promoters (vAcBacGFP and vAcBacDsRed). The reporter gene expression was detected 8 hours after the infection of vAcBacGFP and cells in early and late phases of infection could be distinguished by the fluorescence intensity of the expressed protein. Simultaneous infection with vAcBacGFP and vAcBacDsRed viruses each at 0.5 MOI resulted in 80% of infected cells co-expressing the two fluorescent proteins at 48 hours post infection (hpi), and subsequent infection with the two viruses resulted in similar co-infection rate. Most Sf9 cells were re-infectable within the first several hours post infection, but the re-infection rate then decreased to a very low level by 16 hpi. Our data demonstrate that Sf9 cells were easily super-infectable during baculovirus infection, and super-infection could occur simultaneously at the time of the primary infection or subsequently during secondary infection by progeny viruses. The efficiency of super-infection may explain the difficulties of baculovirus display library screening but would benefit the production of complex proteins requiring co-expression of multiple polypeptides. PMID- 23365678 TI - Diabetes and overexpression of proNGF cause retinal neurodegeneration via activation of RhoA pathway. AB - Our previous studies showed positive correlation between accumulation of proNGF, activation of RhoA and neuronal death in diabetic models. Here, we examined the neuroprotective effects of selective inhibition of RhoA kinase in the diabetic rat retina and in a model that stably overexpressed the cleavage-resistance proNGF plasmid in the retina. Male Sprague-Dawley rats were rendered diabetic using streptozotocin or stably express cleavage-resistant proNGF plasmid. The neuroprotective effects of the intravitreal injection of RhoA kinase inhibitor Y27632 were examined in vivo. Effects of proNGF were examined in freshly isolated primary retinal ganglion cell (RGC) cultures and RGC-5 cell line. Retinal neurodegeneration was assessed by counting TUNEL-positive and Brn-3a positive retinal ganglion cells. Expression of proNGF, p75(NTR), cleaved-PARP, caspase-3 and p38MAPK/JNK were examined by Western-blot. Activation of RhoA was assessed by pull-down assay and G-LISA. Diabetes and overexpression of proNGF resulted in retinal neurodegeneration as indicated by 9- and 6-fold increase in TUNEL positive cells, respectively. In vitro, proNGF induced 5-fold cell death in RGC-5 cell line, and it induced >10-fold cell death in primary RGC cultures. These effects were associated with significant upregulation of p75(NTR) and activation of RhoA. While proNGF induced TNF-alpha expression in vivo, it selectively activated RhoA in primary RGC cultures and RGC-5 cell line. Inhibiting RhoA kinase with Y27632 significantly reduced diabetes- and proNGF-induced activation of proapoptotic p38MAPK/JNK, expression of cleaved-PARP and caspase-3 and prevented retinal neurodegeneration in vivo and in vitro. Taken together, these results provide compelling evidence for a causal role of proNGF in diabetes induced retinal neurodegeneration through enhancing p75(NTR) expression and direct activation of RhoA and p38MAPK/JNK apoptotic pathways. PMID- 23365679 TI - Relationship between carotid intima media thickness and helminth infections on Flores Island, Indonesia. AB - OBJECTIVE: To examine the association between helminth infections and atherosclerosis. BACKGROUND: Chronic helminth infection, which can lead to poor nutritional status and anti-inflammatory response, might protect against the development of atherosclerosis. METHODS: A cross-sectional study was performed in Flores, Indonesia, an area highly endemic for soil-transmitted helminths (STH). Stool samples from 675 participants aged 18-80 years were collected and screened for Trichuris trichiura by microscopy and for Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, and Strongyloides stercoralis by qPCR. We collected data on body mass index (BMI), waist to hip ratio (WHR), blood pressure, fasting blood glucose (FBG), lipid, high sensitive C-reactive protein (hs-CRP), total immunoglobulin-E (TIgE) and Escherichia coli lipopolysaccharide stimulated cytokines (tumor necrosis factor and interleukin-10). In a subset of 301 elderly adults (>=40 years of age) carotid intima media thickness (cIMT) was measured. RESULTS: Participants with any STH infection had lower BMI (kg/m2) (mean difference -0.66, 95%CI [-1.26, -0.06]), WHR (-0.01, [-0.02, -0.00]), total cholesterol (mmol/L) (-0.22, [-0.43, -0.01]) and LDL-cholesterol (mmol/L) (-0.20, [-0.39, -0.00]) than uninfected participants. After additional adjustment for BMI the association between helminth infection and total cholesterol (mean difference -0.17, 95%CI [-0.37, 0.03]) as well as LDL-cholesterol (-0.15, [-0.33, 0.04]) was less pronounced. BMI, WHR, and total cholesterol were negatively associated with number species of helminth co-infections. Participants with high TIgE, an indicator of exposure to helminths, had lower FBG, TC, and HDL. The association between TIgE and TC and HDL remained significant after adjustment with BMI. No clear association was found between STH infection or TIgE and mean cIMT. CONCLUSIONS: This cross-sectional study presents evidence that helminth infections were negatively associated with risk factors for cardiovascular disease, an association at least partially mediated by an effect on BMI. The significance of this finding needs to be determined. PMID- 23365680 TI - Transsulfuration pathway thiols and methylated arginines: the Hunter Community Study. AB - BACKGROUND: Serum homocysteine, when studied singly, has been reported to be positively associated both with the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine [ADMA, via inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity] and with symmetric dimethylarginine (SDMA). We investigated combined associations between transsulfuration pathway thiols, including homocysteine, and serum ADMA and SDMA concentrations at population level. METHODS: Data on clinical and demographic characteristics, medication exposure, C-reactive protein, serum ADMA and SDMA (LC-MS/MS), and thiols (homocysteine, cysteine, taurine, glutamylcysteine, total glutathione, and cysteinylglycine; capillary electrophoresis) were collected from a sample of the Hunter Community Study on human ageing [n = 498, median age (IQR) = 64 (60-70) years]. RESULTS: REGRESSION ANALYSIS SHOWED THAT: a) age (P = 0.001), gender (P = 0.03), lower estimated glomerular filtration rate (eGFR, P = 0.08), body mass index (P = 0.008), treatment with beta-blockers (P = 0.03), homocysteine (P = 0.02), and glutamylcysteine (P = 0.003) were independently associated with higher ADMA concentrations; and b) age (P = 0.001), absence of diabetes (P = 0.001), lower body mass index (P = 0.01), lower eGFR (P<0.001), cysteine (P = 0.007), and glutamylcysteine (P < 0.001) were independently associated with higher SDMA concentrations. No significant associations were observed between methylated arginines and either glutathione or taurine concentrations. CONCLUSIONS: After adjusting for clinical, demographic, biochemical, and pharmacological confounders the combined assessment of transsulfuration pathway thiols shows that glutamylcysteine has the strongest and positive independent associations with ADMA and SDMA. Whether this reflects a direct effect of glutamylcysteine on DDAH activity (for ADMA) and/or cationic amino acid transport requires further investigations. PMID- 23365681 TI - Computational screening of the human TF-glycome provides a structural definition for the specificity of anti-tumor antibody JAA-F11. AB - Recombinant antibodies are of profound clinical significance; yet, anti carbohydrate antibodies are prone to undesirable cross-reactivity with structurally related-glycans. Here we introduce a new technology called Computational Carbohydrate Grafting (CCG), which enables a virtual library of glycans to be assessed for protein binding specificity, and employ it to define the scope and structural origin of the binding specificity of antibody JAA-F11 for glycans containing the Thomsen-Friedenreich (TF) human tumor antigen. A virtual library of the entire human glycome (GLibrary-3D) was constructed, from which 1,182 TF-containing human glycans were identified and assessed for their ability to fit into the antibody combining site. The glycans were categorized into putative binders, or non-binders, on the basis of steric clashes with the antibody surface. The analysis employed a structure of the immune complex, generated by docking the TF-disaccharide (Galbeta1-3GalNAcalpha) into a crystal structure of the JAA-F11 antigen binding fragment, which was shown to be consistent with saturation transfer difference (STD) NMR data. The specificities predicted by CCG were fully consistent with data from experimental glycan array screening, and confirmed that the antibody is selective for the TF-antigen and certain extended core-2 type mucins. Additionally, the CCG analysis identified a limited number of related putative binding motifs, and provided a structural basis for interpreting the specificity. CCG can be utilized to facilitate clinical applications through the determination of the three-dimensional interaction of glycans with proteins, thus augmenting drug and vaccine development techniques that seek to optimize the specificity and affinity of neutralizing proteins, which target glycans associated with diseases including cancer and HIV. PMID- 23365682 TI - Molecular viability testing of bacterial pathogens from a complex human sample matrix. AB - Assays for bacterial ribosomal RNA precursors (pre-rRNA) have been shown to distinguish viable from inactivated bacterial cells in drinking water samples. Because the synthesis of pre-rRNA is rapidly induced by nutritional stimulation, viable bacteria can be distinguished from inactivated cells and free nucleic acids by measuring the production of species-specific pre-rRNA in samples that have been briefly stimulated with nutrients. Here, pre-rRNA analysis was applied to bacteria from serum, a human sample matrix. In contrast to drinking water, serum is rich in nutrients that might be expected to mask the effects of nutritional stimulation. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) assays were used to detect pre-rRNA of four bacterial species: Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and the Mycobacterium tuberculosis complex. These species were chosen for their clinical significance and phylogenetic diversity (Proteobacteria, Firmicutes, and Actinobacteria). To maximize resolving power, pre-rRNA was normalized to genomic DNA of each pathogen. When viable cells were shifted from serum to bacteriological culture medium, rapid replenishment of pre-rRNA was always observed. Cells of P. aeruginosa that were inactivated in the presence of serum exhibited no pre-rRNA response to nutritional stimulation, despite strong genomic DNA signals in these samples. When semi-automated methods were used, pre-rRNA analysis detected viable A. baumannii cells in serum at densities of <=100 CFU/mL in <5.5 hours. Originally developed for rapid microbiological analysis of drinking water, ratiometric pre-rRNA analysis can also assess the viability of bacterial cells derived from human specimens, without requiring bacteriological culture. PMID- 23365683 TI - Profiling of humoral response to influenza A(H1N1)pdm09 infection and vaccination measured by a protein microarray in persons with and without history of seasonal vaccination. AB - BACKGROUND: The influence of prior seasonal influenza vaccination on the antibody response produced by natural infection or vaccination is not well understood. METHODS: We compared the profiles of antibody responses of 32 naturally infected subjects and 98 subjects vaccinated with a 2009 influenza A(H1N1) monovalent MF59 adjuvanted vaccine (Focetria, Novartis), with and without a history of seasonal influenza vaccination. Antibodies were measured by hemagglutination inhibition (HI) assay for influenza A(H1N1)pdm09 and by protein microarray (PA) using the HA1 subunit for seven recent and historic H1, H2 and H3 influenza viruses, and three avian influenza viruses. Serum samples for the infection group were taken at the moment of collection of the diagnostic sample, 10 days and 30 days after onset of influenza symptoms. For the vaccination group, samples were drawn at baseline, 3 weeks after the first vaccination and 5 weeks after the second vaccination. RESULTS: We showed that subjects with a history of seasonal vaccination generally exhibited higher baseline titers for the various HA1 antigens than subjects without a seasonal vaccination history. Infection and pandemic influenza vaccination responses in persons with a history of seasonal vaccination were skewed towards historic antigens. CONCLUSIONS: Seasonal vaccination is of significant influence on the antibody response to subsequent infection and vaccination, and further research is needed to understand the effect of annual vaccination on protective immunity. PMID- 23365684 TI - Functional analysis of the alpha-1,3-glucan synthase genes agsA and agsB in Aspergillus nidulans: agsB is the major alpha-1,3-glucan synthase in this fungus. AB - Although alpha-1,3-glucan is one of the major cell wall polysaccharides in filamentous fungi, the physiological roles of alpha-1,3-glucan remain unclear. The model fungus Aspergillus nidulans possesses two alpha-1,3-glucan synthase (AGS) genes, agsA and agsB. For functional analysis of these genes, we constructed several mutant strains in A. nidulans: agsA disruption, agsB disruption, and double-disruption strains. We also constructed several CagsB strains in which agsB expression was controlled by the inducible alcA promoter, with or without the agsA-disrupting mutation. The agsA disruption strains did not show markedly different phenotypes from those of the wild-type strain. The agsB disruption strains formed dispersed hyphal cells under liquid culture conditions, regardless of the agsA genetic background. Dispersed hyphal cells were also observed in liquid culture of the CagsB strains when agsB expression was repressed, whereas these strains grew normally in plate culture even under the agsB-repressed conditions. Fractionation of the cell wall based on the alkali solubility of its components, quantification of sugars, and (13)C-NMR spectroscopic analysis revealed that alpha-1,3-glucan was the main component of the alkali-soluble fraction in the wild-type and agsA disruption strains, but almost no alpha-1,3-glucan was found in the alkali-soluble fraction derived from either the agsB disruption strain or the CagsB strain under the agsB-repressed conditions, regardless of the agsA genetic background. Taken together, our data demonstrate that the two AGS genes are dispensable in A. nidulans, but that AgsB is required for normal growth characteristics under liquid culture conditions and is the major AGS in this species. PMID- 23365685 TI - Photo(chemo)therapy reduces circulating Th17 cells and restores circulating regulatory T cells in psoriasis. AB - BACKGROUND: Photo(chemo)therapy is widely used to treat psoriasis, the pathogenesis of which might be caused by an imbalance of Th17 cells/regulatory T cells (Treg). In the present study, we evaluated the effects of photo(chemo)therapy on the Th17/Treg balance and Treg function. METHODS: Peripheral blood was obtained from psoriasis patients treated with bath-psoralen ultraviolet A (UVA, n = 50) or narrowband ultraviolet B (UVB, n = 18), and age matched healthy volunteers (n = 20). CD3(+)CD4(+)IL-17A(+) or CD4(+)CD25(+)Foxp3(+)cells were analyzed to estimate Th17 or Treg number by fluorescence-activated cell sorting. Moreover, CD4(+) CD25(-) T cells from patients treated with PUVA(n = 14) were incubated in CFSE and activated with or without CD4(+) CD25(+)T cells, and the suppressive function of CD4(+) CD25(+)T cells were analyzed. RESULTS: Photo(chemo)therapy significantly reduced Th17 levels from 5.66 +/- 3.15% to 2.96 +/- 2.89% in patients with increased Th17 (Th17/CD4>3.01% [mean+SD of controls]). In contrast, photo(chemo)therapy significantly increased Treg levels from 2.77 +/- 0.75 to 3.40 +/- 1.88% in patients with less than 4.07% Treg level, defined as the mean of controls. Furthermore, while Treg suppressed the CD4(+)CD25(-) T cell proliferation to a greater extent in controls (Treg Functional Ratio 94.4 +/- 4.28%) than in patients (70.3+/-25.1%), PUVA significantly increased Treg Functional Ratio to 88.1 +/- 6.47%. Th17 levels in severe patients (>30 PASI) were significantly higher as compared to controls. Th17 levels that were left after treatment in the patients not achieving PASI 50 (3.78 +/- 4.18%) were significantly higher than those in the patients achieving PASI 75 (1.83+/-1.87%). Treg levels in patients achieving PASI 90 (4.89 +/- 1.70%) were significantly higher than those in the patients not achieving PASI 90 (3.90 +/- 1.66%). Treg levels prior to treatment with Th17 high decreased group (5.16 +/- 2.20%) was significantly higher than that with Th17 high increased group (3.33 +/- 1.39%). CONCLUSION: These findings indicate that Treg is dysfunctional in psoriasis patients, and photochemotherapy restores those dysfunctional Treg. Photo(chemo)therapy resolved the Th17/Treg imbalance in patients with psoriasis. PMID- 23365686 TI - Potassium and ionic strength effects on the conformational and thermal stability of two aldehyde dehydrogenases reveal structural and functional roles of K+ binding sites. AB - Many aldehyde dehydrogenases (ALDHs) have potential potassium-binding sites of as yet unknown structural or functional roles. To explore possible K(+)-specific effects, we performed comparative structural studies on the tetrameric betaine aldehyde dehydrogenase from Pseudomonas aeruginosa (PaBADH) and on the dimeric BADH from spinach (SoBADH), whose activities are K(+)-dependent and K(+) independent, respectively, although both enzymes contain potassium-binding sites. Size exclusion chromatography, dynamic light scattering, far- and near-UV circular dichroism, and extrinsic fluorescence results indicated that in the absence of K(+) ions and at very low ionic strength, PaBADH remained tetrameric but its tertiary structure was significantly altered, accounting for its inactivation, whereas SoBADH formed tetramers that maintained the native tertiary structure. The recovery of PaBADH native tertiary-structure was hyperbolically dependent on KCl concentration, indicating potassium-specific structuring effects probably arising from binding to a central-cavity site present in PaBADH but not in SoBADH. K(+) ions stabilized the native structure of both enzymes against thermal denaturation more than did tetraethylammonium (TEA(+)) ions. This indicated specific effects of potassium on both enzymes, particularly on PaBADH whose apparent T(m) values showed hyperbolical dependence on potassium concentration, similar to that observed with the tertiary structure changes. Interestingly, we also found that thermal denaturation of both enzymes performed in low ionic-strength buffers led to formation of heat-resistant, inactive soluble aggregates that retain 80% secondary structure, have increased beta-sheet content and bind thioflavin T. These structured aggregates underwent further thermal-induced aggregation and precipitation when the concentrations of KCl or TEACl were raised. Given that PaBADH and SoBADH belong to different ALDH families and differ not only in amino acid composition but also in association state and surface electrostatic potential, the formation of this kind of beta-sheet pre fibrillar aggregates, not described before for any ALDH enzyme, appear to be a property of the ALDH fold. PMID- 23365687 TI - Substrate recognition and motion mode analyses of PFV integrase in complex with viral DNA via coarse-grained models. AB - HIV-1 integrase (IN) is an important target in the development of drugs against the AIDS virus. Drug design based on the structure of IN was markedly hampered due to the lack of three-dimensional structure information of HIV-1 IN-viral DNA complex. The prototype foamy virus (PFV) IN has a highly functional and structural homology with HIV-1 IN. Recently, the X-ray crystal complex structure of PFV IN with its cognate viral DNA has been obtained. In this study, both Gaussian network model (GNM) and anisotropy network model (ANM) have been applied to comparatively investigate the motion modes of PFV DNA-free and DNA-bound IN. The results show that the motion mode of PFV IN has only a slight change after binding with DNA. The motion of this enzyme is in favor of association with DNA, and the binding ability is determined by its intrinsic structural topology. Molecular docking experiments were performed to gain the binding modes of a series of diketo acid (DKA) inhibitors with PFV IN obtained from ANM, from which the dependability of PFV IN-DNA used in the drug screen for strand transfer (ST) inhibitors was confirmed. It is also found that the functional groups of keto enol, bis-diketo, tetrazole and azido play a key role in aiding the recognition of viral DNA, and thus finally increase the inhibition capability for the corresponding DKA inhibitor. Our study provides some theoretical information and helps to design anti-AIDS drug based on the structure of IN. PMID- 23365688 TI - Habitat characteristics of forest fragments determine specialisation of plant frugivore networks in a mosaic forest landscape. AB - Plant-frugivore networks play a key role in the regeneration of sub-tropical forest ecosystems. However, information about the impact of habitat characteristics on plant-frugivore networks in fragmented forests is scarce. We investigated the importance of fruit abundance, fruiting plant species richness and canopy cover within habitat fragments for the structure and robustness of plant-frugivore networks in a mosaic forest landscape of South Africa. In total, 53 avian species were involved in fruit removal of 31 fleshy-fruiting plant species. Species specialisation was always higher for plants than for frugivores. Both species and network-level specialisation increased with increasing fruit abundance and decreased with increasing fruiting plant species richness and canopy cover within fragments. Interaction diversity was unaffected by fruit abundance and canopy cover, but increased slightly with increasing fruiting plant species richness. These findings suggest that especially the availability of resources is an important determinant of the structure of plant-frugivore networks in a fragmented forest landscape. PMID- 23365689 TI - Cellular robustness conferred by genetic crosstalk underlies resistance against chemotherapeutic drug doxorubicin in fission yeast. AB - Doxorubicin is an anthracycline antibiotic that is among one of the most commonly used chemotherapeutic agents in the clinical setting. The usage of doxorubicin is faced with many problems including severe side effects and chemoresistance. To overcome these challenges, it is important to gain an understanding of the underlying molecular mechanisms with regards to the mode of action of doxorubicin. To facilitate this aim, we identified the genes that are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe. We further demonstrated interplay between factors controlling various aspects of chromosome metabolism, mitochondrial respiration and membrane transport. In the nucleus we observed that the subunits of the Ino80, RSC, and SAGA complexes function in the similar epistatic group that shares significant overlap with the homologous recombination genes. However, these factors generally act in synergistic manner with the chromosome segregation regulator DASH complex proteins, possibly forming two major arms for regulating doxorubicin resistance in the nucleus. Simultaneous disruption of genes function in membrane efflux transport or the mitochondrial respiratory chain integrity in the mutants defective in either Ino80 or HR function resulted in cumulative upregulation of drug-specific growth defects, suggesting a rewiring of pathways that synergize only when the cells is exposed to the cytotoxic stress. Taken together, our work not only identified factors that are required for survival of the cells in the presence of doxorubicin but has further demonstrated that an extensive molecular crosstalk exists between these factors to robustly confer doxorubicin resistance. PMID- 23365690 TI - Systematic functional comparative analysis of four single-stranded DNA-binding proteins and their affection on viral RNA metabolism. AB - The accumulation of single-stranded DNA-binding (SSB) proteins is essential for organisms and has various applications. However, no study has simultaneously and systematically compared the characteristics of SSB proteins. In addition, SSB proteins may bind RNA and play an unknown biological role in RNA metabolism. Here, we expressed a novel species of SSB protein derived from Thermococcus kodakarensis KOD1 (KOD), as well as SSB proteins from Thermus thermophilus (TTH), Escherichia coli, and Sulfolobus Solfataricus P2 (SSOB), abbreviated kod, tth, bl21, and ssob, respectively. These SSB proteins could bind ssDNA and viral RNA. bl21 resisted heat treatment for more than 9 h, Ssob and kod could withstand 95 degrees C for 10 h and retain its ssDNA- and RNA-binding ability. Four SSB proteins promoted the specificity of the DNA polymerase in PCR-based 5- and 9-kb genome fragment amplification. kod also increased the amplification of a 13-kb PCR product, and SSB protein-bound RNA resisted Benzonase digestion. The SSB proteins could also enter the host cell bound to RNA, which resulted in modulation of viral RNA metabolism, particularly ssob and bl21. PMID- 23365691 TI - Wrapping effects within a proposed function-rescue strategy for the Y220C oncogenic mutation of protein p53. AB - Soluble proteins must protect their structural integrity from water attack by wrapping interactions which imply the clustering of nonpolar residues around the backbone hydrogen bonds. Thus, poorly wrapped hydrogen bonds constitute defects which have been identified as promoters of protein associations since they favor the removal of hydrating molecules. More specifically, a recent study of our group has shown that wrapping interactions allow the successful identification of protein binding hot spots. Additionally, we have also shown that drugs disruptive of protein-protein interfaces tend to mimic the wrapping behavior of the protein they replace. Within this context, in this work we study wrapping three body interactions related to the oncogenic Y220C mutation of the tumor suppressor protein p53. Our computational results rationalize the oncogenic nature of the Y220C mutation, explain the binding of a drug-like molecule already designed to restore the function of p53 and provide clues to help improve this function rescue strategy and to apply in other drug design or re-engineering techniques. PMID- 23365692 TI - Genomic and functional analysis of the type VI secretion system in Acinetobacter. AB - The genus Acinetobacter is comprised of a diverse group of species, several of which have raised interest due to potential applications in bioremediation and agricultural purposes. In this work, we show that many species within the genus Acinetobacter possess the genetic requirements to assemble a functional type VI secretion system (T6SS). This secretion system is widespread among Gram negative bacteria, and can be used for toxicity against other bacteria and eukaryotic cells. The most studied species within this genus is A. baumannii, an emerging nosocomial pathogen that has become a significant threat to healthcare systems worldwide. The ability of A. baumannii to develop multidrug resistance has severely reduced treatment options, and strains resistant to most clinically useful antibiotics are frequently being isolated. Despite the widespread dissemination of A. baumannii, little is known about the virulence factors this bacterium utilizes to cause infection. We determined that the T6SS is conserved and syntenic among A. baumannii strains, although expression and secretion of the hallmark protein Hcp varies between strains, and is dependent on TssM, a known structural protein required for T6SS function. Unlike other bacteria, A. baumannii ATCC 17978 does not appear to use its T6SS to kill Escherichia coli or other Acinetobacter species. Deletion of tssM does not affect virulence in several infection models, including mice, and did not alter biofilm formation. These results suggest that the T6SS fulfils an important but as-yet-unidentified role in the various lifestyles of the Acinetobacter spp. PMID- 23365693 TI - Nationwide registry-based analysis of cancer clustering detects strong familial occurrence of Kaposi sarcoma. AB - Many cancer predisposition syndromes are rare or have incomplete penetrance, and traditional epidemiological tools are not well suited for their detection. Here we have used an approach that employs the entire population based data in the Finnish Cancer Registry (FCR) for analyzing familial aggregation of all types of cancer, in order to find evidence for previously unrecognized cancer susceptibility conditions. We performed a systematic clustering of 878,593 patients in FCR based on family name at birth, municipality of birth, and tumor type, diagnosed between years 1952 and 2011. We also estimated the familial occurrence of the tumor types using cluster score that reflects the proportion of patients belonging to the most significant clusters compared to all patients in Finland. The clustering effort identified 25,910 birth name-municipality based clusters representing 183 different tumor types characterized by topography and morphology. We produced information about familial occurrence of hundreds of tumor types, and many of the tumor types with high cluster score represented known cancer syndromes. Unexpectedly, Kaposi sarcoma (KS) also produced a very high score (cluster score 1.91, p-value <0.0001). We verified from population records that many of the KS patients forming the clusters were indeed close relatives, and identified one family with five affected individuals in two generations and several families with two first degree relatives. Our approach is unique in enabling systematic examination of a national epidemiological database to derive evidence of aberrant familial aggregation of all tumor types, both common and rare. It allowed effortless identification of families displaying features of both known as well as potentially novel cancer predisposition conditions, including striking familial aggregation of KS. Further work with high throughput methods should elucidate the molecular basis of the potentially novel predisposition conditions found in this study. PMID- 23365695 TI - Oxidative stress markers in prostate cancer patients after HDR brachytherapy combined with external beam radiation. AB - Assessment of oxidative stress markers was perfomed in prostate cancer (PCa) patients subjected to high-dose brachytherapy (HDR) with external beam radiotherapy (EBRT). Sixty men with PCa were subjected to combined two-fraction treatment with HDR (tot. 20 Gy) and EBRT (46 Gy). Blood samples were taken before treatment, immediately afterwards, after 1.5-3 months, and approx. 2 years. Control group consisted of 30 healthy men. Erythrocyte glutathione peroxidase activity in the patients was lower than in healthy subjects by 34% (P < 0.001), 50% (P < 0.001), 30% (P < 0.05), and 61% (P < 0.001), respectively, at all periods. No significant differences were found by comparing superoxide dismutase and catalase activity in PCa patients with that of the controls. After 2 years of the end of treatment, the activity of studied enzymes demonstrated a decreasing tendency versus before therapy. Blood plasma thiobarbituric acid reactive substances (TBARS) concentration was higher than in the controls at all periods, while erythrocyte TBARS decreased after 2 years to control levels. The results confirm that in the course of PCa, imbalance of oxidant-antioxidant processes occurs. The therapy did not alter the levels of oxidative stress markers, which may prove its applicability. Two years is too short a period to restore the oxidant-antioxidant balance. PMID- 23365694 TI - Age-associated changes in monocyte and innate immune activation markers occur more rapidly in HIV infected women. AB - BACKGROUND: Aging is associated with immune dysfunction and the related development of conditions with an inflammatory pathogenesis. Some of these immune changes are also observed in HIV infection, but the interaction between immune changes with aging and HIV infection are unknown. Whilst sex differences in innate immunity are recognized, little research into innate immune aging has been performed on women. METHODS: This cross-sectional study of HIV positive and negative women used whole blood flow cytometric analysis to characterize monocyte and CD8(+) T cell subsets. Plasma markers of innate immune activation were measured using standard ELISA-based assays. RESULTS: HIV positive women exhibited elevated plasma levels of the innate immune activation markers CXCL10 (p<0.001), soluble CD163 (sCD163, p = 0.001), sCD14 (p = 0.022), neopterin (p = 0.029) and an increased proportion of CD16(+) monocytes (p = 0.009) compared to uninfected controls. Levels of the innate immune aging biomarkers sCD163 and the proportion of CD16(+) monocytes were equivalent to those observed in HIV negative women aged 14.5 and 10.6 years older, respectively. CXCL10 increased with age at an accelerated rate in HIV positive women (p = 0.002) suggesting a synergistic effect between HIV and aging on innate immune activation. Multivariable modeling indicated that age-related increases in innate immune biomarkers CXCL10 and sCD163 are independent of senescent changes in CD8(+) T lymphocytes. CONCLUSIONS: Quantifying the impact of HIV on immune aging reveals that HIV infection in women confers the equivalent of a 10-14 year increase in the levels of innate immune aging markers. These changes may contribute to the increased risk of inflammatory age-related diseases in HIV positive women. PMID- 23365696 TI - Exhaustive training increases uncoupling protein 2 expression and decreases Bcl 2/Bax ratio in rat skeletal muscle. AB - This work investigates the effects of oxidative stress due to exhaustive training on uncoupling protein 2 (UCP2) and Bcl-2/Bax in rat skeletal muscles. A total of 18 Sprague-Dawley female rats were randomly divided into three groups: the control group (CON), the trained control group (TC), and the exhaustive trained group (ET). Malondialdehyde (MDA), superoxide dismutase (SOD), xanthine oxidase (XOD), ATPase, UCP2, and Bcl-2/Bax ratio in red gastrocnemius muscles were measured. Exhaustive training induced ROS increase in red gastrocnemius muscles, which led to a decrease in the cell antiapoptotic ability (Bcl-2/Bax ratio). An increase in UCP2 expression can reduce ROS production and affect mitochondrial energy production. Thus, oxidative stress plays a significant role in overtraining. PMID- 23365697 TI - A rare cause of neural foraminal widening. AB - The differential diagnosis for lesions causing neural foraminal widening is vast. The majority are solitary benign peripheral nerve sheath tumours, such as neurofibromas or schwannomas. We present a case of a rare cause of neural foraminal expansion secondary to a posterior thoracic extradural angiolipoma. We describe the presence of chemical shift artefact on post gadolinium T1-weighted imaging as indirect evidence of a fatty component. This potentially important diagnostic sign may raise the suspicion of angiolipoma, especially in an isointense or hypointense dumbbell lesion on T1-weighted imaging, and has not been described previously in this context. Accurate radiological diagnosis of an angiolipoma is important to reduce unexpected haemorrhagic complications from biopsy or resection of the lesion. PMID- 23365698 TI - A complex pulmonary vein varix -- diagnosis with ECG gated MDCT, MRI and invasive pulmonary angiography. AB - A case of an asymptomatic 32-year-old male with a complex congenital pulmonary vein varix is reported herein. Chest X-ray incidentally revealed a tubular opacity passing from the periphery of the left lingula to the mediastinum. ECG gated multidetector computed tomography showed the opacity to be a vessel emptying into the left atrium via the left superior pulmonary vein. In addition, a second vascular structure was noted within the posterior mediastinum that was emptying into the same pulmonary vein. These findings were also confirmed by magnetic resonance imaging, 4D magnetic resonance angiography and invasive arterial angiography. Based on multimodality imaging findings the diagnosis of complex congenital pulmonary venous varix with posterior mediastinal extension was established. PMID- 23365699 TI - Dermoid cyst of the pancreas: a case report with literature review. AB - Pancreatic dermoid cysts represent a rare entity with 35 cases described in the world literature, including the present one. Pre-operative diagnosis is difficult, with definitive diagnosis usually taking place intra-operatively. We report the case of a 63 year old male with a symptomatic, 6 cm cystic mass in the body of the pancreas. The pre-operative evaluation suggested a cystic neoplasm, but was indeterminate as to whether the lesion was benign or malignant. The diagnosis of dermoid cyst was made intra-operatively with frozen section. Although the diagnosis could not be made pre-operatively this retrospective report highlights the difficulty in evaluating cystic pancreatic lesions by imaging and summarizes the current body of knowledge on this rare entity. PMID- 23365700 TI - Bladder schwannoma -- a case presentation. AB - Bladder schwannomas are exceedingly rare, benign or malignant, nerve sheath tumors that are most often discovered in patients with a known diagnosis of Neurofibromatosis type 1 (NF1). A few sporadic case reports of bladder schwannoma have been published in urologic, obstetric/gynecologic, and pathologic journals. However, this is the first case report in the radiologic literature where computed tomography imaging and radiology-specific descriptions are discussed. Furthermore, the patient presented in this case is only the fifth published patient without NF1 to be diagnosed with a bladder schwannoma, to the best of our knowledge. PMID- 23365701 TI - Chondrosarcoma in childhood: the radiologic and clinical conundrum. AB - Less than 10% of chondrosarcomas occur in children. In addition, as little as 0.5% of low-grade chondrosarcomas arise secondarily from benign chondroid lesions. The presence of focal pain is often used to crudely distinguish a chondrosarcoma (which is usually managed with wide surgical excision), from a benign chondroid lesion (which can be followed by clinical exams and imaging surveillance). Given the difficulty of localizing pain in the pediatric population, initial radiology findings and short-interval follow-up, both imaging and clinical, are critical to accurately differentiate a chondrosarcoma from a benign chondroid lesion. To our knowledge, no case in the literature discusses a chondrosarcoma possibly arising secondarily from an enchondroma in a pediatric patient. We present a clinicopathologic and radiology review of conventional chondrosarcomas. We also attempt to further the understanding of how to manage a chondroid lesion in the pediatric patient with only vague or bilateral complaints of pain. PMID- 23365702 TI - Rare lymphoid malignancies of the breast: report of two cases illustrating potential diagnostic techniques. AB - Two cases of lymphoid malignancy involving the breast are herein presented. Both patients were admitted with a palpable breast mass. Ultrasound demonstrated hypoechoic, ill-defined lesions of the breast in both patients; mammogram also showed spiculated breast densities. Both patients underwent core biopsy, which revealed lymphomatous cells. Total-body evaluation was also performed by computed tomography and positron emission tomography/computed tomography revealing no other fluorodeoxyglucose-avid foci in the first case and supra and subdiaphragmatic disease in the second one. PMID- 23365706 TI - Primary tuberculosis in a malnourished adolescent. AB - Although the overall prevalence of tuberculosis has decreased in the United States, with the increasing prevalence of tuberculosis globally, higher rates of tuberculosis in some states and localities have been reported, with some component probably related to immigrant populations. We report a case of primary pulmonary tuberculosis in a malnourished adolescent. PMID- 23365707 TI - Radiation necrosis of the pons after radiotherapy for nasopharyngeal carcinoma: diagnosis and treatment. AB - We report a case of radiation necrosis in an unusual location, the pons, in a patient who had received chemoradiation for nasopharyngeal carcinoma (NPC) over one year prior to presentation. This patient presented with subacute onset of ataxic hemiparesis and slurred speech. Initial magnetic resonance imaging (MRI) studies showed two 1-2 cm peripherally contrast-enhancing lesions in the pons with extensive surrounding edema. Proton magnetic resonance spectroscopy (MRS) played a key role in narrowing the differential diagnosis to radiation necrosis. The patient underwent biweekly bevacizumab therapy and has remained clinically stable with radiologic improvement of his lesion. In addition to this case, we present an overview of the use of advanced neuroimaging in distinguishing radiation necrosis of the central nervous system (CNS) from other entities as well as the role of bevacizumab in treatment. PMID- 23365708 TI - Esophageal lipoma: a rare tumor. AB - Esophageal lipomas are rare tumors, making up 0.4% of all digestive tract benign neoplasms. Most of these lesions are clinically silent as a result of their small size, however, the majority of lesions over 4 cm have been reported to cause dysphagia, regurgitation and/or epigastralgia. We report a case of a 53 year-old African American female who presented with dysphagia. Computed tomography of the chest and esophagram confirmed esophageal lipoma as the cause of the patient's symptoms. Accurately diagnosing an esophageal lipoma is crucial in order to rule out potential malignant lesions, relieve patient symptoms and plan the appropriate treatment. PMID- 23365709 TI - Ureteral fibroepithelial polyp causing urinary obstruction. AB - Ureteral polyps are rare causes of ureteropelvic junction (UPJ) obstruction, particularly in children. We report a nine year-old boy with UPJ obstruction initially suggestive of an obstructive urinary stone. CT showed intraureteral calcification at the UPJ and hydronephrosis. A retrograde pyelogram showed narrowing at the UPJ and partial obstruction that was found to be a ureteral polyp. This case illustrates a rare cause of UPJ obstruction that should be considered when the imaging findings and presentation are atypical for more common etiologies of ureteral obstruction. PMID- 23365710 TI - Localized cystic disease of the kidney: a rare entity. AB - Localized cystic disease of the kidney is a benign nonsurgical entity and presents with multiple cystic lesions in just one portion of the kidney or involves the entire one kidney. We report a case of localized cystic disease of the kidney in a 16 year-old-male. This patient underwent an ultrasound examination and incidentally found to have multiple cysts in the right kidney whereas the left kidney was normal. Diagnosis was confirmed by typical MRI findings, absence of any family history, normal results of urine analysis and renal function tests. PMID- 23365711 TI - Merosin-deficient congenital muscular dystrophy (MDCMD): a case report with MRI, MRS and DTI findings. AB - Congenital muscular dystrophy (CMD) comprises a heterogeneous group of disorders present at birth with muscle weakness, hypotonia and contractures. Congenital muscular dystrophy (CMD) comprises a heterogeneous group of disorders with muscle weakness, hypotonia and contractures present at birth. A particular subset of classic CMD is characterized by a complete absence of merosin. Merosin-deficient congenital muscular dystrophy (MDCMD) is a rare genetic disease involving the central and peripheral nervous system in the childhood. High signal intensities are often observed throughout the centrum semiovale, periventricular, and sub cortical white matters on T2-weighted images in MRI brain in children with MDCMD. Apparent diffusion coefficient (ADC) map may reveal increased signal intensity and apparent diffusion coefficient values in the periventricular and deep white matters. These white matter findings, observed in late infancy, decrease in severity with age. The pathogenesis of these changes remains uncertain at present. In this article, we outline the specific MR imaging findings seen in a patient with documented MDCMD and also suggest the causes. PMID- 23365712 TI - Unusual appearance and presentation of supratentorial subependymoma in an adult patient. AB - We report a case of a large, heterogeneously enhancing, pathologically proven, supratentorial subependymoma in a 31-year-old male patient presenting with headache, nausea and vomiting as well as gait disturbances. Although most supratentorial subependymomas have distinctive MR features, our case demonstrated imaging findings that made it indistinguishable from other more aggressive malignant supratentorial intraventricular lesions. It is of paramount importance to consider supratentorial subependymomas in the differential diagnosis of supratentorial lesions, even if their radiological features were atypical. PMID- 23365713 TI - Imaging of ruptured endocyst in an isolated intramuscular hydatid cyst--the Scroll appearance. AB - The present article reports a case of a 21 years male that was diagnosed to have isolated intramuscular hydatid cyst of the biceps brachii on Ultrasound and MRI. The 'Scroll appearance' of the ruptured endocyst in this case is likely to be an intervening transient stage in evolution of the disease and also indicates recent rupture of the endocyst. PMID- 23365714 TI - Paraperitoneal inguinal hernia of ureter. AB - Inguinal herniation of ureter is an uncommon finding that can potentially lead to obstructive uropathy. We report a case of inguinal herniation of ureter discovered incidentally during workup for acute renal failure and ultrasound finding of hydronephrosis. PMID- 23365715 TI - Presentation of ileal Burkitt lymphoma in children. AB - Burkitt lymphoma is a highly aggressive form of Non-Hodgkin lymphoma that responds favorably if diagnosed accurately and treated early. Recognition of the various radiologic manifestations of Burkitt lymphoma can help guide the clinician to expedite appropriate chemotherapy. We present two cases that illustrate different radiologic presentations of this aggressive gastrointestinal malignancy in children. Case 1 features a 7-year-old boy who presented to our hospital with recurrent ileocecal intussusception. Case 2 describes a 16-year-old male with history of blood-streaked stools. Ileocectomy was performed in both cases and histologic analysis showed the "starry sky pattern" and t(8;14) translocation, classic for Burkitt lymphoma. Both patients remain disease-free following surgical excision and chemotherapy. PMID- 23365716 TI - Advances in oral anticoagulation treatment: the safety and efficacy of rivaroxaban in the prevention and treatment of thromboembolism. AB - Arterial and venous thromboembolic diseases are a clinical and economic burden worldwide. In addition to traditional agents such as vitamin K antagonists and heparins, newer oral agents - such as the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, and the direct thrombin inhibitor dabigatran - have been shown to be effective across several indications. Rivaroxaban has been shown to have predictable pharmacokinetic and pharmacodynamic properties, including a rapid onset of action. In addition, there is no requirement for routine coagulation monitoring; and no dose adjustment is necessary for age alone, sex, or body weight. Rivaroxaban has successfully met primary efficacy and safety endpoints in large, randomized phase III trials across several indications, including: prevention of venous thromboembolism in orthopedic patients undergoing elective hip or knee replacement surgery; treatment of deep vein thrombosis and secondary prevention of deep vein thrombosis and pulmonary embolism; stroke prevention in patients with atrial fibrillation; and secondary prevention of acute coronary syndrome. Rivaroxaban and the other newer oral anticoagulants are likely to improve outcomes in the prevention and treatment of thromboembolic events, and will offer patients and physicians alternative treatment options. PMID- 23365717 TI - Transplant coordinators' perceived impact of availability of multiple generic immunosuppression therapies on patients, workload, and posttransplant maintenance therapy. AB - Background. No studies have evaluated the impact of multiple generic immunosuppression medications on transplant coordinators (TCs) and patients. Methods. A cross-sectional, multicenter online survey of TCs managing transplant recipients' outpatient immunosuppression was undertaken to assess TCs' perceptions of the impact of multiple generic immunosuppression therapies on patients and workload. Results. Forty-six of 106 transplant centers contacted (43%) completed the survey, with usable information from 34 TCs (53% in centers performing >100 solid organ transplants annually, 82% registered nurses, and 68% with >5-year experience working with transplant patients). TCs indicated that "change in strength," "switching from branded to generics," "heavy pill burden," and "switching from one generic to another" were the four most frequent reasons for patient confusion regarding immunosuppression. TCs reported increased patient confusion over the previous year for patients on generic immunosuppression therapy: 44% answered >=3 patient calls/day regarding confusion over immunosuppression therapy. Most TCs indicated increased workload since the introduction of generic immunosuppression therapy. TCs perceived "acute rejection rates," "rate of graft loss," and "poor patient adherence" as the three most likely consequences of multiple generic immunosuppression therapy. Conclusion. TCs associated availability of multiple generic immunosuppression therapy with increased patient confusion and time spent addressing patient concerns. PMID- 23365718 TI - Helminths: Immunoregulation and Inflammatory Diseases-Which Side Are Trichinella spp. and Toxocara spp. on? AB - Macropathogens, such as multicellular helminths, are considered masters of immunoregulation due to their ability to escape host defense and establish chronic infections. Molecular crosstalk between the host and the parasite starts immediately after their encounter, which influences the course and development of both the innate and adaptive arms of the immune response. Helminths can modulate dendritic cells (DCs) function and induce immunosuppression which is mediated by a regulatory network that includes regulatory T (Treg) cells, regulatory B (Breg) cells, and alternatively activated macrophages (AAMs). In this way, helminths suppress and control both parasite-specific and unrelated immunopathology in the host such as Th1-mediated autoimmune and Th2-mediated allergic diseases. However, certain helminths favour the development or exacerbation of allergic responses. In this paper, the cell types that play an essential role in helminth-induced immunoregulation, the consequences for inflammatory diseases, and the contrasting effects of Toxocara and Trichinella infection on allergic manifestations are discussed. PMID- 23365720 TI - Ischemia induces release of endogenous amino acids from the cerebral cortex and cerebellum of developing and adult mice. AB - Ischemia enhanced release of endogenous neuroactive amino acids from cerebellar and cerebral cortical slices. More glutamate was released in adult than developing mice. Taurine release enhanced by K(+) stimulation and ischemia was more than one magnitude greater than that of GABA or glutamate in the developing cerebral cortex and cerebellum, while in adults the releases were almost comparable. Aspartate release was prominently enhanced by both ischemia and K(+) stimulation in the adult cerebral cortex. In the cerebellum K(+) stimulation and ischemia evoked almost 10-fold greater GABA release in 3-month olds than in 7-day olds. The release of taurine increased severalfold in the cerebellum of 7-day-old mice in high-K(+) media, whereas the K(+)-evoked effect was rather small in adults. In 3-month-old mice no effects of K(+) stimulation or ischemia were seen in the release of aspartate, glycine, glutamine, alanine, serine, or threonine. The releases from the cerebral cortex and cerebellum were markedly different and also differed between developing and adult mice. In developing mice only the release of inhibitory taurine may be large enough to counteract the harmful effects of excitatory amino acids in ischemia in both cerebral cortex and cerebellum, in particular since at that age the release of glutamate and aspartate cannot be described as massive. PMID- 23365719 TI - Infectious keratitis: secreted bacterial proteins that mediate corneal damage. AB - Ocular bacterial infections are universally treated with antibiotics, which can eliminate the organism but cannot reverse the damage caused by bacterial products already present. The three very common causes of bacterial keratitis-Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae-all produce proteins that directly or indirectly cause damage to the cornea that can result in reduced vision despite antibiotic treatment. Most, but not all, of these proteins are secreted toxins and enzymes that mediate host cell death, degradation of stromal collagen, cleavage of host cell surface molecules, or induction of a damaging inflammatory response. Studies of these bacterial pathogens have determined the proteins of interest that could be targets for future therapeutic options for decreasing corneal damage. PMID- 23365721 TI - Role of Renin-Angiotensin system and oxidative stress on vascular inflammation in insulin resistence model. AB - (1) This study aims to demonstrate the causal involvement of renin angiotensin system (RAS) and oxidative stress (OS) on vascular inflammation in an experimental model of metabolic syndrome (MS) achieved by fructose administration to spontaneously hypertensive rats (FFHR) during 12 weeks. (2) Chronic treatment with candesartan (C) (10 mg/kg per day for the last 6 weeks) or 4OH-Tempol (T) (10(-3) mmol/L in drinking water for the last 6 weeks) reversed the increment in metabolic variables and systolic blood pressure. In addition, chronic C treatment reverted cardiovascular remodeling but not T. (3) Furthermore, chronic treatment with C was able to completely reverse the expression of NF-kappaB and VCAM-1, but T only reduced the expression. C reduced the expression of proatherogenic cytokines as CINC2, CINC3, VEGF, Leptin, TNF-alpha, and MCP-1 and also significantly reduced MIP-3, beta-NGF, and INF-gamma in vascular tissue in this experimental model. T was not able to substantially modify the expression of these cytokines. (4) The data suggest the involvement of RAS in the expression of inflammatory proteins at different vascular levels, allowing the creation of a microenvironment suitable for the creation, perpetuation, growth, and destabilization of vascular injury. PMID- 23365722 TI - The Angiotensin-melatonin axis. AB - Accumulating evidence indicates that various biological and neuroendocrine circadian rhythms may be disrupted in cardiovascular and metabolic disorders. These circadian alterations may contribute to the progression of disease. Our studies direct to an important role of angiotensin II and melatonin in the modulation of circadian rhythms. The brain renin-angiotensin system (RAS) may modulate melatonin synthesis, a hormone with well-established roles in regulating circadian rhythms. Angiotensin production in the central nervous system may not only influence hypertension but also appears to affect the circadian rhythm of blood pressure. Drugs acting on RAS have been proven effective in the treatment of cardiovascular and metabolic disorders including hypertension and diabetes mellitus (DM). On the other hand, since melatonin is capable of ameliorating metabolic abnormalities in DM and insulin resistance, the beneficial effects of RAS blockade could be improved through combined RAS blocker and melatonin therapy. Contemporary research is evidencing the existence of specific clock genes forming central and peripheral clocks governing circadian rhythms. Further research on the interaction between these two neurohormones and the clock genes governing circadian clocks may progress our understanding on the pathophysiology of disease with possible impact on chronotherapeutic strategies. PMID- 23365723 TI - Production of Biomass-Degrading Multienzyme Complexes under Solid-State Fermentation of Soybean Meal Using a Bioreactor. AB - Biomass-degrading enzymes are one of the most costly inputs affecting the economic viability of the biochemical route for biomass conversion into biofuels. This work evaluates the effects of operational conditions on biomass-degrading multienzyme production by a selected strain of Aspergillus niger. The fungus was cultivated under solid-state fermentation (SSF) of soybean meal, using an instrumented lab-scale bioreactor equipped with an on-line automated monitoring and control system. The effects of air flow rate, inlet air relative humidity, and initial substrate moisture content on multienzyme (FPase, endoglucanase, and xylanase) production were evaluated using a statistical design methodology. Highest production of FPase (0.55 IU/g), endoglucanase (35.1 IU/g), and xylanase (47.7 IU/g) was achieved using an initial substrate moisture content of 84%, an inlet air humidity of 70%, and a flow rate of 24 mL/min. The enzymatic complex was then used to hydrolyze a lignocellulosic biomass, releasing 4.4 g/L of glucose after 36 hours of saccharification of 50 g/L pretreated sugar cane bagasse. These results demonstrate the potential application of enzymes produced under SSF, thus contributing to generate the necessary technological advances to increase the efficiency of the use of biomass as a renewable energy source. PMID- 23365724 TI - The Effect of D-(-)-arabinose on Tyrosinase: An Integrated Study Using Computational Simulation and Inhibition Kinetics. AB - Tyrosinase is a ubiquitous enzyme with diverse physiologic roles related to pigment production. Tyrosinase inhibition has been well studied for cosmetic, medicinal, and agricultural purposes. We simulated the docking of tyrosinase and D-(-)-arabinose and found a binding energy of -4.5 kcal/mol for theup-formof D-( )-arabinose and -4.4 kcal/mol for thedown-form of D-(-)-arabinose. The results of molecular dynamics simulation suggested that D-(-)-arabinose interacts mostly with HIS85, HIS259, and HIS263, which are believed to be in the active site. Our kinetic study showed that D-(-)-arabinose is a reversible, mixed-type inhibitor of tyrosinase (alpha-value = 6.11 +/- 0.98, K(i) = 0.21 +/- 0.19 M). Measurements of intrinsic fluorescence showed that D-(-)-arabinose induced obvious tertiary changes to tyrosinase (binding constant K = 1.58 +/- 0.02 M(-1), binding number n = 1.49 +/- 0.06). This strategy of predicting tyrosinase inhibition based on specific interactions of aldehyde and hydroxyl groups with the enzyme may prove useful for screening potential tyrosinase inhibitors. PMID- 23365726 TI - Association of serum ceruloplasmin level with obesity: some components of metabolic syndrome and high-sensitive C-reactive protein in Iran. AB - BACKGROUND: One of the mechanisms that has been suggested for obesity related metabolic disturbances is obesity-induced inflammation. Pro-inflammatory cytokines generated in adipose tissue can increase hepatic synthesis of inflammation-sensitive plasma proteins (ISPs) including ceruloplasmin (Cp). In this study we aimed to investigate the relation between serum Cp level and obesity. METHODS: 61 persons with body mass index (BMI) >= 25 kg/m2 (case group) and 61 persons with BMI < 25 kg/m2 (control group) were included in this study with a case-control design. Serum Cp levels, triglyceride level, fating blood glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol and hsCRP were measured in both groups. RESULTS: We did not observe any significant association between serum Cp level and BMI in all subjects [OR: 1.02 (CI, 0.967 to 1.07)] and in case (beta = 0.012, P = 0.86) and control groups (beta = 0.49, P = 0.07) separately. However, in control group, this positive association was marginally significant. We found a positive correlation between serum Cp level and serum triglyceride level. CONCLUSION: Serum Cp level was not related to obesity in this group of subjects. None of the baseline variables could predict obesity in this group of subjects, including serum Cp level, FBS, total cholesterol, LDL and HDL- cholesterols and hsCRP. PMID- 23365727 TI - AIDS and HIV Infection after Thirty Years. PMID- 23365725 TI - NLRP3 Inflammasome and MS/EAE. AB - Inflammasomes are cytosolic sensors that detect pathogens and danger signals in the innate immune system. The NLRP3 inflammasome is currently the most fully characterized inflammasome and is known to detect a wide array of microbes and endogenous damage-associated molecules. Possible involvement of the NLRP3 inflammasome (or inflammasomes) in the development of multiple sclerosis (MS) was suggested in a number of studies. Recent studies showed that the NLRP3 inflammasome exacerbates experimental autoimmune encephalomyelitis (EAE), an animal model of MS, although EAE can also develop without the NLRP3 inflammasome. In this paper, we discuss the NLRP3 inflammasome in MS and EAE development. PMID- 23365728 TI - Risky Behaviors among HIV-Positive Female Sex Workers in Northern Karnataka, India. AB - Purpose. Little is known about the risky sexual behaviors of HIV-positive female sex workers (FSWs) in the developing world, which is critical for programmatic purposes. This study aims to shed light on their condom use with regular clients as well as husband/cohabiting partner, a first in India. Methods. Multivariate logistic regression analyses for consistent condom use with regular clients and husband/cohabiting partner are conducted for the sample of 606 HIV-positive FSWs. Results. Older FSWs are 90% less likely and nonmobile FSWs are 70% less likely to consistently use condoms. FSWs on ART are 3.84 times more likely to use condoms. Additionally, FSWs who changed their occupation after HIV diagnosis are 70% less likely to use condoms. FSWs who are currently cohabiting are more likely to consistently use condoms with repeat clients and are 3.22 times more likely to do so if they have felt stigma associated with being HIV-positive. FSWs who have multiple repeat clients, and who do not know the sexual behavior of these clients, are more likely to use condoms consistently. Conclusion. This study would help inform programs to target the following particularly vulnerable HIV positive FSWs: those who are older, those who changed their occupation post-HIV diagnosis, and those who are nonmobile. PMID- 23365729 TI - Telemedicine intervention improves ICU outcomes. AB - Telemedicine for the intensive care unit (Tele-ICU) was founded as a means of delivering the clinical expertise of intensivists located remotely to hospitals with inadequate access to intensive care specialists. This was a retrospective pre- and postintervention study of adult patients admitted to a community hospital ICU. The patients in the preintervention period (n = 630) and during the Tele-ICU period (n = 2193) were controlled for baseline characteristics, acute physiologic scores (APS), and acute physiologic and health evaluation (APACHE IV) scores. Mean APS scores were 37.1 (SD, 22.8) and 37.7 (SD, 19.4) (P = 0.56), and mean APACHE IV scores were 49.7 (SD, 24.8) and 50.4 (SD, 21.0) (P = 0.53), respectively. ICU mortality was 7.9% during the preintervention period compared with 3.8% during the Tele-ICU period (odds ratio (OR) = 0.46, 95% confidence interval (CI), 0.32-0.66, P < 0.0001). ICU LOS in days was 2.7 (SD, 4.1) compared with 2.2 (SD, 3.4), respectively (hazard ratio (HR) = 1.16, 95% CI, 1.00-1.40, P = 0.01). Implementation of Tele-ICU intervention was associated with reduced ICU mortality and ICU LOS. This suggests that there are benefits of a closed Tele-ICU intervention beyond what is provided by daytime bedside physicians. PMID- 23365730 TI - Retinol and retinyl palmitate in foetal lung mice: sexual dimorphism. AB - In this work, we evaluate the lung retinoids content to study the possible difference between male and female mice during prenatal development and to comprehend if the vitamin A metabolism is similar in both genders. The study occurred between developmental days E15 and E19, and the retinol and retinyl palmitate lung contents were determined by HPLC analysis. We established two main groups: the control, consisting of foetuses obtained from pregnant females without any manipulation, and vitamin A, composed of foetuses from pregnant females submitted to vitamin A administration on developmental day E14. Each of these groups was subdivided by gender, establishing the four final groups. In the lung of control group, retinol was undetected in both genders and retinyl palmitate levels exhibited a sexual dimorphism. In the vitamin A group, we detected retinol and retinyl palmitate in both genders, and we observed a more evident sexual dimorphism for both retinoids. Our study also indicates that, from developmental day E15 to E19, there is an increase in the retinoids content in foetal lung and a gender difference in the retinoids metabolism. In conclusion, there is a sexual dimorphism in the lung retinoids content and in its metabolism during mice development. PMID- 23365732 TI - Comparison of Clinicopathological Characteristics in the Patients with Cardiac Cancer with or without Esophagogastric Junctional Invasion: A Single-Center Retrospective Cohort Study. AB - Background. This study addresses clinicopathological differences between patients with gastric cardia and subcardial cancer with and without esophagogastric junctional invasion. Methods. We performed a single-center, retrospective cohort study. We studied patients who underwent curative surgery for gastric cardia and subcardial cancers. Tumors centered in the proximal 5 cm of the stomach were classed into two types, according to whether they did (Ge) or did not (G) invade the esophagogastric junction. Results. A total of 80 patients were studied; 19 (73.1%) of 26 Ge tumors and 16 (29.6%) of 54 G tumors had lymph nodes metastases. Incidence of nodal metastasis in pT1 tumors was significantly higher in the Ge tumor group. No nodal metastasis in cervical lymph nodes was recognized. Only two patients with Ge tumors had mediastinal lymph node metastases. Incidence of perigastric lymph node metastasis was significantly higher in those with Ge tumors. Ge tumors tended to be staged as progressive disease using the esophageal cancer staging manual rather than the gastric cancer staging manual. Conclusion. Because there are some differences in clinicopathological characteristics, it is thought to be adequate to distinguish type Ge from type G tumor. PMID- 23365731 TI - Chorioamnionitis and lung injury in preterm newborns. AB - There is a strong evidence that histologic chorioamnionitis is associated with a reduction of incidence and severity of respiratory distress syndrome (RDS). Short term maturational effects on the lungs of extremely premature infants seem to be, however, accompanied by a greater susceptibility of the lung, eventually contributing to an increased risk of bronchopulmonary dysplasia (BPD). Genetic susceptibility to BPD is an evolving area of research and several studies have directly related the risk of BPD to genomic variants. There is a substantial heterogeneity across the studies in the magnitude of the association between chorioamnionitis and BPD, and whether or not the association is statistically significant. Considerable variation is largely dependent on differences of inclusion and exclusion criteria, as well as on clinical and histopathological definitions. The presence of significant publication bias may exaggerate the magnitude of the association. Controlling for publication bias may conduct to adjusted results that are no longer significant. Recent studies generally seem to confirm the effect of chorioamnionitis on RDS incidence, while no effect on BPD is seen. Recent data suggest susceptibility for subsequent asthma to be increased on long-term followup. Additional research on this field is needed. PMID- 23365733 TI - Reviewing the literature on the effectiveness of pressure relieving movements. AB - Sitting for prolonged periods of time increases seating interface pressures, which is known to increase the risk of developing pressure ulcers. Those at risk of developing pressure ulcers are advised to perform pressure relieving movements such as "pushups" or "forward leans" in order to reduce the duration and magnitude of pressure acting on the vulnerable ischial tuberosity region. The aim of this review was to synthesize and critique the existing literature investigating the effectiveness of pressure relieving movements on seating interface pressures. The twenty-seven articles included in this paper highlight the need for further research investigating the effect of recommended pressure relieving movements on the pressures around the ischial tuberosities. Furthermore, this review found that the majority of individuals at risk of developing pressure ulcers do not adhere with the pressure relieving frequency or magnitude of movements currently recommended, indicating a need for pressure ulcer prevention to be explored further. PMID- 23365734 TI - The lateral port control pharyngeal flap: a thirty-year evolution and followup. AB - In 1971, Micheal Hogan introduced the Lateral Port Control Pharyngeal Flap (LPCPF) which obtained good results with elimination of VPI. However, there was a high incidence of hyponasality and OSA. We hypothesized that preoperative assessment with videofluoroscopy and nasal endoscopy would enable modification and customization of the LPCPF and result in improvement in the result in both hyponasality and obstructive apnea while still maintaining results in VPI. Thirty consecutive patients underwent customized LPCPF. All patients had preoperative diagnosis of VPI resulting from cleft palate. Patient underwent either videofluoroscopy or nasal endoscopy prior to the planning of surgery. Based on preoperative velar and pharyngeal movement, patients were assigned to wide, medium, or narrow port designs. Patients with significant lateral motion were given wide ports while patients with minimal movement were given narrow ports. There was a 96.66% success rate in the treatment of VPI with one patient with persistent VPI (3.33%). Six patients had mild hyponasality (20 %). Two patients had initial OSA (6.67%), one of which had OSA which lasted longer than six months (3.33%). The modifications of the original flap description have allowed for success in treatment of VPI along with an acceptably low rate of hyponasality and OSA. PMID- 23365735 TI - Isoniazid Toxicity among an Older Veteran Population: A Retrospective Cohort Study. AB - BACKGROUND: our objective was to determine the incidence of toxicity among veterans initiating isoniazid therapy for latent tuberculosis infection (LTBI) and determine whether advancing age was a risk factor for toxicity. METHODS: we performed a retrospective cohort study among all adults initiating isoniazid treatment for LTBI at a Veterans Medical Center from 1999 to 2005. We collected data on patient demographics, co-morbidities, site of initiation, and treatment outcome. RESULTS: 219 patients initiated isoniazid therapy for LTBI during the period of observation, and the completion of therapy was confirmed in 100 patients (46%). Among 18/219 patients (8%) that discontinued therapy due to a documented suspected toxicity, the median time to onset was 3 months (IQR 1-5 months). In an adjusted Cox regression model, there was no association between discontinuation due to suspected toxicity and advancing age (HR 1.03, 95% CI 0.99, 1.07). In contrast, hepatitis C infection was a significant predictor of cessation due to toxicity in the adjusted analysis (HR 3.03, 95% CI 1.08, 8.52). CONCLUSIONS: cessation of isoniazid therapy due to suspected toxicity was infrequently observed among a veteran population and was not associated with advancing age. Alternative LTBI treatment approaches should be further examined in the veteran population. PMID- 23365736 TI - Virtual visual effect of hospital waiting room on pain modulation in healthy subjects and patients with chronic migraine. AB - Environmental context has an important impact on health and well being. We aimed to test the effects of a visual distraction induced by classical hospital waiting room (RH) versus an ideal room with a sea view (IH), both represented in virtual reality (VR), on subjective sensation and cortical responses induced by painful laser stimuli (LEPs) in healthy volunteers and patients with chronic migraine (CM). Sixteen CM and 16 controls underwent 62 channels LEPs from the right hand, during a fully immersive VR experience, where two types of waiting rooms were simulated. The RH simulated a classical hospital waiting room while the IH represented a room with sea viewing. CM patients showed a reduction of laser pain rating and vertex LEPs during the IH vision. The sLORETA analysis confirmed that in CM patients the two VR simulations induced a different modulation of bilateral parietal cortical areas (precuneus and superior parietal lobe), and superior frontal and cingulate girus, in respect to controls. The architectural context may interfere with pain perception, depending upon the status of subject. Many variables may change patients' outcome and support the use of VR technology to test the best conditions for their management. PMID- 23365737 TI - Cardiopulmonary exercise testing. PMID- 23365738 TI - Mechanisms of physical activity limitation in chronic lung diseases. AB - In chronic lung diseases physical activity limitation is multifactorial involving respiratory, hemodynamic, and peripheral muscle abnormalities. The mechanisms of limitation discussed in this paper relate to (i) the imbalance between ventilatory capacity and demand, (ii) the imbalance between energy demand and supply to working respiratory and peripheral muscles, and (iii) the factors that induce peripheral muscle dysfunction. In practice, intolerable exertional symptoms (i.e., dyspnea) and/or leg discomfort are the main symptoms that limit physical performance in patients with chronic lung diseases. Furthermore, the reduced capacity for physical work and the adoption of a sedentary lifestyle, in an attempt to avoid breathlessness upon physical exertion, cause profound muscle deconditioning which in turn leads to disability and loss of functional independence. Accordingly, physical inactivity is an important component of worsening the patients' quality of life and contributes importantly to poor prognosis. Identifying the factors which prevent a patient with lung disease to easily carry out activities of daily living provides a unique as well as important perspective for the choice of the appropriate therapeutic strategy. PMID- 23365739 TI - Lungs in heart failure. AB - Lung function abnormalities both at rest and during exercise are frequently observed in patients with chronic heart failure, also in the absence of respiratory disease. Alterations of respiratory mechanics and of gas exchange capacity are strictly related to heart failure. Severe heart failure patients often show a restrictive respiratory pattern, secondary to heart enlargement and increased lung fluids, and impairment of alveolar-capillary gas diffusion, mainly due to an increased resistance to molecular diffusion across the alveolar capillary membrane. Reduced gas diffusion contributes to exercise intolerance and to a worse prognosis. Cardiopulmonary exercise test is considered the "gold standard" when studying the cardiovascular, pulmonary, and metabolic adaptations to exercise in cardiac patients. During exercise, hyperventilation and consequent reduction of ventilation efficiency are often observed in heart failure patients, resulting in an increased slope of ventilation/carbon dioxide (VE/VCO(2)) relationship. Ventilatory efficiency is as strong prognostic and an important stratification marker. This paper describes the pulmonary abnormalities at rest and during exercise in the patients with heart failure, highlighting the principal diagnostic tools for evaluation of lungs function, the possible pharmacological interventions, and the parameters that could be useful in prognostic assessment of heart failure patients. PMID- 23365740 TI - Pleural fluid cholesterol in differentiating exudative and transudative pleural effusion. AB - Objectives. To study the diagnostic value of pleural fluid cholesterol in differentiating transudative and exudative pleural effusion. To compare pleural fluid cholesterol level for exudates with Light's criteria. Design. Cross sectional descriptive study. Settings. Medical wards of Tribhuvan University Teaching Hospital. Methods. Sixty two cases of pleural effusion with definite clinical diagnosis admitted in TUTH were taken and classified as transudates (19) and exudates (43). The parameters pleural fluid protein/serum protein ratio (pfP/sP), pleural fluid LDH/ serum LDH ratio, pleural fluid LDH (pfLDH) and pleural fluid cholesterol (pCHOL) were compared with clinical diagnosis with regard to their usefulness for distinguishing between pleural exudates and transudates. Results. The pCHOL values determined were 1.92 +/- 0.75 for exudates, 0.53 +/- 0.28 for transudates, the differences between the transudates and others are statistically significant (P < 0.0001). It is seen that pfP/sP ratio has a sensitivity of 81.4% and specificity of 82.6%; pfLDH/sLDH ratio has a sensitivity of 86% and specificity of 94.7% and pCHOL with sensitivity of 97.7% and specificity of 100% for differentiating exudative and transudative PE. Conclusion. The determination of pCHOL is of great value for distinguishing between pleural exudates and transudates and should be included in routine laboratory analysis of pleural effusion. PMID- 23365741 TI - Pulmonary Rehabilitation in COPD: A Reappraisal (2008-2012). AB - Chronic Obstructive Pulmonary Disease (COPD) is a complex pathological condition associated with an important reduction in physical activity and psychological problems that contribute to the patient's disability and poor health-related quality of life. Pulmonary rehabilitation is aimed to eliminate or at least attenuate these difficulties, mainly by promoting muscular reconditioning. The scope of this paper has been the analysis of the literature on pulmonary rehabilitation in COPD patients has appeared in the last five years, focusing on the principal outcomes obtained. The results demonstrate that pulmonary rehabilitation has a beneficial effect on dyspnoea relief, improving muscle strength and endurance. Moreover, pulmonary rehabilitation appears to be a highly effective and safe treatment for reducing hospital admissions mortality and improving health-related quality of life in COPD patients. It represents, therefore, a very important therapeutic option that, along with standard pharmachological therapy, can be used to obtain the best patient management. The favourable results obtained with pulmonary rehabilitation programs should stimulate researchers to improve our understanding of the mechanisms that form the basis of the beneficial effects of this therapeutic intervention. This would in turn increase the effectiveness of pulmonary rehabilitation in COPD patients. PMID- 23365742 TI - Decision Making about Risk of Infection by Young Adults with CF. AB - Young people with cystic fibrosis (CF) are asked to avoid a number of environments associated with increased infection risk, but in practice they need to balance this with competing priorities such as building and sustaining relationships with friends and family. This study explored the process by which young people make these decisions. Mixed methods were used: a vignette study presenting choices around engaging in activities involving a degree of infection risk and a thematic analysis of participant's accounts of their decision making. The eight participants chose to engage in high risk behaviours in 59% of the choices. All participants chose to engage in at least one risky behavior, though this was less likely when the risk was significant. Thematic analysis revealed large areas of misunderstanding and lack of knowledge, leading to some potentially worrying misconceptions about the nature of infections and risk. Young people with CF are not currently making informed decisions around activities that involve increased risk of infection, and there is an urgent need for CF teams to address this in information provision. PMID- 23365743 TI - A practical approach for a wide range of liver iron quantitation using a magnetic resonance imaging technique. AB - The goal of this study is to demonstrate a practical magnetic resonance imaging technique for quantifying a wide range of hepatic iron concentration (HIC) for hematologic oncology patients with transfusion iron overload in a routine clinical setting. To cover a wide range of T(2)* values from hematologic patients, we used a dual-acquisition method with two clinically available acquisition protocols on a 1.5T MRI scanner with different DeltaTEs to acquire data in two breath-holds. An in-house image postprocessing software tool was developed to generate T(2)*, iron maps, and water and fat images, when fat is presented in the liver. The resulting iron maps in DICOM format are transferred to the institutional electronic medical record system for review by radiologists. The measured liver T(2)* values for 28 patients ranged from 0.56 +/- 0.13 to 25.0 +/- 2.1 milliseconds. These T(2)* values corresponded to HIC values ranging from 1.2 +/- 0.1 mg/g to 45.0 +/- 10.0 mg/g (dry weight). A moderate correlation between overall serum ferritin levels and R(2)* was found with a correlation coefficient of 0.83. Repeated phantom scans confirmed that the precision of this method is better than 4% for T(2)* measurements. The dual- acquisition method also improved the ability to quantify HIC of the patients with hepatic steatosis. PMID- 23365744 TI - A synoviocyte model for osteoarthritis and rheumatoid arthritis: response to Ibuprofen, betamethasone, and ginger extract-a cross-sectional in vitro study. AB - This study aimed at determining if synovial cell cultures from rheumatoid arthritis (RA), osteoarthritis (OA), and healthy controls (HC) differ and are suitable disease models in pharmacological studies, and tested their response to some anti-inflammatory drugs. Synovial cells were isolated from synovial membrane or joint fluid. Cells were cultivated and exposed to no or TNF-alpha stimulation without, or in the presence of, betamethasone, ibuprofen, or a standardized ginger extract. Concentrations of a panel of cytokines, growth factors, and chemokines were mapped for each culture and condition. Our cells secreted an increased amount of the cytokines IL-1beta, IL-6, and IL-8 in response to TNF alpha stimulation in all conditions. OA cells showed a higher IL-6 and IL-8 and a lower IL-1beta production, when not stimulated, than RA and HC cells, which were similar. TNF-alpha stimulation caused similar IL-1beta, IL-6, and IL-8 release in all groups. Ibuprofen showed no effect on cytokine production, while ginger extract was similar to betamethasone. Ginger extract was as effective an anti inflammatory agent as betamethasone in this in vitro model. Cultured fibroblast like synoviocytes from OA and RA subjects promise to be a useful pharmacological disease model, but further studies, to support results from such a model are needed. PMID- 23365745 TI - Shoulder osteoarthritis. AB - Osteoarthritis (OA) is the most frequent cause of disability in the USA, affecting up to 32.8% of patients over the age of sixty. Treatment of shoulder OA is often controversial and includes both nonoperative and surgical modalities. Nonoperative modalities should be utilized before operative treatment is considered, particularly for patients with mild-to-moderate OA or when pain and functional limitations are modest despite more advanced radiographic changes. If conservative options fail, surgical treatment should be considered. Although different surgical procedures are available, as in other joints affected by severe OA, the most effective treatment is joint arthroplasty. The aim of this work is to give an overview of the currently available treatments of shoulder OA. PMID- 23365746 TI - Point-of-Care Troponin T Testing in the Management of Patients with Chest Pain in the Swedish Primary Care. AB - Objective. To investigate the diagnostic accuracy and clinical benefit of point of-care Troponin T testing (POCT-TnT) in the management of patients with chest pain. Design. Observational, prospective, cross-sectional study with followup. Setting. Three primary health care (PHC) centres using POCT-TnT and four PHC centres not using POCT-TnT in the southeast of Sweden. Patients. All patients >=35 years old, contacting one of the primary health care centres for chest pain, dyspnoea on exertion, unexplained weakness, and/or fatigue with no other probable cause than cardiac, were included. Symptoms should have commenced or worsened during the last seven days. Main Outcome Measures. Emergency referrals, patients with acute myocardial infarctions (AMI), or unstable angina (UA) within 30 days of study enrolment. Results. 25% of the patients from PHC centres with POCT-TnT and 43% from PHC centres without POCT-TnT were emergently referred by the GP (P = 0.011 ). Seven patients (5.5%) from PHC centres with POCT-TnT and six (8.8%) from PHC centres without POCT-TnT were diagnosed as AMI or UA (P = 0.369). Two patients with AMI or UA from PHC centres with POCT-TnT were judged as missed cases in primary health care. Conclusion. The use of POCT-TnT may reduce emergency referrals but probably at the cost of an increased risk to miss patients with AMI or UA. PMID- 23365747 TI - The Missing Evaluation at the End of GP's Consultation. AB - Evaluation at the end of a consultation is an element of a successful encounter. The doctor should inquire if patient's expectations were fulfilled and sum up the information given, the examinations performed, and the decisions made with the patient. This way the patient would be fully aware of what has been decided and that the problems and expectations of the patient had been taken into account. Twenty consultations of four general practitioners (GPs) in Finland were videotaped. The doctors were men and women, two of them had a long experience and two were trainees in general practice. The data (videotapes, questionnaires, and interviews) were analysed by multiple research methods with investigator and methodological triangulation. MAAS-Global Rating List was used as an assessment tool. The evaluation of the consultation was often missing or having shortages; only one-third was assessed to be better than doubtful. The assessments done by experienced GPs and the medical student were similar. According to the result of this study as well as the information in the current literature, doctors in all periods of their career should repeatedly be reminded about the importance of the evaluation at the end of the consultation. PMID- 23365748 TI - The risk of acute kidney injury and its impact on 30-day and long-term mortality after transcatheter aortic valve implantation. AB - Background. Transcatheter aortic valve implantation (TAVI) is widely used in high risk patients (pts) with aortic stenosis. Underlying chronic kidney disease implicates a high risk of postprocedural acute kidney injury (AKI). We analyzed its occurrence, impact on hospital stay, and mortality. Methods. 150 consecutive pts underwent TAVI in our institution (mean age 81 +/- 7 years; logistic EuroSCORE 24 +/- 15%). AKI definition was a creatinine rise of 26.5 MUmol/L or more within 48 hours postprocedural. Ten patients on chronic hemodialysis were excluded. Results. AKI occurred in 28 pts (20%). Baseline creatinine was higher in AKI pts (126.4 +/- 59.2 MUmol/L versus 108.7 +/- 45.1 MUmol/L, P = 0.09). Contrast media use was distributed evenly. Both, 30-day mortality (29% versus 7%, P < 0.0001) and long-term mortality (43% versus 18%, P < 0.0001) were higher; hospital stay was longer in AKI pts (20 +/- 12 versus 15 +/- 10 days, P = 0.03). Predicted renal failure calculated STS Score was similar (8.0 +/- 5.0% [AKI] versus 7.1 +/- 4.0% [non-AKI], P = 0.32) and estimated lower renal failure rates than observed. Conclusion. AKI remains a frequent complication with increased mortality in TAVI pts. Careful identification of risk factors and development of more suitable risk scores are essential. PMID- 23365749 TI - Bimodal solutions or twice-daily icodextrin to enhance ultrafiltration in peritoneal dialysis patients. AB - The efficacy and safety of icodextrin has been well established. In this paper, we will discuss the pharmacokinetics and biocompatibility of icodextrin and its clinical effect on fluid management in peritoneal dialysis patients. Novel strategies for its prescription for peritoneal dialysis patients with inadequate ultrafiltration are reviewed. PMID- 23365750 TI - Degree of Acute Kidney Injury before Dialysis Initiation and Hospital Mortality in Critically Ill Patients. AB - In a multicenter observational cohort of patients-admitted to intensive care units (ICU), we assessed whether creatinine elevation prior to dialysis initiation in acute kidney injury (AKI-D) further discriminates risk-adjusted mortality. AKI-D was categorized into four groups (Grp) based on creatinine elevation after ICU admission but before dialysis initiation: Grp I > 0.3 mg/dL to <2-fold increase, Grp II >=2 times but <3 times increase, Grp III >=3-fold increase in creatinine, and Grp IV none or <0.3 mg/dl increase. Standardized mortality rates (SMR) were calculated by using a validated risk-adjusted mortality model and expressed with 95% confidence intervals (CI). 2,744 patients developed AKI-D during ICU stay; 36.7%, 20.9%, 31.2%, and 11.2% belonged to groups I, II, III, and IV, respectively. SMR showed a graded increase in Grp I, II, and III (1.40 (95% CI, 1.29-1.42), 1.84 (1.66-2.04), and 2.25 (2.07-2.45)) and was 0.98 (0.78-1.20) in Grp IV. In ICU patients with AKI-D, degree of creatinine elevation prior to dialysis initiation is independently associated with hospital mortality. It is the lowest in those experiencing minor or no elevations in creatinine and may represent reversible fluid-electrolyte disturbances. PMID- 23365751 TI - Advantageous uses of mass spectrometry for the quantification of proteins. AB - Quantitative protein measurements by mass spectrometry have gained wide acceptance in research settings. However, clinical uptake of mass spectrometric protein assays has not followed suit. In part, this is due to the long-standing acceptance by regulatory agencies of immunological assays such as ELISA assays. In most cases, ELISAs provide highly accurate, sensitive, relatively inexpensive, and simple assays for many analytes. The barrier to acceptance of mass spectrometry in these situations will remain high. However, mass spectrometry provides solutions to certain protein measurements that are difficult, if not impossible, to accomplish by immunological methods. Cases where mass spectrometry can provide solutions to difficult assay development include distinguishing between very closely related protein species and monitoring biological and analytical variability due to sample handling and very high multiplexing capacity. This paper will highlight several examples where mass spectrometry has made certain protein measurements possible where immunological techniques have had a great difficulty. PMID- 23365752 TI - Use of physical and intellectual activities and socialization in the management of cognitive decline of aging and in dementia: a review. AB - Lifestyle nonpharmacological interventions can have a deep effect on cognitive aging. We have reviewed the available literature on the effectiveness of physical activity, intellectual stimulation, and socialization on the incidence of dementia and on the course of dementia itself. Even though physical activity appears to be beneficial in both delaying dementia onset and in the course of the disease, more research is needed before intellectual stimulation and socialization can be considered as treatments and prevention of the disease. Through our paper, we found that all three nonpharmacological treatments provide benefits to cognition and overall well-being in patients with age-related cognitive impairments. These interventions may be beneficial in the management of dementia. PMID- 23365753 TI - Bimonthly Evolution of Cortical Atrophy in Early Relapsing-Remitting Multiple Sclerosis over 2 Years: A Longitudinal Study. AB - We investigated the evolution of cortical atrophy in patients with early relapsing-remitting (RR) multiple sclerosis (MS) and its association with lesion volume (LV) accumulation and disability progression. 136 of 181 RRMS patients who participated in the Avonex-Steroids-Azathioprine study were assessed bimonthly for clinical and MRI outcomes over 2 years. MS patients with disease duration (DD) at baseline of <=24 months were classified in the early group (DD of 1.2 years, n = 37), while patients with DD > 24 months were classified in the late group (DD of 7.1 years, n = 99). Mixed effect model analysis was used to investigate the associations. Significant changes in whole brain volume (WBV) (P < 0.001), cortical volume (CV) (P < 0.001), and in T2-LV (P < 0.001) were detected. No significant MRI percent change differences were detected between early and late DD groups over 2 years, except for increased T2-LV accumulation between baseline and year 2 in the early DD group (P < 0.01). No significant associations were found between changes in T2-LV and CV over the followup. Change in CV was related to the disability progression over the 2 years, after adjusting for DD (P = 0.01). Significant cortical atrophy, independent of T2-LV accumulation, occurs in early RRMS over 2 years, and it is associated with the disability progression. PMID- 23365754 TI - Risk factors for cesarean delivery following labor induction in multiparous women. AB - OBJECTIVE: To identify potential risk factors for cesarean delivery following labor induction in multiparous women at term. METHODS: We conducted a retrospective case-control study. Cases were parous women in whom the induction of labor had resulted in a cesarean delivery. For each case, we used the data of two successful inductions as controls. Successful induction was defined as a vaginal delivery after the induction of labor. The study was limited to term singleton pregnancies with a child in cephalic position. RESULTS: Between 1995 and 2010, labor was induced in 2548 parous women, of whom 80 had a cesarean delivery (3%). These 80 cases were compared to the data of 160 parous women with a successful induction of labor. In the multivariate analysis history of preterm delivery (odds ratio (OR) 5.3 (95% CI 1.1 to 25)), maternal height (OR 0.87 (95% CI 0.80 to 0.95)) and dilatation at the start of induction (OR 0.43 (95% CI 0.19 to 0.98)) were associated with failed induction. CONCLUSION: In multiparous women, the risk of cesarean delivery following labor induction increases with previous preterm delivery, short maternal height, and limited dilatation at the start of induction. PMID- 23365755 TI - Management of combat vascular injuries using modern imaging: are we getting better? AB - Background. Vascular injuries often result in life threatening hemorrhage or limb loss. When they present with a single entry or exit wound, surgery is immediately indicated. With multiple injuries, however, imaging such as CTA is necessary for diagnosis and choice of treatment. Methods. For all combat-related vascular cases admitted to our medical center during the Lebanon wars in 1982 and 2006, we compiled and compared presenting signs and symptoms, means of diagnosis, treatments, and results. Results. 126 patients with vascular injuries were admitted (87 in 1982, 39 in 2006). 90% were male; mean age of 29 years (range 20 53). All injuries were accompanied by insult to soft tissue, bones, and viscera. 75% presented with injury to arteries in the extremities. 75% of these patients presented with limb ischemia, and 25% sustained massive blood loss. Treatments included venous interposition graft, end-to-end anastomosis, venous patch, endovascular technique (only in 2006), and ligation/observation. Complications included thrombosis and wound infections. Mortality and amputations occurred only in 1982, and this may be attributed to the use of imaging, advanced technique, and shorter average time from injury to hospital (7 hours). Conclusions. We recommend CTA as the first line modality for diagnosis of vascular injuries, as its liberal use allowed for early and appropriate treatment. Treatment outcomes improved with fast and effective resuscitation, liberal use of tourniquets and fasciotomies, and meticulous treatment by a multidisciplinary team. PMID- 23365756 TI - Merkel cell carcinoma of the head and neck: a single institutional experience. AB - Merkel cell carcinoma (MCC) is a rare cutaneous malignancy occurring mostly in older immunocompromized Caucasian males. A growing incidence of MCC has been reported in epidemiological studies. Treatment of MCC usually consists of surgical excision, pathological lymph node evaluation, and adjuvant radiotherapy. This paper reports the experience of a single tertiary center institution with 17 head and neck Merkel cell carcinoma patients. Median followup for the cohort was 37.5 months. After five years, recurrence-free survival, disease specific survival, and overall survival were 85%, 90%, and 83%, respectively. Our limited data support the use of adjuvant radiotherapy. We also report two cases of MCC located at the vestibule of the nose and two cases of spontaneous regression after diagnostic biopsy. About 40% of our patients were referred to our center for surgical revision and pathological lymph node evaluation. Increased awareness of MCC and an interdisciplinary approach are essential in the management of MCC. PMID- 23365757 TI - Safety and efficacy of 188-rhenium-labeled antibody to melanin in patients with metastatic melanoma. AB - There is a need for effective "broad spectrum" therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of (188)Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM) patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10 mCi (188)Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of (188)Re-6D2 was escalated to 54 mCi. SPECT/CT revealed (188)Re-6D2 uptake in melanoma metastases. The mean effective half-life of (188)Re-6D2 was 12.4 h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that (188)Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma. PMID- 23365758 TI - Aerobiology and its role in the transmission of infectious diseases. AB - Aerobiology plays a fundamental role in the transmission of infectious diseases. As infectious disease and infection control practitioners continue employing contemporary techniques (e.g., computational fluid dynamics to study particle flow, polymerase chain reaction methodologies to quantify particle concentrations in various settings, and epidemiology to track the spread of disease), the central variables affecting the airborne transmission of pathogens are becoming better known. This paper reviews many of these aerobiological variables (e.g., particle size, particle type, the duration that particles can remain airborne, the distance that particles can travel, and meteorological and environmental factors), as well as the common origins of these infectious particles. We then review several real-world settings with known difficulties controlling the airborne transmission of infectious particles (e.g., office buildings, healthcare facilities, and commercial airplanes), while detailing the respective measures each of these industries is undertaking in its effort to ameliorate the transmission of airborne infectious diseases. PMID- 23365761 TI - Late prosthetic shoulder hemiarthroplasty after failed management of complex proximal humeral fractures. AB - Background. The purpose of this study was to report our experience with shoulder hemiarthroplasty in the context of old trauma. Methods. 33 patients with failed treatment for a complex proximal humeral fracture underwent prosthetic hemiarthroplasty. There were 15 men and 18 women with a mean age of 58.1 years. The average period from initial treatment was 14.9 months. Sequelae included 11 malunions, 4 nonunions, 15 cases with avascular necrosis (AVN) and 3 neglected posterior locked dislocations. Follow up investigation included radiological assessment and clinical evaluation using the Constant score and a visual analogue pain scale. Results. After a mean follow up of 82.5 months the median Constant score was 75.7 points, improved by 60% in comparison to preoperative values. Greater tuberosity displacement, large cuff tears and severe malunion were the factors most affected outcome. No cases of stem loosening or severe migration were noted. 60% of the patients were able to do activities up to shoulder level compared with 24% before reconstruction. Conclusions. Late shoulder hemiarthroplasty is technically difficult and the results are inferior to those reported for acute humeral head replacement, nonetheless remains a satisfactory reconstructive option when primary treatment fails. PMID- 23365760 TI - Bioprocessing of "Hair Waste" by Paecilomyces lilacinus as a Source of a Bleach Stable, Alkaline, and Thermostable Keratinase with Potential Application as a Laundry Detergent Additive: Characterization and Wash Performance Analysis. AB - Paecilomyces lilacinus (Thom) Samson LPS 876, a locally isolated fungal strain, was grown on minimal mineral medium containing "hair waste," a residue from the hair-saving unhairing process, and produced a protease with keratinolytic activity. This enzyme was biochemically characterized. The optimum reaction conditions, determined with a response surface methodology, were 60 degrees C and pH 6.0. It was remarkably stable in a wide range of pHs and temperatures. Addition of Ca(2+), Mg(2+), or sorbitol was found to be effective in increasing thermal stability of the protease. PMSF and Hg(2+) inhibited the proteolytic activity indicating the presence of a thiol-dependent serine protease. It showed high stability toward surfactants, bleaching agents, and solvents. It was also compatible with commercial detergents (7 mg/mL) such as Ariel, Skip, Drive, and Ace, retaining more than 70% of its proteolytic activity in all detergents after 1 h of incubation at 40 degrees C. Wash performance analysis revealed that this protease could effectively remove blood stains. From these properties, this enzyme may be considered as a potential candidate for future use in biotechnological processes, as well as in the formulation of laundry detergents. PMID- 23365759 TI - Androgen receptor-target genes in african american prostate cancer disparities. AB - The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter analysis revealed that 382 out of 1,188 genes contained cis acting AR-binding sequences. Chromatin immunoprecipitation confirmed STAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A,1 and PIK3CB genes as novel AR targets in PCa disparities. Moreover, functional screens revealed that androgen-stimulated AR binding and upregulation of RHOA, ITGB5, and PIK3CB genes were associated with increased invasive activity of AA PCa cells, as siRNA-mediated knockdown of each gene caused a loss of androgen-stimulated invasion. In summation, our findings demonstrate that transcriptional changes have preferentially occurred in multiple signaling pathways converging ("transcriptional convergence") on AR signaling, thereby contributing to AR-target gene activation and PCa aggressiveness in AAs. PMID- 23365762 TI - Peripheral cemento-ossifying fibroma: case series literature review. AB - THE CONCEPT OF FIBROOSSEOUS LESIONS OF BONE HAS EVOLVED OVER THE LAST SEVERAL DECADES AND NOW INCLUDES TWO MAJOR ENTITIES: fibrous dysplasia and ossifying fibroma. Peripheral cemento-ossifying fibroma is a relatively rare tumour classified between fibroosseous lesions. It predominantly affects adolescents and young adults, with peak prevalence between 10 and 19 yrs. The cemento-ossifying fibroma is a central neoplasm of bone as well as periodontium which has caused considerable controversy because of confusion regarding terminology and the criteria for its diagnosis. The cemento-ossifying fibroma is odontogenic in origin, whereas ossifying fibroma is of bony origin. Lesions histologically similar to peripheral ossifying fibroma have been given various names in existing literature. Therefore, we present and discuss in this paper a series of cases of peripheral cemento-ossifying fibroma emphasizing the differential diagnosis. PMID- 23365763 TI - Late developing supernumerary premolars: reports of two cases. AB - This paper presents two cases of late developing supernumerary premolars. Case 1 is a female patient with nonsyndromic multiple supernumerary teeth located in the maxillary right premolar-molar region, maxillary left premolar region, and the mandibular right and left premolar regions. In this patient surgical removal of all supernumerary teeth was carried out to avoid complications during orthodontic treatment. Case 2 is a female aged 19 years in whom formation of a mandibular supernumerary premolar was observed which was not present at age 13. The patient was made aware of the supernumerary tooth presence, and periodic radiographic assessment was planned. PMID- 23365764 TI - "Segmental necrotizing granulomatous neuritis": a rare manifestation of hansen disease-report of 2 cases. AB - Segmental necrotizing granulomatous neuritis (SNGN) is a rare condition affecting the nerves of Hansen disease patients. This is usually seen as a complication in association with the skin lesions of Hansen disease. Though very rare, it can also be the first presenting symptom of pure neuritic leprosy. We hereby report 2 cases of SNGN-one case of pure neuritic leprosy with initial presentation as SNGN and another, a treated case of borderline tuberculoid leprosy which relapsed with skin lesions and associated SNGN in the peripheral nerve. PMID- 23365765 TI - Subcorneal pustular dermatosis in childhood: a case report and review of the literature. AB - Subcorneal pustular dermatosis (SCPD, also known as Sneddon-Wilkinson disease) is a rare, benign, chronic, sterile pustular eruption which usually develops in middle-age or elderly women; it is rarely seen in childhood and adolescence. The primary lesions are pea-sized pustules classically described as half-pustular, half-clear flaccid blisters. Histologically the most important feature is a subcorneal accumulation of neutrophils with the absence of spongiosis or acantholysis, although acantholysis may be reported in older lesions. In this paper we present the case of a 7-year-old boy diagnosed with SCPD based on the characteristic clinical and histological features. Dapsone has been successfully used in the treatment of the disease. PMID- 23365766 TI - Arms lift in a case of pseudoxanthoma elasticum. AB - Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder of elastin fibers, characterized by yellowish coalescent papules in flexural surfaces with abnormally lax and corrugated skin. It can be associated to systemic manifestations mostly regarding eyes and vessels. Aesthetic surgery of cutaneous hyperlaxity was described in the international literature only in few cases, mostly as neck lift. A 40-year-old woman presented with cutaneous signs of PXE, demanding brachioplasty. Results after a nine-month followup are quite satisfying, and no signs of local recurrence or scar alterations are present. PMID- 23365767 TI - Growth hormone deficiency in a patient with becker muscular dystrophy: a pediatric case report. AB - Objective. To describe a biochemical growth hormone (GH) deficiency and to evaluate therapeutic result in a six-year-old male with Becker muscular dystrophy (BMD). Methods. GH peak was evaluated after response to arginine and insulin. Bone age was evaluated according to Greulich and Pyle method. Results. The GH supplementary therapy was very effective in terms of growth gain. Conclusion. The possibility of a growth hormone deficiency and treatment with GH in patients with BMD cannot be excluded, especially considering the good therapeutic response. PMID- 23365768 TI - Scleredema in a Patient with AIDS-Related Lipodystrophy Syndrome. AB - Scleredema is a form of cutaneous mucinosis caused by an increased accumulation of collagen and mucin in the dermis. It is characterized by diffused, nonpitting swelling and induration of the skin. Scleredema diabeticorum is one type of scleredema associated with diabetes mellitus. AIDS-related insulin resistance and lipodystrophy syndrome are a newly emerging entities in HIV-infected patients associated with severe metabolic disturbances and insulin resistance. The long standing diabetes in these patients may contribute to the development of scleredema diabeticorum. Here, we report the rare occurrence of scleredema in an HIV-infected patient with AIDS-related lipodystrophy syndrome. PMID- 23365769 TI - Treated follicular lymphoma, recurrent invasive pneumococcal disease, nonresponsiveness to vaccination, and a unique pneumococcus. AB - A nonneutropenic patient with treated low-grade non-Hodgkin's (Follicular) lymphoma and secondary hypogammaglobulinemia recovered from pneumococcal pneumonia and septicemia (serotype 7F; ST191) subsequent to influenza A H1N1 (2009). Both infections were potentially vaccine preventable. The patient then developed pneumococcal meningitis due to a serotype 35F pneumococcus with a unique Multilocus Sequence Type (ST7004) which was not vaccine preventable. Patient management was influenced by host predisposition to pneumococcal infection, antibiotic intolerance, and poor response to polysaccharide pneumococcal vaccine. Indirect immunofluorescence with anti-human immunoglobulin confirmed a poor or intermediate response to Pneumovax II. Prophylactic erythromycin was initiated, and immunoglobulin transfusions were also commenced as a preventive strategy. ST7004 is a single locus variant of ST1635 which has been associated with the serotype 35F capsule in England. The spi gene in ST7004, which differentiates it from ST1635, is the same as the spi gene present in ST191 which could have arisen from the first disease episode suggesting that horizontal gene transfer may have occurred between different populations of pneumococci present within the patient in an attempt to evade vaccination selection pressure. PMID- 23365770 TI - Mycoplasma pneumoniae with atypical stevens-johnson syndrome: a diagnostic challenge. AB - The Stevens-Johnson syndrome (SJS) classically involves a targetoid skin rash and the association of the oral mucosa, genitals, and conjunctivae. Recently, there have been several documentations of an incomplete presentation of this syndrome, without the typical rash, usually associated with the mycoplasma pneumoniae infection. Our case illustrates that this important clinical diagnosis should not be missed due to its atypical presentation. PMID- 23365771 TI - Recovery after delayed surgery in a case of spinal subdural hematoma. AB - Spinal chronic subdural hematoma (SCSH) is a rare pathology usually associated with trauma or hematological alterations or is due to iatrogenic causes; rarely SCSH can be spontaneous. We report a case of a 79-year-old female who underwent a surgical evacuation of a spontaneous SCSH one year after diagnosis. She presented with a severe paraparesis and showed a considerable improvement in sensory-motor performances after surgery. The treatment of spontaneous SCSH is not well defined and universally accepted. Early surgery is mandatory in cases presenting with severe deficits. To the best of our knowledge, this is the first case showing a good outcome in a case of SCSH following a delayed surgery. In our opinion, an aggressive approach should be considered as a viable option in cases of spontaneous SCSH even after a lasting spinal cord compression. PMID- 23365772 TI - A case of multiple sclerosis and celiac disease. AB - Objectives. Multiple sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous system (CNS). Since a correlation between gluten intake and incidence of MS had been reported, the relationship of antigliadin antibodies and MS was debated. Case Report. We report the case of a 45-year-old female MS patient who is under interferon treatment. After seven years of monitoring, during her routine gastroenterological assessment, she was diagnosed with celiac disease. Conclusion. Beside the neurological manifestations that have been demonstrated in about 10% of celiac disease (CD) patients, white-matter abnormalities in brain MRI are uncommon and controversial. But in the literature, MS seems to be associated with CD as in our patient. We suggest that MS patients with gastroenterological complaints should undergo an assessment for CD. PMID- 23365773 TI - Recurrent, delayed hemorrhage associated with edoxaban after deep brain stimulation lead placement. AB - Factor-Xa inhibitors like edoxaban have been shown to have comparable or superior rates of stroke and systemic embolization prevention to warfarin while exhibiting lower clinically significant bleeding rates. The authors report a case of a man who presented with delayed, recurrent intracranial hemorrhage months after successful deep brain stimulator placement for Parkinson disease while on edoxaban for atrial fibrillation. Further reports on the use of novel anticoagulants after intracranial surgery are acutely needed to help assess the true relative risk they pose. PMID- 23365774 TI - Esophageal Achalasia: An Uncommon Complication during Pregnancy Treated Conservatively. AB - A 38-year-old Caucasian woman, gravida 3 para 2, was admitted at 29 weeks of gestation because of vomiting, dysphagia for solids and liquids, and loss of weight. An enlargement of the anterior left neck region was noted on the palpation of the thyroid gland. An MRI of the neck showed a marked esophageal dilatation with the presence of food remnants along its length and the displacement of the trachea to the right. The findings of the upper gastrointestinal endoscopy and manometry were suggestive of esophageal achalasia. Conservative management with total parenteral nutrition (TPN) through a peripheral line proved to be successful. A healthy male baby was born by a cesarean section at 37 weeks. The patient underwent laparoscopic esophageal myotomy and fundoplication seven days postpartum. PMID- 23365775 TI - A case of incomplete central retinal artery occlusion associated with short posterior ciliary artery occlusion. AB - To our knowledge, incomplete central retinal artery occlusion associated with short posterior ciliary artery occlusion is extremely rare. Herein, we describe a case of a 62-year-old man who was referred to our hospital with of transient blindness in his right eye. At initial examination, the patient's best-corrected visual acuity was 18/20 in the right eye. Fundus examination showed multiple soft exudates around the optic disc and mild macular retinal edema in his right eye; however, a cherry red spot on the macula was not detected. Fluorescein angiography revealed delayed dye inflow into the nasal choroidal hemisphere that is supplied by the short posterior ciliary artery. The following day, the patient's visual acuity improved to 20/20. Soft exudates around the optic disc increased during observation and gradually disappeared. His hemodynamic parameters revealed subclavian steal syndrome as examined by cervical ultrasonography and digital subtraction angiography. We speculate that his transient blindness was due to ophthalmic artery spasms. In this particular case, spasms of the ophthalmic artery and occlusion of the short posterior ciliary artery occurred simultaneously. As the short posterior ciliary artery branches from the ophthalmic artery, the anatomical location of the lesion might be near the branching of both arteries. PMID- 23365776 TI - MYC Negative Rectal B-Cell Lymphoma, Unclassifiable, with Features Intermediate between Diffuse Large B-Cell Lymphoma and Burkitt's Lymphoma in an Immunocompetent Patient. AB - B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma (BLUI) is a recently added entity to the World Health Organization (WHO) classification to address a grey zone between large B-cell lymphoma (DLBCL) and Burkitt's lymphoma (BL). These are rare aggressive lymphomas, which were previously also known as Burkitt's-like lymphoma (BLL). BL and BLUI/BLL of the colon mostly involve the ileocecal region. In the rectum, BL and BLUI/BLL almost always affect patients with the acquired immune deficiency syndrome (AIDS). We report the first case of rectal BLUI/BLL in an immunocompetent patient who is also negative for MYC abnormalities and the EBV early RNA (EBER) in situ hybridization. PMID- 23365777 TI - Dealing with the surgical and medical challenges of penetrating brain injuries. AB - Peacetime has reduced the overall incidence of penetrating brain injuries (PBI), and those related to missile penetration are not common anymore at least in western countries. Nevertheless, PBI still occur, and car crashes or work accidents are their main causes. The management of such cases is characterized by many challenges, not only from a surgical and medical point of view, but also for the different and sometimes bizarre dynamics by which they present. Herein we report an unusual deep penetrating brain injury, due to a high-energy crash against a metallic rod in a construction site, with a good surgical outcome despite dramatic clinical conditions on admission. A discussion of the surgical results and functional outcome related to PBI, as found in the English medical literature, is provided. Moreover the most common postoperative complications along with the diagnostic flow charts and therapeutic options useful to prevent inappropriate treatment are highlighted. PMID- 23365778 TI - Mirizzi syndrome: from ultrasound diagnosis to surgery-a case report. AB - The Mirizzi syndrome is a rare disorder that usually presents with jaundice and cholangitis; its lack of recognition in the diagnostic path could have serious consequences for the patient undergoing cholecystectomy. Here we describe the clinical case of a jaundiced patient from the ultrasound suspect of Mirizzi syndrome to the surgical treatment. PMID- 23365779 TI - Multicystic hepatocarcinoma mimicking liver abscess. AB - The diagnosis of hepatocellular carcinoma (HCC) became easier in relation to the improved radiological examinations; however, the neoplasm may occur under atypical presentations mimicking other benign or malignant processes. Multicystic HCC mimicking a liver abscess associated with septic-type fever and leukocytosis is rare, has a poor prognosis, and poses diagnostic and therapeutic dilemmas. We present the case of an 80-year-old patient, who presented with fever, leukocytosis, and large cystic masses involving right and left lobes of the liver initially considered abscesses and finally diagnosed as HCC after open drainage and liver biopsy. Although the patient died on the tenth postoperative day due to pulmonary oedema, the authors emphasize the high index of suspicion needed in the diagnosis of this unusual presentation of HCC. PMID- 23365780 TI - Case of the diffuse form of xanthogranulomatous pyelonephritis. AB - Xanthogranulomatous pyelonephritis (XGP) is a rare entity and constitutes less than 1% of chronic pyelonephritis. A 71-year-old male was introduced to our department with general malaise and abnormal findings of computed tomography (CT). Abnormal findings of complete blood count and laboratory examination included an elevated WBC count and C-reactive protein. Urinalysis showed combined hematuria and pyuria, and Escherichia coli was detected in urine culture. Abdominal CT revealed left hydronephrosis with staghorn renal calculi and thin cortex of the left kidney. Because of poor condition, the patient underwent construction of the left nephrostomy. After that, the remission of the inflammation was achieved. Several months after the construction, frequent obstructions of nephrostomy catheter because of turbid urine and intermittent fever elevation were observed. The patient and his family desired left nephrectomy despite his poor condition in general. Surgical dissection was very difficult due to fixed mass. Not long after that the patient died due to sepsis and cardiovascular failure. Microscopic findings of the left kidney revealed infiltration of lymphocytes and lipid-laden macrophages (xanthoma cells) corresponding to XGP. PMID- 23365781 TI - Percutaneous Stent-Graft Repair of Anastomotic Pseudoaneurysms following Vascular Bypass Procedures: A Report of Two Cases. AB - Anastomotic pseudoaneurysms are common entities following vascular bypass procedures and, if left untreated, serious complications such as thromboses, infection, and rupture can frequently occur. Therefore, attempts to employ various methods of repair have been utilized in treating anastomotic pseudoaneurysms to maximize operational success and future risk reduction. Herein, the authors report two cases of anastomotic pseudoaneurysms which were repaired percutaneously utilizing a combination of strategies such as careful preoperational image planning, multiple commercially available devices, and secondary embolization techniques. PMID- 23365782 TI - Detection of unstable carotid plaque by tissue Doppler imaging and contrast enhanced ultrasound in a patient with recurrent amaurosis fugax. AB - Ultrasound (US) is one of the most important diagnostic tools available for the detection and evaluation of carotid stenosis. The case of a 70-year-old woman with recurrent right-sided amaurosis fugax presented here highlights the way in which tissue Doppler imaging (TDI) and contrast-enhanced US (CEUS) may aid in the diagnosis of carotid plaque vulnerability. Furthermore, the novel inverse fly through technique was used for the three-dimensional visualization of the carotid stenosis. PMID- 23365783 TI - gamma-Secretase Modulators: Can We Combine Potency with Safety? AB - gamma-Secretase modulation has been proposed as a potential disease modifying anti-Alzheimer's approach. gamma-Secretase modulators (GSMs) cause a product shift from the longer amyloid-beta (Abeta) peptide isoforms to shorter, more soluble, and less amyloidogenic isoforms, without inhibiting APP or Notch proteolytic processing. As such, modulating gamma-secretase may avoid some of the adverse effects observed with gamma-secretase inhibitors. Since the termination of the GSM tarenfurbil in 2008 due to negative phase III trial results, a considerable progress has been made towards more potent and better brain penetrable compounds. However, an analysis of their lipophilic efficiency indices indicates that their increased potency can be largely attributed to their increased lipophilicity. The need for early and chronic dosing with GSMs will require high-safety margins. This will be a challenge to achieve with the current, highly lipophilic GSMs. We will demonstrate that by focusing on the drug like properties of GSMs, a combination of high in vitro potency and reduced lipophilicity can be achieved and does result in better tolerated compounds. The next hurdle will be to translate this knowledge into GSMs which are highly efficacious and safe in vivo. PMID- 23365784 TI - Biomarkers in Alzheimer's disease and lewy body disorders with dementia. PMID- 23365785 TI - Nonsteroidal anti-inflammatory drugs for retinal disease. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively in ophthalmology for pain and photophobia after photorefractive surgery and to reduce miosis, inflammation, and cystoid macular edema following cataract surgery. In recent years, the US Food and Drug Administration has approved new topical NSAIDs and previously approved NSAIDs have been reformulated. These changes may allow for greater drug penetration into the retina and thereby offer additional therapeutic advantages. For example, therapeutic effects on diabetic retinopathy and age-related macular degeneration may now be achievable. We provide an updated review on the scientific rationale and clinical use of NSAIDs for retinal disease. PMID- 23365786 TI - Evaluation of Clinical Decision Rules for Bone Mineral Density Testing among White Women. AB - Background. Osteoporosis is a devastating, insidious disease that causes skeletal fragility. Half of women will suffer osteoporotic fractures during their lifetimes. Many fractures occur needlessly, because of inattentiveness to assessment, diagnosis, prevention, and treatment of osteoporosis. Study Purpose. Study Purpose. To evaluate the discriminatory performance of clinical decision rules to determine the need to undergo bone mineral density testing. Methods. A nationally representative sample from the Third National Health and Nutrition Examination Survey consisted of 14,060 subjects who completed surveys, physical examinations, laboratory tests, and bone mineral density exams. Multivariable linear regression tested the correlation of covariates that composed the clinical decision rules with bone mineral density. Results. Increased age and decreased weight were variables in the final regression models for each gender and race/ethnicity. Among the indices, the Osteoporosis Self-Assessment Tool, which is composed of age and weight, performed best for White women. Study Implications. These results have implications for the prevention, assessment, diagnosis, and treatment of osteoporosis. The Osteoporosis Self-Assessment Tool performed best and is inexpensive and the least time consuming to implement. PMID- 23365788 TI - Efficacy of eosin B as a new antimalarial drug in a murine model. AB - The initial success of any adopted anti-infective strategy to malaria is followed by a descent due to the emergence of resistance to it. The search for new drugs and drug targets is a consistent demand in this disease. Eosin B, a common laboratory dye, is reported to have good antiparasitic properties in vitro. It was studied for its antiparasitic effect in vivo on chloroquine-sensitive Plasmodium berghei murine malaria. Eosin B was administered in 2 different doses by either the oral or parenteral route, once or twice daily to mice infected with Plasmodium berghei. Both the doses of eosin B 400 mg/kg and 800 mg/kg gave better results than the controls which were 40 mg/kg chloroquine and 100 mg/kg of arteether with P < 0.005 significance. Percentage suppressive activity by Peter's test of eosin B was better, though at a higher dose than both the controls. Survival rate of mice receiving the higher dose of eosin B was longer than that of the controls. When administered twice daily, the mice were fully cured after 4 days. Eosin B seems to be a promising drug exhibiting good antimalarial effects in the murine model of the disease. PMID- 23365790 TI - The ABC of tDCS: Effects of Anodal, Bilateral and Cathodal Montages of Transcranial Direct Current Stimulation in Patients with Stroke-A Pilot Study. AB - Transcranial direct current stimulation (tDCS) is a noninvasive technique that is emerging as a prospective therapy for different neurologic disorders. Previous studies have demonstrated that anodal and cathodal stimulation can improve motor performance in terms of dexterity and manual force. The objective of this study was to determine whether different electrodes' setups (anodal, cathodal, and simultaneous bilateral tDCS) provide different motor performance and which montage was more effective. As secondary outcome, we have asked to the patients about their satisfaction, and to determine if the bilateral tDCS was more uncomfortable than unilateral tDCS. Nine patients with stroke in subacute phase were enrolled in this study and randomly divided in three groups. Our results showed that tDCS was an effective treatment if compared to Sham stimulation (P = 0.022). In particular, anodal stimulation provided the higher improvement in terms of manual dexterity. Cathodal stimulation seemed to have a little effect in terms of force improvement, not observed with other setups. Bipolar stimulation seemed to be the less effective. No significant differences have been noted for the different set-ups for patients' judgment. These results highlight the potential efficacy of tDCS for patients with stroke in subacute phase. PMID- 23365789 TI - Emerging molecular targets for brain repair after stroke. AB - The field of neuroprotection generated consistent preclinical findings of mechanisms of cell death but these failed to be translated into clinics. The approaches that combine the modulation of the inhibitory environment together with the promotion of intrinsic axonal outgrowth needs further work before combined therapeutic strategies will be transferable to clinic trials. It is likely that only when some answers have been found to these issues will our therapeutic efforts meet our expectations. Stroke is a clinically heterogeneous disease and combinatorial treatments require much greater work in pharmacological and toxicological testing. Advances in genetics and results of the Whole Human Genome Project (HGP) provided new unknown information in relation to stroke. Genetic factors are not the only determinants of responses to some diseases. It was recognized early on that "epigenetic" factors were major players in the aetiology and progression of many diseases like stroke. The major players are microRNAs that represent the best-characterized subclass of noncoding RNAs. Epigenetic mechanisms convert environmental conditions and physiological stresses into long-term changes in gene expression and translation. Epigenetics in stroke are in their infancy but offer great promise for better understanding of stroke pathology and the potential viability of new strategies for its treatment. PMID- 23365791 TI - HPLC method determination of isoliquiritin apioside and isoliquiritin in rat plasma for application in pharmacokinetic study after an oral administration of zhigancao extract. AB - A sensitive HPLC method was developed for the quantitative determination of isoliquiritin apioside (ILA) and isoliquiritin (IL) in rat plasma. After protein precipitation with acetonitrile, chloroform was used to separate lipid-soluble impurities from the plasma samples and remove acetonitrile. A chromatography was carried out on Diamonsil C18 (150 * 4.6 mm; 5 MUm) analytical column, using a mobile phase consisting of water (containing phosphoric acid 0.1%, v/v); acetonitrile (72 : 28, v/v) at a flow rate of 1.0 mL/min. The wavelength switching technology was performed to determine ILA and IL at 360 nm and wogonoside (internal standard, IS) at 276 nm. The calibration curves of ILA and IL were fairly linear over the concentration ranges of 0.060-3.84 MUg/mL (r = 0.9954) and 0.075-4.80 MUg/mL (r = 0.9968), respectively. The average extract recoveries of ILA, IL, and IS were all over 80%. The precision and accuracy for all concentrations of quality controls and standards were within 15%. The lower limit of quantification (LLOQ) was 0.060 MUg/mL for ILA and 0.075 MUg/mL for IL. The method was used in pharmacokinetic study after an oral administration of Zhigancao extract to rats. PMID- 23365792 TI - Current-voltage characteristics of single-molecule diarylethene junctions measured with adjustable gold electrodes in solution. AB - We report on an experimental analysis of the charge transport through sulfur-free photochromic molecular junctions. The conductance of individual molecules contacted with gold electrodes and the current-voltage characteristics of these junctions are measured in a mechanically controlled break-junction system at room temperature and in liquid environment. We compare the transport properties of a series of molecules, labeled TSC, MN, and 4Py, with the same switching core but varying side-arms and end-groups designed for providing the mechanical and electrical contact to the gold electrodes. We perform a detailed analysis of the transport properties of TSC in its open and closed states. We find rather broad distributions of conductance values in both states. The analysis, based on the assumption that the current is carried by a single dominating molecular orbital, reveals distinct differences between both states. We discuss the appearance of diode-like behavior for the particular species 4Py that features end-groups, which preferentially couple to the metal electrode by physisorption. We show that the energetic position of the molecular orbital varies as a function of the transmission. Finally, we show for the species MN that the use of two cyano end groups on each side considerably enhances the coupling strength compared to the typical behavior of a single cyano group. PMID- 23365793 TI - Spring constant of a tuning-fork sensor for dynamic force microscopy. AB - We present an overview of experimental and numerical methods to determine the spring constant of a quartz tuning fork in qPlus configuration. The simple calculation for a rectangular cantilever is compared to the values obtained by the analysis of the thermal excitation and by the direct mechanical measurement of the force versus displacement. To elucidate the difference, numerical simulations were performed taking account of the real geometry including the glue that is used to mount the tuning fork. PMID- 23365794 TI - Pinch-off mechanism in double-lateral-gate junctionless transistors fabricated by scanning probe microscope based lithography. AB - A double-lateral-gate p-type junctionless transistor is fabricated on a low-doped (10(15)) silicon-on-insulator wafer by a lithography technique based on scanning probe microscopy and two steps of wet chemical etching. The experimental transfer characteristics are obtained and compared with the numerical characteristics of the device. The simulation results are used to investigate the pinch-off mechanism, from the flat band to the off state. The study is based on the variation of the carrier density and the electric-field components. The device is a pinch-off transistor, which is normally in the on state and is driven into the off state by the application of a positive gate voltage. We demonstrate that the depletion starts from the bottom corner of the channel facing the gates and expands toward the center and top of the channel. Redistribution of the carriers due to the electric field emanating from the gates creates an electric field perpendicular to the current, toward the bottom of the channel, which provides the electrostatic squeezing of the current. PMID- 23365795 TI - Reversible mechano-electrochemical writing of metallic nanostructures with the tip of an atomic force microscope. AB - We recently introduced a method that allows the controlled deposition of nanoscale metallic patterns at defined locations using the tip of an atomic force microscope (AFM) as a "mechano-electrochemical pen", locally activating a passivated substrate surface for site-selective electrochemical deposition. Here, we demonstrate the reversibility of this process and study the long-term stability of the resulting metallic structures. The remarkable stability for more than 1.5 years under ambient air without any observable changes can be attributed to self-passivation. After AFM-activated electrochemical deposition of copper nanostructures on a polycrystalline gold film and subsequent AFM imaging, the copper nanostructures could be dissolved by reversing the electrochemical potential. Subsequent AFM-tip-activated deposition of different copper nanostructures at the same location where the previous structures were deleted, shows that there is no observable memory effect, i.e., no effect of the previous writing process on the subsequent writing process. Thus, the four processes required for reversible information storage, "write", "read", "delete" and "re write", were successfully demonstrated on the nanometer scale. PMID- 23365787 TI - TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. AB - This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic behaviour of thyroid homeostasis. Explicit usage of this information with mathematical methods promises to deliver a better understanding of thyrotropic feedback control and new options for personalised diagnosis of thyroid dysfunction and targeted therapy, also by permitting a new perspective on the conundrum of the TSH reference range. PMID- 23365796 TI - Tuning the properties of magnetic thin films by interaction with periodic nanostructures. AB - The most important limitation for a significant increase of the areal storage density in magnetic recording is the superparamagnetic effect. Below a critical grain size of the used CoCrPt exchange-decoupled granular films the information cannot be stored for a reasonable time (typically ten years) due to thermal fluctuations arbitrary flipping of the magnetization direction. An alternative approach that may provide higher storage densities is the use of so-called percolated media, in which defect structures are imprinted in an exchange-coupled magnetic film. Such percolated magnetic films are investigated in the present work. We employ preparation routes that are based on (i) self-assembly of Au nanoparticles and (ii) homogeneous size-reduction of self-assembled polystyrene particles. On such non-close-packed nanostructures thin Fe films or Co/Pt multilayers are grown with in-plane and out-of-plane easy axis of magnetization. The impact of the particles on the magnetic switching behavior is measured by both integral magnetometry and magnetic microscopy techniques. We observe enhanced coercive fields while the switching field distribution is broadened compared to thin-film reference samples. It appears possible to tailor the magnetic domain sizes down to the width of an unperturbed domain wall in a continuous film, and moreover, we observe pinning and nucleation at or close to the imprinted defect structures. PMID- 23365797 TI - Physics, chemistry and biology of functional nanostructures. PMID- 23365798 TI - Highly ordered ultralong magnetic nanowires wrapped in stacked graphene layers. AB - We report on the synthesis and magnetic characterization of ultralong (1 cm) arrays of highly ordered coaxial nanowires with nickel cores and graphene stacking shells (also known as metal-filled carbon nanotubes). Carbon-containing nickel nanowires are first grown on a nanograted surface by magnetron sputtering. Then, a post-annealing treatment favors the metal-catalyzed crystallization of carbon into stacked graphene layers rolled around the nickel cores. The observed uniaxial magnetic anisotropy field oriented along the nanowire axis is an indication that the shape anisotropy dominates the dipolar coupling between the wires. We further show that the thermal treatment induces a decrease in the coercivity of the nanowire arrays. This reflects an enhancement of the quality of the nickel nanowires after annealing attributed to a decrease of the roughness of the nickel surface and to a reduction of the defect density. This new type of graphene-ferromagnetic-metal nanowire appears to be an interesting building block for spintronic applications. PMID- 23365799 TI - Pure hydrogen low-temperature plasma exposure of HOPG and graphene: Graphane formation? AB - Single- and multilayer graphene and highly ordered pyrolytic graphite (HOPG) were exposed to a pure hydrogen low-temperature plasma (LTP). Characterizations include various experimental techniques such as photoelectron spectroscopy, Raman spectroscopy and scanning probe microscopy. Our photoemission measurement shows that hydrogen LTP exposed HOPG has a diamond-like valence-band structure, which suggests double-sided hydrogenation. With the scanning tunneling microscopy technique, various atomic-scale charge-density patterns were observed, which may be associated with different C-H conformers. Hydrogen-LTP-exposed graphene on SiO(2) has a Raman spectrum in which the D peak to G peak ratio is over 4, associated with hydrogenation on both sides. A very low defect density was observed in the scanning probe microscopy measurements, which enables a reverse transformation to graphene. Hydrogen-LTP-exposed HOPG possesses a high thermal stability, and therefore, this transformation requires annealing at over 1000 degrees C. PMID- 23365800 TI - Characterization and properties of micro- and nanowires of controlled size, composition, and geometry fabricated by electrodeposition and ion-track technology. AB - The combination of electrodeposition and polymeric templates created by heavy-ion irradiation followed by chemical track etching provides a large variety of poly- and single-crystalline nanowires of controlled size, geometry, composition, and surface morphology. Recent results obtained by our group on the fabrication, characterization and size-dependent properties of nanowires synthesized by this technique are reviewed, including investigations on electrical resistivity, surface plasmon resonances, and thermal instability. PMID- 23365801 TI - Sub-10 nm colloidal lithography for circuit-integrated spin-photo-electronic devices. AB - Patterning of materials at sub-10 nm dimensions is at the forefront of nanotechnology and employs techniques of various complexity, efficiency, areal scale, and cost. Colloid-based patterning is known to be capable of producing individual sub-10 nm objects. However, ordered, large-area nano-arrays, fully integrated into photonic or electronic devices have remained a challenging task. In this work, we extend the practice of colloidal lithography to producing large area sub-10 nm point-contact arrays and demonstrate their circuit integration into spin-photo-electronic devices. The reported nanofabrication method should have broad application areas in nanotechnology as it allows ballistic-injection devices, even for metallic materials with relatively short characteristic relaxation lengths. PMID- 23365802 TI - Advanced atomic force microscopy techniques. PMID- 23365803 TI - Diamond nanophotonics. AB - We demonstrate the coupling of single color centers in diamond to plasmonic and dielectric photonic structures to realize novel nanophotonic devices. Nanometer spatial control in the creation of single color centers in diamond is achieved by implantation of nitrogen atoms through high-aspect-ratio channels in a mica mask. Enhanced broadband single-photon emission is demonstrated by coupling nitrogen vacancy centers to plasmonic resonators, such as metallic nanoantennas. Improved photon-collection efficiency and directed emission is demonstrated by solid immersion lenses and micropillar cavities. Thereafter, the coupling of diamond nanocrystals to the guided modes of micropillar resonators is discussed along with experimental results. Finally, we present a gas-phase-doping approach to incorporate color centers based on nickel and tungsten, in situ into diamond using microwave-plasma-enhanced chemical vapor deposition. The fabrication of silicon-vacancy centers in nanodiamonds by microwave-plasma-enhanced chemical vapor deposition is discussed in addition. PMID- 23365804 TI - Structural and electronic properties of oligo- and polythiophenes modified by substituents. AB - The electronic and structural properties of oligo- and polythiophenes that can be used as building blocks for molecular electronic devices have been studied by using periodic density functional theory calculations. We have in particular focused on the effect of substituents on the electronic structure of thiophenes. Whereas singly bonded substituents, such as methyl, amino or nitro groups, change the electronic properties of thiophene monomers and dimers, they hardly influence the band gap of polythiophene. In contrast, phenyl-substituted polythiophenes as well as vinyl-bridged polythiophene derivatives exhibit drastically modified band gaps. These effects cannot be explained by simple electron removal or addition, as calculations for charged polythiophenes demonstrate. PMID- 23365806 TI - Shift needed in evidence-based medicine. PMID- 23365807 TI - Coding practices affect the cost of distal radius fracture care. AB - The purpose of this study was to determine the impact of an Emergency Medicine Department's billing practices on the total cost of care for distal radius fractures. This study identified patients by International Classification of Diseases, Ninth Revision (ICD-9) billing codes treated by the Department of Orthopaedic Surgery (DOS) and Department of Emergency Medicine (DEM) at the University of Arizona. In every case, the surgical modifier 54 was used. The billing records in each case for the DEM and the DOS were reviewed. When the fracture was manipulated and the DEM was the attending of record for the initial visit, the total cost of fracture care was increased by $500. When the fracture was not manipulated, the total cost of fracture care was increased by $270. Although more than one-third of patients had surgery by the DOS, the DEM used a global billing code that indicates "restorative" treatment. This is an example of the manipulation of Current Procedural Terminology coding to enhance revenue generation with increased cost to the healthcare system, and no added value to outcome. PMID- 23365805 TI - A contribution to the history of the proton channel. AB - The low numbers of hydrogen ions in physiological solutions encouraged the assumption that H(+) currents flowing through conductive pathways would be so small as to be unmeasurable even if theoretically possible. Evidence for an H(+) based action potential in the luminescent dinoflagellate Noctiluca and for an H(+)-conducting channel created by the secretions of the bacterium Bacillus brevis, did little to alter this perception. The clear demonstration of H(+) conduction in molluscan neurons might have provided the breakthrough but the new pathway was without an easily demonstrable function, and escaped general attention. Indeed the extreme measures that must be taken to successfully isolate H(+) currents meant that it was some years before proton channels were identified in mammalian cells. However, with the general availability of patch-clamp techniques and evidence for an important role in mammalian neutrophils, the stage was set for a series of structure/function studies with the potential to make the proton channel the best understood channel of all. In addition, widespread genomic searches have established that proton channels play important roles in processes ranging from fertilization of the human ovum to the progression of breast cancer. (c) 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. PMID- 23365808 TI - Outcomes of open reduction and internal fixation of proximal humerus fractures managed with locking plates. AB - We conducted a study to evaluate the outcomes and complications of open reduction and internal fixation (ORIF) of 2-, 3-, and 4-part proximal humerus fractures using a standard management protocol with locking plates. Of 72 patients with acute proximal humerus fractures managed with ORIF and locking plates, 63 were available at the minimum follow-up of 1 year and met the inclusion criteria. At each follow-up, radiographs were reviewed for healing, hardware failure, osteonecrosis, shoulder range of motion, and DASH (Disabilities of the Arm, Shoulder, and Hand) scores; any complications were recorded. Mean age was 62 years and mean follow-up was 19 months. There were 12 two-part fractures, 42 three-part fractures, and 9 four-part fractures. Thirteen patients had complications. Mean shoulder forward elevation was 135; patients with complications had a significantly lower mean forward elevation (P=.002). DASH scores were significantly lower in patients without complications than in those with complications (P=.01). Although excellent outcomes can be achieved when locking plates are used to manage proximal humerus fractures, complications are possible. Physicians must weigh the functional outcome data when considering management options for these types of injuries. PMID- 23365809 TI - Subchondral bone marrow lesions associated with knee osteoarthritis. AB - Knee osteoarthritis (OA) is a prevalent condition typically measured by the level of joint space thinning. However, it has been shown that the degree of joint space narrowing correlates poorly with the incidence and magnitude of knee pain. A review of recent and past literature suggests that chronic bone marrow edema (BME) or bone marrow lesions may be linked to pain, the progression of cartilage damage, and the acceleration of joint degeneration. The literature further provides strong support that chronic BME may be an additional target for treatment. This case study has shown that a treatment to repair BME by restoring support and relieving abnormal stresses with accepted internal fixation and bone stimulating surgical techniques is effective in relieving knee OA pain. The literature review and case study herein are provided as a basis for the treatment of chronic BME as an important addition to the current knee OA treatment paradigm. PMID- 23365810 TI - Massive subacromial-subdeltoid bursitis with rice bodies secondary to an orthopedic implant. AB - Both early and late complications following open reduction and internal fixation of proximal humerus fractures have been reported extensively in the literature. Although orthopedic implants are known to cause irritation and inflammation, to our knowledge, this is the first case report to describe a patient with rice bodies secondary to an orthopedic implant. Although the etiology of rice bodies is unclear, histological studies reveal that they are composed of an inner amorphous core surrounded by collagen and fibrin. The differential diagnosis in this case included synovial chondromatosis, infection, and the formation of a malignant tumor. Additional imaging studies, such as magnetic resonance imaging, and more specific tests were necessary to differentiate the rice bodies due to bursitis versus neoplasm, prior to excision. The patient presented 5 years following open reduction and internal fixation of a displaced proximal humerus fracture, with swelling in the area of the previous surgical site. Examination revealed a large, painless tumor-like mass on the anterior aspect of the shoulder. The patient's chief concern was the unpleasant aesthetic of the mass; no pain was reported. Upon excision of the mass, the patient's full, painless range of motion returned. PMID- 23365811 TI - Pseudotumor from modular neck corrosion after ceramic-on-polyethylene total hip arthroplasty. AB - Pseudotumor formation after hip arthroplasty is a rare complication that can occur with various head-liner articulation couples. Adverse local tissue reactions and pseudotumors have been shown to present as prosthetic infections or implant failures with a broad array of laboratory and imaging findings. We report a case of pseudotumor formation resulting from modular neckstem corrosion in a well-fixed ceramic-on-polyethylene total hip arthroplasty. The patient underwent successful revision surgery using an extended trochanteric osteotomy, long-stem revision femoral component, and headliner exchange. It is critical that surgeons are aware of the potential complications with increased component modularity and the possibility of adverse local tissue reactions resulting from fretting and crevice corrosion at modular junctions. PMID- 23365812 TI - The spectrum of traumatic Schmorl's nodes: identification and treatment options in 3 patients. AB - Schmorl's nodes may be present as a simple endplate intravertebral herniation following trauma or as a large cystic lesion of the vertebral body. In this article, we report on 3 patients with severe back pain following trauma resulting in traumatic Schmorl's nodes and pathologic fracture of the vertebral body. All 3 cases had antecedent trauma. Radiographs showed a cystic lesion in the vertebral body through the endplate with surrounding bony edema, indicative of fracture. In 2 cases, the integrity of the vertebral body was severely compromised, requiring vertebrectomy and fusion. The wide spectrum of presentation and treatment options of traumatic Schmorl's nodes are presented, ranging from symptoms that are responsive to treatment to pathologic fracture of the vertebral body leading to significant collapse and the need for major surgical stabilization. PMID- 23365813 TI - A biomechanical assessment of tendon repair after radiofrequency treatment. AB - After acute tendon injury, rapid mobilization prevents adhesions and improves the ultimate strength of the repair. Radiofrequency (RF) ablation is proposed to enhance angiogenesis in the early stages of healing. The mechanism and effect of RF have not yet been described in an animal model of tendon injury. To investigate the biomechanical effect of bipolar RF on acute injury in a rabbit model of partial Achilles tendon transection and suture repair, RF-treated tendon repairs were compared to untreated tendons. Cross-sectional area, Young's modulus, and ultimate tensile strength were determined. At 6 and 12 weeks after repair, RF-treated tendons had significant increases in cross-sectional area (P<.001; P< .0001) and ultimate tensile strength (P<.0001; P<.01). Young modulus of RF-treated tendons was increased at 6 weeks but not at 12 weeks (P<.01) Compared with untreated tendons, RF-treated tendons showed faster return to mechanical integrity. This may allow earlier rehabilitation. PMID- 23365815 TI - Preoperative planning for fracture management. PMID- 23365814 TI - Effects of extracorporeal shock wave therapy on fracture nonunions. AB - The purpose of this study was to examine the effect of focused extracorporeal shock wave therapy (ESWT) on the treatment of nonunions. As part of a prospective study, we included 143 patients (average age, 41.4 years) with a diagnosis of nonunion (mean, 14.1 months; range, 6-84 months). High-energy shock wave treatment was applied using shock wave generator. The shock waves were applied in 3-5 sessions of 2500 to 3000 impulses each given at 0.25-0.84 mJ/mm(2), at intervals of 48-72 hours between sessions. A maximum of 3 cycles of treatment was given, at 3-month intervals. The patients were followed during a 12-month period until fracture healing or, in case of failure, until another therapy was adopted. Complete healing was observed in 80 of 143 cases (55.9%) at an average time of 7.6 months (range 2-24 months). Partial healing occurred in 41 cases (28.7%) and no healing was observed in 22 cases (15.4%). Patients with trophic nonunions had a better success rate than patients with atrophic nonunions (P<.05). The results show extracorporeal shock wave therapy is a safe and effective treatment for nonunion. ESWT is more effective for trophic nonunions than atrophic nonunions. PMID- 23365817 TI - Extraction of stationary components in biosignal discrimination. AB - Biosignal recordings are widely used in the medical environment to support the evaluation and the diagnosis of pathologies. Nevertheless, the main difficulty lies in the non-stationary behavior of the biosignals, difficulting the obtention of patterns characterizing the changes in physiological or pathological states. Thus, the obtention of the stationary and non-stationary components of a biosignal is still an open issue. This work proposes a methodology to detect time homogeneities based on time-frequency analysis with aim to extract the non stationary behavior of the biosignal. Results show an increase in the stationarity and in the distance between classes of the reconstructions from the enhanced time-frequency representations. The stationary components extracted with the proposed approach can be used to solve biosignal classification problems. PMID- 23365818 TI - Optimization of heartbeat detection based on clustering and multimethod approach. AB - In this paper, an approach for optimizing heartbeat locations as detected in time by multimethod approach is proposed. The approach builds a two-dimensional representation of heartbeat locations obtained by several independent detection methods. The representation depends on heartbeat time instants and beat-to-beat intervals. It is first transformed into a smoothed two-dimensional histogram of points indicating individual heartbeat detections. Heartbeat time instants are determined as local maxima in the histogram. We tested our approach on signals acquired by optical interferometer. Seven subjects participated in the experiment, beginning by an ergometer exercise until they reached submaximal heart rate. A resting period followed, during which optical interferometric signal was taken unobtrusively in parallel with referential ECG. The proposed detection procedure was capable of tracking the changing heart rhythm by analyzing optical interferometric signals and comparing the results to the referential ECG recordings. Sensitivity 97.13+/-2.00% and precision 97.82+/-2.09% were obtained. Mean absolute error between detected beat-to-beat and referential RR intervals yielded 20.05+/-8.38 ms and corresponding mean relative error 7.47+/ 3.19%. PMID- 23365819 TI - Training using short-time features for OSA discrimination. AB - Heart rate variability (HRV) is one of the promising directions for a simple and noninvasive way for obstructive sleep apnea syndrome detection (OSA). The interaction between the sympathetic and parasympathetic systems on the HRV recordings, gives rise to several non-stationary components added to the signal. Aiming to improve the classifier accuracy for obstructive sleep apnoea detection, the use of more appropriated techniques for leading with non-stationarity and mixed dynamics, are needed. This work aims at searching a convenient training strategy of combining the feature set to be further fed in to the classifier, which should take into consideration the different dynamics in the HRV signal. Therefore, a set of the short-time features, extracted from a given HRV time varying decomposition, and selected by spectral splitting is considered. Additionally, three methods of projection are used: none, simple, and multivariate. Finally, the different approaches are tested and compared, using k nn and support vector machines (SVM) classifiers. Attained results show that using continuous wavelet transform with short-time features and multivariate projection, followed by a SVM classifier, allow to obtain a suitable OSA detection. PMID- 23365820 TI - Instantaneous estimation of high-order nonlinear heartbeat dynamics by Lyapunov exponents. AB - This paper introduces a novel methodology able to provide time varying estimates of the Lyapunov Spectrum within a point process framework. The algorithm is applied to ECG-derived data to characterize heartbeat nonlinear dynamics by using a cubic autoregressive point process model. Estimation of the model parameters is ensured by the Laguerre expansion of the Wiener-Volterra kernels along with a maximum local log-likelihood procedure. In addition to the instantaneous Lyapunov exponents, as well as indices related to higher order dynamic polyspectra, our method is also able to provide all the instantaneous time domain and frequency domain measures of instantaneous heart rate (HR) and heart rate variability (HRV) previously considered. Experimental results show that our method is able to track complex cardiovascular control dynamics during fast transitional gravitational changes. PMID- 23365821 TI - Automated EEG inter-burst interval detection in neonates with mild to moderate postasphyxial encephalopathy. AB - EEG inter-burst interval (IBI) and its evolution is a robust parameter for grading hypoxic encephalopathy and prognostication in newborns with perinatal asphyxia. We present a reliable algorithm for the automatic detection of IBIs. This automated approach is based on adaptive segmentation of EEG, classification of segments and use of temporal profiles to describe the global distribution of EEG activity. A pediatric neurologist has blindly scored data from 8 newborns with perinatal postasphyxial encephalopathy varying from mild to severe. 15 minutes of EEG have been scored per patient, thus totaling 2 hours of EEG that was used for validation. The algorithm shows good detection accuracy and provides insight into challenging cases that are difficult to detect. PMID- 23365822 TI - A state-space model for finger tapping with applications to cognitive inference. AB - Sensory-motor functions have been repeatedly linked to both cognitive and physical functions. One common test of sensory-motor performance frequently used for neuropsychological evaluation is the Halstead-Reitan finger tapping test (FTT). While this test has been normed and used extensively, the underlying sensory, motor and cognitive processes mediating tapping behavior during the test are not well understood. As a first step towards investigating the behavioral aspects manifested by these processes, we describe a state-space model for finger tapping during the FTT. This state-space model exploits quasiperiodicity to decompose tapping into a set of time-varying states corresponding to the instantaneous amplitude of the finger oscillation, the instantaneous frequency (or speed) of tapping, and a phase that keeps track of the current finger position during the cycle. We evaluate the model by showing a good fit between estimated and actual measurements, and outline an experiment that will relate features from the model to cognitive function. PMID- 23365823 TI - Identifying increased risk of post-infarct people with diabetes using multi-lag Tone-Entropy analysis. AB - Diabetes mellitus is associated with multi-organ system dysfunction. One of the key causative factors is the increased blood sugar level that leads to an increase in free radical activity and organ damage including the cardiovascular and nervous system. Heart rhythm is extrinsically modulated by the autonomic nervous system and cardiac autonomic neuropathy or dysautonomia has been shown to lead to sudden cardiac death in people with diabetes due to the decrease in heart rate variability (HRV). Current algorithms for determining HRV describe only beat to-beat variation and therefore do not consider the ability of a heart beat to influence a train of succeeding beats. Therefore mortality risk analysis based on HRV has often not been able to discern the presence of an increased risk. This study used a novel innovation of the tone-entropy algorithm by incorporating increased lag intervals and found that both the sympatho-vagal balance and total activity changed at larger lag intervals. Tone-Entropy was found to be better risk identifier of cardiac mortality in people with diabetes at lags higher than one and best at lag seven. PMID- 23365824 TI - Using Laguerre expansion within point-process models of heartbeat dynamics: a comparative study. AB - Point-process models have been recognized as a distinguished tool for the instantaneous assessment of heartbeat dynamics. Although not thoroughly linked to the physiology, nonlinear models also yield a more accurate quantification of cardiovascular control dynamics. Here, we propose a Laguerre expansion of the linear and nonlinear Wiener-Volterra kernels in order to account for the nonlinear and non-gaussian information contained in the ECG-derived heartbeat series while using a reduced number of parameters. Within an Inverse-Gaussian probability model, up to quadratic nonlinearities were considered to continuously estimate the dynamic spectrum and bispectrum. Results performed on 10 subjects undergoing a stand-up protocol show that this novel methodology improves on the algorithmic performances and, at the same time, more accurately characterizes sympatho-vagal changes to posture. PMID- 23365825 TI - Customization of entropy estimation measures for human arterial hypertension records segmentation. AB - This paper describes a new application of the recently developed Coefficient of Sample Entropy (CosEn) measure. This entropy estimator is specially suited for cases where the length of the time series is extremely short. CosEn has already been used successfully to characterize and detect atrial fibrillation, using as few as 12 heartbeats. We have customized the methodology employed for heartbeat interval series to blood pressure hypertensive (BPHT) human records. Little can be found about BPHT records and its nonlinear regularity analysis. The method described in this paper provides a good segmentation between control and pathologic groups, based on the corresponding labeled BPHT records. The experimental dataset was drawn from the available records at the Hypertension Unit of the University Hospital of Mostoles, in Spain. The hypertension related variables studied were systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP). The hypothesis test yielded the following results in each case: acceptance probability of 0 for SBP, 0.005 for DBP and 0 for MBP. The confidence intervals for the three variables were nonoverlapping. PMID- 23365826 TI - Bispectral analysis of tracheal breath sounds for Obstructive Sleep Apnea. AB - Obstructive Sleep Apnea (OSA) is a respiratory disorder with serious consequences that is characterized by repetitive cessation of breathing for more than 10s often associated with a drop of more than 4% in the blood's Oxygen saturation level. The gold standard for OSA diagnosis is full-night Polysomnography (PSG), which is a time-consuming, inconvenient, and costly assessment. On the other hand, our team has showed that the analysis of tracheal respiratory sounds recorded during wakefulness holds promises to be used as a simple and effective tool for screening moderate and severe OSA. In this paper, we examine the nonlinear characteristics of tracheal breath sounds and the possibility to extract features from Higher Order Spectra (HOS) for OSA screening. The data used in this study were recorded during wakefulness in two body positions, supine and upright, and during mouth and nose breathing. We estimated the bispectrum of the sounds in each respiratory cycle, calculated the median bifrequencies and the energy of the bispectrum, and investigated any statistically significant differences between the extracted features in two groups of non-OSA and severe OSA data. The differences in the features between body positions and nose/mouth breathing were also looked at. One-way ANOVA revealed significant differences in the features between non-OSA individuals and those with severe OSA. The results encourage the use of these features in future studies for OSA screening. PMID- 23365827 TI - Biomedical data analysis by supervised manifold learning. AB - Biomedical data analysis is usually carried out by assuming that the information structure embedded into the biomedical recordings is linear, but that statement actually does not corresponds to the real behavior of the extracted features. In order to improve the accuracy of an automatic system to diagnostic support, and to reduce the computational complexity of the employed classifiers, we propose a nonlinear dimensionality reduction methodology based on manifold learning with multiple kernel representations, which learns the underlying data structure of biomedical information. Moreover, our approach can be used as a tool that allows the specialist to do a visual analysis and interpretation about the studied variables describing the health condition. Obtained results show how our approach maps the original high dimensional features into an embedding space where simple and straightforward classification strategies achieve a suitable system performance. PMID- 23365828 TI - Effect of spontaneous arousals on cardio-respiratory interaction in healthy children. AB - The aim of this paper was to study the effect of spontaneous arousals during night-time sleep on the interactions between R-R intervals and respiratory phases in healthy children. We collected overnight polysomnography data of 40 healthy children and investigated cardio-respiratory interaction before and after spontaneous arousals during stage 2 sleep using joint symbolic dynamics. The R-R time series were extracted from electrocardiograms (ECG) and respiratory phases were obtained from abdominal sensors using the Hilbert transform. Both the series were transformed into ternary symbol vectors based on the changes between two successive R-R intervals or respiratory phases, respectively. Subsequently, words of length '2' were formed and the correspondence between words of the two series was determined to quantify cardio-respiratory interaction for pre- and post spontaneous arousal episodes. We observed a brief but significant shortening in R R and respiratory intervals after arousal. There was also a significant short term increase in cardio-respiratory interaction during the first 30-second post arousal episode as compared to 30-second pre-arousal episode (7.5+/-3.4 vs. 5.2+/ 3.7%, p<0.0001, respectively). In conclusion, spontaneous arousals in healthy children during night-time sleep are associated with a temporal but significant increase in cardio-respiratory interaction. PMID- 23365829 TI - Cortical networks of hemianopia stroke patients: a graph theoretical analysis of EEG signals at resting state. AB - Visual cortical stroke patients may have hemianopia symptom, which affects a number of visual functions. Most studies on hemianopia stroke have mainly focused on cortical activation during visual stimulation, leaving the pattern of functional connectivity between different brain regions uncovered yet. In the present study, we investigate the resting neural networks of hemianopia stroke patients by graph theoretical analysis of functional brain networks constructed with phase synchronization indexes of multichannel electroencephalography (EEG) signals. Our results showed that although the global network topological metrics, i.e., weighted clustering coefficient and characteristic path length of patients and healthy controls are comparable, the left primary visual cortex of patients tend to be less active than that of age-matched healthy subjects. However, hemianopia patients showed greater activation in the ipsilesional (left) temporopolar and orbit frontal areas and the contralesional (right) associative visual cortex. These results may offer new insight into neural substrates of the hemianopia stroke, and the further study of neural plasticity and brain reorganization after hemianopia. PMID- 23365830 TI - Segmentation of atherosclerotic carotid plaque in ultrasound video. AB - The degree of stenosis of the common carotid artery (CCA) but also the characteristics of the arterial wall including plaque size, composition and elasticity represent important predictors used in the assessment of the risk for future cardiovascular events. This paper proposes and evaluates an integrated system for the segmentation of atherosclerotic carotid plaque in ultrasound video of the CCA based on normalization, speckle reduction filtering (with the hybrid median filter) and parametric active contours. The algorithm is initialized in the first video frame of the cardiac cycle with human assistance and the moving atherosclerotic plaque borders are tracked and segmented in the subsequent frames. The algorithm is evaluated on 10 real CCA digitized videos from B-mode longitudinal ultrasound segments and is compared with the manual segmentations of an expert, for every 20 frames in a time span of 3-5 seconds, covering in general 2 cardiac cycles. The segmentation results are very satisfactory with a true negative fraction (TNF) of 79.3%, a true-positive fraction (TPF) of 78.12%, a false-positive fraction (FPF) of 6.7% and a false-negative fraction (FNF) of 19.6% between the ground truth and the presented plaque segmentations, a Williams index (KI) of 80.3%, an overlap index of 71.5%, a specificity of 0.88+/-0.09, a precision of 0.86+/-0.10 and an effectiveness measure of 0.77+/-0.09. The results show that integrated system investigated in this study could be successfully used for the automated video segmentation of the carotid plaque. PMID- 23365831 TI - Applications of supervised learning to biological signals: ECG signal quality and systemic vascular resistance. AB - Discovering information encoded in non-invasively recorded biosignals which belies an individual's well-being can help facilitate the development of low-cost unobtrusive medical device technologies, or enable the unsupervised performance of physiological assessments without excessive oversight from trained clinical personnel. Although the unobtrusive or unsupervised nature of such technologies often results in less accurate measures than their invasive or supervised counterparts, this disadvantage is typically outweighed by the ability to monitor larger populations than ever before. The expected consequential benefit will be an improvement in healthcare provision and health outcomes for all. The process of discovering indicators of health in unsupervised or unobtrusive biosignal recordings, or automatically ensuring the validity and quality of such signals, is best realized when following a proven systematic methodology. This paper provides a brief tutorial review of supervised learning, which is a sub discipline of machine learning, and discusses its application in the development of algorithms to interpret biosignals acquired in unsupervised or semi-supervised environments, with the aim of estimating well-being. Some specific examples in the disparate application areas of telehealth electrocardiogram recording and calculating post-operative systemic vascular resistance are discussed in the context of this systematic approach for information discovery. PMID- 23365833 TI - Vision-based absence seizure detection. AB - In order to diagnose epilepsy, neurologists rely on their experience, performing an equal assessment of the electroencephalogram and the clinical image. Since misdiagnosis reaches a rate of 30% and more than one-third of all epilepsies are poorly understood, a need for leveraging diagnostic precision is obvious. With the aim at enhancing the clinical image assessment procedure, this paper evaluates the suitability of certain facial expression features for detecting and quantifying absence seizures. These features are extracted by means of time varying signal analysis from signals that are gained by applying computer vision techniques, such as face detection, dense optical flow computation and averaging background subtraction. For the evaluation, video sequences of four patients with absence seizures are used. The classification performance of a C4.5 decision tree shows accuracies of up to 99.96% with a worst percentage of incorrectly classified instances of 0.14%. PMID- 23365832 TI - Categorization of COPD patient's health level through the use of the CHRONIOUS wearable platform. AB - The Chronic Obstructive Pulmonary Disease (COPD) is a chronic disease that causes airflow blockage and breathing-related problems. As a Chronic disease it requires specific treatment plan and patient management for a long period of time. Critical factor in the process is the realization of frequent and precise diagnostic tests that describes the health status of the patient. The CHRONIOUS system provides the required easy-to-use wearable platform aiming at the successful management of COPD patients. Several signals and patient's data are stored by the utilization of an ergonomic jacket and through the patient's platform interface. Hybrid techniques based on supervised and unsupervised methodologies were applied for the analysis of the patient's situation. The categorization of health level of the patient to discrete levels is achieved in a continuous base. Useful outcomes in the form of message or advice are extracted appeared on patient's and clinician's devices denoting his health status. PMID- 23365834 TI - The detection of Freezing of Gait in Parkinson's disease patients using EEG signals based on Wavelet decomposition. AB - Freezing of Gait (FOG) is one of the most disabling gait disturbances of Parkinson's disease (PD). The experience has often been described as "feeling like their feet have been glued to the floor while trying to walk" and as such it is a common cause of falling in PD patients. In this paper, EEG subbands Wavelet Energy and Total Wavelet Entropy were extracted using the multiresolution decomposition of EEG signal based on the Discrete Wavelet Transform and were used to analyze the dynamics in the EEG during freezing. The Back Propagation Neural Network classifier has the ability to identify the onset of freezing of PD patients during walking using these features with average values of accuracy, sensitivity and specificity are around 75 %. This results have proved the feasibility of utilized EEG in future treatment of FOG. PMID- 23365835 TI - Under-sampling trajectory design for compressed sensing MRI. AB - The under-sampling trajectory design plays a key role in compressed sensing MRI. The traditional design scheme using probability density function (PDF) is based up observation on energy distribution in k-space rather than systematic optimization, which results in non-deterministic trajectory even with a fixed PDF. Guidance-based method like Bayesian inference scheme is always bothered with high computational complexity on entropy. In this paper, we study how to adaptively design an under-sampling trajectory in the context of CS with systematic optimization and small complexity. Simulation results conducted on images from different slices and dynamic sequence demonstrate the effectiveness of the proposed method by comparing the designed trajectory with those by traditional method. PMID- 23365836 TI - A novel phase-corrected 3D cine ultra-short te (UTE) phase-contrast MRI technique. AB - Phase-contrast (PC) MRI is a non-invasive technique to assess cardiovascular blood flow. However, this technique is not accurate for instance at the carotid bifurcation due to turbulent and disturbed blood flow in atherosclerotic disease. Flow quantification using conventional PC MRI distal to stenotic vessels suffers from intravoxel dephasing and flow artifacts. Previous studies have shown that short echo time (TE) potentially decreases the phase errors. In this work, a novel 3D cine UTE-PC imaging method is designed to measure the blood velocity in the carotid bifurcation using a UTE center-out radial trajectory and short TE time compared to standard PC MRI sequences. With a new phase error correction technique based on autocorrelation method, the proposed 3D cine UTE-PC has the potential to achieve high accuracy for quantification and visualization of velocity jet distal to a stenosis. Herein, we test the feasibility of the method in determining accurate flow waveforms in normal volunteers. PMID- 23365837 TI - DTI for assessing axonal integrity after contusive spinal cord injury and transplantation of oligodendrocyte progenitor cells. AB - We describe the feasibility of using diffusion tensor magnetic resonance imaging (DT-MRI) to study a contusive model of rat spinal cord injury following human stem cell transplantation at and around the site of injury. Rats receiving either a laminectomy or contusion injury were transplanted with oligodendrocyte precursor cells (OPCs). During the course of the study, bioluminescence imaging (BLI; up to 100 days) and somatosensory evoked potentials (SSEPs; up to 42 days) were used to evaluate cell survival and functional outcomes. Spinal cords were then analyzed ex vivo upon termination using diffusion tensor imaging (DTI). Improvements in fractional anisotropy (FA) at day 100 post-transplantation corresponded with cell survival and functional SSEP improvements. Thus, we illustrate the feasibility of DTI for evaluating axonal integrity in SCI after cell replacement therapies, and we provide examples utilizing OPC transplantations in a contusion rat model. PMID- 23365838 TI - Simultaneous ODF estimation and tractography in HARDI. AB - We consider the problem of tracking white matter fibers in high angular resolution diffusion imaging (HARDI) data while simultaneously estimating the local fiber orientation profile. Prior work showed that an unscented Kalman filter (UKF) can be used for this problem, yet existing algorithms employ parametric mixture models to represent water diffusion and to define the state space. To address this restrictive model dependency, we propose to extend the UKF to HARDI data modeled by orientation distribution functions (ODFs), a more generic diffusion model. We consider the spherical harmonic representation of the HARDI signal as the state, enforce nonnegativity of the ODFs, and perform tractography using the directions at which the ODFs attain their peaks. In simulations, our method outperforms filtered two-tensor tractography at different levels of noise by achieving a reduction in mean Chamfer error of 0.05 to 0.27 voxels; it also produced in vivo fiber tracking that is consistent with the neuroanatomy. PMID- 23365839 TI - Diffusion imaging with balanced steady state free precession. AB - Balanced steady state free precession (bSSFP) offers high signal efficiency and relative motion insensitivity. In this study, diffusion weighted bSSFP (DW-bSSFP) was introduced by modifying standard bSSFP sequence with two pairs of balanced bipolar diffusion gradients. The diffusion effect was analyzed and described in closed forms. It was found to be coupled to the transverse and longitudinal relaxation, flip angle and spin phase advance per TR. Such coupling was demonstrated in phantom experiment at 7T. Preliminary DW-bSSFP imaging experiment was performed in rat brain in vivo for diffusion tensor imaging, yielding parametric maps qualitatively similar to those obtained with an 8-shot DW-EPI protocol. The proposed DW-bSSFP approach can provide a new means of diffusion imaging with high resolution, relative motion insensitivity and short diffusion time. Such approach may lead to improved and new diffusion characterization of neural tissues, abdominal organs, myocardium and musculoskeletal tissues. PMID- 23365840 TI - Impact of DTI smoothing on the study of brain aging. AB - Diffusion tensor magnetic resonance imaging (DTI), a method for measuring the integrity of axon fiber tracts in the brain, plays an important role in clarifying brain changes that accompany aging and aging-associated neurodegenerative disease. While DTI smoothing methods theoretically have the potential to enhance such studies by reducing noise, it is unclear whether DTI smoothing has any practical impact on computed associations between fiber tract integrity and scientific variables of interest. Therefore we smoothed DTI images from 154 older adults using three kernel smoothing methods hypothesized to have differing strengths (the affine and log-Euclidean smoothers were hypothesized to enhance highly organized tracts better than the Euclidean smoother). Smoothing increased the strengths of expected associations between DTI and age, cognitive function, and the diagnosis of dementia. However, no particular smoothing method was uniformly superior in strengthening these associations. This data suggests that DTI smoothing enhances the sensitivity of studies of brain aging, but further research is needed to determine which smoothing technique is optimal. PMID- 23365841 TI - Variational level set approach for automatic correction of multiplicative and additive intensity inhomogeneities in brain MR Images. AB - Retrospective correction of intensity inhomogeneities in magnetic resonance images of the brain is an essential pre-processing step before any sophisticated image analysis task can be performed. A popular choice when defining the degradation model in MR images is to use multiplicative intensity inhomogeneities that slowly varying across the image domain; this approach has been extensively used for bias field estimation. However, such a multiplicative model is often insufficient given that some of the most dominant physical causes of intensity inhomogeneities in MRI (such as nonuniform excitation strength) have a non-linear relationship with the receptor signal intensity. In this study, we consider a linear image degradation model with multiplicative and additive intensity inhomogeneity components. We propose a variational level sets approach that combines estimation of intensity inhomogeneity components during the image segmentation process. The evaluation of proposed approach on real MR image datasets demonstrate accurate estimation of multiplicative and additive intensity inhomogeneities improving brain tissue segmentation. PMID- 23365842 TI - Illumination correction in dermatological photographs using multi-stage illumination modeling for skin lesion analysis. AB - A novel algorithm for correcting illumination variation in dermatological photographs via a multi-stage modeling of the underlying illumination is proposed for the purpose of skin lesion analysis. First, an initial illumination estimate is obtained via a non-parametric modeling strategy based on Monte Carlo sampling. Next, a subset of pixels from the non-parametric estimate is used to determine a parametric estimate of the illumination based on a quadratic surface model. Using the parametric illumination estimate, the reflectance map is obtained and used to correct the photograph. The photographs corrected using the proposed algorithm are compared to uncorrected photographs and to a state-of-the-art correction algorithm. Qualitatively, a visual comparison is performed, while quantitatively, the coefficient of variation of skin pixel intensities is calculated and the precision-recall curve for segmentation of skin lesions is graphed. Results show that the proposed algorithm has a lower coefficient of variation and an improved precision-recall curve. PMID- 23365843 TI - MRI non-uniformity correction through interleaved bias estimation and B-spline deformation with a template. AB - We propose a template-based method for correcting field inhomogeneity biases in magnetic resonance images (MRI) of the human brain. At each algorithm iteration, the update of a B-spline deformation between an unbiased template image and the subject image is interleaved with estimation of a bias field based on the current template-to-image alignment. The bias field is modeled using a spatially smooth thin-plate spline interpolation based on ratios of local image patch intensity means between the deformed template and subject images. This is used to iteratively correct subject image intensities which are then used to improve the template-to-image deformation. Experiments on synthetic and real data sets of images with and without Alzheimer's disease suggest that the approach may have advantages over the popular N3 technique for modeling bias fields and narrowing intensity ranges of gray matter, white matter, and cerebrospinal fluid. This bias field correction method has the potential to be more accurate than correction schemes based solely on intrinsic image properties or hypothetical image intensity distributions. PMID- 23365844 TI - 3D nonlinear complex-diffusion filter on GPU. AB - The ramp preserving 2D nonlinear complex-diffusion filter introduced by Gilboa et al. (2004) was extended to 3D (Maduro et al., 2012). We propose a graphical processing unit implementation of the 3D filter for an overall faster processing in order to be used in a clinical setting. We perform a search for the best diffusion parameters (the number of iterations and spread of the diffusivity) for the 2D and 3D filters and compare their results resorting to synthetic spectral domain optical coherence tomography volumetric data and several quantitative metrics. Execution time improvement of our implementation versus a single-core approach is also presented, showing that it allows for a full 3D volume to be processed under 7.5 seconds. PMID- 23365845 TI - Medical image denoising using low pass filtering in sparse domain. AB - In this work, we introduce a new approach for medical image denoising. An innovative method is proposed to extend the concept of low-pass filtering to the sparse representation framework. A weight matrix is applied to the definition of the sparse coding optimization problem intended to reduce coefficients corresponding to atoms with higher frequency contents, which dominantly represent the image noise. In parallel, a new overcomplete Discrete Cosine Transform (DCT) dictionary is constructed to include both frequency and phase information, aiming to remove blocking artifacts without considering patch-overlap. The proposed denoising approach was applied on low-dose Computed Tomography (CT) phantoms. The resultant observations demonstrate qualitative and quantitative improvements, in terms of peak signal to noise ratio (PSNR), in comparison to some previous approaches. PMID- 23365846 TI - A cell counting method for BEVS based on nonlinear Transformed Sliding Band Filter. AB - Insect cell is the host of baculovirus in Baculovirus Expression Vector System (BEVS). However, the insect cell counting is an obstacle that constrains the efficiency in BEVS. In this paper, an insect cell counting method based on Transformed Sliding Band Filter (TSBF) was proposed according to insect cell cultivation manner. The proposed method was then applied to insect cell image datasets, and results exhibited that the average relative error rate was 2.21% compared with manual counting. Growth curve evaluation showed that this method was suitable to the protocol of cell cultivation. These exciting results proved that the proposed method was an ideal automatic counting tool for inset cells in BEVS. PMID- 23365847 TI - Electrical Impedance Tomography for hemodynamic monitoring. AB - Electrical Impedance Tomography (EIT) is a known technique to monitor impedance changes in a cross-section of a body segment, which recently gained increasing interest for regional ventilation monitoring. In this paper, we focus on hemodynamic monitoring using EIT. Past and ongoing research activities to obtain cardiac related signals and regional perfusion information from EIT image streams are summarized. Finally, we present some preliminary results on stroke volume estimation using EIT. PMID- 23365848 TI - Electrical Bioimpedance cerebral monitoring. Preliminary results from measurements on stroke patients. AB - Electrical Bioimpedance Spectroscopy (EBIS) is currently used in different tissue characterization applications. In this work we aim to use EBIS to study changes in electrical properties of the cerebral tissues after an incident of hemorrhage/ischemic stroke. To do so a case-control study was conducted using six controls and three stroke cases. The preliminary results of this study show that by using Cole-based analysis on EBIS measurements and analyzing the Cole parameters R(0) and R(infinity), it is possible to detect changes on electrical properties of cerebral tissue after stroke. PMID- 23365849 TI - Minimally invasive in vivo human lung tissue bioimpedance measurements during the bronchoscopy procedure. AB - Respiratory diseases, which include diseases of the lung, pleura, bronchial tree, trachea, upper respiratory tract and of the respiratory muscles and nerves, are a common and important cause of illness and death among the population. Experimental evidences have shown that tissue lesions have different electrical properties compared with normal tissue. Therefore, lung tissues lesions may be differentiated from lung normal tissue by comparing the tissue passive electrical properties. The manuscript reports a feasibility study for minimally invasive in vivo human lung tissue tetrapolar bioimpedance measurements using a catheter during the bronchoscopy procedure based on multisine Electrical Impedance Spectroscopy (EIS) at 10 kHz - 1 MHz. PMID- 23365850 TI - Binary signals in impedance spectroscopy. AB - Using of binary waveforms in the fast impedance spectroscopy of biological objects is discussed in the paper. There is shown that the energy of binary waveforms can be concentrated onto selected separate frequencies. We can optimize the binary excitation waveform depending on the shape of frequency response of the impedance under study to maximize the levels of signal components with certain selected frequencies. As a result, we are able to receive maximal amount of information about the properties and behavior of the impedance to be studied. We have designed and prototyped the impedance spectroscopy device operating in the frequency range from 100 mHz to 500 kHz to cover alpha- and beta-regions of the bio-impedance spectrum of time-varying subjects as, for example, fast moving cells in micro-fluidic devices, beating heart and breathing lungs or the whole cardiovascular system. PMID- 23365851 TI - Dual energy pulses for Electrical Impedance Spectroscopy with the stochastic Gabor function. AB - This paper introduces the stochastic Gabor function (SGF), an excitation waveform that can be used to design optimal excitation pulses for Electrical Impedance Spectroscopy (EIS) of the brain. The SGF is a Gaussian function modulated by uniformly distributed noise; it has wide frequency spectrum representation regardless of the stimuli pulse length. The SGF was studied in the time-frequency domain. As shown by frequency concentration measurements, the SGF is least compact in the sample frequency phase plane. Numerical results obtained by using a realistic human head model indicate that the SGF may allow for both shallow and deeper tissue penetration than is currently obtainable with conventional stimulus paradigms, potentially facilitating tissue subtraction assessment of parenchymal dielectric changes in frequency. This could be of value in advancing EIS of stroke and hemorrhage. PMID- 23365852 TI - Stroke volume obtained from the brachial artery using transbrachial electrical bioimpedance velocimetry. AB - Stroke volume (SV) is the quantity of blood ejected by the cardiac ventricles per each contraction. When SV is multiplied by heart rate, cardiac output is the result. Cardiac output (CO), in conjunction with hemoglobin concentration and arterial oxygen saturation are the cornerstones of oxygen transport. Measurement of CO is important, especially in sick humans suffering from decompensated heart disease and systemic diseases affecting the contractility or loading conditions of the heart. Although reasonably accurate invasive cardiac output methods are available, their use is restricted to those individuals hospitalized in the intensive care units. Thus, a robust noninvasive alternative is considered desirable. Impedance cardiography (ICG) is one such method, but in patients with severe heart disease and/or excess extravascular lung water, the method is inaccurate. This paper concerns the introduction of a new method, transbrachial electrical bioimpedance velocimetry (TBEV). The technique involves passage of a constant magnitude, high frequency, and low amperage ac from the upper arm to the antecubital fossa. In all other respects, the operational aspects of TBEV are consistent with ICG. There is good evidence suggesting that the TBEV waveform and its derivatives are generated by blood resistivity changes only. PMID- 23365853 TI - An MR safe algometer to study phantom and residual limb pain. AB - Researchers are interested in understanding phantom limb pain (PLP) and residual limb pain (RLP) in amputees and the neural mechanisms leading to it. fMRI can provide information on the intensity and the location of activated centers in the brain that control PLP and RLP. MR safe algometers are important to this work. This paper described the new pneumatically actuated algometer and the evaluation methods for MR safety. Our results indicate that the custom device is an improved MR safe algometer capable of autonomously producing reproducible pressure profiles. PMID- 23365854 TI - Relaxofon: a neuromuscular blockade monitor for patients under general anesthesia. AB - Anesthesia consists of three components: unconsciousness, analgesia and neuromuscular blockade (NMB). A specific drug is administered by the anesthesiologist to control these different components. In this paper we propose a new system for monitoring the neuromuscular blockade in anesthesized patients during surgery. Neuromuscular blockade drugs are used routinely by clinicians to induce muscle relaxation in patients. However, the use of these drugs has some risks, so an adequate monitoring of the effects of these drugs is essential. This paper describes the Relaxofon, a NMB monitoring device based on phonomyography. The Relaxofon is composed of a hardware subsystem that records muscle sounds using microphones and a special circuit to filter out the noise and amplify the signal, and a software subsystem that analyses the acquired signal. We tested the ability of the system to record phonomyographic signals from the adductor pollicis and the corrugator supercilii muscles. We then performed the Bland Altman test to compare the manual Train-of-Four ratio (a measure of the depth of muscle relaxation) calculation against the one performed by the Relaxofon. Finally, we calculated the Pearson correlation coefficient to measure the linear dependence between the two methods. Automatic Train-of-Four ratio calculations using this system showed very good agreement with manual calculations. Results from this work may ultimately lead to integration of NMB monitoring to an automated closed-loop anesthesia system. PMID- 23365855 TI - Quantitative assessment of levodopa-induced dyskinesia using automated motion sensing technology. AB - The objective was to capture levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD) using body-worn motion sensors. Dopaminergic treatment in PD can induce abnormal involuntary movements, including choreatic dyskinesia (brief, rapid, irregular movements). Adjustments in medication to reduce LID often sacrifice control of motor symptoms, and balancing this tradeoff poses a significant challenge for management of advanced PD. Fifteen PD subjects with known LID were recruited and instructed to perform two stationary motor tasks while wearing a compact wireless motion sensor unit positioned on each hand over the course of a levodopa dose cycle. Videos of subjects performing the motor tasks were later scored by expert clinicians to assess global dyskinesia using the modified Abnormal Involuntary Rating Scale (m-AIMS). Kinematic features were extracted from motion data in different frequency bands (1-3Hz and 3-8Hz) to quantify LID severity and to distinguish between LID and PD tremor. Receiver operator characteristic analysis was used to determine thresholds for individual features to detect the presence of LID. A sensitivity of 0.73 and specificity of 1.00 were achieved. A neural network was also trained to output dyskinesia severity on a 0 to 4 scale, similar to the m-AIMS. The model generalized well to new data (coefficient of determination= 0.85 and mean squared error= 0.3). This study demonstrated that hand-worn motion sensors can be used to assess global dyskinesia severity independent of PD tremor over the levodopa dose cycle. PMID- 23365856 TI - Monitoring walking and cycling of middle-aged to older community dwellers using wireless wearable accelerometers. AB - Changes in gait parameters have been shown to be an important indicator of several age-related cognitive and physical declines of older adults. In this paper we propose a method to monitor and analyze walking and cycling activities based on a triaxial accelerometer worn on one ankle. We use an algorithm that can (1) distinguish between static and dynamic functional activities, (2) detect walking and cycling events, (3) identify gait parameters, including step frequency, number of steps, number of walking periods, and total walking duration per day, and (4) evaluate cycling parameters, including cycling frequency, number of cycling periods, and total cycling duration. Our algorithm is evaluated against the triaxial accelerometer data obtained from a group of 297 middle-aged to older adults wearing an activity monitor on the right ankle for approximately one week while performing unconstrained daily activities in the home and community setting. The correlation coefficients between each of detected gait and cycling parameters on two weekdays are all statistically significant, ranging from 0.668 to 0.873. These results demonstrate good test-retest reliability of our method in monitoring walking and cycling activities and analyzing gait and cycling parameters. This algorithm is efficient and causal in time and thus implementable for real-time monitoring and feedback. PMID- 23365857 TI - Static and cyclic performance evaluation of sensors for human interface pressure measurement. AB - Researchers and clinicians often desire to monitor pressure distributions on soft tissues at interfaces to mechanical devices such as prosthetics, orthotics or shoes. The most common type of sensor used for this type of applications is a Force Sensitive Resistor (FSR) as these are convenient to use and inexpensive. Several other types of sensors exist that may have superior sensing performance but are less ubiquitous or more expensive, such as optical or capacitive sensors. We tested five sensors (two FSRs, one optical, one capacitive and one fluid pressure) in a static drift and cyclic loading configuration. The results show that relative to the important performance characteristics for soft tissue pressure monitoring (i.e. hysteresis, drift), many of the sensors tested have significant limitations. The FSRs exhibited hysteresis, drift and loss of sensitivity under cyclic loading. The capacitive sensor had substantial drift. The optical sensor had some hysteresis and temperature-related drift. The fluid pressure sensor performed well in these tests but is not as flat as the other sensors and is not commercially available. Researchers and clinicians should carefully consider the convenience and performance trade-offs when choosing a sensor for soft-tissue pressure monitoring. PMID- 23365858 TI - Evaluation of a smart alarm for intensive care using clinical data. AB - We describe and report the results of an evaluation of a smart alarm algorithm for post coronary artery bypass graft (CABG) patients. The algorithm (CABG-SA) was applied to vital sign data streams recorded in a surgical intensive care unit (SICU) at a hospital in the University of Pennsylvania Health System. In order to determine the specificity of CABG-SA, the alarms generated by CABG-SA were compared against the actual interventions performed by the staff of the critical care unit. Overall, CABG-SA alarmed for 55% of the time relative to traditional alarms while still generating alarms for 12 of the 13 recorded interventions. PMID- 23365859 TI - Implantable ultrasonic dual functional assembly for detection and treatment of anomalous growth. AB - High Intensity Focused Ultrasound (HIFU) is emerging as an accurate, noninvasive method for ablation of certain primary and metastatic tumors. Typically, ablation is performed with an external therapeutic transducer. However, external HIFU treatment suffers from limitations of low therapeutic efficiency for ablation of tumors, deep in internal organs such as liver, kidney and brain. Interstitial HIFU through an internal transducer, implanted locally near the organ of interest, could alleviate some of these limitations. Furthermore, it can be attractive for point-of-care (POC) treatment. In this paper, we propose the design of a dual-functional implantable assembly for image-guided HIFU treatment of anomalous growth. It is realized by effective integration of a central HIFU array with two ultrasonic imaging arrays for high-resolution online monitoring and efficient treatment. We explore the design space for the implant and identify the major design parameters including the power requirement. Using a widely used simulation platform, we show that the proposed implant, besides providing a potential POC solution, achieves a better therapeutic performance for certain tumor positions in internal organs, than the extracorporeal HIFU treatment. PMID- 23365860 TI - Safe teleoperation based on flexible intraoperative planning for robot-assisted laser microsurgery. AB - This paper describes a new intraoperative planning system created to improve precision and safety in teleoperated laser microsurgeries. It addresses major safety issues related to real-time control of a surgical laser during teleoperated procedures, which are related to the reliability and robustness of the telecommunication channels. Here, a safe solution is presented, consisting in a new planning system architecture that maintains the flexibility and benefits of real-time teleoperation and keeps the surgeon in control of all surgical actions. The developed system is based on our virtual scalpel system for robot-assisted laser microsurgery, and allows the intuitive use of stylus to create surgical plans directly over live video of the surgical field. In this case, surgical plans are defined as graphic objects overlaid on the live video, which can be easily modified or replaced as needed, and which are transmitted to the main surgical system controller for subsequent safe execution. In the process of improving safety, this new planning system also resulted in improved laser aiming precision and improved capability for higher quality laser procedures, both due to the new surgical plan execution module, which allows very fast and precise laser aiming control. Experimental results presented herein show that, in addition to the safety improvements, the new planning system resulted in a 48% improvement in laser aiming precision when compared to the previous virtual scalpel system. PMID- 23365861 TI - Effect of irreversible electroporation on three-dimensional cell culture model. AB - Irreversible electroporation (IRE) is a new treatment to necrotize abnormal cells by high electric pulses. Electric potential difference over 1 V across the plasma membrane permanently permeabilizes the cell with keeping the extracellular matrix intact if the thermal damage due to the Joule heating effect is avoided. This is the largest advantage of the IRE compared to the other conventional treatment. However, since the IRE has just started to be used in clinical tests, it is important to predict the necrotized region that depends on pulse parameters and electrode arrangement. We therefore examined the numerical solution to the Laplace equation for the static electric field to predict the IRE-induced cell necrosis. Three-dimensionally (3-D) cultured cells in a tissue phantom were experimentally subjected to the electric pulses through a pair of puncture electrodes. The necrotized area was determined as a function of the pulse repetition and compared with the area that was estimated by the numerical analysis. PMID- 23365862 TI - Thoracoscopic surgery support system using passive RFID marker. AB - This paper proposes a RFID based thoracoscopic surgery support system, which is capable of marking a tumor inside organ tissue. The marker composed of small RFID tags is implanted in the vicinity of tumor found in the endoscopy test. In the thoracoscopic surgery operation for removing the tumor, an RFID detector determines the accurate position of the implanted RFID-tag markers by measuring the strength of the signal emitted from the target tag. Due to limitation in the size of RFID-tag, the proposed system employs a passive RFID. To activate the passive tag implanted in the organ tissue, this paper designs a saddle-shape efficient power supply antenna. A sensitive and frequency-selective receiver is then designed for detecting the weak signal from the tag. The feasibility test confirms that the proposed method is capable of determining the accurate location of RFID tags implanted in the patient's organ tissue. PMID- 23365864 TI - Radiofrequency ablation planning beyond simulation. AB - It is a challenging task to plan a radiofrequency (RF) ablation therapy to achieve the best outcome of the treatment and avoid recurrences at the same time. A patient specific simulation in advance that takes the cooling effect of blood vessels into account is a helpful tool for radiologists, but this needs a very high accuracy and thus high computational costs. In this work, we present various methods, which improve and extend the planning of an RF ablation procedure. First, we discuss two extensions of the simulation model to obtain a higher accuracy, including the vaporization of the water in the tissue and identifying the model parameters and to analyze their uncertainty. Furthermore, we discuss an extension of the planning procedure namely the optimization of the probe placement, which optimizes the overlap of the tumor area with the estimated coagulation in order to avoid recurrences. Since the optimization is constrained by the model, we have to take into account the uncertainties in the model parameters for the optimization as well. Finally, applications of our methods to a real RF ablation case are presented. PMID- 23365863 TI - A method for deriving the coagulation boundary of liver tissue using a relational model of viscoelasticity and temperature in radio frequency ablation. AB - Recently radiofrequency (RF) ablation has become increasingly important in treating liver cancers. RF ablation is ordinarily conducted using elastographic imaging to monitor the ablation procedure and the temperature of the electrode needle is displayed on the RF generator. However, the coagulation boundary of liver tissue in RF ablation is unclear and unconfident. This can lead to both excessive and insufficient RF ablation thereby diminishing the advantages of the procedure. In the present study, we developed a method for determining the coagulation boundary of liver tissue in RF ablation. To investigate this boundary we used the mechanical characteristics of biochemical components as an indicator of coagulation to produce a relational model for viscoelasticity and temperature. This paper presents the data acquisition procedures for the viscoelasticity characteristics and the analytical method used for the coagulation model. We employed a rheometer to measure the viscoelastic characteristics of liver tissue. To determine the model functional relationship between viscoelasticity and temperature, we used a least-square method and the minimum root mean square error was calculated to optimize the model functional relations. The functional relation between temperature and viscoelasticity was linear and non-linear in different temperature regions. The boundary between linear and non-linear functional relation was 58.0 degrees C. PMID- 23365865 TI - Study of cardiac pacemaker excitation using generic ionic models and realistic cell distribution. AB - Generic ionic models optimized to replicate experimentally recorded cardiac action potentials (APs) from the central and peripheral sinoatrial node (SAN), the natural pacemaker of the heart, as well as atrial intact-myocytes are implemented in a realistic 2D model of rabbit SAN geometry. The model was used to investigate two frequently-proposed modes of SAN architecture: the gradient and mosaic hypotheses. In a simplified gradient arrangement, the peripheral SAN region acts as a transition zone between the central SAN and atrium and is required for spontaneous rhythmic initiation of APs from central SAN into the atria. Furthermore, the application of optimized single cell parameters to the realistic 2D rabbit geometry did not accurately replicate experimentally recorded APs. On the other hand, in an adapted mosaic geometry, peripheral SAN cells were not required to produce spontaneous regular excitation. PMID- 23365866 TI - Development of biophysically detailed electrophysiological models for pacemaking and non-pacemaking human pulmonary vein cardiomyocytes. AB - Ectopic foci originating from the pulmonary veins (PVs) have been suggested as the underlying cause for generating atrial arrhythmias that include atrial fibrillation (AF). Recent experimental findings indicate two types of PV cells: pacemaking and non-pacemaking. In this study, we have developed two mathematical models for human PV cardiomyocytes with and without pacemaking activities. The models were reconstructed by modifying an existing model of the human right atrium to incorporate extant experimental data on the electrical differences between the two cell types. Differences in their action potential (AP) profiles and automaticity were reproduced by the models, which can be attributed to the observed differences in the current densities of I(NCX), I(to), I(Na) and I(Ca L), as well as the difference in the channel kinetics of I(Ca-L) and inclusion of the I(f) and I(Ca-T) currents in the pacemaking cells. The developed models provide a useful tool suitable for studying the substrates for generating AF. PMID- 23365867 TI - Arrhythmogenic substrate for atrial fibrillation: insights from an integrative computational model of pulmonary veins. AB - Mechanisms underlying the genesis of re-entrant substrate for atrial fibrillation (AF) in the pulmonary veins (PVs) and left atrium (LA) are not well understood. We develop a biophysically detailed computational model for the PVs and surrounding LA tissue. The model integrates canine PV and LA single cell electrophysiology with the respective 3D tissue geometry and fiber orientation reconstructed from micro-CT data. The model simulations demonstrate that a combination of tissue anisotropy and electrical heterogeneity between the PVs and LA causes a break-down of normal electrical excitation wave-fronts. This leads to the generation of a high-frequency re-entrant source near the PV sleeves. Evidence of such sources have been seen clinically in AF patients. In summary, our modeling results provide new insights into the arrhythmogenic mechanisms of re-entrant excitation waves underlying AF. PMID- 23365868 TI - Suppression of anodal break excitation by electrical stimulation with down staircase waveform for distance-selective nerve recruitment. AB - Electrical nerve stimulation using extracellular electrodes is widely performed in clinical medicine as well as basic medical science. It has been reported that selective recruitment of nerve fibers on the basis of the distance between the electrode and the axon is possible without moving the electrode and only by modifying the waveform of electrical stimulation. However, computer simulations have not reproduced the complete nature of the distance-selectivity of the stimulus owing to the difficulty in numerical analysis. In this paper, we propose a minor modification to the myelinated axon model to overcome this difficulty. We confirm that this modification improves the numerical stability of the simulation and enables us to obtain the spatio-temporal dynamics of axons, including the electrode-to-axon distance-dependency. In addition, we propose a novel stimulation method using a down-staircase waveform for distance-selective nerve recruitment. Simulations confirm that the method works well. We show the spatial distribution of axons activated by the down-staircase stimulation, which would be helpful to determine the stimulation parameters for distance-selective nerve recruitment. PMID- 23365869 TI - Convolution based method for calculating inputs from dendritic fields in a continuum model of the retina. AB - Computational models are valuable tools that can be used to aid the design and test the efficacy of electrical stimulation strategies in prosthetic vision devices. In continuum models of retinal electrophysiology, the effective extracellular potential can be considered as an approximate measure of the electrotonic loading a neuron's dendritic tree exerts on the soma. A convolution based method is presented to calculate the local spatial average of the effective extracellular loading in retinal ganglion cells (RGCs) in a continuum model of the retina which includes an active RGC tissue layer. The method can be used to study the effect of the dendritic tree size on the activation of RGCs by electrical stimulation using a hexagonal arrangement of electrodes (hexpolar) placed in the suprachoroidal space. PMID- 23365870 TI - Using dual-antenna nanosecond pulse near-field sensing technology for non-contact and continuous blood pressure measurement. AB - Long-term and continuous non-invasive blood pressure monitoring has shown that it is the most important to clinical diagnosis of cardiovascular diseases and personal home health care. Currently, there are many preferable non-invasive methods, including optical sensor, pressure-sensitive transducers, and applanation tonometry, to get insight of blood pressure and flow signal detection. However, the operation of traditional monitors is cuff accessories needed, and also the sensing probes needed to exert pressure to the user directly. The measurement procedure is limited by long-term, continuous measurement and also easy to cause discomfort. To improve these issues, the non pressurized and non-invasive measuring method will become an important innovation improvement. In this paper, the novel nanosecond pulse near-field sensing (NPNS) based screening technology with dual-antenna, which includes radio frequency (RF) pulse transmission and two combined flat antenna connected to transceiver of miniature radar, is proposed to derive relative blood pressure parameters from measured blood flow activity (Pulse Wave Velocity, PWV). A dedicated analysis software is also provided to calculate cardiovascular parameters, including PWV, average systolic time, diastolic and systolic pressure, for clinical and homecare applications. To evaluate the performance, the proposed method was applied on blood pressure measurement at the body site of limbs (brachial and leg). As a result, it shows error of DBP and SBP is 5.18+/-1.61 and 4.09 +/- 1.69 mmHg in average compared with the measurement result from commercial product, and performs the capability of continuous long-term monitoring in real-time. PMID- 23365871 TI - Model-based estimation of blood pressure response to epinephrine. AB - In this study, we present a model-based approach to estimation of blood pressure (BP) response to epinephrine. The proposed approach estimates systolic (SBP), mean (MAP) and diastolic (DBP) BP based on a 2-parameter windkessel (WK) model with dose-dependent total peripheral resistance (TPR), arterial compliance (AC) and stroke volume (SV) indices that is driven by the epinephrine dose, heart rate (HR). Using the epinephrine dose and hemodynamic response data collected for young/old normotensive and hypertensive subject groups, four group-specific models as well as a generalized model were developed and then were evaluated for BP estimation performance. The results indicated that the group-specific model is superior to its generalized counterpart; on average, the root-mean-squared SBP, MAP and DBP estimation errors associated with the group-specific model were only 34%, 52% and 69%, respectively, compared with the generalized model. PMID- 23365872 TI - Automated system for imageless evaluation of arterial compliance. AB - Evaluation of arterial compliance is very significant in early detection of coronary heart disease. Here we present an imageless portable system for automated estimation of local arterial compliance, designed to be operated by a general medical practitioner with no prior knowledge of ultrasonography. An algorithm for automatic detection and tracking of the arterial wall locations has been developed to minimize the operator expertise required for measurement. The performance of the automated algorithm was thoroughly characterized using a simulation platform developed for the purpose. Measurements performed on a few human volunteers by untrained personnel clearly illustrated the practical utility of the automatic algorithm during in-vivo tests. The proposed system could be used for developing an inexpensive cardiovascular screening device for large scale deployment in primary health care centers. PMID- 23365873 TI - Perturbationless calibration of pulse transit time to blood pressure. AB - Pulse transit time (PTT) often shows strong correlation with blood pressure (BP) and may therefore represent a means for achieving continuous, non-invasive, and cuff-less BP monitoring. However, construction of the subject-specific curve needed to calibrate PTT to BP conventionally requires simultaneous measurements of PTT and BP during an experimental perturbation that varies BP over a significant range. We propose a technique for perturbationless calibration of PTT to BP. This technique constructs the calibration curve from central and peripheral BP waveforms by exploiting the natural pulsatile variation in the waveforms via a nonlinear tube-load model. We conducted initial testing of the technique in animals by applying it to the waveforms during a baseline period and then predicting mean BP during subsequent major hemodynamic interventions via PTT calibrated with the resulting curve. The bias in the mean BP error was 4.9 mmHg, while the precision in this error was 7.6 mmHg. PMID- 23365874 TI - The comparison of a novel continuous cardiac output monitor based on pulse wave transit time and echo Doppler during exercise. AB - A new technology called estimated continuous cardiac output (esCCO) uses pulse wave transit time (PWTT) obtained from an electrocardiogram and pulse oximeter to measure cardiac output (CO) non-invasively and continuously. This study was performed to evaluate the accuracy of esCCO during exercise testing. We compared esCCO with CO measured by the echo Doppler aortic velocity-time integral (VTIao_CO). The correlation coefficient between esCCO and VTIao_CO was r= 0.87 (n= 72). Bias and precision were 0.33 +/- 0.95 L/min and percentage error was 31%. The esCCO could detect change in VTIao_CO larger than 1 L/min with a concordance rate of 88%. In polar plot, 83% of data are within 0.5 L/min, and 100% of data are within 1 L/min. Those results show the acceptable accuracy and trend ability of esCCO. Change in pre-ejection period (PEP) measured by using M mode of Diagnostic Ultrasound System accounted for approximately half of change in PWTT. This indicates that PEP included in PWTT has an impact on the accuracy of esCCO measurement. In this study, the validity of esCCO during exercise testing was assessed and shown to be acceptable. The result of this study suggests that we can expand its application. PMID- 23365875 TI - Validation of the qCO cardiac output monitor during Valsalva maneuver. AB - Monitoring cardiac output for a variety of patient conditions is essential to ensure tissue perfusion and oxygenation. Cardiac output can be measured either invasively using a pulmonary artery catheter or non-invasively using impedance cardiography (ICG). The objective of the present study was to validate a cardiac output monitor, the qCO (Quantium Medical, Barcelona, Spain). The qCO is based on the ICG principle. Twenty-five volunteers (18-75 years) were enrolled in the study. The duration of the study was 10 min. The subjects were asked to rest quietly in an armchair for a duration of 5 min. At 5 min they were asked to do a Valsalva maneuver which is known to decrease the cardiac output. The baseline value of the normalized cardiac output (qCO index) was compared with the minimum value during the Valsalva maneuver. The results showed (t-test, p<0.0005) significant difference between the cardiac output estimated at baseline and during the Valsalva maneuver. In conclusion, the qCO was able to indicate trend changes of the cardiac output in volunteers. PMID- 23365876 TI - A new method to estimate the real upper limit of the false alarm rate in a 3 accelerometry-based fall detector for the elderly. AB - Falls are a major concern for the elderly and their ability to remain healthy. Fall detection systems may notify emergency responders when no one apart from the injured is present. However, their real-world application is limited by a number of factors such as high false positive rates, low-compliance, poor-usability and short battery lifetime. In order to improve these aspects we have developed a miniaturized 3D accelerometer integrated in a belt buckle, the actibelt((r)), and a fall detection algorithm. We have used a new evaluation method to assess the upper limit of the false alarm rate of our algorithm using a large set of long term standardized acceleration measurements recorded under real life conditions. Our algorithm has a false alarm rate of seventeen false alarms per month and has the potential to be reduced down to at most three false alarms per month when activities which require the sensor to be removed are eliminated. In laboratory settings, the algorithm has a sensitivity of 100%. The algorithm was sucessfully validated using data from a real-world fall. PMID- 23365877 TI - Embedded fall and activity monitoring for a wearable ambient assisted living solution for older adults. AB - With the rapidly increasing over 60 and over 80 age groups in society, greater emphasis will be put on technology to detect emergency situations, such as falls, in order to promote independent living. This paper describes the development and deployment of fall-detection, activity classification and energy expenditure algorithms, deployed in a tele-monitoring system. These algorithms were successfully tested in an end-user trial involving 9 elderly volunteers using the system for 28 days. PMID- 23365878 TI - Automated fall detection on privacy-enhanced video. AB - A privacy-enhanced video obscures the appearance of a person in the video. We consider four privacy enhancements: blurring of the person, silhouetting of the person, covering the person with a graphical box, and covering the person with a graphical oval. We demonstrate that an automated video-based fall detection algorithm can be as accurate on privacy-enhanced video as on raw video. The algorithm operated on video from a stationary in-home camera, using a foreground background segmentation algorithm to extract a minimum bounding rectangle (MBR) around the motion in the video, and using time series shapelet analysis on the height and width of the rectangle to detect falls. We report accuracy applying fall detection on 23 scenarios depicted as raw video and privacy-enhanced videos involving a sole actor portraying normal activities and various falls. We found that fall detection on privacy-enhanced video, except for the common approach of blurring of the person, was competitive with raw video, and in particular that the graphical oval privacy enhancement yielded the same accuracy as raw video, namely 0.91 sensitivity and 0.92 specificity. PMID- 23365879 TI - Doppler radar sensor positioning in a fall detection system. AB - Falling is a common health problem for more than a third of the United States population over 65. We are currently developing a Doppler radar based fall detection system that already has showed promising results. In this paper, we study the sensor positioning in the environment with respect to the subject. We investigate three sensor positions, floor, wall and ceiling of the room, in two experimental configurations. Within each system configuration, subjects performed falls towards or across the radar sensors. We collected 90 falls and 341 non falls for the first configuration and 126 falls and 817 non falls for the second one. Radar signature classification was performed using a SVM classifier. Fall detection performance was evaluated using the area under the ROC curves (AUCs) for each sensor deployment. We found that a fall is more likely to be detected if the subject is falling toward or away from the sensor and a ceiling Doppler radar is more reliable for fall detection than a wall mounted one. PMID- 23365880 TI - Radar walking speed measurements of seniors in their apartments: technology for fall prevention. AB - Falls are a significant cause of injury and accidental death among persons over the age of 65. Gait velocity is one of the parameters which have been correlated to the risk of falling. We aim to build a system which monitors gait in seniors and reports any changes to caregivers, who can then perform a clinical assessment and perform corrective and preventative actions to reduce the likelihood of falls. In this paper, we deploy a Doppler radar-based gait measurement system into the apartments of thirteen seniors. In scripted walks, we show the system measures gait velocity with a mean error of 14.5% compared to the time recorded by a clinician. With a calibration factor, the mean error is reduced to 10.5%. The radar is a promising sensing technology for gait velocity in a day-to-day senior living environment. PMID- 23365881 TI - ARhT: a portable hand therapy system. AB - We introduce ARhT (Automated Relearning hand Therapy), a portable hand therapy system that enables a user to perform physical therapy at the comfort of their own home. This reduces rehabilitation time, enhances the user experience, reduces cost and provides accountability to physical therapy sessions. ARhT complements traditional therapy methods by interacting with the user in real time and providing the patient user friendly instructions, feedback, and progress tracking. The therapist pre-selects the hand gestures that comprise every workout and can view session information on a patient to patient basis within a standalone web application. ARhT incorporates a data acquisition subsystem which houses EMG sensors and a custom computation and communication board. The sensor data is transmitted to an Android smartphone that determines the user performance and interacts with the user through a graphical user interface. Our results show that our system recognizes hand therapy gestures with over 95% accuracy. PMID- 23365882 TI - Highly survivable bed pressure mat remote patient monitoring system for mHealth. AB - The high speed mobile networks like 4G and beyond are making a ubiquitous remote patient monitoring (RPM) system using multiple sensors and wireless sensor networks a realistic possibility. The high speed wireless RPM system will be an integral part of the mobile health (mHealth) paradigm reducing cost and providing better service to the patients. While the high speed wireless RPM system will allow clinicians to monitor various chronic and acute medical conditions, the reliability of such system will depend on the network Quality of Service (QoS). The RPM system needs to be resilient to temporary reduced network QoS. This paper presents a highly survivable bed pressure mat RPM system design using an adaptive information content management methodology for the monitored sensor data. The proposed design improves the resiliency of the RPM system under adverse network conditions like congestion and/or temporary loss of connectivity. It also shows how the proposed RPM system can reduce the information rate and correspondingly reduce the data transfer rate by a factor of 5.5 and 144 to address temporary network congestion. The RPM system data rate reduction results in a lower specificity and sensitivity for the features being monitored but increases the survivability of the system from 1 second to 2.4 minutes making it highly robust. PMID- 23365883 TI - Feasibility of mHealth and Near Field Communication technology based medication adherence monitoring. AB - Poor patients' adherence to intake of prescribed medication has been identified as a serious problem in the treatment of chronically ill patients. Technical solutions are needed to measure and - if necessary - to increase the patients' adherence. A telemonitoring solution was developed to record a patient's medication intake based on smart blisters and mobile phones with NFC functionality. The components allowed recording of drug type, timestamp, and dosage of pills taken. The system's usability and technical feasibility was evaluated in the course of an application study. Over a period of 13 months 59 patients suffering from diabetes were monitored. 1,760 blisters were handed out to these patients and 14,843 takeout events were recorded and transmitted via mobile phone. Results indicate the feasibility of this concept to monitor adherence. Although the system still needs to be optimized for routine use it shows the potential for targeting the problem of poor patient adherence by NFC enabled devices. PMID- 23365884 TI - M-health system for life-style enhancement: WiFIT. AB - In this paper we present a novel m-health system which provides personalized real time recommendations for life-style enhancement. The system, termed WiFIT, is capable of monitoring a wide range of the a priori defined biometric parameters and generates recommendations for achieving or maintaining the desired health and life-style goals. WiFIT is designed as an open platform which could be as complex or as simple as required for a particular application. Its key components include secure wireless broadband links, personal area body area sensory network, and an interactive data base with built-in prediction algorithms. The paper describes the WiFIT architecture and outlines system performance for certain case studies. PMID- 23365885 TI - PAGAS: Portable and Accurate Gait Analysis System. AB - Gait analysis systems are powerful tools in the monitoring and rehabilitation of many health conditions which result in an altered gait (such as Parkinson's disease and rheumatoid arthritis), along with the injury of lower limbs. However, current systems that provide accurate gait monitoring and analysis are large and expensive, and therefore are available only in professional settings. The goal of this research is to develop and test a Portable and Accurate Gait Analysis System, denoted PAGAS, which enables patients to monitor their own gait and track their progress and improvement over time. Moreover, PAGAS will enable therapists to follow the progress of their patients over time without the need for multiple visits required at a rehabilitation facility, thus saving significant healthcare costs. PAGAS includes footswitches and a micro-controller, which connects to an Android Smart-phone using Bluetooth communication. An application on the Smartphone analyzes the raw data to produce temporal gait parameters that are displayed to the user on a graphical user interface. PMID- 23365886 TI - Dynamic subframe allocation for mobile broadband m-health using IEEE 802.16j mobile multihop relay networks. AB - The concept of 4G health will be one of the key focus areas of future m-health research and enterprise activities in the coming years. WiMAX technology is one of the constituent 4G wireless technologies that provides broadband wireless access (BWA). Despite the fact that WiMAX is able to provide a high data rate in a relatively large coverage; this technology has specific limitations such as: coverage, signal attenuation problems due to shadowing or path loss, and limited available spectrum. The IEEE 802.16j mobile multihop relay (MMR) technology is a pragmatic solution designed to overcome these limitations. The aim of IEEE 802.16j MMR is to expand the IEEE 802.16e's capabilities with multihop features. In particular, the uplink (UL) and downlink (DL) subframe allocation in WiMAX network is usually fixed. However, dynamic frame allocation is a useful mechanism to optimize uplink and downlink subframe size dynamically based on the traffic conditions through real-time traffic monitoring. This particular mechanism is important for future WiMAX based m-health applications as it allows the tradeoff in both UL and DL channels. In this paper, we address the dynamic frame allocation issue in IEEE 802.16j MMR network for m-health applications. A comparative performance analysis of the proposed approach is validated using the OPNET Modeler((r)). The simulation results have shown an improved performance of resource allocation and end-to-end delay performance for typical medical video streaming application. PMID- 23365887 TI - Development of m-health monitoring systems in India and Iraq. AB - Two separate projects have been carried out to implement m-health programs in India and Iraq, and, for each, this paper describes the work performed by the teams involved, presents results and details a number of lessons learned. In general, it is found that although India and Iraq have very different medical priorities, they pose similar issues when introducing m-health strategies. PMID- 23365888 TI - ASIC design and data communications for the Boston retinal prosthesis. AB - We report on the design and testing of a custom application-specific integrated circuit (ASIC) that has been developed as a key component of the Boston retinal prosthesis. This device has been designed for patients who are blind due to age related macular degeneration or retinitis pigmentosa. Key safety and communication features of the low-power ASIC are described, as are the highly configurable neural stimulation current waveforms that are delivered to its greater than 256 output electrodes. The ASIC was created using an 0.18 micron Si fabrication process utilizing standard 1.8 volt CMOS transistors as well as 20 volt lightly doped drain FETs. The communication system receives frequency-shift keyed inputs at 6.78 MHz from an implanted secondary coil, and transmits data back to the control unit through a lower-bandwidth channel that employs load shift keying. The design's safety is ensured by on-board electrode voltage monitoring, stimulus charge limits, error checking of data transmitted to the implant, and comprehensive self-test and performance monitoring features. Each stimulus cycle is initiated by a transmitted word with a full 32-bit error check code. Taken together, these features allow researchers to safely and wirelessly tailor retinal stimulation and vision recovery for each patient. PMID- 23365889 TI - Smart image processing system for retinal prosthesis. AB - Retinal prostheses for the blind have demonstrated the ability to provide the sensation of light in otherwise blind individuals. However, visual task performance in these patients remains poor relative to someone with normal vision. Computer vision algorithms for navigation and object detection were evaluated for their ability to improve task performance. Blind subjects navigating a mobility course had fewer collisions when using a wearable camera system that guided them on a safe path. Subjects using a retinal prosthesis simulator could locate objects more quickly when an object detection algorithm assisted them. Computer vision algorithms can assist retinal prosthesis patients and low-vision patients in general. PMID- 23365890 TI - Transformative Reality: improving bionic vision with robotic sensing. AB - Implanted visual prostheses provide bionic vision with very low spatial and intensity resolution when compared against healthy human vision. Vision processing converts camera video to low resolution imagery for bionic vision with the aim of preserving salient features such as edges. Transformative Reality extends and improves upon traditional vision processing in three ways. Firstly, a combination of visual and non-visual sensors are used to provide multi-modal data of a person's surroundings. This enables the sensing of features that are difficult to sense with only a camera. Secondly, robotic sensing algorithms construct models of the world in real time. This enables the detection of complex features such as navigable empty ground or people. Thirdly, models are visually rendered so that visually complex entities such as people can be effectively represented in low resolution. Preliminary simulated prosthetic vision trials, where a head mounted display is used to constrain a subject's vision to 25*25 binary phosphenes, suggest that Transformative Reality provides functional bionic vision for tasks such as indoor navigation, object manipulation and people detection in scenes where traditional processing is unusable. PMID- 23365891 TI - The role of vision processing in prosthetic vision. AB - Prosthetic vision provides vision which is reduced in resolution and dynamic range compared to normal human vision. This comes about both due to residual damage to the visual system from the condition that caused vision loss, and due to limitations of current technology. However, even with limitations, prosthetic vision may still be able to support functional performance which is sufficient for tasks which are key to restoring independent living and quality of life. Here vision processing can play a key role, ensuring that information which is critical to the performance of key tasks is available within the capability of the available prosthetic vision. In this paper, we frame vision processing for prosthetic vision, highlight some key areas which present problems in terms of quality of life, and present examples where vision processing can help achieve better outcomes. PMID- 23365892 TI - The uniqueness of the message in a retinal ganglion cell spike train and its implication for retinal prostheses. AB - We sought to determine whether the messages conveyed in the spike trains of individual retinal ganglion cells are unique or whether, as has been reported for other neurons, they depend in some way on a neuron's state. Our data show convincingly that the messages are unique. PMID- 23365893 TI - Contralaterally controlled functional electrical stimulation for stroke rehabilitation. AB - Contralaterally controlled functional electrical stimulation (CCFES) is an innovative method of delivering neuromuscular electrical stimulation for rehabilitation of paretic limbs after stroke. It is being studied to evaluate its efficacy in improving recovery of arm and hand function and ankle dorsiflexion in chronic and subacute stroke patients. The initial studies provide preliminary evidence supporting the efficacy of CCFES. PMID- 23365894 TI - Variations in neuromuscular electrical stimulation's ability to increase reach and hand opening during voluntary effort after stroke. AB - Functional Electrical Stimulation (FES) has shown potential as a mechanism to augment functional arm and hand movement after stroke. However, neuroprostheses that combine voluntary effort and FES must account for co-activation patterns (synergies) that limit movement. The goal of this study is to explore the conditions under which voluntary effort and FES can be combined to achieve useful reach and hand opening in different subjects. Subjects performed a reach and hand opening task where different levels of voluntary effort and FES were applied to produce reach and hand opening while measuring the resulting hand opening and distance from a target. Initial results indicate that there are significant variations between participants and how much effort can be exerted while still eliciting effective reach and hand opening. PMID- 23365895 TI - Control of a time-delayed 5 degrees of freedom arm model for use in upper extremity functional electrical stimulation. AB - The goal of this work is to design a controller for a functional electrical stimulation (FES) neuroprosthesis aimed at restoring shoulder and elbow function in individuals who have suffered a high-level cervical (C3-C4) spinal cord injury (SCI). The controller is a mathematical algorithm that coordinates the electrical stimulations applied to the paralyzed muscles such that the arm closely tracks a given desired trajectory. An issue that so far has received little attention is that of time-delays. These delays arise from two sources: (1) the muscle excitation-activation dynamics (10-30 ms) and (2) the sampling of the electrical stimulation (80 ms at the typical 12 Hz stimulation frequency). Using a 5 degrees of freedom (5 DOF) arm model we designed and evaluated a novel controller capable of maintaining stable and accurate tracking performance in the presence of time delays. For a desired trajectory consisting of 10 randomized reaches, the controller achieved excellent tracking performance as measured by the root-mean square error (RMSE) between the desired and simulated joint angles (RMSE= [1.48 degrees ; 0.81 degrees ; 2.14 degrees ; 3.11 degrees ; 2.29 degrees ]). PMID- 23365896 TI - A paradigm for the control of upright standing in paraplegic patients. AB - The objective of this paper is to present a new paradigm in control strategy for unsupported paraplegic standing, based on closed-loop control of paraplegics' lower extremities. The main advantage of our approach is taking into account voluntary motions of the upper-part of the body by controlling Center of Mass (CoM) position. The validity of our approach is tested, in computer simulations, using human CoM trajectories estimated from experimental data and by applying perturbations in simulation during quiet standing in order to simulate voluntary upper body movements. From the results presented in this study it can be seen that controller is able to track desired CoM position with sufficient precision and to maintain stability even in the presence of simulated movements of the upper body. PMID- 23365897 TI - Optimal sampling of recruitment curves for functional electrical stimulation control. AB - A major challenge in controlling multiple-input multiple output functional electrical stimulation systems is the large amount of time required to identify a workable system model due to the high dimensionality of the space of inputs. To address this challenge we are exploring optimal methods to sample the input space. In this paper we present two methods for optimally sampling isometric muscle force recruitment curves. One method maximizes the information about the recruitment curve parameters, and the second method minimizes the average variance of the predicted output force. We compared these methods to two previously-used methods in simulation. The simulation model was identified from recruitment data collected during experiments with a human subject with a high spinal cord injury. The optimal sampling methods on average produced estimates of the output force with less error than the two previously-used methods. The optimal sampling methods require fewer system identification experiments to identify models with similar output prediction accuracy. PMID- 23365898 TI - Grasp and release with surface functional electrical stimulation using a Model Predictive Control approach. AB - Stroke often has a disabling effect on the ability to use the hand in a functional manner. Accurate finger and thumb positioning is necessary for many activities of daily living. In the current study, the feasibility of novel FES based approaches for positioning the thumb and fingers for grasp and release of differently sized objects is evaluated. Assistance based on these approaches may be used in rehabilitation of grasp and release after stroke. A model predictive controller (MPC) is compared with a proportional (P) feedback controller. Both methods are compared on their performance in tracking reference trajectories and in the capability of grasping, holding and releasing objects. Both methods are able to selectively activate the fingers such that differently sized objects, selected from the Action Research Arm test, can be grasped. The MPC method is easier to use in practice, as this method is based on a single identification of a model of the biological system. The P-controller has more parameters which need to be set correctly, and therefore needs more time to initialise. The current results are very promising. Evaluation in patients will be done to explore the possibilities to apply these methods in rehabilitation of grasp and release after stroke. PMID- 23365899 TI - Intuitive operability evaluation of surgical robot using brain activity measurement to determine immersive reality. AB - Surgical robots have improved considerably in recent years, but intuitive operability, which represents user inter-operability, has not been quantitatively evaluated. Therefore, for design of a robot with intuitive operability, we propose a method to measure brain activity to determine intuitive operability. The objective of this paper is to determine the master configuration against the monitor that allows users to perceive the manipulator as part of their own body. We assume that the master configuration produces an immersive reality experience for the user of putting his own arm into the monitor. In our experiments, as subjects controlled the hand controller to position the tip of the virtual slave manipulator on a target in a surgical simulator, we measured brain activity through brain-imaging devices. We performed our experiments for a variety of master manipulator configurations with the monitor position fixed. For all test subjects, we found that brain activity was stimulated significantly when the master manipulator was located behind the monitor. We conclude that this master configuration produces immersive reality through the body image, which is related to visual and somatic sense feedback. PMID- 23365900 TI - Enhancing stance phase propulsion during level walking by combining FES with a powered exoskeleton for persons with paraplegia. AB - This paper describes the design and implementation of a cooperative controller that combines functional electrical stimulation (FES) with a powered lower limb exoskeleton to provide enhanced hip extension during the stance phase of walking in persons with paraplegia. The controller utilizes two sources of actuation: the electric motors of the powered exoskeleton and the user's machine (FSM), a set of FES. It consists of a finite-state machine (FSM), a set of proportional derivative (PD) controllers for the exoskeleton and a cycle-to-cycle adaptive controller for muscle stimulation. Level ground walking is conducted on a single subject with complete T10 paraplegia. Results show a 34% reduction in electrical power requirements at the hip joints during the stance phase of the gait cycle with the cooperative controller compared to using electric motors alone. PMID- 23365901 TI - Bio-robots automatic navigation with electrical reward stimulation. AB - Bio-robots that controlled by outer stimulation through brain computer interface (BCI) suffer from the dependence on realtime guidance of human operators. Current automatic navigation methods for bio-robots focus on the controlling rules to force animals to obey man-made commands, with animals' intelligence ignored. This paper proposes a new method to realize the automatic navigation for bio-robots with electrical micro-stimulation as real-time rewards. Due to the reward-seeking instinct and trial-and-error capability, bio-robot can be steered to keep walking along the right route with rewards and correct its direction spontaneously when rewards are deprived. In navigation experiments, rat-robots learn the controlling methods in short time. The results show that our method simplifies the controlling logic and realizes the automatic navigation for rat-robots successfully. Our work might have significant implication for the further development of bio-robots with hybrid intelligence. PMID- 23365902 TI - Brain oscillations in switching vs. focusing audio-visual attention. AB - Selective attention contributes to perceptual efficiency by modulating cortical activity according to task demands. The majority of attentional research has focused on the effects of attention to a single modality, and little is known about the role of attention in multimodal sensory processing. Here we employ a novel experimental design to examine the electrophysiological basis of audio visual attention shifting. We use electroencephalography (EEG) to study differences in brain dynamics between quickly shifting attention between modalities and focusing attention on a single modality for extended periods of time. We also address interactions between attentional effects generated by the attention-shifting cue and those generated by subsequent stimuli. The conclusions from these examinations address key issues in attentional research, including the supramodal theory of attention, or the role of attention in foveal vision. The experimental design and analysis methods used here may suggest new directions in the study of the physiological basis of attention. PMID- 23365903 TI - Combined method for fetal electrocardiogram extraction from noninvasive abdominal recordings. AB - Abdominal electrocardiogram (AECG) recording is a non-invasive method to assess fetal well-being during both pregnancy and delivery. However, AECG recording is contaminated by a series of physiological interferences which make difficult the extraction of morphological and temporal parameters of fetal ECG from the raw signals. In this work, it is proposed a combined method to extract the fetal ECG from AECG recording by removing the interferences on a cascade structure using a priori information about the signals nature. In this work, a total of 54 multichannel AECG recordings taken from 21 to 40 weeks of gestation were enrolled. Experimental results show that the proposed method outperforms conventional independent component analysis, and provides fetal heart rate detection in 80% of the cases. In addition it also permits to obtain fetal ECG morphology from AECG recordings. PMID- 23365904 TI - ICA order selection based on consistency: application to genotype data. AB - Independent component analysis (ICA), a blind source separation method, has been shown to be a useful approach to identify genetic components representing combined effects from multiple mutations. However, the ICA order selection for genotype data has been a challenge, since a genetic component usually accounts for a small amount of variance of the data, and makes it difficult to distinguish true signals from background. To address this issue, we propose to select ICA order based on consistency and implement three strategies in this study. Simulations demonstrate robust performances of all three strategies where the selected orders lead to optimal results regardless of ICA performances. PMID- 23365905 TI - Real time gait pattern classification from chest worn accelerometry during a loaded road march. AB - Accelerometers, whether in smart phones or wearable physiological monitoring systems are becoming widely used to identify movement and activities of free living individuals. Although there has been much work in applying computationally intensive methods to this problem, this paper focuses on developing a real-time gait analysis approach that is intuitive, requires no individual calibration, can be extended to complex gait analysis, and can readily be adopted by ambulatory physiological monitors for use in real time. Chest-mounted tri-axial accelerometry data were collected from sixty-one male U.S. Army Ranger candidates engaged in an 8 or 12 mile loaded (35 Kg packs) timed road march. The pace of the road march was such that volunteers needed to both walk and run. To provide intuitive features we examined the periodic patterns generated from 4s periods of movement from the vertical and longitudinal accelerometer axes. Applying the "eigenfaces" face recognition approach we used Principal Components Analysis to find a single basis vector from 10% of the data (n=6) that could distinguish patterns of walk and run with a classification rate of 95% and 90% (n=55) respectively. Because these movement features are based on a gridded frequency count, the method is applicable for use by body-worn microprocessors. PMID- 23365906 TI - ErpICASSO: a tool for reliability estimates of independent components in EEG event-related analysis. AB - Independent component analysis and blind source separation methods are steadily gaining popularity for separating individual brain and non-brain source signals mixed by volume conduction in electroencephalographic data. Despite the advancements on these techniques, determining the number of embedded sources and their reliability are still open issues. In particular to date no method takes into account trial-to-trial variability in order to provide a reliability measure of independent components extracted in Event Related Potentials (ERPs) studies. In this work we present ErpICASSO, a new method which modifies a data-driven approach named ICASSO for the analysis of trials (epochs). In addition to ICASSO the method enables the user to estimate the number of embedded sources, and provides a quality index of each extracted ERP component by combining trial-to trial bootstrapping and CCA projection. We applied ErpICASSO on ERPs recorded from 14 subjects presented with unpleasant and neutral pictures. We separated potentials putatively related to different systems and identified the four primary ERP independent sources. Standing on the confidence interval estimated by ErpICASSO, we were able to compare the components between neutral and unpleasant conditions. ErpICASSO yielded encouraging results, thus providing the scientific community with a useful tool for ICA signal processing whenever dealing with trials recorded in different conditions. PMID- 23365907 TI - Validation of 3D ultra-short TE (UTE) Phase-Contrast MRI for imaging of steady flow: initial phantom experiments. AB - Assessment of blood flow is an important factor in diagnosis of cardiovascular disease. Vascular stenosis result in disturbed blood flow, flow recirculation, turbulence, and flow jet. These types of flows cause erroneous quantification of blood flow using conventional Phase contrast (PC) MRI techniques. Previous investigations have revealed that shorter Echo Times (TE) can decrease the quantification errors. In this paper, we performed phantom studies under steady flow to validate the UTE technique. Investigation of three different constant flow rates revealed a significant improvement in flow quantification and reduction of flow artifacts in comparison to Cartesian Phase-Contrast MRI. PMID- 23365908 TI - Relationship between marrow perfusion and bone mineral density: a pharmacokinetic study of DCE-MRI. AB - A reduced bone perfusion has been found for osteoporotic subjects in previous studies. However, the physiological changes underlying the varied perfusion function is not well known yet. Tofts model is one of the most frequently used pharmacokinetic models in analyzing perfusion process. This study modified the Tofts model by replacing the arterial input function (AIF) by a new algorithm. The modified model was then employed to analyze vertebral bone marrow perfusion in subjects with different bone mineral density (BMD). Eighty-two male subjects were involved in this study and classified into three groups (normal, osteopenia, and osteoporosis) according to T-score. BMD was measured by dual-energy X-ray absorptiometry (DXA). The quantitative parameters derived from the pharmacokinetic model, K(trans) (extravasation transfer efficiency for blood perfusion) and v(e) (extravascular extracellular space for blood perfusion), showed a significant reduction in subjects with lower BMD, respectively. The results suggested that with the bone mineral content lost, the vascular wall properties as well as the bone marrow content may also vary. The resultant perfusion change may also influence the bone nutrition supply in reverse. PMID- 23365909 TI - Enhanced SWIFT acquisition with chaotic compressed sensing by designing the measurement matrix with hyperbolic-secant signals. AB - Sweep imaging Fourier transform (SWIFT) is an efficient (fast and quiet) specialized magnetic resonance imaging (MRI) method for imaging tissues or organs that give only short-lived signals due to fast spin-spin relaxation rates. Based on the idea of compressed sensing, this paper proposes a novel method for further enhancing SWIFT using chaotic compressed sensing (CCS-SWIFT). With reduced number of measurements, CCS-SWIFT effectively faster than SWIFT. In comparison with a recently proposed chaotic compressed sensing method for standard MRI (CCS-MRI), simulation results showed that CCS-SWIFT outperforms CCS-MRI in terms of the normalized relative error in the image reconstruction and the probability of exact reconstruction. PMID- 23365910 TI - Effect of gadobutrol on VX2 magnetic resonance diffusion-weighted imaging. AB - The aim of this study was to evaluate the effect of contrast agent gadobutrol on the magnetic resonance diffusion-weighted imaging (MR DWI). Gadobutrol has higher relaxivity than Gd-DTPA and it also has higher formulation 1.0 M than Gd-DTPA 0.5 M. VX2 tumor implanted on the left thigh of each New Zealand rabbit was used as the animal model. The MR scanning was performed using a 1.5 T clinical whole-body MR scanner with an 8-channel knee coil. The results showed that there were significant differences in the signal-to-noise ratio (SNR) and apparent diffusion coefficient (ADC) values between tumor and muscle both before and after gadobutrol injection (0.1 mmol/kg). However, there were no significant differences in the SNR and ADC values of tumor or muscle before and after gadobutol administration. There were also no significant difference in the contrast-to-noise ratio (CNR) values of tumor and muscle before and after gadobutrol injection. PMID- 23365911 TI - A software prototype for the assessment of tumor treatment response using diffusion and perfusion MR imaging. AB - Advanced MRI techniques including diffusion and perfusion weighted imaging, has the potential to provide early surrogate biomarkers to detect, characterize and assess treatment response of tumors. However, the widely accepted Response Evaluation Criteria in Solid Tumors (RECIST) are still considered as the gold standard for the evaluation of treatment response in solid tumors, even if according to recent studies RECIST seem to disregard the extent of necrosis, which is the target of all effective locoregional therapies. This is partly due to the fact that measurements of tumor size aren't the best criterion for assessing actual early response. On the other hand, more sophisticated techniques such as the Apparent Diffusion Coefficient (ADC) and perfusion parameters are usually processed manually and evaluated independently using commercial CAD software, not widely available. In this paper we present an open access extensible software platform providing both diffusion and perfusion analysis in a single, user friendly environment that allows the radiologist to easily and objectively evaluate tumor response to therapy. PMID- 23365912 TI - Positive contrast MRI of prostate brachytherapy seeds by susceptibility mapping. AB - MRI can provide high-resolution images to assist physicians during intraoperative and post-operative phases of prostate brachytherapy. However, the brachytherapy seeds usually show as dark spots, i.e. negative contrast, on the MRI images. In this paper, we propose a new method to generate positive contrast seed images by mapping their susceptibility. The method is based on an improved kernel deconvolution algorithm using l1 regularization. Simulation results show the positive contrast seeds can be identified and differentiated using the proposed method. PMID- 23365914 TI - Smoothed random-like trajectory for compressed sensing MRI. AB - In this paper, we explores a rapid imaging method based on a proposed random-like trajectory for compressed sensing (CS) which requires the sampling trajectory should satisfy the Restricted Isometry Property (RIP) condition. In the existing CS literature, the attentions are on randomly sampling points on the conventional trajectories. However, the proposed trajectory is a random-like trajectory generated based on the High Order Chirp (HOC) sequences, which use the Traveling Salesman Problem (TSP) solver to choose a "short" trajectory and design a time optimal gradient waveforms to satisfy the gradient amplitude and slew rate limitation. The MR physical feasibility of the proposed method is verified by the Bloch simulation, and the simulations show that the proposed method can reduce artifacts than conventional Spiral trajectory under the CS framework. PMID- 23365915 TI - Study of magnetization evolution by using composite spin-lock pulses for T1rho imaging. AB - B(0) and B(1) field inhomogeneities may generate banding-like artifacts in T(1rho)-weighted images and hence result in errors of T(1rho) quantification. Several types of composite spin-lock pulses have been proposed to alleviate such artifacts. In this study, magnetization evolution with T(1rho) and T(2rho) relaxation by using these composite spin-lock pulses are theoretically derived. The effectiveness and limitation of each spin-lock pulse are explicitly illustrated in mathematical forms and phantom T(1rho)-weighted images acquired by using each spin-lock pulse are presented. This study also provides a theoretical framework for T(1rho) quantification from T(1rho)-weighted images even with B(0) and B(1) inhomogeneity artifacts. PMID- 23365916 TI - Non-parametric Bayesian estimation of apparent diffusion coefficient from diffusion-weighted magnetic resonance imaging data. AB - A promising approach to prostate cancer diagnosis is multi-parametric MRI. One of the key modalities used in multi-parametric MRI is diffusion weighted MRI. Using multiple diffusion weighted MR acquisitions taken with different magnetic gradient strengths, the apparent diffusion coefficient (ADC) is calculated and can be used to identify tumors in the prostate. Current algorithms used to calculate ADC assume a parametric measurement model, but this assumption is not true due to the presence of additional phenomena during the acquisition process. A novel Non-parametric Estimated ADC (NEstA) algorithm is proposed which uses a Monte Carlo strategy to learn the inherent measurement distribution model based on the underlying statistical behavior of the DWI measurements to estimate the ADC values. The proposed algorithm is compared to the results of the commonly used least-squares (LS) estimation algorithm for computing ADC values. Nine test patient cases with visible tumors in the prostate gland were processed using both algorithms and compared visually. It was found that NEstA produced ADC data with reduced artifacts while preserving structure. Quantitatively, Fisher's criterion measuring the separability of the healthy prostate and tumor tissues was computed for the nine patient cases, comparing the NEstA and LS methods. It was found that Fisher's criterion increased with the NEstA method, meaning the separation of classes was more pronounced. PMID- 23365917 TI - Parallel imaging acceleration of spiral Fourier velocity encoded MRI using SPIRiT. AB - This paper demonstrates parallel imaging acceleration of spiral Fourier velocity encoded MRI using the iterative self-consistent parallel imaging reconstruction (SPIRiT) technique. Magnitude images and time-velocity distributions obtained with image domain SPIRiT and sum-of-squares reconstruction are compared, for 2 fold and 4-fold undersampling. We show that SPIRiT is able to reduce spatial aliasing from undersampled time-velocity distributions, with good results for 2 fold undersampling, and moderately good results for 4-fold undersampling. PMID- 23365918 TI - Quantitative investigative analysis of tumour separability in the prostate gland using ultra-high b-value computed diffusion imaging. AB - High b-value diffusion-weighted imaging is a promising approach for diagnosing and localizing cancer in the prostate gland. However, ultra-high b-value imaging is difficult to achieve at a high signal-to-noise ratio due to hardware limitations. An alternative approach being recently discussed is computed diffusion-weighted imaging, which allows for estimation of ultra-high b-value images from a set of diffusion-weighted acquisitions with different magnetic gradient strengths. This paper presents a quantitative investigative analysis of the improvement in tumour separability in the prostate gland from using ultra high b-value computed diffusion-weighted imaging. The analysis computes ultra high b-value images for six patient cases and investigates the separability of the tumour from the normal prostate gland. Based on quantitative metrics such as expected probability of classification error and the Receiver Operating Characteristic (ROC), it was found that the use of ultra-high computed diffusion weighted imaging may significantly improve tumour separability, with a b-value around 3000 providing optimal separability. PMID- 23365919 TI - Correlation between uncinate fasciculus and memory tasks in healthy individual using diffusion tensor tractography. AB - Tractography is a procedure that can track and demonstrate the 3D neural tracts of the white matter of the brain. The images of the brain are obtained by analyzing the diffusion tensor, identification of which can provide the anatomical connections of the brain. Studying these connections is integral to the understanding of the brain function. Specifically, the uncinate fasciculus (UF), which is the white matter in the human brain, is said to be related to cognitive function. The UF tractography is calculated using diffusion tensor imaging (DTI) parameter. Studies have shown that the DTI parameter of dementia patients is lower than that of healthy individuals. It is also suggested that the DTI parameter of healthy individuals decreases with age. In addition, the WMS-R score, which is indicative of general memory, verbal memory and other cognitive functions, of the elderly are lower than of the young. However, there is no report yet that has holistically investigated DTI parameter and the memory functions. Thus, in this research, we have calculated the correlation coefficient between the DTI parameter of UF and WMS-R score. Our result shows that the correlation coefficient of diffusivity of the fiber direction and visual memory of a left UF is -0.226 at the maximum. Correlation between DTI measurement and memory performance suggests the relationships between the UF and function in memory tasks lateralization. Our finding matches previous reports on the correlation between FA in the left, or L1 in the right UF, and performance on visual memory. PMID- 23365920 TI - Identification of mild Alzheimer's disease through automated classification of structural MRI features. AB - The significant potential for early and accurate detection of Alzheimer's disease (AD) through neuroimaging data is becoming increasingly attractive in view of the possible advent of drugs which are able to modify or delay disease progression. In this paper, we aimed at developing an effective machine learning scheme which leverages structural magnetic resonance imaging features in order to identify and discriminate individuals affected by mild AD on a single subject basis. Selected features included one- and two-way combinations of subcortical and cortical volumes as well as cortical thickness and curvature of numerous brain regions which are known to be vulnerable to AD. Additionally, several feature combinations were fed into support vector machines (SVMs) as well as Naive Bayes classifiers in order to compare scheme accuracy. The most efficient combination of features and classification scheme, which employed both subcortical and cortical volumes feature vectors and a SVM classifier, was able to distinguish mild AD patients from healthy controls with 86% accuracy (82% sensitivity and 90% specificity). While this investigation is of preliminary nature, and further efforts are currently underway towards automated feature selection, best classifier determination and parameter optimization, our results appear very promising in terms of automated high-accuracy discrimination of disease stages which cannot easily be distinguished though routine clinical investigation. PMID- 23365921 TI - Tract-based spatial statistics (TBSS): application to detecting white matter tract variation in mild hypoxic-ischemic neonates. AB - The aim of this study is to employ tract-based spatial statistics (TBSS) to analyze the voxel-wise differences in DTI parameters between normal and mild hypoxic-ischemic (HI) neonatal brains. Forty-one full term neonates (24 normal controls and 17 with mild HI injury) and 31 preterm neonates (20 normal controls and 11 with mild HI injury) underwent T1 weighted imaging, T2 weighted imaging and diffusion tensor imaging (DTI) within 28 days after birth. The voxel differences of fractional anisotropy (FA), lambda1, lambda2, and lambda3 values between mild HI group and control group were analyzed in preterm and full term neonates respectively. The significantly decreased FA with increased lambda2, lambda3 in corticospinal tract, genu of corpus callosum (GCC), external capsule (EC) and splenium of the corpus callosum (SCC) in mild HI neonates suggested deficits or delays in both myelination and premyelination. Such impaired corticospinal tract, in both preterm and term neonates, may directly lead to the subsequent poor motor performance. Impaired EC and SCC, the additional injured sites observed in full term neonates with mild HI injury, may be causally responsible for the dysfunction in coordination and integration. In conclusion, TBSS provides an objective, independent and sensitive method for DTI data analysis of neonatal white matter alterations after mild HI injury. PMID- 23365922 TI - Subzone based multi-frequency magnetic resonance elastography using a Rayleigh damped material model. AB - MR Elastography (MRE) is a relatively novel imaging technique using conventional MRI methods to assess the mechanical properties of tissues. In time-harmonic MRE, a Rayleigh, or proportional, Damping (RD) model incorporates attenuation behavior proportionally related to both elastic and inertial forces, thus providing a more sophisticated description of the elastic energy dissipation occurring in the biological tissue. The overall damping ratio can be extracted from the combined effect of these two components, while an additional measure, called Rayleigh Composition, can be calculated by the ratio between the two components. Thus, RD elastography is capable of not only reconstructing the viscoelastic properties of the material, but also providing additional information about damping behavior and structure. A 3D subzone based reconstruction algorithm using a RD material model has been developed and optimized to reconstruct the viscoelastic properties, damping behavior and elastic energy attenuation mechanism of tissue simulating damping phantoms across multiple frequencies. Results have shown that all three iterative reconstructed parameters are in relatively close agreement for both the tofu and gelatin materials in both phantom configurations across the frequency range. Preliminary results from in-vivo healthy brain are also presented and discussed. PMID- 23365923 TI - Potential of MREIT conductivity imaging to detect breast cancer: experimental and numerical simulation studies. AB - The conductivity values of cancerous tissues in the breast are significantly higher than those of surrounding normal tissues. Breast imaging using MREIT (Magnetic Resonance Electrical Impedance Tomography) may provide a new noninvasive way of detecting breast cancer in its early stage. In breast MREIT, the conductivity image quality highly depends on the amount of injected currents assuming a certain signal-to-noise ratio (SNR) of an MRI scanner. The injected current should not produce any significant adverse effect especially on the nerve conduction system of the heart and still distinguish a small cancerous anomaly inside the breast. In this paper, we present results of experimental and numerical simulation studies of breast MREIT. From breast phantom experiments, we evaluated practical amounts of noise in measured magnetic flux density data. We built a realistic three-dimensional model of the human breast connected to a simplified model of the chest including the heart. We performed numerical simulations of various scenarios in breast MREIT including different amplitudes of injected currents and predicted SNRs of MR images related with imaging parameters. Simulation results are promising to show that we may detect a cancerous anomaly in the breast while restricting the maximal current density inside the heart below a level of nerve excitation. PMID- 23365924 TI - Automatic brain tumor extraction from T1-weighted coronal MRI using fast bounding box and dynamic snake. AB - Brain tumor segmentation from MRI data is an important but challenging task. This paper presents an efficient and fully automatic brain tumor segmentation technique. The proposed technique includes a fuzzy C-means (FCM) based preprocessing to enhance the quality of T1-weighted coronal MR images, a fast bounding box (FBB) detection algorithm to locate a rectangle around tumor, and a new dynamic snake using modified Hausdorff distance (MHD) for the final tumor extraction. PMID- 23365925 TI - Carotid far wall characterization using LBP, Laws' Texture Energy and wall variability: a novel class of Atheromatic systems. AB - In this work, we present a Computer Aided Diagnostic (CAD) technique (a class of Atheromatic systems) that classifies the automatically segmented carotid far wall Intima-Media Thickness (IMT) regions along the common carotid artery into symptomatic and asymptomatic classes. We extracted texture features based on Local Binary Patterns (LBP) and Law's Texture Energy (LTE) and used the significant features to train and test the Support Vector Machine classifier. We developed the classifiers using three-fold stratified cross validation data resampling technique on 342 IMT wall regions. An accuracy of 89.5% was registered. Thus, the proposed technique is accurate, robust, non-invasive, fast, objective, and cost-effective, and hence, will add more value to the existing carotid plaque diagnostics protocol. PMID- 23365926 TI - Automated benign & malignant thyroid lesion characterization and classification in 3D contrast-enhanced ultrasound. AB - In this work, we present a Computer Aided Diagnosis (CAD) based technique for automatic classification of benign and malignant thyroid lesions in 3D contrast enhanced ultrasound images. The images were obtained from 20 patients. Fine needle aspiration biopsy and histology confirmed malignancy. Discrete Wavelet Transform (DWT) and texture based features were extracted from the thyroid images. The resulting feature vectors were used to train and test three different classifiers: K-Nearest Neighbor (K-NN), Probabilistic Neural Network (PNN), and Decision Tree (DeTr) using ten-fold cross validation technique. Our results show that combination of DWT and texture features in the K-NN classifier resulted in a classification accuracy of 98.9%, a sensitivity of 98%, and a specificity of 99.8%. Thus, the preliminary results of the proposed technique show that it could be adapted as an adjunct tool that can give valuable second opinions to the doctors regarding the nature of the thyroid nodule. The technique is cost effective, non-invasive, fast, completely automated and gives more objective and reproducible results compared to manual analysis of the ultrasound images. We however intend to establish the clinical applicability of this technique by evaluating it with more data in the future. PMID- 23365927 TI - Ultrasound imaging of dental implants. AB - Accurate measurement of soft tissue thickness is needed prior to dental implant placement and prior to surgical uncovering of the implant. Ultrasonography has many potential advantages for use in dental implant surgery, but has not yet been made suitable for clinical use. A 2D ultrasound imaging system and a mechanical positioning system were used to scan dental implants embedded in a porcine jaw, covered by soft tissue, submerged in a water tank. Results indicated that ultrasound can be used to accurately detect, locate, and measure dental implant fixtures and measure the thickness of the overlying soft tissue in an ex vivo environment. PMID- 23365928 TI - Echogenicity in transrectal ultrasound is determined by sound speed of prostate tissue components. AB - Typically, conventional transrectal ultrasound (TRUS) imaging of the cancer tissue is hypoechoic in echo texture. However, TRUS does not reliably distinguish between cancerous and non-cancerous tissue in the prostate. In the present study, sound speed of prostate needle biopsy specimens were measured by ultrasound speed microscope (USM) to construct a database for interpreting clinical TRUS images. Biopsy specimens were formalin-fixed and sectioned approximately 5 um in thickness. They were mounted on glass slides without cover slips. The ultrasonic transducer with the central frequency of 120 MHz was mechanically scanned over the specimen to measure sound speed distribution. Echo intensity of TRUS images were qualitatively classified into three categories; hyperechoic, iso-echoic and hypoechoic areas. Sound speed was 1596.9 +/- 28.2 m/s in hyperechoic, 1571.2 +/- 35.8 m/s in iso-echoic and 1562.6 +/- 35.1 m/s in hypoechoic area, respectively. However, echo intensity showed no significant relationship to malignancy of prostatic tissue. Echo intensity of TRUS is significantly affected with tissue components and USM findings would provide important information for interpretation of TRUS images. PMID- 23365929 TI - A prototype system of microwave induced thermo-acoustic tomography for breast tumor. AB - Microwave-induced thermo-acoustic tomography (MITAT) is an innovative technique for tumor's detection. Due to there has high contrast in terms with permittivity and electrical conductivity of tumor versus normal tissue, even if the tumor still in the early phase it can be imaged clearly. For the proposed MITAT system, low energy microwave pulses are used as the irradiating signals, while the received signals are ultrasound, high contrast and high resolution images can be obtained. After some theoretical research and basic fundamental experiments, the first prototype of experimental system is designed and built. It includes the microwave radiator, the arrayed sensor bowl, the circular scanning platform, the system controller and the signal processor. Based on the experimental results using this integral MITAT clinic system, the images contrast can be reached higher than 383:1; while the sub-millimeter special resolution is obtained for a 1cm(3) scale tumor mimic. PMID- 23365930 TI - An accurate calibration method of ultrasound images by center positions of a metal ball. AB - This paper provides a novel method for three-dimensional tracking of ultrasound images. One of the issues to determine the position of a ultrasound image plane is the thickness of the image plane. The proposed methodology address the issue by the calibration phantom using a fiducial sphere with the diameter of 5.5 mm because comet-trail artifact can be observed in the image plane through the center of the sphere. Meanwhile, to measure the sphere center accurately by a tracking device, a pointer tool with the same sphere at the tip is also proposed. To validate the feasibility of the method, simulation and phantom tests were conducted. From the results of the phantom test, the accuracy of the calibration was 0.65, 0.40, and 0.42 mm in 10, 50, 100 points calibration. The results demonstrate that the proposed method has a great potential for accurate US probe calibration. PMID- 23365931 TI - Phase estimation for a phased array therapeutic interstitial ultrasound probe. AB - This paper deals about high intensity ultrasound interstitial therapy simulation. The simulated phased array ultrasound probe allows a dynamic electronic focusing of the therapeutic beam. In order to maximize the power deposit at the focal point we propose a method which allows to optimally defining the phase shift of the electrical control signal for each individual element. PMID- 23365932 TI - Needle identification in high-dose-rate prostate brachytherapy using ultrasound imaging modality. AB - It was observed that the needle tip identification in high-dose-rate (HDR) prostate brachytherapy is challenging due to various uncertainties. The errors in identifying the correct needle position and angulations could compromise patient treatment outcomes. In this article, we propose a method for the needle identification using real-time ultrasound images obtained during the treatment procedure. The developed algorithm is capable to detect both the needle tip in a predefined coordinate system and the needle deflection angle for each frame of the incoming real-time ultrasound video streams. PMID- 23365933 TI - A Correlated Microwave-Acoustic Imaging method for early-stage cancer detection. AB - Microwave-based imaging technique shows large potential in detecting early-stage cancer due to significant dielectric contrast between tumor and surrounding healthy tissue. In this paper, we present a new way named Correlated Microwave Acoustic Imaging (CMAI) of combining two microwave-based imaging modalities: confocal microwave imaging(CMI) by detecting scattered microwave signal, and microwave-induced thermo-acoustic imaging (TAI) by detecting induced acoustic signal arising from microwave energy absorption and thermal expansion. Necessity of combining CMI and TAI is analyzed theoretically, and by applying simple algorithm to CMI and TAI separately, we propose an image correlation approach merging CMI and TAI together to achieve better performance in terms of resolution and contrast. Preliminary numerical simulation shows promising results in case of low contrast and large variation scenarios. A UWB transmitter is designed and tested for future complete system implementation. This preliminary study inspires us to develop a new medical imaging modality CMAI to achieve real-time, high resolution and high contrast simultaneously. PMID- 23365934 TI - Distal wall delineation using automated Dual Snake paradigm: a multi-center and multi-ethnic carotid ultrasound evaluation. AB - We present here a novel and patented completely automated IMT measurement system that we developed for common carotid arterial ultrasound longitudinal images, called Carotid Measurement Using Dual Snakes (CMUDS) - a class of AtheroEdgeTM system. CMUDS is a dual deformable parametric model (snake) system where the dual snakes evolve simultaneously and are forced to maintain a regularized distance to prevent collapsing or diverging. We benchmarked CMUDS against a conventional single snake (CMUSS). CMUDS is totally automatic while CMUSS is semi-automatic. For performance evaluation, two readers manually traced the lumen-intima (LI) and media-adventitia (MA) borders of our multi-institutional, multi-ethnic, and multi scanner database of 655 longitudinal B-Mode ultrasound images. CMUDS and CMUSS correctly processed all 665 images. The average IMT biases were equal to 0.030+/ 0.284 mm and -0.004+/-0.273 mm for CMUDS, and -0.011+/-0.329 mm and -0.045+/ 0.317 mm for CMUSS. The Figure of Merit of the system was 96.0% and 99.6% for CMUDS and 98.5% and 94.4% for CMUSS. CMUDS improved accuracy (Wilcoxon, p<0.02) and reproducibility (Fisher, p<3 10(-2)), proving that the novel CMUDS system is adaptable to large multi-centric studies, where a standard IMT measurement technique is required. PMID- 23365935 TI - An automated 3D annotation method for breast ultrasound imaging. AB - Image spatial annotation is one of the most important steps in breast ultrasound scanning examinations because follow-up evaluation, diagnosis and treatment may be performed based on the annotation. The conventional annotation method is manual and highly dependent on the operator's experience. Therefore, it is time consuming and prone to errors. This paper introduced a novel annotation method for breast ultrasound imaging. A spatial sensor was attached to the ultrasound transducer to obtain the real-time image location information. 3D virtual models of breasts and probe were shown on screen together with ultrasound images to display the spatial data intuitively. A program was developed to acquire ultrasound images and spatial signals, compute the image locations relative to the breast, and display images together with their corresponding 3D annotations. It was demonstrated that this novel annotation method could provide automated and accurate annotations in phantom experiments. This method also showed its potential to continuously annotate breast ultrasound images in relative short time in the preliminary in-vivo experiments. PMID- 23365936 TI - Anthropomorphic ultrasound elastography phantoms - characterization of silicone materials to build breast elastography phantoms. AB - In this paper a mechanical characterization of low cost and simply available materials to build efficient anthropomorphic ultrasound elastography phantoms is described. The class of silicone materials was selected because of their deformability, durability and the possibility of reproducing specific tissue properties and shapes. Innovative formulations of silicone mixtures with echogenic and/or softening additives were tested. The proposed models have good acoustic properties and tactile feedback; moreover they are durable and do not require special storage since they do not dehydrate or decompose over time. PMID- 23365937 TI - Acoustic interrogation and optical visualization of ultrasound contrast agents within microcapsules. AB - The effectiveness of localized drug delivery as a treatment for breast cancer requires sufficiently high therapeutic dose, as well as an ability to image the drug for proper spatial targeting. To balance treatment potential and imaging capabilities, we have begun to design a novel drug reservoir using microcapsules that are large in size (> 30 um) but functionalized with microbubbles or ultrasound contrast agents (UCAs). We term these carriers as 'Acoustically Sensitive Microcapsules' (ASMs). In previous work, we have demonstrated preparation of ASM carriers and their structural changes under therapeutic ultrasound by imaging static changes. In this paper, we describe a combined optical-acoustic setup coupled with a microfluidic device to trap these carriers for imaging and sonication. Using the setup, continuous wave ultrasound (180 kPa, 2.25 MHz, 3 s) produced an average displacement of 3.5 um in UCAs near the ASM boundary, and exhibited displacement as high as 90 um near the center of the microcapsule. Longer exposure time and higher acoustic pressure increased UCA displacement within an ASM. These two parameters can be carefully optimized in the future to cause these UCAs to travel to the membrane boundary to help in the drug elution process. PMID- 23365938 TI - Dynamic staining of Bacillus endospores with Thioflavin T. AB - Rapid detection and identification of endospores presents a range of complex challenges. Dynamic staining approach, developed in our lab, utilizes the time course fluorescence enhancement of an amyloid-staining dye, Thioflavin T (ThT), after mixing with intact endospores. We examined the kinetics of staining Bacillus atrophaeus and Bacillus thuringiensis endospores, and the rates of staining were different for the two bacilli when intact endospores were treated with ThT. This finding demonstrates an avenue for attaining information about the sporulated bacterial species without lysing, germinating or other pretreatment steps. PMID- 23365939 TI - Wearable autonomous microsystem with electrochemical gas sensor array for real time health and safety monitoring. AB - Airborne pollution and explosive gases threaten human health and occupational safety, therefore generating high demand for a wearable autonomous multi-analyte gas sensor system for real-time environmental monitoring. This paper presents a system level solution through synergistic integration of sensors, electronics, and data analysis algorithms. Electrochemical sensors featuring ionic liquids were chosen to provide low-power room-temperature operation, rapid response, high sensitivity, good selectivity, and a long operating life with low maintenance. The system utilizes a multi-mode electrochemical instrumentation circuit that combines all signal condition functions within a single microelectronics chip to minimize system cost, size and power consumption. Embedded sensor array signal processing algorithms enable gas classification and concentration estimation within a real-world mixture of analytes. System design and integration methodologies are described, and preliminary results are shown for a first generation SO(2) sensor and a thumb-drive sized prototype system. PMID- 23365940 TI - Calculation of joint reaction force and joint moments using by wearable walking analysis system. AB - In gait analysis, which is one useful method for efficient physical rehabilitation, the ground reaction force, the center of pressure, and the body orientation data are measured during walking. In the past, these data were measured by a 3D motion analysis system consisting of high-speed cameras and force plates, which must be installed in the floor. However, a conventional 3D motion analysis system can measure the ground reaction force and the center of pressure just on force plates during a few steps. In addition, the subjects' stride lengths are limited because they have to walk on the center of the force plate. These problems can be resolved by converting conventional devices into wearable devices. We used a measuring device consisting of portable force plates and motion sensors. We developed a walking analysis system that calculates the ground reaction force, the center of pressure, and the body orientations and measured a walking subject to estimate this system. We simultaneously used a conventional 3D motion analysis system to compare with our development system and showed its validity for measurements of ground reaction force and the center of pressure. Moreover we calculated joint reactions and joint moment of each joint. PMID- 23365941 TI - Piezoelectric load measurement model in knee implants. AB - This paper explores the feasibility of a new sensing platform for knee implant diagnostics. The proposed unit measures force and transmits the reading information wirelessly to an external receiving unit. This device is to be located in the tibial tray of the knee implant. The system measures force through the use of piezoelectric elements housed in the insert. At the same time, the piezoelectric material can generate enough energy to transmit the measurements without requiring batteries. Only the modeling of the piezoelectric voltage output is discussed at present. The force measurement can provide useful information about ligament balance while helping in the post-operative physical therapy. PMID- 23365942 TI - A programmable FPGA-based 8-channel arbitrary waveform generator for medical ultrasound research activities. AB - In modern ultrasound imaging systems, digital transmit beamformer module typically generates accurate control of the amplitude of individual elements in a multielement array probe, as well as of the time delays and phase between them, to enable the acoustic beam to be focused and/or steered electronically. However, these systems do not provide the ultrasound researchers access to transmit front end module. This paper presents the development of a digital transmit beamformer system for generating simultaneous arbitrary waveforms, specifically designed for research purposes. The proposed architecture has 8 independent excitation channels and uses an FPGA (Field Programmable Gated Array) device for electronic steering and focusing of ultrasound beam. The system allows operation in pulse echo mode, with pulse repetition rate of excitation from 62.5 Hz to 8 kHz, center frequency from 500 kHz to 20 MHz, excitation voltage over 100 Vpp, and individual control of amplitude apodization, phase angle and time delay trigger. Experimental results show that this technique is suitable for generating the excitation waveforms needed for medical ultrasound imaging researches. PMID- 23365943 TI - Design, fabrication, and characterization of an electrochemically-based dose tracking system for closed-loop drug delivery. AB - A real-time integrated electrochemically-based dose tracking system for closed loop drug delivery is presented. Thin film Pt sensors were integrated in an electrolytic MEMS drug delivery pump to allow dose tracking via electrochemical impedance measurement. Measurement electrode placement and composition were investigated. A bolus resolution of 230 nL was demonstrated. The sensor was calibrated for use with water (low conductivity) and 1 * PBS (high conductivity), the selected model aqueous drugs. The impedance response is dependent on delivered volume and not affected by actuation parameters. A graphical user interface was created for real-time impedance based dose tracking and leakage/blockage detection in the system. Drift in the impedance response of an idle system after perturbation (actuation) were investigated and mitigated through the use of Pt wire electrodes as opposed to thin film electrodes. PMID- 23365944 TI - An infrared radiation based thermal biosensor for enzymatic biochemical reactions. AB - In this paper, a thermal biosensor based on the infrared radiation energy is proposed for calorimetric measurement of biochemical reactions. Having a good structure design combined with MEMS technology as well as employing the Si /SiGe quantum well sensing material with a high TCR and low 1/f noise, the sensor shows potentials to be high sensitive and real-time. The urea enzymatic reaction was tested to verify the performance of sensor, which demonstrates a linear detection range from 0.5mM to 150mM and a relative standard deviation less than 1%. For the sensor fabrication, wafer-level transfer bonding is a key process, which makes the integration of quantum well material and a free standing structure possible. It reduces the heat loss from the sensor to the surrounding environment. PMID- 23365945 TI - Surface deformation tracking of a silicone gel skin phantom in response to normal indentation. AB - Identifying the mechanical properties of the skin has been the subject of much study in recent years, as such knowledge can provide insight into wound healing, wrinkling and minimization of scarring through surgical planning. PMID- 23365946 TI - FFLS: an accurate linear device for measuring synergistic finger contractions. AB - After decades of theoretical study in physiology and neurology communities, the paradigm of muscle synergies is now being explored in rehabilitation robotics as a strategy to control mechanical artifacts with many degrees-of-freedom (DoF) in a simple yet effective and human-like way. In particular, muscle synergies during grasping and in graded-force tasks are of great interest for the control of dexterous hand prostheses. To this end, we have designed and tested a novel device to accurately and simultaneously measure fingertip forces. The device, called FFLS (Finger-Force Linear Sensor), measures the forces applied by the human fingertips in both directions (flexion and extension of index, middle, ring and little finger plus thumb rotation and abduction/adduction). It is suited for several different hand sizes, enforces high accuracy in the measurement and its signal is guaranteed to be linear in a high range of forces (100N in both directions for each finger). It outputs six analog voltages (+/-10V), suited for processing with a DAQ card. PMID- 23365947 TI - Arterial strain measurement by implantable capacitive sensor without vessel constriction. AB - Cardiovascular disease caused 32.8% of deaths in the United States in 2008 [1]. The most important medical parameter is the arterial blood pressure. The origin of high or low blood pressure can mostly be found in the vessel compliance. With the presented implantable sensor, we are able to directly measure strain of arteries, as an indicator of arteriosclerosis. The sensor is designed as a cuff with integrated capacitive structures and is wrapped around arteries. With a new and innovative locking method, we could show that the system does not affect the arteries. This is demonstrated by theory as well as experimental in vivo investigations. Biocompatibility tests, confirmed by histological cuts and MRI measurements, showed that no stenosis, allergic reactions or inflammation occurs. The sensor shows excellent linear behavior with respect to stress and strain. PMID- 23365948 TI - A S-parameters-based detection method for a multilayer SPR biosensor. AB - In this paper, S-parameters investigation of a variable incidence angle multilayer SPR biosensor is presented. Both magnitude and phase of the S parameters are taken into account in the investigation. The work presented in this paper is the first attempt to apply S-parameters analysis to a multilayer SPR biosensor. The goal is to improve sensitivity through involving S-parameters including their phase values. In addition, further investigation is carried out to understand the relationship between the S-parameters and thickness of biomolecular layer and also the design parameters including the number of graphene layers. PMID- 23365949 TI - Fluorescence-based Lab-on-Chip spot design for improved signal detection. AB - This work presents a new perspective for fluorescence signal detection using specific optics on Lab-on-Chip devices. An apparatus was designed and implemented in order to assess the performance of a fluorescence technique using different detection spot configurations, using the chip itself as a waveguide for illumination. The experiments conducted investigate the influence of the dimensions - diameter and height - of the spot on the amplitude of the detection output signal. Results show that the configuration of optical interfaces must be considered in order to improve detection output, or to be able to detect less fluorophore molecules in the spot. PMID- 23365950 TI - Post-operative blood loss monitoring device: a new tool for nursing activities. AB - In most medical specialties, after surgery, it is usual to place a drain at the operative site level, in order to assist the blood flow-out if necessary. This drainage allows avoiding the formation of hematomas and contributes to tissues recovery. However, postoperative blood loss can lead to serious consequences. Also, it is necessary to continuously check the blood output volume in order to be able to intervene quickly in case of too significant losses. In daily clinical practice, this task is due to the nursing staff that periodically records the blood level inside the supple bag connected to the drain. However, this method is not accurate about the volume of lost blood and does not reflect the flow of losses which is an important parameter regarding the evolution of the patient setting. We have designed and developed a prototype of a blood loss monitoring device based on the continuous weight measurement of the blood bag connected to the drain. This device is fixed on the bed and is able to instantaneously alert the medical staff in case of abnormal blood flow-out. PMID- 23365951 TI - Multi-signal bathroom scale to assess long-term trends in cardiovascular parameters. AB - This paper describes the circuits and signal processing techniques that convert an electronic bathroom scale intended for bioimpedance analysis (BIA) into a compact system to acquire the electrocardiogram (ECG), the ballistocardiogram (BCG), and the impedance plethysmogram (IPG) using only plantar measurements. The signal processing methods proposed rely on the higher quality of the IPG as compared to the ECG and BCG and they enhance the signal-to-noise ratio (SNR) of these two signals, which otherwise could be too poor in non-controlled environments. The system is suitable for long-term periodic monitoring of cardiovascular function. PMID- 23365952 TI - A real-time detector system for precise timing of audiovisual stimuli. AB - The successful recording of neurophysiologic signals, such as event-related potentials (ERPs) or event-related magnetic fields (ERFs), relies on precise information of stimulus presentation times. We have developed an accurate and flexible audiovisual sensor solution operating in real-time for on-line use in both auditory and visual ERP and ERF paradigms. The sensor functions independently of the used audio or video stimulus presentation tools or signal acquisition system. The sensor solution consists of two independent sensors; one for sound and one for light. The microcontroller-based audio sensor incorporates a novel approach to the detection of natural sounds such as multipart audio stimuli, using an adjustable dead time. This aids in producing exact markers for complex auditory stimuli and reduces the number of false detections. The analog photosensor circuit detects changes in light intensity on the screen and produces a marker for changes exceeding a threshold. The microcontroller software for the audio sensor is free and open source, allowing other researchers to customise the sensor for use in specific auditory ERP/ERF paradigms. The hardware schematics and software for the audiovisual sensor are freely available from the webpage of the authors' lab. PMID- 23365953 TI - Characterization of interdigitated electrode structures for water contaminant detection using a hybrid voltage divider and a vector network analyzer. AB - Interdigitated capacitive electrode structures have been used to monitor or actuate over organic and electrochemical media in efforts to characterize biochemical properties. This article describes a method to perform a pre characterization of interdigitated electrode structures using two methods: a hybrid voltage divider (HVD) and a vector network analyzer (VNA). Both methodologies develop some tests under two different conditions: free air and bi distilled water media. Also, the HVD methodology is used for other two conditions: phosphate buffer with laccase (polyphenoloxidase; EC 1.10.3.2) and contaminated media composed by a mix of phosphate buffer and 3 ethylbenzothiazoline-6-sulfonic acid (ABTS). The purpose of this study is to develop and validate a characterization methodology using both, a hybrid voltage divider and VNA T-# network impedance models of the interdigitated capacitive electrode structure that will provide a shunt RC network of particular interest in detecting the amount of contamination existing in the water solution for the media conditions. This methodology should provide us with the best possible sensitivity in monitoring water contaminant media characteristics. The results show that both methods, the hybrid voltage divider and the VNA methodology, are feasible in determining impedance modeling parameters. These parameters can be used to develop electric interrogation procedures and devices such as dielectric characteristics to identify contaminant substances in water solutions. PMID- 23365954 TI - Adaptive frequency distribution for electrical bioimpedance spectroscopy measurements. AB - This paper presents a novel frequency distribution scheme intended to provide more accurate estimations of Cole parameters. Nowadays a logarithmic frequency distribution is mostly used in Electrical Bioimpedance Spectroscopy (EBIS) applications. However it is not optimized following any criterion. Our hypothesis is that an EBIS signal contains more information where the variation of the measurement regarding the frequency is larger; and that there ought to be more measuring frequencies where there is more information. Results show that for EBIS data with characteristic frequencies up to 200 kHz the error obtained with both frequency distribution schemes is similar. However, for EBIS data with higher values of characteristic frequency the error produced when estimating the values from EBIS measurements using an adaptive frequency distribution is smaller. Thus it may useful for EBIS applications with high values of characteristic frequency, e.g. cerebral bioimpedance. PMID- 23365955 TI - Usefulness of electromagnetic induction type of force transducer and actuator for myofibril mechanics. AB - A high performance device for measuring force and length change during myofibril contraction is fabricated. The principle of a device depends on the law of electromagnetic induction. Homogenized myofibrils were attached between two wires exposed in the uniform magnetic field by silicon adhesive under an inverted microscope. The purpose of this study is to examine performance whether the electromagnetic induction type of device actually works. Sensitivity and time resolution of force transducer was 50nN and 1ms respectively. Working displacement and time resolution of actuator as length transducer was 1-20 um and 1.2 ms. We confirmed the performance of the device by showing appropriate force response to changes in length during myofibrils contraction, and possibility of application of the device to myofibril mechanics is discussed. PMID- 23365956 TI - Multiplexed detection of protein markers with silicon nanowire FET and sol-gel matrix. AB - A new modified top-down based fabrication method has been developed to obtain highly ordered silicon nanowire (SiNW) arrays. With this method, we could produce as many as 500 chips (size dependable) in an 8 inch wafer. The immobilization of multiple proteins on each chip was performed by spotting sol/gel materials encapsulating antibodies on the different regions. The most commonly used protein markers in clinics, such as C-reactive protein (CRP) and prostate specific antigen (PSA), were systematically entrapped in sol-gel materials and used for multiplexed testing. Upon formation, the electrical signal of different concentrations of CRP and PSA could be simultaneously determined in the range of 0.12 ~ 10 ng/mL and 0.18 ~ 8.87 ng/mL, respectively. PMID- 23365957 TI - A data efficient method for characterization of chameleon tongue motion using Doppler radar. AB - A new technique is described for study of the study of high velocity animal movements using a continuous wave Doppler radar operating at 24 GHz. The movement studied was tongue projection kinematics during prey capture by the lizard Chamaeleo Jacksonii. The measurements were verified with a high speed video reference, recorded at 1000 frames per second. The limitations and advantages of both the methodologies are compared and tongue speeds of 3:65 m/s were observed. These results show a useful application of radar to augment visual sensing of biological motion and enable the use of monitoring in a wider range of situations. PMID- 23365958 TI - Aptamer-NASBA LOC as a prospective tool for systemic therapy of cancer: quantitative detection on signaling molecular profiling. AB - As the present technology of cancer treatment cannot cure the diseases, a prospective therapy, named 'systemic therapy', brings forth a new trend in cancer treatment. The aptamer-NASBA-based lab-on-a-chip (LOC) for systemic therapy was designed, fabricated and tested as an ultra-sensitive tool to monitor signaling molecular profiling in serum samples. The chip is divided into four parallel functional areas, corresponding to four groups of signaling molecules (i.e. hormones, neurotransmitters, cytokines and tumor biomarkers). The results can help doctors fully understand the body of patients. The chip is modeled on a 384 well microplate, which is completely compatible with common microplate readers in a biological laboratory. It can distinguish 24 signaling molecules in the same blood sample quantitatively and simultaneously. The chip was made of PDMS and silicon with a deposited gold layer, which was coated by aptamers before bonding; then, the LOC was operated by external valves and a vacuum pump. Its performance was demonstrated by detecting the presence of a synthetic peptide, GnRH (gonadotropin-releasing hormone) in artificial samples. The results indicated that the LOC has the potential to quantify traces of biomarkers even at subfemtomolar levels. Compared with our previous immuno-NASBA LOC, the aptamer NASBA LOC showed an increased sensitivity and better repeatability. PMID- 23365959 TI - A full digital magnetic induction measurement device for non-contact vital parameter monitoring (MONTOS). AB - Magnetic induction measurements enable contactless monitoring of breathing and heart activity. Since this technique is in the scope of many research groups, there are several research devices available. Most of these devices are suitable for tomography approaches, e.g. edema detection or for monitoring technical processes, such as fluid in tubes or metal blocks. However, these devices are less useable for vital parameter monitoring. In this article, we present an new modular magnetic induction measurement system called MONTOS (Monitoring System) for this scenario. Since the implementation is fully digital, each module can easily be applied to several measurement conditions in vital parameter monitoring, i.e. Multi-Frequency measurement modes, Single-Excitation and Multiple-Measurements or Multiple-Excitation and Single-Measurement. Data output is realized via local area networks (LAN), thereby streaming the data to a monitoring computer. Finally, it will be demonstrated that impedance changes due to breathing of a human adult can be detected. PMID- 23365960 TI - Auditory evoked responses from Ear-EEG recordings. AB - A method for brain monitoring based on measuring electroencephalographic (EEG) signals from electrodes placed in-the-ear (Ear-EEG) was recently proposed. The Ear-EEG recording methodology provides a non-invasive, discreet and unobtrusive way of measuring electrical brain signals and has great potential as an enabling method for brain monitoring in everyday life. This work aims at further establishing the Ear-EEG recording methodology by considering auditory evoked potentials, and by comparing Ear-EEG responses with conventional on-scalp recordings and with well established results from the literature. It is shown that both steady state and transient responses can be obtained from Ear-EEG, and that these responses have similar characteristics and quality compared to EEG obtained from conventional on-scalp recordings. PMID- 23365961 TI - Isolation of rare cancer cells from blood cells using dielectrophoresis. AB - In this study, we investigate the application of contactless dielectrophoresis (cDEP) for isolating cancer cells from blood cells. Devices with throughput of 0.2 mL/hr (equivalent to sorting 3*10(6) cells per minute) were used to trap breast cancer cells while allowing blood cells through. We have shown that this technique is able to isolate cancer cells in concentration as low as 1 cancer cell per 10(6) hematologic cells (equivalent to 1000 cancer cells in 1 mL of blood). We achieved 96% trapping of the cancer cells at 600 kHz and 300 V(RMS). PMID- 23365962 TI - Towards ultrahigh throughput microinjection: MEMS-based massively-parallelized mechanoporation. AB - We describe a massively-parallelized, MEMS-based device concept for passively delivering exogeneous molecules into living cells via mechanical membrane penetration, i.e., mechanoporation. Details regarding device design and fabrication are discussed, as are results from preliminary live cell studies focused on device validation at the proof-of-concept level. These efforts represent key steps towards our long-term goal of developing instrumentation capable of ultrahigh throughput (UHT) cellular manipulation via active microinjection. PMID- 23365963 TI - A real-time tracking system for in vivo endofunctional capsule using magnetic sensors. AB - This paper presents a real-time magnetic tracking system to be used for tracking an endofunctional capsule intended to aid in the delivery of biomarkers to specific areas in the gastrointestinal (GI) tract. Magnetic technology is chosen due to its significant advantages over others like RF and Ultrasonics. The tracking system is designed to be used with eight magnetic sensors making it less complex than the other proposed systems. The paper describes a new mathematical model which is more accurate than the existing ones, a linear tracking algorithm and system's performance evaluation for three sensor configurations. The algorithm copes with the problem of magnetic field strength drop due to varying orientation of magnet. The minimum average error obtained is 1.37cm/6.85% in a 20*20*20 cm(3) volume for two dimensional sensor configuration. PMID- 23365964 TI - Magnetic induction measurements with a six channel coil array for vital parameter monitoring. AB - Vital parameter monitoring on neonatal intensive care units is essential but very stressful for patients during daily routine care. For contact-less monitoring of breathing and heart activity, magnetic induction measurements are applicable in research scenarios. For monitoring both vital parameters in newborn intensive care wards, we developed a Multi Channel Simultaneous Magnetic Induction Measurement System (MUSIMITOS2+). In this article we now evaluate the technical requirements of a coil array for vital parameter monitoring and finally present a multichannel coil array with 6 excitation and measurement channels combined as axial gradiometers for the specific measurement scenario. This array will be stored underneath the child. As a test case we will present data of a animal trial with the described coil array and the measurement device MUSIMITOS2+. PMID- 23365965 TI - Assessment of ICA algorithms for the analysis of crackles sounds. AB - Blind source separation by independent component analysis has been applied extensively in the biomedical field for extracting different contributing sources in a signal. Regarding lung sounds analysis to isolate the adventitious sounds from normal breathing sound is relevant. In this work the performance of FastICA, Infomax, JADE and TDSEP algorithms was assessed using different scenarios including simulated fine and coarse crackles embedded in recorded normal breathing sounds. Our results pointed out that Infomax obtained the minimum Amari index (0.10037) and the maximum signal to interference ratio (1.4578e+009). Afterwards, Infomax was applied to 25 channels of recorded normal breathing sound where simulated fine and coarse crackles were added including acoustic propagation effects. A robust blind crackle separation could improve previous results in generating an adventitious acoustic thoracic imaging. PMID- 23365966 TI - High-density surface EMG decomposition based on a convolutive blind source separation approach. AB - A novel automatic approach is developed in the present study to decompose high density surface electromyography (EMG) signals into motor unit (MU) firing patterns. The observed surface EMG signals are first modeled as a convolutive mixture of active MU sources. Contrast function maximization is employed to extract the first source, and separation of other sources is then carried out by an iterative deflation approach. Each extracted source is further processed and verified with the characteristics of motor unit action potential and firing patterns. The performance of the proposed automatic approach is evaluated in well designed computer simulation. Results show that 4.7+/-0.5 and 7.1+/-0.6 MUs were correctly identified in the case of 5 and 10 active MUs respectively. PMID- 23365967 TI - Predicting catheter ablation outcome in persistent atrial fibrillation using atrial dominant frequency and related spectral features. AB - Pre-procedural atrial fibrillation dominant frequency (AFDF) has been reported to play a role as a predictor of catheter ablation (CA) outcome for the treatment of persistent atrial fibrillation (AF). The present study analyzes some spectral features of the atrial signal aimed at evaluating the quality of surface AFDF estimation and discusses their predictive power. First, automated extraction of surface atrial activity (AA) on pre-procedural 12-lead ECG recordings is performed by means of an independent component analysis (ICA) method. AFDF is then estimated by means of short-time Fourier analysis of the extracted atrial sources and simultaneous endocardial electrograms (EGM) used as reference. On a database of 20 patients in persistent AF undergoing CA, AFDF does not appear to play a role as a predictor of CA outcome at follow-up, neither on ECG nor on EGM recordings. The quality of surface AFDF estimation is assessed by means of the correlation coefficient r between surface and EGM AFDF, as well as the spectral concentration (SC) of the estimated atrial signal. It is shown that the quality of surface AFDF estimation is significantly lower for non-terminating CA procedures, both in terms of r and SC. The latter, in particular, seems to play a significant role in distinguishing terminating from non-terminating CA procedures and therefore in the non-invasive prediction of CA outcome. PMID- 23365968 TI - Multidimensional characterization of fibrillatory wave amplitude on surface ECG to describe catheter ablation impact on persistent atrial fibrillation. AB - Radiofrequency catheter ablation (CA) is increasingly employed to treat persistent atrial fibrillation (AF). Nevertheless, its success is not always guaranteed, as selection of patients who could positively respond to this therapy does not rely on systematic criteria and still remains an open issue. Moreover, very little is known about the quantitative effects of this treatment over AF electrophysiology, so their quantitative evaluation is not a trivial task. In this contribution, ablation impact is quantified by a descriptor of fibrillatory wave (f-wave) amplitude, so far regarded as a predictor of short-term CA outcome. By means of principal component analysis (PCA), surface electrocardiogram (ECG) spatial diversity is exploited and contributions from all leads are combined to describe average f-wave peak-to-peak amplitude, whose value is automatically computed by an algorithm based on cubic spline interpolation. Our work demonstrates how CA influences f-wave amplitude during the procedure as quantified by ECG inter-lead spatial variability. In addition, we show how such variations depend on procedural outcome and the duration of the postoperative blanking period. PMID- 23365969 TI - Space time frequency (STF) code tensor for the characterization of the epileptic preictal stage. AB - We evaluate the ability of multiway models to characterize the epileptic preictal period. The understanding of the characteristics of the period prior to the seizure onset is a decisive step towards the development of seizure prediction frameworks. Multiway models of EEG segments already demonstrated that hidden structures may be unveiled using tensor decomposition techniques. We propose a novel approach using a multiway model, Parallel Factor Analysis (PARAFAC), to identify spatial, temporal and spectral signatures of the preictal period. The results obtained, from a dataset of 4 patients, with a total of 30 seizures, suggest that a common structure may be involved in seizure generation. Furthermore, the spatial signature may be related to the ictal onset region and that determined frequency sub-bands may be more relevant in preictal stages. PMID- 23365970 TI - The effect of automatic blink correction on auditory evoked potentials. AB - The effects of blink correction on auditory event-related potential (ERP) waveforms is assessed. Two blink correction strategies are compared. ICA-SSP combines independent component analysis (ICA) with signal space projection (SSP) and ICA-EMD uses empirical mode decomposition (EMD) to improve the performance of the standard ICA method. Five voluntary subjects performed an auditory oddball task. The resulting ERPs are used to compare the two blink correction methods to each other and against blink rejection. The results suggest that both methods qualitatively preserve the ERP waveform but that they underestimate some of the peak amplitudes. ICA-EMD performs slightly better than ICA-SSP. In conclusion, the use of blink correction is justified, especially if blink rejection leads to severe data loss. PMID- 23365971 TI - Simulation environment of X-ray rotational angiography using 3D+t coronary tree model. AB - The newly introduced cardiac rotational angiography (RA) can provide a large amount of projections from different angles which greatly improve the 3D coronary tree reconstruction. However, the reconstruction methods are difficult to be objectively evaluated due to the complicated topology of coronary tree and non linear cardiac motion. In this paper, we present a simulation environment of rotational angiography acquisition system to facilitate the improvements and the evaluations of reconstruction algorithms. A 3D+t coronary tree model reconstructed from MSCT sequence is employed to enhance the reality of simulation. A simulation environment of X-ray coronary angiography is developed based on distance-driven projection algorithm. The static angiography is firstly simulated to verify the dynamic model by comparing the displacements of landmarks with the real static angiography of the same patient. Rotational simulation results are then obtained with real system parameters to provide a complete and true-to-life RA sequence representing the morphology of moving coronary tree. PMID- 23365972 TI - Model-based error analysis of the oscillometric fixed-ratio blood pressure measurement method. AB - We investigated factors affecting the accuracy of the oscillometric fixed-ratio blood pressure measurement method. We specifically applied a parametric sensitivity analysis to a mathematical model of oscillometry. We found that changes in arterial stiffness at zero transmural pressure and pulse pressure represent major factors that can potentially cause large error in the method. In particular, our theoretical analysis demonstrates that the fixed-ratio method predicts (1) higher systolic and lower diastolic blood pressures as the artery stiffen over the zero transmural pressure regime and (2) higher systolic and lower diastolic blood pressures as the pulse pressure increases. Further, the impact of pulse pressure on these errors is more obvious as the artery stiffens. PMID- 23365973 TI - Effect of asymmetry on hemodynamics in fluid-structure interaction model of congenital bicuspid aortic valves. AB - A bicuspid aortic valve (BAV) is a congenital cardiac disorder where the valve consists of only two cusps instead of three in a normal tricuspid valve (TAV). Although 97% of BAVs include asymmetric cusps, little or no prior studies investigated the blood flow through physiological three-dimensional BAV and root. This study presents four fully coupled fluid-structure interaction (FSI) models, including native TAV, asymmetric BAV with or without a raphe and an almost symmetric BAV. The FSI simulations are based on coupled structural and fluid dynamics solvers that allow accurate modeling of the pressure load on both the root and the cusps. The partitioned solver has non-conformal meshes and the flow is modeled employing an Eulerian approach. The cusps tissue in the structural model is composed of hyperelastic finite elements with collagen fiber network embedded in the elastin matrix. The tissues behavior of the aortic sinuses is also hyperelastic. The coaptation is modeled with master-slave contact algorithm. A full cardiac cycle is simulated by imposing the same physiological blood pressure at the upstream and downstream boundaries, for all the TAV and BAV models. The latter have significantly smaller opening area compared to the TAV. Larger stress values were also found in the cusps of the BAV models with fused cusps, both at the systolic and diastolic phases. The asymmetric geometry cause asymmetric vortices and much larger wall shear stress on the cusps, which is a potential cause for early valvular calcification in BAVs. PMID- 23365974 TI - CFD simulation of hemodynamics in sequential and individual coronary bypass grafts based on multislice CT scan datasets. AB - There is still controversy over the differences in the patency rates of the sequential and individual coronary artery bypass grafting (CABG) techniques. The purpose of this paper was to non-invasively evaluate hemodynamic parameters using complete 3D computational fluid dynamics (CFD) simulations of the sequential and the individual methods based on the patient-specific data extracted from computed tomography (CT) angiography. For CFD analysis, the geometric model of coronary arteries was reconstructed using an ECG-gated 64-detector row CT. Modeling the sequential and individual bypass grafting, this study simulates the flow from the aorta to the occluded posterior descending artery (PDA) and the posterior left ventricle (PLV) vessel with six coronary branches based on the physiologically measured inlet flow as the boundary condition. The maximum calculated wall shear stress (WSS) in the sequential and the individual models were estimated to be 35.1 N/m(2) and 36.5 N/m(2), respectively. Compared to the individual bypass method, the sequential graft has shown a higher velocity at the proximal segment and lower spatial wall shear stress gradient (SWSSG) due to the flow splitting caused by the side-to-side anastomosis. Simulated results combined with its surgical benefits including the requirement of shorter vein length and fewer anastomoses advocate the sequential method as a more favorable CABG method. PMID- 23365975 TI - Computational modeling of the transient hemodynamic response in cerebral cortex. AB - Neural activity triggers a vascular response in the brain that leads to transient changes in oxygen transport, and this mechanism is the basis for popular and powerful functional imaging methods. However, there is limited understanding of oxygen delivery to cerebral cortex both in steady state and during transient perturbations. In this study, a computational model for oxygen transport in the brain was developed and used to fit polarographic oxygen measurements during transient stimulation in cerebral cortex. The hemodynamic response function (HRF) was modeled with convection-diffusion transport in a four-compartment system (erythrocyte, intravascular, extravascular, and intracellular) that includes oxygen dissociation from hemoglobin. This model explained the dynamics of oxygen transport in cortex after brief visual stimulation, successfully fitting ~90% of experimental measurements within a realistic range of parameters for steady-state flow speed and oxygen consumption, as well as flow and oxygen uptake perturbations. PMID- 23365977 TI - Numerical simulations of flow through the aorta using both ideal and realistic geometrical models. AB - The effects of curvature and tapering on the flow progression in the aorta were studied using numerical simulations on a realistic geometrical model of the aorta and three different versions of the ideal aorta models. The results showed that tapering increases velocity magnitude and wall shear stress while local curvatures affect the skewness of the velocity profile, the thickness of the boundary layer as well as the recirculation regions. Wall shear stress distribution in the aorta serves as an important determinant in the progression of arterial disease. PMID- 23365978 TI - Simulation of reduction of proximal aortic stiffness by an elastic wrap and effects on pulse pressure. AB - Aortic stiffness is a major cause of age-related increase in arterial pulse pressure (PP) and associated increase in work load for the heart. A method to treat this condition is proposed: wrapping the ascending aortic wall with a highly compliant elastic material such that reducing the vessel diameter will shift the pulsatile load from the aortic wall to the wrap, thus increasing the functional compliance of the ascending aorta and decreasing the cardiac load. A multibranched mathematical model of the arterial system, in which every segment of the arterial tree is represented as a uniform elastic circular tube, has been used to simulate the effect of the wrapping procedure on PP and impedance changes, by varying the radius (R) and the stiffness (E) of the ascending aortic segment. The results of the simulation show that PP decreases with an increase in R and a decrease in E. A similar trend, but with a different sensitivity, is observed for the characteristic impedance (Z(c)) changes. The model shows that PP in the ascending aorta can be lowered by 8.8% by reducing R of 20% and decreasing the functional E by 80%, in good agreement with preliminary results obtained from an in vitro pilot study of elastic wrap in aortas. In conclusion, the modelling study demonstrates that the proposed aortic wrapping procedure is able to compensate for the increase in PP associated with R reduction by a decrease in PP determined by a reduction in functional E. Therefore, it supports the use of the aortic wrap as a potential non-pharmacological treatment of age-related increase in PP. PMID- 23365979 TI - Hemodynamic simulation for surgical treatment of congenital heart disease. AB - Numerical analysis of cardiovascular flow is one of several methods of use for the quantitative evaluation of patient-specific treatments. However, due to the complexity of vascular geometry and flow conditions, the cardiovascular flow simulation continues to be a challenging project. As the flow at the peak of systolic heart beat displayed full turbulence, the congenital heart treatments, Norwood and TCPC procedure, were investigated through the use of computational hemodynamic technology, in the present study. On the other hand, at diastolic period, the flow fell to an almost sedentary state. This indicated that the cardiovascular flow experienced a strange transition of flow from systolic peak to diastole. Thus, in order to accurately simulate this transitional flow, a very small time step was applied in the k - epsilon turbulent model calculation. Energy losses (EL), local pressure and wall shear stress were analyzed to estimate the result of clinical treatments. It was found that the value of EL, including the influence of respiration, was 1.5 times higher than the value of EL, disregarding respiratory influences. These results indicated that the hemodynamic outcomes of TCPC treatment are noticeably influenced by respiration. The effect of respiration plays an important role in estimating the results of TCPC treatment and thus should be included as one of the important conditions of computational hemodynamic analysis. PMID- 23365980 TI - Hysteresis in DI independent mechanisms in threshold for transition between 1:1 and 2:2 rhythms in pigs. AB - Previous studies have shown hysteresis in transition from 1:1 to 2:2 rhythms in action potential durations (APD) during decreasing and increasing cycle length pacing. As cycle lengths were constant, when alternans of APD occurred, so did of preceding diastolic intervals (DIs), which engaged the restitution mechanism, i.e. dependence of APD on preceding DI, making it impossible to determine whether the hysteresis originates from the DI independent or dependent mechanism. By using pacing with explicit control of DI, in the present study we investigated whether hysteresis in activation threshold exists in DI independent mechanism of alternans of APD. Transmembrane potentials were recorded from the left ventricles of 6 farm pigs, and the state transition was obtained from two pacing protocols where DIs decreased and increased in steps of 10 msec between 50 and 20 msec with 30 (15) beats at each DI level. Results showed hysteresis: for the 30 (15) beats protocol, onset and termination of alternans occurred at 27 (33) and 47 (49) msec DIs; average alternans amplitude was 22 (13) and 26 (15) msec for decreasing and increasing DIs. Because constant DI pacing was used, restitution dependent effect was eliminated, therefore, observation of hysteresis in our results suggests that restitution independent mechanisms such as activation memory also contribute to the hysteresis in this state transition. PMID- 23365981 TI - Assessment of the ST segment deviation area as a potential physiological marker of the acute myocardial infarction. AB - The purpose of this article is to present the assessment of the ST segment deviation area as a feature estimated from electrocardiographic signals to improve the current quantitative measures, which have low correlation with standard measures, such as biomarkers. In total 20 subjects were involved in the study. They were classified into two distinct groups (anterior and inferior) related to the localization of the acute myocardial infarction (AMI). The area of the ST segment was calculated by using customized software developed in Matlab(r). From the analysis of this parameter it may be possible to correlate the ST deviation area with the necrosis risk area on myocardial tissue. The correlation between the ST area estimates were compared with Aldrich score, which uses the height of the J point instead of the area. It was calculated the correlation between the ST area, the Aldrich score and biomarkers of myocardial injury in patients. A Spearman correlation coefficient of 0.58 was estimated when comparing Aldrich score and the biomarkers for inferior AMI. The coefficient was 0.99 when correlating the biomarkers to the ST area. Therefore, this feature is a potential physiological marker of inferior AMI. The possibility of estimating the necrosis extent by means of electrocardiographic analysis allows for the reduction of cost and time since there may be no requirement for additional laboratorial exams, consequently improving the treatment efficacy and the prognosis of patients affected by acute myocardial infarction. PMID- 23365982 TI - Effect of rapid delayed rectifier current on hysteresis in restitution of action potential duration in swine. AB - Electrical stability in the heart depends on two important factors; restitution of action potential duration (APD) and memory. Repolarization currents play an important role in determining APD and also affect memory. We determined the effects of blocking the rapid component of the delayed rectifier (I(Kr)) on a quantifiable measure of memory, i.e. hysteresis in restitution of APD, in swine. Transmembrane potentials were recorded from right ventricular endocardial tissues. Two pacing protocols with explicit control of diastolic interval (DI) were used to change DIs in a sequential and sinusoidal pattern to quantify hysteresis in restitution of APD. E-4031 (5 uM/L) was used to block I(Kr). Measures of memory and restitution were quantified by calculating hysteresis loop thickness, area, overall tilt, and maximum and minimum delays between DIs and APDs. Blocking I(Kr) with E-4031 increased the baseline APD, loop thickness, area, and tilt (p<0.05). However, loop thickness did not increase beyond what could be predicted by the increase in baseline APD after block of I(Kr). The substantial change in APD after blocking I(Kr) suggests that this current plays a major role in repolarization in the swine. Loop thickness is a measure of memory, an increase in which is predicted by theory to reduce instability in activation. In our study, the substantial increase in loop thickness could be accounted for by an equally substantial increase in APD and therefore does not necessarily indicate increased memory after blocking I(Kr). Our results also suggest that factors based on restitution and memory need to be considered in the context of operating point, i.e. baseline APD, when they are used to explore mechanisms that affect electrical stability in the heart. PMID- 23365983 TI - Transformation of the Mason-Likar 12-lead electrocardiogram to the Frank vectorcardiogram. AB - Vectorcardiograpic (VCG) parameters can supplement the diagnostic information of the 12-lead electrocardiogram (ECG). Nevertheless, the VCG is seldom recorded in modern-day practice. A common approach today is to derive the Frank VCG from the standard 12-lead ECG (distal limb electrode positions). There is, to date no direct method that allows for a transformation from 12-lead ECGs with proximal limb electrode positions (Mason-Likar (ML) 12-lead ECG), to Frank VCGs. In this research, we develop such a transformation (ML2VCG) by means of multivariate linear regression on a training data set of 545 ML 12-lead ECGs and corresponding Frank VCGs that were both extracted surface potential maps (BSPMs). We compare the performance of the ML2VCG method against an alternative approach (2step method) that utilizes two existing transformations that are applied consecutively (ML 12-lead ECG to standard 12-lead ECG and subsequently to Frank VCG). We quantify the performance of ML2VCG and 2step on an unseen test dataset (181 ML 12 lead ECGs and corresponding Frank VCGs again extracted from BSPMs) through root mean squared error (RMSE) values, calculated over the QRST, between actual and transformed Frank leads. The ML2VCG transformation achieved a reduction of the median RMSE values for leads X (13.9uV; p<.001), Y (15.1uV; p<.001) and Z (2.6uV; p=.001) when compared to the 2step transformation. Our results show that the 2step method may not be optimal when transforming ML 12-lead ECGs to Frank VCGs. The utilization of the herein developed ML2VCG transformation should thus be considered when transforming ML 12-lead ECGs to Frank VCGs. PMID- 23365984 TI - Drug release mechanisms of steroid eluting rings in cardiac pacemaker lead electrodes. AB - This paper reports on the drug release mechanisms of silicone structures with embedded steroids applied in pacing leads. Different derivatives of the steroid dexamethasone, which is associated with the reduction of acute stimulation thresholds, were evaluated together with different matrix based release control mechanisms with the target to potentially match optimal drug release rates during the first month after implantation. By incorporating dexamethasone-21-dihydrogen phosphate in silicone matrices in combination with release rate adaption layers, almost continuous release rates were obtained under physiological test settings. PMID- 23365985 TI - Cardiac fiber rotation distorts surface measurements of anisotropic propagation. AB - Anisotropy is often determined experimentally from epicardial propagation measurements. We hypothesize that the direction of wave propagation on the epicardial surface is not aligned with the epicardial fiber orientation, due to intramural fiber rotation. In this paper, we modeled the effect of cardiac tissue fiber rotation on wave propagation. We used a three dimensional computer model of varying thickness with a 120 degree fiber rotation through the thickness. The angle difference between the direction of propagation and fiber orientation was most pronounced for thin tissue, and decreased with increasing tissue thickness. This angle also increased with the time elapsed since stimulation. Finally, we demonstrated that the fiber rotation from epicardium to endocardium results in inaccurate measurements of conduction velocities at the epicardium, particularly in thin tissues. PMID- 23365986 TI - Defibrillation success rates for electrically-induced fibrillation: hair of the dog. AB - Accidental electrocutions kill about 1000 individuals annually in the USA alone. There has not been a systematic review or modeling of elapsed time duration defibrillation success rates following electrically-induced VF. With such a model, there may be an opportunity to improve the outcomes for industrial electrocutions and further understand arrest-related-deaths where a TASER((r)) electrical weapon was involved. We searched for MedLine indexed papers dealing with defibrillation success following electrically-induced VF with time durations of 1 minute or greater post VF induction. We found 10 studies covering a total of 191 experiments for defibrillation of electrically-induced VF for post-induction durations out to 16 minutes including 0-9 minutes of pre-shock chest compressions. The results were fitted to a logistic regression model. Total minutes of VF and use of pre-shock chest compressions were significant predictors of success (p < .00005 and p= .003 respectively). The number of minutes of chest compressions was not a predictor of success. With no compressions, the 90% confidence of successful defibrillation is reached at 6 minutes and the median time limit for success is 9.5 minutes. However, with pre-shock chest compressions, the modeled data suggest a 90% success rate at 10 minutes and a 50% rate at 14 minutes.1. PMID- 23365987 TI - An ultra-sensitive wearable accelerometer for continuous heart and lung sound monitoring. AB - This paper presents a chest-worn accelerometer with high sensitivity for continuous cardio-respiratory sound monitoring. The accelerometer is based on an asymmetrical gapped cantilever which is composed of a bottom mechanical layer and a top piezoelectric layer separated by a gap. This novel structure helps to increase the sensitivity by orders of magnitude compared with conventional cantilever based accelerometers. The prototype with a resonant frequency of 1100Hz and a total weight of 5 gram is designed, constructed and characterized. The size of the prototype sensor is 35mm*18mm*7.8mm (l*w*t). A built-in charge amplifier is used to amplify the output voltage of the sensor. A sensitivity of 86V/g and a noise floor of 40ng/?Hz are obtained. Preliminary tests for recording both cardiac and respiratory signals are carried out on human body and the new sensor exhibits better performance compared with a high-end electronic stethoscope. PMID- 23365988 TI - Analysis of roots in ARMA model for the classification of patients on weaning trials. AB - One objective of mechanical ventilation is the recovery of spontaneous breathing as soon as possible. Remove the mechanical ventilation is sometimes more difficult that maintain it. This paper proposes the study of respiratory flow signal of patients on weaning trials process by autoregressive moving average model (ARMA), through the location of poles and zeros of the model. A total of 151 patients under extubation process (T-tube test) were analyzed: 91 patients with successful weaning (GS), 39 patients that failed to maintain spontaneous breathing and were reconnected (GF), and 21 patients extubated after the test but before 48 hours were reintubated (GR). The optimal model was obtained with order 8, and statistical significant differences were obtained considering the values of angles of the first four poles and the first zero. The best classification was obtained between GF and GR, with an accuracy of 75.3% on the mean value of the angle of the first pole. PMID- 23365989 TI - A system for the model based emergency detection and communication for the telerehabilitation training of cardiopulmonary patients. AB - Cardiopulmonary diseases affect millions of people and cause high costs in health care systems worldwide. Patients should perform regular endurance exercises to stabilize their health state and prevent further impairment. However, patients are often uncertain about the level of intensity they should exercise in their current condition. The cost of continuous monitoring for these training sessions in clinics is high and additionally requires the patient to travel to a clinic for each single session. Performing the rehabilitation training at home can raise compliance and reduce costs. To ensure safe telerehabilitation training and to enable patients to control their performance and health state, detection of abnormal events during training is a critical prerequisite. Therefore, we created a model that predicts the heart rate of cardiopulmonary patients and that can be used to detect and avoid abnormal health states. To enable external feedback and an immediate reaction in case of a critical situation, the patient should have the possibility to configure the system to communicate warnings and emergency events to clinical and non-clinical actors. To fulfill this task, we coupled a personal health record (PHR) with a new component that extends the classic home emergency systems. The PHR is also used for a training schedule definition that makes use of the predictive HR model. We used statistical methods to evaluate the prediction model and found that our prediction error of 3.2 heart beats per minute is precise enough to enable a detection of critical states. The concept for the communication of alerts was evaluated through focus group interviews with domain experts who judged that it fulfills the needs of potential users. PMID- 23365990 TI - Periodic breathing during ascent to extreme altitude quantified by spectral analysis of the respiratory volume signal. AB - High altitude periodic breathing (PB) shares some common pathophysiologic aspects with sleep apnea, Cheyne-Stokes respiration and PB in heart failure patients. Methods that allow quantifying instabilities of respiratory control provide valuable insights in physiologic mechanisms and help to identify therapeutic targets. Under the hypothesis that high altitude PB appears even during physical activity and can be identified in comparison to visual analysis in conditions of low SNR, this study aims to identify PB by characterizing the respiratory pattern through the respiratory volume signal. A number of spectral parameters are extracted from the power spectral density (PSD) of the volume signal, derived from respiratory inductive plethysmography and evaluated through a linear discriminant analysis. A dataset of 34 healthy mountaineers ascending to Mt. Muztagh Ata, China (7,546 m) visually labeled as PB and non periodic breathing (nPB) is analyzed. All climbing periods within all the ascents are considered (total climbing periods: 371 nPB and 40 PB). The best crossvalidated result classifying PB and nPB is obtained with Pm (power of the modulation frequency band) and R (ratio between modulation and respiration power) with an accuracy of 80.3% and area under the receiver operating characteristic curve of 84.5%. Comparing the subjects from 1(st) and 2(nd) ascents (at the same altitudes but the latter more acclimatized) the effect of acclimatization is evaluated. SaO(2) and periodic breathing cycles significantly increased with acclimatization (p value < 0.05). Higher Pm and higher respiratory frequencies are observed at lower SaO(2), through a significant negative correlation (p-value < 0.01). Higher Pm is observed at climbing periods visually labeled as PB with > 5 periodic breathing cycles through a significant positive correlation (p-value < 0.01). Our data demonstrate that quantification of the respiratory volume signal using spectral analysis is suitable to identify effects of hypobaric hypoxia on control of breathing. PMID- 23365991 TI - Estimation of oxygen consumption during cycling and rowing. AB - The aim of this paper is to develop estimator that can predict oxygen consumption (V(O2)) during cycling and rowing exercises, by using non-invasive and easily measurable quantities such as heart rate (HR), respiratory rate (RespR) and frequency of exercising activity. The frequency of exercise is quantified as a universal measure of exercise intensity and is known as Exercise Rate (ER). This ER is responsible for deviation in V(O2) (DeltaV(O2)), HR (DeltaHR), and RespR (DeltaRespR) from their respective baseline measurements during exercise. Therefore, DeltaV(O2) can be estimated from Delta, DeltaRespR and ER. The resting measured of V(O2) is referred as V(O(2rest)); this is computed from the physical fitness of an individual. The Hammerstein model is adopted for the estimation of DeltaV(O2). Results in this study demonstrate that the developed estimators for each type of exercise are capable of estimating V(O2) by adding up V(O(2rest)) and DeltaV(O2) at various intensities during cycling and rowing. PMID- 23365992 TI - Model based optimization of the cardiopulmonary resuscitation (CPR) procedure. AB - This paper is concerned with the optimization of the cardiopulmonary resuscitation (CPR) procedure, which plays a critical rule in saving the life of patients suffering from cardiac arrest. In this paper, we define the performance index for optimization using the oxygen delivery. A model developed earlier is used to calculate the oxygen delivery through CPR. The free parameters of this model which depend on the rescuer performance are ventilation time, compression speed, tidal volume, and fraction of oxygen in the inspired air. Two different optimization problems are carried out. First, a global optimization is implemented to discover the best values of the free parameters which maximize the oxygen delivery. In addition to this, a sequential optimization scheme is explored which uses a two step optimization in each CPR sequence to maximize the oxygen delivery. Results show that the sequential optimization procedure will enhance the performance of the CPR significantly. PMID- 23365993 TI - Respiratory effort energy estimation using Doppler radar. AB - Human respiratory effort can be harvested to power wearable biosensors and mobile electronic devices. The very first step toward designing a harvester is to estimate available energy and power. This paper describes an estimation of the available power and energy due to the movements of the torso during breathing, using Doppler radar by detecting breathing rate, torso displacement, torso movement velocity and acceleration along the sagittal movement of the torso. The accuracy of the detected variables is verified by two reference methods. The experimental result obtained from a healthy female human subject shows that the available power from circumferential movement can be higher than the power from the sagittal movement. PMID- 23365994 TI - Effects of magnesium on growth and proliferation of human embryonic stem cells. AB - The effects of magnesium on the growth and proliferation of human embryonic stem cells (hESCs) was explored to advance magnesium as an implant biomaterial. When magnesium ions from magnesium salt were added to the culture media at 10, 100, 250, 500, 750, and 1000 ppm (0.4, 4, 10, 20, 30, 40 mM) the rate of increase in viable cell coverage over time was higher for the larger doses of magnesium salt. Thus, the addition of magnesium ions exerted a positive effect on viable cell coverage. When hESCs were cultured with pure magnesium metal strips through transwell inserts, the cells underwent an initial increase in viable cell coverage, followed by rapid cell death within the first 24 hours. This initial increase in viable cell coverage corresponded to the colonies dispersing and losing their tightly packed morphologies. The cell death may be attributed to an increased alkalinity in the culture media incubated with the magnesium metal strips. In conclusion, since the degradation of magnesium results in both magnesium ions and OH- ions (an increase of pH), controlling the degradation of magnesium to obtain the perfect balance of ions is critical for advancing magnesium as an implant biomaterial. PMID- 23365995 TI - Electrodeposition of platinum-iridium alloy nanowires for hermetic packaging of microelectronics. AB - An electrodeposition technique was applied for fabrication of dense platinum iridium alloy nanowires as interconnect structures in hermetic microelectronic packaging to be used in implantable devices. Vertically aligned arrays of platinum-iridium alloy nanowires with controllable length and a diameter of about 200 nm were fabricated using a cyclic potential technique from a novel electrodeposition bath in nanoporous aluminum oxide templates. Ti/Au thin films were sputter deposited on one side of the alumina membranes to form a base material for electrodeposition. Scanning Electron Microscopy (SEM) and Energy Dispersive Spectroscopy (EDS) were used to characterize the morphology and the chemical composition of the nanowires, respectively. SEM micrographs revealed that the electrodeposited nanowires have dense and compact structures. EDS analysis showed a 60:40% platinum-iridium nanowire composition. Deposition rates were estimated by determining nanowire length as a function of deposition time. High Resolution Transmission Electron Microscopy (HRTEM) images revealed that the nanowires have a nanocrystalline structure with grain sizes ranging from 3 nm to 5 nm. Helium leak tests performed using a helium leak detector showed leak rates as low as 1 * 10(-11) mbar L s(-1) indicating that dense nanowires were electrodeposited inside the nanoporous membranes. Comparison of electrical measurements on platinum and platinum-iridium nanowires revealed that platinum iridium nanowires have improved electrical conductivity. PMID- 23365996 TI - Magnetically induced deep brain stimulation of neuronal firing for pain relief. AB - Pain, either acute pain or chronic pain, is usually treated/relieved by chemical means, in which nociceptive signals are blocked from transmitting into the pain registration sites in the brain. However, besides their side effects, chemical means of pain relief are not always effective, causing some serious clinical incidents like anesthesia awareness and chronic pains that are not treatable. A physical means of pain relief that physically modifies pain perception at the brain sites responsible for pain registration could be more effective, for both acute pain and chronic pain. In this paper a novel approach of magnetically induced deep brain modulation of neuronal firing is proposed for pain treatment/relief, in which pain treatment/relief is bioelectronics based and is non-invasive and free of side effects. A novel pulse magnetic field projector has been developed for pain relief through modulation of neuronal firing at the anterior cingulate cortex (ACC). It is based on the neuroscience findings that pain registration in the brain is closely related to the excitation of nociceptive neurons at the ACC, in which the nociceptive neuronal firing rate increases as pain gets more intense. The mechanism of pain relief in the proposed approach is to modify the nociceptive neuronal firing rate at the ACC by magnetically inducing a pulse electric field applying on the neurons in the ACC, hyperpolarizing the neurons that are firing at high frequency during pain perception, resulting in a low level firing rate associated to no pain. A parametric study has been carried out to determine the physical and technical parameters of the proposed approach. The feasibility of the approach has been verified by simulation with the modulation implemented on a reconstructed ACC LV pyramidal cell using Hodgkin-Huxley style model. Action potentials recorded in the soma indicated that the firing frequency can be modulated by the applied pulse electric field. PMID- 23365997 TI - A pilot study on effects of 4*1 high-definition tDCS on motor cortex excitability. AB - High-Definition transcranial Direct Current Stimulation (HD-tDCS) using specialized small electrodes has been proposed as a focal, non-invasive neuromodulatory technique. Here we provide the first evidence of a change in cortical excitability after HD-tDCS of the motor cortex, using TMS motor evoked potential (MEP) as the measure of excitability. Stimulation for 20 minutes at 1 mA with an anode centered over the hand area of the motor cortex and four surrounding return electrodes (anodal 4*1 montage) produced a significant increase in MEP amplitude and variability after stimulation, compared to sham stimulation. Stimulation was well tolerated by all subjects with adverse effects limited to transient sensation under the electrodes. A high-resolution computational model confirmed predictions of increased focality using the 4*1 HD tDCS montage compared to conventional tDCS. Simulations also indicated that variability in placement of the center electrode relative to the location of the target (central sulcus) could account for increasing variability. These results provide support for the careful use of this technique where focal tDCS is desired. PMID- 23365998 TI - Real-time fusion of gaze and EMG for a reaching neuroprosthesis. AB - For rehabilitative devices to restore functional movement to paralyzed individuals, user intent must be determined from signals that remain under voluntary control. Tracking eye movements is a natural way to learn about an intended reach target and, when combined with just a small set of electromyograms (EMGs) in a probabilistic mixture model, can reliably generate accurate trajectories even when the target information is uncertain. To experimentally assess the effectiveness of our algorithm in closed-loop control, we developed a robotic system to simulate a reaching neuroprosthetic. Incorporating target information by tracking subjects' gaze greatly improved performance when the set of EMGs was most limited. In addition we found that online performance was better than predicted by the offline accuracy of the training data. By enhancing the trajectory model with target information the decoder relied less on neural control signals, reducing the burden on the user. PMID- 23365999 TI - Polymeric packaging for fully implantable wireless neural microsensors. AB - We present polymeric packaging methods used for subcutaneous, fully implantable, broadband, and wireless neurosensors. A new tool for accelerated testing and characterization of biocompatible polymeric packaging materials and processes is described along with specialized test units to simulate our fully implantable neurosensor components, materials and fabrication processes. A brief description of the implantable systems is presented along with their current encapsulation methods based on polydimethylsiloxane (PDMS). Results from in-vivo testing of multiple implanted neurosensors in swine and non-human primates are presented. Finally, a novel augmenting polymer thin film material to complement the currently employed PDMS is introduced. This thin layer coating material is based on the Plasma Enhanced Chemical Vapor Deposition (PECVD) process of Hexamethyldisiloxane (HMDSO) and Oxygen (O(2)). PMID- 23366000 TI - New approaches to bridge nerve gaps: development of a novel drug-delivering nerve conduit. AB - Contemporary bridging techniques for repairing nerve gaps caused by trauma require autologous nerve grafts, which are difficult to harvest and handle and result in significant donor site deficit. Several nerve conduits with axon growth enhancing potential have been proposed, developed and tested over the past fifteen years. In this work, prototypes of a nerve conduit designed to bridge large nerve gaps (>=10mm) end-to-end were incorporated with concentric drug reservoirs for constant and controlled drug delivery to enhance axon growth. These devices were designed, fabricated and tested in vitro in amber glass vials with bovine serum albumin in order to determine the drug release kinetics for future application. Our devices have shown the capability to deliver the drug of interest over a 6-day period. PMID- 23366001 TI - Implant positioning system using mutual inductance. AB - Surgical placement of implantable medical devices (IMDs) has limited precision and post-implantation the device can move over time. Accurate knowledge of the position of IMDs allows better interpretation of data gathered by the devices and may allow wireless power to be focused on the IMD thereby increasing power transfer efficiency. Existing positioning methods require device sizes and/or power consumptions which exceed the limits of in-vivo mm-sized IMDs applications. This paper describes a novel implant positioning system which replaces the external transmitting (TX) coil of a wireless power transfer link by an array of smaller coils, measures the mutual inductance between each coil in the TX array and the implanted receiving (RX) coil, and uses the spatial variation in those mutual inductances to estimate the location of the implanted device. This method does not increase the hardware or power consumption in the IMD. Mathematical analysis and electromagnetic simulations are presented which explain the theory underlying this scheme and show its feasibility. A particle swarm based algorithm is used to estimate the position of the RX coil from the measured mutual inductance values. MATLAB simulations show the positioning estimation accuracy on the order of 1 mm. PMID- 23366002 TI - Comprehensive characterization of tungsten microwires in chronic neurocortical implants. AB - The long-term performance of chronic microelectrode array implants for neural ensemble recording is affected by temporal degradation in signal quality due to several factors including structural changes in the recording surface, electrical responses, and tissue immune reactivity. This study combines the information available from the temporal aggregation of both biotic and abiotic metrics to analyze and quantify the combined effects on long-term performance. Study of a 42 day implant showed there was a functional relationship between the measured impedance and the array neuronal yield. This was correlated with structural changes in the recording sites, microglial activation/degeneration, and elevation of a blood biochemical marker for axonal injury. We seek to elucidate the mechanisms of chronic microelectrode array failure through the study of the combined effects of these biotic and abiotic factors. PMID- 23366003 TI - Towards a noise prediction model for in vivo neural recording. AB - The signal-to-noise ratio of in vivo extracellular neural recordings with microelectrodes is influenced by many factors including the impedance of the electrode-tissue interface, the noise of the recording equipment and biological background noise from distant neurons. In this work we study the different noise sources affecting the quality of neural signals. We propose a simplified noise model as an analytical tool to predict the noise of an electrode given its geometrical dimensions and impedance characteristics. With this tool we are able to quantify different noise sources, which is important to determine realistic noise specifications for the design of electronic neural recording interfaces. PMID- 23366004 TI - Wireless hippocampal neural recording via a multiple input RF receiver to construct place-specific firing fields. AB - This paper reports scientifically meaningful in vivo experiments using a 32 channel wireless neural recording system (WINeR). The WINeR system is divided into transmitter (Tx) and receiver (Rx) parts. On the Tx side, we had WINeR-6, a system-on-a-chip (SoC) that operated based on time division multiplexing (TDM) of pulse width modulated (PWM) samples. The chip was fabricated in a 0.5-um CMOS process, occupying 4.9 * 3.3 mm(2) and consuming 15 mW from +/-1.5V supplies. The Rx used two antennas with separate pathways to down-convert the RF signal from a large area. A time-to-digital converter (TDC) in an FPGA converted the PWM pulses into digitized samples. In order to further increase the wireless coverage area and eliminate blind spots within a large experimental arena, two receivers were synchronized. The WINeR system was used to record epileptic activities from a rat that was injected with tetanus toxin (TT) in the dorsal hippocampus. In a different in vivo experiment, place-specific firing fields of place cells, which are parts of the hippocampal-dependent memory, were mapped from a series of behavioral experiments from a rat running in a circular track. Results from the same animal were compared against a commercial hard-wired recording system to evaluate the quality of the wireless recordings. PMID- 23366005 TI - Analog low-power hardware implementation of a Laguerre-Volterra model of intracellular subthreshold neuronal activity. AB - The right level of abstraction for a model mimicking a neural function is often difficult to determine. There are trade-offs between capturing biological complexities on one hand and the scalability and efficiency of the model on the other. In this work, we describe a nonlinear Laguerre-Volterra model of the synaptic temporal integration of input spikes to postsynaptic potentials. This model is then efficiently implemented using analog subthreshold circuits and can serve as a foundation for future large-scale hardware systems that can emulate multi-input multi-output (MIMO) spike transformations in populations of neurons. The normalized mean square error in estimating real data using the circuit implementation of this model is less than 15%. The model components are modular and its parameters are adjustable for modeling temporal integration by neurons in other brain regions. The total power consumption of this nonlinear Laguerre Volterra system is less than 5nW. PMID- 23366006 TI - A superposable silicon synapse with programmable reversal potential. AB - We present a novel log-domain silicon synapse designed for subthreshold analog operation that emulates common synaptic interactions found in biology. Our circuit models the dynamic gating of ion-channel conductances by emulating the processes of neurotransmitter release-reuptake and receptor binding-unbinding in a superposable fashion: Only a single circuit is required to model the entire population of synapses (of a given type) that a biological neuron receives. Unlike previous designs, which are strictly excitatory or inhibitory, our silicon synapse implements-for the first time in the log-domain-a programmable reversal potential (i.e., driving force). To demonstrate our design's scalability, we fabricated in 180nm CMOS an array of 64K silicon neurons, each with four independent superposable synapse circuits occupying 11.0*21.5 um(2) apiece. After verifying that these synapses have the predicted effect on the neurons' spike rate, we explored a recurrent network where the synapses' reversal potentials are set near the neurons' threshold, acting as shunts. These shunting synapses synchronized neuronal spiking more robustly than nonshunting synapses, confirming that reversal potentials can have important network-level implications. PMID- 23366007 TI - Event-driven neural integration and synchronicity in analog VLSI. AB - Synchrony and temporal coding in the central nervous system, as the source of local field potentials and complex neural dynamics, arises from precise timing relationships between spike action population events across neuronal assemblies. Recently it has been shown that coincidence detection based on spike event timing also presents a robust neural code invariant to additive incoherent noise from desynchronized and unrelated inputs. We present spike-based coincidence detection using integrate-and-fire neural membrane dynamics along with pooled conductance based synaptic dynamics in a hierarchical address-event architecture. Within this architecture, we encode each synaptic event with parameters that govern synaptic connectivity, synaptic strength, and axonal delay with additional global configurable parameters that govern neural and synaptic temporal dynamics. Spike based coincidence detection is observed and analyzed in measurements on a log domain analog VLSI implementation of the integrate-and-fire neuron and conductance-based synapse dynamics. PMID- 23366008 TI - 125Mbps ultra-wideband system evaluation for cortical implant devices. AB - This paper evaluates the performance of a 125Mbps Impulse Ratio Ultra-Wideband (IR-UWB) system for cortical implant devices by using low-Q inductive coil link operating in the near-field domain. We examine design tradeoffs between transmitted signal amplitude, reliability, noise and clock jitter. The IR-UWB system is modeled using measured parameters from a reported UWB transceiver implemented in 90nm-CMOS technology. Non-optimized inductive coupling coils with low-Q value for near-field data transmission are modeled in order to build a full channel from the transmitter (Tx) to the receiver (Rx). On-off keying (OOK) modulation is used together with a low-complexity convolutional error correcting code. The simulation results show that even though the low-Q coils decrease the amplitude of the received pulses, the UWB system can still achieve acceptable performance when error correction is used. These results predict that UWB is a good candidate for delivering high data rates in cortical implant devices. PMID- 23366009 TI - A wireless 64-channel ECoG recording electronic for implantable monitoring and BCI applications: WIMAGINE. AB - A wireless, low power, 64-channel data acquisition system named WIMAGINE has been designed for ElectroCorticoGram (ECoG) recording. This system is based on a custom integrated circuit (ASIC) for amplification and digitization on 64 channels. It allows the RF transmission (in the MICS band) of 32 ECoG recording channels (among 64 channels available) sampled at 1 kHz per channel with a 12-bit resolution. The device is powered wirelessly through an inductive link at 13.56 MHz able to provide 100mW (30mA at 3.3V). This integration is a first step towards an implantable device for brain activity monitoring and Brain-Computer Interface (BCI) applications. The main features of the WIMAGINE platform and its architecture will be presented, as well as its performances and in vivo studies. PMID- 23366010 TI - Effects of tissue dielectric properties on the electric field induced in tDCS: a sensitivity analysis. AB - Numerical modeling studies remain the only viable way to accurately predict the electric field (E-field) distribution in transcranial direct current stimulation (tDCS). Despite the existence of multiple studies of this kind, a wide range of different values and properties for the electrical conductivities of the tissues represented is employed. This makes it difficult to predict whether the changes observed between models are due to differences in the geometries of the volume conductors or to the different electrical properties of the tissues. In this study we used the finite element method to calculate the E-field distribution in several spherical head models whose tissues were represented with different isotropic and anisotropic conductivity profiles. Results show that the distribution of the E-field is especially sensitive to the conductivity of the skull, skin and GM. These results might help comparing numerical modeling studies that employ different conductivity values. PMID- 23366011 TI - The use of a novel carbon nanotube coated microelectrode array for chronic intracortical recording and microstimulation. AB - Micro-electrode arrays (MEAs) have been used in a variety of intracortical neural prostheses. While intracortical MEAs have demonstrated their utility in neural prostheses, in many cases MEA performance declines after several months to years of in vivo implantation. The application of carbon nanotubes (CNTs) may increase the functional longevity of intracortical MEAs through enhanced biocompatibility and charge injection properties. An MEA metalized with platinum (Pt) on all electrodes had a CNT coating applied to the electrodes on half of the array. This Pt/Pt-CNT MEA was implanted into feline motor cortex for >1 year. Recordings of action potentials and 1 kHz impedance measurements were made on all electrodes to evaluate device functionality. Additionally, electromyogram (EMG) responses were evoked using micro-stimulation via the MEA to measure device performance. These metrics were compared between Pt and Pt-CNT electrodes. There was no significant difference in the data acquisition or micro-stimulation performance of Pt and the Pt-CNT electrodes. However, impedances were lower on the Pt-CNT electrodes. These results demonstrate the functionality of CNT coatings during chronic in vivo implantation. The lower impedances suggest that for microstimulation applications CNT coatings may impart enhanced interface properties. PMID- 23366012 TI - A 1.5-to-5 V converter for a battery-powered activity-dependent intracortical microstimulation SoC. AB - This paper reports on the design, analysis, implementation, and testing of a 1.5 to-5 V converter as part of a battery-powered activity-dependent intracortical microstimulation (ICMS) system-on-chip (SoC) that converts extracellular neural spikes recorded from one cortical area to electrical stimuli delivered to another cortical area in real time. The highly integrated voltage converter is intended to generate a 5-V supply for the stimulating back-end on the SoC from a miniature primary battery that powers the entire system. It is implemented in AMS 0.35 um two-poly four-metal (2P/4M) complementary metal-oxide-semiconductor (CMOS) technology, employs only one external capacitor (1 uF) for storage, and delivers a maximum dc load current of ~88 uA with power efficiency of 31% with its output voltage adjusted to 5.05 V. This current drive capability affords simultaneous stimulation on all eight channels of the SoC with current amplitude up to ~100 uA and average stimulus rate >500 Hz, which is comfortably higher than firing rate of cortical neurons (<150 spikes per second). The measurement results also agree favorably with theoretical derivations from the analysis of converter operation. PMID- 23366013 TI - A parametric study of intracortical microstimulation in behaving rats for the development of artificial sensory channels. AB - In the framework of developing new brain-machine interfaces, many valuable results have been obtained in understanding which features of neural activity can be used in controlling an external device. Somatosensory real-time feedback is crucial for motor planning and for executing "online" errors correction during the movement. In people with sensory motor disabilities cortical microstimulation can be used as sensory feedback to elicit an artificial sensation providing the brain with information about the external environment. Even if intracortical microstimulation (ICMS) is broadly used in several experiments, understanding the psychophysics of such artificial sensory channel is still an open issue. Here we present the results of a parametric study that aims to define which stimulation parameters are needed to create an artificial sensation. Behaving rats were trained to report by pressing a lever the presence of ICMS delivered through microwire electrodes chronically implanted in the barrel cortex. Psychometric curves obtained by varying pulse amplitude, pulse frequency and train duration, demonstrate that in freely moving animals the perception threshold of microstimulation increased with respect to previous studies with head-restrained rats. PMID- 23366014 TI - Low-cost, flexible polymer arrays for long-term neuronal culture. AB - Conducting polymers are promising materials for fabrication of microelectrode arrays for both neural stimulation and recording. Our ability to engineer the morphology and composition of polypyrrole together with its suitability as an electrically addressable tissue/cell substrate have been used to develop an inexpensive, disposable three-dimensional polymeric array for use in neuronal culture and drug discovery. These arrays could be interfaced with a fixed, parallel stimulation and optical imaging system, amenable to automated handling and data analysis. PMID- 23366015 TI - Measuring the electric field of bioelectrodes in saline during stimulation. AB - In order to provide effective vision in a retinal prosthesis, it is necessary to provide sufficient phosphene quantities ideally by parallel stimulation of multiple electrodes. A common, limiting factor in parallel stimulation is the occurrence of cross talk, which can cause undesired tissue stimulation leading to inconsistent percepts. In this paper we present a system developed for measuring the electric field in an in vitro environment by stimulation of bioelectrodes immersed in an electrolyte. The results from this study provides a better understanding of the electric field generated by stimulating electrodes. Calculation of activation area can provide useful information in regards to electrode separation to eliminate cross talk during parallel stimulation. PMID- 23366016 TI - Transcranial magnetic stimulation induces current pulses in transcranial direct current stimulation electrodes. AB - Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation technique where weak direct current is administered through electrodes placed on the subject's head. Transcranial magnetic stimulation (TMS) is a noninvasive method for focal brain stimulation where small intracranial currents are induced by a pulsed magnetic field. TMS can be applied simultaneously with tDCS to probe brain excitability or to effect synergistic neuromodulation. Delivering TMS simultaneously with tDCS can induce electric current pulses in the tDCS electrodes even when the tDCS device is turned off or is set to 0 mA output, as long as the electrodes are connected to the tDCS current source. The output impedance of commercial tDCS devices is in the range of 2-5 kOmega which can allow substantial currents to be induced by TMS. In a rat TMS-tDCS setup, the induced currents are comparable to the tDCS current magnitude. To mitigate the induced currents, the area of the loop formed by the tDCS electrode leads should be minimized and the impedance of the tDCS circuit at TMS pulses frequencies (1 10 kHz) should be maximized. PMID- 23366017 TI - An economical and convenient experiment setup for electrode investigation. AB - Electrodes are among the critical components of neural stimulation devices. Investigating electrode properties like electrode impedance, charge injection capacity, and electrode corrosion limits plays an important role in electrode development. There are many commercial devices available for this purpose. Although useful, these devices are usually expensive and often offer more functions than required. We propose a versatile setup, composed of a LabVIEW program, a National Instruments multifunctional board, and a circuit built of discrete commercial elements. The system offers basic functions used in electrochemical investigation like current and voltage injection, cyclic voltammetry, and impedance spectroscopy. It offers the functionalities of both a potentiostat and an arbitrary waveform generator. It has already been applied elsewhere. PMID- 23366018 TI - In vitro study of iridium electrodes for neural stimulation. AB - Iridium is one of the main electrode materials for applications like neural stimulation. Iridium has a higher charge injection capacity when activated and transformed into AIROF (activated iridium oxide film) using specific electrical signals. Activation is not possible in stimulating devices, if they do not include the necessary circuitry for activation. We introduce a method for iridium electrode activation requiring minimum additional on-chip hardware. In the main part, the lifetime behavior of iridium electrodes is investigated. These results may be interesting for applications not including on-chip activation hardware, and also because activation has drawbacks such as worse mechanical properties and reproducibility of AIROF. PMID- 23366019 TI - Animal experiments with the microelectronics neural bridge IC. AB - The combination of the neural science and the microelectronics science offers a new way to restore the function of central nervous system. A neural regeneration module is used to be implanted into body to bridge the damaged nerve. A microelectronics neural bridge IC designed in CSMC 0.5?m CMOS process which can detect the neural signal and stimulate the nerve is presented. The neural regeneration module is composed of the microelectronics neural bridge IC and some discrete devices. An animal experiment has been done to check whether the neural signal can be transmitted with the chip normally or not. The animal experiment results suggest that the neural regeneration module can make the neural signal transmit normally. PMID- 23366020 TI - Advantages of voice reproduction and the development of a biomimetic self regulating double-clack valve for a prosthesis of the larynx--a feasibility study. AB - The human larynx is a versatile organ. Main functions are phonation, protection and regulation of the air ways. Patients suffer severely from the diagnosis of a laryngeal carcinoma of the stages T3 and T4. In most cases this diagnosis will lead to a total laryngectomy, which is usually dissatisfying in the sense of postoperative rehabilitation. The postoperative consequences include the loss of the native voice, the loss of regular air ways via mouth and nose, sense of smell, and the inability to build up an abdominal pressure. In this paper we focus on the feasibility of a modular larynx prosthesis which enables the laryngectomee to talk with his native voice, to breathe via the regular air ways, and to build up abdominal pressure. In particular we will give insights for a postoperative solution - a modular prosthesis based on a biomimetic self regulating double clack-valve and on a voice reconstruction module, a so called vocoder. The vocoder is a device to reproduce the natural human voice. Most important for the use is an additional device required to analyze, conserve and manage voice characteristics of the patient before surgery. The self-regulating double clack-valve is designed to build up an abdominal pressure e.g. to cough. Therefore, our valve-system is working in both directions - a two-way valve system. By bridging the gap of the regular air ways lost by laryngectomy, the sense of smell and taste are restored. In the following we will present details and characteristics of these two main components required for a modular prosthesis of the larynx in laryngectomees. PMID- 23366021 TI - The relationship between transcranial current stimulation electrode montages and the effect of the skull orbital openings. AB - Due to its low electric conductivity, the skull has a major impact on the electric field distribution in the brain in transcranial current stimulation (tCS). However, the skull has several openings that are filled with higher conductivity soft tissues, and through which a significant fraction of the injected current may pass. We show that current entering the brain via the orbital openings increases the electric field intensity in the cortical regions near the orbit. Furthermore, this depends on the how far electrodes are placed from the orbital openings. PMID- 23366022 TI - Effect of anesthesia on spontaneous activity and evoked potentials of the cerebellar cortex. AB - Cerebellum is a highly organized structure with a crystalline morphology that has always intrigued neuroscientists. Much of the cerebellar research has been conducted in anesthetized animals, particularly using ketamine and xylazine combination. It is not clear how the cerebellar cortical circuitry is affected by anesthesia. In this study, we have recorded spontaneous and evoked potentials from the cerebellar surface with chronically implanted, flexible-substrate, multi electrode arrays. The frequency contents of the spontaneous activity suggest that ketamine/xylazine anesthesia suppresses most of the components except those below 30 Hz. This preliminary study also showed that multi channels of cerebellar cortical activity can be recorded using flexible multi-electrode arrays in behaving animals, which is very challenging task with single microelectrodes. PMID- 23366024 TI - Motor function rebuilding of limbs based on communication principle and electronic system. AB - In this paper, we report our novel idea on the function rebuilding for hemiplegic limbs and the primary experiments. The main concept is to connect the control lost nerves or neuromuscular junctions by using a multi-channel micro- electronic neural bridge (MENB), regenerate the nervous signal, and rebuild the motor functions of the related limb. Since the injured nervous system in stroke-related hemiplegia is located in the brain and difficult to be identified and operate on, we use another nervous system functioning as a new signal source to supply similar neural signals. In these cases, that means, two independent nervous systems are connected by a MENB. As preclinical experiments, we have made a series of tests on bodies of animals and healthy human. The principle, the system construction and the experimental results will be given. PMID- 23366025 TI - A figure-of-merit for design of high performance inductive power transmission links for implantable microelectronic devices. AB - Wireless power transfer through inductive coupling is used in many applications such as high performance implantable microelectronic devices (IMDs). Power transfer efficiency (PTE) and power delivered to the load (PDL) are two conventional inductive link design merits that determine the energy source and driver specifications, heat dissipation, power transmission range, and risk of interference with other devices. Unfortunately designing the inductive link to achieve a high PTE will drastically reduce the PDL and vice versa. Therefore, we are proposing a new figure-of-merit (FoM), which includes both PTE and PDL with proper weights, to help designers of inductive power transfer links to strike a balance between high PTE and PDL at the same time. Three design examples based on the PTE, PDL, and the new FoM have been presented for IMDs to demonstrate the usage and efficacy of the FoM. Our measurement results show that the inductive link optimized based on the FoM can achieved 1.65 times higher PTE than the one optimized for the PDL (72.5% vs. 44%) and at the same time provide 20.8 times larger PDL compared to the one optimized for the PTE (177 mW vs. 8.5 mW for 1 V driving voltage). The inductive links optimized for the PTE and PDL provide 24% higher PTE and PDL compared to the one optimized based on the FoM, respectively. PMID- 23366026 TI - Compact stacked planar inverted-F antenna for passive deep brain stimulation implants. AB - A compact meandered three-layer stacked circular planar inverted-F antenna is designed and simulated at the UHF band (902.75 - 927.25 MHz) for passive deep brain stimulation implants. The UHF band is used because it offers small antenna size, and high data rate. The top and middle radiating layers are meandered, and low cost substrate and superstrate materials are used to limit the radius and height of the antenna to 5 mm and 1.64 mm, respectively. A dielectric substrate of FR-4 of epsilon(r)= 4.7 and delta= 0.018, and a biocompatible superstrate of silicone of er= 3.7 and d= 0.003 with thickness of 0.2 mm are used in the design. The resonance frequency of the proposed antenna is 918 MHz with a bandwidth of 24 MHz at return loss of -10 dB in free space. The antenna parameter such as 3D gain pattern of the designed antenna within a skin-tissue model is evaluated by using the finite element method. The compactness, wide bandwidth, round shape, and stable characteristics in skin make this antenna suitable for DBS. The feasibility of the wireless power transmission to the implant in the human head is also examined. PMID- 23366027 TI - Recent advances in power efficient output stage for high density implantable stimulators. AB - A major drawback of a current-controlled stimulation is its power efficiency. However, it is commonly used in implantable stimulators due to its safety. The power efficiency of a current-controlled stimulation can be improved by reducing the headroom voltage needed in the current driver. A promising technique is to bias the transistor in triode region whereas improving output impedance through the regulated cascode structure. This comes with a feature of implicit compliance monitor which is used for the supply voltage adaptation. This paper presents an overview on recent power efficient high voltage-compliance output drivers. PMID- 23366028 TI - Transcranial direct current stimulation in pediatric brain: a computational modeling study. AB - Transcranial direct current stimulation (tDCS) is a method of non-invasive brain stimulation which uses weak electric currents applied on the scalp to modulate activity of underlying brain tissue. In addition to being used as a tool for cognitive neuroscience investigations, tDCS has generated considerable interest for use as a therapeutic modality for neurologic disorders. Though the safety and tolerability of tDCS in adults is well-established, there is little information on the safety of tDCS in children. Because there are differences between children and adults in several key parameters (such as skull thickness and cerebrospinal fluid volume) which affect current flow through the brain, special consideration should be given to the stimulation parameters which are used in a pediatric study population. In this study we present cortical electrical field maps at different stimulation intensities and electrode configurations using a high-resolution-MRI derived finite element model of a typically developing, anatomically normal 12 year old child. The peak electrical fields for a given stimulus intensity in the adolescent brain were twice as high as in the adult brain for conventional tDCS and nearly four times as high for a 4X1 High-Definition tDCS electrode configuration. These data suggest that acceptable tDCS stimulation parameters may be different in children compared to adults, and that further modeling studies are needed to help guide decisions about applied current intensity. PMID- 23366029 TI - Programmable high-output-impedance, large-voltage compliance, microstimulator for low-voltage biomedical applications. AB - This paper reports on the design of a programmable, high output impedance, large voltage compliance microstimulator for low-voltage biomedical applications. A 6 bit binary-weighted digital to analog converter (DAC) is used to generate biphasic stimulus current pulses. A compact current mirror with large output voltage compliance and high output resistance conveys the current pulses to the target tissue. Designed and simulated in a standard 0.18um CMOS process, the microstimulator circuit is capable of delivering a maximum stimulation current of 160uA to a 10-kOmega resistive load. Operated at a 1.8-V supply voltage, the output stage exhibits a voltage compliance of 1.69V and output resistance of 160MOmega at full scale stimulus current. Layout of the core microelectrode circuit measures 25.5um*31.5um. PMID- 23366030 TI - The computational study of subdural cortical stimulation: a quantitative analysis of voltage and current stimulation. AB - We investigated the effect of electrode type and stimulation condition (voltage stimulation and current stimulation) in bi-polar subdural cortical stimulation (SCS). For this study, we developed a 3D realistic head model using MRI data with 1 mm(3) spatial resolution and simulated the model using the finite element method (FEM). For each study, we used three types of electrodes - disc, ring, and covered-disc - and three efficiency measures - effective depth of penetration, effective volume, and amount of CSF leakage current - to compare the effectiveness of the stimulation between two stimulation conditions. With voltage stimulation, there was no difference in effectiveness between the disc and ring electrodes. However, the amount of CSF leakage current for the covered-disc type was lower than that for the others. The effective depth of penetration and volume for the ring and disc type electrodes were higher than those for the covered-disc type. The current stimulation using the covered-disc electrode penetrated deeper than the other types of electrodes, and the CSF leakage current was still low. The result for voltage and current stimulation was quite different, as the substrate design manipulated the impedance and output current. In the current simulation, if the electrode was covered with the substrate, more current flowed to the cortex. On the other hand, with voltage stimulation, this substrate design makes the impedance between electrodes high, and the total current is reduced. PMID- 23366031 TI - Removable silicon insertion stiffeners for neural probes using polyethylene glycol as a biodissolvable adhesive. AB - Flexible polymer probes are expected to enable extended interaction with neural tissue by minimizing damage from micromotion and reducing inflammatory tissue response. However, their flexibility prevents them from being easily inserted into the tissue. This paper describes an approach for temporarily attaching a silicon stiffener with biodissolvable polyethylene glycol (PEG) so that the stiffener can be released from the probe and extracted shortly after probe placement. A novel stiffener design with wicking channels, along with flip-chip technology, enable accurate alignment of the probe to the stiffener, as well as uniform distribution of the PEG adhesive. Insertion, extraction, and electrode function were tested in both agarose gel and a rat brain. Several geometric and material parameters were tested to minimize probe displacement during stiffener extraction. We demonstrated average probe displacement of 28 +/- 9 um. PMID- 23366032 TI - An electroencephalographic recording platform for real-time seizure detection. AB - There are currently no clinical devices that can be worn by epilepsy patients who suffer from intractable seizures to warn them of seizure onset. Here we summarize state-of-the-art therapies and devices, and present a second-generation hardware platform in which seizure detection algorithms may be programmed into the device. Bi-polar electrographic data is presented for a prototype device and future implementations are discussed. PMID- 23366033 TI - Myoelectric computer interfaces to reduce co-contraction after stroke. AB - A significant factor in impaired motor function caused by stroke is the inability to activate muscles independently. While the pathophysiology behind this co contraction, sometimes called abnormal muscle synergy, is not clear, reducing the co-contraction could improve overall arm function. This pilot study describes the use of a myoelectric-computer interface (MCI) to retrain arm muscle activation and reduce co-contraction. We found that both healthy subjects and stroke survivors with hemiparesis learned to reduce co-contraction with MCI training. Three out of five stroke survivors experienced some improvement in arm function as well. These results suggest that MCIs could provide a novel, relatively inexpensive paradigm for stroke rehabilitation. PMID- 23366034 TI - Direct inductive stimulation for energy-efficient wireless neural interfaces. AB - Advanced neural stimulator designs consume power and produce unwanted thermal effects that risk damage to surrounding tissue. In this work, we present a simplified architecture for wireless neural stimulators that relies on a few circuit components including an inductor, capacitor and a diode to elicit an action potential in neurons. The feasibility of the design is supported with analytical models of the inductive link, electrode, electrolyte, membrane and channels of neurons. Finally, a flexible implantable prototype of the design is fabricated and tested in vitro on neural tissue. PMID- 23366035 TI - Method of locating ultrasound-powered nerve stimulators. AB - We have previously shown a small simple ultrasound-powered nerve stimulator. The piezoelectric implant receives power from an external driving ultrasound transducer. Focusing the ultrasound beam improves power transfer efficiency, but the implant location must be known to aim the focus. We show that currents driven by the stimulator might be detectable on the skin. By scanning the ultrasound focus and measuring the electrical response, we form an image of the implant location. This could give a feedback signal for aiming the beam, and allow multichannel addressing of several stimulators with no added circuitry in the implant. PMID- 23366036 TI - Electrode assembly design for transcranial Direct Current Stimulation: a FEM modeling study. AB - Despite accelerating progress in transcranial Direct Current Stimulation clinical and cognitive research, there remains remarkably little consistency in the control of electrode design and preparation. Electrode assembly design determines skin sensation and failure at the electrode can lead to skin burns. Though tDCS is generally well tolerated, the desire for rigor in electrode design is motivated by applications in increasingly diverse environments and populations. Generally the tDCS electrode assembly consists of a flat rubber or metal electrode and a saline/water saturated sponge. Here we show using FEM simulations, that each of these factors should be controlled to regulate current flow density across the skin: 1) sponge thickness 2) solution salinity 3) electrode size, 4) electrode placement in the sponge (including surface or pocket configuration) 5) control of excess fluid at the skin surface 6) use of rivets. Two general patterns of current distribution emerge as a result of integrated design: edge concentration or center concentration. Poor control over any of these electrode assembly parameters will result in unpredictable current density at the skin during tDCS. PMID- 23366038 TI - An implantable neural stimulator for intraspinal microstimulation. AB - This paper reports on a wireless stimulator device for use in animal experiments as part of an ongoing investigation into intraspinal stimulation (ISMS) for restoration of walking in humans with spinal cord injury. The principle behind using ISMS is the activation of residual motor-control neural networks within the spinal cord ventral horn below the level of lesion following a spinal cord injury. The attractiveness to this technique is that a small number of electrodes can be used to induce bilateral walking patterns in the lower limbs. In combination with advanced feedback algorithms, ISMS has the potential to restore walking for distances that exceed that produced by other types of functional electrical stimulation. Recent acute animal experiments have demonstrated the feasibility of using ISMS to produce the coordinated walking patterns. Here we described a wireless implantable stimulation system to be used in chronic animal experiments and for providing the basis for a system suitable for use in humans. Electrical operation of the wireless system is described, including a demonstration of reverse telemetry for monitoring the stimulating electrode voltages. PMID- 23366039 TI - A fast torsionally compliant kinematic model of concentric-tube robots. AB - Concentric-tube robots have the potential to become an important surgical tool for robot-assisted percutaneous interventions. They can provide dexterous operation in a small constrained environment. The kinematic model of a concentric tube robot has been well developed in terms of accuracy, but the computational cost places limitations on real-time implementation. In this paper, we propose a new technique that will substantially improve the computational efficiency of evaluating the kinematics of a concentric-tube robot in the context of developing a control strategy without sacrificing the accuracy of the results. In this paper we develop a torsionally compliant kinematic model using global variables. The model is validated by comparing the results obtained by computing the kinematic model corresponding to an experimental setup of a concentric-tube robot to which a force/torque sensor has been mounted at its base with those obtained directly from the experimental setup. The results indicate that it is feasible to compute the kinematics of the concentric-tube robot fast enough to allow the position/force control loop to be implemented at a rate of 1 kHz. PMID- 23366040 TI - Investigation of bioinspired gecko fibers to improve adhesion of HeartLander surgical robot. AB - HeartLander is a medical robot proposed for minimally invasive epicardial intervention on the beating heart. To date, all prototypes have used suction to gain traction on the epicardium. Gecko-foot-inspired micro-fibers have been proposed for repeatable adhesion to surfaces. In this paper, a method for improving the traction of HeartLander on biological tissue is presented. The method involves integration of gecko-inspired fibrillar adhesives on the inner surfaces of the suction chambers of HeartLander. Experiments have been carried out on muscle tissue ex vivo assessing the traction performance of the modified HeartLander with bio-inspired adhesive. The adhesive fibers are found to improve traction on muscle tissue by 57.3 %. PMID- 23366041 TI - Using analytical redundancy to increase safety of a synergistic manually guided instrument for craniotomy. AB - In this paper, two methods for bridging line of sight interruptions occurring during the use of the synergistically operated semiautomatic trepanation system (STS) are presented. In the STS, position information is acquired using an optical tracking system with the disadvantage of possible line-of-sight interruptions. Their compensation is crucial, as a real-time control system automatically adjusts the cutting depth of the instrument on the basis of position information and a-priori data. The surgeon is only responsible for guiding the instrument along the resection line. Hence, availability of position information is crucial for depth control, set point generation, and thus for patient safety. In favour of enhancing reliability of position and orientation acquisition, two approaches were developed which are intended to estimate the position during line of sight interruptions on the basis of a-priori system information and process parameters. To assure patient's safety during this procedure, several parameters of the system (e.g. cutting radius, skull gradient) are used in order to estimate the possible cutting error while the redundant system is activated. These two algorithms and the online risk assessment were implemented, and afterwards evaluated. The evaluation was performed using a skull phantom, and yielded promising results. PMID- 23366042 TI - Needle insertion with duty-cycled rotation into multiple media. AB - Thin, flexible needles can be steered along nonlinear paths to reach deep anatomical structures within the human body. This study builds upon previous work involving steering of bevel-tipped needles by inserting while rotating in a duty cycled fashion. Here we investigate how needle material and radius, duty cycle, and tissue stiffness affect needle curvature. Needles were inserted into media while rotated at a specified duty cycle and the curvature was measured. A linear relationship between duty cycle and curvature was observed across all needle materials and radii, and tissue stiffnesses. Following these observations, we developed a model that encapsulates needle and tissue parameters in order to predict the duty cycle needed to achieve a desired curvature. PMID- 23366043 TI - Smooth path planning for a biologically-inspired neurosurgical probe. AB - Percutaneous intervention involves the insertion of needles to specific locations inside the human body, to perform a variety of surgical procedures. Percutaneous procedures are becoming the preferred choice for many neurosurgeons, due to the additional benefits they provide over conventional open neurosurgery. A neurosurgical flexible and steerable probe named STING is currently being developed for accessing deep brain lesions following curvilinear paths. In this paper, we present a path planning method for generating pre-operative paths for this neurosurgical flexible probe. Since the flexible probe is modeled as a nonholonomic system, a deterministic continuous curvature path planning scheme capable of avoiding obstacles is developed for smooth steering of its tip. Multiple paths are generated by varying arrival angle at the targeted lesion and a path optimization approach is then formulated, with the aim to minimize damage to the tissue (i.e. shortest path) and the risk to the patient (obstacle avoidance). Simulation results are reported using the risk-map generated for a coronal slice of the brain, which confirms the successful design of a path planning scheme that satisfies the nonholonomic constraints of the neurosurgical probe. PMID- 23366044 TI - Real time simulation of grasping procedure of large internal organs during laparoscopic surgery. AB - Surgical simulation systems facilitate safe and efficient training processes of surgical trainees by providing a virtual environment in which the surgical procedure can be repeated unlimitedly in a wide variety of situations. The present study attempted to develop a real time simulation system for the grasping procedure of large internal organs during laparoscopic surgery. A mass-spring damper model was developed to simulate the nonlinear viscoelastic large deformations of the spleen tissue while interacting with a triple-jaw grasper. A novel collision detection algorithm was designed and implemented to determine the contact points between the tissue and the grasper jaws. Force or geometrical based boundary conditions were imposed at the contact nodes, depending upon the relative magnitudes of the external pull force and the tangential component of the contact force. The efficacy of the model to calculate and render the grasper spleen interactions in real time was examined in a number of simulations. The results of the model were qualitatively acceptable. The deformation of the tissue was realistic and its stress relaxation behavior could be reproduced. Also, the tool-tissue interactions in slippage-free and slippage-accompanied grasping conditions could be replicated when appropriate coefficients of friction were employed. PMID- 23366045 TI - Tracking and position control of an MRI-powered needle-insertion robot. AB - The excellent imaging capabilities of MRI technology are standardizing this modality for a variety of interventional procedures. To assist radiologists, MRI compatible robots relying on traditional actuation technologies are being developed. Recently, a robot that is not only MRI compatible but also MRI powered was introduced. This surgical robot is imaged and actuated through interleaved MRI pulses, and can be controlled to perform automated needle insertion. Using the electromagnetic field generated by the MRI scanner, the robot can exercise adequate forces to puncture tissue. Towards the goal of automation, this paper reports results on tracking and control of an MRI-powered robot tagged with a fiducial marker. Tracking is achieved using non-selective RF pulses and balanced gradient readouts. To suppress the signal received from the tissue, spoiler gradients and background suppression are introduced. Their effects on tracking are quantified and are used to optimize the algorithm. Subsequently, a Kalman filter is employed for robustness. The developed algorithm is used to demonstrate position controlled needle insertion ex vivo. PMID- 23366046 TI - A new evaluation and training system for micro-telemanipulation at the middle ear. AB - In this article, a new surgical model for evaluating telemanipulators used in middle ear surgery is presented. The purpose of this work was to develop an evaluation and training system which imitates a typical surgical task of middle ear surgery and which can easily be repeated in order to get significant result. The abstract task can be performed manually or by means of a microsurgical telemanipulator and guaranties stable experimental conditions between different subjects at any time. As a task the stapedotomy was chosen, due to the high demands in positioning and in applying forces to the delicate structures in the middle ear. The manual and telemanipulated performance of 15 ENT surgeons and 17 medical students was compared using this evaluation and training system. PMID- 23366047 TI - Difference of perceiving object softness during palpation through single-node and multi-node contacts. AB - Virtual Reality (VR) simulators can offer alternatives for training procedures in the medical field. Most current VR simulators consider single-node contact for interacting with an object to convey displacement and force on a discrete mesh. However, a single-node contact does not closely simulate palpation, which requires a surface made of a multi-node contact to touch a soft object. Thus, we hypothesize that the softness of a deformable object (such as a virtual breast phantom) palpated through a single-node contact would be perceived differently from that of the same phantom palpated through a multi-node contact with various force arrays. We conducted a study to investigate this hypothesis. Using a co located VR setup that aligns visual and haptic stimuli onto a spatial location, we tested 15 human participants under conditions of both visual and haptic stimuli available and only visual (or haptic) stimulus available. In a trial, each participant palpated and discriminated two virtual breast phantoms of same softness through different contacts with varying force arrays. The results of this study revealed that virtual breast phantoms palpated through a single-node contact were constantly perceived harder than their counterparts palpated through a multi-node contact with varying force arrays, when visual stimuli were available. These results imply a constraint for developing a VR system of training palpation. PMID- 23366048 TI - Design of a two degree-of-freedom, MRI-compatible actuator. AB - A novel compact piezoworm actuator for the MRI (Magnetic Resonance Imaging) environment is presented which is capable of both linear and rotary motion. The actuator will be fabricated from beryllium copper for minimal image distortion. Complementary clamps are integrated to minimize the number of drive channels and to act as a brake in case of a malfunction. Analysis was employed to optimize the selection of the piezostacks and flexures depending on their functional requirements. The device is targeting a maximum speed of 5 mm/s, a force thrust of 9 N and 5 rpm of rotational speed. PMID- 23366049 TI - A stiffness probe based on force and vision sensing for soft tissue diagnosis. AB - this paper introduces a novel approach of stiffness measurement based on force and vision sensing for tissue diagnosis. The developed probe is mainly composed of a force sensor and an image acquisition unit capable of obtaining contact area of probe-soft tissue interaction. By measuring the change of diameter of contact area during indentation test, the indentation depth can be determined. The stiffness of target soft tissue then can be evaluated by measuring indentation force and depth simultaneously. The probe can generalize a mechanical image to visualize the stiffness distribution for localization of abnormalities when sliding over soft tissue. The performance of the developed probe was validated by experiments on multiple materials including silicone phantoms and pork organs. The results show that the probe can perform stiffness measurement effectively when the probe indents or slides on the tissue surface. PMID- 23366050 TI - Optical coherence tomography scanning with a handheld vitreoretinal micromanipulator. AB - An active handheld micromanipulator has been developed that is capable of automated intraocular acquisition of B-mode and C-mode optical coherence tomography scans that are up to 4 mm wide. The manipulator is a handheld Gough Stewart platform actuated by ultrasonic linear motors. The manipulator has been equipped with a Fourier-domain common-path intraocular OCT probe that fits within a 25-gauge needle. The paper describes the systems and techniques involved, and presents preliminary results of B-mode and C-mode scans. PMID- 23366051 TI - Needle deflection estimation using fusion of electromagnetic trackers. AB - We present a needle deflection estimation method to compensate for needle bending during insertion into deformable tissue. We combine a kinematic needle deflection estimation model, electromagnetic (EM) trackers, and a Kalman filter (KF). We reduce the impact of error from the needle deflection estimation model by using the fusion of two EM trackers to report the approximate needle tip position in real-time. One reliable EM tracker is installed on the needle base, and estimates the needle tip position using the kinematic needle deflection model. A smaller but much less reliable EM tracker is installed on the needle tip, and estimates the needle tip position through direct noisy measurements. Using a KF, the sensory information from both EM trackers is fused to provide a reliable estimate of the needle tip position with much reduced variance in the estimation error. We then implement this method to compensate for needle deflection during simulated prostate cancer brachytherapy needle insertion. At a typical maximum insertion depth of 15 cm, needle tip mean estimation error was reduced from 2.39 mm to 0.31 mm, which demonstrates the effectiveness of our method, offering a clinically practical solution. PMID- 23366052 TI - Automated drill-stop by SVM classified audible signals. AB - Neuroscience research often requires direct access to brain tissue in animal models which clearly requires opening of the protective cranium. Minimizing animal numbers requests only well-experienced surgeons, since clumsy performance may lead to premature death of the animal. To minimise those traumatic outcomes, an algorithmic approach for closed-loop control of our Spherical Assistant for Stereotaxic Surgery (SASSU) was designed. Controlling the surgical robot's micro drill unit by audio pattern recognition proved to be a simple and reliable way to automatically stop the automated drill feed. Sound analysis based on the anatomical morphology of a rat skull was used to train a Support Vector Machine (SVM) classification of the time-frequency representations of the drill sound. Fully automated high throughput animal surgeries are the goal of this approach. PMID- 23366053 TI - Compensation for relative velocity between needle and soft tissue for friction modeling in needle insertion. AB - Percutaneous therapies and in particular needle insertion treatments require an accurate model of needle-tissue interaction. Friction is a major interaction force component during needle insertion, and force-velocity mapping is an indicator of the interaction characteristics. However, soft tissue deformation is an inevitable and complex phenomenon that should be taken into account in order to correct the friction-velocity cycle. The main purpose of this study is to provide a means of compensating for the velocity of tissue with respect to a moving needle in the insertion direction. A high-gain observer is presented which can track this relative motion in a simple manner with no need for computer vision that may pose further challenges. To evaluate the performance of the velocity observer, experiments were carried out on gelatin and agar phantoms. PMID- 23366054 TI - State-space control of prosthetic hand shape. AB - In the field of neuroprosthetic control, there is an emerging need for simplified control of high-dimensional devices. Advances in robotic technology have led to the development of prosthetic arms that now approach the look and number of degrees of freedom (DoF) of a natural arm. These arms, and especially hands, now have more controllable DoFs than the number of control DoFs available in many applications. In natural movements, high correlations exist between multiple joints, such as finger flexions. Therefore, discrepancy between the number of control and effector DoFs can be overcome by a control scheme that maps low-DoF control space to high-DoF joint space. Imperfect effectors, sensor noise and interactions with external objects require the use of feedback controllers. The incorporation of feedback in a system where the command is in a different space, however, is challenging, requiring a potentially difficult inverse high-DoF to low-DoF transformation. Here we present a solution to this problem based on the Extended Kalman Filter. PMID- 23366055 TI - Assessment of a multigrasp myoelectric control approach for use by transhumeral amputees. AB - The authors have previously developed a multigrasp myoelectric controller, and assessed the ability of healthy subjects to control the configuration of a multigrasp hand prosthesis using musculature on the anterior and posterior aspects of the forearm, as would be representative of controller use by a transradial amputee population. In this paper, the authors conduct a similar study, this time to assess the capability of a transhumeral amputee to control a multigrasp hand from residual musculature on the upper arm. Specifically, experiments are conducted on five healthy subjects, comparing their ability to obtain one of seven hand postures in a virtual prosthesis from EMG measurement of the respective biceps and triceps musculature. The ability to control the virtual hand prosthesis is compared with their ability to do so with their intact hand, as measured by a dataglove. Results indicate an average transition time using the EMG controller on the biceps and triceps of 1.86 seconds, relative to 0.82 seconds with the dataglove. PMID- 23366056 TI - Line following terrestrial insect biobots. AB - The present day technology falls short in offering centimeter scale mobile robots that can function effectively under unknown and dynamic environmental conditions. Insects, on the other hand, exhibit an unmatched ability to navigate through a wide variety of environments and overcome perturbations by successfully maintaining control and stability. In this study, we use neural stimulation systems to wirelessly navigate cockroaches to follow lines to enable terrestrial insect biobots. We also propose a system-on-chip based ZigBee enabled wireless neurostimulation backpack system with on-board tissue-electrode bioelectrical coupling verification. Such a capability ensures an electrochemically safe stimulation and avoids irreversible damage to the interface which is often misinterpreted as habituation of the insect to the applied stimulation. PMID- 23366057 TI - Motion states extraction with optical flow for rat-robot automatic navigation. AB - The real-time acquisition of precise motion states is significant and difficult for bio-robot automatic navigation. In this paper, we propose a real-time video tracking algorithm to extract motion states of rat-robots in complex environment using optical flow. The rat-robot's motion states, including location, speed and motion trend, are acquired accurately in real time. Compared with the traditional methods based on single frame image, our algorithm using consecutive frames provides more exact and rich motion information for the automatic navigation of bio-robots. The video of the manual navigation experiments on rat-robots in eight arm maze is applied to test this algorithm. The average computation time is 25.76 ms which is less than the speed of image acquisition. The results show that our method could extract the motion states with good performance of accuracy and time consumption. PMID- 23366058 TI - A modular, low-cost robot for zebrafish handling. AB - The zebrafish (danio rerio) is one of the most important model organisms in modern drug discovery and disease modeling. Handling and analyzing large numbers of zebrafish larvae require an immense manpower and involve time-consuming manual processes. A novel modular, robotic platform for high-throughput screening is being developed at BioRobotLab (KIT). In this article the fish sorter, which is a robotic device for the automation of a manual process in bio analysis, is presented. The fish sorter detects randomly spread zebrafish eggs and larvae up to an age of 120 hours post fertilization (hpf) in Petri dishes and transfers them to standard 96- or 384- well plates. The robot is controlled by an advanced algorithm with sensor-based process control. Fast and precise hardware components lead to a high working speed and success rate >= 95%. PMID- 23366059 TI - Development of a Lorentz-force actuated intravitreal jet injector. AB - Intravitreal injection is a common treatment in ophthalmology, but it can lead to numerous complications. Needle-free jet injection has been shown to successfully deliver fluid to various layers of skin, and, by its nature, may reduce intravitreal injection complications. From injection trials into ex vivo rabbit eyes, we find that needle-free jet injection can be used for intravitreal drug delivery. A custom-designed control scheme, characterized in this study, is crucial to this delivery. The system is capable of delivering 40 uL of fluid to the posterior vitreous humor, with an injection duration less than 100 ms and scleral entry site less than 350 um in diameter. PMID- 23366060 TI - Novel device to conduct flash-heat treatment in efforts to reduce mother-to-child HIV transmission in low-resource areas. AB - The objective of this design project was to create a device to prevent mother-to child transmission (MTCT) of HIV through breast milk in preterm infants. Our team created a robust and intuitive device which utilizes Flash Heat Treatment (FHT), an established method to inactivate HIV. The FHT method heats jarred breast milk in boiling water for a short amount of time, enough to denature HIV reverse transcriptase while preserving the nutritional value of breast milk. Thorough observation of users and available resources in Cape Town, South Africa enabled establishment of a design that can be used in urban/peri-urban areas. User research conveyed that low cost and effortless household adaptability were the most important elements of the design. As a result, a modified electric kettle was designed to function as a breast milk pasteurization device. Published data illustrating temperature curves during FHT with corresponding virology tests on the pasteurized milk were used to verify whether the device is likely to function effectively. Experimental results indicate that the device matches the required temperature profile. After virology experimentation is complete, the new device may be incorporated into hospitals as well as households in the Cape Town area, and may be expanded to other low resource periurban/urban areas as well. PMID- 23366061 TI - Characteristics of the pulse wave in patients with chronic gastritis and the healthy in Korean medicine. AB - Chronic gastritis is a disease that occurs in one in every 10 persons in Korea. Endoscopic examination is needed to diagnose chronic gastritis in western medicine, but it causes patients pain, long period of examinations and financial burden. In KM (Korean Medicine), on the other hand, it can be known whether stomach is abnormal or not through a pulse diagnosis. The 'Guan' position of the right wrist is related to a stomach in KM. Thus, the pulse wave of the right-hand "Guan" of patients with chronic gastritis and the healthy were measured. Then, the diagnostic parameter and features to distinguish between the patients with chronic gastritis and the healthy were discovered. Through P-H curve, consequently, it can be concluded that the pulse waves of patients with chronic gastritis appear as a floating pulse, whereas the pulse waves of the healthy appear as a normal pulse. PMID- 23366062 TI - Design and usability of a medical computing system for diagnosis of mild traumatic brain injury. AB - In this paper, we present a prototype design of POCTENA (Point-Of-Care Testing Environment for Neurological Assessment), a medical computing system that will be used to assist with diagnosis of mild traumatic brain injury. The design includes an initial set of neurological tests that are built into the system. Component based usability testing was conducted to examine the effectiveness of the user interface. Results from usability testing are then used to suggest possible system design revisions. PMID- 23366063 TI - Multi-microphone adaptive array augmented with visual cueing. AB - We present the development of an audiovisual array that enables hearing aid users to converse with multiple speakers in reverberant environments with significant speech babble noise where their hearing aids do not function well. The system concept consists of a smartphone, a smartphone accessory, and a smartphone software application. The smartphone accessory concept is a multi-microphone audiovisual array in a form factor that allows attachment to the back of the smartphone. The accessory will also contain a lower power radio by which it can transmit audio signals to compatible hearing aids. The smartphone software application concept will use the smartphone's built in camera to acquire images and perform real-time face detection using the built-in face detection support of the smartphone. The audiovisual beamforming algorithm uses the location of talking targets to improve the signal to noise ratio and consequently improve the user's speech intelligibility. Since the proposed array system leverages a handheld consumer electronic device, it will be portable and low cost. A PC based experimental system was developed to demonstrate the feasibility of an audiovisual multi-microphone array and these results are presented. PMID- 23366064 TI - Flow cytometry as a diagnostic method for colorectal cancer. AB - Intraoperative histopathological investigation plays an important role during surgery. Since the pathologist performs a diagnosis with a limited level of specimen, it may sometimes be difficult to reach a correct diagnosis. To improve the accuracy of the diagnosis, quantitative data from the whole specimen are helpful. It said that the detection capability for DNA aneuploidy (aneuploidy) is low for solid cancer compared with hematopoietic organ cancer. A new method that includes fresh tissue is introduced, the histogram from cancer tissue (cancer) and normal tissue (normal) is compared, new classification criteria are introduced, the Fast Fourier Transform (FFT) pattern (FFT pattern) obtained from FFT on the histogram is analyzed, and the area under the FFT pattern of the histogram (AUC) is compared. This method, named the "FFT-AUC method", which includes comparisons of AUC and the FFT pattern, shows good results. PMID- 23366065 TI - A CAD system for atherosclerotic plaque assessment. AB - Recently, several atherosclerotic plaque characterization methods were proposed based on plaque morphology assessed through 2D ultrasound. It is of extreme importance to establish an objective quantification measure which allows the physicians to determine the risk of plaque rupture, and thus, of brain stroke. Having these, sometimes complex, measures easily and quickly assessed might prove invaluable for the physician an patient alike. This paper is a first attempt to incorporate such scores in a user-friendly software platform for Computer-aided Diagnosis. This tool provides a way to objectively and interactively characterize the atherosclerotic plaque, to store relevant patient data and to use several processing tools to outline the plaque and compute different echogenicity measures. Combinations of these features are used to provide two objective measure with clinical significance, known as activity index and enhanced activity index. PMID- 23366066 TI - Spatiotemporal compression for efficient storage and transmission of high resolution electrocorticography data. AB - High-resolution Electrocorticography (HR-ECoG) has emerged as a key strategic technology for recording localized neural activity with high temporal and spatial resolution with potential applications in brain-computer interfaces (BCI), and seizure detection for epilepsy. However, HR-ECoG has 400 times the resolution of conventional ECoG, making it a challenge to process, transmit and store the HR ECoG data. Therefore, simple and efficient compression algorithms are vital for the feasibility of implantable wireless medical devices for HR-ECoG recordings. In this paper, following the observation that HR-ECoG signals have both high spatial and temporal correlations similar to video/image signals, various compression methods suitable for video/image- compression based on motion estimation, discrete cosine transform (DCT) and discrete wavelet transform (DWT)- are investigated for compressing HR-ECoG data. We first simplify these methods to satisfy the low-power requirements for implantable devices. Then, we demonstrate that spatiotemporal compression methods produce up to 46% more data reduction on HR-ECoG data than compression methods using only spatial compression do. We further show that this data reduction can be achieved with low hardware complexity. In particular, among the methods investigated, spatiotemporal compression using DCT-based methods provide the best trade-off between hardware complexity and compression performance, and thus we conclude that DCT-based compression is a promising solution for ultralow-power implantable devices for HR ECoG. PMID- 23366067 TI - Signal subspace integration for improved seizure localization. AB - A subspace signal processing approach is proposed for improved scalp EEG-based localization of broad-focus epileptic seizures, and estimation of the directions of source arrivals (DOA). Ictal scalp EEGs from adult and pediatric patients with broad-focus seizures were first decomposed into dominant signal modes, and signal and noise subspaces at each modal frequency, to improve the signal-to-noise ratio while preserving the original data correlation structure. Transformed (focused) modal signals were then resynthesized into wideband signals from which the number of sources and DOA were estimated. These were compared to denoised signals via principal components analysis (PCA). Coherent subspace processing performed better than PCA, significantly improved the localization of ictal EEGs and the estimation of distinct sources and corresponding DOAs. PMID- 23366068 TI - Combining time series and frequency domain analysis for a automatic seizure detection. AB - The detection of epileptic seizures in long-term electroencephalographic (EEG) recordings is a time-consuming and tedious task requiring specially trained medical experts. The EpiScan seizure detection algorithm developed by the Austrian Institute of Technology (AIT) has proven to achieve high detection performance with a robust false alarm rate in the clinical setting. This paper introduces a novel time domain method for detection of epileptic seizure patterns with focus on irregular and distorted rhythmic activity. The method scans the EEG for sequences of similar epileptiform discharges and uses a combination of duration and similarity measure to decide for a seizure. The resulting method was tested on an EEG database with 275 patients including over 22000h of unselected and uncut EEG recording and 623 seizures. Used in combination with the EpiScan algorithm we increased the overall sensitivity from 70% to 73% while reducing the false alarm rate from 0.33 to 0.30 alarms per hour. PMID- 23366069 TI - Quantification of spontaneous and evoked HFO's in SEEG recording and prospective for pre-surgical diagnostics. Case study. AB - High frequency oscillations (HFO) in stereo electroencephalographic (SEEG) signals have been recently the focus of attention as biomarkers that can have potential predictive power for the spatial location and possibly the timing of the onset of epileptic seizures. In this work we present a case study where we compare two quantitative paradigms for automated detection of biomarkers, one based on spontaneous SEEG recordings of HFOs and the other using activity induced by direct electrical stimulation (relative Phase Clustering Index algorithm). We compare the performance of these automated methods with manually detected HFO ripples by a trained EEG analyst and explore their potential diagnostic relevance. Intracranial recordings from patients undergoing pre-surgical evaluation are processed with a combination of morphological filtering and the analysis of the auto-correlation function. The results were compared to those obtained by visual inspection and to results from an active paradigm involving stimulation with 20 Hz trains of biphasic pulses. The quantity of HFOs, estimated automatically, or "rippleness", was found to correspond to the findings of a trained EEG analyst. The relative phase clustering index (rPCI) obtained using periodic stimulation appeared to be associated with the closeness to the seizure onset zone (SOZ) detected from ictal epochs. The HFO estimates were also indicative for the SOZ but with less specificity. PMID- 23366070 TI - Electroencephalographic events prior to epileptic major motor seizures. AB - RATIONALE: The goal of this study is to evaluate the electroencephalographic (EEG) events, prior to clonic phases of epileptic motor seizures. Analyzing video sequences we were able to detect these special phases of motor seizures, by image features. This can be used for an early detection and alerting for these events. In the study we analyzed 42 seizures. Based on collected data we compare the quantitative results from video detection of seizures with the features computed from EEG scalp recordings from about 3 minutes prior to the seizure. We analyze the non-stationary frequency spectrum of the EEG recordings and match it against our automated video detection output in order to investigate possible precursory EEG events. METHODS: Video recordings are analyzed by applying optical flow theory, reconstruction of geometrical flow invariants, low and high pass filtering, and suitable normalizations. EEG recordings are processed with use of a Gabor wavelet technique. Comparison is achieved by means of analysis of the cross-correlation function between the derivatives of the Gabor amplitudes and the measure of "seizureness" produced by our video detection algorithm. RESULTS: In the present study certain ranges of EEG frequencies were found, where electro graphical events precede clonic phases of clinical motor seizures from 2-8 up to 30-40 seconds. These results could be used for construction of new generation of methods for automated motor seizure detection. PMID- 23366071 TI - Phase-based brain consciousness analysis. AB - This work provides a novel framework for identifying coma and brain death consciousness states by analysing frequency power and phase synchrony features from electroencephalogram (EEG). The proposed analysis of pairs of EEG electrodes using complex extensions of Empirical Mode Decomposition (EMD) permits the extraction of information related to the state of the brain function. Analysis on 34 subjects in the coma and quasi-brain-death states suggests that phase synchrony constitutes a feasible feature to discriminate quasi-brain-death from coma state. Thus, illustrate the effectiveness of the proposed methods for brain consciousness identification. The predictive power of the features extracted is evaluated by building classification models using support vector machine (SVM) and evaluation the models through receiver operating characteristic (ROC) analysis. PMID- 23366072 TI - Performance bounds for dynamic causal modeling of brain connectivity. AB - The use of complex dynamical models have been proposed for describing the connections and causal interactions between different regions of the brain. The goal of these models is to accurately mimic the event-related potentials observed by EEG/MEG measurement systems, and are useful in understanding overall brain functionality. In this paper, we focus on a class of nonlinear dynamic causal models (DCM) that are described by a set of connectivity parameters. In practice, the DCM parameters are inferred using data obtained by an EEG or MEG sensor array in response to a certain event or stimulus, and the resulting estimates are used to analyze the strength and direction of the causal interactions between different brain regions. The usefulness of the parameter estimates will depend on how accurately they can be estimated, which in turn will depend on noise, the sampling rate, number of data samples collected, the accuracy of the source localization and reconstruction steps, etc. The goal of this paper is to derive Cramer-Rao performance bounds for DCM estimates, and examine the behavior of the bounds under different operating conditions. PMID- 23366073 TI - Estimating electrical conductivity tensors of biological tissues using microelectrode arrays. AB - Finding the electrical conductivity of tissue is important for understanding the tissue's structure and functioning. However, the inverse problem of inferring spatial conductivity from data is highly ill-posed and computationally intensive. In this paper, we propose a novel method to solve the inverse problem of inferring tissue conductivity from a set of transmembrane potential and stimuli measurements made by microelectrode arrays (MEA). We propose a parallel optimization algorithm based on a single-step approximation with a parallel alternating optimization routine. This algorithm simplifies the joint tensor field estimation problem into a set of computationally tractable subproblems, allowing the use of efficient standard optimization tools. PMID- 23366074 TI - Quantitative performance analysis of four methods of evaluating signal nonlinearity: application to uterine EMG signals. AB - Recently, much attention has been paid to the use of nonlinear analysis techniques for the characterization of biological signals. Several measures have been proposed to detect nonlinear characteristics in time series. The sensitivity of several nonlinear methods to the actual nonlinearity level and their sensitivity to noise have never been evaluated. In this paper we perform this analysis for four methods that are widely used in nonlinearity detection: Time reversibility, Sample Entropy, Lyapunov Exponents and Delay Vector Variance. The evolution of methods with complexity degree (CD) and with different Signal to Noise Ratio was computed for the four methods on nonlinear synthetic signals. The methods were then applied to real uterine EMG signals with the aim of using them to distinguish between pregnancy and labor signals. The results show a clear superiority of the Time reversibility method, in classification of pregnancy and labor signals. PMID- 23366075 TI - Nonlinear analysis of the change points between A and B phases during the Cyclic Alternating Pattern under normal sleep. AB - This study analyzes the nonlinear properties of the EEG at transition points of the sequences that build the Cyclic Alternating Pattern (CAP). CAP is a sleep phenomenon built up by consecutive sequences of activations and non-activations observed during the sleep time. The sleep condition can be evaluated from the patterns formed by these sequences. Eleven recordings from healthy and good sleepers were included in this study. We investigated the complexity properties of the signal at the onset and offset of the activations. The results show that EEG signals present significant differences (p<0.05) between activations and non activations in the Sample Entropy and Tsallis Entropy indices. These indices could be useful in the development of automatic methods for detecting the onset and offset of the activations, leading to significant savings of the physician's time by simplifying the manual inspection task. PMID- 23366076 TI - Multi-sparse signal recovery for compressive sensing. AB - Signal recovery is one of the key techniques of compressive sensing (CS). It reconstructs the original signal from the linear sub-Nyquist measurements. Classical methods exploit the sparsity in one domain to formulate the L0 norm optimization. Recent investigation shows that some signals are sparse in multiple domains. To further improve the signal reconstruction performance, we can exploit this multi-sparsity to generate a new convex programming model. The latter is formulated with multiple sparsity constraints in multiple domains and the linear measurement fitting constraint. It improves signal recovery performance by additional a priori information. Since some EMG signals exhibit sparsity both in time and frequency domains, we take them as example in numerical experiments. Results show that the newly proposed method achieves better performance for multi sparse signals. PMID- 23366077 TI - Nonlinear dynamics measures applied to EEG recordings of patients with attention deficit/hyperactivity disorder: quantifying the effects of a neurofeedback treatment. AB - This work presents the application of nonlinear dynamics measures to electroencephalograms (EEG) acquired from patients with Attention Deficit/Hyperactivity Disorder (ADHD) before and after a neurofeedback therapy, with the aim to assess the effects of the neurofeedback in a quantitative way. The database contains EEG registers of seven patients acquired in eyes-closed and eyes-opened conditions, in pre-and post-treatment phases. Five measures were applied: largest Lyapunov exponent, Lempel-Ziv complexity, Hurst exponent, and multiscale entropy on two different scales. The purpose is to test whether these measures are apt to detect and quantify differences from EEG registers between pre- and post-treatment. The results indicate that these measures could have a potential utility for detection of quantitative changes in specific EEG channels. In addition, the performance of some of these measures improved when the bandwidth was reduced to 3-30 Hz. PMID- 23366078 TI - Low complexity algorithm for seizure prediction using Adaboost. AB - This paper presents a novel low-complexity patient-specific algorithm for seizure prediction. Adaboost algorithm is used in two stages of the algorithm: feature selection and classification. The algorithm extracts spectral power features in 9 different sub-bands from the electroencephalogram (EEG) recordings. We have proposed a new feature ranking method to rank the features. The key (top ranked) features are used to make a prediction on the seizure event. Further, to reduce the complexity of classification stage, a non-linear classifier is built based on the Adaboost algorithm using decision stumps (linear classifier) as the base classifier. The proposed algorithm achieves a sensitivity of 94.375% for a total of 71 seizure events with a low false alarm rate of 0.13 per hour and 6.5% of time spent in false alarms using an average of 5 features for the Freiburg database. The low computational complexity of the proposed algorithm makes it suitable for an implantable device. PMID- 23366079 TI - A universal hybrid decision tree classifier design for human activity classification. AB - A system that reliably classifies daily life activities can contribute to more effective and economical treatments for patients with chronic conditions or undergoing rehabilitative therapy. We propose a universal hybrid decision tree classifier for this purpose. The tree classifier can flexibly implement different decision rules at its internal nodes, and can be adapted from a population-based model when supplemented by training data for individuals. The system was tested using seven subjects each monitored by 14 triaxial accelerometers. Each subject performed fourteen different activities typical of daily life. Using leave-one out cross validation, our decision tree produced average classification accuracies of 89.9%. In contrast, the MATLAB personalized tree classifiers using Gini's diversity index as the split criterion followed by optimally tuning the thresholds for each subject yielded 69.2%. PMID- 23366080 TI - Improving seizure detection performance reporting: analysing the duration needed for a detection. AB - Improving seizure detection performance relies not only on novel signal processing approaches but also on new accurate, reliable and comparable performance reporting to give researchers better and fairer tools for understanding the true algorithm operation. This paper investigates the sensitivity of current performance metrics to the duration of data that must be marked as candidate seizure activity before a seizure detection is made. The results demonstrate that not all metrics are insensitive to this high level choice in the algorithm design, and provide new approaches for comparing between reported algorithm performances in a robust and reliable manner. PMID- 23366081 TI - A novel dictionary for neonatal EEG seizure detection using atomic decomposition. AB - The development of automated methods of electroencephalogram (EEG) seizure detection is an important problem in neonatology. This paper proposes improvements to a previously described method of seizure detection based on atomic decomposition by developing a new time-frequency (TF) dictionary that is highly coherent with the newborn EEG seizure. We compare the performance of the proposed dictionary on neonatal EEG signals with that achieved using Gabor, Fourier and wavelet dictionaries. Through the analysis of real newborn EEG data, we show first, that dictionary selection can influence the seizure detection accuracy and second, that the proposed dictionary outperforms other dictionaries by at least 10% in seizure detection accuracy and 5% improvement in the area under the Receiver Operator Characteristic curve. PMID- 23366082 TI - Activity recognition using dynamic multiple sensor fusion in body sensor networks. AB - Multiple sensor fusion is a main research direction for activity recognition. However, there are two challenges in those systems: the energy consumption due to the wireless transmission and the classifier design because of the dynamic feature vector. This paper proposes a multi-sensor fusion framework, which consists of the sensor selection module and the hierarchical classifier. The sensor selection module adopts the convex optimization to select the sensor subset in real time. The hierarchical classifier combines the Decision Tree classifier with the Naive Bayes classifier. The dataset collected from 8 subjects, who performed 8 scenario activities, was used to evaluate the proposed system. The results show that the proposed system can obviously reduce the energy consumption while guaranteeing the recognition accuracy. PMID- 23366083 TI - A new method to estimate abundances of multiple components using multi-spectral fluorescence lifetime imaging microscopy. AB - Multi-Spectral Fluorescent Lifetime Imaging Microscopy (m-FLIM) is a technique that aims to perform noninvasive in situ clinical diagnosis of several diseases. It measures the endogenous fluorescence of molecules, recording their lifetime decay in different wavelength bands. This signal is a mixed response of multiple fluorescent components present in a tissue sample. The goal is to decompose the mixture and estimate the proportional contributions of its constituents. Estimation of such quantitative description will help to characterize the molecular constitution of a given sample. This paper presents a new method to estimate the abundances of multiple components present in a mixture measured using m-FLIM data. It provides a closed-form solution under the fully constrained linear unmixing model and assuming the number of components as well as their ideal lifetime decays are known. Its performance is tested using synthetic samples with three components, where performance can be measured accurately and the percentage error is around 6%. The algorithm was also validated performing unmixing of ex vivo data samples from atherosclerotic human tissue containing collagen, elastin and low-density lipoproteins. These experiments were validated against ground-truth maps, which only give a quantitative description, and the estimated accuracy was around 88%. PMID- 23366084 TI - Evaluation of an image-based tracking workflow using a passive marker and resonant micro-coil fiducials for automatic image plane alignment in interventional MRI. AB - In this paper, an original workflow is presented for MR image plane alignment based on tracking in real-time MR images. A test device consisting of two resonant micro-coils and a passive marker is proposed for detection using image based algorithms. Micro-coils allow for automated initialization of the object detection in dedicated low flip angle projection images; then the passive marker is tracked in clinical real-time MR images, with alternation between two oblique orthogonal image planes along the test device axis; in case the passive marker is lost in real-time images, the workflow is reinitialized. The proposed workflow was designed to minimize dedicated acquisition time to a single dedicated acquisition in the ideal case (no reinitialization required). First experiments have shown promising results for test-device tracking precision, with a mean position error of 0.79 mm and a mean orientation error of 0.24 degrees . PMID- 23366085 TI - Engineering of 7T transmit multi-row arrays. AB - In evaluation of RF transmit array coils, realistic estimation of losses were included in simulations with the aim of obtaining a better match between experimental results and numerical predictions. This required customized design of lossy circuit components, to overcome the limitation of the available built-in capabilities of current simulation tools. Some of the more time-consuming post processing stages were relocated into Matlab, speeding post-processing by up to a factor of 100. The resulting numerical data can support the fabrication of dual row array with as many as 8 elements in each row, and elements overlapped in the Z direction. PMID- 23366086 TI - Gradient-excitation encoding combined with frequency and phase encodings for three-dimensional ultra-low-field MRI. AB - Ultra-low-field magnetic resonance imaging (ULF MRI) in microtesla fields is a new technology with features unseen in tesla-range MRI. Instead of induction coils as sensors, superconducting quantum interference device (SQUID) sensors are used, providing a frequency-independent signal-to-noise ratio (SNR). Owing to its tolerance for large relative imaging-field inhomogeneities, electromagnet shimming is not necessary. ULF MRI can also be combined with magnetoencephalography (MEG) to image the brain with close to millimetre millisecond resolution. In this paper, the hybrid MEG-MRI device developed at Aalto University will be presented, as well as a 3D imaging scheme combining gradient-excitation encoding with frequency and phase and encodings. It is noteworthy that, regarding the presented gradient-excitation encoding in ULF MRI, the kilohertz-range Larmor frequencies allow MR signals to propagate unattenuated through tissue, which is not the case in tesla-range MRI with Larmor frequencies even above 100 MHz. Thus, the presented encoding method is especially compatible with ULF MRI, where the use of three different encoding mechanisms for three dimensional imaging is possible. The feasibility of image reconstruction with the gradient-excitation-encoding method is demonstrated by simulations. PMID- 23366087 TI - Hign acceleration with a rotating radiofrequency coil array (RRFCA) in parallel magnetic resonance imaging (MRI). AB - This study explores the performance of a novel hybrid technology, in which the recently introduced rotating RF coil (RRFC) was combined with the principles of Parallel Imaging (PI) to improve the quality and speed of magnetic resonance (MR) images. To evaluate the system, a low-density naturally-decoupled 4-channel rotating radiofrequency coil array (RRFCA) was modelled and investigated. The traditional SENSitivity Encoding (SENSE) reconstruction method and the means of calculating the geometry factor distribution (g map) were adapted to take into account the transient sensitivity encoding. It was found from simulations at 3T that, continuous rotating motion considerably enhanced the coil sensitivity encoding capability, making higher reduction factors in scan time possible. The sensitivity encoding capability can be further improved by choosing an optimal speed of array rotation. Compared to traditional phased-array coils (PACs) with twice as many coil elements, the RRFCA demonstrated clear advantages in terms of quality of reconstruction and superior noise behaviour in all the cases investigated in this initial study. PMID- 23366088 TI - A novel fast algorithm for parallel excitation: pulse design in MRI. AB - Spatially selective excitations with parallel transmitters have been regarded as a key in solving several high field MRI problems such as inhomogeneity correction and reducing specific absorption rate. However, three-dimensional pulse design in general is very time consuming which may prevent it from real-time applications. In this work, we explore the sparsity in the pulse design system equation. The size of system equation is reduced after a sparse transform and therefore design speed can be significantly increased. Computer simulations in several common scenarios show that the proposed design method can achieve up to an order of magnitude speedup than the conventional design methods while maintaining similar excitation accuracy. PMID- 23366089 TI - Accelerated phosphorus magnetic resonance spectroscopic imaging using compressed sensing. AB - This study aims at assessing the performance of compressed sensing method for faster phosphorus magnetic resonance spectroscopic imaging ((31)P-MRSI) of human brain. A simulated 2D (31)P-MRSI dataset containing a tumor region and a healthy region was created based on the metabolite peak intensities and ratios of a volunteer dataset acquired at 3T. k-space data was randomly undersampled, and reconstructed using compressed sensing algorithm. This simulation study showed that compressed sensing reconstruction could be applied for faster (31)P-MRSI. Future studies will measure the performance of compressed sensing reconstruction for (31)P-MRSI in volunteers and patients with brain tumors. PMID- 23366090 TI - Quantitative volumetric breast imaging with 3D inverse scatter computed tomography. AB - A method was developed to map tissue properties of the entire breast including sound speed and attenuation using fully 3D nonlinear inverse-scattering tomography. Clinical measurements suggest that in breast tissue benign and cancerous lesions may be identified in part by these inherent acoustic parameters. Sound speed accuracy and linearity are very high over a wide range (1325-1700 m/sec) with ~1.5 mm resolution at 2 MHz in transmission mode. Attenuation tomograms provide image contrast over a wide range (0-4 dB/cm/MHz) and assist classification of masses. High resolution 0.6 mm volumetric reflection tomograms are acquired with bandwidth 2-8 MHz, are refraction-corrected with the transmission tissue data and are precisely registered in 3D with the transmission volumes. USCT promises an automated whole-breast scan providing a global view of the entire breast in 3D, facilitating comparison to prior exams in a reproducible geometry. Scanner design, automated operation and results of our trial with over 125 subjects with confirmed breast masses will be presented with detailed comparison to conventional sonography and MRI. PMID- 23366091 TI - Three-dimensional quantitative ultrasound to guide pathologists towards metastatic foci in lymph nodes. AB - The detection of metastases in freshly-excised lymph nodes from cancer patients during lymphadenectomy is critically important for cancer staging, treatment, and optimal patient management. Currently, conventional histologic methods suffer a high rate of false-negative determinations because pathologists cannot evaluate each excised lymph nodes in its entirety. Therefore, lymph nodes are undersampled and and small but clinically relevant metastatic regions can be missed. In this study, quantitative ultrasound (QUS) methods using high-frequency transducers (i.e., > 20 MHz) were developed and evaluated for their ability to detect and guide pathologists towards suspicious regions in lymph nodes. A custom laboratory scanning system was used to acquire radio-frequency (RF) data in 3D from excised lymph nodes using a 26-MHz center-frequency transducer. Overlapping 1-mm cylindrical regions-of-interest (ROIs) of the RF data were processed to yield 13 QUS estimates quantifying tissue microstructure and organization. These QUS methods were applied to more than 260 nodes from more than 160 colorectal-, gastric-, and breast-cancer patients. Cancer-detection performance was assessed for individual estimates and linear combinations of estimates. ROC results demonstrated excellent classification. For colorectal- and gastric-cancer nodes, the areas under the ROC curves (AUCs) were greater than 0.95. Slightly poorer results (AUC=0.85) were obtained for breast-cancer nodes. Images based on QUS parameters also permitted localization of cancer foci in some micrometastatic cases. PMID- 23366092 TI - Quantitative ultrasound from single cells to biophantoms to tumors. AB - There is no underestimating the importance of modern imaging to the improved detection and management of diseases such as cancer. Ultrasound offers a cost effective and safe modern imaging modality. A quantitative approach, termed quantitative ultrasound (QUS), offers the capability to examine the anatomic microstructure of tissue, hence opening up opportunities to quantify/diagnose such microstructure. One approach to improve specificity with QUS techniques, a model-based approach, is to develop ultrasonic scattering models that match the anatomic geometry of the tissue type under investigation. To do so, an approach from simple (individual cells) to moderate complexity (groupings of cells imbedded in a supportive structure) to significant complexity (actual tissue/tumors) has merit, especially if the degrees of complexity are with the same cell type. Therefore, an approach for improved imaging capabilities with quantitative ultrasound is that from single cells to biophantoms to tumors, and is discussed herein. PMID- 23366093 TI - Cortical bone quality assessment using quantitative ultrasound on long bones. AB - The potential of ultrasonic guided waves to identify geometrical and elastic properties of long cortical bone was tested in this feasibility study. In this paper, we present the general framework of the inversion process applied to guided waves measurements performed on test cases and on one in vitro sample of human long cortical bone (forearm). Test cases were flat plates of bone mimicking material. Cortical thickness and direction dependent elastic properties of a long cortical bone were identified from ultrasound guided waves measurements. While the results need to be confirmed on a large set of bone specimens, this study opens new perspectives for axial transmission technique, due to the fact that measurements were performed under actual conditions of clinical measurements, i.e. with a probe and a signal processing dedicated to clinical use. PMID- 23366094 TI - Quantitative ultrasound visualization of cell death: emerging clinical applications for detection of cancer treatment response. AB - Differentiable echogeneities exhibited by living and dead cells enables the monitoring of cell death response via quantitative ultrasound techniques at high frequencies and recently at clinical range frequencies. Such capability can be potentially employed to provide rapid and quantitative functional information in real time, and at the patient bedside for evaluating therapy response early following treatment. This paper summarizes backgrounds on quantitative ultrasound visualization of cell death and highlights its potential capabilities for monitoring cancer treatment response, where favorable results have been reported, according to a recent pilot clinical study. PMID- 23366096 TI - Non-rigid multimodal image registration based on local variability measures and optical flow. AB - In this paper, we present a novel methodology for multimodal non-rigid medical image registration. The proposed approach is based on combining an optical flow technique with a pixel intensity transformation by using a local variability measure, such as statistical variance or Shannon entropy. The methodology is basically composed by three steps: first, we approximate the global deformation using a rigid registration based on a global optimization technique, called particle filtering; second, we transform both target and source images into a new intensity space where they can be compared; and third, we obtain the optical flow between them by using the Horn and Shuck algorithm in an iterative scales-space framework. After these steps, the non-rigid registration is made up by adding the resulting vector fields, computed by the rigid registration, and the optical flow. The proposed algorithm was tested using a synthetic intensity mapping and non-rigid deformation of MRI images. Preliminary results show that the methodology seems to be a good alternative for non-rigid multimodal registration, obtaining an average error of less than two pixels in the estimation of the deformation vector field. PMID- 23366095 TI - Two solutions for registration of ultrasound to MRI for image-guided prostate interventions. AB - Ultrasound-guided prostate interventions could benefit from incorporating the radiologic localization of the tumor which can be acquired from multiparametric MRI. To enable this integration, we propose and compare two solutions for registration of T2 weighted MR images with transrectal ultrasound. Firstly, we propose an innovative and practical approach based on deformable registration of binary label maps obtained from manual segmentation of the gland in the two modalities. This resulted in a target registration error of 3.6+/-1.7 mm. Secondly, we report a novel surface-based registration method that uses a biomechanical model of the tissue and results in registration error of 3.2+/-1.3 mm. We compare the two methods in terms of accuracy, clinical use and technical limitations. PMID- 23366097 TI - Precision analysis of a multi-slice ultrasound sensor for non-invasive 3D kinematic analysis of knee joints. AB - Currently the standard clinical practice for measuring the motion of bones in a knee joint with sufficient precision involves implanting tantalum beads into the bones to act as fiducial markers prior to imaging using X-ray equipment. This procedure is invasive in nature and exposure to ionizing radiation imposes a cancer risk and the patient's movements are confined to a narrow field of view. In this paper, an ultrasound based system for non-invasive kinematic evaluation of knee joints is proposed. The results of an initial analysis show that this system can provide the precision required for non-invasive motion analysis while the patient performs normal physical activities. PMID- 23366098 TI - Medical image registration using sparse coding and belief propagation. AB - Recently, various medical imaging such as CT and MRI imaging has been used more and more widely in clinical and medical research. As a result, there is an increasing interest in accurately relating information in different images for diagnosis, treatment, and the sake of basic science. As images are typically acquired at different times and often by different modalities, registering (or aligning) one image with another is not a simple task in general and it success will affect the effectiveness and accuracy of all subsequent analysis. We propose an efficient medical image registration method based on sparse coding and belief propagation for medical CT imaging. We used 3-D image blocks as features, and then we employed sparse coding to find a set of candidate voxels. To select optimum matches, belief propagation was subsequently applied on these candidate voxels. The outcome of belief propagation was interpreted as probabilistic map between candidate voxels and source voxel. We compared with the state-of-the-art of medical image registration, MIRT and GP-Registration algorithm. Our objective results based on RMSE (Root Mean Square Error) are smaller than those from MIRT and GP-Registration. Our results also proved the effectiveness of our algorithm in registering reference image to source image. PMID- 23366099 TI - Research on 2D representation method of wireless Micro-Ball endoscopic images. AB - Nowadays the interpretation of the images acquired by wireless endoscopy system is a tedious job for doctors. A viable solution is to construct a map, which is the 2D representation of gastrointestinal (GI) tract to reduce the redundancy of images and improve the understandability of them. The work reported in this paper addresses the problem of the 2D representation of GI tract based on a new wireless Micro-Ball endoscopy system with multiple image sensors. This paper firstly models the problem of constructing the map, and then discusses mainly on the issues of perspective distortion correction, image preprocessing and image registration, which lie in the whole problem. The perspective distortion correction algorithm is realized based on attitude angles, while the image registration is based on phase correlation method (PCM) and scale invariant feature transform (SIFT) combined with particular image preprocessing methods. Based on R channels of images, the algorithm can deal with 26.3% to 100% of image registration when the ratio of overlap varies from 25% to 80%. The performance and effectiveness of the algorithms are verified by experiments. PMID- 23366100 TI - Detecting distance between injected microspheres and target tumor via 3D reconstruction of tissue sections. AB - One treatment increasing in use for solid tumors in the liver is radioembolization via the delivery of (90)Y microspheres to the vascular bed within or near the location of the tumor. It is desirable as part of the treatment for the microspheres to embed preferentially in or near the tumor. This work details an approach for analyzing the deposition of microspheres with respect to the location of the tumor. The approach used is based upon thin-slice serial sectioning of the tissue sample, followed by high resolution imaging, microsphere detection, and 3-D reconstruction of the tumor surface. Distance from the microspheres to the tumor was calculated using a fast deterministic point inclusion method. PMID- 23366101 TI - A comprehensive method for magnetic sensor calibration: a precise system for 3-D tracking of the tongue movements. AB - Magnetic localization has been used in a variety of applications, including the medical field. Small magnetic tracers are often modeled as dipoles and localization has been achieved by solving well-defined dipole equations. However, in practice, the precise calculation of the tracer location not only depends on solving the highly nonlinear dipole equations through numerical algorithms but also on the precision of the magnetic sensor, accuracy of the tracer magnetization, and the earth magnetic field (EMF) measurements. We have developed and implemented a comprehensive calibration method that addresses all of the aforementioned factors. We evaluated this method in a bench-top setting by moving the tracer along controlled trajectories. We also conducted several experiments to track the tongue movement in a human subject. PMID- 23366102 TI - Development and preliminary evaluation of an intraoral Tongue Drive System. AB - Tongue Drive System (TDS) is a wireless tongue-operated assistive technology (AT), developed for people with severe physical impediments to control their environments using their tongue motion. We have developed a new intraoral TDS (iTDS) in a form of a dental retainer, which can tightly clasp onto the upper teeth, completely hidden inside the mouth, using commercial off-the-shelf components (COTS). The iTDS retainer was tested by two healthy subjects and their performance was compared with that of an external TDS (eTDS) implemented in the form of a headset. The iTDS retainer showed comparable performance with the eTDS headset. The iTDS is expected to improve the stability and robustness of the TDS, while giving users a certain degree of privacy. PMID- 23366103 TI - A neonatal thorax phantom for contact-less magnetic induction vitalparameter monitoring. AB - For contact-less monitoring of breathing and heart activity, magnetic induction measurements are applicable. For research and the development process of hardware and algorithms for parameter extraction, test cases are computer simulations, animal trials and, at the end, human trials. However, in the first development processes human trials are not suitable due to ethical reasons. Simliarly, animal trials may not be reasonable for only testing different amplifier approaches or basic testing of new coil configurations. There, computer simulations are the only available benchmarks but not suitable for every problem. In this article, we present a neonatal thorax phantom for emulation of lung and heart activity for magnetic induction systems as a test platform. PMID- 23366104 TI - Evolutionary coil design for maximally uniform magnetic fields. AB - Magnetic fields and their applications in medicine and biology are an active area of research in recent years. Some of these applications include chronic wound healing, electrical stimulation of cardiac tissue and medical imaging among others. The effectiveness of these applications strongly relies on the uniformity of the field, a feature closely related to the arrangement of the coils that generates it. In this paper, genetic algorithms are used to create appropriate arrangements of coils in order to generate a field with a wide volume of uniformity. Results show that the proposed methodology is an effective tool for designing coil arrangements capable of generating magnetic field within an arbitrary volume of interest in which field uniformity is higher than in designs using a traditional approach. PMID- 23366105 TI - A novel magnetic plethysmograph for non-invasive evaluation of arterial compliance. AB - Noninvasive evaluation of arterial compliance by measurement of Pulse Wave Velocity (PWV) has proven utility in cardiovascular screening. We present the design of a novel Magnetic PlethysmoGraph (MPG) for non-invasive estimation of PWV. The system uses a Giant Magneto Resistance (GMR) sensor to detect the fluctuations caused by blood flow in an ambient magnetic field encompassing the blood vessel. The design of an Electro Magnet (EM) based MPG transducer is presented. The ability of the proposed transducer to detect the blood pulse waveform is verified by in-vivo tests and an occlusion test. The design is further validated by demonstrating in-vivo measurements of carotid to radial artery PWV. The design of a dual element transducer for evaluation of local PWV is also presented. The proposed dual element plethysmograph is capable of measuring PWV over sections of the arterial tree as small as 15 mm. PMID- 23366106 TI - Study on technology of high-frequency pulsed magnetic field strength measurement. AB - High-frequency transient weak magnetic field is always involved in researches about biomedical engineering field while common magnetic-field sensors cannot work properly at frequencies as high as MHz. To measure the value of MHz-level weak pulsed magnetic-field strength accurately, this paper designs a measurement and calibration method for pulsed magnetic-field. In this paper, a device made of Nonferromagnetic material was independently designed and applied to pulsed magnetic field measurement. It held an accurately relative position between the magnetic field generating coil and the detecting coil. By applying a sinusoidal pulse to the generator, collecting the induced electromotive force of the detector, the final magnetic field strength was worked out through algorithms written in Matlab according to Faraday's Law. Experiments were carried out for measurement and calibration. Experiments showed that, under good stability and consistency, accurate measurement of magnetic-field strength of a sinepulse magnetic-field can be achieved, with frequency at 0.5, 1, 1.5 MHz and strength level at micro-Tesla. Calibration results carried out a measuring relative error about 2.5%. PMID- 23366107 TI - Atrial fibrillation detection using a smart phone. AB - We hypothesized that an iPhone 4s can be used to detect atrial fibrillation (AF) based on its ability to record a pulsatile photoplethysmogram (PPG) signal from a fingertip using the built-in camera lens. To investigate the capability of the iPhone 4s for AF detection, 25 prospective subjects with AF pre- and post electrical cardioversion were recruited. Using an iPhone 4s, we collected 2 minute pulsatile time series. We investigated 3 statistical methods consisting of the Root Mean Square of Successive Differences (RMSSD), the Shannon entropy (ShE) and the Sample entropy (SampE), which have been shown to be useful tools for AF assessment. The beat-to-beat accuracy for RMSSD, ShE and SampE was found to be 0.9844, 0.8494 and 0.9552, respectively. It should be recognized that for clinical applications, the most relevant objective is to detect the presence of AF or normal sinus rhythm (NSR) in the data. Using this criterion, we achieved an accuracy of 100% for both detecting the presence of either AF or NSR. PMID- 23366108 TI - High-efficiency diffuse Raman spectroscopy through a fiber bundle. AB - Conventional spectrometers are limited in the amount of light they accept because of the requirement for narrow input apertures. A trade-off must generally be made between spectral resolution and input aperture width. This is especially a problem for performing spectroscopy on diffuse sources, such as with tissue, from which signal light has a broad spatial distribution. We introduce a method for achieving good spectral resolution from a fiber bundle input. The image of a fiber bundle has a characteristic structure. By distorting this image optically, we generate a pseudo-orthogonal intensity mask at the input of the spectrometer. The pseudo-orthogonal properties of the mask then allow decoupling at the detector plane of wavelength from spatial position. As long as the distorted image of the fiber bundle is well known, a spectrum can be recovered with spectral resolution equivalent to that of a conventional slit-based spectrometer. We demonstrate successful recovery of narrowly spaced spectral features as well as Raman spectra from a highly scattering sample with this method. This method enables probes with much higher throughputs and add fiber bundle-based spectroscopy to endoscopic designs. PMID- 23366109 TI - Custom visible to infrared, multi-wavelength light emitters for pulse oximeter applications. AB - Compact multi-wavelength light sources have been developed to provide flexibility in pulse oximeter device design. Advantages of these light sources include emitting light of multiple wavelengths with a constant ratio of intensity, and a co-linear light propagation path through tissue. These devices can function as normal pulse oximeter to determine oxygen saturation and pulse rate, but this approach potentially reduces circuit complexity, reduces motion artifacts and enables multi-wavelength sensing of different forms of hemoglobin or other blood products. PMID- 23366110 TI - Accuracy and robustness of Kinect pose estimation in the context of coaching of elderly population. AB - The Microsoft Kinect camera is becoming increasingly popular in many areas aside from entertainment, including human activity monitoring and rehabilitation. Many people, however, fail to consider the reliability and accuracy of the Kinect human pose estimation when they depend on it as a measuring system. In this paper we compare the Kinect pose estimation (skeletonization) with more established techniques for pose estimation from motion capture data, examining the accuracy of joint localization and robustness of pose estimation with respect to the orientation and occlusions. We have evaluated six physical exercises aimed at coaching of elderly population. Experimental results present pose estimation accuracy rates and corresponding error bounds for the Kinect system. PMID- 23366111 TI - Dyskinesia and motor state detection in Parkinson's disease patients with a single movement sensor. AB - Parkinson's Disease (PD) is a neurodegenerative disease that alters the patients' motor performance. Patients suffer many motor symptoms: bradykinesia, dyskinesia and freezing of gait, among others. Furthermore, patients alternate between periods in which they are able to move smoothly for some hours (ON state), and periods with motor complications (OFF state). An accurate report of PD motor states and symptoms will enable doctors to personalize medication intake and, therefore, improve response to treatment. Additionally, real-time reporting could allow an automatic management of PD by means of an automatic control of drug administration pump doses. Such a system must be able to provide accurate information without disturbing the patients' daily life activities. This paper presents the results of the MoMoPa study classifying motor states and dyskinesia from 20 PD patients by using a belt-worn single tri-axial accelerometer. The algorithms obtained will be validated in a further study with 15 PD patients and will be enhanced in the REMPARK project. PMID- 23366112 TI - Quantifying freezing of gait in Parkinson's disease during the instrumented timed up and go test. AB - Over half of patients with PD eventually develop freezing of gait (FoG), an intermittent failure to initiate or maintain walking that is often associated with trembling of the legs. We tested 21 PD with FoG, 27 PD without FoG, and 21 healthy elderly people in a clinic with the Intrumented Timed Up and Go test (ITUG). FoG was quantified from the power spectral density of the antero posterior shank acceleration from which a Frequency Ratio was calculated as the square of the total power in the 3-8 Hz band, divided by the square of the total power in the .5-3 Hz band. Spatiotemporal gait parameters calculated from synchronized gyroscopes on the two legs were also measured in these subjects. The Frequency Ratio was significantly larger in freezers than in non-freezers or control subjects. It better differentiated gait disorders between PD subjects with and without FoG than traditional gait measures such as stride length, stride velocity and double support time. The Frequency Ratio was validated as significantly correlated with self-perceived severity of gait and balance confidence. This Freezing Ratio will be useful to quantify FoG during a simple ITUG, a popular clinical test of mobility. PMID- 23366113 TI - An untethered shoe with vibratory feedback for improving gait of Parkinson's patients: the PDShoe. AB - Subjects with Parkinson's disease (PD) often have trouble with ambulation. Some research has shown that auxiliary cueing in the form of vision, audio, or vibration can improve the gait of PD patients. We have developed a new vibratory feedback shoe, known as the PDShoe, which builds on existing research. This device can modulate both frequency and amplitude of feedback for the wearer. It is untethered, and thus can be worn during daily activities. Pressure and tactor status data are transmitted wirelessly over a personal area network to a notebook computer. This computer can also control the tactor actuation and stimulation frequency. This paper describes the details of design and construction of the PDShoe. A preliminary evaluation with four Parkinson's disease subjects and two healthy subjects is included to show the usability of the device. PMID- 23366114 TI - On-demand controlled release of anti-inflammatory and analgesic drugs from conducting polymer films to aid in wound healing. AB - An electronically-controlled drug delivery system (eDDS) for the on-demand release of anti-inflammatory, anti-microbial and analgesic agents to aid in wound healing is currently under development. The loading of several drugs into conductive polymer films and their subsequent on-demand, controlled release upon application of an electrical potential to the polymer film has been demonstrated. The loading and release (active and passive) of Ibuprofen sodium salt - a negatively charged analgesic and anti-inflammatory agent - from polypyrrole films is described. Major challenges identified include precise control over drug loading and passive release from the conducting polymers in the absence of an applied potential. PMID- 23366115 TI - sEMG-based detection of poor posture: a feasibility study. AB - The cost of the medical treatment of low back pain (LBP) was estimated to be $24 billion in the early 90s. Also, 80% of the LBP is estimated to be due to poor or inappropriate posture. The ultimate goal of the project is to develop a surface electromyography (sEMG)-based device that could be used to prevent and treat LBP by postural re-education or simply for on-the-spot sEMG feedback. In this paper we present the results and conclusions of a feasibility study for sEMG-based poor posture classifier. The results show that a s-EMG based poor posture classifier could be possible. The sensitivity for the best linear classifier model was 72% and the specificity was 78%. The same signal feature returned very different results from one participant to another. This inter-subject variability could be due to different muscular activation patterns during posture correction. PMID- 23366117 TI - Quantifying uncertainty in Transcranial Magnetic Stimulation - A high resolution simulation study in ICBM space. AB - Transcranial Magnetic Stimulation offers enormous potential for noninvasive brain stimulation. While it is known that brain tissue significantly "reshapes" induced field and charge distributions, most modeling investigations to-date have focused on single-subject data with limited generality. Further, the effects of the significant uncertainties which exist in the simulation (i.e. brain conductivity distributions) and stimulation (e.g. coil positioning and orientations) setup have not been quantified. In this study, we construct a high-resolution anisotropic head model in standard ICBM space, which can be used as a population representative standard for bioelectromagnetic simulations. Further, we employ Monte-Carlo simulations in order to quantify how uncertainties in conductivity values propagate all the way to induced field and currents, demonstrating significant, regionally dependent dispersions in values which are commonly assumed "ground truth". This framework can be leveraged in order to quantify the effect of any type of uncertainty in noninvasive brain stimulation and bears relevance in all applications of TMS, both investigative and therapeutic. PMID- 23366116 TI - Reinforcement mechanisms in putamen during high frequency STN DBS: A point process study. AB - Despite a pivotal role in the motor loop, dorsolateral striatum (putamen) has been poorly studied thus far under Parkinsonian conditions and Deep Brain Stimulation (DBS). We analyze the activity of the putamen in a monkey by combining single unit recordings and point process models. The animal received DBS (30-130 Hz) in the subthalamic nucleus (STN) while at rest and recordings were acquired both before and after treatment with 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), which induced Parkinsonian-like motor disorders. 141 neurons were collected and, for each neuron, a point process model captured DBS evoked discharge patterns. In the normal animal, spike trains at rest had Poisson like distribution with non-stationary recurrent patterns (RPs) of period 3-7 ms and were mildly changed by low frequency (LF, i.e., < 100 Hz) DBS (i.e., < 20% of neurons affected). With high frequency (HF, i.e., 100-130 Hz) DBS, instead, up to 59% of neurons were affected, the DBS history significantly impacted the neuronal spiking propensity, and the RPs and the post-stimulus activation latency decreased. MPTP evoked inter-neuronal dependencies (INDs) at rest and, compared to normal, LF DBS of the MPTP animal increased RPs and INDs, while HF DBS elicited a faster and wider post-stimulus activation. Overall, HF DBS reduced ongoing non-stationary dynamics by regularizing the discharge patterns both in MPTP and normal putamen, while the combination of MPTP and LF DBS enhanced such dynamics. PMID- 23366118 TI - A coupling method for a cardiovascular simulation model which includes the Kalman filter. AB - Multi-scale models of the cardiovascular system provide new insight that was unavailable with in vivo and in vitro experiments. For the cardiovascular system, multi-scale simulations provide a valuable perspective in analyzing the interaction of three phenomenons occurring at different spatial scales: circulatory hemodynamics, ventricular structural dynamics, and myocardial excitation-contraction. In order to simulate these interactions, multiscale cardiovascular simulation systems couple models that simulate different phenomena. However, coupling methods require a significant amount of calculation, since a system of non-linear equations must be solved for each timestep. Therefore, we proposed a coupling method which decreases the amount of calculation by using the Kalman filter. In our method, the Kalman filter calculates approximations for the solution to the system of non-linear equations at each timestep. The approximations are then used as initial values for solving the system of non-linear equations. The proposed method decreases the number of iterations required by 94.0% compared to the conventional strong coupling method. When compared with a smoothing spline predictor, the proposed method required 49.4% fewer iterations. PMID- 23366119 TI - Prediction of intradialytic morbid events in hemodialysis patients by monitoring the second derivative of relative blood volume. AB - Intradialytic morbid events (IME) are a major issue affecting hemodialysis (HD) patients. Change in relative blood volume (RBV) reflects change in plasma refilling rate (PRR) and variability of ultrafiltration rate (UFR). However, degree of fluid overload influences this relationship. We propose a method using a second derivative of RBV (SDRBV) model to detect decrease in PRR during HD which is a major factor associated with IME. Forty-five HD patients (age 55.7+/ 14 years, height 167.7+/-10 cm, Pre HD weight 79.3+/-16.6 kg) were studied with a total of 245 treatments, with IME occurring in 124 treatments. Predictions of IME with the SDRBV model showed 92 % sensitivity for 124 IME and 43 % specificity of 121 non IME treatments respectively. The average time between prediction and IMEs was -30.8+/-36 minutes. A high positive predictive value was due to 1) using a low-pass filter to reduce possible interferences in the RBV curve and 2) use of 5 minutes sample frequency to apply the SDRBV model. These results indicate that the SDRBV model is a useful tool in clinical practice to predict and prevent IME. PMID- 23366120 TI - Modeling the influences of nanoparticles on neural field oscillations in thalamocortical networks. AB - The purpose of this study is twofold. First, we present a simplified multiscale modeling approach integrating activity on the scale of ionic channels into the spatiotemporal scale of neural field potentials: Resting upon a Hodgkin-Huxley based single cell model we introduced a neuronal feedback circuit based on the Llinas-model of thalamocortical activity and binding, where all cell specific intrinsic properties were adopted from patch-clamp measurements. In this paper, we expand this existing model by integrating the output to the spatiotemporal scale of field potentials. Those are supposed to originate from the parallel activity of a variety of synchronized thalamocortical columns at the quasi microscopic level, where the involved neurons are gathered together in units. Second and more important, we study the possible effects of nanoparticles (NPs) that are supposed to interact with thalamic cells of our network model. In two preliminary studies we demonstrated in vitro and in vivo effects of NPs on the ionic channels of single neurons and thereafter on neuronal feedback circuits. By means of our new model we assumed now NPs induced changes on the ionic currents of the involved thalamic neurons. Here we found extensive diversified pattern formations of neural field potentials when comparing to the modeled activity without neuromodulating NPs addition. This model provides predictions about the influences of NPs on spatiotemporal neural field oscillations in thalamocortical networks. These predictions can be validated by high spatiotemporal resolution electrophysiological measurements like voltage sensitive dyes and multiarray recordings. PMID- 23366121 TI - The Neuroid: A novel and simplified neuron-model. AB - In this paper we introduce a novel computational neuron-model, the Neuroid, which is based on three basic operations that are carried out by nerve cells to process the incoming information, such as comparison, and frequency pulse modulation demodulation. The model was implemented using LabVIEW 10.0, in order to assign to each of these operations, an execution block (Virtual Instrument). The results of its implementation showed a very similar behavior to that exhibited by real neurons. Furthermore, due to its simplicity and low computational requirements, it is expected that the Neuroid can be used to create several software models of biological neural systems, either for research or teaching purposes. PMID- 23366122 TI - Shape-influenced clustering of dynamic patterns of gene profiles. AB - Statistical evaluation of temporal gene expression profiles plays an important role in particular biological processes and conditions. We introduce a clustering method for this purpose, which is based on the expression patterns but is also influenced by temporal changes. We compare the results of our platform with methods based on expression or the rank of temporal changes. The proposed platform is illustrated with a temporal gene expression dataset comprised of primary human chondrocytes and mesenchymal stem cells (MSCs). We derived three clusters in each cell type and compared the content of these classes in terms of temporal changes, which can support biological performance. For statistical evaluation we introduce a validity measure that takes under consideration these temporal changes and we also perform an enrichment analysis of three central genes in each cluster. Even though we can detect certain statistical similarities, these might be due to different biological processes. Our proposed platform contributes to both the statistical and biological validation of temporal profiles. PMID- 23366123 TI - Multi-scale modeling of gene regulatory networks via integration of temporal and topological biological data. AB - Regulome is the dynamic network representation of the regulatory interplay among genes, proteins and other cellular components that control cellular processes. Reconstruction of gene regulatory networks (GRN) delineates one of the main objectives of Systems Biology towards understanding the organization of regulome. Significant progress has been reported the last years regarding GRN reconstruction methods, but the majority of them either consider information originating solely from gene expression data or/and are applied on a small fraction of the experimental dataset. In this paper, we will describe an integrative method, utilizing both temporal information arriving from time-series gene expression profiles, as well as topological properties of protein networks. The proposed methodology detects relations among either groups of genes or specific genes depending on the level of abstraction or resolution requested. Application on real data proved the ability of the method to extract relations in accordance with current biological knowledge as well as discriminate between different experimental conditions. PMID- 23366124 TI - Detection of common copy number variation with application to population clustering from next generation sequencing data. AB - Copy number variation (CNV) is a structural variation in human genome that has been associated with many complex diseases. In this paper we present a method to detect common copy number variation from next generation sequencing data. First, copy number variations are detected from each individual sample, which is formulated as a total variation penalized least square problem. Second, the common copy number discovery from multiple samples is obtained using source separation techniques such as the non-negative matrix factorization (NMF). Finally, the method is applied to population clustering. The results on real data analysis show that two family trio with different ancestries can be clustered into two ethnic groups based on their common CNVs, demonstrating the potential of the proposed method for application to population genetics. PMID- 23366125 TI - Personalized blood glucose models for exercise, meal and insulin interventions in type 1 diabetic children. AB - Modern healthcare is rapidly evolving towards a personalized, predictive, preventive and participatory approach of treatment to achieve better quality of life (QoL) in patients. Identification of personalized blood glucose (BG) prediction models incorporating the lifestyle interventions can help in devising optimal patient specific exercise, food, and insulin prescriptions, which in turn can prevent the risk of frequent hypoglycemic episodes and other diabetes complications. Hence, we propose a modeling methodology based on multi-input single-output time series models, to develop personalized BG models for 12 type 1 diabetic (T1D) children, using the clinical data from Diabetes Research in Children's Network. The multiple inputs needed to develop the proposed models were rate of perceived exertion (RPE) values (which quantify the exercise intensity), carbohydrate absorption dynamics, basal insulin infusion and bolus insulin absorption kinetics. Linear model classes like Box-Jenkins (1 patient), state space (1 patient) and process transfer function models (7 patients) of different orders were found to be the most suitable as the personalized models for 9 patients, whereas nonlinear Hammerstein-Wiener models of different orders were found to be the personalized models for 3 patients. Hence, inter-patient variability was captured by these models as each patient follows a different personalized model. PMID- 23366126 TI - Multiview approach to spectral clustering. AB - In this paper we propose a generic approach to the multiview clustering problem that can be applied to any number of data views and with different topologies, either continuous, discrete, graphs, or other. The proposed method is an extension of the well-established spectral clustering algorithm to integrate the information from several data views in the partition solution. The algorithm, therefore, resolves a joint cluster structure which could be present in all views, which enables researchers to better resolve data structures in data fusion problems The application of this novel clustering approach covers an extended number of machine learning unsupervised clustering problems including biomedical analysis or machine vision. PMID- 23366127 TI - Supercomputing enabling exhaustive statistical analysis of genome wide association study data: Preliminary results. AB - Most published GWAS do not examine SNP interactions due to the high computational complexity of computing p-values for the interaction terms. Our aim is to utilize supercomputing resources to apply complex statistical techniques to the world's accumulating GWAS, epidemiology, survival and pathology data to uncover more information about genetic and environmental risk, biology and aetiology. We performed the Bayesian Posterior Probability test on a pseudo data set with 500,000 single nucleotide polymorphism and 100 samples as proof of principle. We carried out strong scaling simulations on 2 to 4,096 processing cores with factor 2 increments in partition size. On two processing cores, the run time is 317h, i.e. almost two weeks, compared to less than 10 minutes on 4,096 processing cores. The speedup factor is 2,020 that is very close to the theoretical value of 2,048. This work demonstrates the feasibility of performing exhaustive higher order analysis of GWAS studies using independence testing for contingency tables. We are now in a position to employ supercomputers with hundreds of thousands of threads for higher order analysis of GWAS data using complex statistics. PMID- 23366128 TI - Knowledge Editor and execution engine development for optimal ventricular assist device weaning. AB - In this work, the weaning module of the SensorART specialist decision support system (SDSS) is presented. SensorART focuses on the treatment of patients suffering from end-stage heart failure (HF). The use of a ventricular assist device (VAD) is the main treatment for HF patients. However in certain cases, myocardial function recovers and VADs can be explanted after the patient is weaned. In that framework an efficient module is developed responsible for the selection of the most suitable candidates for VAD weaning. In this study we describe all technical specifications concerning its two main sub-modules of the weaning module, of the Clinical Knowledge Editor and the Knowledge Execution Engine. PMID- 23366129 TI - A cross-platform and distributive database system for cumulative tumor measurement. AB - This paper discusses the development of a cross-platform, web accessible, vendor independent database system capable of storing and comparing longitudinal tumor measurements for multiple tumors. This innovative system can create a comprehensive cumulative report that summarizes clinical findings and links to the original image studies, which will clinically enhance the workflow of oncologists. A case study on a pancreatic tumor data set with 524 tumor measurements and 134 patients is demonstrated. PMID- 23366130 TI - Device interoperability and authentication for telemedical appliance based on the ISO/IEEE 11073 Personal Health Device (PHD) Standards. AB - In this study, we focused on the interoperability and authentication of medical devices in the context of telemedical systems. A recent standard called the ISO/IEEE 11073 Personal Health Device (X73-PHD) Standards addresses the device interoperability problem by defining common protocols for agent (medical device) and manager (appliance) interface. The X73-PHD standard however has not addressed security and authentication of medical devices which is important in establishing integrity of a telemedical system. We have designed and implemented a security policy within the X73-PHD standards. The policy will enable device authentication using Asymmetric-Key Cryptography and the RSA algorithm as the digital signature scheme. We used two approaches for performing the digital signatures: direct software implementation and use of embedded security modules (ESM). The two approaches were evaluated and compared in terms of execution time and memory requirement. For the standard 2048-bit RSA, ESM calculates digital signatures only 12% of the total time for the direct implementation. Moreover, analysis shows that ESM offers more security advantage such as secure storage of keys compared to using direct implementation. Interoperability with other systems was verified by testing the system with LNI Healthlink, a manager software that implements the X73-PHD standard. Lastly, security analysis was done and the system's response to common attacks on authentication systems was analyzed and several measures were implemented to protect the system against them. PMID- 23366131 TI - Healthcare standards based sensory data exchange for Home Healthcare Monitoring System. AB - Interoperability is the among the key functionalities of an intelligent systems. Home Healthcare Monitoring Systems (HHMS) investigates patients activities at home, but lacks critical information exchange with Health Management Information System (HMIS). This information is vital for physicians to take necessary steps for timely and effective healthcare provisioning for patients. Physicians can only monitor and prescribe patients in time, if the data is shared with their HMIS. HMIS can be compliant to different healthcare standards. Therefore, mediation system is required to enable interoperability between HHMS and HMIS such that physicians and patients information can easily be exchanged. We propose Interoperability Mediation System (IMS) that provides interoperability services for exchange of information among HHMS and HMIS. We consider that HMIS are compliant to two heterogeneous EHR standards (HL7 CDA and openEHR). Alzheimer's patient case study is described as a proof of concept. Sensory information gathered at HHMS, is communicated with HMIS compliant to EHR based healthcare standards. Sensors information in XML form is converted by interoperability service to HL7 CDA and openEHR instances and communicated to HMIS afterwards. This allows the physicians registered with HHMS to monitor the patient using their HMIS and provide timely healthcare information. PMID- 23366132 TI - Towards a classification model to identify hospice candidates in terminally ill patients. AB - This paper presents a Rough Set Theory (RST) based classification model to identify hospice candidates within a group of terminally ill patients. Hospice care considerations are particularly valuable for terminally ill patients since they enable patients and their families to initiate end-of-life discussions and choose the most desired management strategy for the remainder of their lives. Unlike traditional data mining methodologies, our approach seeks to identify subgroups of patients possessing common characteristics that distinguish them from other subgroups in the dataset. Thus, heterogeneity in the data set is captured before the classification model is built. Object related reducts are used to obtain the minimum set of attributes that describe each subgroup existing in the dataset. As a result, a collection of decision rules is derived for classifying new patients based on the subgroup to which they belong. Results show improvements in the classification accuracy compared to a traditional RST methodology, in which patient diversity is not considered. We envision our work as a part of a comprehensive decision support system designed to facilitate end of-life care decisions. Retrospective data from 9105 patients is used to demonstrate the design and implementation details of the classification model. PMID- 23366133 TI - An analysis of free Web-based PHRs functionalities and I18n. AB - The growth of the Internet, Web technologies, and other electronic tools are allowing the public to become more informed and actively engaged in their health care than was possible in the past. Personal Health Records (PHR) offer users possibility of managing their own health data. Many patients are using PHRs to communicate with doctors in order to improve healthcare quality and efficiency. A large number of companies have emerged to provide consumers with the opportunity to use online PHRs within a healthcare platform, proposing different functionalities and services. This paper analyzes and assesses the functionalities and internationalization (i18n) of free Web based PHRs. PMID- 23366134 TI - A feasibility study of an upper limb rehabilitation system using Kinect and computer games. AB - A new low-cost system for rehabilitation of the impaired upper limb for stroke survivors is presented. A computer game was developed specifically for this purpose and the user's impaired upper extremity is tracked using a downward pointed Kinect, an inexpensive motion capture system commercially available from Microsoft. A Kalman filter was implemented to reduce data jittering. Patients are required to move their impaired arm, sliding it on top of a transparent support, in order to play the game. The game is personalized to the patient through specific settings that adapt to the patient's range of motion and motor control at the start of the game as well as performance during the game. The final score is proportional to the arm's movement speed. A feasibility study was carried out with one stroke survivor. The game was played for ten days and usability surveys were answered before and after the study. The patient was engaged with the game, found it easy to understand and reported willingness to use it in the home environment and enjoyment of the use in the clinic. PMID- 23366135 TI - Tele-healthcare for diabetes management: A low cost automatic approach. AB - In this paper, a telemedicine system for managing diabetic patients with better care is presented. The system is an end to end solution which relies on the integration of front end (patient unit) and backend web server. A key feature of the system developed is the very low cost automated approach. The front-end of the system is capable of reading glucose measurements from any glucose meter and sending them automatically via existing networks to the back-end server. The back end is designed and developed using n-tier web client architecture based on model view-controller design pattern using open source technology, a cost effective solution. The back-end helps the health-care provider with data analysis; data visualization and decision support, and allows them to send feedback and therapeutic advice to patients from anywhere using a browser enabled device. This system will be evaluated during the trials which will be conducted in collaboration with a local hospital in phased manner. PMID- 23366136 TI - Asphyxia screening kit. AB - Infant asphyxia is a condition due to insufficient oxygen intake suffered by newborn babies. A 4 to 9 million occurrences of infant asphyxia are reported each year by WHO. Early diagnosis of asphyxia is important to avoid complications such as damage to the brain, organ and tissue that could lead to fatality. This is possible with the automation of screening of infant asphyxia. Here, a non invasive Asphyxia Screening Kit is developed. It is a Graphical User Interface that automatically detects asphyxia in infants from early birth to 6 months from their cries and displays the outcome of analysis. It is built with Matlab GUI underlied with signal processing algorithms, capable of achieving a classification accuracy of 96.03%. Successful implementation of ASK will assist to screen infant asphyxia for reference to clinicians for early diagnosis. In addition, ASK also provides an interface to enter patient information and images to be integrated with existing Hospital Information Management System. PMID- 23366137 TI - Non-contact monitoring techniques - Principles and applications. AB - This work gives an overview about some non-contact methods for monitoring of physiological activity. In particular, the focus is on ballistocardiography, capacitive ECG, Infrared Thermography, Magnetic Impedance Monitroing and Photoplethymographic Imaging. The principles behind the methods are described and an inside into possible medical applications is offered. PMID- 23366138 TI - Integrating complex business processes for knowledge-driven clinical decision support systems. AB - This paper presents in detail the component of the Complex Business Process for Stream Processing framework that is responsible for integrating complex business processes to enable knowledge-driven Clinical Decision Support System (CDSS) recommendations. CDSSs aid the clinician in supporting the care of patients by providing accurate data analysis and evidence-based recommendations. However, the incorporation of a dynamic knowledge-management system that supports the definition and enactment of complex business processes and real-time data streams has not been researched. In this paper we discuss the process web service as an innovative method of providing contextual information to a real-time data stream processing CDSS. PMID- 23366139 TI - Transductive neural decoding for unsorted neuronal spikes of rat hippocampus. AB - Neural decoding is an important approach for extracting information from population codes. We previously proposed a novel transductive neural decoding paradigm and applied it to reconstruct the rat's position during navigation based on unsorted rat hippocampal ensemble spiking activity. Here, we investigate several important technical issues of this new paradigm using one data set of one animal. Several extensions of our decoding method are discussed. PMID- 23366140 TI - Parameter estimation for maximizing controllability of linear brain-machine interfaces. AB - Brain-machine interfaces (BMIs) must be carefully designed for closed-loop control to ensure the best possible performance. The Kalman filter (KF) is a recursive linear BMI algorithm which has been shown to smooth cursor kinematics and improve control over non-recursive linear methods. However, recursive estimators are not without their drawbacks. Here we show that recursive decoders can decrease BMI controllability by coupling kinematic variables that the subject might expect to be unrelated. For instance, a 2D neural cursor where velocity is controlled using a KF can increase the difficulty of straight reaches by linking horizontal and vertical velocity estimates. These effects resemble force fields in arm control. Analysis of experimental data from one non-human primate controlling a position/velocity KF cursor in closed-loop shows that the presence of these force-field effects correlated with decreased performance. We designed a modified KF parameter estimation algorithm to eliminate these effects. Cursor controllability improved significantly when our modifications were used in a closed-loop BMI simulator. Thus, designing highly controllable BMIs requires parameter estimation techniques that carefully craft relationships between decoded variables. PMID- 23366141 TI - A brain machine interface control algorithm designed from a feedback control perspective. AB - We present a novel brain machine interface (BMI) control algorithm, the recalibrated feedback intention-trained Kalman filter (ReFIT-KF). The design of ReFIT-KF is motivated from a feedback control perspective applied to existing BMI control algorithms. The result is two design innovations that alter the modeling assumptions made by these algorithms and the methods by which these algorithms are trained. In online neural control experiments recording from a 96-electrode array implanted in M1 of a macaque monkey, the ReFIT-KF control algorithm demonstrates large performance improvements over the current state of the art velocity Kalman filter, reducing target acquisition time by a factor of two, while maintaining a 500 ms hold period, thereby increasing the clinical viability of BMI systems. PMID- 23366142 TI - Estimation of a mean template from spike-train data. AB - Computing the template, or the mean, of a set of spike trains is a novel and important task in neural coding. Due to the random nature of spike trains taken from experimental recordings, probabilistic and statistical methods have gained prominence in examining underlying firing patterns. However, these methods focus on modeling neural activity at each given time and therefore their results depend heavily on model assumptions. Taking a model-free and metric-based approach, we analyze the space of spike trains directly and reach algorithms for estimating statistical summaries, such as the mean spike train, of a given set. In our data driven approach the mean is defined directly in a function space in which the spike trains are viewed as individual points. Here we develop an efficient and convergence-proven algorithm to compute the mean spike train in a general scenario. Experimental result from a neural recoding in primate motor cortex indicates that the estimated means successfully capture the typical patterns in spike trains. In addition, these mean spike trains provide an accurate and efficient performance in decoding motor behaviors. PMID- 23366143 TI - Internal models engaged by brain-computer interface control. AB - Internal models have been proposed to explain the brain's ability to compensate for sensory feedback delays by predicting the sensory consequences of movement commands. Single-neuron studies in the oculomotor and vestibulo-ocular systems have provided evidence of internal models, as have behavioral studies in the skeletomotor system. Here, we present evidence of internal models from simultaneously recorded population activity underlying closed-loop brain-computer interface (BCI) control. We studied cursor-based BCI control by a nonhuman primate implanted with a multi-electrode array in motor cortex. Using a novel BCI task, we measured the visual feedback processing delay to be about 130 milliseconds. By examining the task-based appropriateness of the population activity at different time lags, we found evidence that the subject compensates for the feedback delay by predicting upcoming cursor positions, suggesting the use of an internal forward model. Lastly, we examined the time course of internal model adaptation after altering the mapping between population activity and cursor movements. This study suggests that closed-loop BCI experiments combined with novel statistical analyses can provide insight into the neural substrates of feedback motor control and motor learning. PMID- 23366144 TI - Decoding stimuli from multi-source neural responses. AB - Spike trains and local field potentials (LFPs) are two different manifestations of neural activity recorded simultaneously from the same electrode array and contain complementary information of stimuli or behaviors. This paper proposes a tensor product kernel based decoder, which allows modeling the sample from different sources individually and mapping them onto the same reproducing kernel Hilbert space (RKHS) defined by the tensor product of the individual kernels for each source, where linear regression is conducted to identify the nonlinear mapping from the multi-type neural responses to the stimuli. The decoding results of the rat sensory stimulation experiment show that the tensor-product-kernel based decoder outperforms the decoders with either single-type neural activities. PMID- 23366145 TI - A Bionic Neural Link for peripheral nerve repair. AB - Peripheral nerve injuries with large gaps and long nerve regrowth paths are difficult to repair using existing surgical techniques, due to nerve degeneration and muscle atrophy. This paper proposes a Bionic Neural Link (BNL) as an alternative way for peripheral nerve repair. The concept of the BNL is described, along with the hypothetical benefits. A prototype monolithic single channel BNL has been developed, which consists of 16 neural recording channels and one stimulation channel, and is implemented in a 0.35-um CMOS technology. The BNL has been tested in in-vivo animal experiments. Full function of the BNL chip has been demonstrated. PMID- 23366146 TI - Evaluation of volitional control of hand with vertical force assist device for high tetraplegia. AB - Individuals with high tetraplegia have lost motor and sensory function below the neck. This population is highly disabled and requires some method of assistance to accomplish activities of daily living. To date, rehabilitative interventions available in the clinic are limited and have not been designed to exploit residual volitional control. The goal of this study was to validate the presence of volitional control at the hand in individuals with high tetraplegia when the arm is supported against gravity with a vertical assist device. Any volitional control is pertinent to the development of rehabilitative interventions for high tetraplegia because it can be utilized to improve the overall performance and user acceptance of the device. The results from this study provide evidence toward the possibility of an individual with high tetraplegia being able to position their hand and generate forces volitionally in a functional workspace if the weight of their arm is supported by a vertical assist device. PMID- 23366147 TI - A comparison between force and position control strategies in myoelectric prostheses. AB - This work studies the simultaneous and proportional myoelectric force and position estimation of multiple degrees of freedom (DOFs) for unilateral transradial amputees. Two experiments were conducted to compare force and position control paradigms. In the first, a force experiment, subjects performed isometric contractions, while the force applied by the limb and EMG were recorded. In the second, a position experiment, dynamic contractions were permitted during which position of the limb and EMG were measured. Artificial neural networks (ANNs) were trained to estimate force/position from EMG of the contralateral limb during mirrored bilateral contractions. This study involved contractions with combined activations of three DOFs including wrist: flexion/extension, radial/ulnar deviation and forearm supination/pronation. For the given data set, while force estimation demonstrated high accuracy (R(2)=0.84+/-0.02), position estimation performance was relatively poor (R(2)=0.57+/-0.05). Two healthy subjects participated in this work. PMID- 23366148 TI - Real time simultaneous and proportional control of multiple degrees of freedom from surface EMG: Preliminary results on subjects with limb deficiency. AB - We present the real time simultaneous and proportional control of two degrees of freedom (DoF), using surface electromyographic signals from the residual limbs of three subject with limb deficiency. Three subjects could control a virtual object in two dimensions using their residual muscle activities to achieve goal-oriented tasks. The subjects indicated that they found the control intuitive and useful. These results show that such a simultaneous and proportional control paradigm is a promising direction for multi-functional prosthetic control. PMID- 23366149 TI - Implantable multichannel wireless electromyography for prosthesis control. AB - We have developed a prototype implantable device for recording multiple independent channels of EMG and sending those signals wirelessly to an external receiver. This design records multichannel EMG signals for providing simultaneous multi-axis control of prosthetic limbs. This proof-of-concept study demonstrates benchtop performance of the bioamplifier in dry and soaked in saline configurations, as well as system performance in a short-term in vivo study in six dogs. The amplifier was shown to have an input-referred noise of 2.2 uV(RMS), a common mode rejection ratio greater than 55 dB, and neighboring channel isolation averaging 66 dB. The prototype devices were constructed of an amplifier ASIC along with discrete components for wireless function. These devices were coated in silicone and implanted for at least one week in each dog. EMG recorded from each animal as it walked down a hallway had very low noise and swing/stance phases of gait were clearly shown. This study demonstrates this device design can be used to amplify and transmit muscle signals. PMID- 23366150 TI - A computational model of mild traumatic brain injury. AB - Electrical analysis of brain activity reveals the presence of synchronous oscillations over a range of frequencies. These rhythms are readily observed using electroencephalography (EEG). Clinical EEG data shows that Traumatic Brain Injury (TBI) alters these rhythms. Researchers have developed lumped parameter neural mass models (NMM) that can reproduce these various brain rhythms. This paper proposes an NMM based computational model of mild TBI that recreates the clinical EEG changes observed after injury. Specifically, the focus is on recreating changes observed after TBI in the 8-12 Hz alpha and the 4-8Hz theta frequency ranges. Mild TBI is simulated by increasing membrane reactivity and by decreasing synaptic connectivity in the NMM. These results indicate that clinically observed EEG changes with mild TBI are likely due to traumatic synaptic disruption and that with appropriate data, EEG may be used to quantify the extent of TBI in the future. PMID- 23366151 TI - Implementation of topographically constrained connectivity for a large-scale biologically realistic model of the hippocampus. AB - In order to understand how memory works in the brain, the hippocampus is highly studied because of its role in the encoding of long-term memories. We have identified four characteristics that would contribute to the encoding process: the morphology of the neurons, their biophysics, synaptic plasticity, and the topography connecting the input to and the neurons within the hippocampus. To investigate how long-term memory is encoded, we are constructing a large-scale biologically realistic model of the rat hippocampus. This work focuses on how topography contributes to the output of the hippocampus. Generally, the brain is structured with topography such that the synaptic connections formed by an input neuron population are organized spatially across the receiving population. The first step in our model was to construct how entorhinal cortex inputs connect to the dentate gyrus of the hippocampus. We have derived realistic constraints from topographical data to connect the two cell populations. The details on how these constraints were applied are presented. We demonstrate that the spatial connectivity has a major impact on the output of the simulation, and the results emphasize the importance of carefully defining spatial connectivity in neural network models of the brain in order to generate relevant spatiotemporal patterns. PMID- 23366152 TI - Synaptic dynamics: Linear model and adaptation algorithm. AB - Linear model for synapse temporal dynamics and learning algorithm for synaptic adaptation in spiking neural networks are presented. The proposed linear model substantially simplifies analysis and training of spiking neural networks, meanwhile accurately models facilitation and depression dynamics in synapse. The learning rule is biologically plausible and is capable of simultaneously adjusting both of LTP and STP parameters of individual synapses in a network. To prove efficiency of the system, a small size spiking neural network is trained for generating different spike and bursting patterns of cortical neurons. The simulation results revealed that the linear model of synaptic dynamics along with the proposed STDP based learning algorithm can provide a practical tool for simulating and training very large scale spiking neural circuitry comprising of significant number of synapses and neurons. PMID- 23366153 TI - Implementation of activity-dependent synaptic plasticity rules for a large-scale biologically realistic model of the hippocampus. AB - A large-scale computational model of the hippocampus should consider plasticity at different time scales in order to capture the non-stationary information processing behavior of the hippocampus more accurately. This paper presents a computational model that describes hippocampal long-term potentiation/depression (LTP/LTD) and short-term plasticity implemented in the NEURON simulation environment. The LTP/LTD component is based on spike-timing-dependent plasticity (STDP). The short-term plasticity component modifies a previously defined deterministic model at a population synapse level to a probabilistic model that can be implemented at a single synapse level. The plasticity mechanisms are validated and incorporated into a large-scale model of the entorhinal cortex projection to the dentate gyrus. Computational expense of the added plasticity was also evaluated and shown to increase simulation time by less than a factor of two. This model can be easily included in future large-scale hippocampal simulations to investigate the effects of LTP/LTD and short-term plasticity in conjunction with other biological considerations on system function. PMID- 23366154 TI - An influence of spontaneous spike rates on information transmission in a spherical bushy neuron model with stochastic ion channels. AB - This article presents an effect of spontaneous spike firing rates on information transmission of the spike trains in a spherical bushy neuron model of antero ventral cochlear nuclei. In computer simulations, the synaptic current stimuli ascending from auditory nerve fibers (ANFs) were modeled by a filtered inhomogeneous Poisson process modulated with sinusoidal functions, while the stochastic sodium and stochastic high- and low-threshold potassium channels were incorporated into a single compartment model of the soma in spherical bushy neurons. The information rates were estimated from the entropies of the inter spike intervals of the spike trains to quantitatively evaluate information transmission in the spherical busy neuron model. The results show that the information rates increased, reached a maximum, and then decreased as the rate of spontaneous spikes from the ANFs increased, implying a resonance phenomenon dependent on the rate of spontaneous spikes from ANFs. In conclusion, this phenomenon similar to the stochastic resonance would be observed due to that spontaneous random spike firings coming from auditory nerves may act as an origin of fluctuation or noise, and these findings may play a key role in the design of better auditory prostheses. PMID- 23366155 TI - Influence of ionotropic receptor location on their dynamics at glutamatergic synapses. AB - In this paper we study the effects of the location of ionotropic receptors, especially AMPA and NMDA receptors, on their function at excitatory glutamatergic synapses. As few computational models only allow to evaluate the influence of receptor location on state transition and receptor dynamics, we present an elaborate computational model of a glutamatergic synapse that takes into account detailed parametric models of ionotropic receptors along with glutamate diffusion within the synaptic cleft. Our simulation results underscore the importance of the wide spread distribution of AMPA receptors which is required to avoid massive desensitization of these receptors following a single glutamate release event while NMDA receptor location is potentially optimal relative to the glutamate release site thus, emphasizing the contribution of location dependent effects of the two major ionotropic receptors to synaptic efficacy. PMID- 23366156 TI - Antimicrobial properties of biodegradable magnesium for next generation ureteral stent applications. AB - Bacterial infection often causes clinical complications and failure of indwelling medical devices. This is a major problem of current ureteral stents, which are used clinically to treat the blockage of ureteral canals. This study investigates the effectiveness and applicability of magnesium as a novel biodegradable ureteral stent material that has inherent antimicrobial properties. Incubating Escherichia coli with the magnesium samples showed a decrease in the bacterial cell density as compared with the currently used commercial polyurethane stent. Magnesium degradation in the immersion solutions (artificial urine, luria bertani broth, and deionized water) resulted in an alkaline pH shift. Antimicrobial and biodegradation properties of magnesium make it an attractive alternative as next generation ureteral stent material. PMID- 23366157 TI - Altering embryonic cardiac dynamics with optical pacing. AB - Several studies have shown that altering blood flow early in development leads to congenital heart defects. In these studies the perturbations to hemodynamics were very gross manipulations (vessel ligation, conotruncal banding, etc.) that would be inappropriate for probing the delicate mechanisms responsible for mechanically transduced signaling. Also, these perturbations lacked feedback from a monitoring system to determine the exact degree of alteration and the location of its effect. Here, we employed optical pacing (OP) to alter the heart rate in quail embryos and optical coherence tomography (OCT) to measure the resultant shear forces on the endocardium. OP is a new technique utilizing pulsed 1.851 um infrared laser light to noninvasively capture the heart rate to the pulse frequency of the laser without the use of exogenous agents. To measure shear stress on the endocardium, we extended our previous OCT algorithms to enable the production of 4-D shear maps. 4-D shear maps allowed observation of the spatial and temporal distribution of shear stress. Employing both OCT and OP, we were able to develop perturbation protocols that increase regurgitant flow and greatly modify the oscillatory shear index (OSI) in a region of the heart tube where future valves will develop. Regurgitant flow has been linked with valve development and precise perturbations may allow one to determine the role of hemodynamics in valvulogenesis. PMID- 23366158 TI - Cardiac optogenetics. AB - For therapies based on human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) to be effective, arrhythmias must be avoided. Towards achieving this goal, light-activated channelrhodopsin-2 (ChR2), a cation channel activated with 480 nm light, and a first generation halorhodopsin (NpHR1.0), an anion pump activated by 580 nm light, have been introduced into hiPSC. By using in vitro approaches, hiPSC-CM are able to be optogenetically activated and inhibited. ChR2 and NpHR1.0 are stably transduced into undifferentiated hiPSC via a lentiviral vector. Via directed differentiation, both wildtype hiPSC-CM (hiPSC(WT)-CM) and hiPSC(ChR2/NpHR)-CM are produced and subjected to both electrical and optical stimulation. Both hiPSC(WT)-CM and hiPSC(ChR2/NpHR)-CM respond to traditional electrical stimulation and produce similar contractility features but only hiPSC(ChR2/NpHR)-CM can be synchronized and inhibited by optical stimulation. Here it is shown that light sensitive proteins can enable in vitro optical control of hiPSC-CM. For future therapy, in vivo optical stimulation could allow precise and specific synchronization of implanted hiPSC CM with patient cardiac rates and rhythms. PMID- 23366159 TI - Electrode robustness in artificial cerebrospinal fluid for dielectrophoresis based LoC. AB - In this paper, we present hybrid microelectronics / microfluidic Lab-on-Chip (LoC) platform intended for implantable medical microsystems for neurotransmitter detection. In vitro experiments were achieved using artificial cerebrospinal fluid (ACSF) from Tocris Bioscience where microspheres were immersed to test the behaviour of the designed LoC. One of main features of the proposed LoC platform is its thin thickness, including micro-channels and silicon CMOS chip. The latter is integrated into the glass top-layer of the LoC measuring 0.5 mm. The size of the device is 9 mm * 5 mm. the electrode architecture is composed of 8*2*2 L shaped electrodes in a 650 um channel width and 4 sites for interdigitited electrodes. 32 L-shaped electrodes were connected to a electronics circuit for cells manipulation using dielectrophoresis (DEP). The described LoC achieved an efficient separation within a concentration of 50 ul of a solution of microspheres, distilled water (DW) and 500 ul of ACSF. Beyond this concentration, electrode destruction was observed. PMID- 23366160 TI - Development of high resolution, multiplexed electrode arrays: Opportunities and challenges. AB - More than one third of the world's 60 million people with epilepsy have seizures that cannot be controlled by medication. Some of these individuals may be candidates for surgical removal of brain regions that generate seizures, but the chance of being seizure free after epilepsy surgery is as low as 35% in many patients. Even when surgery is successful, patients risk neurological deficits like memory loss and speech difficulties. The need for new treatments is clear. A central barrier to better treatments for epilepsy is technological: we do not have devices capable of interfacing with the brain with small enough electrodes over large enough regions to map epileptic networks in sufficient detail to enable treatment. Our collaborative group has developed new implantable brain devices to address this challenge. Our devices, made from flexible silicon nanoribbons, can record from these very small brain regions, with electrodes 1/2 millimeter apart or less, and can be scaled up to clinically useful sizes, on the order of 64 cm(2). They consist of thousands of individually controllable microelectrodes. PMID- 23366161 TI - Parallel in-vitro and in-vivo techniques for optimizing cellular microenvironments by implementing biochemical, biomechanical and electromagnetic stimulations. AB - Development of novel engineering techniques that can promote new clinical treatments requires implementing multidisciplinary in-vitro and in-vivo approaches. In this study, we have implemented microfluidic devices and in-vivo rat model to study the mechanism of neural stem cell migration and differentiation. These studies can result in the treatment of damages to the neuronal system. In this research, we have shown that by applying appropriate ranges of biochemical and biomechanical factors as well as by exposing the cells to electromagnetic fields, it is possible to improve viability, proliferation, directional migration and differentiation of neural stem cells. The results of this study can be implemented in the design of optimized platforms that can be transplanted into the damaged areas of the neuronal system. PMID- 23366162 TI - Force sensing micro-forceps for robot assisted retinal surgery. AB - Membrane peeling is a standard vitreoretinal procedure, where the surgeon delaminates a very thin membrane from retina surface using surgical picks and forceps. This requires extremely delicate manipulation of the retinal tissue. Applying excessive forces during the surgery can cause serious complications leading to vision loss. For successful membrane peeling, most of the applied forces need to be very small, well below the human tactile sensation threshold. In this paper, we present a robotic system that combines a force sensing forceps tool and a cooperatively-controlled surgical robot. This combination allows us to measure the forces directly at the tool tip and use this information for limiting the applied forces on the retina. This may prevent many iatrogenic injuries and allow safer maneuvers during vitreoretinal procedures. We show that our system can successfully eliminate hand-tremor and excessive forces in membrane peeling experiments on the inner shell membrane of a chicken embryo. PMID- 23366163 TI - Swept source optical coherence tomography based smart handheld vitreoretinal microsurgical tool for tremor suppression. AB - Microsurgeons require the ability to make precise and stable maneuvers in order to achieve surgical objectives and to minimize surgical risks during freehand microsurgical procedures. This work presents a novel common path swept source optical coherence tomography based smart surgical tool that suppresses hand tremor. It allows enhanced tool tip stabilization, more accurate targeting and may lower surgical risk. Here the one dimensional motion tremor of a surgeon's hand is assessed by the surgical instrument. The ability to accurately locate a surgical target and the ability to maintain tool tip offset distances in a chicken embryo model are significantly improved as compared to freehand use. PMID- 23366164 TI - Comparative evaluation of monocular augmented-reality display for surgical microscopes. AB - Medical augmented reality has undergone much development recently. However, there is a lack of studies quantitatively comparing the different display options available. This paper compares the effects of different graphical overlay systems in a simple micromanipulation task with "soft" visual servoing. We compared positioning accuracy in a real-time visually-guided task using Micron, an active handheld tremor-canceling microsurgical instrument, using three different displays: 2D screen, 3D screen, and microscope with monocular image injection. Tested with novices and an experienced vitreoretinal surgeon, display of virtual cues in the microscope via an augmented reality injection system significantly decreased 3D error (p < 0.05) compared to the 2D and 3D monitors when confounding factors such as magnification level were normalized. PMID- 23366165 TI - Towards localizing on the surface of the beating heart. AB - This paper presents preliminary work toward localizing on a surface which undergoes periodic deformation, as an aspect of research on HeartLander, a miniature epicardial crawling robot. Using only position measurements from the robot, the aim of this work is to use the nonuniform movements of the heart as features to aid in localization. Using a particle filter, with motion and observation models which accurately model the robotic system, registration and localization parameters can be quickly and accurately identified. The presented framework is demonstrated in simulation on dynamic 2-D models which approximate the deformation of the surface of the heart. PMID- 23366166 TI - The kinematic architecture of the Active Headframe: A new head support for awake brain surgery. AB - This paper presents the novel hybrid kinematic structure of the Active Headframe, a robotic head support to be employed in brain surgery operations for an active and dynamic control of the patient's head position and orientation, particularly addressing awake surgery requirements. The topology has been conceived in order to satisfy all the installation, functional and dynamic requirements. A kinetostatic optimization has been performed to obtain the actual geometric dimensions of the prototype currently being developed. PMID- 23366167 TI - Handheld micromanipulator for robot-assisted stapes footplate surgery. AB - Stapes footplate surgery is complex and delicate. This surgery is carried out in the middle ear to improve hearing. High accuracy is required to avoid critical tissues and structures near the surgical worksite. By suppressing the surgeon's tremor during the operation, accuracy can be improved. In this paper, a fully handheld active micromanipulator known as Micron is evaluated for its feasibility for this delicate operation. An ergonomic handle, a custom tip, and a brace attachment were designed for stapes footplate surgery and tested in a fenestration task through a fixed speculum. Accuracy was measured during simulated surgery in two different scenarios: Micron off (unaided) and Micron on (aided), both with image guidance. Preliminary results show that Micron significantly reduces the mean position error and the mean duration of time spent in specified dangerous zones. PMID- 23366168 TI - An ensembling approach for optic cup detection based on spatial heuristic analysis in retinal fundus images. AB - Optic cup detection remains a challenging task in retinal image analysis, and is of particular importance for glaucoma evaluation, where disease severity is often assessed by the size of the optic cup. In this paper, we propose spatial heuristic ensembling (SHE), an approach which aims to fuse the advantages of each method based on the specific performance in each defined sector. In this way, we generate an ensembled optic cup which is obtained from the optimal combination of the component methods. We conduct experiments on the ORIGA data set of 650 retinal images and show that the ensemble approach performs better than the individual segmentations, reducing the relative overlap error, and CDR errors by as much as 0.04 CDR units. The results are promising for the continued development of such an approach for improving optic cup segmentation. PMID- 23366169 TI - Efficient optic cup localization using regional propagation based on retinal structure priors. AB - We present a regional propagation approach based on retinal structure priors to localize the optic cup in 2D fundus images, which is the primary image component clinically used for identifying glaucoma. This method provides three major contributions. First, it proposes processing of the fundus images at the superpixel level, which leads to more descriptive and effective features than those employed by pixel based techniques, without additional computational cost. Second, the proposed approach does not need manually labeled training samples, but uses the structural priors on relative cup and disc positions. Third, a refinement scheme that utilizes local context information is adopted to further improve the accuracy. Tested on the ORIGA-light clinical dataset, which comprises of 325 images from a population-based study, the proposed method achieves a 34.9% non-overlap ratio with manually-labeled ground-truth and a 0.104 absolute cup-to disc ratio (CDR) error. This level of accuracy is much higher than the state-of the-art pixel based techniques, with a comparable or even less computational cost. PMID- 23366170 TI - Measurement of retinal arteriolar diameters from auto scale phase congruency with fuzzy weighting and L1 regularization. AB - Manual measurements of small changes in retinal vascular diameter are slow and may be subject to considerable observer-related biases. Among the conventional automatic methods the sliding linear regression filter (SLRF) demonstrates the least scattered and most repeatable coefficients. For optimal performance it relies on the choice of the correct filter scale for different vessel sizes. A small scale extracts fine details at the expense noise sensitivity, while large scales have poor edge localization. Here we use auto scale phase congruency to select the filter scales with fuzzy weighting to reduce noise, and L1 regularization for edge smoothing. Our method uses a one dimensional analysis normal to the vessel and so is faster than the 2D phase congruency. In 65 vessels randomly selected from 20 images the proposed method showed better repeatability and over three times less scattering than conventional SLRF. PMID- 23366171 TI - Computer-aided diagnosis of proliferative diabetic retinopathy. AB - Monitoring the openness of the major temporal arcade (MTA) and how it changes over time could facilitate improved diagnosis and timely treatment of proliferative diabetic retinopathy (PDR). We present methods for user-guided modeling and measurement of the openness of the MTA based on a form of the generalized Hough transform for the detection of parabolas, and to compare it with a method of arcade angle measurement. The methods, implemented via a graphical user interface, were tested with retinal fundus images of 10 normal individuals and 15 patients with PDR. The results using the openness parameters of single- and dual-parabolic models as well as the arcade angle measurements indicate areas under the receiver operating characteristics of A(z)= 0.94, 0.87, and 0.84, respectively. The proposed methods should facilitate improved quantitative analysis of the architecture of the MTA, as well as assist in detection, diagnosis, and improved treatment of PDR. PMID- 23366172 TI - Detecting flash artifacts in fundus imagery. AB - In a telemedicine environment for retinopathy screening, a quality check is needed on initial input images to ensure sufficient clarity for proper diagnosis. This is true whether the system uses human screeners or automated software for diagnosis. We present a method for the detection of flash artifacts found in retina images. We have collected a set of retina fundus imagery from February 2009 to August 2011 from several clinics in the mid-South region of the USA as part of a telemedical project. These images have been screened with a quality check that sometimes omits specific flash artifacts, which can be detrimental for automated detection of retina anomalies. A multi-step method for detecting flash artifacts in the center area of the retina was created by combining characteristic colorimetric information and morphological pattern matching. The flash detection was tested on a dataset of 5218 images representative of the population. The system achieved a sensitivity of 96.54% and specificity of 70.16% for the detection of the flash artifacts. The flash artifact detection can serve as a useful tool in quality screening of retina images in a telemedicine network. The detection can be expected to improve automated detection by either providing special handling for these images in combination with a flash mitigation or removal method. PMID- 23366173 TI - Centroid extraction from Hartmann-Shack images using swarm clustering approach. AB - Image analysis of Hartmann-Shack Wavefront sensor is practically useful to extract complex refractive aberrations in the retina. However due to noises such as lens glares, reflections, occlusions or extreme aberrations, pinpointing centroid locations of these lenslets prove to be a challenging problem. In this paper we propose a novel automatic extraction of lenslet foci using Rapid Centroid Estimation (RCE) and Artificial Centroid Injection (ACI). Using this method we are able to extract as much as 86% of total lenslets' centroids before injection and 97% of total lenslets' centroids after injection on average based on experimental data on 20 Hartmann-Shack images of off-axis aberration in the human eye. Our technique advantage is that it does not require any prior fine tuning. PMID- 23366174 TI - Superpixel classification for initialization in model based optic disc segmentation. AB - Optic disc segmentation in retinal fundus image is important in ocular image analysis and computer aided diagnosis. Because of the presence of peripapillary atrophy which affects the deformation, it is important to have a good initialization in deformable model based optic disc segmentation. In this paper, a superpixel classification based method is proposed for the initialization. It uses histogram of superpixels from the contrast enhanced image as features. In the training, bootstrapping is adopted to handle the unbalanced cluster issue due to the presence of peripapillary atrophy. A self-assessment reliability score is computed to evaluate the quality of the initialization and the segmentation. The proposed method has been tested in a database of 650 images with optic disc boundaries marked by trained professionals manually. The experimental results show an mean overlapping error of 10.0% and standard deviation of 7.5% in the best scenario. The results also show an increase in overlapping error as the reliability score reduces, which justifies the effectiveness of the self assessment. The method can be used for optic disc boundary initialization and segmentation in computer aided diagnosis system and the self-assessment can be used as an indicator of cases with large errors and thus enhance the usage of the automatic segmentation. PMID- 23366176 TI - Segmentation of vessels in retinal images based on directional height statistics. AB - In this paper we present a fast and simple, yet accurate method for the segmentation of retinal blood vessels. Many diseases of the eye result in the distortions of the vessels. The precise location of the major optic veins may be used for the localization of other anatomical parts, such as the macula and the optic disc. Also, many microaneurysm detection methods consider an additional vessel segmentation step. The proposed method realizes the recognition of vessels through considering cross-sections of the image at different orientations. Peaks on the profiles are localized and their heights are measured. This way, a set of height values are assigned to every pixel of the image. Simple statistics are calculated for every pixel, and combined to construct a vessel score map. We apply a simple thresholding procedure and postprocessing step to obtain a binary vessel mask. The method has been tested on the publicly available DRIVE database, and it proved to be competitive with the state-of-the-art. PMID- 23366175 TI - Sector-based optic cup segmentation with intensity and blood vessel priors. AB - The optic cup segmentation is critical for automated cup-to-disk ratio measurement, and hence computer-aided diagnosis of glaucoma. In this paper, we propose a novel sector-based method for optic cup segmentation. The method comprises two parts: intensity-based cup segmentation with shape constraints and blood vessel-based refinement. The initial estimation of the cup is obtained by applying a statistical deformable model on the vessel free image. At the same time, blood vessels within the optic disk are extracted, after which vessel bendings and vessel boundaries in the nasal side are located. Subsequently, these key points in the blood vessels are used to fine tune the cup. The algorithm is evaluated on 650 fundus images from the ORIGA(-light) database. Experimental results show that the Dice coefficient for the optic cup segmentation can be as high as 0.83, which outperforms other existing methods. The results demonstrate good potential for the proposed method to be used in automated optic cup segmentation and glaucoma diagnosis. PMID- 23366177 TI - Classification of diabetic retinopathy images using multi-class multiple-instance learning based on color correlogram features. AB - All people with diabetes have the risk of developing diabetic retinopathy (DR), a vision-threatening complication. Early detection and timely treatment can reduce the occurrence of blindness due to DR. Computer-aided diagnosis has the potential benefit of improving the accuracy and speed in DR detection. This study is concerned with automatic classification of images with microaneurysm (MA) and neovascularization (NV), two important DR clinical findings. Together with normal images, this presents a 3-class classification problem. We propose a modified color auto-correlogram feature (AutoCC) with low dimensionality that is spectrally tuned towards DR images. Recognizing the fact that the images with or without MA or NV are generally different only in small, localized regions, we propose to employ a multi-class, multiple-instance learning framework for performing the classification task using the proposed feature. Extensive experiments including comparison with a few state-of-art image classification approaches have been performed and the results suggest that the proposed approach is promising as it outperforms other methods by a large margin. PMID- 23366178 TI - Differences in blood flow between auditory and visual stimuli in the Psychomotor Vigilance Task and GO/NOGO Task. AB - The Psychomotor Vigilance Task (PVT) and the GO/NOGO task are generally applied to measure the ability of sustained attention. Advances in functional brain imaging equipment, such as functional Magnetic Resonance Imaging (fMRI) and functional Near-Infrared Spectroscopy (fNIRS), have resulted in increased application of brain imaging with these tasks. However, several different stimuli are adopted in these tasks, including both auditory and visual stimuli. Therefore, even when a subject performs these tasks, it can be assumed that the activated brain regions would vary when the different stimuli are given. Furthermore, even when a subject performs the tasks with the same sustained attention, the activated brain regions would vary when the configurations of these tasks are different. In this study, the reaction time and changes in blood flow were measured when a subject performed the PVT and GO/NOGO tasks, and so it is possible to discuss (1) the differences between visual and auditory stimuli and (2) the differences between PVT and GO/NOGO tasks. The results indicated increased blood flow at the left side of the dorsolateral prefrontal cortex in the PVT with visual stimulus compared with the auditory stimulus. In the GO/NOGO task, the blood flow associated with visual stimuli increased at the both sides of the inferior temporal gyrus and the right side of the inferior frontal gyrus compared with auditory stimuli. These observations suggested that the configurations of these tasks, such as the PVT and the GO/NOGO tasks, exert influences on the activated brain regions when a subject performs these tasks. PMID- 23366179 TI - Classification subject effects using changes in cerebral blood flow on the Stroop test. AB - Functional near-infrared spectroscopy (fNIRS) is often used as a diagnostic method for mental illness, because the average patterns of changes in cerebral blood flow vary between such patients and healthy subjects. In addition, indoor environments and psychology alter the average patterns of changes in cerebral blood flow. These observations suggest that it may be possible to classify healthy subjects into different groups according to certain characteristics. The accuracy of fNIRS should be improved once it becomes possible to automatically determine the key factors affecting fNIRS data. The present study was performed first to determine whether there are differences in fNIRS data when the test subjects are classified into groups based on the scores related to task performances and questionnaires, and to determine whether there are differences in score when the test subjects are classified into groups based on fNIRS data. Differences were observed in fNIRS data between groups when the subjects were classified based on incorrect answers on the questionnaire and their degree of fatigue. In addition, there were differences in score between groups when the subjects were classified according to fNIRS data. These results suggested that subjects can be classified into groups automatically based on scores related to both task performance and fNIRS data. PMID- 23366180 TI - Deformation of yellow spot area by compulsory increase of eye pressure. AB - The deformation characteristics of yellow spot of retina under a compulsory eye pressure increase is discussed for both normal and glaucoma eyes. We impart the force corresponding to 50[mmHg] of eye pressure to eyelid through a contact probe with force gauge. We analyze the deformation of yellow spot area for three different layers. An interesting observation is that yellow spot suffered by glaucoma has thinner layer and smaller deformation than that of normal subjects, especially the characteristics is enhanced in both the surface and the bottom layers. PMID- 23366181 TI - Measuring the size of neoplasia in colonoscopy using Depth-From-Defocus. AB - Colonoscopy is the reference medical examination for the diagnosis and treatment of neoplasia in gastroenterology. During the examination, the expert explores the colon cavity with a gastroscope in order to detect neoplasias - abnormal growths of tissue - and to diagnose which ones could be malignant. The Paris classification of superficial neoplastic lesions is the gold standard set of criteria for this type of diagnosis. One of the major criteria is the size. However, this is tremendously difficult to accurately estimate from images. This is because the absolute scale of the observed tissues is not directly conveyed in the 2D endoscopic image. We propose an image-based method to estimate the size of neoplasias. The core idea is to combine Depth-From-Focus (DFF) and Depth-From Defocus (DFD). This allows us to recover the absolute scale by automatically detecting the blur/unblur breakpoint while the expert pulls the gastroscope away from a neoplasia. Our method is passive: it uses the image data only and thus does not require hardware modification of the gastroscope. We report promising experimental results on phantom and patient datasets. PMID- 23366182 TI - Segmentation of diffuse reflectance hyperspectral datasets with noise for detection of Melanoma. AB - We present a segmentation algorithm that allows optical properties to be extracted from diffuse reflectance hyperspectral datasets with a speedup of three orders of magnitude when compared to current methods. Such data could be used for the detection of melanoma. The algorithm first performs dimensionality reduction using principal component analysis, and then the image is segmented using k-means clustering. The mean spectrum from each cluster is then calculated and can be used to extract chemical information. By reducing the number of spectra to be analyzed, extraction of physiological information can be achieved three orders of magnitude faster than methods requiring the analysis of every spectrum in the hyperspectral dataset. The effect of noise on the ability of the algorithm to accurately segment images was tested using digital phantoms, for which the noise level was under the control of the investigators. The analysis showed a linear relationship between the level of noise and the smallest difference in scattering that the algorithm was able to accurately detect and segment. This finding can be used to determine the maximum amount of noise in the imaging system that will still allow detection of the difference in optical properties between non melanoma and melanoma. PMID- 23366183 TI - Computational basis for risk stratification of peripheral neuropathy from thermal imaging. AB - The goal of this paper is to present a computer-based system for analyzing thermal images in the detection of preclinical stages of peripheral neuropathy (PN) or diabetic foot. Today, vibration perception threshold (VPT) and sensory tests with a monofilament are used as simple, noninvasive methods for identifying patients who have lost sensation in their feet. These tests are qualitative and are ineffective in stratifying risk for PN in a diabetic patient. In our system a cold stimulus applied to the foot causes a thermoregulatory and corresponding microcirculation response of the foot. A thermal video monitors the recovery of the microcirculation in the foot plantar. Thermal videos for 8 age-matched subjects were analyzed. Six sites were tracked and an average thermal emittance calculated. Characteristics of the recovery curve were extracted using coefficients from an exponential curve fitting process and compared among subjects. The magnitude of the recovery was significantly different for the two classes of subjects. Our system shows evidence of differences between both groups, which could lead to a quantitative test to screen and diagnose peripheral neuropathy. PMID- 23366184 TI - Computational methods for objective assessment of conjunctival vascularity. AB - Assessment of vascularity of conjunctiva has many diagnostic and prognostic applications, thus creation of computational methods for its fast and objective assessment is of importance. Here we provide two different methods for estimation of conjunctiva's vascularity from color digital images, with our best results showing a correlation coefficient of 0.89 between the predicted and ground truth values using a committee of artificial neural networks. PMID- 23366185 TI - A fresh look at the validity of the diffusion approximation for modeling fluorescence spectroscopy in biological tissue. AB - Fluorescence has become a widely used technique for applications in noninvasive diagnostic tissue spectroscopy. The standard model used for characterizing fluorescence photon transport in biological tissue is based on the diffusion approximation. On the premise that the total energy of excitation and fluorescent photon flows must be conserved, we derive the widely used diffusion equations in fluorescence spectroscopy and show that there must be an additional term to account for the transport of fluorescent photons. The significance of this additional term in modeling fluorescence spectroscopy in biological tissue is assessed. PMID- 23366186 TI - Interactive segmentation of airways from chest X-ray images using active shape models. AB - Classification of airway shapes in chest X-ray images may be useful in computer aided detection of lymphadenopathy associated with pediatric tuberculosis. This paper presents an interactive approach for airway segmentation from chest X-ray images that may be used in an airway shape classification algorithm. A local normalization filter is applied as a preprocessing step to enhance the visibility of the airways. Segmentation is then performed with the aid of active shape models (ASMs), which are warped to a set of manually defined control points on the image to be segmented, using an affine transformation. Two shape models are built, one of which consists of points on the airway edges only and the other consists of points on the airway edges as well as points on the ribs. The ASMs are built from a set of manually segmented images. The Hausdorff distance is used to compute the accuracy of the segmentations with reference to a manual segmentation. PMID- 23366187 TI - Estimated radiation dose reduction using non-linear diffusion method in computed radiography. AB - In this paper we use a non-linear diffusion method to filter the inherent noise in a Computed Radiography (CR) for reducing the dose absorbed by the patients especially children in pediatric applications, related with the exposure mAs. The method is implemented in order to create a lower CR dose based on the selection of lower X-ray exposure and with a reduction of the noise using a non-linear diffusion method. The impact of several milliAmpere-seconds (mAs) setting on image quality has been studied using the RANDO phantom. The obtained results show good agreements between the filtered images and real images in terms of noise variance measurements. The new CR images allow medical researchers to analyze how a low dose affects the patient diagnosis. PMID- 23366188 TI - Realization of spatial compliant virtual fixture using eigenscrews. AB - Virtual fixture is kind of assistance mechanism to limit movement into restricted regions and/or guide movement along desired trajectories in human-machine interactive operation. The structure of geometric and dynamic constraints of reference tasks is analyzed using screw theory. End-effector and the reference frame are elastically coupled by virtual screw springs, which slides along the reference sequences. An allowable motion screw set is constructed, from which the desired spatial compliance and stiffness matrices are synthesized from an allowable motion screw set. The presented virtual fixture are implemented dynamic contour tracking experiment, the effects of control parameters on system performance are also analyzed. The proposed virtual fixtures unites rotation and translation motions, and filter out task-unrelated components from the manual input while augmenting task-related components. PMID- 23366189 TI - Computer assisted detection of liver neoplasm (CADLN). AB - To date, radiologists evaluate neoplasm images manually. Currently there is wide spread attention for developing image processing modules to detect and measure early stage neoplasm growth in liver. We report the fundamentals associated with the development of a multifunctional image processing algorithm useful to measure early growth of neoplasm and the volume of liver. Using CADLN, a radiologist will be able to compare computer generated volumetric data in serial imaging of the patients over time, that eventually will enable assessing progression or regression of neoplasm growth and help in treatment planning. PMID- 23366190 TI - Material depth reconstruction method of multi-energy X-ray images using neural network. AB - With the advent of technology, multi-energy X-ray imaging is promising technique that can reduce the patient's dose and provide functional imaging. Two dimensional photon-counting detector to provide multi-energy imaging is under development. In this work, we present a material decomposition method using multi energy images. To acquire multi-energy images, Monte Carlo simulation was performed. The X-ray spectrum was modeled and ripple effect was considered. Using the dissimilar characteristics in energy-dependent X-ray attenuation of each material, multiple energy X-ray images were decomposed into material depth images. Feedforward neural network was used to fit multi-energy images to material depth images. In order to use the neural network, step wedge phantom images were used for training neuron. Finally, neural network decomposed multi energy X-ray images into material depth image. To demonstrate the concept of this method, we applied it to simulated images of a 3D head phantom. The results show that neural network method performed effectively material depth reconstruction. PMID- 23366191 TI - Electrical impedance tomography reconstruction through simulated annealing with total least square error as objective function. AB - The EIT reconstruction problem can be solved as an optimization problem where the divergence between a simulated impedance domain and the observed one is minimized. This optimization problem can be solved by a combination of Simulated Annealing (SA) for optimization and Finite Element Method (FEM) for simulation of the impedance domain. This combination has usually a very high computational cost, since SA requires an elevated number of objective function evaluations and those, obtained through FEM, are often expansive enough to make the whole process inviable. In here it is presented a new approach for EIT image reconstructions using SA and partial evaluations of objective functions based on overdetermined linear systems. This new reconstruction approach is evaluated with experimental data and compared with previous approaches. PMID- 23366192 TI - Investigation of brain tissue segmentation error and its effect on EEG source localization. AB - Surgical therapy has become an important therapeutic alternative for patients with medically intractable epilepsy. Correct and anatomically precise localization of the epileptic focus, preferably with non-invasive methods, is the main goal of the pre-surgical epilepsy diagnosis to decide if resection of brain tissue is possible. For evaluating the performance of the source localization algorithms in an actual clinical situation, realistic patient-specific human head models that incorporate the heterogeneity nature of brain tissues is required. In this paper, performance of two of the most widely used software packages for brain segmentation, namely FSL and FreeSurfer has been analyzed. Then a segmented head model from a package with better performance is used to investigate the effects of brain tissue segmentation in EEG source localization. PMID- 23366196 TI - An evaluation of EEG scanner's dependence on the imaging technique, forward model computation method, and array dimensionality. AB - EEG source reconstruction involves solving an inverse problem that is highly ill posed and dependent on a generally fixed forward propagation model. In this contribution we compare a low and high density EEG setup's dependence on correct forward modeling. Specifically, we examine how different forward models affect the source estimates obtained using four inverse solvers Minimum-Norm, LORETA, Minimum-Variance Adaptive Beamformer, and Sparse Bayesian Learning. PMID- 23366195 TI - Random location of multiple sparse priors for solving the MEG/EEG inverse problem. AB - MEG/EEG brain imaging has become an important tool in neuroimaging. Current techniques based in Bayesian approaches require an a-priori definition of patch locations on the cortical manifold. Too many patches results in a complex optimisation problem, too few an under sampling of the solution space. In this work random locations of the possible active regions of the brain are proposed to iteratively arrive at a solution. We use Bayesian model averaging to combine different possible solutions. The proposed methodology was tested with synthetic MEG datasets reducing the localisation error of the approaches based on fixed locations. Real data from a visual attention study was used for validation. PMID- 23366197 TI - Mobile brain/body imaging (MoBI): High-density electrical mapping of inhibitory processes during walking. AB - The present study investigated the feasibility of acquiring high-density event related brain potential (ERP) recordings during treadmill walking in human subjects. The work builds upon recent studies testing the applicability of real world tasks while obtaining electroencephalographic (EEG) recordings. Participants performed a response inhibition GO/NOGO task - designed to evoke a P3 component for correct response inhibitions and an error-related negativity (ERN) for incorrect commission errors - while speed of walking was experimentally manipulated. Robust P3 and ERN components were obtained under all experimental conditions - while participants were sitting, walking at moderate speed (2.4 km/hour), or walking rapidly (5 km/hour). Signal-to-noise ratios were remarkably similar across conditions, pointing to the feasibility of high-fidelity ERP recordings under relatively vigorous activity regimens. There is considerable research and clinical motivation to obtain high quality neurophysiological measures under more naturalistic environmental settings such as these. Strong links between cognitive load and gait abnormalities are seen in a number of clinical populations and these MoBI technologies provide highly promising methods for gaining insights into the underlying pathophysiology. PMID- 23366199 TI - Investigation of cross-frequency phase-amplitude coupling in visuomotor networks using magnetoencephalography. AB - Cross-frequency phase-amplitude coupling (PAC) within large neuronal populations is hypothesized to play a functional role in information processing in a range of cognitive tasks. The goal of our study was to examine the putative role of PAC in the brain networks that mediate continuous visuomotor control. We estimated the cortical activity that mediates visuomotor control via magnetoencephalography (MEG) recordings in 15 healthy volunteers. We extracted the cortical signal amplitudes and phases at the frequencies of interest by means of band-pass filtering followed by Hilbert transforms. To quantify task-related changes of PAC, we implemented a technique based on the Kullback-Leibler divergence. The choice of this technique among others was based on the results of comparisons performed on simulations of coupled sources in various noise conditions. The application of PAC to the MEG data revealed a significant task-related increase in coupling between the phase of delta (2-5 Hz) and the amplitude of high-gamma (60-90 Hz) oscillations in the occipital and parietal cortices as well as in the cerebellum. Remarkably, when comparing PAC in the early trials to PAC recorded towards the end of the experiment we found a significant increase in delta-high gamma coupling over time in the superior parietal lobule, possibly reflecting visuomotor adaptation processes. Our results suggest that, in addition to power modulations, cross-frequency interactions play a key role in visuomotor behavior. PMID- 23366198 TI - A physiologically motivated sparse, compact, and smooth (SCS) approach to EEG source localization. AB - Here, we introduce a novel approach to the EEG inverse problem based on the assumption that principal cortical sources of multi-channel EEG recordings may be assumed to be spatially sparse, compact, and smooth (SCS). To enforce these characteristics of solutions to the EEG inverse problem, we propose a correlation variance model which factors a cortical source space covariance matrix into the multiplication of a pre-given correlation coefficient matrix and the square root of the diagonal variance matrix learned from the data under a Bayesian learning framework. We tested the SCS method using simulated EEG data with various SNR and applied it to a real ECOG data set. We compare the results of SCS to those of an established SBL algorithm. PMID- 23366200 TI - High precision semi-automated vertebral height measurement using computed tomography: A phantom study. AB - The measurement of vertebral heights is necessary for the evaluation of many disorders affecting the spine. High precision is particularly important for longitudinal studies where subtle changes are to be detected. Computed tomography (CT) is the modality of choice for high precision studies. Radiography and dual emission X-ray absorptiometry (DXA) use 2D images to assess 3D structures, which can result in poor visualization due to the superimposition of extraneous anatomical objects on the same 2D space. We present a semi-automated computer algorithm to measure vertebral heights in the 3D space of a CT scan. The algorithm segments the vertebral bodies, extracts their end plates and computes vertebral heights as the mean distance between end plates. We evaluated the precision of our algorithm using repeat scans of an anthropomorphic vertebral phantom. Our method has high precision, with a coefficient of variation of only 0.197% and Bland-Altmann 95% limits of agreement of [-0.11, 0.13] mm. For local heights (anterior, middle, posterior) the algorithm was up to 4.2 times more precise than a manual mid-sagittal plane method. PMID- 23366201 TI - GPU acceleration of optical mapping algorithm for cardiac electrophysiology. AB - Optical mapping is an increasingly popular tool for experimentally analyzing the electrical activity in the heart. The optical mapping algorithm is computationally intense and consumes a considerable amount of time even with a highly optimized program running on a state-of-the-art multi-core microprocessor. For example, one second of data requires approximately 5 minutes of computation time (3.66 FPS) with a C++ program parallelized by OpenMP running on a 3.4GHz Quad-Core CPU. This article presents a GPU implementation of the optical mapping algorithm. Our result indicates that the GPU implementation is capable of processing the optical mapping video at 578 FPS which achieves 157.92X speed against the OpenMP optimized CPU implementation. PMID- 23366202 TI - Detection of quiescent phases in echocardiography data using non-linear filtering and boundary detection. AB - In order to detect the quasi-stationary states of the heart within a cardiac cycle from echocardiography data, we present an algorithm that uses non-linear filtering and boundary detection. The non-linear filtering algorithm involves anisotropic diffusion to remove the speckle noise from the data and to smoothen the homogeneous regions while preserving the edges. Following this, we perform binary thresholding and boundary detection, and observe the positional changes in the region of interest. From a series of echocardiography images, we derived the regions of cardiac quiescence, which we then plotted on the electrocardiograph (ECG) R-R interval. It is observed that the quiescence occurs in the diastolic region of the ECG signal, but the position and length of quiescence varies across multiple cardiac cycles for the same individual. PMID- 23366204 TI - Novel method for quantitative assessment of physical workload of healthcare workers by a tetherless ergonomics workstation. AB - Healthcare workers are at risk of physical injury. Our laboratory has developed a tetherless ergonomics workstation that is suitable for studying physicians' and nurses' physical workloads in clinical settings. The workstation uses wearable sensors to record multiple channels of body orientation and muscle activity and wirelessly transmits them to a base station laptop computer for display, storage, and analysis. The ergonomics workstation generates long records of multi-channel data, so it is desired that the workstation automatically process these records and provide graphical and quantitative summaries of the physical workloads experienced by the healthcare workers. This paper describes a novel method of automated quantitative assessment of physical workload, termed joint cumulative amplitude-duration (JCAD) analysis, that has advantages over previous methods and illustrates its use in a comparison of the physical workloads of robotically assisted surgery versus manual video-endoscopic surgery. PMID- 23366203 TI - An investigation into the viability of image processing for the measurement of sarcomere length in isolated cardiac trabeculae. AB - A preliminary investigation was performed into the viability of using frequency domain image processing techniques to determine sarcomere length from bright field images of isolated cardiac trabecula in real-time. Hardware based data processing was used to compute the average sarcomere length in a cardiac trabecula undergoing stretch. Our technique estimated the increase in mean sarcomere length with increasing muscle length as the trabecula was stretched to and beyond the normal physiological limit of 2.4 um. The standard error in the mean sarcomere length extracted from each image was typically10 nm. PMID- 23366205 TI - Towards minimally invasive monitoring for gastroenterology - An external Squamocolumnar Junction Locator. AB - Transient lower oesophageal sphincter relaxations (TLOSRs) occur frequently and are the main mechanism of acid reflux. The only means of currently detecting TLOSRs is intra-luminal manometry and the probes themselves may stimulate TLOSRs. The squamo-columnar junction moves 4-5 centimeters proximally during TLOSRs and this provides a means of detecting such episodes. The objective of this work is to develop a sensor system capable of detecting the movement of a miniature magnet attached to the squamo-columnar junction from outside the body and thus allow detection of TLOSRs without the artifact associated with intraluminal detection probes. A GaAs Hall effect sensor was selected and an alternating current supply was developed with a combination of filters and a Phase Sensitive Detector, to detect the magnet. The oscillation frequency of the current was chosen in order to reduce electronic noise, and filtering outside this frequency means the signal to noise ratio was greatly improved. The phase sensitive detector was employed to accurately convert the amplitude of the sensor's output to a DC signal. With the addition of paired Flux Concentrators increases the range up to 10.2 centimetres, an improvement of 580% over commercial Hall effect sensors. The AC circuit and flux concentrator device far exceeds the sensitivity of the current Hall effect sensors supplied in the market, by rejecting noise and providing accurate measurement over significantly larger distances. The development of this sensor has applications beyond this specific medical device. PMID- 23366206 TI - On the use of evoked potentials for quantification of pain. AB - Pain is a subjective and individual sensation causing major discomfort. So, it is necessary to put into practice methods to objectively quantify it. Several studies indicate that evoked potentials (EP) generate responses which may reflect painful processes. This study reports the results of the application of two different protocols by using biopotentials to objectively measure pain. The first (protocol 1) evaluates the relation between pain, induced by electrical stimulation, and subjective perception and also with nociceptive flexion reflex (NFR) represented by muscle activity (electromyography) detected on the femoral biceps after sural nerve stimulation. The second protocol (protocol 2) verifies whether there is some correlation between M-wave parameters and subjective pain sensation. The results obtained from protocol 1 suggest that the area of the EMG envelope and entropy estimated from the EMG activity are correlated with subjective sensation of pain. The analysis of data obtained from protocol 2 shows a correlation between the global minimum of the M-wave and pain increase. These results contribute to studies which seek to objective measures for pain quantification based on the analysis of biopotentials. PMID- 23366207 TI - Investigation of voltage source design's for Electrical Impedance Mammography (EIM) Systems. AB - According to Jossient, interesting characteristics of breast tissues mostly lie above 1MHz; therefore a wideband excitation source covering higher frequencies (i.e. above 1MHz) is required. The main objective of this research is to establish a feasible bandwidth envelope that can be used to design a constant EIM voltage source over a wide bandwidth with low output impedance for practical implementation. An excitation source is one of the major components in bio impedance measurement systems. In any bio-impedance measurement system the excitation source can be achieved either by injecting current and measuring the resulting voltages, or by applying voltages and measuring the current developed. This paper describes three voltage source architectures and based on their bandwidth comparison; a differential voltage controlled voltage source (VCVS) is proposed, which can be used over a wide bandwidth (>15MHz). This paper describes the performance of the designed EIM voltage source for different load conditions and load capacitances reporting signal-to-noise ratio of approx 90dB at 10MHz frequency, signal phase and maximum of 4.75kOmega source output impedance at 10MHz. Optimum data obtained using Pspice(r) is used to demonstrate the high bandwidth performance of the source. PMID- 23366208 TI - Activity recognition in planetary navigation field tests using classification algorithms applied to accelerometer data. AB - Accelerometer data provide useful information about subject activity in many different application scenarios. For this study, single-accelerometer data were acquired from subjects participating in field tests that mimic tasks that astronauts might encounter in reduced gravity environments. The primary goal of this effort was to apply classification algorithms that could identify these tasks based on features present in their corresponding accelerometer data, where the end goal is to establish methods to unobtrusively gauge subject well-being based on sensors that reside in their local environment. In this initial analysis, six different activities that involve leg movement are classified. The k-Nearest Neighbors (kNN) algorithm was found to be the most effective, with an overall classification success rate of 90.8%. PMID- 23366209 TI - Motion artifact reduction in electrocardiogram using adaptive filtering based on half cell potential monitoring. AB - The electrocardiogram (ECG) is the main measurement parameter for effectively diagnosing chronic disease and guiding cardio-fitness therapy. ECGs contaminated by noise or artifacts disrupt the normal functioning of the automatic analysis algorithm. The objective of this study is to evaluate a method of measuring the HCP variation in motion artifacts through direct monitoring. The proposed wearable sensing device has two channels. One channel is used to measure the ECG through a differential amplifier. The other is for monitoring motion artifacts using the modified electrode and the same differential amplifier. Noise reduction was performed using adaptive filtering, based on a reference signal highly correlated with it. Direct measurement of HCP variations can eliminate the need for additional sensors. PMID- 23366210 TI - Ultra-wearable capacitive coupled and common electrode-free ECG monitoring system. AB - Nowadays, transfer of the health care from ambulance to patient's home needs higher demand on patient's mobility, comfort and acceptance of the system. Therefore, the goal of this study is to proof the concept of a system which is ultra-wearable, less constraining and more suitable for long term measurements than conventional ECG monitoring systems which use conductive electrolytic gels for low impedance electrical contact with skin. The developed system is based on isolated capacitive coupled electrodes without any galvanic contact to patient's body and does not require the common right leg electrode. Measurements performed under real conditions show that it is possible to acquire well known ECG waveforms without the common electrode when the patient is sitting and even during walking. Results of the validation process demonstrate that the system performance is comparable to the conventional ECG system while the wearability is increased. PMID- 23366211 TI - Preliminary study on determining stereotypical motor movements. AB - Stereotypical motor movements are one of the most common and least understood behaviors occurring in individuals with Autism Spectrum Disorder (ASD). To overcome problems with traditional methods for measuring stereotypical motor movements in persons with ASD, the Kinect sensor from Microsoft and gesture recognition algorithms were used to automatically detect hand flapping. This study provides a valuable tool to monitor stereotypes in order to understand and to cope with this problem. At the end it facilitates to identify behavioral patterns especially relevant when studying interaction skills in children with ASD. PMID- 23366212 TI - Non-contact displacement estimation using Doppler radar. AB - Non-contact Doppler radar has been used extensively for detection of physiological motion. Most of the results published to date have been focused on estimation of the physiological rates, such as respiratory rate and heart rate, with CW and modulated waveforms in various settings. Accurate assessment of chest displacement may take this type of monitoring to the new level, by enabling the estimation of associated cardiopulmonary volumes, and possibly pulse pressure. To obtain absolute chest displacement with highest precision, full nonlinear phase demodulation of the quadrature radar outputs must be performed. The accuracy of this type of demodulation is limited by the drifting received RF power, varying dc offset, and channel quadrature imbalance. In this paper we demonstrate that if relatively large motion is used to calibrate the system, smaller motion displacement may be acquired with the accuracy on the order of 30 um. PMID- 23366213 TI - Impedance pneumography using textile electrodes. AB - The acquisition of physiological parameters using textile and textile-integrated sensors has become an important alternative for mobile and long-term monitoring. We analyzed to different commercially available electrically conductive textiles concerning their applicability for textile-based impedance pneumography. We immersed the textiles to four corroding solutions and observed no considerable changes in the absolute value as well as the phase shift of the material impedances. Subsequently, we performed impedance pneumography tests with different current amplitudes and frequencies. Using silver coated synthetic textile electrodes it was possible to detect the correct respiration frequency during normal, flat as well as slow, deep respiration. PMID- 23366214 TI - Statistical analysis of heart rate and heart rate variability monitoring through the use of smart phone cameras. AB - Video recordings of finger tips made using a smartphone camera contain a pulsatile component caused by the cardiac pulse equivalent to that present in a photoplethysmographic signal. By performing peak detection on the pulsatile signal it is possible to extract a continuous heart rate signal. We performed direct comparisons between 5-lead electrocardiogram based heart rate variability measurements and those obtained from an iPhone 4s and Motorola Droid derived pulsatile signal to determine the accuracy of heart rate variability measurements obtained from the smart phones. Monitoring was performed in the supine and tilt positions for independent iPhone 4s (2 min recordings, n=9) and Droid (5 min recordings, n=13) experiments, and the following heart rate and heart rate variability parameters were estimated: heart rate, low frequency power, high frequency power, ratio of low to high frequency power, standard deviation of the RR intervals, and root mean square of successive RR-differences. Results demonstrate that accurate heart rate variability parameters can be obtained from smart phone based measurements. PMID- 23366215 TI - Noncontact ECG system for unobtrusive long-term monitoring. AB - This paper describes measurements made using an ECG system with QUASAR's capacitive bioelectrodes integrated into a pad system that is placed over a chair. QUASAR's capacitive bioelectrode has the property of measuring bioelectric potentials at a small separation from the body. This enables the measurement of ECG signals through fabric, without the removal of clothing or preparation of skin. The ECG was measured through the subject's clothing while the subject sat in the chair without any supporting action from the subject. The ECG pad system is an example of a high compliance system that places minimal requirements upon the subject and, consequently, can be used to generate a long-term record from ECG segments collected on a daily basis, providing valuable information on long term trends in cardiac health. PMID- 23366216 TI - Photoplethysmographic and SpO(2) readings from the neonatal anterior fontanelle: a case study. AB - There is a need for a more reliable, non-invasive and alternative measurement site for the monitoring of arterial blood oxygen saturation in critically ill neonates when peripheral perfusion is poor. The anterior fontanelle, a unique anatomical feature of the neonate, has been presented as an alternative site for the estimation of arterial blood oxygen saturation (SpO(2)). A new fontanelle photoplethysmographic sensor and processing system has been developed to investigate fontanelle photoplethysmographic (PPG) signals and estimate SpO(2) values at this anatomical location. Preliminary clinical trials have shown that good quality PPG signals with large amplitudes and high signal to noise ratio can be obtained from the neonatal fontanelle. The estimation of SpO(2) values from the fontanelle were in broad agreement with a commercial foot pulse oximeter. PMID- 23366217 TI - EEG and eye-tracking based measures for enhanced training. AB - This paper describes a project whose goal was to establish the feasibility of using unobtrusive cognitive assessment methodologies in order to optimize efficiency and expediency of training. QUASAR, EyeTracking, Inc. (ETI), and Safe Passage International (SPI), teamed to demonstrate correlation between EEG and eye-tracking based cognitive workload, performance assessment and subject expertise on X-Ray screening tasks. Results indicate significant correlation between cognitive workload metrics based on EEG and eye-tracking measurements recorded during a simulated baggage screening task and subject expertise and error rates in that same task. These results suggest that cognitive monitoring could be useful in improving training efficiency by enabling training paradigms that adapts to increasing expertise. PMID- 23366218 TI - Development of enhanced piezoelectric energy harvester induced by human motion. AB - In this study, a high frequency piezoelectric energy harvester converted from the human low vibrated motion energy was newly developed. This hybrid energy harvester consists of the unimorph piezoelectric cantilever and a couple of permanent magnets. One magnet was attached at the end of cantilever, and the counterpart magnet was set at the end of the pendulum. The mechanical energy provided through the human walking motion, which is a typical ubiquitous presence of vibration, is converted to the electric energy via the piezoelectric cantilever vibration system. At first, we studied the energy convert mechanism and the performance of our energy harvester, where the resonance free vibration of unimorph cantilever with one permanent magnet under a rather high frequency was induced by the artificial low frequency vibration. The counterpart magnet attached on the pendulum. Next, we equipped the counterpart permanent magnet pendulum, which was fluctuated under a very low frequency by the human walking, and the piezoelectric cantilever, which had the permanent magnet at the end. The low-to-high frequency convert "hybrid system" can be characterized as an enhanced energy harvest one. We examined and obtained maximum values of voltage and power in this system, as 1.2V and 1.2 uW. Those results show the possibility to apply for the energy harvester in the portable and implantable Bio-MEMS devices. PMID- 23366219 TI - An improved ultra wideband channel model including the frequency-dependent attenuation for in-body communications. AB - Ultra wideband (UWB) technology has big potential for applications in wireless body area networks (WBANs). The inherent characteristics of UWB signals make them suitable for the wireless interface of medical sensors. In particular, implanted medical wireless sensors for monitoring physiological parameters, automatic drug provision, etc. can benefit greatly from this ultra low power (ULP) interface. As with any other wireless technology, accurate knowledge of the channel is necessary for the proper design of communication systems. Only a few models that describe the radio propagation inside the human body have been published. Moreover, there is no comprehensive UWB in-body propagation model that includes the frequency-dependent attenuation. Hence, this paper extends a statistical model for UWB propagation channels inside the human chest in the 1-6 GHz frequency range by including the frequency-dependent attenuation. This is done by modeling the spectrum shape of distorted pulses at different depths inside the human chest. The distortion of the pulse was obtained through numerical simulations using a voxel representation of the human body. We propose a mathematical expression for the spectrum shape of the distorted pulses that act as a window function to reproduce the effects of frequency-dependent attenuation. PMID- 23366220 TI - Case study of relevant pressures for an implanted hydrocephalus valve in everyday life. AB - Hydrocephalus patients with increased intracranial pressure are generally treated by draining cerebrospinal fluid (CSF) into the abdomen through an implanted shunt with a passive differential pressure valve. To perfectly adapt the valve's opening pressure to the patient's need, more information on the acutal pressure across the valve in everyday life actions like walking, eating, sleeping etc. is necessary. PMID- 23366221 TI - Vascular stents with rationally-designed surface patterning. AB - Herein, we discuss our recent progress towards realization of next-generation vascular stents that seek to mitigate adverse physiological responses to stenting via rational design of stent surface topography at the nanoscale. Specifically, we will discuss advances in patterning of deep sub-micrometer scale features in titanium (Ti) substrates, creation of cylindrical stents from micromachined planar Ti substrates, and integration of these processes to produce devices that will eventually allow evaluation of rationally-designed nanopatterning in physiologically-relevant contexts. We will also discuss results from mechanical testing and finite element modeling of these devices to assess their mechanical performance. These efforts represent key steps towards our long-term goal of developing a new paradigm for stents in which rationally-designed surface nanopatterning provides a physical means for complementing, or replacing, current pharmacological interventions. PMID- 23366222 TI - Protein immobilization on 3C-SiC (100) as a substrate for detecting the onset of acute myocardial infarction (AMI). AB - Silicon Carbide (SiC), has been shown to be a bio- and hema-compatible substrate that could potentially be used in biosensor applications. The development of a viable biorecognition interface using SiC as the substrate material for bio detection is described. Surface modification with 3-aminopropyltriethoxysilane (APTES) and immobilization via covalent conjugation of antimyoglobin (anti-Myo) on the modified surfaces is achieved, which are initial steps for immunosensing based devices. Successful formation of APTES layers and antibody immobilization were identified with surface water contact angle (SWCA), X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). PMID- 23366223 TI - An ultra-compact green bio-regulator dedicated for brain cortical implant using a dynamic PSR enhancement technique. AB - This article presents an ultra-compact green Bio-regulator dedicated for brain cortical implant using a dynamic PSR enhancement technique. This novel technique enabled the regulator to achieve a very high power supply rejection (PSR) of 58dB and -78dB at 1 MHz and 10MHz respectively. The Bioregulator achieves a very low quiescent current of 2uA coupled with an ultra-low power consumption of 1.8uW. This Bioregulator, simulated with Global Foundries 0.18um CMOS process, yields a stable output voltage of 0.5V with a supply voltage ranging from 0.9 1.2V. Its distinct features, ultra-low power consumption and high PSRR at 1MHz and 10MHz, make it ideally suitable for biomedical brain cortical implant. PMID- 23366224 TI - Signal transmission through human muscle for implantable medical devices using galvanic intra-body communication technique. AB - Signal transmission over human tissues has long been the center research topic for biomedical engineering in both academic and industrial arenas. This is particular important for implantable medical devices (IMD) to communicate with other sensor devices in achieving health care and monitoring functions. Traditional Radio Frequency (RF) transmission technique suffers from not only high attenuation but also potential interference & eavesdropping. This paper has examined the alternate galvanic type Intra-Body Communication Technique (IBC) in transmitting signal across the body tissue (mainly muscle) in both analytical electromagnetic model with simulation results. Comparisons of these results with traditional RF data in literatures show a high promising potential (saving over 10 dB or more in path loss) for IBC transmission. Concrete discussions and several further research directions are also given out at the end of this paper. PMID- 23366225 TI - Multi-layered poly-dimethylsiloxane as a non-hermetic packaging material for medical MEMS. AB - Poly-dimethylsiloxane (PDMS) is an attractive material for packaging implantable biomedical microdevices owing to its biocompatibility, ease in application, and bio-friendly mechanical properties. Unfortunately, devices encapsulated solely by PDMS lack the longevity for use in chronic implant applications due to defect related moisture penetration through the packaging layer caused by conventional deposition processes such as spin coating. This paper describes an effort to improve the performance of PDMS as a packaging material by constructing the encapsulant from multiple, thin roller casted layers of PDMS as a part of a polymeric multi-material package. PMID- 23366226 TI - A transcutaneous power transfer interface based on a multicoil inductive link. AB - This paper presents a transcutaneous power transfer link based on a multicoil structure. Multicoil inductive links using 4-coil or 3-coil topologies have shown significant improvement over conventional 2-coil structures for transferring power transcutaneously across larger distances and with higher efficiency. However, such performance comes at the cost of additional inductors and capacitor in the system, which is not convenient in implantable applications. This paper presents a transcutaneous power transfer interface that takes advantage on a 3 coils inductive topology to achieve wide separation distances and high power transfer efficiency without increasing the size of the implanted device compared to a conventional 2-coil structure. In the proposed link, a middle coil is placed outside the body to act as a repeater between an external transmitting coil and an implanted receiving coil. The proposed structure allows optimizing the link parameters after implantation by changing the characteristics of the repeater coil. Simulation with a multilayer model of the biological tissues and measured results are presented for the proposed link. PMID- 23366227 TI - Optimizing analog-to-digital converters for sampling extracellular potentials. AB - In neural implants, an analog-to-digital converter (ADC) provides the delicate interface between the analog signals generated by neurological processes and the digital signal processor that is tasked to interpret these signals for instance for epileptic seizure detection or limb control. In this paper, we propose a low power ADC architecture for neural implants that process extracellular potentials. The proposed architecture uses the spike detector that is readily available on most of these implants in a closed-loop with an ADC. The spike detector determines whether the current input signal is part of a spike or it is part of noise to adaptively determine the instantaneous sampling rate of the ADC. The proposed architecture can reduce the power consumption of a traditional ADC by 62% when sampling extracellular potentials without any significant impact on spike detection accuracy. PMID- 23366228 TI - Free space optical link for biomedical applications. AB - Free space optics is an interesting alternative for telemetry with medical implants, due to the high data bandwidths available at optical frequencies. Especially implanted brain-computer interfaces gives rise to large data sets that needs to be transmitted transcutaneous. In this paper we show that it is possible to establish such a link at near-IR wavelengths using a modulated reflector in the implant, thus keeping the laser and the detector on the outside. In addition, we show that it will not only work on short, i.e. touch, distances but also at larger distances, in the range of a meter. We have used an electro absorption modulator to modulate the reflection of an external laser source back towards an external detector. The only part of this system that needs to be implanted is the modulator and drive electronics. The study has been done both by Monte-Carlo simulations of a multi-layer model of a rat skull, and with an experiment demonstrating the feasibility of the link when transmitted through biological tissue. The results show that it is possible to establish a transcutaneous link with an external laser source and light detector, and an internal modulated reflector. PMID- 23366229 TI - An inductive-link with a regulated secondary voltage based on frequency adjustment. AB - This paper shows a wireless powering system for implantable biomedical devices that does not need a voltage regulator inside the body. The regulated voltage is obtained in the secondary of an inductive link and is controlled by varying the operating frequency of the inductive link. This frequency operation varies between 950 kHz and 1.2 MHz when the distance between the coils varies between 0mm and 40mm. The results show that it is not necessary to elevate the supply voltage of the external circuit to regulate the internal voltage. This scheme eliminates the necessity of a voltage regulator inside the body, reducing the implant operating temperature. PMID- 23366230 TI - A feed-forward controlled AC-DC boost converter for biomedical implants. AB - Miniaturization is important to make implants clinic friendly. Wireless power transfer is an essential technology to miniaturize implants by reducing their battery size or completely eliminating their batteries. Traditionally, a pair of inductively-coupled coils operating at radio-frequency (RF) is employed to deliver electrical power wirelessly. In this approach, a rectifier is needed to convert the received RF power to a stable DC one. To achieve high efficiency, the induced voltage of the receiving coil must be much higher than the turn-on voltage of the rectifying diode (which could be an active circuit for low turn-on voltage) [1]. In order to have a high induced voltage, the size of the receiving coil often is significantly larger than rest of the implant. A rotating magnets based wireless power transfer has been demonstrated to deliver the same amount of power at much lower frequency (around 100 Hz) because of the superior magnetic strength produced by rare-earth magnets [2]. Taking the advantage of the low operating frequency, an innovative feed-forward controlled AC to DC boost converter has been demonstrated for the first time to accomplish the following two tasks simultaneously: (1) rectifying the AC power whose amplitude (500 mV) is less than the rectifier's turn-on voltage (1.44 V) and (2) boosting the DC output voltage to a much higher level (5 V). Within a range, the output DC voltage can be selected by the control circuit. The standard deviation of the output DC voltage is less than 2.1% of its mean. The measured load regulation is 0.4 V/kOmega. The estimated conversion efficiency excluding the power consumption of the control circuits reaches 75%. The converter in this paper has the potential to reduce the size of the receiving coil and yet achieve desirable DC output voltage for powering biomedical implants. PMID- 23366231 TI - Implantable multilayer microstrip antenna for retinal prosthesis: antenna testing. AB - Retinal prosthesis has come to a more mature stage and become a very strategic answer to Retinitis Pigmentosa (RP) and Age-related Macular Degeneration (AMD) diseases. In a retinal prosthesis system, wireless link holds a great importance for the continuity of the system. In this paper, an implantable multilayer microstrip antenna was proposed for the retinal prosthesis system. Simulations were performed in High Frequency Structure Simulator (HFSS) with the surrounding material of air and Vitreous Humor fluid. The fabricated antenna was measured for characteristic validation in free space. The results showed that the real antenna possessed similar return loss and radiation pattern, while there was discrepancy with the gain values. PMID- 23366232 TI - High-efficiency wireless power delivery for medical implants using hybrid coils. AB - With the exciting developments in the implant technology allowing sophisticated signal processing, stimulation, and drug delivery capabilities, there is new hope for many patients of epilepsy, Parkinson's disease, and stroke to improve their quality of life. Such implants require high power to deliver the promised rich functionality. Yet, delivering high power to implants without damaging the tissue due to heating while keeping the implant footprint small is a challenge. In this paper, we propose a hybrid multi-layer coil as the secondary coil to provide a power and space-efficient solution. The proposed coils can deliver power to an implant for long durations without increasing the skin temperature over 1C. PMID- 23366233 TI - Combination of amplitude and phase features under a uniform framework with EMD in EEG-based Brain-Computer Interface. AB - In a Brain-Computer Interface (BCI) system, the variations of the amplitude and the phase in EEG signal convey subjects' movement intention and underpin the differentiation of the various mental tasks. Combining these two kinds of information under a uniform feature extraction framework can better reflect the brain states and potentially contribute to BCI classification. Here the Common Spatial Pattern (CSP) and the Phase Locking Value (PLV) were used to capture the amplitude and the phase information. To integrate these two feature extraction procedures, the Empirical Mode Decomposition (EMD) is introduced in preprocessing which behaved as filter bank to optimize bands selection automatically for CSP and exactly calculate the instantaneous phase for PLV. The most discriminative features were selected from the feature pool by the sequential floating forward feature selection method (SFFS). The proposed method was applied to both public and recorded datasets (each n=4). Compared with the traditional CSP, the average increment of classification accuracy is 5.4% (2.0% for public and 8.7% for recorded datasets), which both manifests statistically significances (p<0.05). Moreover, we preliminarily investigate the possibility of the online realization of this method and it shows a comparable result with the offline result. PMID- 23366234 TI - Decoding grasp types with high frequency of local field potentials from primate primary dorsal premotor cortex. AB - Recently, local field potentials (LFPs) have been successfully used to extract information of arm and hand movement in some brain-machine interfaces (BMIs) studies, which suggested that LFPs would improve the performance of BMI applications because of its long-term stability. However, the performance of LFPs in different frequency bands has not been investigated in decoding hand grasp types. Here, the LFPs from the monkey's dorsal premotor cortices were collected by microelectrode array when monkey was performing grip-specific grasp task. A K nearest neighbor classifier performed on the power spectrum of LFPs was used to decode grasping movements. The decoding powers of LFPs in different frequency bands, channels and trials used for training were also studied. The results show that the broad high frequency band (200-400Hz) LFPs achieved the best performance with classification accuracy reaching over 0.9. It infers that high frequency band LFPs in PMd cortex could be a promising source of control signals in developing functional BMIs for hand grasping. PMID- 23366235 TI - EEG-based motor imagery classification accuracy improves with gradually increased channel number. AB - The question of how many channels should be sed for classification remains a key issue in the study of Brain-Computer Interface. Several studies have shown that a reduced number of channels can achieve the optimal classification accuracy in the offline analysis of motor imagery paradigm, which does not have real-time feedback as in the online control. However, for the cursor movement control paradigm, it remains unclear as to how many channels should be selected in order to achieve the optimal classification. In the present study, we gradually increased the number of channels, and adopted the time-frequency-spatial synthesized method for left and right motor imagery classification. We compared the effect of increasing channel number in two datasets, an imagery-based cursor movement control dataset and a motor imagery tasks dataset. Our results indicated that for the former dataset, the more channels we used, the higher the accuracy rate was achieved, which is in contrast to the finding in the latter dataset that optimal performance was obtained at a subset number of channels. When gradually increasing the number of channels from 2 to all in the analysis of cursor movement control dataset, the average training and testing accuracies from three subjects improved from 68.7% to 90.4% and 63.7% to 87.7%, respectively. PMID- 23366237 TI - Generation of spatial filters by ICA for detecting motor-related oscillatory EEG. AB - To detect the imagined limb movement from EEG for the use in BCI, the increase (ERS) and decrease (ERD) of the band power of the EEG originated from the sensorimotor cortex are commonly used. A spatial filter using neighboring channels is generally applied to the measured EEG for detecting such brain activity related to the motor imagery. However, the configuration and location of the spatial filter have been selected by the empirical method on trial-and-error basis. In this study, we recorded the EEG during motor imagery of left hand, right hand and feet from five subjects, and the ICA (independent component analysis) was applied to discover the spatial filters for extracting event related EEG components of the motor imagery. It was suggested that the application of ICA might offer the experimenters appropriate local spatial filters, or at least, the "initial guess" for designing or selecting custom local spatial filters. PMID- 23366236 TI - Applying best practices from digital control systems to BMI implementation. AB - Many brain-machine interface (BMI) algorithms, such as the population vector decoder, must estimate neural spike rates before transforming this information into an external output signal. Often, rate estimation is performed via the selection of a bin width corresponding to the effective sampling rate of the decoding algorithm. Here, we implement real-time rate estimation by extending prior work on the optimization of Gaussian filters for offline rate estimation. We show that higher sampling rates result in improved spike rate estimation. We further show that the choice of sampling rate need not dictate the number of parameters which must be used in an autoregressive decoding algorithm. Multiple studies in other neural signal processing contexts suggest that BMI performance could be improved substantially via careful choice of smoothing filter, discrete time decoder representation, and sampling rate. Together, these ensure minimal deviation from the behavior of the modeled continuous-time systems. PMID- 23366238 TI - Development of exoskeletal robotic limbs for a rat controlled by neural signals based on a vehicular neuro-robotic platform RatCar. AB - A pair of exoskeletal limbs for a rat has been developed based on a vehicular Brain-Machine Interface "Rat-Car". The "RatCar" is a whole-body motor prosthesis system for a rat developed by the authors, estimating locomotion velocity according to neural signals pattern to move the rat body by the vehicle instead of its original limbs. In this paper, exoskeletal limbs have displaced the wheels for more natural modality of body control. The system was tested by applying peripheral nerve signals from a behaving rat. PMID- 23366239 TI - High gamma oscillations enhance the subdural visual speller. AB - The N200 speller is a non-flashing visual brain-computer interface (BCI) using motion-onset visual evoked potentials (mVEPs). Previous N200 speller was implemented at the scalp EEG level. Compared to scalp EEG, electrocorticography (ECoG) provides a broader frequency band that could be utilized in BCI. In this study, we investigated whether the high gamma brain activities recorded from human intracranial electrodes can enhance the performance of the subdural speller. The ERP and high gamma responses of one most task-related subdural electrode were used together for BCI classification and showed that high gamma responses did enhance the performance for the subdural visual motion speller resulted in an average increase of over 8% (p<0.05, paired t-test). PMID- 23366240 TI - Speaking mode recognition from functional Near Infrared Spectroscopy. AB - Speech is our most natural form of communication and even though functional Near Infrared Spectroscopy (fNIRS) is an increasingly popular modality for Brain Computer Interfaces (BCIs), there are, to the best of our knowledge, no previous studies on speech related tasks in fNIRS-based BCI. We conducted experiments on 5 subjects producing audible, silently uttered and imagined speech or do not produce any speech. For each of these speaking modes, we recorded fNIRS signals from the subjects performing these tasks and distinguish segments containing speech from those not containing speech, solely based on the fNIRS signals. Accuracies between 69% and 88% were achieved using support vector machines and a Mutual Information based Best Individual Feature approach. We are also able to discriminate the three speaking modes with 61% classification accuracy. We thereby demonstrate that speech is a very promising paradigm for fNIRS based BCI, as classification accuracies compare very favorably to those achieved in motor imagery BCIs with fNIRS. PMID- 23366241 TI - Multiclass classification of single-trial evoked EEG responses. AB - The detection of event-related potentials (ERPs) in the electroencephalogram (EEG) signal has several real-world applications, from cognitive state monitoring to brain-computer interfaces. Current systems based on the detection of ERPs only consider a single type of response to detect. Hence, the classification methods that are considered for ERP detection are binary classifiers (target vs. non target). Here we investigated multiclass classification of single-trial evoked responses during a rapid serial visual presentation task in which short video clips were presented to fifteen observers. Each trial contained potential targets that were human or non-human, stationary or moving. The goal of the classification analysis was to discriminate between three classes: moving human targets, moving non-human targets, and non-moving human targets. The analysis revealed that the mean volume under the ROC surface of 0.878. These results suggest that it is possible to efficiently discriminate between more than two types of evoked responses using single-trial detection. PMID- 23366242 TI - Effects of performing two visual tasks on single-trial detection of event-related potentials. AB - The detection of event-related potentials (ERPs) in brain-computer interface (BCI) depends on the ability of the subject to pay attention to specific stimuli presented during the BCI task. For healthy users, a BCI shall be used as a complement to other existing devices, which involve the response to other tasks. Those tasks may impair selective attention, particularly if the stimuli have the same modality e.g. visual. It is therefore critical to analyze how single-trial detection of brain evoked response is impaired by the addition of tasks concerning the same modality. We tested 10 healthy participants using an application that has two visual target detection tasks. The first one corresponds to a rapid serial visual presentation paradigm where target detection is achieved by brain-evoked single-trial detection in the recorded electroencephalogram (EEG) signal. The second task is the detection of a visual event on a tactical map by a behavioral response. These tasks were tested individually (single task) and in parallel (dual-task). Whereas the performance of single-trial detection was not impaired between single and dual-task conditions, the behavioral performance decreased during the dual-task condition. These results quantify the performance drop that can occur in a dual-task system using both brain-evoked responses and behavioral responses. PMID- 23366243 TI - Pilot study for a Brain-Muscle-Computer Interface using the Extensor Pollicis Longus with preselected frequency bands. AB - We are developing a new class of Brain-Computer Interface that we call a Brain Muscle-Computer Interface, in which surface electromyography (sEMG) recordings from a single muscle site are used to control the movement of a cursor. Previous work in our laboratory has established that subjects can learn to navigate a cursor to targets by manipulating the sEMG from a head muscle (the Auricularis Superior). Subjects achieved two-dimensional control of the cursor by simultaneously regulating the power in two frequency bands that were chosen to suit the individuals. The purposes of the current pilot study were to investigate (i) subjects' abilities to manipulate power in separate frequency bands in other muscles of the body and (ii) whether subjects can adapt to preselected frequency bands. We report pilot study data suggesting that subjects can learn to perform cursor-to-target tasks on a mobile phone by contracting the Extensor Pollicis Longus (a muscle located on the wrist) using frequency bands that are the same for every individual. After the completion of a short training protocol of less than 30 minutes, three subjects achieved 83%, 60% and 60% accuracies (with mean time-to-targets of 3.4 s, 1.4 s and 2.7 s respectively). All three subjects improved their performance, and two subjects decreased their time-to-targets following training. These results suggest that subjects may be able to use the Extensor Pollicis Longus to control the BMCI and adapt to preselected frequency bands. Further testing will more conclusively investigate these preliminary findings. PMID- 23366244 TI - Decoding of finger, hand and arm kinematics using switching linear dynamical systems with pre-motor cortical ensembles. AB - Previous works in Brain-Machine Interfaces (BMI) have mostly used a single Kalman filter decoder for deriving continuous kinematics in the complete execution of behavioral tasks. A linear dynamical system may not be able to generalize the sequence whose dynamics changes over time. Examples of such data include human motion such as walking, running, and dancing each of which exhibit complex constantly evolving dynamics. Switching linear dynamical systems (S-LDSs) are powerful models capable of describing a physical process governed by state equations that switch from time to time. The present work demonstrates the motion state-dependent adaptive decoding of hand and arm kinematics in four different behavioral tasks. Single-unit neural activities were recorded from cortical ensembles in the ventral and dorsal premotor (PMv and PMd) areas of a trained rhesus monkey during four different reach-to-grasp tasks. We constructed S-LDSs for decoding of continuous hand and arm kinematics based on different epochs of the experiments, namely, baseline, pre-movement planning, movement, and final fixation. Average decoding accuracies as high as 89.9%, 88.6%, 89.8%, 89.4%, were achieved for motion-state-dependent decoding across four different behavioral tasks, respectively (p<0.05); these results are higher than previous works using a single Kalman filter (accuracy: 0.83). These results demonstrate that the adaptive decoding approach, or motion-state-dependent decoding, may have a larger descriptive capability than the decoding approach using a single decoder. This is a critical step towards the development of a BMI for adaptive neural control of a clinically viable prosthesis. PMID- 23366247 TI - Visual evoked potentials for attentional gating in a brain-computer interface. AB - For synchronous brain-computer interface (BCI) paradigms tasks that utilize visual cues to direct the user, the neural signals extracted by the computer are representative of voluntary modulation as well as evoked responses. For these paradigms, the evoked potential is often overlooked as a source of artifact. In this paper, we put forth the hypothesis that cue priming, as a mechanism for attentional gating, is predictive of motor imagery performance, and thus a viable option for self-paced (asynchronous) BCI applications. We approximate attention by the amplitude features of visually evoked potentials (VEP)s found using two methods: trial matching to an average VEP template, and component matching to a VEP template defined using independent component analysis (ICA). Templates were used to rank trials that display high vs. low levels of fixation. Our results show that subject fixation, measured by VEP response, fails as a predictor of successful motor-imagery task completion. The implications for the BCI community and the possibilities for alternative cueing methods are given in the conclusions. PMID- 23366246 TI - Stable online control of an electrocorticographic brain-computer interface using a static decoder. AB - A brain computer interface (BCI) system was implemented by recording electrocorticographic signals (ECoG) from the motor cortex of a Rhesus macaque. These signals were used to control two-dimensional cursor movements in a standard center-out task, utilizing an optimal linear estimation (OLE) method. We examined the time course over which a monkey could acquire accurate control when operating in a co-adaptive training scheme. Accurate and maintained control was achieved after 4-5 days. We then held the decode parameters constant and observed stable control over the next 28 days. We also investigated the underlying neural strategy employed for control, asking whether neural features that were correlated with a given kinematic output (e.g. velocity in a certain direction) were clustered anatomically, and whether the features were coordinated or conflicting in their contributions to the control signal. PMID- 23366249 TI - Recursive channel selection techniques for brain computer interfaces. AB - Automated channel selection allows the dimension of EEG data to be reduced without expert knowledge. We introduce Recursive Channel Insertion, an extension to Recursive Channel Elimination, which dramatically reduces calculation time with no loss of accuracy. Furthermore we propose Repeated Recursive Channel Insertion, which shows an improvement in accuracy over the previous methods when tested on a standard dataset. PMID- 23366248 TI - IpsiHand Bravo: an improved EEG-based brain-computer interface for hand motor control rehabilitation. AB - Stroke and other nervous system injuries can damage or destroy hand motor control and greatly upset daily activities. Brain computer interfaces (BCIs) represent an emerging technology that can bypass damaged nerves to restore basic motor function and provide more effective rehabilitation. A wireless BCI system was implemented to realize these goals using electroencephalographic brain signals, machine learning techniques, and a custom designed orthosis. The IpsiHand Bravo BCI system is designed to reach a large demographic by using non-traditional brain signals and improving on past BCI system pitfalls. PMID- 23366250 TI - Decoding arm and hand movements across layers of the macaque frontal cortices. AB - A major goal for brain machine interfaces is to allow patients to control prosthetic devices with high degrees of independent movements. Such devices like robotic arms and hands require this high dimensionality of control to restore the full range of actions exhibited in natural movement. Current BMI strategies fall well short of this goal allowing the control of only a few degrees of freedom at a time. In this paper we present work towards the decoding of 27 joint angles from the shoulder, arm and hand as subjects perform reach and grasp movements. We also extend previous work in examining and optimizing the recording depth of electrodes to maximize the movement information that can be extracted from recorded neural signals. PMID- 23366252 TI - Impact of mental focus on steady-state visually evoked potential under eyes closed condition for binary brain computer interface. AB - The steady-state visually evoked potential (SSVEP), is found to be affected by mental focusing on the stimuli under eyes closed condition. The amplitude d change of the SSVEP in concentrating on flicker stimuli was investigated for a novel brain computer interface (BCI) based on the SSVEP with eyes closed for severely disabilities who were not able to control their eye movement to use conventional SSVEP-based BCIs. The amplitude of the SSVEP in the posterior region was found to be reduced by more than 20 % in 10 out of 11 healthy adults when the subjects concentrated on the flicker stimuli under the conditions of flicker frequency of 10 Hz and stimulus intensity of 5 lx. Such an effect was observed in the occipital region under the condition of 14Hz and 5 lx. These results suggest the possibility of SSVEP-based binary BCI with eyes closed in terms of the mental focus. PMID- 23366251 TI - On the enhancement of training session performance via attention for single frequency/multi-commands based steady state auditory evoked potential BCI. AB - To solve the eye fatigue problem on using the well known steady state visual evoked potential (SSVEP)-based brain-computer interface (BCI) system, the steady state auditory evoked potential (SSAEP) becomes one of the promising BCI modalities. However, SSAEP-based BCI system still suffers from the low accuracy. To increase the accuracy, in this paper, we propose the new training method to enhance the SSAEP training session. The training process is enhanced by making the users control their attention levels simultaneously with the detected auditory stimulus frequency. Furthermore, with the proposed training method, we also propose the corresponding single-frequency/multi-commands BCI paradigm. With the proposed paradigm, four commands can be detected by using only one auditory stimulus frequency. The proposed training system yields approximately 81% accuracy compared with 66% of the session without performing the proposed training. PMID- 23366253 TI - Combining ERPs and EEG spectral features for decoding intended movement direction. AB - The posterior parietal cortex (PPC) plays an important role in visuomotor transformations for movement planning and execution. To investigate how noninvasive electroencephalographic (EEG) signals correlate with intended movement directions in the PPC, this study recorded whole-head EEG during a delayed saccade-or-reach task and found direction-related changes in both event related potentials (ERPs) and the EEG power in the theta and alpha bands in the PPC. Single-trial (left versus right) classification using ERP and EEG spectral features prior to motor execution obtained an average accuracy of 65.4% and 65.6% respectively on 10 subjects. By combining the two types of features, the classification accuracy increased to 69.7%. These results show that ERP and EEG spectral power modulations contribute complementary information to decoding intended movement directions in the PPC. The proposed paradigm might lead to a practical brain-computer interface (BCI) for decoding movement intention of individuals. PMID- 23366254 TI - Discriminating multiple motor imageries of human hands using EEG. AB - We investigated the feasibility of discriminating four different motor imagery (MI) types from both hands using electroencephalography (EEG) through exploring underlying features related to MIs of thumb and fist from one hand. New spectral and spatial features related to different MIs were extracted using principal component analysis (PCA) and squared cross correlation (R(2)). Extracted features were evaluated using a linear discriminant analysis (LDA) classifier, resulting in an average decoding accuracy about 50%, which is significantly higher than the guess level and the 95% confidence level of guess. The preliminary results demonstrate the great potential of extracting features from different MIs from same hands to generate control signals with more degrees of freedom (DOF) for non invasive brain-computer interface applications. In addition, for movement related applications, especially for neuroprosthesis, the present study may facilitate the development of a non-invasive BCI, which is highly intuitive and based on users' spontaneous intentions. PMID- 23366255 TI - Electroencephalography(EEG)-based instinctive brain-control of a quadruped locomotion robot. AB - Artificial intelligence and bionic control have been applied in electroencephalography (EEG)-based robot system, to execute complex brain-control task. Nevertheless, due to technical limitations of the EEG decoding, the brain computer interface (BCI) protocol is often complex, and the mapping between the EEG signal and the practical instructions lack of logic associated, which restrict the user's actual use. This paper presents a strategy that can be used to control a quadruped locomotion robot by user's instinctive action, based on five kinds of movement related neurophysiological signal. In actual use, the user drives or imagines the limbs/wrists action to generate EEG signal to adjust the real movement of the robot according to his/her own motor reflex of the robot locomotion. This method is easy for real use, as the user generates the brain control signal through the instinctive reaction. By adopting the behavioral control of learning and evolution based on the proposed strategy, complex movement task may be realized by instinctive brain-control. PMID- 23366256 TI - EEG character identification using stimulus sequences designed to maximize mimimal hamming distance. AB - In this study, we have improved upon the P300 speller Brain-Computer Interface paradigm by introducing a new character encoding method. Our concept in detection of the intended character is not based on a classification of target and nontarget responses, but based on an identifaction of the character which maximize the difference between P300 amplitudes in target and nontarget stimuli. Each bit included in the code corresponds to flashing character, '1', and non flashing, '0'. Here, the codes were constructed in order to maximize the minimum hamming distance between the characters. Electroencephalography was used to identify the characters using a waveform calculated by adding and subtracting the response of the target and non-target stimulus according the codes respectively. This stimulus presentation method was applied to a 3*3 character matrix, and the results were compared with that of a conventional P300 speller of the same size. Our method reduced the time until the correct character was obtained by 24%. PMID- 23366257 TI - Mushu, a free- and open source BCI signal acquisition, written in Python. AB - The following paper describes Mushu, a signal acquisition software for retrieval and online streaming of Electroencephalography (EEG) data. It is written, but not limited, to the needs of Brain Computer Interfacing (BCI). It's main goal is to provide a unified interface to EEG data regardless of the amplifiers used. It runs under all major operating systems, like Windows, Mac OS and Linux, is written in Python and is free- and open source software licensed under the terms of the GNU General Public License. PMID- 23366258 TI - Auditory display as a prosthetic hand sensory feedback for reaching and grasping tasks. AB - Upper limb amputees have to rely extensively on visual feedback in order to monitor and manipulate successfully their prosthetic device. This situation leads to high consciousness burden, which generates fatigue and frustration. Therefore, in order to enhance motor-sensory performance and awareness, an auditory display was used as a sensory feedback system for the prosthetic hand's spatio-temporal and force information in a complete reaching and grasping setting. The main objective of this study was to explore the effects of using the auditory display to monitor the prosthetic hand during a complete reaching and grasping motion. The results presented in this paper point out that the usage of an auditory display to monitor and control a robot hand improves the temporal and grasping performance greatly, while reducing mental effort and improving their confidence. PMID- 23366259 TI - Design of the multi-channel electroencephalography-based brain-computer interface with novel dry sensors. AB - The traditional brain-computer interface (BCI) system measures the electroencephalography (EEG) signals by the wet sensors with the conductive gel and skin preparation processes. To overcome the limitations of traditional BCI system with conventional wet sensors, a wireless and wearable multi-channel EEG based BCI system is proposed in this study, including the wireless EEG data acquisition device, dry spring-loaded sensors, a size-adjustable soft cap. The dry spring-loaded sensors are made of metal conductors, which can measure the EEG signals without skin preparation and conductive gel. In addition, the proposed system provides a size-adjustable soft cap that can be used to fit user's head properly. Indeed, the results are shown that the proposed system can properly and effectively measure the EEG signals with the developed cap and sensors, even under movement. In words, the developed wireless and wearable BCI system is able to be used in cognitive neuroscience applications. PMID- 23366260 TI - Continuous decoding of motor attempt and motor imagery from EEG activity in spinal cord injury patients. AB - Spinal cord injury (SCI) associates brain reorganization with a loss of cortical representation of paralyzed limbs. This effect is more pronounced in the chronic state, which can be reached approximately 6 months after the lesion. As many of the brain-computer interfaces (BCI) developed to date rely on the user motor activity, loss of this activity hinders the application of BCI technology for rehabilitation or motor compensation in these patients. This work is a preliminary study with three quadriplegic patients close to reaching the chronic state, addressing two questions: (i) whether it is still possible to use BCI technology to detect motor intention of the paralyzed hand at this state of chronicity; and (ii) whether it is better for the BCI decoding to rely on the motor attempt or the motor imagery of the hand as mental paradigm. The results show that one of the three patients had already lost the motor programs related to the hand, so it was not possible to build a motor-related BCI for him. For the other patients it was suitable to design a BCI based on both paradigms, but the results were better using motor attempt as it has broader activation associated patterns that are easier to recognize. PMID- 23366261 TI - How stimulation speed affects Event-Related Potentials and BCI performance. AB - In most paradigms for Brain-Computer Interfaces (BCIs) that are based on Event Related Potentials (ERPs), stimuli are presented with a pre-defined and constant speed. In order to boost BCI performance by optimizing the parameters of stimulation, this offline study investigates the impact of the stimulus onset asynchrony (SOA) on ERPs and the resulting classification accuracy. The SOA is defined as the time between the onsets of two consecutive stimuli, which represents a measure for stimulation speed. A simple auditory oddball paradigm was tested in 14 SOA conditions with a SOA between 50 ms and 1000 ms. Based on an offline ERP analysis, the BCI performance (quantified by the Information Transfer Rate, ITR in bits/min) was simulated. A great variability in the simulated BCI performance was observed within subjects (N=11). This indicates a potential increase in BCI performance (>= 1.6 bits/min) for ERP-based paradigms, if the stimulation speed is specified for each user individually. PMID- 23366262 TI - Measuring steady-state visual evoked potentials from non-hair-bearing areas. AB - Steady-State Visual Evoked Potential (SSVEP)-based Brain-Computer Interface (BCI) applications have been widely applied in laboratories around the world in the recent years. Many studies have shown that the best locations to acquire SSVEPs were from the occipital areas of the scalp. However, for some BCI users such as quadriparetic patients lying face up during ventilation, it is difficult to access the occipital sites. Even for the healthy BCI users, acquiring good quality EEG signals from the hair-covered occipital sites is inevitably more difficult because it requires skin preparation by a skilled technician and conductive gel usage. Therefore, finding an alternative approach to effectively extract high-quality SSVEPs for BCI practice is highly desirable. Since the non hair-bearing scalp regions are more accessible by all different types of EEG sensors, this study systematically and quantitatively investigated the feasibility of measuring SSVEPs from non-hair-bearing regions, compared to those measured from the occipital areas. Empirical results showed that the signal quality of the SSVEPs from non-hair-bearing areas was comparable with, if not better than, that measured from hair-covered occipital areas. These results may significantly improve the practicality of a BCI system in real-life applications; especially used in conjunction with newly available dry EEG sensors. PMID- 23366263 TI - SNR analysis of high-frequency steady-state visual evoked potentials from the foveal and extrafoveal regions of human retina. AB - With brain-computer interface (BCI) applications in mind, we analyzed the amplitudes and the signal-to-noise ratios (SNR) of steady-state visual evoked potentials (SSVEP) induced in the foveal and extra-foveal regions of human retina. Eight subjects (age 20-55) have been exposed to 2 degrees circular and 16 degrees -18 degrees annular visual stimulation produced by white LED lights flickering between 5Hz and 65Hz in 5Hz increments. Their EEG signals were recorded using a 64-channel NeuroScan system and analyzed using non-parametric spectral and canonical convolution techniques. Subjects' perception of flickering and their levels of comfort towards the visual stimulation were also noted. Almost all subjects showed distinctively higher SNR in their foveal SSVEP responses between 25Hz and 45Hz. They also noticed less flickering and felt more comfortable with the visual stimulation between 30Hz and 45Hz. These empirical evidences suggest that lights flashing above the critical flicker fusion rates (CFF) of human vision may be used as effective and comfortable stimuli in SSVEP BCI applications. PMID- 23366264 TI - Control or no-control? Reducing the gap between brain-computer interface and classical input devices. AB - In order to improve Brain Computer Interface usability for real life context, they should be able to adapt their speed to the user's current psychophysical state and to understand from the ongoing EEG when he/she intends to suspend the control. In this work we evaluated an asynchronous classifier which provides these feature with 20 healthy subjects, who were engaged in an environmental control task or in a spelling task. We also demonstrated how the proposed classifier can improve communication efficiency with respect to classical synchronous classifiers. PMID- 23366265 TI - Flashing color on the performance of SSVEP-based brain-computer interfaces. AB - A critical problem in using steady-state visual evoked potential (SSVEP) based brain-computer interfaces (BCIs) for clinical and commercial use is the visual fatigue the user may suffer when staring at flashing stimuli. Aiming at the design of user-friendly BCIs with satisfactory performance, this work is to preliminarily investigate how different colors influence the SSVEP (i.e. frequency or phase) and system performance. The results show that white stimuli can lead to the highest performance, followed by gray, red, green and blue stimuli. PMID- 23366266 TI - Control 2-dimensional movement using a three-class motor imagery based brain computer interface. AB - 2-dimensional movement control is an interesting issue in Brain-Computer Interface. In this paper, we present a motor imagery based 2-D cursor control paradigm. To move the cursor to a random position, two-class motor imagery is simultaneously combined to output 2-D command, which directly points to target position. A center-out experiment (8 targets) is set to verify the proposed paradigm. The results of the online experiment (three subjects participated) validate the proposed strategy very well. PMID- 23366267 TI - Prototype of an auto-calibrating, context-aware, hybrid brain-computer interface. AB - We present the prototype of a context-aware framework that allows users to control smart home devices and to access internet services via a Hybrid BCI system of an auto-calibrating sensorimotor rhythm (SMR) based BCI and another assistive device (Integra Mouse mouth joystick). While there is extensive literature that describes the merit of Hybrid BCIs, auto-calibrating and co adaptive ERD BCI training paradigms, specialized BCI user interfaces, context awareness and smart home control, there is up to now, no system that includes all these concepts in one integrated easy-to-use framework that can truly benefit individuals with severe functional disabilities by increasing independence and social inclusion. Here we integrate all these technologies in a prototype framework that does not require expert knowledge or excess time for calibration. In a first pilot-study, 3 healthy volunteers successfully operated the system using input signals from an ERD BCI and an Integra Mouse and reached average positive predictive values (PPV) of 72 and 98% respectively. Based on what we learned here we are planning to improve the system for a test with a larger number of healthy volunteers so we can soon bring the system to benefit individuals with severe functional disability. PMID- 23366268 TI - Mental task classifications using prefrontal cortex electroencephalograph signals. AB - For an electroencephalograph (EEG)-based brain computer interface (BCI) application, the use of gel on the hair area of the scalp is needed for low impedance electrical contact. This causes the set up procedure to be time consuming and inconvenient for a practical BCI system. Moreover, studies of other cortical areas are useful for BCI development. As a more convenient alternative, this paper presents the EEG based-BCI using the prefrontal cortex non-hair area to classify mental tasks at three electrodes position: Fp1, Fpz and Fp2. The relevant mental tasks used are mental arithmetic, ringtone, finger tapping and words composition with additional tasks which are baseline and eyes closed. The feature extraction is based on the Hilbert Huang Transform (HHT) energy method and the classification algorithm is based on an artificial neural network (ANN) with genetic algorithm (GA) optimization. The results show that the dominant alpha wave during eyes closed can still clearly be detected in the prefrontal cortex. The classification accuracy for five subjects, mental tasks vs. baseline task resulted in average accuracy is 73% and the average accuracy for pairs of mental task combinations is 72%. PMID- 23366269 TI - Development of a non-invasive, multifunctional grasp neuroprosthesis and its evaluation in an individual with a high spinal cord injury. AB - Over the last decade the improvement of a missing hand function by application of neuroprostheses in particular the implantable Freehand system has been successfully shown in high spinal cord injured individuals. The clinically proven advantages of the Freehand system is its ease of use, the reproducible generation of two distinct functional grasp patterns and an analog control scheme based on movements of the contralateral shoulder. However, after the Freehand system is not commercially available for more than ten years, alternative grasp neuroprosthesis with a comparable functionality are still missing. Therefore, the aim of this study was to develop a non-invasive neuroprosthesis and to show that a degree of functional restoration can be provided to end users comparable to implanted devices. By introduction of an easy to handle forearm electrode sleeve the reproducible generation of two grasp patterns has been achieved. Generated grasp forces of the palmar grasp are in the range of the implanted system. Though pinch force of the lateral grasp is significantly lower, it can effectively used by a tetraplegic subject to perform functional tasks. The non-invasive grasp neuroprosthesis developed in this work may serve as an easy to apply and inexpensive way to restore a missing hand and finger function at any time after spinal cord injury. PMID- 23366271 TI - Co-contraction of antagonist muscles during knee extension against gravity: insights for functional electrical stimulation control design. AB - Functional electrical stimulation (FES) involves electrically stimulating the neuromuscular system to generate skeletal muscle contractions in paralyzed muscles. Several new FES applications have been proposed that require closed-loop control systems. Co-contraction of antagonist muscle groups has been postulated as a promising approach for closed-loop control of FES systems. However, this control approach has not yet been used in practical FES applications, in part due to a lack of information concerning how able-bodied subjects use co-contraction of antagonist muscles during standard control tests such as unit step and sinusoidal responses. The purpose of this work is to elucidate how able-bodied individuals use co-contraction by analyzing the EMG activity of antagonist muscles during voluntary knee extension against gravity. The results clearly demonstrate that able-bodied subjects use a co-contraction strategy when executing standard control performance tests, and strengthen the argument for using a co-contraction strategy for closed-loop FES control algorithms. These data will inform the development of new and effective controllers for FES applications. PMID- 23366270 TI - Muscle response to simultaneous stimulated and physiological action potential trains--a simulation study. AB - The objective of this study was to assess the mechanisms responsible for the experimentally observed nonlinear addition of forces produced by voluntary contractions during superimposed electrical stimulation of the same muscle. A model of action potential interaction predicts increased motor unit firing rates during superimposed stimulation. The resulting effects on force production reproduce experimental results, confirming that motor unit force saturation contributes to nonlinear force addition. The model further predicts that the voluntary EMG will be reduced by stimulation, due to collision block and phase resetting of motor unit action potentials. Both effects have implications for the design of FES neuroprosthesis systems. PMID- 23366272 TI - Empirical mode decomposition as a tool to remove the function electrical stimulation artifact from surface electromyograms: preliminary investigation. AB - Rectification of surface EMGs during electrical stimulations (ES) is still a problem to be solved. The broad band frequency components of ES artifact overlap with the EMG spectrum, make this task challenging. In this study, we investigate the potential use of empirical mode decomposition (EMD) method to remove the stimulus artifact from surface EMGs collected during such applications. We hypothesize that the EMD algorithm provides a suitable platform for decomposing the EMG signal into physically meaningful intrinsic modes which can be used to isolate ES artifact. Basic EMD is tested on two signals - ES induced EMG and EMG of voluntary contractions added with simulated ES signal. The algorithm isolates the EMG from ES artifact with considerable success. Further, the EMD method along with the energy operator -TKEO gives even better representation of the EMG signal. However, some high frequency data was lost during reconstruction process. Hence, there is further need to investigate the relationship between the EMD parameters and stimulus artifact properties so that the algorithm can be optimized to reconstruct pure artifact free EMG signal with minimum lost of data. PMID- 23366273 TI - Localized stimulation and recording in the spinal cord with microelectrode arrays. AB - The use of microelectrodes for both recording and stimulation of cortical tissue is a well-established technique in neuroscience. We demonstrate that the use of existing microelectrode arrays and instrumentation can be extended to studying the spinal cord. We show that microelectrode arrays can be used to perform stimulation and recording in the corticospinal tract of an animal model commonly used in spinal cord injury (SCI) research. This technique could not only provide fundamental insights into the structure and function of the spinal cord, but also ultimately serve as the basis of a therapeutic treatment for severe spinal cord injuries. PMID- 23366274 TI - Modulation of ankle EMG in spinally contused rats through application of neuromuscular electrical stimulation timed to robotic treadmill training. AB - While neuromuscular electrical stimulation (NMES) has enabled patients of neuromotor dysfunction to effectively regain some functions, analysis of neuromuscular changes underlying these functional improvements is lacking. We have developed an NMES system for a rodent model of SCI with the long term goal of creating a therapy which restores control over stepping back to the spinal circuitry. NMES was applied to the tibialis anterior (TA) and timed to the afferent feedback generated during robotic treadmill training (RTT). The effect of NMES+RTT on modifications in EMG was compared with that of RTT alone. A longitudinal study with a crossover design was conducted in which group 1 (n=7) received 2 weeks of RTT only followed by 2 weeks of NMES+RTT; group 2 (n=7) received 2 weeks of NMES+RTT followed by RTT only. On average, both types of training helped to modulate TA EMG activity over a gait cycle, resulting in EMG profiles across steps with peaks occurring just before or at the beginning of the swing phase, when ankle flexion is most needed. However, NMES+RTT resulted in concentration of EMG activation during the initial swing phase more than RTT only. In conjunction with these improvements in EMG activation presented here, a more complete analyses comparing changes after NMES+RTT vs. RTT is expected to further support the notion that NMES timed appropriately to hindlimb stepping could help to reinforce the motor learning that is induced by afferent activity generated by treadmill training. PMID- 23366275 TI - Automatic determination of parameters for multipad functional electrical stimulation: application to hand opening and closing. AB - Transcutaneous functional electrical stimulation (FES) is a method used for rehabilitation of patients having suffered a stroke or spinal cord injury. When applying FES a common problem is that stimulation electrodes have to be placed with great care in order to avoid activation of muscles close to the target muscles. A promising approach to circumvent this problem is to employ multipad FES, i.e. to employ electrode arrays containing many small electrodes allowing selective activation of muscles. In this work an algorithm is presented which automatically determines subsets of active electrodes and stimulation currents such that movements with user-specified amplitudes are induced. Using a recently developed portable multipad FES system and a virtual reality dataglove, the algorithm was tested with seven able-bodied subjects. Stimulation with parameters determined by the algorithm led to movements with a median deviation of between 0 degrees and 5 degrees from the specified wrist angle and between 0% and 12% from the specified degree of finger flexion. PMID- 23366276 TI - Step trajectory analysis of spinal cord injured rats trained with neuromuscular electrical stimulation coordinated with robotic treadmill training. AB - Applying neuromuscular electrical stimulation (NMES) during treadmill training (TT) has been shown to improve functional outcomes, such as gait speed and walking distance, in spinal cord injury (SCI) patients. However, ways to improve this combined NMES+TT therapy have not been investigated. We have developed NMES system for a rodent model of SCI to investigate whether and how more precisely timing the stimulation to robotically assisted hindlimb position might achieve rehabilitation of independent stepping after SCI. In our therapy (NMES+RTT), rodent ankle flexor muscles are stimulated while the hindlimbs are robotically driven through pre-programmed trajectories during treadmill training. The objectives of the work presented here were to quantify changes in step trajectory resulting from our combined NMES+RTT therapy and compare those effects with those induced by robotic treadmill training (RTT) alone. Animals were spinally contused to model severe SCI, and either received 2 weeks of NMES+RTT followed by 2 weeks of RTT (n=6) or 2 weeks of RTT followed by 2 weeks of NMES+RTT (n=7). Changes in step trajectories after training were analyzed. According to a deviation measure we developed, the step trajectories improved after either NMES+RTT or RTT training but more closely matched the desired pre-programmed trajectories after NMES+RTT than after RTT only. The step trajectories are also more consistent, as indicated by a coefficient of variation measure, after training and more so after NMES+RTT than after RTT only. These preliminary results from our NMES+RTT vs. RTT study are consistent with the hypothesis that appropriately timing NMES with hindlimb movements during stepping is an effective therapy for restoring the ability to step after spinal cord injury. PMID- 23366277 TI - A novel FES control paradigm based on muscle synergies for postural rehabilitation therapy with hybrid exoskeletons. AB - Hybrid exoskeletons combine robotic orthoses and motor neuroprosthetic devices to compensate for motor disabilities and assist rehabilitation. The basic idea is to take benefits from the strength of each technology, primarily the power of robotic actuators and the clinical advantages of using patient's muscles, while compensating for the respective weaknesses: weight and autonomy for the former, fatigue and stability for the latter. While a wide repertory of solutions have been proposed in literature for the control of robotic orthoses and simple motor neuroprosthesis, the same problem on a complex hybrid architecture, involving a wide number of muscles distributed on multiple articulations, still waits for a practical solution. In this article we present a general algorithm for the control of the neuroprosthesis in the execution of functional coordinated movements. The method extracts muscle synergies as a mean to diagnose residual neuromotor capabilities, and adapts the rehabilitation exercise to patient requirements in a dynamic way. Fatigue effects and unexpected perturbations are compensated by monitoring functional state variables estimated from sensors in the robot. The proposed concept is applied to a case-study scenario, in which a postural balance rehabilitation therapy is presented. PMID- 23366278 TI - Directed causality of the human electrocorticogram during dexterous movement. AB - While significant strides have been made in designing brain-machine interfaces for use in humans, efforts to decode truly dexterous movements in real time have been hindered by difficulty extracting detailed movement-related information from the most practical human neural interface, the electrocorticogram (ECoG). We explore a potentially rich, largely untapped source of movement-related information in the form of cortical connectivity computed with time-varying dynamic Bayesian networks (TV-DBN). We discover that measures of connectivity between ECoG electrodes derived from the local motor potential vary with dexterous movement in 65% of movement-related electrode pairs tested, and measures of connectivity derived from spectral features vary with dexterous movement in 76%. Due to the large number of features generated with connectivity methods, the TV-DBN a promising tool for dexterous decoding. PMID- 23366279 TI - Prosthesis-guided training of pattern recognition-controlled myoelectric prosthesis. AB - Pattern recognition can provide intuitive control of myoelectric prostheses. Currently, screen-guided training (SGT), in which individuals perform specific muscle contractions in sync with prompts displayed on a screen, is the common method of collecting the electromyography (EMG) data necessary to train a pattern recognition classifier. Prosthesis-guided training (PGT) is a new data collection method that requires no additional hardware and allows the individuals to keep their focus on the prosthesis itself. The movement of the prosthesis provides the cues of when to perform the muscle contractions. This study compared the training data obtained from SGT and PGT and evaluated user performance after training pattern recognition classifiers with each method. Although the inclusion of transient EMG signal in PGT data led to decreased accuracy of the classifier, subjects completed a performance task faster than when compared to using a classifier built from SGT data. This may indicate that training data collected using PGT that includes both steady state and transient EMG signals generates a classifier that more accurately reflects muscle activity during real-time use of a pattern recognition-controlled myoelectric prosthesis. PMID- 23366280 TI - Control of tibialis anterior FES envelop for unilateral drop foot gait correction using NARX neural network. AB - In this paper a control methodology based on artificial neural networks (ANN) is proposed for control of ankle dorsiflexion in patients with unilateral drop foot. In the presented strategy, the electrical stimulation intensity for the disabled tibialis anterior (TA) muscle is controlled considering the existing coordination patterns between activities of the ipsilateral ankle dorsiflexor muscles and the contralateral ankle plantarflexor muscles during normal gait. Based on this coordination, in each gait cycle the TA muscle of one leg acts in close simultaneity with the calf muscle of the opposite leg. Therefore in this paper a dynamic ANN has been trained in a predictive manner, to forecast the disabled TA muscle activity based on the input from the healthy calf muscle of the opposite leg. The predicted TA activation is then used to control the TA muscle FES intensity in real time. Seven healthy volunteers participated in the experiments. Surface electromyogram was recorded from TA and calf muscle simultaneously on the opposite legs while walking in different gait frequencies. Results obtained from the controller are quite promising and show impressive generalization ability between subjects. PMID- 23366281 TI - Development of a Bayesian neural network to perform obstacle avoidance for an intelligent wheelchair. AB - This paper presents an extension of a real-time obstacle avoidance algorithm for our laser-based intelligent wheelchair, to provide independent mobility for people with physical, cognitive, and/or perceptual impairments. The laser range finder URG-04LX mounted on the front of the wheelchair collects immediate environment information, and then the raw laser data are directly used to control the wheelchair in real-time without any modification. The central control role is an obstacle avoidance algorithm which is a neural network trained under supervision of Bayesian framework, to optimize its structure and weight values. The experiment results demonstrated that this new approach provides safety, smoothness for autonomous tasks and significantly improves the performance of the system in difficult tasks such as door passing. PMID- 23366282 TI - Biomimetic NMES controller for arm movements supported by a passive exoskeleton. AB - The European Project MUltimodal Neuroprosthesis for Daily Upper limb Support (MUNDUS) aims at the development of an assistive platform for recovering direct interaction capability during daily life activities based on arm reaching and hand functions. Within this project the present study is focused on the design of a biomimetic controller able to modulate the neuromuscular electrical stimulation needed to perform reaching movements supported by a commercial passive exoskeleton for weight relief. Once defined the activities of daily life to be supported by the MUNDUS system, an experimental campaign on healthy subjects was carried out to identify the repeatable kinematics and muscular solution adopted during the target movements. The kinematics resulted to be highly stereotyped, a root mean squared error lower than 5 degrees was found between all the trajectories obtained by healthy subjects in the same movement. A principal component analysis was performed on the EMG signals: less than 5 components explained more than the 85% of the signal variance. This result suggested that the muscular strategy adopted by healthy subjects was stereotyped and can be replicated by a biomimetic NMES controller. The controller was based on a time delay artificial neural network which mapped the dynamic and non-linear relationship between kinematics and EMG activations to determine the stimulation timing. The stimulation levels reproduced the same scaling factors found between muscles in the stereotyped strategy. The controller was tested on 2 healthy subjects and though it was a feedforward controller, it showed good accuracy in reaching the desired target positions. The integration of a feedback controller is foreseen to ensure the complete accomplishment of the task and to compensate for unpredictable conditions such as muscular fatigue. PMID- 23366283 TI - A comparative study of the 3D precentral gyrus model for unipolar and bipolar current stimulations. AB - Cortical stimulation (CS) is an appealing method for treating stroke and other disorders by promoting functional recovery. It is necessary to study the effect of different cortical stimulation types through numerical simulations in order to understand the underlying mechanism. In this paper, we simulated four types of invasive CS - unipolar ECS (epidural CS), bipolar ECS, unipolar SCS (subdural CS), and bipolar SCS - to investigate and compare the effects of stimulation types. Current stimulation was considered to increase the observability of the comparison between ECS and SCS. The simulation results obtained from the 3D precentral gyrus model showed ECS and SCS had similar current density distributions with higher stimulated current. However, the differences between bipolar and unipolar stimulation are significant with higher stimulated current. As stimulated current increased, unipolar CS penetrated deeper and wider regions than bipolar CS, so it can be more effective for functional recovery. PMID- 23366284 TI - Activation using infrared light in a mammalian axon model. AB - Infrared neural stimulation (INS) offers the potential to selectively activate very small populations of neurons. Before it will be possible to design efficient and effective INS interfaces, the mechanisms of INS need to be better understood. The presented study builds on work indicating that INS generates a significant capacitive current by the application of infrared light to cell membranes. A computational model is presented to investigate realistic spatial delivery of INS and to investigate whether axonal structure and ion channel composition are likely to facilitate INS activation through capacitive changes alone. Findings indicate that capacitance changes are unlikely to be the sole mechanism, because the determined thresholds to activation were higher than the capacitance changes observed in previously reported work [1]. PMID- 23366285 TI - Active AFO with ankle joint brake friction control using force observer. AB - Optimum friction control of the ankle joint brake is essential for realizing a stable gait when wearing an active ankle foot orthosis (AFO). An optimum friction control system using a force observer is designed and simulated. The brake friction is controlled in proportion to the observed human force of the lower limb without using force sensors. The simulated results show that the force observer performs well. The force-controlled orthosis is robust and practical because it uses no force sensors. PMID- 23366286 TI - Gait planning and double support phase model for functional electrical stimulation-based walking. AB - Joint or segment angle trajectories of able-bodied persons are often recorded or mimicked as reference trajectories for walking restoration in paraplegia. In this paper, lower limb segment angle trajectories are computed from simple mathematical models developed to represent functional electrical stimulation (FES) and a novel brace based walking. The new models incorporate the double support and single support phases of walking. Dynamic optimization is utilized to design walking trajectories that minimize muscle activations and arm reaction forces generated from the walker. Compared to the voluntary walking trajectories, the new trajectories are more representative of FES-based walking as only a limited number of muscle are stimulated to compute walking trajectories. PMID- 23366287 TI - Performance evaluation of a lower limb exoskeleton for stair ascent and descent with paraplegia. AB - This paper describes the application of a powered lower limb exoskeleton to aid paraplegic individuals in stair ascent and descent. A brief description of the exoskeleton hardware is provided along with an explanation of the control methodology implemented to allow stair ascent and descent. Tests were performed with a paraplegic individual (T10 complete injury level) and data is presented from multiple trials, including the hip and knee joint torque and power required to perform this functionality. Joint torque and power requirements are summarized, including peak hip and knee joint torque requirements of 0.75 Nm/kg and 0.87 Nm/kg, respectively, and peak hip and knee joint power requirements of approximately 0.65 W/kg and 0.85 W/kg, respectively. PMID- 23366288 TI - Towards the use of a lower limb exoskeleton for locomotion assistance in individuals with neuromuscular locomotor deficits. AB - The authors intend to utilize a lower limb exoskeleton for gait assistance in individuals with lower limb neuromuscular deficit. The authors suggest that two foundational elements are required to do so effectively. First, the exoskeleton system must be capable of reliable real-time gait phase detection, in order to determine the nature of gait assistance to provide. Second, in gait phases or circumstances in which the exoskeleton provides minimal assistance, the passive dynamics of the exoskeleton should not hinder the individual (i.e., should have the capability to minimally interfere with gait dynamics). As such, the exoskeleton system should be capable of actively compensating for its passive dynamics, namely the inertial, gravitational, and frictional effects it imposes on the user. This paper describes the implementation of these two foundational elements (real-time gait phase detection and active cancellation of passive dynamics) on a prototype lower limb exoskeleton, and provides experimental data demonstrating their respective efficacy. PMID- 23366290 TI - A taxonomy for user-healthcare robot interaction. AB - This paper evaluates existing taxonomies aimed at characterizing the interaction between robots and their users and modifies them for health care applications. The modifications are based on existing robot technologies and user acceptance of robotics. Characterization of the user, or in this case the patient, is a primary focus of the paper, as they present a unique new role as robot users. While therapeutic and monitoring-related applications for robots are still relatively uncommon, we believe they will begin to grow and thus it is important that the spurring relationship between robot and patient is well understood. PMID- 23366289 TI - Single degree-of-freedom exoskeleton mechanism design for thumb rehabilitation. AB - This paper presents the kinematic design of a spatial, 1-degree-of-freedom closed linkage to be used as an exoskeleton for thumb motion. Together with an already designed finger mechanism, it forms a robotic device for hand therapy. The goal for the exoskeleton is to generate the desired grasping and pinching path of the thumb with one degree of freedom, rather than using a system actuating all its joints independently. In addition to the path of the thumb, additional constraints are added in order to control the position and size of the exoskeleton, reducing physical and sensory interference with the user. PMID- 23366291 TI - Double loop control strategy with different time steps based on human characteristics. AB - This paper proposes a cooperative control strategy in consideration of the force sensitivity of human. The strategy consists of two loops: one is the intention estimation loop whose sampling time can be variable in order to investigate the effect of the sampling time; the other is the position control loop with fixed time step. A high sampling rate is not necessary for the intention estimation loop due to the bandwidth of the mechanoreceptors in humans. In addition, the force sensor implemented in the robot is sensitive to the noise induced from the sensor itself and tremor of the human. Multiple experiments were performed with the experimental protocol using various time steps of the intention estimation loop to find the suitable sampling times in physical human robot interaction. The task involves pull-and-push movement with a two-degree-of-freedom robot, and the norm of the interaction force was obtained for each experiment as the measure of the cooperative control performance. PMID- 23366292 TI - Prosthesis-user-in-the-loop: user-centered design parameters and visual simulation. AB - After an amputation, processes of change in the body image as well as a change in body scheme have direct influences on the quality of living in every patient. Within this paper, a paradigm of experimental induced body illusion (the Rubber Hand Illusion, RHI) is integrated in a prosthetic hardware simulator concept. This concept combines biodynamical and visual feedback to enhance the quality of rehabilitation and to integrate patients' needs into the development of prostheses aiming on user-centered solutions. Therefore, user-centered design parameters are deducted. Furthermore, the basic concept of the visual simulation is presented and a possibility for its implementation is given. Finally, issues and conclusions for future work are described. PMID- 23366293 TI - Electric motor assisted bicycle as an aerobic exercise machine. AB - The goal of this study is to maintain a continuous level of exercise intensity around the aerobic threshold (AT) during riding on an electric motor assisted bicycle using a new control system of electrical motor assistance which uses the efficient pedaling rate of popular bicycles. Five male subjects participated in the experiment, and the oxygen uptake was measured during cycling exercise using this new pedaling rate control system of electrical motor assistance, which could maintain the pedaling rate within a specific range, similar to that in previous type of electrically assisted bicycles. Results showed that this new pedaling rate control system at 65 rpm ensured continuous aerobic exercise intensity around the AT in two subjects, and this intensity level was higher than that observed in previous type. However, certain subjects were unable to maintain the expected exercise intensity because of their particular cycling preferences such as the pedaling rate. It is necessary to adjust the specific pedaling rate range of the electrical motor assist control according to the preferred pedaling rate, so that this system becomes applicable to anyone who want continuous aerobic exercise. PMID- 23366294 TI - An upper limb robot model of children limb for cerebral palsy neurorehabilitation. AB - Robot therapy has emerged in the last few decades as a tool to help patients with neurological injuries relearn motor tasks and improve their quality of life. The main goal of this study was to develop a simple model of the human arm for children affected with cerebral palsy (CP). The Simulink based model presented here shows a comparison for children with and without disabilities (ages 6-15) with normal and reduced range of motion in the upper limb. The model incorporates kinematic and dynamic considerations required for activities of daily living. The simulation was conducted using Matlab/Simulink and will eventually be integrated with a robotic counterpart to develop a physical robot that will provide assistance in activities of daily life (ADLs) to children with CP while also aiming to improve motor recovery. PMID- 23366295 TI - Hidden marker position estimation during sit-to-stand with walker. AB - Motion capture analysis of sit-to-stand task with assistive device is hard to achieve due to obstruction on reflective makers. Previously developed robotic system, Smart Mobile Walker, is used as an assistive device to perform motion capture analysis in sit-to-stand task. All lower limb markers except hip markers are invisible through whole session. The link-segment and regression method is applied to estimate the marker position during sit-to-stand. Applying a new method, the lost marker positions are restored and the biomechanical evaluation of the sit-to-stand movement with a Smart Mobile Walker could be carried out. The accuracy of the marker position estimation is verified with normal sit-to-stand data from more than 30 clinical trials. Moreover, further research on improving the link segment and regression method is addressed. PMID- 23366296 TI - A synchronization system for the analysis of biomedical signals recorded with different devices from mechanically ventilated patients. AB - Conducting research associated with mechanically ventilated patients often requires the recording of several biomedical signals to dispose of multiple sources of information to perform a robust analysis. This is especially important in the analysis of the relationship between pressure, volume and flow, signals available from mechanical ventilators, and other biopotentials such as the electromyogram of respiratory muscles, intrinsically related with the ventilatory process, but not commonly recorded in the clinical practice. Despite the usefulness of recording signals from multiple sources, few medical devices include the possibility of synchronizing its data with other provided by different biomedical equipment and some may use inaccurate sampling frequencies. Even thought a variant or inaccurate sampling rate does not affect the monitoring of critical patients, it restricts the study of simultaneous related events useful in research of respiratory system activity. In this article a device for temporal synchronization of signals recorded from multiple biomedical devices is described as well as its application in the study of patients undergoing mechanical ventilation with research purposes. PMID- 23366297 TI - Evaluation of pelvis slope and flattening on children gymnasts by Biophotogrammetry technique. AB - This work proposes to detect possible affections or abnormalities in pelvic belt region in a group of rhythmic gymnastics due to the need for studies in the field of biomechanics and structural evaluation of human being. The methodology for this study used a tool called Biophotogrammetry. This technique has analyzed, through scanned images, the structural pelvic girdle bone profile of 64 practitioners of rhythmic gymnastics. The results of this study have presented weighted averages of 45.07+/-9.78 degrees between the right pelvic slope (RPS) and left pelvic slope (LPS) and 91.74+/-2.50 degrees for flattening of the pelvis (FP). Therefore, it is concluded that the Biophotogrammetry technique provides data related to the gold standard radiography test, used as reference for the pelvic girdle measurements. PMID- 23366298 TI - Comparison between body fat measurements obtained by portable ultrasound and caliper in young adults. AB - The objective of this study was to compare and correlate the Portable Ultra Sound (US) measuring technique to the skinfold measuring technique (SF) to estimate body fat percentage (%F) in young adults. Sixty military were evaluated, all males, divided in two groups: Group 1 (normal) composed by 30 military with Body Mass Index (BMI) until 24.99 kg/m(2) and Group 2 (overweight) composed by 30 military with BMI > 25 kg/m(2). Weight, height, skinfolds and ultrasound were measured in 9 points (triceps, subscapular, biceps, chest, medium axillary, abdominal, suprailiac, thigh and calf). Body fat average values obtained by skinfold thickness and ultrasound measurements were 13.25 +/- 6.32 % and 12.73 +/ 5.95 % respectively. Despite significant differences in measurements of each anatomical site, it was possible to verify that the total final body fat percentage calculated by both techniques did not present significant differences and that overweight group presented greater similarity between the values obtained using caliper and ultrasound equipment. PMID- 23366301 TI - Full body gait analysis with Kinect. AB - Human gait is an important indicator of health, with applications ranging from diagnosis, monitoring, and rehabilitation. In practice, the use of gait analysis has been limited. Existing gait analysis systems are either expensive, intrusive, or require well-controlled environments such as a clinic or a laboratory. We present an accurate gait analysis system that is economical and non-intrusive. Our system is based on the Kinect sensor and thus can extract comprehensive gait information from all parts of the body. Beyond standard stride information, we also measure arm kinematics, demonstrating the wide range of parameters that can be extracted. We further improve over existing work by using information from the entire body to more accurately measure stride intervals. Our system requires no markers or battery-powered sensors, and instead relies on a single, inexpensive commodity 3D sensor with a large preexisting install base. We suggest that the proposed technique can be used for continuous gait tracking at home. PMID- 23366299 TI - Automated motion sensor quantification of gait and lower extremity bradykinesia. AB - The objective was to develop and evaluate algorithms for quantifying gait and lower extremity bradykinesia in patients with Parkinson's disease using kinematic data recorded on a heel-worn motion sensor unit. Subjects were evaluated by three movement disorder neurologists on four domains taken from the Movement Disorders Society Unified Parkinson's Disease Rating Scale while wearing the motion sensor unit. Multiple linear regression models were developed based on the recorded kinematic data and clinician scores and produced outputs highly correlated to clinician scores with an average correlation coefficient of 0.86. The newly developed models have been integrated into a home-based system for monitoring Parkinson's disease motor symptoms. PMID- 23366302 TI - Development and clinical validation of an unobtrusive ambulatory knee function monitoring system with inertial 9DoF sensors. AB - Patients suffering from end-stage knee osteoarthritis are often treated with total knee arthroplasty, improving their functional mobility. A number of patients, however, report continued difficulty with stair ascent and descent or sportive activity after surgery and are not completely satisfied with the outcome. State-of-the-art analyses to evaluate the outcome and mobility after knee replacement are conducted under supervised settings in specialized gait labs and thus can only reflect a short period of time. A number of external factors may lead to artificial gait patterns in patients. Moreover, clinically relevant situations are difficult to simulate in a stationary gait lab. In contrast to this, inertial sensors may be used additionally for unobtrusive gait monitoring. However, recent notable approaches found in literature concerning knee function analysis have so far not been applied in a clinical context and have therefore not yet been validated in a clinical setting. The aim of this paper is to present a system for unsupervised long-term monitoring of human gait with a focus on knee joint function, which is applicable in patients' everyday lives and to report on the validation of this system gathered during walking with reference to state-of the-art gait lab data using a vision system (VICON Motion System). The system KINEMATICWEAR - developed in close collaboration of computer scientists and physicians performing knee arthroplasty - consists of two sensor nodes with combined tri-axial accelerometer, gyroscope and magnetometer to be worn under normal trousers. Reliability of the system is shown in the results. An overall correlation of 0.99 (with an overall RMSE of 2.72) compared to the state-of-the art reference system indicates a sound quality and a high degree of correspondence. KINEMATICWEAR enables ambulatory, unconstrained measurements of knee function outside a supervised lab inspection. PMID- 23366303 TI - Indoor magnetic navigation for the blind. AB - Indoor navigation technology is needed to support seamless mobility for the visually impaired. This paper describes the construction of and evaluation of a navigation system that infers the users' location using only magnetic sensing. It is well known that the environments within steel frame structures are subject to significant magnetic distortions. Many of these distortions are persistent and have sufficient strength and spatial characteristics to allow their use as the basis for a location technology. This paper describes the development and evaluation of a prototype magnetic navigation system consisting of a wireless magnetometer placed at the users' hip streaming magnetic readings to a smartphone processing location algorithms. Human trials were conducted to assess the efficacy of the system by studying route-following performance with blind and sighted subjects using the navigation system for real-time guidance. PMID- 23366304 TI - A smartphone application of alcohol resilience treatment for behavioral self control training. AB - High relapse rate is one of the most prominent problems in addiction treatment. Alcohol Resilience Treatment (ART), an alcohol addiction therapy, is based on Cue Exposure Treatment, which has shown promising results in preliminary studies. ART aims at optimizing the core area of relapse prevention, and intends to improve patients' capability to withstand craving of alcohol. This method emphasizes the interplay of resilience and resourcefulness. It contains 6 sessions with different topics according to the stage of treatment circuit, and each session consists of 6 steps. Due to the purity and structure of the treatment rationale, it is realistic, reasonable and manageable to transform the method into a smartphone application. An ART app in Android system and an accessory of bilateral tactile stimulation were developed and will be used in a study with behavioral self-control training. This paper presents the design and realization of the smartphone based ART application. The design of a pilot study, which is to examine the benefits of a smartphone application providing behavioral self control training, is also reported in this paper. PMID- 23366305 TI - Towards the run and walk activity classification through step detection--an android application. AB - Falling is one of the most common accidents with potentially irreversible consequences, especially considering special groups, such as the elderly or disabled. One approach to solve this issue would be an early detection of the falling event. Towards reaching the goal of early fall detection, we have worked on distinguishing and monitoring some basic human activities such as walking and running. Since we plan to implement the system mostly for seniors and the disabled, simplicity of the usage becomes very important. We have successfully implemented an algorithm that would not require the acceleration sensor to be fixed in a specific position (the smart phone itself in our application), whereas most of the previous research dictates the sensor to be fixed in a certain direction. This algorithm reviews data from the accelerometer to determine if a user has taken a step or not and keeps track of the total amount of steps. After testing, the algorithm was more accurate than a commercial pedometer in terms of comparing outputs to the actual number of steps taken by the user. PMID- 23366306 TI - The simulation of click and double-click through EMG signals. AB - Patients with severe motor impairments, victims of stroke, amyotrophic lateral sclerosis and spinal cord injury are prevented from oral and gesture communication, demanding alternative channels and methods of communication, possibly using a computer. In order to obtain the complete emulation of a standard mouse, the single-click and double-click actions are desirable functionalities. In this study, the implementation of such actions is executed by the analysis of the electromyographic signal recorded from the Frontalis muscle. Muscle activity is discriminated from noise and this information is used to feed a state-machine that in turn decides which action is intended. The method uses an adaptive threshold, which offers freedom for the selection of the parameters of the system. The rate of successfully detected commands found was up to 100% for the single-click and 92% for the double-click. Even though good results were found for double-clicks, the experiment indicate muscle fatigue in the short term. The time response found was below 300 ms suggesting real-time implementation is feasible. Also, other devices can be operated with this approach, if it is accepted as a two symbols system generator. PMID- 23366307 TI - A laser Doppler system for monitoring of intracerebral microcirculation. AB - A two-channel standard laser Doppler perfusion monitor has been adapted for intracerebral measurements. Software developed in Labview makes it possible to present the microvascular perfusion, total light intensity (TLI), heart rate and trend curves in real-time during surgery. A custom-made optical probe was designed in order to enable easy fixation during brain surgery. The constructed brain probe was evaluated and compared to a standard probe. Both probes presented similar feasibility when used for the skin recordings. In addition, evaluation was done in one patient in relation to tumor resection. Stable perfusion and TLI signals were immediately recorded when the probe was positioned in cerebral tissue. Movement artifacts were clearly seen when the probe was moved to a new site. Recordings in cortex and tumor border showed higher perfusion and lower TLI compared to measurements in subcortical white matter. The calculated heart rate estimate agreed well with the noted value from the electrocardiographic patient monitoring system. PMID- 23366308 TI - A low-impedance, skin-grabbing, and gel-free EEG electrode. AB - Inspired by the extraordinary object grabbing ability of certain insects (e.g., a grasshopper), we have developed a novel dry EEG electrode, called the skin screw electrode. Unlike the traditional disc electrode which requires several minutes to install, the installation of the skin screw electrode can be completed within seconds since no skin preparation and electrolyte application are required. Despite the drastic improvement in the installation time, our experiments have demonstrated that the skin screw electrode has a similar impedance value to that of the disc electrode. The skin screw electrode has a wide range of applications, such as clinical EEG diagnosis, epilepsy monitoring, emergency medicine, and home based human-computer interface. PMID- 23366309 TI - Reliability and validity of the Grip-Ball dynamometer for grip-strength measurement. AB - Grip-strength measurement is a key element in the evaluation of numerous conditions including frailty. An innovative grip-strength evaluation tool, the Grip-Ball has been developed for remote assessment of grip-strength. The Grip Ball is an airtight ball that can be inflated to different pressures, thus varying the stiffness of the ball and the grip-strength dynamics. Three different initial pressures of 100, 125, and 150 kPa were evaluated in respect to reliability and validity, when compared to the Jamar. Reliability was very high, with ICC values of 0.95, 0.98, and 0.99 for 100, 125, and 150 kPa, respectively. The new device was highly correlated with the force measured using the Jamar for all initial pressures (r= 0.88, 0.93, and 0.93 for 100, 125, and 150 kPa, respectively). The possibility of varying the initial pressure would enable the Grip-Ball to be used for standard grip-strength testing and rehabilitation, while still maintaining high reliability and validity. PMID- 23366310 TI - Multi-signal Visualization of Physiology (MVP): a novel visualization dashboard for physiological monitoring of Traumatic Brain Injury patients. AB - To prevent Traumatic Brain Injury (TBI) patients from secondary brain injuries, patients' physiological readings are continuously monitored. However, the visualization dashboards of most existing monitoring devices cannot effectively present all physiological information of TBI patients and are also ineffective in facilitating neuro-clinicians for fast and accurate diagnosis. To address these shortcomings, we proposed a new visualization dashboard, namely the Multi-signal Visualization of Physiology (MVP). MVP makes use of multi-signal polygram to collate various physiological signals, and it also utilizes colors and the concept of "safe/danger zones" to assist neuro-clinicians to achieve fast and accurate diagnosis. Moreover, MVP allows neuro-clinicians to review historical physiological statuses of TBI patients, which can guide and optimize clinicians' diagnosis and prognosis decisions. The performance of MVP is tested and justified with an actual Philips monitoring device. PMID- 23366311 TI - Adaptive cancellation of motion artifact in wearable biosensors. AB - The performance of wearable biosensors is highly influenced by motion artifact. In this paper, a model is proposed for analysis of motion artifact in wearable photoplethysmography (PPG) sensors. Using this model, we proposed a robust real time technique to estimate fundamental frequency and generate a noise reference signal. A Least Mean Square (LMS) adaptive noise canceler is then designed and validated using our synthetic noise generator. The analysis and results on proposed technique for noise cancellation shows promising performance. PMID- 23366312 TI - Negative effects of obesity analyzed through bioimpedance, indirect calorimetry, the sympathovagal index and the orthoclinostatic test. AB - Early analysis of the negative effects of obesity is important to prevent the development of chronic diseases related to this condition. There is a need to monitor these effects through simple instrumentation that measures fat-free mass (FFM) catabolism. Obesity leads to a decrease in the FFM energy expenditure and to an increase in the autonomic nervous system (ANS) activity. Thus, the measurement of FFM dynamic catabolism can provide information regarding the effects of obesity. The hypothesis is that this increased ANS activity produces an increase of energy expenditure of carbohydrates and fats when the subjects are under stress; in this case after an 8-hour fast and while they are undergoing an orthoclinostatic test. A pilot study was conducted on 29 volunteers, 16 women and 13 men. The results show significant statistical differences (p<0.1) in fat and carbohydrate utilization during the orthoclinostatic tests: A move from the clinostatic to the orthostatic positions produced the following: Fat metabolism varied from 97.2 to 105.9 gr/day of fat for women and 24.9 to 35.7 gr/day of fat for men; carbohydrate metabolism changed from 38 to 39 gr/day for women and 239 to 277 gr/day for men; FFM averages were 47 Kg for women and 57.6 Kg for men; changes in the sympathovagal index (SVI) averages were 0.4 to 1.8 for women and 0.8 to 2.7 for men. The conclusions show that the methodology's sensitivity is such that gender differences can be used as a model to prove FFM metabolic differences. We believe that further studies will lead to the development of a robust methodology for the early detection of the negative effects of obesity. PMID- 23366313 TI - Scale-independent stiffness measurement of upper limbs with lymphedema by a circular compression. AB - Lymphedema caused by the dissection of lymphatic node for treating a breast cancer produces serious swelling on the limbs and reduces the quality of life of the patient. For quantitative assessing the disease, this study newly proposed the stiffness measurement method of upper limb with lymphedema. A measurement system, where a roll-up belt was installed to circularly compress the limb by pulling the belt was developed. Both the belt tension and displacement were measured during the compresson of limb. Scale-independent stiffness index was newly derived from the bulk modulus and applied the measured force and displacement. The stiffness index of upper limb with lymphedema was measured. The index of affected limb was larger than that of healthy limb in a patient. PMID- 23366315 TI - Human behavior state profile mapping based on recalibrated speech affective space model. AB - People typically associate health with only physical health. However, health is also interconnected to mental and emotional health. People who are emotionally healthy are in control of their behaviors and experience better quality of life. Hence, understanding human behavior is very important in ensuring the complete understanding of one's holistic health. In this paper, we attempt to map human behavior state (HBS) profiles onto recalibrated speech affective space model (rSASM). Such an approach is derived from hypotheses that: 1) Behavior is influenced by emotion, 2) Emotion can be quantified through speech, 3) Emotion is dynamic and changes over time and 4) the emotion conveyance is conditioned by culture. Empirical results illustrated that the proposed approach can complement other types of behavior analysis in such a way that it offers more explanatory components from the perspective of emotion primitives (valence and arousal). Four different driving HBS; namely: distracted, laughing, sleepy and normal are profiled onto the rSASM to visualize the correlation between HBS and emotion. This approach can be incorporated in the future behavior analysis to envisage better performance. PMID- 23366316 TI - A 3D assessment tool for accurate volume measurement for monitoring the evolution of cutaneous leishmaniasis wounds. AB - Clinical assessment and outcome metrics are serious weaknesses identified on the systematic reviews of cutaneous Leishmaniasis wounds. Methods with high accuracy and low-variability are required to standarize study outcomes in clinical trials. This work presents a precise, complete and noncontact 3D assessment tool for monitoring the evolution of cutaneous Leishmaniasis (CL) wounds based on a 3D laser scanner and computer vision algorithms. A 3D mesh of the wound is obtained by a commercial 3D laser scanner. Then, a semi-automatic segmentation using active contours is performed to separate the ulcer from the healthy skin. Finally, metrics of volume, area, perimeter and depth are obtained from the mesh. Traditional manual 3D and 3D measurements are obtained as a gold standard. Experiments applied to phantoms and real CL wounds suggest that the proposed 3D assessment tool provides higher accuracy (error <2%) and precision rates (error <4%) than conventional manual methods (precision error < 35%). This 3D assessment tool provides high accuracy metrics which deserve more formal prospective study. PMID- 23366317 TI - A remote drip infusion monitoring system employing Bluetooth. AB - We have developed a remote drip infusion monitoring system for use in hospitals. The system consists of several infusion monitoring devices and a central monitor. The infusion monitoring device employing a Bluetooth module can detect the drip infusion rate and an empty infusion solution bag, and then these data are sent to the central monitor placed at the nurses' station via the Bluetooth. The central monitor receives the data from several infusion monitoring devices and then displays graphically them. Therefore, the developed system can monitor intensively the drip infusion situation of the several patients at the nurses' station. PMID- 23366319 TI - Basic study on non-contact measurement of cardiac beat by using grid-based active stereo. AB - We propose a new non-contact measurement of cardiac beat from 3D shape information of body surface by using grid-based active stereo, and basically examine the validity of the proposed method. By simultaneous measurement with our proposed method and ECG, there are sufficient correspondences between peak intervals of inter-frame depth changes measured by our method and R-R intervals measured by ECG. PMID- 23366320 TI - Development of a cuffless blood pressure measurement system. AB - This study constructs a novel blood pressure measurement device without the air cuff to overcome the problem of discomfort and portability. The proposed device measures the blood pressure through a mechanism that is made of silicon rubber and pressure transducer. The system uses a microcontroller to control the measurement procedure and to perform the necessary computation. To verify the feasibility of the constructed device, ten young volunteers were recruited. Ten blood pressure readings were obtained using the new system and were compared with ten blood pressure readings from bedside monitor (Spacelabs Medical, model 90367). The results indicated that, when all the readings were included, the mean pressure, systolic pressure and diastolic pressure from the new system were all higher than those from bedside monitor. The correlation coefficients between these two were 0.15, 0.18 and 0.29, for mean, systolic and diastolic pressures, respectively. After excluding irregular apparatus utilization, the correlation coefficient increased to 0.71, 0.60 and 0.41 for diastolic pressure, mean pressure and systolic pressure, respectively. We can conclude from these results that the accuracy can be improved effectively by defining the user regulation more precisely. The above mentioned irregular apparatus utilization factors can be identified and eliminated by the microprocessor to provide a reliable blood pressure measurement in practical applications in the future. PMID- 23366321 TI - First steps in adaptation of an evidential network for data fusion in the framework of medical remote monitoring. AB - This paper presents a medical remote monitoring application which aims at detecting falls. The detection system is based on three modalities: a wearable sensor, infrared sensors and a sound analysis module. The sound analysis is presented briefly. The multimodal fusion is made using the Dempster Schaffer theory through Evidential Network. A first evaluation of the use of data mining techniques in order to extract blindly data representatives is proposed. These representatives are used to continuously increase the system performances. The system is evaluated on a local recorded data base. PMID- 23366322 TI - Evaluation of novel algorithm embedded in a wearable sEMG device for seizure detection. AB - We implemented a modified version of a previously published algorithm for detection of generalized tonic-clonic seizures into a prototype wireless surface electromyography (sEMG) recording device. The method was modified to require minimum computational load, and two parameters were trained on prior sEMG data recorded with the device. Along with the normal sEMG recording, the device is able to set an alarm whenever the implemented algorithm detects a seizure. These alarms are annotated in the data file along with the signal. The device was tested at the Epilepsy Monitoring Unit (EMU) at the Danish Epilepsy Center. Five patients were included in the study and two of them had generalized tonic-clonic seizures. All patients were monitored for 2-5 days. A double-blind study was made on the five patients. The overall result showed that the device detected four of seven seizures and had a false detection rate of 0.003/h or one in twelve days. PMID- 23366323 TI - A computational model of a controllable needle-free jet injector. AB - We present a mathematical model of the dynamics of a previously developed needle free jet injector (NFJI) that is based upon a servo-controlled Lorentz-force motor. The injector creates a fluid jet that can pierce through the skin and deliver a drug to dermal, subcutaneous and muscular tissue. We use the model to predict the jet speed achieved during an injection. The model simulates the electrical response of the motor coil, the mechanical response of the drug piston and ampoule and the friction incident upon the piston during the time course of the injection. High-speed video measurements of piston movement in response to a step input show that the model predicts piston-tip position during an injection within an RMS error of 287 um. The corresponding jet speed is predicted to be 180 m.s(-1) with a maximum overshoot to 205 m.s(-1). PMID- 23366324 TI - Experimental glucose regulation with a high-order sliding-mode controller. AB - Theoretically High-Order Sliding-Mode Controllers are well suited to perform closed loop glucose regulation because they are insensitive to parameter uncertainties and robust to unknown dynamics that may perturb the system. The implementation of the controller based on the concept of practical relative degree is presented. The controller was tested in Sprague-Dawley rats with steptozotocin induced diabetes. The tests demonstrated high efficacy and robustness of the controller. PMID- 23366325 TI - A new approach to assess the spasticity in hamstrings muscles using mechanomyography antagonist muscular group. AB - Several pathologies can cause muscle spasticity. Modified Ashworth scale (MAS) can rank spasticity, however its results depend on the physician subjective evaluation. This study aims to show a new approach to spasticity assessment by means of MMG analysis of hamstrings antagonist muscle group (quadriceps muscle). Four subjects participated in the study, divided into two groups regarding MAS (MAS0 and MAS1). MMG sensors were positioned over the muscle belly of rectus femoris (RF), vastus lateralis (VL) and vastus medialis (VM) muscles. The range of movement was acquired with an electrogoniometer placed laterally to the knee. The system was based on a LabVIEW acquisition program and the MMG sensors were built with triaxial accelerometers. The subjects were submitted to stretching reflexes and the integral of the MMG (MMG(INT)) signal was calculated to analysis. The results showed that the MMG(INT) was greater to MAS1 than to MAS0 [muscle RF (p = 0.004), VL (p = 0.001) and VM (p = 0.007)]. The results showed that MMG was viable to detect a muscular tonus increase in antagonist muscular group (quadriceps femoris) of spinal cord injured volunteers. PMID- 23366326 TI - Observation of flow variation in capillaries of artificial blood vessel by producing microbubble aggregations. AB - Microbubbles form their aggregations between the neighboring microbubbles by the effect of secondary Bjerknes force under ultrasound exposure. However, because of the difficulty to reproduce a capillary-mimicking artificial blood vessel, the behavior of aggregations in a capillary has not been predicted. Thus we prepared artificial blood vessels including a capillary model, which was made of poly(vinyl alcohol) (PVA) by grayscale lithography method, with minimum diameter of the path of 0.5 mm. By using this model we investigated the possibility of artificial embolization, where the microbubble aggregations might block entire vessels not to penetrate flow in downstream. Confirming that the sizes of flown aggregation were greater than the section area of the minimum path in the capillary model, we investigated the probability of path block in it. As the results we confirmed the probability increased in proportion to sound pressure and inversely to flow velocity. We are going to investigate with more kinds of parameters to enhance the possibility of artificial embolization. PMID- 23366327 TI - Intradermal needle-free powdered drug injection by a helium-powered device. AB - We present a new method for needle-free powdered drug injection via a bench-top gas-powered device. This injector provides an alternative method of vaccine delivery to address the cold chain problem--the cost and risk of transporting temperature sensitive vaccines to developing countries. The device houses interchangeable nozzle inserts to vary orifice geometries and is capable of delivering polymer beads (1-5 um diameter) into the dermal layer of porcine tissue. Results for injection shape and injection depth versus nozzle orifice diameter demonstrate the device's controllability. PMID- 23366328 TI - Dissolution of magnetically marked tablets: investigations in a physical phantom. AB - Pharmacological research is strongly driven by maximizing the bioavailability of new pharmaceuticals. For orally applied drugs the bioavailability highly depends on the process of dissolution in the gastrointestinal tract and is affected by numerous physiological and environmental factors. Available techniques for in vivo monitoring of the dissolution process are very limited and not applicable for large studies. The technique of magnetic marker monitoring provides new prospects for these investigations. However, it is currently limited due to low fields common magnetic markers produce. Hence, only highly sensitive sensors are applicable. In this paper, we performed dissolution tests of novel markers in a physical phantom with magnetoresistive sensors in an unshielded environment. The markers were continuously localized and the movement through the phantom was tracked. By analyzing the changing magnetic moment of the markers we were able to monitor the progress of dissolution in the phantom. We conclude that our proposed phantom and tracking technique is an important step towards new systems for in vivo monitoring of pharmaceutical dissolution processes. PMID- 23366329 TI - Estimation of accelerometer orientation for activity recognition. AB - Tri-axial accelerometers have been widely used for human activity recognition and classification. A main challenge in accelerometer-based activity recognition is the system dependence on the orientation of the accelerometer. This paper presents an approach for overcoming this challenge by calibrating the accelerometer orientation using pre-defined activities alongside automated correction algorithms. This method includes manipulation of data via rotation matrices estimated from the pre-defined activities. The system is subsequently tested with real data where sensors were placed in the wrong orientation. A control set of correctly oriented sensors were also placed for validation purposes. We show that our approach improves the accuracy from 38% to 92% for the wrongly oriented sensors, when the control sensors achieve 95%. A GUI was also created in order to make the tool easily available to other researchers. PMID- 23366330 TI - High resolution wireless body area network with statistically synchronized sensor data for tracking pulse wave velocity. AB - Wireless body area networks (WBANs) will take on more diverse forms in terms of their sensor combinations and communication protocols as their presence is extended to a greater number of monitoring scenarios. This paper presents an application layer protocol that solves issues caused by sensor nodes that must compete for high speed, real-time communication with the receiver. Such applications emphasize the delivery of large amounts of raw data from different sensor nodes in a time-synchronized manner, rather than channels that experience intermittent operation. An example of tracking pulse wave velocity (PWV) is introduced in this paper, where high-precision PWVs are estimated with the help of timeline recovery and feature extraction processes in MATLAB. PMID- 23366331 TI - Energy-efficient process-stacking multiplexing access for 60-GHz mm-wave wireless personal area networks. AB - Millimeter-wave technology shows high potential for future wireless personal area networks, reaching over 1 Gbps transmissions using simple modulation techniques. Current specifications consider dividing the spectrum into effortlessly separable spectrum ranges. These low requirements open a research area in time and space multiplexing techniques for millimeter-waves. In this work a process-stacking multiplexing access algorithm is designed for single channel operation. The concept is intuitive, but its implementation is not trivial. The key to stacking single channel events is to operate while simultaneously obtaining and handling a posteriori time-frame information of scheduled events. This information is used to shift a global time pointer that the wireless access point manages and uses to synchronize all serviced nodes. The performance of the proposed multiplexing access technique is lower bounded by the performance of legacy TDMA and can significantly improve the effective throughput. Work is validated by simulation results. PMID- 23366332 TI - A review of non-contact, low-cost physiological information measurement based on photoplethysmographic imaging. AB - In recent decades, there has been increasing interest in low-cost, non-contact and pervasive methods for measuring physiological information, such as heart rate (HR), respiratory rate, heart rate variability (HRV) and oxyhemoglobin saturation. The conventional methods including wet adhesive Ag/AgCl electrodes for HR and HRV, the capnograph device for respiratory status and pulse oximetry for oxyhemoglobin saturation provide excellent signals but are expensive, troublesome and inconvenient. A method to monitor physiological information based on photoplethysmographic imaging offers a new means for health monitoring. Blood volume can be indirectly assessed in terms of blood velocity, blood flow rate and blood pressure, which, in turn, can reflect changes in physiological parameters. Changes in blood volume can be determined from the spectra of light reflected from or transmitted through body tissues. Images of an area of the skin surface are consecutively captured with the color camera of a computer or smartphone and, by processing and analyzing the light signals, physiological information such as HR, respiratory rate, HRV and oxyhemoglobin saturation can be acquired. In this paper, we review the latest developments in using photoplethysmographic imaging for non-contact health monitoring and discuss the challenges and future directions for this field. PMID- 23366333 TI - Wireless photoplethysmographic device for heart rate variability signal acquisition and analysis. AB - The photoplethysmographic (PPG) signal has the potential to aid in the acquisition and analysis of heart rate variability (HRV) signal: a non-invasive quantitative marker of the autonomic nervous system that could be used to assess cardiac health and other physiologic conditions. A low-power wireless PPG device was custom-developed to monitor, acquire and analyze the arterial pulse in the finger. The system consisted of an optical sensor to detect arterial pulse as variations in reflected light intensity, signal conditioning circuitry to process the reflected light signal, a microcontroller to control PPG signal acquisition, digitization and wireless transmission, a receiver to collect the transmitted digital data and convert them back to their analog representations. A personal computer was used to further process the captured PPG signals and display them. A MATLAB program was then developed to capture the PPG data, detect the RR peaks, perform spectral analysis of the PPG data, and extract the HRV signal. A user friendly graphical user interface (GUI) was developed in LabView to display the PPG data and their spectra. The performance of each module (sensing unit, signal conditioning, wireless transmission/reception units, and graphical user interface) was assessed individually and the device was then tested as a whole. Consequently, PPG data were obtained from five healthy individuals to test the utility of the wireless system. The device was able to reliably acquire the PPG signals from the volunteers. To validate the accuracy of the MATLAB codes, RR peak information from each subject was fed into Kubios software as a text file. Kubios was able to generate a report sheet with the time domain and frequency domain parameters of the acquired data. These features were then compared against those calculated by MATLAB. The preliminary results demonstrate that the prototype wireless device could be used to perform HRV signal acquisition and analysis. PMID- 23366334 TI - Real time digitally assisted analog motion artifact reduction in ambulatory ECG monitoring system. AB - This paper proposes a real time digitally assisted analog motion artifact reduction ASIC with ECG measurement simultaneously. It features one ECG monitoring and in- and quad-phase electrode-skin impedance measurement, which are used to estimate motion artifacts. The implemented ASIC is capable of actual motion artifact reduction in the analog domain before final amplification. PMID- 23366335 TI - Evaluation of a technology enabled garment for older walkers. AB - Walking is often cited as the best form of activity for persons over the age of 60. In this paper we outline the development and evaluation of a smart garment system that aims to monitor the wearer's wellbeing and activity regimes during walking activities. Functional requirements were ascertained using a combination of questionnaires and two workshops with a target cohort. The requirements were subsequently mapped onto current technologies as part of the technical design process. In this paper we outline the development and second round of evaluations of a prototype as part of a three-phase iterative development cycle. The evaluation was undertaken with 6 participants aged between 60 and 73 years of age. The results of the evaluation demonstrate the potential role that technology can play in the promotion of activity regimes for the older population. PMID- 23366336 TI - Speech analysis for mood state characterization in bipolar patients. AB - Bipolar disorders are characterized by an unpredictable behavior, resulting in depressive, hypomanic or manic episodes alternating with euthymic states. A multi parametric approach can be followed to estimate mood states by integrating information coming from different physiological signals and from the analysis of voice. In this work we propose an algorithm to estimate speech features from running speech with the aim of characterizing the mood state in bipolar patients. This algorithm is based on an automatic segmentation of speech signals to detect voiced segments, and on a spectral matching approach to estimate pitch and pitch changes. In particular average pitch, jitter and pitch standard deviation within each voiced segment, are estimated. The performances of the algorithm are evaluated on a speech database, which includes an electroglottographic signal. A preliminary analysis on subjects affected by bipolar disorders is performed and results are discussed. PMID- 23366337 TI - Estimating uncomfortable loudness levels using evoked potentials to auditory stimuli for hearing aid fitting. AB - Determining the loudest sound level that a person can comfortably tolerate (uncomfortable loudness level: UCL) imposes a strain on people suffering from hearing loss. In the present study, we propose a method of estimating UCL based on auditory evoked potentials (AEPs). Adults with normal hearing (18 men aged 25 56 years) participated in the study. Three tone bursts (S1, S2 and S3; a triplet) of the same frequency (either 1k, 2k or 4k Hz) were presented to the right or left ear with an interstimulus interval of 300 ms. The sound intensity decreased gradually by 5 dB HL from 80 dB (S1) to 70 dB HL (S3). The interval between triplets was 450 +/- 50 ms. The frequency of a given triplet differed from the frequency of the preceding triplet. An electroencephalogram was recorded from three scalp electrode sites (Cz, C3, and C4) with the right mastoid reference. The 900-ms period after the onset of the triplet was transformed to a wavelet coefficient and averaged separately by stimulated ear and tone frequency. The UCLs were estimated by linear discriminant analysis on the basis of trained data of the other participants' subjective UCLs and the wavelet coefficients. The mean estimation error was 4.9 +/- 5.0 dB. This result suggests that the UCLs could be estimated successfully on the basis of AEPs to triplets of auditory tones. PMID- 23366338 TI - Speech activity detection using accelerometer. AB - The level of social activity is linked to the overall wellbeing and to various disorders, including stress. In this regard, a myriad of automatic solutions for monitoring social interactions have been proposed, usually including audio data analysis. Such approaches often face legal and ethical issues and they may also raise privacy concerns in monitored subjects thus affecting their natural behaviour. In this paper we present an accelerometer-based speech detection which does not require capturing sensitive data while being an easily applicable and a cost-effective solution. PMID- 23366339 TI - Tailor-made preventive medicine integrating amino acid checkup and its application toward disaster-stricken areas. AB - ICT technologies for healthcare are useful in myriad locations for people with lifestyle-related illnesses and health irregularities. When symptoms turn into actual illnesses, it is difficult for them to be managed, and this situation is relevant for managing the health of victims after large-scale disasters; it is important to keep people healthy to prevent them from acquiring illness. This paper proposes a system of personalized preventive medicine for individuals to maintain their health and receive evidence-based feedback. We introduce general medical checkups, ubiquitous sensing, and plasma amino acid analysis as the system's core components. We evaluate these elements and discuss their applicability toward the disaster-stricken Tohoku area of Japan. This is an initial evaluation, but some functions are being used in the area. There are gaps between research results and actually deployable technologies, but it is important to use and improve the quality of life of victims who are ultimately forced to live in temporary housing for more than five years. PMID- 23366340 TI - Group profile management in ubiquitous healthcare environment. AB - Nowadays, ubiquitous healthcare is of utmost importance in the patient-centric model. Furthermore, the personalization of ubiquitous healthcare services plays a very important role to make the patient-centric model a reality. The personalization of the ubiquitous healthcare services is based on the profiles of the entities participating in these services. In this paper, we propose a group profile management system in a ubiquitous healthcare environment. The proposed system is responsible for the dynamic creation of a group profile and its management. PMID- 23366341 TI - A preliminary study of the effect of electrode placement in order to define a suitable location for two electrodes and obtain sufficiently reliable ECG signals when monitoring with wireless system. AB - Most countries face high and increasing rates of cardiovascular disease. Each year, heart disease kills more Americans than cancer. Therefore, there has been a promising market for portable ECG equipment and it is increasing. To use portable ECG measuring devices, it is essential to define a suitable location for the measuring as we need to reduced electrode size and distance. This research proposes to study how the inter-electrode distance affects the signal and how the electrode pair should be placed on the chest in order to obtain a sufficiently reliable ECG signal to detect heart arrhythmias in any environment, such as home or work. Therefore, we developed a compact, portable patch type ambulatory ECG monitoring system, Heart Tracker, using a microprocessor for preliminary study of signal analysis. To optimize the electrode arrangement in wireless environment, we compared HT and standard 12 lead with changing electrode position. PMID- 23366342 TI - Vital analysis: field validation of a framework for annotating biological signals of first responders in action. AB - First responders are professionals that are exposed to extreme stress and fatigue during extended periods of time. That is why it is necessary to research and develop technological solutions based on wearable sensors that can continuously monitor the health of these professionals in action, namely their stress and fatigue levels. In this paper we present the Vital Analysis smartphone-based framework, integrated into the broader Vital Responder project, that allows the annotation and contextualization of the signals collected during real action. After a contextual study we have implemented and deployed this framework in a firefighter team with 5 elements, from where we have collected over 3300 hours of annotations during 174 days, covering 382 different events. Results are analysed and discussed, validating the framework as a useful and usable tool for annotating biological signals of first responders in action. PMID- 23366343 TI - Protocol for cardiac assessment of recreational athletes. AB - In this work, the development of a database on physical fitness is presented. As initial population to fill this database, people who practice recreational sports at the Universidad Simon Bolivar (USB) were chosen. The goal was studying individual physical fitness in order to structure exercise routines that gives certain benefits without risking the individual health, promoting a less sedentary way of life. Before the study, a low-cost noninvasive protocol was designed to determine the level of physical fitness. The methodology consisted of four steps: a) A review of existing protocols to propose a set of physical fitness (International Physical Activity Questionnaire (IPAQ)), cardiovascular (heart rate variability, heart rate recovery time and arterial blood pressure), anthropomorphic, aerobic (maximum oxygen consumption) and mood state (Profile of Mood State (POMS)) measurements, which allow sketching a complete profile on the sportsman physical fitness. b) Instrumental data collection. c) Electrocardiographic signal processing. d) Data post-processing using multivariate analysis. The database was composed of 26 subject from USB. Ten subjects were soccer players, ten were mountain climbers and six were sedentary people. Results showed that the heart rate recover time after 2-3 min, IPAQ and maximum oxygen consumption have higher weights for classifying individuals according to their habitual physical activity. Heart rate variability, as well as, POMS did not contribute greatly for discriminating recreational sport from sedentary persons. PMID- 23366345 TI - Parameters characterizing nature of personal health in the correlation between energy expenditure/supply and body-fat. AB - Correlations between energy expenditure/supply and body-fat percentage were studied using personally stored daily time-series data. The weighting patterns for the summation of daily time-series energy expenditure and supply data giving the maximum correlations with the variation of daily body-fat percentage data were obtained. The weighting patterns can be expressed by two parameters whose combination is considered to characterize the nature of personal health. The combination of the parameters for a subject was found to show a significant bias in the frequency distribution, independent of season and aging, for the term of seven years, and the combination of the parameters of 20 other subjects showed a tendency to divide into two types. PMID- 23366346 TI - Sleep and activity monitoring for Returning Soldier Adjustment Assessment. AB - This paper describes the development of unobtrusive room sensors to discover relationships between sleep quality and the clinical assessments of combat soldiers suffering from post-traumatic stress disorder (PTSD) and mild traumatic brain injury (TBI). We consider the use of a remote room sensor unit composed of a Doppler radar, light, sound and other room environment sensors. We also employ an actigraphy watch. We discuss sensor implementation, radar data analytics and preliminary results using real data from a Warrior Transition Battalion located in Fort Gordon, GA. Two radar analytical approaches are developed and compared against the actigraphy watch estimates--one, emphasizing system knowledge; and the other, clustering on several radar signal features. The radar analytic algorithms are able to estimate sleep periods, signal absence and restlessness in the bed. In our test cases, the radar estimates are shown to agree with the actigraphy watch. PTSD and mild-TBI soldiers do often show signs of sporadic and restless sleep. Ongoing research results are expected to provide further insight. PMID- 23366348 TI - PersonA: Persuasive social network for physical Activity. AB - Advances in physical activity (PA) monitoring devices provide ample opportunities for innovations in the way the information produced by these devices is used to encourage people to have more active lifestyles. One such innovation is expanding the current use of the information from self-management to social support. We developed a Persuasive social network for physical Activity (PersonA) that combines automatic input of physical activity data, a smartphone, and a social networking system (SNS). This paper describes the motivation for and overarching design of the PersonA and its functional and non-functional features. PersonA is designed to intelligently and automatically receive raw PA data from the sensors in the smartphone, calculate the data into meaningful PA information, store the information on a secure server, and show the information to the users as persuasive and real-time feedbacks or publish the information to the SNS to generate social support. The implementation of self-monitoring, social support, and persuasive concepts using currently available technologies has the potential for promoting healthy lifestyle, greater community participation, and higher quality of life. We also expect that PersonA will enable health professionals to collect in situ data related to physical activity. The platform is currently being used and tested to improve PA level of three groups of users in Pittsburgh, PA, USA. PMID- 23366349 TI - Summarized data to achieve population-wide anonymized wellness measures. AB - The growth in smartphone market share has seen the increasing emergence of individuals collecting quantitative wellness data. Beyond the potential health benefits for the individual in regards to managing their own health, the data is highly related to preventative and risk factors for a number of lifestyle related diseases. This data has often been a component of public health data collection and epidemiological studies due to its large impact on the health system with chronic and lifestyle diseases increasingly being a major burden for the health service. However, collection of this kind of information from large segments of the community in a usable fashion has not been specifically explored in previous work. In this paper we discuss some of the technologies that increase the ease and capability of gathering quantitative wellness data via smartphones, how specific and detailed this data needs to be for public health use and the challenges of such anonymized data collection for public health. Additionally, we propose a conceptual architecture that includes the necessary components to support this approach to data collection. PMID- 23366350 TI - Development of a patch type embedded cardiac function monitoring system using dual microprocessor for arrhythmia detection in heart disease patient. AB - A patch type embedded cardiac function monitoring system was developed to detect arrhythmias such as PVC (Premature Ventricular Contraction), pause, ventricular fibrillation, and tachy/bradycardia. The overall system is composed of a main module including a dual processor and a Bluetooth telecommunication module. The dual microprocessor strategy minimizes power consumption and size, and guarantees the resources of embedded software programs. The developed software was verified with standard DB, and showed good performance. PMID- 23366351 TI - Measurement of food volume based on single 2-D image without conventional camera calibration. AB - Food portion size measurement combined with a database of calories and nutrients is important in the study of metabolic disorders such as obesity and diabetes. In this work, we present a convenient and accurate approach to the calculation of food volume by measuring several dimensions using a single 2-D image as the input. This approach does not require the conventional checkerboard based camera calibration since it is burdensome in practice. The only prior requirements of our approach are: 1) a circular container with a known size, such as a plate, a bowl or a cup, is present in the image, and 2) the picture is taken under a reasonable assumption that the camera is always held level with respect to its left and right sides and its lens is tilted down towards foods on the dining table. We show that, under these conditions, our approach provides a closed form solution to camera calibration, allowing convenient measurement of food portion size using digital pictures. PMID- 23366352 TI - High efficiency video coding for ultrasound video communication in m-health systems. AB - Emerging high efficiency video compression methods and wider availability of wireless network infrastructure will significantly advance existing m-health applications. For medical video communications, the emerging video compression and network standards support low-delay and high-resolution video transmission, at the clinically acquired resolution and frame rates. Such advances are expected to further promote the adoption of m-health systems for remote diagnosis and emergency incidents in daily clinical practice. This paper compares the performance of the emerging high efficiency video coding (HEVC) standard to the current state-of-the-art H.264/AVC standard. The experimental evaluation, based on five atherosclerotic plaque ultrasound videos encoded at QCIF, CIF, and 4CIF resolutions demonstrates that 50% reductions in bitrate requirements is possible for equivalent clinical quality. PMID- 23366353 TI - Validation of heart rate extraction using video imaging on a built-in camera system of a smartphone. AB - As a smartphone is becoming very popular and its performance is being improved fast, a smartphone shows its potential as a low-cost physiological measurement solution which is accurate and can be used beyond the clinical environment. Because cardiac pulse leads the subtle color change of a skin, a pulsatile signal which can be described as photoplethysmographic (PPG) signal can be measured through recording facial video using a digital camera. In this paper, we explore the potential that the reliable heart rate can be measured remotely by the facial video recorded using smartphone camera. First, using the front facing-camera of a smartphone, facial video was recorded. We detected facial region on the image of each frame using face detection, and yielded the raw trace signal from the green channel of the image. To extract more accurate cardiac pulse signal, we applied independent component analysis (ICA) to the raw trace signal. The heart rate was extracted using frequency analysis of the raw trace signal and the analyzed signal from ICA. The accuracy of the estimated heart rate was evaluated by comparing with the heart rate from reference electrocardiogram (ECG) signal. Finally, we developed FaceBEAT, an iPhone application for remote heart rate measurement, based on this study. PMID- 23366354 TI - A mobile-health system to manage chronic obstructive pulmonary disease patients at home. AB - Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality in Australia and globally, and leads to a substantial burden on healthcare services. Effective and timely management of patients with COPD has been essential to alleviate COPD exacerbation, improve the quality of life, and consequently reduce the economic burden. To achieve this, a mobile and internet technologies assisted home care model (M-COPD) was developed to assist clinicians to remotely monitor and manage COPD conditions and events. This paper will focus on the technical aspect of M-COPD system by describing its setup and discussing how the M-COPD could address the clinical needs in monitoring and managing COPD conditions of patients at home. PMID- 23366355 TI - Medication adherence for patients with mental illness. AB - Medication adherence has been studied for some time; however most research has focused on able-bodied patients or the elderly living independently. What has not been studied nearly as much is medication adherence for people with psychiatric or mental illnesses. In this paper, we present a framework that includes the specific challenges in medication adherence for patients with mental illness, algorithms and protocols for evaluating adherence, and some on-going work in developing effective solutions. The architectural framework and associated algorithms leverage the context-aware computing capabilities available on many mobile devices. The system is designed to be able to collect and offer situation aware information on medication use and adherence for healthcare professionals and other designated persons. PMID- 23366356 TI - Biometric identity management for standard mobile medical networks. AB - The explosion of healthcare costs over the last decade has prompted the ICT industry to respond with solutions for reducing costs while improving healthcare quality. The ISO/IEEE 11073 family of standards recently released is the first step towards interoperability of mobile medical devices used in patient environments. The standards do not, however, tackle security problems, such as identity management, or the secure exchange of medical data. This paper proposes an enhancement of the ISO/IEEE 11073-20601 protocol with an identity management system based on biometry. The paper describes a novel biometric-based authentication process, together with the biometric key generation algorithm. The proposed extension of the ISO/IEEE 11073-20601 is also presented. PMID- 23366357 TI - EHS subjects do not perceive RF EMF emitted from smart phones better than non-EHS subjects. AB - As the use of smart phones increases, social concerns have arisen concerning the possible effects of radio frequency-electromagnetic fields (RF-EMFs) emitted from wideband code division multiple access (WCDMA) mobile phones on human health. The number of people with self-reported electromagnetic hypersensitivity (EHS) who complain of various subjective symptoms, such as headache, insomnia, etc., has also recently increased. However, it is unclear whether EHS subjects can detect RF-EMFs exposure or not. In this double-blind study, two volunteer groups of 17 EHS and 20 non-EHS subjects were investigated in regards to their perception of RF-EMFs with real and sham exposure sessions. Experiments were conducted using a WCDMA module inside a dummy phone with an average power of 24 dBm at 1950 MHz and a specific absorption rate of 1.57 W/kg using a dummy headphone for 32 min. In conclusion, there was no indication that EHS subjects perceive RF-EMFs better than non-EHS subjects. PMID- 23366358 TI - Overcoming barriers to development of cooperative medical decision support models. AB - Attempts to automate the medical decision making process have been underway for the at least fifty years, beginning with data-based approaches that relied chiefly on statistically-based methods. Approaches expanded to include knowledge based systems, both linear and non-linear neural networks, agent-based systems, and hybrid methods. While some of these models produced excellent results none have been used extensively in medical practice. In order to move these methods forward into practical use, a number of obstacles must be overcome, including validation of existing systems on large data sets, development of methods for including new knowledge as it becomes available, construction of a broad range of decision models, and development of non-intrusive methods that allow the physician to use these decision aids in conjunction with, not instead of, his or her own medical knowledge. None of these four requirements will come easily. A cooperative effort among researchers, including practicing MDs, is vital, particularly as more information on diseases and their contributing factors continues to expand resulting in more parameters than the human decision maker can process effectively. In this article some of the basic structures that are necessary to facilitate the use of an automated decision support system are discussed, along with potential methods for overcoming existing barriers. PMID- 23366359 TI - Generalized precursor pattern discovery for biomedical signals. AB - With the advent of low-cost, high-fidelity, and long lasting sensors in recent years, it has become possible to acquire biomedical signals cheaply and remotely over a prolonged period of time. Oftentimes different types of sensors are deployed in the hope of capturing precursor patterns that are highly correlated to a particular clinical episode, such as seizure, congestive heart failure etc. While there have been several studies that successfully identify patterns as reliable precursors for specific medical conditions, most of them require domain specific knowledge and expertise. The developed algorithms are also unlikely to be applicable to other medical conditions. In this paper we present a generalized algorithm that discovers potential precursor patterns without prior knowledge or domain expertise. The algorithm makes use of wavelet transform and information theory to extract generic features, and it is also classifier agnostic. Based on experiment results using three distinct datasets collected from real-world patients, our algorithm has attained performance comparable to those obtained from previous studies that rely heavily on domain-expert knowledge. Furthermore, the algorithm also discovers non-trivial knowledge in the process. PMID- 23366360 TI - Identifying relatively high-risk group of coronary artery calcification based on progression rate: statistical and machine learning methods. AB - Coronary artery calcification (CAC) score is an important predictor of coronary artery disease (CAD), which is the primary cause of death in advanced countries. Early prediction of high-risk of CAC based on progression rate enables people to prevent CAD from developing into severe symptoms and diseases. In this study, we developed various classifiers to identify patients in high risk of CAC using statistical and machine learning methods, and compared them with performance accuracy. For statistical approaches, linear regression based classifier and logistic regression model were developed. For machine learning approaches, we suggested three kinds of ensemble-based classifiers (best, top-k, and voting method) to deal with imbalanced distribution of our data set. Ensemble voting method outperformed all other methods including regression methods as AUC was 0.781. PMID- 23366361 TI - Automated knowledge-based fuzzy models generation for weaning of patients receiving ventricular assist device (VAD) therapy. AB - The SensorART project focus on the management of heart failure (HF) patients which are treated with implantable ventricular assist devices (VADs). This work presents the way that crisp models are transformed into fuzzy in the weaning module, which is one of the core modules of the specialist's decision support system (DSS) in SensorART. The weaning module is a DSS that supports the medical expert on the weaning and remove VAD from the patient decision. Weaning module has been developed following a "mixture of experts" philosophy, with the experts being fuzzy knowledge-based models, automatically generated from initial crisp knowledge-based set of rules and criteria for weaning. PMID- 23366363 TI - Multi-label classification for the analysis of human motion quality. AB - Knowing how well an activity is performed is important for home rehabilitation. We would like to not only know if a motion is being performed correctly, but also in what way the motion is incorrect so that we may provide feedback to the user. This paper describes methods for assessing human motion quality using body-worn tri-axial accelerometers and gyroscopes. We use multi-label classifiers to detect subtle errors in exercise performances of eight individuals with knee osteoarthritis, a degenerative disease of the cartilage. We present results obtained using various machine learning methods with decision tree base classifiers. The classifier can detect classes in multi-label data with 75% sensitivity, 90% specificity and 80% accuracy. The methods presented here form the basis for an at-home rehabilitation device that will recognize errors in patient exercise performance, provide appropriate feedback on the performance, and motivate the patient to continue the prescribed regimen. PMID- 23366362 TI - Heart failure analysis dashboard for patient's remote monitoring combining multiple artificial intelligence technologies. AB - In this paper we describe an Heart Failure analysis Dashboard that, combined with a handy device for the automatic acquisition of a set of patient's clinical parameters, allows to support telemonitoring functions. The Dashboard's intelligent core is a Computer Decision Support System designed to assist the clinical decision of non-specialist caring personnel, and it is based on three functional parts: Diagnosis, Prognosis, and Follow-up management. Four Artificial Intelligence-based techniques are compared for providing diagnosis function: a Neural Network, a Support Vector Machine, a Classification Tree and a Fuzzy Expert System whose rules are produced by a Genetic Algorithm. State of the art algorithms are used to support a score-based prognosis function. The patient's Follow-up is used to refine the diagnosis. PMID- 23366364 TI - NEUROZONE: on-line recognition of brain structures in stereotactic surgery- application to Parkinson's disease. AB - The success of stereotactic surgery for Deep Brain Stimulation depends critically on the exact positioning of a microelectrode recording in a target area of the brain. This paper presents the software system NEUROZONE composed of two main applications: first, it allows online recognition of brain structures by the analysis of signals from microelectrode recordings (MER), and second, it processes and analyses off-line databases allowing the inclusion of new trained classifiers for automatic identification. The software serves as a support to the analysis done by a medical specialist during surgery, and seeks to reduce the adverse side effects that may occur because of inadequate identification of the target areas. The software also allows the specialists to label recordings obtained during surgery, in order to generate a new off-line database or increase the amount of records in an already existing off-line database. NEUROZONE has been tested for Deep Brain Stimulation performed at the Institute for Epilepsy and Parkinson of the Eje Cafetero (Colombia), achieving positive identifications of the Subthalamic Nucleus (STN) over to 85% using a naive Bayes classifier. PMID- 23366365 TI - Dynamic self-adaptive remote health monitoring system for diabetics. AB - Diabetes is the seventh leading cause of death in the United States. In 2010, about 1.9 million new cases of diabetes were diagnosed in people aged 20 years or older. Remote health monitoring systems can help diabetics and their healthcare professionals monitor health-related measurements by providing real-time feedback. However, data-driven methods to dynamically prioritize and generate tasks are not well investigated in the remote health monitoring. This paper presents a task optimization technique used in WANDA (Weight and Activity with Blood Pressure and Other Vital Signs); a wireless health project that leverages sensor technology and wireless communication to monitor the health status of patients with diabetes. WANDA applies data analytics in real-time to improving the quality of care. The developed algorithm minimizes the number of daily tasks required by diabetic patients using association rules that satisfies a minimum support threshold. Each of these tasks maximizes information gain, thereby improving the overall level of care. Experimental results show that the developed algorithm can reduce the number of tasks up to 28.6% with minimum support 0.95, minimum confidence 0.97 and high efficiency. PMID- 23366366 TI - Robust, automatic real-time monitoring of the time course of the individual alpha frequency in the time and frequency domain. AB - We analyzed three different approaches to automatic real-time monitoring of the time course of individual alpha frequencies (IAFs) of the human electro encephalograms. Fast Fourier transform and wavelet transform were compared to classical automated cycle counting in the time domain. With fast Fourier and wavelet transform, test results with healthy adult subjects, demented and psychiatric patients revealed typical short-term variations of the instantaneous IAFs of about +/- 2 Hz. When cycles were counted in the time domain, however, variations of only +/- 1 Hz were recorded. Thus, IAF measurement in the time domain appears to be particularly suitable. We also observed long-term IAF trends that typically amounted to about +/- 0.5 to +/- 1.0 Hz. Therefore, our hypothesis is that the IAF does not constitute an intra-individual constant but varies with time and cognitive state. Our fully automatic real-time signal-processing procedure includes pre-processing for artifact detection and for localization of segments with synchronized alpha oscillations where the IAF should preferably be measured. PMID- 23366367 TI - Pre-processing of multi-channel EEG for improved compression performance using SPIHT. AB - A novel technique for Electroencephalogram (EEG) compression is proposed in this article. This technique makes use of the inter-channel redundancy present between different EEG channels of the same recording and the intra-channel redundancy between the different samples of a specific channel. It uses Discrete Wavelet Transform (DWT) and Set partitioning in hierarchical trees (SPIHT) in 2-D to code the EEG channels. Smoothness transforms are added in order to guarantee good performance of SPIHT in 2-D. Experimental results show that this technique is able to provide low distortion values for high compression ratios (CRs). In addition, performance results of this method do not vary a lot between different patients which proves the stability of the method when used with recordings of different characteristics. PMID- 23366368 TI - Optimization of time-variant autoregressive models for tracking REM-non REM transitions during sleep. AB - The aim of this study was the optimization of Time-Variant Autoregressive Models (TVAM) for tracking REM-non REM transitions during sleep, through the analysis of spectral indexes extracted from tachograms. A first improvement of TVAM was achieved by choosing the best typology of forgetting factor in the analysis of a tachogram obtained during a sitting-to-standing test; then, a method for improving robustness of AR recursive identification with respect to outliers was selected by analyzing a tachogram with an ectopic beat. A variable forgetting factor according to the Fortescue method and a specific condition on the prediction error for recursive AR identification gave the best performances. The optimized TVAM was then employed in the analysis of tachograms derived from ECGs recorded during a whole night, through a sensorized T-shirt, from 9 healthy subjects. The spectral indexes (power of tachogram in the LF and HF bands, LF/HF ratio and the absolute value of the spectrum pole in the HF band) were computed from the estimated AR parameters on a beat-to-beat basis. A two groups T-test aimed at comparing values assumed by each spectral index in REM and non-REM sleep epochs was performed. Significant statistical differences (p-value < 0.05) were found in three of the four spectral indexes computed. In conclusion, the combination of the Fortescue variant and of the robustness method based on the prediction error in the TVAM seems to be helpful in the differentiation between REM and non-REM sleep stages. PMID- 23366369 TI - Clinical state assessment in bipolar patients by means of HRV features obtained with a sensorized T-shirt. AB - The aim of this study is to identify parameters extracted from the Heart Rate Variability (HRV) signal that correlate to the clinical state in patients affected by bipolar disorder. 25 ECG and activity recordings from 12 patients were obtained by means of a sensorized T-shirt and the clinical state of the subjects was assessed by a psychiatrist. Features in the time and frequency domain were extracted from each signal. HRV features were also used to automatically compute the sleep profile of each subject by means of an Artificial Neural Network, trained on a control group of healthy subjects. From the hypnograms, sleep-specific parameters were computed. All the parameters were compared with those computed on the control group, in order to highlight significant differences in their values during different stages of the pathology. The analysis was performed by grouping the subjects first on the basis of the depression-mania level and then on the basis of the anxiety level. PMID- 23366370 TI - Analysis of EMG signals of patients with essential tremor focusing on the change of tremor frequency. AB - Essential tremor is a disorder that causes involuntary oscillations in patients while engaging in actions or while maintaining a posture. ET patients have serious difficulties in performing activities of daily living such as eating food, drinking water, and writing. We have thus been developing an EMG-controlled exoskeletal robot to suppress tremors. The EMG signal of ET patients involves a mix of voluntary movement and tremor signals. To control the exoskeletal robot accurately, tremor signals must be removed from the patient's EMG signal. To date, we have been developing a filter to remove tremor signals from the patient's EMG. The design of this filter was based on the hypothesis that the rectified tremor signals are able to be approximated by a powered sine wave. This filter was found to have a large effect on removing tremor signals. However, tremor signals are generated both while performing voluntary movement and while maintaining a posture, and the filter was attenuating both signals. To control this robot accurately, the signal generated while performing voluntary movement is expected not to be attenuated. To accomplish this, we try to use a parameter that reflects a state of the patient's movement, performing a voluntary movement or maintaining a posture, as a switch to activate the powered sine filter. This paper provides an analysis of the favorable parameters. We focus on two parameters: the peak-to-peak interval of the rectified EMG signal, and the interval of the flat and low amplitude area of the rectified EMG signal. Through evaluation, it is affirmed that both parameters change with the state of the patient's movement. However, the latter parameter is superior to the former in terms of variability, which indicates that the interval of the flat and low amplitude area of the rectified EMG signal is a more favorable parameter to promote control of the exoskeletal robot. As a future work, we will mount the parameter to the algorithm and evaluate the robotic system. PMID- 23366371 TI - Discrete wavelet transform coefficients for emotion recognition from EEG signals. AB - In this paper, we propose to use DWT coefficients as features for emotion recognition from EEG signals. Previous feature extraction methods used power spectra density values dervied from Fourier Transform or sub-band energy and entropy derived from Wavelet Transform. These feature extracion methods eliminate temporal information which are essential for analyzing EEG signals. The DWT coefficients represent the degree of correlation between the analyzed signal and the wavelet function at different instances of time; therefore, DWT coefficients contain temporal information of the analyzed signal. The proposed feature extraction method fully utilizes the simultaneous time-frequency analysis of DWT by preserving the temporal information in the DWT coefficients. In this paper, we also study the effects of using different wavelet functions (Coiflets, Daubechies and Symlets) on the performance of the emotion recognition system. The input EEG signals were obtained from two electrodes according to 10-20 system: F(p1) and F(p2). Visual stimuli from International Affective Picture System (IAPS) were used to induce two emotions: happy and sad. Two classifiers were used: Extreme Learning Machine (ELM) and Support Vector Machine (SVM). Experimental results confirmed that the proposed DWT coefficients method showed improvement of performance compared to previous methods. PMID- 23366372 TI - Automated NREM sleep staging using the electro-oculogram: a pilot study. AB - Automatic sleep staging from convenient and unobtrusive sensors has received considerable attention lately because this can enable a large range of potential applications in the clinical and consumer fields. In this paper the focus is on achieving non-REM (NREM) sleep staging from ocular electrodes. From these signals, specific patterns related to sleep such as slow eye movements, K complexes, eye blinks, and spectral features are estimated. Although such patterns are characteristic of the Electroencephalogram, they can also be visible to a lesser extent on signals from ocular electrodes. Automatic sleep staging was implemented using two approaches: i) based on a state-machine and ii) using a neural network. The first one relied on the recommendations of the American Academy of Sleep Medicine, and the second one used a multilayer perceptron which was trained on manually sleep-staged data. Results were obtained on the data of five volunteers who participated in a nap experiment. Manual sleep staging of this data, performed by an expert, was used as reference. Five stages were considered, namely wake with eyes open, wake with eyes closed, and sleep stages N1, N2, and N3. The results were characterized in terms of confusion matrices from which the Cohen's kappa coefficients were estimated. The values of kappa for both the state-machine and neural-network based automatic sleep staging approaches were 0.79 and 0.59 respectively. Thus, the state-machine based approach shows a very good agreement with manual staging of sleep-data. PMID- 23366373 TI - Adaptive automatic sleep stage classification under covariate shift. AB - Current automatic sleep stage classification (ASSC) methods that rely on polysomnographic (PSG) signals suffer from inter-subject differences that make them unreliable in facing with new and different subjects. A novel adaptive sleep scoring method based on unsupervised domain adaptation, aiming to be robust to inter-subject variability, is proposed. We assume that the sleep quality variants follow a covariate shift model, where only the sleep features distribution change in the training and test phases. The maximum overlap discrete wavelet transform (MODWT) is applied to extract relevant features from EEG, EOG and EMG signals. A set of significant features are selected by minimum-redundancy maximum-relevance (mRMR) which is a powerful feature selection method. Finally, an instance weighting method, namely the importance weighted kernel logistic regression (IWKLR) is applied for the purpose of obtaining adaptation in classification. The classification results using leave one out cross-validation (LOOCV), show that the proposed method performs at the state-of-the art in the field of ASSC. PMID- 23366374 TI - A Gaussian model for movement detection during sleep. AB - Quality of sleep is an important attribute of an individual's health state and its assessment is therefore a useful diagnostic feature. Changes in the patterns of mobility in bed during sleep can be a disease marker or can reflect various abnormal physiological and neurological conditions. This paper describes a method for detection of movement in bed that is evaluated on data collected from patients admitted for regular polysomnography. The system is based on load cells installed at the supports of a bed. Since the load cell signal varies the most during movement, the approach uses a weighted combination of the short-term mean square differences of each load cell signal to capture the variations in the signal caused by movement. We use a single univariate Gaussian model to represent each class: movement versus non-movement. We assess the performance of the method against manual annotation performed by a sleep clinic technician from seventeen patients. The proposed detection method achieved an overall sensitivity of 97.9% and specificity of 98.7%. PMID- 23366375 TI - Automated detection of rapid eye movements in children. AB - We present an automated multiple-step tool to identify Rapid Eye Movements (REMs) in the polysomnogram, based on modeling expert criteria. It begins by identifying the polysomnogram segments compatible with REMs presence. On these segments, high energy REMs are identified. Then, vicinity zones around those REMs are defined, and lesser-energy REMs are sought in these vicinities. This strategy has the advantage that it can detect lesser-energy REMs without increasing much the false positive detections. Signal processing, feature extraction, and fuzzy logic tools are used to achieve the goal. The tool was trained and validated on a database consisting of 20 all-night polysomnogram recordings (160 hr) of healthy ten-year old children. Preliminary results on the validation set show 85.5% sensitivity and a false positive rate of 16.2%. Our tool works on complete polysomnogram recordings, without the need of preprocessing, prior knowledge of the hypnogram, or noise-free segments selection. PMID- 23366376 TI - Adding real-time noise suppression capability to the cochlear implant PDA research platform. AB - This paper presents the real-time implementation of an environment-adaptive noise suppression algorithm on an FDA-approved PDA platform for cochlear implant studies. This added capability involves identifying the background noise environment in real-time and adapting a data-driven noise suppression approach to that noise environment on-the-fly. Various software optimization steps are taken in order to achieve a real-time throughput on the PDA platform involving both the speech decomposition and the adaptive noise suppression components. Real-time timing results and a quantitative measure of noise suppression are presented. PMID- 23366377 TI - An actigraphy heterogeneous mixture model for sleep assessment. AB - Wrist actigraphy is a well established procedure to monitor human activity. Among other areas, it has a special relevance in sleep studies where its lightweight and non-intrusive nature make it a valuable tool to access the circadian cycle. While there are several methods to extract information from the data, the differentiation between sleep and wakefulness states is still an open discussion. In this paper, the characteristics of the movements in the different states are assumed to be intrinsically different. These differences are not simply related with magnitude and movement counting, but due to real differences on the statistical distributions describing the actigraphy data. Thus it is possible to refine the discrimination level when detecting these states. The proposed methodology to characterize the actigraphy data is based on a mixture of three canonical distributions; i)Exponential, ii)Rayleigh and iii)Gaussian. It is shown that the weights and parameters estimated in each state are organized into almost separable clusters on the feature space. This suggests the ability of the method to discriminate these states based only on the movements recorded on actigraphy data. PMID- 23366378 TI - In vivo manganese-enhanced MRI for visuotopic brain mapping. AB - This study explored the feasibility of localized manganese-enhanced MRI (MEMRI) via 3 different routes of Mn(2+) administrations for visuotopic brain mapping of retinal, callosal, cortico-subcortical, transsynaptic and horizontal connections in normal adult rats. Upon fractionated intravitreal Mn(2+) injection, Mn enhancements were observed in the contralateral superior colliculus (SC) and lateral geniculate nucleus (LGN) by 45-60% at 1-3 days after initial Mn(2+) injection and in the contralateral primary visual cortex (V1) by about 10% at 2-3 days after initial Mn(2+) injection. Direct, single-dose Mn(2+) injection to the LGN resulted in Mn enhancement by 13-21% in V1 and 8-11% in SC of the ipsilateral hemisphere at 8 to 24 hours after Mn(2+) administration. Intracortical, single dose Mn(2+) injection to the visual cortex resulted in Mn enhancement by 53-65% in ipsilateral LGN, 15-26% in ipsilateral SC, 32-34% in the splenium of corpus callosum and 17-25% in contralateral V1/V2 transition zone at 8 to 24 hours after Mn(2+) administration. Notably, some patchy patterns were apparent near the V1/V2 border of the contralateral hemisphere. Laminar-specific horizontal cortical connections were also observed in the ipsilateral hemisphere. The current results demonstrated the sensitivity of MEMRI for assessing the neuroarchitecture of the visual brains in vivo without depth-limitation, and may possess great potentials for studying the basic neural components and connections in the visual system longitudinally during development, plasticity, pharmacological interventions and genetic modifications. PMID- 23366379 TI - A novel approach of fMRI-guided tractography analysis within a group: construction of an fMRI-guided tractographic atlas. AB - Diffusion Tensor Imaging (DTI) tractography and functional Magnetic Resonance Imaging (fMRI) investigate two complementary aspects of brain networks: white matter (WM) anatomical connectivity and gray matter (GM) function. However, integration standards have yet to be defined; namely, individual fMRI-driven tractography is usually applied and only few studies address group analysis. This work proposes an efficient method of fMRI-driven tractography at group level through the creation of a tractographic atlas starting from the GM areas activated by a verbal fluency task in 11 healthy subjects. The individual tracts were registered to the MNI space. Selection ROIs derived by GM masking and dilation of group activated areas were applied to obtain the fMRI-driven subsets within tracts. An atlas of the tracts recruited among the population was obtained by selecting for each subject the fMRI-guided tracts passing through the high probability voxels (the voxels recruited by the 90% of the subjects) and merging them together. The reliability of this approach was assessed by comparing it with the probabilistic atlas previously introduced in literature. The introduced method allowed to successfully reconstruct activated tracts, which comprehended corpus callosum, left cingulum and arcuate, a small portion of the right arcuate, both cortico-spinal tracts and inferior fronto-occipital fasciculi. Moreover, it proved to give results concordant with the previously introduced probabilistic approach, allowing in addition to reconstruct 3D trajectories of the activated fibers, which appear particularly helpful in the detection of WM connections. PMID- 23366380 TI - Directionality analysis on functional magnetic resonance imaging during motor task using Granger causality. AB - Directionality analysis of signals originating from different parts of brain during motor tasks has gained a lot of interest. Since brain activity can be recorded over time, methods of time series analysis can be applied to medical time series as well. Granger Causality is a method to find a causal relationship between time series. Such causality can be referred to as a directional connection and is not necessarily bidirectional. The aim of this study is to differentiate between different motor tasks on the basis of activation maps and also to understand the nature of connections present between different parts of the brain. In this paper, three different motor tasks (finger tapping, simple finger sequencing, and complex finger sequencing) are analyzed. Time series for each task were extracted from functional magnetic resonance imaging (fMRI) data, which have a very good spatial resolution and can look into the sub-cortical regions of the brain. Activation maps based on fMRI images show that, in case of complex finger sequencing, most parts of the brain are active, unlike finger tapping during which only limited regions show activity. Directionality analysis on time series extracted from contralateral motor cortex (CMC), supplementary motor area (SMA), and cerebellum (CER) show bidirectional connections between these parts of the brain. In case of simple finger sequencing and complex finger sequencing, the strongest connections originate from SMA and CMC, while connections originating from CER in either direction are the weakest ones in magnitude during all paradigms. PMID- 23366381 TI - DWI based thermometry: the effects of b-values, resolutions, signal-to-noise ratio, and magnet strength. AB - Among MR methods, the most clinically applicable temperature measurement method at deep brain might be the diffusion-weighted image (DWI) thermometry. Although only applicable to cerebrospinal fluid (CSF), it is thought to be potentially useful in assessing the thermal pathophysiology of the brain in both patients and healthy subjects. The purpose of this study was to investigate the effects of b value, pixel resolution, magnet strength and signal to noise ratio (SNR) for the DWI-thermometry with healthy volunteer. Formerly, an ADC from b=0 and b=1000 has been thought to be useful for diffusion thermometry, this study revealed b=200 to 800 was more appropriate for DWI thermometry. The SNR was strongly affected the results of DWI thermometry. PMID- 23366382 TI - Spherical finite rate of innovation theory for the recovery of fiber orientations. AB - In this paper, we investigate the reconstruction of a signal defined as the sum of K orientations from samples taken with a kernel defined on the 3D rotation group. A potential application is the recovery of fiber orientations in diffusion magnetic resonance imaging. We propose an exact reconstruction algorithm based on the finite rate of innovation theory that makes use of the spherical harmonics representation of the signal. The number of measurements needed for perfect recovery, which may be as low as 3K, depends only on the number of orientations and the bandwidth of the kernel used. Furthermore, the angular resolution of our method does not depend on the number of available measurements. We illustrate the performance of the algorithm using several simulations. PMID- 23366383 TI - Diffusion kurtosis imaging with tract-based spatial statistics reveals white matter alterations in preschool children. AB - Diffusion kurtosis imaging (DKI), an extension of diffusion tensor imaging (DTI), provides a practical method to describe non-Gaussian water diffusion in neural tissues. The sensitivity of DKI to detect the subtle changes in several chosen brain structures has been studied. However, intuitive and holistic methods to validate the merits of DKI remain to be explored. In this paper, tract-based spatial statistics (TBSS) was used to demonstrate white matter alterations in both DKI and DTI parameters in preschool children (1-6 years; n=10). Correlation analysis was also performed in multiple regions of interest (ROIs). Fractional anisotropy, mean kurtosis, axial kurtosis and radial kurtosis increased with age, while mean diffusivity and radial diffusivity decreased significantly with age. Fractional anisotropy of kurtosis and axial diffusivity were found to be less sensitive to the changes with age. These preliminary findings indicated that TBSS could be used to detect subtle changes of DKI parameters on the white matter tract. Kurtosis parameters, except fractional anisotropy of kurtosis, demonstrated higher sensitivity than DTI parameters. TBSS may be a convenient method to yield higher sensitivity of DKI. PMID- 23366384 TI - Acquisition information spectrum for evaluating sonographic quality. AB - We are developing a first-principles task-based approach to the optimal design and evaluation of ultrasonic imaging systems. Examining five clinical features related to breast lesion diagnosis, we quantified information flow at several stages in the image formation process. We found that the diagnostic performance of a given system configuration will vary with the patient feature, sometimes significantly. Our analysis expresses diagnostic performance of an imaging system for a specific clinical task as a function of patient properties that are separable from instrument properties. Hence it is possible to show how image quality metrics, like spatial and contrast resolution, combine with patient features to determine feature discriminability. In this paper, we describe an information theoretic approach to diagnostic performance evaluation that has given us a new quantity, the acquisition information spectrum (AIS). Like NEQ in radiography, AIS in sonography provides a foundation for medical ultrasonic imaging system design. PMID- 23366385 TI - An ideal observer approach to mechanical limits in b-mode ultrasound imaging. AB - In medical applications, the amplitude of ultrasonic pulses is often constrained by mechanical considerations summarized by a mechanical index. We apply the ideal observer approach in a simulation environment to evaluating the role of mechanical index limits on task performance in b-mode ultrasonic imaging. We simulate a linear array operating at 15 MHz and 60% fractional bandwidth, and consider three tasks related to breast sonography at a depth of 4 cm. The ideal observer suggests that there are gains in performance--and hence the quantity of diagnostic information--as the limit on mechanical index is raised. However these gains are almost completely erased after computation of a standard b-mode envelope. PMID- 23366386 TI - Monitoring cerebral hemodynamics with transcranial Doppler ultrasound during cognitive and exercise testing in adults following unilateral stroke. AB - An observational study was performed as a preliminary investigation into the use of transcranial Doppler ultrasound (TCD) for recording cerebral hemodynamic changes during multiple tasks. TCD is a method of measuring cerebral blood flow (CBF) using ultrasound transducers in contact with the surface of the head. Using the maximum flow envelope of the Doppler spectrum returning from the middle cerebral artery (MCA), standard clinical flow indices can be calculated and displayed in real time providing information concerning perturbations in CBF and their potential cause. These indices as well as flow velocity measurements have been recognized as useful in measuring changes in responses to various stimulus that can be used to indicate cardiovascular health. For this study, the pulsatility index (PI) and resistivity index (RI) were chosen since they indicate composite changes indicative of vasoconstriction and vasodilatation which are normal hemodynamic responses under appropriate conditions. A total of eleven participants were recruited to take part in this study. Nine of these individuals had no known disability (Controls); two had experienced unilateral cerebrovascular accidents (Strokes) in the ipsilateral MCA distribution. Maximum velocity envelopes of the spectral Doppler data were recorded using a fixation device designed to stabilize two ultrasound probes (2 MHz) to sample the bilateral MCAs CBF. These measures were performed separately while the subject performed four activities: 1) rest, 2) cognitive challenge, 3) cardiovascular exercise, and 4) simultaneous exercise and cognitive challenge. Cardiovascular parameters were calculated from the data by extracting maximum (Vs) and minimum flow velocities (Vd), PI, RI, and time signatures for each cardiac cycle. The data for all participants shows significant changes in cardiovascular parameters between states of rest and exercise, as well as slight trends across time. Although the data are preliminary, they show the capability of using Doppler spectral examination of the bilateral MCAs in individuals with physical limitation performing cardiovascular exercise. The novelty of examining a population using dynamic exercise who before could not perform such exercise offers the opportunity to study the impact of exercise on global cerebral recovery in unilateral stroke with significant physical impairment. PMID- 23366387 TI - Source effects in SWIPE: shear-wave-assisted ultrasound imaging. AB - SWIPE is a novel method for ultrasonic image reconstruction that uses echo phase modulation induced by traveling shear waves to decipher lateral k-space image data. Our prior experimental work has demonstrated lateral resolution with SWIPE at higher than expected sidelobe levels. Here we examine the effect of the location of the mechanical excitation source used in SWIPE. Surface and internal sources were simulated using finite element modeling. The interaction of shear and surface (Rayleigh) waves was found to degrade the SWIPE point spread function when surface excitation was employed. Internal excitation was not negatively affected and yielded near-ideal results. Regions of ideal performance, simulated point spread functions, and phase non-linearity measurements for the two methods are presented. The results indicate that internal sources, e.g. acoustic radiation force, can be expected to yield high-quality SWIPE images. PMID- 23366388 TI - Volumetric ultrasound and computer-assisted analysis at the point-of-care: a musculoskeletal exemplar. AB - In this paper we motivate the hypothesis that the use of volumetric ultrasound imaging and automated image analysis tools would improve clinical workflows as well as outcomes at the point-of-care. To make our case, this paper presents results from a rheumatoid arthritis (RA) study where several image analysis techniques have been applied to volumetric ultrasound, highlighting anatomy of interest to better understand disease progression. Pathologies related to RA in joints, manifest themselves commonly as changes in the bone (e.g. erosions) and the region enclosed by the joint-capsule (e.g. synovitis). Automated tools for detecting and segmenting such structures would help significantly towards objective and quantitative assessment of RA in joints. Extracted bone coupled with a simple anatomical model of the joint provides a coarse localization of the joint-capsule region. A probabilistic speckle model is then used to iteratively refine the capsule segmentation. We illustrate the performance of proposed algorithms through quantitative comparisons with expert annotations as well as qualitative results on over 30 scans obtained from 11 subjects. PMID- 23366389 TI - Multi-push (MP) acoustic radiation force (ARF) ultrasound for assessing tissue viscoelasticity, in vivo. AB - Acoustic radiation force (ARF) ultrasound is a method of elastographic imaging in which micron-scale tissue displacements, induced and tracked by ultrasound, reflect clinically relevant tissue mechanical properties. Our laboratory has recently shown that tissue viscoelasticity is assessed using the novel Multi-Push (MP) ARF method. MP ARF applies the Voigt model for viscoelastic materials and compares the displacements achieved by successive ARF excitations to qualitatively or quantitatively represent the relaxation time for constant stress, which is a direct descriptor of the viscoelastic response of the tissue. We have demonstrated MP ARF in custom viscoelastic tissue mimicking materials and implemented the method in vivo in canine muscle and human renal allografts, with strong spatial correlation between MP ARF findings and histochemical features and previously reported mechanical changes with renal disease. These data support that noninvasive MP ARF is capable of clinically relevant assessment of tissue viscoelastic properties. PMID- 23366390 TI - Fully automatic 3D segmentation of iceball for image-guided cryoablation. AB - The efficient extraction of the cryoablation iceball from a time series of 3D images is crucial during cryoablation to assist the interventionalist in determining the coverage of the tumor by the ablated volume. Conventional semi automatic segmentation tools such as ITK-SNAP and 3D Slicer's Fast Marching Segmentation can attain accurate iceball segmentation in retrospective studies, however, they are not ideal for intraprocedure real time segmentation, as they require time-consuming manual operations, such as the input of fiducials and the extent of the segmented region growth. In this paper, we present an innovative approach for the segmentation of the iceball during cryoablation, that executes a fully automatic computation. Our approach is based on the graph cuts segmentation framework, and incorporates prior information of iceball shape evolving in time, modeled using experimentally-derived iceball growth parameters. Modeling yields a shape prior mask image at each timepoint of the imaging time series for use in the segmentation. Segmentation results of our method and the ITK-SNAP method are compared for 8 timepoints in 2 cases. The results indicate that our fully automatic approach is accurate, robust and highly efficient compared to manual and semi-automatic approaches. PMID- 23366391 TI - Semi-automatic vessel tracking and segmentation using epicardial ultrasound in bypass surgery. AB - The purpose of intraoperative quality assessment of coronary artery bypass graft surgery is to confirm graft patency and disclose technical errors to reduce cardiac mortality, morbidity and improve clinical outcome for the patient. Epicardial ultrasound has been suggested as an alternative approach for quality assessment of anastomoses. To make a quantitative assessment of the anastomotic quality using ultrasound images, the vessel border has to be delineated to estimate the area of the vessel lumen. A tracking and segmentation algorithm was developed consisting of an active contour modeling approach and quality control of the segmentations. Evaluation of the tracking algorithm showed 91.96% of the segmentations were segmented correct with a mean error in height and width at 5.65% and 11.50% respectively. PMID- 23366392 TI - Spectral clustering of shape and probability prior models for automatic prostate segmentation. AB - Imaging artifacts in Transrectal Ultrasound (TRUS) images and inter-patient variations in prostate shape and size challenge computer-aided automatic or semi automatic segmentation of the prostate. In this paper, we propose to use multiple mean parametric models derived from principal component analysis (PCA) of shape and posterior probability information to segment the prostate. In contrast to traditional statistical models of shape and intensity priors, we use posterior probability of the prostate region determined from random forest classification to build, initialize and propagate our model. Multiple mean models derived from spectral clustering of combined shape and appearance parameters ensure improvement in segmentation accuracies. The proposed method achieves mean Dice similarity coefficient (DSC) value of 0.96+/-0.01, with a mean segmentation time of 0.67+/-0.02 seconds when validated with 46 images from 23 datasets in a leave one-patient-out validation framework. PMID- 23366393 TI - Unsupervised tumour segmentation in PET based on local and global intensity fitting active surface and alpha matting. AB - This paper proposes an unsupervised tumour segmentation scheme for PET data. The method computes the volume of interests (VOIs) with subpixel precision by considering the limited resolution and partial volume effect. Firstly, it uses local and global intensity active surface modelling to segment VOIs, then an alpha matting method is used to eliminate false negative classification and refine the segmentation results. We have validated our method on real PET images of head-and-neck cancer patients as well as images of a custom designed PET phantom. Experiments show that our method can generate more accurate segmentation results compared with alternative approaches. PMID- 23366394 TI - Aorta segmentation with a 3D level set approach and quantification of aortic calcifications in non-contrast chest CT. AB - Automatic aorta segmentation in thoracic computed tomography (CT) scans is important for aortic calcification quantification and to guide the segmentation of other central vessels. We propose an aorta segmentation algorithm consisting of an initial boundary detection step followed by 3D level set segmentation for refinement. Our algorithm exploits aortic cross-sectional circularity: we first detect aorta boundaries with a circular Hough transform on axial slices to detect ascending and descending aorta regions, and we apply the Hough transform on oblique slices to detect the aortic arch. The centers and radii of circles detected by Hough transform are fitted to smooth cubic spline functions using least-squares fitting. From these center and radius spline functions, we reconstruct an initial aorta surface using the Frenet frame. This reconstructed tubular surface is further refined with 3D level set evolutions. The level set framework we employ optimizes a functional that depends on both edge strength and smoothness terms and evolves the surface to the position of nearby edge location corresponding to the aorta wall. After aorta segmentation, we first detect the aortic calcifications with thresholding applied to the segmented aorta region. We then filter out the false positive regions due to nearby high intensity structures. We tested the algorithm on 45 CT scans and obtained a closest point mean error of 0.52 +/- 0.10 mm between the manually and automatically segmented surfaces. The true positive detection rate of calcification algorithm was 0.96 over all CT scans. PMID- 23366395 TI - Extraction of liver vessel centerlines under guidance of patient-specific models. AB - Fast extraction of blood vessels of abdominal organs is still a challenging task especially in intra-procedural treatments due to large tissue deformation. In this study, we propose a novel joint vessel extraction and registration framework. This vessel extraction technique is under the guidance of prior knowledge patient specific models. The proposed technique automatically provides correspondence between extracted vessels and pre-procedural vessels, which is important for image guidance such as labeled vessels from pre-procedural models, improves the quality of disease diagnosis using multiple images and follow-up, and provides important information for nonrigid image registration. Another key component in our framework is to dynamically update mapped pre-procedural models by rapidly registering the patient model to the current image based on strain energy, point marks and 3D extracted vessels currently available. We have demonstrated the effectiveness of our technique in extraction of vessels from liver MR images. Validation shows a extraction error of 3.99 mm. This technique has the potential to significantly improve the quality of intra-procedural image guidance, diagnosis of disease and treatment planning. PMID- 23366396 TI - High-throughput spectral system for interrogation of dermally-implanted luminescent sensors. AB - Ratiometric luminescent microparticle sensors have been developed for sensing biochemical targets such as glucose in interstitial fluid, enabling use of dermal implants for on-demand monitoring. For these sensor systems to be deployed in vivo, a matched optoelectronic system for interrogation of dermally-implanted sensors was previously designed, constructed, and evaluated experimentally. During evaluation experiments, it revealed that the system efficiency was compromised by losses due to fiber connections of a commercial spectrometer. In this work, a high-throughput spectral system was presented to solve the photon loss problem. This system was designed, constructed, and tested. The throughput was around hundred time more than the previous system we used, and it was cost effective, as well. It enables use of an integrated system for excitation, collection and measurement of luminescent emission, and will be used as a tool for in vivo studies with animal models or human subjects. PMID- 23366397 TI - Fabrication of a thin-film capacitive force sensor array for tactile feedback in robotic surgery. AB - Although surgical robotic systems provide several advantages over conventional minimally invasive techniques, they are limited by a lack of tactile feedback. Recent research efforts have successfully integrated tactile feedback components onto surgical robotic systems, and have shown significant improvement to surgical control during in vitro experiments. The primary barrier to the adoption of tactile feedback in clinical use is the unavailability of suitable force sensing technologies. This paper describes the design and fabrication of a thin-film capacitive force sensor array that is intended for integration with tactile feedback systems. This capacitive force sensing technology could provide precise, high-sensitivity, real-time responses to both static and dynamic loads. Capacitive force sensors were designed to operate with optimal sensitivity and dynamic range in the range of forces typical in minimally invasive surgery (0-40 N). Initial results validate the fabrication of these capacitive force-sensing arrays. We report 16.3 pF and 146 pF for 1-mm(2) and 9-mm(2) capacitive areas, respectively, whose values are within 3% of theoretical predictions. PMID- 23366398 TI - Determination of vessel wall dynamics by optical microsensors. AB - Spectralphotometric measurement methods as, for example, pulse oximetry are established approaches for extracorporeal determination of blood constituents. We measure the dynamics of the arterial distension intracorporeally thus extending the scope of the method substantially. A miniaturized opto-electronic sensor is attached directly to larger arteries without harming the vessel. The transmitted light through the arteries shows a linear correlation with the pulsatile expansion in theory as well as in experiments. Intra-arterial blood pressure also shows a linear interrelationship with the optical signal. Measurements of blood vessel wall dynamics has great potential to quantify arteriosclerosis by this new and innovative approach. PMID- 23366399 TI - Investigating nanoparticle-substrate interaction in LSPR biosensing using the image-charge theory. AB - Localized surface plasmon resonance (LSPR) has been used to develop optical biosensors. Tuning the resonance wavelength to detect target biomolecules with a particular dipolar resonance is essential when designing LSPR biosensors. In this paper, the interaction of nanoparticles (NPs) with glass substrate (SiO(2)) for LSPR wavelength is investigated using the concept of the image-charge theory. Using the FDTD method, it is shown how the NP and substrate size change the plasmon wavelength. Next, this phenomenon is interpreted using the analytical electrostatic eigenvalue method. PMID- 23366400 TI - Development of real-time muscle stiffness sensor based on resonance frequency for physical human robot interactions. AB - This paper presents a new type of muscle contraction sensor for motion intention detection algorithm in physical human robot interaction (pHRI). The resonance frequency shift by muscle contraction was measured by piezoelectric material. The developed sensor can measure muscle activations accurately over clothes and this is an advantage over the conventional surface Electromyography (sEMG). Performances of the sensor are evaluated through isometric wrist flexion motion tests based on maximal voluntary contraction (MVC) in two aspects: accuracy and speed. While the flexor carpi radialis (FCR) contraction tests up to 40% MVC, sensor outputs are compared with force sensor outputs. The result shows that we can measure muscle contraction by the developed sensor with high correlation and fast response, which is desirable for many physical human robot interactions including exoskeleton devices. PMID- 23366401 TI - Noncontact respiratory measurement of volume change using depth camera. AB - In this study, a system is developed to measure human chest wall motion for respiratory volume estimation without any physical contact. Based on depth image sensing technique, respiratory volume is estimated by measuring morphological changes of the chest wall. We evaluated the system and compared with a standard reference device, and the results show strong agreement in respiratory volume measurement [correlation coefficient: r=0.966]. The isovolume test presents small variations of the total respiratory volume during the isovolume maneuver (standard deviation<107 ml). Then, a regional pulmonary measurement test is evaluated by a patient, and the results show visibly difference of pulmonary functional between the diseased and the contralateral sides of the thorax after the thoracotomy. This study has big potential for personal health care and preventive medicine as it provides a novel, low-cost, and convenient way to measure user's respiration volume. PMID- 23366402 TI - Non-contact Doppler radar monitoring of cardiorespiratory motion for Siberian sturgeon. AB - This paper presents the first reported use of Doppler radar to remotely sense heart and ventilation rates of fish. The Radar reported 35 to 40 BPM heart rate and 115 to 145 BPM ventilation rates for Siberian Sturgeon, with agreement from a video reference. Conventional fish vital signs measurements require invasive surgery and human handling--these are problematic for large scale monitoring, for measuring deep sea fish, and other situations which preclude human interaction with each individual subject. These results show a useful application of radar to augment existing cardiovascular and ventilatory activity sensing techniques and enable monitoring in a wider range of situations. PMID- 23366403 TI - Automated hand-forearm ergometer data collection system. AB - Handgrip contractions are a standard exercise modality to evaluate cardiovascular system performance. Most conventional ergometer systems of this nature are manually controlled, placing a burden on the researcher to guide subject activity while recording the resultant data. This paper presents updates to a hand-forearm ergometer system that automate the control and data-acquisition processes. A LabVIEW virtual instrument serves as the centerpiece for the system, providing the subject/researcher interfaces as well as coordinating data acquisition from both traditional and new sensors. Initial data indicate the viability of the system with regard to its ability to obtain consistent and physiologically meaningful data. PMID- 23366404 TI - Heartbeat detection from a hydraulic bed sensor using a clustering approach. AB - Encouraged by previous performance of a hydraulic bed sensor, this work presents a new hydraulic transducer configuration which improves the system's ability to capture a heartbeat signal from four subjects with different body weight and height, gender, age and cardiac history. It also proposes a new approach for detecting the occurrence of heartbeats from ballistocardiogram (BCG) signals through the use of the k-means clustering algorithm, based on finding the location of the J-peaks. Preliminary testing showed that the new transducer arrangement was able to capture the occurrence of heartbeats for all the participants, and the clustering approach achieved correct heartbeat detection ranging from 98.6 to 100% for three of them. Some considerations are discussed regarding adjustments that can be done in order to increase the correct detection of heartbeats for the participant whose percentage of correct detection ranged from 71.0 to 92.5%. PMID- 23366405 TI - A portable system for recording neural activity in indoor and outdoor environments. AB - We present a self-contained portable USB based device that can amplify and record small bioelectric signals from insects and animals. The system combines a purpose built low noise amplifier with off the shelf components to provide a low cost low power system for recording electrophysiological signals. Using open source software the system is programmed as a simple USB device and can be connected to any USB capable computer for recording data. This simple and universal interface provides the ability to connect to a variety of systems. Open source acquisition software was also written to record signals under the linux operating system. Performance analysis shows that our device is able to record good quality signals both indoors and outdoors and delivers this performance at a very low cost. Compared to larger systems our device provides the additional advantage of portability given that it can fit into a pocket and costs a fraction of large systems used in electrophysiology labs. PMID- 23366406 TI - A low-cost, reliable, high-throughput system for rodent behavioral phenotyping in a home cage environment. AB - Inexpensive, high-throughput, low maintenance systems for precise temporal and spatial measurement of mouse home cage behavior (including movement, feeding, and drinking) are required to evaluate products from large scale pharmaceutical design and genetic lesion programs. These measurements are also required to interpret results from more focused behavioral assays. We describe the design and validation of a highly-scalable, reliable mouse home cage behavioral monitoring system modeled on a previously described, one-of-a-kind system. Mouse position was determined by solving static equilibrium equations describing the force and torques acting on the system strain gauges; feeding events were detected by a photobeam across the food hopper, and drinking events were detected by a capacitive lick sensor. Validation studies show excellent agreement between mouse position and drinking events measured by the system compared with video-based observation--a gold standard in neuroscience. PMID- 23366408 TI - Achieving appropriate design for developing world heath care: the case of a low cost autoclave for primary health clinics. AB - In developing world health clinics, incidence of surgical site infection is 2 to 10 times higher than in developed world hospitals. This paper identifies lack of availability of appropriately designed, low-cost autoclaves in developing world health clinics as a major contributing factor to the dramatic gap in surgical site infection rates. The paper describes the process of developing a low-cost autoclave that addresses the unique challenges faced by developing world primary health clinics and discusses how appropriateness of design was determined. The resulting pressure cooker-based autoclave design was fabricated and tested against the CDC specifications. Twelve partnering clinics in Nepal trialed these autoclaves from July until December 2012. PMID- 23366407 TI - Sample concentration and purification for point-of-care diagnostics. AB - The ability to increase the concentration of target analytes in a fixed sample volume can potentially lower the limit of detection for many biosensing techniques, and thus is key in sample preparation for infectious disease diagnosis. Concentration by evaporation is an effective method to achieve target enrichment. However, concentrating human samples, including blood and plasma, by evaporation-based methods is made challenging by high concentrations of proteins and electrolytes. Dehydration of the proteins causes the sample to turn into a gel, hindering further analysis. At the same time, decreasing the volume increases the overall concentration of electrolytes, causing bacterial or viral particle lysis, and making them more difficult to detect in affinity-based biosensors. Thus, we fabricated a microfluidic chip that incorporates both dialysis and concentration in a single design. The chip dialyzes the proteins from the plasma, while maintaining an appropriate concentration of electrolytes and concentrating the sample targets. The process to concentrate plasma or serum samples by a factor of 10 takes less than 30 minutes. As a proof-of-concept, we demonstrated the chip using a defective Human Immunodeficiency Virus (HIV). To distinguish patients on antiretroviral therapy who are failing therapy from those who are not, a diagnostic must be able to detect HIV in plasma down to at least 1000 particles per milliliter. For a number of technical reasons, it is difficult to get on-chip PCR reactions to reach this level of sensitivity, so concentration of HIV from lower viral load samples has the potential to improve the sensitivity of many types of molecular point-of-care viral load tests. PMID- 23366409 TI - Biophotogrammetry model of respiratory motion analysis applied to children. AB - This study aimed to test a protocol of measurements based on Biophotogrammetry to Analysis of Respiratory Mechanics (BARM) in healthy children. Seventeen normal spirometric children (six male and 11 female) were tested. Their performed maneuvers of forced inspiratory vital capacity were recorded in the supine position. The images were acquired by a digital camera, laterally placed to the trunk. Surface markers allowed that the files, exported to CorelDraw(r) software, were processed by irregular trapezoids paths. Compartments were defined in the thoracic (TX), abdominal (AB) and the chest wall (CW). They were defined at the end of an inspiration and expiration, both maximum, controlled by a digital spirometer. The result showed that the measured areas at the inspiratory and expiratory periods were statistically different (p<0.05). It reflects the mobility of CW and compartments. In conclusion, the proposed method can identify the breathing pattern of the measured subject using images in two dimensions (2D). PMID- 23366410 TI - A mathematical model to predict the optimal test line location and sample volume for lateral flow immunoassays. AB - Lateral flow immunoassay (LFIA) platform is one of the most relevant technologies for screening and diagnosing clinical conditions. However due to low sensitivity and poor repeatability of the platform it has been used only for limited and non critical tests. Mathematical models have been used to understand the principles of capillary flow and antibody antigen based immunoreactions in nitrocellulose membrane typically seen in LFIA. The model presented in this paper predicts the optimized location of test line on LFIA strip, sample volume and total reaction time that is needed to achieve the required sensitivity for different analytes on a case to case basis. The membrane properties like capillary flow time (s/cm), concentration and affinity constants of antibodies can be varied and the corresponding effect on strip design can be found. Hence this model can be used as a design tool to optimize the LFIA strip construction and reagent development processes. PMID- 23366411 TI - New automatic cell isolation system for flow cytometry: cell isolation unit and staining reagent kit. AB - Flow cytometry is well-known cell analysis method and useful to gain quantitative information from cells in blood, however, it is not widely used for solid tissues in clinical settings. This is partly because it takes a long time to prepare samples and the operation can be complicated. To resolve these problems, we developed a new automatic cell isolation system which consists of cell isolation unit and staining reagent kit specialized for flow cytometry. With this new system, cell isolation can be done more rapidly and easily. By using this method, we could determine optimum condition to disintegrate porcine colon tissue and stain cells stably in 6 minutes. This result indicates that our method can provide analysis data within 10 minutes. We also evaluated our method in colorectal cancer patients, and the result was promising. All the data suggests that this method can support and facilitate rapid diagnosis. PMID- 23366412 TI - Specific detection of topoisomerase I from the malaria causing P. falciparum parasite using isothermal rolling circle amplification. AB - We present a Rolling-Circle-Enhance-Enzyme-Activity-Detection (REEAD) system with potential use for future point-of-care diagnosis of malaria. In the developed setup, specific detection of malaria parasites in crude blood samples is facilitated by the conversion of single Plasmodium falciparum topoisomerase I (pfTopI) mediated cleavage-ligation events, happening within nanometer dimensions, to micrometer-sized products readily detectable at the single molecule level in a fluorescence microscope. In principle, REEAD requires no special equipment and the readout is adaptable to simple colorimetric detection systems. Moreover, with regard to detection limit the presented setup is likely to outcompete standard gold immuno-based diagnostics. Hence, we believe the presented assay forms the basis for a new generation of easy-to-use diagnostic tools suitable for the malaria epidemic areas in developing countries. PMID- 23366413 TI - Artificial tissue bioreactor (ATB) for biological and imaging applications. AB - Three-dimensional (3D) culture systems are increasingly applied to study tissue biology. In this work, we report on the development of an artificial tissue bioreactor (ATB) designed to simulate the 3D structure and microenvironment of tissues in vivo, with multiple avenues of sampling, including the tissue chamber, for downstream analysis. Additionally, the ATB is integrated with the microPET Focus F220 for in-vivo imaging applications. As a proof-of-concept, we characterized the effects of lipids on glucose utilization using HepG2 cells. ATB studies were performed pre- and post- therapeutic intervention with the PPAR gamma agonist pioglitazone. In parallel, Glucose Tolerance Test (GTT) is performed on media samples to assess glucose uptake by cells as a measures of insulin signaling sensitivity. Fatty acid uptake in the ATB cell chamber is measured using [(11)C]Palmitate with microPET imaging. Overall, the ATB will facilitate the use of existing and novel radiopharmaceuticals in discovery of validating and translating insights derived from ATB studies to pre-clinical animal studies, to clinical evaluation. PMID- 23366415 TI - Injectable macroporous microparticles for soft tissue augmentation. AB - Macroporous polymeric microparticles have been fabricated using a combination of particulate leaching and gas foaming techniques. Controlling the concentration of ammonium bicarbonate particles and the spin speed of the microemulsion in poly (epsilon-caprolactone) (PCL) yields a range of macroporous microparticles with interconnected pores (10-50 um) that may promote cell and tissue ingrowth in vivo when implanted subcutaneously. This fabrication technique introduces a novel template which can be modified to meet a diverse set of material and biological specifications. PMID- 23366414 TI - A low-cost intracellular delivery system based on microbubble and high gravity field. AB - In this paper, we developed a low-cost intracellular delivery system based on microbubble and high gravity field. We successfully delivered FITC-Dextran (40kD) into hard-to-deliver THP-1 cells. The results showed that our method achieved high delivery efficiency up to 80%. It was found that the delivery efficiency and cell viability were closely related to the centrifuge speed. We speculated that the burst of microbubbles causes transient pore opening thus increasing the chance of biomolecules entering cells. This fast, low-cost and easy-to-operate protocol is very promising for delivering therapeutic genes and drugs into any cells which do not actively take up extracellular materials. This method is most effective for in-vitro delivery, but after delivery, treated cells might be injected back to human for in-vivo imaging. PMID- 23366416 TI - In vitro degradation and cytocompatibility of magnesium-zinc-strontium alloys with human embryonic stem cells. AB - Magnesium-based alloys have attracted great interest for medical applications due to their unique biodegradable capability and desirable mechanical properties. When considered for medical applications, the degradation rate of these alloys must be tailored so that: (i) it does not exceed the rate at which the degradation products can be excreted from the body, and (ii) it is slow enough so that the load bearing properties of the implant are not jeopardized and do not conflict prior to and during synthesis of new tissue. Implant integration with surrounding cells and tissues and mechanical stability are critical aspects for clinical success. This study investigated Magnesium-Zinc-Strontium (ZSr41) alloy degradation rates and the interaction of the degradation products with human embryonic stem cells (hESC) over a 72 hour period. An in vitro hESC model was chosen due to the higher sensitivity of ESCs to known toxicants which allows to potentially detect toxicological effects of new biomaterials at an early stage. Four distinct ZSr41 compositions (0.15 wt.%, 0.5 wt.%, 1 wt.%, and 1.5 wt.% Sr) were designed and produced through metallurgical processing. ZSr41 alloy mechanical properties, degradation, and cytocompatibility were investigated and compared to pure polished Magnesium (Mg). Mechanical properties evaluated included hardness, ultimate tensile strength, and elongation to failure. Degradation was characterized by measuring total weight loss of samples and pH change in the cell culture media. Cytocompatibility was studied by comparing fluorescence and phase contrast images of hESCs after co-culture with Mg alloys. Results indicated that the Mg-Zn-Sr alloy with 0.15 wt.% Sr improved cytocompatibility and provided slower degradation as compared with pure Mg. PMID- 23366417 TI - Roles of bioactive sphingolipid metabolites in ovarian cancer cell biomechanics. AB - Bioactive sphingolipid metabolites have emerged as important lipid second messengers in the regulation of cell growth, death, motility and many other events. These processes are important in cancer development and progression; thus, sphingolipid metabolites have been implicated in both cancer development and cancer prevention. Despite recent considerable progress in understanding the multi-faceted functions of these bioactive metabolites, little is known about their influence on the biomechanical property of cells. The biomechanical properties of cancer cells change during progression with aggressive and invasive cells being softer compared to their benign counterparts. In this paper, we investigated the effects of exogenous sphingolipid metabolites on the Young's modulus and cytoskeletal organization of cells representing aggressive ovarian cancer. Our findings demonstrate that the elasticity of aggressive ovarian cancer cells decreased ~15% after treatment with ceramide and sphingosine-1-phosphate. In contrast, sphingosine treatment caused a ~30% increase in the average elasticity which was associated with a more defined actin cytoskeleton organization. This indicates that sphingolipid metabolites differentially modulate the biomechanic properties of cancer cells which may have a critical impact on cancer cell survival and progression, and the use of sphingolipid metabolites as chemopreventive or chemo-therapeutic agents. PMID- 23366418 TI - Study of arrhythmia prevalence in NUVANT Mobile Cardiac Telemetry system patients. AB - The Corventis NUVANTTM Mobile Cardiac Telemetry system is an innovative solution in the field of continuous monitoring of symptomatic and asymptomatic cardiac abnormalities to help physicians diagnose and treat non-lethal cardiac arrhythmias. As an FDA cleared product on the market for more than 2 years, the collected body of patient data represents a unique and powerful source of clinical information. Analysis of a sample of 951 NUVANT patients has revealed interesting statistics on the prevalence of various cardiac arrhythmias in the patient population. The population is non-randomized and largely consists of US patients where a traditional Holter Monitor study was negative. The analysis here is focused on classifying the detected arrhythmias using potential therapy solutions as a classifier. Across the total population, 2.2% of patients presented arrhythmias indicating assessment for clinically significant tachycardia, 19% indications of potential bradycardia, 20% had indications of atrial fibrillation, 1% indicating arrhythmias requiring other conditional treatment, and 58% presenting arrhythmias likely not requiring treatment. PMID- 23366419 TI - Automated skin lesion assessment using mobile technologies and cloud platforms. AB - This paper presents a smart phone based system for storing digital images of skin areas depicting regions of interest (lesions) and performing self-assessment of these skin lesions within these areas. The system consists of a mobile application that can acquire and identify moles in skin images and classify them according their severity into melanoma, nevus and benign lesions. The proposed system includes also a cloud infrastructure exploiting computational and storage resources. This cloud-based architecture provides interoperability and support of various mobile environments as well as flexibility in enhancing the classification model. Initial evaluation results are quite promising and indicate that the application can be used for the task of skin lesions initial assessment. PMID- 23366420 TI - Design challenges for camera oximetry on a mobile phone. AB - The use of mobile consumer devices as medical diagnostic tools allows standard medical tests to be performed anywhere. Cameras embedded in consumer devices have previously been used as pulse oximetry sensors. However, technical limitations and implementation challenges have not been described. This manuscript provides a critical analysis of pulse oximeter technology and technical limitations of cameras that can potentially impact implementation of pulse oximetry in mobile phones. Theoretical and practical examples illustrate difficulties and recommendations to overcome these challenges. PMID- 23366421 TI - Real-time ECG monitoring and arrhythmia detection using Android-based mobile devices. AB - We developed an application for AndroidTM-based mobile devices that allows real time electrocardiogram (ECG) monitoring and automated arrhythmia detection by analyzing ECG parameters. ECG data provided by pre-recorded files or acquired live by accessing a ShimmerTM sensor node via BluetoothTM can be processed and evaluated. The application is based on the Pan-Tompkins algorithm for QRS detection and contains further algorithm blocks to detect abnormal heartbeats. The algorithm was validated using the MIT-BIH Arrhythmia and MIT-BIH Supraventricular Arrhythmia databases. More than 99% of all QRS complexes were detected correctly by the algorithm. Overall sensitivity for abnormal beat detection was 89.5% with a specificity of 80.6%. The application is available for download and may be used for real-time ECG-monitoring on mobile devices. PMID- 23366422 TI - Activity and school attendance monitoring system for adolescents with sickle cell disease. AB - Sickle cell disease, the most common hemoglobin disorder, affects major organ systems with symptoms of pain, anemia and a multitude of chronic conditions. For adolescents, the disease adversely affects school attendance, academic progress and social activity. To effectively study the relationship among school attendance and other factors like demographics and academic performance, studies have relied on self-reporting and school records, all of which have some bias. In this study we design and prototype a system, called SickleSAM (Sickle cell School attendance and Activity Monitoring system), for automatically monitoring school attendance and daily activity of adolescents with sickle cell disease. SickleSAM intends to remove human bias and inaccuracies. The system uses built-in GPS to collect data which will be recorded into a cloud database using Short Messaging Service technology. SickleSAM is developed by Georgia Institute of Technology in conjunction with Children's Healthcare of Atlanta (CHOA). System effectiveness is being evaluated using a trial of 10 adolescents with the disease. PMID- 23366423 TI - Evaluating the usability of a virtual reality-based Android application in managing the pain experience of wheelchair users. AB - Pain constitutes an important medical concern that can have severe implications to a wheelchair user's quality of life. Results from studies indicate that pain is a common problem in this group of individuals, having a reported frequency of always (12%) and everyday (33%). This incidence signifies the need for more applicable and effective pain management clinical tools. As a result, in this paper we present an Android application (PainDroid) that has been enhanced with Virtual Reality (VR) technology for the purpose of improving the management of pain. Our evaluation with a group of wheelchair users revealed that PainDroid demonstrated high usability among this population, and is foreseen that it can make an important contribution in research on the assessment and management of pain. PMID- 23366424 TI - Performance analysis of coexisting IEEE 802.15.4-based health monitoring WBANs. AB - Wireless Body Area Networks (WBANs) for health monitoring systems are required to meet stringent performance demands regarding the tradeoff between reliability, latency, and power efficiency. WBANs feature limited range and bandwidth and they are prone to interference. Considering the life-critical nature of some WBAN systems, we present an in-depth investigation of the situations where the dynamic coexistence of multiple WBANs may severely affect their performances. In this paper, we analytically study the effect of coexistence on the operation of WBANs. We present a mathematical analysis to precisely obtain the probabilities of successful communication and validate this analysis through simulation. Our simulation analysis indicates that in the default mode of operation, coexistence of three WBANs can lead to the loss of 20-85% of data transmissions for typical sensor configurations. PMID- 23366425 TI - Ear-worn reference data collection and annotation for multimodal context-aware hearing instruments. AB - In this work we present a newly developed ear-worn sensing and annotation device to unobtrusively capture head movements in real life situations. It has been designed in the context of developing multimodal hearing instruments (HIs), but is not limited to this application domain. The ear-worn device captures triaxial acceleration, rate of turn and magnetic field and features a one-button-approach for real-time data annotation through the user. The system runtime is over 5 hours at a sampling rate of 128 Hz. In a user study with 21 participants the device was perceived as comfortable and showed a robust hold at the ear. On the example of head acceleration data we perform unsupervised clustering to demonstrate the benefit of head movements for multimodal HIs. We believe the novel technology will help to push the boundaries of HI technology. PMID- 23366426 TI - Automated real-time atrial fibrillation detection on a wearable wireless sensor platform. AB - This paper presents an automated real-time atrial fibrillation (AF) detection approach that relies on the observation of two characteristic irregularities of AF episodes in the electrocardiogram (ECG) signal. The results generated after the analysis of these irregularities are subsequently analyzed in real-time using a new fuzzy classifier. We have optimized this novel AF classification framework to require very limited processing, memory storage and energy resources, which makes it able to operate in real-time on a wearable wireless sensor platform. Moreover, our experimental results indicate that the proposed on-line approach shows a similar accuracy to state-of-the-art off-line AF detectors, achieving up to 96% sensitivity and 93% specificity. Finally, we present a detailed energy study of each component of the target wearable wireless sensor platform, while executing the automated AF detection approach in a real operating scenario, in order to evaluate the lifetime of the overall system. This study indicates that the lifetime of the platform is increased by using the proposed method to detect AF in real-time and diagnose the patient with respect to a streaming application that sends the raw signal to a central coordinator (e.g., smartphone or laptop) for its ulterior processing. PMID- 23366427 TI - Quantified reflex strategy using an iPod as a wireless accelerometer application. AB - A primary aspect of a neurological evaluation is the deep tendon reflex, frequently observed through the patellar tendon reflex. The reflex response provides preliminary insight as to the status of the nervous system. A quantified reflex strategy has been developed, tested, and evaluated though the use of an iPod as a wireless accelerometer application integrated with a potential energy device to evoke the patellar tendon reflex. The iPod functions as a wireless accelerometer equipped with robust software, data storage, and the capacity to transmit the recorded accelerometer waveform of the reflex response wirelessly through email for post-processing. The primary feature of the reflex response acceleration waveform is the maximum acceleration achieved subsequent to evoking the patellar tendon reflex. The quantified reflex strategy using an iPod as a wireless accelerometer application yields accurate and consistent quantification of the reflex response. PMID- 23366428 TI - Capturing basic movements for mobile platforms embedded with motion sensors. AB - A novel experimental setup using accelerometer and gyroscope sensors embedded on a single board along with a distance-based pattern recognition algorithm is presented for accurately identifying basic movements for possible application in gaming using a mobile platform. As an example, we considered some basic step sequences in the popular dance game (e.g., dance dance revolution), and could detect these movements with a reasonably high probability. We envision that the experimental results presented in this paper will motivate future research in the world of mobile gaming applications using advanced smart phones with a dual module design. PMID- 23366429 TI - Prototype ultra wideband-based wireless body area network--consideration of CAP and CFP slot allocation during human walking motion. AB - This paper presents an experimental evaluation of communication during human walking motion, using the medium access control (MAC) evaluation system for a prototype ultra-wideband (UWB) based wireless body area network for suitable MAC parameter settings for data transmission. Its physical layer and MAC specifications are based on the draft standard in IEEE802.15.6. This paper studies the effects of the number of retransmissions and the number of commands of GTS (guaranteed time slot) request packets in the CAP (contention access period) during human walking motion by varying the number of sensor nodes or the number of CFP (contention free period) slots in the superframe. The experiments were performed in an anechoic chamber. The number of packets received is decreased by packet loss caused by human walking motion in the case where 2 slots are set for CFP, regardless of the number of nodes, and this materially decreases the total number of packets received. The number of retransmissions and the GTS request commands increase according to increases in the number of nodes, largely reflecting the effects of the number of CFP slots in the case where 4 nodes are attached. In the cases where 2 or 3 nodes are attached and 4 slots are set for CFP, the packet transmission rate is more than 95%. In the case where 4 nodes are attached and 6 slots are set for CFP, the packet transmission rate is reduced to 88% at best. PMID- 23366430 TI - The depth, waveform and pulse rate for electrical microstimulation of the auditory cortex. AB - Intracortical microstimulation of primary sensory regions of the brain offers a compelling platform for the development of sensory prostheses. However, fundamental questions remain regarding the optimal stimulation parameters. The purpose of this paper is to summarize a series of experiments which were designed to answer the following three questions. 1) What is the best electrode implantation depth? 2) What is the optimal stimulation waveform? 3) What is the maximal useful stimulus pulse rate? The present results suggest the following answers: 1) cortical layers V&IV, 2) biphasic, charge balanced, symmetric, cathode leading pulses with of duration of ~ 100 microseconds per phase, and 3) 80 pulses-per-second. PMID- 23366431 TI - On the design and evaluation of the PDA-based research platform for electric and acoustic stimulation. AB - The aim of the paper is to describe the bimodal (combining electrical stimulation via the implant with acoustic stimulation via hearing aids) design of the PDA based research platform and present results from a short-term evaluation with five bimodal cochlear implant users. The evolution of the PDA platform has been reported earlier in terms of development and its potential in various experiments. This paper focuses on the evaluation of the platform with bimodal users in terms of speech intelligibility in quiet, 10dB and 5dB SNR conditions and compares the results with the users' own clinical processor. The results of this clinical trial will encourage researchers in this area to use the platform in their future studies as it provides unparalleled flexibility along with a large suite of applications to conduct a wide variety of experiments for electric only and combined electric and acoustic stimulation (EAS) for long-term chronic studies with great ease. PMID- 23366432 TI - Improved accuracy using recursive bayesian estimation based language model fusion in ERP-based BCI typing systems. AB - RSVP KeyboardTM is an electroencephalography (EEG) based brain computer interface (BCI) typing system, designed as an assistive technology for the communication needs of people with locked-in syndrome (LIS). It relies on rapid serial visual presentation (RSVP) and does not require precise eye gaze control. Existing BCI typing systems which uses event related potentials (ERP) in EEG suffer from low accuracy due to low signal-to-noise ratio. Henceforth, RSVP KeyboardTM utilizes a context based decision making via incorporating a language model, to improve the accuracy of letter decisions. To further improve the contributions of the language model, we propose recursive bayesian estimation, which relies on non committing string decisions, and conduct an offline analysis, which compares it with the existing naive bayesian fusion approach. The results indicate the superiority of the recursive bayesian fusion and in the next generation of RSVP KeyboardTM we plan to incorporate this new approach. PMID- 23366433 TI - No surprise--sequence event-related potentials for brain-computer interfaces. AB - INTRODUCTION: In the field of Brain-Computer Interfaces (BCI), the original two class oddball paradigm has been extended to multiple stimuli with balanced probabilities and random presentation sequences. Exploiting the differences between standard and deviant ERP responses, these multi-class paradigms are suitable for communication and control. METHODS: The present study investigates the effect of giving up the randomness of stimulation sequences in favor of a repeated, predictable pattern. Data of healthy subjects (n=10) who performed a single session with a 6-class spatial auditory ERP paradigm were analyzed offline. Their auditory evoked potentials (AEP) resulting from the potentially simpler task (using fixed sequences) are compared with the AEP evoked by pseudo randomized stimulation sequences. RESULTS: Class-discriminative EEG responses between target and non-target stimuli were observed for both conditions. The binary classification error estimated for standard epochs of was comparable for both conditions (random: 24%, fixed: 25%). Expanding the standard epochs to include pre-stimulus intervals, we found that the regular structure of the fixed sequence can be exploited. Compared to the standard epoch, the MSE improves by 7%, while in the random condition an improvement could not be observed. PMID- 23366434 TI - The Unlock Project: a Python-based framework for practical brain-computer interface communication "app" development. AB - In this paper we present a framework for reducing the development time needed for creating applications for use in non-invasive brain-computer interfaces (BCI). Our framework is primarily focused on facilitating rapid software "app" development akin to current efforts in consumer portable computing (e.g. smart phones and tablets). This is accomplished by handling intermodule communication without direct user or developer implementation, instead relying on a core subsystem for communication of standard, internal data formats. We also provide a library of hardware interfaces for common mobile EEG platforms for immediate use in BCI applications. A use-case example is described in which a user with amyotrophic lateral sclerosis participated in an electroencephalography-based BCI protocol developed using the proposed framework. We show that our software environment is capable of running in real-time with updates occurring 50-60 times per second with limited computational overhead (5 ms system lag) while providing accurate data acquisition and signal analysis. PMID- 23366435 TI - Electrical stimulation for the management of aspiration during swallowing. AB - Protection of the airway during swallow is often compromised following stroke and other neurological diseases. If a patient fails to recover airway protection with standard therapy, they are often left with few if any options to avoid repeated pneumonia resulting from aspiration. For them, the only option is no food by mouth and a PEG-tube for nutrition. Functional electrical stimulation offers possible solutions for restoring airway protection. Here we report the capabilities of transtracheal stimulation for vocal fold closure and selective stimulation of the XII cranial nerve to produce elevation of the hyolaryngotracheal complex. These stimulation locations add to our toolbox for managing swallowing difficulties and allow patients to maintain oral feeding. PMID- 23366436 TI - Using neuronal states for transcribing cortical activity into muscular effort. AB - We study the relations between the activity of corticomotoneuronal (CM) cells and the forces exerted by fingers. The activity of CM cells, located in the primary motor cortex is recorded in the thumb and index fingers area of a monkey. The activity of the fingers is recorded as they press two levers. The main idea of this work is to establish and use a collection of neuronal states. At any time, the neuronal state is defined by the firing rates of the recorded neurons. We assume that any such neuronal state is related to a typical variation (or absence of variation) in the muscular effort. Our forecasting model uses a linear combination of the firing rates, some synchrony information between spike trains and averaged variations of the positions of the levers. PMID- 23366437 TI - Performance of beamformers on EEG source reconstruction. AB - Recently a number of new beamformers have been introduced for reconstruction and localization of neural sources from EEG and MEG. However, little is known about the relative performance of these beamformers. In this study, 8 scalar beamformers were examined with respect to several parameters to determine how effective they are at reconstruction of a dipole time course from EEG. A simulated EEG signal was produced by means of forward head modelling for projection of an artificial dipole on scalp electrodes then superimposed on background signal. Both real EEG and white noise were applied as background activity. Although the eigenspace beamformer can perform slightly better than other beamformers for small dipoles, and even more so for large dipoles, it is not a contender for real-time beamforming of EEG as it cannot be completely automated. Overall, in terms of performance, robustness to variations in parameters, and ease of application, the minimum variance and Borgiotti-Kaplan beamformers were found to be the best performers. PMID- 23366438 TI - Quantification of event-related desynchronization/synchronization at low frequencies in a semantic memory task. AB - Although several techniques have been developed for the visualization of EEG event-related desynchronization/synchronization (ERD/ERS) in both time and frequency domains, none of the quantification methods takes advantage of the time and frequency resolution at the same time. Existing techniques for the quantification of the ERD/ERS changes compute the average EEG power increase/decrease relative to certain reference value, over fixed time intervals and/or frequency bands (either fixed or individualized). Inaccuracy in the computation of these frequency bands (where the process is actually measured) in combination with the averaging process over time may lead to errors in the computation of any ERD/ERS quantification parameter. In this paper, we present a novel method for the automatic, individual and exact quantification of the most significant ERD/ERS region within a given window of the time-frequency domain. The method is exemplified by quantifying the ERS at low frequencies of 10 subjects performing a semantic memory task, and compared with existing techniques. PMID- 23366439 TI - Nonlocal two dimensional denoising of frequency specific chirp evoked ABR single trials. AB - Recently, we have shown that denoising evoked potential (EP) images is possible using two dimensional diffusion filtering methods. This restoration allows for an integration of regularities over multiple stimulations into the denoising process. In the present work we propose the nonlocal means (NLM) method for EP image denoising. The EP images were constructed using auditory brainstem responses (ABR) collected in young healthy subjects using frequency specific and broadband chirp stimulations. It is concluded that the NLM method is more efficient than conventional approaches in EP imaging denoising, specially in the case of ABRs, where the relevant information can be easily masked by the ongoing EEG activity, i.e., signals suffer from rather low signal-to-noise ratio SNR. The proposed approach is for the a posteriori denoising of single trials after the experiment and not for real time applications. PMID- 23366440 TI - Locating spatial patterns of waveforms during sensory perception in scalp EEG. AB - The spatio-temporal oscillations in EEG waves are indicative of sensory and cognitive processing. We propose a method to find the spatial amplitude patterns of a time-limited waveform across multiple EEG channels. It consists of a single iteration of multichannel matching pursuit where the base waveform is obtained via the Hilbert transform of a time-limited tone. The vector of extracted amplitudes across channels is used for classification, and we analyze the effect of deviation in temporal alignment of the waveform on classification performance. Results for a previously published dataset of 6 subjects show comparable results versus a more complicated criteria-based method. PMID- 23366441 TI - Detection of thermal pain in rodents through wireless electrocorticography. AB - In an effort to detect pain in an objective way, Electrocorticography (ECoG) signals were acquired from male Sprague-Dawley rats in response to thermally induced pain. A wearable, wireless multichannel system was utilized to acquire signals from freely-behaving animals during the experiments. ECoG signals were recorded before (baseline) and during the heat exposure for which animals withdrew their paws in response to the painful feeling. Analysis of the signals revealed a clear, high-amplitude peak at the moment of the paw withdrawal across all four recording channels in each test. Analysis in the frequency domain found the peaks coincided with an abrupt increase of delta rhythms (under 4 Hz). In the baseline, heating, and post-withdrawal segments, these rhythms were relatively low, indicating that the sharp increase in delta activity might be associated with pain. Theta, alpha, beta, and gamma rhythms were also measured, but no significant differences were found between each phase of the signals. These preliminary results are promising; however, more animal models will need to be tested to provide statistically significant results with high confidence. PMID- 23366442 TI - Point process modeling reveals anatomical non-uniform distribution across the subthalamic nucleus in Parkinson's disease. AB - Deep brain stimulation (DBS) is a highly promising therapy for Parkinson's disease (PD). However, most patients do not get full therapeutic benefit from DBS, due to its critical dependence on electrode location in the Subthalamic Nucleus (STN). For this reason, we believe that the development of a novel surgical tool for DBS placement, i.e., an automated intraoperative closed-loop DBS localization system, is essential. In this paper, we analyze single unit spiking activity of 120 neurons in different STN locations collected from 4 PD patients. Specifically, for each neuron, we estimate a point process model (PPM) of the spiking activity for different depths within the STN by which we are able to detect pathological bursting and oscillations. Our results suggest that these signatures are more prominent in the dorsolateral part of the STN. Therefore, accurately placing the DBS electrode in this target may result in maximal therapeutic benefit with less power effort required by DBS. Furthermore, PPMs might be an effective tool for modeling of the STN neuronal activities as a function of location within the STN, which may pave the way towards developing a closed-loop navigation tool for optimal DBS electrode placement. PMID- 23366443 TI - Prediction of single neuron spiking activity using an optimized nonlinear dynamic model. AB - The increasing need of knowledge in the treatment of brain diseases has driven a huge interest in understanding the phenomenon of neural spiking. Researchers have successfully been able to create mathematical models which, with specific parameters, are able to reproduce the experimental neuronal responses. The spiking activity is characterized using spike trains and it is essential to develop methods for parameter estimation that rely solely on the spike times or interspike intervals (ISI). In this paper we describe a new technique for optimization of a single neuron model using an experimental spike train from a biological neuron. We are able to fit model parameters using the gradient descent method. The optimized model is then used to predict the activity of the biological neuron and the performance is quantified using a spike distance measure. PMID- 23366444 TI - Describing relevant indices from the resting state electrophysiological networks. AB - The "Default Mode Network" concept was defined, in fMRI field, as a consistent pattern, involving some regions of the brain, which is active during resting state activity and deactivates during attention demanding or goal-directed tasks. Several fMRI studies described its features also correlating the deactivations with the attentive load required for the task execution. Despite the efforts in EEG field, aiming at correlating the spectral features of EEG signals with DMN, an electrophysiological correlate of the DMN hasn't yet been found. In this study we used advanced techniques for functional connectivity estimation for describing the neuroelectrical properties of DMN. We analyzed the connectivity patterns elicited during the rest condition by 55 healthy subjects by means of Partial Directed Coherence. We extracted some graph indexes in order to describe the properties of the resting network in terms of local and global efficiencies, symmetries and influences between different regions of the scalp. Results highlighted the presence of a consistent network, elicited by more than 70% of analyzed population, involving mainly frontal and parietal regions. The properties of the resting network are uniform among the population and could be used for the construction of a normative database for the identification of pathological conditions. PMID- 23366445 TI - Modeling of visuospatial perspectives processing and modulation of the fronto parietal network activity during action imitation. AB - It has been suggested that the human mirror neuron system (MNS) plays a critical role in action observation and imitation. However, the transformation of perspective between the observed (allocentric) and the imitated (egocentric) actions has received little attention. We expand a previously proposed biologically plausible MNS model by incorporating general spatial transformation capabilities that are assumed to be encoded by the intraparietal sulcus (IPS) and the superior parietal lobule (SPL) as well as investigating their interactions with the inferior frontal gyrus and the inferior parietal lobule. The results reveal that the IPS/SPL could process the frame of reference and the viewpoint transformations, and provide invariant visual representations for the temporo parieto-frontal circuit. This allows the imitator to imitate the action performed by a demonstrator under various perspectives while replicating results from the literatures. Our results confirm and extend the importance of perspective transformation processing during action observation and imitation. PMID- 23366446 TI - Functional connectivity between Layer 2/3 and Layer 5 neurons in prefrontal cortex of nonhuman primates during a delayed match-to-sample task. AB - The prefrontal cortex (PFC) has been postulated to play critical roles in cognitive control and the formation of long-term memories. To gain insights into the neurobiological mechanism of such high-order cognitive functions, it is important to understand the input-output transformational properties of the PFC micro-circuitry. In this study, we identify the functional connectivity between the Layer 2/3 (input) neurons and the Layer 5 (output) neurons using a previously developed generalized Volterra model (GVM). Input-output spike trains are recorded from the PFCs of nonhuman primates performing a memory-dependent delayed match-to-sample task with a customized conformal ceramic multi-electrode array. The GVM describes how the input spike trains are transformed into the output spike trains by the PFC micro-circuitry and represents the transformation in the form of Volterra kernels. Results show that Layer 2/3 neurons have strong and transient facilitatory effects on the firings of Layer 5 neurons. The magnitude and temporal range of the input-output nonlinear dynamics are strikingly different from those of the hippocampal CA3-CA1. This form of functional connectivity may have important implications to understanding the computational principle of the PFC. PMID- 23366447 TI - Effects of electroconvulsive therapy stimulus pulsewidth and amplitude computed with an anatomically-realistic head model. AB - The efficacy and cognitive outcomes of electro-convulsive therapy (ECT) on psychiatric disorders have been shown to depend on variations in treatment technique. In order to investigate this, a high resolution finite element human head model was generated from MRI scans and implemented with tissue heterogeneity and an excitable ionic neural formulations in the brain. The model was used to compare the effects of altered ECT stimulus amplitude and pulse width on the spatial extent of directly activated brain regions. The results showed that decreases in both amplitude and pulse width could effectively lead to reductions in the size of activated brain regions. PMID- 23366448 TI - Versatile broadband electrode assembly for cell electroporation. AB - In this paper, a versatile electrode assembly for cell electroporation is proposed. For validation of the delivery system, biological cell electroporation experiments using 2.5 ns and 5 ns, 10 MV/m pulsed electric fields have been conducted. Electromagnetic, time domain, and frequency analyses demonstrate the broadband behavior of the delivery system. PMID- 23366449 TI - Effects of nanosecond pulsed electric fields on the activity of a Hodgkin and Huxley neuron model. AB - The cell membrane poration is one of the main assessed biological effects of nanosecond pulsed electric fields (nsPEF). This structural change of the cell membrane appears soon after the pulse delivery and lasts for a time period long enough to modify the electrical activity of excitable membranes in neurons. Inserting such a phenomenon in a Hodgkin and Huxley neuron model by means of an enhanced time varying conductance resulted in the temporary inhibition of the action potential generation. The inhibition time is a function of the level of poration, the pore resealing time and the background stimulation level of the neuron. Such results suggest that the neuronal activity may be efficiently modulated by the delivery of repeated pulses. This opens the way to the use of nsPEFs as a stimulation technique alternative to the conventional direct electric stimulation for medical applications such as chronic pain treatment. PMID- 23366450 TI - Automatic system for electroporation of adherent cells growing in standard multi well plates. AB - In this study an automatic system is presented to perform electroporation, also known as electropermeabilization, on adherent cells. It is an intention of this system to apply electric field pulses directly to cells growing in standard multi well plates as a step forward to include this technique in standard laboratory protocols. An interdigitated microelectrode assembly constructed with Printed Circuit Board (PCB) is placed closely above the cell monolayer, and in order to avoid direct contact with cells, small micro-separators were included in the structure. Additionally, distribution of current density was modified by filling the gap between adjacent electrodes with a non conductive material as predicted by electric field simulations. This modification helps to concentrate the electric field intensity in the region where cells are present. The device was tested using C2C12 cell line growing adhered in 24 multi-well plates and fluorescent labeled dextran FD20S as the molecule to be delivered. Successful transfection was observed with minimal invasiveness of the operation reducing the stress caused to cells. PMID- 23366451 TI - Towards a predictive model of electroporation-based therapies using pre-pulse electrical measurements. AB - Electroporation-based therapies have been gaining momentum as minimally invasive techniques to facilitate transport of exogenous agents, or directly kill tumors and other undesirable tissue in a non-thermal manner. Typical procedures involve placing electrodes into or around the treatment area and delivering a series of short and intense electric pulses to the tissue/tumor. These pulses create defects in the cell membranes, inducing non-linear changes in the electric conductivity of the tissue. These dynamic conductivity changes redistribute the electric field, and thus the treatment volume. In this study, we develop a statistical model that can be used to determine the baseline conductivity of tissues prior to electroporation and is capable of predicting the non-linear current response with implications for treatment planning and outcome confirmation. PMID- 23366452 TI - Gene delivery by microfluidic flow-through electroporation based on constant DC and AC field. AB - Electroporation is one of the most widely used physical methods to deliver exogenous nucleic acids into cells with high efficiency and low toxicity. Conventional electroporation systems typically require expensive pulse generators to provide short electrical pulses at high voltage. In this work, we demonstrate a flow-through electroporation method for continuous transfection of cells based on disposable chips, a syringe pump, and a low-cost power supply that provides a constant voltage. We successfully transfect cells using either DC or AC voltage with high flow rates (ranging from 40 ul/min to 20 ml/min) and high efficiency (up to 75%). We also enable the entire cell membrane to be uniformly permeabilized and dramatically improve gene delivery by inducing complex migrations of cells during the flow. PMID- 23366453 TI - On-chip electroporation: characterization, modeling and experimental results. AB - In this paper, we describe an on-chip electroporation (EP) method for high precision nano-injection of bio-molecules into single cells. EP is an electrical stimulation method to create nano-pores on the cell plasma membrane. Herein, we first put forward the computational models of the cultured cells microelectrodes. We thereafter discuss practical considerations by demonstrating the preliminary experimental results. The mouse fibroblast cells are cultured above electrodes while experiencing a low frequency (10 Hz) electrical field (EF) in the presence of propidium iodide (PI). PMID- 23366454 TI - Pulse rate estimation using hydraulic bed sensor. AB - We propose in this paper an effective method to obtain the pulse rate from a hydraulic sensor that is placed under the mattress. The sensor captures the superposition of the ballistocardiogram (BCG) and the respiration signals. The BCG is modeled as the j-peak with a frequency modulation component. The proposed method utilizes the Hilbert transform to effectively capture the j-peak, which allows the pulse rate information to come out distinctively in the frequency domain. Among the five subjects tested, the error in pulse rate estimation is less than 1%. PMID- 23366455 TI - Estimation of central aortic pressure waveform features derived from the brachial cuff volume displacement waveform. AB - There is increasing interest in non-invasive estimation of central aortic waveform parameters in the clinical setting. However, controversy has arisen around radial tonometric based systems due to the requirement of a trained operator or lack of ease of use, especially in the clinical environment. A recently developed device utilizes a novel algorithm for brachial cuff based assessment of aortic pressure values and waveform (SphygmoCor XCEL, AtCor Medical). The cuff was inflated to 10 mmHg below an individual's diastolic blood pressure and the brachial volume displacement waveform recorded. The aortic waveform was derived using proprietary digital signal processing and transfer function applied to the recorded waveform. The aortic waveform was also estimated using a validated technique (radial tonometry based assessment, SphygmoCor, AtCor Medical). Measurements were taken in triplicate with each device in 30 people (17 female) aged 22 to 79 years of age. An average for each device for each individual was calculated, and the results from the two devices were compared using regression and Bland-Altman analysis. A high correlation was found between the devices for measures of aortic systolic (R(2)=0.99) and diastolic (R(2)=0.98) pressure. Augmentation index and subendocardial viability ratio both had a between device R(2) value of 0.82. The difference between devices for measured aortic systolic pressure was 0.5+/-1.8 mmHg, and for augmentation index, 1.8+/ 7.0%. The brachial cuff based approach, with an individualized sub-diastolic cuff pressure, provides an operator independent method of assessing not only systolic pressure, but also aortic waveform features, comparable to existing validated tonometric-based methods. PMID- 23366456 TI - Automatic identification and accurate temporal detection of inhalations in asthma inhaler recordings. AB - Asthma is chronic airways disease characterized by recurrent attacks of breathlessness and wheezing. Adherence to medication regimes is a common failing for asthmatic patients and there exists a requirement to monitor such patients' adherence. The detection of inhalations from recordings of inhaler use can provide empirical evidence about patients' adherence to their asthma medication regime. Manually listening to recordings of inhaler use is a tedious and time consuming process and thus an algorithm which can automatically and accurately carry out this task would be of great value. This study employs a recording device attached to a commonly used dry powder inhaler to record the acoustic signals of patients taking their prescribed medication. An algorithm was developed to automatically detect and accurately demarcate inhalations from the acoustic signals. This algorithm was tested on a dataset of 255 separate recordings of inhaler use in real world environments. The dataset was obtained from 12 asthma outpatients who attended a respiratory clinic over a three month period. Evaluation of the algorithm on this dataset achieved sensitivity of 95%, specificity of 94% and an accuracy of 89% in detecting inhalations compared to manual inhalation detection. PMID- 23366457 TI - Silent aspiration detection by breath and swallowing sound analysis. AB - Detecting aspiration after swallows (the entry of bolus into trachea) is often a difficult task particularly when the patient does not cough; those are called silent aspiration. In this study, the application of acoustical analysis in detecting silent aspiration is investigated. We recorded the swallowing and the breath sounds of 10 individuals with swallowing disorders, who demonstrated silent aspiration during the fiberoptic endoscopic evaluation of swallowing (FEES) assessment. We analyzed the power spectral density (PSD) of the breath sound signals following each swallow; the PSD showed higher magnitude at low frequencies for the breath sounds following an aspiration. Therefore, we divided the frequency range below 300 Hz into 3 sub-bands, over which we calculated the average power as the characteristic features for the classification purpose. Then, the fuzzy k-means unsupervised classification method was deployed to find the two clusters in the data set: the aspirated and non-aspirated groups. The results were evaluated using the FEES assessments provided by the speech language pathologists. The results show 82.3% accuracy in detecting swallows with silent aspiration. Although the proposed method should be verified on a larger dataset, the results are promising for the use of acoustical analysis as a clinical tool to detect silent aspiration. PMID- 23366458 TI - Detection of motion artifacts in photoplethysmographic signals based on time and period domain analysis. AB - The presence of motion artifacts in the photoplethysmographic (PPG) signals is one of the major obstacles in the extraction of reliable cardiovascular parameters in real time and continuous monitoring applications. In the current paper we present an algorithm for motion artifact detection, which is based on the analysis of the variations in the time and period domain characteristics of the PPG signal. The extracted features are ranked using a feature selection algorithm (NMIFS) and the best features are used in a Support Vector Machine classification model to distinguish between clean and corrupted sections of the PPG signal. The results achieved by the current algorithm (SE: 0.827 and SP: 0.927) show that both time and especially period domain features play an important role in the discrimination of motion artifacts from clean PPG pulses. PMID- 23366459 TI - Empirical mode decomposition of respiratory inductive plethysmographic signals for stroke volume variations monitoring: respiratory protocol and comparison with impedance cardiography. AB - We investigate Respiratory Inductive Plethysmography (RIP) to estimate cardiac activity from thoracic volume variations and study cardio-respiratory interactions. The objective of the present study is to evaluate the ability of RIP to monitor stroke volume (SV) variations, with reference to impedance cardiography (IMP). Five healthy volunteers in seated and supine positions were asked to blow into a manometer in order to induce significant SV decreases. Time scale analysis was applied on calibrated RIP signals to extract cardiac volume signals. Averaged SV values, in quasi-stationary states at rest and during the respiratory maneuvers, were then estimated from these cardiac signals and from IMP signals simultaneously acquired. SV variations between rest and maneuvers were finally evaluated for both techniques. We show that SV values as well as SV variations are correlated between RIP and IMP estimations, suggesting that RIP could be used for SV variations monitoring. PMID- 23366460 TI - Highly accurate classification of postures and activities by a shoe-based monitor through classification with rejection. AB - Monitoring human beings' major daily activities is important for many biomedical studies. Some monitoring applications may require highly reliable identification of certain postures and activities with desired accuracies well above 99% mark. This paper suggests a method for performing highly accurate classification of postures and activities from data collected by a wearable shoe monitor (SmartShoe) through classification with rejection. The classifier used in this study is support vector machines that uses posterior probability based on the distance of an observation to the separating hyperplane to reject unreliable observations. The results show that a significant improvement (from 95.2% +/- 3.5% to 99% +/- 1%) of the classification accuracy has been reached after the rejection, as compared to the accuracy reported previously. Such an approach will be especially beneficial in application where high accuracy of recognition is desired while not all observations need to be assigned a class label. PMID- 23366461 TI - Augmenting the decomposition of EMG signals using supervised feature extraction techniques. AB - Electromyographic (EMG) signal decomposition is the process of resolving an EMG signal into its constituent motor unit potential trains (MUPTs). In this work, the possibility of improving the decomposing results using two supervised feature extraction methods, i.e., Fisher discriminant analysis (FDA) and supervised principal component analysis (SPCA), is explored. Using the MUP labels provided by a decomposition-based quantitative EMG system as a training data for FDA and SPCA, the MUPs are transformed into a new feature space such that the MUPs of a single MU become as close as possible to each other while those created by different MUs become as far as possible. The MUPs are then reclassified using a certainty-based classification algorithm. Evaluation results using 10 simulated EMG signals comprised of 3-11 MUPTs demonstrate that FDA and SPCA on average improve the decomposition accuracy by 6%. The improvement for the most difficult to-decompose signal is about 12%, which shows the proposed approach is most beneficial in the decomposition of more complex signals. PMID- 23366462 TI - Muscle categorization using PDF estimation and Naive Bayes classification. AB - The structure of motor unit potentials (MUPs) and their times of occurrence provide information about the motor units (MUs) that created them. As such, electromyographic (EMG) data can be used to categorize muscles as normal or suffering from a neuromuscular disease. Using pattern discovery (PD) allows clinicians to understand the rationale underlying a certain muscle characterization; i.e. it is transparent. Discretization is required in PD, which leads to some loss in accuracy. In this work, characterization techniques that are based on estimating probability density functions (PDFs) for each muscle category are implemented. Characterization probabilities of each motor unit potential train (MUPT) are obtained from these PDFs and then Bayes rule is used to aggregate the MUPT characterization probabilities to calculate muscle level probabilities. Even though this technique is not as transparent as PD, its accuracy is higher than the discrete PD. Ultimately, the goal is to use a technique that is based on both PDFs and PD and make it as transparent and as efficient as possible, but first it was necessary to thoroughly assess how accurate a fully continuous approach can be. Using gaussian PDF estimation achieved improvements in muscle categorization accuracy over PD and further improvements resulted from using feature value histograms to choose more representative PDFs; for instance, using log-normal distribution to represent skewed histograms. PMID- 23366463 TI - Low-cost intracortical spiking recordings compression with classification abilities for implanted BMI devices. AB - Within Brain-Machine Interface systems, cortically implanted microelectrode arrays and associated hardware have a low power budget for data sampling, processing and transmission. It is already possible to reduce neural data rates by on-site spike detection; we propose a method to further compress spiking data at a low computational cost, with the objective of maintaining clustering and classification abilities. The method relies on random binary vector projections, and simulations show that it is possible to achieve a compression ratio of 5 at virtually no cost in terms of classification errors. PMID- 23366464 TI - Whitening of the electromyogram for improved classification accuracy in prosthesis control. AB - The electromyogram (EMG) signal has been used as the command input to myoelectric prostheses. A common control scheme is based on classifying the EMG signals from multiple electrodes into one of several distinct classes of user intent/function. In this work, we investigated the use of EMG whitening as a preprocessing step to EMG pattern recognition. Whitening is known to decorrelate the EMG signal, with improved performance shown in the related applications of EMG amplitude estimation and EMG-torque processing. We reanalyzed the EMG signals recorded from 10 electrodes placed circumferentially around the forearm of 10 intact subjects and 5 amputees. The coefficient of variation of two time-domain features--mean absolute value and signal length--was significantly reduced after whitening. Pre whitened classification models using these features, along with autoregressive power spectrum coefficients, added approximately five percentage points to their classification accuracy. Improvement was best using smaller window durations (<100 ms). PMID- 23366465 TI - Quantification of physiological kinetic tremor and its correlation with aging. AB - Tremor is the most common movement disorder characterized by repetitive and stereotyped movements. The analysis of hand-drawing movements is commonly used in the evaluation of patients with tremor. The data collection conducted under kinetic conditions and while performing a voluntary movement highlights the kinetic tremor. Most investigations on tremor attempt to understand its relation to neuromuscular dysfunctions. Therefore, there is a lack of studies that aim to investigate the complex relation between the physiological tremor and aging, especially in kinetic conditions. In this context, the main motivation of this research was to generalize the results obtained in Almeida et al., a study that quantified age-related changes in the kinetic tremor of clinically healthy individuals. For this, a number of features extracted from tremor activity, obtained from digitized drawings of Archimedes' spirals, were analyzed. The analyses followed the sequence: Linearization of the Archimedes' spiral; Estimate of tremor activity; Data pre-processing; Feature extraction from the tremor activity; and Application of Linear Discriminant Analysis (LDA) technique as described in Almeida et al.. The generalization of the obtained results showed that the method based on LDA allows for a linear correlation between physiological kinetic tremor and aging. PMID- 23366466 TI - Localization and detection of breast cancer tumors with digital image elasto tomography. AB - Digital Image Elasto-Tomography (DIET) is a novel elastic contrast based breast imaging method using time-harmonic motion data obtained from a calibrated array of high resolution digital cameras scanning the tissue surface. The method is currently undergoing initial clinical testing and preliminary results in cases of malignant breast tumors are now available. The method has proved capable of detecting and localizing the stiff lesions within the heterogeneous tissue structure of the beast through the use of an evolution based optimization algorithm implemented in linear finite elements. The method has also proved successful at detecting both inclusion and non-inclusion cases in specially constructed tissue mimicking silicon phantoms. PMID- 23366467 TI - Nanodiamond imaging: a new molecular imaging approach. AB - A new molecular imaging approach is proposed that combines optical detection and magnetic field gradients to achieve high sensitivity and high spatial resolution. Called Nanodiamond Imaging, this new modality images the location of nanodiamonds within a living organism. Since nanodiamonds can be tagged with biologically active molecules and are nontoxic, Nanodiamond Imaging may become an important biomedical research tool with possible clinical application. A Nanodiamond Imaging system actually senses a particular type of defect in the nanodiamond called the nitrogen-vacancy center. A prototype system has been built that was tested by imaging an artificial target within a volume of chicken breast. The resolving power should be <100 um with modest improvements, significantly finer than PET, SPECT, and in-vivo optical imaging. The sensitivity of the imaging system, taking into account foreseen improvements, should be better than a 10 nanomolar concentration of carbon atoms, referenced to a 1 mm(3) voxel volume and one second of measurement time (10 nM.mm(3).Hz(-1/2))--a similar sensitivity to the other molecular imaging techniques, but with a stable, non-radioactive tracer. PMID- 23366468 TI - Frequency-domain measurement of neuronal activity using dynamic optical coherence tomography. AB - We report preliminary results on high-resolution in vivo imaging of fast intrinsic optical signals of neuronal activity in the frequency domain. An optical coherence tomography (OCT) system was used for dynamic imaging of the cross section of rodent somatosensory cortex at 250 frame/s. Neurons in the cortex were excited by contralateral forepaw stimulation, and the ipsilateral forepaw was stimulated as a control. Hemodynamic responses at the cortical surface, which were simultaneously measured using a CCD, confirmed that forepaw stimulation properly evoked neuronal activation. Analysis of the OCT signal in the frequency domain resulted in that the spectrum significantly increased at the stimulation frequency during activation. This spectrum change was only observed during contralateral stimulation and highly localized at the stimulation frequency in the frequency space. Therefore, the spectrum change we observed is likely associated with neuronal activation. PMID- 23366469 TI - 3D reconstruction of coronary arteries using frequency domain optical coherence tomography images and biplane angiography. AB - The aim of this study is to describe a new method for three-dimensional (3D) reconstruction of coronary arteries using Frequency Domain Optical Coherence Tomography (FD-OCT) images. The rationale is to fuse the information about the curvature of the artery, derived from biplane angiographies, with the information regarding the lumen wall, which is produced from the FD-OCT examination. The method is based on a three step approach. In the first step the lumen borders in FD-OCT images are detected. In the second step a 3D curve is produced using the center line of the vessel from the two biplane projections. Finally in the third step the detected lumen borders are placed perpendicularly onto the path based on the centroid of each lumen border. The result is a 3D reconstructed artery produced by all the lumen borders of the FD-OCT pullback representing the 3D arterial geometry of the vessel. PMID- 23366470 TI - Assessment of microcirculatory effects of glycine by intravital microscopy in rats. AB - Experimental studies using laboratory animal models have shown a potential vasoactive effect of natural metabolites such as glycine. The present study used intravital microscopy in laboratory rat models to study the microcirculation in the brain pial and mesentery vessels. To investigate the pial microvasculature, a stereotaxis-like animal fixing device was used. The intravital microscopy unit consisted of a binocular microscope equipped with a digital photo-video camera, processor, monitor and printer. Using reflected light, a special contact lens with an amplified focus depth provided high-resolution images of nontransparent tissue objects that typically have insufficient light exposure. Glycine had a vasodilatory effect on microvessels in the rat brain and mesenterium. The diameter of pial arterioles increased after glycine application especially markedly (up to 250% of initial size). These changes were not observed when physiological saline was used. Even a very small amount of glycine (a drop on the needle) was sufficient to stop the early stages of histamine-induced blood stasis development in 3-5 s in mesenterial microvessels. The vasodilatory effect of glycine on the pial microcirculation correlates with its reported positive therapeutic effect in cerebral ischemic stroke. The ability of glycine to avoid or prevent histamine-induced microcirculatory alterations in mesenterial microvessels may have potential clinical applications. PMID- 23366471 TI - Imaging the early cerebral blood flow changes in rat middle cerebral artery occlusion stroke model. AB - Intraluminal middle cerebral artery occlusion (MCAO) model in rats has been widely used to mimic human ischemic stroke and serves as an indispensable tool in the stroke research field. One limitation of this model is its high variability in infarct volume. The cerebral blood flow (CBF) information after cerebrovascular occlusion may reflect the availability of collateral circulation, which serves as a key factor for brain infarct volume. Laser speckle contrast imaging (LSCI) is a valuable tool for full-field imaging of CBF with high spatial and temporal resolution. In this paper, we investigated the spatio-temporal changes of CBF in rat MCAO stroke model using our self-developed real-time LSCI system. CBF images of adult male Sprague Dawley rats (n=13) were recorded before surgery, during first 1.5 hours after surgery, and 24 hours after stroke. We compared the CBF changes of different functional vessels during this period. In the ipsilateral hemisphere, CBF of veins and arteries both decreased as expected, while CBF of veins increased after occlusion in the contralateral hemisphere. Moreover, we found a linear correlation between early-stage CBF after occlusion and brain infarct volume, which can be utilized for surgery guidance to improve the uniformity of rat MCAO stroke models. PMID- 23366472 TI - AREA: an augmented reality system for epidural anaesthesia. AB - PURPOSE: Spinal needle injection procedures are used for anesthesia and analgesia, such as lumbar epidurals. These procedures require careful placement of a needle, both to ensure effective therapy delivery and to avoid damaging sensitive tissue such as the spinal cord. An important step in such procedures is the accurate identification of the vertebral levels, which is currently performed using manual palpation with a reported 30% success rate for correct identification. METHODS: An augmented reality system was developed to help identify the lumbar vertebral levels. The system consists of an ultrasound transducer tracked in real time by a trinocular camera system, an automatic ultrasound panorama generation module that provides an extended view of the lumbar vertebrae, an image processing technique that automatically identifies the vertebral levels in the panorama image, and a graphical interface that overlays the identified levels on a live camera view of the patient's back. RESULTS: Validation was performed on ultrasound data obtained from 10 subjects with different spine arching. The average success rate for segmentation of the vertebrae was 85%. The automatic level identification had an average accuracy of 6.6 mm. CONCLUSION: The prototype system demonstrates better accuracy for identifying the vertebrae than traditional manual methods. PMID- 23366473 TI - Ultrasound bone detection using patient-specific CT prior. AB - Registration of pre-operative CT datasets to intra-operative 3D freehand ultrasound has been of high interest for computer assisted orthopedic surgery. Feature-based registration relies on an accurate detection of the bone surface in the B-mode ultrasound images. In this work we present a fully automatic bone detection approach for US. The pre-operative CT is utilized to create a patient specific bone model for our joint detection-registration framework. The model provides a geometric constraint for accurate and robust detection. Simultaneously to the detection, our method yields a close estimate of the rigid transformation from US to CT, which can be used as an initialization for further refinement through sophisticated intensity-/feature-based registration methods. We evaluated our approach on datasets of the human femur acquired in a cadaver study and demonstrate a mean bone detection error of below 0.4 mm. PMID- 23366474 TI - Carotid IMT variability (IMTV): its design and validation in symptomatic vs. asymptomatic 142 Italian population. AB - The carotid intima-media thickness (IMT) is a validated marker of cerebrovascular disease risk. This work presents a new parameter, the IMT variability (IMTV), and compares the IMT and IMTV in symptomatic and asymptomatic Italian patients. 142 patients were analyzed (age 59+/-11.2 years, 59% males), 42 of which suffered from TIA (transient ischemic attack) or minor stroke. The lumen-intima (LI) and media-adventitia (MA) interfaces were manually traced by a Reader, and automatically traced by an automated system (AutoEdge). These interfaces were then used to measure the IMT and IMTV along the carotid wall. Wilcoxon and Pearson correlation analyses were performed. There was about a 65% correlation between the manual and automated measurements of IMT. There was no statistical difference between the manual and automated IMTV measurements (Wilcoxon signed rank, p>0.7). The observed mean IMT for symptomatic patients (0.83+/-0.44 mm for Reader vs. 0.82+/-0.35 mm for AutoEdge) was higher compared to asymptomatic patients (0.78+/-0.45 mm for Reader vs. 0.74+/-0.30 mm for AutoEdge). The symptomatic IMTV was about 11% higher than the asymptomatic IMTV when using Reader tracings and 8% higher when using AutoEdge. AutoEdge was very accurate in measuring the IMT and IMTV both for symptomatic and asymptomatic patients. Results showed that the symptomatic subjects had comparable IMT with respect to asymptomatic subjects, but a higher IMTV value. PMID- 23366475 TI - Quantitative ultrasound spectral parametric maps: early surrogates of cancer treatment response. AB - Textural characteristics of quantitative ultrasound spectral parametric maps have been proposed for the first time to predict cancer therapy response, early following treatment initiation. Such an early prediction can facilitate personalized medicine in cancer treatment procedures. Patients (n=10) with locally advanced breast cancer received neo-adjuvant chemotherapy, as "up-front" treatment, followed by mastectomy with axillary nodal clearance. Data collection consisted of acquiring tumor ultrasound radio-frequency data prior to neo adjuvant treatment onset and at 4 times during treatment, in addition to pathological examinations of resected specimens after mastectomy. Several textural features were extracted from parametric maps of mid-band fit and 0-MHz intercept. The relative changes of these features were calculated one week after the treatment commenced, compared to the pre-treatment scan. Statistical analysis performed suggested that five of the applied textural features exhibit statistically significant differences between clinically/pathologically responding and non-responding patients. The promising results obtained represent a substantial step forward towards customizing cancer therapies by using this quantitative imaging modality. This can facilitate the switch of an ineffective treatment for a specific patient to a salvage therapy within weeks, instead of having patient endures months of the ineffective treatment. PMID- 23366476 TI - Evaluation of vortex flow in left ventricle by echo-dynamography and phase contrast magnetic resonance angiography. AB - Echo-dynamography (EDG) is a method for visualizing left ventricular (LV) blood flow based on cardiac Doppler measurement in which blood flow component perpendicular to the ultrasonic beam is deduced by applying fluid dynamics theories to two-dimensional (2D) distribution of blood flow component along the ultrasonic beam. EDG has been validated by numerical simulation and particle image velocimetry of model circulation. However, these validations were too simple to reproduce unstable and asymmetrical flow in a beating heart. In the present study, EDG is compared with three-directional (3D) blood flow distribution on the same plane obtained with phase contrast magnetic resonance angiography (PCMRA) for clinical validation. Moreover, the location and vorticity of the vortex flow in LV are measured quantitatively and the relation to echocardiographic parameters of systolic and diastolic functions is discussed. 3D components of blood flow on a plane were obtained with triple scans of the same plane with ECG trigger and breath holding; 1) phase encode (x-axis), 2) read out (y-axis) and 3) slice selection (z-axis). After the acquisition of MRA dataset, color Doppler dataset of the same plane was acquired and 2D velocity distribution was obtained with EDG in MATLAB programs. EDG and PCMRA showed similar velocity vector distribution and formation of LV vortex flow. The vortex at mid diastolic phase was strongly affected by early diastolic filling while the vortex at isometric contraction was affected by atrial filling. EDG gained a new insight on systolic-diastolic coupling from the view point of LV blood flow such as LV vortex formation. PMID- 23366477 TI - Brain shape regression components. AB - Identifying associations between the shape properties of brain regions, measured from magnetic resonance imaging (MRI), and numerical measures of neurodegenerative disease burden can clarify whether disease processes lead to distinctive spatial patterns of brain atrophy. However, prior methods for identifying such associations between shape and clinical variables either failed to summarize shape patterns into a concise set of summary measurements, or risked failing to discover such associations by extracting summary shape features blinded to the clinical variables. We present a method that overcomes these limitations by directly searching for a small set of linear shape features--shape regression components--that simultaneously account for a large amount of population shape variability and are highly correlated with a numerical clinical variable of interest. When applied to hippocampi of 299 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, the method identified correlations between hippocampal atrophy and markers of AD pathology and cogniton that were stronger than, and covered a more extended spatial region than, those identified by competing approaches. PMID- 23366478 TI - Most edges in Markov random fields for white matter hyperintensity segmentation are worthless. AB - The time and space complexities of Markov random field (MRF) algorithms for image segmentation increase with the number of edges that represent statistical dependencies between adjacent pixels. This has made MRFs too computationally complex for cutting-edge applications such as joint segmentation of longitudinal sequences of many high-resolution magnetic resonance images (MRIs). Here, we show that simply removing edges from full MRFs can reduce the computational complexity of MRF parameter estimation and inference with no notable decrease in segmentation performance. In particular, we show that for segmentation of white matter hyperintensities in 88 brain MRI scans of elderly individuals, as many as 66% of MRF edges can be removed without substantially degrading segmentation accuracy. We then show that removing edges from MRFs makes MRF parameter estimation and inference computationally tractable enough to enable modeling statistical dependencies within and across a larger number of brain MRI scans in a longitudinal series; this improves segmentation performance compared to separate segmentations of each individual scan in the series. PMID- 23366479 TI - Classification of individuals based on sparse representation of brain cognitive patterns: a functional MRI study. AB - Many neurological disorders can change patterns of brain activity observed in functional imaging studies. These functional differences may be useful for classification of individuals into diagnostic categories. However, due to the high dimensionality of the input feature space and small set of subjects that are usually available, classification based on fMRI data is not trivial. Here, we evaluate the use of a Sparse Representation Analysis method within a Fisher Linear Discriminant (FLD) classification method, taking functional patterns characteristic of different cognitive tasks as the data input. As a test dataset, with a clear 'gold-standard' classification, we attempt to classify individuals as young, or older, based only on functional activation patterns in a speech listening task. Thirty two young (age: 19-26) and older (age: 57-73) adults (16 each) were scanned while listening to noise and to sentences degraded with noise, half of which contained meaningful context that could be used to enhance intelligibility. Different functional contrast images were used within K-SVD to generate basis activation sources and their corresponding sparse modulation profiles. Sparse modulation profiles were used in a FLD framework to classify individuals into the young and older categories. The results demonstrate the feasibility of the general approach, and confirm the potential applicability of the proposed method for real-world diagnostic problems. PMID- 23366480 TI - Three-way FMRI-DTI-methylation data fusion based on mCCA+jICA and its application to schizophrenia. AB - Multi-modal fusion is an effective approach in biomedical imaging which combines multiple data types in a joint analysis and overcomes the problem that each modality provides a limited view of the brain. In this paper, we propose an exploratory fusion model, we term "mCCA+jICA", by combining two multivariate approaches: multi-set canonical correlation analysis (mCCA) and joint independent component analysis (jICA). This model can freely combine multiple, disparate data sets and explore their joint information in an accurate and effective manner, so that high decomposition accuracy and valid modal links can be achieved simultaneously. We compared mCCA+jICA with its alternatives in simulation and applied it to real fMRI-DTI-methylation data fusion, to identify brain abnormalities in schizophrenia. The results replicate previous reports and add to our understanding of the neural correlates of schizophrenia, and suggest more generally a promising approach to identify potential brain illness biomarkers. PMID- 23366481 TI - Dual-modal visibility metrics for interactive PET-CT visualization. AB - Dual-modal positron emission tomography and computed tomography (PET-CT) imaging enables the visualization of functional structures (PET) within human bodies in the spatial context of their anatomical (CT) counterparts, and is providing unprecedented capabilities in understanding diseases. However, the need to access and assimilate the two volumes simultaneously has raised new visualization challenges. In typical dual-modal visualization, the transfer functions for the two volumes are designed in isolation with the resulting volumes being fused. Unfortunately, such transfer function design fails to exploit the correlation that exists between the two volumes. In this study, we propose a dual-modal visualization method where we employ 'visibility' metrics to provide interactive visual feedback regarding the occlusion caused by the first volume on the second volume and vice versa. We further introduce a region of interest (ROI) function that allows visibility analyses to be restricted to subsection of the volume. We demonstrate the new visualization enabled by our proposed dual-modal visibility metrics using clinical whole-body PET-CT studies of various diseases. PMID- 23366482 TI - Characterizing non-linear dependencies among pairs of clinical variables and imaging data. AB - Advances in computer-aided diagnosis (CAD) systems have shown the benefits of using computer-based techniques to obtain quantitative image measurements of the extent of a particular disease. Such measurements provide more accurate information that can be used to better study the associations between anatomical changes and clinical findings. Unfortunately, even with the use of quantitative image features, the correlations between anatomical changes and clinical findings are often not apparent and definite conclusions are difficult to reach. This paper uses nonparametric exploration techniques to demonstrate that even when the associations between two-variables seems weak, advanced properties of the associations can be studied and used to better understand the relationships between individual measurements. This paper uses quantitative imaging findings and clinical measurements of 85 patients with pulmonary fibrosis to demonstrate the advantages of non-linear dependency analysis. Results show that even when the correlation coefficients between imaging and clinical findings seem small, statistical measurements such as the maximum asymmetry score (MAS) and maximum edge value (MEV) can be used to better understand the hidden associations between the variables. PMID- 23366483 TI - Detection of acute myocardial infarction from serial ECG using multilayer support vector machine. AB - Acute Myocardial Infarction (AMI) remains a leading cause of mortality in the United States. Finding accurate and cost effective solutions for AMI diagnosis in Emergency Departments (ED) is vital. Consecutive, or serial, ECGs, taken minutes apart, have the potential to improve detection of AMI in patients presented to ED with symptoms of chest pain. By transforming the ECG into 3 dimensions (3D), computing 3D ECG markers, and processing marker variations, as extracted from serial ECG, more information can be gleaned about cardiac electrical activity. We aimed at improving AMI diagnostic accuracy relative to that of expert cardiologists. We utilized support vector machines in a multilayer network, optimized via a genetic algorithm search. We report a mean sensitivity of 86.82%+/-4.23% and specificity of 91.05%+/-2.10% on randomized subsets from a master set of 201 patients. Serial ECG processing using the proposed algorithm shows promise in improving AMI diagnosis in Emergency Department settings. PMID- 23366484 TI - Cardiac output estimation in mechanically ventilated patients: a comparison between prolonged expiration method and thermodilution. AB - A non-invasive method to estimate cardiac output (CO) in mechanically ventilated patients, based on prolonged expiration, has been previously described. With the aim to assess its performances, we prospectively enrolled fifteen cardiac surgery patients, and compared the results obtained with the non-invasive method with the ones obtained using two invasive approaches based on thermodilution. The correlations between the prolonged expiration method with both the thermodilution based ones show high values (rho(2)>0.77 and rho(2)>0.89). This encouraging agreement is also confirmed by the closeness between the measured values of CO: the mean differences considering all patients and the two reference invasive techniques are -0.8 % and -7.5 %. These values show the slight underestimation of CO by the proposed non-invasive method with respect to the gold standard. On the other hand the described method could represent a good compromise between accuracy and non-invasiveness, which fosters the implementation of a new monitoring tool suitable for a semi-continuous CO assessment. PMID- 23366485 TI - Development of an automatic electronic system to human blood typing. AB - Blood typing has a vital contribution to the success of life-saving procedures, such as blood transfusions, and it can be critical, especially in emergency situations. For that, in this paper the main principles to the development of a miniaturized, low cost, portable and automatic system to human blood typing, in emergency situations, are presented. In a previous study, the authors validated a general experimental protocol to be applied in the automatic system. Now, the implementation of a specific light source system by using standard Light Emission Diodes (LEDs) was studied. Moreover, the specification of all electronic components to be used in the prototype device was performed. PMID- 23366486 TI - Identification of hypoglycemia and hyperglycemia in type 1 diabetic patients using ECG parameters. AB - Hypoglycemia and Hyperglycemia are both serious diseases related to diabetes mellitus. Among Type 1 Diabetic patients, there are who experience both hypoglycemic and hyperglycemic events. The aim of this study was to identify of hypoglycemia and hyperglycemia based on ECG changes in this population. An ECG Acquisition and Analysis System based on LabVIEW software has been developed for collecting ECG signals and extracting features with abnormal changes. ECG parameters included Heart rate (HR), corrected QT interval (QTeC), PR interval, corrected RT interval (RTC) and corrected TpTe interval (TpTe(C)). Blood glucose levels were used to classify glycemic states in subjects as hypoglycemic state (<= 60 mml/l, Hypo), as normoglycemic state (80 to 110 mmol/l, Normo), and as hyperglycemic state 150 mml/l, Hyper). The results indicated that hypoglycemic and hyperglycemic states produce significant inverse changes on those ECG parameters. PMID- 23366487 TI - Statistical error detection for clinical laboratory tests. AB - Errors in clinical laboratory tests lead to increased costs and patient risks. Such errors are relatively rare, affecting ~0.5% of samples. Existing techniques for detecting errors have either far too low sensitivity or specificity to be useful. This preliminary study develops statistical sample selection criteria that capture faults upwards of fifty times more efficiently than expected from random sampling. Although this is only the first step towards an integrated discriminant system for reliable detection of laboratory errors, the statistical detection scheme demonstrated here outperforms existing methods. PMID- 23366488 TI - A wearable vital signs monitor at the ear for continuous heart rate and pulse transit time measurements. AB - A continuous, wearable and wireless vital signs monitor at the ear is demonstrated. The device has the form factor of a hearing aid and is wirelessly connected to a PC for data recording and analysis. The device monitors the electrocardiogram (ECG) in a single lead configuration, the ballistocardiogram (BCG) with a MEMS triaxial accelerometer, and the photoplethysmograms (PPG) with 660 nm and 940 nm LED sources and a static photocurrent subtraction analog front end. Clinical tests are conducted, including Valsalva and head-up tilt maneuvers. Peak timing intervals between the ECG, BCG and PPG are extracted and are shown to relate to pre-ejection period and mean arterial blood pressure (MAP). Pulse Transit Time (PTT) extracted from cross-correlation between the PPG and BCG shows improved results compared to the pulse arrival time (PAT) method for tracking changes in MAP. PMID- 23366489 TI - Asynchronous brain computer interface using hidden semi-Markov models. AB - Ideal Brain Computer Interfaces need to perform asynchronously and at real time. We propose Hidden Semi-Markov Models (HSMM) to better segment and classify EEG data. The proposed HSMM method was tested against a simple windowed method on standard datasets. We found that our HSMM outperformed the simple windowed method. Furthermore, due to the computational demands of the algorithm, we adapted the HSMM algorithm to an online setting and demonstrate that this faster version of the algorithm can run in real time. PMID- 23366490 TI - Online semi-supervised learning with KL distance weighting for motor imagery based BCI. AB - Studies had shown that Motor Imagery-based Brain Computer Interface (MI-based BCI) system can be used as a therapeutic tool such as for stroke rehabilitation, but had shown that not all subjects could perform MI well. Studies had also shown that MI and passive movement (PM) could similarly activate the motor system. Although the idea of calibrating MI-based BCI system from PM data is promising, there is an inherent difference between features extracted from MI and PM. Therefore, there is a need for online learning to alleviate the difference and improve the performance. Hence, in this study we propose an online batch mode semi-supervised learning with KL distance weighting to update the model trained from the calibration session by using unlabeled data from the online test session. In this study, the Filter Bank Common Spatial Pattern (FBCSP) algorithm is used to compute the most discriminative features of the EEG data in the calibration session and is updated iteratively on each band after a batch of online data is available for performing semi-supervised learning. The performance of the proposed method was compared with offline FBCSP, and results showed that the proposed method yielded slightly better results in comparison with offline FBCSP. The results also showed that the use of the model trained from PM for online session-to-session transfer compared to the use of the calibration model trained from MI yielded slightly better performance. The results suggest that using PM, due to its better performance and ease of recording is feasible and performance can be improved by using the proposed method to perform online semi supervised learning while subjects perform MI. PMID- 23366491 TI - A framework for relating neural activity to freely moving behavior. AB - Two research communities, motor systems neuroscience and motor prosthetics, examine the relationship between neural activity in the motor cortex and movement. The former community aims to understand how the brain controls and generates movement; the latter community focuses on how to decode neural activity as control signals for a prosthetic cursor or limb. Both have made progress toward understanding the relationship between neural activity in the motor cortex and behavior. However, these findings are tested using animal models in an environment that constrains behavior to simple, limited movements. These experiments show that, in constrained settings, simple reaching motions can be decoded from small populations of spiking neurons. It is unclear whether these findings hold for more complex, full-body behaviors in unconstrained settings. Here we present the results of freely-moving behavioral experiments from a monkey with simultaneous intracortical recording. We investigated neural firing rates while the monkey performed various tasks such as walking on a treadmill, reaching for food, and sitting idly. We show that even in such an unconstrained and varied context, neural firing rates are well tuned to behavior, supporting findings of basic neuroscience. Further, we demonstrate that the various behavioral tasks can be reliably classified with over 95% accuracy, illustrating the viability of decoding techniques despite significant variation and environmental distractions associated with unconstrained behavior. Such encouraging results hint at potential utility of the freely-moving experimental paradigm. PMID- 23366492 TI - Bayesian learning in assisted brain-computer interface tasks. AB - Successful implementation of a brain-computer interface depends critically on the subject's ability to learn how to modulate the neurons controlling the device. However, the subject's learning process is probably the least understood aspect of the control loop. How should training be adjusted to facilitate dexterous control of a prosthetic device? An effective training schedule should manipulate the difficulty of the task to provide enough information to guide improvement without overwhelming the subject. In this paper, we introduce a bayesian framework for modeling the closed-loop BCI learning process that treats the subject as a bandwidth-limited communication channel. We then develop an adaptive algorithm to find the optimal difficulty-schedule for performance improvement. Simulation results demonstrate that our algorithm yields faster learning rates than several other heuristic training schedules, and provides insight into the factors that might affect the learning process. PMID- 23366493 TI - Time-frequency selection in two bipolar channels for improving the classification of motor imagery EEG. AB - Time and frequency information is essential to feature extraction in a motor imagery BCI, in particular for systems based on a few channels. In this paper, we propose a novel time-frequency selection method based on a criterion called Time frequency Discrimination Factor (TFDF) to extract discriminative event-related desynchronization (ERD) features for BCI data classification. Compared to existing methods, the proposed approach generates better classification performances (mean kappa coefficient= 0.62) on experimental data from the BCI competition IV dataset IIb, with only two bipolar channels. PMID- 23366494 TI - Mutual information analysis on non-stationary neuron importance for brain machine interfaces. AB - Decoding with the important neuron subset has been widely used in brain machine interfaces (BMIs), as an effective strategy to reduce computational complexity. Previous works usually assume stationary of neuron importance, which may not be true according to recent research. We propose to conduct a mutual information evaluation to track the time-varying neuron importance over time. We found worth noting changes both in information amount and space distribution in our experiment. When the method is applied with a Kalman filter, the decoding performance achieve is better (with higher correlation coefficient) than when a fixed subset, which shows that time-varying neuron importance should be considered in adaptive algorithms. PMID- 23366496 TI - Continuous estimation of finger joint angles using muscle activation inputs from surface EMG signals. AB - Prediction of dynamic hand finger movements has many clinical and engineering applications in the control of human interface devices such as those used in virtual reality control, robot prosthesis and rehabilitation aids. Surface electromyography (sEMG) signals have often been used in the mentioned applications because these reflect the motor intention of users very well. In this study, we present a method to estimate the finger joint angles of a hand from sEMG signals that considers electromechanical delay (EMD), which is inherent when EMG signals are captured alongside motion data. We use the muscle activation obtained from the sEMG signals as input to a neural network. In this muscle activation model, the EMD is parameterized and automatically obtained through optimization. With this method, we can predict the finger joint angles with sEMG signals in both periodic and nonperiodic free movements of the flexion and extension movement of the fingers. Our results show correlation as high as 0.92 between the actual and predicted metacarpophalangeal (MCP) joint angles for periodic finger flexion movements, and as high as 0.85 for nonperiodic movements, which are more dynamic and natural. PMID- 23366497 TI - Characterization of a novel instrument for vibration exercise. AB - Vibration exercise (VE) has been suggested as an effective option to improve muscle strength and power performance. Several studies link the effects of vibration training to enhanced neuromuscular stimulation and typically to involuntary reflex mechanisms. However, the underlying mechanisms are still unclear and information for the most appropriate vibration training protocols is limited. This study proposes to realize a new vibration exercise system for the biceps brachii. Amplitude, frequency, and baseline of the vibrating load, which is generated by an electromechanical actuator, can be adjusted dynamically by a feedback control loop. A second-order model is employed to identify the relation between the mechanical load and the input voltage driving the actuator. An adaptive normalized least mean square algorithm is proposed to remove the motion artifacts from the measured electromyography (EMG) data. Our results show a high correlation (0.99) between the second-order model fit and the measured data, permitting accurate control on the supplied load for vibrations up to 80 Hz. Furthermore, preliminary validation with 4 volunteers showed an excellent performance in the motion artifact removal, enabling reliable evaluation of the neuromuscular activation. PMID- 23366498 TI - Feasibility of measuring event related desynchronization with electroencephalography during walking. AB - Brain Computer Interfaces could be useful in rehabilitation of movement, perhaps also for gait. Until recently, research on movement related brain signals has not included measuring electroencephalography (EEG) during walking, because of the potential artifacts. We investigated if it is possible to measure the event Related Desynchronization (ERD) and event related spectral perturbations (ERSP) during walking. Six subjects walked on a treadmill with a slow speed, while EEG, electromyography (EMG) of the neck muscles and step cycle were measured. A Canonical Correlation Analysis (CCA) was used to remove EMG artifacts from the EEG signals. It was shown that this method correctly deleted EMG components. A strong ERD in the mu band and a somewhat less strong ERD in the beta band were found during walking compared to a baseline period. Furthermore, lateralized ERSPs were found, depending on the phase in the step cycle. It is concluded that this is a promising method to use in BCI research on walking. These results therefore pave the way for using brain signals related to walking in a BCI context. PMID- 23366499 TI - Preliminary study of the effect of user intent recognition errors on volitional control of powered lower limb prostheses. AB - Previously developed user-intent-recognition (UIR) systems have demonstrated promising accuracy for identifying the user's locomotion mode, which is potentially useful for volitional control of powered artificial legs in ambulation. The fundamental question facing us now is whether or not the prosthesis users are safe when the UIR system is directly integrated with the intrinsic controller to operate powered artificial legs. In this preliminary study, we aimed to address this question by investigating the effect of UIR errors on the walking stability of users, wearing a UIR-controlled powered transfemoral (TF) prosthesis. First, a novel control of powered prosthesis was developed, which hierarchically connected our designed UIR system with an intrinsic controller. Three types of errors were purposely added into the UIR output at different gait phase while an able-bodied subject walked on a treadmill with the powered prosthesis. Subjective opinions were obtained to evaluate the effect of applied UIR errors on the user's walking balance. The kinematics and kinetics of the prosthetic knee were quantified while the errors occurred. The preliminary results showed that not all the UIR errors applied caused a subjective feeling of balance instability. The effects of UIR errors on the prosthesis control and user's balance depended on the gait phase when the errors happened and the amount of mechanical work applied to the knee joint caused by the errors. The results of this study could aid the future design of true bionic prostheses that enable lower limb amputees to perform various activities intuitively and safely. PMID- 23366500 TI - Reduction of the effect of arm position variation on real-time performance of motion classification. AB - A couple of studies have been conducted with able-bodied subjects and/or arm amputees to investigate the impact of arm position changes in the practical use of a multifunctional myoelectric prosthesis. The classification accuracy calculated offline from electromyography (EMG) recordings was used as a performance metric in these studies, which is not a true measure of real-time control performance. In this study, the influence of arm position changes on the real-time performance of EMG pattern recognition (EMG-PR) control was quantitatively evaluated with four real-time metrics including motion response time, motion completion time, motion completion rate, and dynamic efficiency. Ten able-bodied subjects participated in the study and a cascade classifier built with both EMG and mechanomyogram (MMG) recordings was proposed to reduce the impact of arm position variation. The pilot results showed that arm position changes would substantially affect the real-time performance of EMG pattern recognition based prosthesis control. Using a cascade classifier could significantly increase the average real-time completion rate (p-value<0.01). This suggests that the proposed cascade classifier may have potential to reduce the influence of arm position variation on the real-time control performance of a prosthesis. PMID- 23366501 TI - Efficacy of the hexpolar configuration in localizing the activation of retinal ganglion cells under electrical stimulation. AB - Retinal visual prostheses provide hope of restoring sight to patients suffering from retinal degeneration such as retinitis pigmentosa and age-related macular degeneration. Retinal prostheses are used to electrically stimulate residual neurons that are spared in these diseases, namely the retinal ganglion cells (RGCs), eliciting percepts of light termed 'phosphenes'. The elicitation of multiple phosphenes via an electrode array allows patterns to be produced, resulting in a rudimentary form of vision. For such patterns to be produced effectively, the prosthesis must generate well-defined phosphenes. To this end, the hexpolar configuration has been proposed as an alternative to the traditional monopolar or bipolar configurations. It utilizes six electrodes surrounding the stimulating electrode to serve as a combined return, or 'hex guard', purportedly localizing the activation to cells located within them. In this study, the efficacy of the hexpolar configuration in localizing activity was investigated by using patch-clamp electrophysiology to measure the activation thresholds of RGCs to electrical stimulation in isolated rabbit retina. Cells located outside the hex guard were found to have significantly higher relative hexpolar thresholds (>2 fold) as compared to cells located within the hex guard. This confirms the efficacy of the hexpolar configuration in localizing activity to within the hex guard. Furthermore, the effect of using cathodic-first versus anodic-first stimulation on hexpolar threshold and localization was investigated. No significant difference was observed between the two groups, in terms of lowering thresholds or improving localization. PMID- 23366502 TI - Time-to-contact maps for navigation with a low resolution visual prosthesis. AB - The perception of independently moving objects in the scene is an important capability for prosthetic vision, but is impeded by the limited resolution and dynamic range of current and near-term retinal prostheses. We propose a novel, biologically-inspired visual representation for prosthetic vision based on the recovery of time-to-contact (tau) with surfaces in the scene. The representation directly encodes the extent of motion towards the observer, placing greatest emphasis on objects posing an imminent threat of collision. Our results suggest the proposed tau-based representation may facilitate earlier perception of incoming objects, and provide clearer distinction between moving objects and the static structure of the scene compared with intensity and depth-based scene representations. PMID- 23366503 TI - Hermetic glass soldered micro-packages for a vision prosthesis. AB - Micro-packages based on alumina ceramics hermetically sealed with glass solder were fabricated and tested over a 1.5 years period under accelerated aging at 85 degrees C. A device for sealing the 1.2 mm high, and o10mm packages while cooling the critical centre of the package containing the electronics was developed. Heating of the rim up to 550 degrees C while maintaining the package centre below 300 degrees C was successful, allowing a symmetrical heating of the device during the sealing procedure. The fabricated packages with an inner volume of 0.05 cc were backfilled with helium and tested for hermeticity with a fine leak tester. Samples passing the fine leak (1*10(-12) atm*cc/s) test were attached to a larger chamber containing a humidity sensor. Some devices covered in PDMS and some directly exposed were stored at 85 degrees C in water to measure the humidity intrusion into the device due to deterioration of glass solder. 1 out of the 8 successfully fabricated devices failed after 5 years extrapolated lifetime. Two of the devices have kept constant humidity levels while others gradually rise. Nevertheless, 7 out of 8 have maintained a level below 17,000 ppm humidity. Furthermore, the deterioration of glass solder was electrically and optically studied over a year's period showing no corrosion of glass if properly coated in PDMS. PMID- 23366504 TI - Intrinsic activation of iridium electrodes over a wireless link. AB - Activated Iridium Oxide Film (AIROF) microelectrodes are regarded as advantage for stimulation of neural tissue owing to their superior charge injection capabilities, as compared to other noble-metal based electrodes. Including AIROF electrodes within an implantable neural stimulator can be challenging since the stimulator fabrication steps often involve elevated temperatures at which the AIROF can be damaged. In this work, a wireless neural stimulator application specific-integrated-circuit (ASIC) was used to intrinsically activate iridium microelectrodes. This intrinsic activation allows for the growth of the AIROF as the final assembly step after the entire device is assembled, thus avoiding stress on the AIROF. Since a typical neural stimulator is essentially a current controlled driver with voltage compliance limits, its output waveform can be tuned to match the traditional voltage pulsing/ramp activation waveform. Here the feasibility of the current driven activation of iridium electrodes, over a wireless link, is demonstrated. PMID- 23366505 TI - Image segmentation for enhancing symbol recognition in prosthetic vision. AB - Current and near-term implantable prosthetic vision systems offer the potential to restore some visual function, but suffer from poor resolution and dynamic range of induced phosphenes. This can make it difficult for users of prosthetic vision systems to identify symbolic information (such as signs) except in controlled conditions. Using image segmentation techniques from computer vision, we show it is possible to improve the clarity of such symbolic information for users of prosthetic vision implants in uncontrolled conditions. We use image segmentation to automatically divide a natural image into regions, and using a fixation point controlled by the user, select a region to phosphenize. This technique improves the apparent contrast and clarity of symbolic information over traditional phosphenization approaches. PMID- 23366506 TI - A 232-channel retinal vision prosthesis with a miniaturized hermetic package. AB - Miniaturization of implantable devices while drastically increasing the number of stimulation channels is one of the greatest challenges in implant manufacturing because a small but hermetic package is needed that provides reliable protection for the electronics over decades. Retinal vision prostheses are the best example for it. This paper presents a miniaturized 232-channel vision prosthesis, summarizing the studies on the individual technologies that were developed, improved and combined to fabricate a telemetrically powered retinal device sample. The implantable unit, which is made out of a high temperature co-fired alumina ceramic package containing hermetic feedthroughs, electronic circuitry and a radio frequency coil for powering is manufactured through a modified screen printing/lasering process. The package is sealed with solder glass to provide unaffected inductive coupling to the telemetric transmitter. A 0.05 cc inner volume allows helium leak testing and mathematical lifetime estimations for moisture-induced failure of up to 100 years. The feedthroughs contact a thin-film polyimide electrode array that utilizes DLC and SiC coatings for improved interlayer adhesion of the metallic tracks to the polymer carrier. Two metal layers allow integrated wiring of the electrode array within the very limited space. PMID- 23366507 TI - GPU based real-time surgical navigation system with three-dimensional ultrasound imaging for water-filled laparo-endoscope surgery. AB - Presently, a variety of navigation systems are employed in clinical treatments involving neurosurgery, ENT, orthopedic, and head and neck surgery. An ultrasound diagnostic system is used as the navigation system for movable and deformable organs in the abdomen or chest. In this study, we developed a real-time updated 3D ultrasound navigation system that facilitates the high-speed transfer of image data and GPGPU processing for fetal surgery and water-filled laparo-endoscopic surgery (WAFLES). Experimental results showed that our system was able to update every 62 ms. Further, in vivo experimental results showed the ability of our system to guide a surgeon to a target organ during WAFLES in a case where the endoscopic view experienced problems. PMID- 23366508 TI - New software tools for enhanced precision in robot-assisted laser phonomicrosurgery. AB - This paper describes a new software package created to enhance precision during robot-assisted laser phonomicrosurgery procedures. The new software is composed of three tools for camera calibration, automatic tumor segmentation, and laser tracking. These were designed and developed to improve the outcome of this demanding microsurgical technique, and were tested herein to produce quantitative performance data. The experimental setup was based on the motorized laser micromanipulator created by Istituto Italiano di Tecnologia and the experimental protocols followed are fully described in this paper. The results show the new tools are robust and effective: The camera calibration tool reduced residual errors (RMSE) to 0.009 +/- 0.002 mm under 40* microscope magnification; the automatic tumor segmentation tool resulted in deep lesion segmentations comparable to manual segmentations (RMSE= 0.160 +/- 0.028 mm under 40* magnification); and the laser tracker tool proved to be reliable even during cutting procedures (RMSE= 0.073 +/- 0.023 mm under 40* magnification). These results demonstrate the new software package can provide excellent improvements to the previous microsurgical system, leading to important enhancements in surgical outcome. PMID- 23366509 TI - CHIC: cylindrical helix imaging coordinate registration fiducial for MRI-guided interventions. AB - Accurate placement of tubular shaped surgical tools is necessary for a large variety of image-guided medical interventions. In this process, localization of the instrument, or a robotic assistant manipulating the instrument, is crucial for successful registration of physical space to medical image space. Various fiducial frames and registration methods have been proposed and discussed in literature. However, these frames are typically bulky in size or otherwise not appropriate for use with MR imaging. In particular, it is impossible or awkward to integrate them with the surgical tools. This paper presents the design a compact Cylindrical Helix Imaging Coordinate Registration Fiducial (CHIC) and algorithm to precisely and robustly localize the frame in 6 degree of freedom (DOF). The mathematical model of the frame is developed and evaluated with simulation. This cylindrical shaped frame is particularly suitable for mounting to the distal end of tubular shape surgical tools, which provides a direct imaging visualization of frame, tool and possibly the surgical sites. The paper uses MRI-guided surgical procedure as a focusing application, although the broader aim is development of a versatile registration frame that is usable for a variety of image-guided procedures ranging from ultrasound to fluoroscopy and computerized tomography (CT). Accuracy and performance were evaluated in three cases: simulated images with artificial noise, arbitrarily re-sliced 3D MRI volume, and real 3T MRI images. PMID- 23366510 TI - Localized viscoelasticity measurements with untethered intravitreal microrobots. AB - Microrobots are a promising tool for medical interventions and micromanipulation. In this paper, we explore the concept of using microrobots for microrheology. Untethered magnetically actuated microrobots were used to characterize one of the most complex biofluids, the vitreous humor. In this work we began by experimentally characterizing the viscoelastic properties of an artificial vitreous humor. For comparison, its properties were also measured using special microcantilevers in an atomic force microscope (AFM) setup. Subsequently, an untethered device was used to study the vitreous humor of a porcine eye, which is a valid ex-vivo model of a human eye. Its viscoelasticity model was extracted, which was in agreement with the model of the artificial vitreous. The existing characterization methodology requires eye and vitreous humor dissection for the microrheology measurements. We envision that the method proposed here can be used in in vivo. PMID- 23366511 TI - A study on estimation of the deformation behavior in the collapse process of lung. AB - In this paper, finite element methodology was applied to predict the deformation of tissue during lung collapse using pre-operative information. Accurate prediction of lung collapse deformation prior to surgical intervention can provide valuable diagnostic information to clinical staff, allowing a better understanding of the movement of the target segment. This paper describe the methodology to derive the deformed shape of finite element model that satisfy the equilibrium condition using 3-D model developed from the image measured by a multi-slice CT imaging device. The movement of the target segment can be predicted by the finite element model. Previous research studies applied the distributed load on the surface of the lung structure as loading conditions. Here we have suggested a method that considers the deformation of alveoli contraction and elongation while breathing. Specifically, by introducing the governing equations of a reduction in volume strain into the governing equations of the finite element method, lung structure is analyzed. Lung deformation obtained from the analysis was compared with experimental results and compared with the proposed method. The proposed method showed an improvement of deformation prediction accuracy as 0.58%. We confirmed the qualitative similarities between the deformation of the analysis and the experiment, thus demonstrating the effectiveness of the proposed method. PMID- 23366512 TI - Bacterial chemotaxis enabled autonomous sorting of micro-particles. AB - Autonomous manipulation and assembly at micro/nanoscale continues to be one of the main challenges of micro/nanorobotics. Biomotors are increasingly being considered as robust, versatile and cost-effective choices for a variety of micro/nanorobotic tasks. Here we propose utilization of motility and chemotaxis in flagellated bacteria for autonomous sorting of 6 um and 10 um micro-particles within a microfluidic platform. Difference in surface chemistry of the 6 um and 10 um particles are exploited to selectively assemble bacteria onto 6 um particles and separate them from 10 um particles via chemotaxis motility of the attached bacteria. It has been shown that within 1 hour, an increasingly larger number of 6 um particles accumulate within a 600 um radius, near the chemo attractant source. PMID- 23366513 TI - Exploring the use of fuzzy logic models to describe the relation between SBP and RR values. AB - In this work, fuzzy logic based models are used to describe the relation between systolic blood pressure (SBP) and tachogram (RR) values as a function of the SBP level. The applicability of these methods is tested using real data in Lying (L) and Standing (S) conditions and generated surrogate data. The results indicate that fuzzy models exhibit a similar performance in both conditions, and their performance is significantly higher with real data than with surrogate data. These results point out the potential of a fuzzy logic approach to model properly the relation between SBP and RR values. As a future work, it remains to assess the clinical impact of these findings and inherent repercussion on the estimation of time domain baroreflex sensitivity indices. PMID- 23366514 TI - Bivariate point process modeling and joint non-stationary analysis of pulse transit time and heart period. AB - Pulse transit time (PTT) is strictly related to pulse wave velocity and may be used for non-invasive monitoring of arterial stiffness and pressure, whose assessment is fundamental to detect cardiovascular dysfunctions. We propose a new model to characterize instantaneous PTT dynamics, and the interactions between PTT and R-R interval (RRI). In this model, PTT is described as a point process whose probability function depends on previous PTT and RRI values. From the model coefficients, instantaneous powers, coherence and directed coherence of each spectral component are estimated. We used this framework to study the changes that tilt table test provoked in PTT and RRI dynamics in 17 healthy subjects. Time-varying spectral and coherence analysis revealed that, although PTT and RRI were locally correlated, direct contribution of RRI on PTT was low during the entire test in high frequency band, and just after postural changes in low frequency band. We conclude that PTT may add valuable information for a more accurate characterization of cardiovascular regulation. PMID- 23366515 TI - Effects of propofol anesthesia induction on the relationship between arterial blood pressure and heart rate. AB - This paper presents the analysis of autonomic nervous system (ANS) control of heart rate (HR) and of cardiac baroreflex sensitivity (BRS) in patients undergoing general anesthesia for major surgery through spectral analysis techniques and with the Granger causality approach that take into account the causal relationships between HR and arterial blood pressure (ABP) variability. Propofol produced a general decrease in ABP due to its vasodilatory effects, a reduction in BRS, while HR remained unaltered with respect to baseline values before induction of anesthesia. The bivariate model suggests that the feedback pathway of cardiac baroreflex could be blunted by propofol induced anesthesia and that the feedforward pathway could be unaffected by anesthesia. PMID- 23366516 TI - Bayesian combination of multiple plasma glucose predictors. AB - This paper presents a novel on-line approach of merging multiple different predictors of plasma glucose into a single optimized prediction. Various different predictors are merged by recursive weighting into a single prediction using regularized optimization. The approach is evaluated on 12 data sets of type I diabetes data, using three parallel predictors. The performance of the combined prediction is better, or in par, with the best predictor for each evaluated data set. The results suggest that the outlined method could be a suitable way to improve prediction performance when using multiple predictors, or as a means to reduce the risk associated with definite a priori model selection. PMID- 23366517 TI - Disease progression modeling using Hidden Markov Models. AB - The development of novel treatments for many slowly progressing diseases, such as Alzheimer's disease (AD), is dependent on the ability to monitor and detect changes in disease progression. In some diseases the distinct clinical stages of the disease progress far too slowly to enable a quick evaluation of the efficacy of a given proposed treatment. To help improve the assessment of disease progression, we propose using Hidden Markov Models (HMM's) to model, in a more granular fashion, disease progression as compared to the clinical stages of the disease. Unlike many other applications of Hidden Markov Models, we train our HMM in an unsupervised way and then evaluate how effective the model is at uncovering underlying statistical patterns in disease progression by considering HMM states as disease stages. In this study, we focus on AD and show that our model, when evaluated on the cross validation data, can identify more granular disease stages than the three currently accepted clinical stages of "Normal", "MCI" (Mild Cognitive Impairment), and "AD". PMID- 23366518 TI - CIC signal processing embedded system a modulizable platform for multi-domain signal processing. AB - IT (Information Technology) industry is well developed in IC (Integrated Circuit) design, SoC (System-on-a-Chip), embedded, and etc. in Taiwan. Most of the commonly-used platforms are not configurable or modulizable at the moment. The biomedical academia in Taiwan is eager for a flexible biomedical signal sensing platform. This paper presents a novel multi-domain nano-sensor signal processing embedded system. The platform can be tailored for different demands of biomedical signal sensing. PMID- 23366519 TI - Automatic seizure detection based on the activity of a set of current dipoles: first steps. AB - In this paper we show advantages of using an advanced montage scheme with respect to the performance of automatic seizure detection systems. The main goal is to find the best performing montage scheme for our automatic seizure detection system. The new virtual montage is a fix set of dipoles within the brain. The current density signals for these dipoles are derived from the scalp EEG signals based on a smart linear transformation. The reason for testing an alternative approach is that traditional montages (reference, bipolar) have some limitations, e.g. the detection performance depends on the choice of the reference electrode and an extraction of spatial information is often demanding. In this paper we explain the detailed setup of how to adapt a modern seizure detection system to use current density signals. Furthermore, we show results concerning the detection performance of different montage schemes and their combination. PMID- 23366520 TI - Evaluation of a new approach for speech enhancement algorithms in hearing aids. AB - Several studies on hearing impaired people who use hearing aid reveal that speech enhancement algorithms implemented in hearing aids improve listening comfort. However, these algorithms do not improve speech intelligibility too much and in many cases they decrease the speech intelligibility, both in hearing-impaired and in normally hearing people. In fact, current approaches for development of the speech enhancement algorithms (e.g. minimum mean square error (MMSE)) are not optimal for intelligibility improvement. Some recent studies investigated the effect of different distortions on the enhanced speech and realized that by controlling the amplification distortion, the intelligibility improves dramatically. In this paper, we examined, subjectively and objectively, the effects of amplification distortion on the speech enhanced by two algorithms in three background noises at different SNR levels. PMID- 23366521 TI - Stationarity and variability in eyes open and eyes closed EEG signals from able bodied and spinal cord injured persons. AB - This paper examines the assumption of stationarity used in EEG brain activity analyses, despite EEG data often being non-stationary. Transformations necessary to obtain stationary data from measured non-stationary EEG data and methods to assess non-stationarity are illustrated using eyes open (EO) and eyes closed (EC) data. The study shows that even short time EEG records of 10s duration exhibit non-stationary behavior. Examination of the change in variance when going from the EO to the EC state for both able bodied and spinal cord injured participants show that the difference in variance is consistently positive and statistically significant only when stationary data is used. This has implications for brain computer interfaces that utilizes changes in EO and EC EEG signals. PMID- 23366522 TI - Frequency analysis of eyes open and eyes closed EEG signals using the Hilbert Huang transform. AB - Frequency analysis based on the Hilbert-Huang transform (HHT) is examined as an alternative to Fourier spectral analysis in the study of EEG signals. This method overcomes the need for the EEG signal to be linear and stationary, assumptions necessary for the application of Fourier spectral analysis. The HHT method comprises two components: empirical mode decomposition (EMD) of the signal into intrinsic mode functions (IMF's); and the Hilbert transform of the IMF's. This technique is applied here in the study of consecutive eyes open (EO), eyes closed (EC) EEG signals of able bodied and spinal cord injured participants. The study found that in this EO, EC pair the instantaneous frequencies in the EO state were higher compared to the EC state. The Hilbert weighted frequency, a measure of the mean of the instantaneous frequencies present in an IMF, is used here to detect these changes from EO to the EC state in an EEG signal. Although there was a good detection of this change with information obtained from just one IMF (94% in able bodied persons and 84% in SCI persons), almost 100% success in detecting between group differences was achieved using all the IMF's. This result has implications for assistive technology that rely on EEG changes in EO and EC states. PMID- 23366523 TI - Reducing human error in P300 speller paradigm for brain-computer interface. AB - Since the brain-computer interface (BCI) speller paradigm was first introduced by Farwell and Donchin in 1988, there have been many visual modifications to the paradigm. Most of these changes involve the original matrix format such as changes in the number of rows and columns, font size and color, flash time vs. dark time, and flash order. However, recent studies show that there is human error in generating P300 based on this paradigm that none of these changes can help to reduce it. In this study, we analyze this type of error among three paradigms, two based on the matrix structure and one region-based paradigm. It is shown that the human error is reduced significantly in the region-based paradigm. PMID- 23366524 TI - Brain-computer interfacing in discriminative and stationary subspaces. AB - The non-stationary nature of neurophysiological measurements, e.g. EEG, makes classification of motion intentions a demanding task. Variations in the underlying brain processes often lead to significant and unexpected changes in the feature distribution resulting in decreased classification accuracy in Brain Computer Interfacing (BCI). Several methods were developed to tackle this problem by either adapting to these changes or extracting features that are invariant. Recently, a method called Stationary Subspace Analysis (SSA) was proposed and applied to BCI data. It diminishes the influence of non-stationary changes as learning and classification is performed in a stationary subspace of the data which can be extracted by SSA. In this paper we extend this method in two ways. First we propose a variant of SSA that allows to extract stationary subspaces from labeled data without disregarding class-related variations or treating class differences as non-stationarities. Second we propose a discriminant variant of SSA that trades-off stationarity and discriminativity, thus it allows to extract stationary subspaces without losing relevant information. We show that learning in a discriminative and stationary subspace is advantageous for BCI application and outperforms the standard SSA method. PMID- 23366525 TI - Phase-locking factor in a motor imagery Brain-Computer Interface. AB - A Brain-Computer Interface (BCI) attempts to create a direct channel of communication between the brain and a computer. This is especially important for patients that are "locked in", as they have limited motor function and thus require an alternative means of communication. In this scope, a BCI can be controlled through the imagination of motor tasks, i.e. Motor Imagery. This thinking of actions produce changes on the ongoing Electroencephalogram (EEG), such as the so called Event-Related Desynchronization (ERD), that can be detected and measured. Traditionally, ERD is measured through the estimation of EEG signal power in specific frequency bands. In this work, a new method based on the phase information from the EEG channels, through the Phase-Locking Factor (PLF), is proposed. Both feature types were tested in real data obtained from 6 voluntary subjects, who performed 7 motor tasks in an EEG session. The features were classified using Support Vector Machine (SVM) classifiers organized in a hierarchical structure. The results show that the PLF features are better, with an average accuracy of ~ 86%, against an accuracy of ~ 70% for the band power features. Although more research is still needed, the PLF measure shows promising results for use in a BCI system. PMID- 23366526 TI - Segmenting human motion for automated rehabilitation exercise analysis. AB - This paper proposes an approach for the automated segmentation and identification of movement segments from continuous time series data of human movement, collected through motion capture of ambulatory sensors. The proposed approach uses a two stage identification and recognition process, based on velocity and stochastic modeling of each motion to be identified. In the first stage, motion segment candidates are identified based on a unique sequence of velocity features such as velocity peaks and zero velocity crossings. In the second stage, Hidden Markov models are used to accurately identify segment locations from the identified candidates. The approach is capable of on-line segmentation and identification, enabling interactive feedback in rehabilitation applications. The approach is validated on a rehabilitation movement dataset, and achieves a segmentation accuracy of 89%. PMID- 23366527 TI - Theoretical study of bone's microstructural effects on Rayleigh wave propagation. AB - The linear theory of classical elasticity cannot effectively describe bone's mechanical behavior since only homogeneous media and local stresses are assumed. Additionally, it cannot predict the dispersive nature of Rayleigh wave which has been experimental observed. By adopting Mindlin Form II gradient elastic theory and performing Boundary Element (BEM) simulations we also recently demonstrated Rayleigh dispersion. In this work we use this theory to analytically determine the dispersion of Rayleigh wave. We assume an isotropic semi-infinite space with mechanical properties equal to those of bone and microstructure and microstructural effects. Calculations are performed for various combinations between the internal constants l(1), l(2), h(1), h(2) which corresponded to a) values from closed form relations derived from a realistic model and b) values close to the osteon's size. Comparisons are made with the corresponding computational results as well as with the classical elastic case. The agreement between the computational and the analytical results was perfect demonstrating the effectiveness of Mindlin's Form II gradient theory of elasticity to predict the dispersive nature of Rayleigh wave. This study could be regarded as a step towards the ultrasonic characterization of bone. PMID- 23366528 TI - A predictive model of subcutaneous glucose concentration in type 1 diabetes based on Random Forests. AB - In this study, an individualized predictive model of the subcutaneous glucose concentration in type 1 diabetes is presented, which relies on the Random Forests regression technique. A multivariate dataset is utilized concerning the s.c. glucose profile, the plasma insulin concentration, the intestinal absorption of meal-derived glucose and the daily energy expenditure. In an attempt to capture daily rhythms in glucose metabolism, we also introduce a time feature in the predictive analysis. The dataset comes from the continuous multi-day recordings of 27 type 1 patients in free-living conditions. Evaluating the performance of the proposed method by 10-fold cross validation, an average RMSE of 6.60, 8.15, 9.25 and 10.83 mg/dl for 15, 30, 60 and 120 min prediction horizons, respectively, was attained. PMID- 23366529 TI - Patient specific multiscale modelling for plaque formation and progression. AB - We present a three-dimensional model of plaque formation and progression that was tested in a set of patients who underwent coronary Computed Tomography angiography (CTA) for anginal symptoms. The 3D blood flow is described by the Navier-Stokes equations, together with the continuity equation. Mass transfer within the blood lumen and through the arterial wall is coupled with the blood flow and is modeled by a convection-diffusion equation. The Low Density Lipoprotein (LDL) transports in lumen of the vessel and through the vessel tissue (which has a mass consumption term) are coupled by Kedem-Katchalsky equations. The inflammatory process is modeled using three additional reaction-diffusion partial differential equations. A full three-dimensional model was created. Furthermore, features potentially affecting plaque growth, such as patient risk score, circulating biomarkers, localization and composition of the initial plaque, and coronary vasodilating capability were also investigated. The proof of concept of the model effectiveness was assessed 6 months after the baseline evaluation. PMID- 23366530 TI - ECG denoising using angular velocity as a state and an observation in an Extended Kalman Filter framework. AB - In this paper an efficient filtering procedure based on Extended Kalman Filter (EKF) has been proposed. The method is based on a modified nonlinear dynamic model, previously introduced for the generation of synthetic ECG signals. The proposed method considers the angular velocity of ECG signal, as one of the states of an EKF. We have considered two cases for observation equations, in one case we have assumed a corresponding observation to angular velocity state and in the other case, we have not assumed any observations for it. Quantitative evaluation of the proposed algorithm on the MIT-BIH Normal Sinus Rhythm Database (NSRDB) shows that an average SNR improvement of 8 dB is achieved for an input signal of -4 dB. PMID- 23366531 TI - Estimating heart rate using wrist-type Photoplethysmography and acceleration sensor while running. AB - This study provides Heart Rate (HR) Estimation using wrist-type Photoplethysmogpraphy (PPG) sensor while the subject is running. We propose the algorithm to estimate heart rate for the wrist-type PPG sensor. Since body motion artifacts easily affect the arm portion, our method in this study also uses accelerometer built in the wrist-type sensor to improve the accuracy of heart rate estimation. Our method has two components. One is rejecting artifacts with the power spectrum's difference between PPG and acceleration obtained by frequency analysis. The other is the reliability of heart rate estimation, defined by the acceleration. Experimental results while our test subjects were running came closer to the holter Electrocardiogram (ECG) in high accuracy (r = 0.98, SD = 8.7 bpm). We, therefore, report the heart rate estimation method which has a higher degree of usability compared to existing methods using ECG. PMID- 23366532 TI - Estimation of venous oxygenation saturation using the finger Photoplethysmograph (PPG) waveform. AB - In this study, finger photoplethysmograph data obtained from twelve patients undergoing cardiothoracic surgery were analyzed in order to estimate the venous saturation utilizing the modulations created by the positive pressure ventilation in the AC Photoplethysmograph (PPG) signals. The PPG signals were analyzed in the time-domain using a conventional pulse oximetry algorithm to produce estimations of arterial oxygen saturation. The instantaneous arterial and venous saturations were estimated by utilizing time-frequency analysis technique of Smoothed-pseudo Wigner-Ville Distribution (SPWVD). The results showed that there was no significant difference in the traditionally-derived (time-domain) arterial saturation and the instantaneous arterial saturation. However, the instantaneous venous saturation was found to be significantly lower than the time-domain estimated and instantaneous arterial saturation (P=<0.001). PMID- 23366533 TI - Extension of FRI for modeling of electrocardiogram signals. AB - Recent work has developed a modeling method applicable to certain types of signals having a "finite rate of innovation" (FRI). Such signals contain a sparse collection of time- or frequency-limited pulses having a restricted set of allowable pulse shapes. A limitation of past work on FRI is that all of the pulses must have the same shape. Many real signals, including electrocardiograms, consist of pulses with varying widths and asymmetry, and therefore are not well fit by the past FRI methods. We present an extension of FRI allowing pulses having variable pulse width (VPW) and asymmetry. We show example results for electrocardiograms and discuss the possibility of application to signal compression and diagnostics. PMID- 23366534 TI - Automatic QRS complex detection algorithm designed for a novel wearable, wireless electrocardiogram recording device. AB - We have designed and optimized an automatic QRS complex detection algorithm for electrocardiogram (ECG) signals recorded with the DELTA ePatch platform. The algorithm is able to automatically switch between single-channel and multi channel analysis mode. This preliminary study includes data from 11 patients measured with the DELTA ePatch platform and the algorithm achieves an average QRS sensitivity and positive predictivity of 99.57% and 99.57%, respectively. The algorithm was also evaluated on all 48 records from the MIT-BIH Arrhythmia Database (MITDB) with an average sensitivity and positive predictivity of 99.63% and 99.63%, respectively. PMID- 23366535 TI - Assessing normality of heart sound by matching pursuit residue with frequency domain-based templates. AB - The healthiness of the heart is import to human for leading a healthy life. Some of the abnormal conditions of heart could be detected by the heart sound. For example, heart murmur is one of the conditions possibly resulting from the illness of heart valves. In this work, we propose a new template family used in the matching pursuit (MP) algorithm to assess the degree of normality of the heart sound. Not only the rating of normality is generated but also an intuitive visual feedback with abnormal interval highlighted is outputted. In this way, the condition like heart murmur is well-identified by inspecting the matching residue. Comparison with previous work which adopts different template family is also given. Experiment results indicate that the proposed family is more effective to matching the normal heart sound to achieve better assessing result. PMID- 23366536 TI - Multivariate principal oscillation pattern analysis of ICA sources during seizure. AB - Mapping the dynamics of neural source processes critically involved in initiating and propagating seizure activity is important for effective epilepsy diagnosis, intervention, and treatment. Tracking time-varying shifts in the oscillation modes of an evolving seizure may be useful for both seizure onset detection as well as for improved non-surgical interventions such as microstimulation. In this report we apply a multivariate eigendecomposition method to analyze the time varying principal oscillation patterns (POPs, or eigenmodes) of maximally independent (ICA) sources of intracranial EEG data recorded from subdural electrodes implanted in a human patient for evaluation of surgery for epilepsy. Our analysis of a subset of the most dynamically important eigenmodes reveals distinct shifts in characteristic frequency and damping time before, throughout, and following seizures providing insight into the dynamical structure of the system throughout seizure evolution. PMID- 23366537 TI - Real-time source separation on a field programmable gate array platform. AB - In this paper, we present a real-time implementation of the ideal binary-mask algorithm, which is a promising approach for enhancing speech intelligibility. Our implementation is hardware efficient, making it suitable for embedded biomedical devices such as hearing aids and cochlear implants. We tested our algorithm implementation on an FPGA platform, and produced results that verify that it effectively performs source separation with 25 us latency. PMID- 23366538 TI - Investigating brief motor imagery for an ERD/ERS based BCI. AB - This study establishes the effectiveness of event related synchronisation (ERS) features for a system paced brain computer interface (BCI). In particular, the relationship between the duration of motor imagery (MI) and the quality of the features extracted from the ERS is investigated. To this end, two groups of users performed brief (2s) or sustained (4s) MI, and offline single trial BCIs were validated on each group based on features extracted from the EEG before, during and after MI. The BCIs were designed to recognise two intentional control tasks and a no-control state. Cross-validated results indicate that brief MI leads to more informative ERS features than sustained MI. PMID- 23366539 TI - EEG analysis of frontal lobe area in arousal maintenance state against sleepiness. AB - This paper describes EEG analysis of frontal lobe area in arousal maintenance state against sleepiness. Arousal maintenance state is considered different physiological state from the normal sleep onset. To analyze the EEG of frontal area might be important because we believe that the arousal maintenance state against sleepiness causes neuron activities from the frontal lobe, which coordinates behavior, to hypothalamus, which coordinates wakefulness and sleep. It is, however, hard to use EEG signals in the frontal area consistently because blinking artifacts are mixed in the EEG signals. In this paper, we have analyzed the EEG signals of the frontal lobe in arousal maintenance state against sleepiness after removing the eye-blinking artifact from the scalp EEG signals using an ICA denoising method. As a result, the EEG signals of the frontal area in the arousal maintenance state against sleepiness have wide bandwidth as in the EEG of the occipital area. It strengthens our speculation, i.e., the EEG desynchronization occurs because of the neuron activities from the frontal lobe to hypothalamus in order to maintain arousal state against sleepiness. PMID- 23366540 TI - Discrete wavelet transform EEG features of Alzheimer'S disease in activated states. AB - In this study, electroencephalogram (EEG) signals obtained by a single-electrode device from 24 subjects - 10 with Alzheimer's disease (AD) and 14 age-matched Controls (CN) - were analyzed using Discrete Wavelet Transform (DWT). The focus of the study is to determine the discriminating EEG features of AD patients while subjected to cognitive and auditory tasks, since AD is characterized by progressive impairments in cognition and memory. At each recording block, DWT extracts EEG features corresponding to major brain frequency bands. T-test and Kruskal-Wallis methods were used to determine the statistically significant features of EEG signals from AD patients compared to Controls. A decision tree algorithm was then used to identify the dominant features for AD patients. It was determined that the mean value of the low-delta (1 - 2 Hz) frequency band during the Paced Auditory Serial Addition Test with 2.0 (s) interval and the mean value of the delta frequency band (12 - 30 Hz) during 6 Hz auditory stimulation have higher mean values in AD patients than Controls. Due to artifacts, the less reliable low-delta features were removed and it was determined that the mean value of beta frequency band during 6 Hz auditory stimulation followed by the standard deviation of theta (4 - 8 Hz) frequency band of one card learning cognitive task are higher for AD patients compared to Controls and thus the most dominant discriminating features of the disease. PMID- 23366541 TI - Separation of Parkinson's patients in early and mature stages from control subjects using one EOG channel. AB - In this study, polysomnographic left side EOG signals from ten control subjects, ten iRBD patients and ten Parkinson's patients were decomposed in time and frequency using wavelet transformation. A total of 28 features were computed as the means and standard deviations in energy measures from different reconstructed detail subbands across all sleep epochs during a whole night of sleep. A subset of features was chosen based on a cross validated Shrunken Centroids Regularized Discriminant Analysis, where the controls were treated as one group and the patients as another. Classification of the subjects was done by a leave-one-out validation approach using same method, and reached a sensitivity of 95%, a specificity of 70% and an accuracy of 86.7%. It was found that in the optimal subset of features, two hold lower frequencies reflecting the rapid eye movements and two hold higher frequencies reflecting EMG activity. This study demonstrates that both analysis of eye movements during sleep as well as EMG activity measured at the EOG channel hold potential of being biomarkers for Parkinson's disease. PMID- 23366542 TI - Singular spectrum analysis improves analysis of local field potentials from macaque V1 in active fixation task. AB - Local field potentials (LFPs) represent the relatively slow varying components of the neural signal, and their analysis is instrumental in understanding normal brain function. To be properly analyzed, this signal needs to be separated in its fundamental frequency bands. Recent studies have shown that empirical mode decomposition (EMD) can be exploited to pre-process LFP recordings in order to achieve a proper separation. However, depending on the analyzed signal, EMD is known to generate components that may cover a too wide frequency range to be considered as narrow banded. As an alternative, we present here an improved version of the singular spectrum analysis (SSA) algorithm, validated by numerical simulations, and applied to LFP recordings in V1 of a macaque monkey exposed to simple visual stimuli. The components generated by the improved SSA algorithm are shown to be more meaningful than those generated by EMD, paving the way for its use in LFP analysis. PMID- 23366543 TI - Gait episode identification based on wavelet feature clustering of spectrogram images. AB - Measurement of gait parameters can provide important information about a person's health and safety. Automatic analysis of gait using kinematic sensors is a newly emerging area of research. We propose a new approach to detect gait episodes using Neural Network and and clustering of wavelet-decomposed spectrogram images. Signals from a chest-worn inertial measurement unit (IMU) is processed using Explicit Complementary Filter (ECF) to estimate and track torso angle. Using the feature obtained from wavelet decomposition of spectrogram images, we use an Augmented Radial Basis Neural Network (ARBF) to classify walking episodes. Cluster centroids of ARBF are optimized using Rapid Cluster Estimation (RCE). A pilot study of 11 participants suggests that our approach is able to distinguish between walk and non-walk activities with up to 85.71% sensitivity and 91.34% specificity. PMID- 23366545 TI - Subspace matching thalamic microstimulation to tactile evoked potentials in rat somatosensory cortex. AB - We show experimental results that the evoked local field potentials of the rat somatosensory cortex from natural tactile touch of forepaw digits and matched thalamic microstimulation can be qualitatively and quantitively similar. In ongoing efforts to optimize the microstimulation settings (e.g., location, amplitude, etc.) to match the natural response, we investigate whether subspace projection methods, specifically the eigenface approach proposed in the computer vision community (Turk and Pentland 1991 [1]), can be used to choose the parameters of microstimulation such that the response matches a single tactile touch realization. Since the evoked potentials from multiple electrodes are high dimensional spatio-temporal data, the subspace projections improve computational efficiency and can reduce the effect of noisy realizations. In computing the PCA projections we use the peristimulus averages instead of the realizations. The dataset is pruned of unreliable stimulation types. A new subspace is computed for the pruned stimulation type, and is used to estimate a sequence of microstimulations to best match the natural responses. This microstimulation sequence is applied in vivo and quantitative analysis shows that per realization matching does statistically better than choosing randomly from the pruned subset. PMID- 23366544 TI - Automatic newborn cry analysis: a non-invasive tool to help autism early diagnosis. AB - Autism Spectrum Disorders (ASD) are complex developmental disabilities that cause problems with social interaction and communication. ASD are associated with motor development problems, more or less blurred, and with perceptual and sensory brain areas. Crying is the infant's earliest form of communication and recent studies connect this original "language" form with autism disturbs. Being completely non invasive, cry analysis is an appealing approach for early ASD diagnosis to improve rehabilitation. To this aim, we have developed an automatic system to record newborn cry and movements, during the first six months of life with a specific recording protocol. In this work we present first results of acoustic cry analysis in newborns classified as high-risk subjects being siblings of children already diagnosed as autistics. The work aims at finding possible early ASD signs in high-risk subjects as compared to a group of control subjects based on the fundamental frequency and the vocal tract resonance frequencies. Also, voiced and unvoiced parts of signal and cry-episodes duration are analyzed. PMID- 23366546 TI - On just noticeable difference for bionic eye. AB - We propose to use Just Noticeable Difference (JND) as the principle in visualizing results for image processing modules for prosthetic vision. Current Bionic Eye hardware implants have limited levels of separately perceivable brightness (i.e., low dynamic range in visualizing images). Therefore, it is important to ensure that the critical contrast must remain perceivable by maintaining of visual differences in downsampled images with reduced dynamic range. JND provides a mathematical framework for these psychophysics events. An increase by 1 in JND space corresponds to the smallest detectable change in visual space (i.e., just noticeable). Combining this principle and the dynamic range constraint, we cast the visualization problem to a linear optimization problem, which enables us to generate optimal visualization images. We demonstrate the usefulness of this principle on visualizing ground-plane segmentation. Experiments show that the proposed principle effectively provides critical visual information at different dynamic ranges, and generates consistent results for image sequences. PMID- 23366547 TI - Information theoretic inference of the optimal number of electrodes for future cochlear implants using a spiral cochlea model. AB - Contemporary cochlear implants stimulate the auditory nerve with an array of up to 22 electrodes. More electrodes do not typically provide improved hearing performance. Given that this limitation is primarily due to current spread, and that newly developing kinds of electrodes may enable more focused stimulation, we recently proposed an information theoretic modeling framework for estimating how many electrodes might achieve optimal hearing performance under a range of assumptions about electrodes and their placement relative to the nerve. Here, we extend this approach by introducing more realistic three-dimensional spiral geometries for the cochlea and array, and comparing the optimal number of electrodes predicted by our model for this case with that in our original model, which used a linear geometry. PMID- 23366548 TI - Grasping force and slip feedback through vibrotactile stimulation to be used in myoelectric forearm prostheses. AB - User feedback about grasping force or slip of objects is lacking in current myoelectric forearm prostheses, resulting in a high number of prosthesis abandonment, because a high level of concentration is required to hold an object. Several approaches to provide force feedback to the user via vibrotactile stimulation have been described in literature, but none of them have investigated the optimal stimulation parameters. This study describes an evaluation of three modulation techniques to provide force feedback. Furthermore, the same modulation techniques to provide slip feedback were evaluated, which has not been described before. The performance in virtual object holding tasks was significantly improved in most cases compared to the non-feedback situation, but at the cost of an increased task duration. PMID- 23366549 TI - Extraction of control signals from a mixture of source activity in the peripheral nerve. AB - Extracting physiological signals to control external devices such as prosthetics is a field of research that offers great hope for patients suffering from disabilities. In this paper, we present an algorithm for isolating control signals from peripheral nerve cuff recordings. The algorithm is able to extract individual control signals from a mixture of source signal activity while maximizing SNR and minimizing cross-talk between the control signals. Based on fast independent component analysis FICA and an adaptation of Champagne, the proposed algorithm is tested against previously published results obtained using beamforming techniques in an acute preparation of rabbits. Preliminary results demonstrate an improvement in performance. PMID- 23366550 TI - Text image processing for visual prostheses. AB - Retinal diseases are leading causes of severe vision loss and blindness throughout the world. Visual prosthetics has been demonstrated to be an effective therapy to partially restore vision. Reading is one of the most important functional abilities derived from vision. Therefore, we propose a text image processing strategy for visual prostheses. Text information is firstly detected and recognized from images acquired from a camera, and then recognized text is represented by simplified characters so as to be displayed in low-resolution phosphene vision. In this paper, a BP neural network is created to recognize text information in the images acquired from a high-resolution camera. The recognized text is represented using simplified characters with the resolution of 5*7 pixels. In order to mimic the visual percepts and to evaluate potential benefits of this proposed text processing strategy, a simulation model of prosthetic vision is created based on the reported visual characteristics of elicited phosphenes. Simulated prosthetic vision using 25*25 distorted phosphene array covering four letters shows phosphene letters that can be read readily. Compared to the displayed phosphene letters without this strategy, the contours of all the phosphene letters processed by this strategy were more intact and clearer. These results demonstrate benefits of this proposed strategy which is aimed to provide better reading experience for blind patients using prosthetic vision. PMID- 23366551 TI - An face-based visual fixation system for prosthetic vision. AB - Recent studies have shown the success of face recognition using low resolution prosthetic vision, but it requires a zoomed-in and stably-fixated view, which will be challenging for a user with the limited resolution of current prosthetic vision devices. We propose a real-time object detection and tracking system capable of fixating human faces. By integrating both static and temporal information, we are able to improve the robustness of face localization so that it can fixate on faces with large pose variations. Our qualitative and quantitative results demonstrate the viability of supplementing visual prosthetic devices with the ability to visually fixate objects automatically, and provide a stable zoomed-in image stream to facilitate face and expression recognition. PMID- 23366552 TI - Physiological response of normal and RD mouse retinal ganglion cells to electrical stimulation. AB - The epiretinal prosthesis aims to restore functional vision by stimulating electrically the retinal ganglion cells (RGCs) in patients afflicted with degenerative diseases that affect the photoreceptors, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). As degeneration progresses, photoreceptor death is followed by pronounced remodeling and rewiring of remaining inner retinal cells. Despite the loss of rods and cones, a considerable population of RGCs remain receptive to prosthetic stimulation. To stimulate effectively a localized population of RGCs, an improved understanding of the anatomical and physiological properties of these cells is required. Additionally, possible alterations in electrical excitability, produced by the effects of retinal degeneration, needs to be assessed. This study investigates the effect of RGC soma size on the threshold for action potential generation in normal and rd mice and its implications for the rescue of visual function. PMID- 23366553 TI - Epiretinal electrical stimulation and the inner limiting membrane in rat retina. AB - In this paper we aim to quantify the effect of the inner limiting membrane (ILM) of the retina on the thresholds for epiretinal electrical stimulation of retinal ganglion cells by a microelectronic retinal prosthesis. A pair of bipolar stimulating electrodes was placed either above (on the epiretinal surface) or below the ILM while we made whole-cell patch-clamp recordings from retinal ganglion cells in an isolated rat retinal whole-mount preparation. Across our cell population we found no significant difference in the median threshold stimulus amplitudes when the stimulating electrodes were placed below as opposed to above the ILM (p = 0.08). However, threshold stimulus amplitudes did tend to be lower when the stimulating electrodes were placed below the ILM (30 uA vs 56 uA). PMID- 23366554 TI - Effects of rates of spontaneous synaptic vesicle secretions in inner hair cells on information transmission in an auditory nerve fiber model. AB - In this article, we investigate how the rates of spontaneous synaptic vesicle secretions affect information transmission of the spike trains in response to the inner hair cell (IHC) synaptic currents in an auditory nerve fiber (ANF) model through computer simulations. The IHC synaptic currents were modeled by a filtered inhomogeneous Poisson process modulated with sinusoidal functions, while the stochastic ion channel model was incorporated into each node of Ranvier in the ANF model with spiral ganglion. The information rates were estimated from the entropies of the inter-spike intervals of the spike trains to evaluate information transmission in the ANF model. The results show that the information rates increased, reached a maximum, and then decreased as the rate of spontaneous secretion increased, implying a resonance phenomenon dependent on the rate of spontaneous IHC synaptic secretions. In conclusion, this phenomenon similar to the regular stochastic resonance may be observed due to that spontaneous IHC synaptic secretions may act as an origin of fluctuation or noise, and these findings may play a key role in the design of better auditory prostheses. PMID- 23366555 TI - Threshold analysis of a quasimonopolar stimulation paradigm in visual prosthesis. AB - The complexity of surgical implantation has always been a significant obstacle in the development of visual prosthetics. Implanting in the epi and sub-retinal spaces allows the prosthesis direct access to the retina, resulting in lower stimulation thresholds, potentially at the expense of robust mechanical stability and interface longevity. Implanting the stimulating electrode in the supra choroidal space greatly simplifies surgery and improves mechanical stability. This is achieved at the cost of a higher activation threshold and reduced focus of the electric field at the target site of stimulation, given the increased distance between the stimulating electrodes and the target tissue. In order to contain the spread of the stimulating field, the authors proposed a hexagonal arrangement of return electrodes, at a further cost to the stimulation threshold over that of a monopolar stimulation paradigm. This study analyses the effect on activation thresholds of activating simultaneously the hexpolar guard electrodes and the distant monopolar return in what we have termed a quasimonopolar configuration. Results show that introducing a small element of monopolar stimulation significantly lowers the activation threshold otherwise required by a pure hexpolar return. PMID- 23366556 TI - A precise charge balancing and compliance voltage monitoring stimulator front-end for 1024-electrodes retinal prosthesis. AB - In this paper, we present a precise charge balancing and compliance voltage monitoring stimulator front-end for 1024-electrode retinal prosthesis. Our stimulator is based on current mode stimulation. To generate a precisely matched biphasic current pulse, a dynamic current copying technique is applied at the stimulator front-end. A compliance voltage monitoring circuitry is included at the stimulator front-end to detect if a voltage across electrode-tissue interface goes beyond a predefined compliance voltage. Simulation results show the mismatch of a biphasic current pulse (at a maximum stimulation current of 476uA) is less than 0.1%. Also, the stimulator issues alarm signals, when a voltage compliance occurs during stimulation due to high tissue impedance. Our stimulator is implemented using a 65nm low voltage (LV) CMOS process, which helps reducing implementation area and power consumption. PMID- 23366557 TI - Determining the electrical impedance of the retina from a complex voltage map. AB - A method for determining the electrical impedance of the retina from complex valued voltage measurements is described. This is an extension to our previous work which did not consider the permittivity of the retina, or an exploration of the number of voltage measurements required to form an adequate solution. The model considers inhomogeneity in permittivity and conductivity of the tissue in both the x and y directions. This framework is tested on noisy voltage data solved for a synthetic rectangular retinal section. A synthetic retinal section inclusive of fovea is also considered. Estimates of the conductivity and permittivity maps are solved for using finite element analysis for a range of down sampling factors and signal to noise ratios for the voltage data. This is done to assess the potential accuracy of this method in a physical experiment. PMID- 23366558 TI - Minimisation of required charge for desired neuronal spike rate. AB - Retinal implants restore limited visual perception to blind implantees by electrical stimulation of surviving neurons. We consider the efficacy of two electrical stimulation parameters, frequency of stimulation and interphase gap between cathodic and anodic phases, on the required charge to reach a desired neuronal spike rate. Using a Hodgkin-Huxley model of a neuron, we find the most efficient means of achieving a desired spike rate for neurons by electrical stimulation is to use a stimulation frequency identical to the desired spike rate, as well as a long interphase gap. PMID- 23366559 TI - Can electric current steering be used to control perception of a retinal prosthesis patient. AB - We consider a form of current steering to elicit desired perceptions in users of a retinal prosthesis. While it is common to use a single, remote return electrode to balance electrical stimulation, advances in chip design and electrical switching have enabled more flexibility in stimulation paradigms. We have created a finite-element model of a retina and a ten electrode prosthesis in COMSOL. Different configurations of stimulating and return electrodes are considered and employed to predict possible user perception. We investigate charge balance on electrodes in our varying geometries and consider the impact of inhomogeneous resistance between electrodes and the tissue. PMID- 23366560 TI - Electrical potential distribution within the inner ear: a preliminary study for vestibular prosthesis design. AB - Rotational cues in patients that suffer from bilateral vestibular loss can be delivered by vestibular prosthesis. Even though great efforts towards the development of a vestibular implant have been made, many parameters have still to be optimized. Numerical simulations of the neural activation during electrical stimulation can give important indications about the optimal electrode insertion site, stimulation waveform and electrode configuration, in terms of the highest selectivity. The first step of this type of numerical simulation requires the digital reconstruction of the human inner ear and the calculation of the spatial electrical potential distribution by means of finite-element methods. PMID- 23366561 TI - Crosstalk current measurements using multi-electrode arrays in saline. AB - This paper investigates how the configuration of return electrodes in an electrode array affects the amount of current crosstalk when electrodes are driven simultaneously in saline. Two pairs of electrodes in different return configurations were stimulated with different-amplitude biphasic currents. Stimulating electrodes were controlled by current sinks and current sources while return electrodes were connected to supply voltage or ground. Measurement results show that no matter what return configuration was used, the return current was almost equally distributed amongst the return electrodes, which is problematic in bipolar concurrent stimulation, at least in saline. This result is due to the fact that the spreading impedance of saline solution is small compared to the electrode-electrolyte impedance, which makes the saline solution have almost the same potential. This result suggests that monopolar stimulation using a common remote return electrode be used in simultaneous stimulation to avoid crosstalk. PMID- 23366562 TI - Required matching accuracy of biphasic current pulse in multi-channel current mode bipolar stimulation for safety. AB - In neural stimulation, a current mode stimulation is preferred to a voltage mode stimulation, as it has more control over injecting charge into tissue. A matched biphasic current pulse is often employed in current mode stimulation. For safe neural stimulation, in other words, to ensure zero-net charge transfer (charge balance) into tissue, it is required to utilise a precisely matched biphasic current pulse. Mismatch in the biphasic current pulse causes residual charge on stimulating electrodes during stimulation, which will induce DC current flowing into tissue, possibly leading to tissue damage. In this paper, we derive mathematical expressions of the required matching accuracy on the biphasic current pulse under 4 different situations to ensure a safe neural stimulation; 1) single channel stimulation without shorting, 2) single channel stimulation with shorting, 3) multi-channel stimulation without shorting and 4) multi-channel stimulation with shorting. PMID- 23366563 TI - Computational model of electrical stimulation of a retinal ganglion cell with hexagonally arranged electrodes. AB - In retinal prosthetic devices an electrode array is used for electrical stimulation of retinal neurons to induce phosphene perception. The shape and size of the evoked phosphenes are in part dependent on the spatial patterns of retinal activation. In this study, a computational model of a cat beta retinal ganglion cell (RGC) excitation following simulated electrical stimulation was investigated. Seven epiretinal disk electrodes with hexagonal configuration (Hex electrodes) were used. 100 us/phase anodic-first biphasic pulses were injected at the center electrode and one sixth of the total current was returned at each surround electrode. The aim was to obtain a spatial threshold map of the RGC excitation. We found that the spatial threshold pattern was highly dominated by axonal excitation. With 50 um Hex electrodes, relative thresholds for activation of the distal axon was almost the same as that for excitation of the axonal trigger segment (high sodium channel density region), causing an elongated activation pattern. The model presented in this study can be used to investigate the extent to which spatial RGC activation patterns are influenced by cell and stimulus parameters. PMID- 23366564 TI - Designing shoulder prostheses with a small pneumatic actuator driven parallel mechanism for spatial accessibility in daily living use. AB - In this study, several indexes for spatial accessibility were proposed for evaluating the shoulder prosthesis with a small pneumatic actuator driven parallel mechanism in daily living use. Using the spatial accessibility indexes and manipulability indexes, the configuration of the parallel mechanism was optimized. Especially, the effect of biasing spacer and trunk motions on spatial accessibility were taken into consideration. The results showed that biasing spacers could improve the spatial accessibility by moving the center of the working space of the shoulder prosthesis towards the center of two specified spatial regions, which correspond to the expected frequently accessed area and the reachable area for an individual user's upper limb in daily living. And trunk motions could enlarge the working space thus further improve the spatial accessibility. PMID- 23366566 TI - Gait motion analysis in the unrestrained condition of trans-femoral amputee with a prosthetic limb. AB - Trans-femoral amputees must regain moving pattern by refined rehabilitation program using ground reaction forces, joint angles and joint moments applied on a prosthetic limb. On the other hand, understanding those loads and kinematic variables is indispensable for gait analysis based on the biomechanical consideration of trans-femoral amputees. However, conventional prosthetic gait training systems cannot measure long continuous walking motions. In this paper, ground reaction forces and kinematic parameters applied on trans-femoral prosthesis are measured by the prosthetic gait motion analysis system using mobile force plate and attitude sensor for the unrestrained gait measurement. As a result of the experiments, the patterns of antero-posterior axis ground reaction forces and joint moments about the medio-lateral axis are remarkably different among the five activities. Finally, the effectiveness of the developed prosthetic gait training system to consider biomechanics and kinematics in trans femoral prosthesis is validated. PMID- 23366567 TI - Design of a hand prosthesis with precision and conformal grasp capability. AB - This paper presents the design of an anthropomorphic prosthetic hand that provides both precision and conformal grasp capability. Specifically, the design of the hand dedicates three actuators in a direct-drive manner to achieving precision grasp capability. The design additionally dedicates one actuator and six degrees of freedom, in addition to a compliant coupling, to providing a conformal grasping capability to the amputee. The design of the hand is described in this paper, and the various degrees of actuation are characterized with respect to grasp forces and finger speeds. PMID- 23366568 TI - Identification of widely applicable configurations for the electrostimulative total hip revision system. AB - Since the 1980s electrostimulation is used to accelerate the healing of fractures and bone defects. In prior works this effect has been implemented in a numerical model of an electrostimulative hip revision cup which was optimized using a multi objective evolutionary algorithm. The aim of our simulations is to design an implant which provides optimal electric fields in the acetabular region enhancing the reconstruction of the pelvic bone in such way as to improve the fixation of the prosthesis in the surrounding bone. In the present work we will show that this multi-objective algorithm can also be used to identify a small amount of configurations of the implant that will be able to stimulate a wide range of pelvic bones with different acetabular defects. PMID- 23366569 TI - Cortex inspired model for inverse kinematics computation for a humanoid robotic finger. AB - In order to approach human hand performance levels, artificial anthropomorphic hands/fingers have increasingly incorporated human biomechanical features. However, the performance of finger reaching movements to visual targets involving the complex kinematics of multi-jointed, anthropomorphic actuators is a difficult problem. This is because the relationship between sensory and motor coordinates is highly nonlinear, and also often includes mechanical coupling of the two last joints. Recently, we developed a cortical model that learns the inverse kinematics of a simulated anthropomorphic finger. Here, we expand this previous work by assessing if this cortical model is able to learn the inverse kinematics for an actual anthropomorphic humanoid finger having its two last joints coupled and controlled by pneumatic muscles. The findings revealed that single 3D reaching movements, as well as more complex patterns of motion of the humanoid finger, were accurately and robustly performed by this cortical model while producing kinematics comparable to those of humans. This work contributes to the development of a bioinspired controller providing adaptive, robust and flexible control of dexterous robotic and prosthetic hands. PMID- 23366570 TI - Design of a prosthetic hand with remote actuation. AB - One of the main issues of prosthetic hands is to be able to fulfill all the specifications about speed, torque, weight and inertia while placing all the components within the prosthetic hand. This is especially true when full dexterity is required in the prosthesis. In this paper, a new design for a prosthetic hand is presented, which uses remote actuation in order to satisfy most of those requirements. The actuators are to be located in the back of the subject and the transmission is implemented via cables. Other characteristics of this new prosthetic hand include torque limitation and the possibility of switching between underactuated and fully actuated functions. PMID- 23366571 TI - A user-driven treadmill control scheme for simulating overground locomotion. AB - Treadmill-based locomotor training should simulate overground walking as closely as possible for optimal skill transfer. The constant speed of a standard treadmill encourages automaticity rather than engagement and fails to simulate the variable speeds encountered during real-world walking. To address this limitation, this paper proposes a user-driven treadmill velocity control scheme that allows the user to experience natural fluctuations in walking velocity with minimal unwanted inertial force due to acceleration/deceleration of the treadmill belt. A smart estimation limiter in the scheme effectively attenuates the inertial force during velocity changes. The proposed scheme requires measurement of pelvic and swing foot motions, and is developed for a treadmill of typical belt length (1.5 m). The proposed scheme is quantitatively evaluated here with four healthy subjects by comparing it with the most advanced control scheme identified in the literature. PMID- 23366572 TI - Preventing drowsiness by heartbeat-synchronized vibration. AB - The purpose of this study is to develop a stimulation, which has an active physiological influence to prevent severe driver drowsiness while driving. This paper presents a heartbeat-synchronized vibration, which is the rhythmic pulsation of a motor with each beat of the heart, as an effective means to ease drivers' slight deprivation of oxygen with the appearance of cardiorespiratory coordination. The effects of this stimulation were confirmed by the results of an experiment done in cooperation with 15 subjects. The results showed that cardiorespiratory coordination appeared under the stimulation and it played an active influence on the oxygen supply to the body. We conclude that the vibratory stimulation has an active influence to prevent drowsiness. It might be effective to prevent severe drowsiness while driving. PMID- 23366573 TI - Real-time performance of a hands-free semi-autonomous wheelchair system using a combination of stereoscopic and spherical vision. AB - This paper is concerned with the operational performance of a semi-autonomous wheelchair system named TIM (Thought-controlled Intelligent Machine), which uses cameras in a system configuration modeled on the vision system of a horse. This new camera configuration utilizes stereoscopic vision for 3-Dimensional (3D) depth perception and mapping ahead of the wheelchair, combined with a spherical camera system for 360-degrees of monocular vision. The unique combination allows for static components of an unknown environment to be mapped and any surrounding dynamic obstacles to be detected, during real-time autonomous navigation, minimizing blind-spots and preventing accidental collisions with people or obstacles. Combining this vision system with a shared control strategy provides intelligent assistive guidance during wheelchair navigation, and can accompany any hands-free wheelchair control technology for people with severe physical disability. Testing of this system in crowded dynamic environments has displayed the feasibility and real-time performance of this system when assisting hands free control technologies, in this case being a proof-of-concept brain-computer interface (BCI). PMID- 23366574 TI - Assisting control for attendant propelled wheelchair based on force velocity relationship. AB - There is a need to develop an assisting device which can be adapted to the individual capabilities of elderly attendants, which would allow them to maintain a level of fitness when pushing a wheelchair, while minimising the risk of injury to them. Furthermore there is a need to reduce the overall energy consumption of the device in keeping with the current trends of reducing carbon emissions. The control system for attendants pushing wheelchairs that reduces the energy needed by the assisting device is an increasing trend of optimisation of assistive technology devices to individual capabilities to ensure less energy expenditure of the attendant. The control parameters for existing assisting systems for attendant wheelchair propulsion are difficult to optimise for individual capabilities. We focus on the individual propelling performance, and propose an assisting control method based on the force velocity relationship of the individual. Our proposed assisting controller generates an assisting force when the attendant's propelling force exceeds an assisting boundary defined by the force velocity relationship. In this paper, we tested the performance of the assisting controller based on force velocity (FV) relationship using simulation. The simulation used an attendant wheelchair model with parameters determined from experiments. From the simulated results of the assisting force trajectories, the FV assisting system worked as we defined. The FV assisting system used less energy consumption than the existing proportional assisting systems. Also the FV assisting system would have a limit of maximum attendant propelling power, so the distribution between the attendant force and the assisting force can be easily adjusted to the individual's force velocity relationship. Our proposed FV assisting system would be useful as it would allow an optimised system based on individual capabilities to be created for rehabilitation/training systems, which would allow optimum energy consumption when propelling a wheelchair. PMID- 23366575 TI - A data-driven surrogate model to connect scales between multi-domain biomechanics simulations. AB - A data driven surrogate was developed to bridge the gap between finite element and multibody modeling and to expand the information available from a rigid multibody cartilage simulation. An indentation experiment performed on canine stifle cartilage was modeled in both paradigms with acceptable accuracy and the data were used to create the surrogate. Neural networks were found to adequately approximate the von Mises stress calculated by the finite element model based on force values provided from the multibody model with a correlation coefficient over 0.96. PMID- 23366576 TI - Differential-damper topologies for actuators in rehabilitation robotics. AB - Differential-damper (DD) elements can provide a high bandwidth means for decoupling a high inertia, high friction, non-backdrivable actuator from its output and can enable high fidelity force control. In this paper, a port-based decomposition is used to analyze the energetic behavior of such actuators in various physical domains. The general concepts are then applied to a prototype DD actuator for illustration and discussion. It is shown that, within physical bounds, the output torque from a DD actuator can be controlled independently from the input speed. This concept holds the potential to be scaled up and integrated in a compact and lightweight package powerful enough for incorporation with a portable lower limb orthotic or prosthetic device. PMID- 23366577 TI - A task description model for robotic rehabilitation. AB - The desire to produce robots to aid in physical neurorehabilitation has led to the control paradigm Assistance-As-Needed. This paradigm aims to assist patients in performing physical rehabilitation tasks whilst providing the least amount of assistance required, maximizing the patient's effort which is essential for recovery. Ideally the provided assistance equals the gap between the capability required to perform the task and the patient's available capability. Current implementations derive a measure of this gap by critiquing task performance based on some criteria. This paper presents a task description model for tasks performed by a patient's limb, allowing physical requirements to be calculated. Applied to two upper limb tasks typical of rehabilitation and daily activities, the effect of task variations on the task's physical requirements are observed. It is proposed that using the task description model to compensate for changing task requirements will allow better support by providing assistance closer to the true needs of the patient. PMID- 23366578 TI - Integration of a Multigrid ODE solver into an open medical simulation framework. AB - In this paper, we present the implementation of a Multigrid ODE solver in SOFA framework. By combining the stability advantage of coarse meshes and the transient detail preserving virtue of fine meshes, Multigrid ODE solver computes more efficiently than classic ODE solvers based on a single level discretization. With the ever wider adoption of the SOFA framework in many surgical simulation projects, introducing this Multigrid ODE solver into SOFA's pool of ODE solvers shall benefit the entire community. This contribution potentially has broad ramifications in the surgical simulation research community, given that in a single-resolution system, a constitutively realistic interactive tissue response, which presupposes large elements, is in direct conflict with the need to represent clinically relevant critical tissues in the simulation, which are typically be comprised of small elements. PMID- 23366579 TI - Muscle activity onset detection using energy detectors. AB - Muscle activity detection is important for clinical investigations leading to the identification of neuromuscular disorders. Myoelectric signal recorded via electrodes placed at skin surface can reveal important muscle excitation information about underlying limb movement. However, a primary difficulty in the detection of muscle activity period from myoelectric signals lies in the inherent variability of these signals and the noise added during the collection process. In the literature, the double threshold detector has been commonly used for detection of the muscle activity periods from myoelectric signals. In this study, we propose a new scheme based on the log-likelihood ratio test to detect muscle activity periods accurately. This scheme uses energy information contained in the myoelectric signal, which increases with the start of the activity. We demonstrate the viability of energy detection scheme via successful detection performed on synthetic as well as clinical myoelectric signals. PMID- 23366580 TI - Enhanced multi-site EMG-force estimation using contact pressure. AB - A modification method based on integrated contact pressure and surface electromyogram (SEMG) recordings over the biceps brachii muscle is presented. Multi-site sEMGs are modified by pressure signals recorded at the same locations for isometric contractions. The resulting pressure times SEMG signals are significantly more correlated to the force induced at the wrist (FW), yielding SEMG-force models with superior performance in force estimation. A sensor patch, combining six SEMG and six contact pressure sensors was designed and built. SEMG, and contact pressure data over the biceps brachii and induced wrist force data were collected from 5 subjects. Polynomial fitting was used to find a mapping between biceps SEMG and wrist force. Comparison between evaluation values from models trained with modified and non-modified SEMG signals revealed a statistically significant superiority of models trained with the modified SEMG. PMID- 23366581 TI - Fusion of spectral models for dynamic modeling of sEMG and skeletal muscle force. AB - In this paper, we present a method of combining spectral models using a Kullback Information Criterion (KIC) data fusion algorithm. Surface Electromyographic (sEMG) signals and their corresponding skeletal muscle force signals are acquired from three sensors and pre-processed using a Half-Gaussian filter and a Chebyshev Type- II filter, respectively. Spectral models - Spectral Analysis (SPA), Empirical Transfer Function Estimate (ETFE), Spectral Analysis with Frequency Dependent Resolution (SPFRD) - are extracted from sEMG signals as input and skeletal muscle force as output signal. These signals are then employed in a System Identification (SI) routine to establish the dynamic models relating the input and output. After the individual models are extracted, the models are fused by a probability based KIC fusion algorithm. The results show that the SPFRD spectral models perform better than SPA and ETFE models in modeling the frequency content of the sEMG/skeletal muscle force data. PMID- 23366582 TI - Cross-correlation analysis of multichannel uterine EMG signals. AB - The prevention of preterm labor remains one of the primary goals of obstetric research. One way to achieve this goal effectively is to understand the mechanisms regulating the uterine contractility. Herein, we evaluate the correlation between uterine electrical activities recorded from spatially distributed regions by calculating the nonlinear regression coefficient. Results have shown that, during pregnancy, the degree of interdependence between signals is very high whereas, at labor, the correlation between the signals decreases remarkably. We conclude that pregnancy is characterized by the presence of few local potential sources dominating the other sources while at the onset of labor, the number of these sources increases remarkably which affects therefore the correlation between the signals. PMID- 23366583 TI - Detecting missing signals in multichannel recordings by using higher order statistics. AB - In real world applications, a multichannel acquisition system is susceptible of having one or many of its sensors displaced or detached, leading therefore to the loss or corruption of the recorded signals. In this paper, we present a technique for detecting missing or corrupted signals in multichannel recordings. Our approach is based on Higher Order Statistics (HOS) analysis. Our approach is tested on real uterine electromyogram (EMG) signals recorded by 4*4 electrode grid. Results have shown that HOS descriptors can discriminate between the two classes of signals (missing vs. non-missing). These results are supported by statistical analysis using the t-test which indicated good statistical significance of 95% confidence level. PMID- 23366584 TI - An elementary analysis of physiologic shock and multi-organ failure: the autodigestion hypothesis. AB - Physiological shock and subsequent multi-organ failure is one of the most important medical problems from a mortality point of view. No agreement exists for mechanisms that lead to the relative rapid cell and organ failure during this process and no effective treatment. We postulate that the digestive enzymes synthesized in the pancreas and transported in the lumen of the small intestine as requirement of normal food digestion play a central role in multi-organ failure. These powerful enzymes are usually compartmentalized in the lumen of the intestine by the mucosal barrier, but may escape into the wall of the intestine if the permeability of the mucosal lining increases. Entry of the digestive enzymes into the wall of the intestine precipitates an autodigestion process as well as an escape of pancreatic enzymes and breakdown products generated by them into the system circulation. The consequence of autodigestion is multiorgan failure. We discuss the possibility to block the digestive enzymes in acute forms of shock as a potential therapeutic intervention. PMID- 23366585 TI - Early detection of hemorrhage via central pulse pressure derived from a non invasive peripheral arterial blood pressure waveform. AB - There is a profound need for early and convenient detection of hemorrhage in both civilian and military medicine. Due to wave reflection timing, central pulse pressure (PP), but not peripheral PP, is a surrogate of stroke volume (SV) and therefore an early marker of blood loss. However, only peripheral PP is convenient to measure. We tested an adaptive transfer function technique for deriving the central arterial blood pressure (ABP) waveform from a non-invasive peripheral ABP waveform in healthy humans subjected to lower body negative pressure (LBNP), a safe model of early hemorrhage. Our results showed that the derived central PP provided an earlier and more sensitive marker of progressive LBNP and a far more accurate measure of SV than measured peripheral PP. PMID- 23366586 TI - Autonomic control mechanism of maximal lower body negative pressure application. AB - Autonomic control mechanisms during progressive hemorrhage in humans remain complex and unclear. The present study investigates the autonomic reflexes during maximal application of lower body negative pressure (LBNP) that mimics severe hemorrhage in conscious human subjects (n=10) using analyses of heart rate variability (HRV) and systolic blood pressure variability (BPV) and baroreflex sensitivity. Spectral analysis of HRV included linear power spectral density (PSD), and nonlinear principal dynamic modes (PDM) methods. The maximal LBNP application decreased (P<0.01) the systolic and pulse pressures (PP), root mean square successive differences, normalized high frequency (HF) power of HRV, and transfer function gains at low frequency (LF) and HF bands. Meanwhile, increases (P<0.05) in heart rate, diastolic blood pressure (DBP), LFHRV, LF/HFHRV, and sympathetic activity of HRV using PDM were observed during maximal LBNP tolerance. After the termination of LBNP, no significant changes (P>0.05) were found in all the parameters except DBP and PP between recovery and baseline conditions. Rapid application of maximal LBNP that simulated severe hemorrhage was found to be associated with unloading of baroreflex mediated increased sympathetic reflex. PMID- 23366587 TI - Monitoring heartbeat nonlinear dynamics during general anesthesia by using the instantaneous dominant Lyapunov exponent. AB - We present a novel methodology for instantaneous estimation of quantitative correlates of depth of Anesthesia from noninvasive electrocardiographic recordings. The analysis is based on a point process model of heartbeat dynamics that allows for continuous tracking of linear and nonlinear HRV indices, including a novel instantaneous assessment of the Lyapunov Spectrum by using a cubic autoregressive formulation. The effective estimation of the model parameters is ensured by the Laguerre expansion of the Wiener-Volterra kernels along with the maximum local log-likelihood procedure. We apply the proposed assessment to experimental recordings from healthy subjects during propofol anesthesia. The new assessment reveals novel time-varying complex heartbeat dynamics that underlie the quasi-periodic heartbeat fluctuations elicited by the sympatho-vagal balance. Results suggest that such quantification provides important information which is independent from the standard autonomic assessment and significantly correlated with loss of consciousness. Further investigation will focus on evolving our mathematical approach towards a promising monitoring tool for an accurate, noninvasive assessment of general anesthesia. PMID- 23366588 TI - Comparisons of predictors of fluid responsiveness in major surgery. AB - The majority of studies on fluid responsiveness is focused on volume expansion maneuvers in intensive care unit (ICU), while fewer studies have analyzed the same problem during major surgery. Among them, the results are contrasting. The aim of this work was to compare the performance of different hemodynamic indices in the prediction of cardiac output variations following fast fluid infusion. The study was limited to a particular type of major surgery, i.e. liver transplantation and hepatectomy. Our results showed that pulse pressure variation (PPV) estimated according to the definition, i.e. within single respiratory cycles, and PPV estimated by PiCCO monitor system are coherent and very similar. Moreover, PPV and stroke volume variation (SVV) produced good values of sensitivity and specificity in separating the subjects into responsive and non responsive to maneuvers. PMID- 23366589 TI - Adaptive pulse segmentation and artifact detection in photoplethysmography for mobile applications. AB - Pulse oximeters non-invasively measure heart rate and oxygen saturation and have great potential for predicting critical illness. The photoplethysmogram (PPG) recorded from pulse oximetry is often corrupted with artifacts. These artifacts render the derived vital signs inaccurate. PMID- 23366590 TI - Highly comparative fetal heart rate analysis. AB - A database of fetal heart rate (FHR) time series measured from 7 221 patients during labor is analyzed with the aim of learning the types of features of these recordings that are informative of low cord pH. Our 'highly comparative' analysis involves extracting over 9 000 time-series analysis features from each FHR time series, including measures of autocorrelation, entropy, distribution, and various model fits. This diverse collection of features was developed in previous work [1]. We describe five features that most accurately classify a balanced training set of 59 'low pH' and 59 'normal pH' FHR recordings. We then describe five of the features with the strongest linear correlation to cord pH across the full dataset of FHR time series. The features identified in this work may be used as part of a system for guiding intervention during labor in future. This work successfully demonstrates the utility of comparing across a large, interdisciplinary literature on time-series analysis to automatically contribute new scientific results for specific biomedical signal processing challenges. PMID- 23366591 TI - A multiresolution analysis for detection of abnormal lung sounds. AB - Automated analysis and detection of abnormal lung sound patterns has great potential for improving access to standardized diagnosis of pulmonary diseases, especially in low-resource settings. In the current study, we develop signal processing tools for analysis of paediatric auscultations recorded under non ideal noisy conditions. The proposed model is based on a biomimetic multi resolution analysis of the spectro-temporal modulation details in lung sounds. The methodology provides a detailed description of joint spectral and temporal variations in the signal and proves to be more robust than frequency-based techniques in distinguishing crackles and wheezes from normal breathing sounds. PMID- 23366592 TI - Multi-lead QRS detection using window pairs. AB - We designed a novel approach for multi-lead QRS detection. The algorithm uses one equation with two different window widths to generate a feature signal and a detection threshold. This enables it to adapt to various changes in QRS morphology and noise levels, resulting in a detection error rate of just 0.29% on the MIT-BIH Arrhythmia Database. The algorithm is also computationally efficient and capable of resolving differences between multiple leads by automatically attaching a confidence value to each QRS detection. PMID- 23366593 TI - Automated algorithm for Wet/Dry cough sounds classification. AB - Cough is the most common symptom of several respiratory diseases. It is a defense mechanism of the body to clear the respiratory tract from foreign materials inhaled accidentally or produced internally by infections. The identification of wet and dry cough is an important clinical finding, aiding in the differential diagnosis. Wet coughs are more likely to be associated with bacterial infections. At present, the wet/dry decision is based on the subjective judgment of a physician, during a typical consultation session. It is not available for long term monitoring or in the assessment of treatment efficacy. In this paper we address these issues and develop fully automated technology to classify cough into 'Wet' and 'Dry' categories. We propose novel features and a Logistic regression-based model for the classification of coughs into wet/dry classes. The performance of the method was evaluated on a clinical database of pediatric and adult coughs recorded using a bed-side non-contact microphone. The sensitivity and specificity of the classification were obtained as 79+/-9% and 72.7+/-8.7% respectively. These indicate the potential of the method as a useful clinical tool for cough monitoring, especially at home settings. PMID- 23366594 TI - Robust artefact detection in long-term ECG recordings based on autocorrelation function similarity and percentile analysis. AB - Artefacts can pose a big problem in the analysis of electrocardiogram (ECG) signals. Even though methods exist to reduce the influence of these contaminants, they are not always robust. In this work a new algorithm based on easy-to implement tools such as autocorrelation functions, graph theory and percentile analysis is proposed. This new methodology successfully detects corrupted segments in the signal, and it can be applied to real-life problems such as for example to sleep apnea classification. PMID- 23366595 TI - Diffuse optical imaging for monitoring treatment response in breast cancer patients. AB - The necessity for a non-invasive and inexpensive imaging modality to both diagnose and monitor treatment response has lead to renewed interest in the potential of optical imaging. The aim of this study was to investigate the potential of diffuse optical spectroscopy for monitoring of patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy. Fifteen women receiving neoadjuvant treatment for breast cancer had the affected breast scanned 5 times: before, 1 week, 4 weeks, and 8 weeks following initiation of the treatment and prior to surgery. Data was collected using a commercial optical system at four different wavelengths (690 nm, 730 nm, 780 nm, and 830 nm) and used to create three dimensional tomographic images. Mean measured values of deoxyhemoglobin (Hb), oxyhemoglobin (HbO(2)), and water in the entire breast were obtained and integrated over the entire breast volume to calculate the integrated optical index for each parameter. Volume-of-interest weighted tissue Hb, HbO(2), and water corresponding to the tumor were also calculated. Patient response to the treatment was evaluated from clinical and pathological response using whole mount pathology after mastectomy. PMID- 23366596 TI - Single molecule tracking of P-glycoprotein in live cells reveals dynamic heterogeneity. AB - P-glycoprotein transports chemotherapy drugs from the plasma membrane and allows cancer cells to survive treatment. We transiently transfected PGP labeled with enhanced green fluorescent protein (PGP-EGFP) into MES-SA cells and used single molecule tracking techniques to characterize the dynamics on the surface of live cells. PGP exhibits freely diffusive behavior at short times and is confined at long times with a transition to anomalous diffusion at 0.7 s. PMID- 23366597 TI - Performance enhancement and background removal to improve dynamic phase imaging of biological organisms. AB - This paper describes recent advances in enhancing optical imaging performance and removal of background shape for a new, novel interference dynamic microscope system. The specially designed optical system enables instantaneous 4-dimensional video measurements of dynamic motions within and among live cells without the need for labels or contrast agents. This instrument utilizes a pixelated phase mask enabling simultaneous measurement of multiple interference patterns. It incorporates the polarization properties of light to capture phase image movies in real time at video rates enabling tracking of dynamic motions and volumetric changes. Optical thickness data are obtained from phase images after processing to remove the background surface shape to quantify changes in cell position and volume. Data from a number of different biological organisms will be presented. These data highlight examples of the optical image quality and image processing. PMID- 23366598 TI - Anterior chamber angle classification using multiscale histograms of oriented gradients for glaucoma subtype identification. AB - Glaucoma subtype can be identified according to the configuration of the anterior chamber angle(ACA). In this paper, we present an ACA classification approach based on histograms of oriented gradients at multiple scales. In digital optical coherence tomography (OCT) photographs, our method automatically localizes the ACA, and extracts histograms of oriented gradients (HOG) features from this region to classify the angle as an open angle (OA) or an angle-closure(AC). This proposed method has three major features that differs from existing methods. First, the ACA localization from OCT images is fully automated and efficient for different ACA configurations. Second, the ACA is directly classified as OA/AC by using multiscale HOG visual features only, which is different from previous ACA assessment approaches that on clinical features. Third, it demonstrates that visual features with higher dimensions outperform low dimensional clinical features in terms of angle closure classification accuracy. Testing was performed on a large clinical dataset, comprising of 2048 images. The proposed method achieves a 0.835+/-0.068 AUC value and 75.8% +/- 6.4% balanced accuracy at a 85% specificity, which outperforms existing ACA classification approaches based on clinical features. PMID- 23366599 TI - Application of scale-space descriptors for the reliable detection of keypoints for image registration in optical mapping studies in whole heart preparations. AB - Data acquired using Optical Mapping (OM) studies are affected by motion artifacts due to the inherent contraction of the heart. Those artifacts can be reduced by registering the images obtained by the OM system or by the combination of approaches like physical restraint of the heart or ratiometry with image registration. Due to the lack of high contrast features most registration methods are not suitable for this application. This paper is focused on the utilization of scale space theory and local descriptors to enhance the detection of local features in OM images and to describe the movement of keypoints. This information can be used to determine a suitable set of transformations to perform the registration process. PMID- 23366600 TI - Integrated intravascular optical coherence tomography (OCT) - ultrasound (US) catheter for characterization of atherosclerotic plaques in vivo. AB - A miniature integrated intravascular optical coherence tomography (OCT) - ultrasound (US) catheter for real-time imaging of atherosclerotic plaques has been developed, providing high resolution and deep tissue penetration at the same time. This catheter, with an outer diameter of 1.18mm, is suitable for imaging in human coronary arteries. The first in vivo 3D imaging of atherosclerotic microstructure in a rabbit abdominal aorta obtained by an integrated OCT-US catheter is presented. In addition, in vitro imaging of cadaver coronary arteries were conducted to demonstrate the imaging capabilities of this integrated catheter to classify different atherosclerotic plaque types. PMID- 23366601 TI - Performance assessment and optimization of Pulse Wave Imaging (PWI) in ex vivo canine aortas and in vivo normal human arteries. AB - The amplitude, velocity, and morphology of the arterial pulse wave may all provide valuable diagnostic information for cardiovascular pathology. Pulse Wave Imaging (PWI) is an ultrasound-based method developed by our group to noninvasively visualize and map the spatio-temporal variations of the pulse wave induced vessel wall motion. Because PWI is capable of acquiring multiple wall motion waveforms successively along an imaged arterial segment over a single cardiac cycle in vivo, the regional morphological changes, amplitudes, and velocity (i.e. pulse wave velocity, or PWV) of the pulse wave can all be evaluated. In this study, an ex vivo setup was used to assess the effects of varying PWI image acquisition variables (beam density/frame rate and scanning orientation) and signal processing methods (beam sweep compensation scheme and waveform feature tracking) on the PWV estimation in order to validate the optimal parameters. PWI was also performed on the carotid arteries and abdominal aortas of six healthy volunteers for identification of several salient features of the waveforms over the entire cardiac cycle that may aid in assessing the morphological changes of the pulse wave. The ex vivo results suggest that the PWI temporal resolution is more important for PWV estimation than the PWI spatial resolution, and also that the reverse scanning orientation (i.e. beam sweeping direction opposite the direction of fluid flow) is advantageous due to higher precision and less dependence on the frame rate. In the in vivo waveforms, the highest precision PWV measurements were obtained by tracking the 50% upstroke of the waveforms. Finally, the dicrotic notch, reflected wave, and several inflection points were qualitatively identified in the carotid and aortic anterior wall motion waveforms and shown in one representative subject. PMID- 23366602 TI - Organ boundary determination algorithm for detecting internal bleeding. AB - The purpose of this paper is to propose an organ boundary determination method for detecting internal bleeding. Focused assessment with sonography for trauma (FAST) is important for patients who are sent into shock by internal bleeding. However, the FAST has a low sensitivity, approximately 42.7 %. This study aims, therefore, to construct an automatic internal bleeding detection robotic system on the basis of ultrasound (US) image processing to improve the sensitivity. We developed method for determining algorithms of organ boundaries by low-brightness set analysis, and we detected internal bleeding by the proposed method. Experimental results based on clinical US images of internal bleeding between Liver and Kidney showed that proposed algorithms had a sensitivity of 77.8% and specificity of 95.7%. PMID- 23366603 TI - A biventricular multimodal (MRI/ultrasound) cardiac phantom. AB - A cardiac phantom can be of crucial importance in the development and validation of ultrasound and cardiac magnetic resonance (MR) imaging and image analysis methods. A biventricular multimodal cardiac phantom has been manufactured in house that can simulate normal and pathologic hearts with different degrees of infarction. The two-chamber structure can simulate the asymmetric left ventricular motion. Poly Vinyl Alcohol (PVA) is utilized as the basic material since it can simulate the shape, elasticity, and MR and ultrasound properties of the heart. The cardiac shape is simulated using a two-chamber acrylic mold. An additional pathologic heart phantom has been built to simulate aneurysm and infarction. Segmental dyskinesis is modeled based on three inclusions of different shapes and different degrees of elasticity. The cardiac elasticity is adjusted based on freeze-thaw cycles of the PVA cryogel for normal and scarred regions. PMID- 23366604 TI - Noninvasive internal bleeding detection method by measuring blood flow under ultrasound cross-section image. AB - The purpose of this paper is to propose noninvasive internal bleeding detection method by using ultrasound (US) image processing under US cross-section image. In this study, we have developed a robotic system for detecting internal bleeding based on the blood flow measured by using a noninvasive modality like an US imaging device. Some problems related to the measurement error, however, still need to be addressed. In this paper, we focused on US image processing under US cross-section image, and constructed blood flow measurement algorithm under US cross-section image for internal bleeding detection. We conducted preliminary blood flow measurement experiments using a phantom containing artery model and a manipulator equipped with a US probe (BASIS-1). The results present the experimental validation of the proposed method. PMID- 23366605 TI - Volumetric imaging using single chip integrated CMUT-on-CMOS IVUS array. AB - An intravascular ultrasound (IVUS) catheter that can provide forward viewing volumetric ultrasound images would be an invaluable clinical tool for guiding interventions. Single chip integration of front-end electronics with capacitive micromachined ultrasonic transducers (CMUTs) is highly desirable to reduce the interconnection complexity and enable miniaturization in IVUS catheters. For this purpose we use the monolithic CMUT-on-CMOS integration where CMUTs are fabricated directly on top of pre-processed CMOS wafers. This minimizes parasitic capacitances associated with connection lines. We have recently implemented a system design including all the required electronics using 0.35-um CMOS process integrated with a 1.4-mm diameter CMUT array. In this study, we present the experimental volumetric imaging results from an ex-vivo chicken heart phantom. The imaging results demonstrate that the single-chip forward looking IVUS (FL IVUS) system with monolithically integrated electronics has potential to visualize the front view of coronary arteries. PMID- 23366606 TI - Carotid ultrasound symptomatology using atherosclerotic plaque characterization: a class of Atheromatic systems. AB - In this paper, we present a Computer Aided Diagnosis (CAD) based technique (Atheromatic system) for classification of carotid plaques in B-mode ultrasound images into symptomatic or asymptomatic classes. This system, called Atheromatic, has two steps: (i) feature extraction using a combination of Discrete Wavelet Transform (DWT) and averaging algorithms and (ii) classification using Support Vector Machine (SVM) classifier for automated decision making. The CAD system was built and tested using a database consisting of 150 asymptomatic and 196 symptomatic plaque regions of interests which were manually segmented. The ground truth of each plaque was determined based on the presence or absence of symptoms. Three-fold cross-validation protocol was adapted for developing and testing the classifiers. The SVM classifier with a polynomial kernel of order 2 recorded the highest classification accuracy of 83.7%. In the clinical scenario, such a technique, after much more validation, can be used as an adjunct tool to aid physicians by giving a second opinion on the nature of the plaque (symptomatic/asymptomatic) which would help in the more confident determination of the subsequent treatment regime for the patient. PMID- 23366607 TI - Causal Markov random field for brain MR image segmentation. AB - We propose a new Bayesian classifier, based on the recently introduced causal Markov random field (MRF) model, Quadrilateral MRF (QMRF). We use a second order inhomogeneous anisotropic QMRF to model the prior and likelihood probabilities in the maximum a posteriori (MAP) classifier, named here as MAP-QMRF. The joint distribution of QMRF is given in terms of the product of two dimensional clique distributions existing in its neighboring structure. 20 manually labeled human brain MR images are used to train and assess the MAP-QMRF classifier using the jackknife validation method. Comparing the results of the proposed classifier and FreeSurfer on the Dice overlap measure shows an average gain of 1.8%. We have performed a power analysis to demonstrate that this increase in segmentation accuracy substantially reduces the number of samples required to detect a 5% change in volume of a brain region. PMID- 23366608 TI - Fully automated segmentation of the left ventricle applied to cine MR images: description and results on a database of 45 subjects. AB - A fully automated segmentation method of the left ventricle from short-axis cardiac MR images is proposed and evaluated. The segmentation is based on morphological filtering and gradient vector flow snake for which an automatic setting of parameters has already been proposed. The present work focuses on the automatic detection of a region of interest (ROI) surrounding the left ventricle, prior to the segmentation step. The whole process was applied to the MICCAI 2009 Left Ventricle Challenge database containing 45 subjects (9 healthy subjects and 36 with pathology). The automatic detection of the ROI was judged accurate in 86% of the cases. It failed in 2% of the slices and provided an overestimation in 9% of the slices. Furthermore, the endocardial segmentation was accurate in 80% of the slices and the epicardial was judged satisfactory in 71% of the slices. This fully automated procedure can thus be used as a first step in a user controlled approach, in order to reduce the total number of interactions. PMID- 23366609 TI - Automatic segmentation of the left atrium from MRI images using salient feature and contour evolution. AB - We propose an automatic approach for segmenting the left atrium from MRI images. In particular, the thoracic aorta is detected and used as a salient feature to find a seed region that lies inside the left atrium. A hybrid energy that combines robust statistics and localized region intensity information is employed to evolve active contours from the seed region to capture the whole left atrium. The experimental results demonstrate the accuracy and robustness of our approach. PMID- 23366610 TI - A deformable cosegmentation algorithm for brain MR images. AB - Cosegmentation aims to simultaneously segment the common parts in a pair of images, and has recently attracted increasing research attention in the field of computer vision. In this paper, we propose a novel deformable cosegmentation (D C) algorithm to solve the brain MR image segmentation problem by cosegmenting the image and a co-registered atlas. In this manner, the prior heuristic information about brain anatomy that is embedded in the atlas can be transformed into the constraints that control the segmentation of brain MR images. Based on the multiphase Chan-Vese model, the proposed D-C algorithm is implemented using level set techniques. Then, it is compared to the protocol algorithm and the state-of the-art GA-EM algorithm in T1-weighted brain MR images corrupted by different levels of Gaussian noise and intensity non-uniformity. Our results show that the proposed D-C algorithm can differentiate major brain structures more accuratly and produce more robust segmentation of brain MR images. PMID- 23366611 TI - Parcellation of human inferior parietal lobule based on diffusion MRI. AB - The function of a brain region can be constrained by its anatomical connections. The Inferior Parietal Lobule (IPL) is a cortical region with marked functional heterogeneity, involved in visuospatial attention, memory, language and mathematical cognition. In this work three different variants of the normalized graph-cut clustering algorithm were applied to obtain a parcellation of the IPL of living subjects into component regions based on the estimate of anatomical connectivity obtained from diffusion tensor tractography. Results over the three different algorithms were compared and a new metric proposed to measure the quality of individual parcellations by comparing to standard atlas regions. In this study of 19 subjects, an average of 64% overlap with the Juelich brain atlas was observed. PMID- 23366612 TI - Towards on line monitoring the evolution of the myocardium infarction scar with an implantable electrical impedance spectrum monitoring system. AB - The human heart tissue has a limited capacity for regeneration. Tissue and cellular therapies based on the use of stem cells may be useful alternatives to limit the size of myocardial infarction. In this paper, the preliminary results from an experimental campaign for on-line monitoring of myocardium scar infarction are presented. This study has been carried out under a research project that has as main objective the development and application of a bioactive patch implant for regeneration of myocardial infarction. Electrical Impedance Spectroscopy (EIS) has been chosen as a tissue state monitoring technique. What is presented in this communication is the first results of an implantable EIS measurement system which has been implanted in a subset of the animals corresponding to the control group, along one month. In all the animals, the myocardial infarction was induced by the ligation of the first circumflex marginal artery. In the animal group presented, the bioactive patch scaffold and the electrodes were implanted without the stem cells load. The scaffold is a piece of decellularized human pericardium, lyophilized and rehydrated with hydrogel RAD16-I. Nanogold particles were also placed near the electrodes to improve the electrode area conductivity. The results presented correspond to the subset of animals (n = 5), which had implanted the bioimpedance system monitoring the electrical impedance spectrum in vivo during 1 month. Two electrodes were connected to the bioactive patch implant. A total of 14 logarithmically spaced frequencies were measured every 5 minutes, from 100 Hz to 200 kHz. Results show a convergence of low-frequency and high frequency impedance magnitudes along the measurement period, which is coherent with the scar formation. PMID- 23366613 TI - Non-contact cardiopulmonary monitoring algorithm for a 24 GHz Doppler radar. AB - The paper presents the particularities of using a Doppler radar in the 24 GHz band for non-contact cardiopulmonary monitoring. To separate heart beat from respiration we looked for a pattern in time-frequency domain instead of trying to extract directly the distance from phase observation in the baseband signal. By selecting the proper components from the Gabor transform prior expansion we obtained good accuracy for heart beat and respiration rates. Also, with minor correction in frequency, the algorithm leads to usable heartbeat waveform, opening new doors for further information extraction. PMID- 23366614 TI - On the use of smart stents for monitoring in-stent restenosis. AB - In angioplasty with stent placement, re-narrowing of the artery within the stent site may occur due to the body's natural response to "heal" the stented area. This re-narrowing, also known as "in-stent restenosis", usually occurs within 6 months after surgery. To monitor and diagnose in-stent restenosis, passive telemonitoring using smart stents has been already proposed. In this paper, we present a feasibility study and advocate the use of an alternative method, namely active telemonitoring, which uses an integrated circuit embedded on the smart stent. Electromagnetic simulations and in-vitro measurements are presented to find the suitable range of frequency to wirelessly transfer power to the active device embedded on the smart stent. Furthermore, the range of induced power levels are simulated and experimentally verified. PMID- 23366615 TI - Development of an autonomic portable single-board computer based high resolution NIRS device for microcirculation analysis. AB - Near Infrared Spectroscopy (NIRS) is a wellestablished non-invasive technique for measuring metabolic changes in biological tissue. In this paper we describe the design and development of an autonomic portable single board computer based high resolution NIRS device, which allows quantification of these changes. The sensor patch consisting of 8LEDs and 2photo-detectorsprovides8 channels for each detector, offering increased depth resolution for monitoring microcirculatory activity..NIRS data is acquired with a sampling rate of about 2Hz per channel using the data acquisition board which consists of a 16 bit ADC, a LED driver and programmable gain amplifiers. The components on the data acquisition board are controlled via the Advantech's PCM-3355L SBC based on Windows XP platform. The software was created using Visual Basic 6.0 and Microsoft Visual C++ 6.0. It offers optionally a real time 'monitoring' and a static data (offline) visualization mode. The most unique feature of the system is its ability to auto calibrate itself i.e. Adopt the intensity of the LEDs output light to different experimental conditions, e.g. local melanin content, density of the tissue, and emitter-detector distances. To validate the device various experiments have been carried out such as measurements on resting and working gastrocnemius and biceps muscle in ambulatory situations. The achieved results confirmed adequate performance and reliability of the device. PMID- 23366616 TI - Blood pressure estimation using maximum slope of oscillometric pulses. AB - A new oscillometric pulse index (OPI) derived from the maximum slope (MS) of each pulse in the oscillometric blood pressure waveform is proposed for blood pressure estimation. Maximum slope for each pulse is obtained using the first derivative of the pulse and an envelope of the values corresponding to the maximum slopes is obtained. The maximum of the envelope is taken as the mean arterial pressure (MAP) and the systolic blood pressure (SBP) and diastolic blood pressure (DBP) estimates are obtained as a fraction of the MAP, similar to the traditional maximum amplitude algorithm (MAA). The proposed algorithm is tested on 18 healthy subjects. The MAP, SBP and DBP estimates obtained from the proposed algorithm are compared with those obtained from a commercial blood pressure device and with the estimates obtained using the MAA and morphological qualitative measures available in the literature. PMID- 23366617 TI - Plug-and-play, single-chip photoplethysmography. AB - Remote patient monitoring (RPM) relies on low-cost, low-power, wearable sensors for continuous physiological assessment. Photoplethysmographic (PPG) sensors generally require >10 components, occupy an area >300 mm(2), consume >10 mW power, and cost >$20 USD. Although the principle of PPG sensing is straightforward, in practice, a robust implementation requires a careful design including optical alignment, analog circuits, ambient light cancellation, and power management. This paper reports the first use of digital optical proximity sensors (OPS) for "plug-and-play" PPG. OPS have traditionally been used for distance sensing in smartphones and factory automation. Here we show that a digital OPS can perform PPG functions in a single 4*4 mm package which also provides a direct digital interface to a microcontroller. By exploiting its key features, a digital OPS can provide substantial performance advantages over existing state-of-the-art PPGs, including: i) 10X lower power consumption (200 uW) due to pulse operation; ii) high signal to noise ratio (>90), as a result of built-in optical barriers, filters, and ambient light cancellation; iii) 10X lower cost ($2 USD); and iv) 12X smaller area. We show single wavelength PPG measurements in multiple anatomical locations, including fingertips and earlobes. The results suggest that a digital OPS can provide an elegant solution for battery-powered, wearable physiological monitors. To the authors' knowledge, this is the smallest and lowest power PPG sensor reported to date. PMID- 23366618 TI - Application of the Geselowitz relationship to the murine conductance catheter. AB - Conductance catheters are known to have a nonuniform spatial sensitivity due to the distribution of the electric field. The Geselowitz relation is applied to the murine conductance catheter using a finite element model to determine catheter's spatial sensitivity in uniform media. Further analysis of FEM numerical modeling results using the Geselowitz relation provides a true measure of parallel conductance in a simplified murine left ventricle for assessment of the admittance method and hypertonic saline techniques. The spatial sensitivity of blood conductance (G(b)) is determined throughout the cardiac cycle. G(b) is converted to volume using Wei's equation to determine if the presence of myocardium alters the nonlinear relationship through changes to the electric field shape. Results show that the admittance method correctly calculates G(b) in comparison to the Geselowitz relation, and that the relationship between G(b) and volume is accurately fit using Wei's equation. PMID- 23366619 TI - Design of a high sensitive non-faradaic impedimetric sensor. AB - An electrochemical approach towards identifying antigen-antibody binding interactions is studied by using a non-faradaic impedimetric sensor fabricated on a printed circuit board (PCB) chip. An electrical methodology for detecting protein interactions at ultra-low concentrations (in the femtogram/mL) regime has been demonstrated. Nanoporous alumina with pore diameter of 200nm and pore depth of 250 nm was used as the signal amplifying medium. Cardiac biomarker, brain natriuretic peptide (BNP) was used as the study marker in characterizing the sensor's sensitivity. A sensitivity of 10 femtogram/mL was determined based on the impedimetric signal response. Sensitivity was determined through Nyquist plot analysis for the non-faradaic interactions of the protein biomolecules. This paper is the first demonstration of clinically relevant limit of detection with the BNP biomarker. PMID- 23366620 TI - Electrical flow metering of blood for point-of-care diagnostics. AB - We have developed a microfabricated chip that creates a purified white blood cell (WBC) population from whole blood samples and then electrically analyzes the WBCs at the same time as measuring sample volume flown. The flow metering is based on the measurement of the electrical admittance between microelectrodes inside a microfluidic channel. We found that the admittance related to the flow rate linearly. WBC counts which correlated with the flow rate shows how this technique is a viable method in metering and analyzing blood and other biological samples in a point-of-care environment. PMID- 23366621 TI - Electrical impedance spectroscopy for prostate cancer diagnosis. AB - Electrical impedance was recorded at 21 discrete frequencies (1 to 100 kHz) from 27 ex vivo human prostates. These electrical properties were measured by using custom designed Electrical Impedance Spectroscopy (EIS) sensing biopsy (Bx) needles. EIS-Bx needles gauge the electrical properties of tissue in tandem with the tissue extraction (used for histopathological assessment). The EIS-Bx probe has a signal-to-noise ratio (SNR) of 65 dB across the frequency range (1 kHz to 100 kHz). A total of 36 cancers and 288 benign regions were sampled from 27 human prostates. Mean resistance (R) of prostate decreased from 537.27 Omega to 126.74 Omega for benign tissues and 999.52 Omega to 340.67 Omega for malignant tissues across the 1 kHz - 100 kHz spectral range. Likewise, mean reactance (X) ranged from -391.41 Omega to -62.6 Omega for benign and -675.09 Omega to -162.28 Omega for cancer tissues over the same frequency range. Both R and X values are found to be significantly lower in normal prostate tissues than in malignant tissue (p<0.001). Further testing to evaluate the clinical efficacy of this coupled device is underway. PMID- 23366622 TI - Electrical impedance of human blood with and without anticoagulants in the beta dispersion region. AB - Impedance spectroscopy of blood with and without anticoagulants (Acid Citrate Dextrose (ACD), Ethylene Diamine Tetra-acetic Acid (EDTA) and Lithium Heparin (LH)), taken from healthy donors, ages 24-33, are performed in the frequency range 100 kHz-1MHz, using the two electrode impedance measurement method. High frequency data are used in fitting the Cole plot, assuming electrode polarization effects are negligible. It is verified that this is acceptable since the characteristic frequency of the blood is around 1MHz. Cole parameters are used to evaluate the effects of anticoagulants on blood impedance. Interior resistance of red blood cells is not influenced by addition of anticoagulants, whereas plasma resistance, characteristic frequency and depression angle changed. ACD decreases plasma resistance and alpha value of blood, but increases its characteristic frequency. LH significantly increases plasma resistance, but its effect in the characteristic frequency is not clear. No significant effects of EDTA on the electrical properties of blood are detected. PMID- 23366623 TI - The compact electro-acupuncture system for multi-modal feedback electro acupuncture treatment. AB - The compact electro-acupuncture (EA) system is proposed for the multi-modal feedback EA treatment. It is composed of a needle, a smart patch, and an interconnecting conductive thread. The 3cm diameter compact EA patch is implemented with the EA controller integrated circuit (IC) and the small coin battery on the planar-fashionable circuit board (P-FCB) technology. It can achieve the user convenience and the low manufacturing cost at once by removing the wire connections. The EA controller IC programs the stimulation current and also monitors the electromyography (EMG) and the skin temperature during the EA stimulation. The measured data can be wirelessly transmitted to the external EA analyzer through the body channel communication with low power consumption. The external EA analyzer can check the patient's status, such as the muscle fatigue and the change of the skin temperature, and the practitioner can change the stimulation parameters for the optimal curative value. The proposed compact EA system is fully implemented and tested on the human body. PMID- 23366624 TI - First study towards linear control of an upper-limb neuroprosthesis with an EEG based Brain-Computer Interface. AB - In this study we show how healthy subjects are able to use a non-invasive Motor Imagery (MI)-based Brain Computer Interface (BCI) to achieve linear control of an upper-limb neuromuscular electrical stimulation (NMES) controlled neuroprosthesis in a simple binary target selection task. Linear BCI control can be achieved if two motor imagery classes can be discriminated with a reliability over 80% in single trial. The results presented in this work show that there was no significant loss of performance using the neuroprosthesis in comparison to MI where no stimulation was present. However, it is remarkable how different the experience of the users was in the same experiment. The stimulation either provoked a positive reinforcement feedback, or prevented the user from concentrating in the task. PMID- 23366625 TI - Adaptive classification in a self-paced hybrid brain-computer interface system. AB - As the characteristics of EEG signals change over time, updating the classifier of a brain computer interface, BCI, (over time) would improve the performance of the system. Developing an adaptive classifier for a self-paced BCI however is not easy because the user's intention (and therefore the true labels of the EEG signals) are not known during the operation of the system. For certain applications, it may be possible to predict the labels of some of the EEG segments using some information about the user's state (e.g., the error potentials or gaze information). This study proposes a method that adaptively updates the classifier of a self-paced BCI in a supervised or semi-supervised manner, using those EEG segments whose labels can be predicted. We employ the eye position information obtained from an eye-tracker to predict the EEG labels. This eye-tracker is also used along with a self-paced BCI to form a hybrid BCI system. The results obtained from seven individuals show that the proposed algorithm outperforms the non-adaptive and other unsupervised adaptive classifiers. It achieves a true positive rate of 49.7% and lowers the number of false positives significantly to only 2.2 FPs/minute. PMID- 23366626 TI - Self-paced movement intention detection from human brain signals: Invasive and non-invasive EEG. AB - Neural signatures of humans' movement intention can be exploited by future neuroprosthesis. We propose a method for detecting self-paced upper limb movement intention from brain signals acquired with both invasive and non-invasive methods. In the first study with scalp electroencephalograph (EEG) signals from healthy controls, we report single trial detection of movement intention using movement-related potentials (MRPs) in a frequency range between 0.1 to 1 Hz. Movement intention can be detected above chance level (p<0.05) on average 460 ms before the movement onset with low detection rate during the non-movement intention period. Using intracranial EEG (iEEG) from one epileptic subject, we detect movement intention as early as 1500 ms before movement onset with accuracy above 90% using electrodes implanted in the bilateral supplementary motor area (SMA). The coherent results obtained with non-invasive and invasive method and its generalization capabilities across different days of recording, strengthened the theory that self-paced movement intention can be detected before movement initiation for the advancement in robot-assisted neurorehabilitation. PMID- 23366627 TI - Properties of a temporal difference reinforcement learning brain machine interface driven by a simulated motor cortex. AB - Our overall goal is to develop a reinforcement learning (RL) based decoder for brain machine interfaces. As an important step in this process, we determine the basic stability and convergence properties of a Temporal Difference (TD) RL architecture being driven by a simulated motor cortex. PMID- 23366628 TI - Latency correction of error potentials between different experiments reduces calibration time for single-trial classification. AB - One fundamental limitation of EEG-based brain-computer interfaces is the time needed to calibrate the system prior to the detection of signals, due to the wide variety of issues affecting the EEG measurements. For event-related potentials (ERP), one of these sources of variability is the application performed: Protocols with different cognitive workloads might yield to different latencies of the ERPs. In this sense, it is still not clear the effect that these latency variations have on the single-trial classification. This work studies the differences in the latencies of error potentials across three experiments with increasing cognitive workloads. A delay-correction algorithm based on the cross correlation of the averaged signals is presented, and tested with a single-trial classification of the signals. The results showed that latency variations exist between different protocols, and that it is feasible to re-use data from previous experiments to calibrate a classifier able to detect the signals of a new experiment, thus reducing the calibration time. PMID- 23366629 TI - Spoken sentences decoding based on intracranial high gamma response using dynamic time warping. AB - In this study, we explore the discriminability of high gamma activities from speech production cortex during the overt articulation of two sentences. Neural activities were recorded from one intracranial electrode placed approximately over the posterior part of the inferior frontal gyrus. By employing a dynamic time warping (DTW) method to realign single-trial high gamma response during speech productions, averaged temporal activation patterns corresponding to the two spoken sentences were obtained. Single-trial ECoG responses were subsequently classified according to their correlations with these two temporal activation patterns. On average, 77.5% of the trials were correctly classified, which was much higher than the chance-level performance of the SVM classifier without DTW. Our preliminary results shed light on the construction of cortical speech brain computer interfaces on the sentence level. PMID- 23366630 TI - Taking balance measurement out of the laboratory and into the home: discriminatory capability of novel centre of pressure measurement in fallers and non-fallers. AB - We investigated three methods for estimating centre of pressure excursions, as measured using a portable pressure sensor matrix, in order to deploy similar technology into the homes of older adults for longitudinal monitoring of postural control and falls risk. We explored the utility of these three methods as markers of falls risk in a cohort of 120 community dwelling older adults with and without a history of falls (65 fallers, 55 non-fallers). A number of standard quantitative balance parameters were derived using each centre of pressure estimation method. Rank sum tests were used to test for significant differences between fallers and non-fallers while intra-class correlation coefficients were also calculated to determine the reliability of each method. A method based on estimating the changes in the magnitude of pressure exerted on the pressure sensor matrix was found to be the most reliable and discriminative. Our future work will implement this method for home-based balance measurement. PMID- 23366631 TI - Displacement of centre of mass during quiet standing assessed using accelerometry in older fallers and non-fallers. AB - Postural sway during quiet standing is associated with falls risk in older adults. The aim of this study was to investigate the utility of a range of accelerometer-derived parameters of centre of mass (COM) displacement in identifying older adults at risk of falling. A series of instrumented standing balance trials were performed to investigate postural control in a group of older adults, categorised as fallers or non-fallers. During each trial, participants were asked to stand as still as possible under two conditions: comfortable stance (six repetitions) and semi-tandem stance (three repetitions). A tri-axial accelerometer was secured to the lower back during the trials. Accelerometer data were twice integrated to estimate COM displacement during the trials, with numerical techniques used to reduce integration error. Anterior-posterior (AP) and medial-lateral (ML) sway range, sway length and sway velocity were examined, along with root mean squared (RMS) acceleration. All derived parameters significantly discriminated fallers from non-fallers during both comfortable and semi-tandem stance. Results indicate that these accelerometer-based estimates of COM displacement may improve the discriminative power of quiet standing falls risk assessments, with potential for use in unsupervised balance assessment. PMID- 23366632 TI - Joint impedance decreases during movement initiation. AB - The mechanical properties of the joint influence how we interact with our environment and hence are important in the control of both posture and movement. Many studies have investigated how the mechanical properties-specifically the impedance-of different joints vary with different postural tasks. However, studies on how joint impedance varies with movement remain limited. The few studies that have investigated how impedance varies with movement have found that impedance is lower during movement than during posture. In this study we investigated how impedance changed as people transitioned from a postural task to a movement task. We found that subjects' joint impedances decreased at the initiation of movement, prior to increasing at the cessation of movement. This decrease in impedance occurred even though the subjects' torque and EMG levels increased. These findings suggest that during movement the central nervous system may control joint impedance independently of muscle activation. PMID- 23366633 TI - Muscle synergies are consistent when pedaling under different biomechanical demands. AB - In this study we investigate the muscle coordination underlying the execution of a pedaling exercise across different biomechanical demands, by using the muscle synergies paradigm. 9 non professional subjects performed a cycling exercise using their preferred pedaling strategy (Preferred Strategy, PS) and then, through the use of a feedback based on the presentation of a real-time index of mechanical efficiency determined by means of instrumented pedals, they were helped to optimize their pedaling technique (Effective Strategy, ES). EMG activity was recorded from 8 muscles of the dominant leg. Nonnegative Matrix Factorization was applied for the extraction of muscle synergies. 4 modules were sufficient to reconstruct the repertoire of muscle activations for all the subjects during PS condition, and these modules were found consistent across all the subjects (correlation > 83%). 5 muscle synergies were necessary for the characterization in ES condition; 4 out of these modules were shared with PS condition, and the resulting additional module appeared subject-specific. These preliminary results support the existence of a modular motor control in humans. PMID- 23366634 TI - Force adaptation in human walking with symmetrically applied downward forces on the pelvis. AB - The application of external constraints and/or applied forces during movement can lead to reactive as well as adaptive changes in human motion. Previous researches in the literature have usually focused on adaptation in human kinematics when external forces were applied using exoskeletons during the swing phase of gait. This work aims to study adaptation in human walking when externally applied forces are present on the pelvis both during the swing and stance phases of the gait. A novel tethered pelvic assist device (TPAD) was used to passively apply downward forces on the human pelvis while walking. During the experiment, healthy subjects walked on a treadmill at a constant speed while their kinematics and foot pressure data were recorded. Data analysis revealed that the healthy subjects exhibited both reactive as well as adaptive changes in their gait parameters. The immediate response of the subjects was to increase their hip flexion to clear their foot off the ground as they were unable to lift their pelvis to their usual height during normal motion. Seven out of eight subjects in the study resisted the downward forces to move their pelvis up. Eventually, they reached a level of downward force that they could sustain over the training. This adaptation to the downward force was reflected in the heel peak pressure values during the cycles of the gait. On removing the tethers, aftereffects in heel peak pressure during the gait cycles were observed. PMID- 23366635 TI - Subspace identification of Hammerstein systems using B-splines. AB - This paper presents an algorithm for the identification of Hammerstein cascades with hard nonlinearities. The nonlinearity of the cascade is described using a B spline basis with fixed knot locations; the linear dynamics are described using a state-space model. The algorithm automatically estimates both the order of the linear system and the number and locations of the knots used to characterize the nonlinearity. Therefore, it significantly reduces the a priori knowledge about the underlying system required for identification. A simulation study on a model of reflex stiffness shows that the new method estimates the nonlinearity accurately in the presence of output noise. PMID- 23366636 TI - Dynamic image pre-compensation for computer access by individuals with ocular aberrations. AB - Several image enhancement methods have been successfully used to improve the visual perception of patients with eye diseases, such as Age-related Macular Degeneration and Cataracts, on images displayed on TV and computers. However, few developments aim to enhance the visual performance of computer users with general ocular aberrations. This paper proposes an image enhancement approach based on dynamic pre-compensation for improving the visual performance of subjects with ocular aberrations, while interacting with computers. The degradation caused by ocular aberrations is counteracted through the pre-compensation performed on images displayed on the computer screen. As the ocular aberration initially measured as a priori information is related with a specific pupil size, real-time pupil size data are collected to recalculate and update the pre-compensation to match the corresponding aberrations. An icon recognition experiment, involving human subjects, was designed and implemented to evaluate the performance of the proposed method. The experimental results show that the proposed method significantly increased the number of icons correctly recognized, which confirmed that the dynamic pre-compensation is effective in improving the visual performance of computer users with ocular aberrations. PMID- 23366637 TI - The Personal Mobility and Manipulation Appliance (PerMMA): a robotic wheelchair with advanced mobility and manipulation. AB - The Personal Mobility and Manipulation Appliance (PerMMA) is a recently developed personal assistance robot developed to provide people with disabilities and older adults enhanced assistance in both mobility and manipulation, which are two fundamental components for independently activities of daily life performing, community participation, and quality of life. Technologies to assist with mobility and manipulation are among the most important tools for clinicians, end users and caregivers; however, there are currently few systems that provide practical and coordinated assistance with mobility and manipulation tasks. The PerMMA was not only developed and evaluated to provide users and caregivers enhanced mobility and manipulation options, but also as a clinical tool as well as research platform. The development and evaluation of PerMMA are presented in the paper. PMID- 23366638 TI - Alternative design of inductive pointing device for oral interface for computers and wheelchairs. AB - An inductive pointing device was designed and implemented successfully in a tongue controlled oral interface. Sensors were manufactured as an assembly of multilayer coils in the printed circuit board technology on two pads. The sensor pads were encapsulated together with electronics and battery in a mouthpiece, placed in the upper palate of the oral cavity. The PCB technology allowed surface activation of one or more sensors by gliding over the surface of the coils assembly of a small cylindrical unit attached to the tongue. The model consisted of 8 sensors and allowed real time proportional control of both speed and direction similar to a joystick. However, the size of the oral cavity, the number and geometry of the coil loops and characteristics of the activation unit impose limits in designing the sensors and call for an alternative layout design. Two alternative sensor designs are proposed in this paper, aiming to reduce the size of the sensor pad by one third, extending the target group, including children, and increasing the easiness of wear of the oral interface. PMID- 23366639 TI - Reliable neural interface: the first quarter century of the neurotrophic electrode. AB - For development of a long-term, reliable cortical recording electrode, animal and human data support the approach of trapping the brain inside the electrode. PMID- 23366640 TI - Preventing lapse in performance using a drowsiness monitoring and management system. AB - Research on public security, especially the safe manipulation and control of vehicles, has gained increasing attention in recent years. This study proposes a closed-loop drowsiness monitoring and management system that can estimate subjects' driving performance. The system observes electroencephalographic (EEG) dynamics and behavioral changes, delivers arousing feedback to individuals experiencing momentary cognitive lapses, and assesses the efficacy of the feedback. Results of this study showed that the arousing feedback immediately improved subject performance, which was accompanied by concurrent theta- and alpha-power suppression in the bilateral occipital areas. This study further demonstrated the feasibility of accurately assessing the efficacy of arousing feedback presented to drowsy participants by monitoring the changes in their EEG power spectra. PMID- 23366641 TI - An investigation into non-invasive physical activity recognition using smartphones. AB - Technology utilized to automatically monitor Activities of Daily Living (ADL) could be a key component in identifying deviations from normal functional profiles and providing feedback on interventions aimed at improving health. However, if activity recognition systems are to be implemented in real world scenarios such as health and wellness monitoring, the activity sensing modality must unobtrusively fit the human environment rather than forcing humans to adhere to sensor specific conditions. Modern smart phones represent a ubiquitous computing device which has already undergone mainstream adoption. In this paper, we investigate the feasibility of using a modern smartphone, with limited placement constraints, as the sensing modality for an activity recognition system. A dataset of 4 subjects performing 7 activities, using varying sensor placement conditions, is utilized to investigate this. Initial experiments show that a decision tree classifier performs activity classification with precision and recall scores of 0.75 and 0.73 respectively. More importantly, as part of this initial experiment, 3 main problems, and subsequently 3 solutions, relating to unconstrained sensor placement were identified. Using our proposed solutions, classification precision and recall scores were improved by +13% and +14.6% respectively. PMID- 23366642 TI - Effect of arching spine on deformation of the ligamentum flavum during epidural needle insertion. AB - When administering epidural anesthesia, anesthesiologists ask patients to arch their back. Arching the spine is thought to enlarge the gap between neighboring vertebral bones. The author hypothesized that tension inside the ligamentum flavum generated by arching the spine would reduce deformation of the ligamentum flavum during epidural needle insertion. Porcine spines from a slaughterhouse were cut at the vertebral body and separated into 10 pieces. Ligamentum flavum was painted black with liquid ink. A CCD camera recorded the deformation of the ligamentum flavum during needle insertion. To simulate the arching spine, the width of the ligamentum flavum was enlarged by a retractor. The thickness of the ligamentum flavum was measured from the stained images by the Elastica-van Gieson method. The maximum reaction force showed no significant difference between the natural and the enlarged ligamentum flavum. Average deformation was observed a statically significant decrease between the naturally deformed and retractor enlarged ligamentum flavum. For the maximum reaction force the coefficient of variance decreased by dividing raw data with thickness of the ligamentum flavum, which meant that the maximum reaction force correlated with thickness of the ligamentum flavum. Less effect on deformation was observed. Hypothesis was correct in the porcine study, while the difference between the porcine and the patient's spine should be examined in the next research. PMID- 23366643 TI - Specimen specific, 3D modeling of the elbow--prediction of strain in the medial collateral ligament. AB - In this project 3D interactive models of twelve cadaver elbows are developed using the author's kinematic simulation software. The effective flexion-extension axes for each specimen's model are iteratively defined based upon congruent joint motion and individual limits in range-of-motion. Origins and insertions of both parts of the medial collateral ligament are digitized following careful dissection of each specimen. Ligament paths are then defined using cubic B-spline models of the principal fibers of each part, flexion extension motion of each elbow is carried out in real-time and the strain of each fiber model is calculated. Results indicate the existence of two distinct populations of medial collateral ligament - one whose anterior part stretches during flexion of the elbow and the other whose anterior part stretches during extension. PMID- 23366644 TI - Creep evaluation of (orthotic) cast materials during simulated clubfoot correction. AB - The Ponseti method is a widely accepted and highly successful conservative treatment of pediatric clubfoot that relies on weekly manipulations and cast applications. However, the material behavior of the cast in the Ponseti technique has not been investigated. The current study sought to characterize the ability of two standard casting materials to maintain the Ponseti corrected foot position by evaluating creep response. A dynamic cast testing device (DCTD) was built to simulate a typical pediatric clubfoot. Semi-rigid fiberglass and rigid fiberglass casting materials were applied to the device, and the rotational creep was measured at various constant torques. The movement was measured using a 3D motion capture system. A 2-way ANOVA was performed on the creep displacement data at a significance level of 0.05. Among cast materials, the rotational creep displacement was found to be significantly different (p-values ? 0.001). The most creep displacement occurs in the semi-rigid fiberglass (approximately 1.0 degrees), then the rigid fiberglass (approximately 0.4 degrees). There was no effect of torque magnitude on the creep displacement. All materials maintained the corrected position with minimal change in position over time. PMID- 23366645 TI - A spherical parallel three degrees-of-freedom robot for ankle-foot neuro rehabilitation. AB - The ankle represents a fairly complex bone structure, resulting in kinematics that hinders a flawless robot-assisted recovery of foot motility in impaired subjects. The paper proposes a novel device for ankle-foot neuro-rehabilitation based on a mechatronic redesign of the remarkable Agile Eye spherical robot on the basis of clinical requisites. The kinematic design allows the positioning of the ankle articular center close to the machine rotation center with valuable benefits in term of therapy functions. The prototype, named PKAnkle, Parallel Kinematic machine for Ankle rehabilitation, provides a 6-axes load cell for the measure of subject interaction forces/torques, and it integrates a commercial EMG acquisition system. Robot control provides active and passive therapeutic exercises. PMID- 23366646 TI - Preliminary assessment of the efficacy of supplementing knee extension capability in a lower limb exoskeleton with FES. AB - The authors describe a cooperative controller that combines the knee joint actuation of an externally powered lower limb exoskeleton with the torque and power contribution from the electrically stimulated quadriceps muscle group. The efficacy of combining these efforts is experimentally validated with a series of weighted leg lift maneuvers. Measurements from these experiments indicate that the control approach effectively combines the respective efforts of the motor and muscle, such that good control performance is achieved, with substantial torque and energy contributions from both the biological and non-biological actuators. PMID- 23366647 TI - An optimized model for estimation of muscle contribution and human joint torques from sEMG information. AB - This paper develops a Hill model based technique to estimate human elbow torque from sEMG measurements. Some new parameters are included in the optimization process in order to improve the resulting estimated torque. These parameters correspond to activation levels of muscles involved in motion generation. They have not previously been used in other works dealing with this kind of model. Results from experiments with several subjects in different movement conditions and using the new optimized parameters lead to some conclusions about the generality of the optimized models and the influence of the new parameters on the improvement of the estimation. PMID- 23366648 TI - Cole function and conductance-based parasitic capacitance compensation for cerebral electrical bioimpedance measurements. AB - One of the most common measurement artifacts present in Electrical Bioimpedance Spectroscopy measurements (EBIS) comes from the capacitive leakage effect resulting from parasitic stray capacitances. This artifact produces a deviation in the measured impedance spectrum that is most noticeable at higher frequencies. The artifact taints the spectroscopy measurement increasing the difficulty of producing reliable EBIS measurements at high frequencies. In this work, an approach for removing such capacitive influence from the spectral measurement is presented making use of a novel method to estimate the value of the parasitic capacitance equivalent that causes the measurement artifact. The proposed method has been tested and validated theoretically and experimentally and it gives a more accurate estimation of the value of the parasitic capacitance than the previous methods. Once a reliable value of parasitic capacitance has been estimated the capacitive influence can be easily compensated in the EBIS measured data. Thus enabling analysis of EBIS data at higher frequencies, i.e. in the range of 300-500 kHz like measurements intended for cerebral monitoring, where the characteristic frequency is remarkably higher than EBIS measurements i.e. within the range 30 to 50 kHz, intended for body composition assessment. PMID- 23366649 TI - Time-dependent effects of low-frequency repetitive transcranial magnetic stimulation of the supramarginal gyrus. AB - In this paper, we report our studies of the effects of stimulating the bilateral supramarginal gyrus (SMG) with low-frequency transcranial magnetic stimulation (rTMS) or short-term rTMS on brain excitability in humans. We analyzed the effects of various durations of stimulation on P300 latencies of the event related potential (ERP). Magnetic pulses were delivered using a figure-eight flat coil. The intensity of rTMS was set to 80 % of the subject's motor threshold. In each round of rTMS, 100 magnetic pulses were applied over the scalp at frequencies of 1.00, 0.75, and 0.50 Hz. ERPs were measured prior to magnetic stimulation as a control. The effects of magnetic stimulation were then determined by measuring its effects on P300 latencies elicited by an odd-ball task. These latencies were measured before and 0, 5, 10, and 15 min after the magnetic stimulation. 1.00 Hz low-frequency rTMS of the left SMG decreased P300 latencies for approximately 10 min. In contrast, 0.50 Hz rTMS of the left SMG resulted in delayed P300 latencies for approximately 15 min. We furthermore found that 0.75 Hz rTMS of the left SMG and 1.00, 0.75 and 0.5 Hz rTMS of the right SMG did not affect P300 latencies. These results suggest that the duration of the effects of rTMS depend on the frequency of stimulation. PMID- 23366650 TI - An analog circuit implementation of a Huber-Braun cold receptor neuron model. AB - We present the design and implementation of an electronic device that, using off the shelf discrete analog components, implements the mathematical model of a cold receptor neuron called Huber-Braun. This model describes the electrical behavior of certain kinds of receptors when interacting with their environment, and it consists of a set of differential equations that has only been solved by numeric simulations. By these means a chaotic behavior has been found. An analog computer can be relevant for further analysis and validation of the model. The results obtained by means of numeric simulations and through our analog circuit simulator are consistent. In particular, temperature and external current bifurcation diagrams were successfully built. Finally, the electronic device allows the observation of all relevant variables and most of the expected behavior (tonic firing, chaotic, burst discharge, subthreshold oscillation and steady state). PMID- 23366651 TI - Spike-feature based estimation of electrode position in extracellular neural recordings. AB - Detecting and sorting spikes in extracellular neural recordings are common procedures in assessing the activity of individual neurons. In chronic recordings, passive electrode movements introduce changes in the shape of detected spike waveforms, and may thus lead to problems with identification and tracking of spikes recorded at separate instances in time, which is an important step in long-term monitoring of individual neurons. Information about electrode movements after implantation is crucial to the evaluation of mechanical stability of different electrode designs. In this paper, we present a preliminary study of the relationship between electrode movements and the resulting movements of spike features in feature space. We show that there is a characteristic relationship between the two movements and that this relationship can be modeled as a linear transformation between two coordinate systems. Finally, we show how the relationship can be used for estimating electrode positions based on measured spike waveforms without any prior knowledge about the type of neuron by introducing a learning procedure during electrode insertion. PMID- 23366652 TI - Visualization of orbital flow by means of phase contrast MRI. AB - Magnetic Resonance Imaging (MRI) is a high resolution medical imaging technique to image internal anatomical structures. Phase contrast MRI (pcMRI) technique is an add-on specification of MRI devices in order to quantify flow. Although different attempts have been introduced to measure orbital flows, a relationship between different ophthalmic physiological structures including superior ophthalmic vein, ophthalmic artery and optic nerve sheath (containing cerebrospinal fluid) using phase contrast MRI has not been established. In this study we investigate orbital flow in 5 normal subjects using a 3 tesla MRI device. pcMRI technique has been applied to extract flow in the superior ophthalmic vein and optic nerve sheath. Electrocardiogram of each subject was monitored and gated to the MRI in order to extract flow waveforms. Results show multiple peaks when assessing orbital flow waveforms, suggesting possible reflection of flow from back of the eye. These peaks have been characterized and a possible explanation to this phenomenon has been provided. This study enhances understanding of interaction between physiological structures at the retrolaminar portion of the eye which may be responsible for different ophthalmic abnormalities. PMID- 23366653 TI - Architecture of a mixed-mode electrophysiological signal acquisition interface. AB - This paper proposes mixed-mode architecture for the acquisition interface of electrophysiological signals. The architecture advances the analog-to-digital converter (ADC) from the second chopper signal in the conventional approach and performs the second chopper operation in the digital domain. The demanded low pass filter (LPF) is realized with a digital type. The analog LPF in feedback path is substituted with a digital one accompanying with a digital-to-analog converter (DAC). The analog variation is decreased due to the digitization of these operations. The entire architecture is simulated with the ECG input in a behavior model of Simulink. PMID- 23366654 TI - On the relationship between features extracted from EMG and force for constant and dynamic protocols. AB - The main objective of this study was to characterize the relationship between electromyography and force based on the results obtained from a developed analysis tool. The developed tool presents interesting features for the study of this relationship. Among them, it can be highlighted the possibility of simultaneous analysis of various features in the time domain (obtained from electromyographic signals), and the generation of graphics that allow the visualization of the relation between the selected features and the force signal. The tool also allows a feature evaluation based on different models (e.g., linear, quadratic and exponential) allowing a better understanding of the EMG force relationship. In order to evaluate the developed tool and study the EMG force correlation, electromyographic signals (EMG) and force measurements were collected from 15 subjects while executing eight different experimental protocols. The obtained results showed that statistical features (e.g., kurtosis and skewness) are less sensitive to dynamic force protocols; and also that features related to the amplitude of the signal are more appropriate to represent the relationship between EMG and force during the execution of constant force protocols. These results, besides having several practical applications, can be used as part of EMG signals simulators, developed for different applications, such as the evaluation of automatic systems used in the decomposition of EMG signals. PMID- 23366655 TI - Biometric sample extraction using Mahalanobis distance in Cardioid based graph using electrocardiogram signals. AB - In this paper, a person identification mechanism implemented with Cardioid based graph using electrocardiogram (ECG) is presented. Cardioid based graph has given a reasonably good classification accuracy in terms of differentiating between individuals. However, the current feature extraction method using Euclidean distance could be further improved by using Mahalanobis distance measurement producing extracted coefficients which takes into account the correlations of the data set. Identification is then done by applying these extracted features to Radial Basis Function Network. A total of 30 ECG data from MITBIH Normal Sinus Rhythm database (NSRDB) and MITBIH Arrhythmia database (MITDB) were used for development and evaluation purposes. Our experimentation results suggest that the proposed feature extraction method has significantly increased the classification performance of subjects in both databases with accuracy from 97.50% to 99.80% in NSRDB and 96.50% to 99.40% in MITDB. High sensitivity, specificity and positive predictive value of 99.17%, 99.91% and 99.23% for NSRDB and 99.30%, 99.90% and 99.40% for MITDB also validates the proposed method. This result also indicates that the right feature extraction technique plays a vital role in determining the persistency of the classification accuracy for Cardioid based person identification mechanism. PMID- 23366656 TI - Evaluation and adaptive attenuation of the cardiac vibration interference in mechanomyographic signals. AB - The study of the mechanomyographic signal of the diaphragm muscle (MMGdi) is a promising technique in order to evaluate the respiratory muscles effort. The relationship between amplitude and frequency parameters of this signal with the respiratory effort performed during respiration is of great interest for researchers and physicians due to its diagnostic potentials. However, MMGdi signals are frequently contaminated by a cardiac vibration or mechanocardiographic (MCG) signal. An adaptive noise cancellation (ANC) can be used to reduce the MCG interference in the recorded MMGdi activity. In this paper, it is evaluated the proposed ANC scheme by means of a synthetic MMGdi signal with a controlled MCG interference. The Pearson's correlation coefficient (PCC) between both root mean square (RMS) and mean frequency (fm) of the synthetic MMGdi signal are considerably reduced with the presence of cardiac vibration noise (from 0.95 to 0.87, and from 0.97 to 0.76, respectively). With the ANC algorithm proposed the effect of the MCG noise on the amplitude and frequency of MMG parameters is reduced considerably (PCC of 0.93 and 0.97 for the RMS and fm, respectively). The ANC method proposed in this work is an interesting technique to attenuate the cardiac interference in respiratory MMG signals. Further investigation should be carried out to evaluate the performance of the ANC algorithm in real MMGdi signals. PMID- 23366657 TI - ECG signal compression using compressive sensing and wavelet transform. AB - Compressed Sensing (CS) is a novel approach of reconstructing a sparse signal much below the significant Nyquist rate of sampling. Due to the fact that ECG signals can be well approximated by the few linear combinations of wavelet basis, this work introduces a comparison of the reconstructed 10 ECG signals based on different wavelet families, by evaluating the performance measures as MSE (Mean Square Error), PSNR (Peak Signal To Noise Ratio), PRD (Percentage Root Mean Square Difference) and CoC (Correlation Coefficient). Reconstruction of the ECG signal is a linear optimization process which considers the sparsity in the wavelet domain. L1 minimization is used as the recovery algorithm. The reconstruction results are comprehensively analyzed for three compression ratios, i.e. 2∶1, 4∶1, and 6∶1. The results indicate that reverse biorthogonal wavelet family can give better results for all CRs compared to other families. PMID- 23366658 TI - Estimation of arterial baroreflex sensitivity in relation to carotid artery stiffness. AB - Arterial baroreflex has a significant role in regulating blood pressure. It is known that increased stiffness of the carotid sinus affects mecanotransduction of baroreceptors and therefore limits baroreceptors capability to detect changes in blood pressure. By using high resolution ultrasound video signal and continuous measurement of electrocardiogram (ECG) and blood pressure, it is possible to define elastic properties of artery simultaneously with baroreflex sensitivity parameters. In this paper dataset which consist 38 subjects, 11 diabetics and 27 healthy controls was analyzed. Use of diabetic and healthy test subjects gives wide scale of arteries with different elasticity properties, which provide opportunity to validate baroreflex and artery stiffness estimation methods. PMID- 23366659 TI - Cerebral cortex and sub-cortex lateralization in cardiovascular regulation: correlations of BOLD fMRI and heart rate variability. AB - The role of cerebral cortex in cardiovascular regulation has not yet been mapped in detail. Especially the lateralization of different regions that are connected to cardiovascular modulation is still unknown. In this study we used simultaneously measured electrocardiography (ECG) and blood oxygen level dependent (BOLD) fMRI to examine the correlation of cerebral cortex and sub cortex activation and heart rate variability parameters. Correlations were calculated for 11 subjects. Regions of interest (ROIs) were predefined from observations made in previous studies. Lateralization was studied by forming ratios of left and right hemisphere activations in ROIs and calculating correlations of these to heart rate variability (HRV) parameters. Statistically significant correlations were found in every ROI. PMID- 23366660 TI - Detection of baroreceptor activity in rat vagal nerve recording using a multi channel cuff-electrode and real-time coherent averaging. AB - Electrical stimulation of afferent nerve fibers originating from pressure sensors can trigger the baroreflex to reduce blood pressure and might be an alternative to treat patients with hypertension. In this study, baroreceptor compound activity was detected using multi-channel cuff-electrode recordings on rat vagal nerve. In order to isolate the vagal nerve signals from external potentials (such as ECG- and EMG-coupling), a tripolar measuring technique was applied. To eliminate noise and neural signals corresponding to other organs, coherent averaging was used. The baroreceptor-correlated signals appear predominantly in one of the electrode channels, presumably close to the corresponding neural substrate. This localization was done in real-time. PMID- 23366661 TI - Association of autonomic nervous system and EEG scalp potential during playing 2D Grand Turismo 5. AB - Cerebral activation and autonomic nervous system have importance in studies such as mental stress. The aim of this study is to analyze variations in EEG scalp potential which may influence autonomic activation of heart while playing video games. Ten healthy participants were recruited in this study. Electroencephalogram (EEG) and electrocardiogram (ECG) signals were measured simultaneously during playing video game and rest conditions. Sympathetic and parasympathetic innervations of heart were evaluated from heart rate variability (HRV), derived from the ECG. Scalp potential was measured by the EEG. The results showed a significant upsurge in the value theta Fz/alpha Pz (p<0.001) while playing game. The results also showed tachycardia while playing video game as compared to rest condition (p<0.005). Normalized low frequency power and ratio of low frequency/high frequency power were significantly increased while playing video game and normalized high frequency power sank during video games. Results showed synchronized activity of cerebellum and sympathetic and parasympathetic innervation of heart. PMID- 23366663 TI - A combined heartbeat detector based on individual BCG and IPG heartbeat detectors. AB - This paper presents a preliminary approach for heartbeat detection on a weighing scale, using a combined heartbeat detector and an ensemble method. First, two independent sub-detectors are implemented based on the BCG (Ballistocardiogram) and lower-body IPG (Impedance Plethysmogram) signals. Then, the results of these sub-detectors are combined using a higher level decision maker. The BCG, which describes the reaction of the body to cardiac ejection of blood, was measured using the strain gauges in a modified commercial weighing scale. For the lower body IPG, a small amount of current was injected into the subject through the electrodes under the subject's toes, and the resulting differential voltage across the heels was measured. We tested our method on the first 30 seconds of the BCG and IPG signals collected from 8 subjects. The results show the combination significantly improved over individual detector, with a resulting interval accuracy of 97%. PMID- 23366662 TI - Microgravity effects on ventricular response to heart rate changes. AB - The effect of simulated microgravity on ventricular repolarization (VR) has been evaluated on healthy volunteers by a 5-day Head Down (-6 degrees ) Bed Rest (HDBR) maneuver. QT to RR and QT(p) (measured until the peak of the T wave) to RR hystereses have been measured during a tilt table test, and differences between them have been studied to better understand possible changes in the final part of the repolarization. To characterize the hystereses, two indices have been computed: M(90), quantifying adaptation lag in beats, and alpha evaluating the slope of parabolic regression fitting. Significant differences between QT and QT(p) were found before, but not after HDBR. Specifically, before HDBR was considerable lower for QT(p) than for QT, while alpha was significantly higher. After HDBR, M(90) and a took essentially the same values for QT and QT(p). This fact evidenced the different effect of HDBR on QT to RR and QT(p) to RR adaptations, and suggest HDBR could lead to an impairment in ventricular repolarization dispersion. PMID- 23366664 TI - Heart rate variability analysis as an index of emotion regulation processes: interest of the Analgesia Nociception Index (ANI). AB - Autonomic Nervous System (ANS) variations are strongly influence by emotion regulation processes. Indeed, emotional stimuli are at the origin of an activation of the ANS and the way an individual pass from a state of alert in the case of emotional situation to a state of calm is closely coupled with the ANS flexibility. We have previously described and developed an Analgesia Nociception Index (ANI) for real time pain measurement during surgical procedure under general anesthesia. This index, based on heart rate variability analysis, constitutes a measure of parasympathetic tone and can be used in several other environments. In this paper, we hypothesized that such an index could be used as a tool to investigate the processes of emotional regulation of a human subject. To test this hypothesis, we analyzed ANI's response to a negative emotional stimulus. This analysis showed that the index decreases during the emotion induction phase and returns to its baseline after 2 minutes. This result confirms that ANI could be a good indicator of parasympathetic changes in emotional situation. PMID- 23366665 TI - Analysis of heart rate variability using time-varying filtering of heart transplanted patients. AB - In this paper, we analyze the heart rate variability (HRV), obtained by using the time-varying integral pulse frequency modulation (TVIPFM) which is well adapted to the exercise stress testing. PMID- 23366666 TI - Denoising and segmentation of the second heart sound using matching pursuit. AB - We propose a denoising and segmentation technique for the second heart sound (S2). To denoise, Matching Pursuit (MP) was applied using a set of non-linear chirp signals as atoms. We show that the proposed method can be used to segment the phonocardiogram of the second heart sound into its two clinically meaningful components: the aortic (A2) and pulmonary (P2) components. PMID- 23366667 TI - Apnea-hypopnea index estimation from spectral analysis of airflow recordings. AB - This study focuses on the analysis of airflow (AF) recordings to help in sleep apnea-hypopnea syndrome (SAHS) diagnosis. The objective is to estimate the apnea hypopnea index (AHI) by means of spectral features from AF data. Multiple linear regression (MLR) was used for this purpose. A training group is used to obtain two MLR models: the first one consisting of features obtained from the full PSDs (MLR(full)) and the second one consisting of features from a new frequency band of interest (MLR(band)). Then a test group is used to validate the final model. The correlation of spectral features and MLR models with AHI was compared by means of Pearson's coefficient (rho). MLR(band) reached the highest rho (0.809). Four different AHI decision thresholds were used to evaluate MLR(band) ability to distinguish the severity of SAHS. The accuracy achieved was higher as the threshold increased (69.7%, 75.3%, 80.9%, 87.6%) These results suggest that the automated estimation of AHI through spectral features can provide useful knowledge about SAHS severity. PMID- 23366668 TI - Thoraco-abdominal asynchrony in children during quiet sleep using Hilbert transform. AB - We present a technique based on the Hilbert transform to quantify the thoraco abdominal asynchrony (TAA) based on the phase shift between ribcage (RC) and abdomenal (AB) breathing signals acquired using respiratory inductive plethysmography (RIP). We employed this method to investigate RIP during overnight polysomnography (PSG) in 40 healthy children for analysis of their breathing patterns in various stages of sleep (ss 2, 3, 4 and REM) and in two common sleeping positions (supine and lateral). RIP signals free of respiratory or movement artifacts were segmented into 30 second epochs. Those epochs with maximum power in the quiet breathing frequency range and positional invariance throughout were included for further processing. TAA was calculated from corresponding RC and AB excursions. We found a statistically significant influence of sleep position on the level of TAA in all stages of non-REM sleep. In conclusion, the Hilbert transform provides a simple tool for the quantification of thoraco-abdominal asynchrony. PMID- 23366669 TI - Sleep-wake detection based on respiratory signal acquired through a pressure bed sensor. AB - This study proposes an automatic method for the sleep-wake staging in normal and pathologic sleep based only on respiratory effort acquired from a Pressure Bed Sensor (PBS). Motion and respiratory movements were obtained through a PBS and sleep-wake staging was evaluated from those time series. 20 all night polysomnographies, with annotations, used as gold standard and the time series coming from the PBS were used to develop and to evaluate the automatic wake-sleep staging. The database was built up by: 10 healthy subjects and 10 patients with severe sleep apnea. The agreement of the statistical measures between the automatic classification and the human scoring were: 83.59 +/- 6.79 of sensitivity, 83.60 +/- 15.13 of specificity and 81.91 +/- 6.36 of accuracy. These results suggest that some important indexes, such as sleep efficiency, could be computed through a contactless technique. PMID- 23366670 TI - Assessment of photoplethysmogram signal quality using morphology integrated with temporal information approach. AB - Photoplethysmograph (PPG) signal measured from wearable devices for tele-home healthcare is often corrupted by motion artifacts which often cause false extraction of physiological features and lead to erroneous medical decision for monitoring. In this paper we propose an innovative method which combines the morphological characteristics with temporal variability information in the signal series to assess the signal quality and to reject the meaningless segments that are significantly contaminated by artifacts aiming at improving the accuracy of derived vital physiological features. Experimental results using PPG signals collected in our lab demonstrate that our mechanism can achieve an accuracy of 98.92%. PMID- 23366671 TI - A nonintrusive temperature measuring system for estimating deep body temperature in bed. AB - Deep body temperature is an important indicator that reflects human being's overall physiological states. Existing deep body temperature monitoring systems are too invasive to apply to awake patients for a long time. Therefore, we proposed a nonintrusive deep body temperature measuring system. To estimate deep body temperature nonintrusively, a dual-heat-flux probe and double-sensor probes were embedded in a neck pillow. When a patient uses the neck pillow to rest, the deep body temperature can be assessed using one of the thermometer probes embedded in the neck pillow. We could estimate deep body temperature in 3 different sleep positions. Also, to reduce the initial response time of dual-heat flux thermometer which measures body temperature in supine position, we employed the curve-fitting method to one subject. And thereby, we could obtain the deep body temperature in a minute. This result shows the possibility that the system can be used as practical temperature monitoring system with appropriate curve fitting model. In the next study, we would try to establish a general fitting model that can be applied to all of the subjects. In addition, we are planning to extract meaningful health information such as sleep structure analysis from deep body temperature data which are acquired from this system. PMID- 23366672 TI - A new method of saccadic eye movement detection for optokinetic nystagmus analysis. AB - The analysis of eye movements is valuable in both clinical work and research. One of the characteristic type of eye movements is saccade. The accurate detection of saccadic eye movements is the base for further processing of saccade parameters such as velocity, amplitude and duration. This paper concerns an accurate saccade detection method that is based on pre-processing signal and then the proposed non linear detection function can be applied. The described method characterizes less sensitivity for any kind of noise due to an application of the robust myriad filter which is used to eliminate baseline drifts and impulsive artifacts. The congenital nystagmus is one of the field where our method can be applied to detect saccades. The proposed detection function is computationally efficient and precisely determines the time position of saccadic eye movements even when the signal-to-noise ratio is low. The presented method may have potential application in automatic ENG signal processing systems for determining visual acuity. PMID- 23366673 TI - Modeling the impulse response between pairs of EMG signals to estimate conduction delay distribution. AB - Mean electromyogram (EMG) conduction delay is often estimated as the average time delay between two surface EMG recordings arranged along the conduction path. It has previously been shown that the complete distribution of conduction delays can be estimated from the impulse response relating the "upstream" EMG recording to the "downstream" recording. In this work, we examined regularized least squares methods for estimating the impulse response, namely the pseudo-inverse with small singular values discarded and post hoc lowpass filtering. Performance was evaluated by training the model to one recording, then testing on others. Correlation between model-predicted EMG and measured EMG was assessed for 36 subjects, using EMG recordings with 5 mm inter-electrode spacing. The best correlation was 0.86, on average, for both regularization methods. We additionally compared the mean conduction delay computed from the "gold standard" cross-correlation method to the peak time of the impulse response. The best models differed by 0.01 ms, on average, for both regularization methods. Nonetheless, the impulse responses exhibited excessive energy near zero time, causing delay distribution estimates to exhibit high probabilities at unphysiological short time delays. Inter-electrode spacing larger than 5 mm may be required to alleviate this limitation. PMID- 23366674 TI - Simultaneously extracted transient and steady-state evoked responses during general anesthesia: variability of different rates. AB - Unintended intraoperative awareness occurs in one to two individuals out of every one thousand treated with general anesthesia. Patients that experience intraoperative awareness have significant post-operative psychological sequelae. The ability to detect intraoperative awareness is currently suboptimal because the mechanism employed by anesthetic drugs to impair consciousness remains poorly understood. Studies have suggested that evoked potentials (EP) may be used to monitor the depth of anesthesia. Both transient and steady state responses can be simultaneously extracted using the Continuous Loop Averaging Deconvolution (CLAD) method with specially designed CLAD sequences. 20 Hz and 30 Hz jittered CLAD sequences in addition to 5 Hz isochronic and 40 Hz jittered CLAD sequences were applied in baseline awake and general anesthesia conditions. A qualitative method to assess the extracted EPs was developed in this study, termed Randomized Split Set Average (RSSA). The results showed that EPs extracted during general anesthesia require a greater number of sweeps to obtain a signal-to-noise ratio comparable to that observed in EPs extracted during the awake state. Therefore, the development of a real time or quasi real time EP monitoring system for anesthesia provides an increased challenge. The RSSA employed in this study is a useful method for assessing the signal quality of EP responses. PMID- 23366675 TI - Epoch length and autoregressive-order selection for electromyography signals. AB - This study shows how different EMG-epoch lengths affect the selection of the autoregressive-model orders. Electromyography signals were divided in 25ms, 50ms, 100ms, 250ms and 500ms epochs. Order-selection criteria were applied to the least square errors of autoregressive models. The Bayesian Information Criterion and the Minimum Description Length indicated that needle-EMG signals recorded from normal subjects at 25kHz could be represented by autoregressive models using orders below 25 for 500ms epochs, and that smaller orders could be used to represent shorter epochs. PMID- 23366676 TI - Sleep EMG analysis using sparse signal representation and classification. AB - The development of automatic sleep based abnormality detection in patient for sleep related problem is a key field in the recent research. However the sleep signals are obtained as long-time recordings and inhibit complex characteristics, making their analysis computationally challenging. As a result, recognition methods that facilitate efficient dimensionality reduction are developed to suit different applications. In recent years sparse representation schemes provide an effective means for achieving best possible data reduction by comparing the input with pre-formulated dictionaries, especially for huge datasets. Recent research proves the usability of these methods for signal classification. In this paper, a robust technique is provided for sparse representation of small dataset signal types. Here, the signal decomposition is obtained using the l(1)-minimization technique, following which a generalization based on the leave-one-out (LOO) is performed. The dependency of the proposed algorithm is analyzed, using a sparsity measure, in order to verify the dependency between the input data and extracted feature space. Performance measures obtained using long-term sleep data shows an average classification accuracy of 80% and further validates the usefulness of the technique for long term biomedical signal analysis. PMID- 23366677 TI - Fractal based complexity measure and variation in force during sustained isometric muscle contraction: effect of aging. AB - This study has investigated the effect of age on the fractal based complexity measure of muscle activity and variance in the force of isometric muscle contraction. Surface electromyogram (sEMG) and force of muscle contraction were recorded from 40 healthy subjects categorized into: Group 1: Young - age range 20 30; 10 Males and 10 Females, Group 2: Old - age range 55-70; 10 Males and 10 Females during isometric exercise at Maximum Voluntary contraction (MVC). The results show that there is a reduction in the complexity of surface electromyogram (sEMG) associated with aging. The results demonstrate that there is an increase in the coefficient of variance (CoV) of the force of muscle contraction and a decrease in complexity of sEMG for the Old age group when compared with the Young age group. PMID- 23366678 TI - Perfusion and bone mineral density as function of vertebral level at lumbar spine. AB - The objective of this study is to characterize perfusion and bone mineral density (BMD) in the lumbar spine as a function of level and anatomic location. Fourteen male subjects with healthy vertebral endplates were selected to avoid gender and endplate disease influence. The bone perfusion and BMD of different vertebral level (L1-L4) were measured by the dynamic contrast enhancement MRI (DCE MRI) and the dual-energy X-ray absorptiometry (DXA) respectively. Perfusion parameters showed a significant negative correlation with upper to lower vertebral levels while inverse observation was found for BMD. The results indicated that the perfusion and BMD are as function of vertebral level and anatomic location at lumbar spine. The BMD varying with vertebral level may be determined by the biomechanical usage at the lumbar spine, where the lower levels sustain more mechanical forces. Perfusion changes along the lumbar spine level suggested that the bone marrow component could be different when BMD varies, which needs further histological verification. PMID- 23366679 TI - Algorithm for an implantable fluorescence based glucose sensor. AB - This article describes the algorithm for a continuous glucose monitor (CGM). The CGM system consists of an external reader and an insertable fluorescence based sensor. The sensor consists of a miniaturized optical sensor that incorporates a biocompatible macromolecular indicator that selectively binds glucose. It is designed to be subcutaneously inserted and allows for the direct measurement of interstitial fluid (ISF) glucose. PMID- 23366680 TI - Cross-correlation between head acceleration and stabilograms in humans in orthostatic posture. AB - This work aims at evaluating the role of the vestibular system in the postural sway control using the cross correlation function. A sample of 19 young, healthy male adults was monitored with a three axial accelerometer placed over the head during a stabilometric test, standing on a force platform during 3 min in four conditions: eyes closed and open, and feet apart and together. The normalized cross correlation (NCCF) function and the Monte Carlo simulation were used to correlate changes in body sway with head accelerations. Significant NCCF was rarely observed in conditions with opened eyes, and occurred in six subjects with eyes closed and reduced support basis. These results are inconclusive. As no delayed response was observed, the classical negative feedback appears to be absent, and either phasic displacements of the center of pressure and the head or anticipatory control could be occurring. PMID- 23366681 TI - A physiologically motivated ECoG segmentation method for epileptic seizure onset zone detection. AB - In this paper we propose a novel segmentation method based on the relative frequency contributions of ictal multichannel ECoG data. Segments with predominant [[see text]]-activity are classified as epileptic. The seizure onset zone is determined by the temporal delay of the epileptic [[see text]]-activity (4-9Hz) on the different channels. We apply this methodology to three seizures of one patient suffering from focal epilepsy. The resulting segments reflect the visual characteristics of the ictal ECoG well. The seizure onset zone identified by the proposed method is in very good accordance with the clinical findings. PMID- 23366682 TI - Assisting autistic children with wireless EOG technology. AB - We propose a novel intervention to train the speed and accuracy of attention orienting and eye movements in Autism Spectrum Disorder (ASD). Training eye movements and attention could not only affect those important functions directly, but could also result in broader improvement of social communication skills. To this end we describe a system that would allow ASD children to improve their fixation skills while playing a computer game controlled by an eye tracker. Because this intervention will probably be time consuming, this system should be designed to be used at homes. To make this possible, we propose an implementation based on wireless and dry electrooculography (EOG) technology. If successful, this system would develop an approach to therapy that would improve clinical and behavioral function in children and adults with ASD. As our initial steps in this direction, here we describe the design of a computer game to be used in this system, and the predictions of gaze position from EOG data recorded while a subject played this game. PMID- 23366683 TI - Evaluation study of compressed sensing for neural spike recordings. AB - In this paper, an evaluation study of compressed sensing (CS) for neural action potential (spike) signals in MATLAB is presented. State-of-the-art neural recorders use 100 or more parallel channels to measure neural activity resulting in a data rate of 16 - 20 Mbit/s. Since a low-power design is required for an implanted neural recorder, it seems advantageous to compress the neural data prior to the wireless transmission. The continuous neural spike signals are compressed and transmitted to facilitate the possibility of an unrestricted data analysis at the receiver. Synthesized and recorded neural data sets are used to test the performance of CS. The 6-level Daubechies-8 wavelet decomposition matrix and two learned dictionary matrices are utilized as dictionaries for CS. The compression results are evaluated with the spike sorting program OSort. CS is shown to work for the compression of low-noise synthesized neural spike signals with a compression rate of 2.05, but cannot be recommended for the compression of neural spike signals in general. PMID- 23366684 TI - Removal of blink artifacts in single channel EEG. AB - Blinks are one of the main sources of distortion in electroencephalographic (EEG) data. Discarding blink-contaminated segments of EEG data would result in considerable information loss when interpreting and analyzing data. This study presents a simple method of blink filtering using a Savitzky-Golay (SG) smoothing filter and compares it to Independent Component Analysis (ICA), a widely accepted method of blink removal. The SG-based blink filtering method arose from the need for blink removal in EEG systems with a low number of channels and limited processing power, specifically reading from the forehead location where the blink disturbance is severe. Real and simulated data were investigated with respect to the method's performance. Using correlation and mutual information to measure performance, the results reveal that the SG-based method can effectively remove blink artifacts and produces results comparable to those obtained using ICA. PMID- 23366685 TI - An adaptive strategy of classification for detecting hypoglycemia using only two EEG channels. AB - Hypoglycemia is the most common but highly feared side effect of the insulin therapy for patients with Type 1 Diabetes Mellitus (T1DM). Severe episodes of hypoglycemia can lead to unconsciousness, coma, and even death. The variety of hypoglycemic symptoms arises from the activation of the autonomous central nervous system and from reduced cerebral glucose consumption. In this study, electroencephalography (EEG) signals from five T1DM patients during an overnight clamp study were measured and analyzed. By applying a method of feature extraction using Fast Fourier Transform (FFT) and classification using neural networks, we establish that hypoglycemia can be detected non-invasively using EEG signals from only two channels. This paper demonstrates that a significant advantage can be achieved by implementing adaptive training. By adapting the classifier to a previously unseen person, the classification results can be improved from 60% sensitivity and 54% specificity to 75% sensitivity and 67% specificity. PMID- 23366686 TI - Characterization of memory load in an arithmetic task using non-linear analysis of EEG signals. AB - In this paper, we investigate non-linear analysis of electroencephalogram (EEG) signals to examine changes in working memory load during the performance of a cognitive task with varying difficulty levels. EEG signals were recorded during an arithmetic task while the induced load was varying in seven levels from very easy to extremely difficult. The EEG signals were analyzed using three different non-linear/dynamic measures; namely: correlation dimension, Hurst exponent and approximate entropy. Experimental results show that the values of the measures extracted from the delta frequency band of signals acquired from the frontal and occipital lobes of the brain vary in accordance with the task difficulty level induced. The values of the correlation dimension increased as the task difficulty increased, showing a rise in complexity of the EEG signals, while the values of the Hurst exponent and approximate entropy decreased as task difficulty increased, indicating more regularity and predictability in the signals. PMID- 23366687 TI - Removal of peak and spike noise in EEG signals based on the analytic signal magnitude. AB - Peak and spike artifacts in time series represent a serious problem for signal analysis especially in biomedical field. From the last decades, different techniques have been used for their removal mainly based on adaptive filters. This work presents a new approach for removing peak and spike artifacts based on the analytic signal envelope, filtered with a low-pass filter. The proposed algorithm was tested on electroencephalogram signals containing peak and spike artifacts. Results showed that this method permitted to remove the peak and spike artifacts preserving both high correlation (rho>0.9) and spectral coherence equation with the original signal. PMID- 23366688 TI - Investigating linear superposition of multi-species neurotransmitter voltammetric measurements in-vitro. AB - Fast-Scan Cyclic Voltammetry (FSCV) is frequently used to monitor the concentrations of neurotransmitters in real-time. However, few studies have examined the issue of monitoring the concentration of multiple neurotransmitters at the same time, despite their coexistence at brain synapses. This stems from the fact that some neurotransmitters have relatively similar electrochemical profiles. In this work we use Factor Spaces to analyze the current signals obtained using FSCV for both individual and mixed solutions of neurotransmitters. It is shown that the behavior of the current signals during the interaction between the neurotransmitter species approaches the principle of superposition. This potentially results in a significant simplification in the way combined voltammetric data is interpreted. The performance of Principal Component Analysis in extracting suitable Factor Spaces is evaluated. PMID- 23366689 TI - Novel cross correlation technique allows crosstalk resistant reflex detection from surface EMG. AB - Existing methods for withdrawal reflex detection from surface electromyography (sEMG) do not consider the potential presence of electrical crosstalk, which in practical applications may entail reduced detection accuracy. This study estimated muscle fiber conduction velocities (CV) for the tibialis anterior (TA) and soleus (SOL) muscles of both genuine reflexes and identified crosstalk, measured during antagonistic reflex responses. These estimations were used to develop and assess a novel method for reflex detection resistant to crosstalk. Cross correlations of two single differential (SD) sEMG signals recorded along the muscle fibers were performed and two features were extracted from the resulting correlograms (average CV and maximal cross correlation). Reflex detection based on evaluation of the extracted features was compared to a conventional reflex detection method (thresholding of interval peak z-scores), applied on both SD and double differential (DD) sEMG. Intramuscular electromyography (iEMG) was used as validation for reflex detection. Apparent CV due to electrical crosstalk alone were more than one order of magnitude higher than CV estimated for genuine reflexes. Conventional reflex detection showed excellent sensitivity but poor specificity (0.19-0.76) due to the presence of crosstalk. In contrast, cross correlation analysis allowed reflex detection with significantly improved specificity (0.91-0.97). The developed methodology may be readily implemented for more reliable reflex detection. PMID- 23366690 TI - Optical transcutaneous link for low power, high data rate telemetry. AB - A low power and high data rate wireless optical link for implantable data transmission is presented in this paper. In some neural prosthetic applications particularly in regard to neural recording system, there is a demand for high speed communication between an implanted device and an external device. An optical transcutaneous link is a promising implantable telemetry solution, since it shows lower power requirements than RF telemetry. In this paper, this advantage is further enhanced by using a modified on-off keying and a simple custom designed low power VCSEL driver. This transmitter achieves an optical transcutaneous link capable of transmitting data at 50 Mbps through the 4 mm tissue, with a tolerance of 2 mm misalignment and a BER of less than 10(-5), while the power consumption is only 4.1 mW or less. PMID- 23366691 TI - An approach to controlled drug infusion via tracking of the time-varying dose response. AB - Automatic administration of medicinal drugs has the potential of delivering benefits over manual practices in terms of reduced costs and improved patient outcomes. Safe and successful substitution of a human operator with a computer algorithm relies, however, on the robustness of the control methodology, the design of which depends, in turn, on available knowledge about the underlying dose-response model. Real-time estimation of a patient's actual response would ensure that the most suitable control algorithm is adopted, but the potentially time-varying nature of model parameters and the limited number of observation signals may cause the estimation problem to be ill-posed, posing a challenge to adaptive control methods. We propose the use of Bayesian inference through a particle filtering approach as a way to overcome these limitations and improve the robustness of automatic drug administration methods. We report on the results of a simulation study modeling the infusion of vasodepressor drug sodium nitroprusside for the control of mean arterial pressure in acute hypertensive patients. The proposed control architecture was able to meet the required performance objectives under challenging operating conditions. PMID- 23366692 TI - Compact digital implementation of a quadratic integrate-and-fire neuron. AB - A compact fixed-point digital implementation of a quadratic integrate-and-fire (QIF) neural model was developed. Equations were derived to determine the minimum number of bits the digital QIF model requires to represent all four states of the QIF model and control the switching threshold of the output voltage. In addition, the equations were used to minimize the size of the multiplier used for the nonlinear squaring function, V(2). These design equations were used to develop test vectors that could unambiguously show all four states of a digital QIF model. The FPGA implementation of the QIF model was shown to be computationally efficient, requiring only two fixed-point adders and one fixed-point multiplier. PMID- 23366693 TI - Preliminary results of mental workload and task engagement assessment using electroencephalogram in a space suit. AB - In this paper, we present preliminary results of subject's mental workload and task engagement assessment in an experimental space suit. We have quantified the mental workload and task engagement based on changes in electroencephalogram (EEG). EEG signals were collected from subjects scalp using a commercial wireless EEG device in two experimental conditions - when subjects did not wear space suit (control condition) and when subjects wore space suit. Brain state changes were estimated and compared with the direct responses for different tasks and different conditions. We found that the spacesuit experiment introduced a greater mental workload where subject's stress levels were higher than control experiment. PMID- 23366694 TI - Timing detection and seismocardiography waveform extraction. AB - Described herein is a new and robust method to extract heart-beat timing from seismocardiogram (SCG). This timing indicates the precise time location of each heart beat and therefore directly conveys heart rate information. Knowledge of the time location of each occurrence of the underlying SCG waveform allows us to obtain a clean SCG waveform estimate by time averaging noisy segments of an SCG time series. The algorithm can be implemented in wearable SCG-based devices to provide heart monitoring or diagnosis capabilities without relying on any other methodology, such as electrocardiography, as a timing reference. PMID- 23366696 TI - Aftereffects of robotic-assisted treadmill walking on the locomotor pattern in humans. AB - We investigated the possible aftereffects on the locomotor pattern of treadmill walking after walking with the assistance of a robot suit HAL in nine healthy subjects. After walking on a treadmill at a speed of 3.5 km/h for 180 s as a pre condition, each subject walked with robotic assistance to the hip and knee joints of both legs at the same speed for 600 s. The subjects performed normal walking for 300 s as a post-condition after the assisted walking. Compared with normal walking in the pre-condition, gait cycle duration and step length increased significantly during the assisted walking period. The increased gait cycle duration and step length during the assisted walking period returned to that of the pre-condition period soon after the start of the post-condition. In contrast, the range of motion (ROM) within one step cycle during the initial 60 s of the post-condition period gradually increased in the hip joint, but not in the knee joint. Compared with the mean hip ROM in the initial 10 s of the post-condition, significant increases in mean ROM every 10 s were observed in 4 phases of 20-60 s each in the right leg and in 3 phases of 20-50 s each in the left leg. Although strong aftereffects of the robotic assistance on the locomotor pattern were not observed in the present study, small adaptive changes were seen only in hip ROM during the initial normal walking phase immediately after assisted walking. PMID- 23366695 TI - User-in-the-loop continuous and proportional control of a virtual prosthesis in a posture matching task. AB - As the development of dexterous prosthetic hand and wrist units continues, there is a need for command interfaces that will enable a user to operate these multi joint devices in a natural, coordinated manner. In previous work, we have demonstrated that it is possible to simultaneously decode hand and wrist kinematics from myoelectric signals recorded from the forearm in an offline manner. The goal of this study was to quantify the performance of this command interface during real-time control of a kinematic prosthesis. One subject with intact limbs controlled a virtual prosthesis and attempted to match a series of target postures using the proposed control scheme as well as using the movements of the intact limb. Initial results indicate that subjects can complete these target matching tasks in the virtual environment. Future work will evaluate the controllability of the proposed strategy relative to traditional control schemes. PMID- 23366697 TI - Motivating arm-hand use for stroke patients by serious games. AB - We present a novel technology to support playful rehabilitation of arm-hand performance for stroke survivors. The system combines tangible tabletop interaction with wearable technology, to encourage stroke patients to train their arm-hand skills in a task-oriented manner, while a jacket supporting tilt-sensing and vibrotactile feedback guides patients regarding the correct execution of exercises and specifically to avoid compensatory movements. We present the iterative client centered development of this technology and its on going development. PMID- 23366698 TI - Truncation effects on muscular fatigue indexes based on M waves analysis. AB - In this paper, we investigate muscular fatigue. We propose a new fatigue index based on the continuous wavelet transform (CWT) and compare it with the standard fatigue indexes from literature. Fatigue indexes are all based on the electrical activity of muscles (electromyogram) acquired during an electrically stimulated contraction (ES). The stimulator and electromyogram system, which were presented in a previous work, allows real-time analysis. The extracted fatigue parameters are compared between each other and their sensitivity to noise is studied. The effect of truncation of M waves is then investigated, enlightening the robustness of the index obtained using CWT. PMID- 23366699 TI - A mechanism for eye position effects on spontaneous nystagmus. AB - In acute stages of unilateral vestibular deficit, the imbalanced tonic activity on vestibular afferents evokes spontaneous nystagmus. The slow-phase velocity of this nystagmus varies with eye position, such that it is smaller when looking in the direction of slow-phases. The neural mechanism for this behavior is still not understood. Here, using a simple control system model, we show that plausible changes in the neural responses within the central vestibulo-ocular reflex pathway are adequate to cause eye position dependent effects in the nystagmus pattern. The proposed transformations in population response functions could happen immediately following a lesion and can be useful to stabilize gaze in part of the gaze field. PMID- 23366700 TI - A simulation study: effect of the inter-electrode distance, electrode size and shape in transcutaneous electrical stimulation. AB - Transcutaneous Electrical Stimulation (TES) has been used widely to recover motor functions in neurologically impaired individuals by artificially activating skeletal muscles using superficial electrodes. Some simulation studies have investigated the percentage of fibers activated in denervated skeletal muscles, the comfort and selectivity, and the influence of fat thickness in the case of obese people, to optimize the inter-electrode distance and electrode size. However, the effect of the inter-electrode distance, electrode shape and electrode size might be further analyzed using the selectivity, activation depth and activation volume. In this regard, we developed a 3D multi-layer (skin, fat, muscle, and nerve) thigh model coupled with a mammalian nerve model using a finite element method for optimization of TES therapy. Different evaluation indices (motor threshold, activation depth, selectivity and activation volume) were inspected to compare different TES parameters in terms of nerve activation. The simulation results agreed with experimental data and new insights were obtained: selectivity is better in small electrodes; nevertheless, in high current stimulation, small electrodes and large electrodes have similar selectivity. PMID- 23366701 TI - Examination of afterhyperpolarization duration changes in motoneurons innervating paretic muscles in stroke survivors. AB - The after hyperpolarization (AHP) of a motoneuron is a primary determinant of motoneuron firing rate. Any increase in its duration or amplitude could alter normal motor unit (MU) firing rate properties in stroke, and potentially impact muscle force generation. The objective of this preliminary study was to examine potential differences in afterhyperpolarization (AHP) duration of motoneurons innervating paretic and contralateral limb muscles of hemiparetic stroke survivors. A novel surface EMG (sEMG) electrode was used to record from the first dorsal interosseous muscle (FDI) of three hemiparetic stroke survivors. sEMG data was decomposed to derive single motor unit (SMU) events, which were subsequently utilized to produce interval (ISI) histograms of the motor unit discharge. Interval Death Rate (IDR) analysis was then used to transform ISI histograms into death rate plots. [1] The prescribed IDR analysis method [1] involves a final transformation of death rate plots into an estimated AHP time course. The present study uses a modified method of interpreting death rate plots in order to determine AHP duration. AHP durations from this analysis are similar to durations obtained from ISI variability analysis. [2] Results from three subjects indicate that on average, motor units on the paretic side have a longer AHP duration than the contralateral side, potentially contributing to lower firing rates, and to less efficient force production in paretic muscles. PMID- 23366702 TI - Training complexity is not decisive factor for improving adaptation to visual sensory conflict. AB - Ground-based preflight training utilizing unusual visual stimuli is useful for decreasing the susceptibility to space motion sickness (SMS). The effectiveness of the sensorimotor adaptation training is affected by the training tasks, but what kind of task is more effective remains unknown. Whether the complexity is the decisive factor to consider for designing the training and if other factors are more important need to be analyzed. The results from the analysis can help to optimize the preflight training tasks for astronauts. Twenty right-handed subjects were asked to draw the right path of 45 degrees rotated maze before and after 30 min training. Subjects wore an up-down reversing prism spectacle in test and training sessions. Two training tasks were performed: drawing the right path of the horizontal maze (complex task but with different orientation feature) and drawing the L-shape lines (easy task with same orientation feature). The error rate and the executing time were measured during the test. Paired samples t test was used to compare the effects of the two training tasks. After each training, the error rate and the executing time were significantly decreased. However, the training effectiveness of the easy task was better as the test was finished more quickly and accurately. The complexity is not always the decisive factor for designing the adaptation training task, e.g. the orientation feature is more important in this study. In order to accelerate the adaptation and to counter SMS, the task for astronauts preflight adaptation training could be simple activities with the key features. PMID- 23366703 TI - Wavelet transform coherence based investigation of existence of relationship between the cardiovascular and postural control systems during orthostatic challenge. AB - Previous studies have established the effects of orthostatic challenge on the cardiovascular and postural control systems, but the interdependent behavior of the systems under such condition is unclear. In the present study we examined the simultaneous changes in posture muscle electromyography (EMG) and systolic blood pressure (SBP) during quiet standing in healthy young individuals. Photoplethysmography based SBP, surface EMG, electrocardiogram (Lead II ECG) and posturography data were acquired during the experiment. Wavelet transform coherence (WTC) analysis was applied to identify the zones of interdependent behavior of the systems. The WTC thresholds were identified for the specific data under investigation. The coherence was analyzed in three frequency bands namely, LF (0.05 - 0.1 Hz), VLF (0.01-0.05 Hz) and ULF (0.005 - 0.01 Hz). WTC estimates for the EMG - SBP comparison showed greater than threshold values in all three frequency bands (LF: 0.31 +/- 0.02; VLF: 0.41 +/- 0.01; ULF: 0.45 +/- 0.01). In conclusion this study showed the existence of relationship between the posture muscle EMG and blood pressure during natural orthostatic stress, by validation based on wavelet transform coherence. Further validation is required to objectively characterize this relationship between the two systems during orthostatic stress. PMID- 23366704 TI - Electromyographic study in 5 muscles during an isometric fatiguing protocol. AB - In this study, 12 healthy men aging 22.8 +/- 2.2 years old were submitted to a protocol of isometric resistance to fatigue contemplating elbow flexion on three different angles: 45 degrees , 90 degrees and 135 degrees . The objective was to study electromyographic median frequency (MDF) in the following muscles: i) Biceps Brachialis Long Head (BBL), Brachioradialis (BRD), Flexor Digitorum Superficialis (FDS), Triceps Brachialis Long Head (TBL), and Extensor Digitorum (ED). It was verified that, for all muscles, including the muscles that act in opposition to the contraction, fatigue presence was verified by the decrease of MDF value. PMID- 23366705 TI - A modified multi-channel EMG feature for upper limb motion pattern recognition. AB - The EMG signal is a well-known and useful biomedical signal. Much information related to muscles and human motions is included in EMG signals. Many approaches have proposed various methods that tried to recognize human motion via EMG signals. However, one of the critical problems of motion pattern recognition is that the performance of recognition is easily affected by the normalization procedure and may not work well on different days. In this paper, a modified feature of the multi-channel EMG signal is proposed and the normalization procedure is also simplified by using this modified feature. To recognize motion pattern, we applied the support vector machine (SVM) to build the motion pattern recognition model. In training and validation procedures, we used the 2-DoF exoskeleton robot arm system to do the designed pose, and the multi-channel EMG signals were obtained while the user resisted the robot. Experiment results indicate that the performance of applying the proposed feature (94.9%) is better than that of conventional features. Moreover, the performances of the recognition model, which applies the modified feature to recognize the motions on different days, are more stable than other conventional features. PMID- 23366706 TI - Audio-visual feedback for electromyographic control of vowel synthesis. AB - We describe the design and testing of a human machine interface to use surface electromyography (sEMG) collected from a covert location in response audio-visual feedback. Using sEMG collected from the Auricularis Posterior muscle, N=5 healthy participants participated in 6 sessions over multiple days to learn to transition from visual and vowel synthesis feedback to vowel synthesis feedback alone. Results indicate that individuals are able to learn sEMG control of vowel synthesis using auditory feedback alone with an average of 67% accuracy and that this skill can also generalize to new vowel targets. Control of vowel synthesis using covertly-recorded sEMG is a promising step toward more reliable mobile human machine interfaces for communication. PMID- 23366707 TI - Using spike-triggered averaging to characterize motor unit twitch vectors in the first dorsal interosseous. AB - Earlier studies in multifunctional muscles such as the first dorsal interosseous (FDI) have demonstrated that the selection and control of motor units (MUs) can vary as a function of generated force direction. While directionally dependent motor unit recruitment and rate properties imply that there may also be differential mechanical action, this has yet to be directly demonstrated. Our objective was to determine whether there exists a range of force vectors from different motor units in the FDI muscle within individual subjects. We utilized the spike-triggered averaging (STA) method to derive force twitch estimates from single motor units. We derived MU twitch direction from the ratio of individual twitch estimates recorded concurrently from the load cell. Fifteen units from 2 subjects were used to determine MU force vectors. We were able to estimate force twitch vectors from 7-8 different MUs in each subject. The results of our study suggest that there is varied mechanical action of motor units in the FDI. It is thus possible that differential activation of individual MUs in the FDI is a function of varied mechanical action. PMID- 23366708 TI - Modifications of muscle synergies and spinal maps due to absence of visual feedback in patients with unilateral vestibular disease. AB - The present study aimed at describing the modifications of muscle synergies and spinal activity due to the absence of visual feedback, in patients affected by unilateral vestibular disease. Patients were tested both during unperturbed quite stance and walking while the activity of 7 bilateral muscles, from the leg to the trunk, were recorded for the estimation of muscle synergies and spinal activity. Results showed that during locomotion the absence of visual feedback did not significantly modify either the principal roles underlying muscle activity (i.e., synergies) or the spinal bursts. Conversely, during the upright stance, the absence of visual feedback involved a significant coupling of ankle dorsi- and plantar-flexor muscle groups with a consequent shift of the motoneuronal (MN) activity toward most caudal segments. Results revealed that the muscle synergies are able to document an increased activity of sensory-motor afferences leading a more intense role of the forward based mechanism underlying balance control in vestibular patients. PMID- 23366709 TI - Neuromuscular adaptations during submaximal prolonged cycling. AB - This study aims at evaluating the neuromuscular adaptations occurring during submaximal prolonged cycling tasks. In particular, we want to assess changes in surface electromyographic (sEMG) signal recorded during a pedaling task, performed by six subjects on a cycle-simulator at a constant power output, until voluntary exhaustion. Task failure was defined as the instant the subject was no longer able to maintain the required task. Electromyographic activity was recorded from eight muscles of the dominant leg and burst characteristics of sEMG signals were analyzed in order to assess the changes in muscle activity level produced by the occurrence of neuromuscular fatigue. In particular, three features were extracted from the sEMG signal for each burst: amplitude, location of the maxima and mean profile of the burst envelope. We have reported an increase in the amplitude parameter for all subjects only for Vastii while bi articular muscles presented a high variability among subjects. Also the location of the maximal values of the mean envelope of the bursts was found to change when considering bi-articular or mono-articular muscles. The envelope profile was found not to be subject to alterations when comparing the end of the task with the beginning. We speculated that neuromuscular fatigue induces changes essentially in the mono-articular muscles which produce power. This phenomenon is highly correlated with the adopted pedaling strategy which, being not constrained, induces subjects to express the maximal power in the downstroke phase, related to knee extension and involving mainly mono-articular muscles. PMID- 23366710 TI - Na+ channels at postsynaptic muscle membrane affects synaptic transmission at neuromuscular junction: a simulation study. AB - Motor movement is controlled by the brain through transmitting electrochemical signals to the muscle fibers that cause the contraction of the muscles. A motoneuron carrying the impulse creates a synapse with the muscle fiber which is known as Neuromuscular Junction (NMJ). The muscle infolds taking part in the synapse contains large amount of sodium channels. The current that passes through the narrow synaptic cleft affects the adjacent membranes electrical properties in turn modifies the synaptic transmission process. Considering this phenomenon we have studied the effect of sodium channels at the NMJ to find out its effect in the generation of extracellular potentials at the synaptic cleft of the junction. Through simulation results we confirm that the conductivity of the sodium channels present at the postsynaptic muscle membrane and the junction height affect the generation of the extracellular potentials at the junction which modifies the synaptic properties of the NMJ. PMID- 23366711 TI - Design of a gait training device for control of pelvic obliquity. AB - This paper presents the design and testing of a novel device for the control of pelvic obliquity during gait. The device, called the Robotic Gait Rehabilitation (RGR) Trainer, consists of a single actuator system designed to target secondary gait deviations, such as hip-hiking, affecting the movement of the pelvis. Secondary gait deviations affecting the pelvis are generated in response to primary gait deviations (e.g. limited knee flexion during the swing phase) in stroke survivors and contribute to the overall asymmetrical gait pattern often observed in these patients. The proposed device generates a force field able to affect the obliquity of the pelvis (i.e. the rotation of the pelvis around the anteroposterior axis) by using an impedance controlled single linear actuator acting on a hip orthosis. Tests showed that the RGR Trainer is able to induce changes in pelvic obliquity trajectories (hip-hiking) in healthy subjects. These results suggest that the RGR Trainer is suitable to test the hypothesis that has motivated our efforts toward developing the system, namely that addressing both primary and secondary gait deviations during robotic-assisted gait training may help promote a physiologically-sound gait behavior more effectively than when only primary deviations are addressed. PMID- 23366712 TI - Extraction of muscle synergies using temporal segmentation of the record: a preliminary analysis. AB - Muscle synergies are considered as a potential strategy to reduce the computational workload undergoing the estimation of muscle activity during different motor tasks. They are usually extracted by means of algebraic factorization algorithms able to capture the greatest communality of a set of electromyographic (EMG) signals. Usually EMG signals are pooled across different sub-movements (e.g., going forward and backward during reaching) in order to increase the complexity of the data set and, consequently, capture the maximum communality. Despite of these, this preliminary study was designed to investigate how the communality of EMG signals can be explained looking at narrow subset of recorded signals. Results corroborate the hypothesis that using a suitable subset of the whole dataset can significantly modify the values of weight coefficients. In this regard, further methodological investigations of algorithms adopted for synergy extraction are still required. PMID- 23366713 TI - Estimation of excitatory drive from sparse motoneuron sampling. AB - It is possible to replace amputated limbs with mechatronic prostheses, but their operation requires the user's intentions to be detected and converted into control signals sent to the actuators. Fortunately, the motoneurons (MNs) that controlled the amputated muscles remain intact and capable of generating electrical signals, but these signals are difficult to record. Even the latest microelectrode array technologies and targeted motor reinnervation (TMR) can provide only sparse sampling of the hundreds of motor units that comprise the motor pool for each muscle. Simple rectification and integration of such records is likely to produce noisy and delayed estimates of the actual intentions of the user. We have developed a novel algorithm for optimal estimation of motor pool excitation based on the recruitment and firing rates of a small number (2-10) of discriminated motor units. We first derived the motor estimation algorithm from normal patterns of modulated MN activity based on a previously published model of individual MN recruitment and asynchronous frequency modulation. The algorithm was then validated on a target motor reinnervation subject using intramuscular fine-wire recordings to obtain single motor units. PMID- 23366714 TI - Modular control of mediolateral postural sway. AB - Is voluntary motor control of mediolateral rhythmic sway ruled by modular organization? Answering this question has potential implications in diagnosis and rehabilitation of neurologically impairments. Superficial EMG and computerized dynamic posturography has been used in this study to investigate modular control of six healthy subjects. Postural movements have been performed at three different frequencies to also test the influence of speed on the composition of synergies and activations. Results showed that two synergies account for more than 75% of EMG variance and are shared by all subjects across all frequency conditions. These evidences, together with a functional interpretation of computed muscle synergies, support the existence of consistent modular control across healthy subjects during mediolateral voluntary movements. PMID- 23366715 TI - Relating plastic changes of short latency human soleus stretch reflex to changes in task performance induced by training. AB - Recent findings in the field of neurophysiology showed that operant conditioning on the human H-Reflex is possible. This leads to many possible clinical applications as well as possible sophisticated training methods for athletes. Although stretch reflexes have been subject to extensive literature, knowledge about the influence of short latency stretch reflexes on task performance is lacking. Within this study an ankle control task was designed where perturbations in the magnitude of functional relevance were applied. Results analyzing angle over time after perturbation confirm previous findings which used to analyze the EMG and force response to ankle perturbations. Further it was found that after training the response to perturbations shifted from initially containing latencies which indicate conscious support by transcortical pathways to latencies which could only origin from unconscious stretch reflex responses. The trend of the short latency response to shift towards the long latency response and to diminish, while pre-defined performance criteria improved, denote a functional relevance of the short latency stretch reflex to task performance. Whereas short latency reflexes have any importance at all or if improvements emerge only out of enhancements in the long latency response future work making use of operant conditioning on the short latency H-Reflex will have to unravel. PMID- 23366716 TI - Acoustical flow estimation in patients with obstructive sleep apnea during sleep. AB - Tracheal respiratory sound analysis is a simple and non-invasive way to study the pathophysiology of the upper airways; it has recently been used for acoustical flow estimation and sleep apnea diagnosis. However in none of the previous studies, the accuracy of acoustical flow estimation was investigated neither during sleep nor in people with obstructive sleep apnea (OSA). In this study, we recorded tracheal sound, flow rate and head position from 11 individuals with OSA during sleep and wakefulness. We investigated two approaches for calibrating the parameters of acoustical flow estimation model based on the known data recorded during wakefulness and sleep. The results show that the acoustical flow estimation parameters change from wakefulness to sleep. Therefore, if the model is calibrated based on the data recorded during wakefulness, although the estimated flow follows the relative variations of the recorded flow, the quantitative flow estimation error would be high during sleep. On the other hand, when the calibration parameters are extracted from tracheal sound and flow recordings during sleep, the flow estimation error is less than 5%. These results confirm the reliability of acoustical methods for estimating breathing flow during sleep and detecting the partial or complete obstructions of the upper airways during sleep. PMID- 23366717 TI - Modulation of finger photoplethysmographic traces during forced respiration: venous blood in motion? AB - Photoplethysmographic (PPG) signals were recorded from the fingers of 10 healthy volunteers during forced respiratory inspiration. The aim of this pilot study was to assess the effect of negative airway pressure on the blood volumes within the tissue bed of the finger, and the resultant modulation of PPG signals. The acquired signals were analysed and oxygen saturations estimated from the frequency spectra in the cardiac and respiratory frequency ranges. Assuming that respiratory modulation affects blood volumes in veins to a greater extent than in arteries, the local venous oxygen saturation was estimated. Estimated venous oxygen saturation was found to be 3.1% (+/-4.2%) lower than the estimated arterial saturation. PMID- 23366718 TI - Relationship of respiratory sounds to alterations in the upper airway resistance. AB - Respiratory sound analysis is a simple and noninvasive way to study the pathophysiology of the upper airway (UA). Recently, it has been used to diagnose partial or complete UA collapse in patients with obstructive sleep apnea (OSA). In this study, we investigated whether uid accumulation in the neck alters the properties of respiratory sounds in temporal and spectral domains and whether the respiratory sounds analysis can be used to monitor variations in the physiology of the UA, as re ected by UA resistance (R(UA)). We recorded respiratory sounds and R(UA) from 19 individuals while awake. We applied lower body positive pressure (LBPP) to shift uid out of the legs and into the neck, which increased R(UA). We calculated !rst and second formants and energy of inspiratory sound segments. Our results show that during both control (no LBPP) and LBPP arms of the study, the extracted features were different for the sound segments corresponding to low and high R(UA). Also, the features were different during control and LBPP arms of the study. With the application of support vector machine (SVM) based classi!er, we were able to classify the sound segments into two groups of high/low resistance during control and LBPP arms and into two groups of control/LBPP when including all sound segments. The accuracies of non linear SVM classi!er were 74.5 +/- 19.5%, 75.0 +/- 15.4% and 77.1 +/- 12.3% for the control arm, LBPP arm and between the arms, respectively. We also showed that during the LBPP arm, the variations in !rst formant of the sound segments corresponding to low and high R(UA) was much less than during the control arm. This indicates that with application of LBPP and accumulation of uid in the neck, there are less variations in the morphology of the UA in response to changes in R(UA), than during the control arm. These results indicate that acoustic analysis of respiratory sounds can be used to investigate physiology of the UA and how interventions can alter UA properties. PMID- 23366719 TI - Cardiorespiratory coupling during sleep in difficult-to-control asthmatic patients. AB - Heart rate variability (HRV) and respiration recorded during sleep from 8 patients suffering from difficult-to-control asthma were studied to investigate autonomic nervous system control of cardiac and respiratory activities, and of cardio-respiratory coupling during different sleep stages. PMID- 23366721 TI - Sleep-quality assessment from full night audio recordings of sleep apnea patients. AB - In this work, a novel system (method) for sleep quality analysis is proposed. Its purpose is to assist an alternative non-contact method for detecting and diagnosing sleep related disorders based on acoustic signal processing. In this work, audio signals of 145 patients with obstructive sleep apnea were recorded (more than 1000 hours) in a sleep laboratory and analyzed. The method is based on the assumption that during sleep the respiratory efforts are more periodically patterned and consistent relative to a waking state; furthermore, the sound intensity of those efforts is higher, making the pattern more noticeable relative to the background noise level. The system was trained on 50 subjects and validated on 95 subjects. The system accuracy for detecting sleep/wake state is 82.1% (epoch by epoch), resulting in 3.9% error (difference) in detecting sleep latency, 11.4% error in estimating total sleep time, and 11.4% error in estimating sleep efficiency. PMID- 23366720 TI - A novel method to assist the detection of the Cyclic Alternating Pattern (CAP). AB - This study proposes a novel method to assist the detection of the components that build up the Cyclic Alternating Pattern (CAP). CAP is a sleep phenomenon formed by consecutive sequences of activations (A1, A2, A3) and non-activations during nonREM sleep. The main importance of CAP evaluation is the possibility of defining the sleep process more accurately. Ten recordings from healthy and good sleepers were included in this study. The method is based on inferential statistics to define the initial and ending points of the CAP components based only on an initialization point given by the expert. The results show concordance up to 95% for A1, 85% for A2 and 60% for A3, together with an overestimation of 1.5 s in A1, 1.3 s in A2 and 0 s in A3. The total CAP rate presents a total underestimation of 7 min. Those results suggest that the method is able to accurately detect the initial and ending points of the activations, and may be helpful for the physicians by reducing the time dedicated to the manual inspection task. PMID- 23366722 TI - Cardiovascular and cardiorespiratory coupling in unmedicated schizophrenic patients in comparison to healthy subjects. AB - Schizophrenia is associated with a cardiac autonomic dysregulation which is characterized by a decreased vagal modulation. Nevertheless, there are less information about the interrelationships of the cardiovascular and respiratory systems in schizophrenia. PMID- 23366723 TI - Expanding the transfer entropy to identify information subgraphs in complex systems. AB - We propose a formal expansion of the transfer entropy to put in evidence irreducible sets of variables which provide information for the future state of each assigned target. Multiplets characterized by an high value will be associated to informational circuits present in the system, with an informational character (synergetic or redundant) which can be associated to the sign of the contribution. We also present preliminary results on fMRI and EEG data sets. PMID- 23366724 TI - Compensating for instantaneous signal mixing in transfer entropy analysis of neurobiological time series. AB - The transfer entropy (TE) has recently emerged as a nonlinear model-free tool, framed in information theory, to detect directed interactions in coupled processes. Unfortunately, when applied to neurobiological time series TE is biased by signal cross-talk due to volume conduction. To compensate for this bias, in this study we introduce a modified TE measure which accounts for possible instantaneous effects between the analyzed time series. The new measure, denoted as compensated TE (cTE), is tested on simulated time series reproducing conditions typical of neuroscience applications, and on real magnetoencephalographic (MEG) multi-trial data measured during a visuo-tactile cognitive experiment. Simulations show that cTE performs similarly to TE in the absence of signal cross-talk, and prevents false positive detection of information transfer in the case of instantaneous mixing of uncoupled signals. When applied to MEG data, cTE detects significant information flow from the visual cortex to the somatosensory area during task execution, suggesting the activation of mechanisms of multisensory integration. PMID- 23366725 TI - Revisiting Wiener's principle of causality -- interaction-delay reconstruction using transfer entropy and multivariate analysis on delay-weighted graphs. AB - To understand the function of networks we have to identify the structure of their interactions, but also interaction timing, as compromised timing of interactions may disrupt network function. We demonstrate how both questions can be addressed using a modified estimator of transfer entropy. Transfer entropy is an implementation of Wiener's principle of observational causality based on information theory, and detects arbitrary linear and non-linear interactions. Using a modified estimator that uses delayed states of the driving system and independently optimized delayed states of the receiving system, we show that transfer entropy values peak if the delay of the state of the driving system equals the true interaction delay. In addition, we show how reconstructed delays from a bivariate transfer entropy analysis of a network can be used to label spurious interactions arising from cascade effects and apply this approach to local field potential (LFP) and magnetoencephalography (MEG) data. PMID- 23366726 TI - Joint symbolic dynamics as a model-free approach to study interdependence in cardio-respiratory time series. AB - Heart rate and respiration display fluctuations that are interlinked by central regulatory mechanisms of the autonomic nervous system (ANS). Joint assessment of respiratory time series along with heart rate variability (HRV) may therefore provide information on ANS dysfunction. The aim of this study was to investigate cardio-respiratory interaction in patients with Parkinson's disease (PD), a neurodegenerative disorder that is associated with progressive ANS dysfunction. Short-term ECG and respiration were recorded in 25 PD patients and 28 healthy controls during rest. To assess ANS dysfunction we analyzed joint symbolic dynamics of heart rate and respiration, cardio-respiratory synchrograms along with heart rate variability. Neither HRV nor cardio-respiratory synchrograms were significantly altered in PD patients. Symbolic analysis, however, identified a significant reduction in cardio-respiratory interactions in PD patients compared to healthy controls (16 +/- 3.6 % vs. 20 +/- 6.1 %; p= 0.02). In conclusion, joint symbolic analysis of cardio-respiratory dynamics provides a powerful tool to detect early signs of autonomic nervous system dysfunction in Parkinson's disease patients at an early stage of the disease. PMID- 23366727 TI - Granger causality in cardiovascular variability series: comparison between model based and model-free approaches. AB - A linear model-based (MB) approach for the evaluation of Granger causality is compared to a nonlinear model-free (MF) one. The MB method is based on the identification of the coefficients of a multivariate linear regression via least squares procedure. The MF technique is grounded on the concept of local prediction and exploits the k-nearest-neighbors approach. Both the methods optimize the multivariate embedding dimension but MF technique is more parsimonious since the number of components taken from each signal can be different. Both methods were applied to the variability series of heart period (HP), systolic arterial pressure (SAP) and respiration (R) recorded during spontaneous and controlled respiration at 15 breaths/minute (SR and RC15) in 19 healthy humans. Both MB and MF methods revealed the increase of HP predictability during RC15 and the unmodified causality from SAP to HP and from R to HP during RC15, thus suggesting that nonlinear methods are not superior to the linear ones in assessing predictability and causality in healthy humans. PMID- 23366728 TI - Detecting Parkinsons' symptoms in uncontrolled home environments: a multiple instance learning approach. AB - In this paper, we propose to use a weakly supervised machine learning framework for automatic detection of Parkinson's Disease motor symptoms in daily living environments. Our primary goal is to develop a monitoring system capable of being used outside of controlled laboratory settings. Such a system would enable us to track medication cycles at home and provide valuable clinical feedback. Most of the relevant prior works involve supervised learning frameworks (e.g., Support Vector Machines). However, in-home monitoring provides only coarse ground truth information about symptom occurrences, making it very hard to adapt and train supervised learning classifiers for symptom detection. We address this challenge by formulating symptom detection under incomplete ground truth information as a multiple instance learning (MIL) problem. MIL is a weakly supervised learning framework that does not require exact instances of symptom occurrences for training; rather, it learns from approximate time intervals within which a symptom might or might not have occurred on a given day. Once trained, the MIL detector was able to spot symptom-prone time windows on other days and approximately localize the symptom instances. We monitored two Parkinson's disease (PD) patients, each for four days with a set of five triaxial accelerometers and utilized a MIL algorithm based on axis parallel rectangle (APR) fitting in the feature space. We were able to detect subject specific symptoms (e.g. dyskinesia) that conformed with a daily log maintained by the patients. PMID- 23366729 TI - Quantitative assessment of magnetic sensor signal processing algorithms in a wireless tongue-operated assistive technology. AB - In this paper, we evaluate the overall performance of various magnetic-sensor signal processing (mSSP) algorithms for the Tongue Drive System based on a comprehensive dataset collected from trials with a total of eight able-bodied subjects. More specifically, we measure the performance of nine classifiers on the two-stage classification used by the mSSP algorithm, in order to learn how to improve the current algorithm. Results show that is it possible to reduce misclassification error from 5.95% and 20.13% to 3.98% and 5.63%, from the two assessed datasets, respectively, without sacrificing correctness. Furthermore, since the mSSP algorithm must run in real time, the results show where to focus the computational resources when they are constrained by the platforms with limited resources, such as smartphones. PMID- 23366730 TI - Spatial sparsity based indoor localization in wireless sensor network for assistive healthcare. AB - Indoor localization is one of the key topics in the area of wireless networks with increasing applications in assistive healthcare, where tracking the position and actions of the patient or elderly are required for medical observation or accident prevention. Most of the common indoor localization methods are based on estimating one or more location-dependent signal parameters like TOA, AOA or RSS. However, some difficulties and challenges caused by the complex scenarios within a closed space significantly limit the applicability of those existing approaches in an indoor assistive environment, such as the well-known multipath effect. In this paper, we develop a new one-stage localization method based on spatial sparsity of the x-y plane. In this method, we directly estimate the location of the emitter without going through the intermediate stage of TOA or signal strength estimation. We evaluate the performance of the proposed method using Monte Carlo simulation. The results show that the proposed method is (i) very accurate even with a small number of sensors and (ii) very effective in addressing the multi-path issues. PMID- 23366731 TI - Dynamic minimum pause threshold estimation for speech analysis in studies of cognitive function in ageing. AB - Cognitive decline represents the biggest limiting factor to independence in older adults. Speech analysis has emerged as an alternative to standard cognitive assessment tools. Temporal segmentation of speech is reported in many studies and typically employs a static threshold to define a pause. This study investigated the effect of using pause and utterance duration distribution data in differentiating between cognitively healthy and impaired older adults. Three sets of features were extracted from 187 speech recordings: temporal features using a static 250ms threshold; temporal features using a dynamic threshold; and pause and utterance duration distribution parameters. The ability of each of these sets to differentiate between cognitively healthy and cognitively impaired participants was investigated using a Linear Discriminant Analysis (LDA) classifier. Improvements of 0.22% (to 64.20%) in sensitivity, 6.33% (73.12%) in specificity, and 3.27% (68.66%) in overall accuracy were observed in the performance of the classifier using the pause and utterance duration distribution parameters when compared to the static temporal features. The use of the dynamic threshold had a negative impact on the classifier performance, with a decrease of 5.73% (to 58.25%) in sensitivity, 1.10% (65.69%) in specificity, and 3.42% (61.97%) in accuracy. PMID- 23366732 TI - Vestibular spontaneous response as a potential signature for Parkinson's disease. AB - In this paper, we report on a new method for potential diagnosis of Parkinson's Disease (PD) based on the analysis of the spontaneous response of vestibular system recorded by Electrovestibulography (EVestG). EVestG data of 20 individuals with PD and 28 healthy controls were adopted from a previous study. The field potentials and their firing pattern in response to whole body tilt stimuli from both left and right ears were extracted. We investigated several statistical and fractal features of the field potentials and also their firing patterns. One-way analysis of variance (ANOVA) was used to select the features showing the most significant differences between individuals with PD and the age-matched controls. Linear Discriminant analysis classification was applied to every selected feature using a leave-one-out routine. The result of each feature's classifier was used in a heuristic weighted average voting system to diagnose PD patients. The weights of the voting system were the (posterior) probabilities calculated by the designed classifier to indicate a subject related to a specific class. The results show more than 97% accuracy for PD diagnosis. Given that the patients were at different stage of disease, the high accuracy of the results encourages the use of vestibular response for PD diagnosis as a plausible quick and non invasive screening tool. PMID- 23366733 TI - Objective child behavior measurement with naturalistic daylong audio recording and its application to autism identification. AB - Child behavior in the natural environment is a subject that is relevant for many areas of social science and bio-behavioral research. However, its measurement is currently based mainly on subjective approaches such as parent questionnaires or clinical observation. This study demonstrates an objective and unobtrusive child vocal behavior measurement and monitoring approach using daylong audio recordings of children in the natural home environment. Our previous research has shown significant performance in childhood autism identification. However, there remains the question of why it works. In the previous study, the focus was more on the overall performance and data-driven modeling without regard to the meaning of underlying features. Even if a high risk of autism is predicted, specific information about child behavior that could contribute to the automated categorization was not further explored. This study attempts to clarify this issue by exploring the details of underlying features and uncovering additional behavioral information buried within the audio streams. It was found that much child vocal behavior can be measured automatically by applying signal processing and pattern recognition technologies to daylong audio recordings. By combining many such features, the model achieves an overall autism identification accuracy of 94% (N=226). Similar to many emerging non-invasive and telemonitoring technologies in health care, this approach is believed to have great potential in child development research, clinical practice and parenting. PMID- 23366734 TI - Quantification of Cy-5 siRNA signal in the intra-vital multi-photon microscopy images. AB - Transgenic mice with Tie2- green fluorescent protein (GFP) are used as a model to study the kinetic distribution of the Cy5-siRNA delivered by lipid nanoparticles (LNP) into the liver. After the mouse is injected with the LNP, it undergoes a procedure of intra-vital multi-photon microscopy imaging over a period of two hours, during which the process for the nanoparticle to diffuse into the hepatocytes from the vasculature system is monitored. Since the images are obtained in-vivo, the quantification of Cy5 kinetics suffers from the moving field of view (FOV). A method is proposed to register the sequence of images through template matching. Based on the semi-automatic segmentations of the vessels in the common FOV, the registered images are segmented into three regions of interest (ROI) in which the Cy5 signals are quantified. Computation of the percentage signal strength in the ROIs over time allows for the analysis of the diffusion of Cy5-siRNA into the hepatocytes, and helps demonstrate the effectiveness of the Cy5-siRNA delivery vehicle. PMID- 23366735 TI - Single camera system for multi-wavelength fluorescent imaging in the heart. AB - Optical mapping has been a powerful method to measure the cardiac electrophysiological phenomenon such as membrane potential(V(m)), intracellular calcium(Ca(2+)), and the other electrophysiological parameters. To measure two parameters simultaneously, the dual mapping system using two cameras is often used. However, the method to measure more than three parameters does not exist. To exploit the full potential of fluorescence imaging, an innovative method to measure multiple, more than three parameters is needed. In this study, we present a new optical mapping system which records multiple parameters using a single camera. Our system consists of one camera, custom-made optical lens units, and a custom-made filter wheel. The optical lens units is designed to focus the fluorescence light at filter position, and form an image on camera's sensor. To obtain optical signals with high quality, efficiency of light collection was carefully discussed in designing the optical system. The developed optical system has object space numerical aperture(NA) 0.1, and image space NA 0.23. The filter wheel was rotated by a motor, which allows filter switching corresponding with needed fluorescence wavelength. The camera exposure and filter switching were synchronized by phase locked loop, which allow this system to record multiple fluorescent signals frame by frame alternately. To validate the performance of this system, we performed experiments to observe V(m) and Ca(2+) dynamics simultaneously (frame rate: 125fps) with Langendorff perfused rabbit heart. Firstly, we applied basic stimuli to the heart base (cycle length: 500ms), and observed planer wave. The waveforms of V(m) and Ca(2+) show the same upstroke synchronized with cycle length of pacing. In addition, we recorded V(m) and Ca(2+) signals during ventricular fibrillation induced by burst pacing. According to these experiments, we showed the efficacy and availability of our method for cardiac electrophysiological research. PMID- 23366736 TI - Variable field-of-view visible and near-infrared polarization compound-eye endoscope. AB - A multi-functional compound-eye endoscope enabling variable field-of-view and polarization imaging as well as extremely deep focus is presented, which is based on a compact compound-eye camera called TOMBO (thin observation module by bound optics). Fixed and movable mirrors are introduced to control the field of view. Metal-wire-grid polarizer thin film applicable to both of visible and near infrared lights is attached to the lenses in TOMBO and light sources. Control of the field-of-view, polarization and wavelength of the illumination realizes several observation modes such as three-dimensional shape measurement, wide field of-view, and close-up observation of the superficial tissues and structures beneath the skin. PMID- 23366737 TI - Analysis of tight junction formation and integrity. AB - In this paper, we study segmentation of tight junctions and analyze the formation and integrity of tight junctions in large-scale confocal image stacks, a challenging biological problem because of the low spatial resolution images and the presence of breaks in tight junction structure. We present an automated, three-step processing approach for tight junction analysis. In our approach, we first localize each individual nucleus in the image by using thresholding, morphological filters and active contours. By using each nucleus position as a seed point, we automatically segment the cell body based on the active contour. We then use an intensity-based skeletonization algorithm to generate the boundary regions for each cell, and features are extracted from tight junctions associated with each cell to assess tight junction continuity. Based on qualitative results and quantitative comparisons, we show that we are able to automatically segment tight junctions and compute relevant features that provide a quantitative measure of tight junction formation to which the permeability of the cell monolayer can ultimately be correlated. PMID- 23366738 TI - Melanoma screening system using hyperspectral imager attached to imaging fiberscope. AB - Early detection and proper excision of the primary lesions of melanoma are crucial for reducing melanoma-related deaths. In order to support the early detection of melanoma, melanoma screening systems have been extensively studied and developed. Recently we have proposed a melanoma discrimination index derived from hyperspectral data (HSD) in the visible-near infrared wavelength region. The index represents variegation in spectra over a lesion and works well in discriminating melanoma from other pigmented lesions. However the previous hyperspectral imager did not have an enough allowance for measurement of lesions. To overcome the problem with it, we have developed a hyperspectral imager attached to imaging fiberscope. This equipment has been able to accumulate HSD in a view field of phi40 mm within about 10 seconds, from which the above-mentioned melanoma discrimination index has been calculated. Performance of the system has been studied in nine cases of melanoma and 18 cases of non-melanoma, obtained from patients and volunteers, all of whom were Japanese. The index has achieved a sensitivity of 100 % and a specificity of 94.4 %. PMID- 23366739 TI - Establishing spatial correspondence for the analysis of images from highly deforming anatomy. AB - This invited presentation summarizes recent advances in the incorporation of knowledge of the geometry, tissue mechanical properties and imaging characteristics in establishing spatial correspondence between multiple images of highly deforming, soft tissue structures. Spatial correspondence is used to aid diagnosis and in the extraction of quantitative parameters for disease detection, monitoring disease progression and assessing therapeutic response. The work is illustrated through clinical examples of multi-modal imaging of the breast, assessment of small bowel motility and polyp detection in the large bowel. PMID- 23366740 TI - Virtual colon tagging for electronic cleansing in dual-energy fecal-tagging CT colonography. AB - Partial volume effect (PVE) and tagging inhomogeneity are two major causes of artifacts in electronic cleansing (EC) for fecal-tagging CT colonography (CTC). Our purpose was to develop a novel method called "virtual tagging" for electronic cleansing in dual-energy fecal-tagging CTC. A three-material decomposition scheme was first applied in dual-energy CTC to decompose each voxel into a mixture of air, soft tissue, and iodine-tagged fecal material. The entire colonic lumen was then marked by virtually tagging the mixture portion of luminal air at each voxel. As a result, colon lumen including air and tagged materials was segmented and subtracted by their high values in virtually tagged images. Our virtual tagging scheme provides a cleansed colon that is free from artifacts caused by the PVE at air-tagging mixture and inhomogeneous tagging. PMID- 23366741 TI - Volumetric detection of colorectal lesions for noncathartic dual-energy computed tomographic colonography. AB - Noncathartic computed tomographic colonography (CTC) could significantly increase patient adherence to colorectal screening guidelines. However, radiologists find the interpretation of noncathartic CTC images challenging. We developed a fully automated computer-aided detection (CAD) scheme for assisting radiologists with noncathartic CTC. A volumetric method is used to detect lesions within a thick target region encompassing the colonic wall. Dual-energy CTC (DE-CTC) is used to provide more detailed information about the colon than what is possible with conventional CTC. False-positive detections are reduced by use of a random-forest classifier. The effect of the thickness of the target region on detection performance was assessed by use of 22 clinical noncathartic DE-CTC studies including 27 lesions >=6 mm. The results indicate that the thickness parameter can have significant effect on detection accuracy. Leave-one-patient-out evaluation indicated that the proposed CAD scheme detects colorectal lesions at high accuracy in noncathartic CTC. PMID- 23366742 TI - Interventional planning of liver resections: an overview. AB - Liver cancer is the third most common type of cancer. Among available treatment options, a surgical resection offers the best prognosis for long-term survival. It is important that such a surgical procedure is carefully prepared. Modern computer technology offers convenient ways to simulate different resection scenarios and help to determine the best treatment for a given case. This paper provides a non-exhaustive overview of existing computer-based systems for interventional planning of liver resections. They are reviewed according to their medical use case, e.g. if they support typical or atypical resections. PMID- 23366743 TI - Towards more precise, minimally-invasive tumour treatment under free breathing. AB - In recent years, significant advances have been made towards compensating respiratory organ motion for the treatment of tumours, e.g. for the liver. Among the most promising approaches are statistical population models of organ motion. In this paper we give an overview on our work in the field.We explain how 4D motion data can be acquired, how these motion models can then be built and applied in realistic scenarios. The application of the motion models is first shown on a case where 3D surrogate marker data is available. Then we will evaluate the prediction accuracy if only 2D and lastly 1D surrogate marker motion data is available. For all three scenarios we will give quantitative prediction accuracy results. PMID- 23366744 TI - A semi-automatic approach to the segmentation of liver parenchyma from 3D CT images with Extreme Learning Machine. AB - This paper presents a semi-automatic approach to segmentation of liver parenchyma from 3D computed tomography (CT) images. Specifically, liver segmentation is formalized as a pattern recognition problem, where a given voxel is to be assigned a correct label - either in a liver or a non-liver class. Each voxel is associated with a feature vector that describes image textures. Based on the generated features, an Extreme Learning Machine (ELM) classifier is employed to perform the voxel classification. Since preliminary voxel segmentation tends to be less accurate at the boundary, and there are other non-liver tissue voxels with similar texture characteristics as liver parenchyma, morphological smoothing and 3D level set refinement are applied to enhance the accuracy of segmentation. Our approach is validated on a set of CT data. The experiment shows that the proposed approach with ELM has the reasonably good performance for liver parenchyma segmentation. It demonstrates a comparable result in accuracy of classification but with a much faster training and classification speed compared with support vector machine (SVM). PMID- 23366745 TI - Analysis of the voltage response to identify macromolecule quantities in an electrolyte. AB - Current techniques of detecting proteins in solution can prove to be time consuming and expensive. Although low cost techniques are available, these are often slow and inaccurate. The authors propose an innovative technique for detecting the presence of proteins and other organic macromolecules in an electrolyte by analyzing the voltage waveform resulting from a biphasic, constant current, charge-balanced electrical stimulation. Initial experiments have proven the viability of the technique. However due to the limitation of technique accuracy, further refinement of the measurement approach is required. PMID- 23366746 TI - Integrated device for the measurement of systemic and local oxygen transport during physical exercise. AB - Current methods for monitoring exercise exertion rely upon heart rate monitors, which represent a crude and lagging indicator of conditioning. The rationale for the present study is that both systemic and local metabolic mechanisms are responsible for physical performance, and therefore they should be simultaneously quantified to achieve an objective assessment of human conditioning. We propose a compact, wearable near-infrared spectroscopy (NIRS) device integrated with electrocardiography (ECG) and photoplethysmography (PPG) to simultaneously assess the cardiovascular and local response to exercise. The system was tested on subjects performing a graded maximal exercise by comparing our readings with metabolic variables measured with respiratory gas analysis. We found strong correlations between local deoxyhemoglobin concentration [HHb], heart rate and oxygen uptake, as well as between oxyhemoglobin concentration [HbO(2)] and stroke volume. This study shows that combined NIRS, ECG and PPG measurements yield useful information to understand the interplay between systemic and local muscular responses to exercise. PMID- 23366747 TI - Parametric study of antennas for long range Doppler radar heart rate detection. AB - This research presents results obtained from long range measurements of physiological motion pertaining to human cardiac and respiration activity. A pulse pressure sensor was used as reference to verify the results from radar signals. A motion detection and grading algorithm was used to detect the presence of heart rate. In addition to showing that human heart rate and respiration can be measured at distances of 21 and 69 meters respectively, the effect of antenna size, radiation pattern and gain on the range of the radar has also been studied. PMID- 23366748 TI - Adaptive affective response identification for hearing threshold detection. AB - Emotional arousal, or affective patterns, can be probed using observable bioelectric signals, in particular using the fluctuations of electroencephalographic potentials from the human scalp. Hearing impairment related to increased threshold of audio tone detection may cause the loss of intelligibility of speech resulting in an innate automatic emotional response. An adaptive support vector machine can be trained to identify a subject's unique affective response based upon an audiogram hearing test. This paper presents the efficacy of our model, initial SVM classification data, and discusses potential application. PMID- 23366749 TI - Preliminary analysis of physiological changes of nursing students during training. AB - Long-term exposure to stress has been associated with chronic diseases, depression, and immune disorders. The precise detection and assessment of stress depends on personalized physiological monitoring and assessment of influence of personal and workplace factors We monitored nursing students during training on a high fidelity simulator in the Real-time Physiological Monitoring Lab at the University of Alabama in Huntsville. In this paper we present the preliminary results of this pilot study. A total of 14 participants were recorded: 12 female and 2 male subjects, 23-46 years old with an average age of 32.8 years. We analyzed heart rate, Heart Rate Variability (HRV), respiration, and physical activity. The results indicate significant strain on subjects during simulation: heart rate increased 16.7%, from 82.8 to 96.6 bpm (p<0.001), falling to a slightly increased level after the training session (84.9 bpm); Root Mean Square of Successive RR Differences (RMSSD) decreased from 38.9 ms to 37.7 ms; the breathing rate increased during the simulation from 16.9 to 17.7 breaths/min. Distractions also significantly influenced physiological parameters: the first telephone call increased heart rate on average 9 bpm (p<0.001), while the second call increased heart rate 8.6 bpm (p<0.001). The simulated patient-related events created even more prominent response; the average heart rate increased 17.4 bpm (p<0.001) at the onset of "patient in crisis" event. Real-time wearable monitoring may provide assessment of occupational stress. PMID- 23366750 TI - Age-dependent pupillary light reflex parameters in children. AB - Pupillary light reflex (PLR) refers to the phenomenon where pupil size changes in response to stimulation with a flash of light. It is a simple functional test that can reveal dysfunctions associated with the PLR pathway. Although abnormal PLR responses have been reported in many neurological disorders, few studies investigated neurodevelopmental effects on PLR parameters. We studied the effect of age on PLR in a group of 6 to 17 year old children with typical development. A significant and consistent age effect was found on PLR latency in children younger than 10 years old. Age effects were also observed in resting pupil diameter and constriction amplitude. However such age related trends were not observed in children with neurodevelopment disorders. These results suggest that PLR has the potential to be used as a simple noninvasive tool for monitoring neurodevelopment in children. PMID- 23366751 TI - Preliminary results from BCG and ECG measurements in the heart failure clinic. AB - We report on the preliminary deployment of a bathroom scale-based ballistocardiogram (BCG) system for the in-hospital monitoring of patients with heart failure. These early trials provided valuable insights into the challenges and opportunities for such monitoring. In particular, the need for robust algorithms and adapted BCG metric is suggested. The system was designed to be robust and user-friendly, with dual ballistocardiogram (BCG) and electrocardiogram (ECG) capabilities. The BCG was measured from a modified bathroom scale, while the ECG (used as timing reference) was measured using dry handlebar electrodes. The signal conditioning and digitization circuits were USB powered, and data acquisition performed using a netbook. Four patients with a NYHA class III at admission were measured daily for the duration of their treatment at Stanford hospital. A measure of BCG quality, in essence a quantitative implementation of the BCG classes originally defined in the 1950s, is proposed as a practical parameter. PMID- 23366752 TI - Unobtrusive online monitoring of sleep at home. AB - We describe an online sleep monitoring service, based on unobtrusive ballistocardiography (BCG) measurement in an ordinary bed. The novelty of the system is that the sleep tracking web application is based on measurements from a fully unobtrusive sensor. The BCG signal is measured with a piezoelectric film sensor under the mattress topper, and sent to the web server for analysis. Heart rate and respiratory variation, activity, sleep stages, and stress reactions are inferred based on the signal. The sleep information is presented to the user along with measurements of the sleeping environment (temperature, noise, luminosity) and user-logged tags (e.g. stress, alcohol, exercise). The approach is designed for long-term use at home, allowing users to follow the development of their sleep over months and years. The service has also a medical use, as sleep disorder patients can be measured for long periods before and after interventions. PMID- 23366753 TI - HRV analysis and blood pressure monitoring on weighing scale using BCG. AB - Using the Ballistocardiogram(BCG) measured on weighing scale, heart rate variability(HRV) and blood pressure were estimated. BCG was measured while subjects were on weighing scale in resting state and under the Valsalva maneuver and static exercise condition to induce the change in cardiac autonomic rhythm. Time domain, frequency domain and nonlinear HRV parameters were estimated from the measured BCG and compared with the ones calculated from ECG measured simultaneously. For blood pressure(BP) estimation, ECG was measured additionally on the feet using dry electrodes simultaneously installed on weighing scale and R J intervals were extracted as a BP correlated parameter at every beat cycle. HRV estimation results shows the correlation higher than 0.97, and the estimated BP was similar to the measured BP with a reliable correlations. PMID- 23366754 TI - Seismocardiography while sleeping at high altitude. AB - Current advancements in sensor technology allow the prolonged assessment of the seismocadiogram (SCG) out of the laboratory setting. Aim of this study is to evaluate whether SCG, as measured by a recently proposed wearable device, can detect cardio-respiratory alterations during sleep in healthy subjects exposed to high altitude hypoxia. PMID- 23366755 TI - Seismocardiographic adjustment of diastolic timed vibrations. AB - A seismocardiography based methodology is introduced for predicting the start and the end of diastole to be used in diastolic timed vibrations. An accelerometer was placed on the sternum of 142 participants (120 healthy and 22 ischemic heart patients) to record Seismocardiogram (SCG). It is claimed that SCG, in combination with electrocardiogram (ECG), provides a mechanism for predicting diastole. It is demonstrated that prediction of the aortic valve closure point in the SCG signal helps start the vibrator in time to cover most of the isovolumic relaxation period. Also, through prediction of the mitral valve closure point, safety of the technique can be assessed by estimation of the amount of unwanted vibrations applied during the isovolumic contraction period. PMID- 23366756 TI - Myocardial contractility: a seismocardiography approach. AB - Features are extracted from seismocardiogram data to correlate with two indexes of myocardial contractility: dP/dt(max) (maximum first derivative of left ventricular pressure) and stroke volume. In the first study on three pigs, it is shown that the time period between the R peak of the ECG and the first peak of the SCG (R-AO period or pre-ejection period, PEP) correlated (r= -0.86) with dP/dt(max). In the second study, stroke volume is gradually reduced in five human subjects using lower body negative pressure. The same feature as the pigs (R-AO) is correlated the most with stroke volume (r= -0.90). PMID- 23366757 TI - Autonomic-cardiorespiratory regulation: a physiology-based mathematical model. AB - This paper presents a novel physiology-based mathematical model of autonomic cardiorespiratory regulation described by a set of three nonlinear, coupled differential equations. We improved our previously proposed autonomic-cardiac regulation model by considering neuromechanical and mechanical coupling of cardiovascular and respiration systems including lung stretch-receptor reflex and venous return variation. We also introduced a differential equation describing respiration rate regulation which mainly originates in the medullary respiratory center. The results of simulation experiments suggest that the venous return variation generates a higher perturbation on heart rate and blood pressure than lung stretch-receptor reflex. The proposed model is also powerful in determining and removing direct respiratory impacts on parasympathetic activation tone to accurately extract parasympathetic activity caused by emotional states and environmental conditions. PMID- 23366758 TI - Consideration on parameter determination of a new model describing dynamic vagal heart rate control in rats. AB - The dynamic characteristics of vagal heart rate control can be approximated by a first-order low-pass filter with pure dead time in rabbits. However, this model may not necessarily be the best approximation of the vagal transfer function of the heart rate control in rats, because a flatter portion exists in the gain plot above approximately 0.3 Hz. We developed a new model that includes a frequency independent gain term to reproduce the flatter portion of the gain plot seen in the vagal transfer function in rats. The inclusion of the new term increased the coefficient of determination in an external validation of the linear regression relationship between measured and predicted heart rate responses to vagal stimulation, and made the slope of the regression line closer to unity. The parameters of mathematical transfer functions were determined in both the frequency and time domains. The frequency-domain fitting provided a set of parameters that was also able to reproduce the time-domain step response reasonably well. In contrast, the time-domain fitting provided a set of parameters that reproduced the frequency-domain transfer function only up to 0.2 Hz. Determination of proper model parameters was crucial for the development of a new model to describe the dynamic heart rate response to vagal stimulation in rats. PMID- 23366759 TI - Real-time cardiorespiratory coherence detects antinociception during general anesthesia. AB - Heart rate variability (HRV) may provide anesthesiologists with a noninvasive tool for monitoring nociception during general anesthesia. A novel real-time cardiorespiratory coherence (CRC) algorithm has been developed to analyze the strength of linear coupling between heart rate (HR) and respiration. CRC values range from 0 (low coherence, strong nociception) to 1 (high coherence, no nociception). The algorithm uses specially designed filters to operate in real time, minimizing computational complexity and time delay. In the standard HRV high frequency band of 0.15 - 0.4 Hz, the real-time delay is only 5.25 - 3.25 s. We have assessed the algorithm's response to 60 anesthetic bolus events (a large dose of anesthetics given over a short time; strongly antinociceptive) recorded in 47 pediatric patients receiving general anesthesia. Real-time CRC responded strongly to bolus events, changing by an average of 30%. For comparison, three traditional measures of HRV (LF/HF ratio, SDNN, and RMSSD) responded on average by only 3.8%, 14%, and 3.9%, respectively. Finally, two traditional clinical measures of nociception (HR and blood pressure) responded on average by only 3.9% and 0.91%, respectively. CRC may thus be used as a real-time nociception monitor during general anesthesia. PMID- 23366760 TI - Sleep-wake and circadian-dependent variation of cardiorespiratory coherence. AB - The risk of adverse cardiovascular events is elevated in the morning compared to the rest of the day. A circadian and a sleep-wake dependent variation in the regulation of the cardiovascular system could contribute to this increased cardiovascular risk. Using an ultradian sleep-wake cycle (USW) procedure, our aim was to explore the effects of the sleep-wake and circadian cycles on cardiorespiratory coherence (CRC) as a measure of autonomic nervous system (ANS) state. Our results suggest a shift toward parasympathetic dominance with deepening of sleep. Conversely, REM sleep is associated with a sympathetic dominance comparable to levels observed during wakefulness. A circadian rhythm was observed for CRC during wakefulness and all sleep stages. Maximal sympathetic dominance was observed in the morning, as measured by CRC during wakefulness and REM sleep, consistent with studies showing increased cardiac risk in the morning. This study provides evidence that circadian and sleep processes interact to influence the ANS modulation of the heart. PMID- 23366761 TI - Respiratory induced heart rate and blood pressure variability during mechanical ventilation in critically ill and brain death patients. AB - We analysed respiratory induced heart rate and blood pressure variability in mechanically ventilated patients with different levels of sedation and central nervous system activity. Our aim was to determine whether it is possible to distinguish different levels of sedation or human brain activity from heart rate and blood pressure. We measured 19 critically ill and 15 brain death patients ventilated at various respiratory frequencies - 15, 12, 8 and 6 breaths per minute. Basal and deeper sedation was performed in the critically ill patients. We detected and analysed heart rate and blood pressure parameters induced by ventilation. RESULTS: Respiratory induced heart rate variability is the unique parameter that can differentiate between brain death patients and sedated critically ill patients. Significant differences exist, especially during slow deep breathing with a mean period of 10 seconds. The limit values reflecting brain death are: baroreflex lower than 0.5 ms/mmHg and tidal volume normalised heart rate variability lower than 0.5 ms/ml. Reduced heart rate variability parameters of brain death patients remain unchanged even after normalisation to respiration volume. However, differences between basal and deep sedation do not appear significant on any parameter. PMID- 23366762 TI - Heart rate variability and renal organ damage in hypertensive patients. AB - Heart rate variability (HRV), a noninvasive measure of autonomic dysfunction and a risk factor for cardiovascular disease (CVD), has not been systematically studied in hypertensive patients in relation with renal involvement. A retrospective analysis on a cohort of hypertensive patients was performed to show differences in groups of patients categorized according to renal involvement, assessed by glomerular filtration rate (GFR). Patient with 24-h ECG Holter monitoring and other clinical information registered in the database of the Hypertension Clinic of the University of Naples Federico II were selected. Linear standard HRV measures were computed according to international guidelines on 24-h nominal ECG. A total of 200 patients were included in the present study. Decreased ratio of low to high frequency power (LF/HF) was associated with patient with moderate GFR, the highest grade of renal involvement considered in this study. These results were consistent with the findings of previous studies which concluded that depressed HRV was associated with higher risk of progression to end-stage renal disease and suggested that autonomic dysfunction may lead to kidney damage. Further research is needed to define the role of autonomic dysfunction in the development of renal disease and of HRV as a diagnostic or prognostic maker in hypertensive patients. PMID- 23366763 TI - Detection of anticipatory brain potentials during car driving. AB - Recognition of driver's intention from electroencephalogram (EEG) can be helpful in developing an in-car brain computer interface (BCI) systems for intelligent cars. This could be beneficial in enhancing the quality of interaction between the driver and the car to provide the response of the intelligent cars in line with driver's intention. We proposed investigating anticipation as the cognitive state leading to specific actions during car driving. An experimental protocol is designed for recording EEG from 6 subjects while driving the virtual reality driving simulator. The experimental protocol is a variant of the contingent negative variation (CNV) paradigm with Go and No-go conditions in driving framework. The results presented in this study support the presence of the slow cortical anticipatory potentials in EEG grand averages and also confirm the discriminability of these potentials in offline single trial classification with the average of 0.76 +/- 0.12 in area under the curve (AUC). PMID- 23366764 TI - Poor performance in SSVEP BCIs: are worse subjects just slower? AB - Brain-computer interface (BCI) systems translate brain activity into messages or commands. BCI studies that record from a dozen or more subjects typically report substantial variations in performance, as measured by accuracy. Usually, some subjects attain excellent (even perfect) accuracy, while at least one subject performs so poorly that effective communication would not be possible with that BCI. This study aims to further explore the differences between the best and worst performers by studying the changes in estimated accuracy within each trial in an offline simulation of an SSVEP BCI. Results showed that the worst performers not only attained lower accuracies, but needed more time after cue onset before their accuracies improved substantially. This outcome suggests that poor performance may be partly (though not completely) explained by the latency between cue onset and improved accuracy. PMID- 23366765 TI - Motion visual stimulus for SSVEP-based BCI system. AB - Steady-state visual evoked potential (SSVEP)- based brain-computer interface (BCI) system is one of the most accurate assistive technologies for the persons with severe disabilities. However, the existing visual stimulation patterns still lead to the eyes fatigue. Therefore, in this paper, we propose a novel visual stimulator using the idea of the motion visual stimulus to reduce the eyes fatigue while maintaining the merit of the SSVEP phenomena. Two corresponding feature extractions, i.e. 1) attention detection and 2) SSVEP detection, are also proposed to capture the phenomena of the proposed motion visual stimulus. Two class classification accuracy of both features is approximately 80%, where the maximum accuracy using the attention detection is 90%, and the maximum accuracy using the SSVEP detection is 100%. PMID- 23366766 TI - A P300-based EEG-BCI for spatial navigation control. AB - In this study, a Brain Computer Interface (BCI) based on the P300 oddball paradigm has been developed for spatial navigation control in virtual environments. Functionality and efficacy of the system were analyzed with results from nine healthy volunteers. Each participant was asked to gaze at an individual target in a 3*3 P300 matrix containing different symbolic navigational icons while EEG signals were collected. Resulting ERPs were processed online and classification commands were executed to control spatial movements within the MazeSuite virtual environment and presented to the user online during an experiment. Subjects demonstrated on average, ~89% online accuracy for simple mazes and ~82% online accuracy in longer more complex mazes. Results suggest that this BCI setup enables guided free-form navigation in virtual 3D environments. PMID- 23366767 TI - A subjective assessment of a P300 BCI system for lower-limb rehabilitation purposes. AB - Recent research has shown that a P300 system can be used while walking without requiring any specific gait-related artifact removal techniques. Also, standard EEG-based Brain-Computer Interfaces (BCI) have not been really assessed for lower limb rehabilitation/prosthesis. Therefore, this paper gives a first baseline estimation (for future BCI comparisons) of the subjective and objective performances of a four-state P300 BCI plus a non-control state for lower-limb rehabilitation purposes. To assess usability and workload, the System Usability Scale and the NASA Task Load Index questionnaires were administered to five healthy subjects after performing a real-time treadmill speed control. Results show that the P300 BCI approach could suit fitness and rehabilitation applications, whereas prosthesis control, which suffers from a low reactivity, appears too sensitive for risky and crowded areas. PMID- 23366768 TI - Detection of attention shift for asynchronous P300-based BCI. AB - Brain-computer interface (BCI) provides patients suffering from severe neuromuscular disorders an alternative way of interacting with the outside world. The P300-based BCI is among the most popular paradigms in the field and most current versions operate in synchronous mode and assume participant engagement throughout operation. In this study, we demonstrate a new approach for assessment of user engagement through a hybrid classification of ERP and band power features of EEG signals that could allow building asynchronous BCIs. EEG signals from nine electrode locations were recorded from nine participants during controlled engagement conditions when subjects were either engaged with the P3speller task or not attending. Statistical analysis of band power showed that there were significant contrasts of attending only for the delta and beta bands as indicators of features for user attendance classification. A hybrid classifier using ERP scores and band power features yielded the best overall performance of 0.98 in terms of the area under the ROC curve (AUC). Results indicate that band powers can provide additional discriminant information to the ERP for user attention detection and this combined approach can be used to assess user engagement for each stimulus sequence during BCI use. PMID- 23366769 TI - The effects of locomotor training with a robotic-gait orthosis (Lokomat) on neuromuscular properties in persons with chronic SCI. AB - We studied the effects of robotic-assisted locomotor (LOKOMAT) training on neuromuscular abnormality associated with spasticity in persons with incomplete Spinal Cord Injury (SCI). LOKOMAT training was performed 3 days/week for 4 weeks, with up to 45 minutes of training per session. Subjects were evaluated before and after 1, 2, and 4 weeks of training, and the effects of training on the intrinsic (muscular) and reflexive components of the neuromuscular properties were quantified over the ankle range-of-motion. A linear (slope&intercept) regression was fit to the stiffness-angle curve. "Growth mixture" modeling was used to identify recovery classes for these parameters over the training period. Two distinct classes were observed. Class 1 subjects had initially higher reflex stiffness parameters (i.e., intercept and slope vs. ankle position) and reduced significantly over the training period. Class 2 subjects initially had lower reflex stiffness parameters and experienced non-significant reductions. Similar results were observed for the intrinsic stiffness intercept; however, intrinsic slope showed no significant improvement over training for either class. These findings demonstrate that LOKOMAT training is effective in reducing reflex and intrinsic stiffness (which abnormally increase in SCI) and improving the abnormal modulation of reflexes over the ankle range-of-motion. PMID- 23366770 TI - The effect of robot-assisted locomotor training on walking speed. AB - This study was to quantify the effects of Lokomat training on ambulation capacity of patients with incomplete spinal cord injury (SCI), and to examine the potential assistance of anti-spasticity medication on training. Twenty-nine SCI subjects with spastic hypertonia at their ankle participated in a 12-session Lokomat training regimen, with half receiving Lokomat only (LOKO) and half receiving Lokomat combined with tizanidine (LOKO+TIZ). Walking capacity was evaluated in terms of the 10-meter walking (10MW) speed-a major clinical evaluation of SCI rehabilitation-four times (at the baseline, 1-, 2- and 4-weeks after training). Growth Mixture Model (GMM) was used to classify the walking speed into recovery patterns. Two latent classes were found for each treatment group, corresponding to low speed and high speed. Walking speed increased with training for high-walking-capacity subjects in the LOKO group, and for both high- and low-capacity subjects in the LOKO+TIZ group. Improvement magnitude between pre- and post-test varied among latent classes. Within each class, the baseline measure had a significant effect on walking speed improvement. This study shows that the Lokomat training improves walking speed for patients with SCI, and anti spasticity medication, such as tizanidine, can improve the efficacy of Lokomat training, particularly for patients with low walking capacity. PMID- 23366771 TI - Effect of sensory inputs on the motor evoked potentials in the wrist flexor muscle during the robotic passive stepping in humans. AB - The purpose of this study was to reveal whether the stepping-related afferent feedback modulates the motor evoked potentials (MEPs) in the wrist flexor muscle in humans. MEPs generated in flexor carpi radialis muscle (FCR) by transcranial magnetic stimulation (TMS) were recorded during robotic-assisted passive stepping and standing conditions. TMS were applied at fifteen scalp sites (3 * 5 cm grid in anterior-posterior direction and medial-lateral direction, respectively) centered on the "hot spot" which was defined as an optimal site for eliciting the MEP in FCR during passive standing task, The MEP amplitudes were measured for each stimulus sites, and then compared between different conditions. During passive stepping, the MEP amplitudes in FCR muscle were significantly increased in six adjacent stimulus sites of the hot spot, This result suggests that stepping-related afferent feedback induces expansion of excitatory area in motor cortex for FCR muscle. PMID- 23366772 TI - The horizontal angular vestibulo-ocular reflex: a non-linear mechanism for context-dependent responses. AB - A bilateral model for the horizontal angular vestibulo-ocular reflex (AVOR) is presented in this paper. It is shown that by assigning proper non-linear neural computations at the premotor level, the model is capable of replicating target distance dependent VOR responses. Moreover, the model behavior in case of sensory plugging is also consistent with reported experimental observations. PMID- 23366773 TI - Experimental observations on the human arm motion planning under an elbow joint constraint. AB - This paper seeks to define the governing strategies by which the human central nervous system (CNS) finds optimal solutions for an arm reaching motion, when an elbow joint is constrained. The compensated arm reaching motion under the joint kinematic constraint is observed by human experiments. We present an experimental protocol, where subjects perform point-to-point reaching tasks with a lightweight elbow brace to restrict the elbow kinematics with minimal effect on the arm dynamics. The human compensatory strategy is analyzed in terms of hand path kinematics (i.e. spatial and temporal characteristics) and the arm postural configuration. The spatial and temporal characteristics of hand path are approximated by the Euclidean geodesic curves and the well known bell-shaped smooth profile, respectively. Furthermore, the contribution of each joint degree of-freedom (DOF) motion is discussed and its relation to the arm posture selection is elaborated. PMID- 23366774 TI - The role of propriospinal neuronal network in transmitting the alternating muscular activities of flexor and extensor in parkinsonian tremor. AB - It has been shown that normal cyclic movement of human arm and resting limb tremor in Parkinson's disease (PD) are associated with the oscillatory neuronal activities in different cerebral networks, which are transmitted to the antagonistic muscles via the same spinal pathway. There are mono-synaptic and multi-synaptic corticospinal pathways for conveying motor commands. This study investigates the plausible role of propriospinal neuronal (PN) network in the C3 C4 levels in multi-synaptic transmission of cortical commands for oscillatory movements. A PN network model is constructed based on known neurophysiological connections, and is hypothesized to achieve the conversion of cortical oscillations into alternating antagonistic muscle bursts. Simulations performed with a virtual arm (VA) model indicate that without the PN network, the alternating bursts of antagonistic muscle EMG could not be reliably generated, whereas with the PN network, the alternating pattern of bursts were naturally displayed in the three pairs of antagonist muscles. Thus, it is suggested that oscillations in the primary motor cortex (M1) of single and double tremor frequencies are processed at the PN network to compute the alternating burst pattern in the flexor and extensor muscles. PMID- 23366775 TI - Distributed clock gating for power reduction of a programmable waveform generator for neural stimulation. AB - This paper describes how to employ distributed clock gating to achieve an overall low power design of a programmable waveform generator intended for a neural stimulator. The power efficiency is enabled using global timing control combined with local amplitude distribution over a bus to the local stimulator frontends. This allows the combination of local and global clock gating for complete sub blocks of the design. A counter and a shifter employed at the local digital stimulator reduce the design complexity for the waveform generation and thus the overall power consumptions. The average power results indicate that 63% power can be saved for the global stimulator control unit and 89-96% power can be saved for the local digital stimulator by using the proposed approach. The circuit has been implemented and successfully tested in a 0.35 um AMS HVCMOS technology. PMID- 23366776 TI - Flexible multi-electrode array with integrated bendable CMOS-chip for implantable systems. AB - Micro-electrodes and micro-electrode arrays (MEAs) for stimulating neurons or recording action potentials are widely used in medical applications or biological research. For medical implants in many applications like brain implants or retinal implants there is a need for flexible MEAs with a large area and a large number of stimulation electrodes. In this work a flexible MEA with an embedded flexible silicon dummy CMOS-chip facing these challenges has been designed, manufactured and characterized. This approach offers the possibility by connecting and addressing several of these MEAs via a bus system, to increase the number and the density of electrodes significantly. This paper describes the design and fabrication process. Results on the mechanical and electrical behavior will be given and possible improvements for medical applications by this novel approach will be discussed. PMID- 23366777 TI - Hermetic electronic packaging of an implantable brain-machine-interface with transcutaneous optical data communication. AB - Future brain-computer-interfaces (BCIs) for severely impaired patients are implanted to electrically contact the brain tissue. Avoiding percutaneous cables requires amplifier and telemetry electronics to be implanted too. We developed a hermetic package that protects the electronic circuitry of a BCI from body moisture while permitting infrared communication through the package wall made from alumina ceramic. The ceramic package is casted in medical grade silicone adhesive, for which we identified MED2-4013 as a promising candidate. PMID- 23366778 TI - Fabrication and successful in-vivo implantation of a flexible neural implant with a hybrid polyimide-silicon design. AB - A flexible neural implant was designed and fabricated using an novel integration approach that offers the advantages of both silicon and polymer based implants: high density electrodes and precise insertion on one side and mechanical flexibility suitable for reduced tissue strain due to micro-motion during chronic implantation on the other side. This was achieved by separating the device into silicon or polymer areas, depending on their desired functionality. The tip, where the recording and stimulation electrodes would be placed, was kept of silicon: a choice that doesn't call for any compromise to be made regarding the high density electrode and possible local circuit integration later on. The bevel shaped sharp silicon tip also proved to facilitate the probe insertion, offering a behavior very much similar to the classical rigid silicon probes. On the other side, most of the 1 cm long shank of the probe was made out of polyimide. This led to more than one order of magnitude reduction of the forces necessary to bend the shank. The flexible shank proved also to be more robust than silicon probes, sustaining significant deformation in any direction without fracture. The 9mm deep in-vivo implantation were successfully achieved without buckling for 10 um/s and 100 um/s insertion speeds. PMID- 23366779 TI - Virtual electrode stimulation in a multi-channel stimulation system. AB - Virtual electrode stimulation can provide extra selective spatial stimulation sites given if there is a highly configurable and controllable multi-channel stimulator system. The system has to have low latency between the loaded input data and output stimulation pulse, precise timing on simultaneously stimulation and an interface with external device such that a computer or FPGA can directly control each of the stimulation channels. This paper presents a general concept of virtual electrode stimulation and a multi-channel stimulation system that can support such operation. The system is designed in CMOS 0.35um occupies 3.4*2.7mm(2) and consumes 2.3mW. PMID- 23366780 TI - On the cause and control of residual voltage generated by electrical stimulation of neural tissue. AB - Functional electrical stimulation of neural tissue is traditionally performed with symmetric cathodic-first biphasic pulses of current through an electrode/electrolyte interface. When the interface is modeled by a series R-C circuit, as is sometimes done for stimulator circuit design, the appearance of a net residual voltage across the electrode cannot be explained. Residual voltage can cause polarization of the electrode and pose a problem for safe electrical stimulation. This paper aims to (1) theoretically explain one reason for the residual voltage, which is the inclusion of the Faradaic impedance (2) suggest a simple dynamic feedback mechanism to eliminate residual voltage. PMID- 23366781 TI - A robotic interface to train grip strength, grip coordination and finger extension following stroke. AB - A two degree of freedom robotic interface was developed to assist with rehabilitation of three hand impairments following stroke: reduced grip strength, reduced finger extension, and loss of dexterity due to the lack of coordination between finger and wrist muscles. The design and performance characteristics of this interface, which takes advantage of an FPGA-based real-time platform, are discussed. The robotic interface is able to accurately render elastic and viscous loads. Preliminary trials with healthy subjects demonstrate the use of the device. PMID- 23366782 TI - Error amplification to promote motor learning and motivation in therapy robotics. AB - To study the effects of different feedback error amplification methods on a subject's upper-limb motor learning and affect during a point-to-point reaching exercise, we developed a real-time controller for a robotic manipulandum. The reaching environment was visually distorted by implementing a thirty degrees rotation between the coordinate systems of the robot's end-effector and the visual display. Feedback error amplification was provided to subjects as they trained to learn reaching within the visually rotated environment. Error amplification was provided either visually or through both haptic and visual means, each method with two different amplification gains. Subjects' performance (i.e., trajectory error) and self-reports to a questionnaire were used to study the speed and amount of adaptation promoted by each error amplification method and subjects' emotional changes. We found that providing haptic and visual feedback promotes faster adaptation to the distortion and increases subjects' satisfaction with the task, leading to a higher level of attentiveness during the exercise. This finding can be used to design a novel exercise regimen, where alternating between error amplification methods is used to both increase a subject's motor learning and maintain a minimum level of motivational engagement in the exercise. In future experiments, we will test whether such exercise methods will lead to a faster learning time and greater motivation to pursue a therapy exercise regimen. PMID- 23366783 TI - Robot-assisted Guitar Hero for finger rehabilitation after stroke. AB - This paper describes the design and testing of a robotic device for finger therapy after stroke: FINGER (Finger Individuating Grasp Exercise Robot). FINGER makes use of stacked single degree-of-freedom mechanisms to assist subjects in moving individual fingers in a naturalistic grasping pattern through much of their full range of motion. The device has a high bandwidth of control (-3dB at approximately 8 Hz) and is backdriveable. These characteristics make it capable of assisting in grasping tasks that require precise timing. We therefore used FINGER to assist individuals with a stroke (n= 8) and without impairment (n= 4) in playing a game similar to Guitar Hero(c). The subjects attempted to move their fingers to target positions at times specified by notes that were graphically streamed to popular music. We show here that by automatically adjusting the robot gains, it is possible to use FINGER to modulate the subject's success rate at the game, across a range of impairment levels. Modulating success rates did not alter the stroke subject's effort, although the unimpaired subjects exerted more force when they were made less successful. We also present a novel measure of finger individuation that can be assessed as individuals play Guitar Hero with FINGER. The results demonstrate the ability of FINGER to provide controlled levels of assistance during an engaging computer game, and to quantify finger individuation after stroke. PMID- 23366784 TI - Control of robot assistant for rehabilitation of upper extremities. AB - The assisted movement in humans with paresis of upper extremities is becoming popular for neurorehabilitation. We propose a novel method for trajectory selection and assistance control. This paper presents simulation of a planar two degrees of freedom robot that assists horizontal movement of the hand. The control assumes that during the exercise the hand needs to follow healthy alike trajectories. The robot is assumed to provide minimal assistance and operate as a teacher of the movement. PMID- 23366785 TI - Robot-aided rehabilitation task design for inner shoulder muscles. AB - In this paper, we propose a simultaneous design method of motion and external force trajectories for shoulder inner muscles in the robot-aided rehabilitation system, based on a biomechanical analysis of patient's body. The rehabilitation efficiency evaluation function was maximized by Genetic Algorithm (GA), where the structure of spline curves parameters are pre-defined, and the structural parameters are explored to design smooth rehabilitation motion and external force trajectories. PMID- 23366786 TI - Reducing muscle effort in walking through powered exoskeletons. AB - This paper presents a novel assistive control for lower limb exoskeletons. The controller provides the user with a scaled version of the Winter's nominal torque profile, which is adapted online to the specific gait features of the user. The proposed assistive controller is implemented on the ALEX II exoskeleton and tested on two healthy subjects. Experimental results show that when assisted by the exoskeleton users can reduce the muscle effort compared to free walking. PMID- 23366787 TI - Utilization of temporal information for intracranial pressure development trend forecasting in traumatic brain injury. AB - Objective. Our primary objective is to demonstrate and statistically justify that forecasting models that utilize temporal information of the historical readings of ICP and related parameters are superior, in terms of performance, compared with models that do not make use of temporal information. PMID- 23366788 TI - Subpeak regional analysis of intracranial pressure waveform morphology based on cerebrospinal fluid hydrodynamics in the cerebral aqueduct and prepontine cistern. AB - The objective of this study is to investigate the relationship between intracranial pressure (ICP) pulse waveform morphology and selected hydrodynamic metrics of cerebrospinal fluid (CSF) movement using a novel method for ICP pulse pressure regional analysis based on the Morphological Clustering and Analysis of Continuous Intracranial Pulse (MOCAIP) algorithm. PMID- 23366789 TI - Single pulse analysis of intracranial pressure for a hydrocephalus implant. AB - The intracranial pressure (ICP) waveform contains important diagnostic information. Changes in ICP are associated with changes of the pulse waveform. This change has explicitly been observed in 13 infusion tests by analyzing 100 Hz ICP data. An algorithm is proposed which automatically extracts the pulse waves and categorizes them into predefined patterns. A developed algorithm determined 88 %+/-8 % (mean +/-SD) of all classified pulse waves correctly on predefined patterns. This algorithm has low computational cost and is independent of a pressure drift in the sensor by using only the relationship between special waveform characteristics. Hence, it could be implemented on a microcontroller of a future electromechanic hydrocephalus shunt system to control the drainage of cerebrospinal fluid (CSF). PMID- 23366790 TI - Predictive modeling of cardiovascular complications in incident hemodialysis patients. AB - The administration of hemodialysis (HD) treatment leads to the continuous collection of a vast quantity of medical data. Many variables related to the patient health status, to the treatment, and to dialyzer settings can be recorded and stored at each treatment session. In this study a dataset of 42 variables and 1526 patients extracted from the Fresenius Medical Care database EuCliD was used to develop and apply a random forest predictive model for the prediction of cardiovascular events in the first year of HD treatment. A ridge-lasso logistic regression algorithm was then applied to the subset of variables mostly involved in the prediction model to get insights in the mechanisms underlying the incidence of cardiovascular complications in this high risk population of patients. PMID- 23366791 TI - A new algorithm for detection of heart and respiration rate with UWB signals. AB - Proposed is a detection algorithm for physiological monitoring with Ultra Wide Band (UWB) radar. This new algorithm is based on detection of movement energy in a specified band of frequency using wavelet and filter banks. One of the advantages of this algorithm is its ability to detect heart and respiration rates of a subject in an environment containing other motion. The heart movement is detected with the accuracy of 95% and respiration with the 100%. This algorithm has a repeatability of 93% which is a significant characteristic of the method. PMID- 23366792 TI - Multi-Gaussian fitting for the assessment of left ventricular ejection time from the photoplethysmogram. AB - The Left ventricular ejection time (LVET) is one of the primary surrogates of the left ventricular contractility and stroke volume. Its continuous monitoring is considered to be a valuable hypovolumia prognostic parameter and an important risk predictor in cardiovascular diseases such as cardiac and light chain amyloidosis. In this paper, we present a novel methodology for the assessment of LVET based the Photoplethysmographic (PPG) waveform. We propose the use of Gaussian functions to model both systolic and diastolic phases of the PPG beat and consequently determine the onset and offset of the systolic ejection from the analysis of the systolic phase 3(rd) derivative. The results achieved by the proposed methodology were compared with the algorithm proposed by Chan et al. [1], revealing better estimation of LVET (15.84 +/- 13.56 ms vs 23.01 +/- 14.60 ms), and similar correlation with the echocardiographic reference (0.73 vs 0.75). PMID- 23366793 TI - A Bayes optimal matrix-variate LDA for extraction of spatio-spectral features from EEG signals. AB - Classification of mental states from electroencephalogram (EEG) signals is used for many applications in areas such as brain-computer interfacing (BCI). When represented in the frequency domain, the multichannel EEG signal can be considered as a two-directional spatio-spectral data of high dimensionality. Extraction of salient features using feature extractors such as the commonly used linear discriminant analysis (LDA) is an essential step for the classification of these signals. However, multichannel EEG is naturally in matrix-variate format, while LDA and other traditional feature extractors are designed for vector variate input. Consequently, these methods require a prior vectorization of the EEG signals, which ignores the inherent matrix-variate structure in the data and leads to high computational complexity. A matrix-variate formulation of LDA have previously been proposed. However, this heuristic formulation does not provide the Bayes optimality benefits of LDA. The current paper proposes a Bayes optimal matrix-variate formulation of LDA based on a matrix-variate model for the spatio spectral EEG patterns. The proposed formulation also provides a strategy to select the most significant features among the different rows and columns. PMID- 23366794 TI - Morphology-based wavelet features and multiple mother wavelet strategy for spike classification in EEG signals. AB - New wavelet-derived features and strategies that can improve autonomous EEG classifier performance are presented. Various feature sets based on the morphological structure of wavelet subband coefficients are derived and evaluated. The performance of these new feature sets is superior to Guler's classic features in both sensitivity and specificity. In addition, the use of (scalp electrode) spatial information is also shown to improve EEG classification. Finally, a new strategy based upon concurrent use of several mother wavelets is shown to result in increased sensitivity and specificity. Various attempts at reducing feature vector dimension are shown. A non-parametric method, k-NNR, is implemented for classification and 10-fold cross-validation is used for assessment. PMID- 23366795 TI - What does clean EEG look like? AB - Lack of a clear analytical metric for identifying artifact free, clean electroencephalographic (EEG) signals inhibits robust comparison of different artifact removal methods and lowers confidence in the results of EEG analysis. An algorithm is presented for identifying clean EEG epochs by thresholding statistical properties of the EEG. Thresholds are trained on EEG datasets from both healthy subjects and stroke / spinal cord injury patient populations via differential evolution (DE). PMID- 23366796 TI - Detection of event-related desynchronization during attempted and imagined movements in tetraplegics for brain switch control. AB - Motor-impaired individuals such as tetraplegics could benefit from Brain-Computer Interfaces with an intuitive control mechanism, for instance for the control of a neuroprosthesis. Whereas BCI studies in healthy users commonly focus on motor imagery, for the eventual target users, namely patients, attempted movements could potentially be a more promising alternative. In the current study, EEG frequency information was used for classification of both imagined and attempted movements in tetraplegics. Although overall classification rates were considerably lower for tetraplegics than for the control group, both imagined and attempted movement were detectable. Classification rates were significantly higher for the attempted movement condition, with a mean rate of 77%. These results suggest that attempted movement is an appropriate task for BCI control in long-term paralysis patients. PMID- 23366797 TI - Locating the STN-DBS electrodes and resolving their subsequent networks using coherent source analysis on EEG. AB - The deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most effective surgical therapy for Parkinson's disease (PD). The first aim of the study was to locate the STN-DBS electrode by applying source analysis on EEG. Secondly, to identify tremor related areas which are associated with the STN. The Dynamic imaging of coherent sources (DICS) was used to find the coherent sources in the brain. The capability of the source analysis to detect deep sources like STN in the brain using EEG data was tested with two model dipole simulations. The simulations were concentrated on two aspects, the angle of the dipole orientation and the disturbance of the cortical areas on locating subcortical regions. In all the DBS treated Parkinsonian tremor patients the power spectrum showed a clear peak at the stimulated frequency and followed by there harmonics. The DBS stimulated frequency constituted a network of primary sensory motor cortex, supplementary motor area, prefrontal cortex, diencephalon, cerebellum and brainstem. Thus the STN was located in the region of the diencephalon. The resolved network may give better understanding to the pathophysiology of the effected tremor network in PD patients with STN-DBS. PMID- 23366798 TI - Computational modeling for assessment of IBD: to be or not to be? AB - The grading of inflammatory bowel disease (IBD) severity is important to determine the proper treatment strategy and to quantify the response to treatment. Traditionally, ileocolonoscopy is considered the reference standard for assessment of IBD. However, the procedure is invasive and requires extensive bowel preparation. Magnetic resonance imaging (MRI) has become an important tool for determining the presence of disease activity. Unfortunately, only moderate interobserver agreement is reported for most of the radiological severity measures. There is a clear demand for automated evaluation of MR images in Crohn's disease (CD). This paper aims to introduce a preliminary suite of fundamental tools for assessment of CD severity. It involves procedures for image analysis, classification and visualization to predict the colonoscopy disease scores. PMID- 23366799 TI - Segmentation of urinary bladder in CT urography. AB - We are developing a Conjoint Level set Analysis and Segmentation System (CLASS) for bladder segmentation on CTU, which is a critical component for computer aided diagnosis of bladder cancer. A challenge for bladder segmentation is the presence of regions without contrast (NC) and filled with IV contrast (C). According to the characteristics of the bladder in CTU, CLASS is designed to perform number tasks such as preprocessing, initial segmentation, 3D and 2D level set segmentation and post-processing. CLASS segments separately the NC and the C regions of the bladder. In the post-processing stage the final contour is obtained based on the union of the NC and C contours. 70 bladders were segmented. Of the 70 bladders 31 contained lesions, 24 contained wall thickening, and 15 were normal. The performance of CLASS was assessed by rating the quality of the contours on a 5-point scale (1="very poor", 3="fair", 5="excellent"). The average quality ratings for the 12 completely no contrast (NC) and 5 completely contrast filled (C) bladder contours were 3.3+/-1.0 and 3.4+/-0.5, respectively. The average quality ratings for the 53 NC and 53 C regions of the 53 partially contrast-filled bladders were 4.0+/-0.7 and 4.0+/-1.0, respectively. Quality ratings of 4 or above were given for 87% (46/53) NC and 77% (41/53) C regions. Only 4% (2/53) NC and 9% (5/53) C regions had ratings under 3. After combining the NC and C contours for each of the 70 bladders, 66% (46/70) had quality ratings of 4 or above. Only 6% (4/70) had ratings under 3. The average quality rating was 3.8+/-0.7. The results demonstrate the potential of CLASS for automated segmentation of the bladder. PMID- 23366800 TI - Centerline calculation for extracting abdominal aorta in 3-D MRI images. AB - The examination of abdominal aorta is an effective way to diagnose many cardiovascular diseases. Aortic stiffness measured by pulse wave velocity (PWV) calculation is a good estimate of overall cardiovascular health. Calculation of pulse wave velocity requires the length of abdominal aorta as an input parameter, while the structure of abdominal aorta can be used for diagnostic purposes. For the sake of non-invasive diagnostics, non-contrasted MRI images of aorta were used. Due to the "black-blood" imaging, a lot of artifacts are present and a robust centerline extraction method is needed. In this research we develop a novel graph-based method for extracting centerlines of abdominal aorta for length calculation. Our method is robust to artifacts and noise and applicable to any imaging modality. PMID- 23366801 TI - Multi-organ segmentation in abdominal CT images. AB - Automated segmentation of multiple organs in CT data of the upper abdomen is addressed. In order to explicitly incorporate the spatial interrelations among organs, we propose a method for finding and representing the interrelations based on canonical correlation analysis. Furthermore, methods are developed for constructing and utilizing the statistical atlas in which inter-organ constraints are explicitly incorporated to improve accuracy of multi-organ segmentation. The proposed methods were tested to perform segmentation of eight abdominal organs (liver, spleen, kidneys, pancreas, gallbladder, aorta, and inferior vena cava) from various imaging conditions of CT datasets. 87 datasets acquired at two institutions were used for the validation. Significant accuracy improvement was observed for several organs in comparison with the conventional method. PMID- 23366802 TI - Multi-object active shape model construction for abdomen segmentation: preliminary results. AB - The automatic segmentation of abdominal organs is a pre-requisite for many medical applications. Successful methods typically rely on prior knowledge about the to be segmented anatomy as it is for instance provided by means of active shape models (ASMs). Contrary to most previous ASM based methods, this work does not focus on individual organs. Instead, a more holistic approach that aims at exploiting inter-organ relationships to eventually segment a complex of organs is proposed. Accordingly, a flexible framework for automatic construction of multi object ASMs is introduced, employed for coupled shape modeling, and used for co segmentation of liver and spleen based on a new coupled shape/separate pose approach. Our first results indicate feasible segmentation accuracies, whereas pose decoupling leads to substantially better segmentation results and performs in average also slightly better than the standard single-object ASM approach. PMID- 23366803 TI - Scalable, high-performance 3D imaging software platform: system architecture and application to virtual colonoscopy. AB - One of the key challenges in three-dimensional (3D) medical imaging is to enable the fast turn-around time, which is often required for interactive or real-time response. This inevitably requires not only high computational power but also high memory bandwidth due to the massive amount of data that need to be processed. In this work, we have developed a software platform that is designed to support high-performance 3D medical image processing for a wide range of applications using increasingly available and affordable commodity computing systems: multi-core, clusters, and cloud computing systems. To achieve scalable, high-performance computing, our platform (1) employs size-adaptive, distributable block volumes as a core data structure for efficient parallelization of a wide range of 3D image processing algorithms; (2) supports task scheduling for efficient load distribution and balancing; and (3) consists of a layered parallel software libraries that allow a wide range of medical applications to share the same functionalities. We evaluated the performance of our platform by applying it to an electronic cleansing system in virtual colonoscopy, with initial experimental results showing a 10 times performance improvement on an 8-core workstation over the original sequential implementation of the system. PMID- 23366804 TI - Segmentation of zebrafish embryonic images using a geometric atlas deformation. AB - Transgenic zebrafish expressing fluorescent proteins in specific tissues or organs are promising models for studies of normal developmental processes, or perturbations of these. However, for widespread use, reliable quantification of the observed effects is necessary. Therefore, accurate and automatic analysis of images obtained by fluorescent microscopy and depicting zebrafish embryos becomes crucial. In this paper, a segmentation approach for such images is proposed. The segmentation is achieved by fitting a species-specific 2D atlas to the zebrafish data depicted in the images. Experiments performed in a set of 50 images have provided promising results. PMID- 23366805 TI - An incremental approach to pigmented skin lesion segmentation with classification refinements in uncertain regions. AB - Skin lesion segmentation in dermatoscopic images is difficult because there are large inter variations in shape, size, color, and texture between lesions and skin types. Hence, computational features learned from a training set of lesion images may not be applicable to other lesion images. In this paper, we propose an incremental method for lesion segmentation. It leverages the Expectation Maximization algorithm to find an initial segmentation. A new adaptive method is proposed to define two types of segmented regions: the high-confident and the low confident. We train a support vector machine, using computational features from the high-confident regions, to further refine segmentation and, hence, achieve improved results for the low-confident regions. Validation experiments of our proposed method are performed on 319 dermatoscopy images and we have achieved good results with precision and recall to be 0.864 and 0.875 respectively. PMID- 23366806 TI - Active segmentation of 3D axonal images. AB - We present an active contour framework for segmenting neuronal axons on 3D confocal microscopy data. Our work is motivated by the need to conduct high throughput experiments involving microfluidic devices and femtosecond lasers to study the genetic mechanisms behind nerve regeneration and repair. While most of the applications for active contours have focused on segmenting closed regions in 2D medical and natural images, there haven't been many applications that have focused on segmenting open-ended curvilinear structures in 2D or higher dimensions. The active contour framework we present here ties together a well known 2D active contour model [5] along with the physics of projection imaging geometry to yield a segmented axon in 3D. Qualitative results illustrate the promise of our approach for segmenting neruonal axons on 3D confocal microscopy data. PMID- 23366807 TI - Segmentation of small bowel tumor tissue in capsule endoscopy images by using the MAP algorithm. AB - State of the art algorithms for diagnosis of the small bowel by using capsule endoscopic images usually rely on the processing of the whole frame, hence no segmentation is usually required. However, some specific applications such as three-dimensional reconstruction of the digestive wall, detection of small substructures such as polyps and ulcers or training of young medical staff require robust segmentation. Current state of the art algorithms for robust segmentation are mainly based on Markov Random Fields (MRF) requiring prohibitive computational resources not compatible with applications that generate a great amount of data as is the case of capsule endoscopy. However context information given by MRF is not the only way to improve robustness. Alternatives could come from a more effective use of the color information. This paper proposes a Maximum A Posteriori (MAP) based approach for lesion segmentation based on pixel intensities read simultaneously in the three color channels. Usually tumor regions are characterized by higher intensity than normal regions, where the intensity can be measured as the vectorial sum of the 3 color channels. The exception occurs when the capsule is positioned perpendicularly and too close to the small bowel wall. In this case a hipper intense tissue region appears at the middle of the image, which in case of being normal tissue, will be segmented as tumor tissue. This paper also proposes a Maximum Likelihood (ML) based approach to deal with this situation. Experimental results show that tumor segmentation becomes more effective in the HSV than in the RGB color space where diagonal covariance matrices have similar effectiveness than full covariance matrices. PMID- 23366808 TI - Mucosal region detection and 3D reconstruction in wireless capsule endoscopy videos using active contours. AB - Wireless capsule endoscopy (WCE) provides an inner view of the human digestive system. The inner tubular like structure of the intestinal tract consists of two major regions: lumen - intermediate region where the capsule moves, mucosa - membrane lining the lumen cavities. We study the use of the Split Bregman version of the extended active contour model of Chan and Vese for segmenting mucosal regions in WCE videos. Utilizing this segmentation we obtain a 3D reconstruction of the mucosal tissues using a near source perspective shape-from-shading (SfS) technique. Numerical results indicate that the active contour based segmentation provides better segmentations compared to previous methods and in turn gives better 3D reconstructions of mucosal regions. PMID- 23366809 TI - An on-chip chemiresistive polyaniline nanowire-based pH sensor with self calibration capability. AB - A pH sensor based on chemiresistive polyaniline nanowires, which makes use of the pH responsive conductivity of the polymer, requires an electrochemical system during measurements in order to maintain its oxidation state. In this work, we have developed an integrated electrochemical device where a reference, a counter, and a pair of working electrodes are all fabricated on a single chip. The polyaniline nanowires are grown between this pair of working electrodes that are separated by a microscale gap. This device can easily be connected to the external circuit for potential control and current measurements. Taking advantage of the fact that polyaniline becomes insulating when it is fully oxidized or fully reduced, the pH sensor can be electrically reset by controlling the electrochemical potential of the polymer. This paper presents the pH sensing results and the performance of the resetting function of the developed integrated device. PMID- 23366810 TI - A mobile NMR system with full spectroscopy capability. AB - This paper reports our work in developing a mobile nuclear magnetic resonance system with full spectroscopy capability. The system consists of a 0.93 T, portable permanent magnet, a 8-turn 550 um diameter microcoil, and compact electronics systems. The system provides 0.4 parts per million spectrum linewidth and 408 signal-to-noise ratio from a 37 nL water sample with 128 averages. Representative (1)H and (19)F spectra are presented. PMID- 23366811 TI - Dual mode microwave tool for dielectric analysis and thermal ablation treatment of organic tissue. AB - A dual mode tool design to analyze organic tissue and locally perform thermal ablation treatment is presented. The tool is made of an array of split-ring resonators. It can operate on a sensing mode to track the relative dielectric changes from the organic tissue and on a treatment mode to perform thermal ablation at different input powers. The measurements were done with phantoms of human tissue. The tool is able to focus a hot spot of approximately 0.2mm with a temperature of 109 degrees C at an input power of 10W. PMID- 23366812 TI - Finite element lifetime prediction of a miniature adjustable orthopedic device. AB - In Total Knee Arthroplasty (TKA), accurate balancing of the medial and lateral collateral ligaments is considered by orthopedic surgeons as one of the most challenging and complicated tasks to achieve. Therefore, an efficient solution is needed to assist the surgeons in achieving this crucial task without resulting in tibiofemoral misalignment. The required solution consists in developing either a completely automated smart ligament balancer for intraoperative use or adjustable tibial implant for postoperative use. The smart ligament balancer allows the surgeon to accurately balance the collateral ligaments at the time of surgery while the adjustable tibial implant can be controlled in the postoperative period in order to correct the residual ligament imbalance. In this paper, we propose a miniature device that can be used as a smart ligament balancer during TKA or as an adjustable tibial implant in the period following the surgery. Three designs of the smart ligament balancer have been developed using 3-Dimensional (3D) Computer Assisted Design (CAD) software. The proposed balancer can also be used as an adjustable tibial implant after slightly modifying its design. Finite element study of each design has been conducted in order to predict the lifetime of this implant in both cases of intraoperative or postoperative uses. PMID- 23366813 TI - Smelling heart failure from human skin odor with an electronic nose. AB - The human body odor contains different volatile organic compounds which can be used as biomarkers for various diseases. The early detection of heart failure (HF) through periodical screening provides an early treatment application. Therefore we have developed a completely new non-invasive method to identify HF applying an "electronic nose" (e-nose) which provides a "smelling" of the disease based on the analysis of sweat volatile gases from the skin surface. For this e nose a special applicator carrying the sensor chip was developed which can be applied directly on the skin surface. 27 patients with decompensated HF (DHF), 25 patients with compensated HF (CHF, mean age 70.72 +/- 12.02) and 28 controls (CON) were enrolled in this first pilot study. PMID- 23366814 TI - Skin-contact sensor for automatic fall detection. AB - This paper describes an adhesive sensor system worn on the skin that automatically detects human falls. The sensor, which consists of a tri-axial accelerometer, a microcon-troller and a Bluetooth Low Energy transceiver, can be worn anywhere on a subject's torso and in any orientation. In order to distinguish easily between falls and activities of daily living (ADL), a possible fall is detected only if an impact is detected and if the subject is horizontal shortly afterwards. As an additional criterion to reduce false positives, a fall is confirmed if the user activity level several seconds after a possible fall is below a threshold. Intentional falls onto a gymnastics mat were performed by 10 volunteers (total of 297 falls); ADL were performed by 15 elderly volunteers (total of 315 ADL). The fall detection algorithm provided a sensitivity of 99% and a specificity of 100%. PMID- 23366815 TI - Wireless slips and falls prediction system. AB - Accidental slips and falls due to decreased strength and stability are a concern for the elderly. A method to detect and ideally predict these falls can reduce their occurrence and allow these individuals to regain a degree of independence. This paper presents the design and assessment of a wireless, wearable device that continuously samples accelerometer and gyroscope data with a goal to detect and predict falls. Lyapunov-based analyses of these time series data indicate that wearer instability can be detected and predicted in real time, implying the ability to predict impending incidents. PMID- 23366816 TI - Wearable wireless sensor platform for studying autonomic activity and social behavior in non-human primates. AB - A portable system has been designed to enable remote monitoring of autonomic nervous system output in non-human primates for the purpose of studying neural function related to social behavior over extended periods of time in an ambulatory setting. In contrast to prior systems which only measure heart activity, are restricted to a constrained laboratory setting, or require surgical attachment, our system is comprised of a multi-sensor self-contained wearable vest that can easily be transferred from one subject to another. The vest contains a small detachable low-power electronic sensor module for measuring electrodermal activity (EDA), electrocardiography (ECG), 3-axis acceleration, and temperature. The wireless transmission is implemented using a standard Bluetooth protocol and a mobile phone, which enables freedom of movement for the researcher as well as for the test subject. A custom Android software application was created on the mobile phone for viewing and recording live data as well as creating annotations. Data from up to seven monkeys can be recorded simultaneously using the mobile phone, with the option of real-time upload to a remote web server. Sample data are presented from two rhesus macaque monkeys showing stimulus-induced response in the laboratory as well as long-term ambulatory data collected in a large monkey cage. This system enables new possibilities for studying underlying mechanisms between autonomic brain function and social behavior with connection to human research in areas such as autism, substance abuse, and mood disorders. PMID- 23366817 TI - Identification of cigarette smoke inhalations from wearable sensor data using a Support Vector Machine classifier. AB - This study presents a subject-independent model for detection of smoke inhalations from wearable sensors capturing characteristic hand-to-mouth gestures and changes in breathing patterns during cigarette smoking. Wearable sensors were used to detect the proximity of the hand to the mouth and to acquire the respiratory patterns. The waveforms of sensor signals were used as features to build a Support Vector Machine classification model. Across a data set of 20 enrolled participants, precision of correct identification of smoke inhalations was found to be >87%, and a resulting recall >80%. These results suggest that it is possible to analyze smoking behavior by means of a wearable and non-invasive sensor system. PMID- 23366818 TI - Tongue-operated assistive technology with access to common smartphone applications via Bluetooth link. AB - Tongue Drive System (TDS) is a wireless and wearable assistive technology (AT) that enables people with severe disabilities to control their computers, wheelchairs, and electronic gadgets using their tongue motion. We developed the TDS to control smartphone's (iPhone/iPod Touch) built-in and downloadable apps with a customized Bluetooth mouse module by emulating finger taps on the touchscreen. The TDS-iPhone Bluetooth mouse interface was evaluated by four able bodied subjects to complete a scenario consisting of seven tasks, which were randomly ordered by using touch on the iPhone screen with index finger, a computer mouse on iPhone, and TDS-iPhone Bluetooth mouse interface with tongue motion. Preliminary results show that the average completion times of a scenario with touch, mouse, and TDS are 165.6 +/- 14.50 s, 186.1 +/- 15.37 s, and 651.6 +/ 113.4 s, respectively, showing that the TDS is 84.37% and 81.16% slower than touch and mouse for speed of typing with negligible errors. Overall, considering the limited number of commands and unfamiliarity of the subjects with the TDS, we achieved acceptable results for hands-free functionality. PMID- 23366819 TI - On localizing a capsule endoscope using magnetic sensors. AB - In this work, localizing a capsule endoscope within the gastrointestinal tract is addressed. It is assumed that the capsule is equipped with a magnet, and that a magnetic sensor network measures the flux from this magnet. We assume no prior knowledge on the source location, and that the measurements collected by the sensors are corrupted by thermal Gaussian noise only. Under these assumptions, we focus on determining the Cramer-Rao Lower Bound (CRLB) for the location of the endoscope. Thus, we are not studying specific estimators, but rather the theoretical performance of an optimal one. It is demonstrated that the CRLB is a function of the distance and angle between the sensor network and the magnet. By studying the CRLB with respect to different sensor array constellations, we are able to indicate favorable constellations. PMID- 23366820 TI - A framework for myoarchitecture analysis of high resolution cardiac MRI and comparison with diffusion tensor MRI. AB - The ventricular myocardium has a structure of branching laminae through which course regularly orientated myofibers, an architecture important in excitation and contraction. Quantifying this architecture is vital for understanding normal and disease states in the heart and for assessing their impact on electrical function. These data are also highly important in the construction of scientifically and clinically useful computer models of cardiac electrical behavior. Detailed structural information has previously been obtained from serial imaging. In this work we assess the potential for high-resolution (HR) MRI as a means to furnish useful myoarchitecture and compare and contrast this approach with the growing use of DT. Using rat hearts, we conclude that both approaches have strengths and weaknesses, however, HR-MRI may provide a consistently more robust picture of the myoarchitecture in small hearts. PMID- 23366821 TI - Left-ventricular shape analysis for predicting sudden cardiac death risk. AB - Implantation of cardioverter defibrillators is the most widely used primary preventive care for sudden cardiac death (SCD). Current clinical practice of using a left-ventricular ejection fraction threshold as the sole criterion for defibrillator insertion results in many unnecessary implantations. To address the need for alternative criteria, we seek three-dimensional shape metrics of the left ventricle derived from clinical cardiac magnetic resonance images that can predict SCD risk. The present study is a proof-of-concept, where we have combined image-processing and computational anatomy techniques to develop a processing pipeline to statistically compare localized left ventricular shape metrics between patient groups. We tested the methodology with data from a small cohort of patients, classified into two groups based on SCD risk. The results demonstrate that our approach is able to locate systematic wall thickness differences between the two groups. PMID- 23366822 TI - An active contour based method for analyzing cardiac quiescence from echocardiography. AB - A semi-automated method for analyzing cardiac quiescence of anatomical cardiac features from two-dimensional echocardiographic cine data is presented. The method utilizes both active contour and optical flow techniques for feature identification and tracking. A curvature-based potential surface was used in the active contour calculations to attract the contour to regions of inflection on the image surface rather than the standard gradient-based surface that attracts the contour to strong edges. After identifying the feature in each frame, the frame-to-frame correlation matrix of the feature was calculated with correlation values corresponding to how well the feature matched between frames. Therefore prolonged regions of high correlation correspond to periods of cardiac quiescence. The location and duration of these periods were automatically identified from the correlation matrix by finding the largest region around each time index with a mean correlation above a specified threshold. In parallel, the position of the feature was calculated for each frame by finding the centroid of the pixel locations inside the contour. From this trajectory, the magnitude of the two-dimensional velocity was calculated. These methods were used to analyze the quiescence of the interventricular septum from an apical four-chamber echocardiogram performed on a human subject. Correlation-derived quiescent phases were observed to coincide with periods of the cardiac cycle with minimal velocity magnitude. PMID- 23366823 TI - Impact of temporal resolution on LV myocardial regional strain assessment with real-time 3D ultrasound. AB - Non-invasive quantification of regional left ventricular (LV) deformation is crucial for the identification of clinical and subclinical myocardial dysfunction in various conditions. Several software tools now exist to provide regional LV strain estimation for echocardiography images. In this paper, we experimentally investigated the impact of real-time three-dimensional (RT3D) ultrasound temporal resolution on the precision of an integrated speckle-tracking framework. We compared temporal displacement and strain profiles acquired at three different frame rates on five normal volunteers. Results showed that estimated displacement fields and regional strain measurements were more homogeneous and of larger amplitude at higher frame rates. PMID- 23366824 TI - Quantifying tissue heterogeneity using quadtree decomposition. AB - Volumetric computed tomography (CT) imaging provides a three-dimensional map of image intensities from which lung soft tissue density distribution can be estimated. The information gained from analyzing these images can prove valuable in diagnosis of conditions where lung tissue is damaged or has degenerated, and it is also necessary for modeling lung tissue mechanics. This paper presents a new technique for quantifying heterogeneity based on individual CT images, and investigates the heterogeneity of lung tissue in a group of healthy young subjects. It is intended that development of this technique leads to a standard model of classifying heterogeneity in lung tissue, while taking into account variables such as different imaging platforms and resolutions, and the position of the patient during imaging. PMID- 23366825 TI - 3D cardiac motion reconstruction from CT data and tagged MRI. AB - In this paper we present a novel method for left ventricle (LV) endocardium motion reconstruction using high resolution CT data and tagged MRI. High resolution CT data provide anatomic details on the LV endocardial surface, such as the papillary muscle and trabeculae carneae. Tagged MRI provides better time resolution. The combination of these two imaging techniques can give us better understanding on left ventricle motion. The high resolution CT images are segmented with mean shift method and generate the LV endocardium mesh. The meshless deformable model built with high resolution endocardium surface from CT data fit to the tagged MRI of the same phase. 3D deformation of the myocardium is computed with the Lagrangian dynamics and local Laplacian deformation. The segmented inner surface of left ventricle is compared with the heart inner surface picture and show high agreement. The papillary muscles are attached to the inner surface with roots. The free wall of the left ventricle inner surface is covered with trabeculae carneae. The deformation of the heart wall and the papillary muscle in the first half of the cardiac cycle is presented. The motion reconstruction results are very close to the live heart video. PMID- 23366826 TI - Compensating for delays in brain-machine interfaces by decoding intended future movement. AB - Typically, brain-machine interfaces that enable the control of a prosthetic arm work by decoding a subjects' intended hand position or velocity and using a controller to move the arm accordingly. Researchers taking this approach often choose to decode the subjects' desired arm state in the present moment, which causes the prosthetic arm to lag behind the state desired by the user, as the dynamics of the arm (and other control delays) constrain how quickly the controller can change the arm's state. We tested the hypothesis that decoding the subjects' intended future movements would mitigate this lag and improve BMI performance. Offline results show that predictions of future movement (<= 200 ms) can be made with essentially the same accuracy as predictions of present movement. Online results from one monkey show that performance increases as a function of the future prediction time lead, reaching optimum performance at a time lead equal to the delay inherent in the controlled system. PMID- 23366827 TI - Decoding hand trajectories from micro-electrocorticography in human patients. AB - A Kalman filter was used to decode hand trajectories from micro electrocorticography recorded over motor cortex in human patients. In two cases, signals were recorded during stereotyped tasks, and the trajectories were decoded offline, with maximum correlation coefficients between actual and predicted trajectories of 0.51 (x-direction position) and 0.54 (y-direction position). In a third setting, a human patient with full neural control of a computer cursor acquired onscreen targets within 6.24 sec on average, with no algorithmic constraints on the output trajectory. These practical results illustrate the potential utility of signals recorded at the cortical surface with high spatial resolution, demonstrating that surface potentials contain relevant and sufficient information to drive sophisticated brain-computer interface systems. PMID- 23366828 TI - Filling a glass of water: continuously decoding the speed of 3D hand movements from EEG signals. AB - We present a new system for the continuous decoding of hand movement speed in three-dimensional (3D) space from EEG signals. We recorded experimental data of five subjects during mimicking the natural task of filling a glass of water. The proposed system uses filter bank common spatial patterns and linear regression to estimate the speed of hand movements from artifact cleaned EEG signals. Average Pearson correlations between the speed trajectories predicted from EEG and the speed trajectories measured using a high-precision motion tracking system are r=0.41 for the x-axis, r=0.36 for the y-axis, r=0.48 for the z-axis, and r=0.17 for absolute speed in 3D space. PMID- 23366829 TI - Continuous decoding of intention to move from contralesional hemisphere brain oscillations in severely affected chronic stroke patients. AB - Decoding motor information directly from brain activity is essential in robot assisted rehabilitation systems to promote motor relearning. However, patients who suffered a stroke in the motor cortex have lost brain activity in the injured area, and consequently, mobility in contralateral limbs. Such a loss eliminates the possibility of extracting motor information from brain activity while the patient is undergoing therapy for the affected limb. This work proposes to decode motor information from EEG activity of the contralesional hemisphere in patients who suffered a hemiparetic stroke. Four stroke patients participated in this study and the results proved the feasibility of decoding motor information while patients attempted to move the affected limb. PMID- 23366830 TI - Electrocorticographic decoding of ipsilateral reach in the setting of contralateral arm weakness from a cortical lesion. AB - Brain machine interfaces have the potential for restoring motor function not only in patients with amputations or lesions of efferent pathways in the spinal cord and peripheral nerves, but also patients with acquired brain lesions such as strokes and tumors. In these patients the most efficient components of cortical motor systems are not available for BMI control. Here we had the opportunity to investigate the possibility of utilizing subdural electrocorticographic (ECoG) signals to control natural reaching movements under these circumstances. In a subject with a left arm monoparesis following resection of a recurrent glioma, we found that ECoG signals recorded in remaining cortex were sufficient for decoding kinematics of natural reach movements of the nonparetic arm, ipsilateral to the ECoG recordings. The relationship between the subject's ECoG signals and reach trajectory in three dimensions, two of which were highly correlated, was captured with a computationally simple linear model (mean Pearson's r in depth dimension= 0.68, in height= 0.73, in lateral= 0.24). These results were attained with only a small subset of 7 temporal/spectral neural signal features. The small subset of neural features necessary to attain high decoding results show promise for a restorative BMI controlled solely by ipsilateral ECoG signals. PMID- 23366831 TI - Brain-Machine Interface control of a robot arm using actor-critic rainforcement learning. AB - Here we demonstrate how a marmoset monkey can use a reinforcement learning (RL) Brain-Machine Interface (BMI) to effectively control the movements of a robot arm for a reaching task. In this work, an actor-critic RL algorithm used neural ensemble activity in the monkey's motor cortext to control the robot movements during a two-target decision task. This novel approach to decoding offers unique advantages for BMI control applications. Compared to supervised learning decoding methods, the actor-critic RL algorithm does not require an explicit set of training data to create a static control model, but rather it incrementally adapts the model parameters according to its current performance, in this case requiring only a very basic feedback signal. We show how this algorithm achieved high performance when mapping the monkey's neural states (94%) to robot actions, and only needed to experience a few trials before obtaining accurate real-time control of the robot arm. Since RL methods responsively adapt and adjust their parameters, they can provide a method to create BMIs that are robust against perturbations caused by changes in either the neural input space or the output actions they generate under different task requirements or goals. PMID- 23366832 TI - EEG-based Brain-Computer Interface to support post-stroke motor rehabilitation of the upper limb. AB - Brain-Computer Interfaces (BCIs) process brain activity in real time, and mediate non-muscular interaction between and individual and the environment. The subserving algorithms can be used to provide a quantitative measurement of physiological or pathological cognitive processes - such as Motor Imagery (MI) - and feed it back the user. In this paper we propose the clinical application of a BCI-based rehabilitation device, to promote motor recovery after stroke. The BCI based device and the therapy exploiting its use follow the same principles that drive classical neuromotor rehabilitation, and (i) provides the physical therapist with a monitoring instrument, to assess the patient's participation in the rehabilitative cognitive exercise; (ii) assists the patient in the practice of MI. The device was installed in the ward of a rehabilitation hospital and a group of 29 patients were involved in its testing. Among them, eight have already undergone a one-month training with the device, as an add-on to the regular therapy. An improved system, which includes analysis of Electromyographic (EMG) patterns and Functional Electrical Stimulation (FES) of the arm muscles, is also under clinical evaluation. We found that the rehabilitation exercise based on BCI mediated neurofeedback mechanisms enables a better engagement of motor areas with respect to motor imagery alone and thus it can promote neuroplasticity in brain regions affected by a cerebrovascular accident. Preliminary results also suggest that the functional outcome of motor rehabilitation may be improved by the use of the proposed device. PMID- 23366833 TI - Impaired motor unit control in paretic muscle post stroke assessed using surface electromyography: a preliminary report. AB - The objective of this preliminary study was to examine the possible contribution of disordered control of motor unit (MU) recruitment and firing patterns in muscle weakness post-stroke. A novel surface EMG (sEMG) recording and decomposition system was used to record sEMG signals and extract single MU activities from the first dorsal interosseous muscle (FDI) of two hemiparetic stroke survivors. To characterize MU reorganization, an estimate of the motor unit action potential (MUAP) amplitude was derived using spike triggered averaging of the sEMG signal. The MUs suitable for further analysis were selected using a set of statistical tests that assessed the variability of the morphological characteristics of the MUAPs. Our preliminary results suggest a disrupted orderly recruitment based on MUAP size, a compressed recruitment range, and reduced firing rates evident in the paretic muscle compared with the contralateral muscle of one subject with moderate impairment. In contrast, the MU organization was largely similar bilaterally for the subject with minor impairment. The preliminary results suggest that MU organizational changes with respect to recruitment and rate modulation can contribute to muscle weakness post stroke. The contrasting results of the two subjects indicate that the degree of MU reorganization may be associated with the degree of the functional impairment, which reveals the differential diagnostic capability of the sEMG decomposition system. PMID- 23366834 TI - Correlations between statistical models of robotically collected kinematics and clinical measures of upper extremity function. AB - One of the obstacles in the development of rehabilitation robotics has been inadequacy in the measurement of treatment effects due to interventions. A measurement tool that will efficiently produce a large reliable sample of measurements collected during a single session that can also produce a rich set of data which reflects a subject's ability to perform meaningful functional activities has not been developed. This paper presents three linear regression models generated from seven kinematic measures collected during the performance of virtually simulated rehabilitation activities that were integrated with haptic robots by 19 persons with upper extremity hemiparesis due to chronic stroke. One of these models demonstrated a statistically significant correlation with the subjects' scores on the Jebsen Test of Hand Function (JTHF), a battery of six standardized upper extremity functional activities. The second and third models demonstrated a statistically significant correlation with the subjects' change scores on the JTHF. PMID- 23366835 TI - Omitting the intra-session calibration in EEG-based brain computer interface used for stroke rehabilitation. AB - Brain-computer interface (BCI) as a rehabilitation tool has been used in restoring motor functions in patients with moderate to sever stroke impairments. To achieve the best possible outcome in such an application, it is highly desirable to have a stable and accurate operation of BCI. However, since electroencephalogram (EEG) signals considerably vary between sessions of even the same user, typically a long calibration session is recorded at the beginning of each session. This process is time-consuming and inconvenient for stroke patients who undergo long-term BCI sessions with repeating same mental tasks. This paper investigates the possibility of omitting the intra-session calibration for BCI based stroke rehabilitation when large data recorded from the same user are available. For this purpose, a large dataset of EEG signals from 11 stroke patients performing 12 BCI-based stroke rehabilitation sessions over one month is used. Our offline results suggest that after recording a number of stroke rehabilitation sessions, the patient does not require calibration any more. The experimental results show that combining 11 sessions, which each session comprises minimum 60 trials per class, yields a model that averagely outperforms the standard calibration model trained by the data recorded directly before the test session. PMID- 23366837 TI - Reorganization of functional brain networks during the recovery of stroke: a functional MRI study. AB - Studies have demonstrated that reorganization of the cortex after stroke contributed to the recovery of motor function. However, these studies paid much more attention to the reorganization of motor-related brain regions and motor executive network which only contained tens of brain regions, ignoring the change in brain-wide network during the restoration of motor function. Based on this consideration, this paper investigated the functional reorganization of brain wide network during the recovery after stroke from the perspective of graph theory. At four time points (less than 10 days, around 2 weeks, 1 month and 3 months) after stroke onset, we obtained the functional MRI (fMRI) data of stroke patients when they were doing finger tapping task. Based on the fMRI data, we constructed the brain-wide functional network which consisted of 264 putative functional areas for each subject at each time point. Then the topological parameters (e.g., characteristic path length and cluster coefficient) of these brain networks were examined. Results showed that the brain networks shifted towards a non-optimal topological configuration with low small-worldness during the process of recovery. And this finding may broaden our knowledge about the reorganization of brain function during recovery after stroke. PMID- 23366836 TI - Transcranial direct current stimulation and EEG-based motor imagery BCI for upper limb stroke rehabilitation. AB - Clinical studies had shown that EEG-based motor imagery Brain-Computer Interface (MI-BCI) combined with robotic feedback is effective in upper limb stroke rehabilitation, and transcranial Direct Current Stimulation (tDCS) combined with other rehabilitation techniques further enhanced the facilitating effect of tDCS. This motivated the current clinical study to investigate the effects of combining tDCS with MI-BCI and robotic feedback compared to sham-tDCS for upper limb stroke rehabilitation. The stroke patients recruited were randomized to receive 20 minutes of tDCS or sham-tDCS prior to 10 sessions of 1-hour MI-BCI with robotic feedback for 2 weeks. The online accuracies of detecting motor imagery from idle condition were assessed and offline accuracies of classifying motor imagery from background rest condition were assessed from the EEG of the evaluation and therapy parts of the 10 rehabilitation sessions respectively. The results showed no evident differences between the online accuracies on the evaluation part from both groups, but the offline analysis on the therapy part yielded higher averaged accuracies for subjects who received tDCS (n=3) compared to sham-tDCS (n=2). The results suggest towards tDCS effect in modulating motor imagery in stroke, but a more conclusive result can be drawn when more data are collected in the ongoing study. PMID- 23366838 TI - Quantification of uncertainties in brain tissue conductivity in a heterogeneous model of deep brain stimulation using a non-intrusive projection approach. AB - The aim of this study was to examine the effects of uncertainty of the conductivity values on the resulting field distribution in a heterogeneous finite element model of deep brain stimulation (DBS). A non-intrusive projection method was used by expanding the input random variables and the resulting potential on a multidimensional basis called the Polynomial Chaos (PC). The finite element model incorporates an accurate model of a DBS electrode used in clinical treatment extended by an encapsulation layer around the electrode body. Areas of grey matter, white matter and cerebrospinal fluid were derived from averaged magnetic resonance imaging (MRI). The uncertainties of the conductivity values of these tissue types were modelled as uniform random variables using data from literature to obtain their upper and lower boundaries. PMID- 23366839 TI - A neural network-based design of an on-off adaptive control for Deep Brain Stimulation in movement disorders. AB - The current Food and Drug Administration approved system for the treatment of tremor disorders through Deep Brain Stimulation (DBS) of the area of the brain that controls movement, operates open-loop. It does not automatically adapt to the instantaneous patient's needs or to the progression of the disease. This paper demonstrates an adaptive closed-loop controlled DBS that, after switching off stimulation, tracks few physiological signals to predict the reappearance of tremor before the patient experiences discomfort, at which point it instructs the DBS controller to switch on stimulation again. The core of the proposed approach is a Neural Network (NN) which effectively extracts tremor predictive information from non-invasively recorded surface-electromyogram(sEMG) and accelerometer signals measured at the symptomatic extremities. A simple feed-forward back propagation NN architecture is shown to successfully predict tremor in 31 out of 33 trials in two Parkinson's Disease patients with an overall accuracy of 75.8% and sensitivity of 92.3%. This work therefore shows that closed-loop DBS control is feasible in the near future and that it can be achieved without modifications of the electrodes implanted in the brain, i.e., is backward compatible with approved DBS systems. PMID- 23366840 TI - Analyzing neuronal activation with macroelectrode vs. microelectrode array stimulation. AB - Deep Brain Stimulation (DBS) has provided remarkable relief to patients with brain disorders. Traditionally, DBS is performed through a single macroelectrode implanted at a specific deep brain structure (like the subthalamic nucleus for Parkinson's disease). Despite its great success, little is known about its mechanisms of action. We propose that using several microelectrodes for stimulation, instead of a single macroelectrode, may provide advantages including reduced tissue damage and increased brain area activated. We compare the area of brain affected by macroelectrode and microelectrode arrays implanted in rat hippocampus using stimulation-induced c-Fos expression and immunohistochemistry. PMID- 23366841 TI - Contribution of dielectric dispersions to voltage waveforms arising from electrical stimulation. AB - This study presents an analysis of the effect of incorporating a subset of the complete set of dielectric dispersions in electric field models of implanted electrical stimulation. An analytic volume conductor model was used to determine the voltage waveform at a distance of 5mm from a point current stimulus for 17 different biological tissues. The RMS error of the voltage waveform resulting from the incorporation of a subset of all poles with respect to the voltage waveform resulting from the incorporation of the complete set of dispersive poles was calculated. The stimulus amplitude necessary to elicit action potential propagation in a myelinated mammalian nerve fibre in each of the dispersive models was also determined using a multi-compartment cable axon model. It was found that, for all tissues, removal of dispersions with pole frequencies greater than 1 MHz had a negligible effect on the threshold stimulation amplitude, suggesting that they may be neglected when constructing volume conductor models of electrical stimulation. However, removal of low-frequency dispersions below 1 MHz resulted in greater reductions in the threshold stimulus amplitudes necessary for activation of axons, with errors of up to 86% observed. PMID- 23366842 TI - Theoretical investigation of transcranial alternating current stimulation using laminar model. AB - Transcranial alternating current stimulation (tACs) has been gaining an increased interest in the last few years due to its capacity to modulate non-invasively high-order cortical processes, such as decision-making, language and sensory perception. Nevertheless, the underlying mechanisms of activation of this brain stimulation technique are still poorly understood. Herein, we use a finite element modelling (FEM) technique to investigate the penetration and focality of tACs in comparison to a time invariant (DC) stimulation. We show that AC stimulations generate cerebral fields that are an order of magnitude larger in the radial direction, approximately 5 times larger in the tangential direction and more focused than DC stimulations. We argue that the basis for this effect is the reduced scalp's conductivity, which minimizes the surface shunting of the stimulating currents. The outcomes of this study may help tACs users to design better protocols and interpret experimental results. PMID- 23366843 TI - Theoretical investigation of transcranial alternating current stimulation using realistic head model. AB - Transcranial alternating current stimulation (tACs) is an important new technique that allows to modulate non-invasively high-order cortical processes. The underlying mechanisms of activation of this brain stimulation technique are still poorly understood. Herein, we use a finite difference time domain (FDTD) technique to investigate the penetration and focality of tACs in comparison to a time invariant (DC) stimulation. We show that stimulation using 10 Hz generates cerebral fields that are larger (* 2.5) and more focused than DC stimulation and that faster oscillating stimuli of 100 Hz and 1000 Hz, generate smaller and less focused cerebral fields than 10 Hz. The outcomes of this study may help tACs users to design better protocols and interpret experimental results. PMID- 23366844 TI - Prediction of distal arm joint angles from EMG and shoulder orientation for prosthesis control. AB - Current state-of-the-art upper limb myoelectric prostheses are limited by only being able to control a single degree of freedom at a time. However, recent studies have separately shown that the joint angles corresponding to shoulder orientation and upper arm EMG can predict the joint angles corresponding to elbow flexion/extension and forearm pronation/ supination, which would allow for simultaneous control over both degrees of freedom. In this preliminary study, we show that the combination of both upper arm EMG and shoulder joint angles may predict the distal arm joint angles better than each set of inputs alone. Also, with the advent of surgical techniques like targeted muscle reinnervation, which allows a person with an amputation intuitive muscular control over his or her prosthetic, our results suggest that including a set of EMG electrodes around the forearm increases performance when compared to upper arm EMG and shoulder orientation. We used a Time-Delayed Adaptive Neural Network to predict distal arm joint angles. Our results show that our network's root mean square error (RMSE) decreases and coefficient of determination (R(2)) increases when combining both shoulder orientation and EMG as inputs. PMID- 23366845 TI - A preliminary investigation of powered prostheses for improved walking biomechanics in bilateral transfemoral amputees. AB - The authors conducted a preliminary investigation of the extent to which a pair of powered prostheses can provide improved gait biomechanics in bilateral transfemoral amputee walking. Specifically, a finite state-based impedance controller for level ground walking was implemented in a pair of powered knee and ankle prostheses. The efficacy of the powered prostheses and impedance-based controllers was tested on a healthy subject using able-body adapters. Motion capture data was collected while the subject performed treadmill walking with the powered prostheses. This kinematic data is compared to that of healthy subjects, and also to previously published data for bilateral transfemoral amputee gait with passive prostheses. The comparison indicates that the powered prostheses are able to provide a walking gait that is considerably more representative of healthy biomechanical gait relative to passive prostheses. PMID- 23366846 TI - A running controller for a powered transfemoral prosthesis. AB - This paper describes a running controller for a powered knee and ankle prosthesis. The running controller was implemented on a powered prosthesis prototype and evaluated by a transfemoral amputee subject running on a treadmill at a speed of 2.25 m/s (5.0 mph). The ability of the prosthesis and controller to provide the salient features of a running gait was assessed by comparing the kinematics of running provided by the powered prosthesis to the averaged kinematics of five healthy subjects running at the same speed. This comparison indicates that the powered prosthesis and running controller are able to provide essential features of a healthy running gait. PMID- 23366847 TI - Preliminary functional assessment of a multigrasp myoelectric prosthesis. AB - The authors have previously described a multigrasp hand prosthesis prototype, and a two-site surface EMG based multigrasp control interface for its control. In this paper, the authors present a preliminary assessment of the efficacy of the prosthesis and multigrasp controller in performing tasks requiring interaction and manipulation. The authors use as a performance measure the Southampton Hand Assessment Procedure (SHAP), which entails manipulation of various objects designed to emulate activities of daily living, and provides a set of scores that indicate level of functionality in various types of hand function. In this preliminary assessment, a single non-amputee subject performed the SHAP while wearing the multigrasp prosthesis via an able-bodied adaptor. The results from this testing are presented, and compared to recently published SHAP results obtained with commercially available single-grasp and multigrasp prosthetic hands. PMID- 23366848 TI - Design of an exoskeleton as a finger-joint angular sensor. AB - Estimation of joint angles for human joints is important for many applications in Bioengineering. Most of the existing angular joint sensors rely on the assumption of the knowledge of the type of motion and location of the joint. This paper presents a new design for the measurement of finger joint angular motion. The design presented here consists of an exoskeleton, designed to fit the finger motion, in which we can relate the angular displacement of its links to the change in orientation of the phalanx under consideration. Unlike other designs, the exoskeleton does not need any information about the actual anatomy and dimensions of the hand in order to provide with the angular information. The design is to be used in myoelectrical signal identification. PMID- 23366849 TI - Prosthesis-User-in-the-Loop: a user-specific biomechanical modeling and simulation environment. AB - In this paper, a novel biomechanical modeling and simulation environment with an emphasis on user-specific customization is presented. A modular modeling approach for multi-body systems allows a flexible extension by specific biomechanical modeling elements and enables an efficient application in dynamic simulation and optimization problems. A functional distribution of model description and model parameter data in combination with standardized interfaces enables a simple and reliable replacement or modification of specific functional components. The user specific customization comprises the identification of anthropometric model parameters as well as the generation of a virtual three-dimensional character. The modeling and simulation environment is associated with Prosthesis-User-in-the Loop, a hardware simulator concept for the design and optimization of lower limb prosthetic devices based on user experience and assessment. For a demonstration of the flexibility and capability of the modeling and simulation environment, an exemplary application in context of the hardware simulator is given. PMID- 23366850 TI - Recurrence Quantification Analysis as a tool for complex fractionated atrial electrogram discrimination. AB - Atrial fibrillation is the most encountered pathology of the heart rate. The reasons of its occurrence and its particular characteristics remain unknown, resulting from complex phenomena interaction. From these interactions emerges Complex Fractionated Atrial Electrograms (CFAE) which are useful for the ablation procedure. This study presents a method based on nonlinear data analysis, the Recurrence Quantification Analysis (RQA) applied on intracardiac atrial electrograms to detect CFAE particularities. The results obtained on areas previously tagged by a cardilogist show a good sensitivity to CFAE. Combination of RQA features offers a larger discrimination potential for future automated detection. PMID- 23366851 TI - Heart rate variability in children with cyanotic and acyanotic congenital heart disease: analysis by spectral and non linear indices. AB - Congenital heart defects affect the efficiency and functionality of the heart, and autonomic control of heart rate and of circulation can display a pathologic behavior in order to compensate for the hemodynamic alterations due to disease. While previous works have investigated heart rate variability (HRV) in specific pathologies, e.g. tetralogy of Fallot, the goal of this study was to assess HRV in children with a congenital heart malformation taking into account the effects of cyanotic and acyanotic defects, and comparing pathologic children with age matched controls. HRV, approximate entropy (ApEn) and sample entropy (SampEn) were calculated to discuss the dynamics and complexity of heart rhythms, and to evaluate the potential impairment of control mechanisms. Analyses showed that low frequency (LF) power and total power of HRV were significantly higher in children with a condition than in healthy controls, independently of cyanosis. Non linear indices were also significantly higher in pathologic subjects. Significant differences in LF, total power, ApEn and SampEn were found among cyanotic, acyanotic and healthy children. These results suggested that children with a congenital heart condition display more complex HRV and sympathetic overactivity, which may be aimed at compensating for hemodynamic alterations. Further studies should investigate whether corrective surgery and rehabilitation can improve HRV and restore its physiological features. PMID- 23366852 TI - Beat-to-beat spatial and temporal analysis for QRS-T morphology. AB - The aim of this study was to investigate beat-to-beat variations of spatial and temporal QRS and T loop morphology for identifying myocardial infarction (MI) patients. We investigated short-term 12-lead ECG recordings of 84 MI patients (22 female, mean age 63 +/- 12 years and 62 male, mean age 56 +/- 10 years) and 69 healthy control subjects (17 female, mean age 42 +/- 18 years and 52 male, mean age 40 +/- 13 years). To quantify spatial and temporal variations in QRS complex and T-wave morphology, we defined two descriptor parameters: point-to-point distance variability (DV) and mean loop length (MLL). These parameters were extracted from the reconstructed vector ECG, using singular value decomposition. The results showed that the beat-to-beat spatiotemporal point-to-point distance variability for QRS and T loops (DV(QRS); 0.13 +/- 0.04 vs. 0.10 +/- 0.04, p < 0.0001 and DV(T); 0.16 +/- 0.07 vs. 0.13 +/- 0.06, p < 0.05), were significantly higher in MI subjects compared to control subjects. In addition, the mean loop length of QRS and T loops were significantly higher in control subjects than MI (p < 0.001), respectively. In conclusion, the beat-to-beat spatiotemporal DV and MLL may be useful for characterizing conduction and repolarization characteristics in patients with MI. PMID- 23366853 TI - Using recurrence network approach to quantify nonlinear dynamics of skin blood flow in response to loading pressure. AB - This paper presents a recurrence network approach to quantify dynamic complexity of skin blood flow oscillations (BFO) in response to loading pressure. This approach consists of three processes, including 1) phase space reconstruction by means of time delay embedding, 2) construction of a recurrence matrix that represents neighboring states in phase space, and 3) consideration of the recurrence matrix as an adjacency matrix representing links in a network and the use of clustering coefficients to characterize phase space properties. By using the Lorenz system and real data, we demonstrate that the global clustering coefficient is robust to the embedding parameters. We applied this approach to study skin BFO at baseline and during loading pressure, a causative factor of skin breakdown. The results showed that global clustering coefficients of BFO significantly decreased in response to loading ( <0.05). Moreover, surrogate tests indicated that such a decrease was associated with a loss of nonlinearity of BFO. Our results suggest that the recurrence network approach can practically quantify the nonlinear dynamics of BFO. PMID- 23366854 TI - Coronary arterial stiffness is related with a loss of fractal complexity in the aortic pressure. AB - Arterial stiffening is a common but highly variable disorder. Additionally, excessive arterial pulsatility is associated with various common diseases of aging and hypertension. Fractal dimension (FD) quantifies the time series complexity defined by its geometrical representation. OBJECTIVE: Arterial pressure and diameter time series were evaluated in order to assess the relationship between arterial stiffness and FD. METHODS: Three Corriedale male sheep were operated. Left anterior descending artery (LAD) was dissected and the external arterial diameter was measured trough sonomicrometry. Similarly, a pressure microtransducer was positioned in the upper third of the ascending aorta. Simultaneous pressure and diameter were measured in normal state and under smooth muscle activation. Each time series FD were assessed by the application of Higuchi's method while arterial wall elastic modulus was evaluated by means of the pressure-strain relationship. RESULTS: Coronary stiffness was increased from normal state to phenylephrine state (47.32%, 21.12%, 10.87%) while aortic pressure FD was decreased (2.11%, 2.57%, 6.85%), respectively. CONCLUSION: Acute hypertension induced by phenylephrine produces an increase in the coronary wall elastic modulus with a concomitant decrease in the fractal nature of the aortic pressure, suggesting that coronary stiffening is associated with an unwrinkled aortic pressure. PMID- 23366855 TI - Automatic diagnosis of ADHD based on multichannel nonlinear analysis of actimetry registries. AB - Attention-Deficit Hyperactivity Disorder (ADHD) is the most common mental health problem in childhood and adolescence. It is commonly diagnosed by means of subjective methods which tend to overestimate the severity of the pathology. A number of objective methods also exist, but they are either expensive or time consuming. Some recent proposals based on nonlinear processing of activity registries have deserved special attention. Since they rely on actigraphy measurements, they are both inexpensive and non-invasive. Among these methods, those shown to have higher reliability are based on single-channel complexity assessment of the activity patterns. This way, potentially useful information related to the interaction between the different channels is discarded. In this paper we propose a new methodology for ADHD diagnosis based on joint complexity assessment of multichannel activity registries. Results on real data show that the proposed method constitute a useful diagnostic aid tool reaching 87:10% sensitivity and 84.38% specificity. The combination of ADHD indicators extracted with the proposed method with single-channel complexity-based indices previously proposed lead to sensitivity and specifity values above 90%. PMID- 23366856 TI - Non-linear analysis of stabilograms with alcoholic intake. AB - Equilibrium function in the cerebellum (vestibulo-cerebellar system) can deteriorate under the influence of alcohol. In the Romberg posture, the center of gravity, which was measured every 50 ms by stabilometry, appeared to shift with alcohol ingestion. In the previous study, a locus in the center of gravity (stabilogram) was converted to values of statistical indices such as area of sway, total locus length, and locus length per unit area, although these indices could not always distinguish between the statokinesigrams sampled from seven healthy young males in sober and intoxicated states. This measurement was made with an AMTI force plate. In this study, "translation error" was estimated in a d dimensional embedding space in order to compare statokinesigrams recorded before and after the ingestion of doubly diluted brandy in 30 s (1 <= d <= 10). We succeeded in validating a stochastic differential equation as a mathematical model of the body sway. The randomness in the model was preserved after alcohol intake and significantly increased in the medial/lateral direction. Visual information referred by the postural control system when standing might be interfered by the effects of intoxication, which was regarded as disturbance. This method is considered to be useful to diagnose the disorders of the vestibulocerebellar system. PMID- 23366857 TI - Identification of nonlinear fMRI models using Auxiliary Particle Filter and kernel smoothing method. AB - Hemodynamic models have a high potential in application to understanding the functional differences of the brain. However, full system identification with respect to model fitting to actual functional magnetic resonance imaging (fMRI) data is practically difficult and is still an active area of research. We present a simulation based Bayesian approach for nonlinear model based analysis of the fMRI data. The idea is to do a joint state and parameter estimation within a general filtering framework. One advantage of using Bayesian methods is that they provide a complete description of the posterior distribution, not just a single point estimate. We use an Auxiliary Particle Filter adjoined with a kernel smoothing approach to address this joint estimation problem. PMID- 23366858 TI - Influence of delay time on regularity estimation for voice pathology detection. AB - The employment of nonlinear analysis techniques for automatic voice pathology detection systems has gained popularity due to the ability of such techniques for dealing with the underlying nonlinear phenomena. On this respect, characterization using nonlinear analysis typically employs the classical Correlation Dimension and the largest Lyapunov Exponent, as well as some regularity quantifiers computing the system predictability. Mostly, regularity features highly depend on a correct choosing of some parameters. One of those, the delay time tau, is usually fixed to be 1. Nonetheless, it has been stated that a unity tau can not avoid linear correlation of the time series and hence, may not correctly capture system nonlinearities. Therefore, present work studies the influence of the tau parameter on the estimation of regularity features. Three tau estimations are considered: the baseline value 1; a tau based on the Average Automutual Information criterion; and tau chosen from the embedding window. Testing results obtained for pathological voice suggest that an improved accuracy might be obtained by using a tau value different from 1, as it accounts for the underlying nonlinearities of the voice signal. PMID- 23366859 TI - Identification and quantification of mixed air pollutants based on homotopy method for gas sensor array. AB - Accurate recognition of air pollutants and estimation of their concentrations are critical for human health and safety monitoring and can be achieved using gas sensor arrays. In this paper, an efficient method based on a homotopy algorithm is presented for the analysis of sensor arrays responding to binary mixtures. The new method models the responses of a gas sensor array as a system of nonlinear equations and provides a globally convergent way to find the solution of the system. Real data measurement for CH4 and SO2 are used to model sensor responses. The model is applied to the method for prediction and it shows the prediction results are within 1% variation of true values for both gas models. PMID- 23366860 TI - Characterization of detrended fluctuation analysis in the context of glycemic time series. AB - There is a growing interest in the analysis of hyperglycemia and its relationship with other pathologies. The level of glucose in blood is regulated by the flux/reflux and controlled by hyperglycemia hormones and hypoglycemic insulin. Glycemic profiles are characterized by a nonlinear and nonstationary behavior but also influenced by circadian rhythms and patient daily routine which introduce quasi-periodic trends into them. This type of signals are commonly analyzed by Detrended Fluctuation Analysis (DFA) which states that the control system in charge of regulating the glucose level usually holds a long-range negative correlation. But there is an inconsistency about the windowing lengths, as no standard or rules are set. This work studies the influence of the windowing length sequence, and shows that there is a need for selecting the optimal values in order to obtain a good differentiation between different groups, and these values are somehow determined by signal characteristics. PMID- 23366861 TI - Complex networks: application to pathology detection in voice signals. AB - The method of complex networks has been proposed as a novel approach to analyze time series from a new perspective. However, only few studies have applied this methodology to certain types of pseudo-periodic signals. In this article, the network-based technique is applied on voice signals, a kind of pseudo-periodic signals which has not been analyzed using complex networks, to differentiate between a healthy subject and subjects with pathological disorders. The results obtained demonstrated that through a set of statistic computed from the complex networks is possible to differentiate between healthy and non-healthy subjects, contrary to what was observed using well known non-linear statistics, such as Lempel-Ziv complexity and sample entropy. We conclude that by seeing voice signals as complex networks new information can be extracted from the time series that may help in the diagnosis of pathologies. PMID- 23366862 TI - Comparative study between Sample Entropy and Detrended Fluctuation Analysis performance on EEG records under data loss. AB - This study compares two signal entropy measures, Sample Entropy (SampEn) and Detrended Fluctuation Analysis (DFA) over real EEG signals after a randomized sample removal. Both measures have demonstrated their ability to discern between, among others: control and pathologic EEG signals, seizure free or not, control and opened eyes EEG, and side of brain signals. Results show that SampEn behaves better when analyzing control signals, while DFA provides better segmentation results between epileptic signals, in the context of sample loss, particularly when discerning between seizure and seizure free signal intervals. PMID- 23366863 TI - EMG-based detection of muscle fatigue during low-level isometric contraction by recurrence quantification analysis and monopolar configuration. AB - The center frequency (CF) of the power spectral density of a bipolar-configured surface electromyogram is typically used as an index of muscle fatigue. However, this index may be inadequate for measuring wave slowing due to muscle fatigue during low-level contractions. A previous study in which strong muscle fatigue was mimicked by compressing the proximal region of the forearm during isometric contractions showed that the differences in the degree of fatigue under compression and non-compression conditions were undetectable. The purpose of this study was to improve detection sensitivity of surface EMG variation caused by muscle fatigue using two approaches. The first approach employed recurrence quantification analysis (RQA) instead of traditional frequency analysis (FA) to compute the muscle fatigue index. The second approach employed a monopolar configuration for measuring surface EMG. We measured the surface EMG signal by using monopolar and bipolar configurations simultaneously during low-level isometric contractions under blood flow-restricted (BFR) and unrestricted (CON) conditions, and then compared and evaluated the detected differences in muscle fatigue. The results showed that the effect of BFR was better detected by RQA than by FA, and that the fatigability change was larger in the monopolar configuration than in the bipolar configuration. PMID- 23366864 TI - Automatic detection of REM sleep in subjects without atonia. AB - Idiopathic Rapid-Rye-Movement (REM) sleep Behavior Disorder (iRBD) is a strong early marker of Parkinson's Disease and is characterized by REM sleep without atonia (RSWA) and increased phasic muscle activity. Current proposed methods for detecting RSWA assume the presence of a manually scored hypnogram. In this study a full automatic REM sleep detector, using the EOG and EEG channels, is proposed. Based on statistical features, combined with subject specific feature scaling and post-processing of the classifier output, it was possible to obtain an mean accuracy of 0.96 with a mean sensitivity and specificity of 0.94 and 0.96 respectively. PMID- 23366865 TI - A comparison between recording sites of snoring sounds in relation to upper airway obstruction. AB - This paper presents the results of our study on investigating the acoustical properties of snoring sounds (SS) recorded by two microphones (one over trachea and one hung in the air within 30-50 cm away from the subject) in relation to sleep apnea. Several features were extracted from SS segments of 50 snorers with different Apnea-Hypopnea Index (AHI). We used an optimal subset of the sound features to cluster the SS segments into two clusters (A and B). Then, the number of SS segments in cluster A was calculated and normalized by the total number of SS segments for each subject, resulting in 50 * 1 vector R. A correlation analysis was run between AHI and R. The results show a difference in acoustical properties of the tracheal and ambient snoring sounds and their ability to distinguish two types of snoring; the ambient snoring sounds are not as characteristic as tracheal snoring sounds. PMID- 23366866 TI - Validation of a novel automatic sleep spindle detector with high performance during sleep in middle aged subjects. AB - Many of the automatic sleep spindle detectors currently used to analyze sleep EEG are either validated on young subjects or not validated thoroughly. The purpose of this study is to develop and validate a fast and reliable sleep spindle detector with high performance in middle aged subjects. An automatic sleep spindle detector using a bandpass filtering approach and a time varying threshold was developed. The validation was done on sleep epochs from EEG recordings with manually scored sleep spindles from 13 healthy subjects with a mean age of 57.9 +/- 9.7 years. The sleep spindle detector reached a mean sensitivity of 84.6 % and a mean specificity of 95.3 %. The sleep spindle detector can be used to obtain measures of spindle count and density together with quantitative measures such as the mean spindle frequency, mean spindle amplitude, and mean spindle duration. PMID- 23366867 TI - Online estimation of lower and upper bounds for heart sound boundaries in chest sound using Convex-hull algorithm. AB - Heart sound localization in chest sound is an essential part for many heart sound cancellation algorithms. The main difficulty for heart sound localization methods is the precise determination of the onset and offset boundaries of the heart sound segment. This paper presents a novel method to estimate lower and upper bounds for the onset and offset of the heart sound segment, which can be used as anchor points for more precise estimation. For this purpose, first chest sound is divided into frames and then entropy and smoothed entropy features of these frames are extracted, and used in the Convex-hull algorithm to estimate the upper and lower bounds for heart sound boundaries. The Convex-hull algorithm constructs a special type of envelope function for entropy features and if the maximal difference between the envelope function and the entropy is larger than a certain threshold, this point is considered as a heart sound bound. The results of the proposed method are compared with a baseline method which is a modified version of a well-known heart sound localization method. The results show that the proposed method outperforms the baseline method in terms of accuracy and detection error rate. Also, the experimental results show that smoothing entropy features significantly improves the performance of both baseline and proposed methods. PMID- 23366868 TI - Lung water detection using acoustic techniques. AB - The presence of an excessive amount of water in lung is a sign of pulmonary edema which can be caused by heart failure. The current solutions for lung water detection involve the use of X-ray, CT scan or serum biomarkers, which require bulky and expensive instruments as well as long measurement duration. This paper reports on a study conducted on the use of a different sensing modality to detect the presence of water in lung. The main contributions of the paper are twofold: 1) we propose to employ acoustic (or sound) based techniques for lung water detection. The design is simple and can be implemented on a portable or wearable system; 2) we establish the feasibility of sound-based techniques for lung water detection, by carrying out experimental studies using four feature extraction methods combined with two classification methods. The findings of this study will be beneficial to the design of portable devices for rapid and accurate lung water detection. PMID- 23366869 TI - Modified classification of normal lung sounds applying Quantile vectors. AB - In this paper a novel Lung Sound Automatic Verification (LSAV) system and front end Quantile based acoustic models to classify Lung Sounds (LS) are proposed. The utilization of Quantiles allowed an easier and objective assessment with smaller computational demand. Moreover, less-complex Gaussian Mixture Models (GMM) were computed than those previously reported. The LSAV system allowed us to reach practically negligible error in healthy (normal) LS verification. LASV system efficiency and the optimal GMM's were evaluated by using Equal Error Rate (EER) and Bayesian Information Criterion (BIC) techniques respectively. These approaches could provide a tool for broader medical evaluation which does not rely, as it is often the case, on a qualitative and subjective description of LS. PMID- 23366870 TI - Diagnosis of Alzheimer's disease from EEG by means of synchrony measures in optimized frequency bands. AB - Several clinical studies have reported that EEG synchrony is affected by Alzheimer's disease (AD). In this paper a frequency band analysis of AD EEG signals is presented, with the aim of improving the diagnosis of AD using EEG signals. In this paper, multiple synchrony measures are assessed through statistical tests (Mann-Whitney U test), including correlation, phase synchrony and Granger causality measures. Moreover, linear discriminant analysis (LDA) is conducted with those synchrony measures as features. For the data set at hand, the frequency range (5-6 Hz) yields the best accuracy for diagnosing AD, which lies within the classical theta band (4-8 Hz). The corresponding classification error is 4.88% for directed transfer function (DTF) Granger causality measure. Interestingly, results show that EEG of AD patients is more synchronous than in healthy subjects within the optimized range 5-6 Hz, which is in sharp contrast with the loss of synchrony in AD EEG reported in many earlier studies. This new finding may provide new insights about the neurophysiology of AD. Additional testing on larger AD datasets is required to verify the effectiveness of the proposed approach. PMID- 23366871 TI - Time sparsification of EEG signals in motor-imagery based brain computer interfaces. AB - We propose a method of sparsifying EEG signals in the time domain for common spatial patterns (CSP) which are often used for feature extraction in brain computer interfaces (BCI). For accurate classification, it is important to analyze the period of time when a BCI user performs a mental task. We address this problem by optimizing the CSP cost with a time sparsification that removes unnecessary samples from the classification. We design a cost function that has CSP spatial weights and time window as optimization parameters. To find these parameters, we use alternating optimization. In an experiment on classification of motor-imagery EEG signals, the proposed method increased classification accuracy by 6% averaged over five subjects. PMID- 23366872 TI - Sparse linear regression with elastic net regularization for brain-computer interfaces. AB - This paper demonstrates the feasibility of decoding neuronal population signals using a sparse linear regression model with an elastic net penalty. In offline analysis of real electrocorticographic (ECoG) neural data the elastic net achieved a timepoint decoding accuracy of 95% for classifying hand grasps vs. rest, and 82% for moving a cursor in 1-D space towards a target. These results were superior to those obtained using l(2)-penalized and unpenalized linear regression, and marginally better than l(1)-penalized regression. Elastic net and the l(1)-penalty also produced sparse feature sets, but the elastic net did not eliminate correlated features, which could result in a more stable decoder for brain-computer interfaces. PMID- 23366873 TI - EEG-based detection of awakening from isoflurane anesthesia in rats. AB - In animal studies, reliable measures for depth of anesthesia are frequently required. Previous findings suggest that the continuous depth of anesthesia indices developed for humans might not be adequate for rats whose EEG changes during anesthesia represent more of quick transitions between discrete states. In this paper, the automatic EEG-based detection of awakening from anesthesia was studied in rats. An algorithm based on Bayesian Information Criterion (BIC) is proposed for the assessment of the switch-like change in the signal characteristics occurring just before the awakening. The method was tested with EEGs recorded from ten rats recovering from isoflurane anesthesia. The algorithm was shown to be able to detect the sudden change in the EEG related to the moment of awakening with a precision comparable to careful visual inspection. Our findings suggest that monitoring such signal changes may offer an interesting alternative to the application of continuous depth of anesthesia indices when avoiding the awakening of the animal during e.g. a clinical experiment. PMID- 23366874 TI - Pulse Arrival Time as surrogate for systolic blood pressure changes during impending neurally mediated syncope. AB - Blood pressure regulation failures cause neurally mediated syncope often resulting in a fall. A warning device might help to make patients aware of an impending critical event or even trigger the patient to perform countermeasures such as lying down or isometric exercises. We previously demonstrated that the Pulse Arrival Time (PAT) methodology is a potential approach to enable early detection of impending faints. The aim of the present study was to evaluate whether PAT can be used as an easy to measure beat-to-beat surrogate for systolic blood pressure (SBP) changes during a passive standing exercise (head-up tilt table testing (HUTT)). A significant PAT increase of more than 10 % was accompanied with a critical SBP decrease in syncope patients. Although PAT is in general not considered as a good measure of absolute blood pressure we found strong correlations (R>0.89, P<0.01) of SBP and PAT after PAT began to increase. Therefore, our data suggest that the pulse arrival time is useful to monitor blood pressure changes in patients with neurally mediated syncope. This might open up new avenues to prevent falls in these patients. PMID- 23366875 TI - RR-QT interval trend covariability for sudden cardiac death risk stratification. AB - This paper examines the feasibility of the trend covariability between QT and RR Intervals (QTIs and RRIs) be a novel mean of the sudden cardiac death (SCD) risk stratification. Twenty four hour beat to beat QTIs and RRIs are measured from Holter ECG recordings of 25 normal control subjects (SCD-C), 14 low SCD risk patients (SCD-L) with high blood pressure or light cardiac arrhythmia and 11 SCD high risk patients (SCD-H) with heart attack history. The Kalman filtering technique has been applied to decompose 24 hour short term mean QTIs and RRIs sequences into trend components and additive random variations. The correlation coefficients (TC-QT/RR) and cross entropies (TE-QT/RR) between the QT and RR trend signals are estimated. Cross entropy TE-QT/RR achieved the best stratification of subject groups. TE-QT/RR distribution for SCD-C, -L -H subject groups were 1.697 +/- 0.058, 1.160 +/- 0.099, 0.920 +/- 0.067. The differences in entropy values are statistically significant for all classes pairs (SCD-H and -C (p<0.00001); -L and -C (p<0.001); -H and -L (p<0.05) The result indicates that the TE-QT/RR could be a novel index for the SCD risk stratification. PMID- 23366876 TI - Sequential Markov chain Monte Carlo filter with simultaneous model selection for electrocardiogram signal modeling. AB - Constructing statistical models of electrocardiogram (ECG) signals, whose parameters can be used for automated disease classification, is of great importance in precluding manual annotation and providing prompt diagnosis of cardiac diseases. ECG signals consist of several segments with different morphologies (namely the P wave, QRS complex and the T wave) in a single heart beat, which can vary across individuals and diseases. Also, existing statistical ECG models exhibit a reliance upon obtaining a priori information from the ECG data by using preprocessing algorithms to initialize the filter parameters, or to define the user-specified model parameters. In this paper, we propose an ECG modeling technique using the sequential Markov chain Monte Carlo (SMCMC) filter that can perform simultaneous model selection, by adaptively choosing from different representations depending upon the nature of the data. Our results demonstrate the ability of the algorithm to track various types of ECG morphologies, including intermittently occurring ECG beats. In addition, we use the estimated model parameters as the feature set to classify between ECG signals with normal sinus rhythm and four different types of arrhythmia. PMID- 23366877 TI - Improvement of ECG signal quality measurement using correlation and diversity based approaches. AB - A large proportion of cardiovascular diseases might be preventable, however, majority of this diseases occurs in rural areas where there is a poor presence of cardiologists. To overcome this issue, the use of wearable devices within the telemedicine framework would be of benefit. However, implementation of processing algorithms in smart-phones at mobile environments imposes restrictions ensuring high measurement quality of acquired ECG data, while maintaining low computation burden. This work presents an algorithm for scoring the quality of measured ECG recordings is developed. Particularly, a quality score is provided that takes into account the proportional correlation observed in acceptable signals based on a diversity scheme, and their inverse relation with standard deviation. Testing of proposed algorithm is carried out upon two different databases, the first one is of own production, while the second one is obtained from Physionet. As a result, high values of sensitivity and specificity are achieved. PMID- 23366878 TI - Multiscale sample entropy based on discrete wavelet transform for clinical heart rate variability recognition. AB - Traditional multiscale method uses coarse grained average (CGA) to evaluate sample entropy (SE) parameters in different scales for signal characterization. In this study, we propose to use discrete wavelet transform (DWT) to decompose hear rate variability signals into multiscale sequences for the calculation of SE features for the recognition of congestive heart failure (CHF) and atrial fibrillation (AF) from normal sinus rhythm (NSR). The support vector machine (SVM) is used as the classifier and the capability of the features are justified with leave-one-out cross-validation method. The results demonstrate that the system using multiscale SE features calculated from both CGA and DWT with five dyadic scales outperforms that based on tradition multiscale method using CGA and 20 scales. Compared to the 5-scale CGA method, the proposed 5-scale DWT method achieved 6.7% and 0.77% increases in the recognition rates for CHF and AF, respectively, and resulted in an 8.35% raise in the overall recognition accuracy. PMID- 23366879 TI - Mitral valve prolapse detection using landmark extraction from echocardiography sequences. AB - The mitral valve is one of the four valves of the heart, whose function is to keep the blood flow in the physiological direction when the heart contracts. There is no satisfactory method allowing an automated assessment for Mitral Valve Prolapse (MVP) detection. In this paper an algorithm is proposed for detecting MVPs automatically from an echocardiography sequence. Our algorithm has two steps; first landmarks are extracted from the echocardiography sequence. Then landmarks are tracked in the whole frames of a sequence. In order to detect MVP and isolate it from a normal mitral motion, we extracted some features (such as maximum deviation of valve angle and spectral power ratio) from the motion pattern of a mitral valve and we gave these features to a SVM classifier. The results show that the mitral motion trajectory may have good discriminative features for detecting MVP (87% specificity and 84% sensitivity). PMID- 23366880 TI - Classification of cardiosynchronous waveforms by projection to a Legendre Polynomial sub-space. AB - The use of Radio Frequency Impedance Interrogation (RFII) is being investigated for use as a noninvasive hemodynamic monitoring system and in the capacity of a biometric identifier. Biometric identification of subjects by cardiosynchronous waveform generated through RFII technology could allow the identification of subjects in operational and potentially hostile environments. Here, the filtering methods for extracting a unique biometric signature from the RFII signal are examined, including the use of Cepstral analysis for dynamically estimating the filter parameters. METHODS: The projection of that signature to a Legendre Polynomial sub-space is proposed for increased class separability in a low dimensional space. Support Vector Machine (SVM) and k-Nearest Neighbor (k=3) classification are performed in the Legendre Polynomial sub-space on a small dataset. RESULTS: Both the k-Nearest Neighbor and linear SVM methods demonstrated highly successful classification accuracy, with 93-100% accuracy demonstrated by various classification methods. CONCLUSIONS: The results are highly encouraging despite the small sample size. Further analysis with a larger dataset will help to refine this process for the eventual application of RFII as a robust biometric identifier. PMID- 23366881 TI - Biometric identification of cardiosynchronous waveforms utilizing person specific continuous and discrete wavelet transform features. AB - In this paper we explore how a Radio Frequency Impedance Interrogation (RFII) signal may be used as a biometric feature. This could allow the identification of subjects in operational and potentially hostile environments. Features extracted from the continuous and discrete wavelet decompositions of the signal are investigated for biometric identification. In the former case, the most discriminative features in the wavelet space were extracted using a Fisher ratio metric. Comparisons in the wavelet space were done using the Euclidean distance measure. In the latter case, the signal was decomposed at various levels using different wavelet bases, in order to extract both low frequency and high frequency components. Comparisons at each decomposition level were performed using the same distance measure as before. The data set used consists of four subjects, each with a 15 minute RFII recording. The various data samples for our experiments, corresponding to a single heart beat duration, were extracted from these recordings. We achieve identification rates of up to 99% using the CWT approach and rates of up to 100% using the DWT approach. While the small size of the dataset limits the interpretation of these results, further work with larger datasets is expected to develop better algorithms for subject identification. PMID- 23366882 TI - Severity estimation of finger-tapping caused by Parkinson's disease by using linear discriminant regression analysis. AB - We propose a linear discriminant regression analysis (LDRA) that provides an estimated severity marker for discriminating between healthy and patient groups and estimating severities of the patient group simultaneously. This method combines an evaluation function for discriminating between two groups and one for estimating severities of one group. The combined function is optimized to obtain an equation for calculating estimated severities. The method was evaluated with finger-tapping data of healthy and Parkinson's disease (PD) groups and PD severities assessed by a doctor. As a result, the discrimination ability of LDRA (AUC: 0.8835) was higher than that of discriminant analysis (DA. AUC: 0.8442), which is a conventional method for classification, and the regression ability of LDRA (mean square error (MSE): 1.27) was superior to that of multiple regression analysis (MRA. MSE: 1.68), which is a conventional method for regression. The results show that LDRA is an effective method for estimating the presence and severity of Parkinson's disease. PMID- 23366883 TI - Performance of pattern recognition myoelectric control using a generic electrode grid with targeted muscle reinnervation patients. AB - Targeted muscle reinnervation (TMR) is a surgical technique that creates myoelectric prosthesis control sites for high-level amputees. The electromyographic signal patterns provided by the reinnervated muscles are well suited for pattern recognition (PR) control. PR control uses more electrodes compared to conventional amplitude control techniques but their placement on the residual limb is less critical than for conventional amplitude control. In this contribution, we demonstrate that classification error and real-time control performances using a generically placed electrode grid were equivalent or superior to the performance when using targeted electrode placements on two transhumeral amputee subjects with TMR. When using a grid electrode layout, subjects were able to complete actions 0.290 sec to 1 sec faster and with greater accuracy as compared to clinically localized electrode placement (mean classification error of 1.35% and 3.2%, respectively, for a 5 movement-class classifier).These findings indicate that a grid electrode arrangement has the potential to improve control of a myoelectric prosthesis while reducing the time and effort associated with fitting the prosthesis due to clinical localization of control sites on amputee patients. PMID- 23366884 TI - Reducing classification accuracy degradation of pattern recognition based myoelectric control caused by electrode shift using a high density electrode array. AB - The robustness and usability of pattern recognition based myoelectric control systems degrade significantly if the sensors are displaced during usage. This effect inevitably occurs during donning, doffing or using an upper-limb prosthesis over a longer period of time. Electrode shift has been previously studied but remains an unsolved problem. In this study we investigate if increasing the number of electrode channels and recording locations can improve the degraded classification accuracy caused by electrode shift. In our experiment we use a 96 channel high density electrode array to distinguish 11 different hand and wrist movements. Our results show that for electrode shifts up to 1 cm an array of about 32 sensors in combination with state-of-the-art pattern recognition algorithms is sufficient to compensate the electrode displacement effect. PMID- 23366885 TI - Performance evaluation of an Artificial Neural Network automatic spindle detection system. AB - Sleep spindles are transient waveforms found in the electroencephalogram (EEG) of non-rapid eye movement (NREM) sleep. Sleep spindles are used for the classification of sleep stages and have been studied in the context of various psychiatric and neurological disorders, such as Alzheimer's disease (AD) and the so-called Mild Cognitive Impairment (MCI), which is considered to be a transitional stage between normal aging and dementia. The visual processing of whole-night sleep EEG recordings is tedious. Therefore, various techniques have been proposed for automatically detecting sleep spindles. In the present work an automatic sleep spindle detection system, that has been previously proposed, using a Multi-Layer Perceptron (MLP) Artificial Neural Network (ANN), is evaluated in detecting spindles of both healthy controls, as well as MCI and AD patients. An investigation is carried also concerning the visual detection process, taking into consideration the feedback information provided by the automatic detection system. Results indicate that the sensitivity of the detector was 81.4%, 62.2%, and 83.3% and the false positive rate was 34%, 11.5%, and 33.3%, for the control, MCI, and AD groups, respectively. The visual detection process had a sensitivity rate ranging from 46.5% to 60% and a false positive rate ranging from 4.8% to 19.2%. PMID- 23366886 TI - A comparison of direct and pattern recognition control for a two degree-of freedom above elbow virtual prosthesis. AB - Individuals with a transhumeral amputation have a large functional deficit and require basic functions out of their prosthesis. Myoelectric prostheses have used amplitude control techniques for decades to restore one or two degrees of freedom to these patients. Pattern recognition control has also been investigated for transhumeral amputees, but in recent years, has been more focused on transradial amputees or high-level patients who have received targeted muscle reinnervation. This study seeks to use the most recent advances in pattern recognition control and investigate techniques that could be applied to the majority of the transhumeral amputee population that has not had the reinnervation surgery to determine if pattern recognition systems may provide them with improved control. In this study, able-bodied control subjects demonstrated that highly accurate two degree-of-freedom pattern recognition systems may be trained using four EMG channels. Such systems may be used to better control a prosthesis in real-time when compared to conventional amplitude control with mode switching. PMID- 23366887 TI - Determination of neural state classification metrics from the power spectrum of human ECoG. AB - Brain electrical activity exhibits scale-free dynamics that follow power law scaling. Previous works have shown that broadband spectral power exhibits state dependent scaling with a log frequency exponent that systematically varies with neural state. However, the frequency ranges which best characterize biological state are not consistent across brain location or subject. An adaptive piecewise linear fitting solution was developed to extract features for classification of brain state. Performance was evaluated by comparison to an a posteriori based feature search method. This analysis, using the 1/f characteristics of the human ECoG signal, demonstrates utility in advancing the ability to perform automated brain state discrimination. PMID- 23366888 TI - Multi-patient learning increases accuracy for Subthalamic Nucleus identification in deep brain stimulation. AB - Establishing the exact position of basal ganglia is key in several brain surgeries, particularly in deep brain stimulation for patients suffering from Parkinson's disease. There have been recent attempts to introduce automatic systems with the ability to localize, with high accuracy, specific brain regions. These systems usually follow the classical supervised learning paradigm, in which training data from different patients are employed to construct a classifier that is patient-independent. In this paper, we show how by sharing information from different patients, it is possible to increase accuracy for targeting the Subthalamic Nucleus. We do this in the context of multi-task learning, where different but related tasks are used simultaneously to leverage the performance of a learning system. Results show that the multitask framework can outperform the traditional patient-independent scenario in two different real datasets. PMID- 23366889 TI - Using piezoelectric films for classification of upper arm motions: a preliminary report. AB - Recently, it has been reported that finger motions could be recognized from the forearm signal detected by accelerometers. However, accelerometers are sensitive to vibration or unintended motions, which could cause large noise when classifying different hand motions. This is why our research group wanted to explore the usability of other kinds of sensors for upper arm motions classification. Therefore, the objective of this study was to examine the usefulness of a piezoelectric film for hand motion classification and its robustness to unintended motions. Experiments were conducted to record signals from the piezoelectric films for different hand motions, while the subject was asked to move the ipsilateral shoulder, the contralateral hand, or the legs. The results showed that the desired hand motion could be distinguished using a piezoelectric film despite of unintended motions. PMID- 23366890 TI - Performance of respiratory pattern parameters in classifiers for predict weaning process. AB - Weaning trials process of patients in intensive care units is a complex clinical procedure. 153 patients under extubation process (T-tube test) were studied: 94 patients with successful trials (group S), 38 patients who failed to maintain spontaneous breathing and were reconnected (group F), and 21 patients with successful test but that had to be reintubated before 48 hours (group R). The respiratory pattern of each patient was characterized through the following time series: inspiratory time (T(I)), expiratory time (T(E)), breathing cycle duration (T(Tot)), tidal volume (V(T)), inspiratory fraction (T(I)/T(Tot)), half inspired flow (V(T)/T(I)), and rapid shallow index (f/V(T)), where f is respiratory rate. Using techniques as autoregressive models (AR), autoregressive moving average models (ARMA) and autoregressive models with exogenous input (ARX), the most relevant parameters of the respiratory pattern were obtained. We proposed the evaluation of these parameters using classifiers as logistic regression (LR), linear discriminant analysis (LDA), support vector machines (SVM) and classification and regression tree (CART) to discriminate between patients from groups S, F and R. An accuracy of 93% (98% sensitivity and 82% specificity) has been obtained using CART classification. PMID- 23366891 TI - Classification of posture and activities by using decision trees. AB - Obesity prevention and treatment as well as healthy life style recommendation requires the estimation of everyday physical activity. Monitoring posture allocations and activities with sensor systems is an effective method to achieve the goal. However, at present, most devices available rely on multiple sensors distributed on the body, which might be too obtrusive for everyday use. In this study, data was collected from a wearable shoe sensor system (SmartShoe) and a decision tree algorithm was applied for classification with high computational accuracy. The dataset was collected from 9 individual subjects performing 6 different activities--sitting, standing, walking, cycling, and stairs ascent/descent. Statistical features were calculated and the classification with decision tree classifier was performed, after which, advanced boosting algorithm was applied. The computational accuracy is as high as 98.85% without boosting, and 98.90% after boosting. Additionally, the simple tree structure provides a direct approach to simplify the feature set. PMID- 23366892 TI - Detrending knee joint vibration signals with a cascade moving average filter. AB - Knee joint vibration signals are very useful for computer-aided analysis of the pathological conditions in the knee. In a vibration arthrometry test, the legs of patients with knee joint disorders may tremble due to the reaction of pain, which causes the baseline wander that may affect the diagnostic decision making in medical study. This paper presents a new type of cascade moving average filter with hierarchical layers to remove the baseline wander in the raw knee joint vibration signals. The first layer of the cascade filter contains two moving averaging operators with the same order. The five tail inputs of the first moving averaging operator are overlapping with the beginning inputs of the successive operator. The piecewise linear trends estimated by the moving average operators in the first layer were smoothed in the final cascade filter output. The simulation results showed that the cascade filter can effectively remove the baseline wander in the raw knee joint vibration signals. PMID- 23366893 TI - Automatic 3D reconstruction of quasi-planar stereo Scanning Electron Microscopy (SEM) images. AB - Scanning Electron Microscopy (SEM) is widely used in science to characterize the surface roughness of materials. Three-dimensional information can be obtained with SEM based on stereovision techniques. A stereo pair is typically obtained by tilting the sample by a few degrees. In this paper we present a fully automated method for 3D reconstruction from a SEM stereo pair without any particular constraint. Results are presented for corneal stromal surfaces. PMID- 23366894 TI - Saliency-guided compressive fluorescence microscopy. AB - A novel saliency-guided approach is proposed for improving the acquisition speed of compressive fluorescence microscopy systems. By adaptively optimizing the sampling probability density based on regions of interest instead of the traditional unguided random sampling approach, the proposed saliency-guided compressive fluorescence microscopy approach can achieve high-quality microscopy images using less than half of the number of fluorescence microscopy data measurements required by existing compressive fluorescence microscopy systems to achieve the same level of quality. PMID- 23366895 TI - Hermite kernels for slice interpolation in medical images. AB - Univariate Hermite interpolation of the total degree (HTD) is an algebraically demanding interpolation method that utilizes information of the values of the signal to be interpolated at distinct support positions, as well as the values of its derivatives up to a maximum available order. In this work the interpolation kernels of the univariate HTD are derived, using several approximations of the 1st and 2nd order of discrete signal derivative. We assess the derived Hermite kernels in the task of medical image slice interpolation, against several other well established interpolation techniques. Results show that specific Hermite kernels can outperform other established interpolation methods with similar computational complexity, in terms of root mean square error (RMSE), in a number of interpolation experiments, resulting in higher accuracy interpolated images. PMID- 23366896 TI - Fast parallel algorithm for CT image reconstruction. AB - In X-ray computed tomography (CT) the X rays are used to obtain the projection data needed to generate an image of the inside of an object. The image can be generated with different techniques. Iterative methods are more suitable for the reconstruction of images with high contrast and precision in noisy conditions and from a small number of projections. Their use may be important in portable scanners for their functionality in emergency situations. However, in practice, these methods are not widely used due to the high computational cost of their implementation. In this work we analyze iterative parallel image reconstruction with the Portable Extensive Toolkit for Scientific computation (PETSc). PMID- 23366897 TI - Hair detection in dermoscopic images using percolation. AB - The automatic analysis of dermoscopy images is often impaired by artifacts such as air bubbles, specular reflections or dark hair covering the skin lesions. Consequently, an important pre-processing step includes their detection and elimination. The most common and probably the most compromising of these artifacts is the presence of hair and therefore specific algorithms are required for its detection. This paper proposes a method for the detection of hair in dermoscopy images based on an efficient percolation algorithm for image processing recently proposed in [1]. The percolation algorithm locally processes image points by taking into account the intensity and connectivity of neighboring pixels. A cluster of connected points is thus obtained and the shape of this cluster is subsequently analyzed. If the cluster has a shape that is approximately linear then the image point is classified as hair. The performance of the proposed method was investigated on real dermoscopy images and compared with the DullRazor software [2]. Our results indicate that the method provides effective hair detection outperforming the DullRazor method by more than 10%, both in terms of false positive and false negative rates. PMID- 23366898 TI - Medical image restoration with different types of noise. AB - The images obtained by X-Ray or computed tomography (CT) in adverse conditions may be contaminated with noise that can affect the detection of diseases. A large number of image processing techniques (filters) have been proposed to remove noise. These techniques depend on the type of noise present in the image. In this work, we propose a method designed to reduce the Gaussian, the impulsive and speckle noise and combined noise. This filter, called PGNDF, combines a non linear diffusive filter with a peer group with fuzzy metric technique. The proposed filter is able to reduce efficiently the image noise without any information about what kind of noise might be present. To evaluate the filter performance, we use mammographic images from the mini- MIAS database which we have damaged by adding Gaussian, impulsive and speckle noises of different magnitudes. As a result, the proposed method obtains a good performance in most of the different types of noise. PMID- 23366899 TI - Ultrasonic tissue characterization of the upper trapezius muscle in patients with myofascial pain syndrome. AB - Myofascial trigger points (MTrPs) are palpable, tender nodules in skeletal muscle that produce symptomatic referred pain when palpated. MTrPs are characteristic findings in myofascial pain syndrome (MPS). The role of MTrPs in the pathophysiology of MPS is unknown. Objective characterization and quantitative measurement of the properties of MTrPs can improve their localization and diagnosis, as well as lead to clinical outcome measures. MTrPs associated with soft tissue neck pain are often found in the upper trapezius muscle. We have previously demonstrated that MTrPs can be visualized using ultrasound imaging. The goal of this study was to evaluate whether texture-based image analysis can differentiate structural heterogeneity of symptomatic MTrPs and normal muscle. PMID- 23366900 TI - On the performance of improved ICP algorithms for registration of intra ultrasound with pre-MR images; a phantom study. AB - Ultrasound imaging as a simple and being real time has been found very applicable for intra-operative updates of pre-operative MRI data in image guided neurosurgery system. The main challenge here is the presence of speckle noise which influences the accuracy of registration of US-MR images, intra-operatively. In this paper the performance of two improved versions of the well known Iterative Closest Point (ICP) algorithms to deal with noise and outliers are considered and compared with conventional ICP method. To perform this study in a condition close to real clinical setting, a PVA-C brain phantom is made. As the results show improved versions of ICP are found more robust and precise than ICP algorithms in the presence of noise and outliers. Then the effect of various de noising methods including diffusion filters on the accuracy of point-based registration is evaluated. The role of a proper diffusion filter for de-noising of US images has also improved the performance of the ICP algorithm and its variants about 35% and 20%, respectively. PMID- 23366901 TI - Combining multiple feature representations and AdaBoost ensemble learning for reducing false-positive detections in computer-aided detection of masses on mammograms. AB - One of the drawbacks of current Computer-aided Detection (CADe) systems is a high number of false-positive (FP) detections, especially for detecting mass abnormalities. In a typical CADe system, classifier design is one of the key steps for determining FP detection rates. This paper presents the effective classifier ensemble system for tackling FP reduction problem in CADe. To construct ensemble consisting of correct classifiers while disagreeing with each other as much as possible, we develop a new ensemble construction solution that combines data resampling underpinning AdaBoost learning with the use of different feature representations. In addition, to cope with the limitation of weak classifiers in conventional AdaBoost, our method has an effective mechanism for tuning the level of weakness of base classifiers. Further, for combining multiple decision outputs of ensemble members, a weighted sum fusion strategy is used to maximize a complementary effect for correct classification. Comparative experiments have been conducted on benchmark mammogram dataset. Results show that the proposed classifier ensemble outperforms the best single classifier in terms of reducing the FP detections of masses. PMID- 23366902 TI - Body surface area measurement and soft clustering for PASI area assessment. AB - Psoriasis is a common skin disorder with a prevalence of 0.6 - 4.8% around the world. The most common is plaques psoriasis and it appears as red scaling plaques. Psoriasis is incurable but treatable in a long term treatment. Although PASI (Psoriasis Area and Severity Index) scoring is recognised as gold standard for psoriasis assessment, this method is still influenced by inter and intra rater variation. An imaging and analysis system called alpha-PASI is developed to perform PASI scoring objectively. Percentage of lesion area to the body surface area is one of PASI parameter. In this paper, enhanced imaging methods are developed to improve the determination of body surface area (BSA) and lesion area. BSA determination method has been validated on medical mannequin. BSA accuracies obtained at four body regions are 97.80% (lower limb), 92.41% (trunk), 87.72% (upper limb), and 83.82% (head). By applying fuzzy c-means clustering algorithm, the membership functions of lesions area for PASI area scoring have been determined. Performance of scoring result has been tested with double assessment by alpha-PASI area algorithm on body region images from 46 patients. Kappa coefficients for alpha-PASI system are greater than or equal to 0.72 for all body regions (Head - 0.76, Upper limb - 0.81, Trunk - 0.85, Lower limb - 0.72). The overall kappa coefficient for the alpha-PASI area is 0.80 that can be categorised as substantial agreement. This shows that the alpha-PASI area system has a high reliability and can be used in psoriasis area assessment. PMID- 23366903 TI - On the role of texture and color in the classification of dermoscopy images. AB - This paper addresses the detection of melanoma lesions in dermoscopy images, using texture and color features. Although melanoma detection has been studied in several works, using different types of texture, color and shape features, it is not always clear what is the role of each set of features and which features are most discriminative. This papers aims at clarifying the role of texture and color features. Furthermore, the proposed systems is based on features which can be easily implemented and tested by other researchers. It is concluded that both types of features achieve good detection scores when used alone. The best results (SE=94.1%, SP=77.4%) are achieved by combining them both. PMID- 23366905 TI - A wavelet-based approach for a continuous analysis of phonovibrograms. AB - Recently, endoscopic high-speed laryngoscopy has been established for commercial use and constitutes a state-of-the-art technique to examine vocal fold dynamics. Despite overcoming many limitations of commonly applied stroboscopy it has not gained widespread clinical application, yet. A major drawback is a missing methodology of extracting valuable features to support visual assessment or computer-aided diagnosis. In this paper a compact and descriptive feature set is presented. The feature extraction routines are based on two-dimensional color graphs called phonovibrograms (PVG). These graphs contain the full spatio temporal pattern of vocal fold dynamics and are therefore suited to derive features that comprehensively describe the vibration pattern of vocal folds. Within our approach, clinically relevant features such as glottal closure type, symmetry and periodicity are quantified in a set of 10 descriptive features. The suitability for classification tasks is shown using a clinical data set comprising 50 healthy and 50 paralytic subjects. A classification accuracy of 93.2% has been achieved. PMID- 23366904 TI - Scale normalization of histopathological images for batch invariant cancer diagnostic models. AB - Histopathological images acquired from different experimental set-ups often suffer from batch-effects due to color variations and scale variations. In this paper, we develop a novel scale normalization model for histopathological images based on nuclear area distributions. Results indicate that the normalization model closely fits empirical values for two renal tumor datasets. We study the effect of scale normalization on classification of renal tumor images. Scale normalization improves classification performance in most cases. However, performance decreases in a few cases. In order to understand this, we propose two methods to filter extracted image features that are sensitive to image scaling and features that are uncorrelated with scaling factor. Feature filtering improves the classification performance of cases that were initially negatively affected by scale normalization. PMID- 23366906 TI - Advanced characterization of microscopic kidney biopsies utilizing image analysis techniques. AB - Correct annotation and identification of salient regions in Kidney biopsy images can provide an estimation of pathogenesis in obstructive nephropathy. This paper presents a tool for the automatic or manual segmentation of such regions along with methodology for their characterization in terms of the exhibited pathology. The proposed implementation is based on custom code written in Java and the utilization of open source tools (i.e. RapidMiner, ImageJ). The corresponding implementation details along with the initial evaluation of the proposed integrated system are also presented in the paper. PMID- 23366907 TI - Cancer cells detection and pathology quantification utilizing image analysis techniques. AB - This paper presents an advanced image analysis tool for the accurate and fast characterization and quantification of cancer and apoptotic cells in microscopy images utilizing adaptive thresholding and a Support Vector Machines classifier. The segmentation results are also enhanced through a Majority Voting and a Watershed technique. The proposed tool was evaluated by experts on breast cancer images and the reported results were accurate and reproducible. PMID- 23366908 TI - A new ROC analysis method considering the correlation between neighboring pixels. AB - In this paper, we introduce a novel receiver operating characteristic (ROC) analysis method that considers spatial correlation between pixels to evaluate classification algorithms. ROC analysis is one of the most important tools in the evaluation of medical images and computer aided diagnosis (CAD) systems. It provides a comprehensive description of the detection accuracy of the test image. To evaluate the localization performance, operating points of ROC curves are obtained based on the classification results of individual pixels. To this date, the confidence level or intensity value of each pixel is assumed to be independent within the image. However, this assumption is not satisfied in real problems. In this paper, a new ROC analysis algorithm that considers the correlation between neighboring pixels is proposed. Our results show that the new ROC curves provide a more accurate evaluation of the test image. PMID- 23366909 TI - Symmetry and appearance based automated detection of salient anatomical regions in ultrasound. AB - In this paper we present a method for automated detection of enclosed anatomical regions in ultrasound images by utilizing the coarse shape symmetry as well as relative homogeneity of their sonographic appearance. The proposed method comprises of two steps: First, local phase based filtering [2] is used to detect points in the image which are roughly positioned along the axes of spatial symmetry with respect to structures around them. Secondly, the sonographic 'appearance' and location of these points is used to define a distance-map on the image, which is supplied to a simple fast-marching algorithm in order to provide the final feature detections. The method is robust to ultrasound speckle and works well with or without specialized pre-processing (e.g. speckle-reduction filtering). We illustrate the proposed method with qualitative results on in-vivo Ultrasound images. PMID- 23366910 TI - Automated extraction of nested sulcus features from human brain MRI data. AB - Extracting objects related to a fold in the cerebral cortex ("sulcus features") from human brain magnetic resonance imaging data has applications in morphometry, landmark-based registration, and anatomical labeling. In prior work, sulcus features such as surfaces, fundi and pits have been extracted separately. Here we define and extract nested sulcus features in a hierarchical manner from a cortical surface mesh having curvature or depth values. Our experimental results show that the nested features are comparable to features extracted separately using other methods, and that they are consistent across subjects and with manual label boundaries. Our open source feature extraction software will be made freely available as part of the Mindboggle project (http://www.mindboggle.info). PMID- 23366911 TI - Automatic pterygium detection on cornea images to enhance computer-aided cortical cataract grading system. AB - In this paper, we present a new method to detect pterygiums using cornea images. Due to the similarity of appearances and spatial locations between pterygiums and cortical cataracts, pterygiums are often falsely detected as cortical cataracts on retroillumination images by a computer-aided grading system. The proposed method can be used to filter out the pterygium which improves the accuracy of cortical cataract grading system. This work has three major contributions. First, we propose a new pupil segmentation method for visible wavelength images. Second, an automatic detection method of pterygiums is proposed. Third, we develop an enhanced compute-aided cortical cataract grading system that excludes pterygiums. The proposed method is tested using clinical data and the experimental results demonstrate that the proposed method can improve the existing automatic cortical cataract grading system. PMID- 23366912 TI - Geometric correction of deformed chromosomes for automatic Karyotyping. AB - Automatic Karyotyping is the process of classifying chromosomes from an unordered karyogram into their respective classes to create an ordered karyogram. Automatic karyotyping algorithms typically perform geometrical correction of deformed chromosomes for feature extraction; these features are used by classifier algorithms for classifying the chromosomes. Karyograms of bone marrow cells are known to have poor image quality. An example of such karyograms is the Lisbon K(1) (LK(1)) dataset that is used in our work. Thus, to correct the geometrical deformation of chromosomes from LK(1), a robust method to obtain the medial axis of the chromosome was necessary. To address this problem, we developed an algorithm that uses the seed points to make a primary prediction. Subsequently, the algorithm computes the distance of boundary from the predicted point, and the gradients at algorithm-specified points on the boundary to compute two auxiliary predictions. Primary prediction is then corrected using auxiliary predictions, and a final prediction is obtained to be included in the seed region. A medial axis is obtained this way, which is further used for geometrical correction of the chromosomes. This algorithm was found capable of correcting geometrical deformations in even highly distorted chromosomes with forked ends. PMID- 23366913 TI - Quantification of the bone healing process using information of B-Mode ultrasound image. AB - Ultrasound provides a promising non-invasive, safe, objective means of monitoring and quantifying bone healing. In this paper, the relationship between the ultrasound image intensity and the acoustic impedance was exploited to develop a quantitative measure towards assessment and monitoring of the bone healing process. Information theoretic criterion (KLD) was used to quantify the degree of bone healing using the intensity histogram of the callus region obtained from B Mode ultrasound. Results from a pilot experimental study, show that the proposed method is capable of accurately quantifying the degree of bone healing. PMID- 23366914 TI - Ovarian tumor characterization and classification: a class of GyneScanTM systems. AB - In this work, we have developed an adjunct Computer Aided Diagnostic (CAD) technique that uses 3D acquired ultrasound images of the ovary and data mining algorithms to accurately characterize and classify benign and malignant ovarian tumors. In this technique, we extracted image-texture based and Higher Order Spectra (HOS) based features from the images. The significant features were then selected and used to train and test the Decision Tree (DT) classifier. The proposed technique was validated using 1000 benign and 1000 malignant images, obtained from 10 patients with benign and 10 with malignant disease, respectively. On evaluating the classifier with 10-fold stratified cross validation, we observed that the DT classifier presented a high accuracy of 95.1%, sensitivity of 92.5% and specificity of 97.7%. Thus, the four significant features could adequately quantify the subtle changes and nonlinearities in the pixel intensities. The preliminary results presented in this paper indicate that the proposed technique can be reliably used as an adjunct tool for ovarian tumor classification since the system is accurate, completely automated, cost effective, and can be easily written as a software application for use in any computer. PMID- 23366915 TI - A shape constrained parametric active contour model for breast contour detection. AB - Quantitative measures of breast morphology can help a breast cancer survivor to understand outcomes of reconstructive surgeries. One bottleneck of quantifying breast morphology is that there are only a few reliable automation algorithms for detecting the breast contour. This study proposes a novel approach for detecting the breast contour, which is based on a parametric active contour model. In addition to employing the traditional parametric active contour model, the proposed approach enforces a mathematical shape constraint based on the catenary curve, which has been previously shown to capture the overall shape of the breast contour reliably. The mathematical shape constraint regulates the evolution of the active contour and helps the contour evolve towards the breast, while minimizing the undesired effects of other structures such as, the nipple/areola and scars. The efficacy of the proposed approach was evaluated on anterior posterior photographs of women who underwent or were scheduled for breast reconstruction surgery including autologous tissue reconstruction. The proposed algorithm shows promising results for detecting the breast contour. PMID- 23366916 TI - Using Spatio-Temporal Interest Points (STIP) for myoclonic jerk detection in nocturnal video. AB - In this study we introduce a method for detecting myoclonic jerks during the night with video. Using video instead of the traditional method of using EEG electrodes, permits patients to sleep without any attached sensors. This improves the comfort during sleep and it makes long term home monitoring possible. The algorithm for the detection of the seizures is based on spatio-temporal interest points (STIPs), proposed by Ivan Laptev, which is the state-of-the-art in action recognition.We applied this algorithm on a group of patients suffering from myoclonic jerks. With an optimal parameter setting this resulted in a sensitivity of over 75% and a PPV of over 85%, on the patients' combined data. PMID- 23366917 TI - Extracting morphological high-level intuitive features (HLIF) for enhancing skin lesion classification. AB - Feature extraction of skin lesions is necessary to provide automated tools for the detection of skin cancer. High-level intuitive features (HLIF) that measure border irregularity of skin lesion images obtained with standard cameras are presented. Existing feature sets have defined many low-level unintuitive features. Incorporating HLIFs into a set of low-level features gives more semantic meaning to the feature set, and allows the system to provide intuitive rationale for the classification decision. Promising experimental results show that adding a small set of HLIFs to the large state-of-the-art low-level skin lesion feature set increases sensitivity, specificity, and accuracy, while decreasing the cross-validation error. PMID- 23366918 TI - Automated measurement of pediatric cranial bone thickness and density from clinical computed tomography. AB - Skull thickness and density measures of normal pediatric crania would inform multiple disciplines including neurosurgery, optical and magnetoelectrophysiological imaging, and biomechanical modeling of head trauma. We report on a new method for automated extraction of in vivo skull thickness and density measures of pediatric crania based on x-ray computed tomography scans (CT). Data were obtained from a clinical image repository for pediatric populations in whom no pathology was noted. Skull thickness and density measures were systematically obtained across the calvarium. We find a set of measures that correlated with physiological age that are likely to prove useful in multiple disciplines. PMID- 23366919 TI - Architecture design of the multi-functional wavelet-based ECG microprocessor for realtime detection of abnormal cardiac events. AB - Most of the abnormal cardiac events such as myocardial ischemia, acute myocardial infarction (AMI) and fatal arrhythmia can be diagnosed through continuous electrocardiogram (ECG) analysis. According to recent clinical research, early detection and alarming of such cardiac events can reduce the time delay to the hospital, and the clinical outcomes of these individuals can be greatly improved. Therefore, it would be helpful if there is a long-term ECG monitoring system with the ability to identify abnormal cardiac events and provide realtime warning for the users. The combination of the wireless body area sensor network (BASN) and the on-sensor ECG processor is a possible solution for this application. In this paper, we aim to design and implement a digital signal processor that is suitable for continuous ECG monitoring and alarming based on the continuous wavelet transform (CWT) through the proposed architectures--using both programmable RISC processor and application specific integrated circuits (ASIC) for performance optimization. According to the implementation results, the power consumption of the proposed processor integrated with an ASIC for CWT computation is only 79.4 mW. Compared with the single-RISC processor, about 91.6% of the power reduction is achieved. PMID- 23366920 TI - Design and measurements of low power multichannel chip for recording and stimulation of neural activity. AB - A 64-channel Neuro-Stimulation-Recording chip named NRS64 for neural activity measurements has been designed and tested. The NRS64 occupies 5*5 mm2 of silicon area and consumes only 25 uW/channel. A low cut-off frequency can be tuned in the 60 mHz-100 Hz range while a high cut-off frequency can be set to 4.7 kHz or 12 kHz. A voltage gain can be set to 139 V/V or 1100 V/V. A measured input referenced noise is 3.7 uV rms in 100 Hz-12 kHz band and 7.6 uV rms in 3 Hz-12 kHz band. A digital correction is used in each channel to tune the low cut-off frequency and offset voltage. Each channel is equipped additionally with a stimulation circuit with an artifact cancellation circuit. The stimulation circuit can be set with 8-bit resolution in six different ranges from 500 nA-512 uA range. PMID- 23366921 TI - Integrative technology-based approach of microelectromechanical systems (MEMS) for biosensing applications. AB - In this work we simultaneously aim at addressing the design and fabrication of microelectromechanical systems (MEMS) for biological applications bearing actuation and readout capabilities together with adapted tools dedicated to surface functionalization at the microscale. The biosensing platform is based on arrays of silicon micromembranes with piezoelectric actuation and piezoresistive read-out capabilities. The detection of the cytochrome C protein using molecularly imprinted polymers (MIPs) as functional layer is demonstrated. The adapted functionalization tool specifically developed to match the micromembranes' platform is an array of silicon cantilevers incorporating precise force sensors for the trim and force measurements during deposition of biological materials onto the sensors' active area. In either case, associated analog electronics is specifically realized to deal with specific signals treatment fed through the MEMS-based devices. PMID- 23366922 TI - Pulse laser assisted optical tweezers for biomedical applications. AB - Optical tweezers which enables to trap micron to nanometer sized objects by radiation pressure force is utilized for manipulation of particles under a microscope and for measurement of forces between biomolecules. Weak force of optical tweezers causes some limitations such as particle adhesion or steric barrier like lipid membrane in a cell prevent further movement of objects. For biomedical applications we need to overcome these difficulties. We have developed a technique to exert strong instantaneous force by use of a pulse laser beam and to assist conventional optical tweezers. A pulse laser beam has huge instantaneous laser power of more than 1000 times as strong as a conventional continuous-wave laser beam so that the instantaneous force is strong enough to break chemical bonding and molecular force between objects and obstacles. We derive suitable pulse duration for pulse assist of optical tweezers and demonstrate particle manipulation in difficult situations through an experiment of particle removal from sticky surface of glass substrate. PMID- 23366923 TI - A method for stable electrical connection of a multi-channeled polyimide electrode with PCB. AB - We propose a novel packaging method of a thin polyimide multichannel microelectrode. For the simple electrical connection of polyimide (PI) electrodes, we made a via-hole at the interconnection pads of thin PI electrodes, and constructed a Ni ring by electroplating through the via-hole for the stable soldering and strong adhesion of the electrode to PCB. For the construction of a well-organized Ni ring, the electroplating condition was optimized, and the electrical property of the packaged electrode was evaluated. A 40 channel thin PI electrode was fabricated and packaged by the proposed method, and we performed the animal experiment with this packaged electrode for the high-resolution recording of neural signals from the skull of a rat. PMID- 23366924 TI - Low power and high accuracy spike sorting microprocessor with on-line interpolation and re-alignment in 90 nm CMOS process. AB - Accurate spike sorting is an important issue for neuroscientific and neuroprosthetic applications. The sorting of spikes depends on the features extracted from the neural waveforms, and a better sorting performance usually comes with a higher sampling rate (SR). However for the long duration experiments on free-moving subjects, the miniaturized and wireless neural recording ICs are the current trend, and the compromise on sorting accuracy is usually made by a lower SR for the lower power consumption. In this paper, we implement an on-chip spike sorting processor with integrated interpolation hardware in order to improve the performance in terms of power versus accuracy. According to the fabrication results in 90nm process, if the interpolation is appropriately performed during the spike sorting, the system operated at the SR of 12.5 k samples per second (sps) can outperform the one not having interpolation at 25 ksps on both accuracy and power. PMID- 23366925 TI - Posture estimation for a canine machine interface based training system. AB - Dogs and humans have worked in partnership throughout history thanks to dogs' unique capability of detecting signals in human voices or gestures and learning from human inputs. Traditional canine training methods rely solely on subjective visual observations made by trainers. We propose a canine body-area-network (cBAN) to incorporate context-aware sensing with objective detection algorithms to augment the sensitivity and specificity of human trainer's awareness of the dogs they are training. As an initial effort, we developed a Bluetooth-based wireless infrastructure and tested inertial measurement units as cBAN sensor nodes to electronically assess the posture of the dogs. As a result, we were able to optimize the sensor locations and distinguish different postures using the distinct patterns in the measured angles. PMID- 23366926 TI - Motion capture system using Wiimote motion sensors. AB - The purpose of this study is to examine the Wiimote MotionPlus system as a method to capture angular kinematic data of the knee, hip and back of a participant performing a lifting task. Twenty one subjects were recruited and asked to perform a lifting task while having four Wiimotes strapped to the lower leg, upper leg, and back at the hip and below the shoulder blades. The raw signals from the four Wiimotes were filtered and normalized before being combined to obtain the proper change in angular data. The results of the study demonstrate that it is feasible to combine the data from multiple Wiimotes to obtain kinematic data which may be used in ergonomic analysis. PMID- 23366927 TI - Signal agnostic compressive sensing for Body Area Networks: comparison of signal reconstructions. AB - Compressive sensing is a lossy compression technique that is potentially very suitable for use in power constrained sensor nodes and Body Area Networks as the compression process has a low computational complexity. This paper investigates the reconstruction performance of compressive sensing when applied to EEG, ECG, EOG and EMG signals; establishing the performance of a signal agnostic compressive sensing strategy that could be used in a Body Area Network monitoring all of these. The results demonstrate that the EEG, ECG and EOG can all be reconstructed satisfactorily, although large inter- and intra- subject variations are present. EMG signals are not well reconstructed. Compressive sensing may therefore also find use as a novel method for the identification of EMG artefacts in other electro-physiological signals. PMID- 23366928 TI - Low-power system-on-chip implementation for respiratory rate detection and transmission. AB - Recent biosensors can measure respiratory rate non-invasively, but limits patient mobility or requires regular battery replacement. Respiratory effort, which can scavenge mW, may power the sensor, but requires minimal sensor power usage. This paper demonstrates feasibility of respiratory rate measurement by using a comparator instead of ADC. A low-power system-on-chip can implement respiratory rate detection and wireless data transmission with a total power consumption under 82 uW. This approach produces significant power savings, and transmission uses under 30% of total power consumption. PMID- 23366929 TI - Evaluation of the ShapeTape for studying biomechanics in the workplace. AB - Motion capture systems may be difficult to use in harsh environments such as a poultry plant, and therefore should be self-contained, portable, unobtrusive, and not interfere with or be degraded by plant machinery or processes. The purpose of this study was to evaluate the validity, reliability and accuracy of the ShapeTape system as a potential solution. This was accomplished by comparing kinematic data from the ShapeTape against the Vicon system. Subjects performed cyclical movements along a plane angled 45 degrees up from the horizontal using their right arms. Results revealed that the ShapeTape kinematic data was significantly larger than the Vicon data, yet statistically reliable. PMID- 23366930 TI - Comparing adaptive algorithms to measure temporal gait parameters using lower body mounted inertial sensors. AB - The purpose of this research was to compare different adaptive algorithms in terms of their ability to determine temporal gait parameters based on data acquired from inertial measurement units (IMUs). Eight subjects performed 25 walking trials over a force plate under five different conditions; normal, fast, slow, simulated stiff ankle and simulated stiff knee walking. Data from IMUs worn on the shanks and on the feet were used to identify temporal gait features using three different adaptive algorithms (Green, Selles & Sabatini). Each method's ability to estimate temporal events was compared to the gold standard force plate method for stance time (Greene, r= .990, Selles, r= 0.865, Sabatini, r= 0.980) and double support time (Greene, r= .837, Selles, r= .583, Sabatini, r= .745). The Greene method of estimating gait events from inertial sensor data resulted in the most accurate stance and double support times. PMID- 23366931 TI - Towards the prevention of pressure ulcers with a wearable patient posture monitor based on adaptive accelerometer alignment. AB - Pressure ulcers are a serious problem affecting over a million patients every year. Despite accepted guidelines for assessing and repositioning high-risk patients, the prevalence of pressure ulcers continues to rise. This paper presents a wearable, wireless vital sign monitor capable of continuously measuring the duration and orientation of a patient's posture throughout the patient's stay in a hospital. Patient posture is determined using a tri-axial accelerometer attached to a patient's torso. A novel set of algorithms are used to process the accelerometer signals to adaptively identify accelerometer alignment on the patient, calculate patient spine angle, and classify patient orientation. A unique pressure ulcer risk index based on these variables is presented to assess a patient's risk for developing pressure ulcers. Experimental results from an 18 subject trial are also presented. PMID- 23366932 TI - Application of Near-field intra-body communication and spread spectrum technique to vital-sign monitor. AB - As a novel vital sign monitor, we have developed wireless ECG monitoring system with Near-field intra-body communication technique. However, communication reliability is not so high because transmission channel is noisy and unstable. In order to improve the problem, we utilize spread spectrum (SS), which is known as robust communication technique even through poor transmission channel. First of all, we evaluated characteristics of human body to SS signal. The results show that SS can be used even through human body. Based on this result, we developed and tested near-field intra-body communication device enhanced by SS. The test result shows that SS can solve the problem mentioned above. PMID- 23366934 TI - Activity monitoring and motion classification of the lizard Chamaeleo jacksonii using multiple Doppler radars. AB - We describe a simple, non-contact and efficient tool for monitoring the natural activity of a small lizard (Chamaeleo jacksonii) to yield valuable information about their metabolic activity and energy expenditure. It allows monitoring in a non-confined laboratory environment and uses multiple Doppler radars operating at 10.525 GHz. We developed a classification algorithm that can differentiate between fidgeting and locomotion by processing the quadrature baseband signals from the radars. The results have been verified by visual inspection and indicate that the tool could also be used for automated monitoring of the activities of reptiles and other small animals. PMID- 23366933 TI - Enhancing clinical measures of postural stability with wearable sensors. AB - About 30% of individuals over the age of 65, and 50% over age 80, fall at least once per year. Fall-related injuries cost the Canadian health care system $2.8 billion annually. Risk for falls in older adults is commonly assessed in the clinical environment using tools such as the Short Physical Performance Battery (SPPB), which include subjective assessments of postural sway while standing under various sensory conditions. This study uses wearable accelerometers and a force plate to quantify measures of postural stability during these tasks. Four participants were asked to maintain quiet stance in six different conditions, while their center of pressure (COP) and accelerations from six accelerometers were recorded. Standard deviations in signals were used as measures of postural sway. The sway observed in all sensors increased with the difficulty of the stance condition. Manipulation of vision and surface stiffness caused greater changes in sway in the AP than ML direction, while changes in stance configuration were more evident in the ML direction. Furthermore, the ankle sensor was the most sensitive in registering changes in sway when manipulating vision and surface stiffness (showing an increase of 236% over baseline values in AP sway with eyes closed and standing on foam), while the thigh was most sensitive to changes in stance width (showing an increase of 336% over baseline values in ML sway in the tandem stance condition). This study contributes in establishing the utility of wearable sensors for quantifying postural stability under various stance configurations in future studies with high-risk older adults. PMID- 23366935 TI - On the correlation between motion data captured from low-cost gaming controllers and high precision encoders. AB - Gaming controllers are attractive devices for research due to their onboard sensing capabilities and low-cost. However, a proper quantitative analysis regarding their suitability for use in motion capture, rehabilitation and as input devices for teleoperation and gesture recognition has yet to be conducted. In this paper, a detailed analysis of the sensors of two of these controllers, the Nintendo Wiimote and the Sony Playstation 3 Sixaxis, is presented. The acceleration and angular velocity data from the sensors of these controllers were compared and correlated with computed acceleration and angular velocity data derived from a high resolution encoder. The results show high correlation between the sensor data from the controllers and the computed data derived from the position data of the encoder. From these results, it can be inferred that the Wiimote is more consistent and better suited for motion capture applications and as an input device than the Sixaxis. The applications of the findings are discussed with respect to potential research ventures. PMID- 23366936 TI - Effect of frequency, body parts and surrounding on the on-body propagation channel around the torso. AB - Wearable medical devices can be positioned around the torso for monitoring of critical health parameters. The signal transmission between them is through a wireless link over an on-body propagation channel. In this paper, the effect of some factors which could influence the propagation channel around the torso as: (a) frequency of operation (b) positions of the arms (c) material of a chair used, have been investigated. Moreover, a comparison between the link loss around the torso of a full body phantom and a truncated torso phantom has been done. It is found that the frequency of operation and the positions of the arms have a significant influence on the channel. The difference between the link loss of a full body phantom and a truncated phantom is found to be minimal, indicating a possibility of using a truncated torso for a faster simulation. The results presented in the paper gives an insight in to the influence of arms and the frequency of operation on the propagation channel around the torso and thus would be beneficial for designing a reliable wireless link. PMID- 23366937 TI - A wireless trigger for synchronization of wearable sensors to external systems during recording of human gait. AB - Mobile gait analysis focuses on the automatic extraction of gait parameters from wearable sensor data. However, development of algorithms for this task requires kinematic data with accurate and highly synchronous ground truth. In this paper we present a wireless trigger system which allows reliable synchronization of wearable sensors to external systems providing ground truth. To demonstrate the applicability of the system for mobile gait analysis, a Shimmer wireless sensor node with inertial sensors was mounted at the heel of a running shoe and synchronized with an external VICON motion capturing system using the wireless trigger system. Inertial sensor data were recorded during walking and running with the shoe, while kinematic and kinetic ground truth was acquired from the synchronized VICON system. Evaluation of delay and jitter of the system showed a mean delay of 2 ms and low jitter of 20 us. Recording was highly synchronous and the collected kinematics had a correlation of up to 0.99. In the future the proposed system will allow the creation of a database of inertial data from human gait with accurate ground truth synchronization. PMID- 23366938 TI - Wearable mental-health monitoring platform with independent component analysis and nonlinear chaotic analysis. AB - The wearable mental-health monitoring platform is proposed for mobile mental healthcare system. The platform is headband type of 50 g and consumes 1.1 mW. For the mental health monitoring two specific functions (independent component analysis (ICA) and nonlinear chaotic analysis (NCA)) are implemented into CMOS integrated circuits. ICA extracts heart rate variability (HRV) from EEG, and then NCA extracts the largest lyapunov exponent (LLE) as physiological marker to identify mental stress and states. The extracted HRV is only 1.84% different from the HRV obtained by simple ECG measurement system. With the help of EEG signals, the proposed headband mental monitoring system shows 90% confidence level in stress test, which is better than the test results of only HRV. PMID- 23366939 TI - 3D localization of circular feature in 2D image and application to food volume estimation. AB - A novel method to estimate the 3D location of a circular feature from a 2D image is presented and applied to the problem of objective dietary assessment from images taken by a wearable device. Instead of using a common reference (e.g., a checkerboard card), we use a food container (e.g., a circular plate) as a necessary reference before the volumetric measurement. In this paper, we establish a mathematical model formulating the system involving a camera and a circular object in a 3D space and, based on this model, the food volume is calculated. Our experiments showed that, for 240 pictures of a variety of regular objects and food replicas, the relative error of the image-based volume estimation was less than 10% in 224 pictures. PMID- 23366940 TI - Arm movement effect on balance. AB - The background research shows a high incidence of falls and loss of balance related injuries, which cause serious consequences to individual health and quality of life, as well as substantial healthcare impact in services and costs. The literature review emphasizes that arm movements have a potentially significant effect on balance, and indentifies the use of balance boards as a relevant and meaningful tool for dynamic balance evaluation. The primary objective of this initial study was to develop a method to test and evaluate the effect of arm movements on the maintenance of postural stability. Further we investigated the impact of dominant and non-dominant arms, the reaction time of arms, and the amount of activity of arms related to dynamic balance control. The study applied an accelerometer-based balance board test to measure postural stability as related to arm movements. The evaluation consists of accelerometers placed on the two arms and the balance board. Data were acquired from four different subjects and processed accordingly. The finding verified that arms play an important role in the improvement of balance. Our findings suggest that the dominant arm is more active in balance control and that the movement of arms most often occurs just prior to and during loss of balance. The results also suggest that the amount of arm movement activity directly relates to balance control and the use of the dominant arm. PMID- 23366941 TI - Investigation of the Treadport for gait rehabilitation of spinal cord injury. AB - The goal of this study is to compare the effect of training by the University of Utah's Treadport versus a conventional treadmill on gait improvement of spinal cord-injury (SCI) patients. Four incomplete SCI subjects who had reached a rehabilitation plateau were selected to have training first on the treadmill and then the Treadport. Spatiotemporal and gait parameters were utilized to make a comparison between the two training conditions. Overall, the results demonstrated statically significant improvements in most of the spatiotemporal as well as some of the gait parameters during training with the Treadport relative to the traditional treadmill. PMID- 23366942 TI - Resting state functional connectivity and task-related effective connectivity changes after upper extremity rehabilitation: a pilot study. AB - In this study we investigated the effect of 2 weeks of robot-aided virtual reality therapy for the paretic upper limb in stroke patients on changes in brain activation. Brain activation was acquired during the resting state and during visually-guided hand movement. fMRI analysis focused on characterizing functional connectivity with ipsilesional primary motor cortex (iM1) at rest and during execution of paretic hand movement. Two subjects who sustained a stroke more than 6 months ago participated. Before and after the training period, motor function was evaluated (Wolf Motor Function Test [WMFT], Jebsen Test of Hand Function [JTHF]). After the training period, clinical outcomes (WMFT and JTHF) improved in both subjects. The resting state functional connectivity (rsFC) maps and task related functional connectivity with iM1 showed different magnitudes of activation, however, the general directionality of the pattern (increases versus decreases) was similar. Specifically, both the rsFC and the task-related functional connectivity between iM1 and contralesional primary motor cortex (cM1) decreased after the therapy for the first subject and increased for the second subject. Our preliminary data suggest that resting state functional connectivity may be a useful measure of brain reorganization, particularly for subjects with limited volitional control of the paretic limb. PMID- 23366943 TI - Classification of hand preshaping in persons with stroke using Linear Discriminant Analysis. AB - OBJECTIVE: This study describes the analysis of hand preshaping using Linear Discriminant Analysis (LDA) to predict hand formation during reaching and grasping tasks of the hemiparetic hand, following a series of upper extremity motor intervention treatments. The purpose of this study is to use classification of hand posture as an additional tool for evaluating the effectiveness of therapies for upper extremity rehabilitation such as virtual reality (VR) therapy and conventional physical therapy. Classification error for discriminating between two objects during hand preshaping is obtained for the hemiparetic and unimpaired hands pre and post training. METHODS: Eight subjects post stroke participated in a two-week training session consisting of upper extremity motor training. Four subjects trained with interactive VR computer games and four subjects trained with clinical physical therapy procedures of similar intensity. Subjects' finger joint angles were measured during a kinematic reach to grasp test using CyberGlove(r) and arm joint angles were measured using the trackSTARTM system prior to training and after training. RESULTS: The unimpaired hand of subjects preshape into the target object with greater accuracy than the hemiparetic hand as indicated by lower classification errors. Hemiparetic hand improved in preshaping accuracy and time to reach minimum error. CONCLUSION: Classification of hand preshaping may provide insight into improvements in motor performance elicited by robotically facilitated virtually simulated training sessions or conventional physical therapy. PMID- 23366944 TI - Development of a closed-loop feedback system for real-time control of a high dimensional Brain Machine Interface. AB - As the field of neural prosthetics advances, Brain Machine Interface (BMI) design requires the development of virtual prostheses that allow decoding algorithms to be tested for efficacy in a time- and cost-efficient manner. Using an x-ray and MRI-guided skeletal reconstruction, and a graphic artist's rendering of an anatomically correct macaque upper limb, we created a virtual avatar capable of independent movement across 27 degrees-of-freedom (DOF). Using a custom software interface, we animated the avatar's movements in real-time using kinematic data acquired from awake, behaving macaque subjects using a 16 camera motion capture system. Using this system, we demonstrate real-time, closed-loop control of up to 27 DOFs in a virtual prosthetic device. Thus, we describe a practical method of testing the efficacy of high-complexity BMI decoding algorithms without the expense of fabricating a physical prosthetic. PMID- 23366945 TI - Development of computer games for assessment and training in post-stroke arm telerehabilitation. AB - Stroke is the leading cause of long term disability among adults in industrialized nations. The majority of these disabilities include deficiencies in arm function, which can make independent living very difficult. Research shows that better results in rehabilitation are obtained when patients receive more intensive therapy. However this intensive therapy is currently too expensive to be provided by the public health system, and at home few patients perform the repetitive exercises recommended by their therapists. Computer games can provide an affordable, enjoyable, and effective way to intensify treatment, while keeping the patient as well as their therapists informed about their progress. This paper presents the study, design, implementation and user-testing of a set of computer games for at-home assessment and training of upper-limb motor impairment after stroke. PMID- 23366946 TI - Axon terminal polarization induced by weak uniform DC electric fields: a modeling study. AB - Uniform steady state (DC) electric fields, like those generated during transcranial direct current stimulation (tDCS), can affect neuronal excitability depending on field direction and neuronal morphology. In addition to somatic polarization, subthreshold membrane polarization of axon compartments can play a significant role in modulating synaptic efficacy. The aim of this study is to provide an estimation of axon terminal polarization in a weak uniform subthreshold electric field. Simulations based on 3D morphology reconstructions and simplified models indicate that for axons having long final branches compared to the local space constant (L>4lambda) the terminal polarization converges to Elambda for electric fields oriented in the same direction as the branch. In particular we determined how and when analytical approximations could be extended to real cases when considering maximal potential polarization during weak DC stimulation. PMID- 23366947 TI - A dual mode FPGA design for the hippocampal prosthesis. AB - One important step towards the cognitive neural prosthesis design is to achieve real-time prediction of neuronal firing pattern. An FPGA-based hardware computational platform is designed to guarantee this hard real-time signal processing requirement. The proposed platform can work in dual modes: generalized Laguerre-Volterra model parameters estimation and output prediction, and can switch between these two important system functions. Compared with the traditional software-based platform implemented in C, the hardware platform achieves better efficiency in doing the biocomputations by up to thousandfold speedup in this process. PMID- 23366948 TI - Modelling eye-head coordination without pre-planning--a reflex-based approach. AB - The gaze orientation system is a prime example of the CNS using multiple platforms to achieve its goal. To move the gaze in space, the eyes, head, and body cooperate to place the image of the target on the fovea. Understanding the underlying neural circuitry innervating this collaboration could also be a cue to understanding other movement related CNS tasks involving multiple platforms, i.e., posture and locomotion. Basically two major network topologies for modeling the gaze orientation system have been proposed: the independent controller model and the shared gaze feedback controller model. In the independent controller model, each platform (i.e., eyes, head or trunk) receives its own share of the retinal error (distance of the target from the current gaze position) independent from other platform(s) and its goal is to null its individual error, whereas, in the shared gaze feedback controller all platforms collaborate to null the shared global error, which is calculated on the fly using feedback from all platforms or reflexes. Each of the mentioned general topologies has its own supporters and the question is which does the CNS actually use. In this article, based on evidence from neurophysiology and behavior, complemented by simulation data, it will be shown why a shared feedback controller is the better candidate for this task. More specifically, simulations of an updated Prsa-Galiana model (the Shared Sensory-Motor Integration (SMI) model) will be discussed in more detail and, where applicable, compared with other popular models, including independent and shared controller models. It provides plausible explanations for observations on gaze shifts with various interventions. PMID- 23366949 TI - Granger causality analysis of functional connectivity of spiking neurons in orofacial motor cortex during chewing and swallowing. AB - Primate feeding behavior is characterized by a series of jaw movement cycles of different types making it ideal for investigating the role of motor cortex in controlling transitions between different kinematic states. We recorded spiking activity in populations of neurons in the orofacial portion of primary motor cortex (MIo) of a macaque monkey and, using a Granger causality model, estimated their functional connectivity during transitions between chewing cycles and from chewing to swallowing cycles. We found that during rhythmic chewing, the network was dominated by excitatory connections and exhibited a few "out degree" hub neurons, while during transitions from rhythmic chews to swallows, the numbers of excitatory and inhibitory connections became comparable, and more "in degree" hub neurons emerged. These results suggest that networks of neurons in MIo change their operative states with changes in kinematically defined behavioral states. PMID- 23366951 TI - Towards a large-scale biologically realistic model of the hippocampus. AB - Real neurobiological systems in the mammalian brain have a complicated and detailed structure, being composed of 1) large numbers of neurons with intricate, branching morphologies--complex morphology brings with it complex passive membrane properties; 2) active membrane properties--nonlinear sodium, potassium, calcium, etc. conductances; 3) non-uniform distributions throughout the dendritic and somal membrane surface of these non-linear conductances; 4) non-uniform and topographic connectivity between pre- and post-synaptic neurons; and 5) activity dependent changes in synaptic function. One of the essential, and as yet unanswered questions in neuroscience is the role of these fundamental structural and functional features in determining "neural processing" properties of a given brain system. To help answer that question, we're creating a large-scale biologically realistic model of the intrinsic pathway of the hippocampus, which consists of the projection from layer II entorhinal cortex (EC) to dentate gyrus (DG), EC to CA3, DG to CA3, and CA3 to CA1. We describe the computational hardware and software tools the model runs on, and demonstrate its viability as a modeling platform with an EC-to-DG model. PMID- 23366952 TI - Feasibility of recording high frequency oscillations with tripolar concentric ring electrodes during pentylenetetrazole-induced seizures in rats. AB - As epilepsy remains a refractory condition in about 30% of patients with complex partial seizures, electrical stimulation of the brain has recently shown potential for additive seizure control therapy. Previously, we applied noninvasive transcranial focal stimulation via novel tripolar concentric ring electrodes (TCREs) on the scalp of rats after inducing seizures with pentylenetetrazole (PTZ). We developed a close-loop system to detect seizures and automatically trigger the stimulation and evaluated its effect on the electrographic activity recorded by TCREs in rats. In our previous work the detectors of seizure onset were based on seizure-induced changes in signal power in the frequency range up to 100 Hz, while in this preliminary study we assess the feasibility of recording high frequency oscillations (HFOs) in the range up to 300 Hz noninvasively with scalp TCREs during PTZ-induced seizures. Grand average power spectral density estimate and generalized likelihood ratio tests were used to compare power of electrographic activity at different stages of seizure development in a group of rats (n= 8). The results suggest that TCREs have the ability to record HFOs from the scalp as well as that scalp-recorded HFOs can potentially be used as features for seizure onset detection. PMID- 23366953 TI - Computing the trajectory mutual information between a point process and an analog stochastic process. AB - In a number of application areas such as neural coding there is interest in computing, from real data, the information flows between stochastic processes one of which is a point process. Of particular interest is the calculation of the trajectory (as opposed to marginal) mutual information between an observed point process which is influenced by an underlying but unobserved analog stochastic process i.e. a state. Using particle filtering we develop a model based trajectory mutual information calculation for apparently the first time. PMID- 23366954 TI - DataHigh: graphical user interface for visualizing and interacting with high dimensional neural activity. AB - The activity of tens to hundreds of neurons can be succinctly summarized by a smaller number of latent variables extracted using dimensionality reduction methods. These latent variables define a reduced-dimensional space in which we can study how population activity varies over time, across trials, and across experimental conditions. Ideally, we would like to visualize the population activity directly in the reduced-dimensional space, whose optimal dimensionality (as determined from the data) is typically greater than 3. However, direct plotting can only provide a 2D or 3D view. To address this limitation, we developed a Matlab graphical user interface (GUI) that allows the user to quickly navigate through a continuum of different 2D projections of the reduced dimensional space. To demonstrate the utility and versatility of this GUI, we applied it to visualize population activity recorded in premotor and motor cortices during reaching tasks. Examples include single-trial population activity recorded using a multi-electrode array, as well as trial-averaged population activity recorded sequentially using single electrodes. Because any single 2D projection may provide a misleading impression of the data, being able to see a large number of 2D projections is critical for intuition-and hypothesis-building during exploratory data analysis. The GUI includes a suite of additional interactive tools, including playing out population activity timecourses as a movie and displaying summary statistics, such as covariance ellipses and average timecourses. The use of visualization tools like the GUI developed here, in tandem with dimensionality reduction methods, has the potential to further our understanding of neural population activity. PMID- 23366955 TI - Spline- and wavelet-based models of neural activity in response to natural visual stimulation. AB - We present a comparative study of the performance of different basis functions for the nonparametric modeling of neural activity in response to natural stimuli. Based on naturalistic video sequences, a generative model of neural activity was created using a stochastic linear-nonlinear-spiking cascade. The temporal dynamics of the spiking response is well captured with cubic splines with equidistant knot spacings. Whereas a sym4-wavelet decomposition performs competitively or only slightly worse than the spline basis, Haar wavelets (or histogram-based models) seem unsuitable for faithfully describing the temporal dynamics of the sensory neurons. This tendency was confirmed with an application to a real data set of spike trains recorded from visual cortex of the awake monkey. PMID- 23366956 TI - Quantification of listening effort correlates in the oscillatory EEG activity: a feasibility study. AB - So far, a generally accepted objective measure for the listening effort estimation in clinical settings is not existent. Such a measure could support the hearing aid fitting in order to reduce the listening effort in hearing impaired patients by an adequate adaption of their personal hearing aids. In the current study, we propose a new measure for the quantification of large-scale listening effort correlates. This measure takes the phase information of the ongoing oscillatory EEG activity into account. The phase was gained from the 32 channel EEG. Then, the entropy of the extracted phase was calculated. We assume that this angular entropy reflects phase synchronization effects of the ongoing activities due to an increased attention on the relevant (speech) signal. Thus, we expect that smaller values of the angular entropy reflect a more "ordered" process of the phase distribution. The new method was tested in 13 young normal hearing subjects using different auditory tasks consisting of differently adapted sentences to create different listening conditions. The results indicate that the angular entropy can be applied to reveal significantly differences between the solving and the relaxing part of the paradigm, i.e. between a more effortful and a more relaxing listening situation. It is concluded, that the further research includes the development of more effortful listening tasks in order to reveal also differences between the auditory paradigms. PMID- 23366957 TI - Analysis of extrinsic and intrinsic factors affecting event related desynchronization production. AB - Recently there has been an increase in the number of stroke patients with motor paralysis. Appropriate re-afferent sensory feedback synchronized with a voluntary motor intention would be effective for promoting neural plasticity in the stroke rehabilitation. Therefore, BCI technology is considered to be a promising approach in the neuro-rehabilitation. To estimate human motor intention, an event related desynchronization (ERD), a feature of electroencephalogram (EEG) evoked by motor execution or motor imagery is usually used. However, there exists various factors that affect ERD production, and its neural mechanism is still an open question. As a preliminary stage, we evaluate mutual effects of intrinsic (voluntary motor imagery) and extrinsic (visual and somatosensory stimuli) factors on the ERD production. Experimental results indicate that these three factors are not always additively interacting with each other and affecting the ERD production. PMID- 23366958 TI - Robust movement direction decoders from local field potentials using spatio temporal qualitative patterns. AB - A major drawback of using Local Field Potentials (LFP) for Brain Computer Interface (BCI) is their inherent instability and non-stationarity. Specifically, even when a well-trained subject performs the same task over a period of time, the neural data observed are unstable. To overcome this problem in decoding movement direction, this paper proposes the use of qualitative information in the form of spatial patterns of inter-channel ranking of multi-channel LFP recordings. The quality of the decoding was further refined by concentrating on the statistical distributions of the top powered channels. Decoding of movement direction was performed using Support Vector Machines (SVM) to construct decoders, instead of the traditional spatial patterns. Our algorithm provides a decoding power of up to 74% on average over a period of two weeks, compared with the state-of-the-art methods in the literature that yield only 33%. Furthermore, it provides 62.5% direction decoding in novel motor environments, compared with 29.5% with conventional methods. Finally, a comparison with the traditional methods and other surveyed literature is presented. PMID- 23366959 TI - Optimal stimulus current waveshape for a Hodgkin-Huxley model neuron. AB - Traditionally, rectangular Lilly-type current pulses have been employed to electrically stimulate a neuron. In this paper, we utilize a least squares optimisation approach to assess the optimality of rectangular pulses in the context of electrical current stimulation. To this end, an appropriate cost function to minimise the total charge delivered to a neuron while keeping the waveshape sufficiently smooth, is developed and applied to a Hodgkin-Huxley ionic model of the neural action potential. Cubic spline parameters were utilized to find the optimal stimulation profile for a fixed peak current. Simulation results demonstrate that the optimal stimulation profile for a specified single neuron is a non-rectangular pulse whose shape depends upon the maximum allowable current as well as the stimulus duration. PMID- 23366960 TI - Decoding tactile sensation: multiple regression analysis of monkey fingertip afferent mechanoreceptor population responses. AB - How complex tactile sensations are encoded by populations of afferent mechanoreceptors is currently not well understood. While much is known about how individual afferents respond to prescribed stimuli, their behavior as a population distributed across the fingertip has not been well described. In this study, tactile afferent mechanoreceptors in monkey fingertips were mechanically stimulated, using a flat disc shaped probe, with several magnitudes of normal force (1.8, 2.2 and 2.5 N) and torque (2.0 and 3.5 mNm), in clockwise and anticlockwise directions. Afferent nerve responses were acquired from 58 slowly adapting (SA) type-I and 25 fast-adapting (FA) type-I isolated single cutaneous mechanoreceptive afferents, recorded from the median nerve. At 10 ms time intervals after the application of torque begins, a multiple regression model was trained and evaluated to estimate the magnitude of the applied normal force and torque. Averaged results over the 200 ms period after the torque reaches its maximum indicate that SA-I and FA-I afferents can both estimate the applied torque value. FA-I afferents gave the lowest estimation error mean and standard deviation of -0.051 +/- 0.334 mNm for a target torque of 2.0 mNm, and 0.003 +/- 0.414 mNm for a target torque of 3.5 mNm. However, while SA-I afferents could estimate normal force well, there was no significant difference (ANOVA, p=0.173) in the FA-I estimates of normal force, as this force had already been held constant for one second before the torque loading phase under analysis began. PMID- 23366961 TI - Upper alpha neurofeedback training over the motor cortex increases SMR desynchronization in motor tasks. AB - Desynchronization of sensorimotor rhythms (SMR) is a distinctive feature that provides a discriminative pattern for BCI operation. However, individuals such as BCI illiterates can not produce these discriminable patterns with sufficient reliability. Additionally, SMR desynchronization can become deteriorated or extinct in patients with spinal cord injury or a cerebrovascular accident. In all these situations BCI usage is compromised. This paper proposes an intervention based on neurofeedback training of the upper alpha band to improve SMR desynchronization. The feasibility of this intervention is demonstrated in a preliminary study in which five healthy subjects were trained to increase their upper alpha band power. Such increases produced higher SMR desynchronization and better discrimination between rest and execution states of a motor task. PMID- 23366962 TI - Estimation of force direction from functional near-infrared spectroscopy signals using sparse logistic regression. AB - The brain-machine interface (BMI) has been used as a communication tool for a person who has lost body function. Extracting functional information from brain signals is important for controlling a BMI in a realistic and natural way. For a BMI, a pattern classification algorithm, such as linear discriminant analysis (LDA) and support vector machine (SVM), has commonly been used. However, the classifier using brain signals tends to suffer from overfitting because there are too many obtained features compared with the number of samples. On the other hand, sparse logistic regression (SLR), which has been proposed as a new pattern classification method for brain signals, can select small number of features to classify and interpret brain functions. Thus, overfitting can be prevented using SLR. In this study, we measured functional near-infrared spectroscopy (fNIRS) signals during isometric arm movements in four directions and performed direction classification. The features to classify force direction were selected from obtained data sets using SLR and were used in a SVM. We compared the types of fNIRS signals (OxyHb and DeoxyHb) and feature selection methods. As a result, the classification accuracy was highest when both OxyHb and DeoxyHb were used as the features and both time and channel were selected. The peak time of the signal, when the task ends, and a few seconds after the task ends, were particularly well selected. PMID- 23366963 TI - Double-blind single-session neurofeedback training in upper-alpha for cognitive enhancement of healthy subjects. AB - This paper reports on a single-session neurofeedback (NF) training procedure on the user-specific upper alpha band for cognitive enhancement in healthy users. A double-blind study was designed using a NF group and an active control group. Control group performed as the NF group but received sham feedback, minimizing the non-specific factors of training. This design aimed to (i) investigate upper alpha as a NF parameter, (ii) evaluate the NF effects on upper alpha during the execution of a cognitive task, and (iii) evaluate the effects on cognitive performance by means of a cognitive task and a battery of psychological tests. Results of EEG analysis show the key role of the feedback: only the NF group enhanced upper alpha during the training, and it led to a desynchronization increase during the execution of the cognitive task. Regarding the behavioral results, a strong learning effect was observed, with the NF group performing better in almost all measurements but many of them without statistical significance. PMID- 23366964 TI - Towards an intelligent system for clinical guidance on wheelchair tilt and recline usage. AB - We propose to construct an intelligent system for clinical guidance on how to effectively use power wheelchair tilt and recline functions. The motivations fall into the following two aspects. (1) People with spinal cord injury (SCI) are vulnerable to pressure ulcers. SCI can lead to structural and functional changes below the injury level that may predispose individuals to tissue breakdown. As a result, pressure ulcers can significantly affect the quality of life, including pain, infection, altered body image, and even mortality. (2) Clinically, wheelchair power seat function, i.e., tilt and recline, is recommended for relieving sitting-induced pressures. The goal is to increase skin blood flow for the ischemic soft tissues to avoid irreversible damage. Due to variations in the level and completeness of SCI, the effectiveness of using wheelchair tilt and recline to reduce pressure ulcer risks has considerable room for improvement. Our previous study indicated that the blood flow of people with SCI may respond very differently to wheelchair tilt and recline settings. In this study, we propose to use the artificial neural network (ANN) to predict how wheelchair power seat functions affect blood flow response to seating pressure. This is regression learning because the predicted outputs are numerical values. Besides the challenging nature of regression learning, ANN may suffer from the overfitting problem which, when occurring, leads to poor predictive quality (i.e., cannot generalize). We propose using the particle swarm optimization (PSO) algorithm to train ANN to mitigate the impact of overfitting so that ANN can make correct predictions on both existing and new data. Experimental results show that the proposed approach is promising to improve ANN's predictive quality for new data. PMID- 23366965 TI - Optimization of magnetic neurostimulation waveforms for minimum power loss. AB - Magnetic stimulation is a key tool in experimental brain research and several clinical applications. Whereas coil designs and the spatial field properties have been intensively studied in the literature, the temporal dynamics of the field has received little attention. The available pulse shapes are typically determined by the relatively limited capabilities of commercial stimulation devices instead of efficiency or optimality. Furthermore, magnetic stimulation is relatively inefficient with respect to the required energy compared to other neurostimulation techniques. We therefore analyze and optimize the waveform dynamics with a nonlinear model of a mammalian motor axon for the first time, without any pre-definition of waveform candidates. We implemented an unbiased and stable numerical algorithm using variational calculus in combination with a global optimization method. This approach yields very stable results with comprehensible characteristic properties, such as a first phase which reduces ohmic losses in the subsequent pulse phase. We compare the energy loss of these optimal waveforms with the waveforms generated by existing magnetic stimulation devices. PMID- 23366966 TI - The effect of visual cues on the number and duration of freezing episodes in Parkinson's patients. AB - Freezing of gait is a phenomenon common in Parkinson's patients and significantly affects quality of life. Sensory cues have been known to improve walking performance and reduce freezing of gait. Visual cues are reported to be particularly effective for this purpose. So far, sensory cues have generally been provided continuously, even when currently not needed. However, a recent approach suggests the provision of cues just in the case that freezing actually occurs. The arguments in favor of this "on-demand" cueing are reduced intrusiveness and reduced habituation to cues. Here, we analyzed the effect of visual cues on the number and duration of freezing episodes when activated either just "on-demand" or continuously and compare it to the baseline condition where no cue is provided. For this purpose, 7 Parkinson's patients regularly suffering from freezing of gait repeatedly walked a pre-defined course and their reaction to parallel laser lines projected in front of them on the floor was analyzed. The results show that, in comparison to the baseline condition, the mean duration of freezing was reduced by 51% in continuous cueing and by 69% in "on-demand" cueing. Concerning the number of freezing episodes, 43% fewer episodes were observed for continuous cueing and 9% less episodes for "on-demand" cueing. PMID- 23366967 TI - Impact of obstructive sleep apnea on sleep-wake stage ratio. AB - Patients with obstructive sleep apnea (OSA) experience fragmented sleep and exhibit different sleep architectures. While polysomnographic metrics for quantifying sleep architecture are studied, there is little information about the impact of OSA on the ratio of different sleep-wake stages (wake, W; rapid eye movement, REM; non-REM stages 1 to 3, N1 to N3). This study, therefore, aims to investigate the relationship between apnea-hypopnea index (AHI, a measure of OSA severity) and all possible ratios of sleep-wake stages. Sleep architectures of 24 adult subjects with suspected OSA were constructed according to the American Academy of Sleep Medicine scoring manual, and subsequently analyzed through various correlation (Pearson, Spearman, and Kendall) and regression (linear, logarithmic, exponential, and power-law) approaches. Results show a statistically significant positive, linear and monotonic correlation between AHI and REM/N3, as well as between AHI and N1/W (p-values < 0.05). These findings imply that patients with increased severity of OSA may spend more time in REM than deep sleep, and in light sleep than wake (or less time in deep sleep than REM, and in wake than light sleep). A power-law regression model may possibly explain the relationships of AHI-REM/N3 and AHI-N1/W, and predict the value of AHI using REM/N3 or N1/W. PMID- 23366968 TI - Consistency of sleep restoration gain (SRG) as a measure for assessing sleep quality. AB - We propose a new sleep quality measure that assesses the sleep restorative gain of a polysomnography sleep record. In this preliminary investigation, we derive this new measure from manually scored sleep hypnograms. We compare the proposed measure to classical sleep indices such as TST, SE, and ArI, and demonstrate its self-consistency and degree of correlation with these measures. Using 47 sleep records from publicly available sleep databases, we graphically and quantitatively demonstrate the effectiveness of the proposed measure in summarizing the hypnogram of a sleep record. PMID- 23366969 TI - Indication of abnormal peripheral sensory processing of rotational stimulation in ADHD. AB - Attention Deficit Hyperactivity Disorder (ADHD) has been associated with motor abnormalities. Given the importance of the vestibular system in motor control, the investigation of the peripheral vestibular response is a promising area of ADHD research, which could lead to an improved understanding and management of the disorder. This study aimed to investigate the evoked peripheral vestibular response to rotational stimuli in ADHD affected adults, using Electrovestibulography (EVestG). Data was collected from 6 ADHD affected adults (2 males, 4 females) and contrasted with that of a Control group comprised of 30 individuals (10 males, 20 females). Raw data was 120 Hz high pass filtered and analyzed using the Neural Event Extraction Routine to identify local field potentials, which represent the summed activity of the components of the inner ear. The inter field potential intervals (IFPI) were calculated as the time intervals between field potentials. Analysis of the IFPI indicated that the ADHD group exhibited significantly shorter periods between field potentials generated in the right ear during left rotational acceleration than Controls (unpaired, two tailed Student's t-test assuming unequal variance, p<0.05). However there was no significant difference between groups for left ear signal during right rotational acceleration. This preliminary study provides an indication as to the possibility of lateralized, abnormal inner ear responses to kinematic stimuli in the ADHD affected population. However, further studies are required to validate and elucidate this data. PMID- 23366971 TI - Aging curve of neuromotor function by pronation and supination of forearms using three-dimensional wireless acceleration and angular velocity sensors. AB - We have developed an evaluation system for pronation and supination of forearms. The motion of pronation and supination of the forearm is used as a diagnosis method of developmental disability, etc. However, this diagnosis method has a demerit in which diagnosis results between doctors are not consistent. It is hoped that a more quantitative and simple evaluation method is established. Moreover it is hoped a diagnostic criteria obtained from healthy subjects can be established to diagnose developmental disorder patients. We developed a simple and portable evaluation system for pronation and supination of forearms. Three dimensional wireless acceleration and angular velocity sensors are used for this system. In this study, pronation and supination of forearms of 570 subjects (subjects aged 6-12, 21-100) were examined. We could obtain aging curves in the neuromotor function of pronation and supination. These aging curves obtained by our developed system, has the potential to become diagnostic criteria for a developmental disability, etc. PMID- 23366970 TI - The auditory p300-based SSBCI: a door to minimally conscious patients? AB - In this study we report on the evaluation of a novel auditory single-switch BCI in nine patients diagnosed with MCS. The task included a simple and a complex oddball paradigm, the latter uses the tone stream segregation phenomenon. In all patients a significant difference between deviant and frequent tones could be observed in EEG. However, in some cases the deviant tones produce a significant negative peak and in some a very late positive peak. These preliminary findings are relevant in order to address future customization of this auditory ssBCI based paradigm for unresponsive patients. PMID- 23366972 TI - Effect of hypothermia on the thalamocortical function in the rat model. AB - Neuroprotective effects of hypothermia are well documented in many injuries of the central nervous system in animal models as well as clinical studies. However, the underlying mechanisms are not fully understood. An important yet unexplored background issue is the effect of hypothermic cooling on the regional functionality of the healthy CNS. In a pilot study with the rat model, we seek to characterize the effect of moderate bodily cooling on the thalamo-cortical (T-C) function. Multiunit activity (MUA) and local field potentials (LFPs) were recorded from the thalamus (VPL nucleus) and the somatosensory cortex (S1) for normothermic, mild hypothermic and mild hyperthermic conditions in healthy rats and the thalamo-cortical dynamics was characterized with Granger Causal Interaction (GCI). The GCI indicated that the thalamic driving of the cortical activity significantly increases in strength with bodily cooling and weakens with mild heating. These results could have important implications towards understanding of hypothermia. PMID- 23366973 TI - A network analysis of the dynamics of seizure. AB - Seizures are events that spread through the brain's network of connections and create pathological activity. To understand what is occurring in the brain during seizure we investigated the time progression of the brain's state from seizure onset to seizure suppression. Knowledge of a seizure's dynamics and the associated spatial structure is important for localizing the seizure foci and determining the optimal location and timing of electrical stimulation to mitigate seizure development. In this study, we analyzed intracranial EEG data recorded in 2 human patients with drug-resistant epilepsy prior to undergoing resection surgery using network analyses. Specifically, we computed a time sequence of connectivity matrices from iEEG (intracranial electroencephalography) recordings that represent network structure over time. For each patient, connectivity between electrodes was measured using the coherence in the band of frequencies with the strongest modulation during seizure. The connectivity matrices' structure was analyzed using an eigen-decomposition. The leading eigenvector was used to estimate each electrode's time dependent centrality (importance to the network's connectivity). The electrode centralities were clustered over the course of each seizure and the cluster centroids were compared across seizures. We found, for each patient, there was a consistent set of centroids that occurred during each seizure. Further, the brain reliably evolved through the same progression of states across multiple seizures including characteristic onset and suppression states. PMID- 23366974 TI - Seizure detection on/off system using rats' ECoG. AB - We present an enhanced algorithm for seizure onset and offset detection in rats' ECoG. Because a seizure in rats' ECoG evolves much more stereotypically than that in human, analyzing seizure evolution in rats' ECoG is advantageous to understanding the evolution process. The proposed algorithm outperforms a prior automatic seizure detection and termination system in in-vivo rats' ECoG. We improve the algorithm by using relevant frequency bands of 14-22 Hz to onsets and 7-45 Hz to offsets; by using spectral power rather than spectral amplitudes for its feature; and by replacing the 2-point moving-average filter for postprocessing with a 2(nd) order Kalman filter. Not only does the proposed algorithm provide better detection statistics, but it lowers the system's complexity by no longer requiring computation of a fast Fourier transform and by using a single structure with the two different spectral power features for onset and offset detection. PMID- 23366975 TI - Assessing traumatic brain injuries using EEG power spectral analysis and instantaneous phase. AB - Although mild traumatic brain injury (mTBI) occurs commonly, little is known about how multiple mTBI incidents accumulate over time to produce serious morbidity or how the extent of injury can be quantified. This work presents a rat model that uses deceleration-induced brain trauma and an implantable EEG system for recording injury-induced changes in brain activity. Specifically, we present an analysis method to assess and quantify mTBI by combining information derived from EEG power spectral analysis and EEG phase shifts. We found that in different frequency bands, both EEG power spectra and the instantaneous phases of the two EEG channels before the impact were different from those measured after the impact. This study shows that EEG analysis can be used as a tool to identify and assess brain related injuries. PMID- 23366976 TI - Study on differentiation factors for main disease identification of intermittent claudication. AB - Intermittent Claudication is a walking symptom. After a short time walking, patients suffer from pains at lower limbs. But if taking a rest, the pains can be relieved and they can walk again. Unfortunately, it arises from not one but mainly two kinds of diseases: LSS (lumber spinal canal stenosis) and PAD (peripheral arterial disease). Additionally, it is reported that symptom is similar and LSS groups is furthermore divided into two main groups: L4 and L5 groups. Therefore, it is clinically very important to differentiate which diseases the patients suffer from, PAD, L4 or L5. We aims at developing the system to differentiate them from short walking motion data. In our previous paper, we derived differentiation factors, but did not consider the difference between L4 and L5 and the results are limited. This paper focuses on biarticular muscles associated with the diseases, and derive new and effective differentiation factors. The results supports their effectiveness and validity. PMID- 23366977 TI - Circuit topology and control principle for a first magnetic stimulator with fully controllable waveform. AB - Magnetic stimulation pulse sources are very inflexible high-power devices. The incorporated circuit topology is usually limited to a single pulse type. However, experimental and theoretical work shows that more freedom in choosing or even designing waveforms could notably enhance existing methods. Beyond that, it even allows entering new fields of application. We propose a technology that can solve the problem. Even in very high frequency ranges, the circuitry is very flexible and is able generate almost every waveform with unrivaled accuracy. This technology can dynamically change between different pulse shapes without any reconfiguration, recharging or other changes; thus the waveform can be modified also during a high-frequency repetitive pulse train. In addition to the option of online design and generation of still unknown waveforms, it amalgamates all existing device types with their specific pulse shapes, which have been leading an independent existence in the past years. These advantages were achieved by giving up the common basis of all magnetic stimulation devices so far, i.e., the high-voltage oscillator. Distributed electronics handle the high power dividing the high voltage and the required switching rate into small portions. PMID- 23366979 TI - Time-varying functional connectivity for understanding the neural basis of behavioral microsleeps. AB - Episodes of complete failure to respond during attentive tasks--lapses of responsiveness ('lapses')--accompanied by behavioral signs of sleep such as slow eye-closure are known as behavioral microsleeps (BMs). The occurrence of BMs can have serious/fatal consequences, particularly in the transport sectors, and therefore further investigations on neurophysiological correlates of BMs are highly desirable. In this paper we propose a combination of High Resolution EEG techniques and an advanced method for time-varying functional connectivity estimation for reconstructing the temporal evolution of causal relations between cortical regions of BMs occurring during a visuomotor tracking task. The preliminary results highlight connectivity patterns involving parietal and fronto parietal areas both preceding and following the onset of a BM. PMID- 23366978 TI - Measuring MERCI: exploring data mining techniques for examining the neurologic outcomes of stroke patients undergoing endo-vascular therapy at Erlanger Southeast Stroke Center. AB - Mechanical Embolus Removal in Cerebral Ischemia (MERCI) has been supported by medical trials as an improved method of treating ischemic stroke past the safe window of time for administering clot-busting drugs, and was released for medical use in 2004. The importance of analyzing real-world data collected from MERCI clinical trials is key to providing insights on the effectiveness of MERCI. Most of the existing data analysis on MERCI results has thus far employed conventional statistical analysis techniques. To the best of our knowledge, advanced data analytics and data mining techniques have not yet been systematically applied. To address the issue in this thesis, we conduct a comprehensive study on employing state of the art machine learning algorithms to generate prediction criteria for the outcome of MERCI patients. Specifically, we investigate the issue of how to choose the most significant attributes of a data set with limited instance examples. We propose a few search algorithms to identify the significant attributes, followed by a thorough performance analysis for each algorithm. Finally, we apply our proposed approach to the real-world, de-identified patient data provided by Erlanger Southeast Regional Stroke Center, Chattanooga, TN. Our experimental results have demonstrated that our proposed approach performs well. PMID- 23366980 TI - EEG-informed fMRI analysis during a hand grip task. AB - In the last decade, an increasing interest has arisen in investigating the relationship between the electrophysiological and hemodynamic measurements of brain activity, such as EEG and (BOLD) fMRI. In particular, changes in BOLD have been shown to be associated with changes in the spectral profile of neuronal activity, rather than with absolute neural power. On the other hand, though, recent findings showed that different EEG rhythms are independently related to changes in the BOLD signal: therefore, it would be important to distinguish between the contributions of the different EEG rhythms to BOLD fluctuations when modeling the relationship between EEG and BOLD. Here we proposed a novel method to perform EEG-informed fMRI analysis, so that the EEG regressors take into account both the changes in the spectral profile and the rhythms distinction. We applied it to EEG-fMRI data during a bimanual motor task in healthy subjects, and compared the results with those obtained by regressing fMRI data onto a single regressor covering the entire range of frequencies, ignoring the distinction between different EEG rhythms. Our results showed that the proposed method better captures the correlations between BOLD signal and EEG rhythms modulations, identifying task-related well localized activated volumes. PMID- 23366981 TI - Prefrontal cortical activation during arithmetic processing differentiated by cultures: a preliminary fNIRS study. AB - Understanding the neural basis of arithmetic processes could play an important role in improving mathematical education. This study investigates the prefrontal cortical activation among subjects from different cultural backgrounds while performing two difficulty levels of mental arithmetic tasks. The prefrontal cortical activation is measured using a high density 206 channels fNIRS. 8 healthy subjects, consisting of 5 Asians and 3 Europeans, are included in this study. NIRS-SPM is used to compute hemoglobin response changes and generate brain activation map based on two contrasts defined as Easy versus Rest and Hard versus Rest. Differences between the Asian group and the European group are found in both contrasts of Easy versus Rest and Hard versus Rest. The results suggest people with different cultural backgrounds engage different neural pathways during arithmetic processing. PMID- 23366982 TI - Automatic detection of burst synchrony in preterm infants. AB - Electroencephalographic characteristics are useful in assessment of the functional status of specific neuronal connections relative to postmenstrual age. Interhemispheric burst synchrony (IBS) is a measure of the functional connectivity between the hemispheres in the maturing preterm brain. An algorithm was developed to assess IBS and was used in a prospective, longitudinal EEG study on 18 very preterm infants (< 32 weeks gestational age) with normal follow-up at 2 years of age. The preterm infants underwent weekly 4-hour multi-channel EEG recordings, resulting in n = 77 EEGs. After automated detection of bursts, the algorithm defines the start and end of interhemispheric synchronous burst activity, based on selection criteria found in literature. The algorithm was designed to emulate visual inspection, providing objective results in an automated manner. This approach may be applied in clinical use and open novel avenues to automated analysis in EEG monitoring and, moreover, it may facilitate assessment of the functional status of interhemispheric connections. As such, assessment of low interhemispheric synchrony may be associated with brain injury. PMID- 23366983 TI - Tangram solved? Prefrontal cortex activation analysis during geometric problem solving. AB - Recent neuroimaging studies have implicated prefrontal and parietal cortices for mathematical problem solving. Mental arithmetic tasks have been used extensively to study neural correlates of mathematical reasoning. In the present study we used geometric problem sets (tangram tasks) that require executive planning and visuospatial reasoning without any linguistic representation interference. We used portable optical brain imaging (functional near infrared spectroscopy--fNIR) to monitor hemodynamic changes within anterior prefrontal cortex during tangram tasks. Twelve healthy subjects were asked to solve a series of computerized tangram puzzles and control tasks that required same geometric shape manipulation without problem solving. Total hemoglobin (HbT) concentration changes indicated a significant increase during tangram problem solving in the right hemisphere. Moreover, HbT changes during failed trials (when no solution found) were significantly higher compared to successful trials. These preliminary results suggest that fNIR can be used to assess cortical activation changes induced by geometric problem solving. Since fNIR is safe, wearable and can be used in ecologically valid environments such as classrooms, this neuroimaging tool may help to improve and optimize learning in educational settings. PMID- 23366984 TI - Differences in hemodynamic activations between motor imagery and upper limb FES with NIRS. AB - A brain-computer interface (BCI) based on near-infrared spectroscopy (NIRS) could act as a tool for rehabilitation of stroke patients due to the neural activity induced by motor imagery aided by real-time feedback of hemodynamic activation. When combined with functional electrical stimulation (FES) of the affected limb, BCI is expected to have an even greater benefit due to the contingency established between motor imagery and afferent, haptic feedback from stimulation. Yet, few studies have explored such an approach, presumably due to the difficulty in dissociating and thus decoding the hemodynamic response (HDR) between motor imagery and peripheral stimulation. Here, for the first time, we demonstrate that NIRS signals elicited by motor imagery can be reliably discriminated from those due to FES, by first performing a univariate analysis of the NIRS signals, and subsequently by multivariate pattern classification. Our results showing that robust classification of motor imagery from the rest condition is possible support previous findings that imagery could be used to drive a BCI based on NIRS. More importantly, we demonstrate for the first time the successful classification of motor imagery and FES, indicating that it is technically feasible to implement a contingent NIRS-BCI with FES. PMID- 23366985 TI - Cortical potential imaging of somatosensory evoked potential induced by mechanical stimulation. AB - The objective evaluation of somatic sensations is expected without a patient's subjective opinions to reduce social problems such as those related to lawsuits for nerve injuries or malingering. In this study, the somatosensory evoked potential (SEP) using the mechanical stimulations of the tactile sensation was measured and analyzed in spatiotemporal domains. The cortical potential mapping projected onto the realistic-shaped model was estimated to improve the spatial resolution of the SEP maps by application of cortical dipole layer imaging. The experimentally obtained results suggest that the spatiotemporal distributions of the SEPs reflect the differences for positions, strengths, and patterns of somatosensory stimulations. PMID- 23366986 TI - Application of wavelet based denoising techniques to rTMS evoked potentials. AB - This paper presents a new method of removing noise from the EEG response signal recorded during repetitive transcranial magnetic stimulation (rTMS). This noise is principally composed of the residual stimulus artifact and mV amplitude compound muscle action potentials recorded from the scalp muscles and precludes analysis of the cortical evoked potentials, especially during the first 15 ms post stimulus. The method uses the wavelet transform with a fourth order Daubechies mother wavelet and a novel coefficient reduction algorithm based on cortical amplitude thresholds. The approach has been tested and two methods of coefficient reduction compared using data recorded during a study of cortical sensitivity to rTMS at different scalp locations. PMID- 23366987 TI - EEG frontal asymmetry related to pleasantness of music perception in healthy children and cochlear implanted users. AB - Interestingly, the international debate about the quality of music fruition for cochlear implanted users does not take into account the hypothesis that bilateral users could perceive music in a more pleasant way with respect to monolateral users. In this scenario, the aim of the present study was to investigate if cerebral signs of pleasantness during music perception in healthy child are similar to those observed in monolateral and in bilateral cochlear implanted users. In fact, previous observations in literature on healthy subjects have indicated that variations of the frontal EEG alpha activity are correlated with the perceived pleasantness of the sensory stimulation received (approach withdrawal theory). In particular, here we described differences between cortical activities estimated in the alpha frequency band for a healthy child and in patients having a monolateral or a bilateral cochlear implant during the fruition of a musical cartoon. The results of the present analysis showed that the alpha EEG asymmetry patterns observed in a healthy child and that of a bilateral cochlear implanted patient are congruent with the approach-withdrawal theory. Conversely, the scalp topographic distribution of EEG power spectra in the alpha band resulting from the monolateral cochlear user presents a different EEG pattern from the normal and bilateral implanted patients. Such differences could be explained at the light of the approach-withdrawal theory. In fact, the present findings support the hypothesis that a monolateral cochlear implanted user could perceive the music in a less pleasant way when compared to a healthy subject or to a bilateral cochlear user. PMID- 23366988 TI - Common Spatial Pattern Patches: online evaluation on BCI-naive users. AB - Brain-Computer Interfaces (BCI) based on the voluntary modulation of sensorimotor rhythms (SMRs) induced by motor imagery are very prominent because allow a continuous control of the external device. Nevertheless, the design of a SMR based BCI system that provides every user with a reliable BCI control from the first session, i.e., without extensive training, is still a big challenge. Considerable advances in this direction have been made by the machine learning co adaptive calibration approach, which combines online adaptation techniques with subject learning in order to offer the user a feedback from the beginning of the experiment. Recently, based on offline analyses, we proposed the novel Common Spatial Patterns Patches (CSPP) technique as a good candidate to improve the co adaptive calibration. CSPP is an ensemble of localized spatial filters, each of them optimized on subject-specific data by CSP analysis. Here, the evaluation of CSPP in online operation is presented for the first time. Results on three BCI naive participants show indeed promising results. All three users reach the threshold criterion of 70% accuracy within one session, even one candidate for whom the weak SMR at rest predicted deficient BCI control. Concurrent recordings of the SMR during a relax condition as well as the course of BCI performance indicate a clear learning effect. PMID- 23366989 TI - Kinect-based detection of self-paced hand movements: enhancing functional brain mapping paradigms. AB - Monitoring and interpreting (sub)cortical reorganization after stroke may be useful for selecting therapies and improving rehabilitation outcome. To develop computational models that predict behavioral motor improvement from changing brain activation pattern, we are currently working on the implementation of a clinically feasible experimental set-up, which enables recording high quality electroencephalography (EEG) signals during inpatient rehabilitation of upper and lower limbs. The major drawback of current experimental paradigms is the cue guided repetitive design and the lack of functional movements. In this paper, we assess the usability of the Kinect device (Microsoft Inc., Redmond, WA, USA) for tracking self-paced hand opening and closing movements. Three able-bodied volunteers performed self-paced right hand open-close movement sequences while EEG was recorded from sensorimotor areas and electromyography (EMG) from the right arm from extensor carpi radialis and flexor carpi radialis muscles. The results of the study suggest that the Kinect device allows generation of trigger information that is comparable to the information that can be obtained from EMG. PMID- 23366990 TI - Cortical activity and functional hyperconnectivity by simultaneous EEG recordings from interacting couples of professional pilots. AB - Controlling an aircraft during a flight is a compelling condition, which requires a strict and well coded interaction between the crew. The interaction level between the Captain and the First Officer changes during the flight, ranging from a maximum (during takeoff and landing, as well as in case of a failure of the instrumentation or other emergency situations) to a minimum during quiet mid flight. In this study, our aim is to investigate the neural correlates of different kinds and levels of interaction between couples of professional crew members by means of the innovative technique called brain hyperscanning, i.e. the simultaneous recording of the hemodynamic or neuroelectrical activity of different human subjects involved in interaction tasks. This approach allows the observation and modeling of the neural signature specifically dependent on the interaction between subjects, and, even more interestingly, of the functional links existing between the brain activities of the subjects interacting together. In this EEG hyperscanning study, different phases of a flight were reproduced in a professional flight simulator, which allowed, on one side, to reproduce the ecological setting of a real flight, and, on the other, to keep under control the different levels of interaction induced in the crew by means of systematic and simulated failures of the aircraft instrumentation. Results of the procedure of linear inverse estimation, together with functional hyperconnectivity estimated by means of Partial Directed Coherence, showed a dense network of connections between the activity in the two brains in the takeoff and landing phases, when the cooperation between the crew is maximal, while conversely no significant links were shown during the phases in which the activity of the two pilots was independent. PMID- 23366991 TI - Measuring cognition delay caused by gaze movement toward the direction of depth. AB - It is difficult to judge from face images and/or from biological signal (such as brain waves) what the driver's state of cognition is. This paper reports experiments measuring the state of cognition accompanied with gaze movement in the direction of depth. While measuring the cognition time, the experimental setup was able to measure the effect of gaze movement in the direction of depth. When the locations of displays were changed, there was no significant difference in the reaction time for the reflective/discriminative experiment. Experiments conducted to know gaze depth movement show a trend where the longer the gaze moving distance becomes, the more the discernment time increases. Results also show that it takes much more time in moving gaze toward far in the direction of depth as opposed to moving toward the near. PMID- 23366992 TI - A navigation system for the visually impaired an intelligent white cane. AB - In this paper, we describe about a developed navigation system that supports the independent walking of the visually impaired in the indoor space. Our developed instrument consists of a navigation system and a map information system. These systems are installed on a white cane. Our navigation system can follow a colored navigation line that is set on the floor. In this system, a color sensor installed on the tip of a white cane, this sensor senses a color of navigation line and the system informs the visually impaired that he/she is walking along the navigation line by vibration. This color recognition system is controlled by a one-chip microprocessor. RFID tags and a receiver for these tags are used in the map information system. RFID tags are set on the colored navigation line. An antenna for RFID tags and a tag receiver are also installed on a white cane. The receiver receives the area information as a tag-number and notifies map information to the user by mp3 formatted pre-recorded voice. And now, we developed the direction identification technique. Using this technique, we can detect a user's walking direction. A triaxiality acceleration sensor is used in this system. Three normal subjects who were blindfolded with an eye mask were tested with our developed navigation system. All of them were able to walk along the navigation line perfectly. We think that the performance of the system is good. Therefore, our system will be extremely valuable in supporting the activities of the visually impaired. PMID- 23366994 TI - Brain dynamics of mathematical problem solving. AB - The purpose of this study is to examine brain activities of participants solving mental math problems. The research investigated how problem difficulty affected the subjects' responses and electroencephalogram (EEG) in different brain regions. In general, it was found that solution latencies (SL) to the math problems increased with difficulty. The EEG results showed that across subjects, the right-central beta, left-parietal theta, left-occipital theta and alpha, right-parietal alpha and beta, medial-frontal beta and medial central theta power decreased as task difficulty increased. This study further explored the effects of problem-solving performance on the EEG. Slow solvers exhibited greater frontal theta activities in the right hemisphere, whereas an inverse pattern of hemispheric asymmetry was found in fast solvers. Furthermore, analyses of spatio temporal brain dynamics during problem solving show progressively stronger alpha- and beta-power suppression and theta-power augmentation as subjects were reaching a solution. These findings provide a better understanding of cortical activities mediating math-based problem solving and knowledge acquisition that can ultimately benefit math learning and education. PMID- 23366995 TI - Effect of inclined support surface on postural strategy during anterior-posterior platform translations. AB - Previous studies have reported that postural coordination patterns change as a function of translation frequency. However, the effect of inclined support surface on postural strategy was not clear. Therefore, the purpose of this study is to investigate the influence of inclined support surface on postural strategy during platform translations. Eight healthy adults maintained their balance in stance during support surface translations in the anterior-posterior direction at two different frequencies (0.2 and 0.8[Hz]) and at three different base of support condition (LV: Level, TD: Toe Down, TU: Toe Up). For the kinematic data at slow frequency, subjects rode the platform depending on the movement of platform itself, while at fast frequency subjects fixed their head and center of mass (COM) in space. For the kinetic data at slow frequency, the ankle moment amplitude is similar among all support surface conditions, while at fast frequency the ankle moment amplitude for TU is significantly larger than LV. Result shown that the effect of inclined surface on postural strategy changed according to frequency of support surface translations. PMID- 23366996 TI - Effects of 2D/3D visual feedback and visuomotor collocation on motor performance in a Virtual Peg Insertion Test. AB - This paper evaluates the influence of three different types of visual feedback on the motor performance of healthy subjects during the repeated execution of a Virtual Peg Insertion Test developed for the assessment of sensorimotor function of arm and hand in neurologically impaired subjects. One test trial consists of the grasping and insertion of 9 pegs into 9 holes using a haptic display with instrumented grasping handle. Three groups performed 10 trials initially on three different setups (group 1 with standard 2D visual feedback, group 2 with 3D, and group 3 with collocated 3D visual feedback) followed by 10 more trials with the setup with 2D visual feedback. The total execution time and the mean collision force as well as the time and the collision force for 6 different movement phases were compared between groups and analyzed in function of the number of repetitions. Results showed significantly lower time to approach and align the visual cursor with the peg with the 2D setup over the first 10 trials compared to the two other groups, suggesting limitations of the 3D setup. Furthermore, a significant decrease of the total execution time was found in the first 10 trials for all groups. For the 10 following trials, only group 3 showed a significant decrease in the total execution time, suggesting that the learning did not transfer to the 2D setup for this group. PMID- 23366997 TI - A re-examination of the time constant of the oculomotor neural integrator in human. AB - We studied the horizontal oculomotor neural integrator in healthy human subjects during gaze holding in darkness. We found large variability among subjects with respect to the estimated time constants and the integrator's null position. We also found that individual subjects could demonstrate significantly nonlinear drift velocities as a function of eye position. Nevertheless, a consistent trend did not emerge. Consequently, cross subject averaging eliminates idiosyncratic nonlinear patterns and the average can be approximated by a linear function inside the range that was tested. PMID- 23366998 TI - Feature extraction for psychophysiological load assessment in unconstrained scenarios. AB - The relevance of psychophysiological measurements for affective computing and emotion analysis applications has been widely recognized. However, and although several authors have studied the informative content of parameters derived from cardiovascular and other modalities, feature extraction remains an open topic in the field. This is particularly relevant in scenarios where the autonomic nervous system triggering stimuli are unknown. In this paper, we analyze a set of features extracted from multimodal biosignal data, applicable to the assessment of psychophysiological load in unconstrained settings. Experimental evaluation is performed on real world data, collected both from control subjects and subjects with a strong clinical background, in a context of questionnaire-based clinical history reporting. The devised feature set has shown promising properties, making it prone to complement the more traditional measurements. PMID- 23366999 TI - Upper extremity biomechanical model for evaluation of pediatric joint demands during wheelchair mobility. AB - Current methods for evaluating upper extremity (UE) dynamics during pediatric wheelchair use are limited. We propose a new model to characterize UE joint kinematics and kinetics during pediatric wheelchair mobility. The bilateral model is comprised of the thorax, clavicle, scapula, upper arm, forearm, and hand segments. The modeled joints include: sternoclavicular, acromioclavicular, glenohumeral, elbow and wrist. The model is complete and is currently undergoing pilot studies for clinical application. Results may provide considerable quantitative insight into pediatric UE joint dynamics to improve wheelchair prescription, training and long term care of children with orthopaedic disabilities. PMID- 23367000 TI - Real-time index for predicting successful golf putting motion using multichannel EEG. AB - A skill in goal-directed sport performance is an ability involving with many factors of both external and internal concernment. External factors are still developed while internal factors are challenged topic to understand for improving the performance. Internal concernment is explained an effective performance as estimation, solving strategy, planning and decision on the brain. These conjunctions are relevant to somatosensory information, focus attention and fine motor control of cortical activity. Five skilled right-handed golfers were recruited to be subjected of studying the criteria on how to predict golf putt success. Each of their putts was calculated in power spectral analysis by comparing to the pre-movement period. Successful and unsuccessful putt were classified by focusing on the frontal-midline(Fz), parietal-midline(Pz), central midline(Cz), left central(C3) and right central(C4) which supported by few consistency studies that they are related to a primary sensory motor area, focus attention and working memory processing. Results were shown that high alpha power on C4, theta power on Fz, theta power and high alpha power on Pz can be calculated to use as index of predicting golf putt success. Real-time monitoring system with friendly GUI was proposed in this study as promising preliminary study. Expected goal in the future is to apply this real-time golf putting prediction system into a biofeedback system to increase the golf putting's accuracy. However, it still needs more subjects to increase credibility and accuracy of the prediction. PMID- 23367001 TI - Characteristic activities of lower limbs with body weight support ratio. AB - In this study, we investigated a lower limbs muscle activity during body weight support treadmill training (BWSTT). Informed consent was obtained from 16 healthy men. Experimental system consists of force plate, treadmill, three-dimensional motion analysis system, electromyograph, and body weight support device. Body weight support (BWS) was set every 15% increase from 0% to 45%. Walking speed was 4.17 km/h. The measurement data were reaction forces, joint angles, joint moments and lower limbs muscle activities. The vertical reaction force shows two peaks. Two peaks decreased with increase of BWS together. Joint angles did not show significant changes with BWS. However, only the extension of hip angle was decreased with BWS. The peaks of joint moment were decreased. Decrease of ankle joint moment was greatest compared with other moment. Decrease of peaks of muscle activity by BWS was observed during stance phase, and did not almost change during swing phase. PMID- 23367002 TI - Evaluation of vision-based head-trackers for assistive devices. AB - This paper presents a new evaluation methodology for assistive devices employing head-tracking systems based on an adaptation of the Fitts Test. This methodology is used to compare the effectiveness and performance of a new vision-based head tracking system using face, skin and motion detection techniques with two existing head tracking devices and a standard mouse. The application context and the abilities of the user are combined with the results from the modified Fitts Test to help determine the most appropriate devices for the user. The results suggest that this modified form of the Fitts test can be effectively employed for the comparison of different access technologies. PMID- 23367003 TI - The effect of aging on brain temporal perception using Virtual Reality Neurocognitive (VRN) experiments. AB - This paper reports a study conducted to assess brain temporal perception across different age groups. A novel Virtual Reality Neurocognitive (VRN) test, which consists of catching a virtual bouncing ball with a paddle, was employed. A total of 44 volunteers with no cognitive impairments and 3 individuals diagnosed with depression but cognitively healthy, in the age range of 19 to 82 years, participated in this study. Results show that the ability to accurately perceive time deteriorates with age. PMID- 23367004 TI - Design of a Virtual Reality Navigational (VRN) experiment for assessment of egocentric spatial cognition. AB - Virtual reality (VR) experiments are commonly used to assess human brain functions. We orient ourselves in an environment by computing precise self-to object spatial relations (egocentric orientation) as well as object-to-object spatial relations (allocentric orientation). Egocentric orientation involves cues that depend on the position of the observer (i.e. left-right, front-behind), whereas allocentric orientation is maintained through the use of environmental features such as landmarks. As such, allocentric orientation involves short-term memory, whereas egocentric orientation does not. This paper presents a Virtual Reality Navigational (VRN) experiment specifically designed to assess egocentric spatial cognition. The design aimed to minimize the effect of spatial cues or landmarks for human navigation in a naturalistic VR environment. The VRN experiment designed for this study, called the Virtual House, is a symmetric three story cubic building, with 3 windows on each side on every floor, and one entrance on each side of the building. In each trial, a window is marked by a pseudo-random sequence as the objective. The marked window is shown to the participant from an outdoor view. The task is to reach the objective window using the shortest path through the building. The experiment entails 2 sets of 8 trials to cover all possibilities. The participants' performance error is measured by the difference between their traversed distance trajectory and the shortest natural distance (calculated using the VR engine), normalized by the shortest distance, in each trial. Fifty-two cognitively healthy adults participated in the study. The results show no learning effect during the 16 trails, implying that the experiment does not rely on short-term memory. Furthermore, the subjects' normalized performance error showed an almost linear increase with age, implying that egocentric spatial cognition ability declines with age. PMID- 23367005 TI - Simulation of human walking with powered orthosis for designing practical assistive device. AB - To design a powered assistive orthosis for human walking, we have simulated walking motion with an orthosis. The model dynamics of the coupled human-orthosis is represented by a 10-rigid-link system. In this model there exist rotational joints at lumbar, both thighs and both legs for orthosis, and each joints are controlled by a couple of central pattern generators (CPG) which imitates neuronal system in the spinal cord of mammals. The CPG controller modeled by 18 oscillators which have the sensory feedbacks and generates the joint torques to move the skeletal model of the coupled human-orthosis. This means that we use five actuators for controlling orthosis in the both of sagittal and frontal plane. The parameters of the CPG and the connecting gains are optimized by using a genetic algorithm. We have achieved the successful simulation of stable walking against disturbances with this model. The simulation results indicate the possibility of a practical assistive orthosis with five active joints for stable walking. PMID- 23367006 TI - Torque and power outputs on skilled and unskilled users during manual wheelchair propulsion. AB - Manual wheelchair users are at a high risk of pain and injuries to the upper extremities due to mechanical inefficiency of wheelchair propulsion motion. The kinetic analysis of the upper extremities during manual wheelchair propulsion in various conditions needed to be investigated. We developed and calibrated a wheelchair dynamometer for measuring kinetic parameters during propulsion. We utilized the dynamometer to investigate and compare the propulsion torque and power values of skilled and unskilled users under four different conditions. Skilled manual wheelchair users generated lower torques with more power than unskilled users and reacted alertly and sensitively to changing conditions. We expect that these basic methods and results may help to quantitatively evaluate the mechanical efficiency of manual wheelchair propulsion. PMID- 23367007 TI - Simulation of tremor on 3-dimentional musculoskeletal model of wrist joint and experimental verification? AB - A musculoskeletal model that allows to simulate the tremor of wrist joint with three degrees of freedom (DoFs) is developed. The model includes five muscles, extensor carpi radialis brevis, extensor carpi radialis longus, extensor carpi ulnaris, flexor carpi radialis and flexor carpi ulnaris. Simulation of tremor generation based on the 3-DoF model is performed. The tremor disorder can be generated in two directions: flexion-extension and radia-ulnar deviation. Accordingly, experiment is conducted on healthy subjects to verify the feasibility of artificial tremor generation via functional electrical stimulation (FES). Simulation results have shown qualitative agreement with the experimental results. PMID- 23367008 TI - Parameter estimation of the Huxley cross-bridge muscle model in humans. AB - The Huxley model has the potential to provide more accurate muscle dynamics while affording a physiological interpretation at cross-bridge level. By perturbing the wrist at different velocities and initial force levels, reliable Huxley model parameters were estimated in humans in vivo using a Huxley muscle-tendon complex. We conclude that these estimates may be used to investigate and monitor changes in microscopic elements of muscle functioning from experiments at joint level. PMID- 23367009 TI - Contribution of arm swing to dynamic stability based on the nonlinear time series analysis method. AB - It is human nature to swing their arms at the frequency of leg motion during walking, but the contribution of arm swing to dynamic stability of human motion segments was poorly understood. Based on the nonlinear time series analysis method, the objective of this study was to investigate the effects of arm swing in three conditions (natural, active and restricted arm swing) on the dynamic stability of spine and lower extremity joints, and to further assess the contribution of arm swing to the human dynamic stability in relation with age. Gait experiments were carried out for 10 young and 8 middle-aged healthy volunteers while walking with natural, active and restricted arm swing. The maximum finite time lyapunov exponents were calculated to quantify the local dynamic stability of spine and lower extremity joints under three arm swing conditions, and the percentage change of the maximum Lyapunov exponents was compared between two groups to evaluate the effectiveness of active arm swing in relation with age. For both young and middle-aged groups, no significant difference of the maximum lyapunov exponents of all motion segments was found between walking with natural arm swing and with restricted arm swing (P>0.05). However, the maximum lyapunov exponents of all motion segments while walking with active arm swing was significantly lower than those while walking with natural arm swing and restricted arm swing, respectively (P<0.05), and the percentage decrease of the maximum lyapunov exponents for all motion segments while walking with active arm swing was significantly higher in middle-aged group than in young group (P<0.05). These results indicated that active arm swing would help to improve dynamic stability of human motion segments, especially more effective with age. PMID- 23367010 TI - Analyzing gait pathologies using a depth camera. AB - In this paper, we present a new approach to construct a 3D human skeleton model, which is then used to quantify gait pathologies, using a depth camera. First, thanks to the depth map, we obtain a human depth silhouette in 3D, from which our method is based to estimate each body part position. Second, the angle between the upper and lower legs of the 3D skeleton model is calculated. Finally, we show that using only this angle information is enough to quantify motion asymmetry. This result has been verified through an experimental study with 3 different subjects. Due to its advantages (simple, markerless and low-cost), this method is a promising solution for gait clinics in the future. PMID- 23367011 TI - Markerless identification of key events in gait cycle using image flow. AB - Gait analysis has been an interesting area of research for several decades. In this paper, we propose image-flow-based methods to compute the motion and velocities of different body segments automatically, using a single inexpensive video camera. We then identify and extract different events of the gait cycle (double-support, mid-swing, toe-off and heel-strike) from video images. Experiments were conducted in which four walking subjects were captured from the sagittal plane. Automatic segmentation was performed to isolate the moving body from the background. The head excursion and the shank motion were then computed to identify the key frames corresponding to different events in the gait cycle. Our approach does not require calibrated cameras or special markers to capture movement. We have also compared our method with the Optotrak 3D motion capture system and found our results in good agreement with the Optotrak results. The development of our method has potential use in the markerless and unencumbered video capture of human locomotion. Monitoring gait in homes and communities provides a useful application for the aged and the disabled. Our method could potentially be used as an assessment tool to determine gait symmetry or to establish the normal gait pattern of an individual. PMID- 23367012 TI - Three dimensional visualization of the statically equivalent serial chain from kinect recording. AB - We develop and present a portable tool intended for real time estimation of the center of mass (CoM) in human subjects. Using the statically equivalent serial chain (SESC) method we can account for subject specificity after identification of the model's parameters. CoM position estimates are then available from measurements of the subject's limbs orientations. For portability, we make use of widely accessible sensors such as the Kinect and Wii balance board for identification. Use of the Kinect as a measurement device allows us to establish the SESC outside of the laboratory, without many special considerations on the environment. Only Kinect is used for CoM tracking after identification was performed. We present here an overview of the SESC concept and the identification procedure. The aspects involved in the visualization tool are discussed and results are shown in order to verify the performance. PMID- 23367013 TI - 4D human body posture estimation based on a motion capture system and a multi rigid link model. AB - Human motion analysis in various fields such as neurophysiology, clinical medicine, and sports sciences utilizes a multi-rigid link model of a human body for considering kinetics by solving inverse dynamics of a motion, in which a motion capture system with reflective markers are often used to measure the motion, and then the obtained motion are mapped onto the multi-rigid link model. However, algorithms for such a mapping from spatio-temporal positions of the markers to the corresponding posture of the model are not always fully disclosed. Moreover, a common difficulty for such algorithms is an error caused by displacements of the markers attached on the body surface, referred to as the skin motion error. In this study, we developed a simple algorithm that maps positions of the markers to the corresponding posture of a rigid link model, and examined accuracy of the algorithm by evaluating quantitatively differences between the measured and the estimated posture. We also analyzed the skin motion error. It is shown that magnitude of the error was determined not only by the amplitude of the skin motion, but also by the direction of the marker displacement relative to the frame of reference attached to each segment of the body. PMID- 23367014 TI - Real-time measurement of rectus femoris muscle kinematics during drop jump using ultrasound imaging: a preliminary study. AB - We have developed an office based vector tissue Doppler imaging (vTDI) that can be used to quantitatively measure muscle kinematics using ultrasound. The goal of this preliminary study was to investigate if vTDI measures are repeatable and can be used robustly to measure and understand the kinematics of the rectus femoris muscle during a drop jump task. Data were collected from 8 healthy volunteers. Vector TDI along with a high speed camera video was used to better understand the dynamics of the drop jump. Our results indicate that the peak resultant vector velocity of the rectus femoris immediately following landing was repeatable across trials (intraclass correlation coefficient=0.9).The peak velocity had a relatively narrow range in 6 out of 8 subjects (48-62 cm/s), while in the remaining two subjects it exceeded 70 cm/s. The entire drop jump lasted for 1.45 0.27 seconds. The waveform of muscle velocity could be used to identify different phases of the jump. Also, the movement of the ultrasound transducer holder was minimal with peak deflection of 0.91 0.54 degrees over all trials. Vector TDI can be implemented in a clinical setting using an ultrasound system with a research interface to better understand the muscle kinematics in patients with ACL injuries. PMID- 23367015 TI - Analysis of biomechanical data to determine the degree of users participation during robotic-assisted gait rehabilitation. AB - Recent studies have shown evidence indicating that effective robotic rehabilitation is only possible when the user actively participates during training. Providing a complete effective biofeedback to the patient representing his compliance to the therapy and his performance is thought that his active participation will be enhanced significantly, thus, improving his rehabilitation. We have performed a study with the driven gait orthosis (DGO) Lokomat (Hocoma AG, Volketswil, Switzerland). The objective of the present study is the analysis of the effect of different types of participation (attention to the functional task) from subjects receiving robotic assisted gait training on the kinematic and kinetic patterns. The obtained results provide useful evidence of specific biomechanical features that can be used to design more useful, robust, focused and intuitive biomechanical biofeedback during robotic assisted gait rehabilitation in stroke survivors. PMID- 23367016 TI - Development of an evaluation system for foot arch types in the elderly using foot pressure distribution data. AB - The foot arch serves important functions related to shock absorption and the action of walking. Simple and quantitative classifications of foot arch types, such as flat feet and high arches, help to provide health support services for the elderly. To develop an evaluation system for foot arch types using foot pressure distribution data, discriminant analyses were conducted using data from healthy elderly persons. The midfoot pressure ratio was selected and discriminants were derived. For evaluating the performance of the classification method, the derived discriminants were applied to the data from the other group of healthy elderly persons. Results indicate that both sensitivity and specificity of the classified foot arch types were sufficiently high. PMID- 23367017 TI - 3D volumetric muscle modeling for real-time deformation analysis with FEM. AB - Computer simulation is promising numerical tool to study muscle volumetric deformations. However, most models are facing very long computation time and thus are based on simplified wire Hill muscle model. The purpose of this study is to develop a real-time three-dimensional biomechanical model of volumetric muscle based on modified Hill model for the active stress which is controlled from EMG recordings. Finite element model is used to estimate the passive behavior of the muscle and tendons during contraction. We demonstrate that this 3D model implementation is very cost effective with respect to the computation time and the simulation gives good results compared to real measured data. Thus, this effective implementation will allow implementing much more complex and realistic models considering the muscle as volumetric continuum, with moderate computation time. PMID- 23367018 TI - A novel objective function for predicting reasonable muscle forces in subject specific model. AB - Objective functions in adjusting model parameters have been widely used to minimize the variance of joint moments, but it may be insufficient to estimate reasonable muscle forces. The purpose of this study was to introduce a novel objective function based on a correlation coefficient for predicting reliable muscle forces, and compare its performance to the existing objective function. A man with right-sided hemiparesis after stroke participated in the study, and performed the maximum voluntary isometric contractions with a dynamometer at an angular velocity of 30 degrees /s. To compare the effects of the existing and the new objective functions on prediction of muscle forces, the relative root-mean square error and correlation coefficient were calculated for joint moments and individual muscle forces. The new objective function yielded promising results, implying that it could potentially be used to estimate reliable muscle forces. In the future, this approach will be applied to various movements to determine the reliability of muscle forces and to understand mechanisms from the reliable muscle forces. PMID- 23367019 TI - Investigation of the role of crimps in collagen fibers in tendon with a microstructually based finite element model. AB - Tendon has a hierarchical structure that links tendon, fascicle, fibre and fibrils. In particular tendon fibres are made up of fibrils that have distinctive wavy forms called crimps. Experimental and imaging studies have shown that this crimp pattern plays an important role in mechanical properties of tendon but its exact influence has not been identified. We have developed a micro finite element model of tendon that contains accurate crimp patterns embedded in the model. This model utilizes a unique material coordinate system that is aligned in the direction of fibres. The crimp was implemented by performing fibre fitting procedure, which aligns the material coordinate system according to the crimp angle. FE analysis study was performed to identify the influence of crimp morphology on stress distribution pattern in tendon. Introduction of crimp angle to the model produced heterogeneous deformation and stress transfer patterns whereas the one without any crimp patterns predicted a uniform stress pattern. Future works include parametric studies on the influence of crimp pattern and morphology on stress distribution pattern in the tissue. PMID- 23367020 TI - Development and testing of patient-specific knee replacements. AB - This study presents a design methodology for designing and manufacturing patient specific unicompartmental knee replacements. The design methodology uses mathematical modeling and an artificial neural network to predict the original and healthy articulating surfaces of a patient's knee. The models are combined with medical images from the patient to create a knee prosthesis that is patient specific. These patient-specific implants are then compared to conventional implants with respect to contact stresses and kinematics. The patient-specific implant experienced lower contact stresses at the tibiofemoral joint compared to a fixed-bearing design. Both the UKRs showed similar kinematic patterns to the normal knee using two different test rigs. The patient-specific UKR showed good results and with the other benefits it shows potential to dramatically improve clinical outcomes of knee replacement surgery. PMID- 23367021 TI - Relationship between ankle stiffness structure and muscle activation. AB - This paper presents a characterization of the structure of ankle stiffness under multiple levels of muscle activation and the relationship between them. A multi variable impedance estimation method using a wearable ankle robot enabled clear identification of ankle stiffness structure in the space consisting of the sagittal and frontal planes. With visual feedback showing current and target muscle activation levels, all subjects could successfully maintain multiple target levels (5%~30% of the maximum voluntary contraction level). Stiffness increased with muscle activation, but the increase was more pronounced in the dorsiflexion-plantarflexion direction than in the inversion-eversion direction, which resulted in a characteristic "peanut" shape. The relation between measured muscle activation level and ankle stiffness was evaluated. All subjects showed a highly linear relation not only for the two principal axis directions of the ankle, i.e., dorsiflexion-plantarflexion and inversion-eversion, but also for the average stiffness value of all directions. These major findings were consistent both for the tibialis anterior and triceps surae activation. PMID- 23367022 TI - Validation of a subject specific 3-actuator torque-driven model in human vertical jumping. AB - In this study, a forward dynamic subject specific 3-actuator torque-driven model of the human musculoskeletal system was created based on measurements of individual characteristics of a subject. Simulation results were compared with experimental vertical squat jumping with and without adding weights. By analyzing kinematic and kinetic experimental data at the instant of the toe-off for the same initial conditions, it was shown that a simple computer simulation using a suitable cost function could reproduce the real task performed by humans. This investigation is the first step in a wider project that will incorporate elastic components, and that will evaluate the advantages of the individual subject approach in modeling. PMID- 23367023 TI - Development and in vitro evaluation of an artificial spinal disc loading cell. AB - One of the common diseases for chronic low back pain is Disc Degeneration Disease (DDD). In this disease, spinal intervertebral disc loses its ability to safely handle the mechanical stresses. The knowledge of the in-vivo loading on the spinal disk is of great importance in the understanding of low back pain. In this study a loading cell has been developed utilizing an artificial spinal disc which was loaded with strain gauges and piezoresistive sensors in an effort to investigate the behavior of the sensors during in vitro loading of the disc. The artificial disc with all sensors was loaded in a laboratory environment. The in vitro loading produced reliable and repeatable results and therefore suggesting that such approach might aid in the development of an artificial intelligent disc which will contribute in the better understanding of the in vivo loading of the human spine. PMID- 23367024 TI - A robust classification scheme for detection of food intake through non-invasive monitoring of chewing. AB - Automatic methods for food intake detection are needed to objectively monitor ingestive behavior of individuals in a free living environment. In this study, a pattern recognition system was developed for detection of food intake through the classification of jaw motion. A total of 7 subjects participated in laboratory experiments that involved several activities of daily living: talking, walking, reading, resting and food intake while being instrumented with a wearable jaw motion sensor. Inclusion of such activities provided a high variability to the sensor signal and thus challenged the classification task. A forward feature selection process decided on the most appropriate set of features to represent the chewing signal. Linear and RBF Support Vector Machine (SVM) classifiers were evaluated to find the most suitable classifier that can generalize the high variability of the input signal. Results showed that an average accuracy of 90.52% can be obtained using Linear SVM with a time resolution of 15 sec. PMID- 23367025 TI - Consistency and validity of self-reporting scores in stress measurement surveys. AB - Stress has been attributed to physiological and psychological demands that exceed the natural regulatory capacity of a person. Chronic stress is not only a catalyst for diseases such as hypertension, diabetes, insomnia but may also lead to social problems such as marriage breakups, suicide and violence. Objective assessment of stress is difficult so self-reports are commonly used to indicate the severity of stress. However, empirical information on the validity of self reports is limited. The present study investigated the authenticity and validity of different self-report surveys. An analysis, based on a three-pronged strategy, was performed on these surveys. It was concluded that although subjects are prone to systematic error in reporting, self-reports can provide a useful substitute for data modeling specifically in stress evaluation where other objective assessments such as determination of stress using only physiological response are difficult. PMID- 23367026 TI - A linear, time-invariant model for cancerous and normal breast tissue. AB - Electrical properties of biological cells and human tissue have been used to characterize cancerous vs. normal tissue. Commonly, measured dielectric spectra (permittivity and conductivity) are fitted into an empirical function and the best-fit parameters of the function are considered as a tool to differentiate various types of tissue; however, these parameters do not provide any explanation for the underlying molecular structure. In this work, we modeled the frequency dependence of impedance data collected from human breast tissue using a high order, linear, time-invariant filter. The results show that the parameters of the filter not only can be used to classify tissue types, they may provide meaningful information about the properties and structure of tissues. PMID- 23367027 TI - Source analysis of median nerve stimulated somatosensory evoked potentials and fields using simultaneously measured EEG and MEG signals. AB - The sources of somatosensory evoked potentials (SEPs) and fields (SEFs), which is a standard paradigm, is investigated using multichannel EEG and MEG simultaneous recordings. The hypothesis that SEP & SEF sources are generated in the posterior bank of the central sulcus is tested, and analyses are compared based on EEG only, MEG only, bandpass filtered MEG, and both combined. To locate the sources, the forward problem is first solved by using the boundary-element method for realistic head models and by using a locally-fitted-sphere approach for averaged head models consisting of a set of connected volumes, typically representing the skull, scalp, and brain. The location of each dipole is then estimated using fixed MUSIC and current-density-reconstruction (CDR) algorithms. For both analyses, the results demonstrate that the band-pass filtered MEG can localize the sources accurately at the desired region as compared to only EEG and unfiltered MEG. For CDR analysis, it looks like MEG affects EEG during the combined analyses. The MUSIC algorithm gives better results than CDR, and when comparing the two head models, the averaged and the realistic head models showed the same result. PMID- 23367028 TI - Role of vestibular sensor on body sway control: coherence between head acceleration and stabilogram. AB - This work aims at evaluating the role of the vestibular system in the postural sway control using the coherence function. A sample of 19 young, healthy male adults was monitored with a three axial accelerometer placed over the head during a stabilometric test, standing on a force platform during 3 min in four conditions: eyes closed and open, and feet apart and together. The magnitude squared coherence (MSC) function and Monte Carlo simulation was used to correlate changes in body sway with head accelerations. Significant MSC values were found in the frequency range 0.1-0.5 Hz, mainly in conditions of larger oscillations: eyes closed and feet together. These results may be related to utricular otoliths responses and ankle strategy. PMID- 23367029 TI - Using NIRS as a predictor for EEG-based BCI performance. AB - Multimodal recordings of EEG and NIRS of 14 subjects are analyzed in the context of sensory-motor based Brain Computer Interface (BCI). Our findings indicate that performance fluctuations of EEG-based BCI control can be predicted by preceding Near-Infrared Spectroscopy (NIRS) activity. These NIRS-based predictions are then employed to generate new, more robust EEG-based BCI classifiers, which enhance classification significantly, while at the same time minimize performance fluctuations and thus increase the general stability of BCI performance. PMID- 23367030 TI - Temporal evolution of seizure burden for automated neonatal EEG classification. AB - The aim of this paper is to use recent advances in the clinical understanding of the temporal evolution of seizure burden in neonates with hypoxic ischemic encephalopathy to improve the performance of automated detection algorithms. Probabilistic weights are designed from temporal locations of neonatal seizure events relative to time of birth. These weights are obtained by fitting a skew normal distribution to the temporal seizure density and introduced into the probabilistic framework of the previously developed neonatal seizure detector. The results are validated on the largest available clinical dataset, comprising 816.7 hours. By exploiting these priors, the ROC area is increased by 23% (relative) reaching 96.75%. The number of false detections per hour is decreased from 0.72 to 0.36, while maintaining the correct detection of seizure burden at 75%. PMID- 23367031 TI - Dynamic time warping based neonatal seizure detection system. AB - Neonatal seizures patterns evolve with changing frequency, morphology and propagation. This study is an initial attempt to incorporate the characteristics of temporal evolution of neonatal seizures into our developed neonatal seizure detector. The previously designed SVM-based neonatal seizure detector is modified by substituting the Gaussian kernel with the Gaussian dynamic time warping kernel, to enable the SVM to classify variable length sequences of feature vectors of neonatal seizures. The preliminary results obtained compare favorably with the conventional SVM. The fusion of the two approaches is expected to improve the current state of the art neonatal seizure detection system. PMID- 23367032 TI - Selection of abnormal neural oscillation patterns associated with sentence-level language disorder in Schizophrenia. AB - Language disorder is one of the core symptoms in schizophrenia. We propose a new framework based on machine intelligence techniques to investigate abnormal neural oscillations related to this impairment. Schizophrenia patients and healthy control subjects were instructed to discriminate semantically and syntactically correct sentences from syntactically correct but semantically incorrect sentences presented visually, and 248-channel MEG signals were recorded with a whole head machine during the task performance. Oscillation patterns were extracted from the MEG recordings in 8 frequency sub-bands throughout sentence processing, which form a large feature set. A two-step feature selection algorithm combining F score filtering and Support Vector Machine recursive feature elimination (SVM RFE) was designed to pick out a small subset of features which could discriminate patients and controls with high accuracy. We achieved a 90.48% prediction accuracy based on the selected top features, following the leave-one-out cross validation procedure. These top features provide interpretable spectral, spatial, and temporal information about the electrophysiological basis of sentence processing abnormality in schizophrenia which may help understand the underlying mechanism of this disease. PMID- 23367033 TI - Dynamic SVM detection of tremor and dyskinesia during unscripted and unconstrained activities. AB - In this paper, we report an experimental comparison of dynamic support vector machines (SVMs) to dynamic neural networks (DNNs) in the context of a system for detecting dyskinesia and tremor in Parkinson's disease (PD) patients wearing accelerometer (ACC) and surface electromyographic (sEMG) sensors while performing unscripted and unconstrained activities of daily living. These results indicate that SVMs and DNNs of comparable computational complexities yield approximately identical performance levels when using an identical set of input features. PMID- 23367035 TI - Obstructive sleep apnea detection using SVM-based classification of ECG signal features. AB - Sleep apnea is the instance when one either has pauses of breathing in their sleep, or has very low breath while asleep. This pause in breathing can range in frequency and duration. Obstructive sleep apnea (OSA) is the common form of sleep apnea, which is currently tested through polysomnography (PSG) at sleep labs. PSG is both expensive and inconvenient as an expert human observer is required to work over night. New sleep apnea classification techniques are nowadays being developed by bioengineers for most comfortable and timely detection. This paper focuses on an automated classification algorithm which processes short duration epochs of the electrocardiogram (ECG) data. The presented classification technique is based on support vector machines (SVM) and has been trained and tested on sleep apnea recordings from subjects with and without OSA. The results show that our automated classification system can recognize epochs of sleep disorders with a high accuracy of 96.5% or higher. Furthermore, the proposed system can be used as a basis for future development of a tool for OSA screening. PMID- 23367034 TI - On the challenge of classifying 52 hand movements from surface electromyography. AB - The level of dexterity of myoelectric hand prostheses depends to large extent on the feature representation and subsequent classification of surface electromyography signals. This work presents a comparison of various feature extraction and classification methods on a large-scale surface electromyography database containing 52 different hand movements obtained from 27 subjects. Results indicate that simple feature representations as Mean Absolute Value and Waveform Length can achieve similar performance to the computationally more demanding marginal Discrete Wavelet Transform. With respect to classifiers, the Support Vector Machine was found to be the only method that consistently achieved top performance in combination with each feature extraction method. PMID- 23367036 TI - Patch-based automatic retinal vessel segmentation in global and local structural context. AB - In this paper, we extend our published work [1] and propose an automated system to segment retinal vessel bed in digital fundus images with enough adaptability to analyze images from fluorescein angiography. This approach takes into account both the global and local context and enables both vessel segmentation and microvascular centreline extraction. These tools should allow researchers and clinicians to estimate and assess vessel diameter, capillary blood volume and microvascular topology for early stage disease detection, monitoring and treatment. Global vessel bed segmentation is achieved by combining phase invariant orientation fields with neighbourhood pixel intensities in a patch based feature vector for supervised learning. This approach is evaluated against benchmarks on the DRIVE database [2]. Local microvascular centrelines within Regions-of-Interest (ROIs) are segmented by linking the phase-invariant orientation measures with phase-selective local structure features. Our global and local structural segmentation can be used to assess both pathological structural alterations and microemboli occurrence in non-invasive clinical settings in a longitudinal study. PMID- 23367037 TI - Detection of neovascularization in the optic disc using an AM-FM representation, granulometry, and vessel segmentation. AB - Neovascularization, defined as abnormal formation of blood vessels in the retina, is a sight-threatening condition indicative of late-stage diabetic retinopathy (DR). Ischemia due to leakage of blood vessels causes the body to produce new and weak vessels that can lead to complications such as vitreous hemorrhages. Neovascularization on the disc (NVD) is diagnosed when new vessels are located within one disc-diameter of the optic disc. Accurately detecting NVD is important in preventing vision loss due to DR. This paper presents a method for detecting NVD in digital fundus images. First, a region of interest (ROI) containing the optic disc is manually selected from the image. By adaptively combining contrast enhancement methods with a vessel segmentation technique, the ROI is reduced to the regions indicated by the segmented vessels. Textural features extracted by using amplitude-modulation frequency-modulation (AM-FM) techniques and granulometry are used to differentiate NVD from a normal optic disc. Partial least squares is used to perform the final classification. Leave-one-out cross validation was used to evaluate the performance of the system with 27 NVD and 30 normal cases. We obtained an area under the receiver operator characteristic curve (AUC) of 0.85 by using all features, increasing to 0.94 with feature selection. PMID- 23367038 TI - Automatic detection of the macula in retinal fundus images using seeded mode tracking approach. AB - The macula is the part of the eye responsible for central high acuity vision. Detection of the macula is an important task in retinal image processing as a landmark for subsequent disease assessment, such as for age-related macula degeneration. In this paper, we have presented an approach to automatically determine the macula centre in retinal fundus images. First contextual information on the image is combined with a statistical model to obtain an approximate macula region of interest localization. Subsequently, we propose the use of a seeded mode tracking technique to locate the macula centre. The proposed approach is tested on a large dataset composed of 482 normal images and 162 glaucoma images from the ORIGA database and an additional 96 AMD images. The results show a ROI detection of 97.5%, and 90.5% correct detection of the macula within 1/3DD from a manual reference, which outperforms other current methods. The results are promising for the use of the proposed approach to locate the macula for the detection of macula diseases from retinal images. PMID- 23367039 TI - Automatic localization of retinal landmarks. AB - Retinal landmark detection is a key step in retinal screening and computer-aided diagnosis for different types of eye diseases, such as glaucomma, age-related macular degeneration(AMD) and diabetic retinopathy. In this paper, we propose a semantic image transformation(SIT) approach for retinal representation and automatic landmark detection. The proposed SIT characterizes the local statistics of a fundus image and boosts the intrinsic retinal structures, such as optic disc(OD), macula. We propose our salient OD and macular models based on SIT for retinal landmark detection. Experiments on 5928 images show that our method achieves an accuracy of 99.44% in the detection of OD and an accuracy of 93.49% in the detection of macula, while having an accuracy of 97.33% for left and right eye classification. The proposed SIT can automatically detect the retinal landmarks and be useful for further eye-disease screening and diagnosis. PMID- 23367040 TI - Image-level tortuosity estimation in wide-field retinal images from infants with Retinopathy of Prematurity. AB - Tortuosity and dilation of retinal vessels are considered of primary importance for the diagnosis and follow-up of the Retinopathy of Prematurity (ROP) disease. We developed an algorithm to estimate vessel tortuosity in images acquired with a wide-field fundus camera in ROP subjects, offering clinicians a quantitative, objective, and reproducible diagnostic parameter. Vessels were manually traced in 20 images to provide error-free input data for the tortuosity estimation. At first we investigated different vessel-level measures, some including also caliber information. Then we used them to obtain different imagelevel tortuosity measures, which were eventually combined in a supervised approach to provide a tortuosity index capable to reproduce the clinical experts assessment.To provide manual assessment, the 20 images were independently ordered by increasing tortuosity by three clinical graders and three retinal imaging experts. The proposed tortuosity index obtains a Spearman's correlation coefficient of 0.95 with ground truth, a performance comparable to the clinical graders' one and better than the retinal imaging experts' one. PMID- 23367041 TI - Motion-based video retrieval with application to computer-assisted retinal surgery. AB - In this paper, we address the problem of computer-aided ophthalmic surgery. In particular, a novel Content-Based Video Retrieval (CBVR) system is presented : given a video stream captured by a digital camera monitoring the current surgery, the system retrieves, within digital archives, videos that resemble the current surgery monitoring video. The search results may be used to guide surgeons' decisions, for example, let the surgeon know what a more experienced fellow worker would do in a similar situation. With this goal, we propose to use motion information contained in MPEG- 4 AVC/H.264 video standard to extract features from videos. We propose two approaches, one of which is based on motion histogram created for every frame of a compressed video sequence to extract motion direction and intensity statistics. The other combine segmentation and tracking to extract region displacements between consecutive frames and therefore characterize region trajectories. To compare videos, an extension of the fast dynamic time warping to multidimensional time series was adopted. The system is applied to a dataset of 69 video-recorded retinal surgery steps. Results are promising: the retrieval efficiency is higher than 69%. PMID- 23367042 TI - Regional cardiac function assessment in 4D CT: comparison between SQUEEZ and ejection fraction. AB - Recent advances in computed tomography (CT) imaging technology allow fine anatomical structures such as endocardial trabeculae to be resolved. We have developed a method to detect and track such features on the endocardium to extract a measure that reflects local myocardial contraction with minimal human operator interaction. The relative motion of these surface features were used to represent the local contraction of the endocardial surface with a metric we termed "stretch quantifier of endocardial engraved zones" (SQUEEZ). The results were compared against CT function analysis software available through the scanner vendor. SQUEEZ showed significant difference between infarct and remote regions (p<0.0001) as verified by delayed enhanced magnetic resonance imaging. The vendor software showed inferior spatial resolution and stair-step artifacts in regional function maps. PMID- 23367043 TI - Automatic image-based retrospective gating of interventional cardiac X-ray images. AB - Gating of X-ray fluoroscopy images is required for catheter reconstruction for registration of pre-procedural images with fluoroscopy for guidance and biophysical modelling. We propose a novel and clinically useful retrospective method for automatic image-based cardiac and respiratory motion gating. The technique is based on tracking and statistical analysis of the shape of the coronary sinus catheter. We applied our method on five mono-plane imaging sequences comprising a total of 322 frames from five different patients undergoing radiofrequency ablation for the treatment of atrial fibrillation. We established systole, end-inspiration and end-expiration gating with success rates of 100%, 89.47% and 81.25% respectively. PMID- 23367044 TI - PET-CT based automated lung nodule detection. AB - An automatic method is presented in order to detect lung nodules in PET-CT studies. Using the foreground and background mean ratio independently in every nodule, we can detect the region of the nodules properly. The size and intensity of the lesions do not affect the result of the algorithm, although size constraints are present in the final classification step. The CT image is also used to classify the found lesions built on lung segmentation. We also deal with those cases when nearby and similar nodules are merged into one by a split-up post-processing step. With our method the time of the localization can be decreased from more than one hour to maximum five minutes. The method had been implemented and validated on real clinical cases in Interview Fusion clinical evaluation software (Mediso). Results indicate that our approach is very effective in detecting lung nodules and can be a valuable aid for physicians working in the daily routine of oncology. PMID- 23367045 TI - Detecting tuberculosis in radiographs using combined lung masks. AB - Tuberculosis (TB) is a major health threat in many regions of the world, while diagnosing tuberculosis still remains a challenge. Mortality rates of patients with undiagnosed TB are high. Modern diagnostic techniques are often too slow or too expensive for highly-populated developing countries that bear the brunt of the disease. In an effort to reduce the burden of the disease, this paper presents an automated approach for detecting TB on conventional posteroanterior chest radiographs. The idea is to provide developing countries, which have limited access to radiological services and radiological expertise, with an inexpensive detection system that allows screening of large parts of the population in rural areas. In this paper, we present results produced by our TB screening system. We combine a lung shape model, a segmentation mask, and a simple intensity model to achieve a better segmentation mask for the lung. With the improved masks, we achieve an area under the ROC curve of more than 83%, measured on data compiled within a tuberculosis control program. PMID- 23367046 TI - Optimal cutoff threshold for calcium quantification in isotropic CT calcium scans by validating against registered intravascular ultrasound with radiofrequency backscatter. AB - 3D Computed Tomography (CT) provides noninvasive, low-radiation method of coronary artery calcium (CAC) measurement. Conventional CAC images are acquired on multidetector-row CT scanners without contrast, and reconstructed with 3 mm slice thickness. The calcium volume is quantified by registering voxels with attenuation values greater than or equal to 130 Hounsfield Unit (HU). In isotropic CAC images with 0.5 mm slice thickness obtained from 320-detector row CT, the optimal value of attenuation cutoff threshold is unknown. In this paper we find the optimal cutoff threshold for calcium quantification in isotropic CT calcium scans by validating against registered intravascular ultrasound with radiofrequency backscatter (IVUS/VH). From the statistical analysis of calcium data obtained from the images of 9 patients we found a range of optimal thresholds and the conventional threshold of 130 HU was in the range. Further, the optimal values were different for individual patients. PMID- 23367047 TI - Effects of aging on thoracic aorta size and shape: a non-contrast CT study. AB - Measures of atherosclerosis burden like coronary artery calcification are performed using non-contrast heart CT. However, additional information can be derived from these studies, looking beyond the coronary arteries without exposing the patients to further radiation. We present a semi-automated method to assess ascending, arch and descending aorta geometry from non-contrast CT datasets in 250 normotensive patients. We investigated the effect of aging on thoracic aorta morphometry. The algorithm identifies the aortic centerline coordinates following a toroidal path for the curvilinear portion and axial planes for descending aorta. Then it reconstructs oblique planes orthogonal to the centerline direction and a circle fitting process estimates the vessel cross-section. Finally, global thoracic aorta dimensions (diameter, volume and length) and shape (vessel curvature and tortuosity, aortic arch width and height) are calculated. From a multivariate analysis, adjusted for gender and body-size area, aortic volume and arch width were the descriptors that better represented the aortic size and shape alterations with aging. The thoracic aorta suffers an expanding and unfolding process with aging that deserves further attention to prevent aortic aneurisms. PMID- 23367048 TI - CMOS biosensor system for on-chip cell culture with read-out circuitry and microfluidic packaging. AB - A 1.5 mm * 3 mm CMOS chip with sensors for monitoring on-chip cell cultures has been designed. The chip is designed in a 0.5 um CMOS process which has 3 metal layers and 2 poly layers and is a 5 volt process. The chip contains ion sensitive field effect transistors (ISFETs), as well as ISFETs with read-out circuitry, for monitoring the pH of solutions placed on top of the chip. Interdigitated electrode structures (IDESs) are made using the top metal of the process to be used for sensing cellular attachment and proliferation via impendence. IDES read out circuits and IDES test structures are included. The chip also contains test amplifiers, bandgap reference test structures, and connections for post processing. We designed the chip to accommodate packaging into an environment where it will be directly exposed to a cell culture environment. Specifically we designed the chip to have the incorporated sensors near the center of the chip allowing for connections made around the edge of the chip to be sealed off using an epoxy or similar material to prevent shorting. Preliminary electrical characterization results for our amplifier indicate a gain of 48 dB, a bandwidth of 1.65 kHz, and a common mode rejection ratio (CMRR) of 72 dB. We also present a packaging technique using a flexible pcb substrate. PMID- 23367049 TI - A low noise, non-contact capacitive cardiac sensor. AB - The development of sensitive, non-contact electric field sensors to measure weak bioelectric signals will be useful for the development of a number of unobtrusive health sensors. In this paper we summarize our recent work on a number of specific challenges in the development of non-contact ECG sensors. First, we considered the design of a low noise sensor preamplifier. We have adapted circuit designs that incorporate a double feedback loop to cancel the input transistor leakage current while providing stable operation, fast settling time and good low frequency response without the need for ultrahigh value resistors. The measured input referred noise of the preamplifier in the frequency band 0.05-100 Hz is 0.76 uV(rms), which is several times lower than existing ECG preamplifiers. PMID- 23367050 TI - Tunable and label-free bacteria alignment using standing surface acoustic waves. AB - This paper describes a new technique for focusing bacteria in a microfluidic channel and subsequently controlling their trajectory. Bacteria alignment is obtained using standing surface acoustic waves (SSAW) generated by two interdigitated transducer electrodes (IDTs) patterned on a piezoelectric wafer. The bacteria are focused in the standing wave pressure nodes, separated by half a wavelength, the electrode geometry and applied voltage frequency being chosen accordingly. Interestingly, the position of a pressure node can be modulated by introducing a phase shift between the electrical signals applied to both IDTs. The bacteria, trapped in this node, follow it and can therefore be deflected. This technique works with label-free bacteria in their culture medium and induces low power consumption, which is very interesting for portable devices. PMID- 23367051 TI - Detecting particles flowing through interdigitated 3D microelectrodes. AB - Counting cells in a large microchannel remains challenging and is particularly critical for in vitro assays, such as cell adhesion assays. This paper addresses this issue, by presenting the development of interdigitated three-dimensional electrodes, which are fabricated around passivated pillarshaped silicon microstructures, to detect particles in a flow. The arrays of micropillars occupy the entire channel height and detect the passage of the particle through their gaps by monitoring changes in the electrical resistance. Impedance measurements were employed in order to characterize the electrical equivalent model of the system and to detect the passage of particles in real-time. Three different geometrical micropillar configurations were evaluated and numerical simulations that supported the experimental activity were used to characterize the sensitive volume in the channel. Moreover, the signal-to-noise-ratio related to the passage of a single particle through an array was plotted as a function of the dimension and number of micropillars. PMID- 23367052 TI - A microwave powered injectable neural stimulator. AB - An unexpectedly simple implantable device that can achieve wireless neurostimulation consists of a short 1 cm long dipole platinum wire antenna, a Schottky diode, and a pulsed microwave transmitter. Fabricated into a 1 cm long by polyimide tubing, the implant can have a sub-millimeter diameter form factor suited to introduction into tissue by injection. Experiments that chronically implant the device next to a rat sciatic nerve show that a 915 MHz microwave transmitter emitting an average power of 0.5 watts has an ability to stimulate motor events when spaced up to 7 cm from the body surface. Tissue models consisting of saline filled tanks show the possibility of delivering milliampere pulsed current to neurosimulators though 5 centimeters or more of tissue. Such a neurostimulation system driven by microwave energy is limited in functional tissue depth by microwave SAR exposure. This report discusses some of the advantages and limitations of such a neurostimulation approach. PMID- 23367053 TI - A novel sensorized shoe system to classify gait severity in children with cerebral palsy. AB - The clinical management of children with Cerebral Palsy (CP) relies upon periodic assessments of changes in the severity of gait deviations in response to clinical interventions. Current clinical practice is limited to sporadic assessments in a clinical environment and hence it is limited in its ability to estimate the impact of CP-related gait deviations in real-life conditions. Frequent home-based quantitative assessments of the severity of gait deviations would be extremely useful in scheduling clinical visits and gathering feedback about the effectiveness of intervention strategies. The use of a wearable system would allow clinicians to gather information about the severity of gait deviations in the home setting. In this paper, we present ActiveGait, a novel sensorized shoe based system for monitoring gait deviations. The ActiveGait system was used to gather data, under supervised and unsupervised conditions, from a group of 11 children with various levels of CP-related gait deviation severities. We present a methodology to derive severity measures based on features extracted from Center of Pressure (CoP) trajectories. Results show that a Random Forest classifier is able to estimate severity scores based on the Edinburgh Visual Scale with a level of accuracy >80% adequate for clinical use. PMID- 23367054 TI - Wireless pilot monitoring system for extreme race conditions. AB - This paper presents the design and implementation of an assistive device to monitor car drivers under extreme conditions. In particular, this system is designed in preparation for the 2012 Atacama Solar Challenge to be held in the Chilean desert. Actual preliminary results show the feasibility of such a project including physiological and ambient sensors, real-time processing algorithms, wireless data transmission and a remote monitoring station. Implementation details and field results are shown along with a discussion of the main problems found in real-life telemetry monitoring. PMID- 23367055 TI - Development of gait segmentation methods for wearable foot pressure sensors. AB - We present an automated segmentation method based on the analysis of plantar pressure signals recorded from two synchronized wireless foot insoles. Given the strict limits on computational power and power consumption typical of wearable electronic components, our aim is to investigate the capability of a Hidden Markov Model machine-learning method, to detect gait phases with different levels of complexity in the processing of the wearable pressure sensors signals. Therefore three different datasets are developed: raw voltage values, calibrated sensor signals and a calibrated estimation of total ground reaction force and position of the plantar center of pressure. The method is tested on a pool of 5 healthy subjects, through a leave-one-out cross validation. The results show high classification performances achieved using estimated biomechanical variables, being on average the 96%. Calibrated signals and raw voltage values show higher delays and dispersions in phase transition detection, suggesting a lower reliability for online applications. PMID- 23367056 TI - A clip-free eyeglasses-based wearable monitoring device for measuring photoplethysmograhic signals. AB - An eyeglasses-based device has been developed in this work to acquire photoplethysmogram (PPG) from the nose bridge. This device is aimed to provide wearable physiological monitoring without uncomfortable clips frequently used in PPG measurement from finger and ear. Switching control is applied on the LED and photo detector for power saving. An experiment involving postural change and treadmill jogging among 10 healthy young subjects was carried out to evaluate the performance of the device. Electrocardiogram (ECG) and PPG from finger, ear and nose were simultaneously recorded, from which heart rate (HR) and pulse transit time (PTT) were calculated. The results show that PPG measured from nose and ear are more resistant to motion than signal from finger during exercise. In addition, the difference between PTT measured from ear and nose indicates that local vasomotor activities may exist on ear and/or nose channel, and suggests that PPG from different sites should be used for cuff-less PTT-based BP estimation. We conclude that this wearable device has great potential to be used in the healthcare management in the future. PMID- 23367057 TI - A system-on-chip and paper-based inkjet printed electrodes for a hybrid wearable bio-sensing system. AB - This paper presents a hybrid wearable bio-sensing system, which combines traditional small-area low-power and high-performance System-on-Chip (SoC), flexible paper substrate and cost-effective Printed Electronics. Differential bio signals are measured, digitized, stored and transmitted by the SoC. The total area of the chip is 1.5 * 3.0 mm(2). This enables the miniaturization of the wearable system. The electrodes and interconnects are inkjet printed on paper substrate and the performance is verified in in-vivo tests. The quality of electrocardiogram signal sensed by printed electrodes is comparable with commercial electrodes, with noise level slightly increased. The paper-based inkjet printed system is flexible, light and thin, which makes the final system comfortable for end-users. The hybrid bio-sensing system offers a potential solution to the next generation wearable healthcare technology. PMID- 23367058 TI - An ear-worn continuous ballistocardiogram (BCG) sensor for cardiovascular monitoring. AB - Traditionally, ballistocardiogram (BCG) has been measured using large and stationary devices. In this work, we demonstrate a portable and continuous BCG monitor that is wearable at the ear. The device has the form factor of a hearing aid and is wirelessly connected to a PC for data recording and analysis. With the ear as an anchoring point, the device uses a MEMS tri-axial accelerometer to measure BCG at the head. Morphological differences exist between head BCG and traditional BCG, but the principal peaks (J waves) and their vectors are preserved. The frequency of J waves corresponds to heart rate, and when used in conjunction with an electrocardiogram's (ECG) R wave, the timing of J waves yields the RJ interval. Results from our clinical study show linear correlation between the RJ interval and the heart's pre-ejection period during hemodynamic maneuvers, thus revealing important information about cardiac contractility and its regulation. PMID- 23367059 TI - On time interval measurements using BCG. AB - Time intervals measured between the electrocardiogram (ECG), the photoplethysmogram (PPG) or the impedance plethysmogram (IPG), have long been used to noninvasively assess cardiovascular function. Recently, the ballistocardiogram (BCG) has been proposed as an alternative physiological signal to be used in time interval measurements for the same purpose. In this work, we study the behavior of the RJ interval, defined as the time between the R wave of the electrocardiogram (ECG) and the J wave of the BCG, under fast pressure changes induced by paced respiration and tracked by a beat-to-beat blood pressure (SBP and DBP) waveform monitor. The aim of this work is to gain a deeper understanding of these newly proposed time intervals and to further assess their usefulness to determine cardiovascular performance. PMID- 23367060 TI - Recent advances in cardiovascular monitoring using ballistocardiography. AB - Ballistocardiography (BCG) is a non-invasive method for monitoring cardiovascular health. While in the early 1900s, when it was invented, the BCG was intended to be a tool used exclusively in the clinic, the recent resurgence of BCG research has actually focused on extra-clinical applications ranging from home monitoring to measuring signals from astronauts in space. This repositioning of the diagnostic technique has largely been spurred by recent advances in measurement technology: historically, BCG instrumentation was large, cumbersome, and difficult to maintain; currently, it is small, easy-to-use, and does not require any sophisticated maintenance. This review presents the latest technological improvements in BCG instrumentation. These developments should further help to establish the BCG as a useful diagnostic tool in the coming years. PMID- 23367061 TI - Multi-channel optical sensor-array for measuring ballistocardiograms and respiratory activity in bed. AB - Our work covers improvements in sensors and signal processing for unobtrusive, long-term monitoring of cardiac (and respiratory) rhythms using only non-invasive vibration sensors. We describe a system for the unobtrusive monitoring of vital signs by means of an array of novel optical ballistocardiography (BCG) sensors placed underneath a regular bed mattress. Furthermore, we analyze the systems spatial sensitivity and present proof-of-concept results comparing our system to a more conventional BCG system based on a single electromechanical-film (EMFi) sensor. Our preliminary results suggest that the proposed optical multi-channel system could have the potential to reduce beat-to-beat heart rate estimation errors, as well as enable the analysis of more complex breathing patterns. PMID- 23367062 TI - Three dimensional ballisto- and seismo-cardiography: HIJ wave amplitudes are poorly correlated to maximal systolic force vector. AB - Ballistocardiography was recorded in 3-D on a free floating astronaut in space as well as on healthy volunteers participating to the ESA 55(th) and DLR 19(th) parabolic flights campaigns. In this paper we demonstrate further the usefulness of recording and analyzing ballistocardiograms (BCG) in three dimensions. The spatial curves of the displacement, velocity and acceleration vectors are analyzed instead of their individual 2-D components. The maximum magnitude of the force vector is shown to be poorly correlated to the HI and IJ wave amplitude traditionally computed on the longitudinal (feet-to-head) component of acceleration (uni-dimensional BCG). We also suggest that kinetic energy and work are useful parameters to consider for a physiological interpretation of the 3D BCG. The technique presented is invariant from the axis of representation and provides important novel physiological information. We stress further the need of 3D recordings and analysis techniques for Ballisto- and Seismo-cardiography. PMID- 23367063 TI - 24h seismocardiogram monitoring in ambulant subjects. AB - Sternal seismocardiogram (SCG) is the assessment of microvibrations produced by the beating heart as detected by an accelerometer positioned on the sternum. This signal reflects mechanical events of the heart contraction, including the opening and closure of mitral and aortic valves and maximal blood flow acceleration. Traditionally, SCG has been detected in a laboratory setting with the subject lying at rest in supine position. Aims of this study were 1) to investigate the feasibility of a SCG monitoring over the 24 hours in ambulant subjects, and 2) to calculate number and time distribution of the SCG estimates obtainable over the 24 hours. In 5 healthy subjects ECG, respiration, body accelerations and sternal SCG were recorded for 24 hours in a workday by a smart garment recently developed in our laboratory, the MagIC-SCG system. Each recording was split into a series of contiguous 5-s data segments and SCG was estimated in each segment where the magnitude of the acceleration vector was < 4 milli-g (this condition indicates that the subject was not moving).All the 24-h recordings were found of good quality and could be entirely analyzed. A large number of SCG estimates could be obtained over the 24 hours. In particular, more than 100 estimates per hour were available during the day; at night this rate was three times higher.Thus our study indicates that not only the 24h SCG monitoring in daily life is feasible but also that possible changes over time in SCG and its derived parameters may be tracked with an extreme temporal detail. PMID- 23367064 TI - Drivers and restrainers of relevance in graduate BME education - a South African study. AB - Academic biomedical engineering (BME) has the potential to address health care needs through the training of graduates able to work in and build the health care technology industry, and through the production of knowledge and research products that can be exploited to enhance health care. This paper explores factors that drive and restrain the relevance of a graduate BME program, i.e. its contribution to health care technology development and utilization, in South Africa, a middle income country with significant health disparities among its population. A focus on clinical and industrial partnerships is proposed. PMID- 23367065 TI - Biomedical engineering education through global engineering teams. AB - Most industrial projects require a team of engineers from a variety of disciplines. The team members are often culturally diverse and geographically dispersed. Many students do not acquire sufficient skills from typical university courses to function efficiently in such an environment. The Global Engineering Teams (GET) programme was designed to prepare students such a scenario in industry. This paper discusses five biomedical engineering themed projects completed by GET students. The benefits and success of the programme in educating students in the field of biomedical engineering are discussed. PMID- 23367066 TI - Introducing bio- and micro-technology into undergraduate thermal-fluids courses: investigating pipe pressure loss via atomic force microscopy. AB - To introduce bio- and micro-technologies into general undergraduate thermal fluids classes, a hands-on interdisciplinary in-class demonstration is described that juxtaposes classical pressure loss pipe flow experiments against a modern micro-characterization technique, AFM profilometry. Both approaches measure surface roughness and can segue into classroom discussions related to material selection and design of bio-medical devices to handle biological fluids such as blood. Appealing to the range of engineering students populating a general thermal-fluids course, a variety of pipe/hose/tube materials representing a spectrum of disciplines can be tested using both techniques. This in-class demonstration relies on technical content already available in standard thermal fluids textbooks, provides experimental juxtaposition between classical and micro technology-enabled approaches to the same experiment, and can be taught by personnel with no specialized micro- or bio-technology expertise. PMID- 23367067 TI - Analysis of the impact of medical technology assessment subjects on BME curricula. AB - This paper presents and analyzes the factors that have arisen on the implementation of the medical technology assessment and management courses, and the academic methodologies used to deal with them. Five courses that cover topics as Technology Management, Health Economics, Quality Assessment, Innovation and Entrepreneurship were designed as electives for BME curriculum and have been taught for the last two years. The activities carried out within the courses are described and their impact on the comprehension of the course contents are presented. Also, several elements and factors pertaining to the teaching-learning process are discussed. Future perspectives for the students that follow this sub specialty branch of the BME curriculum are presented. PMID- 23367068 TI - Effective collaborative learning in biomedical education using a web-based infrastructure. AB - This paper presents a feature-rich web-based system used for biomedical education at the undergraduate level. With the powerful groupware features provided by the wiki system, the instructors are able to establish a community-centered mentoring environment that capitalizes on local expertise to create a sense of online collaborative learning among students. The web-based infrastructure can help the instructors effectively organize and coordinate student research projects, and the groupware features may support the interactive activities, such as interpersonal communications and data sharing. The groupware features also provide the web-based system with a wide range of additional ways of organizing collaboratively developed materials, which makes it become an effective tool for online active learning. Students are able to learn the ability to work effectively in teams, with an improvement of project management, design collaboration, and technical writing skills. With the fruitful outcomes in recent years, it is positively thought that the web-based collaborative learning environment can perform an excellent shift away from the conventional instructor centered teaching to community- centered collaborative learning in the undergraduate education. PMID- 23367069 TI - Medical imaging education in biomedical engineering curriculum: courseware development and application through a hybrid teaching model. AB - Medical Imaging is a key training component in Biomedical Engineering programs. Medical imaging education is interdisciplinary training, involving physics, mathematics, chemistry, electrical engineering, computer engineering, and applications in biology and medicine. Seeking an efficient teaching method for instructors and an effective learning environment for students has long been a goal for medical imaging education. By the support of NSF grants, we developed the medical imaging teaching software (MITS) and associated dynamic assessment tracking system (DATS). The MITS/DATS system has been applied to junior and senior medical imaging classes through a hybrid teaching model. The results show that student's learning gain improved, particularly in concept understanding and simulation project completion. The results also indicate disparities in subjective perception between junior and senior classes. Three institutions are collaborating to expand the courseware system and plan to apply it to different class settings. PMID- 23367070 TI - TAT-based formal representation of medical guidelines: imatinib case-study. AB - Computer-based interpretation of medical guidelines (GLs) has drawn lots of attention in the past three decades. It is essential to use a formalism for GLs representation that would enable the validation of GLs structural properties, be able to map medical actions into the time scale and support the automatic formal verification of GLs without additional translation paths. In this paper we preset a novel approach based on Timed Automata extended with Tasks (TAT) for the medical protocol formal representation using the TIMES toolbox. We discuss the verification issues with the help of the Imatinib case study. PMID- 23367071 TI - Sequential algorithm for the detection of the shockable rhythms in electrocardiogram. AB - We suggest a sequential algorithm for the detection of the ventricular fibrillation (VF) and ventricular tachycardia (VT) of a rate above 180 bpm, so called shockable rhythms. The built-in algorithm for ECG analysis embedded in the portable bio-signal sensing module is aimed to discriminate between shockable and non-shockable rhythms and its accuracy is analyzed. An algorithm for VF/VT detection is proposed to analyze every 1 s ECG episode using the past 8 s episodes. The method is tested with 844,587 ECG episodes from the widely accepted databases. A sensitivity of 86.8 % and a specificity of 99.4 % were obtained and compared with the previous results. PMID- 23367072 TI - High performance biomedical time series indexes using salient segmentation. AB - The advent of remote and wearable medical sensing has created a dire need for efficient medical time series databases. Wearable medical sensing devices provide continuous patient monitoring by various types of sensors and have the potential to create massive amounts of data. Therefore, time series databases must utilize highly optimized indexes in order to efficiently search and analyze stored data. This paper presents a highly efficient technique for indexing medical time series signals using Locality Sensitive Hashing (LSH). Unlike previous work, only salient (or interesting) segments are inserted into the index. This technique reduces search times by up to 95% while yielding near identical search results. PMID- 23367073 TI - Data-driven modeling of sleep states from EEG. AB - Sleep analysis is critical for the diagnosis, treatment, and understanding of sleep disorders. However, the current standards for sleep analysis are widely considered oversimplified and problematic. The ability to automatically annotate different states during a night of sleep in a manner that is more descriptive than current standards, as well as the ability to train these models on a patient by-patient basis, would provide a complementary approach for sleep analysis. We present a method that discovers latent structure in sleep EEG recordings, by extracting symbols from the continuous EEG signal and learning "topics" for a recording. These sleep topics are derived in a fully automatic and data-driven manner, and can represent the data with mixtures of states. The proposed method allows for identification of states in a patient-specific way, as opposed to the one-size-fits-all approach of the current standard. We demonstrate on a publicly available dataset of 15 sleep recordings that not only do the states discovered by this approach encompass the standard sleep stage structure, they provide additional information about sleep architecture with the potential to provide new insights into sleep disorders. PMID- 23367074 TI - Prediction of extubation failure for neonates with respiratory distress syndrome using the MIMIC-II clinical database. AB - Extubation failure (EF) is an ongoing problem in the neonatal intensive care unit (NICU). Nearly 25% of neonates fail their first extubation attempt, requiring re intubations that are associated with risk factors and financial costs. We identified 179 mechanically ventilated neonatal patients that were intubated within 24 hours of birth in the MIMIC-II intensive care database. We analyzed data from the patients 2 hours prior to their first extubation attempt, and developed a prediction algorithm to distinguish patients whose extubation attempt was successful from those that had EF. From an initial list of 57 candidate features, our machine learning approach narrowed down to six features useful for building an EF prediction model: monocyte cell count, rapid shallow breathing index, fraction of inspired oxygen (FiO(2)), heart rate, PaO(2)/FiO(2) ratio where PaO(2) is the partial pressure of oxygen in arterial blood, and work of breathing index. Algorithm performance had an area under the receiver operating characteristic curve (AUC) of 0.871 and sensitivity of 70.1% at 90% specificity. PMID- 23367075 TI - Improving surgical models through one/two class learning. AB - Only a minority of patients undergoing in-patient surgical procedures experience complications. However, the large number of in-patient surgeries (over 48 million procedures each year in the U.S.) results in substantial overall mortality and morbidity due to these complications. This burden can be decreased through improvements in the ability to evaluate patients by the bedside, and to assess surgical quality and out-comes across hospitals. Unfortunately, the process of developing clinical models for surgical complications is made challenging by the availability of generally small datasets for model training, and by class imbalance due to the diminished prevalence of many important complications. In this paper, we address this issue and explore the idea of jointly leveraging the benefits of both supervised and unsupervised learning to model surgical complications that occur infrequently. In particular, we study an approach where the problems of supervised and unsupervised model development are treated as tasks that can be transferred. Focussing this work on support vector machine (SVM) classification, we describe a transfer learning algorithm that improves performance relative to both supervised (i.e., binary or 2-class SVM) and unsupervised (i.e., 1-class SVM) methods, as well as the use of cost-sensitive weighting techniques, for predicting different surgical complications within the American College of Surgeons National Surgical Quality Improvement Program registry. PMID- 23367076 TI - Resident identification using kinect depth image data and fuzzy clustering techniques. AB - As a part of our passive fall risk assessment research in home environments, we present a method to identify older residents using features extracted from their gait information from a single depth camera. Depth images have been collected continuously for about eight months from several apartments at a senior housing facility. Shape descriptors such as bounding box information and image moments were extracted from silhouettes of the depth images. The features were then clustered using Possibilistic C Means for resident identification. This technology will allow researchers and health professionals to gather more information on the individual residents by filtering out data belonging to non residents. Gait related information belonging exclusively to the older residents can then be gathered. The data can potentially help detect changes in gait patterns which can be used to analyze fall risk for elderly residents by passively observing them in their home environments. PMID- 23367077 TI - Capturing habitual, in-home gait parameter trends using an inexpensive depth camera. AB - Results are presented for measuring the gait parameters of walking speed, stride time, and stride length of five older adults continuously, in their homes, over a four month period. The gait parameters were measured passively, using an inexpensive, environmentally mounted depth camera, the Microsoft Kinect. Research has indicated the importance of measuring a person's gait for a variety of purposes from fall risk assessment to early detection of health problems such as cognitive impairment. However, such assessments are often done infrequently and most current technologies are not suitable for continuous, long term use. For this work, a single Microsoft Kinect sensor was deployed in four apartments, containing a total of five residents. A methodology for generating trends in walking speed, stride time, and stride length based on data from identified walking sequences in the home is presented, along with trend estimates for the five participants who were monitored for this work. PMID- 23367078 TI - Audible vision for the blind and visually impaired in indoor open spaces. AB - In this paper we introduce Audible Vision, a system that can help blind and visually impaired users navigate in large indoor open spaces. The system uses computer vision to estimate the location and orientation of the user, and enables the user to perceive his/her relative position to a landmark through 3D audio. Testing shows that Audible Vision can work reliably in real-life ever-changing environment crowded with people. PMID- 23367079 TI - Safe trajectory estimation at a pedestrian crossing to assist visually impaired people. AB - The aim of this paper is to present a service for blind and people with low vision to assist them to cross the street independently. The presented approach provides the user with significant information such as detection of pedestrian crossing signal from any point of view, when the pedestrian crossing signal light is green, the detection of dynamic and fixed obstacles, predictions of the movement of fellow pedestrians and information on objects which may intersect his path. Our approach is based on capturing multiple frames using a depth camera which is attached to a user's headgear. Currently a testbed system is built on a helmet and is connected to a laptop in the user's backpack. In this paper, we discussed efficiency of using Speeded-Up Robust Features (SURF) algorithm for object recognition for purposes of blind people assistance. The system predicts the movement of objects of interest to provide the user with information on the safest path to navigate and information on the surrounding area. Evaluation of this approach on real sequence video frames provides 90% of human detection and more than 80% for recognition of other related objects. PMID- 23367080 TI - Ubiquitous ambient assisted living solution to promote safer independent living in older adults suffering from co-morbidity. AB - This paper describes the development, deployment and trial results from 9 volunteers using the eCAALYX system. The eCAALYX system is an ambient assisted living telemonitoring system aimed at older adults suffering with co-morbidity. Described is a raw account of the challenges that exist and results in bringing a Telemedicine system from laboratory to real-world implementation and results for usability, functionality and reliability. PMID- 23367081 TI - Combined analysis of sensor data from hand and gait motor function improves automatic recognition of Parkinson's disease. AB - Objective and rater independent analysis of movement impairment is one of the most challenging tasks in medical engineering. Especially assessment of motor symptoms defines the clinical diagnosis in Parkinson's disease (PD). A sensor based system to measure the movement of the upper and lower extremities would therefore complement the clinical evaluation of PD. In this study two different sensor-based systems were combined to assess movement of 18 PD patients and 17 healthy controls. First, hand motor function was evaluated using a sensor pen with integrated accelerometers and pressure sensors, and second, gait function was assessed using a sports shoe with attached inertial sensors (gyroscopes,accelerometers).Subjects performed standardized tests for both extremities.Features were calculated from sensor signals to differentiate between patients and controls. For the latter, pattern recognition methods were used and the performance of four classifiers was compared. In a first step classification was done for every single system and in a second step for combined features of both systems. Combination of both motor task assessments substantially improved classification rates to 97%using the AdaBoost classifier for the experiment patients vs.controls.The combination of two different analysis systems led to enhanced, more stable, objective, and rater independent recognition of motor impairment. The method can be used as a complementary diagnostic tool for movement disorders. PMID- 23367082 TI - Pre-implantation electrochemical characterization of a Parylene C sheath microelectrode array probe. AB - We present the preliminary electrochemical characterization of 3D Parylene C sheath microelectrode array probes towards realizing reliable chronic neuroprosthetic recordings. Electrochemical techniques were used to verify electrode integrity after our novel post-fabrication thermoforming process was applied to flat surface micromachined structures to achieve a hollow sheath probe shape. Characterization of subsequent neurotrophic coatings was performed and accelerated life testing was used to simulate six months in vivo. Prior to probe implantation, crosstalk was measured and electrode surface properties were evaluated through the use of electrochemical impedance spectroscopy. PMID- 23367083 TI - Parylene-coated metal tracks for neural electrode arrays - fabrication approaches and improvements utilizing different laser systems. AB - In the past we developed a method for the fabrication of neural electrodes based on laser-structuring metal foil to form tracks and electrode sites within a silicone rubber substrate. Here, this process was refined by an additional coating of the laser-patterned metal tracks to improve their mechanical properties. Parylene C has been found to be the coating material of choice due to excellent electrical and mechanical characteristics and its well known biocompatibility. An almost ten times increased tensile strength compared to uncoated tracks could be achieved. Investigating the electrical properties of parylene C and silicone rubber attested both materials excellent insulating capabilities by withstanding voltages of more than 400 V(DC) for layer thicknesses as intended to be used in electrode array fabrication (some 10 um). This paper outlines the feasibility of the manufacturing process using a 1064 nm Nd:YAG laser in the nanosecond pulse regime. However, an improvement of the whole processing was demonstrated when a 355 nm Nd:YVO(4) laser in the picosecond regime is used. Benefits of this short pulse duration range from ablating materials independent of their optical properties to increased manufacturing speed and superior processing quality. PMID- 23367084 TI - Improved polyimide thin-film electrodes for neural implants. AB - Thin-film electrode arrays for neural implants are necessary when large integration densities of stimulating or recording channels are required. However, delamination of the metallic layers from the polymer substrate leads to early failure of the device. Based on new adhesion studies of polyimide to SiC and diamond-like carbon (DLC) the authors successfully fabricated a 232-channel electrode array for retinal stimulation with improved adhesion. Layers of SiC and DLC were integrated into the fabrication procedure of polyimide-platinum (Pt) arrays to create fully coated metal wires, which adhere to the polyimide substrate even after 1 year of accelerated aging in saline solution. Studies on the inter-diffusion of Pt and SiC were conducted to establish an optimal thickness for a gold core of the platinum tracks, which is used for reducing the electrical track resistance. Furthermore, the electrochemical behaviour of the stimulating contacts coated with IrOx were studied in a long-term pulse tests over millions of pulses showing no deterioration of the coating. PMID- 23367085 TI - Reduction of current density at disk electrode periphery by shaping current pulse edges. AB - Previous studies reveal that the primary distribution of the current density is sharply enhanced at the edge of a disk electrode submerged into a semi-infinite space of conductive solution. The current enhancement will cause the double layer capacitance at the periphery of the electrode to be charged much faster compared to the center, and can also lead to severe corrosion at the edge. While several studies focused on the geometric design of the electrode to reduce this enhancement, we explore the feasibility of achieving similar effect by shaping the edges of the current input. The simulation uses finite element analysis software to solve the system of partial differential equations and results show that the edge enhancement could be greatly reduced without significantly changing the input efficacy of current and/or charge. PMID- 23367086 TI - A novel technique for increasing charge injection capacity of neural electrodes for efficacious and safe neural stimulation. AB - Neural prostheses require chronically implanted small area penetrating electrode arrays that can stimulate and record neural activity. The fundamental requirement of neural electrodes is to have low interface impedance and large charge injection capacity (CIC). To achieve this fundamental requirement, we developed a novel technique to modify the surface of the Utah Electrode Array (UEA) to increase the real surface area without changing the geometrical surface area. Pt was coated on modified and unmodified (control) UEAs and electrochemical characterization such as impedance and CIC was measured and compared. The surface modified electrode impedance and CIC was ~188 Ohm and ~24 mC/cm(2) respectively. Increasing the real surface area of electrodes decreases the impedance by 1000 times and increases the CIC by 80 times compared to the control samples. The CIC of modified UEA was significantly higher than of any material reported in the literature, higher than sputtered iridium oxide (4 mC/cm(2)) or PEDOT (15 mC/cm(2)). PMID- 23367087 TI - A CMOS-based on-chip neural interface device equipped with integrated LED array for optogenetics. AB - A novel CMOS-based neural interface device equipped with an integrated micro light source array was proposed and demonstrated. Target application of the device is optogenetics. GaInN LED array formed on sapphire substrate was successfully assembled with a multifunctional CMOS image sensor which is capable of injecting current via any of the pixel. We demonstrated addressable LED operation with the present device. The device has advantages such as simultaneous multi-site stimulation and on-chip optical imaging, that are not available with previously reported LED array device for optogenetics. PMID- 23367088 TI - Design techniques and analysis of high-resolution neural recording systems targeting epilepsy focus localization. AB - The design of a high-density neural recording system targeting epilepsy monitoring is presented. Circuit challenges and techniques are discussed to optimize the amplifier topology and the included OTA. A new platform supporting active recording devices targeting wireless and high-resolution focus localization in epilepsy diagnosis is also proposed. The post-layout simulation results of an amplifier dedicated to this application are presented. The amplifier is designed in a UMC 0.18um CMOS technology, has an NEF of 2.19 and occupies a silicon area of 0.038 mm(2), while consuming 5.8 uW from a 1.8-V supply. PMID- 23367089 TI - Sensor integration of multiple tripolar concentric ring electrodes improves pentylenetetrazole-induced seizure onset detection in rats. AB - As epilepsy affects approximately one percent of the world population, electrical stimulation of the brain has recently shown potential for additive seizure control therapy. Previously, we applied noninvasive transcranial focal stimulation via tripolar concentric ring electrodes on the scalp of rats after inducing seizures with pentylenetetrazole. We developed a system to detect seizures and automatically trigger the stimulation and evaluated the system on the electrographic activity from rats. In this preliminary study we propose and validate a novel seizure onset detection algorithm based on exponentially embedded family. Unlike the previously proposed approach it integrates the data from multiple electrodes allowing an improvement of the detector performance. PMID- 23367090 TI - Brain state evolution during seizure and under anesthesia: a network-based analysis of stereotaxic eeg activity in drug-resistant epilepsy patients. AB - Epilepsy is a neurological condition with a prevalence of 1%, and 14-34% have medically refractory epilepsy (MRE). Seizures in focal MRE are generated by a single epileptogenic zone (or focus), thus there is potentially a curative procedure - surgical resection. This procedure depends significantly on correct identification of the focus, which is often uncertain in clinical practice. In this study, we analyzed intracranial stereotaxic EEG (sEEG) data recorded in two human patients with drug-resistant epilepsy prior to undergoing resection surgery. We view the sEEG data as samples from the brain network and hypothesize that seizure foci can be identified based on their network connectivity during seizure. Specifically, we computed a time sequence of connectivity matrices from EEG recordings that represent network structure over time. For each patient, connectivity between electrodes was measured using the coherence in a given frequency band. Matrix structure was analyzed using singular value decomposition and the leading singular vector was used to estimate each electrode's time dependent centrality (importance to the network's connectivity). Our preliminary study suggests that seizure foci may be the most weakly connected regions in the brain during the beginning of a seizure and the most strongly connected regions towards the end of a seizure. Additionally, in one of the patients analyzed, the network connectivity under anesthesia highlights seizure foci. Ultimately, network centrality computed from sEEG activity may be used to develop an automated, reliable, and computationally efficient algorithm for identifying seizure foci. PMID- 23367091 TI - Channel selection for epilepsy seizure prediction method based on machine learning. AB - The studies on seizure prediction problem have shown great improvement these years. Machine learning based seizure prediction method shows great performance by doing pattern recognition on high-dimensional bivariate synchronization features. However, the computation loading of the machine learning based method may be too high to meet wearable or implantable devices with the power and area constraints. In this work, channel selection is proposed to reduce the channel number from 22 to less than 6 channels and therefore more than 93.73% of the computation loading is saved through the method. The best result shows successful rate of 60.6% in 3-channel cases of ECoG database and successful rate of 70% in 3 channel cases of EEG database. PMID- 23367092 TI - Spatio-temporal inter-ictal activity recorded from human epileptic hippocampal slices. AB - Epilepsy is a medical syndrome that produces seizures affecting a variety of mental and physical functions. The actual mechanisms of the onset and termination of the seizure are still unclear. While medical therapies can suppress the symptoms of seizures, 30% of patients do not respond well. Temporal lobectomy is a common surgical treatment for medically refractory epilepsy. Part of the hippocampus is removed from the patient. In this study, we have developed an in vitro epileptic model in human hippocampal slices resected from patients suffering from intractable mesial temporal lobe epilepsy. Using a planar multielectrode array system, spatio-temporal inter-ictal activity can be consistently recorded in high-potassium (8 mM), low-magnesium (0.25 mM) aCSF with additional 100 uM 4-aminopyridine. The induced inter-ictal activity can be recorded in different regions including dentate, CA1 and Subiculum. We hope the experimental model built in this study will help us understand more about seizure generation, as well as providing insights into prevention and novel therapeutics. PMID- 23367093 TI - Efficient epileptic seizure detection by a combined IMF-VoE feature. AB - Automatic seizure detection from the electroen-cephalogram (EEG) plays an important role in an on-demand closed-loop therapeutic system. A new feature, called IMF-VoE, is proposed to predict the occurrence of seizures. The IMF-VoE feature combines three intrinsic mode functions (IMFs) from the empirical mode decomposition of a EEG signal and the variance of the range between the upper and lower envelopes (VoE) of the signal. These multiple cues encode the intrinsic characteristics of seizure states, thus are able to distinguish them from the background. The feature is tested on 80.4 hours of EEG data with 10 seizures of 4 patients. The sensitivity of 100% is obtained with a low false detection rate of 0.16 per hour. Average time delays are 19.4s, 13.2s, and 10.7s at the false detection rates of 0.16 per hour, 0.27 per hour, and 0.41 per hour respectively, when different thresholds are used. The result is competitive among recent studies. In addition, since the IMF-VoE is compact, the detection system is of high computational efficiency and able to run in real time. PMID- 23367094 TI - Partial directed coherence analysis of intracranial neural spikes in epilepsy patients. AB - Intracranial electroencephalograms (EEG) provide a direct observation of neural activity by placing an electrode array on the cortical surface near the suspected epileptic foci. The neural spikes appeared during inter-ictal stages are mainly produced by abnormal neural discharges from epileptic foci. The topological mapping of spikes' potentials is commonly used to identify the epileptogenic zone. However, the propagations among multi-channel spikes are also important to identify the epileptic source activity. In addition, the changes of source activities in a series of consecutive spikes reveal the time-varying neural activations during discharge process, which provide alternative information for interpreting epileptic source activity. This paper proposes a spike classification based on the similarity of phase-space features to select candidate spikes from the intracranial EEGs recorded from an 8*8 electrocorticogram grid. Then, the partial directed coherence (PDC), which can provide the flow of source activity, at each spiking time point is computed. The outflow PDCs of all electrodes are therefore displayed on the grid. Our result showed that the derived source activities in the preceding spikes had high concentrated distributions but decreased in latter spikes. This implied the epileptic discharges were initially induced by a small-area cortex neurons and then spread out. PMID- 23367095 TI - Information transfer along the ventral auditory processing stream in the awake macaque. AB - Few studies have examined the physiology of the auditory cortical processing streams in the context of information transfer among cortical areas. This study examines information transfer in two cortical areas in the ventral auditory processing stream in an awake macaque. We show conditional information examined over different durations of neural responses provides insight into the time scale and direction of cortical hierarchical processing. PMID- 23367096 TI - Functional connectivity analysis of cortical networks in Functional Near Infrared Spectroscopy using phase synchronization. AB - Functional Near Infrared Spectroscopy (fNIRS) is a non invasive functional neuroimaging method used for studying brain activity using blood oxygen level dependent (BOLD) signal. We use phase synchronization between fNIRS channels to detect functional connections between brain regions in a speech study. Data is collected from 22 neonates whose brain activity was monitored by fNIRS while being exposed to two different types of auditory stimuli. The wavelet based phase locking analysis reveals functional connections between temporal regions and most other regions in general and frontal areas in particular. PMID- 23367097 TI - Functional brain connectivity as revealed by singular spectrum analysis. AB - Correlation based measures have widely been used to characterize brain connectivity. In this paper, a new approach based on singular spectrum analysis is proposed to characterize brain connectivity. It is obtained by deriving the common basis vector of two or more trajectory matrices associated with functional brain responses. This approach has the advantage illustrating the existence of joint variations of the functional brain responses and to characterize the correlation structure. The performance of the method are illustrated on both simulated autoregressive data and real fMRI data. PMID- 23367098 TI - Estimating correlation for a real-time measure of connectivity. AB - There has recently been considerable interest in connectivity analysis of fMRI and scalp and intracranial EEG time-series. The computational requirements of the pair-wise correlation (PWC), the core time-series measure used to estimate connectivity, presents a challenge to the real-time estimation of the PWC between all pairs of multiple time-series. We describe a parallel algorithm for computing PWC in real-time for streaming data from multiple channels. The algorithm was implemented on the Intel XeonTM and IBM Cell Broadband EngineTM platforms. We evaluated time to estimate correlation for signals recorded with different acquisition parameters as a comparison to real-time constraints. We demonstrate that the execution time of these efficient implementations meet real-time constraints in most instances. PMID- 23367101 TI - Effect of latency on clustering of P300 recordings for ADHD discrimination. AB - This paper is focused on testing the latency contribution as regards the quality of formed groups for discriminating between healthy and attention deficit hyperactivity disorder children. To this end, two different cases are considered: nonaligned original recordings and aligned signals according to P300 position. For latter case, a novel approach to conduct time location of P300 component is introduced, which is based on derivative of event-related potential signals. The used database holds event-related potentials registered in auditory and visual oddball paradigm. Several experiments are carried out testing both configurations of considered data matrix. For grouping input data matrices, the k-means clustering technique is employed. To assess the quality of formed clusters and the relevance for clustering of latency-based features, relative values of distances between centroids and data points are computed in order to apprise separability and compactness of estimated clusters. Experimental results show that time localization of P300 component is not a decisive feature in formation of compact and well-defined groups within a discrimination framework for two considered data classes under certain conditions. PMID- 23367100 TI - Correlation between intra- and extracranial background EEG. AB - Scalp EEG is the most widely used modality to record the electrical signals of the brain. It is well known that the volume conduction of these brain waves through the brain, cerebrospinal fluid, skull and scalp reduces the spatial resolution and the signal amplitude. So far the volume conduction has primarily been investigated by realistic head models or interictal spike analysis. We have set up a novel and more realistic experiment that made it possible to compare the information in the intra- and extracranial EEG. We found that intracranial EEG channels contained correlated patterns when placed less than 30 mm apart, that intra- and extracranial channels were partly correlated when placed less than 40 mm apart, and that extracranial channels probably were correlated over larger distances. The underlying cortical area that influences the extracranial EEG is found to be up to 45 cm(2). This area is larger than previously reported. PMID- 23367102 TI - Music and emotion: an EEG connectivity study in patients with disorders of consciousness. AB - Human emotion perception is a topic of great interest for both cognitive and clinical neuroscience, but its electrophysiological correlates are still poorly understood. The present study is aimed at evaluating if measures of synchronization and indexes based on graph-theory are a tool suitable to study and quantify electrophysiological changes due to emotional stimuli perception. In particular, our study is aimed at evaluating if different EEG connectivity patterns can be induced by pleasant (consonant) or unpleasant (dissonant) music, in a population of healthy subjects, and in patients with severe disorders of consciousness (DOCs), namely vegetative state (VS) patients. In the control group, pleasant music induced an increase in network number of connections, compared with the resting condition, while no changes were caused by the unpleasant stimuli. However, clustering coefficient and path length, two indexes derived from graph theory, able to characterise segregation and integration properties of a network, were not affected by the stimuli, neither pleasant nor unpleasant. In the VS group, changes were found only in those patients with the less severe consciousness impairment, according to the clinical assessment. In these patients a stronger synchronization was found during the unpleasant condition; moreover we observed changes in the network topology, with decreased values of clustering coefficient and path length during both musical stimuli.Our results show that measures of synchronization can provide new insights into the study of the electro physiological correlates of emotion perception, indicating that these tools can be used to study patients with DOCs, in whom the issue of objective measures and quantification of the degree of impairment is still an open and unsolved question. PMID- 23367103 TI - Modified Log-LMS adaptive filter with low signal distortion for biomedical applications. AB - Life signals from human body, e.g. heartbeat or electrocardiography (ECG), are usually weak and susceptible to external noise and interference. Adaptive filter is a good tool to reduce the influence of ambient noise/interference on the life signals. Least mean squares (LMS) algorithm, as one of most popular adaptive algorithms for active noise cancellation (ANC) by adaptive filtering, has the advantage of easy implementation. In order to further decrease the complexity of LMS algorithm based adaptive filter, a Log-LMS algorithm was proposed, which quantized signals by the function of log2. The algorithm can replace multipliers by simple shifting. However, both LMS algorithm and Log-LMS algorithm have the disadvantage of serious signal distortion in biomedical applications. In this paper, a modified Log-LMS algorithm is presented, which divides the convergence process into two different stages, and utilizes different quantization method in each stage. Two scenarios of biomedical applications are used for analysis, 1) using stethoscope in emergence medical helicopter and 2) measuring ECG under power line interference. The simulated results show that the modified algorithm can achieve fast convergence and low signal distortion in processing periodic life signals. PMID- 23367104 TI - Power line interference cancellation in in-vivo neural recording. AB - This paper presents an algorithm for removing power line interference in neural recording experiments. It does not require any interference reference signal and can reliably track interference changes in frequency, phase, and amplitude. The method includes three major steps. First, it employs a robust frequency estimator to obtain the fundamental frequency of the interference. Second, a series of discrete-time oscillators are used to generate interference harmonics, where harmonic phase and amplitude are obtained using the recursive least squares (RLS) algorithm. Third, the estimated interference harmonics are removed without distorting the neural signals at the interference frequencies. The simple structure and adequate numerical behavior of the algorithm renders it suitable for realtime implementation. Extensive experiments based on both invivo and synthesized data have been performed, where a reliable performance has been observed. PMID- 23367105 TI - Order selection of the hearing aid Feedback Canceller filter based on its impulse response energy. AB - Numerous methods have been proposed to cancel the unpleasant effects of acoustic feedback between the loudspeaker and microphone in hearing aid systems. Adaptive Feedback Cancellation (AFC) methods are often used to estimate an FIR filter for cancelling the feedback path effect. In estimating the AFC FIR filter, it is important to select the order of the filter properly; especially when the feedback path changes from one environment to another and no knowledge about it is available. Choosing improper filter order causes deficient system performance or excessive computations and power usage in the system. We present tracking of the energy of AFC FIR filters and its convergence behavior as a new criterion for determining the proper order for AFC FIR filter. Experimental results show validity of the proposed criterion. PMID- 23367106 TI - Brain source localization based on fast fully adaptive approach. AB - In the electroencephalogram (EEG) or magnetoencephalogram (MEG) context, brain source localization (beamforming) methods often fail when the number of observations is small. This is particularly true when measuring evoked potentials, especially when the number of electrodes is large. Due to the nonstationarity of the EEG/MEG, an adaptive capability is desirable. Previous work has addressed these issues by reducing the adaptive degrees of freedom (DoFs). This paper develops and tests a new multistage adaptive processing for brain source localization that has been previously used for radar statistical signal processing application with uniform linear antenna array. This processing, referred to as the fast fully adaptive (FFA) approach, could significantly reduce the required sample support and computational complexity, while still processing all available DoFs. The performance improvement offered by the FFA approach in comparison to the fully adaptive minimum variance beamforming (MVB) with limited data is demonstrated by bootstrapping simulated data to evaluate the variability of the source location. PMID- 23367107 TI - A ventricular activity cancellation algorithm based on event synchronous adaptive filter for single-lead electrocardiograms. AB - Recently, it has become very important to analyze atrial activity (AA) and to detect arrhythmic AAs and, for this, complete ventricular activity (VA) cancellation is prerequisite. There have been several VA cancellation algorithms for multi-lead ECG but VA cancellation algorithm for single-lead is quite a few. In this study, we have modeled thoracic ECG and, based on this model, proposed a novel VA cancellation algorithm based on event synchronous adaptive filter (ESAF). In this ESAF, the AF ECG was treated as a primary input and event synchronous impulse train (ESIT) as a reference. And, ESIT was generated so to be synchronized with the ventricular activity by detecting QRS complex. To evaluate the performance, it was applied to the AA estimation problem in atrial fibrillation electrocardiograms. As results, even with low computational cost, this ESAF based algorithm showed better performance than the ABS method and comparable performance to algorithm based on PCA (principal component analysis) or SVD (singular value decomposition). We also proposed an expanded version of ESAF for some AF ECGs with bimorphic VAs and this also showed reasonable performance. Ultimately, our proposed algorithm was found to estimate AA precisely even though it is possible to implement in real-time. We expect our algorithm to replace the most widely used method, that is, the ABS (averaged beat subtraction) method. PMID- 23367108 TI - Improving misalignment for feedback path estimation in hearing aid by multiple short-time noise injections. AB - Adaptive Feedback Cancellation (AFC) methods are used to find an FIR filter to cancel the negative effect of acoustic feedback between the loudspeaker and microphone of the hearing aid. Finding the AFC filter of appropriate order/length directly affects the performance and complexity of the system. In this paper, we use noise injection method to find the AFC filter estimating the feedback path model. We show that the optimum length which guarantees a good compromise between the quality and the complexity of the system may be smaller than the length of the actual feedback path model. However, in order to improve the performance of the system in terms of Misalignment criterion, we propose using multiple short time noise injections and averaging method to find the best filter estimate of appropriate length. PMID- 23367109 TI - Fault detection and isolation in motion monitoring system. AB - Pervasive computing becomes very active research field these days. A watch that can trace human movement to record motion boundary as well as to study of finding social life pattern by one's localized visiting area. Pervasive computing also helps patient monitoring. A daily monitoring system helps longitudinal study of patient monitoring such as Alzheimer's and Parkinson's or obesity monitoring. Due to the nature of monitoring sensor (on-body wireless sensor), however, signal noise or faulty sensors errors can be present at any time. Many research works have addressed these problems any with a large amount of sensor deployment. In this paper, we present the faulty sensor detection and isolation using only two on-body sensors. We have been investigating three different types of sensor errors: the SHORT error, the CONSTANT error, and the NOISY SENSOR error (see more details on section V). Our experimental results show that the success rate of isolating faulty signals are an average of over 91.5% on fault type 1, over 92% on fault type 2, and over 99% on fault type 3 with the fault prior of 30% sensor errors. PMID- 23367110 TI - Multimodal emotion recognition by combining physiological signals and facial expressions: a preliminary study. AB - Lately, multimodal approaches for automatic emotion recognition have gained significant scientific interest. In this paper, emotion recognition by combining physiological signals and facial expressions was studied. Heart rate variability parameters, respiration frequency, and facial expressions were used to classify person's emotions while watching pictures with emotional content. Three classes were used for both valence and arousal. The preliminary results show that, over the proposed channels, detecting arousal seem to be easier compared to valence. While the classification performance of 54.5% was attained with arousal, only 38.0% of the samples were classified correctly in terms of valence. In future, additional modalities as well as feature selection will be utilized to improve the results. PMID- 23367111 TI - Support vector regression correlates single-sweep evoked brain potentials to gastrointestinal symptoms in diabetes mellitus patients. AB - Diabetes mellitus (DM) is a multi-factorial and complex disease causing autonomic neuropathy and gastrointestinal symptoms in some patients. The neural mechanisms behind these symptoms are poorly understood, but it is believed that both peripheral and central mechanisms are involved. To gain further knowledge of the central mechanisms, the aim of this study was to identify biomarkers for the altered brain activity in type-1 DM patients compared to healthy volunteers (HV), and to correlate the obtained biomarkers to clinical patient scores. The study included 14 DM patients and 15 HV, with brain activity recorded as multi-channel electroencephalography evoked brain potentials (EPs) elicited by painful electrical stimulations in the esophagus. The single-sweep EPs were decomposed by an optimized discrete wavelet transform (DWT), and averaged for each channel. The DWT features from the DM patients were discriminated from the HV by a support vector machine (SVM) applied in regression mode. For the optimal DWT, the discriminative features were extracted and the SVM regression value representing the overall alteration of the EP was correlated to the clinical scores. A classification performance of 86.2% (P=0.01) was obtained by applying a majority voting scheme to the 5 best performing channels. The biomarker was identified as decreased theta band activity. The regression value was correlated to symptoms reported by the patients (P=0.04). The methodology is an improvement of the present approach to study central mechanisms in diabetes mellitus, and may provide a future application for a clinical tool to optimize treatment in individual patients. PMID- 23367112 TI - The evaluation of the discriminant ability of multiclass SVM in a study of hand motion recognition by using SEMG. AB - Electromyogram (EMG) is a kind of biological signal that is generated because of excitement of muscle according to the motor instruction from a brain. We have been experimentally developing the hand motion recognition system by using 4 channels forearm EMG signals. In our system, in order to classify measured EMG SVM (Support Vector Machine) that has higher discriminability is used. Often SVM is used as a non-linear classifier. But, In the conventional system that we developed, we used a canonical discriminant analysis (CDA) method. CDA method is linear discriminant function, but it has shown good experimental results. Therefore, we have compared the discriminant ability between SVM and CDA. In this report, we will describe about the results of this experiment. PMID- 23367113 TI - Promise of a low power mobile CPU based embedded system in artificial leg control. AB - This paper presents the design and implementation of a low power embedded system using mobile processor technology (Intel AtomTM Z530 Processor) specifically tailored for a neural-machine interface (NMI) for artificial limbs. This embedded system effectively performs our previously developed NMI algorithm based on neuromuscular-mechanical fusion and phase-dependent pattern classification. The analysis shows that NMI embedded system can meet real-time constraints with high accuracies for recognizing the user's locomotion mode. Our implementation utilizes the mobile processor efficiently to allow a power consumption of 2.2 watts and low CPU utilization (less than 4.3%) while executing the complex NMI algorithm. Our experiments have shown that the highly optimized C program implementation on the embedded system has superb advantages over existing PC implementations on MATLAB. The study results suggest that mobile-CPU-based embedded system is promising for implementing advanced control for powered lower limb prostheses. PMID- 23367114 TI - Unobtrusive classification of sleep and wakefulness using load cells under the bed. AB - Poor quality of sleep increases the risk of many adverse health outcomes. Some measures of sleep, such as sleep efficiency or sleep duration, are calculated from periods of time when a patient is asleep and awake. The current method for assessing sleep and wakefulness is based on polysomnography, an expensive and inconvenient method of measuring sleep in a clinical setting. In this paper, we suggest an alternative method of detecting periods of sleep and wake that can be obtained unobtrusively in a patient's own home by placing load cells under the supports of their bed. Specifically, we use a support vector machine to classify periods of sleep and wake in a cohort of patients admitted to a sleep lab. The inputs to the classifier are subject demographic information, a statistical characterization of the load cell derived signals, and several sleep parameters estimated from the load cell data that are related to movement and respiration. Our proposed classifier achieves an average sensitivity of 0.808 and specificity of 0.812 with 90% confidence intervals of (0.790, 0.821) and (0.798, 0.826), respectively, when compared to the "gold-standard" sleep/wake annotations during polysomnography. As this performance is over 27 sleep patients with a wide variety of diagnosis levels of sleep disordered breathing, age, body mass index, and other demographics, our method is robust and works well in clinical practice. PMID- 23367116 TI - Mining pattern sequences in respiratory tumor motion data. AB - Management of respiration induced tumor motion during radiation therapy is crucial to effective treatment. Pattern sequences in the tumor motion signals can be valuable features in the analysis and prediction of irregular tumor motion. In this study, we put forward an approach towards mining pattern sequences in respiratory tumor motion data. We discuss the use of pattern sequence distributions as effective representations of motion characteristics, and find similarities between individual tumor motion instances. We also explore grouping of patients based on similarities in pattern sequence distributions exhibited by their respiratory motion traces. PMID- 23367115 TI - Recursive feature elimination for brain tumor classification using desorption electrospray ionization mass spectrometry imaging. AB - The metabolism and composition of lipids is of increasing interest for understanding and detecting disease processes. Lipid signatures of tumor type and grade have been demonstrated using magnetic resonance spectroscopy. Clinical management and ultimate prognosis of brain tumors depend largely on the tumor type, subtype, and grade. Mass spectrometry, a well-known analytical technique used to identify molecules in a given sample based on their mass, can significantly improve the problem of tumor type classification. This work focuses on the problem of identifying lipid features to use as input for classification. Feature selection could result in improvements in classifier performance, discovery of biomarkers, improved data interpretation, and patient treatment. PMID- 23367117 TI - Toward fewer EEG channels and better feature extractor of non-motor imagery mental tasks classification for a wheelchair thought controller. AB - This paper presents a non-motor imagery tasks classification electroencephalography (EEG) based brain computer interface (BCI) for wheelchair control. It uses only two EEG channels and a better feature extractor to improve the portability and accuracy in the practical system. In addition, two different features extraction methods, power spectral density (PSD) and Hilbert Huang Transform (HHT) energy are compared to find a better method with improved classification accuracy using a Genetic Algorithm (GA) based neural network classifier. The results from five subjects show that using the original eight channels with three tasks, accuracy between 76% and 85% is achieved. With only two channels in combination with the best chosen task using a PSD feature extractor, the accuracy is reduced to between 65% and 79%. However, the HHT based method provides an improved accuracy between 70% and 84% for the classification of three discriminative tasks using two EEG channels. PMID- 23367119 TI - An efficient spike-sorting for implantable neural recording microsystem using hybrid neural network. AB - Automatic efficient spike sorting is one of the biggest challenges for the neural recording microsystem online. An unsupervised spike sorting method is proposed in this paper, based on the hybrid neural network with principal component analysis network (PCAN) and normal boundary response (NBR) self-organizing map network (SOMN) classifier. The PCAN extracted the spike features with the dimension reduced and correlation eliminated; The SOM network perform the spike distribution in the feature space, thus after convergence, the weights of the neurons demonstrate the spike cluster distribution in the feature space; At last the spike sorting was finished by computing the neurons' Normal Boundary Response (NBR) which determined the neurons' classes. The experimental results show that, based on hybrid neural network spiking sorting algorithm, it can achieve the accuracy above 97.91% with signals containing five classes. The novel classification algorithm proposed is to further improve the efficient and adaptive of classification system. PMID- 23367118 TI - Prior estimation of motion using recursive perceptron with sEMG: a case of wrist angle. AB - Muscle activity is followed by myoelectric potentials. Prior estimation of motion by surface electromyography can be utilized to assist the physically impaired people as well as surgeon. In this paper, we proposed a real-time method for the prior estimation of motion from surface electromyography, especially in the case of wrist angle. The method was based on the recursive processing of multi-layer perceptron, which is trained quickly. A single layer perceptron calculates quasi tensional force of muscles from surface electromyography. A three-layer perceptron calculates the wrist's change in angle. In order to estimate a variety of motions properly, the perceptron was designed to estimate motion in a short time period, e.g. 1ms. Recursive processing enables the method to estimate motion in the target time period, e.g. 50ms. The results of the experiments showed statistical significance for the precedence of estimated angle to the measured one. PMID- 23367120 TI - Non-invasive cerebrospinal fluid pressure estimation using multi-layer perceptron neural networks. AB - Cerebrospinal fluid pressure (CSFp) provides vital information in various neurological abnormalities including hydrocephalus, intracranial hypertension and brain tumors. Currently, CSFp is measured invasively through implanted catheters within the brain (ventricles and parenchyma) which is associated with a risk of infection and morbidity. In humans, the cerebrospinal fluid communicates indirectly with the ocular circulation across the lamina cribrosa via the optic nerve subarachnoid space. It has been shown that a relationship between retinal venous pulsation, intraocular pressure (IOP) and CSFp exists with the amplitude of retinal venous pulsation being associated with the trans-laminar pressure gradient (i.e. IOP-CSFp). In this study we use this characteristic to develop a non-invasive approach to estimate CSFp. 15 subjects were included in this study. Dynamic retinal venous diameter changes and IOP were measured and fitted into our model. Artificial neural networks (ANN) were applied to construct a relationship between retinal venous pulsation amplitude, IOP (input) and CSFp (output) and develop an algorithm to estimate CSFp based on these parameters. Results show a mean square error of 2.4 mmHg and 1.27 mmHg for train and test data respectively. There was no significant difference between experimental and ANN estimated CSFp values (p>0.01).This study suggests measurement of retinal venous pulsatility in conjunction with IOP may provide a novel approach to estimate CSFp non invasively. PMID- 23367121 TI - Dimensionality reduction based on fuzzy rough sets oriented to ischemia detection. AB - This paper presents a dimensionality reduction study based on fuzzy rough sets with the aim of increasing the discriminant capability of the representation of normal ECG beats and those that contain ischemic events. A novel procedure is proposed to obtain the fuzzy equivalence classes based on entropy and neighborhood techniques and a modification of the Quick Reduct Algorithm is used to select the relevant features from a large feature space by a dependency function. The tests were carried out on a feature space made up by 840 wavelet features extracted from 900 ECG normal beats and 900 ECG beats with evidence of ischemia. Results of around 99% classification accuracy are obtained. This methodology provides a reduced feature space with low complexity and high representation capability. Additionally, the discriminant strength of entropy in terms of representing ischemic disorders from time-frequency information in ECG signals is highlighted. PMID- 23367122 TI - Heart sound localization in chest sound using temporal fuzzy C-means classification. AB - Most of heart sound cancellation algorithms to improve the quality of lung sound use information about heart sound locations. Therefore, a reliable estimation of heart sound localizations within chest sound is a key issue to enhance the performance of heart sound cancellation algorithms. In this paper, we present a new technique to estimate locations of heart sound segments in chest sound using the temporal fuzzy c-means (TFCM) algorithm. In applying the method, chest sound is first divided into frames and then for each frame, the entropy feature is calculated. Next, by means of these features, the TFCM algorithm is applied to classify a chest sound into two classes: heart sound (heart sound containing lung sound) and non-heart sound (only lung sound). The proposed method was tested on the database used in the liteature and experimetal results are compared with the baseline which is a well-known method in the literature. The experimental results show that the proposed method outperforms the baseline method interms of false negative rate (FNR), false positive rate (FPR) and accuracy (ACC). PMID- 23367123 TI - Individual optimization of EEG channel and frequency ranges by means of genetic algorithm. AB - It is well established that motor action/imagery provokes an event-related desynchronization (ERD) response at specific brain areas with specific frequency ranges, typically the sensory motor rhythm and beta bands. However, there are individual differences in both brain areas and frequency ranges which can be used to identify ERD. This often results in low classification accuracy of ERD, which makes it difficult to implement of BCI application such as the control of external devices and motor rehabilitation. To overcome this problem, an individually optimized solution may be desirable for enhancing the accuracy of detecting motor action/imagery with ERD rather than a global solution for all BCI users. This paper presents a method based on a genetic algorithm to find individually optimized brain areas and frequency ranges for ERD classification. To optimize these two components, we designed a chromosome consisting of 64-bit elements represented by a binary number and another 9-bit elements using 512 pre defined frequency ranges (2^9). The average value of the significant level is set for the properties of the objective function for use in a t-test, (p < 0.01) depending on the random selection from a concurrent population. As a result, contralateral ERD responses in the spatial domain with individually optimized frequency ranges showed a significant difference between resting and motor action. The ERD responses for motor imagery, on the other hand, led to a bilateral pattern with a narrow frequency band compared to motor action. This study provides the possibility of selecting optimized electrode positions and frequency bands which can lead to high levels of ERD classification accuracy. PMID- 23367124 TI - 3D curve constrained deformable registration using a neuro-fuzzy transformation model. AB - Image registration of abdominal organs and soft tissues is considered daunting due to large organ shift and tissue deformation caused by patient motion, respiration, etc. In this study, we propose a novel neuro-fuzzy deformable registration technique that is constrained by 3D curves of vessel centerlines and point marks while minimizing strain energy. We present an analytical global optimal solution in the case when 3D curves, strain energy and point marks are considered, which will provide fast and robust deformable match for internal structures such as blood vessels, and significantly reduce the chance to get trapped in local minima. We have demonstrated the effectiveness of our deformable technique in registering liver MR images. Validation shows a target registration error of 1.98 mm and an average centerline distance error of 1.65 mm. This technique has the potential to significantly improve registration capability and the quality of intra-operative image guidance. PMID- 23367125 TI - Affine transformation registers small scale lung deformation. AB - To evaluate the nature of small scale lung deformation between multiple pulmonary magnetic resonance images, two different kinematic intensity based image registration techniques: affine and bicubic Hermite interpolation were tested. The affine method estimates uniformly distributed deformation metrics throughout the lung. The bicubic Hermite method allows the expression of heterogeneously distributed deformation metrics such as Lagrangian strain. A cardiac triggered inversion recovery technique was used to obtain 10 sequential images of pulmonary vessel structure in a sagittal plane in the right lung at FRC in 4 healthy subjects (Age: 28.5(6.2)). One image was used as the reference image, and the remaining images (target images) were warped onto the reference image using both image registration techniques. The normalized correlation between the reference and the transformed target images within the lung domain was used as a cost function for optimization, and the root mean square (RMS) of image intensity difference was used to evaluate the quality of the registration. Both image registration techniques significantly improved the RMS compared with non registered target images (p= 0.04). The spatial mean (uE) and standard deviation (sigma(E)) of Lagrangian strain were computed based on the spatial distribution of lung deformation approximated by the bicubic Hermite method, and were measured on the order of 10(-3) or less, which is virtually negligible. As a result, small scale lung deformation between FRC lung volumes is spatially uniform, and can be simply characterized by affine deformation even though the bicubic Hermite method is capable of expressing complicated spatial patterns of lung deformation. PMID- 23367126 TI - Methodology for the construction and comparison of 3D models of the human cornea. AB - This paper describes a methodology to build and compare 3D models (or atlases) of the cornea for specific populations. Using topography data of the anterior and posterior corneal surfaces, average and statistical variation maps are computed after registration of individual corneas on a reference sphere. With this methodology, a normal population model is constructed and compared with known eye anatomic data. Comparison of left and right eyes is also performed to see their natural symmetry. Our results demonstrate that spatial normalization is an important step for corneal atlas construction and comparison. PMID- 23367127 TI - Markerless registration for intracerebral hemorrhage surgical system using weighted Iterative Closest Point (ICP). AB - It is required to use a stereotactic frame on a patient's crainial surface to access an intracerebral hematoma in conventional ICH (Intracerebral Hemorrhage) removal surgery. Since ICH using a stereotactic frame is an invasive procedure and also takes a long time, we attempt to develop a robotic ICH removal procedure with a markerless registration system using an optical 3-D scanner. Preoperative planning is performed using a patient's CT (Computed Tomography) images, which include the patient's 3-D geometrical information on the hematoma and internal structures of brain. To register the preplanned data and the intraoperative patient's data, the patient's facial surface is scanned by an optical 3-D scanner on the bed in the operating room. The intraoperatively scanned facial surface is registered to the pose of the patient's preoperative facial surface. The conventional ICP (Iterative Closest Point) algorithm can be used for the registration. In this paper, we propose a weighted ICP in order to improve the accuracy of the registration results. We investigated facial regions that can be used as anatomical landmarks. The facial regions for the landmarks in the preoperative 3-D model are weighted for more accurate registration. We increase weights at the relatively undeformed facial regions, and decrease weights at the other regions. As a result, more accurate and robust registration can be achieved from the preoperative data even with local facial shape changes. PMID- 23367128 TI - Cell tracking and mitosis detection using splitting flow networks in phase contrast imaging. AB - Cell tracking is a crucial component of many biomedical image analysis applications. Many available cell tracking systems assume high precision of the cell detection module. Therefore low performance in cell detection can heavily affect the tracking results. Unfortunately cell segmentation modules often have significant errors, especially in the case of phase-contrast imaging. In this paper we propose a tracking method that does not rely on perfect cell segmentation and can deal with uncertainties by exploiting temporal information and aggregating the results of many frames. Our tracking algorithm is fully automated and can handle common challenges of tracking such as cells entering/exiting the screen and mitosis events. To handle the latter, we modify the standard flow network and introduce the concept of a splitting node into it. Experiment results show that adding temporal information from the video microscopy improves the cell/mitosis detection and results in a better tracking system. PMID- 23367129 TI - Phosphene vision of depth and boundary from segmentation-based associative MRFs. AB - This paper presents a novel low-resolution phosphene visualization of depth and boundary computed by a two-layer Associative Markov Random Fields. Unlike conventional methods modeling the depth and boundary as an individual MRF respectively, our algorithm proposed a two-layer associative MRFs framework by combining the depth with geometry-based surface boundary estimation, in which both variables are inferred globally and simultaneously. With surface boundary integration, the experiments demonstrates three significant improvements as: 1) eliminating depth ambiguities and increasing the accuracy, 2) providing comprehensive information of depth and boundary for human navigation under low resolution phosphene vision, 3) when integrating the boundary clues into downsampling process, the foreground obstacle has been clearly enhanced and discriminated from the surrounding background. In order to gain higher efficiency and lower computational cost, the work is initialized on segmentation based depth plane fitting and labeling, and then applying the latest projected graph cut for global optimization. The proposed approach has been tested on both Middlebury and indoor real-scene data set, and achieves a much better performance with significant accuracy than other popular methods in both regular and low resolutions. PMID- 23367130 TI - Adaptive image segmentation for robust measurement of longitudinal brain tissue change. AB - We present a method that significantly improves magnetic resonance imaging (MRI) based brain tissue segmentation by modeling the topography of boundaries between tissue compartments. Edge operators are used to identify tissue interfaces and thereby more realistically model tissue label dependencies between adjacent voxels on opposite sides of an interface. When applied to a synthetic MRI template corrupted by additive noise, it provided more consistent tissue labeling across noise levels than two commonly used methods (FAST and SPM5). When applied to longitudinal MRI series it provided lesser variability in individual trajectories of tissue change, suggesting superior ability to discriminate real tissue change from noise. These results suggest that this method may be useful for robust longitudinal brain tissue change estimation. PMID- 23367131 TI - Reconstruction of missing cells in fluorescent microscopy. AB - Fluorescent microscopy is one of the several types of imaging techniques used by biologists to study cell activities. One challenge of tracking cells from fluorescence microscopy is that cells in fluorescent images frequently disappear and reappear. The situation is further complicated by cell divisions, which also occur frequently in an image sequence. In this paper, we apply a level set method to reconstruct cells that disappear in an image sequence and in particular, cells that are undergoing cell division. The image frames are stacked together to form a 3D image volume. The disappearance of a cell leads to a broken cell path. We reconstruct the incomplete cell paths by a level set segmentation of the 3D image volume. If the disappearance happens during cell division, the level set method segments the visible cell paths before and after cell division, and then joins them together by extending the cell paths into the missing gap. We also propose a simple and cost-efficient method similar to inpainting techniques to capture the cell appearance when it disappears by making use of the level set function obtained from the segmentation. The idea is that the intensities of a visible cell on a level set contour are copied to the corresponding contours of a disappeared cell. We will present results for reconstruction of cells undergoing cell division for C2C12 cells in fluorescent images to illustrate the effectiveness of our method. PMID- 23367132 TI - Point-guided modeling and segmentation of myocardium for low dose cardiac CT images. AB - Cardiac CT is emerging as a preferable modality to detect myocardial stress/rest perfusion; however the insufficient contrast of myocardium on CT image makes its segmentation difficult. In this paper, we present a point-guided modeling and deformable model-based segmentation method. This method first builds a triangular surface model of myocardium through Bezier contour fitting based on a few points selected by clinicians. Then, a deformable model-based segmentation method is developed to refine the segmentation result. The experiments on 8 cases show the accuracy of the segmentation in terms of true positive volume fraction, false positive volume fractions, and average surface distance can reach 91.0%, 0.3%, and 0.6mm, respectively. The comparison between the proposed method and a graph cut-based method is performed. The results demonstrate that this method is effective in improving the accuracy further. PMID- 23367133 TI - Quantitative characterization and identification of lymph nodes and nasopharingeal carcinoma by coregistered magnetic resonance images. AB - In this study we developed a technique to improve the identification of carcinoma and pathological lymph nodes in cases of Nasopharingeal Carcinoma (NPC), through a quantitative characterization of the tissues based on MR images: 3D VIBE (Volumetric Interpolated Breath-hold Examination) T1-CE (Contrast Enhanced), T1, T2 and Diffusion Weighted Imaging (DWI) for b-values 0,300,500,700,1000. The procedure included two phases: 1) coregistration of volumes and 2) tissue characterization. Concerning the first phase, the DICOM images were reassembled spatially and resampled with isotropic 0.5mm resolution. Coregistration was performed by two multiresolution rigid transformations, merging head and neck volumes, plus a final multiresolution non rigid transformation. The anatomical 3D CE-VIBE volume was taken as reference. The procedure for tissue characterization is semi automated and it required a radiologist to identify an example of tissue from the primary tumor and a metastatic lymph node. We generated a 8-dimensional membership function to perform a fuzzy-like identification of these tissues. The result of this procedure was the generation of two maps, which showed complementary characterization of lymph nodes and carcinoma. A few example will be shown to evidence the potentiality of this method in identification and characterization of NPC lesions. PMID- 23367134 TI - Automated and robust PERCIST-based thresholding framework for whole body PET-CT studies. AB - Positron emission tomography (PET) is unique for quantitatively assessing treatment response before marked morphological changes are detectable by Computed Tomography (CT). PET response criterion (PERCIST) is a widely accepted approach of assessing metabolic response of malignant lesions by using Standardized uptake value (SUV) normalized by lean body mass (LBM) with a volume of interest (VOI) reference defined in the right lobe of liver. However, the operator-dependent delineation of VOI reference is a time consuming and subjective task. Although the VOI reference can be estimated from the co-aligned CT, the low-dose CT data in PET-CT poses challenge in liver segmentation. In this study, we propose a fully automatic framework to calculate the PERCIST-based thresholding for whole body PET-CT studies. The framework consists of multi-atlas registration and voxel classification for CT data to segment liver structure and delineate the VOI reference, which is then mapped to the PET data to derive the value of SUVLBM thresholding for PET to select regions of high metabolism. We evaluated our framework with 28 clinical studies diagnosed with lung cancer or lymphoma, and demonstrated both reliability and efficiency in depicting lesions using PERCIST thresholding. PMID- 23367135 TI - Active contour based segmentation for insulin granule cores in electron micrographs of beta islet cells. AB - Transmission electron microscopy images of beta islet cells contain many complex structures, making it difficult to accurately segment insulin granule cores. Quantification of sub cellular structures will allow biologists to better understand cellular mechanics. Two novel, level set active contour models are presented in this paper. The first utilizes a shape regularizer to reduce oversegmentation. The second contribution is a dual active contour, which achieves accurate core segmentations. The segmentation algorithm proceeds through three stages: an initial rough segmentation using the first contribution, cleaning using morphological techniques and a refining step using the proposed dual active contour. Our method is validated on a set of manually defined ground truths. PMID- 23367136 TI - Dendritic spines detection based on directional morphological filter and shortest path. AB - Dendritic spines are membranous protrusions from neuron's dendrites. They play a very important role in the nervous system. They are very small and have various shapes; hence it is very challenging to detect them in neuron images. This paper presents a novel method for detecting dendritc spines in 2D images. A new dendrite backbone or centerline extraction method is introduced herein which is based on an iterative process between smoothing and extraction. The proposed method iteratively refines the extraction result using both directional morphological filtering and improved Hessian filtering until a satisfactory extraction result is obtained. A shortest path method is applied along a backbone to extract the boundary of the dendrites. Spines are then segmented from the dendrites outside the extracted boundary. The proposed algorithm has been tested with many images and good results are achieved. PMID- 23367137 TI - Color diffusion model for active contours - an application to skin lesion segmentation. AB - Most of the existing diffusion models are defined for gray-scale images. We propose a diffusion model for color images to be used as external energy for active contours. Our diffusion model is based on the first-order moment of the correlation integral expressed using DeltaE distances in the CIE Lab color space. We use a multi-scale approach for active contours, the diffusion being independently computed at various scales. We validate the model on synthetic images, including multi-fractal color textures, as well as medical images representing melanoma. We conclude that the proposed diffusion model is valid for use in skin lesion segmentation in color images using active contours. PMID- 23367138 TI - Automated material map generation from MRI scout pairs for preclinical PET attenuation correction. AB - A novel method is presented to perform material map segmentation from preclinical MRI for corresponding PET attenuation correction. MRI does not provide attenuation ratio, hence segmenting a material map from it is challenging. Furthermore the MRI images often suffer from ghost artifacts. On the contrary MRI has no radiation dose. Our method operated with fast spin echo scout pairs that had perpendicular frequency directions. This way the direction of the ghost artifacts were perpendicular as well. Our body-air segmentation method built on this a priori information and successfully erased the ghost artifacts from the final binary mask. Visual and quantitative validation was performed by two preclinical specialists. Results indicate that our method is effective against MRI scout ghost artifacts and that PET attenuation correction based on MRI makes sense even on preclinical images. PMID- 23367139 TI - Automated segmentation and analysis of the epidermis area in skin histopathological images. AB - In the diagnosis of skin melanoma by analyzing histopathological images, the segmentation of the epidermis area is an important step. This paper proposes a computer-aided technique for segmentation and analysis of the epidermis area in the whole slide skin histopathological images. Before the segmentation technique is employed, a monochromatic color channel that provides a good discriminant information between the epidermis and dermis areas is determined. In order to reduce the processing time and perform the analysis efficiently, we employ multi resolution image analysis in the proposed segmentation technique. At first, a low resolution whole slide image is generated. We then segment the low resolution image using a global threshold method and shape analysis. Based on the segmented epidermis area, the layout of epidermis is determined and the high resolution image tiles of epidermis are generated for further manual or automated analysis. Experimental results on 16 different whole slide skin images show that the proposed technique provides a superior performance, about 92% sensitivity rate, 93% precision and 97% specificity rate. PMID- 23367140 TI - Automatic measurements of choroidal thickness in EDI-OCT images. AB - Enhanced Depth Imaging (EDI) optical coherence tomography (OCT) provides high definition cross-sectional images of the choroid in vivo, and hence is used in many clinical studies. However, measurement of choroidal thickness depends on the manual labeling, which is tedious and subjective of inter-observer differences. In this paper, we propose a fast and accurate algorithm that could measure the choroidal thickness automatically. The lower boundary of the choroid is detected by searching the biggest gradient value above the retinal pigment epithelium (RPE) and the upper boundary is formed by finding the shortest path of the graph formed by valley pixels using dynamic programming. The average of Dice's Coefficient on 10 EDI-OCT images is 94.3%, which shows good consistency of the algorithm with the manual labeling. The processing time for each image is about 2 seconds. PMID- 23367141 TI - Brain anatomical structure segmentation by adaptive bandwidth density estimation. AB - Determination of region in a space of multimodal features of brain MR images requires kernel estimation tecniques with bandwidths that are adapted locally. The bandwidth selection is a critical aspect at the filtering stage of image segmentation. This work presents two methods for determinate the adaptive bandwidth in the application of density estimation, in the segmentation of regions at the feature space of an MRI. Two adaptive methods: sample point and k nearest neighbors, where applied for real and synthetic data, achieved similarity indexes of 0.68 and 0.71 for gray matter and white matter respectively. PMID- 23367142 TI - Improving active contour methods for tracking endothelial cells by the removal of low-confidence edge segments. AB - Previously we developed an active contour method for segmenting and tracking cells in phase-contrast microscopy images. Our method is capable of fine-grained segmentation on noisy image sequences. In this paper, we improve the active contour segmentation model to provide better accuracy, by selectively identifying areas of the contour with low confidence and removing them. The method is applied to HMEC-1 cells (human microvascular endothelial cells). The segmentation provided by the method is quantitavely compared with manually-drawn contours, showing close fit and capability to 'lock' on to cell boundaries for hundreds of frames. PMID- 23367143 TI - Automated segmentation of free-lying cell nuclei in Pap smears for malignancy associated change analysis. AB - This paper presents an automated algorithm for robustly detecting and segmenting free-lying cell nuclei in bright-field microscope images of Pap smears. This is an essential initial step in the development of an automated screening system for cervical cancer based on malignancy associated change (MAC) analysis. The proposed segmentation algorithm makes use of gray-scale annular closings to identify free-lying nuclei-like objects together with marker-based watershed segmentation to accurately delineate the nuclear boundaries. The algorithm also employs artifact rejection based on size, shape, and granularity to ensure only the nuclei of intermediate squamous epithelial cells are retained. An evaluation of the performance of the algorithm relative to expert manual segmentation of 33 fields-of-view from 11 Pap smear slides is also presented. The results show that the sensitivity and specificity of nucleus detection is 94.71% and 85.30% respectively, and that the accuracy of segmentation, measured using the Dice coefficient, of the detected nuclei is 97.30+/-1.3%. PMID- 23367144 TI - An automated method for high-definition transcranial direct current stimulation modeling. AB - Targeted transcranial stimulation with electric currents requires accurate models of the current flow from scalp electrodes to the human brain. Idiosyncratic anatomy of individual brains and heads leads to significant variability in such current flows across subjects, thus, necessitating accurate individualized head models. Here we report on an automated processing chain that computes current distributions in the head starting from a structural magnetic resonance image (MRI). The main purpose of automating this process is to reduce the substantial effort currently required for manual segmentation, electrode placement, and solving of finite element models. In doing so, several weeks of manual labor were reduced to no more than 4 hours of computation time and minimal user interaction, while current-flow results for the automated method deviated by less than 27.9% from the manual method. Key facilitating factors are the addition of three tissue types (skull, scalp and air) to a state-of-the-art automated segmentation process, morphological processing to correct small but important segmentation errors, and automated placement of small electrodes based on easily reproducible standard electrode configurations. We anticipate that such an automated processing will become an indispensable tool to individualize transcranial direct current stimulation (tDCS) therapy. PMID- 23367145 TI - Lesion border detection in Buruli ulcer images. AB - Buruli ulcer, a disease caused by infection with Mycobacterium ulcerans, is one of the most neglected but treatable tropical diseases. In this paper, a novel segmentation scheme is proposed to detect the border of Buruli lesions in cross polarization dermoscopic images that were obtained under white light illumination. The method consists of three main steps: first, segmentations in different color spaces by thresholding are fused to form an initial contour, then a level set segmentation is applied to both the luminance and color components of the image, and finally, decisions for each pixel are made by a support vector machine classifier. Experimental results with 26 images show that the proposed methodology outperforms other state-of-art segmentation approaches for Buruli images. PMID- 23367146 TI - Automated localization and segmentation of lung tumor from PET-CT thorax volumes based on image feature analysis. AB - Positron emission tomography - computed tomography (PET-CT) plays an essential role in early tumor detection, diagnosis, staging and treatment. Automated and more accurate lung tumor detection and delineation from PET-CT is challenging. In this paper, on the basis of quantitative analysis of contrast feature of PET volume in SUV (standardized uptake value), our method firstly automatically localized the lung tumor. Then based on analysing the surrounding CT features of the initial tumor definition, our decision strategy determines the tumor segmentation from CT or from PET. The algorithm has been validated on 20 PET-CT studies involving non-small cell lung cancer (NSCLC). Experimental results demonstrated that our method was able to segment the tumor when adjacent to mediastinum or chest wall, and the algorithm outperformed the other five lung segmentation methods in terms of overlapping measure. PMID- 23367147 TI - Psoriasis segmentation through chromatic regions and Geometric Active Contours. AB - We present a novel approach to the segmentation of psoriasis lesions in "full body" digital photographs potentially involving dozens or even hundreds of separate lesions. Our algorithm first isolates a set of zones that certainly correspond to lesional plaques based on chromatic information, and then expands these zones to achieve an accurate segmentation of plaques through a Geometric Active Contours method. The variability in segmentation between our algorithm and different human operators appears comparable to the variability between human operators. PMID- 23367148 TI - Overlapped chromosome segmentation and separation of touching chromosome for automated chromosome classification. AB - Karyotyping is the process of arranging pairs of the chromosomes in an order to examine chromosomal abnormalities which are the causes for Birth Defects. The overlapping and touching chromosomes of input metaphase spread images should be segmented and disentangled for this process. This paper proposes an algorithm to separate the touching chromosomes and the segmentation of overlapping chromosomes from G-Band metaspread images. Segmentation is performed by obtaining the interesting (concave) points on the image contour and constructing proper hypotheses for segmentation and separation. PMID- 23367149 TI - Objective measurements to evaluate glottal space segmentation from laryngeal images. AB - Objective evaluation of the results of medical image segmentation is a known problem. Applied to the task of automatically detecting the glottal area from laryngeal images, this paper proposes a new objective measurement to evaluate the quality of a segmentation algorithm by comparing with the results given by a human expert. The new figure of merit is called Area Index, and its effectiveness is compared with one of the most used figures of merit found in the literature: the Pratt Index. Results over 110 laryngeal images presented high correlations between both indexes, demonstrating that the proposed measure is comparable to the Pratt Index and it is a good indicator of the segmentation quality. PMID- 23367150 TI - An in-vivo computed tomography approach for quantifying porcine pulmonary arterial morphometry. AB - The objective of this study was to develop an in vivo CT imaging-based approach for pulmonary arterial morphometry measurement, and to improve the geometrical basis for studies of the porcine vasculature. The luminal diameter and distance from the inlet of left and right pulmonary arteries, and pulmonary arteries within the lungs of two porcine subjects were measured at inflation pressure of 25 cmH(2)O. The results suggest that the porcine pulmonary arteries have geometric self-similarity, and that this approach will have utility for systematically quantifying pulmonary arterial vessel dimensions in vivo in a larger group of animals. PMID- 23367151 TI - Electromyographic signal compression based on preprocessing techniques. AB - Recently, electromyographic records have been rearranged into two-dimensional arrays and encoded with image compressors, in the same way as image data. However, as a consequence of this reshaping, the correlation among signal segments is generally lost, which reduces the compression efficiency. In the present work, new preprocessing techniques for encoding electromyographic signals as two-dimensional matrices are presented, namely percentage difference sorting and relative complexity sorting, which have the potential to favor the exploitation of the intersegment dependencies. The experiments were carried out with real isometric records acquired in laboratory, that were first preprocessed and then compressed with a JPEG2000 encoder, showing that the proposed framework is effective and outperforms even state-of-the-art schemes present in the literature, in terms of PRD * Compression Ratio. PMID- 23367152 TI - A graph-based approach to the retrieval of volumetric PET-CT lung images. AB - Combined positron emission tomography and computed tomography (PET-CT) scans have become a critical tool for the diagnosis, localisation, and staging of most cancers. This has led to a rapid expansion in the volume of PET-CT data that is archived in clinical environments. The ability to search these vast imaging collections has potential clinical applications in evidence-based diagnosis, physician training, and biomedical research that may lead to the discovery of new knowledge. Content-based image retrieval (CBIR) is an image search technique that complements conventional text-based retrieval by the use of image features as search criteria. Graph-based CBIR approaches have been found to be exemplary methods for medical CBIR as they provide the ability to consider disease localisation during the similarity measurement. However, the majority of graph based CBIR studies have been based on 2D key slice approaches and did not exploit the rich volumetric data that is inherent to modern medical images, such as multi modal PET-CT. In this paper, we present a graph-based CBIR method that exploits 3D spatial features extracted from volumetric regions of interest (ROIs). We index these features as attributes of a graph representation and use a graph-edit distance to measure the similarity of PET-CT images based on the spatial arrangement of tumours and organs in a 3D space. Our study aims to explore the capability of these graphs in 3D PET-CT CBIR. We show that our method achieves promising precision when retrieving clinical PET-CT images of patients with lung tumours. PMID- 23367153 TI - A statistical model-based technique for accounting for prostate gland deformation in endorectal coil-based MR imaging. AB - In prostate brachytherapy procedures, combining high-resolution endorectal coil (ERC)-MRI with Computed Tomography (CT) images has shown to improve the diagnostic specificity for malignant tumors. Despite such advantage, there exists a major complication in fusion of the two imaging modalities due to the deformation of the prostate shape in ERC-MRI. Conventionally, nonlinear deformable registration techniques have been utilized to account for such deformation. In this work, we present a model-based technique for accounting for the deformation of the prostate gland in ERC-MR imaging, in which a unique deformation vector is estimated for every point within the prostate gland. Modes of deformation for every point in the prostate are statistically identified using a set of MR-based training set (with and without ERC-MRI). Deformation of the prostate from a deformed (ERC-MRI) to a non-deformed state in a different modality (CT) is then realized by first calculating partial deformation information for a limited number of points (such as surface points or anatomical landmarks) and then utilizing the calculated deformation from a subset of the points to determine the coefficient values for the modes of deformations provided by the statistical deformation model. Using a leave-one-out cross-validation, our results demonstrated a mean estimation error of 1mm for a MR-to-MR registration. PMID- 23367154 TI - Joint probability of shape and image similarities to retrieve 2D TRUS-MR slice correspondence for prostate biopsy. AB - This paper presents a novel method to identify the 2D axial Magnetic Resonance (MR) slice from a pre-acquired MR prostate volume that closely corresponds to the 2D axial Transrectal Ultrasound (TRUS) slice obtained during prostate biopsy. The method combines both shape and image intensity information. The segmented prostate contours in both the imaging modalities are described by shape-context representations and matched using the Chi-square distance. Normalized mutual information and correlation coefficient between the TRUS and MR slices are computed to find image similarities. Finally, the joint probability values comprising shape and image similarities are used in a rule-based framework to provide the MR slice that closely resembles the TRUS slice acquired during the biopsy procedure. The method is evaluated for 20 patient datasets, of which 18 results match at least one of the two clinical expert choices. PMID- 23367155 TI - A probability distribution of shape for the dental maxillary arch using digital images. AB - Selected landmarks from each of 47 maxillary dental casts were used to define a Cartesian-coordinate system from which the positions of selected teeth were determined on standardized digital images. The position of the i-th tooth was defined by a line of length (l(i)) joining the tooth to the origin, and the angle (theta(i)) of this line to the horizontal Cartesian axis. Four teeth, the central incisor, lateral incisor, canine and first molar were selected and their position were collectively used to represent the shape of the dental arch. A pilot study using clustering and principal component analysis strongly suggest the existence of 3 groups of arch shape. In this study, the homogeneity of the 3 groups was further investigated and confirmed by the Dunn and Davies-Bouldein validity indices. This is followed by an investigation of the probability distribution of these 3 groups. The main result of this study suggests 3 groups of multivariate (MV) normal distribution. The MV normal probability distribution of these groups may be used in further studies to investigate the issues of variation of arch shape, which is fundamental to the practice of prosthodontics and orthodontics. PMID- 23367156 TI - ZPEG: a hybrid DPCM-DCT based approach for compression of Z-stack images. AB - Modern imaging technology permits obtaining images at varying depths along the thickness, or the Z-axis of the sample being imaged. A stack of multiple such images is called a Z-stack image. The focus capability offered by Z-stack images is critical for many digital pathology applications. A single Z-stack image may result in several hundred gigabytes of data, and needs to be compressed for archival and distribution purposes. Currently, the existing methods for compression of Z-stack images such as JPEG and JPEG 2000 compress each focal plane independently, and do not take advantage of the Z-signal redundancy. It is possible to achieve additional compression efficiency over the existing methods, by exploiting the high Z-signal correlation during image compression. In this paper, we propose a novel algorithm for compression of Z-stack images, which we term as ZPEG. ZPEG extends the popular discrete-cosine transform (DCT) based image encoder to compress Z-stack images. This is achieved by decorrelating the neighboring layers of the Z-stack image using differential pulse-code modulation (DPCM). PSNR measurements, as well as subjective evaluations by experts indicate that ZPEG can encode Z-stack images at a higher quality as compared to JPEG, JPEG 2000 and JP3D at compression ratios below 50?1. PMID- 23367157 TI - Nonlinear mechanics of DNA doule strand: existence of the compact-envelope bright solitary wave. AB - We study the nonlinear dynamics of a homogeneous DNA chain which is based on site dependent finite stacking and pairing enthalpies. We introduce an extended nonlinear Schrodinger equation describing the dynamics of modulated wave in DNA model. We obtain envelope bright solitary waves with compact support as a solution. Analytical criteria of existence of this solution are derived. The stability of bright compactons is confirmed by numerical simulations of the exact equations of the lattice. The impact of the finite stacking energy is investigated and we show that some of these compact bright solitary waves are robust, while others decompose very quickly depending on the finite stacking parameters. PMID- 23367158 TI - Revealing the dynamic modularity of composite biological networks in breast cancer treatment. AB - A major challenge in modern breast cancer treatment is to unravel the effect of drug activity through the systematic rewiring of cellular networks over time. Here, we illustrate the efficacy and discriminative power of our integrative approach in detecting modules that represent the regulatory effect of tamoxifen, widely used in anti-estrogen treatment, on transcriptome and proteome and serve as dynamic sub-network signatures. Initially, composite networks, after integrating protein interaction and time series gene expression data between two conditions (estradiol and estradiol plus tamoxifen), were constructed. Further, the Detect Module from Seed Protein (DMSP) algorithm elaborated on the graphs and constructed modules, with specific 'seed' proteins used as starting points. Our findings provide evidence about the way drugs perturb and rewire the high-order organization of interactome in time. PMID- 23367159 TI - Data assimilation of glucose dynamics for use in the intensive care unit. AB - We know much about the glucose regulatory system, yet the application of this knowledge is limited because simultaneous measurements of insulin and glucose are difficult to obtain. We present a data assimilation framework for combining sparse measurements of the glucose regulatory system, available in the intensive care unit setting, with a nonlinear computational model to estimate unmeasured variables and unknown parameters. We also demonstrate a method for choosing the best variables for measurement. We anticipate that this framework will improve glucose maintenance therapies and shed light on the underlying biophysical process. PMID- 23367160 TI - Nonlinear model for Dynamic Synapse Neural Network. AB - This paper presents a simplified nonlinear model for Dynamic Synapse Neural Network (DSNN) which is based on nonlinear dynamics of neurons in the hippocampus, using a recurrent neural network. The proposed model will be utilized in place of DSNN for various applications which require simpler implementation and faster training, maintaining the same performance as a nonlinear system model, classifier, or pattern recognizer. This model was tested in two different structure and training methods, by learning the input-output relationship of a few DSNNs with sets of experimentally-determined coefficients. The results showed that this model can capture DSNN's complicated nonlinear dynamics in a temporal domain with less computational cost and faster training. PMID- 23367161 TI - Examining intrinsic thalamic resting state networks using graph theory analysis: implications for mTBI detection. AB - A major challenge associated with understanding mild traumatic brain injury (mTBI) is the absence of biomarkers in standard clinical imaging modalities. Furthermore, the inhomogeneity of mTBI location and intensity, combined with latent symptoms further complicates identification and treatment. A growing body of evidence suggests that the thalamus may be injured or susceptible to change as the result of mTBI. A significant number of connections to and from cortical, subcortical, cerebellar and brain stem regions converge at the thalamus. Furthermore, the thalamus is also involved with information processing, integration and the regulation of specific behaviors. We use graph theory analysis to evaluate intrinsic functional networks of the left and right thalamus in mTBI subjects (N=15) and neurologically intact healthy controls (N=12). We also explore neural correlates of the thalamic network architecture with clinical assessments. Our results suggest the presence of distinct unilateral thalamic differences in mTBI subjects. We also observe correlations of the thalamic changes with clinical assessments. The findings from this study have implications for functional networks in the thalamus and its projections for application as a potential biomarker for mTBI detection. PMID- 23367162 TI - Using an adaptive gene network model for self-organizing multicellular behavior. AB - Using the transient interleukin (IL)-2 secretion of effector T helper (T(eff)) cells as an example, we show that self-organizing multicellular behavior can be modeled and predicted by an adaptive gene network model. Incorporating an adaptation algorithm we established previously, we construct a network model that has the parameter values iteratively updated to cope with environmental change governed by diffusion and cell-cell interactions. In contrast to non-adaptive models, we find that the proposed adaptive model for individual T(eff) cells can generate transient IL-2 secretory behavior that is observed experimentally at the population level. The proposed adaptive modeling approach can be a useful tool in the study of self-organizing behavior observed in other contexts in biology, including microbial pathogenesis, antibiotic resistance, embryonic development, tumor formation, etc. PMID- 23367163 TI - Exploring the effective connectivity of resting state networks in mild cognitive impairment: an fMRI study combining ICA and multivariate Granger causality analysis. AB - Mild cognitive impairment (MCI) was recognized as the prodromal stage of Alzheimer's disease (AD). Recent neuroimaging studies have shown that the cognitive and memory decline in AD and MCI patients is coupled with abnormal functions of focal brain regions and disrupted functional connectivity between distinct brain regions, as well as losses of small-world attributes. However, the causal interactions among the spatially isolated but function-related resting state networks (RSNs) are still largely unexplored in MCI patients. In this study, we first identified eight RSNs by independent components analysis (ICA) from resting state functional MRI data of 16 MCI patients and 18 age-matched healthy subjects respectively. Then, we performed a multivariate Granger causality analysis (mGCA) to evaluate the effective connectivity among the RSNs. We found that MCI patients exhibited decreased causal interactions among the RSNs in both intensity and quantity compared with normal controls. Results from mGCA indicated that the causal interactions involving the default mode network (DMN) became weaker in MCI patients, while stronger causal connectivity emerged related to the memory network and executive control network. Our findings suggested that the DMN played a less important role in MCI patients. Increased causal connectivity of the memory network and executive control network may elucidate the dysfunctional and compensatory processes in the brain networks of MCI patients. These preliminary findings may be helpful for further understanding the pathological mechanisms of MCI and provide a new clue to explore the neurophysiological mechanisms of MCI. PMID- 23367164 TI - Connectivity and phase coherence in neural network models of interconnected Z(4) bi-stable units. AB - A phenomenological neural network model with bi-stable oscillatory units is used to model up- and down-states. These states have been observed in vivo in biological neuronal systems and feature oscillatory, limit cycle type of behavior in the up-states. A network is formed by a set of interconnected units. Two different types of network layouts are considered in this work: networks with hierarchical connections and hubs and networks with random connections. The phase coherence between the different units is analyzed and compared to the connectivity distance between nodes. In addition the connectivity degree of a node is associated to the average phase coherence with all other units. The results show that we may be able to identify the set of hubs in a network based on the phase coherence estimates between the different nodes. If the network is very dense or randomly connected, the underlying network structure, however, can not be derived uniquely from the phase coherence. PMID- 23367165 TI - A game-of-life like simulator for design-oriented modeling of BioBricks in synthetic biology. AB - This paper deals with the development of a new simulator that will be very helpful to establish new accurate and predictive design-oriented models for the BioBricks used in synthetic biology. The simulator uses the principle of the game of-life: molecules can move on a grid and, at every iteration, binding and dissociation rules are applied when two molecules are on same node. The principle is elementary but it can highlight interesting biological phenomenon. Those can be modeled by mathematical equations to achieve design-oriented models. In this case, the simulator also helps to make to link between mathematical parameters and the microscopic parameters. A first version of the software has been implemented in MATLAB. It permits to retrieve very interesting results, such as the Hill's equation and the properties of Hill's coefficient. PMID- 23367167 TI - Supporting reconstruction of the blood vessel network using graph theory: an abstraction method. AB - The blood vessel network (BVN) has a complex structure. As this structure is unique for each individual, it is not possible to establish a general model for the BVN. However, many medical applications do rely on this structure. For example, a drug delivery system would be greatly improved if it could control the drug flow towards destination. To address this BVN structure issue, several reconstruction methods have been introduced. In this paper, we describe an abstraction method supporting BVN reconstruction by using graph theory. Starting from an original BVN reconstruction, we define the so-called induced graph of that reconstruction, allowing for an efficient analysis. By applying this method, we were able to improve an original BVN reconstruction of a human kidney by pointing out probable errors inside that original reconstruction. PMID- 23367168 TI - Global optimization for human skin investigation in terahertz. AB - In this paper, the electromagnetic interaction between human skin and terahertz radiation is investigated through the double Debye parameters' extraction algorithm. The changes of skin content are contrasted at the frequencies below one terahertz(THz) but the recent approaches could provide only a rough estimation. We propose an global optimization based identification, which results in globally accurate estimators in the frequency range up to two THz, and thus supports the validity of Debye model for Terahertz wave's propagation and reflection in skin. Simulation results confirm our prominent methodology. PMID- 23367169 TI - A sparse matrix approach for simultaneous quantification of nystagmus and saccade. AB - The vestibulo-ocular reflex (VOR) consists of two intermingled non-linear subsystems; namely, nystagmus and saccade. Typically, nystagmus is analysed using a single sufficiently long signal or a concatenation of them. Saccade information is not analysed and discarded due to insufficient data length to provide consistent and minimum variance estimates. This paper presents a novel sparse matrix approach to system identification of the VOR. It allows for the simultaneous estimation of both nystagmus and saccade signals. We show via simulation of the VOR that our technique provides consistent and unbiased estimates in the presence of output additive noise. PMID- 23367170 TI - Identification of the glucose minimal model by stochastic nonlinear-mixed effects methods. AB - The nonlinear mixed effects models (NLMEM) are widespread modeling techniques in PKPD analysis and epidemiological studies because they can produce a description of not only the individual but also of the population features. Moreover, they are able to deal with individual data sparseness by borrowing the lack of information from the entire population. In this way, the NLMEM do not fail where instead other techniques, such as the traditional individual weighted least squares (WLS), sometimes do. The NLME approach relies on the maximization of a likelihood function that due to model parametric nonlinearity not always has an explicit solution. Various techniques have been proposed to solve this problem including the first order (FO) and the first order conditional (FOCE) estimation methods that approximate the likelihood function through a linearization; the expectation maximization algorithm (EM) that maximize the exact likelihood; the Bayesian estimation method where a third stage of variability, the distribution of the population parameters, is taken into account [1]. Recently, new estimation methods that rely on the EM algorithm have been implemented in the last release of the population software NONMEM [2]. These methods are: the iterative two stage (ITS), Monte Carlo importance sampling EM (IMP), Monte Carlo importance sampling EM assisted by Mode a Posteriori estimation (IMPMAP) and the Stochastic Approximation EM (SAEM). Moreover, another new method is available, the Markov Chain Monte Carlo Bayesian Analysis (BAYES), next to the more known FO and FOCE. With this article we want to complete the Denti et al [3] simulation study by evaluating the newest population methods applied on the IVGTT glucose minimal model. PMID- 23367171 TI - A pipeline for the simulation of transcranial direct current stimulation for realistic human head models using SCIRun/BioMesh3D. AB - The current work presents a computational pipeline to simulate transcranial direct current stimulation from image based models of the head with SCIRun [15]. The pipeline contains all the steps necessary to carry out the simulations and is supported by a complete suite of open source software tools: image visualization, segmentation, mesh generation, tDCS electrode generation and efficient tDCS forward simulation. PMID- 23367172 TI - A novel discrete particle swarm optimization algorithm for estimating dielectric constants of tissue. AB - Global optimization algorithms basically create a set of solutions, classify them, and then search for the best answer, iteratively. In this paper, a new discrete particle swarm optimization algorithm is proposed to estimate the permittivity arrangements of lossy multilayer structures, which represent body tissue models. Microwave imaging (AMI) is the modality in which the proposed algorithm is used for reconstructing the image. The main objective of this article is to depict the flexibility of PSO-based methods in handling complex problems expeditiously and successfully. Our new algorithm improves the estimation time by 85% as compared to our previous proposed one. Here, the impact of various parameters, namely, the AMI frequency, the immersion medium, the number of agents, the smoothing coefficient, and the maximum velocity, on the estimation performance are studied in terms of the maximum estimation error. It is demonstrated that by choosing the parameters correctly, one can achieve estimation results with a maximum error less that 10% in only 0.1 minute. PMID- 23367173 TI - Morphological analysis of T-wave in vectorcardiographic leads system by a bi Gaussian approach in patients under effect of salbutamol. AB - There are several models of decomposition of the electrocardiogram (ECG). Some of these models are intended to describe the ECG signal, and others are more specific to extract the relevant information relating to individual waveform which contributes to explain the P-QRS complex. The latter approach may be particularly suitable for a portion where a morphological analysis of the ECG is of particular interest, as the cardiac repolarization segment or T-wave. This study aims: to model and detect useful patterns in the evaluation of T wave morphology, which explains the different changes in ventricular repolarization during inhalation of Salbutamol. PMID- 23367174 TI - Modeling cell-to-cell stochastic variability in intrinsic apoptosis pathway. AB - Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Dependent on the type of stimulus, apoptosis can be propagated by intrinsic pathway or extrinsic pathway. Previously, we have proposed a deterministic model of intrinsic apoptosis pathway which is bistable in a robust parameter region. Cellular networks, however, are inherently stochastic and significant cell-to-cell variability in apoptosis response has been observed at single cell level. In this work, we examine the impact of intrinsic stochastic fluctuations as well as variation of protein concentrations on behavior of the intrinsic apoptosis network. First, Gillespie Stochastic Simulation Algorithm (SSA) of the model is implemented to account for intrinsic noise. Using histograms of steady-state output at varying input levels, we show that the intrinsic noise in the apoptosis network elicits a wider region of bistability. We further analyze the dependence of system stochasticity due to intrinsic fluctuations, such as steady-state noise level and random response delay time, on the input signal. We find however that the intrinsic noise is insufficient to generate significant stochastic variations at physiologically relevant level of molecular numbers. Finally, extrinsic fluctuation represented by variations of two key proteins is modeled and the resultant stochasticity of apoptosis timing is analyzed. Indeed, these protein variations can induce cell-to-cell stochastic variability at a quantitative level agreeing with experiments. Therefore, we conclude that the heterogeneity in intrinsic apoptosis responses among individual cells plausibly arises from extrinsic rather than intrinsic origin of fluctuations. PMID- 23367175 TI - Modeling spatial population dynamics of stem cell lineage in tissue growth. AB - Understanding the dynamics of cell population allows insight into the control mechanism of the growth and development of mammalian tissues. It is well known that the proliferation and differentiation among stem cells (SCs), intermediate progenitor cells (IPCs), and fully differentiated cells (FDCs) are under different activation and inhibition controls. Secreted factors in negative feedback loops have already been identified as major elements in regulating the numbers of different cell types and in maintaining the equilibrium of cell populations. We have developed a novel spatial dynamic model of cells. We can characterize not only overall cell population dynamics, but also details of temporal-spatial relationship of individual cells within a tissue. In our model, the shape, growth, and division of each cell are modeled using a realistic geometric model. Furthermore, the inhibited growth rate, proliferation and differentiation probabilities of individual cells are modeled through feedback loops controlled by secreted factors of neighboring cells within a proper diffusion radius. With specific proliferation and differentiation probabilities, the actual division type that each cell will take is chosen by a Monte Carlo sampling process. With simulations we found that with proper strengths of inhibitions to growth and stem cell divisions, the whole tissue is capable of achieving a homeostatic size control. We discuss our findings on control mechanisms of the stability of the tissue development. Our model can be applied to study broad issues on tissue development and pattern formation in stem cell and cancer research. PMID- 23367176 TI - Modeling normal and rebound excitation in mammalian retinal ganglion cells. AB - In this study, we used a novel missing currents technique to extend an existing conductance-based ionic current model of retinal ganglion cells (RGCs). The revised model reproduced a variety of biological behaviors. In particular, the model contains a hyperpolarization activated current (I(h)). This model can effectively simulate the mechanisms underlying both normal and rebound action potentials. The technique used in this study is generally applicable to other excitable cell models, reducing the gap between theoretical models and real biological neurons. PMID- 23367177 TI - An analysis of the expression locus of long-term potentiation in hippocampal CA1 neurons. AB - Long-term potentiation (LTP) has long been understood as an increase in the potency of a synaptic connection between two neurons. In this study, we combine a previously developed two-stage cascade model with electrophysiological recordings of rat hippocampal CA1 pyramidal cells both before and after LTP to analyze linear and nonlinear contributions of pre and post-synaptic partners to the strengthening of their synaptic connectivity. The result suggests that the major nonlinear expression locus of LTP exists in the post-synaptic side. Additionally, the report reveals that LTP should be understood not only in the traditional view as a change in the magnitude of communication between two cells, but also as a change in their temporal coding properties of information exchange. PMID- 23367178 TI - Investigation of the electric field components of tDCS via anisotropically conductive gyri-specific finite element head models. AB - Transcranial Direct Current Stimulation (tDCS) is considered as one of the promising techniques for noninvasive brain stimulation and brain disease therapy. In this study, we have investigated the effect of skull and white matter (WM) anisotropy on the induced electric field (EF) by tDCS in two different montages; one using a pair of clinically used rectangular pad electrodes and the other 4(cathodes)+1(anode) ring electrodes. Using a gyri-specific finite element (FE) head model, we simulated tDCS and investigated the radial and tangential components of the induced EF in terms of their distribution over the cortical surface besides the distribution of the transverse and longitudinal components within WM. The results show that the tangential component of the EF on the cortical surface seems to be the main cause of the cortical stimulation of tDCS. Also WM anisotropy seems to increase the dispersion of the transverse component of the EF that affects the dispersion of the EF magnitude within the WM region. PMID- 23367179 TI - Evaluation of cell impedance using a MU-channel. AB - We propose a novel approach for evaluating both the stiffness and internal viscosity of a cell by using a MU-channel. The key idea comes from the fact that cell behavior in the channel can be separated into two phases; one is in the entrance area where the cell heavily deforms within a short distance, and the other is in the remaining area where the cell keeps almost constant shape. By focusing on the cell behavior in the first area, we can evaluate the internal viscosity of a cell. By focusing on the cell behavior in the second area, we can evaluate the stiffness. We conducted experiments with two different initial velocities of red blood cells, and discussed the results from the viewpoint of applicability. PMID- 23367180 TI - Development of multi-compartment model of the liver using image-based meshing software. AB - Computer simulation of biological systems for in silico validation has the potential of increasing the efficiency of pharmaceutical research and development by expanding the number of parameters tested virtually. Then only the most interesting subset of these has to be probed in vivo. By focusing on variables with the greatest influence on clinical end points, valuable drug targets can be advanced more quickly. A large number of methods have been developed to rebuild a three-dimensional (3D) model of a liver, mostly to prepare a liver surgery. These models are often not accurate and most of the them don't take into account the fluidics inside the vessels. The aim of this work is to provide an accurate computational multi-compartement model of the healthy and the pathological liver with their network of blood vessels (vasculature) using a finite-element-modeling software. Computed tomography (CT) slices, in DICOM format, from two different patients were used to provide the datasets of transverse images for the modeling. Each dataset of images was segmented in order to extract the liver's shape and define the vein and artery networks. On CT images, the contrast between the liver and the nearby organs (background) is very low because all these structures are a similar density. Thus, we used semi-automatic tools to determine liver contours. Manual segmentation was used as a last resort. Then, strong filtering (bilateral filter) and confidence-connected-region-growing algorithm were applied to rebuild from each - healthy and pathological - liver a multicompartment model including parenchyma, arteries and veins. The precision of the obtained vasculature model allowed anatomical classification of hepatic segments and the quantification of their volumes. Although our study demonstrated the difficulties in use of CT images for computational modeling of the liver, it also confirmed that semi automatic tools can be used to develop anatomically accurate models of hepatic vasculature. PMID- 23367181 TI - A multibody atomic statistical potential for the prediction of enzyme-inhibitor binding energy. AB - Accurate prediction of enzyme-inhibitor binding energy has the capacity to speed drug design and chemical genomics efforts by helping to narrow the focus of experiments. Here a non-redundant set of three hundred high-resolution crystallographic enzyme-inhibitor structures was compiled for analysis, complexes with known binding energies (DeltaG) based on the availability of experimentally determined inhibition constants (ki). Additionally, a separate set of over 1400 diverse high-resolution macromolecular crystal structures was collected for the purpose of creating an all-atom knowledge-based statistical potential, via application of the Delaunay tessellation computational geometry technique. Next, two hundred of the enzyme-inhibitor complexes were randomly selected to develop a model for predicting binding energy, first by tessellating structures of the complexes as well as the enzymes without their bound inhibitors, then by using the statistical potential to calculate a topological score for each structure tessellation. We derived as a predictor of binding energy an empirical linear function of the difference between topological scores for a complex and its isolated enzyme. A correlation coefficient (r) of 0.79 was obtained for the experimental and calculated DeltaG values, with a standard error of 2.34 kcal/mol. Lastly, the model was evaluated with the held-out set of one hundred complexes, for which structure tessellations were performed in order to calculate topological score differences, and binding energy predictions were generated from the derived linear function. Calculated binding energies for the test data also compared well with their experimental counterparts, displaying a correlation coefficient of r= 0.77 with a standard error of 2.50 kcal/mol. PMID- 23367182 TI - Using digital electronic design flow to create a Genetic Design Automation tool. AB - Synthetic bio-systems become increasingly more complex and their development is lengthy and expensive. In the same way, in microelectronics, the design process of very complex circuits has benefited from many years of experience. It is now partly automated through Electronic Design Automation tools. Both areas present analogies that can be used to create a Genetic Design Automation tool inspired from EDA tools used in digital electronics. This tool would allow moving away from a totally manual design of bio-systems to assisted conception. This ambitious project is presented in this paper, with a deep focus on the tool that automatically generates models of bio-systems directly usable in electronic simulators. PMID- 23367183 TI - SVM-based prediction of the calpain degradome using Bayes Feature Extraction. AB - Calpains belong to a family of calcium-dependent cysteine proteases which are implicated in a myriad of pathologies such as cancer and neurodegeneration. Despite extensive experimental studies on these proteases, our knowledge of the calpain degradome is still limited. Using a dataset of 341 unique, experimentally verified calpain cleavage sites, we conducted extensive sequence analyses and discovered novel residue propensities in the region flanking the cleavage site which could be modeled for prediction using machine learning algorithms. We have developed a series of computational models incorporating support vector machines and Bayes Feature Extraction for the prediction of calpain cleavage sites. The best models achieved AROC and accuracy scores ranging from 0.79 to 0.93 and 71% to 86% respectively when tested on independent test sets. We predicted calpain cleavage sites on proteins from the receptor tyrosine kinase family and discovered potential sites of cleavage at critical regulatory domains. The results suggest a novel role of calpains as a direct regulator of receptor tyrosine kinase activity in cell survival and cell death pathways. PMID- 23367184 TI - Identification of genes for complex diseases by integrating multiple types of genomic data. AB - Combining multi-types of genomic data for integrative analyses can take advantage of complementary information and thus can have higher power to identify genes/variables that would otherwise be impossible with individual data analysis. Here we proposed a sparse representation based clustering (SRC) method for integrative data analyses, and applied the SRC method to the integrative analysis of 376821 SNPs in 200 subjects (100 cases and 100 controls) and expression data for 22283 genes in 80 subjects (40 cases and 40 controls) to identify significant genes for osteoporosis (OP). Comparing our results with previous studies, we identified some genes known related to OP risk, as well as some uncovered novel osteoporosis susceptible genes ('DICER1', 'PTMA', etc.) that may function importantly in osteoporosis etiology. In addition, the SRC method identified genes can lead to higher accuracy for the identification of osteoporosis subjects when compared with the traditional T-test and Fisher-exact test, which further validate the proposed SRC approach for integrative analysis. PMID- 23367186 TI - Building phylogenetic trees by using gene Nucleotide Genomic Signals. AB - Nucleotide genomic signal (NuGS) methodology allows a molecular level approach to determine distances between homologous genes or between conserved equivalent non coding genome regions in various species or individuals of the same species. Therefore, distances between the genes of species or individuals can be computed and phylogenetic trees can be built. The paper illustrates the use of the nucleotide imbalance (N) and nucleotide pair imbalance (P) signals to determine the distances between the genes of several Hominidae. The results are in accordance with those of other genetic or phylogenetic approaches to establish distances between Hominidae species. PMID- 23367185 TI - Visualization of high resolution spatial mass spectrometric data during acquisition. AB - Mass Spectrometric Imaging (MSI) allows the generation of 2D ion density maps that help visualize molecules present in sections of tissues and cells. The combination of spatial resolution and mass resolution results in very large and complex data sets. New capabilities are necessary for efficient analysis and interpretation of this data. This work details the development and application of the capability to process, visualize, query, and analyze spatial mass spectrometry data. Applications include the generation of 2D maps for selected spectra, the manipulation of the heat maps, and the identification of spectral peaks. Heat maps are generated by projecting the sum of intensity vs. time spectra of each pixel for selected m/z value or range. These capabilities take the form of a new interactive software toolkit, MSI QuickView. This software approach is a significant advance over the previous state-of-the art methods that required the conversion of the RAW data using one software, manual assembly of the data, and visualization in another software. PMID- 23367187 TI - An adaptation of Pfam profiles to predict protein sub-cellular localization in Gram positive bacteria. AB - Predicting the sub-cellular localization of a protein can provide useful information to uncover its molecular functions. In this sense, numerous prediction techniques have been developed, which usually have been focused on global information of the protein or sequence alignments. However, several studies have shown that the functional nature of proteins is ruled by conserved sub-sequence patterns known as domains. In this paper, an alternative methodology (PfamFeat) for gram-positive bacterial sub-cellular localization was developed. PfamFeat is based on information provided by Pfam database, which stores a series of HMM-profiles describing common protein domains. The likelihood of a sequence, to be generated by a given HMM-profile, can be used to characterize sequences in order to use pattern recognition techniques. Success rates obtained with a simple one-nearest neighbor classifier demonstrate that this method is competitive with popular sub-cellular prediction algorithms and it constitutes a promising research trend. PMID- 23367188 TI - Potential MiRNAs recognition site identification in 3' UTR regions by DSP methods. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate fundamental cellular processes in diverse organisms and that have an important function in gene expression regulation. miRNAs seem capable to concurrently modulate hundreds of target genes. Their abnormal expression is emerging as important element in many pathological conditions. The identification of microRNA binding sites on those proteins that can be disease biomarker is fundamental to design synthetic artificial oligomers. In this paper we suggest a method, based on signal processing, to filter out potential miRNA recognition sites in the 3' UTR region of mRNAs. PMID- 23367189 TI - Predicting atrial fibrillation and flutter using electronic health records. AB - Electronic Health Records (EHR) contain large amounts of useful information that could potentially be used for building models for predicting onset of diseases. In this study, we have investigated the use of free-text and coded data in Marshfield Clinic's EHR, individually and in combination for building machine learning based models to predict the first ever episode of atrial fibrillation and/or atrial flutter (AFF). We trained and evaluated our AFF models on the EHR data across different time intervals (1, 3, 5 and all years) prior to first documented onset of AFF. We applied several machine learning methods, including naive bayes, support vector machines (SVM), logistic regression and random forests for building AFF prediction models and evaluated these using 10-fold cross-validation approach. On text-based datasets, the best model achieved an F measure of 60.1%, when applied exclusively to coded data. The combination of textual and coded data achieved comparable performance. The study results attest to the relative merit of utilizing textual data to complement the use of coded data for disease onset prediction modeling. PMID- 23367190 TI - Simulink based behavioural modelling of a pulse oximeter for deployment in rapid development, prototyping and verification. AB - The pulse oximeter is a well-known device for measuring the level of oxygen in blood. Since their invention, pulse oximeters have been under constant development in both aspects of hardware and software; however there are still unsolved problems that limit their performance [6], [7]. Many fresh algorithms and new design techniques are being suggested every year by industry and academic researchers which claim that they can improve accuracy of measurements [8], [9]. With the lack of an accurate computer-based behavioural model for pulse oximeters, the only way for evaluation of these newly developed systems and algorithms is through hardware implementation which can be both expensive and time consuming. This paper presents an accurate Simulink based behavioural model for a pulse oximeter that can be used by industry and academia alike working in this area, as an exploration as well as productivity enhancement tool during their research and development process. The aim of this paper is to introduce a new computer-based behavioural model which provides a simulation environment from which new ideas can be rapidly evaluated long before the real implementation. PMID- 23367191 TI - A survival prediction model of rats in hemorrhagic shock using the random forest classifier. AB - Hemorrhagic shock is the cause of one third of deaths resulting from injury in the world. Although many studies have tried to diagnose hemorrhagic shock early and accurately, such attempts were inconclusive due to compensatory mechanisms of humans. The objective of this study was to construct a survival prediction model of rats in hemorrhagic shock using a random forest (RF) model, which is a newly emerged classifier acknowledged for its performance. Heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR), lactate concentration (LC), and perfusion (PF) measured in rats were used as input variables for the RF model and its performance was compared with that of a logistic regression (LR) model. Before constructing the models, we performed a 5-fold cross validation for RF variable selection and forward stepwise variable selection for the LR model to see which variables are important for the models. For the LR model, sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (ROC-AUC) were 1, 0.89, 0.94, and 0.98, respectively. For the RF models, sensitivity, specificity, accuracy, and AUC were 0.96, 1, 0.98, and 0.99, respectively. In conclusion, the RF model was superior to the LR model for survival prediction in the rat model. PMID- 23367192 TI - Individualized performance prediction during total sleep deprivation: accounting for trait vulnerability to sleep loss. AB - Individual differences in vulnerability to sleep loss can be considerable, and thus, recent efforts have focused on developing individualized models for predicting the effects of sleep loss on performance. Individualized models constructed using a Bayesian formulation, which combines an individual's available performance data with a priori performance predictions from a group average model, typically need at least 40 h of individual data before showing significant improvement over the group-average model predictions. Here, we improve upon the basic Bayesian formulation for developing individualized models by observing that individuals may be classified into three sleep-loss phenotypes: resilient, average, and vulnerable. For each phenotype, we developed a phenotype specific group-average model and used these models to identify each individual's phenotype. We then used the phenotype-specific models within the Bayesian formulation to make individualized predictions. Results on psychomotor vigilance test data from 48 individuals indicated that, on average, ~85% of individual phenotypes were accurately identified within 30 h of wakefulness. The percentage improvement of the proposed approach in 10-h-ahead predictions was 16% for resilient subjects and 6% for vulnerable subjects. The trade-off for these improvements was a slight decrease in prediction accuracy for average subjects. PMID- 23367193 TI - Support of a patient-specific therapeutical acoustic stimulation in tinnitus by numerical modeling. AB - The pathogenesis of tinnitus involves multiple hierarchical levels of auditory processing and appraisal of sensory saliency. Early tinnitus onset is most likely attributed to homeostatic plasticity in the periphery, while the chronification and decompensation are tightly linked to brain areas for the allocation of attentional resources, such as e.g., the thalamocortical feedback loops and the limbic system. Increased spontaneous firing after sensory deafferentation might be sufficient to generate a phantom perception, yet the question why not every peripheral hearing loss automatically elicits a tinnitus sensation is still to be addressed. Utilizing quantitative modeling of multiple hierarchical levels in the auditory pathway, we demonstrate the effects of lateral inhibition on increased spontaneous firing and the resulting elevation of firing regularity and synchronization of neural activity. The presented therapeutical approach is based on the idea of disrupting the heightened regularity of the neural population response in the tinnitus frequency range. This neural activity regularity depends on lateral dispersion of common noise and thus is susceptible for edge effects and might be influenced by a change in neural activity in bordering frequency ranges by fitted acoustical stimulation. We propose the use of patient specifically adapted tailor-made notched acoustic stimulation, utilizing modeling results for the optimal adjustment of the stimulation frequencies to archive a therapeutical edge-effect. PMID- 23367194 TI - Flow-dependent vascular heat transfer during microwave thermal ablation. AB - Microwave tumor ablation is an attractive option for thermal ablation because of its inherent benefits over radiofrequency ablation (RFA) in the treatment of solid tumors such as hepatocellular carcinoma (HCC). Microwave energy heats tissue to higher temperatures and at a faster rate than RFA, creating larger, more homogenous ablation zones. In this study, we investigate microwave heating near large vasculature using coupled fluid-flow and thermal analysis. Low-flow conditions are predicted to be more likely to cause cytotoxic heating and, therefore, vessel thrombosis and endothelial damage of downstream tissues. Such conditions may be more prevalent in patient with severe cirrhosis or compromised blood flow. High-flow conditions create the more familiar heat-sink effect that can protect perivascular tissues from the intended thermal damage. These results may help guide placement and use of microwave ablation technologies in future studies. PMID- 23367195 TI - Criteria for study of heart failure derived from ESPVR. AB - In this study, the end-systolic pressure-volume relation (ESPVR) is used to derive new criteria that can help understand the problem of heart failure with normal or preserved ejection fraction (HFpEF). It is shown that the ejection fraction (EF) is just one index of several indexes that can be derived from the parameters describing the ESPVR and related areas under ESPVR. PMID- 23367196 TI - Feasibility of using piezohydraulic pumps as motors for pediatric ventricular assist devices. AB - The feasibility of using piezohydraulic pumps in drivers for pediatric ventricular assist devices is presented in this article. In this study a 0.5 kg piezohydraulic pump is incorporated into a ventricular assist device driver to drive a pulsatile pediatric 30 mL stroke ventricular assist device (VAD). The driver consists of a piezoelectric-hydraulic hybrid actuator and volume amplification section. Mechanical tests were performed on the pump and the hybrid actuator and a maximum power output of 5.4 W and 1.6 W were recorded respectively. The driver was tested running at multiple heart rates from 50-80 beats per minute (BPM) in an in-vitro bench top mock circulation to characterize the performance of the driver under a circulatory load. The maximum drive pressure output by the driver was 35 kPa. Peak flow rate from the VAD driven by the new driver was 6 L/min against a 10 kPa back pressure. Mean flow rate from the VAD outlet was 2.35 L/min for 80 BPM operation. PMID- 23367197 TI - Quantitative assessment of left ventricular diastolic function via longitudinal and transverse flow impedances. AB - Flow impedance has been used to characterize the physical properties of the vascular system by assessing its phasic flow response to pulsatile pressure input in terms of resistance as a function of frequency. Impedance has also been used to characterize global diastolic left ventricular (LV) chamber properties. In early diastole the LV is a mechanical suction pump and accommodates filling by simultaneously expanding in two principal spatial directions: longitudinal (base to-apex, long-axis) and transverse (radial, short-axis). Total (characteristic) impedance Z(C) is the product of longitudinal (Z(L)) and transverse (Z(T)) impedance as Z(C)(2)=Z(L)Z(T) where the two impedances reflect the relative spatial propensity for volume accommodation. In this work we compute Z(L) and Z(T) for the LV in early diastole. We analyze simultaneously recorded dual pressure-transducer and transthoracic echocardiographic flow data obtained during cardiac catheterization in 11 subjects. We found that Z(L) was 2 orders of magnitude smaller than Z(T) in all subjects, providing the first hemodynamic evidence, in concordance with cine-MRI imaging data that longitudinal volume accommodation is indeed, nature's preferred spatial filling mechanism. We also investigated the effect of impaired diastolic function on directional impedances and found that Z(L) increased (becomes worse) while Z(T) decreased (becomes better) indicating that as diastolic function becomes impaired radial filling compensates for decreased longitudinal volume accommodation to preserve stroke volume. These results provide mechanistic insight and show that normal diastolic function defines a properly impedance matched state and that diastolic dysfunction is equivalent to a state of impedance mismatch. PMID- 23367198 TI - Simulation based efficiency prediction of a Brushless DC drive applied in ventricular assist devices. AB - Ventricular Assist Devices (VADs) are mechanical blood pumps that support the human heart in order to maintain a sufficient perfusion of the human body and its organs. During VAD operation blood damage caused by hemolysis, thrombogenecity and denaturation has to be avoided. One key parameter causing the blood's denaturation is its temperature which must not exceed 42 degrees C. As a temperature rise can be directly linked to the losses occuring in the drive system, this paper introduces an efficiency prediction chain for Brushless DC (BLDC) drives which are applied in various VAD systems. The presented chain is applied to various core materials and operation ranges, providing a general overview on the loss dependencies. PMID- 23367199 TI - Carotid-radial pulse wave velocity as an alternative tool for the evaluation of endothelial function during pregnancy: potential role in identifying hypertensive disorders of pregnancy. AB - Preeclampsia/eclampsia syndrome, a major cause of maternal mortality and morbidity, has been recognized as a condition with a globally impaired endothelial function (EF). The possibility of identifying early subclinical endothelial damage during pregnancy could be of value in classifying the different hypertensive states of pregnancy, and have a positive impact in the understanding of this syndrome, as well as on the appropriate treatment of these patients. Reactive hyperemia-related changes in carotid-radial pulse wave velocity (PWVcr) were proposed as an alternative tool for the evaluation of EF in patients with cardiovascular risk factors. If impaired EF, which follows hypertensive disorders of pregnancy can be assessed using PWVcr changes remains still unknown. AIMS: To assess and compare reactive hyperemia-related changes in PWVcr and FMD in pregnant women (healthy and with hypertensive disorders) and non pregnant women. METHODS: Healthy pregnant (HP; n=13), preeclamptic (PE; n=7), non proteinuric hypertensive (NPH; n=6) and non-pregnant (NP; n=32) women were included. Left PWVcr (strain gauge mechano-transducers), left brachial arterial diameter (B-Mode ultrasound) and blood flow velocity (Doppler ultrasound) were measured before (baseline) and after the transient ischemia of the left forearm were determined. RESULTS: One minute after the cuff deflation, PWVcr decreased in HP (6.9 +/- 1.5 to 6.0 +/- 0.9 m/s, p<0.001) and in NP (8.1 +/- 0.9 to 7.4 +/- 0.9 m/s; p<0.001). NPH showed a blunted hyperemic PWVcr response (6.6 +/- 1.4 to 6.7 +/- 1.0 m/s; p=0.91), whereas PE showed a tendency to increase (6.0 +/- 0.7 to 6.4 +/- 0.8 m/s; p=0.10). Reactive hyperemia PWVcr response (DeltaPWVcr in %) differed comparing HP with NPH (-12% vs. +2%; p<0.01) and with PE (-12 vs. +6%; p <0.01), whereas no differences were found between NHP and PE (p=1.00). CONCLUSION: HP showed an enhanced PWVcr reduction, whereas PE and NPH showed a blunted hyperemic PWVcr response. Carotid-radial PWVcr analysis could have a potential role in the assessment of pregnancy to study EF with a potential clinical application in predicting pregnancy induced hypertension and preeclampsia. PMID- 23367200 TI - Utility of noninvasive brachial-ankle pulse wave velocity measurement in people with spinal cord injury. AB - The purpose of the present study was to examine the utility of non-invasive brachial-ankle pulse wave velocity measurement in people with spinal cord injury based on the comparison of the data of the compliance of common femoral artery measured by ultrasonography. Five physically active persons with spinal cord injury volunteered for this study. Subjects were in a supine position on the bed, and estimate brachial-ankle pulse wave velocity and the compliance coefficient of common femoral artery. The brachial-ankle pulse wave velocity measurement is related to was significantly (p<0.05) related to the compliance coefficient of common femoral artery. The brachial-ankle pulse wave velocity measurement may be helpful for assessment of arterial stiffness in people with spinal cord injury. PMID- 23367201 TI - Non invasive assessment of carotid and femoral arterial pressure using B-mode ultrasound diameter waveforms. AB - Non invasive local arterial blood pressure measurement has become a challenge over recent years. The aim of this study was to evaluate in a general population the validity of an alternative method to assess systolic local arterial blood pressure, from the analysis of B-mode diameter waveforms, and to estimate the accuracy when compared to carotid and femoral arterial tonometry. In 190 asymptomatic subjects (51+/-11 years, range: 24-73; pulse pressure: 51+/-11 mmHg, range: 31-93) systolic arterial pressure was obtained at the left carotid and left femoral artery by applanation tonometry (SBP(Car)_Ton and SBP(Fem)_Ton) and by automatic analysis of B-mode echographic images, calibrated using an iterative exponential model. Tonometry and echocardiography-derived pressure estimates correlated significantly (R=0.99, p<0.05). Mean difference between the two methods was only -2.5+/-5.0 mmHg for carotid artery (SBP(Car)_Ton: 122+/-18 mHg), and -2.1+/-5.7 mmHg for femoral artery (SBP(Fem)_Ton: 134+/-21 mmHg), independent of pressure level. In conclusion, alternative method was found to allow an accurate and precise estimation of systolic local arterial pressure, with an underestimation error of ~ 2%. PMID- 23367202 TI - Frequency dependent transmission characteristics between arterial blood pressure and intracranial pressure in rats. AB - The pulsatile energy transmission between arterial blood pressure (BP) and intracranial pressure (ICP) is affected by cerebrospinal fluid (CSF) and brain tissue. Studies in dogs have shown that the transfer function (TF) between BP and ICP shows damping of pulsatile energy around heart rate frequency (1-3Hz) with notch filter characteristics, and the amount of damping is sensitive to cerebral compliance. This investigation aimed to assess whether this notch filter characteristic is an intrinsic property of the brain enclosed in a rigid skull and therefore applies across species with a large difference in body size. This was done by determining the TF between BP and ICP in rats with corresponding significantly smaller body size and higher heart rate (5-7 Hz) compared to dogs. Arterial BP and ICP waveforms were recorded in 8 anaesthetized (urethane) adult male Sprague-Dawley rats with solid state micro-sensor transducer catheters. The TF was computed as the ratio of ICP and arterial BP waveform amplitudes for the first 4 harmonics. Arterial BP and ICP signals were normalized for pulse amplitude such that attenuation or amplification is detected for any TF values significantly different to unity. Mean cardiac frequency was 5.72 Hz (range 4.6 - 7.11 Hz). Of the 4 harmonics only the heart rate frequency band showed a statistically significant attenuation of 17%, while the higher harmonics showed a progressive amplification. Findings show that the rat brain acts as a selective frequency pulsation absorber of energy centered at heart rate frequency. This similarity with larger animals indicates a possible allometric mechanism underlying this phenomenon, with notch filter characteristic frequency scaled to body size. This study suggests that the TF between arterial BP and ICP is an intrinsic property of the brain tissue and CSF enclosed in a rigid compartment and can be used to assess changes in cerebral compliance due to abnormal CSF pressure and flow as occur in hydrocephalus. PMID- 23367203 TI - Investigation of cerebral hemodynamics and collateralization in asymptomatic carotid stenoses. AB - Stroke is the second leading cause of death in the world, and one of the major causes of disability. Approximately 30% of ischemic strokes are due to plaque rupture in the carotid arteries. The most popular diagnostic method uses Doppler ultrasound to find the percent stenosis. However, other factors, such as the hemodynamics around the plaque may play a larger role in identifying the risk of plaque rupture. It has been shown previously in simulations that non-collateral flow in the circle of Willis (COW) could cause an increase of the intraluminal velocity around carotid plaque. This added strain may increase the vulnerability of the plaque to rupture. We investigated asymmetries in flow waveforms in the middle cerebral artery (MCA) in asymptomatic patients with carotid artery stenosis. We compared clinical results of velocity waveforms in the MCA, acquired using transcranial Doppler (TCD), with a simple linear simulation model of the intra- and extracranial arterial network to investigate the relationship between contralateral and ipsilateral flow profiles in the MCA for patients with asymptomatic carotid stenosis. In 17 out of 23 patients we found waveforms consistent with those predicted for a collateralized COW, with minimal differences in delay, velocity magnitude and resistivity index. In 6 cases, some unexpected findings were noted, such as large delays for 2 patients <= 50% stenosis, and a large velocity difference with low delay for 4 patients. More studies are needed to elucidate the role of incomplete intracranial collateralization on the hemodynamics around carotid plaque and to use imaging of the COW to corroborate our results. PMID- 23367204 TI - Aging-related changes and reference values for the carotid intima-media thickness in a Uruguayan population. AB - Carotid intima-media thickness (CIMT) is a well-established subclinical marker of atherosclerosis. Non-invasive vascular evaluation has emerged as a useful tool to aid in individual cardiovascular (CV) risk stratification and diagnose. The use of CIMT in CV risk stratification requires knowing the expected reference values for the population studied. Our aim were: a) to evaluate the relationship between aging and CIMT, b) to analyze gender and side (right vs left) related-differences in CIMT and c) to determine the CIMT reference values for an Uruguayan population taking into account aging-related CIMT changes. METHODS: 367 asymptomatic subjects without known CV disease or risk factors were included in the study. Subjects were divided into six age groups. High-resolution B-mode ultrasound images of both (right and left) common carotid arteries were obtained based on the techniques and recommendations described in international consensus. RESULTS: No significant age-related differences in CIMT between men and women were observed. The mean left CIMT was thicker compared with right CIMT in groups 4, 5 and 6. However, there were no significant differences in those groups. The nomogram model was constructed from data base, in which the 95% confidence interval was considered. Diagnosis thresholds were determined as well. CONCLUSION: We define reference values of CIMT for our population using gold standard techniques which contributes to standard techniques which contributes to an improved insight into clinical practice and can be used routinely for evaluation. PMID- 23367205 TI - Compressed sensing for integral pulse frequency modulation (IPFM)-based heart rate variability spectral estimation. AB - In this paper, a Compressed Sensing (CS) based spectral analysis of Heart Rate Variability (HRV) using the Integral Pulse Frequency Modulation (IPFM) model is introduced. Previous research in literature indicated that the IPFM model is considered as a functional description of the cardiac pacemaker and thus is very useful in modeling the mechanism by which the Autonomic Nervous System (ANS) modulates the Heart Rate (HR). On the other hand, in recent years CS has attracted great attention over many aspects of signal processing applications. According to the IPFM model, we here present a CS-based algorithm for deriving the amplitude spectrum of the modulating signal for HRV assessments. In fact, the application of the CS method into HRV spectral estimation is novel and unprecedented in HRV analysis. Numerical experimental results demonstrated that the proposed approach can robustly yield accurate HRV spectral estimates, even under the situation of a degree of incompleteness in the interbeat interval or RR data caused by ectopic or missing beats. PMID- 23367206 TI - Prediction of extubation readiness in extreme preterm infants based on measures of cardiorespiratory variability. AB - The majority of extreme preterm infants require endotracheal intubation and mechanical ventilation (ETT-MV) during the first days of life to survive. Unfortunately this therapy is associated with adverse clinical outcomes and consequently, it is desirable to remove ETT-MV as quickly as possible. However, about 25% of extubated infants will fail and require re-intubation which is also associated with a 5-fold increase in mortality and a longer stay in the intensive care unit. Therefore, the ultimate goal is to determine the optimal time for extubation that will minimize the duration of MV and maximize the chances of success. This paper presents a new objective predictor to assist clinicians in making this decision. The predictor uses a modern machine learning method (Support Vector Machines) to determine the combination of measures of cardiorespiratory variability, computed automatically, that best predicts extubation readiness. Our results demonstrate that this predictor accurately classified infants who would fail extubation. PMID- 23367207 TI - An investigation of simultaneous variations in cerebral blood flow velocity and arterial blood pressure during sleep apnea. AB - Obstructive Sleep Apnea (OSA) is a major sleep disorder with a prevalence of about 15 % among US adult population and can lead to cardiovascular diseases and stroke. In this study, we have investigated the OSA-induced concurrent rise in cerebral blood flow velocity and blood pressure in 5 positively diagnosed sleep apnea subjects. The subject population had a mean AHI of 57.94+/-25.73 and BMI of 33.66+/-7.27 kg/m(2). The results of this preliminary study yielded a relatively high correlation between rise in blood pressure and rise in cerebral blood flow velocity during apnea episodes (r=0.61+/-0.16) compared to normal breathing (r=0.28+/-0.26). These findings suggest that cerebral autoregulation may be less effective during apnea episodes. PMID- 23367208 TI - A PD control-based QRS detection algorithm for wearable ECG applications. AB - We present a QRS detection algorithm for wearable ECG applications using a proportional-derivative (PD) control. ECG data of arrhythmia have irregular intervals and magnitudes of QRS waves that impede correct QRS detection. To resolve the problem, PD control is applied to avoid missing a small QRS wave followed from a large QRS wave and to avoid falsely detecting noise as QRS waves when an interval between two adjacent QRS waves is large (e.g. bradycardia, pause, and arioventricular block). ECG data was obtained from 78 patients with various cardiovascular diseases and tested for the performance evaluation of the proposed algorithm. The overall sensitivity and positive predictive value were 99.28% and 99.26%, respectively. The proposed algorithm has low computational complexity, so that it can be suitable to apply mobile ECG monitoring system in real time. PMID- 23367209 TI - Heart rate variability analysis using a seismocardiogram signal. AB - Seismocardiography is a simple and non invasive method of recording cardiac activity from the movements of the body caused by heart pumping. In this preliminary study we use a smartphone to record this acceleration and estimate the heart rate. We compare the heart rate variability parameters from the seismocardiogram and ECG reference signal. The results show a great similarity and are strongly influenced by the instability in the sampling frequency of the device. The differences between RR series are lower than 10 ms. PMID- 23367210 TI - HRV based health&sport markers using video from the face. AB - Heart Rate Variability (HRV) is an indicator of health status in the general population and of adaptation to stress in athletes. In this paper we compare the performance of two systems to measure HRV: (1) A commercial system based on recording the physiological cardiac signal with (2) A computer vision system that uses a standard video images of the face to estimate RR from changes in skin color of the face. We show that the computer vision system performs surprisingly well. It estimates individual RR intervals in a non-invasive manner and with error levels comparable to those achieved by the physiological based system. PMID- 23367211 TI - Upper airway occlusion detection using a novel ultrasound technique. AB - Obstructive sleep apnea/hypopnea Syndrome (OSAHS) is the most common form of Sleep Disordered Breathing (SDB) and it is estimated to affect approximately 15% of US adult population. In this paper, we report on the results of in vivo experiments of an ultrasonic device for the non-invasive detection of obstructive sleep apnea/hypopnea (OSAH). A description of the ultrasonic system used is presented, followed by the results of a full night sleep study. The findings show a significant difference in the spectral features extracted from the received ultrasonic waveform during apneic breathing, compared to the hyperventilation that follows. Therefore, the findings indicate the feasibility of developing an ultrasonic detection device for low cost diagnosis of SDB. PMID- 23367212 TI - High frequency analysis of cough sounds in pediatric patients with respiratory diseases. AB - Cough is a common symptom in a range of respiratory diseases and is considered a natural defense mechanism of the body. Despite its critical importance in the diagnosis of illness, there are no golden methods to objectively assess cough. In a typical consultation session, a physician may briefly listen to the cough sounds using a stethoscope placed against the chest. The physician may also listen to spontaneous cough sounds via naked ears, as they naturally propagate through air. Cough sounds carry vital information on the state of the respiratory system but the field of cough analysis in clinical medicine is in its infancy. All existing cough analysis approaches are severely handicapped by the limitations of the human hearing range and simplified analysis techniques. In this paper, we address these problems, and explore the use of frequencies covering a range well beyond the human perception (up to 90 kHz) and use wavelet analysis to extract diagnostically important information from coughs. Our data set comes from a pediatric respiratory ward in Indonesia, from subjects diagnosed with asthma, pneumonia and rhinopharyngitis. We analyzed over 90 cough samples from 4 patients and explored if high frequencies carried useful information in separating these disease groups. Multiple regression analysis resulted in coefficients of determination (R(2)) of 77-82% at high frequencies (15 kHz-90 kHz) indicating that they carry useful information. When the high frequencies were combined with frequencies below 15kHz, the R(2) performance increased to 85 90%. PMID- 23367213 TI - Influence of electrical stimulation on 3D-cultures of adipose tissue derived progenitor cells (ATDPCs) behavior. AB - Tissue engineering has a fundamental role in regenerative medicine. Still today, the major motivation for cardiac regeneration is to design a platform that enables the complete tissue structure and physiological function regeneration of injured myocardium areas. Although tissue engineering approaches have been generally developed for two-dimensional (2D) culture systems, three-dimensional (3D) systems are being spotlighted as the means to mimic better in vivo cellular conditions. This manuscript examines the influence of electrical stimulation on 3D cultures of adipose tissue-derived progenitor cells (ATDPCs). ATDPCs cells were encapsulated into a self-assembling peptide nanoscaffold (RAD16-I) and continuously electro stimulated during 14-20 days with 2-ms pulses of 50mV/cm at a frequency of 1 Hz. Good cellular network formation and construct diameter reduction was observed in electro stimulated samples. Importantly, the process of electro stimulation does not disrupt cell viability or connectivity. As a future outlook, differentiation studies to cardiomyocytes-like cells will be performed analyzing gene profile and protein expression. PMID- 23367214 TI - Computational 3D model of in-vitro cell stimulated by electric and magnetic fields. AB - This work presents the development of 3D computational models that represent two studies about in-vitro cellular experimentation of cell stimulated by magnetic and electric field. The development considered the construction of the stimulation devices, the cell seeding, and the creation of the 3D computational models representing the arrangements. The models and their electromagnetic analysis were done in the ANSYS program. The volumes considered were: source of stimulation, Falcon cell culture plate, cell content, and space for zero potential. The electric field stimulation model considered an applied electric field between 250 V/m and 1 kV/m. While the magnetic field stimulation model considered an applied magnetic field between 0.5 mT and 2.0 mT. For both models, the frequency range was between 5 Hz and 105 Hz. As a result, the error between the stimulation devices and the created models was lower than 5%. The homogeneous area of the magnetic and electric field was established and the behavior of field strength produced by the stimulation devices was the expected one. In both models, the induced current density was the variable evaluated in the cellular material. The current density induced by the applied magnetic field was greater than by the applied electric field. PMID- 23367215 TI - Improved bone marrow stromal cell adhesion on micropatterned titanium surfaces. AB - Implant longevity is desired for all bone replacements and fixatives. Titanium (Ti) implants fail due to lack of juxtaposed bone formation, resulting in implant loosening. Implant surface modifications have shown to affect the interactions between the implant and bone. In clinical applications, it is crucial to improve osseointegration and implant fixation at the implant and bone interface. Moreover, bone marrow derived cells play a significant role for implant and tissue integration. Therefore, the objective of this study is to investigate how surface micropatterning on Ti influences its interactions with bone marrow derived cells containing mesenchymal and hematopoietic stem cells. Bone marrow derived mesenchymal stem cells (BMSC) have the capability of differentiating into osteoblasts that contribute to bone growth, and therefore implant/bone integration. Hematopoietic stem cell derivatives are precursor cells that contribute to inflammatory response. By using all three cells naturally contained within bone marrow, we mimic the physiological environment to which an implant is exposed. Primary rat bone marrow derived cells were seeded onto Ti with surfaces composed of arrays of grooves of equal width and spacing ranging from 0.5 to 50 um, fabricated using a novel plasma-based dry etching technique. Results demonstrated enhanced total cell adhesion on smaller micrometer-scale Ti patterns compared with larger micrometer-scale Ti patterns, after 24-hr culture. Further studies are needed to determine bone marrow derived cell proliferation and osteogenic differentiation potential on micropatterned Ti, and eventually nanopatterned Ti. PMID- 23367217 TI - Signal transduction on enzymes: the effect of electromagnetic field stimuli on superoxide dismutase (SOD). AB - Protein functions and characteristics can highly differ from physiological conditions in presence of chemical, mechanical or electromagnetic stimuli. In this work we provide a rigorous picture of electric field effects on proteins behavior investigating, at atomistic details, the possible ways in which an external signal can be transduced into biochemical effects. Results from molecular dynamics (MD) simulations of a single superoxidismutase (SOD) enzyme in presence of high exogenous alternate electric fields will be discussed. PMID- 23367216 TI - Interactions between aggressive ions and the surface of a magnesium-yttrium alloy. AB - Magnesium alloys possess many desirable properties for biodegradable orthopedic implants. Unfortunately, magnesium degrades too rapidly in vivo. This rapid degradation reduces the alloys' mechanical properties and increases the alkalinity of the local environment. Controlling the degradation rate and mode is an essential step in the development of magnesium based biomaterials. Accomplishing this essential step will require an improved understanding of magnesium alloy degradation. Herein, three interacting factors controlling magnesium degradation were investigated; (1) alloy composition, (2) alloy surface, (3) presence of aggressive ions in the immersion media. The magnesium yttrium alloy was more susceptible to degradation in water than the high purity magnesium alloy. However, the polished surface magnesium-yttrium alloy had the least susceptibility to degradation in phosphate buffered saline (PBS) among all the sample compositions and surfaces. PMID- 23367218 TI - Monolithic graphene transistor biointerface. AB - We report monolithic integration of graphene and graphite for all-carbon integrated bioelectronics. First, we demonstrate that the electrical properties of graphene and graphite can be modulated by controlling the number of graphene layers, and such capabilities allow graphene to be used as active channels and graphite as metallic interconnects for all-carbon bioelectronics. Furthermore, we show that monolithic graphene-graphite devices exhibit mechanical flexibility and robustness while their electrical responses are not perturbed by mechanical deformation, demonstrating their unique electromechanical properties. Chemical sensing capability of all-carbon integrated bioelectronics is manifested in real time, complementary pH detection. These unique capabilities of our monolithic graphene-graphite bioelectronics could be exploited in chemical and biological detection and conformal interface with biological systems in the future. PMID- 23367219 TI - SAR analysis of the improved resonant cavity applicator with electrical shield and water bolus for deep tumors by a 3-D FEM. AB - This paper discusses the improvements of the re-entrant resonant cavity applicator, such as an electromagnetic shield and a water bolus for concentrating heating energy on deep tumors in an abdominal region of the human body. From our previous study, it was found that the proposed heating system using the resonant cavity applicator, was effective for heating brain tumors and also for heating other small objects. However, when heating the abdomen with the developed applicator, undesirable areas such as the neck, arm, hip and breast were heated. Therefore, we have improved the resonant cavity applicator to overcome these problems. First, a cylindrical shield made of an aluminum alloy was installed inside the cavity. It was designed to protect non-tumorous areas from concentrated electromagnetic fields. Second, in order to concentrate heating energy on deep tumors inside the human body, a water bolus was installed around the body. Third, the length of the lower inner electrode was changed to control the heating area. In this study, to evaluate the effectiveness of the proposed methods, specific absorption rate (SAR) distributions were calculated by FEM with the 3-D anatomical human body model reconstructed from MRI images. From these results, it was confirmed that the improved heating system was effective to non invasively heat abdominal deep tumors. PMID- 23367220 TI - A new antenna system for microwave non-invasive hyperthermia lipolysis. AB - In this paper, we present an antenna system for microwave non-invasive hyperthermia lipolysis. The antenna system consists of a circular waveguide antenna radiating electromagnetic waves, AlN (Aluminum Nitride) radome and heat sink. The AlN radome with heat sink helps to extract heat from the skin to keep skin temperature not to rise during heating the lipolysis. The antenna was designed to be operated with TE(21) mode to maintain uniform temperature over wider area. The usability of the proposed system was verified by performing numerical simulation and hyperthermia lipolysis experiments on rats. PMID- 23367221 TI - Theoretical assessment of principal factors influencing laser interstitial thermotherapy outcomes on pancreas. AB - The influence of some therapy-relevant parameters on Laser Induced Interstitial Thermotherapy (LITT) outcomes on pancreas is assessed. The aim is to execute a sensitivity analysis for an optimal treatment strategy on in vivo pancreas. A numerical model based on Bioheat Equation has been implemented to assess the influence of laser settings (power P and energy E), applicator radius (r(f)) and optical properties (effective attenuation coefficient, MU(eff)) on temperature (T) distribution. Effects on pancreas undergoing LITT have been evaluated with a twofold approach: 1) T rise and maximum T (T(max)) in tissue; 2) injured volumes (vaporized and coagulated ones). We consider parameters range in typical LITT values (P from 1.5 W to 6 W, E from 500 J to 1500 J, r(f) from 150 um to 600 um) and optical values reported in literature. Our analysis shows that, among others, P and MU(eff) are the principal influencing factors of thermal effects on pancreas undergoing LITT: P should be carefully chosen by operator to obtain the desired injured volumes, while the accurate measurement of tissue optical properties is crucial to carry out a safe and controlled thermal therapy on pancreas. PMID- 23367222 TI - Accelerating three-dimensional FDTD calculations on GPU clusters for electromagnetic field simulation. AB - Electromagnetic simulation with anatomically realistic computational human model using the finite-difference time domain (FDTD) method has recently been performed in a number of fields in biomedical engineering. To improve the method's calculation speed and realize large-scale computing with the computational human model, we adapt three-dimensional FDTD code to a multi-GPU cluster environment with Compute Unified Device Architecture and Message Passing Interface. Our multi GPU cluster system consists of three nodes. The seven GPU boards (NVIDIA Tesla C2070) are mounted on each node. We examined the performance of the FDTD calculation on multi-GPU cluster environment. We confirmed that the FDTD calculation on the multi-GPU clusters is faster than that on a multi-GPU (a single workstation), and we also found that the GPU cluster system calculate faster than a vector supercomputer. In addition, our GPU cluster system allowed us to perform the large-scale FDTD calculation because were able to use GPU memory of over 100 GB. PMID- 23367223 TI - Heating characteristics with a re-entrant type applicator in consideration of tissue blood flow rate. AB - We have proposed the heating system based on a re-entrant cavity that can heat a localized deep region in a living body noninvasively. This system is superior in a local heating characteristic. However, when the living body was treated as a heating object during thermotherapy (hyperthermia), the effect of blood flow changes on a heating characteristic has to be examined. The purpose of this study was to establish the quantitative evaluation method of heating characteristics for a re-entrant type applicator. The numerical analyses by using three dimensional finite element method in consideration of a blood flow and fundamental experiments with prototype system were carried out. Since the difference of numerical analyses and experiments was as small as about 4.2 [%] by evaluation with full width at half maximum (FWHM), the validity of this numerical analysis was confirmed. PMID- 23367224 TI - Development of a temperature distribution simulator for lung RFA based on air dependence of thermal and electrical properties. AB - Radio frequency ablation (RFA) for lung cancer has increasingly been used over the past few years, because it is a minimally invasive treatment. As a feature of RFA for lung cancer, lung contains air. Air is low thermal and electrical conductivity. Therefore, RFA for this cancer has the advantage that only the cancer is coagulated, because the heated area is confined to the immediate vicinity of the heating point. However, it is difficult for operators to control the precise formation of coagulation zones due to inadequate imaging modalities. We propose a method using finite element method to analyze the temperature distribution of the organ in order to overcome the current deficiencies. Creating an accurate thermal physical model was a challenging problem because of the complexities of the thermal properties of the organ. In this study, we developed a temperature distribution simulator for lung RFA using thermal and electrical properties that were based on the lung's internal air dependence. In addition, we validated the constructed simulator in an in vitro study, and the lung's internal heat transfer during RFA was validated quantitatively. PMID- 23367225 TI - A novel thermal treatment modality for controlling breast tumor growth and progression. AB - The new concept of keeping primary tumor under control in situ to suppress distant foci sheds light on the novel treatment of metastatic tumor. Hyperthermia is considered as one of the means for controlling tumor growth. In this study, a novel thermal modality was built to introduce hyperthermia effect on tumor to suppress its growth and progression using 4T1 murine mammary carcinoma, a common animal model of metastatic breast cancer. A mildly raised temperature (i.e.39 degrees C) was imposed on the skin surface of the implanted tumor using a thermal heating pad. Periodic heating (12 hours per day) was carried out for 3 days, 7 days, 14 days, and 21 days, respectively. The tumor growth rate was found significantly decreased in comparison to the control without hyperthermia. Biological evidences associated with tumor angiogenesis and metastasis were examined using histological analyses. Accordingly, the effect of mild hyperthermia on immune cell infiltration into tumors was also investigated. It was demonstrated that a delayed tumor growth and malignancy progression was achieved by mediating tumor cell apoptosis, vascular injury, degrading metastasis potential and as well as inhibiting the immunosuppressive cell myeloid derived suppressor cells (MDSCs) recruitment. Further mechanistic studies will be performed to explore the quantitative relationship between tumor progression and thermal dose in the near future. PMID- 23367226 TI - Numerical and experimental characterization of radiofrequency ablation in perfused kidneys. AB - We develop a three-dimensional finite element model in order to predict the resulting temperature distribution of a radiofrequency ablation (RFA) treatment in human kidneys. Here, a strong cooling effect results from a high degree of blood perfusion, which is modeled via two different approaches. The influence of big blood vessels for treatments close to renal hilus is modeled by including a cylindrical cooling tube based on the renal artery (or vein) in the kidney model. The influence of the perfusion of small arterioles and capillaries is represented by Pennes' approach in the bioheat equation. The experimental validation is performed by an in vivo RFA treatment on porcine kidney. Prior to the in vivo measurements several ex vivo experiments on fresh kidneys are carried out as a plausibility check for the model. During the treatments temperature profiles are measured using thermocouples which are radially arranged around the RFA applicator trocar. The evaluated data for each sensor show a deviation between 0.01 and 12 % from the simulation results. The approach serves for the design of a preplanning tool for RFA treatment in the future. PMID- 23367227 TI - Validation of accuracy of liver model with temperature-dependent thermal conductivity by comparing the simulation and in vitro RF ablation experiment. AB - Radiofrequency (RF) ablation is increasingly used to treat cancer because it is minimally invasive. However, it is difficult for operators to control precisely the formation of coagulation zones because of the inadequacies of imaging modalities. To overcome this limitation, we previously proposed a model-based robotic ablation system that can create the required size and shape of coagulation zone based on the dimensions of the tumor. At the heart of such a robotic system is a precise temperature distribution simulator for RF ablation. In this article, we evaluated the simulation accuracy of two numerical simulation liver models, one using a constant thermal conductivity value and the other using temperature-dependent thermal conductivity values, compared with temperatures obtained using in vitro experiments. The liver model that reflected the temperature dependence of thermal conductivity did not result in a large increase of simulation accuracy compared with the temperature-independent model in the temperature range achieved during clinical RF ablation. PMID- 23367228 TI - Use of 3D-printers to create intensity-modulated radiotherapy compensator blocks. AB - Intensity-Modulated Radiotherapy (IMRT) is an important tool for cancer treatment. It concentrates high radiation doses in complex target volumes, while sparing the surrounding tissues. IMRT is traditionally performed using Multileaf Collimators (MLC) or Compensator Blocks. The conventional way used to manufacture IMRT compensator blocks, which uses milling machines, is an important drawback over the MLC method, due to high operational and production costs. In this research, we developed a simpler alternative method to manufacture an IMRT compensator block from a fluency map generated by a commercial treatment planning system (TPS). This map was converted into a mold, and then printed using a 3D printer. The final IMRT compensator block was achieved by filling the mold with cerrobend alloy. To validate this method a quality assurance was performed using dosimetric films to compare the measured dose distributions to those predicted by the TPS system. This comparison showed a good agreement among 8 dose profiles from each situation, with a maximum RMS error of 8.84 % for the tested profiles. This suggests that the 3D printers can be effectively used to manufacture IMRT compensator blocks. The main advantage to this approach is that it can be fully conducted inside a radiotherapy facility, which results in lower costs and production times. PMID- 23367229 TI - Measurement of the thermal relaxation time in agar-gelled water. AB - In this study, we presented an experiment to obtain the thermal relaxation time which is necessary to model heat conduction by the hyperbolic heat equation. This experiment was evaluated by finite element simulation to acquire reliably this parameter for biological tissue. Besides that, we measured the thermal relaxation time of agar-gelled water with 2% of concentration at 25 degrees C. The average value of thermal relaxation time for the gel was 7.9630s with standard deviation of 1.4562. PMID- 23367230 TI - Surface EMG analysis and changes in gait following electrical stimulation of quadriceps femoris and tibialis anterior in children with spastic cerebral palsy. AB - PURPOSE: To evaluate the clinical feasibility and effect of neuromuscular electrical stimulation (NMES) therapy of quadriceps femoris (QF) and tibialis anterior (TA) muscles on improving gait and functional outcomes in children with spastic cerebral palsy (CP). METHOD: Ten children with spastic diplegic/hemiplegic CP who were in the age group of 7 to 14 years recruited from a rehabilitation institute were randomly assigned either to a control group or a NMES group. Both groups obtained conventional physiotherapy and muscle strengthening exercises. The NMES group in addition received surface electrical stimulation to QF and TA muscles for four weeks duration. RESULTS: The NMES group showed significant improvements as compared to the control group in walking speed (mean difference: 7.83 meters per min, 95% confidence interval: 3.13 to 12.53, p<0.01) and cadence (mean difference: 23.33 steps per min, 95% confidence interval: 5.90 to 40.77, p<0.01). The NMES group also showed significant reduction in physiological cost index of walking or PCI (mean difference: -1.32 beats per meter, 95% confidence interval: -1.83 to -0.80, p<0.001) indicating greater energy-efficiency of walking. No significant changes were seen in EMG parameters. CONCLUSIONS: The findings of this study suggests that NMES therapy together with conventional physiotherapy more efficiently improves walking ability and functional outcomes as compared to conventional physiotherapy alone in children with spastic CP. PMID- 23367231 TI - Percutaneously injectable fetal pacemaker: electronics, pacing thresholds, and power budget. AB - We are developing a cardiac pacemaker that is designed to be implanted percutaneously into a fetus to treat complete heart block and consequent hydrops fetalis, which is otherwise fatal. One of the most significant considerations for this device is the technical challenges presented by the battery and charging system. The size of the device is limited to about 3 mm in diameter; batteries on this scale have very small charge capacities. The smaller capacity means that the device needs to be designed so that it uses as little current as possible and so that its battery can be recharged wirelessly. We determined the pacing thresholds for a simple relaxation oscillator that can be assembled from discrete, surface mount components and analyzed the power consumption of the device given different electrode configurations and stimulus parameters. An inductive recharging system will be required for some patients; it is feasible within the package constraints and under development. PMID- 23367232 TI - Essentials of low-power electrocution: established and speculated mechanisms. AB - Even though electrocution has been recognized--and studied--for over a century, there remain several common misconceptions among medical professional as well as lay persons. This review focuses on "low-power" electrocutions rather than on the "high-power" electrocutions such as from lightning and power lines. Low-power electrocution induces ventricular fibrillation (VF). We review the 3 established mechanisms for electrocution: (1) shock on cardiac T-wave, (2) direct induction of VF, and (3) long-term high-rate cardiac capture reducing the VF threshold until VF is induced. There are several electrocution myths addressed, including the concept--often taught in medical school--that direct current causes asystole instead of VF and that electrical exposure can lead to a delayed cardiac arrest by inducing a subclinical ventricular tachycardia (VT). Other misunderstandings are also discussed. PMID- 23367233 TI - New implantable therapeutic device for the control of an atrial fibrillation attack using the Peltier element. AB - For the development of the new therapeutic device for the atrial fibrillation, implantable cooling device using Peltier element was developed in this study. An implantable cooling device had been consisted from Peltier element with transcutaneous energy transmission system (TETS). 1st coil can be contacted from outside of the body, when the patients will feel palpitation. Electrical current will be induced to the implanted 2nd coil. Peltier element will able to cool the surface of the atrium. For the confirmation of the effect of the cooling device, trial manufacture model was developed. Animal experiments using six healthy adult goats after animal ethical committee allowance was carried out. Fourth intercostals space had been opened after anesthesia inhalation, and various sensors had been inserted. AF was induced by the electrical current with battery. As the results, AF had been recovered to the normal sinus rhythm after cooling in all six goats. So, this cooling system for the control of AF showed evident effect in these experiments. Smaller size cooling device has been under development aiming at totally implantable type. Catheter type cooling device for the insertion by the use of fiber-scope type is now under planning for the clinical application. This new type device may be able to become good news for the patients with uncontrollable AF. PMID- 23367234 TI - EEG EPs analysis of magnetic stimulation on acupoint of Shenmen(HT7). AB - Acupuncture is a useful irritation therapy clinically. Acupuncture at acupoints is proved to have specific function on human body. Magnetic stimulation is a new kind of stimulating technique of non-invasive, painless and effective. The effect of magnetic stimulation on acupoint is a new subject in recent years. In this paper, the electroencephalogram (EEG) evoked potentials (EPs) of magnetic stimulation by stimulating the acupoint of Shenmen(HT7) are studied. The experiments are divided into four groups: quiet, acupoint stimulation, mock stimulation and mock point stimulation. The EEG EPs are collected and an obvious P150 component is obtained. The amplitudes of P150s are analyzed and compared. The P150s are localized in brain by dipole model and the coronal, sagittal and axial plans are painted and observed. The results show that acupoint stimulation on acupoint of Shenmen(HT7) can evoke stronger nerve activity of somatosensory than stimulation on common surface. The dipole source of acupoint stimulation and common surface stimulation are both focused on the cingulated gyrus which related to somatosensory. PMID- 23367236 TI - An approach towards bronchoscopic-based gene therapy using electrical field accelerated plasmid droplets. AB - Idiopathic pulmonary fibrosis (IPF) is a devastating disease affecting the distal lung, due to failure of the alveolar epithelium to heal after micro-injuries, leading to inefficient gas exchange and resulting in death. Therapeutic options are very limited. A new therapeutic approach based on gene therapy restores the self-healing process within the lung in the experimental setup. A basic requirement of this therapy is the successful transduction of genes into the alveolar epithelium in the distal part of the lung, for which a new therapeutic instrument is required. In this paper we present the concept and first experimental results of a device which uses an electrical field to accelerate the charged droplets of plasmid suspension toward the tissue and which overcomes cell membrane with its impact energy. The aim is to develop a therapeutic device capable of being integrated into minimally invasive procedures such as bronchoscopy. PMID- 23367237 TI - A novel method for medical implant in-body localization. AB - Wireless communication medical implants are gaining an important role in healthcare systems by controlling and transmitting the vital information of the patients. Recently, Wireless Capsule Endoscopy (WCE) has become a popular method to visualize and diagnose the human gastrointestinal (GI) tract. Estimating the exact location of the capsule when each image is taken is a very critical issue in capsule endoscopy. Most of the common capsule localization methods are based on estimating one or more location-dependent signal parameters like TOA or RSS. However, some unique challenges exist for in-body localization due to the complex nature within the human body. In this paper, we propose a novel one-stage localization method based on spatial sparsity in 3D space. In this method, we directly estimate the location of the capsule (as the emitter) without going through the intermediate stage of TOA or signal strength estimation. We evaluate the performance of the proposed method using Monte Carlo simulation with an RF signal following the allowable power and bandwidth ranges according to the standards. The results show that the proposed method is very effective and accurate even in massive multipath and shadowing conditions. PMID- 23367238 TI - A high resolution bladder wall map: feasibility study. AB - The aim of this work is to provide the surgeon-urologist with a system for automatic 2D and 3D-reconstruction of the bladder wall to help him within the treatment of bladder cancer as well as planning and documentation of the interventions. Within this small pilot-framework a fast feasibility study was made to clear if it is generally possible to build a bladder wall model using a special endoscope with an embedded laser-based distance measurement, an optical navigation system and modern image stitching techniques. Some experiments with a realistic bladder phantom have shown that this initial concept is generally acceptable and can be used with some extensions to build a system which can provide an automatic bladder wall reconstruction in real time to be used within a surgical intervention. PMID- 23367239 TI - Development of a new aortoscope system for the use of endovascular intervention. AB - "Balloon aortoscopy" is a technique for viewing inner wall of aorta and used in clinics. By this method, endoluminal aortic surface could be clearly monitored, however, during this period, the aortic blood flow is blocked off by the inflated balloon. To solve this clinical problem, we have been developing a prototype aortoscope system without blocking off aortic flow aiming for the use of an assistive technique for endovascular interventions such as stent-graft placement for aortic aneurysm and have been evaluating through in vitro and in vivo tests. The technique introduced for this purpose was the use of intermittent and instantaneous saline jet controlled by a high-speed electromagnetic valve synchronized to heart beat (diastolic phase). In the previous study, we designed an endoscope with two channels (one for saline discharge and the other for forceps insertion), and confirmed the validity of this method by in vitro and in vivo tests. Based on these findings, in this study, we have newly designed a conventional and low price endoscope system aiming for wide clinical use. From the results of in vitro tests using a mock circulation system, it was confirmed that the newly designed system was capable of visualizing a target installed on an inner surface of the mock system suggesting an availability of the system for an aortoscope without blocking off aortic flow. PMID- 23367240 TI - A structured light-based laparoscope with real-time organs' surface reconstruction for minimally invasive surgery. AB - In this paper we present a new 3-D laparoscopic device based on structured light for minimally invasive surgery. Real-time reconstruction of internal organs' surfaces is very challenging as the numerous geometric and photometric variabilities and disturbances (bloody parts, specularities, smokes,...) often occur during the surgical operation, sometimes with manipulations by several assistants. We then conceived a structured light vision system to illuminate a coded pattern by means of an external video projector device or miniaturized diffractive optical elements and a laser source. Among the structured light techniques, the spatial neighbourhood scheme is the most relevant class of approaches to deal with moving and deformable surfaces, then to capture the depth map with only one shot. Each neighbourhood (a (3 * 3) window) is representing a codeword of length 9, and is unique in the whole pattern, even if there is a lack of information. To do so, a monochromatic subperfect map-based pattern is computed, driven by a desired minimal Hamming distance, H(min), between any couple of codewords. This provides patterns with high correction capabilities (H(min) > 1). For practical considerations, each numerical codeword symbol is associated to a unique visual feature embedding the local orientation of the pattern, which is helpful for the neighbourhood retrieval during the decoding process. Together with the endoscopic device, in vivo real-time reconstructions (in mini-invasive surgical conditions) are presented to assess both the efficiency of the proposed pattern design, the decoding process and the 3-D laparoscope setup realized in the lab. PMID- 23367241 TI - Foam phantom development for artificial vertebrae used for surgical training. AB - Currently the surgical training of kyphoplasty and vertebroplasty is performed on patients or specimens. To improve patient safety, a project was initiated to develop an Augmented Reality simulator for the surgical training of these interventions. Artificial vertebral segments should be integrated to provide realistic haptic feedback. To reach this, resulting forces during needle insertions (trans- and extrapedicular) into formalin-fixed vertebral specimens were measured. The same insertion procedure was also performed on six customized polyurethane blocks with varying mechanical parameters. Based on the results of these measurements, a specific foam phantom was generated and the insertion force measured. Additionally a parametric model for the needle insertion into bone was designed calculating three characteristic parameters for all insertion measurements. The resulting insertion force for the foam phantom was comparable to the specimen measurements and the parametric model provided comprehensible characteristic parameters. Based on the resulting force during needle insertion into human vertebrae, a possible foam recipe for manufacturing artificial segments was found. Furthermore, the parametric model provides characteristic parameters for the assessment of phantoms as well as the development of its production process. PMID- 23367242 TI - X-ray simulation with the Monte Carlo code PENELOPE. Application to Quality Control. AB - A realistic knowledge of the energy spectrum is very important in Quality Control (QC) of X-ray tubes in order to reduce dose to patients. However, due to the implicit difficulties to measure the X-ray spectrum accurately, it is not normally obtained in routine QC. Instead, some parameters are measured and/or calculated. PENELOPE and MCNP5 codes, based on the Monte Carlo method, can be used as complementary tools to verify parameters measured in QC. These codes allow estimating Bremsstrahlung and characteristic lines from the anode taking into account specific characteristics of equipment. They have been applied to simulate an X-ray spectrum. Results are compared with theoretical IPEM 78 spectrum. A sensitivity analysis has been developed to estimate the influence on simulated spectra of important parameters used in simulation codes. With this analysis it has been obtained that the FORCE factor is the most important parameter in PENELOPE simulations. FORCE factor, which is a variance reduction method, improves the simulation but produces hard increases of computer time. The value of FORCE should be optimized so that a good agreement of simulated and theoretical spectra is reached, but with a reduction of computer time. Quality parameters such as Half Value Layer (HVL) can be obtained with the PENELOPE model developed, but FORCE takes such a high value that computer time is hardly increased. On the other hand, depth dose assessment can be achieved with acceptable results for small values of FORCE. PMID- 23367243 TI - Finite element simulation of a scoliotic spine with periodic adjustments of an attached growing rod. AB - Early Onset Scoliosis (EOS) is a deformity of spine which occurs during growth. Spinal growing rod instrumentation is currently a procedure of early onset scoliosis management and newer technologies to treat scoliosis without fusion hold the exciting promise of a new paradigm in spinal deformity care. A Finite Element Model (FEM) of a scoliotic spine was created and enhanced to simulate spine growth after the attachment of a growing rod. Growing rod instrumentation was included utilizing FEA to accurately simulate the required 3D forces and moments to achieve the desired correction. We measured forces on the rods and the spine during adjustment periods (for correction of the spinal deformity) and during growth periods. For this study, a two-year period was simulated with adjustments at six month intervals. The FEM allowed us to collect data during growth periods from sensors which are only accessible during the surgical procedures. PMID- 23367244 TI - MCNP5 Monte Carlo simulation of amorphous silicon EPID dosimetry from MLC radiation therapy treatment beams. AB - The present work is focused on a MCNP Monte Carlo (MC) simulation of a multi-leaf collimator (MLC) radiation therapy treatment unit including its corresponding Electronic Portal Imaging Device (EPID). We have developed a methodology to perform a spatial calibration of the EPID signal to obtain dose distribution using MC simulations. This calibration is based on several images acquisition and simulation considering different thicknesses of solid water slabs, using a 6 MeV photon beam and a square field size of 20 cm x 20 cm. The resulting relationship between the EPID response and the MC simulated dose is markedly linear. This signal to dose EPID calibration was used as a dosimetric tool to perform the validation of the MLC linear accelerator MCNP model. Simulation results and measurements agreed within 2% of dose difference. The methodology described in this paper potentially offers an optimal verification of dose received by patients under complex multi-field conformal or intensity-modulated radiation therapy (IMRT). PMID- 23367245 TI - A micromachined intensity-modulated fiber optic sensor for strain measurements: working principle and static calibration. AB - This paper describes an intensity-modulated fiber optic sensor for strain measurements. The sensing element is a polydimetilsiloxane (PDMS) micro diffraction grating, 15 mm long, 2 mm thick, with channels 150 um wide, spaced apart 200 um. The working principle of the sensor can be summarized as follows: when the sensing element is strained perpendicularly to the grating plane, light passing through the grating undergoes a modulation caused by the phenomenon of diffraction. Since the grating is interposed between a laser source and a fiber optic, the coupled radiation intensity between these two optical elements can be considered as an indirect measure of strain. A static calibration of the measuring system has been performed, showing that the device, with measuring range of about 0.04, is capable to discriminate strain of 0.005 and it presents a sensitivity increase with strain in the whole range of measurements. PMID- 23367246 TI - Demonstration of novel, secure, real-time, portable ultrasound transmission from an austere international location. AB - There is not sufficient access to medical care or medical expertise in many parts of the world. An innovative telemedicine system has been developed to provide expert medical guidance to field caregivers [who have less medical expertise but can reach the patient population in need]. Real-time ultrasound video images have been securely transmitted from the Dominican Republic to Hackensack University Medical Center, Hackensack NJ (HackensackUMC), while the expert physician at HackensackUMC maintained direct voice communication with the field caregiver. Utilizing a portable ultrasound machine (Sonosite) integrated with portable broadcasting device (LiveU), extended Focused Assessment Sonography in Trauma (e FAST) examinations were performed on healthy volunteers and transmitted via the local cellular network. Additionally, two e-FAST examinations were conducted from a remote location without cellular coverage and transmitted via broad ground area network (BGAN) satellites. The demonstration took the technology "out of the lab" and into a real life, austere environment. The conditions of the Dominican Republic ultrasound mission provided experience on how to manage and utilize this innovative technology in areas where reliable communications and medical coverage are not readily available. The resilient transmission capabilities coupled with the security features deem this portable Telesonography (TS) equipment highly useful in the telemedicine forefront by offering healthcare in underdeveloped areas as well as potentially enhancing throughput in disaster situations. PMID- 23367247 TI - Integration of DASH and ICS 3000 devices with Hospital Information System and REPACE central registry. AB - Paper describes the system that is developed by the authors and which allows interconnection of vital signs monitor DASH, implant control system ICS 3000, HIS (Hospital Information System) used at Mestska nemocnice Ostrava and REPACE the central registry of pacemaker implantations. This connection allows users to effectively create, store and visualize operation reports with patient's data. The new system is being developed using C# programming language within .NET environment. The developed application's title is ImplantSys. PMID- 23367248 TI - Development of a wearable system integrated with novel biomedical sensors for ubiquitous healthcare. AB - The world's ageing population has led to an urgent need for long-term and patient centered healthcare solutions. Hence, there is a growing need for wearable systems for physiologic monitoring. While various biosignals are monitored with traditional approaches, it is worthwhile to investigate alternative sensing techniques in order to improve accessibility and understanding of patients' conditions. This paper presents our laboratory's development of such a wearable system, which makes use of unconventional techniques for physiologic monitoring. With its integrated textile electrocardiogram (ECG) electrodes, intelligent finger-ring photoplethysmogram (PPG) sensor, miniaturized optical fiber-based temperature sensor, eye dynamics monitor, global positioning system (GPS) module, and wireless capability, it demonstrates a feasible solution for ubiquitous healthcare. PMID- 23367249 TI - Smart sensing of cardiovascular physiological information from soles without direct skin contact. AB - This study proposes the development of a smart sensing measurement system using a mat-type sensor in order to obtain sole-electrocardiogram data from soles and toe photoplethysmogram data from toes. In addition, the proposed measurement system can calculate pulse wave velocity from sole-ECG and toe-PPG. The subjective experiments revealed that the developed system can measure these parameters even when socks are being worn. Moreover, simultaneous measurements of systolic blood pressure and PWV determined by the developed system indicate a strong correlation was found between SBP and PWV. Therefore, this system can detect cardiovascular diseases or symptoms of common diseases and suggests the possibility to estimate the temporal changes in SBP without required compression using cuffs. PMID- 23367250 TI - Bed occupancy monitoring: data processing and clinician user interface design. AB - Unobtrusive and continuous monitoring of patients, especially at their place of residence, is becoming a significant part of the healthcare model. A variety of sensors are being used to monitor different patient conditions. Bed occupancy monitoring provides clinicians a quantitative measure of bed entry/exit patterns and may provide information relating to sleep quality. This paper presents a bed occupancy monitoring system using a bed pressure mat sensor. A clinical trial was performed involving 8 patients to collect bed occupancy data. The trial period for each patient ranged from 5-10 weeks. This data was analyzed using a participatory design methodology incorporating clinician feedback to obtain bed occupancy parameters. The parameters extracted include the number of bed exits per night, the bed exit weekly average (including minimum and maximum), the time of day of a particular exit, and the amount of uninterrupted bed occupancy per night. The design of a clinical user interface plays a significant role in the acceptance of such patient monitoring systems by clinicians. The clinician user interface proposed in this paper was designed to be intuitive, easy to navigate and not cause information overload. An iterative design methodology was used for the interface design. The interface design is extendible to incorporate data from multiple sensors. This allows the interface to be part of a comprehensive remote patient monitoring system. PMID- 23367251 TI - Quantitative and qualitative evaluation of PERCEPT indoor navigation system for visually impaired users. AB - In this paper we introduce qualitative and quantitative evaluation of PERCEPT system, an indoor navigation system for the blind and visually impaired. PERCEPT system trials with 24 blind and visually impaired users in a multi-story building show PERCEPT system effectiveness in providing appropriate navigation instructions to these users. The uniqueness of our system is that it is affordable and that its design follows Orientation and Mobility principles. These results encourage us to generalize the solution to large indoor spaces and test it with significantly larger visually impaired population in diverse settings. We hope that PERCEPT will become a standard deployed in all indoor public spaces. PMID- 23367252 TI - Flexible and customizable visualization of data generated within intelligent environments. AB - This paper outlines a tool for the visualization of data generated within Intelligent Environments. This tool has been designed with a focus on flexibility and customizability hence facilitating application to a range of areas including institutionalized or home-based healthcare monitoring. Through the use of an object toolbox, non-technical users can rapidly re-create a visual representation (aka a "Scene") of an intelligent environment and connect this scene to an active data repository. Data generated within the environment can be visualized in real time, or summarized using a density ring visualization format that can be customized based on user defined rules to highlight events of particular interest. The tool was tested within a smart lab used as an active research environment. Collection of data over a one week period resulted in 3840 sensor activations. Visualization of this dataset illustrates the potential of the tool to highlight normal and abnormal activity trends within the environment. PMID- 23367253 TI - Ambient Assisted Living and ageing: preliminary results of RITA project. AB - The ageing of population is a social phenomenon that most of worldwide countries are facing. They are, and will be even more in the future, indeed trying to find solutions for improving quality of life of their elderly citizens. The project RITA wants to demonstrate that an update of the current socio-medical services with an Ambient Assisted Living (AAL) approach could improve the service efficiency and the quality of life of both elderly and caregiver. This paper presents the preliminary results obtained in RITA. PMID- 23367254 TI - Impact of physical telerehabilitation on functional outcomes in seniors with mobility limitations. AB - The goal of this project was to objectively assess potential impact of home-based physical telerehabilitation program on functional outcomes in seniors with mobility limitations. Nine consecutive seniors with mobility limitations were enrolled into a 12-week physical telerehabilitation program. At the end of the program, the mean time that patients took to walk 25 feet decreased from 13.5 to 10.6 seconds, and the mean distance that patients walked in 6 minutes improved from 722.4 to 805.7 feet. The Berg Balance Score score also increased from 36.6 to 41.7 over the 12-week period. All changes were statistically significant (p<0.05). Patients demonstrated very high acceptance of the home-based program. PMID- 23367255 TI - Physical activity monitoring and sharing platform for manual wheelchair users. AB - Unlike able-bodied ambulatory population, wheelchair users do not have adequate access to technologies that monitor and motivate physical activity (PA). We developed a physical activity monitoring and sharing platform (PAMS) especially suited for capturing PA that are part of the lifestyle in wheelchair users and motivating them to be physically active via social networking based applications. This paper describes the general infrastructure and components of the prototype PAMS. The monitoring unit is designed to capture the activity type, amount, and associated energy expenditure of wheelchair users. The sharing unit consists of a web-based application and an Android-based mobile application built on top of Facebook platform and allows wheelchair users to self-monitor and share their PA information with their community of interest. The prototype PAMS is being evaluated for its reliability in capturing PA, validity in measuring PA parameters, and usability of the sharing applications among wheelchair users. We expect the PAMS will enable wheelchair users to track their own PA participation and become more physically active, leading to better overall health, greater community participation, and higher quality of life. PMID- 23367256 TI - Distinguishing near-falls from daily activities with wearable accelerometers and gyroscopes using Support Vector Machines. AB - Falls are the number one cause of injury in older adults. An individual's risk for falls depends on his or her frequency of imbalance episodes, and ability to recover balance following these events. However, there is little direct evidence on the frequency and circumstances of imbalance episodes (near falls) in older adults. Currently, there is rapid growth in the development of wearable fall monitoring systems based on inertial sensors. The utility of these systems would be enhanced by the ability to detect near-falls. In the current study, we conducted laboratory experiments to determine how the number and location of wearable inertial sensors influences the accuracy of a machine learning algorithm in distinguishing near-falls from activities of daily living (ADLs). PMID- 23367257 TI - First application of behavoir recognition through the recording of ADL by radio modules in a home. AB - In this contribution the behavior of an elderly couple, recorded by a radio module system in their own home is analyzed. There is an increasing interest in giving elderly people the possibility to live at their own homes as long as possible. Since diseases like dementia are diagnosed through the change of behavior, especially the activities of daily living (ADL), there is a growing need of an objective instrument for measuring behavioral changes. Therefore the Eventlogger was developed and installed for 32 days in a home of an elderly couple. Throughout this paper the outcome of the data collection as well as first steps for analyzing it will be discussed. Furthermore we were able to observe different routines of the diseased and the healthy person. The diseased proband follows a very strict routine whereas the healthy proband routines are dependent on different factors. PMID- 23367258 TI - Location and activity tracking with the cloud. AB - Helping elderly people to live independently within their homes for as long as possible, before transitioning to higher levels of care, can significantly reduce healthcare expenditures. However, achieving this vision requires continuous monitoring of the condition of elderly adults within their homes. In particular, activity, gait velocity, movement, and location of elderly adults are critical biomarkers for healthy aging. We present a prototype integrating a wearable location-tracking sensor with back-end cloud-based data processing, thereby enabling real-time tracking and analysis of a large number of people simultaneously. The resulting vertically-integrated prototype provides a basic infrastructure for future work, including new products and services that offer real-time monitoring and early disease diagnosis to help elderly people live independently for as long as possible. PMID- 23367259 TI - SVM to detect the presence of visitors in a smart home environment. AB - With the rising age of the population, there is increased need to help elderly maintain their independence. Smart homes, employing passive sensor networks and pervasive computing techniques, enable the unobtrusive assessment of activities and behaviors of the elderly which can be useful for health state assessment and intervention. Due to the multiple health benefits associated with socializing, accurately tracking whether an individual has visitors to their home is one of the more important aspects of elders' behaviors that could be assessed with smart home technology. With this goal, we have developed a preliminary SVM model to identify periods where untagged visitors are present in the home. Using the dwell time, number of sensor firings, and number of transitions between major living spaces (living room, dining room, kitchen and bathroom) as features in the model, and self report from two subjects as ground truth, we were able to accurately detect the presence of visitors in the home with a sensitivity and specificity of 0.90 and 0.89 for subject 1, and of 0.67 and 0.78 for subject 2, respectively. These preliminary data demonstrate the feasibility of detecting visitors with in home sensor data, but highlight the need for more advanced modeling techniques so the model performs well for all subjects and all types of visitors. PMID- 23367260 TI - Improve quality of care with remote activity and fall detection using ultrasonic sensors. AB - In this paper a fall detection system is presented that automatically detects the fall of a person and their location using an array of ultrasonic wave transducers connected to a field-programmable gate array (FPGA) processor. Experimental results are provided on a prototype deployment installed at an assisted living community. The system can provide a cost-effective and intelligent method to help caregivers detect a fall quickly so that patients are treated in a timely manner. In addition to room monitoring and local alert functions, the system incorporates a personal computer and wireless connection to enable remote monitoring of patient's activity and health status. PMID- 23367261 TI - Framework for preventing falls in acute hospitals using passive sensor enabled radio frequency identification technology. AB - We describe a distributed architecture for a real-time falls prevention framework capable of providing a technological intervention to mitigate the risk of falls in acute hospitals through the development of an AmbIGeM (Ambient Intelligence Geritatric Management system). Our approach is based on using a battery free, wearable sensor enabled Radio Frequency Identification device. Unsupervised classification of high risk falls activities are used to facilitate an immediate response from caregivers by alerting them of the high risk activity, the particular patient, and their location. Early identification of high risk falls activities through a longitudinal and unsupervised setting in real-time allows the preventative intervention to be administered in a timely manner. Furthermore, real-time detection allows emergency protocols to be deployed immediately in the event of a fall. Finally, incidents of high risk activities are automatically documented to allow clinicians to customize and optimize the delivery of care to suit the needs of patients identified as being at most risk. PMID- 23367262 TI - Radar walk detection in the apartments of elderly. AB - Seniors want to live more independent lifestyles. This comes with some risks including dwindling health and major injuries due to falling. A factor that has been studied and seen to have a correlation to fall risk is change in gait speed. Our goal is to create a passive system that monitors the gait of elderly so that assessments can be given by caregivers if gait changes do occur. This paper will cover a method of using pulse-Doppler radar to detect when walks occur. In unscripted living environments, we are able to detect valid walks. The system does miss walks during the day, but when walks are detected, they are actually valid walks 91.8% of the time using a large data base of radar signals captured in living environments. PMID- 23367263 TI - Improving automatic sound-based fall detection using iVAT clustering and GA-based feature selection. AB - Falls represent an important health problem for older adults. This issue continues to generate interest in the research and development of fall detection systems. In previous work we proposed an acoustic fall detection system (acoustic FADE) that employs an 8-microphone circular array to automatically detect falls. Acoustic-FADE has achieved encouraging results: 100% detection at 3% false alarm rate in laboratory tests. In this paper, we use a dataset from previous work to investigate how to further improve AFADE performance. To analyze the relationship between fall and non-fall signatures we used the improved visual assessment of tendency (iVAT) clustering algorithm in conjunction with a nearest neighbor based distance to find the most challenging false alarms. Then, we employed a genetic algorithm (GA) framework to perform feature selection and find the mel-frequency cepstral coefficients (MFCC) that improve the classification performance. We found that using only three MFCC coefficients (1, 28, 29) instead of our previous choice (1,2,3,4,5,6) improves the classification performance. PMID- 23367264 TI - Interactive Radiology teaching file system: the development of a MIRC-compliant and user-centered e-learning resource. AB - Radiology teaching usually employs a systematic and comprehensive set of medical images and related information. Databases with representative radiological images and documents are highly desirable and widely used in Radiology teaching programs. Currently, computer-based teaching file systems are widely used in Medicine and Radiology teaching as an educational resource. This work addresses a user-centered radiology electronic teaching file system as an instance of MIRC compliant medical image database. Such as a digital library, the clinical cases are available to access by using a web browser. The system has offered great opportunities to some Radiology residents interact with experts. This has been done by applying user-centered techniques and creating usage context-based tools in order to make available an interactive system. PMID- 23367265 TI - Robust lossless watermarking based on circular interpretation of bijective transformations for the protection of medical databases. AB - In this paper, we adapt the image lossless watermarking modulation proposed by De Vleeschouwer et al., based on the circular interpretation of bijective modulations, to the protection of medical relational databases. Our scheme modulates the numerical attributes of the database. It is suited for either copyright protection, integrity control or traitor tracing, being robust to most common database attacks, such as the addition and removal of tuples and the modification of attributes' values. Conducted experiments on a medical database of inpatient hospital stay records illustrate the overall performance of our method and its suitability to the requirements of the medical domain. PMID- 23367266 TI - Losless EEG signal compression. AB - In this work, we study the lossless compression of EEG (electroencephalograph) signals using linear prediction and arithmetic coder. We show that, when we separate the less significant bits of each signal, linear prediction techniques yield better prediction, and with a structured arithmetic coder not only our technique achieves better compression rates than other techniques reported previously, but also our technique is much faster than the others. PMID- 23367267 TI - Improvement of surveillance of hemophilia treatment through ICTs. AB - Hemophilia, in addition of being a chronic disease, is also a rare disease, and as such, quite expensive for the National Health Service (NHS) due to the cost associated with the drugs used in treatments (Clotting Factor Concentrate - CFC). On the other hand, due to the specific characteristics of this type of disorder, it is necessary to ensure that data generated during the treatments are quickly communicated to the clinicians responsible for monitoring those patients. As such, an effective management of this disease, with maximum safety for patients, involves not only an efficient information management process, but also the coordination and management of all the associated resources. This article aims to present one specific component of a technological solution that can help in coordinate actions of patients, physicians and nurses, as well as improve the surveillance of hemophilia treatment, within a specific Comprehensive Hemophilia Diagnostic and Treatment Center (HTC). PMID- 23367268 TI - Bed detection for monitoring system in hospital wards. AB - Patient monitoring system has been providing a means for caregivers to regularly observe patients' condition in a multiple intensive care units from a single remote location in hospitals. In addition, the system may provide an addition layer of care, which includes software tools that support analysis of patients' vital signs, trends etc. To allow visual surveillance, cameras are installed in the patient wards. From the clinical observation, the key area in the hospital are around and on the bed as most of the activities take place and where patients spend most of their time. Therefore detecting the bed is the first basic task in studying and monitoring the patients' behavior. We have developed a novel technique in detecting the patient bed. This technique is based on Canny Edge detector and Hough Transformation. The algorithm is tested and the experimental results show that our proposed method can effectively locate the position of the patient bed. PMID- 23367269 TI - Distributed PACS using distributed file system with hierarchical meta data servers. AB - In this research, we propose a new distributed PACS (Picture Archiving and Communication Systems) which is available to integrate several PACSs that exist in each medical institution. The conventional PACS controls DICOM file into one data-base. On the other hand, in the proposed system, DICOM file is separated into meta data and image data and those are stored individually. Using this mechanism, since file is not always accessed the entire data, some operations such as finding files, changing titles, and so on can be performed in high-speed. At the same time, as distributed file system is utilized, accessing image files can also achieve high-speed access and high fault tolerant. The introduced system has a more significant point. That is the simplicity to integrate several PACSs. In the proposed system, only the meta data servers are integrated and integrated system can be constructed. This system also has the scalability of file access with along to the number of file numbers and file sizes. On the other hand, because meta-data server is integrated, the meta data server is the weakness of this system. To solve this defect, hieratical meta data servers are introduced. Because of this mechanism, not only fault--tolerant ability is increased but scalability of file access is also increased. To discuss the proposed system, the prototype system using Gfarm was implemented. For evaluating the implemented system, file search operating time of Gfarm and NFS were compared. PMID- 23367270 TI - Understanding requirements of novel healthcare information systems for management of advanced prostate cancer. AB - Effective management of chronic diseases is a global health priority. A healthcare information system offers opportunities to address challenges of chronic disease management. However, the requirements of health information systems are often not well understood. The accuracy of requirements has a direct impact on the successful design and implementation of a health information system. Our research describes methods used to understand the requirements of health information systems for advanced prostate cancer management. The research conducted a survey to identify heterogeneous sources of clinical records. Our research showed that the General Practitioner was the common source of patient's clinical records (41%) followed by the Urologist (14%) and other clinicians (14%). Our research describes a method to identify diverse data sources and proposes a novel patient journey browser prototype that integrates disparate data sources. PMID- 23367271 TI - Safety evaluation of a Medical Device Data System. AB - Our hospital became interested in the extraction of electronic data from our bedside monitor network to enrich clinical care, and enable various quality improvement projects, research projects, and future applications involving advanced decision-support. We conducted a range of tests to confirm the safety of deploying BedMaster (Excel Medical Electronics, Jupiter FL, USA), which is third party software sold expressly to provide electronic data extraction and storage from networked General Electric Healthcare bedside patient monitors. We conducted a series of tests examining the changes in network performance when the BedMaster system was on our isolated patient monitor network. We found that use of BedMaster led to measurable, but trivial increases in network traffic and latency. We did not identify any failure scenarios in our analysis and testing. The major value of this report is to highlight potential challenges inherent in data and electronic device integration within the healthcare setting. In describing our strategy for testing the BedMaster system, it is our intention to present one testing protocol and to generate thought and discussion in the broader community about what types of problems can arise with inter-operability, and what types of testing are necessary to mitigate against these risks. Standards for inter-operability would surely reduce the inherent risks. PMID- 23367272 TI - Time based clustering for analyzing acute hospital patient flow. AB - This paper describes a novel approach employing time based clustering of health data for visualization and analysis of patient flow. Clustering inpatient and emergency department patient episodes into hourly slots based on recorded timestamps, and then grouping them on required parameters, the technique provides a powerful tool for visualizing and analyzing interactions and interdependencies between hospital patient flow parameters. To demonstrate the efficacy of the approach, we employ time based clustering to address some typical patient flow related queries and discuss the findings. PMID- 23367273 TI - Improvement of CVD risk assessment tools' performance through innovative patients' grouping strategies. AB - There are available in the clinical community several practical risk tools to assess the risk of occurrence of a cardiovascular event. Although valuable, these tools typically present some lack of performance (low sensitivity/low specificity) when applied to a general (average) patient. This flaw is addressed in this work through an innovative personalization strategy that is supported on the evidence that current risk assessment tools perform differently among different populations/groups of patients. The proposed methodology is based on two main hypotheses: i) patients are grouped through a proper dimension reduction technique complemented with an unsupervised learning algorithm, ii) for each group the most suitable risk assessment tool can be selected improving the risk prediction performance. As a result, risk personalization is simply achieved by the identification of the group that patients belong to. The validation of the strategy is carried out through the combination of three current risk assessment tools (GRACE, TIMI, PURSUIT) developed to predict the risk of an event in coronary artery disease patients. The combination of these tools is validated with a real patient testing dataset: Santa Cruz Hospital, Portugal, N=460 ACS NSTEMI patients. Considering the obtained results with the available dataset it is possible to state that the main objective of this work was achieved. PMID- 23367274 TI - A machine learning approach using P300 responses to investigate effect of clozapine therapy. AB - Clozapine (CLZ) is uniquely effective as a treatment for medication resistant schizophrenia. Information regarding its mechanism of action may offer clues to the pathophysiology of the disease and to improved treatment. In this study we employ a machine learning (ML) analysis of P300 evoked potentials obtained from quantitative electroencephalography (QEEG) data to identify changes in the brain induced by CLZ treatment. We employ brain source localization (BSL) on the EEG signals to extract source waveforms from specified regions of the brain. A subset of 8 features is selected from a large set of candidate features (consisting of spectral coherences between all identified source waveforms at multiple frequencies) that discriminate (by means of a classifier) between the pre- and post-treatment data for the schizophrenics (SCZ) most responsive to CLZ. We show these same selected features also discriminate between pre-treatment most responsive SCZ and healthy volunteers (HV), but not after treatment. Of note, these same features discriminate the least responsive SCZ from HV both pre- and post-treatment. This analysis suggests that the net beneficial effects of CLZ in SCZ are reflected in a normalization of P300 brain-source generators. PMID- 23367275 TI - Feature accentuation in phosphenated images. AB - We present and evaluate different approaches to feature accentuation in phosphenated images for different image resolutions. The goal of this study is to find methods to attract an implantee's visual attention to important image content like faces, obstacles or road signs. We do this by defining an important region in the image and accentuating it by either increasing the brightness of outlining phosphenes or by using elliptical phosphenes to circumscribe the feature. While we only see limited benefit of ellipse phosphenes for a high resolution prosthesis, the use of elliptical phosphenes of different orientations is a promising way to highlight features in a low-resolution phosphene representation of an image. PMID- 23367276 TI - Noise reduction using anisotropic diffusion filter in inverse electrocardiology. AB - Filtering has been widely used in biomedical signal processing and image processing applications to cancel noise effects in signals recorded from the body. However, it is important to keep the desired characteristics of the physiological signal of interest while suppressing the noise characteristics. In this study, we used anisotropic diffusion filter (ADF) to cancel the noise on the body surface potentials measurements (BSPM) with the goal of improving the corresponding solutions of the inverse problem of electrocardiology (ECG). ADFs have been applied to image processing and they have the advantage of preserving sharp edges while rejecting the noise, thus we have chosen ADFs instead of more conventional filtering techniques. We used unfiltered and filtered BSPMs to estimate the epicardial potential distributions. We compared Tikhonov regularization results when the data included measurement noise and geometric errors. In both cases, filtering of BSPMs using the ADF improved our solutions. PMID- 23367277 TI - Effect of duty cycle in different frequency domains on SSVEP based BCI: a preliminary study. AB - Compared with the well learned amplitude-frequency characteristic of Steady State Visual Evoked Potential (SSVEP), the effect of duty cycle is still unclear. In this work, the influence of duty cycle on SSVEP response is investigated in differnt frequency domains. The amplitude surface with the change of both frequencies and duty cycles is plotted. To get a stable response, the experiment arranged in 3 days, and each result is an average of 12 repetitions. It is interesting that the results from power spectral density (PSD) and canonical correlation analysis (CCA) method are not consistent. In addition, the relation between the fundamental component and its second harmonic component with the change of duty cycle is quite different at frequency of 7 Hz, 10 Hz and 13 Hz. Based on the amplitude surface, we try to configure the subject-specific SSVEP based BCI. The frequencies and duty cycles of the stimulus are selected corresponding to the higher SSVEP response in the amplitude surface. Cross validation results show a significant improvement in the performance for the adjustment of duty cycle. PMID- 23367278 TI - Localization of hemorrhage site in stroke patients using multichannel microwave measurements. AB - Microwave measurements from an antenna array placed around the head can be used to detect changes in dielectric properties of the brain. In this paper an algorithm is developed to provide localization information of the site of an intra cerebral hemorrhage. The algorithm is based in the hypothesis that scattering parameters for an antenna pair close to the site of the bleeding will undergo larger changes. The change is measured using a feature derived from the scattering measurements using higher order singular value decomposition and is compared with the feature derived from measurements from a control group of healthy subjects. The proposed algorithm is evaluated on clinical data and the result is compared with computed tomography images of the patients. PMID- 23367279 TI - Application of decision tree in the prediction of periventricular leukomalacia (PVL) occurrence in neonates after heart surgery. AB - This paper is concerned with the prediction of the occurrence of periventricular leukomalacia (PVL) that occurs in neonates after heart surgery. The data which is collected over a period of 12 hours after cardiac surgery contains vital measurements as well as blood gas measurements with different resolutions. Vital data measured using near-inferred spectroscopy (NIRS) at the sampling rate of 0.25 Hz and blood gas measurement up to 12 times with irregular time intervals for 35 patients collected at Children's Hospital of Philadelphia (CHOP) are used for this study. Features derived from the data include statistical moments (mean, variance, skewness and kurtosis), trend and minimum and maximum values of the vital data and rate of change, time weighted mean and a custom defined out of range index (ORI) for the blood gas data. A decision tree is developed for the vital data in order to identify the most important vital measurements. In addition, a decision tree is developed for blood gas data to find important factors for the prediction of PVL occurrence. Results show that in the blood gas data, maximum rate of change of concentration of bicarbonate ions in blood (HCO(3)) and minimum rate of change of partial pressure of dissolved CO(2) in the blood (PaCO(2)) are the two most important factors for prediction of the PVL. Also important are the kurtosis of heart rate and hemoglobin values. PMID- 23367280 TI - A data mining approach to reduce the false alarm rate of patient monitors. AB - Patient monitors in intensive care units trigger alarms if the state of the patient deteriorates or if there is a technical problem, e.g. loose sensors. Monitoring systems have a high sensitivity in order to detect relevant changes in the patient state. However, multiple studies revealed a high rate of either false or clinically not relevant alarms. It was found that the high rate of false alarms has a negative impact on both patients and staff. In this study we apply data mining methods to reduce the false alarm rate of monitoring systems. We follow a multi-parameter approach where multiple signals of a monitoring system are used to classify given alarm situations. In particular we focus on five alarm types and let our system decide whether the triggered alarm is clinically relevant or can be considered as a false alarm. Several classification algorithms (Naive Bayes, Decision Trees, SVM, kNN and Multi-Layer Perceptron) were evaluated. For training and test sets a subset of the freely available MIMIC II database was used. Alarm-specific classification accuracy was between 78.56% and 98.84%. Suppression rates for false alarms were between 75.24% and 99.23%. Classification results strongly depend on available training data, which is still limited in the intensive care domain. However, this study shows that data mining methods are useful and applicable for alarm classification. PMID- 23367281 TI - Discovering shared dynamics in physiological signals: application to patient monitoring in ICU. AB - Modern clinical databases include time series of vital signs, which are often recorded continuously during a hospital stay. Over several days, these recordings may yield many thousands of samples. In this work, we explore the feasibility of characterizing the "state of health" of a patient using the physiological dynamics inferred from these time series. The ultimate objective is to assist clinicians in allocating resources to high-risk patients. We hypothesize that "similar" patients exhibit similar dynamics and the properties and duration of these states are indicative of health and disease. We use Bayesian nonparametric machine learning methods to discover shared dynamics in patients' blood pressure (BP) time series. Each such "dynamic" captures a distinct pattern of evolution of BP and is possibly recurrent within the same time series and shared across multiple patients. Next, we examine the utility of this low-dimensional representation of BP time series for predicting mortality in patients. Our results are based on an intensive care unit (ICU) cohort of 480 patients (with 16% mortality) and indicate that the dynamics of time series of vital signs can be an independent useful predictor of outcome in ICU. PMID- 23367282 TI - Epileptic seizure prediction based on a bivariate spectral power methodology. AB - The spectral power of 5 frequently considered frequency bands (Alpha, Beta, Gamma, Theta and Delta) for 6 EEG channels is computed and then all the possible pairwise combinations among the 30 features set, are used to create a 435 dimensional feature space. Two new feature selection methods are introduced to choose the best candidate features among those and to reduce the dimensionality of this feature space. The selected features are then fed to Support Vector Machines (SVMs) that classify the cerebral state in preictal and non-preictal classes. The outputs of the SVM are regularized using a method that accounts for the classification dynamics of the preictal class, also known as "Firing Power" method. The results obtained using our feature selection approaches are compared with the ones obtained using minimum Redundancy Maximum Relevance (mRMR) feature selection method. The results in a group of 12 patients of the EPILEPSIAE database, containing 46 seizures and 787 hours multichannel recording for out-of sample data, indicate the efficiency of the bivariate approach as well as the two new feature selection methods. The best results presented sensitivity of 76.09% (35 of 46 seizures predicted) and a false prediction rate of 0.15(-1). PMID- 23367283 TI - Spectrum based feature extraction using spectrum intensity ratio for SSVEP detection. AB - Recent years, a Steady-State Visual Evoked Potential (SSVEP) is used as a basis for Brain Computer Interface (BCI)[1]. Various feature extraction and classification techniques are proposed to achieve BCI based on SSVEP. The feature extraction of SSVEP is developed in the frequency domain regardless of the limitation in flickering frequency of visual stimulus caused by hardware architecture. We introduce here the feature extraction using a spectrum intensity ratio. Results show that the detection ratio reaches 84% by using a spectrum intensity ratio with unsupervised classification. It also indicates the SSVEP is enhanced by proposed feature extraction with second harmonic. PMID- 23367284 TI - Automatic exudate detection using active contour model and regionwise classification. AB - Diabetic retinopathy is one the most common cause of blindness in the world. Exudates are among the early signs of this disease, so its proper detection is a very important task to prevent consequent effects. In this paper, we propose a novel approach for exudate detection. First, we identify possible regions containing exudates using grayscale morphology. Then, we apply an active contour based method to minimize the Chan-Vese energy to extract accurate borders of the candidates. To remove those false candidates that have sufficient strong borders to pass the active contour method we use a regionwise classifier. Hence, we extract several shape features for each candidate and let a boosted Naive Bayes classifier eliminate the false candidates. We considered the publicly available DiaretDB1 color fundus image set for testing, where the proposed method outperformed several state-of-the-art exudate detectors. PMID- 23367285 TI - An adaptive weighting approach for ensemble-based detection of microaneurysms in color fundus images. AB - In this paper, we present an adaptive weighting approach to microaneurysm detector ensembles. The basis of the adaptive weighting approach is the spatial location and contrast of the detected microaneurysm. During training, the performance of ensemble members is measured with a respect to these contextual information, which serves as a basis for the optimal weights assigned to detectors. We have tested this approach on two publicly available datasets, where it showed its competitiveness compared with out previously published ensemble based approach for microaneurysm detection. Moreover, the proposed approach outperformed all the investigated individual detectors. PMID- 23367286 TI - Studying disagreements among retinal experts through image analysis. AB - In recent years, many image analysis algorithms have been presented to assist Diabetic Retinopathy (DR) screening. The goal was usually to detect healthy examination records automatically, in order to reduce the number of records that should be analyzed by retinal experts. In this paper, a novel application is presented: these algorithms are used to 1) discover image characteristics that sometimes cause an expert to disagree with his/her peers and 2) warn the expert whenever these characteristics are detected in an examination record. In a DR screening program, each examination record is only analyzed by one expert, therefore analyzing disagreements among experts is challenging. A statistical framework, based on Parzen-windowing and the Patrick-Fischer distance, is presented to solve this problem. Disagreements among eleven experts from the Ophdiat screening program were analyzed, using an archive of 25,702 examination records. PMID- 23367287 TI - Glaucoma risk assessment based on clinical data and automated nerve fiber layer defects detection. AB - Glaucoma is the first leading cause of vision loss in Japan, thus developing a scheme for helping glaucoma diagnosis is important. For this problem, automated nerve fiber layer defects (NFLDs) detection method was proposed, but glaucoma risk assessment using this method was not evaluated. In this paper, computerized risk assessment for having glaucoma was attempted by use of the patients' clinical information, and the performances of the NFLDs detection and the glaucoma risk assessment were compared. The clinical data includes the systemic data, ophthalmologic data, and right and left retinal images. Glaucoma risk assessment was built by using machine learning technique, which were artificial neural network, radial basis function (RBF) network, k-nearest neighbor algorithm, and support vector machine. The inputting parameter was ten clinical ones with/without the results of NFLDs detection. As a result, proposed glaucoma risk assessment showed the higher performance than the NFLD detection. The result of the glaucoma risk assessment indicates that the computerized assessment may be useful for the determination of glaucoma risk. PMID- 23367288 TI - Quantitative assessment of age-related macular degeneration using parametric modeling of the leakage transfer function: preliminary results. AB - Age-related macular degeneration (AMD) is a major cause of blindness and visual impairment in older adults. The wet form of the disease is characterized by abnormal blood vessels forming a choroidal neovascular membrane (CNV), that result in destruction of normal architecture of the retina. Current evaluation and follow up of wet AMD include subjective evaluation of Fluorescein Angiograms (FA) to determine the activity of the lesion and monitor the progression or regression of the disease. However, this subjective evaluation prevents accurate monitoring of the disease progression or regression in response to a pharmacologic agent. In this work, we present a method that allows objective assessment of the activity of a CNV lesion which can be statistically compared across different patient and time points. The method is based on a hypothesis that the discrepancy in the time-intensity signals among the diseased and normal retinal areas are due to an implicit transfer function whose parameters can be used to characterize the retina. The method begins with parametric modeling of the temporal variation of the lesion and background intensities. Then, the values of the model parameters are used to evaluate the change in the activity of the disease. Preliminary results on five datasets show that the calculated parameters are highly correlated with the Visual Acuity (VA) of the patients. PMID- 23367289 TI - New workflows and algorithms of bone scintigraphy based on SPECT-CT. AB - Gold standard bone scintigraphy workflow contains acquisition of planar anterior and posterior images and if necessary, additional SPECTs as well. Planar acquisitions are time consuming and not enough for accurately locating hotspots. Current paper proposes a novel workflow for fast whole body bone SPECT scintigraphy. We present a novel stitching method to generate a whole body SPECT based on the SPECT projections. Our stitching method is performed on the projection series not on the reconstructed SPECTs, thus stitching artifacts are greatly reduced. Our workflow does not require any anterior-posterior image pairs, since these images are derived from the reconstructed whole body SPECT automatically. Our stitching method has been validated on real clinical data performed by medical physicians. Results show that our method is very effective for whole body SPECT generations leaving no signs of artifacts. Our workflow required overall 16 minutes to acquire a whole body SPECT which is comparable to the 60 minutes acquisition time required for gold standard techniques including planar images and additional SPECT acquisitions. PMID- 23367290 TI - A head motion measurement system suitable for 3D cone-beam tomography using markers. AB - Head motion during brain CT studies can degrade the reconstructed image through distortion and other artifacts such as blurring, doubling and thereby contributing to misdiagnosis of diseases. Estimation of motion parameters is essential for mitigating motion artifacts. In this paper, we propose a marker based numerical optimization method to measure six degrees of freedom of head motion in three-dimensional cone-beam CT system without using any external motion sensors. Simulation results demonstrate that our method has prerequisite accuracy, linearity and range compared to the existing external sensor based method. PMID- 23367291 TI - Implementation of digital multiplexing for high resolution X-ray detector arrays. AB - We describe and demonstrate for the first time the use of the novel Multiple Module Multiplexer (MMMIC) for a 2*2 array of new electron multiplying charge coupled device (EMCCD) based x-ray detectors. It is highly desirable for x-ray imaging systems to have larger fields of view (FOV) extensible in two directions yet to still be capable of doing high resolution imaging over regions-of-interest (ROI). The MMMIC achieves these goals by acquiring and multiplexing data from an array of imaging modules thereby enabling a larger FOV, and at the same time allowing high resolution ROI imaging through selection of a subset of modules in the array. MMMIC also supports different binning modes. This paper describes how a specific two stage configuration connecting three identical MMMICs is used to acquire and multiplex data from a 2*2 array of EMCCD based detectors. The first stage contains two MMMICs wherein each MMMIC is getting data from two EMCCD detectors. The multiplexed data from these MMMICs is then forwarded to the second stage MMMIC in the similar fashion. The second stage that has only one MMMIC gives the final 12 bit multiplexed data from four modules. This data is then sent over a high speed Camera Link interface to the image processing computer. X-ray images taken through the 2*2 array of EMCCD based detectors using this two stage configuration of MMMICs are shown successfully demonstrating the concept. PMID- 23367292 TI - A 2*2 array of EMCCD-based solid state x-ray detectors. AB - We have designed and developed a new solid-state x-ray imaging system that consists of a 2*2 array of electron multiplying charge coupled devices (EMCCDs). This system is intended for fluoroscopic and angiographic medical imaging. The key components are the four 1024 * 1024 pixel EMCCDs with a pixel size of 13 * 13 um(2). Each EMCCD is bonded to a fiber optic plate (FOP), and optically coupled to a 350 um thick micro-columnar CsI(TI) scintillator via a 3.22?1 fiber optic taper (FOT). The detector provides x-ray images of 9 line pairs/mm resolution at 15 frames/sec and real-time live video at 30 frames/sec with binning at a lower resolution, independent of the electronic gain applied to the EMCCD. The total field of view (FOV) of the array is 8.45 cm * 8.45 cm. The system is designed to also provide the ability to do region-of- interest imaging (ROI) by selectively enabling individual modules of the array. PMID- 23367293 TI - Brain tissue selection procedures for image derived input functions derived using independent components analysis. AB - Absolute quantification of positron emission tomography (PET) data requires invasive blood sampling in order to obtain the arterial input function (AIF). This procedure involves considerable costs and risks. A less invasive approach is to estimate the AIF directly from images, known as an image derived input function (IDIF). One promising method, EPICA, extracts IDIF by applying independent components analysis (ICA) on dynamic PET data from the entire brain. EPICA requires exclusion of non-brain voxels from the PET images, which is achieved by using a brain mask prior to ICA. Including the entire brain in the mask may degrade the performance of ICA due to noise, artifacts and confounding information. We applied EPICA to 3 [(18)F]FDG and 3 [(11)C]WAY data sets and investigated if altering the brain mask by including or excluding tissue structures improves EPICA performance. EPICA applied to whole brain data yields poor performance but with the appropriate brain mask IDIF curves approximate the AIF well. Different tissue structures are important for different radiotracers suggesting that the kinetics of the radiotracer and its diffusion characteristics in the brain influence IDIF estimation with ICA. PMID- 23367294 TI - An improved FDK algorithm using camera calibration technique for reconstruction of misaligned CBCT system. AB - Cone beam computed tomography (CBCT) is widely applied for medical and industrial use recently. But artifacts are always induced due to the misalignments of CBCT components. An improved Feldkamp-Davis-Kress (FDK) algorithm using camera calibration technique for image reconstruction of misaligned CBCT is applied here to reduce the artifacts. Simulation results show that our improved FDK algorithm can reduce the artifacts significantly compared with standard FDK algorithm in misaligned CBCT system. Through the improved FDK algorithm presented here, we can reconstruct misaligned CBCT images efficiently. PMID- 23367295 TI - Optimization of multi-layer metal neural probe design. AB - We present here a microfabrication process for multi-layer metal, multi-site, polymer-based neural probes. The process has been used to generate 1-, 2-, and 4 layer trace metal neural probes with highly uniform and reproducible electrode characteristics. Typically, increasing the number of metal layers is assumed to both reduce the width of the neural probes and minimize the injury and glial scarring caused at the implantation site. We show, however, that increasing the number of trace metal layers does not always result in the minimal probe cross sectional area. A thorough design analysis reveals that the electrode size, along with other design parameters, have interacting effects on the probe cross sectional area. Moreover, increasing the trace metal layers in the neural probes also increases the design and fabrication cost/time, as well as the likelihood of probe failure. Consequently, all of these factors must be considered when designing a multi-site, neural probe with the objective of minimizing tissue damage. PMID- 23367296 TI - Polymer neural interface with dual-sided electrodes for neural stimulation and recording. AB - We present here a demonstration of a dual-sided, 4-layer metal, polyimide-based electrode array suitable for neural stimulation and recording. The fabrication process outlined here utilizes simple polymer and metal deposition and etching steps, with no potentially harmful backside etches or long exposures to extremely toxic chemicals. These polyimide-based electrode arrays have been tested to ensure they are fully biocompatible and suitable for long-term implantation; their flexibility minimizes the injury and glial scarring that can occur at the implantation site. The creation of dual-side electrode arrays with more than two layers of trace metal enables the fabrication of neural probes with more electrodes without a significant increase in probe size. This allows for more stimulation/recording sites without inducing additional injury and glial scarring. PMID- 23367297 TI - Brain-friendly amperometric enzyme biosensor based on encapsulated oxygen generating biomaterial. AB - A novel first-generation Clark-type biosensor platform that can eliminate the oxygen dependence has been presented. Sufficient oxygen to drive the enzymatic reaction under hypoxic conditions was produced by encapsulated oxygen generating biomaterial, calcium peroxide. The catalase immobilized in chitosan matrix was coated on top of the groove to decompose residual hydrogen peroxide to oxygen. A glucose biosensor was developed on the proposed platform as proof of concept. Under hypoxic conditions, developed glucose biosensors maintained their sensitivity response around 84% of their response at oxygen tension of 151 mmHg. The sensitivity deviation was less than 5.3% with the oxygen tension traversed from 0 to 57 mmHg. Under oxygen tension of 8.3 mmHg, the sensitivity of 37.130 nA/mM and the linear coefficient of R(2)=0.9968 were obtained with the glucose concentration varying from 0.05 to 10mM. This new platform is particularly attractive for injured brain monitoring. PMID- 23367298 TI - Stretchable biocompatible electronics by embedding electrical circuitry in biocompatible elastomers. AB - Stretchable and curvilinear electronics has been used recently for the fabrication of micro systems interacting with the human body. The applications range from different kinds of implantable sensors inside the body to conformable electrodes and artificial skins. One of the key parameters in biocompatible stretchable electronics is the fabrication of reliable electrical interconnects. Although very recent literature has reported on the reliability of stretchable interconnects by cyclic loading, work still needs to be done on the integration of electrical circuitry composed of rigid components and stretchable interconnects in a biological environment. In this work, the feasibility of a developed technology to fabricate simple electrical circuits with meander shaped stretchable interconnects is presented. Stretchable interconnects are 200 nm thin Au layer supported with polyimide (PI). A stretchable array of light emitting diodes (LEDs) is embedded in biocompatible elastomer using this technology platform and it features a 50% total elongation. PMID- 23367299 TI - Baseband signal transmission experiment for intra-brain communication with implantable image sensor. AB - We demonstrate image signal transmission for wireless intra-brain communication. As a preliminary experiment, transmission characteristics of the brain phantom were measured. The baseband output signal from an implantable complementary metal oxide-semiconductor (CMOS) image sensor is transmitted through the phantom. The image was successfully reproduced from the received signal. PMID- 23367300 TI - Realistic modeling of the biological channel for the design of implantable wireless UWB communication systems. AB - Several emerging medical applications require that a miniature data acquisition device be implanted into the head to extract and wirelessly communicate brain activity to other devices. Designing a reliable communication link for such an application requires a realistic model of the surrounding biological tissues. This paper exploits a realistic model of the biological channel to design a suitable wireless ultra wideband communication link in a brain monitoring application. Two scenarios for positioning the implanted transmitting antenna are considered. The 1(st) scenario places the antenna under the skull, whereas the 2(nd) scenario places the antenna under the skin, above the skull. The propagation characteristics of the signal through the tissues of the human head have been determined with full-wave electromagnetic simulation based on Finite Element Method. The implantable antenna and the external antenna are key components to establish an electromagnetic link between an implanted transmitter and an external receiver. The average specific absorption rate (ASAR) of the implantable antennas are evaluated and compared for the two proposed scenarios. Moreover, the maximum available power from the implanted antenna is evaluated to characterize the performance of the communication link established between the implantable antenna and the external antenna, with respect to spectrum and safety regulations. We show how sensitive the receiver must be in order to implement a reliable telemetry link based on the proposed model of the channel. PMID- 23367301 TI - Development of a virtual reality system to evaluate skills needed to drive a cycling wheel-chair. AB - A cycling wheel chair (CWC) is a useful tool to provide physical exercise for patients who face difficulty walking, caused by stroke or other brain disorders. A system has been developed for rehabilitation, which allows patients to practice driving a CWC in a virtual environment. In this study, hardware improvements were developed and methods for evaluating driving skills were investigated to improve the practical application of this system. The hardware was changed to enable users to drive the CWC they were using in their daily lives. In addition, four types of test scenarios that focused on basic and important actions necessary to drive a CWC, such as pedaling and steering, were developed. An experiment with healthy young and elderly persons was conducted to evaluate the validity of the system. Results showed that pedaling and steering skills were improved in both the young and elderly subjects but the improvement patterns differed between them. These results indicate that repeated practice with the proposed system enhances the safety of driving a CWC, particularly for elderly users. PMID- 23367302 TI - Detection and localization of radiotherapy targets by template matching. AB - Radio opaque fiducials are implanted in tumors for the purpose of tracking the target motion using X-ray projections during radiation therapy dose delivery. In this paper we describe and evaluate a novel method based on template matching for detection and localization of arbitrary shaped fiducials. Segmentation methods are not adequate for these fiducials because their appearance in online X-ray projections can vary greatly as a function of imaging angle. The algorithm is based on using the planning CT image to generate templates that correspond to the imaging angles of the online images. We demonstrate successful tracking of complex shape fiducials in clinical images of lung and abdomen. We also validate the algorithm by comparing the results with a segmentation approach for one case in which the fiducials could be tracked by both methods. We also show how by adaptive thresholding of the match scores, we can control the false detection rate. PMID- 23367303 TI - Respiratory motion prediction for tumor following radiotherapy by using time variant seasonal autoregressive techniques. AB - We develop a new prediction method of respiratory motion for accurate dynamic radiotherapy, called tumor following radiotherapy. The method is based on a time variant seasonal autoregressive (TVSAR) model and extended to further capture time-variant and complex nature of various respiratory patterns. The extended TVSAR can represent not only the conventional quasi-periodical nature, but also the residual components, which cannot be expressed by the quasi-periodical model. Then, the residuals are adaptively predicted by using another autoregressive model. The proposed method was tested on 105 clinical data sets of tumor motion. The average errors were 1.28 +/- 0.87 mm and 1.75 +/- 1.13 mm for 0.5 s and 1.0 s ahead prediction, respectively. The results demonstrate that the proposed method can outperform the state-of-the-art prediction methods. PMID- 23367304 TI - Training strategies for a lower limb rehabilitation robot based on impedance control. AB - This paper proposes three training strategies based on impedance control, including passive training, damping-active training and spring-active training, for a 3-DOF lower limb rehabilitation robot designed for patients with paraplegia or hemiplegia. Controllers with similar structure are developed for these training strategies, consisting of dual closed loops, the outer impedance control loop and the inner position/velocity control loop, known as position-based impedance control method. Simulation results verify that position-based impedance control approach is feasible to accomplish the training strategies. PMID- 23367305 TI - Neural network-based data analysis for medical-surgical nursing learning. AB - This paper presents the results of a project on neural network-based data analysis for knowledge clustering in a second-year course on medical-surgical nursing. Data was collected from 208 nursing students which performed one Multiple Choice Question (MCQ) test at the end of the first term. A total of 23 pattern groups were created using snap-drift. Data obtained can be integrated with an on-line MCQ system for training purposes. Findings about how students are classified suggest that the level of knowledge of the individuals can be addressed by customized feedback to guide them towards a greater understanding of particular concepts. PMID- 23367307 TI - In vitro spectrophotometric near infrared measurements of skin absorption and dehydration. AB - The application of Near Infrared Spectroscopy(NIRS) for measuring skin water content has long been established, and has gained w ide interest as a precise, safe, fast and noninvasive technique for determining skin hydration.This paper reports near infrared spectrophotometric measurements using a highly sophisticated spectrophotometer in the region of 1000-2500 nm to study the water uptake and dehydration properties of skin in vitro using samples of porcine skin. Initial results of pure liquid water and skin samples have clearly displayed the prominent bands associated with water content, and desorption tests have been able to verify changes in these bands associated with water content, although a clear correlation between the rates of weight loss and absorbance loss at various hydration periods has not yet been established. These preliminary results are expected to further explain the relationship between water and skin, and its role within, in hope to aid the future development of a portable instrument based on near infrared spectroscopy that would be capable of directly measuring skin hydration and/or water content in a fast and noninvasive manner. PMID- 23367308 TI - Career development initiatives in biomedical health informatics. AB - The disciplines of biomedical engineering and health informatics complement each other. These two scientific fields sometimes strive independently to deliver better health care services. The rapid evolution in data-intensive methods has made practitioners to think about reviewing the educational needs of the biomedical health informatics workforces. This paper discusses the changing skills requirements in biomedical health informatics discipline. The author reports on the challenges faced by IEEE Engineering in Medicine and Biology (EMBS) in the context of continuous career development of the EMBS members. This paper discusses Queensland chapter's initiative towards an integrated career development to address challenges faced by IEEE EMBS. PMID- 23367309 TI - Two dimensional affective state distribution of the brain under emotion stimuli. AB - Emotions are ambiguous. Many techniques have been employed to perform emotion prediction and to understand emotional elicitations. Brain signals measured using electroencephalogram (EEG) are also used in studies about emotions. Using KDE as feature extraction technique and MLP for performing supervised learning on the brain signals. It has shown that all channels in EEG can capture emotional experience. In addition it was also indicated that emotions are dynamic as represented by the level of valence and the intensity of arousal. Such findings are useful in biomedical studies, especially in dealing with emotional disorders which can results in using a two-channel EEG device for neurofeedback applications. PMID- 23367310 TI - Image-guided navigation: a cost effective practical introduction using the Image Guided Surgery Toolkit (IGSTK). AB - Teaching the key technical aspects of image-guided interventions using a hands-on approach is a challenging task. This is primarily due to the high cost and lack of accessibility to imaging and tracking systems. We provide a software and data infrastructure which addresses both challenges. Our infrastructure allows students, patients, and clinicians to develop an understanding of the key technologies by using them, and possibly by developing additional components and integrating them into a simple navigation system which we provide. Our approach requires minimal hardware, LEGO blocks to construct a phantom for which we provide CT scans, and a webcam which when combined with our software provides the functionality of a tracking system. A premise of this approach is that tracking accuracy is sufficient for our purpose. We evaluate the accuracy provided by a consumer grade webcam and show that it is sufficient for educational use. We provide an open source implementation of all the components required for a basic image-guided navigation as part of the Image-Guided Surgery Toolkit (IGSTK). It has long been known that in education there is no substitute for hands-on experience, to quote Sophocles, "One must learn by doing the thing; for though you think you know it, you have no certainty, until you try.". Our work provides this missing capability in the context of image-guided navigation. Enabling a wide audience to learn and experience the use of a navigation system. PMID- 23367311 TI - Non-intrusive head movement analysis of videotaped seizures of epileptic origin. AB - In this work we propose a non-intrusive video analytic system for patient's body parts movement analysis in Epilepsy Monitoring Unit. The system utilizes skin color modeling, head/face pose template matching and face detection to analyze and quantify the head movements. Epileptic patients' heads are analyzed holistically to infer seizure and normal random movements. The patient does not require to wear any special clothing, markers or sensors, hence it is totally non intrusive. The user initializes the person-specific skin color and selects few face/head poses in the initial few frames. The system then tracks the head/face and extracts spatio-temporal features. Support vector machines are then used on these features to classify seizure-like movements from normal random movements. Experiments are performed on numerous long hour video sequences captured in an Epilepsy Monitoring Unit at a local hospital. The results demonstrate the feasibility of the proposed system in pediatric epilepsy monitoring and seizure detection. PMID- 23367312 TI - A proposed Next Generation Service Delivery Platform (NG-SDP) for eHealth domain. AB - Nowadays, providing healthcare personalized services in user's intelligent space is an important issue for improving personal health, supporting predictive care and saving medical costs. In this paper, we propose an architecture for the Next Generation Service Delivery Platform (NG-SDP), suitable for composing and delivering personalized healthcare services. The core component of NG-SDP is a Context Decision Making Enabler (CDME) that assesses user contextual and bio information to yield personalized services. A prototype implementation of the proposed NG-SDP is also demonstrated. Finally a real case study demonstrates the CDME performance. PMID- 23367313 TI - Development of a ubiquitous clinical monitoring solution to improve patient safety and outcomes. AB - This paper highlights the main findings of an integrated and ubiquitous remote wireless based vital signs monitoring solution as trialed in a clinical setting. Results demonstrate the feasibility of utilising a Wi-Fi based solution to monitor early-warning signs such as impedance-based respiration rate changes, heart rate/ECG events, temperature, and motion analysis in a clinical setting and act as an early warning system. PMID- 23367314 TI - Changing communications within hospital and home health care. AB - Over the last decade, new hospitals are integrating Information and Communication Technologies (ICTs) in their facilities. Although e-health is a relatively recent term for healthcare practice supported by electronic processes, ubiquitous healthcare monitoring, also known as m-health, is already an emerging research area. Patient monitoring in diverse environments, such as nursing homes or assisted living, are gaining importance. Traditional methods present some problems, as they don't allow enough patient mobility. In this situation, real time transmission of multiple medical data, wearable computing, wireless access in ubiquitous systems and wearable devices for pervasive healthcare can meet the needs of these environments. However, the software and infrastructure deployed in hospitals is not easy to migrate to wireless systems. In some cases, the migration to new technologies can be costly. This paper focuses on the design of a modular, scalable and economical framework to improve the monitoring and checking of patients in different contexts. The challenge is to produce a system to transmit the patient's biomedical data directly to a hospital for monitoring or diagnosis using new communication modules. The modular designed adopted is intended to provide a future-proofed system, whose functionality may be upgraded by modifying the hardware or software. The modules have been validated in different contexts to prove their versatility. PMID- 23367315 TI - S2DIA: a diagnostic system for Diabetes mellitus using SANA platform. AB - Currently, Diabetes is a very common disease around the world, and with an increase in sedentary lifestyles, obesity and an aging population the number of people with Diabetes worldwide will increase by more than 50%. In this context, the MIT (Massachusetts Institute of Technology) developed the SANA platform, which brings the benefits of information technology to the field of healthcare. It offers healthcare delivery in remote areas, improves patient access to medical specialists for faster, higher quality, and more cost effective diagnosis and intervention. For these reasons, we developed a system for diagnosis of Diabetes using the SANA platform, called S2DIA. It is the first step towards knowing the risks for type 2 Diabetes, and it will be evaluated, especially, in remote/poor areas of Brazil. PMID- 23367316 TI - Telematics integrated system to perform drugs prescription and administration reducing adverse drug events. AB - In this paper we present PHARMA 2.0 a telematics integrated system aimed at reducing Adverse Drug Events (ADEs) in the phases of drug prescription, transcription, distribution and administration. The proposed system is grounded on three sub-systems: a CPOE (Computerized Prescription Order Entry), an RFID based drug container and dispenser and a middleware system. The visualization and management of prescription and administration data are handled through a web application designed to comply with international usability regulation. PMID- 23367317 TI - A social cybernetic analysis of simulation-based, remotely delivered medical skills training in an austere environment: developing a test bed for spaceflight medicine. AB - This paper describes analysis of medical skills training exercises that were conducted at an arctic research station. These were conducted as part of an ongoing effort to establish high fidelity medical simulation test bed capabilities in remote and extreme "space analogue" environments for the purpose studying medical care in spaceflight. The methodological orientation followed by the authors is that of "second order cybernetics," or the science of studying human systems where the observer is involved within the system in question. Analyses presented include the identification of three distinct phases of the training activity, and two distinct levels of work groups-- termed "first-order teams" and "second-order teams." Depending on the phase of activity, first-order and second-order teams are identified, each having it own unique structure, composition, communications, goals, and challenges. Several specific teams are highlighted as case examples. Limitations of this approach are discussed, as are potential benefits to ongoing and planned research activity in this area. PMID- 23367318 TI - Systems modeling of space medical support architecture: topological mapping of high level characteristics and constraints. AB - The challenges associated with providing medical support to astronauts on long duration lunar or planetary missions are significant. Experience to date in space has included short duration missions to the lunar surface and both short and long duration stays on board spacecraft and space stations in low Earth orbit. Live actor, terrestrial analogue setting simulation provides a means of studying multiple aspects of the medical challenges of exploration class space missions, though few if any published models exist upon which to construct systems simulation test beds. Current proposed and projected moon mission scenarios were analyzed from a systems perspective to construct such a model. A resulting topological mapping of high-level architecture for a reference lunar mission with presumed EVA excursion and international mission partners is presented. High level descriptions of crew operational autonomy, medical support related to crew member status, and communication characteristics within and between multiple teams are presented. It is hoped this modeling will help guide future efforts to simulate medical support operations for research purposes, such as in the use of live actor simulations in terrestrial analogue environments. PMID- 23367319 TI - Computer-assisted upper extremity training using interactive biking exercise (iBikE) platform. AB - Upper extremity exercise training has been shown to improve clinical outcomes in different chronic health conditions. Arm-operated bicycles are frequently used to facilitate upper extremity training however effective use of these devices at patient homes is hampered by lack of remote connectivity with clinical rehabilitation team, inability to monitor exercise progress in real time using simple graphical representation, and absence of an alert system which would prevent exertion levels exceeding those approved by the clinical rehabilitation team. We developed an interactive biking exercise (iBikE) platform aimed at addressing these limitations. The platform uses a miniature wireless 3-axis accelerometer mounted on a patient wrist that transmits the cycling acceleration data to a laptop. The laptop screen presents an exercise dashboard to the patient in real time allowing easy graphical visualization of exercise progress and presentation of exercise parameters in relation to prescribed targets. The iBikE platform is programmed to alert the patient when exercise intensity exceeds the levels recommended by the patient care provider. The iBikE platform has been tested in 7 healthy volunteers (age range: 26-50 years) and shown to reliably reflect exercise progress and to generate alerts at pre-setup levels. Implementation of remote connectivity with patient rehabilitation team is warranted for future extension and evaluation efforts. PMID- 23367320 TI - Screening for congenital heart diseases by murmurs using telemedical phonocardiography. AB - A large proportion of congenital heart diseases (CHD) remain undetected during pregnancy or even after birth. Many of them generate turbulent blood flow, resulting heart murmur. Doppler ultrasound cardiotocography (CTG) is suitable for the assessment of the fetal heart rate and some derived parameters, but it is inadequate for detecting heart murmurs. Although comprehensive examination can be carried out with echocardiography, it is expensive and requires expertise; therefore, it is not applicable for widespread screening. This paper presents a new possibility for screening for some CHDs using phonocardiography, which can be combined with Doppler ultrasound CTG as an extension of it. Furthermore it can be carried out at home allowing repeated measurements, which increases also the reliability of filtering out innocent murmurs. The diagnostic capability of this screening method is supported by a large number of evaluated fetal heart sound records. Moreover, according to experiences pregnant women prefer this reliable, easy to use method, which facilitates their examination. PMID- 23367321 TI - Impact of position tracking on the outpatient navigation system. AB - Reduction of waiting time of patients and idle time of doctors is one of the most important factors of outpatient ward management. Although conventional in hospital outpatient navigation and re-scheduling systems free the patients from waiting rooms, the systems often cause additional idle times for the doctors and even several clinical incidents. This paper designed a new patient navigation and re-scheduling system equips position tracking. The authors introduced the system into Kyoto University Hospital. As a result, the system decreased more than 100 hours a day of wasted time and irritations of the patients and the clinical staffs. The results tell that the context-aware feature makes not only the system user friendly but also the users friendly. PMID- 23367322 TI - A robust wheelchair pressure relief monitoring system. AB - It is essential to prevent pressure ulcers for people with spinal cord injuries (SCI). Pressure ulcer is likely to develop when there is excessive pressure on the body tissue for lengthy durations. Therefore, persons with SCI, who usually spend long time sitting in wheelchairs, are advised to perform regular pressure reliefs in their daily lives. This paper proposes a system for the monitoring of wheelchair users' pressure relief behaviors. The system utilizes piezo resistive sensors beneath a wheelchair cushion to monitor pressure, and employs supervised learning techniques to classify a wheelchair user's pressure relief status. Key features of the system include robustness and not interfering with cushion performance or the daily activities of wheelchair users. The system works well on different types of cushions, and achieves 91% sensitivity and 89% specificity based on tests on different wheelchair users. PMID- 23367323 TI - Beyond the standard clinical rating scales: fine-grained assessment of post stroke motor functionality using wearable inertial sensors. AB - Accurate motor function assessment of post-stroke patients plays a critical role in their rehabilitation interventions. In this paper, we propose an approach to use wearable inertial sensing technology to quantitatively evaluate the patients' motor behavior. Different from existing wearable motor function assessment techniques that focus on building mapping functions that correlate sensed movement signals to the standard clinical rating scales, our approach provides a fine-grained assessment by capturing detailed patterns contained in the patients' movements. We collected data on three subjects including two post-stroke patients who have varying degrees of upper extremity hemiparesis. Our experimental results validate our approach and demonstrate that the captured patterns can be used to complement the standard clinical scores to provide fine-grained motor function assessment and help clinicians to track patients' gradual progress during rehabilitation. PMID- 23367324 TI - An automatic and user-driven training method for locomotion mode recognition for artificial leg control. AB - Our previously developed locomotion-mode-recognition (LMR) system has provided a great promise to intuitive control of powered artificial legs. However, the lack of fast, practical training methods is a barrier for clinical use of our LMR system for prosthetic legs. This paper aims to design a new, automatic, and user driven training method for practical use of LMR system. In this method, a wearable terrain detection interface based on a portable laser distance sensor and an inertial measurement unit (IMU) is applied to detect the terrain change in front of the prosthesis user. The mechanical measurement from the prosthetic pylon is used to detect gait phase. These two streams of information are used to automatically identify the transitions among various locomotion modes, switch the prosthesis control mode, and label the training data with movement class and gait phase in real-time. No external device is required in this training system. In addition, the prosthesis user without assistance from any other experts can do the whole training procedure. The pilot experimental results on an able-bodied subject have demonstrated that our developed new method is accurate and user friendly, and can significantly simplify the LMR training system and training procedure without sacrificing the system performance. The novel design paves the way for clinical use of our designed LMR system for powered lower limb prosthesis control. PMID- 23367325 TI - Wearable, battery-powered, wireless, programmable 8-channel neural stimulator. AB - In this paper, a wearable, battery-powered, low-power, low-size, cost-efficient, fully programmable neural stimulator is presented. The system comprises a wearable stimulator module and an external controller. To receive the settings required for the operation of the system, the wearable module is programmed through wireless connection to the external controller. Implemented using off-the shelf components, the wearable neural stimulator weighs 60 g and measures 9 cm * 5 cm * 2 cm. The system is capable of generating independent biphasic stimulations on 8 channels with programmable amplitudes and timings. The neural stimulator consumes about 1.5 mW in the power-down mode and about 51.2 mW in the active mode when all the 8 channels are active. For in-vivo experiments, the system was used to stimulate motor cortex of an anesthetized rat fixed in a stereotaxic instrument. PMID- 23367326 TI - On the design of ergonomic wearable robotic devices for motion assistance and rehabilitation. AB - The appropriate ergonomic design of a wearable robotic device is critical for the effectiveness of the device itself. In this paper we identified two key requirements for a structural ergonomics: the correct kinematic compatibility with the human limb and a comfortable and adaptable physical human-robot interface. We then show how the aforementioned requirements have been faced and implemented in the mechanical design of two wearable devices for elbow and hand rehabilitation, both developed at The BioRobotics Institute of Scuola Superiore Sant' Anna. PMID- 23367327 TI - Longitudinal performance of a vestibular prosthesis as assessed by electrically evoked compound action potential recording. AB - Electrical stimulation of the vestibular end organ with a vestibular prosthesis may provide an effective treatment for vestibular loss if the stimulation remains effective over a significant period of time after implantation of the device. To assess efficacy of electrical stimulation in an animal model, we implanted 3 rhesus monkeys with a vestibular prosthesis based on a cochlear implant. We then recorded vestibular electrically evoked compound action potentials (vECAPs) longitudinally in each of the implanted canals to see how the amplitude of the response changed over time. The results suggest that vECAPs, and therefore electrical activation of vestibular afferent fibers, can remain largely stable over time following implantation. PMID- 23367328 TI - Strategies and synergies underlying replacement of vestibular function with prosthetic feedback. AB - This study investigated changes in movement strategies and muscle synergies when bilateral peripheral vestibular loss (BVL) subjects are provided prosthetic feedback of their pelvis sway during stance. Six BVL subjects performed 3, for them, difficult stance tasks: standing eyes closed, on a firm surface, on a foam surface, and standing eyes open on foam. Movement strategies were recorded as roll and pitch ratios of upper and lower body velocities with body-worn gyroscopes. Surface EMG recordings were taken from two pairs of antagonistic, lower leg and trunk muscles in order to note synergy changes with feedback. Subjects were first assessed without feedback. Then they were provided stance training with vibro-tactile and auditory feedback of pelvis angle sway, and finally reassessed with the same feedback active. For analysis of movement strategies, angle values integrated from angular velocity samples, were split into 3 frequency bands (<0.7, 0.7-3, and >3 Hz). Feedback caused a reduction in pelvis sway angle displacements to values of age-matched healthy controls (HC) for all tasks. Pelvis sway velocity was only reduced for the task with largest angle displacements, standing eyes closed on foam. Movement strategies in each frequency band examined were unaltered by feedback, except for amplitude, and were not different from those of HCs before or after use of feedback. Low frequency motion was in-phase as if the upper and lower body moved as an inverted pendulum, high frequency motion anti-phasic. Amplitudes of EMG were reduced with feedback. Synergies recorded in the form of activity ratios of antagonistic muscle pairs were reduced with feedback. This is the first study that demonstrates how vestibular loss subjects achieve a reduction of sway during stance with prosthetic feedback. Unchanged movement strategies with reduced amplitudes are achieved with reduced antagonistic muscle synergies. This study has implications for the choice of feedback parameters (angle or velocity) and patient groups when using prosthetic devices to reduce sway of those with a tendency to fall. PMID- 23367329 TI - Use of galvanic vestibular feedback for a balance prosthesis. AB - Activation of vestibular afferents by a bilateral bipolar galvanic vestibular stimulus (GVS) evokes medial-lateral (ML) body sway. By applying a GVS feedback signal that is a function of measured ML head motion, the potential exists for GVS to restore a useful vestibular contribution to ML balance control in vestibular-deficient subjects who remain responsive to GVS. A key to developing an effective balance prosthesis using GVS is to determine the functional relationship between GVS and its influence on the brain's internal estimate of head motion. We describe how a model-based interpretation of GVS-evoked body sway can be used to identify this functional relationship. Results indicate that the GVS-evoked internal motion estimate is effectively a low-pass filtered version of the GVS current. With preliminary data, we demonstrate that GVS feedback, compensated for the identified low-pass characteristics, can either remove the ability of a subject with normal vestibular function to use vestibular information for balance control, or can restore the ability of a subject with bilateral vestibular loss to maintain balance in a condition requiring vestibular information for balance control. PMID- 23367330 TI - Vestibular physical therapy intervention: utilizing a computer assisted rehabilitation environment in lieu of traditional physical therapy. AB - Advanced technology such as virtual reality or immersive environments increases the complexities and challenges therapists can impose on their patients. In this study, four patients with mild traumatic brain injury utilized a Computer Assisted Rehabilitation Environment (CAREN) in place of traditional vestibular physical therapy. Patients visited the CAREN twice weekly for 6 weeks. Therapy sessions included a variety of applications that tasked the cognitive and physical capabilities of individual patients. After the 6 weeks, all patients showed improvement on balance, gait and visual measures. Virtual reality based therapy is an engaging and effective tool to treat patients with deficiencies related to a prior brain injury. PMID- 23367331 TI - Vibrotactile feedback of mediolateral trunk tilt or foot pressure increases locomotor performance in healthy older adults--a pilot study. AB - Sensory substitution devices can provide body orientation and somatosensory information through vibrotactile feedback. This pilot study compares the effects of two vibrotactile feedback devices during a locomotor task using similar groups of elder subjects. PMID- 23367332 TI - Effects of co-vibrotactile stimulations around the torso on non-volitional postural responses. AB - The purpose of this study was to characterize the effects of co-vibrotactile stimulations around the torso on non-volitional postural responses in the absence of instructions. Four healthy young adults maintained an upright, erect posture with their eyes closed in two different stance conditions: normal and Romberg stance. Six vibrotactile transducers (tactors) were placed on the skin over the right and left external oblique, internal oblique, and erector spinae muscles. Either a combination of vibration at two locations or all locations around the torso was applied for 5 s during each experimental trial. Regardless of stance condition, vibration applied concurrently over the right and left internal oblique muscle locations and the right and left erector spinae muscle locations induced a postural shift in the anterior and posterior directions, respectively. For these two stimulation conditions, the root-mean-square of sway in the anterior-posterior direction was significantly greater during vibration than before or after stimulation. However, simultaneous activation of all tactors, a combination of right internal oblique and right erector spinae locations, and a combination of left internal oblique and left erector spinae locations did not produce significant directional postural shifts or increases in sway, regardless of the stance condition. These findings suggest that stimuli combinations contribute to a vector summation of individual postural responses described in our previous work and that they could be leveraged in balance-related applications of sensory augmentation vibrotactile displays. PMID- 23367333 TI - Decoupling the influence of systemic variables in the peripheral and cerebral haemodynamics during ECMO procedure by means of oblique and orthogonal subspace projections. AB - Extra-Corporeal Membrane Oxygenation (ECMO) is a life support system for infants and children with cardio-respiratory failure. During ECMO it is possible to have unstable cerebral haemodynamics, due to strong oscillations in the systemic variables, among other factors, which may lead to brain damage in the patients. Therefore, monitoring the coupling between cerebral haemodynamics and systemic signals might alert us of possible imminent brain damage. In this study we explore the use of orthogonal and oblique subspace projections in the decoupling of these variables, by assessing the ratio between the projections of the haemodynamic variables, onto the subspace spanned by the systemic variables, and the original signals. The coupling of these two systems may differ as different protection mechanisms protect the peripheral system and the brain. Subspace projection was able to decompose the heamodynamic variables as a sum of components related to each systemic variable, separately. As expected, stronger coupling was found between the peripheral haemodynamic and the systemic variables. PMID- 23367334 TI - Space-time adaptive processing for improved estimation of preictal seizure activity. AB - Detection of precursory, seizure-related activity in electroencephalograms (EEG) is a clinically important and difficult problem in the field of epilepsy. Seizure detection methods often aim to identify specific features and correlations between preictal EEG signals that differentiate them from interictal/nonictal signals. Typically, these methods use information from nonictal EEGs to establish detection thresholds, and do not otherwise incorporate their characteristics into the detection. A space-time adaptive approach is proposed to improve detection of seizure-related preictal activity in scalp EEG, using multiple patient-specific baseline signals to optimize the estimate of the baseline covariance matrix. A simplified model of the preictal EEG is assumed, which describes this signal as a linear superposition of seizure-related activity and baseline activity (treated as an interference signal). It is shown that when an improved estimate of the baseline covariance is included in the preictal detector, the true positive rate increases significantly and also the false positive rate decreases significantly. PMID- 23367335 TI - Gaussian process regression in vital-sign early warning systems. AB - The current standard of clinical practice for patient monitoring in most developed nations is connection of patients to vital-sign monitors, combined with frequent manual observation. In some nations, such as the UK, manual early warning score (EWS) systems have been mandated for use, in which scores are assigned to the manual observations, and care escalated if the scores exceed some pre-defined threshold. We argue that this manual system is far from ideal, and can be improved using machine learning techniques. We propose a system based on Gaussian process regression for improving the efficacy of existing EWS systems, and then demonstrate the method using manual observation of vital signs from a large-scale clinical study. PMID- 23367336 TI - Extraction of fetal heart rate from maternal surface ECG with provisions for multiple pregnancies. AB - Twin pregnancies carry an inherently higher risk than singleton pregnancies due to the increased chances of uterine growth restriction. It is thus desirable to monitor the wellbeing of the fetuses during gestation to detect potentially harmful conditions. The detection of fetal heart rate from the maternal abdominal ECG represents one possible approach for noninvasive and continuous fetal monitoring. Here, we propose a new algorithm for the extraction of twin fetal heart rate signals from maternal abdominal ECG recordings. The algorithm detects the fetal QRS complexes and converts the QRS onset series into a binary signal that is then recursively scanned to separate the contributions from the two fetuses. The algorithm was tested on synthetic singleton and twin abdominal recordings. It achieved an average sensitivity and accuracy for QRS complex detection of 97.5% and 93.6%, respectively. PMID- 23367337 TI - Determination of glucose concentration from near-infrared spectra using locally weighted partial least square regression. AB - This paper proposes the use of locally weighted partial least square regression (LW-PLSR) as an alternative multivariate calibration method for the prediction of glucose concentration from NIR spectra. The efficiency of the proposed model is validated in experiments carried out in a non-controlled environment or sample conditions using mixtures composed of glucose, urea and triacetin. The collected data spans the spectral region from 2100 nm to 2400 nm with spectra resolution of 1 nm. The results show that the standard error of prediction (SEP) decreases to 23.85 mg/dL when using LW-PLSR in comparison to the SEP values of 49.40 mg/dL, and 27.56 mg/dL using Principal Component Regression (PCR) and Partial Least Square (PLS) regression respectively. PMID- 23367338 TI - Multivariate spectral analysis for identifying the brain activations during olfactory perception. AB - Olfactory perception is a complex phenomenon associated with other processes such as cognition and emotion. Due to this complexity, there are still open issues and challenges regarding olfactory psychophysiology. One challenge concerns the investigation of the hedonic dimension of olfaction, and how it affects the power of the brain oscillations. Although there are some EEG studies exploring the changes in the power of the brain oscillations during olfactory perception, they use simple power spectral analysis techniques and vary much in terms of the reported findings. To reduce this variability, we propose the use of multivariate spectral analysis, to reveal only the frequency patterns of the EEG signals that contribute the most to olfactory perception. The goal is to investigate how these frequency patterns are affected by hedonically different odors throughout the cortex. PMID- 23367339 TI - An association framework to analyze dependence structure in time series. AB - The purpose of this paper is two-fold: first, to propose a modification to the generalized measure of association (GMA) framework that reduces the effect of temporal structure in time series; second, to assess the reliability of using association methods to capture dependence between pairs of EEG channels using their time series or envelopes. To achieve the first goal, the GMA algorithm was updated so as to minimize the effect of the correlation inherent in the time structure. The reliability of the modified scheme was then assessed on both synthetic and real data. Synthetic data was generated from a Clayton copula, for which null hypotheses of uncorrelatedness were constructed for the signal. The signal was processed such that the envelope emulated important characteristics of experimental EEG data. Results show that the modified GMA procedure can capture pairwise dependence between generated signals as well as their envelopes with good statistical power. Furthermore, applying GMA and Kendall's tau to quantify dependence using the extracted envelopes of processed EEG data concords with previous findings using the signal itself. PMID- 23367340 TI - On the improved correlative prediction scheme for aliased electrocardiogram (ECG) data compression. AB - An improved scheme for aliased electrocardiogram (ECG) data compression has been constructed, where the predictor exploits the correlative characteristics of adjacent QRS waveforms. The twin-R correlation prediction and lifting wavelet transform (LWT) for periodical ECG waves exhibits feasibility and high efficiency to achieve lower distortion rates with realizable compression ratio (CR); grey predictions via GM(1, 1) model have been adopted to evaluate the parametric performance for ECG data compression. Simulation results illuminate the validity of our approach. PMID- 23367341 TI - Comparing causality measures of fMRI data using PCA, CCA and vector autoregressive modelling. AB - Extracting the directional interaction between activated brain areas from functional magnetic resonance imaging (fMRI) time series measurements of their activity is a significant step in understanding the process of brain functions. In this paper, the directional interaction between fMRI time series characterizing the activity of two neuronal sites is quantified using two measures; one derived based on univariate autoregressive and autoregressive exogenous (AR/ARX) and other derived based on multivariate vector autoregressive and vector autoregressive exogenous (VAR/VARX) models. The significance and effectiveness of these measures is illustrated on both simulated and real fMRI data sets. It has been revealed that VAR modelling of the regions of interest is robust in inferring true causality compared to principal component analysis (PCA) and canonical correlation analysis (CCA) based causality methods. PMID- 23367342 TI - Synchrony analysis of spontaneous MEG activity in Alzheimer's disease patients. AB - The aim of this study was to analyze the magnetoencephalography (MEG) background activity in Alzheimer's disease (AD) patients using cross-approximate entropy (Cross-ApEn). Cross-ApEn is a nonlinear measure of asynchrony between time series. Five minutes of recording were acquired with a 148-channel whole-head magnetometer in 12 AD patients and 12 age-matched control subjects. We found significantly higher synchrony between MEG signals from AD patients compared with control subjects. Additionally, we evaluated the ability of Cross-ApEn to discriminate these two groups using receiver operating characteristic (ROC) curves with a leave-one-out cross-validation procedure. We obtained an accuracy of 70.83% (66.67% sensitivity, 75% specificity) and a value of area under the ROC curve of 0.83. These results provide evidence of disconnection problems in AD. Our findings show the usefulness of Cross-ApEn to detect the brain dysfunction in AD. PMID- 23367343 TI - Towards the time varying estimation of complex brain connectivity networks by means of a General Linear Kalman Filter approach. AB - One of the main limitations of the brain functional connectivity estimation methods based on Autoregressive Modeling, like the Granger Causality family of estimators, is the hypothesis that only stationary signals can be included in the estimation process. This hypothesis precludes the analysis of transients which often contain important information about the neural processes of interest. On the other hand, previous techniques developed for overcoming this limitation are affected by problems linked to the dimension of the multivariate autoregressive model (MVAR), which prevents from analysing complex networks like those at the basis of most cognitive functions in the brain. The General Linear Kalman Filter (GLKF) approach to the estimation of adaptive MVARs was recently introduced to deal with a high number of time series (up to 60) in a full multivariate analysis. In this work we evaluated the performances of this new method in terms of estimation quality and adaptation speed, by means of a simulation study in which specific factors of interest were systematically varied in the signal generation to investigate their effect on the method performances. The method was then applied to high density EEG data related to an imaginative task. The results confirmed the possibility to use this approach to study complex connectivity networks in a full multivariate and adaptive fashion, thus opening the way to an effective estimation of complex brain connectivity networks. PMID- 23367344 TI - Cortical functional connectivity under different auditory attentional efforts. AB - Auditory attentional effort (AAE) could be tuned to different levels in a top down manner, while its neural correlates are still poorly understood. In this paper, we investigate the cortical connectivity under different levels of AAE. Multichannel EEG signals were recorded from nine subjects (male/female=6=3) in an auditory discrimination task under low or high AAE. Behavioral results showed that subjects paid more attention under high AAE and detected the probe stimuli better than low AAE. Partial directed coherence (PDC) was used to study the cortical functional connectivity within the first 300 ms post-stimulus period which includes the N100 and P200 components in the event-related potential (ERP). Majority of the cortical connections were strengthened with the increase of AAE. The right hemispheric dominance of connectivity in maintaining auditory attention was found under low AAE, which disappeared when the AAE was increased, indicating that the right hemispheric dominance previously reported might be due to a relatively lower AAE. Besides, most cortical connections under high AAE were found to be from the parietal cortex to the prefrontal cortex, which suggested the initiative role of parietal cortex in maintaining a high AAE. PMID- 23367345 TI - Classification of physical activities based on sparse representation. AB - This paper presents a new classification method for physical activity assessment, based on sparse representation. This method bypasses the need for feature extraction and selection that is typically involved for activity classification, and classifies activities using raw sensor signals directly. Higher discriminative power than that from the conventional k-nearest neighbor algorithm has been demonstrated through experiments performed on 105 subjects. PMID- 23367346 TI - Learning dependencies among fetal heart rate features using Bayesian networks. AB - We present preliminary results on the use of Bayesian-network (BN) structure learning algorithms for deciphering dependencies from amongst different fetal heart rate (FHR) features collected from a real database. We used a greedy search and-score procedure known as the K2 algorithm for the estimation of the BN structure. The database consists of a collection of discrete-valued features quantifying presence of morphological changes as prescribed by expert guidelines (updated by the National Institute of Child Health and Human Development (NICHD)) and implemented as rule-based programs. We compare the results of structure learning to the expert-guided structure and use decision functions for classification using posterior probabilities. It was found that the BN estimated from structure learning algorithms had comparable classification performance, but fewer edges, leading to more efficient characterization of conditional probability tables (CPD's). Moreover, structure learning algorithms offer a method of learning novel correlations between FHR features that may be exploited for automatic categorization. PMID- 23367347 TI - Decomposition of intramuscular EMG signals using a knowledge -based certainty classifier algorithm. AB - An automated system for resolving an intramuscular electromyographic (EMG) signal into its constituent motor unit potential trains (MUPTs) is presented. The system is intended mainly for clinical applications where several physiological parameters for each motor unit (MU), such as the motor unit potential (MUP) template and mean firing rate, are required. The system decomposes an EMG signal off-line by filtering the signal, detecting MUPs, and then grouping the detected MUPs using a clustering and a supervised classification algorithm. Both the clustering and supervised classification algorithms use MUP shape and MU firing pattern information to group MUPs into several MUPTs. Clustering is partially based on the K-means clustering algorithm. Supervised classification is implemented using a certainty-based classifier technique that employs a knowledge based system to merge trains, detect and correct invalid trains, as well as adjust the assignment threshold for each train. The accuracy (93.2%+/-5.5%), assignment rate (93.9%+/-2.6%), and error in estimating the number of MUPTs (0.3+/-0.5) achieved for 10 simulated EMG signals comprised of 3-11 MUPTs are encouraging for using the system for decomposing various EMG signals. PMID- 23367348 TI - Optimization strategies for rapid centroid estimation. AB - Particle swarm algorithm has been extensively utilized as a tool to solve optimization problems. Recently proposed particle swarm+/-based clustering algorithm called the Rapid Centroid Estimation (RCE) is a lightweight alteration to Particle Swarm Clustering (PSC). The RCE in its standard form is shown to be superior to conventional PSC algorithm. We have observed some limitations in RCE including the possibility to stagnate at a local minimum combination and the restriction in swarm size. We propose strategies to optimize RCE further by introducing RCE+ and swarm RCE+. Five benchmark datasets from UCI machine learning database are used to test the performance of these new strategies. In Glass dataset swarm RCE+ is able to achieve highest purity centroid combinations with less iteration (90.3%+/-1.1% in 9+/-5 iterations) followed by RCE+ (89%+/ 3.5% in 65+/-62 iterations) and RCE (87%+/-5.9% in 54+/-44). Similar quality is also reflected in other benchmark datasets including Iris, Wine, Breast Cancer, and Diabetes. PMID- 23367349 TI - An efficient strategy for evaluating similarity between time series based on Wavelet / Karhunen-Loeve transforms. AB - The present work aims to present an innovative measure able to efficiently evaluate the similarity between two physiological time series. The proposed methodology combines the Haar wavelet decomposition, in which signals are represented as linear combinations of a set of orthogonal basis, with the Karhunen-Loeve transform, that allows for the optimal reduction of that set of basis. The similarity measure is based on the Euclidean distance, but indirectly calculated through the linear combination coefficients of both time series. Moreover, an iterative scheme for computing the referred coefficients significantly decreases the computational complexity of the method that, due to its simplicity and fast execution, can be easily applicable in clinical applications, namely in computational demanding contexts such as telemonitoring environments. This strategy has been successfully implemented and validated inside HeartCycle project, applied to blood pressure signals collected by a telemonitoring platform (TEN-HMS) in the recognition of hypertension episodes. PMID- 23367350 TI - Incorporating a biopsy needle as an electrode in transrectal electrical impedance imaging. AB - Previous studies have shown that prostate cancer may be detected by a combined transrectal ultrasound and electrical impedance tomography imaging system. However, the sensitivity of the imaging system is limited due to very little current established in the far field distant from the probe surface. Consequently, biopsy needles are introduced to the imaging system to provide current paths in the distal regions. This study demonstrates that image sensitivity can be improved by incorporating the needle electrodes. A phantom experiment is presented to show that contrast to the background is enhanced by 17.4% when imaging with needle electrodes. Simulated reconstructions and some preliminary clinical data also suggest the sensitivity improvement. In summary, TREIT with needle electrodes in the tissue may have great potential in future clinical prostate cancer detection. PMID- 23367351 TI - Sparse electromagnetic source imaging using EEG and MEG. AB - The present study proposed the combined use of EEG and MEG data in a new sparse electromagnetic source imaging (ESI) technique, i.e., variation-based sparse cortical current density (VB-SCCD) method. Monte Carlo simulations were conducted to investigate the performance of the proposed approach in multiple extended brain activations (up to ten) that were randomly generated. Experimental EEG and MEG data from a face recognition task were further used to evaluate the performance of VB-SCCD. The present results indicate that the proposed approach can accurately reconstruct multiple brain activations and their spatial extents. The source imaging results from real data further demonstrate it is capable to recover networked brain activations involving multiple cortical regions, which are consistent with results from functional magnetic resonance imaging in same task paradigm. The present results further indicate the capability of the proposed approach in reconstructing deep brain sources and temporal dynamics of brain sources at millisecond resolutions. It thus suggests that sparse ESI using combined EEG and MEG is a promising technique probing detailed spatiotemporal brain activations. PMID- 23367352 TI - Dynamic seizure imaging in patients with extratemporal lobe epilepsy. AB - Epilepsy is a common neurological disease that affects about 50 million people worldwide. Extratemporal lobe epilepsy, which represents an important type of epilepsy, may involve seizure activity in various lobes and the surgical treatment in these patients tends to have less favorable surgical outcome. Noninvasive seizure imaging in drug-resistant patients is of vital importance to image the seizure onset zones (SOZs) and understand the mechanisms for an improved treatment plan. In this study, we directly imaged the seizure sources in 8 extratemporal lobe partial epilepsy patients from noninvasive EEG. The surgically resected regions and SOZs identified from intracranial EEG (iEEG) recordings were used to evaluate the source imaging results. All of the eight patients underwent resective surgery and the estimated seizure sources were co located with the resection zone. Seven of the patients had iEEG recordings available and the source imaging results were concordant with the SOZs marked on the intracranial recording grid. The present results suggest that dynamic seizure imaging could be potentially useful to image the SOZs of extratemporal lobe seizures and help the pre-surgical planning of epilepsy patients. PMID- 23367353 TI - Non-invasive EEG source localization using particle swarm optimization: a clinical experiment. AB - One of the most important steps of pre-surgical diagnosis in patients with medically intractable epilepsy is to find the precise location of the epileptogenic foci. An Electroencephalography (EEG) is a non-invasive standard tool used at epilepsy surgery center for pre-surgical diagnosis. In this paper a modified particle swarm optimization (MPSO) method is applied to a real EEG data, i.e., a somatosensory evoked potentials (SEPs) measured from a healthy subject, to solve the EEG source localization problem. A high resolution 1 mm hexahedra finite element volume conductor model of the subject's head was generated using T1-weighted magnetic resonance imaging data. An exhaustive search pattern and the MPSO method were then applied to the peak of the averaged SEPs data. The non invasive EEG source analysis methods localized the somatosensory cortex area where our clinical expert expected the received SEPs. The proposed inverse problem solver found the global minima with acceptable accuracy and reasonable number of iterations. PMID- 23367354 TI - A novel spatiotemporal muscle activity imaging approach based on the Extended Kalman Filter. AB - A novel spatiotemporal muscle activity imaging (sMAI) approach has been developed using the Extended Kalman Filter (EKF) to reconstruct internal muscle activities from non-invasive multi-channel surface electromyogram (sEMG) recordings. A distributed bioelectric dipole source model is employed to describe the internal muscle activity space, and a linear relationship between the muscle activity space and the sEMG measurement space is then established. The EKF is employed to recursively solve the ill-posed inverse problem in the sMAI approach, in which the weighted minimum norm (WMN) method is utilized to calculate the initial state and a new nonlinear method is developed based on the propagating features of muscle activities to predict the recursive state. A series of computer simulations was conducted to test the performance of the proposed sMAI approach. Results show that the localization error rapidly decreases over 35% and the overlap ratio rapidly increases over 45% compared to the results achieved using the WMN method only. The present promising results demonstrate the feasibility of utilizing the proposed EKF-based sMAI approach to accurately reconstruct internal muscle activities from non-invasive sEMG recordings. PMID- 23367355 TI - A new image reconstruction algorithm for real-time monitoring of conductivity and permeability changes in Magnetic Induction Tomography. AB - A linear image reconstruction algorithm for solving the Magnetic Induction Tomography inverse problem is presented. It's an optimization process to determine a reconstruction matrix that does the best mapping between a set of training parameter vectors and their respective measurements dictated by a forward model. It allows the simultaneous 3D reconstructions of the electric conductivity, electric permittivity and magnetic permeability. The results were compared with the ones obtained from a single-step regularized Gauss-Newton method and a reduction of 15% in the image error was verified. The behavior of the developed algorithm in a simulated clinical environment was also assessed using a realistic bio-impedance model of the human head, derived from a high resolution magnetic resonance image. PMID- 23367356 TI - Automatic brain MR images diagnosis based on edge fractal dimension and spectral energy signature. AB - A new automatic system to detect pathologies in human brain magnetic resonance (MR) images is presented. The goal is to classify normal versus abnormal images affected by Alzheimer, Glioma, Herpes, Metastatic, and Multiple Sclerosis. The extracted features are the fractal dimension of edges in the Hilbert domain, and the skewness and kurtosis of their spectral energy distribution. The proposed system (FDSE) outperforms the popular discrete wavelet transform (DWT) and principal component analysis (PCA). PMID- 23367357 TI - Cross-device automated prostate cancer localization with multiparametric MRI. AB - Automated cancer localization with supervised techniques plays an important role in guiding biopsy, surgery and treatment. It is crucial to have an accurate training dataset for supervised techniques. Since different devices with e.g. different protocols and/or field strengths cause different intensity profiles, each device/protocol must have an accompanying training dataset which is very costly to obtain. In this paper, we propose a novel method that has the ability to design classifiers obtained from one imaging protocol and/or MRI device to be used on a dataset from another protocol and/or imaging device. As an example problem we consider prostate cancer localization with multiparametric MRI. We show that simple normalization techniques such as z-score are not sufficient to allow for cross-device automated cancer localization. On the other hand, the methods we have originally developed based on relative intensity allows us to successfully use a classifier obtained from one device to be applied on a test patient imaged with another device. PMID- 23367358 TI - Assessment of videolaryngostroboscopy images based on visible vessels of vocal folds. AB - Extraction of vessel structures and the vessel features automatically forms an essential step for computer-aided diagnosis. Visible vessels of vocal folds become a diagnostic aid for vocal fold pathologies by publication of limited number of researches which analyze the effects of vocal fold pathologies on visual characteristics of blood vessels. In this paper we present a novel system that extracts blood vessels centerlines on vocal folds images and detects pathologically altered vocal folds exploiting visual characteristics of vessels. PMID- 23367359 TI - A Decision Support System for the assisted diagnosis of brain tumors: a feasibility study for 18F-FDG PET preclinical studies. AB - Decision support systems for the assisted medical diagnosis offer the main feature of giving assessments which are poorly affected from arbitrary clinical reasoning. Aim of this work was to assess the feasibility of a decision support system for the assisted diagnosis of brain cancer, such approach presenting potential for early diagnosis of tumors and for the classification of the degree of the disease progression. For this purpose, a supervised learning algorithm combined with a pattern recognition method was developed and cross-validated in 18F-FDG PET studies of a model of a brain tumour implantation. PMID- 23367360 TI - Computer vision-based breast self-examination stroke position and palpation pressure level classification using artificial neural networks and wavelet transforms. AB - This paper focuses on breast self-examination (BSE) stroke position and palpation level classification for the development of a computer vision-based BSE training and guidance system. In this study, image frames are extracted from a BSE video and processed considering the color information, shape, and texture by wavelet transform and first order color moment. The new approach using artificial neural network and wavelet transform can identify BSE stroke positions and palpation levels, i.e. light, medium, and deep, at 97.8 % and 87.5 % accuracy respectively. PMID- 23367361 TI - Mycobacterium tuberculosis recognition with conventional microscopy. AB - This paper presents a new method for segmentation of tuberculosis bacillus in conventional sputum smear microscopy. The method comprises three main steps. In the first step, a scalar selection are made for characteristics from the following color spaces: RGB, HSI, YCbCr and Lab. The features used for pixel classification in the segmentation step were the components and subtraction of components of these color spaces. In the second step, a feedforward neural network pixel classifier, using selected characteristics as inputs, is applied to segment pixels that belong to bacilli from the background. In third step geometric characteristics, especially the eccentricity, and a new proposed color characteristic, the color ratio, are used to noise filtering. The best sensitivity achieved in bacilli detection was 91.5%. PMID- 23367362 TI - Viable circulating tumor cell enrichment by flexible micro spring array. AB - We demonstrated a high throughput versatile platform capable of isolating circulating tumor cells (CTCs) from clinically relevant volumes of blood while preserving their viability and ability to proliferate. The enrichment is based on the fact that CTCs are larger compared with normal blood cells. The incorporated system allows size-based separation of CTCs at the micro-scale, while taking advantage of a high throughput and rapid processing speed. Testing results of model systems using cell lines show that this device can enrich CTCs from 7.5 mL of whole blood samples with 90% capture efficiency, higher than 10(4) enrichment, and better than 80% viability in approximately ten minutes without any incidence of clogging. PMID- 23367363 TI - Simultaneous dielectric monitoring of microfluidic channels at microwaves utilizing a metamaterial transmission line structure. AB - The paper presents a technique that allows the simultaneous monitoring of the dielectric properties of liquids in microfluidic channels at microwave frequencies. It is capable of being integrated within the lab-on-a-chip concept and uses a composite right/left-handed transmission line resonator which is detuned by the dielectric loading of the liquids in the channels. By monitoring the change in the resonance spectrum of the resonator the loading profile can be derived with the multi-resonant perturbation method. From the value of the dielectric constant inference on the substances like cells or chemicals in the channels can be drawn. The paper presents concept, design, fabrication and characterization of prototype sensors. The sensors have been designed to operate between 20 and 30 GHz and were tested with water and water ethanol mixtures. PMID- 23367365 TI - A new microfluidic device for electric lysis and separation of cells. AB - This paper demonstrates the potential use of a new microfluidic device embedding thick electrodes for cell lysis and cell separation applications. The system consists of a microfluidic channel featuring conductive walls made of a polydimethylsiloxane (PDMS) matrix mixed with carbon nanoparticles. Cell lysis was performed electrically by applying square pulses across the channel width, which was monitored by fluorimetry. Lysed and unlysed cells showed different dielectrophoretic behavior under appropriate experimental conditions, which suggests that the developed device is suitable to perform both cell lysis and subsequent sorting of viable and dead cells. PMID- 23367364 TI - Counting leukocytes from whole blood using a lab-on-a-chip Coulter counter. AB - A microfluidic lab-on-a-chip Coulter counter was demonstrated to count micro particles and leukocytes from whole blood. Instead of electroplated or deposited metal electrodes, off-the-shelf gold pins were used as electrodes to simplify fabrication process, reduce cost, enhance device durability, and above all, achieve superior uniformity in E-field distribution for improved signal quality. A custom-designed, low-cost demodulation circuit was developed to detect the AC impedance signals of the particles and cells passing the detection area defined by the microfluidic channels. A mixture of polystyrene beads with three different sizes was used to characterize the device. The results showed high throughput at 2000 particles/s and clear separation among different sizes of beads with coefficients of variation (CV) of 13.53%, 10.35% and 5.67% for 7.66 um, 10.5 um and 14.7 umbeads, respectively. To demonstrate the potential for a point-of-care or self-administered device for cancer patients going through chemotherapy, we have used the lab-on-a-chip device to count leukocytes from whole blood, generating encouraging preliminary results comparable to the results from a commercial flow cytometer. PMID- 23367366 TI - Selective E. coli trapping with 3D insulator-based dielectrophoresis using DC biased, AC electric fields. AB - We present the development of a batch trapping, insulator-based dielectrophoretic (iDEP) device with three-dimensional design. The microfluidic devices use DC biased, AC electric fields to selectively manipulate biological particles based on their electric properties. The mold for the polymer microdevices is fabricated using an RIE-lag technique which creates microchannels with varying depths using a single etch process. The resulting three-dimensional insulating constrictions permit operation at low applied voltages. By varying both the applied frequency and the ratio of AC to DC electric fields, the iDEP device can trap and separate polystyrene beads and E. coli cells. PMID- 23367367 TI - Simulation of left ventricle flow dynamics with dilated cardiomyopathy during the filling phase. AB - Dilated cardiomyopathy (DCM) is a common cardiac disease which leads to the deterioration in cardiac performance. A computational fluid dynamics (CFD) approach can be used to enhance our understanding of the disease, by providing us with a detailed map of the intraventricular flow and pressure distributions. In the present work, effect of ventricular size on the intraventricular flow dynamics and intraventricular pressure gradients (IVPGs) was studied using two different implementation methods, i.e. the geometry-prescribed and the fluid structure interaction (FSI) methods. Results showed that vortex strength and IVPGs are significantly reduced in a dilated heart, leading to an increased risk of thrombus formation and impaired ventricular filling. We suggest FSI method as the ultimate method in studying ventricular dysfunction as it provides additional cardiac disease prognostic factors and more realistic model implementation. PMID- 23367368 TI - Fluid structure interaction simulation of left ventricular flow dynamics under left ventricular assist device support. AB - For patient's receiving mechanical circulatory support, malfunction of the left ventricular assist device (LVADs) as well as mal-positioning of the cannula imposes serious threats to their life. It is therefore important to characterize the flow pattern and pressure distribution within the ventricle in the presence of an LVAD. In this paper, we present a 2D axisymmetric fluid structure interaction model of the passive left ventricle (LV) incorporating an LVAD cannula to simulate the effect of the LVAD cannula placement on the vortex dynamics. Results showed that larger recirculation area was formed at the cannula tip with increasing cannula insertion depth, and this is believed to reduce the risk of thrombus formation. Furthermore, we also simulated suction events (collapse of the LV) by closing the inlet. Vortex patterns were significantly altered under this condition, and the greatest LV wall displacement was observed at the part of the myocardium closest to the cannula tip. PMID- 23367369 TI - Implementation and evaluation of hyperelastic model for surgical simulator and navigation. AB - We developed a practical laparoscopic surgical simulator using co-rotated FEM in a linear scheme. This was somewhat of a compromise due to a strong constraint on real-time processing. The spread of surgical simulators and medical simulations for clinical medicine in the near future will impose important demands that cannot be met with this linear scheme. For example, subtle force sensing by forceps used for peeling connective tissues and moving blood vessels is very important for a preoperative surgical simulator, as is precisely predicting the deformation of organs with patient posture during surgery for torocar simulation and surgical navigation. We evaluated several models such as co-rotated FEM, nonlinear FEM, and the hyperelastic model for these advanced real-time medical applications. As a result, we confirmed that the hyperelastic model is the most suitable for the anticipated surgical simulator, and that the co-rotated FEM and nonlinear FEM score almost the same in both processing time and accuracy. In addition, implementation of the hyperelastic model in real time seems possible with current off-the-shelf PCs. PMID- 23367370 TI - Predicting failure in soft tissue phantoms via modeling of non-predetermined tear progression. AB - The advantageous, curved trajectory of bevel-tipped devices in soft tissue is a function of the interplay between material deformation, contact interactions and material failure. Highly detailed modeling of tool-tissue interactions is therefore vital in optimising performance and design. At high resolution, discontinuous failure of soft tissue phantoms has not been demonstrated. An iterative procedure, making incremental additions to the failure path in an otherwise continuous finite element mesh, is presented to achieve this goal. The procedure's efficacy was demonstrated in two materials including a soft tissue phantom. Failure path is shown to respond well to different and evolving shear and normal stress states. The iterative procedure would thus be ideal for analysing and optimising complex tool-tissue interactions, for instance in needle steering systems, where the path taken by the needle also depends on the progression of a tear which develops ahead of the tip during the insertion process. With the method presented here, this behaviour could be modeled and analysed at an unprecedented resolution. PMID- 23367371 TI - Approximate string matching using phase correlation. AB - A novel method for approximate string matching with applications to bioinformatics is presented in this paper. Unlike most methods in the literature, the proposed method does not depend on the computation of the edit distance between two sequences, but uses instead a similarity index obtained by applying the phase correlation method. The resulting algorithm provides a finer control over the false positive rate, allowing users to pick out relevant matchings in less time, and can be applied for both offline and online processing. PMID- 23367372 TI - Improving the prediction of sub-cellular locations of proteins with a particle swarm optimization-based boosting strategy. AB - Learning from imbalanced data sets presents an important challenge to the machine learning community. Traditional classification methods, seeking to minimize the overall error rate of the whole training set, do not perform well on imbalanced data since they assume a relatively balanced class distribution and put too much strength on the majority class. This is a common scenario when predicting sub cellular locations of proteins since proteins belonging to certain specific locations are naturally more abundant or have been more extensively studied. In this work, a new method to learn from imbalanced data, called SwarmBoost, is proposed in order to reduce overlapping and noise of imbalanced datasets and improve prediction performances. The method combines oversampling, subsampling based on particle swarm optimization and ensemble methods. Our results show that SwarmBoost equals and in several cases outperforms other common boosting algorithms like DataBoost-Im and AdaBoost, constituting a useful tool for improving sub-cellular location predictions. PMID- 23367373 TI - Network-based enrichment analysis of gene expression through protein-protein interaction data. AB - High-throughput analysis of gene expression data is subject to technological and statistical issues that confuse the underlying expression-condition associations. In this contribution a network-based candidate gene prioritization strategy was applied to the enrichment of a publicly available gene expression dataset, focused on the study of the mechanosensitivity of genes exposed to altered pulmonary matrix stiffness. Results suggested that some genes which had not been taken into account in the original study could have an important role in the processes causing, or affected by, pulmonary fibrosis. PMID- 23367374 TI - Generation of atomic four-body statistical potentials derived from the delaunay tessellation of protein structures. AB - Delaunay tessellation of the atomic coordinates for a crystallographic protein structure yields an aggregate of non-overlapping and space-filling irregular tetrahedral simplices. The vertices of each simplex objectively identify a quadruplet of nearest neighbor atoms in the protein. Here we apply Delaunay tessellation to 1417 high-resolution structures of single chains that share low sequence identity, for the purpose of determining the relative frequencies of occurrence for all possible nearest neighbor atomic quadruplet types. Alternative distributions are explored by varying two fundamental parameters: atomic alphabet selection and cutoff length for admissible simplex edges. The distributions are then converted to four-body potential functions by implementing the inverted Boltzmann principle, which requires calculating the distribution of the reference state. Two alternative definitions for the reference state are presented, which introduces a third parameter, and we derive and compare an array of such potential functions. These knowledge-based statistical potentials based on higher order interactions complement and generalize the more commonly encountered atom pair potentials, for which a number of approaches are described in the literature. PMID- 23367375 TI - Intelligent detection of hypoglycemic episodes in children with type 1 diabetes using adaptive neural-fuzzy inference system. AB - Hypoglycemia, or low blood glucose, is the most common complication experienced by Type 1 diabetes mellitus (T1DM) patients. It is dangerous and can result in unconsciousness, seizures and even death. The most common physiological parameter to be effected from hypoglycemic reaction are heart rate (HR) and correct QT interval (QTc) of the electrocardiogram (ECG) signal. Based on physiological parameters, an intelligent diagnostics system, using the hybrid approach of adaptive neural fuzzy inference system (ANFIS), is developed to recognize the presence of hypoglycemia. The proposed ANFIS is characterized by adaptive neural network capabilities and the fuzzy inference system. To optimize the membership functions and adaptive network parameters, a global learning optimization algorithm called hybrid particle swarm optimization with wavelet mutation (HPSOWM) is used. For clinical study, 15 children with Type 1 diabetes volunteered for an overnight study. All the real data sets are collected from the Department of Health, Government of Western Australia. Several experiments were conducted with 5 patients each, for a training set (184 data points), a validation set (192 data points) and a testing set (153 data points), which are randomly selected. The effectiveness of the proposed detection method is found to be satisfactory by giving better sensitivity, 79.09% and acceptable specificity, 51.82%. PMID- 23367376 TI - A network clustering algorithm for detection of protein families. AB - Detection of protein families in large scale database is a difficult but important biological problem. Computational clustering methods can effectively address the problem. Although there exist many clustering algorithms, most of them are just based on the threshold. Their computational performances are affected by the weight distribution greatly, and they are only valid for some special networks. A new network clustering algorithm, Markov Finding and Clustering (MFC), is proposed to cluster the proteins into their functionally specific families accurately in this paper. The MFC algorithm makes an improvement in the random walk process and reduces the affection of the noise on the clustering result. It has a good performance on these networks which are not well addressed by existing algorithms sensitive to the noise. Finally, experiments on the protein sequence datasets demonstrate that the algorithm is effective in the detection of protein families and has a better performance than the current algorithms. PMID- 23367377 TI - Detection of breathing segments in respiratory signals. AB - The typical approach for analysis of respiratory records consists of detection of respiratory pauses and elimination of segments corrupted by movement artifacts. This is motivated by established rules used for manual scoring of respiratory events, which focus on pause segmentation and do not define criteria to identify breathing segments. With this strategy, breathing segments can only be inferred indirectly from the absence of abnormalities, yielding an unclear and ambiguous definition. In this work we present novel detectors for synchronous and asynchronous breathing, and compare them with AUREA, a novel system for Automated Unsupervised Respiratory Event Analysis, which performs indirect classification of breathing. Results from analysis of real infant respiratory data show an improvement in the identification of synchronous and asynchronous breathing of 9% and 27% respectively, demonstrating that direct detection of breathing enhances the classification performance. PMID- 23367378 TI - Respiratory and spontaneous arousals in patients with Sleep Apnea Hypopnea Syndrome. AB - Sleep in patients with Sleep Apnea-Hypopnea Syndrome (SAHS) is frequently interrupted with arousals. Increased amounts of arousals result in shortening total sleep time and repeated sleep-arousal change can result in sleep fragmentation. According to the American Sleep Disorders Association (ASDA) an arousal is a marker of sleep disruption representing a detrimental and harmful feature for sleep. The nature of arousals and its role on the regulation of the sleep process raises controversy and has sparked the debate in the last years. In this work, we analyzed and compared the EEG spectral content of respiratory and spontaneous arousals on a database of 45 SAHS subjects. A total of 3980 arousals (1996 respiratory and 1984 spontaneous) were analyzed. The results showed no differences between the spectral content of the two kinds of arousals. Our findings raise doubt as to whether these two kinds of arousals are truly triggered by different organic mechanisms. Furthermore, they may also challenge the current beliefs regarding the underestimation of the importance of spontaneous arousals and their contribution to sleep fragmentation in patients suffering from SAHS. PMID- 23367380 TI - Monitoring torso acceleration for estimating the respiratory flow and efforts for sleep apnea detection. AB - Sleep apnea syndrome is a common sleep breathing disorder classified into two major categories: obstructive and central. In this study, we propose a method based on ensemble learning to estimate the respiratory flow, the thoracic respiratory effort and the abdominal respiratory effort from acceleration of suprasternal notch, the thorax and the abdomen respectively. The estimated flow can be used to detect the breathing cessations and the estimated efforts can be used to classify them into obstructive and central apneas. The estimated signals are compared with the signals recorded by well-established measurement methods to show overall mean errors from 11% for the abdomen effort, 17% for the thorax effort and 16% error for the flow estimation. The presented results demonstrate the feasibility of using the torso acceleration as a simple and inexpensive solution for long term measuring and monitoring of respiratory functions for sleep apnea detection. PMID- 23367379 TI - Swallow monitoring through apnea detection in breathing signal. AB - This paper presents the concepts, design, and algorithms for a wearable swallow monitoring system. Swallow monitoring can be used for assessing a person's overall food and drink intake habits as well as other swallow related disorders. The system works based on the key observation that a person's otherwise continuous breathing process is interrupted by a short apnea when she or he swallows as a part of food intake process. Using a wearable chest-belt, we detect swallows by detecting apneas extracted from breathing signal captured by the chest-belt. A matched filter based template matching framework is developed for swallow detection. A number of matched filter template design, both static and iterative, are developed for high-accuracy swallow detection. PMID- 23367381 TI - Relation between arterial blood pressure and cerebral blood flow velocity in simulated sleep apnea. AB - Obstructive Sleep Apnea (OSA) is one of the most common breathing disorder, affecting approximately 27% of U.S. adults. Limited data have suggested that OSA causes cerebral autoregulation impairment, thus being an important risk factor to stroke. The objective of this paper is to investigate and measure the relation between arterial blood pressure (BP) and cerebral blood flow velocity (CBFV) in simulated apnea. Sixteen healthy subjects (9 male, 7 female) of 29+/-4.89 yrs age and body mass index of 24.07+/-4.84 kg/m(2) participated in the study. Four protocols were used; sitting 30 seconds, 90 s, and supine 30 s and 90 s. Our results showed that systolic BP and peak CBFV were correlated with average r=0.672 +0.265. Also, CBFV exhibited a significantly higher percent rise than BP. Thus, our findings suggest that cerebral autoregulation may be impaired during apnea episodes. PMID- 23367382 TI - Gender dependant snore sound based multi feature obstructive sleep apnea screening method. AB - Obstructive Sleep Apnea (OSA) is a serious sleep disorder that occurs due to collapsing upper airways (UA). More than 80% of OSA sufferers remain undiagnosed and the situation demands simplified, convenient technology for community screening. Almost all OSA patients snore and snoring is the earliest nocturnal symptom of OSA. Snore signals (SS) are produced due to vibration of soft tissues in the narrowed parts of the UA. It is known that the UA properties are gender specific. In this paper, we work under the hypothesis that gender specific analysis of snore sounds should lead to a higher OSA detection performance. We propose a snore based multi-parametric OSA screening technique, which incorporates the gender differences in the algorithm. The multi feature vector was modeled using logistic regression based algorithms to classify subjects into OSA/non-OSA classes. The performance of the proposed method was evaluated by carrying out K-fold cross validation. This procedure was applied to male (n=51) and female (n=36) data sets recorded in a clinical sleep laboratory. Each data set consisted of sound recordings of 6-8 hr. duration. The performance of the method was evaluated against the standard laboratory method of diagnosis known as polysomongraphy. Our gender-specific technique resulted in a sensitivity of 93+/ 9% with specificity 89+/-7% for females and sensitivity of 91+/-8% with specificity 89+/-12% for males. These results establish the possibility of developing cheap, convenient, non-contact and an unattended OSA screening technique. PMID- 23367383 TI - Automated quantification of atrial fibrillation complexity by probabilistic electrogram analysis and fibrillation wave reconstruction. AB - The analysis of high-density activation maps of atrial fibrillation (AF) provides fundamental insights into the fibrillation wave propagation patterns and thus the mechanisms of AF. Current annotation of local activations in unipolar atrial electrograms and the construction of fibrillation waves require labor-intensive manual editing. To enhance the possibilities for spatiotemporal analysis of AF, we developed a rapid and fully automated procedure to accurately identify local, intrinsic atrial deflections and construct fibrillation waves based on these deflections. In this study, the automated procedure was validated using manually annotated electrograms and wave maps. We show that the novel procedure accurately detects intrinsic deflections (sensitivity=87%, positive predictive value=89%) and that reconstructed wave maps correlate well with manually edited wave maps in terms of number of waves (r=0.96), intra-wave conduction velocity (r=0.97), AF cycle length (r=0.97), and wave size (r=0.96) (p<0.01 in all cases). The automated procedure is therefore an adequate substitute for manual annotation. PMID- 23367384 TI - Characterization of fractionated electrograms using a novel time-frequency based algorithm. AB - Atrial fibrillation (AF) arises from complex spatiotemporal atrial activation. Current treatment for patients with AF when antiarrhythmic drugs have failed is catheter ablation which uses Radiofrequency (RF) energy to destroy heart tissues that drive AF. Therefore, AF can be terminated once the AF source is localized and eliminated by RF ablation. There is considerable interest in defining whether complex fractionated atrial electrograms (CFAE) indicate AF-perpetuation sites. This work proposes a novel time-frequency (TF) based algorithm to characterize CFAE electrograms (EGMs). The proposed technique obtains an automated classifier that is trained based on the differences evidenced between the TF structures of CFAE and non-CFAE EGMs. These characteristics are quantified using 5 TF features which are extracted using a TF matrix decomposition method performed on the EGM. The results from 5 patients with AF show that the proposed method is successful in identifying CFAE vs. non-CFAE EGMs, and might open new perspectives for a novel and reliable mapping technique to accurately characterize and understand AF mechanism. PMID- 23367385 TI - Myofiber orientation and electrical activation in human and sheep atrial models. AB - Anatomically realistic computational models provide a powerful platform for investigating mechanisms that underlie atrial rhythm disturbances. In recent years, novel techniques have been developed to construct structurally-detailed, image-based models of 3D atrial anatomy. However, computational models still do not contain full descriptions of the atrial intramural myofiber architecture throughout the entire atria. To address this, a semi-automatic rule-based method was developed for generating multi-layer myofiber orientations in the human atria. The rules for fiber generation are based on the careful anatomic studies of Ho, Anderson and co-workers using dissection, macrophotography and visual tracing of fiber tracts. Separately, a series of high color contrast images were obtained from sheep atria with a novel confocal surface microscopy method. Myofiber orientations in the normal sheep atria were estimated by eigen-analyis of the 3D image structure tensor. These data have been incorporated into an anatomical model that provides the quantitative representation of myofiber architecture in the atrial chambers. In this study, we attempted to compare the two myofiber generation approaches. We observed similar myo-bundle structure in the human and sheep atria, for example in Bachmann's bundle, atrial septum, pectinate muscles, superior vena cava and septo-pulmonary bundle. Our computational simulations also confirmed that the preferential propagation pathways of the activation sequence in both atrial models is qualitatively similar, largely due to the domination of the major muscle bundles. PMID- 23367386 TI - Wavelet variability of SA node originated P waves in atrial fibrillation and in signals with ectopic beats. AB - Atrial fibrillation (AF) is one of the most common cardiac arrhythmia. Electrical properties of the atrial myocardium may be related to the appearance of this type of arrhythmia. However ectopic beats, occurring normally in healthy people, disturb cardiac rhythm. Those beats arise from fiber outside the region of SA node. With this work we aim at highlighting differences in the atrial activity between healthy subjects, healthy subjects presenting many ectopic events and patients with AF. The X-Y-Z leads of vectorcardiography recordings are considered. Wavelet-based parameters are extracted from a window which represents atrial activity originated from SA node and compared between signals of the three groups. Results show differences potentially related to the conduction system of the atrium between healthy people and people with AF, as well as between healthy people and people with ectopic events. No difference was found from the analysis of SA node beats between people with AF and healthy with ectopic events. PMID- 23367387 TI - Realistic training data improve noninvasive reconstruction of heart-surface potentials. AB - The inverse problem of electrocardiography is to noninvasively reconstruct electrical heart activity from body-surface electrocardiograms. Solving this problem is beneficial to clinical practice. However, reconstructions cannot be obtained straightforwardly due to the ill-posed nature of this problem. Therefore, regularization schemes are necessary to arrive at realistic solutions. To date, no electrophysiological data have been used in reconstruction methods and regularization schemes. In this study, we used a training set of simulated heart-surface potentials to create a realistic basis for reconstructions of electrical cardiac activity. We tested this method in computer simulations and in one patient. The quality of reconstruction improved significantly after projection of the results of traditional regularization methods on this new basis, both in silico (p<0.01) and in vivo (p<0.05). Thus, we demonstrate that the novel concept of applying electrophysiological data might be useful to improve noninvasive reconstruction of electrical heart activity. PMID- 23367388 TI - The stability of electrically induced ventricular fibrillation. AB - The first recorded heart rhythm for cardiac arrest patients can either be ventricular fibrillation (VF) which is treatable with a defibrillator, or asystole or pulseless electrical activity (PEA) which are not. The time course for the deterioration of VF to either asystole or PEA is not well understood. Knowing the time course of this deterioration may allow for improvements in emergency service delivery. In addition, this may improve the diagnosis of possible electrocutions from various electrical sources including utility power, electric fences, or electronic control devices (ECDs) such as a TASER((r)) ECD. We induced VF in 6 ventilated swine by electrically maintaining rapid cardiac capture, with resulting hypotension, for 90 seconds. No circulatory assistance was provided. They were then monitored for 40 minutes via an electrode in the right ventricle. Only 2 swine remained in VF; 3 progressed to asystole; 1 progressed to PEA. These results were used in a logistic regression model. The results are then compared to published animal and human data. The median time for the deterioration of electrically induced VF in the swine was 35 minutes. At 24 minutes VF was still maintained in all of the animals. We conclude that electrically induced VF is long-lived--even in the absence of chest compressions. PMID- 23367389 TI - Recognition of household and athletic activities using SmartShoe. AB - The ability to provide real time feedback concerning a person's activity level and energy expenditure can be beneficial for improving activity levels of individuals. Examples include biofeedback systems used for body weight and physical activity management and biofeedback systems for rehabilitation of stroke patients. A critical aspect of any such system is being able to accurately classify data in real-time so that active and timely feedback can be provided. In the paper we demonstrate feasibility of real-time recognition of multiple household and athletic activities on a cell phone using the data collected by a wearable sensor system consisting of SmartShoe sensor and a wrist accelerometer. The experimental data were collected for multiple household and athletic activities performed by a healthy individual. The data was used to train two neural networks, one to be used primarily for sedentary individuals and one for more active individuals. Classification of household activities including ascending stairs, descending stairs, doing the dishes, vacuuming, and folding laundry, achieved 89.62% average accuracy. Classification of athletic activities such as jumping jacks, swing dancing, and ice skating, was performed with 93.13% accuracy. As proof of real-time processing on a mobile platform the trained neural network for healthy individuals was timed and required less than 4 ms to perform each feature vector construction and classification. PMID- 23367390 TI - A new method to determine joint range of movement and stiffness in rheumatoid arthritic patients. AB - Rheumatoid arthritis affects 0.5-1% of the general population. The prediction and prognosis of the disease varies for each individual and its course can detrimentally affect the psychosocial condition of the patient. Clinicians and Therapists aim to quickly diagnose and treat those with this debilitating disease. Detection relies heavily on manual evaluation methods that are dependent on training and can vary between observers. Angle measuring instrument, tape measure and grip strength dynamometer are used to assess the joint range and strength of a patient to determine their hand function. Joint stiffness can be a determining factor when diagnosing the advancement and improvement of Rheumatoid Arthritis (RA). This paper outlines the development of a hand movement measurement tool to accurately quantify patients' flexion, extension, abduction and adduction movement of each finger joint and quantifies the symptom of "early morning stiffness". It also describes the problems that arise when using a data glove to accurately measure Range Of Movement and discusses alternative methods to overcome these issues. PMID- 23367391 TI - A user profile ontology based approach for assisting people with dementia in mobile environments. AB - Personalization and context-aware applications have attracted increasing amounts of attention over recent years due to the emergence of pervasive computing applications. Nevertheless, it still remains a challenge to meet the needs of users while they are on the move. This paper introduces a novel approach for providing personalized, context-aware assistance services for users in mobile environments. Central to the approach is the use of ontological user profile modeling which captures various characteristics of a user in order to create a unique set of profile information. In addition, user profiles can adapt to changing user behavior, thus enabling services to respond to evolving user needs and preferences. We describe the overall system architecture of the proposed approach with special emphasis being placed on the user profile modelling and its expected utility based on a typical use case scenario, i.e., using a smart-phone to address the problem of the outdoor mobility of a person with Dementia. A prototype based on the Android OS is used to illustrate the application. The use of everyday technology for a real world problem highlights the potential and utility of our approach. PMID- 23367392 TI - A laboratory insole for analysis of sensor placement to determine ground reaction force and ankle moment in patients with stroke. AB - An insole system was constructed with 32 sensors inside a size 10 men's shoe. This system allows evaluation of the contributions of individual sensors spread throughout the surface area of the insole. The kinetic variables of interest in this initial study are ground reaction force and anterior-posterior ankle moment. Use of all 32 sensors are able to replicate the shape of the ground reaction force and ankle moment in a stroke patient who has regained a more normal gait, but less so in a stroke patient with impaired gait. Subsets of sensors can now be evaluated in order to ultimately identify an optimum set of sensors for determining kinetic variables necessary to classify presence or absence of a particular gait abnormality or other pathology. PMID- 23367393 TI - Proof of concept of a shoe based human activity monitor. AB - This paper presents the proof of concept of a low power, low cost, wearable activity monitor. The functionality of the system is based on accurate stride detection from signals generated by two force sensing resistors integrated within a normal shoe. A novel algorithm is proposed that is able to differentiate between walking and non-walking activities with high accuracy. The performance of the proof of concept system was validated in five subjects who underwent five repetitions of three different speed walking tests, and five repetitions of five non-walking artefact generating tests. The system achieved a total sensitivity of 96% with 98% specificity and an overall accuracy of 94%. PMID- 23367394 TI - Towards falls prevention: a wearable wireless and battery-less sensing and automatic identification tag for real time monitoring of human movements. AB - Falls related injuries among elderly patients in hospitals or residents in residential care facilities is a significant problem that causes emotional and physical trauma to those involved while presenting a rising healthcare expense in countries such as Australia where the population is ageing. Novel approaches using low cost and privacy preserving sensor enabled Radio Frequency Identification (RFID) technology may have the potential to provide a low cost and effective technological intervention to prevent falls in hospitals. We outline the details of a wearable sensor enabled RFID tag that is battery free, low cost, lightweight, maintenance free and can be worn continuously for automatic and unsupervised remote monitoring of activities of frail patients at acute hospitals or residents in residential care. The technological developments outlined in the paper forms part of an overall technological intervention developed to reduce falls at acute hospitals or in residential care facilities. This paper outlines the details of the technology, underlying algorithms and the results (where an accuracy of 94-100% was achieved) of a successful pilot trial. PMID- 23367395 TI - Decoding of velocities and positions of 3D arm movement from EEG. AB - A brain-computer interface (BCI) can be used to control a limb neuroprosthesis with motor imaginations (MI) to restore limb functionality of paralyzed persons. However, existing BCIs lack a natural control and need a considerable amount of training time or use invasively recorded biosignals. We show that it is possible to decode velocities and positions of executed arm movements from electroencephalography signals using a new paradigm without external targets. This is a step towards a non-invasive BCI which uses natural MI. Furthermore, training time will be reduced, because it is not necessary to learn new mental strategies. PMID- 23367396 TI - Detection of movements with attention or distraction to the motor task during robot-assisted passive movements of the upper limb. AB - Robot-assisted rehabilitation therapies usually focus on physical aspects rather than on cognitive factors. However, cognitive aspects such as attention, motivation, and engagement play a critical role in motor learning and thus influence the long-term success of rehabilitation programs. This paper studies motor-related EEG activity during the execution of robot-assisted passive movements of the upper limb, while participants either: i) focused attention exclusively on the task; or ii) simultaneously performed another task. Six healthy subjects participated in the study and results showed lower desynchronization during passive movements with another task simultaneously being carried out (compared to passive movements with exclusive attention on the task). In addition, it was proved the feasibility to distinguish between the two conditions. PMID- 23367397 TI - Brain-computer interface controlled functional electrical stimulation device for foot drop due to stroke. AB - Gait impairment due to foot drop is a common outcome of stroke, and current physiotherapy provides only limited restoration of gait function. Gait function can also be aided by orthoses, but these devices may be cumbersome and their benefits disappear upon removal. Hence, new neuro-rehabilitative therapies are being sought to generate permanent improvements in motor function beyond those of conventional physiotherapies through positive neural plasticity processes. Here, the authors describe an electroencephalogram (EEG) based brain-computer interface (BCI) controlled functional electrical stimulation (FES) system that enabled a stroke subject with foot drop to re-establish foot dorsiflexion. To this end, a prediction model was generated from EEG data collected as the subject alternated between periods of idling and attempted foot dorsiflexion. This prediction model was then used to classify online EEG data into either "idling" or "dorsiflexion" states, and this information was subsequently used to control an FES device to elicit effective foot dorsiflexion. The performance of the system was assessed in online sessions, where the subject was prompted by a computer to alternate between periods of idling and dorsiflexion. The subject demonstrated purposeful operation of the BCI-FES system, with an average cross-correlation between instructional cues and BCI-FES response of 0.60 over 3 sessions. In addition, analysis of the prediction model indicated that non-classical brain areas were activated in the process, suggesting post-stroke cortical re-organization. In the future, these systems may be explored as a potential therapeutic tool that can help promote positive plasticity and neural repair in chronic stroke patients. PMID- 23367398 TI - Decoding wrist kinematics from local field potentials of the ipsilateral primary motor and dorsal premotor cortices. AB - Local field potentials (LFP) are valuable signals for decoding motor kinematics in brain machine interfaces (BMIs). To take full advantage of LFPs, however, more systematic investigation of the relationship between LFPs and ipsilateral limb movement is required. In this paper we investigated the decoding power of LFPs for the ipsilateral wrist movement from two monkeys performing a 2D center-out task. The results show that LFPs could predict the ipsilateral wrist position and velocity with high accuracy, which is comparable to the accuracy of decoding the contralateral kinematics. Furthermore, similar to contralateral decoding, the low (0.3-5 Hz, 5-15 Hz) and high (100-200 Hz, 200-400 Hz) frequency bands resulted in significantly better decoding performance than the medium frequency bands. These results suggest that ipsilateral LFPs could be used to build better BMIs in similar ways of using contralateral LFPs. PMID- 23367400 TI - On the role of electric field orientation in optimal design of transcranial current stimulation. AB - Transcranial current stimulation (tCS) is a promising noninvasive technique to elicit neuromodulation by passing weak electrical currents through scalp electrodes. While significant effort has been devoted towards designing stimulation protocols which "steer" current to regions of interest, previous work has been almost exclusively focused on the magnitude of the electric field, while ignoring the effects of direction. This is despite previous in vitro studies demonstrating that the angle between the field orientation and the cell axis of symmetry has significant effects on the resulting membrane polarization presumably underlying therapeutic effects. To that end, here we examine the impact of the desired electric field orientation on the optimal placement of electrodes for a given target region. Based on high-resolution head models derived from magnetic resonance scans of patients enrolled in a clinical trial examining the use of tCS in rehabilitation after stroke, we derive and employ an optimization algorithm which computes the montage maximizing directed current flow at the target. The results reveal a strong dependence of the optimal montage on the desired orientation; moreover, the magnitude of the induced electric field at the target region varies widely with the preferred direction. This suggests that identifying the desired electric field orientation at the region of interest is a crucial step in the development of rational electrical stimulation paradigms. PMID- 23367401 TI - Stimulation strength and focality of electroconvulsive therapy with individualized current amplitude: a preclinical study. AB - This study investigates the stimulation strength and focality of electroconvulsive therapy (ECT) with individualized current amplitude in a nonhuman primate (NHP) model. We generated an anatomically realistic finite element model of a NHP head incorporating tissue heterogeneity and white matter conductivity anisotropy based on structural magnetic resonance imaging (MRI) and diffusion tensor MRI data. The electric field spatial distributions of three conventional ECT electrode placements (bilateral, bifrontal, and right unilateral) and an experimental frontomedial electrode configuration were simulated. We calibrated the electric field maps relative to an empirical neural activation threshold and evaluated the stimulation strength and focality of the various ECT electrode configurations with individualized current amplitudes corresponding to the motor threshold and seizure threshold assessed in the anesthetized NHP. Understanding the stimulation strength and focality of various forms of ECT could provide insight into the mechanisms of therapeutic seizure induction, and could provide support for the clinical investigation of ECT with individualized current amplitude as an intervention with potentially improved risk/benefit ratio. PMID- 23367402 TI - A model of variability in brain stimulation evoked responses. AB - The input-output (IO) curve of cortical neuron populations is a key measure of neural excitability and is related to other response measures including the motor threshold which is widely used for individualization of neurostimulation techniques, such as transcranial magnetic stimulation (TMS). The IO curve parameters provide biomarkers for changes in the state of the target neural population that could result from neurostimulation, pharmacological interventions, or neurological and psychiatric conditions. Conventional analyses of IO data assume a sigmoidal shape with additive Gaussian scattering that allows simple regression modeling. However, careful study of the IO curve characteristics reveals that simple additive noise does not account for the observed IO variability. We propose a consistent model that adds a second source of intrinsic variability on the input side of the IO response. We develop an appropriate mathematical method for calibrating this new nonlinear model. Finally, the modeling framework is applied to a representative IO data set. With this modeling approach, previously inexplicable stochastic behavior becomes obvious. This work could lead to improved algorithms for estimation of various excitability parameters including established measures such as the motor threshold and the IO slope, as well as novel measures relating to the variability characteristics of the IO response that could provide additional insight into the state of the targeted neural population. PMID- 23367403 TI - Simulations and visualizations for interpretation of brain microdialysis data during deep brain stimulation. AB - Microdialysis of the basal ganglia was used in parallel to deep brain stimulation (DBS) for patients with Parkinson's disease. The aim of this study was to patient specifically simulate and visualize the maximum tissue volume of influence (TVI(max)) for each microdialysis catheter and the electric field generated around each DBS electrode. The finite element method (FEM) was used for the simulations. The method allowed mapping of the anatomical origin of the microdialysis data and the electric stimulation for each patient. It was seen that the sampling and stimulation targets differed among the patients, and the results will therefore be used in the future interpretation of the biochemical data. PMID- 23367404 TI - Assessment of mental fatigue during car driving by using high resolution EEG activity and neurophysiologic indices. AB - Driving tasks are vulnerable to the effects of sleep deprivation and mental fatigue, diminishing driver's ability to respond effectively to unusual or emergent situations. Physiological and brain activity analysis could help to understand how to provide useful feedback and alert signals to the drivers for avoiding car accidents. In this study we analyze the insurgence of mental fatigue or drowsiness during car driving in a simulated environment by using high resolution EEG techniques as well as neurophysiologic variables such as heart rate (HR) and eye blinks rate (EBR). Results suggest that it is possible to introduce a EEG-based cerebral workload index that it is sensitive to the mental efforts of the driver during drive tasks of different levels of difficulty. Workload index was based on the estimation of increase of EEG power spectra in the theta band over prefrontal areas and the simultaneous decrease of EEG power spectra over parietal areas in alpha band during difficult drive conditions. Such index could be used in a future to assess on-line the mental state of the driver during the drive task. PMID- 23367405 TI - Examination of a muscular activity estimation model using a Bayesian network for the influence of an ankle foot orthosis. AB - In the present paper, we examine the appropriateness of a new model to examine the activity of the foot in gait. We developed an estimation model for foot-ankle muscular activity in the design of an ankle-foot orthosis by means of a statistical method. We chose three muscles for measuring muscular activity and built a Bayesian network model to confirm the appropriateness of the estimation model. We experimentally examined the normal gait of a non-disabled subject. We measured the muscular activity of the lower foot muscles using electromyography, the joint angles, and the pressure on each part of the sole. From these data, we obtained the causal relationship at every 10% level for these factors and built models for the stance phase, control term, and propulsive term. Our model has three advantages. First, it can express the influences that change during gait because we use 10% level nodes for each factor. Second, it can express the influences of factors that differ for low and high muscular-activity levels. Third, we created divided models that are able to reflect the actual features of gait. In evaluating the new model, we confirmed it is able to estimate all muscular activity level with an accuracy of over 90%. PMID- 23367406 TI - Classification of human physical activity and energy expenditure estimation by accelerometry and barometry. AB - Regular exercise and physical activity are among the most important factors influencing the quality of life and make a significant contribution to the maintenance of health and well-being. The assessment of physical activity via accelerometry has become a promising technique often used as means to objectively measure physical activity. This work proposes a simple and reliable method to assess human physical activity and calculate the energy expenditure (EE) by using an acceleration and an air pressure sensor. Our proposed algorithm differentiates between 7 activities with an average accuracy of 98.2% and estimates the second by second EE with an average percent error of 1.59 +/- 8.20% using a single measurement unit attached to the subject's hip. PMID- 23367407 TI - Influence of sound source width on human sound localization. AB - Free-field sound localization experiments generally assume that a loudspeaker can be approximated by a point-source; however, a large loudspeaker may extend beyond the width that two sources can be discriminated. Humans can accurately discriminate sound source locations within a few degrees, thus one might expect localization precision to decrease as a function of sound source diameter, much as precision is lower for localizing the center of a wide, blurry light source. In order to test the degree to which humans differentially localize small and large sound sources, auditory targets were presented using a single 25.4 cm by 10.2 cm elliptical loudspeaker with the primary axis oriented both horizontally and vertically in different sessions. Subjects were seated with their heads fixed by a bite bar in a darkened, echo-attenuating room facing a cylindrical, acoustically transparent screen at a distance of 2 meters. Auditory targets consisted of repeating bursts (5 Hz) of low frequency band-pass noise (0.2 - 1 kHz, 75 dB SPL). Subjects were instructed to quickly and accurately guide a laser pointer mounted on a cylindrical joystick towards targets, presented randomly within a field +/- 40 degrees in azimuth by +/- 10 degrees in elevation, with oversampled points located every ten degrees along the primary meridians. Localization accuracy and precision (mean and standard deviation of localization error at oversampled locations) were not significantly different between speaker orientations, and were comparable to baseline measurements recorded using a 7.6 cm circular speaker. We conclude that low frequency sound localization performance is not dependent upon the size of the sound source as predicted theoretically, and is well approximated by a point source. PMID- 23367408 TI - Normalization strategies for nasal acceleration to assess velopharyngeal function. AB - Velopharyngeal function is essential for intelligible speech production, but can often be impaired. Current clinical care could be improved with the use of reliable and objective methods of assessment appropriate for home use. This paper explores the use of a combined nasal acceleration and acoustic sensor to assess velopharyngeal function. Speech production data in nasalized and non-nasalized contexts is recorded from N=6 healthy participants and three normalization strategies are assessed. Normalizing data to maximally nasal productions results in a reduction of between-speaker variability. Using a filtered speech signal can reduce the effects of intra-speaker variability caused be differences in loudness. The normalization strategies pursued show high discriminability of nasalization in vowels with an inexpensive sensor appropriate for home use. PMID- 23367409 TI - Analysis of muscle fatigue induced by isometric vibration exercise at varying frequencies. AB - An increase in neuromuscular activity, measured by electromyography (EMG), is usually observed during vibration exercise. The underlying mechanisms are however unclear, limiting the possibilities to introduce and exploit vibration training in rehabilitation programs. In this study, a new training device is used to perform vibration exercise at varying frequency and force, therefore enabling the analysis of the relationship between vibration frequency and muscle fatigue. Fatigue is estimated by maximum voluntary contraction measurement, as well as by EMG mean-frequency and conduction-velocity analysis. Seven volunteers performed five isometric contractions of the biceps brachii with a load consisting of a baseline of 80% of their maximum voluntary contraction (MVC), with no vibration and with a superimposed 20, 30, 40, and 50 Hz vibrational force of 40 N. Myoelectric and mechanical fatigue were estimated by EMG analysis and by assessment of the MVC decay, respectively. A dedicated motion artifact canceler, making use of accelerometry, is proposed to enable accurate EMG analysis. Use of this canceler leads to better interpolation of myoelectric fatigue trends and to better correlation between mechanical and myoelectric fatigue. In general, our results suggest vibration at 30 Hz to be the most fatiguing exercise. These results contribute to the analysis of vibration exercise and motivate further research aiming at improved training protocols. PMID- 23367410 TI - Admittance control of an upper limb exoskeleton--reduction of energy exchange. AB - The synergy of human arms and wearable robot systems (e.g. exoskeletons) is enabled by a control algorithm that maximizes the transparency between the two subsystems. The transparency can be improved by integrating the admittance control along with an arm redundancy resolution algorithm. Recent research effort resulted in a new criterion for the human arm redundancy resolution for unconstrained arm motions estimating the swivel angle with prediction errors of less than 5 degrees . The proposed criterion for the arm redundancy resolution defines the mouth as the primary target of the the human hand during unconstrained arm motions in free space. It was postulated based on experimental data analysis that this criterion is based on a neural mechanism directing the hand towards the head for self-feeding. In conjunction with the proposed redundancy resolution criteria a task space admittance control algorithm is introduced based on multiple force sensor inputs obtained at the interface between the human arm and the exoskeleton system. The system performance was evaluated by five healthy subjects performing a peg-in-hole task for three different target locations. The velocities and interaction forces at the upper arm, lower arm, handle and tip were recorded and further used to power exchange between the subject and the device. Results indicated that the proposed control scheme outperforms the purely reactive task space admittance control with energy exchange reduced to 11.22%. Improving the quality of the human control of a wearable robot system may allow the robot to be a natural and transparent extension of the operator's body. PMID- 23367411 TI - Viscoelastic model for redundancy resolution of the human arm via the swivel angle: applications for upper limb exoskeleton control. AB - One of the key research efforts associated with a redundant seven degree of freedom (7-DOF) upper limb exoskeleton robot that is mechanically coupled to the human body is to develop high and low level control algorithms that enable the system to become a natural extension of the human body. Improving the synergistic relationship between the exoskeleton and the operator is manifested in part by decreasing the force exchange between the two entities. Such a reduction is accomplished in part by developing criteria for resolving the human arm redundancy. The redundancy may be represented by a swivel angle which is defined as the angular rotation of the elbow around an axis that passes through the shoulder and wrist joints. The proposed criteria for defining the swivel angle takes into account the dynamics of the human arm along with a viscoelastic muscle like model with variable damping. The swivel angle is estimated using the pseudo inverse of the Jacobian with a secondary objective function that estimates the desired joint angles during human arm movement. The result is then fed to the muscle model to create a more realistic human motion. The estimated swivel angle is then compared with the actual swivel angle measured experimentally by a motion capture system. Results indicate that the average error between the estimated and measured swivel joint angle is 4.4 degrees (in the range [3.7-6] degrees), which are lower than the kinematically based redundant resolution criterion. PMID- 23367412 TI - Robots and therapeutic play: evaluation of a wireless interface device for interaction with a robot playmate. AB - Rehabilitation robots in home environments has the potential to dramatically improve quality of life for individuals who experience disabling circumstances due to injury or chronic health conditions. Unfortunately, although classes of robotic systems for rehabilitation exist, these devices are typically not designed for children. And since over 150 million children in the world live with a disability, this causes a unique challenge for deploying such robotics for this target demographic. To overcome this barrier, we discuss a system that uses a wireless arm glove input device to enable interaction with a robotic playmate during various play scenarios. Results from testing the system with 20 human subjects shows that the system has potential, but certain aspects need to be improved before deployment with children. PMID- 23367413 TI - Human motion analysis with ultrasound and sonomyography. AB - Skeletal muscle is an important tissue of human body, and its contraction can control and regulate body motions, which plays a key role in the human movement. With the development of computer and human motion analysis, the muscle activities are involved into the whole human motion analysis. Currently, muscle assessments in human motion analysis are commonly performed using surface electromyography (SEMG). However SEMG cannot be applied to measure all muscles because its access to deep muscles is very limited, which restricts its application. Sonomyography (SMG), which represents the real-time change of muscle architectural parameters obtained using ultrasound imaging, is an alternative noninvasive method to quantify the muscle dynamic activities during human motion. It is gradually becoming a reliable research and clinical tool and playing increasingly important role in the functional assessment of muscles. In this study, a human motion analysis system with ultrasound and sonomyography which could provide objective data about muscle architectures and their change during muscle contraction in real-time was developed. Preliminary tests were conducted on a normal subject, and the feasibility was demonstrated. PMID- 23367414 TI - New method for liquid-medication filling systems. AB - For the systems used to fill large numbers of containers with liquid medication, a permissible relative error is +/-1.0%. Here, a medication filling and estimating system was designed to improve cycle time. The nonlinear least squares (NLS) method was used with the proposed system, and the results succeeded in providing the medication fill ration meeting certain specifications and below the permissible relative error. The proposed method also realizes medication filling accuracy comparable to that achieved by the conventional method, but additionally made it possible to shorten the time needed to compute the weight value by approx 60%. Moreover, since a low-pass filter does not need to be used with the proposed method, the new method is not subject to the influence of a time delay. PMID- 23367415 TI - Independent ankle motion control improves robotic balance simulator. AB - We present a validation study for the effectiveness of an additional ankle-tilt platform to enhance somatosensory ankle feedback available to subjects actuating a 6-axis robotic balance simulator platform. To address this need, we have developed and integrated a device to permit independent manipulation of ankle rotation while the whole-body is actuated by the balance simulator. The addition of ankle rotation is shown to provide both quantitative and qualitative improvements to the balance simulation experience compared to when the ankle joint is referenced to the motion of the balance simulator. Eight out of ten subjects reported that balancing on the simulator with ankle motion required less conscious effort. This self-reported improvement corresponded to a 32% decrease in the mean-removed RMS amplitude for sway angle, demonstrating better balance control for subjects actuating the simulator. The new ankle-tilt platform enables examination of the contributions of ankle proprioception to the control of standing balance in human subjects. PMID- 23367416 TI - Probabilistic source separation for robust electrocardiography. AB - Blind source separation (BSS) techniques are widely used to extract signals of interest from a mixture with other signals. These methods, however, typically lack possibilities to incorporate any prior knowledge on the mixing of the source signals. Particularly for electrocardiographic signals, knowledge on the mixing is available based on the origin and propagation properties of these signals. In this paper, a novel source separation method is developed that combines the strengths and accuracy of BSS techniques with the robustness of an underlying physiological model of the electrocardiogram (ECG). The method is developed within a probabilistic framework and yields an iterative convergence of the separation matrix towards a maximum a posteriori estimation, where in each iteration the latest estimate of the separation matrix is corrected towards the physiological model. The method is evaluated by comparing its performance to that of FastICA on both simulated and real multi-channel ECG recordings, demonstrating that the developed method outperforms FastICA in terms of extracting the ECG source signals. PMID- 23367417 TI - An optimized DSP implementation of adaptive filtering and ICA for motion artifact reduction in ambulatory ECG monitoring. AB - Noise from motion artifacts is currently one of the main challenges in the field of ambulatory ECG recording. To address this problem, we propose the use of two different approaches. First, an adaptive filter with electrode-skin impedance as a reference signal is described. Secondly, a multi-channel ECG algorithm based on Independent Component Analysis is introduced. Both algorithms have been designed and further optimized for real-time work embedded in a dedicated Digital Signal Processor. We show that both algorithms improve the performance of a beat detection algorithm when applied in high noise conditions. In addition, an efficient way of choosing this methods is suggested with the aim of reduce the overall total system power consumption. PMID- 23367418 TI - Muscle artifact suppression using independent-component analysis and state-space modeling. AB - In this paper, we aim at suppressing the muscle artifacts present in electroencephalographic (EEG) signals with a technique based on a combination of Independent Component Analysis (ICA) and State-Space Modeling (SSM). The novel algorithm uses ICA to provide an initial model for SSM which is further optimized by the maximum-likelihood approach. This model is fitted to artifact-free data. Then it is applied to data with muscle artifacts. The state space is augmented by extracting additional components from the data prediction errors. The muscle artifacts are well separated in the additional components and, hence, a suppression of them can be performed. The proposed algorithm is demonstrated by application to a clinical epilepsy EEG data set. PMID- 23367419 TI - Input interface using event-related potential P3. AB - This paper refers to a basic study toward the goal of developing a simple and easy-to-use input interface based on P3 components of visual, event-related potentials. Because contamination from eye movements and eye blinks is a problem, a method for removing eye movement artifacts from electroencephalogram (EEG) signals by applying an independent component analysis un-mixing matrix was proposed and implemented. Input character decisions were executed using a support vector machine (SVM) for judging the P3 existence of a single stimulus. The performances were compared while varying the number of channels of EEG signals, the types of feature vectors, and the ratio of the number of data used for training the SVM. The results indicated that three EEG signal channels (Fz, Cz, Pz) were enough to remove artifacts related to eye blinks and vertical eye movements and could be used to make a decision about input characters. The number of trials necessary to decide the input characters was ten on average. The best ratio achieved for the number of training data of targets and non-targets was 1?2. These results should be confirmed using a larger number of data sets. PMID- 23367420 TI - Evaluating different combinations of feature selection algorithms and cost functions applied to iPCA tuning in myoelectric control systems. AB - A myoelectric control system extracts information from electromyographic (EMG) signals and uses it to control different types of prostheses, so that people who suffered traumatisms, paralysis or amputations can use them to execute common movements. Recent research shows that the addition of a tuning stage, using the individual component analysis (iPCA), results in improved classification performance. We propose and evaluate a set of novel configurations for the iPCA tuning, based on a biologically inspired optimization procedure, the artificial bee colony algorithm. This procedure is implemented and tested using two different cost functions, the traditional classification error and the proposed correlation factor, which involves lower computational effort. We compare the tuned system's performance, in terms of correct classifications, to that of a system tuned using two standard algorithms, the sequential forward selection and the sequential floating forward selection. The statistical analyses of the results don't find a significant difference among the classification performances associated with the search algorithms (p < 0.01). On the other hand, they establish a significant difference among the classification performances related to the cost functions (p < 0.02). PMID- 23367421 TI - Classification of gait kinematics of anterior cruciate ligament reconstructed subjects using principal component analysis and regressions modelling. AB - The aim of this study was to compare the knee kinematics of anterior cruciate ligament reconstructed (ACL-R) and healthy subjects (CG) during gait and classify the status of normality. Ten healthy and six ACL-R subjects had their gait analyzed at 60 fps. 3D knee angles were calculated and inserted into three separate matrices used to perform the principal component (PC) analysis. The scores of PCs retained in each analysis were used to calculate the standard distances (SD) of each participant in relation to the center of the CG. The PC scores of the three planes were used in a logistic regression to define normality. In the sagittal plane there was no difference between groups. In the frontal and transverse planes ACL-R subjects showed higher SD values than CG. PCs identified that ACL-R subjects showed increased adduction, internal and external rotation. All these subjects had their gait classified as abnormal by logistic regression. Therefore, in the studied ACL-R subjects the gait pattern did not return to normal levels after surgery. This may lead to degenerative injuries, as osteoarthritis, in the future. PMID- 23367422 TI - A NARMAX method for the identification of time-varying joint stiffness. AB - Dynamic joint stiffness defines the dynamic relationship between the position of a joint and the torque acting about it and can be separated into intrinsic and reflex components. Under stationary conditions, these can be identified using a nonlinear parallel-cascade algorithm that models intrinsic stiffness and reflex stiffness as parallel pathways. Experimental results demonstrate that both intrinsic and reflex stiffness depend strongly on the operating point defined by mean joint position and the activation level. Consequently, both intrinsic and reflex stiffness will appear to be time-varying (TV) whenever the operating point changes, as during movement. This paper describes and validates a new method for identification of TV ankle stiffness. The method is based on the TV nonlinear autorregresive, moving average exogenous (NARMAX) model class. Simulation results demonstrated that the algorithm can accurately estimate the TV parameters of the ankle stiffness. We conclude that the algorithm is potentially a powerful new tool for the study of joint stiffness during TV conditions. PMID- 23367423 TI - An adaptive Kalman filter technique for context-aware heart rate monitoring. AB - Traditional physiological monitoring systems convert a person's vital sign waveforms, such as heart rate, respiration rate and blood pressure, into meaningful information by comparing the instant reading with a preset threshold or a baseline without considering the contextual information of the person. It would be beneficial to incorporate the contextual data such as activity status of the person to the physiological data in order to obtain a more accurate representation of a person's physiological status. In this paper, we proposed an algorithm based on adaptive Kalman filter that describes the heart rate response with respect to different activity levels. It is towards our final goal of intelligent detection of any abnormality in the person's vital signs. Experimental results are provided to demonstrate the feasibility of the algorithm. PMID- 23367424 TI - Discovering shared cardiovascular dynamics within a patient cohort. AB - Cardiovascular variables such as heart rate (HR) and blood pressure (BP) are robustly regulated by an underlying control system. Time series of HR and BP exhibit distinct dynamical patterns of interaction in response to perturbations (e.g., drugs or exercise) as well as in pathological states (e.g., excessive sympathetic activation). A question of interest is whether "similar" dynamical patterns can be identified across a heterogeneous patient cohort. In this work, we present a technique based on switching linear dynamical systems for identification of shared dynamical patterns in the time series of HR and BP recorded from a patient cohort. The technique uses a mixture of linear dynamical systems, the components of which are shared across all patients, to capture both nonlinear dynamics and non-Gaussian perturbations. We present exploratory results based on a simulation study of the cardiovascular system, and real recordings from 10 healthy subjects undergoing a tilt-table test. These results demonstrate the ability of the proposed technique to identify similar dynamical patterns present across multiple time series. PMID- 23367425 TI - Output regularization of SVM seizure predictors: Kalman Filter versus the "Firing Power" method. AB - Two methods for output regularization of support vector machines (SVMs) classifiers were applied for seizure prediction in 10 patients with long-term annotated data. The output of the classifiers were regularized by two methods: one based on the Kalman Filter (KF) and other based on a measure called the "Firing Power" (FP). The FP is a quantification of the rate of the classification in the preictal class in a past time window. In order to enable the application of the KF, the classification problem was subdivided in a two two-class problem, and the real-valued output of SVMs was considered. The results point that the FP method raise less false alarms than the KF approach. However, the KF approach presents an higher sensitivity, but the high number of false alarms turns their applicability negligible in some situations. PMID- 23367426 TI - An expectation-maximization algorithm based Kalman smoother approach for single trial estimation of event-related potentials. AB - This paper applies an expectation-maximization (EM) based Kalman smoother (KS) approach for single-trial event-related potential (ERP) estimation. Existing studies assume a Markov diffusion process for the dynamics of ERP parameters which is recursively estimated by optimal filtering approaches such as Kalman filter (KF). However, these studies only consider estimation of ERP state parameters while the model parameters are pre-specified using manual tuning, which is time-consuming for practical usage besides giving suboptimal estimates. We extend the KF approach by adding EM based maximum likelihood estimation of the model parameters to obtain more accurate ERP estimates automatically. We also introduce different model variants by allowing flexibility in the covariance structure of model noises. Optimal model selection is performed based on Akaike Information Criterion (AIC). The method is applied to estimation of chirp-evoked auditory brainstem responses (ABRs) for detection of wave V critical for assessment of hearing loss. Results shows that use of more complex covariances are better estimating inter-trial variability. PMID- 23367427 TI - Gait cycle spectrogram analysis using a torso-attached inertial sensor. AB - Measurement of gait parameters can provide important information about a person's health and safety. Automatic analysis of gait using kinematic sensors is a newly emerging area of research. We describe a new way to detect walking, and measure gait cadence, by using time-frequency signal processing together with spectrogram analysis of signals from a chest-worn inertial measurement unit (IMU). A pilot study of 11 participants suggests that this method is able to distinguish between walk and non-walk activities with up to 88.70% sensitivity and 97.70% specificity. Limitations of the method include instability associated with manual fine-tuning of local and global threshold levels. PMID- 23367428 TI - Scale Invariant Feature Transform as feature tracking method in 4D imaging: a feasibility study. AB - We propose the use of Scale Invariant Feature Transform (SIFT) as a method able to extract stable landmarks from 4D images and to quantify internal motion. We present a preliminary validation of the SIFT method relying on expert user identification of landmarks and then apply it to 4D lung CT and liver MRI data. Results demonstrate SIFT capabilities as an operator-independent feature tracking method. PMID- 23367429 TI - Global and local detection of liver steatosis from ultrasound. AB - Liver steatosis is a common disease usually associated with social and genetic factors. Early detection and quantification is important since it can evolve to cirrhosis. Steatosis is usually a diffuse liver disease, since it is globally affected. However, steatosis can also be focal affecting only some foci difficult to discriminate. In both cases, steatosis is detected by laboratorial analysis and visual inspection of ultrasound images of the hepatic parenchyma. Liver biopsy is the most accurate diagnostic method but its invasive nature suggest the use of other non-invasive methods, while visual inspection of the ultrasound images is subjective and prone to error. In this paper a new Computer Aided Diagnosis (CAD) system for steatosis classification and analysis is presented, where the Bayes Factor, obatined from objective intensity and textural features extracted from US images of the liver, is computed in a local or global basis. The main goal is to provide the physician with an application to make it faster and accurate the diagnosis and quantification of steatosis, namely in a screening approach. The results showed an overall accuracy of 93.54% with a sensibility of 95.83% and 85.71% for normal and steatosis class, respectively. The proposed CAD system seemed suitable as a graphical display for steatosis classification and comparison with some of the most recent works in the literature is also presented. PMID- 23367430 TI - Fourier-based shape feature extraction technique for computer-aided B-Mode ultrasound diagnosis of breast tumor. AB - Early detection of breast tumor is critical in determining the best possible treatment approach. Due to its superiority compared with mammography in its possibility to detect lesions in dense breast tissue, ultrasound imaging has become an important modality in breast tumor detection and classification. This paper discusses the novel Fourier-based shape feature extraction techniques that provide enhanced classification accuracy for breast tumor in the computer-aided B mode ultrasound diagnosis system. To demonstrate the effectiveness of the proposed method, experiments were performed using 4,107 ultrasound images with 2,508 malignancy cases. Experimental results show that the breast tumor classification accuracy of the proposed technique was 15.8%, 5.43%, 17.32%, and 13.86% higher than the previous shape features such as number of protuberances, number of depressions, lobulation index, and dissimilarity, respectively. PMID- 23367431 TI - Mesh-based approach for the 3D analysis of anatomical structures of interest in radiotherapy. AB - In this paper a method based on mesh surfaces approximations for the 3D analysis of anatomical structures in Radiotherapy (RT) is presented. Parotid glands meshes constructed from Megavoltage CT (MVCT) images were studied in terms of volume, distance between center of mass (distCOM) of the right and left parotids, dice similarity coefficient (DICE), maximum distance between meshes (DMax) and the average symmetric distance (ASD). A comparison with the standard binary images approach was performed. While absence of significant differences in terms of volume, DistCOM and DICE indices suggests that both approaches are comparable, the fact that the ASD showed significant difference (p=0.002) and the DMax was almost significant (p=0.053) suggests that the mesh approach should be adopted to provide accurate comparison between 3D anatomical structures of interest in RT. PMID- 23367432 TI - Automated boundary extraction of the spinal canal in MRI based on dynamic programming. AB - The spinal cord is the only communication link between the brain and the body. The abnormalities in it can lead to severe pain and sometimes to paralysis. Due to the growing gap between the number of available radiologists and the number of required radiologists, the need for computer-aided diagnosis and characterization is increasing. To ease this gap, we have developed a computer-aided diagnosis and characterization framework in lumbar spine that includes the spinal cord, vertebrae, and intervertebral discs. In this paper, we propose two spinal cord boundary extraction methods that fit into our framework based on dynamic programming in lumbar spine MRI. Our method incorporates the intensity of the image and the gradient of the image into a dynamic programming scheme and works in a fully-automatic fashion. The boundaries generated by our method is compared against reference boundaries in terms of Frechet distance which is known to be a metric for shape analysis. The experimental results from 65 clinical data show that our method finds the spinal canal boundary correctly achieving a mean Frechet distance of 13.5 pixels. For almost all data, the extracted boundary falls within the spinal cord. So, it can be used as a landmark when marking background regions and finding regions of interest. PMID- 23367433 TI - Trapping of vesicles on patterned surfaces by physisorption for potential biosensing applications. AB - The pre-defined selective positioning of a controlled number of vesicles on a rigid substrate is crucial in many potential applications such as diagnostics, biosensors, lab-on-a chip, microanalyses and reaction chambers. In this paper, the vesicles made up of block copolymer using Poly [-(2-methyloxazoline) -poly- (dimethylsiloxane)-poly- (2-methyloxazoline)] (ABA) with dimensions of 100-200 nm are trapped by physisorption on hydrophilic surfaces. We discuss the protocols established for vesicle trapping. The optimum conditions obtained for physisorption is 15 minutes incubation followed by one cycle of DI water rinse. Trapping of 1-10 vesicles in lobe shape micro-wells fabricated by photo lithography using photoresist on UltraStick(TM) slides was demonstrated. To overcome the issue of amalgamation of emitted light from optically sensitive photoresist and fluorescently tagged vesicles, an alternative approach of Si/SiO(2) microwell array coupled with APTES (3-AminoPropylTriEthoxySilane) treated bottom surfaces was developed. PMID- 23367434 TI - Nanotopography effects on astrocyte attachment to nanoporous gold surfaces. AB - Nanoporous gold, synthesized by a self-assembly process, is a new biomaterial with desirable attributes, including tunable nanotopography, drug delivery potential, electrical conductivity, and compatibility with conventional microfabrication techniques. This study reports on the effect of nanotopography in guiding cellular attachment on nanoporous gold surfaces. While the changes in topography do not affect adherent cell density, average cell area displays a non monotonic dependence on nanotopography. PMID- 23367435 TI - Titanium-based, fenestrated, in-plane microneedles for passive ocular drug delivery. AB - Drug delivery to the eye remains a key challenge, due to limitations inherent to prevailing delivery techniques. For example, while topical delivery offers simplicity and safety, its efficacy is often limited by poor bioavailability, due to natural transport barriers and clearance mechanisms. Similarly, while intravitreal injections performed across the ocular tunic provide means for circumventing such limitations, non-negligible potential for retinal detachment and other complications adversely affects safety. Herein, we discuss our initial efforts to address these limitations through development of titanium-based microneedles (MNs) which seek to provide a safer, simpler, and more efficacious means of ocular drug delivery. Devices with in-plane geometry and through thickness fenestrations that serve as drug reservoirs for passive delivery via diffusive transport from fast-dissolving coatings are demonstrated. Details regarding device design, fabrication, and mechanical testing are presented, as are results from preliminary coating characterization and insertion testing in ex vivo rabbit cornea. PMID- 23367437 TI - Enhanced directionality of bio-hybrid mobile microrobots using non-spherical body geometries. AB - Mobile microrobots are envisioned to be employed for several applications including drug delivery, diagnostic imaging and environmental monitoring. In the bio-hybrid microrobot that is presented here, microparticles are used as the body of the microrobot and bacterial cells are utilized to realize on-board actuation. In this work, the importance of body shape on the dynamics of bacteria-propelled swimming microrobots (BacteriaBots) is investigated. We have shown that, with the use of non-spherical microparticles, average directionality of the BacteriaBots is enhanced compared with the spherical BacteriaBots. PMID- 23367436 TI - Feasibility of multiplex quantum dot stain using primary antibodies from four distinct host animals. AB - We discuss the feasibility of multiplex QD stain for four biomarkers and our progress in finding four suitable biomarkers from four different hosts. There is a demand for using more than three fluorescent probes on a single tissue sample for disease detection to offer a more reliable prediction of disease progression. We developed a protocol for targeting four biomarkers using four primary antibodies from four different animal hosts. We performed primary-secondary antibody binding assays on nitrocellulose paper and stained breast cancer microarray slides with known expression of ER, PR, and HER2. We identified the lack of a standard protocol and the limited supply of primary antibodies from hosts other than rabbit and mouse in the market as key challenges. The results show variable success in both assays, but indicate future potential for this protocol with more development. PMID- 23367438 TI - High performance 3-coil wireless power transfer system for the 512-electrode epiretinal prosthesis. AB - The next-generation retinal prostheses feature high image resolution and chronic implantation. These features demand the delivery of power as high as 100 mW to be wireless and efficient. A common solution is the 2-coil inductive power link, used by current retinal prostheses. This power link tends to include a larger size extraocular receiver coil coupled to the external transmitter coil, and the receiver coil is connected to the intraocular electrodes through a trans-sclera trans-choroid cable. In the long-term implantation of the device, the cable may cause hypotony (low intraocular pressure) and infection. However, when a 2-coil system is constructed from a small-size intraocular receiver coil, the efficiency drops drastically which may induce over heat dissipation and electromagnetic field exposure. Our previous 2-coil system achieved only 7% power transfer. This paper presents a fully intraocular and highly efficient wireless power transfer system, by introducing another inductive coupling link to bypass the trans-sclera trans-choroid cable. With the specific equivalent load of our customized 512 electrode stimulator, the current 3-coil inductive link was measured to have the overall power transfer efficiency around 36%, with 1-inch separation in saline. The high efficiency will favorably reduce the heat dissipation and electromagnetic field exposure to surrounding human tissues. The effect of the eyeball rotation on the power transfer efficiency was investigated as well. The efficiency can still maintain 14.7% with left and right deflection of 30 degree during normal use. The surgical procedure for the coils' implantation into the porcine eye was also demonstrated. PMID- 23367439 TI - Finite Element study of skin and fat delineation in an obese subject for transcranial Direct Current Stimulation. AB - Because of pilot data suggesting the efficacy of transcranial Direct Current Stimulation (tDCS) in treating a range of neuropsychiatric disorders as well as in controlling cravings, there is interest to apply to obese subjects. The abnormal thickness of fat that exist in obese subjects may influence current delivery from scalp electrodes to the brain. MRI-derived Finite Element (FE) models of a morbidly obese subject were created with and without fat delineated. The inclusion of fat to the FE model reduced the effective volume of the relatively conductive skin. This led to greater current penetration to the cortical surface. Electric field was substantially greater (60%) in magnitude and a difference in the spatial profile was noted in the model with fat. Additional models testing the effect of varying fat conductivity revealed an inflection in current penetration as fat conductivity is varied. It was postulated that this may be due to a shunting effect both when the shell of fat surrounding the skull is too resistive for penetration and when the fat is so conductive as to lead current around rather than through the head. Precise FE tDCS model of obese patients requires the precise inclusion of fat. PMID- 23367440 TI - Moving coil pressure algometer produces consistent force gradient and repeated stimulation. AB - Computer-controlled pressure stimulation (algometry) offers seemingly good reliability when it comes to pain assessment methods. It is therefore important to ensure through methodological quantification that moving coil pressure algometer (MCPA) exhibits accurate, fast, and precise tissue stimulation techniques. This study 1) demonstrates that MCPA satisfies force gradient capabilities of a conventional computer-controlled algometry, and 2) reports on effectiveness of the MCPA to produce sustained, fast, and repeated stimulation of a known pulse duration (600 ms) and force magnitude (10 kg). Solicited force gradients of 500, 1000, and 1800 g/s showed high correlation values (R(2) > 0.99) for both rubber mat and direct probe-to-sensor contact cases. Through fast switching between different modes of operation of the actuator, force overshoot was reduced from as much as 300 to 20% for the same force magnitude, at the expense of a slight delay in repeated pulse delivery scheme. PMID- 23367441 TI - A wirelessly programmable chip for multi-channel neural stimulation. AB - This paper presents an implantable inductively powered mix-signal chip for neural stimulation, which is implemented in 0.35-um high-voltage CMOS process. It features 16 stimulating channels and a maximum stimulating rate of 15Kbps. The frequency, amplitude and width of stimulating pulses are all wirelessly programmable. Charge balance is guaranteed by a flexible switch array at the stimulating output stage. And to reduce power consumption, a dual-voltage-source scheme is adopted also at the stimulating output stage. Measurement results show that the proposed chip consumes less than 1mA at typical working conditions. PMID- 23367442 TI - Percutaneously injectable fetal pacemaker: electrodes, mechanical design and implantation. AB - We are developing a self-contained cardiac pacemaker with a small, cylindrical shape (~3 * 20 mm) that permits it to be implanted percutaneously into a fetus to treat complete heart block and consequent hydrops fetalis, which is otherwise fatal. The device uses off-the-shelf components including a rechargeable lithium cell and a highly efficient relaxation oscillator encapsulated in epoxy and glass. A corkscrew electrode made from activated iridium can be screwed into the myocardium, followed by release of the pacemaker and a short, flexible lead entirely within the chest of the fetus to avoid dislodgement from fetal movement. The feasibility of implanting the device percutaneously under ultrasonic imaging guidance was demonstrated in acute adult rabbit experiments. PMID- 23367443 TI - Magnetic resonance based noninvasive RF nerve stimulator. AB - A noninvasive method of stimulating the nerve by applying radiofrequency has been presented. The design is based on the concept of magnetic resonance based power transfer. A comparison between electric field on the nerve at the frequency of 450-550 KHz with vacuum placed under a human tissue and the case where it is replaced with a resonant and non-resonant structure was analysed. Calculations were performed by using Ansoft HFSS. Power savings of 7.15% was observed when resonant structures were used, compared to vacuum. Theoretical calculation and simulation of fields were presented. PMID- 23367445 TI - Modeling of the nervous system: from modulation of glutamatergic and gabaergic molecular dynamics to neuron spiking activity. AB - One of the fundamental characteristics of the brain is its hierarchical and temporal organization: scales in both space and time must be considered to fully grasp the system's underlying mechanisms and their impact on brain function. Complex interactions taking place at the molecular level regulate neuronal activity that further modifies the function of millions of neurons connected by trillions of synapses, ultimately giving rise to complex function and behavior at the system level. Likewise, the spatial complexity is accompanied by a complex temporal integration of events taking place at the microsecond scale leading to slower changes occurring at the second, minute and hour scales. These integrations across hierarchies of the nervous system are sufficiently complex to have impeded the development of routine multi-level modeling methodologies. The present study describes an example of our multiscale efforts to rise from the biomolecular level to the neuron level. We more specifically describe how we integrate biomolecular mechanisms taking place at glutamatergic and gabaergic synapses and integrate them to study the impact of these modifications on spiking activity of a CA1 pyramidal cell in the hippocampus. PMID- 23367446 TI - Integrating degenerative mechanisms in bone and cartilage: a multiscale approach. AB - At the whole organ level, degenerative mechanisms in bone and cartilage are primarily attributed to modifications in loading pattern. Either a change in magnitude or location can initiate a degenerative path. At the micro scale we often see changes in structure such as porosity increase in bone and fibrillation in cartilage. These changes contribute to a reduced structural integrity that weakens the bulk strength of tissue. Finally, at the cell level we have modeling and remodeling pathways that may be disrupted through disease, drugs and altered stimulus from the micro and macro scales. In order to understand this entire process and the roles each level plays a multiscale modeling framework is necessary. This framework can take whole body loadings and pass information through finer spatial scales in order to understand how everyday dynamic movements influence micro and cellular response. In a similar manner, cellular and microstructural processes regulate whole bulk properties and modify whole organ strength. In this study we highlight the multiscale links developed as part of the open-source ontologies for the Physiome Project using the lower limb as an example. We consider the influence of remodeling in (i) anabolic treatments in cortical bone; and (ii) subchondral bone and cartilage degeneration. PMID- 23367447 TI - A computational multiscale model of glioblastoma growth: regulation of cell migration and proliferation via microRNA-451, LKB1 and AMPK. AB - A new computational multiscale model of glioblastoma growth is introduced. This model combines an agent-based model for representing processes on the cellular level with a molecular interaction network for each cell on the subcellular scale. The network is based on recently published work on the interaction of microRNA-451, LKB1 and AMPK in the regulation of glioblastoma cell migration and proliferation. We translated this network into a mathematical description by the use of 17 ordinary differential equations. In our model, we furthermore establish a link from the molecular interaction network of a single cell to cellular actions (e.g. chemotactic movement) on the microscopic level. First results demonstrate that the computational model reproduces a tumor cell development comparable to that observed in in vitro experiments. PMID- 23367448 TI - A program code generator for multiphysics biological simulation using markup languages. AB - To cope with the complexity of the biological function simulation models, model representation with description language is becoming popular. However, simulation software itself becomes complex in these environment, thus, it is difficult to modify the simulation conditions, target computation resources or calculation methods. In the complex biological function simulation software, there are 1) model equations, 2) boundary conditions and 3) calculation schemes. Use of description model file is useful for first point and partly second point, however, third point is difficult to handle for various calculation schemes which is required for simulation models constructed from two or more elementary models. We introduce a simulation software generation system which use description language based description of coupling calculation scheme together with cell model description file. By using this software, we can easily generate biological simulation code with variety of coupling calculation schemes. To show the efficiency of our system, example of coupling calculation scheme with three elementary models are shown. PMID- 23367449 TI - An architecture for integrating cancer model repositories. AB - The TUMOR project aims at developing a European clinically oriented semantic layered cancer digital model repository from existing EU projects that will be interoperable with the US grid-enabled semantic-layered digital model repository platform at CViT.org (Center for the Development of a Virtual Tumor, Massachusetts General Hospital (MGH), Boston, USA) which is NIH/NCI-caGRID compatible. In this paper we describe the modular and federated architecture of TUMOR that effectively addresses model integration, interoperability, and security related issues. PMID- 23367450 TI - Valvular closure prediction using anisotropic and hyperelastic tissue models and individualized anatomy derived from RT3DE. AB - We describe a method for modeling the closure of the Mitral Valve (MV) and to compute realistic strain and stresses in MV tissues. This informs preoperative planning by allowing a surgeon to evaluate various MV repairs options. The modeling method exploits individualized (patient-specific) anatomical structure recovered from real-time 3D echocardiography (RT3DE). This study utilizes hyperelastic models of the MV tissues and employs patient specific leaflets, chordal length assessment and annulus shapes. We report experiments on ten intraoperative test cases, where we compute strain and stresses using several different tissue models from MV empirical studies by May-Newman and Holzapfel. PMID- 23367451 TI - A personalized mitral valve closure simulator. AB - We describe a method for performing modeling and simulation to predict the closure of the Mitral Valve (MV) using patient specific anatomical information derived from 3D Transesophageal Echocardiography (3D TEE). The ability to predict the MV closure behavior is an important step along the way of developing personalized simulation tools that would allow a surgeon to perform preoperative planning and decide between various MV repair options. While the MV is an important use case because of its relevance and prevalence among reconstructive cardiac interventions, the study described here can provide a blueprint to perform pre-operative planning for other cardiac surgical interventions. The method reported here exploits the Saint Venant-Kirchhoff elasticity model that is tuned to match empirical observations of the MV strainstress behavior. Using intraoperative 3D TEE data, the proposed simulator was evaluated over 10 test cases and resulted in mean prediction absolute error values of 1.81 mm. PMID- 23367452 TI - In vitro characterization of an aortic bioprosthetic valve using Doppler echocardiography and qualitative flow visualization. AB - A 19 mm diameter prototype bioprosthetic valve mounted in a cardiac pulse duplicator was characterized using Doppler echocardiography and qualitative flow visualization at a heart rate of 72 bpm. Analysis of the flow visualization images revealed that the prototype and control valve leaflets open symmetrically but close asymmetrically. The asymmetry in the closing of the valves is likely due to the large pressure gradients across the valves and may have implications for the long term mechanical failure of the valves. The relatively high peak systolic velocity of 309.9 cm/s, which was measured in the prototype 19 mm valve, can be attributed to the small valve diameter and the high cardiac output used in the current study. PMID- 23367453 TI - Virtual experiments of heart valve tissues. AB - The heart valve tissue mainly contains collagen fibers and valve interstitial cells (VICs) and constantly experiences different stress states during cardiac cycles. Due to the anisotropic architecture of collagen fibers and highly inhomogeneous cell population, the mechanical behavior of the heart valve becomes more complicated. It is known that external mechanical stimuli can lead to extracellular matrix (ECM) remodeling, cellular mechanotransduction, cell migration, and collagen synthesis; however, the mechanism of matrix-to-cell stress transfer remains unclear. Current study presents heterogeneously distributed collagen fibers responsible for transmitting forces into cells by an image-based finite element analysis incorporating histological photomicrographs of porcine heart valve tissues. Besides, nonlinear and anisotropic material properties tissue models are incorporated to quantify and visualize the overall stress distributions in heart valve tissues. By establishing an effectively predictive method with new computational tools and by performing virtual experiments on the heart valves, the role of load transmission in heart valves is clarified. The current study completely illustrates the stress distribution around cells and demonstrates the force transmission and reception between cells and matrix in the heart valve tissue. Therefore, our developed image-based finite element models provide new insights not only into clarifying the role of the force transmission and reception between heterogeneously distributed collagen fibers, but also a better understanding of relationships between the mechanical stimuli, cellular mechanotransduction, cell migration, matrix synthesis, and tissue remodeling in heart valves. PMID- 23367454 TI - Examination of mitral regurgitation with a goat heart model for the development of intelligent artificial papillary muscle. AB - Annuloplasty for functional mitral or tricuspid regurgitation has been made for surgical restoration of valvular diseases. However, these major techniques may sometimes be ineffective because of chamber dilation and valve tethering. We have been developing a sophisticated intelligent artificial papillary muscle (PM) by using an anisotropic shape memory alloy fiber for an alternative surgical reconstruction of the continuity of the mitral structural apparatus and the left ventricular myocardium. This study exhibited the mitral regurgitation with regard to the reduction in the PM tension quantitatively with an originally developed ventricular simulator using isolated goat hearts for the sophisticated artificial PM. Aortic and mitral valves with left ventricular free wall portions of isolated goat hearts (n=9) were secured on the elastic plastic membrane and statically pressurized, which led to valvular leaflet-papillary muscle positional change and central mitral regurgitation. PMs were connected to the load cell, and the relationship between the tension of regurgitation and PM tension were measured. Then we connected the left ventricular specimen model to our hydraulic ventricular simulator and achieved hemodynamic simulation with the controlled tension of PMs. PMID- 23367455 TI - Real-time strain mapping via biaxial stretching in heart valve tissues. AB - Previous studies show that the collagen fiber architecture is key to the heart valves tissue mechanical property. We report a real-time strain mapping approach that provides displacement vectors and principal strain directions during the mechanical characterization of heart valve tissues. The strain maps reported in the current study allows an individual to quickly identify the approximate strain imposed on a location of the sample. The result shows that when samples are biaxially stretched under 18% strain, less anisotropy is observed in both aortic and pulmonary valve leaflet samples. Moreover, when samples are stretched from 28% to 35%, pulmonary valves leaflet samples exhibits a stronger anisotropic effect than aortic valve. Therefore, a higher degree of straightening is required for collagen fibers to be fully aligned. This work provides an easy approach to quantify mechanical properties with the corresponding strain maps of heart valve tissues and potentially facilitates the developments of tissue engineering heart valves. PMID- 23367456 TI - Ventilatory and cardiac responses to pulmonary embolism: consequences for gas exchange and blood pressure. AB - Acute thromboembolic pulmonary embolism (PE) is a life threatening condition that can lead to pulmonary hypertension and right ventricular dysfunction or failure. There is typically an increase in ventilation rate and cardiac output as a response to PE prior to cardiac failure, which is at least in part due to systemic hypoxemia. Here we assess the response of the lungs to changes in these parameters using anatomically-based computational models of pulmonary perfusion, ventilation and gas exchange. We show that increases in ventilation and cardiac output improve overall gas exchange in PE. However, this comes at the cost of an increased pulmonary blood pressure, which may contribute to pulmonary hypertension as a result of PE. PMID- 23367457 TI - Assessment of hemodynamic load components affecting optimization of cardiac resynchronization therapy by lumped parameter mode. AB - Timing of biventricular pacing devices employed in cardiac resynchronization therapy (CRT) is a critical determinant of efficacy of the procedure. Optimization is done by maximizing function in terms of arterial pressure (BP) or cardiac output (CO). However, BP and CO are also determined by the hemodynamic load of the pulmonary and systemic vasculature. This study aims to use a lumped parameter circulatory model to assess the influence of the arterial load on the atrio-ventricular (AV) and inter-ventricular (VV) delay for optimal CRT performance. PMID- 23367458 TI - A framework for personalization of coronary flow computations during rest and hyperemia. AB - We introduce a Computational Fluid Dynamics (CFD) based method for performing patient-specific coronary hemodynamic computations under two conditions: at rest and during drug-induced hyperemia. The proposed method is based on a novel estimation procedure for determining the boundary conditions from non-invasively acquired patient data at rest. A multi-variable feedback control framework ensures that the computed mean arterial pressure and the flow distribution matches the estimated values for an individual patient during the rest state. The boundary conditions at hyperemia are derived from the respective rest-state values via a transfer function that models the vasodilation phenomenon. Simulations are performed on a coronary tree where a 65% diameter stenosis is introduced in the left anterior descending (LAD) artery, with the boundary conditions estimated using the proposed method. The results demonstrate that the estimation of the hyperemic resistances is crucial in order to obtain accurate values for pressure and flow rates. Results from an exhaustive sensitivity analysis have been presented for analyzing the variability of trans-stenotic pressure drop and Fractional Flow Reserve (FFR) values with respect to various measurements and assumptions. PMID- 23367459 TI - Spontaneous autoresuscitation in a model of respiratory control. AB - We introduce a closed-loop model of respiratory control incorporating a conductance-based central pattern generator (CPG), low-pass filtering of CPG output by the respiratory musculature, gas exchange in the lung, metabolic oxygen demand, and chemosensation. The CPG incorporates Butera, Rinzel and Smith (BRS)'s (1999) conditional pacemaker model. BRS model cells can support quiescent, bursting, or beating activity depending on the level of excitatory drive; we identify these activity modes with apnea (cessation of breathing), eupnea (normal breathing), and tachypnea (excessively rapid breathing). We demonstrate the coexistence of two dynamically stable behaviors in the closed-loop model, corresponding respectively to eupnea and tachypnea. The latter state represents a novel failure mode within a respiratory control model. In addition, the closed loop system exhibits a form of autoresuscitation: conductances intrinsic to the BRS model buffer the CPG against brief episodes of hypoxia, steering the system away from catastrophic collapse as can occur with tachypnea. PMID- 23367460 TI - Simulation of the Fontan circulation during rest and exercise. AB - The Fontan palliation was introduced as surgical repair method for tricuspid atresia, creating a univentricular serial circulation. However, it is used as treatment for other life threatening complex congenital heart diseases as well. The variation of underlying pathologies treated with this palliation makes optimization difficult. To assist the optimization process, we adjusted a lumped parameter computational model of the biventricular circulation (CircAdapt) and evaluated the univentricular circulation. The model simulates beat-to-beat dynamics of the two cardiac chambers, the valves, and the systemic and pulmonary circulations. The univentricular circulation in rest and exercise was simulated. Exercise resulted in increased stroke volume, heart rate, pulse pressure, and stressed blood volume. Central venous pressure rose as a result of the constant pulmonary resistance, reducing systemic pressure drop. Reduced systemic pressure drop implies either reduction of systemic flow or further decrease of systemic resistance. Based on our simulation results, we conclude that exercise capacity in Fontan patients is limited due to increase of central venous pressure and the impossibility to reduce systemic resistance further, restricting systemic flow. PMID- 23367461 TI - Effect of saccular aneurysm and parent artery morphology on hemodynamics of cerebral bifurcation aneurysms. AB - Morphological descriptors of aneurysms have been used to assess aneurysm rupture. This study investigated the relation between the morphological parameters and the flow related parameter of energy loss (EL). Four size indices and one shape index were assessed in idealized middle cerebral artery models with various aneurysm morphologies. Four patient-specific aneurysms (2 ruptured, 2 unruptured) were virtually manipulated by removing the aneurysms from their parent arteries and merging them with the idealized bifurcation models. EL was calculated from the energy difference between inflow and outflow. The results indicate that among size indices, EL is mostly dependent on bottleneck factor and less dependent on the aspect ratio. Results also showed that there is a direct relationship between nonsphericity index (NSI) and EL in manipulated models. No specific correlation was found between EL and NSI in patient-specific models. PMID- 23367462 TI - Detecting stumbles with a single accelerometer. AB - Falls are a common problem in the elderly population, and their prediction has been a major interest for the medical field. The relationship between stumbles and falls has not been very well understood yet. A critical requirement in advancing the study of this relationship is the realization of a realistic and effective stumble detection system. In this paper, we present a system for the detection of stumbles during walking. Our system consists of a single low cost triaxial accelerometer that may be worn by patients and is convenient for a wide range of subjects. We formulate the problem as an anomaly detection and we validate our system with a large data set collected from 9 subjects. The data set contains a total of 100 stumbles and 45 minutes of walking. We compare 7 different placements for the accelerometer, and show that our system achieves a 99% detection rate, with a 0.2% false alarm rate using an accelerometer worn on the chest. PMID- 23367463 TI - Sensor architectural tradeoff for diabetic foot ulcer monitoring. AB - The diabetic foot complications constitute a tremendous challenge for patients, caregivers, and the healthcare system. Studies show up to 25% of diabetic individuals will develop a foot ulcer during their lifetime and many of these patients eventually must undergo amputation as a result of infection due to untreated foot ulcers. With current technology, in-shoe monitoring systems can be implemented to continuously monitor at-risk ulceration sites based on known indicators such as peak pressure. The important parameters in designing a pressure-sensing insole include the number, location and size of sensors. In this paper, we aim at showing the criticality of sensor architectural tradeoff in developing the in-shoe plantar pressure monitoring systems. We evaluate this tradeoff by using our custom-made platform for data collection during normal walking. PMID- 23367464 TI - On the deconvolution analysis of electrodermal activity in bipolar patients. AB - People affected by bipolar disorders experience alternating states of depression with episodes of mania or hypomania. This mental can lead to a poor handling of daily routines, can worsen personal relationships, and often can be life threatening. This preliminary study aims at investigating how the autonomic nervous system, in terms of electrodermal activity, responds to specific controlled emotional stimuli in bipolar patients. More specifically, we present here a method to deploy the analysis of ElectroDermal Activity (EDA) to discriminate clinical mood states. EDA was analyzed by using a deconvolution method to separate tonic from phasic components. The three subjects recruited and the experimental protocol used here is part of the European project PSYCHE. Preliminary results show that the bipolar mood states can be related to electrodermal tonic activity. PMID- 23367465 TI - Vital analysis: annotating sensed physiological signals with the stress levels of first responders in action. AB - First responders such as firefighters are exposed to extreme stress and fatigue situations during their work routines. It is thus desirable to monitor their health using wearable sensing but this is a complex and still unsolved research challenge that requires large amounts of properly annotated physiological signals data. In this paper we show that the information gathered by our Vital Analysis Framework can support the annotation of these vital signals with the stress levels perceived by the target user, confirmed by the analysis of more than 4600 hours of data collected from real firefighters in action, including 717 answers to event questionnaires from a total of 454 different events. PMID- 23367466 TI - Limb joint effects on signal transmission in capacitive coupled intra-body communication systems. AB - This paper contributes empirical measurements towards an understanding of signal attenuation in intra-body communication (IBC) systems due to limb posture effects. Recent studies have shown a degradation of transmission signals for IBC transmissions between limb segments, but these degradations have yet to be quantified with respect to relative limb position and within the transmission frequency range from 300 KHz to 200 MHz. We examine the impact of limb position specifically the effect of elbow joint flexion and extension into account using a portable vector network analyzer. The results presented indicate that the signal attenuation is larger in the case of extension, i.e., when the angle between forearm and upper arm increases. The minimum attenuation was 20.64 dB and 24.81 dB for the fix distance of 15 cm between transmitter and receiver electrodes and the joint angle of 45 and 180 degree respectively. It was found that attenuation decreased at an approximately linear rate over 300 KHz to 100 MHz and increased over the frequency range from 100 MHz to 200 MHz for the input signal frequency range from 300 KHz to 200 MHz. It was concluded that the minimum attenuation for the range of flexions and extensions occurred in the range 80-100 MHz. Future work will explore theoretical models to explain the observed results. PMID- 23367467 TI - Instantaneous Heart Rate detection using short-time autocorrelation for wearable healthcare systems. AB - This report describes a robust method of Instantaneous Heart Rate (IHR) detection from noisy electrocardiogram (ECG) signals. Generally, the IHR is calculated from the interval of R-waves. Then, the R-waves are extracted from the ECG using a threshold. However, in wearable biosignal monitoring systems, various noises (e.g. muscle artifacts from myoelectric signals, electrode motion artifacts) increase incidences of misdetection and false detection because the power consumption and electrode distance of the wearable sensor are limited to reduce its size and weight. To prevent incorrect detection, we use a short-time autocorrelation technique. The proposed method uses similarity of the waveform of the QRS complex. Therefore, it has no threshold calculation Process and it is robust for noisy environment. Simulation results show that the proposed method improves the success rate of IHR detection by up to 37%. PMID- 23367468 TI - Exploring the use of tactile feedback in an ERP-based auditory BCI. AB - Giving direct, continuous feedback on a brain state is common practice in motor imagery based brain-computer interfaces (BCI), but has not been reported for BCIs based on event-related potentials (ERP), where feedback is only given once after a sequence of stimuli. Potentially, direct feedback could allow the user to adjust his strategy during a running trial to obtain the required response. In order to test the usefulness of such feedback, directionally congruent vibrotactile feedback was given during an online auditory BCI experiment. Users received either no feedback, short feedback pulses or continuous feedback. The feedback conditions showed reduced performance both on a behavioral task and in terms of classification accuracy. Several explanations are discussed that give interesting starting points for further research on this topic. PMID- 23367469 TI - Learning to modulate sensorimotor rhythms with stereo auditory feedback for a brain-computer interface. AB - Motor imagery can be used to modulate sensorimotor rhythms (SMR) enabling detection of voltage fluctuations on the surface of the scalp using electroencephalographic (EEG) electrodes. Feedback is essential in learning how to intentionally modulate SMR in non-muscular communication using a brain computer interface (BCI). A BCI that is not reliant upon the visual modality for feedback is an attractive means of communication for the blind and the vision impaired and to release the visual channel for other purposes during BCI usage. The aim of this study is to demonstrate the feasibility of replacing the traditional visual feedback modality with stereo auditory feedback. Twenty participants split into equal groups took part in ten BCI sessions involving motor imagery. The visual feedback group performed best using two performance measures but did not show improvement over time whilst the auditory group improved as the study progressed. Multiple loudspeaker presentation of audio allows the listener to intuitively assign each of two classes to the corresponding lateral position in a free-field listening environment. PMID- 23367470 TI - Simultaneous brain-computer interfacing and motor control: expanding the reach of non-invasive BCIs. AB - Brain-computer interfaces (BCIs) have traditionally been developed for paralyzed and locked-in individuals with no motor control. However, there is a much larger population of patients with some residual motor function as well as the general population of able-bodied individuals, both of whom could benefit significantly from BCIs. An important question that has yet to be systematically studied is: can subjects use BCIs simultaneously with overt motor activity? We present results from a preliminary study aimed at exploring this question. Three subjects used hand motor imagery in an electroencephalographic (EEG) BCI while simultaneously using a joystick to control a cursor. Particular attention was paid to preventing potential muscle artifacts from influencing imagery-based control. All three subjects were able to use the hybrid "imagery+joystick" mode of control over two days, demonstrating the ability to learn and significantly improve performance. These results suggest that subjects can potentially augment their normal human sensorimotor capability by exercising direct brain control over devices concurrently with overt motor control. PMID- 23367471 TI - Control of a biomimetic brain machine interface with local field potentials: performance and stability of a static decoder over 200 days. AB - Brain-machine interfaces (BMIs) have the potential to restore lost function to individuals with severe motor impairments. An important design specification for BMIs to be clinically useful is the ability to achieve high performance over a period of months to years without requiring frequent recalibration. Here, we report the first successful implementation of a biomimetic BMI based on local field potentials (LFPs). A BMI decoder was built from a single recording session of a random-pursuit reaching task for each of two monkeys, and used to control cursor position in real time (online) over a span of 210 days. Performance using this BMI was similar to prior reports using BMIs based on single-unit spikes for 2D cursor control. During this ongoing study, target acquisition rates remained constant (in 1 monkey) or improved slightly (1 monkey) over a 7 month span, and performance metrics of cursor movement (path length and time-to-target) also remained constant or showed mild improvement as the monkeys gained practice. Based on these results, we expect that a stable, high-performance BMI based on LFP signals could serve as a viable alternative to single-unit based BMIs. PMID- 23367472 TI - Anticipation- and error-related EEG signals during realistic human-machine interaction: a study on visual and tactile feedback. AB - The exploitation of EEG signatures of cognitive processes can provide valuable information to improve interaction with brain actuated devices. In this work we study these correlates in a realistic situation simulated in a virtual reality environment. We focus on cortical potentials linked to the anticipation of future events (i.e. the contingent negative variation, CNV) and error-related potentials elicited by both visual and tactile feedback. Experiments with 6 subjects show brain activity consistent with previous studies using simpler stimuli, both at the level of ERPs and single trial classification. Moreover, we observe comparable signals irrespective of whether the subject was required to perform motor actions. Altogether, these results support the possibility of using these signals for practical brain machine interaction. PMID- 23367473 TI - Control of a simulated wheelchair based on a hybrid brain computer interface. AB - In this paper, a hybrid BCI system was described for the control of a simulated wheelchair. This hybrid BCI was based on the motor imagery-based mu rhythm and the P300 potential. With our paradigm, the user may perform left- or right-hand imagery to control the direction (left or right turn) of the simulated wheelchair. Furthermore, a hybrid manner was used for speed control: e.g., foot imagery without button attention for deceleration and a specific button attention without any motor imagery for acceleration. An experiment based on a simulated wheelchair in virtual environment was conducted to assess the BCI control. Subjects effectively steered the simulated wheelchairs by controlling the direction and speed with our hybrid BCI system. Data analysis validated that our hybrid BCI system can be used to control the direction and speed of a simulated wheelchair. PMID- 23367474 TI - Beamforming approach to phase-amplitude modulation analysis of multi-channel EEG. AB - Phase-amplitude modulation is a form of cross frequency coupling where the phase of one frequency influences the amplitude of another higher frequency. It has been observed in neurophysiological recordings during sensory, motor, and cognitive tasks, as well as during general anesthesia. In this paper, we describe a novel beamforming procedure to improve estimation of phase-amplitude modulation. We apply this method to 64-channel EEG data recorded during propofol general anesthesia. The method improves the sensitivity of phase-amplitude analyses, and can be applied to a variety of multi-channel neuroscience data where phase-amplitude modulation is present. PMID- 23367475 TI - Stability of ICA decomposition across within-subject EEG datasets. AB - Independent Component Analysis (ICA) has been successfully used to identify brain related signals and artifacts from multi-channel electroencephalographic (EEG) data. However the stability of ICA decompositions across sessions from a single subject has not been investigated. The goal of this study was to isolate EEG independent components (ICs) across sessions for each subject so as to assess whether ICs are reproducible across sessions. We used 64-channel EEG data recorded from two subjects during a simple mind-wandering experiment. Each subject participated in 11 twenty-minute sessions over a period of five weeks. Extended Infomax ICA decomposition was performed on the continuous data of each session. We used a simple IC clustering technique based on correlation of scalp topographies. Several clusters of homogenous components were identified for each subject. Typical component clusters accounting for eye movement and eye blink artifacts were identified. Both clusters included one component from each recording session. In addition, several clusters corresponding to brain electrical sources, among them clusters exhibiting prominent alpha, beta and Mu band activities, included components from most sessions. These results present evidence that ICA can provide relatively stable solutions across sessions, with important implications for Brain Computer Interface research. PMID- 23367476 TI - Improved recognition of error related potentials through the use of brain connectivity features. AB - Brain error processing plays a key role in goal-directed behavior and learning in human brain. Directed transfer function (DTF) on EEG signal brings unique features for discrimination between correct and error cases in brain-computer interface (BCI) system. We describe the first application of brain connectivity features for recognizing error-related signals in non-invasive BCI. EEG signal were recorded from 16 human subjects when they monitored stimuli moving in either correct or erroneous direction. Classification performance using waveform features, brain connectivity features and their combination were compared. The result of combined features yielded highest classification accuracy, 0:85. In addition, we also show that brain connectivity at theta band around 200 ms after stimuli carry highly discriminant information between error and correct trials. This paper provides evidence that the use of connectivity features improve the performance of an EEG based BCI. PMID- 23367477 TI - Evaluations of sparse source imaging and minimum norm estimate methods in both simulation and clinical MEG data. AB - The aim of the present study is to evaluate the capability of a recently proposed l(1)-norm based regularization method, named as variation-based sparse cortical current density (VB-SCCD) algorithm, in estimating location and spatial coverage of extensive brain sources. Its performance was compared to the conventional minimum norm estimate (MNE) using both simulations and clinical interictal spike MEG data from epilepsy patients. Four metrics were adopted to evaluate two regularization methods for EEG/MEG inverse problems from different aspects in simulation study. Both methods were further compared in reconstructing epileptic sources and validated using results from clinical diagnosis. Both simulation and experimental results suggest VB-SCCD has better performance in localization and estimation of source extents, as well as less spurious sources than MNE, which makes it a promising noninvasive tool to assist presurgical evaluation for surgical treatment in epilepsy patients. PMID- 23367478 TI - A fast iterative greedy algorithm for MEG source localization. AB - Recent dynamic source localization algorithms for the Magnetoencephalographic inverse problem use cortical spatio-temporal dynamics to enhance the quality of the estimation. However, these methods suffer from high computational complexity due to the large number of sources that must be estimated. In this work, we introduce a fast iterative greedy algorithm incorporating the class of subspace pursuit algorithms for sparse source localization. The algorithm employs a reduced order state-space model resulting in significant computational savings. Simulation studies on MEG source localization reveal substantial gains provided by the proposed method over the widely used minimum-norm estimate, in terms of localization accuracy, with a negligible increase in computational complexity. PMID- 23367479 TI - A spatially-regularized dynamic source localization algorithm for EEG. AB - Cortical activity can be estimated from electroencephalogram (EEG) or magnetoencephalogram (MEG) data by solving an ill-conditioned inverse problem that is regularized using neuroanatomical, computational, and dynamic constraints. Recent methods have incorporated spatio-temporal dynamics into the inverse problem framework. In this approach, spatio-temporal interactions between neighboring sources enforce a form of spatial smoothing that enhances source localization quality. However, spatial smoothing could also occur by way of correlations within the state noise process that drives the underlying dynamic model. Estimating the spatial covariance structure of this state noise is challenging, particularly in EEG and MEG data where the number of underlying sources is far greater than the number of sensors. However, the EEG/MEG data are sparse compared to the large number of sources, and thus sparse constraints could be used to simplify the form of the state noise spatial covariance. In this work, we introduce an empirically tailored basis to represent the spatial covariance structure within the state noise processes of a cortical dynamic model for EEG source localization. We augment the method presented in Lamus, et al. (2011) to allow for sparsity enforcing priors on the covariance parameters. Simulation studies as well as analysis of real data reveal significant gains in the source localization performance over existing algorithms. PMID- 23367480 TI - Electrodermal response propagation time as a potential psychophysiological marker. AB - Electrodermal activity is amongst the main psychophysiological arousal indicators used in clinical and affective computing application scenarios. This is mostly due to the relation between the skin conductance responses and the autonomic nervous system activity, in particular, the sympathetic subsystem operation. Although thermal regulation is also controlled by these components of the nervous system, which is expressed as a tonic variation in the electrodermal activity signals, reactions to psychological stimuli can also be detected, in this case, expressed as phasic variations. So far, there is still no clear consensus regarding the relation between the specific responses of the autonomic nervous system activity, and the features typically extracted from the electrodermal activity signals. Therefore, signal processing and feature extraction have been active research topics in the field. In this paper we present an experimental setup and corresponding data analysis for electrodermal response propagation time measurement. Experimental results have revealed interesting properties in this signal, enhancing its potential as a psychophysiological marker, and thus further expanding the toolbox for researchers in the field. PMID- 23367481 TI - A fast Adaptive-Gain Orientation Filter of inertial/magnetic data for human motion tracking in free-living environments. AB - High-resolution, real-time data obtained by human motion tracking systems can be used for gait analysis, which helps better understanding the cause of many diseases for more effective treatments, such as rehabilitation for outpatients or recovery from lost motor functions after a stroke. This paper presents an analytically derived method for an adaptive-gain complementary filter based on the convergence rate from the Gauss-Newton optimization algorithm (GNA) and the divergence rate from the gyroscope, which is referred as Adaptive-Gain Orientation Filter (AGOF) in this paper. The AGOF has the advantages of one iteration calculation to reduce the computing load and accurate estimation of gyroscope measurement error. Moreover, for handling magnetic distortions especially in indoor environments and movements with excessive acceleration, adaptive measurement vectors and a reference vector for Earth's magnetic field selection schemes are introduced to help the GNA find more accurate direction of gyroscope error. Experimental results are presented to verify the performance of the proposed method, which shows better accuracy of orientation estimation than several well-known methods. PMID- 23367482 TI - Exercise training plus calorie restriction causes synergistic protection against cognitive decline via up-regulation of BDNF in hippocampus of stroke-prone hypertensive rats. AB - One of the important organ damage of hypertension is cognitive decline. Cognitive function is determined by the function of hippocampus, and previous studies have suggested that the decrease in brain-derived neurotrophic factor (BDNF) in the hippocampus causes cognitive decline. Protection against cognitive decline is reported not only in pharmacological therapy but also in exercise training or calorie restriction. The aim of the present study was to determine whether exercise training plus calorie restriction cause synergistic protection against cognitive decline via BDNF in the hippocampus or not. Exercise training for 28 days improved cognitive decline determined by Morris water maze test via up regulation of BDNF in the hippocampus of stroke-prone spontaneously hypertensive rats, whereas calorie restriction for 28 days did not. However, exercise training plus calorie restriction causes the protection against cognitive decline to a greater extent than exercise training alone. In conclusion, exercise training plus calorie restriction causes synergistic protection against cognitive decline via up-regulation of BDNF in the hippocampus of stroke-prone hypertensive rats. PMID- 23367483 TI - The effect of aging on human brain spatial processing performance. AB - Cognitive abilities similar to other mental or physical abilities develop and change during the course of life. Spatial processing is a cognitive ability, which has been suggested to deteriorate by age. The focus of this paper is to study the change of real time egocentric spatial processing in humans by age. For this, an interactive computer game played with a 2DOF manipulandum was designed. The game consists of goal-oriented motor tasks, in which the player must move the robot arm toward a desired spatial cue in a virtual 2D environment in every trial for a total number of 72 trials. The spatial cues are four final destinations and a starting location, which change their position in every new trial of the game. 37 individuals with no cognitive impairment were split into 3 groups according to different age range (children, young, and elderly) and participated in this experiment. Their spatial processing ability was assessed and compared between the age groups. The results show the children (7-12 y) and elderly (65(+) y) performed very similar and significantly worse than the young adult participants. PMID- 23367484 TI - A wearable walking monitoring system for gait analysis. AB - In this paper, both hardware and software design to develop a wearable walking monitoring system for gait analysis are presented. For hardware, the mechanism proposed is adaptive to different individuals to wear, and the portability of the design makes it easy to perform outdoor experiments. Four force sensors and two angle displacement sensors were used to measure plantar force distribution and the angles of hip and knee joints. For software design, a novel algorithm was developed to detect different gait phases and the four gait periods during the stance phase. Furthermore, the center of ground contact force was calculated based on the relationships of the force sensors. The results were compared with the VICON motion capture system and a force plate for validation. Experiments showed the behavior of the joint angles are similar to VICON system, and the average error in foot strike time is less than 90 ms. PMID- 23367485 TI - Delayed attentional disengagement from sad face: a study of alpha rhythm by event related desynchronization. AB - This study investigated the influence of different emotional facial cues on the detection of subsequent visual digit targets presented after various cue-target intervals (CTIs). Behavioral results indicated that, compared to neutral faces, happy faces facilitated the response to subsequent tasks only after a short CTI (17 ms), while sad faces would slow or inhibit the processing of following tasks after different CTIs (17, 350, 1000, and 1500 ms). Event-related desynchronization of alpha rhythm (alpha-ERD) showed that the left frontal and parietal cortical areas were more prominently activated by emotional faces than by neutral ones. In particular, happy faces induced more activity in left frontal lobes, starting from the beginning of CTI (post-cue 0~400 ms), while sad faces induced stronger and longer activation during the middle of CTI (post-cue 400~800 ms). Such a later a-ERD in left frontal area suggested that the attentional disengagement was slowed by sad faces. PMID- 23367486 TI - Multi-constrained inverse kinematics for the human hand. AB - Measuring the spatial and temporal characteristics of hand movement is a challenging task due to the large number of degrees of freedom (DOF) in the hand. This paper presents a multi-constrained inverse kinematics (IK) approach for hand motion estimation from motion capture data. The IK approach satisfies a set of prioritized motion and postural constraints for each hand joint and link. The high-priority constraint is fully satisfied, while the fulfillment of the low priority constraints is achieved as long as no conflict with the high-priority constraint exists. The proposed approach can aid marker-based motion capture technologies in accurately reconstructing discontinuities or erroneous marker trajectory segments resulting from occluded, missing, or flipped markers. The performance of the multi-constrained IK approach for the hand is tested for a full range of continuous hand motion. PMID- 23367487 TI - Transfer of learning between the arms during bimanual reaching. AB - This study examined how movement of one arm affects the rate of motor adaptation of the other arm during bimanual reaching in a viscous force-field. Forty healthy adult subjects performed four reaching tasks: (1) by dominant arm, (2) by nondominant arm, (3) by both arms with only dominant arm experiencing force-field and (4) by both arms with only nondominant arm experiencing the force-field. For dominant arm rate of motor adaptation was greater during the bimanual task than the unimanual task. For nondominant arm reaching errors were higher during the bimanual than unimanual task. These results suggest that during bimanual reaching, transfer of learning between arms occur in both directions and movement information transferred depends on arm dominance. PMID- 23367488 TI - Probability density based gradient projection method for inverse kinematics of a robotic human body model. AB - This paper presents the probability density based gradient projection (GP) of the null space of the Jacobian for a 25 degree of freedom bilateral robotic human body model (RHBM). This method was used to predict the inverse kinematics of the RHBM and maximize the similarity between predicted inverse kinematic poses and recorded data of 10 subjects performing activities of daily living. The density function was created for discrete increments of the workspace. The number of increments in each direction (x, y, and z) was varied from 1 to 20. Performance of the method was evaluated by finding the root mean squared (RMS) of the difference between the predicted joint angles relative to the joint angles recorded from motion capture. The amount of data included in the creation of the probability density function was varied from 1 to 10 subjects, creating sets of for subjects included and excluded from the density function. The performance of the GP method for subjects included and excluded from the density function was evaluated to test the robustness of the method. Accuracy of the GP method varied with amount of incremental division of the workspace, increasing the number of increments decreased the RMS error of the method, with the error of average RMS error of included subjects ranging from 7.7 degrees to 3.7 degrees . However increasing the number of increments also decreased the robustness of the method. PMID- 23367489 TI - Lower limb movement asymmetry measurement with a depth camera. AB - The gait movement seems simple at first glance, but in reality it is a very complex neural and biomechanical process. In particular, if a person is affected by a disease or an injury, the gait may be modified. The left-right asymmetry of this movement can be related to neurological diseases, segment length differences or joint deficiencies. This paper proposes a novel method to analyze the asymmetry of lower limb movement which aims to be usable in daily clinical practice. This is done by recording the subject walking on a treadmill with a depth camera and then assessing left-right depth differences for the lower limbs during the gait cycle using horizontal flipping and registration of the depth images half a gait cycle apart. Validation on 20 subjects for normal gait and simulated pathologies (with a 5 cm sole), showed that this system is able to distinguish the asymmetry introduced. The major interest of this method is the low cost of the material needed and its easy setup in a clinical environment. PMID- 23367490 TI - Predicting the initiation of minimum-jerk submovements in three-dimensional target-oriented human arm trajectories. AB - Target-oriented human arm trajectories can be represented as a series of summed minimum-jerk submovements. Under this framework, corrections for errors in reaching trajectories could be implemented by adding another submovement to the ongoing trajectory. It has been proposed that a feedback-feedforward error detection process continuously evaluates trajectory error, but this process initiates corrections at discrete points in time. The present study demonstrates the ability of a feed-forward Artificial Neural Network (ANN) to learn the function of this error-detection process. Experimentally recorded human target oriented arm trajectories were decomposed into submovements. It was assumed that the parameters of each submovement are known at their onset. Trained on these parameters, for each of three participants, an ANN can predict presence of corrections with sensitivity and specificity > 80%, and can predict their timing with R(2) > 40%. PMID- 23367491 TI - The impingement-dislocation risk of total hip replacement: effects of cup orientation and patient maneuvers. AB - Hip dislocation is one of the most frequent complications after total hip arthroplasty. Impingement and dislocation might be caused due to misalignment of the acetabular cup during surgery, or performing dislocation-prone activities afterwards. A finite element model was developed to predict the impingement and dislocation behavior of the prosthetic joint, for different combinations of cup orientation and patient maneuver. Four dislocation-prone activities of daily life and 25 cup orientations were analyzed to determine how close they are to the impingement and subsequent dislocation events. The angular margin results obtained indicated that the sit-to-stand and standing while bending at the waist are prone to dislocation, in particular when the cup anteversion angle is small. PMID- 23367492 TI - 3-D biofabrication using stereolithography for biology and medicine. AB - In this paper, we review our recent work on the potential of stereolithography (SL) for different biomedical applications including tissue engineering, neovessel formation, investigating cell-cell and cell matrix interactions, and development of cellular systems. Also, we show that SL technology can be combined with dielectrophoresis (DEP) to create scaffolds with micro-scale organization, a hallmark of in vivo tissues. PMID- 23367493 TI - Reevaluation of the prevalence of metabolic syndrome in an urban area of Turkey. AB - OBJECTIVE: Our aim was to reveal a change in the prevalence of metabolic syndrome (MS) in the province of Konya in five years. METHODS: We studied 202 obese children and adolescents (body mass index >95th percentile) aged between 7 and 18 years. The diagnosis of impaired glucose tolerance, type 2 diabetes mellitus (T2DM), and MS were defined according to the modified World Health Organization criteria adapted for children. RESULTS: MS was found in 56.4 % with a significantly higher rate among adolescents aged 12-18 years (63.2%) than among prepubertal children aged 7-11 years (47%) (p=0.01). The prevalence figures for insulin resistance, glucose intolerance, and T2DM were 60, 8, and 2% among prepubertal children and 81.8, 12.8, and 0% among adolescents, respectively. The prevalence of fasting hyperinsulinemia in adolescents was significantly higher than in prepubertal children (p<0.001). Hypertension was significantly more common in adolescents (42.8%) than in prepubertal children (32.9%) (p=0.04). CONCLUSIONS: We found that the incidence of MS in the city center of Konya approximately doubled in the last five years with increased rates of morbidity and abnormal lipid profiles. PMID- 23367494 TI - High-sensitivity C-reactive protein levels and metabolic disorders in obese and overweight children and adolescents. AB - OBJECTIVE: To compare high-sensitivity C-reactive protein (hsCRP) levels in obese and overweight children and adolescents to normal-weight individuals as well as to compare hsCRP levels in overweight children/adolescents with and without additional metabolic disorders such as metabolic syndrome (MS), non-alcoholic fatty liver disease (NAFLD), and prediabetes. METHODS: 54 consecutive obese children and adolescents with a body mass index (BMI) >= 95th centile and 50 overweight children and adolescents with BMI values between 85th and 95th centiles were screened for MS, prediabetes and NAFLD. Serum hsCRP levels were measured in all the participants and in 40 age-matched normal-weight individuals (controls). RESULTS: HsCRP levels were significantly increased in obese and overweight subjects as compared to the control group, (0.61 +/- 1.08 vs. 0.05 +/- 0.18 mg/dL,p<0.001 and 0.33 +/- 0.25 vs. 0.05 +/- 0.18 mg/dL, p<0.001, respectively). HsCRP levels were similar between obese and overweight subjects (p=0.109). Obese and overweight children with NAFLD had significantly higher levels of hsCRP compared to their counterparts without NAFLD (0.78 +/- 1.4 vs. 0.34 +/- 0.31 mg/dL, p=0.016). The levels of hsCRP were comparable in the obese and overweight children/adolescents with and without MS and with or without prediabetes(0.95 +/- 1.66 vs. 0.35 +/- 0.27 mg/dL, p = 0.096 and 0.43 +/- 0.34 vs. 0.53 +/- 1.0mg/dL, p=0.589, respectively). CONCLUSIONS: HsCRP is significantly elevated in children and adolescents with excess weight as compared to normal-weight individuals. In addition,children and adolescents with excessive weight and NAFLD show increased levels of hsCRP compared to their counterparts with normal liver. PMID- 23367495 TI - Association between insulin resistance and oxidative stress parameters in obese adolescents with non-alcoholic fatty liver disease. AB - OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases in children. The aim of this study was to investigate the associations of oxidative stress with insulin resistance and metabolic risk factors in obese adolescents with NAFLD. METHODS: Forty-six obese adolescents (23 girls and 23 boys, mean age: 12.8 +/- 2.2 years) and 29 control subjects (15 girls and 14 boys, mean age: 12.7 +/- 2.7 years) were enrolled in the study. The obese subjects were divided into two groups (NAFLD group and non NAFLD group) based on the elevated alanine aminotransferase levels (>30 IU/L) and the presence or absence of liver steatosis detected by ultrasonography. Insulin resistance was evaluated by homeostasis model assessment (HOMA-IR) from fasting samples. Plasma total antioxidant status (TAS) and total oxidant status (TOS) level measurements (REL Assay Diagnostics) were done in all participants. The ratio of TOS to TAS was regarded as an oxidative stress index (OSI), an indicator of the degree of OS. RESULTS: Fasting insulin levels and HOMA-IR values in the NAFLD group were significantly higher than in the non-NAFLD and control groups. TAS measurements were decreased in both obese groups (NAFLD and non-NAFLD) in comparison with the control group. TOS and OSI measurements were higher in the NAFLD group than in the non-NAFLD and control groups. OSI was positively correlated with fasting insulin (r=0.67, p=0.01) and HOMA-IR (r=0.71, p=0.02) in the NAFLD obese group. CONCLUSIONS: In this cross-sectional study, elevated OS markers in obese adolescents with NAFLD were associated with insulin resistance. This data suggest that an antioxidant therapy might have a potential for treating NAFLD associated with insulin resistance. PMID- 23367496 TI - Functioning adrenocortical tumors in children-secretory behavior. AB - OBJECTIVE: Adrenocortical tumors are rare childhood neoplasms. More than 95% are functional and present with virilization, Cushing's syndrome, hypertension, or hyperestrogenism. The objective of this paper is to present the clinical, laboratory and pathological findings of this rare disease and to highlight the secretory behavior of these tumors. METHODS: Clinical and laboratory data of seven Iranian children and adolescents aged between 2 and 16 years with functioning adrenocortical tumors are presented. Five patients had virilization and two had Cushing's syndrome at the time of diagnosis. In all subjects, the tumors were removed successfully by open surgery, during which a blood sample was drawn from the corresponding adrenal vein for hormonal evaluation. RESULTS: Peripheral blood evaluation revealed that in addition to the dominant hormone (testosterone in the cases presenting with virilization and cortisol in those with Cushing's syndrome), significant amounts of other hormones were secreted from these tumors. Adrenal vein evaluation revealed that testosterone, dehydroepiandrosterone sulfate, estradiol, 17(OH) progesterone, and cortisol were directly released from the tumor. The tumors weighed between 36-103 grams. The patients have since been followed for 5 to 20 years, and there have been no signs or symptoms of relapse in any of the patients. CONCLUSIONS: The study shows that functioning adrenocortical tumors should be considered in children and adolescents presenting with hyperandrogenism, Cushing's syndrome, or hyperestrogenism. A diagnosis of a functioning adrenocortical tumor requires surgical removal as early as possible to prevent the untoward effects of virilization or corticosteroid excess. Evaluation of adrenal vein hormones showed that the steroids are secreted directly from the tumor and peripheral conversion has little contribution to the serum levels. PMID- 23367497 TI - Syndrome of extreme insulin resistance (Rabson-Mendenhall phenotype) with atrial septal defect: clinical presentation and treatment outcomes. AB - Syndrome of extreme insulin resistance (SEIR) is a rare spectrum disorder with a primary defect in insulin receptor signalling, noted primarily in children, and is often difficult to diagnose due to the clinical heterogeneity.SEIR was diagnosed in an adolescent girl with facial dysmorphism,exuberant scalp and body hair, severe acanthosis, lipoatrophy, dental abnormalities, and short stature (Rabson-Mendenhall phenotype). She had elevated fasting (422.95 pmol/L) and post glucose insulin levels(>2083 pmol/L). Total body fat was decreased (11%; dual energy X-ray absorptiometry). Basal growth hormone (GH) was increased (7.9 MUg/L)with normal insuline-like growth factor 1 (37.6 nmol/L) suggestive of GH resistance. She had fatty liver and polycystic ovaries. Echocardiography revealed ostium secundum type atrial septal defect (ASD). Blood glucose normalized with pioglitazone (30 mg/day). Delayed development, severe insulin resistance, mild hyperglycemia, absence of ketosis, and remarkable response of hyperinsulinemia and hyperglycemia to pioglitazone which persisted even after 1 year of diagnosis are some of the notable features of this patient. This is perhaps the first report of occurrence of congenital heart disease (ASD) in a patient of SEIR (Rabson-Mendenhall phenotype). This report highlights the clinical features of SEIR and the role of insulin sensitizers like pioglitazone in the management of such patients. PMID- 23367498 TI - CTLA-4 (+49A/G) polymorphism and type-1 diabetes in Turkish children. AB - OBJECTIVE: To evaluate the contribution of cytotoxic T-Iymphocyte antigen-4(CTLA 4)+49A/G polymorphism to the susceptibility to type-1 diabetes (T1D) in Turkish children. METHODS: A case-control study was designed to include 91 Turkish children with T1D and 99 healthy controls. CTLA-4 (+99A/G) gene polymorphism typing was done by PCR amplification followed by restriction fragment length polymorphism method. RESULTS: The genotype and allele frequencies of the CTLA-4 (+99A/G)polymorphism in patients with T1D were not different from those in the controls (p>0.05). The allele frequency of G was 36.2% in patients with T1D,and 31.8% in controls (p>0.05). Additionally, this polymorphism was not associated with the clinical and laboratory characteristics of the patients with T1D (p>0.05). CONCLUSIONS: Our case-control study suggests that the CTLA-4 (+99A/G) gene polymorphism is not associated with T1D in the Turkish population. PMID- 23367499 TI - Primary adrenal insufficiency caused by a novel mutation in DAX1 gene. AB - Adrenal hypoplasia congenita (AHC) is a rare disorder. The X-linked form is related to mutations in the DAX1 (NROB1) gene. Here, we report a newborn who had a novel hemizygous frameshift mutation in DAX1(c.543delA) and presented with primary adrenal failure that was initially misdiagnosed as congenital adrenal hyperplasia. This report highlights the value of genetic testing for definite diagnosis in children with primary adrenal failure due to abnormal adrenal gland development, providing the possibility both for presymptomatic, and in cases with a sibling with this condition, for prenatal diagnosis. PMID- 23367500 TI - Underprescribing of clozapine and unexplained variation in use across hospitals and regions in the Canadian province of Quebec. AB - BACKGROUND: Clozapine remains the antipsychotic of choice for people who, having met the criteria for a diagnosis of schizophrenia or a related psychotic disorder, do not respond adequately to other antipsychotic medications. Utilization rates appear highly variable across jurisdictions, with an overall tendency toward underuse. This paper describes patterns of clozapine use in the province of Quebec, Canada. METHODS: Individuals with a diagnosis of schizophrenia were identified using linked government medical claims and hospitalization records for 2003 and 2004. Linked data on their filled prescriptions in 2004 were then used to determine clozapine-use rates at the level of the province, the region, and the hospital at which individuals received most of their services. Individual predictors of clozapine use were identified using logistic regression. RESULTS: Only 6.7% of the 29,155 individuals identified with schizophrenia received clozapine for six months or longer in 2004. Utilization rates ranged from 3.9 to 9.0% among regions with 1,000 or more people with schizophrenia. Over 8% of 61 hospitals did not prescribe clozapine at all. People with schizophrenia taking clozapine experienced 3.4 fewer days of hospitalization per year than those not taking clozapine-representing a cost offset of about $1,800 per year. Medication costs were higher, however, by about $3,000 per year. CONCLUSIONS: Given the increasingly clear benefits of clozapine for people who do not respond to other antipsychotics, measures to increase access to clozapine for people who can benefit from it are likely to be cost effective and are urgently needed. PMID- 23367501 TI - Attention to medical conditions during mental health clinic visits. AB - With increased attention being devoted to the metabolic effects of antipsychotic medications, it becomes apparent that efforts need to be made to ensure that patients receiving treatment for a mental illness receive appropriate evaluation and treatment of their medical conditions as well. The individual provider may assist by offering relevant screenings, helping patients take responsibility for their own health, decreasing barriers to treatment, enlisting the assistance of support staff, making appropriate referrals, and collaborating with other providers. PMID- 23367502 TI - N-3 fatty acids for hypertriglyceridemia in patients taking second-generation antipsychotics. AB - OBJECTIVE: Cardiovascular disease is a frequent cause of early disability and death in patients with severe mental illness (SMI). Second-generation antipsychotic medications may cause increased risk of cardiovascular disease in some patients by elevating serum triglyceride levels. Idiopathic hypertriglyceridemia can be effectively treated with N-3 fatty acid (N-3 FA) supplementation, but little research has evaluated this treatment for hypertriglyceridemia that can occur in patients using second-generation antipsychotics. METHODS: A six-week, open-label pilot study of N-3 FA, two grams twice daily, was performed to assess efficacy of this supplement in patients with SMI who were being treated with second-generation antipsychotics. Serum triglyceride levels (the main endpoint) were assessed at baseline and six weeks. Levels of C-reactive protein (CRP), cholesterol (total, high density lipoprotein [HDL] and low density lipoprotein [LDL]), fasting glucose, and fasting insulin (to calculate the Homeostatic Model Assessment for Insulin Resistance [HOMA-IR]), as well as weight and blood pressure, were also assessed. RESULTS: Mean triglyceride levels decreased by 70.4+/-50.4 mg/dL (p=0.001). Among secondary endpoints, mean HDL increased by 2.6+/-3.5 (p=0.03). However, LDL and total cholesterol, blood pressure, HOMA-IR and CRP did not significantly change. CONCLUSIONS: In this pilot study, treatment with N-3 FA was associated with improvements in triglyceride and HDL levels. Further study is warranted to assess more completely whether this prescription dietary supplement can reduce triglycerides in patients taking second-generation antipsychotics. PMID- 23367503 TI - Schizophrenia and relationships: the effect of mental illness on sexuality. AB - This paper seeks to investigate the impact of mental illness on the sexuality of patients with a schizophrenic disorder who live in the community in a long-term relationship with a partner. We conducted qualitative, in-depth interviews with five such patients who were in treatment at a psychiatric outpatient clinic, and three of their partners. The data were analyzed by thematic analysis and identified the following areas of concern: relationships outweigh sexuality; uncertainties about one's sexual capacity; the dwindling of sexual fantasies, feelings of desire, and satisfaction; and, a lack of communication and support in sexual matters. Both patients and partners reported feeling overlooked by psychiatric services as sexual beings. They also expressed dissatisfaction with a patient-therapist treatment model that excluded their partners. Our findings indicate that dysfunctional sexuality affects both patients suffering from severe mental illness and their partners. Patients and partners deplore the lack of opportunity to discuss questions related to their sexuality and long-term relationships with psychiatric clinicians. Sexual problems arising from, or exacerbated by, schizophrenia require supportive services, whether in the form of general, psychiatric, or couples therapy. PMID- 23367504 TI - Combining computerized social cognitive training with neuroplasticity-based auditory training in schizophrenia. AB - OBJECTIVE: Social cognitive deficits are an important treatment target in schizophrenia, but it is unclear to what degree they require specialized interventions and which specific components of behavioral interventions are effective. In this pilot study, we explored the effects of a novel computerized neuroplasticity-based auditory training delivered in conjunction with computerized social cognition training (SCT) in patients with schizophrenia. METHODS: Nineteen clinically stable schizophrenia subjects performed 50 hours of computerized exercises that place implicit, increasing demands on auditory perception, plus 12 hours of computerized training in emotion identification, social perception, and theory of mind tasks. All subjects were assessed with MATRICS-recommended measures of neurocognition and social cognition, plus a measure of self-referential source memory before and after the computerized training. RESULTS: Subjects showed significant improvements on multiple measures of neurocognition. Additionally, subjects showed significant gains on measures of social cognition, including the MSCEIT Perceiving Emotions, MSCEIT Managing Emotions, and self-referential source memory, plus a significant decrease in positive symptoms. CONCLUSIONS: Computerized training of auditory processing/verbal learning in schizophrenia results in significant basic neurocognitive gains. Further, addition of computerized social cognition training results in significant gains in several social cognitive outcome measures. Computerized cognitive training that directly targets social cognitive processes can drive improvements in these crucial functions. PMID- 23367505 TI - Correlates of health-related social media use among adults. AB - BACKGROUND: Sixty percent of Internet users report using the Internet to look for health information. Social media sites are emerging as a potential source for online health information. However, little is known about how people use social media for such purposes. OBJECTIVES: The purpose of this study was two-fold: (1) to establish the frequency of various types of online health-seeking behaviors, and (2) to identify correlates of 2 health-related online activities, social networking sites (SNS) for health-related activities and consulting online user generated content for answers about health care providers, health facilities, or medical treatment. METHODS: The study consisted of a telephone survey of 1745 adults who reported going online to look for health-related information. Four subscales were created to measure use of online resources for (1) using SNS for health-related activities; (2) consulting online rankings and reviews of doctors, hospitals or medical facilities, and drugs or medical treatments; (3) posting a review online of doctors, hospitals or medical facilities, and drugs or medical treatments, and (4) posting a comment or question about health or medical issues on various social media. Univariate and multivariate logistic regression analyses were performed. RESULTS: Respondents consulted online rankings or reviews (41.15%), used SNS for health (31.58%), posted reviews (9.9%1), and posted a comment, question, or information (15.19%). Respondents with a chronic disease were nearly twice as likely to consult online rankings (odds ratio [OR] 2.09, 95% CI 1.66-2.63, P<.001). Lower odds of consulting online reviews were associated with less formal education (OR 0.49, 95% CI 0.37-0.65, P<.001) and being male (OR 0.71, 95% CI 0.57-0.87, P<.001). Respondents with higher incomes were 1.5 times as likely to consult online rankings or reviews (OR 1.49, 95% CI 0.10-2.24, P=.05), than respondents with a regular provider (OR 2.05, 95% CI 1.52-2.78, P<.001), or living in an urban/suburban location (OR 1.61, 95% CI 1.17-2.22, P<.001). Older respondents were less likely to use SNS for health-related activities (OR 0.96, 95% CI 0.95-0.97, P<.001), as were males (OR 0.70, 95% CI 0.56-0.87, P<.001), whereas respondents with a regular provider had nearly twice the likelihood of using SNS for health-related activities (OR 1.89, 95% CI 1.43 2.52, P<.001). CONCLUSIONS: People are using social media for seeking health information. However, individuals are more likely to consume information than they are to contribute to the dialog. The inherent value of "social" in social media is not being captured with online health information seeking. People with a regular health care provider, chronic disease, and those in younger age groups are more likely to consult online rankings and reviews and use SNS for health related activities. PMID- 23367506 TI - Binding of lurasidone, a novel antipsychotic, to rat 5-HT7 receptor: analysis by [3H]SB-269970 autoradiography. AB - Lurasidone is a novel antipsychotic agent with high affinity for dopamine D(2) and serotonin 5-HT(7), 5-HT(2A), and 5-HT(1A) receptors. We previously reported that in addition to its antipsychotic action, lurasidone shows beneficial effects on mood and cognition in rats, likely through 5-HT(7) receptor antagonistic actions. In this study, we evaluated binding of lurasidone to 5-HT(7) receptors in the rat brain by autoradiography using [(3)H]SB-269970, a specific radioligand for 5-HT(7) receptors. Brain slices were incubated with 4 nM [(3)H]SB-269970 at room temperature and exposed to imaging plates for 8 weeks before phosphorimager analysis. Using this method, we first investigated 5-HT(7) receptor distribution. We found that 5-HT(7) receptors are abundantly localized in brain limbic structures, including the lateral septum, thalamus, hypothalamus, hippocampus, and amygdala. On the other hand, its distribution was moderate in the cortex and low in the caudate putamen and cerebellum. Secondly, binding of lurasidone, a selective 5-HT(7) receptor antagonist SB-656104-A and an atypical antipsychotic olanzapine to this receptor was examined. Lurasidone, SB-656104-A (10-1000 nM), and olanzapine (100-10,000 nM) showed concentration-dependent inhibition of [(3)H]SB-269970 binding with IC(50) values of 90, 49, and 5200 nM, respectively. Similar inhibitory actions of these drugs were shown in in vitro [(3)H]SB-269970 binding to 5-HT(7) receptors expressed in Chinese hamster ovary cells. Since there was no marked species difference in rat and human 5-HT(7) receptor binding by lurasidone (K(i) = 1.55 and 2.10 nM, respectively), these findings suggest that binding to 5-HT(7) receptors might play some role in its beneficial pharmacological actions in schizophrenic patients. PMID- 23367507 TI - Temporal processing dysfunction in schizophrenia as measured by time interval discrimination and tempo reproduction tasks. AB - OBJECTIVE: Time perception deficiency has been implicated in schizophrenia; however the exact nature of this remains unclear. The present study was designed with the aim to delineate timing deficits in schizophrenia by examining performance of patients with schizophrenia and healthy volunteers in an interval discrimination test and their accuracy and precision in a pacing reproduction replication test. METHODS: The first task involved temporal discrimination of intervals, in which participants (60 patients with schizophrenia and 35 healthy controls) had to judge whether intervals were longer, shorter or equal than a standard interval. The second task required repetitive self-paced tapping to test accuracy and precision in the reproduction and replication of tempos. RESULTS: Patients were found to differ significantly from the controls in the psychoticism scale of EPQ, the proportion of correct responses in the interval discrimination test and the overall accuracy and precision in the reproduction and replication of sound sequences (p < 0.01). Within the patient group bad responders concerning the ability to discriminate time intervals were associated with increased scores in the Positive and Negative Syndrome Scale (PANSS) and in the Brief Psychiatric Rating Scale (BPRS) in comparison to good responders (p < 0.01). There were no gender effects and there were no differences between subgroups of patients taking different kinds or combinations of drugs. CONCLUSIONS: Analysis has shown that performance on timing tasks decreased with increasing psychopathology and therefore that timing dysfunctions are directly linked to the severity of the illness. Different temporal dysfunctions can be traced to different psychophysiological origins that can be explained using the Scalar Expectancy Theory (SET). PMID- 23367509 TI - Rob de Bie. PMID- 23367508 TI - Deep brain stimulation in treatment-resistant depression in mice: comparison with the CRF1 antagonist, SSR125543. AB - Deep brain stimulation (DBS) has been demonstrated to represent a targeted therapeutic alternative for treatment-resistant depression. In this study, we used the unpredictable chronic mild stress (UCMS) test to validate high-frequency electrical stimulation of the cingulate cortex (CC) as a possible treatment to improve behavioral symptoms associated with a depressive-like state in treatment resistant mice. The effects of DBS were compared with those of the CRF(1) antagonist, SSR125543. Mice were subjected to UCMS, which consisted of the sequential and unpredictable application of mild stressors for a total of 8 weeks. From week 4 until the end of week 6, mice received either a saline injection or were treated with the antidepressant, fluoxetine (10 mg/kg, i.p.). At the end of week 6, fluoxetine-treated mice were subdivided into two populations, that is one responding to fluoxetine, and one not responding, based on their fur coat state, an index of depressive-like state in this test. Non responders were subsequently subjected to bilateral DBS (at 80 or 120 Hz, 1 h/day) or were treated with SSR125543 (20 mg/kg, i.p.) for two weeks. Stimulation of the CC at 120 Hz in treatment-resistant mice resulted in a normalization of motivated-like responses, anxiety-related behaviors, hyperactivity and aggressiveness. SSR125543 improved motivated-like and aggressive behaviors. These findings demonstrate that bilateral DBS of the CC and, to a lesser extent, pharmacological blockade of the CRF(1) receptor in treatment-resistant mice can attenuate several aspects of depressive-like behaviors, suggesting further that these approaches may represent valid alternatives for the treatment of drug resistant depressed and/or anxious patients. PMID- 23367510 TI - Treatment failure in osteoporosis. PMID- 23367511 TI - Fifteen medical societies agree on hormone therapy statement. PMID- 23367512 TI - HRT reduces cardiovascular endpoints in ten-year trial. PMID- 23367513 TI - NAPNAP position statement on breastfeeding. PMID- 23367514 TI - European challenges: cross-border care for children. PMID- 23367515 TI - NAPNAP position statement on the Doctorate of Nursing Practice (DNP). PMID- 23367516 TI - First needle marrow biopsy to diagnose a systemic illness. PMID- 23367517 TI - Human granulocytic anaplasmosis. PMID- 23367518 TI - Thirty-six years of the European Paediatric Association-Union of National European Paediatric Societies and Associations (EPA-UNEPSA). PMID- 23367519 TI - What's hot today? Current topics in sports and exercise medicine. PMID- 23367520 TI - The cultural revolution. PMID- 23367521 TI - In memoriam: Charles (Chuck) Crawford Sweeley, Jr. (1930-2012). PMID- 23367522 TI - Exposure to environmental endocrine disruptors and child development. AB - Exposure to exogenous chemicals can affect endocrine function at multiple sites and through numerous specific modes of action, which may have far-reaching effects on human health and development. Widespread human exposure to known or suspected endocrine disrupting chemicals (EDCs) has been documented in the United States and worldwide, as have trends for increased rates of endocrine-related diseases and disorders among children. While human epidemiology studies of exposure to EDCs and children's health remain extremely limited, a growing body of evidence shows that exposure to a number of chemicals commonly found in consumer goods, personal care products, food, drinking water, and other sources may adversely affect child development through altered endocrine function. This narrative review provides a brief introduction to several common EDCs (with a specific focus on persistent organic pollutants, phthalates, bisphenol A, and contemporary-use pesticides, which represent only a small number of all known or suspected EDCs), an overview of the state of the human evidence for adverse effects of EDCs on child development (fetal growth, early reproductive tract development, pubertal development, neurodevelopment, and obesity), guidance for health care providers based on current knowledge, and recommendations for future research. PMID- 23367523 TI - Author's response. PMID- 23367524 TI - Families and food. PMID- 23367525 TI - Lingual frenulum protocol. AB - An efficient lingual frenulum protocol with scores is presented. From a specific lingual frenulum evaluation used until 2004, a new protocol was designed. Ten speech language pathologists experienced in orofacial myology used the new protocol with different groups of subjects. 1235 subjects were evaluated during 3 years. From the experience of these ten speech language pathologists, the protocol was re-structured, and a scoring system was added. Absence of alteration (normal tongue and frenulum) was scored zero. The alterations observed were scored in ascending order. Four additional speech language pathologists experienced in orofacial myology were trained by the researcher to administer the final version of the protocol. The protocol was administered in 2008 and 2009 to 239 subjects: 160 children between 7 years and 2 months old and 11 years and 7 months old; and to 79 adults from 16 years and 8 months or older. From the results of administration of the protocol, a new lingual frenulum protocol with scores was designed. According to the scores, the frenulum can be considered altered or normal. When the sum of general tests is equal or higher than 3, the frenulum may be altered. The interference of the lingual frenulum in the oral functions may be considered when the sum of the functional tests is equal or higher than 25. This new lingual frenulum protocol with scores was designed and has been an efficient tool to diagnose an altered lingual frenulum. PMID- 23367533 TI - Respiratory Medicine Symposium. PMID- 23367532 TI - Major David Eilenberg. PMID- 23367534 TI - Struggling Trainees Symposium. PMID- 23367535 TI - Diabetes Symposium. PMID- 23367536 TI - Abstracts of the Congress of the Berner Fistula Association. November 21-23, 2012. Bern, Switzerland. PMID- 23367537 TI - Facts, controversies, and current trends. PMID- 23367538 TI - Findings of research misconduct. PMID- 23367539 TI - Findings of research misconduct. PMID- 23367540 TI - Findings of research misconduct. PMID- 23367541 TI - Abstracts of the 63rd Annual Conference of the Cardiological Society of India. December 8-11, 2011. Mumbai, India. PMID- 23367542 TI - [What Is the effect of metformin combined to chemotherapy in stage IV colorectal cancer with diabetes?]. PMID- 23367543 TI - [Gastric duplication cyst with ectopic pancreas in a child]. PMID- 23367544 TI - [The success of operations]. PMID- 23367545 TI - [How many body parts will be sacrificed?]. PMID- 23367546 TI - [Call for medical/humanitarian aid to Syria]. PMID- 23367547 TI - [Health care services can boost physical activity on prescription--more people need prescriptions]. PMID- 23367548 TI - [Physical activity on prescription--an underutilized resource. Statistics on prescription shows large variations between counties]. PMID- 23367549 TI - [Organ donation from parent to child. Strong feelings need not be barriers to autonomous decisions]. PMID- 23367550 TI - [High hemoglobin, not always polycythaemia vera. Weak evidence for the effect of venesection in other erythrocytoses]. PMID- 23367551 TI - [Persistent pruritus caused by tropical chiggers. Trip to Brazil caused a phenomenon unknown in Sweden]. PMID- 23367552 TI - [Foreign body in the airways]. PMID- 23367553 TI - [Getting stuck in imagination "Quicksand"]. PMID- 23367554 TI - [New treatment recommendations: Management of pharyngo-tonsillitis in ambulatory care]. PMID- 23367555 TI - ["Whistleblowers" within the union and the right to clear insight]. PMID- 23367556 TI - [On fungus and taste]. PMID- 23367557 TI - [Cloning and functional research of Arp2/3-P40/ARPC1 subunit of Sf9 cells]. AB - The baculovirus-induced actin polymerization is mainly associated with the virus nucleocapsid protein P78/83, which is homologous with WASP proteins that can activate Arp2/3 complex and induce the actin polymerization. In order to explore the role of Arp2/3 complex in the baculovirus replication, the P40 subunit of Arp2/3 complex from Sf9 (Spodoptera frugiperda 9) cell line was cloned and characterized. Immunofluorescent microscopy assay indicated that P40 was recruited to the inner-side of nuclear membrane during virus infection, which was in accordance with nuclear F-actin distribution in virus-infected cells as documented in our previous research, suggesting P40 could be used to track Arp2/3 complex subcellular distribution changes during virus infection. In addition, co immunoprecipitation assay demonstrated that P40 interacted with P78/83 only in virus-infected cells, suggesting that actin polymerization induced by P78/83 Arp2/3 complex during baculovirus infection was regulated by some unidentified virus factors. PMID- 23367558 TI - [Identification of a new subgroup of avian leukosis virus isolated from Chinese indigenous chicken breeds]. AB - In order to clarify Avian leukosis virus (ALV) characteristics from Chinese native chicken breeds, three ALV JS11C1, JS11C2 and JS11C3 were isolated from Chinese native breed "luhua" by inoculation of DF1 cell culture and detection of p27 antigen. Using PCR amplification of env gene, the amplified gp85 genes were analyzed and compared to all six chicken ALV subgroups reported. The gp85 genes of these three viruses were 1 005bp in length and encoded 335 amino acids, and the gp37 genes were 609bp and encoded 203 amino acids. The homology of gp85 among these three isolated strains was 91.9%-97.0%. Comparing to 18 stains of subgroup A, B, C, D, E published in GenBank, the homology was only in the range of 77.7% 84.6%, significantly lower than the gp85 homology observed within the common chicken subgroups A (88.2%-98.5%), B (91.6%-98.8%), and E (97.9%-99.4%). The gp85 homology compared with subgroup J was only 34.2%-36.5%. These results suggested that three isolated strains from Chinese native breed "luhua" belong to a new subgroup different from all six known subgroups from Chickens, and thus designated as subgroup K. PMID- 23367559 TI - [The ALV-A/B specific antibodies correlation between ELISA and IFA detection in chicken serum]. AB - To study the correlation between ELISA and IFA tests in detection of ALV-A/B antibody in chicken sera, ELSA S/P values and IFA titers for different serum samples were measured and statistically analyzed. The results indicated that there was a strong positive correlation between ELISA S/P values and IFA titers (r = 0.97435, P < 0.001). Because the positive correlation between ELISA and IFA was so strong and antibody positive rates were identical in two tests, it suggested that IFA could be used as a alternative method to replace ELISA kit when only limited numbers of samples to be tested to reduce the cost and increase the sensitivity. PMID- 23367560 TI - [Evaluation of antigenic relationship of Guangxi isolates of infectious bronchitis virus]. AB - Monovalent antisera of 3 vaccine strains and 7 representative field isolates were prepared based on the comparison of genetic diversity of the hypervariable region I of S1 gene (HVR I from 3 infectious bronchitis (IB) vaccine strains (H120, Ma5 and 4/91) ,one reference strain M41 and 26 IB field isolates. These 30 strains were classified in 7 different genotypes, respectively. Virus-neutralizing test on tracheal organ cultures (TOC) with chicken embryo were used to evaluate relatedness values of the antigenicity based on the antibody titer, to analyze the antigenic relationships between the isolates and vaccine strains, as well as to determine the serotypes of 26 IB viruses isolated from the field in Guangxi between 1985 and 2008. The results showed 30 strains were classified into 7 distinct serotypes and there were two predominant serotypes within the 26 isolates, serotypes 1 (totally 13 isolates) and serotype 2 (totally 5 isolates), respectively. In addition, there were some differences observed between the results of serotyping and the genotyping (including the S1, N, M and 3'UTR). The results of the study demonstrated that there were different predominant serotypes and multiple serotypes of IBV circulated in Guangxi in recent years, antigenic variation existed between Guangxi field isolates and vaccine strains. PMID- 23367561 TI - [Eukaryotic expression of NS1 major antigen region of PPV and development of an indirect ELISA based on the expressed protein]. AB - To construct secretory expression vector of PPV NS1 gene, the fragment of PPV NS1 gene coding for major antigen region of the NS1 protein was amplified by PCR and inserted into multiple clone site of eukaryotic expression vector pPICZalpha-A. The recombinant pPICZalpha-A-NS1 plasmid was transferred into P. pastoris strain GS115 mediated by electro transform. Recombinant P. pastoris strain GS115 was induced to express the fusion protein by methanol. The expressed and purified protein was analyzed by SDS-PAGE and Western Blot. The recombinant protein was highly-expressed and showed a good immunoreactivity. The indirect ELISA method was developed for detecting antibodies against PPV by checkerboard titration assay. The result showed that the optimal concentration of coated antigen was 3.2 microg/mL and the best dilution of serum was 1 : 80. The positive cut-off value of the ELISA assay was OD450 > 0.4 and OD450 positive serum/OD450 negative serum > 2.0. Compared with HI and commercial ELISA kits, the assay revealed 94.2% and 92.1% agreement respectively. The assay demonstrates good specificity and sensitivity, and can be applied in the detection of porcine parvovirus. PMID- 23367562 TI - [Establishment of a high-throughput screening assay for interaction inhibitor between BST-2 and Vpu]. AB - BST-2 plays an important role in host innate immune response via inhibiting the release of HIV-1. HIV-1 accessory protein Vpu can interact with BST-2 through its transmembrane domains, degrade BST-2, and decrease BST-2 that are transported to the cell surface, thus anti-virus function of BST-2 is antagonized. In our study, we constructed plasmid RB connecting Rluc to the N-termimal of BST-2, and plasmid VE connecting EYFP to the C-terminal of Vpu. The two fusion proteins were co expressed in 293 cells, and the interaction between the two proteins was detected via BRET method. And we further established a stable 293 cell line of dual expression. By using BRET method, and the interaction between BST-2 and Vpu transmembrane domain as the target, a high-throughput screening assay was created that was expected to seek novel interaction inhibitors. PMID- 23367563 TI - [Differences of the regulation on the expression of mucin 1 induced by two single strand RNA viruses, respiratory syncytial virus and influenza virus]. AB - To investigate whether influenza virus (IFZ) could up-regulate the expression of mucin 1 (MUC1) which exists in epithelial cells of upper respiratory track to restrict the inflammation, as respiratory syncytial virus (RSV) does. Quantitative RT-PCR and Western Blot were performed to detect the expression level of MUC1 induced by two single-strand RNA viruses in A549 cell lines. HEp-2 and MDCK cells were used respectively to culture RSV and IFZ. At 24h post A549 cells infection with the same titer of RSV or IFZ, the total RNA was harvest, qRT PCR was then performed to observe the expression level of MUC1 mRNA. Meanwhile, at 24 h and 48 h post A549 cells infection with the same titer of RSV or IFZ, the total protein and supernatant were collected respectively after cell lysis, Western Blot was then used to detect the expression level of MUC1. Results showed that RSV could up-regulate the expression of MUC1 in airway epithelial cells with a significant dose-effect correlation, whereas IFZ could not. This study firstly investigated the differences of the regulation on the expression of MUC1 induced by two single-strand RNA viruses, and demonstrated initially that the mechanism of IFZ self-limiting differed from RSV, which attributed to up-regulation of the expression level of MUC1. PMID- 23367564 TI - [The analysis of human papillomavirus type 16 E6/E7 genetic variability in Yunnan Province, China]. AB - To investigate E6 and E7 gene variations of human papillomavirus type 16 in Yunnan Province, DNA was extracted from 2000 gynecological outpatient samples. For Human papillomavirus (HPV) genotyping, the genomic DNA was first amplified by the consensus MY09/MY11 primer pair followed by nested PCR with GP5+/GP6+ primers, then the PCR products were subjected to direct DNA sequencing. A total of 20 HPV-16 viral DNAs were identified. E6 and E7 genes of HPV-16 viral DNA were then amplified using E6 and E7 specific primers, the PCR products were purified and sequenced. The results showed that mutations were found at nucleotide position 178 of HPV-16 E6 gene in 10 cases,the mutation rate was 50%; For HPV-16 E7 gene, the mutations were found at nucleotide position 647 in 10 cases; the mutation rate was 50%. Phylogenetic analysis showed that Asian (As) variants of HPV-16 were predominated in Yunnan, China. None of African-1, African-2 variants of HPV-16 was found in this region. PMID- 23367565 TI - [Induction of VEGF in human monocytes by DENV infection and the regulatory mechanism]. AB - To investigate the effects of DENV infection on the expression of Vascular endothelial growth factor (VEGF) in monocytes, and to explore which innate immune signaling pathway is responsible for VEGF induction. Real-time PCR was used to determine the expression levels of VEGF in DENV-infected THP-1. We found that different serotype viruses (DENV1, DENV2, DENV3) induced the VEGF expression. Moreover, VEGF expression was significantly increased in human primary monocytes infected with DENV 2. In addition, VEGF induction by DENV2 was significantly impaired by knockdown of TLR3 and interferon-beta promoter stimulator 1 (IPS-1), or by inhibition of ERK, JNK or NF-kappaB. These results demonstrated that DENV induced VEGF expression in monocytes, and the activation of TLR3, IPS-1 signal pathways were required for DENV2-triggered VEGF induction, suggesting that VEGF might be a promising therapeutic target for DHF. PMID- 23367566 TI - [Identification and molecular characterization of human enteroviruses type 74, 80, and 87 isolated in Shandong Province, China]. AB - An increasing number of new types of human enteroviruses (HEV) have been identified with the application of molecular typing method based on VP1 sequence analysis. In this study, the non-polio enteroviruses (NPEV) isolated from acute flaccid paralysis (AFP) cases in Shandong Province, China were typed via molecular typing method, and 1 EV74, 3 EV80 and 1 EV87 strains were identified. Homologous comparison revealed EV74, EV80 and EV87 Shandong strains had 81.4%, 76.4%-81.7%, and 80.3% VP1 identities with prototype strains. Phylogenetic analysis suggested a remote genetic distance with other strains. This is the first report of EV74 and EV87 in mainland China, and the low isolation rate in AFP surveillance suggested these three serotypes has not been the predominant viruses in China. PMID- 23367567 TI - [Identification and genetic characterization of coxsackievirus A24 isolated from patients with acute hemorrhagic conjunctivitis in Shandong Province]. AB - To identify the pathogen of acute hemorrhagic conjunctivitis (AHC) in Shandong Province in 2010, eye mucous swab samples were collected from 26 patients in Qingdao and Linyi City. Real time-PCR assays for EV70, CVA24 and Adenovirus were performed on these samples. The result showed 17 samples (65.39%) were CVA24 positive while all the samples for HEV70 and Adenovirus detection were negative, which implied that CVA24 was the causative pathogen of this outbreak. A total of 10 virus strains isolated on Hep-2 cells were identified as CVA24 through VP1 amplification and nucleotide sequence analysis. The nucleotide and amino acid homologies on VP1 region among these isolates were 99.3%-100.0% and 99.5%-100.0%, respectively, and the strains aggregated together to one clade in phylogenetic tree. These results showed that the CVA24 circulating in Qingdao and Linyi City belonged to one transmission chain. Shandong CVA24s segregated into 5 different clades, and great nucleotide divergence was observed be tween AHC isolates and others. PMID- 23367569 TI - [Genetic characteristics of enterovirus 71 VP1 and epidemiology of hand-foot mouth disease in Xinxiang in 2011]. AB - The study was performed to examine the enterovirus 71(EV71) VP1 genetic feature and the epidemiology of hand-foot-mouth disease (HFMD) in Xinxiang in 2011. Real time RT-PCR was used for the detection of Pan-enterovirus, Coxsackievirus A 16(CA16) and EV71 from stool specimens of HFMD. The VP1 region was amplified from 10 EV71 positive samples and the products were sequenced. EV71 genotypes were characterized by homology and phylogenetic tree analyses. Additionally, epidemic data of Xinxiang HFMD in 2011 was analyzed. The results revealed that 73% of the specimens from severe cases were determined as EV71 positive, which was significantly higher than CA16-positive ones (19%) (P < 0.01). Ten EV71 strains isolated in Xinxiang belonged to C4a cluster of sub-genotype C4, with 2.8% nucleotide and 0.9% amino acid sequences divergence among them. At position 170 in VP1 gene, an alanine(A) was predominant in 9 isolates, while a valine(V) residue was observed in one isolate. Compared to the representative C4a strains which were closely related to Xinxiang isolates, the amino acid variations of the pre-dominant Xinxiang strains generally occurred at position 292, threonine --> alanine (T --> A). A total of 1118 HFMD cases were reported in Xinxiang in 2011, and 92% of them were younger than 3 years old; the incidence rate peaked in April and December, suggesting that it is very necessary to strengthen HFMD prevention and control even in cold weather. PMID- 23367568 TI - [Comparison of different molecular assays for the rapid detection of enterovirus 71 (EV71)]. AB - Molecular detection of enterovirus (EV)71 RNA based on PCR methods is a quick and sensitive approach. At present, different PCR-based methods for EV71 RNA detection are available, but comparisons of results obtained using different approaches are limited. This study is to compare the analytical sensitivity and specificity of different real-time reverse transcription-polymerase chain reaction (rRT-PCR) and conventional reverse transcription-polymerase chain reaction (cRT-PCR) assays for enterovirus and EV71 detection, Altogether, three rRT-PCR assays and one cRT-PCR assay targeting the 5'UTR gene for universal detection of enterovirus; two rRT-PCR assays andone cRT-PCR assay targeting the VP1 gene for specific detection of EV 71 were examined. All assays showed good specificity. The detection sensitivity ranged from 8.19 x 10 to 8.19 x 10(5) copy equivalents. In general, rRT-PCR assays were more sensitive than cRT-PCR assays. All rRT-PCR assays showed 100% sensitivity for clinical specimens. PMID- 23367570 TI - [Research on the gene structure of duck hepatitis B virus and its encoding proteins]. AB - Duck hepatitis B virus (DHBV) belongs to the Avihepadnavirus genus of the Hepadnaviridae, and it not only has the same replication pattern, but also has the similar genomic and antigenic structures to Hepatitis B virus (HBV). The genome of DHBV is a partially double-stranded closed circular DNA. The genome consists of three distinct open reading frames (ORFs): ORF-PreS/S, ORF-PreC/C and ORF-P, which all locate on the negative DNA strand and encode four separate proteins. The ORF-PreS/S encodes envelope proteins L and S, and the ORF-PreC/C and ORF-P encode capsid proteins C and polymerase proteins P, respectively. The characteristics of genome structure,viral proteins features and functions were described in this review in order to provide useful information for the further study of DHBV and the duck model infected by DHBV. PMID- 23367571 TI - [Advance in immunology and immune evasion of PRRSV]. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) continues to be a threat, causing economically significant impacts on the swine industry worldwide. Unfortunately, the traditional control strategies and conventional vaccines fail to provide sustainable disease control, in particular against genetically diverse strains, as they suffer from both antigenic heterogeneity and various immune evasion strategies of PRRSV. In this paper, latest research progress in immunology and immune evasion of PRRSVis summarized to provide a referenc for PRSSV prevention and control as well as the design of new vaccines. PMID- 23367572 TI - Got velcro? Heading into 2013, the healthcare industry could use the ingenuity of inventors like George de Mestral. PMID- 23367573 TI - Bridging the EHR divide. Hospitals, physician practices work toward true interoperability. AB - Moving forward in so many areas, including under meaningful use, will require the establishment of genuine interoperability across the inpatient-outpatient divide, and in particular, far more automated connectivity between hospitals and physicians, including those doctors in private practice. But building bridges in this area is far more complex than it first appears, say healthcare IT leaders who are guiding their organizations forward say the healthcare IT leaders who are guiding their organizations forward nationwide. PMID- 23367574 TI - Healthcare's new connector: the Chief Integration Officer. With value-based population health initiatives on the rise, a new role is emerging to link providers and hospitals in the care continuum. AB - As healthcare moves toward a future in which providers will handle more population level risk, the chief integration officer will play a central role in helping hospitals integrate and align with physicians to build a broad-based care management platform. PMID- 23367575 TI - Mobile documentation: optimizing technology to do more with less. How the University of Missouri Health System adapted its barcode-scanning system for mobile bedside documentation to enhance the quality and safety of patient care. AB - When the University of Missouri Health System sought to optimize its bedside documentation work-flows, it chose to enhance its current medication administration devices to allow mobile point-of-care documentation, an innovation that has led to a dramatic advance in speed to documentation of patient data, ultimately improving patient care. PMID- 23367576 TI - What's next for healthcare on Capitol Hill? A post-November election conversation with Premier's Blair Childs. Interview by Mark Hagland. PMID- 23367577 TI - Making the case for empowerment. Farzad Mostashari, M.D. makes impassioned plea to chime fall forum attendees to share in his dream. PMID- 23367578 TI - Meeting the needs of smaller providers. Moving ahead on integrated practice management and EHR solutions in a smaller-hospital/medical-group integrated system. PMID- 23367579 TI - Physician documentation: balancing clinical and administrative uses. AMIA panel parses the tension between patient narrative and structured documentation. PMID- 23367580 TI - Last man standing? Advice for engaging anesthesia clinicians when implementing an EMR in anesthesiology services. PMID- 23367581 TI - Meeting insurance exchange deadlines. November election impact: States now face a tight deadline for implementing health insurance exchanges--will the I.T. be ready? PMID- 23367582 TI - An uncertain path ahead. Is Medicare reimbursement uncertainty inhibiting advances among medical groups? PMID- 23367583 TI - The case for payer-provider teamwork. With population health, payers and providers have to play nice. PMID- 23367584 TI - Developing hiring standards for temporary workers. Contract workers are proving their value in the new economy by filling gaps in the labor pool, but hiring managers need to be vigilant in the screening process. PMID- 23367585 TI - [Experimental animal science is and stays an art]. PMID- 23367586 TI - [Shock]. PMID- 23367587 TI - [Council and members: together responsible for own quality]. PMID- 23367588 TI - [Where practice meets science]. PMID- 23367589 TI - [Surveillance]. PMID- 23367590 TI - [Zoonoses from ticks and fleas in dogs and cats]. AB - Fleas and ticks may transmit zoonotic diseases. This is an overview of tick- and flea-borne zoonoses where dogs and cats are involved in the epidemiology. PMID- 23367591 TI - [What the practising veterinarian should know about puumala virus]. PMID- 23367592 TI - [Excellent referrals in veterinary medicine strengthens the quality of care]. PMID- 23367593 TI - [Post card reminders: why generic when it can also be personal?]. PMID- 23367594 TI - [Cost calculator: aid to a healthy business model]. PMID- 23367595 TI - [Peer Zwart: the exotic one under the veterinarians]. PMID- 23367596 TI - [Ten years of animal health monitoring in the Netherlands: 'Working together is the motto']. PMID- 23367597 TI - [Care for horses in the First World War]. PMID- 23367598 TI - [Transparent registry makes financial relation with pharmaceuticals public]. PMID- 23367599 TI - [Pension classes]. PMID- 23367600 TI - [Horse with reduced physical endurance and stridor]. PMID- 23367601 TI - [Facebook and twitter saves a cat's life]. PMID- 23367602 TI - Babies have rights, too. PMID- 23367603 TI - Marions' message: more on shoulder dystocia. PMID- 23367604 TI - The doula phenomenon and authentic midwifery: protection as a keyword. PMID- 23367605 TI - The newborn imprint. PMID- 23367606 TI - A doula's bag-of-tricks: what's in it for you? PMID- 23367607 TI - Herbs for the childbearing year. PMID- 23367608 TI - A birth doula for every mother. PMID- 23367609 TI - Freedom for birth: how a documentary filmmaker became a birth warrior. PMID- 23367610 TI - Teaching about birth. PMID- 23367611 TI - Confessions of a 57-year-old rookie doula. PMID- 23367612 TI - Pelvic trauma in childbirth. PMID- 23367613 TI - Supporting empowered births. PMID- 23367614 TI - Martha Ballard: a midwife of Maine, 1778-1812. PMID- 23367616 TI - Oregon's house bill 3311: including doulas in the state medical insurance program. PMID- 23367615 TI - DONA's youngest certified doula. PMID- 23367617 TI - Sing to your belly. PMID- 23367618 TI - My birth trauma story. PMID- 23367619 TI - Help, I'm a guy! Homebirth from a man's point of view. PMID- 23367620 TI - Collusion and negligence in hospitals. PMID- 23367621 TI - From hospital to homebirth. PMID- 23367622 TI - Doulas and midwives laboring together. PMID- 23367623 TI - Problems in American maternal health care. PMID- 23367624 TI - Hypospadias and endocrine-disrupting chemicals. PMID- 23367625 TI - "I am not God" feedback. PMID- 23367626 TI - The midwife and the doula: a tale of two sisters. PMID- 23367627 TI - A week and a question. PMID- 23367628 TI - Homebirth in Bulgaria: a hush-hush affair. PMID- 23367629 TI - Doulas in Europe. PMID- 23367630 TI - Birth in the Netherlands: the current situation. PMID- 23367631 TI - Are friends electronic? PMID- 23367632 TI - Contaminated keyboards and mice. PMID- 23367633 TI - A restorative approach to the clinical and aesthetic management of adult patients with Class II division 2 incisor malocclusions. AB - A Class II division 2 incisor malocclusion may be a cause of aesthetic and/or functional concern for some affected patients. Their particular concerns may include dark spaces around the misaligned teeth or uneven gingival contours. Orthodontic and/or orthognathic treatment can address some of these problems but frequently involves lengthy and expensive treatment in the adult dentition. Sadly, such treatment often produces an unstable result, with significant drawbacks such as the requirement for long-term retention. This article aims to describe alternative strategies for managing patients with this incisor malocclusion. CLINICAL RELEVANCE: This paper outlines a quicker, pragmatic and minimally destructive restorative treatment alternative to conventional orthodontic treatment and the associated long-term retention. PMID- 23367634 TI - The role of the general dental practitioner in managing the oral care of head and neck oncology patients. AB - The general dental practitioner (GDP) plays a critical role in managing head and neck cancer patients. The first and most important role is to offer preventive services, particularly to smokers and to patients who drink alcohol to excess. It is of critical importance that every patient has a systematic examination of oral soft tissues when seen by a GDP. All patients with suspicious lesions should be referred for urgent attention to a specialist centre. Once oral cancer has been diagnosed, GDPs may be presented with patients requiring urgent dentistry, including extractions before commencement of treatment, requiring palliation of symptoms during treatment, or requiring general dentistry after treatment. Radiotherapy provides increased survival but has serious adverse consequences, which may be lifelong, including dry mouth, radiation caries, limitation of mouth opening and high risk of osteonecrosis after extractions. Extraction of teeth in irradiated bone should be referred to specialist centres. Improving survival rates and an ageing population mean that GDPs will see many more survivors of head and neck cancer in the future, with an increased burden of dental care in the longer-term and an increased need for monitoring and secondary prevention. CLINICAL RELEVANCE: The management of patients with head and neck cancer is complex and involves a multi-disciplinary team, both in the primary treatment but also in the long-term care. This paper reviews the consequences of treatment for head and neck cancer and gives practical advice for GDPs and their team in the long-term care of these patients. PMID- 23367635 TI - An removal of gutta-percha and root canal sealer: a literature review and an audit comparing current practice in dental schools. AB - Endodontic failures often require non-surgical retreatment. The most common root canal obturating material is gutta-percha (GP), used in conjunction with various sealers. GP removal can be undertaken thermally and/or mechanically with or without solvents, however, no published guidelines exist. Following a literature review, an audit was undertaken comparing current endodontic practice in Belfast Dental School with the other dental schools across the UK and Republic of Ireland. From the findings, Belfast Dental School decided to introduce rotary files and chloroform to its Conservation Clinic with restrictions for use of the latter, although solvent use is not recommended in every case. CLINICAL RELEVANCE: Efficiency in removing both gutta-percha and root canal sealer would maximize the ability to disinfect the root canal system and therefore increase the likelihood of a successful outcome. PMID- 23367636 TI - Clinical audit--process and outcome for improved clinical practice. AB - Audit is a key aspect of everyday clinical care and essential for the safe as well as efficient functioning of any clinical environment. This applies to clinical care both within primary practice and secondary care within a hospital environment. The undertaking of an audit allows the clinician to analyse his or her own clinical practice in relation to current guidance or 'gold standard' parameters to enable best practice within all aspects of patient care to be implemented. This paper aims to explore the origins and importance of clinical audit as well as the various processes involved in undertaking it successfully. CLINICAL RELEVANCE: This article will enable clinicians to understand the importance of audit and how to incorporate it into their everyday practice. PMID- 23367637 TI - Langerhans cell histiocytosis: a diagnostic dilemma. AB - Langerhans cell histiocytosis (LCH) is a rare clonal neoplastic disorder of unknown aetiology which can present with a diverse range of clinical presentations. It encompasses a diverse number of idiopathic conditions which can involve multiple body systems and is characterized by bone marrow-derived Langerhans cell proliferation. The disease can affect multiple body systems and lesions can be solitary or widespread. We present a case of a multifocal eosinophilic granuloma (LCH) in a young adult female with clinical signs and symptoms similar to aggressive periodontitis. CLINICAL RELEVANCE: Langerhans cell histiocytosis is a rare disease which can have a similar clinical presentation to aggressive periodontitis. PMID- 23367638 TI - Mouthwatering but erosive? A preliminary assessment of the acidity of a basic sauce used in many Indian dishes. AB - The aim of this study was to assess whether some types of Indian cuisine may contain erosive components. Indian dishes were prepared by a previously published method and their pH measured using a pH probe. The results indicated: (i) that some components of Indian cooking, such as tomatoes and red chilli powder, had the potential to erode enamel; (ii) that the pH of some foods was reduced with increasing temperature; and (iii) that all the basic masalas made and tested had a pH of less than 4.5. Within the limitations of the study, it may be concluded that the basic sauce/masala used in north Indian dishes may have erosive potential. CLINICAL RELEVANCE: This information could be considered useful when advising patients who eat Indian curries about causes of acid erosion of their teeth. PMID- 23367639 TI - Anatomy and clinical applications of the maxillary nerve in dentistry: a literature review. AB - Few reports in the literature have addressed the course of the maxillary nerve, its regional branches and their significance in anaesthetic procedures. It was observed that the maxillary nerve varies in its branching pattern and the knowledge of the course and distribution of these branches may be useful for dental surgeons and anaesthetists while working in this region. Keeping these points in view, this review is aimed at presenting information about the course, distribution, possible variations, clinical significance and the anaesthetic applications of the maxillary nerve and its branches in dental procedures. CLINICAL RELEVANCE: Knowledge of the anatomy of the maxillary nerve is of relevance to the regional anaesthetic technique of this nerve. PMID- 23367640 TI - Ionizing radiation regulations and the dental practitioner. PMID- 23367641 TI - Late presentation of an ectopic canine. PMID- 23367642 TI - An uncommon presentation al of dens invaginatus. PMID- 23367643 TI - Oral medicine: 4. Dry mouth and disorders of salivation. PMID- 23367644 TI - Technique tips--management of a precision attachment crown fractured at gingival level. PMID- 23367645 TI - Physical signs for the general dental practitioner. Case 100. Skin ulceration which are ischaemic. PMID- 23367646 TI - Patients as reviewers of quality and safety. PMID- 23367647 TI - A mixed-methods analysis of patient reviews of hospital care in England: implications for public reporting of health care quality data in the United States. AB - BACKGROUND: In the United States patients have limited opportunities to read and write narrative reviews about hospitals. In contrast, the National Health Service (NHS) in England encourages patients to provide feedback to hospitals on their quality-reporting website, NHS Choices. The scope and content of the narrative feedback was studied. METHODS: All NHS hospitals with more than 10 reviews posted on NHS Choices were included in a cross-sectional mixed-methods (qualitative and quantitative) analysis of patients' reviews of 20 randomly selected hospitals. RESULTS: The final sample consisted of 264 hospitals and 2,640 patient responses to structured questions. All 200 reviews from the 20 hospitals randomly selected were subjected to further quantitative and qualitative analysis. Comments about clinicians and staff were common (179 [90%]) and overwhelmingly positive, with 149 (83%) favorable to workers. In 124 (62%) of the 200 reviews, patients commented on technical aspects of hospital care, including quality of care, injuries, errors, and incorrect medical record or discharge documentation. Perceived medical errors were described in 51 (26%) hospital reviews. Comments about the hospital facility appeared in half (52%) of reviews, describing hospital cleanliness, food, parking, and amenities. Hospitals replied to 56% of the patient reviews. DISCUSSION: NHS Choices represents the first government-run initiative that enables any patient to provide narrative feedback about hospital care. Reviews appear to have similar domains to those covered in existing satisfaction surveys but also include detailed feedback that would be unlikely to be revealed by such surveys. Online narrative reviews can therefore provide useful and complementary information to consumers (patients) and hospitals, particularly when combined with systematically collected patient experience data. PMID- 23367648 TI - Cost reductions associated with a quality improvement initiative for patients with ST-elevation myocardial infarction. AB - BACKGROUND: Efforts to reduce door-to-balloon (DTB) times for patients presenting with an ST-elevation myocardial infarction (STEMI) are widespread. Reductions in DTB times have been shown to reduce short-term mortality and decrease inpatient length of stay (LOS) in these high-risk patients. However, there is a limited literature examining the effect that these quality improvement (QI) initiatives have on patient care costs. METHODS: A STEMI QI program (Cardiac Alert Team [CAT]) initiative was instituted in July 2006 at a single tertiary care medical center located in central Massachusetts. Information was collected on cost data and selected clinical outcomes for consecutively admitted patients with a STEMI. Differences in adjusted hospital costs were compared in three cohorts of patients hospitalized with a STEMI: one before the CAT initiative began (January 2005-June 2006) and two after (October 1, 2007-September 30, 2009, and October 1, 2009 September 30, 2011). RESULTS: Before the CAT initiative, the average direct inpatient costs related to the care of these patients was $14,634, which decreased to $13,308 (-9.1%) and $13,567 (-7.3%) in the two sequential periods of the study after the CAT initiative was well established. Mean DTB times were 91 minutes before the CAT initiative and were reduced to 55 and 61 minutes in the follow-up periods (p < .001). There was a nonsignificant reduction in LOS from 4.4 days pre-CAT to 3.6 days in both of the post-CAT periods (p = .11). CONCLUSIONS: A QI program aimed at reducing DTB times for patients with a STEMI also led to a significant reduction in inpatient care costs. The greatest reduction in costs was related to cardiac catheterization, which was not expected and was likely a result of standardization of care and identification of practice inefficiencies. PMID- 23367649 TI - Anticoagulation education: do patients understand potential medication-related emergencies? AB - BACKGROUND: The Joint Commission Venous Thromboembolism (VTE) National Hospital Inpatient Quality Measure VTE-5 outlines four criteria for discharge patient education when starting anticoagulation (usually, warfarin) therapy. The criteria do not specify content regarding patient recognition of potentially dangerous warfarin-related scenarios. A study was conducted to investigate how well patients assess the risks and consequences of potential warfarin-related safety threats. METHODS: From an adult population on long-term warfarin, 480 patients were randomly selected for a telephone-based survey. Warfarin-knowledge questions were drawn from a previous survey; warfarin-associated risk scenarios were developed via focus interviews. Expert anticoagulation pharmacists categorized each scenario as urgent, moderately urgent, or not urgent, as did survey participants. RESULTS: For the 184 patients (38% completion rate), the mean knowledge score was 69% (standard deviation [SD], 0.20). Overall classification accuracy of situational urgency was 59% (95% confidence interval [CI], 57.3% 60.3%). Respondents overestimated non-urgent-severity situations 23% of the time (95% CI, 20.8%-24.7%), while underestimating urgent-severity situations 21% of the time (95% CI, 19.0%-23.9%). A significant percentage of patients failed to recognize the urgency of stroke symptoms (for example, loss of vision), the risk of bleeding after incidental head trauma, or medication mismanagement. CONCLUSIONS: Despite fair factual warfarin knowledge, participants did not appear to recognize well the clinical severity of warfarin-associated scenarios. Warfarin education programs should incorporate patient-centered strategies to teach recognition of high-risk situations that compromise patient safety. PMID- 23367651 TI - The changing nature of ICU charge nurses' decision making: from supervision of care delivery to unit resource management. AB - BACKGROUND: Recent findings that variations in nursing workload may affect inpatient outcomes now highlight nurse workload management and the need for an updated analysis of the role of the charge nurse (CN). METHODS: Observational data for eight CNs, each at one of eight ICUs in a not-for-profit Level 1 Trauma Center, coded to capture interprofessional interactions, decision making, team coordination phases, and support tools. A researcher shadowed each participant for 12 hours. Each shift began and ended with a face-to-face handoff that included summaries of each patient's condition; the current bed census; anticipated admissions, discharges, and transfers; and the number of nurses available to work the current and coming two shifts. The researcher, using a notebook, recorded the substantive content of all work conversations initiated by or directed to the CN from physicians, staff nurses, allied health workers, other employees, and patients/families. The tools used to support conversations were collected as blank forms or computer screen prints and annotated to describe how they were used, when, and for what purpose. FINDINGS: Statistically significant three-way interactions suggest that CNs' conversations with colleagues depend on the team coordination phase and the decision-making level, and that the support tools that CNs use when talking to colleagues depend on the decision-making level and the team coordination phase. CONCLUSIONS: The role of ICU CNs appears to be continuing to evolve, now encompassing unit resource management in addition to supervising care delivery. Effective support tools, together with education that would enhance communication and resource management skills, will be essential to CNs' ability to support unit resilience and adaptability in an increasingly complex environment. PMID- 23367650 TI - A cross-sectional study on the relationship between utilization of root cause analysis and patient safety at 139 Department of Veterans Affairs medical centers. AB - BACKGROUND: Empirical evidence is limited that root cause analysis (RCA), an event analysis tool used in health care to evaluate the systemic factors that lead to adverse events, improves patient safety. A cross-sectional study was conducted to examine the relationship between RCA and patient safety. METHODS: RCA data were collected for the 139 Department of Veteran Affairs medical centers (VAMCs) in the National Center for Patient Safety database from 2004 through 2006. Participants were divided into three RCA utilization categories on the basis of their yearly RCA rate: (1) fewer than 4 RCAs, (2) 4 to 5 RCAs, and (3) 6 or more RCAs per year. An analysis of variance was conducted of each Agency for Healthcare Research and Quality Patient Safety Indicators (PSIs) across the three RCA utilization categories. RESULTS: Facilities completed between 3 and 59 RCAs in the three-year period (mean RCA utilization rate, 4.86 RCAs per year). In this period, RCA actions by facility ranged from 9 to 323 (mean, 28 actions per year per facility). Mean patient-days of care, facility budget, surgical volume, and the number of strong improvement actions were significantly different across RCA utilization categories. The mean rates of PSI 9 (Postoperative Hemorrhage or Hematoma), PSI 10 (Postoperative Physiologic and Metabolic Derangements), and PSI 13 (Postoperative Sepsis) were significantly different across RCA utilization categories. CONCLUSIONS: Large, high-spending VAMCs conduct more RCAs per year than smaller, low-spending facilities. VAMCs that do more RCAs develop more corrective actions. VAMCs that complete fewer than four RCAs per year have higher rates of postoperative complications. It is unclear if RCAs are associated with a functional patient safety program or directly improve patient safety. PMID- 23367652 TI - How Tai Chi is your nursing staff? PMID- 23367653 TI - Review of a research report on postpartum depression impacted by home health visits. AB - The research findings from Tamaki's (2008) study are important to EBNP for both maternity and psychiatric-mental health nurses. Although the findings demonstrated that mental health visits showed improvement in women with postpartum depression, one suggestion would be to implement a study with a larger sample population and in multiple cultures. With support supplied by numerous quantitative and qualitative studies, such as Tamaki's (2008) study, postpartum depression could be treated with a new non-pharmaceutical measure that would be more beneficial and effective to women and their babies. It will also open new doors for EBNP in mental health and revolutionize home health nursing. PMID- 23367654 TI - Improve breastfeeding rates by increasing health care providers knowledge and attitude. PMID- 23367655 TI - Verbal abuse of pediatric nurses by patients and families. AB - OBJECTIVE: The purpose of this study was to determine the extent to which nurses practicing in a pediatric hospital encounter verbal abuse by patients and families and their reactions to this abuse. BACKGROUND: Verbal abuse, the most common type of workplace violence against nurses results in declining morale and job satisfaction, and can negatively impact nurse turnover and quality of patient care. METHODS: The study employed a concurrent triangulation strategy using mixed methods. The 162 nurses who volunteered completed a 3-part questionnaire, and a subgroup participated in one of three focus groups. RESULTS: Eighty-two percent of subjects reported verbal abuse an average of 4 times per month. The majority of these continued to think about the incident for a few hours (25%), a few days (36%), or a week or more (12%). Nearly half reported feeling angry or powerless and 14% said they thought of leaving their position. CONCLUSIONS: The findings of this study described the nature and scope of the problem, and prompted improvement in processes and education to support nurses. PMID- 23367656 TI - The impact of an alcohol education program using social norming. PMID- 23367657 TI - Nursing student voices: reflections on an international service learning experience. AB - For the past decade participation in service and experiential learning in higher education has increased. The purpose of this study was to explore the lived experience of BSN and MSN students participating in a multidisciplinary service learning course in a rural, underserved village in Belize. Researchers analyzed student journals utilizing qualitative data analysis techniques. There were eight consistent themes found in the student journals. The findings indicate that international service learning opportunities increase students' awareness of their place in a global society and the potential contribution they can make in society. For the past decade, service and experiential learning in higher education, including nursing education, has become increasingly important. Simply put, service and experiential learning combine community service activities with a student's academic study for the sole purpose of enriching the academic experience. As faculty, we feel the goal of baccalaureate and graduate nursing education is to produce an educated professional who will become a responsible citizen. PMID- 23367658 TI - [Facets of clinical pharmacy]. PMID- 23367659 TI - [The eye as target of adverse ocular drug reactions. Focus on systemic antiinfective therapy]. AB - The functions of the eye can be disturbed by pharmaceutical agents via various mechanisms. This review describes the complexity of ocular adverse drug reactions and underlines the need for a close interdisciplinary cooperation especially in this field to optimize drug safety. Antimicrobial agents will be used as examples to describe ocular adverse drug reactions. A recent case control study describes fluoroquinolones to be associated with the occurrence of retinal detachments. The high affinity of these agents to melanin may cause intraocular accumulation. Fluoroquinolones exert toxic effects on collagens which may destabilize the structure of the extracellular matrix. The ketolid telithromycin may cause impaired accommodation and binocular vision potentially due to its anticholinergic effect. Linezolid, an oxazolidinone, used against infections with methicillin resistant staphylococcus aureus (MRSA) may lead to progressive, potentially irreversible neuropathies of the optic nerve especially in long-time application. Treatment with rifabutin or the antiviral drug cidofovir may cause intraocular inflammation. In addition, cidofovir may impair the production of the aqueous fluid due to a toxic effect on ciliary epithelial cells. During therapy with voriconazol about one third of patients suffer from reversible visual disturbances. Liver dysfunction or pharmacogenetic variants in the cytochrome P450 system may contribute to a retarded metabolism with high intraocular drug levels. In summary, this review indicates the complexity of ocular adverse drug reactions and points out that an interdisciplinary approach is necessary to improve pharmacovigilance in this field. PMID- 23367660 TI - [Mitochondrial toxicity of drugs]. AB - Considering the complexity of mitochondria, it is not surprising that the pathogenesis of adverse drug events often develop on drug-induced mitochondrial injury. Drug induced mitochondrial toxicity can occur through several mechanisms, such as depletion of mtDNA (e.g. NRTI), inhibition of fatty acid beta-oxidation (e.g. valproic acid), opening of the mitochondrial permeability transition pore (e.g. anthracyclines), formation of mitochondrial oxidative stress and depletion of mitochondrial glutathione pool (e.g. acetaminophen), uncoupling of electron transport from ATP synthesis (e.g. tamoxifen) and inhibition of mitochondrial electron transport chain complexes (e.g. simvastatin). This review focuses on the mitochondrial toxicity of drugs in general and explains the practical relevance of these adverse drug events according to specific drugs (metformin, statins, acetaminophen, valproic acid). Furthermore the significance of mitotropic micronutrients such as coenzyme Q10, L-carnitine and glutathione in the prevention and management ofdrug-induced mitochondrial injury is discussed. PMID- 23367661 TI - [Disorders of phosphate levels. Life-threatening complications in ICU patients]. PMID- 23367662 TI - Long-term monitoring of a Coxiella burnetii-infected sheep flock after vaccination and antibiotic treatment under field conditions. AB - The purpose of this study was to pursue the development of a sheep flock for a period of 18 months after a Q fever outbreak. In a flock with approximately 250 ewes losses of 18% were caused by abortions and weak offspring. Q fever was diagnosed in April 2009 after detection of Coxiella (C.) burnetii in one placenta and two aborted fetuses by PCR. Shortly afterwards Q fever was diagnosed in humans. Between July 2009 and December 2010 the sheep were sampled regularly. Six weeks before lambing the flock was initially immunised with Coxevac. Moreover, pregnant ewes were treated with oxytetracyclines during late gestation until lambing. Seroprevalence increased from 39% before vaccination up to 98% afterwards. After these measures bacteraemia and shedding of C burnetii decreased significantly, indicating that during an acute outbreak the vaccination with Coxevac can reduce the shedding of C burnetii effectively, although vaccination is performed without medical approval for sheep and in late pregnancy. Both measures should be taken into consideration in acute Q fever outbreaks to reduce or even avoid transmission to humans. PMID- 23367663 TI - Viability of microencapsulated probiotic lactobacilli during storage at different temperatures. AB - The aim of this study was to develop technological and microbiological basics for the use of microencapsulated probiotics in meat products. Probiotic Lactobacillus (L.) reuteri, L. rhamnosus, L. paracasei and L. gasseri strains were chosen for potential use in meat products. The effects of spices and NaCI on the microbiological stability were investigated in pilot studies. Lyophilised samples were stored for 6 months withoud additives. Microencapsulation was done with water-soluble and water-insoluble coatings. Samples were stored at 2 degrees C and 20 degrees C for six months in gelatine solutions: without additives, with 5% NaCI, with 10% cloves and with 10% black pepper. Spices and salt exhibited a strong inhibitive effect on the bacterial counts of the tested strains. During storage the lyophilised probiotic strains were stable at 2 degrees C and at 20 degrees C. Protective effects of the microencapsulation however were heterogenous. Although at the beginning protective effects against the antimicrobial activity of cloves were shown for L. rhamnosus, none of the tested coatings were able to protect durably. L. paracasei proved to be very stable in general. The use of probiotic lactobacilli strains in meat products seems possible as protective effects of the microencapsulation were recognised. However, these effects must be tested for each specific application, e.g. strain/additive combination, due to individual strain differences. PMID- 23367664 TI - Comparing the presence of different genes in Salmonella subspecies I-IV and development of a diagnostic multiplex PCR method for identification of Salmonella subspecies. AB - Reptile-associated salmonellosis in humans has become a growing problem worldwide. Reptiles are frequently asymptomatic carriers of Salmonella and therefore, they are considered as an important reservoir for these bacteria. The classical biochemical method for Salmonella subspecies detection is time consuming, especially in samples from reptiles since they frequently carry more than one Salmonella subspecies. The aim of this study was therefore to develop a multiplex PCR assay for a rapid and accurate differentiation of Salmonella subspecies I, II, IIa, IIIb and IV. In the present study, the occurrence of the genes invA, ttrCA, iroB, STM4075, sciA, STM3690, sadA, gatD, foxA, pagN, fljB, iucD, spvB, lacZ, iutA, mdcA and irp2 was examined in 41 Salmonella strains from Middle Eastern animals (mainly reptiles) by monoplex PCR. According to the results a multiplex PCR assay was developed based on the genes ttrCA, sciA, foxA, iutA. Compared to biochemical analysis this method allowed a fast identification of the subspecies from all the Middle Eastern Salmonella strains (n = 41), as well as 79 strains from German children (n = 18) with reptile associated salmonellosis and other humans and animals (n = 61) with salmonellosis.These results revealed the multiplex PCR as a fast assay for a specific identification of Salmonella subspecies I, II, IIIa, and IIIb. PMID- 23367665 TI - Molecular detection of hepatitis E virus in German domestic pigs. AB - In industrial countries, Hepatitis E virus (HEV) transmission to humans is predominantly assumed to be a zoonotic infection. Recently, it has been demonstrated that about 50% of domestic pigs in Germany carry HEV-specific antibodies. However, further investigations concerning the distribution of HEV in different age groups of German domestic pigs, phylogenetic analyses and the viral load in the porcine liver are still pending. Liver samples of all age groups from herds in a pig-dense region in north-western Germany were investigated for the presence and quantity of HEV RNA and subsequently genotyped. Out of 251 liver samples, 34 contained ORF2-specific RNA, whereas 19 samples were positive using ORF1-specific primers, resulting in an overall detection rate of 13.5% and 7.6%, respectively. Especially nursery pigs and growers were tested positive for viral RNA. Furthermore, determination of the HEV copy numbers revealed high replication levels. Up to 10(9) genome copies per g of liver tissue could be detected suggesting a likely high degree of viral spread to the environment. In the HEV positive liver samples we found no hints for pathohistological changes reflecting the HEV status.The HEV sequences showed marked diversity but could be assigned to HEV genotype 3 without exception. However, by comparing two different genomic fragments, we found indications for infections with two different HEV variants in domestic pigs. Apart from this, the current study confirms the outcome of our recent serological HEV survey and for the first time gives direct proof of HEV infections in the German domestic pig population. PMID- 23367666 TI - Efficiency of two commercial on-farm pasteurizers for inactivation of mastitis pathogens in milk intended for feeding of calves. AB - Two commercially available pasteurizers for on farm pasteurization of milk intended for feeding calves were tested for their efficiency to inactivate mastitis pathogens. Raw bulk tank milk of the experimental farm Schaedtbek of the Max Rubner-Institute was artificially contaminated with twelve different strains of mastitis pathogens (intended level 7-8 log10 colony forming units [cfu]/ml). The average contamination level was 7.6 log10 cfu/ml in trials with pasteurizer 1 (P1) and 7.3 log10 cfu/ml in trials with pasteurizer 2 (P2), with lowest counts for yeasts (5.1 log10 cfu/ml for P1 and P2). Average reduction rates of > 5.8 log10 cfu/ml for P1 (72 degrees C, 12 s) and > 6.2 log10 cfu/ml for P2 (64 degrees C, 35 min) revealed an appropriate efficiency of both pasteurizers for practical purposes. Pathogens surviving pasteurization (enterococci in trials with both pasteurizers and of Staphylococcus aureus and Escherichia coli with P1) demonstrate the limits of pasteurization as a function of raw milk quality and emphasize the necessity for appropriate handling of pasteurized milk to prevent excessive multiplication of microbial pathogens. PMID- 23367667 TI - [Phenotyping and microarray based genotyping of the antibiotic resistance of MRSA and MSSA from quarter milk samples of clinically healthy dairy cows]. AB - The aim of this investigation was the comprehensive characterization of the in vitro antibiotic resistance profile and of the detectable resistance determinants in a systematic sampling of Staphylococcus aureus isolates from raw milk from clinically healthy cows. Quarter milk samples from all asymptomatic, milk producing cows from 34 Thuringian dairy herds were taken twice (n = 10421 and 10 417 respectively) and investigated bacteriologically. 189 out of the 1902 detected Staphylococcus aureus isolates were selected and established in terms of their resistance pattern using DNA-microarray analysis and agar diffusion test (AVID 1998) for the determination of the genotypic and phenotypic resistance, respectively. 135 isolates (71.4%) did not carry any resistance gene represented on the array. The penicillin resistance gene blaZ was found in 21 isolates (11.1%), which were tested resistant to penicillin by agar diffusion test. Only four isolates (2.1%) harboured the methicillin resistance gene mecA and were thus defined as methicillin-resistant Staphylococcus aureus (MRSA). They belonged to the clonal complex CC398 and possessed, beside mecA, also tetracycline resistance genes. Other resistance markers were very rare, with macrolide and aminoglycoside resistance genes being found in only one isolate (0.5%) each. On one hand, the present survey shows the (still) limited antimicrobial resistance of Staphylococcus aureus isolated from clinically healthy dairy cows. On the other hand, the study demonstrates that MRSA can be detected in raw milk in small quantities, but these strains show only few additional resistance properties. PMID- 23367668 TI - [Salmonella in laying hens: what does voluntary monitoring tell us?]. AB - Based on voluntary examinations for Salmonella in laying hen flocks in Germany, it was investigated whether a statistically significant trend in Salmonella prevalence could be observed in the period 2003 to 2007. Furthermore, it was studied whether the implementation of Regulation (EC) No 1168/2006 led to an improvement of the collected data and a change in the Salmonella prevalence in 2008. To compensate for differences in data availability, submitted data were weighted by regional laying hen population size and compared with results from the non-weighted data. Between the years 2003 to 2007 a significant reduction of Salmonella prevalence could be observed. Weighting of data by population size improved trend recognition for routine sampling results. This may point towards a real reduction of Salmonella prevalence in German layer flocks in the years till 2007. The obligatory implementation of the control programme in 2008 led to a remarkable increase of examinations performed and an increased frequency of detection of Salmonella in flocks of laying hens. This tendency was statistically highly significant (p < 0,0042) for the overall dataset as well as for data from targeted sampling and other sampling. Again, after weighting data from routine sampling, a statistically significant (p < 0.05) increase of Salmonella prevalence could be shown. The two dominant serovars in human salmonellosis, namely S. Enteritidis and S. Typhimurium were most frequently observed in German laying hen flocks with S. Enteritidis being much more recurrent than S. Typhimurium. It is obvious from the available data that a good data quality is the prerequisite for a realistic evaluation of the Salmonella situation and that weighting may compensate for some of the bias inherent in the data reporting system. PMID- 23367669 TI - Feline cowpoxvirus infections in Germany: clinical and epidemiological aspects. AB - Clinical and epidemiological aspects of cats with cowpox in Germany from the years 2004 to 2010 are described and discussed. Questionnaires were sent to veterinarians and owners of affected cats identified with the help of a number of pathology laboratories. Of 69 mailed questionnaires, 45 veterinary and 26 owner questionnaires were returned and a total of 46 feline poxcases were evaluated. The cases were distributed all over Germany although there was an accumulation of cases in specific geographic areas. The clinical and epidemiological observations match those of other studies. The majority of cats were outdoor cats, came from a rural environment and developed clinical signs in late summer or autumn. All cats showed skin lesions which were predominantly localized on the anterior part of the body, 61% of the cats showed other clinical signs in addition to the skin lesions. Approximately half of the cats lived in a multi-pet household, but in only one case clinical signs typical for cowpox were observed in another cat of the household. In two cases a cat-to-human transmission was assumed. In addition, to evaluate the prevalence of pox virus infections in outdoor cats in areas with previous reports of such infections, 92 apparently unaffected outdoor cats were tested for orthopoxvirus antibodies using an indirect immunofluorescence assay. Sixteen (17%) of the tested serum samples were seropositive against orthopoxvirus (titre between 1:20 and 1:40).This is a higher serum prevalence than in previously published studies from Germany. A possible explanation is selection of a population of outdoor cats from regions with previous known clinical cases. PMID- 23367670 TI - Prevalence of Angiostrongylus vasorum and Crenosomo vulpis in dogs in Bavaria. AB - Worldwide there is increasing awareness of canine lung worm infection in many geographic areas. Especially the metastrongyloid nematode Angiostrongylus (A.) vasorum is associated with a high morbidity and mortality rate in infected dogs. Other pulmonary parasites in dogs include the common fox parasite Crenosoma (C.) vulpis, and the pulmonary parasites Filaroides (Oslerus) osleri, Filaroides hirthi, and the capillarid lungworms Eucoleus aerophilus (Capillaria aerophila) and Eucoleus boehmi. Aim of the study was to investigate the prevalence of A. vasorum and C. vulpis in dogs in Bavaria, Germany, and to evaluate clinical, laboratory, and radiographic changes of dogs with these pulmonary parasites. In total, three separate faecal samples from three consecutive days were collected from 276 dogs from Bavaria and analyzed by Baermann faecal technique. Included were 160 sick dogs that showed acute or chronic respiratory problems (n = 90), neurological signs (n = 47), or coagulopathies (n = 23), as well as 116 healthy controls. A. vasorum was detected in one patient with respiratory signs, and C. vulpis was found in another patient with respiratory problems. All dogs exhibiting neurological signs or coagulopathies and all healthy dogs tested negative. Thus, prevalence for both A. vasorum and C. vulpis infection was 0.36% in all dogs tested, 0.63% in all sick dogs, and 1.11% in all dogs with respiratory signs. The study shows that in contrast to the situation in other parts of Germany and in endemic areas in other European countries, the risk of infection with pulmonary parasites is low for dogs in Bavaria at the moment. PMID- 23367671 TI - [Tick infestation and tick prophylaxis in dogs in the area of Berlin/Brandenburg- results of a questionnaire study]. AB - Ticks can transmit different pathogens to humans and animals. Dogs are frequently exposed to tick infestation, which underscores the importance of tick control measures. The objective of this study was to examine the awareness of dog owners regarding tick infestation and tick prophylaxis by a questionnaire survey. During the period from March to December 2010 a total of 616 owners of 670 dogs completed the questionnaire. According to the questionnaire results, 92% of the dogs were previously infested by ticks; 31% of these showed a moderate tick infestation (1-2 ticks a month), almost one in ten dogs was infested by eight or more ticks a month. 17% of the dogs were examined for ticks by the respective owner not at all or only at irregular intervals, 61% of the dogs were examined at least once a day. A tick prophylaxis was performed in 469 dogs (71%). In 353 dogs (53%), registered pharmaceutical products with appropriate label claims were employed. Spot-on products were used most frequently (93%), followed by collars (5%) and sprays (1%).These products were not used as recommended in 56% of the dogs. For further 33% of the dogs, it was not possible to decide if the products were used correctly or not. According to the dog owner statements, tick borne diseases were diagnosed in approximately 2% of the dogs. Dog specific characters, such as coat length, size, age, and walking habits were significant factors influencing the frequency of tick infestation. In summary it can be concluded that nearly every dog in the area of Berlin/Brandenburg is infested by ticks. In the majority of cases the prophylactic and/or therapeutic measures to prevent infestation are not performed correctly. PMID- 23367673 TI - Clinical research: access to raw data is necessary. PMID- 23367672 TI - [Concentrations of anti-Muellerian-hormone in follicular fluid from antral follicles and their relation to functional characteristics of follicle development in mares]. AB - Anti-Muellerian hormone (AMH) is synthesized only by granulosa cells in female mammals as an inhibiting factor for early follicular recruitment. Especially in preantral and small antral follicles, expression of AMH is very intensive. However, we hypothesize that AMH affects also the development of large follicles by an estrogenesis modification. This current investigation provides for the first time information about concentrations of AMH in equine follicular fluid and demonstrates their relationship to functional characteristics of follicle development. Therefore, fluids of follicles in different developmental stages were obtained by repeated, transvaginal ultrasound guided-follicle aspirations from 8 mares during dioestrus and from preovulatory follicles (after hCG-inducted ovulation) during oestrus. Concentrations of AMH, 1 713-estradiol-, progesterone- and GE-i were measured in the follicular fluids. Data showed significant negative correlations between intra follicular concentrations of AMH and 1 713-estradiol (r = -0.58; p < 0.0001) as well as between AMH and follicle diameter (r = -0.76; p < 0.001), but not between AMH and progesterone or IGF-1. Based on the observed dynamic changes of AMH secretion in large antral follicles during follicle development, a regulatory involvement of AMH in equine follicle development is likely. Due to species-specific features, the results are discussed considering their potential relevance to controlled superovulation in mares. PMID- 23367674 TI - Roflumilast: doubtful efficacy but clear harms in COPD. AB - Avoidance of irritants such as tobacco smoke slows the progression of severe chronic obstructive pulmonary disease (COPD). Drugs have only a modest, purely symptomatic effect; a bronchodilator is combined with an inhaled corticosteroid when exacerbations are frequent. Oxygen therapy prolongs survival in very severe disease. Roflumilast, a nonsteroidal antiinflammatory drug that inhibits type 4 phosphodiesterase, has been authorised in the European Union for the treatment of severe COPD. Roflumilast has not been compared with an inhaled corticosteroid. Its evaluation is primarily based on 8 double-blind, randomised, placebo controlled trials lasting from 24 to 52 weeks, in a total of approximately 9000 patients. In four trials, the average frequency of exacerbations fell by about 0.2 episodes per patient per year, but the statistical significance of the difference was variable. Even in the most favourable trials, roflumilast did not reduce the frequency of hospitalisation for exacerbations. In six trials (including the four previous trials), roflumilast led to a statistically significant increase in forced expiratory volume in one second, by about 50 ml on average, but the clinical relevance of this improvement is questionable. An inherently unreliable indirect comparison suggests that roflumilast is less effective than an inhaled corticosteroid. Treatment was stopped because of adverse reactions in 14% of patients taking roflumilast, versus 8.5% in the placebo groups. The most common adverse effects were gastrointestinal disorders (diarrhoea, nausea), weight loss, and neuropsychiatric disorders (insomnia, anxiety, depression). Concerns have been raised about the carcinogenic potential of roflumilast. Roflumilast is metabolised by cytochrome P450 isoenzymes CYP 3A4 and CYP 1A2, creating a high potential for pharmacokinetic interactions. In practice, it is better not to use roflumilast. For patients with severe COPD and repeated exacerbations, the standard treatment remains an inhaled bronchodilator combined with an inhaled corticosteroid, or oxygen therapy in some cases. PMID- 23367676 TI - Common stem: -stat. PMID- 23367675 TI - Oxycodone + naloxone: choose morphine and optimal laxative therapy instead. AB - At high doses of oxycodone, the fixed-dose combination of oxycodone plus naloxone complicates therapeutic management and will likely have lower analgesic efficacy. PMID- 23367677 TI - Botulinum toxin type A and neurogenic urinary incontinence: sometimes beneficial, if used safely. AB - Patients with spinal cord injury or multiple sclerosis are often troubled by urinary incontinence due to detrusor (bladder muscle) overactivity. For patients who use intermittent self-catheterisation, empirical treatments for urinary incontinence include: optimisation of catheterisation; anticholinergic drugs; and, in some cases, surgery. The indications of botulinum toxin type A (Botox, Allergan) in France have been extended to cover this situation when anticholinergic drugs are ineffective. Clinical evaluation is based on 2 double blind randomised placebo-controlled trials in a total of 691 patients who had an average of about 32 episodes of urinary incontinence per week.These trials tested the efficacy of a total dose of 300 or 200 units of botulinum toxin type A. Six weeks after toxin injection into the bladder wall, about 40% of patients had no further episodes of incontinence, compared to 10% of patients who received placebo injections. The median duration of the effect was 42 to 48 weeks after a dose of 200 units (13 to 18 weeks with placebo). It remains to be shown whether botulinum toxin has any long-term benefits in terms of complications (hospitalisation, urinary tract infections, etc.). The main adverse effects of botulinum toxin injections in these patients were urinary tract infections (51% versus 36% with placebo) and urinary retention (18% versus 3%). Both differences were statistically significant, and these events were most frequent in patients who had not yet started to self-catheterise (mainly patients with multiple sclerosis). Cases of autonomic hyperreflexia with favourable outcome were also reported. Botulinum toxin type A has been marketed since the 1990s in other indications. It has been linked to life-threatening adverse effects on tissues at a distance from the injection site, following its diffusion throughout the body. Muscle weakness, asthenia and constipation have been reported. A negative effect on the course of multiple sclerosis cannot be ruled out. Botulinum toxin type A injection into the bladder wall necessitates cystoscopy, an invasive and very inconvenient procedure that requires antibiotic prophylaxis and sometimes anaesthesia. Cystoscopy also carries a risk of punctures and tears, etc. In practice, existing treatment options are unsatisfactory for patients in whom anticholinergic drugs fail to control urinary incontinence due to neurogenic detrusor overactivity. Botulinum toxin type A temporarily prevents incontinence for a few months in about one-third of patients, but it is difficult to administer. In experienced hands, it may be beneficial for patients with very troublesome incontinence who self-catheterise. PMID- 23367678 TI - Prevention of wrong-site and wrong-patient surgical errors. AB - Surgical errors recorded between 2002 and 2008 in a US medical liability insurance database have been analysed. Twenty-five wrong-patient procedures were recorded, resulting in 5 serious adverse events: three unnecessary prostatectomies were performed after prostate biopsy samples were mislabelled; vitrectomy was performed on the wrong patient in an ophthalmology department after confusion between two patients with identical names; and a child scheduled for adenoidectomy received a tympanic drain. There were also 107 wrong-site procedures, with one death resulting from implantation of a pleural drain on the wrong side. Another 38 patients experienced significant harm: 5 patients had surgery on the wrong vertebrae; 4 had chest tubes placed on the wrong side; 4 underwent vascular surgery at the wrong site; and 4 underwent resection of the wrong segment of the intestine. In addition, there were: 4 organ resection errors; 6 wrong-site or wrong-sided limb surgeries; 2 wrong-sided ovariectomies; 2 wrong-sided eye operations; 2 wrong-sided craniotomies; 2 wrong-sided ureteric procedures; 1 wrong-sided maxillofacial operation; and 2 radiation therapy field errors. Most errors were due to poor communication, incorrect diagnosis, or failure to implement a final set of preoperative checks. Other studies conducted in the United Kingdom and the United States have provided similar results, while data are lacking in France. The World Health Organization Surgical Safety Checklist is an effective way of preventing such errors but its adoption by healthcare professionals is variable. In practice, surgical errors involving the wrong patient or wrong body site are preventable. Final pre-operative checks must be applied methodically and systematically.This includes asking the patient to confirm his/her identity and the intended site of the operation. Healthcare staff must be aware of these measures. PMID- 23367679 TI - Locally advanced prostate cancer: effective treatments, but many adverse effects. AB - Locally advanced prostate tumours, i.e. those that extend beyond the prostate gland but are not metastatic, often carry a poor prognosis: between 10% and 40% of patients die within 5 years after diagnosis. Various treatments are proposed to improve their prognosis. Which treatments have a proven survival benefit, and what are their adverse effects? To answer these questions, we reviewed the literature using the standard Prescrire methodology. Prostatectomy has not been evaluated in controlled trials versus either watchful waiting or radiation therapy alone. Prostatectomy is mainly proposed to patients who are in good general health. Five years after prostatectomy, mortality from prostate cancer is between 2% and 16%, depending on the study.Three-quarters of patients who have surgery at this stage experience erectile dysfunction, and at least 20% of patients develop urinary incontinence. External beam radiation therapy alone has not been compared with watchful waiting or prostatectomy. External beam radiation therapy has documented benefits in patients with locally advanced prostate cancer treated with gonadorelin agonists, preventing 8 to 10 deaths from all causes after 7 to 10 years of follow-up among 100 treated patients. However, about 60% of patients experience erectile dysfunction, about 15% symptomatic radiation proctitis, and about 5% urinary incontinence. When combined with prostatectomy, radiation therapy did not affect the 5-year survival rate but prolonged survival by about 2 years in a trial with more than 10 years of follow-up. When used without concomitant androgen suppression, antiandrogens have no proven impact on overall survival in patients with locally advanced prostate cancer. In the absence of radical prostatectomy or radiation therapy, androgen suppression, by means of orchiectomy or gonadorelin agonist, has a minimal impact on overall survival among patients with locally advanced cancer. In one randomised trial, androgen suppression in combination with prostatectomy prolonged median survival by about 2.5 years among patients with lymph node involvement. In another randomised trial, treatment with a gonadorelin agonist and flutamide for 6 months, started before radiation therapy, reduced the 10-year overall mortality rate to 29%, versus 43% after radiation therapy alone. Androgen suppression for at least 3 years after radiation therapy prevented 10 to 18 deaths from all causes per 100 patients during 10 to 15 years of follow-up in three randomised trials that provided similar results. Shorter durations of treatment appeared to be less effective in 3 other randomised controlled trials. The adverse effects of gonadorelin agonists often undermine patients' quality of life, due to hot flushes, loss of libido, erectile dysfunction, gynaecomastia, osteoporosis, weight gain, cardiovascular events, and diabetes. In mid-2012, European clinical practice guidelines recommend a combination of radiation therapy and androgen suppression for 2 to 3 years for most patients with locally advanced prostate cancer. Before choosing between therapeutic options, it is crucial to take into account the patient's priorities in terms of treatment efficacy and adverse effects, and reversibility of adverse effects. PMID- 23367680 TI - Limiting the adverse effects of androgen suppression. AB - Inform patients of the impact of treatment on quality of life, and discuss strategies to limit adverse effects. PMID- 23367681 TI - Choice of treatment for locally advanced prostate cancer. PMID- 23367682 TI - The price of admission. PMID- 23367683 TI - White coats and recommitment. PMID- 23367684 TI - Comprehensive primary care initiative. Discussion and early reaction by participating physicians and payers. PMID- 23367685 TI - A new immunization information system: Introducing Arkansas WebIZ. PMID- 23367686 TI - Cannabinoid hyperemesis--is it more common than we think? PMID- 23367687 TI - Distribution of human papillomavirus (HPV) types and anti-HPV T-cell immune responses among different racial/ethnic groups in Central Arkansas. AB - The distribution of human papillomavirus (HPV) types and T-cell immune responses were compared among European American, African American, and Hispanic American populations being followed for abnormal Papanicolaou smear results who were attending the same university medical center clinic in Central Arkansas. Statistically significant differences were found for HPV types 55, 58, and 83 among the 37 HPV types tested. However, there were no differences in T-cell immune responses among these racial/ethnic groups. These results are unlikely to have an impact on therapeutic HPV vaccine development since the most prevalent HPV type among all racial/ethnic groups was HPV type 16. PMID- 23367688 TI - AMS-MSS Spring Health Fair. PMID- 23367689 TI - A day in the of diabetes. PMID- 23367690 TI - Trend Spotting. What's new and what's on one device user's wish list. PMID- 23367691 TI - Blood glucose meters. What to look for--and what to know. PMID- 23367692 TI - Insulin pens. Write an Rx for health with this handy tool. PMID- 23367693 TI - Aids for insulin users. These devices may ease your routine. PMID- 23367694 TI - Glucose products. These sweet sources can help treat hypoglycemia. PMID- 23367695 TI - [The future is to share decisions with patients. Interview by Benoit Perrier and Bertrand Kiefer]. PMID- 23367696 TI - [Addiction]. AB - What's new in addiction medicine in 2012? The news are presented according three axes: first, in the field of neuroscience, the process of extinction of addiction memories. Then in the clinical field, a reflexion is reported on how to treat addiction in psychiatric hospitals. At last, in the area of teaching, an e learning development with a virtual patient shows a great interest in addiction psychiatry. PMID- 23367697 TI - [Management of adverse events induced by TNFalpha blocking agents]. AB - TNFalpha blocking agents are effective and essential tools in the management of many inflammatory conditions including rheumatoid arthritis, spondylarthropathies and chronic inflammatory bowel disease. With time, some known side-effects have gained in importance and others have appeared. This article focuses on the potential risks of infection and autoimmunity induced by TNFalpha blocking agents and on the strategy to prevent and treat such adverse events. PMID- 23367698 TI - [Systemic mastocytosis--new therapeutic strategies]. AB - Systemic mastocytosis is characterized by an excessive proliferation of mast cells and their accumulation in different organs. Avoidance of trigger factors leading to anaphylaxis is a general measure valid for all forms of mastocytosis. A premedication is necessary in case of surgery, anesthesia or administration of radiocontrast agents. Symptomatic treatment comprises antihistamines, anti leukotrienes, proton pump inhibitors and topical corticosteroids. Indolent mastocytosis with refractory symptoms, the rare cases of aggressive mastocytosis with organ dysfunction and the even rarer mast cell leukemia require cytoreductive therapy. First-line agents are interferon alpha 2b and imatinib, a tyrosine kinase inhibitor. To date there is no curative treatment. PMID- 23367699 TI - [Interests of recombinant allergens in the practice of allergy]. AB - Compared to total allergenic extracts, recombinant allergens available for specific IgE measurement represent an important advance in the diagnosis and treatment of IgE-mediated allergies. Recombinant allergens lead to define the sensitization profile of allergic patients, to identify markers of sensitization and to understand better polysensitivities related to cross-reactions and markers of severity of allergic reactions. They also contribute to the decision to establish tolerance induction (allergen specific immunotherapy) and the optimal selection of the allergenic composition of the vaccine. PMID- 23367700 TI - [Cardiology]. AB - The present review provides a selected choice of clinical research in the field of interventional cardiology, heart failure and cardiac imaging. We also focused on the new guidelines published by the European society of cardiology in 2012. PMID- 23367701 TI - [Endocrinology in 2012: what's new?]. AB - Maternal hypothyroidism has been associated with intellectual impairment in offspring and, subsequently, routine thyroid screening during pregnancy remains controversial. However current literature has reported no benefit of systematic thyroid screening and substitution with levothyroxine of hypothyroid pregnant women on cognitive function in offspring. Recent studies suggest that subclinical hypothyroidism and hyperthyroidism, especially those with TSH >10 mIU/l or <0.1 mIU/l are associated with cardiovascular morbidity and mortality. Genetic markers are being studied in order to clarify the nature of benign or malignant thyroid nodules after fine-needle aspiration whom cytology is indeterminate. They could avoid the need for surgery in many cases. PMID- 23367702 TI - [Review in geriatric medicine 2012]. AB - 2012 brought additional evidence regarding the benefits of exercise in older persons in showing morbidity compression in those most active. Several studies invite to revise therapeutic targets in older diabetics, especially those with cognitive impairment or dementia where a value of 8 to 9% for HbAlc might be a good compromise. On the dementia side, a study suggests that biological and structural abnormalities associated with Alzheimer's disease might occur as early as 25 years before its first clinical manifestations. On the therapeutic side, ginkgo and the double therapy with memantine and donepezil did not make it in RCTs, and two studies about treatments for behavioral symptoms of dementia showed that interruption could be deleterious. PMID- 23367703 TI - [What's new in gynecology and obstetrics in 2012?]. AB - Intraoperative radiotherapy (IORT) has been shown to be as effective as traditional radiotherapy in the management of early stage breast cancer. IORT is performed in a single session and consists in a single irradiation in the tumorectomy cavity. Medically assisted procreation does not seem to favor neither gynecological nor non-gynecological cancers. Nevertheless medically assisted procreation technique ICSI (intracytoplasmic sperm injection) is associated with an increased risk of birth defect. This is not the case of IVF (in vitro fertilization). The causality of the treatment or of the infertility itself is unclear. During pregnancy, nicotine-replacement patches at usual dosage do not seem to increase abstinence smoking rates. A selective, and not a systematic thyroid screening strategy, is now recommended during first trimester of pregnancy. PMID- 23367704 TI - [Infectious diseases]. AB - Cranberry containing products can protect against recurrent UTIs. The duration of treatment for uncomplicated pyelonephritis can be safely shortened to 7 days when using ciprofloxacin. Early surgical treatment for infective endocarditis in patients with large vegetations (> 10 mm) and valve dysfunction should be considered, even in the absence of urgent indications for surgery. Enterobacteriaceae with ESBL are less transmitted in hospital than in households. Tattoo ink-related mycobacterial infections are increasingly reported, even in Western Switzerland. Differentiating acute bacterial from viral rhinosinusitis on clinical criteria remains difficult. Antibiotic and non-antibiotic prevention of acute exacerbations of COPD is still a hot topic, we propose to discuss here. PMID- 23367705 TI - [HBSC study on young adolescents' health behaviours: some insights for practitioners]. AB - Lifestyle choices exert a major influence over the present and future health of adolescents. The international study "Health Behaviour in School-aged Children (HBSC)" was created to monitor the social determinants, the health and risk behaviours, and the protective and adverse factors that each influence young adolescents' health. The survey is conducted every four years, and the WHO produced its latest edition in the spring of 2012 (using the 2010 data). We have selected and summarised what seem to be the most important insights for Swiss clinicians. The overall results are satisfactory but some weaknesses remind us that prevention is an ongoing challenge both in private practices and in public policy. PMID- 23367706 TI - [Emergency medicine: updates 2012]. AB - We review some of the most influential papers from 2012 in the different aspects of emergency medicine, such as prehospital medicine, resuscitation, early diagnosis and timely ED discharge and treatment. In particular, intramuscular benzodiazepines have been shown to be efficient in prehospital status epilepticus, epinephrines usefulness in cardiopulmonary resuscitation has been challenged, colloids have been shown to be deleterious in the treatment of severe sepsis and septic shock, the time window for thrombolysis in acute stroke will probably be extended, acute pyelonephritis treatment duration can be decreased, new D-dimers thresholds for older patients may prevent further diagnosis tests, and hs-Troponin may allow earlier discharge of low coronary risk patients. PMID- 23367708 TI - [Thyroid associated orbitopathy: from diagnosis to treatment]. AB - Mild to moderate forms of orbitopathy are common in auto-immune thyroid diseases, whereas severe forms are rare. Euthyroidism restoration, no smoking, and ocular local lubricants are necessary for all the patients. In case of mild orbitopathy, treatment by selenium is now indicated. Active forms of thyroid orbitopathy are better treated by IV steroids. Surgery is indicated in optic neuropathy resistant to steroids and in sequellar forms of the disease. PMID- 23367707 TI - [2012: news in neurology]. AB - In 2012, intramuscular midazolam appears as effective as intravenous lorezepam for the first line treatment of convulsive status epilepticus. Perampanel, a new anti-epileptic drug, will be soon available. Two oral treatments are now available for stroke prevention in atrial fibrillation setting. The methylphenidate and the Tai Chi could increase the walk capacity of patients suffering from Parkinson disease. A comprehensive cardiac work-up is essential for some congenital myopathy. A new drug against migraine seems free from vasoconstrictive effect. Antioxidants are harmful in Alzheimer disease. Some oral medication will be available for multiple sclerosis. PMID- 23367709 TI - [Pharmacovigilance update]. AB - Main pharmacovigilance updates in 2012 are reviewed here. Dabigatran: elderly patients with renal failure are at higher risk of bleeding. Dual renin angiotensin-aldosterone system blockade comprising aliskiren is harmful. Incretins: low risk of acute pancreatitis. Interaction between fusidic acid and statins: many reports of rhabdomyolysis. Interactions between boceprevir/telaprevir and antiretroviral therapies: complex, but manageable. Citalopram, ondansetron: maximum recommended doses are reduced. Atomoxetine: significant increase in blood pressure and heart rate in a fraction of exposed patients. Agomelatine: elevated liver enzymes are common. Fingolimod: bradycardia and heart blocks after first dose - stronger safety recommendations regarding use in patients with heart conditions and strengthened cardiovascular monitoring. PMID- 23367710 TI - [Psychiatry]. AB - Contemporary psychiatry uses a variety of complementary approaches which enrich one another. In this paper, we describe the development of a brief psychodynamic approach for hospitalized patients with major depression, as well as the recent commercialization of an atypical neuroleptic depot medication. In addition, we discuss electro-convulsotherapy which, despite it has been widely and understandably condemned on the basis of its abusive and non medical application in certain political contexts, deserves objective assessment on the basis of scientific data stemming from recent research suggesting it is in some contexts a valuable tool. PMID- 23367711 TI - [Medical deserts are talking to us, what do they say?]. PMID- 23367712 TI - [Wisdom of the tree]. PMID- 23367713 TI - [Gerard Depardieu, or cholesterol-made necklace]. PMID- 23367714 TI - [The HIV virus used as antileukemic vector]. PMID- 23367715 TI - [2012, the hybridization is making progress]. PMID- 23367716 TI - Bending rules. There are many ways to save lives. PMID- 23367717 TI - Knowing normal. What it can teach you about the abnormal. PMID- 23367718 TI - Unexpected drop-ins. A multipatient MVC involves victims from out of town. PMID- 23367719 TI - The EMT in court. When you're called to testify, preparation is paramount. PMID- 23367720 TI - Q&A with Todd Stout. How data can assist agencies in managing critical everyday issues. Interview by Jenifer Goodwin. PMID- 23367721 TI - No meat loaf for Lucy. In EMS, opportunities for good food are rare. PMID- 23367722 TI - [What a dentist should know about renal insufficiency: Part A]. AB - The present article is reviewing the expressions of kidney disease emphasizing special precautions needed when treating these patients. For better life quality and prevention of life threatening complications. PMID- 23367723 TI - [What a dentist should know about renal insufficiency: Part B]. AB - The present article is reviewing the expressions of kidney disease emphasizing special precautions needed when treating these patients. For better life quality and prevention of life threatening complications. PMID- 23367724 TI - [Impressions techniques--Part 2]. AB - A dental impression is a positive replica of the teeth, the surrounding gingiva and the border between them; the purpose of which is to create an accurate master model. Two major techniques for impressions exist today: The conventional and the digital impressions. The current article describes both techniques. In the conventional impressions, it is important to choose a proper tray, stock or custom, and to mix the material properly. The commonly used impression techniques for making a conventional impression are described with a review on the effect of the technique on its accuracy. The effect of the wash bulk on the accuracy of the stone dies and/or the restoration is discussed, as well. The digital impressions with their advantages and disadvantages are described in comparison to the conventional impressions. Although, digital impressions eliminate some of the negative characteristics of conventional impressions, proper soft-tissue management and isolation of tooth preparation margins is still mandatory. PMID- 23367725 TI - On advanced dental treatments and adverse reactions of drugs. PMID- 23367726 TI - [The findings and sequence of events leading to termination of pregnancy due to Down's syndrome--before and after the verge of viability: 10 years experience at a single medical center]. AB - OBJECTIVE: To assess the differences in the sequence of events, leading to termination of pregnancy (TOP) due to diagnosis of Down syndrome (DS). The study compared women who were referred to institutional abortion committees (< 23 weeks) to those who were referred to supreme regional abortion committees (> 23 weeks). METHODS: Cases of singleton pregnancy ending in TOP due to DS in our institute during the period January 2000-December 2010 were retrospectively reviewed. The women were divided into two groups according to the gestational age at the time of the TOP. Group 1 included women who underwent TOP prior to 23 weeks of pregnancy; group 2 included women who had TOP at 23 weeks and onwards. The groups were compared regarding their demographic, sonographic and biochemical parameters during the affected pregnancy. Women in group 2 completed a telephone questionnaire about the circumstances leading to a late TOP after 23 weeks. RESULTS: There were 303 cases of DS, which had TOP during this period of time. All cases were diagnosed by fetal karyotyping. A total of 282 cases (93%) had earlier TOP while 21 cases (7%) had late TOP. The mean gestational age in each group was 18 weeks (range 12-22 weeks] versus 24 weeks (18-34 weeks) respectively (p < 0.001). In group 2, there were significantly more abnormal cardiovascular findings (67% vs. 21% in group 1, p < 0.002). No other significant differences were found between the groups regarding the demographic parameters, biochemical screening results (triple test), nuchal translucency (NT) and early and/or late sonographic anomaly scans. In Group 2 a total of 9 (42.8%) out of 21 women agreed to answer the telephone questionnaire. In this group the triple test, was performed in the upper recommended time limit according to the Ministry of Health. This may have led to the delay in the TOP. CONCLUSION: In our institutional experience we found that the circumstances leading to late TOPs because of DS were maternal dependent and not related to the screening findings. This stresses the efficiency of current screening programs, leading to early karyotyping and diagnosis of DS. PMID- 23367727 TI - [Secondary traumatization/trauma among employees in palliative care units--the products of prolonged repeated exposure to suffering and death]. AB - The palliative care philosophy accepts the dying process as a natural phase in the life cycle and provides quality end of life care for terminal patients and their family members. Prolonged exposure to the physical symptoms and pain, as well as the psychological, spiritual, and existential suffering of the dying patient, may be fertile ground for the development of post-traumatic stress symptoms among palliative care teams. Work-related positive outcomes (such as compassion, satisfaction and meaning) and work-related negative outcomes (such as compassion fatigue, secondary traumatization and burnout) can exist side by side, and the unique balance between them will determine the quality of life of the worker. This review presents the current knowledge about the prevalence and causes of work-related stress outcomes among palliative care teams and measurement tools that are available. The literature review discusses secondary traumatization in palliative care teams and relevant messages for the development of treatment options, burnout prevention programs and support interventions for professionals who lead the care for terminal patients in Israel. PMID- 23367728 TI - [Effort thrombosis of the right subclavian vein]. AB - This case report illustrates a primary upper extremity DVT of the right subclavian vein in an otherwise healthy young male. The pathogenesis of primary upper extremity DVT may be anatomical, such as thoracic outlet syndrome, vascular microtrauma e.g. effort thrombosis, or both. After examining the patient's clinical presentation and imaging results, a diagnosis of effort thrombosis, or "Paget-Schroetter syndrome" was made. Due to the clear insulting factor, the mild clinical presentation, and the fast response to anti-coagulant treatment, a conservative treatment was followed, which included anti-coagulation and close follow-up, as advised by the American College of Chest Physician's evidence-based clinical practice guidelines. PMID- 23367729 TI - [Unilateral choanal atresia: a missed diagnosis]. AB - Bilateral choanal atresia is a congenital anomaly usually diagnosed at birth. In contrast, unilateral atresia causes variable degrees of nasal stuffiness and discharge that might mask the diagnosis and delay the proper treatment. We present five cases of unilateral atresia in which the correct diagnosis was delayed and erroneous treatments were instituted--two adults who had undergone unnecessary septal and turbinate surgery, two older children who were treated medically and one patient who was treated for epiphora. Insufficient awareness of this entity occurring in adults and older children and other possible causes of diagnostic error are discussed. A unilateral mucoid or watery rhinorrhea and obstruction, that lasts from early childhood without evidence of sinusitis and not responding to any medical treatment, should alert the physician to consider unilateral atresia and to perform endoscopic and computed tomography examinations at an early age. Careful interpretation of the computed tomography scan including the axial planes is required. PMID- 23367730 TI - [Recurrent infections in an ITP patient treated with rituximab]. AB - Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by hypogammaglobulinemia and recurrent infections. Various mechanisms have been implied in the disease pathophysiology. Patients with CVID are at increased risk of developing ITP (Immune Thrombocytopenia Purpura) and/ or AIHA (Autoimmune Haemolytic Anemia). Rituximab, a humanized anti-CD20 monoclonal antibody, is increasingly being used for autoimmune cytopenias including ITP and AIHA. This is a case history of a patient treated with Rituximab due to refractory ITP. A year after completion of therapy the patient started suffering from an increased frequency of infections. Six years after treatment with Rituximab the patient was diagnosed with CVID and IVIG replacement treatment was started. The main possibilities that this patient presents include aggravation of CVID, first presented as ITP, after Rituximab treatment versus CVID secondary to Rituximab treatment. PMID- 23367731 TI - [Persistent hypogammaglobulinemia in an ITP patient following treatment with rituximab]. AB - In some cases, immune-mediated thrombocytopenia (ITP) is severe, and requires second-line therapies such as splenectomy and/or Rituximab. In most cases Rituximab is beneficial and safe but in some (though rare) it induces significant hypogammaglobulinemia and persistent decreases in the number of B cells. Patients in whom baseline levels of serum IgM or IgG are low become more prone to develop common variable immune deficiency (CVID) especially when more than one cycle of Rituximab is given. In a few case reports, immune-mediated thrombocytopenia was shown to precede the development of CVID. This could possibly develop following a second bout with Rituximab. The assessment of baseline serum immunoglobulins should be routine in all patients with chronic ITP and those who are candidates for Rituximab therapy. PMID- 23367732 TI - [Medical inventions: developments and approaches in employer-employee [correction of worker-employee] relations]. AB - The past twenty years have witnessed a huge increase in research activity on the government health system in Israel. Consequently, a number of questions of enhanced importance arise: to whom the resultant IP (intellectual property) belongs?--to the researcher or the employer? and what compensation should the researcher receive for his inventive efforts? The government found many cases where the IP was registered in the name of the inventor/researcher, thus denying the government ownership of the IP. In 2009, the government sued Omryx over ownership of such an IP. Following these developments, the government issued new rules for management of IP in the government health system. They came into effect in November 2010. In many respects, the new rules are more stringent than the Israeli Patent Law in respect of the inventor. However, the stipulation of awards to the inventor in the new rules is generous. In order for the new rules to be enforceable, the following guidelines are recommended: The new rules should be more aligned with the Patent Law and with the meaning given to the Law by the judicial system, and There is need for the assent and awareness of health system workers to the conditions set out in the new rules, preferably in the form of new work contracts that clearly and concurrently delineate the worker's duties, particularly those pertaining to IP. PMID- 23367733 TI - [Diabetes mellitus and cancer: the different expression of these diseases in Israeli Arabs and Jews]. AB - BACKGROUND: The Arab population of Israel is a separate ethnic group from the Jewish population, embracing a different lifestyle and different nutritional habits and environmental exposures. These variations may lead to dissimilar expressions of certain diseases in the Arab Israeli as compared with the Jewish population. In recent years, the Arab population in Israel has experienced rapid and marked changes toward westernization in lifestyle, and significant increases in the incidence rate of both diabetes mellitus (DM) and cancer This is combined with an increase in known risk factors common to both illnesses. METHODS: Review of recent publications and official health statistics provided the sources of information for this review. RESULTS: Studies show that in recent decades the incidence rate of DM in the Israeli Arab population has increased by 9.1 per 1000 persons annually and of cancer by 1.3 per 1000 person annually among males and by 1.2 per 1000 person among females. In contrast, these rates have decreased in the Jewish population. CONCLUSIONS: Lifestyle change in recent decades (westernization) in the Israeli Arab population has led to a marked increase in the incidence rate of DM and cancer in this group. The most influential risk factors are unhealthy diet, physical inactivity and tobacco smoking. By understanding these processes, effective intervention efforts can be initiated in order to reverse these trends. PMID- 23367734 TI - [The role of medicinal herbs with anti-inflammatory properties in prevention and treatment of cancer]. AB - The association between chronic inflammation and carcinogenesis, as well as neoplastic progression, has been researched and is well-established. Being a central coordinator of immune responses, nuclear factor-kappa B (NFkappaB) signaling plays a critical role in cancer development and progression. The activation of the NFkappaB signaling pathway is highly monitored under normal conditions, and is mainly known as a key pathway in activation of immune responses. Constitutively active NFkappaB has been identified in most tumor cell lines, as well as in a wide variety of tumor tissues derived from cancer patients. Such activation may also affect the cancer's response to therapy, making it less susceptive to radio and chemo treatment. Hence, NFkappaB has become a target for inhibition by chemotherapeutic agents. Traditionally, medicinal herbs have been used to prevent and treat a variety of diseases, including cancer. In this article, we review several natural, herbal-derived compounds shown to have anti-inflammatory and anticancer activities mediated, at least in part, by NFkappaB signaling inhibition. Compounds of this sort may potentially serve as clinically effective anticancer treatments. PMID- 23367735 TI - [Psychological and mental aspects and "tender loving care" among women with recurrent pregnancy losses]. AB - Recurrent pregnancy losses (RPL) represent psychological trauma. This may be due to the fact that in about 50% of the cases the etiology is not found and also as a result of the fear of the results of the next pregnancy. Patients with RPL develop different psychological and psychiatric effects after pregnancy losses. This article reviews the Literature on the psychological aspects that develop after RPL, including depression, anxiety, post-traumatic stress disorder (PTSD) and obsessive compulsive disorder (OCD). In addition to psychological effects due to spontaneous pregnancy loss, only a few studies discuss the psychological and psychiatric treatments for these issues. One of the most common and well-accepted forms of treatment, especiaLly for those with idiopathic RPL, is tender Loving care (TLC). Studies have shown that these treatments may have a significant impact on the chance of a live birth rate in the next pregnancy. In the Soroka University Medical Center a very clear protocol exists including supportive care for couples with RPL. In general, the live birth rate for these couples after admitting to the RPL and performing the evaluation is around 80%. PMID- 23367736 TI - [Review of Peyronie's disease]. AB - Peyronie's disease may be idiopatic or secondary to sexual intercourse. Medical treatment includes vitamin E, colchicine and tamoxifen, which provide a very limited solution. Lately, intralesional injection of verapamil and other substances have achieved a reasonable effect. The best cosmetic result is achieved by surgery which is recommended at least a year after onset of the problem. Surgery may result in penile shortening. PMID- 23367737 TI - [Summary of the occupational aspects in the ERS--European Respiratory Conference Amsterdam 2011]. PMID- 23367738 TI - [How to submit a request for a clinical study to the ethics committee?]. PMID- 23367739 TI - [How to build a predictive model and how to predict the individual outcome?]. PMID- 23367740 TI - [Length and outcome of acute inpatient rehabilitation for hospital-associated deconditioning in the elderly]. AB - INTRODUCTION: Acute illness and prolonged bed rest might be associated with loss of muscle mass and significant decline in functional ability and mobility, regardless of a specific neurological or orthopedic insult. This condition is commonly termed hospital-associated deconditioning (HAD). To the best of our knowledge to date, acute inpatient rehabilitation length and outcome for HAD in the elderly have never been studied in Israel. AIM: To study which variables are independently associated with the length and mobility outcome of acute inpatient rehabilitation for HAD in the elderly. METHODS: A retrospective cross-sectional study was conducted during 2009 at the departments of Geriatric Medicine in the Tel-Aviv Medical Center The medical charts of consecutive elderly (< 65 years) patients admitted for rehabilitation due to HAD were studied for the following measurements: demographics, co-morbidities, causes of HAD, admission albumin serum levels, Mini-Mental Status Examination (MMSE) scores, admission transfer and walking Functional Independence Measure (FIM) scores, discharge transfer and walking FIM scores, and rehabilitation length. RESULTS: The cohort included 103 patients: 57 (55.3%) females and 46 (44.7%) males. The mean age for the entire cohort was 83.6 +/- 6.0 years. The three most common causes of HAD were pneumonia, craniotomy due to intracranial bleeding without neurological insults, and congestive heart failure exacerbation. The mean discharge transfer and walking FIM scores were 5.3 +/- 0.9 and 5.2 +/- 0.8, respectively. The mean length of rehabilitation was 20.4 +/- 13.9 days. Linear regression analysis showed that discharge transfer FIM scores, discharge walking FIM scores, and rehabilitation length were all independently associated with mobility upon admission to rehabilitation (p < 0.0001, p < 0.0001, p = 0.024, respectively). Rehabilitation length was also associated with admission albumin serum levels (p = 0.008). CONCLUSIONS: The length and mobility outcomes of acute inpatient rehabilitation for HAD in the elderly are associated with mobility upon admission to rehabilitation. Acute inpatient rehabilitation length is also associated with admission albumin serum levels. PMID- 23367741 TI - [Five years experience at a community-based comprehensive geriatric assessment unit in southern Israel]. AB - BACKGROUND: The health care of the growing number of older people in the population is predominantly provided by the family physician, who is usually faced with time limitations. A community-based Comprehensive Geriatric Assessment (CGA) unit has the potential to provide the family physician with the necessary support required in managing older patients. OBJECTIVES: To describe and review the structure and clinical experience of a community-based CGA unit over a period of five years. METHODS: The CGA unit comprises a multidisciplinary team that utilizes a comprehensive array of assessment instruments. Specific emphasis is placed on comorbidity, polypharmacy, cognitive and affective status, social support and daily function. RESULTS: Over a period of five years, 456 older patients were evaluated. The mean age was 76.7 +/- 6.1 years and 36.2% were women. A total of 6.57 +/- 2.72 new diagnoses were made, the most common being dementia (60.1%), recurrent falls (43.9%) and social problems (32.5%). There were an average of 7 recommendations provided to the family physician, the majority relating to preventive medicine, fall prevention, improving mobility and social interventions. Based on a sample of files evaluated some six months later, we found that these recommendations had been carried out by family physicians to varying degrees. Prescriptions for new medications were provided for 55.6% of those recommended, 45.5% drugs were discontinued as suggested, and 44.4% investigations were performed. Preventive medicine recommendations were carried out in only 11.4% of patients. PMID- 23367742 TI - [A multicenter intervention study on referral to cardiac rehabilitation after coronary artery bypass graft surgery: a 1-year follow-up of rehabilitation rates among USSR-born and veteran Israeli patients]. AB - BACKGROUND: Despite evidence on the benefits of participating in cardiac rehabilitation (CR) following coronary artery bypass graft (CABG) surgery and the inclusion of CR in the basic "Health Basket", referral and uptake of CR in Israel remain low. OBJECTIVES: To assess the CR participation rate and CR-related outcomes 1-year following CABG-surgery among patients born in the former Soviet Union and veteran-Israelis. METHODOLOGY: An interventional trial was conducted in which 489 and 472 CABG patients from 5 cardiothoracic wards across Israel were interviewed in hospital before surgery, and at home a year later for the control arm and the intervention arm respectively. The intervention included dissemination of information on CR to medical staff and patients. FINDINGS: USSR born patients constituted 22.5% of the sample. They were one year older than veteran-Israelis (median-age: 68 and 67 years, respectively, p = 0.2), had a larger proportion of women (31.5% vs. 22.4% respectively, p = 0.006), and a larger proportion of widows (20.0% vs. 13.6%, respectively, p = 0.02). Following the intervention, the CR participation rate of veteran-Israeli males increased from 24.6% to 40.4% (p < 0.001), and that of USSR-born males increased from 3.7% to 13.4% (p = 0.037). No USSR-born female participated in CR, while participation rates of veteran-Israeli females increased from 14.6% to 26.9%, p = 0.056. CR participants reported better health-related quality of life and higher levels of cardio-respiratory fitness (p < 0.001) at follow-up, compared to patients who did not participate in CR. CONCLUSION: The intervention was effective in increasing the participation in CR programs among all but USSR-born females. Further research is needed to assess the needs of this subgroup and develop effective interventions. PMID- 23367743 TI - [The challenge of geriatric medicine in the twenty-first century]. AB - During the last generation the population in Israel has doubled and the number of hospital beds per capita has declined to the lowest number in the OECD. This has implications on the number of physicians and nurses, as well as the nation's capacity to educate medical staff, while there are no increases in the infrastructure. Shortening the length of stay for acute medical conditions to an average of about three to four days is the main consequence of this situation. About 800,000 elderly people over 65 years of age are now living in Israel. Many of them suffer from acute conditions with complicating chronic morbidities. Currently, they are the main victims of the present crisis in medical services in Israel. Aging is accompanied by a decline in the physiological reserves leading to increased morbidity, decreases in function and a prolonged period for returning to normal function after trauma or acute disease. During the twentieth century, the science of medicine progressed rapidly. The pathogenesis of many conditions, either chronic or acute, was recognized, as well as the structure of the human genome and many pharmaceutical, as well as other technologies, were developed for the cure and care of diseases. Nevertheless, understanding the aging process remains a challenge. Geriatric medicine is a medical specialty that deals with a process--the process of aging, which is like pediatrics, and unlike other specialties that concentrate on systems (cardiovascular, gastroenterology, blood, immune system etc.). The added value of the geriatrician in medical practice is in the knowledge of the scientific background of aging, as well as the practical implications concerning physical and cognitive decline of function with aging and its accompanying morbidity. The practice of Geriatric Medicine is the art of connecting the biological and medical sciences to the function and the environment of the individual aging person. It requires dedicating a lot of time and patience on the part of the physician, to retrieve the information, to build confidence in the relationship with the patient and to lead the patient to continue living with an optimal quality of life in his remaining years. During the last decades, the number of geriatricians in Israel has doubled, obligatory clerkship in Geriatric Medicine is part of the medical schools' curriculum and Geriatric Medicine is part of the board curriculum in Internal Medicine and Family Medicine. Thus, Geriatric Medicine maintains the art of medical practice, using the recent knowledge in biology and medical sciences, and dealing with the population with the highest level of morbidity and lowest function. The Geriatric Medicine approach to the old person who needs medical help has to lead medical practice in the near future, so that we can preserve the great achievements of medicine during the twentieth century. PMID- 23367744 TI - [Raising the retirement age]. AB - Social legislation is an essential hallmark of a welfare state. A few years ago many countries in Europe were proud of the extent and depth of their social welfare policy, but, in the shadow of the continuing economic crisis during recent years, as part of other measures, they were obliged to rehabilitate the situation to cut social legislation. The retirement age is slowly rising, possibly climbing back to the age of 70, the age prescribed by Bismarck. It took a century for European Leaders to realize that the "ideal" age to retire is 70. Bismarck's social legislation related well in anticipation of the future, a prescient sage. However, he was unable to guard his political position. He was forced to resign and retire from the political scene after a quarrel with Wilhelm II who approached the Social Democrats. So what he tried to do throughout those years was to oust the Social Democrats from the law. Finally the tables turned as he was forced to resign. Our Sages--our ancestors quoted: "Because you drowned others, they drowned you; and those that drowned you will eventually be drowned", Ethics of the Fathers (Mishnah Pirkei Avot, 2, 7). PMID- 23367745 TI - [Participation in cardiac rehabilitation after coronary bypass surgery: good news, bad news]. AB - Cardiac rehabilitation programs have the potential to decrease morbidity and mortality and increase quality of life after acute coronary events and coronary bypass surgery (CABG). Unfortunately, the proportion of eligible patients that participate in cardiac rehabilitation remains low, despite coverage of such programs by the Israeli National Health Insurance. A low participation rate is especially prominent in women, elderly, minorities and low socioeconomic classes. In this edition of Harefuah, Gendler et at conducted an interventional study aimed at increasing the participation of patients in cardiac rehabilitation programs after CABG in 5 cardiothoracic wards across Israel. They interviewed 489 patients in the intervention arm and 472 patients in the control arm before surgery and a year later. The intervention included dissemination of information on cardiac rehabilitation to the medical staff and patients. Following the intervention, cardiac rehabilitation increased almost twofold in veteran-Israeli males and females. Although it increased significantly in USSR-born male immigrants, their absolute rate of participation remained low (13.6%). No USSR born female participated in rehabilitation, either before or after the intervention. The good news is that a simple, inexpensive intervention can increase participation in cardiac rehabilitation after CABG surgery. The bad news is that this potentially lifesaving activity remains unattended by most USSR-born immigrants, and particularly by females. Additional research is required to explore the cultural, social and economic barriers of this phenomenon. PMID- 23367746 TI - [Ethical dilemma in research: informed consent in clinical studies on persons with dementia]. AB - With the world's population aging, there is an increase in the number of demented elderly. It is vital to study this phenomenon in epidemiological and clinical studies, particularly the effects on the increasing numbers of demented elderly. Researchers need to understand the factors predicting the general decline in the demented elderly. However, before any research is undertaken, it is necessary to obtain approval from the Local Internal Review Board. This committee is responsible to maintain accepted national and international ethical standards. The basis for recruitment to a study is the signature on the informed consent form, where the patient is required to understand the study, internalize the study's aim, to consider all options and finally, to express an opinion. Potential elderly participants need to have their judgment evaluated before signing the form. In cases where the subject is incapable, some countries, including Israel, require that there be a legal guardianship. This is a long and complicated process that causes researchers not to recruit demented patients into a study which may actually be beneficial to all. Some countries allow a proxy to sign informed consent forms to permit the demented subject to participate in the study. Often the threshold may depend on the invasiveness of the intervention. The problem of proxies to sign informed consent form troubles researchers worldwide. This article addresses the history and development of ethics in research, and raises the issue to promote an official policy for proxy consent signing. PMID- 23367747 TI - [Imparting basic knowledge in geriatric medicine to primary care physicians of the elderly--a challenge for the health system]. AB - The increasing number of elderly and their needs challenge the health care system by addressing community physicians with their complex medical problems. Therefore, these physicians should be trained in basic geriatric knowledge in order to ensure the quality of care and improve the cost/ benefit rate. CONCLUSIONS: A multidisciplinary community-based Comprehensive Geriatric Assessment (CGA) is effective in the evaluation of the frail elderly. However, the degree of implementation of recommendations by family physicians must be improved. PMID- 23367748 TI - [Atypical femoral fractures in long-term osteoporotic treatment with bisphosphonates]. AB - Recently, atypical femoral fractures, especially at the proximal part, were reported in the literature. Most of the reports discussed the relationship between those atypical fractures and chronic use of bisphosphonate drugs as prophylactic treatment for osteoporosis. As a result, the FDA (US Food and Drug Administration) published a statement on October 2010, which was the conclusion of a multidisciplinary working group. The FDA decided to add warnings for every bisphosphonate drug which was given as prophylactic treatment for osteoporosis in the USA. In this review, we will present the bisphosphonate drugs, the presenting symptoms of patients who suffer from the pathologic fracture, the radiologic characteristics and the surgical treatment. We will present the work of a Task Force of the American Society for Bone and Mineral Research and the FDA statements. PMID- 23367749 TI - [Telling the truth to Alzheimer and dementia patients in the early stages of the disease]. AB - Disclosing the diagnosis of Alzheimer's disease to the patient is emotionally difficult and ethically challenging. Arguments against telling the truth include: diagnostic uncertainty, patient's inability to understand the diagnosis, patient's unwillingness to recognize the diagnosis, potential negative social implications, unpredictable emotional reactions and losing hope. Arguments in favor of truth telling include: patient autonomy, relations with the physician based on trust, emotional adaptation, future planning and support for the patients and their family. Current research in Western countries indicates that most patients of all ages wish to know their diagnosis, whereas many relatives and physicians believe that they should conceal it from the patient. Many physicians experience difficulties in delivering the diagnosis to the patient. Studies show that less than half of them reveal the diagnosis to the patient and rarely discuss the prognosis, even though they convey this information to the relatives. Patients' reactions to the diagnosis of Alzheimer's disease is influenced by the way it is delivered, the patients' emotional vulnerability, coping style and past experience with dementia. Reactions vary from denial, anger, fear, sorrow and depression to positive coping. The proper question is how to disclose the diagnosis and not whether it should be told. Disclosing the diagnosis is a complicated and dynamic process that should begin when there is suspicion of a cognitive decline. It demands physician sensitivity flexibility and discretion. Discussing the diagnosis in time enables the patient to be involved in treatment decisions and planning his or her future. PMID- 23367750 TI - [Chronic prostatitis and chronic pelvic pain syndrome]. AB - Acute prostatitis is infrequent and is manifested as a severe systemic infection requiring hospitalization. Some of these cases may result in a chronic infection requiring long-term antibiotic courses. However, chronic non-bacterial prostatitis is much more frequent, and as such, it it is frequently underdiagnosed and maltreated. The symptoms are variant and include pain and discomfort in the pelvic area, perineum, scrotum, penis and pelvis, and are named "Chronic pelvic pain syndrome (CPPS)". Antibiotics prescribed are of temporary relief in some of the cases as the disease does not really fit the criteria of an infectious disease. This review deals with these difficulties and describes new and other methods to fight this frustrating syndrome for both patients and urologists. PMID- 23367751 TI - [Metastatic hormone refractory prostate cancer: new treatment horizon]. AB - Prostate cancer is the second leading cause of cancer death in men in the western world. Most deaths will occur due to the progression of cancer into a hormone refractory state. Until recently, docetaxel-based chemotherapy was the only established treatment (shown to increase survival) for patients with metastatic hormone refractory prostate cancer. The improved understanding of prostate cancer biology in recent years led to the development of drugs directed against precise tumorigenesis-associated molecular pathways, and significant expansion of treatment horizons for these patients. In 2010-2011, three more agents, with different mechanisms of action, were shown to be associated with a survival benefit in mHRPC, including the dendritic cell vaccine sipuleucel-T (immunotherapy), the 17,20 lyase inhibitor abiraterone (hormonal therapy), and the taxane cabazitaxel (chemotherapy). A fourth agent, denosumab (bone targeted therapy) was also recently approved by the FDA for patients with bone metastasis after showing a reduction in the occurrence of skeletal-related events. This review will focus on recent advances in the standard treatments paradigm in mHRPC. PMID- 23367752 TI - [Childhood and adolescent-onset schizophrenia: new information and definitions]. AB - Schizophrenia in children and adolescents is a rare and serious representation of adult schizophrenia that indicates phenotypic and neurobiological continuity with the adult version of the illness. Epidemiological, genetic, cognitive and imaging findings support the centrality of the neuro-developmental model in the etiology of the disease. The diagnostic criteria for schizophrenia in children and adolescents, and in adults are identical. However, many of the children suffering from schizophrenia display higher levels of impaired pre-morbid functionality than adults with schizophrenia, and have a worse prognosis. Similar to adult schizophrenia, prognosis is further worsened by frequent co-morbidities. Currently, treatment mainly consists of anti-psychotic medications, including clozapine. However, there is little evidence as to its effectiveness and side effects are common in younger age. PMID- 23367753 TI - [Age-related macular degeneration and glaucoma: intraocular pressure monitoring after intravitreal injections]. AB - In recent decades the problem of low vision and blindness in elderly people became major and socially significant issue. The number of patients having age related macular degeneration (AMD) in association with glaucoma grows all over the world that attaches medical and social value to this problem. 102 patients with AMD were under follow-up, 7 of them had primary open-angle glaucoma (POAG). Three consecutive injections of ranibizumab resulted in visual acuity increase from 0.21 +/- 0.17 till 0.37 +/- 0.12. The mean retinal thickness in foveal zone decreased from 289.36 +/- 88.73 till 230.47 +/- 88.02 microm. Ocular hypertension within 12 hours after procedure was observed in 13 (12.7%) of 102 patients. In all cases intraocular pressure (IOP) returned to preoperative values in 3 days after hypotensive medical treatment. In one case trabeculectomy was performed simultaneously with ranibizumab intravitreal injection, the next two injections were performed in a month intervals. So the problem of IOP increase after intravitreal injections remains unsolved. Glaucoma is not an absolute contraindication to intravitreal injections in treatment of exudative AMD although patients with associated conditions need individual approach in terms of both IOP compensation and number of ranibizumab injections. PMID- 23367754 TI - [Characteristics of vitreous structure in rhegmatogenous hyaloid membrane detachment]. AB - Special characteristics of volumetric acoustic digital images of different vitreous and hyaloid membrane changes were studied based on the analysis of results of ultrasound spatial examination of young healthy adults (30 patients) and patients with posterior hyaloid membrane detachment (329 patients). Morphological features of vitreous are presented considering topography and its acoustical structure. Spatial characteristics of planar and volumetric images are determined, special acoustic signs are revealed for normal vitreous and in different changes of posterior hyaloid membrane. These presentations are compared with earlier characterized changes of detached hyaloid membrane. Structural changes of vitreous resulted from posterior hyaloid membrane rapture after blunt trauma or total lens dislocation are estimated. PMID- 23367755 TI - [Morphological changes in autoimmune dacryoadenitis associated with thyroid eye disease]. AB - Increase of lacrimal gland (LG) volume was revealed in 1/3 of patients with thyroid eye disease (TED) using visualization methods. Authors show morphological data confirming development of autoimmune process in LG in TED, biopsy samples were studied within 6 hours after exitus. Specific histomorphological characteristics were analysed considering dystrophic and degenerative changes in LG tissue. Quantitative assessment of fibrosis and vascularization extent is determined using fibrosis and vascularization index. PMID- 23367756 TI - [Intrastromal corneal segments implantation in keratoconus]. AB - Comparative analysis of intrastromal corneal segments Keraring implantation using either femtosecond laser or manual technique to create corneal tunnel in 47 patients (47 eyes) with keratoconus stage II-III is presented. Refractional and functional results in groups with femtosecond laser and manual technique did not show significant difference. The main advantage of femtosecond laser revealed in the study is technical simplification of intrastromal tunnels creation. PMID- 23367757 TI - [Diagnostic value of confocal microscopy in primary corneal ectasia]. AB - Diagnostic value of confocal microscopy in subclinical corneal ectasia is analysed. Morphological changes were revealed in 71.2% of cases with subclinical keratoconus. Results of the study let us reveal typical morphological abnormalities in subclinical keratoconus, although these changes are not specific for this condition. The method is also not informative for detecting of early signs of pellucid marginal degeneration. Confocal microscopy may be considered an additional specifying method in diagnostic algorithm of subclinical corneal ectasia. PMID- 23367758 TI - [Comparative study of morphological corneal changes after cataract phacoemulsification using confocal microscopy and optical coherence tomography]. AB - 20 corneas of patients after ultrasound cataract phacoemulsification were studied using contact polarization optical coherence tomography (OCT) and confocal microscopy (CM). It was concluded that results obtained using OCT and CM fairly present morphologic corneal changes after ultrasound cataract phacoemulsification. Thermal damage as a result of ultrasound exposure demonstrated as a corneal tissue shrinkage is better revealed using polarization OCT. PMID- 23367759 TI - [Comparative study of posterior corneal epithelium after different cataract phacoemulsifiication techniques]. AB - Comparative study of posterior corneal epithelium showed that ultrasound torsional phacoemulsification (OZil) at present is the most preserving technique with regard to posterior epithelium damage. Hidromonitoring phacofragmentation has comparable results in grade II nucleus density in terms of posterior epithelial cell loss. Torsional phacoemulsification in patients with grade IV nucleus density is the most effective and preserving low-energy technique of cataract removal. PMID- 23367760 TI - [The first experience of iris-fixated intraocular lens implantation in patients with open-angle glaucoma]. AB - The results of iris-claw intraocular lens (IOL) implantation in patients with lens dislocation, deficiency of capsule support in combination with glaucoma are presented. Iris-claw "Artizan" IOL was used in 16 eyes. IOL was implanted through 5 mm corneal incision into the posterior chamber with haptic fixated to iris stroma. Implantation of this IOL model is minimally traumatic, provides favorable visual outcome and does not lead to intraocular pressure decompensation in patients with glaucoma. PMID- 23367761 TI - [Morphological features of corneal exposure to experimental near infrared emission laser]. AB - Effect of laser radiation with wave length 1,4 microm on exposed cornea of isolated bull eye (in vitro) is studied. Experimental laser coagulator with wave length 1,4 microm based on the semiconductor laser with a fiber radiation output was used in the study. Cornea was exposed at the standardized distance to radiation with different energy settings. Coagulates were morphologically studied, photoregistration and morphometric analysis of obtained images were performed. The depth of radiation absorbtion, type and degree of corneal damage were estimated in the focus and marginal area. The analysis of results shows potential of this laser coagulator to be used for selective effects at different corneal layers. This laser may be applied both for coagulation and therapueutic purposes. PMID- 23367762 TI - [Dystrophic changes of vitreous in ocular chlamydia infection]. AB - Incidence and character of vitreous changes in ocular chlamydia infection was studied. 312 patients were enrolled into the study (175 males and 137 females) aged from 24 to 52 years old (mean age 38.4 +/- 5.2 years). 165 patients (330 eyes) with laboratory confirmed chlamydia conjunctival infection were included in the experimental group. 147 patients (294 eyes) without chlamydia conjunctival infection were enrolled to the comparison group. Each group was subdivided with regard to the age. Dystrophic changes of vitreous and its posterior detachment are more frequently revealed in eyes with Chlamydia trachomatis infection, besides it happens in a younger age. PMID- 23367763 TI - [Combination of microdiathermocoagulation and local express autocytokine therapy in treatment of superficial infectious corneal ulcers]. AB - Current surgical non-keratoplastic options of superficial infectious corneal ulcers treatment are presented. Literature data is analysed and proposed methods are assessed. PMID- 23367764 TI - [Antibacterial agent Oftaquix efficacy in cataract phacoemulsification]. AB - Clinical study is performed to estimate the efficacy of Oftaquix in cataract phacoemulsification with intraocular lens (IOL) implantation. Obtained results show that Oftaquix prescription two days before surgery allows to eliminate bacterial agents from conjunctival cavity on the day of surgery. Significant and stable antibacterial effect is demonstrated. Bacteriological study on the 19-21 day after surgery revealed bacterial growth in 6.7% of patients in experimental group and in 30% of patients in control group. PMID- 23367765 TI - [Analysis of efficacy of prevention and antioxidant therapy in premature infants]. AB - 282 (564 eyes) premature infants born at mean 27 +/- 2,5 weeks of gestation with birth weight 914+/- 247g were enrolled in the study. Comparative study showed preventive treatment with histochrome in infants with risk of retinopathy of prematurity (RP) to decrease the incidence of RP compared to infants treated with emoxipine and no antioxidant therapy. Incidence of RP in infants preventively treated with combination antioxidant agents (dicynon and emoxipine) was significantly lower compared to the group without preventive antioxidant treatment. Use of histochrome in treatment of RP via periocular injections and forced instillations promoted more favorable outcome of the disease. PMID- 23367766 TI - [Central serous chorioretinopathy--uptodate treatment options]. AB - The review of literature is devoted to the uptodate treatment options of central serous chorioretinopathy. PMID- 23367767 TI - [Anatomic and functional ocular characteristics and myopia development]. AB - Literature data dealing with the main anatomic and physiological factors influencing myopia development are reviewed. They are as follows: activity of accomodation structures, haemo- and hidrodynamic changes, rigidity of fibrous tunic. A complex of different examination methods is essential for appropriate management of myopic patients because the degree of influence is variable for every factor and is still completely unknown. PMID- 23367768 TI - [A.E. Evenius and his contribution to teaching of ophthalmology in Moscow University]. AB - Biography of A.E. Evenius is described, his contribution to establishing and development of ophthalmology in Moscow University is estimated. PMID- 23367769 TI - Beware the destiny test. PMID- 23367770 TI - A tale of two internets. PMID- 23367771 TI - A dirty business. PMID- 23367772 TI - Ring theory. PMID- 23367773 TI - Where no tree has gone before. PMID- 23367775 TI - Stopping superbugs. PMID- 23367776 TI - Cloud catcher. PMID- 23367774 TI - Your brain on sports. PMID- 23367777 TI - Boring beetles. PMID- 23367778 TI - Roots of genius. PMID- 23367779 TI - A dangerous game. PMID- 23367780 TI - Out with the real. PMID- 23367781 TI - Brain cells for grandmother. PMID- 23367782 TI - Secrets of primitive meteorites. PMID- 23367783 TI - Shattered ancestry. PMID- 23367784 TI - Rethinking the Gulf stream. PMID- 23367785 TI - The battery-powered bullet. PMID- 23367786 TI - The myth of antioxidants. PMID- 23367787 TI - Data on wings. PMID- 23367788 TI - The left's war on science. PMID- 23367789 TI - Rising risks. PMID- 23367790 TI - [Legal issues of physician-assisted euthanasia part I--terminology and historical overview]. AB - Under German criminal law, euthanasia assisted by the attending physician involves the risk of criminal prosecution. However, in the absence of clear legal provisions, the law concerning euthanasia has been primarily developed by court rulings and jurisprudential literature in the last 30 years. According to a traditional classification there are four categories of euthanasia: help in the dying process, direct active euthanasia, indirect active euthanasia and passive euthanasia. However, there is still no generally accepted definition for the general term "euthanasia". The development of the law on the permissibility of euthanasia was strongly influenced by the conflict between the right of self determination of every human being guaranteed by the Constitution and the constitutional mandate of the state to protect and maintain human life. The decisions of the German Federal Court of Justice on euthanasia in the criminal trials "Wittig" (1984), "Kempten" (1994) and "Putz" (2010) as well as the ruling of the 12th Division for Civil Matters of the Federal Court of Justice (2003) are of special importance. Some of these decisions were significantly influenced by the discussions in the jurisprudential literature. However, the German Bundestag became active for the first time as late as in 2009 when it adopted the 3rd Guardianship Amendment Act, which also contains provisions on the legal validity of a living will independent of the nature and stage of an illness. In spite of the new law, an analysis of the "Putz" case makes it especially clear that the criminal aspects of legal issues at the end of a person's life still remain controversial. It is to be expected that this issue will remain the subject of intensive discussion also in the next few years. PMID- 23367791 TI - [Recovery of blood traces with scenesafe FAST tape]. AB - For complete and conclusive DNA profiling a sufficient amount of DNA must be available. For that, biological traces are recovered from crime scenes using special trace recovery material. The current method to collect biological traces for DNA analysis is to wipe them off with cotton swabs. However, for a few years the use of adhesive tapes has also been described for the recovery of evidence. In 2009, an adhesive tape was launched which was specially developed for the collection of biological traces. This product called Scenesafe FAST Tape (SSF) was investigated in this work to give recommendations for its use in evidence recovery. The results of this work show that the DNA can be extracted from the SSF very well. However, the tapes seem less suitable for direct use at the crime scene, as they are not flexible enough for adaptation to different crime scene conditions and the risk of contamination is higher than when collecting evidence with cotton swabs. Neither SSF nor cotton swabs are optimal for all requirements. The best method to recover biological evidence is still dependent on the surface material and the circumstances at the crime scene. PMID- 23367792 TI - [Homicide by hypothermia]. AB - Death due to hypothermia is normally accidental. Homicides by hypothermia are rare and have been observed especially in cases of abandonment of newborns as a method of infanticide and formerly in criminal experiments on humans in the Dachau concentration camp. 3 deaths due to hypothermia are reported, among them two cases of homicide. Intentional killing by hypothermia is rightly classified as murder as it fulfils the criterion of cruelty. PMID- 23367793 TI - [The history of Polish criminalistics and forensic medicine and their links to Austrian science]. AB - The institution of the medical expert was already known in the early Polish courts. The first Chair of Forensic Medicine on Polish soil was established in 1805 at the Jagiellonian University in Cracow and has existed until today. Among its most prominent forensic scientists are Prof. Fryderyk Hechell (1795-1851), Prof. Leon Blumenstock (1838-1895), who was the first to give regular lectures on forensic medicine for law students, and Prof. Leon Wachholz (1867-1941), who was a student of both Prof. Blumenstock and Prof. Eduard von Hofmann (1837-1897), under whose supervision he worked in Vienna. Under his guidance and supervision, he started to collect material for his habilitation. At that time, Hofmann was considered the pioneer of experimental research in forensic medicine. In Vienna, Wachholz was a guest scientist not only with Prof. von Hofmann, but also in the Psychiatric Hospital of Prof. Richard von Krafft-Ebing. After his return to Cracow, he was head of the Institute of Forensic Medicine of the Jagiellonian University for several decades. Apart from forensic medicine in the strict sense of the word, he also worked in the fields now known as criminalistics, forensic psychiatry and criminology. In these latter fields, the influence of Krafft-Ebing was still noticeable. Three students of Wachholz became professors of forensic medicine: Jan Olbrycht, Stanislaw Horoszkiewicz and Wlodzimierz Sieradzki. Their students founded a whole generation of forensic scientists. Today, all Polish forensic scientists are either directly or indirectly students of Professor Wachholz' successors. PMID- 23367794 TI - The killing fields of inequality. AB - The article presents a multidimensional analysis of inequality, in a global perspective, distinguishing vital, existential, and material resources inequality. These dimensions are interrelated and interacting, but irreducible to each other, and have had different historical trajectories, within and between nations. Over the last half-century, the contrast between advances of existential equalization, on one hand, and persistent, even increasing, vital inequality of life expectancy and health is striking. Inequalities are produced by specific mechanisms, of which distanciation, exclusion, hierarchization, and exploitation are the most important. They have each their corresponding mechanism of equality, of rapprochement or approximation, of inclusion, of organizational flattening or de-hierarchization, and of redistribution, rehabilitation, and recompensation. The mechanisms and their results are illustrated empirically in a systematic global overview. PMID- 23367795 TI - Computed tomography associated cancers and cancer deaths following visits to U.S. emergency departments. AB - We estimated the number of future cancers and cancer deaths following computed tomography scans (CTs) performed in U.S. emergency departments annually and determined whether increases in the proportion of visits resulting in CTs over the past decade were accompanied by changes in markers of severity of illness or primary reason for visit. We applied national estimates of effective dose to adult emergency department visits in the 2008 National Hospital Ambulatory Medical Care Survey. We utilized the Biologic Effects of Ionizing Radiation Model VII to estimate the number of future cancers and cancer deaths caused by CTs performed in U.S. emergency departments. We calculated the proportion of visits resulting in CTs from 1998 to 2008. In 2008, 16,406,921 CTs were performed nationally on adults, which will cause an estimated 3,750 cancers and 1,994 cancer deaths. The increasing proportion of emergency department visits resulting in CTs was not accompanied by proportional increases in markers of severity of illness or primary reason for visit. The substantial number of future cancers and cancer deaths attributable to CTs and increases in CTs without accompanying increases in markers of severity or changes in primary reason for visit highlight the importance of examining the benefits of CTs. PMID- 23367796 TI - Health, behavior, and health care disparities: disentangling the effects of income and race in the United States. AB - The literature on health disparities in the United States typically focuses on race/ethnicity or on socioeconomic status (SES) separately, but not often together. The purpose of the study was to assess the separate effects of race/ethnicity and SES on health status, health behaviors, and health care utilization. Cross-sectional analyses were conducted using the 2008 National Health Interview Survey (n = 17,337 non-elderly adults). SES disparities within specific racial groups were examined, as were race disparities within high and low SES groups. Within each racial/ethnic group, a greater proportion of low versus high SES individuals were in poor health, a lower proportion had healthy behaviors, and a lower proportion had access to care. In both SES groups, blacks and Hispanics had poorer health outcomes than whites. While whites were more likely to exercise than blacks and Hispanics, they are more likely to be smokers and less likely to have no or moderate alcohol consumption. Blacks had similar or better health care use than whites, especially for cancer screening; Hispanics had lower use within each SES group. Race/ethnicity disparities among adults of similar incomes, while important, were dwarfed by the disparities identified between high- and low-income populations within each racial/ethnic group. PMID- 23367797 TI - Do our children become healthier and wiser? A study of the effect of Medicaid coverage on school absenteeism. AB - Children make up nearly half of Medicaid enrollees. While the impact of Medicaid coverage on the use of medical care has been extensively examined, few studies have addressed the impact of Medicaid on children's health and schooling. This article reports estimates of the effect of Medicaid enrollment on children's school absenteeism. Schooling is a particularly important outcome because it influences children's productivity and earnings as adults. I use panel data from five years of the Medical Expenditure Panel Survey to estimate the impact of Medicaid enrollment on the number of school absences in reduced form and structural equation models. The structural model includes equations for children's medical care use, health status, and school absences. Econometric methods employed include instrumental variable techniques, fixed effects estimation, and coarsened exact matching. I find that children with Medicaid coverage have significantly more doctor visits, doctor visits are significantly associated with better health, and children in better health miss significantly fewer days of school. I conclude that Medicaid enrollment significantly reduces school absences. PMID- 23367798 TI - Traumatic death at work: consequences for surviving families. AB - Research and policy on occupational health and safety have understandably focused on workers as the direct victims of workplace hazards. However, serious illness, injury, or death at work also has cascading psychological, social, and economic effects on victims' families and close friends. These effects have been neglected by researchers and policymakers. The number of persons immediately affected by workplace death is significant, even in rich countries with relatively low rates of workplace fatality. Every year, more than 5,000 family members and close friends of Australian workers become survivors of traumatic work-related death (TWD). This study investigated the health, social, and financial consequences of TWD on surviving families. In-depth exploratory interviews were conducted with seven family members who had experienced TWD from one to 20 years before the interviews, with an average of three years. All reported serious health, social, and financial consequences, including prolonged grief and unresolved loss, physical health problems, family disruption and behavioral effects on children, immediate financial difficulties, and disturbance of longer-term commitments such as retirement planning. Recommendations for policy development and improved practice are proposed to minimize the trauma and suffering experienced by families, mitigate consequences, and improve outcomes following a TWD. PMID- 23367799 TI - Caregiving and elderly health in Mexico. AB - Using the National Mexican Health and Aging Study panel dataset, the authors estimate the effect of having informal care on the probability of dying and on the change in elderly health over a two-year period. Three measures of functional health were used: self-reported health, activities of daily living, and instrumental activities of daily living. We develop an empirical strategy that relies on the panel structure of the dataset to sort out the possible correlation between unobservable characteristics that affect both elderly health and an individual's decision to provide informal care. Our findings suggest that informal care provided by daughters reduces the probability of dying. In addition, informal care provided by daughters reduces the probability of having a decline in activities of daily living and instrumental activities of daily living, while it has no effect on the observed changes in self-reported health status. The protective effect of informal care provided by sons is not statistically significant for any health outcomes. A discussion of the policy options to increase elderly health and to improve the role of caregivers is included. PMID- 23367800 TI - Changes in awareness and utilization of social participation mechanisms of the Colombian health care system in the last 10 years. AB - This article seeks to analyze changes in awareness and utilization of social participation mechanisms of the Colombian health care system in the last 10 years by comparing two cross-sectional studies based on surveys among health care users in 2000 and 2010. The results show that while in 2000, the level of awareness and utilization of the mechanisms were low, in 2010 researchers identified a significant tendency toward further diminishing of awareness and utilization. In both surveys, the best-known and most-used participation mechanisms were the market mechanisms. Also in both surveys, individuals from the rural zone were aware of and used the mechanisms. In the first survey, men were more aware of the mechanisms and used them more frequently, but it was women in the second survey who presented higher rates of awareness and use; these differences, however, were not statistically significant. The results herein indicate that effective social participation in the General Social Security System in Health is far from being achieved. The policy has failed to materialize, as evidenced by the lack of balance in the participation of one of the main actors of the General Social Security System in Health: the users. PMID- 23367801 TI - Understanding the oversupply of physicians in Greece: the role of human resources planning, financing policy, and physician power. AB - Planning of the workforce has emerged as a critical issue in European health policy, as the need for human resources for health is changing in light of demographic, epidemiological, and socio-cultural trends and patterns of supply and demand in service provision. Greece represents a country with an oversupply of physicians, having the highest concentration of physicians among European Union countries. The study aims to analyze the factors influencing the high number of physicians in Greece and make policy recommendations. The analysis was conducted through international literature review and database searches. Neither the demography of the physician population in terms of age, gender composition, and geographic dispersion, nor the epidemiology of the Greek population, can explain the relatively high number of physicians in Greece. Despite the physician surplus, Greece faces serious geographical inequities regarding the distribution of physicians. There are also imbalances within the specialist category, with certain specialists (e.g., cardiologists) being in oversupply compared to other European countries, while others (e.g., general practitioners) remain weakly represented. Inadequate planning of human resources for health, inadequate health financing policy regarding primary care, gatekeeping mechanisms, and medical power constitute the primary themes explaining the trends of physicians' population in Greece. PMID- 23367802 TI - Primary care provision by volunteer medical brigades in Honduras: a health record review of more than 2,500 patients over three years. AB - The weak health system in Honduras contributes to poor health indicators. To improve population health, a number of volunteer medical brigades from developed countries provide health services in Honduras. To date, there is little information on the brigades' activities and impact. The primary objective of this article is to increase understanding of the type of health care provided by voluntary medical brigades by evaluating and presenting data on patients' presenting symptoms, diagnoses, and care outcomes. The article focuses on an ongoing medical brigade organized by Canadian health professionals in conjunction with Honduras' largest national non-governmental organization. This is a descriptive study of data that are routinely collected by volunteer Canadian health care professionals. Data on all patients presenting to temporary primary health care facilities across Honduras between 2006 and 2009 were analyzed. The data were used to analyze patient demographics, presenting symptoms, diagnoses, and treatments. We found that the brigades provide additional human resources to the relatively weak Honduran health care system. However, while brigades may increase solidarity between Hondurans and Canadians, concerns persist regarding cost-effectiveness and continuity of care for conditions treated by short-term brigade volunteers. Greater scrutiny is needed to increase brigades' effectiveness and ensure they are supportive of domestic health systems. PMID- 23367803 TI - The social cost of China's economic growth: messages from China's 2012 parliamentary session. AB - The fifth and final session of China's Eleventh National People's Congress (NPC), or parliament, was held in Beijing from March 5 to March 14, 2012. Several episodes stand out in this year's session. One is the abrupt dismissal immediately after the session of Bo Xilai, party chief of a major Chinese municipality and Politburo member. That has been arguably linked to the political and economic model he championed, which incorporated redistributive social policies and proactive government intervention. Also worthy of note is that nearly all NPC delegate seats are occupied by the country's elites, while working people are overwhelmingly under-represented, if not unrepresented. Last but not least, although neoliberalism has been widely discredited since the global economic crisis, the government work report delivered at this year's NPC session signals further embracement of private investment--not only domestic, but also foreign--in key industries and social services controlled by the state. These episodes merit reflection as they send important messages about the challenges facing the country's political economy now and in the future. PMID- 23367804 TI - [Early intervention in Germany. Experiences and developments]. PMID- 23367805 TI - [Having the best intentions is necessary but not sufficient--quality dimensions for early childhood interventions]. AB - Early childhood interventions are a promising strategy to improve the development of children in socially disadvantaged families and to reduce their risk for abuse and neglect. However, proven effects are small with substantial variations between existing programs depending on differences in program planning and implementation. On the basis of international findings on the effectiveness of early childhood intervention, health promotion, and implementation research, we provide an overview of different quality aspects in the development, implementation, and evaluation of early childhood interventions, and a framework for future quality assessment of early childhood intervention programs in Germany. Scaling up of these programs should be accompanied by intensive quality assessment and development in order to achieve the intended outcomes. PMID- 23367806 TI - [Early childhood prevention: implications for applied research and quality management]. AB - The importance of prevention has received increasing recognition the world over. In Germany, laws are being enacted and initiatives are taken to make prevention a firmly anchored and integral part of public health care. Preventive measures in early childhood encompass a great breadth and variety of resources. However, any specific preventive measure can only be justified to the extent that it has been proven to be efficient and effective. In Germany small collection of studies have shown the efficacy of psychosocial prevention and early intervention programs. Quality standards can only be determined when empirical evidence has demonstrated the prerequisites for ensuring successful treatment. Criteria for success must include life quality or academic success (school achievement). The stability of the family must also be assessed both before and after the intervention. PMID- 23367807 TI - [Evaluation of the E-learning training, early prevention and intervention in child protection"]. AB - Prevention, intervention, and child protection in early childhood essentially need well-established interdisciplinary systematic networking. Currently there is a lack of education, training and qualification programs which take the specific demands for interdisciplinary knowledge about the early childhood as well as practical experience about early prevention and intervention in child protection into account. The Internet-based E-Learning training "Early Intervention and Child Protection" was developed to fill this gap. A pilot-study with 45 test users showed, that they learned significantly while using the platform and changed aspects of their everyday routine. Thereupon the platform was opened in June 2011 to all professionals. At the moment 2,300 people are registered and participate at the training. The aim of this study, namely to make a systematic training on early prevention and intervention in child protection wide-ranging available, was achieved PMID- 23367808 TI - [Assessing risk exposure in families within the scope of early intervention: the Heidelberg Stress scale (HBS) and its quality criteria]. AB - The aim of the study presented is to introduce the newly developed instrument to assess stress, the Heidelberg Stress Scale (Heidelberger Belastungsskala--HBS), and to examine its psychometric characteristics. The HBS was developed for a low threshold and multi-professional assessment of a family's stresses and resources after the birth of a child. The HBS can be used in the outreach work of family midwives, for instance, as well as in research. The validity of the HBS was tested in a sample of 284 psychosocially stressed families after the birth of their child; the inter-rater reliability was tested in a sample of 41 families that were also in stress. The HBS exhibits an excellent inter-rater reliability within a homogeneous professional group (psychology students). As relates to the construct validity, a strong positive connection between the HBS and Kindler's screening sheet was found; the HBS exhibits a negative correlation with maternal sensitivity and a positive correlation with maternal stress level. With a high level of stress in the HBS, the risk of taking the child into care is increased by 4.5 times; the sensitivity amounts to 63.6%. The quality criteria are satisfactory. PMID- 23367809 TI - [Differentiated structures of early prevention measures for families at risk using the example of the project "nobody slips through the net"]. AB - Against the background of practical experiences from the Early Prevention model project "Nobody slips through the net" (in three counties of Germany) the necessity of differentiated structures of preventive measures for different groups of families will be discussed. Therefore a distribution in three types of families the visiting qualified person could be confronted with during their work in the families' homes is proposed, especially with respect to the degree of risk and available resources. We conclude by illustrating the implications of this approach by means of a case vignette. PMID- 23367810 TI - On the demise of the backlog and other reflections on the state of RQES. PMID- 23367812 TI - Historical perspective and current status of the physical education graduation requirement at American 4-year colleges and universities. AB - This study gives an overview of the history of required physical education in America's 4 year colleges and universities and provides an update on the requirement status. After randomly identifying 354 institutions, we searched their respective websites to determine whether physical education was a requirement to earn a baccalaureate degree. The major finding was that the physical education requirement declined from an all-time high of 97% in the 1920s and 1930s to an all-time low of 39.55% in 2010. Given society's ongoing health challenges and the important role of physical activity in maintaining health, this seems counterintuitive. It is also inconsistent with the National Physical Activity Plan (2010). PMID- 23367813 TI - Adolescents' self-efficacy to overcome barriers to Physical Activity Scale. AB - This paper describes a revised measure of self-efficacy to overcome barriers to moderate and vigorous physical activity in a sample of 484 high school students in Toronto, Ontario. The students had a mean age of 15.3 years. Principal axis factoring with oblique rotation yielded five factors: self-efficacy to overcome internal, harassment, physical environment, social environment, and responsibilities barriers. Two problematic items were removed, which resulted in a 22-item measure. Subsequent analyses were conducted on responses to this shortened measure. Confirmatory factor analysis supported the five-factor model and demonstrated age- and sex-invariance. The subscales had good internal consistency reliability. Structural regressions demonstrated a strong relationship between the resulting factors and a physical activity measure (energy expenditure), showing predictive validity. PMID- 23367814 TI - Tennis shoes required: the role of the facilitator in professional development. AB - Reform efforts to improve physical education often rely on facilitators to promote positive change. Although it is becoming more common, little is currently understood about the facilitation role. Our purpose was to examine facilitators' collective knowledge and experience with ongoing physical education professional development (PD), specifically regarding conceptions of their role in the process. Participants included 12 experienced PD facilitators. Data sources included formal semistructured and informal conversational interviews and participants' curriculum vitae. Results indicated that facilitators held common beliefs about teacher learning and self-identified actions aligned with those beliefs. Adhering to constructivist views of learning, facilitators underscored the role of prior knowledge and the active and social nature of learning. Their remarkably similar views emphasized multiple aspects of teacher capacity building. PMID- 23367815 TI - Heart rate variability: effect of exercise intensity on postexercise response. AB - The purpose of the present study was to investigate the influence of two exercise intensities (moderate and severe) on heart rate variability (HRV) response in 16 runners 1 hr prior to (-1 hr) and at +1 hr, +24 hr, +48 hr, and +72 hr following each exercise session. Time domain indexes and a high frequency component showed a significant decrease (p < .001) between -1 hr and +1 hr for severe intensity. The low frequency component in normalized units significantly increased (p < .01) for severe intensity at +1 hr. Only severe exercise elicited a change in HRV outcomes postexercise, resulting in a reduction in the parasympathetic influence on the heart at +1 hr; however values returned to baseline levels by +24 hr. PMID- 23367811 TI - Physical activity and pregnancy: past and present evidence and future recommendations. AB - PURPOSE: In this review, we provide researchers and practitioners with an overview of the physical activity and pregnancy literature to promote prenatal physical activity, improve measurement, further elucidate the role of activity in reducing maternal health complications, and inform future research. METHOD: We examined past and present physical activity and pregnancy studies and highlight key papers with a focus on maternal health outcomes to best inform physical activity promotion efforts. RESULTS: We discuss: (a) historical overview of prenatal physical activity relative to the physical activity guidelines, how they have changed over time, and how evidence of the effect of prenatal activity on maternal/fetal health outcomes has affected clinical recommendations; (b) existing tools and challenges associated with measuring prenatal physical activity; (c) empirical evidence on multilevel determinants of prenatal activity to guide future intervention work; (d) empirical evidence of prenatal activity on adverse maternal outcomes (gestational diabetes mellitus, preeclampsia, excessive gestational weight gain) from observational and intervention studies; and (e) summary/recommendations for future research and practice. CONCLUSIONS: The physical activity and pregnancy literature has evolved over the past 50 years, and there is sufficient empirical evidence to support the promotion of moderate to-vigorous prenatal physical activity for maternal health benefits. Future studies and interventions should be carefully designed, theoretically driven, and include validated and reliable activity measures. Researchers and practitioners should also consider the multifaceted determinants and outcomes of prenatal physical activity and intervene to promote physical activity before, during, and after pregnancy. PMID- 23367816 TI - Effect of a periodized power training program on the functional performances and contractile properties of the quadriceps in sprinters. AB - Our purpose was to compare the effect of a periodized preparation consisting of power endurance training and high-intensity power training on the contractile properties of the quadriceps muscle and functional performances in well trained male sprinters (n = 7). After 4 weeks of high-intensity power training, 60-m sprint running time improved by an average of 1.83% (SD = 0.96; p < .05). This improvement was inversely related to an increase in maximal voluntary contraction torque (r = -.89, p < .05) and poorly correlated with changes in the contractile kinetics of the quadriceps muscle (r range from .36 to -.46). These findings suggest that sprint performance is poorly predicted by muscle intrinsic properties and that a neural adaptation appears to explain most of the observed functional adaptations. PMID- 23367817 TI - The relationship between physical activity and thermal protective clothing on functional balance in firefighters. AB - We investigated the relationship between baseline physical training and the use of firefighting thermal protective clothing (TPC) with breathing apparatus on functional balance. Twenty-three male firefighters performed a functional balance test under four gear/clothing conditions. Participants were divided into groups by physical training status, and task performance was analyzed. There was an effect of equipment and training status on performance with the group reporting both aerobic and resistance training performing better than the group reporting no physical training. In conclusion, firefighters walk more slowly as a strategy to maintain balance when wearing TPC, which may be suboptimal given the emergent nature of fire suppression. This result was most prominent in the group reporting no physical training. PMID- 23367818 TI - The relation of mild traumatic brain injury to chronic lapses of attention. AB - We assessed the extent to which failures in sustained attention were associated with chronic mild traumatic brain injury (mTBI) deficits in cognitive control among college-age young adults with and without a history of sport-related concussion. Participants completed the ImPACT computer-based assessment and a modified flanker task. Results indicated that a history of mTBI, relative to healthy controls, was associated with inferior overall flanker task performance with a greater number of omission errors and more frequent sequentially occurring omission errors. Accordingly, these findings suggest that failures in the ability to maintain attentional vigilance may, in part, underlie mTBI-related cognition deficits. PMID- 23367819 TI - Predictive role of physical education motivation: the developmental trajectories of physical activity during grades 7-9. AB - In this study we examined adolescents' physical activity (PA) stability as well as individual differences in PA across grades 7-9. In addition, we tested the predictive role of adolescents' self-determination and goal orientations in physical education at grade 6 in relation to their PA development. Adolescents' (N = 812) self-reported PA was measured five times and physical education motivation once. Results revealed a decreasing trajectory of PA, with individual differences diminishing over time. Although boys' showed a consistently higher PA level, gender did not moderate the change in PA. Finally, self-determination and task orientation (boys only) predicted PA levels but did not predict change in PA. PMID- 23367820 TI - Including overweight or obese students in physical education: a social ecological constraint model. AB - In this review, we propose a social ecological constraint model to study inclusion of overweight or obese students in physical education by integrating key concepts and assumptions from ecological constraint theory in motor development and social ecological models in health promotion and behavior. The social ecological constraint model proposes that constraints exist on five different levels and interact within and across levels to affect overweight students' engagement, learning, and physical activity in physical education. This model can provide a theoretical framework to guide and organize research on the inclusion of overweight students. It can also guide teachers in manipulating these constraints to create a culture for inclusion and provide instruction to meet the needs of overweight or obese students. PMID- 23367821 TI - Weighing in on NBC's The Biggest Loser: governmentality and self-concept on the scale. AB - Previous analyses (i.e., Bernstein & St. John, 2006; Sender & Sullivan, 2008) of the television show The Biggest Loser have detailed its negative presentation of the obese body, potential consequences for viewers, and its role as a technology of governmentality. However there has been little exploration of how audience members conceptualize and enact the messages communicated in the show within these intricate frameworks. The current research used information from semistructured interviews with 40 dedicated viewers to capture the salient meanings they ascribed to The Biggest Loser within the themes of governmentality and self-concept. Overall, the group experienced the program as a transformative, entertaining, and inspirational event that produced little change in their exercise behavior. Thus, the role of reality television in creating healthy behavior change is potentially limited. PMID- 23367822 TI - Trends in no leisure-time physical activity--United States, 1988-2010. AB - PURPOSE: The aim of this study was to examine trends in the prevalence of no leisure-time physical activity (LTPA) from 1988 to 2010. METHOD: Using the Behavioral Risk Factor Surveillance System data, 35 states and the District of Columbia reported information on no LTPA from 1988 to 1994; all states reported no LTPA from 1996 to 2010. RESULTS: No LTPA significantly declined over two decades. Prevalence for all states declined on an average of 0.6% per year from 29.1% in 1996 to 24.1% in 2004 and stabilized from 2005 to 2010, ranging from 24.0% to 25.4%. Prevalence declined for both sexes and all racial/ethnic groups. CONCLUSION: While the no LTPA trends improved over two decades, one in four U.S. adults still report they do not engage in LTPA. PMID- 23367823 TI - A confirmatory factor analysis of the Life Orientation Test-Revised with competitive athletes. AB - Current reviews outside of sport indicate that the Life Orientation Test-Revised (LOT-R) items load on two separate factors (optimism and pessimism) and, therefore, should be treated as independent constructs. However, researchers in the sport sciences continue to use the single composite score reflecting a unidimensional definition of optimism. Hence, I sought to explicitly examine the factor structure of the LOT-R with athletes. Results of this study support the two-factor structure, which is consistent with accumulating evidence outside of sport and exercise science. This contribution is an important first step toward continued examination of this instrument and future work on the influence of optimism (versus pessimism) on sport and exercise behavior. PMID- 23367824 TI - Attentional patterns involved in coping strategies in a sport context. AB - We investigated the relationship between coping strategies and attentional bias after a sport competition. We administered the Ways of Coping Checklist (Paulhan, Nuissier, Quintard, Cousson, & Bourgeois, 1994) to 145 athletes immediately after they had participated in a sport competition. We also assessed attentional bias using a dot probe detection task. Results revealed that emotion-focused coping strategies led athletes to orient their attention away from threat, whereas athletes who adopted problem-focused coping strategies focused their attention toward threat. More precisely, problem-focused coping strategies are related to a facilitated detection of threat, not to disengagement difficulties. The vigilance attentional bias seems to be a compensatory strategy to cope with a stressful situation, such as sport competition. PMID- 23367825 TI - Gymnastic judges benefit from their own motor experience as gymnasts. AB - Gymnastic judges have the difficult task of evaluating highly complex skills. My purpose in the current study was to examine evidence that judges use their sensorimotor experiences to enhance their perceptual judgments. In a video test, 58 judges rated 31 gymnasts performing a balance beam skill. I compared decision quality between judges who could perform the skill themselves on the balance beam (specific motor experience = SME) and those who could not. Those with SME showed better performance than those without SME. These data suggest that judges use their personal experiences as information to accurately assess complex gymnastic skills. [corrected]. PMID- 23367826 TI - [Multicenter study on clinical features and genetic characteristics of Mycobacterium avium strains from patients in Japan with lung disease caused by M. avium]. AB - BACKGROUND: The pulmonary disease caused by Mycobacterium avium shows diverse clinical manifestations. Little is known about the potential association between the genetic characteristics of M. avium strains and disease progression. SUBJECTS AND METHODS: We enrolled 89 patients with disease caused by M. avium, from 12 hospitals in Japan and collected the corresponding M. avium isolates and clinical data. We divided the 89 patients into 2 groups: one group comprising 43 patients with progressive disease despite chemotherapy ("progressive"), and the other group comprising 46 patients with untreated disease ("untreated"). We compared clinical and bacteriological characteristics between these groups. The bacteriological characteristics that we examined were drug susceptibility, variable-number tandem-repeat (VNTR) typing, and presence of the insertion sequence ISMav6. Seventeen patients in the "untreated" group were started on chemotherapy because their condition had clinically deteriorated during follow up. RESULTS: The result of VNTR typing showed that there was no specific clustering according to geographical region or clinical group in the "untreated" or "progressive" groups. Six out of eight cases those of polyclonal infection, and 11 of 12 isolates that were highly resistant to clarithromycin were isolated from patients with progressive disease. The frequency of isolates with ISMav6 inserted into upstream region of the cfp29 gene, which is involved in the induction of interferon-gamma production, was significantly higher in patients with deteriorating disease than in stable patients in the "untreated" group (p = 0.002). CONCLUSION: Polyclonal infection and clarithromycin resistance may be involved in disease progression. ISMav6 inserted into the cfp29 gene is also suggested to be a factor related to the deterioration of pulmonary Mycobacterium avium complex disease. PMID- 23367827 TI - [Can an individual with a positive baseline QuantiFERON test result develop active tuberculosis?]. AB - OBJECTIVES: QuantiFERON-TB Gold (QFT-G) test has been recommended as a new tool for the diagnosis of latent tuberculosis (TB) infection. However, the risk of development of active TB in the future depends on the period after the infection. The aim of this study was to evaluate the risk of development of active TB in individuals who have been infected. METHODS: Clinical development of TB in subjects with positive baseline QFT test results was retrospectively analyzed. The subjects included healthcare workers, since 2003, at the Fukujuji Hospital who were examined at employment. RESULTS: In total, 667 subjects were examined using the QFT-2G test, and 62 subjects were QFT positive at the first examination. One was treated using isoniazid, and 61 subjects were followed up for an average of 4.7 years (286 person-years). None of the subjects developed active TB during the observation period, and the probability of clinical breakdown (95% confidence interval) was 0-0.0104/person-year. CONCLUSION: The risk of development of active TB among subjects with positive QFT-G test results at baseline was low. Treatment of latent TB infection is not recommended, unless an individual has been recently infected. PMID- 23367828 TI - [A case of thymoma and Mycobacterium intracellulare infection]. AB - A 69-year-old man, who underwent total thymectomy 5 years previously, was referred to our division because the chest radiograph revealed abnormal shadows in both the lungs. The chest radiograph and CT scan showed pleural thickening in both apexes and tree-in-bud signs in both the lower lobes, which suggested bronchiolitis. We had retrospectively confirmed similar centrilobular small nodules and tree-in-bud signs on the chest CT scan when the thymoma was diagnosed. Mycobacterium intracellulare was detected in the sputum by acid-fast staining and polymerase chain reaction. The coincidence of thymoma and Mycobacterium intracellulare infection appeared to be incidental. Thus, in patients with thymoma, clinicians should carefully evaluate the lung parenchyma as well as the mediastinum on the chest radiograph to identify occult diseases, including Mycobacterium intracellulare infections. PMID- 23367829 TI - [PET/CT for monitoring the therapeutic response in a patient with abdominal lymph node tuberculosis after colon cancer resection]. AB - In February 2007, a 76-year-old man underwent endoscopic mucosal resection (EMR) for sigmoid colon cancer. Histological examination of the EMR specimen revealed adenocarcinoma in adenoma that was confined to the mucosal layer, and pathological complete resection was achieved. Since then, the patient has been followed up every year with endoscopic examination of the colon, with normal results except for hemorrhoids. In June 2011, a positive result for occult blood was obtained on examination of a stool sample. In July 2011, enhanced computed tomography of the chest and abdomen was performed, and the left supraclavicular, paraaortic, and left common iliac artery lymph nodes were found to be enlarged. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) identified accumulation of 18F-FDG in the enlarged lymph nodes. Histopathological examination of a biopsy specimen from the left supraclavicular lymph node revealed tuberculous changes; therefore, the patient was administered anti-tuberculosis therapy. The culture isolate of the above lymphatic tissue specimen was identified as Mycobacterium tuberculosis by immunochromatographic assay with MPB64 protein (Capilia TB). Laparoscopic examination of abdominal lymph nodes was not performed because the patient's consent could not be obtained. After the anti-tuberculosis therapy, the size of the abdominal lymph nodes was reduced, and subsequently, 18F-FDG accumulation decreased. It is considered that mucosal colon cancer did not spread to the lymph nodes after it was removed completely. For the definitive diagnosis of abdominal lymph node swelling, it would have been necessary to perform laparoscopic examination, which was impossible in this case. When it is difficult to perform invasive examinations, such as laparoscopy in case of swelling of the abdominal lymph node, 18F-FDG PET/CT can be useful for monitoring the therapeutic response of abdominal tuberculosis. PMID- 23367830 TI - [A case of pulmonary Mycobacterium lentiflavum infection diagnosed by microbiological analysis]. AB - In 1998, a 51-year-old woman was diagnosed with Mycobacterium avium infection on the basis of chest radiographic findings, positive smear test results, and positive results of polymerase chain reaction (PCR) specific for Mycobacterium avium DNA in bronchial lavage fluid. Antimycobacterial therapy was administered for 11 months, and the chest radiographic findings improved. In 2001, re treatment was performed because radiographic findings indicated exacerbation of disease and poor response. After 2005, the patient remained both smear and culture positive for mycobacterium. However, the precise species could not be identified using PCR and DNA-DNA hybridization, and her left lung lesions gradually worsened. The culture isolate was subjected to DNA analysis with PCR amplification and sequence analysis; this ultimately revealed the presence of Mycobacterium lentiflavum. Combination antimicrobial therapy was administered for 10 months. The patient's symptoms were alleviated, and the radiographic appearance remained stable. PMID- 23367831 TI - [A case of agranulocytosis caused by rifampicin during treatment of tuberculous lymphadenitis in a chronic renal failure patient]. AB - A 52-year-old woman was admitted to our hospital because of intermittent high fever and chronic renal failure. Computed tomography of the thorax showed swelling of the paratracheal lymph nodes that was confirmed by gallium scintigraphy. Biopsy of the supraclavicular lymph node on the right side showed necrotizing lymphadenitis with Langhans giant cells surrounded by epithelioid cells. Anti-tuberculosis treatment, including isoniazid, rifampicin, ethambutol, and pyrazinamide was initiated. One month after treatment, the patient developed agranulocytosis (white blood cell [WBC], 2100 cells/microl; neutrophils, 5%) accompanied by severe diarrhea. Bone marrow histology showed poor development of granulocytes, but no atypical cells were observed. Therefore, rifampicin was discontinued, and treatment with granulocyte colony-stimulating factor (G-CSF) was initiated. Subsequently, the white blood cell count and the proportion of neutrophils increased to 12500 cells/microL and 80%, respectively. Rifampicin in the anti-tuberculosis chemotherapy regimen was replaced with levofloxacin. This is a rare case of agranulocytosis caused by rifampicin administered during anti tuberculosis treatment in a chronic renal failure patient. PMID- 23367832 TI - [A case of pulmonary Mycobacterium gordonae infection diagnosed by gastric juice culture and successfully treated with multidrug chemotherapy]. AB - In September 2008, a 60-year-old woman presented to our hospital with a complaint of bloody sputum; she was healthy until this event. Chest computed tomography scan revealed a cavity, nodular shadows, and bronchiectasis in the left upper lobe and in the left and right middle lobes. Acid-fast bacilli were detected 2 times on gastric juice culture and Mycobacterium gordonae was identified on biochemical study. No active chemotherapy was administered because the discharge of this strain was considered casual and clinically nonsignificant. However, her radiological findings worsened in the following 1 year and 3 months, and M. gordonae was detected 2 more times on gastric juice culture. Subsequently, she was diagnosed with pulmonary mycobacteriosis caused by M. gordonae and was treated with clarithromycin, rifampicin, and levofloxacin. After 1 month, her gastric juice culture yielded negative results for M. gordonae, and after a year and a half, her radiological findings improved. In this case, gastric juice culture was as useful as sputum examination for diagnosis and evaluation of the disease. Although M. gordonae is usually considered nonpathogenic, our study shows that it can be pathogenic, and M. gordonae infection may require treatment with chemotherapy. PMID- 23367833 TI - [Mycobacterium xenopi lung infection in a patient with multiple lung cysts that responded well to chemotherapy: a case report]. AB - An abnormal shadow was observed on the chest radiograph of a 39-year-old man during health examination. The chest CT scan showed a consolidation around the cysts in the left upper lobe. The patient was diagnosed with Mycobacterium xenopi lung infection based on the presence of acid-fast bacilli in the sputum culture several times, which were identified as Mycobacterium xenopi by DNA-DNA hybridization. Two weeks after the initation of chemotherapy with 4 drugs (isoniazid, rifampicin, ethambutol, and clarithromycin), the patient's sputum smear and culture test results were negative; additionally, the consolidation on the chest CT scan improved after 10 months of treatment. There have been several case reports on Mycobacterium xenopi lung infection in Japan. However, few have studied Mycobacterium xenopi lung infections associated with multiple lung cysts that responded well to chemotherapy are rare. PMID- 23367834 TI - [Evaluation of the effect of DOTS on treatment outcomes in patients with smear positive pulmonary tuberculosis in Osaka City]. AB - PURPOSE: To investigate the possibility of improving the results of therapy, we analyzed the association between the performance of directly observed treatment short course (DOTS) and treatment outcomes in patients with tuberculosis. METHODS: Patients with sputum smear-positive pulmonary tuberculosis who were newly registered in Osaka City between 2007 and 2010 were included in the study. The patients' drug-taking was confirmed at least once a week during DOTS. RESULTS: (1) In total, 2,423 patients were enrolled in the study (676, 563, 631, and 553 in 2007, 2008, 2009, and 2010, respectively). Of these, patients who died, those who were transferred during treatment, and those who remained under treatment at the time of analysis, were excluded. In 2007, 2008, 2009, and 2010, 84.1%, 82.3%, 86.2%, and 92.0% of patients, respectively, underwent DOTS and 91.6%, 91.7%, 92.6%, and 95.1%, respectively, were considered to be cured or to have completed treatment, demonstrating increases in both the parameters. On the other hand, 8.4%, 8.3%, 7.4%, and 4.9% of patients, respectively, were considered to have failed to respond to treatment or defaulted, showing a decreasing trend. (2) We examined the results of treatment of the 2010 cohort of patients with respect to whether a patient was supported by the DOTS service. Four percent of the 377 patients who underwent DOTS failed or defaulted compared with 15.2% of the 33 patients who did not undergo DOTS, which was a significant difference (P<0.01). (3) In total, 131 patients failed to respond to treatment or defaulted between 2007 and 2010, with reasons for such including abandonment of treatment, departure from the hospital, or refusal of treatment in 61 patients (46.6%); premature discontinuation of treatment due to physicians instructions in 33 (25.2%); and side effects in 22 (16.8%). The absence of a DOTS partner was considered a risk factor for discontinuation of treatment in 31 (56.4%) of the 55 patients who failed to respond to treatment or defaulted in 2009 and 2010. CONCLUSION: An increase in the coverage of DOTS may be important for improving treatment outcomes. The most common reasons for patients failing to respond to treatment or defaulting were abandonment of treatment, earlier departure from hospital, or refusal of treatment. The absence of a DOTS partner accounted for more than 50% of cases of premature discontinuation of treatment. Thus, it may be mandatory to adequately evaluate the risk of treatment discontinuation in individual patients and to take appropriate action against it. PMID- 23367835 TI - [Therapeutic application of repetitive transcranial magnetic stimulation for major depression]. AB - It has been reported that approximately one third of patients with major depression are medication-resistant. In spite of partial responsiveness to antidepressants, most of the medication-resistant patients remain incompletely remitted without successful social reintegration. Symptom severity could be mild to moderate for many of them due to the incomplete remission, and, thus, electroconvulsive therapy is not applicable for them. However, they usually feel some difficulty performing cognitive behavioral therapy or social rehabilitation training due to residual symptoms such as thought inhibition and hypobulia. Under such conditions, those patients are longing for treatment options complementary to antidepressants, for less painful social reintegration. In October 2008, the Food and Drug Administration (FDA) of the United States finally approved repetitive Transcranial Magnetic Stimulation (rTMS) for medication-resistant patients with major depression. The main reason for the FDA approval was that rTMS had shown similar effectiveness (effect size around 0.39 in a recent meta analysis) to antidepressants for medication-resistant patients without serious adverse effects. TMS is a brain stimulation methodology employing magnetic energy which can penetrate the skull bone without energy decay, and, thus, eddy currents induced by TMS can stimulate cerebral cortices effectively and locally. When TMS is repetitively delivered over several hundreds of pulses within a session, stimulation effects can be observed beyond the stimulation period as aftereffects. Moreover, when a daily rTMS session is repeated over several weeks, rTMS could have antidepressant effects. Clinical trials of rTMS for depression have employed two kinds of rTMS protocol of high-frequency (facilitatory) rTMS over the left Dorsolateral Prefrontal Cortex (DLPFC) and low-frequency (inhibitory) rTMS over the right DLPFC. Although the antidepressant action of rTMS over DLPFC has not been fully elucidated, the neuronal level hypothesis includes the induction of neuroplasticity and activation of the dopamine system, and the neuronal circuitry level hypothesis includes the activation of the left DLPFC and inhibition of the right DLPFC and (para) limbic system such as the subgenual cingulate cortex and amygdala. On the therapeutic application of rTMS in clinical psychiatry, neuroethics and low invasiveness should be fully considered along with a negative history of punitive electroconvulsive therapy and prefrontal lobotomy. It is important to investigate the neurobiological mechanism of rTMS treatment and to place rTMS in a suitable position within comprehensive treatment algorithms of major depression. PMID- 23367836 TI - [Psychological trauma risks among disaster workers: perspectives on their mental health following the Great East Japan Earthquake]. AB - Following the March 11, 2011 Great Japan East Earthquake and the Fukushima Daiichi Nuclear Power Plant accident, disaster workers have been working day and night for recovery efforts. A large part of disaster workers, i.e., Self-Defense Force, police, fire department, and coast guard personnel, were highly acknowledged by the Japanese public for searching nearly 19,000 dead or missing victims. This recognition will be beneficial for their psychological recovery. On the other hand, dentists and government employees also took a large role in these mortuary missions, but their work was hardly known to the people. Furthermore, local government employees became victims of public criticisms. Similar phenomenon has been seen among Fukushima nuclear plant workers. These workers have experienced a whole array of traumatic stress, including near-death work experiences, irradiation fear, loss of their properties and their loved ones. The electric company has been blamed by the public for their disaster responses, so the public portrays these employees as disaster perpetrators. However, this trend is leading to serious discriminations and harassments, and adversely affecting their mental health. We all hope the recovery efforts to complete as soon as possible. However, when people criticize these workers, their burden of psychological trauma will continue to grow, and their recovery process will be impeded. It is crucial for the society to recognize these hard-working people and to show appreciation and support for their dedications. PMID- 23367837 TI - [Complexities of the stress experienced by employees of the Fukushima nuclear plants]. AB - Fukushima Daiichi Nuclear Power Plants suffered serious damage by the Great East Japan Earthquake and Tsunami. The employees of the plant worked very hard to stabilize the nuclear reactor and to prevent any secondary accidents. They were in one of the most severe situations in this disaster, but they were the people who hesitated most to request help for themselves. We started visiting the Fukushima Daini Plant office that was used as the frontline base for Daiichi Plant workers since July, 2011. These visits were held once or twice a month and we offered mental health support to the employees. We have completed interview with the total number of 339 plant workers by April, 2012. We offered several ways of mental support including clinical treatment, continuous counseling, or one time advice, depending on mental condition of each interviewee. Complexity of huge disaster and individuality of suffering from it were discussed in this article. Like local residents, many plant workers also experienced death/missing of family, loss of housing, refuge life, and dispersion of family. Furthermore, they have been suffering from various kinds of criticism and slander against Tokyo Electric Power Company. Many workers, even though they were not in management positions, seemed to have guilty conscience and sense of responsibility that forced them to stay in the risky working site. We could find some struggling coexistence of sense of guilt (as a causer of disaster) and sense of victim in their mind. It was suggested that continuous effort to listen and pay attention to their talk is important in order to support their mission to stabilize the power plant and to prevent them from over-stress and burnout. PMID- 23367838 TI - [Supporting caregivers for people with alcohol-related problems ways to listen, support, and link with care]. AB - Local caregivers such as psychiatric service providers, mental health welfare workers, and nursing-care staff have a major role to play in the long-term support of survivors of the Great Eastern Japan Earthquake of March 11th, 2011. Alcohol-related problems often cause various problems mentally, physically, economically, and socially. Alcoholics tend to show violent behavior, deny their own alcoholism, cause codependency in significant others, and occasionally relapse. Local caregivers bear the burden of caring for them and feel responsible for their relapse. This leads to exhaustion and discomfort with caring for them. In order to provide continuous and effective support for people with alcohol related problems, it is important for caregivers to know the nature of the illness, the means and stages of recovery, effective support strategies, and how to enjoy providing support. A Leadership Training course on "Mental Health First Aid (MHFA)" was held in November 2011 for caregivers in Iwate Prefecture. MHFA provides help for people suffering from a mental health problem or in a mental health crisis, developed in Australia by Betty A. Kitchener and Anthony F. Jorm. In 2006, the MHFA-Japan (MHFA-J) Project Team translated the program and modified it to fit Japanese culture. The action plan consists of 5 part: 1) Approach the person, assess and assist with any crises, 2) Listen non-judgmentally, 3) Give support and information, 4) Encourage the person to get appropriate, professional help, 5) Encourage other support/self-help. During the leadership training course, MHFA for anxiety disorder, depression, suicidal thoughts, and alcohol related problems was introduced, as well as how to train caregivers in experience based and participatory approaches. The session for alcohol-related problems focused on the process of recovery, including how to deal with relapse, how to listen, how to motivate patients, and how to enjoy being a caregiver. There was also a role-play with two different scenarios: one with a confrontational interview and one with an MHFA-styled interview using a motivational approach. In February 2012, two other seminars focused on alcohol-related problems among the elderly and how to organize a case conference to incorporate requests from participants of the leadership training course. In order to provide long-term support to local caregivers, it is important to convey strategies that focus on caring for others comfortably. PMID- 23367839 TI - [What is important in disaster relief missions associated with the Great East Japan Earthquake: lessons from disaster relief missions to the Japan Self-Defense Forces Sendai Hospital and Haiti peacekeeping deployments]. AB - We assessed the core factors necessary for mental health of disaster workers according to the following experiences: 1) the Japan Self-Defense Force (JSDF) disaster relief missions associated with the Great East Japan Earthquake and the Haiti peacekeeping deployment associated with the Great Haiti Earthquake, 2) conformations of the peacekeeping mission units of various countries deployed to Haiti, and 3) JSDF assistance activities to the Japanese earthquake victims. We learned that the basic life needs were the major premises for maintaining the mental health of the disaster workers. Food, drinking supplies, medical supplies were particularly crucial, yet overlooked in Japanese worker settings compared with forces of other countries. Conversely, the workers tend to feel guilty (moushi wake nai) for the victims when their basic life infrastructures are better than those of the victims. The Japanese workers and disaster victims both tend to find comfort in styles based on their culture, in particular, open-air baths and music performances. When planning workers' environments in disaster settings, provision of basic infrastructure should be prioritized, yet a sense of balance based on cultural background may be useful to enhance the workers' comfort and minimize their guilt. PMID- 23367840 TI - [Creating a reliable therapeutic relationship with the patient]. AB - The factors necessary to create a reliable therapeutic relationship are presented in this paper. They include a demeanor and calmness of temperament as a psychiatric professional, a feeling of respect for the patient that is based on our common sense as human beings, an attitude of listening attentively to what the patient is revealing, maintaining an attitude of receptive neutrality, the ability to withstand the emotional burdens imposed on one by the patient, patience with any difficulty on one's own part to understand the patient, the ability to communicate clearly, including on the patient's negative aspects, and the ability to end psychiatric consultation sessions in a friendly and intimate manner. Creating a beneficial therapeutic relationship is about the building of a trusting relationship, in which the patient can constructively endure being questioned by us, or cope with the tough burdens we may place on them. However, a reliable relationship such as this contains paradoxes. Patients are able to talk to us about their suspicions, anxieties, dissatisfactions or anger only if the therapeutic relationship is good or based on trust. In other words, just like our patients, psychiatrists, too, must deal with what that the patient brings and directs toward us. It is at this point that what we call a true therapeutic relationship starts. PMID- 23367841 TI - [Developing effectively therapeutic relationships]. AB - For good therapeutic relationship, adequate case conceptualization is essential, and clinicians should try to understand both symptoms and resilience of patients. Furthermore, clinicians should displays a satisfactory degree of warmth, concern, confidence, genuineness, and professionalism, organize a session and use time adequately, collaborate with a patient, ask enough questions to help a patient widen his/her points of view, and elicit and respond verbal and non-verbal feedback from patients during a session. PMID- 23367842 TI - [How to create a good relationship between a therapist and patient in clinical psychiatry: to know the patient is indispensable for effective treatment]. AB - It is essential to create a good relationship between a therapist and patient for effective treatment in clinical psychiatry, while we should focus our attention to know the patient's pathology and develop a proper treatment strategy. For this purpose, I always keep five issues in my mind, as follows. First, a good atmosphere will reduce patients' nervousness and anxiety. Second, listening carefully to patients' descriptions of symptoms. Careful listening will help us to understand the meaning of the symptoms for the patients. Also, we will gain the patients' confidence, as it engenders sincerity. Third, we should clarify the treatment plan and goal. Patients can gain hope and will continue the therapy. Fourth, we should support the patients to receive treatment continuously. Praise their attitude for receiving the treatment, and assigning homework will strengthen their continuousness regarding the treatment. Fifth, the treatment should shift from therapists' leadership to patients' self-direction. PMID- 23367843 TI - [Therapeutic interaction to promote patients' recovery]. AB - What the author considers as key points are described regarding how therapists could best interact with patients to promote recovery. 1. Listening to a patient's stories with an open mind. Treatment should start off by therapist's listening to what the patient states as unknown, a new experience, before drawing on theories and past experiences, which should be put on hold. 2. Making efforts to understand. The work to expand understanding of the patient leads to inquiring about his/her life history and situation. Tracing back the history helps to not only explore the cause, but also find potential resources that contribute to treatment. Inquiring about the situation the patient is in provides information not only on how symptoms have developed, but also on how the patient has made efforts to overcome the situation, in which the driving power towards change can be found. 3. Refraining from a hasty understanding. Sometimes therapists can erroneously feel that he/she understands the patient's experience simply by applying specific theories to it. In order to avoid such misperception, therapists needs to continuously test and correct their theoretical hypothesis about patients through practice. 4. Bringing empathy. Not just reflecting on the patient's words, the therapist should also be able to accept anxiety and agony as universal feelings that any human being could have at times. To acknowledge that it is natural to find universal human desire underlying the patient's presenting agony is considered highly empathic. In addition to conditions 1-4 that are necessary to bring about change, the following is mentioned as a condition of therapeutic interaction sufficient to promote recovery. 5. Respecting and promoting natural resilience that a patient possesses. The emphasis is placed on developing environmental conditions that support the expansion of a range of experiences through which a patient's natural resilience is stimulated, which, in turn, could lead to internal change. The practice of such an interaction was illustrated in the treatment of a depressive patient and a patient with PTSD. PMID- 23367844 TI - [The way to proceed in psychotherapy--focusing on the framework of phobias and obsessive-compulsive stories]. AB - Compulsion becomes long-term when treatment is commenced with very severe resistance. Patients showing emotional changes are rare compared to those with conversion and phobic disorders. However, most people improve when careful treatment is carried out. Although there are those in whom drug treatment is effective, drug treatment and psychotherapy are concomitantly used in most cases. In this lecture, the characteristics of compulsion were psychodynamically investigated regarding: 1. Central conflict, 2. Defense mechanisms, 3. Condition of love life (including sex life), 4. Growth history, by comparing with phobias. When the life of the inner-self protrudes, obsessive-compulsive patients try to contradict and deny this. The symptoms sometimes directly represent the mental conflict of the person, and sometimes the symptom formation process may be understood to some extent. It is said that such cases are suitable for psychotherapy. Psychodynamic psychotherapy involves regaining the continuity of emotional life divided due to defenses such as negation, reaction formation, and isolation. Meanwhile, the real nature of phobias is avoidance and escape. Therefore, the trick in proceeding with interviews is to lead the phobia patient to areas which they avoid during interviews and areas which they avoid in daily life, and to have the patient enter these fields at times by encouraging them. PMID- 23367845 TI - [Symptomatic psychosis--to create new things by taking lessons from the past]. AB - Symptomatic psychosis is one of the central problems in research psychosomatic correlational research. My topic forthis lecture is on the research of symptomatic psychosis, which could be called one of the central problems in the field of clinical psychiatry. It is true that if a person is not physically stable, their "brain" and/or "mind" will not be calm. The opposite is equally true. 1. Are delusions of theft symptomatic psychosis In the elderly, there are some physical disease cases which developed into mental illness. For example, delusions of theft were triggered by physical diseases such as knee osteoarthritis, high blood pressure and glaucoma. I think it is possible to position these patients group as having symptomatic psychosis. 2. "Schizophrenia" is symptomatic psychosis We are thinking that there is a group that the biological material (bilirubin) in body fluid by way of hepatic failure did play a role leading to the expression of schizophrenia. Therefore I propose the following hypothesis: "there is a schizophrenia group that is an expression of a very mild kernicterus". This research started from our experiences having patients who had Gilbert's syndrome which has a high indirect (unconjugated) bilirubin. The patients also had schizophrenia. The psychological symptoms of schizophrenia fluctuated depending on the indirect (unconjugated) bilirubin levels. Also, we clarified that the frequency of patients with schizophrenia coexisting with GS is significantly higher than with other psychiatric disorders. PMID- 23367846 TI - [Prospects for the development of new antituberculous drugs based on the drug targets related to virulence factors interfering with host cytokine networks]. AB - Worldwide, tuberculosis remains the most frequent and important infectious disease to cause morbidity and death. However, the development of new drugs for the treatment and prophylaxis of TB has been slow. Therefore, novel types of antituberculous drugs, which act on the unique drug targets in Mycobacterium tuberculosis, particularly the drug targts related to the establishment of mycobacterial dormancy and persistency in host macrophages, are urgently needed. In this context, it should be noted that current antituberculous drugs mostly target the metabolic reactions and proteins which are essential for the growth of M. tuberculosis in extracellular milieus. It may also be promising to develop another type of drug that exhibits an inhibitory action against bacterial virulence factors which cross-talk and interfere with signaling pathways of M. tuberculosis-infected host immunocompetent cells such as macrophages and T cells, thereby changing the intracelluar milieus favorable to intramacrophage survival and growth of infected bacilli. In this review article, I will describe recent approaches to identify and establish novel potential drug targets in M. tuberculosis, especially those related to mycobacterial virulence factors interfering with host cytokine networks, particularly those acting upon intracellular signaling pathways of macrophages. PMID- 23367847 TI - [Analysis of bactericidal material generated by electrical devices advertising bactericidal ability against bacteria on the agar gel plates]. AB - Several Japanese companies sell electrical devices advertised as effective in inactivating viruses and killing bacteria by releasing special materials, e.g., Plasmacluster ions, Nanoe particle and minus ions, into the air. These companies claim that their devices killed bacteria on plates in their own experiments. We tested device effectiveness using the same experiments from the Plasmacluster ioniser SHARP Co., Japan, the Nanoe generator Panasonic Co., Japan, and the Vion KING JIM Co., Japan, to test their advertising claims. Bactericidal ability on agar plate was tested, using Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus cereus, and Enterococcus faecalis as follows: the medium containing a certain amount of each bacterium was put onto an agar plate and smeared. Plates were kept in a closed chamber (inner volume 14.4 m3) or a glove box (inner volume 0.2 m), with one of the devices run for 2 hours. Plates not exposed to any device were used as controls. Each plate was retrieved and put in an incubator to count the number of bacterial colonies formed on the plate. There was no significant difference in the number of colonies on plates exposed to devices compared to control, in the number for all devices, or in all bacteria tested in experiments in the 14.4 m3 chamber. These results strongly suggest that these devices have almost no bactericidal effect, at least in space exceeding this volume. Colony formation was suppressed in the glove box in all devices and in all bacteria tested except P. aeruginosa, although the degree of suppression differed among experiments. The colony formation suppression mechanism was analyzed, and indicated that:colony formation did not change even after the removal of Plasmacluster ions, Nanoe particles, or negative ions from the air, while colony formation was decreased drastically by the removal of ozone from space, which was revealed to be generated inevitably during device operation. These results strongly suggest that the bactericidal effect seen only on the agar plate in narrow space was explained by ozone released in space as a by-product, not by special materials as advertising claimed. It is thus important to analyze the effect of special materials such as those done in this study and to suggest the involvement of ozone as the true cause, as have been done in this study, in evaluating bactericidal effect or viral inactivation as advertised by these companies. PMID- 23367848 TI - [Clinical microbiological investigation of vancomycin intermediate Staphylococcus aureus during glycopeptide therapy]. AB - We isolated three strains of vancomycin intermediate Staphylococcus aureus (VISA) from a blood sample of a patient with infective endocarditis (VISA-1), postoperative pneumonia sputum (VISA-2), and pyogenic spondylitis blood sample (VISA-3). These VISA strains did not carry vanA, vanB, vanC1, or vanC2/C3 genes. Cell wall thickening was observed. VISA-1 and VISA-3 PFGE patterns showed the completely same pattern compared to the PFGE pattern of methicillin-resistant Staphylococcus aureus first isolated from patients 1 and 3. After 10 days on brain heart infusion agar, wall thickening in all three type of VISA was unchanged, but VISA-2 and VISA-3 reversed vancomycin susceptibility. The most suitable use of vancomycin in patients with MRSA infection thus appears to be in reducing the opportunity for cell wall thickening. PMID- 23367849 TI - [Direct PCR detection of food-borne bacteria from mixed human feces]. AB - Mixed human feces were evaluated for simultaneous direct PCR detection of 3 food borne bacteria--verotoxin-producing bacteria, Salmonella, and Shigella. Mixed feces concentrated approximately 2.5% in distilled water, were heated at 95 degrees C for 5 min. The heated suspension was then centrifuged and 5 microL of the supernatant poured into a 45 microL PCR mixture prepared to neutralize PCR inhibitors originating in biological samples. As a result of PCR under the above conditions followed by melting curve analysis (MCA), one positive fecal sample containing food-borne bacteria was detected from among 50 mixed fecal samples, showing the same sensitivity as individual cultivation. Results thus indicate that this method enables rapid, reliable, highly sensitive testing of many fecal samples--especially those of personnel handling food, which requires the simultaneous testing of many samples. PMID- 23367850 TI - [A study for the necessity of virus titer of varicella vaccine presently used]. AB - Recently available varicella vaccine titers are several dozen times higher than the formulation standard in accompanying information, i.e., > or = 1,000 PFU/dose. We investigated changes in immunogenicity associated with vaccination using a reduced dose whose virus titer was close to that used when the vaccine was developed, and examined the need for the virus titer presently used. In a non blinded study of 43 children with no history of varicella infection, we administered 0.1 mL of varicella vaccine (1/5 of the normal dose) to 20 children 1 year 0 month to 4 years 5 months old (median: 1 year 5 months) and the standard 0.5mL dose to 23 children 1 year 2 months to 3 years 7 months old (median: 1 year 9 months). We measured IAHA and gpELISA antibody titer before vaccination and 4 to 6 weeks after vaccination. We defined "positive" as > or = 2 fold of IAHA titer and > or = 50 U of gpELISA antibody titer. We administered an additional 0.5mL of varicella vaccine to children whose IAHA titer failed to show seroconversion and remeasured antibody titer 4 to 6 weeks after revaccination. IAHA seroconversion was 25.0% (5/20) and gpELISA seroconversion 55.0% (11/20) in the 0.1 mL vaccination group, which was lower than that of 76.2% (16/21) and 87.0% (20/23), IAHA p < 0.01, gpELISA p < 0.05, in the 0.5 mL vaccination group. We administered an additional vaccination to 19 children--15 in the 0.1 mL vaccination group and 4 in the 0.5 mL vaccination group-with 100% seroconversion for both methods. Mean antibody titer after revaccination in the 0.1 mL vaccination group (IAHA 2 (6.0), gpELISA 10 (3.7)) was higher than those in the 0.5mL vaccination group who seroconverted following initial vaccination (IAHA 2(4.5), gpELISA 10(2.6)) (p < 0.01). We also measured virus titer in the remaining vaccine following vaccination of 0.1 mL (n = 20), and estimated virus titer administered to the 0.1 mL vaccination group to be 2,600-6,400 PFU/ dose. Varicella vaccine immunogenicity decreased if dosage was reduced to 1/5 of the standard dose, indicating that the present virus titer is necessary to maintain adequate immunogenicity. An additional administration of the standard dose to children who failed to seroconvert after initial 0.1 mL administration produced high antibody titers thought to constitute a booster effect. PMID- 23367851 TI - [Epidemiological analysis and clinical study of pediatric human metapneumovirus detected in patients with acute respiratory infection]. AB - We detected and isolated human metapneumovirus (HMPV) and isolated another respiratory virus in pharyngeal swab specimens from 502 pediatric patients with acute respiratory infection, seen at 3 Kyoto City sentinel hospitals from January to December 2011. Our prospective study detected 43 positive HMPV cases (8.6%). Phylogenetic analysis showed that subgroup A2 was most common, followed by B1 and B2, and that A1 was not detected. HMPV was detected mostly in specimens from patients less than 3 years old, and positive HMPV was identified most in spring, peaking in March. Our clinical study showed that positive HMPV patients had fever above 38 degrees (86%) and cough (65%). Among the 30 whose chest radiography was examined, radiological findings were recognized in 18 cases. We found inflammatory infiltrative shadows around the bronchus and peribronchus near the hilum of the lung. Lobar pneumonia and diffuse infiltrative shadows coinciding with peripheral alveolar involvement were not recognized. No difference affecting illness severity was seen among subgroups, viral isolation results, or mixed coxsackie virus or influenza virus infection. In hospitalization, mean disease lasted significantly longer in those with lower respiratory tract symptoms at first'examination than in those without such symptoms. We detected HMPV RNA in pharyngeal swabs and stool specimens from patients admitted to the hospital for rhabdomyolysis. PMID- 23367852 TI - [A case of hepatitis B virus/human immunodeficiency virus coinfection in a patient who achived hepatitis B surface antigen seroclearance after interferon therapy followed by antiretroviral therapy without developing immune reconstitution inflammatory syndrome]. AB - Coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) is common worldwide. The current guidelines for the treatment of HIV infection recommend that HIV patients coinfected with HBV receive antiretoroviral therapy (ART) with two nucleoside analogs against HBV. However, an increase in liver enzymes that is usually attributed to HBV immune reconstitution inflammatory syndrome (IRIS) sometimes occurs in HBV/HIV-coinfected patients after the commencement of ART. We report a case of HBV/HIV-coinfection in which the chronic hepatitis B was successfully treated using interferon (IFN) therapy followed by ART without the development of IRIS. A Japanese man in thirties was referred to our hospital because of an acute HIV infection two months after the diagnosis of an acute HBV infection, which had progressed to a chronic HBV infection. The laboratory test results were as follows:hepatitis B surface antigen (HBsAg) positive, hepatitis B e antigen (HBeAg) positive, HBV DNA level of 8.8 Log copies/mL, HBV genotype A, alanine aminotransferase of 834 IU/L, HIV RNA level of 5 Log copies/mL, and a CD4+ T cell count of 437/microL. The initial treatment was natural IFNalpha therapy for chronic hepatitis B, and HBeAg seroclearance was achieved 20 weeks after the start of therapy. Four months after the end of IFN therapy for 24 weeks, ART including tenofovir and emtricitabine against HBV was commenced. Six months after starting ART, the patient's serum HBV DNA level had decreased and become undetectable and HBsAg seroclearance was achieved without an elevation in liver enzymes. The present case suggests that IFN therapy prior to ART contributes to a successful outcome for chronic hepatitis B patients coinfected with HIV, if the HIV status does not require the immediate start of ART. PMID- 23367853 TI - [A case of descending necrotizing mediastinitis caused by infection with Streptococcus agalactiae in a patient with diabetes mellitus]. AB - We report a case with an atypical presentation of descending necrotizing mediastinitis (DNM). A 47-year-old woman with a medical history of untreated type 2 diabetes mellitus and influenza type A virus infection 2 weeks prior to admission was referred to our hospital complaining of right cervical pain and right upper limb swelling. A chest enhanced computed tomographic (CT) scan showed a ring-enhanced mass-like shadow extending from the right sternomastoid muscle down to the right upper mediastinum, compressing the right subclavicular vein. We diagnosed the patient as having DNM based on a physical examination and the CT findings. Because the abscess extended from deep in the neck to the upper mediastinum and right upper pleural space, emergent abscess debridement and drainage was required. After hospitalization, antibiotics (Ampicillin/Sulbactam 12 g/day) were also administered based on Gram-stain findings from the drainage fluid, which showed Gram-positive cocci resembling a string of beads. A culture of the drainage fluid identified Streptococcus agalactiae. Aggressive abscess drainage and early antibiotic therapy resulted in a favorable response. She was discharged without complications on the 33rd hospital day. DNM is well known as a rare but lethal disease. In this case, the presence of diabetes mellitus and post influenza infection might have been risk factors for a serious S. agalactiae infection. Early aggressive therapy and adequate drainage are recommended for patients with DNM. PMID- 23367854 TI - [Amebic colitis and liver abscess complicated by high serum procalcitonin in acute myeloid leukemia]. AB - We present a case of amebic colitis and liver abscess complicated by acute myeloid leukemia (AML) with high serum procalcitonin (PCT). A 61-year-old Japanese man seen at our hospital for severe diarrhea and high fever was found to have multiple ulcers in the transverse and sigmoid colon and rectum by colonoscopy and biopsies were conducted. Immature leukocytes with mild anemia and thrombocytopenia were seen in peripheral blood, necessitating bone marrow aspiration and biopsy that yielded a diagnosis of AML (FAB M4Eo). Serum C reactive protein and PCT were extremely elevated. Blood cultures for bacteria and fungi were negative. Multiple low-density areas in the liver were found in abdominal computed tomography. Histological colon biopsy findings revealed amebic colitis, strongly suggesting amebic liver abscess. Metronidazole treatment was initiated for amebiasis and subsequent standard chemotherapy for AML was followed after fever was lowered. Hematological and cytogenetic CR was maintained with good clinical condition. Few case reports have been published in Japan to date on amebic colitis and liver abscess complicated by AML and no reports have been made on PCT elevation caused by amebiasis. In conclusion, differential diagnosis of amebiasis is necessary in addition to that of bacterial or fungal infection in serum PCT elevation. PMID- 23367855 TI - [A case of pacemaker-lead infection by linezolid-resistant methicillin-resistant Staphylococcus aureus in a hemodialysis patient]. AB - A 76-year-old woman undergoing hemodialysis and having a permanent pacemaker during care elsewhere developed a shunt infection with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Vancomycin (VCM) and other antimicrobial agents were not effective even after her artificial shunt vessel was removed. Linezolid (LZD) was administered for 56 days to resolve fever. MRSA was detected repeatedly in blood culture for 7 months except while LZD was being administered, so she was referred to our hospital for further investigation and treatment. Blood culture isolated 3 MRSA strains, all having a minimum inhibitory concentration (MIC) of LZD above 16 microg/mL while that of VCM varied at 24 microg/mL. Based on these findings, combined VCM, rifampicin, and arbekacin therapy was started but did not resolve the MRSA bacteremia problem. Transesophageal echocardiography showed flat vegetation around the pacemaker lead passing through the tricuspid valve. Based on strongly suspected pacemaker-lead infection, the pacemaker system was removed by heart surgeons using radiographic imaging on day 16 after admission. Her blood culture then became negative. She was returned to the previous hospital on day 66 after admission, where combination antibiotic therapy was continued for about one month. MRSA was not detected again after pacemaker system removal. PMID- 23367856 TI - [Gene regulation with cartilage degeneration in rheumatoid arthritis and osteoarthritis]. PMID- 23367857 TI - [The operated case of 89 year-old patient with pleomorphic carcinoma of the lung]. AB - A-89-year-old male patient who complained dry cough was detected lung mass of 3 cm size in diameter at the right upper lobe by CT. FDG-PET seemed to show hilar and mediastinum lymph nodes metastasis. After three weeks, the mass showed rapid growth with 5 cm diameter in size at CT. Therefore the original tumor was supposed to be undifferentiated carcinoma, above all, pleomorphic carcinoma. He had been done pulmonary resection after short period. The right upper lobectomy with combined resection of the partial middle lobe was performed. Hilar and mediastinum lymph nodes dissection was added. In pathological examination, the tumor was proved pleomorphic carcinoma, however, no lymph node metastasis was recognized. He did not refer any complications and discharged back home at the post-operative 11th day. Pleomorphic carcinoma of the lung is known to be difficult to obtain definite diagnosis in early stage because of rapid growth. Therefore many cases are detected in advanced stage. In addition, chemotherapy is generally not effective, so only operative resection seems to be useful. Our patient was 89-year-old, he tolerated the operation and was alive with no trouble during 6 months after resection. When complete resection seems to be possible, operation should be regarded as an initial treatment. PMID- 23367858 TI - [A case of successful multi-venous reconstruction using recipient's jugular vein in right lobe-living donor liver transplantation]. AB - In right lobe-living donor liver transplantation (RT-LDLT), hepatic venous reconstruction of the graft is essential to prevent posttansplant graft congestion and have a good outcome. The patient was a 56-year-old man who had decompensated liver cirrhosis secondary hepatitis C with massive ascites, jaundice and hepatic encephalopathy. He underwent LDLT using his son's right lobe graft. Preoperative simulation by 3D-CT volumetry revealed that the right lobe graft needed multi-venous reconstruction for right inferior hepatic vein (RIHV) and middle hepatic venous tributaries. Preoperative CT scan revealed that the recipient had portal venous thrombus and stenosis, which meant that the recipient's explanted portal vein (EPV) was not suitable for the venous reconstruction of the right lobe graft. Therefore, the recipient's internal and external jugular veins (IJV and EJV) were procured for venous reconstruction. The multiple veins of the right lobe graft were reconstructed to have single co orifice at the backtable, and the co-orifice was anastomosed to inferior vena cava in short time. The recipient discharged on postoperative day 22 with good venous patency. In RT-LDLT unavailable for recipient's EPV, recipient's IJV and EJV grafts are very useful for multi-venous reconstruction. PMID- 23367859 TI - [Overdiagnosis and overtreatment--time to sober up]. PMID- 23367860 TI - [Participating in the rounds is not illegal]. PMID- 23367861 TI - [The Nobel Prize to detailed studies of G protein-coupled receptors. This years Nobel Prize in chemistry provides important knowledge--but it might take a while before it can be practically applied]. PMID- 23367862 TI - [Economic matching theory in renal transplantation. Sveriges Riksbank Prize in Economic Sciences in Memory of Alfred Nobel 2012]. PMID- 23367863 TI - [A lot can go wrong after major abdominal surgery]. PMID- 23367864 TI - [Fainting school helps against troublesome vasovagal syncope. Experiences of the leg crossing method]. PMID- 23367865 TI - [More and more people get acute intestinal ischemia--early diagnosis and treatment saves lives]. PMID- 23367866 TI - [Laparotomy in acute intestinal ischemia--think before you act!]. PMID- 23367867 TI - [Endovascular surgery is the primary choice for vascular surgery in acute intestinal ischemia]. PMID- 23367868 TI - [Nutrition in intestinal failure after intestinal ischemia]. PMID- 23367869 TI - [Time for debate on addiction care]. PMID- 23367870 TI - [Medical education: Increase focus on core subjects and clinical medical education!]. PMID- 23367871 TI - [The poor man's physician who became a versatile scientist]. PMID- 23367872 TI - Modification of Ca(2+)-handling in cardiomyocytes by redox sensitive mechanisms in response to ouabain. AB - We examined the role of redox-sensitive signal transduction mechanisms in modifying the changes in [Ca(2+)](i) produced by ouabain upon incubating adult rat cardiomyocytes with antioxidants or inhibitors of different protein kinases and monitoring alterations in fura-2 fluorescence. Ouabain increased basal [Ca(2+)](i), augmented the KCl-induced increase in [Ca(2+)](i), and promoted oxyradical production in cardiomyocytes. These actions of ouabain were attenuated by an oxyradical scavenging mixture (superoxide dismutase plus catalase), and the antioxidants (N-acetyl-L-cysteine and N-(2-mercaptoproprionyl)glycine). An inhibitor of MAP kinase (PD98059) depressed the ouabain-induced increase in [Ca(2+)], whereas inhibitors of tyrosine kinase (tyrphostin and genistein) and PI3 kinase (Wortmannin and LV294002) enhanced the ouabain-induced increase in [Ca(2+)](i). Inhibitors of protein kinase C (calphostin and bisindolylmalaimide) augmented the ouabain-induced increase in [Ca(2+)](i), whereas stimulation of protein kinase C by a phorbol ester (phorbol 12-myristate 13-acetate) depressed the action of ouabain. These results suggest that ouabain-induced inhibition of Na (+)-K(+) ATPase may alter the redox status of cardiomyocytes through the production of oxyradicals, and increase the activities of various protein kinases. Thus, these redox-sensitive signal transduction mechanisms involving different protein kinases may modify Ca(2+)-handling sites in cardiomyocytes and determine the magnitude of net increase in [Ca(2+)](i) in response to ouabain. PMID- 23367873 TI - Inhibitors of JAK2 and JAK3: an update on the patent literature 2010 - 2012. AB - INTRODUCTION: Janus kinases (JAKs) comprise a family of four enzymes, JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), centrally implicated in cell signaling processes important in cancer and immune-inflammatory diseases. Progression in the field has taken a recent step forward with the approval of ruxolitinib (Jakafi), a selective inhibitor of JAK1/2 and very recently tofacitinib (Xeljanz), a pan-JAK inhibitor. There are many new JAK family enzyme inhibitors in the clinic now with a range of selectivity profiles. More selective JAK2 or JAK3 compounds are now coming through in considerable numbers and this review attempts to provide an update of the recent patent literature of those new compounds. An overview is given on the diversity of core structures employed for inhibitor design showing that the vast majority of compounds are based on classic ATP-competitive kinase inhibitor heterocycles. AREAS COVERED: This review updates new patents claiming JAK2 and/or JAK3 inhibitors published from 2010 to 2012. Pre 2010 patents have been extensively covered in previous reviews. Comments on the context of each chemical series are given where applicable to orientate the readers on the bewildering array of molecular designs now available. This review does not cover JAK1 or TYK2 inhibitors but mention is made of these where they occur within series of JAK2/3 inhibitors. Given the overlap between many pharmacophores, it was not possible to completely separate inhibitors of JAK2 from JAK3, hence the material is organized by JAK2, JAK3 and JAK2/3 and within each section by alphabetical order of the patent assignee, some companies having published five or more patents, such as Ambit (10), Incyte (9), Galapagos (7), Almirall (6) and Biocryst (5). A total of 98 patents are reviewed herein. EXPERT OPINION: JAK inhibitor therapy is entering a significant new era with the advent on the market of the JAK1/2 inhibitor ruxolitinib and the pan-JAK inhibitor tofacitinib, with unprecedented speed of development. Selectivity against the four individual JAK family enzymes, JAK1, 2, 3 and TYK2, is now a key goal since they each play subtly different roles in cytokine-induced cell signaling. The future looks bright for patients as many new drugs are being developed and now combinations of JAK inhibitors with other targeted agents are being studied in the clinic. These advances are expected to lead to further significant progress improving patient outcomes and quality of life. PMID- 23367874 TI - Metacognitive awareness of the associative deficit for words and names. AB - Older adults have considerable impairment in associative recognition despite minimal age differences in item recognition. The magnitude of this associative deficit varies by type of stimuli, strategy utilization, and other mediators and moderators ( Old & Naveh-Benjamin, 2008 , Psychology and Aging, 23, 104-118). Name pair stimuli have not been used to test the associative deficit hypothesis (ADH), although tests using name-face stimuli support the ADH. Additionally, metacognitive awareness of the ADH has not been investigated. We tested the ADH with word and name pair stimuli, and predicted that age-related associative deficits would be larger for words than names because names, unlike most common nouns, lack certain semantic properties that could be used to bind pairs of names together. Results supported the ADH for words but not names: Younger and older adults recognized equivalently fewer names on the associative test relative to the item test. As predicted, self-efficacy was higher for younger than older adults. Surprisingly, self-efficacy for the associative test was higher than for the item test but post-test estimates of performance success (postdictions) were higher for the item test than for the associative test, suggesting sensitivity by participants to different task demands in the item and associative tests following recognition attempts. Metacognitive accuracy was better for words than names and for the item test than associative test, and equivalent between age groups. Overall, participants overestimated their name recognition abilities. Our findings extend support for the ADH to a conceptually important and ecologically valid domain (names) and provide new data on metacognitive aspects of the ADH. PMID- 23367875 TI - Normalizing CO2 in chronic hyperventilation by means of a novel breathing mask: a pilot study. AB - INTRODUCTION: Chronic idiopathic hyperventilation (CIH) is a form of dysfunctional breathing that has proven hard to treat effectively. OBJECTIVES: To perform a preliminary test of the hypothesis that by periodically inducing normocapnia over several weeks, it would be possible to raise the normal resting level of CO2 and achieve a reduction of symptoms. METHODS: Six CIH patients were treated 2 h a day for 4 weeks with a novel breathing mask. The mask was used to induce normocapnia in these chronically hypocapnic patients. Capillary blood gases and acid/base parameters [capillary CO2 tension (PcapCO2 ), pH, and standard base excess (SBE)] were measured at baseline and once each week at least 3 h after mask use, as well as spirometric values, breath-holding tolerance and hyperventilation symptoms as per the Nijmegen Questionnaire (NQ). RESULTS: The mask treatment resulted in a significant increase of resting PcapCO2 (+0.45 kPa, P = 0.028), a moderate increase in SBE (+1.4 mEq/L, P = 0.035) and a small reduction in daily symptoms (-3.8 NQ units, P = 0.046). The effect was most pronounced in the first 2 weeks of treatment. CONCLUSION: By inducing normocapnia with the breathing mask 2 h a day for 4 weeks, the normal resting CO2 and acid/base levels in chronically hyperventilating patients were partially corrected, and symptoms were reduced. PMID- 23367876 TI - Synthetic ligand-coated magnetic nanoparticles for microfluidic bacterial separation from blood. AB - Bacterial sepsis is a serious clinical condition that can lead to multiple organ dysfunction and death despite timely treatment with antibiotics and fluid resuscitation. We have developed an approach to clearing bacteria and endotoxin from the bloodstream, using magnetic nanoparticles (MNPs) modified with bis-Zn DPA, a synthetic ligand that binds to both Gram-positive and Gram-negative bacteria. Magnetic microfluidic devices were used to remove MNPs bound to Escherichia coli , a Gram-negative bacterium commonly implicated in bacterial sepsis, from bovine whole blood at flows as high as 60 mL/h, resulting in almost 100% clearance. Such devices could be adapted to clear bacteria from septicemic patients. PMID- 23367877 TI - ELF-MF transiently increases skeletal myoblast migration: possible role of calpain system. AB - PURPOSE: Cell migration is crucial for myogenesis since it is required for the alignment and fusion of myoblast. Ca(2+) signals are involved in regulating myoblast migration and an extremely low frequency (ELF) magnetic field (MF) increases intracellular calcium levels in C2C12 myoblast. This study was aimed at investigating whether ELF-MF could affect myoblast migration. As calpains contribute to the regulation of myoblast motility, the effect of ELF-MF on MU- and m-calpain was also investigated. MATERIALS AND METHODS: The effect of ELF-MF (1 mT; 50 Hz) on C2C12 cell motility was observed by wound-healing assay. Protein expression of calpains, calpastatin, myristoylated alanine-rich C-kinase substrate (MARCKS) and vinculin were examined by Western blot analysis. Casein zymography and immunofluorescence analysis were carried out to evaluate, respectively, activity levels of calpains and intracellular distribution of calpains, calpastatin and actin. RESULTS: Exposure to ELF-MF resulted in a transient but significant increase of myoblast migration. This stimulatory effect was associated with a marked increase of MU- and m-calpain activity followed by the concomitant variation in their subcellular localization. No significant changes in intracellular distribution and protein levels of calpastatin were detected. Finally, a significant decrease of MARCKS expression and modifications of actin dynamics were reported. CONCLUSIONS: This study clearly outlines an involvement of calpains in ELF-MF-mediated myoblast migration. PMID- 23367878 TI - Clinical features of eosinophilic esophagitis: ten Japanese cases. AB - AIM: We studied eosinophilic esophagitis (EE) to clarify the clinical and endoscopic features of a Japanese case series. METHODS: Records of 10 patients diagnosed with EE at our hospital between May 2010 and December 2011 were examined for age, sex, symptoms, allergic disorder, endoscopic findings, and treatment received. Esophageal wall thickness was measured by endoscopic ultrasonography (EUS). RESULTS: Patients were seven males and three females with a mean age of 48 years. Symptoms included dysphagia, heartburn, food impaction, and chest pain. Nine patients had a history of allergic diseases. Increased peripheral eosinophil count was observed in one patient whereas increased immunoglobulin E level was observed in eight patients. Endoscopic findings included longitudinal furrows in all patients, mucosal edema in nine patients, loss of vascular pattern in nine patients, white exudates in six patients, cobblestone-like appearance in five patients, and concentric rings in three patients. EUS revealed thickening of the esophageal wall in one patient. Histopathological examination revealed eosinophilic infiltration (>=15 eosinophils/high-powered field) in the esophageal epithelium of all patients. Treatment was required in six patients. Proton pump inhibitor (PPI) therapy was given as the first-line treatment but was ineffective in four patients and effective in two patients. Steroid therapy was given to three patients unresponsive to PPI therapy and was effective. CONCLUSIONS: EE was common among relatively young men and was associated with allergic diseases. Longitudinal furrows were observed as the most characteristic endoscopic finding. Esophageal wall thickening was not commonly observed by EUS. PMID- 23367879 TI - Inferring homologous protein-protein interactions through pair position specific scoring matrix. AB - BACKGROUND: The protein-protein interaction (PPI) is one of the most important features to understand biological processes. For a PPI, the physical domain domain interaction (DDI) plays the key role for biology functions. In the post genomic era, to rapidly identify homologous PPIs for analyzing the contact residue pairs of their interfaces within DDIs on a genomic scale is essential to determine PPI networks and the PPI interface evolution across multiple species. RESULTS: In this study, we proposed "pair Position Specific Scoring Matrix (pairPSSM)" to identify homologous PPIs. The pairPSSM can successfully distinguish the true protein complexes from unreasonable protein pairs with about 90% accuracy. For the test set including 1,122 representative heterodimers and 2,708,746 non-interacting protein pairs, the mean average precision and mean false positive rate of pairPSSM were 0.42 and 0.31, respectively. Moreover, we applied pairPSSM to identify ~450,000 homologous PPIs with their interacting domains and residues in seven common organisms (e.g. Homo sapiens, Mus musculus, Saccharomyces cerevisiae and Escherichia coli). CONCLUSIONS: Our pairPSSM is able to provide statistical significance of residue pairs using evolutionary profiles and a scoring system for inferring homologous PPIs. According to our best knowledge, the pairPSSM is the first method for searching homologous PPIs across multiple species using pair position specific scoring matrix and a 3D dimer as the template to map interacting domain pairs of these PPIs. We believe that pairPSSM is able to provide valuable insights for the PPI evolution and networks across multiple species. PMID- 23367881 TI - Optimal fits of diffusion constants from single-time data points of Brownian trajectories. AB - Experimental methods based on single particle tracking (SPT) are being increasingly employed in the physical and biological sciences, where nanoscale objects are visualized with high temporal and spatial resolution. SPT can probe interactions between a particle and its environment but the price to be paid is the absence of ensemble averaging and a consequent lack of statistics. Here we address the benchmark question of how to accurately extract the diffusion constant of one single Brownian trajectory. We analyze a class of estimators based on weighted functionals of the square displacement. For a certain choice of the weight function these functionals provide the true ensemble averaged diffusion coefficient, with a precision that increases with the trajectory resolution. PMID- 23367880 TI - Treatment with a combination of the ErbB (HER) family blocker afatinib and the IGF-IR inhibitor, NVP-AEW541 induces synergistic growth inhibition of human pancreatic cancer cells. AB - BACKGROUND: Aberrant expression and activation of the IGF-IR have been reported in a variety of human cancers and have been associated with resistance to HER targeted therapy. In this study, we investigated the effect of simultaneous targeting of IGF-IR and HER (erbB) family, with NVP-AEW541 and afatinib, on proliferation of pancreatic cancer cells. METHODS: The sensitivity of a panel of human pancreatic cancer cell lines to treatment with NVP-AEW541 used alone or in combination with afatinib, anti-EGFR antibody ICR62, and cytotoxic agents was determined using the Sulforhodamine B colorimetric assay. Growth factor receptor expression, cell-cycle distribution and cell signalling were determined using flow cytometry and western blot analysis. RESULTS: All pancreatic cancer cell lines were found to be IGF-IR positive and NVP-AEW541 treatment inhibited the growth of the pancreatic cancer cell lines with IC50 values ranging from 342 nM (FA6) to 2.73 MUM (PT45). Interestingly, of the various combinations examined, treatment with a combination of NVP-AEW541 and afatinib was superior in inducing synergistic growth inhibition of the majority of pancreatic cancer cells. CONCLUSION: Our results indicate that co-targeting of the erbB (HER) family and IGF-IR, with a combination of afatinib and NVP-AEW541, is superior to treatment with a single agent and encourages further investigation in vivo on their therapeutic potential in IGF-IR and HER positive pancreatic cancers. PMID- 23367882 TI - Localization transition of stiff directed lines in random media. AB - We investigate the localization of stiff directed lines with bending energy by a short-range random potential. Using perturbative arguments, Flory arguments, and a replica calculation, we show that a stiff directed line in 1+d dimensions undergoes a localization transition with increasing disorder for d>2/3. We demonstrate that this transition is accessible by numerical transfer matrix calculations in 1+1 dimensions and analyze the properties of the disorder dominated phase. On the basis of the two-replica problem, we propose a relation between the localization of stiff directed lines in 1+d dimensions and of directed lines under tension in 1+3d dimensions, which is strongly supported by identical free energy distributions. This shows that pair interactions in the replicated Hamiltonian determine the nature of directed line localization transitions with consequences for the critical behavior of the Kardar-Parisi Zhang (KPZ) equation. Furthermore, we quantify how the persistence length of the stiff directed line is reduced by disorder. PMID- 23367883 TI - Kinetic cross coupling between nonconserved and conserved fields in phase field models. AB - We present a phase field model for isothermal transformations of two-component alloys that includes Onsager kinetic cross coupling between the nonconserved phase field and the conserved concentration field o C. We also provide the reduction of the phase field model to the corresponding macroscopic description of the free boundary problem. The reduction is given in a general form. Additionally we use an explicit example of a phase field model and check that the reduced macroscopic description, in the range of its applicability, is in excellent agreement with direct phase field simulations. The relevance of the newly introduced terms to solute trapping is also discussed. PMID- 23367884 TI - Interfacial free energy of a hard-sphere fluid in contact with curved hard surfaces. AB - Using molecular-dynamics simulation, we have calculated the interfacial free energy gamma between a hard-sphere fluid and hard spherical and cylindrical colloidal particles, as functions of the particle radius R and the fluid packing fraction eta=rhosigma(3)/6, where rho and sigma are the number density and hard sphere diameter, respectively. These results verify that Hadwiger's theorem from integral geometry, which predicts that gamma for a fluid at a surface, with certain restrictions, should be a linear combination of the average mean and Gaussian surface curvatures, is valid within the precision of the calculation for spherical and cylindrical surfaces up to eta ~ 0.42. In addition, earlier results for gamma for this system [Bryk et al., Phys. Rev. E 68, 031602 (2003)] using a geometrically based classical density functional theory are in excellent agreement with the current simulation results for packing fractions in the range where Hadwiger's theorem is valid. However, above eta ~ 0.42, gamma(R) shows significant deviations from the Hadwiger form indicating limitations to its use for high-density hard-sphere fluids. Using the results of this study together with Hadwiger's theorem allows one, in principle, to determine gamma for any sufficiently smooth surface immersed in a hard-sphere fluid. PMID- 23367885 TI - Mechanical frustration and spontaneous polygonal folding in active nematic sheets. AB - We analyze the bending response to light or heat of a solid nematic disk with a director twisted from being radial on the upper surface to be azimuthal on the lower. We find a number of curl lobes determined purely by the geometry of the mechanical frustration that arises during the response. PMID- 23367886 TI - Directional sensing of deformed cells under faint gradients. AB - We consider the physical limit of the directional sensing ability of living cells, as in chemotaxis, under a low concentration and shallow chemoattractant gradient. Elliptic cells sense the direction, which is a stochastic variable of a characteristic distribution with peaks at directions not necessarily to the gradient. The peak positions depend on the information of the gradient that cells use to infer the direction and also the shape and orientation of cells. Cells of different shapes may use different inference strategies to increase their directional sensing performance. PMID- 23367887 TI - Shortest-path fractal dimension for percolation in two and three dimensions. AB - We carry out a high-precision Monte Carlo study of the shortest-path fractal dimension d(min) for percolation in two and three dimensions, using the Leath Alexandrowicz method which grows a cluster from an active seed site. A variety of quantities are sampled as a function of the chemical distance, including the number of activated sites, a measure of the radius, and the survival probability. By finite-size scaling, we determine d(min)=1.13077(2) and 1.3756(6) in two and three dimensions, respectively. The result in two dimensions rules out the recently conjectured value d(min)=217/192 [Deng et al., Phys. Rev. E 81, 020102(R) (2010)]. PMID- 23367888 TI - Dissipative Levy random searches: universal behavior at low target density. AB - We investigate the problem of survival at the very low target-density limit and report on a second-order phase transition for one-dimensional random searches in which the energy cost of locomotion is a function of the distance traveled by the searcher. Surprisingly, from analytical calculations (also tested numerically) we find identical critical exponents for arbitrary energy cost functions. We conclude that there is a single universality class that describes this process. PMID- 23367889 TI - Momentum relaxation of a relativistic Brownian particle. AB - The momentum relaxation of a relativistic Brownian particle immersed in a fluid is studied on the basis of the Fokker-Planck equation for the relativistic Ornstein-Uhlenbeck process. An analytical expression is derived for the short time relaxation rate. The relaxation spectrum has both discrete and continuum components. It is shown that the Fokker-Planck equation under consideration is closely related to the Schrodinger equation for the hydrogen atom. Hence it follows that there is an infinite number of discrete states. The momentum autocorrelation function is calculated numerically for a strongly relativistic particle. PMID- 23367890 TI - Specific heats of quantum double-well systems. AB - Specific heats of quantum systems with symmetric and asymmetric double-well potentials have been calculated. In numerical calculations of their specific heats, we have adopted the combined method, which takes into account not only eigenvalues of epsilon(n) for 0 <= n <= N(m) obtained by the energy-matrix diagonalization but also their extrapolated ones for N(m) + 1 <= n /~ 1.2 * 10(4)) isotropically placed at the lattice, percolation cannot occur, even at jamming concentration. PMID- 23367903 TI - Maximum-entropy distributions of correlated variables with prespecified marginals. AB - The problem of determining the joint probability distributions for correlated random variables with prespecified marginals is considered. When the joint distribution satisfying all the required conditions is not unique, the "most unbiased" choice corresponds to the distribution of maximum entropy. The calculation of the maximum-entropy distribution requires the solution of rather complicated nonlinear coupled integral equations, exact solutions to which are obtained for the case of Gaussian marginals; otherwise, the solution can be expressed as a perturbation around the product of the marginals if the marginal moments exist. PMID- 23367904 TI - Quantum transport efficiency and Fourier's law. AB - We analyze the steady-state energy transfer in a chain of coupled two-level systems connecting two thermal reservoirs. Through an analytic treatment we find that the energy current is independent of the system size, hence violating Fourier's law of heat conduction. The classical diffusive behavior in Fourier's law of heat conduction can be recovered by introducing decoherence to the quantum systems constituting the chain. We relate these results to recent discussions of energy transport in biological light-harvesting systems, and discuss the role of quantum coherence and entanglement. PMID- 23367905 TI - Critical dynamics of an isothermal compressible nonideal fluid. AB - A pure fluid at its critical point shows a dramatic slow-down in its dynamics, due to a divergence of the order-parameter susceptibility and the coefficient of heat transport. Under isothermal conditions, however, sound waves provide the only possible relaxation mechanism for order-parameter fluctuations. Here we study the critical dynamics of an isothermal, compressible nonideal fluid via scaling arguments and computer simulations of the corresponding fluctuating hydrodynamics equations. We show that, below a critical dimension of 4, the order parameter dynamics of an isothermal fluid effectively reduces to "model A," characterized by overdamped sound waves and a divergent bulk viscosity. In contrast, the shear viscosity remains finite above two dimensions. Possible applications of the model are discussed. PMID- 23367906 TI - Survival probability of an immobile target in a sea of evanescent diffusive or subdiffusive traps: a fractional equation approach. AB - We calculate the survival probability of an immobile target surrounded by a sea of uncorrelated diffusive or subdiffusive evanescent traps (i.e., traps that disappear in the course of their motion). Our calculation is based on a fractional reaction-subdiffusion equation derived from a continuous time random walk model of the system. Contrary to an earlier method valid only in one dimension (d=1), the equation is applicable in any Euclidean dimension d and elucidates the interplay between anomalous subdiffusive transport, the irreversible evanescence reaction, and the dimension in which both the traps and the target are embedded. Explicit results for the survival probability of the target are obtained for a density rho(t) of traps which decays (i) exponentially and (ii) as a power law. In the former case, the target has a finite asymptotic survival probability in all integer dimensions, whereas in the latter case there are several regimes where the values of the decay exponent for rho(t) and the anomalous diffusion exponent of the traps determine whether or not the target has a chance of eternal survival in one, two, and three dimensions. PMID- 23367907 TI - Quantifying causal coupling strength: a lag-specific measure for multivariate time series related to transfer entropy. AB - While it is an important problem to identify the existence of causal associations between two components of a multivariate time series, a topic addressed in Runge, Heitzig, Petoukhov, and Kurths [Phys. Rev. Lett. 108, 258701 (2012)], it is even more important to assess the strength of their association in a meaningful way. In the present article we focus on the problem of defining a meaningful coupling strength using information-theoretic measures and demonstrate the shortcomings of the well-known mutual information and transfer entropy. Instead, we propose a certain time-delayed conditional mutual information, the momentary information transfer (MIT), as a lag-specific measure of association that is general, causal, reflects a well interpretable notion of coupling strength, and is practically computable. Rooted in information theory, MIT is general in that it does not assume a certain model class underlying the process that generates the time series. As discussed in a previous paper [Runge, Heitzig, Petoukhov, and Kurths, Phys. Rev. Lett. 108, 258701 (2012)], the general framework of graphical models makes MIT causal in that it gives a nonzero value only to lagged components that are not independent conditional on the remaining process. Further, graphical models admit a low-dimensional formulation of conditions, which is important for a reliable estimation of conditional mutual information and, thus, makes MIT practically computable. MIT is based on the fundamental concept of source entropy, which we utilize to yield a notion of coupling strength that is, compared to mutual information and transfer entropy, well interpretable in that, for many cases, it solely depends on the interaction of the two components at a certain lag. In particular, MIT is, thus, in many cases able to exclude the misleading influence of autodependency within a process in an information theoretic way. We formalize and prove this idea analytically and numerically for a general class of nonlinear stochastic processes and illustrate the potential of MIT on climatological data. PMID- 23367908 TI - Comparison of Shannon information entropies in position and momentum space for an electron in one-dimensional nonuniform systems. AB - We investigate numerically the position- and momentum-space Shannon information entropies, S(x)(beta) and S(p)(beta), respectively, of energy eigenstates |beta} for an electron in four kinds of one-dimensional (1D) nonuniform systems, i.e., the Harper model, the slowly varying potential ones, the complex quasiperiodic potential ones, and the random-dimer potential ones. In the former three models, electronic localization properties are well-defined. For them, we find it interesting that, S(x)(beta) is greater than, equal to, and less than S(p)(beta) for delocalized, critical, and localized states in position-space, respectively, which can be used as signatures of the transition from a delocalized phase to a localized ones. With the criterion, we analyze the random-dimer potential model. We give another perspective and propose a consistent interpretation of discrepancies about the random-dimer potential model. Therefore, all these provide us a simple method to discern the nature of states in these 1D nonuniform systems. PMID- 23367909 TI - Effects of random and deterministic discrete scale invariance on the critical behavior of the Potts model. AB - The effects of disorder on the critical behavior of the q-state Potts model in noninteger dimensions are studied by comparison of deterministic and random fractals sharing the same dimensions in the framework of a discrete scale invariance. We carried out intensive Monte Carlo simulations. In the case of a fractal dimension slightly smaller than two d(f) ~/= 1.974636, we give evidence that the disorder structured by discrete scale invariance does not change the first order transition associated with the deterministic case when q = 7. Furthermore the study of the high value q = 14 shows that the transition is a second order one both for deterministic and random scale invariance, but that their behavior belongs to different university classes. PMID- 23367910 TI - Quenched disorder: demixing thermal and disorder fluctuations. AB - We present a finite-size scaling study of the phase transition in the two dimensional Potts model modified by random bond disorder, in which the average is taken over quantities calculated at quasicritical temperatures of individual disorder configurations. We used the recently proposed equilibrium-like invaded cluster algorithm, which allows us to examine separately the fluctuations in the thermodynamical ensemble from the fluctuations induced by changing the disorder configuration. We point out the crucial role of the spatial inhomogeneities on all scales for the critical behavior of the system. These inhomogeneities are formed by "dressing" of the disorder via critical correlations and are demonstrated to exist for any system size despite the critical fluctuations in thermodynamical ensemble. Such inhomogeneities were previously not thought to be relevant in disorder-altered classical systems when critical temperature is finite. However, we confirm that only by averaging at quasicritical temperatures of each disorder configuration is the thermal critical exponent y(tau) not obscured by the influence of the aforementioned spatial inhomogeneities. PMID- 23367911 TI - Spatial log-periodic oscillations of first-passage observables in fractals. AB - For transport processes in geometrically restricted domains, the mean first passage time (MFPT) admits a general scaling dependence on space parameters for diffusion, anomalous diffusion, and diffusion in disordered or fractal media. For transport in self-similar fractal structures, we obtain an expression for the source-target distance dependence of the MFPT that exhibits both the leading power-law behavior, depending on the Hausdorff and spectral dimension of the fractal, as well as small log-periodic oscillations that are a clear and definitive signal of the underlying fractal structure. We also present refined numerical results for the Sierpinski gasket that confirm this oscillatory behavior. PMID- 23367912 TI - Dynamical Bayesian inference of time-evolving interactions: from a pair of coupled oscillators to networks of oscillators. AB - Living systems have time-evolving interactions that, until recently, could not be identified accurately from recorded time series in the presence of noise. Stankovski et al. [Phys. Rev. Lett. 109, 024101 (2012)] introduced a method based on dynamical Bayesian inference that facilitates the simultaneous detection of time-varying synchronization, directionality of influence, and coupling functions. It can distinguish unsynchronized dynamics from noise-induced phase slips. The method is based on phase dynamics, with Bayesian inference of the time evolving parameters being achieved by shaping the prior densities to incorporate knowledge of previous samples. We now present the method in detail using numerically generated data, data from an analog electronic circuit, and cardiorespiratory data. We also generalize the method to encompass networks of interacting oscillators and thus demonstrate its applicability to small-scale networks. PMID- 23367913 TI - Role of conviction in nonequilibrium models of opinion formation. AB - We analyze the critical behavior of a class of discrete opinion models in the presence of disorder. Within this class, each agent opinion takes a discrete value (+/- 1 or 0) and its time evolution is ruled by two terms, one representing agent-agent interactions and the other the degree of conviction or persuasion (a self-interaction). The mean-field limit, where each agent can interact evenly with any other, is considered. Disorder is introduced in the strength of both interactions, with either quenched or annealed random variables. With probability p (1-p), a pairwise interaction reflects a negative (positive) coupling, while the degree of conviction also follows a binary probability distribution (two different discrete probability distributions are considered). Numerical simulations show that a nonequilibrium continuous phase transition, from a disordered state to a state with a prevailing opinion, occurs at a critical point p(c) that depends on the distribution of the convictions, with the transition being spoiled in some cases. We also show how the critical line, for each model, is affected by the update scheme (either parallel or sequential) as well as by the kind of disorder (either quenched or annealed). PMID- 23367914 TI - Bernoulli's formula and Poisson's equations for a confined quantum gas: effects due to a moving piston. AB - We study a nonequilibrium equation of states of an ideal quantum gas confined in the cavity under a moving piston with a small but finite velocity in the case in which the cavity wall suddenly begins to move at the time origin. Confining ourselves to the thermally isolated process, the quantum nonadiabatic (QNA) contribution to Poisson's adiabatic equations and to Bernoulli's formula which bridges the pressure and internal energy is elucidated. We carry out a statistical mean of the nonadiabatic (time-reversal-symmetric) force operator found in our preceding paper [Nakamura et al., Phys. Rev. E 83, 041133 (2011)] in both the low-temperature quantum-mechanical and high-temperature quasiclassical regimes. The QNA contribution, which is proportional to the square of the piston's velocity and to the inverse of the longitudinal size of the cavity, has a coefficient that is dependent on the temperature, gas density, and dimensionality of the cavity. The investigation is done for a unidirectionally expanding three-dimensional (3D) rectangular parallelepiped cavity as well as its 1D version. Its relevance in a realistic nanoscale heat engine is discussed. PMID- 23367915 TI - Aging and crossovers in phase-separating fluid mixtures. AB - We use state-of-the-art molecular dynamics simulations to study hydrodynamic effects on aging during kinetics of phase separation in a fluid mixture. The domain growth law shows a crossover from a diffusive regime to a viscous hydrodynamic regime. There is a corresponding crossover in the autocorrelation function from a power-law behavior to an exponential decay. While the former is consistent with theories for diffusive domain growth, the latter results as a consequence of faster advective transport in fluids for which an analytical justification has been provided. PMID- 23367916 TI - Overdamped dynamics of long-range systems on a one-dimensional lattice: dominance of the mean-field mode and phase transition. AB - We consider the overdamped dynamics of a paradigmatic long-range system of particles residing on the sites of a one-dimensional lattice and in the presence of thermal noise. The internal degree of freedom of each particle is a periodic variable that is coupled to those of other particles with an attractive XY-like interaction. The coupling strength decays with the interparticle separation r in space as 1/r^{alpha}; 0= 3-core model on random graphs and the counter-balance model in two-dimensions--both exhibiting discontinuous transitions. To search for tricriticality, we construct mixtures of these models with other percolation models exhibiting the more typical continuous transition. Using a powerful rate equation approach, we demonstrate that a mixture of k = 2 core and k = 3-core vertices on the random graph exhibits a tricritical point. However, for a mixture of k-core and counter-balance vertices in two dimensions, as the fraction of counter-balance vertices is increased, numerics and heuristic arguments suggest that there is a line of continuous transitions with the line ending at a discontinuous transition, i.e., when all vertices are counter balanced. Interestingly, these heuristic arguments may help identify the ingredients needed for a discontinuous transition in low dimensions. In addition, our results may have potential implications for glassy and jamming systems. PMID- 23367918 TI - Equilibrium states of open quantum systems in the strong coupling regime. AB - In this work we investigate the late-time steady states of open quantum systems coupled to a thermal reservoir in the strong coupling regime. In general such systems do not necessarily relax to a Boltzmann distribution if the coupling to the thermal reservoir is nonvanishing or equivalently if the relaxation time scales are finite. Using a variety of nonequilibrium formalisms valid for non Markovian processes, we show that starting from a product state of the closed system = system+environment, with the environment in its thermal state, the open system which results from coarse graining the environment will evolve towards an equilibrium state at late times. This state can be expressed as the reduced state of the closed system thermal state at the temperature of the environment. For a linear (harmonic) system and environment, which is exactly solvable, we are able to show in a rigorous way that all multitime correlations of the open system evolve towards those of the closed system thermal state. Multitime correlations are especially relevant in the non-Markovian regime, since they cannot be generated by the dynamics of the single-time correlations. For more general systems, which cannot be exactly solved, we are able to provide a general proof that all single-time correlations of the open system evolve to those of the closed system thermal state, to first order in the relaxation rates. For the special case of a zero-temperature reservoir, we are able to explicitly construct the reduced closed system thermal state in terms of the environmental correlations. PMID- 23367919 TI - Limit laws for the asymmetric inclusion process. AB - The Asymmetric Inclusion Process (ASIP) is a unidirectional lattice-gas flow model which was recently introduced as an exactly solvable 'Bosonic' counterpart of the 'Fermionic' asymmetric exclusion process. An iterative algorithm that allows the computation of the probability generating function (PGF) of the ASIP's steady state exists but practical considerations limit its applicability to small ASIP lattices. Large lattices, on the other hand, have been studied primarily via Monte Carlo simulations and were shown to display a wide spectrum of intriguing statistical phenomena. In this paper we bypass the need for direct computation of the PGF and explore the ASIP's asymptotic statistical behavior. We consider three different limiting regimes: heavy-traffic regime, large-system regime, and balanced-system regime. In each of these regimes we obtain-analytically and in closed form-stochastic limit laws for five key ASIP observables: traversal time, overall load, busy period, first occupied site, and draining time. The results obtained yield a detailed limit-laws perspective of the ASIP, numerical simulations demonstrate the applicability of these laws as useful approximations. PMID- 23367920 TI - Analytic treatment of tipping points for social consensus in large random networks. AB - We introduce a homogeneous pair approximation to the naming game (NG) model by deriving a six-dimensional Open Dynamics Engine (ODE) for the two-word naming game. Our ODE reveals the change in dynamical behavior of the naming game as a function of the average degree {k} of an uncorrelated network. This result is in good agreement with the numerical results. We also analyze the extended NG model that allows for presence of committed nodes and show that there is a shift of the tipping point for social consensus in sparse networks. PMID- 23367921 TI - Minimal model for short-time diffusion in periodic potentials. AB - We investigate the dynamics of a single, overdamped colloidal particle, which is driven by a constant force through a one-dimensional periodic potential. We focus on systems with large barrier heights where the lowest-order cumulants of the density field, that is, average position and the mean-squared displacement, show nontrivial (nondiffusive) short-time behavior characterized by the appearance of plateaus. We demonstrate that this "cage-like" dynamics can be well described by a discretized master equation model involving two states (related to two positions) within each potential valley. Nontrivial predictions of our approach include analytic expressions for the plateau heights and an estimate of the "de caging time" obtained from the study of deviations from Gaussian behavior. The simplicity of our approach means that it offers a minimal model to describe the short-time behavior of systems with hindered dynamics. PMID- 23367922 TI - Entropy production and nonlinear Fokker-Planck equations. AB - The entropy time rate of systems described by nonlinear Fokker-Planck equations- which are directly related to generalized entropic forms--is analyzed. Both entropy production, associated with irreversible processes, and entropy flux from the system to its surroundings are studied. Some examples of known generalized entropic forms are considered, and particularly, the flux and production of the Boltzmann-Gibbs entropy, obtained from the linear Fokker-Planck equation, are recovered as particular cases. Since nonlinear Fokker-Planck equations are appropriate for the dynamical behavior of several physical phenomena in nature, like many within the realm of complex systems, the present analysis should be applicable to irreversible processes in a large class of nonlinear systems, such as those described by Tsallis and Kaniadakis entropies. PMID- 23367923 TI - Spectral relations between products and powers of isotropic random matrices. AB - We show that the limiting eigenvalue density of the product of n identically distributed random matrices from an isotropic unitary ensemble is equal to the eigenvalue density of nth power of a single matrix from this ensemble, in the limit when the size of the matrix tends to infinity. Using this observation, one can derive the limiting density of the product of n independent identically distributed non-Hermitian matrices with unitary invariant measures. In this paper we discuss two examples: the product of n Girko-Ginibre matrices and the product of n truncated unitary matrices. We also provide evidence that the result holds also for isotropic orthogonal ensembles. PMID- 23367924 TI - Reductive renormalization of the phase-field crystal equation. AB - It has been known for some time that singular perturbation and reductive perturbation can be unified from the renormalization-group theoretical point of view: Reductive extraction of space-time global behavior is the essence of singular perturbation methods. Reductive renormalization was proposed to make this unification practically accessible; actually, this reductive perturbation is far simpler than most reduction methods, such as the rather standard scaling expansion. However, a rather cryptic exposition of the method seems to have been the cause of some trouble. Here, an explicit demonstration of the consistency of the reductive renormalization-group procedure is given for partial differentiation equations (of a certain type, including time-evolution semigroup type equations). Then, the procedure is applied to the reduction of a phase-field crystal equation to illustrate the streamlined reduction method. We conjecture that if the original system is structurally stable, the reductive renormalization group result and that of the original equation are diffeomorphic. PMID- 23367925 TI - Using fundamental measure theory to treat the correlation function of the inhomogeneous hard-sphere fluid. AB - We investigate the value of the correlation function of an inhomogeneous hard sphere fluid at contact. This quantity plays a critical role in statistical associating fluid theory, which is the basis of a number of recently developed classical density functionals. We define two averaged values for the correlation function at contact and derive formulas for each of them from the White Bear version of the fundamental measure theory functional, using an assumption of thermodynamic consistency. We test these formulas, as well as two existing formulas, against Monte Carlo simulations and find excellent agreement between the Monte Carlo data and one of our averaged correlation functions. PMID- 23367926 TI - Jamming in systems with quenched disorder. AB - We numerically study the effect of adding quenched disorder in the form of randomly placed pinning sites on jamming transitions in a disk packing that jams at a well-defined point J in the clean limit. Quenched disorder decreases the jamming density and introduces a depinning threshold. The onset of a finite threshold coincides with point J at the lowest pinning densities, but for higher pinning densities there is always a finite depinning threshold even well below jamming. We find that proximity to point J strongly affects the transport curves and noise fluctuations, and we observe a change from plastic behavior below jamming, where the system is highly heterogeneous, to elastic depinning above jamming. Many of the general features we find are related to other systems containing quenched disorder, including the peak effect observed in vortex systems. PMID- 23367927 TI - Effect of frictional heat dissipation on the loss of soil strength. AB - In the present paper through a shear test on a fully saturated granular medium, simulated by the discrete element method, the effect of the heat produced by friction on the internal pore water pressure is explored. It is found that the dissipated energy is enough to increase the pore pressure and reduce the soil strength. In adiabatic and impermeable conditions the heat builds up quickly inside the shear band, and the softening is more pronounced. It is found as well that for real geological materials, heat conduction is not enough to reduce the pore pressure, and the softening prevails. Nevertheless, it is observed that the hydraulic conduction may mitigate or completely eliminate the temperature growth inside the shear band. This result provides new understanding on the thermodynamic factors involved in the onset of catastrophic landslides. PMID- 23367928 TI - Effect of cohesion and shear modulus on the stability of a stretched granular layer. AB - The main mechanism of the cellular pattern which forms at the surface of a thin layer of a cohesive granular material submitted to in-plane stretching has been identified as the "strain softening" arising from the features of grain-grain interactions. We perform measurements of the strain field associated with such structures by using a correlation image technique and additionally characterize the cohesion and shear modulus of the samples. We show that for high cohesion, the layer is fragile and the surface deformation is highly nonlinear, whereas at low cohesion, a smooth and linearly growing structure is observed as a function of external stretching. Analysis of the wavelength as a function of cohesion along with independent measurement of the shear modulus indicate that a simple model of strain softening is acceptable if a mechanism of cluster formation due to cohesion is taking place. PMID- 23367929 TI - Influence of particle rotation on the oblique penetration in granular media. AB - The rotation of a particle has significant influence on the dynamic response of a granular bed subjected to the oblique impact of a spherical projectile. Based on the discrete element method, the dynamical behavior of two-dimensional granular media impacted obliquely by rotating particles has been examined in this work, especially for the influence of rotational angular velocity on its penetration depth. The simulations show that the incident rotational velocity will not only act on the characteristics of velocity distribution of the bed after impacting, but also influence the trajectory of the projectile qualitatively. For low angular velocities, particle rotations will significantly increase the vertical penetration depths, while the different directions of rotation will exert opposite effects on the horizontal penetration depths. In addition, the influence of particle rotation on its penetration depth will be enhanced with increasing angular velocity, but such effect will reach an asymptotic plateau for sufficiently large angular velocities. This indicates that the angular velocity has an obvious criticality. Furthermore, the variation of critical angular velocity may be linear with the impact velocity and square with the impacting angle, approximately. Finally, the influence of the initial particle rotation on the scaling law of penetration depth is also considered, and we find that the linear scaling with impact velocity is still applicable for most impact conditions. PMID- 23367930 TI - Breathers in periodic granular chains with multiple band gaps. AB - We consider the localized nonlinear breathing modes that emerge in heterogeneous granular configurations of two materials with a periodicity of three and four beads. We examine as characteristic examples chains with one steel and two aluminum beads, as well as ones with one steel and three aluminum beads, although we briefly touch upon other configurations as well, illustrating their similar characteristics. We analyze the higher order gaps that emerge in such settings and explore the intrinsic localized modes that bifurcate from the edge of the upper bands. A generic surprising feature of such states is that they appear to be more robust than their counterparts bifurcating from the edges of the lower bands. Direct numerical simulations, using driving of the system at suitable frequencies through an actuator or taking advantage of the modulational instabilities of extended band edge states in the system, illustrate the spontaneous formation of localized modes within the corresponding nearest gaps. In these numerical experiments, we also account for the presence of dissipation and analyze its potential role. PMID- 23367931 TI - Wave propagation in square granular crystals with spherical interstitial intruders. AB - We investigate the propagation and scattering of highly nonlinear waves in granular systems composed of spheres in contact arranged in a square packing, and study how the presence of small and light spherical interstitial defects, also referred to as intruders, affects the wave propagation. The effects of a single defect are investigated experimentally and compared to numerical simulations, showing very good quantitative agreement. Transmitted and scattered waves are formed, whose characteristics depend on the material properties of the defect in relation to the properties of the particles in the lattice. Experiments and numerical simulations reveal that stiffer defects are more efficient at redistributing energy outside the impacted chain and soft defects induce a localization of the energy at the defect. Finally, the effects of the presence of two defects, placed diagonally or aligned in the square packing are also investigated, as well as how their interaction depends on their relative positions. PMID- 23367932 TI - Fiber bundle models for stress release and energy bursts during granular shearing. AB - Fiber bundle models (FBMs) offer a versatile framework for representing transitions from progressive to abrupt failure in disordered material. We report a FBM-based description of mechanical interactions and associated energy bursts during shear deformation of granular materials. For strain-controlled shearing, where elements fail in a sequential order, we present analytical expressions for strain energy release and failure statistics. Results suggest that frequency magnitude characteristics of fiber failure vary considerably throughout progressive shearing. Predicted failure distributions were in good agreement with experimentally observed shear stress fluctuations and associated bursts of acoustic emissions. Experiments also confirm a delayed release of acoustic emission energy relative to shear stress buildup, as anticipated by the model. Combined with data-rich acoustic emission measurements, the modified FBM offers highly resolved contact-scale insights into granular media dynamics of shearing processes. PMID- 23367933 TI - Rheological effects in the linear response and spontaneous fluctuations of a sheared granular gas. AB - The decay of a small homogeneous perturbation in the temperature of a dilute granular gas in the steady uniform shear flow state is investigated. Using kinetic theory based on the inelastic Boltzmann equation, a closed equation for the decay of the perturbation is derived. The equation involves the generalized shear viscosity of the gas in the time-dependent shear flow state, and therefore, it predicts relevant rheological effects beyond the quasielastic limit. Good agreement is found when comparing the theory with molecular dynamics simulation results. Moreover, the Onsager postulate on the regression of fluctuations is fulfilled. PMID- 23367934 TI - Bending and elongation effects on the random packing of curved spherocylinders. AB - Studies on the macroscopic and microscopic packing properties of nonconvex particles are scarce. As a common concave form, the curved spherocylinder is used in the simulations, and its bending and elongation effects on the random packings are investigated numerically with sphere assembly models and a relaxation algorithm. The aspect ratio is demonstrated to be the main factor regarding the packing density. However, at certain aspect ratios of low densities around 0.3 0.4, the density of curved spherocylinders may increase by 15% more than that of the straight ones, indicating that bending is also a contributor to the packing density. The excluded volume of the curved spherocylinder decreases with the increase of the bending angle, indicating that the excluded volume is applicable in explaining the bending effect on the packing density variation of nonconvex particles. The packings are verified to be randomly distributed in orientation with no significant layering or in-plane order. The local arrangements are further analyzed from the radial distribution function and contact results. The results show that the random packings of nonconvex particles have significant differences and richer characteristics on both the macroscopic and microscopic properties compared with convex objects. PMID- 23367935 TI - Circular ratchets as transducers of vertical vibrations into rotations. AB - Granular ratchets are well-known devices that when driven vertically produce a counterintuitive horizontal transport of particles. Here we report the experimental observation of a complementary effect: the striking ability of circular ratchets to convert their vertical vibration into their own rotation. The average revolution speed shows a maximum value for an optimal tooth height. With no special effort the rotation speed could be maintained steady during several hours. Unexpected random arrests and reversals of the velocity were also observed abundantly. PMID- 23367936 TI - Jamming of particles in a two-dimensional fluid-driven flow. AB - The jamming of particles under flow is of critical importance in a broad range of natural and industrial settings, such as the jamming of ice in rivers, or the plugging of suspended solids in pipeline transport. Relatively few studies have been carried out on jamming of suspended particles under flow, in comparison to the many studies on jamming in gravity-driven flows that have revealed various features of the jamming process. Fluid-driven particle flows differ in several aspects from gravity-driven flows, particularly in being compatible with a range of particle concentrations and velocities. Additionally, there are fluid-particle interactions and hydrodynamic effects. To investigate particle jamming in fluid driven flows, we have performed both experiments and computer simulations on the flow of circular particles floating over water in an open channel with a restriction. We determined the flow-rate boundary for a dilute-to-dense flow transition, similar to that seen in gravity-driven flows. The maximum particle throughput increased for larger restriction sizes consistent with a Beverloo equation form over the entire range of particle mixtures and restriction sizes. The exponent of ~3/2 in the Beverloo equation is consistent with approximately constant acceleration of grains due to fluid drag in the immediate region of the opening. We verified that the jamming probability from the dense flow gave a geometric distribution in the number of particles escaping before a jam. The probability of jamming in both experiments and simulations was found to be dependent on the ratio of channel opening to particle size, but only weakly dependent on the fluid flow velocity. Flow entrance effects were measured and observed to affect the jamming probability, and dependence on particle friction coefficient was determined from simulation. A comprehensive model for the jamming probability integrating these observations from the different flow regimes was shown to be in good agreement for experimental data on average times before jamming. PMID- 23367937 TI - Dip of the granular shear stress. AB - Recent experiments reveal an unexpected dip of the shear stress as the shear rate increases, from the rate-independent regime to Bagnold flow. Employing granular solid hydrodynamics, it is shown that in uniform systems, such dips occur for given pressure or normal stress, but not for given density. If the shear rate is strongly nonuniform, enforcing a constant volume does not prevent the local density to vary, and a stress dip may still occur. PMID- 23367938 TI - Impact on porous targets: penetration, crater formation, target compaction, and ejection. AB - Using a granular-mechanics code, we study the impact of a sphere into a porous adhesive granular target, consisting of monodisperse silica grains. The model includes elastic repulsive, adhesive, and dissipative forces, as well as sliding, rolling, and twisting friction. Impact velocities of up to 30 m/s and target filling factors (densities) between 19% and 35% have been systematically studied. We find that the projectile is stopped by an effective drag force which is proportional to the square of its velocity. Target adhesion influences projectile stopping only below a critical velocity, which increases with adhesion. The penetration depth depends approximately logarithmically on the impact velocity and is inversely proportional to the target density. The excavated crater is of conical form and is surrounded by a compaction zone whose width increases but whose maximum value decreases with increasing target density. Grain ejection increases in proportion with impactor velocity. Grains are ejected which have originally been buried to a depth of 8R(grain) below the surface; the angular distribution favors oblique ejection with a maximum around 45 degrees . The velocity distribution of ejected grains features a broad low-velocity maximum around 0.5-1 m/s but exhibits a high-velocity tail up to ~15% of the projectile impact velocity. PMID- 23367939 TI - Is axial dispersion within rotating cylinders governed by the Froude number? AB - Axial dispersion rates of particles within horizontal rotating cylinders have been calculated for a decade of cylinder diameters. Throughout the range studied the rate of axial dispersion was found to be independent of the cylinder diameter. This phenomenon has been investigated further by spatially resolving the local contribution to the axial dispersion coefficient. This analysis demonstrates that, although the highest rates of axial dispersion occur at the free surface of the bed, there is a significant contribution to axial dispersion throughout the flowing region of the bed. Finally, based on an analogy with a Galton board, a linear relationship is proposed between the local rate of axial dispersion within a horizontal rotating cylinder and the product of the local particle concentration and the local shear rate in a plane perpendicular to the cylinder axis. PMID- 23367940 TI - Dynamic aerofracture of dense granular packings. AB - A transition in hydraulically induced granular displacement patterns is studied by means of discrete numerical molecular dynamics simulations. During this transition the patterns change from fractures and fingers to finely dispersed bubbles. The dynamics of the displacement patterns are studied in a rectangular Hele-Shaw cell filled with a dense but permeable two-dimensional granular layer. At one side of the cell the pressure of the compressible interstitial gas is increased. At the opposite side from the inlet of the cell a semipermeable boundary is located. This boundary is only permeable towards the gas phase while preventing grains from leaving the cell. The imposed pressure gradient compacts the grains. In the process we can identify and describe a mechanism that controls the transition of the emerging displacement patterns from fractures and fingers to finely dispersed bubbles as a function of the interstitial gas's properties and the characteristics of the granular phase. PMID- 23367941 TI - Experimental study on the effect of surface roughness of the intruder on the Brazil nut problem in a vertically vibrated bed. AB - This study experimentally investigates the influence of intruder surface roughness in the Brazil nut effect in a quasi-two-dimensional vertical vibration granular bed. The intruder dynamics are determined using a particle-tracking method. The results show that surface roughness has a crucial role in the intruder rise dynamics; a rougher intruder has more difficulty rising in the bed because of higher kinetic energy dissipation. This study determined that penetration length and drag length are reduced and drag is enhanced as intruder surface roughness increases. The exponential decay of the penetration length with vibration frequency is shown. The results also show that at higher dimensionless vibration acceleration and lower vibration frequency the variation in rise time between smooth and rough intruders is negligible. PMID- 23367942 TI - Effect of confinement on dense packings of rigid frictionless spheres and polyhedra. AB - We study numerically the influence of confinement on the solid fraction and on the structure of three-dimensional random close-packed granular materials subject to gravity. The effects of grain shape (spherical or polyhedral), material polydispersity, and confining wall friction on this dependence are investigated. In agreement with a simple geometrical model, the solid fraction is found to decrease linearly for increasing confinement no matter the grain shape. Furthermore, this decrease remains valid for bidisperse sphere packings, although the gradient seems to reduce significantly when the proportion of small particles reaches 40% by volume. The confinement effect on the coordination number is also captured by an extension of the aforementioned model. PMID- 23367943 TI - Granular mixing and segregation in zigzag chute flow. AB - Periodic flow inversions have been shown as an effective means to eliminate both density (D system) and size (S system) segregation. The frequency of these inversions, however, is the key to applying this technique and is directly related to the inverse of the characteristic time of segregation. In this work, we study size segregation (S system) and adapt a size segregation model to compliment existing work on density segregation and, ultimately, aid in determining the critical forcing frequency for S systems. We determine the impact on mixing and segregation of both the binary size ratio and the length of each leg of a "zigzag chute". Mixing is observed when L < U tS, where L, U, and t(S) denote the length of each leg of the zigzag chute, the average streamwise flow velocity of the particle, and the characteristic time of segregation, respectively. PMID- 23367944 TI - Viscoelasticity of two-layer vesicles in solution. AB - The dynamic shape relaxation of the two-layer vesicle is calculated. In addition to the undulation relaxation where the two bilayers move in the same direction, the squeezing mode appears when the gap between the two bilayers is small. At a large gap, the inner vesicle relaxes much faster, whereas the slow mode is mainly due to the outer-layer relaxation. We have calculated the viscoelasticity of the dilute two-layer-vesicle suspension. It is found that for a small gap, the applied shear drives the undulation mode strongly while the slow squeezing mode is not much excited. In this limit, the complex viscosity is dominated by the fast-mode contribution. On the other hand, the slow mode is strongly driven by shear for a larger gap. We have determined the crossover gap, which depends on the interaction between the two bilayers. For a series of samples where the gap is changed systematically, it is possible to observe the two amplitude switchings. PMID- 23367945 TI - Rotational ratchets with dipolar interactions. AB - We report results from a computer simulation study on the rotational ratchet effect in systems of magnetic particles interacting via dipolar interactions. The ratchet effect consists of directed rotations of the particles in an oscillating magnetic field, which lacks a net rotating component. Our investigations are based on Brownian dynamics simulations of such many-particle systems. We investigate the influence of both the random and deterministic contributions to the equations of motion on the ratchet effect. As a main result, we show that dipolar interactions can have an enhancing as well as a dampening effect on the ratchet behavior depending on the dipolar coupling strength of the system under consideration. The enhancement is shown to be caused by an increase in the effective field on a particle generated by neighboring magnetic particles, while the dampening is due to restricted rotational motion in the effective field. Moreover, we find a nontrivial influence of the short-range, repulsive interaction between the particles. PMID- 23367946 TI - Structure of electrorheological fluids: a dielectric study of chain formation. AB - A dielectric measurement method has been proposed to apply to the study of the microstructure of electrorheological (ER) fluids. To test our measurement method the dielectric permittivity increment caused by pair and chain formation was measured in dilute Brownian ER fluids composed of silicone oil and nanosized silica particles. The critical values of the electric field required to induce structure formation were experimentally determined from the electric field dependence of the measured permittivity increment. From the electric field induced time evolution of the relative permittivity of ER fluids, the characteristic times of the pair and chain formation were calculated. Our experimental results for the time constants are in good agreement with the corresponding theoretical data obtained from the Eyring theory. PMID- 23367947 TI - Magnetic particle hyperthermia: power losses under circularly polarized field in anisotropic nanoparticles. AB - The deterministic Landau-Lifshitz-Gilbert equation has been used to investigate the nonlinear dynamics of magnetization and the specific power loss in magnetic nanoparticles with uniaxial anisotropy driven by a rotating magnetic field, generalizing the results obtained for the isotropic case found by P. F. de Chatel, I. Nandori, J. Hakl, S. Meszaros, and K. Vad [J. Phys. Condens. Matter 21, 124202 (2009)]. As opposed to many applications of magnetization reversal in single-domain ferromagnetic particles, where losses must be minimized, in this paper, we study the mechanisms of dissipation used in cancer therapy by hyperthermia, which requires the enhancement of energy losses. We show that for circularly polarized field, the energy loss per cycle is decreased by the anisotropy compared to the isotropic case when only dynamical effects are taken into account. Thus, in this case, in the low-frequency limit, a better heating efficiency can be achieved for isotropic nanoparticles. The possible role of thermal fluctuations is also discussed. Results obtained are compared to experimental data. PMID- 23367948 TI - Coupled stochastic dynamics of magnetic moment and anisotropy axis of a magnetic nanoparticle. AB - An algorithm is developed for numerical simulation of coupled stochastic dynamics of magnetic moment and magnetic anisotropy axis of a nanoparticle. Time correlation functions of the magnetic moment and its components longitudinal and transverse to the magnetic anisotropy axis are calculated by averaging along the stochastic trajectory. The longitudinal and transverse relaxation times are found by fitting the time correlation functions. Existing theoretical relations derived by the effective field approach in the limit of small fields are confirmed. The time-correlation functions of magnetic moments of nanoparticles in dependence on their properties are calculated numerically for arbitrary large magnetic fields and it is shown that they may be approximated by a sum of several exponentials. These results are applied for the calculation of relaxivity parameters of nuclear magnetic resonance (NMR) imaging in dependence on the field strength. PMID- 23367949 TI - Possible origin of the crack pattern in deposition films formed from a drying colloidal suspension. AB - The fracture mechanics was usually employed to explain the crack propagation in the deposition produced by drying colloidal suspension. However, more complex than conventional fracture, those cracks periodically distribute and make up a unique pattern. Inspired by the concept of spinodal decomposition, here we develop the theory to illustrate the possible mechanism of the spatial arrangement of the cracks. It indicates that before the cracks develop and propagate in the deposition under the law of fracture mechanics, the periodically distributed flaws are generated by the phase separation of colloidal clusters and solvent. Then the cracks originate at the sites of those flaws in terms of fracture mechanics. It concludes that the crack spacing results from the wavelength of the concentration fluctuation during the phase separation, linearly growing with the increase of the deposition thickness and initial particle concentration, which is consistent with experimental results. PMID- 23367950 TI - Structure and dynamics of nanoemulsions: insights from combining dynamic and static neutron scattering. AB - Despite their lack of thermodynamical stability, nanoemulsions can show a remarkable degree of kinetic stability. Among the various different preparation methods the phase-inversion concentration method is particularly interesting as it occurs spontaneously. Here we investigate such a system composed of a surfactant, cosurfactant, and oil that upon dilution with water forms long time metastable oil-in-water nanoemulsion droplets. The dynamics of the amphiphilic monolayers and its elastic properties is important for their stability and therefore the monolayer dynamics have been investigated by neutron spin echo (NSE). Despite the difficulties arising from the inherently polydisperse nature and the large number of different components necessarily contained in commercial nanoemulsion formulations, information concerning the membrane rigidity was extracted from the combination of small angle neutron scattering and NSE and several different formulations are compared. These results show that small amounts of different admixed ionic surfactants can modify the monolayer rigidity substantially and similarly effects of surface bound polyelectrolytes have been evaluated. PMID- 23367951 TI - Ground-state structures and structural transitions in a monolayer of magnetic dipolar particles in the presence of an external magnetic field. AB - A combination of analytical calculations and Monte Carlo simulations is used to find the ground-state structures in monodisperse ferrofluid monolayers under the influence of an external magnetic field. We study two different regimes, where (i) the direction of an external field is perpendicular to the monolayer plane and (ii) an external magnetic field is in the plane. In the field perpendicular to the plane we observe a transition from an ideal ferroparticle ring to a hexagonal structure. The analytical value of the critical field strength needed for this transition is obtained and shown for relatively large systems to be independent of the number of particles. For smaller systems the value of the critical field is system-size dependent and grows fast to its asymptotic value with increasing number of particles. In the case where the magnetic field is aligned parallel to the layer plane, the critical field needed to break a ring and to create a new ground-state structure, namely a ferroparticle chain, is much smaller than in the case where a field is applied perpendicularly to the plane. The analytical expression for the asymptotic critical field in case of in-plane field is found to be a decreasing function of the total particle number in a system. We characterize both transitions to be of the first-order-type transition, with magnetic susceptibility diverging near the critical point. Our studies show that the domination of the in-plane correlations of dipoles within the ferroparticle ring results in much lower magnetic in-plane susceptibility in comparison to the one perpendicular to the plane. PMID- 23367952 TI - Dynamic structure factor of density fluctuations from direct imaging very near (both above and below) the critical point of SF(6). AB - Large density fluctuations were observed by illuminating a cylindrical cell filled with sulfur hexafluoride (SF(6)), very near its liquid-gas critical point (|T-T(c)|< 300 MUK) and recorded using a microscope with 3 MUm spatial resolution. Using a dynamic structure factor algorithm, we determined from the recorded images the structure factor (SF), which measures the spatial distribution of fluctuations at different moments, and the correlation time of fluctuations. This method authorizes local measurements in contrast to the classical scattering techniques that average fluctuations over the illuminating beam. We found that during the very early stages of phase separation the SF scales with the wave vector q according to the Lorentzian q(-2), which shows that the liquid and vapor domains are just emerging. The critical wave number, which is related to the characteristic length of fluctuations, steadily decreases over time, supporting a sustained increase in the spatial scale of the fluctuating domains. The scaled evolution of the critical wave number obeys the universal evolution for the interconnected domains at high volume fraction with an apparent power law exponent of -0.35 +/- 0.02. We also determined the correlation time of the fluctuations and inferred values for thermal diffusivity coefficient very near the critical point, above and below. The values were used to pinpoint the crossing of T(c) within 13 MUK. PMID- 23367953 TI - Finite-size scaling for the glass transition: the role of a static length scale. AB - Over the past decade, computer simulations have had an increasing role in shedding light on difficult statistical physical phenomena, and in particular on the ubiquitous problem of the glass transition. Here in a wide variety of materials the viscosity of a supercooled liquid increases by many orders of magnitude upon decreasing the temperature over a modest range. A natural concern in these computer simulations is the very small size of the simulated systems compared to experimental ones, raising the issue of how to assess the thermodynamic limit. Here we turn this limitation to our advantage by performing finite size scaling on the system size dependence of the relaxation time for supercooled liquids to emphasize the importance of a growing static length scale in the theory of glass transition. We demonstrate that the static length scale that was discovered by us in Physica A 391, 1001 (2012) fits the bill extremely well, allowing us to provide a finite-size scaling theory for the alpha relaxation time of the glass transition, including predictions for the thermodynamic limit based on simulations in small systems. PMID- 23367954 TI - Theory of kinetic arrest, elasticity, and yielding in dense binary mixtures of rods and spheres. AB - We extend the quiescent and stressed versions of naive mode coupling theory to treat the dynamical arrest, shear modulus, and absolute yielding of particle mixtures where one or more species is a nonrotating nonspherical object. The theory is applied in detail to dense isotropic "chemically matched" mixtures of variable aspect ratio rods and spheres that interact via repulsive and short range attractive site-site pair potentials. A remarkably rich ideal kinetic arrest behavior is predicted with up to eight "dynamical phases" emerging: an ergodic fluid, partially localized states where the spheres remain fluid but the rods can be a gel, repulsive glass or attractive glass, doubly localized glasses and gels, a porous rod gel plus sphere glass, and a narrow window where a type of rod glass and gel localization coexist. Dynamical complexity increases with rod length and the introduction of attractive forces between all species which both enhance gel network formation. Multiple dynamic reentrant features and triple points are predicted, and each dynamic phase has unique particle localization characteristics and mechanical properties. Orders of magnitude variation of the linear shear modulus and absolute yield stress are found as rod length, mixture composition and the detailed nature of interparticle attractions are varied. The interplay of total (high) mixture packing fraction and composition at fixed temperature is also briefly studied. The present work provides a foundation to study more complex rod-sphere mixtures of both biological and synthetic interest that include physical features such as interaction site size asymmetry, rod sphere specific attractions, and/or Coulomb repulsion. PMID- 23367955 TI - Consistent accounting of steric effects for prediction of streaming potential in narrow confinements. AB - The traditional modeling framework for determining streaming potential, when taking into consideration finite size effects, suffers from an oversight in that while the model incorporates the size effects in the ion distribution profiles, it neglects these very same effects in the flux contributions, even though diffusivities are intrinsically linked with ionic friction, which again depends on the size of the ions. This oversight may lead to inconsistent quantitative estimates through ad hoc consideration of diffusivity values, apparently independent of the specific size of the ions, which nevertheless determines the ionic profiles. We remedy this theoretical inconsistency by expressing the diffusivity in terms of the ionic radius and investigate the consequences of such a description of the diffusivity-dependent flux, consistent with the ionic distribution profiles, on streaming potential mediated flow predictions. Additionally, we consider the effects of "charge induced thickening" so that both viscosity and diffusivity are expressed as spatially varying functions. As an unintuitive implication, we also show that calculation of nonzero values of streaming potential under the purview of classical Boltzmann distributions, which consider ions to be pointlike charges, is itself a theoretical inconsistency. We believe that the simple framework presented in this paper will pave the way for more sophisticated modeling efforts in the future. PMID- 23367956 TI - Dynamic behavior of hydration water in calcium-silicate-hydrate gel: a quasielastic neutron scattering spectroscopy investigation. AB - The translational dynamics of hydration water confined in calcium-silicate hydrate (C-S-H) gel was studied by quasielastic neutron scattering spectroscopy in the temperature range from 280 to 230 K. The stretch exponent beta, the self diffusion constant D, the average translational relaxation time {tau}, and the temperature dependence of confinement radius alpha extracted from the elastic fraction of immobile water molecules p(Q) were obtained from the analyses of the low-Q spectra according to the relaxing cage model. Measurements were made using C-S-H of three different water contents, 10%, 17%, and 30%. Among the three samples of C-S-H gel with different water contents, the values of beta decrease with increasing water contents, while alpha increases. The values of D and {tau} are insensitive to temperature for the two lower water contents, as opposed to the 30% case where a slight variation is observed. The trend for violation of the Stokes-Einstein relation is only visible in the case of 30% water content. PMID- 23367957 TI - Induced-charge electro-osmosis beyond weak fields. AB - Standard thin-double-layer modeling of electro-osmotic flows about metal objects typically predicts an induced zeta-potential distribution whose characteristic magnitude varies linearly with the applied voltage. At moderately large zeta potential, comparable with several thermal voltages, surface conduction enters the dominant electrokinetic transport, throttling that linear scaling. We derive here a macroscale model for induced-charge electro-osmosis accounting for that mechanism. Unlike classical analyses of surface conduction about dielectric surfaces, the present nonlinear problem cannot be linearized about a uniform-zeta potential reference state. With the transition to moderately large zeta potentials taking place nonuniformly, the Dukhin number, representing the magnitude of surface conduction, is reinterpreted as a local dimensionless group, varying along the boundary. Debye-scale analysis provides effective boundary conditions about two types of generic boundary points, corresponding to small and moderate Dukhin numbers. The boundary decomposition into the respective asymptotic domains is unknown in advance and must be determined throughout the solution of the macroscale problem, itself hinging upon the proper formulation of effective boundary conditions. This conceptual obstacle is surmounted via introduction of a uniform approximation to these conditions. PMID- 23367958 TI - Patterned surfaces in the drying of films composed of water, polymer, and alcohol. AB - A study of the complex drying dynamics of polymeric mixtures with optical microscopy and gravimetric measurement is presented. Droplet formation is observed, followed by a collapse that leads to the residual craters in the dried film. The process is followed in situ under well-defined temperature and hygrometric conditions to determine the origin and nature of these droplets and craters. The drying process is usually completed within 1 h. The observations are explained using a simple diffusion model based on experimental results collected from mass and optical measurements as well as Raman confocal microspectrometry. Although the specific polymeric mixtures used here are of interest to the cosmetic industry, the general conclusions reached can apply to other polymeric aqueous solutions with applications to commercial and artistic painting. PMID- 23367959 TI - Computer simulation of adsorption on nanoparticles: the case of attractive interactions. AB - A lattice-gas model describing adsorption on nanoparticles of different sizes and shapes is proposed and the adsorption thermodynamics is studied. The nanoparticle is modeled assuming different geometries, and Monte Carlo simulations are performed in the grand canonical ensemble. Adsorption isotherms, differential heats of adsorption, and other relevant thermodynamic properties are analyzed as a function of nanoparticle sizes. The simulations cover a wide range of interactions, ranging from physical to strong chemical bonds. PMID- 23367960 TI - Growth rate distribution of NH4Cl dendrite and its scaling structure. AB - Scaling structure of the growth rate distribution on the interface of a dendritic pattern is investigated. The distribution is evaluated for an NH4Cl quasi-two dimensional crystal by numerically solving the Laplace equation with the boundary condition taking account of the surface tension effect. It is found that the distribution has multifractality and the surface tension effect is almost ineffective in the unscreened large growth region. The values of the minimum singular exponent and the fractal dimension are smaller than those for the diffusion-limited aggregation pattern. The Makarov's theorem, the information dimension equals one, and the Turkevich-Scher conjecture between the fractal dimension and the minimum singularity exponent hold. PMID- 23367961 TI - Sticky steps inhibit step motions near equilibrium. AB - Using a Monte Carlo method on a lattice model of a vicinal surface with a point contact-type step-step attraction, we show that, at low temperature and near equilibrium, there is an inhibition of the motion of macrosteps. This inhibition leads to a pinning of steps without defects, adsorbates, or impurities (self pinning of steps). We show that this inhibition of the macrostep motion is caused by faceted steps, which are macrosteps that have a smooth side surface. The faceted steps result from discontinuities in the anisotropic surface tension (the surface free energy per area). The discontinuities are brought into the surface tension by the point-contact-type step-step attraction. The point-contact-type step-step attraction also originates "step droplets," which are locally merged steps, at higher temperatures. We derive an analytic equation of the surface stiffness tensor for the vicinal surface around the (001) surface. Using the surface stiffness tensor, we show that step droplets roughen the vicinal surface. Contrary to what we expected, the step droplets slow down the step velocity due to the diminishment of kinks in the merged steps (smoothing of the merged steps). PMID- 23367962 TI - Coarsening effect on island-size scaling: the model case InAs/GaAs(001). AB - The distributions of the size of islands and of the capture zones are discussed comparatively, both experimentally and numerically, for the case of a sudden nucleation process with and without coarsening. The experiments were performed by growing InAs islands on GaAs(001) and the coarsening was altered by varying the temperature. In the two-dimensional kinetic Monte Carlo simulations a single species diffusing adatom was taken into account, and the coarsening was altered in this case by modifying the binding energy between adatoms and islands. The results show that size and capture zone distributions overlap only when coarsening can be disregarded. PMID- 23367963 TI - Optical diffractometry of highly anisotropic holographic gratings formed by liquid crystal and polymer phase separation. AB - Optical diffractometry is proposed as a practical method of quantitatively analyzing the microscopic structural origins of a wide range of highly efficient and linearly polarized optical diffraction grating produced from holographic polymer-dispersed liquid crystal. The structure is organized by a spatially periodical distribution of submicrometer-scale liquid crystal (LC) droplets in a polymer matrix. Six independent Bragg diffraction spectra were obtained at two orthogonal polarization states at temperatures below, at, and above the nematic to-isotropic phase transition point. These spectra were simultaneously analyzed by employing anisotropic diffraction theory under the restraint of a simple and widely useful structural model constructed on the basis of the previously reported microscopic observations. The refractive indices of spatially periodic LC- and polymer-rich phases were analyzed using Cauchy's equation as a function of optical wavelength. The present diffractometry was demonstrated for a variety of holographic structures, and the structural parameters were discussed such as the filling ratio of LC droplets to polymer matrix, the orientational order in the droplets, and the thermo-optic properties in the LC droplets. Furthermore, the higher order Bragg diffractions were measured and discussed. The proposed method was examined in consistency by comparisons with polarizing optical microscopy and scanning electron microscopy. PMID- 23367964 TI - Low-frequency oscillations of the director in nematic liquid crystals induced by ultrasonic waves. AB - The director-density coupling theory has been proposed to describe the acousto optic effect in nematic liquid crystals. On the basis of this theory, we make predictions for an experimental test using two superimposed ultrasonic waves. As a result of the analysis, low-frequency oscillations of the director and optical transparency are predicted to occur around their mean values. The possibility of either verifying or invalidating this prediction is important in order to distinguish the theory from other competitive ones. PMID- 23367965 TI - Theory of elastic interaction between arbitrary colloidal particles in confined nematic liquid crystals. AB - We develop the method proposed by Chernyshuk and Lev [Phys. Rev. E 81, 041701 (2010)] for theoretical investigation of elastic interactions between colloidal particles of arbitrary shape and chirality (polar as well as azimuthal anchoring) in the confined nematic liquid crystal (NLC). General expressions for six different types of multipole elastic interactions are obtained in the confined NLC: monopole-monopole (Coulomb type), monopole-dipole, monopole-quadrupole, dipole-dipole, dipole-quadrupole, and quadrupole-quadrupole interactions. The obtained formulas remain valid in the presence of the external electric or magnetic fields. The exact equations are found for all multipole coefficients for the weak anchoring case. For the strong anchoring coupling, the connection between the symmetry of the shape or director and multipole coefficients is obtained, which enables us to predict which multipole coefficients vanish and which remain nonzero. The particles with azimuthal helicoid anchoring are considered as an example. Dipole-dipole interactions between helicoid cylinders and cones are found in the confined NLC. In addition, the banana-shaped particles in homeotropic and planar nematic cells are considered. It is found that the dipole-dipole interaction between banana-shaped particles differs greatly from the dipole-dipole interaction between the axially symmetrical particles in the nematic cell. There is a crossover from attraction to repulsion between banana particles along some directions in nematic cells. It is shown that monopoles do not "feel" the type of nematic cell: monopole-monopole interaction turns out to be the same in homeotropic and planar nematic cells and converges to the Coulomb law as thickness increases, L->infinity. PMID- 23367966 TI - High-resolution calorimetric study of phase transitions in chiral smectic-C liquid crystalline phases. AB - We carried out an improved characterization of phase transitions among chiral smectic-C subphases observed for various antiferroelectric liquid crystals by precise heat capacity measurements. It was found that the phase transitions are intrinsically first order exhibiting a remarkable heat anomaly which involves little pretransitional thermal fluctuation and a finite thermal hysteresis. On the other hand, we also noticed that the critical point of the smectic C(alpha)(*)-smectic-C* transition is induced by the destabilization of the smectic-C(alpha)(*) phase which couples with the fluctuation associated with the smectic-A-smectic-C(alpha)(*) phase transition. PMID- 23367967 TI - Polymer-mediated entropic forces between scale-free objects. AB - The number of configurations of a polymer is reduced in the presence of a barrier or an obstacle. The resulting loss of entropy adds a repulsive component to other forces generated by interaction potentials. When the obstructions are scale invariant shapes (such as cones, wedges, lines, or planes) the only relevant length scales are the polymer size R(0) and characteristic separations, severely constraining the functional form of entropic forces. Specifically, we consider a polymer (single strand or star) attached to the tip of a cone, at a separation h from a surface (or another cone). At close proximity, such that h << R(0), separation is the only remaining relevant scale and the entropic force must take the form F = Ak(B)T/h. The amplitude A is universal and can be related to exponents eta governing the anomalous scaling of polymer correlations in the presence of obstacles. We use analytical, numerical, and epsilon-expansion techniques to compute the exponent eta for a polymer attached to the tip of the cone (with or without an additional plate or cone) for ideal and self-avoiding polymers. The entropic force is of the order of 0.1 pN at 0.1 MUm for a single polymer and can be increased for a star polymer. PMID- 23367968 TI - Local-feature analysis for automated coarse-graining of bulk-polymer molecular dynamics simulations. AB - A method for automated coarse-graining of bulk polymers is presented, using the data-mining tool of local feature analysis. Most existing methods for polymer coarse-graining define superatoms based on their covalent bonding topology along the polymer backbone, but here superatoms are defined based only on their correlated motions, as observed in molecular dynamics simulations. Correlated atomic motions are identified in the simulation data using local feature analysis, between atoms in the same or in different polymer chains. Groups of highly correlated atoms constitute the superatoms in the coarse-graining scheme, and the positions of their seed coordinates are then projected forward in time. Based on only the seed positions, local feature analysis enables the full reconstruction of all atomic positions. This reconstruction suggests an iterative scheme to reduce the computation of the simulations to initialize another short molecular dynamic simulation, identify new superatoms, and again project forward in time. PMID- 23367969 TI - Percolating bulk heterostructures from neutron reflectometry and small-angle scattering data. AB - We generate percolating fullerene-polymer bulk heterostructures that are consistent with the experimental characterization of a nanostructure, in particular neutron reflectometry and small-angle neutron scattering data from as cast and annealed poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl C61-butyric acid methyl ester systems. Transport simulations correlate changes in exciton dissociation efficiency and charge collection efficiency with morphological features including characteristic domain size, fullerene concentration profile, degree of fullerene sequestration, and degree of P3HT crystallization. PMID- 23367970 TI - Cell elongation via intrinsic antipodal stretching forces. AB - To probe the mechanical properties of cells, we investigate a technique to perform deformability-based cytometry that inherently induces normal antipodal surface forces using a single line-shaped optical trap. We show theoretically that these opposing forces are generated simultaneously over curved microscopic object surfaces with optimal magnitude at low numerical apertures, allowing the directed stretching of elastic cells with a single, weakly focused laser source. Matching these findings with concomitant experimental observations, we elongate red blood cells, effectively stretching them within the narrow confines of a steep, optically induced potential well. PMID- 23367971 TI - Trajectories of Listeria-type motility in two dimensions. AB - Force generated by actin polymerization is essential in cell motility and the locomotion of organelles or bacteria such as Listeria monocytogenes. Both in vivo and in vitro experiments on actin-based motility have observed geometrical trajectories including straight lines, circles, S-shaped curves, and translating figure eights. This paper reports a phenomenological model of an actin-propelled disk in two dimensions that generates geometrical trajectories. Our model shows that when the evolutions of actin density and force per filament on the disk are strongly coupled to the disk self-rotation, it is possible for a straight trajectory to lose its stability. When the instability is due to a pitchfork bifurcation, the resulting trajectory is a circle; a straight trajectory can also lose stability through a Hopf bifurcation, and the resulting trajectory is an S shaped curve. We also show that a half-coated disk, which mimics the distribution of functionalized proteins in Listeria, also undergoes similar symmetry-breaking bifurcations when the straight trajectory loses stability. For both a fully coated disk and a half-coated disk, when the trajectory is an S-shaped curve, the angular frequency of the disk self-rotation is different from that of the disk trajectory. However, for circular trajectories, these angular frequencies are different for a fully coated disk but the same for a half-coated disk. PMID- 23367972 TI - Phase-locked cluster oscillations in periodically forced integrate-and-fire-or burst neuronal populations. AB - The minimal integrate-and-fire-or-burst neuron model succinctly describes both tonic firing and postinhibitory rebound bursting of thalamocortical cells in the sensory relay. Networks of integrate-and-fire-or-burst (IFB) neurons with slow inhibitory synaptic interactions have been shown to support stable rhythmic states, including globally synchronous and cluster oscillations, in which network mediated inhibition cyclically generates bursting in coherent subgroups of neurons. In this paper, we introduce a reduced IFB neuronal population model to study synchronization of inhibition-mediated oscillatory bursting states to periodic excitatory input. Using numeric methods, we demonstrate the existence and stability of 1:1 phase-locked bursting oscillations in the sinusoidally forced IFB neuronal population model. Phase locking is shown to arise when periodic excitation is sufficient to pace the onset of bursting in an IFB cluster without counteracting the inhibitory interactions necessary for burst generation. Phase-locked bursting states are thus found to destabilize when periodic excitation increases in strength or frequency. Further study of the IFB neuronal population model with pulse-like periodic excitatory input illustrates that this synchronization mechanism generalizes to a broad range of n:m phase-locked bursting states across both globally synchronous and clustered oscillatory regimes. PMID- 23367973 TI - Denaturation of circular DNA: supercoils and overtwist. AB - The denaturation transition of circular DNA is studied within a Poland-Scheraga type approach, generalized to account for the fact that the total linking number (LK), which measures the number of windings of one strand around the other, is conserved. In the model the LK conservation is maintained by invoking both overtwisting and writhing (supercoiling) mechanisms. This generalizes previous studies, which considered each mechanism separately. The phase diagram of the model is analyzed as a function of the temperature and the elastic constant kappa associated with the overtwisting energy for any given loop entropy exponent c. As in the case where the two mechanisms apply separately, the model exhibits no denaturation transition for c <= 2. For c > 2 and kappa = 0 we find that the model exhibits a first-order transition. The transition becomes of higher order for any kappa > 0. We also calculate the contribution of the two mechanisms separately in maintaining the conservation of the linking number and find that it is weakly dependent on the loop exponent c. PMID- 23367974 TI - Direct measurement of single soft lipid nanotubes: nanoscale information extracted in a noninvasive manner. AB - We investigated the dynamics of single soft nanotubes of phospholipids to extract nanoscale information such as the size of the tube, which were several tens to hundreds of nanometers thick. The dynamic properties of the tubes obtained from direct observation by fluorescent microscopy, such as their persistence length, enable us to access the nanoscale characteristics through a simple elastic model of the membrane. The present methodology should be applicable to the nanosized membrane structure in living cells. PMID- 23367975 TI - DNA translocation through a nanopore in a single-layered doped semiconductor membrane. AB - Recently, we developed a computational model that allowed us to study the influence a semiconductor membrane has on a DNA molecule translocating through a nanopore in this membrane. Our model incorporated both the self-consistent Poisson-Nernst-Planck simulations for the electric potential of a solid state membrane immersed in an electrolyte solution together with the Brownian dynamics of the biomolecule. In this paper, we study how the applied electrolyte bias, the semiconductor membrane bias, and the semiconductor material type (n-Si or p-Si) affect the translocation dynamics of a single-stranded DNA moving through a nanopore in a single-layered semiconductor membrane. We show that the type of semiconductor material used for the membrane has a prominent effect on the biomolecule's translocation time, with DNA exhibiting much longer translocation times through the p-type membrane than through the n type at the same electrolyte and membrane potentials, while the extension of the biomolecule remains practically unchanged. In addition, we find the optimal combination for the membrane-electrolyte system's parameters to achieve the longest translocation time and largest DNA extension. With our single-layered electrically tunable membranes, the DNA translocation time can be manipulated to have an order of magnitude increase. PMID- 23367976 TI - Observed frequency-independent torque in flagellar bacterial motors optimizes space exploration. AB - A surprising feature of many bacterial motors is the apparently conserved form of their torque-frequency relation. Experiments indicate that the torque provided by the bacterial rotary motor is approximately constant over a large range of angular speeds. This is observed in both monotrichous and peritrichous bacteria, independently of whether they are propelled by a proton flux or by a Na(+) ion flux. If the relation between angular speed omega and swimming speed is linear, a omega-independent torque implies that the power spent in active motion is proportional to the instantaneous bacterial speed. Using realistic values of the relevant parameters, we show that a constant torque maximizes the volume of the region explored by a bacterium in a resource-depleted medium. Given that nutrients in the ocean are often concentrated in separate, ephemeral patches, we propose that the observed constancy of the torque may be a trait evolved to maximize bacterial survival in the ocean. PMID- 23367977 TI - Induced spiral motion in cardiac tissue due to alternans. AB - Spiral wave meander is a typical feature observed in cardiac tissue and in excitable media in general. Here, we show for a simple model of excitable cardiac tissue that a transition to alternans--a beat-to-beat temporal alternation in the duration of cardiac excitation--can also induce a transition in the spiral core motion that is related to the presence of synchronization defect lines (SDLs) or nodal lines. While this is similar to what has been predicted and indeed observed for complex-oscillatory media close to onset, we find important qualitative differences. For example, single straight SDLs rotate and induce an additional nonresonant frequency characterizing the core motion of the attached spiral. We analyze this behavior quantitatively as a function of the steepness of the restitution curve and show that the velocity and the directionality of the core motion vary monotonically with the control parameter. Our findings agree with recent observations in rat heart tissue cultures indicating that the described behavior is of rather general nature. In particular, it could play an important role in the context of potentially life-threatening cardiac arrhythmias such as fibrillation for which alternans and spiral waves are known precursors. PMID- 23367978 TI - Simultaneously propagating voltage and pressure pulses in lipid monolayers of pork brain and synthetic lipids. AB - Hydrated interfaces are ubiquitous in biology and appear on all length scales from ions and individual molecules to membranes and cellular networks. In vivo, they comprise a high degree of self-organization and complex entanglement, which limits their experimental accessibility by smearing out the individual phenomenology. The Langmuir technique, however, allows the examination of defined interfaces, the controllable thermodynamic state of which enables one to explore the proper state diagrams. Here we demonstrate that voltage and pressure pulses simultaneously propagate along monolayers comprised of either native pork brain or synthetic lipids. The excitation of pulses is conducted by the application of small droplets of acetic acid and monitored subsequently employing time-resolved Wilhelmy plate and Kelvin probe measurements. The isothermal state diagrams of the monolayers for both lateral pressure and surface potential are experimentally recorded, enabling us to predict dynamic voltage pulse amplitudes of 0.1-3 mV based on the assumption of static mechanoelectrical coupling. We show that the underlying physics for such propagating pulses is the same for synthetic and natural extracted (pork brain) lipids and that the measured propagation velocities and pulse amplitudes depend on the compressibility of the interface. Given the ubiquitous presence of hydrated interfaces in biology, our experimental findings seem to support a fundamentally new mechanism for the propagation of signals and communication pathways in biology (signaling), which is based neither on protein-protein or receptor-ligand interaction nor diffusion. PMID- 23367980 TI - Low-frequency dielectric dispersion of brain tissue due to electrically long neurites. AB - The dielectric properties of brain tissue are important for understanding how neural activity is related to local field potentials and electroencephalograms. It is known that the permittivity of brain tissue exhibits strong frequency dependence (dispersion) and that the permittivity is very large in the low frequency region. However, little is known with regard to the cause of the large permittivity in the low-frequency region. Here, we postulate that the dielectric properties of brain tissue can be partially accounted for by assuming that neurites are of sufficient length to be "electrically long." To test this idea, we consider a model in which a neurite is treated as a long, narrow body, and it is subjected to a stimulus created by electrodes situated in the region external to it. With regard to this electric stimulus, the neurite can be treated as a passive cable. Assuming adequate symmetry so that the tissue packed with multiple cables is equivalent to an isolated system consisting of a single cable and a surrounding extracellular resistive medium, we analytically calculate the extracellular potential of the tissue in response to such an externally created alternating-current electric field using a Green's function that we obtained previously. Our results show that brain tissue modeled by such a cable existing within a purely resistive extracellular medium exhibits a large effective permittivity in the low-frequency region. Moreover, we obtain results suggesting that an extremely large low-frequency permittivity can coexist with weak low-pass filter characteristics in brain tissue. PMID- 23367979 TI - How input fluctuations reshape the dynamics of a biological switching system. AB - An important task in quantitative biology is to understand the role of stochasticity in biochemical regulation. Here, as an extension of our recent work [Phys. Rev. Lett. 107, 148101 (2011)], we study how input fluctuations affect the stochastic dynamics of a simple biological switch. In our model, the on transition rate of the switch is directly regulated by a noisy input signal, which is described as a non-negative mean-reverting diffusion process. This continuous process can be a good approximation of the discrete birth-death process and is much more analytically tractable. Within this setup, we apply the Feynman-Kac theorem to investigate the statistical features of the output switching dynamics. Consistent with our previous findings, the input noise is found to effectively suppress the input-dependent transitions. We show analytically that this effect becomes significant when the input signal fluctuates greatly in amplitude and reverts slowly to its mean. PMID- 23367982 TI - Biofilm growth on rugose surfaces. AB - A stochastic model is used to assess the effect of external parameters on the development of submerged biofilms on smooth and rough surfaces. The model includes basic cellular mechanisms, such as division and spreading, together with an elementary description of the interaction with the surrounding flow and probabilistic rules for extracellular polymeric substance matrix generation, cell decay, and adhesion. Insight into the interplay of competing mechanisms such as the flow or the nutrient concentration change is gained. Erosion and growth processes combined produce biofilm structures moving downstream. A rich variety of patterns are generated: shrinking biofilms, patches, ripplelike structures traveling downstream, fingers, mounds, streamerlike patterns, flat layers, and porous and dendritic structures. The observed regimes depend on the carbon source and the type of bacteria. PMID- 23367981 TI - Anharmonic dynamics of intramolecular hydrogen bonds driven by DNA breathing. AB - We study the effects of the anharmonic strand-separation dynamics of double stranded DNA on the infrared spectra of the intramolecular base-pairing hydrogen bonds. Using the extended Peyrard-Bishop-Dauxois model for the DNA breathing dynamics coupled with the Lippincott-Schroeder potential for N-H. . .N and N-H. . .O hydrogen bonding, we identify a high-frequency (~96 THz) feature in the infrared spectra. We show that this sharp peak arises as a result of the anharmonic base-pair breathing dynamics of DNA. In addition, we study the effects of friction on the infrared spectra. For higher temperatures (~300 K), where the anharmonicity of DNA dynamics is pronounced, the high-frequency peak is always present irrespective of the friction strength. PMID- 23367983 TI - Entropy hysteresis and nonequilibrium thermodynamic efficiency of ion conduction in a voltage-gated potassium ion channel. AB - Here we have studied the nonequilibrium thermodynamic response of a voltage-gated Shaker potassium ion channel using a stochastic master equation. For a constant external voltage, the system reaches equilibrium indicated by the vanishing total entropy production rate, whereas for oscillating voltage the current and entropy production rates show dynamic hysteretic behavior. Here we have shown quantitatively that although the hysteresis loop area vanishes in low and high frequency domains of the external voltage, they are thermodynamically distinguishable. In the very low frequency domain, the system remains close to equilibrium, whereas at high frequencies it goes to a nonequilibrium steady state (NESS) associated with a finite value of dissipation function. At NESS, the efficiency of the ion conduction can also be related with the nonlinear dependence of the dissipation function on the power of the external field. Another intriguing aspect is that, at the high frequency limit, the total entropy production rate oscillates at NESS with half of the time period of the external voltage. PMID- 23367984 TI - Microscopically computing free-energy profiles and transition path time of rare macromolecular transitions. AB - We introduce a rigorous method to microscopically compute the observables which characterize the thermodynamics and kinetics of rare macromolecular transitions for which it is possible to identify a priori a slow reaction coordinate. In order to sample the ensemble of statistically significant reaction pathways, we define a biased molecular dynamics (MD) in which barrier-crossing transitions are accelerated without introducing any unphysical external force. In contrast to other biased MD methods, in the present approach the systematic errors which are generated in order to accelerate the transition can be analytically calculated and therefore can be corrected for. This allows for a computationally efficient reconstruction of the free-energy profile as a function of the reaction coordinate and for the calculation of the corresponding diffusion coefficient. The transition path time can then be readily evaluated within the dominant reaction pathways approach. We illustrate and test this method by characterizing a thermally activated transition on a two-dimensional energy surface and the folding of a small protein fragment within a coarse-grained model. PMID- 23367985 TI - Complex quantum network model of energy transfer in photosynthetic complexes. AB - The quantum network model with real variables is usually used to describe the excitation energy transfer (EET) in the Fenna-Matthews-Olson (FMO) complexes. In this paper we add the quantum phase factors to the hopping terms and find that the quantum phase factors play an important role in the EET. The quantum phase factors allow us to consider the space structure of the pigments. It is found that phase coherence within the complexes would allow quantum interference to affect the dynamics of the EET. There exist some optimal phase regions where the transfer efficiency takes its maxima, which indicates that when the pigments are optimally spaced, the exciton can pass through the FMO with perfect efficiency. Moreover, the optimal phase regions almost do not change with the environments. In addition, we find that the phase factors are useful in the EET just in the case of multiple pathways. Therefore, we demonstrate that the quantum phases may bring the other two factors, the optimal space of the pigments and multiple pathways, together to contribute the EET in photosynthetic complexes with perfect efficiency. PMID- 23367986 TI - Clarification of Onsager reciprocal relations based on thermomass theory. AB - The fluxes in transport processes expressed as a time derivative of state variables is a crucial requirement in Onsager's proof of his reciprocal relations, which is a much debated question existing in nonequilibrium thermodynamics. Thermomass theory is used to show that the linear decay of the fluctuation is a balance between the inertial forces and resistant force. Therefore, products of the drift velocities and relaxation times, namely, the displacements from equilibrium, can be used as the state variables, whose time derivatives give the transport fluxes. The Onsager reciprocal relations can be macroscopically derived from the principle that every action has an equal and opposite reaction, applicable in steady nonequilibrium systems and nonlinear couplings. PMID- 23367987 TI - Accuracy and range of validity of the Wigner surmise for mixed symmetry classes in random matrix theory. AB - Schierenberg et al. [Phys. Rev. E 85, 061130 (2012)] recently applied the Wigner surmise, i.e., substitution of infinity * infinity matrices by their 2 * 2 counterparts for the computation of level spacing distributions, to random matrix ensembles in transition between two universality classes. I examine the accuracy and the range of validity of the surmise for the crossover between the Gaussian orthogonal and unitary ensembles by contrasting them with the large-N results that I evaluated using the Nystrom-type method for the Fredholm determinant. The surmised expression at the best-fitting parameter provides a good approximation for 0 = 0.382508 for the order-5 square tiling, p(c2) >= 0.472043 for its dual, and p(c2)>= 0.275768 for the order-5-4 rhombille tiling. PMID- 23367991 TI - Elastic properties of a confined fluid. AB - Monte Carlo computer simulation is employed to determine the local, wave-number dependent, high-frequency elastic properties of a Lennard-Jones fluid that is confined between two walls. In particular, the elastic constants are calculated from coarse-grained stress correlation functions and then related to the local fluid structure via planar radial distribution functions. We find that local fluid properties correlate with the inhomogeneous fluid density and the strength of the wall-fluid interaction. Finally, we discuss the utility of this analysis in the interpretation of experiments involving the characterization of confined fluids. PMID- 23367992 TI - Return radius and volume of recrystallized material in Ostwald ripening. AB - Within the framework of the Lifshitz-Slyozov-Wagner theory of Ostwald ripening, the amount of volume of the second (solid) phase in a liquid solution that is newly formed by recrystallization is investigated. It is shown that in the late stage, the portion of the newly generated volume formed within an interval from time t(0) to t is a certain function of t/t(0) and an explicit expression of this volume is given. To achieve this, we introduce the notion of the return radius r(t,t(0)), which is the unique radius of a particle at time t(0) such that this particle has-after growing and shrinking-the same radius at time t. We derive a formula for the return radius, which later on is used to obtain the newly formed volume. Moreover, formulas for the growth rate of the return radius and the recrystallized material at time t(0) are derived. PMID- 23367993 TI - Self-similar dynamics of bacterial chemotaxis. AB - Colonies of bacteria grown on thin agar plate exhibit fractal patterns as a result of adaptation to their environments. The bacterial colony pattern formation is regulated crucially by chemotaxis, the movement of cells along a chemical concentration gradient. Here, the dynamics of pattern formation in a bacterial colony is investigated theoretically through a continuum model that considers chemotaxis. In the case of the gradient sensed by the bacterium is nearly uniform, the bacterial colony patterns are self-similar, which means they look the same at every scale. The scaling law of the bacterial colony growth has been revealed explicitly. Chemotaxis biases the movement of the bacterial population in colony to trend toward the chemical attractant. Moreover, the bacterial colonies evolve for a long time as the traveling wave with a sharp front. PMID- 23367994 TI - Failure of the alpha factor in describing dynamical instabilities and chaos in quantum-dot lasers. AB - We show that the long-established concept of a linewidth-enhancement factor alpha to describe carrier-induced refractive index changes in semiconductor lasers breaks down in quantum-dot (QD) lasers when describing complex dynamic scenarios, found, for example, under high-excitation or optical injection. By comparing laser simulations using a constant alpha factor with results from a more complex nonequilibrium model that separately treats gain and refractive index dynamics, we examine the conditions under which an approximation of the amplitude-phase coupling by an alpha factor becomes invalid. The investigations show that while a quasiequilibrium approach for conventional quantum well lasers is valid over a reasonable parameter range, allowing one to introduce an alpha factor as a constant parameter, the concept is in general not applicable to predict QD laser dynamics due to the different time scales of the involved scattering processes. PMID- 23367995 TI - Pearl-necklace-like structures of microparticle strings observed in a dc complex plasma. AB - The observation of a well-developed treelike string structure supported by a gas flow in a three-dimensional dc complex plasma is presented. The dynamically stable strings, comprising 10-20 particles, were up to 5 mm long. The experiments were performed using neon gas at a pressure of 100 Pa and melamine-formaldehyde particles with a diameter of 3.43 MUm. Inside the discharge glass tube a nozzle had been built in to supply the controllable gas (plasma) flux intensity distribution along the tube. The walls of the nozzle were transparent for the laser light illuminating the particles. That gave the opportunity to closely study the particle dynamics deep inside the nozzle. PMID- 23367996 TI - Coupling of high-intensity laser light to fast electrons in cone-guided fast ignition. AB - Cu wires attached to Al cones are used to investigate the energy coupling efficiency of laser light to fast electrons through a cone into a dense plasma. We present experimental and simulation results demonstrating the effect on the energy coupling of effectively placing the cone in a surrounding high density plasma as well as the effect of a large preformed plasma inside the cone. Thick cone walls, simulating plasma surrounding the cone in fast ignition, reduce the energy coupling by a factor of up to 4. An increase in prepulse inside the cone by a factor of 50 further reduces coupling by a factor of 3. Simulations with the pic code lsp that include the laser plasma interaction and the preformed plasma from the flash code show that electron refluxing in thin cone-wall targets enhances coupling to the wire. The implications for full-scale cone-guided fast ignition are discussed. PMID- 23367997 TI - Accuracy of the viscous stress in the lattice Boltzmann equation with simple boundary conditions. AB - Based on the theory of asymptotic analysis, we prove that the viscous stress tensor computed with the lattice Boltzmann equation (LBE) in a two-dimensional domain is indeed second-order accurate in space. We only consider simple bounce back boundary conditions which can be reduced to the periodic boundary conditions by using the method of image. While the LBE with nine velocities on two dimensional square lattice (i.e., the D2Q9 model) and with the Bhatnagar-Gross Krook collision model is used as an example in this work, our proof can be extended to the LBE with any linear relaxation collision models in both two and three dimensions. PMID- 23367998 TI - Monochromaticity in neutral evolutionary network models. AB - Recent studies on epistatic networks of model organisms have unveiled a certain type of modular property called monochromaticity in which the networks are clustered into functional modules that interact with each other through the same type of epistasis. Here, we propose and study three epistatic network models that are inspired by the duplication-divergence mechanism to gain insight into the evolutionary basis of monochromaticity and to test if it can be explained as the outcome of a neutral evolutionary hypothesis. We show that the epistatic networks formed by these stochastic evolutionary models have monochromaticity conflict distributions that are centered close to zero and are statistically significantly different from their randomized counterparts. In particular, the last model we propose yields a strictly monochromatic solution. Our results agree with the monochromaticity findings in real organisms and point toward the possible role of a neutral mechanism in the evolution of this phenomenon. PMID- 23367999 TI - Stability of fronts in the Kuramoto-Sivashinsky equation advected by a Poiseuille flow. AB - We study reaction fronts described by the Kuramoto-Sivashinsky equation subject to a Poiseuille flow. The fronts propagate with or against the flow located inside a two-dimensional slab. Steady front profiles can be flat, axisymmetric, or nonaxisymmetric, depending on the gap between the plates and the average flow speed. We first obtain the steady front solutions, later executing a linear stability analysis to determine the stability of the fronts. Applying fluid flow can turn initially unstable fronts into stable fronts. Stable steady fronts propagating in the adverse direction of the Poiseuille flow are axisymmetric for slow fluid flows. However, for higher speeds an adverse flow can lead to stable nonaxisymmetric fronts. We also show regions of bistability where stable nonaxisymmetric and axisymmetric fronts can coexist. PMID- 23368000 TI - Assortativity decreases the robustness of interdependent networks. AB - It was recently recognized that interdependencies among different networks can play a crucial role in triggering cascading failures and, hence, systemwide disasters. A recent model shows how pairs of interdependent networks can exhibit an abrupt percolation transition as failures accumulate. We report on the effects of topology on failure propagation for a model system consisting of two interdependent networks. We find that the internal node correlations in each of the two interdependent networks significantly changes the critical density of failures that triggers the total disruption of the two-network system. Specifically, we find that the assortativity (i.e., the likelihood of nodes with similar degree to be connected) within a single network decreases the robustness of the entire system. The results of this study on the influence of assortativity may provide insights into ways of improving the robustness of network architecture and, thus, enhance the level of protection of critical infrastructures. PMID- 23368001 TI - PageRank and rank-reversal dependence on the damping factor. AB - PageRank (PR) is an algorithm originally developed by Google to evaluate the importance of web pages. Considering how deeply rooted Google's PR algorithm is to gathering relevant information or to the success of modern businesses, the question of rank stability and choice of the damping factor (a parameter in the algorithm) is clearly important. We investigate PR as a function of the damping factor d on a network obtained from a domain of the World Wide Web, finding that rank reversal happens frequently over a broad range of PR (and of d). We use three different correlation measures, Pearson, Spearman, and Kendall, to study rank reversal as d changes, and we show that the correlation of PR vectors drops rapidly as d changes from its frequently cited value, d_{0}=0.85. Rank reversal is also observed by measuring the Spearman and Kendall rank correlation, which evaluate relative ranks rather than absolute PR. Rank reversal happens not only in directed networks containing rank sinks but also in a single strongly connected component, which by definition does not contain any sinks. We relate rank reversals to rank pockets and bottlenecks in the directed network structure. For the network studied, the relative rank is more stable by our measures around d=0.65 than at d=d_{0}. PMID- 23368002 TI - Thermodynamics of urban population flows. AB - Orderliness, reflected via mathematical laws, is encountered in different frameworks involving social groups. Here we show that a thermodynamics can be constructed that macroscopically describes urban population flows. Microscopic dynamic equations and simulations with random walkers underlie the macroscopic approach. Our results might be regarded, via suitable analogies, as a step towards building an explicit social thermodynamics. PMID- 23368003 TI - Stability-to-instability transition in the structure of large-scale networks. AB - We examine phase transitions between the "easy," "hard," and "unsolvable" phases when attempting to identify structure in large complex networks ("community detection") in the presence of disorder induced by network "noise" (spurious links that obscure structure), heat bath temperature T, and system size N. The partition of a graph into q optimally disjoint subgraphs or "communities" inherently requires Potts-type variables. In earlier work [Philos. Mag. 92, 406 (2012)], when examining power law and other networks (and general associated Potts models), we illustrated that transitions in the computational complexity of the community detection problem typically correspond to spin-glass-type transitions (and transitions to chaotic dynamics in mechanical analogs) at both high and low temperatures and/or noise. The computationally "hard" phase exhibits spin-glass type behavior including memory effects. The region over which the hard phase extends in the noise and temperature phase diagram decreases as N increases while holding the average number of nodes per community fixed. This suggests that in the thermodynamic limit a direct sharp transition may occur between the easy and unsolvable phases. When present, transitions at low temperature or low noise correspond to entropy driven (or "order by disorder") annealing effects, wherein stability may initially increase as temperature or noise is increased before becoming unsolvable at sufficiently high temperature or noise. Additional transitions between contending viable solutions (such as those at different natural scales) are also possible. Identifying community structure via a dynamical approach where "chaotic-type" transitions were found earlier. The correspondence between the spin-glass-type complexity transitions and transitions into chaos in dynamical analogs might extend to other hard computational problems. In this work, we examine large networks (with a power law distribution in cluster size) that have a large number of communities (q?1). We infer that large systems at a constant ratio of q to the number of nodes N asymptotically tend towards insolvability in the limit of large N for any positive T. The asymptotic behavior of temperatures below which structure identification might be possible, T_{*}=O[1/lnq], decreases slowly, so for practical system sizes, there remains an accessible, and generally easy, global solvable phase at low temperature. We further employ multivariate Tutte polynomials to show that increasing q emulates increasing T for a general Potts model, leading to a similar stability region at low T. Given the relation between Tutte and Jones polynomials, our results further suggest a link between the above complexity transitions and transitions associated with random knots. PMID- 23368004 TI - Evolution of cooperation on spatially embedded networks. AB - In this work we study the behavior of classical two-person, two-strategies evolutionary games on networks embedded in a Euclidean two-dimensional space with different kinds of degree distributions and topologies going from regular to random and to scale-free ones. Using several imitative microscopic dynamics, we study the evolution of global cooperation on the above network classes and find that specific topologies having a hierarchical structure and an inhomogeneous degree distribution, such as Apollonian and grid-based networks, are very conducive to cooperation. Spatial scale-free networks are still good for cooperation but to a lesser degree. Both classes of networks enhance average cooperation in all games with respect to standard random geometric graphs and regular grids by shifting the boundaries between cooperative and defective regions. These findings might be useful in the design of interaction structures that maintain cooperation when the agents are constrained to live in physical two dimensional space. PMID- 23368005 TI - Propagation of fronts in the Fisher-Kolmogorov equation with spatially varying diffusion. AB - The propagation of fronts in the Fisher-Kolmogorov equation with spatially varying diffusion coefficients is studied. Using coordinate changes, WKB approximations, and multiple scales analysis, we provide an analytic framework that describes propagation of the front up to the minimum of the diffusion coefficient. We also present results showing the behavior of the front after it passes the minimum. In each case, we show that standard traveling coordinate frames do not properly describe front propagation. Last, we provide numerical simulations to support our analysis and to show, that around the minimum, the motion of the front is arrested on asymptotically significant time scales. PMID- 23368006 TI - Maximal-entropy random walk unifies centrality measures. AB - This paper compares a number of centrality measures and several (dis-)similarity matrices with which they can be defined. These matrices, which are used among others in community detection methods, represent quantities connected to enumeration of paths on a graph and to random walks. Relationships between some of these matrices are derived in the paper. These relationships are inherited by the centrality measures. They include measures based on the principal eigenvector of the adjacency matrix, path enumeration, as well as on the stationary state, stochastic matrix, or mean first-passage times of a random walk. As the random walk defining the centrality measure can be arbitrarily chosen, we pay particular attention to the maximal-entropy random walk, which serves as a very distinct alternative to the ordinary (diffusive) random walk used in network analysis. The various importance measures, defined both with the use of ordinary random walk and the maximal-entropy random walk, are compared numerically on a set of benchmark graphs with varying mixing parameter and are grouped with the use of the agglomerative clustering technique. It is shown that centrality measures defined with the two different random walks cluster into two separate groups. In particular, the group of centrality measures defined by the maximal-entropy random walk does not cluster with any other measures on change of graphs' parameters, and members of this group produce mutually closer results than members of the group defined by the ordinary random walk. PMID- 23368007 TI - Spatial effects in real networks: measures, null models, and applications. AB - Spatially embedded networks are shaped by a combination of purely topological (space-independent) and space-dependent formation rules. While it is quite easy to artificially generate networks where the relative importance of these two factors can be varied arbitrarily, it is much more difficult to disentangle these two architectural effects in real networks. Here we propose a solution to this problem, by introducing global and local measures of spatial effects that, through a comparison with adequate null models, effectively filter out the spurious contribution of nonspatial constraints. Our filtering allows us to consistently compare different embedded networks or different historical snapshots of the same network. As a challenging application we analyze the World Trade Web, whose topology is known to depend on geographic distances but is also strongly determined by nonspatial constraints (degree sequence or gross domestic product). Remarkably, we are able to detect weak but significant spatial effects both locally and globally in the network, showing that our method succeeds in retrieving spatial information even when nonspatial factors dominate. We finally relate our results to the economic literature on gravity models and trade globalization. PMID- 23368008 TI - Effect of network structure on phase transitions in queuing networks. AB - Recently, De Martino et al. [J. Stat. Mech. (2009) P08023; Phys. Rev. E 79, 015101 (2009)] have presented a general framework for the study of transportation phenomena on random networks with annealed disorder. One of their most significant achievements was a deeper understanding of the phase transition from the uncongested to the congested phase at a critical traffic load on uncorrelated networks. In this paper, we also study phase transition in transportation networks using a discrete time random walk model. Our aim is to establish a direct connection between the structure of an uncorrelated random graph with quenched disorder and the value of the critical traffic load. We show that if the network is dense, the quenched and annealed formulas for the critical loading probability coincide. For sparse graphs, higher-order corrections, related to the local structure of the network, appear. PMID- 23368009 TI - Dead leaves and the dirty ground: low-level image statistics in transmissive and occlusive imaging environments. AB - The opacity of typical objects in the world results in occlusion, an important property of natural scenes that makes inference of the full three-dimensional structure of the world challenging. The relationship between occlusion and low level image statistics has been hotly debated in the literature, and extensive simulations have been used to determine whether occlusion is responsible for the ubiquitously observed power-law power spectra of natural images. To deepen our understanding of this problem, we have analytically computed the two- and four point functions of a generalized "dead leaves" model of natural images with parameterized object transparency. Surprisingly, transparency alters these functions only by a multiplicative constant, so long as object diameters follow a power-law distribution. For other object size distributions, transparency more substantially affects the low-level image statistics. We propose that the universality of power-law power spectra for both natural scenes and radiological medical images, formed by the transmission of x-rays through partially transparent tissue, stems from power-law object size distributions, independent of object opacity. PMID- 23368010 TI - Dynamics of link states in complex networks: the case of a majority rule. AB - Motivated by the idea that some characteristics are specific to the relations between individuals and not to the individuals themselves, we study a prototype model for the dynamics of the states of the links in a fixed network of interacting units. Each link in the network can be in one of two equivalent states. A majority link-dynamics rule is implemented, so that in each dynamical step the state of a randomly chosen link is updated to the state of the majority of neighboring links. Nodes can be characterized by a link heterogeneity index, giving a measure of the likelihood of a node to have a link in one of the two states. We consider this link-dynamics model in fully connected networks, square lattices, and Erdos-Renyi random networks. In each case we find and characterize a number of nontrivial asymptotic configurations, as well as some of the mechanisms leading to them and the time evolution of the link heterogeneity index distribution. For a fully connected network and random networks there is a broad distribution of possible asymptotic configurations. Most asymptotic configurations that result from link dynamics have no counterpart under traditional node dynamics in the same topologies. PMID- 23368011 TI - Degree-based attacks and defense strategies in complex networks. AB - We study the stability of random scale-free networks to degree-dependent attacks. We present analytical and numerical results to compute the critical fraction p_{c} of nodes that need to be removed for destroying the network under this attack for different attack parameters. We study the effect of different defense strategies, based on the addition of a constant number of links on network robustness. We test defense strategies based on adding links to either low degree, middegree or high degree nodes. We find using analytical results and simulations that the middegree nodes defense strategy leads to the largest improvement to the network robustness against degree-based attacks. We also test these defense strategies on an internet autonomous systems map and obtain similar results. PMID- 23368012 TI - Wealth distribution on complex networks. AB - We study the wealth distribution of the Bouchaud-Mezard model on complex networks. It is known from numerical simulations that this distribution depends on the topology of the network; however, no one has succeeded in explaining it. Using "adiabatic" and "independent" assumptions along with the central-limit theorem, we derive equations that determine the probability distribution function. The results are compared to those of simulations for various networks. We find good agreement between our theory and the simulations, except for the case of Watts-Strogatz networks with a low rewiring rate due to the breakdown of independent assumption. PMID- 23368013 TI - Exploring complex networks by means of adaptive walkers. AB - Finding efficient algorithms to explore large networks with the aim of recovering information about their structure is an open problem. Here, we investigate this challenge by proposing a model in which random walkers with previously assigned home nodes navigate through the network during a fixed amount of time. We consider that the exploration is successful if the walker gets the information gathered back home, otherwise no data are retrieved. Consequently, at each time step, the walkers, with some probability, have the choice to either go backward approaching their home or go farther away. We show that there is an optimal solution to this problem in terms of the average information retrieved and the degree of the home nodes and design an adaptive strategy based on the behavior of the random walker. Finally, we compare different strategies that emerge from the model in the context of network reconstruction. Our results could be useful for the discovery of unknown connections in large-scale networks. PMID- 23368014 TI - Multifractality in domain wall dynamics of a ferromagnetic film. AB - We investigate the multifractal properties in the dynamics of domain walls of a ferromagnetic film. We apply the Multifractal Detrended Fluctuation Analysis method in experimental Barkhausen noise time series measured in a 1000-nm-thick Permalloy film under different driving magnetic field frequencies, and calculate the fluctuation function F_{q}(s), generalized Hurst exponent h(q), multifractal scaling exponent tau(q), and the multifractal spectrum f(alpha). Based on this procedure, we provide experimental evidence of multifractality in the dynamics of domain walls in ferromagnetic films and identify a rich and strong multifractal behavior, revealed by the changes of the scaling properties of over the entire Barkhausen noise signal, independently of the driving magnetic field rate employed in the experiment. PMID- 23368015 TI - Dynamical model of faulting in two dimensions and self-healing of large fractures. AB - We describe a model for the simulation of extended two-dimensional in-plane dynamical ruptures and for the rapid calculation of statistical properties of repeated model-seismicity events. The discretization involves first- and second nearest neighbors and is isotropic in both compression and shear properties. All rupture events obey a fracture criterion in the appropriate coordinate frame and numerical oscillations in slip velocity at crack tips due to discretization are minimized. The rupture velocities of fractures, in cases of homogeneous stress drop equal to the strength, are the supershear P-wave velocity in the direction of the prestress and the S-wave velocity in the perpendicular direction. We use the model to study the growth and healing of individual faults to understand the formation of propagating slip pulses. We confirm two mechanisms for the generation of isolated rupture pulses that have been proposed, namely, (1) a decrease in the dynamical friction with accelerating slip and (2) the encounter of the growing crack with extended regions of large difference between the threshold fracture stress and the prestress. We describe a third mechanism which is that of a velocity-dependent friction that operates equally on both the phases of increasing and decreasing slip velocities and has a characteristic length scale. It is a proxy for energy loss by radiation in a three-dimensional medium. In the case of an elongated rectangular model fault with an upper free surface and lower rigid boundary, pulses develop due to the influence of stress waves reflected from the rigid bottom boundary. In general, the excess of strength over stress drop controls crack fracture speeds; if it is too large, the crack stops. Under homogeneous stress conditions, isolated slip pulses are controlled by the spatial distribution of heterogeneities and by the velocity-dependent friction parametrization. PMID- 23368016 TI - Scaling behavior of the earthquake intertime distribution: influence of large shocks and time scales in the Omori law. AB - We present a study of the earthquake intertime distribution D(Deltat) for a California catalog in temporal periods of short duration T. We compare experimental results with theoretical predictions and analytical approximate solutions. For the majority of intervals, rescaling intertimes by the average rate leads to collapse of the distributions D(Deltat) on a universal curve, whose functional form is well fitted by a Gamma distribution. The remaining intervals, exhibiting a more complex D(Deltat), are all characterized by the presence of large shocks. These results can be understood in terms of the relevance of the ratio between the characteristic time c in the Omori law and T: Intervals with Gamma-like behavior are indeed characterized by a vanishing c/T. The above features are also investigated by means of numerical simulations of the Epidemic Type Aftershock Sequence (ETAS) model. This study shows that collapse of D(Deltat) is also observed in numerical catalogs; however, the fit with a Gamma distribution is possible only assuming that c depends on the main-shock magnitude m. This result confirms that the dependence of c on m, previously observed for m>6 main shocks, extends also to small m>2. PMID- 23368017 TI - Effect of resource constraints on intersimilar coupled networks. AB - Most real-world networks do not live in isolation but are often coupled together within a larger system. Recent studies have shown that intersimilarity between coupled networks increases the connectivity of the overall system. However, unlike connected nodes in a single network, coupled nodes often share resources, like time, energy, and memory, which can impede flow processes through contention when intersimilarly coupled. We study a model of a constrained susceptible infected-recovered (SIR) process on a system consisting of two random networks sharing the same set of nodes, where nodes are limited to interact with (and therefore infect) a maximum number of neighbors at each epidemic time step. We obtain that, in agreement with previous studies, when no limit exists (regular SIR model), positively correlated (intersimilar) coupling results in a lower epidemic threshold than negatively correlated (interdissimilar) coupling. However, in the case of the constrained SIR model, the obtained epidemic threshold is lower with negatively correlated coupling. The latter finding differentiates our work from previous studies and provides another step towards revealing the qualitative differences between single and coupled networks. PMID- 23368018 TI - Control of cellular automata. AB - We study the problem of master-slave synchronization and control of totalistic cellular automata. The synchronization mechanism is that of setting a fraction of sites of the slave system equal to those of the master one (pinching synchronization). The synchronization observable is the distance between the two configurations. We present three control strategies that exploit local information (the number of nonzero first-order Boolean derivatives) in order to choose the sites to be synchronized. When no local information is used, we speak of simple pinching synchronization. We find the critical properties of control and discuss the best control strategy compared with simple synchronization. PMID- 23368019 TI - Consistency and complexity in coupled semiconductor lasers with time-delayed optical feedback. AB - Consistency of response in a system driven repeatedly by a complex signal has been observed in many nonlinear dynamical systems. We investigate the consistency of unidirectionally coupled semiconductor lasers with optical feedback and measure the complexity of the entire laser system by using the Lyapunov spectrum. The complexity strongly depends on the degree of consistency. It is found that the complexity of the coupled laser system can be classified into three regions. When the system shows consistency, the complexity of the entire laser system corresponds to that of the solitary drive laser. In the inconsistency region, the complexity of the entire laser system corresponds to the sum of the complexity of the uncoupled drive and response lasers. The complexity increases more than the sum of the two solitary lasers near the boundary of the consistency region, where new dynamical fluctuations appear due to the optical carrier interaction between the two lasers. PMID- 23368020 TI - Semiclassical approach to the quantum Loschmidt echo in deep quantum regions: from validity to breakdown. AB - Semiclassical results are usually expected to be valid in the semiclassical regime. An interesting question is, in models in which appropriate effective Planck constants can be introduced, to what extent will a semiclassical prediction stay valid when the effective Planck constant is increased? In this paper, we numerically study this problem, focusing on semiclassical predictions for the decay of the quantum Loschmidt echo in deep quantum regions. Our numerical simulations, carried out in the chaotic regime in the sawtooth model and in the kicked rotator model and also in the critical region of a one dimensional Ising chain in transverse field, show that the semiclassical predictions may work even in deep quantum regions, particularly for perturbation strength in the so-called Fermi-Golden-Rule regime. PMID- 23368021 TI - Complexity of quantum states in the two-dimensional pairing model. AB - It is known that many-fermion systems, such as complex atoms and nuclei, reveal (at some level of excitation energy) local signatures of quantum chaos similar to the predictions of random matrix theory. Here, we study the gradual development of such signatures in a model system of up to 16 fermions interacting through short-range pairing-type forces in a two-dimensional harmonic trap. We proceed from the simplest characteristics of the level spacing distribution to the complexity of eigenstates, strength, and correlation functions. For increasing pairing strength, at first, chaotic signatures gradually appear. However, when the pairing force dominates the Hamiltonian, we see a regression towards regularity. We introduce a "phase correlator" that allows us to distinguish the complexity of a quantum state that originates from its collective nature, from the complexity originating from quantum chaos. PMID- 23368022 TI - Weyl asymptotics: from closed to open systems. AB - We present microwave experiments on the symmetry reduced five-disk billiard studying the transition from a closed to an open system. The measured microwave reflection signal is analyzed by means of the harmonic inversion and the counting function of the resulting resonances is studied. For the closed system this counting function shows the Weyl asymptotic with a leading exponent equal to 2. By opening the system successively this exponent decreases smoothly to a noninteger value. For the open systems the extraction of resonances by the harmonic inversion becomes more challenging and the arising difficulties are discussed. The results can be interpreted as a first experimental indication for the fractal Weyl conjecture for resonances. PMID- 23368023 TI - Optically injected lasers: the transition from class B to class A lasers. AB - We investigate changes in several features of the stability diagram of an optically injected single mode laser as the ratio of the photon lifetime to the carrier lifetime is progressively increased from very low values to very high values. In particular we consider the creation of a region of phase-locked bistability, changes in the nature of codimension-2 bifurcation points, and the presence or otherwise of chaos in the system. We show that many of the features associated with high values of the aforementioned ratio also emerge for very low pump currents regardless of the ratio of the lifetimes. PMID- 23368024 TI - Swing, release, and escape mechanisms contribute to the generation of phase locked cluster patterns in a globally coupled FitzHugh-Nagumo model. AB - We investigate the mechanism of generation of phase-locked cluster patterns in a globally coupled FitzhHugh-Nagumo model where the fast variable (activator) receives global feedback from the slow variable (inhibitor). We identify three qualitatively different mechanisms (swing-and-release, hold-and-release, and escape-and-release) that contribute to the generation of these patterns. We describe these mechanisms and use this framework to explain under what circumstances two initially out-of-phase oscillatory clusters reach steady phase locked and in-phase synchronized solutions, and how the phase difference between these steady state cluster patterns depends on the clusters relative size, the global coupling intensity, and other model parameters. PMID- 23368025 TI - Helical deformation of the filament of a scroll wave. AB - In three-dimensional excitable systems scroll waves may lose their originally straight shape through different instabilities. In experiments, the formation of zigzag-shaped or helical filaments is often observed. Such a deformation may be due to either a twist-induced instability or a 3D meandering instability. We performed a systematic study using a Belousov-Zhabotinsky (BZ) system with a vertical gradient of excitability and determined the necessary twist for the onset of undulation in the filament. Thus, we demonstrate that in the case of a BZ system with a gradient parallel to the filament, the deformation of the filament is induced by a twist-induced instability. PMID- 23368026 TI - Synchronization between two weakly coupled delay-line oscillators. AB - We study theoretically the generation of a continuous-wave signal by two weakly coupled delay-line oscillators. In such oscillators, the cavity length is longer than the wavelength of the signal. We show by using an analytical solution and comprehensive numerical simulations that in delay-line oscillators, the dynamics of the amplitude response cannot be neglected even when the coupling between the oscillators is weak. Therefore, weakly coupled delay-line oscillators cannot be accurately modeled by using coupled phase-oscillator models. In particular, we show that synchronization between the oscillators can be obtained in cases that are not allowed by coupled phase-oscillator models. We study the stability of the continuous-wave solutions. In delay-line oscillators, several cavity modes can potentially oscillate. To ensure stability, the bandwidth of the delay-line oscillator should be limited. We show that the weakly coupled delay-line oscillator model that is described in this paper can be used to accurately model the synchronization between two weakly coupled optoelectronic oscillators. A very good quantitative agreement is obtained between a comprehensive numerical model to study optoelectronic oscillators and the model results given in this paper. PMID- 23368027 TI - Front propagation in one-dimensional spatially periodic bistable media. AB - Front propagation in heterogeneous bistable media is studied using the Schlogl model as a representative example. Spatially periodic modulations in the parameters of the bistable kinetics are taken into account perturbatively. Depending on the ratio L/l (L is the spatial period of the heterogeneity, l is the front width), appropriate singular perturbation techniques are applied to derive an ordinary differential equation for the position of the front in the presence of the heterogeneities. From this equation, the dependence of the average propagation speed on L/l as well as on the modulation amplitude is calculated. The analytical results obtained predict velocity overshoot, different cases of propagation failure, and the propagation speed for very large spatial periods in quantitative agreement with the results of direct numerical simulations of the underlying reaction-diffusion equation. PMID- 23368028 TI - Expanding the transfer entropy to identify information circuits in complex systems. AB - We propose a formal expansion of the transfer entropy to put in evidence irreducible sets of variables which provide information for the future state of each assigned target. Multiplets characterized by a large contribution to the expansion are associated to the informational circuits present in the system, with an informational character which can be associated to the sign of the contribution. For the sake of computational complexity, we adopt the assumption of Gaussianity and use the corresponding exact formula for the conditional mutual information. We report the application of the proposed methodology on two electroencephalography (EEG) data sets. PMID- 23368029 TI - Length scale of a chaotic element in Rayleigh-Benard convection. AB - We describe an approach to quantify the length scale of a chaotic element of a Rayleigh-Benard convection layer exhibiting spatiotemporal chaos. The length scale of a chaotic element is determined by simultaneously evolving the dynamics of two convection layers with a unidirectional coupling that involves only the time-varying values of the fluid velocity and temperature on the lateral boundaries of the domain. In our results we numerically simulate the full Boussinesq equations for the precise conditions of experiment. By varying the size of the boundary used for the coupling we identify a length scale that describes the size of a chaotic element. The length scale of the chaotic element is of the same order of magnitude, and exhibits similar trends, as the natural chaotic length scale that is based upon the fractal dimension. PMID- 23368030 TI - On-manifold localization in open quantum maps. AB - A quantized chaotic map exhibiting localization of wave function intensity is opened. We investigate how such patterns as scars in the Husimi distributions are influenced by the losses through a number of numerical experiments. We find the scars to relocate on the stable or unstable manifolds depending on the position of the opening, and provide a classical argument to explain the observations. For asymmetrically introduced openings mode interaction contributes to determine the localization patterns. We finally show examples of similar localization in a simulated dielectric microcavity. PMID- 23368031 TI - Origin of chaotic transients in excitatory pulse-coupled networks. AB - We develop an approach to understanding long chaotic transients in networks of excitatory pulse-coupled oscillators. Our idea is to identify a class of attractors, sequentially active firing (SAF) attractors, in terms of the temporal event structure of firing and receipt of pulses. Then all attractors can be classified into two groups: SAF attractors and non-SAF attractors. We establish that long transients typically arise in the transitional region of the parameter space where the SAF attractors are collectively destabilized. Bifurcation behavior of the SAF attractors is analyzed to provide a detailed understanding of the long irregular transients. Although demonstrated using pulse-coupled oscillator networks, our general methodology may be useful in understanding the origin of transient chaos in other types of networked systems, an extremely challenging problem in nonlinear dynamics and complex systems. PMID- 23368032 TI - Particle tracking velocimetry and particle image velocimetry study of the slow motion of rough and smooth solid spheres in a yield-stress fluid. AB - We report experimental evidence of an effect opposite to the "solidification" of small bubbles in liquid where the surface can become immobile. Namely, it is demonstrated that smooth solid spheres falling in a yield-stress fluid under the action of gravity can behave similar to drops. Particle tracking velocimetry was used to determine the shape of the yielded region around solid spherical particles undergoing slow stationary motion in 0.07% w/w Carbopol gel due to gravity under creeping flow conditions. The flow field inside the yielded region was determined by particle image velocimetry. It was found that the shape of the yielded region and the flow field around slow-moving rough particles is similar to the published results of numerical simulations, whereas those around smooth spheres resemble the experimental results obtained for viscous drops. The effect was explained by a slip of the gel on the smooth surface. Most likely, the slip originated from seepage of clean water from the gel, forming a thin lubricating layer near the solid surface. PMID- 23368033 TI - Interplay between the Beale-Kato-Majda theorem and the analyticity-strip method to investigate numerically the incompressible Euler singularity problem. AB - Numerical simulations of the incompressible Euler equations are performed using the Taylor-Green vortex initial conditions and resolutions up to 4096^{3}. The results are analyzed in terms of the classical analyticity-strip method and Beale, Kato, and Majda (BKM) theorem. A well-resolved acceleration of the time decay of the width of the analyticity strip delta(t) is observed at the highest resolution for 3.71. The analysis used in those studies cannot be extended to Pr<1 fluids, and it is not clear at present whether such simple scaling relations can be developed for Pr<1 fluids. In the present study, the Pr>1 scalings are shown to perform well for the start-up stage of the Pr<1 flow, but not for the fully developed flow. The Pr>1 scalings are modified to provide unified Prandtl number scalings for fully developed natural-convection boundary layers for both Pr?1 and Pr?1, with the unknown powers obtained empirically via direct numerical simulation. The modified scalings are shown to perform well for the fully developed flow, with the exception being the prediction of the inner viscous boundary-layer thickness. PMID- 23368044 TI - Faraday instability at foam-water interface. AB - A nearly two-dimensional foam is generated inside a Hele-shaw cell and left at rest on its liquid bath. The system is then vertically shaken and, above a well defined acceleration threshold, surface waves appear at the foam-liquid interface. Those waves are shown to be subharmonic. The acceleration threshold is studied and compared to the common liquid-gas case, emphasizing the energy dissipation inside the foam. An empirical model is proposed for this energy loss, accounting for the foam characteristics such as the bubble size but also the excitation parameter, namely the linear velocity. PMID- 23368045 TI - Bouncing of polymeric droplets on liquid interfaces. AB - The effect of polymers on the bouncing behavior of droplets in a highly viscous, vertically shaken silicone oil bath was investigated in this study. Droplets of a sample liquid were carefully placed on a vibrating bath that was maintained well below the threshold of Faraday waves. The bouncing threshold of the plate acceleration depended on the acceleration frequency. For pure water droplets and droplets of aqueous polymer solutions, a minimum acceleration amplitude was observed in the acceleration threshold curves as a function of frequency. The bouncing acceleration amplitude for a droplet of a dilute aqueous polymer solution was higher than the acceleration amplitude for a pure water droplet. Measurements of the center of mass trajectory and the droplet deformations showed that the controlling parameter in the bouncing process was the oscillating elongational rate of the droplet. This parameter can be directly related to the elongational viscosity of the polymeric samples. The large elongational viscosity of the polymer solution droplets suppressed large droplet deformations, resulting in less chaotic bouncing. PMID- 23368046 TI - Facilitating dynamo action via control of large-scale turbulence. AB - The magnetohydrodynamic dynamo effect is considered to be the major cause of magnetic field generation in geo- and astrophysical systems. Recent experimental and numerical results show that turbulence constitutes an obstacle to dynamos; yet its role in this context is not totally clear. Via numerical simulations, we identify large-scale turbulent vortices with a detrimental effect on the amplification of the magnetic field in a geometry of experimental interest and propose a strategy for facilitating the dynamo instability by manipulating these detrimental "hidden" dynamics. PMID- 23368047 TI - Saturation dependence of dispersion in porous media. AB - In this study, we develop a saturation-dependent treatment of dispersion in porous media using concepts from critical path analysis, cluster statistics of percolation, and fractal scaling of percolation clusters. We calculate spatial solute distributions as a function of time and calculate arrival time distributions as a function of system size. Our previous results correctly predict the range of observed dispersivity values over ten orders of magnitude in experimental length scale, but that theory contains no explicit dependence on porosity or relative saturation. This omission complicates comparisons with experimental results for dispersion, which are often conducted at saturation less than 1. We now make specific comparisons of our predictions for the arrival time distribution with experiments on a single column over a range of saturations. This comparison suggests that the most important predictor of such distributions as a function of saturation is not the value of the saturation per se, but the applicability of either random or invasion percolation models, depending on experimental conditions. PMID- 23368048 TI - Morphology of water electrosprays in the simple-jet mode. AB - Experiments were conducted in order to study and characterize electrohydrodynamic atomization in the simple-jet mode for inviscid liquids. The operational window of this mode regarding the electric potential and liquid flow rate is presented. From the data it could be concluded that this mode can be divided by the characteristics of its breakup mechanism and that these characteristics are a function of the liquid Weber number and the electric Bond number for a given setup. Additionally we were also able to calculate the average charge per droplet and define the average size of primary and satellite droplets. The dispersion of the spray was also studied regarding its relation to the liquid Weber number and to the electric Bond number. We conclude that simple-jet mode electrosprays are a good option for applications which require monodisperse micrometer droplets with high throughput. PMID- 23368049 TI - Effect of solutal Marangoni convection on motion, coarsening, and coalescence of droplets in a monotectic system. AB - In this paper, we study the effect of solutal Marangoni convection (SMC) on the microstructure evolution in a monotectic system, using the convective Cahn Hilliard and Navier-Stokes equations with a capillary tensor contributed by the chemical concentration gradient. At first, we simulate the spontaneous motion of two distant droplets induced by SMC and compare our results with an analytical solution. We then compute the coalescence of two droplets in contact and coarsening of two distant droplets considering different sizes. We further study the influence of SMC on the evolution of phase separation processes inside the spinodal region for Fe-50 at %Sn and Fe-40 at %Sn alloys. In the former case, we rationalize our results using Fourier spectra and in the latter case, we compare the size distribution of droplets with the LSW theory. PMID- 23368050 TI - Numerical simulation of the Richtmyer-Meshkov instability in initially nonuniform flows and mixing with reshock. AB - Based on previous instability experiments of the double mode perturbed interface in initially nonuniform flows, we numerically investigate the effect of the nonuniformity of flows on the evolution of instability in a nonlinear regime after reshock by adopting two different nonuniform coefficients (delta_{1} = 0.6162 and delta_{2} = 0.4961) in the Gaussian distribution of the initial nonuniform density. We obtain the evolution of the mixing zone width and vortex structure of the air-SF_{6} interface and compare the circulation discrepancies of the nonuniform and uniform flows before and after reshock. These results indicate that the nonuniformity of the initial flow has great effect on the evolution of instability in the linear regime and the weak nonlinear regime prior to reshock. However, the mixing layer has little dependence on the nonuniformity of the initial flow in the nonlinear regime after reshock; namely, the effect of the nonuniformity is reduced significantly as the instability enters the strongly nonlinear regime after reshock. Although the growth rate of the perturbations has a significant increase, the characteristics of the flow like the mixing width, vorticity, and circulation are close to those of a uniform flow. PMID- 23368051 TI - Decay of Batchelor and Saffman rotating turbulence. AB - The decay rate of isotropic and homogeneous turbulence is known to be affected by the large-scale spectrum of the initial perturbations, associated with at least two canonical self-preserving solutions of the von Karman-Howarth equation: the so-called Batchelor and Saffman spectra. The effect of long-range correlations in the decay of anisotropic flows is less clear, and recently it has been proposed that the decay rate of rotating turbulence may be independent of the large-scale spectrum of the initial perturbations. We analyze numerical simulations of freely decaying rotating turbulence with initial energy spectra ~k^{4} (Batchelor turbulence) and ~k^{2} (Saffman turbulence) and show that, while a self-similar decay can not be identified for the total energy, the decay is indeed affected by long-range correlations. The decay of two- and three-dimensional modes follows distinct power laws in each case, which are consistent with predictions derived from the anisotropic von Karman-Howarth equation, and with conservation of anisotropic integral quantities by the flow evolution. PMID- 23368052 TI - Numerical study of viscosity and inertial effects on tank-treading and tumbling motions of vesicles under shear flow. AB - An inextensible vesicle under shear flow experiences a tank-treading motion on its membrane if the viscosity contrast between the interior and exterior fluids is small. Above a critical threshold of viscosity contrast, the vesicle undergoes a tumbling bifurcation. In this paper, we extend our previous work [Kim and Lai, J. Comput. Phys. 229, 4840 (2010)] to the case of different viscosity and investigate the transition between the tank-treading and tumbling motions in detail. The present numerical results are in a good agreement with other numerical and theoretical studies qualitatively. In addition, we study the inertial effect on this transition and find that the inertial effect might inhibit the tumbling motion in favor of the tank-treading motion, which is observed recently in the literature. The critical viscosity contrast for the transition to the tumbling motion usually increases as the reduced area increases in the Stokes regime. However, we surprisingly observe that the critical viscosity contrast decreases as the reduced area increases to some point in the flow of slightly higher Reynolds number. Our numerical result also shows that the inertial effect has stronger inhibition to tumbling motion when the reduced area is small. PMID- 23368053 TI - Theory for large-amplitude electrostatic ion shocks in quantum plasmas. AB - We present a generalized nonlinear theory for large-amplitude electrostatic (ES) ion shocks in collisional quantum plasmas composed of mildly coupled degenerate electron fluid of arbitrary degeneracy and nondegenerate strongly correlated ion fluid with arbitrary atomic number. For our purposes, we use the inertialess electron momentum equation including the electrostatic force, pressure gradient, and relevant quantum forces, as well as a generalized viscoelastic ion momentum (GVIM) equation for strongly correlated nondegenerate ions. The ion continuity equation, in the quasineutral approximation, then closes our nonlinear system of equations. When the electric field force is eliminated from the GVIM equation by using the inertialess electron momentum equation, we then obtain a GVIM and ion continuity equations, which exhibit nonlinear couplings between the ion number density and the ion fluid velocity. The pair of nonlinear equations is numerically solved to study the dynamics of arbitrarily-large-amplitude planar and nonplanar ES shocks arising from a balance between harmonic generation nonlinearities and the ion fluid viscosity for a wide range of plasma mass densities and ion atomic numbers that are relevant for the cores of giant planets (viz., Jupiter) and compact stars (viz., white dwarfs). Our numerical results reveal that the ES shock density profiles strongly depend on the plasma number density and composition (the atomic-number) parameters. Furthermore, ion density perturbations propagate with Mach numbers which significantly depend on the studied plasma fractional parameters. It is concluded that the dynamics of the ES shocks in the superdense degenerate plasma is quite different in the core of a white dwarf star from that in the lower density crust region. PMID- 23368054 TI - Thermodynamics of atomic and ionized hydrogen: analytical results versus equation of-state tables and Monte Carlo data. AB - We compute thermodynamical properties of a low-density hydrogen gas within the physical picture, in which the system is described as a quantum electron-proton plasma interacting via the Coulomb potential. Our calculations are done using the exact scaled low-temperature (SLT) expansion, which provides a rigorous extension of the well-known virial expansion-valid in the fully ionized phase-into the Saha regime where the system is partially or fully recombined into hydrogen atoms. After recalling the SLT expansion of the pressure [A. Alastuey et al., J. Stat. Phys. 130, 1119 (2008)], we obtain the SLT expansions of the chemical potential and of the internal energy, up to order exp(-|E_{H}|/kT) included (E_{H}?-13.6 eV). Those truncated expansions describe the first five nonideal corrections to the ideal Saha law. They account exactly, up to the considered order, for all effects of interactions and thermal excitations, including the formation of bound states (atom H, ions H^{-} and H_{2}^{+}, molecule H_{2},?) and atom-charge and atom-atom interactions. Among the five leading corrections, three are easy to evaluate, while the remaining ones involve well-defined internal partition functions for the molecule H_{2} and ions H^{-} and H_{2}^{+}, for which no closed-form analytical formula exist currently. We provide accurate low temperature approximations for those partition functions by using known values of rotational and vibrational energies. We compare then the predictions of the SLT expansion, for the pressure and the internal energy, with, on the one hand, the equation-of-state tables obtained within the opacity program at Livermore (OPAL) and, on the other hand, data of path integral quantum Monte Carlo (PIMC) simulations. In general, a good agreement is found. At low densities, the simple analytical SLT formulas reproduce the values of the OPAL tables up to the last digit in a large range of temperatures, while at higher densities (rho~10^{-2} g/cm^{3}), some discrepancies among the SLT, OPAL, and PIMC results are observed. PMID- 23368055 TI - Quantitative comparison of the isotropic and anisotropic Maxwellian velocity space distribution function models in a dusty plasma. AB - Measurements of the velocity space distribution in a weakly coupled dusty plasma are modeled with both the spherically symmetric Maxwellian probability distribution function and the ellipsoidally symmetric trinormal probability distribution function. The effectiveness of the two models is compared quantitatively using an application of Bayesian probability theory which shows that the anisotropy included in the trinormal model provides a much improved description of the system. PMID- 23368056 TI - Nonlinear dust-acoustic solitary waves in strongly coupled dusty plasmas. AB - Dust-acoustic waves are investigated in a three-component plasma consisting of strongly coupled dust particles and Maxwellian electrons and ions. A fluid model approach is used, with the effects of strong coupling being accounted for by an effective electrostatic "pressure" which is a function of the dust number density and the electrostatic potential. Both linear and weakly nonlinear cases are considered by derivation and analysis of the linear dispersion relation and the Korteweg-de Vries equation, respectively. In contrast to previous studies using this model, this paper presents the results arising from an expansion of the dynamical form of the electrostatic pressure, accounting for the variations in its value in the vicinity of the wave. PMID- 23368057 TI - Inhomogeneous kinetic effects related to intermittent magnetic discontinuities. AB - A connection between kinetic processes and two-dimensional intermittent plasma turbulence is observed using direct numerical simulations of a hybrid Vlasov Maxwell model, in which the Vlasov equation is solved for protons, while the electrons are described as a massless fluid. During the development of turbulence, the proton distribution functions depart from the typical configuration of local thermodynamic equilibrium, displaying statistically significant non-Maxwellian features. In particular, temperature anisotropy and distortions are concentrated near coherent structures, generated as the result of the turbulent cascade, such as current sheets, which are nonuniformly distributed in space. Here, the partial variance of increments (PVI) method has been employed to identify high magnetic stress regions within a two-dimensional turbulent pattern. A quantitative association between non-Maxwellian features and coherent structures is established. PMID- 23368058 TI - Hugoniot measurements of double-shocked precompressed dense xenon plasmas. AB - The current partially ionized plasmas models for xenon show substantial differences since the description of pressure and thermal ionization region becomes a formidable task, prompting the need for an improved understanding of dense xenon plasmas behavior at above 100 GPa. We performed double-shock compression experiments on dense xenon to determine accurately the Hugoniot up to 172 GPa using a time-resolved optical radiation method. The planar strong shock wave was produced using a flyer plate impactor accelerated up to ~6 km/s with a two-stage light-gas gun. The time-resolved optical radiation histories were acquired by using a multiwavelength channel optical transience radiance pyrometer. Shock velocity was measured and mass velocity was determined by the impedance-matching methods. The experimental equation of state of dense xenon plasmas are compared with the self-consistent fluid variational calculations of dense xenon in the region of partial ionization over a wide range of pressures and temperatures. PMID- 23368059 TI - Onset of treelike patterns in negative streamers. AB - We present analytical and numerical studies of the initial stage of the branching process based on an interface dynamics streamer model in the fully three dimensional case. This model follows from fundamental considerations on charge production by impact ionization and balance laws, and leads to an equation for the evolution of the interface between ionized and nonionized regions. We compare some experimental patterns with the numerically simulated ones, and give an explicit expression for the growth rate of harmonic modes associated with the perturbation of a symmetrically expanding discharge. By means of full numerical simulation, the splitting and formation of characteristic treelike patterns of electric discharges is observed and described. PMID- 23368060 TI - Electron acoustic shock waves in a collisional plasma. AB - A nonlinear analysis for the finite amplitude electron acoustic wave (EAW) is considered in a collisional plasma. The fluid model is used to describe the two temperature electron species in a fixed ion background. In general, in electron ion plasma, the presence of wave nonlinearity, dispersion, and dissipation (arising from fluid viscosity) give rise to the Korteweg-de Vries Burgers (KdVB) equation which exhibits shock wave. In this work, it is shown that the dissipation due to the collision between electron and ion in the presence of collective phenomena (plasma current) can also introduce an anomalous dissipation that causes the Burgers term and thus leads to the generation of electron acoustic shock wave. Both analytical and numerical analysis show the formation of transient shock wave. Relevance of the results are discussed in the context of space plasma. PMID- 23368061 TI - Exploding-wire experiments and theory for metal conductivity evaluation in the sub-eV regime. AB - Copper and silver wires are subjected to pulsed high current densities producing high density metal plasma in the sub-eV regime with atmospheric air as a background gas. Numerical simulation via application of the one-dimensional magnetohydrodynamic partial differential equations solved simultaneously with the constraining circuit equations is presented. The simulations require accurate knowledge of the material equation of state (EOS) and transport properties; the LANL sesame database is applied for the EOS in all cases. Two electrical conductivity models are applied. First, the Lee-More-Desjarlais (LMD) and its modification, the quantum LMD (QLMD) conductivity, which have been well proven at higher temperatures, are applied. Simulations with the LMD and QLMD data indicate that the conductivity data as well as the MHD methodology are accurate in the sub eV regime of interest. A less computationally involved, empirical conductivity model is applied in the same regime to explore its temperature-density range of applicability compared to the more sophisticated model. PMID- 23368062 TI - Excitation of parasitic waves in forward-wave amplifiers with weak guiding fields. AB - To produce high-power coherent electromagnetic radiation at frequencies from microwaves up to terahertz, the radiation sources should have interaction circuits of large cross sections, i.e., the sources should operate in high-order modes. In such devices, the excitation of higher-order parasitic modes near cutoff where the group velocity is small and, hence, start currents are low can be a serious problem. The problem is especially severe in the sources of coherent, phase-controlled radiation, i.e., the amplifiers or phase-locked oscillators. This problem was studied earlier [Nusinovich, Sinitsyn, and Antonsen, Phys. Rev. E 82, 046404 (2010)] for the case of electron focusing by strong guiding magnetic fields. For many applications it is desirable to minimize these focusing fields. Therefore in this paper we analyze the problem of excitation of parasitic modes near cutoff in forward-wave amplifiers with weak focusing fields. First, we study the large-signal operation of such a device with a signal wave only. Then, we analyze the self-excitation conditions of parasitic waves near cutoff in the presence of the signal wave. It is shown that the main effect is the suppression of the parasitic wave in large-signal regimes. At the same time, there is a region of device parameters where the presence of signal waves can enhance excitation of parasitic modes. The role of focusing fields in such effects is studied. PMID- 23368063 TI - Nonsymmetric laser-pulse propagation in capillary tubes with variable radius. AB - A model describing the nonsymmetrical laser-pulse propagation in capillary tubes with inner radius smoothly varying with the capillary length is proposed. Using this model, the use of capillaries with specially profiled entrance sections (particularly cone matching elements) for improving the coupling of the laser energy into a capillary and avoiding capillary ablation is analyzed. It is shown that cone entrances with a sufficiently small angle (alpha_{cone}?10 mrad) help decrease the longitudinal energy flux and ablation of the entrance face of a capillary, but do not remove the requirements on the precision of laser-pulse focusing necessary to obtain regular laser fields, characterized by a symmetrical intensity distribution, centered on the capillary axis. To achieve regular laser fields without strong transverse gradients, the angle between the laser and capillary axes has to be smaller than 1 mrad for capillaries with an inner radius of the order of tens of microns. PMID- 23368064 TI - Small-scale dynamo at low magnetic Prandtl numbers. AB - The present-day Universe is highly magnetized, even though the first magnetic seed fields were most probably extremely weak. To explain the growth of the magnetic field strength over many orders of magnitude, fast amplification processes need to operate. The most efficient mechanism known today is the small scale dynamo, which converts turbulent kinetic energy into magnetic energy leading to an exponential growth of the magnetic field. The efficiency of the dynamo depends on the type of turbulence indicated by the slope of the turbulence spectrum v(l)?l^{theta}, where v(l) is the eddy velocity at a scale l. We explore turbulent spectra ranging from incompressible Kolmogorov turbulence with theta=1/3 to highly compressible Burgers turbulence with theta=1/2. In this work, we analyze the properties of the small-scale dynamo for low magnetic Prandtl numbers Pm, which denotes the ratio of the magnetic Reynolds number, Rm, to the hydrodynamical one, Re. We solve the Kazantsev equation, which describes the evolution of the small-scale magnetic field, using the WKB approximation. In the limit of low magnetic Prandtl numbers, the growth rate is proportional to Rm^{(1 theta)/(1+theta)}. We furthermore discuss the critical magnetic Reynolds number Rm_{crit}, which is required for small-scale dynamo action. The value of Rm_{crit} is roughly 100 for Kolmogorov turbulence and 2700 for Burgers. Furthermore, we discuss that Rm_{crit} provides a stronger constraint in the limit of low Pm than it does for large Pm. We conclude that the small-scale dynamo can operate in the regime of low magnetic Prandtl numbers if the magnetic Reynolds number is large enough. Thus, the magnetic field amplification on small scales can take place in a broad range of physical environments and amplify week magnetic seed fields on short time scales. PMID- 23368065 TI - Direct molecular dynamics simulation of liquid-solid phase equilibria for a three component plasma. AB - The neutron-rich isotope 22Ne may be a significant impurity in carbon and oxygen white dwarfs and could impact how the stars freeze. We perform molecular dynamics simulations to determine the influence of 22Ne in carbon-oxygen-neon systems on liquid-solid phase equilibria. Both liquid and solid phases are present simultaneously in our simulation volumes. We identify liquid, solid, and interface regions in our simulations using a bond angle metric. In general we find good agreement for the composition of liquid and solid phases between our MD simulations and the semianalytic model of Medin and Cumming. The trace presence of a third component, neon, does not appear to strongly impact the chemical separation found previously for two-component carbon and oxygen systems. This suggests that small amounts of 22Ne may not qualitatively change how the material in white dwarf stars freezes. However, we do find systematically lower melting temperatures (higher Gamma) in our MD simulations compared to the semianalytic model. This difference seems to grow with impurity parameter Q_{imp} and suggests a problem with simple corrections to the linear mixing rule for the free energy of multicomponent solid mixtures that is used in the semianalytic model. PMID- 23368066 TI - Discrete breathers in a nonlinear polarizability model of ferroelectrics. AB - We present a family of discrete breathers, which exists in a nonlinear polarizability model of ferroelectric materials. The core-shell model is set up in its nondimensionalized Hamiltonian form and its linear spectrum is examined in a range of temperatures. Subsequently, seeking localized solutions in the gap of the linear spectrum, we establish that numerically exact and potentially stable discrete breathers exist for a wide range of frequencies therein. In addition, we present nonlinear normal mode, extended spatial profile solutions from which the breathers bifurcate, as well as other associated phenomena such as the formation of phantom breathers within the model. The full bifurcation picture of the emergence and disappearance of the breathers is complemented by direct numerical simulations of their dynamical instability, when the latter arises. The effect of breathers on properties such as nonlinear dielectric response is discussed. PMID- 23368067 TI - Formation of a two-kink soliton pair in perturbed sine-Gordon models due to kink internal-mode instabilities. AB - The existence of two-kink soliton solutions in polynomial potentials was first reported by Bazeia et al. in a special type of scalar field systems [Phys. Rev. Lett. 91, 241601 (2003)]. A general feature of these potentials is that they possess two minima and a local metastable minimum between them. In the present work we investigate the appearance of this special kind of soliton in the sine Gordon model under the perturbation of a space-dependent force. We show that a pair of solitons is emitted during the process of kink breakup by internal mode instabilities. A possible explanation of these phenomena is an interplay between the solitons repelling interaction and the external force, resulting in a separation or a packing of several kinks. PMID- 23368068 TI - N-order bright and dark rogue waves in a resonant erbium-doped fiber system. AB - The rogue waves in a resonant erbium-doped fiber system governed by a coupled system of the nonlinear Schrodinger equation and the Maxwell-Bloch equation (NLS MB equations) are given explicitly by a Taylor series expansion about the breather solutions of the normalized slowly varying amplitude of the complex field envelope E, polarization p, and population inversion eta. The n-order breather solutions of the three fields are constructed using a Darboux transformation (DT) by assuming periodic seed solutions. Moreover, the n-order rogue waves are given by determinant forms with n+3 free parameters. Furthermore, the possible connection between our rouge waves and the generation of supercontinuum generation is discussed. PMID- 23368069 TI - Subwavelength plasmon solitons in a one-dimensional chain of coupled metallic nanorods. AB - We investigate analytically the subwavelength plasmonic lattice solitons excited in an optical plasmonic waveguide consisting of a chain of nanorods embedded in a Kerr nonlinear optical medium with strong near-field interactions. A nonlinear lattice equation with onsite and intersite nonlinear terms describing the plasmon wave propagating along the chain is derived. Stability analysis predicts that modulation instability can occur and that, correspondingly, conditions for localized modes will exist. We analyze the nonlinear excitations for genuine discreteness and nonlinearity enhanced by the fields strongly confined in the nanosized dielectric gaps. Based on a quasidiscreteness approach, we obtain a nonlinear Schrodinger equation and find that the system supports bright and dark soliton solutions in different frequency bands. It is also shown that the existence of different solitons depends strongly on the type of nonlinearity of the embedded medium. PMID- 23368070 TI - Discrete breather and its stability in a general discrete nonlinear Schrodinger equation with disorder. AB - By considering a general discrete nonlinear Schrodinger model with arbitrary values of nonlinearity power and disorder, the existence and stability of a discrete breather (DB) in a general nonlinear lattice are discussed. It is found that nonlinearity and disorder play important roles in determining the existence and stability of the DB. Nonlinearity (expressed by the interparticle interaction) and disorder can enhance the stability of the DB. Remarkably, we find that the DB is most stable when the nonlinearity power is equal to a critical value. The effects of nonlinearity, nonlinearity power, and disorder on the stability of the DB are strongly coupled. PMID- 23368071 TI - Mixed convolved action for classical and fractional-derivative dissipative dynamical systems. AB - The principle of mixed convolved action provides a new rigorous weak variational formalism for a broad range of initial value problems in mathematical physics and mechanics. Here, the focus is initially on classical single-degree-of-freedom oscillators incorporating either Kelvin-Voigt or Maxwell dissipative elements and then, subsequently, on systems that utilize fractional-derivative constitutive models. In each case, an appropriate mixed convolved action is formulated, and a corresponding weak form is discretized in time using temporal shape functions to produce an algorithm suitable for numerical solution. Several examples are considered to validate the mixed convolved action principles and to investigate the performance of the numerical algorithms. For undamped systems, the algorithm is found to be symplectic and unconditionally stable with respect to the time step. In the case of dissipative systems, the approach is shown to be robust and to be accurate with good convergence characteristics for both classical and fractional-derivative based models. As part of the derivations, some interesting results in the calculus of Caputo fractional derivatives also are presented. PMID- 23368072 TI - Crystalline nucleation in undercooled liquids: a Bayesian data-analysis approach for a nonhomogeneous Poisson process. AB - A Bayesian data-analysis approach to data sets of maximum undercooling temperatures recorded in repeated melting-cooling cycles of high-purity samples is proposed. The crystallization phenomenon is described in terms of a nonhomogeneous Poisson process driven by a temperature-dependent sample nucleation rate J(T). The method was extensively tested by computer simulations and applied to real data for undercooled liquid Ge. It proved to be particularly useful in the case of scarce data sets where the usage of binned data would degrade the available experimental information. PMID- 23368073 TI - Lande subtraction method with finite integration limits and application to strong field problems. AB - The Lande subtraction method has been widely used in Coulomb problems, but the momentum coordinate p?(0,infinity) is assumed. In past applications, a very large range of p was used for accuracy. We derive the supplementary formulation with p?(0,p_{max}) at reasonably small p_{max} for practical calculations. With the recipe, accuracy of the hydrogenic eigenspectrum is dramatically improved compared to the ordinary Lande formula by the same momentum grids. We apply the present formulation to strong-field atomic above-threshold ionization and high order harmonic generations. We demonstrate that the proposed momentum space method can be another practical theoretical tool for atomic strong-field problems in addition to the existing methods. PMID- 23368074 TI - No-slip boundary conditions and forced flow in multiparticle collision dynamics. AB - Multiparticle collision dynamics (MPCD) is a particle-based fluid simulation technique that is becoming increasingly popular for mesoscale fluid modeling. However, some confusion and conflicting results persist in literature regarding several important methodological details, in particular the enforcement of the no slip condition and thermostatting in forced flow. These issues persist in simple flows past stationary boundaries, which we exclusively focus on here. We discuss the parametrization of MPCD fluids and its consequences for fluid-solid boundaries in great detail, and show that the method of virtual particles proposed by Lamura et al. and adopted by many others is required only for parameter choices that lead to viscosities dominated by collisional contributions. We test several implementations of the virtual particle method and discuss how to completely eliminate slip at stationary boundaries. We also show that stochastic boundary reflection rules are inherently problematic for forced flow and suggest a possible remedy. Finally, we discuss the most robust way to achieve forced flow and evaluate several thermostatting methods in the process. All discussion is limited to solid objects that do not move as a result of collisions with MPCD particles (i.e., walls). However, the results can be extended to solutes that experience forces and torques due to interactions with MPCD particles (e.g., colloids). The detailed analysis presented for this simple case provides the level of rigor and accuracy to the MPCD method required for the study of more complex systems. PMID- 23368075 TI - Rotation algorithm: generation of Gaussian self-similar stochastic processes. AB - In this paper, we introduce a simple and practical method to generate Gaussian self-similar stochastic processes [fractional Gaussian noises (fGns) and fractional Brownian motions (fBms)] by interpolating between two known series of them. We apply the rotation algorithm to different cases including different pairs of fBms (fGns) and also different pairs each composed of an fBm and an fGn. Our results show that the sensitivity of our method for two fBms (fGns) is higher when approaching the series with a larger (smaller) Hurst exponent and, for the case with one fBm and one fGn by approaching the Hurst exponent of the selected fBm, the Hurst exponent of the produced series changes more. Surprisingly, by using this method, we can generate (positively and/or negatively) correlated series from two uncorrelated ones (one Brownian motion and one white Gaussian noise) or it is possible to generate uncorrelated signals (one or two depending on the choice of two input signals) from two correlated ones. For two fGns, using the rotation algorithm, the evolution starts from larger scales in the system, while for two fBms, the evolution starts from smaller scales in the system. PMID- 23368076 TI - Calibration of Boltzmann distribution priors in Bayesian data analysis. AB - The Boltzmann distribution is commonly used as a prior probability in Bayesian data analysis. Examples include the Ising model in statistical image analysis and the canonical ensemble based on molecular dynamics force fields in protein structure calculation. These models involve a temperature or weighting factor that needs to be inferred from the data. Bayesian inference stipulates to determine the temperature based on the model evidence. This is challenging because the model evidence, a ratio of two high-dimensional normalization integrals, cannot be calculated analytically. We outline a replica-exchange Monte Carlo scheme that allows us to estimate the model evidence by use of multiple histogram reweighting. The method is illustrated for an Ising model and examples in protein structure determination. PMID- 23368077 TI - Phase-field-crystal model of phase and microstructural stability in driven nanocrystalline systems. AB - We present a phase-field-crystal model for driven systems which describes competing effects between thermally activated diffusional processes and those driven by externally imposed ballistic events. The model demonstrates how the mesoscopic Enrique and Bellon [Phys. Rev. Lett. 84, 2885 (2000)] model of externally induced ballistic mixing can be incorporated into the atomistic phase field-crystal formalism. The combination of the two approaches results in a model capable of describing the microstructural and compositional evolution of a driven system while incorporating elastoplastic effects. The model is applied to the study of grain growth in nanocrystalline materials subjected to an external driving. PMID- 23368079 TI - Perturbation method to calculate the density of states. AB - Monte Carlo switching moves ("perturbations") are defined between two or more classical Hamiltonians sharing a common ground-state energy. The ratio of the density of states (DOS) of one system to that of another is related to the ensemble averages of the microcanonical acceptance probabilities of switching between these Hamiltonians, analogously to the case of Bennett's acceptance ratio method for the canonical ensemble [C. H. Bennett, J. Comput. Phys. 22, 245 (1976)]. Thus, if the DOS of one of the systems is known, one obtains those of the others and, hence, the partition functions. As a simple test case, the vapor pressure of an anharmonic Einstein crystal is computed, using the harmonic Einstein crystal as the reference system in one dimension; an auxiliary calculation is also performed in three dimensions. As a further example of the algorithm, the energy dependence of the ratio of the DOS of the square-well and hard-sphere tetradecamers is determined, from which the temperature dependence of the constant-volume heat capacity of the square-well system is calculated and compared with canonical Metropolis Monte Carlo estimates. For these cases and reference systems, the perturbation calculations exhibit a higher degree of convergence per Monte Carlo cycle than Wang-Landau (WL) sampling, although for the one-dimensional oscillator the WL sampling is ultimately more efficient for long runs. Last, we calculate the vapor pressure of liquid gold using an empirical Sutton-Chen many-body potential and the ideal gas as the reference state. Although this proves the general applicability of the method, by its inherent perturbation approach the algorithm is suitable for those particular cases where the properties of a related system are well known. PMID- 23368078 TI - Accuracy of a hybrid finite-element method for solving a scattering Schrodinger equation. AB - This hybrid method [finite-element discrete variable representation (FE-DVR)], introduced by Resigno and McCurdy [Phys. Rev. A 62, 032706 (2000)], uses Lagrange polynomials in each partition, rather than "hat" functions or Gaussian functions. These polynomials are discrete variable representation functions, and they are orthogonal under the Gauss-Lobatto quadrature discretization approximation. Accuracy analyses of this method are performed for the case of a one-dimensional Schrodinger equation with various types of local and nonlocal potentials for scattering boundary conditions. The accuracy is ascertained by a comparison with a spectral Chebyshev integral equation method, accurate to 1:10-11. For an accuracy of the phase shift of 1:10-8, the FE-DVR method is found to be 100 times faster than a sixth-order finite-difference method (Numerov), it is easy to program, and it can routinely achieve an accuracy of better than 1:10-8 for the numerical examples studied. PMID- 23368080 TI - Almost exact boundary condition for one-dimensional Schrodinger equations. AB - An explicit local boundary condition is proposed for finite-domain simulations of the linear Schrodinger equation on an unbounded domain. Based on an exact boundary condition in terms of the Bessel functions, it takes a simple form with 16 neighboring grid points, and it involves no empirical parameter. While the computing load is rather low, the proposed boundary condition is effective in reflection suppression, comparable to the exact convolution treatments. An extension to nonlinear Schrodinger equations is also proposed. Numerical comparisons clearly demonstrate the effectiveness of this ALmost EXact (ALEX) boundary condition for both the linear and the cubic nonlinear Schrodinger equations. PMID- 23368081 TI - Conservation-dissipation structure of chemical reaction systems. AB - In this Brief Report, we show that balanced chemical reaction systems governed by the law of mass action have an elegant conservation-dissipation structure. From this structure a number of important conclusions can be easily deduced. In particular, with the help of this structure we can rigorously justify the classical partial equilibrium approximation in chemical kinetics. PMID- 23368082 TI - Group chase and escape with some fast chasers. AB - We study group chase and escape with some fast chasers. In our model chasers look for the nearest target and move to one of the nearest sites in order to catch the target. On the other hand, targets try to escape from the nearest chaser. When a chaser catches a target, the target is removed from the system and the number of targets decreases. The lifetime of targets, at which all targets caught, decreases as t^{alpha} with increasing the number of chasers. When there are no fast chasers and the total number of chasers is small, the exponent alpha is large. When the total number of chasers is large, alpha becomes small. There is an optimal number of chasers to minimize the cost used in order to catch all targets. However, when we add a few fast chasers, the region with the large alpha vanishes. The optimal number of chasers vanishes, and the cost monotonically increases with increasing the number of chasers. PMID- 23368083 TI - Geometric properties of graph layouts optimized for greedy navigation. AB - The graph layouts used for complex network studies have been mainly developed to improve visualization. If we interpret the layouts in metric spaces such as Euclidean ones, however, the embedded spatial information can be a valuable cue for various purposes. In this work, we focus on encoding useful navigational information to geometric coordinates of vertices of spatial graphs, which is a reverse problem of harnessing geometric information for better navigation. In other words, the coordinates of the vertices are a map of the topology, not the other way around. We use a recently developed user-centric navigation protocol to explore spatial layouts of complex networks that are optimal for navigation. These layouts are generated with a simple simulated annealing optimization technique. We compare these layouts to others targeted at better visualization and discuss the spatial statistical properties of the optimized layouts for better navigability and its implication. PMID- 23368084 TI - Rheological studies of tautomerization kinetics in supercooled glibenclamide drug. AB - Rheological measurements have been applied to study the tautomerization of the pharmaceutically active compound glibenclamide. The rate constant and activation energy of the imidic-acid-amide transformation have been successfully determined by monitoring the evolution of shear viscosity. The kinetic parameters from rheological measurements agree reasonably well with the data previously obtained from dielectric spectroscopy. The present Brief Report demonstrates that rheology can provide a fast and precise way to characterize the reaction kinetics of tautomerization. PMID- 23368085 TI - Early regimes of capillary filling. AB - In this paper we analyze the inviscid regime (for which viscosity is unimportant and the flow occurs due to the balance between the capillary and the inertial effects) that invariably precedes the classical century-old Washburn regime during capillary filling. We demonstrate that a new nondimensional number, namely, the product of the Ohnesorge number and the ratio between the filling length (l) and the radius of the capillary (R), dictates the occurrence of this regime and the other well-known regimes in a capillary filling problem. We also identify that this inviscid regime occurs for the time that is of the order of the capillary time scale and, as has been quantified before [Quere, Eur. Phys. Lett. 39, 533 (1997); Joly, J. Chem. Phys. 135, 214705 (2011)], is characterized by the filling length being linearly proportional to the filling time. We establish the universality of this regime by pinpointing the existence of this regime (showing appropriate dependencies of the capillary radii and density) from existing experimental and Molecular Dynamics Simulation results that signify disparate ranges of length and time scales. PMID- 23368086 TI - Multiple scattering of electromagnetic waves by an array of parallel gyrotropic rods. AB - We study multiple scattering of electromagnetic waves by an array of parallel gyrotropic circular rods and show that such an array can exhibit fairly unusual scattering properties and provide, under certain conditions, a giant enhancement of the scattered field. Among the scattering patterns of such an array at its resonant frequencies, the most interesting is the distribution of the total field in the form of a perfect self-similar structure of chessboard type. The scattering characteristics of the array are found to be essentially determined by the resonant properties of its gyrotropic elements and cannot be realized for arrays of nongyrotropic rods. It is expected that the results obtained can lead to a wide variety of practical applications. PMID- 23368087 TI - Comment on "plasma oscillations and nonextensive statistics". AB - The paper authored by Lima et al. [Phys. Rev. E 61, 3260 (2000)] has discussed the dispersion relation and Landau damping of a Langmuir wave in the context of the nonextensive statistics proposed by Tsallis. However, the results obtained in this paper are not appropriate. In this comment on the paper we shall derive the correct analytic formulas for both the dispersion relation and Landau damping in the Tsallis formalism. We hope that this comment will be useful in providing the correct results. PMID- 23368088 TI - Cytogenetics of extramedullary manifestations in multiple myeloma. AB - Extramedullary disease in patients with multiple myeloma is a rare event, occurring mostly in advanced disease or relapse. Outcome is poor and prognostic factors predicting the development of extramedullary disease have not been defined. We investigated cytogenetic alterations of myeloma cells in different extramedullary manifestations by adapting the fluorescence in situ hybridization (FISH) technique in combination with cytoplasmic immunoglobulin staining to study the cytogenetics of plasma cell tumours on paraffin embedded material. Thirty six patients were investigated: 19 with extramedullary disease, 11 with skeletal extramedullary disease and six with solitary extramedullary plasmacytoma. The first two groups showed the following results: del(17p13) 32% vs. 27%, del(13q14) 35% vs. 27%, MYC-overrepresentation 28% vs. 18% and t(4;14) 37% vs. 18%. We detected an overall higher incidence of del(17p13) in both groups compared to data from bone marrow samples of multiple myeloma reported to date (range 7-16%). The solitary extramedullary plasmacytomas presented overall less cytogenetic aberrations than the other groups. Most important, three patients with extramedullary disease and one with skeletal extramedullary disease presented different FISH findings in the extramedullary tumour compared to their bone marrow plasma cells. del(17p13), occurring additional in three of four cases, seems a strong marker for extramedullary progression of myeloma. PMID- 23368089 TI - Cardiovascular genomics. AB - PURPOSE: This article provides an update on cardiovascular genomics using three clinically relevant exemplars, including myocardial infarction (MI) and coronary artery disease (CAD), stroke, and sudden cardiac death (SCD). ORGANIZATIONAL CONSTRUCT: Recent advances in cardiovascular genomic research, testing, and clinical implications are presented. METHODS: Genomic nurse experts reviewed and summarized recent salient literature to provide updates on three selected cardiovascular genomic conditions. FINDINGS: Research is ongoing to discover comprehensive genetic markers contributing to many common forms of cardiovascular disease (CVD), including MI and stroke. However, genomic technologies are increasingly being used clinically, particularly in patients with long QT syndrome (LQTS) or hypertrophic cardiomyopathy (HCM) who are at risk for SCD. CONCLUSIONS: Currently, there are no clinically recommended genetic tests for many common forms of CVD even though direct-to-consumer genetic tests are being marketed to healthcare providers and the general public. On the other hand, genetic testing for patients with certain single gene conditions, including channelopathies (e.g., LQTS) and cardiomyopathies (e.g., HCM), is recommended clinically. CLINICAL RELEVANCE: Nurses play a pivotal role in cardiogenetics and are actively engaged in direct clinical care of patients and families with a wide variety of heritable conditions. It is important for nurses to understand current development of cardiovascular genomics and be prepared to translate the new genomic knowledge into practice. PMID- 23368091 TI - Primary hepatocyte cultures as prominent in vitro tools to study hepatic drug transporters. AB - Before any drug can be placed on the market, drug efficacy and safety must be ensured through rigorous testing. Animal models are used for this purpose, though currently increasing attention goes to the use of alternative in vitro systems. In particular, liver-based testing platforms that allow the prediction of pharmacokinetic (PK) and pharmacotoxicological properties during the early phase of drug development are of interest. They also enable the screening of potential effects on hepatic drug transporters. The latter are known to affect drug metabolism and disposition, thereby possibly underlying drug-drug interactions, which, in turn, may result in liver toxicity. Clearly, stable in vivo-like functional expression of drug transporters in hepatic in vitro settings is a prerequisite to be applicable in routine PK and pharmacotoxicological testing. In the first part of the article, an updated overview of hepatic drug transporters is provided, followed by a state-of-the-art review of drug-transporter production and activity in primary hepatocyte cultures (PHCs), being the gold-standard in vitro system. Specific focus is hereby put on strategies to maintain long-term functional expression, in casu of drug transporters, in these systems. In the second part, the use of PHCs to assess hepatobiliary transport and transporter mediated interactions is outlined. PMID- 23368090 TI - Regulated proteolysis of a transcription factor complex is critical to cell cycle progression in Caulobacter crescentus. AB - Cell cycle transitions are often triggered by the proteolysis of key regulatory proteins. In Caulobacter crescentus, the G1-S transition involves the degradation of an essential DNA-binding response regulator, CtrA, by the ClpXP protease. Here, we show that another critical cell cycle regulator, SciP, is also degraded during the G1-S transition, but by the Lon protease. SciP is a small protein that binds directly to CtrA and prevents it from activating target genes during G1. We demonstrate that SciP must be degraded during the G1-S transition so that cells can properly activate CtrA-dependent genes following DNA replication initiation and the reaccumulation of CtrA. These results indicate that like CtrA, SciP levels are tightly regulated during the Caulobacter cell cycle. In addition, we show that formation of a complex between CtrA and SciP at target promoters protects both proteins from their respective proteases. Degradation of either protein thus helps trigger the destruction of the other, facilitating a cooperative disassembly of the complex. Collectively, our results indicate that ClpXP and Lon each degrade an important cell cycle regulator, helping to trigger the onset of S phase and prepare cells for the subsequent programmes of gene expression critical to polar morphogenesis and cell division. PMID- 23368092 TI - Sarcoid and the nail: review of the literature. AB - Nail involvement in sarcoidosis is rare, but its presence is often associated with chronic systemic disease. We have reviewed all 33 reported cases of nail involvement with sarcoidosis, including our own case. Nail changes in sarcoidosis, while rare, can include dystrophy (n=10, 30%), onycholysis (n=7, 21%), subungual hyperkeratosis (n=7, 21%), nail hyperkeratosis (n=2, 6%) and longitudinal ridging (n=8, 24%). All reported cases of nail sarcoidosis occurred in the setting of systemic involvement. In almost half of the cases, bony cysts were noted on radiological examination. The presence of nail dystrophy in a patient with sarcoidosis should therefore prompt radiological examination and investigation for systemic involvement. PMID- 23368093 TI - Discovery and analysis of consistent active sub-networks in cancers. AB - Gene expression profiles can show significant changes when genetically diseased cells are compared with non-diseased cells. Biological networks are often used to identify active subnetworks (ASNs) of the diseases from the expression profiles to understand the reason behind the observed changes. Current methodologies for discovering ASNs mostly use undirected PPI networks and node centric approaches. This can limit their ability to find the meaningful ASNs when using integrated networks having comprehensive information than the traditional protein-protein interaction networks. Using appropriate scoring functions to assess both genes and their interactions may allow the discovery of better ASNs. In this paper, we present CASNet, which aims to identify better ASNs using (i) integrated interaction networks (mixed graphs), (ii) directions of regulations of genes, and (iii) combined node and edge scores. We simplify and extend previous methodologies to incorporate edge evaluations and lessen their sensitivity to significance thresholds. We formulate our objective functions using mixed integer programming (MIP) and show that optimal solutions may be obtained. We compare the ASNs obtained by CASNet and similar other approaches to show that CASNet can often discover more meaningful and stable regulatory ASNs. Our analysis of a breast cancer dataset finds that the positive feedback loops across 7 genes, AR, ESR1, MYC, E2F2, PGR, BCL2 and CCND1 are conserved across the basal/triple negative subtypes in multiple datasets that could potentially explain the aggressive nature of this cancer subtype. Furthermore, comparison of the basal subtype of breast cancer and the mesenchymal subtype of glioblastoma ASNs shows that an ASN in the vicinity of IL6 is conserved across the two subtypes. This result suggests that subtypes of different cancers can show molecular similarities indicating that the therapeutic approaches in different types of cancers may be shared. PMID- 23368094 TI - Inferring evolution of gene duplicates using probabilistic models and nonparametric belief propagation. AB - BACKGROUND: Gene duplication, followed by functional evolution of duplicate genes, is a primary engine of evolutionary innovation. In turn, gene expression evolution is a critical component of overall functional evolution of paralogs. Inferring evolutionary history of gene expression among paralogs is therefore a problem of considerable interest. It also represents significant challenges. The standard approaches of evolutionary reconstruction assume that at an internal node of the duplication tree, the two duplicates evolve independently. However, because of various selection pressures functional evolution of the two paralogs may be coupled. The coupling of paralog evolution corresponds to three major fates of gene duplicates: subfunctionalization (SF), conserved function (CF) or neofunctionalization (NF). Quantitative analysis of these fates is of great interest and clearly influences evolutionary inference of expression. These two interrelated problems of inferring gene expression and evolutionary fates of gene duplicates have not been studied together previously and motivate the present study. RESULTS: Here we propose a novel probabilistic framework and algorithm to simultaneously infer (i) ancestral gene expression and (ii) the likely fate (SF, NF, CF) at each duplication event during the evolution of gene family. Using tissue-specific gene expression data, we develop a nonparametric belief propagation (NBP) algorithm to predict the ancestral expression level as a proxy for function, and describe a novel probabilistic model that relates the predicted and known expression levels to the possible evolutionary fates. We validate our model using simulation and then apply it to a genome-wide set of gene duplicates in human. CONCLUSIONS: Our results suggest that SF tends to be more frequent at the earlier stage of gene family expansion, while NF occurs more frequently later on. PMID- 23368095 TI - Discriminating the effects of phylogenetic hypothesis, tree resolution and clade age estimates on phylogenetic signal measurements. AB - Understanding how species traits evolved over time is the central question to comprehend assembly rules that govern the phylogenetic structure of communities. The measurement of phylogenetic signal (PS) in ecologically relevant traits is a first step to understand phylogenetically structured community patterns. The different methods available to estimate PS make it difficult to choose which is most appropriate. Furthermore, alternative phylogenetic tree hypotheses, node resolution and clade age estimates might influence PS measurements. In this study, we evaluated to what extent these parameters affect different methods of PS analysis, and discuss advantages and disadvantages when selecting which method to use. We measured fruit/seed traits and flowering/fruiting phenology of endozoochoric species occurring in Southern Brazilian Araucaria forests and evaluated their PS using Mantel regressions, phylogenetic eigenvector regressions (PVR) and K statistic. Mantel regressions always gave less significant results compared to PVR and K statistic in all combinations of phylogenetic trees constructed. Moreover, a better phylogenetic resolution affected PS, independently of the method used to estimate it. Morphological seed traits tended to show higher PS than diaspores traits, while PS in flowering/fruiting phenology depended mostly on the method used to estimate it. This study demonstrates that different PS estimates are obtained depending on the chosen method and the phylogenetic tree resolution. This finding has implications for inferences on phylogenetic niche conservatism or ecological processes determining phylogenetic community structure. PMID- 23368096 TI - Recent developments in gastric endoscopic submucosal dissection: towards the era of endoscopic resection of layers deeper than the submucosa. AB - With technical advances in endoscopic submucosal dissection (ESD), several variations of endoscopic procedure derived from ESD and fusion procedures of endoscopy and laparoscopy for upper gastrointestinal submucosal tumor and cancer have recently been developed. The former includes endoscopic muscularis dissection (EMD), submucosal endoscopic tumor resection (SET), endoscopic submucosal tunnel dissection (ESTD) and endoscopic full-thickness resection (EFTR), and the latter includes laparoscopic and endoscopic cooperative surgery (LECS), laparoscopy-assisted endoscopic full-thickness resection (LAEFR), and laparoscopic lymphadenectomy without gastrectomy following ESD. In the present article, recent developments in gastric ESD and advanced procedures derived from ESD are discussed. PMID- 23368097 TI - Computer-aided drug design, synthesis and evaluation of new anti-cancer drugs. PMID- 23368098 TI - Classification models for anticancer activity. AB - Despite significant research in understanding of neoplastic diseases, the success rate for oncology drugs is relatively very low. A major challenge before the scientific community is to design new chemical entities that will be highly selective for cancer cells so as to minimize side effects. Classification models (CMs) models play a prominent role in prediction of the biological properties of newly designed compounds before their synthesis and prevent non-optimal use of resources. Though correlation models far outnumber classification models for development of various therapeutic agents but the significance of classification models for development of anti-cancer agents can not be underestimated. Various techniques employed for development of classification models for anti-cancer activity have been briefly reviewed. Moreover, successful use of some of these classification techniques for the development of models for anti-proliferative activity has been illustrated using a data set comprising of 53 analogues of N Benzoylated phenoxazines and phenothiazines. Resulting classification models with high degree of accuracy can play a vital role in providing lead structures for the development of novel anti-proliferative agents for cancer chemotherapy. PMID- 23368099 TI - Fragment-based optimization of small molecule CXCL12 inhibitors for antagonizing the CXCL12/CXCR4 interaction. AB - The chemokine CXCL12 and its G protein-coupled receptor (GPCR) CXCR4 are high priority clinical targets because of their involvement in metastatic cancers (also implicated in autoimmune disease and cardiovascular disease). Because chemokines interact with two distinct sites to bind and activate their receptors, both the GPCRs and chemokines are potential targets for small molecule inhibition. A number of chemokines have been validated as targets for drug development, but virtually all drug discovery efforts focus on the GPCRs. However, all CXCR4 receptor antagonists with the exception of MSX-122 have failed in clinical trials due to unmanageable toxicities, emphasizing the need for alternative strategies to interfere with CXCL12/CXCR4-guided metastatic homing. Although targeting the relatively featureless surface of CXCL12 was presumed to be challenging, focusing efforts at the sulfotyrosine (sY) binding pockets proved successful for procuring initial hits. Using a hybrid structure-based in silico/NMR screening strategy, we recently identified a ligand that occludes the receptor recognition site. From this initial hit, we designed a small fragment library containing only nine tetrazole derivatives using a fragment-based and bioisostere approach to target the sY binding sites of CXCL12. Compound binding modes and affinities were studied by 2D NMR spectroscopy, X-ray crystallography, molecular docking and cell-based functional assays. Our results demonstrate that the sY binding sites are conducive to the development of high affinity inhibitors with better ligand efficiency (LE) than typical protein-protein interaction inhibitors (LE <= 0.24). Our novel tetrazole-based fragment 18 was identified to bind the sY21 site with a K(d) of 24 MUM (LE = 0.30). Optimization of 18 yielded compound 25 which specifically inhibits CXCL12-induced migration with an improvement in potency over the initial hit 9. The fragment from this library that exhibited the highest affinity and ligand efficiency (11: K(d) = 13 MUM, LE = 0.33) may serve as a starting point for development of inhibitors targeting the sY12 site. PMID- 23368100 TI - CORAL: classification model for predictions of anti-sarcoma activity. AB - A modified version of the CORAL software (http://www.insilico.eu/coral) allows building up the classification model for the case of the Yes/No data on the anti sarcoma activity of organic compounds. Three random splits into the sub-training, calibration, and test sets of the data for 3017 compounds were examined. The performance of the proposed approach is satisfactory. The average values of the statistical characteristics for external test set on three random splits are as follows: n=1173-1234, sensitivity = 0.8903+/-0.0390, specificity = 0.9869+/ 0.0013, and accuracy = 0.9759+/-0.0043. Mechanistic interpretation of the suggested model is discussed. PMID- 23368101 TI - Abelson tyrosine-protein kinase 1 as principal target for drug discovery against leukemias. Role of the current computer-aided drug design methodologies. AB - The discovery of anti-cancer agents is an area which continues in accelerated expansion. Leukemias (Lkms) are among the most investigated cancers due to its high and dominant prevalence in children. Computer-aided drug design (CADD) methodologies have been extremely important for the discovery of potent anti-Lkms agents, providing essential insights about the molecular patterns which could be involved in the appearance and development of anti-Lkms activity. The present review is focused on the role of the current CADD methodologies for the discovery of anti-Lkms agents with strong emphasis on the in silico prediction of inhibitors against the primary protein associated with the appearance of Lkms: Abelson tyrosine-protein kinase 1 (TPK-ABL1). In order to make a contribution to the field, we also developed a unified ligand-based approach by exploring Quantitative-Structure Activity Relationships (QSAR) studies. Here, we focused on the construction of two multi-targets (mt) QSAR models by employing a large and heterogeneous database of compounds. These models exhibited excellent statistical quality and predictive power to classifying more than 92% of inhibitors/ no inhibitors against seven proteins associated with Lkms, in both training and prediction sets. By using our unified ligand-based approach we identified several fragments as responsible for the anti-Lkms activity through inhibition of proteins, and new molecules were suggested as versatile inhibitors of the seven proteins under study. PMID- 23368102 TI - Biologically active 4-thiazolidinones: a review of QSAR studies and QSAR modeling of antitumor activity. AB - 4-Thiazolidinone is a promising scaffold for the search of new potential antibacterial, antiviral, antidiabetic and anticancer agents etc. SAR analysis of the most potent compounds and different activities evaluation provide a solid background for de novo design of novel drugs. Current review summarizes recent QSAR studies on the 4-thiazolidinones making the emphasis on both technical and interpretative sides of reported models. Several papers among them are devoted to the anticancer activity of 4-thiazolidinone derivatives and are reporting QSAR models that were obtained via multiple linear regressions (MLR). Additionally, a non-linear approach, namely Gaussian processes, has been applied to identify the relationships between 4-thiazolidinones structure and tumor cell growth inhibition. The interpretation of the reported model highlights the core template for the design of new highly-potent anticancer agents and proposes a hypothesis about key role of Hydrogen at the N-atom three bonds away from thiazolidine in the interaction with biotarget. PMID- 23368103 TI - SAR, QSAR and docking of anticancer flavonoids and variants: a review. AB - Flavonoids are phenolic compounds, secondary metabolites of plants that cause several benefits to our health, including helping the treatment against cancer. These pharmacological properties are associated with the ability of flavonoids in attenuating the generation of reactive oxygen species, acting as chelate compounds or affecting the oxi-redox cycle. In spite of the large number of information in term of SAR and QSAR, no recent review has tabulated and discussed in detail these data. In view of this, we bring here a detailed discussion of the structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) models. We have also analyzed the correlation between the chemical structure of flavonoids and analogues to their anticancer activities. A large number of methodologies have been used to identify the characteristics of these compounds with their potential anticancer: multiple linear regression, principal components analysis, comparative molecular field analysis, comparative molecular similarity indices analysis, partial least squares, neural networks, configuration of classification and regression trees, Free-Wilson, docking; using topological, structural and enthalpies' descriptors. We also discussed the use of docking models, together with QSAR models, for the virtual screening of anticancer flavonoids. The importance of docking models to the medicinal chemistry of anticancer flavonoids has increased in the last decade, especially to help in identifying the structural determinants responsible for the activity. We tabulated here the most important examples of virtual screening determined for anticancer flavonoids and we highlighted the structural determinants. The mode of action, the most potent anticancer flavonoids and hints for the structural design of anticancer flavonoids are revised in details and provided here. PMID- 23368104 TI - Advancement towards tin-based anticancer chemotherapeutics: structural modification and computer modeling approach to drug-enzyme interactions. AB - Three new triphenyltin(IV) complexes, viz., triphenylstannyl 2-((E)-(4-hydroxy-3 ((E)-((4-(methoxycarbonyl)phenyl)imino)methyl)phenyl)-diazenyl)benzoate (Ph(3)SnL(2)H: 2), methyl 2-((E)-(4-hydroxy-3-((E)-((4 (((triphenylstannyl)oxy)carbonyl)phenyl)imino)methyl)phenyl)diazenyl)benzoate (Ph(3)SnL(3)H: 3), and triphenylstannyl 2-((E)-(4-hydroxy-3-((E)-((4 (((triphenylstannyl)oxy)carbonyl)phenyl)imino)methyl)phenyl)diazenyl)benzoate ((Ph(3)Sn)(2)L(4)H: 4) were synthesized and characterized by spectroscopic ((1)H, (119)Sn NMR and IR) techniques in combination with elemental analysis. The (119)Sn NMR spectral data were recorded in a non-coordinating solvent and indicate tetrahedral coordination geometry in solution. In the solid state, a single-crystal X-ray diffraction analysis of the dinuclear complex (Ph(3)Sn)(2)L(4)H (4) revealed a monocapped tetrahedral coordination geometry with anisobidentate coordination modes of the carboxylate groups with average bond angles around the Sn atoms of 113.5 and 112.2 degrees , respectively. In vitro cytotoxicity studies were performed with all three complexes 2-4, along with a previously reported parent aquatriphenylstannyl complex, 2-((3-formyl-4 hydroxyphenyl)diazenyl)benzoate (Ph(3)SnL(1)H.OH(2) (1)) across a panel of human tumor cell lines, viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The screening results were compared with those from related triphenyltin(IV) carboxylates containing (i) imino (11-16) and (ii) diazenyl frameworks (1, 5-10). In general, complexes 2-4 exhibited good cytotoxic activity and among them, compound 4 was found to be the best performer, particularly for EVSA-T and MCF-7 cell lines. Additionally, 4 scored better activity than cisplatin (2-15 folds), 5 fluorouracil and etoposide across a panel of cell lines. Docking studies indicated that the diazenyl and imino nitrogen atoms, and the oxygen atoms of triphenyltin ester, methyl ester and phenolic group play an important role for the complexation of the organotin compounds in the active sites of enzymes such as ribonucleotide reductase (pdb ID: 4R1R), thymidylate synthase (pdb ID: 2G8D), thymidylate phosphorylase (pdb ID: 1BRW) and topoisomerase II (pdb ID: 1QZR). PMID- 23368105 TI - Radical scavengers as ribonucleotide reductase inhibitors. AB - This paper compiled all the previous reports on radical scavengers, an interesting class of ribonucleotide reductase inhibitors. We have highlighted three key research areas: chemical classification of radical scavengers, structural and functional aspects of the radical site, and progress in drug designing for radical scavengers. Under the chemical classification section, we have recorded the discovery of hydroxyurea followed by discussions on hydroxamic acids, amidoximes, hydroxyguanidines, and phenolic compounds. In the next section, we have compiled the structural information for the radical site obtained from different crystallographic and theoretical studies. Finally, we have included the reported ligand based and structure based drug-designing studies. PMID- 23368106 TI - Computational tools in the discovery of new G-quadruplex ligands with potential anticancer activity. AB - Guanine-rich sequences found at telomeres and oncogenes have the capacity to form G-quadruplex (G4) structures. It has been found a relationship between the ability to stabilizing G4 structures and anticancer activity. Guanine quadruplexes stabilization and its implication in cancer phenomena is a therapeutic target relatively recent. Computer-aided drug design has been a very useful tool for the search of new candidates. In last years, methodologies have improved with the development of the computational sciences. The hardware is also enhanced, new techniques are explored. NMR and X-ray information about different targets are discovered continually. The continuous augmentation of new powerful and comprehensive software's with this purpose is other significant factor that contributes to the discovering of new compounds. Nevertheless computer-aided drug design has not been vastly employed in the design of new compound with G4 stabilization activity. All things considered, this review will be focused on the influence of computational techniques on speeding up the discovery of new G4 ligands. PMID- 23368107 TI - Acoustic analog to the dynamical Casimir effect in a Bose-Einstein condensate. AB - We have modulated the density of a trapped Bose-Einstein condensate by changing the trap stiffness, thereby modulating the speed of sound. We observe the creation of correlated excitations with equal and opposite momenta, and show that for a well-defined modulation frequency, the frequency of the excitations is half that of the trap modulation frequency. PMID- 23368108 TI - Measurement of the homogeneous contact of a unitary Fermi gas. AB - By selectively probing the center of a trapped gas, we measure the local, or homogeneous, contact of a unitary Fermi gas as a function of temperature. Tan's contact, C, is proportional to the derivative of the energy with respect to the interaction strength and is thus an essential thermodynamic quantity for a gas with short-range correlations. Theoretical predictions for the temperature dependence of C differ substantially, especially near the superfluid transition, T(c), where C is predicted to either sharply decrease, sharply increase, or change very little. For T/T(F)>0.4, our measurements of the homogeneous gas contact show a gradual decrease of C with increasing temperature, as predicted by theory. We observe a sharp decrease in C at T/T(F)=0.16, which may be due to the superfluid phase transition. While a sharp decrease in C below T(c) is predicted by some many-body theories, we find that none of the predictions fully account for the data. PMID- 23368109 TI - Entanglement and sources of magnetic anisotropy in radical pair-based avian magnetoreceptors. AB - One of the principal models of magnetic sensing in migratory birds rests on the quantum spin dynamics of transient radical pairs created photochemically in ocular cryptochrome proteins. We consider here the role of electron spin entanglement and coherence in determining the sensitivity of a radical pair-based geomagnetic compass and the origins of the directional response. It emerges that the anisotropy of radical pairs formed from spin-polarized molecular triplets could form the basis of a more sensitive compass sensor than one founded on the conventional hyperfine-anisotropy model. This property offers new and more flexible opportunities for the design of biologically inspired magnetic compass sensors. PMID- 23368110 TI - Instability of flat space enclosed in a cavity. AB - We consider a spherically symmetric self-gravitating massless scalar field enclosed inside a timelike worldtube R*S(3) with a perfectly reflecting wall. Numerical evidence is given that arbitrarily small generic initial data evolve into a black hole. PMID- 23368111 TI - Binary black-hole mergers in magnetized disks: simulations in full general relativity. AB - We present results from the first fully general relativistic, magnetohydrodynamic (MHD) simulations of an equal-mass black-hole binary (BHBH) in a magnetized, circumbinary accretion disk. We simulate both the pre- and postdecoupling phases of a BHBH-disk system and both "cooling" and "no-cooling" gas flows. Prior to decoupling, the competition between the binary tidal torques and the effective viscous torques due to MHD turbulence depletes the disk interior to the binary orbit. However, it also induces a two-stream accretion flow and mildly relativistic polar outflows from the BHs. Following decoupling, but before gas fills the low-density "hollow" surrounding the remnant, the accretion rate is reduced, while there is a prompt electromagnetic luminosity enhancement following merger due to shock heating and accretion onto the spinning BH remnant. This investigation, though preliminary, previews more detailed general relativistic, MHD simulations we plan to perform in anticipation of future, simultaneous detections of gravitational and electromagnetic radiation from a merging BHBH disk system. PMID- 23368112 TI - New window into stochastic gravitational wave background. AB - A stochastic gravitational wave background (SGWB) would gravitationally lens the cosmic microwave background (CMB) photons. We correct the results provided in existing literature for modifications to the CMB polarization power spectra due to lensing by gravitational waves. Weak lensing by gravitational waves distorts all four CMB power spectra; however, its effect is most striking in the mixing of power between the E mode and B mode of CMB polarization. This suggests the possibility of using measurements of the CMB angular power spectra to constrain the energy density (Omega(GW)) of the SGWB. Using current data sets (QUAD, WMAP, and ACT), we find that the most stringent constraints on the present Omega(GW) come from measurements of the angular power spectra of CMB temperature anisotropies. In the near future, more stringent bounds on Omega(GW) can be expected with improved upper limits on the B modes of CMB polarization. Any detection of B modes of CMB polarization above the expected signal from large scale structure lensing could be a signal for a SGWB. PMID- 23368114 TI - Bilayers of Rydberg atoms as a quantum simulator for unconventional superconductors. AB - In condensed matter, it is often difficult to untangle the effects of competing interactions, and this is especially problematic for superconductors. Quantum simulators may help: here we show how exploiting the properties of highly excited Rydberg states of cold fermionic atoms in a bilayer lattice can simulate electron phonon interactions in the presence of strong correlation--a scenario found in many unconventional superconductors. We discuss the core features of the simulator, and use numerics to compare with condensed matter analogues. Finally, we illustrate how to achieve a practical, tunable implementation of the simulation using "painted spot" potentials. PMID- 23368115 TI - Role of electronic excitations in ground-state-forbidden inelastic collisions between ultracold atoms and ions. AB - The role of electronic excitation in inelastic collisions between ultracold Ca atoms and Ba(+) ions, confined in a hybrid trap, is studied for the first time. Unlike previous investigations, this system is energetically precluded from undergoing inelastic collisions in its ground state, allowing a relatively simple experimental determination and interpretation of the influence of electronic excitation. It is found that while the electronic state of the ion can critically influence the inelastic collision rate, the polarizability mismatch of the neutral atom electronic states suppresses short-range collisions, and thus inelastic processes, involving electronically excited neutral atoms. As a result of these features, it is experimentally demonstrated that it is possible to mitigate inelastic collision loss mechanisms in these systems, marking an important step toward long-lived hybrid atom-ion devices. PMID- 23368116 TI - Magic radio-frequency dressing of nuclear spins in high-accuracy optical clocks. AB - A Zeeman-insensitive optical clock atomic transition is engineered when nuclear spins are dressed by a nonresonant radio-frequency field. For fermionic species as (87)Sr, (171)Yb, and (199)Hg, particular ratios between the radio-frequency driving amplitude and frequency lead to "magic" magnetic values where a net cancelation of the Zeeman clock shift and a complete reduction of first-order magnetic variations are produced within a relative uncertainty below the 10(-18) level. An Autler-Townes continued fraction describing a semiclassical radio frequency dressed spin is numerically computed and compared to an analytical quantum description including higher-order magnetic field corrections to the dressed energies. PMID- 23368117 TI - Positron binding to lithium excited states. AB - In the last 15 years hundreds of papers have been devoted to the study of positron-atom or positron-molecule interaction. A large body of evidence has accumulated showing that many atoms in their ground state can bind a positron forming an electronically stable system. Studies on the possibility that a positron binds to an atomic excited state, however, are scarce. The first atom that was proved able to bind a positron in its ground state is lithium. Surprisingly, nothing is known on the possibility that a positron could bind to one of its excited states. In this Letter we study the positron attachment to the 1s(2)2p (2)P(o), 1s2s2p (2)P(o) and 2p(3) (4)S(o) excited states of the lithium atom. While the (2)P(o) state cannot bind a positron, and the (4)S(o) could at most form a metastable state, a positron can attach to the (4)P(o) state of lithium forming a bound state with a binding energy of about 0.003 hartree. This state can alternatively be considered an excited state of the system e(+)Li and it could be, in principle, exploited in an experiment to detect e(+)Li, whose existence has been predicted theoretically but has not yet been observed experimentally. PMID- 23368118 TI - Strong coupling and long-range collective interactions in optomechanical arrays. AB - We investigate the collective optomechanics of an ensemble of scatterers inside a Fabry-Perot resonator and identify an optimized configuration where the ensemble is transmissive, in contrast to the usual reflective optomechanics approach. In this configuration, the optomechanical coupling of a specific collective mechanical mode can be several orders of magnitude larger than the single-element case, and long-range interactions can be generated between the different elements since light permeates throughout the array. This new regime should realistically allow for achieving strong single-photon optomechanical coupling with massive resonators, realizing hybrid quantum interfaces, and exploiting collective long range interactions in arrays of atoms or mechanical oscillators. PMID- 23368119 TI - Metascreen-based superdirective antenna in the optical frequency regime. AB - A metascreen designed to achieve near-field subwavelength focusing at a given frequency is shown to operate as a superdirective antenna in the vicinity of that frequency at the far field. A metascreen for microwave frequencies based on a simple perfect electrically conducting screen is initially used to explain the principle of operation as a superdirective antenna and to distinguish this operation mode from that resulting in near-field subwavelength focusing. A similar metascreen design based on a silver screen of a finite thickness is then used to demonstrate superdirectivity with nanoantennas in the optical frequency regime. PMID- 23368120 TI - Measurement of vibrational modes in single SiO2 nanoparticles using a tunable metal resonator with optical subwavelength dimensions. AB - Using a tunable optical subwavelength microcavity, we demonstrate controlled modification of the vibronic relaxation dynamics in a single SiO(2) nanoparticle. By varying the distance between the cavity mirrors we change the electromagnetic field mode structure around a single nanoparticle and the radiative transition probability from the lowest vibronic level of the electronically excited state to the progression of phonon levels in the electronic ground state. We demonstrate redistribution of the photoluminescence spectrum between zero-phonon and phonon assisted bands and modification of the excited state lifetime of the same individual SiO(2) particle measured at different cavity lengths. By comparing the experimental data with a theoretical model, we extract the quantum yield of a single SiO(2) nanoparticle. PMID- 23368121 TI - Experimental demonstration of a free-space cylindrical cloak without superluminal propagation. AB - We experimentally demonstrated an alternative approach of invisibility cloaking that can combine technical advantages of all current major cloaking strategies in a unified manner and thus can solve bottlenecks of individual strategies. A broadband cylindrical invisibility cloak in free space is designed based on scattering cancellation (the approach of previous plasmonic cloaking), and implemented with anisotropic metamaterials (a fundamental property of singular transformation cloaks). Particularly, nonsuperluminal propagation of electromagnetic waves, a superior advantage of non-Euclidian-transformation cloaks constructed with complex branch cuts, is inherited in this design, and thus is the reason of its relatively broad bandwidth. This demonstration provides the possibility for future practical implementation of cloaking devices at large scales in free space. PMID- 23368122 TI - Cascaded phase matching and nonlinear symmetry breaking in fiber frequency combs. AB - We report theoretical, numerical, and experimental studies of cascaded phase matching in fiber frequency combs and show how this mechanism is directly connected to the dynamics of supercontinuum generation. In particular, linking cascaded four-wave mixing with direct higher-order nonlinear processes allows us to derive a simple phase matching condition that governs nonlinear symmetry breaking in the presence of higher-order dispersion. We discuss how this mechanism provides a physical interpretation of soliton-induced Cherenkov radiation and associated spectral recoil in terms of phase-matched frequency mixing pumped by bichromatic pump pairs in the soliton spectrum. Theoretical and numerical predictions are confirmed via experiments using both quasicontinuous wave and picosecond pulse excitation. PMID- 23368123 TI - Simulation of charged systems in heterogeneous dielectric media via a true energy functional. AB - For charged systems in heterogeneous dielectric media, a key obstacle for molecular dynamics (MD) simulations is the need to solve the Poisson equation in the media. This obstacle can be bypassed using MD methods that treat the local polarization charge density as a dynamic variable, but such approaches require access to a true free energy functional, one that evaluates to the equilibrium electrostatic energy at its minimum. In this Letter, we derive the needed functional. As an application, we develop a Car-Parrinello MD method for the simulation of free charges present near a spherical emulsion droplet separating two immiscible liquids with different dielectric constants. Our results show the presence of nonmonotonic ionic profiles in the dielectric with a lower dielectric constant. PMID- 23368124 TI - Realization of all-optical multistate switching in an atomic coherent medium. AB - We have experimentally observed optical multistability (OM) in an optical ring cavity containing three-level Lambda-type Doppler-broadened rubidium atoms. The shape of the OM curve can be significantly modified by changing the power of the control laser field. An all-optical multistate switching or coding element is realized and flexibly controlled by adding a pulse sequence to the input (probe) intensity. PMID- 23368125 TI - Self-similar micron-size and nanosize drops of liquid generated by surface acoustic waves. AB - A planar surface acoustic wave on a solid substrate and its radiated sound into a static liquid drop produce time-averaged, exponentially decaying acoustic and electric Maxwell pressures near the contact line. These localized contact-line pressures are shown to generate two sequences of hemispherical satellite droplets at the tens of microns and submicron scales, both obeying self-similar exponential scaling but with distinct exponents that correspond to viscous dissipation and field leakage length scales, respectively. The acoustic pressure becomes dominant when the film thickness exceeds (1/4pi) of the surface acoustic wave wavelength and it affects the shape and stability of the mother drop. The Maxwell pressure of the nanodrops, which exceeds ten atmospheres, is sensitive to the contact angle. PMID- 23368126 TI - Strong near-field enhancement of radiative heat transfer between metallic surfaces. AB - Near-field heat transfer across a gap between plane-parallel tungsten layers in vacuo was studied experimentally with the temperature of the cold sample near 5 K and the temperature of the hot sample in the range 10-40 K as a function of the gap size d. At gaps smaller than one-third of the peak wavelength lambda(m) given by Wien's displacement law, the near-field effect was observed. In comparison with blackbody radiation, hundred times higher values of heat flux were achieved at d~1 MUm. Heat flux normalized to the radiative power transferred between black surfaces showed scaling (lambda(m)/d)(n), where n~2.6. This Letter describes the results of experiment and a comparison with present theory over 4 orders of magnitude of heat flux. PMID- 23368127 TI - Nondissipative saturation of the magnetorotational instability in thin disks. AB - A new nondissipative mechanism is proposed for the saturation of the axisymmetric magnetorotational (MRI) instability in thin Keplerian disks that are subject to an axial magnetic field. That mechanism relies on the energy transfer from the MRI to stable magnetosonic waves. Such mode interaction is enabled due to the vertical stratification of the disk that results in the discretization of its MRI spectrum, as well as by applying the appropriate boundary conditions. A second order Duffing-like amplitude equation for the initially unstable MRI modes is derived. The solutions of that equation exhibit bursty nonlinear oscillations with a constant amplitude that signifies the saturation level of the MRI. Those results are verified by a direct numerical solution of the full nonlinear reduced set of thin disk magnetohydrodynamics equations. PMID- 23368128 TI - Echo-enabled x-ray vortex generation. AB - A technique to generate high-brightness electromagnetic vortices with tunable topological charge at extreme ultraviolet and x-ray wavelengths is described. Based on a modified version of echo-enabled harmonic generation for free-electron lasers, the technique uses two lasers and two chicanes to produce high-harmonic microbunching of a relativistic electron beam with a corkscrew distribution that matches the instantaneous helical phase structure of the x-ray vortex. The strongly correlated electron distribution emerges from an efficient three dimensional recoherence effect in the echo-enabled harmonic generation transport line and can emit fully coherent vortices in a downstream radiator for access to new research in x-ray science. PMID- 23368129 TI - Dynamic ion structure factor of warm dense matter. AB - The dynamics of the ion structure in warm dense matter is determined by molecular dynamics simulations using an effective ion-ion potential. This potential is obtained from ab initio simulations and has a strong short-range repulsion added to a screened Coulomb potential. Models based on static or dynamic local field corrections are found to be insufficient to describe the data. An extended Mermin approach, a hydrodynamic model, and the method of moments with local constraints are capable of reproducing the numerical results but have rather limited predictive powers as they all need some numerical data as input. The method of moments is found to be the most promising. PMID- 23368130 TI - Simulations of magnetic field generation in unmagnetized plasmas via beat-wave current drive. AB - This work describes the scientific basis and associated simulation results for the magnetization of an unmagnetized plasma via beat-wave current drive. Two dimensional electromagnetic particle-in-cell simulations have been performed for a variety of angles between the injected waves to demonstrate beat-wave generation in agreement with theoretical predictions of the beat-wave wave vector and saturation time, revealing new 2D effects. The simulations clearly demonstrate electron acceleration by the beat waves and resultant current drive and magnetic field generation. The basic process depends entirely on the angle between the parent waves and the ratio of the beat-wave phase velocity to the electron thermal velocity. The wave to magnetic energy conversion efficiency of the cases examined is as high as 0.2%. The technique could enable novel plasma experiments in which the use of magnetic coils is infeasible. PMID- 23368131 TI - Cooperative-motion-induced structural evolution in dusty-plasma liquids with microheterogeneity: rupture, rotation, healing, and growth of ordered domains. AB - The cooperative motion induced structural evolution of the liquid with microheterogeneity is investigated in quasi-2D dusty plasma liquids, through direct optical visualization. A novel bond-dynamics analysis is used to further classify the robust cooperative 2D clusters into static, rotating, and drifting patches, beyond the earlier findings of the cooperative hopping strings and bands. The relative motion between two adjacent clusters causes the formation of a fractal network with narrow shear strips along the cluster interface. The rotation of the large ordered patch through rupturing into multiple rotating patches followed by the healing process, and the growth to a larger ordered patch by aligning the different lattice orientations of the adjacent ordered domains through patch rupturing, rotation, drifting, and merging are the key processes for the microstructural evolution. PMID- 23368132 TI - In situ visualization of birth and annihilation of grain boundaries in an Au nanocrystal. AB - The formation and vanishing processes of a low angle grain boundary (GB) in nanosized Au during tension and release of stress, respectively, were obsvered by in situ high resolution transmission electron microscopy. The nucleation of perfect dislocations led to the formation of a 15 degrees low angle GB inside an Au nanocrystal upon off-axial tensile loading (coupled uniaxial tensile and bending stress). Strikingly, the dislocations were completely annihilated accompanied with the disappearance of the GB after the removal of external stress, indicating that plastic bending is recoverable in the nanocrystal. The back force and surface stress played important roles in such a pseudoelastic behavior. This transient GB dynamics cannot be captured in ex situ experimental investigations. Such pseudoelastic bending deformation in nanosized crystals will have an important impact on the designing of nanomechanical devices with ultrahigh bending capability. PMID- 23368133 TI - Confirmation of the random tiling hypothesis for a decagonal quasicrystal. AB - Mechanisms that stabilize quasicrystals are much discussed but not finally resolved. We confirm the random tiling hypothesis and its predictions in a fully atomistic decagonal quasicrystal model by calculating the free energy and the phason elastic constants over a wide range of temperatures. The Frenkel-Ladd method is applied for the phonon part, and an approach of uncorrelated phason flips is applied for the configurational part. When lowering the temperature, a phase transition to an approximant occurs. Close to the transition temperature, one of the phason elastic constants becomes soft. PMID- 23368134 TI - Fragile-strong fluid crossover and universal relaxation times in a confined hard disk fluid. AB - We show that a system of hard disks confined to a narrow channel exhibits a fragile-strong fluid crossover located at the maximum of the isobaric heat capacity and that the relaxation times for different channel widths fall onto a single master curve when rescaled by the relaxation times and temperatures of the crossover. Calculations of the configurational entropy and the inherent structure equation of state find that the crossover is related to properties of the jamming landscape for the model but that the Adam-Gibbs relation does not predict the relaxation behavior. We also show that a facilitated dynamics description of the system, where kinetically excited regions are identified with local packing arrangements of the disks, successfully describes the fragile-strong crossover. PMID- 23368135 TI - Nuclear quantum effects affect bond orientation of water at the water-vapor interface. AB - Using combined theoretical and experimental approaches, we demonstrate that the bond orientation of water at the water-vapor interface depends markedly on the water isotope (H-D) composition. While the interfacial water structures of H(2)O and D(2)O are indistinguishable, the intramolecular symmetry breaking in HDO is directly reflected at the surface: the OD bonds preferably orient down towards the bulk water, whereas the OH bond tends to orient up into the vapor phase. Path integral molecular dynamics simulations show good agreement with surface-specific sum-frequency generation (SFG) spectroscopy results, revealing that the distinct interfacial bond orientations originate from nuclear quantum effects. The enhanced localization of the heavier D atom leads to stronger hydrogen bonds, giving rise to OD bonds pointing down into the bulk. PMID- 23368136 TI - Metastable wetting on superhydrophobic surfaces: continuum and atomistic views of the Cassie-Baxter-Wenzel transition. AB - In this Letter, we develop a continuum theory for the Cassie-Baxter-Wenzel (CB-W) transition. The proposed model accounts for the metastabilities in the wetting of rough hydrophobic surfaces, allows us to reconstruct the transition mechanism, and identifies the free energy barriers separating the CB and W states as a function of the liquid pressure. This information is crucial in the context of superhydrophobic surfaces, where there is interest in extending the duration of the metastable superhydrophobic CB state. The model is validated against free energy atomistic simulations. PMID- 23368137 TI - Spectral properties of correlated materials: local vertex and nonlocal two particle correlations from combined GW and dynamical mean field theory. AB - We present a fully self-consistent combined GW and dynamical mean field (DMFT) study of the extended two-dimensional Hubbard model. The inclusion of the local dynamical vertex stemming from the DMFT self-energy and polarization is shown to cure the known problems of self-consistent GW. We calculate momentum-resolved spectral functions, two-particle polarizations, and electron-loss spectra, as well as the effective dynamical interaction induced by nonlocal screening. The momentum-dependence introduced by GW into the extended DMFT description leads to a narrowing of the quasiparticle width and more pronounced Hubbard bands in the metallic regime as one approaches the charge-ordering transition. It further affects the shape of collective modes, giving rise to dispersive plasmon-like long-wavelength and stripe modes. PMID- 23368138 TI - Resonant addressing and manipulation of silicon vacancy qubits in silicon carbide. AB - Several systems in the solid state have been suggested as promising candidates for spin-based quantum information processing. In spite of significant progress during the last decade, there is a search for new systems with higher potential [D. DiVincenzo, Nat. Mater. 9, 468 (2010)]. We report that silicon vacancy defects in silicon carbide comprise the technological advantages of semiconductor quantum dots and the unique spin properties of the nitrogen-vacancy defects in diamond. Similar to atoms, the silicon vacancy qubits can be controlled under the double radio-optical resonance conditions, allowing for their selective addressing and manipulation. Furthermore, we reveal their long spin memory using pulsed magnetic resonance technique. All these results make silicon vacancy defects in silicon carbide very attractive for quantum applications. PMID- 23368139 TI - Spin-droplet state of an interacting 2D electron system. AB - We report thermodynamic magnetization measurements of two-dimensional electrons in several high-mobility Si metal-oxide-semiconductor field-effect transistors. We provide evidence for an easily polarizable electron state in a wide density range from insulating to deep into the metallic phase. The temperature and magnetic field dependence of the magnetization is consistent with the formation of large-spin droplets in the insulating phase. These droplets melt in the metallic phase with increasing density and temperature, though they survive up to large densities. PMID- 23368140 TI - Giant anisotropy of spin-orbit splitting at the bismuth surface. AB - We investigate the bismuth (111) surface by means of time and angle resolved photoelectron spectroscopy. The parallel detection of the surface states below and above the Fermi level reveals a giant anisotropy of the spin-orbit spitting. These strong deviations from the Rashba-like coupling cannot be treated in k.p perturbation theory. Instead, first principles calculations could accurately reproduce the experimental dispersion of the electronic states. Our analysis shows that the giant anisotropy of the spin-orbit splitting is due to a large out of plane buckling of the spin and orbital texture. PMID- 23368141 TI - Quasiparticle spectra from a nonempirical optimally tuned range-separated hybrid density functional. AB - We present a method for obtaining outer-valence quasiparticle excitation energies from a density-functional-theory-based calculation, with an accuracy that is comparable to that of many-body perturbation theory within the GW approximation. The approach uses a range-separated hybrid density functional, with an asymptotically exact and short-range fractional Fock exchange. The functional contains two parameters, the range separation and the short-range Fock fraction. Both are determined nonempirically, per system, on the basis of the satisfaction of exact physical constraints for the ionization potential and frontier-orbital many-electron self-interaction, respectively. The accuracy of the method is demonstrated on four important benchmark organic molecules: perylene, pentacene, 3,4,9,10-perylene-tetracarboxylic-dianydride (PTCDA), and 1,4,5,8-naphthalene tetracarboxylic-dianhydride (NTCDA). We envision that for the outer-valence excitation spectra of finite systems the approach could provide an inexpensive alternative to GW, opening the door to the study of presently out of reach large scale systems. PMID- 23368142 TI - Quantum oscillations in the topological superconductor candidate Cu(0.25)Bi2Se3. AB - Quantum oscillations are generally studied to resolve the electronic structure of topological insulators. In Cu(0.25)Bi(2)Se(3), the prime candidate of topological superconductors, quantum oscillations are still not observed in magnetotransport measurement. However, using torque magnetometry, quantum oscillations (the de Haas-van Alphen effect) were observed in Cu(0.25)Bi(2)Se(3). The doping of Cu in Bi(2)Se(3) increases the carrier density and the effective mass without increasing the scattering rate or decreasing the mean free path. In addition, the Fermi velocity remains the same in Cu(0.25)Bi(2)Se(3) as that in Bi(2)Se(3). Our results imply that the insertion of Cu does not change the band structure and that conduction electrons in Cu doped Bi(2)Se(3) sit in the linear Dirac-like band. PMID- 23368143 TI - Electronic subband reconfiguration in a d0-perovskite induced by strain-driven structural transformations. AB - It is well known that transport in lightly n-doped SrTiO(3) involves light and heavy electron bands. We have found that upon application of moderate quasi isotropic pressures, the relative positions of these subbands are changed by a few meV and, eventually, a band inversion occurs at ~1 kbar. Such effects are, however, suppressed in the closely related KTaO(3) perovskite. We show that the extremely subtle electronic reconfiguration in SrTiO(3) is triggered by strain induced structural transformations that are accompanied by remarkable mobility enhancements up to about DeltaMU/MU~300%. Our results provide a microscopic rationale for the recently discovered transport enhancement under strain and underscore the role of the internal structural degrees of freedom in the modulation of the perovskite electronic properties. PMID- 23368144 TI - Current resonances in graphene with time-dependent potential barriers. AB - A method is derived to solve the massless Dirac-Weyl equation describing electron transport in a monolayer of graphene with a scalar potential barrier U(x,t), homogeneous in the y direction, of arbitrary space and time dependence. Resonant enhancement of both electron backscattering and currents, across and along the barrier, is predicted when the modulation frequencies satisfy certain resonance conditions. These conditions resemble those for Shapiro steps of driven Josephson junctions. Surprisingly, we find a nonzero y component of the current for carriers of zero momentum along the y-axis. PMID- 23368145 TI - Charge transport in azobenzene-based single-molecule junctions. AB - Azobenzene-derivative molecules change their conformation as a result of a cis trans transition when exposed to ultraviolet or visible light irradiation and this is expected to induce a significant variation in the conductance of molecular devices. Despite extensive investigations carried out on this type of molecule, a detailed understanding of the charge transport for the two isomers is still lacking. We report a combined experimental and theoretical analysis of electron transport through azobenzene-derivative single-molecule break junctions with Au electrodes. Current-voltage and inelastic electron tunneling spectroscopy (IETS) measurements performed at 4.2 K are interpreted based on first-principles calculations of electron transmission and IETS spectra. This qualitative study unravels the origin of a slightly higher conductance of junctions with the cis isomer and demonstrates that IETS spectra of cis and trans forms show distinct vibrational fingerprints that can be used for identifying the isomer. PMID- 23368146 TI - Electronic strengthening of graphene by charge doping. AB - Graphene is known as the strongest 2D material in nature, yet we show that moderate charge doping of either electrons or holes can further enhance its ideal strength by up to ~17%, based on first-principles calculations. This unusual electronic enhancement, versus conventional structural enhancement, of the material's strength is achieved by an intriguing physical mechanism of charge doping counteracting the strain induced enhancement of the Kohn anomaly, which leads to an overall stiffening of the zone boundary K(1) phonon mode whose softening under strain is responsible for graphene failure. Electrons and holes work in the same way due to the high electron-hole symmetry around the Dirac point of graphene, while overdoping may weaken the graphene by softening other phonon modes. Our findings uncover another fascinating property of graphene with broad implications in graphene-based electromechanical devices. PMID- 23368147 TI - Coexistance of giant tunneling electroresistance and magnetoresistance in an all oxide composite magnetic tunnel junction. AB - We propose, by performing advanced ab initio electron transport calculations, an all-oxide composite magnetic tunnel junction, within which both large tunneling magnetoresistance (TMR) and tunneling electroresistance (TER) effects can coexist. The TMR originates from the symmetry-driven spin filtering provided by an insulating BaTiO(3) barrier to the electrons injected from the SrRuO(3) electrodes. Following recent theoretical suggestions, the TER effect is achieved by intercalating a thin insulating layer, here SrTiO(3), at one of the SrRuO(3)/BaTiO(3) interfaces. As the complex band structure of SrTiO(3) has the same symmetry as that of BaTiO(3), the inclusion of such an intercalated layer does not negatively alter the TMR and in fact increases it. Crucially, the magnitude of the TER also scales with the thickness of the SrTiO(3) layer. The SrTiO(3) thickness becomes then a single control parameter for both the TMR and the TER effect. This protocol offers a practical way to the fabrication of four state memory cells. PMID- 23368148 TI - Magnetoelectric effects in superconducting nanowires with Rashba spin-orbit coupling. AB - Recent experiments in semiconductor nanowires with a spin-orbit coupling and proximity-induced superconductivity exhibit signatures of Majorana bound states predicted to exist in the topological phase. In this Letter we predict that these nanowire systems exhibit unconventional magnetoelectric effects showing a sharp crossover behavior at the topological phase transition. We find that magnetic fields with a component parallel to the spin-orbit field can give rise to currents in equilibrium. Surprisingly, also fields perpendicular to the spin orbit field may induce currents and can be employed in adiabatic charge pumping. The perpendicular field magnetoelectric effect may be regarded as a manifestation of the anomalous Hall effect in one dimension. We discuss how the predicted phenomena could be observed in experiments and employed in probing the topological phase transition. PMID- 23368149 TI - Proposed detection of the topological phase in ring-shaped semiconductor superconductor nanowires using Coulomb blockade transport. AB - In semiconductor-superconductor hybrid structures a topological phase transition is expected as a function of the chemical potential or magnetic field strength. We show that signatures of this transition can be observed in nonlinear Coulomb blockade transport through a ring shaped structure. In particular, on the scale of the superconducting gap and for a fixed electron parity of the ring, the excitation spectrum is independent of flux in the topologically trivial phase but acquires a characteristic h/e periodicity in the nontrivial phase. We relate the h/e periodicity to the recently predicted 4pi periodicity of the Josephson current across a junction formed by two topological superconductors. PMID- 23368151 TI - Topological defect-phase soliton and the pairing symmetry of a two-band superconductor: role of the proximity effect. AB - We suggest a mechanism which promotes the existence of a phase soliton--a topological defect formed in the relative phase of superconducting gaps of a two band superconductor with s(+-) type of pairing. This mechanism exploits the proximity effect with a conventional s-wave superconductor which favors the alignment of the phases of the two-band superconductor which, in the case of s(+ ) pairing, are pi shifted in the absence of proximity. In the case of a strong proximity such an effect can be used to reduce the soliton's energy below the energy of a soliton-free state, thus making the soliton thermodynamically stable. Based on this observation we consider an experimental setup, applicable for both stable and metastable solitons, which can be used to distinguish between ss(+-) and s(++) types of pairing in the iron-based multiband superconductors. PMID- 23368150 TI - Temperature-dependent transformation of the magnetic excitation spectrum on approaching superconductivity in Fe(1+y-x)(Ni/Cu)(x)Te(0.5)Se(0.5). AB - Spin excitations are one of the top candidates for mediating electron pairing in unconventional superconductors. Their coupling to superconductivity is evident in a large number of systems, by the observation of an abrupt redistribution of magnetic spectral weight at the superconducting transition temperature, T(c), for energies comparable to the superconducting gap. Here we report inelastic neutron scattering measurements on Fe-based superconductors, Fe(1+y x)(Ni/Cu)(x)Te(0.5)Se(0.5) that emphasize an additional signature. The overall shape of the low energy magnetic dispersion changes from two incommensurate vertical columns at T?T(c) to a distinctly different U-shaped dispersion at low temperature. Importantly, this spectral reconstruction is apparent for temperatures up to ~3T(c). If the magnetic excitations are involved in the pairing mechanism, their surprising modification on the approach to T(c) demonstrates that strong interactions are involved. PMID- 23368152 TI - Ferromagnetic quantum critical point in heavy-fermion iron oxypnictide Ce(Ru(1 x)Fe(x))PO. AB - We have performed (31)P-NMR measurements on Ce(Ru(1-x)Fe(x))PO in order to investigate ferromagnetic (FM) quantum criticality, since a heavy-fermion (HF) ferromagnet CeRuPO with a two-dimensional structure turns into a HF paramagnet by an isovalent Fe substitution for Ru. We found that Ce(Ru(0.15)Fe(0.85))PO shows critical fluctuations down to ~0.3 K, as well as the continuous suppression of Curie temperature and the ordered moments by the Fe substitution. These experimental results suggest the presence of a FM quantum critical point (QCP) at x~0.86, which is a rare example among itinerant ferromagnets. In addition, we point out that the critical behaviors in Ce(Ru(0.15)Fe(0.85))PO share a similarity with those in YbRh(2)Si(2), where the local criticality of f electrons has been discussed. We reveal that Ce(Ru(1-x)Fe(x))PO is a new system to study FM quantum criticality in HF compounds. PMID- 23368153 TI - Class D spectral peak in Majorana quantum wires. AB - Proximity coupled spin-orbit quantum wires purportedly support midgap Majorana states at critical points. We show that, in the presence of disorder, these systems generate a second band center anomaly, which is of different physical origin but shares key characteristics with the Majorana state: it is narrow in width, insensitive to magnetic fields, carries unit spectral weight, and is rigidly tied to the band center. Depending on the parity of the number of subgap quasiparticle states, a Majorana mode does or does not coexist with the impurity peak. The strong "entanglement" between the two phenomena may hinder an unambiguous detection of the Majorana by spectroscopic techniques. PMID- 23368154 TI - Enhanced zero-bias Majorana peak in the differential tunneling conductance of disordered multisubband quantum-wire/superconductor junctions. AB - A recent experiment Mourik et al. [Science 336, 1003 (2012)] on InSb quantum wires provides possible evidence for the realization of a topological superconducting phase and the formation of Majorana bound states. Motivated by this experiment, we consider the signature of Majorana bound states in the differential tunneling conductance of multisubband wires. We show that the weight of the Majorana-induced zero-bias peak is strongly enhanced by mixing of subbands, when disorder is added to the end of the quantum wire. We also consider how the topological phase transition is reflected in the gap structure of the current-voltage characteristic. PMID- 23368155 TI - Chiral spin waves in Fermi liquids with spin-orbit coupling. AB - We predict the existence of chiral spin waves-collective modes in a two dimensional Fermi liquid with the Rashba or Dresselhaus spin-orbit coupling. Starting from the phenomenological Landau theory, we show that the long wavelength dynamics of magnetization is governed by the Klein-Gordon equations. The standing-wave solutions of these equations describe ''particles" with effective masses, whose magnitudes and signs depend on the strength of the electron-electron interaction. The spectrum of the spin-chiral modes for arbitrary wavelengths is determined from the Dyson equation for the interaction vertex. We propose to observe spin-chiral modes via microwave absorption by standing waves confined by an in-plane profile of the spin-orbit splitting. PMID- 23368156 TI - Persistent spin dynamics intrinsic to amplitude-modulated long-range magnetic order. AB - An incommensurate elliptical helical magnetic structure in the frustrated coupled spin-chain system FeTe(2)O(5)Br is surprisingly found to persist down to 53(3) mK (T/T(N)~1/200), according to neutron scattering and muon spin relaxation. In this state, finite spin fluctuations at T->0 are evidenced by muon depolarization, which is in agreement with specific-heat data indicating the presence of both gapless and gapped excitations. We thus show that the amplitude-modulated magnetic order intrinsically accommodates contradictory persistent spin dynamics and long-range order and can serve as a model structure to investigate their coexistence. PMID- 23368157 TI - Condensation of anyons in frustrated quantum magnets. AB - We derive the exact ground space of a family of spin-1/2 Heisenberg chains with uniaxial exchange anisotropy (XXZ) and interactions between nearest and next nearest-neighbor spins. The Hamiltonian family, H(eff)(Q), is parametrized by a single variable Q. By using a generalized Jordan-Wigner transformation that maps spins into anyons, we show that the exact ground states of H(eff)(Q) correspond to a condensation of anyons with a statistical phase phi=-4Q. We also provide matrix-product state representations of some ground states that allow for the efficient computation of spin-spin correlation functions. PMID- 23368158 TI - Atomic and electronic structure of ultrathin Bi(111) films grown on Bi2Te3(111) substrates: evidence for a strain-induced topological phase transition. AB - We studied the atomic and electronic structures of ultrathin Bi(111) films grown on Bi(2)Te(3) by means of angle-resolved photoemission, first-principles calculations, and low-energy electron diffraction. These Bi films were found to be strained due to the influence of the substrate. Accordingly, the band structure is affected and Bi undergoes a topological phase transition; it is shown that the Z(2) topological invariant in three dimensions switches from +1 (trivial) to -1 (nontrivial or topological). This was clearly confirmed from the change in the surface-state dispersion near the Fermi level. Our discovery offers a method to produce novel topological systems from simple materials. PMID- 23368159 TI - Criticality in dynamic arrest: correspondence between glasses and traffic. AB - Dynamic arrest is a general phenomenon across a wide range of dynamic systems including glasses, traffic flow, and dynamics in cells, but the universality of dynamic arrest phenomena remains unclear. We connect the emergence of traffic jams in a simple traffic flow model directly to the dynamic slowing down in kinetically constrained models for glasses. In kinetically constrained models, the formation of glass becomes a true (singular) phase transition in the limit T >0. Similarly, using the Nagel-Schreckenberg model to simulate traffic flow, we show that the emergence of jammed traffic acquires the signature of a sharp transition in the deterministic limit p->1, corresponding to overcautious driving. We identify a true dynamic critical point marking the onset of coexistence between free flowing and jammed traffic, and demonstrate its analogy to the kinetically constrained glass models. We find diverging correlations analogous to those at a critical point of thermodynamic phase transitions. PMID- 23368160 TI - Emergent surface tension in vibrated, noncohesive granular media. AB - We describe experiments and simulations carried out to investigate spinodal decomposition in a vibrated, dry granular system. The dynamics is found to be similar to that of systems evolving under curvature-driven diffusion, which suggests the presence of an effective surface tension. By studying quasi-2D droplets in the steady state, we find behavior consistent with Laplace's equation, demonstrating the existence of an actual surface tension. Detailed measurements of the pressure tensor in the interfacial region show that the surface tension results predominantly from an anisotropy in the kinetic energy part of the pressure tensor, in contrast to thermodynamic systems where it arises from either the attractive interaction between particles or entropic considerations. PMID- 23368161 TI - Length scale dependence of DNA mechanical properties. AB - Although mechanical properties of DNA are well characterized at the kilobase-pair range, a number of recent experiments have suggested that DNA is more flexible at shorter length scales, which correspond to the regime that is crucial for cellular processes such as DNA packaging and gene regulation. Here, we perform a systematic study of the effective elastic properties of DNA at different length scales by probing the conformation and fluctuations of DNA from the single base pair level up to four helical turns, using trajectories from atomistic simulation. We find evidence that supports cooperative softening of the stretch modulus and identify the essential modes that give rise to this effect. The bend correlation exhibits modulations that reflect the helical periodicity, while it yields a reasonable value for the effective persistence length, and the twist modulus undergoes a smooth crossover--from a relatively smaller value at the single base-pair level to the bulk value--over half a DNA turn. PMID- 23368162 TI - Microscopically resolved simulations prove the existence of soft cluster crystals. AB - We perform extensive monomer-resolved computer simulations of suitably designed amphiphilic dendritic macromolecules over a broad range of densities, proving the existence and stability of cluster crystals formed in these systems, as predicted previously on the basis of effective pair potentials [B. M. Mladek et al., Phys. Rev. Lett. 96, 045701 (2006)]. Key properties of these crystals, such as the adjustment of their site occupancy with density and the possibility to heal defects by dendrimer migration, are confirmed on the monomer-resolved picture. At the same time, important differences from the predictions of the pair potential picture, stemming from steric crowding, arise as well, and they place an upper limit in the density for which such crystals can exist. PMID- 23368163 TI - Comment on "Magnetic structuring of electrodeposits". PMID- 23368167 TI - Semistochastic projector Monte Carlo method. AB - We introduce a semistochastic implementation of the power method to compute, for very large matrices, the dominant eigenvalue and expectation values involving the corresponding eigenvector. The method is semistochastic in that the matrix multiplication is partially implemented numerically exactly and partially stochastically with respect to expectation values only. Compared to a fully stochastic method, the semistochastic approach significantly reduces the computational time required to obtain the eigenvalue to a specified statistical uncertainty. This is demonstrated by the application of the semistochastic quantum Monte Carlo method to systems with a sign problem: the fermion Hubbard model and the carbon dimer. PMID- 23368165 TI - Comment on "Spin-flip limited exciton dephasing in CdSe/ZnS colloidal quantum dots". PMID- 23368168 TI - Observation of free-space single-atom matter wave interference. AB - We observe matter wave interference of a single cesium atom in free fall. The interferometer is an absolute sensor of acceleration and we show that this technique is sensitive to forces at the level of 3.2*10(-27) N with a spatial resolution at the micron scale. We observe the build up of the interference pattern one atom at a time in a free-space interferometer where the mean path separation extends far beyond the coherence length of the atom. Using the coherence length of the atom wave packet as a metric, we directly probe the velocity distribution and measure the temperature of a single atom in free fall. PMID- 23368169 TI - Weak values are universal in von Neumann measurements. AB - We refute the widely held belief that the quantum weak value necessarily pertains to weak measurements. To accomplish this, we use the transverse position of a beam as the detector for the conditioned von Neumann measurement of a system observable. For any coupling strength, any initial states, and any choice of conditioning, the averages of the detector position and momentum are completely described by the real parts of three generalized weak values in the joint Hilbert space. Higher-order detector moments also have similar weak value expansions. Using the Wigner distribution of the initial detector state, we find compact expressions for these weak values within the reduced system Hilbert space. As an application of the approach, we show that for any Hermite-Gauss mode of a paraxial beamlike detector these expressions reduce to the real and imaginary parts of a single system weak value plus an additional weak-value-like contribution that only affects the momentum shift. PMID- 23368170 TI - Anisotropic polarizability of ultracold polar 40K87Rb molecules. AB - We report the measurement of the anisotropic ac polarizability of ultracold polar (40)K(87)Rb molecules in the ground and first rotationally excited states. Theoretical analysis of the polarizability agrees well with experimental findings. Although the polarizability can vary by more than 30%, a "magic" angle between the laser polarization and the quantization axis is found where the polarizability of the |N=0,m(N)=0> and the |N=1,m(N)=0> states match. At this angle, rotational decoherence due to the mismatch in trapping potentials is eliminated, and we observe a sharp increase in the coherence time. This paves the way for precise spectroscopic measurements and coherent manipulations of rotational states as a tool in the creation and probing of novel quantum many body states of polar molecules. PMID- 23368171 TI - Universal four-body states in heavy-light mixtures with a positive scattering length. AB - The number of four-body states known to behave universally is small. This work adds a new class of four-body states to this relatively short list. We predict the existence of a universal four-body bound state for heavy-light mixtures consisting of three identical heavy fermions and a fourth distinguishable lighter particle with a mass ratio kappa>/~9.5 and short-range interspecies interaction characterized by a positive s-wave scattering length. The structural properties of these universal states are discussed, and finite-range effects are analyzed. The bound states can be experimentally realized and probed by utilizing ultracold atom mixtures. PMID- 23368172 TI - Mixed-state evolution in the presence of gain and loss. AB - A model is proposed that describes the evolution of a mixed state of a quantum system for which gain and loss of energy or amplitude are present. Properties of the model are worked out in detail. In particular, invariant subspaces of the space of density matrices corresponding to the fixed points of the dynamics are identified, and the existence of a transition between the phase in which gain and loss are balanced and the phase in which this balance is lost is illustrated in terms of the time average of observables. The model is extended to include a noise term that results from a uniform random perturbation generated by white noise. Numerical studies of example systems show the emergence of equilibrium states that suppress the phase transition. PMID- 23368173 TI - Steady-state many-body entanglement of hot reactive fermions. AB - Entanglement is typically created via systematic intervention in the time evolution of an initially unentangled state, which can be achieved by coherent control, carefully tailored nondemolition measurements, or dissipation in the presence of properly engineered reservoirs. In this Letter we show that two component Fermi gases at ~MUK temperatures naturally evolve, in the presence of reactive two-body collisions, into states with highly entangled (Dicke-type) spin wave functions. The entanglement is a steady-state property that emerges-without any intervention-from uncorrelated initial states, and could be used to improve the accuracy of spectroscopy in experiments with fermionic alkaline earth atoms or fermionic ground state molecules. PMID- 23368174 TI - Continuous-variable blind quantum computation. AB - Blind quantum computation is a secure delegated quantum computing protocol where Alice, who does not have sufficient quantum technology at her disposal, delegates her computation to Bob, who has a fully fledged quantum computer, in such a way that Bob cannot learn anything about Alice's input, output, and algorithm. Protocols of blind quantum computation have been proposed for several qudit measurement-based computation models, such as the graph state model, the Affleck Kennedy-Lieb-Tasaki model, and the Raussendorf-Harrington-Goyal topological model. Here, we consider blind quantum computation for the continuous-variable measurement-based model. We show that blind quantum computation is possible for the infinite squeezing case. We also show that the finite squeezing causes no additional problem in the blind setup apart from the one inherent to the continuous-variable measurement-based quantum computation. PMID- 23368175 TI - Positive Wigner functions render classical simulation of quantum computation efficient. AB - We show that quantum circuits where the initial state and all the following quantum operations can be represented by positive Wigner functions can be classically efficiently simulated. This is true both for continuous-variable as well as discrete variable systems in odd prime dimensions, two cases which will be treated on entirely the same footing. Noting the fact that Clifford and Gaussian operations preserve the positivity of the Wigner function, our result generalizes the Gottesman-Knill theorem. Our algorithm provides a way of sampling from the output distribution of a computation or a simulation, including the efficient sampling from an approximate output distribution in the case of sampling imperfections for initial states, gates, or measurements. In this sense, this work highlights the role of the positive Wigner function as separating classically efficiently simulable systems from those that are potentially universal for quantum computing and simulation, and it emphasizes the role of negativity of the Wigner function as a computational resource. PMID- 23368176 TI - Nonequilibrium phase transitions in systems with long-range interactions. AB - We introduce a generalized Hamiltonian mean field model-an XY model with both linear and quadratic coupling between spins and explicit Hamiltonian dynamics. In addition to the usual paramagnetic and ferromagnetic phases, this model also possesses a nematic phase. The generalized Hamiltonian mean field model can be solved explicitly using Boltzmann-Gibbs statistical mechanics, in both canonical and microcanonical ensembles. However, when the resulting microcanonical phase diagram is compared with the one obtained using molecular dynamics simulations, it is found that the two are very different. We will present a dynamical theory which allows us to explicitly calculate the phase diagram obtained using molecular dynamics simulations without any adjustable parameters. The model illustrates the fundamental role played by dynamics as well the inadequacy of Boltzmann-Gibbs statistics for systems with long-range forces in the thermodynamic limit. PMID- 23368177 TI - Comparison of two independent Sr optical clocks with 1*10(-17) stability at 10(3) s. AB - Many-particle optical lattice clocks have the potential for unprecedented measurement precision and stability due to their low quantum projection noise. However, this potential has so far never been realized because clock stability has been limited by frequency noise of optical local oscillators. By synchronously probing two ^{87}Sr lattice systems using a laser with a thermal noise floor of 1*10(-15), we remove classically correlated laser noise from the intercomparison, but this does not demonstrate independent clock performance. With an improved optical oscillator that has a 1*10(-16) thermal noise floor, we demonstrate an order of magnitude improvement over the best reported stability of any independent clock, achieving a fractional instability of 1*10(-17) in 1000 s of averaging time for synchronous or asynchronous comparisons. This result is within a factor of 2 of the combined quantum projection noise limit for a 160 ms probe time with ~10(3) atoms in each clock. We further demonstrate that even at this high precision, the overall systematic uncertainty of our clock is not limited by atomic interactions. For the second Sr clock, which has a cavity enhanced lattice, the atomic-density-dependent frequency shift is evaluated to be -3.11*10(-17) with an uncertainty of 8.2*10(-19). PMID- 23368178 TI - Ytterbium in quantum gases and atomic clocks: van der Waals interactions and blackbody shifts. AB - We evaluated the C(6) coefficients of Yb-Yb, Yb-alkali, and Yb-group II van der Waals interactions with 2% uncertainty. The only existing experimental result for such quantities is for the Yb-Yb dimer. Our value, C(6)=1929(39) a.u., is in excellent agreement with the recent experimental determination of 1932(35) a.u. We have also developed a new approach for the calculation of the dynamic correction to the blackbody radiation shift. We have calculated this quantity for the Yb 6s(2) (1)S(0)-6s6p (3)P(0)(o) clock transition with 3.5% uncertainty. This reduces the fractional uncertainty due to the blackbody radiation shift in the Yb optical clock at 300 K to the 10(-18) level. PMID- 23368179 TI - Possible daily and seasonal variations in quantum interference induced by Chern Simons gravity. AB - Possible effects of Chern-Simons (CS) gravity on a quantum interferometer turn out to be dependent on the latitude and direction of the interferometer on Earth in orbital motion around the Sun. Daily and seasonal variations in phase shifts are predicted with an estimate of the size of the effects, wherefore neutron interferometry with ~5 m arm length and ~10(-4) phase measurement accuracy would place a bound on a CS parameter comparable to the Gravity Probe B satellite. PMID- 23368180 TI - Construction of solar-wind-like magnetic fields. AB - Fluctuations in the solar wind fields tend to not only have velocities and magnetic fields correlated in the sense consistent with Alfven waves traveling from the Sun, but they also have the magnitude of the magnetic field remarkably constant despite their being broadband. This Letter provides, for the first time, a method for constructing fields with nearly constant magnetic field, zero divergence, and with any specified power spectrum for the fluctuations of the components of the field. Every wave vector, k, is associated with two polarizations; the relative phases of these can be chosen to minimize the variance of the field magnitude while retaining the "random" character of the fields. The method is applied to a case with one spatial coordinate that demonstrates good agreement with observed time series and power spectra of the magnetic field in the solar wind, as well as with the distribution of the angles of rapid changes ("discontinuities"), thus showing a deep connection between two seemingly unrelated issues. It is suggested that using this construction will lead to more realistic simulations of solar wind turbulence and of the propagation of energetic particles. PMID- 23368181 TI - Is dark matter with long-range interactions a solution to all small-scale problems of Lambda cold dark matter cosmology? AB - The cold dark matter paradigm describes the large-scale structure of the Universe remarkably well. However, there exists some tension with the observed abundances and internal density structures of both field dwarf galaxies and galactic satellites. Here, we demonstrate that a simple class of dark matter models may offer a viable solution to all of these problems simultaneously. Their key phenomenological properties are velocity-dependent self-interactions mediated by a light vector messenger and thermal production with much later kinetic decoupling than in the standard case. PMID- 23368182 TI - Compressible matter at a holographic interface. AB - We study the interface between a fractional topological insulator and an ordinary insulator, both described using holography. By turning on a chemical potential we induce a finite density of matter localized at the interface. These are gapless surface excitations which are expected to have a fermionic character. We study the thermodynamics of the system, finding a symmetry preserving compressible state at low temperatures, whose excitations exhibit hyperscaling violation. These results are consistent with the expectation of gapless fermionic excitations forming a Fermi surface at finite density. PMID- 23368185 TI - Chiral anomaly and local polarization effect from the quantum kinetic approach. AB - A power expansion scheme is set up to determine the Wigner function that satisfies the quantum kinetic equation for spin-1/2 charged fermions in a background electromagnetic field. Vector and axial-vector current induced by magnetic field and vorticity are obtained simultaneously from the Wigner function. The chiral magnetic and vortical effect and chiral anomaly are shown as natural consequences of the quantum kinetic equation. The axial-vector current induced by vorticity is argued to lead to a local polarization effect along the vorticity direction in heavy-ion collisions. PMID- 23368186 TI - Unresolved question of the 10He ground state resonance. AB - The ground state of (10)He was populated using a 2p2n-removal reaction from a 59 MeV/u (14)Be beam. The decay energy of the three-body system, (8)He+n+n, was measured and a resonance was observed at E=1.60(25) MeV with a 1.8(4) MeV width. This result is in agreement with previous invariant mass spectroscopy measurements, using the (11)Li(-p) reaction, but is inconsistent with recent transfer reaction results. The proposed explanation that the difference, about 500 keV, is due to the effect of the extended halo nature of (11)Li in the one proton knockout reaction is no longer valid as the present work demonstrates that the discrepancy between the transfer reaction results persists despite using a very different reaction mechanism, (14)Be(-2p2n). PMID- 23368187 TI - Interplay between valence and core excitation mechanisms in the breakup of halo nuclei. AB - The phenomenon of core excitation in the breakup of a two-body halo nucleus is investigated. We show that this effect plays a significant role in the reaction dynamics and, furthermore, its interference with the valence excitation mechanism has sizable and measurable effects on the breakup angular distributions. These effects have been studied in the resonant breakup of (11)Be on a carbon target, populating the resonances at 1.78 MeV (5/2(+)) and 3.41 MeV (3/2(+)). The calculations have been performed using a recent extension of the distorted-wave Born approximation method, which takes into account the effect of core excitation in both the structure of the halo nucleus and in the reaction mechanism. The calculated angular distributions have been compared with the available data [Fukuda et al., Phys. Rev. C 70, 054606 (2004).]. Although each of these resonances is dominated by one of the two considered mechanisms, the angular patterns of these resonances depend in a very delicate way on the interference between them. This is the first clear evidence of this effect but the phenomenon is likely to occur in other similar reactions. PMID- 23368188 TI - Existence of an exotic torus configuration in high-spin excited states of 40Ca. AB - We investigate the possibility of the existence of the exotic torus configuration in the high-spin excited states of (40)Ca. We here consider the spin alignments about the symmetry axis. To this end, we use a three-dimensional cranked Skyrme Hartree-Fock method and search for stable single-particle configurations. We find one stable state with the torus configuration at the total angular momentum J=60 h and an excitation energy of about 170 MeV in all calculations using various Skyrme interactions. The total angular momentum J=60 h consists of aligned 12 nucleons with the orbital angular momenta Lambda=+4, +5, and +6 for spin-up or down neutrons and protons. The obtained results strongly suggest that a macroscopic amount of circulating current breaking the time-reversal symmetry emerges in the high-spin excited state of (40)Ca. PMID- 23368189 TI - Measurement of the -3 keV resonance in the reaction 13C(alpha,n)16O of importance in the s-process. AB - The (13)C(alpha,n)(16)O reaction is the neutron source for the main component of the s-process, responsible for the production of most nuclei in the mass range 90100 ps over a propagation distance of 390 nm, corresponding to a group index n(g)=-(1.0+/-0.1)*10(5), the largest negative group index measured to date. PMID- 23368191 TI - Laser-induced electron diffraction for probing rare gas atoms. AB - Recently, using midinfrared laser-induced electron diffraction (LIED), snapshots of a vibrating diatomic molecule on a femtosecond time scale have been captured [C.I. Blaga et al., Nature (London) 483, 194 (2012)]. In this Letter, a comprehensive treatment for the atomic LIED response is reported, a critical step in generalizing this imaging method. Electron-ion differential cross sections (DCSs) of rare gas atoms are extracted from measured angular-resolved, high energy electron momentum distributions generated by intense midinfrared lasers. Following strong-field ionization, the high-energy electrons result from elastic rescattering of a field-driven wave packet with the parent ion. For recollision energies >=100 eV, the measured DCSs are indistinguishable for the neutral atoms and ions, illustrating the close collision nature of this interaction. The extracted DCSs are found to be independent of laser parameters, in agreement with theory. This study establishes the key ingredients for applying LIED to femtosecond molecular imaging. PMID- 23368192 TI - Dissipative binding of lattice bosons through distance-selective pair loss. AB - We show that in a gas of ultracold atoms distance selective two-body loss can be engineered via the resonant laser excitation of atom pairs to interacting electronic states. In an optical lattice this leads to a dissipative master equation dynamics with Lindblad jump operators that annihilate atom pairs with a specific interparticle distance. In conjunction with coherent hopping between lattice sites this unusual dissipation mechanism leads to the formation of coherent long-lived complexes that can even exhibit an internal level structure which is strongly coupled to their external motion. We analyze this counterintuitive phenomenon in detail in a system of hard-core bosons. While current research has established that dissipation in general can lead to the emergence of coherent features in many-body systems our work shows that strong nonlocal dissipation can effectuate a binding mechanism for particles. PMID- 23368184 TI - Evidence for the eta(b)(2S) and observation of h(b)(1P)->eta(b)(1S)gamma and h(b)(2P)->eta(b)(1S)gamma. AB - We report the first evidence for the eta(b)(2S) using the h(b)(2P) >eta(b)(2S)gamma transition and the first observation of the h(b)(1P) >eta(b)(1S)gamma and h(b)(2P)->eta(b)(1S)gamma transitions. The mass and width of the eta(b)(1S) and eta(b)(2S) are measured to be m(eta(b)(1S))=(9402.4+/-1.5+/ 1.8) MeV/c(2), m(eta(b)(2S))=(9999.0+/-3.5(-1.9)(+2.8)) MeV/c(2), and Gamma(eta(b)(1S))=(10.8(-3.7-2.0)(+4.0+4.5)) MeV. We also update the h(b)(1P) and h(b)(2P) mass measurements. We use a 133.4 fb(-1) data sample collected at energies near the Upsilon(5S) resonance with the Belle detector at the KEKB asymmetric-energy e(+)e(-) collider. PMID- 23368193 TI - Single ions trapped in a one-dimensional optical lattice. AB - We report on three-dimensional optical trapping of single ions in a one dimensional optical lattice formed by two counterpropagating laser beams. We characterize the trapping parameters of the standing-wave using the ion as a sensor stored in a hybrid trap consisting of a radio-frequency (rf), a dc, and the optical potential. When loading ions directly from the rf into the standing wave trap, we observe a dominant heating rate. Monte Carlo simulations confirm rf induced parametric excitations within the deep optical lattice as the main source. We demonstrate a way around this effect by an alternative transfer protocol which involves an intermediate step of optical confinement in a single beam trap avoiding the temporal overlap of the standing-wave and the rf field. Implications arise for hybrid (rf-optical) and pure optical traps as platforms for ultracold chemistry experiments exploring atom-ion collisions or quantum simulation experiments with ions, or combinations of ions and atoms. PMID- 23368194 TI - Pinning an ion with an intracavity optical lattice. AB - We report one-dimensional pinning of a single ion by an optical lattice. A standing-wave cavity produces the lattice potential along the rf-field-free axis of a linear Paul trap. The ion's localization is detected by measuring its fluorescence when excited by standing-wave fields with the same period, but different spatial phases. The experiments agree with an analytical model of the localization process, which we test against numerical simulations. For the best localization achieved, the ion's average coupling to the cavity field is enhanced from 50% to 81(3)% of its maximum possible value, and we infer that the ion is bound in a lattice well with over 97% probability. PMID- 23368196 TI - Zero-energy resonances of hydrogen diatom isotopologs: tuning quasiresonant transitions in vibration space. AB - Highly efficient and specific energy transfer mechanisms that involve rotation rotation, vibration-vibration, and vibration-rotation exchange in diatomic molecules are examined theoretically in ultracold H(2), D(2), and HD self collisions as a function of initial vibrational level v. The three quasiresonant mechanisms are found to operate for all vibrational levels and yield complex scattering lengths which vary smoothly with v. Exceptions to this trend occur at select high values of v where the scattering lengths are modulated by orders of magnitude corresponding to the location of an s-wave zero-energy resonance in "vibration space." The quasiresonant mechanisms, which are not very sensitive to the details of the interaction potential, generally control the final distribution of molecular states for any given initial distribution. The zero energy resonances are more sensitive to the potential and may be used to vibrationally "tune" the interaction strength, similar to methods which vary applied external fields. PMID- 23368195 TI - Coherence-assisted resonance with sub-transit-limited linewidth. AB - We demonstrate a novel approach to obtain a resonance linewidth below the transit limit. The cross correlation between the induced intensity modulation of two lasers coupling the target resonance exhibits a narrow spectrum. 1/30 of the transit-limited width is achieved in a proof-of-principle experiment where two ground states are the target resonance levels. Attainable linewidth is only limited by laser shot noise in principle. The experimental results qualitatively agree with an intuitive analytical model and numerical calculations. This technique can be easily implemented and should be applicable to many atomic, molecular, and solid state spin systems for spectroscopy, metrology, and resonance-based sensing and imaging. PMID- 23368197 TI - Millikelvin reactive collisions between sympathetically cooled molecular ions and laser-cooled atoms in an ion-atom hybrid trap. AB - We report on a study of cold reactive collisions between sympathetically cooled molecular ions and laser-cooled atoms in an ion-atom hybrid trap. Chemical reactions were studied at average collision energies /k(B)>/~20 mK, about 2 orders of magnitude lower than has been achieved in previous experiments with molecular ions. Choosing N(2)(+)+Rb as a prototypical system, we find that the reaction rate is independent of the collision energy within the range studied, but strongly dependent on the internal state of Rb. Highly efficient charge exchange four times faster than the Langevin rate was observed with Rb in the excited (5p) (2)P(3/2) state. This observation is rationalized by a capture process dominated by the charge-quadrupole interaction and a near resonance between the entrance and exit channels of the system. Our results provide a test of classical models for reactions of molecular ions at the lowest energies reached thus far. PMID- 23368198 TI - Van der waals coefficients for nanostructures: fullerenes defy conventional wisdom. AB - The van der Waals coefficients between quasispherical nanostructures can be modeled accurately and analytically by those of classical solid spheres (for nanoclusters) or spherical shells (for fullerenes) of uniform valence electron density, with the true static dipole polarizability. Here, we derive analytically and confirm numerically from this model the size dependencies of the van der Waals coefficients of all orders, showing, for example, that the asymptotic dependence for C(6) is the expected n(2) for pairs of nanoclusters A(n)-A(n), each containing n atoms, but n(2.75) for pairs of single-walled fullerenes C(n) C(n). Large fullerenes are argued to have much larger polarizabilities and dispersion coefficients than those predicted by either the standard atom pair potential model or widely used nonlocal van der Waals correlation energy functionals. PMID- 23368199 TI - Quantum metrology in non-Markovian environments. AB - We analyze precision bounds for a local phase estimation in the presence of general, non-Markovian phase noise. We demonstrate that the metrological equivalence of product and maximally entangled states that holds under strictly Markovian dephasing fails in the non-Markovian case. Using an exactly solvable model of a physically realistic finite bandwidth dephasing environment, we demonstrate that the ensuing non-Markovian dynamics enables quantum correlated states to outperform metrological strategies based on uncorrelated states using otherwise identical resources. We show that this conclusion is a direct result of the coherent dynamics of the global state of the system and environment and therefore the obtained scaling with the number of particles, which surpasses the standard quantum limit but does not achieve Heisenberg resolution, possesses general validity that goes beyond specific models. This is in marked contrast with the situation encountered under general Markovian noise, where an arbitrarily small amount of noise is enough to restore the scaling dictated by the standard quantum limit. PMID- 23368200 TI - Observation and measurement of interaction-induced dispersive optical nonlinearities in an ensemble of cold Rydberg atoms. AB - We observe and measure dispersive optical nonlinearities in an ensemble of cold Rydberg atoms placed inside an optical cavity. The experimental results are in agreement with a simple model where the optical nonlinearities are due to the progressive appearance of a Rydberg blockaded volume within the medium. The measurements allow a direct estimation of the "blockaded fraction" of atoms within the atomic ensemble. PMID- 23368201 TI - Superresolving multiphoton interferences with independent light sources. AB - We propose to use multiphoton interferences from statistically independent light sources in combination with linear optical detection techniques to enhance the resolution in imaging. Experimental results with up to five independent thermal light sources confirm this approach to improve the spatial resolution. Since no involved quantum state preparation or detection is required, the experiment can be considered an extension of the Hanbury Brown-Twiss experiment for spatial intensity correlations of order N>2. PMID- 23368202 TI - Low-pump-power, low-phase-noise, and microwave to millimeter-wave repetition rate operation in microcombs. AB - Microresonator-based frequency combs (microcombs or Kerr combs) can potentially miniaturize the numerous applications of conventional frequency combs. A priority is the realization of broadband (ideally octave spanning) spectra at detectable repetition rates for comb self-referencing. However, access to these rates involves pumping larger mode volumes and hence higher threshold powers. Moreover, threshold power sets both the scale for power per comb tooth and also the optical pump. Along these lines, it is shown that a class of resonators having surface loss-limited Q factors can operate over a wide range of repetition rates with minimal variation in threshold power. A new, surface-loss-limited resonator illustrates the idea. Comb generation on mode spacings ranging from 2.6 to 220 GHz with overall low threshold power (as low as 1 mW) is demonstrated. A record number of comb lines for a microcomb (around 1900) is also observed with pump power of 200 mW. The ability to engineer a wide range of repetition rates with these devices is also used to investigate a recently observed mechanism in microcombs associated with dispersion of subcomb offset frequencies. We observe high-coherence phase locking in cases where these offset frequencies are small enough so as to be tuned into coincidence. In these cases, a record-low microcomb phase noise is reported at a level comparable to an open-loop, high-performance microwave oscillator. PMID- 23368203 TI - Quantitative experimental determination of scattering and absorption cross section spectra of individual optical metallic nanoantennas. AB - Antennas convert propagating radiation to localized electromagnetic energy and to heat. To unambiguously separate between these two aspects, one needs to quantitatively determine the antenna scattering and absorption cross-section spectra. By using a spatial modulation technique combined with a common-path interferometer and lithographically fabricated individual gold nanoantennas, we experimentally determine the scattering and absorption cross-section spectra of different optical antennas simultaneously and quantitatively for the first time. PMID- 23368183 TI - Measurements of B(c)+ production and mass with the B(c)+ -> J/psipi+ decay. AB - Measurements of B(c)(+) production and mass are performed with the decay mode B(c)(+)->J/psipi(+) using 0.37 fb(-1) of data collected in pp collisions at ?[s]=7 TeV by the LHCb experiment. The ratio of the production cross section times branching fraction between the B(c)(+)->J/psipi(+) and the B(+)->J/psiK(+) decays is measured to be (0.68+/-0.10(stat)+/-0.03(syst)+/-0.05(lifetime))% for B(c)(+) and B(+) mesons with transverse momenta p(T)>4 GeV/c and pseudorapidities 2.56sigma resonance demonstrate that the scheme can be used to create ultrashort coherent x-ray pulses. PMID- 23368207 TI - Synchronization of micromechanical oscillators using light. AB - Synchronization, the emergence of spontaneous order in coupled systems, is of fundamental importance in both physical and biological systems. We demonstrate the synchronization of two dissimilar silicon nitride micromechanical oscillators, that are spaced apart by a few hundred nanometers and are coupled through an optical cavity radiation field. The tunability of the optical coupling between the oscillators enables one to externally control the dynamics and switch between coupled and individual oscillation states. These results pave a path toward reconfigurable synchronized oscillator networks. PMID- 23368208 TI - X-ray waveguide mode in resonance with a periodic structure. AB - We present a novel concept for x-ray waveguiding based on electromagnetism in photonic crystals, using a waveguide consisting of a pair of claddings sandwiching a core with a periodic structure. By confining the x rays undergoing multiple interference in the core by total reflection, a characteristic waveguide mode whose field distribution matches the periodicity of the core is formed. The distinctively low propagation loss enables the single-mode propagation of x rays. This concept opens broad application possibilities in x-ray physics from coherent imaging to x-ray quantum optics. PMID- 23368209 TI - Universal quantum localizing transition of a partial barrier in a chaotic sea. AB - Generic 2D Hamiltonian systems possess partial barriers in their chaotic phase space that restrict classical transport. Quantum mechanically, the transport is suppressed if Planck's constant h is large compared to the classical flux, h>>Phi, such that wave packets and states are localized. In contrast, classical transport is mimicked for h<0 the rate of change of this wave function approaches zero. It follows that for small values of nd(2), this state is metastable and is an analog of the super Tonks Girardeau state of bosons with a strong zero-range attraction. The dipolar system is equivalent to a spinor Fermi gas with spin z components sigma(?)=[perpendicular] (perpendicular to the longitudinal axis) and sigma(?)=[parallel] (parallel to the longitudinal axis). A Fermi-Fermi mapping from spinor to spinless Fermi gas followed by the standard 1960 Fermi-Bose mapping reduces the Fermi system to a Bose gas. Potential experiments realizing the sudden spin rotation with ultracold dipolar gases are discussed, and a few salient properties of these states are accurately evaluated by a Monte Carlo method. PMID- 23368220 TI - Observation of self-binding in monolayer 3He. AB - We report clear experimental signatures of the theoretically unexpected gas liquid transition in the first three monolayer systems of (3)He adsorbed on graphite. The transition is inferred from the linear density dependence of the gamma coefficient of the heat capacity measured in the degenerate region (2<=T<=80 mK) below a critical liquid density (rho(c0)). Surprisingly, the measured rho(c0) values (0.6-0.9 nm(-2)) are nearly the same for all these layers in spite of their quite different environments. We conclude that the ground state of (3)He in strictly two dimensions is not a dilute quantum gas but a self-bound quantum liquid with the lowest density ever found. PMID- 23368221 TI - Excitations and stripe phase formation in a two-dimensional dipolar Bose gas with tilted polarization. AB - We present calculations of the ground state and excitations of an anisotropic dipolar Bose gas in two dimensions, realized by a nonperpendicular polarization with respect to the system plane. For sufficiently high density, an increase of the polarization angle leads to a density instability of the gas phase in the direction where the anisotropic interaction is strongest. Using a dynamic many body theory, we calculate the dynamic structure function in the gas phase which shows the anisotropic dispersion of the excitations. We find that the energy of roton excitations in the strongly interacting direction decreases with increasing polarization angle and almost vanishes close to the instability. Exact path integral ground state Monte Carlo simulations show that this instability is indeed a quantum phase transition to a stripe phase, characterized by long-range order in the strongly interacting direction. PMID- 23368222 TI - SU(3) spin-orbit coupling in systems of ultracold atoms. AB - Motivated by the recent experimental success in realizing synthetic spin-orbit coupling in ultracold atomic systems, we consider N-component atoms coupled to a non-Abelian SU(N) gauge field. More specifically, we focus on the case, referred to here as "SU(3) spin-orbit-coupling," where the internal states of three component atoms are coupled to their momenta via a matrix structure that involves the Gell-Mann matrices (in contrast to the Pauli matrices in conventional SU(2) spin-orbit-coupled systems). It is shown that the SU(3) spin-orbit-coupling gives rise to qualitatively different phenomena and in particular we find that even a homogeneous SU(3) field on a simple square lattice enables a topologically nontrivial state to exist, while such SU(2) systems always have trivial topology. In deriving this result, we first establish an equivalence between the Hofstadter model with a 1/N Abelian flux per plaquette and a homogeneous SU(N) non-Abelian model. The former is known to have a topological spectrum for N>2, which is thus inherited by the latter. It is explicitly verified by an exact calculation for N=3, where we develop and use a new algebraic method to calculate topological indices in the SU(3) case. Finally, we consider a strip geometry and establish the existence of three gapless edge states-the hallmark feature of such an SU(3) topological insulator. PMID- 23368223 TI - Nanoplasmonic lattices for ultracold atoms. AB - We propose to use subwavelength confinement of light associated with the near field of plasmonic systems to create nanoscale optical lattices for ultracold atoms. Our approach combines the unique coherence properties of isolated atoms with the subwavelength manipulation and strong light-matter interaction associated with nanoplasmonic systems. It allows one to considerably increase the energy scales in the realization of Hubbard models and to engineer effective long range interactions in coherent and dissipative many-body dynamics. Realistic imperfections and potential applications are discussed. PMID- 23368224 TI - Structural transformations on vitrification in the fragile glass-forming system CaAl2O4. AB - The structure of the fragile glass-forming material CaAl(2)O(4) was measured by applying the method of neutron diffraction with Ca isotope substitution to the laser-heated aerodynamically levitated liquid at 1973(30) K and to the glass at 300(1) K. The results, interpreted with the aid of molecular dynamics simulations, reveal key structural modifications on multiple length scales. Specifically, there is a reorganization on quenching that leads to an almost complete breakdown of the AlO(5) polyhedra and threefold coordinated oxygen atoms present in the liquid, and to their replacement by a predominantly corner-sharing network of AlO(4) tetrahedra in the glass. This process is accompanied by the formation of branched chains of edge and face-sharing Ca-centered polyhedra that give cationic ordering on an intermediate length scale, where the measured coordination number for O around Ca is 6.0(2) for the liquid and 6.4(2) for the glass. PMID- 23368113 TI - Observation of sequential Upsilon suppression in PbPb collisions. AB - The suppression of the individual Upsilon(nS) states in PbPb collisions with respect to their yields in pp data has been measured. The PbPb and pp data sets used in the analysis correspond to integrated luminosities of 150 MUb(-1) and 230 nb(-1), respectively, collected in 2011 by the CMS experiment at the LHC, at a center-of-mass energy per nucleon pair of 2.76 TeV. The Upsilon(nS) yields are measured from the dimuon invariant mass spectra. The suppression of the Upsilon(nS) yields in PbPb relative to the yields in pp, scaled by the number of nucleon-nucleon collisions, R(AA), is measured as a function of the collision centrality. Integrated over centrality, the R(AA) values are 0.56+/-0.08(stat)+/ 0.07(syst), 0.12+/-0.04(stat)+/-0.02(syst), and lower than 0.10 (at 95% confidence level), for the Upsilon(1S), Upsilon(2S), and Upsilon(3S) states, respectively. The results demonstrate the sequential suppression of the Upsilon(nS) states in PbPb collisions at LHC energies. PMID- 23368225 TI - Step-edge-induced oxide growth during the oxidation of Cu surfaces. AB - Using in situ atomic-resolution electron microscopy observations, we report observations of the oxide growth during the oxidation of stepped Cu surfaces. Oxidation occurs via direct growth of Cu(2)O on flat terraces with Cu adatoms detaching from steps and diffusing across the terraces. This process involves neither reconstructive oxygen adsorption nor oxygen subsurface incorporation and is rather different from the mechanism of solid-solid transformation of bulk oxidation that is most commonly postulated. These results demonstrate that the presence of surface steps can promote the development of a flat metal-oxide interface by kinetically suppressing subsurface oxide formation at the metal oxide interface. PMID- 23368227 TI - Universal phase diagram for wetting on mesoscale roughness. AB - The wetting properties of solid substrates with mesoscale (between van der Waals tails and the capillary length) random roughness are considered as a function of the microscopic contact angle of the wetting liquid and its partial pressure in the surrounding gas phase. It is shown that the well-known transition occurring at Wenzel's angle is accompanied by a transition line at which a jump in the adsorbed liquid volume occurs. This should be present generally on surfaces bearing homogeneous, isotropic random roughness. While a similar abrupt filling transition has been reported before for certain idealized groove or trough geometries, it is identified here as a universal phenomenon. Its location can be analytically calculated under certain mild conditions. PMID- 23368228 TI - Commensurability oscillations of hole-flux composite fermions. AB - We report the observation of commensurability oscillations of hole-flux composite fermions near a filling factor of nu=1/2 in a high-mobility two-dimensional hole system confined to a GaAs quantum well and subjected to a weak, strain-induced, unidirectional periodic potential modulation. The oscillations, which are consistent with ballistic transport of fully spin-polarized composite fermions in a weak periodic effective magnetic field, are surprisingly strong and exhibit up to third-order minima. We extract a ballistic mean-free path of about 0.1 MUm for the hole-flux composite fermions. PMID- 23368226 TI - Contact angles on a soft solid: from Young's law to Neumann's law. AB - The contact angle that a liquid drop makes on a soft substrate does not obey the classical Young's relation, since the solid is deformed elastically by the action of the capillary forces. The finite elasticity of the solid also renders the contact angles differently from those predicted by Neumann's law, which applies when the drop is floating on another liquid. Here, we derive an elastocapillary model for contact angles on a soft solid by coupling a mean-field model for the molecular interactions to elasticity. We demonstrate that the limit of a vanishing elastic modulus yields Neumann's law or a variation thereof, depending on the force transmission in the solid surface layer. The change in contact angle from the rigid limit to the soft limit appears when the length scale defined by the ratio of surface tension to elastic modulus gamma/E reaches the range of molecular interactions. PMID- 23368229 TI - Relaxation dynamics of the Holstein polaron. AB - Keeping the full quantum nature of the problem, we compute the relaxation time of the Holstein polaron in one dimension after it was driven far from the equilibrium by a strong oscillatory pulse. Just after the pulse, the polaron's kinetic energy increases and subsequently exhibits a relaxation-type decrease with simultaneous emission of phonons. In the weak coupling regime, partial tunneling of the electron from the polaron self-potential is observed. The inverse relaxation time is for small values of electron-phonon coupling lambda linear with lambda, while it deviates downwards from the linear regime at lambda>/~0.1/omega(0). The imaginary part of the equilibrium self-energy shows good agreement with the inverse relaxation time obtained from nonequilibrium simulations. PMID- 23368230 TI - Fermi surface topology of LaFePO and LiFeP. AB - We perform charge self-consistent density functional theory combined with dynamical mean field theory calculations to study correlation effects on the Fermi surfaces of the iron pnictide superconductors LaFePO and LiFeP. We find a distinctive change in the topology of the Fermi surface in both compounds where a hole pocket with Fe d(z(2)) orbital character changes its geometry from a closed shape in the local-density approximation to an open shape upon inclusion of correlations. The opening of the pocket occurs in the vicinity of the Gamma (Z) point in LaFePO (LiFeP). We discuss the relevance of these findings for the low superconducting transition temperature and the nodal gap observed in these materials. PMID- 23368231 TI - Nonlocal order parameters for the 1D Hubbard model. AB - We characterize the Mott-insulator and Luther-Emery phases of the 1D Hubbard model through correlators that measure the parity of spin and charge strings along the chain. These nonlocal quantities order in the corresponding gapped phases and vanish at the critical point U(c)=0, thus configuring as hidden order parameters. The Mott insulator consists of bound doublon-holon pairs, which in the Luther-Emery phase turn into electron pairs with opposite spins, both unbinding at U(c). The behavior of the parity correlators is captured by an effective free spinless fermion model. PMID- 23368232 TI - Charge-doping-driven evolution of magnetism and non-Fermi-liquid behavior in the filled skutterudite CePt4Ge(12-x)Sb(x). AB - The filled skutterudite compound CePt(4)Ge(12) is situated close to the border between the intermediate valence of Ce and heavy-fermion behavior. Substitution of Ge by Sb drives the system into a strongly correlated and, ultimately, upon further increasing the Sb concentration, an antiferromagnetically ordered state. Our experiments evidence a delicate interplay of emerging Kondo physics and the formation of a local 4f moment. An extended non-Fermi-liquid region, which can be understood in the framework of a Kondo-disorder model, is observed. Band structure calculations support the conclusion that the physical properties are governed by the interplay of electron supply via Sb substitution and the concomitant volume effects. PMID- 23368233 TI - First-principles calculation of the bulk photovoltaic effect in bismuth ferrite. AB - We compute the bulk photovoltaic effect (BPVE) in BiFeO(3) using first-principles shift current theory, finding good agreement with experimental results. Furthermore, we reconcile apparently contradictory observations: by examining the contributions of all photovoltaic response tensor components and accounting for the geometry and ferroelectric domain structure of the experimental system, we explain the apparent lack of BPVE response in striped polydomain samples that is at odds with the significant response observed in monodomain samples. We reveal that the domain-wall-driven response in striped polydomain samples is partially mitigated by the BPVE, suggesting that enhanced efficiency could be obtained in materials with cooperative rather than antagonistic interaction between the two mechanisms. PMID- 23368234 TI - Energy-driven drag at charge neutrality in graphene. AB - Coulomb coupling in graphene heterostructures results in vertical energy transfer between electrons in proximal layers. We show that, in the presence of correlated density inhomogeneity in the layers, vertical energy transfer has a strong impact on lateral charge transport. In particular, for Coulomb drag, its contribution dominates over conventional momentum drag near zero doping. The dependence on doping and temperature, which is different for the two drag mechanisms, can be used to separate these mechanisms in experiments. We predict distinct features such as a peak at zero doping and a multiple sign reversal, which provide diagnostics for this new drag mechanism. PMID- 23368235 TI - Anisotropy of spin relaxation in metals. AB - The concept of anisotropy of spin relaxation in nonmagnetic metals with respect to the spin direction of the injected electrons relative to the crystal orientation is introduced. The effect is related to an anisotropy of the Elliott Yafet parameter, arising from a modulation of the decomposition of the spin-orbit Hamiltonian into spin-conserving and spin-flip terms as the spin quantization axis is varied. This anisotropy, reaching gigantic values for uniaxial transition metals (e.g., 830% for hcp Hf) as density-functional calculations show, is related to extended "spin-flip hot areas" on the Fermi surface created by the proximity of extended sheets of the surface, or "spin-flip hot loops" at the Brillouin zone boundary, and has no theoretical upper limit. Possible ways of measuring the effect as well as consequences in application are briefly outlined. PMID- 23368236 TI - Phonon-mediated interlayer conductance in twisted graphene bilayers. AB - Conduction between graphene layers is suppressed by momentum conservation whenever the layer stacking has a rotation. Here we show that phonon scattering plays a crucial role in facilitating interlayer conduction. The resulting dependence on orientation is radically different than previously expected, and far more favorable for device applications. At low temperatures, we predict diode like current-voltage characteristics due to a phonon bottleneck. Simple scaling relationships give a good description of the conductance as a function of temperature, doping, rotation angle, and bias voltage, reflecting the dominant role of the interlayer beating phonon mode. PMID- 23368237 TI - Transition from fractional to Majorana fermions in Rashba nanowires. AB - We study hybrid superconducting-semiconducting nanowires in the presence of Rashba spin-orbit interaction as well as helical magnetic fields. We show that the interplay between them leads to a competition of phases with two topological gaps closing and reopening, resulting in unexpected reentrance behavior. In addition to the topological phase with localized Majorana fermions (MFs) we find new phases characterized by fractionally charged fermion (FF) bound states of Jackiw-Rebbi type. The system can be fully gapped by the magnetic fields alone, giving rise to FFs that transmute into MFs upon turning on superconductivity. We find explicit analytical solutions for MF and FF bound states and determine the phase diagram numerically by determining the corresponding Wronskian null space. We show by renormalization group arguments that electron-electron interactions enhance the Zeeman gaps opened by the fields. PMID- 23368238 TI - Evidence for reentrant melting in a quasi-one-dimensional Wigner crystal. AB - We demonstrate, for the first time, that a quasi-one-dimensional Wigner crystal formed on superfluid (4)He with only a few electrons in the confined direction shows reentrant melting. By transport measurements, we find oscillations in current as a function of linear density measured at a fixed driving voltage at high temperatures, and detailed analyses of transport data reveal that the oscillations originate from the periodic reduction of the melting temperature as a function of linear density. Comparison with the structural phase diagram suggests that the reduction of the melting temperature occurs at the boundaries between the different structures as the structure evolves from a single, double, followed by a triple chain. PMID- 23368239 TI - Dynamical self-quenching of spin pumping into double quantum dots. AB - Nuclear spin polarization can be pumped into spin-blockaded quantum dots by multiple Landau-Zener passages through singlet-triplet anticrossings. By numerical simulations of realistic systems with 10(7) nuclear spins during 10(5) sweeps, we uncover a mechanism of dynamical self-quenching which results in a fast saturation of the nuclear polarization under stationary pumping. This is caused by screening the random field of the nuclear spins. For moderate spin orbit coupling, self-quenching persists but its patterns are modified. Our finding explains low polarization levels achieved experimentally and calls for developing new protocols that break the self-quenching limitations. PMID- 23368240 TI - Manipulation of topological states and the bulk band gap using natural heterostructures of a topological insulator. AB - We have performed angle-resolved photoemission spectroscopy on (PbSe)(5)(Bi(2)Se(3))(3m), which forms a natural multilayer heterostructure consisting of a topological insulator and an ordinary insulator. For m=2, we observed a gapped Dirac-cone state within the bulk band gap, suggesting that the topological interface states are effectively encapsulated by block layers; furthermore, it was found that the quantum confinement effect of the band dispersions of Bi(2)Se(3) layers enhances the effective bulk band gap to 0.5 eV, the largest ever observed in topological insulators. For m=1, the Dirac-like state is completely gone, suggesting the disappearance of the band inversion in the Bi(2)Se(3) unit. These results demonstrate that utilization of naturally occurring heterostructures is a new promising strategy for manipulating the topological states and realizing exotic quantum phenomena. PMID- 23368241 TI - Suppression of Zeeman gradients by nuclear polarization in double quantum dots. AB - We use electric dipole spin resonance to measure dynamic nuclear polarization in InAs nanowire quantum dots. The resonance shifts in frequency when the system transitions between metastable high and low current states, indicating the presence of nuclear polarization. We propose that the low and the high current states correspond to different total Zeeman energy gradients between the two quantum dots. In the low current state, dynamic nuclear polarization efficiently compensates the Zeeman gradient due to the g-factor mismatch, resulting in a suppressed total Zeeman gradient. We present a theoretical model of electron nuclear feedback that demonstrates a fixed point in nuclear polarization for nearly equal Zeeman splittings in the two dots and predicts a narrowed hyperfine gradient distribution. PMID- 23368242 TI - Quantized Casimir force. AB - We investigate the Casimir effect between two-dimensional electron systems driven to the quantum Hall regime by a strong perpendicular magnetic field. In the large separation (d) limit where retardation effects are essential, we find (i) that the Casimir force is quantized in units of 3hcalpha(2)/8pi(2)d(4) and (ii) that the force is repulsive for mirrors with the same type of carrier and attractive for mirrors with opposite types of carrier. The sign of the Casimir force is therefore electrically tunable in ambipolar materials such as graphene. The Casimir force is suppressed when one mirror is a charge-neutral graphene system in a filling factor nu=0 quantum Hall state. PMID- 23368243 TI - Observation of the Meissner-Ochsenfeld effect and the absence of the Meissner state in UCoGe. AB - We present low field magnetization and susceptibility measurements made on a single crystal of the ferromagnetic superconductor UCoGe. The interplay between ferromagnetism and superconductivity comes into view in the study of hysteresis along the c axis (easy magnetization axis). The Meissner state (perfect diamagnetism) could not be observed in very low magnetic fields for all three crystallographic directions, implying that the sample is always in the mixed state. Notwithstanding, the Meissner-Ochsenfeld effect (reversible flux expulsion) occurs and is found to be anisotropic. For the c axis in low fields, it is proportional to the bulk magnetization M (and thus to the population of domains) and not to the applied magnetic field H. On a microscopic level, our interpretation of these results implies that flux is expelled independently from each domain proportional to its volume. PMID- 23368244 TI - Vanishing Meissner effect as a hallmark of in-plane Fulde-Ferrell-Larkin Ovchinnikov instability in superconductor-ferromagnet layered systems. AB - We demonstrate that in a wide class of multilayered superconductor-ferromagnet structures (e.g., S/F, S/F/N, and S/F/F') the vanishing Meissner effect signals the appearance of the in-plane Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) modulated superconducting phase. In contrast to the bulk superconductors the FFLO instability in these systems can emerge at temperatures close to the critical one and is effectively controlled by the S layer thickness and the angle between magnetization vectors in the F/F' bilayers. The predicted FFLO state is revealed through the critical temperature oscillations vs the perpendicular magnetic field component. PMID- 23368245 TI - Topological superconducting state of lead nanowires in an external magnetic field. AB - Superconductors with an odd number of bands crossing the Fermi energy have topologically protected Andreev states at interfaces, including Majorana states in one-dimensional geometries. We propose here that repeated indentation of a Pb tip on a Pb substrate can lead to nanowires such that the resulting superconducting system has novel topological properties. We have analyzed a number of conductance curves obtained in different nanowires, and observe, in a few cases, very peculiar dependence of the critical current on magnetic field. In these cases, the form of multiple Andreev reflections observed at finite voltages are compatible with topological superconductivity. The nanowires give a low number of 1D channels, large spin orbit coupling, and a sizable Zeeman energy, provided that the applied magnetic field is higher than the Pb bulk critical field. PMID- 23368246 TI - Microscopic model of quasiparticle wave packets in superfluids, superconductors, and paired Hall states. AB - We study the structure of Bogoliubov quasiparticles, bogolons, the fermionic excitations of paired superfluids that arise from fermion (BCS) pairing, including neutral superfluids, superconductors, and paired quantum Hall states. The naive construction of a stationary quasiparticle in which the deformation of the pair field is neglected leads to a contradiction: it carries a net electrical current even though it does not move. However, treating the pair field self consistently resolves this problem: in a neutral superfluid, a dipolar current pattern is associated with the quasiparticle for which the total current vanishes. When Maxwell electrodynamics is included, as appropriate to a superconductor, this pattern is confined over a penetration depth. For paired quantum Hall states of composite fermions, the Maxwell term is replaced by a Chern-Simons term, which leads to a dipolar charge distribution and consequently to a dipolar current pattern. PMID- 23368247 TI - Tailoring population inversion in Landau-Zener-Stuckelberg interferometry of flux qubits. AB - We distinguish different mechanisms for population inversion in flux qubits driven by dc+ac magnetic fields. We show that for driving amplitudes such that there are Landau-Zener-Stuckelberg interferences, it is possible to have population inversion solely mediated by the environmental bath. Furthermore, we find that the degree of population inversion can be controlled by tailoring a resonant frequency Omega(p) in the environmental bath. To observe these effects experiments should be performed for long driving times after full relaxation. PMID- 23368248 TI - Interference phenomena and long-range proximity effect in clean superconductor ferromagnet systems. AB - We study peculiarities of the proximity effect in clean superconductor ferromagnet structures caused by either the spatial or momentum dependence of the exchange field. Even a small modulation of the exchange field along the quasiparticle trajectories is shown to provide a long-range contribution to the supercurrent due to the specific interference of particle- and holelike wave functions. The momentum dependence of the exchange field caused by the spin-orbit interaction results in long-range superconducting correlations even in the absence of a ferromagnetic domain structure and can explain recent experiments on ferromagnetic nanowires. PMID- 23368249 TI - Model for magnetic flux patterns induced by the influence of in-plane magnetic fields on spatially inhomogeneous superconducting interfaces of LaAlO3-SrTiO3 bilayers. AB - The effect of spatial inhomogeneity on the properties of a two-dimensional noncentrosymmetric superconductor in an in-plane magnetic field is investigated, as it can be realized in LaAlO(3)-SrTiO(3) interfaces. We demonstrate that the spatial variation of Rashba spin-orbit coupling yields a local magnetic flux pattern due to the field-induced inhomogeneous helical phase. For sufficiently strong fields, vortices can nucleate at inhomogeneities of the Rashba spin-orbit coupling. PMID- 23368250 TI - Pressure- and composition-induced structural quantum phase transition in the cubic superconductor (Sr, Ca)3Ir4Sn13. AB - We show that the quasi-skutterudite superconductor Sr(3)Ir(4)Sn(13) undergoes a structural transition from a simple cubic parent structure, the I phase, to a superlattice variant, the I' phase, which has a lattice parameter twice that of the high temperature phase. We argue that the superlattice distortion is associated with a charge density wave transition of the conduction electron system and demonstrate that the superlattice transition temperature T(*) can be suppressed to zero by combining chemical and physical pressure. This enables the first comprehensive investigation of a superlattice quantum phase transition and its interplay with superconductivity in a cubic charge density wave system. PMID- 23368251 TI - Stabilization of Majorana modes in magnetic vortices in the superconducting phase of topological insulators using topologically trivial bands. AB - It has been shown that doped topological insulators, up to a certain level of doping, still preserve some topological signatures of the insulating phase such as axionic electromagnetic response and the presence of a Majorana mode in the vortices of a superconducting phase. Multiple topological insulators such as HgTe, ScPtBi, and other ternary Heusler compounds have been identified and generically feature the presence of a topologically trivial band between the two topological bands. In this Letter we show that the presence of such a trivial band can stabilize the topological signature over a much wider range of doping. Specifically, we calculate the structure of vortex modes in the superconducting phase of doped topological insulators, a model that captures the features of HgTe and the ternary Heusler compounds. We show that, due to the hybridization with the trivial band, Majorana modes are preserved over a large, extended doping range for p doping. In addition to presenting a viable system where much less fine-tuning is required to observe the Majorana modes, our analysis opens a route to study other topological features of doped compounds that cannot be modeled using the simple Bi(2)Se(3) Dirac model. PMID- 23368252 TI - Many-body effects in iron pnictides and chalcogenides: nonlocal versus dynamic origin of effective masses. AB - We apply the quasiparticle self-consistent GW approximation (QSGW) to some of the iron pnictide and chalcogenide superconductors. We compute Fermi surfaces and density of states, and find excellent agreement with experiment, substantially improving over standard band-structure methods. Analyzing the QSGW self-energy we discuss nonlocal and dynamic contributions to effective masses. We present evidence that the two contributions are mostly separable, since the quasiparticle weight is found to be essentially independent of momentum. The main effect of nonlocality is captured by the static but nonlocal QSGW effective potential. Moreover, these nonlocal self-energy corrections, absent in, e.g., dynamical mean field theory, can be relatively large. We show, on the other hand, that QSGW only partially accounts for dynamic renormalizations at low energies. These findings suggest that QSGW combined with dynamical mean field theory will capture most of the many-body physics in the iron pnictides and chalcogenides. PMID- 23368253 TI - Evidence for a cos(4phi) modulation of the superconducting energy gap of optimally doped FeTe(0.6)Se(0.4) single crystals using laser angle-resolved photoemission spectroscopy. AB - We study the superconducting-gap anisotropy of the Gamma-centered hole Fermi surface in optimally doped FeTe(0.6)Se(0.4) (T(c)=14.5 K), using laser-excited angle-resolved photoemission spectroscopy. We observe sharp superconducting (SC) coherence peaks at T=2.5 K. In contrast to earlier angle-resolved photoemission spectroscopy studies but consistent with thermodynamic results, the momentum dependence shows a cos(4phi) modulation of the SC-gap anisotropy. The observed SC gap anisotropy strongly indicates that the pairing interaction is not a conventional phonon-mediated isotropic one. Instead, the results suggest the importance of second-nearest-neighbor electronic interactions between the iron sites in the framework of s(+/-)-wave superconductivity. PMID- 23368254 TI - Noncollinear magnetic order stabilized by entangled spin-orbital fluctuations. AB - Quantum phase transitions in the two-dimensional Kugel-Khomskii model on a square lattice are studied using the plaquette mean field theory and the entanglement renormalization Ansatz. When 3z(2)-r(2) orbitals are favored by the crystal field and Hund's exchange is finite, both methods give a noncollinear exotic magnetic order that consists of four sublattices with mutually orthogonal nearest-neighbor and antiferromagnetic second-neighbor spins. We derive an effective frustrated spin model with second- and third-neighbor spin interactions which stabilize this phase and follow from spin-orbital quantum fluctuations involving spin singlets entangled with orbital excitations. PMID- 23368255 TI - Ground state in a half-doped manganite distinguished by neutron spectroscopy. AB - We have measured the spin-wave spectrum of the half-doped bilayer manganite Pr(Ca,Sr)(2)Mn(2)O(7) in its spin, charge, and orbital ordered phase. The measurements, which extend throughout the Brillouin zone and cover the entire one magnon spectrum, are compared critically with spin-wave calculations for different models of the electronic ground state. The data are described very well by the Goodenough model, which has weakly interacting ferromagnetic zig-zag chains in the CE-type arrangement. A model that allows ferromagnetic dimers to form within the zigzags is inconsistent with the data. The analysis conclusively rules out the strongly bound dimer (Zener polaron) model. PMID- 23368256 TI - Fluctuation-induced magnetization dynamics and criticality at the interface of a topological insulator with a magnetically ordered layer. AB - We consider a theory for a two-dimensional interacting conduction electron system with strong spin-orbit coupling on the interface between a topological insulator and the magnetic (ferromagnetic or antiferromagnetic) layer. For the ferromagnetic case we derive the Landau-Lifshitz equation, which features a contribution proportional to a fluctuation-induced electric field obtained by computing the topological (Chern-Simons) contribution from the vacuum polarization. We also show that fermionic quantum fluctuations reduce the critical temperature T[over ~](c) at the interface relative to the critical temperature T(c) of the bulk, so that in the interval T[over ~](c)<=T= 85th percentile (8.2%) slightly exceeded those identified with abdominal obesity, WC >= 80th percentile (7.3%) and WHtR > 0.5 (7.1%). CONCLUSION: The results suggest that an excess of fat deposits, either in the abdominal region or elsewhere in the body, increased the risk of wheezing. Since obesity is an important public health problem worldwide, control of this problem may partially reduce the occurrence of wheezing in youth. PMID- 23368280 TI - Stereochemical control of polymorph transitions in nanoscale reactors. AB - Crystallization of glycine in the cylindrical nanopores of anodic aluminum oxide (AAO) revealed the formation of metastable beta-glycine in pores having diameters less than 200 nm. Two-dimensional X-ray microdiffraction indicated that the [010] axis of the embedded beta-glycine nanocrystals coincided with the pore direction, identical to behavior observed previously in the cylindrical nanopores of polymer monoliths. Whereas the beta-glycine nanocrystals were stable indefinitely in ambient air and persisted upon heating, they transformed to the alpha polymorph upon standing at room temperature and 90% relative humidity (RH). The alpha glycine nanocrystals were oriented with the [010] axis nearly perpendicular to the pore direction, reflecting a nearly 90 degrees rotation of the glycine molecules during the transition. When the beta-glycine nanocrystals were formed in the AAO cylinders in the presence of small amounts of racemic hydrophobic amino acid auxiliaries, which are known to bind selectively to the (010) and (010) faces on the fast-growing end of beta-glycine enantiomorphs, the beta -> alpha phase transition at 90% RH was suppressed. In contrast, beta-glycine nanocrystals grown in the presence of an enantiopure amino acid auxiliary, which binds to the fast-growing end of only one of the enantiomorphs, thus suppressing its formation and leaving the other enantiomorph unperturbed, transformed into the alpha polymorph under the same conditions. This observation confirms that binding of an amino acid to the {010} faces is stereoselective and that access of water to these faces is essential for the transition to the alpha polymorph. PMID- 23368281 TI - Role of mitochondrial translocator protein (18 kDa) on mitochondrial- related cell death processes. AB - The 18 kDa translocator protein (TSPO) is able to modulate several mitochondria related cell death processes due to close association with proteins and other molecules involved to the mitochondrial permeability transition pore. In this way, herein we review cell death mechanisms targeting mitochondria, including programmed cell death type I, II and III. Several proteins involved in these cell death processes and with a possible interplay with the TSPO are also discussed including the voltage dependent anion channel, the adenine nucleotide transporter, cardiolipin, and the Bcl-2 family proteins. Noteworthy, TSPO has been also implicated in various other functions including mitochondrial respiration, immune and phagocytic host-defense response, microglial activation, inflammation, cell growth and differentiation, cancer, cell proliferation, ischemia, and mental and neuropathological disorders. We focused in recent studies of the TSPO particularly on cancer and neurodegeneration, thus presenting the TSPO as a core element in the role of mitochondria in diseases and related processes. Clinical benefit may be attainable by increasing pharmacological knowledge related to the TSPO. Recent patents typically relate to diagnosis and treatment of TSPO-related pathological conditions including cancer, and inflammatory conditions, as well as disorders associated with central nervous system, such as neurodegeneration, convulsions, anxiety, mental disorders, and dementia. PMID- 23368283 TI - Medication management and older adults: opportunities and challenges. PMID- 23368282 TI - Management of oxidative stress by microalgae. AB - The aim of this review is to provide an overview of the current research on oxidative stress in eukaryotic microalgae and the antioxidant compounds microalgae utilize to control oxidative stress. With the potential to exploit microalgae for the large-scale production of antioxidants, interest in how microalgae manage oxidative stress is growing. Microalgae can experience increased levels of oxidative stress and toxicity as a result of environmental conditions, metals, and chemicals. The defence mechanisms for microalgae include antioxidant enzymes such as superoxide dismutase, catalase, peroxidases, and glutathione reductase, as well as non-enzymatic antioxidant molecules such as phytochelatins, pigments, polysaccharides, and polyphenols. Discussed herein are the 3 areas the literature has focused on, including how conditions stress microalgae and how microalgae respond to oxidative stress by managing reactive oxygen species. The third area is how beneficial microalgae antioxidants are when administered to cancerous mammalian cells or to rodents experiencing oxidative stress. PMID- 23368285 TI - Drug for mild AD enters next wave of study. PMID- 23368286 TI - Hydration management. PMID- 23368288 TI - Protein digestion: an overview of the available techniques and recent developments. AB - Several proteomics approaches are available that are defined by the level (protein or peptide) at which analysis takes place. The most widely applied method still is bottom-up proteomics where the protein is digested into peptides that can be efficiently analyzed with a wide range of LC-MS or MALDI-TOF-MS instruments. Sample preparation for bottom-up proteomics experiments requires several treatment steps in order to get from the protein to the peptide level and can be very laborious. The most crucial step in such approaches is the protein digestion, which is often the bottleneck in terms of time consumption. Therefore, a significant gain in throughput may be obtained by speeding up the digestion process. Current techniques allow for reduction of the digestion time from overnight (~15 h) to minutes or even seconds. This advancement also makes integration into online systems feasible, thereby reducing the number of tedious sample handling steps and the risk of sample loss. In this review, an overview is given of the currently available digestion strategies and recent developments in the acceleration of the digestion process. Additionally, tailored approaches for classes of proteins that pose specific challenges are discussed. PMID- 23368290 TI - New type of crossover physics in three-component Fermi gases. AB - A three-component Fermi gas near a broad Feshbach resonance does not have a universal ground state due to the Thomas collapse, while it does near a narrow Feshbach resonance. We explore its universal phase diagram in the plane of the inverse scattering length 1/ak(F) and the resonance range R(*)k(F). For a large R(*)k(F), there exists a Lifshitz transition between superfluids with and without an unpaired Fermi surface as a function of 1/ak(F). With decreasing R(*)k(F), the Fermi surface coexisting with the superfluid can change smoothly from that of atoms to trimers ("atom-trimer continuity"), corresponding to the quark-hadron continuity in a dense nuclear matter. Eventually, there appears a finite window in 1/ak(F) where the superfluid is completely depleted by the trimer Fermi gas, which gives rise to a pair of quantum critical points. The boundaries of these three quantum phases are determined in regions where controlled analyses are possible and are also evaluated based on a mean-field plus trimer model. PMID- 23368291 TI - Criticality in transport through the quantum Ising chain. AB - We consider thermal transport between two reservoirs coupled by a quantum Ising chain as a model for nonequilibrium physics induced in quantum-critical many-body systems. By deriving rate equations based on exact expressions for the quasiparticle pairs generated during the transport, we observe signatures of the underlying quantum phase transition in the steady-state energy current already at finite and different reservoir temperatures. PMID- 23368289 TI - Yohimbine anxiogenesis in the elevated plus maze requires hindbrain noradrenergic neurons that target the anterior ventrolateral bed nucleus of the stria terminalis. AB - The alpha2 adrenergic receptor antagonist yohimbine (YO) increases transmitter release from noradrenergic (NA) terminals in cortical and subcortical brain regions, including the bed nucleus of the stria terminalis (BST). YO activates the hypothalamic-pituitary-adrenal (HPA) stress axis and is potently anxiogenic in rats and humans. We previously reported that hindbrain NA neurons within the caudal nucleus of the solitary tract (NST-A2/C2) and ventrolateral medulla (VLM A1/C1) that innervate the anterior ventrolateral (vl)BST contribute to the ability of YO to activate the HPA stress axis in rats. To determine whether the same NA pathway also contributes to YO-induced anxiogenesis in the elevated plus maze (EPMZ), a selective saporin ribotoxin conjugate (dopamine beta hydroxylase conjugated to saporin toxin, DSAP) was microinjected bilaterally into the anterior vlBST to destroy its NA inputs. Sham-lesioned controls were microinjected with vehicle. Two experiments were conducted to determine DSAP lesion effects on EPMZ behavior. DSAP lesions did not alter maze behavior in rats after intraperitoneal saline, and did not alter the significant effect of prior maze experience to reduce exploratory and open arm maze activities. However, in maze-naive rats, DSAP lesions abolished YO anxiogenesis in the EPMZ. Post-mortem immunocytochemical analyses confirmed that DSAP consistently ablated caudal NST A2/C2 and VLM-A1/C1 neurons that innervate the anterior vlBST. DSAP lesions did not destroy non-NA inputs to the anterior vlBST, and produced inconsistent cell loss within the pontine locus coeruleus (A6 cell group) that was unrelated to YO anxiogenesis. Thus, the ability of YO to increase anxiety-like behavior in the EPMZ depends on hindbrain NA neurons that target the anterior vlBST. PMID- 23368292 TI - Observation of entanglement between itinerant microwave photons and a superconducting qubit. AB - A localized qubit entangled with a propagating quantum field is well suited to study nonlocal aspects of quantum mechanics and may also provide a channel to communicate between spatially separated nodes in a quantum network. Here, we report the on-demand generation and characterization of Bell-type entangled states between a superconducting qubit and propagating microwave fields composed of zero-, one-, and two-photon Fock states. Using low noise linear amplification and efficient data acquisition we extract all relevant correlations between the qubit and the photon states and demonstrate entanglement with high fidelity. PMID- 23368293 TI - Feedback control of a solid-state qubit using high-fidelity projective measurement. AB - We demonstrate feedback control of a superconducting transmon qubit using discrete, projective measurement and conditional coherent driving. Feedback realizes a fast and deterministic qubit reset to a target state with 2.4% error averaged over input superposition states, and allows concatenating experiments more than 10 times faster than by passive initialization. This closed-loop qubit control is necessary for measurement-based protocols such as quantum error correction and teleportation. PMID- 23368294 TI - Quantum walks with nonorthogonal position states. AB - Quantum walks have by now been realized in a large variety of different physical settings. In some of these, particularly with trapped ions, the walk is implemented in phase space, where the corresponding position states are not orthogonal. We develop a general description of such a quantum walk and show how to map it into a standard one with orthogonal states, thereby making available all the tools developed for the latter. This enables a variety of experiments, which can be implemented with smaller step sizes and more steps. Tuning the nonorthogonality allows for an easy preparation of extended states such as momentum eigenstates, which travel at a well-defined speed with low dispersion. We introduce a method to adjust their velocity by momentum shifts, which allows us to experimentally probe the dispersion relation, providing a benchmarking tool for the quantum walk, and to investigate intriguing effects such as the analog of Bloch oscillations. PMID- 23368295 TI - Characterization of addressability by simultaneous randomized benchmarking. AB - The control and handling of errors arising from cross talk and unwanted interactions in multiqubit systems is an important issue in quantum information processing architectures. We introduce a benchmarking protocol that provides information about the amount of addressability present in the system and implement it on coupled superconducting qubits. The protocol consists of randomized benchmarking experiments run both individually and simultaneously on pairs of qubits. A relevant figure of merit for the addressability is then related to the differences in the measured average gate fidelities in the two experiments. We present results from two similar samples with differing cross talk and unwanted qubit-qubit interactions. The results agree with predictions based on simple models of the classical cross talk and Stark shifts. PMID- 23368296 TI - Entanglement of two superconducting qubits in a waveguide cavity via monochromatic two-photon excitation. AB - We report a system where fixed interactions between noncomputational levels make bright the otherwise forbidden two-photon |00}->|11} transition. The system is formed by hand selection and assembly of two discrete component transmon-style superconducting qubits inside a rectangular microwave cavity. The application of a monochromatic drive tuned to this transition induces two-photon Rabi-like oscillations between the ground and doubly excited states via the Bell basis. The system therefore allows all-microwave two-qubit universal control with the same techniques and hardware required for single qubit control. We report Ramsey-like and spin echo sequences with the generated Bell states, and measure a two-qubit gate fidelity of F(g)=90% (unconstrained) and 86% (maximum likelihood estimator). PMID- 23368297 TI - Fluids in extreme confinement. AB - For extremely confined fluids with a two-dimensional density n in slit geometry of an accessible width L, we prove that in the limit L -> 0, the lateral and transversal degrees of freedom decouple, and the latter become ideal-gas-like. For a small wall separation, the transverse degrees of freedom can be integrated out and renormalize the interaction potential. We identify nL(2) as the hidden smallness parameter of the confinement problem and evaluate the effective two body potential analytically, which allows calculating the leading correction to the free energy exactly. Explicitly, we map a fluid of hard spheres in extreme confinement onto a 2D fluid of disks with an effective hard-core diameter and a soft boundary layer. Two-dimensional phase transitions are robust and the transition point experiences a shift O(nL(2)). PMID- 23368298 TI - Black branes as piezoelectrics. AB - We find a realization of linear electroelasticity theory in gravitational physics by uncovering a new response coefficient of charged black branes, exhibiting their piezoelectric behavior. Taking charged dilatonic black strings as an example and using the blackfold approach we measure their elastic and piezolectric moduli. We also use our results to draw predictions about the equilibrium condition of charged dilatonic black rings in dimensions higher than six. PMID- 23368299 TI - Screening modifications of gravity through disformally coupled fields. AB - It is shown that extensions to general relativity, which introduce a strongly coupled scalar field, can be viable if the interaction has a nonconformal form. Such disformal coupling depends upon the gradients of the scalar field. Thus, if the field is locally static and smooth, the coupling becomes invisible in the Solar System: this is the disformal screening mechanism. A cosmological model is considered where the disformal coupling triggers the onset of accelerated expansion after a scaling matter era, giving a good fit to a wide range of background observational data. Moreover, the interaction leaves signatures in the formation of large-scale structure that can be used to probe such couplings. PMID- 23368300 TI - Pulsar glitches: the crust is not enough. AB - Pulsar glitches are traditionally viewed as a manifestation of vortex dynamics associated with a neutron superfluid reservoir confined to the inner crust of the star. In this Letter we show that the nondissipative entrainment coupling between the neutron superfluid and the nuclear lattice leads to a less mobile crust superfluid, effectively reducing the moment of inertia associated with the angular momentum reservoir. Combining the latest observational data for prolific glitching pulsars with theoretical results for the crust entrainment, we find that the required superfluid reservoir exceeds that available in the crust. This challenges our understanding of the glitch phenomenon, and we discuss possible resolutions to the problem. PMID- 23368301 TI - Strict limit on CPT violation from polarization of gamma-ray bursts. AB - We report the strictest observational verification of CPT invariance in the photon sector, as a result of gamma-ray polarization measurement of distant gamma ray bursts (GRBs), which are the brightest stellar-sized explosions in the Universe. We detected gamma-ray polarization of three GRBs with high significance levels, and the source distances may be constrained by a well-known luminosity indicator for GRBs. For the Lorentz- and CPT-violating dispersion relation E(+/ )(2) = p(2) +/- 2xip(3)/M(Pl), where +/- denotes different circular polarization states of the photon, the parameter xi is constrained as |xi| gammagamma signal strength now disagrees with its best-fit SM4 value at more than 4sigma. We perform a likelihood-ratio test to compare the SM and SM4 and show that the SM4 is excluded at 5.3sigma. Without the Tevatron data on H -> bb the significance drops to 4.8sigma. PMID- 23368308 TI - Finite-t and target-mass corrections to deeply virtual compton scattering. AB - We carry out the first complete calculation of kinematic power corrections ~t/Q(2) and ~m(2)/Q(2) to the helicity amplitudes of deeply virtual Compton scattering. This result removes an important source of uncertainties in the quantum chromodynamics predictions for intermediate momentum transfers Q(2) ~ 1 10 GeV(2) that are accessible in the existing and planned experiments. In particular, the finite-t corrections are significant and must be taken into account in the data analysis. PMID- 23368309 TI - Gluon- and quark-jet multiplicities with NNNLO and NNLL accuracy. AB - We present a new approach to consider and include both the perturbative and the nonperturbative contributions to the multiplicities of gluon and quark jets. Thanks to this new method, we have included for the first time new contributions to these quantities obtaining next-to-next-to-leading-logarithmic resummed formulas. Our analytic expressions depend on two nonperturbative parameters with a clear and simple physical interpretation. A global fit of these two quantities shows how our results solve a long-standing discrepancy in the theoretical description of the data. PMID- 23368310 TI - Transverse parton distribution functions at next-to-next-to-leading order: the quark-to-quark case. AB - We present a calculation of the perturbative quark-to-quark transverse parton distribution function at next-to-next-to-leading order based on a gauge invariant operator definition. We demonstrate for the first time that such a definition works beyond the first nontrivial order. We extract from our calculation the coefficient functions relevant for a next-to-next-to-next-to-leading logarithmic Q(T) resummation in a large class of processes at hadron colliders. PMID- 23368312 TI - Attosecond-recollision-controlled selective fragmentation of polyatomic molecules. AB - Control over various fragmentation reactions of a series of polyatomic molecules (acetylene, ethylene, 1,3-butadiene) by the optical waveform of intense few-cycle laser pulses is demonstrated experimentally. We show both experimentally and theoretically that the responsible mechanism is inelastic ionization from inner valence molecular orbitals by recolliding electron wave packets, whose recollision energy in few-cycle ionizing laser pulses strongly depends on the optical waveform. Our work demonstrates an efficient and selective way of predetermining fragmentation and isomerization reactions in polyatomic molecules on subfemtosecond time scales. PMID- 23368313 TI - Synchronizing terahertz wave generation with attosecond bursts. AB - We perform a joint measurement of terahertz waves and high-harmonics generated from argon atoms driven by a fundamental laser pulse and its second harmonic. By correlating their dependence on the phase delay between the two pulses, we determine the generation of THz waves in tens of attoseconds precision. Compared with simulations and models, we find that the laser-assisted soft collision of the electron wave packet with the atomic core plays a key role. It is demonstrated that the rescattering process, being indispensable in high-harmonic generation processes, dominates THz wave generation as well in a more elaborate way. The new finding might be helpful for the full characterization of the rescattering dynamics. PMID- 23368314 TI - Precision measurement of transition matrix elements via light shift cancellation. AB - We present a method for accurate determination of atomic transition matrix elements at the 10(-3) level. Measurements of the ac Stark (light) shift around "magic-zero" wavelengths, where the light shift vanishes, provide precise constraints on the matrix elements. We make the first measurement of the 5s - 6p matrix elements in rubidium by measuring the light shift around the 421 and 423 nm zeros through diffraction of a condensate off a sequence of standing wave pulses. In conjunction with existing theoretical and experimental data, we find 0.3235(9)ea(0) and 0.5230(8)ea(0) for the 5s - 6p(1/2) and 5s - 6p(3/2) elements, respectively, an order of magnitude more accurate than the best theoretical values. This technique can provide needed, accurate matrix elements for many atoms, including those used in atomic clocks, tests of fundamental symmetries, and quantum information. PMID- 23368315 TI - Measurement of a wavelength of light for which the energy shift for an atom vanishes. AB - Light at a magic-zero wavelength causes a zero energy shift for an atom. We measured the longest magic-zero wavelength for ground state potassium atoms to be lambda(zero)=768.9712(15) nm, and we show how this measurement provides an improved experimental benchmark for atomic structure calculations. This lambda(zero) measurement determines the ratio of the potassium atom D1 and D2 line strengths with record precision. It also demonstrates a new application for atom interferometry, and we discuss how decoherence will fundamentally limit future measurements of magic-zero wavelengths. PMID- 23368316 TI - Universal three-body parameter in heteronuclear atomic systems. AB - In Efimov physics, a three-body parameter (3BP), previously regarded as nonuniversal, uniquely defines bound and scattering properties of three particles. A universal 3BP, however, has been recently shown in experiments and theory in ultracold homonuclear gases. Our present study further predicts a universal 3BP for heteronuclear atomic systems near broad Feshbach resonances and provides physical interpretations for its origin. We show that for a system composed of two light and one heavy atom, the physical origin of the universal 3BP is similar to the homonuclear case, while for systems composed by one light and two heavy atoms, the universality of the 3BP is now mostly controlled by the heavy-heavy interatomic properties. This new universality is explained by the universal properties of the van der Waals interactions in a simple Born Oppenheimer picture. Finally, we show the numerically determined 3BPs for some combinations of alkali atoms used in ultracold experiments. PMID- 23368317 TI - Spectrum of the cavity-QED microlaser: strong coupling effects in the frequency pulling at off resonance. AB - We report the first experimental observation of the cavity-QED microlaser spectrum, specifically the unconventional frequency pulling brought by a strong atom-cavity coupling at off resonance. The pulling is enhanced quadratically by the atom-cavity coupling to result in a sensitive response to the number of pumping atoms (2.1 kHz per atom maximally). Periodic variation of the pulling due to the coherent Rabi oscillation is also observed as the number of pumping atoms is increased across multiple thresholds. PMID- 23368318 TI - Experimental observation of a skewed X-type spatiotemporal correlation of ultrabroadband twin beams. AB - This work presents the experimental observation of the nonfactorable near-field spatiotemporal correlation of ultrabroadband twin beams generated by parametric down-conversion, in an interferometric-type experiment using sum frequency generation, where both the temporal and the spatial degrees of freedom of parametric down-conversion light are controlled with high resolution. The revealed correlation is skewed in space-time in accordance with the X structure predicted by the theory. PMID- 23368319 TI - Shock waves in disordered media. AB - We experimentally investigate the interplay between spatial shock waves and the degree of disorder during nonlinear optical propagation in a thermal defocusing medium. We characterize the way the shock point is affected by the amount of disorder and scales with wave amplitude. Evidence for the existence of a phase diagram in terms of nonlinearity and amount of randomness is reported. The results are in quantitative agreement with a theoretical approach based on the hydrodynamic approximation. PMID- 23368320 TI - Mie scattering by a charged dielectric particle. AB - We study for a dielectric particle the effect of surplus electrons on the anomalous scattering of light arising from the transverse optical phonon resonance in the particle's dielectric function. Excess electrons affect the polarizability of the particle by their phonon-limited conductivity, either in a surface layer (negative electron affinity) or the conduction band (positive electron affinity). We show that surplus electrons shift an extinction resonance in the infrared. This offers an optical way to measure the charge of the particle and to use it in a plasma as a minimally invasive electric probe. PMID- 23368321 TI - Modulating sub-THz radiation with current in superconducting metamaterial. AB - We show that subterahertz transmission of the superconducting metamaterial, an interlinked two-dimensional network of subwavelength resonators connected by a continuous superconducting wire loop, can be dynamically modulated by passing electrical current through it. We have identified the main mechanisms of modulation that correspond to the suppression of the superconductivity in the network by magnetic field and heat dissipation. Using the metamaterial fabricated from thin niobium film, we were able to demonstrate a transmission modulation depth of up to 45% and a bandwidth of at least 100 kHz. The demonstrated approach may be implemented with other superconducting materials at frequencies below the superconducting gap in the THz and subterahertz bands. PMID- 23368311 TI - Cold-nuclear-matter effects on heavy-quark production in d+Au collisions at sqrt[S(NN)]=200 GeV. AB - The PHENIX experiment has measured electrons and positrons at midrapidity from the decays of hadrons containing charm and bottom quarks produced in d+Au and p+p collisions at sqrt[S(NN)]=200 GeV in the transverse-momentum range 0.85 <= p(T)(e) <= 8.5 GeV/c. In central d+Au collisions, the nuclear modification factor R(dA) at 1.5 infinity, whereas, for a point charge, the asymptotic value is finite. These findings have a potential impact not only on fundamental electrodynamics but also on accelerator physics and electron spectroscopy. PMID- 23368329 TI - X-ray amplification from a Raman free-electron laser. AB - We demonstrate that a mm-scale free-electron laser can operate in the x-ray range, in the interaction between a moderately relativistic electron bunch, and a transverse high intensity optical lattice. The corrugated light-induced ponderomotive potential acts simultaneously as a guide and as a low-frequency wiggler, triggering stimulated Raman scattering. The gain law in the small signal regime is derived in a fluid approach, and confirmed from particle-in-cell simulations. We describe the nature of bunching, and discuss the saturation properties. The resulting all-optical Raman x-ray laser opens perspectives for ultracompact coherent light sources up to the hard x-ray range. PMID- 23368330 TI - Strong field acceleration and steering of ultrafast electron pulses from a sharp metallic nanotip. AB - We report a strong, laser-field induced modification of the propagation direction of ultrashort electron pulses emitted from nanometer-sized gold tapers. Angle resolved kinetic energy spectra of electrons emitted from such tips are recorded using ultrafast near-infrared light pulses of variable wavelength and intensity for excitation. For sufficiently long wavelengths, we observe a pronounced strong field acceleration of electrons within the field gradient at the taper apex. We find a distinct narrowing of the emission cone angle of the fastest electrons. We ascribe this to the field-induced steering of subcycle electrons as opposed to the diverging emission of quiver electrons. Our findings are corroborated by simulations based on a modified Simpleman model incorporating the curved, vectorial field gradient in the vicinity of the tip. Our results indicate new pathways for designing highly directional nanometer-sized ultrafast electron sources. PMID- 23368331 TI - Excitation of geodesic acoustic modes by external fields. AB - It is planned to use external magnetic perturbations at acoustic frequencies at the DIII-D tokamak to attempt to drive geodesic acoustic modes (GAM) to modify the turbulent transport. We show that this might not only be possible--despite the well-known electrostatic nature of the GAMs--but might be a viable and efficient method to generate GAMs in magnetically confined plasmas, by developing an elegant analytic method which allows us to couple numerical dynamic equilibrium calculations with massively parallel non-Boussinesq turbulence code runs and yields practical estimates of the effectivity of the method. PMID- 23368332 TI - Cluster agglomeration induced by dust-density waves in complex plasmas. AB - Experimental results showing the agglomeration of large carbonaceous particles in a dusty plasma are reported. Experiments were performed in a capacitively coupled rf argon plasma. Acetylene was injected to produce dust particles. When a sufficient amount of nanoparticles is present in the cathodic sheath, self excited dust-density waves occur. The latter ones induce the motion of larger clusters, which vertically oscillate with the displacement of wave fronts. In some cases, the relative velocity of large particles was high enough to overcome the Coulomb repulsion forces, and agglomeration can be observed. The mechanisms underlying this process are discussed. PMID- 23368333 TI - Resonant Kalpha spectroscopy of solid-density aluminum plasmas. AB - The x-ray intensities made available by x-ray free electron lasers (FEL) open up new x-ray matter interaction channels not accessible with previous sources. We report here on the resonant generation of Kalpha emission, that is to say the production of copious Kalpha radiation by tuning the x-ray FEL pulse to photon energies below that of the K edge of a solid aluminum sample. The sequential absorption of multiple photons in the same atom during the 80 fs pulse, with photons creating L-shell holes and then one resonantly exciting a K-shell electron into one of these holes, opens up a channel for the Kalpha production, as well as the absorption of further photons. We demonstrate rich spectra of such channels, and investigate the emission produced by tuning the FEL energy to the K L transitions of those highly charged ions that have transition energies below the K edge of the cold material. The spectra are sensitive to x-ray intensity dependent opacity effects, with ions containing L-shell holes readily reabsorbing the Kalpha radiation. PMID- 23368334 TI - Phase-synchronization, energy cascade, and intermittency in solar-wind turbulence. AB - The energy cascade in solar wind magnetic turbulence is investigated using MESSENGER data in the inner heliosphere. The decomposition of magnetic field time series in intrinsic functions, each characterized by a typical time scale, reveals phase reorganization. This allows for the identification of structures of all sizes generated by the nonlinear turbulent cascade, covering both the inertial and the dispersive ranges of the turbulent magnetic power spectrum. We find that the correlation (or anticorrelation) of phases occurs between pairs of neighboring time scales, whenever localized peaks of magnetic energy are present at both scales, consistent with the local character of the energy transfer process. PMID- 23368335 TI - Isolated attosecond pulses from laser-driven synchrotron radiation. AB - A quantitative theory of attosecond pulse generation in relativistically driven overdense plasma slabs is presented based on an explicit analysis of synchrotron type electron trajectories. The subcycle, field-controlled release, and subsequent nanometer-scale acceleration of relativistic electron bunches under the combined action of the laser and ionic potentials give rise to coherent radiation with a high-frequency cutoff, intensity, and radiation pattern explained in terms of the basic laws of synchrotron radiation. The emerging radiation is confined to time intervals much shorter than the half-cycle of the driver field. This intuitive approach will be instrumental in analyzing and optimizing few-cycle-laser-driven relativistic sources of intense isolated extreme ultraviolet and x-ray pulses. PMID- 23368336 TI - Laser absorption in relativistically underdense plasmas by synchrotron radiation. AB - A novel absorption mechanism for linearly polarized lasers propagating in relativistically underdense solids in the ultrarelativistic (a ~ 100) regime is presented. The mechanism is based on strong synchrotron emission from electrons reinjected into the laser by the space charge field they generate at the front of the laser pulse. This laser absorption, termed reinjected electron synchrotron emission, is due to a coupling of conventional plasma physics processes to quantum electrodynamic processes in low density solids at intensities above 10(22) W/cm(2). Reinjected electron synchrotron emission is identified in 2D QED particle-in-cell simulations and then explained in terms of 1D QED-particle-in cell simulations and simple analytical theory. It is found that between 1% (at 10(22) W/cm(2)) and 14% (at 8 * 10(23) W/cm(2)) of the laser energy is converted into gamma ray photons, potentially providing an ultraintense future gamma ray source. PMID- 23368337 TI - Merging and splitting of plasma spheroids in a dusty plasma. AB - Dust particle growth in a plasma is a strongly disturbing phenomenon for the plasma equilibrium. It can induce many different types of low-frequency instabilities that can be experimentally observed, especially using high-speed imaging. A spectacular case has been observed in a krypton plasma where a huge density of dust particles is grown by material sputtering. The instability consists of well-defined regions of enhanced optical emission that emerge from the electrode vicinity and propagate towards the discharge center. These plasma spheroids have complex motions resulting from their mutual interaction that can also lead to the merging of two plasma spheroids into a single one. The reverse situation is also observed with the splitting of a plasma spheroid into two parts. These results are presented for the first time and reveal new behaviors in dusty plasmas. PMID- 23368338 TI - Generating high-energy highly charged ion beams from petawatt-class laser interactions with compound targets. AB - A new method of generation of high-energy highly charged ion beams is proposed. The method is based on the interaction of petawatt circularly polarized laser pulses with high-Z compound targets consisting of two species of different charge to-mass ratio. It is shown that highly charged ions produced by field ionization can be accelerated up to tens of MeV/u with ion (actually with Z <= 25) beam parameters like density and total charge inaccessible in conventional accelerators. A possibility of further ionization of the accelerated ion bunches in foil is also discussed. PMID- 23368339 TI - Tachyon condensation due to domain-wall annihilation in Bose-Einstein condensates. AB - We show theoretically that a domain-wall annihilation in two-component Bose Einstein condensates causes tachyon condensation accompanied by spontaneous symmetry breaking in a two-dimensional subspace. Three-dimensional vortex formation from domain-wall annihilations is considered a kink formation in subspace. Numerical experiments reveal that the subspatial dynamics obey the dynamic scaling law of phase-ordering kinetics. This model is experimentally feasible and provides insights into how the extra dimensions influence subspatial phase transition in higher-dimensional space. PMID- 23368340 TI - Reentrant BCS-BEC crossover and a superfluid-insulator transition in optical lattices. AB - We study the thermodynamics of a two-species Feshbach-resonant atomic Fermi gas in a periodic potential, focusing in a deep optical potential where a tight binding model is applicable. We show that for a more than half-filled band the gas exhibits a reentrant crossover with decreased detuning (increased attractive interaction), from a paired BCS superfluid to a Bose-Einstein condensate (BEC) of molecules of holes, back to the BCS superfluid, and finally to a conventional BEC of diatomic molecules. This behavior is associated with the nonmonotonic dependence of the chemical potential on detuning and the concomitant Cooper-pair or molecular size, larger in the BCS and smaller in the BEC regimes. For a single filled band we find a quantum phase transition from a band insulator to a BCS-BEC superfluid, and map out the corresponding phase diagram. PMID- 23368341 TI - Ab initio calculations of deep-level carrier nonradiative recombination rates in bulk semiconductors. AB - Nonradiative carrier recombination is of both applied and fundamental interest. Here a novel algorithm is introduced to calculate such a deep level nonradiative recombination rate using the ab initio density functional theory. This algorithm can calculate the electron-phonon coupling constants all at once. An approximation is presented to calculate the phonon modes for one impurity in a large supercell. The neutral Zn impurity site together with a N vacancy is considered as the carrier-capturing deep impurity level in bulk GaN. Its capture coefficient is calculated as 5.57 * 10(-10)cm(3)/s at 300 K. We found that there is no apparent onset of such a nonradiative process as a function of temperature. PMID- 23368342 TI - Method for retrieval of the three-dimensional object potential by inversion of dynamical electron scattering. AB - Dynamical scattering of fast electrons can be inverted by recasting the multislice algorithm as an artificial neural network, enabling the iterative retrieval of the three-dimensional object potential. This allows a nonheuristic treatment of the modulation transfer function of the CCD, partial spatial and temporal coherence, and inelastic scattering through an absorptive potential. Furthermore, prior knowledge about the atomic potential shape and the sparseness and positivity of the object can be used. The method is demonstrated on simulated bright field images recorded at 40 kV. PMID- 23368343 TI - First-principles determination of the structure of magnesium borohydride. AB - The energy landscape of Mg(BH(4))(2) under pressure is explored by ab initio evolutionary calculations. Two new tetragonal structures, with space groups P4 and I4(1)/acd, are predicted to be lower in enthalpy by 15.4 and 21.2 kJ/mol, respectively, than the earlier proposed P4(2)nm phase. We have simulated x-ray diffraction spectra, lattice dynamics, and equations of state of these phases. The density, volume contraction, bulk modulus, and simulated x-ray diffraction patterns of I4(1)/acd and P4 structures are in excellent agreement with the experimental results. PMID- 23368344 TI - Vitreous silica distends in helium gas: acoustic versus static compressibilities. AB - Sound velocities of vitreous silica are measured under He compression in the pressure range of 0-6 GPa by Brillouin light scattering. It is found that the well-known anomalous maximum in the pressure dependence of the compressibility is suppressed by He incorporation into the silica network. This shows that the elastic anomaly relates to the collapse of the largest interstitial voids in the structure. The huge difference between the static and the acoustic compressibilities indicates that the amount of incorporated helium still increases at 6 GPa. PMID- 23368345 TI - Observation of the fcc-to-hcp transition in ensembles of argon nanoclusters. AB - Macroscopic ensembles of weakly interacting argon nanoclusters are studied using x-ray diffraction in low vacuum. As the clusters grow by fusion with increasing temperature, their structure transforms from essentially face-centered cubic (fcc) to hexagonal close packed as the cluster size approaches ~10(5) atoms. The transformation involves intermediate orthorhombic phases. These data confirm extant theoretical predictions. They also indicate that growth kinetics and spatial constraints might play an important role in the formation of the fcc structure of bulk rare-gas solids, which still remains puzzling. PMID- 23368346 TI - Ductilizing bulk metallic glass composite by tailoring stacking fault energy. AB - Martensitic transformation was successfully introduced to bulk metallic glasses as the reinforcement micromechanism. In this Letter, it was found that the twinning property of the reinforcing crystals can be dramatically improved by reducing the stacking fault energy through microalloying, which effectively alters the electron charge density redistribution on the slipping plane. The enhanced twinning propensity promotes the martensitic transformation of the reinforcing austenite and, consequently, improves plastic stability and the macroscopic tensile ductility. In addition, a general rule to identify effective microalloying elements based on their electronegativity and atomic size was proposed. PMID- 23368347 TI - Nonlinear behavior of nematic platelet dispersions in shear flow. AB - Dispersions of platelets in the nematic phase are submitted to large amplitude oscillatory shear flow and probed by high temporal resolution small angle x-ray scattering. The response displays rich dynamic and structural behavior. Under small amplitude deformations we observe an elastic response, while structurally symmetry is broken: a preferential direction of deformation is selected which induces off-plane orientation of the platelets. We associate the elastic responses with the tilting director of the platelets towards the flow direction at all strain amplitudes. At large strain amplitudes there is a yielding transition between elastic and plastic deformation, accompanied by a flipping of the director. At intermediate strain amplitudes the director has a rich dynamic behavior, illustrating the complex motion of platelets in shear flow. These observations are confirmed by steady-shear flow reversal experiments, which underline the unique character of sheared nematic platelet dispersions. PMID- 23368348 TI - Simulation of spatially resolved electron energy loss near-edge structure for scanning transmission electron microscopy. AB - Aberration-corrected scanning transmission electron microscopy yields probe position-dependent energy-loss near-edge structure (ELNES) measurements, potentially providing spatial mapping of the underlying electronic states. ELNES calculations, however, typically describe excitations by a plane wave traveling in vacuum, neglecting the interaction of the electron probe with the local electronic environment as it propagates through the specimen. Here, we report a methodology that combines a full electronic-structure calculation with propagation of a focused beam in a thin film. The results demonstrate that only a detailed calculation using this approach can provide quantitative agreement with observed variations in probe-position-dependent ELNES. PMID- 23368349 TI - Correlation-enhanced effective mass of two-dimensional electrons in Mg(x)Zn(1 x)O/ZnO heterostructures. AB - We performed combined magnetotransport and cyclotron resonance experiments on two dimensional electron systems confined in the Mg(x)Zn(1-x)O/ZnO heterostructures over a wide range of carrier densities, from 1.9 to 12 * 10(11) cm(-2) (3.5 hVSMCs > hVECs. The level of basal reactive oxygen species (ROS) was highest in hVECs and lowest in hVSMCs. However, the Ca(2+) level was highest in hVSMCs and lowest in hVECs. These findings suggest that all types of NOXs exist in hEECs, hVECs, and hVSMCs, although their density and distribution are cell-type dependent. The density of the different NOXs correlated with the ROS level, but not with the Ca(2+) level. In conclusion, NOXs, including NOX3, exist in cardiovascular cells and their nuclei. The nucleus is a major source of ROS generation. The nuclear NOXs may contribute to ROS and Ca(2+) homeostasis, which may affect cell remodeling, including the formation of nuclear T-tubules in vascular diseases and aging. PMID- 23368420 TI - Psychosocial variables are related to future exacerbation risk and perinatal outcomes in pregnant women with asthma. AB - OBJECTIVE: To determine the relationship between psychosocial variables, future exacerbation risk during pregnancy, and perinatal outcomes. METHODS: A secondary analysis of a randomized controlled trial of exhaled nitric oxide versus guideline-based treatment adjustment in pregnant women with asthma. Women were recruited between 12 and 20 weeks gestation and monitored for the remainder of the pregnancy. Psychosocial questionnaires including the Perceived Control of Asthma Questionnaire, the Brief Illness Perception Questionnaire, and the Six Item Short-Form State Trait Anxiety Inventory were assessed at randomization. Exacerbations were defined as hospitalization, emergency visit, unscheduled doctor visit, or oral corticosteroid use for worsening asthma. Perinatal outcomes included preterm birth, small for gestational age, and cesarean section. Multiple logistic regressions were performed with predictor variables, including demographics and psychosocial and clinical variables. RESULTS: The 175 participants had a mean (SD) age = 28.5(5.4) years, forced expiratory volume in 1 second (FEV(1)%) predicted = 95.9(13.4), and asthma control score = 0.88(0.70). Greater perceived control of asthma reduced the odds of subsequent exacerbation (odds ratio (OR) [95%CI] 0.92 [0.85, 0.98], p = .016), cesarean without labor (0.84 [0.75, 0.94], p = .003), and preterm birth (0.84 [0.72, 0.97], p = .019), while increased anxiety increased the odds of subsequent exacerbation (1.05 [1.01, 1.08], p = .008). CONCLUSION: Women's perceptions of asthma control and their psychosocial state (anxiety) are related to future exacerbation risk, cesarean section, and preterm birth. PMID- 23368421 TI - Outcome after first relapse in adult patients with Philadelphia chromosome negative acute lymphoblastic leukaemia. AB - To analyse the outcome of adult patients who developed a first relapse of acute lymphoblastic leukaemia (ALL), we collected the clinical data of 332 patients with Philadelphia-chromosome (Ph) negative ALL, aged 16-65 years, who relapsed after first complete remission (CR1) between 1998 and 2008 in 69 institutions all over Japan, including 58 patients who relapsed after allogeneic haematopoietic stem cell transplantation (Allo-HSCT) in CR1. The overall survival (OS) was 43.4% at 1 year, and 16.3% at 5 years from relapse in patients who received chemotherapy alone in CR1. Among patients who relapsed after chemotherapy alone in CR1, 123 (52.5%) achieved a second remission (CR2) following salvage chemotherapy, of whom 62 subsequently underwent Allo-HSCT during CR2. Allo-HSCT in CR2 was significantly associated with better OS. Moreover, the type of salvage chemotherapy influenced OS from relapse. A doxorubicin, vincristine, and predonisone-based (AdVP-type) regimen was related to better OS in patients with longer CR1 (more than 1 year), but was related to worse OS in patients with shorter CR1. In conclusion, the prognosis of patients with relapsed Ph-negative ALL is poor. Allo-HSCT after a first relapse could improve the prognosis. Selection of the optimal salvage chemotherapy might depend on the duration of CR1. PMID- 23368422 TI - Inference and explanation in counterfactual reasoning. AB - This article reports results from two studies of how people answer counterfactual questions about simple machines. Participants learned about devices that have a specific configuration of components, and they answered questions of the form "If component X had not operated [failed], would component Y have operated?" The data from these studies indicate that participants were sensitive to the way in which the antecedent state is described-whether component X "had not operated" or "had failed." Answers also depended on whether the device is deterministic or probabilistic--whether X's causal parents "always" or only "usually" cause X to operate. Participants' explanations of their answers often invoked non-operation of causally prior components or unreliability of prior connections. They less often mentioned independence from these causal elements. PMID- 23368423 TI - Diabetes nurse case management and motivational interviewing for change (DYNAMIC): results of a 2-year randomized controlled pragmatic trial. AB - BACKGROUND: The aim of the present study was to determine whether the addition of nurse case managers (NCMs) trained in motivational interviewing (MI) to usual care would result in improved outcomes in high-risk type 2 diabetes patients. METHODS: A 2-year randomized controlled pragmatic trial randomized 545 patients to usual care control (n=313) or those who received the intervention (n=232) with additional practice-embedded NCM care, including MI-guided behavior change counseling. The NCMs received intensive MI training with ongoing fidelity assessment. RESULTS: Systolic blood pressure (SBP) was better in the intervention than usual care group (131 +/- 15 vs. 135 +/- 18 mmHg, respectively; P<0.05). Improvements were seen in both the control and intervention groups in terms of HbA1c (from 9.1% to 8.0% and from 8.8% to 7.8%, respectively), low-density lipoprotein (LDL; from 127 to 100 mg/dL and from 128 to 102 mg/dL, respectively), and diastolic blood pressure (from 78 to 74 mmHg and from 80 to 74 mmHg, respectively). Depression symptom scores were better in the intervention group. The reduction in diabetes-related distress approached statistical significance. CONCLUSIONS: The NCMs and MI improved SBP and complications screening. The large decrease in HbA1C and LDL in the control group may have obscured any further intervention effect. Although nurses prompted providers for medication titration, strategies to reduce provider clinical inertia may also be needed. PMID- 23368424 TI - Cytotoxicity and oxidative damage induced by halobenzoquinones to T24 bladder cancer cells. AB - Four halobenzoquinones (HBQs), 2,6-dichloro-1,4-benzoquinone (DCBQ), 2,6-dichloro 3-methyl-1,4-benzoquinone (DCMBQ), 2,3,6-trichloro-1,4-benzoquinone (TCBQ), and 2,6-dibromobenzoquinone (DBBQ), have been recently confirmed as disinfection byproducts (DBPs) in drinking water; however, their toxicological information is scarce. Here, we report that HBQs are cytotoxic to T24 bladder cancer cells and that the IC50 values are 95 MUM for DCBQ, 110 MUM for DCMBQ, 151 MUM for TCBQ, and 142 MUM for DBBQ, after a 24-h exposure. The antioxidant N-acetyl-l-cysteine (NAC) significantly reduces the cytotoxicity induced by the four HBQs, supporting the hypothesis that oxidative stress contributes to the cytotoxicity of HBQs. To further explore the oxidative mechanisms of cytotoxicity, we examined HBQ-induced production of reactive oxygen species (ROS) in T24 cells, and measured 8 hydroxydeoxyguanosine (8-OHdG), protein carbonyls, and malondialdehyde (MDA) adducts of proteins, markers of oxidative damage to DNA, proteins, and lipids, respectively. All four HBQs generated intracellular ROS in T24 cells in a concentration-dependent manner. HBQs also produced 8-OHdG in genomic DNA of T24 cells, with the highest levels of 8-OHdG induced by DCMBQ. Protein carbonylation was significantly increased in T24 cells that were incubated with each of the four HBQs for 24 h. However, MDA adduct formation, a marker of lipid peroxidation, was not affected by any of the four HBQs tested. These results suggest that the ROS-induced oxidative damage to DNA and protein carbonylation are involved in the observed toxicity of HBQs in T24 cells. PMID- 23368425 TI - Adsorption/desorption characteristics and separation of anthocyanins from muscadine (Vitis rotundifolia) juice pomace by use of macroporous adsorbent resins. AB - In this study, the adsorption/desorption characteristics of anthocyanins on five Amberlite resins (FPX-66, XAD-7HP, XAD-16N, XAD-1180, and XAD-761) were evaluated. FPX-66 and XAD-16N showed the highest adsorption and desorption capacities and ratios for anthocyanins from muscadine pomace extract, while XAD 7HP had the lowest adsorption and desorption capacities and ratios. On the basis of static adsorption and desorption tests, three resins (FPX-66, XAD-16N, and XAD 1180) were selected for adsorption kinetics and isotherms. The adsorption mechanism was better explained by the pseudo-first-order kinetics for FPX-66 and XAD-16N; however, for XAD-1180, pseudo-second-order kinetics was the most suitable model. The experimental data fitted best to Langmuir isotherm model for all three resins. Dynamic testing was done on a column packed with FPX-66 resin and breakthrough volume was reached at 17 bed volumes of muscadine pomace water extract during adsorption. Three bed volumes of aqueous ethanol (70%) resulted in complete desorption. Resin adsorption resulted in a concentrated pomace extract that contained 13% (w/w) anthocyanins with no detectable sugars. PMID- 23368426 TI - Enkephalin knockdown in the central amygdala nucleus reduces unconditioned fear and anxiety. AB - The endogenous opioid enkephalins (ENK) are highly expressed in the central nucleus of the amygdaloid complex (CeA) where several lines of evidence point to a potential role in the modulation of fear and anxiety. In this study, we aimed to assess the role of CeA ENK using local injections of a lentiviral vector expressing a short hairpin RNA (shRNA) targeting ENK in Sprague-Dawley rats. We injected this vector in the CeA and a 56% downregulation of ENK mRNA was observed in animals when compared with scrambled shRNA animals. Anxiety-like behaviors were also assessed using the elevated plus maze and social interaction test. There was an increase in exploration of open arms of the elevated plus maze in ENK knockdown animals compared with controls, but no change in social interaction. In addition, we used the contextual fear conditioning procedure to assess fear expression and learning in these animals. There was a reduction in freezing induced by acute shocks during the training procedure. Interestingly, associative learning was not affected, and ENK knockdown animals displayed an equivalent freezing when re-exposed to the conditioning chamber 48 h later. These results contrast with knockout mice studies, which ascribed anxiolytic properties to ENK, and they demonstrate the need for a thorough understanding and characterization of neuroanatomically distinct ENK pathways. PMID- 23368427 TI - Verification of multimarkers for detection of early stage diabetic retinopathy using multiple reaction monitoring. AB - Diabetic retinopathy (DR) is a complication of diabetes and 80% of diabetes mellitus (DM) patients whose DM duration is over 10 years can be expected to suffer with DR. The diagnosis of DR depends on an ophthalmological examination, and no molecular methods of screening DR status exist. Nonproliferative diabetic retinopathy (NPDR) is the early DR which is hard to be noticed in early NPDR, showing significant cause of adult blindness in type 2 diabetes patients. Protein biomarkers have been valuable in the diagnosis of disease and the use of multiple biomarkers has been suggested to overcome the low specificity of single ones. For biomarker development, multiple reaction monitoring (MRM) has been spotlighted as an alternative method to quantify target proteins with no need for immunoassay. In this study, 54 candidate DR marker proteins from a previous study were verified by MRM in plasma samples from NPDR patients in 3 stages (mild, moderate and severe; 15 cases each) and diabetic patients without retinopathy (15 cases) as a control. Notably, 27 candidate markers distinguished moderate NPDR from type 2 diabetic patients with no diabetic retinopathy, generating AUC values (>0.7). Specifically, 28 candidate proteins underwent changes in expression as type 2 diabetic patients with no diabetic retinopathy progressed to mild and moderate NPDR. Further, a combination of 4 markers from these 28 candidates had the improved specificity in distinguishing moderate NPDR from type 2 diabetic patients with no diabetic retinopathy, yielding a merged AUC value of nearly 1.0. We concluded that MRM is a fast, robust approach of multimarker panel determination and an assay platform that provides improved specificity compared with single biomarker assay systems. PMID- 23368428 TI - Protective effect of pravastatin on lipopolysaccharide-induced acute lung injury during neutropenia recovery in mice. AB - Although neutropenia recovery is associated with deterioration of preexisting acute lung injury (ALI), there are few reports of the preventive strategies. Statins have been found to attenuate inflammatory responses in murine models of lipopolysaccharide (LPS)-induced ALI. The aim of this study was to determine whether pravastatin could attenuate ALI during neutropenia recovery in mice. Cyclophosphamide was administered to mice to induce neutropenia. Mice were given intratracheal LPS 7 days after cyclophosphamide administration, after which pravastatin was administered by intraperitoneal injection. In order to study the effects of pravastatin, mice were killed on day 5. Pravastatin attenuated the pulmonary edema and histopathological changes of LPS-induced lung injury. The accumulation of neutrophils and the concentrations of TNF-alpha, IL-1beta, IL-6, and MPO in BAL fluids were also effectively inhibited by pravastatin. The expression levels of Toll-like receptor 4, nuclear factor kappa B, tumor growth factor-beta and matrix metalloproteinase-9 were significantly reduced by pravastatin. Taken together, pravastatin significantly attenuated LPS-induced ALI during neutropenia recovery. These results provide evidence for the potential of pravastatin in the treatment of ALI during neutropenia recovery. PMID- 23368429 TI - Implications of newborn screening for nurses. AB - PURPOSE: Newborn screening has dramatically decreased the morbidity and mortality associated with a wide range of heritable conditions. Continuing advances in screening technology and improvements in the effectiveness of treatment are driving the rapid expansion of newborn screening programs. In this article, we review issues in newborn screening care and opportunities for nurses and nursing faculty to provide education and conduct research to improve the impact of newborn screening. ORGANIZING CONSTRUCT: This article provides (a) an overview of current newborn screening activities, including how conditions are added to newborn screening panels and how implementation occurs at state and national levels; (b) a description of current controversies and ethical considerations; (c) a description of the roles of nurses in the newborn screening process; (d) suggestions for nursing education and research; and (e) a summary of expected future developments in newborn screening, including genome sequencing. CONCLUSIONS: Nurses are uniquely well suited to address the educational needs and future research in newborn screening because of the role that nurses play in the provision of direct clinical care and in population-based healthcare delivery. CLINICAL RELEVANCE: Newborn screening is a public health approach to the identification of rare but treatable conditions in early infancy. In the United States, as in other industrialized countries, newborn screening is rapidly expanding. Nurses, nurse educators, and nurse researchers are positioned to contribute to the field of newborn screening by assuring programs are implemented safely and effectively, by facilitating education of the nursing work force, and by developing and contributing to research programs in newborn screening. PMID- 23368431 TI - Progress of "Current Alzheimer Research" and future direction. PMID- 23368430 TI - Antibacterial activities of the methanol extracts of ten Cameroonian vegetables against Gram-negative multidrug-resistant bacteria. AB - BACKGROUND: Many edible plants are used in Cameroon since ancient time to control microbial infections. This study was designed at evaluating the antibacterial activities of the methanol extracts of ten Cameroonian vegetables against a panel of twenty nine Gram negative bacteria including multi-drug resistant (MDR) strains. METHODS: The broth microdilution method was used to determine the Minimal Inhibitory Concentrations (MIC) and the Minimal Bactericidal Concentrations (MBC) of the studied extracts. When chloramphenicol was used as a reference antibiotic, the MICs were also determined in the presence of Phenylalanine-Arginine beta-Naphtylamide (PAbetaN), an efflux pumps inhibitor (EPI). The phytochemical screening of the extracts was performed using standard methods. RESULTS: All tested extracts exhibited antibacterial activities, with the MIC values varying from 128 to 1024 mg/L. The studied extracts showed large spectra of action, those from L. sativa, S. edule, C. pepo and S. nigrum being active on all the 29 bacterial strains tested meanwhile those from Amaranthus hybridus, Vernonia hymenolepsis, Lactuca.carpensis and Manihot esculenta were active on 96.55% of the strains used. The plant extracts were assessed for the presence of large classes of secondary metabolites: alkaloids, anthocyanins, anthraquinones, flavonoids, phenols, saponins, steroids, tannins and triterpenes. Each studied plant extract was found to contain compounds belonging to at least two of the above mentioned classes. CONCLUSION: These results confirm the traditional claims and provide promising baseline information for the potential use of the tested vegetables in the fight against bacterial infections involving MDR phenotypes. PMID- 23368432 TI - Elevated plasma levels of soluble TNFRs and TACE activity in Alzheimer's disease patients of Northern Han Chinese descent. AB - BACKGROUND: We recently reported elevated cerebrospinal fluid (CSF) levels of soluble tumor necrosis factor (TNF) receptors and TNF-alpha converting enzyme (TACE) activity in subjects with Alzheimer's disease (AD) in a Caucasian population. The TNF receptor-mediated signaling pathway contributes to the production of Abeta and the subsequent cytotoxicity that is observed in AD brains. However, whether the plasma levels of soluble TNF receptors (sTNFRs) are changed is still unclear in AD patients of Han descent. METHODS: In the present study, we analyzed the plasma sTNFR levels using commercially available immunoassay kits in 76 AD patients and 40 age- and sex-matched control subjects of Northern Han Chinese descent. Furthermore, the TACE activity was measured using a solution-based assay containing a fluorescently labeled TACE substrate. RESULTS: AD patients exhibited higher levels of both sTNFR and TACE activity in their plasma compared with age- and sex-matched control subjects. The levels of sTNFR1 strongly correlated with the levels of sTNFR2 (rs =0.526, P < 0.001). In addition, the levels of sTNFR1 were significantly correlated with TACE activity (rs = 0.308, P < 0.01). CONCLUSION: These results suggest that sTNFRs and TACE activity might serve as potential peripheral diagnostic candidate biomarkers in AD. PMID- 23368433 TI - Tackling the elusive challenges relevant to conquering the 100-plus year old problem of Alzheimer's disease. AB - Despite over one hundred years of intense effort studying Alzheimer's disease (AD), we still do not understand its cause(s) and this adversely affects our ability to develop strongly effective treatments and means to prevent it. This is because our research efforts are not aligned to decipher this age-related disorder that, well after its discovery, has become a major cause of death throughout the world. We are therefore recommending a process to analyze some of the principal factors that hinder our progress in this field of research. Recognizing these barriers - and acting on such a recognition by seeking to resolve them experimentally and garnering societal support to do so - will constitute critical steps towards establishing strategies that will lead to a sorely needed paradigm shift in AD research, and ultimately to the prevention and the effective treatment of this devastating condition. This will probably also spur progress in many related neuropsychiatric disorders, and in that sense act as a seminal endeavor with far-reaching consequences. In order to accomplish this complex task, the biomedical community must acknowledge and come to a consensus about the factors that limit our progress, and then work together to generate new algorithms to tackle these fundamental issues rationally, effectively and deliberately. PMID- 23368434 TI - Multi-body optimisation with deformable ligament constraints: influence of ligament geometry 10.1080/10255842.2012.713666. PMID- 23368435 TI - Controlled dephasing of an electron interferometer with a path detector at equilibrium. AB - Controlled dephasing of electrons, via "which path" detection, involves, in general, coupling a coherent system to a current driven noise source. However, here we present a case in which a nearly isolated electron puddle within a quantum dot, at thermal equilibrium and in millikelvin range temperature, fully dephases the interference in a nearby electronic interferometer. Moreover, the complete dephasing is accompanied by an abrupt pi phase slip, which is robust and nearly independent of system parameters. Attributing the robustness of the phenomenon to the Friedel sum rule--which relates a system's occupation to its scattering phases--proves the universality of this powerful rule. The experiment allows us to peek into a nearly isolated quantum dot, which cannot be accessed via conductance measurements. PMID- 23368436 TI - Optimal inequalities for state-independent contextuality. AB - Contextuality is a natural generalization of nonlocality which does not need composite systems or spacelike separation and offers a wider spectrum of interesting phenomena. Most notably, in quantum mechanics there exist scenarios where the contextual behavior is independent of the quantum state. We show that the quest for an optimal inequality separating quantum from classical noncontextual correlations in a state-independent manner admits an exact solution, as it can be formulated as a linear program. We introduce the noncontextuality polytope as a generalization of the locality polytope and apply our method to identify two different tight optimal inequalities for the most fundamental quantum scenario with state-independent contextuality. PMID- 23368437 TI - Transdimensional equivalence of universal constants for Fermi gases at unitarity. AB - I present lattice Monte Carlo calculations for a universal four-component Fermi gas confined to a finite box and to a harmonic trap in one spatial dimension. I obtain the values xi(1D) = 0.370(4) and xi(1D) = 0.372(1), respectively, for the Bertsch parameter, a nonperturbative universal constant defined as the (square of the) energy of the untrapped (trapped) system measured in units of the free gas energy. The Bertsch parameter obtained for the one-dimensional system is consistent to within ~1% uncertainties with the most recent numerical and experimental estimates of the analogous Bertsch parameter for a three-dimensional spin-1/2 Fermi gas at unitarity. The finding suggests the intriguing possibility that there exists a universality between two conformal theories in different dimensions. To lend support to this study, I also compute ground state energies for four and five fermions confined to a harmonic trap and demonstrate the restoration of a virial theorem in the continuum limit. The continuum few-body energies obtained are consistent with exact analytical calculations to within ~1.0% and ~0.3% statistical uncertainties, respectively. PMID- 23368438 TI - Quantum simulation of small-polaron formation with trapped ions. AB - We propose an analog quantum simulation of small-polaron physics using a one dimensional system of trapped ions acted upon by off-resonant standing waves. This system, envisioned as an array of microtraps, in the single-excitation case allows the realization of the antiadiabatic regime of the Holstein model. We show that the strong excitation-phonon coupling regime, characterized by the formation of small polarons, can be reached using realistic values of the relevant system parameters. Finally, we propose measurements of the quasiparticle residue and the average number of phonons in the ground state, experimental probes validating the polaronic character of the phonon-dressed excitation. PMID- 23368439 TI - Path entanglement of continuous-variable quantum microwaves. AB - Path entanglement constitutes an essential resource in quantum information and communication protocols. Here, we demonstrate frequency-degenerate entanglement between continuous-variable quantum microwaves propagating along two spatially separated paths. We combine a squeezed and a vacuum state using a microwave beam splitter. Via correlation measurements, we detect and quantify the path entanglement contained in the beam splitter output state. Our experiments open the avenue to quantum teleportation, quantum communication, or quantum radar with continuous variables at microwave frequencies. PMID- 23368440 TI - Pulse-gated quantum-dot hybrid qubit. AB - A quantum-dot hybrid qubit formed from three electrons in a double quantum dot has the potential for great speed, due to the presence of level crossings where the qubit becomes chargelike. Here, we show how to exploit the level crossings to implement fast pulsed gating. We develop one- and two-qubit dc quantum gates that are simpler than the previously proposed ac gates. We obtain closed-form solutions for the control sequences and show that the gates are fast (subnanosecond) and can achieve high fidelities. PMID- 23368441 TI - Malliavin weight sampling for computing sensitivity coefficients in Brownian dynamics simulations. AB - We present a method for computing parameter sensitivities and response coefficients in Brownian dynamics simulations. The method involves tracking auxiliary variables (Malliavin weights) in addition to the usual particle positions, in an unperturbed simulation. The Malliavin weights sample the derivatives of the probability density with respect to the parameters of interest and are also interesting dynamical objects in themselves. Malliavin weight sampling is simple to implement, applies to equilibrium or nonequilibrium, steady state or time-dependent systems, and scales more efficiently than standard finite difference methods. PMID- 23368442 TI - Large deviations and universality in quantum quenches. AB - We study the large deviation statistics of the intensive work done by globally changing a control parameter in a thermally isolated quantum many-body system. We show that, upon approaching a critical point, large deviations well below the mean work display universal features related to the critical Casimir effect in the corresponding classical system. Large deviations well above the mean are, instead, of quantum nature and not captured by the quantum-to-classical correspondence. For a bosonic system we show that in this latter regime a transition from exponential to power-law statistics, analogous to the equilibrium Bose-Einstein condensation, may occur depending on the parameters of the quench and on the spatial dimensionality. PMID- 23368443 TI - Optimization of the magnetic dynamo. AB - In stars and planets, magnetic fields are believed to originate from the motion of electrically conducting fluids in their interior, through a process known as the dynamo mechanism. In this Letter, an optimization procedure is used to simultaneously address two fundamental questions of dynamo theory: "Which velocity field leads to the most magnetic energy growth?" and "How large does the velocity need to be relative to magnetic diffusion?" In general, this requires optimization over the full space of continuous solenoidal velocity fields possible within the geometry. Here the case of a periodic box is considered. Measuring the strength of the flow with the root-mean-square amplitude, an optimal velocity field is shown to exist, but without limitation on the strain rate, optimization is prone to divergence. Measuring the flow in terms of its associated dissipation leads to the identification of a single optimal at the critical magnetic Reynolds number necessary for a dynamo. This magnetic Reynolds number is found to be only 15% higher than that necessary for transient growth of the magnetic field. PMID- 23368444 TI - Surface singularities in Eddington-inspired Born-Infeld gravity. AB - Eddington-inspired Born-Infeld gravity was recently proposed as an alternative to general relativity that offers a resolution of spacetime singularities. The theory differs from Einstein's gravity only inside matter due to nondynamical degrees of freedom, and it is compatible with all current observations. We show that the theory is reminiscent of Palatini f(R) gravity and that it shares the same pathologies, such as curvature singularities at the surface of polytropic stars and unacceptable Newtonian limit. This casts serious doubt on its viability. PMID- 23368445 TI - Global deep-MOND parameter as a theory discriminant. AB - Different formulations of modified Newtonian dynamics predict somewhat different rotation curves for the same mass distribution. Here I consider a global attribute of the rotation curve that might provide a convenient discriminant between theories when applied to isolated, pure-disk galaxies that are everywhere deep in the modified Newtonian dynamics regime. This parameter is Q = V(2)/V(infinity)(2), where V(2) = M(-1)? 2pirSigma(r)V(2)(r)dr, with Sigma(r) the disk's surface density, M its total mass, and Vinfinity the asymptotic (constant) rotational speed. The comparison between the observed and predicted values of Q is oblivious to the distance, the inclination, the mass, and the size of the disk, and to the form of the interpolating function. For the known modified gravity theories Q is predicted to be a universal constant [independent of Sigma(r)]: Q = 2/3. The predicted Q value for modified-inertia theories does depend on the form of Sigma. However, surprisingly, I find here that it varies only little among a very wide range of mass distributions, Q ~ 0.73 +/- 0.01. While the difference between the theories amounts to only about 5% in the predicted rms velocity, a good enough sample of galaxies may provide the first discerning test between the two classes of theories. PMID- 23368446 TI - Charged-current weak interaction processes in hot and dense matter and its impact on the spectra of neutrinos emitted from protoneutron star cooling. AB - We perform three-flavor Boltzmann neutrino transport radiation hydrodynamics simulations covering a period of 3 s after the formation of a protoneutron star in a core-collapse supernova explosion. Our results show that a treatment of charged-current neutrino interactions in hot and dense matter as suggested by Reddy et al. [Phys. Rev. D 58, 013009 (1998)] has a strong impact on the luminosities and spectra of the emitted neutrinos. When compared with simulations that neglect mean-field effects on the neutrino opacities, we find that the luminosities of all neutrino flavors are reduced while the spectral differences between electron neutrinos and antineutrinos are increased. Their magnitude depends on the equation of state and in particular on the symmetry energy at subnuclear densities. These modifications reduce the proton-to-nucleon ratio of the outflow, increasing slightly their entropy. They are expected to have a substantial impact on nucleosynthesis in neutrino-driven winds, even though they do not result in conditions that favor an r process. Contrary to previous findings, our results show that the spectra of electron neutrinos remain substantially different from those of other (anti)neutrino flavors during the entire deleptonization phase of the protoneutron star. The obtained luminosity and spectral changes are also expected to have important consequences for neutrino flavor oscillations and neutrino detection on Earth. PMID- 23368447 TI - Gravitational waves from quasicircular black-hole binaries in dynamical Chern Simons gravity. AB - Dynamical Chern-Simons gravity cannot be strongly constrained with current experiments because it reduces to general relativity in the weak-field limit. This theory, however, introduces modifications in the nonlinear, dynamical regime, and thus it could be greatly constrained with gravitational waves from the late inspiral of black-hole binaries. We complete the first self-consistent calculation of such gravitational waves in this theory. For favorable spin orientations, advanced ground-based detectors may improve existing solar system constraints by 6 orders of magnitude. PMID- 23368448 TI - Quantum gravity extension of the inflationary scenario. AB - Since the standard inflationary paradigm is based on quantum field theory on classical space-times, it excludes the Planck era. Using techniques from loop quantum gravity, the paradigm is extended to a self-consistent theory from the Planck scale to the onset of slow roll inflation, covering some 11 orders of magnitude in energy density and curvature. This preinflationary dynamics also opens a small window for novel effects, e.g., a source for non-Gaussianities, which could extend the reach of cosmological observations to the deep Planck regime of the early Universe. PMID- 23368449 TI - Direct constraints on charged excitations of dark matter. AB - If the neutral component of weak-scale dark matter is accompanied by a charged excitation separated by a mass gap of less than ~20 MeV, weakly interacting massive particles (WIMPs) can form stable bound states with nuclei. We show that the recent progress in experiments searching for neutrinoless double-beta decay sets the first direct constraint on the exoergic reaction of WIMP-nucleus bound state formation. We calculate the rate for such a process in representative models and show that the double-beta decay experiments provide unique sensitivity to a large fraction of parameter space of the WIMP doublet model, complementary to constraints imposed by cosmology and direct collider searches. PMID- 23368451 TI - Analytic structure of the Landau-gauge gluon propagator. AB - The analytic structure of the nonperturbative gluon propagator contains information on the absence of gluons from the physical spectrum of the theory. We study this structure from numerical solutions in the complex momentum plane of the gluon and ghost Dyson-Schwinger equations in Landau gauge Yang-Mills theory. The resulting ghost and gluon propagators are analytic apart from a distinct cut structure on the real, timelike momentum axis. The propagator violates the Osterwalder-Schrader positivity condition, confirming the absence of gluons from the asymptotic spectrum of the theory. PMID- 23368452 TI - Connected-sea partons. AB - According to the path-integral formalism of the hadronic tensor, the nucleon sea contains two distinct components called the connected sea (CS) and the disconnected sea (DS). We discuss how the CS and DS are accessed in the lattice QCD calculation of the moments of the parton distributions. We show that the CS and DS components of u(x) + d(x) can be extracted by using recent data on the strangeness parton distribution, the CT10 global fit, and the lattice result of the ratio of the strange to u(d) moments in the disconnected insertion. The extracted CS and DS for u(x) + d(x) have a distinct Bjorken x dependence in qualitative agreement with expectation. The analysis also shows that the momentum fraction of u(x) + d(x) is about equally divided between the CS and DS at Q(2) = 2.5 GeV(2). Implications for the future global analysis of parton distributions are presented. PMID- 23368455 TI - Structure and rotations of the Hoyle state. AB - The excited state of the (12)C nucleus known as the "Hoyle state" constitutes one of the most interesting, difficult, and timely challenges in nuclear physics, as it plays a key role in the production of carbon via fusion of three alpha particles in red giant stars. In this Letter, we present ab initio lattice calculations which unravel the structure of the Hoyle state, along with evidence for a low-lying spin-2 rotational excitation. For the (12)C ground state and the first excited spin-2 state, we find a compact triangular configuration of alpha clusters. For the Hoyle state and the second excited spin-2 state, we find a "bent-arm" or obtuse triangular configuration of alpha clusters. We also calculate the electromagnetic transition rates between the low-lying states of (12)C. PMID- 23368456 TI - Symmetric tensor decomposition description of fermionic many-body wave functions. AB - The configuration interaction (CI) is a versatile wave function theory for interacting fermions, but it involves an extremely long CI series. Using a symmetric tensor decomposition method, we convert the CI series into a compact and numerically tractable form. The converted series encompasses the Hartree-Fock state in the first term and rapidly converges to the full-CI state, as numerically tested by using small molecules. Provided that the length of the symmetric tensor decomposition CI series grows only moderately with the increasing complexity of the system, the new method will serve as one of the alternative variational methods to achieve full CI with enhanced practicability. PMID- 23368457 TI - Micromotion-induced limit to atom-ion sympathetic cooling in Paul traps. AB - We present, and derive analytic expressions for, a fundamental limit to the sympathetic cooling of ions in radio-frequency traps using cold atoms. The limit arises from the work done by the trap electric field during a long-range ion-atom collision and applies even to cooling by a zero-temperature atomic gas in a perfectly compensated trap. We conclude that in current experimental implementations, this collisional heating prevents access to the regimes of single-partial-wave atom-ion interaction or quantized ion motion. We determine conditions on the atom-ion mass ratio and on the trap parameters for reaching the s-wave collision regime and the trap ground state. PMID- 23368458 TI - Magnetic control of the pair creation in spatially localized supercritical fields. AB - We examine the impact of a perpendicular magnetic field on the creation mechanism of electron-positron pairs in a supercritical static electric field, where both fields are localized along the direction of the electric field. In the case where the spatial extent of the magnetic field exceeds that of the electric field, quantum field theoretical simulations based on the Dirac equation predict a suppression of pair creation even if the electric field is supercritical. Furthermore, an arbitrarily small magnetic field outside the interaction zone can bring the creation process even to a complete halt, if it is sufficiently extended. The mechanism for this magnetically induced complete shutoff can be associated with a reopening of the mass gap and the emergence of electrically dressed Landau levels. PMID- 23368459 TI - Quantum signatures of the optomechanical instability. AB - In the past few years, coupling strengths between light and mechanical motion in optomechanical setups have improved by orders of magnitude. Here we show that, in the standard setup under continuous laser illumination, the steady state of the mechanical oscillator can develop a nonclassical, strongly negative Wigner density if the optomechanical coupling is comparable to or larger than the optical decay rate and the mechanical frequency. Because of its robustness, such a Wigner density can be mapped using optical homodyne tomography. This feature is observed near the onset of the instability towards self-induced oscillations. We show that there are also distinct signatures in the photon-photon correlation function g(2)(t) in that regime, including oscillations decaying on a time scale not only much longer than the optical cavity decay time but even longer than the mechanical decay time. PMID- 23368460 TI - Relaxation oscillations, stability, and cavity feedback in a superradiant Raman laser. AB - We experimentally study the relaxation oscillations and amplitude stability properties of an optical laser operating deep into the bad-cavity regime using a laser-cooled ^{87}Rb Raman laser. By combining measurements of the laser light field with nondemolition measurements of the atomic populations, we infer the response of the gain medium represented by a collective atomic Bloch vector. The results are qualitatively explained with a simple model. Measurements and theory are extended to include the effect of intermediate repumping states on the closed loop stability of the oscillator and the role of cavity feedback on stabilizing or enhancing relaxation oscillations. This experimental study of the stability of an optical laser operating deep into the bad-cavity regime will guide future development of superradiant lasers with ultranarrow linewidths. PMID- 23368461 TI - Coherent control of microwave pulse storage in superconducting circuits. AB - Coherent pulse control for quantum memory is viable in the optical domain but nascent in microwave quantum circuits. We show how to realize coherent storage and on-demand pulse retrieval entirely within a superconducting circuit by exploiting and extending existing electromagnetically induced transparency technology in superconducting quantum circuits. Our scheme employs a linear array of superconducting artificial atoms coupled to a microwave transmission line. PMID- 23368462 TI - Experimental realization of three-color entanglement at optical fiber communication and atomic storage wavelengths. AB - Entangled states of light including low-loss optical fiber transmission and atomic resonance frequencies are essential resources for future quantum information networks. We present the experimental achievement on the three-color entanglement generation at 852, 1550, and 1440 nm wavelengths for optical continuous variables. The entanglement generation system consists of two cascaded nondegenerated optical parametric oscillators (NOPOs). The flexible selectivity of nonlinear crystals in the two NOPOs and the tunable property of NOPO provide large freedom for the frequency selection of three entangled optical beams. The presented system will hopefully be developed as a practical entangled source to be used in quantum-information networks with atomic storage units and long fiber transmission lines. PMID- 23368463 TI - Magnetic sensitivity beyond the projection noise limit by spin squeezing. AB - We report the generation of spin squeezing and entanglement in a magnetically sensitive atomic ensemble, and entanglement-enhanced field measurements with this system. A maximal m(f) = +/- 1 Raman coherence is prepared in an ensemble of 8.5 * 10(5) laser-cooled (87)Rb atoms in the f = 1 hyperfine ground state, and the collective spin is squeezed by synthesized optical quantum nondemolition measurement. This prepares a state with large spin alignment and noise below the projection-noise level in a mixed alignment-orientation variable. 3.2 dB of noise reduction is observed and 2.0 dB of squeezing by the Wineland criterion, implying both entanglement and metrological advantage. Enhanced sensitivity is demonstrated in field measurements using alignment-to-orientation conversion. PMID- 23368464 TI - Majorana-like modes of light in a one-dimensional array of nonlinear cavities. AB - The search for Majorana fermions in p-wave paired fermionic systems has recently moved to the forefront of condensed matter research. Here we propose an alternative route and show theoretically that Majorana-like modes can be realized and probed in a driven-dissipative system of strongly correlated photons consisting of a chain of tunnel-coupled cavities, where p-wave pairing effectively arises from the interplay between strong on-site interactions and two photon parametric driving. The nonlocal nature of these exotic modes could be demonstrated through cross-correlation measurements carried out at the ends of the chain--revealing a strong photon-bunching signature--and their non-Abelian properties could be simulated through tunnel-braid operations. PMID- 23368465 TI - Coherent random fiber laser based on nanoparticles scattering in the extremely weakly scattering regime. AB - We demonstrate the realization of a coherent random fiber laser (RFL) in the extremely weakly scattering regime, which contains a dispersive solution of polyhedral oligomeric silsesquioxanes nanoparticles (NPs) and laser dye pyrromethene 597 in carbon disulfide that was injected into a hollow optical fiber. Multiple scattering of polyhedral oligomeric silsesquioxanes NPs greatly enhanced by the waveguide confinement effect was experimentally verified to account for coherent lasing observed in our RFL system. This Letter extends the NPs-based RFLs from the incoherent regime to the coherent regime. PMID- 23368466 TI - Nonuniversal intensity correlations in a two-dimensional Anderson-localizing random medium. AB - Complex dielectric media often appear opaque because light traveling through them is scattered multiple times. Although the light scattering is a random process, different paths through the medium can be correlated encoding information about the medium. Here, we present spectroscopic measurements of nonuniversal intensity correlations that emerge when embedding quantum emitters inside a disordered photonic crystal that is found to Anderson-localize light. The emitters probe in situ the microscopic details of the medium, and imprint such near-field properties onto the far-field correlations. Our findings provide new ways of enhancing light-matter interaction for quantum electrodynamics and energy harvesting, and may find applications in subwavelength diffuse-wave spectroscopy for biophotonics. PMID- 23368467 TI - Measuring extreme vacuum pressure with ultraintense lasers. AB - We show that extreme vacuum pressures can be measured with current technology by detecting the photons produced by the relativistic Thomson scattering of ultraintense laser light by the electrons of the medium. We compute the amount of radiation scattered at different frequencies and angles when a Gaussian laser pulse crosses a vacuum tube and design strategies for the efficient measurement of pressure. In particular, we show that a single day experiment at a high repetition rate petawatt laser facility such as Vega, that will be operating in 2014 in Salamanca, will be sensitive, in principle, to pressures p as low as 10( 16)Pa, and will be able to provide highly reliable measurements for p >/~ 10( 14)Pa. PMID- 23368468 TI - Implications of the Monin-Yaglom relation for Rayleigh-Taylor turbulence. AB - The aim of this letter is to assess existing theories for Rayleigh-Taylor small turbulent scales. For this purpose, we propose to adapt the Monin-Yaglom relation to the Rayleigh-Taylor turbulence context. A special emphasis is put on the inhomogeneity of the flow and on the effect of buoyancy forces. This relation is then used to show that, among existing theories, the standard Kolmogorov-Obukhov theory should apply to Rayleigh-Taylor turbulence in the limit of a large Reynolds number, large times, and small scales. PMID- 23368469 TI - Testing a missing spectral link in turbulence. AB - Although the cardinal attribute of turbulence is the velocity fluctuations, these fluctuations have been ignored in theories of the frictional drag of turbulent flows. Our goal is to test a new theory that links the frictional drag to the spectral exponent alpha, a property of the velocity fluctuations in a flow. We use a soap-film channel wherein for the first time the value of alpha can be switched between 3 and 5/3, the two theoretically possible values in soap-film flows. To induce turbulence with alpha = 5/3, we make one of the edges of the soap-film channel serrated. Remarkably, the new theory of the frictional drag holds in both soap-film flows (for either value of the spectral exponent alpha) and ordinary pipe flows (where alpha = 5/3), even though these types of flow are governed by different equations. PMID- 23368470 TI - Heat transport in low-Rossby-number Rayleigh-Benard convection. AB - We demonstrate, via simulations of asymptotically reduced equations describing rotationally constrained Rayleigh-Benard convection, that the efficiency of turbulent motion in the fluid bulk limits overall heat transport and determines the scaling of the nondimensional Nusselt number Nu with the Rayleigh number Ra, the Ekman number E, and the Prandtl number sigma. For E << 1 inviscid scaling theory predicts and simulations confirm the large Ra scaling law Nu-1 ~ C(1)sigma(-1/2)Ra(3/2)E(2), where C(1) is a constant, estimated as C(1) ~ 0.04 +/ 0.0025. In contrast, the corresponding result for nonrotating convection, Nu-1 ~ C(2)Ra(alpha), is determined by the efficiency of the thermal boundary layers (laminar: 0.28 <= alpha <= 0.31, turbulent: alpha ~ 0.38). The 3/2 scaling law breaks down at Rayleigh numbers at which the thermal boundary layer loses rotational constraint, i.e., when the local Rossby number ~ 1. The breakdown takes place while the bulk Rossby number is still small and results in a gradual transition to the nonrotating scaling law. For low Ekman numbers the location of this transition is independent of the mechanical boundary conditions. PMID- 23368471 TI - Electromagnetic vortex fields, spin, and spin-orbit interactions in electron vortices. AB - Electron vortices are shown to possess electric and magnetic fields by virtue of their quantized orbital angular momentum and their charge and current density sources. The spatial distributions of these fields are determined for a Bessel electron vortex. It is shown how these fields lead naturally to interactions involving coupling to the spin magnetic moment and spin-orbit interactions which are absent for ordinary electron beams. The orders of magnitude of the effects are estimated here for angstrom scale electron vortices generated within a typical electron microscope. PMID- 23368472 TI - Femtosecond x-ray pulse characterization in free-electron lasers using a cross correlation technique. AB - We report the first measurements of x-ray single-pulse duration and two-pulse separation at the Linac Coherent Light Source using a cross-correlation technique involving x rays and electrons. An emittance-spoiling foil is adopted as a very simple and effective method to control the output x-ray pulse. A minimum pulse duration of about 3 fs full width at half maximum has been measured together with a controllable pulse separation (delay) between two pulses. This technique provides critical temporal diagnostics for x-ray experiments such as x-ray pump probe studies. PMID- 23368473 TI - Toward astrophysical turbulence in the laboratory. AB - Turbulence is a ubiquitous phenomenon in space and astrophysical plasmas, driving a cascade of energy from large to small scales and strongly influencing the plasma heating resulting from the dissipation of the turbulence. Modern theories of plasma turbulence are based on the fundamental concept that the turbulent cascade of energy is caused by the nonlinear interaction between counterpropagating Alfven waves, yet this interaction has never been observationally or experimentally verified. We present here the first experimental measurement in a laboratory plasma of the nonlinear interaction between counterpropagating Alfven waves, the fundamental building block of astrophysical plasma turbulence. This measurement establishes a firm basis for the application of theoretical ideas developed in idealized models to turbulence in realistic space and astrophysical plasma systems. PMID- 23368474 TI - Relativistic high-current electron-beam stopping-power characterization in solids and plasmas: collisional versus resistive effects. AB - We present experimental and numerical results on intense-laser-pulse-produced fast electron beams transport through aluminum samples, either solid or compressed and heated by laser-induced planar shock propagation. Thanks to absolute K(alpha) yield measurements and its very good agreement with results from numerical simulations, we quantify the collisional and resistive fast electron stopping powers: for electron current densities of ~ 8 * 10(10) A/cm(2) they reach 1.5 keV/MUm and 0.8 keV/MUm, respectively. For higher current densities up to 10(12)A/cm(2), numerical simulations show resistive and collisional energy losses at comparable levels. Analytical estimations predict the resistive stopping power will be kept on the level of 1 keV/MUm for electron current densities of 10(14)A/cm(2), representative of the full-scale conditions in the fast ignition of inertially confined fusion targets. PMID- 23368475 TI - Plasma-based accelerator with magnetic compression. AB - Electron dephasing is a major gain-inhibiting effect in plasma-based accelerators. A novel method is proposed to overcome dephasing, in which the modulation of a modest [~O(10 kG)], axial, uniform magnetic field in the acceleration channel leads to densification of the plasma through magnetic compression, enabling direct, time-resolved control of the plasma wave properties. The methodology is broadly applicable and can be optimized to improve the leading acceleration approaches, including plasma beat wave, plasma wakefield, and laser wakefield acceleration. The advantages of magnetic compression are compared to other proposed techniques to overcome dephasing. PMID- 23368477 TI - Adiabatic cooling of trapped non-neutral plasmas. AB - Non-neutral plasmas can be trapped for long times by means of combined electric and magnetic fields. Adiabatic cooling is achieved by slowly decreasing the trapping frequency and letting the plasma occupy a larger volume. We develop a fully kinetic time-dependent theory of adiabatic cooling for plasmas trapped in a one-dimensional well. This approach is further extended to three dimensions and applied to the cooling of antiproton plasmas, showing excellent agreement with recent experiments [Gabrielse et al., Phys. Rev. Lett. 106, 073002 (2011)]. PMID- 23368476 TI - Ablation pressure driven by an energetic electron beam in a dense plasma. AB - An intense beam of high energy electrons may create extremely high pressures in solid density materials. An analytical model of ablation pressure formation and shock wave propagation driven by an energetic electron beam is developed and confirmed with numerical simulations. In application to the shock-ignition approach in inertial confinement fusion, the energy transfer by fast electrons may be a dominant mechanism of creation of the igniting shock wave. An electron beam with an energy of 30 keV and energy flux 2-5 PW/cm(2) can create a pressure amplitude more than 300 Mbar for a duration of 200-300 ps in a precompressed solid material. PMID- 23368478 TI - Nanomechanical energy storage in twisted nanotube ropes. AB - We determine the deformation energetics and energy density of twisted carbon nanotubes and nanotube ropes that effectively constitute a torsional spring. Using ab initio and parametrized density functional calculations, we identify structural changes in these systems and determine their elastic limits. The deformation energy of twisted nanotube ropes contains contributions associated not only with twisting but also with stretching, bending, and compression of individual nanotubes. We quantify these energy contributions and show that their relative role changes with the number of nanotubes in the rope. PMID- 23368479 TI - Microscopic mechanism of shear bands in amorphous solids. AB - The fundamental instability responsible for the shear localization which results in shear bands in amorphous solids remains unknown despite an enormous amount of research, both experimental and theoretical. As this is the main mechanism for the failure of metallic glasses, understanding the instability is invaluable in finding how to stabilize such materials against the tendency to shear localize. In this Letter we explain the mechanism for shear localization under shear, which is the appearance of highly correlated lines of Eshelby-like quadrupolar singularities which organize the nonaffine plastic flow of the amorphous solid into a shear band. We prove analytically that such highly correlated solutions in which N quadrupoles are aligned with equal orientations are minimum energy states when the strain is high enough. The line lies at 45 degrees to the compressive stress. PMID- 23368480 TI - Fracturing highly disordered materials. AB - We investigate the role of disorder on the fracturing process of heterogeneous materials by means of a two-dimensional fuse network model. Our results in the extreme disorder limit reveal that the backbone of the fracture at collapse, namely, the subset of the largest fracture that effectively halts the global current, has a fractal dimension of 1.22 +/- 0.01. This exponent value is compatible with the universality class of several other physical models, including optimal paths under strong disorder, disordered polymers, watersheds and optimal path cracks on uncorrelated substrates, hulls of explosive percolation clusters, and strands of invasion percolation fronts. Moreover, we find that the fractal dimension of the largest fracture under extreme disorder, d(f) = 1.86 +/- 0.01, is outside the statistical error bar of standard percolation. This discrepancy is due to the appearance of trapped regions or cavities of all sizes that remain intact till the entire collapse of the fuse network, but are always accessible in the case of standard percolation. Finally, we quantify the role of disorder on the structure of the largest cluster, as well as on the backbone of the fracture, in terms of a distinctive transition from weak to strong disorder characterized by a new crossover exponent. PMID- 23368481 TI - Thermodynamic measurements of Fe-Rh alloys. AB - FeRh undergoes an unusual antiferromagnetic-to-ferromagnetic (AFM-FM) transition just above room temperature (T(AFM>FM)) that can be tuned or even completely suppressed with small changes in composition. The underlying temperature dependent entropy difference between the competing AFM and FM states that drives this transition is measured by specific heat as a function of temperature from 2 to 380 K on two nearly equiatomic epitaxial Fe-Rh films, one with a ferromagnetic ground state (Fe-rich) and the other with an antiferromagnetic ground state (Rh rich). The FM state shows an excess heat capacity near 100 K associated with magnetic excitations that are not present in the AFM state. The integrated entropy and enthalpy differences between the two alloys up to T(AFM>FM) agree with the previously measured entropy of the transition (DeltaS = 17 +/- 3 J/kg/K) and yield a T=0 energy difference of 3.4 J/g, consistent with literature calculations and experimental data; this agreement supports the use of the Fe rich FM sample as a proxy for the (unstable) FM state of the AFM Rh-rich sample. From the low-temperature specific heat, along with sound velocity and photoemission measurements, the lattice contribution to the difference (DeltaS(latt) = -33 +/- 9 J/kg/K) and electronic contribution (DeltaS(el) = 8 +/- 1 J/kg/K) to the difference in entropy are calculated, from which the excess heat capacity in the FM phase and the resulting entropy difference are shown to be dominated by magnetic fluctuations (DeltaS(mag) = 43 +/- 9 J/kg/K). The excess magnetic heat capacity is dominated by the magnetic heat capacity of the FM phase, which can be fit to a Schottky-like anomaly with an energy splitting of 16 +/- 1 meV and a multiplicity of 1 per unit cell. PMID- 23368482 TI - Electronic Griffiths phase in the Te-doped semiconductor FeSb2. AB - We report on the emergence of an electronic Griffiths phase in the doped semiconductor FeSb(2), predicted for disordered insulators with random localized moments in the vicinity of a metal-insulator transition. Magnetic, transport, and thermodynamic measurements of Fe(Sb(1-x)Te(x))(2) single crystals show signatures of disorder-induced non-Fermi liquid behavior and a Wilson ratio expected for strong electronic correlations. The electronic Griffiths phase states are found on the metallic boundary between the insulating state (x = 0) and a long-range albeit weak magnetic order (x >= 0.075). PMID- 23368483 TI - Creep, flow, and phase slippage regimes: an extensive view of the sliding charge density wave revealed by coherent X-ray diffraction. AB - Coherent x-ray diffraction experiments have been used to probe the dynamics of the charge density wave (CDW) in the quasi-1D system NbSe(3). The 2k(F) satellite reflection associated with the CDW has been measured with respect to external dc currents, below and above the depinning current. These measurements illustrate for the first time the extensive behavior of a moving electronic crystal: the creep regime, with nucleation of CDW dislocations, the flow regime, with motional ordering, along with phase slippage and the role of strong pinning due to an extrinsic defect. PMID- 23368484 TI - Impurity state and variable range hopping conduction in graphene. AB - The variable range hopping theory, as formulated for exponentially localized impurity states, does not necessarily apply in the case of graphene with covalently attached impurities. We analyze the localization of impurity states in graphene using the nearest-neighbor, tight-binding model of an adatom-graphene system with Green's function perturbation methods. The amplitude of the impurity state wave function is determined to decay as a power law with exponents depending on sublattice, direction, and the impurity species. We revisit the variable range hopping theory in view of this result and find that the conductivity depends as a power law of the temperature with an exponent related to the localization of the wave function. We show that this temperature dependence is in agreement with available experimental results. PMID- 23368485 TI - Electron-phonon bound states in graphene in a perpendicular magnetic field. AB - The spectrum of electron-phonon complexes in monolayer graphene is investigated in the presence of a perpendicular quantizing magnetic field. Despite the small electron-phonon coupling, usual perturbation theory is inapplicable for the calculation of the scattering amplitude near the threshold of optical phonon emission. Our findings, beyond perturbation theory, show that the true spectrum near the phonon-emission threshold is completely governed by new branches, corresponding to bound states of an electron and an optical phonon with a binding energy of the order of alphaomega(0), where alpha is the electron-phonon coupling and omega(0) the phonon energy. PMID- 23368486 TI - Possible anti-Pfaffian pairing of composite fermions at nu = 3/8. AB - We predict that an incompressible fractional quantum Hall state is likely to form at nu = 3/8 as a result of a chiral p-wave pairing of fully spin polarized composite fermions carrying four quantized vortices, and that the pairing is of the anti-Pfaffian kind. Experimental ramifications include quasiparticles with non-Abelian braid statistics and upstream neutral edge modes. PMID- 23368488 TI - Low-doping anomalies in high-Tc cuprate superconductors as evidence of a spin fluctuation-mediated superconducting state. AB - We present a theoretical study of the impact of spin fluctuations on electronic properties when these fluctuations are soft and strong, as in low-doped cuprates. We show that they play a triple role: they mediate d pairing, destroy the coherence of antinodal electrons, and create a spin density wave pseudogap. The competition between these effects is responsible for numerous electron anomalies close to those observed experimentally in the low-doping superconducting state. PMID- 23368487 TI - Atomic and Electronic Structure of the BaTiO(3)(001) (sqrt[5] * sqrt[5])R26.6 degrees Surface Reconstruction. AB - This contribution presents a study of the atomic and electronic structure of the (sqrt[5] * sqrt[5])R26.6 degrees surface reconstruction on BaTiO(3) (001) formed by annealing in ultrahigh vacuum at 1300 K. Through density functional theory calculations in concert with thermodynamic analysis, we assess the stability of several BaTiO(3) surface reconstructions and construct a phase diagram as a function of the chemical potential of the constituent elements. Using both experimental scanning tunneling microscopy (STM) and scanning tunneling spectroscopy measurements, we were able to further narrow down the candidate structures, and conclude that the surface is either TiO(2)-Ti(3/5), TiO(2) Ti(4/5), or some combination, where Ti adatoms occupy hollow sites of the TiO(2) surface. Density functional theory indicates that the defect states close to the valence band are from Ti adatom 3d orbitals (~ 1.4 eV below the conduction band edge) in agreement with scanning tunneling spectroscopy measurements showing defect states 1.56 +/- 0.11 eV below the conduction band minimum (1.03 +/- 0.09 eV below the Fermi level). STM measurements show electronic contrast between empty and filled states' images. The calculated local density of states at the surface shows that Ti 3d states below and above the Fermi level explain the difference in electronic contrast in the experimental STM images by the presence of electronically distinctive arrangements of Ti adatoms. This work provides an interesting contrast with the related oxide SrTiO(3), for which the (001) surface (sqrt[5] * sqrt[5])R26.6 degrees reconstruction is reported to be the TiO(2) surface with Sr adatoms. PMID- 23368454 TI - Measurement of the cross section for electromagnetic dissociation with neutron emission in Pb-Pb collisions at sqrt[s(NN)] = 2.76 TeV. AB - The first measurement of neutron emission in electromagnetic dissociation of ^{208}Pb nuclei at the LHC is presented. The measurement is performed using the neutron zero degree calorimeters of the ALICE experiment, which detect neutral particles close to beam rapidity. The measured cross sections of single and mutual electromagnetic dissociation of Pb nuclei at sqrt[s(NN)]=2.76 TeV with neutron emission are sigma(singleEMD)=187.4 +/- 0.2(stat)(-11.2)(+13.2) (syst) b and sigma(mutualEMD) = 5.7 +/- 0.1(stat) +/- 0.4(syst) b, respectively. The experimental results are compared to the predictions from a relativistic electromagnetic dissociation model. PMID- 23368489 TI - Resonantly tunable Majorana polariton in a microwave cavity. AB - We study the spectrum of a one-dimensional Kitaev chain placed in a microwave cavity. In the off-resonant regime, the frequency shift of the cavity can be used to identify the topological phase transition of the coupled system. In the resonant regime, the topology of the system is sensitive to the presence of photons in the microwave cavity and, moreover, for a large number of photons (classical limit), the physics becomes similar to that of periodically driven systems (Floquet insulators). We also analyze numerically a finite chain and show the existence of a degenerate subspace in the presence of the cavity that can be interpreted as a Majorana polariton. PMID- 23368453 TI - Pion, kaon, and proton production in central Pb-Pb collisions at sqrt[s(NN)] = 2.76 TeV. AB - In this Letter we report the first results on pi(+/-), K(+/-), p, and p production at midrapidity (|y|<0.5) in central Pb-Pb collisions at sqrt[s(NN)] = 2.76 TeV, measured by the ALICE experiment at the LHC. The p(T) distributions and yields are compared to previous results at sqrt[s(NN)] = 200 GeV and expectations from hydrodynamic and thermal models. The spectral shapes indicate a strong increase of the radial flow velocity with sqrt[s(NN)], which in hydrodynamic models is expected as a consequence of the increasing particle density. While the K/pi ratio is in line with predictions from the thermal model, the p/pi ratio is found to be lower by a factor of about 1.5. This deviation from thermal model expectations is still to be understood. PMID- 23368490 TI - Periodic steady regime and interference in a periodically driven quantum system. AB - We study the coherent dynamics of a quantum many-body system subject to a time periodic driving. We argue that in many cases, destructive interference in time makes most of the quantum averages time periodic, after an initial transient. We discuss in detail the case of a quantum Ising chain periodically driven across the critical point, finding that, as a result of quantum coherence, the system never reaches an infinite temperature state. Floquet resonance effects are moreover observed in the frequency dependence of the various observables, which display a sequence of well-defined peaks or dips. Extensions to nonintegrable systems are discussed. PMID- 23368491 TI - Competition between Kondo screening and indirect magnetic exchange in a quantum box. AB - Nanoscale systems of metal atoms antiferromagnetically exchange coupled to several magnetic impurities are shown to exhibit an unconventional reentrant competition between Kondo screening and indirect magnetic exchange interaction. Depending on the atomic positions of the magnetic moments, the total ground-state spin deviates from predictions of standard Ruderman-Kittel-Kasuya-Yosida perturbation theory. The effect shows up on an energy scale larger than the level width induced by the coupling to the environment and is experimentally accessible by studying magnetic field dependencies. PMID- 23368492 TI - Macroscopic magnetic frustration. AB - Although geometrical frustration transcends scale, it has primarily been evoked in the micro- and mesoscopic realm to characterize such phases as spin ice, liquids, and glasses and to explain the behavior of such materials as multiferroics, high-temperature superconductors, colloids, and copolymers. Here we introduce a system of macroscopic ferromagnetic rotors arranged in a planar lattice capable of out-of-plane movement that exhibit the characteristic honeycomb spin ice rules studied and seen so far only in its mesoscopic manifestation. We find that a polarized initial state of this system settles into the honeycomb spin ice phase with relaxation on multiple time scales. We explain this relaxation process using a minimal classical mechanical model that includes Coulombic interactions between magnetic charges located at the ends of the magnets and viscous dissipation at the hinges. Our study shows how macroscopic frustration arises in a purely classical setting that is amenable to experiment, easy manipulation, theory, and computation, and shows phenomena that are not visible in their microscopic counterparts. PMID- 23368493 TI - Electrostatic spin crossover and concomitant electrically operated spin switch action in a ti-based endohedral metallofullerene polymer. AB - Herein, we predict that a 1D chain of Ti@C(32) - C(2) - Ti@C(32) (TEMF) will act as a spin switch in the presence of an electric field. The spin resolved density of states analyses reveal that, surprisingly, both the low- and high-spin states of TEMF are half-metal; however, the metallic density of states comes from the opposite spin channels of the two spin states. More remarkably, it is found that the electric field driven spin crossover between the low and high state in TEMF is achievable at field strength 1.04 V/nm, which eventually leads to the realization of the first ever electrically operated spin switch device. PMID- 23368494 TI - Successive magnetic phase transitions and multiferroicity in the spin-one triangular-lattice antiferromagnet Ba3NiNb2O9. AB - We report the magnetic and electric properties of Ba3NiNb2O9, which is a quasi two-dimensional spin-one triangular-lattice antiferromagnet with trigonal structure. At low T and with increasing magnetic field, the system evolves from a 120 degree magnetic ordering phase (A phase) to an up-up-down (uud) phase (B phase) with a change of slope at 1/3 of the saturation magnetization, and then to an "oblique" phase (C phase). Accordingly, the ferroelectricity switches on at each phase boundary with appearance of spontaneous polarization. Therefore, Ba3NiNb2O9 is a unique triangular-lattice antiferromagnet exhibiting both uud phase and multiferroicity. PMID- 23368495 TI - Aperiodic spin state ordering of bistable molecules and its photoinduced erasing. AB - We describe a novel type of ordering phenomenon associated with the incommensurate occupational modulation of bistable molecular magnetic state in a spin-crossover material. This unusual type of aperiodicity resulting from the ordering of multistable electronic states opens new possibilities for addressing such materials by light. Here we show that light can switch the crystal from four to three-dimensional periodic structure. Mixing aperiodicity, multistability, and photoinduced phenomena opens new perspectives for directing complex order and function in material science. PMID- 23368496 TI - Nature of weak magnetism in SrTiO3/LaAlO3 multilayers. AB - We report the observation of weak magnetism in superlattices of LaAlO(3)/SrTiO(3) using beta-detected nuclear magnetic resonance. The spin lattice relaxation rate of ^{8}Li in superlattices with a spacer layers of 8 and 6 unit cells of LaAlO(3) exhibits a strong peak near ~35 K, whereas no such peak is observed in a superlattice with spacer layer thickness of 3 unit cells. We attribute the observed temperature dependence to slowing down of weakly coupled electronic moments at the LaAlO(3)/SrTiO(3) interface. These results show that the magnetism at the interface depends strongly on the thickness of the spacer layer, and that a minimal thickness of ~4-6 unit cells is required for the appearance of magnetism. A simple model is used to determine that the observed relaxation is due to small fluctuating moments (~0.002MU(B)) in the two samples with a larger LaAlO(3) spacer thickness. PMID- 23368497 TI - Proposed coherent trapping of a population of electrons in a C60 molecule induced by laser excitation. AB - This Letter demonstrates the possibility of generating coherent population trapping in C(60). Similar to a three-level Lambda system, C(60) has a forbidden transition between the highest occupied molecular orbital (HOMO) (|a}) and the lowest unoccupied molecular orbital (LUMO) (|c}), but a dipole-allowed transition between HOMO and LUMO+1 (|b}) and between |b} and |c}. We employ two cw laser fields, one coupling and one probe. The strong coupling field is switched on first to resonantly excite the transition between |b} and |c}. After a delay, the probe is switched on; the coherent interaction between the coupling and probe fields traps the population in |a} and |c}. This forms a partially dark state in C(60), analogous to that in atomic vapors. Turning off the coupling field restores C(60)'s absorption. Pulsed lasers work as well. We use two pulses to steer the system into a dark state; when we send in a cw probe field, the electric polarization of C(60) plunges by five times, in comparison with the noncontrol case. This should be detectable experimentally. PMID- 23368498 TI - Measurement and modeling of a complete optical absorption and scattering by coherent surface plasmon-polariton excitation using a silver thin-film grating. AB - We demonstrate the plasmonic analogue of a coherent photonic effect known as coherent perfect absorption. A periodically nanopatterned metal film perfectly absorbs multiple coherent light beams coupling to a single surface plasmon mode. The perfect absorbing state can be switched to a nearly perfect scattering state by tuning the phase difference between the incident beams. We theoretically explain the plasmonic coherent perfect absorption by considering time-reversal symmetry of surface plasmon amplification by stimulated emission of radiation. We experimentally demonstrate coherent control of the plasmonic absorption in good agreement with a coupled-mode theory of dissipative resonances. Associated potential applications include absorption-based plasmonic switches, modulators, and light-electricity transducers. PMID- 23368499 TI - Microwave loss in the high-performance dielectric Ba(Zn1/3Ta2/3)O3 at 4.2 K. AB - Temperature- and magnetic-field-dependent measurements of the loss tangent in Ba(Zn(1/3)Ta(2/3))O(3) doped with transition metals (Mn, Ni) are compared to those from samples doped with other impurities (Cd, Ga, Mg, and Zr). These results, combined with pulsed electron paramagnetic resonance measurements, show conclusively that microwave loss in transition-metal-doped Ba(Zn(1/3)Ta(2/3))O(3) at cryogenic temperatures is attributable to resonant spin excitations of unpaired transition-metal d electrons in isolated atoms (light doping) or exchange coupled clusters (moderate to high doping), a mechanism that differs from the usual suspects. PMID- 23368500 TI - Effect of 90 degrees domain walls and thermal expansion mismatch on the pyroelectric properties of epitaxial PbZr0.2Ti0.8O3 thin films. AB - We have investigated the contribution of 90 degrees domain walls and thermal expansion mismatch to pyroelectricity in PbZr(0.2)Ti(0.8)O(3) thin films. The first phenomenological models to include extrinsic and secondary contributions to pyroelectricity in polydomain films predict significant extrinsic contributions (arising from the temperature-dependent motion of domain walls) and large secondary contributions (arising from thermal expansion mismatch between the film and the substrate). Phase-sensitive pyroelectric current measurements are applied to model thin films for the first time and reveal a dramatic increase in the pyroelectric coefficient with increasing fraction of in-plane oriented domains and thermal expansion mismatch. PMID- 23368501 TI - Dynamic coupling between a multistable defect pattern and flow in nematic liquid crystals confined in a porous medium. AB - When a nematic liquid crystal is confined in a porous medium with strong anchoring conditions, topological defects, called disclinations, are stably formed with numerous possible configurations. Since the energy barriers between them are large enough, the system shows multistability. Our lattice Boltzmann simulations demonstrate dynamic couplings between the multistable defect pattern and the flow in a regular porous matrix. At sufficiently low flow speed, the topological defects are pinned at the quiescent positions. As the flow speed is increased, the defects show cyclic motions and nonlinear rheological properties, which depend on whether or not they are topologically constrained in the porous networks. In addition, we discover that the defect pattern can be controlled by controlling the flow. Thus, the flow path is recorded in the porous channels owing to the multistability of the defect patterns. PMID- 23368502 TI - Ion solvation in liquid mixtures: effects of solvent reorganization. AB - Using field-theoretic techniques, we study the solvation of salt ions in liquid mixtures, accounting for the permanent and induced dipole moments, as well as the molecular volume of the species. With no adjustable parameters, we predict solvation energies in both single-component liquids and binary liquid mixtures that are in excellent agreement with experimental data. Our study shows that the solvation energy of an ion is largely determined by the local response of the permanent and induced dipoles, as well as the local solvent composition in the case of mixtures, and does not simply correlate with the bulk dielectric constant. In particular, we show that, in a binary mixture, it is possible for the component with the lower bulk dielectric constant but larger molecular polarizability to be enriched near the ion. PMID- 23368503 TI - Nucleation of ligand-receptor domains in membrane adhesion. AB - We present a comprehensive model for the nucleation of domains in membrane adhesion. We determine the critical number of bonds in a nucleus and calculate the probability distribution of nucleation time from a discrete master equation. The latter is characterized by only four effective rates, which account for cooperative effects between bonds. We validate our model by finding excellent agreement with extensive Langevin simulations. In the range of parameters typical for cell adhesion, we find the critical number of bonds to be small. Furthermore, we find a characteristic separation between the bonds at which nucleation is particularly fast, pointing to potential regulatory mechanisms that could be used to control the cell recognition processes. PMID- 23368504 TI - Crowded, confined, and frustrated: dynamics of molecules tethered to nanoparticles. AB - Above a critical chemistry-dependent molecular weight, all polymer molecules entangle and, as a result, exhibit slow dynamics, enhanced viscosity, and elasticity. Herein we report on the dynamics of low molecular weight polymers tethered to nanoparticles and find that even conventionally unentangled chains manifest dynamical features similar to entangled, long-chain molecules. Our findings are shown to imply that crowding and confinement of polymers on particles produce topological constraints analogous to those in entangled systems. PMID- 23368505 TI - Network observability transitions. AB - In the modeling, monitoring, and control of complex networks, a fundamental problem concerns the comprehensive determination of the state of the system from limited measurements. Using power grids as example networks, we show that this problem leads to a new type of percolation transition, here termed a network observability transition, which we solve analytically for the configuration model. We also demonstrate a dual role of the network's community structure, which both facilitates optimal measurement placement and renders the networks substantially more sensitive to "observability attacks." Aside from their immediate implications for the development of smart grids, these results provide insights into decentralized biological, social, and technological networks. PMID- 23368506 TI - Comment on "Growth inside a corner: the limiting interface shape". AB - A Comment on the Letter by J. Olejarz, et al., Phys. Rev. Lett. 108, 016102 (2012). The authors of the Letter offer a Reply. PMID- 23368508 TI - Comment on "Excitons in molecular aggregates with Levy-type disorder: anomalous localization and exchange broadening of optical spectra". AB - A Comment on the Letter by A. Eisfeld et al. Phys. Rev. Lett. 105, 137402 (2010). The authors of the Letter offer a Reply. PMID- 23368511 TI - Effects of cadmium on the actin cytoskeleton in renal mesangial cells. AB - We provide an overview of our studies on cadmium and the actin cytoskeleton in mesangial cells, from earlier work on the effects of Cd(2+) on actin polymerization in vivo and in vitro, to a role of disruption or stabilization of the cytoskeleton in apoptosis and apoptosis-like death. More recent studies implicate cadmium-dependent association of gelsolin and the Ca(2+)/calmodulin dependent protein kinase II (CaMK-II) with actin filaments in cytoskeletal effects. We also present previously unpublished data concerning cadmium and the disruption of focal adhesions. The work encompasses studies on rat, mouse, and human mesangial cells. The major conclusions are that Cd(2+) acts independently of direct effects on cellular Ca(2+) levels to nevertheless activate Ca(2+) dependent proteins that shift the actin polymerization-depolymerization in favour of depolymerization. Cadmium-dependent translocation of CaMK-IIdelta, gelsolin, and a 50 kDa gelsolin cleavage fragment to the filamentous (F-)actin cytoskeleton appear to be involved. An intact filamentous actin cytoskeleton is required to initiate apoptotic and apoptotic-like death, but F-actin depolymerization is an eventual result. PMID- 23368510 TI - Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. AB - AIM: Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin. METHODS: In this 28-day, randomized, open-label, parallel-group, multicentre study (NCT01175473), patients (mean HbA1c 7.3%) received subcutaneous lixisenatide QD (10 ug weeks 1-2, then 20 ug; n = 77) or liraglutide QD (0.6 mg week 1, 1.2 mg week 2, then 1.8 mg; n = 71) 30 min before breakfast. Primary endpoint was change in postprandial plasma glucose (PPG) exposure from baseline to day 28 during a breakfast test meal. RESULTS: Lixisenatide reduced PPG significantly more than liraglutide [mean change in AUC(0:30-4:30h) : -12.6 vs. 4.0 h.mmol/L, respectively; p < 0.0001 (0:30 h = start of meal)]. Change in maximum PPG excursion was -3.9 mmol/l vs. -1.4 mmol/l, respectively (p < 0.0001). More lixisenatide-treated patients achieved 2-h PPG <7.8 mmol/l (69% vs. 29%). Changes in fasting plasma glucose were greater with liraglutide (-0.3 vs. -1.3 mmol/l, p < 0.0001). Lixisenatide provided greater decreases in postprandial glucagon (p < 0.05), insulin (p < 0.0001) and C-peptide (p < 0.0001). Mean HbA1c decreased in both treatment groups (from 7.2% to 6.9% with lixisenatide vs. 7.4% to 6.9% with liraglutide) as did body weight (-1.6 kg vs. -2.4 kg, respectively). Overall incidence of adverse events was lower with lixisenatide (55%) versus liraglutide (65%), with no serious events or hypoglycaemia reported. CONCLUSIONS: Once daily prebreakfast lixisenatide provided a significantly greater reduction in PPG (AUC) during a morning test meal versus prebreakfast liraglutide. Lixisenatide provided significant decreases in postprandial insulin, C-peptide (vs. an increase with liraglutide) and glucagon, and better gastrointestinal tolerability than liraglutide. PMID- 23368512 TI - NBS1 directly activates ATR independently of MRE11 and TOPBP1. AB - NBS1 plays unique and essential roles in ATM activation in response to DNA double strand breaks. We found that CHK1 phosphorylation and FANCD2 ubiquitination induced by various DNA replication-stalling agents were abrogated in Nbs1 knockout DT40 cells but not in conditional Mre11 knockout cells, indicating an MRE11-independent role for NBS1 in ATR activation. The results of in vitro ATR kinase assay indicated that the N-terminal region of NBS1 directly activates ATR independently of TOPBP1, consistent with the findings that this region of NBS1 directly interacts with ATR. This conclusion was furthermore supported by the results of in vivo experiments; the expression of the N-terminal region of NBS1 fused to PCNA induces ATR activation in Rad17 knockout cells, and the expression of the ATR activation domain of TOPBP1 fused to PCNA induces ATR activation in Nbs1 knockout cells. These results therefore indicate that NBS1 and TOPBP1 have the potential to activate ATR independently, although both are required for functional activation of ATR in vivo. PMID- 23368513 TI - Direct incision versus submucosal tunneling as a method of creating transgastric accesses for natural orifice transluminal endoscopic surgery (NOTES) peritoneoscopy: randomized controlled trial. AB - AIM: The optimal approach for creating accesses for transgastric peritoneoscopy is still uncertain. The present study aims to assess the feasibility of carrying out transgastric submucosal tunnel (SMT) peritoneoscopy and to determine whether this approach improves or restricts access to various sectors within the peritoneal cavity. METHODS: This was a randomized comparative study carried out in an in-vivo survival porcine model. Sixty-six beads in six swine were visualized and touched via gastrotomies created by either direct incision (DI) or SMT. The influence of the type of gastrotomy on improving or restricting access to particular sites within the peritoneal cavity for natural orifice transluminal endoscopic surgery (NOTES) peritoneoscopy was compared. The main outcome measurements were localization score of beads, overall procedural time, morbidities and mortalities. RESULTS: A significantly higher mean (SD) localization score was observed in peritoneoscopies carried out in the DI group (P < 0.001). Both the visualization and the touching scores were significantly better with the DI technique, and the overall yield of NOTES peritoneoscopy with DI and SMT were 72.73% and 60.6%, respectively (P = 0.043). Significantly more beads that were not touched in the SMT group were located in the sub-phrenic area (P = 0.013). The overall procedural time was significantly shorter in the DI group (P = 0.004). No major morbidities or mortalities occurred in any procedures. CONCLUSIONS: SMT resulted in lower visualization and touching scores for transgastric NOTES peritoneoscopy. Alternate methods to improve the diagnostic yield to the sub-phrenic area are required. PMID- 23368514 TI - Comparison of autoantibody-positive and autoantibody-negative pediatric participants enrolled in the T1D Exchange clinic registry. AB - OBJECTIVE: To compare characteristics of autoantibody (aAb)-positive and negative cases of type 1 diabetes (T1D) <18 years old in the T1D Exchange clinic registry. METHODS: An aAb-positive status (n = 6239) required at least one of the aAbs to be positive; an aAb-negative status (n = 485) required negative results on testing of at least two different aAbs. RESULTS: The percentage of males was higher (58% vs. 51%; P = 0.002) and total daily insulin dose lower (P = 0.003) in aAb-negative compared with aAb-positive groups, but both groups had similar distributions of race-ethnicity, diagnosis age, family history of T1D, ketoacidosis at diagnosis, body mass index at diagnosis and at most recent office visit, and current HbA1c. CONCLUSIONS: Male gender and lower total daily insulin dose were more likely in aAb-negative than aAb-positive children with T1D, but no other distinguishing characteristics were identified. Further examination of characteristics of aAb-negative cases may help characterize the heterogeneous nature of T1D. PMID- 23368515 TI - Sepsis and hepatitis together with herpes simplex esophagitis in an immunocompetent adult. AB - Herpes simplex virus (HSV)-induced sepsis affects immunocompromised patients. We report here the case of an immunocompetent adult with sepsis, hepatitis, renal failure and esophagitis. The possibility of HSV should be considered in cases of sepsis without any evident cause, even in immunocompetent patients. The characteristic endoscopic and histological findings of the associated esophagitis may assist the etiology of sepsis. PMID- 23368516 TI - Expanding the boundaries of local similarity analysis. AB - BACKGROUND: Pairwise comparison of time series data for both local and time lagged relationships is a computationally challenging problem relevant to many fields of inquiry. The Local Similarity Analysis (LSA) statistic identifies the existence of local and lagged relationships, but determining significance through a p-value has been algorithmically cumbersome due to an intensive permutation test, shuffling rows and columns and repeatedly calculating the statistic. Furthermore, this p-value is calculated with the assumption of normality -- a statistical luxury dissociated from most real world datasets. RESULTS: To improve the performance of LSA on big datasets, an asymptotic upper bound on the p-value calculation was derived without the assumption of normality. This change in the bound calculation markedly improved computational speed from O(pm2n) to O(m2n), where p is the number of permutations in a permutation test, m is the number of time series, and n is the length of each time series. The bounding process is implemented as a computationally efficient software package, FASTLSA, written in C and optimized for threading on multi-core computers, improving its practical computation time. We computationally compare our approach to previous implementations of LSA, demonstrate broad applicability by analyzing time series data from public health, microbial ecology, and social media, and visualize resulting networks using the Cytoscape software. CONCLUSIONS: The FASTLSA software package expands the boundaries of LSA allowing analysis on datasets with millions of co-varying time series. Mapping metadata onto force-directed graphs derived from FASTLSA allows investigators to view correlated cliques and explore previously unrecognized network relationships. The software is freely available for download at: http://www.cmde.science.ubc.ca/hallam/fastLSA/. PMID- 23368517 TI - Migration within China and from China to the USA: the effects of migration networks, selectivity, and the rural political economy in Fujian Province. AB - This paper tests a new strategy for simultaneously studying internal migration within, and international migration from, China. Our theoretical discussion draws on ideas from migration-networks theory and studies of the transition to a market oriented economy. Data collection is modelled on the Mexican Migration Project. We find that education is more important in initiating internal migration than international migration. Second, although the role of migration networks at a community level seems similar to that for Mexico-USA migration, the networks at a family level show a different pattern. Third, there is evidence that internal and international migration are competing options. Finally, we find that individuals with cadres (public officials) in the family are less likely to undertake internal migration, but more likely to participate in international migration, a finding that highlights the continuing significance of the cadres in coastal rural China. PMID- 23368518 TI - A multispecies polyadenylation site model. AB - BACKGROUND: Polyadenylation is present in all three domains of life, making it the most conserved post-transcriptional process compared with splicing and 5' capping. Even though most mammalian poly(A) sites contain a highly conserved hexanucleotide in the upstream region and a far less conserved U/GU-rich sequence in the downstream region, there are many exceptions. Furthermore, poly(A) sites in other species, such as plants and invertebrates, exhibit high deviation from this genomic structure, making the construction of a general poly(A) site recognition model challenging. We surveyed nine poly(A) site prediction methods published between 1999 and 2011. All methods exploit the skewed nucleotide profile across the poly(A) sites, and the highly conserved poly(A) signal as the primary features for recognition. These methods typically use a large number of features, which increases the dimensionality of the models to crippling degrees, and typically are not validated against many kinds of genomes. RESULTS: We propose a poly(A) site model that employs minimal features to capture the essence of poly(A) sites, and yet, produces better prediction accuracy across diverse species. Our model consists of three dior-trinucleotide profiles identified through principle component analysis, and the predicted nucleosome occupancy flanking the poly(A) sites. We validated our model using two machine learning methods: logistic regression and linear discriminant analysis. Results show that models achieve 85-92% sensitivity and 85-96% specificity in seven animals and plants. When we applied one model from one species to predict poly(A) sites from other species, the sensitivity scores correlate with phylogenetic distances. CONCLUSIONS: A four-feature model geared towards small motifs was sufficient to accurately learn and predict poly(A) sites across eukaryotes. PMID- 23368519 TI - The probabilities of conditionals revisited. AB - According to what is now commonly referred to as "the Equation" in the literature on indicative conditionals, the probability of any indicative conditional equals the probability of its consequent of the conditional given the antecedent of the conditional. Philosophers widely agree in their assessment that the triviality arguments of Lewis and others have conclusively shown the Equation to be tenable only at the expense of the view that indicative conditionals express propositions. This study challenges the correctness of that assessment by presenting data that cast doubt on an assumption underlying all triviality arguments. PMID- 23368520 TI - Dopaminergic and GABA-ergic markers of impulsivity in rats: evidence for anatomical localisation in ventral striatum and prefrontal cortex. AB - Accumulating evidence indicates that impulsivity, in its multiple forms, involves cortical and subcortical mechanisms and abnormal dopamine (DA) transmission. Although decreased DA D2/D3 receptor availability in the nucleus accumbens (NAcb) predicts trait-like impulsivity in rats it is unclear whether this neurochemical marker extends to both the NAcb core (NAcbC) and shell (NAcbS) and whether markers for other neurotransmitter systems implicated in impulsivity such as serotonin (5-HT), endogenous opioids and gamma-amino-butyric acid (GABA) are likewise altered in impulsive rats. We therefore used autoradiography to investigate DA transporter (DAT), 5-HT transporter (5-HTT) and D1, D2/D3, MU opioid and GABA(A) receptor binding in selected regions of the prefrontal cortex and striatum in rats expressing low and high impulsive behaviour on the five choice serial reaction-time task. High-impulsive (HI) rats exhibited significantly lower binding for DAT and D2/D3 receptors in the NAcbS and for D1 receptors in the NAcbC compared with low-impulsive (LI) rats. HI rats also showed significantly lower GABA(A) receptor binding in the anterior cingulate cortex. For all regions where receptor binding was altered in HI rats, binding was inversely correlated with impulsive responding on task. There were no significant differences in binding for 5-HTT or MU-opioid receptors in any of the regions investigated. These results indicate that altered D2/D3 receptor binding is localised to the NAcbS of trait-like impulsive rats and is accompanied by reduced binding for DAT. Alterations in binding for D1 receptors in the NAcbC and GABA(A) receptors in the anterior cingulate cortex demonstrate additional markers and putative mechanisms underlying the expression of behavioural impulsivity. PMID- 23368521 TI - Prediction of peptides binding to MHC class I and II alleles by temporal motif mining. AB - BACKGROUND: MHC (Major Histocompatibility Complex) is a key player in the immune response of most vertebrates. The computational prediction of whether a given antigenic peptide will bind to a specific MHC allele is important in the development of vaccines for emerging pathogens, the creation of possibilities for controlling immune response, and for the applications of immunotherapy. One of the problems that make this computational prediction difficult is the detection of the binding core region in peptides, coupled with the presence of bulges and loops causing variations in the total sequence length. Most machine learning methods require the sequences to be of the same length to successfully discover the binding motifs, ignoring the length variance in both motif mining and prediction steps. In order to overcome this limitation, we propose the use of time-based motif mining methods that work position-independently. RESULTS: The prediction method was tested on a benchmark set of 28 different alleles for MHC class I and 27 different alleles for MHC class II. The obtained results are comparable to the state of the art methods for both MHC classes, surpassing the published results for some alleles. The average prediction AUC values are 0.897 for class I, and 0.858 for class II. CONCLUSIONS: Temporal motif mining using partial periodic patterns can capture information about the sequences well enough to predict the binding of the peptides and is comparable to state of the art methods in the literature. Unlike neural networks or matrix based predictors, our proposed method does not depend on peptide length and can work with both short and long fragments. This advantage allows better use of the available training data and the prediction of peptides of uncommon lengths. PMID- 23368522 TI - Analysis of CAG repeats in five SCA loci in Mexican population: epidemiological evidence of a SCA7 founder effect. AB - Spinocerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders. CAG (cytosine-adenine-guanine) trinucleotide repeat expansions in the causative genes have been identified as the cause of different SCA. In this study, we simultaneously genotyped SCA1, SCA2, SCA3, SCA6, and SCA7 applying a fluorescent multiplex polymerase chain reaction assay. We analyzed 10 families with SCA (64 patients) from five different communities of Veracruz, a Mexican southeastern state, and identified 55 patients for SCA7 and 9 for SCA2, but none for SCA1, SCA3, or SCA6. To our knowledge, this sample represents one of the largest series of SCA7 cases reported worldwide. Genotyping of 300 healthy individuals from Mexican population and compiled data from different ethnicities showed discordant results concerning the hypothesis that SCA disease alleles arise by expansion of large normal alleles. PMID- 23368523 TI - Influence of barley varieties on wort quality and performance. AB - Wort from the barley varieties (Hordeum vulgare) Pallas, Fero, and Archer grown on the same location were investigated for their influence on oxidative stability and volatile profile during wort processing. Barley varieties had a small influence on radical formation, thiol-removing capacity, and volatile profile. Wort boiling with and without hops had a large influence on these same parameters. Potentially antioxidative thiols were oxidized in sweet wort, but reduction of thiols using tris(2-carboxyethyl)phosphine hydrochloride revealed that Archer wort had a significantly larger content of total thiols than Pallas and Fero. Oxidized thiols resulted in gel proteins and longer filtration time for Archer wort. Our study shows that wort processing to a large extent will eliminate variations in volatile profile and thiol levels in wort which otherwise might arise from different barley varieties. PMID- 23368524 TI - Novel trialkanolamine derivatives of tin of the type [N(CH2CMe2O)2(CH2)(n)OSnOR]m (m = 1, 2; n = 2, 3; R = t-Bu, 2,6-Me2C6H3) and related tri- and pentanuclear tin(IV) oxoclusters. Syntheses and molecular structures. AB - The syntheses of the novel alkanolamine N(CH(2)CMe(2)OH)(2)(CH(2)CH(2)CH(2)OH) (2), the novel aminotrialkoxides of tin of the type [N(CH(2)CMe(2)O)(2)(CH(2))(n)OSnOR](m) (3: m = 1, n = 2, R = t-Bu; 4: m = 2, n = 3, R = t-Bu; 5: m = n = 2, R = 2,6-Me(2)C(6)H(3); 6: m = 2, n = 3, R = 2,6 Me(2)C(6)H(3)) and the related trinuclear tin oxoclusters [(LSnOSnL)(LSnOR)] [L = N(CH(2)CMe(2)O)(2)(CH(2)CH(2)O), 7: R = t-Bu; 8: R = 2,6-Me(2)C(6)H(3)] and the pentanuclear tin oxocluster [LSnOSn(OH)(2)OSnL.2LSnOH], [9, L = N(CH(2)CMe(2)O)(2)(CH(2)CH(2)O)] are reported. The compounds are characterized by elemental analyses, multinuclear ((1)H, (13)C, (119)Sn, (1)H-(1)H cosy, (1)H (13)C HSQC) NMR spectroscopy, electrospray ionization mass spectrometry, and single crystal X-ray diffraction analyses (3, 4.C(7)H(8), 5, 7, 8.0.5C(7)H(8), 9.6H(2)O). PMID- 23368525 TI - Multiplexed surrogate analysis of glycotransferase activity in whole biospecimens. AB - Dysregulated glycotransferase enzymes in cancer cells produce aberrant glycans- some of which can help facilitate metastases. Within a cell, individual glycotransferases promiscuously help to construct dozens of unique glycan structures, making it difficult to comprehensively track their activity in biospecimens--especially where they are absent or inactive. Here, we describe an approach to deconstruct glycans in whole biospecimens then analytically pool together resulting monosaccharide-and-linkage-specific degradation products ("glycan nodes") that directly represent the activities of specific glycotransferases. To implement this concept, a reproducible, relative quantitation-based glycan methylation analysis methodology was developed that simultaneously captures information from N-, O-, and lipid linked glycans and is compatible with whole biofluids and homogenized tissues; in total, over 30 different glycan nodes are detectable per gas chromatography-mass spectrometry (GC-MS) run. Numerous nonliver organ cancers are known to induce the production of abnormally glycosylated serum proteins. Thus, following analytical validation, in blood plasma, the technique was applied to a group of 59 lung cancer patient plasma samples and age/gender/smoking-status-matched non-neoplastic controls from the Lung Cancer in Central and Eastern Europe (CEE) study to gauge the clinical utility of the approach toward the detection of lung cancer. Ten smoking independent glycan node ratios were found that detect lung cancer with individual receiver operating characteristic (ROC) c-statistics ranging from 0.76 to 0.88. Two glycan nodes provided novel evidence for altered ST6Gal-I and GnT-IV glycotransferase activities in lung cancer patients. In summary, a conceptually novel approach to the analysis of glycans in unfractionated human biospecimens has been developed that, upon clinical validation for specific applications, may provide diagnostic and/or predictive information in glycan-altering diseases. PMID- 23368526 TI - Hyperoxia-induced alterations in the pulmonary proteome of juvenile rats. AB - High inspired concentrations of oxygen (hyperoxia) are often necessary to counteract tissue hypoxia during the treatment of ARDS. Reactive oxygen species generated by hyperoxic therapy may influence the expression of the pulmonary proteome and the application of discovery proteomics to the hyperoxic lung has the potential to divulge mechanisms regulating the expression of specific proteins integral to lung injury and repair. The present study examined the proteome derived from 30-day-old Sprague-Dawley rats exposed to room air (RA) and 95% O2 (Ox) for 24-72 hours using 2-dimensional difference in-gel electrophoresis (2D-DIGE) coupled with MALDI-ToF/ToF mass spectrometry. A total of 870 protein spots were visualized by 2D-DIGE across all gels. Mass spectral analysis identified 51 proteins representing 187 of the 214 significantly altered spots. Molecular and cellular function analysis grouped the identified proteins into free radical scavenging, cell death, cell-to-cell signaling, and cellular movement categories. The majority of the differences in the protein spots between RA and Ox occurred at 72 hours, with albumin, annexin A6 (AnxA6), and transferrin being increased, and mitochondrial Lon peptidase 1 being decreased by at least 20%. In Ox animals, AnxA6 protein expression increased three-fold without an increase in mRNA expression. Bioinformatic analysis of the AnxA6 transcript revealed the presence of a putative internal ribosome entry site within the 5' untranslated region. These findings indicate that hyperoxia induces significant alterations in the pulmonary proteome which are temporally related. In addition, hyperoxia selectively enhances the expression of some proteins whose transcripts contain sequence motifs, which impart translational regulation. PMID- 23368527 TI - Antidiabetic therapy effects on bone metabolism and fracture risk. AB - Patients with diabetes are at greater risk of fractures mostly due to not only to extraskeletal factors, such as propensity to fall, but also to bone quality alteration, which reduces bone strength. In people with diabetes, insulin deficiency and hyperglycaemia seem to play a role in determining bone formation alteration by advanced glycation end product (AGE) accumulation or AGE/RAGE (receptors for AGE) axis imbalance, which directly influence osteoblast activity. Moreover, hyperglycaemia and oxidative stress are able to negatively influence osteocalcin production and the Wnt signalling pathways with an imbalance of osteoblast/osteoclast activity leading to bone quality reduction as global effect. In addition, other factors such as insulin growth factors and peroxisome proliferator-activated receptor-gamma pathways seem to have an important role in the pathophysiology of osteoporosis in diabetes. Although there are conflicting data in literature, adequate glycaemic control with hypoglycaemic treatment may be an important element in preventing bone tissue alterations in both type 1 and type 2 diabetes. Attention should be paid to the use of thiazolidinediones, especially in older women, because the direct negative effect on bone could exceed the positive effect of glycaemic control. Finally, preliminary data on animals and in humans suggest the hypothesis that incretins and dipeptidyl peptidase-4 inhibitors could have a positive effect on bone metabolism by a direct effect on bone cells; however, such issue needs further investigations. PMID- 23368528 TI - Factors predicting the presence of small bowel lesions in patients with obscure gastrointestinal bleeding. AB - AIM: To identify the predictive factors for the presence of small bowel lesions in patients with obscure gastrointestinal bleeding (OGIB). METHODS: A total of 242 patients with OGIB (overt 149: occult 93) were retrospectively included in the present study. Capsule endoscopy (CE) was carried out to investigate the small bowel, and detected lesions were classified according to the P0-P2 system. Only P2 lesions were defined as significant lesions. Univariate and multivariate logistic regression analyses were carried out to define the predictive factors for the presence of small bowel lesions. RESULTS: In patients with overt OGIB, chronic kidney disease (CKD) >=stage 4 (odds ratio [OR] 4.03; 95% confidence interval [CI] 1.45-11.1, P = 0.007) was identified as an independent predictor of the presence of vascular lesions, and a history of non-steroidalanti-inflammatory drug (NSAID) use as that of erosive/ulcerated lesions (OR 4.73; 95% CI 1.47-15.2, P = 0.009). However, in patients with occult OGIB, no significant predictors of the presence of vascular lesions were identified, whereas a history of low-dose aspirin (LDA) (OR 3.57; 95% CI 1.21-10.5, P = 0.02) and proton pump inhibitor (PPI) use (OR 3.18; 95% CI 1.02-9.92, P = 0.05) were identified as independent predictors of the presence of erosive/ulcerated lesions. CONCLUSIONS: Our results indicated that bleeding pattern and clinical characteristics could contribute to predicting the origin of OGIB. PMID- 23368529 TI - Quantitative assessment of the association between the GSTM1-null genotype and the risk of childhood asthma. AB - BACKGROUND: Many studies investigated the association between the glutathione S transferase M 1 (GSTM1)-null genotype and childhood asthma risk, but there was obvious inconsistence among those studies. The aim of this meta-analysis was to quantify the strength of association between the GSTM1-null genotype and risk of childhood asthma. METHODS: We searched the PubMed, Embase, and Wangfang databases for studies relating the association between the GSTM1-null genotype and risk of childhood asthma. We estimated the pooled odds ratio (OR) with its 95% confidence interval (95% CI) to assess the association. RESULTS: Nineteen case-control studies with 4,543 childhood asthma cases and 19,394 controls were included into this meta-analysis. Meta-analysis of all 19 studies showed that the GSTM1-null genotype was associated with increased risk of childhood asthma (OR=1.17, 95% CI 1.03-1.34, p=0.017). Subgroup analyses by ethnicity suggested that the GSTM1-null genotype was associated with an increased risk of childhood asthma in Caucasians and Africans (for Caucasians, fixed-effects OR=1.16, 95% CI 1.07-1.27, p=0.001; for Africans, fixed-effects OR=1.92, 95% CI 1.35-2.74, p<0.001). The cumulative meta-analyses showed a trend of obvious association between the GSTM1-null genotype and risk of childhood asthma as information accumulated in the analyses of both total studies and Caucasians. No evidence of publication bias was observed. CONCLUSION: Meta-analyses of available data suggest a significant association between the GSTM1-null genotype and the risk of childhood asthma, and the GSTM1-null genotype contributes to increased risk of childhood asthma, especially in Caucasians and Africans. PMID- 23368530 TI - Association between genetic variants of DNA repair genes and coronary artery disease. AB - Polymorphisms in DNA repair genes may be associated with differences in the repair efficiency of DNA damage and may influence an individual's risk of atherosclerosis. Genetic research on coronary artery disease (CAD) has traditionally focused on investigation aimed at identifying disease susceptibility genes. The aim of this study was to investigate the relationship between AP-endonuclease-1 (Asp148Glu), XRCC1 (Arg399Gln), XRCC3 (Thr241Met), XPD (Lys751Gln), XPG (Asp1104His), and hOGG1 (Ser326Cys), gene polymorphisms and the risk of developing CAD in a Turkish population. The study population consisted of 197 patients with acute coronary syndrome (ACS) with chronic CAD and 135 healthy subjects' age and sex matched. Gene polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism method. We demonstrated for the first time, a positive association of XRCC3 and hOGG1 DNA repair gene variants with CAD risk. XRCC3 Thr/Thr genotype and Thr allele frequencies were significantly increased in ACS and chronic CAD patients compared with the control group (p<0.05). It was also observed that there is a protective role of XRCC3 Met alleles against both ACS and chronic CAD (p<0.05). hOGG1 Cys alleles were found significantly higher in ACS patients than in the control group and carriers of the Cys allele had a 1.7-fold increased risk for ACS. In addition, we confirmed the association of XRCC3 Thr241Met and hOGG1 Ser326Cys gene variants with CAD by haplotype analysis. We found that CAD risk is associated with XRCC3 Thr: hOGG1 Cys haplotype, whereas XRCC3 Met: hOGG1 Ser haplotype was found to be protective against the disease. The preliminary results suggested that XRCC3 and hOGG1 genetic variants may be risk factors by affecting the enzyme's function that may lead to development of CAD. PMID- 23368531 TI - Transcriptional expression analysis of survivin splice variants reveals differential expression of survivin-3alpha in breast cancer. AB - Survivin, which is a novel member of the inhibitor of apoptosis family proteins, is known to play an important role in the regulation of cell cycle and apoptosis. Differential expression of survivin in tumor tissues introduces it as a new candidate molecular marker for cancer. Here we investigated the expression of survivin and its splice variants in breast tumors, as well as normal adjacent tissues obtained from the same patients. Thirty five tumors and 17 normal adjacent tissues from women diagnosed with breast cancer were explored in this study. Differential expression of different survivin splice variants was detected and semiquantitatively analyzed using reverse transcription-polymerase chain reaction. Results showed that survivin and its splice variants were differentially expressed in tumor specimens compared with normal adjacent tissues. The expression of survivin-3B and survivin-3alpha was specifically detected in tumor tissues compared with normal adjacent ones (53% in tumor tissues compared to 5% in normal adjacent for survivin-3B and 65% in tumor tissues and 0.0% in normal adjacent tissues for survivin-3alpha). Statistical analysis showed that survivin and survivin-DeltaEx3 were upregulated in benign (90%, p<0.034) and malignant (76%, p<0.042) tumors, respectively. On the other hand, our results showed that survivin-2alpha (100% of the cases) was the dominant expressed variant of survivin in breast cancer. The data presented here showed that survivin splice variants were differentially expressed in benign and malignant breast cancer tissues, suggesting their potential role in breast cancer development. Differential expression of survivin-2alpha and survivin-3alpha splice variants highlights their usefulness as new candidate markers for breast cancer diagnosis and prognosis. PMID- 23368532 TI - Is there any association between the Ser326Cys polymorphism of the 8-oxoguanine glycosylase 1 (OGG1) gene and risk of colon polyp and abnormal glucose tolerance in acromegaly patients? AB - AIM: Evidence arising from experimental studies indicates an association between increased levels of the growth hormone/insulin-like growth factor 1 and oxidative stress. The association of the Ser326Cys polymorphism in the 8-oxoguanine glycosylase (OGG1) gene with a colon carcinoma and diabetes mellitus has been examined. The aim of the study was to compare the genotypic distribution of OGG1 Ser326Cys between acromegaly patients and nonacromegalic subjects and to explore whether this polymorphism is associated with a colon polyp risk and abnormal glucose tolerance. METHODS: We examined 98 acromegaly patients, and 99 healthy subjects who can be compared in terms of age and gender. All participants were evaluated by anthropometric and biochemical measurements. Also, a 75-g oral glucose test and colonoscopy was applied to the patients. Genomic DNA was isolated from peripheral blood leucocytes and the genotype was assessed by melting temperature analyses after using a real-time polymerase chain reaction protocol. RESULTS: Colon polyps were detected in 13 (30.2%) of 43 patients who underwent the colonoscopy. Except for diastolic blood pressure, clinical and biochemical characteristics were similar between the patients diagnosed with and without a colon polyp. A higher proportion of acromegaly patients had the Ser326Ser genotype when compared to the control group (p=0.007). Genotypes were similar between the patients with a normal glucose tolerance and an abnormal glucose tolerance (p=0.774). The frequency of the Cys allele was significantly higher in patients with polyps than those without a polyp (38.5% vs. 18.3%) (p=0.029). CONCLUSION: Our results suggest that the Cys allele may influence the colon polyp risk in acromegaly patients. Large-scale studies with acromegaly patients are required to show whether being a carrier of the Cys allele is associated with the risk of a colorectal polyp. PMID- 23368534 TI - H(2)S signaling in redox regulation of cellular functions. AB - Hydrogen sulfide (H(2)S) is traditionally recognized as a toxic gas with a rotten egg smell. In just the last few decades, H(2)S has been found to be one of a family of gasotransmitters, together with nitric oxide and carbon monoxide, and various physiologic effects of H(2)S have been reported. Among the most acknowledged molecular mechanisms for the cellular effects of H(2)S is the regulation of intracellular redox homeostasis and post-translational modification of proteins through S-sulfhydration. On the one side, H(2)S can promote an antioxidant effect and is cytoprotective; on the other side, H(2)S stimulates oxidative stress and is cytotoxic. This review summarizes our current knowledge of the antioxidant versus pro-oxidant effects of H(2)S in mammalian cells and describes the Janus-faced properties of this novel gasotransmitter. The redox regulation for the cellular effects of H(2)S through S-sulfhydration and the role of H(2)S in glutathione generation is also recapitulated. A better understanding of H(2)S-regualted redox homeostasis will pave the way for future design of novel pharmacological and therapeutic interventions for various diseases. PMID- 23368533 TI - Acute and chronic antihypertensive effects of Cinnamomum zeylanicum stem bark methanol extract in L-NAME-induced hypertensive rats. AB - BACKGROUND: Previous study showed that the aqueous extract of the stem bark of Cinnamomum zeylanicum possesses antihypertensive and vasodilatory properties. The present work investigates the acute and chronic antihypertensive effects of the methanol extract of Cinnamomum zeylanicum stem bark (MECZ) in L-NAME-induced hypertensive rats. METHODS: The acute antihypertensive effects of MECZ (5, 10 and 20 mg/kg) administered intravenously were evaluated in rats in which acute arterial hypertension has been induced by intravenous administration of L-NAME (20 mg/kg). For chronic antihypertensive effects, animals were treated with L NAME (40 mg/kg/day) plus the vehicle or L-NAME (40 mg/kg/day) in combination with captopril (20 mg/kg/day) or MECZ (300 mg/kg/day) and compared with control group receiving only distilled water. All drugs were administered per os and at the end of the experiment that lasted for four consecutive weeks, blood pressure was measured by invasive method and blood samples were collected for the determination of the lipid profile. The heart and aorta were collected, weighed and used for both histological analysis and determination of NO tissue content. RESULTS: Acute intravenous administration of C. zeylanicum extract (5, 10 and 20 mg/kg) to L-NAME-induced hypertensive rats provoked a long-lasting decrease in blood pressure. Mean arterial blood pressure decreased by 12.5%, 26.6% and 30.6% at the doses of 5, 10 and 20 mg/kg, respectively. In chronic administration, MECZ and captopril significantly prevented the increase in blood pressure and organs' weights, as well as tissue histological damages and were able to reverse the depletion in NO tissue's concentration. The MECZ also significantly lower the plasma level of triglycerides (38.1%), total cholesterol (32.1%) and LDL cholesterol (75.3%) while increasing that of HDL-cholesterol (58.4%) with a significant low atherogenic index (1.4 versus 5.3 for L-NAME group). CONCLUSION: MECZ possesses antihypertensive and organ protective effects that may result from its ability to increase the production of the endogenous NO and/or to regulate dyslipidemia. PMID- 23368535 TI - Effect of capsule placement with transnasal endoscopy. AB - AIM: One of the prohibiting factors in achieving complete small bowel capsule endoscopy is slow gastric transit of the capsule. The present study retrospectively investigated the success rate of, and the time required for, transnasal endoscope-assisted capsule placement to assess its clinical utility. METHODS: In 24 of 27 patients who underwent capsule placement assisted by a transnasal endoscope, the capsule was successfully transported to and released in the duodenum (capsule placement group). For each patient in the capsule placement group, three age- and sex-matched patients who underwent conventional capsule endoscopy were assigned as controls (n=72). Gastric transit time, small bowel transit time, and rate of capsule arrival at the cecum within 8h were compared between the two patient groups. RESULTS: Among the 27 patients in whom capsule placement was carried out, the capsule was successfully placed in the duodenum in 24 patients (88.9% success rate). In the capsule placement group, gastric transit time was significantly shorter (10.5 vs 46.2min, P=0.0021), small bowel transit time was significantly longer (354.7 vs 301.3min, P=0.0134), and completion rate (capsule arrival at the cecum within 8h) was significantly higher (83.3 vs 61.1%, P=0.0455) than in the control group. There were no procedural accidents associated with capsule placement. CONCLUSION: Transnasal endoscope-assisted capsule placement appears to be a safe and reliable procedure, achieving complete small bowel capsule endoscopy, and is considered clinically useful. PMID- 23368536 TI - The implications of genomics on the nursing care of adults with neuropsychiatric conditions. AB - PURPOSE: Neuropsychiatric disorders contribute substantially to disease burden and quality of life across the lifespan and the globe. The purpose of this article is to review the state of the science regarding genomic contributions to selected common neuropsychiatric conditions and to examine the consequent immediate and future implications for nursing practice and research. ORGANIZING CONSTRUCT: Our work is guided by an ecological model that recognizes that common diseases are complex or multifactorial, meaning that multiple genomic and environmental factors contribute to their etiology. METHODS: A review of the literature was conducted to determine the state of the science in relationship to the genomic contributions to selected neuropsychiatric disorders. FINDINGS: Neuropsychiatric conditions are genomically heterogeneous, both within a single disorder and across groups of disorders. While recent genomic research yields clinically validated and useful information for a small subset of persons (e.g., predictive genetic testing for Huntington disease and early-onset Alzheimer disease), broad clinical application of genetic information is not yet available. In addition, the implications of genomics for the development and targeting of nonpharmacologic treatment strategies is largely unexplored. CONCLUSIONS: Further research is needed to expand knowledge beyond genomic risk for the presence of disease to knowledge about the genomic risk for symptoms, symptom burden, and tailored symptom management interventions. CLINICAL RELEVANCE: Knowledge about the genomic influences on neuropsychiatric conditions suggests important implications for practicing nurses in the identification of persons at risk, provision of follow-up support, and in the administration of medications. PMID- 23368450 TI - Study of the Dijet mass spectrum in pp -> W+jets events at sqrt[s] = 7 TeV. AB - We report an investigation of the invariant mass spectrum of the two jets with highest transverse momentum in pp -> W+2-jet and W+3-jet events to look for resonant enhancement. The data sample corresponds to an integrated luminosity of 5.0 fb(-1) collected with the CMS detector at sqrt[s] = 7 TeV. We find no evidence for the anomalous structure reported by the CDF Collaboration, and establish an upper limit of 5.0 pb at 95% confidence level on the production cross section for a generic Gaussian signal with mass near 150 GeV. Additionally, we exclude two theoretical models that predict a CDF-like dijet resonance near 150 GeV. PMID- 23368537 TI - Hydrophobic molecules infiltrating into the poly(ethylene glycol) domain of the core/shell interface of a polymeric micelle: evidence obtained with anomalous small-angle X-ray scattering. AB - Polymeric micelles have been extensively studied as nanoscale drug carriers. Knowing the inner structure of polymeric micelles that encapsulate hydrophobic drugs is important to design effective carriers. In our study, the hydrophobic compound tetrabromocathecol (TBC) was chosen as a drug-equivalent model molecule. The bromine atoms in TBC act as probes in anomalous small-angle X-ray scattering (ASAXS) allowing for its localization in the polymeric micelles whose shape and size were determined by normal small-angle X-ray scattering (SAXS). Light scattering measurements coupled with field flow fractionation were also carried out to determine the aggregation number of micelles. A core-corona spherical model was used to explain the shape of the micelles, while the distribution of bromine atoms was explained with a hard-sphere model. Interestingly, the radius of the spherical region populated with bromine atoms was larger than the one of the sphere corresponding to the hydrophobic core of the micelle. This result suggests that the TBC molecules infiltrate the PEG hydrophilic domain in the vicinity of the core/shell interface. The results of light scattering and SAXS indicate that the PEG chains at the shell region are densely packed, and thus the PEG domain close to the interface has enough hydrophobicity to tolerate the presence of hydrophobic compounds. PMID- 23368539 TI - Gapless Hamiltonians for the toric code using the projected entangled pair state formalism. AB - We study Hamiltonians which have Kitaev's toric code as a ground state, and show how to construct a Hamiltonian which shares the ground space of the toric code, but which has gapless excitations with a continuous spectrum in the thermodynamic limit. Our construction is based on the framework of projected entangled pair states, and can be applied to a large class of two-dimensional systems to obtain gapless "uncle Hamiltonians." PMID- 23368540 TI - Quasiuniversal transient behavior of a nonequilibrium Mott insulator driven by an electric field. AB - We use a self-consistent strong-coupling expansion for the self-energy (perturbation theory in the hopping) to describe the nonequilibrium dynamics of strongly correlated lattice fermions. We study the three-dimensional homogeneous Fermi-Hubbard model driven by an external electric field showing that the damping of the ensuing Bloch oscillations depends on the direction of the field and that for a broad range of field strengths a long-lived transient prethermalized state emerges. This long-lived transient regime implies that thermal equilibrium may be out of reach of the time scales accessible in present cold atom experiments but shows that an interesting new quasiuniversal transient state exists in nonequilibrium governed by a thermalized kinetic energy but not a thermalized potential energy. In addition, when the field strength is equal in magnitude to the interaction between atoms, the system undergoes a rapid thermalization, characterized by a different quasiuniversal behavior of the current and spectral function for different values of the hopping. PMID- 23368541 TI - Collective interference of composite two-fermion bosons. AB - The composite character of two-fermion bosons manifests itself in the interference of many composites as a deviation from the ideal bosonic behavior. A state of many composite bosons can be represented as a superposition of different numbers of perfect bosons and fermions, which allows us to provide the full Hong Ou-Mandel-like counting statistics of interfering composites. Our theory quantitatively relates the deviation from the ideal bosonic interference pattern to the entanglement of the fermions within a single composite boson. PMID- 23368542 TI - Security of distributed-phase-reference quantum key distribution. AB - Distributed-phase-reference quantum key distribution stands out for its easy implementation with present day technology. For many years, a full security proof of these schemes in a realistic setting has been elusive. We solve this long standing problem and present a generic method to prove the security of such protocols against general attacks. To illustrate our result, we provide lower bounds on the key generation rate of a variant of the coherent-one-way quantum key distribution protocol. In contrast to standard predictions, it appears to scale quadratically with the system transmittance. PMID- 23368543 TI - Generation of Dicke states with phonon-mediated multilevel stimulated Raman adiabatic passage. AB - We generate half-excited symmetric Dicke states of two and four ions. We use multilevel stimulated Raman adiabatic passage whose intermediate states are phonon Fock states. This process corresponds to the spin squeezing operation and half-excited Dicke states are generated during multilevel stimulated Raman adiabatic passage. This method does not require local access for each ion or the preparation of phonon Fock states. Furthermore, it is robust since it is an adiabatic process. We evaluate the Dicke state using a witness operator and determine the upper and lower bounds of the fidelity without using full quantum tomography. PMID- 23368544 TI - Time evolution and dynamical phase transitions at a critical time in a system of one-dimensional bosons after a quantum quench. AB - A renormalization group approach is used to show that a one-dimensional system of bosons subject to a lattice quench exhibits a finite-time dynamical phase transition where an order parameter within a light cone increases as a nonanalytic function of time after a critical time. Such a transition is also found for a simultaneous lattice and interaction quench where the effective scaling dimension of the lattice becomes time dependent, crucially affecting the time evolution of the system. Explicit results are presented for the time evolution of the boson interaction parameter and the order parameter for the dynamical transition as well as for more general quenches. PMID- 23368545 TI - Quantum ripples over a semiclassical shock. AB - The evolution of an initially smooth spatial inhomogeneity in the density of a one-dimensional Fermi gas is well described by classical mechanics. The classical evolution leads to the formation of a shock wave: the density develops kinks in its coordinate dependence. We show that quantum corrections to the shock wave produce density ripples which run off the kinks. Despite their quantum origin, the amplitude and period of the ripples are expressed only in terms of classical objects derived from a smooth density profile. PMID- 23368546 TI - Anomalous thermodynamics at the microscale. AB - Particle motion at the microscale is an incessant tug-of-war between thermal fluctuations and applied forces on one side and the strong resistance exerted by fluid viscosity on the other. Friction is so strong that completely neglecting inertia--the overdamped approximation--gives an excellent effective description of the actual particle mechanics. In sharp contrast to this result, here we show that the overdamped approximation dramatically fails when thermodynamic quantities such as the entropy production in the environment are considered, in the presence of temperature gradients. In the limit of vanishingly small, yet finite, inertia, we find that the entropy production is dominated by a contribution that is anomalous, i.e., has no counterpart in the overdamped approximation. This phenomenon, which we call an entropic anomaly, is due to a symmetry breaking that occurs when moving to the small, finite inertia limit. Anomalous entropy production is traced back to futile phase-space cyclic trajectories displaying a fast downgradient sweep followed by a slow upgradient return to the original position. PMID- 23368547 TI - Cosmic magnetization: from spontaneously emitted aperiodic turbulent to ordered equipartition fields. AB - It is shown that an unmagnetized nonrelativistic thermal electron-proton plasma spontaneously emits aperiodic turbulent magnetic field fluctuations of strength |deltaB|=3.5beta(e)g(1/3)W(e)(1/2) G, where beta(e) is the normalized thermal electron temperature, W(e) the thermal plasma energy density, and g the plasma parameter. For the unmagnetized intergalactic medium, immediately after the reionization onset, the field strengths from this mechanism are about 2*10(-16) G in cosmic voids and 2*10(-10) G in protogalaxies, both too weak to affect the dynamics of the plasma. Accounting for simultaneous viscous damping reduces these estimates to 2*10(-21) G in cosmic voids and 2*10(-12) G in protogalaxies. The shear and/or compression of the intergalactic and protogalactic medium exerted by the first supernova explosions locally amplify these seed fields and make them anisotropic, until the magnetic restoring forces affect the gas dynamics at ordered plasma betas near unity. PMID- 23368548 TI - Azimuthal angle probe of anomalous HWW couplings at a high energy ep collider. AB - A high energy ep collider, such as the proposed LHeC, possesses the unique facility of permitting direct measurement of the HWW coupling without contamination from the HZZ coupling. At such a machine, the fusion of two W bosons through the HWW vertex would give rise to typical charged current events accompanied by a Higgs boson. We demonstrate that azimuthal angle correlations between the observable charged current final states could then be a sensitive probe of the nature of the HWW vertex and hence of the CP properties of the Higgs boson. PMID- 23368551 TI - gammaZ box corrections to weak charges of heavy nuclei in atomic parity violation. AB - We present a new dispersive formulation of the gammaZ box radiative corrections to weak charges of bound protons and neutrons in atomic parity violation measurements on heavy nuclei such as 133Cs and 213Ra. We evaluate for the first time a small but important additional correction arising from Pauli blocking of nucleons in a heavy nucleus. Overall, we find a significant shift in the gammaZ correction to the weak charge of 133Cs, approximately 4 times larger than the current uncertainty on the value of sin2 theta(W), but with a reduced error compared to earlier estimates. PMID- 23368552 TI - Determining the density content of symmetry energy and neutron skin: an empirical approach. AB - The density dependence of nuclear symmetry energy remains poorly constrained. Starting from precise empirical values of the nuclear volume and surface symmetry energy coefficients and the nuclear saturation density, we show how in the ambit of microscopic calculations with different energy density functionals, the value of the symmetry energy slope parameter L along with that for neutron skin can be put in tighter bounds. The value of L is found to be L=64+/-5 MeV. For 208Pb, the neutron skin thickness comes out to be 0.188+/-0.014 fm. Knowing L, the method can be applied to predict neutron skin thicknesses of other nuclei. PMID- 23368553 TI - Coherence-enhanced optical determination of the 229Th isomeric transition. AB - The impact of coherent light propagation on the excitation and fluorescence of thorium nuclei in a crystal lattice environment is investigated theoretically. We find that in the forward direction, the fluorescence signal exhibits characteristic intensity modulations dominated by a sped-up initial decay signal that is orders of magnitude faster. This feature can be exploited for the optical determination of the isomeric transition energy. In order to obtain a unmistakable signature of the isomeric nuclear fluorescence, we put forward a novel scheme for the direct measurement of the transition energy via electromagnetically modified nuclear forward scattering involving two fields that couple to three nuclear states. PMID- 23368554 TI - Do halo nuclei follow Rutherford elastic scattering at energies below the barrier? The case of 11Li. AB - The first measurement of the elastic scattering of the halo nucleus 11Li and its core 9Li on 208Pb at energies near the Coulomb barrier is presented. The 11Li+208Pb elastic scattering shows a strong reduction with respect to the Rutherford cross section, even at energies well below the barrier and down to very small scattering angles. This drastic change of the elastic differential cross section observed in 11Li+208Pb is the consequence of the halo structure of 11Li, as it is not observed in the elastic scattering of its core 9Li at the same energies. Four-body continuum-discretized coupled-channels calculations, based on a three-body model of the 11Li projectile, are found to explain the measured angular distributions and confirm that the observed reduction is mainly due to the strong Coulomb coupling to the dipole states in the low-lying continuum of 11Li. These calculations suggest the presence of a low-lying dipole resonance in 11Li close to the breakup threshold. PMID- 23368555 TI - Multiphoton ionization as a clock to reveal molecular dynamics with intense short x-ray free electron laser pulses. AB - We investigate molecular dynamics of multiple ionization in N2 through multiple core-level photoabsorption and subsequent Auger decay processes induced by intense, short x-ray free electron laser pulses. The timing dynamics of the photoabsorption and dissociation processes is mapped onto the kinetic energy of the fragments. Measurements of the latter allow us to map out the average internuclear separation for every molecular photoionization sequence step and obtain the average time interval between the photoabsorption events. Using multiphoton ionization as a tool of the multiple-pulse pump-probe scheme, we demonstrate the modification of the ionization dynamics as we vary the x-ray laser pulse duration. PMID- 23368556 TI - High-resolution sub-Doppler Lamb dips of the nu2 fundamental band of H3(+). AB - The high-resolution sub-Doppler Lamb dips of the nu2 fundamental band transitions of H3(+) have been observed using an extended negative glow discharge tube as an ion source and a periodically poled lithium niobate optical parametric oscillator as a radiation source. The absolute frequency of the R(1,0) transition was measured to be 81,720,371.550 MHz with an accuracy of 250 kHz using an optical frequency comb. In addition, we have investigated the linewidth of the Lamb-dip signal of the R(3,0) transition systematically and obtained its pressure broadening parameter, which may shed some light on the reaction of H3(+) with H2. This is the first observation of the infrared saturated spectrum and the first determination of the pressure-broadening parameter of the ro-vibrational transitions of a molecular ion. PMID- 23368557 TI - Precise experimental investigation of eigenmodes in a planar ion crystal. AB - The accurate characterization of eigenmodes and eigenfrequencies of two dimensional ion crystals provides the foundation for the use of such structures for quantum simulation purposes. We present a combined experimental and theoretical study of two-dimensional ion crystals. We demonstrate that standard pseudopotential theory accurately predicts the positions of the ions and the location of structural transitions between different crystal configurations. However, pseudopotential theory is insufficient to determine eigenfrequencies of the two-dimensional ion crystals accurately but shows significant deviations from the experimental data obtained from resolved sideband spectroscopy. Agreement at the level of 2.5*10(-3) is found with the full time-dependent Coulomb theory using the Floquet-Lyapunov approach and the effect is understood from the dynamics of two-dimensional ion crystals in the Paul trap. The results represent initial steps towards an exploitation of these structures for quantum simulation schemes. PMID- 23368558 TI - High accuracy correction of blackbody radiation shift in an optical lattice clock. AB - We have determined the frequency shift that blackbody radiation is inducing on the 5s2 (1)S0-5s5p (3)P0 clock transition in strontium. Previously its uncertainty limited the uncertainty of strontium lattice clocks to 1*10(-16). Now the uncertainty associated with the blackbody radiation shift correction translates to a 5*10(-18) relative frequency uncertainty at room temperature. Our evaluation is based on a measurement of the differential dc polarizability of the two clock states and on a modeling of the dynamic contribution using this value and experimental data for other atomic properties. PMID- 23368559 TI - Direct observation of resonant scattering phase shifts and their energy dependence. AB - We scan the collision energy of two clouds of cesium atoms between 12 and 50 MUK in an atomic fountain clock. By directly detecting the difference of s-wave scattering phase shifts, we observe a rapid variation of a scattering phase shift through a series of Feshbach resonances. At the energies we use, resonances that overlap at threshold become resolved. Our statistical phase uncertainty of 8 mrad can be improved in future precision measurements of Feshbach resonances to accurately determine the Cs-Cs interactions, which may provide stringent limits on the time variation of fundamental constants. PMID- 23368560 TI - Coherent control of single-photon absorption and reemission in a two-level atomic ensemble. AB - We demonstrate coherent control of single-photon absorption and reemission in a two-level cold atomic ensemble. This is achieved by interfering the incident single-photon wave packet with the emission (or scattering) wave. For a photon with an exponential growth waveform with a time constant equal to the excited state lifetime, we observe that the single-photon emission probability during the absorption can be suppressed due to the perfect destructive interference. After the incident photon waveform is switched off, the absorbed photon is then reemitted to the same spatial mode as that of the incident photon with an efficiency of 20%. For a photon with an exponential decay waveform with the same time constant, both the absorption and reemission occur within the waveform duration. Our experimental results suggest that the absorption and emission of a single photon in a two-level atomic ensemble may possibly be manipulated by shaping its waveform in the time domain. PMID- 23368561 TI - Coherent logic gate for light pulses based on storage in a Bose-Einstein condensate. AB - A classical logic gate connecting input and output light pulses is demonstrated. The gate operation is based on three steps: First, two incoming light pulses are stored in a Bose-Einstein condensate; second, atomic four-wave mixing generates a new matter wave; and third, the light pulses are retrieved. In the presence of the new matter wave, the retrieval generates a new optical wave. The latter will only be generated if both input light pulses are applied, thus realizing an AND gate. Finally, we show that the gate operation is phase coherent, an essential prerequisite for a quantum logic gate. PMID- 23368562 TI - Hybrid electro-optically modulated microcombs. AB - Optical frequency combs based on mode-locked lasers have proven to be invaluable tools for a wide range of applications in precision spectroscopy and metrology. A novel principle of optical frequency comb generation in whispering-gallery mode microresonators ("microcombs") has been developed recently, which represents a promising route towards chip-level integration and out-of-the-lab use of these devices. Presently, two families of microcombs have been demonstrated: Combs with electronically detectable mode spacing that can be directly stabilized, and broadband combs with up to octave-spanning spectra but mode spacings beyond electronic detection limits. However, it has not yet been possible to achieve these two key requirements simultaneously, as will be critical for most microcomb applications. Here we present a route to overcome this problem by interleaving an electro-optic comb with the spectrum from a parametric microcomb. This allows, for the first time, direct control and stabilization of a microcomb spectrum with large mode spacing (>140 GHz) with no need for an additional mode-locked laser frequency comb. The attained residual 1-sec instability of the microcomb comb spacing is 10(-15), with a microwave reference limited absolute instability of 10(-12) at a 140 GHz mode spacing. PMID- 23368563 TI - Extreme ultraviolet interferometer using high-order harmonic generation from successive sources. AB - We present a new interferometer technique whereby multiple extreme ultraviolet light pulses are generated at different positions within a single laser focus (i.e., from successive sources) with a highly controllable time delay. The interferometer technique is tested with two generating media to create two extreme ultraviolet light pulses with a time delay between them. The delay is found to be a consequence of the Gouy phase shift. Ultimately the apparatus is capable of accessing unprecedented time scales by allowing stable and repeatable delays as small as 100 zs. PMID- 23368564 TI - Magnetic energy harvesting and concentration at a distance by transformation optics. AB - Based on transformation optics, we introduce a magnetic shell with which one can harvest magnetic energy and distribute it as desired in space with unprecedented efficiency at an arbitrary scale. It allows a very large concentration of magnetic energy in a free space region, which can be used for increasing the sensitivity of magnetic sensors, and the transfer of magnetic energy from a source to a given distant point separated by empty space, with possible applications in wireless transmission of energy. PMID- 23368565 TI - Nanoscale radiative heat flow due to surface plasmons in graphene and doped silicon. AB - Owing to its two-dimensional electronic structure, graphene exhibits many unique properties. One of them is a wave vector and temperature dependent plasmon in the infrared range. Theory predicts that due to these plasmons, graphene can be used as a universal material to enhance nanoscale radiative heat exchange for any dielectric substrate. Here we report on radiative heat transfer experiments between SiC and a SiO2 sphere that have nonmatching phonon polariton frequencies, and thus only weakly exchange heat in near field. We observed that the heat flux contribution of graphene epitaxially grown on SiC dominates at short distances. The influence of plasmons on radiative heat transfer is further supported with measurements for doped silicon. These results highlight graphene's strong potential in photonic near field and energy conversion devices. PMID- 23368566 TI - Maximal air bubble entrainment at liquid-drop impact. AB - At impact of a liquid drop on a solid surface, an air bubble can be entrapped. Here, we show that two competing effects minimize the (relative) size of this entrained air bubble: for large drop impact velocity and large droplets, the inertia of the liquid flattens the entrained bubble, whereas for small impact velocity and small droplets, capillary forces minimize the entrained bubble. However, we demonstrate experimentally, theoretically, and numerically that in between there is an optimum, leading to maximal air bubble entrapment. For a 1.8 mm diameter ethanol droplet, this optimum is achieved at an impact velocity of 0.25 m/s. Our results have a strong bearing on various applications in printing technology, microelectronics, immersion lithography, diagnostics, or agriculture. PMID- 23368567 TI - Antibubble dynamics: the drainage of an air film with viscous interfaces. AB - An antibubble is a spherical air film that is immersed in a surfactant mixture and drains under the action of hydrostatic pressure. A dynamical model of this film is proposed that accounts for the surface shear viscosity effects in the case of purely viscous interfaces, which applies for surfactants whose adsorption rate is much larger than advection rate and at a concentration much above the critical micelle concentration. Our model shows that the lifetime of the antibubbles in this case increases with surface shear viscosity, denoted epsilon, whose value is measured independently, all in agreement with experimental measurements. We also found that the critical thickness, h(c), at film rupture due to van der Waals interactions slightly depends on the surface shear viscosity, namely h(c) ? epsilon(1/6). PMID- 23368568 TI - Scaling of convective mixing in porous media. AB - Convective mixing in porous media is triggered by a Rayleigh-Benard-type hydrodynamic instability as a result of an unstable density stratification of fluids. While convective mixing has been studied extensively, the fundamental behavior of the dissolution flux and its dependence on the system parameters are not yet well understood. Here, we show that the dissolution flux and the rate of fluid mixing are determined by the mean scalar dissipation rate. We use this theoretical result to provide computational evidence that the classical model of convective mixing in porous media exhibits, in the regime of high Rayleigh number, a dissolution flux that is constant and independent of the Rayleigh number. Our findings support the universal character of convective mixing and point to the need for alternative explanations for nonlinear scalings of the dissolution flux with the Rayleigh number, recently observed experimentally. PMID- 23368569 TI - Permeability of porous materials determined from the Euler characteristic. AB - We study the permeability of quasi-two-dimensional porous structures of randomly placed overlapping monodisperse circular and elliptical grains. Measurements in microfluidic devices and lattice Boltzmann simulations demonstrate that the permeability is determined by the Euler characteristic of the conducting phase. We obtain an expression for the permeability that is independent of the percolation threshold and shows agreement with experimental and simulated data over a wide range of porosities. Our approach suggests that the permeability explicitly depends on the overlapping probability of grains rather than their shape. PMID- 23368570 TI - Pseudo-single-bunch with adjustable frequency: a new operation mode for synchrotron light sources. AB - We present the concept and results of pseudo-single-bunch (PSB) operation--a new operational mode at the advanced light source--that can greatly expand the capabilities of synchrotron light sources to carry out dynamics and time-of flight experiments. In PSB operation, a single electron bunch is displaced transversely from the other electron bunches using a short-pulse, high-repetition rate kicker magnet. Experiments that require light emitted only from a single bunch can stop the light emitted from the other bunches using a collimator. Other beam lines will only see a small reduction in flux due to the displaced bunch. As a result, PSB eliminates the need to schedule multibunch and timing experiments during different running periods. Furthermore, the time spacing of PSB pulses can be adjusted from milliseconds to microseconds with a novel "kick-and-cancel" scheme, which can significantly alleviate complications of using high-power choppers and substantially reduce the rate of sample damage. PMID- 23368571 TI - Zero-turbulence manifold in a toroidal plasma. AB - Sheared toroidal flows can cause bifurcations to zero-turbulent-transport states in tokamak plasmas. The maximum temperature gradients that can be reached are limited by subcritical turbulence driven by the parallel velocity gradient. Here it is shown that q/epsilon (magnetic field pitch/inverse aspect ratio) is a critical control parameter for sheared tokamak turbulence. By reducing q/epsilon, far higher temperature gradients can be achieved without triggering turbulence, in some instances comparable to those found experimentally in transport barriers. The zero-turbulence manifold is mapped out, in the zero-magnetic-shear limit, over the parameter space (gamma(E), q/epsilon, R/L(T)), where gamma(E) is the perpendicular flow shear and R/L(T) is the normalized inverse temperature gradient scale. The extent to which it can be constructed from linear theory is discussed. PMID- 23368572 TI - Distribution of plasmoids in high-Lundquist-number magnetic reconnection. AB - The distribution function f(psi) of magnetic flux psi in plasmoids formed in high Lundquist-number current sheets is studied by means of an analytic phenomenological model and direct numerical simulations. The distribution function is shown to follow a power law f(psi)~psi(-1), which differs from other recent theoretical predictions. Physical explanations are given for the discrepant predictions of other theoretical models. PMID- 23368573 TI - Inelastic x-ray scattering from shocked liquid deuterium. AB - The Fermi-degenerate plasma conditions created in liquid deuterium by a laser ablation-driven shock wave were probed with noncollective, spectrally resolved, inelastic x-ray Thomson scattering employing Cl Ly(alpha) line emission at 2.96 keV. These first x-ray Thomson scattering measurements of the microscopic properties of shocked deuterium show an inferred spatially averaged electron temperature of 8+/-5 eV, an electron density of 2.2(+/-0.5)*10(23) cm(-3), and an ionization of 0.8 (-0.25, +0.15). Two-dimensional hydrodynamic simulations using equation-of-state models suited for the extreme parameters occurring in inertial confinement fusion research and planetary interiors are consistent with the experimental results. PMID- 23368574 TI - Plasmoid-induced turbulence in collisionless magnetic reconnection. AB - The dissipation mechanism in collisionless magnetic reconnection in a quasisteady period is investigated for the antiparallel field configuration. A three dimensional simulation in a fully kinetic system reveals that a current-aligned electromagnetic mode produces turbulent electron flow that facilitates the transport of the momentum responsible for the current density. It is found that the electromagnetic turbulence is drastically enhanced by plasmoid formations and has a significant impact on the dissipation at the magnetic x-line. The linear analyses confirm that the mode survives in the real ion-to-electron mass ratio, which assures the importance of the turbulence in collisionless reconnection. PMID- 23368575 TI - Coupled ferromagnetic and nematic ordering of fermions in an optical flux lattice. AB - Ultracold atoms in Raman-dressed optical lattices allow for effective momentum dependent interactions among single-species fermions originating from short-range s-wave interactions. These dressed-state interactions combined with the very flat bands encountered in the recently introduced optical flux lattices push the Stoner instability towards weaker repulsive interactions, making it accessible with current experiments. As a consequence of the coupling between spin and orbital degrees of freedom, the magnetic phase features Ising nematic order. PMID- 23368576 TI - Superfluidity of bosons in kagome lattices with frustration. AB - In this Letter we consider spinless bosons in a kagome lattice with nearest neighbor hopping and on-site interaction, and the sign of hopping is inverted by insetting a pi flux in each triangle of the kagome lattice so that the lowest single particle band is perfectly flat. We show that in the high-density limit, despite the infinite degeneracy of the single particle ground states, interaction will select out the Bloch state at the K point of the Brillouin zone for boson condensation at the lowest temperature. As the temperature increases, the single boson superfluid order can be easily destroyed, while an exotic triple-boson paired superfluid order will remain. We establish that this trion superfluid exists in a broad temperature regime until the temperature is increased to the same order of hopping and then the system turns into normal phases. Finally, we show that time-of-flight measurement of the momentum distribution and its noise correlation can be used to distinguish these three phases. PMID- 23368577 TI - Disordered bosons in one dimension: from weak- to strong-randomness criticality. AB - We investigate the superfluid-insulator quantum phase transition of one dimensional bosons with off-diagonal disorder by means of large-scale Monte Carlo simulations. For weak disorder, we find the transition to be in the same universality class as the superfluid-Mott insulator transition of the clean system. The nature of the transition changes for stronger disorder. Beyond a critical disorder strength, we find nonuniversal, disorder-dependent critical behavior. We compare our results to recent perturbative and strong-disorder renormalization group predictions. We also discuss experimental implications as well as extensions of our results to other systems. PMID- 23368579 TI - Extraordinarily long-ranged structural relaxation in defective achiral carbon nanotubes. AB - We present a systematic ab initio density functional theory-based study which demonstrates that even one of the simplest defects in single-wall carbon nanotubes, the reconstructed monovacancy (a pentagonal ring and a single dangling bond known as a 5-1db defect), leads to extraordinarily long-ranged structural distortions. We show that relaxation due to reconstruction can only be modeled accurately through a careful selection of boundary conditions and an appropriately long nanotube fragment. PMID- 23368578 TI - Revealed architectures of adsorbed polymer chains at solid-polymer melt interfaces. AB - We report the chain conformations of polymer molecules accommodated at the solid polymer melt interfaces in equilibrium. Polystyrene "Guiselin" brushes (adsorbed layers) with different molecular weights were prepared on Si substrates and characterized by using x-ray and neutron reflectivity. The results are intriguing to show that the adsorbed layers are composed of the two different nanoarchitectures: flattened chains that constitute the inner higher density region of the adsorbed layers and loosely adsorbed polymer chains that form the outer bulklike density region. In addition, we found that the lone flattened chains, which are uncovered by the additional prolonged solvent leaching (~120 days), are reversibly densified with increasing temperature up to 150 degrees C. By generalizing the chain conformations of bulks, we postulate that the change in probabilities of the local chain conformations (i.e., trans and gauche states) of polymer molecules is the origin of this densification process. PMID- 23368580 TI - Damage mechanisms of porous materials due to in-pore salt crystallization. AB - Pressure exerted by crystallization of salts within porous materials contributes to damage in historic and modern construction. By unequivocally identifying the precipitating phase(s) while simultaneously determining solution supersaturation and associated crystallization pressure in subsurface pores, we show that the formation of a thermodynamically metastable salt phase (heptahydrate; Na2SO4.7H2O) and the resulting transition to a less soluble stable phase (mirabilite; Na2SO4.10H2O) is largely responsible for the high supersaturation and crystallization pressure developed during evaporative crystallization of sodium sulfate, the most damaging salt known. These results help to explain why salts with various (stable and metastable) hydrated phases are the most damaging. We also show that damage associated with metastable-stable phase transitions can be suppressed by the use of crystallization promoters. These results open new ways for the prevention of salt damage to building materials. PMID- 23368581 TI - Power-law creep from discrete dislocation dynamics. AB - We report two-dimensional discrete dislocation dynamics simulations of combined dislocation glide and climb leading to "power-law" creep in a model aluminum crystal. The approach fully accounts for matter transport due to vacancy diffusion and its coupling with dislocation motion. The existence of quasiequilibrium or jammed states under the applied creep stresses enables observations of diffusion and climb over time scales relevant to power-law creep. The predictions for the creep rates and stress exponents fall within experimental ranges, indicating that the underlying physics is well captured. PMID- 23368582 TI - Ab initio simulation of helium-ion microscopy images: the case of suspended graphene. AB - Helium ion microscopy (HIM), which was released in 2006 by Ward et al., provides nondestructive imaging of nanoscale objects with higher contrast than scanning electron microscopy. HIM measurement of suspended graphene under typical conditions is simulated by first-principles time-dependent density functional theory and the 30 keV He+ collision is found to induce the emission of electrons dependent on the impact point. This finding suggests the possibility of obtaining a highly accurate image of the honeycomb pattern of suspended graphene by HIM. Comparison with a simulation of He0 under the same kinetic energy shows that electron emission is governed by the impact ionization instead of Auger process initiated by neutralization of He+. PMID- 23368583 TI - Self-assembly of multicomponent structures in and out of equilibrium. AB - Theories of phase change and self-assembly often invoke the idea of a "quasiequilibrium," a regime in which the nonequilibrium association of building blocks results nonetheless in a structure whose properties are determined solely by an underlying free energy landscape. Here we study a prototypical example of multicomponent self-assembly, a one-dimensional fiber grown from red and blue blocks. We find that if the equilibrium structure possesses compositional correlations different from those characteristic of random mixing, then it cannot be generated without error at any finite growth rate: there is no quasiequilibrium regime. However, by exploiting dynamic scaling, structures characteristic of equilibrium at one point in phase space can be generated, without error, arbitrarily far from equilibrium. Our results, supported by mean field theory in higher dimensions, thus suggest a "nonperturbative" strategy for multicomponent self-assembly in which the target structure is, by design, not the equilibrium one. PMID- 23368584 TI - Suppression of grain boundaries in graphene growth on superstructured Mn-Cu(111) surface. AB - As undesirable defects, grain boundaries (GBs) are widespread in epitaxial graphene using existing growth methods on metal substrates. Employing density functional theory calculations, we first identify that the misorientations of carbon islands nucleated on a Cu(111) surface lead to the formation of GBs as the islands coalesce. We then propose a two-step kinetic pathway to effectively suppress the formation of GBs. In the first step, large aromatic hydrocarbon molecules are deposited onto a sqrt[3]*sqrt[3] superstructured Cu-Mn alloyed surface to seed the initial carbon clusters of a single orientation; in the second step, the seeded islands are enlarged through normal chemical vapor deposition of methane to form a complete graphene sheet. The present approach promises to overcome a standing obstacle in large scale single-crystal graphene fabrication. PMID- 23368585 TI - First-principles molecular dynamics at a constant electrode potential. AB - A simulation scheme for performing first-principles molecular dynamics at a constant electrode potential is presented, opening the way for a more realistic modeling of voltage-driven devices. The system is allowed to exchange electrons with a reservoir at fixed potential, and dynamical equations for the total electronic charge are derived by using the potential energy of the extended system. In combination with a thermostat, this potentiostat scheme reproduces thermal fluctuations of the charge with the correct statistics, implying a realistic treatment of the potential as a control variable. Practically, the dynamics of the charge are decoupled from the electronic structure calculations, making the scheme easily implementable in existing first-principles molecular dynamics codes. Our approach is demonstrated on a test system by considering various test cases. PMID- 23368586 TI - Nanometer-range strain distribution in layered incommensurate systems. AB - We adopt fringe counting from classical moire interferometry on moire patterns observed in scanning tunneling microscopy of strained thin films on single crystalline substrates. We analyze inhomogeneous strain distribution in islands of CeO2(111) on Cu(111) and identify a generic source of strain in heteroepitaxy- a thickness-dependent lattice constant of the growing film. This observation is mediated by the ability of ceria to glide on the Cu substrate. The moire technique we are describing has a potential of nanometer-scale resolution of inhomogeneous two dimensional strain in incommensurate layered systems, notably in supported graphene. PMID- 23368587 TI - Inhibitive influence of oxygen vacancies for photoactivity on TiO2(110). AB - Scanning tunneling microscopy results reveal a pronounced site selectivity in the hole-mediated photooxidation of trimethyl acetate (TMA) on TiO2(110), wherein the reaction readily occurs at regular Ti sites but is completely inhibited at oxygen vacancy (VV(O)) defects. Utilizing electron energy loss spectroscopy and density functional theory, we show that the lack of reactivity of TMA groups adsorbed at V(O)'s cannot be attributed to either a less active adsorption conformation or electron transfer from the V(O) defect. Instead, we propose that the excess unpaired electrons associated with the V(O) promptly recombine with photoexcited holes approaching the surface, effectively "screening" TMA species at the V(O) site. We also show that this screening effect is predominately localized at the V(O), only mildly affecting TMA's at adjacent Ti sites. PMID- 23368588 TI - Fermi nesting between atomic wires with strong spin-orbit coupling. AB - The mutual interplay between superlattice structures, band filling factors, and spin-orbit coupling results in a highly correlated electronic spin and charge state found for an array of atomic Pb wires grown on Si(557). By means of spin- and angle-resolved photoemission spectroscopy, the spin texture close to the Fermi surface was found to be alternating and equidistant; thus, Fermi nesting occurs in between bands with the same spin helicity, giving rise to spin polarized charge-density waves in the direction across the wires. An out-of-phase superposition of both Rashba channels is manifested by an extraordinary large Rashba splitting of Deltak0=0.2 A(-1)=g/2, where g is a reciprocal lattice vector defined by the interwire distance and fits into the model of spin-density waves in antiferromagnetically ordered chain structures. The implications towards spin-polarized transport along the wires will be discussed. PMID- 23368589 TI - To close or not to close: the fate of the superconducting gap across the topological quantum phase transition in Majorana-carrying semiconductor nanowires. AB - We investigate theoretically the low-energy physics of semiconductor Majorana wires in the vicinity of a magnetic field-driven topological quantum phase transition (TQPT). The local density of states at the end of the wire, which is directly related to the differential conductance in the limit of point-contact tunneling, is calculated numerically. We find that the dependence of the end-of wire local density of states on the magnetic field is nonuniversal and that the signatures associated with the closing of the superconducting gap at the Majorana TQPT are essentially invisible within a significant range of experimentally relevant parameters. Our results provide a possible explanation for the recent observation of the apparent nonclosure of the gap at the Majorana TQPT in semiconductor nanowires. PMID- 23368590 TI - Hierarchical Liouville-space approach for accurate and universal characterization of quantum impurity systems. AB - A hierarchical equations of motion based numerical approach is developed for accurate and efficient evaluation of dynamical observables of strongly correlated quantum impurity systems. This approach is capable of describing quantitatively Kondo resonance and Fermi-liquid characteristics, achieving the accuracy of the latest high-level numerical renormalization group approach, as demonstrated on single-impurity Anderson model systems. Its application to a two-impurity Anderson model results in differential conductance versus external bias, which correctly reproduces the continuous transition from Kondo states of individual impurity to singlet spin states formed between two impurities. The outstanding performance on characterizing both equilibrium and nonequilibrium properties of quantum impurity systems makes the hierarchical equations of motion approach potentially useful for addressing strongly correlated lattice systems in the framework of dynamical mean-field theory. PMID- 23368591 TI - Universal dynamical steps in the exact time-dependent exchange-correlation potential. AB - We show that the exact exchange-correlation potential of time-dependent density functional theory displays dynamical step structures that have a spatially nonlocal and time nonlocal dependence on the density. Using one-dimensional two electron model systems, we illustrate these steps for a range of nonequilibrium dynamical situations relevant for modeling of photochemical or physical processes: field-free evolution of a nonstationary state, resonant local excitation, resonant complete charge transfer, and evolution under an arbitrary field. A lack of these steps in the usual approximations yields inaccurate dynamics, for example, predicting faster dynamics and incomplete charge transfer. PMID- 23368592 TI - Tailoring magnetic doping in the topological insulator Bi2Se3. AB - We theoretically investigate the possibility of establishing ferromagnetism in the topological insulator Bi2Se3 via magnetic doping of 3d transition metal elements. The formation energies, charge states, band structures, and magnetic properties of doped Bi2Se3 are studied using first-principles calculations within density functional theory. Our results show that Bi substitutional sites are energetically more favorable than interstitial sites for single impurities. Detailed electronic structure analysis reveals that Cr and Fe doped materials are still insulating in the bulk but the intrinsic band gap of Bi2Se3 is substantially reduced due to the strong hybridization between the d states of the dopants and the p states of the neighboring Se atoms. The calculated magnetic coupling suggests that Cr doped Bi2Se3 is possible to be both ferromagnetic and insulating, while Fe doped Bi2Se3 tends to be weakly antiferromagnetic. PMID- 23368593 TI - Na2IrO3 as a novel relativistic Mott insulator with a 340-meV gap. AB - We study Na2IrO3 by angle-resolved photoemission spectroscopy, optics, and band structure calculations in the local-density approximation (LDA). The weak dispersion of the Ir 5d-t(2g) manifold highlights the importance of structural distortions and spin-orbit (SO) coupling in driving the system closer to a Mott transition. We detect an insulating gap Delta(gap)?340 meV which, at variance with a Slater-type description, is already open at 300 K and does not show significant temperature dependence even across T(N)?15 K. An LDA analysis with the inclusion of SO and Coulomb repulsion U reveals that, while the prodromes of an underlying insulating state are already found in LDA+SO, the correct gap magnitude can only be reproduced by LDA+SO+U, with U=3 eV. This establishes Na2IrO3 as a novel type of Mott-like correlated insulator in which Coulomb and relativistic effects have to be treated on an equal footing. PMID- 23368594 TI - Control and ultrafast dynamics of a two-fluid polariton switch. AB - We investigate the cross interactions in a two-component polariton quantum fluid coherently driven by two independent pumping lasers tuned at different energies and momenta. We show that both the hysteresis cycles and the on-off threshold of one polariton signal can be entirely controlled by a second polariton fluid. Furthermore, we study the ultrafast switching dynamics of a driven polariton state, demonstrating the ability to control the polariton population with an external laser pulse, in less than a few picoseconds. PMID- 23368595 TI - Strongly enhanced thermal transport in a lightly doped Mott insulator at low temperature. AB - We show how a lightly doped Mott insulator has hugely enhanced electronic thermal transport at low temperature. It displays universal behavior independent of the interaction strength when the carriers can be treated as nondegenerate fermions and a nonuniversal "crossover" region where the Lorenz number grows to large values, while still maintaining a large thermoelectric figure of merit. The electron dynamics are described by the Falicov-Kimball model which is solved for arbitrary large on-site correlation with a dynamical mean-field theory algorithm on a Bethe lattice. We show how these results are generic for lightly doped Mott insulators as long as the renormalized Fermi liquid scale is pushed to very low temperature and the system is not magnetically ordered. PMID- 23368596 TI - Electrical suppression of spin relaxation in GaAs(111)B quantum wells. AB - Spin dephasing via the spin-orbit interaction (SOI) is a major mechanism limiting the electron spin lifetime in III-V zincblende quantum wells (QWs). The dephasing can be suppressed in GaAs(111) quantum wells by applying an electric field. The suppression has been attributed to the compensation of the intrinsic SOI associated with the bulk inversion asymmetry of the GaAs lattice by a structural induced asymmetry SOI term induced by an electric field. We provide direct experimental evidence for this mechanism by demonstrating the transition between the bulk inversion asymmetry-dominated to a structural induced asymmetry dominated regime via photoluminescence measurements carried out over a wide range of applied fields. Spin lifetimes exceeding 100 ns are obtained near the compensating electric field, thus making GaAs(111) QWs excellent candidates for the electrical storage and manipulation of spins. PMID- 23368597 TI - Giant topological insulator gap in graphene with 5d adatoms. AB - Two-dimensional topological insulators (2D TIs) have been proposed as platforms for many intriguing applications, ranging from spintronics to topological quantum information processing. Realizing this potential will likely be facilitated by the discovery of new, easily manufactured materials in this class. With this goal in mind, we introduce a new framework for engineering a 2D TI by hybridizing graphene with impurity bands arising from heavy adatoms possessing partially filled d shells, in particular, osmium and iridium. First-principles calculations predict that the gaps generated by this means exceed 0.2 eV over a broad range of adatom coverage; moreover, tuning of the Fermi level is not required to enter the TI state. The mechanism at work is expected to be rather general and may open the door to designing new TI phases in many materials. PMID- 23368598 TI - Band formation in a molecular quantum well via 2D superatom orbital interactions. AB - By scanning tunneling microscopy and spectroscopy, we study nearly free electron band formation of the sigma* lowest unoccupied molecular orbital of C6F6 on a Cu(111) surface. In fractal islands, the lowest unoccupied molecular orbital energy systematically stabilizes with the number of interacting near-neighbor C6F6 molecules. Density functional theory calculations reveal the origin of effective intermolecular orbital overlap in the previously unrecognized superatom character of the sigma* orbital of C6F6 molecules. The discovery of superatom orbitals in planar molecules offers a new universal principle for effective band formation, which can be exploited in designing organic semiconductors with nearly free electron properties. PMID- 23368599 TI - Suppressing leakage by localized doping in Si nanotransistor channels. AB - By first principles atomistic analysis we demonstrate how controlled localized doping distributions in nanoscale Si transistors can suppress leakage currents. We consider dopants (B and P atoms) to be randomly confined to a ~1 nm width doping region in the channel. If this region is located away from the electrodes, roughly 20% of the channel length L, the tunneling leakage is reduced 2* compared to the case of uniform doping and shows little variation. Oppositely, we find the leakage current increases by orders of magnitude and may result in large device variability. We calculate the maximum and minimum conductance ratio that characterizes the tunnel leakage for various values of L. We conclude that doping engineering provides a possible approach to resolve the critical issue of leakage current in nanotransistors. PMID- 23368600 TI - Topological flat bands from dipolar spin systems. AB - We propose and analyze a physical system that naturally admits two-dimensional topological nearly flat bands. Our approach utilizes an array of three-level dipoles (effective S=1 spins) driven by inhomogeneous electromagnetic fields. The dipolar interactions produce arbitrary uniform background gauge fields for an effective collection of conserved hard-core bosons, namely, the dressed spin flips. These gauge fields result in topological band structures, whose band gap can be larger than the corresponding bandwidth. Exact diagonalization of the full interacting Hamiltonian at half-filling reveals the existence of superfluid, crystalline, and supersolid phases. An experimental realization using either ultracold polar molecules or spins in the solid state is considered. PMID- 23368601 TI - Three-dimensional models of topological insulators: engineering of Dirac cones and robustness of the spin texture. AB - We design three-dimensional models of topological insulator thin films, showing a tunability of the odd number of Dirac cones driven by the atomic-scale geometry at the boundaries. A single Dirac cone at the Gamma-point can be obtained as well as full suppression of quantum tunneling between Dirac states at geometrically differentiated surfaces. The spin texture of surface states changes from a spin momentum-locking symmetry to a surface spin randomization upon the introduction of bulk disorder. These findings illustrate the richness of the Dirac physics emerging in thin films of topological insulators and may prove utile for engineering Dirac cones and for quantifying bulk disorder in materials with ultraclean surfaces. PMID- 23368602 TI - Quantum phase transitions and the nu=5/2 fractional Hall state in wide quantum wells. AB - We study the nature of the nu=5/2 quantum Hall state in wide quantum wells under the mixing of electronic subbands and Landau levels. A general method is introduced to analyze the Moore-Read pfaffian state and its particle-hole conjugate, the anti-pfaffian state, under periodic boundary conditions in a "quartered" Brillouin zone scheme containing both even and odd numbers of electrons. By examining the rotational quantum numbers on the torus, we show spontaneous breaking of the particle-hole symmetry can be observed in finite-size systems. In the presence of electronic-subband and Landau-level mixing, the particle-hole symmetry is broken in such a way that the anti-pfaffian state is unambiguously favored, and becomes more robust in the vicinity of a transition to the compressible phase, in agreement with recent experiments. PMID- 23368603 TI - Nodeless superconducting phase arising from a strong (pi, pi) antiferromagnetic phase in the infinite-layer electron-doped Sr(1-x)La(x)CuO2 compound. AB - The asymmetry between electron and hole doping remains one of the central issues in high-temperature cuprate superconductivity, but our understanding of the electron-doped cuprates has been hampered by apparent discrepancies between the only two known families: Re(2-x)Ce(x)CuO4 and A(1-x)La(x)CuO2. Here we report in situ angle-resolved photoemission spectroscopy measurements of epitaxially stabilized Sr(1-x)La(x)CuO2 thin films synthesized by oxide molecular-beam epitaxy. Our results reveal a strong coupling between electrons and (pi, pi) antiferromagnetism that induces a Fermi surface reconstruction which pushes the nodal states below the Fermi level. This removes the hole pocket near (pi/2, pi/2), realizing nodeless superconductivity without requiring a change in the symmetry of the order parameter and providing a universal understanding of all electron-doped cuprates. PMID- 23368604 TI - Zero-bias peaks in the tunneling conductance of spin-orbit-coupled superconducting wires with and without Majorana end-states. AB - One of the simplest proposed experimental probes of a Majorana bound state is a quantized (2e(2)/h) value of zero-bias tunneling conductance. When temperature is somewhat larger than the intrinsic width of the Majorana peak, conductance is no longer quantized, but a zero-bias peak can remain. Such a nonquantized zero-bias peak has been recently reported for semiconducting nanowires with proximity induced superconductivity. In this Letter we analyze the relation of the zero bias peak to the presence of Majorana end states, by simulating the tunneling conductance for multiband wires with realistic amounts of disorder. We show that this system generically exhibits a (nonquantized) zero-bias peak even when the wire is topologically trivial and does not possess Majorana end states. We make comparisons to recent experiments, and discuss the necessary requirements for confirming the existence of a Majorana state. PMID- 23368605 TI - Neutron-diffraction measurements of an antiferromagnetic semiconducting phase in the vicinity of the high-temperature superconducting state of K(x)Fe(2-y)Se2. AB - The recently discovered K-Fe-Se high-temperature superconductor has caused heated debate regarding the nature of its parent compound. Transport, angle-resolved photoemission spectroscopy, and STM measurements have suggested that its parent compound could be insulating, semiconducting, or even metallic [M. H. Fang, H.-D. Wang, C.-H. Dong, Z.-J. Li, C.-M. Feng, J. Chen, and H. Q. Yuan, Europhys. Lett. 94, 27009 (2011); F. Chen et al., Phys. Rev. X 1, 021020 (2011); and W. Li et al., Phys. Rev. Lett. 109, 057003 (2012)]. Because the magnetic ground states associated with these different phases have not yet been identified and the relationship between magnetism and superconductivity is not fully understood, the real parent compound of this system remains elusive. Here, we report neutron diffraction experiments that reveal a semiconducting antiferromagnetic (AFM) phase with rhombus iron vacancy order. The magnetic order of the semiconducting phase is the same as the stripe AFM order of the iron pnictide parent compounds. Moreover, while the sqrt[5]*sqrt[5] block AFM phase coexists with superconductivity, the stripe AFM order is suppressed by it. This leads us to conjecture that the new semiconducting magnetic ordered phase is the true parent phase of this superconductor. PMID- 23368606 TI - Robust nodal d-wave spectrum in simulations of a strongly fluctuating competing order in underdoped cuprate superconductors. AB - We resolve an existing discrepancy between convincing evidence for competing order in underdoped cuprates and spectroscopic data consistent with a homogeneous d-wave superconductor in the very same compounds. Specifically, we show that fluctuations of the competing order generate strongly inhomogeneous states whose spectra are almost indistinguishable from the pure d-wave superconductor. This is in contrast to the commonly studied case of homogeneously coexisting order, which typically generates a reconstructed Fermi surface with closed Fermi pockets. The signatures of the fluctuating competing order can be found mainly in a splitting of the antinodal band, and, for strong magnetic order, in small induced nodal gaps similar to those found in recent experiments on underdoped La(2-x)Sr(x)CuO4. PMID- 23368607 TI - Spin-orbit-coupling-induced domain-wall resistance in diffusive ferromagnets. AB - We investigate diffusive transport through a number of domain wall (DW) profiles of the important magnetic alloy Permalloy taking into account simultaneously noncollinearity, alloy disorder, and spin-orbit-coupling fully quantum mechanically, from first principles. In addition to observing the known effects of magnetization mistracking and anisotropic magnetoresistance, we discover a not previously identified contribution to the resistance of a DW that comes from spin orbit-coupling-mediated spin-flip scattering in a textured diffusive ferromagnet. This adiabatic DW resistance, which should exist in all diffusive DWs, can be observed by varying the DW width in a systematic fashion in suitably designed nanowires. PMID- 23368608 TI - Magnetic frustration, phase competition, and the magnetoelectric effect in NdFe3(BO3)4. AB - We present an element selective resonant magnetic x-ray scattering study of NdFe3(BO3)4 as a function of temperature and applied magnetic field. Our measurements show that the magnetic order of the Nd sublattice is induced by the Fe spin order. When a magnetic field is applied parallel to the hexagonal basal plane, the helicoidal spin order is suppressed and a collinear ordering, where the moments are forced to align in a direction perpendicular to the applied magnetic field, is stabilized. This result excludes a noncollinear spin order as the origin of the magnetically induced electric polarization in this compound. Instead our data imply that magnetic frustration results in a phase competition, which is the origin of the magnetoelectric response. PMID- 23368610 TI - Antiferromagnetism in NiO observed by transmission electron diffraction. AB - Neutron diffraction has been used to investigate antiferromagnetism since 1949. Here, we show that antiferromagnetic reflections can also be seen in transmission electron diffraction patterns from NiO. The diffraction patterns taken here came from regions as small as 10.5 nm, and such patterns could be used to form an image of the antiferromagnetic structure with a nanometer resolution. PMID- 23368609 TI - Entanglement entropy for the long-range Ising chain in a transverse field. AB - We consider the Ising model in a transverse field with long-range antiferromagnetic interactions that decay as a power law with their distance. We study both the phase diagram and the entanglement properties as a function of the exponent of the interaction. The phase diagram can be used as a guide for future experiments with trapped ions. We find two gapped phases, one dominated by the transverse field, exhibiting quasi-long-range order, and one dominated by the long-range interaction, with long-range Neel ordered ground states. We determine the location of the quantum critical points separating those two phases. We determine their critical exponents and central charges. In the phase with quasi long-range order the ground states exhibit exotic corrections to the area law for the entanglement entropy coexisting with gapped entanglement spectra. PMID- 23368611 TI - Understanding nanoscale temperature gradients in magnetic nanocontacts. AB - We have determined the temperature profile in magnetic nanocontacts under applied current densities typical of spin-torque oscillators (~10(8) A/cm2). The study combines experimental measurements of the electrical and magnetic properties of the nanocontacts and full three-dimensional simulations of the heat and current flow in these systems. It is found that the quadratic current-induced increase of the resistance due to Joule heating is independent of the applied temperature from 6 to 300 K. In terms of magnetization dynamics, the measured current-induced vortex nucleation, a thermally activated process, is found to be consistent with local temperatures increases of between 147 and 225 K. Simulations reproduce the experimental findings and show that significant thermal gradients exist out to 450 nm from the nanocontact. PMID- 23368612 TI - Successive phase transitions and extended spin-excitation continuum in the S=1/2 triangular-lattice antiferromagnet Ba3CoSb2O9. AB - Using magnetic, thermal, and neutron measurements on single-crystal samples, we show that Ba3CoSb2O9 is a spin-1/2 triangular-lattice antiferromagnet with the c axis as the magnetic easy axis and two magnetic phase transitions bracketing an intermediate up-up-down phase in magnetic field applied along the c axis. A pronounced extensive neutron-scattering continuum above spin-wave excitations, observed below T(N), implies that the system is in close proximity to one of two spin-liquid states that have been predicted for a 2D triangular lattice. PMID- 23368613 TI - Ferromagnetic coupling of mononuclear Fe centers in a self-assembled metal organic network on Au(111). AB - The magnetic state and magnetic coupling of individual atoms in nanoscale structures relies on a delicate balance between different interactions with the atomic-scale surroundings. Using scanning tunneling microscopy, we resolve the self-assembled formation of highly ordered bilayer structures of Fe atoms and organic linker molecules (T4PT) when deposited on a Au(111) surface. The Fe atoms are encaged in a three-dimensional coordination motif by three T4PT molecules in the surface plane and an additional T4PT unit on top. Within this crystal field, the Fe atoms retain a magnetic ground state with easy-axis anisotropy, as evidenced by x-ray absorption spectroscopy and x-ray magnetic circular dichroism. The magnetization curves reveal the existence of ferromagnetic coupling between the Fe centers. PMID- 23368614 TI - Anisotropic spin dynamics in the Kondo semiconductor CeRu2Al10. AB - Spin dynamics in the new Kondo insulator compound CeRu2Al10 has been studied using unpolarized and polarized neutron scattering on single crystals. In the unconventional ordered phase forming below T0=27.3 K, two excitation branches are observed with significant intensities, the lower one of which has a gap of 4.8+/-0.3 meV and a pronounced dispersion up to ~8.5 meV. Comparison with random-phase approximation magnon calculations assuming crystal-field and anisotropic exchange couplings captures major aspects of the data, but leaves unexplained discrepancies, pointing to a key role of direction-specific hybridization between 4f and conduction band states in this compound. PMID- 23368615 TI - Combined theoretical and experimental study of spin and charge dynamics on the homodinuclear complex [Ni2(II)(L-N4Me2)(emb)]. AB - We present a combined theoretical and experimental study of spin and charge dynamics on the homodinuclear compound [Ni2(II)(L-N4Me2)(emb)]. The theoretically calculated oscillator strengths of the ground-state absorption spectrum show an acceptable agreement with experiment. We predict a local ultrafast laser-induced spin-flip scenario, which involves charge-transfer states. Experimentally, we observe charge dynamics on two different time scales. The two relevant, transient electronic states and their electronic properties are also theoretically characterized. These results provide a joint investigation of the homodinuclear complex and suggest a realistic scenario for ultrafast spin dynamics and other optical-related manipulations. PMID- 23368616 TI - First-principles calculations of luminescence spectrum line shapes for defects in semiconductors: the example of GaN and ZnO. AB - We present a theoretical study of the broadening of defect luminescence bands due to vibronic coupling. Numerical proof is provided for the commonly used assumption that a multidimensional vibrational problem can be mapped onto an effective one-dimensional configuration coordinate diagram. Our approach is implemented based on density functional theory with a hybrid functional, resulting in luminescence line shapes for important defects in GaN and ZnO that show unprecedented agreement with experiment. We find clear trends concerning effective parameters that characterize luminescence bands of donor- and acceptor type defects, thus facilitating their identification. PMID- 23368617 TI - Field-field and photon-photon correlations of light scattered by two remote two level InAs quantum dots on the same substrate. AB - We report the measurement of field-field and photon-photon correlations of light scattered by two InAs quantum dots separated by ~40 MUm. Near 4 K a large fraction of photons can be scattered coherently by each quantum dot leading to one-photon interference at a beam splitter (visibility ~20%). Simultaneously, two photon interference is also observed (visibility ~40%) due to the indistinguishability of photons scattered by the two different quantum emitters. We show how spectral diffusion accounts for the reduction in interference visibility through variations in photon flux. PMID- 23368618 TI - Cavity QED of the graphene cyclotron transition. AB - We investigate theoretically the cavity quantum electrodynamics of the cyclotron transition for Dirac fermions in graphene. We show that the ultrastrong coupling regime characterized by a vacuum Rabi frequency comparable or even larger than the transition frequency can be obtained for high enough filling factors of the graphene Landau levels. Important qualitative differences occur with respect to the corresponding physics of massive electrons in a semiconductor quantum well. In particular, an instability for the ground state analogous to the one occurring in the Dicke model is predicted for an increasing value of the electron density. PMID- 23368619 TI - Drude weight, cyclotron resonance, and the Dicke model of graphene cavity QED. AB - The unique optoelectronic properties of graphene make this two-dimensional material an ideal platform for fundamental studies of cavity quantum electrodynamics in the strong-coupling regime. The celebrated Dicke model of cavity quantum electrodynamics can be approximately realized in this material when the cyclotron transition of its 2D massless Dirac fermion carriers is nearly resonant with a cavity photon mode. We develop the theory of strong matter-photon coupling in this circumstance, emphasizing the essential role of a dynamically generated matter energy term that is quadratic in the photon field and absent in graphene's low-energy Dirac model. PMID- 23368620 TI - Thickness-dependent polarization of strained BiFeO3 films with constant tetragonality. AB - We measure the ferroelectric polarization of BiFeO3 films down to 3.6 nm using low energy electron and photoelectron emission microscopy. The measured polarization decays strongly below a critical thickness of 5-7 nm predicted by continuous medium theory whereas the tetragonal distortion does not change. We resolve this apparent contradiction using first-principles-based effective Hamiltonian calculations. In ultrathin films, the energetics of near open circuit electrical boundary conditions, i.e., an unscreened depolarizing field, drive the system through a phase transition from single out-of-plane polarization to nanoscale stripe domains. It gives rise to an average polarization close to zero as measured by the electron microscopy while maintaining the relatively large tetragonal distortion imposed by the nonzero polarization state of each individual domain. PMID- 23368621 TI - Understanding and revisiting properties of EuTiO3 bulk material and films from first principles. AB - Ab initio computations are performed to investigate properties of bulk material and epitaxial films made of EuTiO3 (ETO). A whole family of nanoscale twinned phases, that present complex oxygen octahedra tilting (OOT) and unusual antiferroelectricity, is found to be degenerate in energy with simpler phases (all possessing typical OOT) in bulk ETO. Such degeneracy provides a successful explanation of recently observed anomalous phenomena. The calculations also lead to revisiting the (rich) phase diagram of ETO films. PMID- 23368622 TI - Multitasking associative networks. AB - We introduce a bipartite, diluted and frustrated, network as a sparse restricted Boltzmann machine and we show its thermodynamical equivalence to an associative working memory able to retrieve several patterns in parallel without falling into spurious states typical of classical neural networks. We focus on systems processing in parallel a finite (up to logarithmic growth in the volume) amount of patterns, mirroring the low-level storage of standard Amit-Gutfreund Sompolinsky theory. Results obtained through statistical mechanics, the signal-to noise technique, and Monte Carlo simulations are overall in perfect agreement and carry interesting biological insights. Indeed, these associative networks pave new perspectives in the understanding of multitasking features expressed by complex systems, e.g., neural and immune networks. PMID- 23368623 TI - Hydrodynamic synchronization and metachronal waves on the surface of the colonial alga Volvox carteri. AB - From unicellular ciliates to the respiratory epithelium, carpets of cilia display metachronal waves, long-wavelength phase modulations of the beating cycles, which theory suggests may arise from hydrodynamic coupling. Experiments have been limited by a lack of organisms suitable for systematic study of flagella and the flows they create. Using time-resolved particle image velocimetry, we report the discovery of metachronal waves on the surface of the colonial alga Volvox carteri, whose large size and ease of visualization make it an ideal model organism for these studies. An elastohydrodynamic model of weakly coupled compliant oscillators, recast as interacting phase oscillators, reveals that orbit compliance can produce fast, robust synchronization in a manner essentially independent of boundary conditions, and offers an intuitive understanding of a possible mechanism leading to the emergence of metachronal waves. PMID- 23368624 TI - Amplification of thermal noise by vesicle dynamics. AB - A novel noise amplification mechanism resulting from the interaction of thermal fluctuations and nonlinear vesicle dynamics is reported. It is observed in a time dependent vesicle state called trembling (TR). High spatial resolution and very long time series of TR compared to the vesicle period allow us to quantitatively analyze the generation and amplification of spatial and temporal modes of the vesicle shape perturbations. During a compression part of each TR cycle, a vesicle finds itself on the edge of the wrinkling instability, where thermally excited spatial modes are amplified. PMID- 23368625 TI - Nonlinear field equations for aligning self-propelled rods. AB - We derive a set of minimal and well-behaved nonlinear field equations describing the collective properties of self-propelled rods from a simple microscopic starting point, the Vicsek model with nematic alignment. Analysis of their linear and nonlinear dynamics shows good agreement with the original microscopic model. In particular, we derive an explicit expression for density-segregated, banded solutions, allowing us to develop a more complete analytic picture of the problem at the nonlinear level. PMID- 23368626 TI - Comment on "Plasma adiabatic lapse rate". PMID- 23368628 TI - Restricted variation in plant barcoding markers limits identification in closely related bryophyte species. AB - Species-level identification and delimitation of bryophytes using the proposed general barcode markers for land plants has been challenging. Bryophyta (mosses) is the second most species-rich group of land plants after angiosperms, and it is thus of great importance to find useful barcoding regions also for this group of plants. We investigated how the plastid regions atpF-atpH, rbcL and trnH-psbA and the nuclear ITS2 region performed as barcode markers on closely related bryophyte taxa of selected moss (Bartramia, Distichium, Fissidens, Meesia and Syntrichia) and liverwort (Blepharostoma) genera from boreal and arctic regions. We also evaluated how sequencing success of herbarium specimens is related to length of the sequenced fragment, specimen age and taxonomic group. Sequencing success was higher for shorter fragments and younger herbarium specimens, but was lower than expected in the genera Distichium and Fissidens, indicating imperfect universality of the primers used. None of the studied DNA barcode regions showed a consistent barcode gap across the studied genera. As a single locus, the region atpF-atpH performed slightly better than rbcL and ITS2 and much better than trnH psbA in terms of grouping conspecific sequences in monophyletic groups. This marker also gave a higher percentage of correct hits when conducting blast searches on a local database of identified sequences. Concatenated data sets of two and three markers grouped more conspecific sequences in monophyletic groups, but the improvement was not great compared with atpF-atpH alone. A discussion of recent studies testing barcode regions for bryophytes is given. We conclude that atpF-atpH, rbcL and ITS2 are to be the most promising barcode markers for mosses. PMID- 23368629 TI - Identifying and describing feelings and psychological flexibility predict mental health in men with HIV. AB - BACKGROUND: Difficulty identifying and describing feelings (DIDF) and psychological flexibility (PF) predict poor emotional adjustment. OBJECTIVE: To examine the relationship between DIDF and PF and whether DIDF and low PF would put men undergoing cancer screening at risk for poor adjustment. DESIGN: Longitudinal self-report survey. METHODS: Two hundred and one HIV-infected men who have sex with men participated in anal cancer screening at two time points over 14 weeks. Psychological flexibility was assessed by the Acceptance and Action Questionnaire II and DIDF by the Toronto Alexithymia Scale-20. We also measured depression, anxiety, stress (DASS) and health-related quality of life (QOL; SF-12). RESULTS: Both DIDF and PF were reliable predictors of mental health. When levels of baseline mental health were controlled, greater DIDF predicted increases in Time 2 depression, anxiety and stress and decreases in mental and physical QOL. The link between PF and mental health was entirely mediated by DIDF. CONCLUSIONS: Being chronically low in PF could lead to greater DIDF and thereby worse mental health. Having more PF promotes the ability to identify and differentiate the nuances of pleasant and unpleasant emotions, which enhances an individual's mental health. Intentionally enhancing men's ability to identify and describe feelings or PF may assist them to better manage a range of difficult life experiences such as health screenings and other potentially threatening information. PMID- 23368630 TI - A novel, radiolabel-free pulse chase strategy to study Kir3 channel ontogeny. AB - Kir3 channels are essential regulators of cellular excitability, maintaining cells at resting membrane potentials. While much research has been dedicated to elucidating the mechanisms regulating Kir3 channel gating, little is known regarding the channel's early associations with signaling partners, its stability at the plasma membrane or mechanisms regulating its internalization and degradation. To address these issues we have established an inducible Kir3.1 cell line that allows monitoring of a discrete "pulse" of channel as it progresses along the biosynthetic pathway. Using this system, we have been able to track Kir3 maturation and the influence of partner subunits on Kir3 lifetime and stability. Of note, we show that Kir3.1, in the absence of trafficking partner subunits, can exit the endoplasmic reticulum (ER) and reach the Golgi (though not the plasma membrane), and that expression of Kir3.3 subunits drastically reduced levels of Kir3.1 in the cell. We also show that interfering with trafficking from the ER to Golgi has a pronounced inhibitory effect on Kir3.1-Kir3.2 interactions, suggesting that this complex is stabilized either en route to the Golgi or in the Golgi itself. Finally, we showed that the Kir3 channel can reach the cell surface as early as 6 h post-induction and that removal of cell surface-localized channel occurs within 48 h. This system can be adapted to study the life cycle of any cellular protein without the confounds associated with radioactive labeling or the complications noted with expressing supraphysiological levels of proteins. PMID- 23368631 TI - Differential chemokine and cytokine production by neonatal bovine gammadelta T cell subsets in response to viral toll-like receptor agonists and in vivo respiratory syncytial virus infection. AB - gammadelta T cells respond to stimulation via toll-like receptors (TLR). Bovine gammadelta T cells express TLR3 and TLR7, receptors that are key for the recognition of viruses such as bovine respiratory syncytial virus (BRSV); however, responses of gammadelta T cells to stimulation via these receptors, and their role during viral infections, remains unclear. Here, we demonstrate that neonatal bovine gammadelta T cells exhibit robust chemokine and cytokine production in response to the TLR3 agonist, Poly(I:C), and the TLR7 agonist, Imiquimod. Importantly, we observe a similar phenotype in gammadelta T-cell subsets purified from calves infected with BRSV. Bovine gammadelta T cells are divided into subsets based upon their expression of WC1, and the response to TLR stimulation and viral infection differs between these subsets, with WC1.1(+) and WC1(neg) gammadelta T cells producing macrophage inflammatory protein-1alpha and granulocyte-macrophage colony-stimulating factor, and WC1.2(+) gammadelta T cells preferentially producing the regulatory cytokines interleukin-10 and transforming growth factor-beta. We further report that the active vitamin D metabolite 1,25 dihydroxyvitamin D3 does not alter gammadelta T-cell responses to TLR agonists or BRSV. To our knowledge, this is the first characterization of the gammadelta T cell response during in vivo BRSV infection and the first suggestion that WC1.1(+) and WC1(neg) gammadelta T cells contribute to the recruitment of inflammatory populations during viral infection. Based on our results, we propose that circulating gammadelta T cells are poised to rapidly respond to viral infection and suggest an important role for gammadelta T cells in the innate immune response of the bovine neonate. PMID- 23368634 TI - Origin of magnetization reversal and exchange bias phenomena in solid solutions of BiFeO3-BiMnO3: intrinsic or extrinsic? AB - Magnetic properties of BiFe(0.7)Mn(0.3)O(3) (with a Neel temperature (T(N)) of 425 K) and BiFe(0.6)Mn(0.4)O(3) (with T(N) = 350 K) were investigated by magnetic measurements between 5 and 400 K. They crystallize in space group Pnma with the ?2a(p) * 4a(p) * 2?2a(p) superstructure (a(p) is the parameter of the cubic perovskite subcell) with a = 5.57800(9) A, b = 15.7038(3) A, and c = 11.22113(16) A for BiFe(0.6)Mn(0.4)O(3). Both compounds show magnetization reversal or negative magnetization phenomena. However, it was found that the magnetization reversal is dependent on magnetic prehistory of a sample and measurement protocols. No magnetization reversal was observed when virgin samples were measured below T(N). Magnetization reversal effects appeared only when the samples were cooled in small magnetic fields from temperatures above T(N) or after the samples were magnetized. The exchange bias effect or a shift of isothermal magnetization curves, depending on the measurement conditions, was also observed. The exchange bias changes its sign as a function of temperature and cooling conditions. Our findings allowed us to propose the extrinsic origin (related to sample inhomogeneities) of the magnetization reversal effect in these two compounds. PMID- 23368632 TI - Evaluation of characteristics of CD44+CD117+ ovarian cancer stem cells in three dimensional basement membrane extract scaffold versus two dimensional monocultures. AB - BACKGROUND: Cancer stem cells (CSCs) are thought to be capable of surviving conventional chemotherapeutic treatments because the cells have more resistant to anticancer drugs than common cancer cells. Most in vitro studies in experimental cancer cells have been done in a two-dimensional (2D) monocultures, while accumulating evidence suggests that cancer cells behave differently when they are grown within a three-dimensional (3D) culture system. RESULTS: The CD44+CD117+cells isolated from human epithelial ovarian cancer SKOV-3 cell line using magnetic-activated cell sorting were found to grow faster than the SKOV-3 cells in the 3D culture and in the nude mice. Anticancer drugs 5FU, docetaxel, cisplatin, and carboplatin were seen to inhibit growth of the CD44+CD117+ cells by 50% in the 2D culture with IC50 concentration, whereas, in the 3D culture, the four drugs inhibited the cell growth by only 34.4%, 40.8%, 34.8% and 21.9% at 3D one, respectively. Effect of paclitaxel on the CD44+CD117+cell viability indicated that fewer cells underwent apoptosis in 3D culture than that in 2D one. In addition, anticancer drugs markedly increased the expression of ABCG2 and ABCB1 of CD44+CD117+cells in 3D culture. CONCLUSION: Our assay demonstrated that human epithelial ovarian cancer CD44+CD117+cells possessed the properties of CSCs that exhibited more chemoresistance in the 3D culture than that of in 2D one. The 3D culture provides a realistic model for study of the CSC response to anticancer drugs. PMID- 23368633 TI - A genome-wide cis-regulatory element discovery method based on promoter sequences and gene co-expression networks. AB - BACKGROUND: Deciphering cis-regulatory networks has become an attractive yet challenging task. This paper presents a simple method for cis-regulatory network discovery which aims to avoid some of the common problems of previous approaches. RESULTS: Using promoter sequences and gene expression profiles as input, rather than clustering the genes by the expression data, our method utilizes co expression neighborhood information for each individual gene, thereby overcoming the disadvantages of current clustering based models which may miss specific information for individual genes. In addition, rather than using a motif database as an input, it implements a simple motif count table for each enumerated k-mer for each gene promoter sequence. Thus, it can be used for species where previous knowledge of cis-regulatory motifs is unknown and has the potential to discover new transcription factor binding sites. Applications on Saccharomyces cerevisiae and Arabidopsis have shown that our method has a good prediction accuracy and outperforms a phylogenetic footprinting approach. Furthermore, the top ranked gene-motif regulatory clusters are evidently functionally co-regulated, and the regulatory relationships between the motifs and the enriched biological functions can often be confirmed by literature. CONCLUSIONS: Since this method is simple and gene-specific, it can be readily utilized for insufficiently studied species or flexibly used as an additional step or data source for previous transcription regulatory networks discovery models. PMID- 23368635 TI - A model of the circadian clock in the cyanobacterium Cyanothece sp. ATCC 51142. AB - BACKGROUND: The over consumption of fossil fuels has led to growing concerns over climate change and global warming. Increasing research activities have been carried out towards alternative viable biofuel sources. Of several different biofuel platforms, cyanobacteria possess great potential, for their ability to accumulate biomass tens of times faster than traditional oilseed crops. The cyanobacterium Cyanothece sp. ATCC 51142 has recently attracted lots of research interest as a model organism for such research. Cyanothece can perform efficiently both photosynthesis and nitrogen fixation within the same cell, and has been recently shown to produce biohydrogen--a byproduct of nitrogen fixation- at very high rates of several folds higher than previously described hydrogen producing photosynthetic microbes. Since the key enzyme for nitrogen fixation is very sensitive to oxygen produced by photosynthesis, Cyanothece employs a sophisticated temporal separation scheme, where nitrogen fixation occurs at night and photosynthesis at day. At the core of this temporal separation scheme is a robust clocking mechanism, which so far has not been thoroughly studied. Understanding how this circadian clock interacts with and harmonizes global transcription of key cellular processes is one of the keys to realize the inherent potential of this organism. RESULTS: In this paper, we employ several state of the art bioinformatics techniques for studying the core circadian clock in Cyanothece sp. ATCC 51142, and its interactions with other key cellular processes. We employ comparative genomics techniques to map the circadian clock genes and genetic interactions from another cyanobacterial species, namely Synechococcus elongatus PCC 7942, of which the circadian clock has been much more thoroughly investigated. Using time series gene expression data for Cyanothece, we employ gene regulatory network reconstruction techniques to learn this network de novo, and compare the reconstructed network against the interactions currently reported in the literature. Next, we build a computational model of the interactions between the core clock and other cellular processes, and show how this model can predict the behaviour of the system under changing environmental conditions. The constructed models significantly advance our understanding of the Cyanothece circadian clock functional mechanisms. PMID- 23368636 TI - A blueprint for genomic nursing science. AB - PURPOSE: This article reports on recommendations arising from an invitational workshop series held at the National Institutes of Health for the purposes of identifying critical genomics problems important to the health of the public that can be addressed through nursing science. The overall purpose of the Genomic Nursing State of the Science Initiative is to establish a nursing research blueprint based on gaps in the evidence and expert evaluation of the current state of the science and through public comment. ORGANIZING CONSTRUCTS: A Genomic Nursing State of the Science Advisory Panel was convened in 2012 to develop the nursing research blueprint. The Advisory Panel, which met via two webinars and two in-person meetings, considered existing evidence from evidence reviews, testimony from key stakeholder groups, presentations from experts in research synthesis, and public comment. FINDINGS: The genomic nursing science blueprint arising from the Genomic Nursing State of Science Advisory Panel focuses on biologic plausibility studies as well as interventions likely to improve a variety of outcomes (e.g., clinical, economic, environmental). It also includes all care settings and diverse populations. The focus is on (a) the client, defined as person, family, community, or population; (b) the context, targeting informatics support systems, capacity building, education, and environmental influences; and (c) cross-cutting themes. It was agreed that building capacity to measure the impact of nursing actions on costs, quality, and outcomes of patient care is a strategic and scientific priority if findings are to be synthesized and aggregated to inform practice and policy. CONCLUSIONS: The genomic nursing science blueprint provides the framework for furthering genomic nursing science to improve health outcomes. This blueprint is an independent recommendation of the Advisory Panel with input from the public and is not a policy statement of the National Institutes of Health or the federal government. CLINICAL RELEVANCE: This genomic nursing science blueprint targets research to build the evidence base to inform integration of genomics into nursing practice and regulation (such as nursing licensure requirements, institutional accreditation, and academic nursing school accreditation). PMID- 23368637 TI - Redox-inflammatory synergy in the metabolic syndrome. AB - Metabolic syndrome (MetS) comprises interrelated disease states including obesity, insulin resistance and type 2 diabetes (T2DM), dyslipidemia, and hypertension. Essential to normal physiological function, and yet massively damaging in excess, oxidative stress and inflammation are pivotal common threads among the pathologies of MetS. Increasing evidence indicates that redox and inflammatory dysregulation parallels the syndrome's physiological, biochemical, and anthropometric features, leading many to consider the pro-oxidative, pro inflammatory milieu an unofficial criterion in itself. Left unchecked, cross promotion of oxidative stress and inflammation creates a feed-forward cycle that can initiate and advance disease progression. Such redox-inflammatory integration is evident in the pathogenesis of obesity, insulin resistance and T2DM, atherogenic dyslipidemia, and hypertension, and is thus hypothesized to be the "common soil" from which they develop. The present review highlights the synergistic contributions of redox-inflammatory processes to each of the components of the MetS. PMID- 23368638 TI - Sulfenate substitution as a complement and alternative to sulfoxidation in the diastereoselective preparation of chiral beta-substituted beta-amino sulfoxides. AB - Building from a previous communication, the reaction of sulfenate anions with chiral N-Boc-protected beta-substituted beta-amino iodides was evaluated as a conceptually different synthetic approach to chiral beta-substituted beta-amino sulfoxides. Using arenesulfenates, yields typically ranged from 71% to 92%, and dr's were often near 9:1. Alkanesulfenates proved less reactive, delivering lower yields and dr's. 1-Alkenesulfenates demonstrated high reactivity, returning chemical yields of 60-86% and dr's often close to 9:1 and as high as 95:5. (S) beta-Amino iodide electrophiles yielded (R(S),S(C))-beta-amino sulfoxides, whereas (R)-amino iodides afford (S(S),R(C))-beta-amino sulfoxides. The absolute configuration of the products makes the sulfenate protocol complementary to other existing preparations, including the commonly employed sulfoxidation of beta amino sulfides. The reactivity of N-Boc-protected 2-benzyl-2-aminoethyl iodide was found to be superior to the less sterically encumbered n-butyl iodide. A transition state model is proposed to account for the stereochemistry of the products and also for the high reactivity of the electrophile. Overall, the chemistry represents a new means of introducing sulfur stereogenicity in a molecule. PMID- 23368639 TI - Efficacy of the ANAM General Neuropsychological Screening Battery (ANAM GNS) for detecting neurocognitive impairment in a mixed clinical sample. AB - The Automated Neuropsychological Assessment Metrics (ANAM) is a computerized neuropsychological assessment battery that has demonstrated utility in a variety of clinical populations including multiple sclerosis, systemic lupus erythematosus, Parkinson's disease, acquired brain injury, migraine headaches, and Alzheimer's disease. This study utilized selected tests from the ANAM General Neuropsychological Screening Battery (ANAM GNS), a newly defined subset of tests from the broader ANAM library designed for general clinical assessment of cognition. ANAM GNS is an expansion of the ANAM Core battery which has been utilized in a military setting. The efficacy of the ANAM GNS was explored in a mixed clinical sample relative to well-established, traditional neuropsychological measure, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). It was hypothesized that scores from the ANAM GNS would accurately predict participants as either impaired (n = 30) or normal (n = 113). Participants were grouped a priori based on RBANS Total Index scores with impairment defined as scores <= 15th percentile. Logistic regression analysis was conducted to evaluate the classification accuracy of the ANAM GNS. The predictor variables were the Throughput scores from seven selected ANAM GNS subtests. The full model significantly predicted impairment status, sensitivity was 81% and specificity was 89.1%. Overall classification rate was 87.9% and the Odds Ratio for the overall model was 34.65. Positive predictive value was 56.7% and negative predictive value was 96.4%. This study represents the first clinical data on the ANAM GNS, and documents that it has good concurrent and predictive validity with a well-established neuropsychological measure. PMID- 23368640 TI - Relative quantitation of glycoisoforms of intact apolipoprotein C3 in human plasma by liquid chromatography-high-resolution mass spectrometry. AB - Glycosylation is one of the most important post-translational modifications to mammalian proteins. Distribution of different glycoisoforms of certain proteins may reflect disease conditions and, therefore, can potentially be utilized as biomarkers. Apolipoprotein C3 (ApoC3) is one of the many plasma glycoproteins extensively studied for association with disease states. ApoC3 exists in three main glycoisoforms, including ApoC3-1 and ApoC3-2, which contain an O-linked carbohydrate moiety consisting of three and four monosaccharide residues, respectively, and ApoC3-0 that lacks the entire glycosylation chain. Changes in the ratio of different glycoisoforms of ApoC3 have been observed in pathological conditions such as kidney disease, liver disease, and diabetes. They may provide important information for diagnosis, prognosis, and evaluation of therapeutic response for metabolic conditions. In this current work, a liquid chromatography (LC)-high-resolution (HR) time-of-flight (TOF) mass spectrometry (MS) method was developed for relative quantitation of different glycoisoforms of intact ApoC3 in human plasma. The samples were processed using a solid-phase extraction (SPE) method and then subjected to LC-full scan HRMS analysis. Isotope peaks for each targeted glycoisoform at two charge states were extracted using a window of 50 mDa and integrated into a chromatographic peak. The peak area ratios of ApoC3 1/ApoC3-0 and ApoC3-2/ApoC3-0 were calculated and evaluated for assay performance. The results indicated that the ratio can be determined with excellent reproducibility in multiple subjects. It has also been observed that the ratios remained constant in plasma exposed to room temperature, freeze-thaw cycles, and long-term frozen storage. The method was applied in preliminary biomarker research of diabetes by analyzing plasma samples collected from normal, prediabetic, and diabetic subjects. Significant differences were revealed in the ApoC3-1/ApoC3-0 ratio and in the ApoC3-2/ApoC3-0 ratio among the three groups. The workflow of intact protein analysis using full scan HRMS established in this current work can be potentially extended to relative quantitation of other glycosylated proteins. To our best knowledge, this is the first time that a systematic approach of relative quantitation of targeted intact protein glycoisoforms using LC-MS has been established and utilized in biomarker research. PMID- 23368641 TI - Is inflammation related to any diseases? PMID- 23368642 TI - How to prepare and present scientific manuscripts in English. PMID- 23368643 TI - Editorial comment to how to prepare and present scientific manuscripts in English. PMID- 23368549 TI - Search for heavy neutrinos and W(R) bosons with right-handed couplings in a left right symmetric model in pp collisions at sqrt[s]=7 TeV. AB - Results are presented from a search for heavy, right-handed muon neutrinos, N(MU), and right-handed W(R) bosons, which arise in the left-right symmetric extensions of the standard model. The analysis is based on a 5.0 fb(-1) sample of proton-proton collisions at a center-of-mass energy of 7 TeV, collected by the CMS detector at the Large Hadron Collider. No evidence is observed for an excess of events over the standard model expectation. For models with exact left-right symmetry, heavy right-handed neutrinos are excluded at 95% confidence level for a range of neutrino masses below the W(R) mass, dependent on the value of M(W(R)). The excluded region in the two-dimensional (M(W(R)), M(N(MU)) mass plane extends to M(W(R))=2.5 TeV. PMID- 23368644 TI - Isolation, structural elucidation, MS profiling, and evaluation of triglyceride accumulation inhibitory effects of benzophenone C-glucosides from leaves of Mangifera indica L. AB - Seventy percent ethanol-water extract from the leaves of Mangifera indica L. (Anacardiaceae) was found to show an inhibitory effect on triglyceride (TG) accumulation in 3T3-L1 cells. From the active fraction, six new benzophenone C glucosides, foliamangiferosides A(3) (1), A(4) (2), C(4) (3), C(5) (4), C(6) (5), and C(7) (6) together with 11 known benzophenone C-glucosides (7-17) were obtained. In this paper, isolation, structure elucidation (1-6), and MS fragment cleavage pathways of all 17 isolates were studied. 1-6 showed inhibitory effects on TG and free fatty acid accumulation in 3T3-L1 cells at 10 MUM. PMID- 23368645 TI - Direct atomic-level observation and chemical analysis of ZnSe synthesized by in situ high-throughput reactive fiber drawing. AB - We demonstrate a high-throughput method for synthesizing zinc selenide (ZnSe) in situ during fiber drawing. Central to this method is a thermally activated chemical reaction occurring across multiple interfaces between alternately layered elemental zinc- (Zn-) and selenium- (Se-) rich films embedded in a preform and drawn into meters of fiber at a temperature well below the melting temperature of either Zn or ZnSe. By depositing 50 nm thick layers of Zn interleaved between 1 MUm thick Se layers, a controlled breakup of the Zn sheet is achieved, thereby enabling a complete and controlled chemical reaction. The thermodynamics and kinetics of this synthesis process are studied using thermogravimetric analysis and differential scanning calorimetry, and the in fiber compound is analyzed by a multiplicity of materials characterization tools, including transmission electron microscopy, Raman microscopy, energy-dispersive X ray spectroscopy, and X-ray diffraction, all resulting in unambiguous identification of ZnSe as the compound produced from the reactive fiber draw. Furthermore, we characterize the in-fiber ZnSe/Se97S3 heterojunction to demonstrate the prospect of ZnSe-based fiber optoelectronic devices. The ability to synthesize new compounds during fiber drawing at nanometer scale precision and to characterize them at the atomic-level extends the architecture and materials selection compatible with multimaterial fiber drawing, thus paving the way toward more complex and sophisticated functionality. PMID- 23368646 TI - Genes and populations in susceptibility to celiac disease. PMID- 23368647 TI - Frequency of MYO9B polymorphisms in celiac patients and controls. AB - INTRODUCTION: the MYO9B gene contributes to the maintenance of the intestinal barrier and it has been postulated as a risk factor of celiac disease (CD). The objective of this study was to compare the frequency and association rs2305764, rs2305767 and rs1457092 MYO09B polymorphisms in pediatric CD patients from and. PATIENTS AND METHODS: the study was made in 104 CD pediatric patients (Chilean and Argentineans) and 104 controls subjects. MYO9B gene polymorphisms were analyzed by Taqman allelic probes. We evaluated the Hardy-Weinberg equilibrium by means of Chi-square and compared the haplotypes distribution using Fisher test. RESULTS: SNPs rs2305767 and rs1457092 were associated with celiac disease (CD); TT genotype in rs2305767 would be a protective factor (p < 0.000, OR = 0.19 CI 0.1-0.4) and the CT genotype would be a risk factor (p < 0.0001, OR = 4.9 CI 2.2 to 11.3). CC genotype in rs1457092 also showed a protective effect for celiac (p < 0.000, OR = 0.07 CI 0.0 to 0.3). CONCLUSION: our findings suggest that genetic variation MYO9B gene is associated with CD, as a protective or a risk factor depending on the polymorphism studied. PMID- 23368648 TI - Colorectal cancer survival: results from a hospital-based cancer registry. AB - INTRODUCTION: colorectal cancer is one of the most common malignancies in developed countries. Data on specific and 10-year survival are scarce. This study analyzes overall and disease-specific survival for patients with colorectal cancer and assesses the value of clinical factors on disease-specific survival. METHODS: a retrospective cohort study of newly diagnosed invasive colorectal cancer cases diagnosed from 1992 to 2007 were identified through the Hospital del Mar Cancer Registry. Five-and 10-year survival functions were estimated using Kaplan-Meier method. Cox proportional hazard models were used to assess prognostic factors. RESULTS: a total of 2,080 patients with colorectal cancer were identified. The median age at diagnosis was 72 years and 58.5%were men. By the end of the follow-up period (December 2008), 1,225 patients had died and 68.4% of deaths were due to colorectal cancer. The 5- and 10-year cancer-specific survival rates were 55.5% (95%CI 53.9-57.9%) and 48.5% (95%CI 45.6-51.3%), respectively. The 5-year specific survival rate improved in the last period (2003 2007) (60.4%, 95%CI 55.4-65.0) compared with 1992-1997(53.4%; 95%CI 49.2-57.4) and 1998-2002 (52.0%; 95%CI 47.8-56.2). Various factors were independently associated with excess CRC mortality: male sex (HR 1.21), age at diagnosis > 75 years(HR 1.97), rectal location (HR 1.33), more advanced stages (stage IV: HR 18.54), poorly differentiated/undifferentiated tumors (HR 1.80), and admission through the emergency department (HR 1.52). CONCLUSIONS: cancer-specific survival improved from 1992 to 2007. This improvement could be due to more effective treatment, since changes in stage distribution or age at diagnosis were not observed during the study period. Overall survival rates should notably improve with the implementation of a population-based colorectal cancer screening program in Spain. PMID- 23368650 TI - Relationship between quality of life and clinical status in patients with gastrointestinal cancer. AB - BACKGROUND: previous studies with patients having cancer have shown that quality of life scores depend on the clinical stage of the disease (the more advanced the disease, the worst quality of life). METHODS: in a prospective study we studied 317 patients with gastric or colorectal cancer attending the Instituto Nacional de Cancerologia between 2010 and 2011; the patients completed the EORTC QLQ-C30 before receiving treatment. This instrument measures quality of life in 15 domains. Scores of each domain were compared according to tumor stage. Differential Item Functioning was measured across neoplasm staging and tumor localization. RESULTS: 145 patients (45.7%) were diagnosed with colorectal cancer. According to clinical staging, differences in quality of life scores were observed in 4 of 15 domains (physical and social functioning, anorexia). Most of the differences in quality of life domains depended on tumor localization (patients with colorectal cancer had the highest scores in quality of life) and sex (women reported better scores). These differences seemed to be independent of item properties. The construct was more adequately measured with items that explore the construct using a general approach. CONCLUSION: in this group of patients with colorectal and gastric cancer quality of life scores were more related with tumor localization than with clinical stage. PMID- 23368649 TI - Using of magnetic resonance enterography in the management of Crohn's disease of the small intestine: first year of experience. AB - OBJECTIVE: to describe the experience at two tertiary centres during the first year of use of magnetic resonance enterography (MRE) for the management of Crohn's disease (CD): indications and influence of the technique in clinical decision making. MATERIALS AND METHODS: retrospective descriptive study in which patients who underwent MRE were included consecutively. Epidemiological and clinical data were collected from the patients, as well as the indication for the study and how it influenced clinical decision making in the 10 days following the radiological study. RESULTS: 24 MREs were performed in suspected CD and 126 known CD; partial bowel obstruction in 53 patients (42%), monitoring of medical treatment in 34 (27%), due to incomplete ileocolonoscopy in 16 (13%), extension study of the small intestine in 15 (12%) and suspected complicated CD in 8 patients (6%). The MRE influenced in a change in treatment in 83 (55.3%) patients: 16 (10.7%) started with immunosuppressants, 41 (27.3%) with anti TNFalpha were started on or switched, 15 (10%) were ordered surgery and in 3 (2%) changed from combined therapy to monotherapy. The MRE had less influence on clinical decision making in the group in which the indication was suspected CD (p < 0.05). CONCLUSIONS: the use of MRE helped on decision making in more than half of patients, especially with regards to decisions related to the use of biological therapies and the indication for surgery. MRE was less useful in suspected CD patients. PMID- 23368651 TI - Influence of genetics on tumoral pathologies: the example of the adenocarcinoma arising in Barrett's esophagus. AB - Barrett's esophagus (BE) refers to an abnormal change (metaplasia) in the cells of the inferior portion of the esophagus. About 10% of patients with symptomatic gastroesophageal reflux disease (GERD) have BE. In some cases, BE develops as an advanced stage of erosive esophagitis. The risk of esophageal cancer appears to be increased in patients with BE. The only way to diagnose BE is by endoscopy and histology. Some studies suggest that intensive treatment of Barrett's esophagus with effective acid suppression can reduce the amount of abnormal lining in the esophagus. It is not clear whether such treatment also prevents esophageal cancer. Generally, the cancer starts out as carcinoma of the esophagus on the surface, and then invades the surrounding tissue. Surgery offers the best chance of long-term survival. There are many events that occur in Barrett's esophagus that lead to the development of cancer and most of them appear to occur early, before high-grade dysplasia or cancer develops. No one knows what the late events are and how cells acquire the ability to leave their normal growth boundaries. It is now widely accepted that the development of most cancers is due to something called genomic or genetic instability. The aim of this review is to show BE pathology in its progression to cancer looking for new biomarkers to distinguish between BE -dysplasia (low grade and high grade)- adenocarcinoma (ADC) and to characterize the ADC, giving more hope for its treatment. PMID- 23368652 TI - Fatal acute pancreatitis following sclerosis of a bleeding duodenal ulcer complicated by an intramural duodenal hematoma. PMID- 23368653 TI - Successful endoscopic mesh removal after laparoscopic Nissen fundoplication. PMID- 23368654 TI - Should the host reaction to anisakiasis influence the treatment? Different clinical presentations in two cases. AB - Gastrointestinal anisakiasis is a parasitic infection occurring in people that consume raw or inadequately cooked fish or squid. It is frequently characterized by severe epigastric pain, nausea and vomiting caused by the penetration of the larvae into the gastric wall. Acute gastric anisakiasis with severe chest discomfort is rarely reported in Italy. On the other hand, gastro-allergic anisakiasis with rash, urticaria and isolated angioedema or anaphylaxis is a clinical entity that has been described only recently. Also, if patients usually develop symptoms within 12 hours after raw seafood ingestion, not always endoscopic exploration can promptly identify the Anisakis larvae. Moreover, some authors consider the prevailing allergic reaction as a natural and effective defense against the parasitic attack. We report two cases of peculiar manifestations of anisakiasis in both acute and chronic forms (severe chest discomfort and anaphylactoid reaction). PMID- 23368655 TI - [Patient information. Submucosal lesions of the gastrointestinal tract]. PMID- 23368656 TI - Incarcerated Spigelian hernia: diagnosis by computed tomography. PMID- 23368657 TI - Subtotal distal pancreatectomy for metachronous metastatic renal clear cell carcinoma. PMID- 23368658 TI - Upper gastrointestinal bleeding secondary to renal tumor. PMID- 23368659 TI - Beyond Heyde's syndrome. PMID- 23368660 TI - Recurrent cholestasis by amoxicillin-clavulanic acid: the importance of a correct diagnosis of hepatotoxicity. PMID- 23368661 TI - Liver toxicity due to olanzapine. PMID- 23368662 TI - Dysglycaemia in the critically ill - significance and management. AB - Hyperglycaemia frequently occurs in the critically ill, in patients with diabetes, as well as those who were previously glucose-tolerant. The terminology 'stress hyperglycaemia' reflects the pathogenesis of the latter group, which may comprise up to 40% of critically ill patients. For comparable glucose concentrations during acute illness outcomes in stress hyperglycaemia appear to be worse than those in patients with type 2 diabetes. While several studies have evaluated the optimum glycaemic range in the critically ill, their interpretation in relation to clinical recommendations is somewhat limited, at least in part because patients with stress hyperglycaemia and known diabetes were grouped together, and the optimum glycaemic range was regarded as static, rather than dynamic, phenomenon. In addition to hyperglycaemia, there is increasing evidence that hypoglycaemia and glycaemic variability influence outcomes in the critically ill adversely. These three categories of disordered glucose metabolism can be referred to as dysglycaemia. While stress hyperglycaemia is most frequently managed by administration of short-acting insulin, guided by simple algorithms, this does not treat all dysglycaemic categories; rather the use of insulin increases the risk of hypoglycaemia and may exacerbate variability. The pathogenesis of stress hyperglycaemia is complex, but hyperglucagonaemia, relative insulin deficiency and insulin resistance appear to be important. Accordingly, novel agents that have a pathophysiological rationale and treat hyperglycaemia, but do not cause hypoglycaemia and limit glycaemic variability, are appealing. The potential use of glucagon-like peptide-1 (or its agonists) and dipeptyl-peptidase-4 inhibitors is reviewed. PMID- 23368663 TI - Where are we going with ulcerative colitis management? AB - Impressive progress has been made in the treatment of ulcerative colitis. Corticosteroids are nowadays limited to short-term use. The mainstay of current therapy consists of the immunosuppressive drugs (largely thiopurine analogs) and the biologics, often in combination. The calcineurin inhibitors are still in use for acute severe colitis in many centers. However, gastroenterologists can now choose between calcineurin inhibitors and biologics for administration to patients with fulminant disease, although the criteria for selection are not yet resolved. Given the success rates of current therapies, it is obvious that new and better drug development is required if surgery is to disappear from the armamentarium of treatments. PMID- 23368664 TI - Classification of patients who experience a higher distress level to transoral esophagogastroduodenoscopy than to transnasal esophagogastroduodenoscopy. AB - BACKGROUND: In Japanese routine clinical practice, endoscopy is generally carried out without sedation. The present study aimed to identify the factors essential for appropriate selection of transnasal esophagogastroduodenoscopy (TN-EGD) as an alternative to unsedated transoral esophagogastroduodenoscopy (TO-EGD). PATIENTS AND METHODS: Subjects in this prospective cohort study comprised consecutive outpatients who underwent EGD at a single center. Factors predicting TO-EGD induced distress were evaluated on a visual analog scale (VAS) and analyzed. Patients were classified into a two-layered system on the basis of these predictive factors, and the severity of distress between the TN-EGD and TO-EGD groups was compared using VAS and the change in the rate-pressure product as subjective and objective indices, respectively. RESULTS: In total, 728 outpatients (390 male, 338 female; mean age, 63.1 +/- 0.5 years; TO-EGD group, 630; TN-EGD group, 98)met the inclusion criteria. Multivariate logistic regression analysis confirmed that age <65 years (P < 0.01; odds ratio [OR], 1.69; 95% confidence interval [CI], 1.14-2.52), gender (female; P < 0.01; OR,1.97; 95% CI, 1.34-2.91), marital status (single; P < 0.01; OR, 1.96; 95% CI, 1.18-3.27), and anxiety towards TO-EGD (P < 0.001; OR, 3.62; 95% CI, 2.44-5.37) were independently associated with intolerance. Both indices were significantly higher in the TO-EGD subgroup than in the TN-EGD subgroup in the high predictive class, but not in the low predictive class. CONCLUSION: Predictive factors for detecting intolerance to unsedated TO-EGD may be useful to appropriately select patients who transpose unsedated TO-EGD to TN-EGD. PMID- 23368665 TI - Kallmann syndrome in women: from genes to diagnosis and treatment. AB - Kallmann syndrome (KS) can be characterized as genetic disorder marked by hypogonadotropic hypogonadism and anosmia. Franz Jozef Kallmann was the first who described this disease in 1944. He suggested, that this disease has hereditary background. At present, six genes are regarded as causal genes of KS. These genes can be listed in chronological order: KAL1, FGFR1, FGF8, CHD7, PROKR2 and PROK2. The sensitivity of molecular testing of KS is only about 30%. Diagnosis based on clinical findings is therefore such important. Cardinal features of patients with KS include hypogonadotropic hypogonadism and anosmia or hyposmia. Some non reproductive, non-olfactory symptoms can also be present, depending on the genetic form of disease. Some patients with KS present midline cranial anomalies (cleft lip, cleft palate and imperfect fusion). Sometimes patients can also suffer from missing teeth (dental agenesis). Optic problems, such as colour blindness or optic atrophy also can occur in KS patients. Very characteristic symptom in KS patients is mirror movements of the upper limbs (imitation synkinesis for contralateral limbs). The type of treatment in women with KS depends on the goal of therapy. After the diagnosis of syndrome, the main goal of the treatment is to induce and maintain secondary sex characteristic (estrogen progestin therapy). The further goal in some patients can be related to enable fertility (gonadotropin, gonadotropin-releasing hormone therapy). PMID- 23368666 TI - Endoscopy-assisted breast-conserving surgery for early breast cancer. AB - INTRODUCTION: Endoscopic surgery is reportedly associated with smaller scars and greater patient satisfaction. Herein we evaluate the early results of endoscopy assisted breast-conserving surgery(E-BCS). METHODS: Between May 2009 and October 2010, 61 women with breast cancer underwent E-BCS. We performed E-BCS on patients with tumors measuring less than 2 cm, without skin or pectoralis muscles invasion. Any patients with microcalcified lesions or axillary lymph node metastasis were excluded. We used an endoscopic vein retractor to dissect the dorsal layer of the mammary gland from a small axillar incision. We dissected the subcutaneous layer and cut the mammary gland vertically from a periareolar incision. We evaluated the clinicopathological characteristics, the surgical outcomes, and early cosmetic results. RESULTS: The mean age of the patients was 58.5 years, and the mean tumor size was 1.4 cm. Sentinel node biopsy was positive in seven patients, all of whom underwent axillary node dissection. An additional intraoperative resection of the breast was performed in 12 patients. The mean length of the operation was 167 min, and the mean blood loss was 27 mL. Eight patients received a boost to the tumor bed. The cosmetic results were satisfactory, and the wound scar was inconspicuous in most patients. CONCLUSION: Herein we demonstrate that E-BCS is a feasible and safe procedure for patients with early breast cancer. It allows for a better cosmetic scar location and offers patients favorable aesthetic results in the short-term follow-up results. PMID- 23368667 TI - The impact of routine cryptococcal antigen screening on survival among HIV infected individuals with advanced immunosuppression in Kenya. AB - OBJECTIVES: To test the hypothesis that a screening and treatment intervention for early cryptococcal infection would improve survival among HIV-infected individuals with low CD4 cell counts. METHODS: Newly enrolled patients at Family AIDS Care and Education Services (FACES) in Kenya with CD4 <= 100 cells/MUl were tested for serum cryptococcal antigen (sCrAg). Individuals with sCrAg titre >= 1:2 were treated with high-dose fluconazole. Cox proportional hazard models of Kaplan-Meier curves were used to compare survival among individuals with CD4 <= 100 cells/MUl in the intervention and historical control groups. RESULTS: The median age was 34 years [IQR: 29,41], 54% were female, and median CD4 was 43 cells/MUl [IQR: 18,71]. Follow-up time was 1224 person-years. In the intervention group, 66% (514/782) were tested for sCrAg; of whom, 11% (59/514) were sCrAg positive. Mortality was 25% (196/782) in the intervention group and 25% (191/771) in the control group. There was no significant difference between the intervention and control group in overall survival [hazard ratio (HR): 1.1 (95%CI:0.9,1.3)] or three-month survival [HR: 1.0 (95%CI:0.8,1.3)]. Within the intervention group, sCrAg-positive individuals had significantly lower survival rates than sCrAg-negative individuals [HR:1.8 (95%CI: 1.0, 3.0)]. CONCLUSIONS: A screening and treatment intervention to identify sCrAg-positive individuals and treat them with high-dose fluconazole did not significantly improve overall survival among HIV-infected individuals with CD4 counts <= 100 cells/MUl compared to a historical control, perhaps due to intervention uptake rates or poor efficacy of high-dose oral fluconazole. PMID- 23368668 TI - Endoscopic radial incision and cutting method for refractory esophageal stricture after endoscopic submucosal dissection of superficial esophageal carcinoma. AB - A 59-year-old woman and a 69-year-old man had esophageal strictures that were refractory to over 10 therapeutic attempts with endoscopic balloon dilation (EBD) after endoscopic submucosal dissections (ESD) for superficial esophageal carcinoma (SEC). The strictured lesions in both patients improved remarkably with a new endoscopic modality (endoscopic radial incision and cutting [ERIC]), which was carried out one to three times, and stricture recurrence was not noted throughout the follow-up period. ERIC is a safe and efficient method for treating refractory strictures after EBD caused by ESD for SEC. PMID- 23368670 TI - An evaluation of the stress-negative affect model in explaining alcohol use: the role of components of negative affect and coping style. AB - The stress-negative affect model for alcohol use was examined. The mediating roles of different components of negative affect were tested in the context of coping style. Data from 1,057 drinking adults (Mage = 44.45) and 352 drinking college students (Mage = 19.07) collected during 2001-2005 and in 2010, respectively, were examined separately. Participants completed self-administered measures of alcohol use, coping strategies, negative life events, and negative affect. A structural equation modeling framework detected stress-related drinking only in the adult sample. Sadness, anger, and guilt were significant mediators and the significant pathways differed based on coping style. The implications and limitations of the study are discussed. PMID- 23368669 TI - Sexual orientation disparities in substance misuse: the role of childhood abuse and intimate partner violence among patients in care at an urban community health center. AB - This study examined disparities in lifetime substance misuse by sexual orientation among 2,653 patients engaged in care at an urban community health center in Boston, MA, as well as the potential mediating roles of childhood abuse 0.84), but intervention-arm subjects who completed all assigned cases answered an average of 3.2 more questions correctly on the post-test than others, controlling for pre test scores (p = 0.003). CONCLUSIONS: Completion of the case-based intervention improved respondents' test scores, with those who completed all six email cases scoring roughly 10% better than those who failed to complete this task and those in the control arm. There was only suggestive evidence that intensive case work improved ethical issue identification, although there was limited ability to assess this outcome due to a high drop-out rate. PMID- 23368700 TI - Pilot validation of the Boston Bowel Preparation Scale in China. AB - BACKGROUND AND AIM: The Boston Bowel Preparation Scale (BBPS) is a novel bowel cleanliness rating scale that has undergone validation at Boston University Medical Center, Boston, MA, USA. Thus far, there is no standard recognized bowel preparation scale in China. The aim of the present study was to analyze the reliability and validity of the BBPS for the assessment of bowel preparation quality (BPQ) in China. METHODS: A group of 49 participants from several hospitals in Guangdong province viewed a video demonstration of BBPS provided by Boston Medical Center and participated in a continuing education seminar. Inter observer reliability was assessed for three testing colonoscopies in the video. Three months later, 13 of the participants repeated the test, and intra-observer reliability was assessed. The BBPS was then applied prospectively in 1012 screening colonoscopies and BBPS scores were compared with polyp-detection rate. Intraclass correlation coefficients (ICC) and weighted Kappa values assessed inter- and intra-rater reliability, respectively. The association of BBPS scores with polyp-detection rates was calculated by chi(2) tests. RESULTS: The inter observer ICC of BBPS scores was 0.987 (95% CI, 0.949-1.0). The weighted Kappa for BBPS scores was 0.671 (95%CI, 0.507-0.841). For 1012 screening colonoscopies, the mean BBPS score was 6.9 +/- 1.8. BBPS scores >= 5 were associated with a higher polyp-detection rate (35%) than scores < 5 (18%) (P < 0.05). CONCLUSION: The BBPS is a valid and reliable measure of BPQ, and this validity and reliability was maintained for Chinese physicians taught via video. PMID- 23368701 TI - Effects of hyaluronic acid and carboxymethylcellulose on urethral stricture after transurethral resections of the prostate for benign prostatic hyperplasia: a multicenter, single blinded, randomized controlled study. AB - PURPOSE: To evaluate the effect of hyaluronic acid (HA) and carboxymethylcellulose (CMC) instillation after transurethral resection of the prostate (TURP) on preventing urethral stricture. PATIENTS AND METHODS: A total of 180 patients underwent TURP for benign prostatic hyperplasia. Recruited patients were randomly divided into two groups: Groups A and B. Patients in group A (90 patients, experimental group) received HA/CMC instillation, and patients in the group B (90 patients, control group) received lubricant instillation after TURP. Each patient was evaluated at 4 weeks (V1), 12 weeks (V2), and 24 weeks (V3) after the surgery. The effectiveness of HA/CMC instillation was evaluated based on the International Prostate Symptom Score/Quality of Life, peak urine flow rate, voided volume, and postvoid residual volume. The visual analogue scale (VAS) pain score and degree of satisfaction were also determined for each participant. RESULTS: Among 180 initial participants, 80 patients in group A and 81 patients in group B had completed the experiment. VAS pain scores were 0.75+/ 0.75 and 1.75+/-1.37 (P<0.001), and degrees of satisfaction were 0.63+/-0.66 and 0.91+/-0.51 in group A and group B at 1 month after surgery (P=0.002). By retrograde urethrography, urethral stricture after TURP was seen in 1 of 80 subjects in group A and 7 of 81 subjects in group B. CONCLUSIONS: HA/CMC instillation after TURP decreased the incidence of urethral stricture. In addition, HA/CMC was effective at reducing pain during the early postoperative period, with no adverse effects. PMID- 23368702 TI - FitSearch: a robust way to interpret a yeast fitness profile in terms of drug's mode-of-action. AB - BACKGROUND: Yeast deletion-mutant collections have been successfully used to infer the mode-of-action of drugs especially by profiling chemical-genetic and genetic-genetic interactions on a genome-wide scale. Although tens of thousands of those profiles are publicly available, a lack of an accurate method for mining such data has been a major bottleneck for more widespread use of these useful resources. RESULTS: For general usage of those public resources, we designed FitRankDB as a general repository of fitness profiles, and developed a new search algorithm, FitSearch, for identifying the profiles that have a high similarity score with statistical significance for a given fitness profile. We demonstrated that our new repository and algorithm are highly beneficial to researchers who attempting to make hypotheses based on unknown modes-of-action of bioactive compounds, regardless of the types of experiments that have been performed using yeast deletion-mutant collection in various types of different measurement platforms, especially non-chip-based platforms. CONCLUSIONS: We showed that our new database and algorithm are useful when attempting to construct a hypothesis regarding the unknown function of a bioactive compound through small-scale experiments with a yeast deletion collection in a platform independent manner. The FitRankDB and FitSearch enhance the ease of searching public yeast fitness profiles and obtaining insights into unknown mechanisms of action of drugs. FitSearch is freely available at http://fitsearch.kaist.ac.kr. PMID- 23368703 TI - Estimating the prevalence of crack dependence using capture-recapture with institutional and field data: a three-city study in The Netherlands. AB - The aim of this study was to estimate the prevalence of crack dependence in the three largest Dutch cities (Amsterdam, Rotterdam, The Hague), stratified by gender and age. Three-sample capture-recapture, using data (collected between 2009 and 2011) from low threshold substitution treatment (n = 1,764), user rooms (n = 546), and a respondent-driven sample (n = 549), and applying log-linear modeling (covariates: gender, age, and city), provided a prevalence rate of 0.51% (95% CI: 0.46%-0.60%) for the population aged 15-64 years, with similar estimates for the three cities. Females (23.0% of total estimate) and younger crack users (12.8% aged <35 years) might be underrepresented in drug user treatment services. PMID- 23368704 TI - Predictors for dropping-out from methadone maintenance therapy programs among heroin users in southern Taiwan. AB - This study examined the methadone maintenance therapy (MMT) retention rates of heroin users in Taiwan and the predictors for dropout in the 18-month period after starting MMT. We consecutively recruited 368 intravenous heroin users receiving MMT in 2007-2008 and applied Cox proportional hazards regression analysis to determine the predictive effect of pre- and in-treatment variables on early discontinuation of MMT. The retention rate at 18 months was 32.3%. High heroin expenses, more severe harm caused by heroin use, perceived lower family support, and lower methadone dosage at 3 months after starting MMT increased the risk of dropout in the follow-up period. PMID- 23368705 TI - Anti-Mullerian hormone trend after laparoscopic surgery in women with ovarian endometrioma. AB - Operative laparoscopy is the gold standard in the treatment of endometriotic ovarian cysts. Excisional surgery is the best technique to prevent recurrences and improve symptoms but it may result in ovarian reserve damage due to the removal of healthy ovarian cortex. The aim of this study was to investigate the extent of the ovarian reserve damage after stripping technique of unilateral endometriomas, by dosing the Anti-Mullerian Hormone (AMH). This prospective study was conducted at the Center of Minimally Invasive Pelvic Surgery of the Department of Health of Woman and Child, University of Padua, from October 2010 to June 2012. Twenty-five women underwent excision of monolateral endometriosis ovarian cyst by stripping without accessing a bipolar coagulation and performing an intracortical suture. The AMH serum levels were estimated in the early proliferative phase of the cycle, before surgery (time 0), 24 h after surgery (time 1), the first menstrual cycle after surgery (time 2) and the third menstrual cycle after surgery (time 3). We found a nonstatistically significant decreases in serum AMH levels after surgical excision of the cysts. Our results suggest that an appropriate surgical technique, without the use of the bipolar coagulation of ovarian border, does not determine a significant reduction of ovarian reserve. PMID- 23368706 TI - Spiral search: a hydrophobic-core directed local search for simplified PSP on 3D FCC lattice. AB - BACKGROUND: Protein structure prediction is an important but unsolved problem in biological science. Predicted structures vary much with energy functions and structure-mapping spaces. In our simplified ab initio protein structure prediction methods, we use hydrophobic-polar (HP) energy model for structure evaluation, and 3-dimensional face-centred-cubic lattice for structure mapping. For HP energy model, developing a compact hydrophobic-core (H-core) is essential for the progress of the search. The H-core helps find a stable structure with the lowest possible free energy. RESULTS: In order to build H-cores, we present a new Spiral Search algorithm based on tabu-guided local search. Our algorithm uses a novel H-core directed guidance heuristic that squeezes the structure around a dynamic hydrophobic-core centre. We applied random walks to break premature H cores and thus to avoid early convergence. We also used a novel relay-restart technique to handle stagnation. CONCLUSIONS: We have tested our algorithms on a set of benchmark protein sequences. The experimental results show that our spiral search algorithm outperforms the state-of-the-art local search algorithms for simplified protein structure prediction. We also experimentally show the effectiveness of the relay-restart. PMID- 23368707 TI - Postoperative complication rates and invasiveness of laparoscopy-assisted distal gastrectomy and open distal gastrectomy based on the American Society of Anesthesiologists classification system. AB - INTRODUCTION: We investigated potential advantages of laparoscopy-assisted distal gastrectomy (LADG) in high-risk gastric cancer patients. We examined the differences among various risk groups by comparing the incidence of postoperative complications and invasiveness of LADG with those of open distal gastrectomy (ODG) based on the American Society of Anesthesiologists (ASA) criteria. METHODS: A total of 639 patients with stage IA or IB gastric cancer were included in this study. ODG was performed between 2003 and 2005, and LADG was performed between 2006 and 2011. RESULTS: The incidence of postoperative complications in the LADG group (ASA1, 5.6%; ASA2, 3.8%; and ASA3, 5.7%) was significantly lower than that in the ODG group in all the ASA classes (ASA1, 16.9%; ASA2, 12.5%; and ASA3, 20%). Changes in the pain scores, body temperatures and blood analyses revealed that LADG was less invasive than ODG in all ASA classes. However, as the ASA class increased, the less invasive nature of LADG decreased. CONCLUSION: LADG may be less invasive than ODG, even in ASA3 patients. Hence, LADG may reduce the incidence of postoperative complications in ASA1, ASA2, and ASA3 patients. PMID- 23368708 TI - Does life history shape sexual size dimorphism in anurans? A comparative analysis. AB - BACKGROUND: The evolution of sexual size dimorphism (SSD) is likely constrained by life history. Using phylogenetic comparative methods, we examined correlations between SSD among anurans and their life history traits, including egg size, clutch size, mating combat, and parental care behaviour. We used sexual dimorphism index (SDI = Body-size(female) /Body-size(male) -1) as the measurement for SSD. Body size, life history and phylogenetic data were collected from published literature. Data were analysed at two levels: all anuran species and within individual families. RESULTS: Female-biased SSD is the predominant form in anurans. SSD decreases along with the body size increase, following the prediction of Rensch's rule, but the magnitude of decrease is very small. More importantly, female body size is positively correlated with both fecundity related traits, egg size and clutch size, and SDI is also positively correlated with clutch size, suggesting fecundity advantage may have driven the evolution of female body size and consequently leads to the evolution of female-biased SSD. Furthermore, the presence of parental care, male parental care in particular, is negatively correlated with SDI, indicating that species with parental care tend to have a smaller SDI. A negative correlation between clutch size and parental care further suggests that parental care likely reduces the fecundity selection pressure on female body size. On the other hand, there is a general lack of significant correlation between SDI and the presence of male combat behaviour, which is surprising and contradictory to previous studies. CONCLUSIONS: We find clear evidence to support the 'fecundity advantage hypothesis' and the 'parental care hypothesis' in shaping SSD in anurans. Nevertheless, the relationships of both parental care and combat behaviour to the evolution of SSD are complex in anurans and the extreme diversity of life history traits may have masked some potential interesting relationships. Our study represents the most comprehensive study of SSD in anurans to date. PMID- 23368709 TI - Synthesis, structures, and luminescent properties of uranyl terpyridine aromatic carboxylate coordination polymers. AB - Six novel uranyl terpyridine aromatic carboxylate coordination polymers, [UO(2)(C(6)H(2)O(4)S)(C(15)H(11)N(3))] (1), [UO(2)(C(6)H(2)O(4)S)(C(15)H(10)N(3)Cl)].H(2)O (2), [UO(2)(C(8)H(4)O(4))(C(15)H(11)N(3))] (3), [UO(2)(C(8)H(4)O(4))(C(15)H(10)N(3)Cl)] (4), [UO(2)(C(12)H(6)O(4))(C(15)H(11)N(3))] (5), and [UO(2)(C(12)H(6)O(4))(C(15)H(10)N(3)Cl)] (6), were synthesized under solvothermal conditions and characterized by single-crystal and powder X-ray diffraction and luminescence and UV-vis spectroscopy. Compounds 1, 2, and 5 crystallize as molecular uranyl dimers, whereas compounds 3, 4, and 6 contain ladder motifs of uranyl centers. Fluorescence spectra of 1-4 show characteristic UO(2)(2+) emission, wherein bathochromic and hypsochromic shifts are noted as a function of organic species. In contrast, uranyl emission from 5 and 6 is quenched by the naphthalene dicarboxylic acid linker molecules. PMID- 23368710 TI - The impact of functionalization on the stability, work function, and photoluminescence of reduced graphene oxide. AB - Reduced graphene oxide (rGO) is a promising material for a variety of thin-film optoelectronic applications. Two main barriers to its widespread use are the lack of (1) fabrication protocols leading to tailored functionalization of the graphene sheet with oxygen-containing chemical groups, and (2) understanding of the impact of such functional groups on the stability and on the optical and electronic properties of rGO. We carry out classical molecular dynamics and density functional theory calculations on a large set of realistic rGO structures to decompose the effects of different functional groups on the stability, work function, and photoluminescence. Our calculations indicate the metastable nature of carbonyl-rich rGO and its favorable transformation to hydroxyl-rich rGO at room temperature via carbonyl-to-hydroxyl conversion reactions near carbon vacancies and holes. We demonstrate a significant tunability in the work function of rGO up to 2.5 eV by altering the composition of oxygen-containing functional groups for a fixed oxygen concentration, and of the photoluminescence emission by modulating the fraction of epoxy and carbonyl groups. Taken together, our results guide the application of tailored rGO structures in devices for optoelectronics and renewable energy. PMID- 23368711 TI - Genomics and autism spectrum disorder. AB - PURPOSE: To present the current state of the evidence regarding translation of genetics (the study of single genes) and genomics (the study of all genes and gene-gene or gene-environment interactions) into health care of children with autism spectrum disorder (ASD). METHODS: This article presents an overview of ASD as an international health challenge, the emerging science related to broad diagnostic criteria, and the role of the nurse in research, education, and practice. FINDINGS: Much progress is being made in the understanding of genetics and genomics of ASD. Environmental factors are thought to contribute to the risk of developing ASD by interacting with a number of genes in different ways, thus suggesting causal heterogeneity. The rising identified prevalence of ASD, the changing diagnostic criteria for ASD, and the complexity of the core and associated features have made it difficult to define the ASD phenotype (observable behaviors that result from gene-environment interaction). Because early identification improves opportunities for intervention, researchers are looking for a useful biomarker to detect ASD. This search is complicated by the likelihood that there are multiple causes for multiple expressions that are defined as the autism spectrum. CONCLUSIONS: To date, genetic and genomic research on ASD have underscored the complexity of the causes of ASD indicating that there are very complex genetic processes involved that are still not well understood. CLINICAL RELEVANCE: Nurses will benefit from new knowledge related to early identification, diagnosis, and implications for the family to promote early intervention. Families who have a child with ASD will require nursing support for advocacy for optimal health outcomes. PMID- 23368712 TI - A new model for interprofessional collaboration at a student-run free clinic. AB - The Case Western Reserve University Student-Run Free Clinic represents a unique model of interprofessional collaboration for medical and nursing students. This clinic operates on two Saturdays a month to provide acute medical services at the Free Medical Clinic of Greater Cleveland. We describe how this clinic promotes a sense of mutual investment and interdependence among students, who contribute to the clinic through leadership, planning and patient care. Students may also develop a broader perspective and deeper respect for their professional colleagues, which translates well to a future practice with team-based coordination of clinical services and an increasing emphasis on patient-centered care. PMID- 23368713 TI - Colony life history and lifetime reproductive success of red harvester ant colonies. AB - 1. We estimate colony reproductive success, in numbers of offspring colonies arising from a colony's daughter queens, of colonies of the red harvester ant, Pogonomyrmex barbatus. 2. A measure of lifetime reproductive success is essential to understand the relation of ecological factors, phenotype and fitness in a natural population. This was possible for the first time in a natural population of ant colonies using data from long-term study of a population of colonies in south-eastern Arizona, for which ages of all colonies are known from census data collected since 1985. 3. Parentage analyses of microsatellite data from 5 highly polymorphic loci were used to assign offspring colonies to maternal parent colonies in a population of about 265 colonies, ages 1-28 years, sampled in 2010. 4. The estimated population growth rate Ro was 1.69 and generation time was 7.8 years. There was considerable variation among colonies in reproductive success: of 199 possible parent colonies, only 49 (~ 25%) had offspring colonies on the site. The mean number of offspring colonies per maternal parent colony was 2.94 and ranged from 1 to 8. A parent was identified for the queen of 146 of 247 offspring colonies. There was no evidence for reproductive senescence; fecundity was about the same throughout the 25-30 year lifespan of a colony. 5. There were no trends in the distance or direction of the dispersal of an offspring relative to its maternal parent colony. There was no relationship between the number of gynes produced by a colony in 1 year and the number of offspring colonies subsequently founded by its daughter reproductive females. The results provide the first estimate of a life table for a population of ant colonies and the first estimate of the female component of colony lifetime reproductive success. 6. The results suggest that commonly used measures of reproductive output may not be correlated with realized reproductive success. This is the starting point for future investigation asking whether variation in reproductive success is related to phenotypic variation among colonies in behavioural and ecological traits. PMID- 23368714 TI - Electrofugalities of 1,3-diarylallyl cations. AB - Heterolysis rate constants k1 of differently substituted 1,3-diarylallyl halides and carboxylates have been determined in various solvents. The linear free energy relationship log k1 = s(f)(N(f) + E(f)) was found to predict the heterolysis rates (log k1) of 1,3-diarylallyl derivatives with a standard deviation of 0.26, corresponding to a factor of 1.82 in k1, and maximum deviation in k1 of a factor of 5. Some systematic deviations are evident, however. Thus, 1,3-diarylallyl carboxylates always react faster and 1,3-diarylallyl chlorides always react more slowly than calculated by the quoted correlation equation when both types of leaving groups were used to determine the electrofugality parameters E(f). As 1,3 diarylalyl cations are generated faster in solvolysis reactions and also react faster with nucleophiles than benzhydrylium ions of similar thermodynamic stabilities, i.e., Lewis acidities, one can conclude that the reactions involving 1,3-diarylallyl cations proceed with lower intrinsic barriers than those involving benzhydrylium ions. The electrofugality parameters E(f) of 1,3 diarylallylium ions determined in this work were combined with the electrophilicity parameters E of the corresponding cations as well as with the results on ion pair dynamics reported in preceding papers for generating the full mechanistic spectrum of 1,3-diarylallyl solvolyses. PMID- 23368715 TI - The true risk of blood transfusion after nephrectomy for renal masses: a population-based study. AB - OBJECTIVE: To examine blood transfusion rates after nephrectomy for renal masses at the population-level. PATIENTS AND METHODS: We performed a population-based, retrospective observational study using a national discharge abstract database. The study cohort consisted of 10,902 patients who were treated by radical nephrectomy (RN) or partial nephrectomy (PN) for a renal mass between 1 April 2003 and 31 March 2008. The association between blood transfusion and various explanatory variables was examined using the chi-squared test and multivariable logistic regression. RESULTS: The overall blood transfusion rate was 18.1%. Transfusions occurred after 28.2%, 12.7%, 9.2% and 8.6% of open RN, open PN, laparoscopic RN and laparoscopic PN, respectively (P < 0.001). Transfusion rates were found to be strongly associated with age and comorbidity, such that patients aged <50 years with Charlson scores of 0 were transfused 11.2% and 14.5% of the time compared to 28.2% and 40.7% in patients aged >=80 years with Charlson scores of >=3, respectively (P < 0.001). On multivariable logistic regression, age (P < 0.001), Charlson score (P < 0.001), procedure type (P < 0.001), surgeon (P < 0.001) and hospital volume quartile (P < 0.001) were all found to be associated with the rate of blood transfusions, whereas year of surgery, sex and income quintile were not. CONCLUSIONS: The transfusion rate after nephrectomy in general clinical practice is higher than that reported in the urological literature. Patient and provider factors appear to contribute to the considerable variability that exists in the observed transfusion rate. A more detailed understanding of these factors may help with respect to preoperative patient counselling and informed consent. PMID- 23368716 TI - High-throughput directed self-assembly of core-shell ferrimagnetic nanoparticle arrays. AB - Magnetic nanoparticles (MNPs) provide a set of building blocks for constructing stimuli-responsive nanoscale materials with properties that are unique to this scale. The size and the composition of MNPs are tunable to meet the requirements for a range of applications including biosensors and data storage. Although many of these technologies would significantly benefit from the organization of nanoparticles into higher-order architectures, the precise placement and arrangement of nanoparticles over large areas of a surface remain a challenge. Herein, we demonstrate the viability of magnetic nanoparticles for patterned recording media utilizing a template-directed self-assembly process to afford well-defined nanostructures of magnetic nanoparticles and access these assemblies using magnetic force microscopy and a magnetic recording head. Photolithographically defined holes were utilized as templates to form assemblies of ferrimagnetic nanoparticle rings or pillars selectively over a large area (>1 cm(2)) in just 30 s. This approach is applicable to other nanoparticle systems as well and enables their high-throughput self-assembly for future advanced device fabrication. PMID- 23368718 TI - Interaction of NuMA protein with the kinesin Eg5: its possible role in bipolar spindle assembly and chromosome alignment. AB - Bipolar spindle assembly in mitotic cells is a prerequisite to ensure correct alignment of chromosomes for their segregation to each daughter cell; spindle microtubules are tethered at plus ends to chromosomes and focused at minus ends to either of the two spindle poles. NuMA (nuclear mitotic apparatus protein) is present solely in the nucleus in interphase cells, but relocalizes during mitosis to the spindle poles to play a crucial role in spindle assembly via focusing spindle microtubules to each pole. In the present study we show that the kinesin 5 family motor Eg5 is a protein that directly interacts with NuMA, using a proteomics approach and various binding assays both in vivo and in vitro. During mitosis Eg5 appears to interact with NuMA in the vicinity of the spindle poles, whereas the interaction does not occur in interphase cells, where Eg5 is distributed throughout the cytoplasm but NuMA exclusively localizes to the nucleus. Slight, but significant, depletion of Eg5 in HeLa cells by RNA interference results in formation of less-focused spindle poles with misaligned chromosomes in metaphase; these phenotypes are similar to those induced by depletion of NuMA. Since NuMA is less accumulated at the spindle poles in Eg5 depleted cells, Eg5 probably contributes to spindle assembly via regulating NuMA localization. Furthermore, depletion of cytoplasmic dynein induces mislocalization of NuMA and phenotypes similar to those observed in NuMA-depleted cells, without affecting Eg5 localization to the spindles. Thus dynein appears to control NuMA function in conjunction with Eg5. PMID- 23368717 TI - Algorithm for dermocosmetic use in the management of cutaneous side-effects associated with targeted therapy in oncology. AB - Currently, numerous patients who receive targeted chemotherapy for cancer suffer from disabling skin reactions due to cutaneous toxicity, which is a significant problem for an increasing number of patients and their treating physicians. In addition, using inappropriate personal hygiene products often worsens these otherwise manageable side-effects. Cosmetic products for personal hygiene and lesion camouflage are part of a patients' well-being and an increasing number of physicians feel that they do not have adequate information to provide effective advice on concomitant cosmetic therapy. Although ample information is available in the literature on pharmaceutical treatment for cutaneous side-effects of chemotherapy, little is available for the concomitant use of dermatological skin care products with medical treatments. The objective of this consensus study is to provide an algorithm for the appropriate use of dermatological cosmetics in the management of cutaneous toxicities associated with targeted chemotherapy such as epidermal growth factor receptor inhibitors and other monoclonal antibodies. These guidelines were developed by a French and German expert group of dermatologists and an oncologist for oncologists and primary care physicians who manage oncology patients. The information in this report is based on published data and the expert group's opinion. Due to the current lack of clinical evidence, only a review of published recommendations including suggestions for concomitant cosmetic use was conducted. PMID- 23368719 TI - Direct site-selective arylation of enamides via a decarboxylative cross-coupling reaction. AB - An efficient Pd-catalyzed decarboxylative cross-coupling reaction of simple enamides was achieved. Depending on the choice of the nitrogen-protecting group, a site-selective synthesis of mono- or diarylated framework(s) was performed under mild conditions. This unprecedented reactivity could be applied to the synthesis of a range of 2- or 2,4-diarylated nitrogen-containing bioactive derivatives. PMID- 23368720 TI - Barriers to the implementation of preconception care guidelines as perceived by general practitioners: a qualitative study. AB - BACKGROUND: Despite strong evidence of the benefits of preconception interventions for improving pregnancy outcomes, the delivery and uptake of preconception care and periconceptional folate supplementation remain low. General practitioners play a central role in the delivery of preconception care. Understanding general practitioners' perceptions of the barriers and enablers to implementing preconception care allows for more appropriate targeting of quality improvement interventions. Consequently, the aim of this study was to examine the barriers and enablers to the delivery and uptake of preconception care guidelines from general practitioners' perspective using theoretical domains related to behaviour change. METHODS: We conducted a qualitative study using focus groups consisting of 22 general practitioners who were recruited from three regional general practice support organisations. Questions were based on the theoretical domain framework, which describes 12 domains related to behaviour change. General practitioners' responses were classified into predefined themes using a deductive process of thematic analysis. RESULTS: Beliefs about capabilities, motivations and goals, environmental context and resources, and memory, attention and decision making were the key domains identified in the barrier analysis. Some of the perceived barriers identified by general practitioners were time constraints, the lack of women presenting at the preconception stage, the numerous competing preventive priorities within the general practice setting, issues relating to the cost of and access to preconception care, and the lack of resources for assisting in the delivery of preconception care guidelines. Perceived enablers identified by general practitioners included the availability of preconception care checklists and patient brochures, handouts, and waiting room posters outlining the benefits and availability of preconception care consultations. CONCLUSIONS: Our study has identified some of the barriers and enablers to the delivery and uptake of preconception care guidelines, as perceived by general practitioners. Relating these barriers to a theoretical domain framework provides a clearer understanding of some of the psychological aspects that are involved in the behaviour of general practitioners towards the delivery and uptake of preconception care. Further research prioritising these barriers and the theoretical domains to which they relate to is necessary before a methodologically rigorous intervention can be designed, implemented, and evaluated. PMID- 23368721 TI - Automated pipeline for de novo metabolite identification using mass-spectrometry based metabolomics. AB - Metabolite identification is one of the biggest bottlenecks in metabolomics. Identifying human metabolites poses experimental, analytical, and computational challenges. Here we present a pipeline of previously developed cheminformatic tools and demonstrate how it facilitates metabolite identification using solely LC/MS(n) data. These tools process, annotate, and compare MS(n) data, and propose candidate structures for unknown metabolites either by identity assignment of identical mass spectral trees or by de novo identification using substructures of similar trees. The working and performance of this metabolite identification pipeline is demonstrated by applying it to LC/MS(n) data of urine samples. From human urine, 30 MS(n) trees of unknown metabolites were acquired, processed, and compared to a reference database containing MS(n) data of known metabolites. From these 30 unknowns, we could assign a putative identity for 10 unknowns by finding identical fragmentation trees. For 11 unknowns no similar fragmentation trees were found in the reference database. On the basis of elemental composition only, a large number of candidate structures/identities were possible, so these unknowns remained unidentified. The other 9 unknowns were also not found in the database, but metabolites with similar fragmentation trees were retrieved. Computer assisted structure elucidation was performed for these 9 unknowns: for 4 of them we could perform de novo identification and propose a limited number of candidate structures, and for the other 5 the structure generation process could not be constrained far enough to yield a small list of candidates. The novelty of this work is that it allows de novo identification of metabolites that are not present in a database by using MS(n) data and computational tools. We expect this pipeline to be the basis for the computer-assisted identification of new metabolites in future metabolomics studies, and foresee that further additions will allow the identification of even a larger fraction of the unknown metabolites. PMID- 23368722 TI - A comparison of computed tomography scans and digital periapical radiographs ridge height measurements. AB - To investigate the agreement between computerized tomography scans (CT) and intraoral periapical digital radiographs (PA) alveolar ridge height measurements in maxillary and mandibular posterior regions. We reviewed 100 implant patient radiographic records and identified 27 mandibular sites in 19 patients and 23 maxillary sites in 13 patients with available CT scans and matching PA radiographs. The distance from the crest of the ridge to the floor of the maxillary sinus or to the superior border of the inferior alveolar canal was measured. PAs were measured with Dexis software v. 8.0 and CTs were measured with Simplant software v. 11.02. Two examiners (RJ and MM) recorded the measurements separately; each examiner recorded two readings. The average of the 4 readings was used for data analysis. Absolute agreement: Paired t test comparing ridge height measurements between the two imaging methods showed no differences for maxillary sites (P > 0.2) and significant differences for the mandibular sites (CT > PA, P = 0.0009). Relative agreement: Kendall rank correlation analysis of ridge-height measurements between the 2 imaging methods showed a high positive correlation for maxillary sites (Kendall's tau = 0.76, P = 0.0001) and moderate correlation for the mandibular sites (Kendall's tau = 0.46, P = 0.001). Maxillary PAs tend to approximate CT ridge-height measurements. By contrast mandibular PAs tend to underestimate the distance from the crest of the ridge to the inferior alveolar canal. PMID- 23368723 TI - BayesHammer: Bayesian clustering for error correction in single-cell sequencing. AB - Error correction of sequenced reads remains a difficult task, especially in single-cell sequencing projects with extremely non-uniform coverage. While existing error correction tools designed for standard (multi-cell) sequencing data usually come up short in single-cell sequencing projects, algorithms actually used for single-cell error correction have been so far very simplistic.We introduce several novel algorithms based on Hamming graphs and Bayesian subclustering in our new error correction tool BAYESHAMMER. While BAYESHAMMER was designed for single-cell sequencing, we demonstrate that it also improves on existing error correction tools for multi-cell sequencing data while working much faster on real-life datasets. We benchmark BAYESHAMMER on both k-mer counts and actual assembly results with the SPADES genome assembler. PMID- 23368724 TI - Massage therapy for patients with metastatic cancer: a pilot randomized controlled trial. AB - OBJECTIVES: The study objectives were to determine the feasibility and effects of providing therapeutic massage at home for patients with metastatic cancer. DESIGN: This was a randomized controlled trial. SETTINGS/LOCATION: Patients were enrolled at Oncology Clinics at a large urban academic medical center; massage therapy was provided in patients' homes. SUBJECTS: Subjects were patients with metastatic cancer. INTERVENTIONS: There were three interventions: massage therapy, no-touch intervention, and usual care. OUTCOME MEASURES: Primary outcomes were pain, anxiety, and alertness; secondary outcomes were quality of life and sleep. RESULTS: In this study, it was possible to provide interventions for all patients at home by professional massage therapists. The mean number of massage therapy sessions per patient was 2.8. A significant improvement was found in the quality of life of the patients who received massage therapy after 1-week follow-up, which was not observed in either the No Touch control or the Usual Care control groups, but the difference was not sustained at 1 month. There were trends toward improvement in pain and sleep of the patients after therapeutic massage but not in patients in the control groups. There were no serious adverse events related to the interventions. CONCLUSIONS: The study results showed that it is feasible to provide therapeutic massage at home for patients with advanced cancer, and to randomize patients to a no-touch intervention. Providing therapeutic massage improves the quality of life at the end of life for patients and may be associated with further beneficial effects, such as improvement in pain and sleep quality. Larger randomized controlled trials are needed to substantiate these findings. PMID- 23368725 TI - Association between sex hormone levels and abnormal metabolism in a population of elderly Chinese men. AB - OBJECTIVE: Low testosterone levels may be a signal of poor health. This study aimed to investigate the effects of age and abnormal metabolism on sex hormones in Chinese male. METHODS: Three hundred and thirty-seven elder men were enrolled into this single-center, cross-sectional study, and their sex hormone levels and metabolic parameters were assessed. RESULTS: Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and sex-hormone-binding globulin (SHBG) concentrations increased with age, while free testosterone index (FTI), testosterone secretion index (TSI), estradiol (E2)/SHBG and progestin (PROG) decreased. Abnormal metabolisms were related to androgen indices (TT, FT, BT, FTI, TSI, T/E2), SHBG and E2/SHBG even after adjusting by age and macrovascular disease. Obesity and overweight, hyperglycemia and dyslipidemia were the most important abnormal metabolism that related to decreased androgen indices. Including SHBG in the stepwise regression increased the explanation effect of TT and BT by 32.7% and 28.5%, respectively, and all metabolic indices were excluded. Abnormal metabolism indies (BMI and PBG) were correlated to the decrease in SHBG levels, while age and LH was positively correlated to SHBG levels. CONCLUSIONS: Age and abnormal metabolism were independently important factors associated with the sex hormone levels in elderly Chinese men, which were all mediated by SHBG. PMID- 23368726 TI - New role of the dual knife for precut papillotomy in difficult bile duct cannulation. AB - The dual knife is usually used for endoscopic submucosal dissection (ESD). To date, however, there have been no clinical trials of the safety and effectiveness of precut papillotomy using the dual knife for biliary access in patients failing conventional endoscopic retrograde cholangiopancreatography (ERCP) cannulation. We herein report 18 patients who underwent precut papillotomy with the dual knife. All had intact papilla, and had failed deep cannulation of the bile ducts. After successful biliary cannulation and standard endoscopic sphincterotomy, if necessary, stone removal or plastic or metal stent insertion was attempted. Selective bile-duct cannulation was achieved in all 18 patients (100%), at an average time of 4.2 min (range, 3-6 min). Of these 18 patients, six had malignant bile duct obstruction and 12 had common bile duct stones. One patient developed post-ERCP pancreatitis, which resolved after conservative management. There were no deaths related to the procedure. PMID- 23368727 TI - Relapse of multiple myeloma presenting with melena. PMID- 23368728 TI - Stoichiometric control of lead chalcogenide nanocrystal solids to enhance their electronic and optoelectronic device performance. AB - We investigate the effects of stoichiometric imbalance on the electronic properties of lead chalcogenide nanocrystal films by introducing excess lead (Pb) or selenium (Se) through thermal evaporation. Hall-effect and capacitance-voltage measurements show that the carrier type, concentration, and Fermi level in nanocrystal solids may be precisely controlled through their stoichiometry. By manipulating only the stoichiometry of the nanocrystal solids, we engineer the characteristics of electronic and optoelectronic devices. Lead chalcogenide nanocrystal field-effect transistors (FETs) are fabricated at room temperature to form ambipolar, unipolar n-type, and unipolar p-type semiconducting channels as prepared and with excess Pb and Se, respectively. Introducing excess Pb forms nanocrystal FETs with electron mobilities of 10 cm(2)/(V s), which is an order of magnitude higher than previously reported in lead chalcogenide nanocrystal devices. Adding excess Se to semiconductor nanocrystal solids in PbSe Schottky solar cells enhances the power conversion efficiency. PMID- 23368729 TI - Adaptive bi-level programming for optimal gene knockouts for targeted overproduction under phenotypic constraints. AB - BACKGROUND: Optimization procedures to identify gene knockouts for targeted biochemical overproduction have been widely in use in modern metabolic engineering. Flux balance analysis (FBA) framework has provided conceptual simplifications for genome-scale dynamic analysis at steady states. Based on FBA, many current optimization methods for targeted bio-productions have been developed under the maximum cell growth assumption. The optimization problem to derive gene knockout strategies recently has been formulated as a bi-level programming problem in OptKnock for maximum targeted bio-productions with maximum growth rates. However, it has been shown that knockout mutants in fact reach the steady states with the minimization of metabolic adjustment (MOMA) from the corresponding wild-type strains instead of having maximal growth rates after genetic or metabolic intervention. In this work, we propose a new bi-level computational framework--MOMAKnock--which can derive robust knockout strategies under the MOMA flux distribution approximation. METHODS: In this new bi-level optimization framework, we aim to maximize the production of targeted chemicals by identifying candidate knockout genes or reactions under phenotypic constraints approximated by the MOMA assumption. Hence, the targeted chemical production is the primary objective of MOMAKnock while the MOMA assumption is formulated as the inner problem of constraining the knockout metabolic flux to be as close as possible to the steady-state phenotypes of wide-type strains. As this new inner problem becomes a quadratic programming problem, a novel adaptive piecewise linearization algorithm is developed in this paper to obtain the exact optimal solution to this new bi-level integer quadratic programming problem for MOMAKnock. RESULTS: Our new MOMAKnock model and the adaptive piecewise linearization solution algorithm are tested with a small E. coli core metabolic network and a large-scale iAF1260 E. coli metabolic network. The derived knockout strategies are compared with those from OptKnock. Our preliminary experimental results show that MOMAKnock can provide improved targeted productions with more robust knockout strategies. PMID- 23368730 TI - Hypothalamic amenorrhea in a Camurati-Engelmann disease--a case report. AB - OBJECTIVE: A case report of a patient diagnosed with Camurati-Engelmann Disease (CED) in association with the functional hypothalamic amenorrhea disturbances. CED is a very rare genetically determined disorder classified as a type of bone dysplasia. DESIGN: Case report. SETTING: Department of Gynecological Endocrinology, 3rd grade Medical University Hospital. PATIENT: Twenty-one years old female patient with CED admitted to the hospital because of primary amenorrhea. Her history revealed skeletal deformities and hearing impairment. METHODS: Clinical examination, ultrasound, laboratory evaluations (including serum gonadotropins (FSH, LH) at basal state and after stimulation with gonadotropin-releasing hormone, serum basal estradiol) radiological studies (X ray of the head, the lumbar spine and lower extremities; a computed tomography of the head), G-banding karyotype, polymerase chain reaction and DNA sequencing. Hormonal serum evaluations were made using an enzyme-linked immunosorbent assay. The exon 4 of the transforming growth factor beta 1 gene was amplified by a polymerase chain reaction and the product was directly sequenced. RESULTS: The hormonal analysis was characteristic for the hypogonadotropic hypogonadism. Radiological and molecular analyses confirmed CED diagnosis. CONCLUSIONS: The hypothalamic amenorrhea in a patient with CED may be explained as a consequence of fat hypotrophy and very low body mass index. Therefore, impairment within hypothalamic-pituitary axis in patients with CED should be treated with special attention. PMID- 23368731 TI - An overview of the genomics of metabolic syndrome. AB - PURPOSE: This article provides a brief overview of the diagnostic criteria and genomic risk factors for the components of metabolic syndrome (MetS). ORGANIZING CONSTRUCTS: Contributions of cardiovascular, obesity, and diabetes genomic risk factors to the development of MetS as reported in the literature have been reviewed. FINDINGS: The genomic risk factors for the development of MetS are strongly linked to the genomic risk factors that make up the components of the disease. Many of the cardiovascular and renal genomic risk factors for MetS development are similar to those found in the development of hypertension and dyslipidemia. Obesity may act as a master trigger to turn on the gene expression changes necessary for the other components of the disease. Studies in the genomics of type 2 diabetes show a number of overlapping genes and polymorphisms that influence both the development of diabetes and MetS. CONCLUSIONS: Although health practitioners now have some insights into the genomics of risk factors associated with MetS, the overall understanding of MetS remains inadequate. Clinical applications based on some of the discussed genomic risk factors are being developed but are not yet available for the diagnosis and treatment of MetS. CLINICAL RELEVANCE: A broad knowledge of the genomic contributions to disease processes will enable the clinician to better utilize genomics to assess and tailor management of patients. PMID- 23368732 TI - Cucurbitacins: potential candidates targeting mitogen-activated protein kinase pathway for treatment of melanoma. AB - Cucurbitacins (Cucs) have been classified as signal transducer and activator of transcription 3 inhibitors. Kinase inhibition has been a validated drug target in multiple types of malignancies. B-RAF mutations are highly expressed in the melanoma. Our hypothesis is the Cucs can be a potential candidate to inhibit the signaling kinase pathway. The research presented is the evaluation of Cucs, as B RAF and MEK1 kinase inhibitors. Virtual screening methods were employed to identify lead compounds. The hypothesis was tested on mutant B-RAF cell lines, A 375 and Sk-Mel-28 cell lines to determine the activity toward melanoma. A series of natural Cucs show an improved activity toward Sk-Mel-28 and A-375 cell lines. Cucs show potential inhibition for the total and phosphorylated ERK using ELISA kits. Cucs could be potential candidate for inhibiting cell growth. PMID- 23368733 TI - Structural acid-base chemistry in the metallic state: how MU3-neutralization drives interfaces and helices in Ti21Mn25. AB - Intermetallic phases remain a large class of compounds whose vast structural diversity is unaccounted for by chemical theory. A recent resurgence of interest in intermetallics, due to their potential in such applications as catalysis and thermoelectricity, has intensified the need for models connecting their compositions to their structures and stability. In this Article, we illustrate how the MU3-acidity model, an extension of the acid/base concept based on the Method of Moments, offers intuitive explanations for puzzling structural progressions occurring in intermetallics formed between transition metals. Simple CsCl-type structures are frequently observed for phases with near 1:1 ratios of transition metals. However, in two compounds, TiCu and Ti21Mn25, structures are adopted which deviate from this norm. MU3-Acidity analysis shows that the formation of CsCl-type phases in these exceptional systems would yield an imbalance in the acid/base strength pairing, resulting in overneutralization of the weaker partner and thus instability. Intriguing geometrical features emerge in response, which serve to improve the neutralization of the constituent elements. In both TiCu and Ti21Mn25, part of the structure shields weaker acids or bases from their stronger partners by enhancing homoatomic bonding in the sublattice of the weaker acid or base. In TiCu, this protection is accomplished by developing doubled layers of Ti atoms to reduce their heteroatomic contacts. In Ti21Mn25 the structural response is more extreme: Ti-poor TiMn2 domains are formed to guard Mn from the Ti atoms, while the remaining Ti segregates to regions between the TiMn2 domains. The geometrical details of this arrangement fine-tune the acid/base interactions for an even greater level of stability. The most striking of these occurs in the Ti-rich region, where a paucity of Mn neighbors leads to difficulty in achieving strong neutralization. The Ti atoms arrange themselves in helical tubes, maximizing the surface area for Ti-Mn interactions. Through these examples, we show how the MU3-acidity model provides simple explanations for some of the beautiful structural motifs observed in intermetallic crystals. The foundation of the model in the Method of Moments makes it applicable to a variety of other contexts, including glasses, defects, and nanostructured surfaces. PMID- 23368734 TI - Molecular cytotoxic mechanisms of chlorpromazine in isolated rat hepatocytes. AB - Chlorpromazine (CPZ), a member of the largest class of first-generation antipsychotic agents, is known to cause hepatotoxicity in the form of cholestasis and hepatocellular necrosis in some patients. The mechanism of CPZ hepatotoxicity is unclear, but is thought to result from reactive metabolite formation. The goal of this research was to assess potential cytotoxic mechanisms of CPZ using the accelerated cytotoxicity mechanism screening (ACMS) technique with freshly isolated rat hepatocytes. This study identified CPZ cytotoxicity and inhibition of mitochondrial membrane potential (MMP) to be concentration-dependent. Furthermore, inhibition of cytochrome P450s (CYPs), including CYP2D1 and 1A2, delayed CPZ cytotoxicity, suggesting a role for CYP activation of CPZ to a toxic metabolite(s) in this model. Metabolism studies also demonstrated glucuronide and glutathione (GSH) requirement for CPZ detoxification in hepatocytes. Inactivating the 2-electron reduction pathway, NAD(P)H quinone oxidoreductase (NQO1), caused a significant increase in hepatocyte susceptibility to CPZ, indicating quinoneimine contribution to CPZ cytotoxicity. Nontoxic concentrations of peroxidase/H(2)O(2) (inflammatory model) increased cytotoxicity in CPZ-treated hepatocytes and caused additional mitochondrial toxicity. Inflammation further depleted GSH and increased oxidized glutathione (GSSG) levels. Results suggest activation of CPZ to reactive metabolites by 2 pathways in hepatocytes: (i) a CYP-catalyzed quinoneimine pathway, and (ii) a peroxidase-catalyzed oxidation of CPZ to CPZ radicals. PMID- 23368735 TI - The contrasting activity of iodido versus chlorido ruthenium and osmium arene azo and imino-pyridine anticancer complexes: control of cell selectivity, cross resistance, p53 dependence, and apoptosis pathway. AB - Organometallic half-sandwich complexes [M(p-cymene)(azo/imino-pyridine)X](+) where M = Ru(II) or Os(II) and X ? Cl or I, exhibit potent antiproliferative activity toward a range of cancer cells. Not only are the iodido complexes more potent than the chlorido analogues, but they are not cross-resistant with the clinical platinum drugs cisplatin and oxaliplatin. They are also more selective for cancer cells versus normal cells (fibroblasts) and show high accumulation in cell membranes. They arrest cell growth in G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis. The iodido complexes retain potency in p53 mutant colon cells. All complexes activate caspase 3. In general, antiproliferative activity is greatly enhanced by low levels of the glutathione synthase inhibitor l-buthionine sulfoxime. The work illustrates how subtle changes to the design of low-spin d(6) metal complexes can lead to major changes in cellular metabolism and to potent complexes with novel mechanisms of anticancer activity. PMID- 23368737 TI - Answer to: 'Reply to: Severe diffuse non-scarring hair loss in systemic lupus erythematosus - clinical and histopathological analysis of four cases'. PMID- 23368738 TI - Cost-effectiveness of TAVR in the non-surgical population. PMID- 23368736 TI - Genome-wide identification, characterization, and expression analysis of lineage specific genes within zebrafish. AB - BACKGROUND: The genomic basis of teleost phenotypic complexity remains obscure, despite increasing availability of genome and transcriptome sequence data. Fish specific genome duplication cannot provide sufficient explanation for the morphological complexity of teleosts, considering the relatively large number of extinct basal ray-finned fishes. RESULTS: In this study, we performed comparative genomic analysis to discover the Conserved Teleost-Specific Genes (CTSGs) and orphan genes within zebrafish and found that these two sets of lineage-specific genes may have played important roles during zebrafish embryogenesis. Lineage specific genes within zebrafish share many of the characteristics of their counterparts in other species: shorter length, fewer exon numbers, higher GC content, and fewer of them have transcript support. Chromosomal location analysis indicated that neither the CTSGs nor the orphan genes were distributed evenly in the chromosomes of zebrafish. The significant enrichment of immunity proteins in CTSGs annotated by gene ontology (GO) or predicted ab initio may imply that defense against pathogens may be an important reason for the diversification of teleosts. The evolutionary origin of the lineage-specific genes was determined and a very high percentage of lineage-specific genes were generated via gene duplications. The temporal and spatial expression profile of lineage-specific genes obtained by expressed sequence tags (EST) and RNA-seq data revealed two novel properties: in addition to being highly tissue-preferred expression, lineage-specific genes are also highly temporally restricted, namely they are expressed in narrower time windows than evolutionarily conserved genes and are specifically enriched in later-stage embryos and early larval stages. CONCLUSIONS: Our study provides the first systematic identification of two different sets of lineage-specific genes within zebrafish and provides valuable information leading towards a better understanding of the molecular mechanisms of the genomic basis of teleost phenotypic complexity for future studies. PMID- 23368739 TI - TAVI: reveal the truth, the whole truth, and nothing but the truth. PMID- 23368740 TI - Current role of image-guided robotic radiosurgery (Cyberknife((r)) ) for prostate cancer treatment. AB - OBJECTIVES: To describe the most recent data from phase I and II clinical trials of stereotactic body radiation therapy (SBRT) using image-guided robotic radiosurgery, specifically the Cyberknife((r)) (Accuracy Incorporated, Sunnyvale, CA, USA). To better determine thecurrent role of this type of radiosurgery in prostate cancer (PCa) management. MATERIALS AND METHODS: Current clinical trials and relevant retrospective studies were identified from the literature, clinical trial databases, websites and conference abstracts. The indications, technical aspects, efficacy and toxicity of SBRT using the Cyberknife((r)) system were summarized. RESULTS: The Cyberknife((r)) system is an experimental treatment mostly used for localized PCa in stage cT1/T2a-b N0 M0 with a Gleason score <= 7 and PSA level <= 20 ng/mL. Hypofractionated radiation therapy was delivered in five fractions of 7-7.25 Gy for a total dose of 35-36.25 Gy. After treatment, the median PSA levelfell from 4.9-8.3 ng/mL to 0.1-1.6 ng/mL at a median follow-up of 4-60 months. The biochemical progression-free survival rates ranged from 78.3 to 100%. Acute and late toxicities were mostly grade 1/2 rectal or urinary complications. Few grade 3 and no grade 4 toxicities occurred during follow-up; however, erectile dysfunction and testes toxicity were also reported. CONCLUSIONS: The use of the Cyberknife((r)) system is limited mainly by its pretreatment and maintenance costs. Despite encouraging preliminary results, longer-term follow-up and randomized controlled phase III clinical trials are necessary before the Cyberknife((r)) system becomes a standard treatment method. PMID- 23368742 TI - Successful closing of duodenal ulcer after endoscopic submucosal dissection with over-the-scope clip to prevent delayed perforation. AB - Closure of post-endoscopic submucosal dissection (ESD) duodenal artificial ulcer is not common in the clinical setting. We consider that post-ESD ulcer closure by an over-the-scope-clip (OTSC) method is one of the most effective ways to prevent delayed perforation. We report here two cases of mucosal duodenal cancer in a 65 year-old woman and in a 78-year-old man. Pathological examinations of the resected specimens revealed well-differentiated adenocarcinomas. In these two clinical cases, we successfully carried out complete closures of post-ESD duodenal ulcer using OTSC without any complications. PMID- 23368743 TI - Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter. AB - Zinc is critical for a multitude of cellular processes, including gene expression, secretion and enzymatic activities. Cellular zinc is controlled by zinc-chelating proteins and by zinc transporters. The recent identification of zinc permeability of the lysosomal ion channel TRPML1 (transient receptor potential mucolipin 1), and the evidence of abnormal zinc levels in cells deficient in TRPML1, suggested a role for TRPML1 in zinc transport. In the present study we provide new evidence for such a role and identify additional cellular components responsible for it. In agreement with the previously published data, an acute siRNA (small interfering RNA)-driven TRPML1 KD (knockdown) leads to the build-up of large cytoplasmic vesicles positive for LysoTrackerTM and zinc staining, when cells are exposed to high concentrations of zinc. We now show that lysosomal enlargement and zinc build-up in TRPML1-KD cells exposed to zinc are ameliorated by KD of the zinc-sensitive transcription factor MTF-1 (metal-regulatory-element-binding transcription factor-1) or the zinc transporter ZnT4. TRPML1 KD is associated with a build-up of cytoplasmic zinc and with enhanced transcriptional response of mRNA for MT2a (metallothionein 2a). TRPML1 KD did not suppress lysosomal secretion, but it did delay zinc leak from the lysosomes into the cytoplasm. These results underscore a role for TRPML1 in zinc metabolism. Furthermore, they suggest that TRPML1 works in concert with ZnT4 to regulate zinc translocation between the cytoplasm and lysosomes. PMID- 23368744 TI - Genome reassembly with high-throughput sequencing data. AB - MOTIVATION: Recent studies in genomics have highlighted the significance of structural variation in determining individual variation. Current methods for identifying structural variation, however, are predominantly focused on either assembling whole genomes from scratch, or identifying the relatively small changes between a genome and a reference sequence. While significant progress has been made in recent years on both de novo assembly and resequencing (read mapping) methods, few attempts have been made to bridge the gap between them. RESULTS: In this paper, we present a computational method for incorporating a reference sequence into an assembly algorithm. We propose a novel graph construction that builds upon the well-known de Bruijn graph to incorporate the reference, and describe a simple algorithm, based on iterative message passing, which uses this information to significantly improve assembly results. We validate our method by applying it to a series of 5 Mb simulation genomes derived from both mammalian and bacterial references. The results of applying our method to this simulation data are presented along with a discussion of the benefits and drawbacks of this technique. PMID- 23368745 TI - Annotation: parathyroid hormone and fracture healing. AB - This annotation describes some early rat studies which conclude that parathyroid hormone (PTH) has more dramatic stimulatory effects on bone repair than on untraumatized bone. It also suggests, based on the effects of PTH on osteoblasts, that it is more likely to accelerate normal fracture healing than to prevent non union. The only 2 controlled clinical trials that have been published are critically discussed. Although both are encouraging and appear to show acceleration of normal fracture healing, they have methodological shortcomings that preclude definitive conclusions. PMID- 23368746 TI - Instrumentation in lumbar fusion improves back pain but not quality of life 2 years after surgery. A study of 1,310 patients with degenerative disc disease from the Swedish Spine Register SWESPINE. AB - BACKGROUND AND PURPOSE: Instrumented and non-instrumented methods of fusion have been compared in several studies, but the results are often inconsistent and conflicting. We compared the 2-year results of 3 methods of lumbar fusion when used in degenerative disc disease (DDD), using the Swedish Spine Register (SWESPINE). METHODS: All patients registered in SWESPINE for surgical treatment of DDD between January 1, 2000 and October 1, 2007 were eligible for the study. Patients who had completed the 2-year follow-up were included in the analysis. The outcomes of 3 methods of surgical fusion were assessed. RESULTS: Of 1,310 patients enrolled, 115 had undergone uninstrumented fusion, 620 instrumented posterolateral fusion, and 575 instrumented interbody fusion. Irrespective of the surgical procedure, quality of life (QoL) improved and back pain diminished. Change in QoL and functional disability and return to work was similar in the 3 groups. Patients who had undergone uninstrumented fusion had more back pain than the patients with instrumented interbody fusion at the 2-year follow-up (p = 0.02), although the difference was only 7 visual analog scale (VAS) units (95% CI: 1-13) on a 100-point scale. Moreover, 83% of the patients with uninstrumented fusion used analgesics at the end of follow-up as compared to 68% of the patients who had undergone surgery with one of the 2 instrumented fusion techniques. INTERPRETATION: In comparison with instrumented interbody fusion, uninstrumented fusion was associated with higher levels of back pain 2 years after surgery. We found no evidence for differences in QoL between uninstrumented fusion and instrumented interbody fusion. PMID- 23368747 TI - Reduced medium-term mortality following primary total hip and knee arthroplasty with an enhanced recovery program. A study of 4,500 consecutive procedures. AB - BACKGROUND AND PURPOSE: Our unit started to use routine multimodal techniques to enhance recovery for hip and knee arthroplasty in 2008. We have previously reported earlier discharge, a trend toward a reduction in complications, and a statistically significant reduction in mortality up to 90 days after surgery. In this study, we evaluated the same cohort to determine whether survival benefits were maintained at 2 years. PATIENTS AND METHODS: We prospectively evaluated 4,500 unselected consecutive total hip and knee replacements. The first 3,000 underwent a traditional protocol (TRAD) and the later 1,500 underwent an enhanced recovery protocol (ER). Mortality data were collected from the Office of National Statistics (UK). RESULTS: There was a difference in death rate at 2 years (TRAD vs. ER: 3.8% vs. 2.7%; p = 0.05). Survival probability up to 3.7 years post surgery was significantly better in patients who underwent an ER protocol. INTERPRETATION: This large prospective case series of unselected consecutive patients showed a reduction in mortality rate at 2 years following elective lower limb hip and knee arthroplasty following the introduction of a multimodal enhanced recovery protocol. This survival benefit supports the routine use of an enhanced recovery program for hip and knee arthroplasty. PMID- 23368748 TI - Hip prosthesis introduction and early revision risk. A nationwide population based study covering 39,125 operations. AB - BACKGROUND AND PURPOSE: Little is known about the effect of the learning curve for different types of total hip arthroplasties (THAs). We investigated the prostheses survival of THAs just after the implementation of a model new to the hospital, and compared these results with the results of THAs done when more than 100 implantations had been undertaken. In addition, we investigated whether differences exist between different types of femoral stems and acetabular cups at the early implementation phase. PATIENTS AND METHODS: We used comprehensive registry data from all units (n = 76) that performed THAs for primary osteoarthritis in Finland between 1998 and 2007. Complete data including follow up data to December 31, 2010 or until death were available for 33,819 patients (39,125 THAs). The stems and cups used were given order numbers in each hospital and classified into 5 groups: operations with order number (a) 1-15, (b) 16-30, (c) 31-50, (d) 51-100, and (e) > 100. We used Cox's proportional hazards modeling for calculation of the adjusted hazard ratios for the risk of revision during the 3 years following the implementation of a new THA endoprosthesis type in the groups. RESULTS: Introduction of new endoprosthesis types was common, as more than 1 in 7 patients received a type that had been previously used in 15 or less operations. For the first 15 operations after a stem or cup type was introduced, there was an elevated risk of revision (hazard ratio (HR) = 1.3, 95% CI: 1.1 1.5). There were differences in the risk of early revision between stem and cup types at implementation. INTERPRETATION: The first 15 operations with a new stem or cup model had an increased risk of early revision surgery. Stems and cups differed in their early revision risk, particularly at the implementation phase. Thus, the risk of early revision at the implementation phase should be considered when a new type of THA is brought into use. PMID- 23368749 TI - Development of novel nanocomposite membrane for water purification. AB - In the area of water purification, nanotechnology provides efficient removal of pollutants and germs. Electrospun nanofibers membrane has a potential for water purification due to its high large surface area, and good mechanical strength. In the present study, PAMAM dendrimers composite nylon-6 nanofibers membrane was prepared by crosslinking method using glutaraldehyde. Modified membrane has drastically improved water purification efficiency. Further, the efficacy of the modified membrane can be renewed by mere exposure of the saturated membrane with the solution having acidic pH. The modified membrane can be used as an effective tool for water purification. PMID- 23368750 TI - Direct economic burden of hepatitis B virus related diseases: evidence from Shandong, China. AB - BACKGROUND: Although the expenses of liver cirrhosis are covered by a critical illness fund under the current health insurance program in China, the economic burden associated with hepatitis B virus (HBV) related diseases is not well addressed. In order to provide evidence to address the economic disease burden of HBV, we conducted a survey to investigate the direct economic burden of acute and chronic hepatitis B, cirrhosis and liver cancer caused by HBV-related disease. METHODS: From April 2010 to November 2010, we conducted a survey of inpatients with HBV-related diseases and who were hospitalized for seven or more days in one of the seven tertiary and six secondary hospitals in Shandong, China. Patients were recorded consecutively within a three-to-five month time period from each sampled hospital; an in-person survey was conducted to collect demographic and socio-economic information, as well as direct medical and nonmedical expenses during the last month and last year prior to the current hospitalization. Direct medical costs included total outpatient, inpatient, and self-treatment expenditures; direct nonmedical costs included spending on nutritional supplements, transportation, and nursing. Direct medical costs during the current hospitalization were also obtained from the hospital financial database. The direct economic cost was calculated as the sum of direct medical and nonmedical costs. Our results call for the importance of implementing clinical guideline, improving system accountability, and helping secondary and smaller hospitals to improve efficiency. This has important policy implication for the on-going hospital reform in China. RESULTS: Our data based on inpatients with HBV-related diseases suggested that the direct cost in US dollars for acute hepatitis B, severe hepatitis B, chronic hepatitis B, compensated cirrhosis, decompensated cirrhosis and primary liver cancer was $2954, $10834, $4552, $7400.28, $6936 and $10635, respectively. These costs ranged from 30.72% (for acute hepatitis B) to 297.85% (for primary liver cancer) of the average annual household income in our sample. Even for patients with health insurance, direct out-of-pocket cost of all HBV-related diseases except acute hepatitis B exceeded 40.00% of the patient's disposable household income, making it a catastrophic expenditure for the household. CONCLUSION: Hepatitis B imposes considerable economic burden on a family. Our findings will help health policy makers' understanding of the magnitude of the economic burden of HBV-related diseases in China. Evidence from our study also contributes to our understanding of potential benefits to society from allocating more resources to preventing and treating HBV infection, as well as increasing insurance coverage in China. These findings have important policy implications for health care reform efforts currently underway in China focusing on how to reduce the burden of catastrophic disease for its citizens. PMID- 23368751 TI - Neutrophil counts distinguish between malignancy and arthritis in children with musculoskeletal pain: a case-control study. AB - BACKGROUND: To identify the predictive factors for malignancies using basic clinical and laboratory information in children presenting with musculoskeletal pain and eventually diagnosed with juvenile idiopathic arthritis (JIA) or malignancy. METHODS: A retrospective case-control chart review research examining laboratory data from patients referred for musculoskeletal pain in 2001-2010 and diagnosed with malignancy or JIA was performed. The validity of each test for the diagnosis of neoplasia was assessed by calculating the sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV) and likelihood ratios. RESULTS: A total of 134 patients were enrolled. Statistically significant differences were found in neutrophil count, Hb, LDH, IgA and C4 values, ANA, anti EA EBV IgG and anti-CMV IgG titres. High LDH value and anti-CMV IgG were the most predictive factors for neoplasia. High specificity factors for neoplasia were abnormal values of neutrophil count, Hb, IgA and C4, and the presence of anti-EA EBV and anti-CMV IgG. High PPV were recorded for abnormal neutrophil count, Hb value and anti-CMV titre. A low NPV was found only for anti-EA EBV and anti-CMV titres. CONCLUSIONS: In this setting of patients, minimum changes in neutrophil count, particularly if associated with low Hb and high LDH levels, are to be thoroughly considered, because they appear as the most predictive factors for the diagnosis of tumour. PMID- 23368752 TI - Amphimedosides A-C: synthesis, chemoselective glycosylation, and biological evaluation. AB - The amphimedosides, discovered in 2006, are the first examples of naturally occurring glycosylated alkoxyamines. We report syntheses of amphimedosides A-C that feature a stereoselective oxyamine neoglycosylation and found that these alkaloids display modest cytotoxicity toward seven diverse human cancer cell lines, exhibiting IC(50) values ranging from 3.0 MUM to greater than 100 MUM. PMID- 23368753 TI - Metastable Cu(I)-niobate semiconductor with a low-temperature, nanoparticle mediated synthesis. AB - A nanoparticle synthetic strategy for the preparation of a new metastable Cu(I) niobate is described, and that involves multipored Li3NbO4 nanoparticles as a precursor. A hydrothermal reaction of HNbO3 and LiOH.H2O in PEG200 and water at ~180 degrees C yields ~15-40 nm Li3NbO4 particles. These particles are subsequently used in a solvothermal copper(I)-exchange reaction with excess CuCl at 150 degrees C. Heating these products within the used CuCl flux (mp = 430 degrees C) to 450 degrees C for 30 min yields ~4-12 nm Cu2Nb8O21 crystalline nanoparticles, and for a heating time of 24 h yields MUm-sized, rod-shaped crystals. The new structure was characterized by single-crystal X-ray diffraction to have a condensed network consisting of NbO7 polyhedra and chains of elongated CuO4 tetrahedra. The compound thermally decomposes starting at ~250 degrees C and higher temperatures, depending on the particle sizes, owing to the loss of the weakly coordinated Cu(I) cations from the structure and a concurrent disproportionation reaction at its surfaces. Thus, conventional solid-state reactions involving higher temperatures and bulk reagents have proven unsatisfactory for its synthesis. The measured bandgap size is ~1.43-1.65 eV (indirect) and shows a dependence on the particle sizes. Electronic structure calculations based on density functional theory show that the bandgap transition results from the excitation of electrons at the band edges between filled Cu(I) 3d10-orbitals and empty Nb(V) 4d0-orbitals, respectively. The p-type nature of the Cu2Nb8O21 particles was confirmed in photoelectrochemical measurements on polycrystalline films that show a strong photocathodic current under visible light irradiation in aqueous solutions. These results demonstrate the general utility of reactive nanoscale precursors in the synthetic discovery of new Cu(I) based semiconducting oxides and which also show promise for use in solar energy conversion applications. PMID- 23368755 TI - Oxidative stress. Preface. PMID- 23368754 TI - Shades of red: bird-pollinated flowers target the specific colour discrimination abilities of avian vision. AB - Colour signals are a major cue in putative pollination syndromes. There is evidence that the reflectance spectra of many flowers target the distinctive visual discrimination abilities of hymenopteran insects, but far less is known about bird-pollinated flowers. Birds are hypothesized to exert different selective pressures on floral colour compared with hymenopterans because of differences in their visual systems. We measured the floral reflectance spectra of 206 Australian angiosperm species whose floral visitors are known from direct observation rather than inferred from floral characteristics. We quantified the match between these spectra and the hue discrimination abilities of hymenopteran and avian vision, and analysed these metrics in a phylogenetically informed comparison of flowers in different pollination groups. We show that bird-visited flowers and insect-visited flowers differ significantly from each other in the chromatic cues they provide, and that the differences are concentrated near wavelengths of optimal colour discrimination by whichever class of pollinator visits the flowers. Our results indicate that angiosperms have evolved the spectral signals most likely to reinforce their pollinators' floral constancy (the tendency of individual pollinators to visit flowers of the same species) in communities of similarly coloured floral competitors. PMID- 23368756 TI - Liquid crystalline human recombinant collagen: the challenge and the opportunity. AB - Collagen is a key component of the extracellular matrix, and by far the most prominent constituent of all load-bearing tissues. Its abundance and self assembly capacities render it a practical scaffold material for tissue repair and regeneration applications. However, some difficulties exist in artificially regenerating functional collagen structures to match native tissues and their respective performances. There are two major limitations of existing collagen based scaffolds: The first one is poor mechanical performance, and the second one is the failure to closely mimic natural tissues as to provide the necessary topographic and mechanical cues required for cell propagation and differentiation. The complexity of inducing sufficient order and alignment stands at the base of the impediments to successful formation of artificial collagen scaffolds, which closely match native tissue strength and morphology. Recombinant human collagen produced in transgenic tobacco plants has the capacity of forming highly concentrated liquid crystalline dope that can be aligned by application of shear force. Leveraging shear alignment of liquid crystalline recombinant human collagen opens new possibilities toward obtaining scaffolds that may be able to provide the necessary mechanical support, while closely mimicking the molecular signals and mechanical cues displayed to natural cell milieu. Such scaffolds may prove advantageous in the development of improved medical devices in fields, such as ophthalmology, neurology, and orthopedics. PMID- 23368757 TI - Unusual finding of Trichuris trichiura on colonoscopy in a patient with a recent change in bowel habits. PMID- 23368758 TI - The role of cytokines in polycystic ovarian syndrome. AB - Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Inflammation has been implicated in the metabolic disturbances and menstrual irregularities, which characterize this condition. Various inflammatory proteins have been investigated in women with PCOS including C reactive protein, interleukin-6, interleukin-18 and tumor necrosis factor-alpha. The data is suggestive of the presence of a chronic low-grade inflammatory state, especially in case of obesity, insulin resistance and hyperandrogenism. Targeting this inflammatory process by means of anti-inflammatory agents might be a therapeutic alternative to the current treatment. PMID- 23368759 TI - A practical O(n log2 n) time algorithm for computing the triplet distance on binary trees. AB - The triplet distance is a distance measure that compares two rooted trees on the same set of leaves by enumerating all sub-sets of three leaves and counting how often the induced topologies of the tree are equal or different. We present an algorithm that computes the triplet distance between two rooted binary trees in time O (n log2 n). The algorithm is related to an algorithm for computing the quartet distance between two unrooted binary trees in time O (n log n). While the quartet distance algorithm has a very severe overhead in the asymptotic time complexity that makes it impractical compared to O (n2) time algorithms, we show through experiments that the triplet distance algorithm can be implemented to give a competitive wall-time running time. PMID- 23368760 TI - Ultra-marathon runners are different: investigations into pain tolerance and personality traits of participants of the TransEurope FootRace 2009. AB - INTRODUCTION: Susceptibility to pain varies among individuals and may predispose to a higher risk for pain disorders. Thus, it is of interest to investigate subjects who exhibit higher resistance to pain. We therefore tested pain tolerance and assessed personality traits of ultra-marathon athletes who are able to run 4487 km (2789 mi) over 64 days without resting days and compare the results to controls. METHODS: After approval of the local ethics committee and with informed consent, 11 participants of the TransEurope FootRace (TEFR09 participants) and 11 matched (age, sex, and ethnicity) controls without marathon experience in the last 5 years were enrolled. They were tested for cold pain tolerance (cold pressor [CP] test), and the 240 item trait and character inventory (TCI) as well as the general self-efficacy (GSE) test were obtained. RESULTS: TransEurope FootRace participants had a highly significant greater cold pain tolerance in the CP test than controls (P = 0.0002). While the GSE test showed no differences, the TCI test provided TEFR09 participants to be less cooperative and reward dependent but more spiritually transcendent than the controls. Significant positive correlations were found between the CP test pain score at 180 seconds and several TCI subscales showing that higher pain scores correlate with higher reward dependence, dependence, cooperativeness, empathy, and pure-hearted conscience. CONCLUSIONS: Personality profiles as well as pain tolerance of our sample of TEFR09 participants differ from normal controls and-as obtained in previous studies-probably also from chronic pain patients. Low pain perception may predispose a person to become a long-distance runner. It remains unclear, however, whether low pain perception is cause or consequence of continuous extreme training. PMID- 23368761 TI - Seventh International Meeting on Computational Intelligence Methods for Bioinformatics and Biostatistics (CIBB 2010) Palermo, Italy, 16-18 September 2010. Introduction. PMID- 23368762 TI - White opaque substance represents an intracytoplasmic accumulation of lipid droplets: immunohistochemical and immunoelectron microscopic investigation of 26 cases. AB - BACKGROUND AND AIM: White opaque substance (WOS) in gastric neoplasias is a unique finding visualized in magnifying endoscopy (ME) with narrow band imaging (NBI) and it represents intramucosal accumulation of lipid droplets using oil red O staining. METHODS: Subjects were 26 WOS-positive (13 adenomas and 13 well differentiated adenocarcinomas) and 27 WOS-negative gastric epithelial neoplasias. We carried out immunohistochemical staining using a monoclonal antibody specific for adipophilin as a marker of lipids. Immunoelectron microscopy was used to evaluate morphology of the lipid droplets. RESULTS: Adipophilin was detected in 24 of 25 (96.0%) WOS-positive neoplasias, but it was detected in only two of 27 (7.4%) WOS-negative neoplasias. Lipid droplets were only seen in the surface epithelium in 10 of 11 (91.1%) adenomas, whereas the lipid droplets also existed in the cryptal epithelium in seven of 13 (53.8%) adenocarcinomas. Immunoelectron microscopy revealed numerous lipid droplets mainly existing in the subnuclear cytoplasm of the epithelium. The shape of the lipid droplets in adenomas was round and uniform, whereas that in adenocarcinomas was irregular. CONCLUSIONS: The present study confirmed that the presence of WOS in gastric neoplasias was dependent upon intramucosal accumulation of lipid droplets using anti-adipophilin staining. Intraepithelial distribution and morphology of the lipid droplets differed between adenoma and adenocarcinoma. PMID- 23368763 TI - Evaluation of naproxen and cromolyn activities against cancer cells viability, proliferation, apoptosis, p53 and gene expression of survivin and caspase-3. AB - We previously reported the inhibitory profiles of naproxen and cromolyn against glycogen synthase kinase-3beta, which partly explain the molecular mechanisms of their anti-cancer properties. In this study, we performed a detailed biochemical evaluation of the two drugs against colorectal adenocarcinoma (Caco2), hepatocellular carcinoma (HepG2), mammary gland carcinoma (MCF7), epitheloid cervix carcinoma (Hela), lung carcinoma (A5W9) and epidermoid larynx carcinoma (Hep2) cell lines. Additionally, we performed cellular viability tests using trypan blue, proliferation MTT assay, apoptosis, p53 and real-time polymerase chain reaction for gene expression of survivin and caspase-3. Not only the two drugs were found to significantly reduce the viability of different cell lines, but they also were shown to have potent dose-dependent reduction of cellular proliferation. They exhibited cytotoxicity IC50 values of 3.69 and 4.16 MUM for naproxen and cromolyn, respectively. Viability and proliferation results clearly correlated with apoptosis and p53 experiments in showing that both drugs significantly raised apoptotic percentages. Furthermore, we observed a significant reduction in survivin and elevation of caspase-3 gene expression upon exposure to the two drugs. It can be concluded that both naproxen and cromolyn have significant anti-cancer properties. PMID- 23368764 TI - Formation and degradation of layer-by-layer-assembled polyelectrolyte polyrotaxane capsules. AB - We report the preparation of degradable capsules via layer-by-layer assembly using polyelectrolyte (PE) polyrotaxanes (PRXs). The PRX capsules were prepared by the sequential deposition of PRXs onto silica particles followed by the dissolution of the silica cores. The colloidal stability of the PRX capsules that are formed depends on the salt/buffer solution used in the assembly process. Various salt/buffer combinations were examined to avoid aggregation of the core shell particles during PRX assembly and core dissolution. Using appropriate assembly conditions, we prepared colloidally stable, robust capsules. PRX capsules consisting of eight layers of PE PRXs had a wall thickness of ~15 nm. The degradation of the PRX capsules was demonstrated through the disassembly of the PE PRXs using glutathione, which cleaves the disulfide bonds linking the end capping groups of the PE PRXs. Given the supramolecular noncovalent structure of PRXs and their adjustable properties, it is expected that PRXs will be used as building blocks for assembling advanced capsules with unique and tailored properties. PMID- 23368766 TI - Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1alpha in amyotrophic lateral sclerosis. AB - We investigated the mechanisms underlying abnormal vascular endothelial growth factor (VEGF) production in amyotrophic lateral sclerosis (ALS). We immunohistochemically studied VEGF, its receptors VEGFR1 and 2, and hypoxia inducible factor-1alpha (HIF-1alpha) in autopsied ALS spinal cords. We also chronologically assessed the expression of HIF-1alpha, karyopherin beta1, karyopherin beta-cargo protein complex inhibitors and nuclear pore complex proteins in G93A mutant superoxide dismutase 1 (mSOD1) transgenic mice at presymptomatic, symptomatic and end stages. In ALS patients, compared with controls, HIF-1alpha immunoreactivity in the cytoplasm of anterior horn cells (AHCs) was significantly increased, while immunoreactivities for VEGF and VEGFRs were significantly decreased. Similar changes in HIF-1alpha and VEGF levels were observed in mSOD1 transgenic mice. HIF-1alpha co-localized with karyopherin beta1 in the cytoplasm of AHCs and karyopherin beta1 co-localized with nucleoporin 62 (Nup62) on the nuclear envelope. From the presymptomatic stage of mSOD1 transgenic mice, karyopherin beta1 immunoreactivity in AHC nuclei significantly decreased and morphological irregularities of the Nup62-immunostained nuclear envelope became more pronounced with disease progression. Thus, in AHCs from mSOD1 transgenic mice, transport of cytoplasmic HIF-1alpha to the nuclear envelope and into the nucleus is impaired from the presymptomatic stage, suggesting that impaired cytoplasmic-nuclear transport of HIF-1alpha through the nuclear pore might precede motor neuron degeneration. PMID- 23368765 TI - Genome-wide identification of soybean microRNAs and their targets reveals their organ-specificity and responses to phosphate starvation. AB - BACKGROUND: Phosphorus (P) plays important roles in plant growth and development. MicroRNAs involved in P signaling have been identified in Arabidopsis and rice, but P-responsive microRNAs and their targets in soybean leaves and roots are poorly understood. RESULTS: Using high-throughput sequencing-by-synthesis (SBS) technology, we sequenced four small RNA libraries from leaves and roots grown under phosphate (Pi)-sufficient (+Pi) and Pi-depleted (-Pi) conditions, respectively, and one RNA degradome library from Pi-depleted roots at the genome wide level. Each library generated ~21.45-28.63 million short sequences, resulting in ~20.56-27.08 million clean reads. From those sequences, a total of 126 miRNAs, with 154 gene targets were computationally predicted. This included 92 new miRNA candidates with 20-23 nucleotides that were perfectly matched to the Glycine max genome 1.0, 70 of which belong to 21 miRNA families and the remaining 22 miRNA unassigned into any existing miRNA family in miRBase 18.0. Under both +Pi and -Pi conditions, 112 of 126 total miRNAs (89%) were expressed in both leaves and roots. Under +Pi conditions, 12 leaf- and 2 root-specific miRNAs were detected; while under -Pi conditions, 10 leaf- and 4 root-specific miRNAs were identified. Collectively, 25 miRNAs were induced and 11 miRNAs were repressed by Pi starvation in soybean. Then, stem-loop real-time PCR confirmed expression of four selected P-responsive miRNAs, and RLM-5' RACE confirmed that a PHO2 and GmPT5, a kelch-domain containing protein, and a Myb transcription factor, respectively are targets of miR399, miR2111, and miR159e-3p. Finally, P responsive cis-elements in the promoter regions of soybean miRNA genes were analyzed at the genome-wide scale. CONCLUSIONS: Leaf- and root-specific miRNAs, and P-responsive miRNAs in soybean were identified genome-wide. A total of 154 target genes of miRNAs were predicted via degradome sequencing and computational analyses. The targets of miR399, miR2111, and miR159e-3p were confirmed. Taken together, our study implies the important roles of miRNAs in P signaling and provides clues for deciphering the functions for microRNA/target modules in soybean. PMID- 23368767 TI - Epidermolysis bullosa acquisita. AB - Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune subepidermal bullous disease with clinical features similar to the genetic form of dystrophic epidermolysis bullosa. EBA is characterized by the presence of autoantibodies against type VII collagen which is a major component of the anchoring fibrils at the dermal-epidermal junction. EBA can be divided into two main clinical types; mechanobullous and inflammatory EBA. Mechanobullous EBA, referred to as classic EBA, presents with skin fragility, blisters and dystrophic changes on trauma prone areas. Inflammatory EBA resembles other autoimmune subepidermal bullous diseases. Compelling evidence from mouse models supports a pathogenic role of autoantibodies against type VII collagen in EBA. Treatment of EBA is often unsatisfactory. The most widely used systemic treatment is corticosteroids. Colchicine and dapsone have been reported to be good treatment modalities when combined with corticosteroids. Some intractable cases of EBA have successfully been treated with intravenous immunoglobulin or rituximab. PMID- 23368768 TI - The road not taken: retreat and diverge in local search for simplified protein structure prediction. AB - BACKGROUND: Given a protein's amino acid sequence, the protein structure prediction problem is to find a three dimensional structure that has the native energy level. For many decades, it has been one of the most challenging problems in computational biology. A simplified version of the problem is to find an on lattice self-avoiding walk that minimizes the interaction energy among the amino acids. Local search methods have been preferably used in solving the protein structure prediction problem for their efficiency in finding very good solutions quickly. However, they suffer mainly from two problems: re-visitation and stagnancy. RESULTS: In this paper, we present an efficient local search algorithm that deals with these two problems. During search, we select the best candidate at each iteration, but store the unexplored second best candidates in a set of elite conformations, and explore them whenever the search faces stagnation. Moreover, we propose a new non-isomorphic encoding for the protein conformations to store the conformations and to check similarity when applied with a memory based search. This new encoding helps eliminate conformations that are equivalent under rotation and translation, and thus results in better prevention of re visitation. CONCLUSION: On standard benchmark proteins, our algorithm significantly outperforms the state-of-the art approaches for Hydrophobic-Polar energy models and Face Centered Cubic Lattice. PMID- 23368769 TI - Endoscopic removal of large gastric lipomas: en bloc resection with submucosal dissection or partial resection with unroofing technique? PMID- 23368771 TI - A novel self-sequence reaction network involving a set of six reactions in one pot: the synthesis of substituted benzothiazoles from aromatic ketones and anilines. AB - Employing simple and readily available aromatic ketones and anilines as starting materials resulted in the construction of 2-acylbenzothiazoles via a novel self sequence reaction network, which assembles six reactions in one pot. The reaction network not only supplied a novel method for constructing complex molecules but also provided a typical example for logical self-organization synthesis. PMID- 23368770 TI - Treatment with a copper-selective chelator causes substantive improvement in cardiac function of diabetic rats with left-ventricular impairment. AB - BACKGROUND: Defective copper regulation is implicated as a causative mechanism of organ damage in diabetes. Treatment with trientine, a divalent-copper-selective chelator, improves arterial and renal structure/function in diabetes, wherein it also ameliorates left-ventricular (LV) hypertrophy. However, direct in vivo evidence that trientine can improve cardiac function in heart failure has hitherto been lacking. METHODS: To determine whether trientine treatment could improve in vivo outcome, we measured cardiac function in groups of trientine treated diabetic (TETA-DIA), non-drug-treated diabetic (DIA) and sham-treated control (SHAM) rats, by using in vivo high-field cardiac magnetic-resonance imaging (cMRI) and an ex vivo isolated-perfused working heart method. Forty age matched animals underwent a cMRI scan after which 12 were randomized to the SHAM group and 28 underwent streptozotocin-injection; of these, 25 developed stable diabetes, and 12 were then randomized to receive no treatment for 16 weeks (DIA) and the other 13 to undergo 8-weeks' untreated diabetes followed by 8-weeks' drug treatment (TETA-DIA). Animals were studied again by cMRI at 8 and 16 weeks following disease induction, and finally by measurement of ex vivo cardiac function. RESULTS: After eight weeks diabetes, rats (DIA/TETA-DIA) had developed significant impairment of LV function, as judged by impairment of ejection fraction (LVEF), cardiac output (CO), and LV mass (LVM)/body-mass (all P < 0.001), as well as other functional indexes. LVEF, CO (both P < 0.001) and the other indexes deteriorated further at 16 weeks in DIA, whereas trientine (TETA DIA) improved cardiac function by elevating LVEF and CO (both P < 0.001), and also partially reversed the increase in LVM/body-mass (P < 0.05). In ex vivo hearts from DIA, the CO response to increasing preload pressure was deficient compared with SHAM (P < 0.001) whereas the preload-CO relationship was significantly improved in TETA-DIA animals (P < 0.001). CONCLUSIONS: Trientine treatment significantly improved cardiac function in diabetic rats with substantive LV impairment. These results implicate impaired copper regulation in the pathogenesis of impaired cardiac function caused by diabetic cardiomyopathy, and support ongoing studies of trientine treatment in patients with heart failure. PMID- 23368772 TI - Timing of appearance of Gyrodactylus colemanensis (Monogenea) on young-of-the year Salvelinus fontinalis in a Nova Scotia stream and contribution of these infections to total parasite standing crop. AB - Young-of-the-year (YOY) brook trout (Salvelinus fontinalis) were collected at 2 wk intervals (15 April to 4 June 2012) after emergence from redds and occurrence of the ectoparasite Gyrodactylus colemanensis (Monogenea) recorded. Emergent YOY were not infected. Infected trout (14%) first appeared 15 May, with host age estimated to be 4 wk or less post-emergence. Prevalence and intensity increased over the study period and reached, respectively, 93% and 8.2 +/- 6.1 by 4 June. Prevalence and intensity of infection was also determined for older cohorts (1+, >1+) on 6 June, with G. colemanensis occurring on representatives of all age groups. The number of hosts in each age group was estimated by mark/recapture electrofishing over a 100 m reach of the stream. Combining estimated host numbers by age group with parasite prevalence and intensity data from those groups allowed calculation of parasite total standing crop. The results indicate that, by late spring, the new host recruits already carried 64% of the parasite population in the stream, serving to illustrate the remarkable efficiency of transmission by this viviparous monogenean in a temperate stream system. PMID- 23368773 TI - Ecological, evolutionary, and conservation implications of incubation temperature dependent phenotypes in birds. AB - Incubation is a vital component of reproduction and parental care in birds. Maintaining temperatures within a narrow range is necessary for embryonic development and hatching of young, and exposure to both high and low temperatures can be lethal to embryos. Although it is widely recognized that temperature is important for hatching success, little is known about how variation in incubation temperature influences the post-hatching phenotypes of avian offspring. However, among reptiles it is well known that incubation temperature affects many phenotypic traits of offspring with implications for their future survival and reproduction. Although most birds, unlike reptiles, physically incubate their eggs, and thus behaviourally control nest temperatures, variation in temperature that influences embryonic development still occurs among nests within a population. Recent research in birds has primarily been limited to populations of megapodes and waterfowl; in each group, incubation temperature has substantial effects on hatchling phenotypic traits important for future development, survival, and reproduction. Such observations suggest that incubation temperature (and incubation behaviours of parents) is an important but underappreciated parental effect in birds and may represent a selective force instrumental in shaping avian reproductive ecology and life-history traits. However, much more research is needed to understand how pervasive phenotypic effects of incubation temperature are among birds, the sources of variation in incubation temperature, and how effects on phenotype arise. Such insights will not only provide foundational information regarding avian evolution and ecology, but also contribute to avian conservation. PMID- 23368774 TI - Antimicrobial stewardship: Time for change. PMID- 23368775 TI - Report of the third Havemeyer workshop on infection control in equine populations. PMID- 23368777 TI - Eukaryotic initiation factor 5A dephosphorylation is required for translational arrest in stationary phase cells. AB - The protein known as eIF5A (eukaryotic initiation factor 5A) has an elusive role in translation. It has a unique and essential hypusine modification at a conserved lysine residue in most eukaryotes. In addition, this protein is modified by phosphorylation with unknown functions. In the present study we show that a phosphorylated state of eIF5A predominates in exponentially growing Trypanosoma cruzi cells, and extensive dephosphorylation occurs in cells in stationary phase. Phosphorylation occurs mainly at Ser(2), as shown in yeast eIF5A. In addition, a novel phosphorylation site was identified at Tyr(21). In exponential cells, T. cruzi eIF5A is partially associated with polysomes, compatible with a proposed function as an elongation factor, and becomes relatively enriched in polysomal fractions in stationary phase. Overexpression of the wild-type eIF5A, or eIF5A with Ser(2) replaced by an aspartate residue, but not by alanine, increases the rate of cell proliferation and protein synthesis. However, the presence of an aspartate residue instead of Ser(2) is toxic for cells reaching the stationary phase, which show a less-pronounced protein synthesis arrest and a decreased amount of eIF5A in dense fractions of sucrose gradients. We conclude that eIF5A phosphorylation and dephosphorylation cycles regulate translation according to the growth conditions. PMID- 23368778 TI - Revisited: Decomposition or melting? Formation mechanism investigation of LiCoO2 via in-situ time-resolved X-ray diffraction. AB - We report the first in-situ time-resolved X-ray diffraction investigation in conjunction with a non-isothermal kinetic study using the model-free isoconversional kinetic method to determine the formation mechanism for the solid state synthesis of electrochemically active LiCoO(2) from Li(2)CO(3) and Co(3)O(4). Detailed information on the phase evolution as well as thermal events during the heating process was clearly observed, explained, and supported. This investigation provides structural as well as kinetic evidence for a multistep reaction and proposes the first plausible formation mechanism for the solid-state synthesis of LiCoO(2). PMID- 23368779 TI - Caries infiltrant combined with conventional adhesives for sealing sound enamel in vitro. AB - OBJECTIVE: To test the null hypothesis that combining low-viscosity caries infiltrant with conventional adhesive resins would not improve sealing of sound enamel against demineralization in vitro. MATERIALS AND METHODS: Bovine enamel discs (N = 60) with diameter of 3 mm were randomly assigned to six groups (n = 10). The discs were etched with 37% phosphoric acid for 30 seconds and treated with resins of different monomer content forming the following groups: (1) Icon (DMG), (2) Transbond XT Primer (3M ESPE), (3) Heliobond (Ivoclar Vivadent), (4) Icon + Transbond XT Primer, and (5) Icon + Heliobond. Untreated etched samples served as the negative control. Specimens were subjected to demineralization by immersion in hydrochloric acid (pH 2.6) for 80 hours. Calcium dissolution into the acid was assessed by colorimetric analysis using Arsenazo III method at 16 hour intervals. Groups presenting high protection against demineralization were subjected to further acidic challenge for 15 days with calcium measurements repeated at 24-hour intervals. Data were analyzed by Kruskal-Wallis test and Mann Whitney U-test. RESULTS: Untreated specimens showed the highest amount of demineralization. Icon and Transbond XT primer decreased the mineral loss significantly compared to the control. Heliobond performed significantly better than both Icon and Transbond XT primer. Combination of Icon both with Transbond XT primer or Heliobond served as the best protective measures and maintained the protective effect for the additional 15-day acidic challenge. CONCLUSIONS: Within the limitations of this in vitro study, it could be concluded that the use of low viscosity caries infiltrant prior to application of the tested conventional adhesives increases their protective effect against demineralization. PMID- 23368780 TI - Comparison of Chinese and white Bolton standards at age 13. AB - OBJECTIVES: To create a combined male-female Chinese Bolton standard for age 13 and to compare it to the combined Bolton standard for white 13 year olds. MATERIALS AND METHODS: Thirty-two Chinese and 32 white subjects (16 adolescent boys and 16 adolescent girls aged 13 years in each ethnic group) who fulfilled the selection criteria used to create the original Bolton standards were enrolled. Their cephalograms were traced and then averaged two at a time following the Bolton method. In addition to creating the template from the 32 subjects in each group, 43 linear and angular variables were measured and compared between the two ethnic groups and between the two sexes in each ethnic group using independent t-tests. A P value of .05 was used to assign statistical significance. The male-female combined templates for 13 year olds were also compared superimposing either in the Bolton relation or by soft tissue. RESULTS: No sexual dimorphism was found in the white subjects, whereas the Chinese girls had decreased upper face height (Na-ANS), more protrusive incisors (SNA-U1), and shorter cranial base (Ba-Na) and posterior cranial base (S-Ba) compared with the Chinese boys. In terms of ethnic comparison, the Chinese subjects presented shorter sagittal facial dimensions, a clockwise rotated mandible with a more acute gonial angle, and a convex facial profile with a less prominent nose and chin. However, overall vertical dimensions were similar. CONCLUSIONS: A 13-year old combined male-female Chinese Bolton standard was created that demonstrated visually and with metric comparisons that Chinese and white clinically normal subjects have different craniofacial characteristics. These differences should be taken into consideration when an individualized orthodontic treatment plan is developed. PMID- 23368781 TI - Tracing the migration history of metal catalysts in metal-assisted chemically etched silicon. AB - Three-dimensional (3D) visualization of complex embedded nanopore networks in silicon requires expensive machinery and tedious sample preparation procedures such as electron tomography, also known as 3D transmission electron microscopy. In this article, we report a new, fast, powerful, and low-cost three-dimensional imaging technique with sub-5 nm resolution. This new imaging method is applied to metal-assisted chemically etched monocrystalline Si to demonstrate its capabilities. The AFEI (atomic layer deposition-fill-etch-imaging) technique consists of three simple process steps that are available in most material research settings. First the porous substrate is conformally coated with an atomic layer deposition (ALD) metal oxide layer. ALD is able to penetrate deep into complex, high aspect ratio pores, as it is a sequential gas-phase deposition process. Next, the cross-section of the ALD-filled porous Si substrate is etched with high-density fluorine-based plasma processing, which yields very high selectivity toward Si (e.g., >400:1 for Si:ZnO). This step removes the bulk Si and exposes the metal oxide structures grown inside the pores. In the last step, the sample cross-section is examined using a standard scanning electron microscope at various angles, which allows precise imaging of hidden features and reconstruction of a 3D model of the embedded pore network. PMID- 23368782 TI - Albumin-induced coagulopathy is less severe and more effectively reversed with fibrinogen concentrate than is synthetic colloid-induced coagulopathy. AB - BACKGROUND: Synthetic colloids cause dilutional coagulopathy. The aims of our study were to determine whether the natural colloid albumin induces a lesser degree of coagulopathy compared to synthetic colloids, and the comparative effectiveness of fibrinogen concentrate to reverse coagulopathy following dilution with these solutions. METHODS: Coagulation was assessed with rotational thrombelastometry after stimulation with tissue factor (EXTEM) and in the presence of a platelet inhibitor (FIBTEM). With EXTEM, clotting time (CT), clot formation time CFT), alpha angle (AA) and maximum clot firmness (MCF) were recorded. With FIBTEM, only MCF was recorded. These parameters were assessed ex vivo in blood from 10 healthy volunteers; diluted 1:1 with either saline, Ringer's acetate, buffered/unbuffered hydroxyethyl starch, buffered/unbuffered dextran (synthetic colloids) or 5% albumin. Samples were analyzed before/after addition of fibrinogen concentrate. RESULTS: FIBTEM MCF decreased significantly upon dilution (> 50% reduced) with all colloid solutions (p <= 0.02), although a significantly greater coagulopathic effect was seen for samples diluted with synthetic colloids versus albumin (p <= 0.001). A significant reduction in the platelet component of clot strength (EXTEM MCF - FIBTEM MCF) was seen for samples diluted with synthetic colloids (p < 0.001) but not albumin (p = 0.10). Following addition of fibrinogen, FIBTEM MCF, EXTEM MCF and AA were significantly higher, and CFT was significantly shorter in samples diluted with albumin versus those treated with synthetic colloids (p <= 0.001). CONCLUSION: Hemodilution using albumin induced a lesser degree of coagulopathy compared with the synthetic colloids. In addition, albumin-induced coagulopathy was more effectively reversed following addition of fibrinogen concentrate compared with coagulopathy induced by synthetic colloids. PMID- 23368783 TI - Improved moderation for gene-wise variance estimation in RNA-Seq via the exploitation of external information. AB - BACKGROUND: The cost of RNA-Seq has been decreasing over the last few years. Despite this, experiments with four or less biological replicates are still quite common. Estimating the variances of gene expression estimates becomes both a challenging and interesting problem in these situations of low replication. However, with the wealth of microarray and other publicly available gene expression data readily accessible on public repositories, these sources of information can be leveraged to make improvements in variance estimation. RESULTS: We have proposed a novel approach called Tshrink+ for inferring differential gene expression through improved modelling of the gene-wise variances. Existing methods share information between genes of similar average expression by shrinking, or moderating, the gene-wise variances to a fitted common variance. We have been able to achieve improved estimation of the common variance by using gene-wise sample variances from external experiments, as well as gene length. CONCLUSIONS: Using biological data we show that utilising additional external information can improve the modelling of the common variance and hence the calling of differentially expressed genes. These sources of additional information include gene length and gene-wise sample variances from other RNA-Seq and microarray datasets, of both related and seemingly unrelated tissue types. The results of this are promising, with our differential expression test, Tshrink+, performing favourably when compared to existing methods such as DESeq and edgeR when considering both gene ranking and sensitivity. These improved variance models could easily be implemented in both DESeq and edgeR and highlight the need for a database that offers a profile of gene variances over a range of tissue types and organisms. PMID- 23368784 TI - Silent cerebrovascular ischemias following transcatheter atrial fibrillation ablation: definition and cerebral magnetic resonance protocols. PMID- 23368785 TI - CoNVEX: copy number variation estimation in exome sequencing data using HMM. AB - BACKGROUND: One of the main types of genetic variations in cancer is Copy Number Variations (CNV). Whole exome sequencing (WES) is a popular alternative to whole genome sequencing (WGS) to study disease specific genomic variations. However, finding CNV in Cancer samples using WES data has not been fully explored. RESULTS: We present a new method, called CoNVEX, to estimate copy number variation in whole exome sequencing data. It uses ratio of tumour and matched normal average read depths at each exonic region, to predict the copy gain or loss. The useful signal produced by WES data will be hindered by the intrinsic noise present in the data itself. This limits its capacity to be used as a highly reliable CNV detection source. Here, we propose a method that consists of discrete wavelet transform (DWT) to reduce noise. The identification of copy number gains/losses of each targeted region is performed by a Hidden Markov Model (HMM). CONCLUSION: HMM is frequently used to identify CNV in data produced by various technologies including Array Comparative Genomic Hybridization (aCGH) and WGS. Here, we propose an HMM to detect CNV in cancer exome data. We used modified data from 1000 Genomes project to evaluate the performance of the proposed method. Using these data we have shown that CoNVEX outperforms the existing methods significantly in terms of precision. Overall, CoNVEX achieved a sensitivity of more than 92% and a precision of more than 50%. PMID- 23368786 TI - Visualization of protein interaction networks: problems and solutions. AB - BACKGROUND: Visualization concerns the representation of data visually and is an important task in scientific research. Protein-protein interactions (PPI) are discovered using either wet lab techniques, such mass spectrometry, or in silico predictions tools, resulting in large collections of interactions stored in specialized databases. The set of all interactions of an organism forms a protein protein interaction network (PIN) and is an important tool for studying the behaviour of the cell machinery. Since graphic representation of PINs may highlight important substructures, e.g. protein complexes, visualization is more and more used to study the underlying graph structure of PINs. Although graphs are well known data structures, there are different open problems regarding PINs visualization: the high number of nodes and connections, the heterogeneity of nodes (proteins) and edges (interactions), the possibility to annotate proteins and interactions with biological information extracted by ontologies (e.g. Gene Ontology) that enriches the PINs with semantic information, but complicates their visualization. METHODS: In these last years many software tools for the visualization of PINs have been developed. Initially thought for visualization only, some of them have been successively enriched with new functions for PPI data management and PIN analysis. The paper analyzes the main software tools for PINs visualization considering four main criteria: (i) technology, i.e. availability/license of the software and supported OS (Operating System) platforms; (ii) interoperability, i.e. ability to import/export networks in various formats, ability to export data in a graphic format, extensibility of the system, e.g. through plug-ins; (iii) visualization, i.e. supported layout and rendering algorithms and availability of parallel implementation; (iv) analysis, i.e. availability of network analysis functions, such as clustering or mining of the graph, and the possibility to interact with external databases. RESULTS: Currently, many tools are available and it is not easy for the users choosing one of them. Some tools offer sophisticated 2D and 3D network visualization making available many layout algorithms, others tools are more data-oriented and support integration of interaction data coming from different sources and data annotation. Finally, some specialistic tools are dedicated to the analysis of pathways and cellular processes and are oriented toward systems biology studies, where the dynamic aspects of the processes being studied are central. CONCLUSION: A current trend is the deployment of open, extensible visualization tools (e.g. Cytoscape), that may be incrementally enriched by the interactomics community with novel and more powerful functions for PIN analysis, through the development of plug-ins. On the other hand, another emerging trend regards the efficient and parallel implementation of the visualization engine that may provide high interactivity and near real-time response time, as in NAViGaTOR. From a technological point of view, open-source, free and extensible tools, like Cytoscape, guarantee a long term sustainability due to the largeness of the developers and users communities, and provide a great flexibility since new functions are continuously added by the developer community through new plug-ins, but the emerging parallel, often closed-source tools like NAViGaTOR, can offer near real-time response time also in the analysis of very huge PINs. PMID- 23368787 TI - The utilization of perforated bioinert chambers to generate an in vivo isolated space for tissue engineering involving chondrocytes, mesenchymal stem cells, and fibroblasts. AB - Vascular invasion and admixture of the nude mouse cells with seeded cells make it difficult to reapply the regenerated tissues to the restoration of host tissue defects. Therefore, a device that is capable of allowing for autologous or allogenic tissue growth while preventing host tissue invasion will be a valuable tool for in vivo tissue engineering. We have previously fabricated a novel silicon-perforated chamber. The aim of this study was to evaluate whether this chamber, after being implanted subcutaneously in experimental animals, would hinder host tissue ingrowth while providing an environment inside its cavity for in vivo growth of either autologous or allogenic implant cells. We found that the chamber did not induce severe foreign body reaction, and the chambers with perforated pores of 1-3 mm in diameter effectively inhibited the host granulation tissue or vascular invasion for as long as 3 months. In addition, the exudates rich in vascular endothelial growth factor, basic fibroblast growth factor, transforming growth factor-beta, insulin-like growth factor-1, and platelet derived growth factor-BB were steadily generated and collected in the chambers. In vitro cell culture studies revealed that the exudates were able to support the viability and proliferation of rabbit chondrocytes, rat mesenchymal stem cells, and human fibroblasts. The results indicate that this novel chamber could potentially provide an environment favorable for in vivo tissue engineering while effectively preventing host tissue or vascular invasion. PMID- 23368790 TI - Molecular characterization of Saccharomyces cerevisiae alpha-pheromone by mass spectrometry-based peptidomics. AB - Using modern peptide analytical MS technology ('Peptidomics'), it is possible to analyze yeast alpha-pheromone both qualitatively and semi-quantitatively directly from conditioned cell culture media. MS/MS analysis shows both forms of alpha pheromone (MFalpha and MFalpha') detectable and identifiable straight from WT supernatants. In addition to the mature intact alpha-pheromones, also post translationally modified alpha-pheromone peptides and fragments thereof are found to be present in the culture medium. This molecular analytical technique is complementary to the recently described quantitation method by Rogers et al. (2012, FEMS Yeast Res. 12:668) based on ELISA. PMID- 23368788 TI - Preschool anxiety disorders: comprehensive assessment of clinical, demographic, temperamental, familial, and life stress correlates. AB - This study examined correlates of preschoolers' anxiety disorders using a comprehensive, multimethod design. Participants included a community sample of 541 three-year-old children, of whom 106 (19.6%) met criteria for at least 1 anxiety disorder. Child and parental psychopathology and life stress were assessed with clinical interviews. Child temperament and parenting behavior were assessed with laboratory observations. Mothers and fathers reported on their parenting styles. Compared to preschoolers with no anxiety disorder, preschoolers with an anxiety disorder were more likely to meet criteria for comorbid depressive and oppositional defiant disorders and to exhibit greater temperamental behavioral inhibition and lower positive affectivity, and more sleep problems. Children with anxiety disorders also experienced more stressful life events in the previous 6 months, and their mothers had a higher rate of current anxiety disorders. Compared to children with other anxiety disorders, children with only specific phobia exhibited a somewhat different pattern of associations than children with other anxiety disorders. Overall, the findings suggest that many of the correlates observed in older youth with anxiety disorders are also observed in preschoolers. PMID- 23368791 TI - High incidence of pulmonary tuberculosis in children admitted with severe pneumonia in Uganda. AB - BACKGROUND: A high prevalence of tuberculosis (TB) in children presenting with severe pneumonia has previously been reported in South Africa. However, little is known about TB among children with pneumonia in Uganda and other resource limited countries. Moreover, TB is associated with high morbidity and mortality among such children. We conducted this study to establish the burden of pulmonary TB in children admitted with severe pneumonia in our setting. METHODS: A cross sectional study was conducted at Mulago, a National Referral and teaching hospital in Uganda. Hospitalised children 2 months to 12 years of age with severe pneumonia based on WHO case definition were enrolledfrom February to June 2011. Children with a previous TB diagnosis or receiving anti-TB treatment were excluded. Each child was screened for TB using Tuberculin skin test, Chest X-ray, induced sputum samples and blood culture for mycobacterium. Sputum smears were examined using fluorescent microscopy, and cultured on both Lowenstein Jensen media (LJ) and Mycobacterial Growth Indicator Tubes (MGIT). RESULTS: Of the 270 children with severe pneumonia who were recruited over a 5-month period in 2011, the incidence ratio of pulmonary TB in children admitted with severe pneumonia was 18.9% (95% CI 14.6 - 23.9). The proportion of culture confirmed PTB was 6.3% (95% CI 3.8 - 9.7). Age group under 1 year and 1 to 5 years (OR 2.8 (95% CI 1.7 - 7.4) and OR 2.4 (95% CI 1.05 - 5.9) respectively) were more likely to be associated with pulmonary TB compared to those children over 5 years of age. A history of TB smear positive contact was associated with pulmonary TB (OR 3.0 (95% CI 1.3-6.5). CONCLUSIONS: We found a high burden of pulmonary TB in children admitted with severe pneumonia. These data highlight the need for TB screening in children admitted with severe pneumonia so as to improve TB case finding and child survival. PMID- 23368792 TI - Copper-catalyzed C-H alkoxylation of azoles. AB - We achieved copper-catalyzed intramolecular and intermolecular alkoxylation of azoles. This reaction is a rare example of transition-metal-catalyzed C-H alkoxylation of heteroaromatic compounds. In addition, the alkoxylation reaction proceeded well even in gram scale. In most intermolecular alkoxylations, the use of an excess amount of alcohols (in some cases, alcohols are used as a solvent) is indispensable to efficiently promote the alkoxylation reaction, but this alkoxylation reaction proceeded using only 1 equiv of alcohols. PMID- 23368793 TI - Gamete fertility and ovule number variation in selfed reciprocal F1 hybrid triploid plants are heritable and display epigenetic parent-of-origin effects. AB - Polyploidy and hybridization play major roles in plant evolution and reproduction. To investigate the reproductive effects of polyploidy and hybridization in Arabidopsis thaliana, we analyzed fertility of reciprocal pairs of F1 hybrid triploids, generated by reciprocally crossing 89 diploid accessions to a tetraploid Ler-0 line. All F1 hybrid triploid genotypes exhibited dramatically reduced ovule fertility, while variation in ovule number per silique was observed across different F1 triploid genotypes. These two reproductive traits were negatively correlated suggesting a trade-off between increased ovule number and ovule fertility. Furthermore, the ovule fertility of the F1 hybrid triploids displayed both hybrid dysgenesis and hybrid advantage (heterosis) effects. Strikingly, both reproductive traits (ovule fertility, ovule number) displayed epigenetic parent-of-origin effects between genetically identical reciprocal F1 hybrid triploid pairs. In some F1 triploid genotypes, the maternal genome excess F1 hybrid triploid was more fertile, whilst for other accessions the paternal genome excess F1 hybrid triploid was more fertile. Male gametogenesis was not significantly disrupted in F1 triploids. Fertility variation in the F1 triploid A. thaliana is mainly the result of disrupted ovule development. Overall, we demonstrate that in F1 triploid plants both ovule fertility and ovule number are subject to parent-of-origin effects that are genome dosage-dependent. PMID- 23368794 TI - [2Fe-2S] proteins in Chlorosomes: redox properties of CsmI, CsmJ, and CsmX of the Chlorosome envelope of Chlorobaculum tepidum. AB - The chlorosome envelope of Chlorobaculum tepidum contains 10 polypeptides, three of which, CsmI, CsmJ, and CsmX, have an adrenodoxin-like domain harboring a single [2Fe-2S] cluster. Mutants that produced chlorosomes containing two, one, or none of these Fe-S proteins were constructed [Li, H., et al. (2013) Biochemistry 52, preceding paper in this issue ( DOI: 10.1021/bi301454g )]. The electron paramagnetic resonance (EPR) spectra, g values, and line widths of the Fe-S clusters in individual CsmI, CsmJ, and CsmX proteins were obtained from studies with isolated chlorosomes. The Fe-S clusters in these proteins were characterized by EPR and could be differentiated on the basis of their g values and line widths. The EPR spectrum of wild-type chlorosomes could be simulated by a 1:1 admixture of the CsmI and CsmJ spectra. No contribution of CsmX to the EPR spectrum of chlorosomes was observed because of its low abundance. In chlorosomes that contained only CsmI or CsmJ, the midpoint potential of the [2Fe-2S] clusters was -205 or 8 mV, respectively; the midpoint potential of the [2Fe-2S] cluster in CsmX was estimated to be more oxidizing than -180 mV. In wild-type chlorosomes, the midpoint potentials of the [2Fe-2S] clusters were -348 mV for CsmI and 92 mV for CsmJ. The lower potential for CsmI in the presence of CsmJ, and the higher potential for CsmJ in the presence of CsmI, were attributed to interactions that occur when these proteins form complexes in the chlorosome envelope. The redox properties of CsmI and CsmJ are consistent with their proposed participation in the transfer of electrons to and from quenchers of energy transfer in chlorosomes. PMID- 23368795 TI - Plasma drug concentrations and clinical effects of a peripheral alpha-2 adrenoceptor antagonist, MK-467, in horses sedated with detomidine. AB - OBJECTIVE: To investigate plasma drug concentrations and the effect of MK-467 (L 659'066) on sedation, heart rate and gut motility in horses sedated with intravenous (IV) detomidine. STUDY DESIGN: Experimental randomized blinded crossover study. ANIMALS: Six healthy horses. METHODS: Detomidine (10 MUg kg(-1) IV) was administered alone (DET) and in combination with MK-467 (250 MUg kg(-1) IV; DET + MK). The level of sedation and intestinal sounds were scored. Heart rate (HR) and central venous pressure (CVP) were measured. Blood was collected to determine plasma drug concentrations. Repeated measures anova was used for HR, CVP and intestinal sounds, and the Student's t-test for pairwise comparisons between treatments for the area under the time-sedation curve (AUCsed ) and pharmacokinetic parameters. Significance was set at p < 0.05. RESULTS: A significant reduction in HR was detected after DET, and HR was significantly higher after DET + MK than DET alone. No heart blocks were detected in any DET + MK treated horses. DET + MK attenuated the early increase in CVP detected after DET, but later the CVP decreased with both treatments. Detomidine-induced intestinal hypomotility was prevented by MK-467. AUCsed was significantly higher with DET than DET + MK, but maximal sedations scores did not differ significantly between treatments. MK-467 lowered the AUC of the plasma concentration of detomidine, and increased its volume of distribution and clearance. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 prevented detomidine induced bradycardia and intestinal hypomotility. MK-467 did not affect the clinical quality of detomidine induced sedation, but the duration of the effect was reduced, which may have been caused by the effects of MK-467 on the plasma concentration of detomidine. MK-467 may be useful clinically in the prevention of certain peripheral side effects of detomidine in horses. PMID- 23368796 TI - Stem cell therapy in stroke treatment: is it a viable option? PMID- 23368797 TI - Can fMRI be used to predict the course of treatment for social anxiety disorder? PMID- 23368799 TI - Perampanel: newly approved, novel antiepileptic medication for partial-onset seizures. PMID- 23368800 TI - Metacognitions in generalized anxiety disorder: theoretical and practical perspectives. AB - Cognitive behavioral therapy has been found to be efficacious in the treatment of generalized anxiety disorder (GAD). However, reviews of the clinical significance has indicated that approximately 50% of patients with GAD return to a 'well' status following treatment. So how might the field advance? One way is to base new treatments on GAD maintenance mechanisms. A treatment that does this is metacognitive therapy (MCT), which targets the beliefs about worrying, instead of worrying itself. So far, MCT has been evaluated in two open trials, and two randomized controlled trials, all of which achieved quite favorable results. That is, MCT achieved statistically significant decreases in GAD symptoms, with large effect sizes and high recovery rates, and was found to be superior to two forms of cognitive behavioral therapy. In this article, an overview of MCT and results of the studies on the effectiveness of MCT for GAD is given. PMID- 23368801 TI - The challenges of translating stem cells for spinal cord injury and related disorders: what are the barriers and opportunities? AB - Stem cell therapies have significant potential to treat spinal cord injury (SCI), but it remains difficult to translate these therapies from 'bench to bedside'. Identifying barriers to translation and understanding how these barriers are viewed by stakeholders in the field of stem cell research are key steps to clinical translation. The Stem Cell Global Blueprint Conference, held in Toronto (ON, Canada) presented a unique opportunity to analyze the perspectives of multiple stakeholders on the future of stem cell therapies for SCI treatment. This article is an analysis of data collected at the conference, including a consensus-building process and pre- and in-conference questionnaires. The authors used these data to assess current perceptions of stem cell research and compared the findings with the literature. The authors identified the major barriers according to a wide range of stakeholders and what strategies they suggested to overcome these obstacles, with the aim of forwarding discussion on stem cell research. It is not a systematic review of the area, but rather a presentation of expert opinion with literature citations to give context and support to their arguments and suggestions. The authors believe that the international SCI community is ready for larger-scale clinical translation, which will require the continued cooperation of all stakeholders in the stem cell and SCI communities. PMID- 23368802 TI - Commonly asked questions in transient ischemic attack. AB - With the advent of modern neuroimaging techniques, transient ischemic attack (TIA) has been redefined as, "a transient episode of neurological dysfunction caused by focal brain, spinal cord or retinal ischemia, without acute infarction." If infarct is evident on neuroimaging, the event is a stroke. It is important to recognize and correctly diagnose TIA and minor stroke because of the substantial early risk of stroke. Much of the early stroke risk is attributable to large artery atherosclerosis. Stroke-risk stratification in TIA patients can be done based on clinical grounds using an ABCD(2) score. There is, however, abundant data to support inclusion of neuroimaging in stroke-risk determination, which can also be combined with a clinical risk assessment. The hybrid ABCDE? score further refines early stroke risk. Rapid assessment and treatment in the emergency department or in specially designed 'TIA clinics' appear to reduce stroke rate. PMID- 23368803 TI - Commonly asked questions: thrombolytic therapy in the management of acute stroke. AB - Questions about thrombolytic management arise frequently, often with the intent of ascertaining safety and efficacy in specific situations. Thrombolytic therapy is generally safe, even if a nonruptured intracranial aneurysm is present. The risk of cardiac rupture with tamponade is low, except for the first 7 weeks following myocardial infarction. Over this duration, there is an increased risk of intravenous thrombolytic therapy in specific patient groups. Stroke infrequently occurs during cardiac catheterization. Its infrequent occurrence has limited large treatment trials. Basilar artery occlusion management will be reviewed. Thrombolytic therapy is generally safe in the context of pre-existing cerebral microhemorrhages and cervical artery dissections. Additionally, the role of multimodal penumbral imaging in planning stroke therapy will be reviewed. PMID- 23368804 TI - Commonly asked questions in the management of perioperative stroke. AB - Certain surgical interventions increase stroke risk. Perioperative stroke significantly increases perioperative morbidity and mortality. Several interventions, such as perioperative continuation of antithrombotic therapy during selected surgical interventions, may decrease stroke risk without significantly increasing rates of adverse effects. Commonly asked questions in the management of perioperative stroke includes: What are the mechanisms of perioperative stroke? What are the stroke risk factors and perioperative risks? What is the perioperative stroke risk with discontinuation of antithrombotic medications? What risk modifications strategies can be implemented to decrease perioperative stroke risk? What is the role of neuroimaging in the management of perioperative stroke? What is the evidence for the management of perioperative acute ischemic stroke? This article provide an evidence-based review to these questions and comments on potential interventions in the management of these patients. PMID- 23368806 TI - Augmentation strategies in obsessive-compulsive disorder. AB - Around 40-60% of patients with obsessive-compulsive disorder do not show adequate response to selective serotonin reuptake inhibitors (SSRIs). Augmentation strategies are recommended in people who show partial response to SSRI treatment or poor response to multiple SSRIs. In this article, the authors review the evidence for augmentation strategies. The available evidence is predominantly based on small-scale, randomized controlled trials, open-label trials and case series. Antipsychotic augmentation, especially risperidone, haloperidol, aripiprazole and cognitive-behavior therapy have shown the best evidence. Ondansetron, memantine, riluzole, clomipramine, mirtazapine and repetitive transcranial magnetic stimulation over supplementary motor area show some preliminary evidence. Ablative neurosurgery or deep brain stimulation may be tried in carefully selected treatment refractory patients. PMID- 23368805 TI - Use of intravenous recombinant tissue plasminogen activator in patients outside the defined criteria: safety and feasibility issues. AB - Currently, intravenous thrombolysis is by far the most effective treatment of acute ischemic stroke, and its use can independently strongly increase the proportion of stroke patients surviving. While the use of recombinant tissue plasminogen activator in accordance to licensed criteria has continuously risen, off-label use is also frequent. In this review the most important reasons to transcend current license criteria are discussed and evidence is summarized from new studies, such as IST-3, contributing to the balance of increased benefit as opposed to possible harm in situations of off-label use of recombinant tissue plasminogen activator in stroke. In addition, several scores to predict risk and outcome in patients undergoing thrombolysis are compared. PMID- 23368807 TI - Cyberchondria: towards a better understanding of excessive health-related Internet use. AB - Looking for information about symptoms and illnesses on the Internet is common and often serves useful purposes. However, a number of people who are overly distressed or anxious about their health perform excessive or repeated health related searches on the Internet, only to become more distressed or frightened - a pattern defined here as cyberchondria. This behavior, which can also be construed as a form of reassurance seeking and occurs as a manifestation of health anxiety and hypochondriasis, is the focus of this article. The antecedents of cyberchondria, factors that maintain it and its consequences are examined conceptually and in light of the relatively little research that has been performed so far. Managing cyberchondria poses a challenge, and several approaches as part of the treatment of health anxiety and hypochondriasis are described. The article makes suggestions for further research on cyberchondria. PMID- 23368810 TI - Evaluation of narrow-band imaging in the diagnosis of colorectal lesions: is a learning curve involved? AB - BACKGROUND: The usefulness of endoscopy narrow-band imaging (NBI) in differentiating colorectal lesions has been demonstrated. However, the learning curve associated with this technique is a concern for endoscopists. METHODS: Prior to carrying out these colonoscopies, four endoscopists attended a training course designed to teach the principles of NBI and application of the Sano Capillary Pattern (CP) classification criteria. Following a pre-test, endoscopists used NBI with magnification and CP analysis for real-time colonoscopy exams to predict lesion histology. Three sets of 15 lesions were imaged. These three sets included both lesions requiring endoscopic treatment (e.g. target lesions) and lesions that were not, or could not be, treated by endoscopy (e.g. non-target lesions). The diagnostic accuracy of each endoscopist for each set of lesions was evaluated to assess the learning curve associated with the application of NBI. RESULTS: Overall accuracy, sensitivity, and specificity for differentiating neoplastic and non-neoplastic lesions were 95.4%, 98.0%, and 92.0%, respectively. For target lesions versus non-target lesions, the diagnostic accuracy associated with the second set of lesions was better than that achieved with the first set of lesions (78.3% vs 96.7% (P = 0.02) and 70.0% vs 96.7% ( P < 0.01), respectively in each case). In contrast, the difference in diagnostic accuracy between the second and third sets of lesions was not significant. CONCLUSION: NBI with magnification is a useful tool for the diagnosis of colorectal lesions. Moreover, following a short training program and with minimal clinic practice, less experienced endoscopists were able to become competent in the method. PMID- 23368811 TI - Tetranuclear iron complexes bearing benzenetetrathiolate bridges as four-electron transformation templates and their electrocatalytic properties for proton reduction. AB - Two tetranuclear iron-sulfur complexes, (MU,MU-pbtt)[Fe(2)(CO)(6)](2) (pbtt = benzene-1,2,4,5-tetrathiolato, 3) and (MU,MU-obtt)[Fe(2)(CO)(6)](2) (obtt = benzene-1,2,3,4-tetrathiolato, 4), were prepared from reaction of Fe(3)(CO)(12) and the corresponding tetramercaptobenzene in THF, respectively. Complexes 5 and 6, (MU,MU-pbtt)[Fe(2)(CO)(5)L(1)][Fe(2)(CO)(5)L(2)] (L(1) = CO, L(2) = PPyr(3) (Pyr = N-pyrrolyl), 5; L(1) = L(2) = PPyr(3), 6) were obtained by controlling CO displacement of 3 with PPyr(3). Molecular structures of 3-6 were determined by spectroscopic and single-crystal X-ray analyses. All-CO Fe(4)S(4) complexes 3 and 4 each display four-electron reduction processes in consecutive chemically reversible two-electron reduction events with relatively narrow potential spans in the cyclic voltammograms. Phosphine-substituted Fe(4)S(4) complexes 5 and 6 exhibit two consecutive two-electron reduction events, which are not fully reversible. The electrocatalytic properties of 3 and 4 for proton reduction were studied using a series of carboxylic acids of increasing strength (CH(3)COOH, CH(2)ClCOOH, CHCl(2)COOH, CCl(3)COOH, and CF(3)COOH). The mechanisms for electrochemical proton reduction to hydrogen catalyzed by complex 3 as a function of acid strength are discussed. PMID- 23368808 TI - Next-generation sequencing in understanding complex neurological disease. AB - Next-generation sequencing techniques have made vast quantities of data on human genomes and transcriptomes available to researchers. Huge progress has been made towards understanding the basis of many Mendelian neurological conditions, but progress has been considerably slower in complex neurological diseases (multiple sclerosis, migraine, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and so on). The authors review current next-generation sequencing methodologies and present selected studies illustrating how these have been used to cast light on the genetic etiology of complex neurological diseases with specific focus on multiple sclerosis. The authors highlight particular pitfalls in next-generation sequencing experiments and speculate on both clinical and research applications of these sequencing platforms for complex neurological disorders in the future. PMID- 23368812 TI - A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism. AB - The different steps of the human Top1 (topoisomerase I) catalytic cycle have been analysed in the presence of a pentacyclic-diquinoid synthetic compound. The experiments indicate that it efficiently inhibits the cleavage step of the enzyme reaction, fitting well into the catalytic site. Surprisingly the compound, when incubated with the binary topoisomerase-DNA cleaved complex, helps the enzyme to remove itself from the cleaved DNA and close the DNA gap, increasing the religation rate. The compound also induces the religation of the stalled enzyme CPT (camptothecin)-DNA ternary complex. Analysis of the molecule docked over the binary complex, together with its chemical properties, suggests that the religation enhancement is due to the presence on the compound of two oxygen atoms that act as hydrogen acceptors. This property facilitates the deprotonation of the 5' DNA end, suggesting that this is the limiting step in the topoisomerase religation mechanism. PMID- 23368813 TI - Respiratory diseases and their effects on respiratory function and exercise capacity. AB - Given that aerobic metabolism is the predominant energy pathway for most sports, the respiratory system can be a rate-limiting factor in the exercise capacity of fit and healthy horses. Consequently, respiratory diseases, even in mild forms, are potentially deleterious to any athletic performance. The functional impairment associated with a respiratory condition depends on the degree of severity of the disease and the equestrian discipline involved. Respiratory abnormalities generally result in an increase in respiratory impedance and work of breathing and a reduced level of ventilation that can be detected objectively by deterioration in breathing mechanics and arterial blood gas tensions and/or lactataemia. The overall prevalence of airway diseases is comparatively high in equine athletes and may affect the upper airways, lower airways or both. Diseases of the airways have been associated with a wide variety of anatomical and/or inflammatory conditions. In some instances, the diagnosis is challenging because conditions can be subclinical in horses at rest and become clinically relevant only during exercise. In such cases, an exercise test may be warranted in the evaluation of the patient. The design of the exercise test is critical to inducing the clinical signs of the problem and establishing an accurate diagnosis. Additional diagnostic techniques, such as airway sampling, can be valuable in the diagnosis of subclinical lower airway problems that have the capacity to impair performance. As all these techniques become more widely used in practice, they should inevitably enhance veterinarians' diagnostic capabilities and improve their assessment of treatment effectiveness and the long term management of equine athletes. PMID- 23368814 TI - Blastocystis spp.: frequency and subtype distribution in iron deficiency anemic versus non-anemic subjects from Egypt. AB - Many helminthic and protozoal infections have been implicated in iron deficiency anemia (IDA) but few reports have suggested a link between Blastocystis sp. infection and IDA. Herein, we investigated the frequency and the association of the Blastocystis sp. genotype with IDA. Two-hundred and six stool samples were examined for Blastocystis sp. Samples were obtained from 96 cases with a confirmed diagnosis of IDA and 110 matched non-anemic controls. The prevalence of the parasite was significantly higher in the IDA group (54.2%) when compared to controls (17.3%) and was 34.5% in all study subjects. Thus, a relationship between Blastocystis sp. infection and IDA was confirmed. PCR amplification of isolates from cases with IDA and controls using subtype-specific sequenced-tagged site primers found that subtype 3 was the most common (83.3%), followed by subtype 1 (16.7%), and both had similar prevalence in both groups. Therefore, there was no correlation found between the Blastocystis sp. genotype and the occurrence of IDA. PMID- 23368815 TI - Protein disulfide topology determination through the fusion of mass spectrometric analysis and sequence-based prediction using Dempster-Shafer theory. AB - BACKGROUND: Disulfide bonds constitute one of the most important cross-linkages in proteins and significantly influence protein structure and function. At the state-of-the-art, various methodological frameworks have been proposed for identification of disulfide bonds. These include among others, mass spectrometry based methods, sequence-based predictive approaches, as well as techniques like crystallography and NMR. Each of these frameworks has its advantages and disadvantages in terms of pre-requisites for applicability, throughput, and accuracy. Furthermore, the results from different methods may concur or conflict in parts. RESULTS: In this paper, we propose a novel and theoretically rigorous framework for disulfide bond determination based on information fusion from different methods using an extended formulation of Dempster-Shafer theory. A key advantage of our approach is that it can automatically deal with concurring as well as conflicting evidence in a data-driven manner. Using the proposed framework, we have developed a method for disulfide bond determination that combines results from sequence-based prediction and mass spectrometric inference. This method leads to more accurate disulfide bond determination than any of the constituent methods taken individually. Furthermore, experiments indicate that the method improves the accuracy of bond identification as compared to leading extant methods at the state-of-the-art. Finally, the proposed framework is extensible in that results from any number of approaches can be incorporated. Results obtained using this framework can especially be useful in cases where the complexity of the bonding patterns coupled with specificities of the fragmentation pattern or limitations of computational models impair any single method to perform consistently across a diverse set of molecules. PMID- 23368816 TI - Scalable high-power redox capacitors with aligned nanoforests of crystalline MnO2 nanorods by high voltage electrophoretic deposition. AB - It is commonly perceived that reduction-oxidation (redox) capacitors have to sacrifice power density to achieve higher energy density than carbon-based electric double layer capacitors. In this work, we report the synergetic advantages of combining the high crystallinity of hydrothermally synthesized alpha-MnO2 nanorods with alignment for high performance redox capacitors. Such an approach is enabled by high voltage electrophoretic deposition (HVEPD) technology which can obtain vertically aligned nanoforests with great process versatility. The scalable nanomanufacturing process is demonstrated by roll-printing an aligned forest of alpha-MnO2 nanorods on a large flexible substrate (1 inch by 1 foot). The electrodes show very high power density (340 kW/kg at an energy density of 4.7 Wh/kg) and excellent cyclability (over 92% capacitance retention over 2000 cycles). Pretreatment of the substrate and use of a conductive holding layer have also been shown to significantly reduce the contact resistance between the aligned nanoforests and the substrates. High areal specific capacitances of around 8500 MUF/cm(2) have been obtained for each electrode with a two-electrode device configuration. Over 93% capacitance retention was observed when the cycling current densities were increased from 0.25 to 10 mA/cm(2), indicating high rate capabilities of the fabricated electrodes and resulting in the very high attainable power density. The high performance of the electrodes is attributed to the crystallographic structure, 1D morphology, aligned orientation, and low contact resistance. PMID- 23368817 TI - ANGUSTIFOLIA is a central component of tissue morphogenesis mediated by the atypical receptor-like kinase STRUBBELIG. AB - BACKGROUND: During plant tissue morphogenesis cells have to coordinate their behavior to allow the generation of the size, shape and cellular patterns that distinguish an organ. Despite impressive progress the underlying signaling pathways remain largely unexplored. In Arabidopsis thaliana, the atypical leucine rich repeat receptor-like kinase STRUBBELIG (SUB) is involved in signal transduction in several developmental processes including the formation of carpels, petals, ovules and root hair patterning. The three STRUBBELIG-LIKE MUTANT (SLM) genes DETORQUEO (DOQ), QUIRKY (QKY) and ZERZAUST (ZET) are considered central elements of SUB-mediated signal transduction pathways as corresponding mutants share most phenotypic aspects with sub mutants. RESULTS: Here we show that DOQ corresponds to the previously identified ANGUSTIFOLIA gene. The genetic analysis revealed that the doq-1 mutant exhibits all additional mutant phenotypes and conversely that other an alleles show the slm phenotypes. We further provide evidence that SUB and AN physically interact and that AN is not required for subcellular localization of SUB. CONCLUSIONS: Our data suggest that AN is involved in SUB signal transduction pathways. In addition, they reveal previously unreported functions of AN in several biological processes, such as ovule development, cell morphogenesis in floral meristems, and root hair patterning. Finally, SUB and AN may directly interact at the plasma membrane to mediate SUB-dependent signaling. PMID- 23368818 TI - The efficacy of single dose ivermectin in the treatment of hookworm related cutaneous larva migrans varies depending on the clinical presentation. AB - BACKGROUND: Treatment of hookworm-related cutaneous larva migrans (HrCLM) with a single dose of oral ivermectin has not been adequately evaluated to date. Response rates reported in three large studies varied from 77% to more than 95%. OBJECTIVES: We evaluated the efficacy of ivermectin in the treatment of HrCLM. METHODS: We retrospectively studied all returning travellers with HrCLM who consulted in our institution. Patients were then treated with a single, 200 MUg/kg dose of ivermectin, orally. RESULTS: Sixty-two travellers (35 female, 27 male, mean age 35.6 years) with HrCLM and creeping dermatitis were included. Six patients (10%) also had associated hookworm folliculitis. Fifty-nine patients (95%) completely responded with one ivermectin dose. The response rate was 98% in the 56 patients presenting with only creeping dermatitis and 66% in the six patients presenting with additional hookworm folliculitis (P = 0.02). CONCLUSION: The efficacy of a single dose of oral ivermectin is higher in patients with only creeping dermatitis than in those with associated hookworm folliculitis. PMID- 23368819 TI - Genome-wide analysis of human hotspot intersected genes highlights the roles of meiotic recombination in evolution and disease. AB - BACKGROUND: Meiotic recombination events are not randomly located, but rather cluster at hotspot regions. Recently, the fine-scale mapping of genome-wide human recombination hotspots was performed. Here, we systematically analyzed the evolutionary and disease-associated features of hotspots that overlapped with protein-coding genes. RESULTS: In this study, we defined hotspot intersected genes as HI genes. We found that HI genes were prone to be located in the extracellular part and were functionally enriched in cell-to-cell communication. Tissue-specific genes and secreted protein encoding genes were overrepresented in HI genes, while housekeeping genes were underrepresented. Compared to slowly evolving housekeeping genes and random genes with lower recombination rates, HI genes evolved faster. The fact that brain and blood specific genes were overrepresented in HI genes indicates that they may be involved in the evolution of human intelligence and the immune system. We also found that genes related to disease were enriched in HI genes, especially genes with disease-associated chromosomal rearrangements. Hotspot sequence motifs were overrepresented in common sequences of HI genes and genes with disease-associated chromosomal rearrangements. We further listed repeat elements that were enriched both in hotspots and genes with disease-associated chromosomal rearrangements. CONCLUSION: HI genes are evolving and may be involved in the generation of key features of human during evolution. Disease-associated genes may be by-products of meiotic recombination. In addition, hotspot sequence motifs and repeat elements showed the connection between meiotic recombination and genes with disease-associated chromosomal rearrangements at the sequence level. Our study will enable us to better understand the evolutionary and biological significance of human meiotic recombination. PMID- 23368820 TI - Prospective, randomized, double-blind, placebo-controlled trial of ulinastatin for prevention of hyperenzymemia after double balloon endoscopy via the antegrade approach. AB - BACKGROUND: Double balloon endoscopy (DBE) allows the entire small intestine to be viewed using a combination of antegrade and retrograde approaches. Acute pancreatitis is a serious complication of antegrade DBE with no effective prophylactic treatment currently available. Ulinastatin has been shown to be effective for the prevention of pancreatitis following endoscopic retrograde cholangiopancreatography. We therefore assessed the efficacy of ulinastatin for hyperenzymemia after antegrade DBE. PATIENTS AND METHODS: Forty-four patients were enrolled in this prospective, randomized, double-blind, placebo-controlled trial. Patients in the ulinastatin group received 150 000 U ulinastatin by i.v. drip infusion for 2 h from the start of the procedure. Serum concentrations of pancreatic amylase and lipase were measured before and 3 and 18 h after antegrade DBE. RESULTS: The study was terminated after interim analysis. Of the 44 patients, 23 were randomized to ulinastatin and 21 to placebo.The groups were similar with regard to sex ratio, age, type of endoscope, insertion time, total procedure time, number of endoscope pull-back procedures, and baseline pancreaticamylase and lipase concentrations. Post-DBE hyperenzymemia was observed in 35.0% and 47.8% of patients in the placebo and ulinastatin groups, respectively. The higher frequency of hyperenzymemia in the ulinastatin group was unexpected, but the difference was not statistically significant. One patient in the placebo group (5.0%) and none in the ulinastatin group experienced acute pancreatitis, but the difference was not statistically significant. CONCLUSION: The results of this trial suggest that ulinastatin does not prevent hyperenzymemia following antegrade DBE. PMID- 23368821 TI - The influence of vigorous running and cycling exercise on hunger perceptions and plasma acylated ghrelin concentrations in lean young men. AB - Vigorous running suppresses plasma acylated ghrelin concentrations but the limited literature on cycling suggests that acylated ghrelin is unchanged, perhaps because body mass is supported during cycling. It is important from a research and applied perspective to determine whether acylated ghrelin and hunger responses are exercise-mode specific. This study sought to examine this. Eleven recreationally active males fasted overnight and completed three 4-h trials: control, running, and cycling, in a random order. Participants rested throughout the control trial and ran or cycled at 70% of mode-specific maximal oxygen uptake for the first hour during exercise trials, resting thereafter. Hunger was measured every 0.5 h using visual analogue scales. Eight venous blood samples were collected to determine acylated ghrelin concentrations and a standardised meal was consumed at 3 h. Compared with the control trial, acylated ghrelin concentrations were suppressed to a similar extent at 0.5 and 1 h during the running (p < 0.005) and cycling (p < 0.001) trials. Area under the curve values for ghrelin concentration over time were lower during exercise trials versus control (Control: 606 +/- 379; Running: 455 +/- 356; Cycling: 448 +/- 315 pg.mL( 1).4 h(-1); mean +/- SD, p < 0.05). Hunger values did not differ significantly between trials but an interaction effect (p < 0.05) indicated a tendency for hunger to be suppressed during exercise. Thus, at similar relative exercise intensities, plasma acylated ghrelin concentrations are suppressed to a similar extent during running and cycling. PMID- 23368822 TI - Metabolic and neuromuscular responses at critical power from the 3-min all-out test. AB - The purpose of this study was to determine the specific metabolic and neuromuscular responses at critical power (CP) from the 3-min all-out test. Nine men (mean +/- SD: aged 23.7 +/- 3.3 years) performed an incremental test for the determination of peak oxygen consumption (VO(2peak)) and gas exchange threshold. CP was estimated for each subject from the 3-min all-out test. Oxygen consumption (VO(2)), the ventilation versus carbon dioxide production ratio (V(E)/VCO(2) ratio), electromyographic (EMG) amplitude, and EMG mean power frequency (MPF) were examined during exhaustive rides at CP for each subject. There was no significant difference between the VO(2) at exhaustion (40.6 +/- 7.5 mL.kg( 1).min(-1)) and VO(2peak) (42.9 +/- 7.3 mL.kg(-1).min(-1)). Furthermore, there were significant increases in EMG amplitude and the V(E)/VCO(2) ratio during the exhaustive rides at CP. There was, however, no significant change in EMG MPF over time. Therefore, the current findings indicated that the 3-min all-out test overestimated CP and the demarcation between the heavy- and severe-intensity domains. Specifically, the VO(2), ventilatory, and EMG amplitude responses were consistent with those observed during continuous exercise in the severe exercise intensity domain. It is likely that the ventilatory and EMG amplitude responses were associated with a common mechanism of fatigue that is different from what affects EMG MPF. PMID- 23368823 TI - Cold-induced vasodilatation response in the fingers at 4 different water temperatures. AB - We evaluated the cold-induced vasodilatation (CIVD) response at 4 different water temperatures. Nine healthy young male subjects immersed their right hands in 35 degrees C water for 5 min, and immediately thereafter for 30 min in a bath maintained at either 5, 8, 10, or 15 degrees C. The responses of finger skin temperatures, subjective ratings of thermal comfort and temperature sensation scores were compared between the 4 immersion trials. The number of subjects who exhibited a CIVD response was higher during immersion of the hand in 5 and 8 degrees C (100%) compared with 10 and 15 degrees C water (87.5% and 37.5%, respectively). The CIVD temperature amplitude was 4.2 +/- 2.6, 3.4 +/- 2.0, 2.1 +/- 1.6, and 2.8 +/- 2.0 degrees C at 5, 8, 10, and 15 degrees C trials, respectively; higher in 5 and 8 degrees C compared with 10 and 15 degrees C water (p = 0.003). No differences in CIVD were found between the 5 and 8 degrees C immersions. However, during immersion in 5 degrees C, subjects felt "uncomfortable" while in the other trials felt "slightly uncomfortable" (p = 0.005). The temperature sensation score was "cold" for 5 degrees C and "cool" for the other trials, but no statistical differences were observed. Immersion of the hand in 8 degrees C elicits a CIVD response of similar magnitude as immersion in 5 degrees C, but with less thermal discomfort. PMID- 23368824 TI - The effects of hypohydration and fatigue on neuromuscular activation performance. AB - This study investigated the effects of hypohydration by fluid restriction on voluntary and evoked indices of neuromuscular performance at a functional joint angle. Measures of static volitional peak force (2-3-s maximal muscle actions) and evoked peak twitch force, electromechanical delay, and rate of force development were obtained from the knee extensors (30 degrees knee flexion) of 10 males (age, 24 (4) years; height, 1.76 (0.10) m; body mass, 78.7 (9.13) kg (mean (SD))) prior to and immediately following 24 h of (i) euhydration (EU) and (ii) hypohydration (HYP). Neuromuscular performance was also assessed in response to a fatiguing task (3 * 30-s maximal static knee extensions) following each condition. Repeated-measures ANOVAs showed that HYP was associated with a significant 2.1% loss in body mass (p < 0.001) and a 7.8% reduction in volitional peak force (p < 0.05). Following fatigue, data indicated statistically similar levels of impairment to volitional peak force (11.6%, p < 0.01) and rate of force development (21.0%, p < 0.01) between conditions (EU; HYP). No changes to any other indices of performance were observed. The substantive hypohydration-induced deficits to muscle strength at this functional joint angle might convey a decreased performance capability and should be considered by the hypohydrated athlete. Whilst hypohydration did not affect fatigue-related performance of the knee extensors, the additive changes associated with lower baseline levels of strength performance (7.8%) and fatigue (11.6%) coupled with slower rate of muscle force production (from 0-100 ms) following fatigue may present significant challenges to the maintenance of dynamic knee joint stability, particularly at this vulnerable joint position. PMID- 23368825 TI - Validation of a portable bioelectrical impedance analyzer for the assessment of body composition. AB - One of the major challenges in field research has been the difficulty to adequately measure body composition, such as % body fat and fat-free mass (FFM). Therefore, the purpose of the present study was to investigate the convergent validity of the portable bioelectrical impedance body composition analyzer, the Inbody 230, with dual X-ray absorptiometry (DXA) (General Electric Lunar Prodigy). The study population consisted of 145 men and women (age, 44.6 +/- 20 years; BMI, 24.5 +/- 3.8 kg.m(-2)). We measured body composition (fat mass, % body fat, total FFM, trunk FFM, and appendicular FFM) using DXA and the Inbody 230. Results show strong significant correlations between both methods for fat mass, % body fat, total FFM, and trunk FFM (r = 0.94-0.99). Furthermore, we showed a modest significant correlation between both methods for appendicular FFM (r = 0.63). Finally, as shown by Bland-Altman analysis, no significant biases were observed between Inbody 230 and DXA for fat mass, % body fat, and total FFM. However, trunk and appendicular FFM were shown to have significant biases between the Inbody 230 and DXA. In conclusion, the present study indicated that the portable Inbody 230 may be an acceptable device to measure fat mass, % body fat, and total FFM (except for women) in healthy adults. In addition, there appears to be a systematic bias for the estimation of trunk and appendicular FFM with the Inbody 230 in men and women. PMID- 23368826 TI - High-fat feeding, but not strenuous exercise, increases blood oxidative stress in trained men. AB - Two prevalent origins of oxidative stress in Western society are the ingestion of high-fat meals and the performance of strenuous exercise. The purpose of this investigation was to compare the magnitude of increase in blood oxidative stress following acute feeding and acute exercise. Twelve exercise-trained men consumed a high-fat meal or performed 1 of 3 exercise bouts (steady-state aerobic; high intensity, moderate-duration interval sprints; maximal intensity, short-duration interval sprints) in a random order, crossover design. Blood was collected before and at times following feeding and exercise. Samples were analyzed for trigylcerides, malondialdehyde (MDA), hydrogen peroxide (H(2)O(2)), advanced oxidation protein products (AOPP), nitrate/nitrite (NOx), trolox-equivalent antioxidant capacity (TEAC), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). A significant condition effect was noted for MDA (p = 0.01), H(2)O(2) (p < 0.0001), and AOPP (p = 0.0006), with values highest for the meal condition. An increase of 88%, 247%, and 96% was noted from pre- to post feeding for MDA, H(2)O(2), and AOPP, respectively. A condition effect was also noted for TEAC (p = 0.04) and CAT (p = 0.05), with values lowest for the meal condition (TEAC) and the meal and aerobic exercise condition (CAT). NOx, SOD, and GPx were relatively unaffected by feeding and exercise, while MDA, H(2)O(2), and AOPP experienced little change from pre- to postexercise (p > 0.05). These results illustrate that the magnitude of blood oxidative stress following a high fat meal is significantly greater than that elicited by either aerobic or anaerobic exercise in a sample of exercise-trained men. PMID- 23368827 TI - Increased blood cholesterol after a high saturated fat diet is prevented by aerobic exercise training. AB - A high saturated fatty acids diet (HSFAD) deteriorates metabolic and cardiovascular health while aerobic training improves them. The aim of this study was to investigate in physically inactive and overweight people if 2 weeks of HSFAD leads to hyperlipemia or insulin resistance and if concurrent aerobic exercise training counteracts those effects. Fourteen overweight (body mass index, 27.5 +/- 0.6 kg.m(-2)), healthy, young individuals (aged 24.8 +/- 1.8 years) were randomly assigned to a diet (D) or a diet plus exercise (D + E) group. During 14 consecutive days both groups increased dietary saturated fatty acids from 31 +/- 10 to 52 +/- 14 g.day(-1) (p < 0.001) while maintaining total fat intake. Concurrent to the diet, the D + E group underwent 11 cycle-ergometer sessions of 55 min at 60% peak oxygen uptake (VO(2peak)). Before and after intervention, insulin sensitivity and body composition were estimated, and blood lipids, resting blood pressure, and VO(2peak) were measured. Body weight and composition, plasma free fatty acids composition and concentration, and insulin sensitivity remained unchanged in both groups. However, post-intervention total cholesterol (T(C)) and low-density lipoprotein cholesterol (LDL-C) increased above pre-intervention values in the D group (147 +/- 8 to 161 +/- 9 mg.dL(-1), p = 0.018 and 71 +/- 10 to 82 +/- 10 mg.dL(-1), p = 0.034, respectively). In contrast, in the D + E group, T(C) and LDL-C remained unchanged (153 +/- 20 to 157 +/- 24 mg.dL(-1) and 71 +/- 21 to 70 +/- 25 mg.dL(-1)). Additionally, the D + E group lowered systolic blood pressure (6 +/- 2 mm Hg, p = 0.029) and increased VO(2peak) (6 +/- 2 mL.kg(-1).min(-1), p = 0.020). Increases in T(C) and LDL-C concentration induced by 14 days of HSFAD can be prevented by concurrent aerobic exercise training, which, in addition, improves cardiorespiratory fitness. PMID- 23368828 TI - A moderate dose of caffeine ingestion does not change energy expenditure but decreases sleep time in physically active males: a double-blind randomized controlled trial. AB - Research on the effect of caffeine on energy expenditure (EE), physical activity (PA), and total sleep time (TST) during free-living conditions using objective measures is scarce. We aimed to determine the impact of a moderate dose of caffeine on TST, resting EE (REE), physical activity EE (PAEE), total EE (TEE), and daily time spent in sedentary, light, moderate, and vigorous intensity activities in a 4-day period and the acute effects on heart rate (HR) and EE in physically active males. Using a double-blind crossover trial (ClinicalTrials.gov ID: NCT01477294) with two conditions (4 days each with 3-day washout) randomly ordered as caffeine (5 mg/kg of body mass/day) and placebo (maltodextrin) administered twice per day (2.5 mg/kg), 30 nonsmoker males, low-caffeine users (<100 mg/day), aged 20-39, were followed. Body composition was assessed by dual energy X-ray absorptiometry. PA was assessed by accelerometry, while a combined HR and movement sensor estimated EE and HR on the second hour after the first administration dose. REE was assessed by indirect calorimetry, and PAEE was calculated as [TEE - (REE + 0.1TEE)]. TST and daily food records were obtained. Repeated measures ANOVA and ANCOVA were used. After a 4-day period, adjusting for fat-free mass, PAEE, and REE, TST was reduced (p = 0.022) under caffeine intake, while no differences were found between conditions for REE, PAEE, TEE, and PA patterns. Also, no acute effects on HR and EE were found between conditions. Though a large individual variability was observed, our findings revealed no acute or long-term effects of caffeine on EE and PA but decreased TST during free living conditions in healthy males. PMID- 23368829 TI - Comparative effect of a 1 h session of electrical muscle stimulation and walking activity on energy expenditure and substrate oxidation in obese subjects. AB - It has previously been shown that low-frequency neuromuscular electrical stimulation (NMES) techniques can induce increases in energy expenditure similar to those associated with exercise. This study investigated the metabolic and cardiovascular effects of a 1 h session of lower limb NMES and compared cardiovascular response with that observed during walking in nine obese subjects (three males) (age = 43.8 +/- 3.0 years; body mass index (BMI) = 41.5 +/- 1.8 kg/m(2)). The NMES protocol consisted of delivering a complex pulse pattern to the thigh muscles for 1 h. The walking test consisted of five 4-min bouts starting at 2 km/h with 1 km/h increments up to 6 km/h. In both tests, an open circuit gas analyser was used to assess O(2) consumption ([Formula: see text]O(2)), CO(2) production ([Formula: see text]CO(2)), respiratory exchange ratio (RER), and heart rate (HR). Rates of fat oxidation (RFO) and carbohydrate oxidation (CHO) were estimated by indirect calorimetry. One hour of NMES significantly increased [Formula: see text]O(2), HR, RER, and mean energy expenditure compared with resting values, reaching 8.7 +/- 1.3 mL.min(-2).kg(-1) (47% of [Formula: see text]O(2peak)), 114.8 +/- 7.5 bpm, 0.95, and 318.5 +/- 64.3 kcal/h, respectively. CHO, but not RFO, increased during 1 h of NMES. With NMES, CHO was greater and RFO was less than at all walking speeds except 6 km/h. Lactate also increased more with NMES, to 3.5 +/- 0.7 mmol versus a maximum of 1.5 +/- 0.3 mmol with the walking protocol. These results suggest that NMES can be used in an obese population to induce an effective cardiovascular exercise response. In fact, the observed increase in energy expenditure induced by 1 h of NMES is clinically important and comparable with that recommended in weight management programs. PMID- 23368830 TI - Effects of acute exercise on appetite hormones and ad libitum energy intake in men and women. AB - Acute exercise suppresses relative energy intake; however, it remains unclear whether this occurs in both men and women exposed to the same relative exercise treatment. Eleven healthy men (22 +/- 2 years; 16% +/- 6% body fat (BF); 26 +/- 4 body mass index (BMI); 42.9 +/- 6.5 mL.kg(-1).min(-1) peak oxygen consumption ([Formula: see text]O(2peak))) and 10 healthy women (21 +/- 2 years; 24 +/- 2 BMI; 23% +/- 3% BF; 39.9 +/- 5.5 mL.kg(-1).min(-1) [Formula: see text]O(2peak)) rested for 60 min or exercised on a cycle ergometer at 70% [Formula: see text]O(2peak) until 30% of total daily energy expenditure was expended (men, expenditure = 975 +/- 195 kcal in 82 +/- 13 min; women, expenditure = 713 +/- 86 kcal in 84 +/- 17 min) in a counterbalanced, crossover fashion. Appetite hormones and appetite ratings were assessed in response to each condition. Forty minutes after both conditions, ad libitum total and relative energy intake (energy intake minus energy cost of exercise) were assessed at a buffet meal. There was no significant sex or condition effect in appetite hormones (PYY(3-36), acylated ghrelin, insulin) and appetite ratings (hunger, satisfaction, fullness). Total energy intake in men was significantly higher (P < 0.05) in exercise and rest conditions (1648 +/- 950, 1216 +/- 633 kcal, respectively) compared with women (591 +/- 183, 590 +/- 231 kcal, respectively). Relative energy intake was significantly lower (P < 0.05) after exercise compared with rest in men (672 +/- 827, 1133 +/- 619 kcal, respectively) and women (-121 +/- 243, 530 +/- 233 kcal, respectively). These data highlight the effectiveness of acute exercise to suppress relative energy intake regardless of sex. PMID- 23368831 TI - Fluid ingestion is more effective in preventing hyperthermia in aerobically trained than untrained individuals during exercise in the heat. AB - It is unclear if fluid ingestion during exercise in the heat alleviates the thermoregulatory and cardiovascular strain similarly in aerobically trained and untrained individuals. It is also unknown at what exercise intensity the effects of rehydration are greater. Ten aerobically trained (T) and 10 healthy untrained (UT) subjects ([Formula: see text]O(2peak), 60 +/- 6 vs. 44 +/- 3 mL O(2).kg( 1).min(-1), respectively; P < 0.05) pedalled in a hot, dry environment (36 +/- 1 degrees C; 25% +/- 2% relative humidity; airflow, 2.5 m.s(-1)) at 40%, 60%, and 80% [Formula: see text]O(2peak) while ingesting fluids (Fluid). The results were compared with those from our previous study [Mora-Rodriguez et al., Eur. J. Appl. Physiol. 109(5): 973-981 (2010)] with no fluid ingestion (No Fluid). Subjects were not heat-acclimated. At 40% [Formula: see text]O(2peak), Fluid reduced rectal temperature (T(RE)) in T and UT (0.31 +/- 0.08 and 0.32 +/- 0.07 degrees C; respectively). At 60% [Formula: see text]O(2peak), Fluid reduced T(RE) in T more than in UT (0.30 +/- 0.10 degrees C vs. 0.18 +/- 0.10 degrees C; P < 0.05) but had no effect at 80% [Formula: see text]O(2peak) in any group. At similar relative intensity, heart rates (HR) were similar between groups. Fluid lowered heart rate (i.e., HR) similarly in the T and UT at 40% and 60% [Formula: see text]O(2peak) (11% and 6%, respectively; P < 0.05) but not at 80% [Formula: see text]O(2peak) (P > 0.05). At similar metabolic heat production (i.e., 60% for T vs. 80% [Formula: see text]O(2peak) for UT), Fluid lowered T(RE) only in the T individuals (P < 0.05). In summary, rehydration during low- and moderate intensity exercise reduces T(RE) and HR more than during high-intensity exercise (80% [Formula: see text]O(2peak)) in T and UT subjects. Fluid replacement is more effective on preventing the rise in T(RE) in T than in UT individuals during moderate-intensity exercise (60% [Formula: see text]O(2peak)), as well as when exercising at a similar heat production rate. PMID- 23368832 TI - Objectively measured physical activity levels of children and adolescents in rural South Africa: high volume of physical activity at low intensity. AB - There is limited evidence on objectively measured physical activity from Africa. This study quantified physical activity by accelerometry in rural South African children at ages 7, 11, and 15 years. Total physical activity was generally high (mean accelerometer counts per minute ranged 485-1017 across the 3 groups), but moderate- to vigorous-intensity physical activity was low: <1% of the sample met international recommendations. A low intensity, high volume of physical activity is present in rural South African children and adolescents. PMID- 23368833 TI - Increasing the quality of life from womb to grave: the importance of pregnancy and birth cohorts. AB - Epigenetics is revealing how "nature is nurtured", with environmental factors such as nutrition, environmental neurotoxicants, and psychological stress influencing DNA expression. In this current opinion paper, we argue that understanding the dynamic interplay between the genome acquired at conception and environmental exposures throughout life requires pregnancy and birth cohorts, and that greater Canadian national commitment to the infrastructure needed for sustaining such cohorts is warranted. We present a framework that is now being implemented in Alberta. PMID- 23368835 TI - Prediction of disulfide connectivity in proteins with machine-learning methods and correlated mutations. AB - BACKGROUND: Recently, information derived by correlated mutations in proteins has regained relevance for predicting protein contacts. This is due to new forms of mutual information analysis that have been proven to be more suitable to highlight direct coupling between pairs of residues in protein structures and to the large number of protein chains that are currently available for statistical validation. It was previously discussed that disulfide bond topology in proteins is also constrained by correlated mutations. RESULTS: In this paper we exploit information derived from a corrected mutual information analysis and from the inverse of the covariance matrix to address the problem of the prediction of the topology of disulfide bonds in Eukaryotes. Recently, we have shown that Support Vector Regression (SVR) can improve the prediction for the disulfide connectivity patterns. Here we show that the inclusion of the correlated mutation information increases of 5 percentage points the SVR performance (from 54% to 59%). When this approach is used in combination with a method previously developed by us and scoring at the state of art in predicting both location and topology of disulfide bonds in Eukaryotes (DisLocate), the per-protein accuracy is 38%, 2 percentage points higher than that previously obtained. CONCLUSIONS: In this paper we show that the inclusion of information derived from correlated mutations can improve the performance of the state of the art methods for predicting disulfide connectivity patterns in Eukaryotic proteins. Our analysis also provides support to the notion that improving methods to extract evolutionary information from multiple sequence alignments greatly contributes to the scoring performance of predictors suited to detect relevant features from protein chains. PMID- 23368837 TI - The Canadian total diet study design: 1992-1999. AB - This paper describes the design of the fourth phase of the Canadian total diet study, conducted for the period 1992-1999. During this phase, complete sets of foods were purchased from eight cities (from one of them twice). For each of the sets, individual foods were prepared as for consumption into about 140 different food composites at Kemptville College, homogenised and bottled. Water from Kemptville, Ontario, was used for the preparation of the foods. The composites were stored frozen at -20 degrees C and then analysed in the Food Research Division for chlorinated dioxins and dibenzofurans, pesticides, PCBs and trace elements. The analytical results were combined with average food consumption values for different age/sex groups, and dietary intakes were calculated. The design of the total diet study provided information to achieve the following goals: (a) background concentrations of the chemicals in the 140 different food composites, (b) average dietary intakes of the chemicals by the population and by different age/sex groups, (c) percent contribution of individual foods and food groups to the dietary intakes, (d) identification of individual contaminated foods and (e) identification of trends in human exposure with time. PMID- 23368836 TI - Longitudinal associations between depression and problematic substance use in the Youth Partners in Care study. AB - Large-scale treatment studies suggest that effective depression treatment and reduced depression are associated with improved substance use outcomes. Yet information is limited regarding the longitudinal association between depressive symptoms and problematic substance use and its predictors, particularly in real world practice settings. Using latent growth modeling, we examined the (a) longitudinal association between depressive symptoms and problematic substance use, (b) impact of depressive symptoms on problematic substance use, (c) impact of problematic substance use on depressive symptoms, and (d) role of co-occurring symptoms on depression and problematic substance use. Participants were part of the Youth Partners in Care study, an effectiveness trial evaluating a quality improvement intervention for youth depression through primary care. This ethnically diverse sample included youths aged 13 to 21 years screening positive for depression from 5 health care organizations. Participants were followed 4 times over an 18-month period and assessed for both depressive symptoms and problematic substance use. Both depressive symptoms and problematic substance use declined over time. Higher baseline depressive symptoms predicted a slower decline in problematic substance use, but baseline problematic substance use did not predict changes in depressive symptoms. These prospective associations remained robust controlling for co-occurring symptoms. Results support prior large-scale depression studies indicating depression burden negatively impacts substance use outcome and extends these findings to real-world practice settings. Findings underscore the importance of addressing depression severity in youth with concurrent substance use problems, even in the context of comorbid symptoms of anxiety, delinquency, and aggression. PMID- 23368838 TI - Submuscular submammarian internal pulse generator implantation in a patient with Tourette's syndrome and obsessive compulsive behavior. PMID- 23368839 TI - The contribution of the nonhomologous region of Prs1 to the maintenance of cell wall integrity and cell viability. AB - The gene products of the five-membered PRS gene family in Saccharomyces cerevisiae have been shown to exist as three minimal functional entities, Prs1/Prs3, Prs2/Prs5, and Prs4/Prs5, each capable of supporting cell viability. The Prs1/Prs3 heterodimer can be regarded as the most important because its loss causes temperature sensitivity. It has been shown that the GFP signal generated by an integrated GFP-Prs1 construct is lost in the absence of Prs3. In addition to interacting with Prs3, Prs1 also interacts with Slt2, the MAPK of the cell wall integrity (CWI) pathway. Lack of the nonhomologous region (NHR1-1) located centrally in Prs1 abolished the temperature-induced increase in Rlm1 expression. Furthermore, in vitro point mutations generated in PRS1 corresponding to missense mutations associated with human neuropathies or in the divalent cation and/or 5 phosphoribosyl-1(alpha)-pyrophosphate binding sites also display increased Rlm1 expression at 30 degrees C and 37 degrees C and most give rise to caffeine sensitivity. Human PRPS1 cDNA cannot rescue the synthetic lethality of a prs1Delta prs5Delta strain because it lacks sequences corresponding to NHR1-1 of yeast Prs1. The correlation between caffeine sensitivity and increased basal expression of Rlm1 in the altered versions of PRS1 can be extended to their inability to rescue the synthetic lethality of a prs1Delta prs5Delta strain implying that impaired CWI may contribute to the observed loss of viability. PMID- 23368840 TI - N-bromosuccinimide/1,8-diazabicyclo[5.4.1]undec-7-ene combination: beta-amination of chalcones via a tandem bromoamination/debromination sequence. AB - A one-pot cascade transformation of chalcones into beta-imidoketones has been developed, in which NBS provides both electrophilic bromine and nucleophilic nitrogen sources, and DBU functions as a nucleophilic reagent to activate NBS to be a more electrophilic bromine species and to further remove the bromine of alpha-bromoketones. The whole process involves tandem bromoamination and debromination, which represents a unique example of preparing beta-aminoketones by the reaction of chalcones with the NBS/DBU combination. PMID- 23368841 TI - Effects of pulses of elevated carbon dioxide concentration on stomatal conductance and photosynthesis in wheat and rice. AB - Systems for exposing plants to elevated concentrations of CO2 may expose plants to pulses of CO2 concentrations considerably above the control set point. The importance of such pulses to plant function is unknown. Single leaves of wheat (Triticum aestivum cv Choptank) and rice (Oryza sativa cv Akitakomachi) were exposed for 30 minutes to pulses of elevated CO2 similar to the frequency, duration and magnitude of pulses observed in free-air CO2 enrichment systems. Stomatal conductance decreased within a few minutes of exposure to once per minute pulses of high CO2 of all the durations tested, in both species. Both species had 20-35% lower stomatal conductance for at least 30 min after the termination of the pulses. After the pulses had stopped, in all cases photosynthesis was below the values expected for the observed substomatal CO2 concentration, which suggests that either patchy stomatal closure occurred or that photosynthesis was directly inhibited. It was also found that a single, 2 s pulse of elevated CO2 concentration reaching a maximum of 1000 umol mol-1 decreased stomatal conductance in both species. On the basis of these results, it is probable that plants in many CO2 enrichment systems have lower photosynthesis and stomatal conductance than would plants exposed to the same mean CO2 concentration but without pulses of higher concentration. PMID- 23368843 TI - TWIST1, A novel androgen-regulated gene, is a target for NKX3-1 in prostate cancer cells. AB - BACKGROUND: TWIST1 plays a key role in EMT-mediated tumor invasion and metastasis. Since bone metastasis is a hallmark of advanced prostate cancer and is detected in at least 85% of patients who die of this disease, it is of great importance to understand the regulation of the cellular signaling pathways involved in the metastatic process. METHODS: Prostatic cell lines were analyzed using real time RT-PCR, chromatin immunoprecipitations (ChIP) and transfection of siRNA's and reporter constructs. RESULTS: We report in this paper that TWIST1 is an androgen-regulated gene under tight regulation of NKX3-1. Androgens repress the expression of TWIST1 via NKX3-1, which is a prostate-specific tumor suppressor that is down-regulated in the majority of metastatic prostate tumors. We show that NKX3-1 binds to the TWIST1 promoter and that NKX3-1 over-expression reduces the activity of a TWIST1 promoter reporter construct, whereas NKX3-1 siRNA up-regulates endogenous TWIST1 mRNA in prostate cancer cells. CONCLUSION: Our finding that NKX3-1 represses TWIST1 expression emphasizes the functional importance of NKX3-1 in regulating TWIST1 expression during prostate cancer progression to metastatic disease. PMID- 23368842 TI - The effect of fentanyl on the end-tidal sevoflurane concentration needed to prevent motor movement in dogs. AB - OBJECTIVE: The objectives of this study were to determine the effects of fentanyl on the end-tidal concentration of sevoflurane needed to prevent motor movement (MACNM ) in response to noxious stimulation, and to evaluate if acute tolerance develops. STUDY DESIGN: Randomized cross-over experimental study. ANIMALS: Six healthy, adult (2-3 years old), intact male, mixed-breed dogs weighing 16.2 +/- 1.1 kg. METHODS: Six dogs were randomly assigned to receive one of three separate treatments over a 3 week period. After baseline sevoflurane MACNM (MACNM-B) determination, fentanyl treatments (T) were administered as a loading dose (Ld) and constant rate infusion (CRI) as follows: T1-Ld of 7.5 MUg kg(-1) and CRI at 3 MUg kg(-1) hour(-1); T2-Ld of 15 MUg kg(-1) and CRI at 6.0 MUg kg (-1) hour(-1); T3-Ld of 30 MUg kg(-1) and CRI at 12 MUg kg(-1) hour(-1). The MACNM was defined as the minimum end-tidal sevoflurane concentration preventing motor movement. The first post-treatment MACNM (MACNM-I) determination was initiated 90 minutes after the start of the CRI, and a second MACNM (MACNM - II) determination was initiated 3 hours after MACNM-I was established. RESULTS: The overall least square mean MACNM-B for all groups was 2.66%. All treatments decreased (p < 0.05) MACNM, and the decrease from baseline was 22%, 35% and 41% for T1, T2 and T3, respectively. Percentage change in T1 differed (p < 0.05) from T2 and T3; however, T2 did not differ from T3. MACNM-I was not significantly different from MACNM-II within treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl doses in the range of 3 12 MUg kg(-1) hour(-1) significantly decreased the sevoflurane MACNM. Clinically significant tolerance to fentanyl did not occur under the study conditions. PMID- 23368844 TI - Role of antisecretory agents for gastric endoscopic submucosal dissection. AB - Gastric endoscopic submucosal dissection (ESD) causes artificial gastric ulcers and there is no consensus regarding the optimal perioperative management in terms of prevention of intra- or postoperative bleeding and promotion of healing. Traditionally, 8-week administration of proton pump inhibitors (PPI) and mucosal protective agents were used in the same way as for peptic ulcer management. However, recent studies have revealed that prior use of PPI might reduce intraoperative bleeding or early-phase postoperative bleeding, and combination of histamine-2 receptor antagonist (H2RA), and second-look endoscopy might have a similar effect on postoperative bleeding to PPI. Additionally, the advantage of PPI over H2RA is not proven and the optimal duration of PPI may be shortened until 2 weeks when the deteriorating factors for ESD ulcer are excluded. Furthermore, mucosal protective agents may facilitate ulcer healing. Further studies are needed to determine the optimal treatment protocol before and after ESD for both prevention of bleeding complication and promotion of ulcer healing, by using available antisecretory agents and mucosal protective agents. PMID- 23368845 TI - [2Fe-2S] proteins in Chlorosomes: CsmI and CsmJ participate in light-dependent control of energy transfer in Chlorosomes of Chlorobaculum tepidum. AB - Chlorosomes of Chlorobaculum tepidum are formed from stacks of syn-anti coordinated bacteriochlorophyll c dimers, which form a suprastructure comprised of coaxial nanotubes and are surrounded by a glycolipid monolayer envelope containing 10 proteins. Three of these proteins, CsmI, CsmJ, and CsmX, have sequences very similar in their N-terminal domains to those of [2Fe-2S] ferredoxins of the adrenodoxin/putidaredoxin subfamily. The roles of these proteins in chlorosomes were studied in single-, double-, and triple-mutant strains. In each mutant, only the protein(s) corresponding to the mutated gene(s) was missing, and the amounts of other chlorosome proteins did not vary significantly. Electrophoretic analyses and immunoblotting showed that CsmX was much less abundant than CsmI or CsmJ. The growth rates and the pigment and isoprenoid quinone contents of isolated chlorosomes of the mutants were similar to wild-type values. Quenching and recovery of energy transfer in isolated chlorosomes and intact cells were studied by measuring fluorescence emission after exposure to or removal of oxygen. Oxygen-induced activation of the quencher in isolated chlorosomes or in intact cells was largely independent of CsmI and CsmJ. This may be because oxygen can diffuse across the chlorosome envelope easily and directly reacts with the quencher. However, CsmI and CsmJ were required to restore energy transfer fully after isolated chlorosomes were exposed to oxygen. Studies with intact cells suggested that cells contain both light dependent and light-independent pathways for reducing the quenching species in chlorosomes and that CsmI and CsmJ are components of a light-dependent pathway. PMID- 23368846 TI - Requirements for the import of neisserial Omp85 into the outer membrane of human mitochondria. AB - beta-Barrel proteins are present only in the outer membranes of Gram-negative bacteria, chloroplasts and mitochondria. Fungal mitochondria were shown to readily import and assemble bacterial beta-barrel proteins, but human mitochondria exhibit certain selectivity. Whereas enterobacterial beta-barrel proteins are not imported, neisserial ones are. Of those, solely neisserial Omp85 is integrated into the outer membrane of mitochondria. In this study, we wanted to identify the signal that targets neisserial beta-barrel proteins to mitochondria. We exchanged parts of neisserial Omp85 and PorB with their Escherichia coli homologues BamA and OmpC. For PorB, we could show that its C terminal quarter can direct OmpC to mitochondria. In the case of Omp85, we could identify several amino acids of the C-terminal beta-sorting signal as crucial for mitochondrial targeting. Additionally, we found that at least two POTRA (polypeptide-transport associated) domains and not only the beta-sorting signal of Omp85 are needed for its membrane integration and function in human mitochondria. We conclude that the signal that directs neisserial beta-barrel proteins to mitochondria is not conserved between these proteins. Furthermore, a linear mitochondrial targeting signal probably does not exist. It is possible that the secondary structure of beta-barrel proteins plays a role in directing these proteins to mitochondria. PMID- 23368847 TI - Collaboration-for whose benefit? PMID- 23368848 TI - Adapting team awareness and replication. PMID- 23368849 TI - Teaching facilitation of patient choice at the end of life. PMID- 23368850 TI - "People like numbers": a descriptive study of cognitive assessment methods in clinical practice for Aboriginal Australians in the Northern Territory. AB - BACKGROUND: Achieving culturally fair assessments of cognitive functioning for Aboriginal people is difficult due to a scarcity of appropriately validated tools for use with this group. As a result, some Aboriginal people with cognitive impairments may lack fair and equitable access to services. The objective of this study was to examine current clinical practice in the Northern Territory regarding cognitive assessment for Aboriginal people thereby providing some guidance for clinicians new to this practice setting. METHOD: Qualitative enquiry was used to describe practice context, reasons for assessment, and current practices in assessing cognition for Aboriginal Australians. Semi-structured interviews were conducted with 22 clinicians working with Aboriginal clients in central and northern Australia. Results pertaining to assessment methods are reported. RESULTS: A range of standardised tests were utilised with little consistency across clinical practice. Nevertheless, it was recognised that such tests bear severe limitations, requiring some modification and significant caution in their interpretation. Clinicians relied heavily on informal assessment or observations, contextual information and clinical judgement. CONCLUSIONS: Cognitive tests developed specifically for Aboriginal people are urgently needed. In the absence of appropriate, validated tests, clinicians have relied on and modified a range of standardised and informal assessments, whilst recognising the severe limitations of these. Past clinical training has not prepared clinicians adequately for assessing Aboriginal clients, and experience and clinical judgment were considered crucial for fair interpretation of test scores. Interpretation guidelines may assist inexperienced clinicians to consider whether they are achieving fair assessments of cognition for Aboriginal clients. PMID- 23368851 TI - Cognitive function in first episode major depressive disorder: poor inhibition and semantic fluency performance. AB - INTRODUCTION: Executive Functions (EF) has been documented to be impaired in patients with recurrent Major Depressive Disorder (MDD) in several studies. Longitudinal studies have suggested that these impairments may be a result of several episodes of depression or they may represent stable traits in this patient group. However, few studies have addressed these issues and investigated cognitive functioning with a particular focus on EF in patients who experience MDD for the first time. METHODS: In the present study, the executive functions of inhibition, verbal fluency, mental flexibility, and planning and problem solving were investigated in a group of patients diagnosed with first episode MDD. Thirty patients and 30 control subjects were included in the study. RESULTS: The patient group performed significantly more poorly in the cognitive functions of inhibition and semantic fluency. In addition, the patient group showed a reduced speed of mental processing on some of the measures. However, the results showed that reduced processing speed alone could not account for the poor performance in inhibition and semantic fluency. There were no differences between the two groups in the other measures of EF, indicating that functioning of mental flexibility, phonemic fluency, planning, and problem solving was intact in the patient group. CONCLUSIONS: The results show that impaired inhibition and semantic fluency are present early in the course of MDD. The present findings indicate that poor inhibition and performance in semantic fluency may represent stable traits in MDD, independent of symptom severity and the number of depressive episodes. PMID- 23368852 TI - Vitamin D deficiency is associated with greater tumor size and poorer outcome in Merkel cell carcinoma patients. AB - BACKGROUND: Merkel cell polyomavirus has been recognized to be associated with Merkel cell carcinoma (MCC), but the evolution of this cancer probably depends on various factors. Vitamin D deficiency, defined by serum 25-hydroxyvitamin D levels <50 nmol/L, seems to influence cancer behavior and progression, but has never been assessed in MCC patients. OBJECTIVES: First, to evaluate whether vitamin D deficiency was associated with tumor characteristics and prognosis in a cohort of MCC patients. Second, to assess expression of the vitamin D receptor (VDR) in MCC tumors. METHODS: Clinical findings, Merkel cell polyomavirus markers and vitamin D status were assessed in a cohort of French MCC patients. The study was limited to the 89 patients for whom the serum sample had been collected within 3 years after the diagnosis of MCC. Correlation between vitamin D deficiency and MCC characteristics and outcome were determined in regression analyses. VDR expression in MCC tumours was assessed by immunohistochemistry. RESULTS: Vitamin D deficiency was noted in 65.1% of the patients and was independently associated with greater tumor size at diagnosis (P = 0.006) and with metastasis recurrence (HR, 2.89; 95% CI, 1.03 to 8.13; P = 0.043), but not with death from MCC, although there was a trend (HR, 5.28; 95% CI, 0.75 to 36.96; P = 0.093). VDR was found to be strongly expressed in all 28 MCC tumor specimens investigated. CONCLUSION: The association between vitamin D deficiency and MCC characteristics and outcome, together with detection of the VDR in MCC cells, suggest that vitamin D could influence the biology of MCC. PMID- 23368853 TI - Hydrogenated ZnO core-shell nanocables for flexible supercapacitors and self powered systems. AB - Although MnO2 is a promising material for supercapacitors (SCs) due to its excellent electrochemical performance and natural abundance, its wide application is limited by poor electrical conductivity. Inspired by our results that the electrochemical activity and electrical conductivity of ZnO nanowires were greatly improved after hydrogenation, we designed and fabricated hydrogenated single-crystal ZnO@amorphous ZnO-doped MnO2 core-shell nanocables (HZM) on carbon cloth as SC electrodes, showing excellent performance such as areal capacitance of 138.7 mF/cm(2) and specific capacitance of 1260.9 F/g. Highly flexible all solid-state SCs were subsequently assembled with these novel HZM electrodes using polyvinyl alcohol/LiCl electrolyte. The working devices achieved very high total areal capacitance of 26 mF/cm(2) and retained 87.5% of the original capacitance even after 10 000 charge/discharge cycles. An integrated power pack incorporating series-wound SCs and dye-sensitized solar cells was demonstrated for stand-alone self-powered systems. PMID- 23368855 TI - Role of Napsin A and TTF1 as a diagnostic marker for lung adenocarcinoma. PMID- 23368854 TI - Warning for unprincipled colorectal endoscopic submucosal dissection: accurate diagnosis and reasonable treatment strategy. AB - Piecemeal endoscopic mucosal resection (EMR) is generally indicated for laterally spreading tumors (LST) >2 cm in diameter. However, the segmentation of adenomatous parts does not affect the histopathological diagnosis and completeness of cure. Thus, possible indications for piecemeal EMR are both adenomatous homogenous-type granular-type LST (LST-G) and LST-G as carcinoma in adenoma without segmentalizing the carcinomatous part. Diagnosis of the pit pattern using magnifying endoscopy is essential for determining the correct treatment and setting segmentation borders. In contrast, endoscopic submucosal dissection (ESD) is indicated for lesions requiring endoscopic en bloc excision, as it is difficult to use the snare technique for en bloc excisions such as in non-granular-type LST (LST-NG), especially for the pseudodepressed type, tumors with a type VI pit pattern, shallow invasive submucosal carcinoma, largedepressed tumors and large elevated lesions, which are often malignant (e.g. nodular mixed type LST-G). Other lesions, such as intramucosal tumor accompanied by submucosal fibrosis, induced by biopsy or peristalsis of the lesion; sporadic localized tumors that occur due to chronic inflammation, including ulcerative colitis; and local residual early carcinoma after endoscopic treatment, are also indications for ESD. In clinical practice, an efficient endoscopic treatment with segregation of ESD from piecemeal EMR should be carried out after a comprehensive evaluation of the completeness of cure, safety, clinical simplicity, and cost-benefit, based on an accurate preoperative diagnosis. PMID- 23368856 TI - Validation of KRAS testing for anti-EGFR therapeutic decisions for patients with metastatic colorectal carcinoma. PMID- 23368857 TI - College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference on good laboratory practices in gynecologic cytology: background, rationale, and organization. AB - CONTEXT: Gynecologic cytopathology is a heavily regulated field, with Clinical Laboratory Improvement Amendments of 1988 mandating the collection of many quality metrics. There is a lack of consensus regarding methods to collect, monitor, and benchmark these data and how these data should be used in a quality assurance program. Furthermore, the introduction of human papilloma virus testing and proficiency testing has provided more data to monitor. OBJECTIVE: To determine good laboratory practices in quality assurance of gynecologic cytopathology. DATA SOURCES: Data were collected through a written survey consisting of 98 questions submitted to 1245 Clinical Laboratory Improvement Amendments-licensed or Department of Defense laboratories. There were 541 usable responses. Additional input was sought through a Web posting of results and questions on the College of American Pathologists Web site. Four senior authors who authored the survey and 28 cytopathologists and cytotechnologists were assigned to 5 working groups to analyze data and present statements on good laboratory practices in gynecologic cytopathology at the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference. Ninety-eight attendees at the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference discussed and voted on good laboratory practice statements to obtain consensus. CONCLUSIONS: This paper describes the rationale, background, process, and strengths and limitations of a series of papers that summarize good laboratory practice statements in quality assurance in gynecologic cytopathology. PMID- 23368858 TI - The role of monitoring interpretive rates, concordance between cytotechnologist and pathologist interpretations before sign-out, and turnaround time in gynecologic cytology quality assurance: findings from the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference working group 1. AB - CONTEXT: The College of American Pathologists (CAP) conducted a national survey of gynecologic cytology quality assurance (QA) practices. Experts in gynecologic cytology were asked to join 5 working groups that studied the survey data on different aspects of QA. Evaluating the survey data and follow-up questions online, together with a review of pertinent literature, the working groups developed a series of preliminary statements on good laboratory practices in cytology QA. These were presented at a consensus conference and electronic voting occurred. OBJECTIVE: To evaluate a set of QA monitors in gynecologic cytology. Working group 1 evaluated (1) monitoring interpretive rate categories for Papanicolaou tests (Pap tests), (2) concordance of cytotechnologist and pathologist interpretations before sign-out, and (3) turnaround time for Pap tests. DATA SOURCES: The statements are based on a survey of gynecologic cytology QA practice patterns and of opinions from working group members and consensus conference attendees. CONCLUSIONS: The outcomes of this process demonstrate the current state of practice patterns in gynecologic cytology QA. Monitoring interpretive rates for all Bethesda System categories is potentially useful, and it is most useful to monitor interpretive rates for cytotechnologists individually and in comparison to the entire laboratory. Laboratories need to determine what level of discrepancy between cytotechnologist and pathologist interpretations of Pap tests is important to track. Laboratories should consider formalizing procedures and policies to adjudicate such discrepant interpretations. Turnaround time should be monitored in gynecologic cytology, but individual laboratories should determine how to measure and use turnaround time internally. PMID- 23368859 TI - Prospective and retrospective review of gynecologic cytopathology: findings from the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference working group 2. AB - CONTEXT: Two quality metrics for gynecologic cytology are the subject of this review: "prospective rescreening" and "retrospective rescreening." OBJECTIVE: To offer consensus best practice approaches based on the College of American Pathologists' laboratory-based survey funded by the Centers for Disease Control and Prevention. DESIGN: The College of American Pathologists submitted a paper based survey to 1245 laboratories. After review of initial results, follow-up Web based survey results, and a literature review, consensus best practice statements were presented at a national consensus conference. These statements were discussed and voted upon by conference participants. Results.-A total of 541 laboratories responded to survey questions about prospective and retrospective rescreening. Most laboratories (>85%) prospectively rescreen more than 10% of Pap tests interpreted as negative for intraepithelial lesion or malignancy. Most (72%) report inclusion of less than 20% high-risk cases. Most laboratories use multiple measures to define "high risk." Most laboratories (96.2%) retrospectively rescreen Pap tests from the preceding 5 years only. In most laboratories (71.4%) only Pap test results with high-grade squamous intraepithelial lesion or worse prompt retrospective review. CONCLUSIONS: The number of Pap tests from high-risk patients should be maximized in prospective and retrospective rescreening. Unsatisfactory Pap tests should also be included. All readily identifiable high-risk human papillomavirus-positive cases with an interpretation of negative for intraepithelial lesion or malignancy should be prospectively rescreened. Cervical biopsy results with high-grade cervical intraepithelial neoplasia or worse (CIN 2+) should trigger retrospective rescreening. Regular feedback should be provided to cytotechnologists and cytopathologists. Upgraded diagnoses from negative for intraepithelial lesion or malignancy to atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, should be monitored. PMID- 23368860 TI - The role of proficiency testing in ensuring quality: findings from the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference working group 3. AB - CONTEXT: Implementation of proficiency testing for gynecologic cytology was delayed 20 years because of challenges addressing the subjective nature of cytologic interpretation and replicating normal working conditions. Concern remains regarding test scoring, slide validation, test environment, and other issues. How these test results are, or should be, used in quality management has never been explored. OBJECTIVE: To provide information on good laboratory practices for gynecologic cytology proficiency testing based on findings from the College of American Pathologists' survey-based project funded by the Centers for Disease Control and Prevention. DATA SOURCES: An expert working group evaluated results from a Web-based, national laboratory survey plus responses from follow up questions and findings from the literature. The group created statements on good laboratory practices pertinent to proficiency testing and its role in quality management, which were discussed and voted on at a consensus conference. CONCLUSIONS: Two-thirds of laboratories report having an individual with an unsuccessful proficiency testing score. More than 90% did not initiate any remedial action for 1 or 2 unsuccessful tests; 84% of laboratories reported they actively monitored results from proficiency testing, but most laboratories did not initiate any remedial action for cytotechnologists (81.4%; 376 of 462) or pathologists (87.7%; 405 of 462) who passed a proficiency test but who did not score 100%. Proficiency testing pass-fail rates should be monitored globally for the laboratory and for each individual. Proficiency testing slides should be prescreened by cytotechnologists for pathologists who are not primary screeners. Remedial action should not be required for a passed, but imperfect, test. No remedial action is required for an unsuccessful, first proficiency test result before retesting. PMID- 23368861 TI - General quality practices in gynecologic cytopathology: findings from the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference working group 3. AB - CONTEXT: There are many long-standing quality monitors for cytopathology laboratories and their cytotechnologists and pathologists. Many of these monitors are based on tradition and empirical good intentions. There is no established standard as to how results of these monitors should be used in a quality assurance program. OBJECTIVE: To review practices that are typically part of a general quality program in cytopathology laboratories and to provide statements regarding good laboratory practices that laboratories may find useful in a quality assurance program in their own setting. DATA SOURCES: An expert working group evaluated results from a national laboratory survey, responses from follow up questions posted on a Web site, and findings from the literature. The group created statements on good laboratory practices related to general quality practices and quality assurance in gynecologic cytopathology. These were discussed and voted on at a consensus conference. CONCLUSIONS: Laboratories follow many metrics. Most laboratories facilitate comparison of individual metrics against the laboratory's metrics: 81.1% for cytotechnologists and 59.6% for pathologists. The majority of laboratories facilitate comparison of individual cytotechnologist metrics with other cytotechnologists, but less frequently metrics from pathologists with other individuals. The most common methods to recognize variance in performance in individuals were by identifying outliers from the data or by user-defined action limits. The most common method to address variance was an attempt to identify the cause of the variance and conduct a focused review. Quality metrics should be monitored for the laboratory as a whole and in selected cases for both individual pathologists and cytotechnologists. Results should be shared with individuals, and newly hired primary screeners should be monitored. Reviewing selected cases is a useful quality tool. Low-volume methodologies, such as conventional Papanicolaou tests, should have additional oversight. PMID- 23368862 TI - Quality improvement opportunities in gynecologic cytologic-histologic correlations: findings from the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference working group 4. AB - CONTEXT: Cytopathology experts, interested stakeholders, and representatives from the College of American Pathologists, the Centers for Disease Control and Prevention, the American Society of Cytopathology, the Papanicolaou Society of Cytopathology, the American Society for Clinical Pathology, and the American Society of Cytotechnology convened the Gynecologic Cytopathology Quality Consensus Conference to present preliminary consensus statements developed by working groups, including the Cytologic-Histologic Correlations Working Group 4, using results from surveys and literature review. Conference participants voted on statements, suggested changes where consensus was not achieved, and voted on proposed changes. OBJECTIVES: To document existing practices in gynecologic cytologic-histologic correlation, to develop consensus statements on appropriate practices, to explore standardization, and to suggest improvement in these practices. DATA SOURCES: The material is based on survey results from 546 US laboratories, review of the literature from 1988 to 2011, and the College of American Pathologists Web site for consensus comments and additional survey questions. CONCLUSIONS: Cytologic-histologic correlations can be performed retrospectively, during initial case review, or both. At minimum, all available slides should be reviewed for a high-grade squamous intraepithelial lesion Papanicolaou test with negative biopsies. The preferred monitor for correlations is the positive predictive value of a Papanicolaou test. Laboratories should design cytologic-histologic correlation programs to explore existing or perceived quality deficiencies. PMID- 23368864 TI - Utilization of stat test priority in the clinical laboratory: a College of American Pathologists q-probes study of 52 institutions. AB - CONTEXT: Utilization of stat testing priority is a balance between safe, efficient patient management and resource expenditure. OBJECTIVE: To determine the rate of stat testing, compare rates among institutions, and determine the distribution of turnaround time expectations for different turnaround time priorities. DESIGN: During a 7-day period, participants prospectively determined the total number of chemistry, hematology, and coagulation billable tests from inpatients and emergency department patients. Among these, the total numbers of billable tests performed stat were identified. Laboratories also reported the levels of test priority they offered and turnaround expectations for each level of test priority. RESULTS: Fifty institutions submitted data for the study, with 2 additional participants submitting partial results. Participants identified 639 589 chemistry, hematology, and coagulation billable tests, with 229 896 (35.9%) performed stat. The stat rate varied from 21.3% at the 10th percentile to 55.4% at the 90th percentile, with a median of 37.0% of participants' tests performed stat. Laboratories include a mean of 206 tests in chemistry, hematology, and coagulation test menus, with 67% of these tests offered stat. The fraction of the test menu offered stat varied from 29.0% at the 10th percentile to 97.8% at the 90th percentile, with a median of 73.3% of tests on the menu offered stat. The most common number of testing priorities offered by participating laboratories was 3 (44.2%). CONCLUSIONS: Among the 52 participating laboratories, the median stat testing rate was 37.0% and a median 73.3% of the test menu was offered stat. PMID- 23368863 TI - Monitoring and ordering practices for human papillomavirus in cervical cytology: findings from the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference working group 5. AB - CONTEXT: The association of certain types of human papillomavirus with cervical carcinoma is well established. Human papillomavirus testing is now routinely used to screen for cervical carcinoma and precursor lesions of the cervix (cotesting and reflex testing) and these results are considered in patient triage and management. OBJECTIVE: To provide information about current laboratory practices in human papillomavirus testing and consensus best practice statements based on results from the College of American Pathologists' laboratory-based survey funded by the Centers for Disease Control and Prevention. DESIGN: The College of American Pathologists submitted a paper-based survey to 1245 laboratories in the United States. After review of the initial results, follow-up Web-based survey results, and a literature review by an expert working group, consensus best practice statements were constructed by working group members for presentation at a national consensus conference. These best practice statements were discussed and then voted upon by conference participants. RESULTS: A total of 525 laboratories responded to survey questions about human papillomavirus ordering and monitoring practices, whereas 546 responded to the overall survey. In most laboratories (87.6%), the high-risk human papillomavirus test is ordered as a reflex test by providers. A minority of laboratories (11.9%) routinely bundle low and high-risk human papillomavirus tests. Most laboratories (84.4%) do not limit testing in patients with atypical squamous cells to women older than 20 years. More than half of laboratories (53.3%) monitor human papillomavirus positive rates in Papanicolaou tests with atypical squamous cells of undetermined significance. CONCLUSIONS: It is not appropriate for laboratories to offer low risk human papillomavirus testing for any clinical circumstance in gynecologic cytology. Laboratories should not order human papillomavirus testing to resolve diagnostic discrepancies. It is a valuable broad measure of laboratory quality to monitor the human papillomavirus-positive rates in Papanicolaou tests with atypical squamous cells. PMID- 23368865 TI - Accounting for the professional work of pathologists performing autopsies. AB - CONTEXT: With an increasing trend toward fee-code-based methods of measuring the clinical professional productivity of pathologists, those pathologists whose clinical activities include the performance of autopsies have been disadvantaged by the lack of generally accepted workload equivalents for autopsy performance and supervision. OBJECTIVE: To develop recommended benchmarks to account for this important and often overlooked professional activity. DESIGN: Based on the professional experience of members of the Autopsy Committee of the College of American Pathologists, a survey of autopsy pathologists, and the limited additional material available in the literature, we developed recommended workload equivalents for the professional work associated with performing an autopsy, which we elected to express as multiples of established Current Procedural Terminology codes. RESULTS: As represented in Table 3 , we recommend that the professional work associated with a full adult autopsy be equivalent to 5.5 * 88309-26. Additional professional credit of 1.5 * 88309-26 should be added for evaluation of the brain and for a detailed clinical-pathologic discussion. The corresponding value for a fetal/neonatal autopsy is 4.0 * 88309-26. CONCLUSION: Although we recognize that autopsy practices vary significantly from institution to institution, it is hoped that our proposed guidelines will be a valuable starting point that individual practices can then adapt, taking into account the specifics of their practice environment. PMID- 23368866 TI - Connective tissue growth factor immunohistochemical expression is associated with gallbladder cancer progression. AB - CONTEXT: Gallbladder cancer (GBC) is an aggressive neoplasia associated with late diagnosis, unsatisfactory treatment, and poor prognosis. Molecular mechanisms involved in GBC pathogenesis remain poorly understood. Connective tissue growth factor (CTGF) is thought to play a role in the pathologic processes and is overexpressed in several human cancers, including GBC. No information is available about CTGF expression in early stages of gallbladder carcinogenesis. Objective.- To evaluate the expression level of CTGF in benign and malignant lesions of gallbladder and its correlation with clinicopathologic features and GBC prognosis. DESIGN: Connective tissue growth factor protein was examined by immunohistochemistry on tissue microarrays containing tissue samples of chronic cholecystitis (n = 51), dysplasia (n = 15), and GBC (n = 169). The samples were scored according to intensity of staining as low/absent and high CTGF expressers. Statistical analysis was performed using the chi(2) test or Fisher exact probability test with a significance level of P < .05. Survival analysis was assessed by the Kaplan-Meier method and the log-rank test. RESULTS: Connective tissue growth factor expression showed a progressive increase from chronic cholecystitis to dysplasia and then to early and advanced carcinoma. Immunohistochemical expression (score >=2) was significantly higher in advanced tumors, in comparison with chronic cholecystitis (P < .001) and dysplasia (P = .03). High levels of CTGF expression correlated with better survival (P = .04). CONCLUSIONS: Our results suggest a role for CTGF in GBC progression and a positive association with better prognosis. In addition, they underscore the importance of considering the involvement of inflammation on GBC development. PMID- 23368867 TI - Low-grade clear cell renal cell carcinoma mimicking hemangioma of the kidney: a series of 4 cases. AB - CONTEXT: Clear cell renal cell carcinoma (CCRCC) has a rich, sinusoid-like vascularity frequently used as a diagnostic criterion. CCRCC with predominantly vascular architecture has not been described. OBJECTIVE: To describe 4 unusual CCRCC cases, primarily presenting with hemangioma-like morphologic pattern. DESIGN: Clinicopathologic and selected immunohistochemical analysis of 4 cases of CCRCC mimicking hemangioma. RESULTS: Cases were seen in 1 woman and 3 men (average age, 48.8 years; range, 40-66 years). Grossly, tumors were red-brown (3 of 4) with scant bright-yellow foci in 1. The average tumor size was 4 cm (range, 2.5-5.5 cm). Microscopically, all were composed of varying proportions of a rich, arborizing, sinusoid-like vasculature with focal hobnail appearance of endothelial cells. Entrapment of renal tubules between blood vessels was seen at the periphery of the tumors. This morphology was reminiscent of anastomosing hemangioma. Isolated tumor cells resembling lymphocytes with clear halos were sparsely interspersed between vessels. Cytokeratin immunostain confirmed the diagnosis of CCRCC. CONCLUSION: Extensive sampling and immunohistochemical workup of what is deemed to be a benign vascular neoplasm of the kidney is needed to rule out the presence of individual carcinoma cells or small viable carcinoma cell clusters. PMID- 23368868 TI - Wolf isotopic response manifesting as postherpetic granuloma annulare: a case series. AB - CONTEXT: Wolf isotopic response has infrequently been reported in the literature, mainly as isolated case reports. OBJECTIVE: To aid in recognition of the occurrence of postherpetic granuloma annulare for accurate histologic interpretation of granulomatous dermatitides. DESIGN: We report 5 cases of patients with Wolf isotopic response manifesting as granuloma annulare, developing in a site of previous herpes zoster, and discuss the clinicopathologic findings. RESULTS: Previous infection with herpes zoster or herpes simplex virus was found in 5 of 5 cases reported. The differential diagnosis of a dermal lymphohistiocytic infiltrate with multinucleated giant cells includes postherpetic granuloma annulare. CONCLUSIONS: All cases of postherpetic Wolf isotopic response reported in this series revealed granuloma annulare, with a perineurovascular or perifollicular pattern of lymphohistiocytic infiltration including multinucleated giant cells, and occurred following herpes zoster or herpes simplex infection, although herpes viral infection was not always associated with a subsequent isotopic eruption. Awareness of this entity can aid in the clinicopathologic diagnosis of granuloma annulare occurring at the site of prior herpes viral infection. PMID- 23368869 TI - Diagnostic complexities of eosinophilia. AB - CONTEXT: The advent of molecular tools capable of subclassifying eosinophilia has changed the diagnostic and clinical approach to what was classically called hypereosinophilic syndrome. OBJECTIVES: To review the etiologies of eosinophilia and to describe the current diagnostic approach to this abnormality. DATA SOURCES: Literature review. CONCLUSION: Eosinophilia is a common, hematologic abnormality with diverse etiologies. The underlying causes can be broadly divided into reactive, clonal, and idiopathic. Classically, many cases of eosinophilia were grouped together into the umbrella category of hypereosinophilic syndrome, a clinical diagnosis of exclusion. In recent years, an improved mechanistic understanding of many eosinophilias has revolutionized the way these disorders are understood, diagnosed, and treated. As a result, specific diagnoses can now be assigned in many cases that were previously defined as hypereosinophilic syndrome. Most notably, chromosomal rearrangements, such as FIP1L1-PDGFRA fusions caused by internal deletions in chromosome 4, are now known to be associated with many chronic eosinophilic leukemias. When present, these specific molecular abnormalities predict response to directed therapies. Although an improved molecular understanding is revolutionizing the treatment of patients with rare causes of eosinophilia, it has also complicated the approach to evaluating and treating eosinophilia. Here, we review causes of eosinophilia and present a framework by which the practicing pathologist may approach this diagnostic dilemma. Finally, we consider recent cases as clinical examples of eosinophilia from a single institution, demonstrating the diversity of etiologies that must be considered. PMID- 23368870 TI - Approach to intraoperative consultation for donor liver biopsies. AB - CONTEXT: As demand for organs to treat end-stage liver disease increases, donor livers once deemed only marginally suitable for donation are being considered for transplantation. Pathologists are increasingly being asked to evaluate these livers for acceptability. This article provides guidelines for frozen section evaluation of livers for transplantation. OBJECTIVE: This article concentrates on the histopathologic features of transplant suitability with appropriate clinicopathologic correlation for the practicing pathologist. Recommendations for proper handling and sampling of tissue are discussed. Relative and absolute contraindications as well as artifacts and benign conditions are emphasized. DATA SOURCES: Sources include a compilation of the authors' experiences in academic and community liver transplantation centers. In addition, relevant medical literature was reviewed, as well as Web sites specializing in organ transplantation, such as Transplant Pathology Internet Services and the Organ Procurement and Transplantation Network. CONCLUSIONS: Malignancy and extensive necrosis in the liver are absolute contraindications to transplantation. Evaluation of macrosteatosis, fibrosis, hepatitis, and necrosis depends on the severity of disease and correlation with the clinical situation. Donor age of greater than 60 years does not preclude transplantation. Artifacts and benign conditions need to be understood to prevent wastage of precious organs and to ensure that an appropriate organ is provided for the recipient. PMID- 23368871 TI - Ovarian serous carcinoma associated with a distinct "corded and hyalinized" pattern. AB - The "corded and hyalinized" pattern, described in endometrioid carcinoma, has not been previously reported in association with serous carcinoma. We describe a unique case of serous neoplasm of low malignant potential with low-grade serous carcinoma combined with a distinct pattern of high-grade carcinoma characterized by cords of epithelioid and spindled cells enmeshed in a hyalinized, collagenous stroma. This pattern was the predominant architecture in the patient's recurrence and caused a diagnostic challenge, as the splenic recurrence was initially diagnosed as a second primary high-grade spindle cell neoplasm. Both ovarian and splenic tumors displayed positive immunohistochemical staining for cytokeratin 7, cytokeratin 8/18, estrogen receptor, and paired box gene 8 (PAX-8) in the conventional serous carcinoma and the corded and hyalinized component, confirming the diagnosis of recurrent carcinoma. The behavior in this unique case of serous carcinoma associated with a distinct corded and hyalinized pattern was more aggressive than low-grade serous carcinoma, but more favorable than malignant mixed mullerian tumor. PMID- 23368872 TI - Anaplastic large cell lymphoma: a potential pitfall in the differential diagnosis of melanoma. AB - The diagnosis of metastatic melanoma can be complicated by absent characteristic cytology, melanin, or antigen expression in a suspect tumor, putting the pathologist at risk for incorrectly diagnosing recurrent melanoma while missing a second malignancy. We report a 69-year-old man with a history of acral melanoma, metastatic to inguinal nodes, presenting with an ipsilateral thigh nodule. Histology showed a proliferation of pleomorphic cells in the dermis and subcutis, suspicious for melanoma. S100, Melan-A, and HMB-45 immunohistochemistry were negative. However, microphthalmia-associated transcription factor and CD117 labeled the neoplasm, prompting consideration of a late metastatic melanoma with loss of antigen expression. Subsequent immunolabeling for CD4, CD43, and CD30 and clonal T-cell gene rearrangements enabled the correct diagnosis of cutaneous anaplastic large cell lymphoma. This case illustrates a pitfall in evaluating tumors in patients with known metastatic melanoma, and emphasizes the need for broad-spectrum immunohistochemistry in cases that are not clear-cut. PMID- 23368873 TI - Microcystic/reticular schwannoma of the proximal sigmoid colon: case report with review of literature. AB - We report a case of microcystic/reticular schwannoma of the proximal sigmoid colon in a 61-year-old man. A 12-mm polyp was detected while the patient was undergoing screening for colorectal neoplasm. This rare variant of schwannoma was initially described in 2008 and shows a predilection for the visceral organs, predominantly the gastrointestinal tract. We also review 11 other reported cases of microcystic/reticular schwannomas in the gastrointestinal tract. Unlike conventional gastrointestinal schwannomas, which are more common in the stomach, this variant appears to be more common in the large intestine. Histologic examination of this polyp showed predominant lipoblast-like vacuolated cells within a myxoid stroma with focal spindle cell areas. Features suggestive of malignancy, like nuclear pleomorphism, mitosis, or necrosis, were absent. Immunohistochemistry for S100 protein showed strong nuclear and cytoplasmic positivity, whereas cytokeratin and CD117 stains were negative. It is important to entertain microcystic/reticular schwannoma in the differential diagnosis of a signet ring cell adenocarcinoma or a myxoid gastrointestinal stromal tumor, particularly on small biopsy specimens. PMID- 23368874 TI - Kaposi sarcoma. AB - Kaposi sarcoma (KS) is a low-grade vascular tumor associated with Kaposi sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8) infection. Kaposi sarcoma lesions predominantly present at mucocutaneous sites, but may involve all organs and anatomic locations. Recognized epidemiologic-clinical forms of KS include classic, African (endemic), AIDS-associated (epidemic), and iatrogenic KS. New clinical manifestations have been described, such as antiretroviral therapy related KS regression or flares. Kaposi sarcoma lesions evolve from early (patch stage) macules into plaques (plaque stage) that grow into larger nodules (tumor stage). Newer histologic variants include anaplastic, hyperkeratotic, lymphangioma-like, bullous, telangiectatic, ecchymotic, keloidal, pyogenic granuloma-like, micronodular, intravascular, glomeruloid and pigmented KS, as well as KS with sarcoidlike granulomas and KS with myoid nodules. Latency associated nuclear antigen (HHV8) is the most specific immunohistochemical marker available to help distinguish KS from its mimics. Since KS remains one of the most common AIDS-defining malignancies, it is important that pathologists be able to recognize KS and its contemporary manifestations. PMID- 23368875 TI - Molecular docking analysis of 2009-H1N1 and 2004-H5N1 influenza virus HLA-B*4405 restricted HA epitope candidates: implications for TCR cross-recognition and vaccine development. AB - BACKGROUND: The pandemic 2009-H1N1 influenza virus circulated in the human population and caused thousands deaths worldwide. Studies on pandemic influenza vaccines have shown that T cell recognition to conserved epitopes and cross reactive T cell responses are important when new strains emerge, especially in the absence of antibody cross-reactivity. In this work, using HLA-B*4405 and DM1 TCR structure model, we systematically generated high confidence conserved 2009 H1N1 T cell epitope candidates and investigated their potential cross-reactivity against H5N1 avian flu virus. RESULTS: Molecular docking analysis of differential DM1-TCR recognition of the 2009-H1N1 epitope candidates yielded a mosaic epitope (KEKMNTEFW) and potential H5N1 HA cross-reactive epitopes that could be applied as multivalent peptide towards influenza A vaccine development. Structural models of TCR cross-recognition between 2009-H1N1 and 2004-H5N1 revealed steric and topological effects of TCR contact residue mutations on TCR binding affinity. CONCLUSIONS: The results are novel with regard to HA epitopes and useful for developing possible vaccination strategies against the rapidly changing influenza viruses. Yet, the challenge of identifying epitope candidates that result in heterologous T cell immunity under natural influenza infection conditions can only be overcome if more structural data on the TCR repertoire become available. PMID- 23368876 TI - Accurate prediction of protein enzymatic class by N-to-1 Neural Networks. AB - We present a novel ab initio predictor of protein enzymatic class. The predictor can classify proteins, solely based on their sequences, into one of six classes extracted from the enzyme commission (EC) classification scheme and is trained on a large, curated database of over 6,000 non-redundant proteins which we have assembled in this work. The predictor is powered by an ensemble of N-to-1 Neural Network, a novel architecture which we have recently developed. N-to-1 Neural Networks operate on the full sequence and not on predefined features. All motifs of a predefined length (31 residues in this work) are considered and are compressed by an N-to-1 Neural Network into a feature vector which is automatically determined during training. We test our predictor in 10-fold cross validation and obtain state of the art results, with a 96% correct classification and 86% generalized correlation. All six classes are predicted with a specificity of at least 80% and false positive rates never exceeding 7%. We are currently investigating enhanced input encoding schemes which include structural information, and are analyzing trained networks to mine motifs that are most informative for the prediction, hence, likely, functionally relevant. PMID- 23368877 TI - pH control of the electrostatic binding of gold and iron oxide nanoparticles to tobacco mosaic virus. AB - We report the binding of nanoparticles (NPs) to wild type (unmodified) tobacco mosaic virus (TMV). The viruses are simply mixed with citrate-coated, negatively charged gold and iron oxide nanoparticles (IONPs) in acidic solution. This results in TMV decorated along its whole length by the respective particles. Such a decoration usually requires chemical modification or mutation of TMV (e.g., cysteine residues), but here we simply reduce TMV's natural negative charge by protonation. The particles are protonated to a much smaller extent. This charge based mechanism does not operate for neutral particles. PMID- 23368878 TI - Hb Plasencia [alpha125(H8)Leu->Arg (alpha2)] is a frequent cause of alpha+ thalassemia in the Portuguese population. AB - Hb Plasencia is a thalassemic hemoglobin (Hb) mutation caused by a leucine to arginine replacement at residue 125 of the alpha2-globin chain (HBA2:c.377T>G). This variant was first described in the heterozygous state in association with a very mild alpha-thalassemic phenotype in three members of a Spanish family from Plasencia, Western Spain. Reviewing the molecular characterization of 308 Portuguese individual suspected of having alpha-thalassemia (alpha-thal) we found Hb Plasencia to be the second most frequent mutation after the -alpha(3.7) deletion. PMID- 23368880 TI - Catalytic asymmetric [4 + 2] cycloadditions and Hosomi-Sakurai reactions of alpha alkylidene beta-keto imides. AB - Highly enantioselective catalytic asymmetric reactions of rationally designed alpha-alkylidene beta-keto imides are described. The [4 + 2] cycloadditions and Hosomi-Sakurai reactions of alpha-alkylidene beta-keto imides proceed with high enantioselectivity and yield. The [4 + 2] cycloadditions of the imides with various dienes afford products bearing an all-carbon quaternary stereogenic center at the ring junction. alpha-Alkylidene beta-keto imides should be useful for the enantioselective total synthesis of natural products and other catalytic asymmetric applications. PMID- 23368881 TI - Erythromelagia: a rare and hard-to-treat condition: a 9-year-old boy responsive to intravenous lidocaine and oral mexilitene. PMID- 23368879 TI - PuF, an antimetastatic and developmental signaling protein, interacts with the Alzheimer's amyloid-beta precursor protein via a tissue-specific proximal regulatory element (PRE). AB - BACKGROUND: Alzheimer's disease (AD) is intimately tied to amyloid-beta (Abeta) peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein (APP) account for a small proportion of AD cases, suggesting that regulation of the associated gene (APP) may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" (PRE), at -76/-47, from the +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay (EMSA) and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 (AP2), nm23 nucleoside diphosphate kinase/metastatic inhibitory protein (PuF), and specificity protein 1 (SP1). These sites crossed a known single nucleotide polymorphism (SNP). EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. PMID- 23368882 TI - Differential expression of calcium/calmodulin-regulated SlSRs in response to abiotic and biotic stresses in tomato fruit. AB - Calcium has been shown to enhance stress tolerance, maintain firmness and reduce decay in fruits. Previously we reported that seven tomato SlSRs encode calcium/calmodulin-regulated proteins, and that their expressions are developmentally regulated during fruit development and ripening, and are also responsive to ethylene. To study their expressions in response to stresses encountered during postharvest handling, tomato fruit at the mature-green stage was subjected to chilling and wounding injuries, infected with Botrytis cinerea and treated with salicylic acid or methyl jasmonate. Gene expression studies revealed that the seven SlSRs differentially respond to different stress signals. SlSR2 was the only gene upregulated by all the treatments. SlSR4 acted as a late pathogen-induced gene; it was upregulated by salicylic acid and methyl jasmonate, but downregulated by cold treatment. SlSR3L was cold- and wound-responsive and was also induced by salicylic acid. SlSR1 and SlSR1L were repressed by cold, wounding and pathogen infection, but were upregulated by salicylic acid and methyl jasmonate. Overall, results of these expression studies indicate that individual SlSRs have distinct roles in responses to the specific stress signals, and SlSRs may act as a coordinator(s) connecting calcium-mediated signaling with other stress signal transduction pathways during fruit ripening and storage. PMID- 23368883 TI - Laryngeal cleft repair: the anesthetic perspective. AB - INTRODUCTION: Laryngeal cleft is a rare congenital malformation that is being reported with increasing frequency. Diagnosis requires suspension microlaryngoscopy under general anesthesia during spontaneous respiration. Repair may be attempted by a minimally invasive endoscopic approach or open surgical repair. The authors report on their experience with total intravenous anesthesia (TIVA) and spontaneous ventilation without an endotracheal tube during suspension laryngoscopy and CO2 laser application for this specific surgical procedure. Of particular interest were the rate at which this technique failed and rescue techniques were employed and the ability to predict patients in whom this might occur. METHODS: Between July 2004 and September 2012, 110 endoscopic laryngeal cleft repairs were completed under TIVA with spontaneous ventilation without an endotracheal tube. Anesthetic induction was achieved by inhalation of sevoflurane and oxygen by mask or infusion of propofol at 300 mcg kg(-1) min(-1) and remifentanil at 0.05-1.0 mcg kg(-1) min. The vocal cords and surgical site were sprayed with up to 2 mg kg(-1) of 4% lidocaine. If the oxygen saturation decreased during the procedure or the patient became apneic, a rescue process utilizing jet ventilation or intermittent intubation was instituted. RESULTS: Ten (9.1%) of the 110 cases required rescue (95% confidence interval [CI]: 5.0 15.8%). The most prevalent comorbidities included reactive airway disease, chronic lung disease, failure to thrive, developmental delay, and an unrelated syndrome. Thirty-nine patients (36%) had reactive airway disease and twelve (11%) had chronic lung disease. Intraoperative complications included six cases requiring a brief, temporary period of intubation (5.5%) and four cases requiring a brief period of jet ventilation (3.6%). CONCLUSION: The technique of TIVA with spontaneous respirations without an endotracheal tube is a safe and effective technique for laryngeal cleft repair. Although the potential for intraoperative adverse events may be high, the actual rate was very low. The need to convert to other techniques is not significant although the children who did require brief periods of jet ventilation or intubation tended to have reactive airway disease or chronic lung disease. PMID- 23368884 TI - Potent and selective inhibition of histone deacetylase 6 (HDAC6) does not require a surface-binding motif. AB - Hydroxamic acids were designed, synthesized, and evaluated for their ability to selectively inhibit human histone deacetylase 6 (HDAC6). Several inhibitors, including compound 14 (BRD9757), exhibited excellent potency and selectivity despite the absence of a surface-binding motif. The binding of these highly efficient ligands for HDAC6 is rationalized via structure-activity relationships. These results demonstrate that high selectivity and potent inhibition of HDAC6 can be achieved through careful choice of linker element only. PMID- 23368885 TI - In vitro antimicrobial effects of two antihalitosis mouth rinses on oral pathogens and human tongue microbiota. AB - OBJECTIVES: The aim of the study was to compare the antimicrobial activity of a mouth rinse containing chlorhexidine and cetylpyridinium chloride (MR1) with a stannous fluoride-based mouth rinse (MR2) in vitro. MATERIALS AND METHODS: Samples of the tongues from 10 subjects with and 10 subjects without halitosis were inoculated on blood agar plates. The agar was perforated, and the cylindrical holes were filled either with mouth rinse MR1 or with mouth rinse MR2. After incubation, inhibition zones of the whole tongue microbiota and Fusobacterium nucleatum were measured. In addition, MR1 and MR2 were applied in a short interval killing test (SIKT) on four oral pathogens Porphyromonas gingivalis, Prevotella intermedia, F. nucleatum and Aggregatibacter actinomycetemcomitans. Total viable cell counts were made after two minutes of incubation with increasing concentrations of MR1 and MR2. RESULTS: MR1 showed a significantly higher in vitro antimicrobial activity against the whole tongue microbiota and F. nucleatum than MR2 in both groups of subjects. In the SIK test, MR1 showed a significantly greater killing capacity than MR2. The results show that a mouth rinse with low concentrations of chlorhexidine and 0.05% cetylpyridinium chloride appears to be more effective in inhibiting growth of the human tongue microbiota in vitro than a fluoride/stannous fluoride-containing mouth rinse. CONCLUSION: This in vitro observation supports the use of chlorhexidine and cetylpyridinium chloride in the treatment of oral halitosis. PMID- 23368886 TI - Reactivity of atomic oxygen radical anions bound to titania and zirconia nanoparticles in the gas phase: low-temperature oxidation of carbon monoxide. AB - Titanium and zirconium oxide cluster anions with dimensions up to nanosize are prepared by laser ablation and reacted with carbon monoxide in a fast low reactor. The cluster reactions are characterized by time-of-flight mass spectrometry and density functional theory calculations. The oxygen atom transfers from (TiO(2))(n)O(-) (n = 3-25) to CO and formations of (TiO(2))(n)(-) are observed, whereas the reactions of (ZrO(2))(n)O(-) (n = 3-25) with CO generate the CO addition products (ZrO(2))(n)OCO(-), which lose CO(2) upon the collisions (studied for n = 3-9) with a crossed helium beam. The computational study indicates that the (MO(2))(n)O(-) (M = Ti, Zr; n = 3-8) clusters are atomic radical anion (O(-)) bonded systems, and the energetics for CO oxidation by the O(-) radicals to form CO(2) is strongly dependent on the metals as well as the cluster size for the titanium system. Atomic oxygen radical anions are important reactive intermediates, while it is difficult to capture and characterize them for condensed phase systems. The reactivity pattern of the O(-)-bonded (TiO(2))(n)O(-) and (ZrO(2))(n)O(-) correlates very well with different behaviors of titania and zirconia supports in the low-temperature catalytic CO oxidation. PMID- 23368887 TI - The dependence of FMD% on baseline diameter: a problem solved by allometric scaling - no problem in this case. PMID- 23368888 TI - Evaluating audio computer assisted self-interviews in urban South African communities: evidence for good suitability and reduced social desirability bias of a cross-sectional survey on sexual behaviour. AB - BACKGROUND: Efficient HIV prevention requires accurate identification of individuals with risky sexual behaviour. However, self-reported data from sexual behaviour surveys are prone to social desirability bias (SDB). Audio Computer Assisted Self-Interviewing (ACASI) has been suggested as an alternative to face to-face interviewing (FTFI), because it may promote interview privacy and reduce SDB. However, little is known about the suitability and accuracy of ACASI in urban communities with high HIV prevalence in South Africa. To test this, we conducted a sexual behaviour survey in Cape Town, South Africa, using ACASI methods. METHODS: Participants (n = 878) answered questions about their sexual relationships on a touch screen computer in a private mobile office. We included questions at the end of the ACASI survey that were used to assess participants' perceived ease of use, privacy, and truthfulness. Univariate logistic regression models, supported by multivariate models, were applied to identify groups of people who had adverse interviewing experiences. Further, we constructed male female ratios of self-reported sexual behaviours as indicators of SDB. We used these indicators to compare SDB in our survey and in recent FTFI-based Demographic and Health Surveys (DHSs) from Lesotho, Swaziland, and Zimbabwe. RESULTS: Most participants found our methods easy to use (85.9%), perceived privacy (96.3%) and preferred ACASI to other modes of inquiry (82.5%) when reporting on sexual behaviours. Unemployed participants and those in the 40-70 year old age group were the least likely to find our methods easy to use (OR 0.69; 95% CI: 0.47-1.01 and OR 0.37; 95% CI: 0.23-0.58, respectively). In our survey, the male-female ratio for reporting >2 sexual partners in the past year, a concurrent relationship in the past year, and > 2 sexual partners in a lifetime was 3.4, 2.6, and 1.2, respectively- far lower than the ratios observed in the Demographic and Health Surveys. CONCLUSIONS: Our analysis suggests that most participants in our survey found the ACASI modality to be acceptable, private, and user-friendly. Moreover, our results indicate lower SDB than in FTFI techniques. Targeting older and unemployed participants for ACASI training prior to taking the survey may help to improve their perception of ease and privacy. PMID- 23368889 TI - In vitro interaction of artemisinin derivatives or the fully synthetic peroxidic anti-malarial OZ277 with thapsigargin in Plasmodium falciparum strains. AB - BACKGROUND: Semi-synthetic artemisinin derivatives are powerful peroxidic drugs in artemisinin-based combination therapy (ACT) recommended as first-line treatment of Plasmodium falciparum malaria in disease-endemic countries. Studies by Eckstein-Ludwig and co-workers showed both thapsigargin and artemisinin specifically inhibit the sarcoplasmic reticulum Ca2+-ATPase of Plasmodium falciparum (PfATP6). In the present study the type of interaction between thapsigargin and artemisinin derivatives as well as the ozonide OZ277 (RBx11160 or arterolane) was evaluated in parasite cultures. The latter compound is an adamantane-based peroxide and the first fully synthetic clinical candidate recently registered in India by Ranbaxy Laboratories Ltd. for anti-malarial combination therapy. METHODS: Drug interaction studies were performed using a previously described fixed ratio method and anti-malarial activity measured using the [3H] hypoxanthine incorporation assay. RESULTS: The sum 50% and 90% fractional inhibitory concentration (?FIC50, 90) of the interaction of thapsigargin with OZ277, artemether or artesunate, against NF54 and K1 strains of P. falciparum ranged from 0.9 to 1.4. CONCLUSION: The interaction of thapsigargin with OZ277, artesunate or artemether was additive, data consistent with previous observations indicating that activity of anti-malarial peroxides does not derive from reversible interactions with parasite targets. PMID- 23368890 TI - Use of social media by Spanish hospitals: perceptions, difficulties, and success factors. AB - This exploratory study has two aims: (1) to find out if and how social media (SM) applications are used by hospitals in Spain and (2) to assess hospital managers' perception of these applications in terms of their evaluation of them, reasons for use, success factors, and difficulties encountered during their implementation. A cross-sectional survey has been carried out using Spanish hospitals as the unit of analysis. Geographical differences in the use of SM were found. Social networks are used most often by larger hospitals (30% by medium size, 28% by large-size). They are also more frequently used by public hospitals (19%, p<0.01) than by private ones. Respondents with a negative perception of SM felt that there is a chance they may be abused by healthcare professionals, whereas those with a positive perception believed that they can be used to improve communication both within and outside the hospital. Reasons for the use of SM include the idea of maximizing exposure of the hospital. The results show that Spanish hospitals are only just beginning to use SM applications and that hospital type can influence their use. The perceptions, reasons for use, success factors, and difficulties encountered during the implementation of SM mean that it is very important for healthcare professionals to use SM correctly and adequately. PMID- 23368891 TI - Wire-guided biliary cannulation technique does not reduce the risk of post-ERCP pancreatitis: multicenter randomized controlled trial. AB - AIM: To evaluate the effect of wire-guided biliary cannulation (WGC) on the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). METHODS: We investigated the impact of the WGC technique on the incidence of PEP by comparing the conventional cannulation (CC) technique in selective bile duct cannulation during ERCP with a cross-over design in a prospective multicenter randomized controlled trial and the potential risk factors for PEP. This involved six tertiary referral centers and three university hospitals. A total of 322 patients with indications for ERCP requiring selective biliary cannulation were enrolled from April 2008 to March 2009. RESULTS: One hundred and sixty-three patients were assigned to the WGC group and 159 to the CC group. The incidence of PEP was the same between the groups (6.1% vs 6.3%, P = 0.95). Primary successful biliary cannulation was achieved in 136 patients (83%) in the WGC group and in 138 (87%) in the CC group (P = 0.40). The mean time required for primary successful biliary cannulation was 7.4 +/- 8.3 min and 7.2 +/- 7.9 min, respectively (P = 0.83). Multivariate analysis demonstrated that accidental guidewire insertions and unintended injections of contrast into the main pancreatic duct were the only independent risk factors for PEP (P = 0.001, relative risk [RR]: 8.70, 95% confidence interval [CI]: 2.46-30.81). CONCLUSION: The WGC technique does not reduce the risk of PEP and also does not improve the success rate of selective bile duct cannulation. PMID- 23368893 TI - A herbal antifungal formulation of Thymus serpillum, Origanum vulgare and Rosmarinus officinalis for treating ovine dermatophytosis due to Trichophyton mentagrophytes. AB - A number of herbal products with anti-inflammatory, antiseptic and antimycotic properties are available for dermatological usage. The successful treatment of 13 sheep affected by ringworm due to Trichophyton mentagrophytes with a mixture consisting of essential oils (EOs) of Thymus serpillum 2%, Origanum vulgare 5% and Rosmarinus officinalis 5% in sweet almond (Prunus dulcis) oil. The effectiveness of EOs and of the major components of the mixture (thymol, carvacrol, 1,8 cineole, alpha-pinene, p-cymene, gamma-terpinene) against the fungal clinical isolate was evaluated by a microdilution test. Thirteen animals were topically administered with the mixture twice daily for 15 days. The other sheep were administered with a conventional treatment (seven animals) or left untreated (two animals). Minimum inhibitory concentration (MIC) values were 0.1% for T. serpillum, 0.5% for O. vulgare, 2.5% for I. verum and 5% for both R. officinalis and C. limon. Thymol and carvacrol showed MICs of 0.125% and 0.0625%. A clinical and aetiological cure was obtained at the end of each treatment regimen in only the treated animals. Specific antimycotic drugs licenced for food producing sheep are not available within the European Community. The mixture tested here appeared to be a versatile tool for limiting fungal growth. PMID- 23368894 TI - Guided online treatment in routine mental health care: an observational study on uptake, drop-out and effects. AB - BACKGROUND: Due to limited resources patients in the Netherlands often have to wait for a minimum of six weeks after registration for mental health care to receive their first treatment session. Offering guided online treatment might be an effective solution to reduce waiting time and to increase patient outcomes at relatively low cost. In this study we report on uptake, drop-out and effects of online problem solving treatment that was implemented in a mental health center. METHODS: We studied all 104 consecutive patients aged 18-65 years with elevated symptoms of depression, anxiety and/or burnout who registered at the center during the first six months after implementation. They were offered a five week guided online treatment. At baseline, five weeks and twelve weeks we measured depressive (BDI-II), anxiety (HADS-A) and burnout symptoms (MBI). RESULTS: A total of 55 patients (53%) agreed to start with the online treatment. Patients who accepted the online treatment were more often female, younger and lower educated than those who refused. There were no baseline differences in clinical symptoms between the groups. There were large between group effect sizes after five weeks for online treatment for depression (d = 0.94) and anxiety (d = 1.07), but not for burnout (d = -.07). At twelve weeks, when both groups had started regular face-to-face treatments, we no longer found significant differences between the groups, except for anxiety (d = 0.69). CONCLUSION: The results of this study show that the majority of patients prefer online guided online treatment instead of waiting for face-to-face treatment. Furthermore, online PST increases speed of recovery and can therefore be offered as a first step of treatment in mental healthcare. PMID- 23368895 TI - Efficacy and safety of degludec insulin: a meta-analysis of randomised trials. AB - OBJECTIVES: Degludec is a novel long-acting insulin analogue, providing an adequate supply of basal insulin over 24 hours with one daily injection, with a supposed greater reproducibility and flexibility than other basal insulins. METHODS: An extensive search of Medline and the Cochrane Library for 'degludec' was performed, up to July 1st, 2012, collecting all randomised trials with a duration of at least 16 weeks and enrolling patients with diabetes. The principal outcome was the effect of degludec, compared with other basal insulins, on endpoint HbA1c and hypoglycaemia. Secondary outcomes included BMI, FPG at endpoint, and the incidence of cardiovascular events and cancer. RESULTS: In the four trials comparing degludec with glargine, endpoint HbA1c was similar in the two groups, whereas FPG was significantly lower in degludec-treated patients. Degludec was associated with a lower rate of overall and nocturnal hypoglycaemia in type 2 and type 1 diabetes, respectively. No differences were observed for cardiovascular events and cancer. STUDY LIMITATIONS: The number of available trials and the duration of exposure were limited, so the results obtained should be considered preliminary. CONCLUSIONS: Degludec appears to be associated with a lower incidence of hypoglycaemia in comparison with glargine, for similar levels of glycaemic control. The use of this agent could represent one step further in insulin therapy. PMID- 23368896 TI - Further data on beta-blockers and cancer risk: observational study and meta analysis of randomized clinical trials. AB - BACKGROUND: The aim of the present paper is to provide some further data on the relationship between beta-blocker treatment and the incidence of cancer, using two different approaches (epidemiological study and meta-analysis of clinical trials). METHODS: In a consecutive series of 1340 diabetic patients starting insulin therapy, 112 cases of cancer during a mean follow-up of 75.9 months were identified as first hospital admission or death. For each case, the controls were chosen randomly from those members of the cohort matched for age, sex and BMI. The main predefined analysis was the comparison of cases and controls for length of exposure to beta-blockers and proportion of patients exposed using a conditional logistic regression which takes into account the matching structure. For the meta-analytic sub-study, an extensive search of Medline and the Cochrane Library (any date up to December 31st, 2011) was performed for all trials in which a beta-blocker was used. Mantel-Haenszel Odds Ratios (MH-OR) with 95% confidence intervals for incident malignancies were calculated using a random effect model. RESULTS: After adjusting for mean daily dose of glargine and metformin, and ischemic heart disease, exposure to beta-blockers was associated with a reduced overall risk of cancer (HR 0.33 [0.13; 0.83], p = 0.019; HR for each month of exposure 0.87 [0.77; 0.98], p = 0.025). In the meta-analysis sub study, performed on nine trials, beta-blockers were associated with a non significant trend toward lower risk of cancer (MH-OR 0.93 [0.86; 1.01], p = 0.070). STUDY LIMITATION: Limitations of the observational study are the small sample size that limits the statistical power of analyses, that it was performed on diabetic patients only, and that diagnoses of malignancies were derived from administrative data. CONCLUSIONS: In conclusion, this research seem to confirm a possible beneficial effect of beta-blockers against the risk of cancer development. PMID- 23368897 TI - Efficacy and safety profile of fluticasone/formoterol combination therapy compared to its individual components administered concurrently in asthma: a randomised controlled trial. AB - BACKGROUND: The potent inhaled corticosteroid, fluticasone propionate (fluticasone), and the long-acting beta2-agonist with a rapid onset of action, formoterol fumarate (formoterol), have now been combined in a single aerosol inhaler, fluticasone/formoterol (flutiform). This study investigated the efficacy and safety of fluticasone/formoterol combination therapy compared with its individual components administered concurrently via two separate inhalers. METHODS: Patients >= 12 years (N = 210) with mild to moderate-severe persistent, reversible asthma were evenly randomised to 12 weeks of treatment (b.i.d.) with fluticasone/formoterol combination therapy (100/10 MUg b.i.d. or 250/10 MUg b.i.d.) or fluticasone plus formoterol (Flixotide Evohaler, pMDI, Flovent [HFA]; Foradil, DPI, Foradil Aerolizer) administered concurrently (fluticasone + formoterol; 100 MUg + 12 MUg b.i.d. or 250 MUg + 12 MUg b.i.d.) in an open-label, parallel-group, multicentre study. The primary objective of this study was to show non-inferiority of fluticasone/formoterol compared with fluticasone + formoterol based on mean post-dose FEV1. RESULTS: The mean FEV1 30-60 minutes post-dose on Day 84 was approximately 2.6 L in both the fluticasone/formoterol combination and the fluticasone + formoterol treatment groups (per protocol sets; treatment difference least squares (LS) mean: -0.03 L; 95% CI: -0.148, 0.081). The lower limit of the 95% CI (-0.148 L) was above the non-inferiority threshold of >=-0.2 L. Analyses of other pulmonary function tests, patient reported outcomes, rescue medication use, asthma exacerbations and quality of life questionnaires were also comparable. The safety profiles of the two study groups were similar overall. TRIAL REGISTRATION: Fluticasone/formoterol combination therapy had comparable efficacy to its individual components administered concurrently, when measured by post-dose FEV1 in patients aged >= 12 years with mild to moderate-severe asthma. The safety and tolerability profile of fluticasone/formoterol combination therapy was similar to that of its individual components administered concurrently. Although this was an open-label study, the results remain compelling: the primary efficacy measure was a physical endpoint and study statisticians were blinded to treatment allocations until analysis was completed. PMID- 23368898 TI - The (not completely irreversible) population of a misfolded state of cytochrome c under folding conditions. AB - This paper reports the discovery of a (meta)stable partially unfolded state of horse heart ferricytochrome c that was obtained after exposing the protein to a solution with an alkaline pH of 11.5 for 1 week. Thereafter, the protein did not undergo any detectable change in its secondary and tertiary structure upon adjusting the solution to folding promoting conditions at neutral pH. Spectroscopic data suggest that the misfolded protein exhibits a hexacoordinated low-spin state with a hydroxyl ion as the likely ligand. Below pH 6, a new ligation state emerges with the spectroscopic characteristics of a pentacoordinated quantum mixed state of the heme iron. Gel electrophoresis revealed substantial formation of soluble dimers and trimers at submillimolar concentrations, whereas monomers were dominant at lower, micromolar concentrations. Ultraviolet circular dichroism spectra indicate that oxidized monomers are pre-molten globule to globule-like with a substantial fraction of secondary (helical) structure reminiscent of alkaline state V. The oligomers contain even more helical structure, which suggests domain swapping as the underlying mechanism of their formation. A substantial fraction of the submillimolar mixture of monomers and oligomers underwent a reduction of the heme iron. Its dependence on pH suggests the coupling to a proton transfer process. Altogether, our data indicate a partially unfolded ferricytochrome c conformation with spectroscopic characteristics reminiscent of the recently discovered alkaline isomer V(b), which is stabilized under folding conditions by exposing the protein to a very alkaline pH for an extended period of time. PMID- 23368899 TI - SymGRASS: a database of sugarcane orthologous genes involved in arbuscular mycorrhiza and root nodule symbiosis. AB - BACKGROUND: The rationale for gathering information from plants procuring nitrogen through symbiotic interactions controlled by a common genetic program for a sustainable biofuel production is the high energy demanding application of synthetic nitrogen fertilizers. We curated sequence information publicly available for the biofuel plant sugarcane, performed an analysis of the common SYM pathway known to control symbiosis in other plants, and provide results, sequences and literature links as an online database. METHODS: Sugarcane sequences and informations were downloaded from the nucEST database, cleaned and trimmed with seqclean, assembled with TGICL plus translating mapping method, and annotated. The annotation is based on BLAST searches against a local formatted plant Uniprot90 generated with CD-HIT for functional assignment, rpsBLAST to CDD database for conserved domain analysis, and BLAST search to sorghum's for Gene Ontology (GO) assignment. Gene expression was normalized according the Unigene standard, presented as ESTs/100 kb. Protein sequences known in the SYM pathway were used as queries to search the SymGRASS sequence database. Additionally, antimicrobial peptides described in the PhytAMP database served as queries to retrieve and generate expression profiles of these defense genes in the libraries compared to the libraries obtained under symbiotic interactions. RESULTS: We describe the SymGRASS, a database of sugarcane orthologous genes involved in arbuscular mycorrhiza (AM) and root nodule (RN) symbiosis. The database aggregates knowledge about sequences, tissues, organ, developmental stages and experimental conditions, and provides annotation and level of gene expression for sugarcane transcripts and SYM orthologous genes in sugarcane through a web interface. Several candidate genes were found for all nodes in the pathway, and interestingly a set of symbiosis specific genes was found. CONCLUSIONS: The knowledge integrated in SymGRASS may guide studies on molecular, cellular and physiological mechanisms by which sugarcane controls the establishment and efficiency of endophytic associations. We believe that the candidate sequences for the SYM pathway together with the pool of exclusively expressed tentative consensus (TC) sequences are crucial for the design of molecular studies to unravel the mechanisms controlling the establishment of symbioses in sugarcane, ultimately serving as a basis for the improvement of grass crops. PMID- 23368900 TI - Cu2+ inhibition of gel secretion in the xylem and its potential implications for water uptake of cut Acacia holosericea stems. AB - Maintaining a high rate of water uptake is crucial for maximum longevity of cut stems. Physiological gel/tylosis formation decreases water transport efficiency in the xylem. The primary mechanism of action for post-harvest Cu(2+) treatments in improving cut flower and foliage longevity has been elusive. The effect of Cu(2+) on wound-induced xylem vessel occlusion was investigated for Acacia holosericea A. Cunn. ex G. Don. Experiments were conducted using a Cu(2+) pulse (5 h, 2.2 mM) and a Cu(2+) vase solution (0.5 mM) vs a deionized water (DIW) control. Development of xylem blockage in the stem-end region 10 mm proximal to the wounded stem surface was examined over 21 days by light and transmission electron microscopy. Xylem vessels of stems stood into DIW were occluded with gels secreted into vessel lumens via pits from surrounding axial parenchyma cells. Gel secretion was initiated within 1-2 days post-wounding and gels were detected in the xylem from day 3. In contrast, Cu(2+) treatments disrupted the surrounding parenchyma cells, thereby inhibiting gel secretion and maintaining the vessel lumens devoid of occlusions. The Cu(2+) treatments significantly improved water uptake by the cut stems as compared to the control. PMID- 23368901 TI - Influence of chain length and double bond on the aqueous behavior of choline carboxylate soaps. AB - In preceding studies, we demonstrated that choline carboxylates ChC(m) with alkyl chain lengths of m = 12 - 18 are highly water-soluble (for m = 12, soluble up to 93 wt % soap and 0 degrees C). In addition, choline soaps are featured by an extraordinary lyotropic phase behavior. With decreasing water concentration, the following phases were found: micellar phase (L(1)), discontinuous cubic phase (I(1)' and I(1)"), hexagonal phase (H(1)), bicontinuous cubic phase (V(1)), and lamellar phase (L(alpha)). The present work is also focused on the lyotropic phase behavior of choline soaps but with shorter alkyl chains or different alkyl chain properties. We have investigated the aqueous phase behavior of choline soaps with C(8) and C(10) chain-lengths (choline octanoate and choline decanoate) and with a C(18) chain-length with a cis-double bond (choline oleate). We found that choline decanoate follows the lyotropic phase behavior of the longer-chain homologues mentioned above. Choline octanoate in water shows no discontinuous cubic phases, but an extended, isotropic micellar solution phase. In addition, choline octanoate is at the limit between a surfactant and a hydrotrope. The double bond in choline oleate leads also to a better solubility in water and a decrease of the solubilization temperature. It also influences the Gaussian curvature of the aggregates which results in a loss of discontinuous cubic phases in the binary phase diagram. The different lyotropic mesophases were identified by the penetration scan technique with polarizing light microscope and visual observations. To clarify the structural behavior small (SAXS) and wide (WAXS) angle X-ray scattering were performed. To further characterize the extended, isotropic micellar solution phase in the binary phase diagram of choline octanoate viscosity and conductivity measurements were also carried out. PMID- 23368902 TI - Self-assembly of symmetric brush diblock copolymers. AB - Self-assembled structures of brush block copolymers (BrBCPs) with polylactide (PLA) and polystyrene (PS) side chains were studied. The polynorbornene-backbone based BrBCPs containing approximately equal volume fractions of each block self assembled into highly ordered lamellae with domain spacing ranging from 20 to 240 nm by varying molecular weight of the backbone in the bulk state, as revealed by small-angle X-ray scattering (SAXS). The domain size increased approximately linearly with backbone length, which indicated an extended conformation of the backbone in the ordered state. In situ SAXS measurements suggested that the BrBCPs self-assemble with an extremely fast manner which could be attributed to a reduced number of entanglements between chains. The strong segregation theory and Monte Carlo simulation also confirmed this near-linear dependence of the domain spacing on backbone length, rationalizing experimental results. PMID- 23368903 TI - Bladder and bowel dysfunction and the resolution of urinary incontinence with successful management of bowel symptoms in children. AB - AIM: To investigate the effect of treating defecation problems on urinary incontinence in children suffering from combined urinary bladder and bowel dysfunction (BBD). METHODS: We established a clinical database from medical records of all children referred to the urinary incontinence and gastroenterology outpatient clinics with BBD. The following variables were extracted: symptoms of constipation, faecal incontinence, urinary incontinence, age at onset of symptoms, treatment, including duration and response. All children went through the same treatment protocol. Faecal disorders were treated primarily and once relieved, the daytime incontinence was managed and followed by intervention for nocturnal enuresis. RESULTS: In total, 73 children were included in the study. The treatment regimen resulted in resolution of the defecation disorder in 96% of the patients. Of the children with daytime urinary incontinence, 68% had at least a 50% reduction in number of daytime incontinence episodes by successful relief of bowel dysfunction and 27% became completely continent during daytime. Only 17% of the children suffering from enuresis had a significant reduction in number of wet nights after relief of their faecal problem. CONCLUSION: The empirical treatment approach of managing bowel symptoms before intervening for bladder dysfunction in children with BBD is found to be appropriate. PMID- 23368904 TI - Usefulness of a continuous suction mouthpiece during percutaneous endoscopic gastrostomy: a single-center, prospective, randomized study. AB - BACKGROUND: No mouthpiece has been designed to control salivary flow during endoscopic procedures. A new continuous suction mouthpiece (CSM) was developed, and its usefulness for percutaneous endoscopic gastrostomy (PEG) was evaluated. PATIENTS AND METHODS: Seventy-two patients who were scheduled to undergo PEG or the exchange of a gastrostomy button or tube were assigned to one of two groups: the group using the CSM and the group using the conventional mouthpiece. Aspiration pneumonia, procedure duration, extent of salivary flow, frequency of saliva suction, and number of choking episodes during the procedures were evaluated and compared between the two groups. RESULTS: The same number of patients was randomly allocated to each group. There were no significant differences between the two groups in sex, age, procedure type, duration of procedure,depth of sedation, and indication for the procedure. The grade of salivary flow was significantly lower in patients with the CSM than in patients with the conventional mouthpiece (P < 0.001). Significantly fewer suctions and choking episodes were observed in patients with the CSM than in patients with the conventional mouthpiece (P = 0.013, and P = 0.015, respectively). Aspiration pneumonia and other significant adverse events were not observed in either group. CONCLUSIONS: CSM reduced the number of episodes associated with salivary flow in PEG-related procedures. The device is expected to reduce complications such as aspiration not only in PEG but in other upper endoscopic procedures. PMID- 23368905 TI - Characterising RNA secondary structure space using information entropy. AB - Comparative methods for RNA secondary structure prediction use evolutionary information from RNA alignments to increase prediction accuracy. The model is often described in terms of stochastic context-free grammars (SCFGs), which generate a probability distribution over secondary structures. It is, however, unclear how this probability distribution changes as a function of the input alignment. As prediction programs typically only return a single secondary structure, better characterisation of the underlying probability space of RNA secondary structures is of great interest. In this work, we show how to efficiently compute the information entropy of the probability distribution over RNA secondary structures produced for RNA alignments by a phylo-SCFG, and implement it for the PPfold model. We also discuss interpretations and applications of this quantity, including how it can clarify reasons for low prediction reliability scores. PPfold and its source code are available from http://birc.au.dk/software/ppfold/. PMID- 23368906 TI - Reactions of difluorocarbene with organozinc reagents. AB - Reactions of difluorocarbene with benzyl and alkylzinc halides leading to fluorinated organozinc species have been described. The generated alpha difluorinated organozinc reagents are reasonably stable in solution and can be quenched with external electrophiles (iodine, bromine, proton), affording compounds containing the CF(2) fragment. PMID- 23368907 TI - Discovery of 2-(phenoxypyridine)-3-phenylureas as small molecule P2Y1 antagonists. AB - Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that P2Y1 and P2Y12 inhibition provide equivalent antithrombotic efficacy, while targeting P2Y1 has the potential for reduced bleeding liability. In this account, the discovery of a 2 (phenoxypyridine)-3-phenylurea chemotype that inhibited ADP-mediated platelet aggregation in human blood samples is described. Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-4 (trifluoromethoxy)phenylurea, which demonstrated a 68 +/- 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively, in provoked rat bleeding time models. These results suggest that a P2Y1 antagonist could potentially provide a safe and efficacious antithrombotic profile. PMID- 23368908 TI - Effects of green tea, black tea, and coffee consumption on the risk of esophageal cancer: a systematic review and meta-analysis of observational studies. AB - Epidemiological studies regarding the associations of tea and coffee consumption with esophageal cancer (EC) risk are still inconsistent and this meta-analysis was conducted to examine these associations. PubMed, ISI -Web of Science, China National Knowledge Infrastructure (CNKI), and Chinese VIP database up to October 2011 were searched and manual search for reference lists of relevant studies were conducted. Random effects model was used to pool the odds ratios (OR). Twenty four case-control and cohort studies with 7376 EC cases were included in this meta-analysis. The pooled OR of EC was 0.77 [95% confidence intervals (95% CI): 0.57, 1.04] for highest vs. non/lowest green tea consumption; but it was statistically significant for case-control studies (OR = 0.70; 95% CI: 0.51, 0.96) and for studies conducted in China (OR = 0.64; 95% CI: 0.44, 0.95). No significant association was observed for the highest vs. non/lowest black tea consumption against EC risk (OR = 1.35; 95% CI: 0.86, 2.11). A borderline significantly inverse association of highest vs. non/lowest coffee consumption against EC risk was found (OR = 0.88; 95% CI: 0.76, 1.01). In conclusion, our data showed that both green tea and coffee consumption, but not black tea consumption, have protective effects on EC. PMID- 23368909 TI - Reliability of selected antioxidants and compounds involved in one-carbon metabolism in two Dutch cohorts. AB - Many epidemiological studies assess nutritional status based on single blood measurements, without verifying if these remain reliable over repeated measurements. This study assessed the reliability over a period of 2 to 5 yr of plasma carotenoids, vitamin C, retinol, tocopherols, and serum compounds involved in 1-carbon metabolism in a subsample of Dutch participants of European Prospective Investigation into Cancer and Nutrition (EPIC). Blood samples from 38 men from MORGEN-EPIC and 35 women from Prospect-EPIC were collected between 1993 and 1997 and again after 2 to 5 yr. The reliability of plasma carotenoids, retinol, vitamin C, and tocopherols, and of serum folate, homocysteine, and vitamins B6 and B12 was estimated using an intraclass correlation coefficient (ICC). Serum homocysteine and vitamin B12 were highly reliable biomarkers, with ICCs of 0.91 and 0.75, respectively. All other analyzed biomarkers had a slight or fair reliability over several years (ICCs ranged from 0.17 to 0.56). Most examined biomarkers showed reliability values that may lead to considerable attenuation of the risk estimate when used as exposure assessment in a risk model. If multiple measurements are not available, the risk estimates can be adjusted for the regression dilution using the ICC as adjustment coefficient. PMID- 23368910 TI - The relationship between nutritional status and the Glasgow prognostic score in patients with cancer of the esophagus and stomach. AB - A relationship between weight loss and inflammation has been described in patients with cancer. In the present study, the relationship between subjective global assessment (SGA) and the severity of inflammation, as defined by Glasgow prognostic score (GPS), as well as the relationship of both of these measures with the presence of complications and survival time, was assessed. In addition, we compared the diagnosis given by SGA with parameters of nutritional assessment, such as body mass index, triceps skinfold, midarm circumference (MAC), midarm muscle circumference (MAMC), phase angle (PA), adductor pollicis muscle thickness (APMT), and handgrip strength (HGS). According to the SGA, the nutritional status was associated with the GPS (P < 0.05), and both the SGA and GPS were associated with the presence of complications. However, the GPS [area under the curve (AUC): 0.77, P < 0.05, confidence interval (CI) = 0.580, 0.956] seems to be more accurate in identifying complications than the SGA (AUC: 0.679, P < 0.05, CI = 0.426, 0.931). Only GPS was associated with survival time. Comparing the different nutritional assessment methods with the SGA suggested that the MAC, MAMC, APMT, PA, and HGS parameters may be helpful in differentiating between nourished and malnourished patients, if new cutoffs are adopted. PMID- 23368911 TI - Long-term weight gain among Hispanic and non-Hispanic White women with and without breast cancer. AB - Weight gain following breast cancer diagnosis is common, but limited data exists on whether this gain is in excess of that gained during normal aging. This study investigated weight patterns among women with and without breast cancer to determine the effects of the breast cancer experience on weight change. Using the SHINE 4-Corners Breast Cancer Study, 305 women with breast cancer and 345 women without were followed prospectively. Weight change of >=5% was defined as the difference between the self-reported weight measurements obtained at breast cancer diagnosis (or referent date for women without breast cancer) and about 6 yr later. Multiple logistic regression analyses were used. Within this cohort, 60% of women were overweight or obese and 37% of women gained weight. No significant greater weight gain was observed between women with vs. without breast cancer [adjusted odds ratio (ORadj) = 1.15, 95% CI 0.79-1.68] or between Hispanic vs. non-Hispanic White women (ORadj = 1.09, 95% CI 0.72-1.66) after adjustment. Weight gain was associated with being younger and having a lower body mass index. Among breast cancer survivors, cancer treatment factors were not associated with weight gain. These results suggest that weight management approaches are needed, especially those targeted to at-risk populations such as breast cancer survivors. PMID- 23368912 TI - Body mass index, weight change, and survival in non-Hodgkin lymphoma patients in Connecticut women. AB - Evidence is emerging that obesiy and weight gain may affect the prognosis of several types of cancer. We investigated the impact of body mass index (BMI) as well as pre-and postdiagnosis weight changes on non-Hodgkin lymphoma (NHL) prognosis. A cohort of 573 female incident NHL cases diagnosed during 1996-2000 in Connecticut was followed for a median of 7.8 yr. Self-reported height and weight at 3 time points before and after diagnosis were collected. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazard models adjusting for factors believed to be associated with overall survival of NHL. Underweight (BMI < 18.5; HR = 2.84; 95% CI = 1.12-7.15) before diagnosis was associated with poorer survival compared to being normal weight (18.5 <= BMI < 25). Prediagnosis weight loss (HR = 1.42; 95% CI = 1.02-1.97) and posttreatment weight loss (HR = 1.98; 95% CI = 1.14-3.45) and weight gain (HR = 1.85; 95% CI = 1.04-3.32) were associated with poorer survival. NHL patients who were underweight, lost weight prediagnosis, or change weight after treatment were found to have a poorer survival. PMID- 23368913 TI - Intakes of fruits, vegetables, and related vitamins and lung cancer risk: results from the Shanghai Men's Health Study (2002-2009). AB - Most epidemiological studies evaluating the association of fruit and vegetable intakes on lung cancer risk were conducted in North American and European countries. We investigated the association of intakes of fruits, vegetables, dietary vitamins A and C, and folate with lung cancer risk among 61,491 adult Chinese men who were recruited into the Shanghai Men's Health Study, a population based, prospective cohort study. Baseline dietary intake was assessed through a validated food frequency questionnaire during in-home visits. Multivariate Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of lung cancer risk associated with dietary intakes. During a median follow up of 5.5 yr, 359 incident lung cancer cases accrued after the first year of follow-up and 68.8% of them were current smokers. Intakes of green leafy vegetables, beta-carotene-rich vegetables, watermelon, vitamin A, and carotenoids were inversely associated with lung cancer risk; the corresponding HR (95% CI) comparing the highest with the lowest quartiles were 0.72 (0.53-0.98), 0.69 (0.51 0.94), 0.65 (0.47-0.90), 0.63 (0.44-0.88), and 0.64 (0.46-0.88). Intake of all fruits and vegetables combined was marginally associated with lower risk. Our study suggests that the consumption of carotenoid-rich vegetables is inversely associated with lung cancer risk. PMID- 23368914 TI - The impact of nutritional status, nutritional risk, and nutritional treatment on clinical outcome of 2248 hospitalized cancer patients: a multi-center, prospective cohort study in Chinese teaching hospitals. AB - To better understand the impact of undernutrition, nutritional risk, and nutritional treatment on the clinical outcomes of hospitalized cancer patients in China, the authors conducted a multicenter, cross-sectional study with 2248 cancer patients from 20 hospitals from January to June 2010. The authors defined 19.7% and 26.8% patients as undernourished at baseline and reassessment, respectively. Patients with gastrointestinal malignancies had a higher rate of undernutrition than other patients. The nutritional risk rate was 24.6% and 40.2% at baseline and reassessment, respectively. For patients with nutritional risk, the relative risk (RR) of adverse events (AEs) significantly increased with and without nutritional treatment. In comparison with the nonnutritional treatment subgroup, patients who received enteral nutrition (EN) or total parenteral nutrition (TPN) significantly reduced the RR of AE development. The RR of AEs for EN and TPN were 0.08 (95% CI: 0.01-0.62) and 0.56 (95% CI: 0.33-0.96), respectively. Separated nutrient infusion increased the risk of AEs. The authors concluded that undernutrition and nutritional risk are general problems that impact the outcomes of hospitalized cancer patients in China. Higher NRS2002 scores are related to AE risk but not weight loss. In nutritional treatment, EN and TPN can significantly reduce the risk of AEs. PMID- 23368915 TI - Fish oil-supplemented parenteral nutrition in patients following esophageal cancer surgery: effect on inflammation and immune function. AB - Our aim was to investigate whether adding omega-3 polyunsaturated fatty acids (PUFAs) to parenteral nutrition (PN) could reduce inflammation and improve immune function in patients following esophageal cancer surgery. In this pilot study, 60 patients with esophageal cancer were divided into 2 groups (30 patients in each group). All patients had total scores of more than or equal to 3 on the nutritional risk screening (NRS2002) test recommended by the European Society of Parenteral Enteral Nutrition, which showed that all patients had nutritional risk and should receive nutritional support. Both groups received isocaloric and isonitrogenous PN. One group received a omega-3 PUFAs supplement. Key indicators of inflammation [serum procalcitonin (PCT) level and the ratio of CD4(+) to CD8(+) (CD4(+)/CD8(+) ratio)] were determined intraoperatively and 24, 72, and 144 h postoperatively. PCT level was notably lower and CD4(+)/CD8(+) ratio was markedly higher in the omega-3 PUFAs group (P = 0.007 for PCT level and P = 0.012 for CD4(+)/CD8(+) ratio) on postoperative day 6 but not on postoperative days 1 and 3. omega-3 PUFAs supplemented PN can reduce inflammation and improve immune function in patients following esophageal cancer surgery. A larger trial is required to see whether omega-3 PUFAs supplementation of PN improves the clinical outcomes of patients following esophageal cancer surgery. PMID- 23368916 TI - More than 10% weight loss in head and neck cancer patients during radiotherapy is independently associated with deterioration in quality of life. AB - The authors prospectively assessed the independent association between weight loss and deterioration in quality of life (QOL) in patients treated by radiotherapy for head and neck cancer. In 533 head and neck cancer patients treated by curative radiotherapy, changes in weight and QOL were assessed between baseline (before radiotherapy) and follow-up (12 wk after the start of radiotherapy). Patients were categorized into 4 weight loss categories: 0%, 0.1% 5.0%, 5.1%-10.0%, and >10% weight loss. The association between weight loss and change in QOL was analyzed by linear regression analysis, adjusted for sociodemographic and tumor-related characteristics, and additionally for disease specific symptoms and tube feeding. Thirty percent of patients lost 0.1%-5.0% weight, 26% lost 5.1%-10.0% weight, and 24% lost >10% weight. Adjusted regression analyses showed a significant association between weight loss and deterioration of global QOL, physical functioning, social functioning, social eating, and social contact. After additional adjustment for disease-specific symptoms and tube feeding, weight loss (>10%) remained significantly associated with global QOL, social eating, and social contact (P < 0.05). More than 10% weight loss during and directly after radiotherapy has a significant impact on social eating, social contact, and QOL in head and neck cancer patients. PMID- 23368917 TI - Probiotics Lactobacillus rhamnosus GG, Lactobacillus acidophilus suppresses DMH induced procarcinogenic fecal enzymes and preneoplastic aberrant crypt foci in early colon carcinogenesis in Sprague Dawley rats. AB - Diet makes an important contribution to colorectal cancer (CRC) risk implying risks for CRC are potentially reducible. Therefore, the probiotics have been suggested as the prophylactic measure in colon cancer. In this study, different probiotics were used to compare their protective potential against 1,2 dimethylhydrazine dihydrochloride (DMH)-induced chemical colon carcinogenesis in Sprague Dawley rats. Animals belonging to different probiotic groups were fed orally with 1 * 10(9) lactobacilli daily for 1 week, and then a weekly injection of DMH was given intraperitoneally for 6 wks with daily administration of probiotic. Lactobacillus GG and L.acidophilus + DMH-treated animals had maximum percent reduction in ACF counts. A significant decrease (P < 0.05) in fecal nitroreductase activity was observed in L.casei + DMH and L.plantarum + DMH treated rats whereas beta-glucuronidase activity decreased in L.GG + DMH and L.acidophilus + DMH-treated rats. Animals treated with Bifidobacterium bifidum + DMH had significant decreased beta-glucosidase activity. However, not much difference was observed in the colon morphology of animals belonging to various probiotic + DMH-treated rats compared with DMH-treated alone. The results indicated that probiotics, L.GG, and L.acidophilus can be used as the better prophylactic agents for experimental colon carcinogenesis. PMID- 23368918 TI - Modulation of Fourier transform infrared spectra and total sialic acid levels by selenium during 1,2 dimethylhydrazine-induced colon carcinogenesis in rats. AB - The present study investigated the modulatory potential of selenium supplementation, if any, on Fourier transform infrared (FTIR) spectra in brush border membranes (BBM) of colons and on serum total sialic acid as well as lipid bound sialic acid during 1,2 dimethyl hydrazine (DMH)-induced colorectal carcinogenesis in rats. The FTIR spectra of BBM from the colons of DMH-treated rats revealed a significant increase in the lipid contents but showed a significant decline in the protein contents. Further, decrease in the collagen as well as creatine contents was also noticed in the colons of DMH-treated rats. Supplementation with selenium appreciably restored protein as well as collagen contents and resulted in decreased lipids levels in the colons of DMH-treated rats. Interestingly, a significant increase in the levels of total sialic acid in serum of DMH-treated rats was observed which, however, got moderated significantly upon selenium supplementation. Moreover, no significant changes were observed in the levels of lipid bound sialic acid in all the treated groups as compared to controls. In conclusion, the present study suggested that supplementation of selenium act as a chemopreventive agent and delays considerably the process of colon carcinogenesis. PMID- 23368919 TI - Glucose starvation induces apoptosis in a model of acute T leukemia dependent on caspase-3 and apoptosis-inducing factor: a therapeutic strategy. AB - Reactivation of apoptosis appears as an ultimate goal to eliminate cancer cells. By using light and fluorescent microscopy, flow cytometry, immunohistochemistry staining, DNA fragmentation analysis, and pharmacological inhibition, we provide evidence that 2 pathways of cell death induced by glucose-starvation (GS)/oxidative stress (OS) run in parallel: apoptosis-inducing factor (AIF) dependent and caspase-3 dependent mechanisms. However, the supremacy of 1 pathway over the other one relies on the availability of glucose, which is essential for the proper functioning of antioxidant cellular systems. It is shown that GS generates superoxide anion radical (O(2)(-))/hydrogen peroxide (H(2)O(2)), which are linked to the death ~45%-70% cells by AIF/mitochondria depolarization/chromatin condensation pathway and ~15%-30% death by nuclear factor-kappa B/p53/c-Jun/c-Jun N-terminal kinase /mitochondria depolarization/caspase-3 activation/DNA fragmentation mechanism at 24-48 h. Remarkably, chromatin condensation/nuclei fragmentation appeared to occur partially independent of the loss of the mitochondrial transmembrane potential (DeltaPsi(m)) and plasma membrane damage. Interestingly, signaling inhibitors, antioxidants, or glucose protected cells if added immediately to culture devoid of glucose (P < 0.001), but only vitamin E and glucose significantly rescued cells at 3 h of GS compared to control. Taken together these data suggest that glucose deprivation might efficiently eliminate leukemia cells via apoptosis. PMID- 23368920 TI - Icariside II induces apoptosis of melanoma cells through the downregulation of survival pathways. AB - This study evaluated the antitumor effects of icariside II (IS), isolated from Herba Epimedii, on in vitro and in vivo models of melanoma and determined its mechanism of apoptosis. Mouse (B16) and human (A375, SK-MEL-5) melanoma cell lines were treated with IS at different concentrations (0-100 MUM). Cell viability and proliferation was detected by WST-1 assay and with the xCELLigence system, respectively. Apoptosis was measured by the annexin-V/PI flow cytometric assay. Western blot was used to measure cleaved caspase 3, survivin, P-STAT3, P ERK and P-AKT. B16 and A375 cells were injected subcutaneously into C57BL/6J and BALB/c-nu mice, respectively. After 1 wk, IS solution at (50 mg/kg, 100 mg/kg) was administered by intraperitoneal injection 3 times for a week. Tumor size was measured with an electronic digital caliper. IS inhibited the proliferation of melanoma cells in a dose- and time-dependent manner. Treatment of A375 cells with IS resulted in an increased number of apoptotic cells ranging from 5.6% to 26.3% mirrored by increases in cleaved caspase-3 and a decrease in survivin expression. IS significantly inhibited the activation of the JAK-STAT3 and MAPK pathways but promoted an unsustained activation peak of the PI3K-AKT pathway. IS administration (50 mg/kg) resulted in a 47.5% decreased tumor volume in A375 bearing mice. Furthermore, IS administration (50 mg/kg, 100 mg/kg) resulted in 41% and 49% decreased tumor volume in B16 bearing mice, respectively. IS dramatically inhibited the proliferation of melanoma cells in vivo and in vitro through the regulation of apoptosis. These effects demonstrate the ability of IS to effectively overcome the survival signals of tumor cells, which support further preclinical evaluation of IS in cancer as a new potential chemotherapeutic agent. PMID- 23368922 TI - Degraded iota-carrageenan can induce apoptosis in human osteosarcoma cells via the Wnt/beta-catenin signaling pathway. AB - Osteosarcoma (OS) is a high-grade malignant bone tumor. Therefore, using both in vitro and in vivo assays, the effects of degraded iota-Carrageenan (iota-CGN) on a human osteosarcoma cell line, HOS, were examined. Degraded iota-CGN was observed to induce apoptosis and G(1) phase arrest in HOS cells. Moreover, degraded iota-CGN suppressed tumor growth in established xenograft tumor models. Accordingly, the survival rate of these mice was significantly higher than that of mice bearing tumors treated with native iota-CGN or PBS. In addition, the formation of intratumoral microvessels was inhibited following treatment with degraded iota-CGN. In Western blot assays, degraded iota-CGN was found to inhibit the Wnt/beta-catenin signaling pathway. Overall, these studies demonstrate the antitumor activity of degraded iota-CGN toward the OS cell line, HOS. Moreover, valuable insight into the mechanisms mediated by degraded iota-CGN was obtained, potentially leading to the identification of novel treatments for OS. However, additional studies are needed to confirm these results in other cell types, particularly in human umbilical vein endothelial cells. PMID- 23368921 TI - Black raspberry-derived anthocyanins demethylate tumor suppressor genes through the inhibition of DNMT1 and DNMT3B in colon cancer cells. AB - We previously reported that oral administration of black raspberry powder decreased promoter methylation of tumor suppressor genes in tumors from patients with colorectal cancer. The anthocyanins (ACs) in black raspberries are responsible, at least in part, for their cancer-inhibitory effects. In the present study, we asked if ACs are responsible for the demethylation effects observed in colorectal cancers. Three days of treatment of ACs at 0.5, 5, and 25 MUg/ml suppressed activity and protein expression of DNMT1 and DNMT3B in HCT116, Caco2 and SW480 cells. Promoters of CDKN2A, and SFRP2, SFRP5, and WIF1, upstream of Wnt pathway, were demethylated by ACs. mRNA expression of some of these genes was increased. mRNA expression of beta-catenin and c-Myc, downstream of Wnt pathway, and cell proliferation were decreased; apoptosis was increased. ACs were taken up into HCT116 cells and were differentially localized with DNMT1 and DNMT3B in the same cells visualized using confocal laser scanning microscopy. Although it was reported that DNMT3B is regulated by c-Myc in mouse lymphoma, DNMT3B did not bind with c-Myc in HCT116 cells. In conclusion, our results suggest that ACs are responsible, at least in part, for the demethylation effects of whole black raspberries in colorectal cancers. PMID- 23368923 TI - Antiproliferative activity of the dietary isothiocyanate erucin, a bioactive compound from cruciferous vegetables, on human prostate cancer cells. AB - It is becoming increasingly clear that many dietary agents, such as isothiocyanates (ITCs) from cruciferous vegetables, can retard or prevent the process of prostate carcinogenesis. Erucin (ER) is a dietary ITC, which has been recently considered a promising cancer chemopreventive phytochemical. The potential protective activity of ER against prostate cancer was investigated using prostate adenocarcinoma cells (PC3), to analyze its effects on pathways involved in cell growth regulation, such as the cyclin-dependent kinase (CDKs) inhibitor p21(WAF1/CIP1) (p21), phosphatidylinositol-3 kinase/AKT, and extracellular signal-regulated kinases (ERK)1/2 signaling pathways. We have shown for the first time that ER increases significantly p21 protein expression and ERK1/2 phosphorylation in a dose-dependent manner to inhibit PC3 cell proliferation (P <= 0.01). Compared to the structurally related sulforaphane, a well-studied broccoli-derived ITC, ER showed lower potency in inhibiting proliferation of PC3 cells, as well as in modulating p21 and pERK1/2 protein levels. Neither of the naturally occurring ITCs was able to affect significantly pAKT protein levels in prostate cells at all concentrations tested (0-25 MUM). It is clearly important for the translation of laboratory findings to clinical approaches to investigate in animal and cell studies the molecular mechanisms by which ITCs may exert health promoting effects. PMID- 23368924 TI - Trans fatty acids affect cellular viability of human intestinal Caco-2 cells and activate peroxisome proliferator-activated receptors. AB - Trans fatty acids (TFA) are hypothesized to have an impact not only on coronary heart diseases but also on the development of colon cancer. To analyze if TFA exhibit cellular and molecular effects which could be involved in colon tumor progression, cells of the human colorectal adenocarcinoma-derived cell line Caco 2 were treated with various TFA isomers differing in the number and position of trans double bonds. The TFA tested in this study did not increase cellular proliferation but displayed growth-inhibitory effects at concentrations higher than 500 MUM. In case of the TFA isomer C18:3 t9, t11, t13, an IC50 value of 23 MUM was estimated for cytotoxicity indicating a high cytotoxic potential of this compound. In addition to the cytotoxicity studies, the TFA isomers were tested for their ability to activate peroxisome proliferator-activated receptors (PPAR) by taking advantage of a PPAR-dependent reporter gene assay. In contrast to PPARgamma that was not activated by the TFA isomers tested in this study, the substances were shown to moderately activate PPARalpha, and strong activation was observed for PPARdelta. The putative impact of TFA on colon cancer development with respect to PPARdelta activation is being discussed. PMID- 23368925 TI - Oleuropein, a secoiridoid derived from olive tree, inhibits the proliferation of human colorectal cancer cell through downregulation of HIF-1alpha. AB - Oleuropein (OL) is the most prominent phenolic compound in the fruit of olive tree. Although OL has shown powerful anticancer activity the underlying action mechanism remains largely unknown. The present study evaluated the effects of OL on hydroxityrosol (HT)-29 human colon adenocarcinoma cells in comparison to hydroxytyrosol, its hydrolysis product, and to elucidate the underlying anticancer molecular mechanisms involved. Cell proliferation was determined using SRB assay. Cell cycle and apoptosis were assessed by flow cytometry and changes in MAPK cascade protein expression, HIF-1alpha, p53, PPARgamma, and NFKbeta signaling pathways by Western blot. Although OL showed less potency than HT, in terms of cell growth inhibition, induced significant changes in cell cycle analysis and caused a significant increase in the apoptotic population. Both compounds produced a remarkable decrease in HIF-1alpha protein and an upregulation of p53 protein expression. However, no significant changes in IkB alpha and MAPK cascade protein expressions were observed. HT produced a significant upregulation in peroxisome proliferator-activated receptor gamma (PPARgamma) expression whereas OL failed. PPARgamma upregulation may be one of the principal mechanisms of the tumor shrinkage by HT. Our novel findings demonstrate that OL limits the growth and induces apoptosis in HT-29 cells via p53 pathway activation adapting the HIF-1alpha response to hypoxia. PMID- 23368926 TI - Dietary patterns and risk of pancreatic cancer in a large population-based case control study in the San Francisco Bay Area. AB - Pancreatic cancer is highly lethal, and identifying modifiable risk factors could have substantial public health impact. In this population-based case-control study (532 cases, 1701 controls), we used principal component analysis and multivariable unconditional logistic regression models to examine whether a particular dietary pattern was associated with risk of pancreatic cancer, adjusting for other known risk factors. A prudent dietary pattern, characterized by greater intake of vegetables, fruit, fish, poultry, whole grains, and low-fat dairy, was associated with an approximate 50% reduction in pancreatic cancer risk among men [odds ratio (OR) = 0.51, 95% confidence intervals (CI) = 0.31-0.84, P trend = 0.001] and women (OR = 0.51, 95% CI = 0.29-0.90, P trend = 0.04). A Western dietary pattern, characterized by higher intake of red and processed meats, potato chips, sugary beverages, sweets, high fat dairy, eggs, and refined grains, was associated with a 2.4-fold increased risk of pancreatic cancer among men (95% CI = 1.3-4.2, P trend = 0.008) but was not associated with risk among women. Among men, those in the upper quintiles of the Western diet and lower quintiles of the prudent diet had a threefold increased risk. Consistent with what has been recommended for several other chronic diseases, consuming a diet rich in plant-based foods, whole grains, and white meat, might reduce risk of pancreatic cancer. PMID- 23368929 TI - Determinants of chronic pain 3 years after moderate or serious injury. AB - OBJECTIVE: Patients with pain 3 years after injury are at risk of lifetime pain. It is not known if the predictors of chronic pain at 3 years are the same as those for earlier time points or whether other factors become important. Clarifying these factors will aid our understanding of the development of long term pain and further inform the development of models for screening and early intervention for pain in the aftermath of injury. DESIGN: Patients admitted to two trauma centers underwent a comprehensive physical and psychological assessment of known and potential risk factors for chronic pain during their index admission. Three years after injury, these patients were assessed for the presence of chronic pain (score was >=5 on an 11-point numerical rating scale during the last episode of pain, and present in the last month and at least two times in the past week) and pain-related disability. Logistic regression was used to identify independent risk factors for the presence of chronic pain and disability. RESULTS: Two hundred and twenty patients (75.9% of the original cohort) were assessed at 3 years. Of these, 146 (66.7%) reported some pain and 52 (23.7%) reported chronic pain. Factors (present at the time of injury) that predicted chronic pain were lower socioeconomic status, pain severity, and injury severity. The predictive power of these combined factors was modest. CONCLUSIONS: Three years after serious injury, almost a quarter of patients report chronic pain, and more than a third report at least moderate pain-related disability. The predicative power of measures taken in the acute setting is not enough to support discharge screening alone as a method of triaging high-risk patients to early intervention. PMID- 23368928 TI - The effect of larval nutritional deprivation on the life history and DDT resistance phenotype in laboratory strains of the malaria vector Anopheles arabiensis. AB - BACKGROUND: Anopheles arabiensis is a major malaria vector in Africa. It thrives in agricultural areas and has been associated with increased malaria incidence in areas under rice and maize cultivation. This effect may be due to increased adult size and abundance as a consequence of optimal larval nutrition. The aim of this study was to examine the effect of larval nutrition on the life history and expression of insecticide resistance in adults of laboratory reared An. arabiensis. METHODS: Larvae drawn from an insecticide susceptible An. arabiensis strain (SENN) as well as a DDT-resistant strain (SENN-DDT) were subjected to three fasting regimes: 1 mg of food per larva offered once per day, once every second day and once every third day. Control cohorts included larvae offered 1 mg food thrice per day. The rate of larval development was compared between matched cohorts from each strain as well as between fasted larvae and their respective controls. The expression of DDT resistance/tolerance in adults was compared between the starved cohorts and their controls by strain. Factors potentially affecting variation in DDT resistance/tolerance were examined including: adult body size (wing length), knock-down resistance (kdr) status and levels of detoxification enzyme activity. RESULTS AND CONCLUSION: Anopheles arabiensis larval development is prolonged by nutrient deprivation and adults that eclose from starved larvae are smaller and less tolerant to DDT intoxication. This effect on DDT tolerance in adults is also associated with reduced detoxification enzyme activity. Conversely, well fed larvae develop comparatively quickly into large, more DDT tolerant (SENN) or resistant (SENN-DDT) adults. This is important in those instances where cereal farming is associated with increased An. arabiensis transmitted malaria incidence, because large adult females with high teneral reserves and decreased susceptibility to insecticide intoxication may also prove to be more efficient malaria vectors. In general, larval nutrient deprivation in An. arabiensis has important implications for subsequent adults in terms of their size and relative insecticide susceptibility, which may in turn impact on their malaria vector capacity in areas where insecticide based control measures are in place. PMID- 23368927 TI - From accuracy to patient outcome and cost-effectiveness evaluations of diagnostic tests and biomarkers: an exemplary modelling study. AB - BACKGROUND: Proper evaluation of new diagnostic tests is required to reduce overutilization and to limit potential negative health effects and costs related to testing. A decision analytic modelling approach may be worthwhile when a diagnostic randomized controlled trial is not feasible. We demonstrate this by assessing the cost-effectiveness of modified transesophageal echocardiography (TEE) compared with manual palpation for the detection of atherosclerosis in the ascending aorta. METHODS: Based on a previous diagnostic accuracy study, actual Dutch reimbursement data, and evidence from literature we developed a Markov decision analytic model. Cost-effectiveness of modified TEE was assessed for a life time horizon and a health care perspective. Prevalence rates of atherosclerosis were age-dependent and low as well as high rates were applied. Probabilistic sensitivity analysis was applied. RESULTS: The model synthesized all available evidence on the risk of stroke in cardiac surgery patients. The modified TEE strategy consistently resulted in more adapted surgical procedures and, hence, a lower risk of stroke and a slightly higher number of life-years. With 10% prevalence of atherosclerosis the incremental cost-effectiveness ratio was ? 4,651 and ? 481 per quality-adjusted life year in 55-year-old men and women, respectively. In all patients aged 65 years or older the modified TEE strategy was cost saving and resulted in additional health benefits. CONCLUSIONS: Decision analytic modelling to assess the cost-effectiveness of a new diagnostic test based on characteristics, costs and effects of the test itself and of the subsequent treatment options is both feasible and valuable. Our case study on modified TEE suggests that it may reduce the risk of stroke in cardiac surgery patients older than 55 years at acceptable cost-effectiveness levels. PMID- 23368930 TI - Obscure gastrointestinal bleeding and Turner syndrome. AB - Gastrointestinal bleeding in individuals with Turner syndrome is relatively rare and there have been only a handful of reported cases in the literature. Here, we present two patients with Turner syndrome who were evaluated for obscure gastrointestinal bleeding. Our first patient presented with iron deficiency anemia and the work-up for a possible gastrointestinal bleed was pertinent only for polyps and a non-bleeding vein in the colon seen on colonoscopy. Our second patient had a history of unexplained recurrent melena and iron deficiency anemia, with previously normal esophagogastroduodenoscopies, colonoscopies and a Meckel's diverticulum scan. Both patients were subsequently diagnosed with gastrointestinal vascular malformations via capsule endoscopy. PMID- 23368931 TI - Harnessing the power of the grassroots to conduct public health research in sub Saharan Africa: a case study from western Kenya in the adaptation of community based participatory research (CBPR) approaches. AB - BACKGROUND: Community-based participatory research (CBPR) is a collaborative approach to research that involves the equitable participation of those affected by an issue. As the field of global public health grows, the potential of CBPR to build capacity and to engage communities in identification of problems and development and implementation of solutions in sub-Saharan Africa has yet to be fully tapped. The Orphaned and Separated Children's Assessments Related to their Health and Well-Being (OSCAR) project is a longitudinal cohort of orphaned and non-orphaned children in Kenya. This paper will describe how CBPR approaches and principles can be incorporated and adapted into the study design and methods of a longitudinal epidemiological study in sub-Saharan Africa using this project as an example. METHODS: The CBPR framework we used involves problem identification, feasibility and planning; implementation; and evaluation and dissemination. This case study will describe how we have engaged the community and adapted CBPR methods to OSCAR's Health and Well-being Project's corresponding to this framework in four phases: 1) community engagement, 2) sampling and recruitment, 3) retention, validation, and follow-up, and 4) analysis, interpretation and dissemination. RESULTS: To date the study has enrolled 3130 orphaned and separated children, including children living in institutional environments, those living in extended family or other households in the community, and street involved children and youth. Community engagement and participation was integral in refining the study design and identifying research questions that were impacting the community. Through the participation of village Chiefs and elders we were able to successfully identify eligible households and randomize the selection of participants. The on-going contribution of the community in the research process has been vital to participant retention and data validation while ensuring cultural and community relevance and equity in the research agenda. CONCLUSION: CBPR methods have the ability to enable and strengthen epidemiological and public health research in sub-Saharan Africa within the social, political, economic and cultural contexts of the diverse communities on the continent. This project demonstrates that adaptation of these methods is crucial to the successful implementation of a community-based project involving a highly vulnerable population. PMID- 23368933 TI - Coverage- and temperature-controlled isomerization of an imine derivative on Au(111). AB - The isomerization behavior of photochromic molecular switches is strongly influenced by adsorption on metal surfaces. For (E)-3,5-di-tert-butyl-N-(3,5-di tert-butylbenzylidene)aniline (abbreviated as TBI for tetra-tert-butyl imine), it is found that a layer adsorbed on Au(111) can undergo an isomerization from the trans to the cis and back to the trans configuration when continuously increasing the sample temperature and accordingly decreasing the sample coverage. The conformation and adsorption geometry of TBI are determined from near-edge X-ray absorption fine structure measurements in agreement with density functional theory calculations taking into account the van der Waals interaction between adsorbate and metal surface. The coverage- and temperature-controlled conformational transitions are reversible and are driven by the higher packing density of the less stable cis-isomer in combination with the low thermal activation barrier of the trans- to cis-isomerization typical for imine derivatives. This unexpected scenario is corroborated by thermal desorption and vibrational spectroscopy as well as scanning tunneling microscopy. PMID- 23368932 TI - High quality de novo sequencing and assembly of the Saccharomyces arboricolus genome. AB - BACKGROUND: Comparative genomics is a formidable tool to identify functional elements throughout a genome. In the past ten years, studies in the budding yeast Saccharomyces cerevisiae and a set of closely related species have been instrumental in showing the benefit of analyzing patterns of sequence conservation. Increasing the number of closely related genome sequences makes the comparative genomics approach more powerful and accurate. RESULTS: Here, we report the genome sequence and analysis of Saccharomyces arboricolus, a yeast species recently isolated in China, that is closely related to S. cerevisiae. We obtained high quality de novo sequence and assemblies using a combination of next generation sequencing technologies, established the phylogenetic position of this species and considered its phenotypic profile under multiple environmental conditions in the light of its gene content and phylogeny. CONCLUSIONS: We suggest that the genome of S. arboricolus will be useful in future comparative genomics analysis of the Saccharomyces sensu stricto yeasts. PMID- 23368934 TI - Incidence of onychomycosis among psoriatic patients with nail involvement: a descriptive study. PMID- 23368935 TI - Antitumor activities of extracts from selected desert plants against HepG2 human hepatocellular carcinoma cells. AB - CONTEXT: Phytochemicals are produced by desert plants to protect themselves against stressful environments. They have been shown to be useful in preventing and fighting adverse pathophysiological conditions and complex diseases, including cancer. Although many desert plants have been investigated for their antitumor properties, a large number of them still remain to be explored for possible therapeutic applications in oncologic diseases. OBJECTIVE: To screen the antitumor effects of selected desert plants, namely Achillea fragrantissima (Forssk.) Sch. Bip. (Compositae), Ochradenus baccatus Delile (Resedaceae), Origanum dayi Post (Lamiaceae), Phlomis platystegia Post (Lamiaceae) and Varthemia iphionoides Boiss (Compositae), against an in vitro tumor model utilizing HepG2 human hepatocellular carcinoma cells. MATERIALS AND METHODS: The aqueous extracts of aerial parts of the aforementioned plants were prepared and used for the in vitro experiments. The HepG2 cells were exposed to varying concentrations (0-4 mg/mL) of each plant extract for 24 or 48 h and the cytotoxicity was measured by the MTT assay. RESULTS: Following 24 h exposure, O. dayi extract exhibited a substantial antiproliferative effect in HepG2 cells (IC50 = 1.0 mg/mL) followed by O. baccatus (IC50 = 1.5 mg/mL). All plant extracts displayed cytotoxicity following 48 h exposure. Nevertheless, a substantial effect was observed with O. dayi (IC50 = 0.35 mg/mL) or O. baccatus (IC50 = 0.83 mg/mL). CONCLUSION: The aqueous extracts from aerial parts of O. dayi and O. baccatus possess antitumor effects against human liver cancer cells. These desert plants represent valuable resources for the development of potential anticancer agents. PMID- 23368936 TI - Pharmaceutical properties and toxicology of Dioclea grandiflora. AB - CONTEXT: Since the beginning of civilization, herbal medicines have been an important source for human beings to treat their ailments. Despite the large number of synthetic remedies available in the market, the use of plants is seen as a great challenge in the search for new substances endowed with therapeutic properties. One example is Dioclea grandiflora Mart. ex Benth. (Leguminosae) employed in traditional medicine to treat prostate disorders and kidney stones. OBJECTIVES: This work presents a brief overview of D. grandiflora, including a description of the plant, its chemical composition and pharmacological properties. METHODS: This review gathers information available in the scientific literature compiled from databases such as Science Direct, PubMed, Dr. Dukes Phytochemical and Ethnobotany, Missouri Botanical Garden and The International Plant Names Index. RESULTS: The information found in the literature showed that flavonoids are the major constituents of D. grandiflora that account for most of the pharmacological properties so far disclosed. Several studies have revealed that D. grandiflora possesses antinociceptive, cardiovascular, antioxidant and anti-inflammatory activities. CONCLUSION: Research shows that D. grandiflora is a potential source of compounds pertaining medicinal applications. It provides an interesting subject in the search for new drugs of natural origin. PMID- 23368937 TI - Phenolic composition, antioxidant and anti-acetylcholinesterase activities of the Tunisian Scabiosa arenaria. AB - CONTEXT: There is a need for the discovery of novel natural antioxidants and acetylcholinesterase inhibitors (AChEIs) that are safe and effective at a global level. This is the first study on antioxidant and anti-acethylcholinesterase activity of Scabiosa arenaria Forssk (Dipsacaceae). OBJECTIVE: The antioxidant potential and anti-acetylcholinesterase (AChE) activity of S. arenaria were investigated. MATERIAL AND METHODS: The crude, ethyl acetate (EtOAc), butanol (n BuOH) and water extracts prepared from flowers, fruits and stems and leaves of S. arenaria were tested to determine their total polyphenol content (TPC), total flavonoid content (TFC), total condensed tannin content (CTC) and their antioxidant activity by using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2' azinobis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), reducing power and beta carotene bleaching inhibition activity. Anti-AChE activity was also determined. RESULTS: EtOAc and n-BuOH fractions of fruits had both the highest (TPC) (269.09 mg gallic acid equivalents/g dry weight). The crude extract of stems and leaves had the highest TFC (10.9 mg quercetin equivalent/g dry weight). The n-BuOH fraction of stems and leaves had the highest CTC (489.75 mg catechin equivalents/g dry weight). The EtOAc fraction of flowers exhibit a higher activity in each antioxidant system with a special attention for DPPH assay (IC50 = 0.017 mg/mL) and reducing power (EC50 = 0.02 mg/mL). The EtOAc and n-BuOH fractions of stems and leaves showed strong inhibition of AChE (IC50 = 0.016 and 0.029 mg/mL, respectively). DISCUSSION AND CONCLUSIONS: These results suggest the potential of S. arenaria as a possible source of novel compounds and as an alternative antioxidant and AChEIs. PMID- 23368938 TI - Antidiabetic potential of phycocyanin: effects on KKAy mice. AB - CONTEXT: Phycocyanin (PC) has been proven to have many therapeutic properties, but its effects on diabetes have not been investigated. OBJECTIVE: Antidiabetic activity of PC isolated from Spirulina platensis was evaluated in this study. MATERIALS AND METHODS: Oral administration of PC (100 mg/kg, once per day for 3 weeks) on KKAy mice were investigated by monitoring the changes in body weight, food intake, fasting plasma glucose level, 24 h random blood glucose levels, oral glucose tolerance tests (OGTTs), glycosylated serum protein (GSP), fasting serum insulin (FINS), glycogen, triglyceride (TG), total cholesterol (TC), total antioxidative capability (T-AOC) and malondialdehyde (MDA). Histopathological changes in the pancreas were also examined with hematoxylin-eosin staining. RESULTS: Administration of PC significantly decreased the body weight, fasting plasma glucose, 24 h random blood glucose levels, FINS and GSP levels, TG and TC content in serum and livers, MDA content in livers (p < 0.05 or p < 0.01). On the other hand, glucose tolerance to glucose administration, T-AOC, and the content of glycogen in liver and muscle were enhanced following PC treatment (p < 0.05 or p < 0.01). Histopathological results showed that PC administration suppressed the abnormal enlargement of islets observed in the pancreas of KKAy mice. DISCUSSION AND CONCLUSION: The antidiabetic effect of PC on KKAy mice is most likely due to its ability to enhance insulin sensitivity, amelioration of insulin resistance of peripheral target tissues and regulation of glucolipide metabolism. Therefore, PC may have a potential clinical utility in combating type-2 diabetes. PMID- 23368939 TI - The association effect of insulin and clonazepam on oxidative stress in liver of an experimental animal model of diabetes and depression. AB - CONTEXT: It is known that oxidative stress occurs in peripheral blood in an experimental animal model of diabetes and depression, and acute treatment with insulin and clonazepam (CNZ) has a protective effect on oxidative stress in this model. OBJECTIVE: This study evaluated the effect of insulin plus CNZ on oxidative stress parameters in the liver of diabetic male rats induced with streptozotocin (STZ) and subjected to forced swimming test (FST). MATERIALS AND METHODS: Diabetes was induced by a single intraperitoneal (i.p.) dose of STZ 60 mg/kg in male Wistar rats. Insulin (4 IU/kg) plus CNZ acute i.p. treatment (0.25 mg/kg) was administered 24, 5 and 1 h before the FST. Nondiabetic control rats received i.p. injections of saline (1 mL/kg). Protein oxidative damage was evaluated by carbonyl formation and the antioxidant redox parameters were analyzed by the measurements of enzymatic activities of the superoxide dismutase (SOD), catalase and glyoxalase I (GLO). Glycemia levels also were determined. RESULTS: Our present study has shown an increase in carbonyl content from diabetic rats subjected to FST (2.04 +/- 0.55), while the activity of catalase (51.83 +/- 19.02) and SOD (2.30 +/- 1.23) were significantly decreased in liver from these animals, which were reverted by the treatment. Also, the activity of GLO (0.15 +/- 0.02) in the liver of the animals was decreased. DISCUSSION AND CONCLUSION: Our findings showed that insulin plus CNZ acute treatment ameliorate the antioxidant redox parameters and protect against protein oxidative damage in the liver of diabetic rats subjected to FST. PMID- 23368940 TI - Neurobehavioral assessment of hydroalcoholic extract of Trigonella foenum-graecum seeds in rodent models of Parkinson's disease. AB - CONTEXT: Neuroprotective therapy to rescue dopaminergic neurons is an important trait in the management of Parkinson's disease (PD). OBJECTIVE: The present study identified and evaluated SFSE-T, a standardized hydroalcoholic extract of Trigonella foenum-graecum L. seeds (Fabaceae), in animal models of PD. MATERIALS AND METHODS: The identification of SFSE-T was carried out by high-performance liquid chromatography for the marker compound trigonelline (TGN). The effects of single dose oral treatment of SFSE-T (10, 30 or 100 mg/kg) were studied using animal models of PD, namely, 6-hydroxydopamine (6-OHDA)-induced unilateral lesions in rats, and 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration in C57BL/6 mice. The effects of SFSE-T on monoamino oxidase (MAO) enzyme in vitro as well as possible side effects of SFSE-T in vivo were also evaluated. RESULTS: The concentration of TGN in a test sample of SFSE-T was found to be 82%. SFSE-T (30 mg/kg, oral) showed a significant increase in the number of ipsilateral rotations (45.67 rotations in 30-min period) as compared with vehicle control group (no rotations) when tested in 6-OHDA-induced unilateral lesioned rats. SFSE-T (30 mg/kg, oral) showed significant reversal of motor dysfunction (spontaneous motor activity scores, speed, distance traveled and number of square crossed) caused by MPTP induced lesions in C57BL/6 mice in pretreatment (1 h) schedule but not in post-treatment (1 h) schedule. SFSE-T neither showed anticholinergic effects nor showed selective MAO-B enzyme inhibition in vitro. DISCUSSION AND CONCLUSION: SFSE-T showed reversal of motor symptoms in an animal model of PD probably through neuroprotective properties. PMID- 23368941 TI - Hypotensive activity of auraptene, a monoterpene coumarin from Citrus spp. AB - CONTEXT: Citrus spp. (Rutaceae) are well-documented for their cardioprotective properties. Auraptene is a bioactive monoterpene coumarin ether abundantly present in the Citrus spp. OBJECTIVE: To investigate the hypotensive activity of auraptene. METHODS: Different groups of normotensive rats (n = 5 in each group) were subjected to single intravenous injections of auraptene (125, 250 and 500 ug/kg), nifedipine (as positive control; 63, 125 and 250 ug/kg) or negative control [DMSO/normal saline (1:3)]. Mean arterial blood pressure (MABP) and heart rate (HR) were evaluated following each treatment. RESULTS: A dose-dependent hypotensive effect was observed following auraptene injection, which was significant at 250 and 500 ug/kg (p < 0.001) but not 125 ug/kg (p > 0.05). With respect to the positive control, nifedipine reduced MABP at all tested doses, dose-dependently and significantly (p < 0.001). The MABP lowering effect of auraptene was found to be significantly lower than that of nifedipine (p < 0.001). CONCLUSION: In light of the present findings, auraptene has moderate hypotensive activity. Further investigations are recommended to explore the effects of higher doses as well as oral administration of this phytochemical. PMID- 23368942 TI - The management of skin toxicity during erlotinib in advanced non-small cell lung cancer: how much does it cost? AB - INTRODUCTION: The aim of this study is to estimate the costs for the foreseeable management of skin toxicity (papulo-pustular reactions) in patients treated with erlotinib for non-small cell lung cancer (NSCLC) in order to value the direct medical economical impact. No studies like the above have been published until now. MATERIALS AND METHODS: We retrospectively analyzed all consecutive patients with NSCLC treated with erlotinib at Clinical Oncology Unit of University Hospital of Ferrara, Italy from June 2007 to May 2011. We evaluated severity and median duration of papulo-pustular reactions for each grade and we identified costs for the different therapeutic interventions. RESULTS: We evaluated 25 patients. Median time follow-up was 18.65 months (range 5.69-88.36). Finally, follow-up 7 patients (28.0%) were alive with metastases and 18 patients (72.0%) were deceased. Nineteen patients (76.0%) developed papulo-pustular reactions: 2 patients (10.5%) mild rash, 11 patients (57.9%) moderate rash and 6 patients (31.6%) severe rash; no case of hospitalization was observed. Median duration of mild rash was 97 days (costs-range: 157.7-452.2 ?), median duration of moderate rash was 89 days (costs-range: 438.7-1035.6 ?) and median duration of severe rash was 34 days (costs-range: 460.3-1057.2 ?). CONCLUSIONS: Our experience, though the analysis of not selected case study, showed that management of skin toxicities related to erlotinib is not so expensive, especially for low grade; therefore, we also recommended to give particular attention to low grade of toxicities for reducing progression to high grade and consequent risk of hospitalization, which really impact on costs. PMID- 23368943 TI - Papillomaviral DNA sequences are not amplifiable from canine subungual squamous cell carcinomas. AB - AIM: To determine if papillomaviral DNA is more frequently present within canine subungual squamous cell carcinomas (SCCs) than in non-SCC digit lesions. METHODS: Total DNA was extracted from 23 canine subungual SCCs and 23 non-SCC digit lesions. The presence of amplifiable DNA within each sample was confirmed by amplifying a section of the glyceraldehyde-3-phosphate dehydrogenase (GADPH) gene. Two different consensus PCR primer sets were used to amplify papillomaviral DNA from the samples. RESULTS: The consensus primers only amplified papillomaviral DNA from the positive control samples. None of the 46 canine digit samples contained DNA that was amplifiable by the consensus PCR primers. CONCLUSION: Papillomaviruses are unlikely to be a significant cause of canine subungual SCCs. CLINICAL RELEVANCE: While circumstantial evidence suggests that canine subungual SCCs could develop due to papillomaviral infection, this study did not reveal any evidence to support papillomaviral aetiology of these neoplasms. PMID- 23368944 TI - Improving levels of evidence in studies published in spinal journals from 1983 to 2011. AB - INTRODUCTION: The evidence basis for spinal surgical practice is closely related to the quality of clinical studies published. In the hierarchy of study designs, the quality of evidence from a randomised controlled trial (RCT) and meta analysis are considered better than other types of prospective and retrospective study designs. We assessed the level of evidence in studies published from 1983 to 2011 in 4 journals, publishing predominantly on spine related topics. METHODS: Computerised search of the Medline database was undertaken to evaluate the articles published in 4 'spinal' journals (Spine, European Spine Journal, Journal of Spinal Disorders and Techniques and Spinal Cord) from 1983 to 2011. The numbers of RCTs, meta-analyses and other clinical trials (non-RCT) over the time periods 1983-7, 1988-92, 1993-7, 1998-2002, 2003-7 and 2008-11 were compared. RESULTS: From a total number of 21775 articles evaluated, there were 888 (4.1%) RCTs, 93 (0.4%) meta-analyses and 1355 (6.2%) other clinical trials. Overall, comparing the time periods 1983-7 with 2008-11, there were increases in the proportion of RCTs (1.6% to 5.1%), meta-analysis (0% to 0.6%) and other clinical trials (0.9% to 6.3%) and a decrease in the proportion of other articles published (97.6% to 88.1%). These changes appear to have plateaued after 2003-7. CONCLUSIONS: Although RCTs, meta-analysis and other clinical trials form a small proportion of the studies published in leading 'spinal' journals, there have been an encouraging increase in their proportion over the years. This is comparable with other larger surgical specialities and provides a better evidence basis for clinical practice in spinal disorders. PMID- 23368945 TI - Experimental observation of double-walled peptide nanotubes and monodispersity modeling of the number of walls. AB - Self-assembled nanoarchitectures based on biological molecules are attractive because of the simplicity and versatility of the building blocks. However, size control is still a challenge. This control is only possible when a given system is deeply understood. Such is the case with the lanreotide acetate, an octapeptide salt that spontaneously forms monodisperse nanotubes when dissolved into pure water. Following a structural approach, we have in the past demonstrated the possibility to tune the diameter of these nanotubes while keeping a strict monodispersity, either by chemical modification of one precise amino acid on the peptide sequence or by changing the size of the counterions. On the basis of these previous studies, we replaced monovalent counterions by divalent ones to vary the number of walls. Indeed, in the present work, we show that lanreotide associated with a divalent counterion forms double-walled nanotubes while keeping the average diameter constant. However, the strict monodispersity of the number of walls was unexpected. We propose that the divalent counterions create an adhesion force that can drive the wall packing. This adhesion force is counterbalanced by a mechanical one that is related to the stiffness of the peptide wall. By taking into account these two opposite forces, we have built a general model that fully explains why the lanreotide nanotubes formed with divalent counterions possess two walls and not more. PMID- 23368946 TI - Increased levels of serum and gingival crevicular fluid monocyte chemoattractant protein-1 in smokers with periodontitis. AB - BACKGROUND: Smoking alters the host response, including vascular function, neutrophil/monocyte activities, adhesion molecule expression, antibody production, and cytokine and inflammatory mediator release. Monocyte chemoattractant protein-1 (MCP-1) is involved in the activation and recruitment of inflammatory and immune cells to infected sites, thereby mediating a variety of pathophysiologic conditions. Estimation of serum and gingival crevicular fluid (GCF) MCP levels could be a reliable indicator of periodontal disease activity. Hence, the objective of this study is to analyze the serum and GCF MCP-1 levels of smokers and never-smokers with periodontitis and compare them with those in periodontally healthy individuals. METHODS: A total of 90 participants (30 periodontally healthy individuals, 30 non-smoking individuals with periodontitis, and 30 smokers with periodontitis) formed the study group. Serum and GCF samples were collected, and MCP-1 levels were estimated using enzyme-linked immunosorbent assay. RESULTS: Mean MCP-1 levels in serum and GCF were found to be highest in smokers with periodontitis, followed by the periodontitis group, and then by the healthy controls. The values were statistically significant (P <0.001). CONCLUSIONS: It can be concluded that the high levels of both serum and GCF MCP-1 found in smokers could explain the severity of periodontitis in smokers. More longitudinal, prospective studies will help to verify the observations of the present study. Further research in this direction could reveal reliable markers to forecast the progression of periodontitis in high-risk groups. PMID- 23368947 TI - Triclosan blocks MMP-13 expression in hormone-stimulated osteoblasts. AB - BACKGROUND: Matrix metalloproteinase-13 (MMP-13) is an important enzyme for the modulation of bone turnover and gingival recession. Elevated levels of MMP-13 are associated with alveolar bone resorption, periodontal ligament breakdown, and gingival attachment loss, which are the clinical symptoms of periodontal disease. Evidence continues to suggest that periodontal disease contributes to oral tissue breakdown and is linked to numerous systemic conditions. Triclosan (TCN) is a long-standing, proven antibacterial and anti-inflammatory agent found in the only Food and Drug Administration-approved dentifrice for the treatment of plaque and gingivitis. METHODS: This study examines the inhibitory effects of TCN on lipopolysaccharide-, parathyroid hormone (PTH)-, and prostaglandin E2 (PGE2) induced expression of MMP-13 in UMR 106-01 cells, an osteoblastic osteosarcoma cell line. The cells were stimulated with PTH or PGE2 to induce MMP-13 mRNA expression, and real-time reverse transcription-polymerase chain reaction was performed to determine gene expression levels. Western blot analysis assessed the presence or absence of protein degradation or inhibition of protein synthesis. MMP-13 promoter reporter assay was used to explore possible direct effects of TCN on the MMP-13 promoter. RESULTS: TCN significantly reduced PTH or PGE2 elevated expression of MMP-13 in osteoblastic cells without affecting basal levels of the mRNA. Surprisingly, TCN enhanced the expression of c-fos and amphiregulin mRNA. A promoter assay indicated that TCN directly inhibits the activation of the PTH responsive minimal promoter of MMP-13. CONCLUSION: The present study appears to have identified a nuclear mechanism of action of TCN that accounts for the ability of TCN to inhibit PTH- or PGE2-induced MMP-13 expression in osteoblastic cells. PMID- 23368948 TI - Randomized controlled clinical trial evaluating connective tissue graft plus resin-modified glass ionomer restoration for the treatment of gingival recession associated with non-carious cervical lesion: 2-year follow-up. AB - BACKGROUND: The aim of this clinical study is to evaluate the 2-year term results of gingival recession (GR) associated with non-carious cervical lesions (NCCLs) treated by connective tissue graft (CTG) alone or in combination with a resin modified glass ionomer restoration (CTG+R). METHODS: Thirty-six patients with Miller Class I buccal GR associated with NCCLs completed the follow-up. The defects were randomly assigned to receive either CTG or CTG+R. Bleeding on probing (BOP), probing depth (PD), relative GR, clinical attachment level (CAL), and cervical lesion height coverage were measured at baseline, 6 months, 1 year, and 2 years after treatment. RESULTS: Both groups showed statistically significant gains in CAL and soft-tissue coverage. The differences between groups were not statistically significant in BOP, PD, relative GR, or CAL after 2 years. Cervical lesion height coverage was 79.31% +/- 18.51% for CTG and 71.95% +/- 13.25% for CTG+R (P >0.05). Estimated root coverage was 91.56% +/- 11.74% for CTG and 93.29% +/- 7.97% for CTG+R (P >0.05). CONCLUSIONS: Within the limits of the present study, it can be concluded that both procedures provide comparable soft tissue coverage after 2 years of follow-up. PMID- 23368950 TI - Neuropsychiatric symptoms in Nigerian patients with Parkinson's disease. AB - BACKGROUND: Neuropsychiatric symptoms are common in Parkinson's disease and may precede onset of motor symptoms. They are also known to increase caregiver's burden. OBJECTIVE: The aim of this study was to assess neuropsychiatric symptoms in a cohort of Nigerian patients with idiopathic Parkinson's disease and compare with systemic hypertension. METHOD: Fifty patients with idiopathic Parkinson's disease were compared with fifty demographically matched controls with systemic hypertension. Diagnosis of Parkinson's disease was based on the United Kingdom Parkinson Disease Society (UKPDS) Brain Bank Clinical diagnostic Criteria. Diagnosis of hypertension was based on recorded blood pressure of >=140/90 mmHg on two different occasions. The Neuropsychiatric Inventory (NPI) was applied to caregivers of both patients and controls. RESULTS: There were significant differences in frequency of neuropsychiatric symptoms in patients and controls (P < 0.05). Significant differences were found in mean distress scores for some neuropsychiatric symptoms and the total mean distress score. In all cases, patients with Parkinson's disease had higher scores when compared with controls. Severity of motor symptoms, as measured by the UKPDS, correlated with total NPI severity scores (P = 0.000). CONCLUSION: Neuropsychiatric symptoms occur more frequently in Parkinson's disease than matched controls, and the presence of these symptoms is associated with caregivers' distress. There is a need for early and adequate treatment for motor and behavioural symptoms of Parkinson's disease. PMID- 23368949 TI - Epigenetic regulation of TNFA expression in periodontal disease. AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the molecular pathogenesis of periodontal disease. However, the epigenetic regulation attributable to microbial and inflammatory signals at the biofilm-gingival interface are poorly understood. In this study, the DNA methylation alteration within the TNFA promoter in human gingival biopsies from different stages of periodontal disease is investigated and the regulatory mechanism of TNFA transcription by DNA methylation is explored. METHODS: Gingival biopsies were obtained from 17 patients with chronic periodontitis (CP) and 18 periodontally healthy individuals. Another 11 individuals participated in an experimentally induced gingivitis study, and gingival biopsies were collected at the baseline, induction, and resolution phase. To confirm that TNFA promoter methylation modulated TNFA transcription, THP.1 cells were treated with a DNA methyltransferase inhibitor, 5-Aza-2-deoxycytidine (5-Aza-2dC), and an RAW294.7 cell line transfected with a TNFA promoter-specific luciferase reporter system with or without methylation was used. RESULTS: In gingival biopsies from individuals with severe CP, two individual cytosine-guanine dinucleotides (CpG sites) within the TNFA promoter (at -163 and -161 bp) displayed increased methylation in CP samples compared to those with gingival health (16.1% +/- 5.1% versus 11.0% +/- 4.6%, P = 0.02 and 19.8% +/- 4.1% versus 15.4% +/- 3.6%, P = 0.04, respectively). The methylation level at -163 bp was inversely associated with the transcription level of TNFA (P = 0.018). However, no significant difference in the TNFA promoter methylation pattern was observed in samples biopsied during the induction or resolution phase of experimentally induced gingivitis, which represented a reversible periodontal lesion. THP.1 cells treated with 5-Aza-2dC demonstrated a time-dependent increase in TNFA messenger level. It was also found that the luciferase activity decreased 2.6-fold in a construct containing an in vitro methylated TNFA promoter when compared to the unmethylated insert (P = 0.03). CONCLUSION: Although the biopsy samples represented a mixed cell population, the change in promoter methylation status in chronic periodontal disease suggested that DNA methylation may be an important regulatory mechanism in controlling TNFA transcriptional expression in periodontal disease. PMID- 23368951 TI - A negative selection heuristic to predict new transcriptional targets. AB - BACKGROUND: Supervised machine learning approaches have been recently adopted in the inference of transcriptional targets from high throughput trascriptomic and proteomic data showing major improvements from with respect to the state of the art of reverse gene regulatory network methods. Beside traditional unsupervised techniques, a supervised classifier learns, from known examples, a function that is able to recognize new relationships for new data. In the context of gene regulatory inference a supervised classifier is coerced to learn from positive and unlabeled examples, as the counter negative examples are unavailable or hard to collect. Such a condition could limit the performance of the classifier especially when the amount of training examples is low. RESULTS: In this paper we improve the supervised identification of transcriptional targets by selecting reliable counter negative examples from the unlabeled set. We introduce an heuristic based on the known topology of transcriptional networks that in fact restores the conventional positive/negative training condition and shows a significant improvement of the classification performance. We empirically evaluate the proposed heuristic with the experimental datasets of Escherichia coli and show an example of application in the prediction of BCL6 direct core targets in normal germinal center human B cells obtaining a precision of 60%. CONCLUSIONS: The availability of only positive examples in learning transcriptional relationships negatively affects the performance of supervised classifiers. We show that the selection of reliable negative examples, a practice adopted in text mining approaches, improves the performance of such classifiers opening new perspectives in the identification of new transcriptional targets. PMID- 23368952 TI - Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. AB - Obstructive lung diseases (OLD) such as asthma and chronic obstructive pulmonary disease (COPD) are very prevalent conditions. Disease phenotypes (e.g. chronic bronchitis, emphysema, etc.) often overlap, and significant confusion exists about their optimal nosologic characterization. Obstructive sleep apnoea (OSA) is also a common condition that features bidirectional interactions with OLD. OSA appears to be more commonly seen in patients with OLD, perhaps as a result of shared risk factors, for example obesity, smoking, increased airway resistance, local and systemic inflammation, anti-inflammatory therapy. Conversely, OSA is associated with worse clinical outcomes in patients with OLD, and continuous positive airway pressure therapy has potential beneficial effects on this vicious pathophysiological interaction. Possible shared mechanistic links include increased parasympathetic tone, hypoxaemia-related reflex bronchoconstriction/vasoconstriction, irritation of upper airway neural receptors, altered nocturnal neurohormonal secretion, pro-inflammatory mediators, within and inter-breath interactions between upper and lower airways, lung volume airway dependence, etc. While the term overlap syndrome has been defined as the comorbid association of COPD and OSA, the interaction between asthma and OSA has not been integrated yet nosologically; in this review, the latter will be called alternative overlap syndrome. In an effort to bolster further investigations in this area, an integrated, lumping nomenclature for OSA in the setting of OLD is proposed here--OLDOSA (obstructive lung disease and obstructive sleep apnoea) syndrome. PMID- 23368953 TI - Micronutrients and pregnancy; effect of supplementation on pregnancy and pregnancy outcomes: a systematic review. AB - INTRODUCTION: Every year more than 20 million infants are born with low birth weight worldwide. About 3.6 million infants die during the neonatal period. More than one third of child deaths are thought to be attributable to maternal and child under nutrition. OBJECTIVES: To systematically review the effect of supplementing various combinations and types of micronutrients on the course and outcomes of pregnancy. METHODS: Electronic search of Medline, Pub Med, Health Internetwork access to Research Initiative, and Google Scholar databases was conducted. Outcomes of interest were birth weight, low birth weight, small size for gestational age, prenatal mortality and neonatal mortality. After exclusion of irrelevant /incomplete ones, 17 out of 115 articles were considered for the final analysis. FINDINGS: Majority of the articles reviewed favored the supplementation of micronutrients to pregnant mother. Some studies suggested calcium supplementation is associated with a significant protective benefit in the prevention of pre-eclampsia. The remaining articles reviewed, showed significant benefit of Multiple Micronutrients supplementation during pregnancy in reducing low birth weight, small for Gestational Age births as compared to the usual iron-folate supplements. CONCLUSIONS: Supplying micronutrients, mainly multiple micronutrients have beneficial effect in reducing the risk of low birth weight and other complications. Further studies at various combination and doses of micronutrient supplements are recommended. PMID- 23368954 TI - Intracoronary thrombus in an infant with Kawasaki disease and giant coronary aneurysm. PMID- 23368955 TI - Water intubation method can reduce patients' pain and sedation rate in colonoscopy: a meta-analysis. AB - Several randomized controlled trials (RCT) have shown that water infusion in lieu of air insufflation reduces sedation rate and pain score and increases cecal intubation rate in colonoscopy. The aim of the present study was to confirm the beneficial effects of the water intubation method over the air method. Electronic databases were searched to identify RCT reporting colonoscopy detection using the water method. The pooled data of sedation rate, pain score and other procedure related outcomes were analyzed. Then, 15 full-text articles were selected and assessed. Nine trials with high-quality scores were enrolled into this meta analysis including a total of 1414 participants. Pooled odds ratio (OR) of sedation rate was 0.392 (95% confidence interval (CI): 0.288-0.533, P = 0.000). Pooled weighted mean difference (WMD) of pain score was -1.543 (95% CI: -2.107- 1.069,P = 0.000). Pooled OR of cecal intubation rate was 1.90 (95% CI: 1.29-2.82, P = 0.001). Pooled OR of polyp detection rate and adenoma detection rate were 0.805 (95% CI: 0.606-1.069, P = 0.134) and 0.913 (95% CI: 0.681-1.223, P = 0.168), respectively. Pooled WMD of cecal intubation time was 0.701 (95% CI: 0.486-1.889, P = 0.247). This meta-analysis confirmed that the water method significantly reduced sedation rate and degree of pain without decreasing cecal intubation rate and disease detection rate and without requiring more cecal intubation time, suggesting that the novel water method is better than the conventional air method in colonoscopy detection. PMID- 23368956 TI - Construction of an artifact to the suitability of sitting posture in children with cerebral palsy and multiple disabilities. AB - INTRODUCTION: Cerebral palsy (CP) may involve muscle imbalance between the spastic muscles and their antagonists leading to weak postural changes, decreased mobility and chest deformities. OBJECTIVE: To improve postural condition in children with CP using physiotherapy and assistive technology (AT). MATERIALS AND METHODS: Five children with CP and multiple disabilities and postural changes like scoliosis were included in this study. AT involved the use of low-cost custom made cushion seat and backrest for the wheelchairs to achieve 90 degrees of trunk flexion. This was performed in 10 sessions after the beginning of physiotherapy. As evaluation-intervention tool, photographs were taken at the beginning and end of each session, and then analyzed using software for postural assessment (SAPO). RESULTS: Twenty-five per cent of the participants had an improvement of trunk angulations at the end of the treatment program. CONCLUSION: The use of AT with physiotherapy treatment proved efficient in the postural alignment of children with CP children in a wheelchair. IMPLICATIONS FOR REHABILITATION: Wheelchairs are manufactured in standard size, which makes difficult the adaptation of individuals with peculiar postures. Even the most sophisticated, with adjustments and special accessories, not always allow adjustments to shape up properly to deformities in children with cerebral palsy. It is hoped that this research will be useful in order to show rehabilitation professionals the ability to minimize the difficulties of keeping children with cerebral palsy and multiple disabilities properly seated in the wheelchair, facilitating posture, movement, breathing and swallowing. The construction of these artifacts has the advantage of being low cost, and must pass through stages of adequacy and modeling in order to replace the seat and side of the wheelchair. PMID- 23368957 TI - Asymmetric total syntheses of ansamacrolactams (+)-Q-1047H-A-A and (+)-Q-1047H-R A. AB - The total syntheses of ansamacrolactams (+)-Q-1047H-A-A (16) and (+)-Q-1047H-R-A (17) have been achieved for the first time in 17 steps, leading to the reassignment of the relative stereochemistries and absolute configurations of their natural counterparts. The key steps in the synthetic work included an asymmetric chelation-controlled vinylogous Mukaiyama aldol reaction for the stereoselective synthesis of the syn-aldol adduct 7b and an intramolecular SmI(2) mediated Reformatsky reaction for the formation of the macrocyclic lactam 14. PMID- 23368958 TI - Comparison of high-spin and low-spin nonheme Fe(III)-OOH complexes in O-O bond homolysis and H-atom abstraction reactivities. AB - The geometric and electronic structures and reactivity of an S = 5/2 (HS) mononuclear nonheme (TMC)Fe(III)-OOH complex are studied by spectroscopies, calculations, and kinetics and compared with the results of previous studies of S = 1/2 (LS) Fe(III)-OOH complexes to understand parallels and differences in mechanisms of O-O bond homolysis and electrophilic H-atom abstraction reactions. The homolysis reaction of the HS [(TMC)Fe(III)-OOH](2+) complex is found to involve axial ligand coordination and a crossing to the LS surface for O-O bond homolysis. Both HS and LS Fe(III)-OOH complexes are found to perform direct H atom abstraction reactions but with very different reaction coordinates. For the LS Fe(III)-OOH, the transition state is late in O-O and early in C-H coordinates. However, for the HS Fe(III)-OOH, the transition state is early in O-O and further along in the C-H coordinate. In addition, there is a significant amount of electron transfer from the substrate to the HS Fe(III)-OOH at transition state, but that does not occur in the LS transition state. Thus, in contrast to the behavior of LS Fe(III)-OOH, the H-atom abstraction reactivity of HS Fe(III)-OOH is found to be highly dependent on both the ionization potential and the C-H bond strength of the substrate. LS Fe(III)-OOH is found to be more effective in H-atom abstraction for strong C-H bonds, while the higher reduction potential of HS Fe(III)-OOH allows it to be active in electrophilic reactions without the requirement of O-O bond cleavage. This is relevant to the Rieske dioxygenases, which are proposed to use a HS Fe(III)-OOH to catalyze cis-dihydroxylation of a wide range of aromatic compounds. PMID- 23368959 TI - Exploring the potential for using results-based financing to address non communicable diseases in low- and middle-income countries. AB - BACKGROUND: The burden of disease due to non-communicable diseases (NCDs) is rising in low- and middle-income countries (LMICs) and funding for global health is increasingly limited. As a large contributor of development assistance for health, the US government has the potential to influence overall trends in NCDs. Results-based financing (RBF) has been proposed as a strategy to increase aid effectiveness and efficiency through incentives for positive performance and results in health programs, but its potential for addressing NCDs has not been explored. METHODS: Qualitative methods including literature review and key informant interviews were used to identify promising RBF mechanisms for addressing NCDs in resource-limited settings. Eight key informants identified by area of expertise participated in semi-structured interviews. RESULTS: The majority of RBF schemes to date have been applied to maternal and child health. Evidence from existing RBF programs suggests that RBF principles can be applied to health programs for NCDs. Several options were identified for US involvement with RBF for NCDs. CONCLUSION: There is potential for the US to have a significant impact on NCDs in LMICs through a comprehensive RBF strategy for global health. RBF mechanisms should be tested for use in NCD programs through pilot programs incorporating robust impact evaluations. PMID- 23368960 TI - A unified electrocatalytic description of the action of inhibitors of nickel carbon monoxide dehydrogenase. AB - Several small molecules and ions, notably carbon monoxide, cyanide, cyanate, and hydrogen sulfide, are potent inhibitors of Ni-containing carbon monoxide dehydrogenases (Ni-CODH) that catalyze very rapid, efficient redox interconversions of CO(2) and CO. Protein film electrochemistry, which probes the dependence of steady-state catalytic rate over a wide potential range, reveals how these inhibitors target particular oxidation levels of Ni-CODH relating to intermediates (C(ox), C(red1), and C(red2)) that have been established for the active site. The following properties are thus established: (1) CO suppresses CO(2) reduction (CO is a product inhibitor), but its binding affinity decreases as the potential becomes more negative. (2) Cyanide totally inhibits CO oxidation, but its effect on CO(2) reduction is limited to a narrow potential region (between -0.5 and -0.6 V), below which CO(2) reduction activity is restored. (3) Cyanate is a strong inhibitor of CO(2) reduction but inhibits CO oxidation only within a narrow potential range just above the CO(2)/CO thermodynamic potential--EPR spectra confirm that cyanate binds selectively to C(red2). (4) Hydrogen sulfide (H(2)S/HS(-)) inhibits CO oxidation but not CO(2) reduction--the complex on/off characteristics are consistent with it binding at the same oxidation level as C(ox) and forming a modified version of this inactive state rather than reacting directly with C(red1). The results provide a new perspective on the properties of different catalytic intermediates of Ni-CODH- uniting and clarifying many previous investigations. PMID- 23368962 TI - Comparison of endoscopic ultrasonography-guided fine-needle aspiration cytology results with and without the stylet in 3364 cases. AB - BACKGROUND AND AIM: Endoscopic ultrasound-guided fine-needle aspiration cytology (EUS-FNA) is traditionally carried out with the stylet, as it is believed to prevent blockage or contamination of the needle by tissue coming from the gastrointestinal wall. However, this recommendation has not been demonstrated on an empirical basis. The aim of the present study was to compare the yield of EUS FNA in a very large series of patients with (S+) and without (S-) the stylet. METHODS: Until 2004, the stylet was used for EUS-FNA in our center. After that, the stylet was never used. The results of all EUS-FNA in solid lesions carried out by one endosonographer with the same needle type were compared before and after stylet use was stopped. RESULTS: 3364 EUS-FNA procedures (in 3078 patients) in solid lesions were included (1483 S+ and 1881 S-). There was no significant difference between the S+ and S- results for any variable other than the number of passes required. The number of passes was significantly lower in the S- group when sampling lymph nodes, wall lesions and when carrying out biopsies through the gastric or rectal wall. However the statistical differences disappeared after controlling for malignancy, location and lesion size. CONCLUSION: This very large comparative study showed no benefit in diagnostic yield when using the stylet for EUS-FNA. PMID- 23368963 TI - Measuring the impact of a restrictive transfusion guideline in patients with acute myeloid leukaemia. AB - Interventions to change physician transfusion behavior are often evaluated by examining the amount of red blood cell (RBC) units transfused or the proportion of patients transfused before and after the intervention. The pre-transfusion haemoglobin concentration is a sensitive measure of transfusion practice, but has not been used to evaluate behavioral interventions. We examined the effect of a Danish National Board of Health December 2007 transfusion guideline on the behavior of clinicians treating acute myeloid leukaemia (AML). We compared the effect of the guideline on pre-transfusion haemoglobin concentrations with other measures of transfusion behavior, including use of RBC units and proportion of patients transfused. No change in transfusion behavior could be demonstrated by examining amount of RBC units transfused and proportion of patients transfused. Conversely, the pre-transfusion haemoglobin concentration fell significantly. Pre transfusion haemoglobin determination is a sensitive measure of the effect of an intervention to change physician transfusion behaviour. PMID- 23368961 TI - Mutagenesis of a specificity-determining residue in tyrosine hydroxylase establishes that the enzyme is a robust phenylalanine hydroxylase but a fragile tyrosine hydroxylase. AB - The aromatic amino acid hydroxylases tyrosine hydroxylase (TyrH) and phenylalanine hydroxylase (PheH) have essentially identical active sites; however, PheH is nearly incapable of hydroxylating tyrosine, while TyrH can readily hydroxylate both tyrosine and phenylalanine. Previous studies have indicated that Asp425 of TyrH is important in determining the substrate specificity of that enzyme [Daubner, S. C., Melendez, J., and Fitzpatrick, P. F. (2000) Biochemistry 39, 9652-9661]. Alanine-scanning mutagenesis of amino acids 423-427, a mobile loop containing Asp425, shows that only mutagenesis of Asp425 alters the activity of the enzyme significantly. Saturation mutagenesis of Asp425 results in large (up to 10(4)) decreases in the V(max) and V(max)/K(tyr) values for tyrosine hydroxylation, but only small decreases or even increases in the V(max) and V(max)/K(phe) values for phenylalanine hydroxylation. The decrease in the tyrosine hydroxylation activity of the mutant proteins is due to an uncoupling of tetrahydropterin oxidation from amino acid hydroxylation with tyrosine as the amino acid substrate. In contrast, with the exception of the D425W mutant, the extent of coupling of tetrahydropterin oxidation and amino acid hydroxylation is unaffected or increases with phenylalanine as the amino acid substrate. The decrease in the V(max) value with tyrosine as the substrate shows a negative correlation with the hydrophobicity of the amino acid residue at position 425. The results are consistent with a critical role of Asp425 being to prevent a hydrophobic interaction that results in a restricted active site in which hydroxylation of tyrosine does not occur. PMID- 23368964 TI - A novel subgradient-based optimization algorithm for blockmodel functional module identification. AB - Functional module identification in biological networks may provide new insights into the complex interactions among biomolecules for a better understanding of cellular functional organization. Most of existing functional module identification methods are based on the optimization of network modularity and cluster networks into groups of nodes within which there are a higher-than expectation number of edges. However, module identification simply based on this topological criterion may not discover certain kinds of biologically meaningful modules within which nodes are sparsely connected but have similar interaction patterns with the rest of the network. In order to unearth more biologically meaningful functional modules, we propose a novel efficient convex programming algorithm based on the subgradient method with heuristic path generation to solve the problem in a recently proposed framework of blockmodel module identification. We have implemented our algorithm for large-scale protein-protein interaction (PPI) networks, including Saccharomyces cerevisia and Homo sapien PPI networks collected from the Database of Interaction Proteins (DIP) and Human Protein Reference Database (HPRD). Our experimental results have shown that our algorithm achieves comparable network clustering performance in comparison to the more time consuming simulated annealing (SA) optimization. Furthermore, preliminary results for identifying fine-grained functional modules in both biological networks and the comparison with the commonly adopted Markov Clustering (MCL) algorithm have demonstrated the potential of our algorithm to discover new types of modules, within which proteins are sparsely connected but with significantly enriched biological functionalities. PMID- 23368965 TI - Invasive fungal infections secondary to acute-on-chronic liver failure: a retrospective study. AB - Although the consequences of invasive fungal infections (IFIs) secondary to chronic hepatitis B infections secondary IFIs are serious, the incidence and main pathogenic factors of IFIs in acute-on-chronic liver failure (ACLF) patients remain unclear. This study included 1200 hepatitis B patients who were treated in the Department of Infectious Diseases, Shanghai Changzheng Hospital from January 2006 to January 2009. Patients with ACLF were screened according to the diagnostic guidelines for liver failure. Patients with ACLF and secondary IFI were the disease group, and patients with ACLF without secondary IFI were the controls. The incidence of IFI, mortality, and possible IFI causes in two groups were evaluated retrospectively. Sixty patients with ACLF had secondary IFI, of which 14 were confirmed cases and 46 were suspected cases. The incidence of IFI was 47.62% for ACLF patients. Logistic regression analysis showed that the level of hepatitis B viral (HBV) DNA was an important risk factor for secondary IFI in ACLF patients. Receiver operating characteristic curve analysis suggested that when the number of HBV DNA copies was higher than 3.16 * 10(3) copies ml(-1) , the possibility of secondary IFI in ACLF patients increased significantly, while white blood cell levels showed protective effects for these patients. The incidence of IFI is high in ACLF patients and high hepatitis B virus DNA levels may be an independent risk factor of secondary IFI in these patients. PMID- 23368966 TI - Antiviral phenolic compounds from Arundina gramnifolia. AB - Five new phenolic compounds, gramniphenols C-G (1-5), and eight known compounds (6-13) were isolated from the whole plant of Arundina gramnifolia. Compounds 1, 4, and 5 showed anti-tobacco mosaic virus activity, with IC(50) values of 20.8, 40.8, and 57.7 MUM, respectively. Compounds 1-10 were also tested for their anti HIV-1 activity; compounds 2, 3, and 6 displayed anti-HIV-1 activity with therapeutic index values above 100:1. PMID- 23368967 TI - Adherence to pharmacological treatment of chronic nonmalignant pain in individuals aged 65 and older. AB - BACKGROUND: Medication nonadherence is a frequent problem in the treatment of chronic conditions. OBJECTIVE: To study the adherence to pharmacological treatment of chronic nonmalignant pain, as well as factors and patient attitudes related to nonadherence in patients aged >=65 years. METHODS: The cross-sectional study was conducted with a self-administered questionnaire among 100 patients aged >=65 years by five family physicians at the Health Care Centre Mostar, Bosnia and Herzegovina. RESULTS: According to their own statements, 57% of the patients were nonadherent, while 84% exhibited some form of nonadherence on the Morisky scale. The patients reported a mean pain intensity of 6.6 +/- 2.2 on a visual analog scale. The most common deviation from the prescribed therapy was self-adjustment of the dose and medical regimen based on the severity of pain. Polymedication correlated positively with nonadherence. Nonsteroidal anti inflammatory drugs were the most frequently prescribed medications. The majority of the participants (59%) believed that higher pain intensity indicates progression of the disease, and half of the participants believed that one can easily become addicted to pain medications. Nonadherence was associated with patient attitudes about addiction to analgesics and ability of analgesics to control pain. CONCLUSION.: High pain intensity and nonadherence found in this study suggest that physicians should monitor older patients with chronic nonmalignant pain more closely and pay more attention to patients' beliefs regarding analgesics to ensure better adherence to pharmacological therapy. PMID- 23368969 TI - Comparison of intravitreal vancomycin and daptomycin application in experimental methicillin-resistant Staphylococcus aureus (MRSA) endophthalmitis in rabbits. AB - PURPOSE: To compare bactericidal activities of daptomycin and vancomycin in an experimental rabbit model of methicillin-resistant Staphylococcus aureus (MRSA) endophthalmitis. METHODS: The right eyes of 19 New Zealand rabbits weighing 2 to 2.5 kg were used. Each eye was inoculated with 1000 colony-forming units (cfu) of MRSA into the vitreous cavity. 24 h after the inoculation, the rabbits were randomly distributed into three groups: control group (n = 5) was given 0.1 ml of balanced saline solution, daptomycin group 2 (n = 7) was given 0.2 mg/0.1 ml daptomycin and vancomycin group 3 (n = 7) was given 1 mg/0.1 ml vancomycin intravitreally. Clinical examination scores were recorded and vitreous aspirates were obtained for microbiological analysis on days 2 and 3 after MRSA inoculation. Rabbits were sacrificed, and the eyes were enucleated for histopathological examination. RESULTS: There was no difference between the daptomycin group, vancomycin group and control in terms of the clinical grading of endophthalmitis 24 h after the inoculation. In all treatment groups, mean number of cfu and histopathological scores were significantly lower compared to the control group. There was no difference between the daptomycin and vancomycin group in terms of the histopathological and clinical examination scores. Culture negativity achieved on day 3 was 71.4% and 57.1% in the daptomycin treatment group and the vancomycin treatment group, respectively. CONCLUSIONS: Although both daptomycin and vancomycin are effective in treatment of experimental MRSA endophthalmitis, daptomycin has superior bactericidal activity 72 h after inoculation. PMID- 23368968 TI - Direct observation of aminoglycoside-RNA binding by localized surface plasmon resonance spectroscopy. AB - RNA is involved in fundamental biological functions when bacterial pathogens replicate. Identifying and studying small molecules that can interact with bacterial RNA and interrupt cellular activities is a promising path for drug design. Aminoglycoside (AMG) antibiotics, prominent natural products that recognize RNA specifically, exert their biological functions by binding to prokaryotic ribosomal RNA and interfering with protein translation, ultimately resulting in bacterial cell death. The decoding site, a small internal loop within the 16S rRNA, is the molecular target for the AMG antibiotics. The specificity of neomycin B, a highly potent AMG antibiotic, to the ribosomal decoding RNA site, was previously studied by observing AMG-RNA complexes in solution. Here, we study this interaction using localized surface plasmon resonance (LSPR) transducers comprising gold island films prepared by evaporation on glass and annealing. Small molecule AMG receptors were immobilized on the Au islands via polyethylene glycol (PEG)-thiol linkers, and the interaction with target RNA in solution was studied by monitoring the change in the LSPR optical response upon binding. The results show high-affinity binding of neomycin to 27 nucleotide model A-site RNA sequence in the nanomolar range, while no specific binding is observed for synthetic RNA oligomers (e.g., poly-U). The impact of specific base substitutions in the A-site RNA constructs on binding affinity and selectivity is determined quantitatively. It is concluded that LSPR is a powerful tool for providing molecular insight into small molecule-RNA interactions and for the design and screening of selective antimicrobial drugs. PMID- 23368970 TI - An extensible six-step methodology to automatically generate fuzzy DSSs for diagnostic applications. AB - BACKGROUND: The diagnosis of many diseases can be often formulated as a decision problem; uncertainty affects these problems so that many computerized Diagnostic Decision Support Systems (in the following, DDSSs) have been developed to aid the physician in interpreting clinical data and thus to improve the quality of the whole process. Fuzzy logic, a well established attempt at the formalization and mechanization of human capabilities in reasoning and deciding with noisy information, can be profitably used. Recently, we informally proposed a general methodology to automatically build DDSSs on the top of fuzzy knowledge extracted from data. METHODS: We carefully refine and formalize our methodology that includes six stages, where the first three stages work with crisp rules, whereas the last three ones are employed on fuzzy models. Its strength relies on its generality and modularity since it supports the integration of alternative techniques in each of its stages. RESULTS: The methodology is designed and implemented in the form of a modular and portable software architecture according to a component-based approach. The architecture is deeply described and a summary inspection of the main components in terms of UML diagrams is outlined as well. A first implementation of the architecture has been then realized in Java following the object-oriented paradigm and used to instantiate a DDSS example aimed at accurately diagnosing breast masses as a proof of concept. CONCLUSIONS: The results prove the feasibility of the whole methodology implemented in terms of the architecture proposed. PMID- 23368971 TI - Genome-wide analysis uncovers high frequency, strong differential chromosomal interactions and their associated epigenetic patterns in E2-mediated gene regulation. AB - BACKGROUND: An emerging Hi-C protocol has the ability to probe three-dimensional (3D) architecture and capture chromatin interactions in a genome-wide scale. It provides informative results to address how chromatin organization changes contribute to disease/tumor occurrence and progression in response to stimulation of environmental chemicals or hormones. RESULTS: In this study, using MCF7 cells as a model system, we found estrogen stimulation significantly impact chromatin interactions, leading to alteration of gene regulation and the associated histone modification states. Many chromosomal interaction regions at different levels of interaction frequency were identified. In particular, the top 10 hot regions with the highest interaction frequency are enriched with breast cancer specific genes. Furthermore, four types of E2-mediated strong differential (gain- or loss-) chromosomal (intra- or inter-) interactions were classified, in which the number of gain-chromosomal interactions is less than the number of loss-chromosomal interactions upon E2 stimulation. Finally, by integrating with eight histone modification marks, DNA methylation, regulatory elements regions, ERalpha and Pol II binding activities, associations between epigenetic patterns and high chromosomal interaction frequency were revealed in E2-mediated gene regulation. CONCLUSIONS: The work provides insight into the effect of chromatin interaction on E2/ERalpha regulated downstream genes in breast cancer cells. PMID- 23368972 TI - Desmosomal adhesion and pemphigus vulgaris: the first half of the story. AB - Pemphigus vulgaris (PV) is a paradigm of autoimmune disease affecting intercellular adhesion. The mechanisms that lead to cell-cell detachment (acantholysis) have crucial therapeutic implications and are currently undergoing major scrutiny. The first part of this review focuses on the classical view of the pathogenesis of PV, which is dominated by the cell adhesion molecules of the desmosome, namely desmogleins (Dsgs). Cloning of the DSG3 gene, generation DSG3 knock-out mice and isolation of monoclonal anti-Dsg3 IgG have aided to clarify the pathogenic mechanisms of PV, which are in part dependent on the fate of desmosomal molecules. These include perturbation of the desmosomal network at the transcriptional, translational, and interaction level, kinase activation, proteinase-mediated degradation, and hyper-adhesion. By the use of PV models, translational research has in turn helped shed light into the basic structure, function, and dynamics of assembly of desmosomal cadherins. The combined efforts of basic and applied research has resulted in tremendous advance into the understanding of epidermal adhesion and helped debunk old myths on the supposedly unique role of desmogleins in the mechanisms of cell-cell detachment in PV. PMID- 23368973 TI - Proton transport in mesoporous silica SBA-16 thin films with three-dimensional cubic structures. AB - Mesoporous silica SBA-16 thin films with highly ordered 3D cubic structures were synthesized by an evaporation-induced self-assembly method, using an F127 triblock copolymer as the structure-directing agent via dip coating, to investigate the proton transport of aqueous solutions confined in mesopores. Using electrochemical measurements of ionic current under DC electric fields, we elucidated proton transport phenomena through mesopores of SBA-16 thin films. At low concentrations, ranging from 10(-7) to 10(-5) M, the I-V curves of KCl and HCl aqueous solutions were nonlinear. However, at 10(-4) and 10(-3) M, while I-V curves of KCl aqueous solutions displayed nonlinear behavior, those of HCl aqueous solutions were almost linear. The linear behavior can be attributed to a decrease in the electric potential barrier owing to a reduction in the surface charge density, which is caused by the protonation of silanol groups on the inner surface of mesopores. At high concentrations, ranging from 10(-2) to 1 M, the I-V curves of KCl and HCl aqueous solutions were almost linear because the effect of surface charge of mesopores on ion transport was marginal. PMID- 23368974 TI - Is the cause of gastric mucosal damage due only to aspirin use? PMID- 23368975 TI - Ultrasound velocity through the tibia is not affected by prolonged inhaled steroid therapy in children. AB - AIM: To evaluate in a prospective, cross-sectional cohort study the impact of inhaled corticosteroids (ICS) on bone speed of sound (SOS) in asthmatic children. METHODS: Children with mild-to-moderate asthma from a pulmonary clinic were assessed over a 2-month period. We recorded clinical and demographic data related to asthma severity, its treatment, participation in sports and dairy intake. Tibial SOS was measured using the Sunlight Omnisense 7000S quantitative ultrasound bone sonometer. RESULTS: Eighty-five mild-to-moderate asthmatic children were studied. Age range was 1.4-17 years (71.7% boys). Average disease duration was approximately 5 years, and the average cumulative duration of ICS therapy was approximately 1.5 years. Average SOS Z-score was slightly negative and varied between -3.5 and +1.9 SD. In univariate analysis, SOS Z-score was negatively correlated with asthma duration (R(2) = 5.7%, p = 0.028) and ICS duration (R(2) = 4.9%, p = 0.042). In backward stepwise multiple regression, where SOS Z-score was the dependent variable, the only variables that remained significant in the final analysis were gender (p = 0.015), asthma duration (p = 0.003) and BMI (p = 0.048) (R(2) for the model 17.52% p = 0.01). CONCLUSION: Prolonged inhaled steroid therapy appears to have no deleterious effect upon SOS in children with mild-to-moderate persistent asthma. PMID- 23368976 TI - Retigabine as add-on treatment of refractory epilepsy--a cost-utility study in a Swedish setting. AB - OBJECTIVES: To calculate comparative incremental cost-effectiveness ratios (cost per quality-adjusted life year, QALY) and net marginal benefits for retigabine as add-on treatment for patients with uncontrolled focal seizures as compared to add on lacosamide treatment and no add-on treatment, respectively. MATERIALS & METHODS: Calculations were performed using a validated decision-tree model. The study population consisted of adult patients with focal-onset epilepsy in published randomized placebo-controlled add-on trials of retigabine or lacosamide. Healthcare utilization and QALY for each treatment alternative were calculated. Probabilistic sensitivity analysis was performed using the specification of this model as a basis for Monte Carlo simulations. 2009 prices were used for all costs. RESULTS: Results were reported for a 2-year follow-up period. Retigabine add-on treatment was both more effective and less costly than lacosamide add-on treatment, and the cost per additional QALY for the retigabine no add-on (standard) therapy comparison was estimated at 2009? 15,753. Using a willingness-to-pay threshold for a QALY of ? 50,000, the net marginal values were estimated at 2009? 605,874 for retigabine vs lacosamide and 2009? 2,114,203 for retigabine vs no add-on, per 1,000 patients. The probabilistic analyses showed that the likelihood that retigabine treatment is cost-effective is at least 70%. CONCLUSIONS: The estimated cost per additional QALY, for the retigabine vs no add on treatment comparison, is well within the range of newly published estimates of willingness to pay for an additional QALY. Thus, add-on retigabine treatment for people with focal-onset epilepsy with no/limited response to standard antiepileptic treatment appears to be cost-effective. PMID- 23368977 TI - How useful is a history of rubella vaccination for determination of disease susceptibility? A cross-sectional study at a public funded health clinic in Malaysia. AB - BACKGROUND: Identification of pregnant women susceptible to rubella is important as vaccination can be given postpartum to prevent future risks of congenital rubella syndrome. However, in Malaysia, rubella antibody screening is not offered routinely to pregnant women in public funded health clinics due to cost constraint. Instead, a history of rubella vaccination is asked to be provided to establish the women's risk for rubella infection. The usefulness of this history, however, is not established. Thus, this paper aimed to determine the usefulness of a history of rubella vaccination in determining rubella susceptibility in pregnant women. METHODS: A cross-sectional study was conducted on 500 pregnant women attending a public funded health clinic. Face-to-face interviews were conducted, and demographic data and history of rubella vaccination were obtained. Anti-rubella IgG test was performed. RESULTS: A majority of the women (66.6%) had a positive vaccination history. Of these, 92.2% women were immune. A third (33.4%) of the women had a negative or unknown vaccination history, but 81.4% of them were immune to rubella. The sensitivity and specificity of a history of rubella vaccination in identifying disease susceptibility was 54.4% (95% CI: 40.7, 67.4%) and 69.3% (95% CI: 64.7, 73.5%) respectively; the positive predictive value was 18.6% (95% CI: 13.1, 25.5%) and the negative predictive value was 92.2% (95% CI: 88.6, 94.7%). CONCLUSIONS: A vaccination history of rubella had a poor diagnostic value in predicting rubella susceptibility. However, obtaining a vaccination history is inexpensive compared with performing a serological test. A cost-utility analysis would be useful in determining which test (history versus serological test) is more cost-effective in a country with resource constraint. PMID- 23368978 TI - "It hurts to know... and it helps": exploring how surrogates in the ICU cope with prognostic information. AB - BACKGROUND: Surrogates of critically ill patients in the intensive care unit (ICU) want honest prognostic information, but they also want to hear good news. There has been little examination of how surrogates navigate these dual needs or how clinicians should respond. OBJECTIVE: The aim of this study was explore how surrogates in the ICU experience and cope with prognostic information and describe their recommendations for clinicians. METHODS: We conducted a qualitative interview study with 30 surrogates facing life-sustaining treatment decisions in five ICUs in Pittsburgh, Pennsylvania. In-depth, semi-structured interviews with surrogates in the ICU focused on general experiences, emotional needs, informational needs, and recommendations for clinicians. We inductively analyzed transcripts for key themes using constant comparative methods. RESULTS: Surrogates experience a tension between wanting to know what to expect and needing to remain hopeful. This tension underlies their experience receiving prognostic information and may lead to behaviors that allow continued hope in the face of bad news, including: 1) focusing on small details rather than the big picture, 2) relying on gut instincts or personal beliefs about the patient, 3) seeking more positive prognostic information from other sources, and, for a minority, 4) avoiding or disbelieving prognostic information. Surrogates emphasize the importance of frequent communication and call on physicians to gently help them prepare for the worst and hope for the best. CONCLUSIONS: Surrogates in the ICU experience conflicting emotional and informational needs. They describe behaviors that give the appearance of avoiding bad news while simultaneously asking physicians to help them cope with prognostic information. PMID- 23368979 TI - The Lisbon Challenge: acknowledging palliative care as a human right. AB - Access to palliative care has been advocated as a human right by international associations, based on the right to the highest attainable standard of physical and mental health. It has been argued that failure to provide palliative care for patients facing severe pain could constitute cruel, inhuman, or degrading treatment. Yet the governments of many countries throughout the world have still not acknowledged a human right to access palliative care for all those who need it. The European Association for Palliative Care (EAPC), the International Association for Hospice and Palliative Care (IAHPC), and Human Rights Watch (HRW) discussed this at the EAPC congress in 2011 and formulated the Lisbon Challenge: Governments must: (1) put in place health policies that address the needs of patients with life-limiting or terminal illnesses; (2) ensure access to essential medicines, including controlled medications, to all who need them; (3) ensure that health care workers receive adequate training on palliative care and pain management at undergraduate levels; and (4) facilitate and promote the implementation of palliative care services as part of available health services. PMID- 23368980 TI - Repeat dose opioids may be effective for breathlessness in chronic heart failure if given for long enough. AB - BACKGROUND: The longer-term effects of opioids for breathlessness are not known in people with chronic heart failure (CHF). OBJECTIVE: Our aim was to assess the longer-term effect of oral opioids on breathlessness due to CHF. METHODS: We conducted a 3-month open-label extension to a crossover randomized controlled trial (RCT) comparing 4 days of morphine, oxycodone, and placebo. Thirty-five participants from a tertiary cardiology clinic completed the RCT. Thirty-three were followed for 3 months, continuing open-label opioids if they wished. Thirteen participants continued an opioid; 20 did not. Four measures of breathlessness intensity (0-10 numerical rating scale [NRS] and modified Borg score, each recording worst and average breathlessness during 24 hours) were combined using principal component analysis to give a single measure for the primary analysis. Groups were compared using analysis of covariance. Secondary measures included quality of life (SF-12((r)) Health Survey), cardiorespiratory, and global impression of change in breathlessness at 3 months. RESULTS: At 3 months, the composite breathlessness measure improved to a greater extent in the opioid group (p=0.017). The opioid group had an improvement in global impression of change (mean 2.62 [opioids] versus -0.65 [nonopioids]; p=0.0009). The SF-12 physical component improved more in the opioid group (p=0.014). Cardiorespiratory variables were unchanged. CONCLUSIONS: Opioids given for 3 months were well tolerated and safe. Opioid-related improvement in breathlessness in people with CHF might not be seen until longer-term administration. We cannot conclude from these data that they are effective and a longer-term RCT is needed. PMID- 23368981 TI - Preparation and characterization of methotrexate-loaded microcapsules. AB - Methotrexate (MTX) has toxic effect to healthy tissues. Microencapsulation coats particles with a functional coat to optimize storage stability and to modulate release. In the present study, a new MTX encapsulated microcapsules were synthesized for controlling MTX release. Controlled drug release provides releasing of efficient dose and prevent drug side effect to tissues and also protects MTX from oxygen, pH and other interactions. MTX was encapsulated through biocompatible hyaluronic acid (HA) and sodium alginate (SA) with an encapsulation system to reduce its toxicity and for controlled release. The microcapsules prepared by vibrating nozzle were cross-linked with SA, HA and calcium chloride. Nozzle diameter and MTX concentration were changed according to loaded MTX and encapsulation efficiency were determined using HPLC. For the reliability of the data, validation studies of the HPLC method were performed. The precision of the method was demonstrated using intra- and inter-day assay relative standard deviation (RSD) values which are less than 2% in all instances. For the characterization of microcapsules, particle size, drug loading and in vitro drug release studies were performed. Diameters of MTX-loaded microcapsules were acquired approximately 160, 400 and 800 um. Surface morphology of encapsulated microcapsules were displayed with light microscope. Eighty-nine percent MTX encapsulation efficiencies were achieved. Encapsulated MTX microcapsules showed controlled release when compared to pure MTX. While powder MTX dissolved completely in 10 min in the dissolution medium, MTX release from encapsulated MTX microcapsules became 40 h in 0.1 M PBS pH 7.4, including NaCl. MTX release from MTX-loaded microcapsules was reached to 79%. Moreover, drug efficiency was examined in vitro cell culture tests. Viability of 5RP7 cells were decreased to 88.5% for 96 h. When MTX was given directly to 5RP7 cells, viability of 5RP7 cells was decreased to 49.7% for 96 h. Flow cytometry studies also showed that, MTX microcapsules induced apoptosis. The goal of this study is to provide controlled release of MTX and to reduce the toxic effect of MTX. PMID- 23368982 TI - Analysis of different model-based approaches for estimating dFRC for real-time application. AB - BACKGROUND: Acute Respiratory Distress Syndrome (ARDS) is characterized by inflammation, filling of the lung with fluid and the collapse of lung units. Mechanical ventilation (MV) is used to treat ARDS using positive end expiratory pressure (PEEP) to recruit and retain lung units, thus increasing pulmonary volume and dynamic functional residual capacity (dFRC) at the end of expiration. However, simple, non-invasive methods to estimate dFRC do not exist. METHODS: Four model-based methods for estimating dFRC are compared based on their performance on two separate clinical data cohorts. The methods are derived from either stress-strain theory or a single compartment lung model, and use commonly controlled or measured parameters (lung compliance, plateau airway pressure, pressure-volume (PV) data). Population constants are determined for the stress strain approach, which is implemented using data at both single and multiple PEEP levels. Estimated values are compared to clinically measured values to assess the reliability of each method for each cohort individually and combined. RESULTS: The stress-strain multiple breath (at multiple PEEP levels) method produced an overall correlation coefficient R2 = 0.966. The stress-strain single breath method produced R2 = 0.530. The single compartment single breath method produced R2 = 0.415. A combined method at single and multiple PEEP levels produced R2 = 0.963. CONCLUSIONS: The results suggest that model-based, single breath and non invasive approaches to estimating dFRC may be viable in a clinical scenario, ensuring no interruption to MV. The models provide a means of estimating dFRC at any PEEP level. However, model limitations and large estimation errors limit the use of the methods at very low PEEP. PMID- 23368983 TI - HPA-5 typing discrepancy reveals an Ile503Leu substitution in platelet GPIa (alpha2 integrin). AB - BACKGROUND AND OBJECTIVES: In fetal/neonatal thrombocytopenia, maternal alloimmunization is diagnosed by the identification of the maternal alloantibody and the offending paternal antigen inherited by the foetus/neonate. Today, for practical reasons, most laboratories perform platelet genotyping instead of phenotyping. Here, we report the case of a human platelet antigen (HPA)-5 genotype/phenotype discrepancy observed in a mother who delivered a mildly thrombocytopenic newborn. MATERIALS AND METHODS: Platelet antibody detection and platelet phenotyping were performed using the MAIPA assay; platelet genotypes were determined using BeadChip technology (BioArray), PCR-SSP, PCR-RFLP and sequencing. RESULTS: Serological investigations revealed the presence of maternal anti-GPIIbIIIa autoantibodies. No alloantibodies were detected. No feto-maternal platelet incompatibility was observed for HPA-1 to -21. The mother and newborn were genotyped as HPA-5aa using BeadChips, but as HPA-5a (weak b) with PCR-SSP and HPA-5ab with PCR-RFLP. Mother's platelets were phenotyped as HPA-5b(+). GPIa exon 13 sequencing confirmed the HPA-5ab genotype of the mother and newborn, and revealed an NM_002203.3:c.1594A>C mutation near the HPA-5 polymorphism (5' side), leading to an I503L amino acid change. CONCLUSION: Feto-maternal alloimmunization was ruled out: the neonatal thrombocytopenia probably resulted from maternal anti GPIIbIIIa autoantibodies. This case highlights that platelet typing should be performed using two different methods to avoid false diagnosis. PMID- 23368984 TI - Heavy metal-associated isoprenylated plant protein (HIPP): characterization of a family of proteins exclusive to plants. AB - Metallochaperones are key proteins for the safe transport of metallic ions inside the cell. HIPPs (heavy metal-associated isoprenylated plant proteins) are metallochaperones that contain a metal binding domain (HMA) and a C-terminal isoprenylation motif. In this study, we provide evidence that proteins of this family are found only in vascular plants and may be separated into five distinct clusters. HIPPs may be involved in (a) heavy metal homeostasis and detoxification mechanisms, especially those involved in cadmium tolerance, (b) transcriptional responses to cold and drought, and (c) plant-pathogen interactions. In particular, our results show that the rice (Oryza sativa) HIPP OsHIPP41 gene is highly expressed in response to cold and drought stresses, and its product is localized in the cytosol and the nucleus. The results suggest that HIPPs play an important role in the development of vascular plants and in plant responses to environmental changes. PMID- 23368986 TI - Complications of gastric endoscopic submucosal dissection. AB - Endoscopic resection is now a widely accepted treatment for early gastric cancer, having a negligible risk of lymph-node metastasis. Endoscopic submucosal dissection (ESD) is a relatively new endoscopic resection method developed in the mid-1990 s that facilitates en-bloc resection even in patients with large or ulcerative lesions difficult to resect using conventional endoscopic mucosal resection (EMR). However, compared to EMR, ESD requires a longer procedure time and a higher level of technical expertise, in addition to having a slightly greater risk of complications. Endoscopists must be aware of not only the risk factors for, and incidence of, complications, but also how to effectively treat such complications. Perforation and bleeding are the major complications associated with gastric ESD. The perforation and delayed bleeding rates have been reported to range from 1.2% to 5.2% and 0% to 15.6%, respectively, and can usually be managed with appropriate endoscopic treatment. Immediate bleeding during gastric ESD is quite common and controlling such bleeding, which is primarily achieved by carrying out electrocautery, plays a critical role in the successful completion of ESD. PMID- 23368987 TI - Characterization of phenolic compounds, carotenoids, vitamins and antioxidant activities of selected Malaysian wild edible plants. AB - This study was carried out to characterize phenolic compounds, carotenoids, vitamins and the antioxidant activity of selected wild edible plants. Plant extracts were purified, and phenolic compounds comprising 11 phenolic acids (hydroxybenzoic acid and hydrocinnamic acid) and 33 flavonoids (including catechin, glycosides and aglycones) were analysed using High Performance Liquid Chromatography - Diode Array Detector (HPLC-DAD). Furthermore, the contents of ascorbic acid and tocopherol ((alpha and gamma tocopherol) and carotenoids (lutein and beta-carotene) were also determined. The major phenolics identified consisted of glycosides of flavones (apigenin and luteolin) and flavonols (kaempferol and quercetin). Among the phenolic acids identified after hydrolysis, coumaric acid was the predominant phenolic acid in all the extracts of wild plants. Ascorbic acid [53.8 mg/100 g fresh weight (FW)] and beta-carotene (656.5 mg/100 g FW) showed the highest content in the leaf of Heckeria umbellatum. In conclusion, the leaves of H. umbellatum, Aniseia martinicensis and Gonostegia hirta have excellent potential in the future to emerge as functional ingredients. PMID- 23368985 TI - The quiet renaissance of protein nuclear magnetic resonance. AB - From roughly 1985 through the start of the new millennium, the cutting edge of solution protein nuclear magnetic resonance (NMR) spectroscopy was to a significant extent driven by the aspiration to determine structures. Here we survey recent advances in protein NMR that herald a renaissance in which a number of its most important applications reflect the broad problem-solving capability displayed by this method during its classical era during the 1970s and early 1980s. PMID- 23368988 TI - Growth of Aspergillus in blood cultures: proof of invasive aspergillosis in patients with chronic obstructive pulmonary disease? PMID- 23368989 TI - Practitioner perspectives of the economic coping experiences of women of domestic violence abuse. AB - Through this case study the author investigates women's coping experiences with economic challenges in the spectrum of domestic violence abuse. Women of abuse cope with financial difficulties compounded by other ecologically contributing factors. Eight non-abused, social service practitioners from four different agencies, two providers per agency, described the economic coping experiences of women of abuse they serve. Comprehensive and interdisciplinary care is necessary to meet women's multifaceted, complex economic needs. Study results corroborate with research. Service delivery of care for women of abuse coping with family, schooling, and economic hardships are enhanced through schools and service agencies working together, collaborating networking, and sharing of resources in order to better advocate for women and children. PMID- 23368990 TI - Improving service practices: collaborative care for women of abuse. AB - This original qualitative research inquiry is based on a phenomenological research dissertation case study. This article information and content that is gathered helps to better inform providers in the field of social services and those who are social workers and administrators in social services. This research investigated key factors, traits, or attributes that strive to improve service care for women of domestic violence abuse. Findings support current and relevant research to enhance aid to women of abuse. Results strongly detail that professionals must work more cooperatively as an all-channels network of comprehensive care to women. Because women of domestic violence abuse require such multifaced complex care due to the interwoven issues familial abuse brings, results support that service practitioners can best meet the needs of these women through an ecological or life-space understanding for improved care, achieved by infusing an inter-disciplinary systems-based, inter-agency and intra-agency framework. PMID- 23368991 TI - Organizational development structure: improvements for service agencies aiding women of abuse. AB - Through this article the author explains how systems-based structures provide enhanced care for women of domestic violence abuse via intra-agency and inter agency initiatives. Qualitative data was collected through interviews with eight leaders of four different agencies that were included in this case study. Organizational development models of service agencies aiding women were investigated. Results indicate that systems-based structures are the most beneficial organizational design to enhance services to abused women, as they require simultaneous, complex, and multifaceted care. This ideal structure best provides women with comprehensive, collaborative, and effective care when agencies cooperate to meet women's diverse needs. PMID- 23368992 TI - Themes of coping in the spectrum of domestic violence abuse: a review of the literature. AB - Women's coping experiences in the spectrum of domestic violence abuse are complex and multifaceted. The spectrum stages of abuse include when a woman is in, out, or returning to the abuse situation. In this article the author discusses the obstacles with which women cope and the service delivery initiatives to better serve women. The themes of women's coping in the spectrum of abuse for this research review include psycho-physiological, economic, education, family, and childcare factors. Service practitioners must fully recognize the factors with which women of abuse cope. Included are suggestions for service professionals aiding women to improve services as women utilize multiple services simultaneously. PMID- 23368993 TI - Women's coping experiences in the spectrum of domestic violence abuse. AB - Through this phenomenological case study the author investigates the experience of coping by women in the spectrum of domestic violence abuse. An ecological view of women's coping is critically reviewed. Women of abuse cope with many factors simultaneously in their lives as there are numerous, multifaceted, and diverse issues that comprise and contribute to an abusive situation. Eight providers from four different agencies, two providers per agency, describe the coping experiences of women both in and out of the abusive situation. Study results corroborate with research and demonstrate that women's coping, both in and out of the abusive relationship is unique and complex. PMID- 23368994 TI - Leadership styles of service professionals aiding women of abuse: enhancing service delivery. AB - Leadership styles of service professionals--including social workers and teachers -in the area of family abuse were investigated. Leadership characteristics of the professionals were measured by their responses to a survey. Results indicated that the interviewed service professionals demonstrated productive leadership traits. Study findings are congruent with leadership styles described in the research. Holistic and collaborative services are required to enhance care for women of abuse, as their needs are multifaceted and complex. Specific leadership styles promote better care for women; leaders need to collaboratively initiate and deliver more interdisciplinary and unified service. PMID- 23368995 TI - A knowledge-based decision support system in bioinformatics: an application to protein complex extraction. AB - BACKGROUND: We introduce a Knowledge-based Decision Support System (KDSS) in order to face the Protein Complex Extraction issue. Using a Knowledge Base (KB) coding the expertise about the proposed scenario, our KDSS is able to suggest both strategies and tools, according to the features of input dataset. Our system provides a navigable workflow for the current experiment and furthermore it offers support in the configuration and running of every processing component of that workflow. This last feature makes our system a crossover between classical DSS and Workflow Management Systems. RESULTS: We briefly present the KDSS' architecture and basic concepts used in the design of the knowledge base and the reasoning component. The system is then tested using a subset of Saccharomyces cerevisiae Protein-Protein interaction dataset. We used this subset because it has been well studied in literature by several research groups in the field of complex extraction: in this way we could easily compare the results obtained through our KDSS with theirs. Our system suggests both a preprocessing and a clustering strategy, and for each of them it proposes and eventually runs suited algorithms. Our system's final results are then composed of a workflow of tasks, that can be reused for other experiments, and the specific numerical results for that particular trial. CONCLUSIONS: The proposed approach, using the KDSS' knowledge base, provides a novel workflow that gives the best results with regard to the other workflows produced by the system. This workflow and its numeric results have been compared with other approaches about PPI network analysis found in literature, offering similar results. PMID- 23368996 TI - Structures and cytotoxic evaluation of new and known acyclic Ene-Ynes from an American Samoa Petrosia sp. Sponge. AB - Four new compounds, (-)-petrosynoic acids A-D (1-4), and five known congeners, pellynols A (5), C (6), D (7), F (8), and I (9), were isolated from a Petrosia sp. marine sponge collected in American Samoa. Isolation work was guided by cytotoxicity against human lung cancer cells (H460). The structures of the C31 C33 polyacetylenes (1-9) were determined on the basis of 1D- and 2D-NMR analysis, mass spectrometry, and comparison of specific rotation values. Compounds 1-9 were found to be broadly cytotoxic with limited selectivity for cancer cells, as they were all moderately active against the A2058 (melanoma), H522-T1 (lung), and H460 (lung) human cancer cell lines as well as IMR-90 quiescent human fibroblast cells. PMID- 23368997 TI - Genome mining of a prenylated and immunosuppressive polyketide from pathogenic fungi. AB - Activation of the polycyclic polyketide prenyltransferase (pcPTase)-containing silent clusters in Aspergillus fumigatus and Neosartorya fischeri led to isolation of a new metabolite neosartoricin (3). The structure of 3 was solved by X-ray crystallography and NMR to be a prenylated anthracenone. 3 exhibits T-cell antiproliferative activity with an IC(50) of 3 MUM, suggestive of a physiological role as an immunosuppressive agent. PMID- 23368998 TI - Surface-induced orientation control of CuPc molecules for the epitaxial growth of highly ordered organic crystals on graphene. AB - The epitaxial growth and preferred molecular orientation of copper phthalocyanine (CuPc) molecules on graphene has been systematically investigated and compared with growth on Si substrates, demonstrating the role of surface-mediated interactions in determining molecular orientation. X-ray scattering and diffraction, scanning tunneling microscopy, scanning electron microscopy, and first-principles theoretical calculations were used to show that the nucleation, orientation, and packing of CuPc molecules on films of graphene are fundamentally different compared to those grown on Si substrates. Interfacial dipole interactions induced by charge transfer between CuPc molecules and graphene are shown to epitaxially align the CuPc molecules in a face-on orientation in a series of ordered superstructures. At high temperatures, CuPc molecules lie flat with respect to the graphene substrate to form strip-like CuPc crystals with micrometer sizes containing monocrystalline grains. Such large epitaxial crystals may potentially enable improvement in the device performance of organic thin films, wherein charge transport, exciton diffusion, and dissociation are currently limited by grain size effects and molecular orientation. PMID- 23368999 TI - A cross-sectional study of secondhand smoke exposure and respiratory symptoms in non-current smokers in the U.S. trucking industry: SHS exposure and respiratory symptoms. AB - BACKGROUND: Previous studies have suggested associations of adult exposures to secondhand smoke (SHS) with respiratory symptoms, but no study has focused on blue-collar industrial environments. We assessed the association between SHS and respiratory symptoms in 1,562 non-current smoking U.S. trucking industry workers. METHODS: Information on SHS exposure and respiratory health was obtained by questionnaire. Multiple logistic regression analyses were used to assess the associations of recent and lifetime exposures to SHS with chronic phlegm, chronic cough, and any wheeze, defined by American Thoracic Society criteria. RESULTS: In analyses adjusted for age, gender, race, childhood SHS exposure, former smoking, pack-years of smoking and years since quitting, body mass index, job title, region of the country, and urban residence, recent exposures to SHS were associated with all three respiratory symptoms (odds ratio (OR) = 1.46; 95% confidence interval (CI) = 1.00-2.13) for chronic cough, 1.55 (95% CI = 1.08 2.21) for chronic phlegm, and 1.76 (95% CI = 1.41-2.21) for any wheeze). Workplace exposure was the most important recent exposure. Childhood exposure to SHS was also associated with all three symptoms, but only statistically significantly for chronic phlegm (OR = 1.84; 95% CI = 1.24-2.75). Additional years of living with a smoker were associated with an increased risk, but there was no evidence of a dose-response, except for chronic phlegm. CONCLUSIONS: In this group of trucking industry workers, childhood and recent exposures to SHS were related to respiratory symptoms. PMID- 23369001 TI - Comparison of class 2 transposable elements at superfamily resolution reveals conserved and distinct features in cereal grass genomes. AB - BACKGROUND: Class 2 transposable elements (TEs) are the predominant elements in and around plant genes where they generate significant allelic diversity. Using the complete sequences of four grasses, we have performed a novel comparative analysis of class 2 TEs. To ensure consistent comparative analyses, we re annotated class 2 TEs in Brachypodium distachyon, Oryza sativa (rice), Sorghum bicolor and Zea mays and assigned them to one of the five cut-and-paste superfamilies found in plant genomes (Tc1/mariner, PIF/Harbinger, hAT, Mutator, CACTA). We have focused on noncoding elements because of their abundance, and compared superfamily copy number, size and genomic distribution as well as correlation with the level of nearby gene expression. RESULTS: Our comparison revealed both unique and conserved features. First, the average length or size distribution of elements in each superfamily is largely conserved, with the shortest always being Tc1/mariner elements, followed by PIF/Harbinger, hAT, Mutator and CACTA. This order also holds for the ratio of the copy numbers of noncoding to coding elements. Second, with the exception of CACTAs, noncoding TEs are enriched within and flanking genes, where they display conserved distribution patterns, having the highest peak in the promoter region. Finally, our analysis of microarray data revealed that genes associated with Tc1/mariner and PIF/Harbinger noncoding elements have significantly higher expression levels than genes without class 2 TEs. In contrast, genes with CACTA elements have significantly lower expression than genes without class 2 TEs. CONCLUSIONS: We have achieved the most comprehensive annotation of class 2 TEs to date in these four grass genomes. Comparative analysis of this robust dataset led to the identification of several previously unknown features of each superfamily related to copy number, element size, genomic distribution and correlation with the expression levels of nearby genes. These results highlight the importance of distinguishing TE superfamilies when assessing their impact on gene and genome evolution. PMID- 23369002 TI - Gastric balloon to treat obesity: filled with air or fluid? AB - BACKGROUND: Our aim was to study the efficacy and safety of different types of intragastric balloon in morbidly obese patients. PATIENTS AND METHODS: From 2005 to 2011, intragastric balloons were inserted endoscopically into 32 patients. Intragastric balloons were used in morbidly obese (body mass index [BMI] >= 35 kg/m(2) ) individuals who were non-responsive to 6-month medical therapy and diet. Balloons were endoscopically removed after 6 months. RESULTS: Thirty-six balloons were inserted in a total of 32 patients. Mean age of the patients was 37.28 +/- 12.08 (17-64) years and mean height was 169.81 +/- 8.17 (150-185) cm. Initial mean weight was 128.87 +/- 23.31 kg and BMI was 45.26 +/- 8.48 kg/m(2) . At month 6, mean bodyweight was 116.93 +/- 23.18 and BMI was 40.96 +/- 7.96 kg/m(2) (P < 0.001, P < 0.001, respectively). At the end of 6 months, while the excessweight loss (EWL) median was 13.0 kg, [interquartile range IQR: 5.0-16.0] and percent EWL median was 21.92, [IQR: 12.72-28.49] in the Heliosphere BAG patients, the EWL median was 19.0 kg, [IQR: 14.47-26.72] and the percent EWL median was 38.26, [IQR: 19.73-47.79] in the BioEnterics Intragastric Balloon patients (P = 0.006, P = 0.010, respectively for EWL median and percent EWL median). One patient died (3.1%) of cardiac arrest due to aspiration at day 13 after BIB placement. CONCLUSION: Although not without risk, intragastric balloon placement is an effective method for weight loss. BioEnterics Intragastric Balloon is more effective in helping weight loss than the Heliosphere BAG balloon. PMID- 23369003 TI - The prospective association between behavioural problems and asthma outcome in young asthma patients. AB - AIM: The aim of this prospective study was to examine the association between behavioural problems and medical and psychological outcomes in clinically treated children and adolescents with asthma. METHODS: Patients (n = 134) were recruited from two high-altitude asthma clinics in Switzerland and one asthma clinic in the Netherlands. Outcome measures were Asthma Control Test (ACT), Paediatric Asthma Quality of Life Questionnaire (PAQLQ(S)), forced expiratory volume in 1 sec (FEV1 ) and fractional concentration of exhaled nitric oxide (FeNO). Parents completed the Child Behaviour Checklist (CBCL) (predictor variable). Data were collected at the start and end of treatment. Multiple regression analysis was used while adjusting for demographic variables, clinic and length of stay. RESULTS: More severe internalizing behavioural problems were associated with less improvement of total quality of life (t = -2.26, p = 0.03) and the domains symptoms (t = 2.04, p = 0.04) and emotions (t = -2.3, p = 0.02) after clinical treatment. Behavioural problems were not associated with a change of lung function measurements (FEV1 and FeNO) and asthma control (ACT) during treatment. CONCLUSION: A focus of healthcare professionals on the treatment of internalizing behavioural problems may optimize the quality of life in clinically treated youth with asthma. PMID- 23369005 TI - Androgen up-regulates vascular endothelial growth factor expression in prostate cancer cells via an Sp1 binding site. AB - BACKGROUND: Vascular Endothelial Growth Factor (VEGF) is regulated by a number of different factors, but the mechanism(s) behind androgen-mediated regulation of VEGF in prostate cancer are poorly understood. RESULTS: Three novel androgen receptor (AR) binding sites were discovered in the VEGF promoter and in vivo binding of AR to these sites was demonstrated by chromatin immunoprecipitation. Mutation of these sites attenuated activation of the VEGF promoter by the androgen analog, R1881 in prostate cancer cells. The transcription factors AR and Sp1 were shown to form a nuclear complex and both bound the VEGF core promoter in chromatin of hormone treated CWR22Rv1 prostate cancer cells. The importance of the Sp1 binding site in hormone mediated activation of VEGF expression was demonstrated by site directed mutagenesis. Mutation of a critical Sp1 binding site (Sp1.4) in the VEGF core promoter region prevented activation by androgen. Similarly, suppression of Sp1 binding by Mithramycin A treatment significantly reduced VEGF expression. CONCLUSIONS: Our mechanistic study of androgen mediated induction of VEGF expression in prostate cancer cells revealed for the first time that this induction is mediated through the core promoter region and is dependent upon a critical Sp1 binding site. The importance of Sp1 binding suggests that therapy targeting the AR-Sp1 complex may dampen VEGF induced angiogenesis and, thereby, block prostate cancer progression, helping to maintain the indolent form of prostate cancer. PMID- 23369006 TI - Changes in exhaled breath condensate pH in healthy and asthmatic pregnant women. AB - OBJECTIVE: Asthma is a common chronic disease complicating pregnancy with a risk for perinatal complications. Control of airway inflammation in the asthmatic pregnancy improves pregnancy outcomes. Our aim was to evaluate pH of exhaled breath condensate (EBC), a non-invasive method for the assessment of asthmatic airway inflammation, in healthy and asthmatic pregnancies. DESIGN: Cross sectional study. SETTING: Hungarian university clinics. POPULATION: Seventeen healthy pregnant women, 21 asthmatic pregnant women, 23 healthy non-pregnant women and 22 asthmatic non-pregnant women. METHODS: EBC samples were collected using a portable condenser, EBC pH was measured after argon deaeration. MAIN OUTCOME MEASURE: EBC pH. RESULTS: EBC pH (mean +/- SD) of healthy non-pregnant and asthmatic non-pregnant women was similar (7.75 +/- 0.27 vs. 7.54 +/- 0.57; p = 0.118), probably indicating an optimal control of airway inflammation in asthmatic women. On the other hand, EBC pH was higher in healthy pregnant women compared with healthy non-pregnant women (8.02 +/- 0.43 vs. 7.75 +/- 0.27; p = 0.017). Higher EBC pH accompanying healthy pregnancy was absent in asthmatic pregnant patients whose EBC pH was lower (7.65 +/- 0.38) than that of healthy pregnant women (p = 0.006), and it was similar to that in asthmatic and healthy non-pregnant women (p = 0.470 and p = 0.300, respectively). The EBC pH in asthmatic pregnant women correlated positively with birthweight (r = 0.49, p = 0.047) and negatively with forced vital capacity (r = 0.45, p = 0.039). EBC pH was not related to blood pH. CONCLUSIONS: EBC pH is higher in healthy pregnant women but not in asthmatic pregnant women compared with data from healthy non pregnant women, indicating that oxidative inflammatory processes induced by asthma may compromise the regulatory mechanisms causing alkaline pH in the airways during pregnancy. PMID- 23369007 TI - Farm-derived Gram-positive bacterium Staphylococcus sciuri W620 prevents asthma phenotype in HDM- and OVA-exposed mice. AB - BACKGROUND: Farm-derived dust samples have been screened for bacteria with potential allergo-protective properties. Among those was Staphylococcus sciuri W620 (S. sciuri W620), which we tested with regard to its protective capacities in murine models of allergic airway inflammation. METHODS: We employed two protocols of acute airway inflammation in mice administering either ovalbumin (OVA) or house dust mite extract (HDM) for sensitization. Mechanistic studies on the activation of innate immune responses to S. sciuri W620 were carried out using human primary monocytic dendritic cells (moDC) and co-culture with autologous T cells. RESULTS: The allergo-protective properties of S. sciuri W620 were proven in a T(H)2-driven OVA model as well as in a mixed T(H)1/T(H)2 phenotype HDM model as demonstrated by abrogation of eosinophils and neutrophils in the airways after intranasal treatment. In the HDM model, lymph node cell T(H)1/T(H)2 signature cytokines were decreased in parallel. Studies on human moDC revealed an activation of TLR2 and NOD2 receptors and initiation of DC maturation following incubation with S. sciuri W620. Cytokine expression analyses after exposure to S. sciuri W620 showed a lack of IL-12 production in moDC due to missing transcription of the IL-12p35 mRNA. However, such DC selectively supported T(H)1 cytokine release by co-cultured T cells. CONCLUSION AND CLINICAL RELEVANCE: Our proof-of-concept experiments verify the screening system of farm derived dust samples as suitable to elucidate new candidates for allergo protection. S. sciuri W620 was shown to possess preventive properties on airway inflammation providing the basis for further mechanistic studies and potential clinical implication. PMID- 23369008 TI - Polymeric micelles and vesicles: biological behavior evaluation using radiolabeling techniques. AB - The application of combined diagnosis and therapy through nanotechnology applications is attracting increasing attention worldwide. Polymeric self assembled nanoparticles (NPs) have been studied for this purpose. Micelles and vesicles with or without a magnetic core can efficiently carry diagnostic and/or therapeutic agents to a desired target. The biological behavior of these NPs has been evaluated in this study, after radiolabeling with (99m)Tc. In vitro stability, in media that mimic the environment of the living body, was better for vesicles than for micelles at 1 h and decreased for both as time passed. After administration to healthy animals, all NPs presented major uptake at liver and spleen as expected. Biodistribution and imaging studies confirmed the higher uptake in these organs for the hybrid NPs and at higher extent for the ones with larger size, indicating that the magnetic load and size play an important role on in vivo distribution. PMID- 23369009 TI - Use of locally made off-loading techniques for diabetic plantar foot ulcer in Karachi, Pakistan. AB - The aim of this study was to evaluate the effectiveness of applying locally made pressure off-loading techniques on plantar foot ulcer in individuals with diabetes. This prospective study of 70 diabetic patients was conducted at the foot clinic of Baqai Institute of Diabetology & Endocrinology. Plantar foot ulcer, stages 1A and 2A according to the University of Texas classification, was treated by using three off-loading techniques: modified foot wear (sandal), modified plaster of Paris cast with plywood platform and Scotchcast boot. The outcome was assessed at either complete wound healing (defined as complete epithelialisation) or at 12 weeks, whichever came first. Of the 70 patients, 24 were in modified foot wear group, 23 in modified plaster of Paris cast and 23 in Scotchcast boot group. There was almost equal proportion of patients healed within 12 weeks period treated with these three off-loading techniques, i.e. 22 (95.7%) for modified foot wear group, 19 (95%) for modified plaster cast and 18 (94.7%) for Scotchcast boot group. No significant difference was observed in median healing time and cumulative wound survival at 12 weeks in the three off loading techniques. Modified foot wear group was the most cost effective ($7) amongst the three off-loading techniques. It is concluded that in this cohort, no significant difference in healing time was observed in the three off-loading techniques, although modified foot wear (sandal) was found to be a more cost effective treatment modality. PMID- 23369010 TI - Patient abandonment in the name of opioid safety. PMID- 23369011 TI - A simple and reliable liquid chromatography-tandem mass spectrometry method for determination of ochratoxin A in hard cheese. AB - This paper reports a simple and reliable mass spectrometry hyphenated chromatographic method for ochratoxin A determination in hard cheese. The method is based on a simple extraction using an acetonitrile:water (84:16, v/v) solution acidified with 2.5% acetic acid. After a defatting step with n-hexane, the extract was directly analysed by LC-MS/MS without any further clean-up step. The method showed good linearity and specificity, and it was in-house validated in the range of 1-16 MUg/kg, resulting in 93.75% mean overall recovery (confidence interval 1.36%) and 3.42% coefficient of variatioin (CV). The analytical performances were also satisfactory in terms of sensitivity (limit of quantification = 1 MUg/kg); although no legal limits have been set up for cheese, this value is consistent with the tolerances fixed for other regulated foods. Preliminary results on 40 commercial samples of grated hard cheese are presented. PMID- 23369012 TI - pH-dependent motion of self-propelled droplets due to Marangoni effect at neutral pH. AB - Oil droplets loaded with surfactant propel themselves with a velocity up to 6 mm s(-1) when they are placed in an aqueous phase of NaOH solution or buffer solution. The required driving force for such motion is generated on the interface of the droplets by the change in interfacial tension, due to deprotonation of the surfactant. This force induces Marangoni convection, which gives rise to a circulating flow inside the droplets. The droplets begin to move when the axis of this circulation deviates from the vertical line. This motion depends on the pH condition of the aqueous phase. When the initial value of pH is adjusted such that the pH exceeds the threshold at the equilibrium state, the droplets move spontaneously. It was seen that the droplets were independent of the material of the solid substrates because the droplets were not directly in contact with the surface of the substrate. The condition for the onset of this spontaneous motion was verified by comparing the prediction from the linear stability analysis with experiments. The stability analysis overestimates the value of the driving force, causing instability. PMID- 23369013 TI - Loss of retinal nerve fibre layer axons indicates white but not grey matter damage in early multiple sclerosis. AB - BACKGROUND AND PURPOSE: Optical coherence tomography (OCT) has shown thinning of the retinal nerve fibre layer (RNFL) and total macular volume (TMV) in multiple sclerosis (MS) patients. Measures of retinal atrophy are associated with the brain parenchymal fraction (BPF) assessed by magnetic resonance imaging (MRI). However, in MS, data on the relation of OCT measures and grey and white matter volumes are contradictory. We performed a prospective cross-sectional study with a statistically pre-defined endpoint to test our hypothesis that OCT measures of neuro-axonal degeneration are related to global and partial brain atrophy in early forms of MS. METHODS AND RESULTS: Forty-four patients with clinically isolated syndrome (n = 10) or relapsing-remitting MS (n = 34; mean disease duration = 3.2 years, median EDSS = 1.5) were enrolled in the study. Peripapillary- and volumetric OCT scans of the macula were performed using latest spectral-domain OCT technology. BPF as well as white and grey matter fractions (WMF/GMF) were assessed by 1.5 Tesla MRI scans. Generalized estimating equation models adjusted for age and linear regression statistics were used to assess the association between OCT and MRI measures. RNFL thickness, TMV and age were significantly associated with BPF. RNFL thickness and TMV independently predicted WMF (P = 0.003 and P = 0.032) but not GMF (P = 0.717 and P = 0.357) when corrected for age. In contrast, age was strongly associated with GMF (P < 0.001) but not WMF. CONCLUSION: Our study suggests that, in early MS, OCT measures of retinal atrophy are related to volumetric changes in the white but not grey matter compartment as assessed by MRI. It further substantiates the association of retinal thinning and brain tissue loss in MS. PMID- 23369014 TI - The regenerated bone quality by implantation of octacalcium phosphate collagen composites in a canine alveolar cleft model. AB - OBJECTIVE: Synthetic octacalcium phosphate and porcine atelocollagen composites significantly enhanced bone regeneration more than beta-tricalcium phosphate collagen composite and hydroxyapatite collagen composite in a rat cranial defect model. However, the long-term stability and quality of octacalcium phosphate collagen (OCP/Col) composites-derived regenerated bone, when implanted in a canine alveolar cleft model, have yet to be elucidated. The present study investigated the longterm stability and quality of bone regenerated by OCP/Col. DESIGN: Disks of OCP/Col or collagen were implanted in a canine alveolar-cleft model (n = 6). Then, bone regeneration in the implanted areas was investigated macroscopically, radiographically, and histologically at 10 months after implantation. In addition, three-dimensional quantitative images of regenerated bone were analyzed by microcomputed tomography. RESULTS: Macroscopically, the OCP/Col treated alveolus was clearly augmented, and radio-opacity in the OCP/Col implanted area was comparable to that of the original alveolus bone. On histological analysis, the area was mostly filled with newly formed bone, and a few granules of implanted OCP/Col were enclosed in it. In the microcomputed tomography analysis, the regenerated bone volume in the OCP/Col group was larger than that in the collagen group. OCP/Col-derived bone consisted of outer cortical and inner cancellous structure with dense trabeculae and seemed like the original bone structure. CONCLUSIONS: OCP/Co composites could be a useful bone regenerative material to substitute for autogenous bone because their implantation could elicit high bone regeneration and active structural reconstitution. PMID- 23369015 TI - Transsutural distraction and tissue regeneration of the midfacial skeleton: experimental studies in growing dogs. AB - Objective : The purpose of this study was to evaluate the effect of different mechanical forces on the expansion of the palatine suture using transsutural distraction osteogenesis. Methods : A total of 48 dogs were used in this study. The experimental groups were treated with a custom-designed internal distractor. Bone regeneration was determined with x-rays and histology. The computed values underwent statistical analyses using analysis of variance. Results : The maxillary complex was most noticeably advanced with an applied mechanical force of 600 g (20.15 +/- 1.36 mm), compared with forces of 400 g (19.88 +/- 1.41 mm) and 800 g (2.24 +/- 0.93 mm). Immunohistochemical staining showed that the expression of bone morphogenetic protein-2 and bone morphogenetic protein-4 fluctuated with different mechanical forces. These changes were statistically significant when 600 g of force was applied within 30 days of distraction (P < .05). Conclusions : Transsutural distraction osteogenesis in the growing dog should be safe and well tolerated in inducing bony lengthening of the maxilla, and the optimal force is 600 * g. Bone morphogenetic protein-2 and bone morphogenetic protein-4 may play an important roles in the signaling pathways that link mechanical forces and biological responses. PMID- 23369016 TI - Three-dimensional assessment of facial appearance following surgical repair of unilateral cleft lip and palate. AB - BACKGROUND AND OBJECTIVE: Objective assessment of postsurgical facial asymmetry can be difficult, but three-dimensional (3D) imaging techniques have made this possible. The objective of this study was to assess residual asymmetry in surgically repaired unilateral cleft lip (UCL) and unilateral cleft lip and palate (UCLP) patients and to compare this with noncleft controls. DESIGN: Retrospective multicohort comparative study. PATIENTS AND METHODS: Fifty-one 10 year-old children with surgically managed UCLP and 44 children with UCL were compared with a control group of 68 ten-year-olds. The 3D facial models at rest and with maximum smile were created using a 3D imaging system. Asymmetry scores were produced using both anatomical landmarks and a novel method of facial curve analysis. RESULTS: Asymmetry for the whole face was significantly higher in both cleft groups compared with controls (P < .001). UCLP asymmetry was higher than UCL (P < .001). In cleft patients, the upper lip and nasal rim were the most asymmetric (P < .001 to .05). Control subjects also displayed a degree of facial asymmetry. Maximum smile did not significantly affect the symmetry of the whole face, but it increased asymmetry of the vermillion border and nasal rim in all three groups (P < .001). CONCLUSIONS: Despite surgical intervention at an early age, asymmetry remains significant in cleft patients at 10 years of age. Three dimensional imaging is a noninvasive objective assessment tool that identifies specific areas of the face responsible for asymmetry. Facial curve analysis describes the face more comprehensively and characterizes soft tissue contours. PMID- 23369017 TI - Mass spectrometry-based protein identification by integrating de novo sequencing with database searching. AB - BACKGROUND: Mass spectrometry-based protein identification is a very challenging task. The main identification approaches include de novo sequencing and database searching. Both approaches have shortcomings, so an integrative approach has been developed. The integrative approach firstly infers partial peptide sequences, known as tags, directly from tandem spectra through de novo sequencing, and then puts these sequences into a database search to see if a close peptide match can be found. However the current implementation of this integrative approach has several limitations. Firstly, simplistic de novo sequencing is applied and only very short sequence tags are used. Secondly, most integrative methods apply an algorithm similar to BLAST to search for exact sequence matches and do not accommodate sequence errors well. Thirdly, by applying these methods the integrated de novo sequencing makes a limited contribution to the scoring model which is still largely based on database searching. RESULTS: We have developed a new integrative protein identification method which can integrate de novo sequencing more efficiently into database searching. Evaluated on large real datasets, our method outperforms popular identification methods. PMID- 23369018 TI - Obstacles to getting ahead: how assimilation mechanisms impact undocumented mexican immigrant families. AB - This study explores the roles played by U.S. schools, workplaces, churches, and peers in the acculturation process of immigrant adolescents. Qualitative interviews were conducted with members of 10 undocumented Mexican families (12 adolescents and 14 of their parents) who had immigrated within the past 7 years. Results indicated that assimilation was prompted by two powerful mechanisms: monolingualism and discrimination. Monolingualism and discrimination in interpersonal interactions and social policies directed Mexican adolescents and their parents to learn English and to conform to host culture norms, appearance, and behaviors to advance in school and in their work. These assimilation mechanisms contributed to female adolescents' and parents' feelings of anxiety and depression. Male adolescents reported feeling angry and ready to physically defend themselves. Mexican families found a refuge from assimilation stress in church. Churches valued biculturalism and religious faith was used to handle daily assimilation stress. Implications for social policy were discussed. PMID- 23369019 TI - An initial validation of a measure of sexual perceptions regarding breastfeeding. AB - Increasing breastfeeding initiation and duration in the United States has been identified as a major public health goal. This article presents an initial validation of the Sexual Perceptions of Breastfeeding Scale (SPBFS). The SPBFS was designed to assess the presence of sexual perceptions regarding breastfeeding that may interfere with a mother's choice to breastfeed an infant. This study establishes the initial psychometric properties of the SPBFS based on a sample of 140 mothers participating in the federal supplemental food program Women, Infants, and Children. RESULTS/CONCLUSIONS: the SPBFS was developed as a three factor instrument. Preliminary findings confirm this structure and indicate that the SPBFS shows promise for helping explore how sexual perceptions of breastfeeding interact with the decisions a mother makes regarding breastfeeding. PMID- 23369020 TI - Correlates of health literacy among latinos in Arkansas. AB - Although research on acculturation and its effects on Latino health continue to grow, there is a dearth of knowledge on how acculturation levels shape health literacy. Health literacy is an important aspect of health to consider with the Latino population because a number of studies have found that this group has the lowest levels of health literacy in the United States. The purpose of this study was to examine how acculturation and sociodemographic characteristics contribute to the health literacy of Latinos adults. Cross-sectional data was collected from a nonprobability sample of 123 Latinos living in various Arkansas communities. Multiple regression results suggest that Latinos who were more acculturated and were educated beyond high school were significantly more likely to have increased levels of health literacy. Findings also show that age, gender, income, and citizenship status were not significant predictors of health literacy. Implications and future research are discussed. PMID- 23369021 TI - "A Breast Ain't Nothing but a Sandwich": narratives of Ella, an African American social worker breast cancer survivor. AB - Breast cancer mortality rates continue to increase among African American women making it imperative to develop culturally tailored programs to help reduce these rates. In this study, narratives of Ella an African American breast cancer survivor who is also a social worker were constructed. Prevalent themes were self identity, perceptions of women living with cancer, and the socialization of African Americans in cancer prevention. Her perspective as a survivor and social worker offers insight on how the intersection of race and gender impacts breast cancer survival and has implications for future research in cancer awareness among African Americans. PMID- 23369022 TI - Quality of health care in seven countries: an implication for health reform in the United States. AB - Survey findings of health care systems in seven countries show that health care performance in the United States, despite spending twice as much as other developed countries, is no better than other countries and that there is room for substantial improvement in the United States. The data show that the quality of care in the United States was only adequate at best and was rated inadequate in the areas of waiting time for treatment, and administration of the service. This article recommends several reform measures to improve the health system in the United States. PMID- 23369024 TI - Evaluation of selective cyclooxygenase-2 inhibitor-induced small bowel injury: randomized cross-over study compared with loxoprofen in healthy subjects. AB - AIM: Non-steroidal anti-inflammatory drugs have the potential to injure the mucosa of the upper digestive tract and small bowel, whereas celecoxib (a selective cyclooxygenase-2 inhibitor) has less influence on the entire digestive tract mucosa. The present study was conducted to compare the extents of small bowel mucosal injury induced by celecoxib and loxoprofen (the most frequently used non-steroidal anti-inflammatory drugs in Japan). METHODS: Ten healthy adult males were given celecoxib (200 mg/day, Group C) and loxoprofen (180 mg/day, Group L) in a cross-over design for 14 days, and the influence of each drug on small bowel mucosa was evaluated by comparing pre- and post-treatment capsule endoscopy findings. We measured the percentage of patients with small bowel mucosal injury following administration of these drugs as primary endpoint. Additionally, mean number of small bowel mucosal injuries per subject was analyzed as secondary endpoint. RESULTS: The percentage of subjects experiencing small bowel mucosal injury as primary endpoint was 10% in Group C and 70% in Group L after treatment. This magnitude of the difference of between Group C and Group L was statistically significant (P = 0.031). The number of small bowel mucosal injuries as secondary endpoint differed significantly between the two groups, and the influence of celecoxib on small bowel injury was less than that of loxoprofen. CONCLUSION: These results indicate that celecoxib has less influence on small bowel mucosa than loxoprofen and can be used safely. PMID- 23369025 TI - Major variations in Aspergillus fumigatus arising within aspergillomas in chronic pulmonary aspergillosis. AB - Aspergillomas develop from progressive layers of mycelial growth on the walls of pulmonary cavities over months. Aspergillomas are characteristic of chronic pulmonary aspergillosis and are a risk factor for azole resistance. We investigated genotypic and phenotypic alterations in Aspergillus fumigatus recovered from aspergillomas. Aspergillomas were removed from three patients (two at surgery, one at autopsy) and dissected. Overall 92 colonies of A. fumigatus were isolated. Microsatellite typing was conducted to determine genetic type. Itraconazole, voriconazole and posaconazole susceptibilities were performed. The cyp51A gene was sequenced in 22 isolates. Isolates from Patient 1 (n = 25) were azole susceptible and resistant, although all cyp51A sequences were wild type, the isolates split into two distinct clades. In Patient 2, isolates were less variable (n = 10), all were azole susceptible. In Patient 3 only azole-resistant strains (n = 57) were isolated, with M220K or M220T Cyp51A alterations, and microevolution was indicated. Marked diversity was observed in isolates from these patients; revealing differences in azole susceptibility, mechanism of resistance and genetic type. Importantly, routine sampling from respiratory specimens proved suboptimal in all cases; azole resistance was missed (Patient 1), cultures were negative (Patient 2) and high-level posaconazole resistance was not detected (Patient 3). PMID- 23369026 TI - Efficient asymmetric synthesis of P-chiral phosphine oxides via properly designed and activated benzoxazaphosphinine-2-oxide agents. AB - A general, efficient, and highly diastereoselective method for the synthesis of structurally and sterically diverse P-chiral phosphine oxides was developed. The method relies on sequential nucleophilic substitution on the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide, which features enhanced and differentiated P-N and P-O bond reactivity toward nucleophiles. The reactivities of both bonds are fine-tuned to allow cleavage to occur even with sterically hindered nucleophiles under mild conditions. PMID- 23369027 TI - Risk factors for delayed post-polypectomy hemorrhage: a case-control study. AB - BACKGROUND AND AIM: Delayed post-polypectomy hemorrhage is a rare but serious complication. The aim of this study was to identify risk factors for the development of delayed post-polypectomy hemorrhage. METHODS: This was a retrospective case-control study of patients who developed delayed hematochezia after receiving colonoscopic polypectomy. The control patients underwent uneventful polypectomy and were selected at a 4:1 ratio. RESULTS: Of the 7447 lesions examined from the 3253 patients who received colonoscopic polypectomy, 53 lesions (0.7%) of 42 patients (1.3%) developed delayed hemorrhage, and 168 patients were selected as controls. According to multivariate logistic regression analysis, a polyp larger than 10 mm (odds ratio [OR] 2.355, 95% confidence interval [CI] 1.225-4.528, P = 0.010), a pedunculated polyp (OR 3.473, 95% CI 1.576-7.657, P = 0.002), and a polyp located in the right hemi-colon (OR 2.690, 95% CI 1.465-4.940, P = 0.001) were significant risk factors for delayed post polypectomy hemorrhage. The presence of comorbidities did not increase the risk of delayed hemorrhage. CONCLUSION: Polyp size (large), shape (pedunculated), and location (right hemi-colon) represented substantial risk factors for the development of delayed hemorrhage after colonoscopic polypectomy. PMID- 23369028 TI - Endoscopic therapy in the treatment of caustic esophageal stricture: a retrospective case series study. AB - BACKGROUND: Endoscopic procedures, such as balloon/bougie dilation and stent implantation, have gained increasing potential as the treatment of corrosive esophageal stricture. The purpose of the present retrospective case series study was to assess clinical outcomes of endoscopic therapy of esophageal strictures after caustic injury. PATIENTS AND METHODS: Between January 2003 and December 2009, 13 admitted patients that developed esophageal stricture after caustic agent ingestion underwent endoscopic therapy at the First Affiliated Hospital of Nanjing Medical University. Data such as age, gender, caustic agents, site of burn, type of treatment, effectiveness and outcome of endoscopic therapy were recorded. RESULTS: The average follow up was 39 months with a range of 29-70 months. Successful endoscopic therapy was achieved in 12 of 13 patients (92%). Duration of stricture resolution was between 4 and 48 months (mean, 15 months). Among them, seven patients required dilations only, whereas the other five patients received both dilations and stent implantation. There were no severe complications in these patients. CONCLUSIONS: These data suggest that endoscopic therapy is feasible, less invasive and effective for the management of caustic esophageal stricture. After repeat dilation and stenting, patients can achieve stricture resolution in approximately 15 months and avoid surgery. PMID- 23369032 TI - Synthesis and charge-carrier transport properties of poly(phosphole P alkanesulfonylimide)s. AB - A new class of polyphospholes bearing alkanesulfonylimino moieties on the phosphorus(V) centers was prepared by the Pd-CuI-promoted Stille coupling reaction to investigate the charge-carrier transport properties of the pi networks of polyphospholes. Time-of-flight measurements have revealed that the poly(phosphole P-imide)s possess ambipolar charge-carrier mobilities of up to MU(electron) = 6 * 10(-3) cm(2) V(-1) s(-1) and MU(hole) = 4 * 10(-3) cm(2) V(-1) s(-1). PMID- 23369031 TI - Nondisclosure prosecutions and population health outcomes: examining HIV testing, HIV diagnoses, and the attitudes of men who have sex with men following nondisclosure prosecution media releases in Ottawa, Canada. AB - BACKGROUND: During the past decade, the intersection of HIV and criminal law has become increasingly discussed. The majority of studies to date have approached this topic from a sociological or legal perspective. As a result, the potential effect of nondisclosure prosecutions on population health and HIV prevention work remains mostly unknown. METHODS: A descriptive quantitative-qualitative study was undertaken to examine HIV testing, HIV diagnoses, and the attitudes of men who have sex with men following regional media releases about a local nondisclosure prosecution. As part of this study, first, we reviewed the trends in HIV testing and HIV diagnoses from 2008 through 2011 in Ottawa, Canada. Second, we explored the attitudes and beliefs of local MSM about HIV, HIV prevention, HIV serostatus disclosure, nondisclosure prosecutions, and public health. RESULTS: Quantitatively, the findings of this study revealed that, in comparison to the period preceding the media releases about a local nondisclosure prosecution, HIV testing and HIV diagnoses among men who have sex with men did not significantly change after the media releases of interest. Qualitatively, a subgroup of 27 men who have sex with men (12 HIV-positive, 15 HIV-negative) noted their beliefs that the local public health department openly shares information about people living with HIV with the police. Moreover, some HIV-positive participants stated that this perceived association between the local public health department and police services caused them to not access public health department services, notwithstanding their desires to seek assistance in maintaining safer sexual practices. CONCLUSIONS: Nondisclosure prosecutions likely undermine HIV prevention efforts. PMID- 23369030 TI - The effect of two iso-caloric meals containing equal amounts of fats with a different fat composition on the inflammatory and metabolic markers in apparently healthy volunteers. AB - BACKGROUND: Little is known about the time-course of the postprandial appearance of macronutrient-induced inflammatory response. Our aim was to investigate the postprandial inflammatory and metabolic response following high fat, high caloric popular meals in apparently healthy participants. METHODS: Fifty four apparently healthy normal weight volunteers (BMI of 25.9+/-0.9) were given two iso-caloric meals with similar amounts but different composition of fats: a meal high in monounsaturated fats (MUFA), and a meal high in saturated fat (SFA). Three main effects and the interactions between them were analyzed: the time (before and 2 and 4 hours following the meals), the meal (MUFA or SFA) and the gender. RESULTS: The effect of time from the meal on hs-CRP level was highly significant (p=0.004). The highest responses were observed 2 hours after the meal (p=0.002). A statistically significant interaction was found between the time and the meal (p<=0.0001), which reflects the higher increase in hs-CRP values 2 hours after the SFA meal, with no effect by the MUFA meal. The white blood cell counts were affected significantly by the time (p<=0.0001) however, other inflammatory markers (fibrinogen, IL-6, TNFalpha, ICAM and VICAM) were not. All the metabolic markers (insulin, glucose, HOMA-R, QUICKI and triglycerides) were affected by the time (p<=0.0001), with no interactions observed. CONCLUSIONS: Metabolic and modest inflammatory changes occur within a few hours after the ingestion of a high SFA meal in apparently healthy adults. PMID- 23369033 TI - Left, right, or both? On the configuration of the phenanthroindolizidine alkaloid tylophorine from Tylophora indica. AB - The alkaloid (-)-tylophorine was isolated from a sample of Tylophora indica, and the crude extract was analyzed by HPLC/MS(n) and chiral HPLC/MS. While the literature states that the naturally occurring form of this alkaloid is the R enantiomer and that its S-antipode is usually not found in nature, we confirmed the hypothesis of Govindachari and Nagarajan that natural levorotatory tylophorine is indeed a nearly racemic mixture with a slight excess of the R enantiomer. PMID- 23369035 TI - Comparison of combined, biochemical and nuchal translucency screening for Down syndrome in first trimester in Northern Finland. AB - OBJECTIVE: To compare the efficacy of fetal nuchal translucency screening, maternal serum screening and combined screening for Down syndrome. DESIGN: A prospective study. SETTING: University hospital and its public health care district in Northern Finland. POPULATION: A total of 35,314 women participated in the first-trimester screening for Down syndrome within the public healthcare system in 2002-08. There were 95 pregnancies involving Down syndrome. Serum samples were obtained from 35,314 women, nuchal translucency was measured in 27,144 pregnancies and full combined screening was performed in those pregnancies, including 76 involving Down syndrome. METHODS: The adjusted estimated risk for Down syndrome was calculated using the Perkin Elmer AutoDELFIA(r) time-resolved fluoroimmunoassay kit for the measurement of pregnancy-associated plasma protein-A and free beta-human chorionic gonadotropin. Nuchal translucency was measured by trained personnel in a university or district hospital. Risk cut-off figures 1:250 and 1:300 at term were used. MAIN OUTCOME MEASURES: Differences in detection rate, false-positive rate, positive and negative predictive values between nuchal translucency screening, serum screening and combined screening. RESULTS: Using the risk cut-off figure 1:250, the detection rates for serum screening, nuchal translucency screening and combined screening were 64.2, 64.5 and 72.4%, respectively and the false-positive rates were 7.8, 4.4 and 4.0%, respectively. CONCLUSIONS: Combined screening is the method of choice for Down syndrome screening in Finland. PMID- 23369036 TI - Relationship between serum fibronectin levels and carnitine administration: an experimental study in rats. AB - We aimed to investigate the relationship between dorsal flap viability and serum fibronectin levels in carnitine-administered rats. A total of 24 rats were equally divided into three groups and operated on. Group 1 (sham group n = 8): following surgery, no agent was given. Group 2 (control group, n = 8): following surgery, sterile saline solution at 0.9% with a dose of 100 mg/kg per day for 7 days was administered intraperitoneally. Group 3 (study group, n = 8): following surgery, carnitine with a dose of 100 mg/kg per day for 7 days was administered intraperitoneally. The flap model used was a 10 * 3 cm dorsal flap extending from the tip of the scapula to the hip joint. This was elevated, and then sutured back to its original site. At the end of postoperative day 8, the animals were anaesthetised and blood samples were collected from intracardiac space. Then, the animals were euthanised. Flap viability was then evaluated measuring the surviving area, using a transparent graph paper. Finally, excised tissue was examined histopathologically. The percentages of viable areas in groups 1, 2 and 3 were 64.68 +/- 3.37%, 67.35 +/- 5.82% and 75.15 +/- 3.56%, respectively. The mean value of fibronectin levels in groups 1, 2 and 3 were 22.3 +/- 3.5, 23.1 +/- 3.5 and 31 +/- 6.8 mg/dl, respectively. The results of this study demonstrated that 100 mg/kg carnitine administration led to an increase in flap viability, and increased serum fibronectin levels might have a role in this process. PMID- 23369034 TI - Asthma in patients hospitalized with pandemic influenza A(H1N1)pdm09 virus infection-United States, 2009. AB - BACKGROUND: Asthma was the most common co-morbidity among patients hospitalized with pandemic influenza A(H1N1)pdm09 [pH1N1] infection. The objective was to compare characteristics of hospitalized pH1N1 patients with and without asthma and assess factors associated with severity among asthma patients. METHODS: Patient data were derived from two 2009 pandemic case-series of U.S. pH1N1 hospitalizations. A case was defined as a person >= 2 years old hospitalized with laboratory-confirmed pH1N1. Asthma status was determined through chart review. RESULTS: Among 473 cases, 29% had asthma. Persons with asthma were more likely to be 2-17 years old (39% vs. 30%, p = 0.04) and black (29% vs. 18%, p < 0.01), and have chronic obstructive pulmonary disease (13% vs. 9%, p = 0.04) but less likely to have pneumonia (37% vs. 47%, p = 0.05), need mechanical ventilation (13% vs. 23%, p = 0.02), and die (4% vs. 10%, p = 0.04) than those without asthma. Among patients with asthma, those admitted to an intensive care unit (ICU) or who died (n = 38) compared with survivors not admitted to an ICU (n = 99) were more likely to have pneumonia on admission (60% vs. 27%, p < 0.01) or acute respiratory distress syndrome (24% vs. 0%, p < 0.01) and less likely to receive influenza antiviral agents <= 2 days of admission (73% vs. 92%, p = 0.02). CONCLUSIONS: The majority of persons with asthma had an uncomplicated course; however, severe disease, including ICU admission and death, occurred in asthma patients who presented with pneumonia. Influenza antiviral agents should be started early in hospitalized patients with suspected influenza, including those with asthma. PMID- 23369037 TI - A methodology to assess the intrinsic discriminative ability of a distance function and its interplay with clustering algorithms for microarray data analysis. AB - BACKGROUND: Clustering is one of the most well known activities in scientific investigation and the object of research in many disciplines, ranging from statistics to computer science. Following Handl et al., it can be summarized as a three step process: (1) choice of a distance function; (2) choice of a clustering algorithm; (3) choice of a validation method. Although such a purist approach to clustering is hardly seen in many areas of science, genomic data require that level of attention, if inferences made from cluster analysis have to be of some relevance to biomedical research. RESULTS: A procedure is proposed for the assessment of the discriminative ability of a distance function. That is, the evaluation of the ability of a distance function to capture structure in a dataset. It is based on the introduction of a new external validation index, referred to as Balanced Misclassification Index (BMI, for short) and of a nontrivial modification of the well known Receiver Operating Curve (ROC, for short), which we refer to as Corrected ROC (CROC, for short). The main results are: (a) a quantitative and qualitative method to describe the intrinsic separation ability of a distance; (b) a quantitative method to assess the performance of a clustering algorithm in conjunction with the intrinsic separation ability of a distance function. The proposed procedure is more informative than the ones available in the literature due to the adopted tools. Indeed, the first one allows to map distances and clustering solutions as graphical objects on a plane, and gives information about the bias of the clustering algorithm with respect to a distance. The second tool is a new external validity index which shows similar performances with respect to the state of the art, but with more flexibility, allowing for a broader spectrum of applications. In fact, it allows not only to quantify the merit of each clustering solution but also to quantify the agglomerative or divisive errors due to the algorithm. CONCLUSIONS: The new methodology has been used to experimentally study three popular distance functions, namely, Euclidean distance d2, Pearson correlation dr and mutual information dMI. Based on the results of the experiments, we have that the Euclidean and Pearson correlation distances have a good intrinsic discrimination ability. Conversely, the mutual information distance does not seem to offer the same flexibility and versatility as the other two distances. Apparently, that is due to well known problems in its estimation. since it requires that a dataset must have a substantial number of features to be reliable. Nevertheless, taking into account such a fact, together with results presented in Priness et al., one receives an indication that dMI may be superior to the other distances considered in this study only in conjunction with clustering algorithms specifically designed for its use. In addition, it results that K-means, Average Link, and Complete link clustering algorithms are in most cases able to improve the discriminative ability of the distances considered in this study with respect to clustering. The methodology has a range of applicability that goes well beyond microarray data since it is independent of the nature of the input data. The only requirement is that the input data must have the same format of a "feature matrix". In particular it can be used to cluster ChIP-seq data. PMID- 23369038 TI - A novel paracetamol 1,000 mg sustained release formulation vs conventional paracetamol 500 mg formulation in patients with fever and pain: a randomized noninferiority trial. AB - OBJECTIVE: To compare the efficacy and safety of newly developed paracetamol 1,000 mg sustained release (SR) tablets (test product) with conventional paracetamol 500 mg tablets (reference product) in patients with fever and pain. DESIGN: An open label, multicentric, comparative, randomized, noninferiority trial. METHODOLOGY: Eligible patient, as per predefined inclusion and exclusion criteria, were randomized to receive either one tablet of test product twice daily or one tablet of reference product four times a day for 3 consecutive days. Primary efficacy parameter (an antipyretic activity) was measured through recording changes in body temperature while secondary efficacy parameter (an analgesic activity) was measured by recording changes in visual analog scale (VAS) from the baseline. Safety assessment was done by recording adverse drug reactions occurred during treatment period. Analysis of variance was used for the statistical evaluation of data. RESULTS: Of 500 randomized patients, 249 were received paracetamol 1,000 mg SR tablets (Group-I), and 247 were received conventional paracetamol 500 mg tablets (Group-II). Group-I reported temperature reduction from 101.35 +/- 1.23 degrees F to 98.80 +/- 0.72 degrees F while temperature reduction in Group-II was from 101.42 +/- 1.33 degrees F to 98.9 +/- 0.85 degrees F. Group-I reported reduction in mean VAS was from 6.16 +/- 2.37 to 1.44 +/- 1.70 in comparison to Group-II from 5.97 +/- 2.45 to 1.38 +/- 1.78. No significant adverse reactions were observed in either group. CONCLUSION: Both the formulations of paracetamol were clinically and statically equivalent. Paracetamol 1,000 mg SR formulation is noninferior to conventional paracetamol 500 mg tablets. PMID- 23369039 TI - Novel phospholipid-based topical formulations of tamoxifen: evaluation for antipsoriatic activity using mouse-tail model. AB - OBJECTIVE: Tamoxifen (TAM) is widely employed in the treatment of breast malignancies and is also found to be effective in psoriasis treatment. The current studies aimed to explore the antipsoriatic potential of topical TAM encapsulated in the new generation phospholipid-based vesicular and micellar systems, i.e. flexible membrane vesicles (FMVs) and pluronic lecithinized organogels (PLOs). METHODS: TAM-loaded-FMVs were prepared by thin-film hydration technique, while TAM-PLOs were prepared by simple mixing. Mouse-tail model was used to evaluate the antipsoriatic activity of the novel formulations. The mouse tails were treated once-a-day with different formulations for a period of four weeks and prepared for longitudinal histological sections by hematoxylin-eosin staining technique. The length of the orthokeratotic regions in stratum granulosum was measured on 10 sequential scales per tail section as percentage of the full length of the scale, and the drug activity was calculated further. RESULTS: Evaluation of antipsoriatic activity on mice tail revealed significantly higher (p < 0.01) efficacy of TAM-FMV gel (i.e. 35.8%) and TAM-PLO (i.e. 24.6%) vis-a-vis the conventional TAM-hydrogel (i.e. 10.2%). CONCLUSIONS: The results of these studies demonstrated immense potential of the topically applied TAM encapsulated vesicular and micellar systems in psoriasis, thus calling for more comprehensive investigations to establish the role of TAM in the management of psoriasis. PMID- 23369040 TI - High-mobility group box 1 protein and hematologic malignancies with severe inflammation: therapeutic intervention with recombinant thrombomodulin. PMID- 23369041 TI - 18F-fluorodeoxyglucose positron emission tomography in the staging and prognosis of T cell lymphoma. AB - We previously reported that (18)F-fluorodeoxyglucose positron emission tomography scan (FDG-PET) is almost universally positive in patients with T cell lymphoma. In the present analysis we examined the impact of FDG-PET on the initial staging of peripheral T cell lymphomas (PTCLs), and the prognostic value of interim FDG PET. This retrospective analysis identified patients with mature T or natural killer (NK) lymphomas who had PET scans as part of initial staging or staging at relapse [(n = 95) (staging cohort)] in the PTCL database at Memorial Sloan Kettering Cancer Center. A subset of these patients had repeat PET for interim restaging during initial therapy with curative intent [(n = 50) (interim restaging cohort)]. The frequency of specific T cell histologies included in this analysis were: PTCL not otherwise specified (NOS) (n = 35); angioimmunoblastic T cell lymphoma (AITL) (n = 17); anaplastic large cell lymphoma (ALCL), ALK-1+ (n = 11) and ALK-1- (n = 12); adult T cell lymphoma/leukemia (ATLL) (n = 7); NK/T cell lymphoma (NKTCL) (n = 10); and enteropathy-associated T cell lymphoma (EATL) (n = 3). In the staging cohort, 77 patients were newly diagnosed, and 18 had relapsed disease. Pretreatment FDG-PET was positive in 96% of patients. PET identified additional disease sites in 47/95 patients (50%) when added to conventional staging. Most frequently identified additional sites were: other nodal (n = 24); bone (n = 10); skin (n = 8); nasopharynx (n = 4); spleen (n = 3); and lung (n = 2). However, FDG-PET modified computed tomography (CT)-based staging in only 5/95 patients (5.2%): two patients were upstaged and three patients were downstaged. FDG-PET-based staging did not alter planned treatment for any patient. Interim restaging with PET was performed after a median of 4 cycles of chemotherapy. In this cohort, treatment regimens included cyclophosphamide, doxorubicin, vincristine and prednisone CHOP (n = 19); CHOP/ifosfamide, carboplatin and etoposide (ICE) (n = 26); and other (n = 7). Subsequently, 29 patients were consolidated with either autologous (n = 22) or allogeneic (n = 7) stem cell transplant. After a median follow-up of 3.4 years for surviving patients, those with negative interim PET had superior progression-free survival (PFS) compared to patients with positive interim PET (p = 0.03). There were no differences in overall survival (OS). In PTCL, FDG-PET commonly identifies additional sites of disease but infrequently impacts CT-based staging and does not influence therapy. Interim FDG-PET may predict for PFS. FDG-PET should be integrated into prospective trials to confirm these findings. PMID- 23369042 TI - A case of polycythemia rubra vera transforming into chronic phase JAK2 V617F mutation-negative Philadelphia chromosome-positive chronic myelogenous leukemia. PMID- 23369043 TI - CHAG priming regimen containing of cytarabine, aclacinomycin homoharringtonine and G-CSF for relapsed refractory acute myelogenous leukemia: a modified combination chemotherapeutic combination. PMID- 23369044 TI - Taste for chiral guests: investigating the stereoselective binding of peptides to beta-cyclodextrins. AB - Obtaining compounds of diastereomeric purity is extremely important in the field of biological and pharmaceutical industry, where amino acids and peptides are widely employed. In this work, we theoretically investigate the possibility of chiral separation of peptides by beta-cyclodextrins (beta-CDs), providing a description of the associated interaction mechanisms by means of molecular dynamics (MD) simulations. The formation of host/guest complexes by including a model peptide in the macrocycle cavity is analyzed and discussed. We consider the terminally blocked phenylalanine dipeptide (Ace-Phe-Nme), in the L- and D configurations, to be involved in the host/guest recognition process. The CD peptide free energies of binding for the two enantiomers are evaluated through a combined approach that assumes: (1) extracting a set of independent molecular structures from the MD simulation, (2) evaluating the interaction energies for the host/guest complexes by hybrid quantum mechanics/molecular mechanics (QM/MM) calculations carried out on each structure, for which we also compute, (3) the solvation energies through the Poisson-Boltzmann surface area method. We find that chiral discrimination by the CD macrocycle is of the order of 1 kcal/mol, which is comparable to experimental data for similar systems. According to our results, the Ace-(D)Phe-Nme isomer leads to a more stable complex with a beta-CD compared to the Ace-(L)Phe-Nme isomer. Nevertheless, we show that the chiral selectivity of beta-CDs may strongly depend on the secondary structure of larger peptides. Although the free energy differences are relatively small, the predicted selectivities can be rationalized in terms of host/guest hydrogen bonds and hydration effects. Indeed, the two enantiomers display different interaction modes with the cyclodextrin macrocavity and different mobility within the cavity. This finding suggests a new interpretation for the interactions that play a key role in chiral recognition, which may be exploited to design more efficient and selective chiral separations of peptides. PMID- 23369045 TI - Use of digital gene expression to discriminate gene expression differences in early generations of resynthesized Brassica napus and its diploid progenitors. AB - BACKGROUND: Polyploidy is an important evolutionary mechanism in flowering plants that often induces immediate extensive changes in gene expression through genomic merging and doubling. Brassica napus L. is one of the most economically important polyploid oil crops and has been broadly studied as an example of polyploid crop. RNA-seq is a recently developed technique for transcriptome study, which could be in choice for profiling gene expression pattern in polyploids. RESULTS: We examined the global gene expression patterns of the first four generations of resynthesized B. napus (F1-F4), its diploid progenitors B. rapa and B. oleracea, and natural B. napus using digital gene expression analysis. Almost 42 million clean tags were generated using Illumina technology to produce the expression data for 25959 genes, which account for 63% of the annotated B. rapa genome. More than 56% of the genes were transcribed from both strands, which indicate the importance of RNA-mediated gene regulation in polyploidization. Tag mapping of the B. rapa genome generated 19023, 18547, 24383, 20659, 18881, 20692, and 19955 annotated genes for the B. rapa, B. oleracea, F1-F4 of synthesized B. napus, and natural B. napus libraries, respectively. The unambiguous tag-mapped genes in the libraries were functionally categorized via gene ontological analysis. Thousands of differentially expressed genes (DEGs) were identified and revealed the substantial changes in F1-F4. Among the 20 most DEGs are DNA binding/transcription factor, cyclin-dependent protein kinase, epoxycarotenoid dioxygenase, and glycine-rich protein. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the DEGs suggested approximately 120 biological pathways. CONCLUSIONS: The systematic deep sequencing analysis provided a comprehensive understanding of the transcriptome complexity of early generations of synthesized B. napus. This information broadens our understanding of the mechanisms of B. napus polyploidization and contributes to molecular and genetic research by enriching the Brassica database. PMID- 23369046 TI - Restless legs syndrome in end-stage renal disease: a multicenter study in Taiwan. AB - BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is an underestimated movement disorder in patients with end-stage renal disease (ESRD). Several clinical and laboratory factors were inconsistently reported to associate with RLS. We aim to perform a large-scale multicenter study to investigate the possible associated risk factors of RLS in patients with ESRD in Taiwan, a country with the highest incidence of uremia in the world. METHODS: From October 2009 to October 2011, we constitutively recruited 1130 patients with ESRD from 17 hemodialysis centers. Demographic, laboratory data, presence and severity of RLS were collected. Odds ratios (ORs) were estimated by logistic regression models. RESULTS: We found the prevalence of RLS to be 25.3% in patients with ESRD. Having type 2 diabetes [OR = 3.61 (2.27-5.77), P < 0.01], low serum transferrin saturation [OR = 1.42 (1.01-2.03), P < 0.05] and duration of dialysis [OR = 1.09 (1.03-1.14), P < 0.01] were associated with RLS. In contrast, high serum hemoglobin level was inversely associated with RLS [OR = 0.61 (0.40-0.89), P < 0.05]. RLS has a significant impact on sleep quality in dialysis patients. Among patients with RLS, history of type 2 diabetes [OR = 4.04 (1.65-10.79), P < 0.05], low serum hemoglobin level [OR = 5.41 (2.43-13.12), P < 0.01] and duration of dialysis [OR = 1.01 (1.01-1.02), P < 0.01] were associated with increased severity of RLS. CONCLUSIONS: Our findings demonstrated that RLS is common in Taiwanese dialysis patients. Clinicians should have a high suspicion for the presence of RLS symptoms in patients with ESRD, especially those with type 2 diabetes, anemia, low serum iron status and long duration of dialysis. PMID- 23369047 TI - Serum galactomannan assay for the diagnosis of invasive aspergillosis in children with haematological malignancies. AB - Diagnostic efficacy of Galactomannan (GM) assay for invasive aspergillosis (IA) is variably reported. Data from developing countries are scant. Children with haematological malignancies and fever were enrolled prospectively. Blood sample for GM was drawn on the day of admission; levels were measured with Platellia Aspergillus enzyme immunoassay. Diagnostic criteria were adapted from EORTC-MSG 2002. Proven, probable and possible episodes were considered as the disease group. One hundred febrile episodes in 78 patients were evaluated. The mean age was 6.1 years. Majority (75%) episodes were in patients with acute lymphoblastic leukaemia. One episode each was diagnosed with proven and probable IA, while 23 were diagnosed with possible IA. Best results were obtained with a cut-off value of 1.0, with sensitivity, specificity, positive and negative predictive value of 60%, 93%, 75 and 87 respectively. The sensitivity dropped to 40%, at cut-off value of 1.5 and specificity was 38%, at a cut-off of 0.5. A higher value of GM correlated with pulmonary nodules (P = 0.037) and mortality (P = 0.001). GM assay is adjunctive to clinical/radiological evidence. A negative GM assay may not reassure the physician against the use of amphotericin in patients with febrile neutropenia, as it does not exclude the diagnosis of clinically relevant other fungal infections, particular mucormycosis. PMID- 23369048 TI - Synthesis and characterization of a matrix-metalloproteinase responsive silk elastinlike protein polymer. AB - Silk-elastinlike protein polymers (SELPs) are recombinant polymers consisting of tandem repeats of silk (GAGAGS) and elastin (GVGVP) units. By modification of the length and composition of these repeats, the properties of SELP hydrogels can be controlled for specific applications including nucleic acid and virus delivery and tissue engineering. Here, the structure of SELPs is further modified to include a sequence that is sensitive to matrix-metalloproteinases (MMPs). MMPs are a ubiquitous family of extracellular matrix-modifying enzymes that are commonly associated with numerous vital processes. Increased levels of MMPs are found at high levels locally in many types of solid tumors. By modifying the SELP backbone with MMP-sensitive peptide sequences, a hydrogel that is degradable by MMPs was produced. The MMP-sensitivity of the polymer was examined by incubation with MMP-2 and MMP-9, which yielded complete cleavage of all full-length polymers by 36 hours and 48 hours, respectively, with no observable effect on unmodified SELP. Hydrogel sensitivity was tested by exposure to MMP-2 or MMP-9 for 2 weeks, during which samples were taken to analyze protein loss from the hydrogel and release of 100 nm fluorescent beads. Following the incubation period, hydrogels were tested in mechanical compression to examine the loss of hydrogel stiffness due to degradation. It was found that MMP-2 and MMP-9 caused 63% and 44% increased protein loss and 65% and 95% increased release from MMP-sensitive hydrogels, while the compressive modulus decreased by 41% and 29%. These results suggest the potential of MMP-responsive SELPs for localized delivery of bioactive agents where MMPs are overexpressed. PMID- 23369049 TI - Efficient known ncRNA search including pseudoknots. AB - BACKGROUND: Searching for members of characterized ncRNA families containing pseudoknots is an important component of genome-scale ncRNA annotation. However, the state-of-the-art known ncRNA search is based on context-free grammar (CFG), which cannot effectively model pseudoknots. Thus, existing CFG-based ncRNA identification tools usually ignore pseudoknots during search. As a result, dozens of sequences that do not contain the native pseudoknots are reported by these tools. When pseudoknot structures are vital to the functions of the ncRNAs, these sequences may not be true members. RESULTS: In this work, we design a pseudoknot search tool using multiple simple sub-structures, which are derived from knot-free and bifurcation-free structural motifs in the underlying family. We test our tool on a contiguous 22-Mb region of the Maize Genome. The experimental results show that our work competes favorably with other pseudoknot search methods. CONCLUSIONS: Our sub-structure based tool can conduct genome scale pseudoknot-containing ncRNA search effectively and efficiently. It provides a complementary pseudoknot search tool to Infernal. The source codes are available at http://www.cse.msu.edu/~chengy/knotsearch. PMID- 23369050 TI - Clinical advantages of a metal stent with an S-shaped anti-reflux valve in malignant biliary obstruction. AB - BACKGROUND AND AIM: Transpapillary stent insertion is the standard treatment for palliating malignant biliary obstruction. However, luminal occlusion often occurs due to sludge formation, tumor ingrowth, or tumor overgrowth. Currently, influx of duodenal contents by duodenobiliary reflux is considered a mechanism of stent obstruction. The aim of the present study was to evaluate the efficacy and safety of a metal stent with an anti-reflux valve in distal malignant biliary obstruction. METHODS: Thirty-two patients diagnosed with unresectable malignant biliary obstruction were enrolled. This trial was conducted at two tertiary hospitals in Korea from June 2009 to June 2011. An uncovered metal stent (M.I.Tech) with an S-type anti-reflux valve was placed. RESULTS: A total of 32 patients were enrolled. The technical success rate of stent insertion was 100%. The median duration of stent patency was 14.4 months. Stent occlusion occurred in 11 cases, which was caused by sludge formation in six cases, tumor ingrowth in four cases, and migration of the stent membrane in one case. During the follow-up period, there were no episodes of ascending cholangitis, acute pancreatitis, or bleeding. CONCLUSIONS: The new metal stent with an S-shaped anti-reflux valve demonstrated a relatively long duration of stent patency. This was attributable to reductions in duodenobiliary reflux by the anti-reflux valve. Also, the stent with an S-shaped anti-reflux valve is technically feasible and very safe. However, further prospective, randomized comparison studies of stents with anti reflux valves and conventional stents are needed to evaluate the duration of stent patency. PMID- 23369051 TI - Probing carbon nanotube-surfactant interactions with two-dimensional DOSY NMR. AB - Two-dimensional diffusion ordered spectroscopy (2D DOSY) NMR was used to probe the micellar structure of sodium dodecyl sulfate (SDS) and sodium cholate (SC) in aqueous solutions with and without semiconducting and metallic single-walled carbon nanotubes (SWCNTs). The solutions contain SDS and SC at weight ratios of 1:4 and 3:2, the ratios commonly used to isolate semiconducting and metallic SWCNTs through density gradient ultracentrifugation (DGU). These results show that the coverage of surfactant on the semiconducting and metallic SWCNTs is nearly identical in the 1:4 surfactant mixture, and a lower degree of bundling is responsible for the greater buoyancy of semiconducting SWCNTs. In the 3:2 surfactant mixture, the metallic SWCNTs are only encapsulated in SC while the semiconducting SWCNTs remain encapsulated in a poorly packed two-surfactant micelle, leading to a large buoyant density difference between the electronic species. This work provides insight into future directions to increase the purity of semiconducting and metallic SWCNTs sorted through DGU and demonstrates the utility of 2D DOSY NMR in probing SWCNT-surfactant complexes. PMID- 23369052 TI - Multiple sclerosis spasticity symptoms management. Endocannabinoid system modulator data beyond clinical trials. Foreword. PMID- 23369053 TI - Multiple sclerosis spasticity daily management: retrospective data from Europe. AB - Multiple sclerosis (MS) is a distressing and debilitating disease, which often leads to a state of progressive deterioration for the individual. Spasticity is a common and disabling neurological feature with increasing presence and severity throughout the progression of MS. Management of this spasticity is a key component of day-to-day care for patients with MS. Data from recent epidemiological studies in Spain (the '6E' and '5E' studies) and Germany (the 'MOVE 1' study) confirm the frequent occurrence of spasticity symptoms in patients with MS. Despite the difficulties experienced by MS patients with spasticity, the condition is largely undertreated because current treatment options do not provide adequate control of MS spasticity. With worsening MS spasticity there is an increase in individual patient symptoms, worsening of quality of life and impairment of daily living. From a healthcare/societal perspective, MS spasticity has been shown to be associated with substantial costs. Many of these costs relate to the increased disability (and consequent need for rehabilitation and caregiver support) that are associated with moderate to-severe spasticity. Consequently, newer drugs that can provide better symptomatic relief and may slow progression to more severe forms of disability will be a step forward in the level of care that we can provide for MS patients. PMID- 23369054 TI - Endocannabinoid system modulator use in everyday clinical practice in the UK and Spain. AB - Spasticity is a disabling complication of multiple sclerosis. Some commonly used oral medications include baclofen, tizanidine, anticonvulsants and benzodiazepines, but their benefits are modest. Sativex(r) (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain) is a unique cannabinoid-based medicine with two main active ingredients; 9-delta tetrahydrocannabinol, which acts mainly on cannabinoid 1 receptors in the CNS and plays a key role in the modulation of spasticity and spasms, and cannabidiol, which has different properties, including minimization of the psychoactivity associated with 9-delta-tetrahydrocannabinol. Sativex is indicated for symptomatic improvement in adult patients with moderate-to-severe multiple sclerosis-related spasticity who have not responded adequately to other first- or second-line antispasticity medications, and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. Over the past couple of years, Sativex has been approved for use in a number of European countries and ongoing postmarketing studies are evaluating the possible risks associated with Sativex treatment by systematically collecting all suspected adverse reactions that occur in patients from the start of treatment. Interim data from the UK as well as Spanish Sativex safety registries confirm that clinical benefit is maintained over the longer term despite the expected trend for deterioration owing to disease progression. Even after more than 2 years of use, no new safety/tolerability signals have emerged with Sativex, including no evidence of driving impairment and no relevant incidence of falls or other adverse events of concern, such as psychiatric or nervous system events. Sativex appears to be a well-tolerated and useful add-on therapy in patients who have not achieved an adequate response with traditional antispastic agents. PMID- 23369055 TI - A new multiple sclerosis spasticity treatment option: effect in everyday clinical practice and cost-effectiveness in Germany. AB - Sativex(r) (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain), a cannabinoid oromucosal spray containing a 1:1 ratio of 9 delta-tetrahydrocannabinol and cannabidiol, has been licensed in Germany since July 2011 as add-on therapy for moderate-to-severe multiple sclerosis (MS) treatment-resistant spasticity symptoms. The 'MOVE 2' study evaluated clinical outcomes, treatment satisfaction, quality of life (QoL) and provision of care in MS patients with spasticity receiving Sativex in everyday clinical practice. Data from 300 patients were collected from 42 specialized MS centers across Germany and were available for this analysis. Assessments, including the MS spasticity 0 10 numerical rating scale, modified Ashworth scale, patients' and physicians' clinical impressions, and QoL scales were rated at baseline and at 1 and 3 months after starting treatment with Sativex. Sativex provided relief of MS-related spasticity in the majority of patients who were previously resistant to treatment. In addition, clear improvements were noted in MS spasticity-associated symptoms (e.g., sleep quality, bladder function and mobility), activities of daily living and QoL. Sativex was generally well tolerated. The majority of patients (84%) reported no adverse events, and there was only a limited risk of serious adverse reactions. Furthermore, based on data from Sativex clinical trials, a Markov model-based analysis has shown that Sativex is a cost-effective treatment option for patients with MS spasticity in Germany. PMID- 23369056 TI - Multiple sclerosis spasticity: 'state-of-the-art' questionnaire survey of specialized healthcare professionals. AB - Spasticity (muscle rigidity and spasms) is a frequent and disabling feature of multiple sclerosis (MS), and it can have a marked negative impact on the patient's overall wellbeing and quality of life through a range of symptoms including impaired mobility, bladder dysfunction, stiffness, spasms and sleep disorders. Numerous antispastic agents such as baclofen and tizanidine, as well as others, are available for the management of MS spasticity but, overall, they offer limited clinical benefit. The current questionnaire survey assessed the epidemiology and management of MS spasticity globally and across the EU, among 157 healthcare professionals (>95% of all respondents were neurologists) attending a large, international MS congress (European Committee for Treatment and Research in Multiple Sclerosis, Lyon, France, 10-13 October 2012). Survey results showed similarity between the EU and rest-of-world respondents in the epidemiology of MS spasticity, the use of assessment tools to monitor patients, the incidence and severity of symptoms, and management options. Respondents indicated that approximately 40% of their MS patients had spasticity and it was rated as mild in approximately 40%, moderate in 35% and severe in 25% of patients. At least 40% of practitioners were dissatisfied with treatment options in their patients with moderate-to-severe MS; this highlights the unmet needs and challenges facing specialists in the management of MS patients with moderate-to severe spasticity. PMID- 23369057 TI - Exercise training prevents the development of cardiac dysfunction in the low-dose streptozotocin diabetic rats fed a high-fat diet. AB - This study tested the hypothesis that exercise training would prevent the development of diabetes-induced cardiac dysfunction and altered expression of sarcoplasmic reticulum Ca(2 +)-transport proteins in the low-dose streptozotocin induced diabetic rats fed a high-fat diet (HFD+STZ). Male Sprague-Dawley rats (4 weeks old; 125-150 g) were made diabetic using a high-fat diet (40% fat, w/w) and a low-dose of streptozotocin (35 mg.(kg body mass)(-1)) by intravenous injection. Diabetic animals were divided among a sedentary group (Sed+HFD+STZ) or an exercise-trained group (Ex+HFD+STZ) that accumulated 3554 +/- 338 m.day(-1) of voluntary wheel running (mean +/- SE). Sedentary animals fed a low-fat diet served as the control (Sed+LFD). Oral glucose tolerance was impaired in the sedentary diabetic group (1179 +/- 29; area under the curve (a.u.c.)) compared with that in the sedentary control animals (1447 +/- 42 a.u.c.). Although left ventricular systolic function was unchanged by diabetes, impaired E/A ratios (i.e., diastolic function) and rates of pressure decay (-dP/dt) indicated the presence of diastolic dysfunction. Diabetes also reduced SERCA2a protein content and maximal SERCA2a activity (V(max)) by 21% and 32%, respectively. In contrast, the change in each parameter was attenuated by exercise training. Based on these data, it appears that exercise training prevented the development of diabetic cardiomyopathy and the dysregulation of sarcoplasmic reticulum protein content in an inducible animal model of type 2 diabetes. PMID- 23369059 TI - Social and ecological change over a decade in a village hunting system, central Gabon. AB - Despite widespread recognition of the major threat to tropical forest biological diversity and local food security posed by unsustainable bushmeat hunting, virtually no long-term studies tracking the socioecological dynamics of hunting systems have been conducted. We interviewed local hunters and collected detailed hunting data to investigate changes in offtake and hunter characteristics over 10 years (2001-2010) in Dibouka and Kouagna villages, central Gabon, in the context of hunter recollections of longer term trends since the 1950s. To control for changes in hunter behavior, such as trap location and characteristics, we report hunting offtake data per trap. Our results suggest the hunting area was already highly depleted by 2001; local hunters reported that 16 large-bodied prey species had become rare or locally extirpated over the last 60 years. Overall, we observed no significant declines in hunting offtake or changes in species composition from 2001 to 2010, and offtakes per trap increased slightly between 2004 and 2010. However, trapping distance from the villages increased, and there was a switch in hunting techniques; a larger proportion of the catch was hunted with guns in 2010. The number of hunters declined by 20% from 2004 to 2010, and male livelihood activities shifted away from hunting. Hunters with the lowest hunting incomes in 2004 were more likely than successful hunters to have moved away from the village by 2010 (often in response to alternative employment opportunities). Therefore, changes in trap success (potentially related to biological factors) were interacting with system-level changes in hunter number and composition (related to external socioeconomic factors) to produce a relatively static overall offtake. Our results highlight the importance of understanding the small-scale context of hunting to correctly interpret changes or apparent stasis in hunting effort and offtake over time. PMID- 23369058 TI - Diagnosis of Helicobacter pylori infection in gastric mucosa by endoscopic features: a multicenter prospective study. AB - BACKGROUND: Endoscopic features corresponding to pathological findings in the Sydney System have not been identified, and endoscopic diagnosis of chronic gastritis has not yet been established. To establish the diagnosis of Helicobacter pylori (H. pylori) infection in gastric mucosa by endoscopic features, a prospective multicenter study was carried out. PATIENTS AND METHODS: Two hundred and ninety-seven registered patients from 24 facilities between March 2008 and February 2009 were enrolled. Association between endoscopic findings (conventional findings and indigocarmine contrast (IC) method findings) and diagnosis of H. pylori infection made by microscopic observation of biopsy specimens was investigated in the corpus and antrum and their diagnostic accuracies were investigated. RESULTS: Two hundred and seventy-five patients were analyzed. The area under the receiver operating characteristic (ROC) curve for H. pylori infection of conventional endoscopy was 0.811 in thecorpus and 0.707 in the antrum (P = 0.006). Evaluation of diffuse redness, spotty redness and mucosal swelling by conventional endoscopy and swelling of areae gastricae by the indigocarmine contrast (IC) method were useful for diagnosing H. pylori infection. Regular arrangement of collecting venules (RAC) in the angle, fundic gland polyposis, hemorrhagic erosion and bleeding spot in the corpus and red streaks, and erosions (flat, raised, hemorrhagic and bleeding spot) in the antrum may be used as diagnostic features suggesting negative H. pylori infection. CONCLUSION: It is suggested that endoscopic diagnosis of H. pylori infection in gastric mucosa by conventional endoscopy and the IC method is mostly possible. PMID- 23369060 TI - Eosinophils in human oral squamous carcinoma; role of prostaglandin D2. AB - Eosinophils are often predominant inflammatory leukocytes infiltrating oral squamous carcinoma (OSC) sites. Prostaglandins are secreted by oral carcinomas and may be involved in eosinophil infiltration. The objective of this study was to determine the factors contributing to eosinophil migration and potential anti neoplastic effects on OSC. Eosinophil degranulation was evaluated by measuring release of eosinophil peroxidase (EPO). Eosinophil chemotaxis towards OSC cells was assessed using artificial basement membrane. Eosinophil infiltration was prominent within the tissue surrounding the OSC tumor mass. We observed growth inhibition of the OSC cell line, SCC-9, during co-culture with human eosinophils, in vitro, which correlated with EPO activity that possesses growth inhibitory activity. The PGD2 synthase inhibitor, HQL-79, abrogated migration towards SCC-9. Our data suggest that OSC-derived PGD2 may play an important role via CRTH2 (the PGD2 receptor on eosinophils) in eosinophil recruitment and subsequent anti-tumor activity through the action of eosinophil cationic proteins. PMID- 23369062 TI - Osmium-catalyzed oxidative cyclization of dienes and their derivatives. AB - The development and application of novel methods for accomplishing the synthesis of heterocycles via osmium-catalyzed oxidative cyclization onto an alkene is described in this Perspective. Beginning with a fortuitous discovery, an extensive examination of the possible mechanism of cyclization has been carried out, and the method was continuously developed until it had been transformed into an extremely efficient and powerful new catalytic reaction for the formation of tetrahydrofurans and pyrrolidines with complete control over all aspects of relative and absolute stereochemistry. By working with Os(VI) rather than the more familiar Os(VIII), a highly potent yet mild set of reaction conditions were developed. In addition to the method development studies, this work also sets out some synthetic challenges against which the methodology was tested. Pleasingly, the catalytic oxidative cyclization has proved itself to be an efficient and functional group tolerant process that was pivotal to the completion of several natural product syntheses. PMID- 23369061 TI - Expression dynamics and genome distribution of osmoprotectants in soybean: identifying important components to face abiotic stress. AB - BACKGROUND: Despite the importance of osmoprotectants, no previous in silico evaluation of high throughput data is available for higher plants. The present approach aimed at the identification and annotation of osmoprotectant-related sequences applied to short transcripts from a soybean HT-SuperSAGE (High Throughput Super Serial Analysis of Gene Expression; 26-bp tags) database, and also its comparison with other transcriptomic and genomic data available from different sources. METHODS: A curated set of osmoprotectants related sequences was generated using text mining and selected seed sequences for identification of the respective transcripts and proteins in higher plants. To test the efficiency of the seed sequences, these were aligned against four HT-SuperSAGE contrasting libraries generated by our group using soybean tolerant and sensible plants against water deficit, considering only differentially expressed transcripts (p <= 0.05). Identified transcripts from soybean and their respective tags were aligned and anchored against the soybean virtual genome. RESULTS: The workflow applied resulted in a set including 1,996 seed sequences that allowed the identification of 36 differentially expressed genes related to the biosynthesis of osmoprotectants [Proline (P5CS: 4, P5CR: 2), Trehalose (TPS1: 9, TPPB: 1), Glycine betaine (BADH: 4) and Myo-inositol (MIPS: 7, INPS1: 8)], also mapped in silico in the soybean genome (25 loci). Another approach considered matches using Arabidopsis full length sequences as seed sequences, and allowed the identification of 124 osmoprotectant-related sequences, matching ~10.500 tags anchored in the soybean virtual chromosomes. Osmoprotectant-related genes appeared clustered in all soybean chromosomes, with higher density in some subterminal regions and synteny among some chromosome pairs. CONCLUSIONS: Soybean presents all searched osmoprotectant categories with some important members differentially expressed among the comparisons considered (drought tolerant or sensible vs. control; tolerant vs. sensible), allowing the identification of interesting candidates for biotechnological inferences. The identified tags aligned to corresponding genes that matched 19 soybean chromosomes. Osmoprotectant-related genes are not regularly distributed in the soybean genome, but clustered in some regions near the chromosome terminals, with some redundant clusters in different chromosomes indicating their involvement in previous duplication and rearrangements events. The seed sequences, transcripts and map represent the first transversal evaluation for osmoprotectant-related genes and may be easily applied to other plants of interest. PMID- 23369064 TI - Chronic perineal pain relieved by steroid injection and physical therapy. PMID- 23369066 TI - Multitarget cannabinoids as novel strategy for Alzheimer disease. AB - During the last years the development of approaches to multitarget drug design and discovery is gaining acceptance. The cannabinoids are potentially excellent multi-target drug candidates because of their interesting pharmacological profiles, among which stands out the dual capacity of cannabinoid ligands to act as cannabinoid agonist and cholinesterase inhibitors. In this article, inhibition, kinetics studies and docking simulations with a representative set of cannabinoids are presented. The results of these studies showed the inhibitory capacity of some agonist cannabinoids with selectivity at AChE or BuChE enzymes. The kinetic and modelling studies allowed us to postulate the potential mode of action and the binding site of the cannabinoids. In general, the studied cannabinoids showed a mixed type inhibition mode of action. The exception to this behaviour was found for the agonist CP-55,940 that showed a non-competitive inhibition, suggesting that this cannabinoid only binds to the peripheral site. PMID- 23369065 TI - Prognostic factors of all-cause mortalities in continuous ambulatory peritoneal dialysis: a cohort study. AB - BACKGROUND: The role of small solute clearance on mortalities in patients with CAPD has been controversial. We therefore conducted a study with 3 years' follow up in adult patients who participated in the CAPD-first policy. METHODS: There were 11,523 patients with end-stage renal disease who participated in the CAPD first policy between 2008 and 2011. Among them, 1,177 patients were included in the retrospective cohort study. A receiver operating characteristic curve was applied to calibrate the cutoffs of tKt/V, rKt/V and tCrcl. Kaplan-Meier and Cox regression models with time varying covariates were applied to estimate overall death rate, probability of death and prognosis, respectively. RESULTS: The cutoffs of rKt/V and tKt/V were 0.25 and 1.75, respectively. The Cox regression suggested that the higher these clearance parameters, the lower the risks of death after adjusting for covariables. The risks of death for those above these cutoffs were 57% (HR = 0.43, 95% CI: 0.31, 0.60) and 29% (HR = 0.71, 95% CI: 0.52, 0.98) lower for rKt/V and tKt/V, respectively. Age, serum albumin, hemoglobin, systolic blood pressure, and ultra-filtration volume significantly affected the mortality outcome. CONCLUSIONS: Our study suggested that the cutoffs of 0.25 and 1.75 for rKt/V and tKt/V might be associated with mortality in CAPD patients. A minimum tKt/V of 1.75 should be targeted, but increased dialysis dosage to achieve tKt/V > 2.19 adds no further benefit. Serum albumin, hemoglobin, SBP, and UF volume are also associated with mortality. However, our study may face with selection and other unobserved confounders, so further randomized controlled trials are required to confirm these cutoffs. PMID- 23369067 TI - Effects of craniosacral therapy as adjunct to standard treatment for pelvic girdle pain in pregnant women: a multicenter, single blind, randomized controlled trial. AB - OBJECTIVE: Pelvic girdle pain (PGP) is a disabling condition affecting 30% of pregnant women. The aim of this study was to investigate the efficacy of craniosacral therapy as an adjunct to standard treatment compared with standard treatment alone for PGP during pregnancy. DESIGN: Randomized, multicenter, single blind, controlled trial. SETTING: University hospital, a private clinic and 26 maternity care centers in Gothenburg, Sweden. POPULATION: A total of 123 pregnant women with PGP. METHODS: Participants were randomly assigned to standard treatment (control group, n = 60) or standard treatment plus craniosacral therapy (intervention group, n = 63). MAIN OUTCOME MEASURES: PRIMARY OUTCOME MEASURES: pain intensity (visual analog scale 0-100 mm) and sick leave. SECONDARY OUTCOMES: function (Oswestry Disability Index), health-related quality of life (European Quality of Life measure), unpleasantness of pain (visual analog scale), and assessment of the severity of PGP by an independent examiner. RESULTS: Between group differences for morning pain, symptom-free women and function in the last treatment week were in favor of the intervention group. Visual analog scale median was 27 mm (95% confidence interval 24.6-35.9) vs. 35 mm (95% confidence interval 33.5-45.7) (p = 0.017) and the function disability index was 40 (range 34-46) vs. 48 (range 40-56) (p = 0.016). CONCLUSIONS: Lower morning pain intensity and less deteriorated function was seen after craniosacral therapy in conjunction with standard treatment compared with standard treatment alone, but no effects regarding evening pain and sick-leave. Treatment effects were small and clinically questionable and conclusions should be drawn carefully. Further studies are warranted before recommending craniosacral therapy for PGP. PMID- 23369068 TI - Six years after a modified constraint induced movement therapy (CIMT) program- what happens when the children have become young adults? AB - The aim is to describe the development of hand function in young adults with unilateral cerebral palsy (CP), who participated in a 2-week Constraint Induced Movement Therapy (CIMT) camp 6 years earlier. Eleven participants, 16-21 years at follow-up, were assessed at three occasions during 2005 and once in 2011. At the 6-year follow-up, performance on the Assisting Hand Assessment and the Jebsen Taylor Hand Function test remained unchanged (P > 0.05) from the first assessment before the camp. Grip strength (Grippit(r)) increased in both the involved (+80.9%) and non-involved hand (+94.4%) (P < 0.05), while performance on the Melbourne Assessment tended to decrease (-7%). In conclusion, it seems that young adults with unilateral CP maintain their hand function performance at the same level as in the early adolescent period. Interestingly, the grip strength increased over time also for the involved hand. PMID- 23369069 TI - Measuring the spectral diffusion of chlorophyll a using two-dimensional electronic spectroscopy. AB - Ultrafast two-dimensional electronic spectroscopy has been used to study the spectral diffusion of the Qy transition of chlorophyll a in methanol. The two time frequency-fluctuation correlation function (FFCF) of the transition has been measured using the center line slope method, together with optimized fitting of the linear spectrum. The FFCF was measured to decay over four time scales. The three fastest time constants of which were measured to be ~65 fs, ~0.5 ps, and ~7 ps. These are assigned as the inertial component of solvation and spectrally diffusive solvation processes respectively. The fourth time constant (>1 ns) may be attributed to the chromophore structural inhomogeneity. PMID- 23369070 TI - A unified approach for allele frequency estimation, SNP detection and association studies based on pooled sequencing data using EM algorithms. AB - BACKGROUND: Genome-wide association studies (GWAS) have identified many common polymorphisms associated with complex traits. However, these associated common variants explain only a small fraction of the phenotypic variances, leaving a substantial portion of genetic heritability unexplained. As a result, searches for "missing" heritability are drawing increasing attention, particularly for rare variant studies that often require a large sample size and, thus, extensive sequencing effort. Although the development of next generation sequencing (NGS) technologies has made it possible to sequence a large number of reads economically and efficiently, it is still often cost prohibitive to sequence thousands of individuals that are generally required for association studies. A more efficient and cost-effective design would involve pooling the genetic materials of multiple individuals together and then sequencing the pools, instead of the individuals. This pooled sequencing approach has improved the plausibility of association studies for rare variants, while, at the same time, posed a great challenge to the pooled sequencing data analysis, essentially because individual sample identity is lost, and NGS sequencing errors could be hard to distinguish from low frequency alleles. RESULTS: A unified approach for estimating minor allele frequency, SNP calling and association studies based on pooled sequencing data using an expectation maximization (EM) algorithm is developed in this paper. This approach makes it possible to study the effects of minor allele frequency, sequencing error rate, number of pools, number of individuals in each pool, and the sequencing depth on the estimation accuracy of minor allele frequencies. We show that the naive method of estimating minor allele frequencies by taking the fraction of observed minor alleles can be significantly biased, especially for rare variants. In contrast, our EM approach can give an unbiased estimate of the minor allele frequency under all scenarios studied in this paper. A SNP calling approach, EM-SNP, for pooled sequencing data based on the EM algorithm is then developed and compared with another recent SNP calling method, SNVer. We show that EM-SNP outperforms SNVer in terms of the fraction of db-SNPs among the called SNPs, as well as transition/transversion (Ti/Tv) ratio. Finally, the EM approach is used to study the association between variants and type I diabetes. CONCLUSIONS: The EM-based approach for the analysis of pooled sequencing data can accurately estimate minor allele frequencies, call SNPs, and find associations between variants and complex traits. This approach is especially useful for studies involving rare variants. PMID- 23369071 TI - Effect of intravenous lipid emulsion and octreotide on enteric thiopentone absorption; a pilot study. PMID- 23369072 TI - Biobased polyesters with composition-dependent thermomechanical properties: synthesis and characterization of poly(butylene succinate-co-butylene azelate). AB - Environmentally friendly poly(butylenesuccinate-co-butyleneazelate) (P(BS-co BAz)s) aliphatic copolyesters with composition-dependent thermomechanical properties were synthesized from succinic acid (SuA), 1,4-butanediol (BDO), and dimethylazelate (DMAz) through a two-step polycondensation reaction. The molar SuA/AzA ratio was varied from 4:1 to 1:4, and the chemical structure and molecular characteristics of resulting (co)polyesters were characterized by NMR and SEC, whereas thermal properties and crystallinity were studied by differential scanning calorimetry (DSC), dynamic mechanical thermal analyses (DMTA), and X-ray diffraction (XRD). A good agreement between theoretical and experimental SuA/AzA molar ratios in the copolyesters was achieved, together with the recovery of semicrystalline random copolymers of uniform composition along the chains. NMR, DSC, DMTA, and XRD results show that depending on their composition the P(BS-co-BAz) copolyesters might find applications from elastomers to high-impact thermoplastics. PMID- 23369073 TI - The complete mitochondrial genome of Barbus capito (Cypriniformes, Cyprinidae). AB - The mitogenome of Barbus capito was 16,603 bp long containing 1 D-loop region, 2 rRNA, 22 tRNA, and 13 protein-coding genes. Eight tRNA genes and one protein coding gene were encoded on light strand, the others on heavy strand. The base composition and gene arrangement of B. capito mitogenome were identical to typical vertebrate. PMID- 23369074 TI - Endothelin-1 acutely reduces the permeability of visceral sheep peritoneum in vitro through both endothelin-A and endothelin-B receptors. AB - Mesothelium is an important part of the peritoneal barrier for water and ion transport, essential for effective peritoneal dialysis (PD). Peritoneal fibrosis has been associated with PD treatment failure. Endothelin-1 (ET-1) is a potent vasoactive peptide, involved in pathologic fibrotic processes. Its action is mediated mainly by endothelin type A (ETA ) and type B (ETB ) receptors. The aim of this study was to investigate, by Ussing chamber experiments, the effect of ET 1 on the transmesothelial electrical resistance (RTM ) of the isolated visceral sheep peritoneum. Intact sheets of visceral peritoneum were obtained from 40 adult sheep and mounted in Ussing-type chambers. ET-1 (10(-7) M), BQ-123 (ETA receptor antagonist; 10(-6) M), BQ-788 (ETB receptor antagonist; 10(-6) M), and their combinations were added on the apical and the basolateral side of the peritoneum. RTM was measured before and serially after addition of the substances, and changes were registered as percentage (DeltaRTM %). RTM increased within 1 min after addition of ET-1 apically (DeltaRTM 65.03 +/- 15.87%; P < 0.05) or basolaterally (DeltaRTM 85.5 +/- 20.86%; P < 0.05). BQ-123 and BQ-788 and their combination significantly reduced (P < 0.05) the effect of ET-1 to a similar degree in all cases. These results clearly indicate that ET-1 reduces ionic permeability of the visceral sheep peritoneum in vitro. Additionally, it is obvious that this inhibitory effect is mediated through both ETA and ETB receptors. PMID- 23369076 TI - Non-Aspergillus fungal infections in chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) is a congenital immunodeficiency, characterised by significant infections due to an inability of phagocyte to kill catalase-positive organisms including certain fungi such as Aspergillus spp. Nevertheless, other more rare fungi can cause significant diseases. This report is a systematic review of all published cases of non-Aspergillus fungal infections in CGD patients. Analysis of 68 cases of non-Aspergillus fungal infections in 65 CGD patients (10 females) published in the English literature. The median age of CGD patients was 15.2 years (range 0.1-69), 60% of whom had the X-linked recessive defect. The most prevalent non-Aspergillus fungal infections were associated with Rhizopus spp. and Trichosporon spp. found in nine cases each (13.2%). The most commonly affected organs were the lungs in 69.9%. In 63.2% of cases first line antifungal treatment was monotherapy, with amphotericin B formulations being the most frequently used antifungal agents in 45.6% of cases. The overall mortality rate was 26.2%. Clinicians should take into account the occurrence of non-Aspergillus infections in this patient group, as well as the possibility of a changing epidemiology in fungal pathogens. Better awareness and knowledge of these pathogens can optimise antifungal treatment and improve outcome in CGD patients. PMID- 23369075 TI - The benefits of exercise training in interstitial lung disease: protocol for a multicentre randomised controlled trial. AB - BACKGROUND: Interstitial lung disease encompasses a diverse group of chronic lung conditions characterised by distressing dyspnoea, fatigue, reduced exercise tolerance and poor health-related quality of life. Exercise training is one of the few treatments to induce positive changes in exercise tolerance and symptoms, however there is marked variability in response. The aetiology and severity of interstitial lung disease may influence the response to treatment. The aims of this project are to establish the impact of exercise training across the range of disease severity and to identify whether there is an optimal time for patients with interstitial lung disease to receive exercise training. METHODS/DESIGN: One hundred and sixteen participants with interstitial lung disease recruited from three tertiary institutions will be randomised to either an exercise training group (supervised exercise training twice weekly for eight weeks) or a usual care group (weekly telephone support). The 6-minute walk distance, peripheral muscle strength, health-related quality of life, dyspnoea, anxiety and depression will be measured by a blinded assessor at baseline, immediately following the intervention and at six months following the intervention. The primary outcome will be change in 6-minute walk distance following the intervention, with planned subgroup analyses for participants with idiopathic pulmonary fibrosis, dust related interstitial lung disease and connective-tissue related interstitial lung disease. The effects of disease severity on outcomes will be evaluated using important markers of disease severity and survival, such as forced vital capacity, carbon monoxide transfer factor and pulmonary hypertension. DISCUSSION: This trial will provide certainty regarding the role of exercise training in interstitial lung disease and will identify at what time point within the disease process this treatment is most effective. The results from this study will inform and optimise the clinical management of people with interstitial lung disease. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611000416998. PMID- 23369077 TI - Effects of glycated low-density lipoprotein on cell viability, proliferation, and growth factors of mouse embryo fibroblasts. AB - The predominant cause of death in diabetic patients is atherosclerotic coronary artery disease (CAD). Major gross cellular changes in the vascular wall of persons with CAD include endothelial injury and foam cell formation, as well as smooth muscle cell and fibroblast proliferation. This study examined the effects of glycated low density lipoprotein (glyLDL), a biochemical marker of diabetes, on cell viability, proliferation, and the expression of multiple growth factors in mouse embryo fibroblasts (MEF). The results demonstrated that exposure to >=150 MUg/mL of glyLDL for 24 h or 100 MUg/mL of glyLDL for >=48 h either significantly reduced cell viability or increased DNA fragmentation in MEF. GlyLDL treatment (25-100 MUg/mL for up to 12 h) significantly increased the abundance of proliferating cell nuclear antigen (PCNA) and achieved a peak after 4 h exposure to glyLDL. Abundances of fibroblast growth factor-basic (FGF), transforming growth factor-beta (TGF), and platelet-derived growth factor-A (PDGF) in MEF reached maximal levels after 2 h exposure to 50 MUg/mL of glyLDL. The maximal increase of vascular endothelial growth factor (VEGF) was detected in MEF after 4 h of exposure to 50 MUg/mL of glyLDL. Inhibitors for FGF (AZD4547), VEGF, or PDGF receptors (Axitinib), but not that for TGF receptor (LY364947), significantly decreased the abundance of (PCNA) in endothelial cells. The findings suggest that early exposure to a low dosage of glyLDL transiently increases the proliferation of MEF through the upregulation of FGF, VEGF, and (or) PDGF, and prolonged exposure to high concentrations of glyLDL reduced cell viability, which possibly accelerates atherogenesis under diabetic condition. PMID- 23369078 TI - Circulating rotaviral RNA in children with rotavirus antigenemia. AB - BACKGROUND: Rotavirus antigenemia is a common phenomenon in children with rotavirus diarrhea, but information is scarce on aspects of this phenomenon, such as genotype specificity, presence of intact viruses and correlation between genomic RNA and antigen concentration. Such information may help in understanding rotavirus pathogenesis and eventually be useful for diagnosis, treatment and prevention. METHODS AND FINDINGS: Serum samples were collected from children who presented at hospitals with diarrhea. Antigenemia was present in 162/250 (64.8%) samples from children with rotavirus diarrhea. No specific rotavirus genotype was found to be associated with antigenemia. Rotavirus particles could not be found by electron microscopy in concentrated serum from children with high levels of antigenemia. In passaged rotavirus suspension a significant correlation (r=0.9559; P=0.0029) was found between antigen level and viral copy number, but no significant correlation (r=0.001480; P=0.9919) was found between antigenemia level and viral copy number in serum. When intact rotavirus was treated with benzonase endonuclease, genomic double-stranded (ds) RNA was not degraded, but when sera of patients with antigenemia were treated with benzonase endonuclease, genomic dsRNA was degraded, indicating genomic dsRNA was free in sera and not inside virus capsid protein. CONCLUSIONS: Antigenemia is present in a significant number of patients with rotavirus diarrhea. Rotavirus viremia was absent in the children with rotavirus diarrhea who participated in our study, and was not indicated by the presence of antigenemia. The significance of circulating rotavirus antigen and genomic dsRNA in serum of patients with diarrhea deserves further study. PMID- 23369081 TI - Hepatobiliary alveolar echinococcosis infiltration of the hepatic hilum diagnosed by endoscopic ultrasonography-guided fine-needle aspiration. PMID- 23369080 TI - Widespread evidence of viral miRNAs targeting host pathways. AB - BACKGROUND: MicroRNAs (miRNA) are regulatory genes that target and repress other RNA molecules via sequence-specific binding. Several biological processes are regulated across many organisms by evolutionarily conserved miRNAs. Plants and invertebrates employ their miRNA in defense against viruses by targeting and degrading viral products. Viruses also encode miRNAs and there is evidence to suggest that virus-encoded miRNAs target specific host genes and pathways that may be beneficial for their infectivity and/or proliferation. However, it is not clear whether there are general patterns underlying cellular targets of viral miRNAs. RESULTS: Here we show that for several of the 135 known viral miRNAs in human viruses, the human genes targeted by the viral miRNA are enriched for specific host pathways whose targeting is likely beneficial to the virus. Given that viral miRNAs continue to be discovered as technologies evolve, we extended the investigation to 6809 putative miRNAs encoded by 23 human viruses. Our analysis further suggests that human viruses have evolved their miRNA repertoire to target specific human pathways, such as cell growth, axon guidance, and cell differentiation. Interestingly, many of the same pathways are also targeted in mice by miRNAs encoded by murine viruses. Furthermore, Human Cytomegalovirus (CMV) miRNAs that target specific human pathways exhibit increased conservation across CMV strains. CONCLUSIONS: Overall, our results suggest that viruses may have evolved their miRNA repertoire to target specific host pathways as a means for their survival. PMID- 23369082 TI - Mucosal cutting biopsy technique for histological diagnosis of suspected gastrointestinal stromal tumors of the stomach. AB - BACKGROUND AND AIM: The Japanese Gastrointestinal Stromal Tumor (GIST) therapeutic guidelines recommend endoscopic ultrasound-guided fine-needle aspiration biopsy for histological diagnosis. However, before 2010, this technique was only carried out at a minority of medical institutions in Japan. In the present study, we investigated the usefulness of mucosal cutting biopsy. METHODS: In 18 asymptomatic gastric submucosal tumors, mucosal cutting biopsies were carried out. We examined tumor size, tumor site (lower third: L; middle third: M; upper third: U), histopathological diagnostic yield and complications. In cases that proceeded to surgical resection with a diagnosis of GIST, we compared the pre- and postoperative histopathological diagnosis, and the histological degrees of malignancy. RESULTS: The tumors had a mean size of 20.3 mm and were located at the L site in five cases, M in four, and U in nine. Histological diagnosis of submucosal tumor was obtained in all the cases. (GIST, n = 13; heterotopic pancreas, n = 2; and leiomyoma, n = 3). No complications (e.g. bleeding, perforation or peritonitis) were seen after this procedure. In all 11 patients with GIST who underwent surgical resection, the histopathological findings from the mucosal cutting biopsy specimens were similar to those from the surgically resected specimens, with agreement between the immunostaining findings and the histological degree of malignancy (90.9%) in 10 patients. CONCLUSIONS: The mucosal cutting biopsy technique is a useful diagnostic modality for the diagnosis of gastric GIST and for selection of the appropriate treatment. PMID- 23369083 TI - Cancer patient and clinician acceptability and feasibility of a supportive care screening and referral process. AB - BACKGROUND: Incorporating supportive care into routine cancer care is an increasing priority for the multi-disciplinary team with growing evidence of its importance to patient-centred care. How to design and deliver a process which is appropriate for patients, clinicians and health services in rural areas needs further investigation. OBJECTIVE: To (i) examine the patient and clinician acceptability and feasibility of incorporating a supportive care screening and referral process into routine cancer care in a rural setting, and (ii) explore any potential influences of patient variables on the acceptability of the process. METHODS: A total of 154 cancer patients and 36 cancer clinicians across two rural areas of Victoria, Australia participated. During treatment visits, patients and clinicians participated in a supportive care process involving screening, discussion of problems, and provision of information and referrals. Structured questionnaires with open and closed questions were used to measure patient and clinician acceptability and feasibility. RESULTS: Patients and clinicians found the supportive care process highly acceptable. Screening identified relevant patient problems (90%) and problems that may not have otherwise been identified (83%). The patient-clinician discussion helped patients realize help was available (87%) and enhanced clinician-patient rapport (72%). Patients received useful referrals to services (76%). Feasibility issues included timing of screening for newly diagnosed patients, privacy in discussing problems, clinician time and availability of referral options. No patient demographic or disease factors influenced acceptability or feasibility. CONCLUSIONS: Patients and clinicians reported high acceptability for the supportive care process, although mechanisms for incorporating the process into health care need to be further developed. PMID- 23369084 TI - Procedural effectiveness of a novel 1.20 mm diameter angioplasty catheter: clinical and angiographic outcomes. AB - OBJECTIVE: To evaluate clinical and angiographic outcomes using a 1.20 mm diameter angioplasty catheter as part of a predilation strategy for coronary lesion treatment. BACKGROUND: Development of an angioplasty catheter with low crossing profile and small balloon diameter represents an opportunity to facilitate percutaneous revascularization of complex coronary disease. METHODS: Clinical and angiographic outcomes were evaluated following a predilation treatment strategy using a low profile, 1.20 mm angioplasty catheter. The primary end-point of procedural success was defined as successful device delivery, performance and lesion treatment without occurrence of perforation, flow-limiting dissection, reduction in baseline TIMI grade, or clinically significant arrhythmias, and with final achievement of TIMI 3 flow. In-hospital major adverse events were also determined. RESULTS: Among 71 patients (83 lesions), angiographic characteristics included: de novo lesion, 75.9%; saphenous vein graft 9.6%; lesion length (mean +/- standard deviation), 12.27 +/- 5.96 mm; reference vessel diameter, 2.61 +/- 0.57 mm; lesion classification B2/C, 59.0%; baseline TIMI 0/1 flow, 4.8%. Procedural success was achieved for 98.5% (66/67) of patients. Catheter delivery to the target lesion was achieved in all patients, and the rate of device success with luminal improvement after predilation was 96.2% (75/78). No acute procedural complications were observed, and in-hospital target lesion failure occurred in 6 patients (8.5%) related to peri-procedural non-Q wave myocardial infarction. CONCLUSIONS: Coronary lesion predilation with a low profile, 1.20 mm angioplasty catheter is associated with favorable procedural safety and efficacy and may represent an effective treatment for complex coronary anatomy. PMID- 23369085 TI - Finding reproducible cluster partitions for the k-means algorithm. AB - K-means clustering is widely used for exploratory data analysis. While its dependence on initialisation is well-known, it is common practice to assume that the partition with lowest sum-of-squares (SSQ) total i.e. within cluster variance, is both reproducible under repeated initialisations and also the closest that k-means can provide to true structure, when applied to synthetic data. We show that this is generally the case for small numbers of clusters, but for values of k that are still of theoretical and practical interest, similar values of SSQ can correspond to markedly different cluster partitions. This paper extends stability measures previously presented in the context of finding optimal values of cluster number, into a component of a 2-d map of the local minima found by the k-means algorithm, from which not only can values of k be identified for further analysis but, more importantly, it is made clear whether the best SSQ is a suitable solution or whether obtaining a consistently good partition requires further application of the stability index. The proposed method is illustrated by application to five synthetic datasets replicating a real world breast cancer dataset with varying data density, and a large bioinformatics dataset. PMID- 23369086 TI - Frequency of anticipatory trunk muscle onsets in children with and without developmental coordination disorder. AB - This study used electromyography to compare the frequency of anticipatory postural adjustments for three bilateral trunk muscles and unilateral tibialis anterior muscle between children with and without developmental coordination disorder (DCD; n = 22, ages 7 to 14 years) during three tasks (kicking a ball, stepping onto a step, standing on one foot). Between-group comparisons demonstrated significantly less frequent anticipatory activation of ipsilateral tibialis anterior, ipsilateral transversus abdominis/internal oblique, and bilateral external oblique muscles in children with DCD. Odds ratios indicated that children with DCD utilized anticipatory contractions of these muscles one half to one quarter as often as the typically developing children did, while performing the same tasks. These results suggest that the movement difficulties experienced by children with DCD may be associated with less frequent anticipatory adjustments. For these children, inconsistent preparatory activation may contribute to postural control difficulties, excessive movement variability and poor movement quality. PMID- 23369087 TI - Characterization of neutralizing monoclonal antibodies directed against tetanus toxin fragment C. AB - Clostridium tetani causes a life-threatening infectious disease by production of tetanus neurotoxin (TeNT), a 150 kDa molecule composed of light (LC) and heavy chain (HC) polypeptides. The TeNT HC contains an N-terminal domain critical for LC translocation and a C-terminal toxin receptor-binding domain known as fragment C. Despite extensive investigations on epitope specificity of anti-TeNT antibodies, the immunodominant neutralizing epitopes of the toxin are poorly defined. This study describes the generation and characterization of four monoclonal antibodies (MAb) specific for TeNT. The characteristics of each MAb were explored in terms of isotype, specificity, affinity, and immuno-globulin heavy chain variable region (IGHV) gene usage using ELISA, Western blotting, and sequencing techniques. The toxin neutralizing activity of the MAbs was also investigated using the in vitro GT1b neutralizing assay. The data demonstrated that all MAbs bind to tetanus toxin and toxoid. Sub-fragments binding analysis showed that two MAbs react with fragment C, one with both fragment C and LC, and one with LC. Only the two fragment C-specific MAbs were able to neutralize the toxin. Sequencing of the expressed VH and VL genes revealed rearrangements of various VH and VL gene segments in all hybridoma clones. Clonality of the hybridomas was also confirmed by a competition assay that showed recognition of distinct epitopes by these MAbs. The results suggest the importance of TeNT fragment C in terms of immunogenicity and toxin neutralization activity. PMID- 23369088 TI - Decoding pain from the facial display of patients with dementia: a comparison of professional and nonprofessional observers. AB - OBJECTIVE: Patients with dementia, whose ability to provide self-report of pain is often impaired, are in crucial need of observers who can detect and judge the patients' pain-indicative behaviors appropriately, in order to initiate treatment. The facial display of pain promises to be especially informative for that purpose. The major aim of the study was to investigate, whether facial pain displays of patients with dementia can be as easily interpreted as facial displays of individuals without cognitive impairment and whether nurses have learned-through their professional training and work experience-to better read the facial display of pain compared with a control group. DESIGN, SUBJECTS AND OUTCOME MEASURES: For that purpose, 21 nurses and 21 age-matched controls watched 120 video clips, showing facial expressions of young and old individuals with and without dementia during slight and moderate noxious stimulation. After each clip, subjects were asked to rate how much pain the observed individual might have experienced. RESULTS: The observer ratings did not differ between nurses and controls as regards pain level and concordance. On the other hand, level and concordance of the pain judgments were strongly influenced by the cognitive status, age, and gender of the observed individuals, with higher and more accurate pain judgments for older and for female individuals. CONCLUSION: Without further contextual information, "professional" observers do not show a superior competence in inferring pain in others by reading their facial display. Therefore, additional training seems needed to reliably prevent that pain goes unnoticed in patients with dementia. PMID- 23369089 TI - Mitochondrial DNA mutations may not be frequent in patients with polycystic ovary syndrome. PMID- 23369090 TI - Recent advances in aqueous actinide chemistry and thermodynamics. PMID- 23369091 TI - Sum of parts is greater than the whole: inference of common genetic history of populations. AB - BACKGROUND: Reconstructability of population history, from genetic information of extant individuals, is studied under a simulation setting. We do not address the issue of accuracy of the reconstruction algorithms: we assume the availability of the theoretical best algorithm. On the other hand, we focus on the fraction (1 - f) of the common genetic history that is irreconstructible or impenetrable. Thus the fraction, f, gives an upper bound on the extent of estimability. In other words, there exists no method that can reconstruct a fraction larger than f of the entire common genetic history. For the realization of such a study, we first define a natural measure of the amount of genetic history. Next, we use a population simulator (from literature) that has at least two features. Firstly, it has the capability of providing samples from different demographies, to effectively reflect reality. Secondly, it also provides the underlying relevant genetic history, captured in its entirety, where such a measure is applicable. Finally, to compute f, we use an information content measure of the relevant genetic history. The simulator of choice provided the following demographies: Africans, Europeans, Asians and Afro-Americans. RESULTS: We observe that higher the rate of recombination, lower the value of f, while f is invariant over varying mutation rates, in each of the demographies. The value of f increases with the number of samples, reaching a plateau and suggesting that in all the demographies at least about one-third of the relevant genetic history is impenetrable. The most surprising observation is that the the sum of the reconstructible history of the subsegments is indeed larger than the reconstructible history of the whole segment. In particular, longer the chromosomal segment, smaller the value of f, in all the demographies. CONCLUSIONS: We present the very first framework for measuring the fraction of the relevant genetic history of a population that is mathematically elusive. Our observed results on the tested demographies suggest that it may be better to aggregate the analysis of smaller chunks of chromosomal segments than fewer large chunks. Also, no matter the richness of samples in a population, at least one third of the population genetic history is impenetrable. The framework also opens up possible new lines of investigation along the following. Given the characteristics of a population, possibly derived from observed extant individuals, to estimate the (1) optimal sample size and (2) optimal sequence length for the most informative analysis. PMID- 23369092 TI - Enhancing the bioavailability of magnolol in rabbits using melting solid dispersion with polyvinylpyrrolidone. AB - OBJECTIVE: Preparation of magnolol-loaded amorphous solid dispersion was investigated for improving the bioavailability. MATERIALS AND METHODS: A solid dispersion of magnolol was prepared with polyvinylpyrrolidone K-30 (PVP) by melting method, and the physical properties were characterized by using differential scanning calorimetry, powder X-ray diffractometry, Fourier transformation-infrared spectroscopy and scanning electron microscope. In addition, dissolution test was also performed. Subsequently, the bioavailability of magnolol pure compound, its physical mixture and solid dispersion were compared in rabbits. The blood samples withdrawn via marginal ear vein at specific time points were assayed by HPLC method. RESULTS: Oral administration of the solid dispersion of magnolol with PVP significantly increased the systemic exposures of magnolol and magnolol sulfates/glucuronides by 80.1% and 142.8%, respectively, compared to those given with magnolol pure compound. CONCLUSION: Magnolol-loaded amorphous solid dispersion with PVP has demonstrated enhanced bioavailability of magnolol in rabbits. PMID- 23369093 TI - Formulation, in vitro evaluation and study of variables on tri-layered gastro retentive delivery system of diltiazem HCl. AB - CONTEXT: Tri-layered floating tablets using only one grade of polyethylene oxide (PEO) would enable easy manufacturing, reproducibility and controlled release for highly soluble drugs. OBJECTIVE: To evaluate the potential of PEO as a sole polymer for the controlled release and to study the effect of formulation variables on release and gastric retention of highly soluble Diltiazem hydrochloride (DTZ). METHODS: Tablets were compressed with middle layer consisting of drug and polymer while outer layers consisted of polymer with sodium bicarbonate. Design of formulation to obtain 12 h, zero-order release and rapid floatation was done by varying the grades, quantity of PEO and sodium bicarbonate. Dissolution data were fitted in drug release models and swelling/erosion studies were undertaken to verify the drug release mechanism. Effect of formulation variables and tablet surface morphology using scanning electron microscopy were studied. RESULTS AND DISCUSSION: The optimized formula passed the criteria of USP dissolution test I and exhibited floating lag-time of 3-4 min. Drug release was faster from low molecular weight (MW) PEO as compared to high MW. With an increase in the amount of sodium bicarbonate, faster buoyancy was achieved due to the increased CO2 gas formation. Drug release followed zero order and gave a good fit to the Korsmeyer-Peppas model, which suggested that drug release was due to diffusion through polymer swelling. CONCLUSION: Zero order, controlled release profile with the desired buoyancy can be achieved by using optimum formula quantities of sodium bicarbonate and polymer. The tri layered system shows promising delivery of DTZ, and possibly other water-soluble drugs. PMID- 23369094 TI - Preparation, characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting. AB - OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder manifested by cognitive, memory deterioration and variety of neuropsychiatric symptoms. Donepezil is a reversible cholinesterase inhibitor used for the treatment of AD. The purpose of this work is to prepare a nanoparticulate drug delivery system of donepezil using poly(lactic-co-glycolic acid) (PLGA) for sustained release and efficient brain targeting. MATERIALS AND METHODS: PLGA nanoparticles (NPs) were prepared by the solvent emulsification diffusion evaporation technique and characterized for particle size, particle-size distribution, zeta potential, entrapment efficiency, drug loading and interaction studies and in vivo studies using gamma scintigraphy techniques. RESULTS AND DISCUSSION: The size of drug-loaded NPs (drug polymer ratio 1:1) was found to be 89.67 +/- 6.43 nm. The TEM and SEM images of the formulation suggested that particle size was within 20-100 nm and spherical in shape, smooth morphology and coating of Tween-80 on the NPs was clearly observed. The release behavior of donepezil exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous sustained release. The biodistribution studies of donepezil-loaded PLGA NPs and drug solution via intravenous route revealed higher percentage of radioactivity per gram in the brain for the nanoparticulate formulation as compared with the drug solution (p < 0.05). CONCLUSION: The high concentrations of donepezil uptake in brain due to coated NPs may help in a significant improvement for treating AD. But further, more extensive clinical studies are needed to check and confirm the efficacy of the prepared drug delivery system. PMID- 23369095 TI - IDO+ DCs and signalling pathways. AB - Dendritic cells (DCs) have traditionally been viewed as constituting an 'information management' system that functions solely to integrate a diverse array of incoming signals, in order to induce immune reactivity. In recent years, however, there has been a shift towards viewing these cells as key regulators in the orchestration of immunological tolerance, with increasing recognition that they are capable of suppressing T-cell responses depending on signalling processes and localised biochemical conditions. Indoleamine 2,3-dioxygenase (IDO) competent (IDO+) DCs are a subset of human DCs which are programmed to a tolerogenic state and play a vital role in establishing and maintaining a tumour suppressing milieu. The expression of IDO in these DCs represents a key mechanism responsible for inducing the tolerogenic state. However, the mechanisms by which IDO becomes dysregulated in this subset of DCs have not yet been described. In this review, the function of IDO+ DCs within the cancer-tolerogenic milieu, as well as the signals responsible for expression of IDO in this subset, will be discussed. PMID- 23369096 TI - P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer: current status and future perspectives. AB - One of the major causes of failure in cancer chemotherapy is multidrug resistance (MDR), where cancer cells simultaneously become resistant to different anticancer drugs. Over-expression of membrane efflux pumps like P-glycoprotein (P-gp) that recognizes different chemotherapeutic agents and transports them out of the cell, plays a major role in MDR. The shortcoming of P-gp inhibitors in clinic has been attributed to their non-specific action on P-gp and/or non-selective distribution to non-target organs that leads to intolerable side effects by the P-gp inhibitor at doses required for P-gp inhibition upon systemic administration. Another major issue is the reduced elimination of P-gp substrates (e.g. anticancer drugs) and intolerable toxicities by anticancer drugs when co-administered with P-gp inhibitors. To overcome these shortcomings, new generation of P-gp inhibitors with improved specificity for P-gp have been developed. More recently, attention has been paid to the use of drug delivery systems primarily to restrict P-gp inhibition to tumor and reduce the non-selective inhibition of P-gp in non-target organs. This review will provide an overview and update on the status of P-gp inhibition approaches and the role of drug delivery systems in overcoming P-gp mediated MDR. PMID- 23369097 TI - Water sorption and glass transition of pig gastric mucin studied by QCM-D. AB - Hydration of films of pig gastric mucin was studied using a quartz crystal microbalance with dissipation monitoring (QCM-D) equipped with a humidity module. As a prerequisite, the water adsorption isotherm of a clean silica surface was determined. Atomic force microscopy was used to characterize the changes occurring on the silica surface after repeated sorption/desorption and cleaning cycles. The water sorption isotherms of several hundreds of nanometers thick mucin films were obtained in QCM-D experiments using analysis of overtone behavior. The results show that the sorption isotherms are not dependent on the film thicknesses and are in good agreement with sorption calorimetric data on mucin in the bulk phase. Moreover, hydration-induced changes of rheological properties of mucin films were investigated using a model-free approach. The ratio of G'/G" was evaluated as a function of relative humidity. The transition from solidlike behavior to liquidlike behavior was observed in the same humidity range as in sorption calorimetric experiments. Thus, ability of QCM-D to monitor glass transition in biopolymers was demonstrated. PMID- 23369098 TI - Using a decline in serum hCG between days 0-4 to predict ectopic pregnancy treatment success after single-dose methotrexate: a retrospective cohort study. AB - BACKGROUND: The current measure of treatment efficacy of single-dose methotrexate for ectopic pregnancy, is a fall in serum hCG of >=15% between days 4-7 of treatment, which has a positive predictive value of 93% for treatment success. Two small studies have proposed a fall in serum hCG between days 0-4 after treatment confers similar, earlier prognostic information, with positive predictive values of 100% and 88% for treatment success. We sought to validate this in a large, independent cohort because of the potentially significant clinical implications. METHODS: We conducted a retrospective study of women (n=206) treated with single-dose methotrexate for ectopic pregnancy (pre treatment serum hCG levels <=3000 IU/L) at Scottish hospitals between 2006-2011. Women were divided into two cohorts based on whether their serum hCG levels rose or fell between days 0-4 after methotrexate. Treatment outcomes of women in each cohort were compared, and the test performance characteristics calculated. This methodology was repeated for the current measure (>=15% fall in serum hCG between days 4-7 of treatment) and an alternate early measure (<20% fall in serum hCG between days 0-4 of treatment), and all three measures were compared for their ability to predict medical treatment success. RESULTS: In our cohort, the positive predictive value of the current clinical measure was 89% (95% CI 84-94%) (121/136). A falling serum hCG between days 0-4 predicted treatment success in 85% (95% CI 79-92%) of cases (94/110) and a <20% fall in serum hCG between days 0 4 predicted treatment success in 94% (95% CI 88-100%) of cases (59/63). There was no significant difference in the ability of these tests to predict medical treatment success. CONCLUSIONS: We have verified that a decline in serum hCG between days 0-4 after methotrexate treatment for ectopic pregnancies, with pre treatment serum hCG levels <=3000 IU/L, provides an early indication of likelihood of treatment success, and performs just as well as the existing measure, which only provides prognostic information on day 7. PMID- 23369099 TI - So close, so far away: analysis of surnames in a town of twins (Candido Godoi, Brazil). AB - Candido Godoi is a small Brazilian town known for high rates of twin birth. In 2011, a genetic study showed that this localized high rate of twin births could be explained by a genetic founder effect. Here we used isonymic analysis and surname distribution to identify population subgroups within 5316 inhabitants and 665 different surnames. Four clusters were constructed based on different twin rates (P < 0.001; MRPP test). Fisher's alpha and consanguinity index showed low and high values, respectively, corresponding with observed values in isolated communities with high levels of genetic drift. Values of A and B estimators confirmed population isolation. Three boundaries were identified with Monmonier's maximum difference algorithm (P = 0.007). Inside the isolated sections, surnames of different geographic origins, language, and religion were represented. With an adequate statistical methodology, surname analyses provided a close approximation of historic and socioeconomic background at the moment of colony settlement. In this context, the maintenance of social and cultural practices had strong implications for the population's structure leading to drift processes in this small town, supporting the previous genetic study. PMID- 23369100 TI - Tandem stent placement as a rescue for stent misplacement in endoscopic ultrasonography-guided hepaticogastrostomy. PMID- 23369101 TI - Influence of the gel thickness on in vivo hyaline cartilage regeneration induced by double-network gel implanted at the bottom of a large osteochondral defect: short-term results. AB - BACKGROUND: A double-network (DN) gel, which is composed of poly(2-acrylamido-2 methylpropanesulfonic acid) and poly(N,N'-dimethyl acrylamide), can induce hyaline cartilage regeneration in vivo in a large osteochondral defect. The purpose of this study was to clarify the influence of the thickness of the implanted DN gel on the induction ability of hyaline cartilage regeneration. METHODS: Thirty-eight mature rabbits were used in this study. We created an osteochondral defect having a diameter of 4.3-mm in the patellofemoral joint. The knees were randomly divided into 4 groups (Group I: 0.5-mm thick gel, Group II: 1.0-mm thick gel, Group III: 5.0-mm thick gel, and Group IV: untreated control). Animals in each group were further divided into 3 sub-groups depending on the gel implant position (2.0-, 3.0-, or 4.0-mm depth from the articular surface) in the defect. The regenerated tissues were evaluated with the Wayne's gross and histological grading scales and real time PCR analysis of the cartilage marker genes at 4 weeks. RESULTS: According to the total Wayne's score, when the depth of the final vacant space was set at 2.0 mm, the scores in Groups I, II, and III were significantly greater than that Group IV (p<0.05), although there were no significant differences between Groups I and IV at a 3.0-mm deep vacant space. The expression levels of type-2 collagen in Groups II and III were significantly higher (p<0.05) than that in Group IV. CONCLUSIONS: The 1.0-mm thick DN gel sheet had the same ability to induce hyaline cartilage regeneration as the 5.0-mm thick DN gel plug. However, the induction ability of the 0.5-mm thick sheet was significantly lower when compared with the 1.0-mm thick gel sheet. The 1.0-mm DN gel sheet is a promising device to establish a cell-free cartilage regeneration strategy that minimizes bone loss from the gel implantation. PMID- 23369102 TI - Microbial community potentially responsible for acid and metal release from an Ostrobothnian acid sulfate soil. AB - Soils containing an approximately equal mixture of metastable iron sulfides and pyrite occur in the boreal Ostrobothnian coastal region of Finland, termed 'potential acid sulfate soil materials'. If the iron sulfides are exposed to air, oxidation reactions result in acid and metal release to the environment that can cause severe damage. Despite that acidophilic microorganisms catalyze acid and metal release from sulfide minerals, the microbiology of acid sulfate soil (ASS) materials has been neglected. The molecular phylogeny of a depth profile through the plough and oxidized ASS layers identified several known acidophilic microorganisms and environmental clones previously identified from acid- and metal-contaminated environments. In addition, several of the 16S rRNA gene sequences were more similar to sequences previously identified from cold environments. Leaching of the metastable iron sulfides and pyrite with an ASS microbial enrichment culture incubated at low pH accelerated metal release, suggesting microorganisms capable of catalyzing metal sulfide oxidation were present. The 16S rRNA gene analysis showed the presence of species similar to Acidocella sp. and other clones identified from acid mine environments. These data support that acid and metal release from ASSs was catalyzed by indigenous microorganisms adapted to low pH. PMID- 23369103 TI - Stem cell transplantation after reduced-intensity conditioning for sickle cell disease. AB - Sickle cell disease (SCD) is still associated with substantial morbidity and reduced life expectancy. Disease-related mortality rises to 14% in adolescents and young adults. Overall and disease-free survival following haematopoietic stem cell transplantation (HSCT) is 90% and 95%, respectively. To reduce transplant associated late effects, the feasibility of a highly immunosuppressive reduced intensity conditioning (RIC) regimen was explored in children with SCD and a matched sibling donor. Eight patients (median age, 9 yr) and symptomatic SCD were included. The conditioning regimen consisted of fludarabine, melphalan and either thiotepa or total lymphoid irradiation plus antithymocyte globuline or alemtuzumab. The graft was bone marrow in seven and cord blood in one case. The conditioning regimen was well tolerated and no severe infectious complications occurred. All patients displayed mixed chimaerism on day +28. After a median follow-up of 4 yr, 3/8 patients have mixed leucocyte chimaerism and 8/8 patients have 100% donor erythropoiesis. HSCT from matched sibling donors following a RIC regimen was well tolerated and resulted in cure in all patients studied. If confirmed in larger patient cohorts, these observations will have important implications for the indications of HSCT in children with SCD. PMID- 23369104 TI - Changes in endoscopic findings of gastritis after cure of H. pylori infection: multicenter prospective trial. AB - BACKGROUND AND AIM: Successful eradication of H. pylori changes pathological findings of gastritis dramatically. However, change of endoscopic mucosal findings is not fully understood. To clarify the short-term changes of endoscopic mucosal findings after cure of H. pylori infection, a multicenter prospective trial was conducted. METHODS: One hundred and forty-seven patients with H. pylori infection from 12 institutions were enrolled into this prospective cohort trial. Nineteen endoscopic findings using high-resolution white light electronic endoscopy were assessed before and 2-4 months after eradication treatment of H. pylori. H. pylori infection was diagnosed by pathology of three stomach sites using hematoxylin-eosin stain or H. pylori-specific immunostaining. Endoscopic features of the successful eradication group and the failed eradication group were compared. The change of severity of endoscopic features before and after H. pylori eradication were compared between successful eradication and failed eradication. RESULTS: One hundred and twenty-six patients were analyzed. Eradication rate was 81% (102/126). Non-transparency of gastric juice, diffuse redness of fundic mucosa, enlarged fold, spotty redness of fundic mucosa, flat erosion of stomach, and hemoglobin index of fundic mucosa were significantly different between the successful eradication group and the failed eradication group. Gastric flat erosion was of higher frequency in the successful eradication group. When eradication was successful, spotty redness of fundic gland improved significantly. CONCLUSION: Assessment of endoscopic findings of spotty redness after eradication treatment is useful in the diagnosis of H. pylori eradication. PMID- 23369105 TI - Improving valuation sampling of EQ-5D health states. AB - BACKGROUND: The original valuation exercise which formed the basis of the UK EQ 5D time trade-off social tariff of health states, employed a sampling scheme involving 43 health states. Neither that study, nor other published international valuations studies have used explicit quantifiable criteria to justify the choice of sampled states. New criteria are proposed and methods described to aid researchers in designing improved sampling schemes for future EQ-5D sampling exercises. METHOD: Four such criteria are described, and applied to assess the merits of four sampling schemes previously reported, using three large observational databases to quantify relative performance. An alternative sampling design conforming to these criteria is described, which aims to generate improved performance. RESULTS: Previous published approaches are shown to perform poorly against the measured criteria. The alternative sampling design is demonstrated to provide superior performance on all measures. CONCLUSION: Future valuation exercises using sampled health states based on this approach may be expected to offer benefits in terms of greater precision, avoidance of bias in favour of less severe states, and a higher proportion of research observations valued directly rather than dependent on extrapolation modelling. PMID- 23369106 TI - SNPranker 2.0: a gene-centric data mining tool for diseases associated SNP prioritization in GWAS. AB - BACKGROUND: The capability of correlating specific genotypes with human diseases is a complex issue in spite of all advantages arisen from high-throughput technologies, such as Genome Wide Association Studies (GWAS). New tools for genetic variants interpretation and for Single Nucleotide Polymorphisms (SNPs) prioritization are actually needed. Given a list of the most relevant SNPs statistically associated to a specific pathology as result of a genotype study, a critical issue is the identification of genes that are effectively related to the disease by re-scoring the importance of the identified genetic variations. Vice versa, given a list of genes, it can be of great importance to predict which SNPs can be involved in the onset of a particular disease, in order to focus the research on their effects. RESULTS: We propose a new bioinformatics approach to support biological data mining in the analysis and interpretation of SNPs associated to pathologies. This system can be employed to design custom genotyping chips for disease-oriented studies and to re-score GWAS results. The proposed method relies (1) on the data integration of public resources using a gene-centric database design, (2) on the evaluation of a set of static biomolecular annotations, defined as features, and (3) on the SNP scoring function, which computes SNP scores using parameters and weights set by users. We employed a machine learning classifier to set default feature weights and an ontological annotation layer to enable the enrichment of the input gene set. We implemented our method as a web tool called SNPranker 2.0 (http://www.itb.cnr.it/snpranker), improving our first published release of this system. A user-friendly interface allows the input of a list of genes, SNPs or a biological process, and to customize the features set with relative weights. As result, SNPranker 2.0 returns a list of SNPs, localized within input and ontologically enriched genes, combined with their prioritization scores. CONCLUSIONS: Different databases and resources are already available for SNPs annotation, but they do not prioritize or re-score SNPs relying on a-priori biomolecular knowledge. SNPranker 2.0 attempts to fill this gap through a user friendly integrated web resource. End users, such as researchers in medical genetics and epidemiology, may find in SNPranker 2.0 a new tool for data mining and interpretation able to support SNPs analysis. Possible scenarios are GWAS data re-scoring, SNPs selection for custom genotyping arrays and SNPs/diseases association studies. PMID- 23369107 TI - An enhanced computational platform for investigating the roles of regulatory RNA and for identifying functional RNA motifs. AB - BACKGROUND: Functional RNA molecules participate in numerous biological processes, ranging from gene regulation to protein synthesis. Analysis of functional RNA motifs and elements in RNA sequences can obtain useful information for deciphering RNA regulatory mechanisms. Our previous work, RegRNA, is widely used in the identification of regulatory motifs, and this work extends it by incorporating more comprehensive and updated data sources and analytical approaches into a new platform. METHODS AND RESULTS: An integrated web-based system, RegRNA 2.0, has been developed for comprehensively identifying the functional RNA motifs and sites in an input RNA sequence. Numerous data sources and analytical approaches are integrated, and several types of functional RNA motifs and sites can be identified by RegRNA 2.0: (i) splicing donor/acceptor sites; (ii) splicing regulatory motifs; (iii) polyadenylation sites; (iv) ribosome binding sites; (v) rho-independent terminator; (vi) motifs in mRNA 5' untranslated region (5'UTR) and 3'UTR; (vii) AU-rich elements; (viii) C-to-U editing sites; (ix) riboswitches; (x) RNA cis-regulatory elements; (xi) transcriptional regulatory motifs; (xii) user-defined motifs; (xiii) similar functional RNA sequences; (xiv) microRNA target sites; (xv) non-coding RNA hybridization sites; (xvi) long stems; (xvii) open reading frames; (xviii) related information of an RNA sequence. User can submit an RNA sequence and obtain the predictive results through RegRNA 2.0 web page. CONCLUSIONS: RegRNA 2.0 is an easy to use web server for identifying regulatory RNA motifs and functional sites. Through its integrated user-friendly interface, user is capable of using various analytical approaches and observing results with graphical visualization conveniently. RegRNA 2.0 is now available at http://regrna2.mbc.nctu.edu.tw. PMID- 23369108 TI - Dexamethasone inhibits and meloxicam promotes proliferation of bovine NK cells. AB - Due to the unrecognized effect of dexamethasone (DEX) and meloxicam (MEL) on bovine natural killer (NK) cells, studies have been undertaken in order to determine whether the above medications can affect these cells in respect of their counts, apoptosis, proliferation and production of selected cytokines. Peripheral blood mononuclear cells (PBMCs) were treated with the drugs in concentrations reflecting their plasma levels achieved in vivo at therapeutic doses and in 10-fold lower concentrations. The effect of DEX and MEL on percentages and absolute counts of NK cells was determined 6, 12, 48 and 168 h after the exposure of PBMCs to the drugs. At each time point, it was found out that DEX reduced the absolute count of NK cells, an effect attributed to the proapoptotic and anti-proliferative influence of the drug on these cells. DEX lowered the production of IFN-gamma by the analyzed cells and raised the percentage of IL-10-producing cells. Thus, the above effects are important elements contributing to the complex mechanism responsible for the anti inflammatory and immunosuppressive properties of the drug. MEL neither affects the apoptosis of NK cells nor did it reduce their count. Moreover, one-week exposure to MEL raised the absolute count of these cells, which was the result of their more intense proliferation in the presence of the drug. Thus, the influence of MEL with respect to the proliferation and count of NK cells was immunostimulating. On the other hand, MEL reduced the percentage of IFN-gamma producing NK cells, which in turn is an immunosuppressive effect. PMID- 23369109 TI - Effects of hypo- and hyperthyroidism on proliferation, angiogenesis, apoptosis and expression of COX-2 in the corpus luteum of female rats. AB - Although thyroid dysfunction occurs frequently in humans and some animal species, the mechanisms by which hypo- and hyperthyroidism affect the corpus luteum have not been thoroughly elucidated. This study evaluated the levels of proliferative activity, angiogenesis, apoptosis and expression of cyclooxygenase-2 in the corpus luteum of female rats with thyroid dysfunction. These processes may be important in understanding the reproductive changes caused by thyroid dysfunction. A total of 18 adult female rats were divided into three groups (control, hypothyroid and hyperthyroid) with six animals per group. Three months after treatment to induce thyroid dysfunction, the rats were euthanized in the dioestrus phase. The ovaries were collected and immunohistochemically analysed for expression of the cell proliferation marker CDC-47, vascular endothelial growth factor (VEGF), VEGF receptor Flk-1 and cyclooxygenase-2 (COX-2). Apoptosis was evaluated using the TUNEL assay. Hypothyroidism reduced the intensity and area of COX-2 expression in the corpus luteum (p < 0.05), while hyperthyroidism did not alter COX-2 expression in the dioestrus phase. Hypothyroidism significantly reduced the expression of CDC-47 in endothelial cells and pericytes in the corpus luteum, whereas hyperthyroidism did not induce a detectable change in CDC-47 expression (p > 0.05). Hypothyroidism reduced the level of apoptosis in luteal cells (p < 0.05) and increased VEGF expression in the corpus luteum. In contrast, hyperthyroidism increased the level of apoptosis in the corpus luteum (p < 0.05). In conclusion, thyroid dysfunction differentially affects the levels of proliferative activity, angiogenesis and apoptosis and COX-2 expression in the corpus luteum of female rats. PMID- 23369110 TI - Expectations and values about expanded newborn screening: a public engagement study. AB - OBJECTIVES: Newborn bloodspot screening (NBS) panels have expanded to include conditions for which treatment effects are less certain, creating debate about population-based screening criteria. We investigated Canadian public expectations and values regarding the types of conditions that should be included in NBS and whether parents should provide consent. METHODS: Eight focus groups (FG; n = 60) included education, deliberative discussion and pre-/post-questionnaires. Data were analysed quantitatively and qualitatively. RESULTS: Quantitatively, the majority supported NBS for serious disorders for which treatment is not available (95-98, 82%). A majority endorsed screening without explicit consent (77-88%) for treatable disorders, but 62% supported unpressured choice for screening for untreatable disorders. Qualitatively, participants valued treatment-related benefits for infants and informational benefits for families. Concern for anxiety, stigma and unwanted knowledge depended upon disease context and strength of countervailing benefits. CONCLUSIONS: Anticipated benefits of expanded infant screening were prioritized over harms, with information provision perceived as a mechanism for mitigating harms and enabling choice. However, we urge caution around the potential for public enthusiasm to foster unlimited uptake of infant screening technologies. PMID- 23369112 TI - Demand valve oxygen: a promising new oxygen delivery system for the acute treatment of cluster headache. AB - OBJECTIVE: To show that demand valve oxygen is an effective acute treatment for cluster headache and to compare this oxygen delivery technique with standard cluster headache therapy of continuous flow oxygen. METHODS: Single-center, open label, two-period, two-treatment crossover design, pilot study was used. Subjects treated with one of two sequences: first, headache treated with continuous flow oxygen (100% oxygen at 15 liters per minute), and subsequent with demand valve oxygen, or vice versa. Treatment began when pain was at least moderate. Subjects taught a specific breathing technique for demand valve oxygen that included initial period of hyperventilation. Primary end point was headache response (moderate-to-very-severe pain reduced to mild or none) after 30 minutes of treatment. RESULTS: Three subjects completed the trial, while a fourth completed demand valve oxygen only. All had chronic cluster headache. All subjects treated with demand valve oxygen became pain-free (time in minutes: 15, 19, 6, 8). Three of four had no recurrence within 24 hours. Demand valve oxygen reduced cranial autonomic symptoms in all and resolved them in two subjects. For continuous flow oxygen, two of three subjects became pain-free (20, 10 minutes). Continuous flow oxygen reduced but did not eliminate cranial autonomic symptoms. Continuous flow oxygen had higher recurrence rates. No adverse events noted with either treatment. CONCLUSION: Demand valve oxygen appears to be an effective acute treatment for cluster headache. All subjects became headache-free. Time to pain freedom was fast (average 12 minutes). The small number of study subjects does not allow a direct comparison of efficacy between demand valve oxygen and continuous high flow oxygen. PMID- 23369111 TI - Health-related quality of life and economic impact of urinary incontinence due to detrusor overactivity associated with a neurologic condition: a systematic review. AB - BACKGROUND: Patients with neurologic diseases often have neurogenic detrusor overactivity (NDO), which can result in a loss of voluntary bladder control and uncontrollable urinary incontinence (UI).The impact of UI due to NDO on patients' lives has not been well studied. The objective of this review was to assess the health-related quality of life (HRQoL) and economic burden in patients with urgency UI due to NDO in select countries in North America, the European Union, Asia, and Australia. METHODS: Systematic literature searches and reviews of articles published in English (January 2000 to February 2011) were conducted using MEDLINE(r), EMBASE(r), and the Cochrane Library. Studies assessing the impact of UI on HRQoL of patients with an underlying neurologic condition of interest (i.e., multiple sclerosis, spinal cord injury, Parkinson's disease, stroke, or spina bifida) were included. Economic studies in urgency UI also were included. RESULTS: Of 876 citations generated in the initial search, a total of 27 articles were deemed relevant: 16 articles presented HRQoL data and 11 articles presented information on the economic burden of UI. Humanistic studies used a range of HRQoL instruments to measure HRQoL burden, and the economic studies included different cost components to quantify the economic burden, making meaningful comparisons challenging. Despite this heterogeneity, the literature suggests that HRQoL in patients with UI due to NDO is worse than patients with UI in general or those with the same underlying neurologic condition without UI. In addition, urgency UI also results in substantial economic costs. CONCLUSIONS: Incontinent patients with underlying neurologic conditions have impaired HRQoL as well as substantial economic burden attributable to UI due to NDO. There is a need for urgency UI treatments that improve HRQoL of these patients and alleviate the economic burden of this condition. PMID- 23369113 TI - A probabilistic method for identifying rare variants underlying complex traits. AB - BACKGROUND: Identifying the genetic variants that contribute to disease susceptibilities is important both for developing methodologies and for studying complex diseases in molecular biology. It has been demonstrated that the spectrum of minor allelic frequencies (MAFs) of risk genetic variants ranges from common to rare. Although association studies are shifting to incorporate rare variants (RVs) affecting complex traits, existing approaches do not show a high degree of success, and more efforts should be considered. RESULTS: In this article, we focus on detecting associations between multiple rare variants and traits. Similar to RareCover, a widely used approach, we assume that variants located close to each other tend to have similar impacts on traits. Therefore, we introduce elevated regions and background regions, where the elevated regions are considered to have a higher chance of harboring causal variants. We propose a hidden Markov random field (HMRF) model to select a set of rare variants that potentially underlie the phenotype, and then, a statistical test is applied. Thus, the association analysis can be achieved without pre-selection by experts. In our model, each variant has two hidden states that represent the causal/non causal status and the region status. In addition, two Bayesian processes are used to compare and estimate the genotype, phenotype and model parameters. We compare our approach to the three current methods using different types of datasets, and though these are simulation experiments, our approach has higher statistical power than the other methods. The software package, RareProb and the simulation datasets are available at: http://www.engr.uconn.edu/~jiw09003. PMID- 23369114 TI - Health impact assessment of air pollution in megacity of Tehran, Iran. AB - The aims of the present study were to provide quantitative data on the impact of air pollution on the health of people living in Tehran city, the most populated city of Iran. The approach proposed by the World Health Organization (WHO) was applied using the AirQ 2.2.3 software developed by the WHO European Centre for Environment and Health, Bilthoven Division. Concentrations of ozone, nitrogen dioxide, sulfur dioxide and particulate matter of aerodynamic diameter <= 10 MUm (PM10) were used to assess human exposure and health impacts in terms of attributable proportion of the health outcome, annual number of excess cases of mortality for all causes, and cardiovascular and respiratory diseases. The annual average of PM10, SO2, NO2 and O3 in Tehran were 90.58, 89.16, 85 and 68.82 MUg/m3, respectively. Considering short-term effects, PM10 had the highest health impact on the 8,700,000 inhabitants of Tehran city, causing an excess of total mortality of 2194 out of 47284 in a year. Sulfur dioxide, nitrogen dioxide and ozone caused about, respectively, 1458, 1050 and 819 excess cases of total mortality. Results indicate that the magnitude of the health impact estimated for the city of Tehran underscores the need for urgent action to reduce the health burden of air pollution. PMID- 23369115 TI - Investigation of natural effective gamma dose rates case study: Ardebil Province in Iran. AB - Gamma rays pose enough energy to induce chemical changes that may be biologically important for the normal functioning of body cells. The external exposure of human beings to natural environmental gamma radiation normally exceeds that from all man-made sources combined. In this research natural background gamma dose rates and corresponding annual effective doses were determined for selected cities of Ardebil province. Outdoor gamma dose rates were measured using an Ion Chamber Survey Meter in 105 locations in selected districts. Average absorbed doses for Ardebil, Sar-Ein, Germy, Neer, Shourabil Recreational Lake, and Kosar were determined as 265, 219, 344, 233, 352, and 358 nSv/h, respectively. Although dose rates recorded for Germi and Kosar are comparable with some areas with high natural radiation background, however, the dose rates in other districts are well below the levels reported for such locations. Average annual effective dose due to indoor and outdoor gamma radiation for Ardebil province was estimated as 1.73 (1.35-2.39) mSv, which is on average 2 times higher than the world population weighted average. PMID- 23369116 TI - Editorial: violence against women across the globe. PMID- 23369117 TI - Reflective components in undergraduate mental health nursing curricula: some issues for consideration. AB - After reflective practice took nursing by storm 20 years ago it is timely to re examine its influence and implementation on undergraduate teaching. Elements of reflection in relation to learning, matters that affect students and teachers in the classroom and on clinical placements, are reiterated. Interpersonal ethical concerns and issues associated with students' emotional responses to the situations on which they reflect also are considered. We have identified a number of elements that must be considered from both the student's and educator's perspectives to ensure safe and appropriate reflection activities are used in mental health-specific or non-specific undergraduate nursing subjects. PMID- 23369118 TI - Trauma and its aftermath for commercially sexually exploited women as told by front-line service providers. AB - Commercial sexual exploitation of women and girls through forced prostitution and sex-trafficking is a human rights and public health issue, with survivors facing complex mental health problems from trauma and violence. An international and domestic problem, the average age of recruitment into sex-trafficking is between 11 and 14 years old. Given its secrecy and brutality, such exploitation remains difficult to study, which results in a lack of knowledge related to trauma and how best to develop specific services that effectively engage and meet the unique needs of survivors. This qualitative research, using thematic analysis, explored the stories of trauma and its aftermath for commercially sexually exploited women as told by front-line service providers. Three themes emerged regarding the experience of sex-trafficking and its outcomes-Pimp Enculturation, Aftermath, and Healing the Wound-along with seven subthemes. These have important implications for all service and healthcare providers. PMID- 23369119 TI - Experiences of the first days of postpartum psychosis: an interview study with women and next of kin in Sweden. AB - The aim of this study was to explore accounts of the first days of postpartum psychosis from different perspectives, that is, that of the women and their next of kin. Interviews were conducted with seven women with postpartum psychosis and six interviews were done with the next of kin. The overall theme was Shades of Black with A Ray of Light, revealing a difficult experience of darkness, despair, and suffering. For the women, the experience cannot be shared fully other than with those who have lived through it themselves. For the next of kin, the illness is incomprehensible and it proved difficult to express in words what these relatives believe the women were going through. The women and their next of kin spoke about loss of sleep, being in an unreal world, thoughts that moved from having a wanted to an unwanted baby, being infanticidal, and having suicidal ideation. The women and their next of kin described the situations in different ways. The women gave an account of their illness in the strongest of terms, while the language used by the next of kin was much milder. The findings underscore the importance of recognizing the next of kin as key sources in early recognition of the disorder, which would make early treatment possible and support recovery. PMID- 23369120 TI - Depression training in nursing homes: lessons learned from a pilot study. AB - Late-life depression is common among nursing home residents, but often is not addressed by nurses. Using a self-directed CD-based depression training program, this pilot study used mixed methods to assess feasibility issues, determine nurse perceptions of training, and evaluate depression-related outcomes among residents in usual care and training conditions. Of 58 nurses enrolled, 24 completed the training and gave it high ratings. Outcomes for 50 residents include statistically significant reductions in depression severity over time (p < 0.001) among all groups. Depression training is an important vehicle to improve depression recognition and daily nursing care, but diverse factors must be addressed to assure optimal outcomes. PMID- 23369121 TI - Sexual orientation and demographic, cultural, and psychological factors associated with the perpetration and victimization of intimate partner violence among Hispanic men. AB - Hispanics are disproportionately affected by intimate partner violence (IPV). Most of the research describing factors associated with intimate partner violence among Hispanics has focused on Hispanic women or Hispanics in heterosexual relationships. The purpose of this study was to explore the relationship among sexual orientation (heterosexual, homosexual, and bisexual), and demographic, cultural, and psychological factors and intimate partner violence among Hispanic men. A cross sectional questionnaire was administered to 160 Hispanic heterosexual men and men who have sex with men. Demographic factors (age, education, and income), acculturation, depressive symptoms, and self-esteem were assessed using standardized instruments. Data was analyzed using ANOVA, and simple and multiple logistical regression. Differences in education, income, and self-esteem were noted across participants identifying as heterosexual, homosexual, and bisexual. Bisexual Hispanic men had almost four times greater odds of reporting the perpetration of IPV than homosexual Hispanic men, even when differences in education, income, and self-esteem were controlled for (AOR = 3.92, 95%CI = 1.11, 14.19). This study suggests the importance of specifically targeting bisexual Hispanic men in IPV research and services. PMID- 23369122 TI - Objective and subjective sleep disturbances in individuals with psychiatric disabilities. AB - Sleep disturbances are common complaints in individuals with psychiatric disabilities, frequently occurring at onset and with exacerbation of illness. A small descriptive study of community-based overweight individuals (N = 9) completed the Pittsburgh Sleep Quality Index, wore an ActiGraph and kept a sleep diary for 7 to 14 days. All but two participants had poor sleep efficiency based on actigraphy scores, an objective measure of sleep. These scores were in agreement with the Pittsburgh Sleep Quality Index, a self-report measure, in all but one participant. The findings indicate the Pittsburgh Sleep Quality Index is a comprehensive measure to use in assessing sleep in individuals who have psychiatric disabilities. PMID- 23369123 TI - The influence of physical environmental qualities on the social climate of supported housing facilities for people with severe mental illness. AB - The study investigates the extent to which the perceived physical environmental quality of housing facilities for people with severe mental illness accounts for perceived social environmental quality. Twenty facilities were assessed by people with psychiatric disabilities (residents), staff, and experts with regard to the physical environmental aspects of visual pleasantness, indirect environmental effects, overall physical quality, and the social environmental indicator of social relationship. The results suggest that residents' and staff's physical environmental quality perception accounts for social relationship quality perception, whereas experts' environmental assessment does not. Moreover, the staff reported a more positive social relationship perception than the residents. PMID- 23369124 TI - Attitude disentangled: a cross-sectional study into the factors underlying attitudes of nurses in Dutch rehabilitation centers toward patients with comorbid mental illness. AB - In rehabilitation centers, many patients suffer a comorbid mental illness. Nurses have different attitudes toward these patients. A cross-sectional, questionnaire based study among nurses in Dutch rehabilitation centers was undertaken to clarify the factors that underlie attitudes toward patients with comorbid mental illness. The main factors associated with attitudes were feelings of competence and experiences with dealing with patients with mental illness. Other associations were perceived support; frequency of caring for patients with comorbid mental illness; work experience in mental health care; additional psychiatric training; and the personality traits "extraversion," "emotional stability," and "openness to experience." Perceived support had the strongest association with feelings of competence. PMID- 23369125 TI - Culture and memory. PMID- 23369126 TI - Teaching mental health nursing is, at the very least, a craft, an art, and a science. PMID- 23369129 TI - Deep infection in tumor endoprosthesis around the knee: a multi-institutional study by the Japanese musculoskeletal oncology group. AB - BACKGROUND: The incidence of endoprosthesis failure has been well studied, but few studies have described the clinical characteristics of deep infection in tumor prostheses. This study aimed to analyze the characteristics of deep infection in tumor endoprostheses around the knee. METHODS: We analyzed clinical data of 57 patients with deep infections involving tumor endoprostheses around the knee enrolled from the Japanese Musculoskeletal Oncology Group. Profile of clinical presentation including time between surgery and infection, initial symptoms/blood tests and microbial cultures was evaluated. In addition pre-, intra-, and postoperative clinical factors influencing clinical presentation and treatment outcomes of infections were analyzed. RESULTS: Mean interval between the initial operation and diagnosis was 13 months, and mean time required for infection control was 12 months. The most common pathogen was Staphylococcus. Infection control rates were significantly higher when prostheses were removed rather than salvaged. Ten-year prosthesis survival and limb salvage rates were 41.6% and 75.6%, respectively. Analysis of underlying clinical factors suggested that soft-tissue condition significantly influenced the duration of the infection control period and likelihood of limb salvage. CONCLUSIONS: Infection control is a prolonged process. Deep infection frequently results in amputation or prosthesis loss. Intensive analysis of clinical characteristics may aid infection control. PMID- 23369128 TI - Genetic polymorphism of the OPG gene associated with breast cancer. AB - BACKGROUND: The receptor activator of NF-kappaB (RANK), its ligand (RANKL) and osteoprotegerin (OPG) have been reported to play a role in the pathophysiological bone turnover and in the pathogenesis of breast cancer. Based on this we investigated the role of single nucleotide polymorphisms (SNPs) within RANK, RANKL and OPG and their possible association to breast cancer risk. METHODS: Genomic DNA was obtained from Caucasian participants consisting of 307 female breast cancer patients and 396 gender-matched healthy controls. We studied seven SNPs in the genes of OPG (rs3102735, rs2073618), RANK (rs1805034, rs35211496) and RANKL (rs9533156, rs2277438, rs1054016) using TaqMan genotyping assays. Statistical analyses were performed using the chi2-tests for 2 x 2 and 2 x 3 tables. RESULTS: The allelic frequencies (OR: 1.508 CI: 1.127-2.018, p=0.006) and the genotype distribution (p=0.019) of the OPG SNP rs3102735 differed significantly between breast cancer patients and healthy controls. The minor allele C and the corresponding homo- and heterozygous genotypes are more common in breast cancer patients (minor allele C: 18.4% vs. 13.0%; genotype CC: 3.3% vs. 1.3%; genotype CT: 30.3% vs. 23.5%). No significantly changed risk was detected in the other investigated SNPs. Additional analysis showed significant differences when comparing patients with invasive vs. non-invasive tumors (OPG rs2073618) as well as in terms of tumor localization (RANK rs35211496) and body mass index (RANKL rs9533156 and rs1054016). CONCLUSIONS: This is the first study reporting a significant association of the SNP rs3102735 (OPG) with the susceptibility to develop breast cancer in the Caucasian population. PMID- 23369130 TI - Diagnosis of laterally spreading tumors (LST) in the rectum and selection of treatment: characteristics of each of the subclassifications of LST in the rectum. AB - BACKGROUND: In recent years, endoscopic submucosal dissection (ESD) has often been used for the treatment of laterally spreading tumors (LST) of the rectum. The present study was carried out with the aim of clarifying the characteristics of each of the subtypes of LST in the rectum that are often treated by ESD. PATIENTS AND METHODS: This study involved 141 rectal LST that were initially treated at our hospital between March 2005 and December 2010 and whose endoscopic images and histopathological specimens could be re-examined. The LST were divided into LST-G-H (homogeneous type), LST-G-MIX (nodular mixed type), LST-NG-F (flat type) and LST-NG-PD (pseudo-depressed type) type lesions, and tumor diameter and depth of invasion of each of these tumor types were investigated. RESULTS: Regarding the depth of invasion, the proportion of submucosa-massive (SM-m) lesions was high in the LST-NG-PDtumors, even among tumors measuring <20 mm in diameter; both the rate of cancer and proportion of SM-m lesions were significantly higher in the LST-NG-PD tumors than in the LST-NG-F tumors (P < 0.05). In both LST-NG-MIX and LST-NG-PD tumors, the proportion of SM-m lesions was significantly higher in the lower rectum than in the upper rectum (P < 0.05). CONCLUSION: For LST of the rectum (particularly of the lower rectum), it is necessary to carefully select the treatment considering LST subclass and tumor diameter from the standpoint of the presence of malignancy, quality of life, and prognosis of patients. PMID- 23369131 TI - Radioprotective efficacy and toxicity of a new family of aminothiol analogs. AB - PURPOSE: A family of 17 new nucleophilic-polyamine and aminothiol structures was designed and synthesized to identify new topical or systemic radioprotectors with acceptable mammalian toxicity profiles. design elements included: (i) Length and charge of the DNA-interacting, alkylamine backbone, (ii) nucleophilicity of the reactive oxygen species (ROS)-scavenging group, and (iii) non-toxic drug concentration achievable in animal tissues. MATERIALS AND METHODS: Mouse maximum tolerated doses (MTD) were determined by increasing intraperitoneal (IP) doses. To assess radioprotective efficacy, mice received IP 0.5 MTD doses prior to an LD95 radiation dose (8.63 Gy), and survival was monitored. Topically applied aminothiol was also scored for prevention of radiation-induced dermatitis (17.3 Gy to skin). RESULTS: The most radioprotective aminothiols had 4-6 carbons and 1 2 amines, and unlike amifostine and its analogs, displayed a terminal thiol from an alkyl side chain that projected the thiol away from the DNA major groove into the environment surrounding the DNA. The five carbon, single thiol, alkylamine, PrC-210, conferred 100% survival to an otherwise 100% lethal dose of whole-body radiation and achieved 100% prevention of Grade 2-3 radiation dermatitis. By mass spectrometry analysis, the one aminothiol that was tested formed mixed disulfides with cysteine and glutathione. CONCLUSIONS: Multiple, highly radioprotective, aminothiol structures, with acceptable systemic toxicities, were identified. PMID- 23369132 TI - Intercoalescence time distribution of incomplete gene genealogies in temporally varying populations, and applications in population genetic inference. AB - Tracing back to a specific time T in the past, the genealogy of a sample of haplotypes may not have reached their common ancestor and may leave m lineages extant. For such an incomplete genealogy truncated at a specific time T in the past, the distribution and expectation of the intercoalescence times conditional on T are derived in an exact form in this paper for populations of deterministically time-varying sizes, specifically, for populations growing exponentially. The derived intercoalescence time distribution can be integrated to the coalescent-based joint allele frequency spectrum (JAFS) theory, and is useful for population genetic inference from large-scale genomic data, without relying on computationally intensive approaches, such as importance sampling and Markov Chain Monte Carlo (MCMC) methods. The inference of several important parameters relying on this derived conditional distribution is demonstrated: quantifying population growth rate and onset time, and estimating the number of ancestral lineages at a specific ancient time. Simulation studies confirm validity of the derivation and statistical efficiency of the methods using the derived intercoalescence time distribution. Two examples of real data are given to show the inference of the population growth rate of a European sample from the NIEHS Environmental Genome Project, and the number of ancient lineages of 31 mitochondrial genomes from Tibetan populations. PMID- 23369133 TI - Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies. AB - The association between subclinical thyroid dysfunction and cardiovascular outcomes has been recently clarified with the publication of three individual participant data (IPD) analyses from the Thyroid Studies Collaboration. We identified original cohort studies with a systematic review and pooled individual data from over 70'000 participants to obtain a more precise estimate of the risks of cardiovascular outcomes associated with subclinical thyroid dysfunction. Subclinical hypothyroidism and subclinical hyperthyroidism, defined as normal thyroxine (FT4) levels with increased or decreased Thyroid-Stimulating Hormones (TSH or thyrotropin) respectively, are associated with increased risk of cardiovascular outcomes compared to euthyroid state, particularly in those with a more pronounced thyroid dysfunction. Specifically, subclinical hypothyroidism is associated with an increased risk of coronary heart disease (CHD) events, CHD mortality and heart failure (HF) events in individuals with higher TSH levels, particularly in those with TSH levels >=10.0 mIU/L. Conversely, subclinical hyperthyroidism is associated with an increased risk of total mortality, CHD mortality, HF and atrial fibrillation, particularly in those with suppressed TSH levels <0.10 mIU/L. Pending ongoing randomized controlled trials, these observational findings allow identifying potential TSH thresholds for thyroid medication initiation based on risk of clinical outcomes, although clinical decision based solely on observational data need caution. The impact of thyroid replacement among the elderly with subclinical hypothyroidism is currently studied in a multicenter international randomized controlled trial (Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial, TRUST trial). PMID- 23369134 TI - Subclinical hypothyroidism and heart failure risk in older people. AB - CONTEXT: Although the negative impact of subclinical hypothyroidism (sHT) in terms of cardiovascular risk in young adults is mostly acknowledged it remains to be established in the elderly, especially in the oldest old. EVIDENCE ACQUISITION: We searched Medline for reports published with the following search words: hypothyroidism, sHT, ageing, elderly, L-thyroxin, thyroid, guidelines, treatment, quality of life, cardiovascular risk, heart failure (HF), ischemic heart disease (IHD), endothelial dysfunction. The search was restricted to reports published in English since 1980, but some reports published before 1980 were also incorporated. We supplemented the search with records from personal files and references of relevant articles and textbooks. Parameters analyzed included epidemiology of sHT and thyroid failure the effect of thyroid hormone on ageing process and cardiovascular function as well as the potential benefits of L thyroxin therapy on quality of life, HF progression and events. EVIDENCE SYNTHESIS: TSH levels increase with age, even in older patients without thyroid disease, in whom higher TSH value might favor longevity; better quality of life and lower IHD mortality in the oldest old population has been reported yet. However, at odds with the relationship between sHT and IHD risk and mortality, which shows a clear age dependent feature, vanishing in the last decades of life, the detrimental effect of sHT on HF progression and events remains evident also in older patients, although no data are available in the oldest old population. CONCLUSIONS: The lack of specific randomized trials enrolling either old or very old subjects, aimed at evaluate the efficacy of hormonal replacement on overall survival and cardiovascular risk reduction along with the negative effects of possible over-treatment, makes the decision to treat older people a still unresolved clinical challenge. Moreover, the possibility that restoring euthyroidism may be harmful in the elderly should be always taken into account. PMID- 23369135 TI - Thyroid disorders in chronic heart failure: from prognostic set-up to therapeutic management. AB - Thyroid hormones have relevant activity at cardiac and vascular level, by influencing heart rate, myocardial excitability as well as inotropic and lusitropic status, systemic vascular resistance and blood pressure. Moreover, they interact with neuro-hormonal systems such as sympathetic nervous system and renin-angiotensin-aldosterone system thus also indirectly influencing cardiovascular function. Due to these effects, both hypothyroidism and hyperthyroidism, either in their overt or subclinical forms, can have an unfavourable impact in the setting of cardiovascular diseases. The aim of this review is to focus on the prognostic consequences of thyroid disorders in heart failure patients. Moreover, the therapeutical approach and the possible beneficial effects of restoring euthyroidism are reviewed. PMID- 23369136 TI - Diabetes and chronic heart failure: from diabetic cardiomyopathy to therapeutic approach. AB - Diabetes and chronic heart failure are interrelated conditions with major medical and economic impact that have to be treated as a distinct entity. Several pathological mechanisms have been investigated and proposed to explain the structural and functional changes associated with diabetic cardiomyopathy. These mechanisms are likely to act synergically and may potentiate one the other. This review outlines recent advances in the pathophysiological mechanisms implicated in the development and progression of diabetic cardiomyopathy and in current therapeutic strategies. PMID- 23369137 TI - Obesity and heart failure. AB - Epidemiological studies have recently shown that obesity, and abdominal obesity in particular, is an independent risk factor for the development of heart failure (HF). Higher cardiac oxidative stress is the early stage of heart dysfunction due to obesity, and it is the result of insulin resistance, altered fatty acid and glucose metabolism, and impaired mitochondrial biogenesis. Extense myocyte hypertrophy and myocardial fibrosis are early microscopic changes in patients with HF, whereas circumferential strain during the left ventricular (LV) systole, LV increase in both chamber size and wall thickness (LV hypertrophy), and LV dilatation are the early macroscopic and functional alterations in obese developing heart failure. LV hypertrophy leads to diastolic dysfunction and subendocardial ischemia in obesity, and pericardial fat has been shown to be significantly associated with LV diastolic dysfunction. Evolving abnormalities of diastolic dysfunction may include progressive hypertrophy and systolic dysfunction, and various degrees of eccentric and/or concentric LV hypertrophy may be present with time. Once HF is established, overweight and obese have a better prognosis than do their lean counterparts with the same level of cardiovascular disease, and this phenomenon is called "obesity paradox". It is mainly due to lower muscle protein degradation, brain natriuretic peptide circulating levels and cardio-respiratory fitness than normal weight patients with HF. PMID- 23369138 TI - Sarcopenia, cachexia and congestive heart failure in the elderly. AB - Skeletal muscle abnormalities and loss are frequently present in patients with mild or moderate cardiac heart failure (CHF) and may contribute to fatigue and dyspnea. These muscle abnormalities may be associated with age related body composition changes, such as sarcopenia. Muscle damage has also been observed in subjects with cardiac cahexia, a serious CHF complication, associated with poor prognosis independently of functional disease severity, age, and measures of exercise capacity and cardiac function. Loss of muscle mass is a feature of cachexia, whereas most sarcopenic subjects are not cachectic. Individuals with no weight loss, no anorexia, and no measurable systemic inflammatory response may be sarcopenic. Patients with severe CHF show multiple marked histological abnormalities of skeletal muscle, such as muscle fiber atrophy. These abnormalities are different in sarcopenia and cachexia. The majority of mechanisms involved in sarcopenia play a role even in the determination of cachexia and they are amplified in cachexia where they may induce both muscle damage as well as other abnormalities, such as fat and weight loss, through activation of lypolisis or anorexia. To distinguish cachexia and sarcopenia in CHF patients, even if not easy, should be clinically relevant, because no specific treatment is available for cachectic patients whereas treatment options are possible for sarcopenia. PMID- 23369139 TI - Neuroimmune activation in chronic heart failure. AB - Cardiac hypertrophy/remodeling manifests as a critical condition which may likely predispose to the risk of fatal heart failure and multiple organ dysfunction if not efficiently addressed, as a result of irreversible neuroendocrine, autonomic and immune system imbalances. Undeniably, the over-excitation of sympathetic and/or the breakdown of central parasympathetic tone play a significant role to be the basis of the persistent immune activation in chronic heart failure (CHF) which, to a certain extent, is primed by inflammatory reactions in the Central Nervous System. Moreover, till today, the clinical management of CHF seeks the identification of molecularly targeted drugs in comparison to those considered so far. This review focuses on the possible neuroimmune-mediated pathways involved in CHF and throws light on the current therapeutic strategies. PMID- 23369140 TI - The GH/IGF-1 axis in chronic heart failure. AB - The classic model of Chronic Heart Failure (CHF) is rooted in the overexpression of neurohormonal molecules. To complement this paradigm, increasing evidence indicates that a variety of hormones may be down-regulated in CHF patients. The list includes growth hormone (GH) and its tissue effector insulin-like growth factor-1 (IGF-1). The GH/IGF-1 axis regulates cardiac growth, stimulates myocardial contractility, and influences the vascular system. The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous studies in animals models and confirmed by the cardiac derangements secondary to both GH excess and deficiency in humans. Impaired activity of the GH/IGF-1 axis in CHF has been described by several independent groups and includes a wide array of abnormalities, including low IGF-1 levels, GH deficiency (GHD), and GH resistance that may be related to the severity of heart disease. According to several observations, these derangements are associated with poor clinical status and outcome. Since the first study of GH therapy in CHF in 1996, several placebo-controlled trials have been conducted with conflicting results. These discordant findings are likely explained by the degree of CHF associated GH/IGF-1 impairment that may impact on individual responsiveness to GH administration. Biological actions of GH and IGF-1, cardiovascular implication of GH deficiency and GH excess, relation between somatotrophic axis and CHF are discussed. Results from trials of GH therapy, emerging therapeutic strategies, safety issues, and lack in evidence are also reported. PMID- 23369141 TI - Testosterone deficiency in male: a risk factor for heart failure. AB - Testosterone deficiency syndrome (TDS) induces several negative effects that generally involve different organs such as testis, bone, skeletal muscle, and heart, leading to reduction in testis function, causing osteoporosis, strongly reducing muscle mass, decreasing exercise capacity and strength and facilitating heart failure. Approximately 25% of patients affected by chronic heart failure (CHF) is characterized by plasma Testosterone (T) levels below normal ranges also related to disease progression. In addition, reduction of circulating testosterone levels may contribute to some specific features of CHF, such as abnormal energy handling, weakness, dyspnoea and cachexia in particular. According to some recent evidence it has emerged that testosterone replacement therapy (TRT) may improve muscle strength and functional pulmonary capacity in CHF men with TDS. This review will place emphasis on the pathophysiological role of testosterone deficiency in CHF men as well as the effects of the testosterone replacement therapy. PMID- 23369142 TI - Parathyroid hormone and heart failure: novel biomarker strategy. AB - Heart failure (HF) is a clinical syndrome featuring cardiac pump failure along with signs and symptoms arising from salt and water retention mediated by activated renin-angiotensin-aldosterone system (RAAS). In addition to this cardiorenal perspective, HF is accompanied by a systemic illness, especially in advanced stages characterized by oxidative stress in various tissues, causing damage to soft tissue and bone. Secondary hyperparathyroidism (SHPT) which is also considered to contribute this systemic illness is therefore prominent in advanced HF. SHPT in HF occurs as a result of RAAS activation, prominent hyperaldosteronism, loop diuretic usage and decreased calcitriol level, all of which results in calcium excretion. We review the evidence that high parathyroid hormone (PTH) is associated with advanced HF, as well as evidence that it's associated with HF with preserved ejection fraction (HFPEF). PMID- 23369143 TI - The role of n-3 polyunsaturated fatty acids in human heart failure. AB - n-3 polyunsaturated fatty acids (PUFA) have been proposed as potential treatments for human heart failure. The cardioprotective effects of n-3 PUFA are supported by extensive cell culture, animal and human studies. Animal studies with n-3 PUFA have shown marked improvements in many independent risk factors for heart failure, including obesity, type II diabetes, insulin resistance, hypertension and inflammation. However, the evidence from observational studies, randomised controlled trials and meta-analyses that these benefits on risk factors lead to improvements in the symptoms of heart failure in patients is much less convincing. Further, most studies have used marine n-3 PUFA; the role of the plant-derived PUFA, alpha-linolenic acid (ALA), is even less clear. This discontinuity of scientific evidence from animal to human studies suggests that future studies should focus on defining the optimal dosage range and the efficacy of n-3 PUFA compared to standard treatments using standardised study designs. Further studies on ALA would seem justified. PMID- 23369144 TI - The impact of dietary habits and nutritional deficiencies in urban African patients living with heart failure in Soweto, South Africa--a review. AB - In South Africa, rapid urbanisation and epidemiological transition have left the black urban population vulnerable to diseases of lifestyle such as diabetes, high blood pressure, obesity and heart disease, as well as chronic heart failure. This is in part due to the fact that changes in dietary patterns during urbanisation play an important role in the increase of risk factors of these diseases. The South African population is made up of many different ethnic and cultural groups, each with its own way of eating and food choices. The black African population is one such an ethnic group, with its own distinct eating patterns and food choices. The diets of people living in rural areas tend to still be higher in carbohydrates, lower in fat, lower in sugar and higher in fibre, corresponding to the more traditional way of eating. With urbanisation their diet has changed to a more westernised diet with the resultant decrease in carbohydrates and fibre and an increased fat, processed food and salt consumption. Factors that might contribute to this change in dietary patterns include lack of awareness and knowledge around nutritional recommendations for persons suffering from chronic heart failure, urbanisation, socio-economic circumstances, food insecurity and level of education. Nutritional recommendations and intervention programs for the prevention and management of CHF focusing on food that is culturally sensitive and affordable should be implemented. PMID- 23369145 TI - Managing erectile dysfunction in heart failure. AB - Nowadays, erectile dysfunction (ED) is considered an increasingly important clinical condition in men with heart failure (HF) which may influence the therapeutic approach to these patients. Since there is cogent evidence that ED is a "sentinel marker" of acute cardiovascular events especially in men younger than 65 years or in those affected by type 2 diabetes mellitus, it deserves an early diagnosis and an appropriate treatment. In NYHA III-IV class HF patients, sexual activity could lead to acute cardiovascular events and this should be taken into account when approaching ED patients. Moreover, it is well known that some classes of drugs, normally employed in the treatment of HF patients (e.g.thiazide diuretics, spironolactone and beta-blockers), might worsen or even contribute to ED development. On the other hand, growing evidence suggests that PDE 5 inhibitors (vardenafil, tadalafil and sildenafil) seem to better satisfy the needs of NYHA HF I- II class men suffering from ED. In fact, they show few side effects, while improving both cardiopulmonary parameters and quality of life. Therefore, the aim of this review is to sum up the most recent evidence regarding the management of ED in men suffering from HF. PMID- 23369146 TI - Fentanyl enhances the excitability of rapidly adapting receptors to cause cough via the enhancement of histamine release in the airways. AB - BACKGROUND: Although the mechanism of fentanyl-induced cough is unclear, several lines of evidence suggest that allergic mediators, such as histamine, may play a role in the production of fentanyl-induced coughs. The aim of this study was to explore the effects of fentanyl on cough sensitivity to inhaled citric acid and on histamine release in BALF in mice. METHODS: The cough reflex was induced by the inhalation of citric acid. Male ICR mice were exposed to a nebulized solution of citric acid at a concentration of 0.1 M under conscious and identical conditions using a body plethysmograph. The number of coughs produced per 3-min period of exposure to citric acid was counted. Histamine content in BALF was analyzed by HPLC post-column derivatization and fluorescence detection. RESULTS: Intravenous administration of fentanyl increased the number of citric acid induced coughs. The fentanyl-induced enhancement of the number of citric acid induced coughs was abolished in mice that had been pretreated with moguisteine, a rapidly adapting receptor (RAR) antagonist or fexofenadine, a histamine H1 receptor antagonist. Fentanyl significantly increased the concentration of histamine in BALF. CONCLUSION: The results of this study suggest that fentanyl enhances the excitability of RARs to cause cough, and enhancement of histamine release in the airways may some how be related to this change. PMID- 23369147 TI - Shape and secondary structure prediction for ncRNAs including pseudoknots based on linear SVM. AB - BACKGROUND: Accurate secondary structure prediction provides important information to undefirstafinding the tertiary structures and thus the functions of ncRNAs. However, the accuracy of the native structure derivation of ncRNAs is still not satisfactory, especially on sequences containing pseudoknots. It is recently shown that using the abstract shapes, which retain adjacency and nesting of structural features but disregard the length details of helix and loop regions, can improve the performance of structure prediction. In this work, we use SVM-based feature selection to derive the consensus abstract shape of homologous ncRNAs and apply the predicted shape to structure prediction including pseudoknots. RESULTS: Our approach was applied to predict shapes and secondary structures on hundreds of ncRNA data sets with and without psuedoknots. The experimental results show that we can achieve 18% higher accuracy in shape prediction than the state-of-the-art consensus shape prediction tools. Using predicted shapes in structure prediction allows us to achieve approximate 29% higher sensitivity and 10% higher positive predictive value than other pseudoknot prediction tools. CONCLUSIONS: Extensive analysis of RNA properties based on SVM allows us to identify important properties of sequences and structures related to their shapes. The combination of mass data analysis and SVM-based feature selection makes our approach a promising method for shape and structure prediction. The implemented tools, Knot Shape and Knot Structure are open source software and can be downloaded at: http://www.cse.msu.edu/~achawana/KnotShape. PMID- 23369148 TI - Histological diagnosis of follicular lymphoma by biopsy of small intestinal normal mucosa. AB - Due to advances in double-balloon endoscopy, various types of malignant lymphoma of the small intestine have been observed at very early stages. We report here that after remission of diffuse large B-cell lymphoma, follicular lymphoma recurred in the mucosa of the small intestine. Furthermore, these lesions were diagnosed by biopsy from normal mucosa as diminutive erosions and reddish looking. If a small intestinal lesion is suspected of being a malignant lymphoma, a double-balloon endoscopy should be carried out, and a biopsy should be taken and inspected. PMID- 23369149 TI - Atypical rearrangement involving 3'-IGH@ and a breakpoint at least 400 Kb upstream of an intact MYC in a CLL patient with an apparently balanced t(8;14)(q24.1;q32) and negative MYC expression. AB - The t(8;14)(q24.1;q32), the cytogenetic hallmark of Burkitt's lymphoma, is also found, but rarely, in cases of chronic lymphocytic leukemia (CLL). Such translocation typically results in a MYC-IGH@ fusion subsequently deregulating and overexpressing MYC on der 14q32. In CLL, atypical rearrangements resulting in its gain or loss, within or outside of IGH@ or MYC locus, have been reported, but their clinical significance remains uncertain. Herein, we report a 67 year-old male with complex cytogenetic findings of apparently balanced t(8;14) and unreported complex rearrangements of IGH@ and MYC loci. His clinical, morphological and immunophenotypic features were consistent with the diagnosis of CLL.Interphase FISH studies revealed deletions of 11q22.3 and 13q14.3, and an extra copy of IGH@, indicative of rearrangement. Karyotype analysis showed an apparently balanced t(8;14)(q24.1;q32). Sequential GPG-metaphase FISH studies revealed abnormal signal patterns: rearrangement of IGH break apart probe with the 5'-IGH@ on derivative 8q24.1 and the 3'-IGH@ retained on der 14q; absence of MYC break apart-specific signal on der 8q; and, the presence of unsplit 5'-MYC-3' break apart probe signals on der 14q. The breakpoint on 8q24.1 was found to be at least 400 Kb upstream of 5' of MYC. In addition, FISH studies revealed two abnormal clones; one with 13q14.3 deletion, and the other, with concurrent 11q deletion and atypical rearrangements. Chromosome microarray analysis (CMA) detected a 7.1 Mb deletion on 11q22.3-q23.3 including ATM, a finding consistent with FISH results. While no significant copy number gain or loss observed on chromosomes 8, 12 and 13, a 455 Kb microdeletion of uncertain clinical significance was detected on 14q32.33. Immunohistochemistry showed co-expression of CD19, CD5, and CD23, positive ZAP-70 expression and absence of MYC expression. Overall findings reveal an apparently balanced t(8;14) and atypical complex rearrangements involving 3'-IGH@ and a breakpoint at least 400 Kb upstream of MYC, resulting in the relocation of the intact 5'-MYC-3' from der 8q, and apposition to 3'-IGH@ at der 14q. This case report provides unique and additional cytogenetic data that may be of clinical significance in such a rare finding in CLL. It also highlights the utility of conventional and sequential metaphase FISH in understanding complex chromosome anomalies and their association with other clinical findings in patients with CLL. To the best of our knowledge, this is the first CLL reported case with such an atypical rearrangement in a patient with a negative MYC expression. PMID- 23369151 TI - Study of head scatter factor in 4MV photon beam used in radiotherapy. AB - The 4 MV photon beam offers equal build-up region behavior like Co-60 beam and it plays a major role in head and neck and pediatric radiotherapy. In this study an attempt is made to study the head scatter factor (SC) for 4 MV photon beam using locally designed PMMA and Brass miniphantoms. The SC is measured in combination of PMMA miniphantom with 0.6 cc chamber and Brass miniphantom with 0.6 cc and 0.13 cc chambers. The measured SC is compared with the literature data and it agrees within +/- 1.98%. The study reveals that either 0.13 cc or 0.6 cc chamber with PMMA or Brass phantom materials can be used for SC measurements in a 4 MV photon beam. The variation of SSD does not alter the head scatter factor. The collimator exchange effect is found to be within 1, and it is less than that of other linear accelerators. It is also found that the presence of internal wedge has significant contribution to head scatter factor. The Phantom scatter factor is also calculated and it agrees within +/-1% with published data. PMID- 23369152 TI - Irreversible electroporation for unresectable hepatocellular carcinoma: initial experience and review of safety and outcomes. AB - The aims of this study were to evaluate the safety, feasibility and tumour response of _irreversible electroporation, a non-thermal ablation technique, for the treatment of unresectable hepatocellular carcinoma. The endpoints were safety and local treatment efficacy. Patients with unresectable tumours and tumours not amenable for radiofrequency _ablation because of their vicinity to organs vulnerable to thermal damage such as the bowel or because they were close to large blood vessels that would limit efficacy of ablation due to the heat sink effect were treated with irreversible electroporation using percutaneous _ultrasound and/or computed tomography guided electrode placement between November 2008 and _December 2009. Early, late, minor and major complications were recorded. Tumour response was determined on triphasic helical computed tomography follow-up at one month, then every three months post-procedure. Eleven patients received IRE therapy to 18 HCC lesions (Mean diameter 2.44 +/- 0.99 cm; range 1.0 6.1 cm) with five patients having more than one treated HCC. Mean follow-up was 18 months (range 14-24 months). Six patients required repeat treatments for local residual or recurrent disease; two of these also had IRE for distant intrahepatic recurrence. No serious complications were observed despite seven lesions lying adjacent to important structures or organs. Four patients developed transient urinary retention and seven developed transient local post-procedure pain. After IRE therapy, 13 (72%) lesions were completely ablated with 93% success for lesions <= 3 cm (13/14). The local recurrence-free period was 18 +/- 4 months and the distance recurrence free period was 14 +/- 6 months. These preliminary results suggest that IRE is a safe and feasible technique for local ablation of HCC, particularly for lesions less than 3 cm. No major complications were encountered during this study even for tumours close to essential structures or organs. PMID- 23369153 TI - Dosimetry investigation of MOSFET for clinical IMRT dose verification. AB - In IMRT, patient-specific dose verification is followed regularly at each centre. Simple and efficient dosimetry techniques play a very important role in routine clinical dosimetry QA. The MOSFET dosimeter offers several advantages over the conventional dosimeters such as its small detector size, immediate readout, immediate reuse, multiple point dose measurements. To use the MOSFET as routine clinical dosimetry system for pre-treatment dose verification in IMRT, a comprehensive set of experiments has been conducted, to investigate its linearity, reproducibility, dose rate effect and angular dependence for 6 MV x ray beam. The MOSFETs shows a linear response with linearity coefficient of 0.992 for a dose range of 35 cGy to 427 cGy. The reproducibility of the MOSFET was measured by irradiating the MOSFET for ten consecutive irradiations in the dose range of 35 cGy to 427 cGy. The measured reproducibility of MOSFET was found to be within 4% up to 70 cGy and within 1.4% above 70 cGy. The dose rate effect on the MOSFET was investigated in the dose rate range 100 MU/min to 600 MU/min. The response of the MOSFET varies from -1.7% to 2.1%. The angular responses of the MOSFETs were measured at 10 degrees intervals from 90 to 270 degrees in an anticlockwise direction and normalized at gantry angle zero and it was found to be in the range of 0.98 +/- 0.014 to 1.01 +/- 0.014. The MOSFETs were calibrated in a phantom which was later used for IMRT verification. The measured calibration coefficients were found to be 1 mV/cGy and 2.995 mV/cGy in standard and high sensitivity mode respectively. The MOSFETs were used for pre-treatment dose verification in IMRT. Nine dosimeters were used for each patient to measure the dose in different plane. The average variation between calculated and measured dose at any location was within 3%. Dose verification using MOSFET and IMRT phantom was found to quick and efficient and well suited for a busy radiotherapy department. PMID- 23369154 TI - Acute radiation esophagitis caused by high-dose involved field radiotherapy with concurrent cisplatin and vinorelbine for stage III non-small cell lung cancer. AB - Purpose of this study is to obtain dose-volume histogram (DVH) predictors and threshold values for radiation esophagitis caused by high-dose involved field radiotherapy (IFRT) with concurrent chemotherapy in patients with stage III non small cell lung cancer (NSCLC). Thirty-two patients treated by 66 Gy/33 Fr, 72 Gy/36 Fr, and 78 Gy/39 Fr thoracic radiotherapy without elective nodal irradiation plus concurrent cisplatin and vinorelvine were reviewed. Acute radiation esophagitis was evaluated according to common terminology criteria for adverse events version 4.0, and correlations between grade 2 or worse radiation esophagitis and DVH parameters were investigated. Grade 0-1, 2, 3, and 4-5 of radiation esophagitis were seen in 11 (34.4%), 20 (62.5%), 1 (3.1%), and 0 (0%) of the patients, respectively. Multivariate analysis revealed that whole esophagus V35 is a predictor of radiation esophagitis (OR = 0.74 [95%CI; 0.60 0.91], p = 0.006). There is a significant difference (38.4% vs. 89.4%, p = 0.027) in the cumulative rates of acute esophagitis according to V35 values of more than 20% versus less. As compared with other factors concerning patient and tumor and treatment factors, V35 <= 20% of the esophagus was an independent predictor (HR 5 0.29 [95%CI; 0.09-0.85], p 5 0.025). In conclusion, whole esophagus V35 < 20% is proposed in high-dose IFRT with concurrent chemotherapy for stage III NSCLC patients. PMID- 23369155 TI - Stereotactic body radiation therapy for curative treatment of adrenal metastases. AB - The detection of oligometastatic adrenal metastases is increasing and there are limited data supporting the use of curative intent stereotactic body radiation therapy (SBRT) to treat patients with limited metastatic disease with adrenal involvement. Therefore, we utilized a prospectively maintained database of consecutive patients treated with SBRT for limited metastatic disease (<=5 sites) to identify patients with adrenal metastases. Patients were either treated on a three-fraction dose escalation protocol or a ten fraction off-protocol regimen. Outcomes including treated-metastasis control (TMC), distant control (DC), and overall survival (OS) were calculated by the Kaplan-Meier method. Ten patients with 13 adrenal metastases were identified for this case series. The median follow-up was 14.9 months. No patient experienced grade 3 toxicity. The most common grade 1-2 acute toxicities were fatigue (80%) and GI toxicity (40%). One patient experienced late grade 2 adrenal insufficiency. Overall, the 1-year TMC rate was 73%, DC was 30%, and OS was 90%. Three treated adrenal metastases progressed, all receiving the lowest BED10 (43.2 Gy), corresponding to 24 Gy in 3 fractions. After treatment of adrenal metastases with SBRT, the median time to salvage chemotherapy was 5.3 months (range 1.0-38.8 months) and 1-year freedom from salvage chemotherapy was 44%. These results suggest that SBRT to adrenal metastases was tolerated with low toxicity in limited metastatic patients and control rates are promising. This study supports the growing body of literature treating patients with adrenal metastases with SBRT. PMID- 23369157 TI - Individual beam sharpening improves composite dose fall-off near a target for non isocentric cyberknife radiosurgery. AB - Stereotactic radiosurgery (SRS) refers to a high dose of radiation delivered to a focal region of interest while maximizing the steep dose gradient to minimize dose to the surrounding normal tissues. Multiple factors can influence the dose fall-off, and the relative importance of such factors have not yet been characterized for non-isocentric Cyberknife SRS. Our aim was to investigate whether the composite dose fall-off near a target may be enhanced via sharpening the lateral beam profile (or penumbra) of each individual beam. Cyberknife beam profiles were fitted and parameterized to obtain a characteristic penumbra function for each collimator size. Simulated beam profiles with progressively sharper penumbras were then generated, and used to perform simulated treatment planning on seven pediatric intracranial arteriovenous malformations (AVMs) cases. Penumbra size was found to significantly influence the peripheral dose fall-off. Peripheral dose volumes were reduced by 5 to 10% with reductions in penumbra size ranging from 40 to 80%. Dose conformality and homogeneity were not significantly changed with decreasing penumbra size. Therefore, individual beam sharpening provides a straightforward way of improving the composite dose fall off for non-isocentric Cyberknife SRS. PMID- 23369156 TI - A comparative evaluation of ultrasound molecular imaging, perfusion imaging, and volume measurements in evaluating response to therapy in patient-derived xenografts. AB - Most pre-clinical therapy studies use the change in tumor volume as a measure for disease response. However, tumor size measurements alone may not reflect early changes in tumor physiology that occur as a response to treatment. Ultrasonic molecular imaging (USMI) and Dynamic Contrast Enhanced-Perfusion Imaging (DCE-PI) with ultrasound are two attractive alternatives to tumor volume measurements. Since these techniques can provide information prior to the appearance of gross phenotypic changes, it has been proposed that USMI and DCE-PI could be used to characterize response to treatment earlier than traditional methods. This study evaluated the ability of tumor volume measurements, DCE-PI, and USMI to characterize response to therapy in two different types of patient-derived xenografts (known responders and known non-responders). For both responders and non-responders, 7 animals received a dose of 30 mg/kg of MLN8237, an investigational aurora-A kinase inhibitor, for 14 days or a vehicle control. Volumetric USMI (target integrin:alpha av beta3) and DCE-PI were performed on day 0, day 2, day 7, and day 14 in the same animals. For USMI, day 2 was the earliest point at which there was a statistical difference between the untreated and treated populations in the responder cohort (Untreated: 1.20 +/- 0.53 vs. Treated: 0.49 +/- 0.40; p < 0.05). In contrast, statistically significant differences between the untreated and treated populations as detected using DCE PI were not observed until day 14 (Untreated: 0.94 +/- 0.23 vs. Treated: 1.31 +/- 0.22; p < 0.05). Volume measurements alone suggested no statistical differences between treated and untreated populations at any readpoint. Monitoring volumetric changes is the "gold standard" for evaluating treatment in pre-clinical studies, however, our data suggests that volumetric USMI and DCE-PI may be used to earlier classify and robustly characterize tumor response. PMID- 23369158 TI - Assessing feasibility of real-time ultrasound monitoring in stereotactic body radiotherapy of liver tumors. AB - To monitor tumor motion during stereotactic body radiotherapy (SBRT) for patients with liver cancer, an integrated ultrasound and kilo-voltage cone-beam computed tomography (KV-CBCT) system has been proposed. The presence of an ultrasound probe may interfere with the radiation beams. The purpose of this study is to minimize this interference by altering orientations of the ultrasound probe and directions of radiation beams while not compromising the quality of SBRT plans. Ten patients, who received SBRT of liver cancer, were randomly selected for this study. To simulate the presence of an ultrasound probe, a virtual probe was oriented either parallel or vertical to the longitudinal axis of the patient's body and was added on the surface of the patient's body at the nearest location to the tumor. For both the parallel and vertical probe orientations, 2 new SBRT (Probe-Para and Probe-Vert) plans that minimize the interference between the probe and radiation beams were created for each patient. These SBRT plans were compared to the original clinically accepted SBRT plans, with a treatment goal of 37.5 Gy to the planning target volume (PTV) in 3 fractions. Specific dosimetric endpoints were evaluated, including doses to 95% (D95), of the PTV plan conformal index (CI), homogeneity index (HI), and relevant endpoint doses to organs at risk. For 2 patients with superficially located tumors, no clinically acceptable SBRT plans could be produced without the interference between the probe and radiation beams. For the remaining 8 patients, the Probe-Para plans allowed 7 patients to be treated with coplanar radiation beams (without moving the treatment couch during treatment) and 1 patient to be treated with non-coplanar beams (by moving the treatment couch during treatment). The Probe-Vert plans allowed 2 patients to be treated with coplanar beams and 6 patients to be treated with non-coplanar beams. The average D95 of the PTV were 38.63 Gy +/- 0.14 (r = 0.65) for Probe-Para plans, 38.48 Gy +/- 0.31 (r = 0.33) for Probe-Vert plans, and 38.72 Gy +/- 0.14 for clinical SBRT plans. There were no significant differences (p > 0.05) in CI and HI of all SBRT plans. The endpoint doses to the liver, heart, esophagus, right kidney, and stomach also had no significant differences (p > 0.05). Except for superficial lesions, real-time ultrasound monitoring during liver SBRT is clinically feasible. Placing the ultrasound probe parallel to the longitudinal axis of the patient allows a greater probability of utilizing preferred coplanar beams. PMID- 23369159 TI - Moyamoya syndrome with sickle cell trait. PMID- 23369160 TI - Multi-channel acoustic recording and automated analysis of Drosophila courtship songs. AB - BACKGROUND: Drosophila melanogaster has served as a powerful model system for genetic studies of courtship songs. To accelerate research on the genetic and neural mechanisms underlying courtship song, we have developed a sensitive recording system to simultaneously capture the acoustic signals from 32 separate pairs of courting flies as well as software for automated segmentation of songs. RESULTS: Our novel hardware design enables recording of low amplitude sounds in most laboratory environments. We demonstrate the power of this system by collecting, segmenting and analyzing over 18 hours of courtship song from 75 males from five wild-type strains of Drosophila melanogaster. Our analysis reveals previously undetected modulation of courtship song features and extensive natural genetic variation for most components of courtship song. Despite having a large dataset with sufficient power to detect subtle modulations of song, we were unable to identify previously reported periodic rhythms in the inter-pulse interval of song. We provide detailed instructions for assembling the hardware and for using our open-source segmentation software. CONCLUSIONS: Analysis of a large dataset of acoustic signals from Drosophila melanogaster provides novel insight into the structure and dynamics of species-specific courtship songs. Our new system for recording and analyzing fly acoustic signals should therefore greatly accelerate future studies of the genetics, neurobiology and evolution of courtship song. PMID- 23369161 TI - Unraveling overlapping deletions by agglomerative clustering. AB - BACKGROUND: Structural variations in human genomes, such as deletions, play an important role in cancer development. Next-Generation Sequencing technologies have been central in providing ways to detect such variations. Methods like paired-end mapping allow to simultaneously analyze data from several samples in order to, e.g., distinguish tumor from patient specific variations. However, it has been shown that, especially in this setting, there is a need to explicitly take overlapping deletions into consideration. Existing tools have only minor capabilities to call overlapping deletions, unable to unravel complex signals to obtain consistent predictions. RESULT: We present a first approach specifically designed to cluster short-read paired-end data into possibly overlapping deletion predictions. The method does not make any assumptions on the composition of the data, such as the number of samples, heterogeneity, polyploidy, etc. Taking paired ends mapped to a reference genome as input, it iteratively merges mappings to clusters based on a similarity score that takes both the putative location and size of a deletion into account. CONCLUSION: We demonstrate that agglomerative clustering is suitable to predict deletions. Analyzing real data from three samples of a cancer patient, we found putatively overlapping deletions and observed that, as a side-effect, erroneous mappings are mostly identified as singleton clusters. An evaluation on simulated data shows, compared to other methods which can output overlapping clusters, high accuracy in separating overlapping from single deletions. PMID- 23369162 TI - Metagenomic profile of gut microbiota in children during cholera and recovery. AB - BACKGROUND: The diverse bacterial communities colonizing the gut (gastrointestinal tract) of infants as commensal flora, which play an important role in nutrient absorption and determining the state of health, are known to alter due to diarrhea. METHOD: Bacterial community dynamics in children suffering from cholera and during recovery period were examined in the present study by employing metagenomic tool, followed by DNA sequencing and analysis. For this, bacterial community DNA was extracted from fecal samples of nine clinically confirmed cholera children (age 2-3 years) at day 0 (acute cholera), day 2 (antibiotic therapy), day 7 and, and day 28, and the variable region of 16S rRNA genes were amplified by universal primer PCR. RESULTS: 454 parallel sequencing of the amplified DNA followed by similarity search of the sequenced data against an rRNA database allowed us to identify V. cholerae, the cause of cholera, in all nine children at day 0, and as predominant species in six children, accounting for 35% of the total gut microbiota on an average in all the nine children. The relative abundance (mean +/- sem %) of bacteria belonging to phyla Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria, was 55 +/- 7, 18 +/- 4, 13 +/- 4, and 8 +/- 4, respectively, at day 0, while these values were 12 +/- 4, 43 +/- 4, 33 +/- 3, and 12 +/- 2, respectively, at day 28. As antibiotic therapy began, V. cholerae count declined significantly (p< 0.001) and was found only in four children at day 2 and two children at day 7 with the relative abundance of 3.7% and 0.01%, respectively, which continued up to day 28 in the two children. Compared to acute cholera condition (day 0), the relative abundance of Escherichia coli, Enterococcus, and Veillonella increased at day 2 (antibiotic therapy) while Bifidobacterium, Bacteroides, and Ruminococcus decreased. CONCLUSION: Cholera results expulsion of major commensal bacteria of phyla Bacteroidetes, Firmicutes, and Actinobacteria, and increase of harmful Proteobacteria to colonize the gut during acute and convalescence states. The observed microbiota disruption might explain the prevalent malnutrition in children of Bangladesh where diarrheal diseases are endemic. PMID- 23369163 TI - Enhanced expression of farnesoid X receptor in human hepatocellular carcinoma. AB - AIM: The aim of this study was to investigate the expression of farnesoid X receptor (FXR) in human hepatocellular carcinoma (HCC) tissues and cell lines and evaluate its clinicopathological significance. METHODS: Expression levels of FXR protein and mRNA in hepatocytes, hepatic stellate cells (SC), and HCC cells in human liver, HCC tissues and cultured cell lines were analyzed using immunohistochemical methods, western blotting (WB), and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The relationship between FXR expression and clinicopathological parameters was also investigated. RESULTS: Immunoreactivity for FXR was observed in nuclei of hepatocytes, SC and HCC cells. The intensity of nuclear FXR positive staining was comparable or increased in tumor cells of all HCC tissues when compared with hepatocytes of non-tumorous liver tissues of the same patients as well as in comparison with metastatic colon cancers. A significant level of FXR expression in four of six human HCC cell lines was also confirmed, while it was undetectable in three cholangiocarcinoma cell lines. However, FXR protein and mRNA levels in HCC tissues determined by WB and qRT-PCR were lower than those in non-tumorous liver tissues because of the high level of FXR expression in SC nuclei as detected by immunohistochemical double stain. Statistically significant relationships between FXR immunostaining intensity and high Ki-67 labeling indices or a history of transcatheter arterial chemoembolization in HCC patients were also disclosed. CONCLUSION: Contrary to previous reports, preserved or enhanced expression levels of nuclear FXR were detected in HCC, indicating that FXR may play significant roles in the biological behavior of HCC. PMID- 23369164 TI - Algal production of extra and intra-cellular polysaccharides as an adaptive response to the toxin crude extract of Microcystis aeruginosa. AB - This is an investigation concerned with studying the possible adaptive response of four different unicellular algae, Anabaena PCC 7120, Oscillatoria angustissima, Scendesmus obliquus and Chlorella vulgaris, to the toxin of Microcystis aeruginosa (Kutzing). The effects of four different concentrations, 25, 50, 100 and 200 MUg mL-1 of microcystins crude extract of M. aeruginosa, on both intra and extra-cellular polysaccharide levels, in log phase, of the four tested algae were studied. The obtained results showed differential increase in the production levels for both intra and extra-cellular polysaccharides by the tested algae, compared with the control. S. obliquus and C. vulgaris showed a resistance to crude toxin higher than Anabaena PCC 7120 and O. angustissima. The highly production of polysaccharides by green algal species under this toxic stress indicated the involvement of these polysaccharides in protecting the algal cells against toxic species and, reflect the biological behavior of particular algal species to the environmental stresses. PMID- 23369165 TI - Relationship between the solution thermodynamic properties of naproxen in organic solvents and its release profiles from PLGA microspheres. AB - Naproxen (NPX)-loaded poly-(D,L-lactic-co-glycolic acid) (PLGA) microparticles were prepared by the emulsion-solvent evaporation method. The different organic solvents used significantly affects the properties of the microparticles obtained. These microparticles exhibited a controlled release profile that extends up to 15 days depending on the organic solvent used. The formulations did not exhibit zero- or first-order release kinetics and no agreement with Higuchi or Korsmeyer-Peppas models was obtained. In all cases, the dissolution profiles were fitted to the model proposed by Gallagher and Corrigan for PLGA systems. It was found that this model fully describes the dissolution processes. An interesting relationship between the NPX solubility in the organic solvents studied and some parameters obtained for the dissolution model of the microparticles prepared with the same solvents is thus obtained. Accordingly, it can be proposed that the drug solubility in organic solvents is relevant to estimate the physical characteristics of microparticles other than its dissolution profiles. PMID- 23369167 TI - Letter: Is visceral adiposity index a predictor of liver histology in patients with non-alcoholic fatty liver disease? PMID- 23369166 TI - Osteopathology associated with bone resorption inhibitors - which role does Actinomyces play? A presentation of 51 cases with systematic review of the literature. AB - BACKGROUND: Bone resorption inhibitor-related osteopathology of the jaw (BRIOJ) is a severe complication in patients treated with bisphosphonates or denosumab. However, the precise pathogenesis of BRIOJ is not yet fully understood. Recent studies discovered the presence of Actinomyces colonies in biopsy material from BRIOJ patients. The aim of this study was to analyze current knowledge concerning the impact of Actinomyces on the pathogenesis of this condition and to present data from our own patients. METHODS: Data from 51 patients with histopathological diagnoses of BRIOJ were retrospectively analyzed. In addition, a systematic literature search for studies describing the presence of Actinomyces was performed. RESULTS: Actinomyces was present in 86% of our cases and 63.3% of 371 cases presented in the literature. All of our patients and 85% of patients described in the literature had a clearly defined local focus in association with osteopathology. A clear picture of whether Actinomyces colonizes the previously necrotic bone or contributes to inflammation causing subsequent bone necrosis is lacking in the literature. CONCLUSION: The pathogenesis of BRIOJ remains unknown; however, there seems to be a role for Actinomyces, and possibly other pathogens, in the development of osteopathology of the jaws, which is not exclusive to bisphosphonate therapy. This study supports the hypothesis that an infectious component is of utmost importance for the pathogenesis of BRIOJ. PMID- 23369168 TI - Letter: First-line monotherapies for chronic hepatitis B - indirect comparison between entecavir and tenofovir. PMID- 23369169 TI - Design of COSMIC: a randomized, multi-centre controlled trial comparing conservative or early surgical management of incomplete cervical cord syndrome without spinal instability. AB - BACKGROUND: Incomplete cervical cord syndrome without spinal instability is a very devastating event for the patient and the family. It is estimated that up to 25% of all traumatic spinal cord lesions belong to this category. The treatment for this type of spinal cord lesion is still subject of discussion. From a biological point of view early surgery could prevent secondary damage due to ongoing compression of the already damaged spinal cord. Historically, however, conservative treatment was propagated with good clinical results. Proponents for early surgery as well those favoring conservative treatment are still in debate. The proposed trial will contribute to the discussion and hopefully also to a decrease in the variability of clinical practice. METHODS/DESIGN: A randomized controlled trial is designed to compare the clinical outcome of early surgical strategy versus a conservative approach. The primary outcome is clinical outcome according to mJOA. This also measured by ASIA score, DASH score and SCIM III score. Other endpoints are duration of the stay at a high care department (medium care, intensive care), duration of the stay at the hospital, complication rate, mortality rate, sort of rehabilitation, and quality of life. A sample size of 36 patients per group was calculated to reach a power of 95%. The data will be analyzed as intention-to-treat at regular intervals, but the end evaluation will take place at two years post-injury. DISCUSSION: At the end of the study, clinical outcomes between treatments attitudes can be compared. Efficacy, but also efficiency can be determined. A goal of the study is to determine which treatment will result in the best quality of life for the patients. This study will certainly contribute to more uniformity of treatment offered to patients with a special sort of spinal cord injury. TRIAL REGISTRATION: Gov: NCT01367405. PMID- 23369170 TI - Versatile inhibitory effects of the flavonoid-derived PI3K/Akt inhibitor, LY294002, on ATP-binding cassette transporters that characterize stem cells. AB - Stem cells are undifferentiated cells capable of proliferation, self-renewal, and production of a large number of differentiated progeny. Stem cells exist even in malignancies. They are called cancer stem cells, which may represent the origin of these tumors and may be one of the reasons of chemoresistance. The phosphatidylinositol-3-kinase (PI3K)/Akt pathway is important for the maintenance of pluripotency in stem cells. Flow cytometry assay for identifying stem cells defines a side population of cells that displays low fluorescent dye and is highly enriched for stem cells. The dye efflux is attributed to expression of ATP binding cassette transporters such as P-glycoprotein and breast cancer resistance protein (BCRP)/ABCG2, which also transport a variety of anticancer drugs. The PI3K/Akt pathway can modulate functions of ABC transporters through various mechanisms. Reportedly, inhibition of the PI3K/Akt pathway caused BCRP translocation in hematopoietic stem cells and glioma stem-like cells. On the other hand, a PI3K inhibitor, LY294002, reversed multidrug resistance in cancer cells that overexpress BCRP not by affecting BCRP translocation but putatively as a competitive inhibitor. Other PI3K inhibitors, wortmannin and PI-103, did not reverse BCRP-mediated drug resistance. Since LY294002 is a derivative of quercetin that is a naturally occurring flavonoid, its chemical structure is similar to those of a group of flavonoids but those of wortmannin and PI-103 are quite different. It is known that many flavonoids are inhibitors of BCRP and PI3K. LY294002 has also been reported to exert inhibitory effects on multidrug resistance-associated protein 1 (MRP1) function via dual mechanisms, competitive block of substrate transport and modulation of expression. Furthermore, LY294002 has been found to antagonize transport activity of P-glycoprotein without influencing its expression. Taken together, LY294002 can inhibit all BCRP, P glycoprotein, and MRP1, which are three major ABC transporters that are highly expressed in stem cells and cause multidrug resistance. Due to its versatile effects, LY294002 could be a lead compound for developing more effective and tolerable reagents for cancer treatment. PMID- 23369171 TI - iStable: off-the-shelf predictor integration for predicting protein stability changes. AB - BACKGROUND: Mutation of a single amino acid residue can cause changes in a protein, which could then lead to a loss of protein function. Predicting the protein stability changes can provide several possible candidates for the novel protein designing. Although many prediction tools are available, the conflicting prediction results from different tools could cause confusion to users. RESULTS: We proposed an integrated predictor, iStable, with grid computing architecture constructed by using sequence information and prediction results from different element predictors. In the learning model, several machine learning methods were evaluated and adopted the support vector machine as an integrator, while not just choosing the majority answer given by element predictors. Furthermore, the role of the sequence information played was analyzed in our model, and an 11-window size was determined. On the other hand, iStable is available with two different input types: structural and sequential. After training and cross-validation, iStable has better performance than all of the element predictors on several datasets. Under different classifications and conditions for validation, this study has also shown better overall performance in different types of secondary structures, relative solvent accessibility circumstances, protein memberships in different superfamilies, and experimental conditions. CONCLUSIONS: The trained and validated version of iStable provides an accurate approach for prediction of protein stability changes. iStable is freely available online at: http://predictor.nchu.edu.tw/iStable. PMID- 23369173 TI - The effect of observational learning on students' performance, processes, and motivation in two creative domains. AB - BACKGROUND: Previous research has shown that observation can be effective for learning in various domains, for example, argumentative writing and mathematics. The question in this paper is whether observational learning can also be beneficial when learning to perform creative tasks in visual and verbal arts. AIMS: We hypothesized that observation has a positive effect on performance, process, and motivation. We expected similarity in competence between the model and the observer to influence the effectiveness of observation. Sample. A total of 131 Dutch students (10(th) grade, 15 years old) participated. METHOD: Two experiments were carried out (one for visual and one for verbal arts). Participants were randomly assigned to one of three conditions; two observational learning conditions and a control condition (learning by practising). The observational learning conditions differed in instructional focus (on the weaker or the more competent model of a pair to be observed). RESULTS: We found positive effects of observation on creative products, creative processes, and motivation in the visual domain. In the verbal domain, observation seemed to affect the creative process, but not the other variables. The model similarity hypothesis was not confirmed. CONCLUSIONS: Results suggest that observation may foster learning in creative domains, especially in the visual arts. PMID- 23369174 TI - Addressing the struggle to link form and understanding in fractions instruction. AB - BACKGROUND: Although making explicit links between procedures and concepts during instruction in mathematics is important, it is still unclear the precise moments during instruction when such links are best made. AIMS: The objective was to test the effectiveness of a 3-week classroom intervention on the fractions knowledge of grade 5/6 students. The instruction was based on a theory that specifies three sites during the learning process where concepts and symbols can be connected (Hiebert, 1984): symbol interpretation, procedural execution, and solution evaluation. Sample. Seventy students from one grade 5/6 split and two grade 6 classrooms in two public elementary schools participated. METHOD: The students were randomly assigned to treatment and control. The treatment (Sites group) received instruction that incorporated specific connections between fractions concepts and procedures at each of the three sites specified by the Sites theory. Before and after the intervention, the students' knowledge of concepts and procedures was assessed, and a random subsample of 30 students from both conditions were individually interviewed to measure their ability to make specific connections between concepts and symbols at each of the three sites. RESULTS: While all students gained procedural skill (p < .001), the students in the Sites condition acquired significantly more knowledge of concepts than the control group (p < .01) and were also better able to connect fractions symbols to conceptual referents (p < .025). CONCLUSIONS: The current study contributes to the literature because it describes when it might be important to link concepts and procedures during fractions instruction. PMID- 23369175 TI - It's never too late for 'us' to meet 'them': prior intergroup friendships moderate the impact of later intergroup friendships in educational settings. AB - BACKGROUND: In this paper, we focused on mixing in educational settings between members of Catholic and Protestant ethnoreligious groups in Northern Ireland. AIMS: In Study 1, we examined whether opportunities for contact at home and at university were associated with greater actual out-group friendships, and whether this friendship was associated with a reduction in prejudice. We also assessed whether the impact of out-group friendships at university was moderated by experience of out-group friendships outside university, such that the prejudice reducing effect of university friendships was stronger for those with fewer friendships at home. In Study 2, we assessed opportunities for contact and actual out-group friendships at prior stages of the educational system and their relationship with prejudice. Sample(s). In both studies, our participants were students at universities in Northern Ireland (Study 1 N= 304 and Study 2 N= 157). METHODS: We analysed the data using multiple regression and structural equation modelling. RESULTS: First, opportunities for contact were positively associated with self-reported out-group friendships in all domains and stages of the educational system. Second, having more out-group friends was associated with reduced prejudice. Finally, the relationship between out-group friendships and current levels of prejudice was moderated by prior levels of out-group friendships (at home in Study 1; and at secondary and primary school in Study 2). CONCLUSIONS: Contact, in the form of out-group friendships, was more powerful when it was a novel feature in a person's life. We discuss these findings in terms of the impact of mixing in educational contexts, especially in Northern Ireland, and outline suggestions for future research. PMID- 23369176 TI - The impact of the development of verbal recoding on children's early writing skills. AB - BACKGROUND: The spontaneous recoding of visual stimuli into a phonological code to aid short-term retention has been associated with progress in learning to read (Palmer, 2000b). AIM: This study examined whether there was a comparable association with the development of writing skills. SAMPLE: One hundred eight children (64 males) in the second year of the UK educational system (mean age 5:8 years, SD = 4 months) were recruited to the study. METHODS: The children participated in tasks to assess their general cognitive abilities, reading skills, and their predominant short-term memory (STM) strategy for retaining visually presented stimuli. On the basis of their memory profile, children were classified as either engaging in verbal recoding of the stimuli (N = 31) or not (N = 77). Writing performance was indexed as alphabet transcription, spelling, and early text production skills. RESULTS: Children classified as verbal recoders demonstrated better spelling performance and produced more individual letters, words, and T-units in their texts than did children who persisted with a visual memory strategy. In contrast, the alphabet transcription abilities of the groups did not differ. Hierarchical regression analyses revealed that variance in text production skills was associated with STM capacity and that moreover, significant independent variance in the number of words and T-units in the children's texts was predicted by individual differences in verbal recoding abilities. CONCLUSION: The results suggest that the development of verbal recoding skills in STM may play a role in children's early progress in writing, particularly their text generation skills. PMID- 23369177 TI - Validation of Assessment for Learning Questionnaires for teachers and students. AB - BACKGROUND: Assessment can be a powerful force in promoting student learning. Still, few measures exist to gauge Assessment for Learning (AFL) in the classroom. Literature on AFL suggests that it encompasses both a monitor to track student progress as well as a scaffold to show or help students recognize in what areas they need to improve. AIMS: Based on a review of recent attempts to measure the AFL, we constructed Assessment for Learning Questionnaires for Teachers (TAFL Q) and for students (SAFL-Q) for evaluating perceptions regarding AFL practices in classrooms using matching items. SAMPLE: The total sample included 1,422 students (49% girls, 51% boys) and 237 teachers (43% females, 57% males) in lower vocational secondary education. METHODS: The 28-item questionnaires were examined by means of confirmatory factor analysis (CFA) using EQS on one random half of the sample. The CFA was cross-validated on the second half. Measurement invariance tests were conducted to compare the students and teacher versions of the questionnaires. RESULTS: CFA revealed a stable second-order two-factor structure that was cross-validated: perceived monitoring, and perceived scaffolding subsumed under a common factor: AFL. Tests for measurement invariance showed that the parallel constructs were measured similarly for both students and teachers. CONCLUSION: The TAFL-Q and SAFL-Q capture the construct AFL in two subscales: Monitoring and Scaffolding, and allows for comparisons between teacher and student perceptions. The instruments can be useful tools for teachers and students alike to identify and scrutinize assessment practices in classroom. PMID- 23369178 TI - Morningness-eveningness and educational outcomes: the lark has an advantage over the owl at high school. AB - BACKGROUND: Chronotype refers to individuals' preference for morning or evening activities. Its two dimensions (morningness and eveningness) are related to a number of academic outcomes. AIMS: The main goal of the study was to investigate the incremental validity of chronotype as a predictor of academic achievement after controlling for a number of traditional predictors. In so doing, a further aim was ongoing validation of a chronotype questionnaire, the Lark-Owl Chronotype Indicator. SAMPLE: The sample comprised 272 students attending 9th and 10th grades at five German high schools. Data was also obtained from 132 parents of these students. METHOD: Students were assessed in class via self-report questionnaires and a standardized cognitive test. Parents filled out a questionnaire at home. The incremental validity of chronotype was investigated using hierarchical linear regression. Validity of the chronotype questionnaire was assessed by correlating student ratings of their chronotype with behavioural data on sleep, food intake, and drug consumption and with parent ratings of chronotype. RESULTS: Eveningness was a significant (negative) predictor of overall grade point average (GPA), math-science GPA, and language GPA, after cognitive ability, conscientiousness, need for cognition, achievement motivation, and gender were held constant. Validity evidence for the chronotype measure was established by significant correlations with parent-ratings and behavioural data. CONCLUSIONS: Results point to the possible discrimination of adolescents with a proclivity towards eveningness at school. Possible explanations for the relationship between chronotype and academic achievement are presented. Implications for educational practice are also discussed. PMID- 23369179 TI - The mediators of minority ethnic underperformance in final medical school examinations. AB - BACKGROUND: UK-trained medical students and doctors from minority ethnic groups underperform academically. It is unclear why this problem exists, which makes it difficult to know how to address it. AIM: To investigate whether demographic and psychological factors mediate the relationship between ethnicity and final examination scores. SAMPLE: Two consecutive cohorts of Year 5 (final year) UCL Medical School students (n= 703; 51% minority ethnic). A total of 587 (83%) had previously completed a questionnaire in Year 3. METHODS: Participants were administered a questionnaire in 2005 and 2006 that included a short version of the NEO-PI-R, the Study Process Questionnaire, and the General Health Questionnaire (GHQ) as well as socio-demographic measures. Participants were then followed up to final year (2007-2010). White and minority ethnic students' questionnaire responses and final examination grades were compared using univariate tests. The effect of ethnicity on final year grades after taking into account the questionnaire variables was calculated using hierarchical multiple linear regression. RESULTS: Univariate ethnic differences were found on age, personality, learning styles, living at home, first language, parental factors, and prior education. Minority ethnic students had lower final exam scores, were more likely to fail, and less likely to achieve a merit or distinction in finals. Multivariate analyses showed ethnicity predicted final exam scores even after taking into account questionnaire factors. CONCLUSIONS: Ethnic differences in the final year performance of two cohorts of UCL medical students were not due to differences in psychological or demographic factors, which suggests alternative explanations are responsible for the ethnic attainment gap in medicine. PMID- 23369180 TI - Task complexity, student perceptions of vocabulary learning in EFL, and task performance. AB - BACKGROUND: The study deepened our understanding of how students' self-efficacy beliefs contribute to the context of teaching English as a foreign language in the framework of cognitive mediational paradigm at a fine-tuned task-specific level. AIM: The aim was to examine the relationship among task complexity, self efficacy beliefs, domain-related prior knowledge, learning strategy use, and task performance as they were applied to English vocabulary learning from reading tasks. SAMPLE: Participants were 120 second-year university students (mean age 21) from a Chinese university. METHOD: This experiment had two conditions (simple/complex). A vocabulary level test was first conducted to measure participants' prior knowledge of English vocabulary. Participants were then randomly assigned to one of the learning tasks. Participants were administered task booklets together with the self-efficacy scales, measures of learning strategy use, and post-tests. Data obtained were submitted to multivariate analysis of variance (MANOVA) and path analysis. RESULTS: Results from the MANOVA model showed a significant effect of vocabulary level on self-efficacy beliefs, learning strategy use, and task performance. Task complexity showed no significant effect; however, an interaction effect between vocabulary level and task complexity emerged. Results from the path analysis showed self-efficacy beliefs had an indirect effect on performance. Our results highlighted the mediating role of self-efficacy beliefs and learning strategy use. CONCLUSIONS: Our findings indicate that students' prior knowledge plays a crucial role on both self-efficacy beliefs and task performance, and the predictive power of self efficacy on task performance may lie in its association with learning strategy use. PMID- 23369182 TI - Multivariate statistical assessment of heavy metal pollution sources of groundwater around a lead and zinc plant. AB - The contamination of groundwater by heavy metal ions around a lead and zinc plant has been studied. As a case study groundwater contamination in Bonab Industrial Estate (Zanjan-Iran) for iron, cobalt, nickel, copper, zinc, cadmium and lead content was investigated using differential pulse polarography (DPP). Although, cobalt, copper and zinc were found correspondingly in 47.8%, 100.0%, and 100.0% of the samples, they did not contain these metals above their maximum contaminant levels (MCLs). Cadmium was detected in 65.2% of the samples and 17.4% of them were polluted by this metal. All samples contained detectable levels of lead and iron with 8.7% and 13.0% of the samples higher than their MCLs. Nickel was also found in 78.3% of the samples, out of which 8.7% were polluted. In general, the results revealed the contamination of groundwater sources in the studied zone. The higher health risks are related to lead, nickel, and cadmium ions. Multivariate statistical techniques were applied for interpreting the experimental data and giving a description for the sources. The data analysis showed correlations and similarities between investigated heavy metals and helps to classify these ion groups. Cluster analysis identified five clusters among the studied heavy metals. Cluster 1 consisted of Pb, Cu, and cluster 3 included Cd, Fe; also each of the elements Zn, Co and Ni was located in groups with single member. The same results were obtained by factor analysis. Statistical investigations revealed that anthropogenic factors and notably lead and zinc plant and pedo-geochemical pollution sources are influencing water quality in the studied area. PMID- 23369181 TI - The skin prick test - European standards. AB - Skin prick testing is an essential test procedure to confirm sensitization in IgE-mediated allergic disease in subjects with rhinoconjunctivitis, asthma, urticaria, anapylaxis, atopic eczema and food and drug allergy. This manuscript reviews the available evidence including Medline and Embase searches, abstracts of international allergy meetings and position papers from the world allergy literature. The recommended method of prick testing includes the appropriate use of specific allergen extracts, positive and negative controls, interpretation of the tests after 15 - 20 minutes of application, with a positive result defined as a wheal >=3 mm diameter. A standard prick test panel for Europe for inhalants is proposed and includes hazel (Corylus avellana), alder (Alnus incana), birch (Betula alba), plane (Platanus vulgaris), cypress (Cupressus sempervirens), grass mix (Poa pratensis, Dactilis glomerata, Lolium perenne, Phleum pratense, Festuca pratensis, Helictotrichon pretense), Olive (Olea europaea), mugwort (Artemisia vulgaris), ragweed (Ambrosia artemisiifolia), Alternaria alternata (tenuis), Cladosporium herbarum, Aspergillus fumigatus, Parietaria, cat, dog, Dermatophagoides pteronyssinus, Dermatophagoides farinae, and cockroach (Blatella germanica). Standardization of the skin test procedures and standard panels for different geographic locations are encouraged worldwide to permit better comparisons for diagnostic, clinical and research purposes. PMID- 23369183 TI - Hormone-sensing cells require Wip1 for paracrine stimulation in normal and premalignant mammary epithelium. AB - INTRODUCTION: The molecular circuitry of different cell types dictates their normal function as well as their response to oncogene activation. For instance, mice lacking the Wip1 phosphatase (also known as PPM1D; protein phosphatase magnesium-dependent 1D) have a delay in HER2/neu (human epidermal growth factor 2), but not Wnt1-induced mammary tumor formation. This suggests a cell type specific reliance on Wip1 for tumorigenesis, because alveolar progenitor cells are the likely target for transformation in the MMTV(mouse mammary tumor virus) neu but not MMTV-wnt1 breast cancer model. METHODS: In this study, we used the Wip1-knockout mouse to identify the cell types that are dependent on Wip1 expression and therefore may be involved in the early stages of HER2/neu-induced tumorigenesis. RESULTS: We found that alveolar development during pregnancy was reduced in Wip1-knockout mice; however, this was not attributable to changes in alveolar cells themselves. Unexpectedly, Wip1 allows steroid hormone-receptor positive cells but not alveolar progenitors to activate STAT5 (signal transducer and activator of transcription 5) in the virgin state. In the absence of Wip1, hormone-receptor-positive cells have significantly reduced transcription of RANKL (receptor activator of nuclear factor kappa-B ligand) and IGF2 (insulin-like growth factor 2), paracrine stimulators of alveolar development. In the MMTV-neu model, HER2/neu activates STAT5 in alveolar progenitor cells independent of Wip1, but HER2/neu does not override the defect in STAT5 activation in Wip1-deficient hormone-sensing cells, and paracrine stimulation remains attenuated. Moreover, ERK (extracellular signal-regulated kinase) activation by HER2/neu in hormone sensing cells is also Wip1 dependent. CONCLUSIONS: We identified Wip1 as a potentiator of prolactin and HER2/neu signaling strictly in the molecular context of hormone-sensing cells. Furthermore, our findings highlight that hormone sensing cells convert not only estrogen and progesterone but also prolactin signals into paracrine instructions for mammary gland development. The instructive role of hormone-sensing cells in premalignant development suggests targeting Wip1 or prolactin signaling as an orthogonal strategy for inhibiting breast cancer development or relapse. PMID- 23369184 TI - Characterization of Myxococcus xanthus MazF and implications for a new point of regulation. AB - During development, Myxococcus xanthus cells undergo programmed cell death (PCD) whereby 80% of vegetative cells die. Previously, the MazF RNA interferase has been implicated in this role. Recently, it was shown that deletion of the mazF gene does not eliminate PCD in wild-type strain DK1622 as originally seen in DZF1. To clarify the role of MazF, recombinant enzyme was characterized using a highly sensitive assay in the presence and absence of the proposed antitoxin MrpC. In contrast to previous reports that MrpC inhibits MazF activity, the hydrolysis rate was enhanced in a concentration-dependent manner with MrpC or MrpC2, an N-terminally truncated form of MrpC. Furthermore, MazF transcripts were not detected until 6-8 h post-induction, suggesting an antitoxin is unnecessary earlier. Potential MazF targets were identified and their transcript levels were shown to decline in DK1622 while remaining steady in a mazF deletion strain. Elimination of the mazF hydrolysis site in the nla6 transcript resulted in overproduction of the mRNA. Thus, MazF negatively regulates specific transcripts. Additionally, we show that discrepancies in the developmental phenotypes caused by removal of mazF in DK1622 and DZF1 are due to the presence of the pilQ1 allele in the latter strain. PMID- 23369185 TI - Naphthalimide derivatives with therapeutic characteristics: a patent review. AB - INTRODUCTION: Naphthalimides are important aromatic heterocycles with immense pharmacological significance as they serve as core scaffold for many antitumor, anti-inflammatory, antidepressant, antiprotozoal and antiviral agents, etc. The tricyclic planar ring system of naphthalimide is primarily responsible for its intercalation with DNA to perturb the cellular events and the substitution pattern of the molecule leads to several other applications. The promising pharmacological activity profile and ease of synthesis have been attractive in design and development of new class of naphthalimides and their conjugates as various potential therapeutic agents. Few of such molecules are currently under preclinical and clinical evaluations. AREAS COVERED: Important patents focusing on naphthalimides as potential class of therapeutics, published between the period of 2006 - 2011 have been covered. The reports are presented together with a review of the related structural chemical space. This review mainly focuses on the therapeutic applications, structural modifications of naphthalimide scaffold, their conjugates and heterocyclics bearing naphthalimide moiety. EXPERT OPINION: The tricyclic planar ring system of naphthalimide restrains important pharmaceutical properties along with excellent fluorescent after proper substitution pattern. Linking these active naphthalimide derivatives with other active pharmacophore has become an interesting area of research. The utility of naphthalimide derivatives as novel pharmaceutical and photochemical agents can be further enhanced by introducing polar side chains and fusing functionalized heterocyclic rings with naphthalimide cores. PMID- 23369186 TI - PDX1-engineered embryonic stem cell-derived insulin producing cells regulate hyperglycemia in diabetic mice. AB - BACKGROUND: Type 1 diabetes can be treated by the transplantation of cadaveric whole pancreata or isolated pancreatic islets. However, this form of treatment is hampered by the chronic shortage of cadaveric donors. Embryonic stem (ES) cell derived insulin producing cells (IPCs) offer a potentially novel source of unlimited cells for transplantation to treat type 1 and possibly type 2 diabetes. However, thus far, the lack of a reliable protocol for efficient differentiation of ES cells into IPCs has hindered the clinical exploitation of these cells. METHODS: To efficiently generate IPCs using ES cells, we have developed a double transgenic ES cell line R1Pdx1AcGFP/RIP-Luc that constitutively expresses pancreatic beta-cell-specific transcription factor pancreatic and duodenal homeobox gene 1 (Pdx1) as well as rat insulin promoter (RIP) driven luciferase reporter. We have established several protocols for the reproducible differentiation of ES cells into IPCs. The differentiation of ES cells into IPCs was monitored by immunostaining as well as real-time quantitative RT-PCR for pancreatic beta-cell-specific markers. Pancreatic beta-cell specific RIP became transcriptionally active following the differentiation of ES cells into IPCs and induced the expression of the luciferase reporter. Glucose stimulated insulin secretion by the ES cell-derived IPCs was measured by ELISA. Further, we have investigated the therapeutic efficacy of ES cell-derived IPCs to correct hyperglycemia in syngeneic streptozotocin (STZ)-treated diabetic mice. The long term fate of the transplanted IPCs co-expressing luciferase in syngeneic STZ induced diabetic mice was monitored by real time noninvasive in vivo bioluminescence imaging (BLI). RESULTS: We have recently demonstrated that spontaneous in vivo differentiation of R1Pdx1AcGFP/RIP-Luc ES cell-derived pancreatic endoderm-like cells (PELCs) into IPCs corrects hyperglycemia in diabetic mice. Here, we investigated whether R1Pdx1AcGFP/RIP-Luc ES cells can be efficiently differentiated in vitro into IPCs. Our new data suggest that R1Pdx1AcGFP/RIP-Luc ES cells efficiently differentiate into glucose responsive IPCs. The ES cell differentiation led to pancreatic lineage commitment and expression of pancreatic beta cell-specific genes, including Pax4, Pax6, Ngn3, Isl1, insulin 1, insulin 2 and PC2/3. Transplantation of the IPCs under the kidney capsule led to sustained long-term correction of hyperglycemia in diabetic mice. Although these newly generated IPCs effectively rescued hyperglycemic mice, an unexpected result was teratoma formation in 1 out of 12 mice. We attribute the development of the teratoma to the presence of either non-differentiated or partially differentiated stem cells. CONCLUSIONS: Our data show the potential of Pdx1-engineered ES cells to enhance pancreatic lineage commitment and to robustly drive the differentiation of ES cells into glucose responsive IPCs. However, there is an unmet need for eliminating the partially differentiated stem cells. PMID- 23369187 TI - Mesenchymal stem cells enhance ovarian cancer cell infiltration through IL6 secretion in an amniochorionic membrane based 3D model. AB - BACKGROUND: The early peritoneal invasion of epithelial ovarian cancer (EOC) by tumoral aggregates presents in ascites is a major concern. The role of the microenvironment seems to be important in this process but the lack of adequate models to study cellular interactions between cancer cells and stromal cells does not allow to uncover the molecular pathways involved. Our goal was to study the interactions between ovarian cancer cells (OCC) and mesenchymal stem cells (MSC) using a 3D model. METHODS: We used millimetric pieces of amniochorionic membrane referred to as amniotic membrane scaffold (AMS) - to create 3D peritoneal nodules mimicking EOC early invasion. We were able to measure the distribution and the depth of infiltration using confocal microsopy. We extracted MSC from the amniochorionic membrane using the markers CD34-, CD45-, CD73+, CD90+, CD105+ and CD29+ at the Fluorescence Activated Cell Sorting (FACS) analysis. We used transwell and wound healing tests to test OCC migration and invasion in vitro. RESULTS: Here we show that OCC tumors were located in regions rich in MSC (70%). The tumors infiltrated deeper within AMS in regions rich in MSC (p<0.001). In vitro tests revealed that higher IL6 secretion in a context of MSC-OCC co-culture could enhance migration and invasion of OCC. After IL6 receptor antagonism, OCC infiltration was significantly decreased, mostly in regions rich in MSCs, indicating that recruitment and tridimensional invasion of OCC was dependent of IL6 secretion. CONCLUSIONS: The use of tridimensional models using AMS could be a useful tool to decipher early molecular events in ovarian cancer metastasis. Cytokine inhibitors interrupting the cross-talk between OCCs and MSCs such as IL6 should be investigated as a new therapeutic approach in ovarian cancer. PMID- 23369188 TI - The current trend of genomics research for human diseases. AB - This is an introduction to the supplement to BMC Medical Genomics that includes 16 papers selected from the 2011 World Congress in Computer Science, Computer Engineering, Applied Computing as well as other sources with a focus on genomics studies with a focus on human diseases. PMID- 23369189 TI - Accelerating read mapping with FastHASH. AB - With the introduction of next-generation sequencing (NGS) technologies, we are facing an exponential increase in the amount of genomic sequence data. The success of all medical and genetic applications of next-generation sequencing critically depends on the existence of computational techniques that can process and analyze the enormous amount of sequence data quickly and accurately. Unfortunately, the current read mapping algorithms have difficulties in coping with the massive amounts of data generated by NGS.We propose a new algorithm, FastHASH, which drastically improves the performance of the seed-and-extend type hash table based read mapping algorithms, while maintaining the high sensitivity and comprehensiveness of such methods. FastHASH is a generic algorithm compatible with all seed-and-extend class read mapping algorithms. It introduces two main techniques, namely Adjacency Filtering, and Cheap K-mer Selection.We implemented FastHASH and merged it into the codebase of the popular read mapping program, mrFAST. Depending on the edit distance cutoffs, we observed up to 19-fold speedup while still maintaining 100% sensitivity and high comprehensiveness. PMID- 23369190 TI - Encephalopathy: a vicious cascade following forebrain ischemia and hypoxia. AB - Post ischemic/hypoxic encephalopathy is a progressive and widespread damage syndrome in human brain, which includes production of new ischemic foci as well as neurodegeneration associated with accumulation of amyloid protein (Abeta), which emerges within days after the primary ischemic or hypoxic ictus. Patients may suddenly suffer severe dementia and Parkinson's syndrome after a symptom-free period averaging 2 weeks following resuscitation. Death of neurons in the cortex, limbic system, globus pallidus (GP) and substantia nigra (SN) and damage to white matter are responsible. From experimental studies in animals evidence is obtained to reveal the mechanisms. Injured endothelia and activated platelets lead to secondary injury via thrombosis and vasoconstriction resulting in infarction and new foci of necrosis. Blood-brain barrier (BBB) breakdown allows penetration of blood-borne toxic substances into brain resulting in neuronal degeneration and enhanced inflammatory destruction. These secondary injuries happen within two weeks after moderate global ischemia. As these pathological changes cycle between the vascular and neuronal compartments, the damage expands and worsens. Abeta, beta amyloid precursor protein (betaAPP) and the inflammation mediator cyclooxygenase-2 (COX2) as well as gamma-aminobutyric acid (GABA) system degeneration participate in producing secondary injury. Thus, implementing multi targeted prophylaxis before or at the brain-at-risk stage is desirable. A combination of protecting endothelia, inhibiting platelet activity and improving cerebral circulation is a fundamental strategy to block this vicious cascade, thereby ameliorating or preventing the encephalopathy. PMID- 23369191 TI - Open questions in biology - a tenth anniversary series. PMID- 23369192 TI - Conserved structure and inferred evolutionary history of long terminal repeats (LTRs). AB - BACKGROUND: Long terminal repeats (LTRs, consisting of U3-R-U5 portions) are important elements of retroviruses and related retrotransposons. They are difficult to analyse due to their variability.The aim was to obtain a more comprehensive view of structure, diversity and phylogeny of LTRs than hitherto possible. RESULTS: Hidden Markov models (HMM) were created for 11 clades of LTRs belonging to Retroviridae (class III retroviruses), animal Metaviridae (Gypsy/Ty3) elements and plant Pseudoviridae (Copia/Ty1) elements, complementing our work with Orthoretrovirus HMMs. The great variation in LTR length of plant Metaviridae and the few divergent animal Pseudoviridae prevented building HMMs from both of these groups.Animal Metaviridae LTRs had the same conserved motifs as retroviral LTRs, confirming that the two groups are closely related. The conserved motifs were the short inverted repeats (SIRs), integrase recognition signals (5'TGTTRNR...YNYAACA 3'); the polyadenylation signal or AATAAA motif; a GT-rich stretch downstream of the polyadenylation signal; and a less conserved AT rich stretch corresponding to the core promoter element, the TATA box. Plant Pseudoviridae LTRs differed slightly in having a conserved TATA-box, TATATA, but no conserved polyadenylation signal, plus a much shorter R region.The sensitivity of the HMMs for detection in genomic sequences was around 50% for most models, at a relatively high specificity, suitable for genome screening.The HMMs yielded consensus sequences, which were aligned by creating an HMM model (a 'Superviterbi' alignment). This yielded a phylogenetic tree that was compared with a Pol-based tree. Both LTR and Pol trees supported monophyly of retroviruses. In both, Pseudoviridae was ancestral to all other LTR retrotransposons. However, the LTR trees showed the chromovirus portion of Metaviridae clustering together with Pseudoviridae, dividing Metaviridae into two portions with distinct phylogeny. CONCLUSION: The HMMs clearly demonstrated a unitary conserved structure of LTRs, supporting that they arose once during evolution. We attempted to follow the evolution of LTRs by tracing their functional foundations, that is, acquisition of RNAse H, a combined promoter/ polyadenylation site, integrase, hairpin priming and the primer binding site (PBS). Available information did not support a simple evolutionary chain of events. PMID- 23369193 TI - Measurements of single molecules in solution and live cells over longer observation times than those currently possible: the meaningful time. AB - Monitoring translational diffusion of single molecules in solution or in a living cell, particularly DNA and proteins brings valuable information unperturbed by interaction with an artificial surface. The article derives theoretical relationships for time intervals during which just one molecule in the effective probe region can be studied, the time we call meaningful time. This time is greater than the transit time of the molecule through the detection volume, as a single molecule will likely reenter the detection volume several times during measurement. From the infinitely stretched molecular Poisson distribution of single molecules or particles, we select the contribution of the selfsame molecule or particle by applying rules for choosing appropriate statistics for the single-molecule trajectories. The results point to a useful and sensitive predictive power of the derived relationships. The meaningful time relationships are the criteria to check the experimental single molecule data measured under conditions of normal and anomalous Brownian diffusion of the molecules of interest. At femtomolar bulk concentration, it would be possible to observe an individual molecule over a second time interval or longer during which biological processes - and not conformational biophysical changes - are just starting. PMID- 23369194 TI - Scoring relevancy of features based on combinatorial analysis of Lasso with application to lymphoma diagnosis. AB - One challenge in applying bioinformatic tools to clinical or biological data is high number of features that might be provided to the learning algorithm without any prior knowledge on which ones should be used. In such applications, the number of features can drastically exceed the number of training instances which is often limited by the number of available samples for the study. The Lasso is one of many regularization methods that have been developed to prevent overfitting and improve prediction performance in high-dimensional settings. In this paper, we propose a novel algorithm for feature selection based on the Lasso and our hypothesis is that defining a scoring scheme that measures the "quality" of each feature can provide a more robust feature selection method. Our approach is to generate several samples from the training data by bootstrapping, determine the best relevance-ordering of the features for each sample, and finally combine these relevance-orderings to select highly relevant features. In addition to the theoretical analysis of our feature scoring scheme, we provided empirical evaluations on six real datasets from different fields to confirm the superiority of our method in exploratory data analysis and prediction performance. For example, we applied FeaLect, our feature scoring algorithm, to a lymphoma dataset, and according to a human expert, our method led to selecting more meaningful features than those commonly used in the clinics. This case study built a basis for discovering interesting new criteria for lymphoma diagnosis. Furthermore, to facilitate the use of our algorithm in other applications, the source code that implements our algorithm was released as FeaLect, a documented R package in CRAN. PMID- 23369195 TI - Organ preservation using a photosynthetic solution. AB - BACKGROUND: Organs harvested from a body lapsing into circulatory deficit are exposed to low O2/high CO2, and reach a critical point where original functionality after transplantation is unlikely. The present study evaluates the effect of respiratory assistance using Chlorella photosynthesis on preservation of the rat pancreas from the viewpoint of donation after cardiac death (DCD). METHODS: Gas was exchanged through the peritoneum of rats under controlled ventilation with or without Chlorella photosynthetic respiratory assistance. A gas permeable pouch containing Chlorella in solution was placed in the peritoneum and then the space between the pouch and the peritoneum was filled with an emulsified perfluorocarbon gas carrier. Rat DCD pancreases procured 3 h after cardiac arrest were preserved for 30 min in a cold or mildly hypothermic environment or in a mildly hypothermic environment with photosynthetic respiratory support. The pancreases were then heterotopically transplanted into rats with STZ-induced diabetes. RESULTS: Levels of blood oxygen (PaO2) and carbon dioxide (PaCO2) increased and significantly decreased, respectively, in rats with mechanically reduced ventilation and rats given intraperitoneal photosynthetic respiratory support when compared with those without such support. Transplantation with DCD pancreases that had been stored under photosynthetic respiratory support resulted in the survival of all rats, which is impossible to achieve using pancreases that have been maintained statically in cold storage. CONCLUSION: Respiratory assistance using photosynthesis helps to improve not only blood gas status in the event of respiratory insufficiency, but also graft recovery after pancreas transplantation with a DCD pancreas that has been damaged by prolonged warm ischemia. PMID- 23369196 TI - Relationship between serum osteocalcin levels and non-alcoholic fatty liver disease in Chinese men. AB - The present study was designed to investigate the relationship between serum osteocalcin levels and non-alcoholic fatty liver disease (NAFLD) in Chinese men. In all, 1558 men (21-78 years old) were recruited to the study. Serum osteocalcin, glucose and lipid profiles were determined. Demographic and clinical characteristics were recorded. All participants underwent hepatic ultrasonographic examination. Serum osteocalcin levels were significantly lower in subjects with NAFLD than those without (P < 0.01). All study subjects were divided into four subgroups according to quartiles of serum osteocalcin levels. The frequency of NAFLD increased progressively with declining serum osteocalcin levels (P(trend) < 0.01). Serum osteocalcin levels were inversely correlated with NAFLD (P < 0.01). However, the significant association between serum osteocalcin levels and NAFLD disappeared in logistic regression analyses. Furthermore, multiple stepwise regression analysis showed that serum osteocalcin levels were independently associated with serum alanine aminotransferase levels in Chinese men (P < 0.01). The findings of the present study suggest that serum osteocalcin levels are not directly correlated with NAFLD. PMID- 23369197 TI - Phenology of Spondias tuberosa Arruda (Anacardiaceae) under different landscape management regimes and a proposal for a rapid phenological diagnosis using local knowledge. AB - BACKGROUND: Studies aimed at investigating the influence of habitat change on species phenology. Studies that investigate people's perceptions of the phenology of certain species still area few; yet this approach is important for effective decision-making for conservation. The aim of this study was to investigate the phenology of Spondias tuberosa Arruda (Anacardiaceae), a native species of economic and ecological importance in northeastern Brazil, in five landscape units (LUs) (Mountain, Mountain Base, Pasture, Cultivated Areas and Homegardens) of a Caatinga region in Altinho, Pernambuco, northeastern Brazil. These data could then be compared with local people's perceptions of the species' phenophases. METHOD: Collection of phenological data was carried out monthly from February 2007 to January 2009 and included activity, intensity and synchronization of reproductive and vegetative phenophases. Ethnobotanical data were gathered using a collaborative approach to access local people's knowledge about the species' phenological schedule. RESULTS: There were no significant differences in the intensity of phenophases among LUs, and there was a correspondence between people's perception of phenophases and the phenological data collected. The data show that the different management practices for LUs did not influence the phenology of the species. CONCLUSION: The main conclusion of this study is the use of traditional knowledge as interesting tool for rapid phenological diagnosis. However further studies need to be developed to test this tool in other environments and cultural contexts. PMID- 23369198 TI - Development and promotion in translational medicine: perspectives from 2012 sino american symposium on clinical and translational medicine. AB - BACKGROUND: Clinical translational medicine (CTM) is an emerging area comprising multidisciplinary research from basic science to medical applications and entails a close collaboration among hospital, academia and industry. FINDINGS: This Session focused discussing on new models for project development and promotion in translational medicine. The conference stimulated the scientific and commercial communication of project development between academies and companies, shared the advanced knowledge and expertise of clinical applications, and created the environment for collaborations. CONCLUSIONS: Although strategic collaborations between corporate and academic institutions have resulted in a state of resurgence in the market, new cooperation models still need time to tell whether they will improve the translational medicine process. PMID- 23369199 TI - Selenium status in soil, water and essential crops of Iran. AB - As a contributing factor to health, the trace element selenium (Se) is an essential nutrient of special interest for humans and all animals. It is estimated that 0.5 to 1 billion people worldwide suffer from Se deficiency. In spite of the important role of Se, its concentrations in soil, water and essential crops have not been studied in Iran. Therefore, the main aim of the current study was to determine the Se content of soil, water, and essential crops (rice in North, wheat in Center, date, and pistachio in South) of different regions of Iran. Sampling was performed in the North, South, and Central regions of Iran. In each selected area in the three regions, 17 samples of surface soil were collected; samples of water and essential crops were also collected at the same sampling points. Upon preliminary preparation of all samples, the Se concentrations were measured by ICP-OES Model Varian Vista-MPX. The amount of soil-Se was found to be in the range between 0.04 and 0.45 ppm in the studied areas; the Se content of soil in the central region of Iran was the highest compared to other regions (p<0.0001). The average Se concentration in irrigation water of different areas was less than 0.01 mg/L, and the mean concentrations of Se in the rice, wheat, date, and pistachio samples were 0.95, 0.74, 0.46, and 0.40 ppm, respectively. Although Se-soil and water-Se level in different regions were low, the typical levels of Se in the essential crops were relatively high. PMID- 23369200 TI - Genome-wide prediction and analysis of human tissue-selective genes using microarray expression data. AB - BACKGROUND: Understanding how genes are expressed specifically in particular tissues is a fundamental question in developmental biology. Many tissue-specific genes are involved in the pathogenesis of complex human diseases. However, experimental identification of tissue-specific genes is time consuming and difficult. The accurate predictions of tissue-specific gene targets could provide useful information for biomarker development and drug target identification. RESULTS: In this study, we have developed a machine learning approach for predicting the human tissue-specific genes using microarray expression data. The lists of known tissue-specific genes for different tissues were collected from UniProt database, and the expression data retrieved from the previously compiled dataset according to the lists were used for input vector encoding. Random Forests (RFs) and Support Vector Machines (SVMs) were used to construct accurate classifiers. The RF classifiers were found to outperform SVM models for tissue specific gene prediction. The results suggest that the candidate genes for brain or liver specific expression can provide valuable information for further experimental studies. Our approach was also applied for identifying tissue selective gene targets for different types of tissues. CONCLUSIONS: A machine learning approach has been developed for accurately identifying the candidate genes for tissue specific/selective expression. The approach provides an efficient way to select some interesting genes for developing new biomedical markers and improve our knowledge of tissue-specific expression. PMID- 23369201 TI - Quality of life after adult living donor liver transplantation: A longitudinal prospective follow-up study. AB - AIM: Patient survival after living donor liver transplantation (LDLT) has improved, but improvement of the health-related quality of life (HRQOL) of LDLT recipients is also an important issue. The aim of this study was to assess the HRQOL of LDLT recipients from the preoperative period to 18 months following transplantation by prospectively evaluating Short Form-36 Version 2 (SF-36v2) scores. METHODS: Complete longitudinal SF-36v2 scores were collected from 35 consecutive LDLT recipients prior to surgery and at 3, 6, 12 and 18 months after transplantation. RESULTS: HRQOL scores were severely impaired in all dimensions preoperatively. Although the scores improved significantly up to 18 months after transplantation, they remained lower than those of healthy controls in the majority of domains. Impaired scores preoperatively were significantly associated with severity of liver disease represented by a higher Model for End-Stage Liver Disease (MELD) score and Child-Turcotte-Pugh class C, and scores in such patients improved significantly after LDLT in every dimension at 12 months, indicating that the greater the impairment at the pretransplant stage, the greater the improvement in both physical and mental conditions. Preoperative lower HRQOL scores and higher MELD scores were independently associated with significant physical and mental score gains during the first year after LDLT. CONCLUSION: The findings of the present study may facilitate the development of measures aimed at improving recipient's post-transplant life and establishing realistic expectations for LDLT recipients. PMID- 23369202 TI - Open questions - in brief: beyond -omics, missing motor proteins, and getting from molecules to organisms. PMID- 23369203 TI - An interesting application of lung ultrasonography. AB - In the previous issue of Critical Care, Raimondi and colleagues investigate whether lung ultrasonography has utility for the assessment of respiratory distress in the neonate. This commentary reviews the results and implications of their study. PMID- 23369204 TI - Municipal solid waste landfill leachate treatment by fenton, photo-fenton and fenton-like processes: Effect of some variables. AB - Advanced oxidation processes like Fenton and photo-Fenton have been effectively applied to oxidize the persistent organic compounds in solid waste leachate and convert them to unharmful materials and products. However, there are limited data about application of Fenton-like process in leachate treatment. Therefore, this study was designed with the objective of treating municipal landfill leachate by Fenton, Fenton-like and photo-Fenton processes to determine the effect of different variables, by setting up a pilot system. The used leachate was collected from a municipal unsanitary landfill in Qaem-Shahr in the north of Iran. Fenton and Fenton-like processes were conducted by Jar-test method. Photo Fenton process was performed in a glass photo-reactor. In all processes, H2O2 was used as the oxidant. FeSO4.7H2O and FeCl3.6H2O were used as reagents. All parameters were measured based on standard methods. The results showed that the optimum concentration of H2O2 was equal to 5 g/L for the Fenton-like process and 3 g/L for the Fenton and photo-Fenton processes. The optimum ratio of H2O2: Fe+2/Fe+3 were equal to 8:1 in all processes. At optimum conditions, the amount of COD removal was 69.6%, 65.9% and 83.2% in Fenton, Fenton-like and photo-Fenton processes, respectively. In addition, optimum pH were 3, 5 and 3 and the optimum contact time were 150, 90 and 120 minutes, for Fenton, Fenton-like and photo Fenton processes, respectively. After all processes, the biodegradability (BOD5/COD ratio) of the treated leachate was increased compared to that of the raw leachate and the highest increase in BOD5/COD ratio was observed in the photo Fenton process. The efficiency of the Fenton-like process was overally less than Fenton and photo-Fenton processes, meanwhile the Fenton-like process was at higher pH and did not show problems. PMID- 23369205 TI - Referrals to chiropractors and osteopaths: a survey of general practitioners in rural and regional New South Wales, Australia. AB - BACKGROUND: Chiropractic and osteopathy form a significant part of the healthcare setting in rural and regional Australia, with national registration of practitioners, public subsidies for services and high utilisation by the Australian public. However, despite their significant role in rural and regional Australia, there has been little exploration of the interface between chiropractic and osteopathy and conventional primary health care practitioners in this area. The study aim was to examine the referral practices and factors that underlie referral to chiropractors and osteopaths by rural and regional Australian general practitioners (GPs), by drawing on a sample of GPs in rural and regional New South Wales. METHODS: A 27-item questionnaire was sent to all 1486 GPs currently practising in rural and regional Divisions of General Practice in New South Wales, Australia. RESULTS: A total of 585 GPs responded to the questionnaire, with 49 questionnaires returned as "no longer at this address" (response rate: 40.7%). The majority of GPs (64.1%) referred to a chiropractor or osteopath at least a few times per year while 21.7% stated that they would not refer to a chiropractor or osteopath under any circumstances. Patients asking the GP about CAM (OR=3.59; CI: 1.12, 11.55), GP's use of CAM practitioners as a major source of information (OR=4.39; 95% CI: 2.04, 9.41), lack of other treatment options (OR=2.41; 95% CI: 1.18, 5.12), access to a wide variety of medical specialists (OR=12.5; 95% CI: 2.4, 50.0), GP's belief in the efficacy of chiropractic and osteopathy services (OR=3.39; 95% CI: 2.19, 5.25) and experiencing positive results from patients using these services previously (OR=1.67; CI: 1.02, 2.75) were all independently predictive of increased referral to chiropractic and osteopathy services amongst the rural GPs. CONCLUSIONS: There is a significant interface between chiropractic and osteopathy and Australian rural and regional general practice in New South Wales. Although there is generally high support for chiropractic and osteopathy among Australian GPs, this was not absolute and the heterogeneity of responses suggests that there remain tensions between the professions. The significant interface between chiropractic and osteopathy may be due in part to the inclusion of these professions in the publicly subsidised national healthcare delivery scheme. The significant impact of chiropractic and osteopathy and general practice in rural and regional Australian healthcare delivery should serve as an impetus for increased research into chiropractic and osteopathy practice, policy and regulation in these areas. PMID- 23369206 TI - Recent progress and challenges in the discovery of new neuraminidase inhibitors. AB - INTRODUCTION: At present, the key public health concern is to define the way in which the next influenza pandemic should be controlled. While influenza vaccines are available, their effectiveness could be significantly reduced if new strains differ significantly from those of the vaccines. Therefore, antiviral drugs play an important role in the prevention and management of influenza. The influenza neuraminidase (NA), a surface-glycoprotein enzyme involved in releasing the virus from the host cell, has been considered as an essential therapeutic target for treatment and prophylaxis of influenza infection. It is a highly conserved feature of the active site across all influenza A and B viruses and is of particular interest because compounds NA inhibitors (NAIs) can be cross-reactive against multiple types and subtypes of influenza. Currently, there are two NAI drugs which are licensed worldwide: oseltamivir and zanamivir, and two more drugs which have received recent approval in Japan: peramivir and laninamivir. Sudden changes in NAI susceptibility have stressed the urgent need in searching for novel inhibitors. AREAS COVERED: In this review, a potential pitfall in NA-based assays and the progress in the chemical synthesis of all patented NAIs from February 2006 to July 2012 are discussed. EXPERT OPINION: Both NA enzyme inhibition and X-ray crystallography data have suggested that the strategy of designing NAIs binding to the highly conserved region of NA can lead to inhibitors that are effective against all influenza NA subtypes. A number of new synthetic entries having unique structural frameworks that were designed based on computational study of X-ray structures of NA. They strongly exhibited the activity of NA in the low nanomolar range such as phosphonate congeners of zanamivir and oseltarmivir. Screening strategies based on the chemical diversity of natural products have revealed that flavonoids are the most prominent scaffolds possessing NA inhibitory activity. However, these substituted phenyl benzopyrane compounds have been reported to exert a considerable quenching effect, causing false-positive results in the commonly used method of enzyme based NA inhibition assays, and thus, reliability of the flavonoid-based NAIs reported in the literature. PMID- 23369207 TI - Anaemia and iron deficiency between 2003 and 2007 in Amazonian children under 2 years of age: trends and associated factors. AB - OBJECTIVE: To describe trends in the prevalence of anaemia and Fe deficiency in children under 2 years of age living in a town in western Brazilian Amazonia. DESIGN: Temporal analysis of two cross-sectional population-based surveys. Information on socio-economic status, morbidity and breast-feeding was obtained using a structured questionnaire. Child weight and length were measured for anthropometric evaluation. Concentrations of blood Hb, plasma ferritin and soluble transferrin receptor were measured. SETTING: The town of Acrelandia, state of Acre, north-west Brazil. SUBJECTS: A total of 170 and 224 participants of the 2003 and 2007 surveys, respectively. RESULTS: Comparison between the 2003 and 2007 surveys revealed no statistically significant differences in the prevalence of anaemia (48 (95% CI 39, 56)% to 40 (95% CI 33, 47)%) or Fe deficiency anaemia (39 (95% CI 30, 48)% to 37 (95% CI 30, 45)%), respectively. However, an increase in the overall prevalence of Fe deficiency from 62 (95% CI 51, 68)% to 81 (95% CI 75, 86)% was observed (chi2 test, P<=0.001). In age- and sex-adjusted analyses for risk of Fe deficiency, only early introduction of cow's milk (<90 d) was associated with Fe deficiency in 2003 (prevalence ratio (PR)=0.76; 95% CI 0.57, 1.01), while caesarean section (PR=1.18; 95% CI 1.03, 1.35) and birth weight <3500 g (PR=1.15; 95% CI 1.00, 1.34) were associated with Fe deficiency in 2007. CONCLUSIONS: No improvements were observed in the prevalence of anaemia, exposing a worrying scenario for public health, while a significant increase was found in the prevalence of Fe deficiency in the studied infants and toddlers. PMID- 23369208 TI - Chronic condition management and self-management in Aboriginal communities in South Australia: outcomes of a longitudinal study. AB - OBJECTIVES: This paper describes the longitudinal component of a larger mixed methods study into the processes and outcomes of chronic condition management and self-management strategies implemented in three Aboriginal communities in South Australia. The study was designed to document the connection between the application of structured systems of care for Aboriginal people and their longer term health status. METHODS: The study concentrated on three diverse Aboriginal communities in South Australia; the Port Lincoln Aboriginal Health Service, the Riverland community, and Nunkuwarrin Yunti Aboriginal Health Service in the Adelaide metropolitan area. Repeated-measure clinical data were collected for individual participants using a range of clinical indicators for diabetes (type 1 and 2) and related chronic conditions. Clinical data were analysed using random effects modelling techniques with changes in key clinical indicators being modelled at both the individual and group levels. RESULTS: Where care planning has been in place longer than in other sites overall improvements were noted in BMI, cholesterol (high density and low density lipids) and HbA1c. These results indicate that for Aboriginal patients with complex chronic conditions, participation in and adherence to structured care planning and self-management strategies can contribute to improved overall health status and health outcomes. CONCLUSIONS: The outcomes reported here represent an initial and important step in quantifying the health benefits that can accrue for Aboriginal people living with complex chronic conditions such as diabetes, heart disease and respiratory disease. The study highlights the benefits of developing long-term working relationships with Aboriginal communities as a basis for conducting effective collaborative health research programs. WHAT IS KNOWN ABOUT THE TOPIC? Chronic condition management and self-management programs have been available to Aboriginal people in a range of forms for some time. We know that some groups of patients are keen to engage with care planning and self-management protocols and we have anecdotal evidence of this engagement leading to improved quality of life and health outcomes for Aboriginal people. WHAT DOES THIS PAPER ADD? This paper provides early evidence of sustained improvement over time for a cohort of Aboriginal people who are learning to deal with a range of chronic illnesses through accessing structured systems of support and care. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? This longitudinal evidence of improved outcomes for Aboriginal people is encouraging and should lead on to more definitive studies of outcomes accruing for people engaged in structured systems of care. Not only does this finding have implications for the overall management of chronic illness in Aboriginal communities, but it points the way to how health services might best invest their resources and efforts to improve the health status of people with chronic conditions and, in the process, close the gap between the life expectancy of Aboriginal people and that of other community groups in Australia. PMID- 23369210 TI - Thrombolytics decrease mortality in elderly patients with unstable pulmonary embolism. PMID- 23369209 TI - Correlations between cytoplasmic CSE1L in neoplastic colorectal glands and depth of tumor penetration and cancer stage. AB - BACKGROUND: Colorectal carcinomas spread easily to nearby tissues around the colon or rectum, and display strong potential for invasion and metastasis. CSE1L, the chromosome segregation 1-like protein, is implicated in cancer progression and is located in both the cytoplasm and nuclei of tumor cells. We investigated the prognostic significance of cytoplasmic vs. nuclear CSE1L expression in colorectal cancer. METHODS: The invasion- and metastasis-stimulating activities of CSE1L were studied by in vitro invasion and animal experiments. CSE1L expression in colorectal cancer was assayed by immunohistochemistry, with tissue microarray consisting of 128 surgically resected specimens; and scored using a semiquantitative method. The correlations between CSE1L expression and clinicopathological parameters were analyzed. RESULTS: CSE1L overexpression was associated with increased invasiveness and metastasis of cancer cells. Non neoplastic colorectal glands showed minimal CSE1L staining, whereas most colorectal carcinomas (99.2%, 127/128) were significantly positive for CSE1L staining. Cytoplasmic CSE1L was associated with cancer stage (P=0.003) and depth of tumor penetration (P=0.007). Cytoplasmic CSE1L expression also correlated with lymph node metastasis of the disease in Cox regression analysis CONCLUSIONS: CSE1L regulates the invasiveness and metastasis of cancer cells, and immunohistochemical analysis of cytoplasmic CSE1L in colorectal tumors may provide a useful aid to prognosis. PMID- 23369211 TI - Varicella zoster with extended prodrome: a case series. AB - BACKGROUND: Traditionally, varicella zoster (herpes zoster) is believed to have a prodrome of 1-3 days. The objective of our article is to emphasize the importance of including herpes zoster in the differential diagnosis of unilateral pain syndromes without vesicular lesions present for >3 days. METHODS/RESULTS: We report a case series from one primary care physician's practice at a tertiary care teaching hospital documenting herpes zoster prodromes of 6-18 days. CONCLUSIONS: Our findings expand the clinical picture of herpes zoster, which hopefully will lead to cases of improved diagnoses that translate into the timely and cost-effective implementation of appropriate treatment. PMID- 23369212 TI - New oral anticoagulants in elderly patients with atrial fibrillation. AB - The prevalence of atrial fibrillation increases with age, augmenting the risk of embolic stroke in elderly individuals. Clinical practice guidelines recommend the long-term use of oral anticoagulation in elderly patients with atrial fibrillation to reduce risk of stroke. Until recently, vitamin K antagonists (eg, warfarin) were the only oral anticoagulants available, but using warfarin in elderly patients can be challenging. Newer oral anticoagulants may offer specific benefits and increased convenience for elderly patients, because they have predictable pharmacologic profiles, a rapid onset of action, a wide therapeutic window, no requirement for routine coagulation monitoring, and fewer and better defined food and drug interactions compared with warfarin. This review highlights the benefits and challenges of warfarin use in elderly patients with atrial fibrillation and discusses potential efficacy and safety benefits for newer oral agents in these patients. The potential for increased rates of major bleeding in the elderly, particularly those with numerous concomitant medications or renal impairment, also is discussed. Practical considerations for the use of long-term anticoagulation in elderly patients also are discussed. PMID- 23369213 TI - Great Ormond Street Hospital treatment guidelines for use of propranolol in infantile isolated subglottic haemangioma. AB - OBJECTIVE: Treatment options for large subglottic haemangioma include steroids, laser ablation, open excision, tracheostomy and, more recently, propranolol. This article aims to present the Great Ormond Street Hospital guidelines for using propranolol to treat infantile isolated subglottic haemangioma by ENT surgeons. METHODS: The vascular malformations multidisciplinary team at Great Ormond Street Hospital has developed guidelines for treating infantile haemangioma with propranolol. RESULTS: The Great Ormond Street Hospital guidelines for propranolol treatment for infantile subglottic haemangioma include investigation, treatment and follow up. Propranolol is started at 1 mg/kg/day divided into three doses, increasing to 2 mg/kg/day one week later. On starting propranolol and when increasing the dose, the pulse rate and blood pressure must be checked every 30 minutes for the first 2 hours. Lesion response to treatment is assessed via serial endoscopy. CONCLUSION: Recent reports of dramatic responses to oral propranolol in children with haemangioma and acute airway obstruction have led to increased use. We advocate caution, and have developed guidelines (including pre treatment investigation and monitoring) to improve treatment safety. Propranolol may in time prove to be the best medical treatment for subglottic haemangioma, but at present is considered to be still under evaluation. PMID- 23369214 TI - Fully embeddable chitosan microneedles as a sustained release depot for intradermal vaccination. AB - This study introduces a microneedle transdermal delivery system, composed of embeddable chitosan microneedles and a poly(L-lactide-co-D,L-lactide) (PLA) supporting array, for complete and sustained delivery of encapsulated antigens to the skin. Chitosan microneedles were mounted to the top of a strong PLA supporting array, providing mechanical strength to fully insert the microneedles into the skin. When inserted into rat skin in vivo, chitosan microneedles successfully separated from the supporting array and were left within the skin for sustained drug delivery without requiring a transdermal patch. The microneedle penetration depth was approximately 600 MUm (i.e. the total length of the microneedle), which is beneficial for targeted delivery of antigens to antigen-presenting cells in the epidermis and dermis. To evaluate the utility of chitosan microneedles for intradermal vaccination, ovalbumin (OVA; MW = 44.3 kDa) was used as a model antigen. When the OVA-loaded microneedles were embedded in rat skin in vivo, histological examination showed that the microneedles gradually degraded and prolonged OVA exposure at the insertion sites for up to 14 days. Compared to traditional intramuscular immunization, rats immunized by a single microneedle dose of OVA showed a significantly higher OVA-specific antibody response which lasted for at least 6 weeks. These results suggest that embeddable chitosan microneedles are a promising depot for extended delivery of encapsulated antigens to provide sustained immune stimulation and improve immunogenicity. PMID- 23369215 TI - Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of cancer cell internalization in vivo. AB - The cell membrane is a critical barrier to effective delivery for many therapeutics, including those which are nanoparticle-based. Improving nanoparticle transport across the cell membrane remains a fundamental challenge. Cancer cells preferentially internalized pegylated calcium phosphate nanoparticles over normal epithelial cells. Furthermore, non-cytotoxic levels of doxorubicin markedly amplified this difference by increasing free unbound caveolin-1 and resulted in enhanced caveolin-mediated nanoparticle endocytosis in cancer cells. Engineered pegylated siRNA-loaded triple-shell calcium phosphate nanoconstructs incorporating ultra-low levels of doxorubicin recapitulated these effects and delivered increased numbers of siRNA into cancer cells with target specific results. Systemic administration of nanoparticles in vivo demonstrated highly preferential entry into tumors, little bystander organ biodistribution, and significant tumor growth arrest. In conclusion, siRNA-loaded calcium phosphate nanoparticles incorporating non-cytotoxic amounts of doxorubicin markedly enhances nanoparticle internalization and results in increased payload delivery with concomitant on-target effects. PMID- 23369216 TI - A small molecule approach to engineering vascularized tissue. AB - The repertoire of growth factors determines the biological engagement of human mesenchymal stromal cells (hMSCs) in processes such as immunomodulation and tissue repair. Hypoxia is a strong modulator of the secretome and well known stimuli to increase the secretion of pro-angiogenic molecules. In this manuscript, we employed a high throughput screening assay on an hMSCs cell line in order to identify small molecules that mimic hypoxia. Importantly, we show that the effect of these small molecules was cell type/species dependent, but we identified phenanthroline as a robust hit in several cell types. We show that phenanthroline induces high expression of hypoxia-target genes in hMSCs when compared with desferoxamine (DFO) (a known hypoxia mimic) and hypoxia incubator (2% O(2)). Interestingly, our microarray and proteomics analysis show that only phenanthroline induced high expression and secretion of another angiogenic cytokine, interleukin-8, suggesting that the mechanism of phenanthroline-induced hypoxia is distinct from DFO and hypoxia and involves the activation of other signaling pathways. We showed that phenanthroline alone was sufficient to induce blood vessel formation in a Matrigel plug assay in vivo paving the way to its application in ischeamic-related diseases. PMID- 23369217 TI - Size-controllable networked neurospheres as a 3D neuronal tissue model for Alzheimer's disease studies. AB - Intensive in vitro studies on the neurotoxicity of amyloid beta have been conducted for decades; however, a three-dimensional neuronal tissue model for Alzheimer's disease has not yet been achieved. In this study, we developed size controllable networked neurospheres comprised of cerebral cortical neuronal cells that mimics the cytoarchitecture of the cortical region of the brain. The toxicity of amyloid beta on the neurosphere model was assessed quantitatively and qualitatively. Decreased cell viability after amyloid beta exposure was demonstrated using MTT and live/dead assays. Neurite degeneration after amyloid beta exposure was evident in both SEM and fluorescence images. Ultrastructural features of apoptotic neurons were analyzed and quantitative analysis of synapsin II concentration and an acetylcholine assay were also performed. The three dimensional neurospheres, produced using a concave microwell array, are a potential in vitro model for Alzheimer's disease studies. PMID- 23369218 TI - Targeting mesoporous silica-encapsulated gold nanorods for chemo-photothermal therapy with near-infrared radiation. AB - Mesoporous silica-encapsulated gold nanorods (GNRs@mSiO(2)) have great potential both in photothermal therapy and drug delivery. In this paper, we firstly developed GNRs@mSiO(2) as a synergistic therapy tool for delivery heat and drug to the tumorigenic region. We studied the ablation of tumor both in vitro and in vivo by the combination of photothermal therapy and chemotherapy using doxorubicin (DOX)-loaded GNRs@mSiO(2). Significantly greater cell killing was observed when A549 cells incubated with DOX-loaded GNRs@mSiO(2) were irradiated with near-infrared (NIR) illumination, attributable to both GNRs@mSiO(2)-mediated photothermal ablation and cytotoxicity of light-triggered DOX release. We then performed in vivo therapy studies and observed a promising tumor treatment. Compared with chemotherapy or photothermal treatment alone, the combined treatment showed a synergistic effect, resulting in higher therapeutic efficacy. Furthermore, the lower systematic toxicity of GNRs@mSiO(2) has been validated. PMID- 23369219 TI - Bifunctional bisphosphonates for delivering PTH (1-34) to bone mineral with enhanced bioactivity. AB - The objective of this work was to demonstrate the bioactivity of parathyroid hormone (1-34) (PTH) delivered through a single molecule of bisphosphonate to improve tissue/cell interactions. Bifunctional hydrazine-bisphosphonates (HBPs) with varying length and lipophilicity were used as a drug delivery vehicle. PTH was oxidized with periodate treatment to obtain an N-terminal aldehyde that was then conjugated to HBPs. The toxicity and apoptotic properties of HBPs and HBP PTH conjugates were studied with macrophages (RAW 264.7). It was found that one of the HBPs had significant apoptotic characteristics similar to alendronate, which is a widely prescribed drug in the treatment of osteoporosis. The improved binding affinity of PTH following conjugation to HBP was determined using a hydroxyapatite binding assay. The amount of PTH delivered to bone through HBPs was not affected by the length or lipophilicity of the HBPs. Furthermore, the improved bioactivity of PTH delivered to bone through HBPs, in comparison to adsorbed PTH, was demonstrated by quantifying the cAMP produced by pre osteoblastic (MC3T3-E1) cells in response to PTH. The delivery of bioactive PTH to bone tissue by HBP conjugation demonstrates the potential use of HBPs in delivering therapeutic macromolecules to bone for the treatment of several skeletal diseases. PMID- 23369220 TI - Network insights on oxaliplatin anti-cancer mechanisms. AB - Oxaliplatin has been a crucial component of combination therapies since admission into the clinic causing modest gains in survival across multiple malignancies. However, oxaliplatin functions in a non-targeted manner, posing a difficulty in ascertaining precise efficacy mechanisms. While previously thought to only affect DNA repair mechanisms, Platinum-protein adducts (Pt-Protein) far outnumber Pt-DNA adducts leaving a big part of oxaliplatin function unknown. Through preliminary network modeling of high throughput data, this article critically reviews the efficacy of oxaliplatin as well as proposes a better model for enhanced efficacy based on a network approach. In our study, not only oxaliplatin's function in interrupting DNA-replication was confirmed, but also its role in initiating or intensifying tumorigenesis pathways was uncovered. From our data we present a novel picture of competing signaling networks that collectively provide a plausible explanation of chemotherapeutic resistance, cancer stem cell survival, as well as invasiveness and metastases. Here we highlight oxaliplatin signaling networks, their significance and the clinical implications of these interactions that verifies the importance of network modeling in rational drug design. PMID- 23369221 TI - Multi-institutional comparison of volumetric modulated arc therapy vs. intensity modulated radiation therapy for head-and-neck cancer: a planning study. AB - BACKGROUND: Compared to static beam Intensity-Modulated Radiation Therapy (IMRT), the main advantage of Volumetric Modulated Arc Therapy (VMAT) is a shortened delivery time, which leads to improved patient comfort and possibly smaller intra fraction movements. This study aims at a treatment planner-independent comparison of radiotherapy treatment planning of IMRT and VMAT for head-and-neck cancer performed by several institutes and based on the same CT- and contouring data. METHODS: Five institutes generated IMRT and VMAT plans for five oropharyngeal cancer patients using either Pinnacle3 or Oncentra Masterplan to be delivered on Elekta linear accelerators. RESULTS: Comparison of VMAT and IMRT plans within the same patient and institute showed significantly better sparing for almost all OARs with VMAT. The average mean dose to the parotid glands and oral cavity was reduced from 27.2 Gy and 39.4 Gy for IMRT to 25.0 Gy and 36.7 Gy for VMAT, respectively. The dose conformity at 95% of the prescribed dose for PTVboost and PTVtotal was 1.45 and 1.62 for IMRT and 1.37 and 1.50 for VMAT, respectively. The average effective delivery time was reduced from 13:15 min for IMRT to 5:54 min for VMAT. CONCLUSIONS: Independently of institution-specific optimization strategies, the quality of the VMAT plans including double arcs was superior to step-and-shoot IMRT plans including 5-9 beam ports, while the effective treatment delivery time was shortened by ~50% with VMAT. PMID- 23369222 TI - Renal replacement therapy: is it effective in critically ill patients with acute kidney injury? PMID- 23369224 TI - Phospho-specific flow cytometry for pharmacodynamic monitoring of immunosuppressive therapy in transplantation. AB - Organ transplant recipients frequently suffer from toxicity or from lack of efficacy of immunosuppressive drugs, which can be attributed to individual variations in drug sensitivity. This problem can be resolved by applying pharmacodynamic monitoring that focuses on measuring the biological effects of drugs. Here we discuss the new technique called phospho-specific flow cytometry to monitor the activity of intracellular immune signaling pathways at the single cell level in whole blood samples. Through this tool the efficacy of immunosuppressive medication can be assessed, novel targets can be identified, and differences in drug sensitivity between cells and patients can be clarified. PMID- 23369223 TI - Pharmacokinetic and pharmacodynamic analysis of 5-aza-2'-deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy. AB - 5-Aza-2'-deoxycytidine (5-AZA-CdR, decitabine), an epigenetic drug that inhibits DNA methylation, is currently used to treat myelodysplastic syndrome (MDS), and is under investigation for treating acute myeloid leukemia (AML) and other malignancies. 5-AZA-CdR can reactivate tumor suppressor genes silenced by aberrant DNA methylation, a frequent event in all types of cancer. Because this epigenetic change is reversible, it is a good target for 5-AZA-CdR therapy. We have reviewed the preclinical data of 5-AZA-CdR to analyze the concentrations and exposure times required to eradicate cancer stem cells. We analyzed the dose schedules used in animal models that show potent antineoplastic activity of 5-AZA CdR. We attempted to correlate the preclinical data with the responses obtained in clinical trials of 5-AZA-CdR in patients with cancer. The pharmacokinetics and drug distribution of 5-AZA-CdR are key parameters because adequate therapeutic drug levels are required to eliminate cancer stem cells in all anatomic compartments. The plasma half-life of 5-AZA-CdR in humans is approximately 20 minutes due to the high levels in the liver of cytidine deaminase, the enzyme that inactivates this analogue. This provides a rationale to use an inhibitor of cytidine deaminase in combination with 5-AZA-CdR. Low-dose 5-AZA-CdR is effective for MDS and AML and can induce complete remissions (CR). However, maintenance of CR with low-dose 5-AZA-CdR is difficult. Based on analyses of preclinical and clinical data, low dose 5-AZA-CdR has the potential to be an effective form of therapy in some patients with cancer. For patients who do not respond to low dose therapy we recommend dose-intensive treatment with 5-AZA-CdR. Patients who are candidates for intensive dose 5-AZA-CdR should have a good bone marrow status so as to permit adequate recovery from myelosuppression, the major toxicity of 5-AZA CdR. Solid tumors are also interesting targets for therapy with 5-AZA-CdR. Both low dose and intensive therapy with 5-AZA-CdR can reduce the proliferative potential of tumor stem cells in animal models. We propose novel dose schedules of 5-AZA-CdR for investigation in patients with cancer. The full chemotherapeutic potential of 5-AZA-CdR to treat cancer merits further clinical investigation and can only be realized when its optimal dose-schedule is determined. PMID- 23369225 TI - Peroxisome proliferator-activated receptors modulate cardiac dysfunction in diabetic cardiomyopathy. AB - Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). Chronic inflammation and derangement of myocardial energy and lipid homeostasis are common features of DM. The transcription factors of peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily, which are important in regulating energy and lipid homeostasis. There are three PPAR isoforms, alpha, gamma, and delta, and their roles have been increasingly recognized to be important in CVD. These three isoforms are expressed in the heart and play pivotal roles in myocardial lipid metabolism, as well as glucose and energy homeostasis, and contribute to extra metabolic roles with effects on inflammation and oxidative stress. Moreover, regulation of PPARs may have significant effects on cardiac electrical activity and arrhythmogenesis. This review describes the roles of PPARs and their agonists in DM cardiomyopathy, inflammation, and cardiac electrophysiology. PMID- 23369226 TI - Diabetes mellitus in patients with schizophrenia in West-Bank, Palestine. AB - AIMS: The main aims of the study were to investigate the prevalence of pre diabetes and diabetes mellitus (DM) in patients with schizophrenia, to compare it with those published in the general population, and to assess significant associations with dysglycemia defined as having either pre-DM or DM. METHODS: A cross-sectional study carried out in 4 governmental primary psychiatric healthcare centers in Northern West-Bank, Palestine. Fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) were measured. The World Health Organization (WHO) criteria for defining pre-DM and DM were used. Dysglycemia was defined as FBG >110mg/dl. RESULTS: Based on WHO criteria, 27 patients (10.8%) had diabetes and 34 (13.6%) had pre-diabetes. The prevalence of DM in patients with schizophrenia was not significantly higher than that reported in the general population of Palestine. However, the prevalence of pre-DM was significantly higher than that reported in the general population of Palestine. Regression analysis showed that advancing age and abnormal waist circumference were significant predictors of dysglycemia in patients with schizophrenia. CONCLUSIONS: This study confirmed the high prevalence of dysglycemia in patients with schizophrenia, supporting the need for monitoring of blood glucose in this category of patients. The presence of primary risk factors is more important in the development of dysglycemia in patients with schizophrenia than exposure to antipsychotic drugs. PMID- 23369227 TI - Serum irisin levels in new-onset type 2 diabetes. AB - AIMS: Irisin has been identified as a novel myokine that drives brown-fat-like conversion of white adipose tissue. In this cross-sectional study, we investigated whether serum irisin levels are decreased in patients with type 2 diabetes (T2D) compared with control subjects with normal glucose tolerance (NGT), and assessed the association between serum irisin levels and various metabolic parameters. METHODS: The study population was selected from a population-based study and included 104 subjects with NGT and 104 subjects with new-onset T2D. Serum irisin and adiponectin levels and metabolic parameters were measured. Multivariate logistic regression analysis was performed to assess the association between irisin levels and newly diagnosed T2D. RESULTS: Serum irisin levels were significantly decreased in the new-onset T2D group compared with the NGT control group (p=0.003). In a multivariable model adjusted for various metabolic parameters, increased irisin levels were associated with reduced odds (OR 0.64, 95% CI 0.47-0.88, p=0.006) of prevalent newly diagnosed T2D. Furthermore, multiple regression analysis showed that 2 h plasma glucose was an independent variable influencing serum irisin levels (p=0.004). CONCLUSION: In the present study, we found that serum irisin levels were decreased in T2D patients and inversely associated with newly diagnosed T2D, suggesting that irisin may play a crucial role in glucose intolerance and T2D. PMID- 23369228 TI - Severity of diabetic retinopathy is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. AB - AIM: The aim of the study was to examine the association of severity of diabetic retinopathy (DR) with left ventricular diastolic dysfunction (LVDD). METHODS: The subjects were 120 patients with type 2 diabetes mellitus (T2DM). All patients underwent clinical evaluation, laboratory tests, and echocardiographic examination. Doppler echocardiographic indices including peak early diastolic mitral annular velocity (e') and early diastolic myocardial velocity (E) were obtained in each patient. RESULTS: The patients were divided into three groups based on the presence and severity of DR: no DR (n=80), simple DR (n=20), and preproliferative or proliferative DR (n=20). No patients showed systolic impairment of left ventricular ejection fraction (LVEF>50%), whereas impaired LV diastolic function (E/e'>8) occurred in 104 cases (87%) and LVDD (E/e'>15) was detected in 19 cases (16%). E/e' was correlated with age, sex, diabetic duration, DR stage, systolic blood pressure, and serum creatinine level. In multiple regression analysis, age (beta=0.322, p<0.001) and DR stage (beta=0.266, p=0.002) were independently correlated with E/e'. CONCLUSIONS: The results of the study show that almost all subjects had asymptomatic LVDD and that the severity of DR was associated with LVDD in patients with T2DM. PMID- 23369229 TI - Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance. AB - AIM: To evaluate the effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance. METHODS: Seventy six patients with diabetes and glucose intolerance were enrolled in this study. At baseline and 12 weeks after treatment with ezetimibe 10mg/day, we measured the levels of lipid and glucose parameters. RESULTS: Ezetimibe reduced the mean levels of low-density lipoprotein cholesterol (LDL-C) (-20%, P<0.001), remnant like particle cholesterol (-22%, P<0.001), small dense-LDL (-19%, P<0.001), apolipoprotein B-48 (-2%, P<0.01), malondialdehyde modified-LDL (-15%, P<0.001), and serum immunoreactive insulin (IRI) (-4%, P<0.01). In the insulin resistance subgroup, ezetimibe reduced the abdominal circumference (-1%, P<0.05) and mean levels of fasting plasma glucose (-7%, P<0.05), IRI (-36%, P<0.01), s-CPR (-27%, P<0.01), HOMA-IR (-39%, P<0.01) and HbA1c tended to decrease (-2%, P=0.06). CONCLUSIONS: Ezetimibe reduced atherogenic lipoproteins in patients with diabetes and glucose intolerance; besides, it improved glucose metabolism in patients with insulin resistance. PMID- 23369231 TI - Soluble microbial products (SMPs) release in activated sludge systems: a review. AB - This review discusses the characterization, production and implications of soluble microbial products (SMPs) in biological wastewater treatment. The precise definition of SMPs is open to talk about, but is currently regarded as "the pool of organic compounds that are released into solution from substrate metabolism and biomass decay"'. Some of the SMPs have been identified as humic acids, polysaccharides, proteins, amino acids, antibiotics, extracellular enzymes and structural components of cells and products of energy metabolism. They adversely affect the kinetic activity, flocculating and settling properties of sludge. This review outlines some important findings with regard to biodegradability and treatability of SMPs and also the effect of process parameters on their production. As SMPs are produced during biological treatment process, their trace amounts normally remain in the effluent that defines the highest COD removal efficiency. Their presence in effluent represents a high potential risk of toxic by-product formation during chlorine disinfection. Studies have indicated that among all wastewater post-treatment processes, the adsorption by granular activated carbon combined with biologically induced degradation is the most effective method for removal of SMPs. However, it may be concludes that the knowledge regarding SMPs is still under progress and more work is required to fully understand their contribution to the treatment process. PMID- 23369230 TI - Screening for HbA1c-defined prediabetes and diabetes in an at-risk greek population: performance comparison of random capillary glucose, the ADA diabetes risk test and skin fluorescence spectroscopy. AB - BACKGROUND: We examined the accuracy of random capillary glucose (RCG) and two noninvasive screening methods, the ADA diabetes risk test (DRT) and skin fluorescence spectroscopy (SFS) as measured by Scout DS for detecting HbA1c defined dysglycemia or type 2 diabetes in an at-risk cohort. METHODS: Subjects were recruited at two clinical sites for a single non-fasting visit. Each subject had measurements of height, weight and waist circumference. A diabetes score was calculated from skin fluorescence measured on the left forearm. A finger prick was done to measure RCG and HbA1c (A1C). Health questionnaires were completed for the DRT. Increasing dysglycemia was defined as A1C >= 5.7% (39 mmol/mol) or >= 6.0% (42 mmol/mol). Type 2 diabetes was defined as A1C >= 6.5% (47.5 mmol/mol). RESULTS: 398 of 409 subjects had complete data for analysis with means for age, body mass index, and waist of 52 years, 27 kg/m(2) and 90 cm. 51% were male. Prevalence of A1C >= 5.7%, >= 6.0% and >= 6.5% were 54%, 34% and 12%, respectively. Areas under the curve (AUC) for detection of increasing levels dysglycemia or diabetes for RCG were 63%, 66% and 72%, for the ADA DRT the AUCs were 75%, 76% and 81% and for SFS the AUCs were 82%, 84% and 90%, respectively. For each level of dysglycemia or diabetes, the SFS AUC was significantly higher than RCG or the ADA DRT. CONCLUSIONS: The noninvasive skin fluorescence spectroscopy measurement outperformed both RCG and the ADA DRT for detection of A1C-defined dysglycemia or diabetes in an at-risk cohort. PMID- 23369232 TI - Open questions: Chromosome condensation - why does a chromosome look like a chromosome? PMID- 23369233 TI - Photocatalytic degradation of 4-chlorophenol by UV/H2O2/NiO process in aqueous solution. AB - The removal of 4-chlorophenol from aqueous phase continues to be an important environmental issue. In this work, the photochemical oxidation of 4-chlorophenol in aqueous solutions in a batch reactor using ultraviolet irradiation, hydrogen peroxide and nickel oxide was studied. The efficiency of the system was evaluated with respect to reaction time, pH, feed concentration of reactants, catalyst load, light intensity, and the reaction rate constant. The concentrations of 4 chlorophenol and chloride ions were determined by high performance liquid chromatography and ion chromatography, respectively. Pure nanosized nickel oxide was characterized by X-ray diffraction and scanning electron microscopy. The results showed that the optimum conditions (the complete 4-chlorophenol removal (100%) at 60 min) were obtained at a neutral pH, with 0.2 mol/L H2O2, and 0.05 g/L of nickel oxide. However, no pH effects were observed in the range of 4-10. Analytical profiles on 4-chlorophenol transformation were consistent with the best line fit of the first-order kinetics. Moreover, the degradation rate constant increased with both UV light intensity and decreasing initial concentration of 4-chlorophenol. Finally, the results of mineralization and chloride ions studies indicated that dechlorination was better accomplished but more time was required to completely mineralize 4-chlorophenol into water and carbon dioxide. PMID- 23369234 TI - Changes in primary care physician's management of low back pain in a model of interprofessional collaborative care: an uncontrolled before-after study. AB - BACKGROUND: Tracking how clinicians treat patients provides an opportunity to explore how the clinical management of common musculoskeletal disorders evolves over time. We present an uncontrolled before-after study of a primary care physician's management of low back pain and describe how his involvement in an interprofessional collaborative practice was associated with a change in the management of patients with low back pain. METHOD: Data from the electronic medical record of one primary care physician who participated in a study of a model of chiropractic-medical collaboration were retrospectively collected. Records of a sample of consecutive patients prior to the start (i.e. pre-study, n = 51) and at the end of the collaborative study (i.e. study, n = 49) were collected. RESULTS: Demographics were similar in both groups but median number of physician visits (2.5 and 1.0), average prescriptions per patients (1.24 and 0.47), and total number of narcotic prescriptions (14 and 6) differed between pre study and study groups, respectively. Separate analysis of only the records of low back pain study patients revealed that 61% were referred for chiropractic care during the study period. Patients who were not referred had more neurological deficits and leg pain but back pain severity and average number of prescriptions was about the same. Referred patients in the study group had about 25% fewer physician visits and imaging requests. CONCLUSION: Based on this study of a single primary care physician, we hypothesize that doctors may change their prescribing behaviours and consultation rate for patients with low back pain when engaged in interprofessional collaborative care. Further research is required to test this observation in the population. PMID- 23369236 TI - A novel method for finding non-small cell lung cancer diagnosis biomarkers. AB - BACKGROUND: One of the most common causes of worldwide cancer premature death is non-small cell lung carcinoma (NSCLC) with a very low survival rate of 8%-15%. Since patients with an early stage diagnosis can have up to four times the survival rate, discovering cost-effective biological markers that can be used to improve the diagnosis and prognosis of the disease is an important clinical challenge.In the last few years, significant progress has been made to address this challenge with identified biomarkers ranging from 5-gene signatures to 133 gene signatures. However, A typical molecular sub-classification method for lung carcinomas would have a low predictive accuracy of 68%-71% because datasets of gene-expression profiles typically have tens of thousands of genes for just few hundreds of patients. This type of datasets create many technical challenges impacting the accuracy of the diagnostic prediction. RESULTS: We discovered that a small set of nine gene-signatures (JAG1, MET, CDH5, ABCC3, DSP, ABCD3, PECAM1, MAPRE2 and PDF5) from the dataset of 12,600 gene-expression profiles of NSCLC acts like an inference basis for NSCLC lung carcinoma and hence can be used as genetic markers. This very small and previously unknown set of biological markers gives an almost perfect predictive accuracy (99.75%) for the diagnosis of the disease the sub-type of cancer. Furthermore, we present a novel method that finds genetic markers for sub-classification of NSCLC. We use generalized Lorenz curves and Gini ratios to overcome many challenges arose from datasets of gene expression profiles. Our method discovers novel genetic changes that occur in lung tumors using gene-expression profiles. CONCLUSIONS: While proteins encoded by some of these gene-signatures (e.g., JAG1 and MAPRE2) have been showed to involve in the signal transduction of cells and proliferation control of normal cells, specific functions of proteins encoded by other gene-signatures have not yet been determined. Hence, this work opens new questions for structural and molecular biologists about the role of these gene-signatures for the disease. PMID- 23369237 TI - Does Australia have the appropriate health reform agenda to close the gap in Indigenous health? AB - This paper provides an analysis of the national Indigenous reform strategy - known as Closing the Gap - in the context of broader health system reforms underway to assess whether current attempts at addressing Indigenous disadvantage are likely to be successful. Drawing upon economic theory and empirical evidence, the paper analyses key structural features necessary for securing system performance gains capable of reducing health disparities. Conceptual and empirical attention is given to the features of comprehensive primary healthcare, which encompasses the social determinants impacting on Indigenous health. An important structural prerequisite for securing genuine improvements in health outcomes is the unifying of all funding and policy responsibilities for comprehensive primary healthcare for Indigenous Australians within a single jurisdictional framework. This would provide the basis for implementing several key mutually reinforcing components necessary for enhancing primary healthcare system performance. The announcement to introduce a long-term health equality plan in partnership with Aboriginal people represents a promising development and may provide the window of opportunity needed for implementing structural reforms to primary healthcare. WHAT IS KNOWN ABOUT THE TOPIC? Notwithstanding the intention of previous policies, considerable health disparity exists between Indigenous and non-Indigenous Australians. Australia has now embarked on its most ambitious national Indigenous health reform strategy, but there has been little academic analysis of whether such reforms are capable of eliminating health disadvantage for Aboriginal people.WHAT DOES THE PAPER ADD? This paper provides a critical analysis of Indigenous health reforms to assess whether such policy initiatives are likely to be successful and outlines key structural changes to primary healthcare system arrangements that are necessary to secure genuine system performance gains and improve health outcomes for Indigenous Australians.WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? For policymakers, the need to establish genuine partnership and engagement between Aboriginal people and the Australian government in pursuing a national Indigenous reform agenda is of critical importance. The establishment of the National Congress of Australia's First Peoples provides the opportunity for policy makers to give special status to Indigenous Australians in health policy development and create the institutional breakthrough necessary for effecting primary healthcare system change. PMID- 23369235 TI - Cis-Golgi cisternal assembly and biosynthetic activation occur sequentially in plants and algae. AB - The cisternal progression/maturation model of Golgi trafficking predicts that cis Golgi cisternae are formed de novo on the cis-side of the Golgi. Here we describe structural and functional intermediates of the cis cisterna assembly process in high-pressure frozen algae (Scherffelia dubia, Chlamydomonas reinhardtii) and plants (Arabidopsis thaliana, Dionaea muscipula; Venus flytrap) as determined by electron microscopy, electron tomography and immuno-electron microscopy techniques. Our findings are as follows: (i) The cis-most (C1) Golgi cisternae are generated de novo from cisterna initiators produced by the fusion of 3-5 COPII vesicles in contact with a C2 cis cisterna. (ii) COPII vesicles fuel the growth of the initiators, which then merge into a coherent C1 cisterna. (iii) When a C1 cisterna nucleates its first cisterna initiator it becomes a C2 cisterna. (iv) C2-Cn cis cisternae grow through COPII vesicle fusion. (v) ER resident proteins are recycled from cis cisternae to the ER via COPIa-type vesicles. (vi) In S. dubia the C2 cisternae are capable of mediating the self assembly of scale protein complexes. (vii) In plants, ~90% of native alpha mannosidase I localizes to medial Golgi cisternae. (viii) Biochemical activation of cis cisternae appears to coincide with their conversion to medial cisternae via recycling of medial cisterna enzymes. We propose how the different cis cisterna assembly intermediates of plants and algae may actually be related to those present in the ERGIC and in the pre-cis Golgi cisterna layer in mammalian cells. PMID- 23369238 TI - Characterization of PPAR dual ligand MCC-555 in AOM-induced colorectal tumorigenesis. AB - Colorectal cancer (CRC) is one of the most commonly diagnosed cancers. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists represent a potentially important family of chemopreventive/therapeutic compounds for cancer treatment by affecting cell proliferation, differentiation, and apoptosis. Dual ligands for PPARalpha and PPARgamma, such as netoglitazone (MCC-555), have been developed to improve treatment of metabolic syndromes, including hyperglycemia and hyperlipidemia. Interestingly, these dual ligands also possess anti proliferative activities against a variety of cancer cell lines with a greater potency than conventional PPARgamma specific ligands. In this study, chemopreventive properties of MCC-555 in colorectal tumorigenesis were evaluated using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in A/J mice. We found that MCC-555 suppressed AOM-induced ACF in A/J mice, compared to the control group. Administration of MCC-555 resulted in decreased mitoses and increased apoptotic cells in the colon. Furthermore, expression of tumor suppressor protein MUC2 was increased in MCC-555 treated mice. Our data clearly suggest that MCC-555 has an effect on the early events of colon carcinogenesis, thus providing evidence that MCC-555 could be a potential preventive compound for CRC. PMID- 23369239 TI - New insight in colistin induced neurotoxicity with the mitochondrial dysfunction in mice central nervous tissues. AB - In the present study, the mechanism of colistin-induced neurotoxicity was investigated with a focus on behavioral characters, mitochondrial ultrastructures and functions of the central nerve tissues in mice followed by administrating intravenously 15 (divided into two dose and 12 h apart), 7.5 and 5 mg/kgbw colistin sulfate for 1, 3 or 7 days successively. To assess the recoverability of colistin-induced neurotoxicity, the neurotoxicity was also examined on day 15 (8 post colistin sulfate administration for 7 days). The results showed that, the spontaneous activities of mice were significantly decreased on days 3 and 7 in the 15 mg/kg group compared with the correspondingly control group. The abnormal ultrastructure changes of mitochondria were presented in their nervous tissues and changed in a dose- and time-dependent manner, e.g. severe vacuolation and fission on days 3 and 7 in the 15 mg/kg group and more slight on day 7 in the 7.5 mg/kg group. In addition, mitochondrial permeability transition (MPT), membrane potential (Deltapsim) and activities of mitochondrial succinate dehydrogenase changed, showing that colistin affected the mitochondrial functions. The recoverability of colistin-induced neurotoxicity was showed and only slight injury occurred in the nerve tissues of mice on day 15 in the 15 mg/kg group and it had no abnormal changes in the behavioral and neuropathology characters in mice on day 15 in the 7.5 and 5 mg/kg groups. The results suggested that mitochondrial dysfunction might partly account for the mechanism of neurotoxicity induced by colistin sulfate. PMID- 23369240 TI - Thickened area of external granular layer and Ki-67 positive focus are early events of medulloblastoma in Ptch1+/- mice. AB - Patched1 (Ptch1) encodes a receptor for Sonic hedgehog (Shh) and is major gene related to human medulloblastoma (MB) in the Shh subgroup. MB is thought to arise from residual granule cell precursors (GCPs) located in the external granular layer (EGL) of the developing cerebellum. As the detailed preneoplastic changes of MB remain obscure, we immunohistochemically clarified the derived cell, early events of MBs, and the cerebellar developmental processes of Ptch1(+/-) (Ptch1) mice, an animal model of human MB of the Shh subgroup. In Ptch1 mice, the earliest proliferative lesions were detected at PND10 as focal thickened areas of outer layer of the EGL. This area was composed of GCP-like cells with atypia and nuclei disarrangement. In the latter cerebellar developmental period, GCP-like cell foci were detected at high incidence in the outermost area of the cerebellum. Their localization and morphological similarities indicated that the foci were derived from GCPs in the EGL. There were two types of the foci. A Ki-67 positive focus was found in Ptch1 mice only. This type resembled the GCPs in the outer layer of EGL characterized by having proliferating activity and a lack of neuronal differentiation. Another type of focus, Ki-67-negative, was observed in both genotypes and exhibited many of the same features of mature internal granule cells, suggesting that the focus had no preneoplastic potential. Due to morphological, immunohistochemical characteristics, our results indicate that the focal thickened area of EGL and Ki-67-positive foci are preneoplastic lesions of MB. PMID- 23369241 TI - Development and validation of a new model of desirable dietary pattern (N-DDP) score for Chinese diets. AB - OBJECTIVE: To develop a new model of desirable dietary pattern (N-DDP) score for Chinese diets and to validate it against the nutrient-rich foods (NRF) index. DESIGN: The N-DDP score model followed the principles of the traditional DDP (T DDP) score model (DDP-China for 2000) proposed in 1991 and of food grouping in the dietary pagoda for Chinese residents in 2007, and made detailed ratings by expressing the food weight coefficient, reasonable maximum limit of the score and an algorithm of the deserved score for each group of foods after considering current nutritional problems of Chinese residents. The N-DDP score model was validated against the NRF9.3 index with linear regression analysis and compared with the T-DDP score model. Settings One set of dietary data was extracted from the diet recommended by the dietary pagoda for Chinese residents in 2007 and the literature on dietary surveys in China. The other two sets of dietary data were from a dietary survey in 2011. DDP scores for all three dietary data sets were calculated with the N-DDP score model and the T-DDP score model. SUBJECTS: All items of dietary records in the three dietary data sets were included in the present study. RESULTS: All DDP scores obtained with the N-DDP score model were positively correlated (P = 0.000) with the NRF9.3 index. DDP scores obtained with the N-DDP score model had higher R 2 with the NRF9.3 index than those of the T DDP score model, as well as higher beta values. CONCLUSIONS: It can be considered that the N-DDP score is a more accurate and convenient tool to evaluate current individual and group diet for Chinese residents. PMID- 23369242 TI - Functional analysis of the impact of ORMDL3 expression on inflammation and activation of the unfolded protein response in human airway epithelial cells. AB - BACKGROUND: The gene ORMDL3 was shown to be associated with early-onset asthma susceptibility in multiple independent genome-wide and candidate-gene association studies. Asthmatic patients have elevated expression levels of this gene. ORMDL3 encodes a transmembrane protein localized in the endoplasmic reticulum (ER) that may be involved in ER stress and inflammation. It is essential to validate the genetic associations linking ORMDL3 with asthma through functional studies that confirm the biological relevance of this gene in disease. We investigated the effects of manipulating ORMDL3 expression levels in vitro in airway cells on innate immune inflammatory responses, ER stress and activation of the unfolded protein response (UPR). METHODS: ORMDL3 expression levels were manipulated in airway cells using an overexpression plasmid and siRNA technologies. Successful modulation of ORMDL3 was confirmed at both the gene and protein level. The functional impact of modulation of ORMDL3 expression levels on inflammatory responses and activation of the UPR were quantified using complementary cellular and molecular immunology techniques. RESULTS: Cells with altered ORMDL3 levels responded equally well to innate immune stimuli and produced similar levels of pro-inflammatory cytokines compared to wild-type cells. Treatment with ER stress inducers, thapsigargin and tunicamycin, resulted in activation of the unfolded protein response (UPR). However, we observed no difference in UPR activation in cells with ORMDL3 knockdown compared to cells with normal ORMDL3 levels. CONCLUSIONS: Our results suggest that ORMDL3 variation in the airway epithelium is unlikely to play a significant role in modulating innate immune responses and the UPR in the lung. PMID- 23369243 TI - First molecular characterization of Cryptosporidium in Yemen. AB - Cryptosporidium is a protozoan parasite of humans and animals and has a worldwide distribution. The parasite has a unique epidemiology in Middle Eastern countries where the IId subtype family of Cryptosporidium parvum dominates. However, there has been no information on Cryptosporidium species in Yemen. Thus, this study was conducted in Yemen to examine the distribution of Cryptosporidium species and subtype families. Fecal samples were collected from 335 patients who attended hospitals in Sana'a city. Cryptosporidium species were determined by PCR and sequence analysis of the 18 s rRNA gene. Cryptosporidium parvum and C. hominis subtypes were identified based on sequence analysis of the 60 kDa glycoprotein (gp60) gene. Out of 335 samples, 33 (9.9%) were positive for Cryptosporidium. Of them, 97% were identified as C. parvum whilst 1 case (3%) was caused by C. hominis. All 7 C. parvum isolates subtyped belonged to the IIaA15G2R1 subtype. The common occurrence of the zoonotic IIa subtype family of C. parvum highlights the potential occurrence of zoonotic transmission of cryptosporidiosis in Yemen. However, this postulation needs confirmation with future molecular epidemiological studies of cryptosporidiosis in both humans and animals in Yemen. PMID- 23369244 TI - Male human papillomavirus infection post-kidney transplant: an overlooked disease. AB - While immunosuppressive regimens improve the overall survival of renal transplant recipients, they also contribute to the long-term complications of post-transplant malignancies. Chronic immune suppression in renal transplant recipients (RTR) increases the risk of viral-associated cancers. In male RTR, human papillomavirus (HPV) is implicated in the development of penile, anal, oropharyngeal, and non-melanoma skin carcinomas. Despite the significance of this virus in RTR, there is an overall deficiency in the understanding of the natural history of HPV infection in male RTR. In the next 20 years, it is believed that cancers will be the leading cause of death in kidney transplant recipients. HPV associated carcinomas are of particular interest since they are sexually transmitted and in theory may be preventable diseases. This commentary highlights some of the progress made in understanding how HPV is transmitted amongst couples in the general population. It also summarizes the current knowledge of HPV infection in male RTR and describes the deficiencies in published medical literature. PMID- 23369245 TI - English language proficiency and the accommodations for language non-concordance amongst patients utilizing chiropractic college teaching clinics. AB - BACKGROUND: The number of households in the United States that are not proficient in the English language is growing and presenting a challenge to the health care system. Over nineteen percent of the US population speak a language other than English in the home. This increase in language discordance generates a greater need to find and implement accommodations in the clinical setting to insure accurate and efficient diagnosis and treatment as well as provide for patient safety. AIM: The purpose of this study is to determine the percentage of patients accessing the chiropractic college teaching clinics who are not proficient in the English language and to what extent the colleges provide accommodations for that language disparity. METHODS: The clinic directors and deans of the Association of Chiropractic Colleges were surveyed via an on-line survey engine. The survey queried the percentage of the patient population that is not English language proficient, the accommodations the college currently has in place, if the college has a language specific consent to treat document and if the college has a written policy concerning patients without English proficiency. RESULTS: Fifty percent of the contacted chiropractic colleges responded to the survey. In the respondent college clinics 16.5% of the patient population is not proficient in English, with over 75% speaking Spanish. All but one of the respondents provide some level of accommodation for the language non-concordance. Forty five percent of the responding colleges employ a language specific consent to treat form. The implementation of accommodations and the use of a language specific consent to treat form is more prevalent at colleges with a higher percentage of non-English speaking patients. CONCLUSIONS: The percentage of patients with limited English proficiency accessing services at the teaching clinics of the chiropractic colleges mirrors the numbers in the general population. There is a wide disparity in the accommodations that the individual colleges make to address this language discordance. There is a need to further develop accurate and meaningful accommodations to address language disparity in the chiropractic teaching clinics. PMID- 23369246 TI - Chemoradiation in patients with isolated recurrent pancreatic cancer - therapeutical efficacy and probability of re-resection. AB - BACKGROUND: In the present retrospective analysis we analysed the therapeutic outcome of a set of patients, who were treated with chemoradiation (CRT) for recurrent pancreatic cancer (RPC) in a single institution. PATIENTS AND METHODS: Forty-one patients had a history of primary resection for pancreatic cancer. In case of an unresectable recurrency patients were treated with CRT at our institution between 2002 and 2010 with a median dose of 48.4 Gy (range 39.6-54 Gy). Concurrent chemotherapy regimes included Gemcitabine (GEM) in 37/41 patients (90%) and Fluorouracil (FU) or Capecitabine (CAP) in 4/41 patients (10%). Patients were re-evaluated after CRT with computed tomography and/or explorative laparotomy. During re-resection or laparotomy 15 patients received an additional intraoperative radiotherapy (IORT) with a median dose of 15 Gy (range 12-15 Gy). Median age was 65 years (range 39-76 years) and there were 26 male and 15 female patients. RESULTS: The median overall survival (mOS), local control (LC) and progression-free survival (PFS) were 16.1, 13.8 and 6.9 months respectively for all patients after the first day of CRT. Re-resection was possible in five patients (12%) and a complete remission (CR) as defined by tumor-free biopsy was seen in 6 patients (15%). When re-resection could be achieved after CRT mOS was improved to 28.3 months (n = 5 patients, 95%-CI 10.2 - 46.3 months). Patients receiving IORT had a significantly improved mOS compared to no IORT (p = 0.034). Fifteen patients (37%) experienced a local tumour progression and main site of distant metastasis was the liver (11 patients, 27%).Overall treatment-related toxicity was mild, grade III hematologic toxicity was observed in 11 patients (27%). CONCLUSION: In summary we observed a good therapeutic response with mild to moderate toxicity levels for CRT in RPC. Overall survival and PFS were clearly improved in case of induction of a complete remission (tumor-free biopsies) or after achieving a re-resection, thus providing a curative intended therapy even in case of disease recurrence. PMID- 23369247 TI - Integrated lipidomics and transcriptomic analysis of peripheral blood reveals significantly enriched pathways in type 2 diabetes mellitus. AB - BACKGROUND: Insulin resistance is a key element in the pathogenesis of type 2 diabetes mellitus. Plasma free fatty acids were assumed to mediate the insulin resistance, while the relationship between lipid and glucose disposal remains to be demonstrated across liver, skeletal muscle and blood. METHODS: We profiled both lipidomics and gene expression of 144 total peripheral blood samples, 84 from patients with T2D and 60 from healthy controls. Then, factor and partial least squares models were used to perform a combined analysis of lipidomics and gene expression profiles to uncover the bioprocesses that are associated with lipidomic profiles in type 2 diabetes. RESULTS: According to factor analysis of the lipidomic profile, several species of lipids were found to be correlated with different phenotypes, including diabetes-related C23:2CE, C23:3CE, C23:4CE, ePE36:4, ePE36:5, ePE36:6; race-related (African-American) PI36:1; and sex related PE34:1 and LPC18:2. The major variance of gene expression profile was not caused by known factors and no significant difference can be directly derived from differential gene expression profile. However, the combination of lipidomic and gene expression analyses allows us to reveal the correlation between the altered lipid profile with significantly enriched pathways, such as one carbon pool by folate, arachidonic acid metabolism, insulin signaling pathway, amino sugar and nucleotide sugar metabolism, propanoate metabolism, and starch and sucrose metabolism. The genes in these pathways showed a good capability to classify diabetes samples. CONCLUSION: Combined analysis of gene expression and lipidomic profiling reveals type 2 diabetes-associated lipid species and enriched biological pathways in peripheral blood, while gene expression profile does not show direct correlation. Our findings provide a new clue to better understand the mechanism of disordered lipid metabolism in association with type 2 diabetes. PMID- 23369248 TI - Elevated reporting of unprotected anal intercourse and injecting drug use but no difference in HIV prevalence among Indigenous Australian men who have sex with men compared with their Anglo-Australian peers. AB - BACKGROUND: Although half of the HIV notifications among Aboriginal and Torres Strait Islander people ('Indigenous Australians') are attributed to homosexual transmission, there has been little research examining sexual and drug use risk practices among Indigenous Australian men who have sex with men (MSM). METHODS: Respondents were Indigenous Australian (n=1278) and Anglo-Australian men (n=24002) participating in the routine cross-sectional Gay Community Periodic Surveys conducted in Australia from 2007 to 2011. Sociodemographic characteristics, sexual risk practices, drug use, HIV testing and HIV status of Indigenous and Anglo-Australian men were compared and evaluated to discover whether Indigenous status was independently associated with HIV risk practices. RESULTS: Although an equivalent proportion of Indigenous and Anglo-Australian men reported being HIV-positive (9.6%), Indigenous MSM were more likely to report unprotected anal intercourse with casual partners in the previous 6 months (27.9% v. 21.5%; Adjusted odds ratio (AOR)=1.29, 95% confidence interval (CI): 1.11 1.49). Indigenous men were more likely than Anglo-Australian men to report use of several specific drugs and twice as likely to report injecting drug use in the previous 6 months (8.8% v. 4.5%; AOR=1.43, 95% CI: 1.11-1.86). CONCLUSIONS: Despite a higher proportion of Indigenous men reporting sexual and drug use practices that increase the risk of HIV transmission, there were no differences in the HIV status of Indigenous and Anglo-Australian men. However, the elevated rates of risk practices suggest that Indigenous MSM should remain a focus for HIV prevention, care and support. PMID- 23369249 TI - Translational health research: perspectives from health education specialists. AB - The phrase "from bench to bedside to curbside" is a common definition of translational research among health disparities researchers. Health Education Specialists can make important contributions to the field of clinical translational medicine, particularly in light of U.S. health care reform and a renewed emphasis on medical home or health care home models.Health Education Specialists have the training and experience to engage in and facilitate translational research, as well as the opportunity to learn from the translational efforts of other professions and enhance our research, practice, and community partnerships through translational efforts. In this paper, a Translational Health Education Research framework for health education researchers is suggested to foster increased translational efforts within our profession as well as to promote interdisciplinary collaborations to translate a variety of health-related research. A conceptual framework adapted from translational health disparities research that highlights the level and scope of translational research necessary for changes in practice and policy is also provided. PMID- 23369252 TI - An estimation of traffic related CO2 emissions from motor vehicles in the capital city of, Iran. AB - Vehicle exhaust is a major source of anthropogenic carbon dioxide (CO2) in metropolitan cities. Popular community mode (buses and taxies) and about 2.4 million private cars are the main emission sources of air pollution in Tehran. A case survey has conducted to measure CO2 in four popular vehicles, bus, taxi, private car and motorcycle, which moved in the city with respectively 7800, 82358, 560000 and 2.4 million per day in 2012. Results indicated that the contribution of CO2 emissions increased in the following order: private car, motorcycle, bus and taxi. The overall average for the contribution of CO2 emissions in the private car, motorcycle, bus, and taxi were 26372, 1648, 1433 and 374 tons per day, respectively. Our results also showed that the urban transport operation consume an estimated 178 and 4224 million liter diesel and petrol per year, respectively, that have released about 10 million tons of CO2. The average contribution of CO2 emissions of private cars in Tehran was higher (88%) than other vehicles. It was concluded that high volume of traffic, transport consumption of fossil fuels and shortage of adequate public transport system are responsible for the high CO2 level in environment in Tehran. Thus, it is to be expected that CO2 as a greenhouse gas has risen in Tehran more than ever in the following years and this would be a matter of concern for the authorities to have a comprehensive plan to mitigate this phenomena. PMID- 23369251 TI - Host genomic influences on HIV/AIDS. AB - The AIDS era has seen multiple advances in the power of genetics research; scores of host genetic protective factors have been nominated and several have translated to the bedside. We discuss how genomics may inform HIV/AIDS prevention, treatment and eradication. PMID- 23369253 TI - Characterization of the novel Trypanosoma brucei inosine 5'-monophosphate dehydrogenase. AB - There is an alarming rate of human African trypanosomiasis recrudescence in many parts of sub-Saharan Africa. Yet, the disease has no successful chemotherapy. Trypanosoma lacks the enzymatic machinery for the de novo synthesis of purine nucleotides, and is critically dependent on salvage mechanisms. Inosine 5' monophosphate dehydrogenase (IMPDH) is responsible for the rate-limiting step in guanine nucleotide metabolism. Here, we characterize recombinant Trypanosoma brucei IMPDH (TbIMPDH) to investigate the enzymatic differences between TbIMPDH and host IMPDH. Size-exclusion chromatography and analytical ultracentrifugation sedimentation velocity experiments reveal that TbIMPDH forms a heptamer, different from type 1 and 2 mammalian tetrameric IMPDHs. Kinetic analysis reveals calculated K m values of 30 and 1300 MU m for IMP and NAD, respectively. The obtained K m value of TbIMPDH for NAD is approximately 20-200-fold higher than that of mammalian enzymes and indicative of a different NAD binding mode between trypanosomal and mammalian IMPDHs. Inhibition studies show K i values of 3.2 MU m, 21 nM and 3.3 nM for ribavirin 5'-monophosphate, mycophenolic acid and mizoribine 5'-monophosphate, respectively. Our results show that TbIMPDH is different from its mammalian counterpart and thus may be a good target for further studies on anti-trypanosomal drugs. PMID- 23369254 TI - Bioclimatic regions influence genetic structure of four Jordanian Stipa species. AB - Strong environmental gradients can affect the genetic structure of plant populations, but little is known as to whether closely related species respond similarly or idiosyncratically to ecogeographic variation. We analysed the extent to which gradients in temperature and rainfall shape the genetic structure of four Stipa species in four bioclimatic regions in Jordan. Genetic diversity, differentiation and structure of Stipa species were investigated using amplified fragment length polymorphism (AFLP) molecular markers. For each of the four study species, we sampled 120 individuals from ten populations situated in distinct bioclimatic regions and assessed the degree of genetic diversity and genetic differentiation within and among populations. The widespread ruderals Stipa capensis and S. parviflora had higher genetic diversity than the geographically restricted semi-desert species S. arabica and S. lagascae. In three of the four species, genetic diversity strongly decreased with precipitation, while genetic diversity increased with temperature in S. capensis. Most genetic diversity resided among populations in the semi-desert species (Phi(ST) = 0.572/0.595 in S. arabica/lagascae) but within populations in the ruderal species (Phi(ST) = 0.355/0.387 S. capensis/parviflora). Principal coordinate analysis (PCoA) and STRUCTURE analysis showed that Stipa populations of all species clustered ecogeographically. A genome scan revealed that divergent selection at particular AFLP loci contributed to genetic differentiation. Irrespective of their different life histories, Stipa species responded similarly to the bioclimatic gradient in Jordan. We conclude that, in addition to predominant random processes, steep climatic gradients might shape the genetic structure of plant populations. PMID- 23369255 TI - Removal of Co(II), Cu(II) and Pb(II) ions by polymer based 2-hydroxyethyl methacrylate: thermodynamics and desorption studies. AB - Removal thermodynamics and desorption studies of some heavy metal ions such as Co(II), Cu(II) and Pb(II) by polymeric surfaces such as poly 2-hydroxyethyl methacrylate (PHEMA) and copolymer 2-hydroxyethyl methacrylate with monomer methyl methacrylate P(MMA-HEMA) as adsorbent surfaces from aqueous single solution were investigated with respect to the changes in pH of solution, adsorbent composition, contact time and temperature in the individual aqueous solution. The linear correlation coefficients of Langmuir and Freundlich isotherms were obtained and the results revealed that the Langmuir isotherm fitted the experiment results better than Freundlich isotherm. Using the Langmuir model equation, the monolayer removal capacity of PHEMA surface was found to be 0.7388, 0.8396 and 3.0367 mg/g for Co(II), Cu(IotaIota) and Pb(II) ions and removal capacity of P(MMA-HEMA) was found to be 28.8442, 31.1526 and 31.4465 mg/g for Co(II), Cu(IotaIota) and Pb(II) ions, respectively. Changes in the standard Gibbs free energy (DeltaG0), standard enthalpy (DeltaH0) and standard entropy (DeltaS0) showed that the removals of mentioned ions onto PHEMA and P(MMA-HEMA) are spontaneous and exothermic at 293-323 K. The maximum desorption efficiency was 75.26% for Pb(II) using 0.100 M HNO3, 70.10% for Cu(II) using 0.100 M HCl, 59.20% for 0.100 M HCl 63.67% Co(II). PMID- 23369257 TI - High levels of household food insecurity on the Navajo Nation. AB - OBJECTIVE: To assess levels of and identify factors associated with food insecurity on the Navajo Nation. DESIGN: A cross-sectional study was conducted utilizing the ten-item Radimer/Cornell food insecurity instrument. Sociodemographic, psychosocial and anthropometric data were collected. SETTING: Navajo Nation, USA. SUBJECTS: Two hundred and seventy-six members of the Navajo Nation were randomly selected at food stores and other community locations. RESULTS: Of the sample, 76.7% had some level of food insecurity. Less education (mean years of schooling: P = 0.0001; non-completion of higher education: P = 0.0003), lower full-time employment rates (P = 0.01), and lower material style of life (P = 0.0001), food knowledge (P = 0.001) and healthy eating self-efficacy (P < 0.0001) scores were all positively associated with food insecurity. Perceived expensiveness (P < 0.0001) and perceived inconvenience (P = 0.0001) of healthy choices were also positively associated with food insecurity. CONCLUSIONS: Food insecurity rates on the Navajo Nation are the highest reported to date in the USA and are likely attributable to the extremely high rates of poverty and unemployment. Reducing food insecurity on the Navajo Nation will require increasing the availability of affordable healthy foods, addressing poverty and unemployment, and providing nutrition programmes to increase demand. PMID- 23369256 TI - The global burden of neonatal hypothermia: systematic review of a major challenge for newborn survival. AB - BACKGROUND: To provide evidence on the global epidemiological situation of neonatal hypothermia and to provide recommendations for future policy and research directions. METHODS: Using PubMed as our principal electronic reference library, we searched studies for prevalence and risk factor data on neonatal hypothermia in resource-limited environments globally. Studies specifying study location, setting (hospital or community based), sample size, case definition of body temperature for hypothermia, temperature measurement method, and point estimates for hypothermia prevalence were eligible for inclusion. RESULTS: Hypothermia is common in infants born at hospitals (prevalence range, 32% to 85%) and homes (prevalence range, 11% to 92%), even in tropical environments. The lack of thermal protection is still an underappreciated major challenge for newborn survival in developing countries. Although hypothermia is rarely a direct cause of death, it contributes to a substantial proportion of neonatal mortality globally, mostly as a comorbidity of severe neonatal infections, preterm birth, and asphyxia. Thresholds for the definition of hypothermia vary, and data on its prevalence in neonates is scarce, particularly on a community level in Africa. CONCLUSIONS: A standardized approach to the collection and analysis of hypothermia data in existing newborn programs and studies is needed to inform policy and program planners on optimal thermal protection interventions. Thermoprotective behavior changes such as skin-to-skin care or the use of appropriate devices have not yet been scaled up globally. The introduction of simple hypothermia prevention messages and interventions into evidence-based, cost-effective packages for maternal and newborn care has promising potential to decrease the heavy global burden of newborn deaths attributable to severe infections, prematurity, and asphyxia. Because preventing and treating newborn hypothermia in health institutions and communities is relatively easy, addressing this widespread challenge might play a substantial role in reaching Millennium Development Goal 4, a reduction of child mortality. PMID- 23369258 TI - The study of leachate treatment by using three advanced oxidation process based wet air oxidation. AB - Wet air oxidation is regarded as appropriate options for wastewater treatment with average organic compounds. The general purpose of this research is to determine the efficiency of three wet air oxidation methods, wet oxidation with hydrogen peroxide and absorption with activated carbon in removing organic matter and nitrogenous compounds from Isfahan's urban leachate. A leachate sample with the volume of 1.5 liters entered into a steel reactor with the volume of three liters and was put under a 10-bar pressure, at temperatures of 100, 200, and 300 degrees as well as three retention times of 30, 60, and 90 minutes. The sample was placed at 18 stages of leachate storage ponds in Isfahan Compost Plant with the volume of 20 liters, using three WPO, WAO methods and a combination of WAO/GAC for leachate pre-treatment. Thirty percent of pure oxygen and hydrogen peroxide were applied as oxidation agents. The COD removal efficiency in WAO method is 7.8-33.3%, in BOD is 14.7-50.6%, the maximum removal percentage (efficiency) for NH4-N is 53.3% and for NO3-N is 56.4-73.9%. The removal efficiency of COD and BOD5 is 4.6%-34 and 24%-50 respectively in WPO method. Adding GAC to the reactor, the removal efficiency of all parameters was improved. The maximum removal efficiency was increased 48% for COD, 31%-43.6 for BOD5 by a combinational method, and the ratio of BOD5/COD was also increased to 90%. In this paper, WAO and WPO process was used for Leachate pre-treatment and WAO/GAC combinational process was applied for improving the organic matter removal and leachate treatment; it was also determined that the recent process is much more efficient in removing resistant organic matter. PMID- 23369260 TI - Access to kidney transplantation: outcomes of the non-referred. AB - BACKGROUND: There is a concern that some, especially older people, are not referred and could benefit from transplantation. METHODS: We retrospectively examined consecutive incident end stage renal disease (ESRD) patients at our center from January 2006 to December 2009. At ESRD start, patients were classified into those with or without contraindications using Canadian eligibility criteria. Based on referral for transplantation, patients were grouped as CANDIDATE (no contraindication and referred), NEITHER (no contraindication and not referred) and CONTRAINDICATION. The Charlson Comorbidity Index (CCI) was used to assess comorbidity burden. RESULTS: Of the 437 patients, 133 (30.4%) were CANDIDATE (mean age 50 and CCI 3.0), 59 (13.5%) were NEITHER (age 76 and CCI 4.4), and 245 (56.1%) were CONTRAINDICATION (age 65 and CCI 5.5). Age was the best discriminator between NEITHER and CANDIDATES (c-statistic 0.96, P <0.0001) with CCI being less discriminative (0.692, P <0.001). CANDIDATES had excellent survival whereas those patients designated NEITHER and CONTRAINDICATION had high mortality rates. NEITHER patients died or developed a contraindication at very high rates. By 1.5 years 50% of the NEITHER patients were no longer eligible for a transplant. CONCLUSIONS: There exists a relatively small population of incident patients not referred who have no contraindications. These are older patients with significant comorbidity who have a small window of opportunity for kidney transplantation. PMID- 23369259 TI - Conducting practice-based projects among chiropractors: a manual. AB - INTRODUCTION: Practice-based research is a challenge as clinicians are busy with their patients and any participation in research activities will be secondary to the needs of the patients and the clinic. As a result, it is difficult to obtain high compliance among clinicians. A method to enhance compliance in multicentre practice-based research has been developed and refined for use in the chiropractic setting and possibly also by other researchers in different settings. METHOD: This manual provides a stringent step-by-step approach for conducting clinic-based research. It describes the competencies and requirements of an effective working group, how to recruit participating clinicians and how to empower, encourage and support these clinicians to obtain good compliance. DISCUSSION: The main advantage of the method is the high compliance of participating clinicians compared to many other clinical studies. Difficulties with the method are described and suggestions for solutions are presented. CONCLUSIONS: This manual is a description of a method that may be of use for clinical researchers in the chiropractic setting. PMID- 23369261 TI - Ethical, legal, and social issues in the translation of genomics into health care. AB - PURPOSE: The rapid continuous feed of new information from scientific discoveries related to the human genome makes translation and incorporation of information into the clinical setting difficult and creates ethical, legal, and social challenges for providers. This article overviews some of the legal and ethical foundations that guide our response to current complex issues in health care associated with the impact of scientific discoveries related to the human genome. ORGANIZING CONSTRUCT: Overlapping ethical, legal, and social implications impact nurses and other healthcare professionals as they seek to identify and translate into practice important information related to new genomic scientific knowledge. METHODS: Ethical and legal foundations such as professional codes, human dignity, and human rights provide the framework for understanding highly complex genomic issues. Ethical, legal, and social concerns of the health provider in the translation of genomic knowledge into practice including minimizing harms, maximizing benefits, transparency, confidentiality, and informed consent are described. Additionally, nursing professional competencies related to ethical, legal, and social issues in the translation of genomics into health care are discussed. CONCLUSIONS: Ethical, legal, and social considerations in new genomic discovery necessitate that healthcare professionals have knowledge and competence to respond to complex genomic issues and provide appropriate information and care to patients, families, and communities. CLINICAL RELEVANCE: Understanding the ethical, legal, and social issues in the translation of genomic information into practice is essential to provide patients, families, and communities with competent, safe, effective health care. PMID- 23369262 TI - Preferences for rapid point-of-care HIV testing in Nova Scotia, Canada. AB - Rapid point-of-care (POC) testing for HIV has been shown to increase the uptake of testing, rates of clients receiving test results, numbers of individuals aware of their status and timely access to care for those who test positive. In addition, several studies have shown that rapid POC testing for HIV is highly acceptable to clients in a variety of clinical and community-based health care settings. Most acceptability studies conducted in North America, however, have been conducted in large, urban environments where concentrations of HIV testing sites and testing innovations are greatest. Using a survey of client preferences at a sexual health clinic in Halifax, Nova Scotia, we suggest that HIV test seekers living in a region outside of Canada's major urban HIV epicentres find rapid POC testing highly acceptable. We compare the results of the Halifax survey with existing acceptability studies of rapid POC HIV testing in North America and suggest ways in which it might be of particular benefit to testing clients and potential clients in Nova Scotia and other regions of Canada that currently have few opportunities for anonymous or rapid testing. Overall, we found that rapid POC HIV testing was highly desirable at this study site and may serve to overcome many of the challenges associated with HIV prevention and testing outside of well resourced metropolitan environments. PMID- 23369263 TI - Clinical and translational medicine: Integrative and practical science. PMID- 23369264 TI - Genome sequencing of the important oilseed crop Sesamum indicum L. AB - The Sesame Genome Working Group (SGWG) has been formed to sequence and assemble the sesame (Sesamum indicum L.) genome. The status of this project and our planned analyses are described. PMID- 23369265 TI - A prospective observational study with dose volume parameters predicting rectosigmoidoscopic findings and late rectosigmoid bleeding in patients with uterine cervical cancer treated by definitive radiotherapy. AB - PURPOSE: We assessed the value of dose-volumetric parameters predicting rectosigmoid mucosal changes (RMC) and late rectosigmoid complications (LRC). METHODS: Between January 2004 and February 2006, 77 patients with stage IB-IIIB cervical cancer underwent external beam radiotherapy and computed tomography (CT) based intracavitary irradiation. Total dose to the rectal point and several dose volumetric parameters for rectosigmoid colon (D20cc, D15cc, D10cc, D5cc, D2cc, D1cc, and D0.1cc , defined as the minimal doses received by the highest irradiated volumes of 20, 15, 10, 5, 2, 1, and 0.1 cc, respectively), were calculated using the equivalent dose in 2 Gy fractions (alpha/beta = 3, Gy3). The RMC and LRC were graded by rectosigmoidoscopy and Radiation Therapy Oncology Group criteria every 6 months, respectively. RESULTS: Of 77 patients, 27 (35.1%) patients developed RMC >= score 3 and 22 (28.6 %) patients developed LRC >= grade 2. There was a positive correlation between RMC score and LRC grade (r = 0.728, p < 0.001). In multivariate analyses, D5cc, among the dose-volumetric parameters, was significant parameter for the risks of RMC >= score 3 and LRC >= grade 2 (p < 0.05). CONCLUSIONS: D5cc may be a more reliable estimate than other dose volumetric parameters for predicting the risk of RMC >= score 3 and LRC >= grade 2 in CT-based brachytherapy. PMID- 23369266 TI - CpGIMethPred: computational model for predicting methylation status of CpG islands in human genome. AB - DNA methylation is an inheritable chemical modification of cytosine, and represents one of the most important epigenetic events. Computational prediction of the DNA methylation status can be employed to speed up the genome-wide methylation profiling, and to identify the key features that are correlated with various methylation patterns. Here, we develop CpGIMethPred, the support vector machine-based models to predict the methylation status of the CpG islands in the human genome under normal conditions. The features for prediction include those that have been previously demonstrated effective (CpG island specific attributes, DNA sequence composition patterns, DNA structure patterns, distribution patterns of conserved transcription factor binding sites and conserved elements, and histone methylation status) as well as those that have not been extensively explored but are likely to contribute additional information from a biological point of view (nucleosome positioning propensities, gene functions, and histone acetylation status). Statistical tests are performed to identify the features that are significantly correlated with the methylation status of the CpG islands, and principal component analysis is then performed to decorrelate the selected features. Data from the Human Epigenome Project (HEP) are used to train, validate and test the predictive models. Specifically, the models are trained and validated by using the DNA methylation data obtained in the CD4 lymphocytes, and are then tested for generalizability using the DNA methylation data obtained in the other 11 normal tissues and cell types. Our experiments have shown that (1) an eight-dimensional feature space that is selected via the principal component analysis and that combines all categories of information is effective for predicting the CpG island methylation status, (2) by incorporating the information regarding the nucleosome positioning, gene functions, and histone acetylation, the models can achieve higher specificity and accuracy than the existing models while maintaining a comparable sensitivity measure, (3) the histone modification (methylation and acetylation) information contributes significantly to the prediction, without which the performance of the models deteriorate, and, (4) the predictive models generalize well to different tissues and cell types. The developed program CpGIMethPred is freely available at http://users.ece.gatech.edu/~hzheng7/CGIMetPred.zip. PMID- 23369267 TI - Suboptimal health: a new health dimension for translational medicine. AB - BACKGROUND: One critical premise of disease-related biomarkers is the definition of the counterpart normality. Contrary to pre-clinical models that can be carefully tailored according to scientific need, heterogeneity and uncontrollability is the essence of humans in health studies. Fully characterization of consistent parameters that define the normal population is the basis to individual differences normalization irrelevant to a given disease process. Self claimed normal status may not represent health because asymptomatic subjects may carry chronic diseases or diseases at their early stage such as cancer, diabetes and hypertension. METHODS: This paper exemplifies the characterization of the suboptimal health status (SHS) which represents a new public health problem in a population with ambiguous health complaints such as general weakness, unexplained medical syndrome and chronic fatigue. We applied clinical informatics approaches and developed a questionnaire for measuring SHS. The validity and reliability of this approach were evaluated in a small pilot study and then in a cross-sectional study of 3,405 individuals. RESULTS: The final questionnaire congregated into a score (SHSQ-25) which could significantly distinguish among several abnormal conditions. CONCLUSION: SHSQ-25 could be used as a translational medicine instrument for health measuring in the general population. PMID- 23369268 TI - Effectiveness of photochemical and sonochemical processes in degradation of Basic Violet 16 (BV16) dye from aqueous solutions. AB - In this study, degradation of Basic Violet 16 (BV16) by ultraviolet radiation (UV), ultrasonic irradiation (US), UV/H2O2 and US/H2O2 processes was investigated in a laboratory-scale batch photoreactor equipped with a 55W immersed-type low pressure mercury vapor lamp and a sonoreactor with high frequency (130kHz) plate type transducer at 100W of acoustic power. The effects of initial dye concentration, concentration of H2O2 and solution pH and presence of Na2SO4 was studied on the sonochemical and photochemical destruction of BV16 in aqueous phase. The results indicated that in the UV/H2O2 and US/H2O2 systems, a sufficient amount of H2O2 was necessary, but a very high H2O2 concentration would inhibit the reaction rate. The optimum H2O2 concentration was achieved in the range of 17 mmol/L at dye concentration of 30 mg/L. A degradation of 99% was obtained with UV/H2O2 within 8 minutes while decolorization efficiency by using UV (23%), US (<6%) and US/H2O2(<15%) processes were negligible for this kind of dye. Pseudo-first order kinetics with respect to dyestuffs concentrations was found to fit all the experimental data. PMID- 23369269 TI - Biodegradation of high concentrations of benzene vapors in a two phase partition stirred tank bioreactor. AB - The present study examined the biodegradation rate of benzene vapors in a two phase stirred tank bioreactor by a bacterial consortium obtained from wastewater of an oil industry refinery house. Initially, the ability of the microbial consortium for degrading benzene was evaluated before running the bioreactor. The gaseous samples from inlet and outlet of bioreactor were directly injected into a gas chromatograph to determine benzene concentrations. Carbone oxide concentration at the inlet and outlet of bioreactor were also measured with a CO2 meter to determine the mineralization rate of benzene. Influence of the second non-aqueous phase (silicon oil) has been emphasized, so at the first stage the removal efficiency (RE) and elimination capacity (EC) of benzene vapors were evaluated without any organic phase and in the second stage, 10% of silicon oil was added to bioreactor media as an organic phase. Addition of silicon oil increased the biodegradation performance up to an inlet loading of 5580 mg/m3, a condition at which, the elimination capacity and removal efficiency were 181 g/m3/h and 95% respectively. The elimination rate of benzene increased by 38% in the presence of 10% of silicone oil. The finding of this study demonstrated that two phase partition bioreactors (TPPBs) are potentially effective tools for the treatment of gas streams contaminated with high concentrations of poorly water soluble organic contaminant, such as benzene. PMID- 23369270 TI - Genetic discrimination and life insurance: a systematic review of the evidence. AB - BACKGROUND: Since the late 1980s, genetic discrimination has remained one of the major concerns associated with genetic research and clinical genetics. Europe has adopted a plethora of laws and policies, both at the regional and national levels, to prevent insurers from having access to genetic information for underwriting. Legislators from the United States and the United Kingdom have also felt compelled to adopt protective measures specifically addressing genetics and insurance. But does the available evidence really confirm the popular apprehension about genetic discrimination and the subsequent genetic exceptionalism? METHODS: This paper presents the results of a systematic, critical review of over 20 years of genetic discrimination studies in the context of life insurance. RESULTS: The available data clearly document the existence of individual cases of genetic discrimination. The significance of this initial finding is, however, greatly diminished by four observations. First, the methodology used in most of the studies is not sufficiently robust to clearly establish either the prevalence or the impact of discriminatory practices. Second, the current body of evidence was mostly developed around a small number of 'classic' genetic conditions. Third, the heterogeneity and small scope of most of the studies prevents formal statistical analysis of the aggregate results. Fourth, the small number of reported genetic discrimination cases in some studies could indicate that these incidents took place due to occasional errors, rather than the voluntary or planned choice, of the insurers. CONCLUSION: Important methodological limitations and inconsistencies among the studies considered make it extremely difficult, at the moment, to justify policy action taken on the basis of evidence alone. Nonetheless, other empirical and theoretical factors have emerged (for example, the prevalence and impact of the fear of genetic discrimination among patients and research participants, the (un)importance of genetic information for the commercial viability of the private life insurance industry, and the need to develop more equitable schemes of access to life insurance) that should be considered along with the available evidence of genetic discrimination for a more holistic view of the debate. PMID- 23369271 TI - Modeling perchloroethylene degradation under ultrasonic irradiation and photochemical oxidation in aqueous solution. AB - Sonolysis and photochemical degradation of different compounds such as chlorinated aliphatic hydrocarbons are among the recent advanced oxidation processes. Perchloroethylene is one of these compounds that has been mainly used as a solvent and degreaser. In this work, elimination of perchloroethylene in aqueous solution by ultrasonic irradiation, andphotochemical oxidation by ultra violet ray and hydrogen peroxide were investigated. Three different initial concentrations of perchloroethylene at different pH values, detention periods, and concentrations of hydrogen peroxide were investigated. Head space gas chromatography with FID detector was used for analyses of perchloroethylene. This research was performed in 9 months from April through December 2011.Results showed that perchloroethylene could be effectively and rapidly degraded by ultrasonic irradiation, photochemical oxidation by ultra violet ray, hydrogen peroxide and a combination of these methods. Kinetics of perchloroethylene was strongly influenced by time, initial concentration and pH value. Degradation of Perchloroethylene increased with decrease in the initial concentration of perchloroethylene from 0.3 to 10 mg/L at all initial pH. The results showed an optimum degradation condition achieved at pH = 5 but did not affect significantly the perchloroethylene destruction in the various pH values. Kinetic modeling applied for the obtained results showed that the degradation of perchloroethylene by ultrasound and photo-oxidation followed first order and second order model. The percentage of removal in the hybrids reactor was higher than each of the reactors alone, the reason being the role of hydroxyl radical induced by ultrasound and photochemical reaction. PMID- 23369272 TI - Parental satisfaction and seizure outcome after corpus callosotomy in patients with infantile or early childhood onset epilepsy. AB - PURPOSE: To elucidate the benefit of corpus callosotmy in terms of parental satisfaction and seizure outcome. METHOD: This study included 16 consecutive patients with infantile or early childhood onset epilepsy who underwent total corpus callosotomy for alleviation of seizures. Questionnaires were sent anonymously to the parents asking about relative changes in seizures and about parental satisfaction for the post-operative outcome. RESULTS: The improvements in frequency, intensity, and duration of seizures were correlated with the level of satisfaction (Spearman's rank-order correlation coefficient, rho=0.87, 0.93, and 0.75, respectively). The highest level of satisfaction was only seen in patients who achieved freedom from all seizures or drop attacks. CONCLUSION: Complete seizure freedom and freedom from drop attacks are important goals of corpus callosotomy for parental satisfaction. These factors should be considered in assessing post-operative outcome after corpus callosotomy. PMID- 23369274 TI - Diagnosis and treatment of coronary artery disease in hemodialysis patients evaluated for transplant. AB - We present a review of current strategies for the diagnosis and treatment of coronary artery disease (CAD) in patients with advanced chronic kidney disease who are on the waiting list for transplants, based on data from the literature and originated from a single-center cohort of 1,250 patients with maximum follow up of 12 years. We discuss the best way to select patients to be tested for CAD, how to choose the more adequate screening test for CAD and cardiovascular disease, how to select patients for invasive treatment studies and how to treat patients with significant CAD. We also suggest new research avenues to be explored to resolve some problems in this area. PMID- 23369275 TI - Current metabolomics: practical applications. AB - The field of metabolomics continues to grow rapidly over the last decade and has been proven to be a powerful technology in predicting and explaining complex phenotypes in diverse biological systems. Metabolomics complements other omics, such as transcriptomics and proteomics and since it is a 'downstream' result of gene expression, changes in the metabolome is considered to best reflect the activities of the cell at a functional level. Thus far, metabolomics might be the sole technology capable of detecting complex, biologically essential changes. As one of the omics technology, metabolomics has exciting applications in varied fields, including medical science, synthetic biology, medicine, and predictive modeling of plant, animal and microbial systems. In addition, integrated applications with genomics, transcriptomics, and proteomics provide greater understanding of global system biology. In this review, we discuss recent applications of metabolomics in microbiology, plant, animal, food, and medical science. PMID- 23369273 TI - XENON in medical area: emphasis on neuroprotection in hypoxia and anesthesia. AB - Xenon is a medical gas capable of establishing neuroprotection, inducing anesthesia as well as serving in modern laser technology and nuclear medicine as a contrast agent. In spite of its high cost, its lack of side effects, safe cardiovascular and organoprotective profile and effective neuroprotective role after hypoxic-ischemic injury (HI) favor its applications in clinics. Xenon performs its anesthetic and neuroprotective functions through binding to glycine site of glutamatergic N-methyl-D-aspartate (NMDA) receptor competitively and blocking it. This blockage inhibits the overstimulation of NMDA receptors, thus preventing their following downstream calcium accumulating cascades. Xenon is also used in combination therapies together with hypothermia or sevoflurane. The neuroprotective effects of xenon and hypothermia cooperate synergistically whether they are applied synchronously or asynchronously. Distinguishing properties of Xenon promise for innovations in medical gas field once further studies are fulfilled and Xenon's high cost is overcome. PMID- 23369276 TI - Molecular recognition moiety and its target biomolecule interact in switching enzyme activity. AB - We conjugated a molecular recognition moiety, biotin, with an enzyme site specifically near to its active site and succeeded in inactivating the enzyme by binding the specific target biomolecule avidin to biotin. Bacterial P450 was used as a model enzyme, which has attracted much attention in several fields. Site directed mutagenesis was conducted to produce a mutant P450 that could attach biotin site-specifically. The activity of the conjugate decreased markedly to one tenth of that of biotinylated P450 after binding to avidin. Ultraviolet-visible spectroscopy of the carbon monoxide-bound P450, circular dichroism data, and the ratio of the active form to the sum of the active form and the inactive form indicated that this decrease in activity was because of a conformational change in the tertiary structure surrounding the active center after avidin binding, while the secondary structure of P450 remained unchanged. PMID- 23369277 TI - Haemophilus influenzae and the lung (Haemophilus and the lung). AB - Haemophilus influenzae is present as a commensal organism in the nasopharynx of most healthy adults from where it can spread to cause both systemic and respiratory tract infection. This bacterium is divided into typeable forms (such as type b) or nontypeable forms based on the presence or absence of a tough polysaccharide capsule. Respiratory disease is predominantly caused by the nontypeable forms (NTHi). Haemophilus influenzae has evolved a number of strategies to evade the host defense including the ability to invade into local tissue. Pathogenic properties of this bacterium as well as defects in host defense may result in the spread of this bacterium from the upper airway to the bronchi of the lung. This can result in airway inflammation and colonization particularly in chronic obstructive pulmonary disease. Treatment of respiratory tract infection with Haemophilus influenzae is often only partially successful with ongoing infection and inflammation. Improvement in patient outcome will be dependent on a better understanding of the pathogenesis and host immune response to this bacterium. PMID- 23369278 TI - Constructing narratives of heroism and villainy: case study of Myriad's BRACAnalysis((r)) compared to Genentech's Herceptin((r)). AB - BACKGROUND: The development of Herceptin((r)) is welcomed as a major advance in breast cancer treatment, while Myriad's development of BRACAnalysis((r)) is a widely used diagnostic. However useful and successful this product is, its presence in the public eye is tainted by predominantly negative press about gene patenting and business practices. DISCUSSION: While retrospection invites a sharp contrast between Genentech's triumphal narrative of scientific achievement and Myriad's public image as a controversial monopolist, a comparative history of these companies' products reveals two striking consistencies: patents and public discontent. Despite these similarities, time has reduced the narrative to that of hero versus villain: Genentech is lauded - at least for the final outcome of the Herceptin((r)) story - as a corporate good citizen, Myriad as a ruthless mercenary. Since patents undergird both products yet the narratives are so different, the stories raise the question: why have patents taken the fall as the scapegoat in current biotechnology policy debate? SUMMARY: A widely publicized lawsuit and accompanying bad press have cast Myriad as a villain in the evolving narrative of biotechnology. While the lawsuit suggests that this villainy is attributable to Myriad's intellectual property, we suggest through a comparative case study that, at least in the Myriad case, it is not simply about the patents but also other business strategies the company chose to pursue. Patents were a necessary but not sufficient cause of controversy. PMID- 23369279 TI - A novel method for the normalization of microRNA RT-PCR data. AB - BACKGROUND: MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate mRNA transcript levels and translation. Deregulation of microRNAs is indicated in a number of diseases and microRNAs are seen as a promising target for biomarker identification and drug development. miRNA expression is commonly measured by microarray or real-time polymerase chain reaction (RT-PCR). The findings of RT PCR data are highly dependent on the normalization techniques used during preprocessing of the Cycle Threshold readings from RT-PCR. Some of the commonly used endogenous controls themselves have been discovered to be differentially expressed in various conditions such as cancer, making them inappropriate internal controls. METHODS: We demonstrate that RT-PCR data contains a systematic bias resulting in large variations in the Cycle Threshold (CT) values of the low abundant miRNA samples. We propose a new data normalization method that considers all available microRNAs as endogenous controls. A weighted normalization approach is utilized to allow contribution from all microRNAs, weighted by their empirical stability. RESULTS: The systematic bias in RT-PCR data is illustrated on a microRNA dataset obtained from primary cutaneous melanocytic neoplasms. We show that through a single control parameter, this method is able to emulate other commonly used normalization methods and thus provides a more general approach. We explore the consistency of RT-PCR expression data with microarray expression by utilizing a dataset where both RT-PCR and microarray profiling data is available for the same miRNA samples. CONCLUSIONS: A weighted normalization method allows the contribution of all of the miRNAs, whether they are highly abundant or have low expression levels. Our findings further suggest that the normalization of a particular miRNA should rely on only miRNAs that have comparable expression levels. PMID- 23369280 TI - Misperceptions regarding protective barrier method use for safer sex among African-American women who have sex with women. AB - BACKGROUND: Barrier methods for HIV and sexually transmissible infection (STI) prevention among women who have sex with women (WSW) are available, although their effectiveness has not been systematically investigated. These methods are infrequently used by WSW. As part of a larger study on STI risk perceptions and safer sex among African-American WSW, we discovered several misperceptions regarding barrier methods that may be associated with their limited use. METHODS: Participants were recruited from the Jefferson County Health Department STI Clinic and through word of mouth in Birmingham, Alabama, for focus group discussions exploring perceptions of STI risk and safer sex. RESULTS: Seven focus groups with 29 participants were conducted (age range: 19-43 years). Several misperceptions regarding barrier methods were identified, notably the conflation of dental dams and female condoms. Descriptions of the use of barrier methods were qualified with phrases suggesting their hypothetical, rather than actual, use. Additional evidence that barrier methods are not actually used came from beliefs that dental dams and female condoms are available in major grocery stores or department store chains. CONCLUSIONS: Those providing sexual health services to WSW should be cautious in assuming that WSW have accurate information regarding barrier methods for safer sex. Sexual health services provided to WSW should include an accurate description of what barrier methods are, how to distinguish them from barrier methods more commonly used during heterosexual sex (female and male condoms), and how to use them correctly. Future studies are needed to address how effectively these measures reduce transmission of STIs among WSW. PMID- 23369281 TI - Effect of extremely low frequency electromagnetic field exposure on sleep quality in high voltage substations. AB - This study aims to investigate the effect of extremely low frequency electromagnetic fields exposure on sleep quality in high voltage substations (132, 230 and 400 KV) in Kerman city and the suburbs. For this purpose, the electric field intensity and magnetic flux density were measured in different parts of substations, and then the occupational exposure was estimated by averaging electric field intensity and magnetic flux density in a shift work. The cases comprised 67 workers who had been exposed to electromagnetic fields in age range of 24-57 and the controls were 110 persons the age ranged 24-50 years. Sleep quality of both groups was evaluated by the Pittsburgh Sleep Quality Index questionnaire (PSQI). Finally, these data were subjected to statistical analysis. The results indicated that 90.5% of cases and 85.3% of controls had the poor quality sleep according to PSQI (P-value=0.615). Total sleep quality score mean for the case and control groups were 10.22 +/- 3.4 and 9.74 +/- 3.62 (P value=0.415) ,respectively. Meantime to fall asleep for cases(35.68 +/- 26.25 min) was significantly higher than for controls (28.89 +/- 20.18 min) (P value=0.002). Cases had average sleep duration of 5.49 +/- 1.31 hours, which was lower ascompared with control subjects (5.90 +/- 1.67hours). Although there was a higher percentage for the case group with poor sleep quality than the control group, but no statistically significant difference was observed. PMID- 23369282 TI - Efficacy of low-dose radiotherapy in painful gonarthritis: experiences from a retrospective East German bicenter study. AB - PURPOSE: To evaluate the efficacy of low-dose radiotherapy in painful gonarthritis. METHODS: We assessed the medical records of 1037 patients with painful gonarthritis who had undergone low-dose radiotherapy between 1981 and 2008. The subjective patient perception of the response to irradiation as graded immediately or up to two months after the completion of a radiotherapy series was evaluated and correlated with age, gender, radiological grading and the duration of symptoms before radiotherapy. Moreover, we performed a mail survey to obtain additional long-term follow-up information and received one hundred and six evaluable questionnaires. RESULTS: We assessed 1659 series of radiotherapy in 1037 patients. In 79.3% of the cases the patients experienced a slight, marked or complete pain relief immediately or up to two months after the completion of radiotherapy. Gender, age and the duration of pain before radiotherapy did not have a significant influence on the response to irradiation. In contrast, severe signs of osteoarthritis were associated with more effective pain relief. In more than 50% of the patients who reported a positive response to irradiation a sustained period of symptomatic improvement was observed. CONCLUSIONS: Our results confirm that low-dose radiotherapy is an effective treatment for painful osteoarthritis of the knee. In contrast to an earlier retrospective study, severe signs of osteoarthritis constituted a positive prognostic factor for the response to irradiation. A randomized trial is urgently required to compare radiotherapy with other treatment modalities. PMID- 23369283 TI - Rapamycin and mTOR: a serendipitous discovery and implications for breast cancer. AB - Rapamycin was discovered more than thirty years ago from a soil sample from the island of Rapa Nui. It was isolated from Streptomyces hygroscopicus and initial characterization focused on its antifungal activities. Subsequent characterization showed that it has immunosuppressive properties and has been used successfully to reduce organ rejection with kidney transplantation. Rapamycin has proven to be a versatile compound with several seemingly unrelated properties, including antifungal, immunosuppressive, and anticancer. The National Cancer Institute (NCI) Developmental Therapeutics Program demonstrated that rapamycin inhibited cell growth in tumor cell lines. These observations stimulated research to explore the underlying mechanism of anti-tumor activities. Cell growth inhibition involves binding to the mammalian Target of Rapamycin (mTOR). The mTOR signaling pathway is critical to cell growth, proliferation, and survival and rapamycin inhibits these hallmark processes of cancer. Binding of growth factors activates mTOR signaling, which in turn leads to downstream phosphorylation of protein kinases, e.g., p70S6 kinase and lipid kinases in the phosphorylation of phosphoinositides. Understanding of mTOR signaling provided the biological basis for targeted chemotherapeutics development, including several rapamycin analogues for treating breast and other cancers. PMID- 23369284 TI - Temperature and cardiovascular and respiratory mortality in desert climate. A case study of Kerman, Iran. AB - Many studies have suggested that cardiovascular and respiratory disease mortality may change with fluctuations in temperature. In this study the relation between temperature and mortality has been studied in a city with desert climate. Four years data on daily temperature, cardiovascular, respiratory mortality and air pollution was acquired for Kerman, Iran. Time series, regression and correlation analyses were performed. Results showed an inverse relationship between mortality and temperature in Kerman, in which decreases in temperature were associated with increases in mortality. This pattern is similar to some foreign studies which show acclimatization of people living in southern warmer climates and less negative effects of warm temperatures. Among the pollutants only dust (p=0.003) and SO2 (p<0.001) showed a positive correlation with respiratory mortality. PMID- 23369285 TI - Degradation of a textile reactive azo dye by a combined biological-photocatalytic process: Candida tropicalis Jks2 -Tio2/Uv. AB - In the present study, the decolorization and degradation of Reactive Black 5 (RB5) azo dye was investigated by biological, photocatalytic (UV/TiO2) and combined processes. Application of Candida tropicalis JKS2 in treatment of the synthetic medium containing RB5 indicated complete decolorization of the dye with 200 mg/L in less than 24 h. Degradation of the aromatic rings, resulting from the destruction of the dye, did not occur during the biological treatment. Mineralization of 50 mg/L RB5 solution was obtained after 80 min by photocatalytic process (in presence of 0.2 g/L TiO2). COD (chemical oxygen demand) was not detectable after complete decolorization of 50 mg/L RB5 solution. However, photocatalytic process was not effective in the removal of the dye at high concentrations (>=200 mg/L). With 200 mg/L concentration, 74.9% of decolorization was achieved after 4 h illumination under photocatalytic process and the absorbance peak in UV region (attributed to aromatic rings) was not completely removed. A two-step treatment process, namely, biological treatment by yeast followed by photocatalytic degradation, was also assessed. In the combined process (with 200 mg/L RB5), absorbance peak in UV region significantly disappeared after 2 h illumination and about 60% COD removal was achieved in the biological step. It is suggested that the combined process is more effective than the biological and photocatalytic treatments in the remediation of aromatic rings. PMID- 23369286 TI - Self-assembled free-standing graphene oxide fibers. AB - It is a great challenge to directly assemble two-dimensional (2D) graphene oxide (GO) sheets into 1D fibers without any polymer or surfactant for their promising multifunctional applications. Herein, a facile self-assembly strategy is proposed to fabricate neat GO fibers from cost-efficient, aqueous GO suspension at a liquid/air interface based on the repulsive electrostatic forces, attractive van der Waals forces, and pi-pi stacking. During the self-assembly process and ultrasonic cleaning, the morphology variated from the source graphite powder through GO sheets to GO fibers and finally to neat GO fiber films. It is interesting to note that the electrical property of the GO fiber films was improved dramatically after subsequent low-temperature thermal annealing. The morphological evolution process and formation mechanism were analyzed on the basis of optical microscopy, scanning electron microscopy, and transmission electron microscopy observation, and the electrical characteristics was also discussion. PMID- 23369288 TI - Peptidomic profiles of post myocardial infarction rats affinity depleted plasma using matrix-assisted laser desorption/ionization time of flight (MALDI-ToF) mass spectrometry. AB - BACKGROUND: Despite major advances in drug development, effective cardiovascular therapies and suitable cardiovascular biomarkers remain limited. The aim of this study was to leverage mass spectrometry (MS) based peptide profiling strategies to identify changes that occur in peptidomic profiles of rat plasma following coronary artery ligation generated myocardial infarction (MI). METHODS: One week after MI, rats were randomized to receive either an ACE inhibitor (ramipril, Ram 1 mg/kg/day), or vehicle (Veh) for 12 weeks. Echocardiography and hemodynamic measurements were made before sacrifice and plasma collection. High abundance proteins were depleted with affinity capture before MS profiling. Differentially expressed peptide ions were identified using proprietary software (ClinProtTools). RESULTS: MI increased heart/body weight (18%), lung/body weight (56%), and left ventricular (LV) end diastolic pressure (LVEDP, 247%); and significantly reduced percentage fractional shortening (FS, 75%) and rate of pressure rise in the LV (dP/dtmax, 20%). Ram treatment significantly attenuated the changes in LVEDP (61%) and FS (27%). Analysis of MALDI-ToF generated mass spectra demonstrated that peptide ions 1271, 1878, 1955, 2041 and 2254 m/z were consistently decreased by Ram treatment (p < 0.001) and thus may be associated with the agent's therapeutic effects. Among peptides that were significantly changed, synapsin-2, adenomatous polyposis coli protein and transcription factor jun-D were identified as significantly reduced by Ram treatment. CONCLUSIONS: This approach allows us to screen for potential biomarkers in a window of the blood proteome that previously has been difficult to access. The data obtained from such an approach may potentially useful in prognosis, diagnosis, and monitoring of treatment response. PMID- 23369287 TI - Differential activation of human T cells to allogeneic endothelial cells, epithelial cells and fibroblasts in vitro. AB - BACKGROUND: In the direct pathway, T cells recognize intact donor major histocompatability complexes and allogeneic peptide on the surface of donor antigen presenting cells (APCs). Indirect allorecognition results from the recognition of processed alloantigen by self MHC complexes on self APCs. In this study, we wished to evaluate the relative contribution of different intragraft cells to the alloactivation of nave and memory T cells though the direct and the indirect pathway of allorecognition. METHODS: The processing of membrane fragments from IFN-treated single donor endothelial cells (EC), fibroblasts or renal epithelial cells (RPTEC) was evaluated by DiOC labeling of each cell type and flow cytometry following interaction with PBMC. Direct pathway activation of nave CD45RA+ or memory CD45RO+ CD4+ T cells was evaluated following coculture with IFN-treated and MHC class II-expressing EC, fibroblasts or RPTEC. Indirect pathway activation was assessed using CD45RA+ or CD45RO+ CD4+ T cells cocultured with autologous irradiated APCs in the absence or presence of sonicates derived from IFN-treated allogeneic EC, fibroblasts or RPTEC. Activation of T cells was assessed by [3H]thymidine incorporation and by ELISpot assays. RESULTS: We find that CD14+ APCs readily acquire membrane fragments from fibroblasts and RPTEC, but fail to acquire membrane fragments from intact EC. However, APCs process membranes from EC undergoing apoptosis.There was a notable direct pathway alloproliferative response of CD45RO+ CD4+ T cells to IFN-treated EC, but not to fibroblasts or RPTEC. Also, there was a minimal direct pathway response of CD45RA+ CD4+ T cells to all cell types. In contrast, we found that both CD45RA+ and CD45RO+ CD4+ T cells proliferated following coculture with autologous APCs in the presence of sonicates derived from IFN-treated EC, fibroblasts or RPTEC. By ELISpot, we found that these T cells stimulated via the indirect pathway also produced the cytokines IFN, IL-2, IL-4 and IL-5. CONCLUSIONS: Recipient APCs may readily process membrane fragments from allogeneic intragraft cells, but not from EC unless they are undergoing apoptosis. This processing is sufficient for indirect pathway alloactivation of both CD45RA+ and CD45RO+ CD4+ T cells. Only graft vascular EC mediate direct pathway reactivation of CD4+ T cells. PMID- 23369289 TI - Reduced cilia frequencies in human renal cell carcinomas versus neighboring parenchymal tissue. AB - BACKGROUND: Cilia are essential organelles in multiple organ systems, including the kidney where they serve as important regulators of renal homeostasis. Renal nephron cilia emanate from the apical membrane of epithelia, extending into the lumen where they function in flow-sensing and ligand-dependent signaling cascades. Ciliary dysfunction underlies renal cyst formation that is in part caused by deregulation of planar cell polarity and canonical Wnt signaling. Renal cancer pathologies occur sporadically or in heritable syndromes caused by germline mutations in tumor suppressor genes including VHL. Importantly, Von Hippel-Lindau (VHL) patients frequently develop complex renal cysts that can be considered a premalignant stage. One of the well-characterized molecular functions of VHL is its requirement for the maintenance of cilia. In this study, tissue from 110 renal cancer patients who underwent nephrectomy was analyzed to determine if lower ciliary frequency is a common hallmark of renal tumorigenesis by comparing cilia frequencies in both tumor and adjacent parenchymal tissue biopsies from the same kidney. METHODS: We stained sections of human renal material using markers for cilia. Preliminary staining was performed using an immunofluorescent approach and a combination of acetylated-alpha-tubulin and pericentrin antibodies and DAPI. After validation of an alternative, higher throughput approach using acetylated-alpha-tubulin immunohistochemistry, we continued to manually quantify cilia in all tissues. Nuclei were separately counted in an automated fashion in order to determine ciliary frequencies. Similar staining and scoring for Ki67 positive cells was performed to exclude that proliferation obscures cilia formation potential. RESULTS: Samples from renal cell carcinoma patients deposited in our hospital tissue bank were previously used to compose a tissue microarray containing three cores of both tumor and parenchymal tissue per patient. Cilia frequencies in a total of eighty nine clear cell, eight papillary, five chromophobe renal cell carcinomas, two sarcomatoid renal tumors and six oncocytomas were determined. A marked decrease of primary cilia across renal cell carcinoma subtypes was observed compared to adjacent nontumorigenic tissue. CONCLUSIONS: Our study shows that cilia are predominantly lost in renal cell carcinomas compared to tissue of the tumor parenchyma. These results suggest that ciliary loss is common in renal tumorigenesis, possibly participating in the sequence of cellular events leading to malignant tumor development. Future therapies aimed at restoring or circumventing cilia signaling might therefore aid in current treatment efficacy. PMID- 23369290 TI - A decade plus of translation: what do we understand? AB - It has been more than a decade that the term "Translational" (medicine, Research, Science) has trickled through the minds of academics, clinicians, business persons, regulators, policy makers, patients and their families, patient advocates, politicians and the public. Although the term means different things for different stake holders, it reflect and eagerness to see a fruitful outcome of the resources invested in biotechnology to benefit primarily the patients but also provide financial return for those who invested. Skeptics remain who feel the concept if abused by those attempting to deviate funds for basic or clinical research to a new domain performing similar tasks under a different egida. In reality, translational sciences are not different in scope any from previous efforts to focus the goals of research toward the relevant object of helping the disabled. The difference is that, in recent decades, awareness has risen about the difficulties of reaching this goal. In particular, it has become clear that the difficulties are not limited to scientific challenges, but to a myriad of hurdles that make testing and licensing of novel concepts unnecessarily burdensome. Moreover, it was recognized that the infrastructure to support clinical research is frequently outdated and inappropriate. The biggest hurdle, however, remains the cost and the length of clinical testing that could prolong of decades the application of even the most successful treatments. As for any expanding field, a plethora of journals has appeared with "Translational" in their title. This is a positive sign of the growth in interest for the field and the need to respond to a need for editorial boards competent in the challenges of judging clinical testing. In this editorial, we will discuss the meaning of translational medicine, its goals and needs; we will summarize the remaining challenges and will provide a personal overview of the strategies that remain to be implemented. PMID- 23369291 TI - 2012 highlights in translational 'omics. PMID- 23369292 TI - Development of a novel DNA sequencing method not only for hepatitis B virus genotyping but also for drug resistant mutation detection. AB - BACKGROUND: In HBV-infected patients, different genotypes of the hepatitis B virus influence liver disease progression and response to antiviral therapy. Moreover, long-term antiviral therapy will eventually select for drug-resistant mutants. Detection of mutations associated to antiviral therapy and HBV genotyping are essential for monitoring treatment of chronic hepatitis B patients. RESULTS: In this study, a simple method of partial-S gene sequencing using a common PCR amplification was established for genotyping clinical HBV isolates sensitively, which could detect the drug-resistant mutations successfully at the same time. CONCLUSIONS: The partial S gene sequencing assay developed in this study has potential for application in HBV genotyping and drug resistant mutation detection. It is simpler and more convenient than traditional S gene sequencing, but has nearly the same sensitivity and specificity when compared to S gene sequencing. PMID- 23369293 TI - The prevalence of sexually transmissible infections among female sex workers from countries with low and high prevalences in Melbourne. AB - OBJECTIVES: To assess the proportion of female sex workers (FSWs) from low prevalence ('other') and high-prevalence countries (HPCs) for sexually transmissible infections (STIs) in Melbourne. METHODS: Retrospective data analysis from the Melbourne Sexual Health Centre database for February 2002-May 2011. RESULTS: Some 1702 HPC FSWs, 2594 other FSWs and 13?644 nonFSW women were included, with 12?891 and 21?611 consultations, respectively, for HPC FSWs and other FSWs. Proportions of HPC FSWs with chlamydia (Chlamydia trachomatis) (4.2% v. 3.3%, P=0.14), gonorrhoea (Neisseria gonorrhoeae) (0.24% v. 0.31%, P=0.66) or trichomonas (0.65 v. 0.46, P=0.42) at first visit were similar to those of other FSWs, but nonFSWs had a higher prevalence of chlamydia and gonorrhoea (P<0.01). On return visits, chlamydia (1.2% v. 0.92%, P<0.05) and gonorrhoea (0.29% v. 0.10%, P=<0.05) were more common in HPC FSWs than other FSWs. The presence of any of these STIs among FSWs was predicted by having private nonpaying partners in the last year (adjusted odds ratio (AOR): 1.99 (95% confidence interval (CI): 1.52-2.61)), having private partners from overseas (AOR: 1.69 (95% CI: 1.33 2.16)) and being a HPC FSW (AOR: 1.38 (95% CI: 1.12-1.72)). Injecting drug use was less common in HPC FSWs than in other FSWs (0.82% v. 16.54%, P<0.0001). CONCLUSIONS: STI prevalence was low among FSWs from countries with high and low background STI. Among FSWs having private sex partners and private partners from overseas were the primary predictors for STIs. PMID- 23369295 TI - Biosorption of methyl blue onto tartaric acid modified wheat bran from aqueous solution. AB - Tartaric acid modified wheat bran was utilized as adsorbent to remove methyl blue, a basic dye from aqueous solution. Batch experiments were carried out to study the effect of various experimental parameters such as initial solution pH, contact time, initial dye concentration and adsorbent dosage, on dye adsorption. The results showed that the modification of wheat bran by tartaric acid significantly improved its adsorption capacity, and made this material a suitable adsorbent to remove methyl blue. The adsorption capacity of modified wheat bran was about 1.6 times higher than that of unmodified one. The amount of methyl blue adsorbed was found to vary with initial solution pH, adsorbent dosage, contact time and initial methyl blue concentration. Kinetics study showed that the overall adsorption rate of methyl blue was illustrated by pseudo-second-order kinetic model. The applicability of the Langmuir and Freundlich models for the data was tested. Both models adequately described the experimental data of the biosorption of methyl blue. The maximum adsorption capacity for methyl blue calculated from Langmuir model was 25.18 mg/g. The study has shown the effectiveness of modified wheat bran in the removal of methyl blue, and that it can be considered as an attractive alternative to the more expensive technologies used in wastewater treatment. PMID- 23369294 TI - Hypofractionated stereotactic body radiation therapy as monotherapy for intermediate-risk prostate cancer. AB - BACKGROUND: Hypofractionated stereotactic body radiation therapy (SBRT) has been advanced as monotherapy for low-risk prostate cancer. We examined the dose distributions and early clinical outcomes using this modality for the treatment of intermediate-risk prostate cancer. METHODS: Forty-one sequential hormone-naive intermediate-risk prostate cancer patients received 35-36.25 Gy of CyberKnife delivered SBRT in 5 fractions. Radiation dose distributions were analyzed for coverage of potential microscopic ECE by measuring the distance from the prostatic capsule to the 33 Gy isodose line. PSA levels, toxicities, and quality of life (QOL) measures were assessed at baseline and follow-up. RESULTS: All patients completed treatment with a mean coverage by the 33 Gy isodose line extending >5 mm beyond the prostatic capsule in all directions except posteriorly. Clinical responses were documented by a mean PSA decrease from 7.67 ng/mL pretreatment to 0.64 ng/mL at the median follow-up of 21 months. Forty patients remain free from biochemical progression. No Grade 3 or 4 toxicities were observed. Mean EPIC urinary irritation/obstruction and bowel QOL scores exhibited a transient decline post-treatment with a subsequent return to baseline. No significant change in sexual QOL was observed. CONCLUSIONS: In this intermediate-risk patient population, an adequate radiation dose was delivered to areas of expected microscopic ECE in the majority of patients. Although prospective studies are needed to confirm long-term tumor control and toxicity, the short-term PSA response, biochemical relapse-free survival rate, and QOL in this interim analysis are comparable to results reported for prostate brachytherapy or external beam radiotherapy. TRIAL REGISTRATION: The Georgetown Institutional Review Board has approved this retrospective study (IRB 2009-510). PMID- 23369296 TI - Cell therapies and regenerative medicine - the dawn of a new age or more hype than hope? PMID- 23369297 TI - Fluorescent detection of lead in environmental water and urine samples using enzyme mimics of catechin-synthesized Au nanoparticles. AB - A facile, cost-effective, and sensitive fluorescent method for Pb2+ ion detection had been developed using catechin synthesized gold nanoparticles (C-Au NPs). The Pb-catechin complexes and Pb-Au alloys that formed on the C-Au NPs surfaces allowed NPs to exhibit peroxidase-mimicking catalytic activity in the H2O2 mediated oxidation of Amplex UltraRed (AUR). In 5 mM Tris-acetate buffers at pH 7.0, the H2O2-AUR-C-Au NP probe was highly selective (>100-fold) for Pb2+ ions in the presence of other tested metal ions (K+, Ag+, Na+, Cd2+, Ni2+, Ca2+, Hg2+, Sr2+, Co2+, Cu2+, Ba2+, Fe2+, Mg2+, Cr3+, and Fe3+ ions). The fluorescence intensity (excitation/emission maxima ~540/588 nm) of the AUR product was proportional to the concentration of Pb2+ ions in the range of 10 nM-1.0 MUM with a linear correlation (R2 = 0.99). The H2O2-AUR-C-Au NP probe detected Pb2+ ions with a limit of detection (signal-to-noise ratio: 3) of 1.5 nM. The practicality of the H2O2-AUR-C-Au NP probe was validated for the determination of Pb2+ ion concentration in environmental water and urine samples, demonstrating its advantages of simplicity, selectivity, and sensitivity. PMID- 23369298 TI - Decolorization and detoxification of Synozol red HF-6BN azo dye, by Aspergillus niger and Nigrospora sp. AB - In the present investigation the fungi, Aspergillus niger and Nigrospora sp. were employed for decolorization of Synozol red HF-6BN. Decolorization study showed that Aspergillus niger and Nigrospora sp. were able to decolorize 88% and 96% Synozol red 6BN, respectively, in 24 days. It was also studied that 86% and 90% Synozol red containing of dye effluent was decolorized by Aspergillus niger and Nigrospora sp. after 28 days of incubation at room temperature. A fungal-based protein with relative molecular mass of 70 kDa was partially purified and examined for enzymatic characteristics. The enzyme exhibited highest activity at temperature ranging from 40-50 degrees C and at pH=6.0. The enzyme activity was enhanced in the presence of metal cations. High performance liquid chromatography analysis confirmed that these fungal strains are capable to degrade Synozol red dye into metabolites. No zones of inhibition on agar plates and growth of Vigna radiata in the presence of dye extracted sample, indicated that the fungal degraded dye metabolites are nontoxic to beneficial micro-flora and plant growth. Aspergillus niger and Nigrospora sp. have promising potential in color removal from textile wastewater-containing azo dyes. PMID- 23369299 TI - Magntic susceptibility as a proxy to heavy metal content in the sediments of Anzali wetland, Iran. AB - Heavy metal concentrations and magnetic susceptibility of sediment samples were analyzed as indicators of urban and industrial contamination in Anzali wetland in Gilan, Iran. The aim was to investigate the suitability of magnetic properties measurements for indicating heavy metal pollution. The concentration of six heavy metals (Ni, Cr, Cd, Zn, Fe, and Pb) was determined in different depths of four sediment core samples within four different regions of the wetland (Abkenar, Hendekhaleh, Shijan and Siakeshim). Average concentration of heavy metals in the sediment cores was higher than the severe effect level (SEL) for Ni, Cr and Fe (77.26, 113.63 ppm and 5.2%, respectively) and lower than SEL for Cd, Zn and Pb (0.84, 137.7, 29.77 ppm, respectively). It was found that the trend of metal concentrations with the depth is different in each core and is related to the pollution discharges into the rivers entering the wetland. Core magnetic susceptibility measurements also showed different magnetic properties in each core. Cluster analysis was applied using Pearson correlation coefficient between heavy metal concentrations and magnetic properties across each core. Significant relationship was found to exist between magnetic susceptibility and the concentration of Ni in Abkenar and the concentration of Fe in other regions. Whereas Abkenar is almost the isolated and uncontaminated region of the wetland, it revealed a difference in magnetic properties between contaminated and uncontaminated sediments. It was concluded that magnetic properties of samples from contaminated zone were mostly related to Fe content. The result of this study demonstrated that magnetic susceptibility measurements could be applied as a proxy method for heavy metal pollution determination in marine environments in Iran especially as a rapid and cost-effective introductory site assessments. PMID- 23369300 TI - Stimulation of food intake after central galanin is associated with arcuate nucleus activation and does not differ between genetically selected low and high body weight lines of chickens. AB - Galanin, a 29 residue peptide found in the hypothalamus, causes orexigenic effects in a variety of species. In the present study, we investigated appetite associated effects of galanin in chicks from lines which have been selected from a common founder population for either low or high body weight. The low line consists of some anorexic individuals and there are obese individuals in the high line. Central galanin caused increased food intake in both lines with the magnitude of response similar in both lines. We also quantified the number of c Fos immunoreactive cells in several hypothalamic nuclei that are associated with appetite. Only the arcuate nucleus had an increase in the number of reactive cells, a response that was similar for both lines. From these results we concluded that selection for body weight likely did not affect galanin function on induction of feeding in either lines, and that the effect of galanin is associated with arcuate nucleus activation in chicks. PMID- 23369302 TI - Cadaveric limb analysis of tendon length discrepancy of posterior tibial tendon transfer through the interosseous membrane. AB - The posterior tibial tendon transfer through the interosseous membrane, as popularized by Watkins in 1954, is a procedure for treating reducible eversion and dorsiflexory paresis used by lower extremity foot and ankle surgeons. The posterior tibial tendon has been transferred to various locations on the midfoot for equinus and equinovarus deformities. Dorsiflexory paresis is a common symptom in equinovarus deformity, clubfoot deformity, Charcot-Marie-Tooth disease, leprosy, mononeuropathy, trauma to the common peroneal nerve, cerebrovascular accident, and Duchenne's muscular dystrophy. The main difficulty with this procedure, often discussed by surgeons, is inadequate tendon length, making anchoring to the cuneiforms or cuboid difficult. The goal of our cadaveric study was threefold. First, we sought to determine whether the tendon length is sufficient when transferring the posterior tibial tendon to the dorsum of the foot through the interosseous membrane for a dynamic or a static transfer. Second, we wished to describe the surgical technique designed to obtain the maximal length. Finally, we sought to discuss the strategies used when the tendon length for transfer is insufficient. PMID- 23369303 TI - A comparison of methicillin-resistant and methicillin-susceptible Staphylococcus aureus reveals no clinical and epidemiological but molecular differences. AB - Most studies on Staphylococcus aureus have focused on the molecular epidemiology of methicillin-resistant S. aureus (MRSA) infections. In contrast, little information is available regarding the molecular epidemiology of currently circulating methicillin-susceptible S. aureus (MSSA) isolates in hospital settings, an epoch when the epidemiology of S. aureus has undergone significant changes. We conducted a cross-sectional study to compare the clinical, epidemiological, and genetic characteristics of MSSA and MRSA isolates at 3 tertiary-care hospitals in Medellin, Colombia, from February 2008 to June 2010. The infections were classified according to the Centers for Disease Control and Prevention (CDC) definitions. Genotypic analysis included spa typing, multilocus sequence typing (MLST) and staphylococcal cassette chromosome (mec) (SCCmec) typing. A total of 810 patients was enrolled. One hundred infections (12.3%) were classified as community-associated (31 CA-MSSA, 69 CA-MRSA), 379 (46.8%) as healthcare-associated community-onset (136 HACO-MSSA, 243 HACO-MRSA), and 331 (40.9%) as healthcare-associated hospital-onset (104 HAHO-MSSA, 227 HAHO-MRSA). Genotype analyses showed a higher diversity and a more varied spa type repertoire in MSSA than in MRSA strains. Most of the clinical-epidemiological characteristics and risk factors evaluated did not allow for discriminating MRSA- from MSSA-infected patients. The lack of equivalence among the genetic backgrounds of the major MSSA and MRSA clones would suggest that the MRSA clones are imported instead of arising from successful MSSA clones. This study emphasizes the importance of local surveillance to create public awareness on the changing S. aureus epidemiology. PMID- 23369304 TI - Rapid and high-resolution distinction of community-acquired and nosocomial Staphylococcus aureus isolates with identical pulsed-field gel electrophoresis patterns and spa types. AB - Methicillin-resistant Staphylococcus aureus (MRSA) represent a serious threat for public health worldwide. Of particular concern is the emergence of community acquired MRSA, which is often difficult to distinguish from nosocomial MRSA due to a lack of suitable typing methods for early detection. For example, the USA300 pulsed-field gel electrophoresis (PFGE) pattern includes both the 'classical' community-acquired USA300 clone with spa type t008 and an epidemiologically unrelated nosocomial clone with spa type t024. Likewise, spa typing cannot distinguish the classic USA300 from nosocomial MRSA with the spa type t008. Since the fast and high-resolution distinction of these S. aureus types is important for infection prevention and surveillance, we investigated whether multiple-locus variable number tandem repeat fingerprinting (MLVF) can be applied to overcome these limitations. Indeed, MLVF correctly grouped 91 MRSA isolates belonging to the classic USA300 lineage, nosocomial MRSA isolates with the USA300 PFGE profile and spa type t024, and nosocomial MRSA isolates with spa type t008 into 3 distinct clusters. Importantly, several sub-clusters were also identified, reflecting epidemiological relationships between the respective isolates. We conclude that MLVF has the discriminatory power needed to rapidly distinguish very similar community-acquired and nosocomial MRSA isolates and that MLVF-based sub-clustering of isolates is highly useful for epidemiological investigations, outbreak prevention, and control. PMID- 23369305 TI - Overexpression of polyphosphate kinase gene (ppk) increases bioinsecticide production by Bacillus thuringiensis. AB - Polyphosphate (polyP), synthesized by polyP kinase (PPK) using the terminal phosphate of ATP as substrate, performs important functions in every living cell. The present work reports on the relationship between polyP metabolism and bioinsecticide production in Bacillus thuringiensis subsp. israelensis (Bti). The ppk gene of Bti was cloned into vector pHT315 and the effect of its overexpression on endotoxin production was determined. Endotoxin production by the recombinant strain was found to be consistently higher than that by the wild type strain and the strain that carried the empty plasmid. The toxicity of the recombinant mutant strain (LC50 5.8+/-0.6ngml(-1)) against late 2nd instar Culex quinquefasciatus was about 7.7 times higher than that of Bti (LC50 44.9+/-7ngml( 1)). To our knowledge this is the first reported study which relates polyP metabolism with bioinsecticide biosynthesis. PMID- 23369306 TI - Cloning, expression and characterization of D-aminoacylase from Achromobacter xylosoxidans subsp. denitrificans ATCC 15173. AB - D-Aminoacylase catalyzes the conversion of N-acyl-D-amino acids to d-amino acids and fatty acids. The aim of this study was to identify the D-aminoacylase gene from Achromobacter xylosoxidans subsp. denitrificans ATCC 15173 and investigate the biochemical characterization of the enzyme. A previously uncharacterized D aminoacylase gene (ADdan) from this organism was cloned and sequenced. The open reading frame (ORF) of ADdan was 1467 bp in size encoding a 488-amino acid polypeptide. ADdan, with a high amino acid similarity to N-acyl-D-aspartate amidohydrolase from Alcaligenes A6, showed relatively low sequence similarities to other characterized D-aminoacylases. The recombinant ADdan protein was expressed in Escherichia coli BL21 (DE3) using pET-28a with a T7 promoter. The enzyme was purified in a single chromatographic step using nickel affinity gel column. The molecular mass of the expressed protein, calculated by SDS-PAGE, was about 52 kDa. The purified ADdan showed optimal activity at pH 8.0 and 50 degrees C, and was stable at pH 6.0-8.0 and up to 45 degrees C. Its activity was inhibited by Cu(2+), Fe(2+), Ca(2+), Mn(2+), Ni(2+), Zn(2+) and Hg(2+), whereas Mg(2+) had no significant influence on this recombinant D-aminoacylase. This is the first report on the characterization of D-aminoacylase with activity towards both N-acyl derivatives of neutral D-amino acids and N-acyl-D-aspartate. The characteristics of ADdan could prove to be of interest in industrial production of D-amino acids. PMID- 23369307 TI - The role of axillary ultrasound in the detection of metastases from primary breast cancers. AB - BACKGROUND: The value of diagnostic axillary ultrasound (AUS) in the preoperative evaluation of lymph nodes for breast cancer patients has yet to be completely clarified. METHODS: Results of AUS were reviewed for all patients with invasive cancers who were clinically node negative (cN0) and had subsequent axillary lymphadenectomy. Patients with positive ultrasound-guided node core biopsies bypassed sentinel lymph node biopsy (SLNB) and had axillary lymph node dissection, whereas those with sonographically normal nodes or benign/nondiagnostic biopsy results had SLNB. RESULTS: Of 128 cN0 patients with invasive cancer, 23 (18%) had abnormal axillary AUS. Of 18 core biopsies, 12 (67%) were malignant. SLNB was positive in 19 of 110 (17%) patients. ALND was performed in 32 (25%) patients. For determining axillary metastases, AUS sensitivity was 16 of 31 (52%), specificity was 90 of 97 (93%), the positive predictive value was 16 of 23 (69%), and the negative predictive value was 90 of 105 (86%). CONCLUSIONS: AUS examination was a valuable method for evaluating the axilla in newly diagnosed cN0 breast cancer patients. PMID- 23369308 TI - Levothyroxine replacement dosage determination after thyroidectomy. AB - BACKGROUND: The goal of this study was to identify a simple and effective way of calculating levothyroxine doses for postsurgical hypothyroidism. METHODS: Levothyroxine dosage was calculated using a weight (MUg/kg)-based formula for patients who underwent thyroidectomy for benign disease from 2001 to 2011. Other formulas using age, sex, ideal body weight, body mass index, and body surface area were also evaluated. RESULTS: Four hundred four patients were included; 85% were women. The mean initial levothyroxine dosage was 1.4 MUg/kg, which resulted in thyroid-stimulating hormone normalization in 59%, suppression in 23%, and elevation in 18% of patients. After dose adjustments, the mean therapeutic levothyroxine doses after total thyroidectomy and lobectomy were 1.5 and 1.3 MUg/kg, respectively. A regression model incorporating other patient factors did not produce a more reliable dosing regimen. CONCLUSION: A 1.5- and 1.3-MUg/kg dosage calculation based on actual weight is currently the best estimation for levothyroxine replacement therapy after thyroidectomy. PMID- 23369309 TI - Surgery and sailing. PMID- 23369310 TI - Ascites and malnutrition are predictive factors for incomplete cytoreductive surgery for peritoneal carcinomatosis from gastric cancer. AB - BACKGROUND: Prognosis in peritoneal carcinomatosis from gastric cancer has improved with cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy. The aim of this study was to identify predictive factors for incomplete CS. METHODS: Forty-five patients undergoing laparotomy for gastric cancer with peritoneal carcinomatosis were prospectively included from January 2000 to December 2010. In case of optimal CS, patients (n = 14) received hyperthermic intraperitoneal chemotherapy. Otherwise, the laparotomy was closed or a palliative procedure was performed if necessary. All preoperative data were compared between the 2 groups. RESULTS: Ascites (hazard ratio, .09; 95% confidence interval, .010-.48; P = .0103) and nutritional status evaluated by the prognostic nutrition index (hazard ratio, .11; 95% confidence interval, .0019 .54; P = .027) were independent predictive factors for incomplete CS. CONCLUSIONS: The selection of patients for CS plus hyperthermic intraperitoneal chemotherapy should include the assessment of nutritional status and the detection of an ascites. PMID- 23369311 TI - Elective versus emergency surgery for ulcerative colitis: a National Surgical Quality Improvement Program analysis. AB - BACKGROUND: It is unclear whether advances in the medical management of ulcerative colitis (UC) have altered outcomes for medically intractable disease. Therefore, it is essential to understand the current impact of elective versus emergency surgery for UC. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to compare outcomes for elective versus emergency UC surgery between 2005 and 2010. RESULTS: Four thousand nine hundred sixty-two patients were eligible for study (94% elective and 6% emergent). Emergency surgery patients were significantly older and frequently underwent open surgery. Emergency cases were associated with a higher frequency of cardiac, pulmonary, and renal comorbidities; postoperative complications; longer hospital stays; and higher rates of return to the operating room. CONCLUSIONS: In the era of advanced UC medical therapy, the need for emergency surgery still exists and is associated with substantial morbidity and mortality. Data are needed to determine if earlier selection of surgery would be beneficial. PMID- 23369313 TI - AJIC's peer review process: striving for ever-increasing excellence. PMID- 23369314 TI - Perceived strength of evidence supporting practices to prevent health care associated infection: results from a national survey of infection prevention personnel. AB - BACKGROUND: Limited data exist describing the perceived strength of evidence behind practices to prevent common health care-associated infections (HAIs). We conducted a national survey of infection prevention personnel to assess perception of the evidence for various preventive practices. We were also curious whether lead infection preventionist certification in infection prevention and control (CIC) correlated with perceptions of the evidence. METHODS: In 2009, we mailed surveys to 703 infection prevention personnel using a national random sample of US hospitals and all Veterans Affairs hospitals; the response rate was 68%. The survey asked the respondent to grade the strength of evidence behind prevention practices. We considered "strong" evidence as being 4 and 5 on a Likert scale. Multivariable logistic regression models assessed associations between CIC status and the perceived strength of the evidence. RESULTS: The following practices were perceived by 90% or more of respondents as having strong evidence: alcohol-based hand rub, aseptic urinary catheter insertion, chlorhexidine for antisepsis prior to central venous catheter insertion, maximum sterile barriers during central venous catheter insertion, avoiding the femoral site for central venous catheter insertion, and semirecumbent positioning of the ventilated patient. CIC status was significantly associated with the perception of the evidence for several practices. CONCLUSION: Successful implementation of evidence-based practices should consider how key individuals in the translational process assess the strength of that evidence. PMID- 23369315 TI - Sustained reduction of central line-associated bloodstream infections in an intensive care unit using a top-down and bottom-up approach. PMID- 23369316 TI - National survey of suboptimal and unnecessary practices for central line placement and management in Thailand. AB - We conducted a national survey among hospitals in Thailand regarding practices associated with central line placement and management. Results of the survey identified that both suboptimal and unnecessary practices are being conducted. Connectors and hubs were not disinfected before access (49%), multidose vial use (43%), and routine culture of catheter tips (21%). Physician leadership and designated catheter insertion teams were associated with less unnecessary or suboptimal reported practices. PMID- 23369317 TI - Outbreak of Pseudomonas aeruginosa infections in a neonatal care unit associated with feeding bottles heaters. AB - This report describes an outbreak caused by Pseudomonas aeruginosa in a neonatal care unit possibly linked to feeding bottles heaters. Infection control measures were undertaken such as reinforcement of contact isolation precautions, environmental microbiologic sampling, educational sessions on hand hygiene, and use of sterilized water to refill feeding bottles heaters. The sustained eradication of P aeruginosa isolates after implementing control measures on feeding bottles heaters strongly suggests those as the source of the outbreak. PMID- 23369318 TI - Cryo-preserved porcine kidneys are feasible for teaching and training renal biopsy: "the bento kidney". AB - BACKGROUND: The use of patients as the primary teaching modality for learning procedures is being questioned. While there have been advancements in the technology used for performing needle biopsies in both native and transplanted kidneys, there has been little advancement in teaching and training tools. We have developed a portable ex-vivo kidney, the Bento Kidney, using cryo-preserved porcine kidneys for teaching this procedure. METHODS: The kidney is thawed, perfused by a pump, covered with skin for realistic haptic feedback, and then used with existing biopsy technology to teach the technique. RESULTS: Thirty porcine kidneys were used in this pilot research, and nine were shipped to physicians at a distant facility. Renal biopsy was then performed using a core biopsy needle and ultrasound guidance. There was some leakage of fluid from all kidneys noted. All trainees felt that the model was realistic, and judged at a mean score of 8.7 (SD 0.8) on a scale of 1 (not useful) to 10 (very useful). CONCLUSIONS: This feasibility study demonstrates that cryo-preserved porcine kidneys can be successfully used to teach and train renal biopsy techniques, and provides haptic feedback as well as realistic real-time ultrasound images. Further large scale studies are needed to demonstrate value from the educational point of view for nephrology and transplantation. PMID- 23369319 TI - Psychological treatments for common mental health problems experienced by informal carers of adults with chronic physical health conditions (Protocol). AB - BACKGROUND: Improved life expectancy is resulting in increased outpatient treatment of people with chronic physical health conditions and reliance on the provision of informal care in the community. However, informal care is also associated with increased risk of experiencing common mental health difficulties such as depression and anxiety. Currently there is a lack of evidence-based treatments for such difficulties, resulting in poor health outcomes for both the informal carer and care recipient. METHODS/DESIGN: Electronic databases will be systemically searched for randomised controlled trials examining the effectiveness of psychological interventions targeted at treating depression or anxiety experienced by informal carers of patients with chronic physical health conditions. Database searches will be supplemented by contact with experts, reference and citation checking and grey literature. Both published and unpublished research in English language will be reviewed with no limitations on year or source. Individual, group and patient-carer dyad focused interventions will be eligible. Primary outcomes of interest will be validated self-report or clinician administered measures of depression or anxiety. If data allows a meta analysis will examine: (1) the overall effectiveness of psychological interventions in relation to outcomes of depression or anxiety; (2) intervention components associated with effectiveness. DISCUSSION: This review will provide evidence on the effectiveness of psychological interventions for depression and anxiety experienced by informal carers of patients with chronic physical health conditions. In addition, it will examine intervention components associated with effectiveness. Results will inform the design and development of a psychological intervention for carers of people with chronic physical health conditions experiencing depression and anxiety. PROSPERO registration number: CRD42012003114. PMID- 23369320 TI - Peritoneal adhesion index (PAI): proposal of a score for the "ignored iceberg" of medicine and surgery. AB - Peritoneal adhesions describe a condition in which pathological bonds form between the omentum, the small and large bowels, the abdominal wall, and other intra-abdominal organs. Different classification systems have been proposed, but they do not resolve the underlying problem of ambiguity in the quantification and definition of adhesions. We therefore propose a standardized classification system of adhesions to universalize their definition based on the macroscopic appearance of adhesions and their diffusion to different regions of the abdomen. By scoring with these criteria, the peritoneal adhesion index (PAI) can range from 0 to 30, unambiguously specifying precise adhesion scenarios. The standardized classification and quantification of adhesions would enable different studies to more meaningfully integrate their results, thereby facilitating a more comprehensive approach to the treatment and management of this pathology. PMID- 23369321 TI - Measurement of acute nonspecific low back pain perception in primary care physical therapy: reliability and validity of the brief illness perception questionnaire. AB - BACKGROUND: The eight-item Brief Illness Perception Questionnaire is used as a screening instrument in physical therapy to assess mental defeat in patients with acute low back pain, besides patient perception might determine the course and risk for chronic low back pain. However, the psychometric properties of the Brief Illness Perception Questionnaire in common musculoskeletal disorders like acute low back pain have not been adequately studied. Patients' perceptions vary across different populations and affect coping styles. Thus, our aim was to determine the internal consistency, test-retest reliability and validity of the Dutch language version of the Brief Illness Perception Questionnaire in acute non specific low back pain patients in primary care physical therapy. METHODS: A non experimental cross-sectional study with two measurements was performed. Eighty four acute low back pain patients, in multidisciplinary health care center in Dutch primary care with a sample mean (SD) age of 42 (12) years, participated in the study. Internal consistency (Cronbach's alpha) and test-retest procedures (Intraclass Correlation Coefficients and limits of agreement) were evaluated at a one-week interval. The concurrent validity of the Brief Illness Perception Questionnaire was examined by using the Mental Health Component of the Short Form 36 Health Survey. RESULTS: The Cronbach's alpha for internal consistency was 0.73 (95% CI, 0.67 - 0.83); and the Intraclass Correlation Coefficient test-retest reliability was acceptable: 0.72 (95% CI, 0.53 - 0.82), however, the limits of agreement were large. The Intraclass Correlation Coefficient measuring concurrent validity 0.65 (95% CI, 0.46 - 0.80). CONCLUSION: The Dutch version of the Brief Illness Perception Questionnaire is an appropriate instrument for measuring patients' perceptions in acute low back pain patients, showing acceptable internal consistency and reliability. Concurrent validity is adequate, however, the instrument may be unsuitable for detecting changes in low back pain perception over time. PMID- 23369323 TI - Impact of leachate on groundwater pollution due to non-engineered municipal solid waste landfill sites of erode city, Tamil Nadu, India. AB - Leachate and groundwater samples were collected from Vendipalayam, Semur and Vairapalayam landfill sites in Erode city, Tamil Nadu, India, to study the possible impact of leachate percolation on groundwater quality. Concentrations of various physicochemical parameters including heavy metals (Cd, Cr, Cu, Fe, Ni, Pb, Fe and Zn) were determined in leachate samples and are reported. The concentrations of Cl-, NO3-, SO42-, NH4+ were found to be in considerable levels in the groundwater samples particularly near to the landfill sites, likely indicating that groundwater quality is being significantly affected by leachate percolation. Further they were proved to be the tracers for groundwater contamination near Semur and Vendipalayam dumpyards. The presence of contaminants in groundwater particularly near the landfill sites warns its quality and thus renders the associated aquifer unreliable for domestic water supply and other uses. Although some remedial measures are suggested to reduce further groundwater contamination via leachate percolation, the present study demands for the proper management of waste in Erode city. PMID- 23369322 TI - HDAM: a resource of human disease associated mutations from next generation sequencing studies. AB - BACKGROUND: Next generation sequencing (NGS) technologies have greatly facilitated the rapid and economical detection of pathogenic mutations in human disorders. However, mutation descriptions are hard to be compared and integrated due to various reference sequences and annotation tools adopted in different articles as well as the nomenclature of diseases/traits. DESCRIPTION: The Human Disease Associated Mutation (HDAM) database is dedicated to collect, standardize and re-annotate mutations for human diseases discovered by NGS studies. In the current release, HDAM contains 1,114 mutations, located in 669 genes and associated with 125 human diseases through literature mining. All mutation records have uniform and unequivocal descriptions of sequence changes according to the Human Genome Sequence Variation Society (HGVS) nomenclature recommendations. Each entry displays comprehensive information, including mutation location in genome (hg18/hg19), gene functional annotation, protein domain annotation, susceptible diseases, the first literature report of the mutation and etc. Moreover, new mutation-disease relationships predicted by Bayesian network are also presented under each mutation. CONCLUSION: HDAM contains hundreds rigorously curated human mutations from NGS studies and was created to provide a comprehensive view of these mutations that confer susceptibility to the common disorders. HDAM can be freely accessed at http://www.megabionet.org/HDAM. PMID- 23369324 TI - A short-term educational program improved physicians' adherence to guidelines for COPD and asthma in Shanghai. AB - BACKGROUND: Chronic pulmonary diseases such as chronic obstructive pulmonary disease (COPD) and asthma exert increasing burden on society while the management of them is far from adequate. The objective of this study is to evaluate adherence to guidelines through a patient study, and then investigate the effects of a short-term quality improvement educational program among clinicians in Shanghai, China. METHODS: A prescription survey was performed in a random sample of 100 COPD and asthma outpatients to assess their pharmacological therapy. Then, an educational program was conducted in young pulmonary physicians from 83 hospitals in Shanghai. The training course was divided into 7 sessions of 2 hours delivered over 4 days from July 2010 to August 2011. Three months later, all of the participants were asked to take a written examination to assess the efficiency of training. RESULTS: Prescription survey among the patients indicated the prescriptions are not consistent with the recommendations of current GOLD and GINA guidelines. The mainly existing issue is the overuse of inhaled glucocorticosteroid. For the educational program, 161 pulmonary physicians have attended the training course, and 110 clinicians finished the tests with an attendance rate of 68.3%. Although most of the clinicians recognized the increasing burden of COPD and asthma, they do not know well about the core elements of guidelines and their clinical practice is not fully in agreement with current recommendations. Through crossover comparison, our results suggested clinicians' knowledge of the guidelines was improved after training. CONCLUSIONS: We concluded that application of continuous educational programs among physicians might promote their adherence to guidelines, and by that improve the quality of healthcare. PMID- 23369325 TI - [Prophylaxis in cardioembolic apoplexy]. PMID- 23369326 TI - [Omission of treatment or euthanasia]. PMID- 23369327 TI - [Anticoagulant therapy in stroke patients]. AB - Stroke is a common disease, which is associated with high morbidity and high mortality. Up to 25% of cerebral ischaemic infarcts are caused by cardio-embolic events, most commonly associated with atrial fibrillation. It has previously been shown that antithrombotic therapy is insufficiently used in patients at increased risk of stroke. This article reviews evidence and practical management of anticoagulant therapy in stroke patients and provides an update on risk stratification for thromboembolism and bleeding complications in patients with atrial fibrillation. PMID- 23369328 TI - [Omission of treatment of severely ill neonates]. AB - For the past two decades it has been common practice in Denmark to withhold or withdraw medical care from neonates born before 28 weeks of gestation if they have poor survival chances or risk of future complications (poor quality of life). This practice is neither supported by the Danish Health Law, a law which furthermore does not include a consideration to quality of life, nor fully recognized as neonatal euthanasia. This is unacceptable as it results in a lack of proper guidelines relating to moral aspects and a failure to understand the full moral impact of neonatal euthanasia. PMID- 23369329 TI - [The use of foeticide in late termination of pregnancies in Denmark]. AB - As a result of prenatal screening the number of late terminations of pregnancy is increasing in Denmark. The fact that the foetus sometimes shows signs of life after the termination is a large concern for health-care staff and parents. In other countries foeticide is performed intrauterinely to ensure that the foetus is dead before the delivery. In Denmark this method is legally used in foetal reduction, but not in late termination of pregnancy. In the light of international literature on the subject, perspectives on foeticide in late termination of pregnancy are explored. PMID- 23369331 TI - [The use of electronic medical records can contribute in diagnosing a case of battered child]. AB - Child abuse is a very serious offence and is often underdiagnosed. This case report shows how the use of electronic medical records from different hospitals aided in diagnosing a case of battered child in a 16-month-old girl with an unusual acromion fracture. This illustrates the need for thorough investigation of the records in cases where a fracture might not raise suspicion on its own. PMID- 23369330 TI - [Treatment of idiopathic peripheral facial nerve paralysis (Bell's palsy)]. AB - Bell's palsy is defined as an idiopathic peripheral facial nerve paralysis of sudden onset. It affects 11-40 persons per 100,000 per annum. Many patients recover without intervention; however, up to 30% have poor recovery of facial muscle control and experience facial disfigurement. The aim of this study was to make an overview of which pharmacological treatments have been used to improve outcomes. The available evidence from randomized controlled trials shows significant benefit from treating Bell's palsy with corticosteroids but shows no benefit from antivirals. PMID- 23369332 TI - [Cerebrotendinous xanthomatosis is a rare disorder, which requires a specific treatment]. AB - Cerebrotendinous xanthomatosis (CTX) is a rare, but treatable lipid storage disorder caused by mutation in the CYP27A1 gene. The disorder results in deposition of cholestanol in various tissues. The classical CTX phenotype includes diarrhoea, juvenile cataract, xanthoma and progressive neurological symptoms. Studies have shown that progression of symptoms can be halted or even reversed, if treatment with chenodeoxycholic acid is initiated early. The diagnosis of CTX is often delayed due to lack of awareness of the disease. We describe the history, clinical features, biochemical, genetic and magnetic resonance imaging findings of the first reported case of CTX in Denmark. PMID- 23369333 TI - [Shoulder pain as the first sign of disseminated lung cancer]. AB - The diagnosis of non-small cell lung cancer is in 50% of the cases not made until the metastatic stage. Distant metastases commonly involve the adrenal glands, the liver, the bones and the central nervous system. Metastases are very rarely seen in skeletal muscles. We report a case with a 47-year-old man, who suffered from strong pain in his right shoulder. The symptoms turned out to be the initial presentation of a disseminated lung cancer. A magnetic resonance scan showed skeletal muscle metastases to m. subscapularis and m. infraspinatus. Metastases to skeletal muscles are rare but should be kept in mind as part of the differential diagnosis in cases where atypical shoulder pain is the only symptom. PMID- 23369334 TI - [Positron-emission tomography and computed tomography as diagnostic tool for giant cell arteritis]. PMID- 23369335 TI - Experimental study of dye removal from industrial wastewater by membrane technologies of reverse osmosis and nanofiltration. AB - Currently, biological method has been utilized in the treatment of wastewater containing synthetic dyes used by textile industries in Iraq. The present work was devoted to study the operating feasibility using reverse osmosis (RO) and nanofiltration (NF) membrane systems as an alternative treatment method of wastewater discharged from Iraqi textile mills. Acid red, reactive black and reactive blue dyes were selected, based on the usage rate in Iraq. Effects of dye concentration, pH of solution, feed temperature, dissolved salts and operating pressure on permeate flux and dye rejection were studied. Results at operating conditions of dye concentration = 65 mg/L, feed temperature = 39 degrees C and pressure = 8 bar showed the final dye removal with RO membrane as 97.2%, 99.58% and 99.9% for acid red, reactive black and reactive blue dyes, respectively. With NF membrane, the final dye removal were as 93.77%, 95.67%, and 97% for red, black and blue dyes, respectively. The presence of salt (particularly NaCl) in the dye solution resulted in a higher color removal with a permeate flux decline. It was confirmed that pH of solution had a positive impact on dye removal while feed temperature showed a different image. A comparison was made between the results of dye removal in biological and membrane methods. The results showed that membrane method had higher removal potential with lower effective cost. The present study indicates that the use of NF membrane in dye removal from the effluent of Iraqi textile mills is promising. PMID- 23369336 TI - Changes in the visual-evoked P1 potential as a function of schizotypy and background color in healthy young adults. AB - Research has suggested a hypoactive visual magnocellular (M) pathway in individuals with schizophrenia-spectrum disorders and traits, along with a unique response of this pathway to red light. As these abnormalities only appear in a subset of these samples, they may reflect unknown subtypes with unique etiologies and corresponding neuropathologies. The P1 transient visual-evoked component has been found to be influenced by M-pathway activity; therefore, the current study assessed the P1 component in response to a 64% contrast checker stimulus on white, red, and green background conditions. The sample consisted of 28 undergraduate participants (61% male) who endorsed a continuous range of total scores from the Schizotypal Personality Questionnaire (SPQ). Participants with higher total SPQ scores had a reduced P1 mean amplitude with the white (baseline) background, which was primarily related to the SPQ Magical Thinking subscale score. In addition, while participants with lower total SPQ scores showed the expected reduction in P1 amplitude to the red (vs. green) background, participants with higher total SPQ scores showed no change, which was primarily related to the SPQ Ideas of Reference subscale. This differential change to the red background remained after covarying for the P1 amplitude to the green background, thus representing a relatively independent effect. Further confirmation of these early visual processing relationships to particular clusters of symptoms in related psychiatric samples may assist in revealing unique, currently unknown, subtypes of particular psychiatric disorders such as schizophrenia. This can direct treatment efforts toward more homogeneous neuropathology targets. PMID- 23369337 TI - Animal-assisted interventions for elderly patients affected by dementia or psychiatric disorders: a review. AB - OBJECTIVE: The aim of this literature review was to assess the effects of Animal Assisted Interventions (AAI) on elderly patients with dementia or various psychiatric disorders. METHODS: We conducted a comprehensive literature search using the online PubMed network of the US National Library of Medicine & National Institutes of Health, Embase, PsycINFO, with the purpose of investigating AAI effects on cognitive functions, mood, and behaviour. RESULTS: A total of 18 articles on dementia and 5 on psychiatric disorders were included in the present review. AAI were found to have positive influences on demented patients by reducing degree of agitation and by improving degree and quality of social interaction. Few studies have assessed the effects of AAI on mood, and even fewer have assessed its consequences on cognitive functions. The results that are available indicate a positive effect on communication and coping ability, but none on cognitive performance. A substitute pet robot yielded encouraging results, but its use requires further investigation. The few studies conducted for elderly patients presenting a variety of psychiatric diagnoses produced controversial findings. CONCLUSIONS: In spite of the encouraging results of AAI, much more research examining the issue of optimal AAI duration, frequency of sessions, and suitable target group is needed. PMID- 23369338 TI - Sequence-only evolutionary and predicted structural features for the prediction of stability changes in protein mutants. AB - BACKGROUND: Even a single amino acid substitution in a protein sequence may result in significant changes in protein stability, structure, and therefore in protein function as well. In the post-genomic era, computational methods for predicting stability changes from only the sequence of a protein are of importance. While evolutionary relationships of protein mutations can be extracted from large protein databases holding millions of protein sequences, relevant evolutionary features for the prediction of stability changes have not been proposed. Also, the use of predicted structural features in situations when a protein structure is not available has not been explored. RESULTS: We proposed a number of evolutionary and predicted structural features for the prediction of stability changes and analysed which of them capture the determinants of protein stability the best. We trained and evaluated our machine learning method on a non redundant data set of experimentally measured stability changes. When only the direction of the stability change was predicted, we found that the best performance improvement can be achieved by the combination of the evolutionary features mutation likelihood and SIFT score in conjunction with the predicted structural feature secondary structure. The same two evolutionary features in the combination with the predicted structural feature accessible surface area achieved the lowest error when the prediction of actual values of stability changes was assessed. Compared to similar studies, our method achieved improvements in prediction performance. CONCLUSION: Although the strongest feature for the prediction of stability changes appears to be the vector of amino acid identities in the sequential neighbourhood of the mutation, the most relevant combination of evolutionary and predicted structural features further improves prediction performance. Even the predicted structural features, which did not perform well on their own, turn out to be beneficial when appropriately combined with evolutionary features. We conclude that a high prediction accuracy can be achieved knowing only the sequence of a protein when the right combination of both structural and evolutionary features is used. PMID- 23369340 TI - De novo stress urinary incontinence after vaginal repair for pelvic organ prolapse: one-year follow-up. AB - OBJECTIVE: A few studies have reported a wide range (2-43%) in incidence of de novo stress urinary incontinence (SUI) following surgical repair of pelvic organ prolapse (POP) in previously continent women. The aim of this study was to re examine this incidence up to one year following vaginal repair of prolapse. STUDY DESIGN: Retrospective review of a cohort of women who underwent reconstructive vaginal repair of POP without a concomitant anti-incontinence procedure between 2003 and 2007 at two tertiary referral centers. Women were considered eligible if they were stress continent by symptoms and objective assessment (including urodynamics testing) prior to surgical repair. All women who had had any anti incontinence procedure previously were excluded. The endpoint was subjective SUI that prompted the patient to undergo any treatment within one year from their prolapse surgery. RESULTS: 64 women, with a mean age of 61 (+/-11) years, were eligible for the study: 26 (41%) had preoperative symptoms of overactive bladder. Fifty-four patients were available for analysis at the one-year visit. Seven women (13.5%) had symptoms of SUI but only one (2%) was found to have SUI objectively. Another patient underwent anti-incontinence surgery following her prolapse surgery. CONCLUSION: The incidence of de novo SUI requiring treatment in previously continent women who underwent vaginal repairs for POP without concomitant anti-incontinence surgery is low (4%). A large-scale prospective study is necessary to further evaluate this finding. PMID- 23369341 TI - Effect of human interferon-alpha-2b on experimental endometriosis in rats: comparison between short and long series of treatment. AB - OBJECTIVE: A randomised and controlled experimental study was carried out to determine the effect of short and long series of treatment with recombinant human interferon-alpha-2b on surgically induced endometriosis in rats. STUDY DESIGN: Ninety-six Wistar adult female rats, which had undergone an autotransplant into the peritoneal cavity of four endometrial fragments measuring 4.5mm at the side, were randomly divided into three groups. One third of the animals were manipulated like the treated animals but were not given treatment and served as control (group C). Another third (group S) were treated with three doses (one every 48 h, 100,000 U per dose) of recombinant human interferon-alpha-2b (subcutaneous route), and the last third (group L) were treated with fifteen doses of interferon (100,000 U every 48 h). RESULTS: Before interferon was administered, there were no differences between groups in the average growth of experimental endometriosis per animal (17.3+/-6.7, 18.1+/-9.2, 16.4+/-5.6mm in groups C, S and L respectively). After the treatment, experimental endometriosis per animal was significantly smaller in the groups treated with interferon than in the control non-treated group (p<0.001), and in the group treated with 15 doses versus the group treated with 3 doses (p<0.05), (17.6+/-7.5, 14.0+/-9.5, 9.4+/-6.0mm in groups C, S, and L respectively). While the implants of the animals in the control group showed no change in size throughout the study (120 days) (+1.96% of variation), the mean size of the implants in the treated rats decreased, (22.7% with the short and 42.8% with the long series of treatment with interferon). Only one implant in group C (0.8%) disappeared, while this occurred in 27 cases (22.5%) in group S (p<0.001) and in 45 (37.5%) in group L (p<0.001 versus group C and p<0.05 versus group S). CONCLUSION: The long series of treatment with human interferon-alpha-2b was more effective than the short one in reducing the size of surgically induced endometriosis in the peritoneal cavity of the rat. PMID- 23369339 TI - Perivascular mesenchymal stem cells in the adult human brain: a future target for neuroregeneration? AB - Perivascular adult stem cells have been isolated from several tissues, including the adult human brain. They have unique signatures resembling both pericytes and mesenchymal stem cells. Understanding the nature of these cells in their specific vascular niches is important to determine their clinical potential as a new adult stem cell source. Indeed, they have promising features in vitro in terms of multipotency, immunomodulation and secretion of growth factors and cytokines. However, their in vivo function is less known as yet. Recent emerging data show a crucial role of perivascular mesenchymal stem cells in tissue homeostasis and repair. Furthermore, these cells may play an important role in adult stem cell niche regulation and in neurodegeneration. Here we review the recent literature on perivascular mesenchymal stem cells, discuss their different in vitro functions and highlight especially the specific properties of brain-derived perivascular mesenchymal stem cells. We summarize current evidence that suggests an important in vivo function of these cells in terms of their regenerative potential that may indicate a new target cell for endogenous tissue regeneration and repair. PMID- 23369342 TI - 6-gingerol prevents adipogenesis and the accumulation of cytoplasmic lipid droplets in 3T3-L1 cells. AB - 6-Gingerol ((S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone) is one of the pungent constituents of Zingiber zerumbet (L) Smith (Zingiberaceae family). In this study, we investigated the effects of 6-gingerol on the inhibition of adipogenesis in 3T3-L1 cells. After treatment with 6-gingerol in differentiation medium for 4 or 8 days, the 3T3-L1 cells were lysed for experimental analysis. Cells were stained with Oil-Red-O to detect oil droplets in adipocytes. The 3T3 L1 cells were lysed and measured for triglyceride contents. The protein expression of adipogenesis-related transcription factor was evaluated by Western blot analysis. 6-Gingerol suppressed oil droplet accumulation and reduced the droplet size in a concentration (5-15 MUg/ml)- and time-dependent manner. Treatment of 3T3-L1 cells with 6-gingerol reduced the protein levels of peroxisome proliferator-activated receptor (PPAR)gamma and CCAAT/enhancer-binding protein (C/EBP)alpha. Additionally, the protein levels of fatty acid synthase (FAS) and adipocyte-specific fatty acid binding protein (aP2) decreased upon treatment with 6-gingerol. Meanwhile, 6-gingerol diminished the insulin stimulated serine phosphorylation of Akt (Ser473) and GSK3beta (Ser9). These results suggest that 6-gingerol effectively suppresses adipogenesis and that it exerts its role mainly through the significant down-regulation of PPARgamma and C/EBPalpha and subsequently inhibits FAS and aP2 expression. 6-Gingerol also inhibited differentiation in 3T3-L1 cells by attenuating the Akt/GSK3beta pathway. Our findings provide important insights into the mechanisms underlying the anti-adipogenic activity of 6-gingerol. PMID- 23369343 TI - Evaluation of in vivo anti-hyperglycemic and antioxidant potentials of alpha santalol and sandalwood oil. AB - Sandalwood finds numerous mentions across diverse traditional medicinal systems in use worldwide. The objective of this study was to evaluate the in vivo anti hyperglycemic and antioxidant potential of sandalwood oil and its major constituent alpha-santalol. The in vivo anti-hyperglycemic experiment was conducted in alloxan-induced diabetic male Swiss albino mice models. The in vivo antioxidant experiment was performed in d-galactose mediated oxidative stress induced male Swiss albino mice models. Intraperitoneal administration of alpha santalol (100mg/kg BW) and sandalwood oil (1g/kg BW) for an week modulated parameters such as body weight, blood glucose, serum bilirubin, liver glycogen, and lipid peroxides contents to normoglycemic levels in the alloxan-induced diabetic mice. Similarly, intraperitoneal administration of alpha-santalol (100mg/kg BW) and sandalwood oil (1g/kg BW) for two weeks modulated parameters such as serum aminotransferases, alkaline phosphatase, bilirubin, superoxide dismutase, catalase, free sulfhydryl, protein carbonyl, nitric oxide, liver lipid peroxide contents, and antioxidant capacity in d-galactose mediated oxidative stress induced mice. Besides, it was observed that the beneficial effects of alpha-santalol were well complimented, differentially by other constituents present in sandalwood oil, thus indicating synergism in biological activity of this traditionally used bioresource. PMID- 23369344 TI - Endothelium-dependent vasodilatation effects of the essential oil from Fructus alpiniae zerumbet (EOFAZ) on rat thoracic aortic rings in vitro. AB - Fructus Alpiniae Zerumbet (FAZ) is an herb widely used to treat vascular disorders in Guizhou province, China, the essential oil has been identified as one of it vasodilation effect active components, and especial, the composition was significantly difference from the leaves. Vasodilation effects and mechanism of essential oil from FAZ (EOFAZ) were investigated. The EOFAZ showed significant vasodilation effect on endothelium-with rat thoracic aortic rings preincubated with norepinephrine (NE, 1.0MUM) or KCl (60mM) in a concentration-dependent manner (1.14-72.96MUg/ml). The non-selective nitric oxide synthase inhibitor l NAME, as well as the soluble guanylate cyclase inhibitor MB, attenuated the relaxation of EOFAZ in endothelium-intact rat thoracic aortic rings. However, there were not significantly affected the vasodilation effects pretreated with cyclooxygenase inhibition by indomethacin (Indo) or beta-noradrenergic inhibition by propranolol (Prop). The present results first demonstrated that vasodilation effect of EOFAZ depending upon the endothelium and concentration, and the mechanism involvement of NOS-cGMP system. In contrast, prostacyclin and beta adrenoceptor may not be associated with EOFAZ-induced vasorelaxation. PMID- 23369345 TI - Massive hiatus hernia mimicking a left atrial mass. AB - Echocardiography is the investigational tool of choice for identifying cardiac masses. However, extracardiac masses may lead to a misdiagnosis. We present a unique case of a massive hiatus hernia in a 93 year-old woman, compressing on the left atrium, mimicking a left atrial mass. Echocardiographic features suggestive of a hiatus hernia are discussed. PMID- 23369346 TI - Responsible use of child welfare and administrative datasets to build the capacity of child abuse and neglect prevention research internationally. PMID- 23369347 TI - Childhood abuse affects emotional closeness with family in mid- and later life. AB - OBJECTIVE: Knowledge about the effects of early life adversity on kin relationships in later years is sparse. The purpose of this study was to examine if childhood abuse and adversity negatively influences emotional closeness with family in mid- and later life. A second goal was to determine the role of psychosocial resources and personality traits in buffering the effects of early adversities. Gender and cohort differences were explored to see if men were differentially affected than women and whether middle-aged adults (35-49 years old) were differentially affected than older adults (50-74 years old) by the effects of childhood abuse and adversity. METHODS: Using retrospective accounts of early family abuse and adversities of 1,266 middle aged adults and 1,219 older adults from a large population-based survey, the National Survey of Midlife Development in United States (MIDUS), separate multiple regression analyses were conducted for the two cohorts to examine the effects of childhood emotional and physical abuse and family adversities on perceived emotional closeness with family. Interaction effects between childhood abuse and adversity (e.g., being expelled from school, death of sibling, parental divorce, losing a home to a natural disaster) with psychosocial resources (perceived control and self acceptance), personality characteristics (extraversion and neuroticism), and gender were examined. RESULTS: Results of OLS regressions suggest emotional and physical abuse predicted family closeness in middle-aged adults. Conversely, only emotional abuse predicted family closeness in older adults. Moderation models revealed that high levels of self acceptance were associated with better maintenance of emotional closeness among middle-aged adults who were emotionally and physically abused as children. Older adults with lower extraversion who experienced emotional abuse or reported greater number of adversities in childhood were found to be at higher risk for lower emotional closeness with family. Early life adversities were more detrimental for women. CONCLUSIONS: Findings suggest that the aftermath of childhood abuse does not dissipate with time, but continues to influence family relationships in mid- and later life. Identifying the links between childhood adversities and adult relationships can help identify strategic points for intervention to reduce the long-term effects of accumulated adverse experiences over the life course. PMID- 23369348 TI - Role of SUMO-1 and SUMO interacting motifs in rhesus TRIM5alpha-mediated restriction. AB - BACKGROUND: TRIM5alpha is a member of the tripartite motif family of proteins that restricts retroviral infection in a species-specific manner. The restriction requires an interaction between the viral capsid lattice and the B30.2/SPRY domain of TRIM5alpha. Previously, we determined that two SUMO interacting motifs (SIMs) present in the B30.2/SPRY domain of human TRIM5alpha (huTRIM5alpha) were important for the restriction of N-tropic Murine Leukemia Virus. Here, we examined whether SUMO expression and the SIM1 and SIM2 motifs in rhesus monkey TRIM5alpha (rhTRIM5alpha) are similarly important for Human Immunodeficiency Type 1 (HIV-) restriction. RESULTS: We found that mutation of SIM1 and SIM2 of rhTRIM5alpha abolished the restriction of HIV-1 virus. Further, knockdown of SUMO 1 in rhTRIM5alpha expressing cells abolished restriction of HIV-1. These results may be due, in part, to the ability of SUMO-1 to stabilize rhTRIM5alpha protein expression, as SUMO-1 knockdown increased rhTRIM5alpha turnover and the mutations in SIM1 and SIM2 led to more rapid degradation than the wild type protein. The NF kappaB signaling ability of rhTRIM5alpha was also attenuated by SUMO-1 knockdown. Finally, upon inhibition of CRM1-dependent nuclear export with Leptomycin B (LMB), wild type rhTRIM5alpha localized to SUMO-1 bodies in the nucleus, while the SIM1 and SIM2 mutants did not localize to SUMO-1. CONCLUSIONS: Our results suggest that the rhTRIM5alpha B30.2/SPRY domain is not only important for the recognition of the HIV-1 CA, but it is also important for its association with SUMO-1 or SUMO-1 modified proteins. These interactions help to maintain TRIM5alpha protein levels and its nuclear localization into specific nuclear bodies. PMID- 23369349 TI - Reoperation after acute type a aortic dissection repair: a series of 104 patients. AB - BACKGROUND: Our objective was to analyze the causes, timing, and results of reoperation after primary repair for acute type A dissection. METHODS: One hundred and four consecutive patients underwent a reoperation after previous type A aortic dissection repair (1972 to 2008). Supracoronary ascending aorta replacement (SCAR) was commonly performed during primary repair and it was associated with aortic root replacement in 13 cases and with hemiarch replacement in 26 patients. Progression of aortic dilatation was seen in 91 patients (87%), aortic regurgitation in 21 (20%), and false aneurysm in 15 patients (14%). A redo Bentall procedure was performed in 34 cases, arch replacement in 42 patients, and thoracoabdominal aorta replacement in 20 patients. The median follow-up was 6.5 years (range 0.3 to 23.8 years). RESULTS: The in-hospital mortality after redo surgery was 7.7%. The global survival rate at 1, 5, and 10 years was 92%, 82%, and 58%, respectively. Proximal reoperations were more frequent in patients who had SCAR and flap extension into the aortic root. Patients with an unresected intimal tear and distal extension of dissection flap experienced a higher rate of aortic arch and thoracoabdominal aorta redo procedures. CONCLUSIONS: More extensive acute dissection repair results in a lower rate of reoperation. Mortality for redo surgery after type A acute dissection repair is acceptable. This finding should be taken into account in proposing a widespread of more complex and extensive surgery for type A acute dissection. PMID- 23369350 TI - A new method to predict postoperative lung function: quantitative breath sound measurements. AB - BACKGROUND: Currently, predicted postoperative (PPO) lung function (forced expiratory volume in 1 second [PPO-FEV(1)] and diffusion capacity of the lung for carbon monoxide [PPO-Dlco]) estimated from spirometry and regional perfusion is used to select patients for lung resection. Vibration response imaging (VRI) analyzes lung sounds and quantifies regional acoustic energy. Single-center studies suggest that this noninvasive, radiation-free method of quantifying lung function is comparable to the reference standard. METHODS: A prospective, multiinstitutional United States study comparing VRI with perfusion in patient assessment for lung resection enrolled 163 patients, with 135 currently available for analysis. PPO values were calculated by subtracting the fraction of segments to be resected in a lung (113 lobectomies, 20 pneumonectomies) multiplied by the percentage of acoustic energy (VRI) or perfusion of that lung. We compared the two methods with each other, with actual postoperative pulmonary function tests, and the rate of complications as predicted by PPO values above or below 40%. RESULTS: Good agreement was found between calculated estimations of postoperative lung function using VRI and perfusion measurements (PPO-FEV(1)%: r = 0.95; -8% to 11.5%; PPO-Dlco: r = 0.97; -6.6% to 9.5%), although larger discrepancies were noted between the actual VRI and perfusion measurements (-17 to 24). The VRI and perfusion methods provided excellent agreement in categorization of patients into low or elevated risk based on PPO values of above or below 40% (95% for PPO FEV(1)%; 94% for PPO-Dlco) and similar correlations with actual postoperative values (r = 0.74 and r = 0.67 for FEV(1); r = 0.72 and r = 0.67 for Dlco). CONCLUSIONS: VRI may offer a simple, noninvasive, and radiation-free alternative to lung scintigraphy for predicting postoperative lung function in patients with lung malignancies. PMID- 23369352 TI - Preliminary study on optimization of pH, oxidant and catalyst dose for high COD content: solar parabolic trough collector. AB - In the present study, solar photocatalytic oxidation has been investigated through laboratory experiments as an alternative to conventional secondary treatment for the organic content reduction of high COD wastewater. Experiments have been performed on synthetic high COD wastewater for solar photocatalytic oxidation using a parabolic trough reactor. Parameters affecting the oxidation of organics have been investigated.The experimental design followed the sequence of dark adsorption studies of organics, followed by photolytic studies (in absence of catalyst) and finally photocatalytic studies in presence and absence of additional oxidant (H2O2). All the experimental studies have been performed at pH values of 2, 4, 6,8,10 and the initial pH value of the wastewater (normal pH). For photocatalytic studies, TiO2 has been used as a photocatalyst. Optimization of catalyst dose, pH and H2O2 concentration has been done. Maximum reduction of organic content was observed at the normal pH value of the wastewater (pH = 6.8). The reaction rate was significantly enhanced in presence of hydrogen peroxide. The optimum pH other than the Normal was in the alkaline range. Acidic pH was not found to be favourable for organic content reduction. pH was found to be a dominant factor affecting reaction rate even in presence of H2O2 as an additional oxidant. Also, the solar detoxification process was effective in treating a waste with a COD level of more than 7500 mg/L, which is a otherwise a difficult waste to treat. It can therefore be used as a treatment step in the high organic wastewater treatment during the primary stage also as it effectively reduces the COD content by 86%. PMID- 23369351 TI - A simplified subnormothermic machine perfusion system restores ischemically damaged liver grafts in a rat model of orthotopic liver transplantation. AB - BACKGROUND: Liver donor shortages stimulate the development of strategies that incorporate damaged organs into the donor pool. Herein we present a simplified machine perfusion system without the need for oxygen carriers or temperature control, which we validated in a model of orthotopic liver transplantation. METHODS: Rat livers were procured and subnormothermically perfused with supplemented Williams E medium for 3 hours, then transplanted into healthy recipients (Fresh-SNMP group). Outcome was compared with static cold stored organs (UW-Control group). In addition, a rat liver model of donation after cardiac death was adapted using a 60-minute warm ischemic period, after which the grafts were either transplanted directly (WI group) or subnormothermically perfused and transplanted (WI-SNMP group). RESULTS: One-month survival was 100% in the Fresh-SNMP and UW-Control groups, 83.3% in the WI-SNMP group and 0% in the WI group. Clinical parameters, postoperative blood work and histology did not differ significantly between survivors. CONCLUSION: This work demonstrates for the first time in an orthotopic transplantation model that ischemically damaged livers can be regenerated effectively using practical subnormothermic machine perfusion without oxygen carriers. PMID- 23369354 TI - Indo-Pacific bottlenose dolphin (Tursiops aduncus) habitat preference in a heterogeneous, urban, coastal environment. AB - BACKGROUND: Limited information is available regarding the habitat preference of the Indo-Pacific bottlenose dolphin (Tursiops aduncus) in South Australian estuarine environments. The need to overcome this paucity of information is crucial for management and conservation initiatives. This preliminary study investigates the space-time patterns of habitat preference by the Indo-Pacific bottlenose dolphin in the Port Adelaide River-Barker Inlet estuary, a South Australian, urbanised, coastal environment. More specifically, the study aim was to identify a potential preference between bare sand substrate and seagrass beds, the two habitat types present in this environment, through the resighting frequency of recognisable individual dolphins. RESULTS: Photo-identification surveys covering the 118 km2 sanctuary area were conducted over 2 survey periods May to August 2006 and from March 2009 to February 2010. Sighting frequency of recognisable individual Indo-Pacific bottlenose dolphins established a significant preference for the bare sand habitat. More specifically, 72 and 18% of the individuals sighted at least on two occasions were observed in the bare sand and seagrass habitats respectively. This trend was consistently observed at both seasonal and annual scales, suggesting a consistency in the distinct use of these two habitats. CONCLUSIONS: It is anticipated that these results will benefit the further development of management and conservation strategies. PMID- 23369353 TI - 2013 ACCF/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on clinical data standards (writing committee to develop acute coronary syndromes and coronary artery disease clinical data standards). PMID- 23369355 TI - Creating gradients by morphogen shuttling. AB - Morphogen gradients are used to pattern a field of cells according to variations in the concentration of a signaling molecule. Typically, the morphogen emanates from a confined group of cells. During early embryogenesis, however, the ability to define a restricted source for morphogen production is limited. Thus, various early patterning systems rely on a broadly expressed morphogen that generates an activation gradient within its expression domain. Computational and experimental work has shed light on how a sharp and robust gradient can be established under those situations, leading to a mechanism termed 'morphogen shuttling'. This mechanism relies on an extracellular shuttling molecule that forms an inert, highly diffusible complex with the morphogen. Morphogen release from the complex following cleavage of the shuttling molecule by an extracellular protease leads to the accumulation of free ligand at the center of its expression domain and a graded activation of the developmental pathway that decreases significantly even within the morphogen-expression domain. PMID- 23369357 TI - Potential stocks and increments of woody biomass in the European Union under different management and climate scenarios. AB - BACKGROUND: Forests play an important role in the global carbon flow. They can store carbon and can also provide wood which can substitute other materials. In EU27 the standing biomass is steadily increasing. Increments and harvests seem to have reached a plateau between 2005 and 2010. One reason for reaching this plateau will be the circumstance that the forests are getting older. High ages have the advantage that they typical show high carbon concentration and the disadvantage that the increment rates are decreasing. It should be investigated how biomass stock, harvests and increments will develop under different climate scenarios and two management scenarios where one is forcing to store high biomass amounts in forests and the other tries to have high increment rates and much harvested wood. RESULTS: A management which is maximising standing biomass will raise the stem wood carbon stocks from 30 tC/ha to 50 tC/ha until 2100. A management which is maximising increments will lower the stock to 20 tC/ha until 2100. The estimates for the climate scenarios A1b, B1 and E1 are different but there is much more effect by the management target than by the climate scenario. By maximising increments the harvests are 0.4 tC/ha/year higher than in the management which maximises the standing biomass. The increments until 2040 are close together but around 2100 the increments when maximising standing biomass are approximately 50 % lower than those when maximising increments. Cold regions will benefit from the climate changes in the climate scenarios by showing higher increments. CONCLUSIONS: The results of this study suggest that forest management should maximise increments, not stocks to be more efficient in sense of climate change mitigation. This is true especially for regions which have already high carbon stocks in forests, what is the case in many regions in Europe. During the time span 2010-2100 the forests of EU27 will absorb additional 1750 million tC if they are managed to maximise increments compared if they are managed to maximise standing biomass. Incentives which will increase the standing biomass beyond the increment optimal biomass should therefore be avoided. Mechanisms which will maximise increments and sustainable harvests need to be developed to have substantial amounts of wood which can be used as substitution of non sustainable materials. PMID- 23369356 TI - Biological profile of the less lipophilic and synthetically more accessible bryostatin 7 closely resembles that of bryostatin 1. AB - The bryostatins are a group of 20 macrolides isolated by Pettit and co-workers from the marine organism Bugula neritina. Bryostatin 1, the flagship member of the family, has been the subject of intense chemical and biological investigations due to its remarkably diverse biological activities, including promising indications as therapy for cancer, Alzheimer's disease, and HIV. Other bryostatins, however, have attracted far less attention, most probably due to their relatively low natural abundance and associated scarcity of supply. Among all macrolides in this family, bryostatin 7 is biologically the most potent protein kinase C (PKC) ligand (in terms of binding affinity) and also the first bryostatin to be synthesized in the laboratory. Nonetheless, almost no biological studies have been carried out on this agent. We describe herein the total synthesis of bryostatin 7 based on our pyran annulation technology, which allows for the first detailed biological characterizations of bryostatin 7 with side-by side comparisons to bryostatin 1. The results suggest that the more easily synthesized and less lipophilic bryostatin 7 may be an effective surrogate for bryostatin 1. PMID- 23369359 TI - Towards a "4I" approach to personalized healthcare. AB - Personalized healthcare holds the promise of ensuring that every patient receives optimal wellness promotion and clinical care based upon his or her unique and multi-factorial phenotype, informed by the most up-to-date and contextually relevant science. However, achieving this vision requires the management, analysis, and delivery of complex data, information, and knowledge. While there are well-established frameworks that serve to inform the pursuit of basic science, clinical, and translational research in support of the operationalization of the personalized healthcare paradigm, equivalent constructs that may enable biomedical informatics innovation and practice aligned with such objectives are noticeably sparse. In response to this gap in knowledge, we propose such a framework for the advancement of biomedical informatics in order to address the fundamental information needs of the personalized healthcare domain. This framework, which we refer to as a "4I" approach, emphasizes the pursuit of research and practice that is information-centric, integrative, interactive, and innovative. PMID- 23369358 TI - Exploring the pathogenetic association between schizophrenia and type 2 diabetes mellitus diseases based on pathway analysis. AB - BACKGROUND: Schizophrenia (SCZ) and type 2 diabetes mellitus (T2D) are both complex diseases. Accumulated studies indicate that schizophrenia patients are prone to present the type 2 diabetes symptoms, but the potential mechanisms behind their association remain unknown. Here we explored the pathogenetic association between SCZ and T2D based on pathway analysis and protein-protein interaction. RESULTS: With sets of prioritized susceptibility genes for SCZ and T2D, we identified significant pathways (with adjusted p-value < 0.05) specific for SCZ or T2D and for both diseases based on pathway enrichment analysis. We also constructed a network to explore the crosstalk among those significant pathways. Our results revealed that some pathways are shared by both SCZ and T2D diseases through a number of susceptibility genes. With 382 unique susceptibility proteins for SCZ and T2D, we further built a protein-protein interaction network by extracting their nearest interacting neighbours. Among 2,104 retrieved proteins, 364 of them were found simultaneously interacted with susceptibility proteins of both SCZ and T2D, and proposed as new candidate risk factors for both diseases. Literature mining supported the potential association of partial new candidate proteins with both SCZ and T2D. Moreover, some proteins were hub proteins with high connectivity and interacted with multiple proteins involved in both diseases, implying their pleiotropic effects for the pathogenic association. Some of these hub proteins are the components of our identified enriched pathways, including calcium signaling, g-secretase mediated ErbB4 signaling, adipocytokine signaling, insulin signaling, AKT signaling and type II diabetes mellitus pathways. Through the integration of multiple lines of information, we proposed that those signaling pathways, which contain susceptibility genes for both diseases, could be the key pathways to bridge SCZ and T2D. AKT could be one of the important shared components and may play a pivotal role to link both of the pathogenetic processes. CONCLUSIONS: Our study is the first network and pathway-based systematic analysis for SCZ and T2D, and provides the general pathway-based view of pathogenetic association between two diseases. Moreover, we identified a set of candidate genes potentially contributing to the linkage between these two diseases. This research offers new insights into the potential mechanisms underlying the co-occurrence of SCZ and T2D, and thus, could facilitate the inference of novel hypotheses for the co-morbidity of the two diseases. Some etiological factors that exert pleiotropic effects shared by the significant pathways of two diseases may have important implications for the diseases and could be therapeutic intervention targets. PMID- 23369360 TI - Cost-effectiveness of laser Doppler imaging in burn care in the Netherlands. AB - BACKGROUND: Early accurate assessment of burn depth is important to determine the optimal treatment of burns. The method most used to determine burn depth is clinical assessment, which is the least expensive, but not the most accurate.Laser Doppler imaging (LDI) is a technique with which a more accurate (>95%) estimate of burn depth can be made by measuring the dermal perfusion. The actual effect on therapeutic decisions, clinical outcomes and the costs of the introduction of this device, however, are unknown. Before we decide to implement LDI in Dutch burn care, a study on the effectiveness and cost-effectiveness of LDI is necessary. METHODS/DESIGN: A multicenter randomised controlled trial will be conducted in the Dutch burn centres: Beverwijk, Groningen and Rotterdam. All patients treated as outpatient or admitted to a burn centre within 5 days post burn, with burns of indeterminate depth (burns not obviously superficial or full thickness) and a total body surface area burned of <= 20% are eligible. A total of 200 patients will be included. Burn depth will be diagnosed by both clinical assessment and laser Doppler imaging between 2-5 days post burn in all patients. Subsequently, patients are randomly divided in two groups: 'new diagnostic strategy' versus 'current diagnostic strategy'. The results of the LDI-scan will only be provided to the treating clinician in the 'new diagnostic strategy' group. The main endpoint is the effect of LDI on wound healing time.In addition we measure: a) the effect of LDI on other patient outcomes (quality of life, scar quality), b) the effect of LDI on diagnostic and therapeutic decisions, and c) the effect of LDI on total (medical and non-medical) costs and cost effectiveness. DISCUSSION: This trial will contribute to our current knowledge on the use of LDI in burn care and will provide evidence on its cost-effectiveness. TRIAL REGISTRATION: NCT01489540. PMID- 23369361 TI - Application of iron nanaoparticles in landfill leachate treatment - case study: Hamadan landfill leachate. AB - This study was performed with the objective of determining the efficiency of iron nanoparticles for reducing chemical oxygen demand (COD), 5-day biological oxygen demand (BOD5), total solids (TS) and color of Hamadan city landfill leachate. Experiments were performed in a batch reactor and the main effective factors of pH, reaction time and concentration of iron nanoparticles were investigated. The obtained data were analyzed with One-Way ANOVA statistical test and SPSS-13 software. Maximum removal efficiencies were 47.94%, 35%, 55.62% and 76.66% for COD, BOD5, TS and color, respectively (for 2.5 g/L iron nanoparticles dosage, pH = 6.5 and 10 min reaction time). The results showed that the removal of COD, BOD5 and color had reverse relationship with contact time and TS removal followed a direct relationship (P < 0.05). Iron nanoparticles could remove averagely 53% of leachate COD, BOD5, TS and color in a short contact time (10 min) increasing pH up to 6.5, increased the removal efficiency for COD, BOD5, TS and color and then removal efficiency decreased with increasing pH to 8.5. Increasing the dosage of nanoparticles to 2.5 g/L increased the efficiency of process. High compatibility and efficiency of this process was proven by landfill leachate pre-treatment or post-treatment, so this removal method may be recommended for municipal solid waste landfill leachate treatment plants. PMID- 23369362 TI - The effect of fibroblast activation on vascularization in transplanted pancreatic islets. AB - BACKGROUND: Insufficient revascularization of transplanted pancreatic islets is an important reason why the long-term effects of pancreatic islet transplantation on type I diabetes patients have been so limited. The goal of this study was to investigate the role of fibroblasts (FBs) activated by tumor cell supernatants on the vascularization of transplanted pancreatic islets. MATERIALS AND METHODS: Pancreatic islets and activated or inactivated FBs were used for subrenal capsule transplantation. Mouse melanoma cell supernatants were used to activate FBs; the tests of the purity of the pancreatic islet cells of the donor, survival rate, and function of insulin secretion were performed to ensure high-quality transplants. Mice receiving the allogeneic transplantation were given tacrolimus and sirolimus to prevent rejection. The diabetic model was induced by streptozotocin. RESULTS: Conditioned medium made of tumor cell supernatants was found to stimulate the expression of alpha-smooth muscle actin and vascular endothelial growth factor A to an extent notably greater than that of pancreatic islet transplantation alone or pancreatic islet transplantation combined with inactivated FBs. FBs from the recipient were associated with capillary density in the transplanted pancreatic islet most closely to that observed in isogenically transplanted pancreatic islets and the original pancreatic islet. In this way, activated FBs derived from the recipient combined with pancreatic transplantation were able to treat diabetes, and long-term survival was achieved. CONCLUSIONS: The current research sheds new light on the revascularization of transplanted pancreatic islets: activated FBs derived from the recipients, when transplanted alongside pancreatic tissue, can promote revascularization inside the transplanted pancreatic islet. PMID- 23369363 TI - Application of receptor models on water quality data in source apportionment in Kuantan River Basin. AB - Recent techniques in the management of surface river water have been expanding the demand on the method that can provide more representative of multivariate data set. A proper technique of the architecture of artificial neural network (ANN) model and multiple linear regression (MLR) provides an advance tool for surface water modeling and forecasting. The development of receptor model was applied in order to determine the major sources of pollutants at Kuantan River Basin, Malaysia. Thirteen water quality parameters were used in principal component analysis (PCA) and new variables of fertilizer waste, surface runoff, anthropogenic input, chemical and mineral changes and erosion are successfully developed for modeling purposes. Two models were compared in terms of efficiency and goodness-of-fit for water quality index (WQI) prediction. The results show that APCS-ANN model gives better performance with high R2 value (0.9680) and small root mean square error (RMSE) value (2.6409) compared to APCS-MLR model. Meanwhile from the sensitivity analysis, fertilizer waste acts as the dominant pollutant contributor (59.82%) to the basin studied followed by anthropogenic input (22.48%), surface runoff (13.42%), erosion (2.33%) and lastly chemical and mineral changes (1.95%). Thus, this study concluded that receptor modeling of APCS-ANN can be used to solve various constraints in environmental problem that exist between water distribution variables toward appropriate water quality management. PMID- 23369364 TI - Therapeutic potential of targeting IL-17 and IL-23 in sepsis. AB - Severe sepsis is a major concern of public health in industrialized countries. It is estimated that in the United States 200,000-400,000 cases occur annually and resulting in an extensive burden for the health care systems. To date, no FDA approved pharmacologic agents for the treatment or prevention of human sepsis are available. The current modalities of therapy in sepsis include the standard arsenal of supportive interventions in critical care medicine and pharmacotherapy, with use of antibiotics and catecholamines. Despite such efforts, the mortality rates of sepsis have remained around 30-50 %. Extensive scientific studies have utilized animal models of disease and aimed for a better understanding of the pathophysiologic mechanisms during sepsis. Members of the IL 17 family of cytokines, as well as the functionally related IL-23, have been identified as new players in the molecular events during sepsis. Strategies for targeting these mediators with neutralizing antibodies during experimental sepsis in rodents have demonstrated efficacy, resulting in improved survival outcomes. Currently, it is not clear whether such findings can be translated to human sepsis. This review highlights the current knowledge on the biology of IL-17 isoforms and IL-23 as well as potential applications to clinical medicine. PMID- 23369365 TI - Atrial fibrillation: management strategies in the emergency department. AB - Atrial fibrillation and atrial flutter are the most common dysrhythmias seen in the emergency department. As the aging population continues to grow, atrial fibrillation and atrial flutter are expected to affect 6 million people by 2050. This will lead to an increase in emergency department visits for symptoms from the disease itself or its complications, such as heart failure or thromboembolic disease. This review examines the recent literature on the diagnosis and management of atrial fibrillation. Evidence-based recommendations are provided, including cost-effective strategies to evaluate new-onset arrhythmias and unstable patients with atrial fibrillation, rate control strategies, the use of medical and direct current cardioversion for new-onset atrial fibrillation/atrial flutter, whom and when to anticoagulate, and the use of the novel anticoagulation agents. PMID- 23369366 TI - Hormone-sensitive lipase deficiency disturbs the fatty acid composition of mouse testis. AB - Hormone-sensitive lipase (HSL) is a key enzyme in the mobilization of fatty acids from intracellular stores. In mice, HSL deficiency results in male sterility caused by a major defect in spermatogenesis. The testes contain high concentrations of PUFA and specific PUFA are essential for spermatogenesis. We investigated the fatty acid composition and the mRNA levels of key enzymes involved in fatty acid metabolism in testis of HSL-knockout mice. HSL deficiency altered fatty acid composition in the testis but not in plasma. The most important changes were decreases in the essential n-6 PUFA LNA and the n-3 PUFA ALA, and an increase in the corresponding synthesis intermediates C22:4n-6 and C22:5n-3 without changes in DPAn-6 or DHA acids. Mead acid, which has been associated with an essential fatty acid deficit leading to male infertility, was increased in the testis from HSL-knockout mice. Moreover, the expression of SCD 1, FADS1, and FADS2 was increased while expression of ELOVL2, an essential enzyme for the formation of very-long PUFA in testis, was decreased. Given the indispensability of these fatty acids for spermatogenesis, the changes in fatty acid metabolism observed in testes from HSL-knockout male mice may underlie the infertility of these animals. PMID- 23369368 TI - Telaprevir versus boceprevir in chronic hepatitis C: a meta-analysis of data from phase II and III trials. AB - BACKGROUND: Telaprevir and boceprevir are protease inhibitors now added to therapy for patients with chronic hepatitis C virus (HCV) genotype 1 infection who either are treatment naive or have a history of relapse or recurrence following a previous course of treatment with pegylated interferon + ribavirin (Peg-IFN + RBV). Because these agents are fairly new to the market, providers may have limited experience with them in the management of chronic HCV. OBJECTIVE: This meta-analysis compared 24- and 48-week sustained viral responses (SVR) and drug-related adverse events (AEs) between telaprevir and boceprevir triple therapy regimens in the treatment of chronic HCV infection. METHODS: MEDLINE, EMBASE, and Cochrane databases were searched for articles published from January 1995 to October 2012 on randomized controlled trials that reported SVR at >=24 weeks in patients with HCV receiving triple-therapy regimens that included telaprevir or boceprevir or placebo + pegylated interferon + ribavirin (Peg-IFN + RBV). Pooled odds ratios (ORs) were calculated and used to compare SVR at 24 and 48 weeks. Secondary end points included common drug-related AEs and treatment discontinuations. RESULTS: Eight studies were included in this meta-analysis (N = 4144 treatment-naive and treatment-experienced patients). With telaprevir, the ORs (95% CI) for SVR at 24 weeks in treatment-naive and treatment-experienced patients were 3.31 (2.27-4.82; P < 0.0001) and 4.21 (1.83-9.72; P = 0.001), respectively. Telaprevir triple therapy did not result in more drug-related discontinuations but did cause additional rash, pruritis, and anemia. With boceprevir, the ORs (95% CI) were improved in both treatment-naive and treatment experienced patients (3.55 [2.66-4.56; P < 0.0001] and 7.34 [3.92-13.9; P < 0.0001]), but with more treatment-related anemia and dysgeusia. CONCLUSIONS: Based on the findings from this meta-analysis, telaprevir or boceprevir combined with Peg-IFN + RBV had favorable short-term data on SVR while resulting in more drug-related AEs. Extended follow-up is required to determine whether these agents offer a reduction in the risk for chronic hepatitis C genotype 1-related mortality and/or hospitalization. PMID- 23369367 TI - Identification of low molecular weight nuclear complexes containing integrase during the early stages of HIV-1 infection. AB - BACKGROUND: HIV-1 replication requires integration of its reverse transcribed viral cDNA into a host cell chromosome. The DNA cutting and joining reactions associated to this key step are catalyzed by the viral protein integrase (IN). In infected cells, IN binds the viral cDNA, together with viral and cellular proteins, to form large nucleoprotein complexes. However, the dynamics of IN complexes formation is still poorly understood. RESULTS: Here, we characterized IN complexes during the early stages of T-lymphocyte infection. We found that following viral entry into the host cell, IN was rapidly targeted to proteasome mediated degradation. Interactions between IN and cellular cofactors LEDGF/p75 and TNPO3 were detected as early as 6 h post-infection. Size exclusion chromatography of infected cell extracts revealed distinct IN complexes in vivo. While at 2 h post-infection the majority of IN eluted within a high molecular weight complex competent for integration (IN complex I), IN was also detected in a low molecular weight complex devoid of full-length viral cDNA (IN complex II, ~440 KDa). At 6 h post-infection the relative proportion of IN complex II increased. Inhibition of reverse transcription or integration did not alter the elution profile of IN complex II in infected cells. However, in cells depleted for LEDGF/p75 IN complex II shifted to a lower molecular weight complex (IN complex III, ~150 KDa) containing multimers of IN. Notably, cell fractionation experiments indicated that both IN complex II and III were exclusively nuclear. Finally, IN complex II was not detected in cells infected with a virus harboring a mutated IN defective for LEDGF/p75 interaction and tetramerization. CONCLUSIONS: Our findings indicate that, shortly after viral entry, a significant portion of DNA-free IN that is distinct from active pre-integration complexes accumulates in the nucleus. PMID- 23369369 TI - Current pharmacogenomic studies on hERG potassium channels. AB - Genetic polymorphisms in human ether-a-go-go-related gene (hERG) potassium channels are associated with many complex diseases and sensitivity to channel related drugs. Genotypes may underlie different sensitivities to the same drug, and different drugs selectively repair the functional deficits caused by individual mutations. In fact, not all drugs that block hERG function have adverse effects as previously thought. This suggests that the severe adverse reactions observed clinically may only occur in subjects with a particular genotype, but to others may be safe. Similarly, a drug that is ineffective in one population may be both safe and effective in another. Therefore, detecting polymorphisms in KCNH2 encoding hERG1 is of great significance in guiding the prevention and treatment of related diseases, re-evaluating drug safety, and individualizing treatment. This article reviews current pharmacogenomic studies on hERG potassium channels to provide a reference for developing individualized treatments and evaluating their safety. PMID- 23369370 TI - The effect of dynamic sitting on trunk muscle activation: a systematic review. AB - The purpose of this systematic review was to investigate the effect of dynamic sitting on trunk muscle activation in sitting. Electronic databases were searched by two independent reviewers. Studies were included if they compared the effect of dynamic sitting on trunk muscle activation to a more static sitting condition. Seven studies were eligible for inclusion, six of which were rated as "high quality" using the PEDro scale. Five studies reported no difference in trunk muscle activation. Two studies reported a difference in trunk muscle activation, yet this was associated with increased discomfort, increased fatigue and greater spinal shrinkage. Furthermore, the changes reported in these two studies may be more related to the absence of a backrest rather than dynamic sitting. Therefore, the findings of this review suggest dynamic sitting does not significantly change trunk muscle activation. No randomised clinical trials or longitudinal design studies were found which evaluated the effect of dynamic sitting on trunk muscle activation, limiting the ability to make definitive conclusions about causality. The implications of the results, and recommendations for future research, are discussed. PMID- 23369371 TI - Treatment of bone loss in patients with chronic liver disease awaiting liver transplantation. AB - BACKGROUND: Most of the patients awaiting liver transplantation already have osteopenia or even osteoporosis by end-stage liver disease.In a retrospective study, we investigated the effect of pre-treatment with oral monthly ibandronate (150 mg), vitamin D3 (800 IU/day) and calcium (1 g/day) for osteopenia and osteoporosis caused by end-stage liver disease in patients before and after liver transplantation (LT). METHODS: The bone mineral density (BMD) of the lumbar spine (LS) and the femoral neck was measured prospectively pre- and post-LT in 31 patients with existing pre-transplant osteopenia. Patients had osteopenia of the LS prior to LT (T-score -1.8 +/- 1.5) so that the treatment medication was initiated immediately after the diagnosis. RESULTS: The study group showed a permanently increased BMD with significant differences (g/cm2) from baseline up to 12 months post LT at the lumbar spine (LS: pre-LT 0.80 +/- 0.11 g/cm2, three months: 0.90 +/- 0.08 (P <0.005); six months: 0.95 +/- 0.11 (P < 0.008); 12 months: 1.00 +/- 0.09 -0.85 (P <0.012). CONCLUSION: The combined pre- and post operative treatment with oral ibandronate had significantly improved bone mineral density of the lumbar spine at 3, 6 and 12 months post LT. The immediate post operative bone loss after LT can be significantly avoided by pre-treatment of liver transplant candidates affected by osteopenia. PMID- 23369372 TI - Bacterial diversity of the rock-water interface in an East Antarctic freshwater ecosystem, Lake Tawani(P)?. AB - Schirmacher Oasis is one of the few ice-free plateaus in East Antarctica that maintains a unique distribution of over 120 microbial-rich, dynamic freshwater lakes, most of which are unexplored. In this study, we describe the bacterial diversity of the rock-water interface in Lake Tawani(P) using culture-independent Bacterial Tag Encoded FLX Amplicon Pyrosequencing (bTEFAP), clone library construction, and culture-based analysis targeting the eubacterial 16S rRNA gene. Lake Tawani(P)was formed in a fossil valley by the accumulation of snow and glacial melt through surface channels into a low-catchment depression. Overall this lake exhibited thirteen bacterial phyla and one-hundred and twelve genera. The Qiime bioinformatics analysis on the bTEFAP alone exhibited higher coverage of the bacterial composition in Lake Tawani(P) than the clone library construction or culture-based methodology. Particularly due to the higher sensitivity of the bTEFAP approach, we detected and differentiated members of the phyla: Chloroflexi, Gemmatimonadetes, Planctomycetes, Nitrospira, and Candidate Division TM7 that other methods were unable to reveal. Nevertheless we found that the use of multiple approaches identified a more complete bacterial community than by using any single approach. Investigating the bacterial diversity of the Schirmacher Oasis lakes, especially those connected through surface channels and encompassed by valleys, will help unravel the dynamic nature of these unique seasonal, freshwater lakes, which potentially harbors highly adapted bacterial taxa with defined ecological functions. PMID- 23369373 TI - "There's no cure for this condition": how physicians discuss advance care planning in heart failure. AB - OBJECTIVE: To evaluate the extent to which physicians engage in recommended elements of advance care planning (ACP) communication during outpatient clinic visits with heart failure (HF) patients. METHODS: We conducted a qualitative content analysis of 71 audio-recorded and transcribed outpatient visits with 52 patients >=65 years recently hospitalized for HF and their physicians (n=44). RESULTS: We identified 25 instances of ACP-related communication over 15 of the 71 visits: in 17 instances, physicians explained the nature of HF but only once was the life-limiting potential of HF mentioned. Physicians discussed goals of care in 6 instances but elicited their patients' preferences in only 2 of those instances. Finally, physicians encouraged documentation of preferences in 2 instances. CONCLUSIONS: Despite recommendations for early ACP with HF patients, physicians rarely engaged in fundamental elements of ACP discussions during outpatient visits. We suggest a stepwise approach to supporting the process of ACP communication in practice. PRACTICE IMPLICATIONS: Given the importance of ACP in helping patients plan for their future care, outpatient clinicians should be helped to incorporate these discussions in the routine care of their HF patients. Using a simple heuristic might help physicians engage in fundamental elements of ACP during busy outpatient visits. PMID- 23369374 TI - Talking about obesity with clients: preferred terms and communication styles of U.K. pre-registration dieticians, doctors, and nurses. AB - OBJECTIVE: To describe trainee healthcare professionals' preferred terms when talking about obesity, their beliefs about initiating discussions about weight, and their confidence about consulting with obese people. METHODS: A self completed questionnaire collected data on demographics, preferred terms, beliefs about initiation of discussions, confidence and training needs from 1036 pre registration dieticians, nurses and doctors. RESULTS: Participants' preferred terms when raising the issue of obesity with clients were BMI (mean=.96), weight (mean=.71) and unhealthy BMI (mean=.43). When defining a client's bodyweight, students endorsed the euphemism 'your weight may be damaging your health' (67.6%). A proactive, collaborative communication style was preferred by 34.9% of participants. 58.2% of participants felt confident about discussing obesity with clients and 95.1% felt that that more training would be useful. CONCLUSION: It is reassuring that U.K. trainee healthcare professionals avoid value-laden terms and broadly endorse words preferred by people with obesity. It is, however, concerning that the majority of participants did not favor a proactive, collaborative communication style. PRACTICE IMPLICATIONS: Educators of tomorrow's healthcare professionals could take advantage of students' desire for more training on how to effectively talk to clients with obesity about their weight. Such training would, however, require the development of clear guidelines on terminology and communication styles. PMID- 23369375 TI - 'They've just got symptoms without science': Medical trainees' acquisition of negative attitudes towards patients with medically unexplained symptoms. AB - OBJECTIVE: Doctors find patients with medically unexplained symptoms (MUS) challenging to manage and some hold negative attitudes towards these patients. It is unknown when and how these views form. This study examines medical trainees' beliefs and influences about MUS. METHODS: Semi-structured interviews with 43 medical trainees. Using an iterative approach, initial emergent themes were explored in subsequent interviews. Data generation continued until thematic saturation was achieved. RESULTS: Participants had received no training in MUS but had developed views about causes and management. They struggled with the concept of 'diagnosis by exclusion'. Attitudes towards patients had developed through informal clinical observation and interactions with doctors. Many welcomed formal training but identified a need to integrate theoretical learning with clinical application. CONCLUSION: Despite limited teaching, medical trainees are aware of the challenges in diagnosing and managing patients with MUS, acquiring attitudes through a hidden curriculum. To be welcomed, training must be evidence-based, theoretically informed, but clinically applicable. PRACTICAL IMPLICATIONS: Current medical training fails to equip doctors to engage with MUS and potentially fosters the development of unhelpful views of these patients. Informed teaching on diagnosis and management of MUS is necessary at a trainee level to limit the development of negative attitudes. PMID- 23369376 TI - Patients' perspectives on psychiatric consultations in the Gender Identity Clinic: implications for patient-centered communication. AB - OBJECTIVE: To explore transsexual patients' perceptions of communication with psychiatrists in a Gender Identity Clinic and advance understanding of patient centered communication (PCC) in psychiatric, 'gatekeeping' settings. METHODS: 21 qualitative interviews with a convenience sample of clinic patients. Interviews were coded at a semantic level and subject to an inductive thematic analysis. RESULTS: Patients' perceptions clustered into three themes: (1) aspects of communication that patients described liking; (2) aspects of communication that patients described disliking; and (3) aspects of communication that patients deemed challenging but necessary or useful. CONCLUSION: Patients described liking or disliking aspects of communication that reflect existing understandings of PCC. However, a striking feature of their accounts was how they were able to rationalize and reflect pragmatically on their negative communication experiences, welcoming doctors' challenges as an opportunity to consider their life-changing decision to transition from their natal gender. PRACTICE IMPLICATIONS: In certain clinical settings, current operationalizations of PCC may not apply. Patients' perceptions of communication may be enhanced if an analysis of their experiences formed part of the professional training of doctors, who could be invited to consider the functional specificity of communication across settings and the consequences (both immediate and post hoc) of their communication practices. PMID- 23369377 TI - Potential of urinary metabolites for diagnosing multiple sclerosis. AB - A definitive diagnostic test for multiple sclerosis (MS) does not exist; instead physicians use a combination of medical history, magnetic resonance imaging, and cerebrospinal fluid analysis (CSF). Significant effort has been employed to identify biomarkers from CSF to facilitate MS diagnosis; however, none of the proposed biomarkers have been successful to date. Urine is a proven source of metabolite biomarkers and has the potential to be a rapid, noninvasive, inexpensive, and efficient diagnostic tool for various human diseases. Nevertheless, urinary metabolites have not been extensively explored as a source of biomarkers for MS. We demonstrate that urinary metabolites have significant promise for monitoring disease-progression, and response to treatment in MS patients. NMR analysis of urine permitted the identification of metabolites that differentiate experimental autoimmune encephalomyelitis (EAE)-mice (prototypic disease model for MS) from healthy and MS drug-treated EAE mice. PMID- 23369378 TI - Development of a versatile TaqManTM real-time quantitative PCR (RT-qPCR) compliant anchor sequence to quantify bacterial gene transcripts from RNA samples containing carryover genomic DNA. AB - BACKGROUND: In bacterial systems, the sequence congruence of genomic DNA (gDNA) and cDNA obtained following reverse transcription of RNA, makes gDNA an automatic target for qPCR primers. This could lead to aberrant gene expression quantification. This is why a rigorous treatment of bacterial RNA with DNase I is usually required to remove any traces of carryover gDNA. As bacterial RNA is known to be extremely labile, any procedure that affects RNA yield, such as DNase I treatment, can be logically assumed to also influence detection and quantification of gene transcripts, leading to either an underestimation or no detection at all. To address such problems, we have developed a novel and versatile TaqMan RT-qPCR compliant anchor sequence (MYT4) for quantifying bacterial gene transcripts without the need for DNase I treatment. RESULTS: A non genomic anchor sequence, henceforth referred to as MYT4 was designed using a synthetic DNA sequence called myIC, previously shown to share no significant homology to any known accession in the GenBank database. The sequence characteristic of MYT4 was kept within the design parameters required for the TaqMan RT-qPCR platform. The specificity and robustness of the novel MYT4 sequence was validated on RNA extracted from the bacterium Pseudomonas sp. LBUM300, grown under liquid culture and spiked soil conditions. Two transcripts, namely hcnC and phlD, were quantified from these two experimental systems. Using the MYT4 anchor, no RT-qPCR signal was detected from non-DNase I treated RNA, while strong signals were obtained using conventional reverse primers and RT qPCR, indicating the presence of carryover gDNA in the RNA, extracted from either liquid culture or soil. Serial treatment of the RNA samples with DNase I (required to achieve absolute gDNA elimination) resulted in 50-70% loss of RNA which, when submitted to conventional RT-qPCR, significantly altered the transcript numbers detected when compared to the MYT4-based approach. CONCLUSIONS: Implementation of the versatile approach described in this study, which can be "retrofitted" to any existing TaqMan RT-qPCR system, should contribute to reducing the time and lowering the costs required to perform adequate bacterial RNA purification for downstream quantification of gene transcripts. PMID- 23369379 TI - Study of Mo (VI) removal from aqueous solution: application of different mathematical models to continuous biosorption data. AB - Molybdenum (VI) biosorption process was investigated by marine algae Cystoseria indica pretreated with 0.1 M CaCl2 solution in a packed bed column. The biosorbent was characterized by FTIR, BET and SEM analyses. The results showed that Mo (VI) ions should be chelated with the hydroxyl, carboxyl and amine groups of the biomass. The effects of inlet metal concentration and flow rate on biosorption process were investigated and the experimental breakthrough curves were obtained. Results showed that the maximum biosorption capacity of Ca pretreated C. indica for Mo (VI) was found to be 18.32 mg/g at optimum flow rate of (1.4 mL/min). The controlled-rate step shifted from external to internal mass transfer limitations, as the flow rate increased. Also, it was observed that the breakthrough and exhaustion time decreased from 17.14 hr to 9.05 hr and from 0.006 h to 0.002 hr respectively, with the increase of flow rate from 0.7 to 2.1 ML/min. The increase in the initial concentration of Mo (VI) solution from 30 to 95 ml min-1 increases the adsorption capacity from 18.32 to 30.19 mg/g and decreases the percentage of Mo (VI) removal from 61 to 38%. Also, the treated volume was the greatest (1.42 L) at the lowest inlet concentration. Column data obtained under different conditions were described using the Thomas, Yoon and Nelson, Yan and Belter models. The breakthrough curve predictions by Belter model were found to be very satisfactory. PMID- 23369380 TI - Case study for the assessment of the biogeophysical effects of a potential afforestation in Europe. AB - BACKGROUND: A regional-scale sensitivity study has been carried out to investigate the climatic effects of forest cover change in Europe. Applying REMO (regional climate model of the Max Planck Institute for Meteorology), the projected temperature and precipitation tendencies have been analysed for summer, based on the results of the A2 IPCC-SRES emission scenario simulation. For the end of the 21st century it has been studied, whether the assumed forest cover increase could reduce the effects of the greenhouse gas concentration change. RESULTS: Based on the simulation results, biogeophysical effects of the hypothetic potential afforestation may lead to cooler and moister conditions during summer in most parts of the temperate zone. The largest relative effects of forest cover increase can be expected in northern Germany, Poland and Ukraine, which is 15-20% of the climate change signal for temperature and more than 50% for precipitation. In northern Germany and France, potential afforestation may enhance the effects of emission change, resulting in more severe heavy precipitation events. The probability of dry days and warm temperature extremes would decrease. CONCLUSIONS: Large contiguous forest blocks can have distinctive biogeophysical effect on the climate on regional and local scale. In certain regions of the temperate zone, climate change signal due to greenhouse gas emission can be reduced by afforestation due to the dominant evaporative cooling effect during summer. Results of this case study with a hypothetical land cover change can contribute to the assessment of the role of forests in adapting to climate change. Thus they can build an important basis of the future forest policy. PMID- 23369381 TI - Determination of lead, cadmium and arsenic in infusion tea cultivated in north of Iran. AB - Tea is one of the most common drinks in all over the world. Rapid urbanization and industrialization in recent decades has increased heavy metals in tea and other foods. In this research, heavy metal contents such as lead (Pb), cadmium (Cd) and arsenic (As) were determined in 105 black tea samples cultivated in Guilan and Mazandaran Provinces in north of Iran and their tea infusions. The amount of heavy metals in black tea infusions were analyzed using Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP - AES).The mean +/- SD level of Pb in 5, 15 and 60 min in infusion tea samples were 0.802 +/- 0.633, 0.993 +/- 0.667 and 1.367 +/- 1.06 mg/kg of tea dry weight, respectively. The mean level of Cd in 5, 15 and 60 min in infusion tea samples were 0.135 +/- 0.274, 0.244 +/- 0.46 and 0.343 +/- 0.473 mg/kg of tea dry weight, respectively. The mean level of As in 5, 15 and 60 min in infusion tea samples were 0.277 +/- 0.272, 0.426 +/- 0.402 and 0.563 +/- 0.454 mg/kg of tea dry weight, respectively. Also, the results showed that the locations and the infusion times influenced upon the amount of these metals (P < 0.05). PMID- 23369382 TI - Reliability and discriminatory testing of a client-based metrology instrument, feline musculoskeletal pain index (FMPI) for the evaluation of degenerative joint disease-associated pain in cats. AB - The objective of this study was to test the readability, reliability, repeatability and discriminatory ability of an owner-completed instrument to assess feline degenerative joint disease (DJD)-associated pain (feline musculoskeletal pain index, FMPI). Readability was explored using four different formulas (Flesch, Fry, SMOG and FOG) and the final FMPI instrument was produced. To assess the instrument, client-owned cats that were defined as normal (normal group) or as having DJD-associated pain and mobility impairment (pain-DJD group) were recruited. A total of 32 client-owned cats were enrolled in the study (normal, n=13; pain-DJD, n=19). Owners completed the FMPI on two occasions, 14days apart. Internal consistency (reliability) and repeatability (test-retest) were explored using Cronbach's alpha and weighted kappa statistic, respectively. Data from the two groups were compared using analysis of covariance (controlling for age) to evaluate discriminatory ability. The FMPI was constructed with 21 questions covering activity, pain intensity and overall quality of life. It had a 6th grade readability score. Reliability of the FMPI was excellent (Cronbach's alpha>0.8 for all groupings of questions in normal and pain-DJD cats) and repeatability was good (weighted kappa statistic >0.74) for normal and pain-DJD cats. All components of the FMPI were able to distinguish between normal cats and cats with DJD (P<0.001 for all components). This initial evaluation of the FMPI suggests that this instrument is worthy of continued investigation. PMID- 23369383 TI - Changes in the serum proteome of canine lymphoma identified by electrophoresis and mass spectrometry. AB - The serum proteome of canine lymphoma was characterised by one dimensional (1D) serum protein electrophoresis (SPE) on agarose gels, two dimensional (2D) polyacrylamide gel electrophoresis (PAGE) and tandem mass spectrometry (MS). Results were compared with serum proteome data collected previously from the sera of healthy dogs. Twenty-one dogs with high grade multicentric lymphoma had significantly elevated quantities of alpha2 globulins on 1D SPE. Further separation of the serum proteins was performed on three dogs using a 2D PAGE system. Thirty-six different proteins were identified in 38 bands submitted for MS. Most of the proteins were the same as those previously identified in the sera of healthy dogs. Haptoglobin was identified in the sera of all three dogs with lymphoma and could account for the increased levels of alpha2 globulins. alpha2 Macroglobulin, alpha-antichymotrypsin and inter-alpha-trypsin inhibitor were also present in dogs with lymphoma. Clusterin, an anti-apoptotic protein, was identified in the serum of one dog with lymphoma. Kininogen, which is present in the sera of healthy dogs, was absent in all three dogs with lymphoma. The 2D electrophoresis technique identified alterations in the serum proteome of dogs with lymphoma and supported previous findings that canine lymphoma has an inflammatory component. PMID- 23369384 TI - Identification of dasatinib as an in vitro potent growth inhibitor of canine histiocytic sarcoma cells. AB - Canine histiocytic sarcoma (HS) is an aggressive and fatal neoplasm that has a high recurrence rate and metastatic nature. In the present report, compounds were screened for their growth inhibitory activity in two HS cell lines using a chemical library known to target specific signalling pathways. Among 171 compounds screened, dasatinib, which targets several types of kinases, clearly inhibited cell growth in one of the two HS lines. The growth inhibitory properties of dasatinib were then examined using six HS cell lines and MDCK cells. Dasatinib demonstrated potent growth inhibitory activity against four HS cell lines with calculated IC50 values of 5.4-54.5nM, while the IC50 values in the other cell lines were in the micromolar range. In conclusion, a kinase enzyme targeted by dasatinib appears to be crucial for growth in some subsets of HS and the on-target activity of dasatinib could underlie the marked growth inhibition in HS cells. PMID- 23369385 TI - Current attitudes of bovine practitioners, claw-trimmers and farmers in Switzerland to pain and painful interventions in the feet in dairy cattle. AB - The attitudes of bovine practitioners, claw-trimmers and farmers towards painful therapeutic claw-trimming of dairy cattle were surveyed and differences between the respondents were assessed. A total of 77 farmers and 32 claw-trimmers were interviewed, and 137 bovine practitioners completed an equivalent online survey. No veterinary consultation for common painful interventions in the feet of cattle was reported by 52% of farmers (i.e. procedures in these herds were performed without local anaesthesia). Only ~30% of practitioners always carried out such interventions under local anaesthesia and, in general, practitioners considered pain reduction to the lowest possible level less important than did farmers. Furthermore, 47% of practitioners and 33% of claw-trimmers, compared to only 11% of farmers, agreed with the statement that the cost of pain management was a major concern for farmers. There was a particular lack of awareness by farmers regarding the obligation to carry out painful therapeutic claw-trimming under analgesia and the application of local anaesthesia during the trimming of sole ulcers was considered reasonable by significantly fewer farmers (41.6%) and claw trimmers (46.9%), than practitioners (78.6%). Overall, the attitudes of those involved in painful therapeutic claw-trimming contrasted with Swiss national legislation and with farmer opinion on the importance of reducing pain to the lowest level possible. PMID- 23369386 TI - Characterisation of the normal canine serum proteome using a novel electrophoretic technique combined with mass spectrometry. AB - One dimensional (1D) serum protein electrophoresis (SPE) on agarose gels is a frequently used diagnostic tool for canine diseases; however, little is known regarding the precise composition of the different protein fractions in normal or diseased animals. In this study, to analyse the canine serum proteome in more detail, conventional 1D SPE was combined with second dimension (2D) polyacrylamide gel electrophoresis (PAGE), followed by tandem mass spectrometry (MS). One dimensional SPE was performed on the sera of 17 healthy dogs to establish normal reference ranges for the albumin and globulin sub-fractions. Two representative serum samples from healthy dogs were further separated using a novel method of 2D PAGE, leading to the generation of 26 distinct bands across the six main sub-fractions, which were subjected to MS analysis. Thirty-two proteins were identified, most of which were found in both dogs. Twenty proteins belonged specifically to the species Canis lupus familiaris, with the remaining 12 proteins belonging to other mammalian species, likely reflecting incomplete sequencing knowledge of canine proteins. Two dimensional electrophoresis and MS allowed identification of canine serum albumin precursor, serpin peptidase inhibitor, kininogen-1, vitamin D binding protein, haemopexin, complement C4 and a variety of immunoglobulin class molecules, along with localisation of these proteins within serum protein subfractions. PMID- 23369387 TI - From molecular to genomic epidemiology: transforming surveillance and control of infectious diseases. PMID- 23369388 TI - Use of multilocus variable-number tandem repeat analysis (MLVA) in eight European countries, 2012. AB - Genotyping of important medical or veterinary prokaryotes has become a very important tool during the last decades. Rapid development of fragment-separation and sequencing technologies has made many new genotyping strategies possible. Among these new methods is multilocus variable-number tandem repeat analysis (MLVA). Here we present an update on the use of MLVA in eight European countries (Denmark, France, Germany, Ireland, Italy, the Netherlands, Norway and Sweden). Researchers in Europe have been active in developing and implementing a large array of different assays. MLVA has been used as a typing tool in several contexts, from aiding in resolving outbreaks of foodborne bacteria to typing organisms that may pose a bioterrorist threat, as well as in scientific studies. PMID- 23369389 TI - Overview of molecular typing methods for outbreak detection and epidemiological surveillance. AB - Typing methods for discriminating different bacterial isolates of the same species are essential epidemiological tools in infection prevention and control. Traditional typing systems based on phenotypes, such as serotype, biotype, phage type, or antibiogram, have been used for many years. However, more recent methods that examine the relatedness of isolates at a molecular level have revolutionised our ability to differentiate among bacterial types and subtypes. Importantly, the development of molecular methods has provided new tools for enhanced surveillance and outbreak detection. This has resulted in better implementation of rational infection control programmes and efficient allocation of resources across Europe. The emergence of benchtop sequencers using next generation sequencing technology makes bacterial whole genome sequencing (WGS) feasible even in small research and clinical laboratories. WGS has already been used for the characterisation of bacterial isolates in several large outbreaks in Europe and, in the near future, is likely to replace currently used typing methodologies due to its ultimate resolution. However, WGS is still too laborious and time-consuming to obtain useful data in routine surveillance. Also, a largely unresolved question is how genome sequences must be examined for epidemiological characterisation. In the coming years, the lessons learnt from currently used molecular methods will allow us to condense the WGS data into epidemiologically useful information. On this basis, we have reviewed current and new molecular typing methods for outbreak detection and epidemiological surveillance of bacterial pathogens in clinical practice, aiming to give an overview of their specific advantages and disadvantages. PMID- 23369390 TI - Bioinformatics in bacterial molecular epidemiology and public health: databases, tools and the next-generation sequencing revolution. AB - Advances in typing methodologies have been the driving force in the field of molecular epidemiology of pathogens. The development of molecular methodologies, and more recently of DNA sequencing methods to complement and improve phenotypic identification methods, was accompanied by the generation of large amounts of data and the need to develop ways of storing and analysing them. Simultaneously, advances in computing allowed the development of specialised algorithms for image analysis, data sharing and integration, and for mining the ever larger amounts of accumulated data. In this review, we will discuss how bioinformatics accompanied the changes in bacterial molecular epidemiology. We will discuss the benefits for public health of specialised online typing databases and algorithms allowing for real-time data analysis and visualisation. The impact of the new and disruptive next-generation sequencing methodologies will be evaluated, and we will look ahead into these novel challenges. PMID- 23369391 TI - Automated extraction of typing information for bacterial pathogens from whole genome sequence data: Neisseria meningitidis as an exemplar. AB - Whole genome sequence (WGS) data are increasingly used to characterise bacterial pathogens. These data provide detailed information on the genotypes and likely phenotypes of aetiological agents, enabling the relationships of samples from potential disease outbreaks to be established precisely. However, the generation of increasing quantities of sequence data does not, in itself, resolve the problems that many microbiological typing methods have addressed over the last 100 years or so; indeed, providing large volumes of unstructured data can confuse rather than resolve these issues. Here we review the nascent field of storage of WGS data for clinical application and show how curated sequence-based typing schemes on websites have generated an infrastructure that can exploit WGS for bacterial typing efficiently. We review the tools that have been implemented within the PubMLST website to extract clinically useful, strain-characterisation information that can be provided to physicians and public health professionals in a timely, concise and understandable way. These data can be used to inform medical decisions such as how to treat a patient, whether to instigate public health action, and what action might be appropriate. The information is compatible both with previous sequence-based typing data and also with data obtained in the absence of WGS, providing a flexible infrastructure for WGS-based clinical microbiology. PMID- 23369392 TI - Laboratory-based surveillance in the molecular era: the TYPENED model, a joint data-sharing platform for clinical and public health laboratories. AB - Laboratory-based surveillance, one of the pillars of monitoring infectious disease trends, relies on data produced in clinical and/or public health laboratories. Currently, diagnostic laboratories worldwide submit strains or samples to a relatively small number of reference laboratories for characterisation and typing. However, with the introduction of molecular diagnostic methods and sequencing in most of the larger diagnostic and university hospital centres in high-income countries, the distinction between diagnostic and reference/public health laboratory functions has become less clear-cut. Given these developments, new ways of networking and data sharing are needed. Assuming that clinical and public health laboratories may be able to use the same data for their own purposes when sequence-based testing and typing are used, we explored ways to develop a collaborative approach and a jointly owned database (TYPENED) in the Netherlands. The rationale was that sequence data - whether produced to support clinical care or for surveillance -can be aggregated to meet both needs. Here we describe the development of the TYPENED approach and supporting infrastructure, and the implementation of a pilot laboratory network sharing enterovirus sequences and metadata. PMID- 23369393 TI - Current application and future perspectives of molecular typing methods to study Clostridium difficile infections. AB - Molecular typing is an essential tool to monitor Clostridium difficile infections and outbreaks within healthcare facilities. Molecular typing also plays a key role in defining the regional and global changes in circulating C. difficile types. The patterns of C. difficile types circulating within Europe (and globally) remain poorly understood, although international efforts are under way to understand the spatial and temporal patterns of C. difficile types. A complete picture is essential to properly investigate type-specific risk factors for C. difficile infections (CDI) and track long-range transmission. Currently, conventional agarose gel-based polymerase chain reaction (PCR) ribotyping is the most common typing method used in Europe to type C. difficile. Although this method has proved to be useful to study epidemiology on local, national and European level, efforts are made to replace it with capillary electrophoresis PCR ribotyping to increase pattern recognition, reproducibility and interpretation. However, this method lacks sufficient discriminatory power to study outbreaks and therefore multilocus variable-number tandem repeat analysis (MLVA) has been developed to study transmission between humans, animals and food. Sequence-based methods are increasingly being used for C. difficile fingerprinting/typing because of their ability to discriminate between highly related strains, the ease of data interpretation and transferability of data. The first studies using whole genome single nucleotide polymorphism typing of healthcare-associated C. difficile within a clinically relevant timeframe are very promising and, although limited to select facilities because of complex data interpretation and high costs, these approaches will likely become commonly used over the coming years. PMID- 23369394 TI - From theory to practice: molecular strain typing for the clinical and public health setting. AB - The persistence and transmission of infectious disease is one of the most enduring and daunting concerns in healthcare. Over the years, epidemiological analysis especially of bacterial etiological agents has undergone a remarkable evolutionary metamorphosis. While initially relying on purely phenotypic characterisation, advances in molecular biology have found translational application in a number of approaches to strain typing which commonly centre either on 'epityping' (molecular epidemiology) to characterise outbreaks, perform surveillance, and trace evolutionary pathways, or 'pathotyping' to compare strains based on the presence or absence of specific virulence or resistance genes. A perspective overview of strain typing is presented here considering the issues surrounding analyses which are employed in the localised clinical setting as well as at a more regional/national public health level. The discussion especially considers the shortcomings inherent in epidemiological analysis: less than full isolate characterisation by the typing method and limitations imposed by the available data, context, and time constraints of the epidemiological investigation (i.e. the available epidemiological window). However, the promises outweigh the pitfalls as one considers the potential for advances in genomic characterisation and information technology to provide an unprecedented aggregate of epidemiological information and analysis. PMID- 23369395 TI - The need for ethical reflection on the use of molecular microbial characterisation in outbreak management. AB - Current thinking on the development of molecular microbial characterisation techniques in public health focuses mainly on operational issues that need to be resolved before incorporation into daily practice can take place. Notwithstanding the importance of these operational challenges, it is also essential to formulate conditions under which such microbial characterisation methods can be used from an ethical perspective. The potential ability of molecular techniques to show relational patterns between individuals with more certainty brings a new sense of urgency to already difficult ethical issues associated with privacy, consent and a moral obligation to avoid spreading a disease. It is therefore important that professionals reflect on the ethical implications of using these techniques in outbreak management, in order to be able to formulate the conditions under which they may be applied in public health practice. PMID- 23369396 TI - A new vision of definition, commentary, and understanding in clinical and translational medicine. AB - There is growing evidence to the importance of translational science and medicine in the improvement of patient outcome, even though the definitions of translational science, translational medicine, and clinical and translational medicine need to be further clarified. In the present perspective, we collected commentaries and descriptions about clinical and translational medicine from some members of Clinical and Translational Medicine editorial board to stimulate the discussion and help the understanding better. PMID- 23369398 TI - Triphasic waves vs stimulus-induced rhythmic, periodic, or ictal discharges: are we talking of the same thing. PMID- 23369397 TI - The international effort: building the bridge for Translational Medicine: Report of the 1st International Conference of Translational Medicine (ICTM). AB - BACKGROUND: Supported by the International Society for Translational Medicine (ISTM), Wenzhou Medical College and the First Affiliated Hospital of Wenzhou Medical College, the International Conference on Translational Medicine (ICTM) was held on October 22-23, 2011 in Wenzhou, China. Nearly 800 registrants attended the meeting, primarily representing institutes and hospitals in Europe, The United States of America, And Asia, and China. The meeting was chaired and organized by Dr. Xiangdong Wang, Xiaoming Chen, Richard Coico, Jeffrey M. Drazen, Richard Horton, Francesco M. Marincola, Laurentiu M. Popescu, Jia Qu and Aamir Shahzad. FINDINGS: The meeting focused on the communication of the need to foster translational medicine (TM) by building and broadening bridges between basic research and clinical studies at the international level. The meeting included distinguished TM experts from academia, the pharmaceutical and diagnostics industries, government agencies, regulators, and clinicians and provided the opportunity to identify shared interests and efforts for collaborative approaches utilizing cutting edge technologies, innovative approaches and novel therapeutic interventions. The meeting defined the concept of TM in its two-way operational scheme and emphasized the need for bed to bench efforts based directly on clinical observation. CONCLUSIONS: It was the meeting participants' realization that the shared main goals of TM include breaking the separation between clinic practice and basic research, establishing positive feedback by understanding the basis of expected and unexpected clinical outcomes and accelerating basic research relevant to human suffering. The primary objectives of the meeting were two-fold: to accelerate the two-way translation by informing the participants representing the different disciplines about the state of art activities around TM approaches; and to identify areas that need to be supported by redirecting limited resources as well as identifying new sources of funding. This report summarizes key concepts presented during the meeting representing the state-of art translational research and salient aspects of the ensuing discussions. PMID- 23369399 TI - Nocturnal carbon dioxide monitoring in patients with idiopathic intracranial hypertension. AB - BACKGROUND: Idiopathic intracranial hypertension may be associated with sleep apnea. This study evaluated the incidence of sleep breathing disorders in patients with idiopathic intracranial hypertension. MATERIALS AND METHODS: Overnight respiratory monitoring was performed in 22 untreated patients with idiopathic intracranial pressure diagnosed at a tertiary medical center over a two-year period and 12 sex- and age-matched control subjects. Breathing measures included heart rate, respiratory rate,oxygen saturation, and continuous end-tidal capnography. Sleep quality and daily fatigue were assessed by self-report questionnaires. RESULTS: Mean age of the study group was 32.6+/-12.2 years and of the control group, 37.0+/-12.9 years. Neither group had significant findings of hypoxia or hypercarbia during sleep, and there were no between-group differences in mean carbon dioxide level (patients, 35.8+/-4.41 mmHg; controls, 37.6+/-4.38 mmHg; p>0.02) or minimal oxygen saturation (96.35+/-1.99% and 5.69+/-1.71%, respectively; p>0.02). The study group had significantly more events of apnea (CO2) per hour of sleep than the control group (1.21+/-1.38 and 0.92+/-0.56, respectively; p=0.02), although values were still within normal range (<5/hr). CONCLUSION: Idiopathic intracranial hypertension is not associated with a clinically significant nocturnal breathing abnormality, and hypercarbia is apparently not involved in the pathogenesis. However, it is possible that a subtle increase in paroxysmal sleep apnea (CO2) events might be sufficient to cause vasodilatation of the cerebral blood vessels, thereby increasing intracranial pressure. Screening for sleep apnea may be appropriate in idiopathic intracranial hypertension patients, and further studies are needed to clarify this issue. PMID- 23369400 TI - Delayed rupture of iatrogenic cerebral pseudoaneurysms after neurosurgical procedures: report of two cases. PMID- 23369401 TI - Epidemiology and trend of neurological diseases associated to HIV/AIDS. Experience of Mexican patients 1995-2009. AB - OBJECTIVE: The aim of this study was to identify the main neurological conditions associated with HIV/AIDS in Mexican patients treated at the National Institute of Neurology and Neurosurgery (NINN) in Mexico city, the main referral center for patients with disorders of the central and peripheral nervous system. METHODS: An observational, transversal and descriptive analysis was performed. We reviewed the databases from the Department of Epidemiology and the medical records of patients with AIDS seen during the period from January 1st, 1995 to December 31, 2009. RESULTS: 320 patients were detected, the main conditions related to HIV/AIDS were brain toxoplasmosis (42%), cerebral criptoccocosis (28%), tuberculous meningitis (8.7%), linfoma no Hodking (3.75%), acute HIV infection (3.4%) and AIDS dementia complex (3%). No specific trend on morbility and mortality were detected during the period of study. CONCLUSIONS: In Mexico the most common neurological complications of HIV/AIDS are opportunistic infections. PMID- 23369402 TI - Foix-Chavany-Marie syndrome after unilateral anterior opercular contusion: a case report. PMID- 23369403 TI - Characteristics of temporal lobe epilepsy with no ictal impairment of consciousness. AB - INTRODUCTION: The predominant manifestations of temporal lobe epilepsy (TLE) are partial seizures with impairment of consciousness (type I.B of ILAE classification), although consciousness impairment is not necessary in all seizures of patients with TLE. Nevertheless, there have been very few reports of TLE patients with exclusive seizures with no impairment of consciousness (i.e. isolated auras). The objective of this study was to determine any differential characteristics of this subgroup of TLE patients. MATERIAL AND METHODS: Retrospective case-control study in 163 consecutive TLE patients from our hospital database. The patients were divided between those with and without ictal impairment of consciousness, based on directed semi-structured questionnaire to the patient and relatives and on video-EEG records. Ten independent variables (8 clinical and 2 paraclinical) were compared between the groups. RESULTS: 14 patients (8.5%) formed the "TLE without ictal impairment of consciousness" group. This group was less refractory to medical treatment [Odds Ratio: 0.14 (0.03 0.64); p<0.01] and had frequent ictal motor behaviour [Odds ratio: 5.33 (1.65 17.14); p=0.008] and less frequent presence of automatisms [p<0.001]. Non significant tendencies were observed for a higher frequency of lesional substrate and fewer generalization episodes. DISCUSSION: TLE without ictal impairment of consciousness appears to be more frequent than previously thought. This subgroup of TLE patients shows differential characteristics that may possibly result from a differential propagation of the original epileptic activity towards frontal areas rather than towards neocortical and diencephalic structures, which may be related to the more frequent presence of structural lesions. PMID- 23369404 TI - A 73-year-old patient with adult-onset type II citrullinemia successfully treated by sodium pyruvate and arginine. PMID- 23369405 TI - Inherited manganism. PMID- 23369407 TI - 50/500 rule and minimum viable populations: response to Jamieson and Allendorf. PMID- 23369406 TI - Short and long term gene expression variation and networking in human proximal tubule cells when exposed to cadmium. AB - Cadmium (Cd2+) is a known nephrotoxin causing tubular necrosis during acute exposure and potentially contributing to renal failure in chronic long-term exposure. To investigate changes in global gene expression elicited by cadmium, an in-vitro exposure system was developed from cultures of human renal epithelial cells derived from cortical tissue obtained from nephrectomies. These cultures exhibit many of the qualities of proximal tubule cells. Using these cells, a study was performed to determine the cadmium-induced global gene expression changes after short-term (1 day, 9, 27, and 45 MUM) and long-term cadmium exposure (13 days, 4.5, 9, and 27 MUM). These studies revealed fundamental differences in the types of genes expressed during each of these time points. The obtained data was further analyzed using regression to identify cadmium toxicity responsive genes. Regression analysis showed 403 genes were induced and 522 genes were repressed by Cd2+ within 1 day, and 366 and 517 genes were induced and repressed, respectively, after 13 days. We developed a gene set enrichment analysis method to identify the cadmium induced pathways that are unique in comparison to traditional approaches. The perturbation of global gene expression by various Cd2+ concentrations and multiple time points enabled us to study the transcriptional dynamics and gene interaction using a mutual information-based network model. The most prominent network module consisted of INHBA, KIF20A, DNAJA4, AKAP12, ZFAND2A, AKR1B10, SCL7A11, and AKR1C1. PMID- 23369408 TI - Native valve right sided infective endocarditis. AB - Right-sided infective endocarditis (RSIE) accounts for 5-10% of all cases of infective endocarditis (IE), and is predominantly encountered in the injecting drug user (IDU) population, where HIV and HCV coinfections often coexist. Staphylococcus aureus is the most common pathogen. The pathogenesis of RSIE is still not well understood. RSIE usually presents as a persistent fever with respiratory symptoms whilst signs of systemic embolisation as seen in left-sided IE are notably absent. The prompt diagnosis of RSIE thus requires a high index of suspicion. Transthoracic echocardiography (TTE) can detect the majority of RSIE, whilst transoesophageal echocardiography (TOE) can increase sensitivity. Virulence of the causative organism and vegetation size are the major determinants of prognosis. Most cases of RSIE resolve with appropriate antibiotic administration. PMID- 23369409 TI - The pig as a model for translational research: overview of porcine animal models at Jichi Medical University. AB - To improve the welfare of experimental animals, investigators seek to respect the 3R principle (Replacement, Reduction, and Refinement). Even when large animal studies are essential before moving to clinical trials, it is important to look for ways to reduce the number of experimental animals used. At the Center for the Development of Advanced Medical Technology, we consider 'medical' pigs to be ideal preclinical model systems.We have been using both wild-type and genetically modified pigs. We began using this approach about 10 years ago with a 'total pig system' to model human health and disease for the purposes of both medical skill education and the development of new devices and therapeutic strategies.At our Center, medical students and residents use pigs to gain experience with surgical skills and train for emergency procedures after appropriate simulation training. Senior clinicians have also used these models to advance the development of innovative tools for endo- and laparoscopic procedures. The Center focuses on translational research for organ transplantation and stem cell therapy. Several pig models have been established for liver, intestine, kidney, pancreas, and lung transplantation. Mesenchymal stromal cells have been established in green fluorescent protein- and red fluorescent protein-transgenic pigs and tested to trans-differentiate organogenesis. A program to establish induced pluripotent stem cells in the pig is ongoing at our Center.Here, we review our 10 years of activity in this field. Based on our experience in surgical education and research, experimental pigs are valuable models in translational research. PMID- 23369410 TI - Open new possibilities in Transplantation Research. PMID- 23369411 TI - No easy route to a pandemic influenza vaccine. PMID- 23369413 TI - Corticosteroids for prevention of mortality in people with tuberculosis: a systematic review and meta-analysis. AB - BACKGROUND: The effects of corticosteroids are systemic, but their benefits in tuberculosis are thought to be organ specific, with clinicians using them routinely to treat some forms of tuberculosis (such as meningitis), but not others. We aimed to assess the effects of steroids on mortality attributable to all forms of tuberculosis across organ systems. METHODS: We did a systematic review and meta-analysis to estimate the efficacy of steroids for the prevention of mortality in all forms of tuberculosis, and to quantify heterogeneity in this outcome between affected organ systems. We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Central Register of Controlled Trials, Medline, Embase, and Literatura Latino-Americana e do Caribe em Ciencias da Saude (LILACS) for studies published up to Sept 6, 2012, and checked reference lists of included studies and relevant reviews. We included all trials in people with tuberculosis in any organ system, with tuberculosis defined clinically or microbiologically. There were no restrictions by age, comorbidity, publication language, or type, dose, or duration of steroid treatment. We used the Mantel Haenszel method to summarise mortality across trials. FINDINGS: We identified 41 eligible trials, 18 of which assessed pulmonary tuberculosis. 20 of the 41 trials (including 13 of those for pulmonary tuberculosis) were done before the introduction of modern rifampicin-containing antituberculosis chemotherapy. Meta analysis stratified by affected organ systems identified no heterogeneity; steroids reduced mortality by 17% (risk ratio [RR] 0.83, 95% CI 0.74-0.92; I(2) 0%), consistent across all organ groups. In a sensitivity analysis that only included trials that used rifampicin-containing regimens, the results were similar (RR 0.85, 95% CI 0.74-0.98; I(2) 21%). A sensitivity analysis in pulmonary tuberculosis that excluded trials with high potential risks of bias suggested a slight benefit, but the point estimate was closer to no effect and the difference was not significant (RR 0.93, 95% CI 0.60-1.44). INTERPRETATION: Steroids could be effective in reducing mortality for all forms of tuberculosis, including pulmonary tuberculosis. However, further evidence is needed since few recent trials have assessed the effectiveness of corticosteroids in patients with pulmonary tuberculosis. FUNDING: UK Department for International Development. PMID- 23369412 TI - Safety and immunogenicity of an oral, replicating adenovirus serotype 4 vector vaccine for H5N1 influenza: a randomised, double-blind, placebo-controlled, phase 1 study. AB - BACKGROUND: Replication-competent virus vector vaccines might have advantages compared with non-replicating vector vaccines. We tested the safety and immunogenicity of an oral adenovirus serotype 4 vector vaccine candidate (Ad4-H5 Vtn) expressing the haemagglutinin from an avian influenza A H5N1 virus. METHODS: We did this phase 1 study at four sites in the USA. We used a computer-generated randomisation list (block size eight, stratified by site) to assign healthy volunteers aged 18-40 years to receive one of five doses of Ad4-H5-Vtn (10(7) viral particles [VP], 10(8) VP, 10(9) VP, 10(10) VP, 10(11) VP) or placebo (3:1). Vaccine or placebo was given on three occasions, about 56 days apart. Participants, investigators, and study-site personnel were masked to assignment throughout the study. Subsequently, volunteers received a boost dose with 90 MUg of an inactivated parenteral H5N1 vaccine. Primary immunogenicity endpoints were seroconversion by haemagglutination-inhibition (HAI), defined as a four-times rise compared with baseline titre, and HAI geometric mean titre (GMT). We solicited symptoms of reactogenicity daily for 7 days after each vaccination and recorded symptoms that persisted beyond 7 days as adverse events. Primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01006798. FINDINGS: We enrolled 166 participants (125 vaccine; 41 placebo) between Oct 19, 2009, and Sept 9, 2010. HAI responses were low: 13 of 123 vaccinees (11%, 95% CI 6-17) and three of 41 placebo recipients (7%, 2-20) seroconverted. HAI GMT was 6 (95% CI 5-7) for vaccinees, and 5 (5-6) for placebo recipients. However, when inactivated H5N1 vaccine became available, one H5N1 boost was offered to all participants. In this substudy, HAI seroconversion occurred in 19 of 19 participants in the 10(11) VP cohort (100%; 95% CI 82-100) and eight of 22 placebo recipients (36%; 17-59); 17 of 19 participants in the 10(11) VP cohort (89%; 67-99) achieved seroprotection compared with four of 22 placebo recipients (18%; 5-40); GMT was 135 (89-205) with 10(11) VP, compared with 13 (7-21) with placebo. The cumulative frequency of abdominal pain, diarrhoea, and nasal congestion after all three vaccinations was significantly higher in vaccinees than placebo recipients (21 [16.8%] of 125 vs one [2.4%] of 41, p=0.017; 24 [19.2%] of 125 vs two [4.9%] of 41, p=0.027; 41 [32.8%] of 125 vs six [14.6%] of 41, p=0.028; respectively). No serious treatment-related adverse events occurred. INTERPRETATION: Oral Ad4 vector priming might enhance the efficacy of poorly immunogenic vaccines such as H5N1. FUNDING: Wellcome Trust Foundation, PaxVax. PMID- 23369414 TI - Adjunctive corticosteroids for all forms of tuberculosis? PMID- 23369415 TI - A randomized trial evaluating a parent based intervention to reduce college drinking. AB - This study evaluated the effectiveness of a parent based intervention (PBI) in reducing drinking among first year college students (N=443). Students were assigned to one of three conditions: PBI, PBI plus booster brochures (PBI-B), and an assessment only control group (CNT). At a 4-month post-intervention follow-up, results indicated students in the PBI-B group reported significantly less drinking to intoxication and peak drinking relative to the PBI group and CNT group. No significant differences were found between the PBI group and CNT group. Results provide further support for PBIs to reduce college student drinking and suggest that a booster brochure increases the effectiveness of PBIs. PMID- 23369416 TI - HIV and coronary heart disease: time for a better understanding. AB - Cardiovascular disease, and particularly coronary heart disease, is an emerging area of concern in the HIV population. Since the advent of efficient antiretroviral therapies and the consequent longer patient life span, an increased risk for myocardial infarction has been observed in HIV-infected patients compared with the general population in Western countries. The pathophysiology of this accelerated atherosclerotic process is complex and multifactorial. Traditional cardiovascular risk factors-overrepresented in the HIV population-associated with uncontrolled viral replication and exposure to antiretroviral drugs (per se or through lipid and glucose disturbances) could promote acute ischemic events. Thus, despite successful antiviral therapy, numerous studies suggest a role of chronic inflammation, together with immune activation, that could lead to vascular dysfunction and atherothrombosis. It is time for physicians to prevent coronary heart disease in this high-risk population through the use of tools employed in the general population. Moreover, the lower median age at which acute coronary syndromes occur in HIV-infected patients should shift prevention to include patients <45 years of age. Available cardiovascular risk scores in the general population usually fail to screen young patients at risk for myocardial infarction. Moreover, the novel vascular risk factors identified in HIV-related atherosclerosis, such as chronic inflammation, immune activation, and some antiretroviral agents, are not taken into account in the available risk scores, leading to underestimation of cardiovascular risk in the HIV population. Cardiovascular prevention in HIV-infected patients is a challenge for both cardiologists and physicians involved in HIV care. We require new tools to assess this higher risk and studies to determine whether intensive primary prevention is warranted. PMID- 23369417 TI - Bupropion for smoking cessation in patients hospitalized with acute myocardial infarction: a randomized, placebo-controlled trial. AB - OBJECTIVES: The purpose of this study was to examine smoking cessation rates among smokers with AMI to determine whether bupropion, started in-hospital, is safe and can improve cessation rates at 1 year. BACKGROUND: Bupropion doubles quit rates in otherwise healthy smokers and patients with stable cardiovascular disease. Although 2 previous trials examined the use of bupropion in patients hospitalized with acute cardiovascular disease, these studies have been inconclusive with respect to its safety and efficacy in patients with acute myocardial infarction (AMI). METHODS: We conducted a multicenter, double-blind, placebo-controlled, randomized trial in smokers hospitalized with AMI. Participants received bupropion or placebo for 9 weeks and were followed for 12 months. Both groups received low-intensity counseling. Point prevalence abstinence was assessed by 7-day recall and biochemical validation of expired carbon monoxide. RESULTS: A total of 392 patients were randomized (mean age 53.9 +/- 10.3 years); 83.5% were male; 64.9% had ST-segment elevation myocardial infarction). Patients smoked a mean of 23.2 +/- 10.6 cigarettes/day for a mean of 32.9 +/- 12.4 years. At 12 months, point prevalence abstinence rates were 37.2% in the bupropion group and 32.0% in the placebo group (p = 0.33; % difference after adjusting for between center differences 3.9%). Continuous abstinence rates were 26.8% and 22.2%, respectively (p = 0.34). Major adverse cardiac event rates were similar (13.0% vs. 11.0%, respectively; p = 0.64). CONCLUSIONS: Two-thirds of patients return to smoking by 12 months after AMI. Bupropion is well tolerated and seems to be safe to use in the immediate post-AMI period. However, bupropion is not effective for smoking cessation in patients post-AMI. PMID- 23369418 TI - Smoking cessation after acute myocardial infarction. PMID- 23369419 TI - Combining body mass index with measures of central obesity in the assessment of mortality in subjects with coronary disease: role of "normal weight central obesity". AB - OBJECTIVES: This study sought to assess the mortality risk of patients with coronary artery disease (CAD) based ona combination of body mass index (BMI) with measures of central obesity. BACKGROUND: In CAD patients, mortality has been reported to vary inversely with BMI ("obesity paradox"). In contrast,central obesity is directly associated with mortality. Because of this bidirectionality, we hypothesized that CAD patients with normal BMI but central obesity would have worse survival compared to individuals with other combinations of BMI and central adiposity. METHODS: We included 15,547 participants with CAD who were part of 5 studies from 3 continents. Multivariate stratifiedCox-proportional hazard models adjusted for potential confounders were used to assess mortality risk according to different patterns of adiposity that combined BMI with measures of central obesity. RESULTS: Mean age was 66 years, 60% were men. There were 5,507 deaths over a median follow-up of 2.4 years (IQR: 0.5 to 7.4 years). Individuals with normal weight central obesity had the worst long-term survival: a person with BMI of 22 kg/m2 and waist circumference (WC) of 101 cm had higher mortality than a person with similar BMI but WC of 85 cm (HR: 1.10[95% CI: 1.05 to 1.17]), than a person with BMI of 26 kg/m2 and WC of 85 cm (HR: 1.20 [95% CI: 1.09 to 1.31]), than a person with BMI of 30 kg/m2 and WC of 85 cm (HR: 1.61 [95% CI: 1.39 to 1.86]) and than a person with BMI of 30kg/m2 and WC of 101 cm (HR: 1.27 [95% CI: 1.18 to 1.39), p < 0.0001 for all). CONCLUSIONS: In patients with CAD, normal weight with central obesity is associated with the highest risk of mortality [corrected]. PMID- 23369421 TI - President's page: public reporting of cardiovascular care: an opportunity to shape the future. PMID- 23369420 TI - Spontaneous multivessel coronary artery dissection causing massive myocardial infarction. PMID- 23369422 TI - Double orifice mitral valve. PMID- 23369424 TI - Preparation of a new adsorbent from activated carbon and carbon nanofiber (AC/CNF) for manufacturing organic-vacbpour respirator cartridge. AB - In this study a composite of activated carbon and carbon nanofiber (AC/CNF) was prepared to improve the performance of activated carbon (AC) for adsorption of volatile organic compounds (VOCs) and its utilization for respirator cartridges. Activated carbon was impregnated with a nickel nitrate catalyst precursor and carbon nanofibers (CNF) were deposited directly on the AC surface using catalytic chemical vapor deposition. Deposited CNFs on catalyst particles in AC micropores, were activated by CO2 to recover the surface area and micropores. Surface and textural characterizations of the prepared composites were investigated using Brunauer, Emmett and Teller's (BET) technique and electron microscopy respectively. Prepared composite adsorbent was tested for benzene, toluene and xylene (BTX) adsorption and then employed in an organic respirator cartridge in granular form. Adsorption studies were conducted by passing air samples through the adsorbents in a glass column at an adjustable flow rate. Finally, any adsorbed species not retained by the adsorbents in the column were trapped in a charcoal sorbent tube and analyzed by gas chromatography. CNFs with a very thin diameter of about 10-20 nm were formed uniformly on the AC/CNF. The breakthrough time for cartridges prepared with CO2 activated AC/CNF was 117 minutes which are significantly longer than for those cartridges prepared with walnut shell- based activated carbon with the same weight of adsorbents. This study showed that a granular form CO2 activated AC/CNF composite could be a very effective alternate adsorbent for respirator cartridges due to its larger adsorption capacities and lower weight. PMID- 23369425 TI - Eccentric training in chronic heart failure: feasibility and functional effects. Results of a comparative study. AB - OBJECTIVES: To evaluate, in chronic heart failure (CHF) patients, feasibility, safety, compliance and functional improvements of an eccentric (ECC) cycle training protocol personalized by the rate of perceived exertion (RPE; 9-11 Borg Scale), compared to concentric (CON) training at workload corresponding to the first ventilatory threshold. METHODS: Thirty patients were randomly allocated to ECC or CON training (20 sessions). Compliance was evaluated with RPE, visual analog scale for muscle soreness and monitoring of heart rate (HR). Functional parameters were measured by the distance walked and the VO(2) uptake during the 6 minute walk test (6MWT) before and after training. RESULTS: Two patients were excluded due to adverse effects in each group. RPE was 9-11 in ECC training while it reached 12-14 in CON training. HR remained stable in ECC group during exercise whereas it increased during CON exercise. 6MWT distance improved in both group (ECC: +53 m; CON: +33 m). 6MWT VO(2) uptake remained stable in ECC group whereas it increased in CON group. CONCLUSION: ECC training tailored by RPE appears to be an efficient and safe alternative for CHF patients. Indeed, it induces functional improvement similar to conventional CON training with lower demand on the cardiovascular system during exercise. PMID- 23369426 TI - Evaluation of various ways to deliver information concerning non-steroidal anti inflammatory drugs to osteoarthritis patients. AB - INTRODUCTION: It is essential to provide complete information to patients using non-steroidal anti-inflammatory drugs (NSAIDs) because of the risk of side effects. Today, most healthcare professionals recommend and privilege oral information regarding NSAIDs. OBJECTIVE: Evaluate the impact of three standardized NSAIDs information-delivery modalities on knowledge, anxiety and satisfaction of patients hospitalized in a Physical Medicine and Rehabilitation unit for debilitating and degenerative locomotor diseases. METHOD: Randomized prospective study with an alternate month design. Two control groups were provided with only one type of information modality: written (information sheet) or oral (presentation). The intervention group received both modalities of information. The information included: the definition of NSAIDs, advantages and side effects, and practical advice regarding proper use. The main evaluation criterion was knowledge progression assessed by a specific questionnaire. Secondary criteria were anxiety evolution (STAI-Y questionnaire) and satisfaction related to the information delivered. RESULTS: One hundred and forty patients were included. Knowledge was improved in the three groups, with a greater score improvement in the group that received both modalities (P=0.05). No intergroup difference was noted on anxiety or satisfaction. DISCUSSION AND CONCLUSION: Associating both information-delivery modalities (written+oral) contributes to improving knowledge but does not seem to have an impact on the anxiety of patients treated with NSAIDs for their degenerative locomotor disease. Using standardized information sheets with a validated content could help pharmacists in their role as healthcare education provider and effectively complement the information delivered orally. PMID- 23369427 TI - Complications arising after thoracic aortic surgery: a case report on an unusual spinal cord infarction. Physiopathological and clinical considerations. AB - Even though new prevention techniques have been developed and are being used during thoraco-abdominal aortic repairs, spinal cord infarction remains a severe and relatively frequent complication of aortic surgery. Infarctions in the territory of the anterior spinal artery are considered the most common. Different clinical pictures related to spinal cord transverse extension wounds are drawn up. In this paper, we present a case report of a subject having presented an isolated motor deficit of the lower limbs and a favorable prognosis, suggesting selective involvement of the anterior horns of the spinal cord subsequent to surgical repair of an aortic dissection. We wish to review the relevant anatomical, clinical and diagnostic characteristics along with current techniques of spinal cord ischemia prevention during and after surgery. PMID- 23369428 TI - Colloidal branched semiconductor nanocrystals: state of the art and perspectives. AB - Colloidal inorganic nanocrystals are versatile nanoscale building blocks. Advances in their synthesis have yielded nanocrystals with various morphologies including spheres, polyhedra, rods, disks, sheets, wires, and a wide range of branched shapes. Recent developments in chemical methods have allowed the synthesis of colloidal nanocrystals made of sections of different inorganic materials connected together. Many research groups are investigating these nanocrystals' structural and photophysical properties experimentally and theoretically, and many have examined their prospects for commercial applications. Branched nanocrystals, in particular, are gaining attention, in part for their potential applications in solar cells or electronic devices. In this Account, we review recent developments in synthesis and controlled assembly of colloidal branched nanocrystals. Synthesis of branched nanocrystals builds on previous work with spherical nanocrystals and nanorods, but a unique factor is the need to control the branching event. Multiple arms can branch from a nucleus, or secondary branches can form from a growing arm. Branching can be governed by mechanisms including twinning, crystal splitting, polymorphism, oriented attachment, and others. One of the most relevant parameters is the choice of appropriate surfactant molecules, which can bind selectively to certain crystal facets or can even promote specific crystallographic phases during nucleation and growth. Also, seeded growth approaches recently have allowed great progress in the synthesis of nanocrystals with elaborate shapes. In this approach, nanocrystals with a specified chemical composition, size, shape, crystalline habit, and phase act as seeds on which multiple branches of a second material nucleate and grow. These approaches yield nanostructures with improved homogeneity in distribution of branch length and cross section. Ion exchange reactions allow further manipulation of branched nanocrystals by transforming crystals of one material into crystals with the same size, shape, and anion sublattice but with a new cation. Combining seeded growth with ion exchange provides a method for greatly expanding the library of branched nanocrystals. Assembly of morphologically complex nanocrystals is evolving in parallel to developments in chemical synthesis. While researchers have made many advances in the past decade in controlled assembly of nanocrystals with simple polyhedral shapes, modeling and experimental realization of ordered superstructures of branched nanocrystals are still in their infancy. In the only case of ordered superstructure reported so far, the assembly proceeds by steps in a hierarchical fashion, in analogy to several examples of assembly found in nature. Meanwhile, disordered assemblies of branched nanocrystals are also interesting and may find applications in various fields. PMID- 23369429 TI - Evaluation and comparison of aluminum-coated pumice and zeolite in arsenic removal from water resources. AB - In this research the potential of aluminum-coated pumice and zeolite in arsenic, As (V) removal was investigated and compared. Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD) and X-Ray Flaorescence Spectrometry (XRF) were carried out to determine the properties of the adsorbents. Several parameters including adsorbent dosage] pH, contact time, and initial As(V) concentration were studied. The optimum pH obtained for both adsorbents was pH = 7. As(V) adsorption by both adsorbents followed the Freundlich isotherm (for aluminum-coated pumice and zeolite respectively with R2 > 0.98 and R2 > 0.99). The obtained data from kinetics showed that the pseudo-second order model could better explain As(V) adsorption for both aluminum-coated pumice and zeolite (R2 > 0.98 and R2 > 0.99 respectively). Because of low cost, both adsorbents may be economically used, but aluminum-coated zeolite showed high efficiency of, due to its porosity and surface area. More than 96% of As(V) with initial concentration of 250 MUg/L was removed by 10 g/L aluminum-coated zeolite at pH = 7 and in 60 minutes to achieve As(V) concentration of 10 MUg/L, while only 71% of As(V) could be removed by aluminum-coated pumice. PMID- 23369430 TI - HPV vaccines and cancer prevention, science versus activism. AB - The rationale behind current worldwide human papilloma virus (HPV) vaccination programs starts from two basic premises, 1) that HPV vaccines will prevent cervical cancers and save lives and, 2) have no risk of serious side effects. Therefore, efforts should be made to get as many pre-adolescent girls vaccinated in order to decrease the burden of cervical cancer. Careful analysis of HPV vaccine pre- and post-licensure data shows however that both of these premises are at odds with factual evidence and are largely derived from significant misinterpretation of available data. PMID- 23369431 TI - Performance evaluation of reverse osmosis technology for selected antibiotics removal from synthetic pharmaceutical wastewater. AB - This study addresses the possibility for low pressure reverse osmosis membrane (RE 2521, CSM) process to serve as an alternative to remove selected antibiotics (ampicillin and amoxicillin) from synthetic wastewater by changing operating conditions such as pH = 3, 6.5 and 10; Pressure = 9, 11 and13 (bar); antibiotic concentration = 10, 255 and 500(mg/L), and temperature = 20, 30 and 40 degrees C. The experiment was designed based on Box-benken, which is a Response Surface methodology design (RSM), using Design Expert software. The concentration of antibiotics was measured by applying a UV-spectrophotometer (Cecil), at the wavelength of 254 nm. Results showed a range of rejection percentage from 73.52% to 99.36% and 75.1% to 98.8%, for amoxicillin and ampicillin, respectively. Considering the solute rejections and the membrane porosity show that the prevailing rejection mechanism of the examined antibiotics by the membrane was the size exclusion effect. The permeate flux for both of the antibiotics was 12 18.73 L/m2.h. Although the permeate flux and antibiotic rejection are influenced by operating pressure, pH, and temperature individually, the interaction between operating parameters did not have noticeable effects. According to the results obtained in this study, the application of RO membrane is recommended for the selected antibiotics to be removed to a considerable degree (up to 95%). PMID- 23369432 TI - Trichospirura aethiopica n. sp. (Nematoda: Rhabdochonidae) from Malacomys longipes (Rodentia: Muridae) in Gabon, first record of the genus in the Ethiopian Realm. AB - Trichospirura aethiopica n. sp. is described from unidentified tubular structures (pancreatic ducts?) near the stomach of the murid Malacomys longipes Milne Edwards, 1877 in Gabon. The extremely long and narrow buccal capsule, posterior position of the vulva, unequal spicules and absence of caudal alae readily identified the specimens as belonging to Trichospirura Smith & Chitwood, 1967, but a combination of several characters distinguished them from the described species in this genus. Males of the new species are characterized by the absence of precloacal papillae, the presence of four pairs of postcloacal papillae and a left spicule length of 165-200 MUm. With only five nominal and one unnamed species, the host range of Trichospirura extends into the Neotropical, Indo Malayan and Ethiopian Realms and comprises three classes of vertebrates, Amphibia, Reptilia and Mammalia, suggesting a larger species diversity than that currently recorded. Detection is difficult as predilection sites are often outside the gut lumen. It was noted that, irrespective of their geographic origin, species from mammals share certain characters (shorter left spicule and absence of precloacal papillae) that oppose them to those from amphibians and reptiles. A hypothesis for the origin of Trichospirura in mammals through a remote host-switching event in tupaiids in southern Asia, likely facilitated by the intermediate hosts, and for their subsequent migration to the Ethiopian and finally Neotropical Realm is proposed. Regarding the two species from anurans and saurians in the Antilles, one or two host-switching events are considered equally possible, based on morphological characters. PMID- 23369433 TI - Molecular characterization and analysis of a novel calcium-dependent protein kinase from Eimeria tenella. AB - The calcium-dependent protein kinases (CDPKs) are unique enzymes found only in plants, green algae, ciliates and apicomplexan parasites. In this study, a novel CDPK gene of Eimeria tenella, designed EtCDPK3, was cloned using rapid amplification of cDNA ends (RACE) based on the expressed sequence tag (EST). The entire cDNA of EtCDPK3 contained 1637 nucleotides encoding 433 amino acids and the deduced EtCDPK3 protein had canonical characteristic domains identified in other CDPKs, including a well-conserved amino-terminal kinase domain and a carboxy-terminal calmodulin-like structure with 4 EF-hand motifs for calcium binding. The expression profiles of the EtCDPK3 gene in different development stages were investigated by real-time quantitative PCR. Messenger RNA levels from the EtCDPK3 gene were higher in sporozoites than in other stages (unsporulated oocysts, sporulated oocysts and merozoites). Western blot analysis showed that rabbit antiserum against recombinant EtCDPK3 could recognize a native 49 kDa protein band of parasite. Indirect immunofluorescent antibody labelling revealed dispersed localization of EtCDPK3 during the first schizogony and intense specific staining. EtCDPK3 was located at the apical end of the sporozoites after early infection of DF-1 cells and the protein was highly expressed. Inhibition of EtCDPK3 function using specific antibodies reduced the ability of E. tenella to invade host cells. These results suggested that EtCDPK3 may be involved in invasion and survival of the parasite intracellular stages of E. tenella. Because this kinase family is absent from hosts, it represents a valid target that could be exploited for chemotherapy against Eimeria spp. PMID- 23369434 TI - Relationship of white potato to other vegetable consumption by schoolchildren and adolescents in the U.S.A: National Health and Nutrition Examination Survey, 2003 2008. AB - OBJECTIVE: Intake of white potatoes in and out of school was estimated to provide context for a recent proposal by the U.S. Department of Agriculture to limit provision of white potatoes in U.S. school meals. DESIGN: Mean daily servings of white potatoes and other vegetables consumed in and out of school for school-aged children were estimated from two days of 24 h dietary recall data from the National Health and Nutrition Examination Surveys (NHANES). Total energy intake and percentage energy contribution from discretionary oils and solid fats were also estimated for all white potato dishes consumed. SETTING: The NHANES is nationally representative of the U.S. civilian noninstitutionalized population. SUBJECTS: Children and adolescents aged 6-19 years (n 8466) from three combined NHANES cycles (2003-2004, 2005-2006 and 2007-2008). RESULTS: White potatoes represented 32% of all vegetable servings consumed by U.S. children and adolescents. Preparations high in fats and oils, including French fries, were most popular both in and out of school. Mean consumption of white potatoes obtained from school cafeterias was approximately 0.05 servings/d among all children and adolescents, and about 0.15 servings/d among children and adolescents acquiring at least one item from the school cafeteria, implying current weekly intake levels well below the limit of 2 servings/week proposed by the U.S. Department of Agriculture. CONCLUSIONS: Although white potatoes represent a substantial proportion of vegetable consumption among school-aged children, it is unclear that proposed limits would influence white potato intake from school cafeterias. Policy makers should consider targeting preparation methods to improve the healthfulness of white potato dishes. PMID- 23369435 TI - Recursive SVM biomarker selection for early detection of breast cancer in peripheral blood. AB - BACKGROUND: Breast cancer is worldwide the second most common type of cancer after lung cancer. Traditional mammography and Tissue Microarray has been studied for early cancer detection and cancer prediction. However, there is a need for more reliable diagnostic tools for early detection of breast cancer. This can be a challenge due to a number of factors and logistics. First, obtaining tissue biopsies can be difficult. Second, mammography may not detect small tumors, and is often unsatisfactory for younger women who typically have dense breast tissue. Lastly, breast cancer is not a single homogeneous disease but consists of multiple disease states, each arising from a distinct molecular mechanism and having a distinct clinical progression path which makes the disease difficult to detect and predict in early stages. RESULTS: In the paper, we present a Support Vector Machine based on Recursive Feature Elimination and Cross Validation (SVM RFE-CV) algorithm for early detection of breast cancer in peripheral blood and show how to use SVM-RFE-CV to model the classification and prediction problem of early detection of breast cancer in peripheral blood.The training set which consists of 32 health and 33 cancer samples and the testing set consisting of 31 health and 34 cancer samples were randomly separated from a dataset of peripheral blood of breast cancer that is downloaded from Gene Express Omnibus. First, we identified the 42 differentially expressed biomarkers between "normal" and "cancer". Then, with the SVM-RFE-CV we extracted 15 biomarkers that yield zero cross validation score. Lastly, we compared the classification and prediction performance of SVM-RFE-CV with that of SVM and SVM Recursive Feature Elimination (SVM-RFE). CONCLUSIONS: We found that 1) the SVM-RFE-CV is suitable for analyzing noisy high-throughput microarray data, 2) it outperforms SVM-RFE in the robustness to noise and in the ability to recover informative features, and 3) it can improve the prediction performance (Area Under Curve) in the testing data set from 0.5826 to 0.7879. Further pathway analysis showed that the biomarkers are associated with Signaling, Hemostasis, Hormones, and Immune System, which are consistent with previous findings. Our prediction model can serve as a general model for biomarker discovery in early detection of other cancers. In the future, Polymerase Chain Reaction (PCR) is planned for validation of the ability of these potential biomarkers for early detection of breast cancer. PMID- 23369437 TI - Urinary proteomic shotgun approach for identification of potential acute rejection biomarkers in renal transplant recipients. AB - BACKGROUND: Acute rejection (AR) episodes in renal transplant recipients are suspected when plasma creatinine is elevated and other potential causes out ruled. Graft biopsies are however needed for definite diagnosis. Non-invasive AR biomarkers is an unmet clinical need. The urinary proteome is an interesting source in the search for such a biomarker in this population. METHODS: In this proof of principle study, serial urine samples in the early post transplant phase from 6 patients with biopsy verified acute rejections and 6 age-matched controls without clinical signs of rejection were analyzed by shotgun proteomics. RESULTS: Eleven proteins fulfilled predefined criteria for regulation in association with AR. They presented detectable regulation already several days before clinical suspicion of AR (increased plasma creatinine). The regulated proteins could be grouped by their biological function; proteins related to growth and proteins related to immune response. Growth-related proteins (IGFBP7, Vasorin, EGF and Galectin-3-binding protein) were significantly up-regulated in association with AR (P = 0.03) while proteins related to immune response (MASP2, C3, CD59, Ceruloplasmin, PiGR and CD74) tended to be up-regulated ( P = 0.13). CONCLUSION: The use of shotgun proteomics provides a robust and sensitive method for identification of potentially predictive urinary biomarkers of AR. Further validation of the current findings is needed to establish their potential clinical role with regards to clinical AR diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00139009. PMID- 23369438 TI - Sun, sangria and sandflies: Leishmaniasis in an immunosuppressed patient returning from Spain. AB - Despite the global financial downturn, millions of people continue to travel abroad each year. Many travel with co-morbidities such as immunosuppression, placing them at greater risk of bacterial, viral and parasitic infections.(1) Leishmaniasis is one of the principal neglected tropical diseases.(2) Although it threatens 350 million people each year(3) it is not an infection that most General Physicians would associate with travel to Southern Europe. A case of visceral leishmaniasis is described in a lady with mild immunosuppression caused by systemic lupus erythematosus, following a holiday in Southern Spain, a destination not normally associated with this leishmaniasis. PMID- 23369439 TI - MRI of plants and foods. AB - The importance and prospects for MRI as applied to intact plants and to foods are presented in view of one of humanity's most pressing concerns, the sustainable and healthy feeding of a worldwide increasing population. Intact plants and foods have in common that their functionality is determined by complex multiple length scale architectures. Intact plants have an additional level of complexity since they are living systems which critically depend on transport and signalling processes between and within tissues and organs. The combination of recent cutting-edge technical advances and integration of MRI accessible parameters has the perspective to contribute to breakthroughs in understanding complex regulatory plant performance mechanisms. In food science and technology MRI allows for quantitative multi-length scale structural assessment of food systems, non-invasive monitoring of heat and mass transport during shelf-life and processing, and for a unique view on food properties under shear. These MRI applications are powerful enablers of rationally (re)designed food formulations and processes. Limitations and bottlenecks of the present plant and food MRI methods are mainly related to short T2 values and susceptibility artefacts originating from small air spaces in tissues/materials. We envisage cross fertilisation of solutions to overcome these hurdles in MRI applications in plants and foods. For both application areas we witness a development where MRI is moving from highly specialised equipment to mobile and downscaled versions to be used by a broad user base in the field, greenhouse, food laboratory or factory. PMID- 23369440 TI - Integrative medicine and human health - the role of pre-, pro- and synbiotics. AB - Western lifestyle is associated with a sustained low grade increase in inflammation -increased levels of endotoxin in the body and increased activation of Toll-like receptors and neutrophils, which leads to impaired immunity and reduced resistance to disease, changes which might explain the epidemic of chronic diseases spreading around the globe. The immune system cannot function properly without access to bacteria and raw plants, rich not only in bacteria but also in plant fibre, antioxidants, healthy fats and numerous other nutrients. Modern food technology with plant breeding, separation, condensation of food ingredients, heating, freezing, drying, irradiation, microwaving, are effective tool to counteract optimal immune function, and suspected to be a leading cause of so called Western diseases. Supply of pre-, pro-, and synbiotics have sometimes proved to be effective tools to counteract, especially acute diseases, but have often failed, especially in chronic diseases. Thousands of factors contribute to unhealth and numerous alterations in life style and food habits are often needed, in order to prevent and cure "treatment-resistant" chronic diseases. Such alterations include avoiding processed foods rich in pro inflammatory molecules, but also a focus on consuming substantial amounts of foods with documented anti-inflammatory effects, often raw and fresh green vegetables and tubers such as turmeric/curcumin. PMID- 23369441 TI - Modern X-ray scattering studies of complex biological systems. AB - X-ray scattering is one of the most prominent structural characterization techniques in biology. The key advantage of X-ray scattering is its ability to penetrate and weakly interact with the bare studied materials. In addition, X-ray scattering does not require any tags, markers or modification to the sample under examination, and is not limited by the nature of the surrounding environment. The main handicapping limitation of X-ray scattering is the subject of particles polydispersity. However, the monodispersity in biological complexes and supra molecular interactions makes them ideal for structural and interaction studies in particular when combined with higher (e.g. NMR) and/or lower resolution (e.g. optical microscopy) techniques. This review seeks to highlight some of the major recent achievements in the field of X-ray scattering as being implemented for complex biological systems. PMID- 23369443 TI - Clinical results of arthroscopic superior capsule reconstruction for irreparable rotator cuff tears. AB - PURPOSE: The objective of this study was to investigate the clinical outcome and radiographic findings after arthroscopic superior capsule reconstruction (ASCR) for symptomatic irreparable rotator cuff tears. METHODS: From 2007 to 2009, 24 shoulders in 23 consecutive patients (mean, 65.1 years) with irreparable rotator cuff tears (11 large, 13 massive) underwent ASCR using fascia lata. We used suture anchors to attach the graft medially to the glenoid superior tubercle and laterally to the greater tuberosity. We added side-to-side sutures between the graft and infraspinatus tendon and between the graft and residual anterior supraspinatus/subscapularis tendon to improve force coupling. Physical examination, radiography, and magnetic resonance imaging (MRI) were performed before surgery; at 3, 6, and 12 months after surgery; and yearly thereafter. Average follow-up was 34.1 months (24 to 51 months) after surgery. RESULTS: Mean active elevation increased significantly from 84 degrees to 148 degrees (P < .001) and external rotation increased from 26 degrees to 40 degrees (P < .01). Acromiohumeral distance (AHD) increased from 4.6 +/- 2.2 mm preoperatively to 8.7 +/- 2.6 mm postoperatively (P < .0001). There were no cases of progression of osteoarthritis or rotator cuff muscle atrophy. Twenty patients (83.3%) had no graft tear or tendon retear during follow-up (24 to 51 months). The American Shoulder and Elbow Surgeons (ASES) score improved from 23.5 to 92.9 points (P < .0001). CONCLUSIONS: ASCR restored superior glenohumeral stability and function of the shoulder joint with irreparable rotator cuff tears. Our results suggest that this reconstruction technique is a reliable and useful alternative treatment for irreparable rotator cuff tears. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23369442 TI - Mucosal transmissibility, disease induction and coreceptor switching of R5 SHIVSF162P3N molecular clones in rhesus macaques. AB - BACKGROUND: Mucosally transmissible and pathogenic CCR5 (R5)-tropic simian-human immunodeficiency virus (SHIV) molecular clones are useful reagents to identity neutralization escape in HIV-1 vaccine experiments and to study the envelope evolutionary process and mechanistic basis for coreceptor switch during the course of natural infection. RESULTS: We observed progression to AIDS in rhesus macaques infected intrarectally with molecular clones of the pathogenic R5 SHIVSF162P3N isolate. Expansion to CXCR4 usage was documented in one diseased macaque that mounted a neutralizing antibody response and in another that failed to do so, with the latter displaying a rapid progressor phenotype. V3 loop envelop glycoprotein gp120 sequence changes that are predictive of a CXCR4 (X4) using phenotype in HIV-1 subtype B primary isolates, specifically basic amino acid substations at positions 11 (S11R), 24 (G24R) and 25 (D25K) of the loop were detected in the two infected macaques. Functional assays showed that envelopes with V3 S11R or D25K mutation were dual-tropic, infecting CD4+ target cells that expressed either the CCR5 or CXCR4 coreceptor. And, consistent with findings of coreceptor switching in macaques infected with the pathogenic isolate, CXCR4 using variant was first detected in the lymph node of the chronically infected rhesus monkey several weeks prior to its presence in peripheral blood. Moreover, X4 emergence in this macaque coincided with persistent peripheral CD4+ T cell loss and a decline in neutralizing antibody titer that are suggestive of immune deterioration, with macrophages as the major virus-producing cells at the end stage of disease. CONCLUSIONS: The data showed that molecular clones derived from the R5 SHIVSF162P3N isolate are mucosally transmissible and induced disease in a manner similar to that observed in HIV-1 infected individuals, providing a relevant and useful animal infection model for in-depth analyses of host selection pressures and the env evolutionary changes that influence disease outcome, coreceptor switching and vaccine escape. PMID- 23369444 TI - Single-bundle anterior cruciate ligament reconstruction in active young men using bone-tendon achilles allograft versus free tendon achilles allograft. AB - PURPOSE: The purpose was to prospectively compare the outcomes of anterior cruciate ligament (ACL) reconstruction using bone-tendon Achilles allograft with those of free tendon Achilles allograft in 2 groups of active young men. METHODS: We enrolled 72 subjects in the study. Of these, 33 subjects who had ACL reconstruction with Achilles allograft with calcaneal bone block on its end (group I) and 34 who had ACL reconstruction with free tendon Achilles allograft (group II) were followed up for a minimum of 2 years. The Lachman test, pivot shift test, and 1-leg hop test were evaluated at the last follow-up. The International Knee Documentation Committee classification, Lysholm score, and side-to-side difference were assessed preoperatively and at the last follow-up. The Tegner activity scale was evaluated before injury and at the last follow-up. RESULTS: The mean follow-up period was 30.9 months (range, 26 to 38 months). At the last follow-up, there were no statistically significant differences between the 2 groups for the Lachman test, pivot-shift test, 1-leg hop test, International Knee Documentation Committee classification, Lysholm score, and side-to-side difference (P > .05). Three subjects in group I and three in group II showed an activity level 2 steps below the preinjury activity level. The rest of the subjects returned to the preinjury activity level or showed a level 1 step below the preinjury activity level. CONCLUSIONS: There were no significant differences in clinical outcomes of ACL reconstructions using Achilles allograft between the bone-tendon group and the free tendon group in active young men. Free tendon Achilles allograft may be considered an option for ACL reconstruction. LEVEL OF EVIDENCE: Level II, therapeutic study, randomized controlled trial. PMID- 23369445 TI - Histologic, biomechanical, and biological evaluation of fan-folded iliotibial band allografts for anterior cruciate ligament reconstruction. AB - PURPOSE: The purpose of this study was to thoroughly characterize the fan-folded iliotibial band (FITB) allograft and compare it with anterior tibialis tendons (ATs) and native anterior cruciate ligaments (ACLs) to determine whether it measures up to those tissues. METHODS: We compared the histologic structure, tensile strength to failure, creep, and stress-relaxation properties of FITBs with those of ATs and ACLs. In vitro cytotoxicity and biocompatibility of FITBs were also compared with ATs. RESULTS: No structural difference was observed between the tissues studied. FITB ultimate tensile strength (3,459 +/- 939 N) was not significantly different (P > .9999) from ultimate tensile strength of ATs (3,357 +/- 111 N) and was significantly greater (P = .0005) than that of ACLs (886 +/- 254 N). No significant difference (P > .9999) was observed in the increase in length resulting from creep testing between FITBs (9.5 +/- 3.0 mm) and ATs (9.7 +/- 4.0 mm). During stress-relaxation testing, FITBs reached 181 +/- 46 N, which was not significantly different (P > .9999) from ATs (166 +/- 40 N). Finally, we showed that cytotoxicity of FITBs and ATs was negligible. In vitro biocompatibility of FITBs and ATs was very good, whereas FITBs had a higher propensity to favor the attachment and infiltration of cells that proliferated for at least 4 weeks on their contact. CONCLUSIONS: We found that FITBs, ACLs, and ATs shared a similar structure made of aligned collagen fibers. No significant difference was observed between FITB and AT ultimate tensile strength, creep, and stress-relaxation viscoelastic properties. Ultimate tensile strength to failure of ACLs was lower than that of FITBs and ATs, whereas ACLs were superior to both FITBs and ATs during creep and stress-relaxation testing. FITBs and ATs showed low cytotoxicity and excellent biocompatibility in vitro, with a somewhat higher propensity of FITBs to favor cell attachment and infiltration over time. CLINICAL RELEVANCE: This study suggests that FITBs have the potential to perform as well as ATs for ACL reconstruction. PMID- 23369446 TI - Enlightened publics for public health: assessing disease in colonial Mexico. AB - In the eighteenth century, a new genre of periodical literature appeared from Mexico City's presses that focused on disseminating scientific and medical knowledge to the colonial public. In part a natural extension of the healing manuals published for laypeople in previous centuries, the journals sought to introduce quantitative methods of environmental study and control and to expand the sphere of those residents who would take responsibility for their health. This article examines the content and format of these journals before turning to the response of urban publics during outbreaks of epidemics, when the broader social participation envisioned by enlightenment men of letters came to fruition through pasquinades and rumors conveying dissent, skepticism, and protest. PMID- 23369447 TI - Confirmation of Fructans biosynthesized in vitro from [1-13C]glucose in asparagus tissues using MALDI-TOF MS and ESI-MS. AB - Accumulation of Fructans was confirmed in asparagus tissues that had been cultured for 2 days on media supplemented with glucose. It is very common that Fructans are biosynthesized from sucrose. We hypothesized however that Fructans could also be biosynthesized from glucose. Stem tissues of in vitro-cultured asparagus were subcultured for 72 h on a medium containing 0.5M of [1 (13)C]glucose. A medium containing 0.5M of normal ((12)C) glucose was used as control. Carbohydrates were extracted from the tissues and analyzed using HPLC, MALDI-TOF MS and ESI-MS. HPLC results indicated that the accumulation of short chain Fructans was similar in both (13)C-labelled and control samples. Short chain Fructans of DP=3-7 were detected using MALDI-TOF MS. The molecular mass of each oligomer in the (13)C-labelled sample was higher than the mass of the natural sample by 1 m/z unit per sugar moiety. The results of ESI-MS on the HPLC fractions of neokestose and 1-kestose showed that these oligomers (DP=3) were biosynthesized from exogenous glucose added to the medium. We conclude that not only exogenous sucrose but glucose can induce Fructan biosynthesis; fructans of both inulin type and inulin neoseries are also biosynthesized from glucose accumulated in asparagus tissues; the glucose molecules (or its metabolic products) were incorporated into Fructans as structural monomers. PMID- 23369449 TI - Methicillin-resistant Staphylococcus aureus containing mecC in Swedish dairy cows. AB - BACKGROUND: Hitherto, methicillin-resistant Staphylococcus aureus (MRSA) has not been detected in Swedish cattle. However, due to the report of mecC, a novel homologue to the mecA gene, there was reason to re-evaluate susceptibility results from strain collections of Staphylococcus aureus and test suspected isolates for the presence of mecC. FINDINGS: Bovine isolates of S. aureus with elevated minimum inhibitory concentrations of beta-lactams were retrospectively tested for presence of mecC. In four of the isolates mecC was detected. CONCLUSION: In Sweden, this is the first finding of MRSA in cattle and the first detection of MRSA harbouring mecC of domestic animal origin. MRSA in animal populations has implications as a potential reservoir with risk for spread to humans. Occurrence of MRSA among Swedish cattle appears still very limited. PMID- 23369450 TI - The prognostic role of time to diagnosis and presenting symptoms in patients with pancreatic cancer. AB - BACKGROUND: The aim of this study was to investigate the prognostic role of diagnostic delay and clinical presentation (regarding pain, jaundice, and weight loss) in pancreatic carcinoma. METHODS: One hundred and seventy patients with pancreatic cancer were diagnosed and treated in the decade 2001-2010 (100 males and 70 females, with a mean age of 65.8 years [range, 36-91]). Patients were staged with spiral computed tomography and 75% were found to have advanced disease (28 stage III, 99 stage IV disease). Ductal adenocarcinoma was diagnosed in 147 cases, other subtypes of carcinoma in the remaining 23. Fifty patients were operated with radical intent, 19 had palliative surgery, 101 were considered inoperable because of advanced disease or heavy anesthesiologic risk; 31 of these inoperable patients underwent biliary decompression by insertion of an endoluminal or percutaneous stent. Gemcitabine-containing regimens were administered to 143 patients and radiotherapy was combined in 19. Overall and relative survival were the parameters studied. Multivariate analysis was performed by multiple regressions applied to proportional-hazards model. RESULTS: From all the clinical, pathological and therapeutical factors evaluated the statistically significant ones were time to diagnosis and surgery. Among symptoms pain was related to the shortest mean time to diagnosis, weight loss to the longest, with corresponding differences in survival. These differences of observed survival were substantially confirmed in terms of relative survival. CONCLUSIONS: The poor prognosis of pancreatic carcinoma seems to depend, in part, on diagnostic delay and this, in turn, is influenced by the type of presenting symptoms. PMID- 23369451 TI - Sludge reduction by lumbriculus variegatus in Ahvas wastewater treatment plant. AB - Sludge production is an avoidable problem arising from the treatment of wastewater. The sludge remained after municipal wastewater treatment contains considerable amounts of various contaminants and if is not properly handled and disposed, it may produce extensive health hazards. Application of aquatic worm is an approach to decrease the amount of biological waste sludge produced in wastewater treatment plants. In the present research reduction of the amount of waste sludge from Ahvaz wastewater treatment plant was studied with the aquatic worm Lumbriculus variegatus in a reactor concept. The sludge reduction in the reactor with worm was compared to sludge reduction in a blank reactor (without worm). The effects of changes in dissolved oxygen (DO) concentration up to 3 mg/L (run 1) and up to 6 mg/L (run 2) were studied in the worm and blank reactors. No meaningful relationship was found between DO concentration and the rate of total suspended solids reduction. The average sludge reductions were obtained as 32% (run 1) and 33% (run 2) in worm reactor and 16% (run 1) and 12% (run 2) in the blank reactor. These results showed that the worm reactors may reduce the waste sludge between 2 and 2.75 times higher than in the blank conditions. The obtained results showed that the worm reactor has a high potential for use in large-scale sludge processing. PMID- 23369448 TI - Contribution of uric acid to cancer risk, recurrence, and mortality. AB - Two risk factors for the development and progression of cancers that are amenable to life style modification are chronic inflammation and the metabolic syndrome. This review proposes two new targets that may mechanistically integrate inflammation and metabolic syndrome, have been largely ignored, and are known to be druggable. Recent evidence has demonstrated that elevated serum uric acid (hyperuricemia) is associated with excess cancer risk, recurrence, and mortality. Although uric acid (UA) can function as a systemic antioxidant, its pro inflammatory properties have been postulated to play an important role in the pathogenesis of cancer. Furthermore, obesity, Type 2 Diabetes Mellitus (T2DM), and the metabolic syndrome (MetS) are also associated with excess cancer, chronic inflammation, and with hyperuricemia, suggesting that UA may represent an important link between these disorders and the development of cancer. While pharmacological modulation of hyperuricemia could in principal augment anti cancer therapeutic strategies, some cancer cells express low intracellular levels of the enzyme Xanthine Oxidoreductase (XOR) that are associated with increased cancer aggressiveness and poor clinical outcome. Thus, systemic pharmacological inhibition of XOR may worsen clinical outcome, and specific strategies that target serum uric acid (SUA) without inhibiting tumor cell XOR may create new therapeutic opportunities for cancer associated with hyperuricemia. This review will summarize the evidence that elevated SUA may be a true risk factor for cancer incidence and mortality, and mechanisms by which UA may contribute to cancer pathogenesis will be discussed in the hope that these will identify new opportunities for cancer management. PMID- 23369452 TI - Adsorption kinetics of Rhodamine-B on used black tea leaves. AB - Rhodamine B (Rh-B) is one of the most common pollutants in the effluents of textile industries effluents in developing countries. This study was carried out to evaluate the applicability of used black tea leaves (UBTL) for the adsorptive removal of Rh-B from aqueous system by investigating the adsorption kinetics in batch process. The effects of concentration and temperature on adsorption kinetics were examined. First-, second- and pseudo-second order kinetic equations were used to investigate the adsorption mechanism. The adsorption of Rh-B on UBTL followed pseudo-second order kinetics. The equilibrium amount adsorbed and the equilibrium concentration were calculated from pseudo-second-order kinetic plots for different initial concentrations of Rh-B to construct the adsorption isotherm. The adsorption isotherm was well expressed by Langmuir equation. The maximum adsorption capacity of UBTL to Rh-B was found to be 53.2 mg/g at pH = 2.0. The equilibrium amount adsorbed, calculated from pseudo-second-order kinetic plots, increased with temperature increase. The positive value of enthalpy of adsorption, DeltaHads = 31.22 kJ/mol, suggested that the adsorption of Rh-B on UBTL at pH = 2.0 is an endothermic process. PMID- 23369453 TI - Impact excitation and electron-hole multiplication in graphene and carbon nanotubes. AB - In semiconductor photovoltaics, photoconversion efficiency is governed by a simple competition: the incident photon energy is either transferred to the crystal lattice (heat) or transferred to electrons. In conventional materials, energy loss to the lattice is more efficient than energy transferred to electrons, thus limiting the power conversion efficiency. Quantum electronic systems, such as quantum dots, nanowires, and two-dimensional electronic membranes, promise to tip the balance in this competition by simultaneously limiting energy transfer to the lattice and enhancing energy transfer to electrons. By exploring the optical, thermal, and electronic properties of quantum materials, we may perhaps find an ideal optoelectronic material that provides low cost fabrication, facile systems integration, and a means to surpass the standard limit for photoconversion efficiency. Nanoscale carbon materials, such as graphene and carbon nanotubes, provide ideal experimental quantum systems in which to explore optoelectronic behavior for applications in solar energy harvesting. Within essentially the same material, researchers can achieve a broad spectrum of energetic configurations, from a gapless semimetal to a large band gap semiconducting nanowire. Owing to their nanoscale dimensions, graphene and carbon nanotubes exhibit electronic and optical properties that reflect strong electron-electron interactions. Such strong interactions may lead to exotic low energy electron transport behavior and high-energy electron scattering processes such as impact excitation and the inverse process of Auger recombination. High energy processes, which become very important under photoexcitation, may be particularly efficient in nanoscale carbon materials due to the relativistic like, charged particle band structure and sensitivity to the dielectric environment. In addition, due to the covalently bonded carbon framework that makes up these materials, electron-phonon coupling is very weak. In carbon nanomaterials, strong electron-electron interactions combined with weak electron phonon interactions results in excellent optical, thermal and electronic properties, the exploration of which promises to reveal fundamentally new physical processes and deliver advanced nanotechnologies. In this Account, we review the results of novel optoelectronic experiments that explore the intrinsic photoresponse of carbon nanomaterials integrated into nanoscale devices. By fabricating gate voltage-controlled photodetectors composed of atomically thin sheets of graphene and individual carbon nanotubes, we are able to fully explore electron transport in these systems under optical illumination. We find that strong electron-electron interactions play a key role in the intrinsic photoresponse of both materials, as evidenced by hot carrier transport in graphene and highly efficient multiple electron-hole pair generation in nanotubes. In both of these quantum systems, photoexcitation leads to high-energy electron-hole pairs that relax energy predominantly into the electronic system, rather than heating the lattice. Due to highly efficient energy transfer from photons into electrons, graphene and carbon nanotubes may be ideal materials for solar energy harvesting devices with efficiencies that could exceed the Shockley Queisser limit. PMID- 23369454 TI - First description of heterogeneity in 18S rRNA genes in the haploid genome of Cryptosporidium andersoni Kawatabi type. AB - The Apicomplexan Cryptosporidium andersoni, is a species of gastric Cryptosporidium, is frequently detected in older calves and adult cattle. Genotyping analyses based on 18S ribosomal RNA gene sequences have been performed on a novel C. andersoni genotype, namely the Kawatabi type, and the oocysts were classified into two distinct groups genotypically: Type A (the sequence in GenBank) and Type B (with a thymine nucleotide insertion not in Type A). This study analyzed 3775 cattle at a slaughterhouse and 310 cattle at a farm using microscopy and found 175 Cryptosporidium-positive animals: 171 from the slaughterhouse and four from the farm, and all infecting parasites were determined to be C. andersoni from 18S rRNA gene sequences determined from fecal DNA. In genotyping analyses with single isolated oocysts, about a half of analyzed ones were clearly classified into well known two genotypes (Type A and B). In addition to these two known genotypes, we have detected some oocysts showing mixed signals of Types A and B in the electropherogram from the automated sequencer (the Type C genotype). To determine the genotypic composition of sporozoites carried by the Type C oocysts, we analyzed their 18S rRNA gene sequences using a single sporozoite isolation procedure. Some sporozoites were classified as either Type A or Type B. However, more than half of the analyzed isolated sporozoites showed a mixed signal identical to that of Type C oocysts, and both the Type A and B signals were surely detectable from such sporozoites after a cloning procedure. In conclusion, C. andersoni carries two different genotypes heterogeneously in its haploid genome. PMID- 23369455 TI - Study on biodegradation of Mazut by newly isolated strain Enterobacter cloacae BBRC10061: improving and kinetic investigation. AB - Mazut as a source content of various hydrocarbons is hard to be degraded and its cracking could turn mazut into useful materials. Nevertheless degradation of mazut by routine methods is too expensive but application of indigenous microorganisms as biocatalysts could be effective and important to lower the costs and expand its consumption. Mazut biodegradation can be improved using various strategies; Therefore in this study newly isolated strain Enterobacter cloacae BBRC 10061 was used in a method of gradual addition of mazut into medium and its results were compared with simple addition method. To investigate degradation of mazut by BBRC 10061, influence of increase of mazut concentration was assayed based on gradual addition method. Also different kinetic models were used to evaluate kinetics of the process. Results showed that gradual addition method has been a beneficial technique for improvement of mazut degradation because bacterial induction to produce biosurfactant and essential enzymes for cracking mazut was higher during process. Although addition of more mazut increased the rate of biodegradation but percentage of degradation decreased. pH of medium decreased during biodegradation period while electric potential increased. Also the biodegradation kinetics was not fitted with the biokinetic models; therefore kinetics of biodegradation of mazut has to be studied by new models. PMID- 23369457 TI - The ONE Study compares cell therapy products in organ transplantation: introduction to a review series on suppressive monocyte-derived cells. PMID- 23369456 TI - Identification of regulatory regions of bidirectional genes in cervical cancer. AB - BACKGROUND: Bidirectional promoters are shared promoter sequences between divergent gene pair (genes proximal to each other on opposite strands), and can regulate the genes in both directions. In the human genome, > 10% of protein coding genes are arranged head-to-head on opposite strands, with transcription start sites that are separated by < 1,000 base pairs. Many transcription factor binding sites occur in the bidirectional promoters that influence the expression of 2 opposite genes. Recently, RNA polymerase II (RPol II) ChIP-seq data are used to identify the promoters of coding genes and non-coding RNAs. However, a bidirectional promoter with RPol II ChIP-Seq data has not been found. RESULTS: In some bidirectional promoter regions, the RPol II forms a bi-peak shape, which indicates that 2 promoters are located in the bidirectional region. We have developed a computational approach to identify the regulatory regions of all divergent gene pairs using genome-wide RPol II binding patterns derived from ChIP seq data, based upon the assumption that the distribution of RPol II binding patterns around the bidirectional promoters are accumulated by RPol II binding of 2 promoters. In HeLa S3 cells, 249 promoter pairs and 1094 single promoters were identified, of which 76 promoters cover only positive genes, 86 promoters cover only negative genes, and 932 promoters cover 2 genes. Gene expression levels and STAT1 binding sites for different promoter categories were therefore examined. CONCLUSIONS: The regulatory region of bidirectional promoter identification based upon RPol II binding patterns provides important temporal and spatial measurements regarding the initiation of transcription. From gene expression and transcription factor binding site analysis, the promoters in bidirectional regions may regulate the closest gene, and STAT1 is involved in primary promoter. PMID- 23369458 TI - A pilot study of reduced dose cyclosporine and corticosteroids to reduce new onset diabetes mellitus and acute rejection in kidney transplant recipients. AB - BACKGROUND: New onset diabetes mellitus (NODM) and acute rejection (AR) are important causes of morbidity and risk factors for allograft failure after kidney transplantation. METHODS: In this multi-center, open label, single-arm pilot study, 49 adult (>=18 years of age), low immunologic risk, non-diabetic recipients of a first deceased or living donor kidney transplant received early steroid reduction to 5 mg/day combined with Thymoglobulin(r) (Genzyme Transplant, Cambridge, MA, USA) induction, low dose cyclosporine (2-hour post-dose (C2) target of 600 to 800 ng/ml) and mycophenolic acid (MPA) therapy. RESULTS: Six months after transplantation, two patients (4%) developed NODM and one patient (2%) developed AR. Four patients had impaired fasting glucose tolerance based on 75-g oral glucose tolerance testing (OGTT). There was one patient death. There were no episodes of cytomegalovirus (CMV) infection or BK virus nephritis. In contrast, in a historical cohort of n = 27 patients treated with Thymoglobulin induction, and conventional doses of cyclosporine and corticosteroids, the incidence of NODM and AR was 18% and 15%. CONCLUSIONS: The pilot study results suggest that Thymoglobulin induction combined with early steroid reduction, reduced cyclosporine exposure and MPA, may reduce the incidence of both NODM and AR in low immunological risk patients. A future controlled study enriched for patients at high risk for NODM is under consideration. TRIAL REGISTRATION: ClinicalTrials.gov: http://NCT00706680. PMID- 23369459 TI - Precision medicine: an approach to R&D for delivering superior medicines to patients. AB - Pharmaceutical R&D productivity has declined over the last decade despite increasing investments. Recent trends, however, indicate a potential reversal of this trend fueled by a wave of new biologics, vaccines and highly selective NCEs directed against targets validated by human genetics, focus on new disease areas including orphan and genetic diseases and more precise tailoring of medicines to their target populations. PMID- 23369460 TI - Autoinflammatory bone disorders. AB - Autoinflammatory bone disorders are characterized by chronic non-infectious osteomyelitis and inflammation-induced bone resorption and result from aberrant activation of the innate immune system. Sporadic chronic non-bacterial osteomyelitis (CNO) is the most common disease subtype. The clinical picture is highly variable and the exact underlying pathophysiology remains to be determined. Recently, novel insights in the pathophysiology of sterile bone inflammation have been gathered by analyzing patients with rare, monogenic inflammatory diseases. In this overview CNO and Majeed syndrome, cherubism, hypophosphatasia and primary hypertrophic osteoarthropathy will be discussed. For the latter four disorders, a genetic cause affecting bone metabolism and leading to chronic bone inflammation has been described. The exact pathophysiology of CNO remains to be determined. Insights from monogenic autoinflammatory bone diseases and the identification of distinct inflammatory pathways may help to understand the pathogenesis of bone inflammation and inflammation-induced bone resorption in more common diseases. PMID- 23369461 TI - Role of kairomones in host location of the pennellid copepod parasite, Lernaeocera branchialis (L. 1767). AB - The life cycle of the parasitic copepod Lernaeocera branchialis involves 2 hosts, typically a pleuronectiform host upon which development of larvae and mating of adults occurs and a subsequent gadoid host, upon which the adult female feeds and reproduces. Both the copepodid and adult female stages must therefore locate and identify a suitable host to continue the life cycle. Several mechanisms are potentially involved in locating a host and ensuring its suitability for infection. These may include mechano-reception to detect host movement and chemo reception to recognize host-associated chemical cues, or kairomones. The aim of this study was to identify the role of kairomones in host location by adult L. branchialis, by analysing their behaviour in response to fish-derived chemicals. Experiments demonstrated that water conditioned by immersion of whiting, Merlangius merlangus, elicited host-seeking behaviour in L. branchialis, whereas cod- (Gadus morhua) conditioned water did not. Lernaeocera branchialis are considered a genetically homogeneous population infecting a range of gadoids. However, their differential response to whiting- and cod-derived chemicals in this study suggests that either there are genetically determined subspecies of L. branchialis or there is some form of environmental pre-conditioning that allows the parasite to preferentially recognize the host species from which it originated. PMID- 23369462 TI - Obesity prevalence in Mexico: impact on health and economic burden. AB - OBJECTIVE: Along with other countries having high and low-to-middle income, Mexico has experienced a substantial change in obesity rates. This rapid growth in obesity prevalence has led to high rates of obesity-related diseases and associated health-care costs. DESIGN: Micro-simulation is used to project future BMI trends. Additionally thirteen BMI-related diseases and health-care costs are estimated. The results are simulated for three hypothetical scenarios: no BMI reduction and BMI reductions of 1 % and 5 % across the population. SETTING: Mexican Health and Nutrition Surveys 1999 and 2000, and Mexican National Health and Nutrition Survey 2006. SUBJECTS: Mexican adults. RESULTS: In 2010, 32 % of men and 26 % of women were normal weight. By 2050, the proportion of normal weight will decrease to 12 % and 9 % for males and females respectively, and more people will be obese than overweight. It is projected that by 2050 there will be 12 million cumulative incidence cases of diabetes and 8 million cumulative incidence cases of heart disease alone. For the thirteen diseases considered, costs of $US 806 million are estimated for 2010, projected to increase to $US 1.2 billion and $US 1.7 billion in 2030 and 2050 respectively. A 1 % reduction in BMI prevalence could save $US 43 million in health-care costs in 2030 and $US 85 million in 2050. CONCLUSIONS: Obesity rates are leading to a large health and economic burden. The projected numbers are high and Mexico should implement strong action to tackle obesity. Results presented here will be very helpful in planning and implementing policy interventions. PMID- 23369463 TI - T-cadherin loss promotes experimental metastasis of squamous cell carcinoma. AB - T-cadherin is gaining recognition as a determinant for the development of incipient invasive squamous cell carcinoma (SCC). However, effects of T-cadherin expression on the metastatic potential of SCC have not been studied. Here, using a murine model of experimental metastasis following tail vein injection of A431 SCC cells we report that loss of T-cadherin increased both the incidence and rate of appearance of lung metastases. T-cadherin-silenced SCC metastases were highly disordered with evidence of single cell dissemination away from main foci whereas SCC metastases overexpressing T-cadherin developed as compact, tightly organised sheets. SCC cell adhesion to vascular endothelial cells (EC) in culture was increased for T-cadherin-silenced SCC and decreased for T-cadherin-overexpressing SCC. Confocal microscopy showed that T-cadherin-silenced SCC adherent on EC display an elongated morphology with long thin extensions and a high degree of intercalation within the EC monolayer, whereas SCC overexpressing T-cadherin formed poorly-spread multicellular aggregates that remain on the outer surface of the EC monolayer. T-cadherin-deficient SCC or human keratinocyte cells exhibited increased transendothelial migration in vitro which could be attenuated in the presence of EGFR inhibitor gefitinib. Our data suggest that loss of T-cadherin can increase metastatic potential and aggressiveness of SCC, possibly due to facilitating arrest and extravasation through the vascular wall and/or more efficient establishment of metastases in the new microenvironment. PMID- 23369464 TI - Potential utility of early metabolic response by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in a selected group of breast cancer patients receiving preoperative chemotherapy. AB - INTRODUCTION: To assess (18)F-2-fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography's ((18)F-FDG-PET/CT) potential clinical utility to allow early treatment changes during preoperative chemotherapy (PCT) in patients with early/locally advanced breast cancer (BC). PATIENTS AND METHODS: Sixty newly diagnosed early/locally advanced BC patients received 6-8 cycles of PCT. Optimal pathologic response (pR) was the absence of cancer cells in breast and axillary lymph nodes. All other conditions were defined as pathologic non-response (pNR). (18)F-FDG-PET/CT maximum standardised uptake value (SUV(max)) was measured at baseline and after 2 cycles of PCT. Metabolic response was defined as SUV(max) percentage changes (Delta-SUV) >50% and was compared with pR rates. RESULTS: Thirteen (22%) patients achieved pR; according to immunohistochemistry, 16% of ER positive/HER2-negative patients, 29% and 27% of HER2-positive and triple negative patients respectively achieved pR. (18)F-FDG-PET/CT showed the highest specificity (38%) and negative predictive value (100%) in ER-positive/HER2 negative patients. In this subgroup, at a median follow-up of 36.6 months, median disease-free survival was still not reached in metabolic responders while it was 37 months in metabolic non-responders (p=0.049). DISCUSSION: Early metabolic non response was always associated to pNR and poor prognosis in ER-positive/HER2 negative patients. In this subgroup, (18)F-FDG-PET/CT might be useful to select patients who will probably benefit from early therapeutic strategy modifications. PMID- 23369465 TI - Malignant peripheral nerve sheath tumor as a cause of chronic cardiac insufficiency in cattle. AB - Chronic cardiac insufficiency was associated with a malignant peripheral nerve sheath tumor in a cow. An eight-year-old cow developed a progressive condition (over a period of three months) characterized by an enhanced abdominal volume, reluctance to move, a positive jugular pulse, watery diarrhea and death. At necropsy, moderate subcutaneous edema and an enhanced hepatic lobular pattern were observed. A 23x20x11 cm firm, grayish-white mass adhered to and infiltrated the right atrium. Multiple firm, yellowish-white nodules of 0.5 to 12 cm in diameter were diffusely scattered in the epicardium and parietal pericardium. Histologically, the tumor was poorly circumscribed with foci of infiltration of the myocardium. The neoplastic cells had two major histologic patterns, Antoni types A and B. Within occasional foci, pleomorphic cells with an epithelioid appearance were present in addition to multinucleated cells with periodic acid Schiff (PAS)-positive cytoplasmic globules. Foci of cartilaginous and granular differentiations were interspersed among the neoplastic cells. Multiple vessels presented wall hyalinization and tumoral embolus. Large necrotic foci with mineralization and cholesterol clefts were also observed. Immunohistochemically, the tumor was positive for S100 protein, vimentin and neuron-specific enolase labeling. PMID- 23369466 TI - Rapid environmental contamination of a new nursing home with antimicrobial resistant organisms preceding occupation by residents. AB - Nursing homes are reservoirs for antimicrobial-resistant organisms (AROs). This study examined the time to environmental contamination with AROs in a new-build nursing home. Environmental sites in an occupied nursing home (N = 18) and a newly built replacement nursing home (N = 21) were monitored during an 11-week period before and after residents transferred between buildings. Meticillin resistant Staphylococcus aureus was detected during commissioning in the new building and was a frequent finding throughout the building after residents had moved in. Extended-spectrum beta-lactamase-producing E. coli O25b:ST131 was detected once. PMID- 23369467 TI - The elephant in the room: on the routine use of hydrogen peroxide vapour decontamination systems in health care. PMID- 23369468 TI - Impact of acute kidney injury on mortality and medical costs in patients with meticillin-resistant Staphylococcus aureus bacteraemia: a retrospective, multicentre observational study. AB - BACKGROUND: Despite the frequent occurrence of acute kidney injury (AKI) associated with meticillin-resistant Staphylococcus aureus (MRSA) infection during treatment, the adverse impact of renal injury on clinical and economic outcomes has not been evaluated. AIM: To study the clinical and economic burdens of MRSA bacteraemia and the impact of AKI occurring during treatment on outcomes. METHODS: Medical records of patients hospitalized for MRSA bacteraemia between March 2010 and February 2011 in eight hospitals in Korea were reviewed retrospectively to evaluate the risk factors for AKI and mortality. Direct medical costs per patient of MRSA bacteraemia during treatment were estimated from the medical resources consumed. FINDINGS: In all, 335 patients were identified to have MRSA bacteraemia. AKI occurred in 135 patients (40.3%) during first-line antibiotic therapy. Independent risk factors for AKI were male sex, underlying renal disease, intra-abdominal and central venous catheter infection, and increase in Pitt bacteraemia score. Seventy-seven (23.0%) patients died during the study period. Underlying solid tumour, high Pitt bacteraemia score, and occurrence of AKI were independent risk factors for mortality. The mean total medical cost per MRSA patient was estimated as South Korean Won 5,435,361 (US$4,906), and occurrence of AKI and ICU admission were identified as independent predictors of increased direct medical costs. Compared with patients who retained their baseline renal function, patients with AKI had a 45% increase in medical costs. CONCLUSIONS: Patients who developed AKI showed significantly higher mortality rate and greater direct medical costs compared with patients who retained baseline renal function. PMID- 23369469 TI - Effect on biocidal efficacy of hydrogen peroxide vapour by catalase activity of nosocomial bacteria. PMID- 23369470 TI - Nosocomial infections in neonatal intensive care units in developed and developing countries: how can we narrow the gap? PMID- 23369471 TI - Prolonged outbreak of meticillin-resistant Staphylococcus aureus in a cardiac surgery unit linked to a single colonized healthcare worker. AB - BACKGROUND: In low- as well as in high-prevalence settings, healthcare workers (HCWs) may be a substantial, under-recognized, reservoir of meticillin-resistant Staphylococcus aureus (MRSA) and an important potential source of transmission to patients. AIM: To report an outbreak of MRSA in a cardiac surgery unit in England over a 10-month period. METHODS: Cases were defined as patients and staff on the cardiac surgery unit from whom the outbreak strain was newly isolated between 20 May 2011 and 16 March 2012. Representative isolates from all cases were characterized by spa-typing, pulsed-field gel electrophoresis and multi-locus variable-number tandem-repeat analysis (MLVA). FINDINGS: Four patients appeared to acquire MRSA during their inpatient stay on the cardiac surgery unit. All four patients and one HCW were found to be carrying an identical epidemic (E)MRSA-15 strain (spa t032, pulsotype A, MLVA profile 16-6-3-1-1-17-1-4). No other members of staff were found to be colonized with MRSA. The colonized HCW was thought to be the source of the outbreak and was decolonized using a combination of nasal mupirocin, chlorhexidine body wash and oral rifampicin and doxycycline. CONCLUSIONS: This report highlights recent changes in the epidemiology of MRSA in England and suggests an important role for colonized HCWs in the transmission of MRSA to patients. Screening HCWs may provide an increasingly valuable strategy in managing linked hospital acquisitions and well-defined outbreaks where initial investigation does not reveal a source. PMID- 23369472 TI - Good things come in a green package. PMID- 23369473 TI - Authors' reply. PMID- 23369474 TI - Measurement of bone mineral density in anterior cruciate ligament-injured patients by computed tomography scan. PMID- 23369475 TI - Tensile forces on repaired medial meniscal root tears. AB - PURPOSE: The goals of this study were to measure the tensile forces acting on repaired medial meniscal root lesions and to investigate how they depend on femorotibial rotation, flexion, and compressive load. METHODS: In 6 human cadaveric knees, the posterior medial meniscal root was completely detached and then repaired with a pullout suture. A force transducer was installed such that it measured tensile forces acting on the suture. The resultant tension at the posterior medial meniscal root was measured for flexion angles up to 120 degrees at 2 levels of femorotibial compressive load (100 and 500 N) in neutral, internal, and external rotation of the knee. RESULTS: Rotation had a highly significant effect on root tension (P < .001). Internal rotation of the femur increased the resultant tension, whereas external rotation decreased it. The tension at the meniscal root was related to the femorotibial load (P < .001). Although no significance was reached, a trend toward higher flexion angles causing more tension was observed. The highest mean tension of 60.1 +/- 20.2 N was generated with internal rotation, a 500-N load, and 90 degrees flexion. CONCLUSIONS: Our study shows in a human in vitro model that motion and weight loading of the knee can generate considerable tensile forces in the posterior medial meniscal root. Internal rotation of the femur increases the resultant tension substantially, whereas external rotation has the opposite effect. CLINICAL RELEVANCE: The data can potentially aid the surgeon in finding appropriate rehabilitation exercises after a medial meniscal root repair. PMID- 23369476 TI - Second-look arthroscopic findings after open-wedge high tibia osteotomy focusing on the posterior root tears of the medial meniscus. AB - PURPOSE: This study examined, at second-look arthroscopy, the results of open wedge high tibial osteotomy (HTO) focusing on root tear of the medial meniscus posterior horn (RTMMP). METHODS: Among 31 consecutive patients who underwent HTO without a meniscectomy or pullout repair for RTMMP, 20 patients were available for second-look arthroscopic evaluation. All patients had medial unicompartmental arthritis. The healing status of the RTMMP was classified as complete, incomplete, and no healing. The difference in the weight bearing line from presurgery to the last follow-up was evaluated. Osteoarthritis and chondral lesions were evaluated, as were clinical results. Correlations between healing status and other variables (weight bearing line, cartilage status, and clinical scores) were assessed. The healed (10 patients) and nonhealed (incomplete 6 patients + no healing 4 patients) groups were also evaluated with respect to other variables. RESULTS: There were 10 (50%) cases with complete healing, 6 (30%) with incomplete healing, and 4 (20%) with no healing. Kellgren-Lawrence grade did not improve according to the standing plain radiograph (P = .09). Progression of chondral lesions was not observed at second-look arthroscopy; some improvement was even observed (P = .002). The median Lysholm score improved from 58 preoperatively to 88.5 at the last follow-up. The median Hospital for Special Surgery (HSS) score also increased significantly from 62.4 (range, 50 to 76) to 87.2 (range, 80 to 92; P = .003). The comparison between healed and nonhealed groups revealed no statistical differences in all variables. CONCLUSIONS: This study revealed a high rate of healing of RTMMP after HTO without attempted repair. Healing of the meniscus was not associated with an improved clinical outcome. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23369477 TI - Survival analysis of microfracture in the osteoarthritic knee-minimum 10-year follow-up. AB - PURPOSE: The aim of this study was to evaluate the survival of microfractures in patients with degenerative osteoarthritic knees and to analyze the factors affecting length of time before total knee arthroplasty (TKA) is performed. METHODS: This study reviewed 134 knees in 124 patients in whom microfracture was performed and for whom a minimum of 10 years of follow-up data were available. Mean follow-up was 11.2 years. The survival rate was evaluated. Failure was defined as the need for TKA. Another definition of failure was substantial symptoms in a patient whose pain score during follow-up was lower than the preoperative pain score or <60. We evaluated factors affecting survival, including size of the cartilage defect and severity of the preoperative varus deformity. The mechanical axis percentage (MA%) was defined as the percentage by which the mechanical axis bisected the total width of the tibia. RESULTS: The survival rate was 88.8% at 5 years and 67.9% at 10 years. Fifty-one patients proceeded to TKA a mean of 6.8 years after microfracture, and 6 knees were categorized as clinical failures. Age, gender, body mass index (BMI), and presence of meniscus lesions did not affect the survival of microfractures. Survival of microfractures in patients with a cartilage defect on the medial femoral condyle <2 cm(2) in size was better than that of microfractures in patients with larger defects. Survival of microfractures in patients with MA% >25% was better than that of patients with MA% <25%. CONCLUSIONS: Among 134 knees, 51 knees (38.1%) proceeded to TKA a mean of 6.8 years after microfracture in this study, and 6 knees were categorized as clinical failures. The survival rate was 88.8% at 5 years and decreased over time to 67.9% at 10 years. When considering microfracture, surgeons must consider factors affecting survival, such as size of the cartilage defect and severity of the preoperative varus deformity. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23369478 TI - Sensitivity of preoperative magnetic resonance imaging and magnetic resonance arthrography in detection of panlabral tears of the glenohumeral joint. AB - PURPOSE: The purpose of this study was to evaluate the sensitivity of preoperative magnetic resonance imaging (MRI) in detecting combined lesions of the glenoid labrum involving tears of the anterior, posterior, and superior labrum. METHODS: Preoperative MRI findings were available in 46 cases of arthroscopic repair of combined tears of the anterior, posterior, and superior labrum (mean age, 31 years), including 23 noncontrast MRI studies and 24 magnetic resonance (MR) arthrography studies (1 patient had both). MRI findings were compared with the status of the labrum at the time of arthroscopy, and the sensitivity of MRI was determined. RESULTS: MRI showed evidence of combined lesions of the anterior, posterior, and superior labrum in only 10 of 47 studies (21.3%). Only 2 of 23 (8.7%) tears were detected by noncontrast MRI, compared with 8 of 24 (33.3%) by MR arthrography (P = .07). Non-contrast MRI showed evidence of labral pathology in more than one direction in 10 of 23 studies (43.5%), compared with 20 of 24 MR arthrography studies (83.3%) (P = .006). Noncontrast MRI showed no evidence of a labral tear in 3 of 23 patients (13.0%), whereas no MR arthrogram was completely negative for a labral tear (0%) (P = .11). CONCLUSIONS: Combined tears of the anterior, posterior, and superior glenoid labrum are infrequent injuries that are typically not completely defined by either noncontrast MRI or MR arthrography. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 23369479 TI - Clinical and ultrasonographic outcomes of arthroscopic suture bridge repair for massive rotator cuff tear. AB - PURPOSE: The purpose of this study was to analyze the outcomes of arthroscopic suture bridge repairs of massive rotator cuff tears. METHODS: Thirty-six patients with massive rotator cuff tears that had been repaired by arthroscopic suture bridge repair were enrolled in this study. The mean follow-up period after surgery was 37.6 +/- 8.9 months (range, 25 to 56). Arthroscopic en masse suture bridge repair was used in delaminated tears. The integrity of the repaired rotator cuff was examined by ultrasonography 4.5 months, 1 year, and 2 years after surgery. Functional outcomes were evaluated using the American Shoulder and Elbow Surgeons (ASES) shoulder score, Constant score, range of motion, and muscle power. RESULTS: Twenty-seven cases (75%) showed complete healing on serial ultrasonography, whereas recurrent tears were detected in the remaining 9 cases (25%). Five retears were smaller than, and the other 4 were the same as or larger than, the initial tear. Overall mean functional scores and values improved after surgery. Although the 4 larger retears had a poorer outcome with respect to ASES score than the healed group (P = .005), the Constant score for these 4 retears did not significantly differ at the last follow-up (P = .175). Mean ASES and Constant scores for the larger tear group were also relatively satisfactory (64.2 and 63.0, respectively). Fatty degeneration of the supraspinatus on preoperative magnetic resonance images was associated with a high retear rate (P = .003, odds ratio = 13.664). CONCLUSIONS: Massive rotator cuff tears can be treated successfully by arthroscopic en masse suture bridge repair with satisfactory results. Larger retears had some adverse effects on functional outcome, whereas patients with smaller retears did not significantly differ in functional outcome from the healed group. Fatty degeneration of the supraspinatus on preoperative magnetic resonance images is a poor prognostic indicator. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23369480 TI - Arthroscopic single-row versus double-row rotator cuff repair: a meta-analysis of the randomized clinical trials. AB - PURPOSE: The purpose of this meta-analysis was to critically assess whether there are differences in clinical outcomes between single-row and double-row rotator cuff repair in prospective randomized Level I studies. METHODS: Using Medline, Scopus, Scirus, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and the Cochrane Library, as well as a hand search, we searched for randomized prospective trials comparing single-row and double-row rotator cuff repair. The functional outcome scores included the American Shoulder and Elbow Surgeons shoulder scale, the Constant shoulder score, and the University of California, Los Angeles shoulder rating scale. A test of heterogeneity was performed to determine whether there was a difference across the included studies. RESULTS: Five studies met our inclusion criteria. A test of heterogeneity showed no difference across these studies. The functional American Shoulder and Elbow Surgeons; Constant; and University of California, Los Angeles outcomes scores showed no difference between single- and double-row rotator cuff repair. CONCLUSIONS: We found no significant differences in clinical outcomes between single-row and double-row rotator cuff repair in a meta-analysis of Level I studies. LEVEL OF EVIDENCE: Level I, meta-analysis of Level I randomized controlled studies. PMID- 23369481 TI - Outcomes of anterior cruciate ligament reconstruction using single-bundle versus double-bundle technique: meta-analysis of 19 randomized controlled trials. AB - PURPOSE: The purpose of this study was to test the hypothesis that double-bundle anterior cruciate ligament reconstruction yields better improvement in stability and functional recovery than the single-bundle technique. METHODS: An Internet search was performed of the Pubmed, Embase, AMED, Cochrane Library, CNKI, Wanfang and VIP databases to find all published randomized controlled trials of anterior cruciate ligament reconstruction treated with the double-bundle versus single bundle technique. Outcomes of stability improvement and functional recovery were meta-analyzed. RESULTS: One thousand six hundred sixty-seven patients in 19 randomized controlled trials were involved in the meta-analysis. The overall relative risk (with 95% confidence interval) calculated with the random effects model in the pivot shift test and the International Knee Documentation Committee (IKDC) objective score for single-bundle versus double-bundle ACL reconstruction were 0.77 (0.67, 0.89) and 0.80 (0.68, 0.93), respectively. The overall relative risk calculated with the fixed effects model in the Lachman test was 0.84 (0.78 to 0.92). The overall standard mean differences (with 95% confidence interval) calculated with the random effects model were 0.26 (0.05, 0.46) for anterior side to-side difference; -0.08 (-0.28,0.12) for Lysholm score; Tegner activity scale, 0.41 (-0.85, 0.03) for Tegner activity score; and -0.08 (-0.32, 0.15) for IKDC subjective score. CONCLUSIONS: Meta-analysis of random controlled trials revealed that double-bundle anterior cruciate ligament reconstruction resulted in significantly better anterior and rotational stability and higher IKDC objective scores compared with single-bundle reconstruction. However, the meta-analysis did not detect any significant differences in subjective outcome measures between double-bundle and single-bundle reconstruction, as evidenced by the Lysholm score, Tegner activity scale, and IKDC subjective score. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I and II studies. PMID- 23369482 TI - Transosseous-equivalent rotator cuff repair: a systematic review on the biomechanical importance of tying the medial row. AB - PURPOSE: Double-row and transosseous-equivalent repair techniques have shown greater strength and improved healing than single-row techniques. The purpose of this study was to determine whether tying of the medial-row sutures provides added stability during biomechanical testing of a transosseous-equivalent rotator cuff repair. METHODS: We performed a systematic review of studies directly comparing biomechanical differences. RESULTS: Five studies met the inclusion and exclusion criteria. Of the 5 studies, 4 showed improved biomechanical properties with tying the medial-row anchors before bringing the sutures laterally to the lateral-row anchors, whereas the remaining study showed no difference in contact pressure, mean failure load, or gap formation with a standard suture bridge with knots tied at the medial row compared with knotless repairs. CONCLUSIONS: The results of this systematic review and quantitative synthesis indicate that the biomechanical factors ultimate load, stiffness, gap formation, and contact area are significantly improved when medial knots are tied as part of a transosseous equivalent suture bridge construct compared with knotless constructs. Further studies comparing the clinical healing rates and functional outcomes between medial knotted and knotless repair techniques are needed. CLINICAL RELEVANCE: This review indicates that biomechanical factors are improved when the medial row of a transosseous-equivalent rotator cuff is tied compared with a knotless repair. However, this has not been definitively proven to translate to improved healing rates clinically. PMID- 23369483 TI - Current concepts in the treatment of acromioclavicular joint dislocations. AB - PURPOSE: To conduct a systematic review of the literature in relation to 3 considerations in determining treatment options for patients with acromioclavicular (AC) joint dislocations: (1) operative versus nonoperative management, (2) early versus delayed surgical intervention, and (3) anatomic versus nonanatomic techniques. METHODS: The PubMed database was searched in October 2011 using the single term acromioclavicular and the following search limits: any date, humans, English, and all adult (19+). Studies were included if they compared operative with nonoperative treatment, early with delayed surgical intervention, or anatomic with nonanatomic surgical techniques. Exclusion criteria consisted of the following: Level V evidence, laboratory studies, radiographic studies, biomechanical studies, fractures or revisions, meta analyses, and studies reporting preliminary results. RESULTS: This query resulted in 821 citations. Of these, 617 were excluded based on the title of the study. The abstracts and articles were reviewed, which resulted in the final group of 20 studies that consisted of 14 comparing operative with nonoperative treatment, 4 comparing early with delayed surgical intervention, and 2 comparing anatomic with nonanatomic surgical techniques. The lack of higher level evidence prompted review of previously excluded studies in an effort to explore patterns of publication related to operative treatment of the AC joint. This review identified 120 studies describing 162 techniques for operative reconstruction of the AC joint. CONCLUSIONS: There is a lack of evidence to support treatment options for patients with AC joint dislocations. Although there is a general consensus for nonoperative treatment of Rockwood type I and II lesions, initial nonsurgical treatment of type III lesions, and operative intervention for Rockwood type IV to VI lesions, further research is needed to determine if differences exist regarding early versus delayed surgical intervention and anatomic versus nonanatomic surgical techniques in the treatment of patients with AC joint dislocations. LEVEL OF EVIDENCE: Level III, systematic review of Level II and Level III studies and one case series. PMID- 23369485 TI - Promising development from translational or perhaps anti-translational research in breast cancer. AB - BACKGROUND: A great deal of the public's money has been spent on cancer research but demonstrable benefits to patients have not been proportionate. We are a group of scientists and physicians who several decades ago were confronted with bimodal relapse patterns among early stage breast cancer patients who were treated by mastectomy. Since the bimodal pattern was not explainable with the then well accepted continuous growth model, we proposed that metastatic disease was mostly inactive before surgery but was driven into growth somehow by surgery. Most relapses in breast cancer would fall into the surgery-induced growth category thus it was highly important to understand the ramifications of this process and how it may be curtailed. With this hypothesis, we have been able to explain a wide variety of clinical observations including why mammography is less effective for women age 40-49 than it is for women age 50-59, why adjuvant chemotherapy is most effective for premenopausal women with positive lymph nodes, and why there is a racial disparity in outcome. METHODS: We have been diligently looking for new clinical or laboratory information that could provide a connection or correlation between the bimodal relapse pattern and some clinical factor or interventional action and perhaps lead us towards methods to prevent surgery initiated tumor activity. RESULTS: A recent development occurred when a retrospective study appeared in an anesthesiology journal that suggested the perioperative NSAID analgesic ketorolac seems to reduce early relapses following mastectomy. Collaborating with these anesthesiologists to understand this effect, we independently re-examined and updated their data and, in search of a mechanism, focused in on the transient systemic inflammation that follows surgery to remove a primary tumor. We have arrived at several possible explanations ranging from mechanical to biological that suggest the relapses avoided in the early years do not show up later. CONCLUSIONS: We present the possibility that a nontoxic and low cost intervention could prevent early relapses. It may be that preventing systemic inflammation post surgery will prevent early relapses. This could be controlled by the surgical anesthesiologist's choice of analgesic drugs. This development needs to be confirmed in a randomized controlled clinical trial and we have identified triple negative breast cancer as the ideal subset with which to test this. If successful, this would be relatively easy to implement in developing as well as developed countries and would be an important translational result. PMID- 23369487 TI - Influence of liquid and gas flow rates on sulfuric acid mist removal from air by packed bed tower. AB - The possible emission of sulfuric acid mists from a laboratory scale, counter current packed bed tower operated with a caustic scrubbing solution was studied. Acid mists were applied through a local exhaust hood. The emissions from the packed bed tower were monitored in three different categories of gas flow rate as well as three liquid flow rates, while other influencing parameters were kept almost constant. Air sampling and sulfuric acid measurement were carried out iso kinetically using USEPA method 8. The acid mists were measured by the barium thorin titration method. According to the results when the gas flow rate increased from 10 L/s to 30 L/s, the average removal efficiency increased significantly (p < 0.001) from 76.8 +/- 1.8% to 85.7 +/- 1.2%. Analysis of covariance method followed by Tukey post-hoc test of 92 tests did not show a significant change in removal efficiency between liquid flow rates of 1.5, 2.5 and 3.5 L/min (p = 0.811). On the other hand, with fixed pressure loss across the tower, by increasing the liquid/gas (L/G) mass ratio, the average removal efficiency decreased significantly (p = 0.001) from 89.9% at L/G of <2 to 83.1% at L/G of 2-3 and further to 80.2% at L/G of >3, respectively. L/G of 2-3 was recommended for designing purposes of a packed tower for sulfuric acid mists and vapors removal from contaminated air stream. PMID- 23369486 TI - Fuchs' endothelial corneal dystrophy: subjective grading versus objective grading based on the central-to-peripheral thickness ratio. AB - PURPOSE: To assess interobserver agreement between 2 corneal specialists grading Fuchs' dystrophy clinically and to determine if the corneal central-to-peripheral thickness ratio (CPTR) may be an alternative and objective metric of disease severity. DESIGN: Cross-sectional study. PARTICIPANTS: Forty-five eyes (26 subjects) with mild and moderate Fuchs' dystrophy, 73 eyes (60 subjects) with advanced Fuchs' dystrophy, and 267 eyes (142 subjects) with normal corneas. METHODS: Corneas with Fuchs' dystrophy were graded by 2 corneal specialists based on the confluence and area of guttae and the presence or absence of edema. Central corneal thickness (CCT) and peripheral corneal thickness at 4 mm from the center (PCT4) were measured by using scanning-slit pachymetry. The value of CPTR4 was the quotient of CCT and PCT4. MAIN OUTCOME MEASURES: Interobserver agreement for clinical grade and CPTR4. RESULTS: Interobserver agreement for clinical grading of Fuchs' dystrophy was moderate (kappa = 0.32; 95% confidence interval, 0.19-0.45). In normal corneas, CCT was not correlated with age (r = -0.10; P = 0.28; n = 267), PCT4 decreased with age (r = -0.33; P<0.001; n = 254), and CPTR4 increased with age (r = 0.59; P<0.001; n = 254). Central corneal thickness was higher in Fuchs' dystrophy (652 +/- 61 MUm; n = 118) than in normal corneas (559 +/- 31 MUm; n = 267; P<0.001). Also, PCT4 was higher in Fuchs' dystrophy (650 +/- 51 MUm; n = 107) than in normal corneas (643 +/- 43 MUm; n = 254; P<0.001 after adjusting thickness for age). Furthermore, CPTR4 was higher in advanced Fuchs' dystrophy (1.03 +/- 0.07; n = 65) than in mild and moderate Fuchs' dystrophy (0.95 +/- 0.07; n = 42; age-adjusted P<0.001), which in turn was higher than in normal corneas (0.87 +/- 0.05; n = 254; age-adjusted P<0.001). Finally, CPTR4 was highly correlated with clinical grade of Fuchs' dystrophy (r = 0.77; P<0.001; n = 361), was repeatable (median coefficient of variation, 1.3%), and provided excellent discrimination between Fuchs' dystrophy and normal corneas (area under the receiver operator characteristic curve, 0.93). CONCLUSIONS: Agreement between corneal specialists for the subjective and morphologic clinical grading of Fuchs' dystrophy is only moderate. The corneal CPTR is an objective, repeatable, and possibly functional, metric of severity of Fuchs' dystrophy that warrants further investigation to determine its role in monitoring disease progression and predicting the need for keratoplasty. PMID- 23369488 TI - Left and right ventricular diastolic function in adults with surgically repaired tetralogy of Fallot: a multi-institutional study. AB - BACKGROUND: Our purpose was to assess the prevalence and clinical implications of left ventricular (LV) and right ventricular (RV) diastolic dysfunction (DD) in patients with repaired tetralogy of Fallot (TOF). METHODS: Adults with repaired TOF at 11 North American congenital heart disease centres were included. Of 556 patients analyzed, 325 had sufficient Doppler data to evaluate for LV DD, defined as mitral lateral e' < 10 cm/s and E/e' ratio > 9. Abnormal RV diastolic function was defined as tricuspid E/A ratio of 0.8 to 2.1 with E/e' ratio > 6 or a tricuspid ratio E/A > 2.1 with a deceleration time < 120 milliseconds, and 105 patients were found to have sufficient Doppler data. RESULTS: Abnormal LV diastolic Doppler indices were prevalent in 13.8% and associated with hypertension, dyslipidemia, 3 or more cardiac operations, and a history of ventricular tachycardia. Abnormal RV indices were prevalent in 52.4% and associated with hypertension, dyslipidemia, diabetes mellitus, and 3 or more cardiac operations. Ventricular tachycardia was more common in those with abnormal RV diastolic function. CONCLUSION: Further prospective studies are needed to evaluate these associations with DD and the impact of treatment risk factors on diastolic function and arrhythmia burden. PMID- 23369489 TI - Comparison of 4-chloro-2-nitrophenol adsorption on single-walled and multi-walled carbon nanotubes. AB - The adsorption characteristics of 4-chloro-2-nitrophenol (4C2NP) onto single walled and multi-walled carbon nanotubes (SWCNTs and MWCNTs) from aqueous solution were investigated with respect to the changes in the contact time, pH of solution, carbon nanotubes dosage and initial 4C2NP concentration. Experimental results showed that the adsorption efficiency of 4C2NP by carbon nanotubes (both of SWCNTs and MWCNTs) increased with increasing the initial 4C2NP concentration. The maximum adsorption took place in the pH range of 2-6. The linear correlation coefficients of different isotherm models were obtained. Results revealed that the Langmuir isotherm fitted the experimental data better than the others and based on the Langmuir model equation, maximum adsorption capacity of 4C2NP onto SWCNTs and MWCNTs were 1.44 and 4.42 mg/g, respectively. The observed changes in the standard Gibbs free energy, standard enthalpy and standard entropy showed that the adsorption of 4C2NP onto SWCNTs and MWCNTs is spontaneous and exothermic in the temperature range of 298-328 K. PMID- 23369490 TI - [Reflexivity and positionality tools to promote theoretical-methodological congruency on commencing a qualitative study]. AB - The interest in responding to socially determined health needs has led to an increased use of qualitative methodology by researchers and health professionals. This situation has prompted a search for new tools that will facilitate implementation and promote the quality of their research. The researcher's reflexivity and positionality have been described as very useful rigour strategies to promote theoretical-methodological congruency in qualitative research, as well as in generating new knowledge with a greater impact on health. Two methodological tools are presented here in the form of self-reflective questions, with some examples from qualitative health studies conducted in Spain, which can help novice researchers to plan how to commence a qualitative project. Some implications for the health research, practice and policy are discussed. PMID- 23369491 TI - [Are stages 1 and 2 ulcers always caused by pressure?]. PMID- 23369492 TI - Breast cancer subtyping from plasma proteins. AB - BACKGROUND: Early detection of breast cancer in blood is both appealing clinically and challenging technically due to the disease's illusive nature and heterogeneity. Today, even though major breast cancer subtypes have been characterized, i.e., luminal A, luminal B, HER2+, and basal-like, little is known about the heterogeneity of breast cancer in blood, which could help to discover minimally invasive protein biomarkers with which clinical researchers can detect, classify, and monitor different breast cancer subtypes. RESULTS: In this study, we performed an integrative pathway-assisted clustering analysis of breast cancer subtypes from plasma proteome samples collected from 80 patients diagnosed with breast cancer and 80 healthy women. First, four breast cancer subtypes and additionally unknown subtype (according to existing annotation) were determined based on pathology lab test results in primary tumors of enrolled patients. Next, we developed and applied four distance metrics, i.e., Protein Intensity, Q-Value, Pathway Profile, and Distance Score Function, to measure and characterize these cancer subtypes. Then, we developed a permutation test to evaluate the significant protein level changes in each biological pathway for each breast cancer subtype, using q-value. Lastly, we developed a pathway-protein matrix for each of the four distance methods to estimate the distance between breast cancer subtypes, for which further Pathway Association Network analysis were performed. CONCLUSIONS: We found that 1) the luminal group (luminal A and luminal B) are clustered together, as well as the basal group (basal-like and HER2+) and 2) luminal A and luminal B are more close to each other than basal-like and HER2+ to each other. Our results were consistent with a recent independent breast cancer research from the Cancer Genome Atlas Network using genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our results showed that changes of different breast cancer subtypes at the pathway level are more profound and less variable than those at the molecular level. Similar subtypes share distinct yet similar pathway activation networks, while dissimilar subtypes are different also at the level of pathway activation networks. The results also showed that distance or similarity of cancer subtypes based on pathway analysis might be able to provide further insight into the intrinsic relationship of breast cancer subtypes. We believe integrative pathway-assisted proteomics analysis described here can become a model for reliable clustering or classification of other cancer subtypes. PMID- 23369493 TI - Mesenchymal stem cell-educated macrophages. AB - Mesenchymal stem cells (MSC) mediate their immunosuppressive effects via a variety of mechanisms. One of these mechanisms involves the induction of macrophages with immunomodulatory capacities. This effect of MSC may be exploited when MSC are used as a cell therapeutic product. Furthermore, MSC are resident in tissues where they may locally target infiltrating macrophages to adapt more regulatory properties. The present review discusses the interaction between MSC and macrophages, the induction of MSC-educated macrophages, how these cells position between other immune regulatory cells, and how they may be used in the clinic. PMID- 23369496 TI - Retroperitoneal approach to the intervertebral disc for the annular puncture model of intervertebral disc degeneration in the rabbit. AB - BACKGROUND CONTEXT: The rabbit annular puncture model of degeneration is among the most widely used models of intervertebral disc (IVD) degeneration. There are no published reports of the specific surgical technique used to produce this model. PURPOSE: To describe the model in detail in an effort to reduce center-to center variability and hopefully improve the reproducibility of future experimental results. STUDY DESIGN: Technical report of surgical approach and experience. PATIENT SAMPLE: New Zealand White Rabbits. METHODS: A detailed report of the annular puncture technique in rabbits is provided including preparation of the animals, instrumentation, a description of retroperitoneal approach to the lumbar area, and the technique for IVD injury. Common pitfalls and complications of the procedure are described. CONCLUSIONS: The methods described can serve to standardize the implementation of this important preclinical model of disc degeneration. PMID- 23369497 TI - Intervertebral disc viability after burst fractures of the thoracic and lumbar spine treated with pedicle screw fixation and direct end-plate restoration. AB - BACKGROUND CONTEXT: Controversies persist for the best treatment of burst fractures of the thoracolumbar spine. Anterior corpectomy and discectomy followed by reconstruction with intervertebral cage and posterior fixation, for example, are based mainly on the widespread assumption that intervertebral discs involved in burst-type fractures, typically, do not survive the traumatic event and will degenerate irrevocably. PURPOSE: To evaluate whether intervertebral discs, located adjacent to traumatic burst fractures and treated with pedicle screw fixation and direct end-plate restoration, survive the traumatic event or irrevocably progress to severe disc degeneration. STUDY DESIGN: Prospective trial. PATIENT SAMPLE: Twenty adult patients with traumatic burst fractures of the thoracolumbar spine and treated with pedicle screw fixation and direct end plate reduction were included. OUTCOME MEASURES: Disc degeneration according to the Pfirrmann classification. METHODS: Magnetic resonance imaging scans were obtained preoperatively, 1 month after surgery and 1 month after pedicle screw removal 12 to 18 months after index surgery. Degeneration of the intervertebral discs adjacent to the fracture was assessed using the Pfirrmann classification. Grade 1/2/3 was defined as mild-to-moderate degeneration of the intervertebral disc (MDID), whereas Grade 4/5 was defined as severe-to-endstage degeneration of the intervertebral disc (SDID). Repeated measure analysis was performed to detect significant differences between MDID and SDID scores. RESULTS: A total of 19 patients (38 discs) were fully documented and available for study. All discs showed MDID preoperatively, and while five discs (13%) progressed to SDID at 12 to 18 months posttrauma, the other discs did not show progression of degeneration. CONCLUSIONS: Intervertebral discs adjacent to traumatic burst fractures treated with pedicle screw instrumentation and direct end-plate restoration do not routinely seem to progress to severe degeneration at 12 to 18 months postinjury. PMID- 23369495 TI - Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration. AB - BACKGROUND CONTEXT: Destruction of extracellular matrix (ECM) leads to intervertebral disc degeneration (IDD), which underlies many spine-related disorders. Matrix metalloproteinases (MMPs), and disintegrins and metalloproteinases with thrombospondin motifs (ADAMTSs) are believed to be the major proteolytic enzymes responsible for ECM degradation in the intervertebral disc (IVD). PURPOSE: To summarize the current literature on gene expression and regulation of MMPs, ADAMTSs, and tissue inhibitors of metalloproteinases (TIMPs) in IVD aging and IDD. METHODS: A comprehensive literature review of gene expression of MMP, ADAMTS, and TIMP in human IDD and reported studies on regulatory factors controlling their expressions and activities in both human and animal model systems. RESULTS: Upregulation of specific MMPs (MMP-1, -2, -3, -7, 8, -10, and -13) and ADAMTS (ADAMTS-1, -4, and -15) were reported in human degenerated IVDs. However, it is still unclear from conflicting published studies whether the expression of ADAMTS-5, the predominant aggrecanase, is increased with IDD. Tissue inhibitors of metalloproteinase-3 is downregulated, whereas TIMP 1 is upregulated in human degenerated IVDs relative to nondegenerated IVDs. Numerous studies indicate that the expression levels of MMP and ADAMTS are modulated by a combination of many factors, including mechanical, inflammatory, and oxidative stress, some of which are mediated in part through the p38 mitogen activated protein kinase pathway. Genetic predisposition also plays an important role in determining gene expression of MMP-1, -2, -3, and -9. CONCLUSIONS: Upregulation of MMP and ADAMTS expression and enzymatic activity is implicated in disc ECM destruction, leading to the development of IDD. Future IDD therapeutics depends on identifying specific MMPs and ADAMTSs whose dysregulation result in pathological proteolysis of disc ECM. PMID- 23369498 TI - [Wunderlich syndrome in patient anticoagulated with dabigatran]. PMID- 23369499 TI - [Nebulized colistin versus tobramycin in the treatment of chronic Pseudomonas colonization in cystic fibrosis patients]. AB - BACKGROUND AND OBJECTIVE: To compare the efficacy, safety and treatment satisfaction with inhaled colistin versus tobramycin in the cure of chronic Pseudomonas colonization in cystic fibrosis patients. PATIENTS AND METHOD: A quasi-experimental open paired data trial in which patients with cystic fibrosis and chronic colonization by Pseudomonas aeruginosa were included. Patients performed 2 periods of 6 consecutive months of nebulized antibiotics: inhaled tobramycin at a dose of 300 mg/12 h (Pari LC Plus((r))) and colistimethate (I neb((r))) at a dose of 1 MIU twice a day. Visits were made monthly and at the beginning and the end of each period; we evaluated the body mass index, lung function, number of exacerbations and sputum microbiology. Patient satisfaction was assessed with 2 questionnaires of satisfaction on the treatment and the inhalation devices. RESULTS: A group of 25 patients (8 men and 6 under 14 years) with a mean age of 21.4 (7.2) years and 59.8 (21.1) % of forced expiratory volume in one second (FEV1) were included. During the second period, clinical benefits were obtained in terms of lung function with an FEV1 gain of 5% at 6 months of treatment and reducing the number of exacerbations (1.84 [1.2] vs 0.8 [0.8]; P=.001). The questionnaire score was higher in period 2. CONCLUSIONS: Colistimethate sodium administered through the misting system I-neb((r)) provides clinical benefits in terms of exacerbations and improvement of lung function and patient satisfaction for the nebulized antibiotic treatment. PMID- 23369501 TI - Understanding drug uptake and binding within targeted disease micro-environments in patients: a new tool for translational medicine. AB - BACKGROUND: For many common global diseases, such as cancer, diabetes, neurodegenerative and cardiovascular diseases there is an unmet need for diagnosing early indications of disease that could enable medical intervention and early treatment. The treatment of these diseases will require detailed knowledge of targeted pathways involved in disease pathogenesis but also the mode of drug actions at the biological location on these targets. Translational medicine is a new area of research where expert from different disciplines involved in basic science and clinical disciplines meet and join forces. Mode-of drug-action mechanisms elucidation is key in the characterization of drugs that can relate to both efficacy and safety. METHODS: Matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used providing evidence into the fate (destinations and distributions) of administered drugs within tumor regions of lung compartments. RESULTS: We hereby present a pulmonary study in which we have isolated lung tissue after inhaled drug administration and then localized the drug within airway wall compartments. The histology also provides evidence of drug binding to smooth muscle cell microenvironments. We also identified lung tissue regions with tumor cell invasion in these COPD patients. CONCLUSIONS: The ultimate goal is to identify bridging comprehension that forms a knowledge base that can be used by society to develop a better treatment and medicine for patients. Our results demonstrated that robust imaging data could be generated confirming drug localization in pulmonary regions of COPD patients with tumor pathology. TRIAL REGISTRATION: Tallinn Medical Research Ethical Committee decision #1724, 18.06.2009. PMID- 23369494 TI - Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair? AB - BACKGROUND CONTEXT: Degeneration and injuries of the intervertebral disc (IVD) result in large alterations in biomechanical behaviors. Repair strategies using biomaterials can be optimized based on the biomechanical and biological requirements of the IVD. PURPOSE: To review the present literature on the effects of degeneration, simulated degeneration, and injury on biomechanics of the IVD, with special attention paid to needle puncture injuries, which are a pathway for diagnostics and regenerative therapies and the promising biomaterials for disc repair with a focus on how those biomaterials may promote biomechanical repair. STUDY DESIGN: A narrative review to evaluate the role of biomechanics on disc degeneration and regenerative therapies with a focus on what biomechanical properties need to be repaired and how to evaluate and accomplish such repairs using biomaterials. Model systems for the screening of such repair strategies are also briefly described. METHODS: Articles were selected from two main PubMed searches using keywords: intervertebral AND biomechanics (1,823 articles) and intervertebral AND biomaterials (361 articles). Additional keywords (injury, needle puncture, nucleus pressurization, biomaterials, hydrogel, sealant, tissue engineering) were used to narrow the articles down to the topics most relevant to this review. RESULTS: Degeneration and acute disc injuries have the capacity to influence nucleus pulposus (NP) pressurization and annulus fibrosus (AF) integrity, which are necessary for an effective disc function and, therefore, require repair. Needle injection injuries are of particular clinical relevance with the potential to influence disc biomechanics, cellularity, and metabolism, yet these effects are localized or small and more research is required to evaluate and reduce the potential clinical morbidity using such techniques. NP replacement strategies, such as hydrogels, are required to restore the NP pressurization or the lost volume. AF repair strategies including cross-linked hydrogels, fibrous composites, and sealants offer promise for regenerative therapies to restore AF integrity. Tissue engineered IVD structures, as a single implantable construct, may promote greater tissue integration due to the improved repair capacity of the vertebral bone. CONCLUSIONS: IVD height, neutral zone characteristics, and torsional biomechanics are sensitive to specific alterations in the NP pressurization and AF integrity and must be addressed for an effective functional repair. Synthetic and natural biomaterials offer promise for NP replacement, AF repair, as an AF sealant, or whole disc replacement. Meeting mechanical and biological compatibilities are necessary for the efficacy and longevity of the repair. PMID- 23369503 TI - Golden hamster (Mesocricetus auratus) as an experimental model for Leishmania (Viannia) braziliensis infection. AB - The lack of an adequate model for Leishmania (Viannia) braziliensis infection is a limiting factor for studying American tegumentary leishmaniasis (ATL). The golden hamster (Mesocricetus auratus) is a promising model because besides being highly susceptible to dermotropic Leishmania infection, the lesions are very similar to cutaneous leishmaniasis (CL) in humans. However, different Leishmania isolates or species and/or protocols have resulted in different outcomes, whereas no study has evaluated the reproducibility of L. braziliensis infection in this model. The natural history of L. braziliensis infection in 34 hamsters was evaluated by using a single parasite isolate in 8 independent experiments under similar experimental conditions. Clinical, histological and immunological analyses were performed. The hamsters presented skin ulcers similar to those observed in ATL. The intra-experiment lesion increment tended to show an intermediary variance. Histological analysis of infected skins showed granulomatous reaction, scarce amastigotes, and Schaumann's bodies. Blood lymphocytes proliferated in response to leishmanial antigens. The severity of the infection was positively correlated to spleen weight, and the titres of anti Leishmania IgG antibodies. Our findings indicate that the hamster is an appropriate model for immunopathogenesis studies of CL caused by L. braziliensis, supporting its use in clinical, vaccine and chemotherapy experimental protocols. PMID- 23369502 TI - Effect of initial moisture content on the in-vessel composting under air pressure of organic fraction of municipal solid waste in Morocco. AB - This study aimed to evaluate the effect of initial moisture content on the in vessel composting under air pressure of organic fraction of municipal solid waste in Morocco in terms of internal temperature, produced gases quantity, organic matter conversion rate, and the quality of the final composts.For this purpose, in-vessel bioreactor was designed and used to evaluate both appropriate initial air pressure and appropriate initial moisture content for the composting process. Moreover, 5 experiments were carried out within initial moisture content of 55%, 65%, 70%, 75% and 85%. The initial air pressure and the initial moisture content of the mixture showed a significant effect on the aerobic composting. The experimental results demonstrated that for composting organic waste, relatively high moisture contents are better at achieving higher temperatures and retaining them for longer times.This study suggested that an initial moisture content of around 75%, under 0.6 bar, can be considered as being suitable for efficient composting of organic fraction of municipal solid waste. These last conditions, allowed maximum value of temperature and final composting product with good physicochemical properties as well as higher organic matter degradation and higher gas production. Moreover, final compost obtained showed good maturity levels and can be used for agricultural applications. PMID- 23369504 TI - Analysis of oxysterols and cholesterol in prefrontal cortex of suicides. AB - Brain oxysterol levels, which are enzymatic oxidation products of cholesterol (Chl), have been proposed to reflect the dynamic process of physiological synapse maintenance and repair of nerve terminals within the central nervous system (CNS), due to the turnover of membrane Chl. Modifications of oxysterols have important implications in neurological conditions, especially in neurodegenerative and psychiatric disorders in which alterations of synaptic plasticity or cell signalling are implicated, such as depression. Oxysterols can diffuse across the blood-brain barrier and have been hypothesized to provide a mechanism by which the brain can eliminate excess Chl to maintain a steady state. Relations of 24-hydroxycholesterol (24OH) and 27-hydroxycholesterol (27OH) specifically may provide a depiction of CNS Chl homeostasis. Thus, the objective of this study was to integrate oxysterol measures and gene expression measures in an effort to identify how they may relate to depression and suicide. Using post mortem human prefrontal cortex tissue, quantification of metabolites by GC-MS and gene expression by qRT-PCR were performed with the aim to provide a characterization of enzymatic oxidative Chl homeostasis. Results show a significant increase in 24OH, which suggests a higher turnover of Chl to 24OH in the prefrontal cortex of suicide cases. An increase in 24OH may, in combination with liver-X receptor activation, explain the observed reduction of low central and peripheral Chl in suicide and would have implications for synapse maintenance and loss in the neuropathology of depression and suicide. PMID- 23369505 TI - The role of timing in the induction of neuromodulation in perceptual learning by transcranial electric stimulation. AB - BACKGROUND: Transcranial electric stimulation (tES) protocols are able to induce neuromodulation, offering important insights to focus and constrain theories of the relationship between brain and behavior. Previous studies have shown that different types of tES (i.e., direct current stimulation - tDCS, and random noise stimulation - tRNS) induce different facilitatory behavioral effects. However to date is not clear which is the optimal timing to apply tES in relation to the induction of robust facilitatory effects. OBJECTIVE/HYPOTHESIS: The goal of this work was to investigate how different types of tES (tDCS and tRNS) can modulate behavioral performance in the healthy adult brain in relation to their timing of application. We applied tES protocols before (offline) or during (online) the execution of a visual perceptual learning (PL) task. PL is a form of implicit memory that is characterized by an improvement in sensory discrimination after repeated exposure to a particular type of stimulus and is considered a manifestation of neural plasticity. Our aim was to understand if the timing of tES is critical for the induction of differential neuromodulatory effects in the primary visual cortex (V1). METHODS: We applied high-frequency tRNS, anodal tDCS and sham tDCS on V1 before or during the execution of an orientation discrimination task. The experimental design was between subjects and performance was measured in terms of d' values. RESULTS: The ideal timing of application varied depending on the stimulation type. tRNS facilitated task performance only when it was applied during task execution, whereas anodal tDCS induced a larger facilitation if it was applied before task execution. CONCLUSION: The main result of this study is the finding that the timing of identical tES protocols yields opposite effects on performance. These results provide important guidelines for designing neuromodulation induction protocols and highlight the different optimal timing of the two excitatory techniques.